PMID- 28830362 TI - Impact of intrathecal morphine analgesia on the incidence of pulmonary complications after cardiac surgery: a single center propensity-matched cohort study. AB - BACKGROUND: Acute pain and systemic opioids may both negatively impact respiratory function after cardiac surgery. This study analyzes the local practice of using intrathecal morphine analgesia (ITMA) with minimal parenteral opioid administration in cardiac surgery, specifically the impact on postoperative pulmonary complications (PPCs). METHODS: Data from adult patients who underwent elective cardiac surgery between January 2002, and December 2013 in a single center were analyzed. Propensity scores estimating the likelihood of receiving ITMA were used to match (1:1) patients with ITMA and patients with intravenous analgesia (IVA). Primary outcome was PPCs, a composite endpoint including pneumonia, adult respiratory distress syndrome, and any type of acute respiratory failure. Secondary outcomes were in-hospital mortality, cardiovascular complications, and length of stay in the intensive care unit (ICU) and hospital. RESULTS: From a total of 1'543 patients, 920 were treated with ITMA and 623 with IVA. No adverse event consequent to the spinal puncture was reported. Propensity score matching created 557 balanced pairs. The occurrence of PPCs in patients with ITMA was 8.1% vs. 12.8% in patients with IVA (odds ratio, 0.6; 95% CI, 0.40-0.89; p = 0.012). Fewer patients with ITMA had a prolonged stay in the ICU (> 4 days; 16.5% vs. 21.2%, p = 0.047) or in the hospital (> 15 days; 25.5% vs. 31.8%. p = 0.024). In-hospital mortality and cardiovascular complications did not differ significantly between the two groups. CONCLUSION: In this study involving cardiac surgical patients, ITMA was safely applied and was associated with fewer PPCs. PMID- 28830363 TI - Recovery and prediction of postoperative muscle power - is it still a problem? AB - BACKGROUND: In the postoperative period, immediate recovery of muscular power is essential for patient safety, but this can be affected by anaesthetic drugs, opioids and neuromuscular blocking agents (NMBA). In this cohort study, we evaluated anaesthetic and patient-related factors contributing to reduced postoperative muscle power and pulse oximetric saturation. METHODS: We prospectively observed 615 patients scheduled for minor surgery. Premedication, general anaesthesia and respiratory settings were standardized according to standard operating procedures (SOP). If NMBAs were administered, neuromuscular monitoring was applied to establish a Train of four (TOF)-Ratio of >0.9 before extubation. After achieving a modified fast track score > 10 at 4 time points up to 2 h postoperatively, we measured pulse oximetric saturation and also static and dynamic muscle power, using a high precision digital force gauge. Loss of muscle power in relation to the individual preoperative baseline value was analysed in relation to patient and anaesthesia-related factors using the T-test, simple and multiple stepwise regression analysis. RESULTS: Despite having achieved a TOF ratio of >0.9 a decrease in postoperative muscle power was detectable in most patients and correlated with reduced postoperative pulse oximetric saturation. Independent contributing factors were use of neuromuscular blocking agents (p < 0.001), female gender (p = 0.001), TIVA (p = 0.018) and duration of anaesthesia >120 min (p = 0.019). CONCLUSION: Significant loss of muscle power and reduced pulse oximetric saturation are often present despite a TOF-Ratio > 0.9. Gender differences are also significant. A modified fast track score > 10 failed to predict recovery of muscle power in most patients. TRIAL REGISTRATION: German Clinical Trial Register DRKS-ID DRKS00006032 ; Registered: 2014/04/03. PMID- 28830364 TI - GaMYB85, an R2R3 MYB gene, in transgenic Arabidopsis plays an important role in drought tolerance. AB - BACKGROUND: MYB transcription factors (TFs) are one of the largest families of TFs in higher plants and are involved in diverse biological, functional, and structural processes. Previously, very few functional validation studies on R2R3 MYB have been conducted in cotton in response to abiotic stresses. In the current study, GaMYB85, a cotton R2R3 MYB TF, was ectopically expressed in Arabidopsis thaliana (Col-0) and was functionally characterized by overexpression in transgenic plants. RESULTS: The in-silico analysis of GaMYB85 shows the presence of a SANT domain with a conserved R2R3 MYB imperfect repeat. The GaMYB85 protein has a 257-amino acid sequence, a molecular weight of 24.91 kD, and an isoelectric point of 5.58. Arabidopsis plants overexpressing GaMYB85 exhibited a higher seed germination rate in response to mannitol and salt stress, and higher drought avoidance efficiency than wild-type plants upon water deprivation. These plants had notably higher levels of free proline and chlorophyll with subsequent lower water loss rates and higher relative water content. Germination of GaMYB85 transgenics was more sensitive to abscisic acid (ABA) and extremely liable to ABA induced inhibition of primary root elongation. Moreover, when subjected to treatment with different concentrations of ABA, transgenic plants with ectopically expressed GaMYB85 showed reduced stomatal density, with greater stomatal size and lower stomatal opening rates than those in wild-type plants. Ectopic expression of GaMYB85 led to enhanced transcript levels of stress-related marker genes such as RD22, ADH1, RD29A, P5CS, and ABI5. CONCLUSIONS: Our results indicate previously unknown roles of GaMYB85, showing that it confers good drought, salt, and freezing tolerance, most probably via an ABA-induced pathway. These findings can potentially be exploited to develop improved abiotic stress tolerance in cotton plants. PMID- 28830365 TI - Minimal shedding of the glycocalyx layer during abdominal hysterectomy. AB - BACKGROUND: Surgery with and without hypervolaemia may cause shedding (breakdown) of the endothelial glycocalyx layer, but the severity of this problem is unclear. METHODS: In this preliminary report of a larger clinical trial, the plasma and urine concentrations of three biomarkers of glycocalyx shedding (syndecan-1, hyaluronic acid and heparan sulfate) were measured in seven patients before, during, and after open hysterectomy. The fluid therapy consisted of 25 ml/kg (approximately 2 l) of Ringer's lactate, which was infused over 30 min when the surgery started. The resulting plasma volume expansion at the end of the infusion was estimated from the haemodilution. RESULTS: The mean plasma concentration of syndecan-1 was 21.7 ng/ml before surgery and averaged 19.7 ng/ml during and after the surgery. The plasma concentration of hyaluronic acid decreased from 38.0 to 27.7 ng/ml (P < 0.05), while heparan sulfate increased from 3.4 to 5.5 MUg/ml (P < 0.05). The urine concentrations of syndecan-1 decreased significantly, while they increased for hyaluronic acid and heparan sulfate. Despite the vigorous fluid load, the urine flow did not exceed 1 ml/min. CONCLUSIONS: No clear evidence was found for shedding of the endothelial glycocalyx layer when 2 l of Ringer's lactate was infused over 30 min during abdominal hysterectomy. Urine analyses yielded patterns of changes that differed from those in plasma. TRIAL REGISTRATION: ISRCTN81005631 . Registered May 17, 2016. PMID- 28830366 TI - Adequate interval for the monitoring of vital signs during endotracheal intubation. AB - BACKGROUND: In the perioperative period, it may be inappropriate to monitor vital signs during endotracheal intubation using the same interval as during a hemodynamically stable period. The aim of the present study was to determine whether it is appropriate to use the same intervals used during the endotracheal intubation and stable periods to monitor vital signs of patients under general anesthesia. METHODS: The mean arterial pressure (MAP) and heart rate (HR) were continuously measured during endotracheal intubation (15 min after intubation) and hemodynamically stable (15 min before skin incision) periods in 24 general anesthesia patients. Data was considered "unrecognized" when continuously measured values were 30% more or less than the monitored value measured at 5- or 2.5-min intervals. The incidence of unrecognized data during endotracheal intubation was compared to that during the hemodynamically stable period. RESULT: There were significantly more unrecognized MAP data measured at 5-min intervals during endotracheal intubation than during the hemodynamically stable period (p value <0.05). However, there was no difference in the incidence of unrecognized MAP data at 2.5 min intervals or HR data at 5 or 2.5 min intervals between during the endotracheal intubation and hemodynamically stable periods. CONCLUSION: A 5 min interval throughout the operation period was not appropriate for monitoring vital signs. Therefore, , a 2.5-min interval is recommended for monitoring the MAP during endotracheal intubation. PMID- 28830367 TI - miR-941 as a promising biomarker for acute coronary syndrome. AB - BACKGROUND: Circulating miRNAs can function as biomarkers for diagnosis, treatment, and prevention of diseases. However, it is unclear whether miRNAs can be used as biomarkers for acute coronary syndrome (ACS). To this end, we applied gene chip technology to analyze miRNA expression in patients with stable angina (SA), non-ST elevation ACS (NSTE-ACS), and ST-segment elevation myocardial infarction (STEMI). METHODS: We enrolled patients with chest pain who underwent diagnostic coronary angiography, including five patients each with SA, NSTE-ACS, or STEMI, and five controls without coronary artery disease (CAD) but with three or more risk factors. After microarray analysis, differential miRNA expression was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Compared with those in patients with STEMI, differentially expressed microRNAs in controls and patients with SA or NSTE-ACS were involved in inflammation, protein phosphorylation, and cell adhesion. Pathway analysis showed that differentially expressed miRNAs were related to the mitogen-activated protein kinase signaling, calcium ion pathways, and cell adhesion pathways. Compared with their expression levels in patients with STEMI, miR-941, miR-363-3p, and miR-182-5p were significantly up-regulated (fold-change: 2.0 or more, P < 0.05) in controls and patients with SA or NSTE-ACS. Further, qRT PCR showed that plasma miR-941 level was elevated in patients with NSTE-ACS or STEMI as compared with that in patients without CAD (fold-change: 1.65 and 2.28, respectively; P < 0.05). Additionally, miR-941 expression was significantly elevated in the STEMI group compared with that in the SA (P < 0.01) and NSTE-ACS groups (P < 0.05). Similarly, miR-941 expression was higher in patients with ACS (NSTE-ACS or STEMI) than in patients without ACS (without CAD or with SA; P < 0.01). There were no significant differences in miR-182-5p and miR-363-3p expression. The areas under the receiver operating characteristic curves were 0.896, 0.808, and 0.781 for patients in the control, SA, and NSTE-ACS groups, respectively, compared with that for patients with STEMI; that for the ACS group compared with the non-ACS group was 0.734. CONCLUSION: miR-941 expression was relatively higher in patients with ACS and STEMI. Thus, miR-941 may be a potential biomarker of ACS or STEMI. PMID- 28830368 TI - Allelic variants in vitamin D receptor gene are associated with adiposity measures in the central-European population. AB - BACKGROUND: There is an increasing body of evidence suggesting that vitamin D is involved in ethiopathogenesis of obesity and therefore the aim of the study was to investigate whether 5 selected SNPs in VDR (vitamin D receptor) gene are associated also with anthropometry in the obese and non-obese Central-European population. METHODS: A total of 882 Central European Caucasian individuals of Czech origin were recruited (n = 882, 232 M/650 F) and weight, height, BMI, lean body mass, fat mass, body fat, waist and hip circumference, waist-hip ratio (WHR) and skinfold thickness were measured. Univariate and multivariate models were constructed in order to investigate the relationship between anthropometry and VDR polymorphisms. RESULTS: In the univariate modeling, the CC genotype of FokI SNP was associated with reduced waist circumference (beta = -3.48; 95%CI: 7.11;0.15; p = 0.060), sum of skin fold thickness (beta = -6.53, 95% CI: -12.96; 0.11; p = 0.046) as well as total % of body fat (beta = -3.14, 95% CI: -5.18; 1.09; p = 0.003) compared to TT genotype. The AC genotype of ApaI SNP was associated with reduced waist circumference compared to AA genotype (beta = 4.37, 95% CI: -7.54;-1.20; p = 0.007). GG genotype of EcoRV SNP was associated with reduced sum of skin fold thickness compared to AA genotype (beta = -7.77, 95% CI: -14.34;-1.21; p = 0.020). In the multivariate modelling, multiple significant associations of VDR with investigated traits were observed, too. CONCLUSION: Our study suggests that genetic variability in the VDR region may be an important factor influencing anthropometric characteristics associated with obesity. PMID- 28830369 TI - Dislocation of a previously successful XEN glaucoma implant into the anterior chamber: a case report. AB - BACKGROUND: XEN glaucoma implant (XEN gel stent, Aquesys, Inc) is a new minimally invasive device approved for the treatment of glaucoma. CASE PRESENTATION: A 45 year old female was being followed and treated for primary open angle glaucoma in our tertiary referral center. Due to failure of medical treatment in controlling the glaucoma, surgery was offered to the patient. The XEN 45 MU-fistula implant was successfully placed in both eyes and adequate intraocular pressure control was achieved for 4 months. The left eye pressure then increased and the XEN implant was found in the anterior chamber. Topical intraocular pressure lowering therapy had to be re-initiated to achieve adequate pressure control. CONCLUSION: We describe a new potential complication of the XEN glaucoma implant. PMID- 28830370 TI - Active smoking and risk of breast cancer in a Danish nurse cohort study. AB - BACKGROUND: No scientific consensus has been reached on whether active tobacco smoking causes breast cancer. We examine the association between active smoking and breast cancer risk in Denmark, which has some of the highest smoking and breast cancer rates in women worldwide. METHODS: We used the data from a nationwide Danish Nurse Cohort on 21,867 female nurses (age > 44 years) who at recruitment in 1993 or 1999 reported information on smoking status, onset, duration, and intensity, as well as breast cancer risk factors. We obtained data on incidence of breast cancer from Danish Cancer Registry until 2013, and used Cox regression models to analyze the association between smoking and breast cancer. RESULTS: Of 21,831 women (mean age 53.2 years) 1162 developed breast cancer during 15.7 years of follow-up. 33.7% of nurses were current and 30.0% former smokers at cohort baseline. Compared to never smokers, we found increased risk of breast cancer of 18% in ever (hazard ratio and 95% confidence interval: 1.18; 1.04-1.34) and 27% in current (1.27; 1.11-1.46) smokers. We detected a dose response relationship with smoking intensity with the highest breast cancer risk in women smoking >15 g/day (1.31; 1.11-1.56) or >20 pack-years (1.32; 1.12-1.55). Parous women who smoked heavily (>10 pack-years) before first childbirth had the highest risk of breast cancer (1.58; 1.20-2.10). Association between smoking and breast cancer was not modified by menopausal status, obesity, alcohol or hormone therapy use, and seemed to be limited to the estrogen receptor positive breast cancer subtype. CONCLUSIONS: Active smoking increases risk of breast cancer, with smoking before first birth being the most relevant exposure window. PMID- 28830371 TI - Why statistical inference from clinical trials is likely to generate false and irreproducible results. AB - One area of biomedical research where the replication crisis is most visible and consequential is clinical trials. Why do outcomes of so many clinical trials contradict each other? Why is the effectiveness of many drugs and other medical interventions so low? Why have prescription medications become the third leading cause of death in the US and Europe after cardiovascular diseases and cancer? In answering these questions, the main culprits identified so far have been various biases and conflicts of interest in planning, execution and analysis of clinical trials as well as reporting their outcomes. In this work, we take an in-depth look at statistical methodology used in planning clinical trials and analyzing trial data. We argue that this methodology is based on various questionable and empirically untestable assumptions, dubious approximations and arbitrary thresholds, and that it is deficient in many other respects. The most objectionable among these assumptions is that of distributional homogeneity of subjects' responses to medical interventions. We analyze this and other assumptions both theoretically and through clinical examples. Our main conclusion is that even a totally unbiased, perfectly randomized, reliably blinded, and faithfully executed clinical trial may still generate false and irreproducible results. We also formulate a few recommendations for the improvement of the design and statistical methodology of clinical trials informed by our analysis. PMID- 28830372 TI - Tuberculosis active case finding in Cambodia: a pragmatic, cost-effectiveness comparison of three implementation models. AB - BACKGROUND: Globally, almost 40% of tuberculosis (TB) patients remain undiagnosed, and those that are diagnosed often experience prolonged delays before initiating correct treatment, leading to ongoing transmission. While there is a push for active case finding (ACF) to improve early detection and treatment of TB, there is extremely limited evidence about the relative cost-effectiveness of different ACF implementation models. Cambodia presents a unique opportunity for addressing this gap in evidence as ACF has been implemented using different models, but no comparisons have been conducted. The objective of our study is to contribute to knowledge and methodology on comparing cost-effectiveness of alternative ACF implementation models from the health service perspective, using programmatic data, in order to inform national policy and practice. METHODS: We retrospectively compared three distinct ACF implementation models - door to door symptom screening in urban slums, checking contacts of TB patients, and door to door symptom screening focusing on rural populations aged above 55 - in terms of the number of new bacteriologically-positive pulmonary TB cases diagnosed and the cost of implementation assuming activities are conducted by the national TB program of Cambodia. We calculated the cost per additional case detected using the alternative ACF models. RESULTS: Our analysis, which is the first of its kind for TB, revealed that the ACF model based on door to door screening in poor urban areas of Phnom Penh was the most cost-effective (249 USD per case detected, 737 cases diagnosed), followed by the model based on testing contacts of TB patients (308 USD per case detected, 807 cases diagnosed), and symptomatic screening of older rural populations (316 USD per case detected, 397 cases diagnosed). CONCLUSIONS: Our study provides new evidence on the relative effectiveness and economics of three implementation models for enhanced TB case finding, in line with calls for data from 'routine conditions' to be included in disease control program strategic planning. Such cost-effectiveness comparisons are essential to inform resource allocation decisions of national policy makers in resource constraint settings. We applied a novel, pragmatic methodological approach, which was designed to provide results that are directly relevant to policy makers, costing the interventions from Cambodia's national TB program's perspective and using case finding data from implementation activities, rather than experimental settings. PMID- 28830373 TI - Statistical methods for elimination of guarantee-time bias in cohort studies: a simulation study. AB - BACKGROUND: Aspirin has been considered to be beneficial in preventing cardiovascular diseases and cancer. Several pharmaco-epidemiology cohort studies have shown protective effects of aspirin on diseases using various statistical methods, with the Cox regression model being the most commonly used approach. However, there are some inherent limitations to the conventional Cox regression approach such as guarantee-time bias, resulting in an overestimation of the drug effect. To overcome such limitations, alternative approaches, such as the time dependent Cox model and landmark methods have been proposed. This study aimed to compare the performance of three methods: Cox regression, time-dependent Cox model and landmark method with different landmark times in order to address the problem of guarantee-time bias. METHODS: Through statistical modeling and simulation studies, the performance of the above three methods were assessed in terms of type I error, bias, power, and mean squared error (MSE). In addition, the three statistical approaches were applied to a real data example from the Korean National Health Insurance Database. Effect of cumulative rosiglitazone dose on the risk of hepatocellular carcinoma was used as an example for illustration. RESULTS: In the simulated data, time-dependent Cox regression outperformed the landmark method in terms of bias and mean squared error but the type I error rates were similar. The results from real-data example showed the same patterns as the simulation findings. CONCLUSIONS: While both time-dependent Cox regression model and landmark analysis are useful in resolving the problem of guarantee-time bias, time-dependent Cox regression is the most appropriate method for analyzing cumulative dose effects in pharmaco-epidemiological studies. PMID- 28830374 TI - EMX2 gene expression predicts liver metastasis and survival in colorectal cancer. AB - BACKGROUND: The Empty Spiracles Homeobox (EMX-) 2 gene has been associated with regulation of growth and differentiation in neuronal development. While recent studies provide evidence that EMX2 regulates tumorigenesis of various solid tumors, its role in colorectal cancer remains unknown. We aimed to assess the prognostic significance of EMX2 expression in stage III colorectal adenocarcinoma. METHODS: Expression levels of EMX2 in human colorectal cancer and adjacent mucosa were assessed by qRT-PCR technology, and results were correlated with clinical and survival data. siRNA-mediated knockdown and adenoviral delivery mediated overexpression of EMX2 were performed in order to investigate its effects on the migration of colorectal cancer cells in vitro. RESULTS: Compared to corresponding healthy mucosa, colorectal tumor samples had decreased EMX2 expression levels. Furthermore, EMX2 down-regulation in colorectal cancer tissue was associated with distant metastasis (M1) and impaired overall patient survival. In vitro knockdown of EMX2 resulted in increased tumor cell migration. Conversely, overexpression of EMX2 led to an inhibition of tumor cell migration. CONCLUSIONS: EMX2 is frequently down-regulated in human colorectal cancer, and down-regulation of EMX2 is a prognostic marker for disease-free and overall survival. EMX2 might thus represent a promising therapeutic target in colorectal cancer. PMID- 28830375 TI - A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome. AB - BACKGROUND: Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically. CASE PRESENTATION: We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation. CONCLUSIONS: Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia. PMID- 28830376 TI - Hydrophilic intraocular lens opacification after posterior lamellar keratoplasty a material analysis with special reference to optical quality assessment. AB - BACKGROUND: Laboratory analysis and optical quality assessment of explanted hydrophilic intraocular lenses (IOLs) with clinically significant opacification after posterior lamellar keratoplasty (DMEK and DSAEK). METHODS: Thirteen opacified IOLs after posterior lamellar keratoplasty, 8 after descemet stripping automated endothelial keratoplasty (DSAEK), 3 after descemet membrane endothelial keratoplasty (DMEK) and 2 after both DSAEK and DMEK were analysed in our laboratory. Analyses included optical bench assessment for optical quality, light microscopy, scanning electron microscopy (SEM) and energy dispersive X-Ray spectroscopy (EDS). RESULTS: In all IOLs the opacification was caused by a thin layer of calciumphosphate that had accumulated underneath the anterior optical surface of the IOLs in the area spared by the pupil/anterior capsulorhexis. The calcifications lead to a significant deterioration of the modulation transfer function across all spatial frequencies of the affected IOLs. CONCLUSIONS: The instillation of exogenous material such as air or gas into the anterior chamber increases the risk for opacification of hydrophilic IOLs irrespective of the manufacturer or the exact composition of the hydrophilic lens material. It is recommended to avoid the use of hydrophilic acrylic IOLs in patients with endothelial dystrophy that will likely require procedures involving the intracameral instillation of air or gas, such as DMEK or DS(A)EK. PMID- 28830377 TI - Comprehensive catwalk gait analysis in a chronic model of multiple sclerosis subjected to treadmill exercise training. AB - BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease with a wide range of symptoms including walking impairment and neuropathic pain mainly represented by mechanical allodynia. Noteworthy, exercise preconditioning may affect both walking impairment and mechanical allodynia. Most of MS symptoms can be reproduced in the animal model named experimental autoimmune encephalomyelitis (EAE). Usually, neurological deficits of EAE are recorded using a clinical scale based on the development of disease severity that characterizes tail and limb paralysis. Following paralysis recovery, subtle motor alterations and even mechanical allodynia investigation are difficult to record, representing sequels of peak disease. The aim of the present study was to investigate the walking dysfunction by the catwalk system (CT) in exercised and non-exercised C57BL/6 mice submitted to EAE with MOG35-55 up to 42 days post-induction (dpi). METHODS: Twenty-four C57BL/6 female mice were randomly assigned to unexercised (n = 12) or exercised (n = 12) groups. The MOG35-55 induced EAE model has been performed at the beginning of the fifth week of the physical exercise training protocol. In order to characterize the gait parameters, we used the CT system software version XT 10.1 (Noldus Inc., The Netherlands) from a basal time point (before induction) to 42 days post induction (dpi). Statistical analyses were performed with GraphPad Prisma 4.0 software. RESULTS: Data show dynamic gait changes in EAE mice including differential front (FP) and hind paw (HP) contact latency. Such findings are hypothesized as related to an attempt to maintain balance and posture similar to what has been observed in patients with MS. Importantly, pre exercised mice show differences in the mentioned gait compensation, particularly at the propulsion sub-phase of HP stand. Besides, we observed reduced intensity of the paw prints as well as reduced print area in EAE subjects, suggestive of a development of chronic mechanical allodynia in spite of being previously exercised. CONCLUSIONS: Our data suggest that Catwalk system is a useful tool to investigate subtle motor impairment and mechanical allodynia at chronic time points of the EAE model, improving the functional investigation of gait abnormalities and demyelination sequelae. PMID- 28830378 TI - Prognostic impact of a new score using neutrophil-to-lymphocyte ratios in the serum and malignant pleural effusion in lung cancer patients. AB - BACKGROUNDS: Various studies have reported that the neutrophil-to-lymphocyte ratio in the serum (sNLR) may serve as a cost-effective and useful prognostic factor in patients with various cancer types. However, no study has reported the prognostic impact of the NLR in malignant pleural effusion (MPE). To address this gap, we investigated the clinical impact of NLR as a prognostic factor in MPE (mNLR) and a new scoring system that use NLRs in the serum and MPE (smNLR score) in lung cancer patients. METHODS: We retrospectively reviewed all of the patients who were diagnosed with lung cancer and who presented with pleural effusion. To maintain the quality of the study, only patients with malignant cells in the pleural fluid or tissue were included. The patients were classified into three smNLR score groups, and clinical variables were investigated for their correlation with survival. RESULTS: In all, 158 patients were classified into three smNLR score groups as follows: 84 (53.2%) had a score of 0, 58 (36.7%) had a score of 1, and 16 (10.1%) had a score of 2. In a univariate analysis, high sNLR, mNLR, and increments of the smNLR score were associated with shorter overall survival (p < 0.001, p = 0.004, and p < 0.001, respectively); moreover, age, Eastern Cooperative Oncology Group performance status (ECOG PS), histology, M stage, hemoglobin level, albumin level, and calcium level were significant prognostic factors. A multivariable analysis confirmed that ECOG PS (p < 0.001), histology (p = 0.001), and smNLR score (p < 0.012) were independent predictors of overall survival. CONCLUSIONS: The new smNLR score is a useful and cost-effective prognostic factor in lung cancer patients with MPE. Although further studies are required to generalize our results, this information will benefit clinicians and patients in determining the most appropriate therapy for patients with MPE. PMID- 28830379 TI - Visual function improvement using photocromic and selective blue-violet light filtering spectacle lenses in patients affected by retinal diseases. AB - BACKGROUND: To evaluate functional visual parameters using photocromic and selective blue-violet light filtering spectacle lenses in patients affected by central or peripheral scotoma due to retinal diseases. Sixty patients were enrolled in this study: 30 patients affected by central scotoma, group 1, and 30 affected by peripheral scotoma, group 2. Black on White Best Corrected Visual Acuity (BW-BCVA), White on Black Best Corrected Visual Acuity (WB-BCVA), Mars Contrast Sensitivity (CS) and a Glare Test (GT) were performed to all patients. Test results with blue-violet filter, a short-pass yellow filter and with no filters were compared. RESULTS: All scores from test results increased significantly with blue-violet filters for all patients. The mean BW-BCVA increased from 0.30 +/- 0.20 to 0.36 +/- 0.21 decimals in group 1 and from 0.44 +/- 0.22 to 0.51 +/- 0.23 decimals in group 2 (Mean +/- SD, p < 0.0001 in both cases). The mean WB-BCVA increased from 0.31 +/- 0.19 to 0.38 +/- 0.23 decimals in group 1 and from 0.46 +/- 0.20 to 0.56 +/- 0.22 decimals in group 2 (Mean +/- SD, p < 0.0001 in both cases). The letter count for the CS test increased from 26.7 +/- 7.9 to 30.06 +/- 7.8 in group 1 (Mean +/- SD, p = 0.0005) and from 31.5 +/- 7.6 to 33.72 +/- 7.3 in group 2 (Mean +/- SD, p = 0.031). GT was significantly reduced: the letter count increased from 20.93 +/- 5.42 to 22.82 +/ 4.93 in group 1 (Mean +/- SD, p < 0.0001) and from 24.15 +/- 5.5 to 25.97 +/- 4.7 in group 2 (Mean +/- SD, p < 0.0001). Higher scores were recorded with the Blue filter compared to Yellow filter in all tests (p < 0.05). No significant differences in any test results could be detected between the Yellow filter and the No filter condition. CONCLUSIONS: The use of a combination of photocromic lens with a selective blue-violet light filter showed functional benefit in all evaluated patients. PMID- 28830380 TI - Primary care physician referral patterns in Ontario, Canada: a descriptive analysis of self-reported referral data. AB - BACKGROUND: In many countries, the referral-consultation process faces a number of challenges from inefficiencies and rising demand, resulting in excessive wait times for many specialties. We collected referral data from a sample of family doctors across the province of Ontario, Canada as part of a larger program of research. The purpose of this study is to describe referral patterns from primary care to specialist and allied health services from the primary care perspective. METHODS: We conducted a prospective study of patient referral data submitted by primary care providers (PCP) from 20 clinics across Ontario between June 2014 and January 2016. Monthly referral volumes expressed as a total number of referrals to all medical and allied health professionals per month. For each referral, we also collected data on the specialty type, reason for referral, and whether the referral was for a procedure. RESULTS: PCPs submitted a median of 26 referrals per month (interquartile range 11.5 to 31.8). Of 9509 referrals eligible for analysis, 97.8% were directed to medical professionals and 2.2% to allied health professionals. 55% of medical referrals were directed to non-surgical specialties and 44.8% to surgical specialties. Medical referrals were for procedures in 30.8% of cases and non-procedural in 40.9%. Gastroenterology received the largest share (11.2%) of medical referrals, of which 62.3% were for colonoscopies. Psychology received the largest share (28.3%) of referrals to allied health professionals. CONCLUSION: We described patterns of patient referral from primary care to specialist and allied health services for 30 PCPs in 20 clinics across Ontario. Gastroenterology received the largest share of referrals, nearly two-thirds of which were for colonoscopies. Future studies should explore the use of virtual care to help manage non-procedural referrals and examine the impact that procedural referrals have on wait times for gastroenterology. PMID- 28830381 TI - Comparing the intestinal transcriptome of Meishan and Large White piglets during late fetal development reveals genes involved in glucose and lipid metabolism and immunity as valuable clues of intestinal maturity. AB - BACKGROUND: Maturity of intestinal functions is critical for neonatal health and survival, but comprehensive description of mechanisms underlying intestinal maturation that occur during late gestation still remain poorly characterized. The aim of this study was to investigate biological processes specifically involved in intestinal maturation by comparing fetal jejunal transcriptomes of two representative porcine breeds (Large White, LW; Meishan, MS) with contrasting neonatal vitality and maturity, at two key time points during late gestation (gestational days 90 and 110). MS and LW sows inseminated with mixed semen (from breed LW and MS) gave birth to both purebred and crossbred fetuses. We hypothesized that part of the differences in neonatal maturity between the two breeds results from distinct developmental profiles of the fetal intestine during late gestation. Reciprocal crossed fetuses were used to analyze the effect of parental genome. Transcriptomic data and 23 phenotypic variables known to be associated with maturity trait were integrated using multivariate analysis with expectation of identifying relevant genes-phenotypic variable relationships involved in intestinal maturation. RESULTS: A moderate maternal genotype effect, but no paternal genotype effect, was observed on offspring intestinal maturation. Four hundred and four differentially expressed probes, corresponding to 274 differentially expressed genes (DEGs), more specifically involved in the maturation process were further studied. In day 110-MS fetuses, Ingenuity(r) functional enrichment analysis revealed that 46% of DEGs were involved in glucose and lipid metabolism, cell proliferation, vasculogenesis and hormone synthesis compared to day 90-MS fetuses. Expression of genes involved in immune pathways including phagocytosis, inflammation and defense processes was changed in day 110 LW compared to day 90-LW fetuses (corresponding to 13% of DEGs). The transcriptional regulator PPARGC1A was predicted to be an important regulator of differentially expressed genes in MS. Fetal blood fructose level, intestinal lactase activity and villous height were the best predicted phenotypic variables with probes mostly involved in lipid metabolism, carbohydrate metabolism and cellular movement biological pathways. CONCLUSIONS: Collectively, our findings indicate that the neonatal maturity of pig intestine may rely on functional development of glucose and lipid metabolisms, immune phagocyte differentiation and inflammatory pathways. This process may partially be governed by PPARGC1A. PMID- 28830382 TI - Rates of switching to second-line antiretroviral therapy and impact of delayed switching on immunologic, virologic, and mortality outcomes among HIV-infected adults with virologic failure in Rakai, Uganda. AB - BACKGROUND: Switch from first to second-line ART is recommended by WHO for patients with virologic failure. Delays in switching may contribute to accumulated drug resistance, advanced immunosuppression, increased morbidity and mortality. The 3rd 90' of UNAIDS 90:90:90 targets 90% viral suppression for persons on ART. We evaluated the rate of switching to second-line antiretroviral therapy (ART), and the impact of delayed switching on immunologic, virologic, and mortality outcomes in the Rakai Health Sciences Program (RHSP) Clinical Cohort Study which started providing ART in 2004 and implemented 6 monthly routine virologic monitoring beginning in 2005. METHODS: Retrospective cohort study of HIV-infected adults on first-line ART who had two consecutive viral loads (VLs) >1000 copies/ml after 6 months on ART between June 2004 and June 2011 was studied for switching to second-line ART. Immunologic decline after virologic failure was defined as decrease in CD4 count of >=50 cells/ul and virologic increase was defined as increase of 0.5 log 10 copies/ml. Competing risk models were used to summarize rates of switching to second-line ART while cox proportional hazard marginal structural models were used to assess the risk of virologic increase or immunologic decline associated with delay to switch first line ART failing patients. RESULTS: The cumulative incidence of switching at 6, 12, and 24 months following virologic failure were 30.2%, 44.6%, and 65.0%, respectively. The switching rate was increased with higher VL at the time of virologic failure; compared to those with VLs <= 5000 copies/ml, patients with VLs = 5001-10,000 copies/ml had an aHR = 1.81 (95% CI = 0.9-3.6), and patients with VLs > 10,000 copies/ml had an aHR = 3.38 (95%CI = 1.9-6.2). The switching rate was also increased with CD4 < 100 cells/ul at ART initiation, compared to those with CD4 >= 100 cells/ul (aHR = 2.30, 95% CI = 1.5-3.6). Mortality in patients not switched to second-line ART was 11.9%, compared to 1.2% for those who switched (p = 0.009). Patients switched after 12 months of of virologic failure were more likely to experience CD4 decline and/or further VL increases. CONCLUSIONS: Intervention strategies that aid clinicians to promptly switch patients to second line ART as soon as virologic failure on 1st line ART is confirmed should be prioritized. PMID- 28830383 TI - Midwives' and patients' perspectives on disrespect and abuse during labor and delivery care in Ethiopia: a qualitative study. AB - BACKGROUND: It is increasingly recognized that disrespect and abuse of women during labor and delivery is a violation of a woman's rights and a deterrent to the use of life-saving, facility-based labor and delivery services. In Ethiopia, rates of skilled birth attendance are still only 28% despite a recent dramatic national scale up in the numbers of trained providers and facilities. Concerns have been raised that womens' perceptions of poor quality of care and fear of mistreatment might contribute to this low utilization. This study examines the experiences of disrespect and abuse in maternal care from the perspectives of both providers and patients. METHODS: We conducted 45 in-depth interviews at four health facilities in Debre Markos, Ethiopia with midwives, midwifery students, and women who had given birth within the past year. Students and providers also took a brief quantitative survey on patients' rights during labor and delivery and responded to clinical scenarios regarding the provision of stigmatized reproductive health services. RESULTS: We find that both health care providers and patients report frequent physical and verbal abuse as well as non-consented care during labor and delivery. Providers report that most abuse is unintended and results from weaknesses in the health system or from medical necessity. We uncovered no evidence of more systematic types of abuse involving detention of patients, bribery, abandonment or ongoing discrimination against particular ethnic groups. Although health care providers showed good basic knowledge of confidentiality, privacy, and consent, training on the principles of responsive and respectful care, and on counseling, is largely absent. Providers indicated that they would welcome related practical instruction. Patient responses suggest that women are aware that their rights are being violated and avoid facilities with reputations for poor care. CONCLUSIONS: Our results suggest that training on respectful care, offered in the professional ethics modules of the national midwifery curriculum, should be strengthened to include greater focus on counseling skills and rapport-building. Our findings also indicate that addressing structural issues around provider workload should complement all interventions to improve midwives' interpersonal interactions with women if Ethiopia is to increase provision of respectful, patient-centered maternity care. PMID- 28830384 TI - Emergence and clonal transmission of multi-drug-resistant tuberculosis among patients in Chad. AB - BACKGROUND: Emergence of Multidrug-resistant (MDR) strains constitutes a significant public health problem worldwide. Prevalence of MDR tuberculosis from Chad is unavailable to date. METHODS: We collected samples from consecutive TB patients nationwide in the seven major cities of Chad between 2007 and 2012 to characterize drug resistance and the population structure of circulating Mycobacterium tuberculosis complex (MTBC) strains. We tested drug sensitivity using Line Probe Assays and phenotypic drug susceptibility testing (DST) were used for second line drugs. We genotyped the isolates using spoligotype analysis and MIRU-VNTR. RESULTS: A total of 311 cultures were isolated from 593 patients. The MDR prevalence was 0.9% among new patients and 3.5% among retreatment patients, and no second line drug resistance was identified. The distribution of genotypes suggests a dissemination of MDR strains in the Southern city of Moundou, bordering Cameroon and Central African Republic. CONCLUSION: Emerging MDR isolates pose a public health threat to Southern Chad, with risk to neighboring countries. This study informs public health practitioners, justifying the implementation of continuous surveillance with DST for all retreatment cases as well as contacts of MDR patients, in parallel with provision of adequate 2nd line regimens in the region. PMID- 28830385 TI - Strengthening general practice/family medicine in Europe-advice from professionals from 30 European countries. AB - BACKGROUND: Substantial variations are still to be found in the strength of general practice/family medicine (GP/FM) across Europe regarding governance, workforce competence and performance, as well as academic development and position. Governments are encouraged by the WHO to secure high quality primary health care to their population, a necessity for reaching the goal "Health for all". The present study aimed at investigating the opinions of council members of the European Academy of Teachers in General Practice (EURACT) on necessary actions to strengthen the position of GP/FM in their country. METHODS: The study used a mixed methods exploratory sequential design. EURACT representatives from 32 European countries first participated in brain-storming on how to strengthen GP/FM in Europe. Later, representatives from 37 countries were asked to individually score the relevance of the proposed actions for their country on a 9 point Likert scale. They were also asked to evaluate the status of GP/FM in their country on four dimensions. RESULTS: Respondents from 30 European countries returned complete questionnaires. To build and secure GP/FM as an academic discipline comprising teaching and research was seen as essential, regardless the present status of GP/FM in the respective country. To build GP/FM as a specialty on the same level as other specialties was seen as important in countries where GP/FM held a strong or medium strong position. The importance of common learning objectives and a defined bibliography were stated by respondents from countries where GP/FM presently has a weak position. CONCLUSIONS: In order to strengthen GP/FM throughout Europe, EURACT and other professional organizations must establish common goals and share expertise between countries. To influence decision makers through information on cost-effectiveness of a GP/FM-based health care system is also important. PMID- 28830386 TI - Association among oral symptoms, oral health-related quality of life, and health related quality of life in a sample of adults living with HIV/AIDS in Malaysia. AB - BACKGROUND: Health-related quality of life (HRQOL) is a multidimensional construct that refers to an individual's self-perceived well-being. This study used the revised Wilson and Cleary HRQOL model to investigate the associations among oral symptoms, oral health-related quality of life (OHRQOL), and HRQOL of people living with HIV/AIDS (PLWHA) in Malaysia. METHODS: A total of 121 PLWHA receiving medical care in Kota Bharu (Kelantan, Malaysia) participated in this cross-sectional study. The Malay version of the short Oral Health Impact Profile (S-OHIP(M)) and the Malay version of the 36-item Medical Outcome Study Short Form (SF-36) were used to assess OHRQOL and HRQOL, respectively. A higher S-OHIP(M) score indicates greater oral impact and worse OHRQOL; a higher SF-36 score indicates better HRQOL. An additional structured self-administered questionnaire was used to obtain other variables of interest from the participants. RESULTS: Most participants had at least one oral symptom (69.4%), and the most common oral symptom was a cavitated tooth (55.4%). The prevalence of oral impacts was 33.9%, and the mean S-OHIP(M) score was 8.8 (SD = 7.92). The mean S-OHIP(M) score was significantly higher in participants who had toothaches, cavitated teeth, gum abscesses, and bad breath. In addition, participants with lower S-OHIP(M) scores had significantly higher scores in all SF-36 domains. CONCLUSIONS: Our study provides evidence for an association among oral symptoms, OHRQOL, and HRQOL in PLWHA from Malaysia. In particular, the presence of oral symptoms was significantly associated with more severe oral impacts and poorer OHRQOL. The presence of less severe oral impacts was associated with a better HRQOL. PMID- 28830387 TI - Adult ADHD and comorbid disorders: clinical implications of a dimensional approach. AB - Attention-deficit/hyperactivity disorder (ADHD) in the adult population is frequently associated with comorbid psychiatric diseases that complicate its recognition, diagnosis and management.The prevalence of ADHD in the general adult population is 2.5% and it is associated with substantial personal and individual burden. The most frequent comorbid psychopathologies include mood and anxiety disorders, substance use disorders, and personality disorders. There are strong familial links and neurobiological similarities between ADHD and the various associated psychiatric comorbidities. The overlapping symptoms between ADHD and comorbid psychopathologies represent challenges for diagnosis and treatment. Guidelines recommend that when ADHD coexists with other psychopathologies in adults, the most impairing condition should generally be treated first.Early recognition and treatment of ADHD and its comorbidities has the potential to change the trajectory of psychiatric morbidity later in life. The use of validated assessment scales and high-yield clinical questions can help identify adults with ADHD who could potentially benefit from evidence-based management strategies. PMID- 28830388 TI - Total knee Arthroplasty: risk factors for allogeneic blood transfusions in the South Asian population. AB - BACKGROUND: Total knee arthroplasty (TKA) is the recommended treatment for end stage knee osteoarthritis. Considering the various risks associated with intra and postoperative blood transfusions, better understanding is required with respect to the risk factors contributing to a greater possibility of blood transfusion during or after surgery. Although literature highlights several such factors, our study is among the first to identify these risk factors in the South Asian population which differs from other populations in several ways. METHODS: The study consists of a review of 658 patients undergoing TKA from 2005 to 2015. Data was obtained from patient medical records and was analysed using logistic regression analysis. The relationship between each predictor and the outcome variable was calculated as an Odds ratio (OR), the threshold of significance for which was p = 0.25 and p = 0.05 for univariate and multivariable analysis respectively. RESULTS: The mean age of the patient population was 63 years (78% female), 25% of whom received one or more blood transfusions. Multivariable analysis revealed 5 significant independent predictors for increased risk of blood transfusions including bilateral knee surgery (OR:5.51), preoperative anemia (OR:4.15), higher ASA (American Society of Anaesthesiologists) status (3 4) (OR:1.92), female sex (OR:3.44) and BMI (Body mass index) <=30 (OR:1.79) while increasing co-morbidities and age (>60) were found to be insignificant. CONCLUSIONS: The factors identified for the South Asian population are largely similar to those for other populations. Identification of high risk patients will permit the application of an international multipronged approach which not only targets the modifiable risk factors but also the decision making process and blood management protocols in order to minimize the transfusion associated risks for a patient undergoing a TKA. PMID- 28830389 TI - Occupational class differences in diagnostic-specific sickness absence: a register-based study in the Finnish population, 2005-2014. AB - BACKGROUND: Musculoskeletal diseases and mental disorders are major causes of long-term sickness absence in Western countries. Although sickness absence is generally more common in lower occupational classes, little is known about class differences in diagnostic-specific absence over time. Focusing on Finland during 2005-2014, we therefore set out to examine the magnitude of and changes in absolute and relative occupational class differences in long-term sickness absence due to major diagnostic causes. METHODS: A 70-per-cent random sample of Finns aged 25-64 linked to register data on medically certified sickness absence (of over 10 working days) in 2005-2014 was retrieved from the Social Insurance Institution of Finland. Information on occupational class was obtained from Statistics Finland and linked to the data. The study focused on female (n = 658,148-694,142) and male (n = 604,715-642,922) upper and lower non-manual employees and manual workers. The age-standardised prevalence, the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII) were calculated for each study year to facilitate examination of the class differences. RESULTS: The prevalence of each diagnostic cause of sickness absence declined during the study period, the most common causes being musculoskeletal diseases, mental disorders and injuries. The prevalence of other causes under scrutiny was less than 1 % annually. By far the largest absolute and relative differences were in musculoskeletal diseases among both women and men. Moreover, the absolute differences in both genders (p < 0.0001) and the relative differences in men (p < 0.0001) narrowed over time as the prevalence declined most among manual workers. Both genders showed modest and stable occupational class differences in mental disorders. In the case of injuries, no major changes occurred in absolute differences but relative differences narrowed over time in men (p < 0.0001) due to a strong decline in prevalence among manual workers. Class differences in the other studied diagnostic causes under scrutiny appeared negligible. CONCLUSIONS: By far the largest occupational class differences in long-term sickness absence concerned musculoskeletal diseases, followed by injuries. The results highlight potential targets for preventive measures aimed at reducing sickness absence and narrowing class differences in the future. PMID- 28830390 TI - "If I have only two children and they die... who will take care of me?" -a qualitative study exploring knowledge, attitudes and practices about family planning among Mozambican female and male adults. AB - BACKGROUND: By focusing upon family planning counselling services, the Mozambican government has significantly enhanced the general health of female and male clients. However, little is known about the experiences of family planning by female and male adults. This article focuses on knowledge, attitudes and practices regarding contraceptive methods and fertility intentions. METHODS: An in-depth qualitative study of female and male clients was conducted in two settings in Maputo province - Ndlavela and Boane. A total of sixteen in-depth interviews, four informal conversations, and observations were equally divided between both study sites. The analysis followed a constructionist approach. Three steps were considered in the analysis: examining commonalities, differences and relationships. RESULTS: Although there was a high level of family planning knowledge, there were discrepancies in clients' everyday practices. Male and female clients are confronted with a variety of expectations concerning fertility intentions and family size, and are under pressure in numerous ways. Social pressures include traditional expectations and meanings connected to having children, as well as religious factors. Short interaction time between clients and health workers is a problem. Additionally, imposed contraceptive methods, and typically brief conversations about birth control between couples only adds to the burden. Because family planning is largely viewed as a woman's concern, most clients have never attended counselling sessions with their partners. Attitudes towards responsibility for contraceptive use and risk-taking are strongly gendered. CONCLUSIONS: Female and male clients have differing expectations about contraceptive use and fertility intentions. They participate differently in family planning programs leading to their inconsistent and ambivalent practices as well as vague perceptions of risk-taking. Therefore, policymakers must address the reasons behind ambivalence and inconsistency regarding contraceptives and family planning. PMID- 28830391 TI - Colony stimulating factor-1 and leukemia inhibitor factor expression from current cycle cannula isolated endometrial cells are associated with increased endometrial receptivity and pregnancy. AB - BACKGROUND: Poor endometrial quality is associated with more than a third of embryo implantation failures. Current ultrasonography technology lacks the capacity to determine efficiently the endometrial receptivity during ongoing cycle transfers. We analyzed the relationship between the gene expression profile associated with implantation and clinical pregnancy from endometrial cells taken during embryo transfer. METHODS: Seventy-six patients submitted to a standard ovarian stimulation protocol, in vitro fertilization, and good quality embryos were collected (morphological assessment). Endometrial samples were taken with ultrasonography guidance and cells were Hematoxylin and Eosin stained for morphological identification. Total RNA was extracted and the expression of Mucin 1 (MUC1), Homeobox A10 (HOXA-10), Leukemia Inhibitor Factor (LIF), Colony Stimulating Factor-1 (CSF-1), and ribosomal 18 s (endogenous control) were analyzed using RT-qPCR. Presence of a gestational sac, beta-hGC (>=10 mIU/mL on Day 20), and a fetal heartbeat were used to determine a positive embryo implantation and pregnancy. RESULTS: Samples collected from same cycle embryo transfer showed clear morphological staining for endometrial cells (80-90% of the cells). Cells in the sample were molecularly identified as the endometrium (HOXA 10 positive and MUC-1 negative). CSF-1 expression was 4.55-fold and LIF expression was 12.25-fold higher in patients who became pregnant. Both increases were statistically significant (p < 0.05). CONCLUSIONS: Here, we provide evidence of a new method to assess endometrial receptivity. Furthermore, we demonstrate that the expression profile, based on LIF and CSF-1, showed a difference between a receptive and a non-receptive endometrium. PMID- 28830392 TI - Prevalence and risk factors of low bone mineral density in spondyloarthritis and prevalence of vertebral fractures. AB - BACKGROUND: Investigate the prevalence and risk factors of low bone mineral density (BMD) in patients with axial spondyloarthritis as well as investigating the prevalence of vertebral fractures. METHODS: Patients underwent BMD measurements with dual-energy X-ray absorptiometry (DXA) in the anterior posterior lumbar spine, lateral spine and hip. We screened for vertebral fractures using vertebral fracture assessment, and then checked for syndesmophytes on the VFA images. Sociodemographic and clinical variables were collected. RESULTS: A total of 89 patients (41,6% female) took part in the study with a mean age of 44 +/- 14 years and disease duration 10.2 +/- 10.6 years. According to World Health Organization (WHO) criteria, 48,3% of patients displayed osteopenia and 6,7% osteoporosis. In the subgroup of women who underwent measurement at all sites including the lateral spine, the prevalence of osteopenia was 39.3% in the anterior-posterior spine, 32.1% in the lateral spine, and 64.3% with all sites together. VFA led to the diagnosis of at least one vertebral fracture in 6.2% of patients. On VFA, syndesmophytes were found in 24.3% of patients. The variables associated in multivariate analyses with low BMD in different measurement sites were low body mass index (BMI), a high physician's global assessment score, a high Bath Ankylosing Spondylitis Functional Index (BASFI) score and female gender. CONCLUSION: Our study found a high prevalence (around 50%) of low BMD in SpA. Conversely, the prevalence of osteoporosis (6.7% according to WHO criteria) and vertebral fractures (6.2%) was lower than generally reported in the literature. While lateral spine BMD measurement did little to improve the detection of osteopenia in women, the sample size was not large enough to enable us to draw definite conclusions. PMID- 28830393 TI - Evaluation of HIV-DNA and inflammatory markers in HIV-infected individuals with different viral load patterns. AB - BACKGROUND: Persistent residual viremia (RV) and low grade inflammation and immune activation have been associated with non-AIDS defining events. The impact of persistent RV and HIV-DNA load on immune activation/inflammation remains unclear. The purpose of this study was to gain new insights into the relation between viremia, markers of inflammation and HIV-DNA levels. METHODS: Three hundred and twenty-one HIV-infected patients were studied. A retrospective analysis of viremia values, prospectively collected for 48 months, was performed. Patients were separated into three groups: 113 TND (Target Not Detected, patients with sustained undetectable viremia); 113 RV (Residual Viremia, patients who had at least three detectable viral load (VL) values <37 copies/ml); 95 LLV (Low Level Viremia, patients with at least two VL values >37 but <200 copies/ml). HIV DNA, TNF-alpha, IL-6 and sCD14 were analyzed. RESULTS: HIV-DNA, sCD14 and TNF alpha were significantly lower in the TND group than in the RV and LLV groups. In addition, RV patients showed lower levels of HIV-DNA and sCD14 than LLV individuals. HIV-DNA load was not related to markers of inflammation. The ordinal logistic analysis showed that two independent variables were significantly associated with VL pattern: sCD14, HIV-DNA. In addition NRTIs plus NNRTIs and NRTIs plus PIs were negatively associated to VL pattern compared to INI containing regimen. CONCLUSIONS: Persistent undetectable viremia was associated with lower levels of inflammatory markers and HIV-DNA. However, the lack of normalization of these biomarkers in the TND group and the fact that HIV-DNA load was not associated with inflammation strongly suggest that other mechanisms play a major role in maintaining inflammation over time. PMID- 28830394 TI - Young women's perceptions of transactional sex and sexual agency: a qualitative study in the context of rural South Africa. AB - BACKGROUND: Evidence shows that HIV prevalence among young women in sub-Saharan Africa increases almost five-fold between ages 15 and 24, with almost a quarter of young women infected by their early-to mid-20s. Transactional sex or material exchange for sex is a relationship dynamic that has been shown to have an association with HIV infection. METHODS: Using five focus group discussions and 19 in-depth interviews with young women enrolled in the HPTN 068 conditional cash transfer trial (2011-2015), this qualitative study explores young women's perceptions of transactional sex within the structural and cultural context of rural South Africa. The analysis also considers the degree to which young women perceive themselves as active agents in such relationships and whether they recognise a link between transactional sex and HIV risk. RESULTS: Young women believe that securing their own financial resources will ultimately improve their bargaining position in their sexual relationships, and open doors to a more financially independent future. Findings suggest there is a nuanced relationship between sex, love and gifts: money has symbolic meaning, and money transfers, when framed as gifts, indicates a young woman's value and commitment from the man. This illustrates the complexity of transactional sex; the way it is positioned in the HIV literature ignores that "exchanges" serve as fulcrums around which romantic relationships are organised. Finally, young women express agency in their choice of partner, but their agency weakens once they are in a relationship characterised by exchange, which may undermine their ability to translate perceived agency into STI and HIV risk reduction efforts. CONCLUSIONS: This research underscores the need to recognise that transactional sex is embedded in adolescent romantic relationships, but that certain aspects make young women particularly vulnerable to HIV. This is especially true in situations of restricted choice and circumscribed employment opportunities. HIV prevention educational programmes could be coupled with income generation trainings, in order to leverage youth resilience and protective skills within the confines of difficult economic and social circumstances. This would provide young women with the knowledge and means to more successfully navigate safer sexual relationships. PMID- 28830395 TI - Antenatal depressive symptoms and perinatal complications: a prospective study in rural Ethiopia. AB - BACKGROUND: Antenatal depressive symptoms affect around 12.3% of women in in low and middle income countries (LMICs) and data are accumulating about associations with adverse outcomes for mother and child. Studies from rural, low-income country community samples are limited. This paper aims to investigate whether antenatal depressive symptoms predict perinatal complications in a rural Ethiopia setting. METHODS: A population-based prospective study was conducted in Sodo district, southern Ethiopia. A total of 1240 women recruited in the second and third trimesters of pregnancy were followed up until 4 to 12 weeks postpartum. Antenatal depressive symptoms were assessed using a locally validated version of the Patient Health Questionnaire (PHQ-9) that at a cut-off score of five or more indicates probable depression. Self-report of perinatal complications, categorised as maternal and neonatal were collected by using structured interviewer administered questionnaires at a median of eight weeks post-partum. Multivariate analysis was conducted to examine the association between antenatal depressive symptoms and self-reported perinatal complications. RESULT: A total of 28.7% of women had antenatal depressive symptoms (PHQ-9 score >= 5). Women with antenatal depressive symptoms had more than twice the odds of self-reported complications in pregnancy (OR=2.44, 95% CI: 1.84, 3.23), labour (OR= 1.84 95% CI: 1.34, 2.53) and the postpartum period (OR=1.70, 95% CI: 1.23, 2.35) compared to women without these symptoms. There was no association between antenatal depressive symptoms and pregnancy loss or neonatal death. CONCLUSION: Antenatal depressive symptoms are associated prospectively with self-reports of perinatal complications. Further research is necessary to further confirm these findings in a rural and poor context using objective measures of complications and investigating whether early detection and treatment of depressive symptoms reduces these complications. PMID- 28830396 TI - Missed opportunities in the evaluation of public health interventions: a case study of physical activity programmes. AB - BACKGROUND: Evidence-based approaches are requisite in evaluating public health programmes. Nowhere are they more necessary than physical activity interventions where evidence of effectiveness is often poor, especially within hard to reach groups. Our study reports on the quality of the evaluation of a government funded walking programme in five 'Walking Cities' in England. Cities were required to undertake a simple but robust evaluation using the Standard Evaluation Framework (SEF) for physical activity interventions to enable high quality, consistent evaluation. Our aim was not to evaluate the outcomes of this programme but to evaluate whether the evaluation process had been effective in generating new and reliable evidence on intervention design and what had worked in 'real world' circumstances. METHODS: Funding applications and final reports produced by the funder and the five walking cities were obtained. These totalled 16 documents which were systematically analysed against the 52 criteria in the SEF. Data were cross checked between the documents at the bid and reporting stage with reference to the SEF guidance notes. RESULTS: Generally, the SEF reporting requirements were not followed well. The rationale for the interventions was badly described, the target population was not precisely specified, and neither was the method of recruitment. Demographics of individual participants, including socio-economic status were reported poorly, despite being a key criterion for funding. CONCLUSIONS: Our study of the evaluations demonstrated a missed opportunity to confidently establish what worked and what did not work in walking programmes with particular populations. This limited the potential for evidence synthesis and to highlight innovative practice warranting further investigation. Our findings suggest a mandate for evaluability assessment. Used at the planning stage this may have ensured the development of realistic objectives and crucially may have identified innovative practice to implement and evaluate. Logic models may also have helped in the development of the intervention and its means of capturing evidence prior to implementation. It may be that research-practice partnerships between universities and practitioners could enhance this process. A lack of conceptual clarity means that replicability and scaling-up of effective interventions is difficult and the opportunity to learn from failure lost. PMID- 28830397 TI - The reproducibility of self-reported age at menarche: The Tromso Study. AB - BACKGROUND: Previous studies of the reproducibility of self-reported age at menarche have been limited because of small study samples, short follow-up and the limited age span of the women included. METHODS: The present study assessed the reproducibility of age at menarche in 6731 women with a wide variation of age when giving the information about age at menarche. The women reported age at menarche in a self-administered questionnaire, both in 1986-1987 and 1994-1995. They were all residents of Tromso, Norway, and aged 25-73 in 1994-1995. In order to investigate the agreement between self-reported age at menarche at the two points in time, Pearson's correlation coefficient was applied to assess the linear correlation between the reported menarcheal age at the two occasions. Analyses were stratified for age. A Bland-Altman plot was produced and limits of agreement computed. RESULTS: We found a high correlation and a strong agreement between self-reported age at menarche in 1986-1987 and 1994-1995. The overall Pearson's correlation coefficient was 0.84 and was not attenuated by increasing age of the women. The Bland-Altman plot showed a strong agreement in self reported age at menarche. The mean difference between self-reported age at menarche was 0.01 years with limits of agreement -1.52 to 1.54. CONCLUSION: We found high reproducibility of self-reported age at menarche. The mean menarcheal age in the two surveys was identical (13.2 years) with 95% of the women reporting the same age at menarche or with a difference of 1 year. Only 0.7% of the women reported age at menarche with a difference of more than 2 years in 1986-1987 and 1994-1995. PMID- 28830398 TI - Reasons for delay in decision making and reaching health facility among obstetric fistula and pelvic organ prolapse patients in Gondar University hospital, Northwest Ethiopia. AB - BACKGROUND: Obstetric fistula and pelvic organ prolapse remain highly prevalent in sub-Saharan Africa, where women have poor access to modern health care. Women having these problems tend to stay at home for years before getting treatment. However, information regarding the reasons contributing to late presentation to treatment is scarce, especially at the study area. The objective of this study was to assess the reasons whywomen with obstetric fistula and pelvic organ prolapse at Gondar University Hospital delay treatment. METHOD: A hospital based cross-sectional study was conducted among 384 women. Delay was evaluated by calculating symptom onset and time of arrival to get treatment at Gondar University Hospital. Regression analysis was conducted to elicit predictors of delay for treatment. RESULT: Of the total 384 participants, 311 (80.9%) had pelvic organ prolapse and 73(19.1%) obstetric fistula. The proportion of women who delayed treatment of pelvic organ prolapse was 82.9% and that of obstetric fistula 60.9%. Fear of disclosing illness due to social stigma (AOR = 2; 1.03, 3.9) and lack of money (AOR = 1.97; 1.01, 3.86) were associated with the delay of treatment for pelvic organ prolapse,while increasing age (AOR =1.12; 1.01, 1.24) and divorce (AOR = 16.9; 1.75, 165.5) were were responsible for delaying treatment forobstetric fistula. CONCLUSION: A large numberof women with pelvic organ prolapse and obstetric fistula delayed treatment. Fear of disclosure due to social stigma and lack of moneywere the major factors that contributed to thedelay to seek treatment for pelvic organ prolapse,while increasing age and divorce were the predictors for delaying treatment for obstetric fistula. PMID- 28830399 TI - Why older workers work beyond the retirement age: a qualitative study. AB - BACKGROUND: The aims of the present study were to: 1) gain insight into reasons for working beyond the statutory retirement age from older workers' perspectives, and 2) explore how the domains of the research framework Study on Transitions in Employment, Ability and Motivation (STREAM) can be applied to working beyond retirement age. METHODS: A qualitative research design included individual interviews (n = 15) and three focus groups (n = 18 participants) conducted with older workers aged 65 years and older continuing in a paid job or self employment. Interview participants were recruited from an existing STREAM cohort study. Focus group participants were recruited from companies and employment agencies. The data were subjected to thematic analysis. RESULTS: The most important motives for working beyond retirement age were maintaining daily routines and financial benefit. Good health and flexible work arrangements were mentioned as important preconditions. The themes emerging from the categorization of the motives and preconditions corresponded to the domains of health, work characteristics, skills and knowledge, and social and financial factors from the STREAM research framework. However, our analysis revealed one additional theme purpose in life. CONCLUSION: This study offers important new insights into the various preconditions and motives that influence working beyond retirement age. In addition, the five domains of the STREAM research framework, including the additional domain of 'purpose in life', seem to be applicable to working beyond retirement age. This knowledge contributes to the development of work-related interventions that enhance older workers' motivation to prolong their working lives. PMID- 28830400 TI - Reducing waiting time and raising outpatient satisfaction in a Chinese public tertiary general hospital-an interrupted time series study. AB - BACKGROUND: It is globally agreed that a well-designed health system deliver timely and convenient access to health services for all patients. Many interventions aiming to reduce waiting times have been implemented in Chinese public tertiary hospitals to improve patients' satisfaction. However, few were well-documented, and the effects were rarely measured with robust methods. METHODS: We conducted a longitudinal study of the length of waiting times in a public tertiary hospital in Southern China which developed comprehensive data collection systems. Around an average of 60,000 outpatients and 70,000 prescribed outpatients per month were targeted for the study during Oct 2014-February 2017. We analyzed longitudinal time series data using a segmented linear regression model to assess changes in levels and trends of waiting times before and after the introduction of waiting time reduction interventions. Pearson correlation analysis was conducted to indicate the strength of association between waiting times and patient satisfactions. The statistical significance level was set at 0.05. RESULTS: The monthly average length of waiting time decreased 3.49 min (P = 0.003) for consultations and 8.70 min (P = 0.02) for filling prescriptions in the corresponding month when respective interventions were introduced. The trend shifted from baseline slight increasing to afterwards significant decreasing for filling prescriptions (P =0.003). There was a significant negative correlation between waiting time of filling prescriptions and outpatient satisfaction towards pharmacy services (r = -0.71, P = 0.004). CONCLUSIONS: The interventions aimed at reducing waiting time and raising patient satisfaction in Fujian Provincial Hospital are effective. A long-lasting reduction effect on waiting time for filling prescriptions was observed because of carefully designed continuous efforts, rather than a one-time campaign, and with appropriate incentives implemented by a taskforce authorized by the hospital managers. This case provides a model of carrying out continuous quality improvement and optimizing management process with the support of relevant evidence. PMID- 28830401 TI - Estimating the variation in need for community-based social care by body mass index in England and associated cost: population-based cross-sectional study. AB - BACKGROUND: Adult obesity is linked to a greater need for social care because of its association with the development of long term conditions and because obese adults can have physical and social difficulties which inhibit daily living. Obesity thus has considerable social care cost implications but the magnitude of these costs is currently unknown. This paper outlines an approach to estimating obesity-related social care costs in adults aged over 65 in England. METHODS: We used univariable and multivariable logistic regression models to investigate the relation between the self-reported need for social care and potential determinants, including body mass index (BMI), using data from Health Survey for England. We combined these modelled estimates of need for social care with the mean hours of help received, conditional on receiving any help, to calculate the expected hours of social care received per adult by BMI. RESULTS: BMI is positively associated with self-reported need for social care. A one unit (ie 1 kg/m2) increase in BMI is on average associated with a 5% increase in the odds of need for help with social care (odds ratio 1.05, 95% CI 1.04 to 1.07) in an unadjusted model. Adjusting for long term illness and sociodemographic characteristics we estimate the annual cost of local authority funded care for those who receive it is L599 at a BMI of 23 but L1086 at a BMI of 40. CONCLUSION: BMI is positively associated with self-reported need for social care after adjustment for sociodemographic factors and limiting long term illness. The increase in need for care with BMI gives rise to additional costs in social care provision which should be borne in mind when calculating the cost-effectiveness of interventions aimed at reducing obesity. PMID- 28830402 TI - Tourniquet use in arthroscopic anterior cruciate ligament reconstruction: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: To assess the effects of tourniquet use in arthroscopic anterior cruciate ligament (ACL) reconstruction surgery. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) that compared surgical outcomes following tourniquet use against non-tourniquet use during ACL reconstruction surgery. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE for relevant RCTs. We used the Cochrane Collaboration's tool to assess the risk of bias of included RCTs, and performed a random-effects meta-analysis in calculating the pooled risk estimates. The primary outcomes was postoperative pain measured by visual analogue scale, verbal rating scale, or required morphine dose. The secondary outcomes were blood loss in drainage, operative time, muscle strength, and calf and thigh girth. RESULTS: We included 5 RCTs with 226 participants (116 in the tourniquet group and 110 in the non-tourniquet group). Postoperative pain and morphine doses were not significantly different between the two groups. Compared to the non-tourniquet group, the tourniquet group had a significantly increased blood loss in the drain (mean difference: 94.40 ml; 95% CI 3.65-185.14; P = 0.04). No significant differences in the operative time and muscle strength were found between the two groups. Tourniquet use was associated with a greater decrease in thigh girth but not in calf girth. CONCLUSIONS: The current evidence shows that compared to tourniquet use, ACL reconstruction surgery without tourniquet does not appear to have any major disadvantages and does not prolong operation time. There might be less drain blood loss associated with tourniquet use, though drains are no longer routinely used in ACL reconstruction surgery. PMID- 28830403 TI - Minilaparoscopic versus single incision cholecystectomy for the treatment of cholecystolithiasis: a meta-analysis and systematic review. AB - BACKGROUND: Over the past decade, mini-laparoscopic cholecystectomy (MLC) and single-port laparoscopic cholecystectomy (SILC) have been the two main successful mini-invasive surgical interventions for the treatment of cholecystolithiasis since the advent of laparoscopic cholecystectomy (LC). In this study, we conducted a meta-analysis to compare the two treatment alternatives. METHODS: We searched PubMed, CNKI and the Cochrane library for trials that compared MLC and SILC. Risk difference (RD) and mean difference (MD) were calculated with a 95% confidence interval (CI). RESULTS: Four randomized controlled trials (RCTs) and 2 non-randomized comparative studies (nRCSs) involving 2764 patients were identified. A longer operating time (MD -10.49; 95% CI -18.10, -2.88; P = 0.007) and a shorter wound length (MD 3.65; 95% CI 0.51, 6.78; P = 0.02) were found to be associated with SILC compared with MLC. No significant differences were revealed in conversion, hospital stay, pain relief and cosmetic results. Although a lower incidence of complications was observed with MLC (8.2%) compared with SILC (15.9%), but the difference was not statistically significant (RD -0.06; 95% CI -0.12, 0.00; P = 0.07). CONCLUSIONS: MLC has an advantage over SILC in terms of operating time rather than hospital stay, pain relief, cosmetic results. Though conversion and complication rates were higher with SILC, there existed no statistically differences in the two measures between the two procedures. Whether MLC confers any benefits in terms of conversion or complications still warrants further studies. PMID- 28830404 TI - Effects of prolonged exercise versus multiple short exercise sessions on risk for metabolic syndrome and the atherogenic index in middle-aged obese women: a randomised controlled trial. AB - BACKGROUND: Many people, although they may recognise the positive effects of exercise, do not exercise regularly owing to lack of time. This study aimed to investigate the effects of prolonged single-session exercise and multiple short sessions of exercise on the risk of metabolic syndrome and the atherogenic index in middle-aged obese women. METHODS: Thirty-six participants were divided into the single-session group, multiple-session group, and control group. The single session group engaged in one session of treadmill exercise for 30 min a day; the multiple-session group had three sessions of 10 min a day. Both groups exercised 3 days/week for 12 weeks. The control group did not perform any exercise. RESULTS: The single-session group showed decreases in weight (0.97 kg [95% C.I. = 0.09-1.83], p < .05), body mass index (0.43 kg/m2 [95% C.I. = 0.03-0.81], p < .05), and fat mass (1.65 kg, [95% C.I. = 0.78-2.51], p < .01). Systolic blood pressure dropped in the single-session group (6.66 mmHg, [95% C.I. = 1.44-11.88], p < .05), and diastolic blood pressure dropped in the multiple-session group (3.38 mmHg, [95% C.I. = 1.44-5.88], p < .01). High-density lipoprotein cholesterol rose in the single-session group (4.08 mg/dL, [95% C.I. = -8.08-( )0.07], p < .05) and dropped in the control group (10.75 mg/dL [95% C.I. = 1.95 19.54], p < .01). According to post hoc analysis, high-density lipoprotein cholesterol increased more in the single-session group than the control group (95% C.I. = 0.61-21.88, p < .05). Glucose levels decreased in both the single session group (16 mg/dL [95% C.I. = 5.64-26.35], p < .01) and the multiple session group (12.16 mg/dL, [95% C.I. = 2.18-22.14], p < .05). Waist circumference decreased in the single-session group (2.65 cm [95% C.I. = 1.46 3.83], p < .001) and multiple-session group (2.04 cm, [95% C.I. = 1.51-2.73], p < .001). Low-density lipoprotein cholesterol levels rose in both the multiple session group (-15.79 mg/dL [95% C.I. = -34.24-(-)3.78], p < .05) and the control group (-22.94 mg/dL [95% C.I. = -44.63-(-)1.24], p < .05). The atherogenic index increased in the control group (-1.06 [95% C.I. = -1.69-(-)0.41], p < .01). CONCLUSIONS: The findings indicate that prolonged exercise is superior to multiple short sessions for improving the risk of metabolic syndrome and the atherogenic index in middle-aged obese women. However, multiple short sessions can be recommended as an alternative to prolonged exercise when the goal is to decrease blood glucose or waist circumference. PMID- 28830405 TI - A scoping review of the potential for chart stimulated recall as a clinical research method. AB - BACKGROUND: Chart-stimulated recall (CSR) is a case-based interviewing technique, which is used in the assessment of clinical decision-making in medical education and professional certification. Increasingly, clinical decision-making is a concern for clinical research in primary care. In this study, we review the prior application and utility of CSR as a technique for research interviews in primary care. METHODS: Following Arksey & O'Malley's method for scoping reviews, we searched seven databases, grey literature, reference lists, and contacted experts in the field. We excluded studies on medical education or competence assessment. Retrieved citations were screened by one reviewer and full texts were ordered for all potentially relevant abstracts. Two researchers independently reviewed full texts and performed data extraction and quality appraisal if inclusion criteria were met. Data were collated and summarised using a published framework on the reporting of qualitative interview techniques, which was chosen a priori. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines informed the review report. RESULTS: From an initial list of 789 citations, eight studies using CSR in research interviews were included in the review: six from North America, one from the Netherlands, and one from Ireland. The most common purpose of included studies was to examine the influence of guidelines on physicians' decisions. The number of interviewees ranged from seven to twenty nine, while the number of charts discussed per interview ranged from one to twelve. CSR gave insights into physicians' reasoning for actions taken or not taken; the unrecorded social and clinical influences on decisions; and discrepancies between physicians' real and perceived practice. Ethical concerns and the training and influence of the researcher were poorly discussed in most of the studies. Potential pitfalls included the risk of recall, selection and observation biases. CONCLUSIONS: Despite the proven validity, reliability and acceptability of CSR in assessment interviews in medical education, its use in clinical research is limited. Application of CSR in qualitative research brings interview data closer to the reality of practice. Although further development of the approach is required, we recommend a role for CSR in research interviews on decision-making in clinical practice. PMID- 28830406 TI - Exploring attitudes and perceptions of patients and staff towards an after-hours co-pay clinic supplementing free HIV services in Kampala, Uganda. AB - BACKGROUND: There has been a rapid scale up of HIV services and access to anti retroviral therapy in Africa over the last 10 years as a result of multilateral donor funding mechanisms. However, in order to continue to expand and to sustain these services it is important that "in country" options are explored. This study sought to explore attitudes and perceptions of people living with HIV (PLHIV) and health care staff towards using a fee-based "after hours" clinic (AHC) at the Infectious Diseases Institute (IDI) in Kampala, Uganda. METHODS: A cross sectional study design, using qualitative methods for data collection was used. A purposeful sample of 188 adults including PLHIV accessing care at IDI and IDI staff were selected. We conducted 14 focus group discussions and 55 in-depth interviews. Thematic content analysis was conducted and Nvivo Software Version 10 was used to manage data. RESULTS: Findings suggested that some respondents were willing to pay for consultation, brand-name drugs, laboratory tests and other services. Many were willing to recommend the AHC to friends and/or relatives. However, there were concerns expressed of a risk that the co-pay model may lead to reduction in quality or provision of the free service. Respondents agreed that, as a sign of social responsibility, fees for service could help underprivileged patients. CONCLUSION: The IDI AHC clinic is perceived as beneficial to PLHIV because it provides access to HIV services at convenient times. Many PLHIV are willing to pay for this enhanced service. Innovations in HIV care delivery such as quality private-public partnerships may help to improve overall coverage and sustain quality HIV services in Uganda in the long term. PMID- 28830407 TI - Understanding middle managers' influence in implementing patient safety culture. AB - BACKGROUND: The past fifteen years have been marked by large-scale change efforts undertaken by healthcare organizations to improve patient safety and patient centered care. Despite substantial investment of effort and resources, many of these large-scale or "radical change" initiatives, like those in other industries, have enjoyed limited success - with practice and behavioural changes neither fully adopted nor ultimately sustained - which has in large part been ascribed to inadequate implementation efforts. Culture change to "patient safety culture" (PSC) is among these radical change initiatives, where results to date have been mixed at best. DISCUSSION: This paper responds to calls for research that focus on explicating factors that affect efforts to implement radical change in healthcare contexts, and focuses on PSC as the radical change implementation. Specifically, this paper offers a novel conceptual model based on Organizational Learning Theory to explain the ability of middle managers in healthcare organizations to influence patient safety culture change. We propose that middle managers can capitalize on their unique position between upper and lower levels in the organization and engage in 'ambidextrous' learning that is critical to implementing and sustaining radical change. This organizational learning perspective offers an innovative way of framing the mid-level managers' role, through both explorative and exploitative activities, which further considers the necessary organizational context in which they operate. PMID- 28830408 TI - The KTx360 degrees -study: a multicenter, multisectoral, multimodal, telemedicine based follow-up care model to improve care and reduce health-care costs after kidney transplantation in children and adults. AB - BACKGROUND: Follow-up care after kidney transplantation is performed in transplant centers as well as in local nephrologist's practices in Germany. However, organized integrated care of these different sectors of the German health care system is missing. This organizational deficit as well as non adherence of kidney recipients and longterm cardiovascular complications are major reasons for an impaired patient and graft survival. METHODS: The KTx360 degrees study is supported by a grant from the Federal Joint Committee of the Federal Republic of Germany. The study will include 448 (39 children) incident patients of all ages with KTx after study start in May 2017 and 963 (83 children) prevalent patients with KTx between 2010 and 2016. The collaboration between transplant centers and nephrologists in private local practices will be supported by internet-based case-files and scheduled virtual visits (patient consultation via video conferencing). At specified points of the care process patients will receive cardiovascular and adherence assessments and respective interventions. Care will be coordinated by an additional case management. The goals of the study will be evaluated by an independent institute using claims data from the statutory health insurances and data collected from patients and their caregivers during study participation. To model longitudinal changes after transplantation and differences in changes and levels of immunosuppresive therapy after transplantation between study participants and historical data as well as data from control patients who do not participate in KTx360 degrees , adjusted regression analyses, such as mixed models with repeated measures, will be used. Relevant confounders will be controlled in all analyses. DISCUSSION: The study aims to prolong patient and graft survival, to reduce avoidable hospitalizations, co-morbidities and health care costs, and to enhance quality of life of patients after kidney transplantation. TRIAL REGISTRATION: ISRCTN29416382 (retrospectively registered on 05.05.2017). PMID- 28830409 TI - Word2Vec inversion and traditional text classifiers for phenotyping lupus. AB - BACKGROUND: Identifying patients with certain clinical criteria based on manual chart review of doctors' notes is a daunting task given the massive amounts of text notes in the electronic health records (EHR). This task can be automated using text classifiers based on Natural Language Processing (NLP) techniques along with pattern recognition machine learning (ML) algorithms. The aim of this research is to evaluate the performance of traditional classifiers for identifying patients with Systemic Lupus Erythematosus (SLE) in comparison with a newer Bayesian word vector method. METHODS: We obtained clinical notes for patients with SLE diagnosis along with controls from the Rheumatology Clinic (662 total patients). Sparse bag-of-words (BOWs) and Unified Medical Language System (UMLS) Concept Unique Identifiers (CUIs) matrices were produced using NLP pipelines. These matrices were subjected to several different NLP classifiers: neural networks, random forests, naive Bayes, support vector machines, and Word2Vec inversion, a Bayesian inversion method. Performance was measured by calculating accuracy and area under the Receiver Operating Characteristic (ROC) curve (AUC) of a cross-validated (CV) set and a separate testing set. RESULTS: We calculated the accuracy of the ICD-9 billing codes as a baseline to be 90.00% with an AUC of 0.900, the shallow neural network with CUIs to be 92.10% with an AUC of 0.970, the random forest with BOWs to be 95.25% with an AUC of 0.994, the random forest with CUIs to be 95.00% with an AUC of 0.979, and the Word2Vec inversion to be 90.03% with an AUC of 0.905. CONCLUSIONS: Our results suggest that a shallow neural network with CUIs and random forests with both CUIs and BOWs are the best classifiers for this lupus phenotyping task. The Word2Vec inversion method failed to significantly beat the ICD-9 code classification, but yielded promising results. This method does not require explicit features and is more adaptable to non-binary classification tasks. The Word2Vec inversion is hypothesized to become more powerful with access to more data. Therefore, currently, the shallow neural networks and random forests are the desirable classifiers. PMID- 28830410 TI - Collaboration in teams with nurse practitioners and general practitioners during out-of-hours and implications for patient care; a qualitative study. AB - BACKGROUND: Increasingly, nurse practitioners (NPs) are deployed in teams along with general practitioners (GPs) to help meet the demand for out-of-hours care. The purpose of this study was to explore factors influencing collaboration between GPs and NPs in teams working out-of-hours. METHODS: A descriptive qualitative study was done using a total of 27 semi-structured interviews and two focus group discussions. Data was collected between June, 2014 and October, 2015 at an out-of-hours primary care organisation in the Netherlands. Overall, 38 health professionals (GPs, NPs, and support staff) participated in the study. The interviews were audio-taped and transcribed verbatim. Two researchers conducted an inductive content analysis, involving the identification of relevant items in a first phase and clustering into themes in a second phase. RESULTS: The following four themes emerged from the data: clarity of NP role and regulation, shared caseload and use of skills, communication concerning professional roles, trust and support in NP practice. Main factors influencing collaboration between GPs and NPs included a lack of knowledge regarding the NPs' scope of practice and regulations governing NP role; differences in teams in sharing caseload and using each other's skills effectively; varying support of GPs for the NP role; and limited communication between GPs and NPs regarding professional roles during the shift. Lack of collaboration was perceived to result in an increased risk of delay for patients who needed treatment from a GP, especially in teams with more NPs. Collaboration was not perceived to improve over time as teams varied across shifts. CONCLUSION: In out-of-hours primary care teams constantly change and team members are often unfamiliar with each other or other's competences. In this environment, knowledge and communication about team members' roles is continuously at stake. Especially in teams with more NPs, team members need to use each other's skills to deliver care to all patients on time. PMID- 28830411 TI - Impact of Moringa oleifera lam. Leaf powder supplementation versus nutritional counseling on the body mass index and immune response of HIV patients on antiretroviral therapy: a single-blind randomized control trial. AB - BACKGROUND: To achieve effective antiretroviral therapy (ART) outcomes, adherence to an antiretroviral regimen and a good immunometabolic response are essential. Food insecurity can act as a real barrier to adherence to both of these factors. Many people living with human immunodeficiency virus (PLHIV) treated with ART in the Democratic Republic of the Congo (DRC) are faced with nutritional challenges. A significant proportion are affected by under nutrition, which frequently leads to therapeutic failure. Some HIV care facilities recommend supplementation with Moringa oleifera (M.O.) Lam. leaf powder to combat marginal and major nutritional deficiencies. This study aims to assess the impact of M.O. Lam. leaf powder supplementation compared to nutritional counseling on the nutritional and immune status of PLHIV treated with ART. METHODS: A single-blind randomized control trial was carried out from May to September 2013 at an outpatient clinic for HIV infected patients in Kinshasa (DRC). Sixty adult patients who were at stable HIV/AIDS clinical staging 2, 3 or 4 according to the World Health Organization (WHO), and were undergoing ART were recruited. After random allocation, 30 patients in the Moringa intervention group (MG) received the M.O. Lam. leaf powder daily over 6 months, and 30 in the control group (CG) received nutritional counseling over the same period. Changes in the body mass index (BMI) were measured monthly and biological parameters were measured upon admission and at the end of the study for the patients in both groups. RESULTS: The two study groups were similar in terms of long-term nutritional exposure, sociodemographic, socioeconomic, clinical, and biological features. At 6 months follow-up, patients in the MG exhibited a significantly greater increase in BMI and albumin levels than those in the CG. The interaction between the sociodemographic, clinical, and biological characteristics of patients in the two groups was not significant, with the exception of professional activity. CONCLUSIONS: Under medical supervision, M.O. Lam. leaf powder supplementation may represent a readily available and effective local solution to improve the nutritional intake and nutritional status of PLHIV undergoing ART. TRIAL REGISTRATION: The study was retrospectively registered in the Pan African Clinical Trial Registry on 15 May 2015, no. PACTR201505001076143. PMID- 28830413 TI - A network perspective on patient experiences and health status: the Medical Expenditure Panel Survey 2004 to 2011. AB - BACKGROUND: There is a growing emphasis on the need to engage patients in order to improve the quality of health care and improve health outcomes. However, we are still lacking a comprehensive understanding on how different measures of patient experiences interact with one another or relate to health status. This study takes a network perspective to 1) study the associations between patient characteristics and patient experience in health care and 2) identify factors that could be prioritized to improve health status. METHODS: This study uses data from the two-year panels from the Medical Expenditure Panel Survey (MEPS) initiated between 2004 and 2011 in the United States. The 88 variables regarding patient health and experience with health care were identified through the MEPS documentation. Sex, age, race/ethnicity, and years of education were also included for analysis. The bnlearn package within R (v3.20) was used to 1) identify the structure of the network of variables, 2) assess the model fit of candidate algorithms, 3) cross-validate the network, and 4) fit conditional probabilities with the given structure. RESULTS: There were 51,023 MEPS interviewees aged 18 to 85 years (mean = 44, 95% CI = 43.9 to 44.2), with years of education ranging from 1 to 19 (mean = 7.4, 95% CI = 7.40 to 7.46). Among all, 55% and 74% were female and white, respectively. There were nine networks identified and 17 variables not linked to others, including death in the second years, sex, entry years to the MEPS, and relations of proxies. The health status in the second years was directly linked to that in the first years. The health care ratings were associated with how often professionals listened to them and whether professionals' explanation was understandable. CONCLUSIONS: It is feasible to construct Bayesian networks with information on patient characteristics and experiences in health care. Network models help to identify significant predictors of health care quality ratings. With temporal relationships established, the structure of the variables can be meaningful for health policy researchers, who search for one or a few key priorities to initiate interventions or health care quality improvement programs. PMID- 28830412 TI - Body composition and personality traits in so-Yang type males. AB - BACKGROUND: The purpose of the present study was to examine the body composition of So-Yang type males according to Sasang constitutional medicine, which is popular in Korea. Different Sasang constitutional types are associated with different muscle distributions, body shapes, and disease susceptibilities. We used the Sasang Personality Questionnaire (SPQ) as a measure of the temperament of each Sasang type. METHODS: In total, 953 subjects aged over 20 years were recruited in Korea. We collected anthropometric parameters and bioimpedence information from the subjects and administered the SPQ. A logistic regression was conducted to calculate propensity scores. RESULTS: The percentage of skeletal muscle mass in So-Yang (SY) and non-So-Yang (non-SY) males was 45.8 +/- 2.7 and 44.2 +/- 3.3, respectively, before matching and 45.8 +/- 2.6 and 44.9 +/- 3.0, respectively, after propensity score matching. The extracellular water (ECW)/intracellular water (ICW) and extracellular water (ECW)/total body water (TBW) ratios and SPQ scores were significantly different between the SY and non SY types. CONCLUSIONS: This study suggested that the SY type may be significantly and independently associated with body composition and could be associated with personality. PMID- 28830414 TI - Diabetes knowledge and utilization of healthcare services among patients with type 2 diabetes mellitus in Dhaka, Bangladesh. AB - BACKGROUND: Diabetes is a significant global public health concern. Poor knowledge of disease and healthcare utilization is associated with worse health outcomes, leading to increasing burden of diabetes in many developing countries. This study aimed to determine diabetes related knowledge and factors affecting utilization of healthcare services among patients with type 2 diabetes mellitus in Bangladesh. METHODS: This analytical study was conducted among 318 patients with type 2 diabetes (T2DM) attending two large tertiary hospitals in Dhaka, Bangladesh between August 2014 and January 2015. Interviewer assisted semi structured survey questionnaire was used to collect data on diabetes knowledge (measured by a validated Likert scale) and self-reported utilization of service for diabetes. Univariate and bivariate analyses were conducted to determine the factors associated with diabetes knowledge and healthcare utilization. RESULTS: The mean (+/-SD) age of participants was 52 (+/-10) years. Majority of the participants were females (58%) and urban residents (74%). Almost two-third (66%) of the participants had an average level of knowledge of T2DM. One-fifth (21%) of the participants had poor knowledge which was significantly associated with gender (P < 0.002), education (P < 0 .001) and income (P < 0.001). The median travel and waiting time at the facility was 30 and 45 min respectively. More than one-third (37%) of the participants checked their blood glucose monthly. Most patients were satisfied regarding the family (55%) and hospital (67%) support. CONCLUSION: T2DM patients had average knowledge of diabetes which might affect the utilization of healthcare services for diabetes management. Innovations in increasing diabetes knowledge and health behavior change are recommended specially for females, those with lower education and less income. PMID- 28830415 TI - Anti-cancer effects of Ajwa dates (Phoenix dactylifera L.) in diethylnitrosamine induced hepatocellular carcinoma in Wistar rats. AB - BACKGROUND: Hepatocellular carcinoma (HCC) accounts for major cancer-related deaths despite current advanced therapies. Treatment and prognosis of HCC is better in patients with preserved liver function. Many natural products including ajwa dates (Phoenix dactylifera L.), are claimed to have hepatoprotective and HCC inhibitory effects, but most lack scientific validation. To prove our hypothesis, we attempted to evaluate the HCC inhibitory effects, and other beneficial properties of the aqueous extract of ajwa dates (ADE) in a rat model of diethylnitrosamine (DEN) induced liver cancer. METHODS: Thirty-two male rats were divided into four groups of eight each as follows, Group A: untreated control; Group B: DEN control (180 mg/kg bw), Group C: DEN + ADE 0.5 g/kg bw; and Group D: DEN +1.0 g/kg bw. Rats from all groups were assessed for liver cancer progression or inhibition by evaluating histological, biochemical, antioxidant enzyme status, cytokines and gene expression profiles. RESULTS: DEN treatment Groups (B, C, D) showed histological features of HCC and in rats treated with ADE (Groups C, D) partial to complete reversal of normal liver architecture was observed. Antioxidant enzymes such as superoxide dismutase (SOD), glutathione reductase (GR), glutatione peroxidase (GPx) and catalase (CAT) were increased, while the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels and lipid peroxidation were significantly decreased in Group C and Group D compared to Group B. Pro-inflammatory cytokines such as interleukin (IL)-1alpha, IL-1beta,, GM-CSF) were increased in the serum of rats in Group B while the anti-tumor cytokines (IL-2, IL-12) were increased in ADE treated Groups (C, D). In addition, Alpha-Feto Protein (AFP) and IL-6 gene expression levels were upregulated in Group B, while they were significantly downregulated in ADE treated Groups (C, D). CONCLUSIONS: ADE helped in the reversal of DEN damaged liver towards normal. Restoration of anti-oxidant enzymes, liver enzymes, cytokines balance and gene expression to normal levels following ADE treatment indicates that ADE improves liver function and inhibits HCC. ADE can, therefore, be used together with conventional therapeutics for HCC. PMID- 28830416 TI - The safety attitudes questionnaire in Chinese: psychometric properties and benchmarking data of the safety culture in Beijing hospitals. AB - BACKGROUND: In China, increasing attention has been devoted to the patient safety culture within health administrative departments and healthcare organizations. However, no official version of a patient safety culture assessment tool has been published or is widely used, and little is known about the status of the safety culture in Chinese hospitals. The aims of this study were to examine the reliability and validity of the Safety Attitudes Questionnaire in Chinese and to establish benchmark data on the safety culture in Beijing. METHODS: Across sectional survey on patient safety culture was conducted from August to October 2014 using the Safety Attitudes Questionnaire in Chinese. Using a stratified random sampling method, we investigated departments from five integrative teaching hospitals in Beijing; frontline healthcare workers in each unit participated in the survey on a voluntary basis. The internal consistency and reliability were tested via Cronbach's alpha, and the structural validity of the questionnaire was tested using a correlation analysis and confirmatory factor analysis. The patient safety culture in the five hospitals was assessed and analyzed. RESULTS: A total of 1663 valid questionnaires were returned, for a response rate of 87.9%. Cronbach's alpha of the total scale was 0.945, and Cronbach's alpha for the six dimensions ranged from 0.785 to 0.899. The goodness of-fit indices in the confirmatory factor analysis showed an acceptable but not ideal model fit. The safety attitude score of healthcare workers in the five hospitals was 69.72, and the positive response rate was 38.57% overall. The positive response rates of the six dimensions were between 20.80% and 59.31%. CONCLUSIONS: The Safety Attitudes Questionnaire in Chinese has good internal consistency, and the structural validity and reliability are acceptable. This questionnaire can be used to assess the safety culture in Beijing hospitals, but some items require further refinement. The patient safety culture in Beijing hospitals must be improved in certain key areas. PMID- 28830417 TI - Empirical advances with text mining of electronic health records. AB - BACKGROUND: Korian is a private group specializing in medical accommodations for elderly and dependent people. A professional data warehouse (DWH) established in 2010 hosts all of the residents' data. Inside this information system (IS), clinical narratives (CNs) were used only by medical staff as a residents' care linking tool. The objective of this study was to show that, through qualitative and quantitative textual analysis of a relatively small physiotherapy and well defined CN sample, it was possible to build a physiotherapy corpus and, through this process, generate a new body of knowledge by adding relevant information to describe the residents' care and lives. METHODS: Meaningful words were extracted through Standard Query Language (SQL) with the LIKE function and wildcards to perform pattern matching, followed by text mining and a word cloud using R(r) packages. Another step involved principal components and multiple correspondence analyses, plus clustering on the same residents' sample as well as on other health data using a health model measuring the residents' care level needs. RESULTS: By combining these techniques, physiotherapy treatments could be characterized by a list of constructed keywords, and the residents' health characteristics were built. Feeding defects or health outlier groups could be detected, physiotherapy residents' data and their health data were matched, and differences in health situations showed qualitative and quantitative differences in physiotherapy narratives. CONCLUSIONS: This textual experiment using a textual process in two stages showed that text mining and data mining techniques provide convenient tools to improve residents' health and quality of care by adding new, simple, useable data to the electronic health record (EHR). When used with a normalized physiotherapy problem list, text mining through information extraction (IE), named entity recognition (NER) and data mining (DM) can provide a real advantage to describe health care, adding new medical material and helping to integrate the EHR system into the health staff work environment. PMID- 28830418 TI - Medical students' preparedness for professional activities in early clerkships. AB - BACKGROUND: Sufficient preparedness is important for transitions to workplace participation and learning in clinical settings. This study aims to analyse medical students' preparedness for early clerkships using a three-dimensional, socio-cognitive, theory-based model of preparedness anchored in specific professional activities and their supervision level. METHODS: Medical students from a competency-based undergraduate curriculum were surveyed about preparedness for 21 professional activities and level of perceived supervision during their early clerkships via an online questionnaire. Preparedness was operationalized by the three dimensions of confidence to carry out clerkship activities, being prepared through university teaching and coping with failure by seeking support. Factors influencing preparedness and perceived stress as outcomes were analysed through step-wise regression. RESULTS: Professional activities carried out by the students (n = 147; 19.0%) and their supervision levels varied. While most students reported high confidence to perform the tasks, the activity-specific analysis revealed important gaps in preparation through university teaching. Students regularly searched for support in case of difficulty. One quarter of the variance of each preparedness dimension was explained by self-efficacy, supervision quality, amount of prior clerkship experience and nature of professional activities. Preparedness contributed to predicting perceived stress. CONCLUSIONS: The applied three-dimensional concept of preparedness and the task specific approach provided a detailed and meaningful view on medical students' workplace participation and experiences in early clerkships. PMID- 28830419 TI - Prevalence, patterns, and perceived value of complementary and alternative medicine among HIV patients: a descriptive study. AB - BACKGROUND: Use of complementary and alternative medicine (CAM) is widespread among different patient populations despite the availability of evidence-based conventional medicine and lack of supporting evidence for the claims of most CAM types. This study explored the prevalence, patterns, and perceived value of CAM among human immunodeficiency virus (HIV) patients. METHODS: This quantitative descriptive study was conducted between November 1, 2014 and March 31, 2015 among a cross-sectional, convenience sample of attendees of the HIV clinic of a public tertiary health care institution. Face-to-face interviews using a 34-item questionnaire were conducted. Data analysis included descriptive statistics, chi square tests, and binary logistic regression analysis. RESULTS: CAM was used by 113 (32.8%) of a total of 343 HIV patients, but <1% informed their health care providers of CAM usage. Medicinal herbs were the most common type of CAM used (n = 110, 97.3%) followed by spiritual therapy (n = 56, 49.6%), including faith healing/prayer and meditation. The most used medicinal herbs were Aloe vera (n = 54, 49.1%), ginger (n = 33, 30.0%), and garlic (n = 23, 20.9%). The most used vitamins were complex B vitamins (n = 70, 61.9%), followed by vitamin A (n = 58, 51.3%), vitamin E (n = 51, 45.1%), and vitamin D (n = 42, 37.1%). Most CAM users continued using conventional medicine in addition to CAM and were willing to use CAM without supervision and without informing their health care provider. Patients were generally satisfied with CAM therapy (n = 91, 80.5%). The main reasons for CAM use were the desire to take control of their treatment (8.8%) or just trying anything that could help (18.8%). Main influences were the mass media (32.7%) and non-hospital health personnel (19.5%). Predictors of CAM use were being 30-50 years, married and having a secondary school education. CONCLUSION: About one-third of HIV patients used CAM, but virtually none informed their healthcare provider. Medicinal herbs were the most common type of CAM, followed by spiritual therapy and vitamins. A patient's decision to use CAM was influenced for the most part by the mass media and non- hospital health care personnel. PMID- 28830420 TI - A randomised, controlled, two-Centre open-label study in healthy Japanese subjects to evaluate the effect on biomarkers of exposure of switching from a conventional cigarette to a tobacco heating product. AB - BACKGROUND: Smoking is a leading cause of numerous human disorders including lung cancer, chronic obstructive pulmonary disease, and atherosclerotic cardiovascular disease. The development of modified risk tobacco products (MRTPs) has been suggested as a possible way to reduce the risks of tobacco smoking by reducing exposure to cigarette smoke toxicants. This study is designed to investigate whether biomarkers of such exposure are reduced when smokers switch from smoking commercial cigarettes to using either a novel or a commercially-available tobacco heating product (THP). DESIGN AND METHODS: This study will assess biomarkers of exposure in current smokers who either remain smoking, switch to THP use, or quit all tobacco use completely, for 5 days. The study is an in-clinic (confinement) two-centre, randomised controlled clinical study with a forced-switching design. Subjects of either gender will be aged 23-55 years (minimum legal smoking age plus 3 years), of Japanese origin and with a verified smoking status (assessed by exhaled breath carbon monoxide and urinary cotinine levels). Subjects will have a usual brand cigarette within the International Organisation for Standardisation (ISO) tar band of 6-8 mg and will be judged to be healthy by medical history, physical examination, vital signs, electrocardiography (ECG), clinical biochemistry and lung function tests. The primary objective of this study is to assess changes within groups in selected biomarkers of exposure (BoE) and of biological effect (BoBE) after a forced switch from a commercial control cigarette to either a menthol or a non-menthol THP. Secondary objectives are to assess between-group differences, to determine nicotine pharmacokinetics for cigarettes and THPs, to assess subject's satisfaction with the study products, and to monitor additional endpoints related to safety and product use. DISCUSSION: Data from this study will advance our scientific understanding of the changes in exposure to cigarette smoke toxicants in smokers who switch to using a THP. TRIAL REGISTRATIONS: UMIN000024988 (25th November 2016); ISRCTN14301360 (14th December 2016). PMID- 28830421 TI - Health care needs assessment among adolescents in correctional institutions in Zambia: an ethical analysis. AB - BACKGROUND: While health care needs assessments have been conducted among juveniles or adolescents by researchers in developed countries, assessments using an ethics framework particularly in developing countries are lacking. We analysed the health care needs among adolescents at the Nakambala Correctional Institution in Zambia, using the Beauchamp and Childress ethics framework. The ethics approach facilitated analysis of moral injustices or dilemmas triggered by health care needs at the individual (adolescent) level. METHODS: The research team utilized 35 in-depth interviews with juveniles, 6 key informant interviews and 2 focus group discussions to collect data. We analysed the data using thematic analysis. The use of three sources of data facilitated triangulation of data. RESULTS: Common health problems included HIV/AIDS, STIs, flu, diarrhoea, rashes, and malaria. Although there are some health promotion strategies at the Nakambala Approved School, the respondents classified the health care system as inadequate. The unfavourable social context which included clouded rooms and lack of adolescent health friendly services unfairly exposed adolescents to several health risks and behaviours thus undermining the ethics principle of social justice. In addition, the limited prioritisation of adolescent centres by the stakeholders and erratic funding also worsened injustices by weakening the health care system. Whereas the inadequate medical and drug supplies, shortage of health workers in the nearby health facilities and weak referral systems excluded the juveniles from enjoying maximum health benefits thus undermining adolescents' wellbeing or beneficence. Inadequate medical and drug supplies as well as non availability of adolescent friendly health services at the nearest health facility did not only affect social justice and beneficence ethics principles but also threatened juveniles' privacy, liberty and confidentiality as well as autonomy with regard to health service utilisation. CONCLUSION: Adequately addressing the health needs in correctional institutions may require adopting an ethics framework in conducting health needs assessment. An ethics approach is important because it facilitates understanding of moral dilemmas that arise due to health needs. Furthermore, strategies for addressing health needs related to one ethics principle may have a positive ripple effect over other health needs as the principles are intertwined thus facilitating a comprehensive response to health needs. PMID- 28830422 TI - Hospital quality measures: are process indicators associated with hospital standardized mortality ratios in French acute care hospitals? AB - BACKGROUND: Results of associations between process and mortality indicators, both used for the external assessment of hospital care quality or public reporting, differ strongly across studies. However, most of those studies were conducted in North America or United Kingdom. Providing new evidence based on French data could fuel the international debate on quality of care indicators and help inform French policy-makers. The objective of our study was to explore whether optimal care delivery in French hospitals as assessed by their Hospital Process Indicators (HPIs) is associated with low Hospital Standardized Mortality Ratios (HSMRs). METHODS: The French National Authority for Health (HAS) routinely collects for each hospital located in France, a set of mandatory HPIs. Five HPIs were selected among the process indicators collected by the HAS in 2009. They were measured using random samples of 60 to 80 medical records from inpatients admitted between January 1st, 2009 and December 31, 2009 in respect with some selection criteria. HSMRs were estimated at 30, 60 and 90 days post-admission (dpa) using administrative health data extracted from the national health insurance information system (SNIIR-AM) which covers 77% of the French population. Associations between HPIs and HSMRs were assessed by Poisson regression models corrected for measurement errors with a simulation extrapolation (SIMEX) method. RESULTS: Most associations studied were not statistically significant. Only two process indicators were found associated with HSMRs. Completeness and quality of anesthetic records was negatively associated with 30 dpa HSMR (0.72 [0.52-0.99]). Early detection of nutritional disorders was negatively associated with all HSMRs: 30 dpa HSMR (0.71 [0.54-0.95]), 60 dpa HSMR (0.51 [0.39-0.67]) and 90 dpa HSMR (0.52 [0.40-0.68]). CONCLUSION: In absence of gold standard of quality of care measurement, the limited number of associations suggested to drive in-depth improvements in order to better determine associations between process and mortality indicators. A smart utilization of both process and outcomes indicators is mandatory to capture aspects of the hospital quality of care complexity. PMID- 28830423 TI - Migrant's access to preventive health services in five EU countries. AB - BACKGROUND: Preventive health services (PHSs) form part of primary healthcare with the aim of screening to prevent disease. Migrants show significant differences in lifestyle, health beliefs and risk factors compared with the native populations. This can have a significant impact on migrants' access to health systems and participation in prevention programmes. Even in countries with widely accessible healthcare systems, migrants' access to PHSs may be difficult. The aim of the study was to compare access to preventive health services between migrants and native populations in five European Union (EU) countries. METHODS: Information from Health Interview Surveys of Belgium, Italy, Malta, Portugal and Spain were used to analyse access to mammography, Pap smear tests, colorectal cancer screening and flu vaccination among migrants. The comparative risk of not accessing PHSs was calculated using a mixed-effects multilevel model, adjusting for potential confounding factors (sex, education and the presence of disability). Migrant status was defined according to citizenship, with a distinction made between EU and non-EU countries. RESULTS: Migrants, in particular those from non-EU countries, were found to have poorer access to PHSs. The overall risk of not reporting a screening test or a flu vaccination ranged from a minimum of 1.8 times (colorectal cancer screening), to a high of 4.4 times (flu vaccination) for migrants. The comparison among the five EU countries included in the study showed similarities, with particularly limited access recorded in Italy and in Belgium for non-EU migrants. CONCLUSIONS: The findings of this study are in accordance with evidence from the scientific literature. Poor organization of health services, in Italy, and lack of targeted health policies in Belgium may explain these findings. PHSs should be responsive to patient diversity, probably more so than other health services. There is a need for diversity-oriented, migrant-sensitive prevention. Policies oriented to removing impediments to migrants' access to preventive interventions are crucial, to encourage more positive action for those facing the risk of intersectional discrimination. PMID- 28830424 TI - Safety of primaquine given to people with G6PD deficiency: systematic review of prospective studies. AB - BACKGROUND: Haemolysis risk with single dose or short course primaquine was evaluated in glucose-6-phosphate dehydrogenase (G6PD) deficient people. METHODS: Major electronic databases (to August 2016) were searched for single or short course 8-aminoquinolines (8-AQ) in (1) randomized comparisons against placebo in G6PD deficient people; and (2) observational comparisons in G6PD deficient compared to replete people. Two authors independently assessed eligibility, risk of-bias, and extracted data. RESULTS: Five randomized controlled trials and four controlled observational cohorts were included. In G6PD deficient individuals, high-dose (0.75 mg/kg) PQ resulted in lower average haemoglobin levels at 7 days (mean difference [MD] -1.45 g/dl, 95% CI -2.17 to -0.74, 2 trials) and larger percentage fall from baseline to day 7 (MD -10.31%, 95% CI -17.69 to -2.92, 3 trials) compared to placebo. In G6PD deficient compared to replete people, average haemoglobin was lower at 7 days (MD -1.19 g/dl, 95% CI -1.94 to -0.44, 2 trials) and haemoglobin change from baseline to day 7 was greater (MD -9.10%, 95% CI -12.55 to -5.65, 5 trials). One small trial evaluated mid-range PQ dose (0.4 0.5 mg/kg) in G6PD deficient people, with no difference detected in average haemoglobin at day 7 compared to placebo. In one cohort comparing G6PD deficient and replete people there was a greater fall with G6PD deficiency (MD -4.99%, 95% CI -9.96 to -0.02). For low-dose PQ (0.1-0.25 mg/kg) in G6PD deficient people, haemoglobin change from baseline was similar to the placebo group (MD 1.72%, 95% CI -1.89 to 5.34, 2 trials). Comparing low dose PQ in G6PD deficient with replete people, the average haemoglobin was lower in the G6PD deficient group at 7 days ( 0.57 g (95% CI -0.97 to -0.17, 1 trial)); although change from baseline was similar (MD -1.45%, 95% CI -5.69 to 2.78, 3 trials). CONCLUSIONS: Falls in average haemoglobin are less marked with the 0.1 to 0.25 mg/kg PQ than with the 0.75 mg/kg dose, and severe haemolytic events are not common. However, data were limited and the evidence GRADE was low or very low certainty. PMID- 28830425 TI - Improved yield of canine islet isolation from deceased donors. AB - BACKGROUND: Canine diabetes is a strikingly prevalent and growing disease, and yet the standard treatment of a twice-daily insulin injection is both cumbersome to pet owners and only moderately effective. Islet transplantation has been performed with repeated success in canine research models, but has unfortunately not been made available to companion animals. Standard protocols for islet isolation, developed primarily for human islet transplantation, include beating heart organ donation, vascular perfusion of preservation solutions, specialized equipment. Unfortunately, these processes are prohibitively complex and expensive for veterinary use. The aim of the study was to develop a simplified approach for isolating canine islets that is compatible with the financial and logistical restrictions inherent to veterinary medicine for the purpose of translating islet transplantation to a clinical treatment for canine diabetes. RESULTS: Here, we describe simplified strategies for isolating quality islets from deceased canine donors without vascular preservation and with up to 90 min of cold ischemia time. An average of more than 1500 islet equivalents per kg of donor bodyweight was obtained with a purity of 70% (N = 6 animals). Islets were 95% viable and responsive to glucose stimulation for a week. We found that processing only the body and tail of the pancreas increased isolation efficiency without sacrificing islet total yield. Islet yield per gram of tissue increased from 773 to 1868 islet equivalents when the head of the pancreas was discarded (N = 3/group). CONCLUSIONS: In summary, this study resulted in the development of an efficient and readily accessible method for obtaining viable and functional canine islets from deceased donors. These strategies provide an ethical means for obtaining donor islets. PMID- 28830426 TI - Using random forests for assistance in the curation of G-protein coupled receptor databases. AB - BACKGROUND: Biology is experiencing a gradual but fast transformation from a laboratory-centred science towards a data-centred one. As such, it requires robust data engineering and the use of quantitative data analysis methods as part of database curation. This paper focuses on G protein-coupled receptors, a large and heterogeneous super-family of cell membrane proteins of interest to biology in general. One of its families, Class C, is of particular interest to pharmacology and drug design. This family is quite heterogeneous on its own, and the discrimination of its several sub-families is a challenging problem. In the absence of known crystal structure, such discrimination must rely on their primary amino acid sequences. METHODS: We are interested not as much in achieving maximum sub-family discrimination accuracy using quantitative methods, but in exploring sequence misclassification behavior. Specifically, we are interested in isolating those sequences showing consistent misclassification, that is, sequences that are very often misclassified and almost always to the same wrong sub-family. Random forests are used for this analysis due to their ensemble nature, which makes them naturally suited to gauge the consistency of misclassification. This consistency is here defined through the voting scheme of their base tree classifiers. RESULTS: Detailed consistency results for the random forest ensemble classification were obtained for all receptors and for all data transformations of their unaligned primary sequences. Shortlists of the most consistently misclassified receptors for each subfamily and transformation, as well as an overall shortlist including those cases that were consistently misclassified across transformations, were obtained. The latter should be referred to experts for further investigation as a data curation task. CONCLUSION: The automatic discrimination of the Class C sub-families of G protein coupled receptors from their unaligned primary sequences shows clear limits. This study has investigated in some detail the consistency of their misclassification using random forest ensemble classifiers. Different sub-families have been shown to display very different discrimination consistency behaviors. The individual identification of consistently misclassified sequences should provide a tool for quality control to GPCR database curators. PMID- 28830427 TI - Influence of parameter perturbations on the reachability of therapeutic target in systems with switchings. AB - BACKGROUND: Examination of physiological processes and the influences of the drugs on them can be efficiently supported by mathematical modeling. One of the biggest problems is related to the exact fitting of the parameters of a model. Conditions inside the organism change dynamically, so the rates of processes are very difficult to estimate. Perturbations in the model parameters influence the steady state so a desired therapeutic goal may not be reached. Here we investigate the effect of parameter deviation on the steady state in three simple models of the influence of a therapeutic drug on its target protein. Two types of changes in the model parameters are taken into account: small perturbations in the system parameter values, and changes in the switching time of a specific parameter. Additionally, we examine the systems response in case of a drug concentration decreasing with time. RESULTS: The models which we analyze are simplified, because we want to avoid influences of complex dynamics on the results. A system with a negative feedback loop is the most robust and the most rapid, so it requires the largest drug dose but the effects are observed very quickly. On the other hand a system with positive feedback is very sensitive to changes, so small drug doses are sufficient to reach a therapeutic target. In systems without feedback or with positive feedback, perturbations in the model parameters have a bigger influence on the reachability of the therapeutic target than in systems with negative feedback. Drug degradation or inactivation in biological systems enforces multiple drug applications to maintain the level of a drug's target under the desired threshold. The frequency of drug application should be fitted to the system dynamics, because the response velocity is tightly related to the therapeutic effectiveness and the time for achieving the goal. CONCLUSIONS: Systems with different types of regulation vary in their dynamics and characteristic features. Depending on the feedback loop, different types of therapy may be the most appropriate, and deviations in the model parameters have different influences on the reachability of the therapeutic target. PMID- 28830428 TI - The effect of oligofructose-enriched inulin supplementation on gut microbiota, nutritional status and gastrointestinal symptoms in paediatric coeliac disease patients on a gluten-free diet: study protocol for a pilot randomized controlled trial. AB - BACKGROUND: A lifelong gluten-free diet (GFD) is regarded as the only proven and accepted therapy for coeliac disease (CD). However, even patients who strictly follow a GFD often suffer from intestinal symptoms and malabsorption. Selective modulation of intestinal microbiota with prebiotics could remedy various symptoms associated with CD. The use of prebiotics in the treatment of intestinal diseases remains insufficiently investigated. To our knowledge, this study makes the first attempt to evaluate the effect of prebiotic supplementation on gastrointestinal symptoms and nutritional status of children with CD. We hypothesized that adherence to a GFD supplemented with oligofructose-enriched inulin (Synergy 1) would deliver health benefits to children suffering from CD without any side effects, and that it would alleviate intestinal inflammation, restore and stabilize gut microbial balance and reverse nutritional deficiencies through enhanced absorption of vitamins and minerals. METHODS: A randomized, placebo controlled clinical trial was designed to assess the impact of the Synergy 1 on paediatric CD patients following a GFD. We randomized 34 children diagnosed with CD into an intervention group receiving 10 g of the Synergy 1 supplement daily and a placebo group (receiving maltodextrin) during a 12-week nutritional intervention. Selected biochemical parameters, nutritional status and the characteristics of faecal bacteria will be determined in samples collected before and after the intervention. Analysis of vitamins and amino acids concentration in biological fluids will allow to assess the dietary intake of crucial nutrients. The compliance to a GFD will be confirmed by a Food Frequency Questionnaire (FFQ 6) and the analysis of serum anti-tissue transglutaminase and faecal gluten immunogenic peptides (GIP). CONCLUSION: The identification of the beneficial effects of the Synergy 1 supplement on children with CD could have important implications for nutritional recommendations for CD patients and for alleviating the harmful effects of the disease. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT03064997 . PMID- 28830429 TI - Molecular study on Pasteurella multocida and Mannheimia granulomatis from Kenyan Camels (Camelus dromedarius). AB - BACKGROUND: Outbreaks of a Haemorrhagic Septicaemia (HS) like disease causing large mortalities in camels (Camelus dromedarius) in Asia and in Africa have been reported since 1890. Yet the aetiology of this condition remains elusive. This study is the first to apply state of the art molecular methods to shed light on the nasopharyngeal carrier state of Pasteurellaceae in camels. The study focused on HS causing Pasteurella multocida capsular types B and E. Other Pasteurellaceae, implicated in common respiratory infections of animals, were also investigated. METHODS: In 2007 and 2008, 388 nasopharyngeal swabs were collected at 12 locations in North Kenya from 246 clinically healthy camels in 81 herds that had been affected by HS-like disease. Swabs were used to cultivate bacteria on blood agar and to extract DNA for subsequent PCR analysis targeting P. multocida and Mannheimia-specific gene sequences. RESULTS: Forty-five samples were positive for P. multocida genes kmt and psl and for the P. multocida Haemorrhagic Septicaemia (HS) specific sequences KTSP61/KTT72 but lacked HS associated capsular type B and E genes capB and capE. This indicates circulation of HS strains in camels that lack established capsular types. Sequence analysis of the partial 16S rRNA gene identified 17 nasal swab isolates as 99% identical with Mannheimia granulomatis, demonstrating a hitherto unrecognised active carrier state for M. granulomatis or a closely related Mannheimia sp. in camels. CONCLUSIONS: The findings of this study provide evidence for the presence of acapsular P. multocida or of hitherto unknown capsular types of P. multocida in camels, closely related to P. multocida strains causing HS in bovines. Further isolations and molecular studies of camelid P. multocida from healthy carriers and from HS-like disease in camels are necessary to provide conclusive answers. This paper is the first report on the isolation of M. granulomatis or a closely related new Mannheimia species from camelids. PMID- 28830430 TI - Tick-borne encephalitis in a naturally infected sheep. AB - BACKGROUND: Tick-borne encephalitis (TBE) is the most important viral tick borne zoonosis in Europe. In Germany, about 250 human cases are registered annually, with the highest incidence reported in the last years coming from the federal states Bavaria and Baden-Wuerttemberg. In veterinary medicine, only sporadic cases in wild and domestic animals have been reported; however, a high number of wild and domestic animals have tested positive for the tick-borne encephalitis virus (TBEV) antibody. CASE PRESENTATION: In May 2015, a five-month-old lamb from a farm with 15 Merino Land sheep and offspring in Nersingen/Bavaria, a TBEV risk area, showed impaired general health with pyrexia and acute neurological signs. The sheep suffered from ataxia, torticollis, tremor, nystagmus, salivation and finally somnolence with inappetence and recumbency. After euthanasia, pathological, histopathological, immunohistochemical, bacteriological, parasitological and virological analyses were performed. Additionally, blood samples from the remaining, healthy sheep in the herd were taken for detection of TBEV antibody titres. At necropsy and accompanying parasitology, the sheep showed a moderate to severe infection with Trichostrongylids, Moniezia and Eimeria species. Histopathology revealed mild to moderate necrotising, lymphohistiocytic and granulocytic meningoencephalitis with gliosis and neuronophagia. Immunohistochemistry for TBEV was negative. RNA of a TBEV strain, closely related to the Kumlinge A52 strain, was detected in the brain by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and subsequent PCR product sequencing. A phylogenetic analysis revealed a close relationship to the TBEV of central Europe. TBEV was cultured from brain tissue. Serologically, one of blood samples from the other sheep in the herd was positive for TBEV in an enzyme linked immunosorbent assay (ELISA) and in a serum neutralisation test (SNT), and one was borderline in an ELISA. CONCLUSION: To the authors' knowledge this is the first report of a natural TBEV infection in a sheep in Europe with clinical manifestation, which describes the clinical presentation and the histopathology of TBEV infection. PMID- 28830431 TI - Erratum to: Enhanced biosurfactant production through cloning of three genes and role of esterase in biosurfactant release. PMID- 28830432 TI - Utility of autoimmune serology testing in the assessment of uncharacterized interstitial lung disease: a large retrospective cohort review. AB - BACKGROUND: Autoimmune serologies are often obtained in the initial evaluation of uncharacterized interstitial lung disease (ILD). Whether this practice is helpful in delineating connective-tissue disease related ILD (CTD-ILD) is not well known. We assessed the frequency of incident CTD-ILD as detected by autoimmune serology testing and presenting clinical signs and symptoms. METHODS: Consecutive patients seen at our institution over a four year period with newly diagnosed uncharacterized ILD and autoimmune serologic testing were included. Serologic assessment was performed as a standardized order set of 13 laboratory tests. Presenting demographics and clinical signs or symptoms suggestive of autoimmune disease were correlated with the presence or absence of positive serology studies and final CTD-ILD diagnoses. RESULTS: Overall prevalence of newly diagnosed CTD ILD was 6.9% (42 of 605). Positive serology was seen in 35.2% (213 of 605) of screened ILD. CTD-ILD was diagnosed in 19.2% of those with positive serology, and 52.8% of those with both positive serology and suggestive clinical signs or symptoms. Only 1.4% of those with positive serology and negative review of systems were diagnosed with CTD-ILD. CTD-ILD diagnoses were made more frequently in younger patients <=60 years with no diagnoses made after the age of 80 (P = 0.009). Positive serology in non-CTD-ILD cases did not appear to confer any survival advantage. CONCLUSIONS: The yield of autoimmune serology testing in uncharacterized ILD appears greatest in those with suggestive clinical signs or symptoms on presentation for CTD-ILD. PMID- 28830434 TI - Rational confederation of genes and diseases: NGS interpretation via GeneCards, MalaCards and VarElect. AB - BACKGROUND: A key challenge in the realm of human disease research is next generation sequencing (NGS) interpretation, whereby identified filtered variant harboring genes are associated with a patient's disease phenotypes. This necessitates bioinformatics tools linked to comprehensive knowledgebases. The GeneCards suite databases, which include GeneCards (human genes), MalaCards (human diseases) and PathCards (human pathways) together with additional tools, are presented with the focus on MalaCards utility for NGS interpretation as well as for large scale bioinformatic analyses. RESULTS: VarElect, our NGS interpretation tool, leverages the broad information in the GeneCards suite databases. MalaCards algorithms unify disease-related terms and annotations from 69 sources. Further, MalaCards defines hierarchical relatedness-aliases, disease families, a related diseases network, categories and ontological classifications. GeneCards and MalaCards delineate and share a multi-tiered, scored gene-disease network, with stringency levels, including the definition of elite status-high quality gene-disease pairs, coming from manually curated trustworthy sources, that includes 4500 genes for 8000 diseases. This unique resource is key to NGS interpretation by VarElect. VarElect, a comprehensive search tool that helps infer both direct and indirect links between genes and user-supplied disease/phenotype terms, is robustly strengthened by the information found in MalaCards. The indirect mode benefits from GeneCards' diverse gene-to-gene relationships, including SuperPaths-integrated biological pathways from 12 information sources. We are currently adding an important information layer in the form of "disease SuperPaths", generated from the gene-disease matrix by an algorithm similar to that previously employed for biological pathway unification. This allows the discovery of novel gene-disease and disease-disease relationships. The advent of whole genome sequencing necessitates capacities to go beyond protein coding genes. GeneCards is highly useful in this respect, as it also addresses 101,976 non-protein-coding RNA genes. In a more recent development, we are currently adding an inclusive map of regulatory elements and their inferred target genes, generated by integration from 4 resources. CONCLUSIONS: MalaCards provides a rich big-data scaffold for in silico biomedical discovery within the gene-disease universe. VarElect, which depends significantly on both GeneCards and MalaCards power, is a potent tool for supporting the interpretation of wet-lab experiments, notably NGS analyses of disease. The GeneCards suite has thus transcended its 2-decade role in biomedical research, maturing into a key player in clinical investigation. PMID- 28830433 TI - Transcranial direct current stimulation as a motor neurorehabilitation tool: an empirical review. AB - The present review collects the most relevant empirical evidence available in the literature until date regarding the effects of transcranial direct current stimulation (tDCS) on the human motor function. tDCS in a non-invasive neurostimulation technique that delivers a weak current through the brain scalp altering the cortical excitability on the target brain area. The electrical current modulates the resting membrane potential of a variety of neuronal population (as pyramidal and gabaergic neurons); raising or dropping the firing rate up or down, depending on the nature of the electrode and the applied intensity. These local changes additionally have shown long-lasting effects, evidenced by its promotion of the brain-derived neurotrophic factor. Due to its easy and safe application and its neuromodulatory effects, tDCS has attracted a big attention in the motor neurorehabilitation field among the last years. Therefore, the present manuscript updates the knowledge available about the main concept of tDCS, its practical use, safety considerations, and its underlying mechanisms of action. Moreover, we will focus on the empirical data obtained by studies regarding the application of tDCS on the motor function of healthy and clinical population, comprising motor deficiencies of a variety of pathologies as Parkinson's disease, stroke, multiple sclerosis and cerebral palsy, among others. Finally, we will discuss the main current issues and future directions of tDCS as a motor neurorehabilitation tool. PMID- 28830435 TI - Non-linear optical microscopy of cartilage canals in the distal femur of young pigs may reveal the cause of articular osteochondrosis. AB - BACKGROUND: Articular osteochondrosis is a common cause of leg weakness in pigs and is defined as a focal delay in the endochondral ossification of the epiphysis. The first demonstrated steps in the pathogenesis consist of loss of blood supply and subsequent chondronecrosis in the epiphyseal growth cartilage. Blood vessels in cartilage are located in cartilage canals and become incorporated into the secondary ossification centre during growth. It has been hypothesized that vascular failure occurs during this incorporation process, but it is not known what predisposes a canal to fail. To obtain new information that may reveal the cause of vascular failure, the distal femur of 4 pigs aged 82-140 days was sampled and examined by non-linear optical microscopy. This novel technique was used for its ability to reveal information about collagen by second harmonic generation and cellular morphology by two-photon-excited fluorescence in thick sections without staining. The aims were to identify morphological variations between cartilage canal segments and to examine if failed cartilage canals could be followed back to the location where the blood supply ceased. RESULTS: The cartilage canals were shown to vary in their content of collagen fibres (112/412 segments), and the second harmonic and fluorescence signals indicated a variation in the bundling of collagen fibrils (245/412 segments) and in the calcification (30/412 segments) of the adjacent cartilage matrix. Failed cartilage canals associated with chondronecrosis were shown to enter the epiphyseal growth cartilage from not only the secondary ossification centre, but also the attachment site of the caudal cruciate ligament. CONCLUSION: The variations between cartilage canal segments could potentially explain why the blood supply fails at the osteochondral junction in only a subset of the canals. Proteins linked to these variations should be examined in future genomic studies. Although incorporation can still be a major cause, it could not account for all cases of vascular failure. The role of the caudal cruciate ligament in the cause of osteochondrosis should therefore be investigated further. PMID- 28830436 TI - Effects of background statin therapy on glycemic response and cardiovascular events following initiation of insulin therapy in type 2 diabetes: a large UK cohort study. AB - AIM: Statins may increase the risk of new-onset diabetes and adversely affect glycaemic control, but their effects on the glycemic response and mortality outcomes following commencement of insulin therapy in patients with Type 2 Diabetes (T2D) are unclear. METHODS: A retrospective cohort study was conducted in 12,725 insulin initiators with T2D using The Health Improvement Network (THIN) UK database. Changes in HbA1c at 6, 12, 24 and 36 months, and the 5-year risk of mortality and (3-point) major adverse cardiovascular events (MACE), were compared between prior users (n = 10,682) and non-users (n = 2043) of statin therapy who were newly commenced on insulin treatment. Cox proportional hazard models were used to estimate the hazard ratios of the different outcomes. RESULTS: Mean age of the cohort was 58.7 +/- 14.0 years (51% male) and mean baseline HbA1c was 8.7 +/- 1.8%. A greater initial reduction in HbA1c was observed following insulin initiation in the non-users of statins compared with the users, which was significant in the short term (-0.34% vs -0.26% at 6 months; mean diff = -0.09%, p = 0.004) but not in the long term: -0.31% versus -0.35% at 3 years (mean diff = 0.05%, p = 0.344). CV events (3-point MACE) were 878 versus 217 in statin users versus non-users (20.7 vs 30.9 per 1000 person-years; adjusted Hazard Ratio (aHR) 1.36 (95% CI 1.15-1.62; p < 0.0001). In a subgroup analysis of individual statins, HbA1c was higher throughout the study duration with all statins relative to non-users of statin therapy (p < 0.05). The aHRs for 3-point MACE for atorvastatin, simvastatin, rosuvastatin and pravastatin were 0.82 (95% CI 0.68 0.98), 0.67 (0.55-0.82), 0.56 (0.39-0.81) and 0.78 (0.60-1.01), respectively. CONCLUSIONS: Following initiation of insulin therapy in patients with T2D in routine care, concurrent use of a statin was associated with less good glycaemic control in the short-term but a much lower risk of major adverse CV events. PMID- 28830437 TI - An Exploratory Descriptive Study of Antimicrobial Resistance Patterns of Staphylococcus Spp. Isolated from Horses Presented at a Veterinary Teaching Hospital. AB - BACKGROUND: Antimicrobial resistant Staphylococcus are becoming increasingly important in horses because of the zoonotic nature of the pathogens and the associated risks to caregivers and owners. Knowledge of the burden and their antimicrobial resistance patterns are important to inform control strategies. This study is an exploratory descriptive investigation of the burden and antimicrobial drug resistance patterns of Staphylococcus isolates from horses presented at a veterinary teaching hospital in South Africa. METHODS: Retrospective laboratory clinical records of 1027 horses presented at the University of Pretoria veterinary teaching hospital between 2007 and 2012 were included in the study. Crude and factor-specific percentages of Staphylococcus positive samples, antimicrobial resistant (AMR) and multidrug resistant (MDR) isolates were computed and compared across Staphylococcus spp., geographic locations, seasons, years, breed and sex using Chi-square and Fisher's exact tests. RESULTS: Of the 1027 processed clinical samples, 12.0% were Staphylococcus positive. The majority of the isolates were S. aureus (41.5%) followed by S. pseudintermedius (14.6%). Fifty-two percent of the Staphylococcus positive isolates were AMR while 28.5% were MDR. Significant (p < 0.05) differences in the percentage of samples with isolates that were AMR or MDR was observed across seasons, horse breeds and Staphylococcus spp. Summer season had the highest (64.3%) and autumn the lowest (29.6%) percentages of AMR isolates. Highest percentage of AMR samples were observed among the Boerperds (85.7%) followed by the American saddler (75%) and the European warm blood (73.9%). Significantly (p < 0.001) more S. aureus isolates (72.5%) were AMR than S. pseudintermedius isolates (38.9%). Similarly, significantly (p < 0.001) more S. aureus (52.9%) exhibited MDR than S. pseudintermedius (16.7%). The highest levels of AMR were towards beta-lactams (84.5%) followed by trimethoprim/sulfamethoxazole (folate pathway inhibitors) (60.9%) while the lowest levels of resistance were towards amikacin (14.%). CONCLUSIONS: This exploratory study provides useful information to guide future studies that will be critical for guiding treatment decisions and control efforts. There is a need to implement appropriate infection control, and judicious use of antimicrobials to arrest development of antimicrobial resistance. A better understanding of the status of the problem is a first step towards that goal. PMID- 28830438 TI - Feature ranking and rank aggregation for automatic sleep stage classification: a comparative study. AB - BACKGROUND: Nowadays, sleep quality is one of the most important measures of healthy life, especially considering the huge number of sleep-related disorders. Identifying sleep stages using polysomnographic (PSG) signals is the traditional way of assessing sleep quality. However, the manual process of sleep stage classification is time-consuming, subjective and costly. Therefore, in order to improve the accuracy and efficiency of the sleep stage classification, researchers have been trying to develop automatic classification algorithms. Automatic sleep stage classification mainly consists of three steps: pre processing, feature extraction and classification. Since classification accuracy is deeply affected by the extracted features, a poor feature vector will adversely affect the classifier and eventually lead to low classification accuracy. Therefore, special attention should be given to the feature extraction and selection process. METHODS: In this paper the performance of seven feature selection methods, as well as two feature rank aggregation methods, were compared. Pz-Oz EEG, horizontal EOG and submental chin EMG recordings of 22 healthy males and females were used. A comprehensive feature set including 49 features was extracted from these recordings. The extracted features are among the most common and effective features used in sleep stage classification from temporal, spectral, entropy-based and nonlinear categories. The feature selection methods were evaluated and compared using three criteria: classification accuracy, stability, and similarity. RESULTS: Simulation results show that MRMR MID achieves the highest classification performance while Fisher method provides the most stable ranking. In our simulations, the performance of the aggregation methods was in the average level, although they are known to generate more stable results and better accuracy. CONCLUSIONS: The Borda and RRA rank aggregation methods could not outperform significantly the conventional feature ranking methods. Among conventional methods, some of them slightly performed better than others, although the choice of a suitable technique is dependent on the computational complexity and accuracy requirements of the user. PMID- 28830439 TI - Household beliefs about malaria testing and treatment in Western Kenya: the role of health worker adherence to malaria test results. AB - BACKGROUND: Although use of malaria diagnostic tests has increased in recent years, health workers often prescribe anti-malarial drugs to individuals who test negative for malaria. This study investigates how health worker adherence to malaria case management guidelines influences individuals' beliefs about whether their illness was malaria, and their confidence in the effectiveness of artemisinin-based combination therapy (ACT). METHODS: A survey was conducted with 2065 households in Western Kenya about a household member's treatment actions for a recent febrile illness. The survey also elicited the individual's (or their caregiver's) beliefs about the illness and about malaria testing and treatment. Logistic regressions were used to test the association between these beliefs and whether the health worker adhered to malaria testing and treatment guidelines. RESULTS: Of the 1070 individuals who visited a formal health facility during their illness, 82% were tested for malaria. ACT rates for malaria-positive and negative individuals were 89 and 49%, respectively. Overall, 65% of individuals/caregivers believed that the illness was "very likely" malaria. Individuals/caregivers had higher odds of saying that the illness was "very likely" malaria when the individual was treated with ACT, and this was the case both among individuals not tested for malaria [adjusted odds ratio (AOR) 3.42, 95% confidence interval (CI) [1.65 7.10], P = 0.001] and among individuals tested for malaria, regardless of their test result. In addition, 72% of ACT-takers said the drug was "very likely" effective in treating malaria. However, malaria negative individuals who were treated with ACT had lower odds of saying that the drugs were "very likely" effective than ACT-takers who were not tested or who tested positive for malaria (AOR 0.29, 95% CI [0.13 0.63], P = 0.002). CONCLUSION: Individuals/caregivers were more likely to believe that the illness was malaria when the patient was treated with ACT, regardless of their test result. Moreover, malaria-negative individuals treated with ACT had lower confidence in the drug than other individuals who took ACT. These results suggest that ensuring health worker adherence to malaria case management guidelines will not only improve ACT targeting, but may also increase patient/caregivers' confidence in malaria testing and treatment. PMID- 28830440 TI - Cross-sectional association between soda consumption and body mass index in a community-based sample of twins. AB - BACKGROUND: Consumption of sugar-sweetened beverages, such as soda, have been shown to play an important role in weight gain. Although soda consumption has been associated with body mass index (BMI) in many studies, it has been difficult to ascertain a true causal relationship between soda consumption and BMI for two reasons. First, findings have been based largely on observational and cross sectional studies, with much less evidence from randomized controlled trials. Second, the reported relationships may be confounded by genetic and shared environmental factors that affect both soda consumption and BMI. In the present study, we used the twin design to better understand the relationship between soda consumption and BMI by accounting for measured and unmeasured confounds in non experimental data. Associations from genetically informed tests in twins are considered "quasi-causal," suggesting that our confidence in the causal underpinning of the association between soda consumption and BMI has been strengthened. We hypothesized that the association between soda consumption and BMI would be significant both between and within twins. METHODS: This was a cross sectional study of 5787 same sex adult twin pairs (18-97 years, 66% female) from the community based Washington State Twin Registry. Structural equation modeling (SEM) was employed to investigate associations between soda consumption and BMI in the population (the phenotypic association between exposure and outcome among all twins treated as individuals) and within pairs of identical and fraternal twins (the quasi-causal association controlling for between pair genetic and environmental confounds). RESULTS: Among all twins, there was a significant phenotypic association between soda consumption and BMI that held when controlling for age, sex, race, annual household income, and education level (P < 0.05). In the quasi-causal model, however, the effect of soda consumption on BMI was greatly reduced and no longer significant, with a large genetic confound in both men and women (P < 0.05). CONCLUSION: Among a large group of adult twin pairs, increased soda consumption was associated with increased BMI; however, the observed association was mediated by a genetic background common to both. PMID- 28830441 TI - Patient reported outcome measures for measuring dignity in palliative and end of life care: a scoping review. AB - BACKGROUND: Patient reported outcome measures are frequently used standard questionnaires or tools designed to collect information from patients regarding their health status and care. Their use enables accurate and relevant insight into changes in health, quality of life, and symptom severity to be acquired. The purpose of this scoping review was to identify PROMs that had been subject to rigorous development and were suitable for use in palliative and end of life care for clinical practice and/or research purposes. The review had a specific focus on measures which could be used to assess perceptions of dignity in these contexts. METHODS: A scoping review of English-language papers published between 2005 and 2015. Searches were devised in conjunction with an information science specialist and were undertaken in Medline; PsycINFO; EMBASE; CINAHL; Social Science Citation Index; ASSIA; CENTRAL; CDSR; DARE; HTA; Oxford PROM Bibliography; PROQOLID, using dignity related terms such as personhood; dignity or dignified; patient-centred care; which were linked (via the Boolean operator "AND") to care-related terms such as terminal care; hospice care; palliative care; end of life. Papers were assessed against inclusion criteria and appraised for quality. RESULTS: The search strategy produced an initial 7845 articles. After three rounds of eligibility assessment, eight articles discussing eight patients reported outcome measures were found to meet the inclusion criteria and were included in the final review. These underwent a thorough critical appraisal process. All seven studies were empirical research focused on the development and testing of a PROM. CONCLUSIONS: The eight patient reported outcome measures had all undergone some psychometric testing, and covered dignity aspects suggesting that they could be considered for use for research purposes to assess dignity. There were also indications that some could be implemented into a clinical setting. However, each measure had limitations and scope for further development. PMID- 28830442 TI - Modeling EphB4-EphrinB2 protein-protein interaction using flexible docking of a short linear motif. AB - BACKGROUND: Many protein-protein interactions are mediated by a short linear motif. Usually, amino acid sequences of those motifs are known or can be predicted. It is much harder to experimentally characterize or predict their structure in the bound form. In this work, we test a possibility of using flexible docking of a short linear motif to predict the interaction interface of the EphB4-EphrinB2 complex (a system extensively studied for its significance in tumor progression). METHODS: In the modeling, we only use knowledge about the motif sequence and experimental structures of EphB4-EphrinB2 complex partners. The proposed protocol enables efficient modeling of significant conformational changes in the short linear motif fragment during molecular docking simulation. For the docking simulations, we use the CABS-dock method for docking fully flexible peptides to flexible protein receptors (available as a server at http://biocomp.chem.uw.edu.pl/CABSdock/ ). Based on the docking result, the protein-protein complex is reconstructed and refined. RESULTS: Using this novel protocol, we obtained an accurate EphB4-EphrinB2 interaction model. CONCLUSIONS: The results show that the CABS-dock method may be useful as the primary docking tool in specific protein-protein docking cases similar to EphB4-EphrinB2 complex that is, where a short linear motif fragment can be identified. PMID- 28830443 TI - Regular group exercise contributes to balanced health in older adults in Japan: a qualitative study. AB - BACKGROUND: While community-wide interventions to promote physical activity have been encouraged in older adults, evidence of their effectiveness remains limited. We conducted a qualitative study among older adults participating in regular group exercise to understand their perceptions of the physical, mental, and social changes they underwent as a result of the physical activity. METHODS: We conducted a qualitative study with purposeful sampling to explore the experiences of older adults who participated in regular group exercise as part of a community wide physical activity intervention. Four focus group interviews were conducted between April and June of 2016 at community halls in Fujisawa City. The participants in the focus group interviews were 26 older adults with a mean age of 74.69 years (range: 66-86). The interviews were analysed using the constant comparative method in the grounded theory approach. We used qualitative research software NVivo10(r) to track the coding and manage the data. RESULTS: The finding 'regular group exercise contributes to balanced health in older adults' emerged as an overarching theme with seven categories (regular group exercise, functional health, active mind, enjoyment, social connectedness, mutual support, and expanding communities). Although the participants perceived that they were aging physically and cognitively, the regular group exercise helped them to improve or maintain their functional health and enjoy their lives. They felt socially connected and experienced a sense of security in the community through caring for others and supporting each other. As the older adults began to seek value beyond individuals, they gradually expanded their communities beyond geographical and generational boundaries. CONCLUSIONS: The participants achieved balanced health in the physical, mental, and social domains through regular group exercise as part of a community-wide physical activity intervention and contributed to expanding communities through social connectedness and mutual support. Health promotion through physical activity is being increasingly emphasized. The study results can help to develop effective physical activity programs for older adults in the community. PMID- 28830444 TI - Origins and consequences of technology acquirement by independent-living seniors: towards an integrative model. AB - BACKGROUND: Living independently can be challenging for seniors. Technologies are expected to help older adults age in place, yet little empirical research is available on how seniors develop a need for technologies, how they acquire these technologies, and how these subsequently affect their lives. Aging is complex, dynamic and personal. But how does this translate to seniors' adoption and acceptance of technology? To better understand origins and consequences of technology acquirement by independent-living seniors, an explorative longitudinal qualitative field study was set up. METHODS: Home visits were made to 33 community-dwelling seniors living in the Netherlands, on three occasions (2012 2014). Semi-structured interviews were conducted on the timeline of acquirements, and people and factors involved in acquirements. Additionally, participants were interviewed on experiences in using technologies since acquirement. Thematic analysis was employed to analyze interview transcripts, using a realist approach to better understand the contexts, mechanisms and outcomes of technology acquirements. RESULTS: Findings were accumulated in a new conceptual model: The Cycle of Technology Acquirement by Independent-Living Seniors (C-TAILS), which provides an integrative perspective on why and how technologies are acquired, and why these may or may not prove to be appropriate and effective, considering an independent-living senior's needs and circumstances at a given point in time. We found that externally driven and purely desire-driven acquirements led to a higher risk of suboptimal use and low levels of need satisfaction. CONCLUSIONS: Technology acquirement by independent-living seniors may be best characterized as a heterogeneous process with many different origins, pathways and consequences. Furthermore, technologies that are acquired in ways that are not congruent with seniors' personal needs and circumstances run a higher risk of proving to be ineffective or inappropriate. Yet, these needs and circumstances are subject to change, and the C-TAILS model can be employed to better understand contexts and mechanisms that come into play. PMID- 28830445 TI - Responses of rat and mouse primary microglia to pro- and anti-inflammatory stimuli: molecular profiles, K+ channels and migration. AB - BACKGROUND: Acute CNS damage is commonly studied using rat and mouse models, but increasingly, molecular analysis is finding species differences that might affect the ability to translate findings to humans. Microglia can undergo complex molecular and functional changes, often studied by in vitro responses to discrete activating stimuli. There is considerable evidence that pro-inflammatory (M1) activation can exacerbate tissue damage, while anti-inflammatory (M2) states help resolve inflammation and promote tissue repair. However, in assessing potential therapeutic targets for controlling inflammation, it is crucial to determine whether rat and mouse microglia respond the same. METHODS: Primary microglia from Sprague-Dawley rats and C57BL/6 mice were cultured, then stimulated with interferon-gamma + tumor necrosis factor-alpha (I + T; M1 activation), interleukin (IL)-4 (M2a, alternative activation), or IL-10 (M2c, acquired deactivation). To profile their activation responses, NanoString was used to monitor messenger RNA (mRNA) expression of numerous pro- and anti-inflammatory mediators, microglial markers, immunomodulators, and other molecules. Western analysis was used to measure selected proteins. Two potential targets for controlling inflammation-inward- and outward-rectifier K+ channels (Kir2.1, Kv1.3)-were examined (mRNA, currents) and specific channel blockers were applied to determine their contributions to microglial migration in the different activation states. RESULTS: Pro-inflammatory molecules increased after I + T treatment but there were several qualitative and quantitative differences between the species (e.g., iNOS and nitric oxide, COX-2). Several molecules commonly associated with an M2a state differed between species or they were induced in additional activation states (e.g., CD206, ARG1). Resting levels and/or responses of several microglial markers (Iba1, CD11b, CD68) differed with the activation state, species, or both. Transcripts for several Kir2 and Kv1 family members were detected in both species. However, the current amplitudes (mainly Kir2.1 and Kv1.3) depended on activation state and species. Treatment-induced changes in morphology and migratory capacity were similar between the species (migration reduced by I + T, increased by IL-4 or IL-10). In both species, Kir2.1 block reduced migration and Kv1.3 block increased it, regardless of activation state; thus, these channels might affect microglial migration to damage sites. CONCLUSIONS: Caution is recommended in generalizing molecular and functional responses of microglia to activating stimuli between species. PMID- 28830446 TI - Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. AB - BACKGROUND: Loss-of-function CECR1 mutations cause polyarteritis nodosa (PAN) with childhood onset, an autoinflammatory disorder without significant signs of autoimmunity. Herein we describe the unusual presentation of an autoimmune phenotype with constitutive type I interferon activation in siblings with adenosine deaminase 2 (ADA2) deficiency. CASE PRESENTATION: We describe two siblings with early-onset recurrent strokes, arthritis, oral ulcers, discoid rash, peripheral vascular occlusive disease and high antinuclear antibody titers. Assessment of interferon signatures in blood revealed constitutive type I interferon activation. Aicardi-Goutieres syndrome (AGS) was suspected, but no mutation in the known AGS genes were detected. Whole exome sequencing identified compound heterozygosity for a known and a novel mutation in the CECR1 gene. Functional consequences of the mutations were demonstrated by marked reduction in ADA2 catalytic activity. CONCLUSIONS: Our findings demonstrate that ADA2 deficiency can cause an unusual autoimmune phenotype extending the phenotypic spectrum of PAN. Constitutive interferon I activation in patient blood suggests a possible role of type I interferon in disease pathogenesis which may have therapeutic implications. PMID- 28830447 TI - Nanostructured biosensor using bioluminescence quenching technique for glucose detection. AB - BACKGROUND: Most methods for monitoring glucose level require an external energy source which may limit their application, particularly in vivo test. Bioluminescence technique offers an alternative way to provide emission light without external energy source by using bioluminescent proteins found from firefly or marine vertebrates and invertebrates. For quick and non-invasive detection of glucose, we herein developed a nanostructured biosensor by applying the bioluminescence technique. RESULTS: Luciferase bioluminescence protein (Rluc) is conjugated with beta-cyclodextrin (beta-CD). The bioluminescence intensity of Rluc can be quenched by 8 +/- 3 nm gold nanoparticles (Au NPs) when Au NPs covalently bind to beta-CD. In the presence of glucose, Au NPs are replaced and leave far from Rluc through a competitive reaction, which results in the restored bioluminescence intensity of Rluc. A linear relationship is observed between the restored bioluminescence intensity and the logarithmic glucose concentration in the range of 1-100 uM. In addition, the selectivity of this designed sensor has been evaluated. The performance of the senor for determination of the concentration of glucose in the blood of diabetic rats is studied for comparison with that of the concentration of glucose in aqueous. CONCLUSIONS: This study demonstrates the design of a bioluminescence sensor for quickly detecting the concentration of glucose sensitively. PMID- 28830448 TI - Significant decrease of saturation index in erythrocytes membrane from subjects with non-alcoholic fatty liver disease (NAFLD). AB - BACKGROUND: The lipidomic profiling of erythrocyte membranes is expected to provide a peculiar scenario at molecular level of metabolic and nutritional pathways which may influence the lipid balance and the adaptation and homeostasis of the organism. Considering that lipid accumulation in the cell is important in promoting tissue inflammation, the purpose of this study is to analyze the fatty acid profile in red blood cell membranes of patients with Non-Alcoholic Fatty Liver Disease (NAFLD), in order to identify and validate membrane profiles possibly associated with the degree of hepatic damage. METHODS: This work presents data obtained at baseline from 101 subjects that participated to a nutritional trial (registration number: NCT02347696) enrolling consecutive subjects with NAFLD. Diagnosis of liver steatosis was performed by using vibration-controlled elastography implemented on FibroScan. Fatty acids, extracted from phospholipids of erythrocyte membranes, were quantified by gas chromatography method. RESULTS: The subjects with severe NAFLD showed a significant decrease of the ratio of stearic acid to oleic acid (saturation index, SI) compared to controls, 1.281 +/- 0.31 vs 1.5 +/- 0.29, respectively. Low levels of SI in red blood cell membranes, inversely associated with degree of liver damage, suggest that an impairment of circulating cell membrane structure can reflect modifications that take place in the liver. Subjects with severe NAFLDalso showed higher levels of elongase 5 enzymatic activity, evaluated as vaccenic acid to palmitoleic acid ratio. CONCLUSIONS: Starting from these evidences, our findings show the importance of lipidomic approach in the diagnosis and the staging of NAFLD. PMID- 28830449 TI - Psychosocial factors associated with the mental health of indigenous children living in high income countries: a systematic review. AB - BACKGROUND: Indigenous children living in high income countries have a consistently high prevalence of mental health problems. We aimed to identify psychosocial risk and protective factors for mental health in this setting. METHODS: A systematic review of studies published between 1996 and 2016 that quantitatively evaluated the association between psychosocial variables and mental health among Indigenous children living in high income countries was conducted. Psychosocial variables were grouped into commonly occurring domains. Individual studies were judged to provide evidence for an association between a domain and either good mental health, poor mental health, or a negligible or inconsistent association. The overall quality of evidence across all studies for each domain was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: Forty-seven papers were eligible (mainland US 30 [64%], Canada 8 [17%], Australia 7 [15%], Hawaii 4 [9%]), including 58,218 participants aged 4-20 years. Most papers were cross sectional (39, 83%) and measured negative mental health outcomes (41, 87%). Children's negative cohesion with their families and the presence of adverse events appeared the most reliable predictors of increased negative mental health outcomes. Children's substance use, experiences of discrimination, comorbid internalising symptoms, and negative parental behaviour also provided evidence of associations with negative mental health outcomes. Positive family and peer relationships, high self-esteem and optimism were associated with increased positive mental health outcomes. CONCLUSIONS: Quantitative research investigating Indigenous children's mental health is largely cross-sectional and focused upon negative outcomes. Indigenous children living in high income countries share many of the same risk and protective factors associated with mental health. The evidence linking children's familial environment, psychological traits, substance use and experiences of discrimination with mental health outcomes highlights key targets for more concerted efforts to develop initiatives to improve the mental health of Indigenous children. PMID- 28830451 TI - Bacterial pathogens associated with external ocular infections alongside eminent proportion of multidrug resistant isolates at the University of Gondar Hospital, northwest Ethiopia. AB - BACKGROUND: External ocular infection is a public health problem in Ethiopia. The aim of this study was to determine the prevalence and antimicrobial susceptibility pattern of external ocular bacterial infections. METHODS: A cross sectional study was conducted at the University of Gondar Hospital among patients seeking health services at the Department of Ophthalmology from January to April, 2016. All patients with suspected external ocular infections were examined under slit lamp microscope. External ocular samples were collected using aseptic techniques. All samples were investigated by culture and bacteria were identified using standard methods. Drug susceptibility test was done using the Kirby-Bauer Disk diffusion method according to the guidelines of Clinical and Laboratory Standard Institute (CLSI). RESULT: A total of 312 samples were collected and 58.3% were culture positive. The proportion of Gram positive bacterial pathogens was (88%), and Staphylococcus aureus (50.3%) was the predominantly isolated pathogen, followed by Coagulase negative staphylococci (CoNS) (33.5%) and Klebsiella species (4.7%). Conjunctivitis was the dominant clinical feature, but a high positive result for bacterial pathogens was observed among patients with dacryocystitis cases. The Gram positive bacterial isolates were susceptible to ciprofloxacin, chloramphinicol, amoxicillin-clavulanate and ceftriaxone. However, 65% of these Gram positive bacterial pathogens showed resistance to penicillin, ampicillin and amoxicillin. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infection was 24% and multidrug resistance (MDR) was observed in 87% of the isolated bacteria. CONCLUSION: Conjunctivitis was the dominant ophthalmic disease followed by blepharitis. The dominant bacteria species was S. aureus and MRSA infection is increasingly prevalent. The overall MDR bacterial pathogen proportion was very high. The high prevalence of MRSA and MDR bacterial pathogens dictate the need for effective prevention as important as for therapies. PMID- 28830450 TI - MicroRNA-218 functions as a tumor suppressor in lung cancer by targeting IL 6/STAT3 and negatively correlates with poor prognosis. AB - BACKGROUND: Aberrant expression of microRNAs in different human cancer types has been widely reported. MiR-218 acts as a tumor suppressor in diverse human cancer types impacting regulation of multiple genes in oncogenic pathways. Here, we evaluated the expression and function of miR-218 in human lung cancer and ALDH positive lung cancer cells to understand the potential mechanisms responsible for disease pathology. Also, the association between its host genes and the target genes could be useful towards the better understanding of prognosis in clinical settings. METHODS: Publicly-available data from The Cancer Genome Atlas (TCGA) was mined to compare the levels of miR-218 and its host gene SLIT2/3 between lung cancer tissues and normal lung tissues. Transfection of miR-218 to investigate its function in lung cancer cells was done and in vivo effects were determined using miR-218 expressing lentiviruses. Aldefluor assay and Flow cytometry was used to quantify and enrich ALDH positive lung cancer cells. Levels of miR-218, IL-6R, JAK3 and phosphorylated STAT3 were compared in ALDH1A1 positive and ALDH1A1 negative cells. Overexpression of miR-218 in ALDH positive cells was carried to test the survival by tumorsphere culture. Finally, utilizing TCGA data we studied the association of target genes of miR-218 with the prognosis of lung cancer. RESULTS: We observed that the expression of miR-218 was significantly down-regulated in lung cancer tissues compared to normal lung tissues. Overexpression of miR-218 decreased cell proliferation, invasion, colony formation, and tumor sphere formation in vitro and repressed tumor growth in vivo. We further found that miR-218 negatively regulated IL-6 receptor and JAK3 gene expression by directly targeting the 3'-UTR of their mRNAs. In addition, the levels of both miR-218 host genes and the components of IL-6/STAT3 pathway correlated with prognosis of lung cancer patients. CONCLUSIONS: MiR-218 acts as a tumor suppressor in lung cancer via IL-6/STAT3 signaling pathway regulation. PMID- 28830452 TI - Phylogenetic characterisation of circulating, clinical influenza isolates from Bali, Indonesia: preliminary report from the BaliMEI project. AB - BACKGROUND: Human influenza represents a major public health concern, especially in south-east Asia where the risk of emergence and spread of novel influenza viruses is particularly high. The BaliMEI study aims to conduct a five year active surveillance and characterisation of influenza viruses in Bali using an extensive network of participating healthcare facilities. METHODS: Samples were collected during routine diagnostic treatment in healthcare facilities. In addition to standard clinical and molecular methods for influenza typing, next generation sequencing and subsequent de novo genome assembly were performed to investigate the phylogeny of the collected patient samples. RESULTS: The samples collected are characteristic of the seasonally circulating influenza viruses with indications of phylogenetic links to other samples characterised in neighbouring countries during the same time period. CONCLUSIONS: There were some strong phylogenetic links with sequences from samples collected in geographically proximal regions, with some of the samples from the same time-period resulting to small clusters at the tree-end points. However this work, which is the first of its kind completely performed within Indonesia, supports the view that the circulating seasonal influenza in Bali reflects the strains circulating in geographically neighbouring areas as would be expected to occur within a busy regional transit centre. PMID- 28830453 TI - Experiences of antipsychotic use in patients with early psychosis: a two-year follow-up study. AB - BACKGROUND: Non-adherence is a major public health problem despite treatment advances. Poor drug adherence in patients with psychosis is associated with more frequent relapse, re-hospitalization, increased consumption of health services and poor outcomes on a variety of measures. Adherence rate in patients with first episode psychosis have been found to vary from 40 to 60%. However, most previous studies have addressed the consequences of non-adherence rather than its potential causes. The purpose of this study was, therefore, to investigate experiential factors which may affect adherence to medication in adults with psychotic disorders, during the 24-month period after the onset of treatment. METHODS: Twenty first episode patients (7 male, 13 female) were included in our qualitative sub-study from the ongoing TIPS2 (Early Intervention in Psychosis study). Each person participated in semi-structured interviews at 2-year follow up. All had used antipsychotics, with some still using them. Data were analyzed within an interpretative-phenomenological framework using an established meaning condensation procedure. RESULTS: The textual analysis revealed four main themes that affected adherence largely: 1) Positive experiences of admission, 2) Sufficient timely information, 3) Shared decision-making and 4) Changed attitudes to antipsychotics due to their beneficial effects and improved insight into illness. CONCLUSION: Patients reported several factors to have a prominent impact on adherence to their antipsychotics. The patients do not independently choose to jeopardize their medication regime. Health care staff play an important role in maintaining good adherence by being empathetic and supportive in the admission phase, giving tailored information according to patients' condition and involving patients when making treatment decisions. PMID- 28830454 TI - Examining changes in maternal and child health inequalities in Ethiopia. AB - BACKGROUND: Ethiopia has made considerable progress in maternal, newborn, and child health in terms of health outcomes and health services coverage. This study examined how different groups have fared in the process. It also looked at possible factors behind the inequalities. METHODS: The study examined 11 maternal and child health outcomes and services: stunting, underweight, wasting, neonatal mortality, infant mortality, under-5 mortality, measles vaccination, full immunization, modern contraceptive use by currently married women, antenatal care visits, and skilled birth attendance. It explored trends in inequalities by household wealth status based on Demographic and Health Surveys conducted in 2000, 2005, 2011, and 2014. The study also investigated the dynamics of inequality, using concentration curves for different years. Decomposition analysis was used to identify the role of proximate determinants. RESULTS: The study found substantial improvements in health outcomes and health services: Although there is still a considerable gap between the rich and the poor, inequalities in health services have been reduced. However, child nutrition outcomes have mainly improved for the rich. The changes observed in wealth related inequality tend to reflect the changing direct effect of household wealth on child health and health service use. CONCLUSIONS: The country's efforts to improve access to health services have shown some positive results, but attention should now turn to service quality and to identifying multisectoral interventions that can change outcomes for the poorest. PMID- 28830455 TI - Prognostic significance of the total number of harvested lymph nodes for lymph node-negative gastric cancer patients. AB - BACKGROUND: The relationship between the number of harvested lymph nodes (HLNs) and prognosis of gastric cancer patients without an involvement of lymph nodes has not been well-evaluated. The objective of this study is to further explore this issue. METHODS: We collected data from 399 gastric cancer patients between November 2006 and October 2011. All of them were without metastatic lymph nodes. RESULTS: Survival analyses showed that statistically significant differences existed in the survival outcomes between the two groups allocated by the total number of HLNs ranging from 16 to 22. Therefore, we adopted 22 as the cut-off value of the total number of HLNs for grouping (group A: HLNs <22; group B: HLNs>=22). The intraoperative and postoperative characteristics, including operative blood loss (P=0.096), operation time (P=0.430), postoperative hospital stay (P=0.142), complications (P=0.552), rate of reoperation (P=0.966) and postoperative mortality (P=1.000), were comparable between the two groups. T stage-stratified Kaplan-Meier analyses revealed that the 5-year survival rate of patients at the T4 stage was better in group B than in group A (76.9% vs. 58.5%; P=0.004). An analysis of multiple factors elucidated that the total number of HLNs, T stage, operation time and age were independently correlated factors of prognosis. CONCLUSIONS: Regarding gastric cancer patients without the involvement of lymph nodes, an HLN number >=22 would be helpful in prolonging their overall survival, especially for those at T4 stage. The total number of HLNs was an independent prognostic factor for this population of patients. PMID- 28830456 TI - Body image in head and neck cancer patients treated with radiotherapy: the impact of surgical procedures. AB - BACKGROUND: In this study, we aimed to investigate the impact of surgical procedures on the body image of head and neck cancer patients treated with radiotherapy and with or without radical surgery. METHODS: A cross-sectional survey of 150 patients with head and neck cancer was conducted. Sixty patients had nasopharyngeal cancer treated with definitive radiotherapy without surgery, and 90 patients had oral cavity cancer treated with radical surgery plus adjuvant radiotherapy. All participants completed a 10-item Body Image Scale (BIS) questionnaire to assess body image dissatisfaction. Among all patients, the socio demographic and clinical variables were age, gender, partnership, education, employment, and radical surgery. In surgically-treated patients, the clinical variables were facial skin sacrificed, mouth angle sacrificed, glossectomy, maxillectomy, and mandibulectomy. ANOVAs, t-tests, and multiple regressions were used to evaluate the relationships between these variables and BIS results. RESULTS: In all patients, radical surgery was the strongest independent predictor of BIS scores. Surgically-treated patients had significantly worse BIS scores than the patients without surgery. In surgically-treated patients, facial skin sacrificed, mouth angle sacrificed, maxillectomy, and mandibulectomy were significantly associated with body image. According to multivariable analyses, inferior maxillectomy and segmental mandibulectomy were independent prognosticators of a poor BIS score in surgically-treated patients. CONCLUSION: Radical surgery for head and neck cancer patients has a significant impact on their body image, especially for those undergoing facial bone destructive surgery. PMID- 28830457 TI - Growth and weight gain in children with juvenile idiopathic arthritis: results from the ReACCh-Out cohort. AB - BACKGROUND: With modern treatments, the effect of juvenile idiopathic arthritis (JIA) on growth may be less than previously reported. Our objective was to describe height, weight and body mass index (BMI) development in a contemporary JIA inception cohort. METHODS: Canadian children newly-diagnosed with JIA 2005 2010 had weight and height measurements every 6 months for 2 years, then yearly up to 5 years. These measurements were used to calculate mean age- and sex standardized Z-scores, and estimate prevalence and cumulative incidence of growth impairments, and the impact of disease activity and corticosteroids on growth. RESULTS: One thousand one hundred forty seven children were followed for median 35.5 months. Mean Z-scores, and the point prevalence of short stature (height < 2.5th percentile, 2.5% to 3.4%) and obesity (BMI > 95th percentile, 15.8% to 16.4%) remained unchanged in the whole cohort. Thirty-three children (2.9%) developed new-onset short stature, while 27 (2.4%) developed tall stature (>97.5th percentile). Children with systemic arthritis (n = 77) had an estimated 3-year cumulative incidence of 9.3% (95%CI: 4.3-19.7) for new-onset short stature and 34.4% (23-49.4) for obesity. Most children (81.7%) received no systemic corticosteroids, but 1 mg/Kg/day prednisone-equivalent maintained for 6 months corresponded to a drop of 0.64 height Z-scores (0.56-0.82) and an increase of 0.74 BMI Z-scores (0.56-0.92). An increase of 1 in the 10-cm physician global assessment of disease activity maintained for 6 months corresponded to a drop of 0.01 height Z-scores (0-0.02). CONCLUSIONS: Most children in this modern JIA cohort grew and gained weight as children in the general population. About 1 in 10 children who had systemic arthritis, uncontrolled disease and/or prolonged corticosteroid use, had increased risk of growth impairment. PMID- 28830458 TI - Role of MEK partner-1 in cancer stemness through MEK/ERK pathway in cancerous neural stem cells, expressing EGFRviii. AB - BACKGROUND: Glioma stem cells (GSCs) are a major cause of the frequent relapse observed in glioma, due to their high drug resistance and their differentiation potential. Therefore, understanding the molecular mechanisms governing the 'cancer stemness' of GSCs will be particularly important for improving the prognosis of glioma patients. METHODS: We previously established cancerous neural stem cells (CNSCs) from immortalized human neural stem cells (F3 cells), using the H-Ras oncogene. In this study, we utilized the EGFRviii mutation, which frequently occurs in brain cancers, to establish another CNSC line (F3.EGFRviii), and characterized its stemness under spheroid culture. RESULTS: The F3.EGFRviii cell line was highly tumorigenic in vitro and showed high ERK1/2 activity as well as expression of a variety of genes associated with cancer stemness, such as SOX2 and NANOG, under spheroid culture conditions. Through meta-analysis, PCR super array, and subsequent biochemical assays, the induction of MEK partner-1 (MP1, encoded by the LAMTOR3 gene) was shown to play an important role in maintaining ERK1/2 activity during the acquisition of cancer stemness under spheroid culture conditions. High expression of this gene was also closely associated with poor prognosis in brain cancer. CONCLUSION: These data suggest that MP1 contributes to cancer stemness in EGFRviii-expressing glioma cells by driving ERK activity. PMID- 28830459 TI - Reducing calorie sales from supermarkets - 'silent' reformulation of retailer brand food products. AB - BACKGROUND: Food product reformulation is seen as one among several tools to promote healthier eating. Reformulating the recipe for a processed food, e.g. reducing the fat, sugar or salt content of the foods, or increasing the content of whole-grains, can help the consumers to pursue a healthier life style. In this study, we evaluate the effects on calorie sales of a 'silent' reformulation strategy, where a retail chain's private-label brands are reformulated to a lower energy density without making specific claims on the product. METHODS: Using an ecological study design, we analyse 52 weeks' sales data - enriched with data on products' energy density - from a Danish retail chain. Sales of eight product categories were studied. Within each of these categories, specific products had been reformulated during the 52 weeks data period. Using econometric methods, we decompose the changes in calorie turnover and sales value into direct and indirect effects of product reformulation. RESULTS: For all considered products, the direct effect of product reformulation was a reduction in the sale of calories from the respective product categories - between 0.5 and 8.2%. In several cases, the reformulation led to indirect substitution effects that were counterproductive with regard to reducing calorie turnover. However, except in two insignificant cases, these indirect substitution effects were dominated by the direct effect of the reformulation, leading to net reductions in calorie sales between -3.1 and 7.5%. For all considered product reformulations, the reformulation had either positive, zero or very moderate negative effects on the sales value of the product category to which the reformulated product belonged. CONCLUSIONS: Based on these findings, 'silent' reformulation of retailer's private brands towards lower energy density seems to contribute to lowering the calorie intake in the population (although to a moderate extent) with moderate losses in retailer's sales revenues. PMID- 28830460 TI - Gene mutational pattern and expression level in 560 acute myeloid leukemia patients and their clinical relevance. AB - BACKGROUND: Cytogenetic aberrations and gene mutations have long been regarded as independent prognostic markers in AML, both of which can lead to misexpression of some key genes related to hematopoiesis. It is believed that the expression level of the key genes is associated with the treatment outcome of AML. METHODS: In this study, we analyzed the clinical features and molecular aberrations of 560 newly diagnosed non-M3 AML patients, including mutational status of CEBPA, NPM1, FLT3, C-KIT, NRAS, WT1, DNMT3A, MLL-PTD and IDH1/2, as well as expression levels of MECOM, ERG, GATA2, WT1, BAALC, MEIS1 and SPI1. RESULTS: Certain gene expression levels were associated with the cytogenetic aberration of the disease, especially for MECOM, MEIS1 and BAALC. FLT3, C-KIT and NRAS mutations contained conversed expression profile regarding MEIS1, WT1, GATA2 and BAALC expression, respectively. FLT3, DNMT3A, NPM1 and biallelic CEBPA represented the mutations associated with the prognosis of AML in our group. Higher MECOM and MEIS1 gene expression levels showed a significant impact on complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) both in univariate and multivariate analysis, respectively; and an additive effect could be observed. By systematically integrating gene mutational status results and gene expression profile, we could establish a more refined system to precisely subdivide AML patients into distinct prognostic groups. CONCLUSIONS: Gene expression abnormalities contained important biological and clinical informations, and could be integrated into current AML stratification system. PMID- 28830461 TI - The approaches to measuring the potential spatial access to urban health services revisited: distance types and aggregation-error issues. AB - BACKGROUND: The potential spatial access to urban health services is an important issue in health geography, spatial epidemiology and public health. Computing geographical accessibility measures for residential areas (e.g. census tracts) depends on a type of distance, a method of aggregation, and a measure of accessibility. The aim of this paper is to compare discrepancies in results for the geographical accessibility of health services computed using six distance types (Euclidean and Manhattan distances; shortest network time on foot, by bicycle, by public transit, and by car), four aggregation methods, and fourteen accessibility measures. METHODS: To explore variations in results according to the six types of distance and the aggregation methods, correlation analyses are performed. To measure how the assessment of potential spatial access varies according to three parameters (type of distance, aggregation method, and accessibility measure), sensitivity analysis (SA) and uncertainty analysis (UA) are conducted. RESULTS: First, independently of the type of distance used except for shortest network time by public transit, the results are globally similar (correlation >0.90). However, important local variations in correlation between Cartesian and the four shortest network time distances are observed, notably in suburban areas where Cartesian distances are less precise. Second, the choice of the aggregation method is also important: compared with the most accurate aggregation method, accessibility measures computed from census tract centroids, though not inaccurate, yield important measurement errors for 10% of census tracts. Third, the SA results show that the evaluation of potential geographic access may vary a great deal depending on the accessibility measure and, to a lesser degree, the type of distance and aggregation method. Fourth, the UA results clearly indicate areas of strong uncertainty in suburban areas, whereas central neighbourhoods show lower levels of uncertainty. CONCLUSION: In order to accurately assess potential geographic access to health services in urban areas, it is particularly important to choose a precise type of distance and aggregation method. Then, depending on the research objectives, the choices of the type of network distance (according to the mode of transportation) and of a number of accessibility measures should be carefully considered and adequately justified. PMID- 28830462 TI - Factors associated with diarrheal morbidity among under-five children in Jigjiga town, Somali Regional State, eastern Ethiopia: a cross-sectional study. AB - BACKGROUND: The prevalence of underfive diarrhea in Somali Regional State, Ethiopia is one of the highest in the country. This study attempted to examine the multiple factors associated with underfive diarrhea and how they might influence its prevalence in Jigjiga, Somali regional state, Ethiopia. METHODS: A community based cross-sectional study was conducted from February 15 to 28, 2015. Multistage sampling technique was used to collect data from 492 mothers via household survey. A pre-tested, structured questionnaire was used to collect data through face-to-face interview. Ethical clearance was obtained before data collection. Stepwise multivariable logistic regression was used to calculate adjusted odds ratios. RESULTS: The two weeks prevalence of under five diarrhea in Jigjiga town was 14.6%. Up on multivariable analysis, maternal educational level of primary school and above was found to be protective against childhood diarrhea [AOR: 0.227(0.100-0.517)] whereas, unavailability of water [AOR: 2.124(1.231 3.664)] and lack of hand washing facility [AOR: 1.846(1.013-3.362)] were associated with diarrhea. CONCLUSION: Poor water supply, lack of hand washing facilities and lack of formal maternal education were associated with underfive diarrhea in the study area. Improved access to water supply along with environmental health intervention programs designed to promote good hygiene behavior could be of paramount importance to alleviate burden of childhood diarrhea. PMID- 28830463 TI - Diffusion tensor MR imaging characteristics of cerebral white matter development in fetal pigs. AB - BACKGROUND: The purpose of this study was to investigate the anisotropic features of fetal pig cerebral white matter (WM) development by magnetic resonance diffusion tensor imaging, and to evaluate the developmental status of cerebral WM in different anatomical sites at different times. METHODS: Fetal pigs were divided into three groups according to gestational age: E69 (n = 8), E85 (n = 11), and E114 (n = 6). All pigs were subjected to conventional magnetic resonance imaging (MRI) and diffusion tensor imaging using a GE Signa 3.0 T MRI system (GE Healthcare, Sunnyvale, CA, USA). Fractional anisotropy (FA) was measured in deep WM structures and peripheral WM regions. After the MRI scans,the animals were sacrificed and pathology sections were prepared for hematoxylin & eosin (HE) staining and luxol fast blue (LFB) staining. Data were statistically analyzed with SPSS version 16.0 (SPSS, Chicago, IL, USA). A P-value < 0.05 was considered statistically significant. Mean FA values for each subject region of interest (ROI), and deep and peripheral WM at different gestational ages were calculated, respectively, and were plotted against gestational age with linear correlation statistical analyses. The differences of data were analyzed with univariate ANOVA analyses. RESULTS: There were no significant differences in FAs between the right and left hemispheres. Differences were observed between peripheral WM and deep WM in fetal brains. A significant FA growth with increased gestational age was found when comparing E85 group and E114 group. There was no difference in the FA value of deep WM between the E69 group and E85 group. The HE staining and LFB staining of fetal cerebral WM showed that the development from the E69 group to the E85 group, and the E85 group to the E114 group corresponded with myelin gliosis and myelination, respectively. CONCLUSIONS: FA values can be used to quantify anisotropy of the different cerebral WM areas. FA values did not change significantly between 1/2 way and 3/4 of the way through gestation but was then increased dramatically at term, which could be explained by myelin gliosis and myelination ,respectively. PMID- 28830464 TI - Using Bayesian statistics to estimate the likelihood a new trial will demonstrate the efficacy of a new treatment. AB - BACKGROUND: The common frequentist approach is limited in providing investigators with appropriate measures for conducting a new trial. To answer such important questions and one has to look at Bayesian statistics. METHODS: As a worked example, we conducted a Bayesian cumulative meta-analysis to summarize the benefit of patient-specific instrumentation on the alignment of total knee replacement from previously published evidence. Data were sourced from Medline, Embase, and Cochrane databases. All randomised controlled comparisons of the effect of patient-specific instrumentation on the coronal alignment of total knee replacement were included. The main outcome was the risk difference measured by the proportion of failures in the control group minus the proportion of failures in the experimental group. Through Bayesian statistics, we estimated cumulatively over publication time of the trial results: the posterior probabilities that the risk difference was more than 5 and 10%; the posterior probabilities that given the results of all previous published trials an additional fictive trial would achieve a risk difference of at least 5%; and the predictive probabilities that observed failure rate differ from 5% across arms. RESULTS: Thirteen trials were identified including 1092 patients, 554 in the experimental group and 538 in the control group. The cumulative mean risk difference was 0.5% (95% CrI: -5.7%; +4.5%). The posterior probabilities that the risk difference be superior to 5 and 10% was less than 5% after trial #4 and trial #2 respectively. The predictive probability that the difference in failure rates was at least 5% dropped from 45% after the first trial down to 11% after the 13th. Last, only unrealistic trial design parameters could change the overall evidence accumulated to date. CONCLUSIONS: Bayesian probabilities are readily understandable when discussing the relevance of performing a new trial. It provides investigators the current probability that an experimental treatment be superior to a reference treatment. In case a trial is designed, it also provides the predictive probability that this new trial will reach the targeted risk difference in failure rates. TRIAL REGISTRATION: CRD42015024176 . PMID- 28830465 TI - Emerging (val)ganciclovir resistance during treatment of congenital CMV infection: a case report and review of the literature. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) infection is an important illness that is a common cause of hearing loss in newborn infants and a major cause of disability in children. For that reason, treatment of symptomatic patients with either ganciclovir or its pro-drug valganciclovir is recommended. Treatment duration of 6 months has been shown to be more beneficial than shorter courses; however, there is uncertainty regarding emergence of resistance strains, secondary effects and long term sequelae. CASE PRESENTATION: Here we present a female infant with symptomatic cCMV who was treated from day 5 of life with oral valganciclovir. In spite of close monitoring of her drug levels and increments of her treatment dose according to weight gain, she developed ganciclovir resistance after 4 months of treatment, with increasing viraemia and petechiae. Adherence to treatment was assessed and felt to be good. Clinically, although she had marked developmental delay, she was making steady progress. In view of the development of resistance treatment was stopped at 5 months of age. No secondary effects of ganciclovir were noted during the whole course. CONCLUSIONS: There were few cases in the literature reporting resistance to ganciclovir for cCMV before the new recommendations for a 6 months treatment course for this infection were published. As demonstrated in our patient, surveillance with periodic viral loads and drug monitoring are vital to identify emerging resistance and optimise antiviral dosing according to weight gain. PMID- 28830466 TI - Methods for significance testing of categorical covariates in logistic regression models after multiple imputation: power and applicability analysis. AB - BACKGROUND: Multiple imputation is a recommended method to handle missing data. For significance testing after multiple imputation, Rubin's Rules (RR) are easily applied to pool parameter estimates. In a logistic regression model, to consider whether a categorical covariate with more than two levels significantly contributes to the model, different methods are available. For example pooling chi-square tests with multiple degrees of freedom, pooling likelihood ratio test statistics, and pooling based on the covariance matrix of the regression model. These methods are more complex than RR and are not available in all mainstream statistical software packages. In addition, they do not always obtain optimal power levels. We argue that the median of the p-values from the overall significance tests from the analyses on the imputed datasets can be used as an alternative pooling rule for categorical variables. The aim of the current study is to compare different methods to test a categorical variable for significance after multiple imputation on applicability and power. METHODS: In a large simulation study, we demonstrated the control of the type I error and power levels of different pooling methods for categorical variables. RESULTS: This simulation study showed that for non-significant categorical covariates the type I error is controlled and the statistical power of the median pooling rule was at least equal to current multiple parameter tests. An empirical data example showed similar results. CONCLUSIONS: It can therefore be concluded that using the median of the p-values from the imputed data analyses is an attractive and easy to use alternative method for significance testing of categorical variables. PMID- 28830467 TI - BiClamp(r) vessel-sealing device for open hepatic resection of malignant and benign liver tumours: a single-institution experience. AB - BACKGROUND: Intraoperative blood loss during hepatectomy worsens prognosis, and various tools have been used to improve perioperative safety and feasibility. We aimed to retrospectively evaluate the feasibility and safety of the BiClamp(r) device for open liver resection. METHODS: We included 84 patients undergoing liver resection from a single centre, with all patients operated by the same surgical group. All hepatectomies were performed using BiClamp(r) (Erbe Elektromedizin GmbH, Tubingen, Germany), an electrosurgical device that simultaneously transects liver parenchyma and seals vessels <7 mm in diameter. We collected data on intraoperative blood loss, resection time, and perioperative complications, comparing cirrhotic and non-cirrhotic patients. RESULTS: The 84 patients enrolled in this study included 56 cirrhotic and 28 non-cirrhotic patients. All patients underwent hepatectomy (30 major and 54 minor hepatectomies) using the BiClamp(r), exclusively, and 54 patients required inflow occlusion (Pringle manoeuvre). Overall intraoperative blood loss (mean +/- standard deviation) was 523.5 +/- 558.6 ml, liver parenchymal transection time was 36.3 +/- 16.5 min (range, 13-80 min), and the mean parenchymal transection speed was 3.0 +/- 1.9 cm2/min. Twelve patients received perioperative blood transfusion. The cost of BiClamp(r) for each patient was 800 RMB (approximately 109?). There were no deaths, and the morbidity rate was 25%. The mean (standard deviation) hospital stay was 9.3 (2.3) days. Comparisons between cirrhotic and non-cirrhotic patients revealed no difference in blood loss (491.0 +/- 535.7 ml vs 588.8 +/- 617.5 ml, P = 0.598), liver parenchymal transection time (34.1 +/- 14.8 min vs 40.9 +/- 19.2 min, P = 0.208), mean parenchymal transection speed (3.3 +/- 2.1 cm2/min vs 2.5 +/- 1.3 cm2/min, P = 0.217), and operative morbidity (28.6% vs 14.3%, P = 0.147). CONCLUSIONS: The reusable BiClamp(r) vessel-sealing device allows for safe and feasible major and minor hepatectomy, even in patients with cirrhotic liver. TRIAL REGISTRATION: This trial was retrospectively registered and the detail information was as followed. Registration number: ChiCTR-ORC-17011873 (Chinese Clinical Trial Registry). Registration Date: 2017-07 05. PMID- 28830468 TI - Prediction of future cardiovascular disease with an equation to estimate apolipoprotein B in patients with high cardiovascular risk: an analysis from the TNT and IDEAL study. AB - BACKGROUND: Apolipoprotein B (apoB) is known to be a more powerful predictor of cardiovascular disease than conventional lipids. We aimed to determine the clinical relevance of a newly developed equation to estimate serum apoB levels based on total cholesterol, HDL cholesterol, and triglycerides in patients with high cardiovascular risk. METHODS: The occurrence of a major cardiovascular event (MCVE) was assessed using the data from the Treating to New Targets (TNT) and Incremental Decrease in End points through Aggressive Lipid lowering (IDEAL) trials. RESULTS: Pooled analysis of these two data sets showed that both directly measured apoB (HR per 1-SD (95% CI): 1.16 (1.11-1.21), P < 0.001) and apoB estimated from the eq. (HR per 1-SD (95% CI): 1.14 (1.09-1.19), P < 0.001) were significantly associated with the development of a future MCVE. Prediction of MCVEs by the apoB eq. (C statistic 0.650) was nearly identical to that of directly-measured apoB (0.651). In addition, the net reclassification indices indicated no difference in the prediction of MCVEs between models including the apoB equation and directly-measured apoB (1% (-1.3-4.0), P = 0.31). CONCLUSIONS: Our equation to predict apoB levels showed MCVE risk prediction comparable to directly-measured apoB in high risk patients with previous coronary heart disease. PMID- 28830470 TI - Determining optimal gestational weight gain in the Korean population: a retrospective cohort study. AB - BACKGROUND: The World Health Organization (WHO) international body mass index (BMI) cut-off points defining pre-pregnancy BMI categories in the Institute of Medicine (IOM) guidelines are not directly applicable to Asians. We aimed to define the optimal gestational weight gain (GWG) for the Korean population based on Asia-specific BMI categories. METHODS: Data from 2702 live singleton deliveries in three tertiary centers between 2010 and 2011 were analyzed retrospectively. A multivariable logistic regression analysis was conducted to determine the lowest aggregated risk of composite perinatal outcomes based on Asia-specific BMI categories. The perinatal outcomes included gestational hypertensive disorder, emergency cesarean section, and fetal size for gestational age. In each BMI category, the GWG value corresponding to the lowest aggregated risk was defined as the optimal GWG. RESULTS: Among the study population, 440 (16.3%) were underweight (BMI < 18.5), 1459 (54.0%) were normal weight (18.5 <= BMI < 23), 392 (14.5%) were overweight (23 <= BMI < 25) and 411 (15.2%) were obese (BMI >= 25). The optimal GWG by Asia-specific BMI category was 20.8 kg (range, 16.7 to 24.7) for underweight, 16.6 kg (11.5 to 21.5) for normal weight, 13.1 kg (8.0 to 17.7) for overweight, and 14.4 kg (7.5 to 21.9) for obese. CONCLUSION: Considerably higher and wider optimal GWG ranges than recommended by IOM are found in our study in order to avoid adverse perinatal outcomes. Revised IOM recommendations for GWG could be considered for Korean women according to Asian BMI categories. Further prospective studies are needed in order to determine the optimal GWG for the Korean population. PMID- 28830469 TI - Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies. AB - Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity. PMID- 28830471 TI - Relationship between the triglyceride glucose index and coronary artery calcification in Korean adults. AB - BACKGROUND: The triglyceride glucose (TyG) index has been considered a simple surrogate marker of insulin resistance. However, few studies have investigated the relationship between the TyG index and coronary artery calcification (CAC). Thus, we investigated the relationship between the TyG index and CAC in healthy Korean adults. METHODS: In total, 4319 participants who underwent cardiac computed tomography (CT) in a health promotion center were enrolled. Anthropometric profiles and multiple cardiovascular risk factors were measured. The TyG index was calculated as ln [fasting triglycerides (mg/dL) * fasting glucose (mg/dL)/2], and the insulin resistance index of homeostasis model assessment (HOMA-IR) was estimated. The CAC was measured using multidetector CT, and CAC presence was defined as an Agatston score of >0. RESULTS: All subjects were stratified into four groups based on their TyG indices. Significant differences were observed in cardiovascular parameters among the groups, and the prevalence of CAC significantly increased with increasing TyG index. In the logistic regression analysis after adjustment for multiple risk factors, the odds ratio for the prevalence of CAC, when comparing the highest and lowest quartiles of the TyG index was 1.95 (95% CI 1.23-3.11; P for trend = 0.01); the odds ratio for the prevalence of CAC, when comparing the highest and lowest quartiles of HOMA-IR was 1.64 (95% CI 1.12-2.40; P for trend = 0.04). In the receiver operating characteristics analysis, the TyG index was superior to HOMA-IR in predicting CAC. CONCLUSION: The TyG index is more independently associated with the presence of coronary artery atherosclerosis than is HOMA-IR in healthy Korean adults. PMID- 28830472 TI - A process for developing multisectoral strategies for zoonoses: the case of leptospirosis in Fiji. AB - BACKGROUND: Zoonotic diseases such as leptospirosis occur as a result of the often complex interactions that exist at the human-animal-environment interface. The most obvious consequence of this complexity is the need for the health sector to partner with institutions in other sectors of society such as agriculture, labour and local government. This multisectoral engagement is complicated by the different agendas and cultures of the various institutions and their ability to "see" their role and ant benefits in a collaborative response. METHODS: The research used a realist review methodology combined with systems thinking frameworks to determine the optimal strategy and governance for the prevention and control of leptospirosis in Fiji. The process included facilitated workshops with multiple stakeholders to determine the needs, issues and potential interventions that was guided by a synthesis of locally available data and information on the impact of leptospirosis. This process was informed by interviews with bureaucrats from different government ministries. RESULTS: Stakeholders concurred that leptospirosis generally only received wide-spread attention in outbreaks, when there is media coverage of deaths or a large number of hospitalisations. In general, all ministries expressed support for a multisectoral strategy but saw the Ministry of Health and Medical Services as the lead agency with overall responsibility. The final consultation workshop yielded a clearly articulated goal to reduce the case fatality rate attributable to leptospirosis by 50% by 2020 and 4 overarching strategies: 1) improved clinical management of leptospirosis, 2) improved surveillance for leptospirosis, 3) enhanced communication to minimise risk and improve health seeking behaviours, and 4) strengthening coordination and governance structures. CONCLUSION: Human mortality and morbidity remained the primary drive for government action, defining leptospirosis as a human health problem. The process of deliberative consultation, and the engagement of multidisciplinary partners has provided a platform for collaborative policy development, and a consensus for a National Action Plan from which further negotiated collaboration will be possible. PMID- 28830473 TI - Survival outcomes of hepatectomy for stage B Hepatocellular carcinoma in the BCLC classification. AB - BACKGROUND: Because hepatectomy is not recommended in patients with stage B hepatocellular carcinoma (HCC) of the Barcelona Clinic Liver Cancer (BCLC) staging, we evaluated the survival outcomes of hepatectomy for stage B in the BCLC system. METHODS: Data were collected from 297 consecutive adult stage B patients who underwent curative hepatectomy for HCC between 1996 and 2014 in Hokkaido University Hospital. Overall survival (OS), disease-free survival (DFS), and risk factors were analyzed using the Kaplan-Meier method. Independent prognostic factors were evaluated using a Cox proportional hazards regression model. AP-factor (alpha-fetoprotein [AFP] * protein induced by vitamin K absence or antagonism factor II [PIVKA-II]) was categorized according to the serum concentrations of AFP and PIVKA-II: AP1 (AFP < 200 ng/ml and PIVKA-II < 100 mAU/ml), AP2 (AFP * PIVKA-II < 105), and AP3 (AFP * PIVKA-II >= 105). RESULTS: There were 130 deaths among our 297 stage B patients (43.8%). The causes of death in these cases were HCC recurrence (n = 106; 81.5%), liver failure (n = 7; 5.4%), and other causes (n = 17; 16.1%). The operative mortality rate was 0.34% (1/297). The 5-year OS and DFS rates for the stage B cases were 54.3 and 21.9%, respectively. By multivariate analysis, tumor number and AP-factor were risk factors for both survival and recurrence that were tumor related and could be evaluated preoperatively. The study patients with stage B HCC were classified into three groups by tumor number (B1, 1; B23, 2 or 3; B4over: >=4) and into three groups stratified by AP-factor (AP1, AP2, and AP3). The 5-year OS rates of B1, B23, and B4over were 63.6, 52.3, and 29.0%. The 5-year OS rates of AP1, AP2, and AP3 were 67.6, 65.2, and 39.1%. Stratified by the 5-year OS rate, stage B HCC patients were classified into three subgroups (A-C).The 5-year OS rates of groups A (B1 or B23 and AP-1 or AP-2), B (B1 or B23 and AP-3, or B4over and AP-1 or AP 2), and C (B4over and AP-3) were 69.5, 43.7, and 21.3%. CONCLUSION: Stage B HCC patients with a tumor number <= 3 and/or AP-factor < 1 * 105 show acceptable 5 year OS rates and could be treated by hepatectomy. PMID- 28830474 TI - A health dialogue intervention reduces cardiovascular risk factor levels: a population based randomised controlled trial in Swedish primary care setting with 1-year follow-up. AB - BACKGROUND: The total number of cardiovascular (CVD) deaths accounted for almost a third of all deaths globally in 2013. Population based randomised controlled trials, managed within primary care, on CVD risk factor interventions are scarce. The aim of the study was to evaluate the effects of a health dialogue intervention in a primary care setting offered to a population at the age of 55 years, focusing on CVD risk factors. METHODS: The study was performed in five primary health care centres in the county of Vastmanland, Sweden between April 2011 and December 2012. Men and women were randomly assigned to intervention (n = 440) and control groups (n = 440). At baseline, both groups filled in a health questionnaire and serum cholesterol, fasting plasma glucose, glycated haemoglobin (HbA1c), weight, height, waist (WC) and hip circumference, waist hip ratio (WHR) and systolic/diastolic blood pressure were measured. Intervention group attended a health dialogue, supported by a visualised health profile, with a possibility for further activities. Participation rates at baseline were 53% and 52% respectively. A 1-year follow-up was carried out. RESULTS: The intervention group (n = 165) showed reductions compared to the control group (n = 177) concerning body mass index (BMI) (0.3 kg/m2, p = .031), WC (2.1 cm, p <= .001) and WHR (.002, p <= .001) at the 1-year follow-up. No differences between the intervention and control groups were found in other variables. Intervention group, compared to baseline, had reduced weight, BMI, WC, WHR, HbA1c, and diet, while the men in the control group had reduced their alcohol consumption. CONCLUSIONS: A health dialogue intervention at the age of 55 years, conducted in ordinary primary care, showed a moderate effect on CVD risk factor levels, in terms of BMI, WC and WHR. TRIAL REGISTRATION NUMBER: BioMed Central, ISRCTN22586871 , date assigned; 10/12/2015. PMID- 28830475 TI - Preoperative intensity-modulated radiotherapy with a simultaneous integrated boost combined with Capecitabine in locally advanced rectal cancer: short-term results of a multicentric study. AB - BACKGROUND: Preoperative radiotherapy (RT) in combination with fluoropyrimidine based chemotherapy (CT) is the standard of care in patients with locally advanced, T3-T4 N0-2, rectal cancer (LARC). Given the correlation between RT dose tumor response and the prognostic role of the tumor regression grade (TRG), treatment intensification represents an area of active investigation. The aim of the study was to analyze the role of RT dose-intensification in the preoperative treatment of LARC in terms of feasibility, efficacy and toxicity. METHODS: We retrospectively analyzed patients with LARC treated with intensity-modulated radiotherapy (IMRT) and simultaneous integrated boost (SIB) at five Italian radiation oncology centers. Concurrent Capecitabine was administered. Treatment response was evaluated in terms of disease down-staging and TRG. Acute toxicity was evaluated according to the CTC-AE 4.0 scale. RESULTS: A total of 76 patients were identified for this analysis. A dose of 45 Gy was prescribed to the entire mesorectum and pelvic lymph nodes with a median SIB dose of 54 Gy (range 52.5 57.5) to the tumor and corresponding mesorectum. Overall, 74/76 (97.4%) patients completed the planned RT, whereas 64/76 (84.2%) patients completed the prescribed CT. Eight (10.5%) patients developed grade 3-4 acute toxicity. Overall, 72/76 patients underwent surgery. The tumor and nodal down-staging was documented in 51 (70.8%) and 43 (67%) patients, respectively. Twenty (27.8%) patients obtained a pathologic complete response. Surgical morbidity was reported in 13/72 patients (18.1%). CONCLUSIONS: Although retrospective in design, this study indicates that IMRT-SIB with a dose range of 52.5-57.5 Gy (median 54 Gy) and concomitant Capecitabine appears feasible, well tolerated and effective in terms of disease down-staging and pathological complete response. Long-term toxicity and the impact on disease control and patient survival will be evaluated with a longer follow-up time. TRIAL REGISTRATION: NA. PMID- 28830476 TI - Comparison of continuous infusion versus bolus injection of factor concentrates for blood management after total knee arthroplasty in patients with hemophilia. AB - BACKGROUND: Total knee arthroplasty (TKA) has become the treatment of choice for end-stage hemophilic arthropathy of the knee. Theoretically in hemophilia A, perioperative continuous infusion (CI) of factor VIII (FVIII) would provide a more consistent FVIII level than general bolus injections (BI) in TKA. Current study was designed to evaluate the effectiveness of CI of coagulation factor concentrates during the perioperative period compared to BI. METHODS: A total of 42 TKAs were performed in 31 patients with severe hemophilia A. Under the supervision of a multidisciplinary hemophilia team, CI and BI were monitored during application of a standardized regimen. Perioperative clinical parameters including postoperative hemoglobin drop, drained blood volume, transfusion rate, total consumption of FVIII, and perioperative complications were assessed. RESULTS: The difference in the postoperative hemoglobin drop was significant between two groups with a lower decrease in the CI group (p = 0.002). The drained blood volume for postoperative 24 h was significantly lower in the CI than the BI groups (p = 0.037). Total consumption of factor concentrates for postoperative 5 days was greater in the CI group than in the BI group (p = 0.000). One postoperative hematoma and wound dehiscence occurred in BI group and no other complication developed. CONCLUSIONS: Although good control of hemostasis could be achieved using either method during the perioperative period of TKA, CI seems more tolerable and effective than BI to provide perioperative blood management undergoing TKA in patients with hemophilia. TRIAL REGISTRATION: The study was retrospectively registered in WHO ICTRP under identifier KCT0002404 (date of registration: August 04, 2017). PMID- 28830477 TI - Hyperfibrinolysis in severe isolated traumatic brain injury may occur without tissue hypoperfusion: a retrospective observational multicentre study. AB - BACKGROUND: Hyperfibrinolysis is a critical complication in severe trauma. Hyperfibrinolysis is traditionally diagnosed via elevated D-dimer or fibrin/fibrinogen degradation product levels, and recently, using thromboelastometry. Although hyperfibrinolysis is observed in patients with severe isolated traumatic brain injury (TBI) on arrival at the emergency department (ED), it is unclear which factors induce hyperfibrinolysis. The present study aimed to investigate the factors associated with hyperfibrinolysis in patients with isolated severe TBI. METHODS: We conducted a multicentre retrospective review of data for adult trauma patients with an injury severity score >= 16, and selected patients with isolated TBI (TBI group) and extra cranial trauma (non-TBI group). The TBI group included patients with an abbreviated injury score (AIS) for the head >= 4 and an extra-cranial AIS < 2. The non-TBI group included patients with an extra-cranial AIS >= 3 and head AIS < 2. Hyperfibrinolysis was defined as a D-dimer level >= 38 mg/L on arrival at the ED. We evaluated the relationships between hyperfibrinolysis and injury severity/tissue injury/tissue perfusion in TBI patients by comparing them with non-TBI patients. RESULTS: We enrolled 111 patients in the TBI group and 126 in the non-TBI group. In both groups, patients with hyperfibrinolysis had more severe injuries and received transfusion more frequently than patients without hyperfibrinolysis. Tissue injury, evaluated on the basis of lactate dehydrogenase and creatine kinase levels, was associated with hyperfibrinolysis in both groups. Among patients with TBI, the mortality rate was higher in those with hyperfibrinolysis than in those without hyperfibrinolysis. Tissue hypoperfusion, evaluated on the basis of lactate level, was associated with hyperfibrinolysis in only the non-TBI group. Although the increase in lactate level was correlated with the deterioration of coagulofibrinolytic variables (prolonged prothrombin time and activated partial thromboplastin time, decreased fibrinogen levels, and increased D-dimer levels) in the non-TBI group, no such correlation was observed in the TBI group. CONCLUSIONS: Hyperfibrinolysis is associated with tissue injury and trauma severity in TBI and non-TBI patients. However, tissue hypoperfusion is associated with hyperfibrinolysis in non-TBI patients, but not in TBI patients. Tissue hypoperfusion may not be a prerequisite for the occurrence of hyperfibrinolysis in patients with isolated TBI. PMID- 28830478 TI - Chemical composition and evaluation of the antibacterial and Cytotoxic activities of the essential oil from the leaves of Myracrodruon urundeuva. AB - BACKGROUND: This study evaluated the in vitro activity of essential oil extracted from the leaves of Myracrodruon urundeuva. METHODS: The oil was obtained by hydro distillation and characterized by Gas Chromatography coupled to Mass Spectrometry (GC-MS) and Gas Chromatography with Flame Ionization Detector (GC-FID). The antibacterial activity was evaluated by the broth microdilution technique and the MIF was determined by using growth indicator CTT (2,3,5-triphenyl-tetrazolium) and CBM in BHI agar. The oil's cytotoxicity was evaluated in HeLa, HEK-293, and Vero E6 cells using MTT, 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium. RESULTS: The oil showed chemical markers, including alpha-pinene (87.85%), trans caryophyllene (1.57%), limonene (1.49%) and beta -pinene (1.42%), and activity against all strains: Staphylococcus aureus (MIC = MBC = 0.22 mg/mL), Staphylococcus epidermidis (MIC = 0.11 mg/mL and MBC = 0.22 mg/mL), Escherichia coli (MIC = 0.88 mg/mL and MBC = 1.75 mg/mL), Pseudomonas aeruginosa (MIC = MBC = 7 mg/mL) and Salmonella Enteritidis (MIC = MBC = 0.44 mg/mL). In vitro cytotoxicity tests showed that the oil is not toxic and has slight antitumor activity. CONCLUSIONS: We conclude that the M. urundeuva oil results are promising, with prospects of being pharmacologically viable. PMID- 28830479 TI - Costs and expected gain in lifetime health from intensive care versus general ward care of 30,712 individual patients: a distribution-weighted cost effectiveness analysis. AB - BACKGROUND: Clinicians, hospital managers, policy makers, and researchers are concerned about high costs, increased demand, and variation in priorities in the intensive care unit (ICU). The objectives of this modelling study are to describe the extra costs and expected health gains associated with admission to the ICU versus the general ward for 30,712 patients and the variation in cost effectiveness estimates among subgroups and individuals, and to perform a distribution-weighted economic evaluation incorporating extra weighting to patients with high severity of disease. METHODS: We used a decision-analytic model that estimates the incremental cost per quality-adjusted life year (QALY) gained (ICER) from ICU admission compared with general ward care using Norwegian registry data from 2008 to 2010. We assigned increasing weights to health gains for those with higher severity of disease, defined as less expected lifetime health if not admitted. The study has inherent uncertainty of findings because a randomized clinical trial comparing patients admitted or rejected to the ICU has never been performed. Uncertainty is explored in probabilistic sensitivity analysis. RESULTS: The mean cost-effectiveness of ICU admission versus ward care was ?11,600/QALY, with 1.6 QALYs gained and an incremental cost of ?18,700 per patient. The probability (p) of cost-effectiveness was 95% at a threshold of ?22,000/QALY. The mean ICER for medical admissions was ?10,700/QALY (p = 97%), ?12,300/QALY (p = 93%) for admissions after acute surgery, and ?14,700/QALY (p = 84%) after planned surgery. For individualized ICERs, there was a 50% probability that ICU admission was cost-effective for 85% of the patients at a threshold of ?64,000/QALY, leaving 15% of the admissions not cost-effective. In the distributional evaluation, 8% of all patients had distribution-weighted ICERs (higher weights to gains for more severe conditions) above ?64,000/QALY. High severity admissions gained the most, and were more cost-effective. CONCLUSIONS: On average, ICU admission versus general ward care was cost-effective at a threshold of ?22,000/QALY (p = 95%). According to the individualized cost effectiveness information, one in six ICU admissions was not cost-effective at a threshold of ?64,000/QALY. Almost half of these admissions that were not cost effective can be regarded as acceptable when weighted by severity of disease in terms of expected lifetime health. Overall, existing ICU services represent reasonable resource use, but considerable uncertainty becomes evident when disaggregating into individualized results. PMID- 28830481 TI - Merger mania: mergers and acquisitions in the generic drug sector from 1995 to 2016. AB - BACKGROUND: Drug shortages and increasing generic drug prices are associated with low levels of competition. Mergers and acquisitions impact the level of competition. Record merger and acquisition activity was reported for the pharmaceutical sector in 2014/15, yet information on mergers and acquisitions in the generic drug sector are absent from the literature. This information is necessary to understand if and how such mergers and acquisitions can be a factor in drug shortages and increasing prices. METHODS: Data on completed merger and acquisition deals that had a generic drug company being taken over (i.e. 'target') were extracted from Bloomberg Finance L.P. The number and announced value of deals are presented globally, for the United States, and globally excluding the United States annually from 1995 to 2016 in United States dollars. RESULTS: Generic drug companies comprised 9.3% of the value of all deals with pharmaceutical targets occurring from 1995 to 2016. Globally, in 1995 there were no deals, in 2014 there were 22 deals worth $1.86 billion, in 2015 there were 34 deals totalling $33.56 billion, and in 2016 there were 42 deals worth in excess of $44 billion. This substantial increase was partially attributed to Teva's 2016 acquisition of Allergan's generic drug business. The surge in mergers and acquisitions for 2015/16 was driven by deals in the United States, where they represented 89.7% of the dollar value of deals in those years. CONCLUSIONS: The recent blitz in mergers and acquisitions signals that the generic drug industry is undergoing a transformation, especially in the United States. This restructuring can negatively affect the level of competition that might impact prices and shortages for some products, emphasizing the importance of updating regulations and procurement policies. PMID- 28830480 TI - Recorded time periods of bispectral index values equal to zero predict neurological outcome after out-of-hospital cardiac arrest. AB - BACKGROUND: Prognostication in out-of-hospital cardiac arrest (OHCA) survivors is often difficult. Recent studies have shown the predictive ability of bispectral index (BIS) monitoring to assist with early neuroprognostication. The aim of this study was to investigate whether characteristics of BIS values equal to zero (BIS 0) (i.e. duration and/or uni- versus bilateral presence) instead of simply their occurrence are better indicators for poor neurological outcome after OHCA by aiming at a specificity of 100%. METHODS: Between 2011 and 2015, all successfully resuscitated OHCA patients were treated with targeted temperature management (TTM) at 33 degrees C for 24 hours followed by rewarming over 12 hours (0.3 degrees C/h). In total, BIS values were registered in 77 OHCA patients. The occurrence of unilateral (BIS 0 at one hemisphere) and bilateral (BIS 0 at both hemispheres) BIS 0 values as well as their total duration were calculated. Receiver operating characteristic (ROC) curves were constructed using the total duration with BIS 0 values calculated from the initiation of TTM onwards to determine poor neurological outcome. RESULTS: In 30 of 77 OHCA patients (39%), at least one BIS 0 value occurred during the first 48 hours after admission. Of these 30 patients, six (20%) had a good (cerebral performance category (CPC) 1-2) and 24 (80%) a poor neurological outcome (CPC3-5) at 180 days post-CA. Within these 30 patients, the incidence of bilateral BIS 0 values was higher in patients with poor neurological outcome (CPC1-2: 2 (33%) vs. CPC3-5: 19 (79%); p = 0.028). The presence of a BIS 0 value predicted poor neurological outcome with a sensitivity of 62% and specificity of 84% (AUC: 0.729; p = 0.001). With a ROC analysis, a total duration of 30,3 minutes with BIS 0 values calculated over the first 48 hours predicted poor neurological outcome with a sensitivity of 63% and specificity of 100% (AUC: 0.861; p = 0.007). CONCLUSIONS: This study shows that a prolonged duration with (bilateral) BIS 0 values serves as a better outcome predictor after OHCA as compared to a single observation. PMID- 28830482 TI - A retrospective feasibility study of biweekly, reduced-dose docetaxel in Asian patients with castrate-resistant, metastatic prostate cancer. AB - BACKGROUND: The aim of this retrospective study was to evaluate the clinical outcomes of reduced dose, biweekly docetaxel chemotherapy for Korean patients with castrate-resistant prostate cancer (CRPC). METHODS: We retrospectively reviewed the medical records of 48 patients with metastatic CRPC who were treated with a biweekly regimen (intravenous docetaxel 40 mg/m2 on day 1 plus prednisolone 5 mg twice daily) between 2012 and 2015 at Samsung Medical Center (Seoul, Korea). Prior to the adoption of a biweekly regimen in Oct 2013, our institutional standard chemotherapy was docetaxel 75 mg/m2 every 3 weeks for patients with CRPC (n = 24). After Oct 2013, all chemotherapy-naive patients with CRPC received a 40 mg/m2 biweekly regimen (n = 24). The primary end point was a PSA response, defined as a greater than 50% decline in PSA level from baseline. RESULTS: The baseline characteristics of the patients in the two treatment groups were similar. The most common cause of treatment discontinuation was disease progression, which was exhibited by 17 patients (71%) in the 3-weekly group and 20 (75%) in the biweekly group. PSA responses were observed in 12 (50%) and 11 (46%) patients in the 3-weekly and biweekly groups, respectively (p = 0.683). Time to treatment failure (TTTF, 4.5 vs 3.9 months) and time-to-progression (TTP, 5.0 vs 4.2 months) were not significantly different between the 3-weekly and biweekly groups. CONCLUSIONS: Within the limitations of a retrospective study, the biweekly reduced dose docetaxel regimen was active and well-tolerated in Korean patients with metastatic CRPC. PMID- 28830483 TI - Results of a pilot study in the U.S. and Vietnam to assess the utility and acceptability of a multi-level pregnancy test (MLPT) for home monitoring of hCG trends after assisted reproduction. AB - BACKGROUND: To evaluate the utility and acceptability of using multi-level pregnancy tests (MLPTs) at home to monitor hCG trends following assisted reproductive technology (ART). METHODS: One hundred and four women presenting for ART at either Stanford Medicine Fertility and Reproductive Health Clinic (Stanford, CA) or Hung Vuong Hospital (Ho Chi Minh City, Vietnam) participated in this pilot study. Women were asked to perform the MLPT at home, primarily on days when they were also scheduled to receive standard clinic-based serum hCG testing. These tests were administered up to 6 times over the 6-week period following embryo transfer or intrauterine insemination (IUI). Concordance of serial hCG readings for each time point was assessed by comparing trends in urine MLPT results with trends in serum hCG. Stable or increasing hCG level was interpreted as an indication of a progressing pregnancy, while a declining hCG was interpreted as a lack of established or progressing pregnancy. At study end, all participants were asked about the acceptability and convenience of using the MLPT at home for monitoring hCG trends following ART. RESULTS: Data from both urine and serum testing are available for 156 of 179 clinic visits (87.2%). There was high concordance of serial trend results between the two types of tests: among the 156 sets of serum and urine hCG data points, 150 (96.2%) showed a matching trend in hCG pattern and 6 (3.8%) resulted in a discordant trend. Seventy-three percent of women reported being satisfied or very satisfied with using the MLPTs at home. Almost all (96.6%) said that the MLPT was easy or very easy to use. CONCLUSION: The MLPT offers women and health care providers a client-friendly diagnostic tool to detect very early pregnancy and monitor its progress. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov as NCT01846403 (May 1, 2013), and NCT01919502 (August 5, 2013). PMID- 28830484 TI - Oncological and functional results of the surgical treatment of vertebral metastases in patients with multiple myeloma". AB - BACKGROUND: In nearly 30% of patients with myeloma, pathological fractures are found to occur in the spine. If the patients are not treated promptly and satisfactorily, the quality of their lives diminishes. Currently, the standard treatment for metastatic lesions of the spine is radiotherapy, but surgical intervention is becoming more frequent. It is very important to quickly identify metastases and implement surgical treatment before any fracture/s occur. METHODS: Over the period of 2010-2014 in our department, a total of 129 patients were treated for metastatic spinal myeloma. 73 patients underwent vertebroplasty and 56 patients were operated on through various methods. Indications for the surgery, its course, technique and outcome were subsequently evaluated. The majority of patients (76%) admitted for treatment, exhibited vertebral fractures. Most lesions were multiplace and involved the vertebral bodies. In 42% of the patients, radiological examinations showed symptoms of compression of the nervous structures, while clinical signs were observed in only 16% of the patients. The functional status of the patients was assessed using the Karnofsky scale, while pain intensity was measured in a VAS score, before and after the surgery. The oncological results were assessed as a survival rate and local recurrence rate. RESULTS: The average follow-up was conducted within 31 months (min 18, max 48). The patients after vertebroplasty survived 42 months, and the patients after surgery 23 months. Local recurrence of the disease was observed in 12 patients. In 10 patients, among a group of 21 with paresis, their neurological conditions improved. The average results of both their VAS score and Karnofsky performance score in patients after surgery was seen to have improved. Only sporadic postoperative complications after vertebroplasty and surgery were reported. CONCLUSIONS: Early diagnosis of myeloma spine metastasis is essential to achieve the desired results of treatment. Vertebroplasty, as advised, should be performed as early as possible. Both the functional and oncological results after vertebroplasty are beneficial and the complication rates are low. Three relevant factors were found in our study: patient's age over 65 years, initial diagnosis over 3 years and stage III of disease were related, significantly and statistically to survival. PMID- 28830485 TI - Re-development of mental health first aid guidelines for supporting Aboriginal and Torres Strait Islanders who are engaging in non-suicidal self-injury. AB - BACKGROUND: Non-suicidal self-injury (NSSI) disproportionally affects Indigenous Australians. Friends, family and frontline workers (for example, teachers, youth workers) are often best positioned to provide initial assistance if someone is engaging in NSSI. Culturally appropriate expert consensus guidelines on how to provide mental health first aid to Australian Aboriginal and Torres Strait Islanders who are engaging in NSSI were developed in 2009. This study describes the re-development of these guidelines to ensure they contain the most current recommended helping actions. METHODS: The Delphi consensus method was used to elicit consensus on potential helping statements to be included in the guidelines. These statements describe helping actions that Indigenous community members and non-Indigenous frontline workers can take, and information they should have, to help someone who is engaging in NSSI. The statements were sourced from systematic searches of peer-reviewed literature, grey literature, books, websites and online materials, and existing NSSI courses. A panel was formed, comprising 26 Aboriginal and Torres Strait Islanders with expertise in NSSI. The panellists were presented with the helping statements via online questionnaires and were encouraged to suggest re-wording of statements and any additional helping statements that were not included in the original questionnaire. Statements were only accepted for inclusion in the guidelines if they were endorsed by >=90% of panellists as essential or important. RESULTS: From a total of 185 statements shown to the expert panel, 115 were endorsed as helping statements to be included in the re-developed guidelines. CONCLUSIONS: A panel of Aboriginal and Torres Strait Islander people with expertise in NSSI were able to reach consensus on appropriate strategies for providing mental health first aid to an Aboriginal and Torres Strait Islander engaging in NSSI. The re-development of the guidelines has resulted in more comprehensive guidance than the earlier version. The re-developed guidelines will form the basis of an Aboriginal mental health first aid short course on NSSI for Indigenous community members and non Indigenous frontline workers that will be evaluated in an upcoming trial. PMID- 28830486 TI - Rapid evolution of the PB1-F2 virulence protein expressed by human seasonal H3N2 influenza viruses reduces inflammatory responses to infection. AB - Influenza A virus (IAV) PB1-F2 protein has been linked to viral virulence. Strains of the H3N2 subtype historically express full-length PB1-F2 proteins but during the 2010-2011 influenza seasons, nearly half of the circulating H3N2 IAVs encoded truncated PB1-F2 protein. Using a panel of reverse engineered H3N2 IAVs differing only in the origin of the PB1 gene segment, we found that only the virus encoding the avian-derived 1968 PB1 gene matching the human pandemic strain enhanced cellular infiltrate into the alveolar spaces of infected mice. We linked this phenomenon to expression of full-length PB1-F2 protein encompassing critical "inflammatory" residues. PMID- 28830487 TI - A large left atrial lipoma combined with coronary artery disease. AB - BACKGROUND: Primary benign tumors of the heart are extremely rare and usually difficult to diagnose for their asymptomatic signs. CASE PRESENTATION: A 66-year old woman was admitted for shortness of breath caused by a large left atrial lipoma combined with coronary artery disease. Next, we successfully performed simultaneous curative surgery for the large cardiac lipoma and coronary artery bypass grafting with a "starfish" and no cardiopulmonary bypass was used.The patient was discharged on the eighth postoperative day in a good condition, and has remained asymptomatic at the 5-month follow-up. CONCLUSIONS: Lipomas are rare and difficult to diagnose, while computed tomography and computed tomography angiography can give us very important clues. Surgery is necessary. We can introduce a "starfish"to the operationand the cardiopulmonary bypass is unnecessary for the left lipoma with coronary artery disease. PMID- 28830488 TI - Trends in the prescription of benzodiazepines for the elderly in Korea. AB - BACKGROUND: This study examined trends in the prescription of benzodiazepines for the elderly (age over 65 years) in Korea, a country with a higher level of spending on pharmaceuticals compared to that in other Organization for Economic Cooperation and Development (OECD) countries, and identified factors related to the inappropriate use of such drugs. METHODS: We used the National Health Insurance Claims Data (NHICD) for the period 2009-2013, including all reimbursed drug-prescribing information. Following the OECD's prescribing quality indicators (PQIs), we looked at the prevalence, quantities, durations, and inappropriate (long-term or high-quantity) use of benzodiazepines, some of the most widely prescribed, but potentially inappropriate, drugs for the elderly. We also performed multivariate logistic regression analyses to identify factors related to the inappropriate use of these drugs. RESULTS: The annual prevalence of benzodiazepine prescribing for elderly subjects decreased slightly over time but remained high (37.9% in 2009 and 35.1% in 2013). There were also small decreases in the inappropriate long-term use of benzodiazepines over the five years, with a 0.6 decrease in the Defined Daily Dose and a 4.1 per 1,000 decreases in elderly user-days. The proportion of subjects using long-acting benzodiazepines also fell from 263.6 to 220.4 per 1,000 elderly patients. The regression analyses found that the inappropriate long-term use of benzodiazepines in the elderly was significantly related to the patients visiting several institutions and physicians prescribing more than 30 days' worth of medication. CONCLUSIONS: The prevalence of prescribing potentially inappropriate drugs, such as benzodiazepines, remains high in Korea. Policy efforts, such as a periodic assessment of prescribing, restricting prescribing days, and more practical guidelines, are needed to improve the quality of prescribing. PMID- 28830489 TI - The role of South-North partnerships in promoting shared learning and knowledge transfer. AB - While it is clear that hospitals in developing countries need to improve quality of health services and improve patient safety, hospitals in high resource countries need to do the same. Most often the focus on improvement through institutional health partnerships involves hospital teams from high resource settings attempting to aid and teach hospital staff in low resource settings, particularly in Africa. However these efforts to provide assistance may be more satisfying and sustainable if we understand that partnership learning is bi directional whereby hospital teams from high resource settings also benefit. One particular partnership-based model that demonstrates this benefit to high resource partners is the World Health Organization African Partnerships for Patient Safety (APPS). Johns Hopkins Medicine Armstrong Institute for Patient Safety & Quality (AI) through the APPS model has co-created twinning partnerships with hospitals in Uganda, South Sudan & Liberia. This commentary aims to deconstruct specific learnings that have benefited the Johns Hopkins AI community through the APPS partnership. PMID- 28830490 TI - Characteristics and properties of nano-LiCoO2 synthesized by pre-organized single source precursors: Li-ion diffusivity, electrochemistry and biological assessment. AB - BACKGROUND: LiCoO2 is one of the most used cathode materials in Li-ion batteries. Its conventional synthesis requires high temperature (>800 degrees C) and long heating time (>24 h) to obtain the micronscale rhombohedral layered high temperature phase of LiCoO2 (HT-LCO). Nanoscale HT-LCO is of interest to improve the battery performance as the lithium (Li+) ion pathway is expected to be shorter in nanoparticles as compared to micron sized ones. Since batteries typically get recycled, the exposure to nanoparticles during this process needs to be evaluated. RESULTS: Several new single source precursors containing lithium (Li+) and cobalt (Co2+) ions, based on alkoxides and aryloxides have been structurally characterized and were thermally transformed into nanoscale HT-LCO at 450 degrees C within few hours. The size of the nanoparticles depends on the precursor, determining the electrochemical performance. The Li-ion diffusion coefficients of our LiCoO2 nanoparticles improved at least by a factor of 10 compared to commercial one, while showing good reversibility upon charging and discharging. The hazard of occupational exposure to nanoparticles during battery recycling was investigated with an in vitro multicellular lung model. CONCLUSIONS: Our heterobimetallic single source precursors allow to dramatically reduce the production temperature and time for HT-LCO. The obtained nanoparticles of LiCoO2 have faster kinetics for Li+ insertion/extraction compared to microparticles. Overall, nano-sized LiCoO2 particles indicate a lower cytotoxic and (pro-)inflammogenic potential in vitro compared to their micron-sized counterparts. However, nanoparticles aggregate in air and behave partially like microparticles. PMID- 28830491 TI - A randomized double-blind placebo-controlled trial to investigate the effectiveness and safety of a novel green-lipped mussel extract -BioLex(r) -for managing pain in moderate to severe osteoarthritis of the hip and knee. AB - BACKGROUND: Extracts from perna canaliculus, the Green Lipped Mussel (GLM) are widely used as a complimentary therapy by patients with osteoarthritis (OA). The current study investigated the potential of a novel GLM formulation as a treatment for OA. A randomized double-blind placebo-controlled trial was undertaken to assess potential impacts on pain and quality of life following 12 weeks of treatment. METHODS: Eighty patients with moderate to severe OA of the hip or knee were randomized to receive either 600 mg of BioLex(r)-GLM daily or placebo for 12 weeks. Entry criteria included a minimum 100 mm Visual Analogue Scale pain score (VAS) of 30 mm at baseline. The primary outcome was patient reported pain, measured by the Western Ontario and McMasters OA Index (WOMAC) pain subscale and VAS pain scale. Secondary outcomes included: quality of life (OAQol), total WOMAC score, WOMAC -20 responder criteria, and change in medication use over the study period. Participants were assessed at baseline, 12 weeks (end of therapy) and 15 weeks (3-weeks post-intervention). RESULTS: At week 12, there were no significant differences in VAS or WOMAC pain subscale between active and placebo groups, nor significant improvement in the WOMAC-20 responder criteria or OAQol. Joint stiffness (measured by WOMAC-B stiffness) in the GLM group improved compared with placebo (p = 0.046). There was a significant difference in paracetamol use between the GLM treated group and the placebo group after week 12 (p = 0.001). CONCLUSIONS: BioLex(r) -GLM extract did not confer clinical benefit in moderate to severe OA over the intervention period, however, a significant difference in paracetamol use in the post-intervention period was observed between the BioLex(r) -GLM group and placebo group. Higher doses and/or longer treatment periods are worthy of future investigation. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: no. ACTRN12611000256976 . PMID- 28830492 TI - Exploring provider perspectives on respectful maternity care in Kenya: "Work with what you have". AB - BACKGROUND: Promoting respect and dignity is a key component of providing quality care during facility-based childbirth and is becoming a critical indicator of maternal health care. Providing quality care requires essential skills and attitudes from healthcare providers, as their role is central to optimizing interventions in maternity settings. METHODS: In 13 facilities in Kenya we conducted a mixed methods, pre-post study design to assess health providers' perspectives of a multi-component intervention (the Heshima project), which aimed to mitigate aspects of disrespect and abuse during facility-based childbirth. Providers working in maternity units at study facilities were interviewed using a two-part quantitative questionnaire: an interviewer-guided section on knowledge and practice, and a self-administered section focusing on intrinsic value systems and perceptions. Eleven distinct composite scores were created on client rights and care, provider emotional wellbeing, and work environments. Bivariate analyses compared pre- and post-scores. Qualitative in-depth interviews focused on underlying factors that affected provider attitudes and behaviors including the complexities of service delivery, and perceptions of the Heshima interventions. RESULTS: Composite scales were developed on provider knowledge of client rights (Chronbach alpha = 0.70), client-centered care (alpha = 0.80), and HIV care (alpha = 0.81); providers' emotional health (alpha = 0.76) and working relationships (alpha = 0.88); and provider perceptions of management (alpha = 0.93), job fairness (alpha = 0.68), supervision (alpha = 0.84), promotion (alpha = 0.83), health systems (alpha = 0.85), and work environment (alpha = 0.85). Comparison of baseline and endline individual item scores and composite scores showed that provider knowledge of client rights and practice of a rights-based approach, treatment of clients living with HIV, and client-centered care during labor, delivery, and postnatal periods improved (p < 0.001). Changes in emotional health, perceptions of management, job fairness, supervision, and promotion seen in composite scores did not directly align with changes in item-specific responses. Qualitative data reveal health system challenges limit the translation of providers' positive attitudes and behaviors into implementation of a rights based approach to maternity care. CONCLUSION: Behavior change interventions, central to promoting respectful care, are feasible to implement, as seen in the Heshima experience, but require sustained interaction with health systems where providers practice. Provider emotional health has the potential to drive (mis)treatment and affect women's care. PMID- 28830493 TI - Unsatisfactory colposcopy: clinical decision-making in conditions of uncertainty. AB - BACKGROUND: Unsatisfactory colposcopy, where the cells of interest are not visible in women with a positive cervical screening test, is a common area of clinical uncertainty due to the lack of clear evidence and guidance. Colposcopists' opinions and experiences are likely to have a significant influence on service provision and the development of national policy. The aim of this study was to analyse decision-making when applied to women with unsatisfactory colposcopy. METHODS: A multi-centre qualitative study utilizing a series of focus groups in an English healthcare region. Sampling aimed to ensure heterogeneity of experience and healthcare provider demographics. A topic guide covered a range of clinical and cytological variables and was compiled by the researchers and three expert Colposcopists. Using an iterative approach, thematic analysis was selected as the most appropriate method to identify factors affecting decision-making. RESULTS: Twenty-three Colposcopists from four units participated. The decision to treat was easier in women with high-grade cytology and high risk women with low-grade cytology such as heavy smokers, poor attenders, older women, those who had completed their families and women opting for treatment. Where decision-making was more complex, intuition and a multi disciplinary approach were used to guide management. Areas of dissonance, which are affected by paucity of evidence and emotive factors, included cytological collection device, clinical setting and length of conservative follow-up and depth of excision in women at high risk of treatment-related morbidity. CONCLUSIONS: Anxiety of missing a cancer deters long-term cytological follow-up, resulting in heterogeneity of care and higher than anticipated excisional treatments in women with low-grade screening and unsatisfactory colposcopy. In areas of clinical uncertainty when decisions are dominated by affect, clinical guidance can reduce the difficulty and anxiety of decision-making. PMID- 28830494 TI - In vivo evaluation of hot water extract of Acorus gramineus root against benign prostatic hyperplasia. AB - BACKGROUND: Acorus gramineus has been reported to exhibit various pharmacological effects including inhibition of cholesterol synthesis, enhancement of lipid metabolism, prevention of dementia and inhibition of mast cell growth. According to the Chinese compendium of materia media, it has been reported that Acorus spp. is effective for sedation, dementia prevention as well as diuretic effect. In addition, it showed more than equivalent activity compared to furosoemide, a drug known to be effective in diuretic action in animal model study. However, their effectiveness against benign prostatic hyperplasia (BPH) of Acorus gramineus has not been reported. This study was designed to evaluate the effect of Acorus gramineus root hot water extract (AG) against BPH in vivo. METHODS: Male rats, 10 weeks of age and weighing 405 g +/- 10 g, were used for this study. Biomarkers were evaluated including prostate weight, prostate weight ratio, hormonal changes, 5-alpha reductase type II androgen receptor (AR) of the prostate gland and anti-oxidant activation factors related to BPH. These biomarkers were measured in vivo test. RESULTS: AG showed significant effect at the 250 and 500 mg/kg/day in rats. Groups treated with AG displayed significantly lower levels of prostate gland weight (0.79 g) compared to the BPH induced group (1.19 g). Also, dihydrotestosterone (DHT) level was decreased from 61.8 to 100% and androgen receptor expression level was decreased from 111 to 658%. Any hematological toxicity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level wasn't observed. CONCLUSION: This study indicated that AG was effective for reducing BPH symptoms. TRIAL REGISTRATION: Not applicable. PMID- 28830495 TI - New insights into HCV replication in original cells from Aedes mosquitoes. AB - BACKGROUND: The existing literature about HCV association with, and replication in mosquitoes is extremely poor. To fill this gap, we performed cellular investigations aimed at exploring (i) the capacity of HCV E1E2 glycoproteins to bind on Aedes mosquito cells and (ii) the ability of HCV serum particles (HCVsp) to replicate in these cell lines. METHODS: First, we used purified E1E2 expressing baculovirus-derived HCV pseudo particles (bacHCVpp) so we could investigate their association with mosquito cell lines from Aedes aegypti (Aag-2) and Aedes albopictus (C6/36). We initiated a series of infections of both mosquito cells (Ae aegypti and Ae albopictus) with the HCVsp (Lat strain - genotype 3) and we observed the evolution dynamics of viral populations within cells over the course of infection via next-generation sequencing (NGS) experiments. RESULTS: Our binding assays revealed bacHCVpp an association with the mosquito cells, at comparable levels obtained with human hepatocytes (HepaRG cells) used as a control. In our infection experiments, the HCV RNA (+) were detectable by RT-PCR in the cells between 21 and 28 days post-infection (p.i.). In human hepatocytes HepaRG and Ae aegypti insect cells, NGS experiments revealed an increase of global viral diversity with a selection for a quasi-species, suggesting a structuration of the population with elimination of deleterious mutations. The evolutionary pattern in Ae albopictus insect cells is different (stability of viral diversity and polymorphism). CONCLUSIONS: These results demonstrate for the first time that natural HCV could really replicate within Aedes mosquitoes, a discovery which may have major consequences for public health as well as in vaccine development. PMID- 28830496 TI - What can the CF registry tell us about rare CFTR-mutations? A Belgian study. AB - BACKGROUND: CFTR2 provides clinical and functional information of the most common CFTR-mutations. Rare mutations (RMs) occur in only a few patients with limited reported clinical data. Their role in CF-disease liability is hardly documented. METHODS: Belgian CF-Registry 2013 data were analyzed to identify CF with at least 1 RM (CF+RM). Clinical data and sweat chloride of CF+RM were compared to CF controls, carrying 2 class 1 to 3 mutations (CFclassic). Disease severity was compared between both groups. To avoid bias in the comparison, transplanted patients were excluded from each group. RESULTS: Seventy-seven CF+RM were identified (77/1183 = 6.5%). Sixty-four different RM were detected, of which 21 had not been previously reported. All RMs, corresponding to HGVS (Human Genome Variation Society) nomenclature, were listed in supplementary data. Seven transplanted CF+RM were excluded for further analysis. CF+RM had higher age at diagnosis [median (IQR)] [3.7 y (0.3-18.3) vs. 0.3y (0.1-2,0) (p < 0.0001)], lower sweat chloride [96 mmol/L (64-107) vs. 104 mmol/L (97-115) (p < 0.0001)], higher FEV1%pred [77%pred (58-96) vs. 68%pred (48-86) (p = 0.017)], were less frequently pancreatic insufficient [56% vs. 98% (p < 0.0001)], Pseudomonas aeruginosa colonized [24% vs. 44% (p = 0.0093)] and needed fewer IV antibiotics [36% vs. 51% (p = 0.041)] than CFclassic. However, a wide spectrum of disease severity was seen amongst CF+RM. CONCLUSIONS: CF-patients with a RM cover 6.5% of the Belgian CF-population. Rare mutations can be found in severely ill patients, but more often in late diagnosed, pancreatic sufficient patients. PMID- 28830497 TI - Combining quantitative and qualitative breast density measures to assess breast cancer risk. AB - BACKGROUND: Accurately identifying women with dense breasts (Breast Imaging Reporting and Data System [BI-RADS] heterogeneously or extremely dense) who are at high breast cancer risk will facilitate discussions of supplemental imaging and primary prevention. We examined the independent contribution of dense breast volume and BI-RADS breast density to predict invasive breast cancer and whether dense breast volume combined with Breast Cancer Surveillance Consortium (BCSC) risk model factors (age, race/ethnicity, family history of breast cancer, history of breast biopsy, and BI-RADS breast density) improves identifying women with dense breasts at high breast cancer risk. METHODS: We conducted a case-control study of 1720 women with invasive cancer and 3686 control subjects. We calculated ORs and 95% CIs for the effect of BI-RADS breast density and VolparaTM automated dense breast volume on invasive cancer risk, adjusting for other BCSC risk model factors plus body mass index (BMI), and we compared C-statistics between models. We calculated BCSC 5-year breast cancer risk, incorporating the adjusted ORs associated with dense breast volume. RESULTS: Compared with women with BI-RADS scattered fibroglandular densities and second-quartile dense breast volume, women with BI-RADS extremely dense breasts and third- or fourth-quartile dense breast volume (75% of women with extremely dense breasts) had high breast cancer risk (OR 2.87, 95% CI 1.84-4.47, and OR 2.56, 95% CI 1.87-3.52, respectively), whereas women with extremely dense breasts and first- or second-quartile dense breast volume were not at significantly increased breast cancer risk (OR 1.53, 95% CI 0.75-3.09, and OR 1.50, 95% CI 0.82-2.73, respectively). Adding continuous dense breast volume to a model with BCSC risk model factors and BMI increased discriminatory accuracy compared with a model with only BCSC risk model factors (C-statistic 0.639, 95% CI 0.623-0.654, vs. C-statistic 0.614, 95% CI 0.598 0.630, respectively; P < 0.001). Women with dense breasts and fourth-quartile dense breast volume had a BCSC 5-year risk of 2.5%, whereas women with dense breasts and first-quartile dense breast volume had a 5-year risk <= 1.8%. CONCLUSIONS: Risk models with automated dense breast volume combined with BI-RADS breast density may better identify women with dense breasts at high breast cancer risk than risk models with either measure alone. PMID- 28830498 TI - Validation of the Italian version of the Non-Communicating Children's Pain Checklist-Postoperative Version. AB - BACKGROUND: This study evaluated the validity and reliability of the Italian version of the Non-Communicating Children's Pain Checklist-Postoperative version (I-NCCPC-PV). METHODS: The original NCCPC-PV version was translated into Italian following the guidelines for "the translation, adaptation, and validation of instruments or scales for cross-cultural healthcare research". We tested the Italian NCCPC-PV version (I-NCCPC-PV) in 40 children (3-18 years of age) with severe to profound Intellectual Disability and no verbal communication. Each child's behavior was observed by a parent or caregiver and by an external observer in a quiet situation and a painful one. They independently assessed the child's level of pain using the translated Italian version of the NCCPCPV (I NCCPC-PV). RESULTS: The results from 80 assessments showed that children's behavioral signs differed significantly between painful and calm situations (p < 0.001). The inter-rater reliability was poor in a quiet condition (ICC 0.62) and fair in a painful situation (ICC 0.77). The inter-rater agreement was good in both calm and painful conditions (72.50% and 77.50% respectively). CONCLUSION: The Italian version of the NCCPC-PV (I-NCCPC-PV) can be used for pain assessment in children with Intellectual Disability who lack verbal communication. PMID- 28830499 TI - Longitudinal evaluation of a pilot e-portfolio-based supervision programme for final year medical students: views of students, supervisors and new graduates. AB - BACKGROUND: Little is known about how best to implement portfolio-based learning in medical school. We evaluated the introduction of a formative e-portfolio-based supervision pilot for final year medical students by seeking views of students, supervisors and graduates on use and educational effects. METHODS: Students and supervisors were surveyed by questionnaire, with free text comments invited. Interviews were held with new graduates in their first Foundation Programme placement. RESULTS: Most students used the e-portfolio (54%) and met with their supervisor (62%) 'once or twice' only. Students had more negative views: 22% agreed that the pilot was beneficial, while most supervisors thought that e portfolio (72%) and supervision (86%) were a 'good idea'. More students reported supervision meetings benefited learning (49%) and professional development (55%) than the e-portfolio did (16%; 28%). Only 47% of students felt 'prepared' for future educational processes, though graduates noted benefits for navigating and understanding e-portfolio building and supervision. Factors limiting engagement reflected 'burden', while supervision meetings and early experience of postgraduate processes offered educational value. CONCLUSION: Final year students have negative attitudes to a formative e-portfolio, though benefits for easing the educational transition are recognised by graduates. Measures to minimize time, repetition and redundancy of processes may encourage use. Engagement is influenced by the supervisor relationship and educational value may be best achieved by supporting supervisors to develop strategies to facilitate, and motivate self-directed learning processes in undergraduates. PMID- 28830500 TI - Trade in medicines and the public's health: a time series analysis of import disruptions during the 2015 India-Nepal border blockade. AB - BACKGROUND: Nepal was struck by devastating earthquakes in April-May 2015, followed by the India-Nepal border blockade later that year. METHODS: We used the United Nations Commodity Trade Statistics (UN Comtrade) database to analyse exports of various health commodities from India to Nepal from January 2011 September 2016. We used time-series regressions of trading volume vs. unit price to ask how well Nepal's trading history with India prior to the earthquake and blockade was able to predict unit prices of health commodities imported into Nepal during and after the earthquake and the blockade. Regression residuals were used to quantify the extent to which the blockade impacted the price of healthcare commodities crossing into Nepal. RESULTS: During the blockade period (September 2015-early February 2016), the volume of all retail medicines traded across the India-Nepal border was reduced by 46.5% compared to same months in 2014-2015. For medical dressings, large volumes were exported from India to Nepal during and shortly after the earthquakes (May-June 2015), but decreased soon thereafter. During the earthquake, the difference between observed and predicted values of unit price (residuals) for all commodities show no statistical outliers. However, during the border blockade, Nepal paid USD 22.3 million more for retail medicines than one would have predicted based on its prior trading history with India, enough to provide healthcare to nearly half of Kathmandu's citizens for 1 year. CONCLUSION: The India-Nepal blockade was a geopolitical natural experiment demonstrating how a land-locked country is vulnerable to the vagaries of its primary trading partner. Although short-lived, the blockade had an immediate impact on traded medicine volumes and prices, and provided a large opportunity cost with implications for public health. PMID- 28830501 TI - High-density lipoproteins suppress Abeta-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture. AB - BACKGROUND: Alzheimer's Disease (AD), characterized by accumulation of beta amyloid (Abeta) plaques in the brain, can be caused by age-related failures to clear Abeta from the brain through pathways that involve the cerebrovasculature. Vascular risk factors are known to increase AD risk, but less is known about potential protective factors. We hypothesize that high-density lipoproteins (HDL) may protect against AD, as HDL have vasoprotective properties that are well described for peripheral vessels. Epidemiological studies suggest that HDL is associated with reduced AD risk, and animal model studies support a beneficial role for HDL in selectively reducing cerebrovascular amyloid deposition and neuroinflammation. However, the mechanism by which HDL may protect the cerebrovascular endothelium in the context of AD is not understood. METHODS: We used peripheral blood mononuclear cell adhesion assays in both a highly novel three dimensional (3D) biomimetic model of the human vasculature composed of primary human endothelial cells (EC) and smooth muscle cells cultured under flow conditions, as well as in monolayer cultures of ECs, to study how HDL protects ECs from the detrimental effects of Abeta. RESULTS: Following Abeta addition to the abluminal (brain) side of the vessel, we demonstrate that HDL circulated within the lumen attenuates monocyte adhesion to ECs in this biofidelic vascular model. The mechanism by which HDL suppresses Abeta-mediated monocyte adhesion to ECs was investigated using monotypic EC cultures. We show that HDL reduces Abeta induced PBMC adhesion to ECs independent of nitric oxide (NO) production, miR-233 and changes in adhesion molecule expression. Rather, HDL acts through scavenger receptor (SR)-BI to block Abeta uptake into ECs and, in cell-free assays, can maintain Abeta in a soluble state. We confirm the role of SR-BI in our bioengineered human vessel. CONCLUSION: Our results define a novel activity of HDL that suppresses Abeta-mediated monocyte adhesion to the cerebrovascular endothelium. PMID- 28830502 TI - Relationship between GNAS1 T393C polymorphism and aseptic loosening after total hip arthroplasty. AB - BACKGROUND: Aseptic loosening is a main cause for revision surgery after total hip arthroplasty (THA) and there is no reliable marker for the early detection of patients at high risk. This study has been performed to validate association of the T393C polymorphism (rs7121) in the GNAS1 gene, encoding for the alpha-subunit of heterotrimeric G-protein Gs, with risk for and time to aseptic loosening after THA, which has been demonstrated in our previous study. METHODS: 231 patients with primary THA and 234 patients suffering from aseptic loosening were genotyped for dependency on GNAS1 genotypes and analyzed. RESULTS: Genotyping revealed almost similar minor allele frequencies of 0.49 and 0.46, respectively. Consistently, genotype distributions of both groups were not significantly different (p = 0.572). Neither gender nor GNAS1 genotype showed a statistically significant association with time to loosening (p = 0.501 and p = 0.840). Stratification by gender, as performed in our previous study, was not able to show a significant genotype-dependent difference in time (female p = 0.313; male p = 0.584) as well as median time to aseptic loosening (female p = 0.353; male p = 0.868). CONCLUSION: This study was not able to confirm the results of our preliminary study. An association of the GNAS1 T393C polymorphisms with risk for and time to aseptic loosening after THA is unlikely. PMID- 28830503 TI - An economic evaluation of the healthcare cost of tinnitus management in the UK. AB - BACKGROUND: There is no standard treatment pathway for tinnitus patients in the UK. Possible therapies include education and reassurance, cognitive behavioural therapies, modified tinnitus retraining therapy (education and sound enrichment), or amplification of external sound using hearing aids. However, the effectiveness of most therapies is somewhat controversial. As health services come under economic pressure to deploy resources more effectively there is an increasing need to demonstrate the value of tinnitus therapies, and how value may be continuously enhanced. The objective of this project was to map out existing clinical practice, estimate the NHS costs associated with the management approaches used, and obtain initial indicative estimates of cost-effectiveness. METHODS: Current treatment pathways, costs and health outcomes were determined from the tinnitus literature, national statistics, a patient survey, and expert opinion. These were used to create an Excel-based economic model of therapy options for tinnitus patients. The probabilities associated with the likelihood of an individual patient receiving a particular combination of therapies was used to calculate the average cost of treatment per patient, average health outcome per patient measured in QALYs gained, and cost-effectiveness, measured by the average cost per QALY gained. RESULTS: The average cost of tinnitus treatment per patient per year is GBL717, equating to an NHS healthcare bill of GBL750 million per year. Across all pathways, tinnitus therapy costs L10,600 per QALY gained. Results were relatively insensitive to restrictions on access to cognitive behaviour therapy, and a subsequent reliance on other therapies. CONCLUSIONS: NHS provisions for tinnitus are cost-effective against the National Institute for Health and Care Excellence cost-effective threshold. Most interventions help, but education alone offers very small QALY gains. The most cost-effective therapies in the model were delivered within audiology. PMID- 28830504 TI - Trends in substance use admissions among older adults. AB - BACKGROUND: Substance abuse is a growing, but mostly silent, epidemic among older adults. We sought to analyze the trends in admissions for substance abuse treatment among older adults (aged 55 and older). METHODS: Treatment Episode Data Set - Admissions (TEDS-A) for period between 2000 and 2012 was used. The trends in admission for primary substances, demographic attributes, characteristics of substance abused and type of admission were analyzed. RESULTS: While total number of substance abuse treatment admissions between 2000 and 2012 changed slightly, proportion attributable to older adults increased from 3.4% to 7.0%. Substantial changes in the demographic, substance use pattern, and treatment characteristics for the older adult admissions were noted. Majority of the admissions were for alcohol as the primary substance. However there was a decreasing trend in this proportion (77% to 64%). The proportion of admissions for following primary substances showed increase: cocaine/crack, marijuana/hashish, heroin, non prescription methadone, and other opiates and synthetics. Also, admissions for older adults increased between 2000 and 2012 for African Americans (21% to 28%), females (20% to 24%), high school graduates (63% to 75%), homeless (15% to 19%), unemployed (77% to 84%), and those with psychiatric problems (17% to 32%).The proportion of admissions with prior history of substance abuse treatment increased from 39% to 46% and there was an increase in the admissions where more than one problem substance was reported. Ambulatory setting continued to be the most frequent treatment setting, and individual (including self-referral) was the most common referral source. The use of medication assisted therapy remained low over the years (7% - 9%). CONCLUSIONS: The changing demographic and substance use pattern of older adults implies that a wide array of psychological, social, and physiological needs will arise. Integrated, multidisciplinary and tailored policies for prevention and treatment are necessary to address the growing epidemic of substance abuse in older adults. PMID- 28830505 TI - Ultrasonographic findings in goats with contagious caprine pleuropneumonia caused by Mycoplasma capricolum subsp. capripneumoniae. AB - BACKGROUND: In goats, contagious caprine pleuropneumonia (CCPP) is a cause of major economic losses in Africa, Asia and in the Middle East. There is no information emphasising the importance of diagnostic ultrasound in goats with CCPP caused by Mycoplasma capricolum subsp. capripneumoniae (Mccp). This study was designed to describe the ultrasonographic findings in goats with CCPP caused by Mccp and to correlate ultrasonographic with post-mortem findings. To this end, 55 goats with CCPP were examined. Twenty-five healthy adult goats were used as a control group. RESULTS: Major clinical findings included harried, painful respiration, dyspnoea and mouth breathing. On ultrasonography, a liver-like echotexture was imaged in 13 goats. Upon post-mortem examination, all 13 goats exhibited unilateral pulmonary consolidation. Seven goats had a unilateral hypoechoic pleural effusion. At necropsy, the related lung was consolidated and the pleural fluid appeared turbid and greenish. Pleural abscessiation detected in five goats was confirmed post-mortem. Twenty-eight goats had a bright, fibrinous matrix extending over the chest wall containing numerous anechoic fluid pockets with medial displacement and compression of lung tissue. Echogenic tags imaged floating in the fluid were found upon post-mortem examination to be fibrin. In two goats, a consolidated right parenchyma was imaged together with hypoechoic pericardial effusions with echogenic tags covering the epicardium. At necropsy, the right lung was consolidated in three goats and fibrin threads were found covering the epicardium and pericardium. CONCLUSIONS: In goats with CCPP, the extension and the severity of the pulmonary changes could not be verified with clinical certainty in most cases, whereas this was possible most of the time with sonography, thus making the prognosis easier. Ultrasonographic examination of the pleurae and the lungs helped in the detection of various lesions. PMID- 28830506 TI - A coiled conformation of amyloid-beta recognized by antibody C706. AB - BACKGROUND: beta-Amyloid (Abeta) peptide is believed to play a pivotal role in the development of Alzheimer's disease. Passive immunization with anti-Abeta monoclonal antibodies may facilitate the clearance of Abeta in the brain and may thus prevent the downstream pathology. Antibodies targeting the immunodominant N terminal epitope of Abeta and capable of binding both the plaques and soluble species have been most efficacious in animal models. Structural studies of such antibodies with bound Abeta peptides provided the basis for understanding the mechanisms of action and the differences in potency. To gain further insight into the structural determinants of antigen recognition and the preferential Abeta conformations, we determined the crystal structure of murine antibody C706 in complex with the N-terminal Abeta 1-16 peptide sequence. METHODS: The antigen binding fragment of C706 was expressed in HEK293 cells and was crystallized in complex with the Abeta peptide. The X-ray structure was determined at 1.9-A resolution. RESULTS: The binding epitope of C706 is centered on residues Arg5 and His6, which provide the majority of interactions. Unlike most antibodies, C706 recognizes a coiled rather than extended conformation of Abeta. CONCLUSIONS: Comparison with other antibodies targeting the N-terminal section of Abeta suggests that the conformation of the bound peptide may be linked to the immunization protocol and may reflect the preference for the extended conformation in the context of a longer Abeta peptide as opposed to the coiled conformation in the isolated short peptide. PMID- 28830507 TI - Relationship preferences and experience of primary care patients in continuity of care: a case study in Beijing, China. AB - BACKGROUND: Continuity of care can bring a wide range of benefits to consumers, providers and health care systems. This study aimed to understand the relationship preferences of primary care patients and their associations with patient experience of continuity of care. METHODS: A questionnaire survey was conducted on 700 patients who sought medical care from a community health organisation in Beijing. The survey contained four items examining the relationship preferences of the respondents, and a modified Questionnaire of Continuity between Care Levels (CCAENA) measuring patient experience of continuity of care based on a three dimensional (relational, informational and managerial) model. The associations between the relationship preferences and the experience of respondents in continuity of care was tested using a linear regression model controlling for age, sex, education, medical insurance, personal income and servicing facilities. RESULTS: The respondents experienced relatively lower levels of informational and managerial continuity compared with relational continuity of care. More than 80% of respondents preferred free choice and a continuing relationship with doctors, compared with 59% who endorsed community facility control over hospital appointments. A preference for a continuing relationship with doctors was associated with all aspects of continuity of care. A preference in favour of community facility control over hospital appointments was a strong predictor of managerial continuity (beta = 0.333, p < 0.001) and informational continuity (beta = 0.256, p < 0.001). Patient preference for free choice of doctors was positively associated with relational continuity with specialists (p < 0.001), but not with primary care providers (p > 0.08). Perceived importance of information exchange was associated with relational and managerial continuity (p < 0.05), but not with informational continuity (p = 0.34). CONCLUSIONS: Patients prefer a high level of freedom of choice and sustained individual relationship with doctors. Relationship preferences of patients are associated with their experience of continuity of care. But patient strong preference for free choice of doctors is not aligned with relational continuity with primary care, a desirable feature of cost-effective healthcare systems. PMID- 28830508 TI - An optimized swine dysentery murine model to characterize shedding and clinical disease associated with "Brachyspira hampsonii" infection. AB - BACKGROUND: The development of a mouse model as an in vivo pathogenicity screening tool for Brachyspira spp. has advanced the study of these economically important pathogens in recent years. However, none of the murine models published to date have been used to characterize the clinical signs of disease in mice, instead focusing on pathology following oral inoculation with various Brachyspira spp. The experiments described herein explore modifications of published models to characterize faecal consistency, faecal shedding and pathology in mice challenged with "Brachyspira hampsonii" clade II (Bhamp). METHODS AND RESULTS: In Experiment 1, 24 CF-1 mice were randomly allocated to one of three inoculation groups: sham (Ctrl), Bhamp, or B. hyodysenteriae (Bhyo; positive control). Half of each group was fed normal mouse chow (RMH) while the other received a low-zinc diet (TD85420). In Experiment 2, eight CF-1 mice and nine C3H/HeN mice were divided into Ctrl or Bhamp inoculation groups, and all fed TD85420. In Experiment 1, mice fed TD85420 demonstrated more severe mucoid faeces (P = 0.001; Kruskal Wallis) and faecal shedding for a significantly greater number of days (P = 0.005; Kruskal Wallis). Mean faecal scores of Bhamp inoculated mice trended higher than Ctrl (P = 0.06; Wilcoxon rank-sum) as did those of Bhyo mice (P = 0.0; Wilcoxon rank-sum). In Experiment 2, mean faecal scores of inoculated CF-1 mice were significantly greater than in C3H mice (P = 0.049; Kruskal Wallis) but no group differences in faecal shedding were observed. In both experiments, mice clustered based on the severity of colonic and caecal histopathology but high lesion scores were not always concurrent with high fecal scores. CONCLUSION: In our laboratory, CF-1 mice and the lower-zinc TD85420 diet provide a superior murine challenge model of "Brachyspira hampsonii" clade II. PMID- 28830509 TI - Peri-operative factors predisposing to pharyngocutaneous fistula after total laryngectomy: analysis of a large multi-institutional patient cohort. AB - BACKGROUND: Pharyngocutaneous fistula (PCF) is a problematic complication following total laryngectomy. Disagreement remains regarding predisposing factors. This study examines perioperative factors predicting PCF following total laryngectomy using a large multicenter data registry. METHODS: Retrospective cohort analysis was performed using patients undergoing total laryngectomy in the ACS-NSQIP database for 2006-2014. Sub-analysis was performed based on reconstruction type. Outcome of interest was PCF development within 30 days. RESULTS: Multivariate analysis of 971 patients was performed. Three variables showed statistical significance in predicting PCF: wound classification of 3 and 4 vs. 1-2 (OR 6.42 P < 0.0004 and OR 8.87, P < 0.0042), pre-operative transfusion of > 4 units of packed red blood cells (OR 6.28, P = 0.043), and free flap versus no flap reconstruction (OR 2.81, P = 0.008). CONCLUSIONS: This study identifies important risk factors for development of PCF following total laryngectomy in a large, multi-institutional cohort of patients, thereby identifying a subset of patients at increased risk. PMID- 28830510 TI - Prevalence of methicillin-resistant Staphylococcus aureus carriage on admission among patients attending regional hospitals in Dar es Salaam, Tanzania. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen responsible for hospital and community acquired infection. Colonization with MRSA is associated with a high risk of developing infection. This study aimed to determine the rate of MRSA carriage on admission and the associated risk factors among patients attending regional hospitals, in Dar es Salaam, Tanzania. RESULTS: A total of 258 patients were included in this study. Nasal swabs were collected on admission to the hospital and after 48 h of hospital stay for detection of MRSA. Of 258 patients enrolled, 89 (34.5%) were colonized with S. aureus and out them 22 (24.7%) were carriers of MRSA, giving an overall MRSA nasal carriage rate of 8.5% (22/258). One patient acquired MRSA while admitted in the hospital. Most of the S. aureus isolates 85 (95.5%) were resistant to penicillin. Resistance to gentamycin, ciprofloxacin, kanamycin, linezolid and mupirocin were 14.6, 11.2, 11.2, 3.4 and 1.1%, respectively. The prevalence of inducible clindamycin resistance, constitutive clindamycin resistance, MS phenotype (resistance to erythromycin alone), and multidrug resistance was 21.3, 3.4, 12.4, and 16.9%, respectively. We observed a statistically significant association between MRSA and multiple drugs resistance among S. aureus isolates (p = 0.001). Of the risk factors investigated none were statistically significant associated with MRSA. CONCLUSION: There is a high prevalence of MRSA among patients on admission at the two municipal hospitals in Dar es Salaam. The high prevalence of MRSA and the increased rates of resistance to commonly used antimicrobials among MRSA isolates call for attention to the importance of including the screening of MRSA in our hospitals setting in order to prevent further spread of MRSA strains to other patients and to the communities. Control and prevention strategies should be emphasized including decolonization. PMID- 28830511 TI - Wrist-ankle acupuncture (WAA) for primary dysmenorrhea (PD) of young females: study protocol for a randomized controlled trial. AB - BACKGROUND: Primary dysmenorrhea (PD) is one of the most common health complaints all over the world, specifically among young females. Acupuncture has been employed to relieve the pain-based symptoms and to avoid the side effects of conventional medication, and wrist-ankle acupuncture (WAA) has confirmed analgesic efficacy for various types of pain. The aim of this study is to evaluate the immediate analgesia effect of WAA on PD of young females. METHODS/DESIGN: This study will carry out a randomized parallel controlled single blind trial to observe the immediate analgesia effect of WAA in PD of young females. Sixty participants who meet inclusion criteria will be recruited from September 2016 to September 2017 in Changhai hospital of China. They are randomly assigned to WAA therapy or sham acupuncture groups (30 patients for each group), and then receive real or sham acupuncture treatment, respectively. In this trial, the primary outcome measure is simple form of McGill pain questionnaire (SF-MPQ), while expectation and treatment credibility scale (ETCS), safety assessment, the COX menstrual symptom scale (CMSS), questionnaire about the feeling of being punctured are included in the secondary outcomes. DISCUSSION: This trial will be the first study protocol designed to evaluate the immediate analgesia effect of WAA in PD of young females. The strengths in methodology, including rigorous randomized, sham-controlled, participants-blinded and assessors-blinded, will guarantee the quality of this study. WAA doesn't require any needling sensation, so non-penetrating sham acupuncture can serve as an effective placebo intervention in this trial. TRIALS REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR-IOR-16008546 ; registration date: 27 May 2016). PMID- 28830512 TI - Histone 4 lysine 8 acetylation regulates proliferation and host-pathogen interaction in Plasmodium falciparum. AB - BACKGROUND: The dynamics of histone modifications in Plasmodium falciparum indicates the existence of unique mechanisms that link epigenetic factors with transcription. Here, we studied the impact of acetylated histone code on transcriptional regulation during the intraerythrocytic developmental cycle (IDC) of P. falciparum. RESULTS: Using a dominant-negative transgenic approach, we showed that acetylations of histone H4 play a direct role in transcription. Specifically, these histone modifications mediate an inverse transcriptional relationship between the factors of cell proliferation and host-parasite interaction. Out of the four H4 acetylations, H4K8ac is likely the rate-limiting, regulatory step, which modulates the overall dynamics of H4 posttranslational modifications. H4K8ac exhibits maximum responsiveness to HDAC inhibitors and has a highly dynamic distribution pattern along the genome of P. falciparum during the IDC. Moreover, H4K8ac functions mainly in the euchromatin where its occupancy shifts from intergenic regions located upstream of 5' end of open reading frame into the protein coding regions. This shift is directly or indirectly associated with transcriptional activities at the corresponding genes. H4K8ac is also active in the heterochromatin where it stimulates expression of the main antigenic gene family (var) by its presence in the promoter region. CONCLUSIONS: Overall, we demonstrate that H4K8ac is a potential major regulator of chromatin-linked transcriptional changes during P. falciparum life cycle which is associated not only with euchromatin but also with heterochromatin environment. This is potentially a highly significant finding that suggests a regulatory connection between growth and parasite-host interaction both of which play a major role in malaria parasite virulence. PMID- 28830513 TI - Etlingera elatior Extract promotes cell death in B16 melanoma cells via down regulation of ERK and Akt signaling pathways. AB - BACKGROUND: Torch ginger (Etlingera elatior, EE) is a ginger plant that found in Southeast Asia. Previous study showed its flowers and leaves composed of several flavonoids with anti-cancer activity. This study aims to investigate the mechanism of EE extract on cell death induction in melanoma cells. METHODS: To carry out this study, the cytotoxic effect of EE extract was performed using MTT assay. Nuclear morphological change and loss of mitochondrial membrane potential were observed using Hoechst 33,342 and JC-1 staining. Flow cytometry using Annexin V/PI double staining assessed apoptosis, necrosis and viability. Caspase activity was detected by caspase activity kits. The expression of Bcl-2 family proteins, ERK and Akt signaling pathways were examined by Western blot analysis. RESULTS: The treatment of EE extract resulted in a dose- and time-dependent reduction in cell viability in B16 cells. It also induced nuclear condensation, phosphatidylserine exposure, and loss of mitochondrial membrane potential, which are markers of apoptosis. Furthermore, the expression of Bim was increased instead of Bax and Bcl-2. The results also showed caspase-independent activity and the down-regulation of ERK and Akt signaling pathway. CONCLUSION: The results suggest that EE extract induced caspase-independent cell death via down regulation of ERK and Akt pathways in B16 cells. This may be beneficial as a chemopreventive or chemotherapeutic agent in melanoma treatment. PMID- 28830514 TI - Effect of smoking and comorbidities on survival in idiopathic pulmonary fibrosis. AB - BACKGROUND: Cigarette smoking has been associated with the risk of idiopathic pulmonary fibrosis (IPF). Certain comorbidities have been associated with reduced survival although some studies have indicated that current smokers have a longer survival than ex-smokers. Comorbidities in relation to smoking history have not been previously analyzed. METHODS: Retrospective data was collected and patients were categorized according to gender and smoking habits. Comorbidities and medications were collected. Predictive values for mortality were identified by COX proportional hazard analyses. RESULTS: We examined 45 non-smokers (53.3% female), 66 ex-smokers (9.1% female) and 17 current smokers (17.6% female) with IPF. Current smokers were younger at baseline (58.1 +/- 8.74 years) compared to non-smokers (71.4 +/- 8.74, p < 0.001) and ex-smokers (72.5 +/-7.95, p <0.001). Median survival of non-smokers and current smokers was longer (55.0 and 52.0 months, respectively) than that of ex-smokers (36.0 months) (p=0.028 and 0.034, respectively). In age and severity adjusted analyses, smoking was not related to survival. Cardiovascular diseases (CVD) (72.7 %) were the most common comorbidities, current smokers had more chronic obstructive pulmonary disease (COPD) and lung cancer compared to ex-smokers (p<0.001). CVD, COPD and use of insulin were related to poorer survival in adjusted analyses. CONCLUSIONS: Smoking seems to influence the course of disease in IPF since current smokers developed the disease at a younger age in comparison to non-smokers and ex smokers. No significant differences in the major comorbidities were detected between IPF patients with different smoking histories. The mechanism through which smoking influences IPF progression requires further investigation. PMID- 28830515 TI - Social conditions of becoming homelessness: qualitative analysis of life stories of homeless peoples. AB - BACKGROUND: It is increasingly acknowledged that homelessness is a more complex social and public health phenomenon than the absence of a place to live. This view signifies a paradigm shift, from the definition of homelessness in terms of the absence of permanent accommodation, with its focus on pathways out of homelessness through the acquisition and maintenance of permanent housing, to understanding the social context of homelessness and social interventions to prevent it. However, despite evidence of the association between homelessness and social factors, there is very little research that examines the wider social context within which homelessness occurs from the perspective of homeless people themselves. This study aims to examine the stories of homeless people to gain understanding of the social conditions under which homelessness occurs, in order to propose a theoretical explanation for it. METHOD: Twenty-six semi-structured interviews were conducted with homeless people in three centres for homeless people in Cheshire North West of England. RESULTS: The analysis revealed that becoming homeless is a process characterised by a progressive waning of resilience capacity to cope with life challenges created by series of adverse incidents in one's life. The data show that final stage in the process of becoming homeless is complete collapse of relationships with those close to them. Most prominent pattern of behaviours participants often describe as main causes of breakdown of their relationships are: 1. engaging in maladaptive behavioural lifestyle including taking drugs and/or excessive alcohol drinking 2. Being in trouble with people in authorities. CONCLUSION: Homeless people describe the immediate behavioural causes of homelessness, however, the analysis revealed the social and economic conditions within which homelessness occurred. The participants' descriptions of the social conditions in which were raised and their references to maladaptive behaviours which led to them becoming homeless, led us to conclude that they believe that their social condition affected their life chances: that these conditions were responsible for their low quality of social connections, poor educational attainment, insecure employment and other reduced life opportunities available to them. PMID- 28830516 TI - Cost of diagnosing dementia in a German memory clinic. AB - BACKGROUND: Little is known about diagnostic work-ups or the costs of diagnosing dementia in specialized care. Here, we analyzed the costs of diagnosing dementia according to specific dementia disorders. METHODS: A prospective descriptive design was used to analyze the cost of diagnosing dementia for 120 patients with suspected dementia at a German memory clinic. The duration of clinical consultations and use of technical procedures were recorded by the memory clinic staff. To detect cost drivers, a multiple linear regression model was used. RESULTS: Of patients with suspected dementia, 44% were diagnosed with dementia. The total cost per patient and diagnostic process amounted to 501 ? across all patients and 659 ? for patients who were diagnosed with dementia. The costs varied between 649 ? for patients with Alzheimer's disease, 662 ? for patients with vascular or mixed dementia, and 705 ? for patients with unspecific dementia. A final diagnosis of dementia was the only factor that was significantly associated with the diagnostic cost (b = 356, CI- 182, CI+ 531, p = 0.001). CONCLUSION: The high range of costs reflects differences in diagnostic demands depending on the etiology of dementia. This variation needs to be transferred into reimbursement. Further studies are needed to assess the influence of the type of cognitive impairment and of the setting on diagnostic costs. PMID- 28830517 TI - Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial. AB - BACKGROUND: Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). METHODS/DESIGN: FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost effectiveness. DISCUSSION: The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. TRIAL REGISTRATION: ISRCTN01844152 . Registered on 8 August 2014, EudraCT number 2013-001944-76 . Registered on 26 April 2013. PMID- 28830518 TI - Discovering associations between adverse drug events using pattern structures and ontologies. AB - BACKGROUND: Patient data, such as electronic health records or adverse event reporting systems, constitute an essential resource for studying Adverse Drug Events (ADEs). We explore an original approach to identify frequently associated ADEs in subgroups of patients. RESULTS: Because ADEs have complex manifestations, we use formal concept analysis and its pattern structures, a mathematical framework that allows generalization using domain knowledge formalized in medical ontologies. Results obtained with three different settings and two different datasets show that this approach is flexible and allows extraction of association rules at various levels of generalization. CONCLUSIONS: The chosen approach permits an expressive representation of a patient ADEs. Extracted association rules point to distinct ADEs that occur in a same group of patients, and could serve as a basis for a recommandation system. The proposed representation is flexible and can be extended to make use of additional ontologies and various patient records. PMID- 28830519 TI - Piloting a programme tool to evaluate malaria case investigation and reactive case detection activities: results from 3 settings in the Asia Pacific. AB - BACKGROUND: Case investigation and reactive case detection (RACD) activities are widely-used in low transmission settings to determine the suspected origin of infection and identify and treat malaria infections nearby to the index patient household. Case investigation and RACD activities are time and resource intensive, include methodologies that vary across eliminating settings, and have no standardized metrics or tools available to monitor and evaluate them. METHODS: In response to this gap, a simple programme tool was developed for monitoring and evaluating (M&E) RACD activities and piloted by national malaria programmes. During the development phase, four modules of the RACD M&E tool were created to assess and evaluate key case investigation and RACD activities and costs. A pilot phase was then carried out by programme implementers between 2013 and 2015, during which malaria surveillance teams in three different settings (China, Indonesia, Thailand) piloted the tool over a period of 3 months each. This study describes summary results of the pilots and feasibility and impact of the tool on programmes. RESULTS: All three study areas implemented the RACD M&E tool modules, and pilot users reported the tool and evaluation process were helpful to identify gaps in RACD programme activities. In the 45 health facilities evaluated, 71.8% (97/135; min 35.3-max 100.0%) of the proper notification and reporting forms and 20.0% (27/135; min 0.0-max 100.0%) of standard operating procedures (SOPs) were available to support malaria elimination activities. The tool highlighted gaps in reporting key data indicators on the completeness for malaria case reporting (98.8%; min 93.3-max 100.0%), case investigations (65.6%; min 61.8-max 78.4%) and RACD activities (70.0%; min 64.7-max 100.0%). Evaluation of the SOPs showed that knowledge and practices of malaria personnel varied within and between study areas. Average monthly costs for conducting case investigation and RACD activities showed variation between study areas (min USD $844.80-max USD $2038.00) for the malaria personnel, commodities, services and other costs required to carry out the activities. CONCLUSION: The RACD M&E tool was implemented in the three pilot areas, identifying key gaps that led to impacts on programme decision making. Study findings support the need for routine M&E of malaria case reporting, case investigation and RACD activities. Scale-up of the RACD M&E tool in malaria-eliminating settings will contribute to improved programme performance to the high level that is required to reach elimination. PMID- 28830520 TI - Automated identification of reference genes based on RNA-seq data. AB - BACKGROUND: Gene expression analyses demand appropriate reference genes (RGs) for normalization, in order to obtain reliable assessments. Ideally, RG expression levels should remain constant in all cells, tissues or experimental conditions under study. Housekeeping genes traditionally fulfilled this requirement, but they have been reported to be less invariant than expected; therefore, RGs should be tested and validated for every particular situation. Microarray data have been used to propose new RGs, but only a limited set of model species and conditions are available; on the contrary, RNA-seq experiments are more and more frequent and constitute a new source of candidate RGs. RESULTS: An automated workflow based on mapped NGS reads has been constructed to obtain highly and invariantly expressed RGs based on a normalized expression in reads per mapped million and the coefficient of variation. This workflow has been tested with Roche/454 reads from reproductive tissues of olive tree (Olea europaea L.), as well as with Illumina paired-end reads from two different accessions of Arabidopsis thaliana and three different human cancers (prostate, small-cell cancer lung and lung adenocarcinoma). Candidate RGs have been proposed for each species and many of them have been previously reported as RGs in literature. Experimental validation of significant RGs in olive tree is provided to support the algorithm. CONCLUSION: Regardless sequencing technology, number of replicates, and library sizes, when RNA-seq experiments are designed and performed, the same datasets can be analyzed with our workflow to extract suitable RGs for subsequent PCR validation. Moreover, different subset of experimental conditions can provide different suitable RGs. PMID- 28830521 TI - Addressing geographic access barriers to emergency care services: a national ecologic study of hospitals in Brazil. AB - BACKGROUND: Unequal distribution of emergency care services is a critical barrier to be overcome to assure access to emergency and surgical care. Considering this context it was objective of the present work analyze geographic access barriers to emergency care services in Brazil. A secondary aim of the study is to define possible roles to be assumed by small hospitals in the Brazilian healthcare network to overcome geographic access challenges. METHODS: The present work can be classified as a cross-sectional ecological study. To carry out the present study, data of all 5843 Brazilian hospitals were categorized among high complexity centers and small hospitals. The geographical access barriers were identified through the use of two-step floating catchment area method. Once concluded the previous step an evaluation using the Getis-Ord-Gi method was performed to identify spatial clusters of municipalities with limited access to high complexity centers but well covered by well-equipped small hospitals. RESULTS: The analysis of accessibility index of high complexity centers highlighted large portions of the country with nearly zero hospital beds by inhabitant. In contrast, it was possible observe a group of 1595 municipalities with high accessibility to small hospitals, simultaneously with a low coverage of high complexity centers. Among the 1595 municipalities with good accessibility to small hospitals, 74% (1183) were covered by small hospitals with at least 60% of minimum emergency service requirements. The spatial clusters analysis aggregated 589 municipalities with high values related to minimum emergency service requirements. Small hospitals in these 589 cities could promote the equity in access to emergency services benefiting more than eight million people. CONCLUSIONS: There is a spatial disequilibrium within the country with prominent gaps in the health care network for emergency services. Taking this challenge into consideration, small hospitals could be a possible solution and foster equity in access to emergency and surgical care. However more investments in are necessary to improve small hospitals capabilities to fill this gap. PMID- 28830522 TI - Identification of informative features for predicting proinflammatory potentials of engine exhausts. AB - BACKGROUND: The immunotoxicity of engine exhausts is of high concern to human health due to the increasing prevalence of immune-related diseases. However, the evaluation of immunotoxicity of engine exhausts is currently based on expensive and time-consuming experiments. It is desirable to develop efficient methods for immunotoxicity assessment. METHODS: To accelerate the development of safe alternative fuels, this study proposed a computational method for identifying informative features for predicting proinflammatory potentials of engine exhausts. A principal component regression (PCR) algorithm was applied to develop prediction models. The informative features were identified by a sequential backward feature elimination (SBFE) algorithm. RESULTS: A total of 19 informative chemical and biological features were successfully identified by SBFE algorithm. The informative features were utilized to develop a computational method named FS CBM for predicting proinflammatory potentials of engine exhausts. FS-CBM model achieved a high performance with correlation coefficient values of 0.997 and 0.943 obtained from training and independent test sets, respectively. CONCLUSIONS: The FS-CBM model was developed for predicting proinflammatory potentials of engine exhausts with a large improvement on prediction performance compared with our previous CBM model. The proposed method could be further applied to construct models for bioactivities of mixtures. PMID- 28830523 TI - Factors influencing institutional delivery service utilization in Dembecha district, Northwest Ethiopia: A community based cross sectional study. AB - BACKGROUND: The risk of death from complications relating to pregnancy and childbirth over the course of a woman's lifetime is higher in the developing countries. Improving the health of mothers and children through well-organized institutional delivery service is central to achieve reduced maternal and child morbidity and mortality. So, factors that underlie the level of institutional delivery service utilization need to be investigated, especially in areas where little is known about the problem. Therefore, the objective of this study was to assess factors influencing institutional delivery service utilization in Dembecha district, Northwest Ethiopia. METHODS: Community based quantitative cross sectional study was conducted from March 1 to 30, 2015 among 674 mothers who gave birth within the last two years preceding the study using interviewer administered questionnaire. Multi-stage sampling with stratification sampling technique was used. Descriptive statistics were done to characterize the study population using different variables. Bivariate and multivariable logistic regression models were fitted to determine association. Odds ratios with 95% confidence intervals were computed. Statistical significance was declared at p value <0.05. RESULTS: Of all 674 respondents, 229(34%, 95% CI: 29.8%-37.9%) of them utilized health institutions for their last delivery. History of still birth (AOR (adjusted odds ratio) =0.25, 95% CI (confidence interval) =0.07-0.77), number of ANC visit (AOR = 38.51, 95% CI = 22.35-66.33), functional media (AOR = 2.61, 95% CI = 1.59-4.28) and distance to nearby health facility (AOR = 0.52, 95% CI = 0.32-0.83) were found to be significantly associated with institutional delivery service utilization. CONCLUSION: In this research the level of institutional delivery service utilization is still low compared to government initiatives. History of still birth, low number of ANC visit, unavailability of functional media and existence of distant health facilities were found to be significantly associated with low utilization of the service. So, concerned bodies should contribute their share to improve institutional delivery service utilization in the study area by tackling modifiable risk factors. PMID- 28830524 TI - Lipases and lipid droplet-associated protein expression in subcutaneous white adipose tissue of cachectic patients with cancer. AB - BACKGROUND: Cancer cachexia is a multifactorial metabolic syndrome characterized by marked loss of adipose tissue and skeletal muscle. Fat loss from adipose tissue in cancer cachexia is partly the result of increased lipolysis. Despite the growing amount of studies focused on elucidating the mechanisms through which lipolysis-related proteins regulate the lipolytic process, there are scarce data concerning that profile in the adipose tissue of cancer cachectic patients. Considering its fundamental importance, it was our main purpose to characterize the expression of the lipolysis-related proteins in the white adipose tissue of cachectic cancer patients. METHODS: Patients from the University Hospital were divided into three groups: control, cancer cachexia (CC), and weight-stable cancer patients (WSC). To gain greater insight into adipose tissue wasting during cancer cachexia progression, we have also analyzed an experimental model of cachexia (Walker 256 carcinosarcoma). Animals were divided into: control, intermediate cachexia (IC) and terminal cachexia (TC). Subcutaneous white adipose tissue of patients and epidydimal white adipose tissue of animals were investigated regarding molecular aspects by determining the protein content and gene expression of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), perilipin 1, leptin, adiponectin, visfatin, and tumour necrosis factor alpha (TNF-alpha). RESULTS: We found augmented lipolysis in CC associated with increased HSL expression, as well as upregulation of ATGL expression and reduction in perilipin 1 content. In IC, there was an imbalance in the secretion of pro- and anti-inflammatory factors. The alterations at the end-stage of cachexia were even more profound, and there was a reduction in the expression of almost all proteins analyzed in the animals. CONCLUSIONS: Our findings show that cachexia induces important morphological, molecular, and humoral alterations in the white adipose tissue, which are specific to the stage of the syndrome. PMID- 28830525 TI - DEMQOL and DEMQOL-Proxy: a Rasch analysis. AB - BACKGROUND: DEMQOL and DEMQOL-Proxy are widely used patient reported outcome measures (PROMs) of health related quality of life in people with dementia (PWD). Growing interest in routine use of PROMs in health care calls for more robust instruments that are potentially fit for reliable and valid comparisons at the micro-level (patients) and meso-level (clinics, hospitals, care homes). METHODS: We used modern psychometric methods (based on the Rasch model) to re-evaluate DEMQOL (1428 PWDs) and DEMQOL-Proxy (1022 carers) to ensure they are fit for purpose. We evaluated scale to sample targeting, ordering of item thresholds, item fit to the model, and differential item functioning (sex, age, relationship), local independence, unidimensionality and reliability on the full set of items and a smaller item set. RESULTS: For both DEMQOL and DEMQOL-Proxy the smaller item set performed better than the original item set. We developed revised scores using the items from the smaller set. CONCLUSIONS: We have improved the scoring of DEMQOL and DEMQOL-Proxy using the Rasch measurement model. Future work should focus on the problems identified with content and response options. PMID- 28830526 TI - Prevalence of hepatitis-C virus genotypes and potential transmission risks in Malakand Khyber Pakhtunkhwa, Pakistan. AB - BACKGROUND: Hepatitis C virus (HCV) is a leading cause of chronic liver disease and frequently progresses towards liver cirrhosis and Hepatocellular Carcinoma (HCC). This study aimed to determine the prevalence of HCV genotypes and their association with possible transmission risks in the general population of Malakand Division. METHODOLOGY: Sum of 570 serum samples were collected during March 2011 to January 2012 from suspected patients visited to different hospitals of Malakand. The suspected sera were tested using qualitative PCR and were then subjected to molecular genotype specific assay. Quantitative PCR was also performed for determination of pre-treatment viral load in confirmed positive patients. RESULTS: Out of 570 serum samples 316 sera were seen positive while 254 sera were found negative using qualitative PCR. The positive samples were then subjected to genotyping assay out of 316, type-specific PCR fragments were seen in 271 sera while 45 samples were found untypable genotypes. Genotype 3a was seen as a predominant genotype (63.3%) with a standard error of +/-2.7%. Cramer's V statistic and Liklihood-Ratio statistical procedures are used to measure the strength and to test the association, respectively, between the dependent variable, genotype, and explanatory variables (e.g. gender, risk, age and area/districts). The dependent variable, genotype, is observed statistically significant association with variable risk factors. This implies that the genotype is highly dependent on how the patient was infected. In contrast, the other covariates, for example, gender, age, and district (area) no statistical significant association are observed. The association between gender-age indicates that the mean age of female was older by 10.5 +/- 2.3 years with 95% confidence level using t-statistic. CONCLUSION: It was concluded from the present study that the predominant genotype was 3a in the infected population of Malakand. This study also highlights the high prevalence rate of untypable genotypes which an important issue of health care setup in Malakand and create complications in therapy of infected patients. Major mode of HCV transmission is multiple uses and re-uses of needles/injections. TRIAL REGISTRATION: ISRCTN ISRCTN73824458. Registered: 28 September 2014. PMID- 28830527 TI - Development of a dynamic framework to explain population patterns of leisure-time physical activity through agent-based modeling. AB - Despite the increasing body of evidences on the factors influencing leisure-time physical activity, our understanding of the mechanisms and interactions that lead to the formation and evolution of population patterns is still limited. Moreover, most frameworks in this field fail to capture dynamic processes. Our aim was to create a dynamic conceptual model depicting the interaction between key psychological attributes of individuals and main aspects of the built and social environments in which they live. This conceptual model will inform and support the development of an agent-based model aimed to explore how population patterns of LTPA in adults may emerge from the dynamic interplay between psychological traits and built and social environments. We integrated existing theories and models as well as available empirical data (both from literature reviews), and expert opinions (based on a systematic expert assessment of an intermediary version of the model). The model explicitly presents intention as the proximal determinant of leisure-time physical activity, a relationship dynamically moderated by the built environment (access, quality, and available activities) - with the strength of the moderation varying as a function of the person's intention- and influenced both by the social environment (proximal network's and community's behavior) and the person's behavior. Our conceptual model is well supported by evidence and experts' opinions and will inform the design of our agent-based model, as well as data collection and analysis of future investigations on population patterns of leisure-time physical activity among adults. PMID- 28830528 TI - Non-physician clinicians in rural Africa: lessons from the Medical Licentiate programme in Zambia. AB - BACKGROUND: Most sub-Saharan African countries struggle to make safe surgery accessible to rural populations due to a shortage of qualified surgeons and the unlikelihood of retaining them in district hospitals. In 2002, Zambia introduced a new cadre of non-physician clinicians (NPCs), medical licentiates (MLs), trained initially to the level of a higher diploma and from 2013 up to a BSc degree. MLs have advanced clinical skills, including training in elective and emergency surgery, designed as a sustainable response to the surgical needs of rural populations. METHODS: This qualitative study aimed to describe the role, contributions and challenges surgically active MLs have experienced. Based on 43 interviewees, it includes the perspective of MLs, their district hospital colleagues-medical officers (MOs), nurses and managers; and surgeon-supervisors and national stakeholders. RESULTS: In Zambia, MLs play a crucial role in delivering surgical services at the district level, providing emergency surgery and often increasing the range of elective surgical cases that would otherwise not be available for rural dwellers. They work hand in hand with MOs, often giving them informal surgical training and reducing the need for hospitals to refer surgical cases. However, MLs often face professional recognition problems and tensions around relationships with MOs that impact their ability to utilise their surgical skills. CONCLUSIONS: The paper provides new evidence concerning the benefits of 'task shifting' and identifies challenges that need to be addressed if MLs are to be a sustainable response to the surgical needs of rural populations in Zambia. Policy lessons for other countries in the region that also use NPCs to deliver essential surgery include the need for career paths and opportunities, professional recognition, and suitable employment options for this important cadre of healthcare professionals. PMID- 28830529 TI - Oral hygiene in intensive care unit patients with photodynamic therapy: study protocol for randomised controlled trial. AB - BACKGROUND: In intensive care units (ICUs), nosocomial infections are prevalent conditions and they have been related to high mortality indexes. Some studies have suggested that inefficient oral hygiene and ventilator-associated pneumonia (VAP) are related. Nowadays, in the Brazilian public health system there is no well-defined protocol for oral hygiene in an ICU. Due to the drawbacks of the use of antibiotics, photodynamic therapy (PDT) has emerged as an interesting technique in order to reduce antimicrobial-resistant pathogens. Methylene blue (MB) is the most common chemical agent for PDT in Brazil. However, new formulations for improved effectiveness are still lacking. The objective of this study is to evaluate the use of an MB mouthwash as an effective oral-hygiene procedure in an ICU and to show that oral hygiene using PDT with MB mouthwash may reduce VAP frequency to rates similar to, or higher than, chlorhexidine. METHODS: Phase 1 will evaluate the most effective cleaning procedure, while phase 2 will correlate oral hygiene to VAP incidence. At the start of phase 1, the ICU patients will be randomly allocated into three different groups (10 patients/group): the efficacy of chlorhexidine, classical MB-PDT, and mouthwash MB-PDT will all be measured for the quantification of viable bacteria, both pre- and post-treatment, by a Reverse Transcription Polymerase Chain Reaction (RT PCR). In phase 2, the most effective procedure found in phase 1 and a mechanical cleaning with filtered water will be carried out daily, once a day, over 5 days, with a total of 52 ICU patients randomly allocated into the two groups. The clinical records will be evaluated in order to find any pneumonic diagnoses. DISCUSSION: Since a variety of bacterial species are related to VAP, a universal primer for bacteria will be used in order to quantify the total bacteria count in the participants' samples. In order to quantify only the living bacteria before DNA extraction, the samples will be treated with propidium monoazide. This will infiltrate the dead bacteria and will intercalate the DNA bases, avoiding their DNA amplification. This will be the first trial to evaluate MB-PDT in a mouthwash formula that can increase the effectiveness due to the control of MB aggregation. The results of this study will be able to generate an easy and low-cost protocol to be used in an ICU for the Brazilian public health system. TRIAL REGISTRATION: This protocol was approved by the Research Ethics Committee of the Conjunto Hospitalar do Mandaqui (1.317.834, CAAE: 49273515.9.3001.5551) and it was registered in Registro Brasileiro de Ensaios Clinicos (ReBEC number: RBR 94bvrc;). First received: 12 July 2015; 1st version 6 June 2016. Data will be published in a peer-reviewed journal. PMID- 28830531 TI - Seroprevalence of Hepatitis B virus surface antigen and factors associated among pregnant women in Dawuro zone, SNNPR, Southwest Ethiopia: a cross sectional study. AB - BACKGROUND: Hepatitis B is the world's most common serious liver infection. Infection by hepatitis B virus during pregnancy has high rate of vertical transmission and adverse effect on both the mother and child. Data on seroprevalence and associated factors among pregnant women in Dawuro or surrounding was scarce. Therefore, the aim of this study was to assess prevalence of hepatitis B virus and factors associated among pregnant women in Dawuro Zone. METHODS: Institution based cross-sectional study was conducted from 1st April to May 31, 2015 in Dawuro zone. Venous blood was collected, plasma was separated and hepatitis B virus surface antigen was screened using rapid test. Logistic regression was employed with 95% CI and p value of <0.05 was used as statistically significant. RESULTS: Data were collected on 289 women. The overall prevalence from this study was (p = 3.5%, 95% CI 1.4-5.6%) multivariate analysis using logistic regression showed multiple sexual partner (AOR = 6.923; 95% CI 1.685-28.441), and abortion history (AOR = 4.975; 95% CI 1.21-20.456), were significantly associated with hepatitis B virus surface antigen (HBsAg) infection. CONCLUSION: This seroprevalence was categorized as intermediate endemicity according to WHO classification criteria. Health education on sexual transmission of hepatitis B virus and inclusion of screening hepatitis b virus as routine antenatal care service is recommended. PMID- 28830530 TI - Prenatal tobacco smoke exposure predisposes offspring mice to exacerbated allergic airway inflammation associated with altered innate effector function. AB - BACKGROUND: Epidemiological studies suggest that prenatal and early life environmental exposures have adverse effects on pulmonary function and are important contributors in the development of childhood asthma and allergic disease. The mechanism by which environmental tobacco smoke (ETS) exposure in utero promotes the development of allergic asthma remains unclear. In this study, we investigated the immunological consequences of prenatal exposure to ETS in order to understand events responsible for the development or exacerbation of allergic asthma. METHODS: Pregnant C57BL/6 mice were exposed to either ETS or filtered air throughout gestation and the effect on pulmonary inflammation in the offspring were examined and compared. Specifically, the effects on eosinophilic inflammation, airway hyperreactivity, goblet cell hyperplasia, properties of pulmonary natural killer (NK) cells and type 2 cytokines elicited in response to inhaled house dust mite (HDM) allergen were investigated in the progeny. RESULTS: Exposure to ETS prenatally significantly exacerbated HDM-induced airway eosinophilic inflammation, hyperreactivity, mucus secretion, cysteinyl leukotriene biosynthesis and type 2 cytokine production in the offspring. Consistently, lung mononuclear cells from ETS-exposed offspring secreted higher levels of IL-13 when stimulated in vitro with anti-alphabeta TCR antibody or HDM allergen. Moreover, offspring from ETS-exposed dams exhibited a higher frequency of CD11b+ dendritic cells and CD3+CD4+ T lymphocytes in the lungs following allergen inhalation compared to air-exposed mice. Unexpectedly, the exacerbated allergic inflammation in the ETS-exposed offspring was associated with a reduction in CD3-CD19-NK1.1+CD94+ NK cell numbers and their IFN-gamma production, highlighting a role for altered innate immunity in the enhanced allergic response. CONCLUSION: Our results reveal that prenatal exposure to ETS predisposes offspring to an exacerbated allergic airway inflammation that is associated with a reduction in pulmonary NK cell function, suggesting that NK cells play a key role in controlling asthma severity. PMID- 28830532 TI - Intermediate-term outcome after PSMA-PET guided high-dose radiotherapy of recurrent high-risk prostate cancer patients. AB - BACKGROUND: By the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far. METHODS: Patients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0). RESULT: Findings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naive SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up. CONCLUSION: PSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed. TRIAL REGISTRATION: No trial registration was performed due to retrospective evaluation. PMID- 28830533 TI - Volatile organic compounds in ventilated critical care patients: a systematic evaluation of cofactors. AB - BACKGROUND: Expired gas (exhalome) analysis of ventilated critical ill patients can be used for drug monitoring and biomarker diagnostics. However, it remains unclear to what extent volatile organic compounds are present in gases from intensive care ventilators, gas cylinders, central hospital gas supplies, and ambient air. We therefore systematically evaluated background volatiles in inspired gas and their influence on the exhalome. METHODS: We used multi capillary column ion-mobility spectrometry (MCC-IMS) breath analysis in five mechanically ventilated critical care patients, each over a period of 12 h. We also evaluated volatile organic compounds in inspired gas provided by intensive care ventilators, in compressed air and oxygen from the central gas supply and cylinders, and in the ambient air of an intensive care unit. Volatiles detectable in both inspired and exhaled gas with patient-to-inspired gas ratios < 5 were defined as contaminating compounds. RESULTS: A total of 76 unique MCC-IMS signals were detected, with 39 being identified volatile compounds: 73 signals were from the exhalome, 12 were identified in inspired gas from critical care ventilators, and 34 were from ambient air. Five volatile compounds were identified from the central gas supply, four from compressed air, and 17 from compressed oxygen. We observed seven contaminating volatiles with patient-to-inspired gas ratios < 5, thus representing exogenous signals of sufficient magnitude that might potentially be mistaken for exhaled biomarkers. CONCLUSIONS: Volatile organic compounds can be present in gas from central hospital supplies, compressed gas tanks, and ventilators. Accurate assessment of the exhalome in critical care patients thus requires frequent profiling of inspired gases and appropriate normalisation of the expired signals. PMID- 28830534 TI - Accuracy of gestational age estimation from last menstrual period among women seeking abortion in South Africa, with a view to task sharing: a mixed methods study. AB - BACKGROUND: The requirement for ultrasound to establish gestational age among women seeking abortion can be a barrier to access. Last menstrual period dating without clinical examination should be a reasonable alternative among selected women, and if reliable, can be task-shared with non-clinicians. This study determines the accuracy of gestational age estimation using last menstrual period (LMP) assessed by community health care workers (CHWs), and explores providers' and CHWs' perspectives on task sharing this activity. The study purpose is to expand access to early medical abortion services. METHODS: We conducted a multi center cross-sectional study at four urban non-governmental reproductive health clinics in South Africa. CHWs interviewed women seeking abortion, recorded their LMP and gestational age from a pregnancy wheel if within 63 days. Thereafter, providers performed a standard examination including ultrasound to determine gestational age. Lastly, investigators calculated gestational age for all LMP dates recorded by CHWs. We compared mean gestational age from LMP dates to mean gestational age by ultrasound using t-tests and calculated proportions for those incorrectly assessed as eligible for medical abortion from LMP. In addition, in depth interviews were conducted with six providers and seven CHWs. RESULTS: Mean gestational age was 5 days (by pregnancy wheel) and 9 days (by LMP calculation) less than ultrasound gestational age. Twelve percent of women were eligible for medical abortion by LMP calculation but ineligible by ultrasound. Uncertainty of LMP date was associated with incorrect assessment of gestational age eligibility for medical abortion (p = 0.015). For women certain their LMP date was within 56 days, 3% had ultrasound gestational ages >70 days. In general, providers and CHWs were in favour of task sharing screening and referral for abortion, but were doubtful that women reported accurate LMP dates. Different perspectives emerged on how to implement task sharing gestational age eligibility for medical abortion. CONCLUSIONS: If LMP recall is within 56 days, most women will be eligible for early medical abortion and LMP can substitute for ultrasound dating. Task sharing gestational age estimation is feasible in South Africa, but its implementation should meet women's privacy needs and address healthcare workers' concerns on managing any procedural risk. PMID- 28830535 TI - Association of bariatric surgery with risk of acute care use for hypertension related disease in obese adults: population-based self-controlled case series study. AB - BACKGROUND: Hypertension carries a large societal burden. Obesity is known as a risk factor for hypertension. However, little is known as to whether weight loss interventions reduce the risk of hypertension-related adverse events, such as acute care use (emergency department [ED] visit and/or unplanned hospitalization). We used bariatric surgery as an instrument for investigating the effect of large weight reduction on the risk of acute care use for hypertension-related disease in obese adults with hypertension. METHODS: We performed a self-controlled case series study of obese patients with hypertension who underwent bariatric surgery using population-based ED and inpatient databases that recorded every bariatric surgery, ED visit, and hospitalization in three states (California, Florida, and Nebraska) from 2005 to 2011. The primary outcome was acute care use for hypertension-related disease. We used conditional logistic regression to compare each patient's risk of the outcome event during sequential 12-month periods, using pre-surgery months 13-24 as the reference period. RESULTS: We identified 980 obese patients with hypertension who underwent bariatric surgery. The median age was 48 years (interquartile range, 40-56 years), 74% were female, and 55% were non-Hispanic white. During the reference period, 17.8% (95% confidence interval [CI], 15.4-20.2%) had a primary outcome event. The risk remained unchanged in the subsequent 12-month pre-surgery period (18.2% [95% CI, 15.7-20.6%]; adjusted odds ratio [aOR] 1.02 [95% CI, 0.83-1.27]; P = 0.83). In the first 12-month period after bariatric surgery, the risk significantly decreased (10.5% [8.6-12.4%]; aOR 0.58 [95% CI, 0.45-0.74]; P < 0.0001). Similarly, the risk remained significantly reduced in the 13-24 months after bariatric surgery (12.9% [95% CI, 10.8-15.0%]; aOR 0.71 [95% CI, 0.57 0.90]; P = 0.005). By contrast, there was no significant reduction in the risk among obese patients who underwent non-bariatric surgery (i.e., cholecystectomy, hysterectomy, spinal fusion, or mastectomy). CONCLUSIONS: In this population based study of obese adults with hypertension, we found that the risk of acute care use for hypertension-related disease decreased by 40% after bariatric surgery. The data provide the best evidence on the effectiveness of substantial weight loss on hypertension-related morbidities, underscoring the importance of discussing options for weight reduction when treating obese patients with hypertension. PMID- 28830536 TI - The preventive effect of the bounding exercise programme on hamstring injuries in amateur soccer players: the design of a randomized controlled trial. AB - BACKGROUND: Hamstring injuries are the most common muscle injury in amateur and professional soccer. Most hamstring injuries occur in the late swing phase, when the hamstring undergoes a stretch-shortening cycle and the hamstring does a significant amount of eccentric work. The incidence of these injuries has not decreased despite there being effective injury prevention programmes focusing on improving eccentric hamstring strength. As this might be because of poor compliance, a more functional injury prevention exercise programme that focuses on the stretch-shortening cycle might facilitate compliance. In this study, a bounding exercise programme consisting of functional plyometric exercises is being evaluated. METHODS: A cluster-randomized controlled trial (RCT). Male amateur soccer teams (players aged 18-45 years) have been randomly allocated to intervention and control groups. Both groups are continuing regular soccer training and the intervention group is additionally performing a 12-week bounding exercise programme (BEP), consisting of a gradual build up and maintenance programme for the entire soccer season. The primary outcome is hamstring injury incidence. Secondary outcome is compliance with the BEP during the soccer season and 3 months thereafter. DISCUSSION: Despite effective hamstring injury prevention programmes, the incidence of these injuries remains high in soccer. As poor compliance with these programmes may be an issue, a new plyometric exercise programme may encourage long-term compliance and is expected to enhance sprinting and jumping performance besides preventing hamstring injuries. TRIAL REGISTRATION: NTR6129 . Retrospectively registered on 1 November 2016. PMID- 28830537 TI - Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics. AB - BACKGROUND: Although major improvements have been made in surgical management, chemotherapeutic, and radiotherapeutic of prostate cancer, many prostate cancers remain refractory to treatment with standard agents. Therefore, the identification of new molecular targets in cancer progression and development of novel therapeutic strategies to target them are very necessary for achieving better survival for patients with prostate cancer. Activation of small GTPases such as Ras and Arf1 is a critical component of the signaling pathways for most of the receptors shown to be upregulated in advanced prostate cancer. METHODS: The drug effects on cell proliferation were measured by CellTiter 96(r) AQueous One Solution Cell Proliferation Assay. The drug effects on cell migration and invasion were determined by RadiusTM 24-well and Matrigel-coated Boyden chambers. The drug effects on apoptosis were assessed by FITC Annexin V Apoptosis Detection Kit with 7-AAD and Western blot with antibodies against cleaved PARP and Caspase 3. A NOD/SCID mouse model generated by subcutaneous injection was used to assess the in vivo drug efficacy in tumor growth. ERK activation and tumor cell proliferation in xenografts were examined by immunohistochemistry. RESULTS: We show that Exo2, a small-molecule inhibitor that reduces Arf1 activation, effectively suppresses prostate cancer cell proliferation by blocking ERK1/2 activation. Exo2 also has other effects, inhibiting migration and invasion of PCa cells and inducing apoptosis. The Ras inhibitor salirasib augments Exo2-induced cytotoxicity in prostate cancer cells partially by enhancing the suppression of ERK1/2 phosphorylation. In a xenograft mouse model of prostate cancer, Exo2 reduces prostate tumor burden and inhibits ERK1/2 activation at a dose of 20 mg/kg. Synergistic treatment of salirasib and Exo2 exhibits a superior inhibitory effect on prostate tumor growth compared with either drug alone, which may be attributed to the more efficient inhibition of ERK1/2 phosphorylation. CONCLUSION: This study suggests that simultaneous blockade of Arf1 and Ras activation in prostate cancer cells is a potential targeted therapeutic strategy for preventing prostate cancer development. PMID- 28830538 TI - Pertussis outbreak investigation of Mekdela district, South Wollo zone, Amhara region, North-West Ethiopia. AB - BACKGROUND: Pertussis is a highly contagious respiratory illness caused by Bordetella pertussis. It is one of the most common vaccine-preventable bacterial infections that affects all susceptible individuals, regardless of age. Investigation was done to verify the existence of an outbreak and to identify associated risk factors contributed for the occurrence of an outbreak in Tork and Warkaye villages of Mekdela district. METHODS: Unmatched community based case control and descriptive cross sectional investigation were conducted with one to two ratios. We used structured questionnaire to collect data from cases and controls. RESULTS: A total of 215 cases and eight deaths were identified with an overall attack rate of 1.3 per 1000 population. The mean age of the cases was 3.7 years which was ranged from 3 months to 45 years. The more affected groups were females. On multivariate logistic regression analysis, the risk factor that remained independently statically significant associated with developing pertussis was presence of infected person in the family AOR (adjusted odds ratio): 5.859, (95% CI 2.526-13.589). But previously sick with pertussis AOR: 0.053, (95% CI 0.006-0.460) and receiving full dose of vaccine AOR: 0.256, (95% CI 0.080-0.818) were remained as protective factors from pertussis infection. CONCLUSIONS: The suspected pertussis outbreak was occurred in remote pocket villages/kebeles of Mekdela district. Routine immunization was not given regularly and functional refrigerators were not available in the health posts. Routine immunization services and treatment of infected patients with appropriate antibiotics should be intensified. PMID- 28830539 TI - Endoscopically-assisted transmastoid approach to the geniculate ganglion and labyrinthine facial nerve. AB - BACKGROUND: Endoscopic transcanal approaches to the facial nerve allow excellent exposure of the tympanic facial nerve. This approach becomes limited when access is required to the more proximal geniculate ganglion and labyrinthine portion of the facial nerve. The aim of this report was to determine the feasibility of a transmastoid endoscopically assisted approach to the geniculate ganglion and labyrinthine facial nerve. This is an endoscopic cadaveric dissection and video review at a university anatomical laboratory. METHODS: A total of 12 endoscopic cadaveric dissections were performed. A cortical mastoidectomy and perilabyrinthine air cell removal was performed using an operating microscope. Beyond this, dissection was performed with an endoscope. RESULTS: In all dissections, an endoscopically assisted transmastoid approach allowed complete access to the geniculate ganglion, and at least 1.5 mm of the distal labyrinthine facial nerve. Further transcrusal drilling through the anterior crus of the superior semicircular canal allowed access to the entire labyrinthine facial nerve. CONCLUSIONS: The entire geniculate ganglion and labyrinthine facial nerve is difficult to access with microscopic techniques. Adding endoscopic visualization allows for complete visualization of the geniculate ganglion. Clinical reports will further strengthen these preliminary cadaveric results. PMID- 28830540 TI - Mapping mHealth (mobile health) and mobile penetrations in sub-Saharan Africa for strategic regional collaboration in mHealth scale-up: an application of exploratory spatial data analysis. AB - BACKGROUND: Mobile health (mHealth), a term used for healthcare delivery via mobile devices, has gained attention as an innovative technology for better access to healthcare and support for performance of health workers in the global health context. Despite large expansion of mHealth across sub-Saharan Africa, regional collaboration for scale-up has not made progress since last decade. METHODS: As a groundwork for strategic planning for regional collaboration, the study attempted to identify spatial patterns of mHealth implementation in sub Saharan Africa using an exploratory spatial data analysis. In order to obtain comprehensive data on the total number of mHelath programs implemented between 2006 and 2016 in each of the 48 sub-Saharan Africa countries, we performed a systematic data collection from various sources, including: the WHO eHealth Database, the World Bank Projects & Operations Database, and the USAID mHealth Database. Additional spatial analysis was performed for mobile cellular subscriptions per 100 people to suggest strategic regional collaboration for improving mobile penetration rates along with the mHealth initiative. Global Moran's I and Local Indicator of Spatial Association (LISA) were calculated for mHealth programs and mobile subscriptions per 100 population to investigate spatial autocorrelation, which indicates the presence of local clustering and spatial disparities. RESULTS: From our systematic data collection, the total number of mHealth programs implemented in sub-Saharan Africa between 2006 and 2016 was 487 (same programs implemented in multiple countries were counted separately). Of these, the eastern region with 17 countries and the western region with 16 countries had 287 and 145 mHealth programs, respectively. Despite low levels of global autocorrelation, LISA enabled us to detect meaningful local clusters. Overall, the eastern part of sub-Saharan Africa shows high-high association for mHealth programs. As for mobile subscription rates per 100 population, the northern area shows extensive low-low association. CONCLUSIONS: This study aimed to shed some light on the potential for strategic regional collaboration for scale-up of mHealth and mobile penetration. Firstly, countries in the eastern area with much experience can take the lead role in pursuing regional collaboration for mHealth programs in sub-Saharan Africa. Secondly, collective effort in improving mobile penetration rates for the northern area is recommended. PMID- 28830541 TI - Cardioprotective effect of Platycodon grandiflorum in patients with early breast cancer receiving anthracycline-based chemotherapy: study protocol for a randomized controlled trial. AB - BACKGROUND: Anthracyclines, alone or in combination with other drugs, are among the most effective chemotherapeutic agents to treat breast cancer both in the adjuvant and neoadjuvant setting. Unfortunately, anthracycline-associated dose dependent cardiotoxicity is a limiting factor in clinical use. Extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity. However, most cardioprotective agents have shown little effect in clinical trials. Herbal medicines are pure, natural substances that have been used for centuries in many countries, including China. This trial aims to evaluate the cardioprotective effects and safety of Platycodon grandiflorum granules compared to placebo granules in patients with early breast cancer receiving anthracycline-based chemotherapy. METHOD/DESIGN: This study is a single center, double-blinded, randomized, placebo-controlled, parallel-group trial. A total of 120 patients will be randomly allocated in a 1:1 ratio to receive either P. grandiflorum granules or placebo granules twice daily for 12 weeks. The primary outcome is heart failure (either clinical or subclinical). The secondary outcomes include all-cause mortality, cardiac death, electrocardiogram (ECG) findings, left ventricular diastolic function, longitudinal systolic strain and velocities measured by tissue Doppler imaging, cardiac biomarkers, such as troponin I (TnI), brain natriuretic peptide (BNP), and creatine kinase isoenzymes (CK-MB). Assessments will be performed at baseline (before randomization) and 3, 6, 9, 12, 16, and 20 weeks after randomization. DISCUSSION: This will be the first clinical trial to evaluate the cardioprotective effects and safety of P. grandiflorum in patients with early breast cancer receiving anthracycline-based chemotherapy. We are also performing this trial to assess the feasibility of a larger-scale clinical trial in the future. TRAIL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-16009256 . Registered on 23 September 2016. PMID- 28830542 TI - Using mobile phones to ensure that referred tuberculosis patients reach their treatment facilities: a call that makes a difference. AB - BACKGROUND: Over the last decade, the availability and use of mobile phones have grown exponentially globally and in Cambodia. In the Sihanouk Hospital Centre of Hope(SHCH) in Cambodia about half of all tuberculosis patients referred out to peripheral health facilities for TB treatment initiation or continuation were lost to contact after referral ranging from 19 to 69% between 2008 and 2013. To address this, we implemented a mobile phone-based patient tracking intervention. Here, we report the number and proportion of referred TB patients who could be contacted through a mobile phone and retained in care after the introduction of mobile phone tracking. METHODS: A descriptive study involving follow-up of TB patients referred out from SHCH to peripheral health facilities during May October 2014. Standard operating procedures were used to contact individual patients and/or health facilities using a mobile phone. RESULTS: Among 109 TB patients referred to peripheral health facilities, 107(98%) had access to a mobile phone of whom, 103(97%) could be contacted directly while 5(2%) were contacted through their health care providers. A total of 108(99%) of 109 referred TB patients in intervention period were thus placed on TB treatment. CONCLUSIONS: This study provides preliminary, but promising evidence that using mobile phones was accompanied with improved retention of referred TB patients compared to historical cohorts. Given the limitations associated with historical controls, we need better designed studies with larger sample size to strengthen the evidence before national scale-up. PMID- 28830543 TI - Chinese non-psychiatric hospital doctors' attitudes toward management of psychological/psychiatric problems. AB - BACKGROUND: Psychiatric comorbidities are common among patients treated for physical disorders. Attitudes of non-psychiatric doctors toward psychological/psychiatric problems have significant implications for care provision in the general hospital setting. Our objective was to investigate non psychiatric doctors' attitudes in China. METHOD: An anonymous online questionnaire pertaining to relevant attitudes was distributed to Chinese hospital-based non-psychiatric doctors using a mobile App. RESULTS: A total of 306 non-psychiatric doctors in China voluntarily completed the questionnaire. All but two (99.3%) respondents agreed with the importance of psychological factors underlying physical illness and 85.6% agreed they had a high degree of responsibility for management of patients' emotional problems. Most respondents endorsed routine assessment of patients' psychological factors and were willing to consider psychiatric referrals for patients in need; despite 52.0% believing that mental health care by general hospital doctors was impractical. Almost all respondents welcomed more contact with psychiatric services and indicated a need for more time and professional help to manage psychological issues. Respondents' demographic characteristics and vocational status had some influence on attitudes; female doctors were more likely and surgeons less likely to consider psychological assessment and emotional care for patients with physical illness. More doctors working in hospitals with established consultation-liaison psychiatric services did not feel responsible for their patients' emotional care (17.7% vs. 6.6%, P = 0.012). CONCLUSIONS: Our pilot survey demonstrates a potential generally positive attitude toward management of patients' psychological problems and an urgent need for more time and specialist support for non-psychiatric doctors in China. PMID- 28830544 TI - IL-18 associated with lung lymphoid aggregates drives IFNgamma production in severe COPD. AB - BACKGROUND: Increased interferon gamma (IFNgamma) release occurs in Chronic Obstructive Pulmonary Disease (COPD) lungs. IFNgamma supports optimal viral clearance, but if dysregulated could increase lung tissue destruction. METHODS: The present study investigates which mediators most closely correlate with IFNgamma in sputum in stable and exacerbating disease, and seeks to shed light on the spatial requirements for innate production of IFNgamma, as reported in mouse lymph nodes, to observe whether such microenvironmental cellular organisation is relevant to IFNgamma production in COPD lung. RESULTS: We show tertiary follicle formation in severe disease alters the dominant mechanistic drivers of IFNgamma production, because cells producing interleukin-18, a key regulator of IFNgamma, are highly associated with such structures. Interleukin-1 family cytokines correlated with IFNgamma in COPD sputum. We observed that the primary source of IL-18 in COPD lungs was myeloid cells within lymphoid aggregates and IL-18 was increased in severe disease. IL-18 released from infected epithelium or from activated myeloid cells, was more dominant in driving IFNgamma when IL-18 producing and responder cells were in close proximity. CONCLUSIONS: Unlike tight regulation to control infection spread in lymphoid organs, this local interface between IL-18-expressing and responder cell is increasingly supported in lung as disease progresses, increasing its potential to increase tissue damage via IFNgamma. PMID- 28830545 TI - A protocol for CABS-dock protein-peptide docking driven by side-chain contact information. AB - BACKGROUND: The characterization of protein-peptide interactions is a challenge for computational molecular docking. Protein-peptide docking tools face at least two major difficulties: (1) efficient sampling of large-scale conformational changes induced by binding and (2) selection of the best models from a large set of predicted structures. In this paper, we merge an efficient sampling technique with external information about side-chain contacts to sample and select the best possible models. METHODS: In this paper we test a new protocol that uses information about side-chain contacts in CABS-dock protein-peptide docking. As shown in our recent studies, CABS-dock enables efficient modeling of large-scale conformational changes without knowledge about the binding site. However, the resulting set of binding sites and poses is in many cases highly diverse and difficult to score. RESULTS: As we demonstrate here, information about a single side-chain contact can significantly improve the prediction accuracy. Importantly, the imposed constraints for side-chain contacts are quite soft. Therefore, the developed protocol does not require precise contact information and ensures large-scale peptide flexibility in the broad contact area. CONCLUSIONS: The demonstrated protocol provides the extension of the CABS-dock method that can be practically used in the structure prediction of protein peptide complexes guided by the knowledge of the binding interface. PMID- 28830546 TI - The use of primary murine fibroblasts to ascertain if Spirocerca lupi secretory/excretory protein products are mitogenic ex vivo. AB - BACKGROUND: Spirocerca lupi is a nematode that parasitizes vertebrates in particular canids, by forming nodules in the thoracic cavity specifically in the oesophagus. In 25% of Spirocerca infections of the domestic dog, nodules progress from inflammatory to pre-neoplastic to sarcomatous neoplasia. With the mechanism of neoplastic transformation being incompletely understood, this study investigates if S. lupi parasite proteinaceous secretory/excretory products (ESPs) play a role in the neoplastic transformation. METHODS: To facilitate collection of ESPs, we maintained naturally harvested adult parasites in the laboratory under artificial conditions. Media in which the parasites were grown was subsequently evaluated for the presence of proteinaceous compounds using a mass spectroscopy library as well as for their ability to be mitogenic in primary murine fibroblastic cells. RESULTS: Chromatrography of the ethyl acetate extracted incubation media showed the presence of 9 protein compounds, of which three were identified as non-specific proteins isolated from Nematostella vectensis, Caenorhabditis brenneri and Sus scrofa, with the rest being unknown. Acetone, methanol, hexane and ethylacetate extracted culture media were unable to induce a mitogenic change in primary murine fibroblasts in comparison to the controls. CONCLUSION: While no mitogenic effect was evident, further studies are required to understand the role of worm excretory/secretory products on clastogenesis under chronic exposure. In addition, while not of primary importance for this study, the observed duration of parasite survival indicates that ex vivo studies on S. lupi are possible. For the latter we believe that the worm culture method can be further optimized if longer survival times are required. PMID- 28830547 TI - Relative abundance of Mycobacterium bovis molecular types in cattle: a simulation study of potential epidemiological drivers. AB - BACKGROUND: The patterns of relative species abundance are commonly studied in ecology and epidemiology to provide insights into underlying dynamical processes. Molecular types (MVLA-types) of Mycobacterium bovis, the causal agent of bovine tuberculosis, are now routinely recorded in culture-confirmed bovine tuberculosis cases in Northern Ireland. In this study, we use ecological approaches and simulation modelling to investigate the distribution of relative abundances of MVLA-types and its potential drivers. We explore four biologically plausible hypotheses regarding the processes driving molecular type relative abundances: sampling and speciation; structuring of the pathogen population; historical changes in population size; and transmission heterogeneity (superspreading). RESULTS: Northern Irish herd-level MVLA-type surveillance shows a right-skewed distribution of MVLA-types, with a small number of types present at very high frequencies and the majority of types very rare. We demonstrate that this skew is too extreme to be accounted for by simple neutral ecological processes. Simulation results indicate that the process of MVLA-type speciation and the manner in which the MVLA-typing loci were chosen in Northern Ireland cannot account for the observed skew. Similarly, we find that pathogen population structure, assuming for example a reservoir of infection in a separate host, would drive the relative abundance distribution in the opposite direction to that observed, generating more even abundances of molecular types. However, we find that historical increases in bovine tuberculosis prevalence and/or transmission heterogeneity (superspreading) are both capable of generating the skewed MVLA type distribution, consistent with findings of previous work examining the distribution of molecular types in human tuberculosis. CONCLUSION: Although the distribution of MVLA-type abundances does not fit classical neutral predictions, our simulations show that increases in pathogen population size and/or superspreading are consistent with the pattern observed, even in the absence of selective pressures acting on the system. PMID- 28830548 TI - Paradoxical worsening of hypoxemia in a patient treated by noninvasive positive pressure ventilation for obesity hypoventilation syndrome with concomitant obstructive sleep apnea: a case report. AB - BACKGROUND: Noninvasive positive pressure ventilation is frequently prescribed to obese patients with obstructive sleep apnea syndrome and obesity hypoventilation syndrome. However, mechanical ventilation with a positive end-expiratory pressure can induce or worsen a right-to-left shunt through a patent foramen ovale associated with systemic hypoxemia. Thus, in obese patients treated with noninvasive positive pressure ventilation, a paradoxical worsening of hypoxemia may reveal the existence of a patent foramen ovale. CASE PRESENTATION: A 50-year old African woman was referred to our sleep center for severe obstructive sleep apnea syndrome and obesity hypoventilation syndrome. Because she had alveolar hypoventilation and had failed previous obstructive sleep apnea syndrome therapy, noninvasive positive pressure ventilation was started. In May 2015, she had a normal residual apnea/hypopnea index calculated by the ventilator software with no hypoventilation. Six months later, severe hypoxemia without hypercapnia was noted. Contrast transthoracic echocardiography showed right-to-left shunt through a patent foramen ovale. This finding prompted a decrease in expiratory and inspiratory positive airway pressures, after which the ventilator software recorded a normal residual apnea/hypopnea index and the blood gas values improved. CONCLUSION: Noninvasive positive pressure ventilation therapy for combined obstructive sleep apnea syndrome and obesity hypoventilation syndrome must be monitored by arterial blood gas measurements, both to reassess the hypercapnia and to look for worsening hypoxemia due to a patent foramen ovale. PMID- 28830549 TI - Lactobacillus delivery of bioactive interleukin-22. AB - BACKGROUND: Interleukin-22 (IL-22) plays a prominent role in epithelial regeneration and dampening of chronic inflammatory responses by protecting intestinal stem cells from immune-mediated tissue damage. IL-22 has a considerable therapeutic potential in graft-versus-host disease (GVHD), which is a frequent and challenging complication following allogeneic stem cell transplantation. The aim of our study was to engineer Lactobacillus for delivery of IL-22 directly to the intestinal mucosa as a new therapeutic strategy for GVHD. RESULTS: The secretion and surface anchoring of mouse IL-22 by Lactobacillus paracasei BL23 was demonstrated by Western blot and flow cytometry. Both secreted and anchored mouse IL-22 produced by Lactobacillus was biologically active, as determined by its ability to induce IL-10 secretion in the Colo 205 human colon cancer cell line. CONCLUSIONS: We have demonstrated the secretion and surface anchoring of bioactive IL-22 by Lactobacillus. Our results suggest that IL-22 expressing lactobacilli may potentially be a useful mucosal therapeutic agent for the treatment of GVHD, provided that chromosomal integration of the IL 22 expression cassettes can be achieved. PMID- 28830550 TI - Detection and measurement of alpha-amylase in canine saliva and changes after an experimentally induced sympathetic activation. AB - BACKGROUND: Salivary alpha-amylase (sAA) is considered a biomarker of sympathetic activation in humans, but there is controversy regarding the existence of sAA in dogs. The hypothesis of this study was that sAA exists in dogs and it could change in situations of sympathetic stimulation. Therefore, the aims of this study were: 1) to demonstrate the presence of alpha-amylase in saliva of dogs by Western-Blot, 2) to validate an spectrophotometric method for the measurement of sAA activity and 3) to evaluate the possible changes in sAA activity after the induction of an ejaculation in dogs which is known to produce a sympathetic activation. RESULTS: Western-Blot demonstrated a band in dog saliva specimens between 60 kDa and 50 kDa, similar to purified sAA. The spectrophotometric assay validated showed an adequate inter- and intra-assay precision, and a high correlation coefficient (r = 0.999) in the linearity under dilution study. sAA median activity significantly increased just after ejaculation compared with just before the ejaculation (2.06-fold, P = 0.005). CONCLUSIONS: This study demonstrated the existence of alpha-amylase in saliva of dogs and that this enzyme can be measured by a spectrophotometric assay. In addition, results showed that sAA increase after a sympathetic activation and could be potentially used as non-invasive biomarker of sympathetic activity in this species. PMID- 28830551 TI - Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer. AB - BACKGROUND: Emerging studies show that long noncoding RNAs (lncRNAs) play important roles in carcinogenesis and cancer progression. The lncRNA ZEB1 antisense 1 (ZEB1-AS1) derives from the promoter region of ZEB1 and we still know little about its expressions, roles and mechanisms. METHODS: RACE was used to obtain the sequence of ZEB1-AS1. RNA interference was used to decrease ZEB1-AS1 expression. Adenovirus expression vector was used to increase ZEB1-AS1 expression. CHIP and RIP were used to detect the epigenetic mechanisms by which ZEB1-AS1 regulated ZEB1. CCK8 assay, wound healing assay and transwell assay were used to measure proliferation and migration of prostate cancer cells. RESULTS: In this study, in prostate cancer cells, we found that RNAi-mediated downregulation of ZEB1-AS1 induced significant ZEB1 inhibition while artificial overexpression of ZEB1-AS1 rescued ZEB1 expression, which means that ZEB1-AS1 promotes ZEB1 expression. Also, ZEB1-AS1 indirectly inhibited miR200c, the well-known target of ZEB1, and upregulated miR200c's target BMI1. Mechanistically, ZEB1-AS1 bound and recruited histone methyltransferase MLL1 to the promoter region of ZEB1, induced H3K4me3 modification therein, and activated ZEB1 transcription. Biologically, ZEB1-AS1 promoted proliferation and migration of prostate cancer cells. CONCLUSIONS: Collectively, ZEB1-AS1 functions as an oncogene in prostate cancer via epigenetically activating ZEB1 and indirectly regulating downstream molecules of ZEB1. PMID- 28830552 TI - Evaluation of cervical posture improvement of children with cerebral palsy after physical therapy based on head movements and serious games. AB - BACKGROUND: This paper presents the preliminary results of a novel rehabilitation therapy for cervical and trunk control of children with cerebral palsy (CP) based on serious videogames and physical exercise. MATERIALS: The therapy is based on the use of the ENLAZA Interface, a head mouse based on inertial technology that will be used to control a set of serious videogames with movements of the head. METHODS: Ten users with CP participated in the study. Whereas the control group (n = 5) followed traditional therapies, the experimental group (n = 5) complemented these therapies with a series of ten sessions of gaming with ENLAZA to exercise cervical flexion-extensions, rotations and inclinations in a controlled, engaging environment. RESULTS: The ten work sessions yielded improvements in head and trunk control that were higher in the experimental group for Visual Analogue Scale, Goal Attainment Scaling and Trunk Control Measurement Scale (TCMS). Significant differences (27% vs. 2% of percentage improvement) were found between the experimental and control groups for TCMS (p < 0.05). The kinematic assessment shows that there were some improvements in the active and the passive range of motion. However, no significant differences were found pre- and post-intervention. CONCLUSIONS: Physical therapy that combines serious games with traditional rehabilitation could allow children with CP to achieve larger function improvements in the trunk and cervical regions. However, given the limited scope of this trial (n = 10) additional studies are needed to corroborate this hypothesis. PMID- 28830553 TI - Immunogenicity of glycosylphosphatidylinositol-anchored micronemal antigen in natural Plasmodium vivax exposure. AB - BACKGROUND: Plasmodium vivax is the most geographically widespread malaria species and codominates with Plasmodium falciparum, the deadliest form of the malaria parasite. For the last few years, the number of vivax malaria cases has increased, but vivax malaria is still considered a neglected disease. During the blood stages of their life cycle, P. vivax parasites export several hundred proteins into host red blood cells. Some of these exported proteins have been discovered and studied for use as a blood-stage malaria vaccine. The P. vivax glycosylphosphatidylinositol (GPI)-anchored micronemal antigen (PvGAMA) was identified in previous study, which plays an important role in parasite invasion. To support the hypothesis that PvGAMA can induce an immune response in natural exposure, the antibody responses and cellular immunity against this antigen was demonstrated during and post-infection. METHODS: The recombinant protein PvGAMA was expressed and purified by wheat germ cell-free (WGCF) system. The analysis of humoral and cellular immune responses to the PvGAMA antigen during infection and post-infection with the P. vivax parasite were done by enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: During P. vivax infection, 95% of patients showed significant antibody responses to PvGAMA antigen. The cytophilic IgG1 and IgG3 isotypes were the major isotypes produced in response to PvGAMA. A cross-sectional study of anti-PvGAMA responses during and post infection with P. vivax found that the majority of individuals, approximately 54% of patients, were shown to maintain a positive anti-PvGAMA titre at 3 months post infection, and some patients had the ability to maintain an antibody response for up to 12 months post-infection. Moreover, PvGAMA had the ability to stimulate a cellular immune response that was characterized by the production of the cytokines IL-2, IFN-gamma and IL-10. The levels of the cytokines IFN-gamma and IL 10 were significantly increased in PvGAMA-stimulated lymphocyte cultures. CONCLUSIONS: Taken together, PvGAMA had potential to induce an immune response both humoral and cellular immunity in naturally acquired P. vivax infection individuals during infection and post-infection. Therefore, PvGAMA could be as a vaccine candidate to stimulate immune response against P. vivax infection. PMID- 28830554 TI - Extreme diversity and multiple SCCmec elements in coagulase-negative Staphylococcus found in the Clinic and Community in Beijing, China. AB - BACKGROUND: Coagulase-negative staphylococci (CoNS) are recognized as a large reservoir of staphylococcal cassette chromosome mec (SCCmec) harboured by Staphylococcus aureus. However, data of SCCmec in CoNS are relatively absent particularly in China. METHODS: Seventy-eight CoNS clinical and 47 community isolates were collected in Beijing. PCR was performed to classify SCCmec types. Under oxacillin treatment, quantitative real-time reverse transcription PCR (qRT PCR) was performed to compare mecA mRNA levels and mRNA half-life between isolates with single SCCmec element and those with multiple one. Their growth curves were analysed. Their bacterial cell wall integrity was also compared by performing a Gram stain. All ccr complex segments were sequenced and obtained ccr segments were analysed by phylogenetic analyses. RESULTS: All 78 clinical isolates had mecA segments compared with 38% in community isolates (total 47). Only 29% clinical isolates and 33% community isolates (among mecA positive isolates) harboured a single previously identified SCCmec type; notably, 17% clinical isolates and 28% community isolates had multiple SCCmec types. Further studies indicated that isolates with multiple SCCmec elements had more stable mecA mRNA expression compared with isolates with single SCCmec elements. CoNS with multiple SCCmec elements demonstrated superior cell wall integrity. Interestingly, phylogenetic analyses of obtained 70 ccr segments indicated that horizontal gene transfer of the ccr complex might exist among various species of clinical CoNS, community CoNS and S. aureus. CONCLUSIONS: CoNS recovered from patients carried extremely diverse but distinctive SCCmec elements compared with isolates from the community. More attention should be given to CoNS with multiple SCCmec not only because they had superior cell wall integrity, but also because CoNS and S. aureus might acquire multiple SCCmec through the ccr complex. PMID- 28830555 TI - Work-focused cognitive behavioral intervention for psychological complaints in patients on sick leave due to work-related stress: Results from a randomized controlled trial. AB - BACKGROUND: Work-related stress is a global problem with negative implications for individuals and society. The purpose of the current study was to evaluate a stress management intervention for patients on sick leave due to work-related stress complaints using a three-armed randomized controlled design. METHODS: Participants were patients referred from three municipalities to the regional Department of Occupational Medicine. Inclusion criteria were: 1) sick leave due to work-related stress complaints, 2) a diagnosis of adjustment disorder or reactions to severe stress (ICD 10 code: F43,2 - F 43,9 not PTSD) or mild depressive episode (F 32.0). Through a double randomization procedure patients (n = 163) were randomized to either an intervention group (n = 58), a 'control group A' receiving a clinical examination (n = 56), or 'control group B' (n = 49) receiving no offers at the department. The intervention comprised six sessions of individual cognitive behavioral therapy and the offer of a small workplace intervention. Questionnaire data were analyzed with multivariate repeated measurements analysis. Primary outcomes assessed were perceived stress and general mental health. Secondary outcomes were sleep quality and cognitive failures. Follow-up was at four and 10 months after baseline. RESULTS: Complaints were significantly reduced in all groups over time. No group effects were observed between the intervention group and control group A that was clinically assessed. Significant group effects were found for perceived stress and memory when comparing the intervention group to group B, but most likely not due to an intervention effect. CONCLUSION: Psychological complaints improved substantially over time in all groups, but there was no significant treatment effect on any outcomes when the intervention group was compared to control group A that received a clinical assessment. TRIAL REGISTRATION: ISRCTN ISRCTN91404229. Registered 03 August 2012 (retrospectively registered). PMID- 28830556 TI - Transmission and characterization of bla NDM-1 in Enterobacter cloacae at a teaching hospital in Yunnan, China. AB - BACKGROUND: In recent years, New Delhi metallo-beta-lactamases 1 (bla NDM-1) has been reported with increasing frequency and become prevalent. The present study was undertaken to investigate the epidemiological dissemination of the bla NDM-1 gene in Enterobacter cloacae isolates at a teaching hospital in Yunnan, China. METHODS: Antimicrobial susceptibility testing was performed using VITEK 2 system and E test gradient strips. The presence of integrons and insertion sequence common region 1 were examined by PCR and sequencing. Clonal relatedness was assessed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Conjugation experiments and Southern blot hybridization were performed to determine the transferability of plasmids. RESULTS: Ten E. cloacae isolates and their Escherichia coli transconjugants were exhibited similar resistant patterns to carbapenems, cephalosporins and penicillins. 8 (80%) of E. cloacae isolates carried class 1 integron and 1 (12.5%) carried class 2 integron. Integron variable regions harbored the genes which encoded resistance to aminoglycosides (aadA1, aadA2, aadA5, aadB, aac(6')-Ib-cr), sulfamethoxazole/trimethoprim (dfrA17, dfrA12, dfrA15) and Streptozotocin (sat2). Six E. cloacae isolates belonged to ST74 and exhibited highly similar PFGE patterns. Each isolate shared an identical plasmid with ~33.3 kb size that carried the bla NDM-1 gene, except T3 strain, of which the bla NDM-1 gene was located on a ~50 kb plasmid. CONCLUSIONS: Our findings suggested that plasmid was able to contribute to the dissemination of bla NDM-1. Hence, more attention should be devoted to monitor the dissemination of the bla NDM-1 gene due to its horizontal transfer via plasmid. In addition, nosocomial surveillance system should actively monitor the potential endemic clone of ST74 to prevent their further spread. PMID- 28830557 TI - Membrane-anchored CCL20 augments HIV Env-specific mucosal immune responses. AB - BACKGROUND: Induction of broad immune responses at mucosal site remains a primary goal for most vaccines against mucosal pathogens. Abundance of evidence indicates that the co-delivery of mucosal adjuvants, including cytokines, is necessary to induce effective mucosal immunity. In the present study, we set out to evaluate the role of a chemokine, CCL20, as an effective mucosal adjuvant for HIV vaccine. METHODS: To evaluate the role of CCL20 as a potent adjuvant for HIV vaccine, we examined its effects on antigen-specific antibody responses, level of antibody secreting cells, cytokine production and intestinal homing of plasma cells in vaccine immunized mice. RESULTS: CCL20-incorporated VLP administered by mucosal route (intranasal (n = 10, p = 0.0085) or intravaginal (n = 10, p = 0.0091)) showed much higher potency in inducing Env-specific IgA antibody response than those administered by intramuscular route (n = 10). For intranasal administration, the HIV Env-specific IFN-gamma(751 pg/ml), IL-4 (566 pg/ml), IL-5 (811 pg/ml) production and IgA-secreting plasma cells (62 IgA-secreting plasma cells/106 cells) in mucosal lamina propria were significantly augmented in CCL20 incorporated VLP immunized mice as compared to those immunized with Env only VLPs (p = 0.0332, 0.0398, 0.033, 0.0302 for IFN-gamma, IL-4, IL-5, and IgA-secreting plasma cells, respectively). Further, anti-CCL20 mAb partially suppressed homing of Env-specific IgA ASCs into small intestine in mice immunized with CCL20 incorporated VLP by intranasal (62 decreased to 16 IgA- secreting plasma cells/106 cells, p = 0.0341) or intravaginal (52 decreased to 13 IgA- secreting plasma cells/106 cells, p = 0.0332) routes. CONCLUSION: Our data indicated that the VLP-incorporated CCL20 can enhance HIV Env-specific immune responses in mice, especially those occurring in the mucosal sites. We also found that i.m. prime followed by mucosal boost is critical and required for CCL20 to exert its full function as an effective mucosal adjuvant. Therefore, co-incorporation of CCL20 into Env VLPs when combined with mucosal administration could represent a novel and promising HIV vaccine candidate. PMID- 28830559 TI - Erratum to: A study protocol for facility assessment and follow-up evaluations of the barriers to access, availability, utilization and readiness of contraception, abortion and postabortion services in Zika affected areas. PMID- 28830558 TI - Identification of a homogenous structural basis for oligomerization by retroviral Rev-like proteins. AB - BACKGROUND: Rev-like proteins are post-transcriptional regulatory proteins found in several retrovirus genera, including lentiviruses, betaretroviruses, and deltaretroviruses. These essential proteins mediate the nuclear export of incompletely spliced viral RNA, and act by tethering viral pre-mRNA to the host CRM1 nuclear export machinery. Although all Rev-like proteins are functionally homologous, they share less than 30% sequence identity. In the present study, we computationally assessed the extent of structural homology among retroviral Rev like proteins within a phylogenetic framework. RESULTS: We undertook a comprehensive analysis of overall protein domain architecture and predicted secondary structural features for representative members of the Rev-like family of proteins. Similar patterns of alpha-helical domains were identified for Rev like proteins within each genus, with the exception of deltaretroviruses, which were devoid of alpha-helices. Coiled-coil oligomerization motifs were also identified for most Rev-like proteins, with the notable exceptions of HIV-1, the deltaretroviruses, and some small ruminant lentiviruses. In Rev proteins of primate lentiviruses, the presence of predicted coiled-coil motifs segregated within specific primate lineages: HIV-1 descended from SIVs that lacked predicted coiled-coils in Rev whereas HIV-2 descended from SIVs that contained predicted coiled-coils in Rev. Phylogenetic ancestral reconstruction of coiled-coils for all Rev-like proteins predicted a single origin for the coiled-coil motif, followed by three losses of the predicted signal. The absence of a coiled-coil signal in HIV-1 was associated with replacement of canonical polar residues with non-canonical hydrophobic residues. However, hydrophobic residues were retained in the key 'a' and 'd' positions, and the alpha-helical region of HIV-1 Rev oligomerization domain could be modeled as a helical wheel with two predicted interaction interfaces. Moreover, the predicted interfaces mapped to the dimerization and oligomerization interfaces in HIV-1 Rev crystal structures. Helical wheel projections of other retroviral Rev-like proteins, including endogenous sequences, revealed similar interaction interfaces that could mediate oligomerization. CONCLUSIONS: Sequence-based computational analyses of Rev-like proteins, together with helical wheel projections of oligomerization domains, reveal a conserved homogeneous structural basis for oligomerization by retroviral Rev-like proteins. PMID- 28830560 TI - In vitro aggregating beta-lactamase-polyQ chimeras do not induce toxic effects in an in vivo Caenorhabditis elegans model. AB - BACKGROUND: A series of human diseases are caused by the misfolding and aggregation of specific proteins or peptides into amyloid fibrils; nine of these diseases, referred to as polyglutamine diseases, are associated with proteins carrying an expanded polyglutamine (polyQ) region. While the presence of this latter is thought to be the determinant factor for the development of polyQ diseases, the non-polyQ regions of the host proteins are thought to play a significant modulating role. METHOD: In order to better understand the role of non-polyQ regions, the toxic effects of model proteins bearing different polyQ regions (containing up to 79 residues) embedded at two distinct locations within the beta-lactamase (BlaP) host enzyme were evaluated in Caenorhabditis elegans. This small organism can be advantageous for the validation of in vitro findings, as it provides a multicellular context yet avoids the typical complexity of common studies relying on vertebrate models. Several phenotypic assays were performed in order to screen for potential toxic effects of the different BlaP polyQ proteins. RESULTS: Despite the significant in vitro aggregation of BlaP polyQ proteins with long polyQ regions, none of the BlaP-polyQ chimeras aggregated in the generated transgenic in vivo models. CONCLUSION: The absence of a toxic effect of the expression of BlaP-polyQ chimeras may find its cause in biochemical mechanisms present in vivo to cope with protein aggregation (e.g. presence of chaperones) or in C. elegans' limitations such as its short lifespan. It is plausible that the aggregation propensities of the different BlaP chimeras containing embedded polyQ sequences are too low in this in vivo environment to permit their aggregation. These experiments emphasize the need for several comparative and in vivo verification studies of biologically relevant in vitro findings, which reveal both the strengths and limitations of widely used model systems. PMID- 28830562 TI - Ciliated muconodular papillary tumors of the lung with KRAS/BRAF/AKT1 mutation. AB - BACKGROUND: Ciliated muconodular papillary tumors (CMPTs) are newly recognized rare peripheral lung nodules that are histologically characterized by ciliated columnar, goblet, and basal cells. Although recent studies have shown that CMPTs constitute a neoplastic disease, the complete histogenesis of CMPTs is not fully understood and molecular data are limited. METHODS: We reviewed four cases of CMPT and performed immunohistochemical and genomic analyses to establish CMPT profiles. RESULTS: All cases were positive for hepatocyte nuclear factor-4alpha and mucin 5B and negative for programmed death ligand 1 expression, as determined by immunohistochemistry. The genetic analysis revealed three pathogenic mutations (BRAF V600E, AKT1 E17K, and KRAS G12D), with the KRAS mutation reported here for the first time. CONCLUSION: Histological and genetic profiles indicate that CMPTs are likely neoplastic and exhibit features similar to mucinous adenocarcinoma. This suggests that some CMPTs may be a precursor lesion of mucinous adenocarcinoma. PMID- 28830561 TI - Altered chromatin compaction and histone methylation drive non-additive gene expression in an interspecific Arabidopsis hybrid. AB - BACKGROUND: The merging of two diverged genomes can result in hybrid offspring that phenotypically differ greatly from both parents. In plants, interspecific hybridization plays important roles in evolution and speciation. In addition, many agricultural and horticultural species are derived from interspecific hybridization. However, the detailed mechanisms responsible for non-additive phenotypic novelty in hybrids remain elusive. RESULTS: In an interspecific hybrid between Arabidopsis thaliana and A. lyrata, the vast majority of genes that become upregulated or downregulated relative to the parents originate from A. thaliana. Among all differentially expressed A. thaliana genes, the majority is downregulated in the hybrid. To understand why parental origin affects gene expression in this system, we compare chromatin packing patterns and epigenomic landscapes in the hybrid and parents. We find that the chromatin of A. thaliana, but not that of A. lyrata, becomes more compact in the hybrid. Parental patterns of DNA methylation and H3K27me3 deposition are mostly unaltered in the hybrid, with the exception of higher CHH DNA methylation in transposon-rich regions. However, A. thaliana genes enriched for the H3K27me3 mark are particularly likely to differ in expression between the hybrid and parent. CONCLUSIONS: It has long been suspected that genome-scale properties cause the differential responses of genes from one or the other parent to hybridization. Our work links global chromatin compactness and H3K27me3 histone modification to global differences in gene expression in an interspecific Arabidopsis hybrid. PMID- 28830563 TI - ORF1a of highly pathogenic PRRS attenuated vaccine virus plays a key role in neutralizing antibody induction in piglets and virus neutralization in vitro. AB - BACKGROUND: Currently, porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important viral pathogens in swine in most countries, especially China. Two PRRSV attenuated live vaccine strains (HuN4 F112 and CH-1R) are currently widely used in China. Our previous study showed that HuN4-F112, but not CH-1R, induced high anti-nucleocapsid (N) antibody and neutralizing antibody (NA) titers. Additionally, sera from HuN4-F112 inoculated pigs induced low cross neutralization of CH-1R. METHODS: In the present study, 6 chimeric viruses through exchanging 5' untranslated region (UTR) + open reading frame (ORF)1a, ORF1b, and ORF2-7 + 3'UTR between HuN4-F112 and CH-1R were constructed and rescued based on the infectious clones of rHuN4-F112 and rCH-1R. The characteristics of these viruses were investigated in vitro and vivo. RESULTS: All the three fragments, 5'UTR + ORF1a, ORF1b, and ORF2-7 + 3'UTR, could affect the replication efficiencies of rHuN4-F112 and rCH-1R in vitro. Additionally, both 5'UTR + ORF1a and ORF2-7 + 3'UTR affected the anti-N antibody and NA responses targeting rHuN4-F112 and rCH-1R in piglets. CONCLUSIONS: The 5'UTR + ORF1a region of HuN4-F112 played a key role in inducing NAs in piglets. Furthermore, we confirmed for the first time that ORF1a contains a neutralization region. This study provides important information that can be used for further study of the generation of anti-PRRSV NAs. PMID- 28830564 TI - Availability of healthcare resources and epithelial ovarian cancer stage of diagnosis and mortality among Blacks and Whites. AB - BACKGROUND: The purpose of this study is to examine whether racial disparities in epithelial ovarian cancer stage at diagnosis and survival may be explained by geographic availability of healthcare resources among Blacks and Whites. METHODS: Data from the Surveillance, Epidemiology and End Results (SEER) database was used to identify White and Black women ages 40 years and above diagnosed with epithelial ovarian cancer between 2000 and 2010. Data on county-level availability of healthcare resources was obtained from the Area Resource File. Multi-level regression models, overall and stratified by race and age, were used to examine the associations of health care access (HCA) and socioeconomic status (SES) with stage at diagnosis while Cox proportional hazards models were used to examine the association with survival. RESULTS: Among 46,423 women diagnosed with epithelial ovarian cancer, Blacks were more likely to reside in counties with fewer average number of oncology hospitals (p < 0.05) and hospitals with ultrasound (p < 0.001), but higher number of medical doctors (p < 0.0001) and Ob/Gyn (p < 0.001). Black patients had higher odds of late stage diagnosis of epithelial ovarian cancer (OR: 1.13, 95% CI: 1.04-1.25) and higher risk of epithelial ovarian cancer mortality (HR: 1.25, 95% CI: 1.19-1.32) compared with White patients after accounting for differential availability of healthcare resources. Among Black patients, residing in counties with fewer medical doctors was associated with increased odds of late stage diagnosis (OR: 1.86, 95% CI: 1.10-3.13), and the racial disparity in late stage diagnosis and mortality was larger among patients ages <65 years compared with older patients. CONCLUSION: Racial disparities in availability and utilization of healthcare resources likely contributes to adverse epithelial ovarian cancer outcomes among Black women in the US. PMID- 28830565 TI - Determinants of follow-up care associated with incident antidepressant use in older adults. AB - OBJECTIVES: To determine the proportion of older adults receiving guideline concordant antidepressant therapy and to determine patient, prescriber and organizational factors associated with adequate antidepressant therapy. METHODS: The study included secondary analyses of data collected in the Etude sur la Sante des Aines (ESA) Services study on older adults recruited while consulting in primary care clinics in one of the largest health regions of the province of Quebec. Antidepressant users (n = 349) were identified from information collected from the Regie de l'Assurance Maladie du Quebec (RAMQ) pharmaceutical database which holds information on all drugs dispensed to all residents covered under the public drug plan. Adequacy of antidepressant treatment was measured using three criteria: adequacy of daily dose; length of prescription (>=455 days); and >=3 visits to the antidepressant-prescribing physician in the first 3 months after initiation of therapy. Multivariate logistic regression analyses were used to study antidepressant treatment adequacy as a function of individual, provider and healthcare system factors. RESULTS: Among the antidepressant users, 44% received an adequate antidepressant treatment filling all three criteria. None of the factors studied were associated with the probability of receiving adequate treatment filling all three criteria. Psychological distress was associated with having an adequate number of visits in the 3 months following initiation. Males and those living in a metropolitan and urban area were less likely to receive an adequate dose. CONCLUSIONS: Future research should consider factors associated with perceived effectiveness and patient treatment preferences that may explain receipt of adequate antidepressant treatment in older adults. PMID- 28830566 TI - The ninth ENBDC Weggis meeting: growth and in-depth characterisation of normal and neoplastic breast cells. AB - Mammary gland biologists gathered for the ninth annual workshop of the European Network for Breast Development and Cancer (ENBDC) at Weggis on the shores of Lake Lucerne in March 2017. The main themes were oestrogen receptor alpha signalling, new techniques for mammary cell culture, CRISPR screening and proteogenomics. PMID- 28830567 TI - Usefulness of a topical combination of dinotefuran and pyriproxyfen for long-term control of clinical signs of allergic dermatitis in privately-owned cats in Ile de-France region. AB - BACKGROUND: The present study assessed the activity of a combination of dinotefuran and pyriproxyfen (Vectra(r) Felis) for long-term control (3 months) of allergic dermatitis (AD) in privately-owned cats under common household conditions in Ile-de-France region. METHODS: This was an open pre-treatment vs post-treatment study. Twenty-eight client-owned cats with clinical signs of AD were enrolled in the study. They received topical application of the combination of dinotefuran and pyriproxyfen on days 0, 28, 56 and 84. Two parameters (clinical signs and pruritus severity) were used to assess the animals' condition on days 0, 28 and 84. Fleas were counted if they were observed. RESULTS: Of the 28 cats initially enrolled, 26 were presented on day 28 and 20 for the final evaluation on day 84. A significant improvement in clinical signs and pruritus was observed in cats for which fleas and/or flea feces were detected on day 0. Globally, the post-treatment AD clinical scores on days 28 and 84 were different from that of the pre-treatment on day 0, with a reduction of 30% and 71%, respectively. For cats with fleas and/or flea feces, the reduction on days 28 and 84 was 33% and 85%, respectively. The improvement of clinical signs and pruritus was not significant in cats with no visible fleas and no flea feces at the beginning of the trial (n = 8). CONCLUSIONS: The present study indicated that the treatment with a combination of dinotefuran and pyriproxyfen should be considered as useful in controlling fleas on cats without additional environmental treatment and useful for long-term control of clinical signs and pruritus in allergic cats. PMID- 28830568 TI - Increasing the provision of preventive care by community healthcare services: a stepped wedge implementation trial. AB - BACKGROUND: Although clinical guidelines recommend the provision of care to reduce client chronic disease risk behaviours, such care is provided sub optimally by primary healthcare providers. A study was undertaken to determine the effectiveness of an intervention in increasing community-based clinician implementation of multiple elements of recommended preventive care for four risk behaviours. METHODS: A three-group stepped-wedge trial was undertaken with all 56 community-based primary healthcare facilities in one health district in New South Wales, Australia. A 12-month implementation intervention was delivered sequentially in each of three geographically and administratively defined groups of facilities. The intervention consisted of six key strategies: leadership and consensus processes, enabling systems, educational meetings and training, audit and feedback, practice change support, and practice change information and resources. Client-reported receipt of three elements of preventive care: assessment; brief advice; referral for four behavioural risks: smoking, inadequate fruit and/or vegetable consumption, alcohol overconsumption, and physical inactivity, individually, and for all such risks combined were collected for 56 months (October 2009-May 2014). Segmented logistic regression models were developed to assess intervention effectiveness. RESULTS: A total of 5369 clients participated in data collection. Significant increases were found for receipt of four of five assessment outcomes (smoking OR 1.53; fruit and/or vegetable intake OR 2.18; alcohol consumption OR 1.69; all risks combined OR 1.78) and two of five brief advice outcomes (fruit and/or vegetable intake OR 2.05 and alcohol consumption OR 2.64). No significant increases in care delivery were observed for referral for any risk behaviour, or for physical inactivity. CONCLUSIONS: The implementation intervention was effective in enhancing assessment of client risk status but less so for elements of care that could reduce client risk: provision of brief advice and referral. The intervention was ineffective in increasing care addressing physical inactivity. Further research is required to identify barriers to the provision of preventive care and the effectiveness of practice change interventions in increasing its provision. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12611001284954 . Registered 15 December 2011. Retrospectively registered. PMID- 28830569 TI - Comparative study on the nocturnal activity of phlebotomine sand flies in a highland and lowland foci of visceral leishmaniasis in north-western Ethiopia with special reference to Phlebotomus orientalis. AB - BACKGROUND: Leishmania donovani, the causative agent of visceral leishmaniasis (VL), is most probably vectored by Phlebotomus orientalis in north-western Ethiopia. The aim of this study was to determine and compare the nocturnal activity patterns of Ph. orientalis in VL endemic foci of Libo-Kemkem (highland) and Metema (lowland) districts of north-western Ethiopia. METHODS: Sampling of sand flies was conducted bimonthly from January-May 2012 in the highland and from March-June 2013 in the lowland. Sand flies were sampled using two CDC light traps placed in compounds occupied by both cattle and humans. Sampling of sand flies started at 18:00 h and ended at 06:00 h. Every hour, a cage was replaced by another cage. RESULTS: In total, 9479 nocturnally active sand flies were collected from both study areas. Six Phlebotomus species (Ph. orientalis, Ph. duboscqi, Ph. papatasi, Ph. bergeroti, Ph. rodhaini and Ph. martini) and several Sergentomyia spp. were identified. In both areas, of the six Phlebotomus spp., Ph. orientalis was the preponderate. In the highland, the hourly activity pattern of Ph. orientalis females was higher before midnight with a peak in density between 22:00-23:00 h, whereas in the lowland after midnight between 03:00-04:00 h. CONCLUSIONS: The present study showed that Ph. orientalis females exhibited different nocturnal activity patterns with a peak in the early part of the night in the highland and in the latter part of the night in the lowland areas. As the risk of acquiring L. donovani infections vary in the two areas, appropriate control strategies should be developed according to the activity of Ph. orientalis in the respective areas. PMID- 28830570 TI - Identifying additional studies for a systematic review of retention strategies in randomised controlled trials: making contact with trials units and trial methodologists. AB - BACKGROUND: Search strategies for systematic reviews aim to identify all evidence relevant to the research question posed. Reports of methodological research can be difficult to find leading to biased results in systematic reviews of research methodology. Evidence suggests that contact with investigators can help to identify unpublished research. To identify additional eligible randomised controlled trials (RCTs) for a Cochrane systematic review of strategies to improve retention in RCTs, we conducted a survey of UK clinical trials units (CTUs) and made contact with RCT methodologists. METHODS: Key contacts for all UK CTUs were sent a personalised email with a short questionnaire and summary protocol of the Cochrane methodology review. The questionnaire asked whether a RCT evaluating strategies to improve retention embedded in a RCT had ever been conducted by the CTU. Questions about the stage of completion and publication of such RCTs were included. The summary protocol outlined the aims, eligibility criteria, examples of types of retention strategies, and the primary outcome for the systematic review. Personal communication with RCT methodologists and presentations of preliminary results of the review at conferences were also used to identify additional eligible RCTs. We checked the results of our standard searches to see if eligible studies identified through these additional methods were also found using our standard searches. RESULTS: We identified 14 of the 38 RCTs included in the Cochrane methodology review by contacting trials units and methodologists. Eleven of the 14 RCTs identified by these methods were either published in grey literature, in press or unpublished. Three remaining RCTs were fully published at the time. Six of the RCTs identified were not found through any other searches. The RCTs identified represented data for 6 of 14 RCTs of incentive strategies (52% of randomised participants included in the review), and 6 of 14 RCTs of communication strategies (52% of randomised participants included in the Cochrane review). Data were unavailable for two of the RCTs identified. CONCLUSIONS: Methodological evaluations embedded in RCTs may be unpublished, published in the grey literature or where published, poorly indexed in bibliographic databases. To identify such studies and minimise selection bias in systematic reviews of methodological evaluations, reviewers should consider contacting CTUs and trial methodologists. PMID- 28830571 TI - Anti-HERV-K (HML-2) capsid antibody responses in HIV elite controllers. AB - BACKGROUND: Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and while the majority are transcriptionally silent, the most recently integrated HERV, HERV-K (HML-2), remains active. During HIV infection, HERV-K (HML-2) specific mRNA transcripts and viral proteins can be detected. In this study, we aimed to understand the antibody response against HERV-K (HML-2) Gag in the context of HIV-1 infection. RESULTS: We developed an ELISA assay using either recombinant protein or 164 redundant "15mer" HERV-K (HML-2) Gag peptides to test sera for antibody reactivity. We identified a total of eight potential HERV-K (HML-2) Gag immunogenic domains: two on the matrix (peptides 16 and 31), one on p15 (peptide 85), three on the capsid (peptides 81, 97 and 117), one on the nucleocapsid (peptide 137) and one on the QP1 protein (peptide 157). Four epitopes (peptides 16, 31, 85 and 137) were highly immunogenic. No significant differences in antibody responses were found between HIV infected participants (n = 40) and uninfected donors (n = 40) for 6 out of the 8 epitopes tested. The antibody response against nucleocapsid (peptide 137) was significantly lower (p < 0.001), and the response to QP1 (peptide 157) significantly higher (p < 0.05) in HIV-infected adults compared to uninfected individuals. Among those with HIV infection, the level of response against p15 protein (peptide 85) was significantly lower in untreated individuals controlling HIV ("elite" controllers) compared to untreated non-controllers (p < 0.05) and uninfected donors (p < 0.05). In contrast, the response against the capsid protein (epitopes 81 and 117) was significantly higher in controllers compared to uninfected donors (p < 0.001 and <0.05 respectively) and non-controllers (p < 0.01 and <0.05). Peripheral blood mononuclear cells (PBMCs) from study participants were tested for responses against HERV-K (HML-2) capsid recombinant peptide in gamma interferon (IFN-gamma) enzyme immunospot (Elispot) assays. We found that the HERV K (HML-2) Gag antibody and T cell response by Elispot were significantly correlated. CONCLUSIONS: HIV elite controllers had a strong cellular and antibody response against HERV-K (HML-2) Gag directed mainly against the Capsid region. Collectively, these data suggest that anti-HERV-K (HML-2) antibodies targeting capsid could have an immunoprotective effect in HIV infection. PMID- 28830572 TI - The influence of contextual factors on healthcare quality improvement initiatives: what works, for whom and in what setting? Protocol for a realist review. AB - BACKGROUND: Context shapes the effectiveness of knowledge implementation and influences health improvement. Successful healthcare quality improvement (QI) initiatives frequently fail to transfer to different settings, with local contextual factors often cited as the cause. Understanding and overcoming contextual barriers is therefore crucial to implementing effective improvement; yet context is still poorly understood. There is a paucity of information on the mechanisms underlying how and why QI projects succeed or fail in given settings. A realist review of empirical studies of healthcare QI initiatives will be undertaken to examine the influence and impact of contextual factors on quality improvement in healthcare settings and explore whether QI initiatives can work in all contexts. METHODS: The review will explore which contextual factors are important, and how, why, when and for whom they are important, within varied settings. The dynamic nature of context and change over time will be explored by examining which aspects of context impact at key points in the improvement trajectory. The review will also consider the influence of context on improvement outcomes (provider- and patient-level), spread and sustainability. The review process will follow five iterative steps: (1) clarify scope, (2) search for evidence, (3) appraise primary studies and extract data, (4) synthesise evidence and draw conclusions and (5) disseminate findings. The reviewers will consult with experts and stakeholders in the early stages to focus the review and develop a programme theory consisting of explanatory 'context-mechanism-outcome' configurations. Searches for primary evidence will be conducted iteratively. Data will be extracted and tested against the programme theory. A review advisory group will oversee the review process. Review findings will follow RAMESES guidelines and will be disseminated via a report, presentations and peer-reviewed publications. DISCUSSION: The review will update and consolidate evidence on the contextual conditions for effective improvement and distil new knowledge to inform the design and development of context-sensitive QI initiatives. This review ties in with the study of improvement programmes as vehicles of change and the development of an evidence base around healthcare improvement by addressing whether QI initiatives can work in all contexts. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017062135. PMID- 28830574 TI - The nature and efficacy of culturally-adapted psychosocial interventions for schizophrenia: a systematic review and meta-analysis. AB - BACKGROUND: Evidence-based psychosocial treatments for schizophrenia founded on Western belief systems and values may not be efficacious in different cultures without adaptation. This systematic review analyses the nature and outcomes of culturally-adapted psychosocial interventions in schizophrenia, examining how interventions have been adapted, their efficacy and what features drive heterogeneity in outcome. METHOD: Articles identified by searching electronic databases from inception to 3 March 2016, reference lists and previous reviews were independently screened by two authors for eligible controlled trials. Data on the nature of adaptations was analysed inductively using thematic analyses. Meta-analyses were conducted using random effects models to calculate effect sizes (Hedges' g) for symptoms. RESULTS: Forty-six studies with 7828 participants were included, seven adapted for minority populations. Cultural adaptations were grouped into nine themes: language, concepts and illness models, family, communication, content, cultural norms and practices, context and delivery, therapeutic alliance, and treatment goals. Meta-analyses showed significant post treatment effects in favour of adapted interventions for total symptom severity (n = 2345, g: -0.23, 95% confidence interval (CI) -0.36 to -0.09), positive (n = 1152, g: -0.56, 95% CI -0.86 to -0.26), negative (n = 855, g: -0.39, 95% CI -0.63 to -0.15), and general (n = 525, g: -0.75, CI -1.21 to -0.29) symptoms. CONCLUSIONS: The adaptation process can be described within a framework that serves as a benchmark for development or assessment of future adaptations. Culturally adapted interventions were more efficacious than usual treatment in proportion to the degree of adaptation. There is insufficient evidence to show that adapted interventions are better than non-adapted interventions. Features of context, intervention and design influenced efficacy. Investigating whether adaptation improves efficacy, most importantly amongst ethnic minorities, requires better designed trials with comparisons against unadapted interventions. PMID- 28830575 TI - A cross-sectional study of acute diarrhea in Pudong, Shanghai, China: prevalence, risk factors, and healthcare-seeking practices. AB - Diarrhea is a common cause of morbidity and mortality and the incidence of diarrhea in the world has changed little over the past four decades. To assess the prevalence of and healthcare practices for diarrhea, a cross-sectional study was conducted in Pudong, Shanghai, China. In October 2014, a total of 5324 community residents were interviewed. Respondents were asked if they had experienced diarrhea (defined as ?3 passages of watery, loose, bloody, or mucoid stools within a 24-h period) in the previous month prior to the interview. The monthly prevalence of diarrhea was 4.1% (95% CI: 3.3-4.8), corresponding to an incidence rate of 0.54 episodes per person-year. The proportion of individuals with diarrhea who sought healthcare was 21.2% (95% CI: 13.4-29.0). Diarrhea continues to impose a considerable burden on the community and healthcare system in Pudong. Young age and travel were identified as predictors of increased diarrhea occurrence. PMID- 28830576 TI - Role of Demographic and Clinical Factors in Cognitive Functioning of Persons with Relapsing-Remitting and Progressive Multiple Sclerosis. AB - BACKGROUND: Age and time post-diagnosis can significantly impact cognitive and motor functions in multiple sclerosis (MS); however, studies often fail to account for these factors when assessing differences between disease courses. OBJECTIVES: Examine differences between relapsing-remitting and progressive MS in cognition, motor function, and everyday activities, controlling for age, education, and time post-diagnosis. METHODS: Twenty-one persons with relapsing remitting MS (RRMS group), 21 with progressive MS (PMS group), and 21 healthy participants (HCs), matched on age, education, and time post-diagnosis, completed tests of cognitive abilities, motor functions, and everyday functional activities. RESULTS: The two groups with MS did not differ on cognitive performance. Poorer performance in processing speed was noted in both MS groups in comparison with the HC group. Motor function was worse for the PMS group compared with the HC and RRMS groups. The RRMS group showed poorer upper limb functioning compared to the HC group. The PMS group had more difficulty with everyday activities as compared with both the RRMS and HC group. CONCLUSIONS: When comparing differences in functioning between MS disease courses, attention should be paid to the demographic characteristics of the samples. (JINS, 2018, 24, 139-146). PMID- 28830573 TI - Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes. AB - BACKGROUND: Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer. METHODS: A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS. RESULTS: The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1-97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival. CONCLUSIONS: In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients' outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis. TRIAL REGISTRATION: PHARE cohort: NCT00381901 , Sept. 26, 2006 - SIGNAL cohort: INCa RECF1098, Jan. 28, 2009. PMID- 28830577 TI - Optimization of Glioblastoma Mouse Orthotopic Xenograft Models for Translational Research. AB - Glioblastoma is an aggressive primary brain tumor predominantly localized to the cerebral cortex. We developed a panel of patient-derived mouse orthotopic xenografts (PDOX) for preclinical drug studies by implanting cancer stem cells (CSC) cultured from fresh surgical specimens intracranially into 8-wk-old female athymic nude mice. Here we optimize the glioblastoma PDOX model by assessing the effect of implantation location on tumor growth, survival, and histologic characteristics. To trace the distribution of intracranial injections, toluidine blue dye was injected at 4 locations with defined mediolateral, anterioposterior, and dorsoventral coordinates within the cerebral cortex. Glioblastoma CSC from 4 patients and a glioblastoma nonstem-cell line were then implanted by using the same coordinates for evaluation of tumor location, growth rate, and morphologic and histologic features. Dye injections into one of the defined locations resulted in dye dissemination throughout the ventricles, whereas tumor cell implantation at the same location resulted in a much higher percentage of small multifocal ventricular tumors than did the other 3 locations tested. Ventricular tumors were associated with a lower tumor growth rate, as measured by in vivo bioluminescence imaging, and decreased survival in 4 of 5 cell lines. In addition, tissue oxygenation, vasculature, and the expression of astrocytic markers were altered in ventricular tumors compared with nonventricular tumors. Based on this information, we identified an optimal implantation location that avoided the ventricles and favored cortical tumor growth. To assess the effects of stress from oral drug administration, mice that underwent daily gavage were compared with stress-positive and -negative control groups. Oral gavage procedures did not significantly affect the survival of the implanted mice or physiologic measurements of stress. Our findings document the importance of optimization of the implantation site for preclinical mouse models of glioblastoma. PMID- 28830578 TI - Characterization of Demodex musculi Infestation, Associated Comorbidities, and Topographic Distribution in a Mouse Strain with Defective Adaptive Immunity. AB - A colony of B6.Cg-Rag1tm1Mom Tyrp1B-w Tg(Tcra,Tcrb)9Rest (TRP1/TCR) mice presented with ocular lesions and ulcerative dermatitis. Histopathology, skin scrapes, and fur plucks confirmed the presence of Demodex spp. in all clinically affected and subclinical TRP1/TCR mice examined (n = 48). Pasteurella pneumotropica and Corynebacterium bovis, both opportunistic pathogens, were cultured from the ocular lesions and skin, respectively, and bacteria were observed microscopically in abscesses at various anatomic locations (including retroorbital sites, tympanic bullae, lymph nodes, and reproductive organs) as well as the affected epidermis. The mites were identified as Demodex musculi using the skin fragment digestion technique. Topographic analysis of the skin revealed mites in almost all areas of densely haired skin, indicating a generalized demodecosis. The percentage of infested follicles in 8- to 10-wk-old mice ranged from 0% to 21%, and the number of mites per millimeter of skin ranged from 0 to 3.7. The head, interscapular region, and middorsum had the highest proportions of infested follicles, ranging from 2.3% to 21.1% (median, 4.9%), 2.0% to 16.6% (8.1%), and 0% to 17% (7.6%), respectively. The pinnae and tail skin had few or no mites, with the proportion of follicles infested ranging from 0% to 3.3% (0%) and 0% to 1.4% (0%), respectively. The number of mites per millimeter was strongly correlated with the percentage of infested follicles. After administration of amoxicillin-impregnated feed (0.12%), suppurative infections were eliminated, and the incidence of ulcerative dermatitis was dramatically reduced. We hypothesize that the Rag1-null component of the genotype makes TRP1/TCR mice susceptible to various opportunistic infestations and infections, including Demodex mites, P. pneumotropica, and C. bovis. Therefore, Rag1-null mice may serve as a useful model to study human and canine demodecosis. D. musculi should be ruled out as a contributing factor in immunocompromised mouse strains with dermatologic manifestations. PMID- 28830579 TI - Use of Microcomputed Tomography to Measure the Relaxin-induced Expansion of Intrapubic Ligaments in Mice. AB - Relaxin is a 6-kDa peptide in the insulin superfamily of hormones. In addition to its effects on reproductive and musculoskeletal ligaments, relaxin has demonstrated beneficial effects on cardiac, renal, and vascular systems in preclinical models. The mouse intrapubic ligament ex vivo bioassay is the current standard for measuring in vivo relaxin bioactivity. However, this bioassay necessitates euthanasia and dissection of large cohorts to measure the intrapubic ligament at specified time points. We hypothesized that MUCT imaging could be used to reduce the number of animals necessary for the intrapubic ligament bioassay by enabling a single animal to be followed longitudinally throughout the study rather than euthanizing different cohorts at established time points. Female CD1 mice were used to compare MUCT imaging with the current standard. Both protocols revealed significant differences in intrapubic ligament length, with the MUCT data having greater power when corrected for baseline imaging. From these data, we concluded that using MUCT to measure the intrapubic ligament in mice primed with estrogen and dosed with relaxin is a viable refinement and will allow the use of fewer animals in longitudinal studies and provide more robust data, because animals can serve as their own controls. PMID- 28830580 TI - Antibiotic-associated Manipulation of the Gut Microbiota and Phenotypic Restoration in NOD Mice. AB - Segmented filamentous bacterium (SFB) a gram-positive, anaerobic, and intestinal commensal organism directly influences the development of Th17 helper cells in the small intestine of mice. In NOD mice, SFB colonization interferes with the development of type 1 diabetes (T1D), a T-cell-mediated autoimmune disease, suggesting that SFB may influence Th17 cells to inhibit Th1 populations associated with the anti-beta-cell immune response. This effect is a serious concern for investigators who use NOD mice for diabetes research because the expected incidence of disease decreases markedly when they are colonized by SFB. A room housing mice for T1D studies at The Jackson Laboratory was determined by fecal PCR testing to have widespread SFB colonization of multiple NOD strains after a steady decline in the incidence of T1D was noted. Rederivation of all NOD related mouse strains was not feasible; therefore an alternative treatment using antibiotics to eliminate SFB from colonized mice was undertaken. After antibiotic treatment, soiled bedding from NOD mouse strains housed in SFB-free high-health status production barrier rooms was used to reintroduce the gastrointestinal microbiota. Over the past 16 mo since treating the mice and disinfecting the mouse room, regular PCR testing has shown that no additional SFB colonization of mice has occurred, and the expected incidence of T1D has been reestablished in the offspring of treated mice. PMID- 28830581 TI - Severe Dermatitis Associated with Spontaneous Staphylococcus xylosus Infection in Rag-/-Tpl2-/- Mice. AB - Staphylococcus xylosus is a commensal bacterium found on the skin and mucosal surfaces of SPF mice. S. xylosus is rarely pathogenic, most often causing skin lesions and dermatitis in immunocompromised mice, particularly those with impaired NADPH oxidase function. Here we report spontaneous infection with S. xylosus in Rag1-/-Tpl2-/- mice. Infection was characterized by the presence of alopecia, crusts, and scaly skin. S. xylosus was detected in the feces, skin, lymph nodes, and lungs of Rag1-/-Tpl2-/- mice and led to mortality or euthanasia due to humane endpoints. C57BL/6 mice were culture-positive for S. xylosus on the skin, and Rag1-/- and Tpl2-/- mice were culture-positive on the skin and occasionally in the feces. However, S. xylosus did not cause clinical symptoms in C57BL/6, Rag1-/-, or Tpl2-/- mice. Compared with those in Rag1-/- mice, relative concentrations of circulating monocytes, but not neutrophils or lymphocytes, were increased in Rag1-/-Tpl2-/- mice, consistent with their increased incidence of clinical symptoms. Overall, this case study suggests a novel role for Tpl2 in T cell-independent host resistance to the otherwise commensal organism S. xylosus. PMID- 28830582 TI - Differences in Vascular Response between Balloon Overstretch and Stent Overexpansion in Nonatherosclerotic Porcine Coronary Arteries. AB - Which preclinical models are best suited for restenosis research remains uncertain. Here we compared the restenotic responses after balloon or stent overstretch injury in a porcine coronary artery. A total of 30 coronary lesions in 5 pigs were treated by balloon overdilatation or oversized stent implantation at various balloon-to-artery (B:A) ratios. Four weeks later, the lesions were examined in vivo by using coronary angiography, intravascular ultrasound, and optical coherence tomography (OCT). At follow-up, the lumen area stenosis and plaque burden at the minimal lumen area site were greater in stented sites than in balloon injury site (lumen area stenosis, 21.7 +/- 8.9% compared with 32.8 +/- 12.1%; plaque burden, 30.1% +/- 10.1% compared with 44.7% +/- 10.1%, respectively). The remodeling index was significantly smaller for the balloon injury group than the stent group (0.86 +/- 0.11 compared with 1.00 +/-0.04). Only the stent group that was dilated at a high B:A ratio resulted in increased plaque burden. In the balloon-injury sites, high B:A ratios were significantly associated with greater negative remodeling. Tissue morphology assessment by OCT revealed that the predominant pattern in balloon injury sites was homogeneous, whereas that in stented sites was a layered to heterogeneous pattern. Neointimal proliferation was significantly greater after oversized stenting than after balloon overstretch injury. Together these findings suggest that stent overexpansion of porcine coronary arteries might be appropriate for researching restenosis than is the balloon overstretch injury model. PMID- 28830583 TI - A Simple Way to Eradicate Methicillin-Resistant Staphylococcus aureus in Cynomolgus Macaques (Macaca fascicularis). AB - Our investigation of indoor-housed cynomolgus macaques (Macaca fascicularis) by using automated identification followed by antibiotic susceptibility testing revealed 1 of 7 immunocompetent animals and 2 of 9 immunosuppressed monkeys as carriers of methicillin-resistant Staphylococcus aureus (MRSA). Follow-up management involving mupirocin treatment resulted in the conversion of the 3 MRSA carriers into MRSA-negative cases. Prospective assessment of newly imported monkeys involving 24-h culture of nasal swabs on chromogenic agar revealed that 22% (18 of 82 animals) were MRSA-positive. Mupirocin treatment successfully converted all of the MRSA-positive macaques into non-carriers, suggesting the feasibility of this simple, one-step screening procedure for rapidly identifying MRSA carriers in large cohorts. In addition, 8 animals that had been diagnosed MRSA-positive and subsequently treated with mupirocin demonstrated no recolonization during follow-up, even under immunosuppressive conditions. We propose rapid screening using chromogenic agar followed by mupirocin treatment as a time- and cost-effective regimen for managing MRSA in cynomolgus monkeys. PMID- 28830584 TI - Immune Activation of Platelets in Response to Serial Phlebotomy in Pigtailed Macaques (Macaca nemestrina). AB - Serial phlebotomy is a common sampling practice for repeated-measures studies in biomedical research. In NHP, the effect of serial blood collection on RBC parameters has been characterized, but the effects on platelet parameters and other aspects of the hemogram have not been well studied. We sought to characterize the circulating platelet phenotype throughout the course of 7 serial phlebotomies spanning 30 d in pigtailed macaques (Macaca nemestrina). Phlebotomy was performed on 23 animals at days 0, 2, 4, 7, 10, 21, and 30 to quantify the circulating platelet count and markers of both hemostatic and immune platelet activation. Platelet immune activation was characterized by increases in surface MHC class I and II expression and increases in circulating platelet-leukocyte aggregates. These changes occurred in the absence of increases in the prohemostatic markers P-selectin and CD40L and without evidence of adverse clinical effects. Mild increases in platelet count, mean platelet volume, and immune activation occurred early in the study. After day 21, mean platelet volume and other hematologic parameters returned to baseline while changes in platelet count and immune activation were greater than during the first 10 d of the study. These data demonstrate that serial phlebotomy in NHP has delayed effects on platelet parameters, which may be a source of clinically silent, immunologic and physiologic variability within repeated measures studies. The impact of these effects on research aims should be considered when designing protocols requiring serial phlebotomy in NHP. PMID- 28830585 TI - Mycobacterium kansasii Isolated from Tuberculinpositive Rhesus Macaques (Macaca mulatta) in the Absence of Disease. AB - Mycobacterial infections are of primary health concern in NHP colonies in biomedical research. NHP are constantly monitored and screened for Mycobacterium spp. We report 6 Chinese-origin rhesus macaques infected with Mycobacterium kansasii that exhibited positive tuberculin skin tests in the absence of disease. Two of these macaques were being used for research purposes; the remaining 4 macaques were residing at the contract quarantine company. Histopathology and acid-fast staining of fixed tissues from all macaques showed that all were free of disease. Thoracic radiographs were negative for any signs of disease or infection. Samples from bronchial lavage and tissues including lung, spleen, hilar and mesenteric lymph nodes tested negative by PCR assay for Mycobacterium spp. One of the research macaques tested culture-positive for M. kansasii and a poorly characterized M. avium complex organism. One macaque from the contract quarantine facility tested culture positive for M. kansasii. Genomic testing and target gene RNA expression analysis of the 2 M. kansasii isolates were performed to evaluate possible kinship and affected genes that might contribute to susceptibility to mycobacterial infection. Genotyping of the 2 isolates revealed 2 genetically distinct strains (strains 1 and 4). The presence of positive tuberculin skin tests in the absence of disease raises serious concerns regarding diagnostic methods used for infected NHP. PMID- 28830587 TI - Correlation between measures of perceptual assessment of GRB and contact quotient (CQ). AB - OBJECTIVE: The aim of the present workis to correlate the perceptual parameters grade, roughness and breathiness of the GRB scale with the contact quotient (CQ) obtained by electroglotography. MATERIAL AND METHOD: 70 samples of normal and pathological voices were analyzed by means of auditory-perceptual analysis and electroglotography. The perceptual analysis was carried out by two expert judges depending on the parameters grade, roughness and breathiness. The CQ values were obtained through the VoceVista System Version 3.3.7. RESULTS: The results show a strong correlation between CQ and breathiness (r = -0.869), whereas between grade of dysphonia and CQ (r = -0.567), and roughness and CQ (r = 0.643) the correlation is average. CONCLUSIONS: It is possible to establish relationships between the vibrational behavior of the vocal folds and the resulting phenomenon that we perceive auditively. The most relevant parameter in this respect was breathiness. The correlation between grade, roughness and CQ was weaker. PMID- 28830586 TI - Uterus-like Masses in a Rhesus Macaque (Macaca mulatta). AB - Endometriosis is a relatively common condition in women and some populations of adult female rhesus macaques. However, endometriosis with extensive smooth muscle proliferation, as occurs in endomyometrioma and uterus-like mass (ULM), is rare in women. This report describes a case of endometriosis with extensive smooth muscle metaplasia resembling multiple ULM in a 20-y-old female rhesus macaque. During a protocol-related procedure, a large, smooth, globoid, freely moveable mass was palpated in the midabdomen. Ultrasonography revealed a cystic structure from which dark brown fluid was aspirated. During exploratory laparotomy, an 8-cm spherical mass in the greater omentum and 3 additional masses (diameter, 2 to 5 cm) attached to the omentum were excised. Microscopic examination of the masses revealed numerous foci of ectopic endometrial glands and stroma frequently surrounded by bundles of smooth muscle and fibrous connective tissue. The gross and histologic lesions in this macaque bore many similarities to ULM in women. To our knowledge, this case represents the first report of endometriosis resembling a uteruslike mass in a NHP. PMID- 28830589 TI - A label-free detector for liquid chromatography systems using mm-wave technology: First proof of concept. AB - The development of millimeter-wave (mm-wave) technology has enabled the study of bio-molecular interactions by means of electromagnetic waves with frequencies between 30 and 300GHz. In this study, an attempt has been made to exploit the possibility of mm-wave technology as alternative detection technique for liquid chromatographic (LC) systems. The goal is to design and fabricate a label-free mm wave detector that is compatible with LC systems. As proof-of-concept experiments, the UV absorbing compounds praziquantel and trans-stilbene-oxide as well as a non-UV absorbing compound sorbitol are injected in an open capillary as well as a capillary with stationary phase and measured by both mm-wave and UV detectors. The in-house developed mm-wave detector is capable of detecting all compounds without the need for labelling. Although the detection limit of such detector still needs to be verified and occasionally improved in the future, it already shows great potential as an additional detection technique for LC systems. PMID- 28830588 TI - Chemotyping of new hop (Humulus lupulus L.) genotypes using comprehensive two dimensional gas chromatography with quadrupole accurate mass time-of-flight mass spectrometry. AB - Comprehensive two-dimensional gas chromatography with quadrupole accurate mass time-of-flight mass spectrometry (GC*GC-Q-TOFMS) is employed to profile Humulus lupulus L. (hop) essential oils. Comparison of characterised essential oils allows discrimination among chemotypes. Experimental and commercial hop genotypes displayed distinguishable chemotypic patterns among the volatile secondary metabolites making up their essential oils. In total, 210-306 unique compounds were detected (depending on specific genotype), with 99 of these compounds either positively or tentatively identified. Identified volatile secondary metabolites were grouped into esters, monoterpene hydrocarbons, oxygenated monoterpenes, sesquiterpene hydrocarbons, oxygenated sesquiterpenes and ketones. Terpenoids were the dominant chemical families across all hop genotypes analysed, representing between 67% and 90% of the total ion count. The multidimensional chromatographic profiles of hop essential oils are extremely information-rich, making GC*GC-Q-TOFMS useful for fast screening of new hybrid hop genotypes, and therefore informing breeding strategies to derive new commercial hop cultivars for the development of distinctive and desirable beers. PMID- 28830590 TI - The use of a single inertial sensor to estimate 3-dimensional ground reaction force during accelerative running tasks. AB - The purpose of this investigation was to determine the feasibility of using a single inertial measurement unit (IMU) placed on the sacrum to estimate 3 dimensional ground reaction force (F) during linear acceleration and change of direction tasks. Force plate measurements of F and estimates from the proposed IMU method were collected while subjects (n=15) performed a standing sprint start (SS) and a 45 degrees change of direction task (COD). Error in the IMU estimate of step-averaged component and resultant F was quantified by comparison to estimates from the force plate using Bland-Altman 95% limits of agreement (LOA), root mean square error (RMSE), Pearson's product-moment correlation coefficient (r), and the effect size (ES) of the differences between the two systems. RMSE of the IMU estimate of step-average F ranged from 37.70 N to 77.05 N with ES between 0.04 and 0.47 for SS while for COD, RMSE was between 54.19 N to 182.92 N with ES between 0.08 and 1.69. Correlation coefficients between the IMU and force plate measurements were significant (p<=0.05) for all values (r=0.53 to 0.95) except the medio-lateral component of step-average F. The average angular error in the IMU estimate of the orientation of step-average F was <=10 degrees for all tasks. The results of this study suggest the proposed IMU method may be used to estimate sagittal plane components and magnitude of step-average F during a linear standing sprint start as well as the vertical component and magnitude of step-average F during a 45 degrees change of direction task. PMID- 28830591 TI - Consistent trilayer biomechanical modeling of aortic valve leaflet tissue. AB - Aortic valve tissue exhibits highly nonlinear, anisotropic, and heterogeneous material behavior due to its complex microstructure. A thorough understanding of these characteristics permits us to develop numerical models that can shed insight on the function of the aortic valve in health and disease. Herein, we take a closer look at consistently capturing the observed physical response of aortic valve tissue in a continuum mechanics framework. Such a treatment is the first step in developing comprehensive multiscale and multiphysics models. We highlight two important aspects of aortic valve tissue behavior: the role of the collagen fiber microstructure and the native prestressing. We propose a model that captures these two features as well as the heterogeneous layer-scale topology of the tissue. We find the model can reproduce the experimentally observed multiscale mechanical behavior in a manner that provides intuition on the underlying mechanics. PMID- 28830592 TI - Understanding population-wide haplotype frequencies of human leukocyte antigen (HLA) alleles in linkage disequilibrium is important for hematopoietic stem cell transplantation. PMID- 28830593 TI - Adjusting thresholds of serum ferritin for iron deficiency: a moving target. PMID- 28830594 TI - Challenges in the diagnosis of iron deficiency anemia in aged people. PMID- 28830595 TI - New agents in relapsed/refractory Hodgkin's lymphoma. PMID- 28830596 TI - BCR-ABL1 level monitoring in chronic myeloid leukemia by real time polymerase chain reaction in Brazil - not so real. PMID- 28830597 TI - Scientific comment on: "Quantitative flow cytometric evaluation of CD200, CD123, CD43 and CD52 as a tool for the differential diagnosis of mature B-cell neoplasms". PMID- 28830598 TI - Do immunoglobulin G and immunoglobulin E anti-l-asparaginase antibodies have distinct implications in children with acute lymphoblastic leukemia? A cross sectional study. AB - BACKGROUND: l-Asparaginase is essential in the treatment of childhood acute lymphoblastic leukemia. If immunoglobulin G anti-l-asparaginase antibodies develop, they can lead to faster plasma clearance and reduced efficiency as well as to hypersensitivity reactions, in which immunoglobulin E can also participate. This study investigated the presence of immunoglobulin G and immunoglobulin E anti-l-asparaginase antibodies and their clinical associations. METHODS: Under 16 year-old patients at diagnosis of B-cell acute lymphoblastic leukemia confirmed by flow cytometry and treated with a uniform l-asparaginase and chemotherapy protocol were studied. Immunoglobulin G anti-l-asparaginase antibodies were measured using an enzyme-linked immunosorbent assay. Intradermal and prick skin testing was performed to establish the presence of specific immunoglobulin E anti l-asparaginase antibodies in vivo. Statistical analysis was used to investigate associations of these antibodies with relevant clinical events and outcomes. RESULTS: Fifty-one children were studied with 42 (82.35%) having anti-l asparaginase antibodies. In this group immunoglobulin G antibodies alone were documented in 10 (23.8%) compared to immunoglobulin E alone in 18 (42.8%) patients. Immunoglobulin G together with immunoglobulin E were simultaneously present in 14 patients. Children who produced exclusively immunoglobulin G or no antibodies had a lower event-free survival (p-value=0.024). Eighteen children (35.3%) relapsed with five of nine of this group who had negative skin tests suffering additional relapses (range: 2-4), compared to none of the nine children who relapsed who had positive skin tests (p-value<0.001). CONCLUSION: Children with acute lymphoblastic leukemia and isolated immunoglobulin G anti-l asparaginase antibodies had a higher relapse rate, whereas no additional relapses developed in children with immunoglobulin E anti-l-asparaginase antibodies after the first relapse. PMID- 28830599 TI - Molecular response to imatinib mesylate of Brazilian patients with chronic myeloid leukemia. AB - BACKGROUND: Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia leading to significant reductions of BCR-ABL1 transcript levels in peripheral blood. OBJECTIVE: To evaluate the response to imatinib mesylate treatment (400mg/day) in Brazilian patients in the chronic phase of chronic myeloid leukemia monitored by quantitative real time polymerase chain reaction. METHODS: Between October 2002 and October 2010, 3169 peripheral blood samples were collected from 1403 patients from 3 to 5 months, 6 to 11 months, 12 to 17 months, 18 to 23 months and >=24 months after beginning imatinib treatment. Eighty-two patients had samples available and analyzed for all time intervals. BCR-ABL1 quantification was performed by quantitative real time polymerase chain reaction using the ABL1 gene as the control. Results of the BCR-ABL1 ratio as a percentage were reported by the international scale (IS) using the laboratory conversion factor (0.51). RESULTS: In the first interval, 80.8% of patients achieved the optimal response (BCR-ABL1IS<=10%). In the second period, 69.1% achieved optimal response (BCR-ABL1IS<=1%) and, between 12 and 17 months, 47.3% achieved major molecular response (BCR-ABL1IS<=0.1%). CONCLUSIONS: The results of this retrospective study show that the response to imatinib treatment (400mg/day) of Brazilian patients in the chronic phase of chronic myeloid leukemia is within the expected profile when compared to patients reported in international prospective randomized studies. PMID- 28830600 TI - Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience. AB - BACKGROUND: Despite all the scientific progress that has been made on understanding the disease, prognosis for patients with relapsed and refractory Hodgkin's lymphoma remains poor and the treatment is palliative in the majority of the cases. Thus, the aim of this study was to present the results on the compassionate use of everolimus in a group of patients who were monitored at nine different centers in Brazil. METHODS: A 10-mg oral dose of everolimus was given to each patient daily. Response time was evaluated from the beginning of medication use until loss of response, toxicity or medical decision to cease treatment. RESULTS: Thirty-three patients were evaluated. The median age at the beginning of medication administration was 29 years. Patients had received a median of five prior therapies. Overall response rate was 45.4%, with 13 patients achieving partial response, two achieved clinical response, 14 remained with stable disease, two had disease progression, and two were not evaluated. Patients received a median of 14 cycles. Progression-free survival was nine months, and overall survival was estimated to be 36 months. Three patients used the medication for more than four years. The most frequently reported adverse events were thrombocytopenia and hypercholesterolemia. Three patients had pulmonary toxicity. Grade III and IV adverse events occurred in 39% of the patients. CONCLUSION: Everolimus was found to provide a response in a group of patients with refractory or relapsed Hodgkin's lymphoma who had adequate tolerability to the drug. PMID- 28830601 TI - Ability of serum ferritin to diagnose iron deficiency anemia in an elderly cohort. AB - BACKGROUND: Diagnosis and treatment of iron deficiency anemia in older subjects improves their quality of life. Serum ferritin as a marker of iron stores is an acute phase protein. In older subjects who usually have many concomitant chronic medical conditions, serum ferritin may increase in response to inflammatory processes irrespective of iron stores. This study was performed to determine the diagnostic properties of serum ferritin in the diagnosis of iron deficiency anemia in older subjects. METHODS: This case-control study included all the inhabitants of Amirkola town who participated in the Amirkola Health and Aging Project. Diagnosis of anemia was confirmed based on a hemoglobin level <13g/dL in men and <12g/dL in women and iron deficiency anemia by percent transferrin saturation <15%. A receiver operating characteristic curve was constructed to determine an optimal serum ferritin cutoff value to differentiate patients with and without iron deficiency anemia at the highest sensitivity and specificity. RESULTS: Eighty patients with iron deficiency anemia and 160 cases of anemia without iron deficiency (mean age: 72.9+/-8 and 71.6+/-7.6 years, respectively; p value=0.37) were analyzed. In iron deficiency anemia, the mean serum ferritin was significantly lower (p-value=0.036) compared to patients without iron deficiency anemia. Serum ferritin with a cutoff level of 100ng/mL differentiated patients with and without iron deficiency anemia with a sensitivity of 60% and specificity of 59% and area under the receiver operating characteristic curve of 0.615+/ 0.040 (95% confidence interval: 0.536-0.694; p-value=0.004). CONCLUSION: These findings indicate that in elderly subjects, iron deficiency anemia may develop with higher levels of serum ferritin. Hence, the conventional cutoff of serum ferritin for the diagnosis of iron deficiency anemia in young adults is not appropriate for the elderly population. PMID- 28830602 TI - Human leukocyte antigen allele linkage disequilibrium and haplotype structure in volunteer bone marrow donors of Parana State. AB - BACKGROUND: Bone marrow transplantation has been used in the treatment of various diseases, especially hematologic diseases. The success of this treatment, among other factors, requires human leukocyte antigens (HLA) compatibility between patient and donor. Knowing the human leukocyte antigens allele group and haplotype frequencies as well as the linkage disequilibrium between alleles of different human leukocyte antigens loci can shorten the search time for a compatible bone marrow donor. OBJECTIVE: To assemble and analyze data on human leukocyte antigens frequencies available in the Laboratory of Immunogenetics and Histocompatibility (LIGH) database of the Universidade Federal do Parana adding an estimation of the Hardy-Weinberg equilibrium and linkage disequilibrium. METHODS: The sample was composed of seven populations grouped by self-declared ancestry or inferred from the surname as follows: Laboratory of Immunogenetics and Histocompatibility database (all groups), descendants of Italians, Poles, and Asians, Afro-Brazilians, Mulattos (mixed ancestry) and Amerindians. Human leukocyte antigens genotyping was carried out using the polymerase chain reaction sequence specific primers (PCR-SSP) and -sequence specific oligonucleotide (PCR SSO) technologies. RESULTS: There were high frequencies of the HLA-A*02, HLA-B*35 and HLA-DRB1*13 allelic groups in all groups. The same was observed for the HLA A*01-B*08-DRB1*03 haplotype except for Asian descendants. It was observed that the human leukocyte antigens Laboratory of Immunogenetics and Histocompatibility database and the Asian group are not in Hardy-Weinberg equilibrium. The Italian, Polish, Asian, Mulatto and Amerindian descendants showed haplotypes in complete linkage disequilibrium. Our results were compared with data on the human leukocyte antigens in the Parana population available from the Brazilian Voluntary Bone Marrow Donor Registry (REDOME) and data published on the population of Curitiba and the northern region of Parana. CONCLUSIONS: Haplotypes frequent in the Asian group were not the most frequently observed in the Laboratory of Immunogenetics and Histocompatibility database and the National Bone Marrow Donor Registry for the state of Parana. Linkage disequilibrium information may prove useful in the search for bone marrow donors for patients awaiting a suitable donor. PMID- 28830603 TI - Comparison of microRNA expression in high-count monoclonal B-cell lymphocytosis and Binet A chronic lymphocytic leukemia. AB - BACKGROUND: Evidence suggests that monoclonal B-cell lymphocytosis precedes all chronic lymphocytic leukemia cases, although the molecular mechanisms responsible for disease progression are not understood. Aberrant miRNA expression may contribute to the pathogenesis of chronic lymphocytic leukemia. The objective of this study was to compare miRNA expression profiles of patients with Binet A chronic lymphocytic leukemia with those of subjects with high-count monoclonal B cell lymphocytosis and healthy volunteers (controls). METHODS: Twenty-one chronic lymphocytic leukemia patients, 12 subjects with monoclonal B-cell lymphocytosis and ten healthy volunteers were enrolled in this study. Flow cytometry CD19+CD5+ based cell sorting was performed for the chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis groups and CD19+ cells were sorted to analyze the control group. The expressions of miRNAs (miR-15a, miR-16-1, miR-29b, miR-34a, miR-181a, miR-181b and miR-155) were determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: Significant differences between the expressions in the chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis groups were restricted to the expression of miR 155, which was higher in the former group. A comparison between healthy controls and monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia patients revealed higher miR-155 and miR-34a levels and lower miR-15a, miR-16-1, miR-181a and miR-181b in the latter group. CONCLUSIONS: Our results show a progressive increase of miR-155 expression from controls to monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia. The role of miR-155 in the development of overt chronic lymphocytic leukemia in individuals with monoclonal B-cell lymphocytosis must be further analyzed. PMID- 28830604 TI - Blood/Injection Fear Scale: Portuguese version, cultural adaptation and psychometric properties in a large sample of primary health care users. AB - BACKGROUND: Blood/injection phobia may have important consequences for health. These phobic individuals, in most cases, avoid contact with health systems, postpone or avoid medical procedures, avoid invasive treatments and do not participate in health promotion and early detection of disease initiatives such as vaccination, consultations, preventive exams or blood donation. Thus, specific and validated instruments are necessary to assess this variable. In addition, a lack of studies on this theme may be associated with the low availability of instruments. This study aimed to propose a Portuguese version of the Blood/Injection Fear Scale (BIFS-P) and assess its psychometric properties. METHODS: Translation and back-translation were performed. Content validity was assessed in two steps by a panel of 20 experts. The psychometric properties were assessed in a stratified and representative sample of primary health care service users of Ribeirao Preto, southeastern Brazil. Exploratory and confirmatory factor analyses were conducted using a polychoric correlation matrix. RESULTS: A total of 1054 primary health care users participated; 79.7% were female and the mean age was 40.6 (standard deviation=15.16) years. According to the exploratory factor analysis, the items can be grouped into three or five factors with best fits being detected for the three- and five-factor models in confirmatory factor analysis. CONCLUSION: Blood/Injection Fear Scale (Portuguese version) is easy to understand and apply in the general population, showed adequate psychometric properties, and represents an alternative in the assessment of blood/injection phobia for future studies. PMID- 28830605 TI - Quantitative flow cytometric evaluation of CD200, CD123, CD43 and CD52 as a tool for the differential diagnosis of mature B-cell neoplasms. AB - BACKGROUND: Distinction between mature B-cell neoplasms can be difficult due to overlapping of immunologic features and clinical manifestations. This study investigated whether quantifying mean fluorescence intensity of four monoclonal antibodies in a flow cytometry panel is useful for the differential diagnosis and characterization of these disorders. METHODS: The expressions of CD52, CD200, CD123 and CD43 were analyzed in samples from 124 patients with mature B-cell neoplasms. The quantitative estimation of these antigens was assessed by mean fluorescence intensity. RESULTS: The cases included were 78 chronic lymphocytic leukemias, three atypical chronic lymphocytic leukemias, six marginal zone lymphomas, 11 splenic marginal zone lymphomas, nine lymphoplasmacytic lymphomas, six mantle cell lymphomas, two hairy cell leukemias, two hairy cell leukemias variant, five follicular lymphomas, one Burkitt lymphoma and one diffuse large B cell lymphoma. The mean fluorescence intensity of CD200 was higher in atypical chronic lymphocytic leukemia, chronic lymphocytic leukemia and hairy cell leukemia cases. CD123 showed higher mean fluorescence intensities in hairy cell leukemia cells. Chronic lymphocytic leukemia, atypical chronic lymphocytic leukemia and mantle cell lymphoma had higher expression of CD43 and all follicular lymphoma cases had very low mean fluorescence intensity values. CD52 expression was consistently positive among all cases. CONCLUSION: Quantitative evaluation of these markers can be a useful additional tool to better identify some types of mature B-cell neoplasms. PMID- 28830606 TI - Thrombin generation assays for global evaluation of the hemostatic system: perspectives and limitations. AB - The existing techniques to evaluate hemostasis in clinical laboratories are not sensitive enough to detect hypercoagulable and mild hypocoagulable states. Under different experimental conditions, the thrombin generation test may meet these requirements. This technique evaluates the overall balance between procoagulant and anticoagulant forces and has provided new insights in our understanding of the coagulation cascade, as well as of the diagnosis of hypocoagulability and hypercoagulability conditions. Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non clotting plasma sample. The calibrated automated thrombogram method is an open system, in which different antibodies, proteins, enzymes and peptides can be introduced to answer specific questions regarding hemostatic processes. The thrombin generation test has great clinical potential, such as in monitoring patients taking anticoagulants and antiplatelet drugs, screening for genetic or acquired thrombotic disorders, and evaluating bleeding risk control in patients with hemophilia using bypass agents or replacement therapy. Different to conventional coagulation tests, the thrombin generation test can be used for an overall evaluation of hemostasis, the results of which can then be used to evaluate specific characteristics of hemostasis, such as prothrombin time, activated partial thromboplastin time, and levels of fibrinogen and other coagulation factors. The introduction of this method will contribute to a better understanding and evaluation of overall hemostatic processes; however, this method still requires standardization and clinical validation. PMID- 28830607 TI - Partnership of the Sociedade Brasileira de Oncologia Pediatrica and International Society of Pediatric Oncology to improve nutritional care for children with cancer in Brazil. AB - The authors present a proposal of a partnership between the Sociedade Brasileira de Oncologia Pediatrica (SOBOPE) and the International Society of Pediatric Oncology (SIOP) to promote the standardization and improvement of nutritional care of kids under cancer treatment in Brazil. The results of the first meeting in Brazil as well as plans for future meetings are described. PMID- 28830609 TI - Flow cytometry to identify bone-marrow relapse in blastic plasmacytoid dendritic cell neoplasm: a case report. PMID- 28830608 TI - Small cell variant of anaplastic large cell lymphoma with leukemic presentation: a diagnostic challenge. PMID- 28830610 TI - Erythrovirus B19 induced persistent bicytopenia in a healthy child. PMID- 28830612 TI - FMS-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD): a villain among others. PMID- 28830611 TI - Is karyotyping still needed in the diagnosis and monitoring of chronic myeloid leukemia? PMID- 28830613 TI - Patients with very severe anemia: a case series. PMID- 28830614 TI - Assessment of the Matos & Carvalho index for distinguishing thalassemia from iron deficiency anemia. PMID- 28830615 TI - Response to the assessment of the Matos & Carvalho index by Hoffmann and Urrechaga. PMID- 28830616 TI - Impact of a do-not-do intervention on 12 laboratory measurements. AB - OBJECTIVES: In recent years, various scientific societies and healthcare organisations have created recommendations aimed at decreasing the use of healthcare interventions that have shown no efficacy or effectiveness. The aim of this study was to assess the impact of an intervention on 12 do-not-do recommendations regarding the laboratory in 7 hospital centres. METHODS: Before after study conducted in 7 hospital centres of Cordoba and Jaen during 2015 and 2016. Based on the recommendations of existing scientific societies, a consensus was reached on various actions regarding laboratory measurements. We analysed the number and cost of measuring 6 tumour markers (carcinoembryonic antigen, prostate specific antigen, carbohydrate antigen [CA] 15.3, CA125, CA19.9 and alpha fetoprotein), thyrotropin, T3, T4, glycated haemoglobin, urea, ferritin and antigliadin antibodies, before and after implementing the consensus. RESULTS: Compared with the previous year, there were 55,902 fewer laboratory measurements (-19%) in 2016, with an overall savings of ?82,100. The reduction in the number of measurements occurred mainly in plasma urea (-50.3%) and in the tumour markers CA125 (-16%), CA19.9 (-11.6%) and CA15.3 (-10.5%). The most pronounced savings were achieved in the measurements of urea (-?21,002), thyroid hormones (-?12,716) and thyrotropin (-?7,638). CONCLUSIONS: The adoption and consensus of do-not-do recommendations among healthcare levels resulted in a significant reduction in unnecessary measurements. PMID- 28830617 TI - Cancer-promoting mechanisms of tumor-associated neutrophils. AB - IMPORTANCE: Neutrophils have classically been considered to mount a defensive response against tumor cells, yet recent evidence suggests tumors modulate neutrophil function to support tumor growth and progression. OBSERVATIONS: Tumor associated neutrophils (TANs) are phenotypically distinct from circulating neutrophils in terms of their surface protein composition and cyto/chemokine activity and response. Although TANs have been shown to both promote and inhibit tumor advancement, the preponderant activity augments tumor progression. This review discusses these cancer-promoting molecular pathways, relevant diagnostic studies in patients, and subsequent treatment modalities. The tumor promoting mechanisms of TANs include dampening of CD8+ response via Arginase-1; a neutrophil-secreted neutrophil elastase (NE) upregulation of tumor cellular proliferation pathways; degradation of basement membrane and ECM via NE and MMP 9; upregulation of angiogenesis by VEGF, and HGF; and ICAM-1 dependent tumor intravasation, immune protection in circulation, and extravasation into distant, metastatic tissue beds. Clinicians are constrained in treating TANs systemically as it may induce neutropenia, therefore targeting TANs-mediated tumor progression pathways surgically on a loco-regional level is a viable adjuvant treatment modality. CONCLUSION AND RELEVANCE: TANs modulate the tumor microenvironment promoting tumor progression. Mechanistic understanding of TANs role in tumor progression will provide unique therapeutic alternatives. PMID- 28830619 TI - Corrigendum to "Mitochondrial complex I impairment in leukocytes from type 2 diabetic patients". PMID- 28830618 TI - Erratum to "Antiplatelet effects of dietary nitrate in healthy volunteers: Involvement of cGMP and influence of sex" [Free Radic. Biol. Med. 65 (2013) 1521 1532]. PMID- 28830620 TI - Quality of systematic reviews and meta-analyses published in pediatric surgery. AB - AIMS: Systematic reviews (SRs) and meta-analyses (MAs) studies may influence and direct surgical practice. Against this background we have analyzed the quality of systematic reviews and meta-analyses published in the specialty field of pediatric surgery using the Assessment of Multiple Systematic Reviews 11-item tool (AMSTAR). METHODS: MEDLINE and EMBASE databases and the three major journals in pediatric surgery were searched for SRs and MAs in pediatric surgery. Studies involving predominantly adult populations were excluded. Two reviewers independently scored included studies against AMSTAR criteria and disagreements were resolved by consensus. A total rating of 4 or less was considered 'poor' methodological quality, 5-8 as 'fair to good' and 9 or greater as 'good'. RESULTS: Original searching retrieved 1,281 articles. 126 articles were included for final analysis. Examining recent trends, 4 studies were published in 1995 2000 compared to 78 in 2011-2014. Using AMSTAR scoring criteria, 35 reviews (28%) were regarded as 'poor' in terms of methodological quality, 59 (47%) 'fair', and 32 (25%) 'good' quality. We observed no improvement in AMSTAR score before and after the development of the tool (mean score pre-2008 6.8, post-2008 5.9, p = 0.136). CONCLUSIONS: Despite an increase in the number of SRs / MAs published in pediatric surgery, a quarter of all studies were considered poor in terms of their quality and scientific validity. Journals must define and apply minimum criteria to ensure pediatric surgeons seeking to publish high quality SRs / MAs achieve these requirements. PMID- 28830621 TI - Symptomatic recurrence upon proton pump inhibitor discontinuation correlated with results of Bravo(r) wireless esophageal pH monitoring in patients with gastroesophageal reflux disease. PMID- 28830622 TI - Common and Uncommon Causes of Ventriculoperitoneal Shunt Malfunction Diagnosed on Plain Radiographs. AB - Thousands of patients with hydrocephalus are treated successfully with ventriculoperitoneal shunts. Ventriculoperitoneal shunts are known to have high malfunction rates, most of which are owing to mechanical causes. When shunt malfunction is suspected, shunt series are often performed to evaluate the mechanical causes of malfunction. These initial radiographs have proven critical in guiding subsequent management. This article is designed to review the various causes of shunt malfunction that can be diagnosed with radiographs. PMID- 28830623 TI - Remifentanil: A help in topical strabismus surgery. AB - OBJECTIVE: To analyze the analgesic effect of remifentanil, side effects and complications in topical strabismus surgery. To study the results of strabismus surgery with this type of anesthesia. MATERIAL AND METHOD: Retrospective descriptive study. We included 39 patients undergoing strabismus surgery with topical anesthesia and analgesia-based sedation with remifentanil. The data of the anesthetic and surgical technique, surgical results and stability of the deviation angle were analyzed. RESULTS: Thirty nine patients (54% women) were included, the average age was 37,4years old. The mean follow-up was 24,5months. The preoperative diagnoses were exotropia (21 patients), esotropia (12), paresis strabismus (4) and Duane's Syndrome (2). 15% patients had preoperative diplopia and 13 had received previous treatments. The dose range of remifentanil used was 0.05 to 0.2MUg/kg/min. The side effects presented were 2 cases of vomit and one of bad collaboration during the intraoperative adjustment, one of the patient reported pain and one case of thoracic rigidity was reported. 79% of the patients obtained a good surgical result and 82% reported being satisfied with the results. The reintervention rate was 5%. CONCLUSIONS: Analgesia-based sedation with remifentanil is an useful complement to topical strabismus surgery because it reduces pain during surgery and allows the patient to collaborate during intraoperative adjustment due to its pharmacokinetic characteristics. PMID- 28830624 TI - Single-entry models (SEMs) for scheduled services: Towards a roadmap for the implementation of recommended practices. AB - BACKGROUND: Long waiting times for elective services continue to be a challenging issue. Single-entry models (SEMs) are used to increase access to and flow through the healthcare system. This paper provides a roadmap for healthcare decision makers, managers, physicians, and researchers to guide implementation and management of successful and sustainable SEMs. METHODS: The roadmap was informed by an inductive qualitative synthesis of the findings from a deliberative process (a symposium on SEMs, with clinicians, researchers, senior policy-makers, healthcare managers, and patient representatives) and focus groups with the symposium participants. RESULTS: SEMs are a promising strategy to improve the management of referrals and represent one approach to reduce waiting times. The SEMs roadmap outlines current knowledge about SEMs and critical success factors for SEMs' implementation and management. CONCLUSIONS: This SEM roadmap is intended to help clinicians, decision-makers, managers, and researchers interested in developing new or strengthening existing SEMs. We consider this roadmap to be a living document that will continue to evolve as we learn more about implementing and managing sustainable SEMs. PMID- 28830625 TI - Testosterone reactivity to infant crying and caregiving in women: The role of oral contraceptives and basal cortisol. AB - Several studies have shown that mothers and fathers have significant lower levels of testosterone (T) than non-mothers and non-fathers, and that in men caregiving is related to a decrease in T. To date, only a few studies have examined T in women. We examined T reactivity to a crying infant simulator in 160 women. Use of oral contraceptives (OC), basal cortisol (CORT) levels and childhood experiences of maternal love withdrawal were taken into account. T levels were consistently significantly higher in women not using OC. In women not using OC, high basal CORT was related to higher initial T levels and larger decreases of T during caregiving. No effect of basal CORT was found in women with OC use. Childhood experiences of maternal love withdrawal did not affect T levels. This is the first study to show support for a decrease of T in women while taking care of a crying infant, supporting the Challenge hypothesis and the Steroid/Peptide Theory of Social Bonds. PMID- 28830626 TI - Aquaculture and urban marine structures facilitate native and non-indigenous species transfer through generation and accumulation of marine debris. AB - Both the invasion of non-indigenous marine species (NIMS) and the generation and accumulation of anthropogenic marine debris (AMD) are pervasive problems in coastal urban ecosystems. The biosecurity risks associated with AMD rafting NIMS have been described, but the role of aquaculture derived AMD has not yet been investigated as a biosecurity vector and pathway. This preliminary study targeted 27 beaches along the Coromandel Peninsula, New Zealand, collecting debris from belt transects. Plastic (specifically plastic rope) was the dominant AMD present on beaches. The most common biofouling taxa were hydroids, bryozoans, algae and polychaetes, with one NIMS pest species, Sabella spallanzanii, detected fouling plastic rope. Our findings demonstrate that aquaculture is an AMD (plastic rope) generating activity that creates biosecurity risk by enhancing the spread of NIMS. The rafting of S. spallanzanii on AMD generated at aquaculture facilities is currently an unmanaged pathway within New Zealand that needs attention. PMID- 28830627 TI - Environmental drivers of sheltering behaviour in large reef fishes. AB - Studies of shelter use can provide key insights into the ecology, and structural needs of mobile organisms. Using videos, we examined the usage of tabular corals by large reef fishes, over a 10week period, compared to multiple environmental drivers: visibility, tide (and depth), irradiance, wind speed (as a proxy for wave energy) and water temperature. We found that two of these predictor variables (visibility and wind speed) had a significant effect and together accounted for almost half of the variation in tabular coral usage by fishes. Increases in both variables correlated with increased shelter use. To date use of shelters by fishes has primarily been attributed to UV avoidance. Our results support this notion as more turbid conditions (reduced visibility) have an attenuating effect on UV irradiance. Additionally, tabular corals may reduce the energetic costs of increased wave energy by reducing incidental water velocity beneath the structure. PMID- 28830628 TI - Effect of kisspeptin on the proliferation and apoptosis of bovine granulosa cells. AB - Previous studies have shown that kisspeptin (Kp-10) is expressed in mammalian ovaries; however, the expression and role of Kp-10 in bovine ovarian granulosa cells are still unclear. In this study, we assessed the expression of Kp-10 and its effects on the proliferation and apoptosis of bovine granulosa cells. Immunohistochemical analysis showed that Kp-10 was expressed in the cytoplasm of bovine ovarian granulosa cells. Moreover, MTT assays showed that 100nM Kp-10 significantly inhibited the viability of granulosa cells (P<0.05). Flow cytometry analysis showed that Kp-10 could significantly increase accumulation of cells in the G1 phase, decrease accumulation of cells in the S phase, and promote apoptosis in bovine granulosa cells (P<0.05). Additionally, Kp-10 decreased the mRNA levels of Bcl-2, an anti-apoptotic gene; increased the mRNA levels of caspase-3, a pro-apoptotic gene; and increased the mRNA levels of Fas and Fasl (P< 0.05). Thus, our findings demonstrated for the first time that Kp-10 inhibited proliferation and promoted apoptosis in bovine ovarian granulosa cells. These findings provide insights into our understanding of the role of Kp-10 in mediating the proliferation of bovine granulosa cells. PMID- 28830629 TI - Expression of bone morphogenetic protein receptors in bovine oviductal epithelial cells: Evidence of autocrine BMP signaling. AB - Members of the transforming growth factor beta (TGF-beta) family, including bone morphogenetic proteins (BMPs), are expressed in the epithelial cells of the mammalian oviduct. These signaling molecules play important roles in development and tissue homeostasis; however, little is known about their function in the mammalian oviduct. In the present study, RT-qPCR was used to analyze the mRNA abundance of BMP type I (BMPR1A, BMPR1B, ACVR1) and type II receptors (BMPR2, ACVR2A, ACVR2B) in the bovine oviduct epithelial cells (BOEC) isolated from ampulla and isthmus at both the follicular (FP) and the luteal (LP) phase of the estrous cycle. Results indicate that mRNAs for all the BMP receptors studied are expressed in the BOEC. Significant mRNA abundance differences were observed for both BMPR1B and ACVR2B when comparing both the ampulla and isthmus regions with the greater abundance at the isthmus. When both FP and LP samples were compared, ACVR2B mRNA showed greater abundance during the LP, with significant differences in the isthmus region. These variations highlight differences between the isthmus and ampulla regions of the oviduct. By means of wound healing assays on BOEC primary cultures, exogenous recombinant human BMP5 induced a significant increase in wound healing at 24h. The observed changes at the mRNA abundance of components of the signaling pathway and the BMP5 effect on oviductal epithelial cells suggest a possible autocrine role for the BMP pathway that could affect epithelial cell functions necessary for normal physiology and reproductive success in BOEC homeostasis. PMID- 28830630 TI - False positive immunoassay for acetyl choline receptor antibody (AChR Ab) in patients exposed to polyvalent antisnake venom. AB - Acute flaccid paralysis is a neuromuscular emergency characterized by rapidly worsening weakness that evolves quickly to cause diaphragmatic failure. The challenge for the treating physician is to stabilize the patient, generate the differential diagnosis and determine the management; all in quick time. Neurotoxic snake bites have inadequate signs of inflammation and are easily missed. Myasthenic crisis, on the other hand, could be the first sign of myasthenia gravis in up to 20% of patients. Both present with acute respiratory failure and inadequate history. Two of our patients presented with similar clinical picture, and received polyvalent anti-snake venom obtained from hyperimmunised horses (Equus caballus). Both tested positive for anti-acetyl choline receptor antibody. After recovery, both patients narrated a history suggestive of neurotoxic envenomation. We later discovered that patients, who are exposed to polyvalent anti-snake venom (Equus caballus) prior to radioimmunoassay, demonstrate high titers of Anti-AChR Ab in their serum erroneously. PMID- 28830631 TI - Reversal of hypogonadotropic hypogonadism with spontaneous pregnancy in beta thalassaemia major with transfusional haemosiderosis. PMID- 28830632 TI - Health-related quality of life in active duty military: A secondary data analysis of two randomized controlled trials. AB - BACKGROUND: Military service members with lower extremity injuries are at risk for compromised health-related quality of life during rehabilitation. PURPOSE: The purpose of this secondary data analysis was to examine changes in self perceived physical and mental health in two clinical trials of military service members during rehabilitation for a lower extremity injury. METHODS: This study is a secondary analysis of existing data from two cohorts of active duty military service members with lower extremity injuries as they participated in separate randomized controlled trials. DISCUSSION: A similar pattern for both physical and mental health was observed in both groups of participants. Perceptions of physical health improved significantly in both studies, whereas mental health perceptions may or may not have declined. CONCLUSION: Increased attention to mental health may be important during rehabilitation after major and minor lower extremity injuries. Although perceptions of physical health improve, corresponding changes may not occur in mental health perceptions. PMID- 28830633 TI - Activities at the Council. PMID- 28830634 TI - Characterization of bilateral frontal lobe cerebral oxygen saturation in patients with mild traumatic brain injury. AB - BACKGROUND: There is clear evidence of the potential for long-term neuro behavioral and cognitive sequelae following a mild traumatic brain injury (mTBI). Although the source of these persistent behavioral and cognitive issues is unclear, several studies have suggested a cerebral vascular disorder is a likely contributor. PURPOSE: Measure and compare cerebral blood oxygen saturation values in frontal brain lobes of subjects with and without a history of mTBI. METHODS: Bilateral frontal brain lobe blood oxygen saturation was measured using near infrared spectroscopy in mTBI and non-brain injured subjects while alternately breathing room air and a mildly hypoxic gas mixture. RESULTS: Subjects with a history of mTBI displayed a significantly different trajectory of change in their cerebral oxygen saturation values during exposure to mild hypoxia compared to controls. DISCUSSION: The finding confirms and adds to previous research that indicates there is likely a vascular component to this mild form of brain injury. PMID- 28830635 TI - Access to a healthy future. PMID- 28830636 TI - The relationship between emergency department volume and patient complexity. AB - INTRODUCTION: Forecasting emergency department (ED) visits is a well-studied topic. The importance of understanding the complexity of patients along with the days and times of varying patient volumes is critical for planning medical and ancillary staffing. Though multiple studies stratify their results based on severity of disease, severity was determined by triage status. The goal of this study was to utilize a novel method to evaluate the correlation between daily emergency department patient complexity, based on Current Procedure Terminology (CPT) code, and day of the week. METHODS: This was a retrospective study of subjects presenting to the ED between January 1, 2010 and December 31, 2015. We identified the correlation between subjects with each CPT code who were evaluated on a specific day of the week and evaluated the day before, the day of and the day after a legal holiday. RESULTS: During the study period 312,550 (48%) male and 336,348 (52%) female subjects were identified. No correlation between daily ED patient complexity, based on CPT code, and day of the week (p=0.75) or any legal holidays were identified. Individual significant differences were noted among day of the week and particular CPT code as well as legal holiday and particular CPT code with no appreciable trend or pattern. CONCLUSIONS: There was no correlation between daily ED patient complexity based on CPT code and day of the week or daily ED patient acuity and legal holiday. In light of these data, emergency department staffing and resource allocation patterns may need to be revisited. PMID- 28830637 TI - The predictive value of serum calcium for acute pancreatitis with persistent organ failure. PMID- 28830638 TI - Circulatory collapse, right ventricular dilatation, and alveolar dead space: A triad for the rapid diagnosis of massive pulmonary embolism. PMID- 28830639 TI - T cell acute lymphoblastic leukemia (T-ALL): New insights into the cellular origins and infiltration mechanisms common and unique among hematologic malignancies. AB - T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% and 25% of total childhood and adult ALL cases, respectively. During T-ALL, patients are at risk of organ infiltration by leukemic T-cells. Infiltration is a major consequence of disease relapse and correlates with poor prognosis. Transendothelial migration of leukemic cells is required to exit the blood stream into target organs. While mechanisms of normal T-cell transmigration are well known, the mechanisms of leukemic T-cell extravasation remain elusive; but involvement of chemokines, integrins and Notch signaling play critical roles. Here, we summarize current knowledge about molecular mechanisms of leukemic T-cell infiltration with special emphasis on the newly identified subtype early T-cell-progenitor (ETP)-ALL. Furthermore, we compare the extravasation potential of T-ALL cells with that of other hematologic malignancies such as B-ALL and acute myeloid leukemia (AML). PMID- 28830640 TI - The 'radical combined approach' in cerebral arteriovenous malformation treatment: Technical note. AB - AVMs are vessel anomalies where a connection between arterial and venous systems is present and the capillary bed is absent between the two. AVMs tend to present with seizures, headaches, focal neurological deficits and hemorrhage. Hemorrhage is the most common form of presentation. AVM's have a 2-4% annual risk of hemorrhage. Certain studies report this rate as 1%. The greatest discussion in AVM treatment is whether to use interventional treatment or monitor with medical treatment. There are 3 modalities that can be used for interventional treatment; microsurgical resection, endovascular embolization and stereotactic radiosurgery. Combined techniques are also possible. We defined the 'radical combined approach' combines embolization and microsurgery. We will discuss this procedure in this article as we believe it has several advantages. PMID- 28830641 TI - Corrigendum to 'A system to measure the pupil response to steady lights in freely behaving mice' [J. Neurosci. Methods 273 (2016) 74-85]. PMID- 28830642 TI - Vector Flow Visualization of Urinary Flow Dynamics in a Bladder Outlet Obstruction Model. AB - Voiding dysfunction that results from bladder outlet (BO) obstruction is known to alter significantly the dynamics of urine passage through the urinary tract. To non-invasively image this phenomenon on a time-resolved basis, we pursued the first application of a recently developed flow visualization technique called vector projectile imaging (VPI) that can track the spatiotemporal dynamics of flow vector fields at a frame rate of 10,000 fps (based on plane wave excitation and least-squares Doppler vector estimation principles). For this investigation, we designed a new anthropomorphic urethral tract phantom to reconstruct urinary flow dynamics under controlled conditions (300 mm H2O inlet pressure and atmospheric outlet pressure). Both a normal model and a diseased model with BO obstruction were developed for experimentation. VPI cine loops were derived from these urinary flow phantoms. Results show that VPI is capable of depicting differences in the flow dynamics of normal and diseased urinary tracts. In the case with BO obstruction, VPI depicted the presence of BO flow jet and vortices in the prostatic urethra. The corresponding spatial-maximum flow velocity magnitude was estimated to be 2.43 m/s, and it is significantly faster than that for the normal model (1.52 m/s) and is in line with values derived from computational fluid dynamics simulations. Overall, this investigation demonstrates the feasibility of using vector flow visualization techniques to non invasively examine internal flow characteristics related to voiding dysfunction in the urethral tract. PMID- 28830643 TI - Measurement of Liver Stiffness Using Shear Wave Elastography in a Rat Model: Factors Impacting Stiffness Measurement with Multiple- and Single-Tracking Location Techniques. AB - The clinical use of elastography for monitoring fibrosis progression is challenged by the subtle changes in liver stiffness associated with early-stage fibrosis and the comparatively large variance in stiffness estimates provided by elastography. Single-tracking-location (STL) shear wave elasticity imaging (SWEI) is an ultrasound elastography technique previously found to provide improved estimate precision compared with multiple-tracking-location (MTL) SWEI. Because of the improved precision, it is reasonable to expect that STL-SWEI would provide improved ability to differentiate liver fibrosis stage compared with MTL-SWEI. However, this expectation has not been previously challenged rigorously. In this work, the performance of STL- and MTL-SWEI in the setting of a rat model of liver fibrosis is characterized, and the advantages of STL-SWEI in staging fibrosis are explored. The purpose of this study was to determine what advantages, if any, arise from using STL-SWEI instead of MTL-SWEI in the characterization of fibrotic liver. Thus, the ability of STL-SWEI to differentiate livers at various METAVIR fibrosis scores, for ex vivo postmortem measurements, is explored. In addition, we examined the effect of the common confounding factor of fluid versus solid boundary conditions in SWEI experiments. Sprague-Dawley rats were treated with carbon tetrachloride over several weeks to produce liver disease of varying severity. STL and MTL stiffness measurements were performed ex vivo and compared with the METAVIR scores from histological analysis and the duration of treatment. A strong association was observed between liver stiffness and weeks of treatment with the liver toxin carbon tetrachloride. Direct comparison of STL- and MTL-SWEI measurements revealed no significant difference in ability to differentiate fibrosis stages based on SWEI mean values. However, image interquartile range was greatly improved in the case of STL-SWEI, compared with MTL-SWEI, at small beam spacing. PMID- 28830644 TI - Ultrasound-Guided Fine-Needle Aspiration of Non-palpable and Suspicious Axillary Lymph Nodes with Subsequent Removal after Tattooing: False-Negative Results and Concordance with Sentinel Lymph Nodes. AB - Ultrasonography-guided fine-needle aspiration (US-guided FNA) for axillary lymph nodes (ALNs) is currently used with various techniques for the initial staging of breast cancer and tagging of ALNs. With the implementation of the tattooing of biopsied ALNs, the rate of false-negative results of US-guided FNA for non palpable and suspicious ALNs and concordance with sentinel lymph nodes were determined by node-to node analyses. A total of 61 patients with breast cancer had negative results for metastasis on US-guided FNA of their non-palpable and suspicious ALNs. The biopsied ALNs were tattooed with an injection of 1-3 mL Charcotrace (Phebra, Lane Cove West, Australia) ink and removed during sentinel lymph node biopsy or axillary dissection. We determined the rate of false negative results and concordance with the sentinel lymph nodes by a retrospective review of surgical and pathologic findings. The association of false-negative results with clinical and imaging factors was evaluated using logistic regression. Of the 61 ALNs with negative results for US-guided FNA, 13 (21%) had metastases on final pathology. In 56 of 61 ALNs (92%), tattooed ALNs corresponded to the sentinel lymph nodes. Among the 5 patients (8%) without correspondence, 1 patient (2%) had 2 metastatic ALNs of 1 tattooed node and 1 sentinel lymph node. In multivariate analysis, atypical cells on FNA results (odds ratio = 20.7, p = 0.040) was independently associated with false-negative FNA results. False negative ALNs after US-guided FNA occur at a rate of 21% and most of the tattooed ALNs showed concordance with sentinel lymph nodes. PMID- 28830645 TI - iCTC drug resistance (CDR) Testing ex vivo for evaluation of available therapies to treat patients with epithelial ovarian cancer. AB - GOALS: Management of epithelial ovarian cancer (EOC) could use serial measurements of invasive circulating tumor cells (iCTCs) for monitoring therapeutic response and early detection of disease progression/recurrence. Goals of this study are to develop an iCTC drug resistance (CDR) assay and to evaluate clinical significance of patient-derived, cultured iCTCs in selecting available therapies. METHODS: The CDR assay using Taxol-Carboplatin and eight other EOC drugs at the concentration used for patients was performed. Blood was donated by six patients before primary Taxol-Carboplatin chemotherapy, one recurrent patient, six patients during and after their course of chemotherapy, and two patients with benign disease for procedure control. CDR score above and below 100 indicates sensitivity and resistance, respectively, to that drug. RESULTS: Five of six pre-therapy samples had >20 iCTCs/>111 CDR for Taxol-Carboplatin sensitivity, and one had 40 iCTCs/23 CDR for resistance. The recurrent sample had 58 iCTCs/5 CDR for resistance. Four of six post-therapy patients had iCTCs decreased to 0/>153 CDR indicating sensitivity, while two patients had >45 iCTCs/<85 CDR indicating resistance. The patients' treatment history and follow up confirmed that patients were in response or remission when iCTCs were sensitive to Taxol-Carboplatin, and patients were in relapse or recurrence when iCTCs were resistant to Taxol-Carboplatin. CONCLUSION: Further investigation on the CDR assay is warranted to examine its use in selecting drugs before treating a patient. PMID- 28830647 TI - Utility of Prognostic Markers in Second-line Treatment of Metastatic Urothelial Cancer. PMID- 28830646 TI - Dynamics of patient reported quality of life and symptoms in the acute phase of online adaptive external beam radiation therapy for locally advanced cervical cancer. AB - OBJECTIVE: For locally advanced cervical cancer patients, treated with External Beam Radiotherapy (EBRT), Quality of Life (QoL) questionnaires arefrequently used to evaluate treatment-related symptoms and functioning scales. Currently, it is unknown how those evolve during the radiation treatment course. In this prospective study we report on weekly-captured patient-reported QoL and symptoms during image-guided adaptive radiotherapy (IGART) of cervical cancer patients. MATERIAL AND METHODS: Between January 2012 and September 2016, all locally advanced cervical cancer patients treated with IGART and brachytherapy with or without chemotherapy or hyperthermia, were eligible. QoL was assessed at baseline; weekly during the first five weeks of treatment; 1week, 1 and 3months after treatment, using the EORTC QLQ-C30 and the QLQ-CX24 questionnaires. Comparisons were made with an age-matched norm population. RESULTS: Among the 138 (70%) responders, most symptoms showed a moderate-to-large increase, reaching a maximum at the end of treatment, or first week after treatment with return to baseline value at 3months after treatment. While most symptoms gradually increased during the first five weeks, diarrhea and bowel cramps already markedly increased within the first three weeks to reach a plateau at the 5th week of treatment. Global health and functioning were temporarily decreased and returned to a plateau at baseline level 3months after treatment, except for cognitive functioning. CONCLUSION: A profound impact on QoL was observed during the radiation treatment course, temporarily affecting functioning. The maximum impaired was reached at the end of EBRT. PMID- 28830648 TI - Feasibility of corifollitropin alfa/GnRH antagonist protocol combined with GnRH agonist triggering and freeze-all strategy in polycystic ovary syndrome patients. AB - BACKGROUND/PURPOSE: The long-acting corifollitropin alfa is comparable to FSH in terms of pregnancy outcomes in normal responders and poor responders. Corifollitropin alfa has never been studied in polycystic ovary syndrome (PCOS) patients because of concerns of excessive ovarian stimulation and ovarian hyperstimulation syndrome (OHSS). The purpose of the study was to evaluate if corifollitropin alfa can be used in PCOS patients. METHODS: Forty PCOS patients who were going to undergo in vitro fertilization were enrolled in this study. A single injection of corifollitropin alfa was administered on cycle day 2 or day 3. From stimulation day 8 onwards, daily FSH was administered until the day of final oocyte maturation. Cetrorelix was administered from stimulation day 5 to prevent premature LH surge. Final oocyte maturation was triggered by: acetate. All embryos were cryopreserved and replaced in subsequent cycles. RESULTS: All 40 patients were subjected to oocyte retrieval, and none developed moderate or severe ovarian hyperstimulation syndrome (0%, 95% CI 0-0.088). For each patient, an average of 23.4 (+/-7.4; 95% CI 21.0-25.7) oocytes were retrieved and a mean of 11.7 (+/-6.4; 95% CI 9.6-13.8) embryos were frozen. Mean serum estradiol level on the day of GnRHa triggering was 7829.9 pg/ml (+/-3297; 95% CI 6775-8885). The cumulated ongoing pregnancy rate after 3 frozen-thawed embryo transfers was 75.0% (95% CI 61.6%-88.4%). CONCLUSION: The results suggest that corifollitropin alfa/GnRH antagonist protocol can be used in PCOS patients, in combination with GnRHa triggering and embryo cryopreservation. PMID- 28830649 TI - Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model. AB - Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL 17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients. PMID- 28830650 TI - Basics of bone metabolism and osteoporosis in common pediatric neuromuscular disabilities. AB - Bone modeling is a process that starts with fetal life and continues during adolescence. Complex factors such as hormones, nutritional and environmental factors affect this process. In addition to these factors, physical conditioning and medications that have toxic effects on bony tissue should be carefully considered in patient follow-up. Osteoporosis is a significant problem in pediatric population because of ongoing growth and development of skeletal system. Two types of osteoporosis are primary and secondary types and children with neuromuscular disabilities constitute a major group with secondary osteoporosis. Low bone mass in patients with cerebral palsy, spina bifida, and Duchenne muscular dystrophy cause increased bone fragility in even slight traumas. Maximizing peak bone mass and prevention of bone loss are very important to reduce the fracture risk in neuromuscular diseases. This article aims to review the determinants of bone physiology and bone loss in children with cerebral palsy, spina bifida, and Duchenne muscular dystrophy. PMID- 28830651 TI - Development and validation of optimal cut-off value in inter-arm systolic blood pressure difference for prediction of cardiovascular events. AB - BACKGROUND: An inter-arm systolic blood pressure difference (IAD) is associated with cardiovascular disease. The aim of this study was to develop and validate the optimal cut-off value of IAD as a predictor of major adverse cardiac events in patients with arteriosclerosis risk factors. METHODS: From 2009 to 2014, 1076 patients who had at least one cardiovascular risk factor were included in the analysis. We defined 700 randomly selected patients as a development cohort to confirm that IAD was the predictor of cardiovascular events and to determine optimal cut-off value of IAD. Next, we validated outcomes in the remaining 376 patients as a validation cohort. The blood pressure (BP) of both arms measurements were done simultaneously using the ankle-brachial blood pressure index (ABI) form of automatic device. The primary endpoint was the cardiovascular event and secondary endpoint was the all-cause mortality. RESULTS: During a median period of 2.8 years, 143 patients reached the primary endpoint in the development cohort. In the multivariate Cox proportional hazards analysis, IAD was the strong predictor of cardiovascular events (hazard ratio: 1.03, 95% confidence interval: 1.01-1.05, p=0.005). The receiver operating characteristic curve revealed that 5mmHg was the optimal cut-off point of IAD to predict cardiovascular events (p<0.001). In the validation cohort, the presence of a large IAD (IAD >=5mmHg) was significantly associated with the primary endpoint (p=0.021). CONCLUSIONS: IAD is significantly associated with future cardiovascular events in patients with arteriosclerosis risk factors. The optimal cut-off value of IAD is 5mmHg. PMID- 28830652 TI - Hepatocyte growth factor (HGF) optimizes oral traumatic ulcer healing of mice by reducing inflammation. AB - OBJECTIVE: To evaluate the influence of overexpression HGF on the healing of traumatic ulcer of oral mucosa of mice. MATERIAL AND METHODS: Mice were divided into two groups: wild type C57BL6(WT) and HGF high expression transgenic (HGF-Tg) mice. Traumatic ulcer of all mice were made by number 15 scalpel blade. Mice were sacrificed after 5days and the inflammation score and expression of TNFalpha, IFNgamma, c-Met, apoptosis (TUNEL) and 40 serum inflammation cytokines were estimated. RESULTS: HGF-Tg mice presented a lower inflammation score (p=0.011), Serum TNFalpha expression in HGF-Tg ulcers is 1.3 times than WT ulcer and the difference is statistical significance (t test, p=0.003). Serum c-Met protein in HGF-Tg mice were significantly higher than WT mice (t test, p=0.004). No statistical difference was observed in the serum IFNgamma between WT ulcer and HGF-Tg ulcer (t test, p=0.268). TNFalpha positive cytoplasm expression cells in connective tissue of HGF-Tg mice is significantly lower than that of WT group (t test, p=0.029). C-Met positive cytoplasm expression cells in both epithelium and connective tissue of HGF-Tg group is significantly higher than that of WT group (t test, p=0.040, p=0.000). Samples in HGF-Tg group showed a lower number of positive cells of epithelium TUNEL staining compared with that in the WT group (t test, p=0.035). CONCLUSIONS: HGF exhibited anti-inflammatory potential in oral traumatic ulcer through the reduction of epithelial apoptosis, connective tissue TNFalpha expression and induction of c-Met expression. PMID- 28830653 TI - Recombinant human IgG1 based Fc multimers, with limited FcR binding capacity, can effectively inhibit complement-mediated disease. AB - There is a lack of effective targeted therapies for the treatment of complement dependent diseases. We developed two recombinant Fc multimers, G207 and G211, with limited ability to interact with low/moderate affinity FcgammaRs, but with high avidity for C1q. These drugs effectively inhibited complement dependent cytotoxicity (CDC) in vitro, and prevented the deposition of C1q, C3b and MAC, on the surface of Ab-opsonized cells. Importantly, these inhibitory effects were both C1q dependent and independent. In order to determine the biologic relevance of our findings, we evaluated the clinical efficacy of these drugs in three different animal models, acute RBC hemolysis, anti-Thy-1 nephritis and passive Heymann's nephropathy (PHN), in which disease pathophysiology relies preferentially on complement activation. While G207 was protective in the anti Thy-1 nephritis and PHN models, G211 was protective in all of the models tested and could effectively treat PHN. In the anti-Thy-1 nephritis model, G211 prevented the characteristic histologic changes associated with the disease and limited glomerular deposition of C3. Collectively, these data suggest that "complement preferential" Fc multimers offer a novel approach to the treatment of complement mediated diseases. PMID- 28830654 TI - Social Determinants of Overweight and Obesity Rates by Elementary School in a Predominantly Hispanic School District. AB - OBJECTIVE: This study analyzes the social determinants associated with the overweight or obesity prevalence of 85 elementary schools during the 2010-11 academic year in a predominantly Hispanic school district. METHODS: A binomial logistic regression is used to analyze the aggregate overweight or obesity rate of a school by the percent of Hispanic students in each school, selected school and neighborhood characteristics, and its geographical location. RESULTS: The proportion of Hispanic enrollment more readily explains a school's aggregate overweight or obesity rate than social determinants or spatial location. Number of fast food establishments and the academic ranking of a school appear to slightly impact the aggregate prevalence rate. Spatial location of school is not a significant factor, controlling for other determinants. CONCLUSIONS: An elementary school's overall overweight or obesity rate provides a valuable health indicator to study the social determinants of obesity among Hispanics and other students within a local neighborhood. PMID- 28830655 TI - Phenotypic approaches to positional therapy for obstructive sleep apnoea. PMID- 28830656 TI - Using the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey to Predict the Occurrence of Short-Term Coronary Heart Disease Events in Women. AB - BACKGROUND: Few instruments capture symptoms that predict cardiac events in the short-term. This study examines the ability of the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey to predict acute cardiac events within 3 months of administration and to identify the prodromal symptoms most associated with short-term risk in women without known coronary heart disease. METHODS: The McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey was administered to 1,097 women referred to a cardiologist for initial coronary heart disease evaluation. Logistic regression models were used to examine prodromal symptoms individually and in combination to identify the subset of symptoms most predictive of an event within 3 months. RESULTS: Fifty-one women had an early cardiac event. In bivariate analyses, 4 of 30 prodromal symptoms were significantly associated with event occurrence within 90 days. In adjusted analyses, women reporting arm pain or discomfort and unusual fatigue were more likely (OR, 4.67; 95% CI, 2.08-10.48) to have a cardiac event than women reporting neither. CONCLUSIONS: The McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey may assist in predicting short-term coronary heart disease events in women without known coronary heart disease. PMID- 28830657 TI - The role of propionic acid at diagnosis predicts mortality in patients with severe sepsis: Methodological issues. PMID- 28830658 TI - Inotropes for the management of acute heart failure and their renal repercussions: Are they all the same? PMID- 28830659 TI - Nutrition therapy for diabetes: Implications for decreasing cardiovascular complications. PMID- 28830660 TI - Population characteristics associated with pharmacy-based influenza vaccination in United States survey data. AB - OBJECTIVES: To examine the population characteristics associated with the health behavior of receiving an influenza vaccine from a pharmacy-based setting. DESIGN: Secondary analysis of data from states that participated in an optional influenza module in the 2014 Behavioral Risk Factor Surveillance System, a state-based observational survey of U.S. adults. SETTING AND PARTICIPANTS: Analytic sample of 28,954 respondents from 8 states and Puerto Rico who reported receiving an influenza vaccination in the past year. MAIN OUTCOME MEASURES: The main outcome was a self-reported categoric variable indicating the setting of the most recent seasonal influenza vaccination: doctor's office, pharmacy-based store, or other setting. RESULTS: Multinomial logistic regression results showed that environmental, predisposing, enabling, and need factors in the Andersen model were salient features associated with odds of using pharmacy-based influenza vaccination settings instead of a doctor's office. Residents of states that allowed pharmacists as immunizers before 1999 reported greater use of pharmacy based store settings (odds ratio [OR] 1.31). Compared with young adults, individuals 65 years of age and older were more likely to choose a pharmacy-based store than a doctor's office (OR 1.41) and less likely to use other community settings (OR 0.45). Compared with non-Hispanic whites, black respondents were less likely to use pharmacy-based store vaccination (OR 0.51), and multiracial and Hispanic respondents were more likely to use other settings (ORs 1.47 and 1.60, respectively). Enabling and need factors were also associated with setting. CONCLUSION: Based on this dataset of selected states from 2014, almost one-fourth of U.S. adults who reported receiving an annual influenza vaccination did so from a pharmacy-based store; 35% reported using other community-based settings that may enlist pharmacists as immunizers. There were striking disparities in use of nontraditional vaccination settings by age and race or ethnicity. Pharmacists and pharmacies should address missed opportunities for vaccination by targeting outreach efforts based on environmental and predisposing characteristics. PMID- 28830661 TI - First-Time Manager: Transitioning Into a Leadership Role. PMID- 28830662 TI - Letting Patients Decide How to Receive Their Imaging Results; A Good Idea or a Dangerous Practice? Part 2: Counterpoint: Patients Should Not Have Unchaperoned Access to Radiology Reports. PMID- 28830663 TI - The Clinician-Educator Pathway in Radiology: An Analysis of Institutional Promotion Criteria. AB - PURPOSE: To provide radiology departmental promotional committees and vice chairs of education with a more global perspective on the types of academic activity valued by institutions to aid in their faculty mentoring and standardizing of the Clinician-Educator (ClinEd) pathway. METHODS: Ninety-two research schools were ranked into three tiers. Ranking was correlated with the presence of a ClinEd track. Thirty promotion documents (ten from each tier) were analyzed to identify common criteria. Differences in guidelines between tiers were assessed by the frequency distribution of criteria. RESULTS: Tier 1 had a significantly greater proportion of schools with a ClinEd track than tier 2 (73% versus 44%, p < 0.05). Thirty-nine criteria were identified and organized into four categories teaching (13), scholarship (12), service/clinical excellence (7), and research (7). The top five included meeting presentations, trainee evaluations, leadership in committees, development of teaching methodologies and materials, and publication of book chapters. First and second tier schools were most similar in frequency distribution. CONCLUSIONS: The criteria for the ClinEd promotion track still vary across institutions, though many commonalities exist. A handful of innovative criteria reflect the changing structure of modern health care systems, such as incorporation of online teaching modules and quality improvement efforts. As health care changes, guidelines and incentive structures for faculty should change as well. The information gathered may provide promotion committees with a more global perspective on the types of academic activity valued by modern-day institutions to aid in the national standardization of this pathway and to assist in faculty mentoring. PMID- 28830664 TI - The management and outcome of Bacillus Calmette-Guerin vaccine overdose. PMID- 28830666 TI - Depression may negatively affect the change in freezing of gait following subthalamic nucleus stimulation in Parkinson's disease. AB - OBJECTIVE: To assess the influence of preoperative depression on the change in freezing of gait (FOG) following subthalamic nucleus stimulation (STN-DBS) in patients with Parkinson's disease (PD). METHODS: One hundred and twelve PD patients were included who received bilateral STN-DBS. Of these, 33 had no preoperative depression (PD-ND) and the other 79 had preoperative depression (PD D). Each PD-ND patient was matched with one PD-D patient by the propensity score for which sex, age at PD onset, disease duration, UPDRS-III score during off medication state, levodopa-equivalent daily dose, and mini mental state examination were the independent variables. We compared both a FOG-questionnaire (FOG-Q) and the axial score from UPDRS-III between the two groups over 12-month follow-up. RESULTS: During the off-medication state, FOG-Q at 12-month was decreased with STN-DBS in both PD-ND (-52.9%, p < 0.001) and PD-D (-24.2%, p < 0.001) with a significant difference in the change of FOG in favor of PD-ND (p = 0.001). Similarly, there was an improvement in the axial score for both PD-ND ( 66.1%, p < 0.001) and PD-D (-45.3%, p < 0.001) at 12-month with a significant difference between the groups. (p = 0.005). During the on-medication state, both the FOG-Q and axial score at 12-month were not improved with STN-DBS in the PD-ND and PD-D with no difference between the groups. CONCLUSIONS: Our findings suggest that preoperative depression negatively affects the outcome of FOG following STN DBS in the off-medication state but not in the on-medication state. PMID- 28830667 TI - Plasma exchange in kidney transplantation: Still a valuable option for nephrotic syndrome recurrence. AB - About 30% of the cases of steroid resistant nephrotic syndrome display a genetically determined disease and will not recur after kidney transplant; the other cases with fully or partially immunological pathogenesis display a high risk of post transplant recurrence. Although lots of studies were carried out in the last 50 years the pathogenetic mechanism is still obscure and the therapeutic approach mostly empirical. The cornerstones principles of the therapies are based on removal of a still undefined "permeability factor" through plasma-exchange or other apheresis techniques and inhibition of its synthesis by the immunological system through different drugs. The probability of successfully inducing persistant remission is nowadays around 30%through the different schemes experimented so far which mostly include plasmapheresis. Rituximab in the last years has significantly increased the efficacy of the treatments. Non responders are rapidly evolving to graft loss and will most probably recur also in subsequent transplant. Apart from genetics no other risk factors are predictive for recurrence. PMID- 28830665 TI - The Intersection of Immune Responses, Microbiota, and Pathogenesis in Giardiasis. AB - Giardia lamblia is one of the most common infectious protozoans in the world. Giardia rarely causes severe life-threatening diarrhea, and may even have a slight protective effect in this regard, but it is a major contributor to malnutrition and growth faltering in children in the developing world. Giardia infection also appears to be a significant risk factor for postinfectious irritable bowel and chronic fatigue syndromes. In this review we highlight recent work focused on the impact of giardiasis and the mechanisms that contribute to the various outcomes of this infection, including changes in the composition of the microbiota, activation of immune responses, and immunopathology. PMID- 28830668 TI - Evaluation of AnyplexTM II RV16 and RB5 real-time RT-PCR compared to Seeplex(r) RV15 OneStep ACE and PneumoBacter ACE for the simultaneous detection of upper respiratory pathogens. AB - This prospective study was performed to evaluate and compare the performance of the multiplex PCR Seeplex(r) assays and AnyplexTM II assays. From May 2014 until April 2016, a total of 247 respiratory samples were collected in Okinawa, Japan. Multiple respiratory pathogens were detected in 37% of patients with positive results. The most prevalent pathogens were influenza A virus and respiratory syncytial virus B. Despite minor differences in capabilities, both the Seeplex(r) assays and AnyplexTM II assays can be easily implemented in diagnostic or research laboratories to optimize the detection and management of respiratory pathogen induced diseases. PMID- 28830669 TI - Central systolic blood pressure and aortic stiffness response to dietary sodium in young and middle-aged adults. AB - High dietary sodium intake can lead to hypertension and increased incidence of cardiovascular disease. We sought to determine the effect of short-term dietary sodium loading on central blood pressure and arterial stiffness in young (YG; 22 40 years) and middle-aged (MA; 41-60 years) normotensive adults. YG (n = 49; age: 27 +/- 1 years) and MA (n = 36; age: 52 +/- 1 years) subjects were randomized, in a cross-over design, to 7 days of low-sodium (LS; 20 mmol/d) or high-sodium (HS; 300 mmol/d) diet. On the last day of each diet, central pressures, forward and reflected wave amplitudes (via radial artery applanation tonometry), and carotid femoral pulse wave velocity were assessed. Central systolic blood pressure (cSBP) was greater after HS in both YG (LS: 96 +/- 1 vs. HS: 99 +/- 1 mm Hg; P = .012) and MA (LS: 106 +/- 2 vs. HS: 115 +/- 3 mm Hg; P < .001). However, the increase in cSBP was greater in MA (YG: 4 +/- 1 vs. MA: 9 +/- 2; P = .02). In MA subjects, HS elicited greater forward (LS: 25 +/- 1 vs. HS: 29 +/- 1 mm Hg; P < .001) and reflected (LS: 19 +/- 1 vs. HS: 23 +/- 1 mm Hg; P < .001) wave amplitudes. Carotid-femoral pulse wave velocity was also greater in MA on HS but after adjustment for mean arterial pressure, the difference was no longer significant. Our data indicate that HS intake leads to a greater increase in cSBP in MA adults, which may be the result of increased forward and reflected wave amplitudes. PMID- 28830670 TI - Ultrasound gel as an unrecognized source of exposure to phthalates and phenols among pregnant women undergoing routine scan. AB - BACKGROUND: Systemic absorption of phthalates and parabens has been demonstrated after dermal application of body lotion, and medical devices such as intravenous bags and tubing have been identified as a source of exposure to di(2-ethylhexyl) phthalate (DEHP). However, use of products during medical procedures such as aqueous gel applied during obstetrical ultrasound in pregnancy has not been investigated as a potential source of endocrine disrupting chemical (EDC) exposure. Human studies have associated EDCs with various adverse pregnancy outcomes. There is a need to identify sources of inadvertent exposure to EDCs especially during vulnerable developmental periods such as pregnancy. OBJECTIVES: We conducted a pilot study to determine whether use of gel during routine obstetrical ultrasound increased urinary concentrations of phthalate and phenol biomarkers. METHODS: We recruited 13 women from the Massachusetts General Hospital who provided spot urine samples at the time of their second trimester anatomic survey. The first sample was collected prior to the procedure (pre exposure, time 1), and two additional samples were obtained at approximately 1-2h (time 2) and 7-12h (time 3) post-exposure following the scan. RESULTS: Urinary concentrations of several DEHP metabolites and metabolite of diisononyl cyclohexane-1,2-dicarboxylate (DINCH) increased across time. For example, the geometric mean concentrations of mono(2-ethyl-5-hydroxyhexyl) phthalate increased from 3.1ng/ml to 7.1ng/ml (p-value=0.03) between time 1 and time 3. We also observed significant differences in concentrations of metabolites of butylbenzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP). For example, mono-n-butyl phthalate (metabolite of DnBP) decreased from 3.5ng/ml to 1.8ng/ml (p-value=0.04) between time 1 and time 2, but then increased to 6.6ng/ml (p-value=0.002) at time 3. Propylparaben concentrations increased from 8.9ng/ml to 33.6ng/ml between time 1 and time 2 (p-value=0.005), followed by a decrease to 12.9ng/ml at time 3 (p-value=0.01). However, we cannot rule out the possibility that some of the observed differences are due to other sources of exposure to these compounds. CONCLUSIONS: While additional research is needed, this pilot study potentially identifies a previously unknown source of phthalate and paraben exposure among pregnant women undergoing routine ultrasound examination. PMID- 28830671 TI - Inducible Enhancement of T Cell Function and Anti-tumor Activity after Adoptive Transfer. PMID- 28830672 TI - Vascular Adverse Events During Long-term Nilotinib Therapy in Patients With Chronic Myeloid Leukemia. PMID- 28830673 TI - Response to: Tropical Arthritogenic Alphaviruses. PMID- 28830674 TI - Posterior Ankle Impingement Syndrome. PMID- 28830675 TI - Expansion of blood IgG4+ B, TH2, and regulatory T cells in patients with IgG4 related disease. AB - BACKGROUND: IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition affecting various organs and has a diverse clinical presentation. Fibrosis and accumulation of IgG4+ plasma cells in tissue are hallmarks of the disease, and IgG4-RD is associated with increased IgG4 serum levels. However, disease pathogenesis is still unclear, and these cellular and molecular parameters are neither sensitive nor specific for the diagnosis of IgG4-RD. OBJECTIVE: Here we sought to develop a flow cytometric gating strategy to reliably identify blood IgG4+ B cells to study their cellular and molecular characteristics and investigate their contribution in disease pathogenesis. METHODS: Sixteen patients with histologically confirmed IgG4-RD, 11 patients with sarcoidosis, and 30 healthy subjects were included for 11-color flow cytometric analysis of peripheral blood for IgG4-expressing B cells and TH subsets. In addition, detailed analysis of activation markers and chemokine receptors was performed on IgG4-expressing B cells, and IgG4 transcripts were analyzed for somatic hypermutations. RESULTS: Cellular and molecular analyses revealed increased numbers of blood IgG4+ memory B cells in patients with IgG4-RD. These cells showed reduced expression of CD27 and CXCR5 and increased signs of antibody maturation. Furthermore, patients with IgG4-RD, but not patients with sarcoidosis, had increased numbers of circulating plasmablasts and CD21low B cells, as well as TH2 and regulatory T cells, indicating a common disease pathogenesis in patients with IgG4-RD. CONCLUSION: These results provide new insights into the dysregulated IgG4 response in patients with IgG4-RD. A specific "peripheral lymphocyte signature" observed in patients with IgG4-RD, could support diagnosis and treatment monitoring. PMID- 28830676 TI - Gluten related illnesses and severe mental disorders: a comprehensive review. AB - The putative role of gluten in the pathophysiology of severe mental illnesses remains uncertain and there is doubt about the possible benefit of gluten-free diets for individuals affected by psychosis and mood disorders. The objective of this review was to summarize the findings linking gluten related conditions to pathophysiological substrates implicated in schizophrenia and mood disorders and review the evidences of potential benefits of glute-free diets in these populations. A literature search was conducted within PubMed and Scielo databases including references from inception until March 1st 2017. The strategy search was to use the key words "gluten", "celiac disease", "wheat", "bipolar disorder", "mood disorders", "psychosis", "schizophrenia", "depression". In the review about the potential efficacy of gluten-free diets in severe mental illnesses, we included only studies with original data, including cross sectional and longitudinal studies and clinical trials. Book chapters, review articles and meta analysis and republished data were excluded. Although the current available evidences suggest that people with celiac disease or gluten allergy could have a slightly higher risk of schizophrenia and mood disorders compared to the general population, the literature review reveals significant inaccuracies in the data. There is insufficient evidence to recommend gluten-free diets for populations with psychosis and mood disorders. PMID- 28830677 TI - HMGA2 upregulation mediates Cd-induced migration and invasion in A549 cells and in lung tissues of mice. AB - Cadmium (Cd) is a toxic metal widely found in a number of environmental matrices, and it induces serious adverse effects in various organs and tissues. In this study, the role of high mobility group A2 (HMGA2) in promoting migration and invasion in Cd-treated A549 cells and lung tissues of mice was investigated. Our findings showed that exposure to Cd (2 MUM) for 48 h or subcutaneous injection of Cd daily for 6 weeks significantly enhanced the expression of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-2 (MMP-2), phosphorylated focal adhesion kinase (p-FAK), and HMGA2 in A549 cells or lung tissues of mice. In A549 cells, HMGA2 knockdown significantly decreased expression of MMP-9, MMP-2 and p-FAK and inhibited the migration and invasion compared to that of only Cd treated cultures. Overexpression of HMGA2 in HEK-293T cells increased expression of MMP-9, MMP-2 and p-FAK and enhanced the migration and invasion compared with the empty vector transfection group. In conclusion, upregulation of HMGA2 plays an important role in Cd-enhanced migration and invasion. Suppressing HMGA2 expression might have potential values in prevention of Cd-resulted toxicities. PMID- 28830678 TI - Expression and purification of functional insulin and insulin-like growth factor 1 holoreceptors from mammalian cells. AB - The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) are receptor tyrosine kinases (RTKs) involved in the regulation of many important cellular processes. The current proposed models of activation are derived from structural studies using soluble extracellular domains and cytoplasmic tyrosine kinase domains. Preparations of full length IR and IGF1R have been hampered by the need for unconventional affinity chromatography resins and/or harsh eluting conditions. Here, we present a purification protocol to obtain full-length, detergent solubilized IR and IGF1R at quantities suitable for biochemical and structural characterization. We screened a panel of 24 structurally diverse detergents for optimal ligand activation. The receptors purified in n-dodecyl beta-D-maltoside showed ligand-stimulated autophosphorylation and kinase activity, suggesting an intact transmembrane signaling mechanism. This convenient purification protocol can be used to produce high quantities of IR, IGF1R, or other RTKs, and can be adapted for other challenging membrane proteins. PMID- 28830680 TI - Neural signatures of recognition memory in 10- to 12-month-old infants. AB - Understanding memory mechanisms is crucial in the study of infant social and cognitive development. Here, we show that the Nc ERP component, known to reflect frequency-related attentional and/or memory processes, is a good candidate to investigate infant recognition memory. Previous paradigms have only investigated the effect of frequency during on-line stimulus presentation, but not during stimulus encoding. In this paper, we present a novel method for measuring the neural correlates of recognition memory and the 'degree' of familiarity in 10- to 12-month-old infants. During a familiarization phase, two images were presented frequently, while another two images were presented infrequently to the infants. In the test phase, the infrequent familiar, the frequent familiar, and the novel stimuli, were all presented with equal probability. We found larger Nc amplitudes following the familiar stimuli compared to the novel ones. The 'degree' of familiarity, on the other hand, did not modulate the Nc amplitude. These results can only be explained with memory-related processes, since in our paradigm the on line presentation frequency did not vary. Furthermore, the lack of familiarization frequency effect suggests that the Nc might be a neural correlate of declarative memory. PMID- 28830679 TI - Angeli's Salt, a nitroxyl anion donor, reverses endothelin-1 mediated vascular dysfunction in murine aorta. AB - Nitroglycerin (Gtn) is a treatment for cardiovascular patients due to its vasodilatory actions, but induces tolerance when given chronically. A proposed mechanism is the superoxide (O2-)-oxidative stress hypothesis, which suggests that Gtn increases O2- production. Nitric oxide (NO) exists in three different redox states; the protonated, reduced state, nitroxyl anion (HNO) is an emerging candidate in vascular regulation. HNO is resistant to scavenging and of particular interest in conditions where high levels of reactive oxygen species (ROS) exist. We hypothesize that treatment with Gtn will exacerbate endothelin 1 (ET-1) induced vascular dysfunction via an increase in ROS, while treatment with Angeli's Salt (AS), an HNO donor, will not. Aorta from mice were isolated and divided into four groups: vehicle, ET-1 [0.1MUM, 1MUM], ET-1+Gtn [Gtn 1MUM] and ET-1+AS [AS 1MUM]. Concentration response curves (CRCs) to acetylcholine (ACh) and phenylephrine (Phe) were performed. Aorta incubated with ET-1 (for 20-22h) exhibited a decreased relaxation response to ACh and an increase in Phe-mediated contraction. Aorta incubated with AS exhibited a reversal in ET-1 induced vascular and endothelial dysfunction. ET-1 increased ROS in aortic vascular smooth muscle cells (VSMCs), visualized by dihydroethidium (DHE) staining. AS incubated reduced this ROS generation, yet maintained with Gtn treatment. These data suggest that aorta incubated with the HNO donor, AS, can reverse ET-1 mediated vascular dysfunction, which may be through a decrease or prevention of ROS generation. We propose that HNO may be vasoprotective and that HNO donors studied as a therapeutic option where other organic nitrates are contraindicative. PMID- 28830681 TI - Cloning and characterization of an insect apolipoprotein (apolipophorin-II/I) involved in the host immune response of Antheraea pernyi. AB - Apolipoproteins are protein components of lipoprotein particles, and are increasingly recognized to be functioning in the innate immune systems of both insects and mammals. Mammalian apolipoprotein B (apoB) is associated with a diverse range of innate immune defenses including suppression of bacterial pathogenesis, virus toxicity neutralization, and inhibition of cytokine releases from immune cells. However, little is known about apoB homologous insect apolipophorin-II/I (apoLp-II/I) in controlling of specific pathogen-host encounters such as microbial infections. In the present study, we describe cDNA cloning and characterization of an apoLp-II/I from Chinese oak silk worm, Antheraea pernyi. The apoLp-II/I cDNA is 10237bp in length, which possesses an open reading frame encoding 3305 amino acids. A consensus cleavage site RGRR presenting from Arg710 to Arg713 implies posttranslational cleavage of this protein. Ap-apoLp-II/I shares high sequence identities with apoLp-II/I in lepidoptera and other insects. In addition, considerable similarities also exist between Ap-apoLp-II/I and human apoB, which basically positioned in first 1000 residues of the amino termini. Tissue distribution and time-course expression results demonstrate that Ap-apoLp-II/I transcripts were detected predominantly in the fat body, less in epidermis and rarely in midgut, while the synthetic apoLp II/I protein was abundant in hemocytes and plasma instead of the fatbody. Expression of Ap-apoLp-II/I was stimulated in response to bacterial challenge. In addition, our preliminary studies established a novel role for Ap-apoLp-II/I in regulating prophenoloxidase activation system. Taken together, apoLp-II/I may play an essential role in innate responses of Antheraea pernyi. PMID- 28830682 TI - From cholesterol to consciousness. AB - The nature of consciousness has been debated for centuries. It can be understood as part and parcel of the natural progression of life from unicellular to multicellular, calcium fluxes mediating communication within and between cells. Consciousness is the vertical integration of calcium fluxes, mediated by the Target of Rapamycin gene integrated with the cytoskeleton. The premise of this paper is that there is a fundamental physiologic integration of the organism with the environment that constitutes consciousness. PMID- 28830683 TI - Implementation of point-of-care testing in a general internal medicine practice: A confirmation study. AB - BACKGROUND: In a previous study we reported on the impact of point-of-care testing (POCT) on practice efficiency in an academic primary care practice that was established to develop new models of care delivery. Here we report a follow on confirmation study in a more typical primary care practice in the community. METHODS: In this observational study with a retrospective comparison analysis we measured metrics of practice efficiency on two patient cohorts: those that did not receive POCT and those that did. RESULTS: In the patient cohort that received POCT there was a 99% reduction in letters to patients (p<0.001), a 75% decrease in calls to patients (not significant due to small numbers), a 50% reduction in follow-up tests per visit (p=0.044) and a 38% reduction in follow-up visits due to abnormal test results (p=0.178). Financial analysis including testing costs, revenues and efficiency gains to the practice demonstrated a net financial benefit of $11.90-14.74 per patient visit. CONCLUSIONS: Our data confirm the earlier published findings that POCT can improve metrics of practice efficiency in a primary care practice. PMID- 28830684 TI - Axin1 up-regulated 1 accelerates stress-induced cardiomyocytes apoptosis through activating Wnt/beta-catenin signaling. AB - Stress-induced cardiomyocyte apoptosis contributes to the pathogenesis of a variety of cardiovascular diseases, but how stress induces cardiomyocyte apoptosis remains largely unclear. The present study aims to investigate the effects of Axin1 up-regulated 1 (Axud1), a novel pro-apoptotic protein, on the cardiomyocyte survival and the underlying mechanisms. To this end, a rat model under restraint stress (RS) was established and in vitro stress-induced cardiomyocytes culture was achieved. Our data showed that Axud1 was upregulated in the rat myocardia after exposure to RS. Anti-apoptotic Bcl-2 was decreased, whereas pro-apoptotic Bax and Cleaved caspase-3 (Cc3) were increased in a time dependent manner. The Wnt/beta-catenin signaling was observed to be interestingly activated in heart undergoing RS. In addition, the treatment of norepinephrine (NE) to in vitro cardiomyocytes increased Axud1 level and induced cell apoptosis. Wnt/beta-catenin signaling was consistently activated. Knockdown of Axud1 using specific siRNA blunted NE-induced cardiomyocytes apoptosis and also inactivated the Wnt/beta-catenin signaling. XAV-939, an inhibitor of Wnt/beta-catenin signaling, partially reversed the pro-apoptotic effect of NE. In conclusion, Axud1 accelerated stress-induced cardiomyocytes apoptosis through activation of Wnt/beta-catenin signaling pathway. Our data provided novel evidence that therapeutic strategies against Axud1 or Wnt/beta-catenin signaling might be promising in relation to RS-induced myocardial injury. PMID- 28830686 TI - Multistability in the corticothalamic system. AB - Neural field theory of the corticothalamic system is used to analyze the properties of its steady-state solutions, including their linear stability, in the parameter space of synaptic couplings for physiological parameter ranges representing normal arousal waking states in adult humans. The independent connections of the corticothalamic model define an eight-dimensional parameter space, while specific combinations of these connections parameterize intracortical, corticothalamic, and intrathalamic loops. Multistable regions are systematically identified and the existence of up to five steady-state solutions is confirmed, up to three of which are linearly stable. A key determinant for the existence of five steady states is found to be the number of nonzero connections. This finding had not been previously proposed as the determining factor of high multiplicities of multistability in mesoscopic models of the brain. In the corticothalamic model presented here, multistability occurs when the intrathalamic loop is present (i.e., the reticular nucleus inhibits the relay nuclei), and when the net synaptic effect of the intracortical loop is inhibitory. The signature of these additional waking states is an overall increased level of thalamic activity. It is argued that the additional steady states found may represent hyperarousal states which occur when the corticothalamic projections do not attenuate the activity of the cortex. PMID- 28830685 TI - Upregulation of PD-L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma. AB - Tumor-associated macrophages (TAMs) polarization represents a key regulatory process of tumor progression. However, the underlying mechanisms are unclear. This study aimed to investigate the relationship between secreted phosphoprotein 1 (SPP1) and TAMs in lung adenocarcinoma cells. THP-1 monocytes were differentiated into macrophages using PMA. PMA-treated THP-1 cells were co cultured with human A549 cells culture supernatant. SPP1 expression in TAMs isolated from lung adenocarcinoma tissues and PMA-treated THP-1 cells were measured. Macrophage polarization was identified by flow cytometric analysis. Cell migration and apoptosis were assessed by Transwell migration assays and flow cytometric analysis, respectively. SPP1 is highly expressed in tumor tissues and TAMs isolated from patients with an advanced TNM stage, and also in PMA-treated THP-1 cells. Co-culture with A549 cells strongly induced SPP-1 expression as well as M2 polarization of THP-1 cells, but it had little effect on short hairpin SPP1 (shSPP1)-transfected THP-1 cells. Interestingly, programmed death ligand 1 (PD L1), a critical regulator of M2 polarization, was downregulated in SPP1 knockdown THP-1 cells. Inhibition of PD-L1 induced a greater decline of the M2 markers IL 10 and Arg-1 but an increase in the M1 markers IL-12 and TNF-alpha. In addition, SPP1 knockdown in THP-1 cells can mitigate migration but promote apoptosis of A549 cells, and PD-L1 inhibition can further enhance this effect. THP-1 cells co cultured with A549 cells attenuated CD4+ T-cell activation, whereas SPP1 inhibition restored T-cell activation. These results highlight the importance of SPP1 in mediating macrophage polarization and lung cancer evasion, suggesting a potential therapeutic target for lung cancer. PMID- 28830688 TI - Non-linear optical imaging and quantitative analysis of the pathological changes in normal and carcinomatous human colorectal muscularis. AB - Non-linear optical (NLO) imaging based on two-photon excitation (2PE) and second harmonic generation (SHG) has been widely used to image microstructures of biomedical specimens over the last two decades. We employed NLO imaging technology to investigate the histology of normal and carcinomatous human colorectal muscularis in transverse and longitudinal views. Results show there are different patterns of pathological changes of muscularis in tissue structure and cell morphology from both views. The NLO imaging provides identical histological information as the H&E images but requires neither stain nor tissue processing. Our study indicates that NLO imaging technology shows more detailed microstructure, which is a critical complementary tool in pathological diagnosis of colorectal tumours. It suggests that NLO imaging could be a very important diagnostic tool to help pathologists realise the real time early detection of human colorectal tumours in the foreseeable future. PMID- 28830687 TI - Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype. AB - Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1 /Delta mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence associated beta-galactosidase activity, gammaH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss. PMID- 28830690 TI - Interdigitating dendritic cell sarcoma: diagnostic pitfalls, treatment challenges and role of transdifferentation in pathogenesis. PMID- 28830689 TI - Clinicopathological and molecular stability and methylation analyses of gastric papillary adenocarcinoma. AB - The molecular alterations and pathological features of gastric papillary adenocarcinoma (GPA) remain unknown. We examined GPA samples and compared their molecular and pathological characteristics with those of gastric tubular adenocarcinoma (GTA). Additionally, we identified pathological and molecular features of GPA that vary with microsatellite stability. In the present study, samples from 63 GPA patients and 47 GTA patients were examined using a combination of polymerase chain reaction (PCR)-microsatellite assays and PCR pyrosequencing in order to detect microsatellite instability (microsatellite instability, MSI; microsatellite stable, MSS), methylation status (low methylation, intermediate methylation and high methylation level), and chromosomal AI in multiple cancer-related loci. Additionally, the expression levels of TP53 and Her2 were evaluated using immunohistochemistry. GTA and GPA are statistically different in their frequency of pathological features, including mucinous, poorly differentiated and invasive micropapillary components. Clear genetic patterns differentiating GPA and GTA could not be identified with a hierarchical cluster analysis, but microsatellite stability was linked with TP53 and Her2 overexpression. Methylation status in GPA was also associated with the development of high microsatellite instability. However, no pathological differences were associated with microsatellite stability. We suggest that although molecular alterations in a subset of GPAs are closely associated with microsatellite stability, they play a minor role in GPA carcinogenesis. PMID- 28830691 TI - High grade adenocarcinoma in the ectopic prostate accompanied by a low grade adenocarcinoma in the orthotopic prostate: an unusual diagnostic pitfall. PMID- 28830692 TI - Hearts, minds, nudges and shoves: (How) can we mobilise communities for vaccination in a marketised society? PMID- 28830693 TI - Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus vaccine. AB - OBJECTIVES: Randomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAXTM (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults>=50years of age (NCT02519855). METHODS: Overall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015-2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4. IMMUNOGENICITY ENDPOINTS: Varicella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4weeks postvaccination was measured by hemagglutination inhibition (HAI) assay. SAFETY ENDPOINTS: Injection-site and systemic adverse experiences (AEs) within 28days following any vaccination and serious AEs throughout the study. RESULTS: The adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed. CONCLUSION: The concomitant administration of ZV and IIV4 to adults>=50years of age induced VZV specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated. PMID- 28830694 TI - Vaccine hesitancy, refusal and access barriers: The need for clarity in terminology. AB - Although vaccination uptake is high in most countries, pockets of sub-optimal coverage remain posing a threat to individual and population immunity. Increasingly, the term 'vaccine hesitancy' is being used by experts and commentators to explain sub-optimal vaccination coverage. We contend that using this term to explain all partial or non-immunisation risks generating solutions that are a poor match for the problem in a particular community or population. We propose more precision in the term 'vaccine hesitancy' is needed particularly since much under-vaccination arises from factors related to access or pragmatics. Only with clear terminology can we begin to understand where the problem lies, measure it accurately and develop appropriate interventions. This will ensure that our interventions have the best chance of success to make vaccines available to those who want them and in helping those who are uncertain about their vaccination decision. PMID- 28830695 TI - Unintentional contaminant transfer from groundwater to the vadose zone during source zone remediation of volatile organic compounds. AB - Historical heavy use of chlorinated solvents in conjunction with improper disposal practices and accidental releases has resulted in widespread contamination of soils and groundwater in North America and worldwide. As a result, remediation of chlorinated solvents is required at many sites. For source zone treatment, common remediation strategies include in-situ chemical oxidation (ISCO) using potassium or sodium permanganate, and the enhancement of biodegradation by primary substrate addition. It is well known that these remediation methods tend to generate gas (carbon dioxide (CO2) in the case of ISCO using permanganate, CO2 and methane (CH4) in the case of bioremediation). Vigorous gas generation in the presence of chlorinated solvents, which are categorized as volatile organic contaminants (VOCs), may cause gas exsolution, ebullition and stripping of the contaminants from the treatment zone. This process may lead to unintentional 'compartment transfer', whereby VOCs are transported away from the contaminated zone into overlying clean sediments and into the vadose zone. To this extent, benchtop column experiments were conducted to quantify the effect of gas generation during remediation of the common chlorinated solvent trichloroethylene (TCE/C2Cl3H). Both ISCO and enhanced bioremediation were considered as treatment methods. Results show that gas exsolution and ebullition occurs for both remediation technologies. Facilitated by ebullition, TCE was transported from the source zone into overlying clean groundwater and was subsequently released into the column headspace. For the case of enhanced bioremediation, the intermediate degradation product vinyl chloride (VC) was also stripped from the treatment zone. The concentrations measured in the headspace of the columns (TCE ~300ppm in the ISCO column, TCE ~500ppm and VC ~1380ppm in the bioremediation column) indicate that substantial transfer of VOCs to the vadose zone is possible. These findings provide direct evidence for the unintended spreading of contaminants as a result of remediation efforts, which can, under some circumstances, result in enhanced risks for soil vapour intrusion. PMID- 28830696 TI - Human genetics contributes to the understanding of disease pathophysiology and drug discovery. AB - BACKGROUND: Today, sequencing technology has markedly reduced the cost and time needed to read the human genome than ever before. Genome-wide association studies have successfully identified a number of disease risk genes. CONTRIBUTION TO UNDERSTANDING OF DISEASE PATHOPHYSIOLOGY: Recent advancements in genomic technology have substantially furthered our understanding of the pathophysiology of many diseases, such as rheumatoid arthritis. TOWARD DRUG DISCOVERY AND FUTURE DIRECTION: Accumulating genomic information is now expected to accelerate the discovery of novel drugs. Rapidly growing multi-dimensional information in life sciences would make human genetics significantly important in the near future. PMID- 28830697 TI - A vascularized medial femoral condyle cortico-periosteal graft for total lunate reconstruction. PMID- 28830698 TI - Burned patients who die from causes other than the burn affect the model used to predict mortality: a national exploratory study. AB - INTRODUCTION: The Baux score - the sum of age and total body surface area burned (TBSA %) - is a good predictor of mortality has a high specificity but low sensitivity. Our aim was to examine the causes of death in patients who die with Baux scores of <100, which may explain the lower sensitivity and possibly affect the prediction of mortality. METHODS: All patients admitted to our centre for burn care from 1993 to 2015 (n=1946) were included in this retrospective, descriptive, exploratory study. The study group comprised those patients who died with Baux scores of <100 (n=23), and their medical charts were examined for the cause of death and for coexisting diseases. RESULTS: Crude mortality was 5% (93/1946) for the overall cohort, and a quarter of the patients who died (23/93) had Baux scores of less than 100 (range 64-99). In this latter group, flame burns were the most common (18/23), the median (10th-90th centile) age was 70 (46-86) years and for TBSA 21 (5.0-40.5) %, of which 7 (0-27.0) % of the area was full thickness. The main causes of death in 17 of the 23 were classified as "other than burn", being cerebral disease (n=9), cardiovascular disease (n=6), and respiratory failure (n=2). Among the remaining six (burn-related) deaths, multiple organ failure (predominantly renal failure) was responsible. When we excluded the cases in which the cause of death was not related to the burn, the Baux mortality prediction value improved (receiver operating characteristics area under the curve, AUC) from 0.9733 (95% CI 0.9633-0.9834) to 0.9888 (95% CI 0.9839 0.9936) and the sensitivity estimate increased from 45.2% to 53.9%. CONCLUSION: Patients with burns who died with a Baux score <100 were a quarter of all the patients who died. An important finding is that most of these deaths were caused by reasons other than the burn, usually cerebrovascular disease. This may be the explanation why the sensitivity of the Baux score is low, as factors other than age and TBSA % explain the fatal outcome. PMID- 28830699 TI - The effect of new complete denture fabrication and simplified dietary advice on nutrient intake and masticatory function of edentulous elderly: A randomized controlled trial. AB - BACKGROUND & AIM: Combination of new complete denture fabrication and tailored dietary counseling is necessary to improve nutrient intake of the edentulous elderly. However, there is no evidence on the effect of simple dietary advice combined with new complete denture fabrication on the nutrient intake of the edentulous elderly. The aim of this study was to clarify the combined effect of new complete denture fabrication and simple dietary advice, using a uniform pamphlet, on the nutrient intake and masticatory function of edentulous elderly. The null hypothesis was that there would be no difference in the nutrient intake and masticatory function between edentulous elderly patients provided with simple dietary advice and new complete dentures and those provided with new dentures alone. METHODS: A double-blind, randomized-controlled, parallel clinical trial was performed on the healthy edentulous elderly who were required to fabricate a new pair of complete denture. The participants were randomly divided into two groups, and each group received different advice: the intervention group received simple dietary advice using a uniform pamphlet, whereas the control group received denture care advice. During the process of new complete denture fabrication, two 20-min one-on-one advice sessions were conducted by a dentist. The primary outcome of this trial was protein intake, which was calculated from the responses in the brief-type self-administered diet history questionnaire (BDHQ). Secondary outcome was masticatory function, which was measured with a color-changeable chewing gum and a test gummy jelly. Outcome assessment was conducted twice, at baseline and at 3 months post-treatment. RESULTS: Among 70 participants who were randomized, 62 completed this trial. Protein intake in the intervention group significantly increased compared with that in the control group. Masticatory function was not significantly different between groups, but significantly increased at 3 months post-treatment compared with the baseline in both groups. CONCLUSION: Simple dietary advice using a uniform pamphlet and a new complete denture fabrication increased nutrient intake and masticatory function of healthy edentulous elderly. CLINICAL TRIAL REGISTRATION NUMBER: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000020716 UMIN000017879. PMID- 28830700 TI - Effects of maternal omega-3 fatty acids supplementation during pregnancy/lactation on body composition of the offspring: A systematic review and meta-analysis. AB - BACKGROUND & AIMS: The effect of maternal omega-3 fatty acids intake on the body composition of the offspring is unclear. The aim of this study was to conduct a systematic review and meta-analysis to confirm the effects of omega-3 fatty acids supplementation during pregnancy and/or lactation on body weight, body length, body mass index (BMI), waist circumference, fat mass and sum of skinfold thicknesses of offspring. METHODS: Human intervention studies were selected by a systematic search of PubMed, Web of Science, the Cochrane Library and references of related reviews and studies. Randomized controlled trials of maternal omega-3 fatty acids intake during pregnancy or lactation for offspring's growth were included. The data were analyzed with RevMan 5.3 and Stata 12.0. Effect sizes were presented as weighted mean differences (WMD) or standardized mean difference (SMD) with 95% confidence intervals (95% CI). RESULTS: Twenty-six studies comprising 10,970 participants were included. Significant increases were found in birth weight (WMD = 42.55 g, 95% CI: 21.25, 63.85) and waist circumference (WMD = 0.35 cm, 95% CI: 0.04, 0.67) in the omega-3 fatty acids group. There were no effects on birth length (WMD = 0.09 cm, 95% CI: -0.03, 0.21), postnatal length (WMD = 0.13 cm, 95% CI: -0.11, 0.36), postnatal weight (WMD = 0.04 kg, 95% CI: 0.07, 0.14), BMI (WMD = 0.09, 95% CI: -0.05, 0.23), the sum of skinfold thicknesses (WMD = 0.45 mm, 95% CI: -0.30, 1.20), fat mass (WMD = 0.05 kg, 95% CI: -0.01, 0.11) and the percentage of body fat (WMD = 0.04%, 95% CI: -0.38, 0.46). CONCLUSIONS: This meta-analysis showed that maternal omega-3 fatty acids supplementation can increase offspring's birth weight and postnatal waist circumference. However, it did not appear to influence children's birth length, postnatal weight/length, BMI, sum of skinfold thicknesses, fat mass and the percentage of body fat during postnatal period. Larger, well-designed studies are recommended to confirm this conclusion. PMID- 28830701 TI - A priori and a posteriori derived dietary patterns in infancy and cardiometabolic health in childhood: The role of body composition. AB - BACKGROUND & AIMS: Cardiometabolic risk has its origins in early life. However, it is unclear whether diet during early childhood is associated with cardiometabolic health, and what the role is of obesity. We aimed to study whether overall diet during early childhood is associated with cardiometabolic health and to examine if difference in body composition explain this association. METHODS: We examined associations of different types of dietary patterns in infancy with cardiometabolic health at school age among 2026 Dutch children participating in a population-based cohort in the Netherlands. Food intake at the age of 1 year was assessed with a food-frequency questionnaire. Three dietary pattern approaches were used: 1) An a priori-defined diet quality score; 2) dietary patterns based on variation in food intake, derived from principal component analysis (PCA); and 3) dietary patterns based on variations in fat and fat-free mass index, derived with reduced-rank regression (RRR). At the children's age of 6 years, we measured their body composition, systolic and diastolic blood pressure, and serum concentrations of insulin, triglycerides, and HDL-cholesterol, which we combined in a cardiometabolic risk-factor score. RESULTS: We observed that, after adjustment for confounders, children with higher adherence to a 'Health-conscious' PCA-derived pattern had a lower cardiometabolic risk-factor score (-0.07 SD (95%CI -0.12; -0.02) per SD). This association did not change after adjustment for fat and fat-free mass index. The RRR-derived dietary patterns based on variations in body composition were not associated with the cardiometabolic risk-factor score. CONCLUSIONS: Our results suggest that diet in early childhood may affect cardiometabolic health independent of differences in body composition. PMID- 28830702 TI - Cardiac complexity and emotional dysregulation in children. AB - OBJECTIVE: Sample entropy (SampEn) gives an estimate of signal complexity in cardiac time series and can give information beyond linear heart rate variability. Lower cardiac SampEn is associated with psychopathology in adults. Emotional dysregulation is widely present in adult psychopathology and a forerunner to later mental problems in children. Therefore, this study investigated whether SampEn relates to emotional dysregulation in children. METHODS: Participants were 32 children between 9 and 13years with internalizing difficulties and 25 controls. Parents filled out the "Emotional Problems" subscale in the Strengths and Difficulties questionnaire and the "Lability/Negativity" scale in the Emotion Regulation Checklist. SampEn, root mean square of successive differences (RMSSD), normalized power of high frequency (HFnu) components of the cardiac signal and pre-ejection period (PEP) were computed at rest. The study investigated the predictive power of SampEn, RMSSD and HFnu on the measures of emotional dysregulation. It also tested whether RMSSD or PEP were related to SampEn. RESULTS: SampEn was a significant predictor of both measures of emotional dysregulation, while RMSSD and HFnu were not. RMSSD and PEP were both significant predictors of SampEn. CONCLUSIONS: SampEn is a potential marker of dysregulation in the underlying neurovisceral processes vital for emotion regulation, and an important complementary measure to linear cardiac indices, explaining more of the variance in emotional dysregulation than RMSSD and HFnu in this study. Lower SampEn can also be linked to both higher vagal and sympathetic activation via RMSSD and PEP. PMID- 28830703 TI - Brief periods of NREM sleep do not promote early offline gains but subsequent on task performance in motor skill learning. AB - Sleep modulates motor learning, but its detailed impact on performance curves remains to be fully characterized. This study aimed to further determine the impact of brief daytime periods of NREM sleep on 'offline' (task discontinuation after initial training) and 'on-task' (performance within the test session) changes in motor skill performance (finger tapping task). In a mixed design (combined parallel group and repeated measures) sleep laboratory study (n=17 'active' wake vs. sleep, n=19 'passive' wake vs. sleep), performance curves were assessed prior to and after a 90min period containing either sleep, active or passive wakefulness. We observed a highly significant, but state- (that is, sleep/wake)-independent early offline gain and improved on-task performance after sleep in comparison to wakefulness. Exploratory curve fitting suggested that the observed sleep effect most likely emerged from an interaction of training-induced improvement and detrimental 'time-on-task' processes, such as fatigue. Our results indicate that brief periods of NREM sleep do not promote early offline gains but subsequent on-task performance in motor skill learning. PMID- 28830704 TI - A Grounded Theory Study of HIV-Related Stigma in U.S.-Based Health Care Settings. AB - Despite progress made in the treatment and care of people living with HIV (PLWH), HIV-related stigma has remained persistent. Health care settings and workers have been identified as important sources of stigma. Studies have addressed the construct of stigma in U.S. health care settings, but mainly from the perspectives of PLWH. We used Grounded Theory to understand how health care workers conceptualized HIV-related stigma and to develop a model to project a purposive view of stigma in health care settings. Our model indicates that stigma may be rooted in historically derogatory representations of HIV and intensified by power inequalities. Stigma may be triggered by fear, inadequate clinical education and training, unintentional behaviors, and limited contact with PLWH. Study participants perceived stigma as injurious to patient and provider health outcomes. Additional research on provider perceptions of stigma and programs that encourage empowerment, communication, and training may be necessary for stigma reduction. PMID- 28830705 TI - Caffeine and Insomnia in People Living With HIV From the Miami Adult Studies on HIV (MASH) Cohort. AB - We explored the relationship between caffeine consumption, insomnia, and HIV disease progression (CD4+ T cell counts and HIV viral loads). Caffeine intake and insomnia levels were measured using the Modified Caffeine Consumption Questionnaire and the Pittsburgh Insomnia Rating Scale (PIRS) in 130 clinically stable participants who were living with HIV, taking antiretroviral therapy, and recruited from the Miami Adult Studies on HIV cohort. Linear regressions showed that caffeine consumption was significantly and adversely associated with distress score, quality-of-life score, and global PIRS score. Linear regression analyses also showed that global PIRS score was significantly associated with lower CD4+ T cell counts and higher HIV viral loads. Caffeine could have precipitated insomnia in susceptible people living with HIV, which could be detrimental to their disease progression states. PMID- 28830706 TI - Underutilization of antiplatelet and statin therapy after postoperative myocardial infarction following vascular surgery. AB - OBJECTIVE: The objective of this study was to investigate adherence to practice guidelines for antiplatelet and statin use after postoperative myocardial infarction (POMI) and its effect on late mortality following vascular surgery in a multicenter registry. METHODS: Antiplatelet and statin use was examined in 1749 vascular surgery procedures with POMI within the Vascular Quality Initiative (VQI) from 2005 to 2015. Our primary aim was to assess cardiac medication (CM) use at discharge, defined as (1) single antiplatelet therapy (SAPT; aspirin or P2Y12 inhibitor) or dual antiplatelet therapy (DAPT; aspirin and P2Y12 inhibitor) and (2) statin therapy. Long-term mortality in patients with POMI was analyzed on the basis of discharge CM. A proportional hazards model was developed to control for factors associated with mortality. Regional differences in CM use at discharge after POMI were compared. RESULTS: Overall discharge CM use after POMI included aspirin (81%), P2Y12 inhibitor (38%), statin therapy (76%), and combined antiplatelet and statin (74%). At discharge, 26% of patients were not receiving combined antiplatelet and statin therapy. SAPT (50%) was more common than DAPT (35%; P < .001). Patients with POMI undergoing carotid endarterectomy were more likely to be discharged on CM (80%) compared with patients undergoing infrainguinal bypass (78%), suprainguinal bypass (72%), endovascular aneurysm repair (71%), and open abdominal aortic aneurysm repair (59%; P < .001). Patients receiving SAPT or DAPT plus statin therapy had improved survival (79%) compared with those receiving noncombination or no therapy (69%) with mean follow-up of 5.5 years and 4.9 years, respectively (log-rank, P = .001). After adjustment for covariates including preoperative medications, treatment with SAPT or DAPT plus statin at discharge was associated with lower late mortality compared with noncombination or no therapy (hazard ratio, 0.72; 95% confidence interval, 0.56 0.93; P = .01). Regional variation in CM at discharge following POMI was also observed with a range of 33% to 100% (P = .05). CONCLUSIONS: Within the VQI, regional and procedure-specific variation exists in CM regimen after POMI following vascular surgery. Absence of combined antiplatelet and statin therapy at discharge after POMI was associated with higher late mortality and represents an area for quality improvement in the care of these patients. PMID- 28830707 TI - Endovascular stent grafting for ascending aorta diseases. AB - OBJECTIVE: Conventional open surgery encompassing cardiopulmonary bypass has been traditionally used for the treatment of ascending aorta diseases. However, more than one in five of these patients will be finally considered unfit for open repair. We conducted a systematic review and meta-analysis to investigate the role of thoracic endovascular aortic repair (TEVAR) for aortic diseases limited to the ascending aorta. METHODS: The current meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We investigated patients' baseline characteristics along with early (30 days/in-hospital stay) and late (beyond 30 days/in-hospital stay) outcomes after TEVAR limited to the ascending aorta and not involving the arch vessels. Separate analyses for case reports and case series were conducted, and pooled proportions with 95% confidence intervals (CIs) of outcome rates were calculated. RESULTS: Approximately 67% of the patients had a prior cardiac operation. TEVAR was performed mainly for acute or chronic Stanford type A dissection (49%) or pseudoaneurysm (28%). The device was usually delivered through the femoral artery (67%), and rapid ventricular pacing was used in nearly half of the patients. Technical success of the method was 95.5% (95% CI, 87.8-99.8). Among the early outcomes, conversion to open repair was 0.7% (95% CI, 0.1-4.8), whereas mortality was 2.9% (95% CI, 0.02-8.6). We estimated a pooled rate of 1.8% (95% CI, 0.1-7.0) for neurologic events (stroke or transient ischemic attack) and 0.8% (95% CI, 0.1 5.6) for myocardial infarction. Late endoleak was recorded in 16.4% (95% CI, 8.2 26.0), and 4.4% (95% CI, 0.1-12.4) of the population died in the postoperative period. Finally, reoperation was recorded in 8.9% (95% CI, 3.1-16.4) of the study sample. CONCLUSIONS: TEVAR in the ascending aorta seems to be safe and feasible for selected patients with various aortic diseases, although larger studies are required. PMID- 28830708 TI - Analysis of origin of the supra-aortic trunks from the aortic arch. AB - OBJECTIVE: The objective of this study was to describe in the general population the anatomy of the supra-aortic trunks (SATs: brachiocephalic trunk [BCT], left common carotid artery [LCCA], and left subclavian artery [LSA]) arising from the aortic arch in terms of mutual distances from the valvular aortic plane (VAP), ostial diameters, and clock face orientation from the sagittal aortic axis, with an analysis of each distribution. METHODS: Measurements of 252 computed tomography angiograms of the aortic arch and SATs in three groups of patients (84 without any disease of the aortic arch, group A; 84 with dilation of the aortic arch, group B; 84 with dilation of the descending thoracic aorta below the LSA, group C) were retrospectively collected and analyzed. The Shapiro-Wilk test was used to assess normality of each distribution. RESULTS: The ostial diameters of the SATs followed a gaussian distribution in all groups. In group A, only VAP-BCT and LCCA-LSA distances were normal, being in 95% of cases between 46.6 and 88.2 mm and between 8 and 23.3 mm, respectively. In both groups B and C, the distance VAP-BCT and the takeoff angle of both LCCA and LSA were gaussian distributed (being in 95% of cases between 48.5 and 102.1 mm, -17.6 degrees and 33 degrees , and -17.7 degrees and 23.4 degrees , respectively, in group B; and between 51.3 and 101.1 mm, -28.2 degrees and 33.7 degrees , and -28.7 degrees and 31.3 degrees , respectively, in group C). VAP-BCT distance and BCT angle were lower in group A compared with group B (P < .001 and P = .008, respectively) and group C (P < .001 and P = .04, respectively). Irrespective of the group, all SAT mutual distances and ostial diameters were related to the aortic diameters, being greater for increasing aortic diameters. Neither BCT angle nor LSA angle was related to the aortic diameters, whereas LCCA angle was inversely correlated. CONCLUSIONS: Most of the analyzed variables did not show a gaussian distribution, both in healthy and in diseased patients. Irrespective of the group, all SAT mutual distances and ostial diameters were related to the aortic diameters, being greater for increasing aortic diameters. PMID- 28830709 TI - Early carotid endarterectomy performed 2 to 5 days after the onset of neurologic symptoms leads to comparable results to carotid endarterectomy performed at later time points. AB - BACKGROUND: Timing of carotid endarterectomy (CEA) after onset of neurologic symptoms remains controversial. We assessed the association of CEA timing with postoperative outcomes. METHODS: The Vascular Study Group of New England (VSGNE) database (2003-2014) was queried to identify CEA performed for symptomatic carotid stenosis during the same hospitalization. Cases were divided into four groups based on the time from onset of neurologic symptoms to CEA: group I, <2 days; group II, 2 to 5 days; group III, >=6 days; and group IV, same-day CEA. The chi2 test and t-test were used to compare demographics, medical history, modified Rankin scores, and outcomes (30-day postoperative death, stroke, myocardial infarction, and aggregate events [stroke/myocardial infarction]). Multivariable logistic regression was used to compare the association of time to surgery with outcomes while adjusting for confounding variables. Kaplan-Meier and Cox proportional hazards regression analyses were performed at 1 year to evaluate survival and stroke rates between the groups. RESULTS: There were 989 of 14,864 VSGNE CEA cases that fit the inclusion criteria. The frequency of cases was highest in group II (36.6%), followed by groups I (31.9%), III (18.9%), and IV (12.4%). Age, gender, and comorbidity compositions were similar between groups, although group III had the highest rates of diabetes mellitus, coronary artery disease, coronary artery bypass graft procedures, congestive heart failure, and American Society of Anesthesiologists class 4 and the highest modified Rankin score (P < .05). Stroke rates were highest in group I (7.3%; P = .016), whereas group III had the highest rate of discharges to nursing facilities (37.2%; P < .001); other adverse outcomes were comparable among groups. CEAs in group I had significantly increased adjusted odds of stroke; adverse outcomes of CEAs in groups II and III were comparable to those in group IV. CONCLUSIONS: Our results suggest that CEAs performed 2 to 5 days after a neurologic event have similar outcomes to CEAs performed >=6 days later. Early CEA should be considered an area for quality improvement among these patients. PMID- 28830710 TI - Microbe and host lipids. PMID- 28830711 TI - Changes in growth, blood immune parameters and expression of immune related genes in rainbow trout (Oncorhynchus mykiss) in response to diet supplemented with Ducrosia anethifolia essential oil. AB - An 8- week feeding trial was conducted to investigate the effects of Ducrosia anethifolia essential oil on growth, blood immune parameters and immune related genes expression in juvenile rainbow trout (Oncorhynchus mykiss). Fish were allocated into 4 groups and fed on diet containing different levels of essential oil (0, 0.001, 0.01 and 0.1%) to apparent satiation in 30 min 3 times daily. Growth and immunological parameters were measured every ten days and tissue samples were taken from kidney and spleen on days 10, 30 and 50 to study the expression of IL-1beta and TNF-alpha. The changes of measured parameters in different treatments and over sampling time series were statistically analysis based on repeated measurement method (P < 0.05). Results showed that growth did not affected by essential oil at different treatments. The highest level of hematocrit was observed in 0.001 treatment. The mean of RBC showed no significant differences among treatments. The mean of WBC in 0.01 and 0.1 groups were higher than those in 0.001 and control groups. Total protein, albumin and globulin and serum bactericidal activity showed no significant difference in different treatments. Neither treatments nor sampling times affected serum lysozyme activity. The highest mean of respiratory burst activity was observed in 0.01 group. The highest expression of both IL-1beta and TNF-alpha genes in kidney was observed at 0.001 dose on day 30, while in spleen, the highest expression of IL 1beta and TNF-alpha was obtained on day 30 at doses 0.1 and 0.01%, respectively. In conclusion the results of this study showed that feeding with lower and medium level of D. anethifolia for 30 days led to immunostimulatory effects in juvenile rainbow trout. PMID- 28830712 TI - Effects of nanostructured zeolite and aflatoxin B1 in growth performance, immune parameters and pathological conditions of rainbow trout Oncorhynchus mykiss. AB - The reduction of Aflatoxin B1 (AF) in juvenile rainbow trout (Oncorhynchus mykiss) diet was analyzed after supplementing Nanostructured Zeolite (NZ) in a 56 day experiment. Two hundred and seventy juveniles with an average weight of 23 +/ 3.7 g were placed in 6 different groups of C (control as a basal diet), NZ0.5 (basal diet + 0.5% NZ), NZ1 (basal diet + 1% NZ), AF5 (basal diet + 5 mg AFB1), AF5 NZ0.5 (basal diet + 5 mg AFB1 + 0.5% NZ), AF5 NZ1 (basal diet + 5 mg AFB1 + 1% NZ) with three replications and were fed four times a day based on their satiation. No significant differences were observed in terms of growth performance among the experimental groups (P > 0.05). However, hepatosomatic index in fish fed by AF5 NZ0.5 was reduced compared with NZ0.5 group (P < 0.05). The carcass moisture content showed a higher amount in treatment AF5 NZ0.5 compared to the control group (P < 0.05). There was a decrease in fat content in treatment AF5 compared to that of the control group (P < 0.05). Serum total protein, albumin and globulin levels in fish fed with aflatoxin were lower than in fish fed the diet without AF for all levels of NZ (P < 0.05); however, the interaction between AF and NZ was not significant (P > 0.05). Concentrations of C3, C4 and immunoglobulin M together with serum lysozyme activity showed no significant differences among all treatments (P > 0.05). No considerable histopathological lesions were observed in liver, kidney and spleen for all treatments. Based on the results, NZ showed some effects on physiological functions in juvenile rainbow trout fed by 0.5% dietary NZ which could improve performance in this species. PMID- 28830713 TI - Characterization of loperamide-mediated block of hERG channels at physiological temperature and its proarrhythmia propensity. AB - BACKGROUND: Loperamide (Immodium(r)) is indicated for symptomatic control of diarrhea. It is a MU-opioid receptor agonist, and recently has been associated with misuse and abuse. At therapeutic doses loperamide has not been associated with cardiotoxicity. However, loperamide overdose is associated with proarrhythmia and death - two effects that are likely attributable to its block of cardiac ion channels that are critical for generating action potentials. In this study, we defined loperamide-hERG channel interaction characteristics, and used a ventricular myocyte action potential model to compare loperamide's proarrhythmia propensity to twelve drugs with defined levels of clinical risk. METHODS AND RESULTS: Whole-cell voltage-clamp recordings were performed at 37 degrees C on a HEK293 cell line stably expressing the hERG channel proteins, and loperamide was bath-applied to assess its effects on hERG current. Loperamide suppressed hERG current in a use- and voltage-dependent but frequency-independent manner, with a half-maximal inhibitory concentration <90nM. The onset of current suppression was concentration-dependent and appeared to follow a first-order reaction. Loperamide also altered the voltage-dependence of steady state hERG current properties. Electrophysiological data were integrated into a myocyte model that simulated dynamic drug-hERG channel interaction to estimate Torsade de Pointes risk through comparisons with reference drugs with defined clinical risk. In the context of overdose that would result in loperamide levels far exceeding those produced by therapeutic doses, loperamide is placed in the high risk category, alongside quinidine, bepridil, dofetilide, and sotalol. CONCLUSIONS: The combined in vitro and in silico approach provides mechanistic insight regarding the potential for loperamide to generate cardiotoxicity in overdose situations. This strategy holds promise for improving cardiac safety assessment. PMID- 28830715 TI - Neurological outcome after cardiac arrest managed with targeted temperature management: Are hemodynamic variables useful? PMID- 28830714 TI - Bis(benzofuran-thiazolidinone)s and bis(benzofuran-thiazinanone)s as inhibiting agents for chikungunya virus. AB - There are currently still no approved antiviral drugs to treat or prevent chikungunya virus (CHIKV) infections despite the fact that this arbovirus continues to cause outbreaks in Africa, Asia, and South- and Central-America. Thus 20 new conjugated compounds in the families of bis(benzofuran-1,3 thiazolidin-4-one)s and bis(benzofuran-1,3-thiazinan-4-one)s were designed based on the structural features of suramin. These new compounds were synthesized by chemical methods and their structures were confirmed spectroscopically. In CPE reduction assays, six of these new bis-conjugates inhibited CHIKV replication in Vero E6 cells with EC50 in the range of 1.9-2.7 MUM and selectivity index values of ~75 or higher. These results and compounds provide a starting point for further optimization, design, and synthesis of new antiviral agents for this (re)emerging disease. PMID- 28830716 TI - Clinical profile of patients with cardiac arrest induced by aortic disease. PMID- 28830717 TI - Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT. MATERIAL AND METHODS: Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression. RESULTS: 91% of patients had concurrent chemotherapy. Median follow up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid radiotherapy scans showed early out-of-field progression. All of these patients died. CONCLUSIONS: Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor. PMID- 28830718 TI - Cocaine modifies brain lipidome in mice. AB - Lipids are predominant components of the brain and key regulators for neural structure and function. The neuropsychopharmacological effect of cocaine has been intensively investigated; however, the impact of cocaine on brain lipid profiles is largely unknown. In this study, we used a LC-MS-based lipidomic approach to investigate the impact of cocaine on brain lipidome in two mouse models, cocaine conditioned place preference (CPP) and hyperlocomotor models and the lipidome was profoundly modified in the nucleus accumbens (NAc) and striatum respectively. We comprehensively analyzed the lipids among 21 subclasses across 7 lipid classes and found that cocaine profoundly modified brain lipidome. Notably, the lipid metabolites significantly modified were sphingolipids and glycerophospholipids in the NAc, showing a decrease in ceramide and an increase in its up/downstream metabolites levels, and decrease lysophosphatidylcholine (LPC) and lysophosphoethanolamine (LPE) and increase phosphatidylcholine (PC) and phosphatidylethanolamines (PE) levels, respectively. Moreover, long and polyunsaturated fatty acid phospholipids were also markedly increased in the NAc. Our results show that cocaine can markedly modify brain lipidomic profiling. These findings reveal a link between the modified lipidome and psychopharmacological effect of cocaine, providing a new insight into the mechanism of cocaine addiction. PMID- 28830719 TI - Discovery of novel inhibitors of multidrug-resistant Acinetobacter baumannii. AB - The recent emergence of multidrug-resistant Acinetobacter baumannii strains and the non-efficacy of currently available antibiotics against such infections have led to an urgent need for the development of novel antibacterials. In an effort to address this problem, we have identified three novel inhibitors, namely, D5, D12 and D6 using in silico screening with a homology model of the outer membrane protein W2 (OmpW2) from A. baumannii, as the proposed new drug target. OmpW is an eight-stranded beta-barrel protein involved in the transport of hydrophobic molecules across the outer membrane and maintenance of homeostasis under cellular stress. The antimicrobial activities of compounds D5, D12 and D6 were evaluated against a panel of clinical isolates of A. baumannii strains. These compounds inhibited the growth of the strains with minimum inhibitory concentration (MIC) ranges of 1-32MUg/mL. Time-kill kinetic studies with the highly virulent and multidrug-resistant strain, A. baumannii 5075, indicated that D6 exhibited the highest bactericidal activity asa>=3log10 CFU/mL (99.9%) reduction in colony count from the initial inoculum was observed after 30min incubation. D5 and D12 reduced at least 1log10 CFU/mL (90%) of the initial inoculum after 24h. In conclusion, these three lead inhibitors have provided two distinct chemical scaffolds for further analog design and optimizations, using chemical synthesis, to develop more potent inhibitors of the pathogen. PMID- 28830720 TI - Development and in vivo evaluation of chitosan beads for the colonic delivery of azathioprine for treatment of inflammatory bowel disease. AB - Azathioprine is a highly efficient immunosuppressant drug used for treatment of inflammatory bowel disease (IBD). Systemic administration of azathioprine results in delayed therapeutic effect and serious adverse reactions. In the current study, we have developed, for the first time, colon-targeted chitosan beads for delivery of azathioprine in colitis rabbit model. Several characterizations were performed for the azathioprine-loaded beads (e.g. drug encapsulation efficiency, drug loading capacity, yield, size, shape and compatibility with other ingredients). The in vitro release profiles of acid-resistant capsules filled with azathioprine-loaded beads showed that most of azathioprine was released in IBD colon simulating medium. The therapeutic effects of azathioprine-loaded beads and azathioprine crude drug were examined on acetic acid-induced colitis rabbit model. Improved therapeutic outcomes were observed in the animals treated with the azathioprine-loaded beads, as compared to the untreated animal controls and the animals treated with the azathioprine free drug, based on the clinical activity score, index of tissue edema, mortality rate, colon macroscopic score and colon histopathological features. In the animals treated with the azathioprine-loaded beads, the levels of the inflammatory mediators, myeloperoxidase enzyme and tumor necrosis factor-alpha, were significantly reduced to levels similar to those observed in the normal rabbits. Furthermore, the activities of the antioxidant enzymes, superoxide dismutase and catalase, were restored considerably in the animals treated with the drug-loaded beads. The azathioprine-loaded beads developed in the current study might have great potential in the management of IBD. PMID- 28830721 TI - Food addiction among sexual minorities. AB - Although sexual minorities represent a small proportion of the general population, this group has been observed to be at an increased risk of developing various pathologies, including substance use and eating disorders. Research suggests that foods high in added fat and refined carbohydrates may trigger an addictive response, especially in at-risk individuals. Consequently, food addiction is associated with elevated risk for obesity, diet-related disease, and psychological distress. However, there is limited research on whether food addiction, like substance use, may be elevated among sexual minorities, and whether self-compassion may be a protective factor. Thus, the current study aims to test whether food addiction is elevated in sexual minorities (relative to heterosexuals) and if discrimination and self-compassion may be related to food addiction among sexual minorities. In a community sample of 356 participants (43.3% sexual minority), sexual minorities had almost twice the prevalence of food addiction (16.9%) as heterosexuals (8.9%). Also, sexual minorities on average experienced more food addiction symptoms (M = 2.73, SD = 1.76) than heterosexuals (M = 1.95, SD = 1.59). For sexual minorities, heterosexist harassment was associated with increased food addiction, while self-compassion appeared to be a protective factor. Further research needs to examine between group differences among sexual minorities for better treatment and interventions for food addiction. PMID- 28830722 TI - Problematic issues of air protection during thermal processes related to the energetic uses of sewage sludge and other waste. Case study: Co-combustion in peaking power plant. AB - Currently, it is necessary to deal with issues related to the emissions as there is a constantly increasing interest in combusting sludge from sewage treatment plants in the boilers for wood. An analysis of the energetic importance of the combustion of sewage sludge has already been carried out, but the effects of various treatments of the sludge are not always clear, e.g. composting and subsequent combustion to the air pollution. Investments in other thermal processes of energetic utilisation of sewage sludge and organic waste are not always successfully implemented. The objective of this paper is to point out some problematic cases for acceptance of thermal processes related to energetic use of waste in terms of the air protection. The other aim is to mention the experience with solutions of such issues in Slovakia. There are mentioned first results of the operational validation experiments during the energy generation in circulating fluidized bed boiler in peaking power plant (Power 110MW) with the addition of the so-called alternative fuel based on wood and sewage sludge to the main fuel - black coal (anthracite). And there has already been achieved the highest share of 12.4%w. (dry matter) of sewage sludge in form of compost in blend with black coal, which is technologically viable. Moreover analyzed the problems of the authorization and operation of the co-combustion of sewage sludge and of combustion of products of various kinds of pyrolysis waste - pyrolysis gas and pyrolysis oil are analyzed. PMID- 28830723 TI - Selective recovery of silver from waste low-temperature co-fired ceramic and valorization through silver nanoparticle synthesis. AB - Considering the value of silver metal and silver nanoparticles, the waste generated during manufacturing of low temperature co-fired ceramic (LTCC) were recycled through the simple yet cost effective process by chemical-metallurgy. Followed by leaching optimization, silver was selectively recovered through precipitation. The precipitated silver chloride was valorized though silver nanoparticle synthesis by a simple one-pot greener synthesis route. Through leaching-precipitation optimization, quantitative selective recovery of silver chloride was achieved, followed by homogeneous pure silver nanoparticle about 100nm size were synthesized. The reported recycling process is a simple process, versatile, easy to implement, requires minimum facilities and no specialty chemicals, through which semiconductor manufacturing industry can treat the waste generated during manufacturing of LTCC and reutilize the valorized silver nanoparticles in manufacturing in a close loop process. Our reported process can address issues like; (i) waste disposal, as well as value-added silver recovery, (ii) brings back the material to production stream and address the circular economy, and (iii) can be part of lower the futuristic carbon economy and cradle to-cradle technology management, simultaneously. PMID- 28830724 TI - Skin suturing and cortical surface viral infusion improves imaging of neuronal ensemble activity with head-mounted miniature microscopes. AB - BACKGROUND: In vivo optical imaging of neural activity provides important insights into brain functions at the single-cell level. Cranial windows and virally delivered calcium indicators are commonly used for imaging cortical activity through two-photon microscopes in head-fixed animals. Recently, head mounted one-photon microscopes have been developed for freely behaving animals. However, minimizing tissue damage from the virus injection procedure and maintaining window clarity for imaging can be technically challenging. NEW METHOD: We used a wide-diameter glass pipette at the cortical surface for infusing the viral calcium reporter AAV-GCaMP6 into the cortex. After infusion, the scalp skin over the implanted optical window was sutured to facilitate postoperative recovery. The sutured scalp was removed approximately two weeks later and a miniature microscope was attached above the window to image neuronal activity in freely moving mice. RESULTS: We found that cortical surface virus infusion efficiently labeled neurons in superficial layers, and scalp skin suturing helped to maintain the long-term clarity of optical windows. As a result, several hundred neurons could be recorded in freely moving animals. COMPARISON WITH EXISTING METHODS: Compared to intracortical virus injection and open-scalp postoperative recovery, our methods minimized tissue damage and dura overgrowth underneath the optical window, and significantly increased the experimental success rate and the yield of identified neurons. CONCLUSION: Our improved cranial surgery technique allows for high-yield calcium imaging of cortical neurons with head-mounted microscopes in freely behaving animals. This technique may be beneficial for other optical applications such as two-photon microscopy, multi-site imaging, and optogenetic modulation. PMID- 28830725 TI - A high-sensitive nano-modified biosensor for dynamic monitoring of glutamate and neural spike covariation from rat cortex to hippocampal sub-regions. AB - BACKGROUND: Hippocampus is a critical part of brain tissue involved in many cognitive neural activities. They are controlled by various neurotransmitters such as glutamate (Glu), and affected by electrophysiology. NEW METHOD: Herein, we fabricated a 16-site (25MUm in diameter) microelectrode array (MEA) biosensor applied in dual-mode tests including Glu and neural spike measurements. METHODS: All the 16 recording sites were electrodeposited with platinum nanoparticles (PtNPs) and 8 sites were used for electrical recording. Glutamate oxidase enzyme (Gluox) and 1,3-Phenylenediamine (mPD) layer were specially modified on the other 8 sites for Glu recording. The dual-mode MEA was implanted from cortex to hippocampus of anesthetized rat to record Glu content and firing rate. RESULTS: The electrical sites showed much lower impedance. The Glu sites showed much higher sensitivity(7.807 pA/MUM), and ideal selectivity to the major molecules in brain. The post calibration sensitivity (3.935 pA/MUM) maintained on a positive level. Different Glu content peaks including cortex (18.32MUM) and hippocampal CA1 (4.39MUM), CA3 (10.16MUM), dentate gyrus (DG, two layers: 5.36MUM and 10.34MUM) have detected. The corresponded firing rate was recorded, too. COMPARISON WITH EXISTING METHODS: This modification showed much lower impedance and much higher sensitivity. We obtained more neuron activities simultaneously by dual-mode recording. The covariation of Glu and neural spike signals was discovered in the specific hippocampus sub-region. CONCLUSIONS: The covariation between Glu and firing rate changes were synchronous, and effected by regions. The dual-mode signals were useful to find the neurology disease mechanism. PMID- 28830726 TI - Pulse wave velocity differs between ulcerative colitis and chronic kidney disease. AB - BACKGROUND: We hypothesized that a reversal of the physiological stiffness gradient, previously reported in end-stage renal disease, begins in the early stages of chronic kidney disease (CKD) and that chronic inflammation produces a different arterial phenotype in patients with ulcerative colitis (UC). OBJECTIVES: To assess the extent of arterial stiffening in the central (carotid femoral pulse wave velocity, cf.-PWV) and peripheral arteries (carotid-radial pulse wave velocity, cr-PWV) and to explore the determinants of the stiffness gradient in UC and in CKD. METHODS: We enrolled 45 patients with UC, 45 patients with stage 3-4 CKD and 45 matched controls. RESULTS: Despite the comparable cf. PWV, the cr-PWV was higher in patients with UC than in those with CKD (median: 8.7 vs. 7.5m/s; p<0.001) and, consequently, the PWV ratio was lower (median: 0.97 vs. 1.12; p<0.001). In patients with CKD a stiffness mismatch was reported starting from stage 3B. The PWV ratio was associated with age and C-reactive protein (beta: 0.08 z-score, 95%CI 0.02-0.14; p=0.01) or active disease (beta: 0.43 z-score, 95%CI 0.003-0.857; p=0.048) in patients with UC and with age and glomerular filtration rate (beta: -0.56 z-score, 95%CI -1.05 to -0.07; p=0.02) in patients with CKD. CONCLUSIONS: The arterial phenotype differed between UC and CKD. The reversal of the arterial stiffness gradient is evident in CKD patients starting from stage 3B but not in patients with UC and comparable cf.-PWV. In patients with UC, the stiffness of both elastic and muscular arteries is increased as a consequence of inflammation. PMID- 28830727 TI - Uncertainty of determination of 158Tb in the RBMK nuclear reactor waste. AB - The activity of 158Tb was measured in waste samples from the Ignalina NPP Unit I RBMK-1500 reactor using gamma-ray spectrometry. The origin of 158Tb and the other observed gamma-ray emitters has been studied by using SCALE 6.1 modeling and comparing radionuclide ratios in the RBMK-1500 radioactive waste. The results of the calculation of the massic activity of gamma-ray emitters were used for interpretation of the total gamma-ray spectrum and the determination of 158Tb massic activity uncertainty in the waste of RBMK-1500. PMID- 28830728 TI - The large-area multi-wire proportional counting system for 2pi alpha and beta emission measurement at the NIM China. AB - An alpha/beta emission rate counting system which comprises of a large-area windowless multi-wire proportional counter and a digital pulse processing module has been established at the National Institute of Metrology of China, aiming at realizing the absolute measurement of emission rate for alpha and beta sources. Performance of the detector, including high-voltage plateaus and uniformity were measured. Measured emission rates for large-area 241Am and 90Sr/90Y sources when compared with certificated values showed difference within 1.0%, and good agreements achieved. PMID- 28830729 TI - Patient Exposure during Fluoroscopy-guided Pacemaker Implantation Procedures. AB - A pacemaker, which is used for heart resynchronization with electrical impulses, is used to manage many clinical conditions. Recently, the frequency of pacemaker implantation procedures has increased to more than 50% worldwide. During this procedure, patients can be exposed to excessive radiation exposure. Wide range of doses has been reported in previous studies, suggesting that optimization of this procedure has not been fulfilled yet. The current study evaluated patient radiation exposure during cardiac pacemaker procedures and quantified the patient effective dose. A total of 145 procedures were performed for five pacemaker procedures (VVI, VVIR, VVD, VVDR, and DDDR) at two hospitals. Patient doses were measured using the kerma-area product meter. Effective doses were estimated using software based on Monte Carlo simulation from the National Radiological Protection Board (NRPB, now The Health Protection Agency). The effective dose values were used to estimate cancer risk from the pacemaker procedure. Patient demographic data and exposure parameters for fluoroscopy and radiography were quantified. The mean patient doses +/- SD per procedure (Gycm2) for VVI, VVIR, VVD, VVDR, and DDDR were 1.52 +/- 0.13 (1.43-1.61), 3.28 +/- 2.34 (0.29-8.73), 3.04 +/- 1.67 (1.57-4.86), 6.04 +/- 2.326 3.29-8.58), and 8.8 +/- 3.6 (4.5 26.20), respectively. The overall patient effective dose was 1.1mSv per procedure. It is obvious that the DDDR procedure exposed patients to the highest radiation dose. Patient dose variation can be attributed to procedure type, exposure parameter settings, and fluoroscopy time. The results of this study showed that patient doses during different pacemaker procedures are lower compared to previous reported values. Patient risk from pacemaker procedure is low, compared to other cardiac interventional procedures. Patients' exposures were mainly influenced by the type of procedures and the clinical indication. PMID- 28830730 TI - Identification and distribution of neuronal nitric oxide synthase and neurochemical markers in the neuroepithelial cells of the gill and the skin in the giant mudskipper, Periophthalmodon schlosseri. AB - Mudskippers are amphibious fishes living in mudflats and mangroves. These fishes hold air in their large buccopharyngeal-opercular cavities where respiratory gas exchange takes place via the gills and higher vascularized epithelium lining the cavities and also the skin epidermis. Although aerial ventilation response to changes in ambient gas concentration has been studied in mudskippers, the localization and distribution of respiratory chemoreceptors, their neurochemical coding and function as well as physiological evidence for the gill or skin as site for O2 and CO2 sensing are currently not known. In the present study we assessed the distribution of serotonin, acetylcholine, catecholamines and nitric oxide in the neuroepithelial cells (NECs) of the mudskipper gill and skin epithelium using immunohistochemistry and confocal microscopy. Colocalization studies showed that 5-HT is coexpressed with nNOS, Na+/K+-ATPase, TH and VAChT; nNOS is coexpressed with Na+/K+-ATPase and TH in the skin. In the gill 5-HT is coexpressed with nNOS and VAhHT and nNOS is coexpressed with Na+/K+-ATPase and TH. Acetylcholine is also expressed in chain and proximal neurons projecting to the efferent filament artery and branchial smooth muscle. The serotonergic cells c labeled with VAChT, nNOS and TH, thus indicating the presence of NEC populations and the possibility that these neurotransmitters (other than serotonin) may act as primary transmitters in the hypoxic reflex in fish gills. Immunolabeling with TH antibodies revealed that NECs in the gill and the skin are innervated by catecholaminergic nerves, thus suggesting that these cells are involved in a central control of branchial functions through their relationships with the sympathetic branchial nervous system. The Na+/K+-ATPase in mitochondria rich cells (MRCs), which are most concentrated in the gill lamellar epithelium, is colabeled with nNOS and associated with TH nerve terminals. TH-immunopositive fine varicosities were also associated with the numerous capillaries in the skin surface and the layers of the swollen cells. Based on the often hypercapnic and hypoxic habitat of the mudskippers, these fishes may represent an attractive model for pursuing studies on O2 and CO2 sensing due to the air-breathing that increases the importance of acid/base regulation and the O2-related drive including the function of gasotransmitters such as nitric oxide that has an inhibitory (regulatory) function in ionoregulation. PMID- 28830731 TI - Presence of microbiota reverses the relative performance of Daphnia on two experimental diets. AB - The outcomes of host-symbiont interactions may differ according to environmental context, and symbioses may enable host adaptation to diverse environments. We find that the effects of two different experimental diets, algae and yeast, on the water flea Daphnia magna depend on whether the animals possess microbiota, suggesting that the presence of microbiota determines which diet is superior. Our study hints at both diet-dependent and diet-independent effects of microbiota on Daphnia fitness. PMID- 28830732 TI - cGAS-STING and Cancer: Dichotomous Roles in Tumor Immunity and Development. AB - cGMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) sensing has emerged as a key regulator of innate immune responses to both exogenous and endogenous DNA. Recent studies reveal critical roles for this pathway in natural antitumor immunity across cancer types as well as in immune checkpoint blockade therapy. However, it is also clear that some tumors evade cGAS-STING-mediated immune responses, and immunomodulatory therapeutics are currently being explored to target this pathway. Finally, we also discuss recent observations that cGAS STING-mediated inflammation may promote tumor initiation, growth, and metastasis in certain malignancies and how this may complicate the utility of this pathway in therapeutic development. PMID- 28830733 TI - The Mechanisms of T Cell Selection in the Thymus. AB - T cells undergo positive and negative selection in the thymic cortex and medulla, respectively. A promiscuous expression of a wide array of self-antigens in the thymus is essential for the negative selection of self-reactive T cells and the establishment of central tolerance. Aire was originally thought to be the exclusive factor regulating the expression of tissue-restricted antigens, but Fezf2 recently emerged as a critical transcription factor in this regulatory activity. Fezf2 is selectively expressed in thymic medullary epithelial cells, regulates a large number of tissue-restricted antigens and suppresses the onset of autoimmune responses. Here, we discuss novel findings on the transcriptional mechanisms of tissue restricted-antigen expression in the medullary thymic epithelial cells and its effects on T cell selection. PMID- 28830734 TI - Post-Translational Peptide Splicing and T Cell Responses. AB - CD8+ T cell specificity depends on the recognition of MHC class I-epitope complexes at the cell surface. These epitopes are mainly produced via degradation of proteins by the proteasome, generating fragments of the original sequence. However, it is now clear that proteasomes can produce a significant portion of epitopes by reshuffling the antigen sequence, thus expanding the potential antigenic repertoire. MHC class I-restricted spliced epitopes have been described in tumors and infections, suggesting an unpredicted relevance of these peculiar peptides. We review current knowledge about proteasome-catalyzed peptide splicing (PCPS), the emerging rules governing this process, and the potential implications for our understanding and therapeutic use of CD8+ T cells, as well as mechanisms generating other non-canonical antigenic epitopes targeted by the T cell response. PMID- 28830735 TI - Targeting vasa vasorum dysfunction to prevent atherosclerosis. AB - Vasa vasorum are blood microvessels which penetrate the adventitia and outer layers of the media of large blood vessels, supplying them with nutrients and oxygen. A growing body of evidence suggests that vasa vasorum play a central role in the pathogenesis of atherosclerosis. In this review, we will make a case for the role of microvascular dysfunction in the initiation of disease. When seen through this lens, new therapeutic opportunities for prevention can be envisioned. In particular, we discuss how targeting the cellular metabolism and epigenetic machinery of vasa vasorum neovessels could be harnessed to render vasa vasorum endothelial cells less sensitive to atherogenic stimuli. PMID- 28830736 TI - [Evaluation of the toxicity of Basidiomycota fungi on the hatching of Artemia franciscana cysts]. AB - BACKGROUND: The consumption of wild mushrooms has increased in recent years. However, not all mushrooms are edible and some of them may cause poisoning. Therefore, their toxicity needs to be studied. Artemia franciscana is a crustacean used in toxicity tests including toxins of fungi. AIMS: To determine the percentage of inhibition and mortality produced by extracts of several basidiomycetes on the hatching of A. franciscana cysts. METHODS: Aqueous extracts were prepared from 15 species of mushrooms collected from Jalisco state, Mexico. Different concentrations of the extracts were assayed in order to test their toxicity. Potassium dichromate and artificial seawater were the positive and negative controls, respectively. The percentages of hatching and mortality of the cysts were evaluated. RESULTS: Inhibition of hatching greater than 80% in all the concentrations tested was found in 13 of the 15 species studied, in contrast to the positive control, which inhibited cyst hatching less than 50% in all cases. The highest percentage of mortality in the cysts was caused by the aqueous extracts of Amanita virosa, Leucopaxillus amarus, and Tylopilus violatinctus, and the lowest by Macrolepiota mastoidea. CONCLUSIONS: The brine shrimp bioassay appeared to be useful in the evaluation of the toxicity of several basidiomycetes, with the exception of Scleroderma texense, a mushroom considered poisonous, which showed no toxicity over A. franciscana. PMID- 28830737 TI - Chemotherapy and radiation treatment decision-making experiences of older adults with cancer: A qualitative study. AB - PURPOSE: Little is known about the perspectives of older adults (OAs) with newly diagnosed cancer on their experiences with cancer treatment decision-making. The objective of this study was to explore the factors that were important for accepting or refusing cancer treatment by older adults undergoing chemotherapy and/or radiation therapy. PATIENTS AND METHODS: A qualitative study using semi structured interviews with 20 OAs aged >=65years with newly diagnosed cancer (<6months) receiving either curative or palliative chemotherapy and/or radiation or who had declined therapy. The COREQ reporting guideline was utilized. RESULTS: The majority of patients accepted the recommended cancer treatment. Most OAs followed their oncologist's recommendation, but spoke of making their own decisions and felt confident about their decisions. Second opinions were not commonly sought. Themes emerged can be divided into two categories: 1) pertaining to cancer treatment decision-making, which includes: "Trust in oncologist", "prolong life", "expected outcomes of treatment", "other people's experience", skeptical about going online" and "assertion of independence", and 2) pertaining to oncologist-patient interactions, which includes "communication". CONCLUSION: Older patients largely followed their cancer specialists' treatment recommendations. Most patients were satisfied with their treatment decision and were confident in their decisions. Seeking of second opinions was rare. More needs to be done to address the communication gaps and support needs of this population. PMID- 28830738 TI - Mastoid Epidermoid Tumor and Associated Dural Arteriovenous Fistula with Venous Sinus Occlusion. AB - BACKGROUND: Dural arteriovenous fistula (DAVF) is an abnormal vascular connection between arterial and venous channels within dura mater. Although DAVFs have been linked to other types of intracranial tumors, this is the first case reporting the association between DAVF and an epidermoid tumor. CASE DESCRIPTION: A middle aged patient with chronic headache presented with Borden type II DAVF draining into the right transverse sigmoid junction and was also found to have an epidermoid tumor over the right mastoid. The patient underwent staged embolization of the fistula through both transvenous and transarterial routes. Continuous intraoperative venous pressure monitoring confirmed marked reduction in intracranial venous pressure, and the patient's symptoms completely resolved. However, the fistula still remained. The residual DAVF was then surgically disconnected, and the epidermoid tumor was resected in the same procedure. CONCLUSIONS: This case demonstrates a DAVF can be associated with an epidermoid tumor. Tumor can compromise the venous outflow, which can then lead to intracranial venous hypertension and development of the DAVF. Venous pressure monitoring offers an objective method to verify resolution of venous hypertension, which might correlate with resolution of clinical symptoms. PMID- 28830739 TI - Molecular bases for multidrug resistance in Yersinia pseudotuberculosis. AB - The enteropathogen Yersinia pseudotuberculosis causes gastrointestinal infections in humans. Although this species is usually susceptible to antibiotics active against Gram-negative bacteria, we identified three multidrug resistant (MDR) strains of Y. pseudotuberculosis that were isolated from the environment in Russia and from a patient in France. The resistance traits of the two Russian isolates were transferable at high frequencies (~2*10-1/donor CFU) to Y. pseudotuberculosis. In contrast no transfer of the antibiotic resistances carried by the French strain was observed. Sequencing of the plasmid extracts of the Y. pseudotuberculosis transconjugants for the Russian isolates revealed the presence of conjugative plasmids of the IncN group that carried genes conferring resistance to four to six classes of antibiotics. The French strain harbored a large MDR plasmid of the IncHI2 group that carried resistance genes to six families of antibiotics, and contained a truncated set of transfer genes, accounting for the lack of plasmid transfer. All three Y. pseudotuberculosis plasmids were homologous to MDR plasmids found in various enterobacteria. A phylogenetic analysis showed that the two Russian strain plasmids were closely related to each other and were more distant from the French plasmid. To the best of our knowledge, this is the first molecular characterization of MDR plasmids in Y. pseudotuberculosis. Due to the propensity of this species to acquire exogenous plasmids, the risk of emergence of new MDR Y. pseudotuberculosis isolates should be seriously taken into consideration. PMID- 28830740 TI - How Do Psychological Risk Factors Predict Sexual Outcomes? A Comparison of Four Models of Young Women's Sexual Outcomes. AB - BACKGROUND: Recent research findings suggest that women who report high anxiety sensitivity (AS; the fear of physiologic sensations associated with anxiety) also report increased sexual dysfunction and decreased sexual satisfaction. Moreover, findings suggest that maladaptive emotion regulation (ER) can contribute to the relation between AS and psychological distress, thereby indirectly influencing sexual outcomes. Identifying relations among these variables and how they specifically relate to sexual outcomes could be vital for diagnostic and therapeutic purposes. As such, a comparison of different models of sexual outcomes that encompass psychological and sexual risk factors is needed. AIM: To compare four psychological models of women's sexual outcomes in a cross-sectional sample and specifically to investigate whether psychological factors (ie, AS, ER, psychological distress) uniquely or jointly predict related, but distinct, sexual outcomes in women: sexual functioning, sexual quality of life, and frequency of sexual activity. METHODS: Women (N = 316) completed an online survey that included the Anxiety Sensitivity Index-3, Difficulties with Emotion Regulation Scale, Depression Anxiety Stress Scales, Sexual Quality of Life Scale-Female, Female Sexual Function Index, and Sexual Experiences Questionnaire-Female. OUTCOMES: Outcome variables included women's self-reported sexual functioning, sexual quality of life, and frequency of sexual activity. RESULTS: Path analysis models demonstrated that psychological factors predicted orgasm, sexual pain, sexual quality of life, and frequency of partnered sexual activity in women but predicted sexual desire, arousal, lubrication, and frequency of solitary sexual activity to a lesser degree. We found that ER significantly accounted for the relation between AS and psychological distress through mediation and moderation pathways. CLINICAL TRANSLATION: Clinicians would benefit from incorporating psychological risk factors in their assessment and interventions of women's sexual concerns. STRENGTHS AND LIMITATIONS: This is the first study to compare models of women's sexual lives using indicators of mental and sexual health. However, our study was limited to a cross-sectional sample of young women in one university setting. CONCLUSIONS: AS, ER, and psychological distress are related to sexual functioning, sexual quality of life, and frequency of partnered sexual activity in young women. Psychological risk factors should be taken into consideration to better understand women's sexual lives. Tutino JS, Ouimet AJ, Shaughnessy K. How Do Psychological Risk Factors Predict Sexual Outcomes? A Comparison of Four Models of Young Women's Sexual Outcomes. J Sex Med 2017;14:1232-1240. PMID- 28830741 TI - Effects of Omega-3 in the treatment of violent schizophrenia patients. AB - OBJECTIVE: This study was designed to explore the relationship in between the daily consumption of fish oil (360mg DHA+540mg EPA), and reduction of symptoms and violent behavior among patients with schizophrenia. METHOD: Fifty inpatients meeting ICD-10 criteria for schizophrenia and scoring more than four of Modified Overt Aggression Scale (MOAS) with antipsychotics treatment were randomly assigned to receive either fish oil (N=28) or a placebo (N=22) in a twelve week, double-blind supplementation trial. Assessments were performed at baseline and at weeks 4, 8 and 12. RESULTS: The PANSS and CGI scores decreased at the week of 4, 8 and 12, but no differences were found between the two groups. MOAS scores declined significantly at weeks 4, 8 and 12. At week 12, MOAS scores of the fish oil group declined significantly than the placebo group (t=-2.40, P<0.05). CONCLUSIONS: violent schizophrenia patients treated with fish oil (360mg DHA+540mg EPA) demonstrated a decrease in violence, but improvement in positive and negative symptoms was no greater than patients treated with the placebo after twelve weeks. PMID- 28830742 TI - Emotion discrimination in humans: Its association with HSV-1 infection and its improvement with antiviral treatment. AB - BACKGROUND: Herpes simplex virus, type 1 (HSV-1) infects over 3.4 billion people, world-wide. Though it can cause encephalitis, in the vast majority it is asymptomatic, with lifelong latent infection in neurons. HSV-1 infected individuals have greater cognitive dysfunction than uninfected individuals, particularly persons with schizophrenia - even without encephalitis. We investigated whether HSV-1 related cognitive dysfunction is progressive or remediable. METHODS: In a prospective naturalistic follow up sample (PNFU), temporal changes in cognitive functions were analyzed in relation to baseline HSV 1 infection in persons with/without schizophrenia (N=226). Independently, in a randomized controlled trial (RCT), HSV-1 infected, clinically stabilized SZ outpatients received Valacyclovir (VAL, an HSV-1 specific antiviral, 1.5G twice daily for 16weeks) or placebo (PLA) added to standard antipsychotic treatment, using a stratified randomization design, following placebo run-in (N=67). In both samples, HSV-1 infection (seropositivity) was estimated using serum IgG antibodies. Clinical evaluations were blinded to HSV-1 or treatment status. Standardized Z scores for accuracy on eight cognitive domains were analyzed for temporal trajectories using generalized linear models (PNFU) and VAL/PLA differences compared with intent to treat analyses (RCT). RESULTS: PNFU: At baseline, HSV-1 infected participants had significantly lower accuracy scores for Emotion Identification and Discrimination (EMOD), Spatial memory and Spatial ability, regardless of SZ diagnosis (p=0.025, 0.029, 0.046, respectively). They also had significantly steeper temporal worsening for EMOD (p=0.03). RCT: EMOD improved in VAL-treated patients (p=0.048, Cohen's d=0.43). CONCLUSIONS: A proportion of age related decline in EMOD is attributable to HSV-1 infection. PMID- 28830743 TI - AFM contribution to unveil pro- and eukaryotic cell mechanical properties. AB - Atomic force microscopy is nowadays a well-established technique that permits the investigation of numerous parameters of living matter. In particular, it allows the exploration of the mechanical properties of living organisms in almost physiological conditions. Here, we focus on the use of this technology to review recent contributions that relates the physiology and pathology of bacteria, yeast, plant and mammalian cells to their nano-mechanical properties. PMID- 28830745 TI - Baculovirus-induced recombinant protein expression in human mesenchymal stromal stem cells: A promoter study. AB - Human mesenchymal stem cells (hMSCs) are the current workhorses of regenerative medicine and gene therapy. The corresponding vectors are usually based on lentiviruses, adenoviruses, retroviruses or adeno-associated viruses, but recently they have been joined by baculoviruses, which are more widely known for their role in the development of pesticides and vaccines. Here we show that gene transfer to an immortalized human mesenchymal stroma cell line can be achieved by baculovirus transduction. We also compared the performance of five different constitutive promoters controlling GFP expression. The human elongation factor 1alpha promoter (EF1alpha) achieved the strongest GFP expression, whereas the mouse phosphoglycerate kinase 1 promoter (PGK) was the weakest. The human EF1alpha promoter is therefore recommended for the regulation of genes introduced into hMSC-TERTs by baculovirus vectors. PMID- 28830744 TI - Mechanosensing in the immune response. AB - Cells have a remarkable ability to sense and respond to the mechanical properties of their environment. Mechanosensing is essential for many phenomena, ranging from cell movements and tissue rearrangements to cell differentiation and the immune response. Cells of the immune system get activated when membrane receptors bind to cognate antigen on the surface of antigen presenting cells. Both T and B lymphocyte signaling has been shown to be responsive to physical forces and mechanical cues. Cytoskeletal forces exerted by cells likely mediate this mechanical modulation. Here, we discuss recent advances in the field of immune cell mechanobiology at the molecular and cellular scale. PMID- 28830746 TI - Risk factors and molecular epidemiology of Acinetobacter baumannii bacteremia in neonates. AB - BACKGROUND: Acinetobacter baumannii infections in neonates are not uncommon but rarely studied. METHODS: Clinical and molecular epidemiology of 40 patients with A. baumannii bacteremia in the neonatal intensive care units (NICUs) of a medical center from 2004 to 2014 was analyzed. RESULTS: Multi-drug resistance was found in only 3 isolates (7.5%). Sequence types (STs) of A. baumannii defined by multilocus sequencing typing were diverse, and 72.4% identified isolates belonged to novel STs. Majority of the isolates were susceptible to antibiotics tested. Among the 3 imipenem-resistant A. baumannii (IRAB) isolates, 2 (66.7%) belonged to ST684, a novel ST. All of the 3 isolates were susceptible to tigecycline and colistin. The predominant mechanism of imipenem resistance in these neonatal isolates is ISAba1-blaOXA-80, which has never been reported in Asia before. Most infected newborns were premature (95%), with very low birth weight (70% < 1500 g), prolonged intubation, usage of percutaneous central venous catheter (65%) and long-term usage of total parenteral nutrition or intravenous lipid (95%). IRAB infection, inappropriate initial therapy, 1-minute Apgar score and early onset infection within the first 10 days of life were found to correlate with mortality by log-rank test. Prior use of imipenem for at least 5 days and use of high frequency oscillation ventilation (HFOV) were statistically significant risk factors for acquiring IRAB infections. CONCLUSIONS: To reduce mortality of IRAB infection, it is crucial to consider giving effective agents, such as colistin, in 2 days for high risk neonates who has been given imipenem or used HFOV. PMID- 28830747 TI - A consumer's guide for probiotics: 10 golden rules for a correct use. AB - Probiotics are used all over the world as their beneficial effects on the human organism have been widely demonstrated. Certain probiotics can down-regulate production of pro-inflammatory cytokines and promote intestinal epithelial barrier functions, increasing an anti-inflammatory response and contributing to the host's overall health. The main mechanisms by which probiotic microorganisms can interact with the host are by modulating the immune system and the epithelial cell functions and interacting with intestinal gut microbiota. To date, hundreds of different microorganisms are used for the formulation of numerous probiotic products; therefore, it is very difficult to choose the best probiotic product for specific or more general needs. Therefore, physicians are getting more and more confused due to the high number of commercial products which are often lacking healthy effects on the host. Therefore, the aim of this paper is to demonstrate the main characteristics that probiotic microorganisms and products should possess to have a positive impact on the host's health. To this purpose, this review suggests "10 golden rules" or "commandments" that clinicians should follow to properly select the optimal probiotic product and avoid misidentifications, mislabelling and "pie in the sky" stories. PMID- 28830749 TI - Comparison of outcomes in new-generation versus early-generation heart valve in transcatheter aortic valve implantation: A systematic review and meta-analysis. AB - BACKGROUND: New-generation (NG) valves for transcatheter aortic valve implantation (TAVI) has recently been widely used in real-world practice, yet its comparative outcomes with early-generation (EG) valves remain under-explored. METHODS: An electronic literature search using PUBMED and EMBASE was conducted from inception to April 2017 for matched-cohort studies. Articles that compared the outcomes of NG vs. EG valves post TAVI with at least one of the following clinical outcome reported were included: all-cause mortality, major or life threatening bleeding, major vascular complications (MVC), significant (more than moderate) paravalvular regurgitation (PVR), cerebrovascular events, significant (stage 2 or 3) acute kidney injury (AKI) and new permanent pacemaker implantation (PPI) that occurred either in-hospital or within 30-days. RESULTS: A total of 6 observational matched-cohort studies with 585 and 647 patients included in NG and EG valves, respectively, were included. EG valves were associated with a lower incidence of major or life-threatening bleeding (5.7% vs. 15.7%, p<0.00001), significant paravalvular regurgitation (5.3% vs. 14.4%, p=0.001), and significant AKI (4.4% vs. 7.5, p=0.03). All-cause mortality (3.5% vs. 5.0, p=0.43), cerebrovascular events (3.4% vs. 2.3%, p=0.34) and new PPI (11.0% vs. 14.6%, p=0.52) were similar between the two groups. NG demonstrated lower tendency of MVC (2.5% vs. 7.2, p=0.09) compared to EG valves. CONCLUSIONS: NG demonstrated lower rates of significant AKI, significant PVR and major or life-threatening bleeding while all-cause mortality, new PPI, and cerebrovascular events remained similar compared to EG valves. PMID- 28830748 TI - Effects of androgens on the leptin system in immature male Atlantic salmon parr. AB - Leptin modulates all levels of the reproductive endocrine axis in mammals, and in turn, both leptin and the leptin receptor are regulated by sex steroids. The aim of this study was to investigate if sex steroids regulate the leptin system also in fish. Immature one-year old male Atlantic salmon parr were implanted with Silclear capsules that were either empty or filled with 11-ketoandrostenedione (11KA) or testosterone (T) and the effects of 35-days treatment were investigated on measures of maturation, gene expression of leptin (lepa1, lepa2), leptin receptor (lepra1) and circulating plasma leptin. Both 11-KA and T stimulated the reproductive axis by increasing testes weight and up-regulated pituitary lh-beta mRNA levels and for T also fsh-beta. T up-regulated transcription levels of lepa1 and lepra1 in the pituitary, while 11-KA had no effect. Leptin receptor expression in the testis was unaltered by either androgen. T up-regulated lepa1 mRNA levels significantly also in the liver, but had no effect on lepa2, and 11KA did not affect hepatic gene expression of either lepa1 or lepa2. Plasma leptin levels did not differ significantly between treatments. The results indicate that androgens regulate gene expression of leptin and the leptin receptor in different tissues in fish and that the effects of leptin might be tissue specific considering plasma levels remained unaltered. Overall, the results suggest a role for leptin in fish reproduction, where sex steroids are able to regulate components of the leptin system differentially in liver and important tissues of the reproductive axis. PMID- 28830750 TI - Neurological recovery from multiple cardiac arrests due to acute massive pulmonary embolism managed by cardiopulmonary resuscitation and extracorporeal membrane oxygenation. AB - Cardiac arrest is one of the leading causes of death worldwide. Anoxic-ischemic encephalopathy resulting from cardiac arrest is the third leading cause of coma requiring admission to the intensive care unit (following trauma and drug overdose). In this article, we aim to report a case of multiple cardiac arrests due to acute massive pulmonary embolism managed by cardiopulmonary resuscitation (CPR) and extracorporeal membrane oxygenation (ECMO) with an excellent neurological recovery. The present case illustrates that a good neurologic recovery can be achieved following multiple cardiac arrests and prolonged CPR for a massive pulmonary embolism. The use of ECMO in such case is believed to reduce the mortality rate and increase the likelihood of survival with good neurological outcomes. Given the potential for success and the lifesaving results, ECMO should be considered in all cases of massive pulmonary embolism with cardiopulmonary compromise. PMID- 28830751 TI - Treatment of de novo coronary artery bifurcation lesions with drug coated balloons: A reappraisal according to the available scientific data. AB - The treatment of coronary artery bifurcation often represents a challenge for interventional cardiologist. Although several stenting techniques are available for the treatment of de novo coronary bifurcation lesions, over the last years, different studies have proposed and analysed the use of drug-coated balloon (DCB) in the treatment of coronary artery bifurcation lesions as an alternative treatment. To date, even considering those studies which have analysed a combined strategy (DCB+stenting) or a DCB-only approach, the evidences are scant and the results debatable. We review the available scientific data regarding the use of DCB in the treatment of naive coronary bifurcation lesions. PMID- 28830752 TI - Eastern brown snake (Pseudonaja textilis) envenomation in dogs and cats: Clinical signs, coagulation changes, brown snake venom antigen levels and treatment with a novel caprylic acid fractionated bivalent whole IgG equine antivenom. AB - This report describes the diagnosis and treatment of 16 confirmed cases of snakebite from the Australian eastern brown snake (Pseudonaja textilis) in dogs and cats. The clinical signs, brown snake venom antigen concentrations, coagulation parameters, and treatment outcomes following administration of an experimental caprylic acid fractionated bivalent whole IgG antivenom are documented. A brown snake venom antigen specific sandwich ELISA was used to retrospectively quantify venom levels in serum and urine. The characteristic clinical signs of envenomation in all cases were neurotoxicity to a variable extent and coagulation disturbances. The median serum venom concentration at presentation was 122 ng/mL and ranged from 1.9 to 3607 ng/mL. The median urine venom concentration at presentation was 55 ng/mL and ranged from 3.3 to 2604 ng/mL. Mechanical ventilation was used to successfully support respiration in three severely paralysed cases for 1-30 h. In four cases where serum samples were available post-antivenom treatment, venom was no longer detectable. Coagulation parameters measured on citrated plasma samples collected prior to antivenom from each case were abnormally prolonged to variable degrees in all cases. Three cases (2 dogs; 1 cat) were euthanized within four hours of presentation for either cost based reasons (2) or poor prognosis (1). One dog developed massive and potentially fatal pulmonary haemorrhage and was euthanazed. In vitro testing of the venom procoagulant neutralising efficacy of the experimental antivenom demonstrated it was 9.6-72 times more effective when compared to two other commercial veterinary antivenom products. This is the first detailed report of a case series of P. textilis envenomation in dogs and cats. The envenomation syndrome in dogs and cats differed to that reported humans, dominated by neurotoxicity and coagulopathy; unlike in humans, where coagulopathy is of primary clinical significance. PMID- 28830753 TI - Bladder Reconstruction Rates Differ among Centers Participating in National Spina Bifida Patient Registry. AB - PURPOSE: We performed an exploratory analysis of data from the NSBPR (National Spina Bifida Patient Registry) to assess variation in the frequency of bladder reconstruction surgeries among NSBPR centers. MATERIALS AND METHODS: We queried the 2009-2014 NSBPR to identify patients who had ever undergone bladder reconstruction surgeries. We evaluated demographic characteristics, spina bifida type, functional level, mobility and NSBPR center to determine whether any of these factors were associated with reconstructive surgery rates. Multivariable logistic regression was used to simultaneously adjust for the impact of these factors. RESULTS: We identified 5,528 patients with spina bifida enrolled in the NSBPR. Of these patients 1,129 (20.4%) underwent bladder reconstruction (703 augmentation, 382 continent catheterizable channel, 189 bladder outlet procedure). Surgical patients were more likely older, female, nonHispanic white, with a higher lesion level, myelomeningocele diagnosis, nonambulators (all p <0.001) and nonprivately insured (p=0.018). Bladder reconstruction surgery rates varied among NSBPR centers (range 12.1% to 37.9%, p <0.001). After correcting for known confounders NSBPR center, spina bifida type, mobility, gender and age (all p <0.001) were significant predictors of surgical intervention. Race (p=0.19) and insurance status (p=0.11) were not associated with surgical intervention. CONCLUSIONS: There is significant variation in rates of bladder reconstruction surgery among NSBPR centers. In addition to clinical factors such as mobility status, lesion type and lesion level, nonclinical factors such as patient age, gender and treating center are also associated with the likelihood of an individual undergoing bladder reconstruction. PMID- 28830754 TI - Focal Therapy Eligibility Determined by Magnetic Resonance Imaging/Ultrasound Fusion Biopsy. AB - PURPOSE: We assessed focal therapy eligibility in men who underwent multiparametric magnetic resonance imaging and targeted biopsy with correlation to whole mount histology after radical prostatectomy. MATERIALS AND METHODS: Subjects were selected from among the 454 men in whom targeted biopsy proven prostate cancer was derived from regions of interest on multiparametric magnetic resonance imaging from 2010 to 2016. Focal therapy eligibility was limited to a maximum Gleason score of 4 + 3 in regions of interest with or without other foci of low risk prostate cancer (Gleason score 3 + 3 and less than 4 mm). Men who did not meet NCCN(r) intermediate risk criteria were classified as ineligible for focal therapy. Of the 454 men 64 underwent radical prostatectomy and biopsy findings were compared to final pathology findings. RESULTS: Of the 454 men with a biopsy proven region of interest 175 (38.5%) were eligible for focal therapy. Fusion biopsy, which combined targeted and template biopsy, had 80.0% sensitivity (12 of 15 cases), 73.5% specificity (36 of 49) and 75.0% accuracy (48 of 64) for focal therapy eligibility. Targeted cores alone yielded 73.3% sensitivity (11 of 15 cases), 47.9% specificity (23 of 48) and 54.7% accuracy (35 of 64). Gleason score and extension across the midline differed in 4 and 9, respectively, of the 13 cases that showed discordant biopsy and whole mount histology. CONCLUSIONS: Using intermediate risk eligibility criteria more than a third of men with a targeted biopsy proven lesion identified on multiparametric magnetic resonance imaging would have been eligible for focal therapy. Eligibility determined by fusion biopsy was concordant with whole mount histology in 75% of cases. Improved selection criteria are needed to reliably determine focal therapy eligibility. PMID- 28830755 TI - Naringin attenuates thioacetamide-induced liver fibrosis in rats through modulation of the PI3K/Akt pathway. AB - AIMS: Naringin (NR) is a flavanone glycoside extracted from grapefruits and citrus fruits. The aim of this study is to investigate the antifibrotic efficacy of NR in thioacetamide (TAA)-induced hepatic fibrosis in rats through evaluating NR effect on the PI3K/Akt pathway. MAIN METHODS: Hepatic fibrosis was induced in rats by intraperitoneal injection of TAA (200mg/kg) twice per week for 6weeks. Simultaneously, NR (40mg/kg/day, p.o.) was given along with TAA injection. The ratio of P-Akt/Akt was assessed in hepatic homogenate as well as antioxidant enzymes (catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx)) and lipid peroxidation marker, malondialdehyde (MDA). Serum level of interleukin (IL) 6 were measured using ELISA. Hepatic tissues were examined histopathologically using hematoxylin and eosin (H&E) and Masson trichome staining. Tissue expression of alpha smooth muscle actin (alpha-SMA), transforming growth factor beta1 (TGF beta1), caspase-3 and fibronectin were scored immunohistochemically. Finally, the mRNA level of cytokine genes (IL-1beta, IL-6, IL-10, interferon gamma (IFN gamma)), caspase-3, TGF-beta1 and fibronectin were quantified using qPCR. KEY FINDINGS: NR significantly suppressed Akt phosphorylation associated with increased number of caspase-3 positive cells especially in the fibrotic areas. Liver tissues of treated rats showed restoration of normal liver histology and decrease in collagen and fibronectin deposition. Furthermore, NR treatment ameliorated oxidative stress and inflammatory cytokine production. SIGNIFICANCE: NR alleviated experimental liver fibrosis through inhibition of PI3K/Akt pathway beside its anti-inflammatory and antioxidant effects. Therefore, NR is a promising therapeutic candidate for hepatic fibrosis. PMID- 28830756 TI - Re: Reply to Drs. Joob and Wiwanikit. PMID- 28830757 TI - Therapeutic hypothermia for ischemic stroke; pathophysiology and future promise. AB - Therapeutic hypothermia, or cooling of the body or brain for the purposes of preserving organ viability, is one of the most robust neuroprotectants at both the preclinical and clinical levels. Although therapeutic hypothermia has been shown to improve outcome from related clinical conditions, the significance in ischemic stroke is still under investigation. Numerous pre-clinical studies of therapeutic hypothermia has suggested optimal cooling conditions, such as depth, duration, and temporal therapeutic window for effective neuroprotection. Several studies have also explored mechanisms underlying the mechanisms of neuroprotection by therapeutic hypothermia. As such, it appears that cooling affects multiple aspects of brain pathophysiology, and regulates almost every pathway involved in the evolution of ischemic stroke. This multifaceted mechanism is thought to contribute to its strong neuroprotective effect. In order to carry out this therapy in optimal clinical settings, methodological and pathophysiological understanding is crucial. However, more investigation is still needed to better understand the underlying mechanisms of this intervention, and to overcome clinical barriers which seem to preclude the routine use therapeutic hypothermia in stroke. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 28830758 TI - The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. AB - The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacological profile of raw kratom extracts, although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiological effects in man based on this preclinical data and comparison to both anecdotal human experience and multiple epidemiological surveys. Kratom exposure alone has not been causally associated with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28830759 TI - Phencyclidine-like in vivo effects of methoxetamine in mice and rats. AB - Methoxetamine (MXE) is a novel drug of abuse that is structurally similar to phencyclidine (PCP). In the present study, rats were trained to discriminate PCP from saline and substitution tests were performed with arylcyclohexylamines PCP, eticyclidine (PCE), tenocyclidine (TCP), and MXE. PCP and PCE engendered PCP lever selection in all subjects, whereas MXE and TCP produced PCP-lever selection in animals that did not display behavioral disruption. Last, the substituted tryptamine dipropyltryptamine (DPT) produced moderate PCP-lever selection and elicited behavioral disruption in all subjects at the highest dose tested. Immediately following the final substitution test in the drug discrimination experiment, the same rats and a separate group of experimentally-naive rats were implanted with osmotic mini-pumps delivering continuous PCP infusions for 11 days. Consistent with PCP withdrawal, disruption of food-maintained operant responding was observed when the pumps were removed, but cumulative MXE administration dose-dependently reversed this effect. A third group of rats self administered several unit doses of PCP and MXE. Results of the self administration tests revealed that MXE was a less effective reinforcer than PCP. Lastly, mice were implanted with radiotelemetry probes to simultaneously monitor thermoregulatory and locomotor responses following injections of PCP, PCE, or MXE. All three arylcyclohexylamines elicited dose-dependent hypothermic effects, but only PCP produced increases in locomotor activity. Together, these findings indicate that MXE elicits PCP-like interoceptive effects, but reduced reinforcing and locomotor stimulant effects in vivo. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28830760 TI - Sex-specific effects of social isolation on ageing in Drosophila melanogaster. AB - Social environments can have a major impact on ageing profiles in many animals. However, such patterns in variation in ageing and their underlying mechanisms are not well understood, particularly because both social contact and isolation can be stressful. Here, we use Drosophila melanogaster fruitflies to examine sex specific effects of social contact. We kept flies in isolation versus same-sex pairing throughout life, and measured actuarial (lifespan) and functional senescence (declines in climbing ability). To investigate underlying mechanisms, we determined whether an immune stress (wounding) interacted with effects of social contact, and assessed behaviours that could contribute to differences in ageing rates. Pairing reduced lifespan for both sexes, but the effect was greater for males. In contrast, pairing reduced the rate of decline in climbing ability for females, whereas for males, pairing caused more rapid declines with age. Wounding reduced lifespan for both sexes, but doubled the negative effect of pairing on male lifespan. We found no evidence that these effects are driven by behavioural interactions. These findings suggest that males and females are differentially sensitive to social contact, that environmental stressors can impact actuarial and functional senescence differently, and that these effects can interact with environmental stressors, such as immune challenges. PMID- 28830761 TI - Nutrition modifies critical thermal maximum of a dominant canopy ant. AB - While adaptive responses to climate gradients are increasingly documented, little is known about how individuals alter their upper thermal tolerances. Long-term increases in dietary carbohydrates can elevate upper thermal tolerances in insects. We explored how the nutritional state of a Neotropical canopy ant governs its CTmax - the temperature at which individuals lose muscle control. We predicted that Azteca chartifex workers recently fed a carbohydrate-rich diet, such as honeydew and extrafloral nectar, would use that energy to increase their CTmax. Moreover, if a carbohydrate-rich diet increases CTmax, then we predicted that ants from colonies with high CTmaxs feed at a lower trophic level, and thus have a higher carbon:nitrogen ratio. We used A. chartifex colonies from a long term fertilization experiment where phosphorus addition increased A. chartifex foraging activity with respect to controls. As foraging activity can be governed by resource availability, we first measured CTmax of field collected colonies. In freshly collected field colonies, CTmax was 2 degrees C higher in control plots. This difference disappeared when ants were provided with only water for 10h. Ants were then provided with a 10% sucrose solution ad lib which increased CTmax by 5 degrees C. We thus support the hypothesis that enhanced carbohydrate nutrition enables higher thermal tolerance, but this does not appear to be linked to colony trophic status, higher carbon:nitrogen ratios, or higher total body phosphorus. This short-term thermal plasticity linked to carbohydrate nutrition demonstrates the importance of ant diet in shaping their physiological traits. It is especially relevant to ant species that maintain high abundance by feeding on plant exudates. In a rapidly warming world, carbohydrate availability and use may represent a new element for predicting population and community responses of herbivorous insects. PMID- 28830763 TI - Carvacrol promotes angiogenic paracrine potential and endothelial differentiation of human mesenchymal stem cells at low concentrations. AB - OBJECTIVES: Phenolic monoterpene compound, named Carvacrol, has been found to exert different biological outcomes. It has been accepted that the angiogenic activity of human mesenchymal stem cells was crucial in the pursuit of appropriate regeneration. In the current experiment, we investigated the contribution of Carvacrol on the angiogenic behavior of primary human mesenchymal stem cells. METHODS: Mesenchymal stem cells were exposed to Carvacrol in a dose ranging from 25 to 200MUM for 48h. We measured cell survival rate by MTT assay and migration rate by a scratch test. The oxidative status was monitored by measuring SOD, GPx activity. The endothelial differentiation was studied by evaluating the level of VE-cadherin and vWF by real-time PCR and ELISA analyses. The content of VEGF and tubulogenesis behavior was monitored in vitro. We also conducted Matrigel plug in vivo CAM assay to assess the angiogenic potential of conditioned media from human mesenchymal stem cells after exposure to Carvacrol. RESULTS: Carvacrol was able to increase mesenchymal stem cell survival and migration rate (p<0.05). An increased activity of SOD was obtained while GPx activity unchanged or reduced. We confirmed the endothelial differentiation of stem cells by detecting vWF and VE-cadherin expression (p<0.05). The VEGF expression was increased and mesenchymal stem cells conditioned media improved angiogenesis tube formation in vitro (p<0.05). Moreover, histological analysis revealed an enhanced microvascular density at the site of Matrigel plug in CAM assay. CONCLUSIONS: Our data shed lights on the possibility of a Carvacrol to induce angiogenesis in human mesenchymal stem cells by modulating cell differentiation and paracrine angiogenic response. PMID- 28830762 TI - Contribution of amygdala CRF neurons to chronic pain. AB - We investigated the role of amygdala corticotropin-releasing factor (CRF) neurons in the perturbations of descending pain inhibition caused by neuropathic pain. Forced swim increased the tail-flick response latency in uninjured mice, a phenomenon known as stress-induced analgesia (SIA) but did not change the tail flick response latency in mice with neuropathic pain caused by sciatic nerve constriction. Neuropathic pain also increased the expression of CRF in the central amygdala (CeAmy) and DeltaFosB in the dorsal horn of the spinal cord. Next, we injected the CeAmy of CRF-cre mice with cre activated AAV-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) vectors. Activation of CRF neurons by DREADD/Gq did not affect the impaired SIA but inhibition of CRF neurons by DREADD/Gi restored SIA and decreased allodynia in mice with neuropathic pain. The possible downstream circuitry involved in the regulation of SIA was investigated by combined injections of retrograde cre-virus (CAV2-cre) into the locus ceruleus (LC) and cre activated AAV-diphtheria toxin (AAV-FLEX DTX) virus into the CeAmy. The viral injections were followed by a sciatic nerve constriction ipsilateral or contralateral to the injections. Ablation of amygdala projections to the LC on the side of injury but not on the opposite side, completely restored SIA, decreased allodynia and decreased DeltaFosB expression in the spinal cord in mice with neuropathic pain. The possible lateralization of SIA impairment to the side of injury was confirmed by an experiment in which unilateral inhibition of the LC decreased SIA even in uninjured mice. The current view in the field of pain research attributes the process of pain chronification to abnormal functioning of descending pain inhibition. Our results demonstrate that the continuous activity of CRF neurons brought about by persistent pain leads to impaired SIA, which is a symptom of dysregulation of descending pain inhibition. Therefore, an over-activation of amygdala CRF neurons is very likely an important contributing factor for pain chronification. PMID- 28830764 TI - Sensory-biased attention networks in human lateral frontal cortex revealed by intrinsic functional connectivity. AB - Human frontal cortex is commonly described as being insensitive to sensory modality, however several recent studies cast doubt on this view. Our laboratory previously reported two visual-biased attention regions interleaved with two auditory-biased attention regions, bilaterally, within lateral frontal cortex. These regions selectively formed functional networks with posterior visual-biased and auditory-biased attention regions. Here, we conducted a series of functional connectivity analyses to validate and expand this analysis to 469 subjects from the Human Connectome Project (HCP). Functional connectivity analyses replicated the original findings and revealed a novel hemispheric connectivity bias. We also subdivided lateral frontal cortex into 21 thin-slice ROIs and observed bilateral patterns of spatially alternating visual-biased and auditory-biased attention network connectivity. Finally, we performed a correlation difference analysis that revealed five additional bilateral lateral frontal regions differentially connected to either the visual-biased or auditory-biased attention networks. These findings leverage the HCP dataset to demonstrate that sensory-biased attention networks may have widespread influence in lateral frontal cortical organization. PMID- 28830765 TI - A theoretical signal processing framework for linear diffusion MRI: Implications for parameter estimation and experiment design. AB - The data measured in diffusion MRI can be modeled as the Fourier transform of the Ensemble Average Propagator (EAP), a probability distribution that summarizes the molecular diffusion behavior of the spins within each voxel. This Fourier relationship is potentially advantageous because of the extensive theory that has been developed to characterize the sampling requirements, accuracy, and stability of linear Fourier reconstruction methods. However, existing diffusion MRI data sampling and signal estimation methods have largely been developed and tuned without the benefit of such theory, instead relying on approximations, intuition, and extensive empirical evaluation. This paper aims to address this discrepancy by introducing a novel theoretical signal processing framework for diffusion MRI. The new framework can be used to characterize arbitrary linear diffusion estimation methods with arbitrary q-space sampling, and can be used to theoretically evaluate and compare the accuracy, resolution, and noise-resilience of different data acquisition and parameter estimation techniques. The framework is based on the EAP, and makes very limited modeling assumptions. As a result, the approach can even provide new insight into the behavior of model-based linear diffusion estimation methods in contexts where the modeling assumptions are inaccurate. The practical usefulness of the proposed framework is illustrated using both simulated and real diffusion MRI data in applications such as choosing between different parameter estimation methods and choosing between different q space sampling schemes. PMID- 28830767 TI - Influence of dual-tasking with different levels of attention diversion on characteristics of the movement-related cortical potential. AB - Dual tasking is defined as performing two tasks concurrently and has been shown to have a significant effect on attention directed to the performance of the main task. In this study, an attention diversion task with two different levels was administered while participants had to complete a cue-based motor task consisting of foot dorsiflexion. An auditory oddball task with two levels of complexity was implemented to divert the user's attention. Electroencephalographic (EEG) recordings were made from nine single channels. Event-related potentials (ERPs) confirmed that the oddball task of counting a sequence of two tones decreased the auditory P300 amplitude more than the oddball task of counting one target tone among three different tones. Pre-movement features quantified from the movement related cortical potential (MRCP) were changed significantly between single and dual-task conditions in motor and fronto-central channels. There was a significant delay in movement detection for the case of single tone counting in two motor channels only (237.1-247.4ms). For the task of sequence counting, motor cortex and frontal channels showed a significant delay in MRCP detection (232.1 250.5ms). This study investigated the effect of attention diversion in dual-task conditions by analysing both ERPs and MRCPs in single channels. The higher attention diversion lead to a significant reduction in specific MRCP features of the motor task. These results suggest that attention division in dual-tasking situations plays an important role in movement execution and detection. This has important implications in designing real-time brain-computer interface systems. PMID- 28830766 TI - Functional magnetic resonance imaging of auditory cortical fields in awake marmosets. AB - The primate auditory cortex is organized into a network of anatomically and functionally distinct processing fields. Because of its tonotopic properties, the auditory core has been the main target of neurophysiological studies ranging from sensory encoding to perceptual decision-making. By comparison, the auditory belt has been less extensively studied, in part due to the fact that neurons in the belt areas prefer more complex stimuli and integrate over a wider frequency range than neurons in the core, which prefer pure tones of a single frequency. Complementary approaches, such as functional magnetic resonance imaging (fMRI), allow the anatomical identification of both the auditory core and belt and facilitate their functional characterization by rapidly testing a range of stimuli across multiple brain areas simultaneously that can be used to guide subsequent neural recordings. Bridging these technologies in primates will serve to further expand our understanding of primate audition. Here, we developed a novel preparation to test whether different areas of the auditory cortex could be identified using fMRI in common marmosets (Callithrix jacchus), a powerful model of the primate auditory system. We used two types of stimulation, band pass noise and pure tones, to parse apart the auditory core from surrounding secondary belt fields. In contrast to most auditory fMRI experiments in primates, we employed a continuous sampling paradigm to rapidly collect data with little deleterious effects. Here we found robust bilateral auditory cortex activation in two marmosets and unilateral activation in a third utilizing this preparation. Furthermore, we confirmed results previously reported in electrophysiology experiments, such as the tonotopic organization of the auditory core and regions activating preferentially to complex over simple stimuli. Overall, these data establish a key preparation for future research to investigate various functional properties of marmoset auditory cortex. PMID- 28830768 TI - Reversal of oxycodone and hydrocodone tolerance by diazepam. AB - The Centers for Disease Control has declared opioid abuse to be an epidemic. Overdose deaths are largely assumed to be the result of excessive opioid consumption. In many of these cases, however, opioid abusers are often polydrug abusers. Benzodiazepines are one of the most commonly co-abused substances and pose a significant risk to opioid users. In 2016, the FDA required boxed warnings - the FDA's strongest warning - for prescription opioid analgesics and benzodiazepines about the serious risks associated with using these medications at the same time. The point of our studies was to evaluate the interactions between these two classes of drugs. We investigated whether diazepam adds to the depressant effects of opioids or do they alter the levels of tolerance to opioids. In the present study, we have found that the antinociceptive tolerance that developed to repeated administration of oxycodone was reversed by an acute dose of diazepam. Antinociceptive tolerance to hydrocodone was also reversed by acute injection of diazepam; however, a fourfold higher dose of diazepam was required when compared to reversal of oxycodone-induced tolerance. These doses of diazepam did not potentiate the acute antinociceptive effect of either opioid. The same dose of diazepam that reversed oxycodone antinociceptive tolerance also reversed oxycodone locomotor tolerance while having no potentiating effects. These studies show that diazepam does not potentiate the acute effect of prescription opioids but reverses the tolerance developed after chronic administration of the drugs. PMID- 28830769 TI - Plasmalogen precursor mitigates striatal dopamine loss in MPTP mice. AB - Ethanolamine plasmalogens (PlsEtn) are a class of glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position that play an important role in the structure and function of membranes. Previous reports have suggested a link between reduced blood and brain PlsEtn levels and Parkinson's disease (PD). We recently reported that the DHA containing plasmalogen precursor PPI-1011 protected striatal dopamine (DA) against MPTP toxicity in mice. In this paper, we further investigate the specificity requirements of the lipid side chains by testing the oleic acid-containing plasmalogen precursor PPI-1025. Male mice were treated for 10days with daily oral administration of PPI-1025 (10, 50 or 200mg/kg). On day 5 mice received MPTP and were sacrificed on Day 11. Treatment with PPI-1025 prevented MPTP-induced decrease of DA and serotonin, as well as their metabolites. In addition, PPI-1025 treatment prevented the MPTP-induced decrease of the striatal dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding. Significant positive correlations were measured between striatal DA concentrations and DAT or VMAT2 specific binding, as well as with serum plasmalogen concentrations. The neuroprotective effect of PPI 1025 displayed a bell-curve dose-dependency losing effect at the highest dose tested. The similar protective response of oleic and docosahexaenoic acid (DHA) containing plasmalogen precursors suggests that the neuroprotection observed is not only due to DHA but to the oleic substituent and the plasmalogen backbone. PMID- 28830770 TI - Age-related language lateralization assessed by fMRI: The effects of sex and handedness. AB - Previous studies focusing on the relationship between lateralization of language function and age suffer from lack of a balanced distribution of age and handedness among participants, especially in the extremes of age. This limits our understanding of the influence of these factors on lateralization of language circuitry. The hemispheric asymmetry reduction in older adults (HAROLD) model suggests that under similar circumstances, involvement in cognitive processes of prefrontal (and potentially other) cortical areas tends to be less lateralized with age. In this study, we aimed to investigate the link between age, gender, and language lateralization in a large group of healthy participants with a relatively even distribution of age and handedness in order to further test the HAROLD model. 99 healthy men (33 left-handed; age range 18-74years) and 125 women (44 left-handed; age range 19-76) were recruited. All participants underwent fMRI at 3T with a semantic decision and a verb generation tasks and received a battery of linguistic tests. Lateralization indexes (LI) were calculated for each participant based on fMRI results for each task separately. LIs were found to be significantly decreasing with age only in right-handed men and only in temporo parietal cortical area. LIs did not change with age in other brain regions or in left-handed subjects. Our results do not support the HAROLD model and suggest a potentially different relationship between aging and lateralization of language functions. PMID- 28830771 TI - In vitro polyphenol effects on apoptosis: An update of literature data. AB - Polyphenols are secondary plant metabolites which have been studied extensively for their health-promoting properties, and which could also exert pharmacological activities ranging from anti-inflammatory effects, to cytotoxic activity against cancer cells. The main mechanism for programmed cell death is represented by apoptosis, and its dysregulation is involved in the etiopathology of cancer. As such, substances able to induce apoptosis in cancer cells could be used as new anticancer agents. The aim of this paper is to review literature data on the apoptotic effects of polyphenols and the molecular mechanisms through which they induce these effects in cancer cells. In addition, a brief summary of the new delivery forms used to increase the bioavailability, and clinical impact of polyphenols is provided. The studies reported show that many polyphenol rich plant extracts, originating from food and herbal medicine, as well as isolated polyphenols administered individually or in combination, can regulate cell apoptosis primarily through intrinsic and extrinsic mechanisms of action in in vitro conditions. Due to these promising results, the use of polyphenols in the treatment of cancer should therefore be deeply investigated. In particular, because of the low number of clinical trials, further studies are required to evaluate the anticancer activity of polyphenols in in vivo conditions. PMID- 28830772 TI - Covalent and non-covalent chemical engineering of actin for biotechnological applications. AB - The cytoskeletal filaments are self-assembled protein polymers with 8-25nm diameters and up to several tens of micrometres length. They have a range of pivotal roles in eukaryotic cells, including transportation of intracellular cargoes (primarily microtubules with dynein and kinesin motors) and cell motility (primarily actin and myosin) where muscle contraction is one example. For two decades, the cytoskeletal filaments and their associated motor systems have been explored for nanotechnological applications including miniaturized sensor systems and lab-on-a-chip devices. Several developments have also revolved around possible exploitation of the filaments alone without their motor partners. Efforts to use the cytoskeletal filaments for applications often require chemical or genetic engineering of the filaments such as specific conjugation with fluorophores, antibodies, oligonucleotides or various macromolecular complexes e.g. nanoparticles. Similar conjugation methods are also instrumental for a range of fundamental biophysical studies. Here we review methods for non-covalent and covalent chemical modifications of actin filaments with focus on critical advantages and challenges of different methods as well as critical steps in the conjugation procedures. We also review potential uses of the engineered actin filaments in nanotechnological applications and in some key fundamental studies of actin and myosin function. Finally, we consider possible future lines of investigation that may be addressed by applying chemical conjugation of actin in new ways. PMID- 28830773 TI - Polysaccharide from Ephedra sinica Stapf inhibits inflammation expression by regulating Factor-beta1/Smad2 signaling. AB - Mahuang, a famous traditional Chinese medicine, is widely used for the treatment of common cold and inflammatory diseases in China. We investigated the protective effects of polysaccharide from Ephedra sinica Stapf (ESP-B4) against airway and pulmonary inflammation. Animal model was made in SD rats via intratracheal instillation of Lipopolysaccharides (LPS) on day1 and 14 and inhalation of Cigarette Smoke (CS) for 4 weeks. ESP-B4 was administered by oral gavage for 2 weeks. We studied the number of inflammatory cells in serum, production of TNF alpha, IL-6, IL-8 and MMP-9 in lung homogenization buffer, and the expression of TGF-beta1, P-Smad2 and P-Smad3 in lung tissue. In vitro, model was made in A549 cells with LPS and cigarette smoke extract. We investigated the levels of TNF alpha, IL-6 and IL-8, and the expression of TGF-beta1, P-Smad2, P-Smad3 and Smad7. Our results revealed that ESP-B4 lowered the recruitment of inflammatory cells; and decreased the production of TNF-alpha, IL-6, IL-8 and MMP-9, significantly reduced the expression of TGF-beta1, P-Smad2 and P-Smad3, increased the expression of Smad7. These results indicated that ESP-B4 reduced airway and pulmonary inflammation by regulating inflammatory cytokines and the TGF beta1/Smad2 pathway, thus providing a potential treatment for chronic obstructive pulmonary diseases (COPD). PMID- 28830774 TI - Purification, biochemical characterization and antioxidant property of ZCPG, a cysteine protease from Zingiber montanum rhizome. AB - Zingiber montanum cysteine protease glycoprotein (ZCPG) was purified to homogeneity by DEAE- cellulose and Sephadex G50 resulting in sixteen fold purification and total activity of 39.4U/mg. ZCPG presented a prominent single peak in HPLC chromatogram with an estimated molecular weight of 48kDa on native PAGE. SDS-PAGE gave two subunits of ~24.3 and ~24.6kDa showing its heterodimeric form. Protein sequencing was studied by MALDI-TOF MS/MS. Isoelectrofocusing exhibited two isoforms with pI values of 4.8 and 5.1. Analysis of the total carbohydrate by GC-MS/MS showed the presence of glucose, mannose, fucose and xylose. The pH and temperature optimum were 9 and 60 degrees C respectively while Km and Vmax values were 0.5+/-0.03MUg and 13.73+/-2.07U/ml respectively. ZCPG was strongly inhibited by NEM indicating the cysteine-type. Substrates such as casein, azocasein, gelatin, BSA and haemoglobin showed high relative activity. Metal ions of CuCl2, CoCl2, HgCl2 and ZnCl2 showed partial inhibition at 1mM concentration. Furthermore, ZCPG exhibited promising antioxidant activity in biochemical systems as well as THP-1 cells. These findings suggested, ZCPG with significant antioxidant activity might have potential applications in therapeutic and food industry. PMID- 28830775 TI - Characterization of lignins isolated with alkali from the hydrothermal or dilute acid pretreated rapeseed straw during bioethanol production. AB - A better understanding of the lignin in the straw of rapeseed, Brassica campestris L., is a prerequisite for promoting the biorefinery industry of rapeseed. Two different methods for fractionating lignin from rapeseed straw were proposed in this study. Lignin in the raw material was isolated with alkaline solution and recovered by acid precipitation. A comparison between two lignin preparations obtained from two different methods has been made in terms of yield and purity. The structural features were investigated by gel permeation chromatography, FT-IR spectroscopy, 2D-HSQC NMR and 31P NMR. Taking into consideration of the yield and purity, the proposed methods are effective for extracting lignin. NMR results showed that syringyl (S) was the predominant unit over guaiacyl (G) or p-hydroxyphenyl (H) units in the lignin preparations, and linkages beta-O-4', beta-beta' and beta-5' were also identified and quantified by NMR techniques. This study demonstrated that the combination of hydrothermal or dilute-acid pretreatment and alkaline process could efficiently isolate the lignins from the rapeseed straw to further applications for industries. It was found that the enzymatic hydrolysis of the two-step pretreated rapeseed straw increased 5.9 times than the straw without treatment, which is benefit for bioethanol production from rapeseed straw. PMID- 28830776 TI - The crystallization behavior of poly(lactic acid) with different types of nucleating agents. AB - The effects of six nucleating agents (NAs), i.e., orotic acid (OA), potassium salt of 3,5-bis(methoxycarbonyl)benzenesulfonate (LAK-301), substituted-aryl phosphate salts (TMP-5), talc (TALC), N'1,N'6-dibenzoyladipohydrazide (TMC-306) and N1,N1'-(ethane-1,2-diyl)bis(N2-phenyloxalamide) (OXA), on the crystallization behavior of poly(lactic acid) (PLA) were compared by DSC. Under the same dosing of 0.5wt%, the nucleation effect of the NAs for PLA declines in the order of TMC 306~OXA>TALC?TMP-5~LAK-301~OA. The nucleation efficiency (NE) of TMC-306 and OXA is around 50%, which is almost 2 times of the NE of TALC. In the best case of the PLA/TMC-0.5% sample, the half-time of crystallization decreases from 30s to 9s with decreasing the crystallization temperature from 120 degrees C to 100 degrees C, which is of great significance to the fast production of highly crystallized PLA materials. As high-efficient NAs, TMC-306 and OXA are able to accelerate the crystallization rate of PLA even upon fast cooling at 50 degrees C/min, while make no difference on PLA crystal form, as identified by WAXD. DMA analysis shows that the storage modulus of PLA is significantly improved by TMC-306 and OXA. PMID- 28830777 TI - Biological evaluation of p-toluene sulphonylhydrazone as carbonic anhydrase IX inhibitors: An approach to fight hypoxia-induced tumors. AB - To find potential inhibitors of human carbonic anhydrase IX (CAIX), we have successfully deigned, synthesized and characterized three p-toluene sulphonylhydrazone derivatives (1-3). Molecular docking studies provided the structural basis of CAIX inhibition and a deeper insight into the protein-ligand interactions. p-Toluene sulphonylhydrazone derivatives show a well organized conformational compatibility with the active site of CAIX. The protein-ligand complex was stabilized by several non-covalent interactions offered by residues present in the active site cavity. The actual binding affinity of synthesized compounds with CAIX was experimentally measured by fluorescence and isothermal titration calorimetry (ITC). Results of both fluorescence binding and ITC measurements show the binding affinity of p-Toluene sulphonylhydrazone derivatives to the CAIX in the MUM range. CAIX enzyme inhibition assay showed the IC50 values in nM range. Though all the three compounds (1-3) showed a good binding with CAIX, compound 2 showed the best inhibition of CAIX activity. These compounds were non-toxic on normal cell lines (HEK-293) and significantly inhibit the proliferation of hypoxic cancer cells. All compounds induce apoptosis in the hypoxic cancer cells. These compounds may be further exploited as promising therapeutic agents to control the hypoxia-induced tumors. PMID- 28830778 TI - Strategies for optimization of heterologous protein expression in E. coli: Roadblocks and reinforcements. AB - E. coli is most preferred system used for the production of recombinant proteins in bacteria and the availability of improved genetic tools/methods are making it more valuable than ever. Major challenges faced by this expression system are the expression of unusually difficult/complex proteins with rare codons or membrane and toxic proteins. The proteins expressed either in large amount or hydrophobic in nature tend to form insoluble mass. Despite the appropriate expression system, some proteins express at very low level or not at all. Choosing the correct expression system/protocols are obligatory for the substantial expression of protein in the native form. A number of vectors, their compatible hosts and culture conditions can be used to express recombinant proteins in large amounts and in native form. Also, vectors with the fusion tags/chaperons facilitate protein expression in soluble fraction and assist in proper protein folding besides restoring the native structure of protein. The recovery of native proteins from insoluble inclusion bodies can be achieved by optimization of refolding conditions. In the present review, we discussed recent updates on prokaryotic expression system for successful heterologous gene expression in E. coli and focused on strategies to maximize the yields of native recombinant proteins. PMID- 28830779 TI - Altered blood cytokines, CD4 T cells, NK and neutrophils in patients with obstructive sleep apnea. AB - BACKGROUND: There are contradictory reports on the effects of obstructive sleep apnea (OSA) on the immune system. In order to clarify the effect of OSA on the different components of the immune system, we studied the association of OSA with changes in cytokine and chemokine levels, proliferative patterns of CD4 and CD8 T lymphocytes as well as NK cells ex vivo and neutrophil functions. METHODS: We investigated the association of OSA with potential alterations in 14 Th1/Th2 and inflammatory cytokines and chemokines, CD4 and CD8 T cells, NK cells, and the NADPH oxidase activation and phagocytic functions in neutrophils. RESULTS: Our results suggest that the increase in CD4 T cell frequency in OSA is associated with an increased expression of the nuclear protein Ki67 (p<0.05; power>0.8), and is correlated with the levels of IL-1beta (p<0.05; power>0.8). The levels of IL 1beta as well as IL-6 showed a potential increase, while the levels of IFN-gamma (p<0.05; power>0.8) and the ratio IFN-gamma/IL-4 in the blood were possibly decreased in OSA. Additionally, we observed a potential increase in the expression of Ki67 in CD8hi and CD8lo NK cells (p<0.05; power>0.8). Our results also suggest that neutrophils have a decreased capacity to phagocytose bacteria and activate NADPH oxidase in OSA patients (p<0.05; power>0.8). CONCLUSION: OSA may be associated with inflammatory and pro-Th2 immune responses, an increased proliferative potential of NK and CD4 T cells and a decreased capacity of neutrophils to phagocytose bacteria and produce ROS. PMID- 28830780 TI - Influence of epistatic segregation distortion loci on genetic marker linkages in Japanese flounder. AB - For genetic linkage analysis of Japanese flounder, 160 doubled haploids (DH) were artificially produced using mitotic gynogenesis and were genotyped for 458 simple sequence repeat (SSR) markers, 101 of which show distortional segregation. The genetic linkage map was constructed by modifying recombination fractions between the distorted markers. Between the corrected and uncorrected genetic maps, there were considerable differences in genetic distance, but not in relative locations among markers. Using a liability model, a segregation distortion locus (SDL), with an additive genetic effect of 1.772, was mapped between markers BDHYP387 and Poli56TUF of chromosome 24 in the corrected genetic map. Additionally, six pairs of epistatic SDLs were identified on chromosomes 1, 5, 8, 9, 23, and 24. Changes in genetic distances between markers did not occur on chromosome regions with main effect SDLs. However, most chromosome regions where genetic distances changed covered the detected epistatic SDLs. This study concluded that epistatic SDLs decrease linkages between markers and lengthen genetic distances in Japanese flounder. This finding has been partially validated in other DH populations derived from three female Japanese flounders. PMID- 28830781 TI - Formulation and characterization of biocompatible and stable I.V. itraconazole nanosuspensions stabilized by a new stabilizer polyethylene glycol-poly(beta Benzyl-l-aspartate) (PEG-PBLA). AB - Amphiphilic block copolymers, PEG-PBLA with different molecular weights, were synthesized and used as new stabilizers for Itraconazole nannosuspensions (ITZ PBLA-Nanos). ITZ-PBLA-Nanos were prepared by the microprecipitation-high pressure homogenization method, and the particle size and zeta potential were measured using a ZetaSizer Nano-ZS90. Morphology and crystallinity were studied using TEM, DSC and powder X-ray. The effect of the PEG-to-PBLA ratio, and the drug-to stabilizer ratio were investigated to obtain the optimal formulation. It was found that the optimal length of hydrophobic block was 25 BLA-NCA molecules and the optimal ratio of drug/stabilizer was 1:1, where the resulted average particle size of ITZ-PBLA-Nanos was 262.1+/-7.13nm with a PDI value of 0.163+/-0.011. The images of TEM suggest that ITZ-PBLA-Nanos were rectangular in shape. ITZ existed as crystals in the nanoparticles as suggested by the DSC and XRD results. Compared with the crude drug suspensions, the dissolution rate of ITZ nanocrystals, was significantly increased and was similar to Sporanox(r) injection. The ITZ-PBLA-Nanos also demonstrated better dilution stability and storage stability compared with ITZ-F68-Nanos. The particle size of ITZ-PBLA Nanos did not change significantly after incubated in rat plasma for 24h which is a good attribute for I.V. administration. Acute toxicity tests showed that ITZ PBLA-Nanos has the highest LD50 compared with ITZ-F68-Nanos and Sporanox(r) injection. ITZ-PBLA-Nanos also showed stronger inhibiting effect on the growth of Candida albicans compared with Sporanox(r) injection. Therefore, PEG-PBLA has a promising potential as a biocompatible stabilizer for ITZ nanosuspensions and potentially for other nanosuspensions as well. PMID- 28830782 TI - Mechanism study on ion-pair complexes controlling skin permeability: Effect of ion-pair dissociation in the viable epidermis on transdermal permeation of bisoprolol. AB - Though ion-pair strategy has been widely used in transdermal drug delivery system, knowledge about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes is still limited. In the present study, a homologous series of fatty acids were chosen to form model ion-pair complexes with bisoprolol (BSP) to rule out the influence of functional groups on polar surface area, stability and other physicochemical properties of ion-pair complexes. The ion-pair complexes were characterized by FTIR, thermal analysis, and 1H NMR. The skin permeability of BSP as well as its ion-pair complexes was investigated by in vitro skin permeation experiments then visualized by CLSM. The skin permeability coefficient (kp) of BSP ion-pair complex was negatively related to its n-octanol/water apparent partition coefficient (P'o/w) in the hydrophobic vehicle caprylic/capric triglyceride, (log kp=-1.657-1.229 log P'o/w), suggesting that the instability of ion-pair complexes due to their dissociation in the viable epidermis (VED) played an important role in controlling the skin permeability of BSP, which was further proved by 1H NMR and molecular docking. These findings broadened our understanding about the molecular mechanisms involved in the skin permeation processes of ion-pair complexes. PMID- 28830783 TI - Powder aerosol delivery through nasal high-flow system: In vitro feasibility and influence of process conditions. AB - We aimed to obtain fundamental information for potential pulmonary delivery of powder aerosols using a clinically-approved nasal high-flow system (AIRVO), with spray-dried mannitol (SD-Man) being a model powder. Compressed air exiting the AIRVO at set 'dispersion' air flow rates dispersed SD-Man loaded in an Osmohaler(r) into a human nasal airway replica (NAR) coupled downstream to a Next Generation Impactor (NGI) running at specific 'inspiratory' flow rates. Increasing the dispersion flow rate from 30 to 60L/min increased powder deposition in the NAR from 50 to 70% of the emitted dose, while decreased the NGI deposition from 50 to 30% of the emitted dose. The inspiratory flow rate did not affect powder deposition in the NAR and NGI. In contrast, as the inspiratory flow rate was increased from 15 to 40L/min, powder recovery, emitted fraction, and fine particle fraction below 5MUm (as aerosol performance indices) were increased from 90, 30 and 5% to 97, 45 and 8% of the loaded dose, respectively. The dispersion flow rate did not change the performance indices. Importantly, heating and humidification of dispersion airflow, loaded doses, and nasal cannula sizes did not greatly affect the aerosol characteristics. PMID- 28830784 TI - Electrospun tri-layered zein/PVP-GO/zein nanofiber mats for providing biphasic drug release profiles. AB - Simple sequential electrospinning was utilized to create a functional tri-layered nanofiber mesh that achieves time-regulated biphasic drug release behavior. A tri layered nanofiber mesh -composed of zein and poly(vinylpyrrolidone) (PVP) as the top/bottom and middle layers, respectively - was constructed through sequential electrospinning with ketoprofen (KET) as the model drug. PVP was blended with graphene oxide (GO) to improve the drug release functionality of PVP nanofiber as well as its mechanical properties. Scanning electron microscopy confirmed that the resultant nanofibers had a linear morphology, smooth surface, and tri-layered structure. In addition, X-ray diffraction patterns, differential scanning calorimetric analyses, and Fourier transform infrared spectra verified that the drugs were uniformly dispersed throughout the nanofiber due to good compatibility between the polymer and KET induced by hydrogen interaction. In vitro release test of the tri-layered structure, each component of which had distinct release features, successfully demonstrated time-regulated biphasic drug release. Also, it was confirmed that the drug release rate and duration can be controlled by designing a morphological feature - namely, mesh thickness - which was achieved by simply regulating the spinning time of the first and third layer. This multilayered electrospun nanofiber mesh fabricated by sequential electrospinning could provide a useful method of controlling drug release behavior over time, which will open new routes for practical applications and stimulate further research in the development of effective drug release carriers. PMID- 28830785 TI - Antibacterial and anti-encrustation biodegradable polymer coating for urinary catheter. AB - Bacterial biofilm and crystalline deposits are the common causes of failure of long-term indwelling urinary catheter. Bacteria colonise the catheter surface causing serious infections in the urinary tract and encrustations that can block the catheter and induce trauma in patients. In this study, the strategy used to resist bacterial adhesion and encrustation represents a combination of the antibacterial effects of norfloxacin and silver nanoparticles and the PLGA-based neutralisation of alkali products of urea hydrolysis gained through the degradation of the polymer in an aqueous milieu. Silver nanoparticles were coated with tetraether lipids (TEL) to avoid aggregation when dispersed in acetone and during the film formation. The polymer films loaded with the two antibacterial agents were applied on Polyurethane (PUR) and Silicon sheets. We demonstrated the antibacterial and anti-adhesion effectiveness of the coatings whereby commercially available biocompatible polymers PUR and Silicon were used as controls. Using artificial urine and an in vitro encrustation model, it was shown that the coatings resist the encrustation for at least 2 weeks. This combination of a biodegradable polymer and wide-range antibacterial agents represents a potentially attractive biocompatible coating for urinary catheters. PMID- 28830786 TI - Relation between serum levels of chemotaxis-related factors and the presence of coronary artery calcification as expression of subclinical atherosclerosis. AB - BACKGROUND: Atherosclerotic plaque formation is characterized by recruitment of monocytes/macrophages, which contributes to its calcification by releasing pro osteogenic cytokines. Chemotaxis-related proteins, including netrin-1, gremlin-1 and macrophage inflammatory protein-1beta (MIP-1beta), regulate immune cell migration. However, their relation with the presence of subclinical atherosclerosis, assessed by measures of coronary artery calcifications (CAC) in patients without known coronary artery disease (CAD), remains unclear. AIMS: To examine whether these chemoattractant-related proteins are associated with the presence of CAC in patients without known CAD. METHODS: A retrospective case control observational study was conducted in 120 outpatients without CAD, undergoing a CAC evaluation by computed tomography with the Agatston Calcium score, categorized as CAC- (none) and CAC+ (>=1). Serum biomarkers were quantified by ELISA. RESULTS: Lpa, dyslipidaemia and smoking were significantly higher (p=0.006, p<=0.0001 and p=0.001, respectively) in CAC+ patients. Serum netrin-1 levels were lower in CAC+ than in CAC- patients (196.8+/-127.8pg/ml versus 748.3+/-103.2pg/ml, p<=0.0001), and a similar pattern was found for gremlin-1 (1.14+/-0.39ng/ml versus 4.33+/-1.20ng/ml, p<=0.0001). However, TNFalpha and MIP-1beta were strongly upregulated in CAC+ patients (447.56+/ 74pg/ml versus 1104+/-144pg/ml and 402.00+/-94pg/ml versus 905.0+/-101.6pg/ml, respectively, p<=0.001). Multivariate analyses revealed that low netrin-1 and gremlin-1 levels and high TNFalpha and MIP-1beta amounts were associated with CAC presence, after adjustment for clinical and biochemical variables. CONCLUSIONS: We found a netrin-1 and gremlin-1 deficiency and a TNFalpha and MIP-1beta overproduction in CAC+ patients' serum. These proteins may be used to identify individuals with subclinical atherosclerosis. Further research is warranted in a larger cohort of patients to establish these chemotactic-related proteins as biomarkers that improve CAD risk stratification. PMID- 28830787 TI - Epigenetic dysregulation in adrenocortical carcinoma, a systematic review of the literature. AB - Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a poor prognosis. Diagnosis and treatment of this tumor remains challenging. The Weiss score, the current gold standard for the histopathological diagnosis of ACC, lacks diagnostic accuracy of borderline tumors (Weiss score 2 or 3) and is subject to inter observer variability. Furthermore, adjuvant and palliative systemic therapy have limited effect and no proven overall survival benefit. A better insight in the molecular background of ACC might identify markers that improve diagnostic accuracy, predict treatment response or even provide novel therapeutic targets. This systematic review of the literature aims to provide an overview of alterations in DNA methylation, histone modifications and their potential clinical relevance in ACC. PMID- 28830788 TI - Zearalenone and alpha-zearalenol inhibit the synthesis and secretion of pig follicle stimulating hormone via the non-classical estrogen membrane receptor GPR30. AB - Zearalenone (ZEA) is one of the most popular endocrine-disrupting chemicals and is mainly produced by fungi of the genus Fusarium. The excessive intake of ZEA severely disrupts human and animal fertility by affecting the reproductive axis. However, most studies on the effects of ZEA and its metabolite alpha-zearalenol (alpha-ZOL) on reproductive systems have focused on gonads. Few studies have investigated the endocrine-disrupting effects of ZEA and alpha-ZOL on pituitary gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The present study was designed to investigate the effects of ZEA and alpha-ZOL on the synthesis and secretion of FSH and LH and related mechanisms in female pig pituitary. Our in vivo and in vitro results demonstrated that ZEA significantly inhibited the synthesis and secretion of FSH in the pig pituitary gland, but ZEA and alpha-ZOL had no effects on LH. Our study also showed that ZEA and alpha-ZOL decreased FSH synthesis and secretion through non-classical estrogen membrane receptor GPR30, which subsequently induced protein kinase cascades and the phosphorylation of PKC, ERK and p38MAPK signaling pathways in pig pituitary cells. Furthermore, our study showed that the LIM homeodomain transcription factor LHX3 was involved in the mechanisms of ZEA and alpha-ZOL actions on gonadotropes in the female pig pituitary. These findings elucidate the mechanisms behind the physiological alterations resulting from endocrine disrupting chemicals and further show that the proposed key molecules of the alpha-ZOL signaling pathway could be potential pharmacological targets. PMID- 28830789 TI - New amide and dioxopiperazine derivatives from leaves of Breynia nivosa. AB - The first chemical investigation of leaves of Breynia nivosa from Nigeria resulted in the isolation of two new amide derivatives breynivosamides A and B (1 and 2) and two new dioxopiperazine derivatives breynivosines A and B (4 and 5) together with seven known compounds (3, 6-11). The structures of the new compounds were elucidated by 1D, 2D NMR and HRESIMS data as well as by comparison with the literature. All isolated compounds were tested for the cytotoxic and antimicrobial activities. Only cristatin A (6) showed cytotoxicity against the L5178Y mouse lymphoma cell line with an IC50 value of 13.9MUM while breynivosamide A (1) exhibited moderate antimicrobial activity against Mycobacterium tuberculosis with an MIC value of 25MUM. PMID- 28830790 TI - Increased delivery of chemotherapy to the vitreous by inhibition of the blood retinal barrier. AB - : Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P=0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma. CHEMICAL COMPOUNDS INCLUDED IN THIS MANUSCRIPT: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962). PMID- 28830791 TI - Injectable nanomedicine hydrogel for local chemotherapy of glioblastoma after surgical resection. AB - Glioblastoma (GBM) treatment includes, when possible, surgical resection of the tumor followed by radiotherapy and oral chemotherapy with temozolomide, however recurrences quickly develop around the resection cavity borders leading to patient death. We hypothesize that the local delivery of Lauroyl-gemcitabine lipid nanocapsule based hydrogel (GemC12-LNC) in the tumor resection cavity of GBM is a promising strategy as it would allow to bypass the blood brain barrier, thus reaching high local concentrations of the drug. The cytotoxicity and internalization pathways of GemC12-LNC were studied on different GBM cell lines (U251, T98-G, 9L-LacZ, U-87 MG). The GemC12-LNC hydrogel was well tolerated when injected in mouse brain. In an orthotopic xenograft model, after intratumoral administration, GemC12-LNC significantly increased mice survival compared to the controls. Moreover, its ability to delay tumor recurrences was demonstrated after perisurgical administration in the GBM resection cavity. In conclusion, we demonstrate that GemC12-LNC hydrogel could be considered as a promising tool for the post-resection management of GBM, prior to the standard of care chemo radiation. PMID- 28830792 TI - Functional analysis of the selective autophagy related gene Acatg11 in Acremonium chrysogenum. AB - Autophagy is a highly conserved degradation system in eukaryotes. Selective autophagy is used for the degradation of selective cargoes. Selective autophagic processes of yeast include pexophagy, mitophagy, and cytoplasm-to-vacuole targeting (Cvt) pathway in which particular vacuolar proteins, such asaminopeptidase I (Ape1), are selectively transported to vacuoles. However, the physiological role of selective autophagy remains elusive in filamentous fungi. ATG11 family proteins asa basic scaffold are essential for most selective autophagy pathways in yeast. Here, Acatg11, encoding a putative ATG11 family protein, was identified and cloned from the cephalosporin producing strain Acremonium chrysogenum based on the sequence similarity of ATG11 superfamily proteins. Disruption of Acatg11 inhibited the maturation of preApe1 during fermentation indicating that Acatg11 is involved in Cvt pathway. In addition, pexophagy and mitophagy were blocked in the Acatg11 disruption mutant (DeltaAcatg11). Intriguingly, the nonselective autophagy was deficient in DeltaAcatg11 under starvation induction or during fermentation. Disruption of Acatg11 significantly enhanced fungal conidiation, but reduced cephalosporin production. These results indicated that Acatg11 is required for both selective and nonselective autophagy during fermentation and has a strong impact on morphological differentiation and cephalosporin production of A. chrysogenum. PMID- 28830793 TI - Piperine inhibits aflatoxin B1 production in Aspergillus flavus by modulating fungal oxidative stress response. AB - Aspergillus flavus, a soil-borne pathogen, represents a danger for humans and animals since it produces the carcinogenic mycotoxin Aflatoxin B1 (AFB1). Approaches aiming the reduction of this fungal contaminant mainly involve chemicals that may also be toxic. Therefore, identification and characterization of natural anti-aflatoxigenic products represents a sustainable alternative strategy. Piperine, a major component of black and long peppers, has been previously demonstrated asan AFB1-inhibitor; nevertheless its mechanism of action was yet to be elucidated. The aim of the present study was to evaluate piperine's molecular mechanism of action in A. flavus with a special focus on oxidative stress response. For that, the entire AFB1 gene cluster as well asa targeted gene network coding for fungal stress response factors and cellular receptors were analyzed. In addition to this, fungal enzymatic activities were also characterized. We demonstrated that piperine inhibits aflatoxin production and fungal growth in a dose-dependent manner. Analysis of the gene cluster demonstrated that almost all genes participating in aflatoxin's biosynthetic pathway were down regulated. Exposure to piperine also resulted in decreased transcript levels of the global regulator veA together with an over-expression of genes coding for several basic leucine zipper (bZIP) transcription factors such as atfA, atfB and ap-1 and genes belonging to superoxide dismutase and catalase's families. Furthermore, this gene response was accompanied by a significant enhancement of catalase enzymatic activity. In conclusion, these data demonstrated that piperine inhibits AFB1 production while positively modulating fungal antioxidant status in A. flavus. PMID- 28830795 TI - Indications for Postmastectomy Radiation After Neoadjuvant Chemotherapy in ypN0 and ypN1-3 Axillary Node-Positive Women. AB - INTRODUCTION: Downstaging with neoadjuvant chemotherapy (NAC) might obscure indications for postmastectomy radiation (PMRT). The degree of downstaging that results in local-regional recurrence (LRR) rates low enough to omit PMRT remains controversial. We examined the rate of LRR in women who received NAC who underwent mastectomy without PMRT. PATIENTS AND METHODS: Between 2004 and 2013, 81 women with stage I to IIIA breast cancer had NAC and mastectomy; 48 patients (59%) were clinical N0 and 33 patients (41%) were clinical N1; median age was 45 years; 33 patients (41%) had hormone receptor-positive (HR+)HER2-, 21 patients (26%) HR+HER2+, 19 patients (23%) HR- HER2-, and 7 patients (9%) HR-HER2+ disease. We explored how LRR rates varied with age, BRCA status, Grade, receptor status, clinical N status, pathologic response, lymphovascular invasion, and mastectomy margins. Median follow-up was 4.9 years. RESULTS: After NAC, 35 patients (43%) had a pathologic complete response (pCR), 33 patients (41%) were ypN0, and 13 patients (16%) were ypN1-3+. There were 8 LRRs (6 chest wall, 1 axillary, 1 supraclavicular node). The 5-year cumulative incidence of LRR was 8% for all patients, 3% for pCR, 16% for ypN0, 10% for ypN1-3+, 6% for HR+HER2-, 25% for HR+HER2+, 0% for HR-HER2-, and 0% for HR-HER2+. LRR was 31% in the ypN0 and 33% in the ypN1-3+ HR+HER2+ women, and 12% in the ypN0 and 0% in the ypN1 to ypN3+ HR+HER2- patients. CONCLUSION: This study is unique. All HER2+ patients received trastuzumab and LRR was analyzed according to treatment response, clinicopathologic factors, and receptor status. pCR patients including young women and clinical stage IIIA had low LRR rates. However, ypN0 and ypN1-3+ HR+HER2+ patients had higher rates of LRR compared with other receptor subgroups and on the basis of limited data should be considered for PMRT. PMID- 28830794 TI - Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor. AB - Bipolar Disorder (BD) is a prevalent and disabling condition, determined by gene environment interactions, possibly mediated by epigenetic mechanisms. The present study aimed at investigating the transcriptional regulation of BD selected target genes by DNA methylation in peripheral blood mononuclear cells of patients with a DSM-5 diagnosis of type I (BD-I) and type II (BD-II) Bipolar Disorders (n=99), as well as of healthy controls (CT, n=42). The analysis of gene expression revealed prodynorphin (PDYN) mRNA levels significantly reduced in subjects with BD-II but not in those with BD-I, when compared to CT. Other target genes (i.e. catechol-O methyltransferase (COMT), glutamate decarboxylase (GAD67), serotonin transporter (SERT) mRNA levels remained unaltered. Consistently, an increase in DNA methylation at PDYN gene promoter was observed in BD-II patients vs CT. After stratifying data on the basis of pharmacotherapy, patients on mood-stabilizers (i.e., lithium and anticonvulsants) were found to have lower DNA methylation at PDYN gene promoter. A significantly positive correlation in promoter DNA methylation was observed in all subjects between PDYN and brain derived neurotrophic factor (BDNF), whose methylation status had been previously found altered in BD. Moreover, among key genes relevant for DNA methylation establishment here analysed, an up-regulation of DNA Methyl Transferases 3b (DNMT3b) and of the methyl binding protein MeCP2 (methyl CpG binding protein 2) mRNA levels was also observed again just in BD-II subjects. A clear selective role of DNA methylation involvement in BD-II is shown here, further supporting a role for BDNF and its possible interaction with PDYN. These data might be relevant in the pathophysiology of BD, both in relation to BDNF and for the improvement of available treatments and development of novel ones that modulate epigenetic signatures. PMID- 28830797 TI - Sexual Orientation Differences in Adolescent Health Care Access and Health Promoting Physician Advice. AB - PURPOSE: Physician screening and advice on health-related behaviors are an integral part of adolescent health care. Sexual minority adolescents encounter more barriers to health services; yet, no prior research has examined whether they also experience disparity in physician screening and advice. We examined possible sexual orientation disparities in health care access, physician screening, and advice on six health-related behaviors. METHODS: Data were from a national sample of U.S. adolescents who participated in wave 2 of the NEXT Generation Health Study (n = 2023). Poisson regressions were conducted separately for males and females to estimate sexual orientation differences in health care access and health-related screening and advice. RESULTS: Compared with heterosexual males, sexual minority males were more likely to report unmet medical needs in the past year (adjusted relative risk [ARR] = 2.23) but did not differ with respect to receiving physician advice concerning health-related behaviors. Compared with heterosexual females, sexual minority females were more likely to report no routine physical checkup in the past year (ARR = 1.67) but were more likely to receive physician advice to reduce or stop drinking, smoking, drug use, increase physical activity, and improve diet (ARRs = 1.56-1.99), even after controlling for corresponding health-related behaviors. Sexual minority females were also more likely to receive advice about risk associated with sexual behavior (ARR = 1.35) and advice to avoid sexually transmitted diseases (ARR = 1.49). CONCLUSIONS: Both sexual minority males and females experienced disparities in some aspects of health care access. Improved health-promoting advice would better serve sexual minority males. PMID- 28830796 TI - RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer. AB - INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm. PMID- 28830798 TI - Implementation of Depression Screening and Global Health Assessment in Pediatric Subspecialty Clinics. AB - PURPOSE: Adolescents with chronic illness face greater risk of psychosocial difficulties, complicating disease management. Despite increased calls to screen for patient-reported outcomes, clinical implementation has lagged. Using quality improvement methods, this study aimed to investigate the feasibility of standardized screening for depression and assessment of global health and to determine recommended behavioral health follow-up, across three pediatric subspecialty clinics. METHODS: A total of 109 patients aged 12-22 years (median = 16.6) who were attending outpatient visits for treatment of diabetes (80% type 1), inflammatory bowel disease, or cystic fibrosis completed the 9-item Patient Health Questionnaire (PHQ-9) depression and Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health measures on electronic tablets. Patients screening positive on the PHQ-9 received same-day behavioral health assessment and regular phone check-ins to facilitate necessary follow-up care. RESULTS: Overall, 89% of 122 identified patients completed screening during a 6-month window. Patients completed measures in a timely manner (within 3 minutes) without disruption to clinic flow, and they rated the process as easy, comfortable, and valuable. Depression scores varied across disease type. Patients rated lower global health relative to a previously assessed validation cohort. Depression and global health related significantly to certain medical outcomes. Fifteen percent of patients screened positive on the PHQ-9, of whom 50% confirmed attending behavioral health appointments within 6 months of screening. CONCLUSIONS: A standardized depression and global health assessment protocol implemented across pediatric subspecialties was feasible and effective. Universal behavioral health screening for adolescents and young adults living with chronic disease is necessary to meet programmatic needs in pediatric subspecialty clinics. PMID- 28830799 TI - Timing of First Alcohol Use and First Sex in Male and Female Adolescents. AB - PURPOSE: We examined associations between timing of first alcohol use and first sexual intercourse in adolescent males and potential differences in observed associations between males and females. METHODS: Data were drawn from 4,079 male and 4,059 female participants of the National Longitudinal Study of Youth 1997, aged 12-16 years at the first assessment. Cox proportional hazards regression models were estimated predicting age at first sexual intercourse from age at first alcohol use, without and with adjustment for correlated sociodemographic and individual- and family-level risk factors. Analyses were conducted separately for males and females, with interactions between alcohol use and respondent sex (female vs. male) modeled in subsidiary analyses. RESULTS: Onset of first drink was strongly predictive of earlier sexual intercourse for both males and females, with effects of drinking most pronounced for females during early adolescence. CONCLUSIONS: Results highlight age at first alcohol use as an important predictor of sexual onset in male as well as female adolescents and suggest that effective prevention efforts focusing on delay of sexual intercourse might also focus on delay on alcohol use. PMID- 28830800 TI - Initiation of the age-related decline of odor identification in humans: A meta analysis. AB - BACKGROUND: Aging is an important contributor to olfactory system deterioration in humans, leading to increased health and safety risks as well as affecting the quality of life. However, it is currently unknown when age-related olfactory deterioration begins in humans and thus when to initiate interventions to prevent or slow it. OBJECTIVE: To determine the decade in which olfactory function begins to deteriorate in healthy humans by determining when odor identification is first impaired. DATA SOURCE AND STUDY SELECTION: Studies cited in the PubMed database were searched from its inception to March 2017 using the terms "olfac*" or "smell" and "ag*". The effect size of each comparison was calculated. RESULTS: In this meta-analysis, the effect sizes as determined using Cohen's d for the comparisons between 30 and 39.9- and 40-49.9-year-olds was 0.06 (95% CI: -0.17 to 0.29), between 40-49.9-year-olds was 0.62 (95% CI: 0.20-1.04), considered a medium effect size, and between 35-55-year-olds and those >55years old was 1.12 (95% CI: 1.06-1.45), considered a very large effect. CONCLUSION: Olfactory function deterioration, as determined by an impaired ability to identify odors, starts in the fifth decade of life in healthy humans. PMID- 28830801 TI - Presence of fluorescent in situ hybridization abnormalities is associated with plasma cell burden in light chain amyloidosis. AB - OBJECTIVE/BACKGROUND: To assess abnormalities found on CD138-enriched fluorescent in situ hybridization (FISH) studies on pre-treatment bone marrow in systemic amyloid light-chain amyloidosis (AL) and correlate findings between these abnormalities with organ involvement and 1-year survival. METHODS: We reviewed 107 patients with systemic AL to identify the impact of a diagnostic FISH study done on plasma cell-enriched bone marrow in our institution between January 2010 and January 2015; 77 had pre-treatment testing performed. RESULTS: A total of 77 (61%) patients had abnormal FISH including: hyperdiploidy (29%), t(11;14), (20%), hypodiploidy (16%), t(4;14), (1%), del17p (5%), and+1q21 (5%). Abnormal FISH studies were more likely in those patients with plasma cell involvement>=10% (p=.002). FISH abnormalities were not shown to correlate with stage, cardiac involvement, or survival at 1year. One-year survival was significantly affected by stage at diagnosis and presence of cardiac and hepatic amyloid involvement. CONCLUSION: We conclude that in AL, FISH abnormalities are associated with clonal burden. We found no impact of these markers on the type of organ involvement or 1 year survival. PMID- 28830802 TI - Impact of vitamin D deficiency on increased blood eosinophil counts. AB - OBJECTIVE/BACKGROUND: Vitamin D has been increasingly recognized as an immunomodulatory agent. Its deficiency has been associated with immune-mediated diseases such as asthma, rhinitis, and atopic dermatitis. These allergic conditions are dependent on T-helper type 2 (Th2) cells secreting interleukins, overproduction of immunoglobulin E (IgE), and eosinophil activation. We investigated the association between serum vitamin D levels and blood absolute eosinophil count. METHODS: We carried out a cross-sectional study of 669 men and women referred to a clinical pathology laboratory who underwent 25-hydroxyvitamin D testing and complete blood count analysis on the same day. RESULTS: Vitamin D levels were stratified into four ranges: severely deficient (<10ng/mL), deficient (>=10ng/mL and <20ng/mL), insufficient (>=20ng/mL and <30ng/mL), or sufficient (>=30ng/mL). The mean/median eosinophil count in the four groups was 267/254cells/MUL, 245/238cells/MUL, 191/159cells/MUL, and 182/146cells/MUL, respectively, (p=.001). The difference was significant between the severe deficiency group and each of the other three groups (p=.012, p=.002, and p=.001, respectively). There was no statistical difference among the four groups in terms of total leukocyte counts (p=.151), neutrophils (p=.177), or lymphocytes (p=.582). CONCLUSION: Vitamin D deficiency was associated with higher blood eosinophil count. These results support the possible role of vitamin D in the eosinophil immune response. PMID- 28830803 TI - Acute promyelocytic leukemia in a patient with chronic lymphocytic leukemia-A case report. AB - Chronic lymphocytic leukemia (CLL) is known to be associated rarely with myeloid malignancies such as acute myelogenous leukemia. In this article, we report an extremely rare occurrence of acute promyelocytic leukemia in a patient with CLL. A 71-year-old man first presented to our clinic with a diagnosis of CLL and worsening motor neuropathy symptoms. It was suspected that his CLL might be contributing to the neuropathy as a paraneoplastic syndrome, and he was treated with rituximab monotherapy in weekly doses for the 1st month and monthly treatments thereafter. By the end of his sixth monthly course of rituximab, the patient noted significant improvement in neuropathy symptoms but reported experiencing a new-onset worsening fatigue. He had new-onset cytopenias (white blood cells 1.6k/uL, hemoglobin 11.7g/dL, and platelet count 77k/uL). A bone marrow examination was performed; it showed a high percentage of progranulocytes (21%), which stained positive for myeloperoxidase (MPO) and demonstrated a fine granular pattern on the promyelocytic leukemia (PML) oncogenic domain immunofluorescence test. The diagnosis of acute promyelocytic leukemia was confirmed by fluorescence in situ hybridization, which showed a PML/RARalpha rearrangement in 46% of interphases. Flow cytometry was consistent with immunophenotype of acute promyelocytic leukemia and minimal residual CLL (0.07%). The patient was started promptly on all-trans-retinoic acid and arsenic trioxide induction regimen. Molecular remission was achieved after the first consolidation cycle. The patient is currently past his fourth consolidation cycle of all-trans retinoic acid/arsenic trioxide and continues to be in complete remission. Our case illustrates that it is important for the physicians to be aware of coexistent hematologic and solid tumor malignancies in CLL, and maintain a low threshold for diagnostic testing based on grounds of low clinical suspicion. PMID- 28830805 TI - Impact of pneumococcal polysaccharide vaccine on incidence and mortality after pneumonia in adults aged >=60 years-a population-based retrospective cohort study. AB - OBJECTIVES: The 23-valent pneumococcal polysaccharide vaccine (PPV) is recommended for prevention of pneumococcal diseases in adults at risk. Few data exist on time-, age- and sex-dependent vaccine effectiveness on outcomes in pneumonia. METHODS: We performed a population-based cohort study including adults >=60 years of age (n = 738 927) based on statutory health insurance data from 2005 to 2011. Primary outcomes were all-cause pneumonia incidence and 30-day all cause mortality. Pneumonia was identified by International Classification of Diseases, 10th Revision, German Modification (ICD-10-GM) codes, with ambulatory cases validated by antibiotic prescription within 7 days. The effect of PPV within 5 years was analysed after propensity score-based matching (three controls per case with PPV vaccination) including comorbidities, care status, age, sex and influenza vaccination. Evaluations were stratified by age group, sex and time of PPV. RESULTS: Two-year incidence of all-cause pneumonia in 213 431 vaccinated individuals was 7501 (3.51%) of 213 431 vs. 23 243 (3.63%) of 640 293 in matched controls (difference -0.11, 95% confidence interval (CI) -0.22 to -0.002, p 0.046). After sex-dependent analysis, PPV effectiveness on pneumonia incidence was observed only in women (difference -0.15, 95% CI -0.28 to -0.02, p 0.02). Thirty-day mortality in vaccinated individuals with pneumonia was 1302 (17.36%) of 7501 vs. 4267 (18.96%) of 22 503 in matched controls (difference -1.60%, 95% CI -2.83 to -0.38, p 0.011). After analysis according to age group, significant mortality reduction was present only in adults aged 60 to 79 years (difference 2.31, 95% CI -3.79 to -0.83, p 0.002). Year of PPV vaccination showed no effect on outcomes. CONCLUSIONS: The findings support consideration of sex and age dependence of PPV effectiveness in future studies. PMID- 28830804 TI - Klebsiella pneumoniae (ST1519) producing KPC-19 carbapenemase in a patient undergoing selective digestive decontamination before liver transplantation. PMID- 28830806 TI - An outbreak of Clostridium difficile infections due to new PCR ribotype 826: epidemiologic and microbiologic analyses. AB - OBJECTIVES: To investigate an unusual outbreak of five patients with a total of eight episodes of a Clostridium difficile infection on a gastrointestinal surgical ward of a Dutch tertiary-care, university-affiliated hospital. METHODS: Clinical case investigations and laboratory analyses were performed. Laboratory analyses included PCR ribotyping, multiple-locus variable-number tandem repeat analysis typing, toxin typing, antimicrobial susceptibility testing and whole genome sequencing. RESULTS: The outbreak was associated with recurrent and severe disease in two of five patients. All episodes were due to a unique ribotype that was not recognized in the collection of an international network of reference laboratories and was assigned PCR ribotype 826. PCR ribotype 826 is a toxin A-, toxin B- and binary toxin-positive ribotype which according to molecular typing belongs to clade 5 and resembles the so-called hypervirulent ribotype 078. The presence of a clonal outbreak was confirmed by whole genome sequencing, yet the source of this newly identified ribotype remained unclear. CONCLUSIONS: This newly identified C. difficile PCR ribotype 826 is part of clade 5 and might also have increased virulence. The recognition of this outbreak highlights the need for ongoing C. difficile infection surveillance to monitor new circulating ribotypes with assumed increased virulence. PMID- 28830807 TI - The relationship between Gram-negative colonization and bloodstream infections in neonates: a systematic review and meta-analysis. AB - OBJECTIVES: Neonates admitted to neonatal intensive care units (NICU) are at significant risk of developing bloodstream infections (BSIs). Gram-negative bacteria (GNB) both colonize and infect, but the association between these entities is unclear. By conducting a systematic literature review, we aimed to explore the impact of factors on the association between GN colonization and GN BSI at both baby-level and unit-level. METHODS: We searched Medline, Embase, and Cochrane Library. Observational cohort studies published after 2000 up to June 2016 reporting data on the total number of neonates (0-28 days) colonized with GNB assessed by rectal/skin swab culture and the total number of neonates with GN BSI (same bacteria) were included. Studies were excluded if data on skin/rectal colonization, neonates, and GNB could not be identified separately. Meta-analyses along with multivariate meta-regression with a random-effect model were performed to investigate factors associated with the GN colonization and GN-BSI at baby level and unit-level. RESULTS: Twenty-seven studies fulfilled our inclusion criteria, 15 for the baby-level and 12 for the unit-level analysis. Study heterogeneity was high, with suboptimal overall quality of reporting assessed by the STROBE-NI statement (44.8% of items adequately reported). In 1984 colonized neonates, 157 (7.9%) developed GN-BSI compared with 85 of 3583 (2.4%) non colonized neonates. Considerable heterogeneity was observed across studies. Four factors were included in the meta-regression model: gross domestic product (GDP), pathogen, outbreak, and frequency of screening. There was no statistically significant impact of these factors on GN colonization and GN-BSI in baby-level. We were unable to perform the multivariate meta-regression because of insufficient reported data for unit-level. CONCLUSIONS: Study limitations include the small number and the high heterogeneity of the included studies. While this report shows a correlation between colonization and BSI risk, these data currently do not support routine screening for GNB. Analysis of large cohorts of colonized neonates with clinical outcomes is still needed to define the major determinants leading from colonization to infection. PMID- 28830808 TI - New drugs - will they solve the problem of resistance to antibiotics? PMID- 28830809 TI - Hydrogel film loaded with new formula from manuka honey for treatment of chronic wound infections. AB - OBJECTIVES: Chronic wound infections can be effectively treated using hydrogel loaded with an extract from manuka honey. METHODS: This study was performed on bacterial isolates from patients with infected wounds at Alexandria Main University Hospital (Alexandria, Egypt). Isolates were exposed to hydrogel sheets composed of chitosan and gelatin and loaded with a new formula from manuka honey. RESULTS: The results illustrate the antibacterial activity of the formula extracted from manuka honey against Staphylococcus aureus, Streptococcus pyogenes, Acinetobacter baumannii, Pseudomonas aeruginosa and Proteus mirabilis. Screening of the hydrogel by electron microscopy showed the ultrastructure of the gel. CONCLUSIONS: A hydrogel sheet composed of chitosan and gelatin loaded with a new formula extracted from manuka honey can be used as a dressing for chronic infected wounds. PMID- 28830810 TI - Rho signaling inhibitor, CCG-1423, inhibits axonal elongation and dendritic complexity of rat cortical neurons. AB - CCG-1423, a chemical inhibitor of Rho signaling, blocks serum response factor (SRF)/megakaryoblastic leukemia 1 (MKL1)-mediated gene expression by inhibiting the nuclear accumulation of MKL1. Several studies have suggested that CCG-1423 interacts not only with MKL1, which has a critical role in the regulation of neuronal morphology, but also with phosphatase and actin regulator 1 (Phactr1), which is localized at synapses. However, the effect of CCG-1423 on neuronal cells, especially on neuronal morphology, remains to be determined. In this study, we focused on the effect of CCG-1423 on axonal elongation, dendritic length, dendritic complexity and dendritic spine morphology. Incubation of cortical neuron cultures with up to 10 MUM CCG-1423 for 72 h did not significantly affect cell viability. CCG-1423 inhibited axonal elongation and blocked the increase of dendritic length and complexity, but did not affect dendritic spine morphology. Here, we demonstrated for the first time that CCG 1423 affects neurite elongation, except for dendritic spines, without affecting neuronal cell viability. This study provides a better understanding of the effects of CCG-1423 on neurons, which may be useful for the assessment of the potential clinical application of CCG-1423 and its derivatives. PMID- 28830812 TI - Crystal structure of 5-enolpyruvylshikimate-3-phosphate synthase from a psychrophilic bacterium, Colwellia psychrerythraea 34H. AB - To survive at low temperatures, psychrophiles seem to produce cold-adapted enzymes with a high flexibility around active sites for high catalytic efficiency. To gain insights into the cold-adaptation of psychrophilic enzymes in atomic detail, we determined the crystal structure of 5-enolpyruvylshikimate-3 phosphate synthase (CpsEPSPS) from Colwellia psychrerythraea, a psychrophilic bacterium. EPSPS is the primary target for the broad-spectrum herbicide, glyphosate, and a promising target for the development of antimicrobial and antiparasitic agents since it is absent in animals. The crystal structure of unliganded, open CpsEPSPS was determined at 2.2 A resolution in space group P21 with two protomers per asymmetric unit. Superposition of separate domain I and II of CpsEPSPS structure with those of Escherichia coli EPSPS (EcoEPSPS) structure showed relatively small differences of RMSD values of 0.423 A and 0.693 A for domains I and II, respectively, implying the residues in ligand binding and catalysis of cold-adapted CpsEPSPS showed no significant flexibility. This result is conflicting to other cases of cold-adapted proteins. We also observed that hydrogen-bond forming residues in the surface of EcoEPSPS was mutated to non- or lesser hydrogen-bond forming one in CpsEPSPS, which makes the protein surface softer and eventually makes the protein more active at low temperature. In addition, domain rotation angle between open and closed states of CpsEPSPS was smaller than those of any EPSPSs whose structures are known. The restriction of the domain closure, which reduces the entropy cost of ligand binding and catalysis, may be a novel molecular adaptations of cold-adapted enzymes. PMID- 28830811 TI - Inactivation of glyceraldehyde-3-phosphate dehydrogenase by the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde. AB - BACKGROUND: The aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL) is an endogenous neurotoxin implicated in Parkinson's Disease. Elucidating protein targets of DOPAL is essential in understanding it's pathology. The enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a target of DOPAL. METHODS: GAPDH activity was measured via reduction of NAD+ cofactor (340 nm). Protein aggregation was assessed with SDS-PAGE methods and specific modification via chemical probes. RESULTS: Low micromolar levels of DOPAL caused extensive GAPDH aggregation and irreversibly inhibited enzyme activity. The inactivation of GAPDH was dependent on both the catechol and aldehyde moieties of DOPAL. It is suggested that Cys are modified and oxidized by DOPAL. CONCLUSIONS: The mechanism by which DOPAL modifies GAPDH can serve as a mechanistic explanation to the pathological events in Parkinson's Disease. PMID- 28830813 TI - Nobiletin attenuates adverse cardiac remodeling after acute myocardial infarction in rats via restoring autophagy flux. AB - BACKGROUND: Our previous study showed that autophagy flux was impaired with sustained heart ischemia, which exacerbated adverse cardiac remodeling after acute myocardial infarction (AMI). Here we investigated whether Nobiletin, a citrus polymethoxylated flavonoids, could restore the autophagy flux and improve cardiac prognosis after AMI. AMI was induced by ligating left anterior descending (LAD) coronary artery in rats. Nobiletin improved the post-infarct cardiac dysfunction significantly and attenuated adverse cardiac remodeling. Meanwhile, Nobiletin protected H9C2 cells against oxygen glucose deprivation (OGD) in vitro. The impaired autophagy flux due to ischemia was ameliorated after Nobiletin treatment by testing the autophagy substrate, LC3BII and P62 protein level both in vivo and in vitro. GFP-mRFP-LC3 adenovirus transfection also supported that Nobiletin restored the impaired autophagy flux. Specifically, the autophagy flux inhibitor, chloroquine, but not 3 MA, alleviated Nobiletin-mediated protection against OGD. Notably, Nobiletin does not affect the activation of classical upstream autophagy signaling pathways. However, Nobiletin increased the lysosome acidation which also supported that Nobiletin accelerated autophagy flux. Taken together, our findings suggested that Nobiletin restored impaired autophagy flux and protected against acute myocardial infarction, suggesting a potential role of autophagy flux in Nobiletin-mediated myocardial protection. PMID- 28830814 TI - p-Coumaric acid enhances long-term potentiation and recovers scopolamine-induced learning and memory impairments. AB - Due to the improvement of medical level, life expectancy increased. But the increased incidence of cognitive disorders is an emerging social problem. Current drugs for dementia treatment can only delay the progress rather than cure. p Coumaric acid is a phenylpropanoic acid derived from aromatic amino acids and known as a precursor for flavonoids such as resveratrol and naringenin. It was shown to reduce oxidative stress, inhibit genotoxicity and exert neuroprotection. Based on these findings, we evaluated whether p-coumaric acid can protect scopolamine induced learning and memory impairment by measuring LTP in organotypic hippocampal slice and cognitive behaviors in rats. p-Coumaric acid dose-dependently increased the total activity of fEPSP after high frequency stimulation and attenuated scopolamine-induced blockade of fEPSP in the hippocampal CA1 area. In addition, while scopolamine shortened the step-through latency in the passive avoidance test and prolonged the latency as well as reduced the latency in the target quadrant in the Morris water maze test, co treatment of p-coumaric acid improved avoidance memory and long-term retention of spatial memory in behavioral tests. Since p-coumaric acid improved electrophysiological and cognitive functional deterioration by scopolamine, it may have regulatory effects on central cholinergic synapses and is expected to improve cognitive problems caused by abnormality of the cholinergic nervous system. PMID- 28830815 TI - A novel mechanism of pre-transplant insulin resistance contributing to post transplant complications: Cyclosporin A-induced O-GlcNAcylation. AB - Pre-transplant insulin resistance has been proved to be an important risk factor for organ transplantation, predicting increased post-transplant complications and worse survival outcomes. However, the underlying mechanism is still unclear. Cyclosporin A (CsA) is widely used as an immunosuppressant after organ transplantation, while emerging evidence has shown that CsA increases the risk of post-transplant complications. Thus, in this study, using a cellular model of palmitate-induced insulin resistance, we evaluate the effect of CsA on apoptosis in skeletal muscle C2C12 cells with palmitate-induced insulin resistance. Western blot and flow cytometric analysis showed that CsA induced apoptosis in insulin resistant C2C12 cells. Mechanistically, a sustained increase of global protein O GlcNAcylation was observed after CsA treatment, and suppression of protein O GlcNAcylation with its inhibitors (alloxan or 5-oxo-6-diazo-norleucine) resulted in decreased O-GlcNAcylation levels and apoptosis. Furthermore, CsA increased mitochondrial membrane potential and intracellular ROS production in insulin resistant C2C12 cells, and inhibition of ROS production with SS-31 suppressed CsA induced O-GlcNAcylation. In summary, our results suggest that CsA treatment induced apoptosis in insulin-resistant C2C12 cells, partly via CsA-induced ROS production and resultant O-GlcNAcylation, indicating that O-GlcNAcylation serves as a potent therapeutical target for organ transplantation. PMID- 28830816 TI - KLF15 regulates dopamine D2 receptor and participates in mouse models of neuropathic pain. AB - Neuropathic pain is caused by damage to the nervous system, resulting in aberrant pain. The mechanism underlying neuropathic pain remains largely unknown. Kruppel like factor 15 (KLF15) is a member of the Kruppel-like factor family of transcriptional factors. Here in this study, we aimed to investigate the potential role of the transcriptional factor KLF15 in neuropathic pain. The mRNA and protein levels of Klf15 were significantly increased in the neurons of mouse undergoing neuropathic pain induced by sciatic nerve chronic constrictive injury (CCI) or unilateral spared nerve injury (SNI). In neurons, the upregulation of Klf15 was triggered by the inflammatory factor tumor necrosis factor alpha (TNF alpha). As a transcriptional factor, KLF15 promoted the expression of dopamine D2 receptor (Drd2), which is a receptor essentially involved in neuropathic pain. KLF15 bound to the promoter of Drd2 directly and promoted the promoter activity of Drd2. Finally, we showed that knockout of Klf15 repressed the sensitivity in neuropathic pain induced by CCI or SNI. In conclusion, KLF15 is induced in neuropathic pain via a TNF-alpha-dependent manner and contributes to neuropathic pain partially through promoting the expression of dopamine D2 receptor. PMID- 28830817 TI - Evaluation of the aphrodisiac potential of a chemically characterized aqueous extract of Tamarindus indica pulp. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tamarindus indica is an ingredient in the traditional aphrodisiac formulations in Africa and India. It is also a widely used food ingredient in other tropical countries. AIM OF THE STUDY: The present study was aimed to evaluate the aphrodisiac potential and reproductive safety profile of aqueous extract of Tamarindus indica in male Wistar rats. MATERIALS AND METHODS: The aqueous extract was prepared by maceration of pulp followed by reduction of volume in rotavapor under heat followed by freeze drying. The prepared extract was characterized for contents of total phenol, flavonoid, and saponin. It was also subjected to phytoconstituent analysis using GCMS. Further, the extract was evaluated for acute toxicity study. The aphrodisiac and reproductive toxicity potential were evaluated in animals after grouping them in four with six animals each namely, normal control, standard (Sildenafil citrate, 4mg/kg p.o.) and extract of Tamarindus indica treated groups at two dose levels, 125 and 250mg/kg p.o. The study was conducted for 54 days with daily once dosing of extract and standard. Equal number of females was grouped without treatment for evaluation of parameters of sexual desire (mount frequency and intromission frequency) and parameters of sexual arousal (mount latency and intromission latency). These parameters were evaluated on day 14, 28, 42 and 54. Animals were sacrificed on day 54, testes were removed and studied for histopathological changes. RESULTS: The extract showed 6.6mg gallic acid equivalent/g of total phenol, 2.3mg catechin equivalent/g of flavonoid and 11.6% saponin. Forty chemical constituents were identified by GCMS analysis. In acute toxicity study, the extract was found to be safe till 2000mg/kg p.o. Efficacy study showed significant (p<0.05) improvement in parameters of sexual desire (mount frequency and intromission frequency) and parameters of sexual arousal on all observed days except mount frequency for 125mg/kg on 42nd day and intromission frequency for both doses of tamarind compared to normal control. Improvements in these parameters were comparable to the standard drug. Histopathology study and sperm count suggested an increase in sperm production without any sign of toxicity in testis. Sperm motility significantly (p<0.05) increased in the treatment groups that received extract at 250mg/kg compared to normal control. CONCLUSION: Aqueous extract of Tamarindus indica possessed aphrodisiac activity together with spermatogenic potential. PMID- 28830818 TI - Review of anti-inflammatory, immune-modulatory and wound healing properties of molluscs. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This review focuses on traditional and contemporary anti-inflammatory uses of mollusc-derived products summarising all the in vitro, in vivo and human clinical trials that have tested the anti inflammatory activity of molluscan natural products. Inflammatory conditions, burns and wounds have been an ongoing concern for human health since the early era of civilisation. Many texts from ancient medicine have recorded the symptoms, signs and treatments for these conditions. Natural treatments are well-documented in traditional European medicine, Traditional Chinese Medicine (TCM), Siddha and ancient Mediterranean and African traditional medicine and include a surprisingly large number of molluscan species. MATERIALS AND METHODS: An extensive review of the Materia Medica and scientific literature was undertaken using key word searches for "mollusc" and "anti-inflammatory" or "immunomodulatory" or "wound healing". RESULTS: Molluscs have been used in ethnomedicine by many traditional cultures to treat different aspects of inflammatory conditions. We found 104 different anti-inflammatory preparations from a variety of molluscan species, of which 70 were from the well-documented Traditional Chinese Medicine (TCM). This traditional use of molluscs has driven the testing for inflammatory activity in extracts from some species in the phylum Mollusca, with 20 in vitro studies, 40 in vivo animal studies and 14 human clinical trials performed to substantiate the anti-inflammatory and wound healing activity of molluscs. Some of these studies have led to the approval of mollusc-derived products to be used as over-the counter (OTC) nutraceuticals, like Lyprinol(r) and BiolaneTM from the New Zealand green lipped mussel Perna canaliculus. CONCLUSION: Natural products provide important leads for the development of pharmaceuticals, including anti inflammatory agents. Only a small proportion of the molluscan traditional medicines have been tested to confirm their anti-inflammatory activity and most screening studies have tested crude extracts from molluscs without any chemical characterisation. This highlights the need for further research to strategically identify the anti-inflammatory compounds in molluscan medicines to provide leads for novel anti-inflammatory drugs in the future. PMID- 28830819 TI - Operant models of relapse in zebrafish (Danio rerio): Resurgence, renewal, and reinstatement. AB - Zebrafish are a widely used animal model in biomedical research, as an alternative to mammals, for having features such as a fully sequenced genome, high fecundity, and low-cost maintenance, but behavioral research with these fish remains scarce. The present study investigated whether zebrafish could be a new animal model for studies on the relapse of behavior (e.g., addiction and overeating) after the behavior has been extinguished. Specifically, we examined whether zebrafish would show three different types of relapse commonly studied with other species: resurgence, renewal, and reinstatement. For resurgence, a target response (i.e., approaching a sensor) was established by presenting a reinforcer (i.e., shrimp eggs) contingent upon the response in Phase 1; the target response was extinguished while introducing reinforcement for an alternative response in Phase 2; neither response produced the reinforcer in Phase 3. For renewal, a target response was established under Context A in Phase 1 and was extinguished under Context B in Phase 2; the fish were placed back in Context A in Phase 3, where extinction remained in effect. For reinstatement, a target response was established in Phase 1 and was extinguished in Phase 2; the reinforcer was presented independently of responding in Phase 3. Each type of relapse occurred in Phase 3. These results replicate and extend previous findings on relapse to a new species and suggest that zebrafish can be a useful animal model for studying the interactions of biological and environmental factors that lead to relapse. PMID- 28830821 TI - The effect of badminton training on the ability of same-domain action anticipation for adult novices: Evidence from behavior and ERPs. AB - Many transverse studies have found that athletes can better anticipate the outcome of sequential actions belonging to their domain of motor expertise than non-athletes. However, few studies have causally investigated this issue. Using badminton training as an example, the present study attempted to explore whether sports training affected the same-domain action anticipation ability of adult novices and the related neural mechanisms. To address this issue, participants in the training group attended a 12-week badminton training course (1h/time, 3 times/week). Both the training and control groups were asked to view badminton video clips and predict the landing position of a shuttle before and after 12 weeks. Compared to the control group, the training group showed a decrease in the inverse efficiency score, indicating that badminton training did improve trainees' action anticipation ability. Furthermore, the training group produced larger N2 and P3 components of event-related potential after the training. These findings suggest that sport training may affect inhibitory processes and memory encoding during same-domain action anticipation. PMID- 28830822 TI - Human microglia and astrocytes express cGAS-STING viral sensing components. AB - While microglia and astrocytes are known to produce key inflammatory and anti viral mediators following infection with replicative DNA viruses, the mechanisms by which these cell types perceive such threats are poorly understood. Recently, cyclic GMP-AMP synthase (cGAS) has been identified as an important cytosolic sensor for DNA viruses and retroviruses in peripheral leukocytes. Here we confirm the ability of human microglial and astrocytic cell lines and primary human glia to respond to foreign intracellular double stranded DNA. Importantly, we provide the first demonstration that human microglia and astrocytes show robust levels of cGAS protein expression at rest and following activation. Furthermore, we show these cell types also constitutively express the critical downstream cGAS adaptor protein, stimulator of interferon genes (STING). The present finding that human glia express the principle components of the cGAS-STING pathway provides a foundation for future studies to investigate the relative importance of these molecules in clinically relevant viral CNS infections. PMID- 28830820 TI - Cough in Ambulatory Immunocompromised Adults: CHEST Expert Panel Report. AB - BACKGROUND: Cough is a common symptom prompting patients to seek medical care. Like patients in the general population, patients with compromised immune systems also seek care for cough. However, it is unclear whether the causes of cough in immunocompromised patients who are deemed unlikely to have a life-threating condition and a normal or unchanged chest radiograph are similar to those in persons with cough and normal immune systems. METHODS: We conducted a systematic review to answer the question: What are the most common causes of cough in ambulatory immunodeficient adults with normal chest radiographs? Studies of patients >= 18 years of age with immune deficiency, cough of any duration, and normal or unchanged chest radiographs were included and assessed for relevance and quality. Based on the systematic review, suggestions were developed and voted on using the American College of Chest Physicians (CHEST) methodology framework. RESULTS: The results of the systematic review revealed no high-quality evidence to guide the clinician in determining the likely causes of cough specifically in immunocompromised ambulatory patients with normal chest radiographs. CONCLUSIONS: Based on a systematic review, we found no evidence to assess whether or not the proper initial evaluation of cough in immunocompromised patients is different from that in immunocompetent persons. A consensus of the panel suggested that the initial diagnostic algorithm should be similar to that for immunocompetent persons but that the context of the type and severity of the immune defect, geographic location, and social determinants be considered. The major modifications to the 2006 CHEST Cough Guidelines are the suggestions that TB should be part of the initial evaluation of patients with cough and HIV infection who reside in regions with a high prevalence of TB, regardless of the radiographic findings, and that specific causes and immune defects be considered in all patients in whom the initial evaluation is unrevealing. PMID- 28830823 TI - Lack of association between SLC5A7 polymorphisms and Tourette syndrome in a Chinese Han population. AB - Although Tourette syndrome (TS) is a chronic neuropsychiatric disorder whose pathogenesis remains unclear, genetic factors play an important role in the occurrence and development. A variety of studies have been shown that the candidate genes related to cholinergic neurons may be associated with the onset of TS. To investigate the association between the SLC5A7 polymorphisms and Tourette syndrome (TS) in the Chinese Han population, the SNP rs1013940, rs2433718, and rs4676169 were genotyped in 401 TS trios and 400 controls. The transmission disequilibrium test (TDT) and haplotype relative risk (HRR) compared genetic distributions of trios, while the chi-square test compared patients and controls. However, no transmission disequilibrium was found between the three SLC5A7 SNPs and TS. Therefore, we think that this gene may not be the main risk factor on the onset of TS. However, these results should be further validated in different populations. PMID- 28830824 TI - A structural motor network correlates with motor function and not impairment post stroke. AB - Combining structural and functional magnetic resonance imaging may provide insight into how residual motor networks contribute to motor outcomes post stroke. The purpose of this study was to examine whether a structural motor network (SMN), generated with fMRI guided diffusion-based tractography, relates to motor function post-stroke. Twenty-seven individuals with mild to moderate upper limb impairment post stroke underwent diffusion magnetic resonance imaging. A bilateral motor network mask guided white matter tractography for each participant. Fractional anisotrophy (FA) was calculated for the SMN and corticospinal tracts (CST). The Wolf Motor Function Test (WMFT) rate and Fugl Meyer Upper Limb (FM) tests characterized arm function and impairment respectively. The SMN and ipsilesional CST together explained approximately 35% of the variance in paretic arm function (WMFT-rate p=0.006). This study demonstrates that a broader motor network, like the SMN, is functionally meaningful. Given that the motor network is widely distributed, the proposed SMN warrants further investigation as a potential adjunct biomarker to characterize recovery potential after stroke. PMID- 28830825 TI - The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal. AB - OBJECTIVE: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. METHODS: We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants. RESULTS: We identified six rare mutations (1.6%) and two low frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p=0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p=0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p=0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r2 0.95). CONCLUSIONS: Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD. PMID- 28830826 TI - Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications. PMID- 28830828 TI - Molecular mass of Poly-3-hydroxybutyrate (P3HB) produced by Azotobacter vinelandii is influenced by the polymer content in the inoculum. AB - Poly-3-hydroxybutyrate (P3HB) is a biopolymer produced by Azotobacter vinelandii. The physicochemical properties and applications of P3HB are strongly influenced by its weight-average molecular mass (Mw), and in A. vinelandii, it could be influenced by the culture conditions. The aim of this study was to evaluate the effect of the P3HB content of the inoculum on the Mw of the polymer produced by A. vinelandii OP in bioreactor cultures. A. vinelandii cells containing 20, 50 and 70% of P3HB were used as inoculum. The P3HB content in the inoculum affected the volumetric P3HB productivity (qP3HB) and the Mw of P3HB. Those cultures inoculated with cells containing 20% of P3HB, achieved the highest qP3HB (0.17+/ 0.018gP3HBL-1h-1); whereas a P3HB content of 70% was reflected as a low qP3HB (0.021+/-0.002gP3HBL-1h-1). On the other hand, using an inoculum with 70% of polymer content, the Mw of the biopolymer remained stable at values close to 3200kDa; whereas, when an inoculum with 20% of P3HB was used, the Mw decreased drastically during early stages of cultivation. These results show that manipulating the P3HB content of the inoculum is possible to produce biopolymers with a suitable Mw. PMID- 28830829 TI - Phylogenetic insights into the diversity of homocytous cyanobacteria from Amazonian rivers. AB - The Amazon Rainforest holds great tropical biodiversity, mainly because of its favourable climatic conditions. The high temperatures, luminosity and humidity coupled with the nutritional simplicity of cyanobacteria allow undiscovered diversity to flourish within this group of microorganisms. Some efforts to reveal this diversity have been attempted; however, most were focused on the microscopic observation of environmental samples without any genetic information. Very few studies focusing on morphological, ecological and molecular criteria have been conducted, and none have been devoted to homocytous cyanobacteria forms in Amazonia region. Therefore, the genetic relationships amongst strains retrieved from this ecosystem with regard to other environments from Brazil and the world have not been tested and, consequently, the Amazonian strains would naturally be assumed as novel to science. To examine these relationships, cultured homocytous cyanobacteria isolated from two Amazonian rivers (Amazonas and Solimoes) were evaluated using a phylogenetic perspective, considering the 16S rRNA gene sequence. A total of eleven homocytous cyanobacterial strains were isolated. Morphologically, they were identified as Pseudanabaena, Leptolyngbya, Planktothrix and Phormidium, but genetically they were included in the typical clusters of Planktothrix, Pseudanabaena, Cephalothrix, Pantanalinema and Alkalinema. These three latter genera have been detected in other Brazilian ecosystems only (Pantanal, Atlantic Rainforest and Pampa), while those remaining have been extensively found in many parts of the world. The data provided here indicate that Amazonian rivers support a homocytous cyanobacterial diversity previously reported from other geographical and ecological environments. PMID- 28830827 TI - Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families. AB - Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co inherited with CDKN2A and may influence carcinogenesis. PMID- 28830830 TI - Evolutionary relationships of the hexon and penton base genes of novel squirrel adenovirus. AB - Squirrel adenovirus (SqAdV) was reported previously. However, only partial sequences of its hexon and polymerase genes have been revealed. For the first time, we report the full-length genome of SqAdV including the complete hexon and penton base genes. From internal body organs of 59 red squirrels archived in Korea Bank for Pathogenic Viruses, the hexon, penton base, and full-length genome of SqAdV were determined by a PCR method. Of the internal body organs examined, the spleen showed the highest detection rate (25.42%) for SqAdV whereas the kidney and lung exhibited 18.64% and 3.39% rates, respectively. Based on the phylogenetic relationships of the hexon and penton base genes, SqAdV appears to belong to the genus Mastadenovirus, and, at least in our study, the hexon of SqAdV exhibits the closest relationship to that of an alpaca AdV. Compared with the hexon, the penton base of SqAdV appears to be genetically more divergent from that of other mastadenoviruses. It was also revealed that the full-length SqAdV genome retained AT nucleotide content similar level to AT-rich atadenoviruses, which is unusual for mastadenoviruses. Our results emphasize that SqAdV is classified into the genus Mastadenovirus and demonstrate the AT-biased nucleotide constitution of SqAdV. PMID- 28830831 TI - The confounding effects of hybridization on phylogenetic estimation in the New Zealand cicada genus Kikihia. AB - Phylogenetic studies of multiple independently inherited nuclear genes considered in combination with patterns of inheritance of organelle DNA have provided considerable insight into the history of species evolution. In particular, investigations of cicadas in the New Zealand genus Kikihia have identified interesting cases where mitochondrial DNA (mtDNA) crosses species boundaries in some species pairs but not others. Previous phylogenetic studies focusing on mtDNA largely corroborated Kikihia species groups identified by song, morphology and ecology with the exception of a unique South Island mitochondrial haplotype clade-the Westlandica group. This newly identified group consists of diverse taxa previously classified as belonging to three different sub-generic clades. We sequenced five nuclear loci from multiple individuals from every species of Kikihia to assess the nuclear gene concordance for this newly-identified mtDNA lineage. Bayes Factor analysis of the constrained phylogeny suggests some support for the mtDNA-based hypotheses, despite the fact that neither concatenation nor multiple species tree methods resolve the Westlandica group as monophyletic. The nuclear analyses suggest a geographic distinction between clearly defined monophyletic North Island clades and unresolved South Island clades. We suggest that more extreme habitat modification on South Island during the Pliocene and Pleistocene resulted in secondary contact and hybridization between species pairs and a series of mitochondrial capture events followed by subsequent lineage evolution. PMID- 28830832 TI - Asymmetric larval head and mandibles of Hydrophilus acuminatus (Insecta: Coleoptera, Hydrophilidae): Fine structure and embryonic development. AB - The larvae of a water scavenger beetle, Hydrophilus acuminatus, have strongly asymmetric mandibles; the right one is long and slender, whereas the left one is short and stout. The fine structure and embryonic development of the head capsule and mandibles of this species were examined using light and scanning electron microscopy, and asymmetries in shape were detected in these structures applying an elliptic Fourier analysis. The larval mandibles are asymmetric in the following aspects: whole length, the number, structure and arrangement of retinacula (inner teeth), and size and shape of both the molar and incisor regions. The larval head is also asymmetric; the left half of the head capsule is larger than the right, and the left adductor muscle of the mandible is much thicker than the right. The origin and developmental process of asymmetric mandibles were traced in developing embryos whose developmental period is about 270 h and divided into 10 stages. Mandibular asymmetries are produced by the cumulative effects of six stepwise modifications that occur from about 36% of the total developmental time onward. The significance of these modifications was discussed with respect to the functional advantages of asymmetries and the phylogeny of members of the Hydrophilidae. PMID- 28830833 TI - The European wool-carder bee (Anthidium manicatum) eavesdrops on plant volatile organic compounds (VOCs) during trichome collection. AB - The plant-pollinator relationship is generally considered mutualistic. This relationship is less clear, however, when pollinators also cause tissue damage. Some Megachilidae bees collect plant material for nests from the plants they pollinate. In this study, we examined the relationship between Anthidium manicatum, the European wool-carder bee, and the source of its preferred nesting material - Stachys byzantina, lamb's ear. Female A. manicatum use their mandibles to trim trichomes from plants for nesting material (a behaviour dubbed "carding"). Using volatile organic compound (VOC) headspace analysis and behavioural observations, we explored (a) how carding effects S. byzantina and (b) how A. manicatum may choose specific S. byzantina plants. We found that removal of trichomes leads to a dissimilar VOC bouquet compared to intact leaves, with a significant increase in VOC detection following damage. A. manicatum also visit S. byzantina plants with trichomes removed at a greater frequency compared to plants with trichomes intact. Our data suggest that A. manicatum eavesdrop on VOCs produced by damaged plants, leading to more carding damage for individual plants due to increased detectability by A. manicatum. Accordingly, visitation by A. manicatum to S. byzantina may incur both a benefit (pollination) and cost (tissue damage) to the plant. PMID- 28830834 TI - Food contact materials and gut health: Implications for toxicity assessment and relevance of high molecular weight migrants. AB - Gut health is determined by an intact epithelial barrier and balanced gut microbiota, both involved in the regulation of immune responses in the gut. Disruption of this system contributes to the etiology of various non-communicable diseases, including intestinal, metabolic, and autoimmune disorders. Studies suggest that some direct food additives, but also some food contaminants, such as pesticide residues and substances migrating from food contact materials (FCMs), may adversely affect the gut barrier or gut microbiota. Here, we focus on gut related effects of FCM-relevant substances (e.g. surfactants, N-ring containing substances, nanoparticles, and antimicrobials) and show that gut health is an underappreciated target in the toxicity assessment of FCMs. Understanding FCMs' impact on gut health requires more attention to ensure safety and prevent gut related chronic diseases. Our review further points to the existence of large population subgroups with an increased intestinal permeability; this may lead to higher uptake of compounds of not only low (<1000 Da) but also high (>1000 Da) molecular weight. We discuss the potential toxicological relevance of high molecular weight compounds in the gut and suggest that the scientific justification for the application of a molecular weight-based cut-off in risk assessment of FCMs should be reevaluated. PMID- 28830835 TI - Bioinformatics analysis to assess potential risks of allergenicity and toxicity of HRAP and PFLP proteins in genetically modified bananas resistant to Xanthomonas wilt disease. AB - Banana Xanthomonas wilt (BXW) disease threatens banana production and food security throughout East Africa. Natural resistance is lacking among common cultivars. Genetically modified (GM) bananas resistant to BXW disease were developed by inserting the hypersensitive response-assisting protein (Hrap) or/and the plant ferredoxin-like protein (Pflp) gene(s) from sweet pepper (Capsicum annuum). Several of these GM banana events showed 100% resistance to BXW disease under field conditions in Uganda. The current study evaluated the potential allergenicity and toxicity of the expressed proteins HRAP and PFLP based on evaluation of published information on the history of safe use of the natural source of the proteins as well as established bioinformatics sequence comparison methods to known allergens (www.AllergenOnline.org and NCBI Protein) and toxins (NCBI Protein). The results did not identify potential risks of allergy and toxicity to either HRAP or PFLP proteins expressed in the GM bananas that might suggest potential health risks to humans. We recognize that additional tests including stability of these proteins in pepsin assay, nutrient analysis and possibly an acute rodent toxicity assay may be required by national regulatory authorities. PMID- 28830836 TI - Ethyl Glucuronide in Hair Is an Accurate Biomarker of Chronic Excessive Alcohol Use in Patients With Alcoholic Cirrhosis. PMID- 28830837 TI - Toxicity evaluation of two polyoxotungstates with anti-acetylcholinesterase activity. AB - A toxicity evaluation of two Keggin-type heteropolytungstates, K7[Ti2PW10O40].6H2O and K6H[SiV3W9O40].3H2O, with different inhibitory potencies toward acetylcholinesterase activity (IC50 values of 1.04*10-6 and 4.80*10 4mol/L, respectively) was performed. Wistar albino rats were orally treated with single doses (5 and 50mg/kg) of both investigated compounds. The biochemical parameters of renal (serum urea and creatinine) and liver function (direct and total bilirubin, alanine transaminase, and aspartate aminotransferase) were determined after 24h and 14days. A histopathological analysis of liver tissue was carried out 14days after the polyoxotungstate administration. Both applied doses of the investigated compounds did not induce statistically significant alterations of the renal function markers. However, the polyoxotungstate treatment caused an increase in the activities of serum alanine transaminase and aspartate aminotransferase in a time- and concentration-dependent manner, although statistically significant changes in bilirubin concentrations were not observed. Furthermore, the detected hepatotoxic effect was confirmed by histhopathological analysis that suggested some reversible liver tissue damage two weeks after the treatment, especially in the case of K6H[SiV3W9O40].3H2O. Accordingly, the toxicity of these two polyoxotungstates with anti acetylcholinesterase effect cannot be considered as a severe one, but their potential clinical application would require a more complex toxicological study. PMID- 28830838 TI - Members of FOX family could be drug targets of cancers. AB - FOX families play important roles in biological processes, including metabolism, development, differentiation, proliferation, apoptosis, migration, invasion and longevity. Here we are focusing on roles of FOX members in cancers, FOX members and drug resistance, FOX members and stem cells. Finally, FOX members as drug targets of cancer treatment were discussed. Future perspectives of FOXC1 research were described in the end. PMID- 28830839 TI - The potential for targeted rewriting of epigenetic marks in COPD as a new therapeutic approach. AB - Chronic obstructive pulmonary disease (COPD) is an age and smoking related progressive, pulmonary disorder presenting with poorly reversible airflow limitation as a result of chronic bronchitis and emphysema. The prevalence, disease burden for the individual, and mortality of COPD continues to increase, whereas no effective treatment strategies are available. For many years now, a combination of bronchodilators and anti-inflammatory corticosteroids has been most widely used for therapeutic management of patients with persistent COPD. However, this approach has had disappointing results as a large number of COPD patients are corticosteroid resistant. In patients with COPD, there is emerging evidence showing aberrant expression of epigenetic marks such as DNA methylation, histone modifications and microRNAs in blood, sputum and lung tissue. Therefore, novel therapeutic approaches may exist using epigenetic therapy. This review aims to describe and summarize current knowledge of aberrant expression of epigenetic marks in COPD. In addition, tools available for restoration of epigenetic marks are described, as well as delivery mechanisms of epigenetic editors to cells. Targeting epigenetic marks might be a very promising tool for treatment and lung regeneration in COPD in the future. PMID- 28830840 TI - Binge-eating disorder: Clinical and therapeutic advances. AB - Binge-eating disorder (BED) is the most prevalent eating disorder with estimates of 2-5% of the general adult population. Nonetheless, its pathophysiology is poorly understood. Furthermore, there exist few therapeutic options for its effective treatment. Here we review the current state of binge-eating neurobiology and pharmacology, drawing from clinical therapeutic, neuroimaging, cognitive, human genetic and animal model studies. These studies, which are still in their infancy, indicate that while there are many gaps in our knowledge, several key neural substrates appear to underpin binge-eating and may be conserved between human and animals. This observation suggests that behavioral intermediate phenotypes or endophenotypes relevant to BED may be modeled in animals, facilitating the identification and testing of novel pharmacological targets. The development of novel, safe and effective pharmacological therapies for the treatment of BED will enhance the ability of clinicians to provide optimal care for people with BED. PMID- 28830841 TI - Molecular pathogenesis and therapeutic implications in pediatric high-grade gliomas. AB - High-grade gliomas (HGG) are the most common malignant brain tumors in the pediatric population and account for a large subset of all pediatric central nervous system neoplasms. The management of pediatric HGG continues to be challenging, with poor outcome in many cases despite aggressive treatments. Consequently, parallel research efforts have been focused on identifying the underlying genetic and biological basis of pediatric HGG in order to more clearly define prognostic subgroups for treatment stratification as well as identify new treatment targets. These cutting-edge advances have revolutionized pediatric neuro-oncology and have revealed novel oncogenic vulnerabilities that are being therapeutically leveraged. Promising treatments - including pathway-targeting small molecules as well as epigenetic therapy - are being evaluated in clinical trials, and recent genomic discoveries in rare glioma subgroups have led to the identification of additional new potentially-actionable alterations. This review summarizes the current state of knowledge about the molecular characterization of pediatric HGG in correlation to the revised World Health Organization (WHO) classification, as well as provides an overview of some targeted treatment approaches in the modern clinical management of high-grade gliomas. PMID- 28830842 TI - Clinical, epidemiological and microbiological characteristics of relapse and re infection in Clostridium difficile infection. AB - Recurrent diarrhea is a common complication of Clostridium difficile infection (CDI). Recurrent CDI (r-CDI) may be produced by the persistence of spores (relapse) or by the acquisition of a new strain (reinfection). In this study, we analyze epidemiological, clinical, microbiological and laboratory data from patients with r-CDI, relapse, and reinfection-CDI over 5 years and compared with a control group (non r-CDI). Among 60 patients with r-CDI, 36 patients had stool samples collected from two or more episodes, which were molecularly analyzed. Based on ribotyping, 63.9% of the samples were relapse, and 36.1% reinfection. In a multivariable logistic regression analysis, previous antibiotic exposure was found to be a risk factor for r-CDI (OR: 2.23; 95% CI: 1.0-4.9; p = 0.04). Patients with relapse had previous antibiotic exposure more frequently than did patients with reinfection (p = 0.03), and patients with reinfection suffered more frequently from chronic liver disease (p = 0.02) than did relapse patients. Relapse patients compared with the control group had a higher percentage of previous antibiotic exposure, although the difference was statistically no significant (73.9% vs. 91.3 p = 0.06). No significant differences for the selected variables were observed between the reinfection and control groups, although we observed a higher percentage of patients with chronic liver disease (30.8% vs 13.3%; p = 0.08). All isolates were sensitive to metronidazole and vancomycin. No significant differences in antibiotic susceptibility were found between the different groups. Sporulation and germination frequency of r-CDI were higher than non r-CDI (p = 0.02 and p < 0.01, respectively). Nevertheless, there were statistically not significant differences between the relapse and reinfection groups. Both frequencies were compared between the first and second episode of CDI for the relapse and reinfection groups, but differences were not observed to be statistically significant. In conclusion, our study showed that the recurrence of CDI was associated with antibiotic use and sporulation/germination frequency, regardless of relapse or reinfection. The use of antibiotics would produce a dysbiosis and favor the persistence of the C. difficile spores and relapse. A possible alteration of the intestinal microbiota and the bile salts produced by chronic liver disease could favor reinfection. PMID- 28830844 TI - Hyperkinetic motor seizures: a common semiology generated by two different cortical seizure origins. AB - We report a 37-year-old, right-handed patient with drug-resistant focal epilepsy whose seizures were characterized by explosive hyperkinetic behaviour. Video-SEEG revealed bifocal organization of epilepsy with two distinct cortical origins of seizures: the right temporal pole and left temporal lateral and perisylvian cortex. Irrespective of the cortical pattern of seizure onset, the hyperkinetic semiology was extremely similar. This supports a major role for "final common pathway" subcortical circuits in the genesis of the hyperkinetic semiology in this patient. PMID- 28830845 TI - Brain connectivity changes during ictal aggression (a strangulation attempt). AB - Ictal aggressive behaviour is a rare manifestation of focal seizures. We report an episode of ictal aggression occurring during an intracerebrally recorded seizure (using stereoelectroencephalography) in a patient with drug-resistant temporal lobe epilepsy. Aggression occurred during the last part of the seizure and was coincident with marked EEG slowing of the frontal regions and persistent ictal activity in the medial temporal lobe. A functional connectivity study (h2 estimation of interdependencies) showed a bilateral massive hypersynchronization between frontal and temporal regions. This case illustrates the occurrence of aggression during imbalance between the electrical activity in the temporal limbic cortex and prefrontal cortex, in agreement with the current neurobiological theories of aggression. PMID- 28830843 TI - Inhibition of tPA-induced hemorrhagic transformation involves adenosine A2b receptor activation after cerebral ischemia. AB - Tissue plasminogen activator (tPA) is administered after ischemic stroke to dissolve intravascular clots, but its use can lead to hemorrhagic transformation (HT). Therapeutic strategies to reduce hemorrhagic complications of tPA might be of benefit for stroke patients. Adenosine A2b receptor (A2bR) plays pivotal roles in regulating vascular protection in peripheral organs. This study explored whether A2bR agonist BAY 60-6583 reduces hemorrhage risk after tPA usage. Using a rat transient middle cerebral artery occlusion model, we showed that mRNA and protein expression of A2bR increased to a greater extent after ischemia reperfusion than did expression of the other three adenosine receptors (A1, A2a, and A3). tPA administration reduced A2bR expression in ischemic brain microvessels. Post-treatment with BAY 60-6583 (1mg/kg) at the start of reperfusion reduced lesion volume in the absence or presence of tPA (10mg/kg) and attenuated brain swelling, blood-brain barrier disruption, and tPA-exacerbated HT at 24h. Additionally, BAY 60-6583 mitigated sensorimotor deficits in the presence of tPA. BAY 60-6583 inhibited tPA-enhanced matrix metalloprotease-9 activation, probably through elevation of tissue inhibitor of matrix metalloproteinases-1 expression, and thereby reduced degradation of tight junction proteins. These effects would likely protect cerebrovascular integrity. A2bR agonists as an adjuvant to tPA could be a promising strategy for decreasing the risk of HT during treatment for ischemic stroke. PMID- 28830846 TI - Diffusion-weighted MRI for differentiating Wilms tumor from neuroblastoma. AB - PURPOSE: Wilms tumor (WT) and neuroblastoma (NB) are the most common pediatric abdominal malignant neoplasms of the kidney and adrenal gland. Differentiating them from each other is essential since their treatments are different. Here, we aimed to show the diffusion characteristics of WT and NB for differentiation. METHODS: Diffusion-weighted imaging (DWI) of 17 histopathologically diagnosed lesions (10 NB and 7 WT in 8 female and 9 male patients) was evaluated retrospectively. The apparent diffusion coefficient (ADC) value for each tumor was calculated using region-of-interest (ROI) measurements by two observers. The mean ADC values were compared, and receiver operating characteristics (ROC) curve analysis was performed. Intraclass correlation was evaluated for the reliability of ADC measurement. RESULTS: The mean ADC values measured by two observers were 0.787+/-0.09 *10-3 mm2/s and 0.768+/-0.08 *10-3 mm2/s for WT, and 0.524+/-0.16 *10-3 mm2/s and 0.529+/-0.16 *10-3 mm2/s for NB, respectively (P = 0.006 and P = 0.011). Intraclass correlation coefficient was 0.955. Utilizing ROC curve analysis, a cutoff ADC value of <=0.645 *10-3 mm2/s was obtained to differentiate NB from WT. CONCLUSION: ADC values of NBs were significantly lower than WT with a perfect interobserver agreement. We suggest that DWI may have a role in differentiating the two tumors. PMID- 28830847 TI - Lesion characteristics, histopathologic results, and follow-up of breast lesions after MRI-guided biopsy. AB - PURPOSE: We aimed to assess the effectiveness of magnetic resonance imaging (MRI) guided vacuum-assisted breast biopsy (VABB), evaluate and compare the characteristics and histopathologic findings of lesions, and overview the follow up results of benign lesions. METHODS: MRI findings and histopathologic results of breast lesions biopsied by MRI-guided VABB between 2013 and 2016 were retrospectively analyzed. MRI findings closely related with malignancy were investigated in particular. Follow-up results of benign lesions were evaluated. RESULTS: MRI-guided VABB was applied to 116 lesions of 112 women. Of the lesions, 75 (65%) were benign, while 41 (35%) were malignant. Segmental (94%), clustered (89%), and clustered ring (67%) non-mass-like enhancement patterns were found to be more related with malignancy. False-negative rate of MRI-guided VABB was 12%, underestimation rate was 21%. One of the 54 followed-up benign lesions had a malignant result. CONCLUSION: MRI-guided VABB is a reliable method for the diagnosis of breast lesions that are positive only on MRI. Follow-up results show that cancer detection rate is low for radio-pathologically concordant lesions. Further multicenter studies with larger patient population are needed to elucidate these results. PMID- 28830848 TI - MRI and clinical features of maple syrup urine disease: preliminary results in 10 cases. AB - PURPOSE: We aimed to evaluate the magnetic resonance imaging (MRI) and clinical features of maple syrup urine disease (MSUD). METHODS: This retrospective study consisted of 10 MSUD patients confirmed by genetic testing. All patients underwent brain MRI. Phenotype, genotype, and areas of brain injury on MRI were retrospectively reviewed. RESULTS: Six patients (60%) had the classic form of MSUD with BCKDHB mutation, three patients (30%) had the intermittent form (two with BCKDHA mutations and one with DBT mutation), and one patient (10%) had the thiamine-responsive form with DBT mutation. On diffusion-weighted imaging, nine cases presented restricted diffusion in myelinated areas, and one intermittent case with DBT mutation was normal. The classic form of MSUD involved the basal ganglia in six cases; the cerebellum, mesencephalon, pons, and supratentorial area in five cases; and the thalamus in four cases, respectively. The intermittent form involved the cerebellum, pons, and supratentorial area in two cases. The thiamine-responsive form involved the basal ganglia and supratentorial area. CONCLUSION: Our preliminary results indicate that patients with MSUD presented more commonly in classic form with BCKDHB mutation and displayed extensive brain injury on MRI. PMID- 28830849 TI - Birt-Hogg-Dube syndrome: characteristic CT findings differentiating it from other diffuse cystic lung diseases. AB - Birt-Hogg-Dube (BHD) syndrome is an uncommon, autosomal dominant, multiorgan systemic disorder manifesting as cutaneous fibrofolliculomas, lung cysts with or without spontaneous pneumothorax, and renal tumors. Spontaneous pneumothorax and lung cysts on chest computed tomography (CT) should lead to the inclusion of BHD syndrome in the differential diagnosis, because these findings may develop earlier than other clinical manifestations. Here, we review and describe the characteristic findings of BHD syndrome. The number, shape, size, and distribution of the lung cysts can help to differentiate BHD syndrome from other diffuse cystic lung diseases. Knowledge of the chest CT findings of BHD syndrome may lead to a correct diagnosis and the initiation of an appropriate work-up in order to prevent pneumothorax and for the early detection of renal tumors. PMID- 28830850 TI - Irreversible electroporation for the treatment of localized prostate cancer: a summary of imaging findings and treatment feedback. AB - PURPOSE: Imaging plays a crucial role in ablative therapies for prostate cancer (PCa). Irreversible electroporation (IRE) is a new treatment modality used for focal treatment of PCa. We aimed to demonstrate what imaging modalities can be used by descriptively reporting contrast-enhanced ultrasonography (CEUS), multiparametric magnetic resonance imaging (mpMRI), and grey-scale transrectal ultrasound (TRUS) results. Furthermore, we aimed to correlate quantitatively the ablation zone seen on mpMRI and CEUS with treatment planning to provide therapy feedback. METHODS: Imaging data was obtained from two prospective multicenter trials on IRE for localized low- to intermediate-risk PCa. The ablation zone volume (AZV) seen on mpMRI and CEUS was 3D reconstructed to correlate with the planned AZV. RESULTS: Descriptive examples are provided using mpMRI, TRUS, and CEUS for treatment planning and follow-up after IRE. The mean AZV on T2-weighted imaging 4 weeks following IRE was 12.9 cm3 (standard deviation [SD]=7.0), 5.3 times larger than the planned AZV. Linear regression showed a positive correlation (r=0.76, P = 0.002). For CEUS the mean AZV was 20.7 cm3 (SD=8.7), 8.5 times larger than the planned AZV with a strong positive correlation (r=0.93, P = 0.001). Prostate volume is reduced over time (mean= -27.5%, SD=11.9%) due to ablation zone fibrosis and deformation, illustrated by 3D reconstruction. CONCLUSION: The role of imaging in conjunction with IRE is of crucial importance to guide clinicians throughout the treatment protocol. CEUS and mpMRI may provide essential treatment feedback by visualizing the ablation zone dimensions and volume. PMID- 28830851 TI - Barriers and Facilitators for the Use of a Medical Mobile App to Prevent Work Related Risks in Pregnancy: A Qualitative Analysis. AB - BACKGROUND: The number of women participating in the labor market in Europe has increased over the last several decades. At the same time, there is growing evidence that certain conditions of employment during pregnancy may have a negative influence on pregnancy outcomes. In order to better inform pregnant women, we aim to develop an app to help assess the health risk as a result of personal and work-related factors and provide personal advice for these women and their health care providers. OBJECTIVE: The aim of this study was to compose a thematic overview of the perceived facilitators and barriers according to pregnant women, medical professionals, and employers for the use of a mobile app in obstetrical care to prevent occupational-related pregnancy complications. METHODS: Two multidisciplinary focus group meetings with in total 14 participants were conducted with pregnant women, occupational physicians, general practitioners, midwives, obstetricians, and representatives of trade unions and employer organizations. Transcripts were analyzed by qualitatively coding procedures and constant comparative methods. RESULTS: We identified 24 potential facilitators and 12 potential barriers for the use of the app in 4 categories: content of the app, the app as a mean to provide information, ease of use, and external factors. The 3 main facilitators identified were the need for a good interaction between the app and the user, apps were viewed as a more practical source of information, and the information should be understandable, according to the existing guidelines, and well-dosed. The 2 main barriers for use were extensive battery and memory use of the smartphone and sending frequent push notifications. CONCLUSIONS: The results of this study are important considerations in the developing process of a medical app implementing a guideline or evidence-based information in practice. PMID- 28830852 TI - Web-Based Physician Ratings for California Physicians on Probation. AB - BACKGROUND: Web-based physician ratings systems are a popular tool to help patients evaluate physicians. Websites help patients find information regarding physician licensure, office hours, and disciplinary records along with ratings and reviews. Whether higher patient ratings are associated with higher quality of care is unclear. OBJECTIVE: The aim of this study was to characterize the impact of physician probation on consumer ratings by comparing website ratings between doctors on probation against matched controls. METHODS: A retrospective review of data from the Medical Board of California for physicians placed on probation from December 1989 to September 2015 was performed. Violations were categorized into nine types. Nonprobation controls were matched by zip code and specialty with probation cases in a 2:1 ratio using the California Department of Consumer Affairs website. Web-based reviews were recorded from vitals.com, healthgrades.com, and ratemds.com (ratings range from 1-5). RESULTS: A total of 410 physicians were placed on probation for 866 violations. The mean (standard deviation [SD]) number of ratings per doctor was 5.2 (7.8) for cases and 4 (6.3) for controls (P=.003). The mean rating for physicians on probation was 3.7 (1.6) compared with 4.0 (1.0) for controls when all three rating websites were pooled (P<.001). Violations for medical documentation, incompetence, prescription negligence, and fraud were found to have statistically significant lower rating scores. Conversely, scores for professionalism, drugs or alcohol, crime, sexual misconduct, and personal illness were similar between cases and controls. In a univariate analysis, probation was found to be associated with lower rating, odds ratio=1.5 (95% CI 1.0-2.2). This association was not significant in a multivariate model when we included age and gender. CONCLUSIONS: Web-based physician ratings were lower for doctors on probation indicating that patients may perceive a difference. Despite these statistical findings, the absolute difference was quite small. Physician rating websites have utility but are imperfect proxies for competence. Further research on physician Web-based ratings is warranted to understand what they measure and how they are associated with quality. PMID- 28830855 TI - NHS expands overseas GP recruitment drive despite slow progress so far. PMID- 28830854 TI - A Mobile Device App to Reduce Medication Errors and Time to Drug Delivery During Pediatric Cardiopulmonary Resuscitation: Study Protocol of a Multicenter Randomized Controlled Crossover Trial. AB - BACKGROUND: During pediatric cardiopulmonary resuscitation (CPR), vasoactive drug preparation for continuous infusions is complex and time-consuming. The need for individual specific weight-based drug dose calculation and preparation places children at higher risk than adults for medication errors. Following an evidence based and ergonomic driven approach, we developed a mobile device app called Pediatric Accurate Medication in Emergency Situations (PedAMINES), intended to guide caregivers step-by-step from preparation to delivery of drugs requiring continuous infusion. In a prior single center randomized controlled trial, medication errors were reduced from 70% to 0% by using PedAMINES when compared with conventional preparation methods. OBJECTIVE: The purpose of this study is to determine whether the use of PedAMINES in both university and smaller hospitals reduces medication dosage errors (primary outcome), time to drug preparation (TDP), and time to drug delivery (TDD) (secondary outcomes) during pediatric CPR when compared with conventional preparation methods. METHODS: This is a multicenter, prospective, randomized controlled crossover trial with 2 parallel groups comparing PedAMINES with a conventional and internationally used drug infusion rate table in the preparation of continuous drug infusion. The evaluation setting uses a simulation-based pediatric CPR cardiac arrest scenario with a high-fidelity manikin. The study involving 120 certified nurses (sample size) will take place in the resuscitation rooms of 3 tertiary pediatric emergency departments and 3 smaller hospitals. After epinephrine-induced return of spontaneous circulation, nurses will be asked to prepare a continuous infusion of dopamine using either PedAMINES (intervention group) or the infusion table (control group) and then prepare a continuous infusion of norepinephrine by crossing the procedure. The primary outcome is the medication dosage error rate. The secondary outcome is the time in seconds elapsed since the oral prescription by the physician to drug delivery by the nurse in each allocation group. TDD includes TDP. Stress level during the resuscitation scenario will be assessed for each participant by questionnaire and recorded by the heart rate monitor of a fitness watch. The study is formatted according to the Consolidated Standards of Reporting Trials Statement for Randomized Controlled Trials of Electronic and Mobile Health Applications and Online TeleHealth (CONSORT-EHEALTH) and the Reporting Guidelines for Health Care Simulation Research. RESULTS: Enrollment and data analysis started in March 2017. We anticipate the intervention will be completed in late 2017, and study results will be submitted in early 2018 for publication expected in mid-2018. Results will be reported in line with recommendations from CONSORT-EHEALTH and the Reporting Guidelines for Health Care Simulation Research . CONCLUSIONS: This paper describes the protocol used for a clinical trial assessing the impact of a mobile device app to reduce the rate of medication errors, time to drug preparation, and time to drug delivery during pediatric resuscitation. As research in this area is scarce, results generated from this study will be of great importance and might be sufficient to change and improve the pediatric emergency care practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03021122; https://clinicaltrials.gov/ct2/show/NCT03021122 (Archived by WebCite at http://www.webcitation.org/6nfVJ5b4R). PMID- 28830853 TI - Sugarsquare, a Web-Based Patient Portal for Parents of a Child With Type 1 Diabetes: Multicenter Randomized Controlled Feasibility Trial. AB - BACKGROUND: Raising a child with type 1 diabetes (T1D) means combining the demands of the disease management with everyday parenting, which is associated with increased levels of distress. A Web-based patient portal, Sugarsquare, was developed to support parents, by providing online parent-professional communication, online peer support and online disease information. OBJECTIVE: The first aim of this study was to assess the feasibility of conducting a multicenter, randomized controlled trial in Dutch parents of a child with T1D. The second aim was to assess the feasibility of implementing Sugarsquare in clinical practice. METHODS: The parents of 105 children (N=105) with T1D below the age of 13 participated in a 6-month multicenter randomized controlled feasibility trial. They were randomly assigned to an experimental (n=54, usual care and Sugarsquare) or a control group (n=51, usual care). Attrition rates and user statistics were gathered to evaluate feasibility of the trial and implementation. To determine potential efficacy, the parenting stress index (PSI SF) was assessed at baseline (T0) and after 6 months (T1). RESULTS: Of a potential population of parents of 445 children, 189 were willing to participate (enrollment refusal=57.5%, n=256), 142 filled in the baseline questionnaire (baseline attrition rate=25%, n=47), and 105 also filled in the questionnaire at T1 (post randomization attrition rate during follow-up=26%, n=32). As such, 24% of the potential population participated. Analysis in the experimental group (n=54) revealed a total of 32 (59%) unique users, divided into 12 (38%) frequent users, 9 (28%) incidental users, and 11 (34%) low-frequent users. Of the total of 44 professionals, 34 (77%) logged in, and 32 (73%) logged in repeatedly. Analysis of the user statistics in the experimental group further showed high practicability and integration in all users, moderate acceptability and demand in parents, and high acceptability and demand in health care professionals. Baseline parenting stress index scores were related to the parents' frequency of logging on (rho=.282, P=.03) and page-views (rho=.304, P=.01). No significant differences in change in parenting stress between experimental and control group were found (F3,101=.49, P=.49). CONCLUSIONS: The trial can be considered feasible, considering the average enrollment refusal rate, baseline attrition rate and postrandomization attrition rate, compared to other eHealth studies, although lower than hypothesized. Implementing Sugarsquare in clinical practice was partly feasible, given moderate demand and acceptability in parent users and lack of potential efficacy. Parents who reported higher levels of parenting stress used Sugarsquare more often than other parents, although Sugarsquare did not reduce parenting stress. These results indicate that Web-based interventions are a suitable way of providing parents of children with T1D with additional support. Future studies should determine how Sugarsquare could reduce parenting stress, for instance by adding targeted interventions. Factors potentially contributing to successful implementation are suggested. TRIAL REGISTRATION: Nederlands Trial Register Number: NTR3643; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3643 (Archived by WebCite at http://www.webcitation.org/6qihOVCi6). PMID- 28830856 TI - BMA laments "disappointing" pace of increase in GP numbers. PMID- 28830857 TI - Flooding in south Asia raises fear of disease outbreaks. PMID- 28830858 TI - Substance misuse in older people. PMID- 28830859 TI - Does the use of non-steroidal anti-inflammatory drugs in children with varicella increase the risk of soft tissue infections? PMID- 28830860 TI - Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/- mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491-502. (c)2017 AACR. PMID- 28830861 TI - Addressing the Social Needs of Hypertensive Patients: The Role of Patient Provider Communication as a Predictor of Medication Adherence. AB - BACKGROUND: Poor medication adherence is a pervasive problem in patients with hypertension. Despite research documenting an association between patient provider communication and medication adherence, there are no empirical data on how the informational and relational aspects of communication affect patient's actual medication-taking behaviors. The aim of this study was to evaluate the impact of patient-provider communication on medication adherence among a sample of primary care providers and their black and white hypertensive patients. METHODS AND RESULTS: Cohort study included 92 hypertensive patients and 27 providers in 3 safety-net primary care practices in New York City. Patient provider encounters were audiotaped at baseline and coded using the Medical Interaction Process System. Medication adherence data were collected continuously during the 3-month study with an electronic monitoring device. The majority of patients were black, 58% women, and most were seeing the same provider for at least 1 year. Approximately half of providers were white (56%), 67% women, and have been in practice for an average of 5.8 years. Fifty-eight percent of patients exhibited poor adherence to prescribed antihypertensive medications. Three categories of patient-provider communication predicted poor medication adherence: lower patient centeredness (odds ratio: 3.08; 95% confidence interval: 1.04-9.12), less discussion about patients' sociodemographic circumstances (living situation, relationship with partner; odds ratio: 6.03; 95% confidence interval: 2.15-17), and about their antihypertensive medications (odds ratio: 6.48; 95% confidence interval: 1.83-23.0). The effect of having less discussion about patients' sociodemographic circumstances on medication adherence was heightened in black patients (odds ratio: 8.01; 95% confidence interval: 2.80 22.9). CONCLUSIONS: The odds of poor medication adherence are greater when patient-provider interactions are low in patient centeredness and do not address patients' sociodemographic circumstances or their medication regimen. PMID- 28830862 TI - Talking With Patients Is Better Than Talking to Patients. PMID- 28830864 TI - Commentary on "Effectiveness of Treatment Modalities on Kidney Stone Recurrence". PMID- 28830866 TI - HEE moves towards ending "exit exam" status of MRCGP. PMID- 28830867 TI - Creation of a certification requirement for pharmacists in direct patient care roles. AB - PURPOSE: Steps taken by a large health system to require certification for all pharmacists in direct patient care roles are detailed. SUMMARY: Major supply chain changes and rising payer expectations are reshaping pharmacy practice, resulting in expanded responsibilities for pharmacists and a heightened need for certification in specialized practice areas. In response, the pharmacy leadership team at UW Health, the integrated health system of the University of Wisconsin Madison, used an iterative process and a "rolling" FAQ format to develop and implement a certification requirement. Key decisions during the process included decisions to accept only rigorous certifications (mainly those offered by the Board of Pharmacy Specialties), to provide institutional support for continuing education-based recertification, and to use an accepted definition of direct patient care in determining which pharmacists need to be certified. The team obtained the support of the UW Health human relations department by drafting a policy and rewriting all pharmacist position descriptions to incorporate the certification requirement. An all-pharmacist forum was held to build staff commitment. As a result of the requirement, 73 pharmacists were required to obtain certification by 2018 at a total cost to UW Health of $44,000; ongoing support of certification maintenance will cost an estimated $40,000 per year. CONCLUSION: Health systems can be successful in establishing uniform certification expectations for pharmacists in direct patient care roles, even across diverse practice settings, by aligning expectations with organizational goals. PMID- 28830863 TI - Effectiveness of Treatment Modalities on Kidney Stone Recurrence. AB - Nephrolithiasis is highly prevalent across all demographic groups in the Western world and beyond, and its incidence rates are rising. In addition to the morbidity of the acute event, stone disease often becomes a lifelong problem that requires preventative therapy to diminish ongoing morbidity. Across the majority of stone types, increased fluid intake and targeted dietary modifications are mainstays of therapy. Specific dietary interventions associated with reduced calcium stone risk include adequate dietary calcium intake and restriction of sodium, protein, and oxalate intake, among others. Pharmaceutical therapy may be required if lifestyle changes are insufficient to minimize risk of stone recurrence, and must be targeted to the specific metabolic abnormalities portending risk for a given patient. Therapeutic options for idiopathic calcium stone disease include thiazides, citrate salts, and uric acid-lowering agents. Alkali salts are also the treatment of choice for uric acid stone disease. Management of struvite stone disease is largely surgical, but acetohydroxamic acid is a proven second line therapy. Cystinuria requires lifestyle modifications and may call for thiol-binding agents. Significant heterogeneity of the clinical population with stone disease has previously limited opportunities for large randomized controlled trials. However, as clinical phenotypes and genotypes are increasingly clarified, there are mounting opportunities for targeted randomized controlled trials in stone prevention. In the meantime, the currently available evidence for both lifestyle and pharmacologic interventions is reviewed herein. PMID- 28830865 TI - Suicide and suicide attempts among women in the Manitoba Mothers and Fetal Alcohol Spectrum Disorder cohort: a retrospective matched analysis using linked administrative data. AB - BACKGROUND: Women who give birth to children with fetal alcohol spectrum disorder (FASD) may be at increased risk for suicide; however, there are few data in this area. The objective of this study was to compare rates of suicide between women who had given birth to children with FASD and women who had not given birth to children with FASD during critical periods in their lives, including before pregnancy, during pregnancy, during the postpartum period (maternal death) and until the end of the study period. METHODS: We conducted a retrospective cohort analysis of women with children born in Manitoba between Apr. 1, 1984, and Mar. 31, 2012 in whom FASD was diagnosed between Apr. 1, 1999, and Mar. 31, 2012, with follow-up until Dec. 1, 2013 (FASD group; n = 702). We generated a comparison group of women who had not given birth to children with FASD (n = 2097), matched up to 1:3 on date of birth of the index child, socioeconomic status and region of residence. We used linked administrative data to investigate suicide attempt and completion rates in the 2 groups. Regression modelling produced relative rates (RRs) adjusted for socioeconomic status and age at birth of the index child and was used to assess suicide risk. RESULTS: The 2799 participants produced 40 390.21 person-years until the end of the study period. Compared to the comparison group, the FASD group had higher rates of suicide completion (adjusted RR 6.20 [95% confidence interval (CI) 2.36-16.31]), a higher number of women who attempted suicide after the postpartum period until the end of the study period (adjusted RR 4.62 [95% CI 2.53-8.43]) and a higher number of attempts after the postpartum period until the end of the study period (adjusted RR 3.92 [95% CI 2.30-6.09]). INTERPRETATION: This study identified a group of women with increased rates of social complexities, mental disorders and alcohol use, which places them at risk for suicide. Interventions are needed that screen for suicidal behaviour in women who are at high risk to consume alcohol during pregnancy and have mental disorders. PMID- 28830868 TI - Efficient and effective precepting of pharmacy students in acute and ambulatory care rotations: A Delphi expert panel study. AB - PURPOSE: Using the Delphi process, a panel of experienced preceptors achieved consensus on best practices to increase preceptor efficiency and effectiveness. METHODS: The Delphi panelists completed 3 survey rounds and a face-to-face meeting. Survey questions covered several topics, including preparation of students for rotations, preceptor efficiency and effectiveness, potential resident contributions to precepting, methods of developing critical-thinking skills and providing assessment and feedback, precepting time metrics, and barriers to preceptor effectiveness. Panel consensus was defined as agreement of >=80%. RESULTS: Fifteen of 36 invited preceptors (42%) completed all 3 survey rounds. The expert panel reached consensus on 6 essentials for effective rotations, 8 precepting contributions that could be made by appropriately trained residents, precepting barriers, 4 strategies for teaching critical thinking, and 5 valuable characteristics of the One Minute Preceptor model. Panelists reported on time spent with students presenting new patient cases (median, 10 minutes per case), time devoted to assessment of students' clinical performance (median, 22 minutes per student weekly), and time dedicated to student professional development (median, 20 minutes per student weekly). CONCLUSION: Important strategies for preceptors identified by the panel included (1) a thorough orientation to logistics, expectations, and scheduling of activities, (2) using appropriately trained residents in student training, (3) providing opportunities for critical thinking and therapeutic decision-making, (4) giving frequent, quality feedback on clinical activities, and (5) giving feedback to learners on a regular basis. PMID- 28830870 TI - Good practice or positive action? Using Q methodology to identify competing views on improving gender equality in academic medicine. AB - OBJECTIVES: The number of women entering medicine has increased significantly, yet women are still under-represented at senior levels in academic medicine. To support the gender equality action plan at one School of Medicine, this study sought to (1) identify the range of viewpoints held by staff on how to address gender inequality and (2) identify attitudinal barriers to change. DESIGN: Q methodology. 50 potential interventions representing good practice or positive action, and addressing cultural, organisational and individual barriers to gender equality, were ranked by participants according to their perception of priority. SETTING: The School of Medicine at the University of Leeds, UK. PARTICIPANTS: Fifty-five staff members were purposively sampled to represent gender and academic pay grade. RESULTS: Principal components analysis identified six competing viewpoints on how to address gender inequality. Four viewpoints favoured positive action interventions: (1) support careers of women with childcare commitments, (2) support progression of women into leadership roles rather than focus on women with children, (3) support careers of all women rather than just those aiming for leadership, and (4) drive change via high-level financial and strategic initiatives. Two viewpoints favoured good practice with no specific focus on women by (5) recognising merit irrespective of gender and (6) improving existing career development practice. No viewpoint was strongly associated with gender, pay grade or role; however, latent class analysis identified that female staff were more likely than male to prioritise the setting of equality targets. Attitudinal barriers to the setting of targets and other positive action initiatives were identified, and it was clear that not all staff supported positive action approaches. CONCLUSIONS: The findings and the approach have utility for those involved in gender equality work in other medical and academic institutions. However, the impact of such initiatives needs to be evaluated in the longer term. PMID- 28830869 TI - Anesthesia and bariatric surgery gut preparation alter plasma acylcarnitines reflective of mitochondrial fat and branched-chain amino acid oxidation. AB - The period around bariatric surgery offers a unique opportunity to characterize metabolism responses to dynamic shifts in energy, gut function, and anesthesia. We analyzed plasma acylcarnitines in obese women (n = 17) sampled in the overnight fasted/postabsorptive state approximately 1-2 wk before surgery (condition A), the morning of surgery (prior restriction to a 48-h clear liquid diet coupled in some cases a standard polyethylene glycol gut evacuation: condition B), and following induction of anesthesia (condition C). Comparisons tested if 1) plasma acylcarnitine derivatives reflective of fatty acid oxidation (FAO) and xenometabolism would be significantly increased and decreased, respectively, by preoperative gut preparation/negative energy balance (condition A vs. B), and 2) anesthesia would acutely depress markers of FAO. Acylcarnitines associated with fat mobilization and FAO were significantly increased in condition B: long-chain acylcarnitines (i.e., C18:1, ~70%), metabolites from active but incomplete FAO [i.e., C14:1 (161%) and C14:2 (102%)] and medium- to short-chain acylcarnitines [i.e., C2 (91%), R-3-hydroxybutyryl-(245%), C6 (45%), and cis-3,4-methylene-heptanoyl-(17%), etc.]. Branched-chain amino acid markers displayed disparate patterns [i.e., isobutyryl-(40% decreased) vs. isovaleryl carnitine (51% increased)]. Anesthesia reduced virtually every acylcarnitine. These results are consistent with a fasting-type metabolic phenotype coincident with the presurgical "gut preparation" phase of bariatric surgery, and a major and rapid alteration of both fat and amino acid metabolism with onset of anesthesia. Whether presurgical or anesthesia-associated metabolic shifts in carnitine and fuel metabolism impact patient outcomes or surgical risks remains to be evaluated experimentally. PMID- 28830871 TI - Cell-Free Circulating DNA Integrity Based on Peripheral Blood as a Biomarker for Diagnosis of Cancer: A Systematic Review. AB - Background: Cell-free DNA integrity (cfDI) has been identified as a potential diagnostic biomarker for different types of cancer, suggesting the importance of liquid biopsy.Methods: This systematic review aims to assess the diagnostic performance of cfDI in cancer. After an extensive search of literature published through February 28, 2017, 25 articles that included 40 studies were identified. The descriptions of all the studies were analyzed. The sensitivity, specificity, positive and negative likelihood ratios, diagnostic ORs, weighted symmetric summary receiver operating characteristic curve, and the area under the curve (AUC) of cfDI in these studies were calculated.Results: Aberrant results of cfDI were observed. Some studies observed an increased cfDI in cancer patients, while some studies confirmed a decreased cfDI compared with healthy or benign controls.Conclusions: This review suggests that cfDI is controversial as a blood based biomarker of cancers, although the sensitivity and AUC were relatively high.Impact: cfDI shows heterogeneity between different studies; more perspective studies are needed to further assess its diagnostic performance, especially with other markers in combination. Cancer Epidemiol Biomarkers Prev; 26(11); 1595-602. (c)2017 AACR. PMID- 28830872 TI - Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations. AB - Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3alpha,17beta-diol glucuronide (3alpha-diol G) explained the highest variance of tissue concentrations of 3alpha-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660-6. (c)2017 AACR. PMID- 28830873 TI - Vasectomy and Risk of Prostate Cancer in a Screening Trial. AB - Background: Vasectomy has been implicated as a risk factor for prostate cancer in multiple epidemiologic studies over the past 25 years. Whether this relationship is causal remains unclear. This study examines the association between vasectomy and prostate cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, which randomized men to usual care or annual prostate cancer screening.Methods: We performed a retrospective analysis of 13-year screening and outcomes data from the PLCO trial. Multivariable Cox proportional hazards regression stratified by study arm and age at vasectomy was performed.Results: There was an increased risk of prostate cancer in men who had undergone a vasectomy and were randomized to the usual care arm of the study (adjusted HR, 1.11; 95% confidence interval, 1.03-1.20; P = 0.008). There was no association between vasectomy and diagnosis of prostate cancer in men randomized to the prostate cancer screening arm. Only men undergoing vasectomy at an older age in the usual care arm of the study, but not the prostate cancer screening arm, were at increased risk of being diagnosed with prostate cancer.Conclusions: Vasectomy was not associated with prostate cancer risk among men who were screened for prostate cancer as part of a clinical trial, but was associated with prostate cancer detection in men receiving usual care.Impact: The positive association between vasectomy and prostate cancer is likely related to increased detection of prostate cancer based on patterns of care rather than a biological effect of vasectomy on prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(11); 1653-9. (c)2017 AACR. PMID- 28830874 TI - Single-Nucleotide Polymorphisms in Vitamin D-Related Genes May Modify Vitamin D Breast Cancer Associations. AB - Background: We previously observed that high serum 25-hydroxyvitamin D (25(OH)D; >38.0 ng/mL) was inversely associated with breast cancer. Here, we examined effect modification by SNPs in vitamin D-related genes.Methods: The Sister Study enrolled 50,884 U.S. women who had a sister with breast cancer, but who had never had breast cancer themselves. Using a case-cohort design, we compared 1,524 women who developed breast cancer within 5 years to 1,810 randomly selected participants. We estimated ratios of HRs (RHRs) for the 25(OH)D-breast cancer association per copy of the minor allele using Cox proportional hazards models. We considered 82 SNPs in 7 vitamin D-related genes (CYP24A1, CYP27B1, CYP2R1, GC, DHCR7/NADSYN1, RXRA, and VDR). We also tested gene-based interactions with 25(OH)D.Results: The SNP with the smallest interaction P value was rs4328262 in VDR (P = 0.0008); the 25(OH)D HR was 0.92 [95% confidence interval (CI), 0.68 1.24] among those homozygous for the common allele, and the minor allele was estimated to decrease the HR by 33% per copy (RHR = 0.67; 95% CI, 0.53-0.85). Five other VDR SNPs showed evidence of interaction at P < 0.05, as did one SNP in CYP2R1 and one in RXRA As a group, the 82 SNPs showed evidence of multiplicative interaction with 25(OH)D (P = 0.04). In gene-based tests, only VDR showed strong evidence of interaction (P = 0.04).Conclusions: SNPs in vitamin D-related genes may modify the association between serum 25(OH)D and breast cancer.Impact: This work strengthens the evidence for protective effects of vitamin D. Cancer Epidemiol Biomarkers Prev; 26(12); 1761-71. (c)2017 AACR. PMID- 28830876 TI - Mobile phone messaging delivering encouragement, reminders and education increases patient compliance with recommended exercise and results in positive short-term health behaviours. PMID- 28830875 TI - Influences of Breakfast on Clock Gene Expression and Postprandial Glycemia in Healthy Individuals and Individuals With Diabetes: A Randomized Clinical Trial. AB - OBJECTIVE: The circadian clock regulates glucose metabolism by mediating the activity of metabolic enzymes, hormones, and transport systems. Breakfast skipping and night eating have been associated with high HbA1c and postprandial hyperglycemia after lunch and dinner. Our aim was to explore the acute effect of breakfast consumption or omission on glucose homeostasis and clock gene expression in healthy individuals and individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a crossover design, 18 healthy volunteers and 18 volunteers with 14.5 +/- 1.5 years diabetes, BMI 30.7 +/- 1.1 kg/m2, and HbA1c 7.6 +/- 0.1% (59.6 +/- 0.8 mmol/mol) were randomly assigned to a test day with breakfast and lunch (YesB) and a test day with only lunch (NoB). Postprandial clock and clock-controlled gene expression, plasma glucose, insulin, intact glucagon-like peptide 1 (iGLP-1), and dipeptidyl peptidase IV (DPP-IV) plasma activity were assessed after breakfast and lunch. RESULTS: In healthy individuals, the expression level of Per1, Cry1, Roralpha, and Sirt1 was lower (P < 0.05) but Clock was higher (P < 0.05) after breakfast. In contrast, in individuals with type 2 diabetes, Per1, Per2, and Sirt1 only slightly, but significantly, decreased and Roralpha increased (P < 0.05) after breakfast. In healthy individuals, the expression level of Bmal1, Roralpha, and Sirt1 was higher (P < 0.05) after lunch on YesB day, whereas the other clock genes remained unchanged. In individuals with type 2 diabetes, Bmal1, Per1, Per2, Rev-erbalpha, and Ampk increased (P < 0.05) after lunch on the YesB day. Omission of breakfast altered clock and metabolic gene expression in both healthy and individuals with type 2 diabetes. CONCLUSIONS: Breakfast consumption acutely affects clock and clock-controlled gene expression leading to normal oscillation. Breakfast skipping adversely affects clock and clock-controlled gene expression and is correlated with increased postprandial glycemic response in both healthy individuals and individuals with diabetes. PMID- 28830877 TI - Critical care nursing: caring for patients who are agitated. AB - EBN engages readers through a range of Online social media activities to debate issues important to nurses and nursing. EBN Opinion papers highlight and expand on these debates. PMID- 28830879 TI - Outcomes Associated With Extraction Versus Capping and Abandoning Pacing and Defibrillator Leads. AB - BACKGROUND: Lead management is an increasingly important aspect of care in patients with cardiac implantable electronic devices; however, relatively little is known about long-term outcomes after capping and abandoning leads. METHODS: Using the 5% Medicare sample, we identified patients with de novo cardiac implantable electronic device implantations between January 1, 2000, and December 31, 2013, and with a subsequent lead addition or extraction >=12 months after the de novo implantation. Patients who underwent extraction for infection were excluded. Using multivariable Cox proportional hazards models, we compared cumulative incidence of all-cause mortality, device-related infection, device revision, and lead extraction at 1 and 5 years for the extraction versus the cap and abandon group. RESULTS: Among 6859 patients, 1113 (16.2%) underwent extraction, whereas 5746 (83.8%) underwent capping and abandonment. Extraction patients tended to be younger (median, 78 versus 79 years; P<0.0001), were less likely to be male (65% versus 68%; P=0.05), and had shorter lead dwell time (median, 3.0 versus 4.0 years; P<0.0001) and fewer comorbidities. Over a median follow-up of 2.4 years (25th, 75th percentiles, 1.0, 4.3 years), the overall 1 year and 5-year cumulative incidence of mortality was 13.5% (95% confidence interval [CI], 12.7-14.4) and 54.3% (95% CI, 52.8-55.8), respectively. Extraction was associated with a lower risk of device infection at 5 years relative to capping (adjusted hazard ratio, 0.78; 95% CI, 0.62-0.97; P=0.027). There was no association between extraction and mortality, lead revision, or lead extraction at 5 years. CONCLUSIONS: Elective lead extraction for noninfectious indications had similar long-term survival to that for capping and abandoning leads in a Medicare population. However, extraction was associated with lower risk of device infections at 5 years. PMID- 28830880 TI - Alternative diagnoses in patients with chronic back pain not diagnosed with axial spondyloarthritis: data from the SPACE cohort. PMID- 28830881 TI - Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study. AB - OBJECTIVES: To determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout. METHODS: People, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was >=6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24. RESULTS: The mean (SE) change in SU from month 12 to 24 was -1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups. CONCLUSIONS: The majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment. TRIAL REGISTRATION NUMBER: ACTRN12611000845932. PMID- 28830878 TI - Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells. AB - Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238-47. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 1201. PMID- 28830882 TI - Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series. AB - BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with numerous cancers. However, these therapies are associated with immune-related adverse events (irAEs), which are inflammatory side effects potentially affecting any organ. Cases of ICI-induced inflammatory arthritis have also been reported. In general, mild irAEs are treated with corticosteroids, while tumour necrosis factor-alpha (TNFalpha) inhibitors are reserved for refractory cases. However, prolonged use of TNFalpha inhibitor (TNFalphai) can induce widespread, significant immunosuppression, which can negatively impact the antitumour efficacy of ICI therapy. Therefore, in clinical scenarios where patients develop severe immunotherapy-induced irAEs, an unmet need exists for alternative therapeutic strategies that are effective and without immune dampening effects. CASE REPORTS: The anti-interleukin (IL)-6 receptor antibody, tocilizumab, is a biological agent Food and Drug Administration approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Here, we report on three patients who developed severe polyarthritis while receiving ICI therapy and were treated with tocilizumab. All three patients demonstrated significant clinical improvement; one patient maintained a durable antitumour response derived from checkpoint inhibition. CONCLUSIONS: These three cases suggest that anti-IL-6 receptor antibody may be an effective alternative to corticosteroids or TNFalphai for the treatment of arthritis irAEs. PMID- 28830883 TI - Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: an updated meta-analysis. PMID- 28830884 TI - Shared epitope positivity is related to efficacy of abatacept in rheumatoid arthritis. PMID- 28830885 TI - Concerns on glucocorticoid use for Japanese patients with established rheumatoid arthritis. PMID- 28830886 TI - Suicide on TV: minimising the risk to vulnerable viewers. PMID- 28830887 TI - HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies. AB - Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan-HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti-CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors. PMID- 28830888 TI - NOX5 and p22phox are 2 novel regulators of human monocytic differentiation into dendritic cells. AB - Dendritic cells (DCs) are a heterogeneous population of professional antigen presenting cells and are key cells of the immune system, acquiring different phenotypes in accordance with their localization during the immune response. A subset of inflammatory DCs is derived from circulating monocytes (Mo) and has a key role in inflammation and infection. The pathways controlling Mo-DC differentiation are not fully understood. Our objective was to investigate the possible role of nicotinamide adenine dinucleotide phosphate reduced form oxidases (NOXs) in Mo-DC differentiation. In this study, we revealed that Mo-DC differentiation was inhibited by NOX inhibitors and reactive oxygen species scavengers. We show that the Mo-DC differentiation was dependent on p22phox, and not on gp91phox/NOX2, as shown by the reduced Mo-DC differentiation observed in chronic granulomatous disease patients lacking p22phox. Moreover, we revealed that NOX5 expression was strongly increased during Mo-DC differentiation, but not during Mo-macrophage differentiation. NOX5 was expressed in circulating myeloid DC, and at a lower level in plasmacytoid DC. Interestingly, NOX5 was localized at the outer membrane of the mitochondria and interacted with p22phox in Mo-DC. Selective inhibitors and small interfering RNAs for NOX5 indicated that NOX5 controlled Mo-DC differentiation by regulating the JAK/STAT/MAPK and NFkappaB pathways. These data demonstrate that the NOX5-p22phox complex drives Mo-DC differentiation, and thus could be critical for immunity and inflammation. PMID- 28830890 TI - Increased risk of leukemia among sickle cell disease patients in California. PMID- 28830891 TI - Autoimmune HIT due to apheresis catheter heparin flushes for stem cell harvesting before autotransplantation for myeloma. PMID- 28830892 TI - Life-threatening intraoperative anaphylaxis as a result of chlorhexidine present in Instillagel. AB - A 70-year-old man with left lower limb critical ischaemia was admitted to our vascular unit for a femoral-popliteal bypass. He had experienced a skin reaction to chlorhexidine 6 months previously during an angioplasty procedure. After intubation, once in the operating theatre, the patient had a urinary catheter inserted using Instillagel. Around 30 min later the patient had a full-blown anaphylactic reaction that required aggressive medical management and the abandoning of surgery. Postoperative allergy testing confirmed that the suspected primary trigger for the anaphylaxis was indeed chlorhexidine, which was present in Instillagel. The patient was also found to have allergies to atracurium and teicoplanin, which had been given on induction. This case report highlights the importance of recognising that Instillagel contains chlorhexidine, and that indeed intraurethral use during routine urinary catheterisation can be a cause of life-threatening anaphylaxis. PMID- 28830889 TI - Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. AB - Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age <=65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8+ T cells. Long-term OS was correlated with interferon-gamma+ and tumor necrosis factor-alpha+ WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8+ T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224. PMID- 28830893 TI - A typical presentation of a hepatocellular carcinoma in a middle-aged patient. PMID- 28830895 TI - Isolated tricuspid valve Libman-Sacks endocarditis in a patient with antiphospholipid antibody syndrome. PMID- 28830896 TI - Patient with Niemann-Pick disease type C: over 20 years' follow-up. AB - We report a 37-year-old woman with Niemann-Pick disease type C (NPC) 1. At the age of 8 years, she presented slow running followed by both fingers dystonia at the age of 10 years. At the age of 16 years, she developed declined scholastic achievement. On her first visit at the age of 17 years, she showed dystonia, ataxic gait and vertical supranuclear gaze palsy. We suspected it was NPC. She presented atrophies in the frontal lobes, brainstem and cerebellum in a brain MRI. She presented hepatomegalies and splenomegalies in an abdominal CT. At the age of 26 years, she undertook perpetually tracheal fistula because of recurrent aspiration pneumonia. Diagnosis of NPC1 was made by filipin staining and existence of foamy cells in the bone marrow and NPC1 gene analysis. We obtained informed consent of genetic analysis. Miglustat therapy was started at the age of 32 years. Improvements in swallowing capacity and in muscle tonus were seen. PMID- 28830894 TI - Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance. AB - Shc homology 2-containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3 kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2Delta/+). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2Delta/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2Delta/+ mice had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase, although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2Delta/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine induced vasodilation was also impaired in ECSHIP2Delta/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2Delta/+ ECs and was suppressed by PI3K and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction. PMID- 28830897 TI - TSH and PRL, side-effect markers in aripiprazole treatment: adjunctive aripiprazole-induced thyrotropin oversuppression in a young man with schizophrenia. AB - A 26-year-old Japanese man was admitted to our unit with exacerbated paranoid schizophrenia. Prior to his admission, daily administration of olanzapine had been sufficient to maintain a partial remission of his schizophrenia, but due to an exacerbation of his delusions, he had then also been prescribed aripiprazole, which had been followed by no improvement in symptoms and a gradual further exacerbation of auditory delusions. Physical examinations, brain MRI and neurophysiological assessment were unremarkable. Blood analysis, however, revealed extremely low thyroid-stimulating hormone (TSH) and prolactin-releasing hormone (PRL) concentration. Interestingly, after aripiprazole discontinuation, he returned to partial remission with an increase in plasma TSH and PRL concentration. PMID- 28830898 TI - Primary gastric Burkitt lymphoma: a rare cause of life-threatening haematemesis. AB - Lymphomas are the second most common gastric malignancy following gastric adenocarcinoma. The majority of gastric lymphomas are either mucosa-associated lymphoid tissue lymphomas or diffuse large B-cell lymphomas. Primary gastric Burkitt lymphoma is a subtype of non-Hodgkin's lymphoma and represents an aggressive and rare malignancy with only a small number of cases reported worldwide. Clinical and radiological presentation is non-specific and mimics other gastric lymphomas. Diagnosis is established with pathological evaluation. Due to the paucity of cases, treatment of this condition is not well studied and is extrapolated from paediatric and adult literature of Burkitt lymphoma not isolated to the stomach. We present the case of a male patient with primary gastric Burkitt lymphoma who initially presented with life-threatening haematemesis, later achieving complete remission with treatment. We discuss the epidemiology, presentation and management of gastric Burkitt lymphoma. PMID- 28830899 TI - Primary adrenal lymphoma with initial presentation concerning for bilateral adrenal pheochromocytomas. AB - Primary adrenal non-Hodgkin's lymphoma is rarely encountered. Clinical presentation is non-specific with fatigue, abdominal pain and B-symptoms being more commonly reported. We report a case of primary bilateral adrenal lymphoma who initially presented with clinical features suspicious for pheochromocytoma. The patient was recently diagnosed with hypertension and had a family history of early ischaemic heart disease. Plasma free metanephrines were also elevated. Pheochromocytoma was deemed unlikely following multiple investigations and the diagnosis of lymphoma was made following adrenal biopsy. Partial response was noted on positron emission tomography CT scan following four cycles of chemotherapy but failed to remit after six cycles of chemotherapy. Subsequently, he received 20 fractions of radiation to his adrenal glands and is now awaiting further imaging. The presentation of primary adrenal lymphoma can be variable and given that the diagnosis is obtained through tissue sampling, pheochromocytoma should be excluded due to risk of a potentially fatal adrenergic crisis. PMID- 28830900 TI - Mycoplasma pneumoniae-induced rash and mucositis: a recently described entity. AB - Mycoplasmapneumoniae is a common cause of respiratory infections. Although most cases are mild, some patients have extrapulmonary complications including mucocutaneous eruptions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and erythemamultiforme (EM). Recently, a new entity, called M. pneumoniae-induced rash and mucositis (MIRM) was described. The authors present a clinical case difficult to classify attending to the classical classification of epidermolytic syndromes that meets the criteria proposed for the diagnosis of MIRM. The mucocutaneous disease associated with M. pneumoniae presents predominant mucositis, with scarce or absent cutaneous involvement. Because of the distinct morphology, pathophysiology and benign clinical course, MIRM should be considered as a new entity, distinct from SJS/TEN and EM. PMID- 28830901 TI - Drug rash with eosinophilia and systemic symptoms (DRESS) caused by phenytoin. AB - Drug rash with eosinophilia and systemic symptoms (DRESS) is a rare but potentially life-threatening condition with high mortality. Diagnosis is challenging due to variable clinical presentation and a protracted latency period following initiation of the offending drug. DRESS is a complex interplay that starts by introduction of the offending drug, reactivation of viruses and activation of the immune system. Herpes virus reactivation is considered a diagnostic marker and indicator of illness severity. Prompt recognition and the removal of offending agent remain the key to successful treatment. In cases of severe organ involvement, corticosteroids, immunoglobulins, antiviral and specialist consultation may be helpful. Here we present a case of a 36-year-old African-American male who presented with symptoms mimicking sepsis with an associated skin eruption that was diagnosed as DRESS. PMID- 28830902 TI - Zoster vaccine-associated primary varicella infection in an immunocompetent host. AB - A 64-year-old immunocompetent man developed a widespread pruritic and vesicular rash 2 weeks after receiving the zoster vaccine (Zostavax). He had fever, bandaemia with normal total white blood cell count and mild transaminitis. PCR testing of serum and skin was positive for varicella zoster virus (VZV), while serum VZV IgG was negative. The analysis of single nucleotide polymorphism by PCR and sequencing from the skin swab was consistent with the vaccine strain. The patient received 1 week of intravenous acyclovir and was discharged after all lesions had crusted. He continues to do well on follow-up with no significant complications. PMID- 28830903 TI - Rose thorn injury. PMID- 28830904 TI - Optic disc coloboma with pit treated as glaucoma: diagnostic utility of ultrasound and swept source optical coherence tomography. PMID- 28830905 TI - Large atrial mass in a patient with Crohn's disease: organised thrombus mimicking a myxoma. PMID- 28830906 TI - Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant. AB - BACKGROUND: Heterozygous mutations in COL10A1 underlie metaphyseal chondrodysplasia, Schmid type (MCDS), an autosomal dominant skeletal dysplasia. OBJECTIVE: To identify the causative variant in a large consanguineous Pakistani family with severe skeletal dysplasia and marked lower limb deformity. METHODS: Whole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. In silico variant pathogenicity predictions and amino acid conservation analyses were performed. RESULTS: A homozygous c.133 C>T (p.Pro45Ser) variant was identified in COL10A1 in all six severely affected individuals (adult heights 119-130 cm, mean ~-6.33 SD). The individuals heterozygous for the variant had mild phenotype of short stature (adult heights 140-162 cm, mean ~-2.15 SD) but no apparent skeletal deformities. The variant was predicted to be pathogenic by in silico prediction tools and was absent from public databases and hundred control chromosomes. Pro45 is conserved in orthologues and is located in the non-collagenous 2 domain of COL10A1, variants of which have never been associated with skeletal dysplasia. CONCLUSIONS: This first report of individuals with a homozygous variant in COL10A1 defines a new type of autosomal recessive skeletal dysplasia. The observations in COL10A1 variant carriers suggest a phenotypic overlap between the mildest forms of MCDS and idiopathic short stature. PMID- 28830907 TI - Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction. AB - Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII containing HDL (-28% and -44.8%, respectively) and of medium-sized HDL (-10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (-18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (-25.5, -41.1 and -30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1 CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction. PMID- 28830908 TI - Preservation of bacterial DNA in 10-year-old guaiac FOBT cards and FIT tubes. PMID- 28830909 TI - Efforts to enhance blood stem cell engraftment: Recent insights from zebrafish hematopoiesis. AB - Hematopoietic stem cell transplantation (HSCT) is an important therapy for patients with a variety of hematological malignancies. HSCT would be greatly improved if patient-specific hematopoietic stem cells (HSCs) could be generated from induced pluripotent stem cells in vitro. There is an incomplete understanding of the genes and signals involved in HSC induction, migration, maintenance, and niche engraftment. Recent studies in zebrafish have revealed novel genes that are required for HSC induction and niche regulation of HSC homeostasis. Manipulation of these signaling pathways and cell types may improve HSC bioengineering, which could significantly advance critical, lifesaving HSCT therapies. PMID- 28830910 TI - Redefining thymus medulla specialization for central tolerance. AB - During alphabetaT cell development, the thymus medulla represents an essential microenvironment for T cell tolerance. This functional specialization is attributed to its typical organized topology consisting of a branching structure that contains medullary thymic epithelial cell (mTEC) networks to support negative selection and Foxp3+ T-regulatory cell (T-reg) development. Here, by performing TEC-specific deletion of the thymus medulla regulator lymphotoxin beta receptor (LTbetaR), we show that thymic tolerance mechanisms operate independently of LTbetaR-mediated mTEC development and organization. Consistent with this, mTECs continue to express Fezf2 and Aire, regulators of intrathymic self-antigens, and support T-reg development despite loss of LTbetaR-mediated medulla organogenesis. Moreover, we demonstrate that LTbetaR controls thymic tolerance by regulating the frequency and makeup of intrathymic dendritic cells (DCs) required for effective thymocyte negative selection. In all, our study demonstrates that thymus medulla specialization for thymic tolerance segregates from medulla organogenesis and instead involves LTbetaR-mediated regulation of the thymic DC pool. PMID- 28830911 TI - Nitric oxide stimulates cellular degradation of human CYP51A1, the highly conserved lanosterol 14alpha-demethylase. AB - Nitric oxide (NO) is known to down-regulate drug-metabolizing cytochrome P450 enzymes in an enzyme-selective manner. Ubiquitin-proteasome-dependent and independent pathways have been reported. Here, we studied the regulation of expression of human CYP51A1, the lanosterol 14alpha-demethylase required for synthesis of cholesterol and other sterols in mammals, which is found in every kingdom of life. In Huh7 human hepatoma cells, treatment with NO donors caused rapid post-translational down-regulation of CYP51A1 protein. Human NO synthase (NOS)-dependent down-regulation was also observed in cultured human hepatocytes treated with a cytokine mixture and in Huh7 cells expressing human NOS2 under control of a doxycycline-regulated promoter. This down-regulation was partially attenuated by proteasome inhibitors, but only trace levels of ubiquitination could be found. Further studies with inhibitors of other proteolytic pathways suggest a possible role for calpains, especially when the proteasome is inhibited. NO donors also down-regulated CYP51A1 mRNA in Huh7 cells, but to a lesser degree, than the down-regulation of the protein. PMID- 28830912 TI - Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer. AB - OBJECTIVE: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. DESIGN: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets. RESULTS: By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer. CONCLUSIONS: BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453). TRIAL REGISTRATION NUMBER: NCT02884453; Pre results. PMID- 28830913 TI - Risk Factors for Respiratory Decompensation Among Healthy Infants With Bronchiolitis. AB - BACKGROUND: Although most children with bronchiolitis only require supportive care, some decompensate and require ventilatory support. We examined predictors of respiratory decompensation among hospitalized children to identify which patients may benefit from expectant monitoring. METHODS: We examined children <=24 months old with bronchiolitis admitted to the general infant and toddler floor. Children with pneumonia or comorbidities were excluded. Demographic and clinical characteristics were abstracted from a clinical database and medical records. Respiratory decompensation was defined as the need for initiating high flow nasal cannula oxygen, continuous positive airway pressure, nasal intermittent mandatory ventilation, bilevel positive airway pressure, or intubation. A multivariable logistic regression model was constructed to identify independent predictors of respiratory decompensation. RESULTS: A total of 1217 children were included. The median age was 6.9 months, 41% were girls, 49% were Hispanic, 21% were black, and 18% were premature. Significant independent predictors of respiratory decompensation were age <=3 months (odds ratio [OR]: 3.25; 95% confidence interval [CI]: 2.09-5.07), age 3 to 6 months (OR: 1.76; 95% CI: 1.04-3.0), black race (OR: 1.94; 95% CI: 1.27-2.95), emergency department hypoxemia (OR: 2.34; 95% CI: 1.30-4.21), and retractions or accessory muscle use (OR: 2.26; 95% CI: 1.48-3.46). Children with 0 of 4 predictors were found to have a low risk of decompensation (3%). CONCLUSIONS: Young age, black race, emergency department hypoxemia, and retractions or accessory muscle use were associated with respiratory decompensation in children with bronchiolitis. These factors should be considered at presentation, as they identify children who require a higher level of respiratory monitoring and support and others who may not benefit. PMID- 28830915 TI - In This Issue of Diabetes. PMID- 28830917 TI - Comment on Rodriguez-Calvo et al. Increase in Pancreatic Proinsulin and Preservation of beta-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset. Diabetes 2017;66:1334-1345. PMID- 28830918 TI - Response to Comment on Rodriguez-Calvo et al. Increase in Pancreatic Proinsulin and Preservation of beta-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset. Diabetes 2017;66:1334-1345. PMID- 28830919 TI - UK doctor is suspended after certifying taxi drivers without seeing medical records. PMID- 28830914 TI - N-Acetyl-l-Cysteine Protects Astrocytes against Proteotoxicity without Recourse to Glutathione. AB - N-acetyl-l-cysteine (NAC) exhibits protective properties in brain injury models and has undergone a number of clinical trials. Most studies of NAC have focused on neurons. However, neuroprotection may be complemented by the protection of astrocytes because healthier astrocytes can better support the viability of neurons. Here, we show that NAC can protect astrocytes against protein misfolding stress (proteotoxicity), the hallmark of neurodegenerative disorders. Although NAC is thought to be a glutathione precursor, NAC protected primary astrocytes from the toxicity of the proteasome inhibitor MG132 without eliciting any increase in glutathione. Furthermore, glutathione depletion failed to attenuate the protective effects of NAC. MG132 elicited a robust increase in the folding chaperone heat shock protein 70 (Hsp70), and NAC mitigated this effect. Nevertheless, three independent inhibitors of Hsp70 function ablated the protective effects of NAC, suggesting that NAC may help preserve Hsp70 chaperone activity and improve protein quality control without need for Hsp70 induction. Consistent with this view, NAC abolished an increase in ubiquitinated proteins in MG132-treated astrocytes. However, NAC did not affect the loss of proteasome activity in response to MG132, demonstrating that it boosted protein homeostasis and cell viability without directly interfering with the efficacy of this proteasome inhibitor. The thiol-containing molecules l-cysteine and d-cysteine both mimicked the protective effects of NAC, whereas the thiol-lacking molecule N acetyl-S-methyl-l-cysteine failed to exert protection or blunt the rise in ubiquitinated proteins. Collectively, these findings suggest that the thiol group in NAC is required for its effects on glial viability and protein quality control. PMID- 28830920 TI - Tracking of BMI z Scores for Severe Obesity. AB - BACKGROUND: Although the Centers for Disease Control (CDC) growth charts are widely used in studies of childhood obesity, BMI z scores are known to be inaccurate at values greater than the 97th percentile. METHODS: We used longitudinal data from 6994 children in the Bogalusa Heart Study who were examined multiple times to compare tracking of 3 BMI metrics: BMI-for-sex/age z score (BMIz), BMI expressed as a percentage of the 95th percentile (%BMIp95), and levels of BMI z score that adjust for the compression of very high z scores (adjusted z score [BMIaz]). The later 2 metrics, unlike BMIz, do not have an upper limit. The mean interval between examinations was 2.8 years. We were particularly interested in these metrics among children with obesity or severe obesity (%BMIp95 >=120%). RESULTS: Although there was little difference in the tracking of the 3 metrics in the overall sample, among 247 children with severe obesity, the correlation of BMIz levels between examinations (r = 0.46) was substantially weaker than those for BMIaz and %BMIp95 (r = 0.65 and 0.61). Age stratified analyses indicated that the weak tracking of BMIz was particularly evident before the age of 10 years (r = 0.36 vs 0.57 and 0.60). Several children with severe obesity showed BMIz decreases between examinations despite having BMI increases of over 5. CONCLUSIONS: Among children with severe obesity, the tracking of BMIz is weak. This is because of the constraints in converting very high BMIs into z scores based on the CDC growth charts. Rather than using BMIz, it would be preferable to express very high BMIs relative to the CDC 95th percentile or to use BMIaz. PMID- 28830921 TI - Time to Adopt New Measures of Severe Obesity in Children and Adolescents. PMID- 28830922 TI - Deletion of 11q in Neuroblastomas Drives Sensitivity to PARP Inhibition. AB - Purpose: Despite advances in multimodal therapy, neuroblastomas with hemizygous deletion in chromosome 11q (20%-30%) undergo consecutive recurrences with poor outcome. We hypothesized that patients with 11q-loss may share a druggable molecular target(s) that can be exploited for a precision medicine strategy to improve treatment outcome.Experimental Design: SNP arrays were combined with next generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma etiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both in vitro and in vivo models.Results: We detected that ATM haploinsufficiency and ATM allelic variants are common genetic hallmarks of 11q-loss neuroblastomas. On the basis of the distinct DNA repair pathways triggered by ATM and PARP, we postulated that 11q-loss may define a subgroup of neuroblastomas with higher sensitivity to PARP inhibitors. Noteworthy, concomitant treatment with olaparib and DNA alkylating agent temozolomide potently inhibited growth of cell lines harboring 11q-loss. This drug synergism was less potent when temozolomide was exchanged for cisplatin or irinotecan. Intact 11q cells concomitantly treated with ATM inhibitor displayed growth arrest and enhanced apoptosis, revealing a role for ATM in the mechanism that mediates sensitivity to temozolomide-olaparib. Interestingly, functional TP53 is required for efficacy of this treatment. In an in vivo model, coadministration of temozolomide-olaparib resulted in sustained xenograft regression.Conclusions: Our findings reveal a potent synergism between temozolomide and olaparib in treatment of neuroblastomas with 11q-loss and provide a rationale for further clinical investigation. Clin Cancer Res; 23(22); 6875-87. (c)2017 AACR. PMID- 28830923 TI - Frequent Genetic Aberrations in the CDK4 Pathway in Acral Melanoma Indicate the Potential for CDK4/6 Inhibitors in Targeted Therapy. AB - Purpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma.Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a , by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated.Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss.Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946-57. (c)2017 AACR. PMID- 28830924 TI - CONE: Community Oriented Network Estimation Is a Versatile Framework for Inferring Population Structure in Large-Scale Sequencing Data. AB - Estimation of genetic population structure based on molecular markers is a common task in population genetics and ecology. We apply a generalized linear model with LASSO regularization to infer relationships between individuals and populations from molecular marker data. Specifically, we apply a neighborhood selection algorithm to infer population genetic structure and gene flow between populations. The resulting relationships are used to construct an individual level population graph. Different network substructures known as communities are then dissociated from each other using a community detection algorithm. Inference of population structure using networks combines the good properties of: (i) network theory (broad collection of tools, including aesthetically pleasing visualization), (ii) principal component analysis (dimension reduction together with simple visual inspection), and (iii) model-based methods (e.g., ancestry coefficient estimates). We have named our process CONE (for community oriented network estimation). CONE has fewer restrictions than conventional assignment methods in that properties such as the number of subpopulations need not be fixed before the analysis and the sample may include close relatives or involve uneven sampling. Applying CONE on simulated data sets resulted in more accurate estimates of the true number of subpopulations than model-based methods, and provided comparable ancestry coefficient estimates. Inference of empirical data sets of teosinte single nucleotide polymorphism, bacterial disease outbreak, and the human genome diversity panel illustrate that population structures estimated with CONE are consistent with the earlier findings. PMID- 28830925 TI - Duplication and Sub/Neofunctionalization of Malvolio, an Insect Homolog of Nramp, in the Subsocial Beetle Nicrophorus vespilloides. AB - With growing numbers of sequenced genomes, increasing numbers of duplicate genes are being uncovered. Here we examine Malvolio, a gene in the natural resistance associated macrophage protein (Nramp) family, that has been duplicated in the subsocial beetle, Nicrophorus vespilloides, which exhibits advanced parental behavior. There is only one copy of Mvl in honey bees and Drosophila, whereas in vertebrates there are two copies that are subfunctionalized. We first compared amino acid sequences for Drosophila, beetles, mice, and humans. We found a high level of conservation between the different species, although there was greater variation in the C-terminal regions. A phylogenetic analysis across multiple insect orders suggested that Mvl has undergone several independent duplications. To examine the potential for different functions where it has been duplicated, we quantified expression levels of Mvl1 and Mvl2 in eight tissues in N. vespilloides We found that while Mvl1 was expressed ubiquitously, albeit at varying levels, expression of Mvl2 was limited to brain and midgut. Because Mvl has been implicated in behavior, we examined expression during different behavioral states that reflected differences in opportunity for social interactions and expression of parental care behaviors. We found differing expression patterns for the two copies, with Mvl1 increasing in expression during resource preparation and feeding offspring, and Mvl2 decreasing in these same states. Given these patterns of expression, along with the protein analysis, we suggest that Mvl in N. vespilloides has experienced sub/neofunctionalization following its duplication, and may be evolving differing and tissue-specific roles in behavior and physiology. PMID- 28830926 TI - Maximum Voluntary Ventilation in a Population Residing at 2,240 Meters Above Sea Level. AB - BACKGROUND: Measured maximum voluntary ventilation (MVV) correlates with maximum ventilatory capacity during exercise. As a shortcut, MVV is often estimated by multiplying measured FEV1 times 35 or 40, but this index varies with altitude due to reduced air density. The objective was to describe MVV in healthy individuals residing at 2,240 m above sea level and compare it with the reference values customarily employed. METHODS: We recruited a convenience sample of respiratory healthy, non-obese volunteers >10 y of age who had resided for >2 y in Mexico City. All participants performed forced spirometry and MVV according to current standards. Multiple regression models were fitted, including age, height, and measured FEV1, separately for males and females to obtain reference values. The impact of lower air density on MVV at this elevation was estimated from the reported increase in peak flow in relation to altitude. RESULTS: We studied 381 individuals (210 females [55.1%]) age 10-80 y with a mean MVV of 145.6 +/- 48 L/min. Both FEV1 * 35 and FEV1 * 40 underestimated the MVV observed: in males by approximately 26% and in females by approximately 10%. MVV for our population approached FEV1 * 45 (98 +/- 15.6% of real MVV). Multiple regression models including height, weight, and measured FEV1 explained 70% of residual variability once sex was taken into account. CONCLUSIONS: At an altitude of 2,240 m, MVV is about 45 times the measured FEV1, and it can be estimated for other altitudes. The best predicting equations for MVV were calculated separately for females and males and included the following predictors: age, age2, and measured FEV1. The study found that reference values for MVV from studies conducted at sea level are inaccurate at this altitude. PMID- 28830927 TI - Physical Activity Counseling for Children With Cystic Fibrosis. AB - BACKGROUND: Physical activity is recommended as a component of the cystic fibrosis (CF) treatment regimen. However, to date, there is limited research examining the effects of behavioral counseling interventions aimed at increasing physical activity. The aim of this study was to assess the feasibility of a theoretically informed, parent-mediated counseling intervention in increasing habitual physical activity and quality of life among children and youth with CF. METHODS: Participants were recruited from the pediatric respirology clinic at the Children's Hospital of Winnipeg. Participants ranged in age between 8 and 18 y. A randomized control feasibility trial was implemented, and participants were randomized to the intervention (n = 7) or control group (n = 6). Intervention group participants engaged in 4 counseling sessions to examine the acceptability and feasibility of physical activity counseling in the care of children with CF. The primary outcome was study feasibility, as measured by recruitment, retention, adherence, acceptability, and the frequency of adverse events. Secondary outcomes included physical activity and quality of life, as measured by accelerometry and the Pediatric Quality of Life Inventory. RESULTS: Thirteen subjects completed the study. No adverse events were found in this trial. The intervention was found to be feasible and acceptable with good recruitment, retention, adherence, and acceptability. Positive trends were also reported in terms of increases in physical activity, reductions in time spent being sedentary, and improvements in most dimensions of quality of life pre- to post-intervention. CONCLUSIONS: The findings suggest that counseling is feasible for the CF community. An appropriately powered randomized controlled trial is required in the future to investigate the utility of counseling as a means to enhance quality of life and physical activity behavior. PMID- 28830928 TI - Evaluation of Simulated Ventilation Techniques With the Upright and Conventional Self-Inflating Neonatal Resuscitators. AB - BACKGROUND: The study assessed the impact of simulated ventilation techniques using upright and conventional self-inflating neonatal resuscitators on delivered tidal volume (VT) and pressure. METHODS: We analyzed videos of participants ventilating a manikin using an upright (upright, n = 33) and a conventional resuscitator (conventional, n = 32) under normal and low lung compliance. Mask hold, number of fingers squeezing the bag, and degree of bag squeeze were compared with VT and peak inspiratory pressure (PIP). RESULTS: VT and PIP values were higher when using the upright resuscitator than when using the conventional resuscitator. With low compliance, differences in VT were insignificant except with the use of the OK/C hold, (upright, 29.6 +/- 4.0 mL, vs conventional, 24.8 +/- 6.0 mL, P = .02). PIP was significantly higher when using the upright resuscitator with the OK hold (upright, 36.3 +/- 4.4 mL, vs conventional, 30.3 +/ 6.6 mL, P = .009) and when the bag was squeezed by more than half (upright, 33.8 +/- 16.3 mL, vs conventional, 29.3 +/- 9.5 mL, P = .046). With normal compliance, VT was high with both resuscitators, being significantly higher when using the upright resuscitator with the OK hold (upright, 64.3 +/- 9.5 mL, vs conventional, 45.8 +/- 9.4 mL; P < .001), and when the bag was squeezed using more than 2 fingers (upright, 58.0 +/- 17.2 mL, vs conventional, 45.7 +/- 12.6 mL, P = .01) and by more than half (upright, 58.7 +/- 16.6 mL, vs conventional, 45.8 +/- 12.2 mL, P = .004). PIP, too, was significantly higher when using the upright resuscitator with the OK hold (upright, 29.3 +/- 3.5 mL, vs conventional, 21.5 +/ 4.0 mL, P = <.001) and when the bag was squeezed using more than 2 fingers (upright, 27.2 +/- 7.0 mL, vs conventional, 21.6 +/- 5.7 mL, P = .005), and by more than half (upright, 27.6 +/- 6.6 mL, vs conventional, 21.7 +/- 5.4 mL, P = .001). CONCLUSIONS: Improved mask design, larger bag volume, and upright orientation of the upright resuscitator likely contributed to higher VT and PIP. However, high VT was observed with both resuscitators, possibly due to excessive squeezing of the bag, especially during low compliance. Thus, the design of the resuscitator and manner in which the device is utilized can both significantly influence the VT and PIP attained. PMID- 28830929 TI - Discovery of a widespread prokaryotic 5-oxoprolinase that was hiding in plain sight. AB - 5-Oxoproline (OP) is well-known as an enzymatic intermediate in the eukaryotic gamma-glutamyl cycle, but it is also an unavoidable damage product formed spontaneously from glutamine and other sources. Eukaryotes metabolize OP via an ATP-dependent 5-oxoprolinase; most prokaryotes lack homologs of this enzyme (and the gamma-glutamyl cycle) but are predicted to have some way to dispose of OP if its spontaneous formation in vivo is significant. Comparative analysis of prokaryotic genomes showed that the gene encoding pyroglutamyl peptidase, which removes N-terminal OP residues, clusters in diverse genomes with genes specifying homologs of a fungal lactamase (renamed prokaryotic 5-oxoprolinase A, pxpA) and homologs of allophanate hydrolase subunits (renamed pxpB and pxpC). Inactivation of Bacillus subtilis pxpA, pxpB, or pxpC genes slowed growth, caused OP accumulation in cells and medium, and prevented use of OP as a nitrogen source. Assays of cell lysates showed that ATP-dependent 5-oxoprolinase activity disappeared when pxpA, pxpB, or pxpC was inactivated. 5-Oxoprolinase activity could be reconstituted in vitro by mixing recombinant B. subtilis PxpA, PxpB, and PxpC proteins. In addition, overexpressing Escherichia coli pxpABC genes in E. coli increased 5-oxoprolinase activity in lysates >=1700-fold. This work shows that OP is a major universal metabolite damage product and that OP disposal systems are common in all domains of life. Furthermore, it illustrates how easily metabolite damage and damage-control systems can be overlooked, even for central metabolites in model organisms. PMID- 28830932 TI - Rethinking Vo2max: right problem, wrong solution (Letter to the Editor regarding Poole and Jones' "Measurement of the maximum oxygen uptake Vo2max: Vo2peak is no longer acceptable"). PMID- 28830930 TI - Increased heme synthesis in yeast induces a metabolic switch from fermentation to respiration even under conditions of glucose repression. AB - Regulation of mitochondrial biogenesis and respiration is a complex process that involves several signaling pathways and transcription factors as well as communication between the nuclear and mitochondrial genomes. Under aerobic conditions, the budding yeast Saccharomyces cerevisiae metabolizes glucose predominantly by glycolysis and fermentation. We have recently shown that altered chromatin structure in yeast induces respiration by a mechanism that requires transport and metabolism of pyruvate in mitochondria. However, how pyruvate controls the transcriptional responses underlying the metabolic switch from fermentation to respiration is unknown. Here, we report that this pyruvate effect involves heme. We found that heme induces transcription of HAP4, the transcriptional activation subunit of the Hap2/3/4/5p complex, required for growth on nonfermentable carbon sources, in a Hap1p- and Hap2/3/4/5p-dependent manner. Increasing cellular heme levels by inactivating ROX1, which encodes a repressor of many hypoxic genes, or by overexpressing HEM3 or HEM12 induced respiration and elevated ATP levels. Increased heme synthesis, even under conditions of glucose repression, activated Hap1p and the Hap2/3/4/5p complex and induced transcription of HAP4 and genes required for the tricarboxylic acid (TCA) cycle, electron transport chain, and oxidative phosphorylation, leading to a switch from fermentation to respiration. Conversely, inhibiting metabolic flux into the TCA cycle reduced cellular heme levels and HAP4 transcription. Together, our results indicate that the glucose-mediated repression of respiration in budding yeast is at least partly due to the low cellular heme level. PMID- 28830933 TI - Reply to Cooper's letter in reference to: Measurement of the maximum oxygen uptake Vo2max: Vo2peak is no longer acceptable. PMID- 28830931 TI - At the confluence of ribosomally synthesized peptide modification and radical S adenosylmethionine (SAM) enzymology. AB - Radical S-adenosylmethionine (RS) enzymology has emerged as a major biochemical strategy for the homolytic cleavage of unactivated C-H bonds. At the same time, the post-translational modification of ribosomally synthesized peptides is a rapidly expanding area of investigation. We discuss the functional cross-section of these two disciplines, highlighting the recently uncovered importance of protein-protein interactions, especially between the peptide substrate and its chaperone, which functions either as a stand-alone protein or as an N-terminal fusion to the respective RS enzyme. The need for further work on this class of enzymes is emphasized, given the poorly understood roles performed by multiple, auxiliary iron-sulfur clusters and the paucity of protein X-ray structural data. PMID- 28830935 TI - Differences in miRNA expression profiles between wild-type and mutated NIFTPs. AB - Noninvasive encapsulated follicular variants of papillary thyroid carcinomas have been recently reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). NIFTPs exhibit a behavior that is very close to that of follicular adenomas but different from the infiltrative and invasive follicular variants of papillary thyroid carcinomas (FVPTCs). The importance of miRNAs to carcinogenesis has been reported in recent years. miRNAs seem to be promising diagnostic and prognostic molecular markers for thyroid cancer, and the combination of miRNA expression and mutational status might improve cytological diagnosis. The aim of the present study was to evaluate the miRNA expression profile in wild-type, RAS- or BRAF-mutated NIFTPs, infiltrative and invasive FVPTCs, and follicular adenomas using the nCounter miRNA Expression assay (NanoString Technologies). To identify the significant Kyoto Encyclopedia of Genes and Genomes (KEGG) molecular pathways associated with deregulated miRNAs, we used the union of pathways option in DNA Intelligent Analysis (DIANA) miRPath software. We have shown that the miRNA expression profiles of wild-type and mutated NIFTPs could be different. The expression profile of wild-type NIFTPs seems comparable to that of follicular adenomas, whereas mutated NIFTPs have an expression profile similar to that of infiltrative and invasive FVPTCs. The upregulation of 4 miRNAs (miR-221-5p, miR-221-3p, miR-222-3p, miR-146b-5p) and the downregulation of 8 miRNAs (miR-181a-3p, miR-28-5p, miR-363-3p, miR-342-3p, miR-1285-5p, miR-152-3p, miR-25-3p, miR-30e-3) in mutated NIFTPs compared to wild type ones suggest a potential invasive-like phenotype by deregulating the specific pathways involved in cell adhesion and cell migration (Hippo signaling pathway, ECM-receptor interaction, adherens junction, regulation of actin cytoskeleton, fatty acid biosynthesis and metabolism). PMID- 28830934 TI - OP449 inhibits breast cancer growth without adverse metabolic effects. AB - Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/AKT/mTOR pathway. OP449, a SET inhibitor, decreases AKT/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (P < 0.05), and IR phosphorylation was 4.5-fold higher in these mice (P < 0.05). Human and murine breast cancer tumors treated with OP449 were 47% and 39% smaller than controls (P < 0.05, for both, respectively). AKT and S6RP phosphorylation were 82% and 34% lower in OP449-treated tumors compared with controls (P < 0.05, P = 0.06, respectively). AKT and S6RP phosphorylation in response to insulin was 30% and 12% lower in cells, pre-treated with OP449, compared with control cells (P < 0.01, P < 0.05, respectively). However, even with decreased AKT/mTOR activation, body weights and composition, blood glucose and plasma insulin, glucose tolerance, serum triglyceride and cholesterol levels were similar between OP449 treated mice and controls. Xenografts and liver tissue from OP449-treated mice showed a 64% and 70% reduction in STAT5 activation, compared with controls (P < 0.01 and P = 0.06, respectively). Our data support an anti-neoplastic effect of OP449 on human breast cancer cells in vitro and in xenografts in the setting of hyperinsulinemia. OP449 led to the inhibition of AKT/mTOR signaling, albeit, not leading to metabolic derangements. PMID- 28830936 TI - The microenvironment induces collective migration in SDHB-silenced mouse pheochromocytoma spheroids. AB - Pheochromocytomas (Pheos) and paragangliomas (PGLs) are neuroendocrine tumors. Approximately 30-40% of Pheos/PGLs are due to germline mutations in one of the susceptibility genes, including those encoding the succinate dehydrogenase subunits A-D (SDHA-D). Up to 2/3 of patients affected by SDHB mutated Pheo/PGL develop metastatic disease with no successful cure at present. Here, for the first time, we evaluated the effects of SDHB silencing in a three dimension (3D) culture using spheroids of a mouse Pheo cell line silenced or not (wild type/wt/control) for the SDHB subunit. We investigated the role of the microenvironment on spheroid growth and migration/invasion by co-culturing SDHB silenced or wt spheroids with primary cancer-activated fibroblasts (CAFs). When spheroids were co-cultured with fibroblasts, SDHB-silenced cells showed a significant increase in matrigel invasion as demonstrated by the computation of the migratory areas (P < 0.001). Moreover, cells detaching from the SDHB-silenced spheroids moved collectively, unlike the cells of wt spheroids that moved individually. Additionally, SDHB-silenced spheroids developed long filamentous formations along which clusters of cells migrated far away from the spheroid, whereas these structures were not present in wt spheroids. We found that lactate, largely secreted by CAFs, plays a specific role in promoting migration only of SDHB-silenced cells. In this study, we demonstrated that SDHB silencing per se increases tumor cell migration/invasion and that microenvironment, as represented by CAFs, plays a pivotal role in enhancing collective migration/invasion in Pheo SDHB-silenced tumor cells, suggesting their role in increasing the tumor metastasizing potential. PMID- 28830937 TI - The BABY BOOM Transcription Factor Activates the LEC1-ABI3-FUS3-LEC2 Network to Induce Somatic Embryogenesis. AB - Somatic embryogenesis is an example of induced cellular totipotency, where embryos develop from vegetative cells rather than from gamete fusion. Somatic embryogenesis can be induced in vitro by exposing explants to growth regulators and/or stress treatments. The BABY BOOM (BBM) and LEAFY COTYLEDON1 (LEC1) and LEC2 transcription factors are key regulators of plant cell totipotency, as ectopic overexpression of either transcription factor induces somatic embryo formation from Arabidopsis (Arabidopsis thaliana) seedlings without exogenous growth regulators or stress treatments. Although LEC and BBM proteins regulate the same developmental process, it is not known whether they function in the same molecular pathway. We show that BBM transcriptionally regulates LEC1 and LEC2, as well as the two other LAFL genes, FUSCA3 (FUS3) and ABSCISIC ACIDINSENSITIVE3 (ABI3). LEC2 and ABI3 quantitatively regulate BBM-mediated somatic embryogenesis, while FUS3 and LEC1 are essential for this process. BBM-mediated somatic embryogenesis is dose and context dependent, and the context-dependent phenotypes are associated with differential LAFL expression. We also uncover functional redundancy for somatic embryogenesis among other Arabidopsis BBM-like proteins and show that one of these proteins, PLETHORA2, also regulates LAFL gene expression. Our data place BBM upstream of other major regulators of plant embryo identity and totipotency. PMID- 28830938 TI - Clathrin Heavy Chain Subunits Coordinate Endo- and Exocytic Traffic and Affect Stomatal Movement. AB - The current model for vesicular traffic to and from the plasma membrane is accepted, but the molecular requirements for this coordination are not well defined. We have identified the hot ABA-deficiency suppressor1 mutant, which has a stomatal function defect, as a clathrin heavy chain1 (CHC1) mutant allele and show that it has a decreased rate of endocytosis and growth defects that are shared with other chc1 mutant alleles. We used chc1 alleles and the related chc2 mutant as tools to investigate the effects that clathrin defects have on secretion pathways and plant growth. We show that secretion and endocytosis at the plasma membrane are sensitive to CHC1 and CHC2 function in seedling roots and that chc mutants have physiological defects in stomatal function and plant growth that have not been described previously. These findings suggest that clathrin supports specific functions in multiple cell types. Stomata movement and gas exchange are altered in chc mutants, indicating that clathrin is important for stomatal regulation. The aberrant function of chc mutant stomata is consistent with the growth phenotypes observed under different water and light conditions, which also are similar to those of the secretory SNARE mutant, syp121 The syp121 and chc mutants have impaired endocytosis and exocytosis compared with the wild type, indicating a link between SYP121-dependent secretion and clathrin-dependent endocytosis at the plasma membrane. Our findings provide evidence that clathrin and SYP121 functions are important for the coordination of endocytosis and exocytosis and have an impact on stomatal function, gas exchange, and vegetative growth in Arabidopsis (Arabidopsis thaliana). PMID- 28830939 TI - A Transcriptional Regulatory Mechanism Finely Tunes the Firing of Type VI Secretion System in Response to Bacterial Enemies. AB - The ability to detect and measure danger from an environmental signal is paramount for bacteria to respond accordingly, deploying strategies that halt or counteract potential cellular injury and maximize survival chances. Type VI secretion systems (T6SSs) are complex bacterial contractile nanomachines able to target toxic effectors into neighboring bacteria competing for the same colonization niche. Previous studies support the concept that either T6SSs are constitutively active or they fire effectors in response to various stimuli, such as high bacterial density, cell-cell contact, nutrient depletion, or components from dead sibling cells. For Serratia marcescens, it has been proposed that its T6SS is stochastically expressed, with no distinction between harmless or aggressive competitors. In contrast, we demonstrate that the Rcs regulatory system is responsible for finely tuning Serratia T6SS expression levels, behaving as a transcriptional rheostat. When confronted with harmless bacteria, basal T6SS expression levels suffice for Serratia to eliminate the competitor. A moderate T6SS upregulation is triggered when, according to the aggressor-prey ratio, an unbalanced interplay between homologous and heterologous effectors and immunity proteins takes place. Higher T6SS expression levels are achieved when Serratia is challenged by a contender like Acinetobacter, which indiscriminately fires heterologous effectors able to exert lethal cellular harm, threatening the survival of the Serratia population. We also demonstrate that Serratia's RcsB dependent T6SS regulatory mechanism responds not to general stress signals but to the action of specific effectors from competitors, displaying an exquisite strategy to weigh risks and keep the balance between energy expenditure and fitness costs.IMPORTANCESerratia marcescens is among the health-threatening pathogens categorized by the WHO as research priorities to develop alternative antimicrobial strategies, and it was also recently identified as one major component of the gut microbiome in familial Crohn disease dysbiosis. Type VI secretion systems (T6SSs) stand among the array of survival strategies that Serratia displays. They are contractile multiprotein complexes able to deliver toxic effectors directed to kill bacterial species sharing the same niche and, thus, competing for vital resources. Here, we show that Serratia is able to detect and measure the extent of damage generated through T6SS-delivered toxins from neighboring bacteria and responds by transcriptionally adjusting the expression level of its own T6SS machinery to counterattack the rival. This strategy allows Serratia to finely tune the production of costly T6SS devices to maximize the chances of successfully fighting against enemies and minimize energy investment. The knowledge of this novel mechanism provides insight to better understand bacterial interactions and design alternative treatments for polymicrobial infections. PMID- 28830940 TI - The Toxoplasma Centrocone Houses Cell Cycle Regulatory Factors. AB - Our knowledge of cell cycle regulatory mechanisms in apicomplexan parasites is very limited. In this study, we describe a novel Toxoplasma gondii factor that has a vital role in chromosome replication and the regulation of cytoplasmic and nuclear mitotic structures, and we named this factor ECR1 for essential for chromosome replication 1. ECR1 was discovered by complementation of a temperature sensitive (ts) mutant that suffers lethal, uncontrolled chromosome replication at 40 degrees C similar to a ts mutant carrying a defect in topoisomerase. ECR1 is a 52-kDa protein containing divergent RING and TRAF-Sina-like zinc binding domains that are dynamically expressed in the tachyzoite cell cycle. ECR1 first appears in the unique spindle compartment of the Apicomplexa (centrocone) of the nuclear envelope in early S phase and then in the nucleus in late S phase where it reaches maximum expression. Following nuclear division, but before daughter parasites separate from the mother parasite, ECR1 is downregulated and is absent in new daughter parasites. The proteomics of ECR1 identified interactions with the ubiquitin-mediated protein degradation machinery and the minichromosome maintenance complex, and the loss of ECR1 led to increased stability of a key member of this complex, MCM2. ECR1 also forms a stable complex with the cyclin dependent kinase (CDK)-related kinase, Tgondii Crk5 (TgCrk5), which displays a similar cell cycle expression and localization during tachyzoite replication. Importantly, the localization of ECR1/TgCrk5 in the centrocone indicates that this Apicomplexa-specific spindle compartment houses important regulatory factors that control the parasite cell cycle.IMPORTANCE Parasites of the apicomplexan family are important causes of human disease, including malaria, toxoplasmosis, and cryptosporidiosis. Parasite growth is the underlying cause of pathogenesis, yet despite this importance, the molecular basis for parasite replication is poorly understood. Filling this knowledge gap cannot be accomplished by mining recent whole-genome sequencing data because apicomplexan cell cycles differ substantially and lack many of the key regulatory factors of well-studied yeast and mammalian cell division models. We have utilized forward genetics to discover essential factors that regulate cell division in these parasites using the Toxoplasma gondii model. An example of this approach is described here with the discovery of a putative E3 ligase/protein kinase mechanism involved in regulating chromosome replication and mitotic processes of asexual stage parasites. PMID- 28830941 TI - MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis. AB - While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-kappaB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward.IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants. PMID- 28830942 TI - Diabetes Exacerbates Infection via Hyperinflammation by Signaling through TLR4 and RAGE. AB - For more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing. We confirmed that diabetic mice were hypersusceptible to bacteremia caused by Gram-negative bacteria (GNB), dying at inocula nonlethal to nondiabetic mice. Contrary to the pervasive paradigm that diabetes impedes phagocytic function, the bacterial burden was no greater in diabetic mice despite excess mortality. However, diabetic mice did exhibit dramatically increased levels of proinflammatory cytokines in response to GNB infections, and immunosuppressing these cytokines with dexamethasone restored their resistance to infection, both of which are consistent with excess inflammation. Furthermore, disruption of the receptor for advanced glycation end products (RAGE), which is stimulated by heightened levels of AGEs in diabetic hosts, protected diabetic but not nondiabetic mice from GNB infection. Thus, rather than immunosuppression, diabetes drives lethal hyperinflammation in response to GNB by signaling through RAGE. As such, interventions to improve the outcomes from GNB infections should seek to suppress the immune response in diabetic hosts.IMPORTANCE Physicians and scientists have subscribed to the dogma that diabetes predisposes the host to worse outcomes from infections because it suppresses the immune system. This understanding was based largely on ex vivo studies of blood from patients and animals with diabetes. However, we have found that the opposite is true and worse outcomes from infection are caused by overstimulation of the immune system in response to bacteria. This overreaction occurs by simultaneous ligation of two host receptors: TLR4 and RAGE. Both signal via a common downstream messenger, MyD88, triggering hyperinflammation. In summary, contrary to hundred-year-old postulations about immune suppression in diabetic hosts, we find that diabetes instead predisposes to more severe infections because of additional inflammatory output through dual activation of MyD88 by not only TLR4 but also RAGE. It is the activation of RAGE during GNB infections in those with diabetes that accounts for their heightened susceptibility to infection compared to nondiabetic hosts. PMID- 28830943 TI - Capsule Type and Amount Affect Shedding and Transmission of Streptococcus pneumoniae. AB - The capsular polysaccharide (CPS) of Streptococcus pneumoniae is characterized by its diversity, as it has over 95 known serotypes, and the variation in its thickness as it surrounds an organism. While within-host effects of CPS have been studied in detail, there is no information about its contribution to host-to-host transmission. In this study, we used an infant mouse model of intralitter transmission, together with isogenic capsule switch and cps promoter switch constructs, to explore the effects of CPS type and amount. The determining factor in the transmission rate in this model is the number of pneumococci shed in nasal secretions by colonized hosts. Two of seven capsule switch constructs showed reduced shedding. These constructs were unimpaired in colonization and expressed capsules similar in size to those of the wild-type strain. A cps promoter switch mutant expressing ~50% of wild-type amounts of CPS also displayed reduced shedding without a defect in colonization. Since shedding from the mucosal surface may require escape from mucus entrapment, a mucin-binding assay was used to compare capsule switch and cps promoter switch mutants. The CPS type or amount constructs that shed poorly were bound more robustly by immobilized mucin. These capsule switch and cps promoter switch constructs with increased mucin-binding affinity and reduced shedding also had lower rates of pup-to-pup transmission. Our results demonstrate that CPS type and amount affect transmission dynamics and may contribute to the marked differences in prevalence among pneumococcal types.IMPORTANCEStreptococcus pneumoniae, a leading cause of morbidity and mortality, is readily transmitted, especially among young children. Its structurally and antigenically diverse capsular polysaccharide is the target of currently licensed pneumococcal vaccines. Epidemiology studies show that only a subset of the >95 distinct serotypes are prevalent in the human population, suggesting that certain capsular polysaccharide types might be more likely to be transmitted within the community. Herein, we used an infant mouse model to show that both capsule type and amount are important determinants in the spread of pneumococci from host to host. Transmission rates correlate with those capsule types that are better at escaping mucus entrapment, a key step in exiting the host upper respiratory tract. Hence, our study provides a better mechanistic understanding of why certain pneumococcal serotypes are more common in the human population. PMID- 28830944 TI - Genome-Wide Mutation Rate Response to pH Change in the Coral Reef Pathogen Vibrio shilonii AK1. AB - Recent application of mutation accumulation techniques combined with whole-genome sequencing (MA/WGS) has greatly promoted studies of spontaneous mutation. However, such explorations have rarely been conducted on marine organisms, and it is unclear how marine habitats have influenced genome stability. This report resolves the mutation rate and spectrum of the coral reef pathogen Vibrio shilonii, which causes coral bleaching and endangers the biodiversity maintained by coral reefs. We found that its mutation rate and spectrum are highly similar to those of other studied bacteria from various habitats, despite the saline environment. The mutational properties of this marine bacterium are thus controlled by other general evolutionary forces such as natural selection and genetic drift. We also found that as pH drops, the mutation rate decreases and the mutation spectrum is biased in the direction of generating G/C nucleotides. This implies that evolutionary features of this organism and perhaps other marine microbes might be altered by the increasingly acidic ocean water caused by excess CO2 emission. Nonetheless, further exploration is needed as the pH range tested in this study was rather narrow and many other possible mutation determinants, such as carbonate increase, are associated with ocean acidification.IMPORTANCE This study explored the pH dependence of a bacterial genome-wide mutation rate. We discovered that the genome-wide rates of appearance of most mutation types decrease linearly and that the mutation spectrum is biased in generating more G/C nucleotides with pH drop in the coral reef pathogen V. shilonii. PMID- 28830945 TI - Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease. AB - F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials.IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity. PMID- 28830946 TI - Analysis of Spleen-Induced Fimbria Production in Recombinant Attenuated Salmonella enterica Serovar Typhimurium Vaccine Strains. AB - Salmonella enterica serovar Typhimurium genome encodes 13 fimbrial operons. Most of the fimbriae encoded by these operons are not produced under laboratory conditions but are likely to be synthesized in vivo We used an in vivo expression technology (IVET) strategy to identify four fimbrial operons, agf, saf, sti, and stc that are expressed in the spleen. When any three of these operons were deleted, the strain retained wild-type virulence. However, when all four operons were deleted, the resulting strain was completely attenuated, indicating that these four fimbriae play functionally redundant roles critical for virulence. In mice, oral doses of as low as 1 * 105 CFU of the strain with four fimbrial operons deleted provided 100% protection against challenge with 1 * 109 CFU of wild-type S Typhimurium. We also examined the possible effect of these fimbriae on the ability of a Salmonella vaccine strain to deliver a guest antigen. We modified one of our established attenuated vaccine strains, chi9088, to delete three fimbrial operons while the fourth operon was constitutively expressed. Each derivative was modified to express the Streptococcus pneumoniae antigen PspA. Strains that constitutively expressed saf or stc elicited a strong Th1 response with significantly greater levels of anti-PspA serum IgG and greater protective efficacy than strains carrying saf or stc deletions. The isogenic strain in which all four operons were deleted generated the lowest anti-PspA levels and did not protect against challenge with virulent S. pneumoniae Our results indicate that these fimbriae play important roles, as yet not understood, in Salmonella virulence and immunogenicity.IMPORTANCESalmonella enterica is the leading cause of bacterial food-borne infection in the United States. S. Typhimurium is capable of producing up to 13 distinct surface structures called fimbriae that presumably mediate its adherence to surfaces. The roles of most of these fimbriae in disease are unknown. Identifying fimbriae produced during infection will provide important insights into how these bacterial structures contribute to disease and potentially induce protective immunity to Salmonella infection. We identified four fimbriae that are produced during infection. Deletion of all four of these fimbriae results in a significant reduction in virulence. We explored ways in which the expression of these fimbriae may be exploited for use in recombinant Salmonella vaccine strains and found that production of Saf and Stc fimbriae are important for generating a strong immune response against a vectored antigen. This work provides new insight into the role of fimbriae in disease and their potential for improving the efficacy of Salmonella-based vaccines. PMID- 28830947 TI - Two Distinct Mechanisms Govern RpoS-Mediated Repression of Tick-Phase Genes during Mammalian Host Adaptation by Borrelia burgdorferi, the Lyme Disease Spirochete. AB - The alternative sigma factor RpoS plays a key role modulating gene expression in Borrelia burgdorferi, the Lyme disease spirochete, by transcribing mammalian host phase genes and repressing sigma70-dependent genes required within the arthropod vector. To identify cis regulatory elements involved in RpoS-dependent repression, we analyzed green fluorescent protein (GFP) transcriptional reporters containing portions of the upstream regions of the prototypical tick-phase genes ospAB, the glp operon, and bba74 As RpoS-mediated repression occurs only following mammalian host adaptation, strains containing the reporters were grown in dialysis membrane chambers (DMCs) implanted into the peritoneal cavities of rats. Wild-type spirochetes harboring ospAB- and glp-gfp constructs containing only the minimal (-35/-10) sigma70 promoter elements had significantly lower expression in DMCs relative to growth in vitro at 37 degrees C; no reduction in expression occurred in a DMC-cultivated RpoS mutant harboring these constructs. In contrast, RpoS-mediated repression of bba74 required a stretch of DNA located between -165 and -82 relative to its transcriptional start site. Electrophoretic mobility shift assays employing extracts of DMC-cultivated B. burgdorferi produced a gel shift, whereas extracts from RpoS mutant spirochetes did not. Collectively, these data demonstrate that RpoS-mediated repression of tick-phase borrelial genes occurs by at least two distinct mechanisms. One (e.g., ospAB and the glp operon) involves primarily sequence elements near the core promoter, while the other (e.g., bba74) involves an RpoS-induced transacting repressor. Our results provide a genetic framework for further dissection of the essential "gatekeeper" role of RpoS throughout the B. burgdorferi enzootic cycle.IMPORTANCEBorrelia burgdorferi, the Lyme disease spirochete, modulates gene expression to adapt to the distinctive environments of its mammalian host and arthropod vector during its enzootic cycle. The alternative sigma factor RpoS has been referred to as a "gatekeeper" due to its central role in regulating the reciprocal expression of mammalian host- and tick-phase genes. While RpoS dependent transcription has been studied extensively, little is known regarding the mechanism(s) of RpoS-mediated repression. We employed a combination of green fluorescent protein transcriptional reporters along with an in vivo model to define cis regulatory sequences responsible for RpoS-mediated repression of prototypical tick-phase genes. Repression of ospAB and the glp operon requires only sequences near their core promoters, whereas modulation of bba74 expression involves a putative RpoS-dependent repressor that binds upstream of the core promoter. Thus, Lyme disease spirochetes employ at least two different RpoS dependent mechanisms to repress tick-phase genes within the mammal. PMID- 28830948 TI - Flavivirus Infection of Ixodes scapularis (Black-Legged Tick) Ex Vivo Organotypic Cultures and Applications for Disease Control. AB - Ixodes scapularis ticks transmit many infectious agents that cause disease, including tick-borne flaviviruses (TBFVs). TBFV infections cause thousands of human encephalitis cases worldwide annually. In the United States, human TBFV infections with Powassan virus (POWV) are increasing and have a fatality rate of 10 to 30%. Additionally, Langat virus (LGTV) is a TBFV of low neurovirulence and is used as a model TBFV. TBFV replication and dissemination within I. scapularis organs are poorly characterized, and a deeper understanding of virus biology in this vector may inform effective countermeasures to reduce TBFV transmission. Here, we describe short-term, I. scapularis organ culture models of TBFV infection. Ex vivo organs were metabolically active for 9 to 10 days and were permissive to LGTV and POWV replication. Imaging and videography demonstrated replication and spread of green fluorescent protein-expressing LGTV in the organs. Immunohistochemical staining confirmed LGTV envelope and POWV protein synthesis within the infected organs. LGTV- and POWV-infected organs produced infectious LGTV and POWV; thus, the ex vivo cultures were suitable for study of virus replication in individual organs. LGTV- and POWV-infected midgut and salivary glands were subjected to double-stranded RNA (dsRNA) transfection with dsRNA to the LGTV 3' untranslated region (UTR), which reduced infectious LGTV and POWV replication, providing a proof-of-concept use of RNA interference in I. scapularis organ cultures to study the effects on TBFV replication. The results contribute important information on TBFV localization within ex vivo I. scapularis organs and provide a significant translational tool for evaluating recombinant, live vaccine candidates and potential tick transcripts and proteins for possible therapeutic use and vaccine development to reduce TBFV transmission.IMPORTANCE Tick-borne flavivirus (TBFV) infections cause neurological and/or hemorrhagic disease in humans worldwide. There are currently no licensed therapeutics or vaccines against Powassan virus (POWV), the only TBFV known to circulate in North America. Evaluating tick vector targets for antitick vaccines directed at reducing TBFV infection within the arthropod vector is a critical step in identifying efficient approaches to controlling TBFV transmission. This study characterized infection of female Ixodes scapularis tick organ cultures of midgut, salivary glands, and synganglion with the low neurovirulence Langat virus (LGTV) and the more pathogenic POWV. Cell types of specific organs were susceptible to TBFV infection, and a difference in LGTV and POWV replication was noted in TBFV-infected organs. This tick organ culture model of TBFV infection will be useful for various applications, such as screening of tick endogenous dsRNA corresponding to potential control targets within midgut and salivary glands to confirm restriction of TBFV infection. PMID- 28830949 TI - The Fusion Loops of the Initial Prefusion Conformation of Herpes Simplex Virus 1 Fusion Protein Point Toward the Membrane. AB - All enveloped viruses, including herpesviruses, must fuse their envelope with the host membrane to deliver their genomes into target cells, making this essential step subject to interference by antibodies and drugs. Viral fusion is mediated by a viral surface protein that transits from an initial prefusion conformation to a final postfusion conformation. Strikingly, the prefusion conformation of the herpesvirus fusion protein, gB, is poorly understood. Herpes simplex virus (HSV), a model system for herpesviruses, causes diseases ranging from mild skin lesions to serious encephalitis and neonatal infections. Using cryo-electron tomography and subtomogram averaging, we have characterized the structure of the prefusion conformation and fusion intermediates of HSV-1 gB. To this end, we have set up a system that generates microvesicles displaying full-length gB on their envelope. We confirmed proper folding of gB by nondenaturing electrophoresis-Western blotting with a panel of monoclonal antibodies (MAbs) covering all gB domains. To elucidate the arrangement of gB domains, we labeled them by using (i) mutagenesis to insert fluorescent proteins at specific positions, (ii) coexpression of gB with Fabs for a neutralizing MAb with known binding sites, and (iii) incubation of gB with an antibody directed against the fusion loops. Our results show that gB starts in a compact prefusion conformation with the fusion loops pointing toward the viral membrane and suggest, for the first time, a model for gB's conformational rearrangements during fusion. These experiments further illustrate how neutralizing antibodies can interfere with the essential gB structural transitions that mediate viral entry and therefore infectivity.IMPORTANCE The herpesvirus family includes herpes simplex virus (HSV) and other human viruses that cause lifelong infections and a variety of diseases, like skin lesions, encephalitis, and cancers. As enveloped viruses, herpesviruses must fuse their envelope with the host membrane to start an infection. This process is mediated by a viral surface protein that transitions from an initial conformation (prefusion) to a final, more stable, conformation (postfusion). However, the prefusion conformation of the herpesvirus fusion protein (gB) is poorly understood. To elucidate the structure of the prefusion conformation of HSV type 1 gB, we have employed cryo-electron microscopy to study gB molecules expressed on the surface of vesicles. Using different approaches to label gB's domains allowed us to model the structures of the prefusion and intermediate conformations of gB. Overall, our findings enhance our understanding of HSV fusion and lay the groundwork for the development of new ways to prevent and block HSV infection. PMID- 28830951 TI - Excess mortality due to indirect health effects of the 2011 triple disaster in Fukushima, Japan: a retrospective observational study. AB - BACKGROUND: Evidence on the indirect health impacts of disasters is limited. We assessed the excess mortality risk associated with the indirect health impacts of the 2011 triple disaster (earthquake, tsunami and nuclear disaster) in Fukushima, Japan. METHODS: The mortality rates in Soma and Minamisoma cities in Fukushima from 2006 to 2015 were calculated using vital statistics and resident registrations. We investigated the excess mortality risk, defined as the increased mortality risk between postdisaster and predisaster after excluding direct deaths attributed to the physical force of the disaster. Multivariate Poisson regression models were used to estimate the relative risk (RR) of mortality after adjusting for city, age and year. RESULTS: There were 6163 and 6125 predisaster and postdisaster deaths, respectively. The postdisaster mortality risk was significantly higher in the first month following the disaster (March 2011) than in the same month during the predisaster period (March 2006 2010). RRs among men and women were 2.64 (95% CI 2.16 to 3.24) and 2.46 (95% CI 1.99 to 3.03), respectively, demonstrating excess mortality risk due to the indirect health effects of the disaster. Age-specific subgroup analyses revealed a significantly higher mortality risk in women aged >=85 years in the third month of the disaster compared with predisaster baseline, with an RR (95% CI) of 1.73 (1.23 to 2.44). CONCLUSIONS: Indirect health impacts are most severe in the first month of the disaster. Early public health support, especially for the elderly, can be an important factor for reducing the indirect health effects of a disaster. PMID- 28830950 TI - Host Cell S Phase Restricts Legionella pneumophila Intracellular Replication by Destabilizing the Membrane-Bound Replication Compartment. AB - Legionella pneumophila grows within cells ranging from environmental amoebae to human macrophages. In spite of this conserved strategy of pathogenesis, identification of host factors that restrict L. pneumophila intracellular replication has not been extended outside components of the mammalian innate immune response. We performed a double-stranded RNA (dsRNA) screen against more than 50% of the Drosophila melanogaster annotated open reading frames (ORFs) to identify host cell factors that restrict L. pneumophila The majority of analyzed dsRNAs that stimulated L. pneumophila intracellular replication were directed against host proteins involved in protein synthesis or cell cycle control. Consistent with disruption of the cell cycle stimulating intracellular replication, proteins involved in translation initiation also resulted in G1 arrest. Stimulation of replication was dependent on the stage of cell cycle arrest, as dsRNAs causing arrest during S phase had an inhibitory effect on intracellular replication. The inhibitory effects of S phase arrest could be recapitulated in a human cell line, indicating that cell cycle control of L. pneumophila replication is evolutionarily conserved. Synchronized HeLa cell populations in S phase and challenged with L. pneumophila failed to progress through the cell cycle and were depressed for supporting intracellular replication. Poor bacterial replication in S phase was associated with loss of the vacuole membrane barrier, resulting in exposure of bacteria to the cytosol and their eventual degradation. These results are consistent with the model that S phase is inhibitory for L. pneumophila intracellular survival as a consequence of failure to maintain the integrity of the membrane surrounding intracellular bacteria.IMPORTANCELegionella pneumophila has the ability to replicate within human macrophages and amoebal hosts. Here, we report that the host cell cycle influences L. pneumophila intracellular replication. Our data demonstrate that the G1 and G2/M phases of the host cell cycle are permissive for bacterial replication, while S phase is toxic for the bacterium. L. pneumophila replicates poorly within host cells present in S phase. The inability of L. pneumophila to replicate relies on its failure to control the integrity of its vacuole, leading to cytosolic exposure of the bacteria and eventual degradation. The data presented here argue that growth-arrested host cells that are encountered by L. pneumophila in either the environment or within human hosts are ideal targets for intracellular replication because their transit through S phase is blocked. PMID- 28830953 TI - In This Issue of Diabetes Care. PMID- 28830954 TI - Declines in the Incidence of Diabetes in the U.S.-Real Progress or Artifact? AB - National surveillance data show a sustained decline in the incidence rate of diagnosed diabetes, which has been heralded as a success in the battle against diabetes in the U.S. In this Perspective, we take a closer look at these data and provide additional insights to help interpret these trends. We examine multiple sources of data on the prevalence and incidence of diabetes in the U.S. as well as data on trends in diabetes risk factors to provide context for these national surveillance findings. Although some of the incidence decline may represent real progress against diabetes, it is likely that there are also nonbiological factors at play, especially changes in diagnostic criteria for diabetes. We present and discuss data that suggest improved detection and changes in screening and diagnostic practices may have resulted in the depletion of the "susceptible population." Providing this context for the recent declines in new diabetes diagnoses observed in national data is critical to help avoid misinterpretation. We argue that it is premature to declare victory against the epidemic of diabetes in the U.S. and discuss how we might better focus current public health efforts, including a specific emphasis to address prediabetes. PMID- 28830955 TI - Composite Primary End Points in Cardiovascular Outcomes Trials Involving Type 2 Diabetes Patients: Should Unstable Angina Be Included in the Primary End Point? AB - Reductions in cardiovascular (CV) outcomes in recently reported trials, along with the recent approval by the U.S. Food and Drug Administration of an additional indication for empagliflozin to reduce the risk of CV death in type 2 diabetes patients with evidence of CV disease, have renewed interest in CV outcome trials (CVOTs) of glucose-lowering drugs. Composite end points are a pragmatic necessity in CVOTs to ensure that sample size and duration of follow-up remain reasonable. Combining clinical outcomes into a composite end point increases the numbers of events ascertained and thus statistical power and precision. Historically, composite CV end points in diabetes trials have included a larger number of components, while more recent CVOTs almost exclusively use a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke the so-called three-point major adverse CV event (3P-MACE) composite-or add hospitalization for unstable angina (HUA) to these three outcomes (4P-MACE). The inclusion of HUA increases the number of events for analysis, but noteworthy disadvantages include clinical subjectivity in ascertainment of HUA and its lower prognostic relevance compared with CV death, MI, or stroke. Furthermore, results from recent CVOTs indicate that glucose-lowering agents seem to have minimal impact on HUA. Its inclusion therefore potentially favors a shift of the hazard ratio (HR) toward the null, which is especially problematic in trials designed to demonstrate noninferiority. The primary outcome of 3P-MACE may offer a better balance than 4P-MACE between statistical efficiency, operational complexity, the likelihood of diagnostic precision (and therefore clinical relevance) for each of the component outcomes, clinical importance, and the aim to adequately capture any potential treatment effect of the intervention. Nevertheless, as individual medications may mechanistically differ in their impact on CV outcomes, no particular individual or composite end point can be seen as a "gold standard" for CVOTs of all glucose-lowering drugs. PMID- 28830952 TI - Is atmospheric pollution exposure during pregnancy associated with individual and contextual characteristics? A nationwide study in France. AB - BACKGROUND: Exposure to atmospheric pollutants is a danger for the health of pregnant mother and children. Our objective was to identify individual (socioeconomic and behavioural) and contextual factors associated with atmospheric pollution pregnancy exposure at the nationwide level. METHOD: Among 14 921 women from the French nationwide ELFE (French Longitudinal Study of Children) mother-child cohort recruited in 2011, outdoor exposure levels of PM2.5, PM10 (particulate matter <2.5 um and <10 um in diameter) and NO2 (nitrogen dioxide) were estimated at the pregnancy home address from a dispersion model with 1 km resolution. We used classification and regression trees (CART) and linear regression to characterise the association of atmospheric pollutants with individual (maternal age, body mass index, parity, education level, relationship status, smoking status) and contextual (European Deprivation Index, urbanisation level) factors. RESULTS: Patterns of associations were globally similar across pollutants. For the CART approach, the highest tertile of exposure included mainly women not in a relationship living in urban and socially deprived areas, with lower education level. Linear regression models identified different determinants of atmospheric pollutants exposure according to the residential urbanisation level. In urban areas, atmospheric pollutants exposure increased with social deprivation, while in rural areas a U-shaped relationship was observed. CONCLUSION: We highlighted social inequalities in atmospheric pollutants exposure according to contextual characteristics such as urbanisation level and social deprivation and also according to individual characteristics such as education, being in a relationship and smoking status. In French urban areas, pregnant women from the most deprived neighbourhoods were those most exposed to health-threatening atmospheric pollutants. PMID- 28830956 TI - The War Is Not Yet Won. PMID- 28830957 TI - George Alberti: A Myriad of Contributions to Diabetes and Beyond. PMID- 28830958 TI - Diabetes and Hypertension: A Position Statement by the American Diabetes Association. PMID- 28830960 TI - Comment on Gagnum et al. Long-term Mortality and End-Stage Renal Disease in a Type 1 Diabetes Population Diagnosed at Age 15-29 Years in Norway. Diabetes Care 2017;40:38-45. PMID- 28830961 TI - Response to Comment on Gagnum et al. Long-term Mortality and End-Stage Renal Disease in a Type 1 Diabetes Population Diagnosed at Age 15-29 Years in Norway. Diabetes Care 2017;40:38-45. PMID- 28830962 TI - Comment on Young-Hyman et al. Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2126-2140. PMID- 28830963 TI - Comment on Young-Hyman et al. Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2126-2140. PMID- 28830964 TI - Comment on Young-Hyman et al. Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2126-2140. PMID- 28830965 TI - Response to Comments on Young-Hyman et al. Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39:2126-2140. PMID- 28830966 TI - Comment on Timmers et al. Resveratrol as Add-on Therapy in Subjects With Well Controlled Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care 2016;39:2211-2217. PMID- 28830967 TI - Response to Comment on Timmers et al. Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care 2016;39:2211-2217. PMID- 28830968 TI - Comment on Ekblad et al. Insulin Resistance Predicts Cognitive Decline: An 11 Year Follow-up of a Nationally Representative Adult Population Sample. Diabetes Care 2017;40:751-758. PMID- 28830969 TI - Response to Comment by Ayubi and Safiri. Insulin Resistance Predicts Cognitive Decline: An 11-Year Follow-up of a Nationally Representative Adult Population Sample. Diabetes Care 2017;40:751-758. PMID- 28830970 TI - Letter by Sallustio et al Regarding Article, "Endovascular Thrombectomy and Stroke Physicians: Equity, Access, and Standards". PMID- 28830972 TI - Letter by Tsuda Regarding Article, "Association of Vegetable Nitrate Intake With Carotid Atherosclerosis and Ischemic Cerebrovascular Disease in Older Women". PMID- 28830973 TI - Tumor Necrosis Factor Receptor 1 and 2 Are Associated With Risk of Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Raised plasma concentrations of tumor necrosis factor receptors (TNFR) have been linked to arterial stiffness, cerebral microbleeds, and vascular events. The aim of this study was to investigate the association of circulating levels of TNFR1 and TNFR2 with risk for future intracerebral hemorrhage (ICH). METHODS: The population-based MDCS cohort (Malmo Diet and Cancer Study; n=28 449) was conducted in 1991 to 1996. A nested case-control study was performed in the MDCS, including 220 cases who experienced ICH during the follow-up period (mean age at inclusion 62 years, 48% men) and 244 matched controls. Of the 220 ICH cases, 68 died within 28 days. Conditional logistic regression was used to study the association between plasma levels of TNFR1 and TNFR2 and incident ICH, adjusting for known ICH risk factors. RESULTS: Concentrations of both TNFR1 and TNFR2 were significantly higher in subjects who developed ICH during the follow-up. The associations remained after adjustment for ICH risk factors (TNFR1: odds ratio [OR], 2.28; 95% confidence interval [CI], 1.26-4.11; P=0.006; TNFR2: OR, 1.77; CI, 1.16-2.70; P=0.008). ORs were somewhat higher for nonlobar ICH (3.04; CI, 1.29-7.14 and 2.39; CI, 1.32-4.32, respectively) than for lobar ICH (2.03; CI, 0.93-4.41 and 1.35; CI, 0.78-2.37, respectively). TNFR1 and TNFR2 were also associated with increased risk of fatal ICH (TNFR1: OR, 4.42; CI, 1.67-11.6; TNFR2: OR, 2.90; CI, 1.50-5.58) and with poor functional outcome according to the modified Rankin Scale. CONCLUSIONS: High plasma levels of TNFR1 and TNFR2 were associated with incident ICH, most clearly with ICH of nonlobar location. The results suggest that tumor necrosis factor mediated inflammation could be associated with vascular changes preceding ICH. PMID- 28830974 TI - Response by Bondonno et al to Letter Regarding Article, "Association of Vegetable Nitrate Intake With Carotid Atherosclerosis and Ischemic Cerebrovascular Disease in Older Women". PMID- 28830971 TI - Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke: Primary Results of the STRATIS Registry. AB - BACKGROUND AND PURPOSE: Mechanical thrombectomy with stent retrievers has become standard of care for treatment of acute ischemic stroke patients because of large vessel occlusion. The STRATIS registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) aimed to assess whether similar process timelines, technical, and functional outcomes could be achieved in a large real world cohort as in the randomized trials. METHODS: STRATIS was designed to prospectively enroll patients treated in the United States with a Solitaire Revascularization Device and Mindframe Capture Low Profile Revascularization Device within 8 hours from symptom onset. The STRATIS cohort was compared with the interventional cohort of a previously published SEER patient-level meta-analysis. RESULTS: A total of 984 patients treated at 55 sites were analyzed. The mean National Institutes of Health Stroke Scale score was 17.3. Intravenous tissue-type plasminogen activator was administered in 64.0%. The median time from onset to arrival in the enrolling hospital, door to puncture, and puncture to reperfusion were 138, 72, and 36 minutes, respectively. The Core lab-adjudicated modified Thrombolysis in Cerebral Infarction >=2b was achieved in 87.9% of patients. At 90 days, 56.5% achieved a modified Rankin Scale score of 0 to 2, all-cause mortality was 14.4%, and 1.4% suffered a symptomatic intracranial hemorrhage. The median time from emergency medical services scene arrival to puncture was 152 minutes, and each hour delay in this interval was associated with a 5.5% absolute decline in the likelihood of achieving modified Rankin Scale score 0 to 2. CONCLUSIONS: This largest-to-date Solitaire registry documents that the results of the randomized trials can be reproduced in the community. The decrease of clinical benefit over time warrants optimization of the system of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02239640. PMID- 28830975 TI - Unexplained Variation for Hospitals' Use of Inpatient Rehabilitation and Skilled Nursing Facilities After an Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Rehabilitation is recommended after a stroke to enhance recovery and improve outcomes, but hospital's use of inpatient rehabilitation facilities (IRFs) or skilled nursing facility (SNF) and the factors associated with referral are unknown. METHODS: We analyzed clinical registry and claims data for 31 775 Medicare beneficiaries presenting with acute ischemic stroke from 918 Get With The Guidelines-Stroke hospitals who were discharged to either IRF or SNF between 2006 and 2008. Using a multilevel logistic regression model, we evaluated patient and hospital characteristics, as well as geographic availability, in relation to discharge to either IRF or SNF. After accounting for observed factors, the median odds ratio was reported to quantify hospital-level variation in the use of IRF versus SNF. RESULTS: Of 31 775 patients, 17 662 (55.6%) were discharged to IRF and 14 113 (44.4%) were discharged to SNF. Compared with SNF patients, IRF patients were younger, more were men, had less health-service use 6 months prestroke, and had fewer comorbid conditions and in-hospital complications. Use of IRF or SNF varied significantly across hospitals (median IRF use, 55.8%; interquartile range, 34.8%-75.0%; unadjusted median odds ratio, 2.59; 95% confidence interval, 2.44-2.77). Hospital-level variation in discharge rates to IRF or SNF persisted after adjustment for patient, clinical, and geographic variables (adjusted median odds ratio, 2.87; 95% confidence interval, 2.68-3.11). CONCLUSIONS: There is marked unexplained variation among hospitals in their use of IRF versus SNF poststroke even after accounting for clinical characteristics and geographic availability. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02284165. PMID- 28830977 TI - Lack of direct effect of adiponectin on vascular smooth muscle cell BKCa channels or Ca2+ signaling in the regulation of small artery pressure-induced constriction. AB - The aim of this study was to investigate mechanisms by which adiponectin influences vascular Ca2+ signaling, K+ channel activity and thus contractile tone of small arteries. Vasodilation to adiponectin was studied in mesenteric resistance arteries constricted with intraluminal pressure. Ca2+ signals were characterized using high speed confocal microscopy of intact arteries. Patch clamp investigated the effect of adiponectin on individual VSMC potassium (K+) channel currents. Adiponectin dilated arteries constricted with pressure-induced tone by approximately 5% and the induced vasodilation was only transient. The dilation to adiponectin was reduced by pharmacological interruption of the Ca2+ spark/large conductance activated K+ (BK) channel pathway but from a physiological perspective, interpretation of the data was limited by the small effect. Neither Adiponectin nor the presence of intact perivascular adipose tissue (PVAT) influenced Ca2+ spark or Ca2+ wave frequency or characteristics. Studied using a perforated patch approach, Adiponectin marginally increased current through the VSMC BK channel but this effect was lost using the whole cell technique with dialysis of the cytoplasm. Adiponectin did not change the frequency or amplitude of Ca2+ spark-induced transient outward currents (STOC). Overall, our study shows that Adiponectin induces only a small and transient dilation of pressure constricted mesenteric arteries. This vasodilatory effect is likely to be independent of Ca2+ sparks or direct BK channel activation. PMID- 28830976 TI - Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts. AB - BACKGROUND AND PURPOSE: The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke. METHODS: We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses' Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta analysis. RESULTS: A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results. CONCLUSIONS: In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid. PMID- 28830978 TI - Evidence for ammonium conductance in a mouse thick ascending limb cell line. AB - In this study, we examined an ammonium conductance in the mouse thick ascending limb cell line ST-1. Whole cell patch clamp was performed to measure currents evoked by NH4Cl in the presence of BaCl2, tetraethylammonium, and BAPTA Application of 20 mmol/L NH4Cl induced an inward current (-272 +/- 79 pA, n = 9). In current-voltage (I-V) relationships, NH4Cl application caused the I-V curve to shift down in an inward direction. The difference in current before and after NH4Cl application, which corresponds to the current evoked by NH4Cl, was progressively larger at more negative potentials. The reversal potential for NH4Cl was +15 mV, higher than the equilibrium potential for chloride, indicating that the current should be due to NH4+ We then injected ST-1 poly(A) RNA into Xenopus oocytes and performed two-electrode voltage clamp. NH4Cl application in the presence of BaCl2 caused the I-V curve to be steeper. The NH4+ current was retained at pH 6.4, where endogenous oocyte current was abolished. The NH4+ current was unaffected by 10 MUmol/L amiloride but abolished after incubation in Na+-free media. These results demonstrate that the renal cell line ST-1 produces an NH4+ conductance. PMID- 28830980 TI - Acute heat stress activated inflammatory signaling in porcine oxidative skeletal muscle. AB - Despite well-studied clinical manifestations, intracellular mechanisms of prolonged hyperthermic injury remain unclear, especially in skeletal muscle. Given muscle's large potential to impact systemic inflammation and metabolism, the response of muscle cells to heat-mediated injury warrants further investigation. We have previously reported increased activation of NF-kappaB signaling and increased NF-kappaB and AP-1-driven transcripts in oxidative skeletal muscle following 12 h of heat stress. The purpose of this investigation was to examine early heat stress-induced inflammatory signaling in skeletal muscle. We hypothesized that heat stress would increase NF-kappaB and AP-1 signaling in oxidative skeletal muscle. To address this hypothesis, 32 gilts were randomly assigned to one of four treatment groups (n = 8/group): control (0 h: 21 degrees C) or exposed to heat stress conditions (37 degrees C) for 2 h (n = 8), 4 h (n = 8), or 6 h (n = 8). Immediately following environmental exposure pigs were euthanized and the red portion of the semitendinosus muscle (STR) was harvested. We found evidence of NF-kappaB pathway activation as indicated by increased protein abundance of NF-kappaB activator IKK-alpha following 4 h and increased total NF-kappaB protein abundance following 6 h of heat stress. Heat stress also stimulated AP-1 signaling as AP-1 protein abundance was increased in nuclear fractions following 4 h of heat stress. Interleukin-6 protein abundance and activation of the JAK/STAT pathway were decreased in heat stressed muscle. These data indicate that heat stress activated inflammatory signaling in the porcine STR muscle via the AP-1 pathway and early activation of the NF-kappaB pathway. PMID- 28830979 TI - Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats. AB - Despite the fact that skeletal muscle insulin resistance is the hallmark of type 2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type-2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased beta hydroxyacyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase activities, despite reduced mitochondrial mass. Long-chain acyl-CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long-chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type-2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart. PMID- 28830981 TI - Nfib hemizygous mice are protected from hyperoxic lung injury and death. AB - Nuclear Factor I (Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild-type (Wt) littermates were exposed to 100% O2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real-time PCR Unexpectedly, Nfib hemizygous mice (0/14-0%) had significantly lower mortality compared to Wt mice (10/22-45%) at 80 h of hyperoxia (P < 0.003). LD50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP-2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild-type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild-type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development. PMID- 28830982 TI - Targeting TAO Kinases Using a New Inhibitor Compound Delays Mitosis and Induces Mitotic Cell Death in Centrosome Amplified Breast Cancer Cells. AB - Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death, and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes, and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome-amplified cancer cells preferentially, while sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells, and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur. Mol Cancer Ther; 16(11); 2410-21. (c)2017 AACR. PMID- 28830984 TI - Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization. AB - Tumor cells-even if nonauxotrophic-are often highly sensitive to arginine deficiency. We hypothesized that arginine deprivation therapy (ADT) if combined with irradiation could be a new treatment strategy for glioblastoma (GBM) patients because systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle in vitro study was performed with ADT being mimicked by application of recombinant human arginase or arginine-free diets. ADT inhibited two-dimensional (2-D) growth and cell-cycle progression, and reduced growth recovery after completion of treatment in four different GBM cell line models. Cells were less susceptible to ADT alone in the presence of citrulline and in a three-dimensional (3-D) environment. Migration and 3-D invasion were not unfavorably affected. However, ADT caused a significant radiosensitization that was more pronounced in a GBM cell model with p53 loss of function as compared with its p53-wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase or argininosuccinate lyase protein expression and not abrogated by the presence of citrulline. The radiosensitizing potential was maintained or even more distinguishable in a 3-D environment as verified in p53-knockdown and p53-wildtype U87-MG cells via a 60-day spheroid control probability assay. Although the underlying mechanism is still ambiguous, the observation of ADT-induced radiosensitization is of great clinical interest, in particular for patients with GBM showing high radioresistance and/or p53 loss of function. Mol Cancer Ther; 17(2); 393-406. (c)2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." PMID- 28830983 TI - HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer. AB - Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701-10. (c)2017 AACR. PMID- 28830986 TI - Obstructive Airway Disease: Rational, Evidence-Based Bronchodilator Therapy. PMID- 28830987 TI - Development and Testing of a Bubble Positive Airway Pressure System: Why Didn't I Think of That? PMID- 28830985 TI - Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance. AB - Approximately 10% of non-small cell lung cancer (NSCLC) patients in the United States and 40% of NSCLC patients in Asia have activating epidermal growth factor receptor (EGFR) mutations and are eligible to receive targeted anti-EGFR therapy. Despite an extension of life expectancy associated with this treatment, resistance to EGFR tyrosine kinase inhibitors and anti-EGFR antibodies is almost inevitable. To identify additional signaling routes that can be cotargeted to overcome resistance, we quantified tumor-specific molecular changes that govern resistant cancer cell growth and survival. Mass spectrometry-based quantitative proteomics was used to profile in vivo signaling changes in 41 therapy-resistant tumors from four xenograft NSCLC models. We identified unique and tumor-specific tyrosine phosphorylation rewiring in tumors resistant to treatment with the irreversible third-generation EGFR-inhibitor, osimertinib, or the novel dual targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific increases in tyrosine phosphorylated peptides from EGFR family members, Shc1 and Gab1 or Src family kinase (SFK) substrates were observed, underscoring a differential ability of tumors to uniquely escape EGFR inhibition. Although most resistant tumors within each treatment group displayed a marked inhibition of EGFR as well as SFK signaling, the combination of EGFR inhibition (osimertinib) and SFK inhibition (saracatinib or dasatinib) led to further decrease in cell growth in vitro This result suggests that residual SFK signaling mediates therapeutic resistance and that elimination of this signal through combination therapy may delay onset of resistance. Overall, analysis of individual resistant tumors captured unique in vivo signaling rewiring that would have been masked by analysis of in vitro cell population averages. Mol Cancer Ther; 16(11); 2572-85. (c)2017 AACR. PMID- 28830988 TI - Does Global Lung Initiative Obviate the Need for Lung Volume Measurements? PMID- 28830989 TI - Prognosis of Cancer Patients in the ICU: Much Work Remains. PMID- 28830990 TI - Prognosis of Cancer Patients in the ICU: Much Work Remains-Reply. PMID- 28830992 TI - Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics. AB - The human placenta is a dynamic and heterogeneous organ critical in the establishment of the fetomaternal interface and the maintenance of gestational well-being. It is also the major source of cell-free fetal nucleic acids in the maternal circulation. Placental dysfunction contributes to significant complications, such as preeclampsia, a potentially lethal hypertensive disorder during pregnancy. Previous studies have identified significant changes in the expression profiles of preeclamptic placentas using whole-tissue analysis. Moreover, studies have shown increased levels of targeted RNA transcripts, overall and placental contributions in maternal cell-free nucleic acids during pregnancy progression and gestational complications, but it remains infeasible to noninvasively delineate placental cellular dynamics and dysfunction at the cellular level using maternal cell-free nucleic acid analysis. In this study, we addressed this issue by first dissecting the cellular heterogeneity of the human placenta and defined individual cell-type-specific gene signatures by analyzing more than 24,000 nonmarker selected cells from full-term and early preeclamptic placentas using large-scale microfluidic single-cell transcriptomic technology. Our dataset identified diverse cellular subtypes in the human placenta and enabled reconstruction of the trophoblast differentiation trajectory. Through integrative analysis with maternal plasma cell-free RNA, we resolved the longitudinal cellular dynamics of hematopoietic and placental cells in pregnancy progression. Furthermore, we were able to noninvasively uncover the cellular dysfunction of extravillous trophoblasts in early preeclamptic placentas. Our work showed the potential of integrating transcriptomic information derived from single cells into the interpretation of cell-free plasma RNA, enabling the noninvasive elucidation of cellular dynamics in complex pathological conditions. PMID- 28830994 TI - Exotic birds provide unique insight into species invasions. PMID- 28830993 TI - Caterpillars lack a resident gut microbiome. AB - Many animals are inhabited by microbial symbionts that influence their hosts' development, physiology, ecological interactions, and evolutionary diversification. However, firm evidence for the existence and functional importance of resident microbiomes in larval Lepidoptera (caterpillars) is lacking, despite the fact that these insects are enormously diverse, major agricultural pests, and dominant herbivores in many ecosystems. Using 16S rRNA gene sequencing and quantitative PCR, we characterized the gut microbiomes of wild leaf-feeding caterpillars in the United States and Costa Rica, representing 124 species from 15 families. Compared with other insects and vertebrates assayed using the same methods, the microbes that we detected in caterpillar guts were unusually low-density and variable among individuals. Furthermore, the abundance and composition of leaf-associated microbes were reflected in the feces of caterpillars consuming the same plants. Thus, microbes ingested with food are present (although possibly dead or dormant) in the caterpillar gut, but host specific, resident symbionts are largely absent. To test whether transient microbes might still contribute to feeding and development, we conducted an experiment on field-collected caterpillars of the model species Manduca sexta Antibiotic suppression of gut bacterial activity did not significantly affect caterpillar weight gain, development, or survival. The high pH, simple gut structure, and fast transit times that typify caterpillar digestive physiology may prevent microbial colonization. Moreover, host-encoded digestive and detoxification mechanisms likely render microbes unnecessary for caterpillar herbivory. Caterpillars illustrate the potential ecological and evolutionary benefits of independence from symbionts, a lifestyle that may be widespread among animals. PMID- 28830995 TI - Covariations in ecological scaling laws fostered by community dynamics. AB - Scaling laws in ecology, intended both as functional relationships among ecologically relevant quantities and the probability distributions that characterize their occurrence, have long attracted the interest of empiricists and theoreticians. Empirical evidence exists of power laws associated with the number of species inhabiting an ecosystem, their abundances, and traits. Although their functional form appears to be ubiquitous, empirical scaling exponents vary with ecosystem type and resource supply rate. The idea that ecological scaling laws are linked has been entertained before, but the full extent of macroecological pattern covariations, the role of the constraints imposed by finite resource supply, and a comprehensive empirical verification are still unexplored. Here, we propose a theoretical scaling framework that predicts the linkages of several macroecological patterns related to species' abundances and body sizes. We show that such a framework is consistent with the stationary-state statistics of a broad class of resource-limited community dynamics models, regardless of parameterization and model assumptions. We verify predicted theoretical covariations by contrasting empirical data and provide testable hypotheses for yet unexplored patterns. We thus place the observed variability of ecological scaling exponents into a coherent statistical framework where patterns in ecology embed constrained fluctuations. PMID- 28830996 TI - Lucky kindlin: A cloverleaf at the integrin tail. PMID- 28830997 TI - Mechanistic target of rapamycin (mTOR): A mediator of social development. PMID- 28830998 TI - Profile of Margaret J. McFall-Ngai. PMID- 28830999 TI - Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA. AB - Blood circulates throughout the human body and contains molecules drawn from virtually every tissue, including the microbes and viruses which colonize the body. Through massive shotgun sequencing of circulating cell-free DNA from the blood, we identified hundreds of new bacteria and viruses which represent previously unidentified members of the human microbiome. Analyzing cumulative sequence data from 1,351 blood samples collected from 188 patients enabled us to assemble 7,190 contiguous regions (contigs) larger than 1 kbp, of which 3,761 are novel with little or no sequence homology in any existing databases. The vast majority of these novel contigs possess coding sequences, and we have validated their existence both by finding their presence in independent experiments and by performing direct PCR amplification. When their nearest neighbors are located in the tree of life, many of the organisms represent entirely novel taxa, showing that microbial diversity within the human body is substantially broader than previously appreciated. PMID- 28831000 TI - Inactivation of CREBBP expands the germinal center B cell compartment, down regulates MHCII expression and promotes DLBCL growth. AB - The genes encoding the histone acetyl-transferases (HATs) CREB binding protein (CREBBP) and EP300 are recurrently mutated in the activated B cell-like and germinal center (GC) B cell-like subtypes of diffuse large B cell lymphoma (DLBCL). Here, we introduced a patient mutation into a human DLBCL cell line using CRISPR and deleted Crebbp and Ep300 in the GC B cell compartment of mice. CREBBP-mutant DLBCL clones exhibited reduced histone H3 acetylation, expressed significantly less MHCII, and grew faster than wild-type clones in s.c. and orthotopic xenograft models. Mice lacking Crebbp in GC B cells exhibited hyperproliferation of their GC compartment upon immunization, had reduced MHCII surface expression on GC cells, and developed accelerated MYC-driven lymphomas. Ep300 inactivation reproduced some, but not all, consequences of Crebbp inactivation. MHCII deficiency phenocopied the effects of CREBBP loss in spontaneous and serial transplantation models of MYC-driven lymphomagenesis, supporting the idea that the mutational inactivation of CREBBP promotes immune evasion. Indeed, the depletion of CD4+ T cells greatly facilitated the engraftment of lymphoma cells in serial transplantation models. In summary, we provide evidence that both HATs are bona fide tumor suppressors that control MHCII expression and promote tumor immune control; mutational inactivation of CREBBP, but not of EP300, has additional cell-intrinsic engraftment and growth promoting effects. PMID- 28831001 TI - Auxin minimum triggers the developmental switch from cell division to cell differentiation in the Arabidopsis root. AB - In multicellular organisms, a stringent control of the transition between cell division and differentiation is crucial for correct tissue and organ development. In the Arabidopsis root, the boundary between dividing and differentiating cells is positioned by the antagonistic interaction of the hormones auxin and cytokinin. Cytokinin affects polar auxin transport, but how this impacts the positional information required to establish this tissue boundary, is still unknown. By combining computational modeling with molecular genetics, we show that boundary formation is dependent on cytokinin's control on auxin polar transport and degradation. The regulation of both processes shapes the auxin profile in a well-defined auxin minimum. This auxin minimum positions the boundary between dividing and differentiating cells, acting as a trigger for this developmental transition, thus controlling meristem size. PMID- 28831002 TI - Foldamer hypothesis for the growth and sequence differentiation of prebiotic polymers. AB - It is not known how life originated. It is thought that prebiotic processes were able to synthesize short random polymers. However, then, how do short-chain molecules spontaneously grow longer? Also, how would random chains grow more informational and become autocatalytic (i.e., increasing their own concentrations)? We study the folding and binding of random sequences of hydrophobic ([Formula: see text]) and polar ([Formula: see text]) monomers in a computational model. We find that even short hydrophobic polar (HP) chains can collapse into relatively compact structures, exposing hydrophobic surfaces. In this way, they act as primitive versions of today's protein catalysts, elongating other such HP polymers as ribosomes would now do. Such foldamer catalysts are shown to form an autocatalytic set, through which short chains grow into longer chains that have particular sequences. An attractive feature of this model is that it does not overconverge to a single solution; it gives ensembles that could further evolve under selection. This mechanism describes how specific sequences and conformations could contribute to the chemistry-to-biology (CTB) transition. PMID- 28831003 TI - Vertebrate-like CRYPTOCHROME 2 from monarch regulates circadian transcription via independent repression of CLOCK and BMAL1 activity. AB - Circadian repression of CLOCK-BMAL1 by PERIOD and CRYPTOCHROME (CRY) in mammals lies at the core of the circadian timekeeping mechanism. CRY repression of CLOCK BMAL1 and regulation of circadian period are proposed to rely primarily on competition for binding with coactivators on an alpha-helix located within the transactivation domain (TAD) of the BMAL1 C terminus. This model has, however, not been tested in vivo. Here, we applied CRISPR/Cas9-mediated mutagenesis in the monarch butterfly (Danaus plexippus), which possesses a vertebrate-like CRY (dpCRY2) and an ortholog of BMAL1, to show that insect CRY2 regulates circadian repression through TAD alpha-helix-dependent and -independent mechanisms. Monarch mutants lacking the BMAL1 C terminus including the TAD exhibited arrhythmic eclosion behavior. In contrast, mutants lacking the TAD alpha-helix but retaining the most distal C-terminal residues exhibited robust rhythms during the first day of constant darkness (DD1), albeit with a delayed peak of eclosion. Phase delay in this mutant on DD1 was exacerbated in the presence of a single functional allele of dpCry2, and rhythmicity was abolished in the absence of dpCRY2. Reporter assays in Drosophila S2 cells further revealed that dpCRY2 represses through two distinct mechanisms: a TAD-dependent mechanism that involves the dpBMAL1 TAD alpha-helix and dpCLK W328 and a TAD-independent mechanism involving dpCLK E333. Together, our results provide evidence for independent mechanisms of vertebrate-like CRY circadian regulation on the BMAL1 C terminus and the CLK PAS B domain and demonstrate the importance of a BMAL1 TAD-independent mechanism for generating circadian rhythms in vivo. PMID- 28831004 TI - Hydrodynamic and entropic effects on colloidal diffusion in corrugated channels. AB - In the absence of advection, confined diffusion characterizes transport in many natural and artificial devices, such as ionic channels, zeolites, and nanopores. While extensive theoretical and numerical studies on this subject have produced many important predictions, experimental verifications of the predictions are rare. Here, we experimentally measure colloidal diffusion times in microchannels with periodically varying width and contrast results with predictions from the Fick-Jacobs theory and Brownian dynamics simulation. While the theory and simulation correctly predict the entropic effect of the varying channel width, they fail to account for hydrodynamic effects, which include both an overall decrease and a spatial variation of diffusivity in channels. Neglecting such hydrodynamic effects, the theory and simulation underestimate the mean and standard deviation of first passage times by 40% in channels with a neck width twice the particle diameter. We further show that the validity of the Fick-Jacobs theory can be restored by reformulating it in terms of the experimentally measured diffusivity. Our work thus shows that hydrodynamic effects play a key role in diffusive transport through narrow channels and should be included in theoretical and numerical models. PMID- 28831005 TI - Protective major histocompatibility complex allele prevents type 1 diabetes by shaping the intestinal microbiota early in ontogeny. AB - Certain MHC-II or HLA-D alleles dominantly protect from particular autoimmune diseases. For example, expression of the MHC-II Ealpha:Ebeta complex potently protects nonobese diabetic (NOD) mice, which normally lack this isotype, from spontaneous development of type 1 diabetes. However, the underlying mechanisms remain debated. We investigated MHC-II-mediated protection from type 1 diabetes using a previously reported NOD mouse line expressing an Ealpha transgene and, thereby, the Ealpha:Ebeta complex. Ealpha16/NOD females vertically protected their NOD offspring from diabetes and insulitis, an effect that was dependent on the intestinal microbiota; moreover, they developed autoimmunity when treated with certain antibiotics or raised in a germ-free environment. Genomic and proteomic analyses revealed NOD and Ealpha16/NOD mice to host mild but significant differences in the intestinal microbiotas during a critical early window of ontogeny, and transfer of cecal contents from the latter to the former suppressed insulitis. Thus, protection from autoimmunity afforded by particular MHC/HLA alleles can operate via intestinal microbes, highlighting potentially important societal implications of treating infants, or even just their pregnant mothers, with antibiotics. PMID- 28831006 TI - Reconstruction of normal forms by learning informed observation geometries from data. AB - The discovery of physical laws consistent with empirical observations is at the heart of (applied) science and engineering. These laws typically take the form of nonlinear differential equations depending on parameters; dynamical systems theory provides, through the appropriate normal forms, an "intrinsic" prototypical characterization of the types of dynamical regimes accessible to a given model. Using an implementation of data-informed geometry learning, we directly reconstruct the relevant "normal forms": a quantitative mapping from empirical observations to prototypical realizations of the underlying dynamics. Interestingly, the state variables and the parameters of these realizations are inferred from the empirical observations; without prior knowledge or understanding, they parametrize the dynamics intrinsically without explicit reference to fundamental physical quantities. PMID- 28831007 TI - Exposure to rising inequality shapes Americans' opportunity beliefs and policy support. AB - Economic inequality has been on the rise in the United States since the 1980s and by some measures stands at levels not seen since before the Great Depression. Although the strikingly high and rising level of economic inequality in the nation has alarmed scholars, pundits, and elected officials alike, research across the social sciences repeatedly concludes that Americans are largely unconcerned about it. Considerable research has documented, for instance, the important role of psychological processes, such as system justification and American Dream ideology, in engendering Americans' relative insensitivity to economic inequality. The present work offers, and reports experimental tests of, a different perspective-the opportunity model of beliefs about economic inequality. Specifically, two convenience samples (study 1, n = 480; and study 2, n = 1,305) and one representative sample (study 3, n = 1,501) of American adults were exposed to information about rising economic inequality in the United States (or control information) and then asked about their beliefs regarding the roles of structural (e.g., being born wealthy) and individual (e.g., hard work) factors in getting ahead in society (i.e., opportunity beliefs). They then responded to policy questions regarding the roles of business and government actors in reducing economic inequality. Rather than revealing insensitivity to rising inequality, the results suggest that rising economic inequality in contemporary society can spark skepticism about the existence of economic opportunity in society that, in turn, may motivate support for policies designed to redress economic inequality. PMID- 28831008 TI - Balancing public safety and individual rights in street policing. PMID- 28831009 TI - Band gap formation and Anderson localization in disordered photonic materials with structural correlations. AB - Disordered dielectric materials with structural correlations show unconventional optical behavior: They can be transparent to long-wavelength radiation, while at the same time have isotropic band gaps in another frequency range. This phenomenon raises fundamental questions concerning photon transport through disordered media. While optical transparency in these materials is robust against recurrent multiple scattering, little is known about other transport regimes like diffusive multiple scattering or Anderson localization. Here, we investigate band gaps, and we report Anderson localization in 2D disordered dielectric structures using numerical simulations of the density of states and optical transport statistics. The disordered structures are designed with different levels of positional correlation encoded by the degree of stealthiness [Formula: see text] To establish a unified view, we propose a correlation-frequency ([Formula: see text]-[Formula: see text]) transport phase diagram. Our results show that, depending only on [Formula: see text], a dielectric material can transition from localization behavior to a band gap crossing an intermediate regime dominated by tunneling between weakly coupled states. PMID- 28831011 TI - Reply to Fattorini et al.: Children's selected avoidance of wild greenspace is driven by more than cultural factors. PMID- 28831012 TI - Children's preferences for less diverse greenspaces do not disprove biophilia. PMID- 28831010 TI - Nasopharyngeal carcinoma super-enhancer-driven ETV6 correlates with prognosis. AB - Nasopharyngeal carcinoma (NPC) most frequently occurs in southern China and southeast Asia. Epidemiology studies link NPC to genetic predisposition, Epstein Barr virus (EBV) infection, and environmental factors. Genetic studies indicate that mutations in chromatin-modifying enzymes are the most frequent genetic alterations in NPC. Here, we used H3K27ac chromatin immune precipitation followed by deep sequencing (ChIP-seq) to define the NPC epigenome in primary NPC biopsies, NPC xenografts, and an NPC cell line, and compared them to immortalized normal nasopharyngeal or oral epithelial cells. We identified NPC-specific enhancers and found these enhancers were enriched with nuclear factor kappaB (NF kappaB), IFN-responsive factor 1 (IRF1) and IRF2, and ETS family members ETS1 motifs. Normal cell-specific enhancers were enriched with basic leucine zipper family members and TP53 motifs. NPC super-enhancers with extraordinarily broad and high H3K27ac signals were also identified, and they were linked to genes important for oncogenesis including ETV6. ETV6 was also highly expressed in NPC biopsies by immunohistochemistry. High ETV6 expression correlated with a poor prognosis. Furthermore, we defined the EBV episome epigenetic landscapes in primary NPC tissue. PMID- 28831013 TI - 'Altmetrics'! Can you afford to ignore it? PMID- 28831014 TI - Diagnosis of acute groin injuries in athletes. PMID- 28831015 TI - Infographic: Elite athletes' anxiety over illness ups risk of injury in competition. PMID- 28831016 TI - Infographic: we need minimum reporting standards for biologics. PMID- 28831017 TI - Early comprehensive physiotherapy after lumbar spine surgery (PEDro synthesis). PMID- 28831019 TI - Multiplex quantitative assays indicate a need for reevaluating reported small molecule TrkB agonists. AB - Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes. To examine key pharmacological parameters of these compounds in detail, we have developed and optimized a series of complementary quantitative assays that measure TrkB receptor activation, TrkB dependent downstream signaling, and gene expression in different cellular contexts. Although BDNF and other neurotrophic factors elicited robust and dose dependent receptor activation and downstream signaling, we were unable to reproduce these activities using the reported small-molecule TrkB agonists. Our findings indicate that experimental results obtained with these compounds must be carefully interpreted and highlight the challenge of developing reliable pharmacological activators of this key molecular target. PMID- 28831020 TI - Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP. AB - Parkinson's disease (PD) is a neurodegenerative disorder in which the loss of dopaminergic neurons in the midbrain (mDA neurons) causes progressive loss of motor control and function. Using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells, we investigated the mechanisms controlling the survival of mDA neurons. We found that the extracellular matrix protein laminin-511 (LM511) promoted the survival and differentiation of mDA neurons. LM511 bound to integrin alpha3beta1 and activated the transcriptional cofactor YAP. LM511-YAP signaling enhanced cell survival by inducing the expression of the microRNA miR-130a, which suppressed the synthesis of the cell death-associated protein PTEN. In addition, LM511-YAP signaling increased the expression of transcription factors critical for mDA identity, such as LMX1A and PITX3, and prevented the loss of mDA neurons in response to oxidative stress, a finding that warrants further investigation to assess therapeutic potential for PD patients. We propose that by enhancing LM511-YAP signaling, it may be possible to prevent mDA neuron degeneration in PD or enhance the survival of mDA neurons in cell replacement therapies. PMID- 28831022 TI - The adaptor molecule RIAM integrates signaling events critical for integrin mediated control of immune function and cancer progression. AB - Lymphocyte activation requires adhesion to antigen-presenting cells. This is a critical event linking innate and adaptive immunity. Lymphocyte adhesion is accomplished through LFA-1, which must be activated by a process referred to as inside-out integrin signaling. Among the few signaling molecules that have been implicated in inside-out integrin activation in hematopoietic cells are the small guanosine triphosphatase (GTPase) Rap1 and its downstream effector Rap1 interacting molecule (RIAM), a multidomain protein that defined the Mig10-RIAM lamellipodin (MRL) class of adaptor molecules. Through its various domains, RIAM is a critical node of signal integration for activation of T cells, recruits monomeric and polymerized actin to drive actin remodeling and cytoskeletal reorganization, and promotes inside-out integrin signaling in T cells. As a regulator of inside-out integrin activation, RIAM affects multiple functions of innate and adaptive immunity. The effects of RIAM on cytoskeletal reorganization and integrin activation have implications in cell migration and trafficking of cancer cells. We provide an overview of the structure and interactions of RIAM, and we discuss the implications of RIAM functions in innate and adaptive immunity and cancer. PMID- 28831021 TI - A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch. AB - Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene-related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-Z pentenyl-E-epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy 12,13-trans-epoxy-(9Z)-octadecenoate elicited C-fiber-mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies to manage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13-trans-epoxy-(9Z) octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13-trans-epoxy-(10E)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch. PMID- 28831023 TI - Mild cold induced thermogenesis: are BAT and skeletal muscle synergistic partners? AB - There are two well-described thermogenic sites; brown adipose tissue (BAT) and skeletal muscle, which utilize distinct mechanisms of heat production. In BAT, mitochondrial metabolism is the molecular basis of heat generation, while it serves only a secondary role in supplying energy for thermogenesis in muscle. Here, we wanted to document changes in mitochondrial ultrastructure in these two tissue types based upon adaptation to mild (16 degrees C) and severe (4 degrees C) cold in mice. When reared at thermoneutrality (29 degrees C), mitochondria in both tissues were loosely packed with irregular cristae. Interestingly, adaptation to even mild cold initiated ultrastructural remodeling of mitochondria including acquisition of more elaborate cristae structure in both thermogenic sites. The shape of mitochondria in the BAT remained mostly circular, whereas the intermyofibrilar mitochondria in the skeletal muscle became more elongated and tubular. The most dramatic remodeling of mitochondrial architecture was observed upon adaptation to severe cold. In addition, we report cold-induced alteration in levels of humoral factors: fibroblast growth factor 21 (FGF21), IL1alpha, peptide YY (PYY), tumor necrosis factor alpha (TNFalpha), and interleukin 6 (IL6) were all induced whereas both insulin and leptin were down-regulated. In summary, adaptation to cold leads to enhanced cristae formation in mitochondria in skeletal muscle as well as the BAT. Further, the present study indicates that circulating cytokines might play an important role in the synergistic recruitment of the thermogenic program including cross-talk between muscle and BAT. PMID- 28831024 TI - Effect of Liuweibuqi capsules on the balance between MMP-9 and TIMP1 and viability of alveolar macrophages in COPD. AB - The present study aims to investigate the effect of Liuweibuqi (LWBQ) capsules on the expression of matrix metalloproteinase (MMP)-9 and TIMP1 and cell viability of alveolar macrophages (AMs) in chronic obstructive pulmonary disease (COPD). Rats were randomly divided into normal control (NC) group, model control (MC) group, Jinshuibao (JSB) group, spleen aminopeptidase (PAT) group, and low dose of LWBQ (LWBQ low), mid dose of LWBQ (LWBQ mid), and high dose of LWBQ (LWBQ high) group (n=10). Lung function was measured with a spirometer. Serum cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were detected using ELISA. The expressions of MMP-9 and TIMP1 were detected by quantitative real-time PCR (qRT-PCR) and Western blot. MTT assay and flow cytometry were used to measure cell viability and apoptosis. Compared with the NC group, body weight and lung function were reduced in the MC group. In addition, the serum levels of IL-6 and TNF-alpha were higher in the MC group than those in the NC group. The expression of MMP-9 protein in the AMs from rats was higher, and TIMP1 protein was lower in the MC group compared with the NC group. After LWBQ capsules treatment, compared with the MC group, the expression of inflammatory cytokines and MMP-9 were lower and TIMP1 was higher. Moreover, after LWBQ-medicated serum treatment, the release of inflammatory cytokines was reduced from AMs. Besides, LWBQ-medicated serum decreased the expression of MMP-9 and increased the expression of TIMP1 and cell viability compared with those in MC group. In conclusion, LWBQ capsules can inhibit the release of inflammatory cytokines, promote cell viability in AMs, and regulate the expression of MMP-9 and TIMP1. PMID- 28831026 TI - Science and Culture: Arctic photographers bring climate change into focus. PMID- 28831025 TI - LncRNA-XIST interacts with miR-29c to modulate the chemoresistance of glioma cell to TMZ through DNA mismatch repair pathway. AB - Temozolomide (TMZ) is the most commonly used alkylating agent in glioma chemotherapy. However, growing resistance to TMZ remains a major challenge for clinicians. Recent evidence emphasizes the key regulatory roles of non-coding RNAs (lncRNAs and miRNAs) in tumor biology, including the chemoresistance of cancers. However, little is known about the role and regulation mechanisms of lncRNA cancer X-inactive specific transcripts (XIST) in glioma tumorigenesis and chemotherapy resistance. In the present study, higher XIST expression was observed in glioma tissues and cell lines, which was related to poorer clinicopathologic features and shorter survival time. XIST knockdown alone was sufficient to inhibit glioma cell proliferation and to amplify TMZ-induced cell proliferation inhibition. Moreover, XIST knockdown can sensitize TMZ-resistant glioma cells to TMZ. XIST can inhibit miR-29c expression by directly targetting TMZ-resistant glioma cells. DNA repair protein O6-methylguanine-DNA methytransferase (MGMT) plays a key role in TMZ resistance; transcription factor specificity protein 1 (SP1), a regulator of DNA mismatch repair (MMR) key protein MSH6, has been reported to be up-regulated in TMZ-resistant glioma cell lines. In the present study, we show that XIST/miR-29c coregulates SP1 and MGMT expression in TMZ-resistant glioma cell lines. Our data suggest that XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR-29c via SP1 and MGMT. XIST/miR-29c may be a potential therapeutic target for glioma treatment. PMID- 28831027 TI - Core Concept: Probing the phytobiome to advance agriculture. PMID- 28831030 TI - FDA's new plan to reduce the nicotine in cigarettes to sub-addictive levels could be a game-changer. PMID- 28831031 TI - Two-Component Signal Transduction: a Special Issue in the Journal of Bacteriology. PMID- 28831032 TI - Salidroside Reduces High-Glucose-Induced Podocyte Apoptosis and Oxidative Stress via Upregulating Heme Oxygenase-1 (HO-1) Expression. AB - BACKGROUND Hyperglycemia is one of the most dangerous factors causing diabetic nephropathy. Salidroside is considered to have the effects of reducing oxidative stress damage and improving cell viability. This study was performed to investigate whether and how salidroside reduces high-glucose (HG)-induced apoptosis in mouse podocytes. MATERIAL AND METHODS We examined whether salidroside could decrease HG-induced podocyte oxidative stress and podocyte apoptosis in vitro. The potential signaling pathways were also investigated. Podocytes (immortalized mouse epithelial cells) were treated with normal glucose (5.5 mM) as control or HG (30 mM), and then exposed to salidroside treatment. RESULTS HG enhanced the generation of intracellular reactive oxygen species (ROS) and apoptosis in podocytes. Salidroside reduced HG-induced apoptosis-related consequences via promoting HO-1 expression. Salidroside increased the expression level of phosphorylated Akt (p-Akt) and phosphorylated ILK (p-ILK), p-JNK, and p ERK and localization of Nrf-2. JNK inhibitor and ILK inhibitor decreased HO-1 expression to different degrees. Moreover, specific siRNAs of ILK, Nrf-2, and HO 1, and inhibitors of HO-1 and ILK significantly increased ROS generation and Caspase9/3 expression in the presence of salidroside and HG. CONCLUSIONS The results suggest that salidroside reduces HG-induced ROS generation and apoptosis and improves podocytes viability by upregulating HO-1 expression. ILK/Akt, JNK, ERK1/2, p38 MAPK, and Nrf-2 are involved in salidroside-decreased podocyte apoptosis in HG condition. PMID- 28831033 TI - Joining smallholder farmers' traditional knowledge with metric traits to select better varieties of Ethiopian wheat. AB - Smallholder farming communities face highly variable climatic conditions that threaten locally adapted, low-input agriculture. The benefits of modern crop breeding may fail to reach their fields when broadly adapted genetic materials do not address local requirements. To date, participatory methods only scratched the surface of the exploitability of farmers' traditional knowledge in breeding. In this study, 30 smallholder farmers in each of two locations in Ethiopia provided quantitative evaluations of earliness, spike morphology, tillering capacity and overall quality on 400 wheat genotypes, mostly traditional varieties, yielding altogether 192,000 data points. Metric measurements of ten agronomic traits were simultaneously collected, allowing to systematically break down farmers' preferences on quantitative phenotypes. Results showed that the relative importance of wheat traits differed by gender and location. Farmer traits were variously contributed by metric traits, and could only partially be explained by them. Eventually, farmer trait values were used to produce a ranking of the 400 wheat varieties identifying the trait combinations most desired by farmers. The study scale and methods lead to a better understanding of the quantitative basis of Ethiopian smallholder farmer preference in wheat, broadening the discussion for the future of local, sustainable breeding efforts accommodating farmers' knowledge. PMID- 28831034 TI - Stimulatory Effect of Intermittent Hypoxia on the Production of Corticosterone by Zona Fasciculata-Reticularis Cells in Rats. AB - Hypoxia or intermittent hypoxia (IH) have known to alter both synthesis and secretion of hormones. However, the effect of IH on the production of adrenal cortical steroid hormones is still unclear. The aim of present study was to explore the mechanism involved in the effect of IH on the production of corticosterone by rat ZFR cells. Male rats were exposed at 12% O2 and 88% N2 (8 hours per day) for 1, 2, or 4 days. The ZFR cells were incubated at 37 degrees C for 1 hour with or without ACTH, 8-Br-cAMP, calcium ion channel blockers, or steroidogenic precursors. The concentration of plasma corticosterone was increased time-dependently by administration of IH hypoxia. The basal levels of corticosterone production in cells were higher in the IH groups than in normoxic group. IH resulted in a time-dependent increase of corticosterone production in response to ACTH, 8-Br-cAMP, progesterone and deoxycorticosterone. The production of pregnenolone in response to 25-OH-C and that of progesterone in response to pregnenolone in ZFR cells were enhanced by 4-day IH. These results suggest that IH in rats increases the secretion of corticosterone via a mechanism at least in part associated with the activation of cAMP pathway and steroidogenic enzymes. PMID- 28831035 TI - Molecular Phylogeny and Revision of Copepod Orders (Crustacea: Copepoda). AB - For the first time, the phylogenetic relationships between representatives of all 10 copepod orders have been investigated using 28S and 18S rRNA, Histone H3 protein and COI mtDNA. The monophyly of Copepoda (including Platycopioida Fosshagen, 1985) is demonstrated for the first time using molecular data. Maxillopoda is rejected, as it is a polyphyletic group. The monophyly of the major subgroups of Copepoda, including Progymnoplea Lang, 1948 (=Platycopioida); Neocopepoda Huys and Boxshall, 1991; Gymnoplea Giesbrecht, 1892 (=Calanoida Sars, 1903); and Podoplea Giesbrecht, 1892, are supported in this study. Seven copepod orders are monophyletic, including Platycopioida, Calanoida, Misophrioida Gurney, 1933; Monstrilloida Sars, 1901; Siphonostomatoida Burmeister, 1834; Gelyelloida Huys, 1988; and Mormonilloida Boxshall, 1979. Misophrioida (=Propodoplea Lang, 1948) is the most basal Podoplean order. The order Cyclopoida Burmeister, 1835, is paraphyletic and now encompasses Poecilostomatoida Thorell, 1859, as a sister to the family Schminkepinellidae Martinez Arbizu, 2006. Within Harpacticoida Sars, 1903, both sections, Polyarthra Lang, 1948, and Oligoarthra Lang, 1948, are monophyletic, but not sister groups. The order Canuelloida is proposed while maintaining the order Harpacticoida s. str. (Oligoarthra). Cyclopoida, Harpacticoida and Cyclopinidae are redefined, while Canuelloida ordo. nov., Smirnovipinidae fam. nov. and Cyclopicinidae fam. nov are proposed as new taxa. PMID- 28831037 TI - The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress alpha-synuclein aggregation. AB - A major hallmark of Parkinson's disease (PD) is the presence of Lewy bodies (LBs) in certain neuronal tissues. LBs are protein-rich inclusions, in which alpha synuclein (alpha-syn) is the most abundant protein. Since these inclusions are not present in healthy individuals, despite the high concentration of alpha-syn in neurons, it is important to investigate whether natural control mechanisms are present to efficiently suppress alpha-syn aggregation. Here, we demonstrate that a CRISPR/Cas9-mediated knockout (KO) of a DnaJ protein, DNAJB6, in HEK293T cells expressing alpha-syn, causes a massive increase in alpha-syn aggregation. Upon DNAJB6 re-introduction into these DNAJB6-KO HEK293T-alpha-syn cells, aggregation is reduced to the level of the parental cells. We then show that the suppression of alpha-syn aggregation is dependent on the J-domain of DNAJB6, as the catalytically inactive protein, which carries the H31Q mutation, does not suppress aggregation, when re-introduced into DNAJB6-KO cells. We further demonstrate, that the suppression of alpha-syn aggregation is dependent on the molecular chaperone Hsp70, which is consistent with the well-known function of J domains of transferring unfolded and misfolded proteins to Hsp70. These data identify a natural control strategy to suppress alpha-syn aggregation and suggest potential therapeutic approaches to prevent or treat PD and related disorders. PMID- 28831036 TI - BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. AB - Complete loss of BRCA1 or BRCA2 function is associated with sensitivity to DNA damaging agents. However, not all BRCA1 and BRCA2 germline mutation-associated tumors respond. Herein we report analyses of 160 BRCA1 and BRCA2 germline mutation-associated breast and ovarian tumors. Retention of the normal BRCA1 or BRCA2 allele (absence of locus-specific loss of heterozygosity (LOH)) is observed in 7% of BRCA1 ovarian, 16% of BRCA2 ovarian, 10% of BRCA1 breast, and 46% of BRCA2 breast tumors. These tumors have equivalent homologous recombination deficiency scores to sporadic tumors, significantly lower than scores in tumors with locus-specific LOH (ovarian, P = 0.0004; breast P < 0.0001, two-tailed Student's t-test). Absence of locus-specific LOH is associated with decreased overall survival in ovarian cancer patients treated with platinum chemotherapy (P = 0.01, log-rank test). Locus-specific LOH may be a clinically useful biomarker to predict primary resistance to DNA damaging agents in patients with germline BRCA1 and BRCA2 mutations.Most tumours associated with germline BRCA1/BRCA2 loss of function mutations respond to DNA damaging agents, however, some do not. Herein, the authors identify that a subset of breast/ovarian tumors retain a normal allele, which is associated with decreased overall survival after DNA damage-inducing platinum chemotherapy. PMID- 28831038 TI - Caesarean Section is associated with reduced perinatal cytokine response, increased risk of bacterial colonization in the airway, and infantile wheezing. AB - The relationship between cesarean section (CS) and allergic disorders such as asthma and wheezing has been inconsistent, and the mechanisms for their connection remained largely unknown. We aimed to investigate whether CS is associated with infantile wheeze and to explore the connection between CS and several risk factors known to correlate with allergy development. Mononuclear cells were isolated from cord blood and assessed for cytokine responses by ELISA. Bacteria from nasopharyngeal specimens were identified with traditional culture methods. Infant lung function tests were performed at 6 and 12 months of age. IgE levels and clinical outcomes were assessed at 12 months. The result showed that children delivered by CS were associated with increased risk of wheezing (aHR 1.63; 95% CI: 1.01-2.62) and decreased compliance of the respiratory system at 12 months (p = 0.045). In addition, CS was associated with reduced TLR1-2- triggered TNF-alpha and IL-6 responses at birth. By12 months of age, children delivered by CS had significantly less airway bacterial clearance. Our findings suggested that CS was associated with decreased pro-inflammatory cytokine response to TLR1-2 stimulation, followed by higher abundance of bacterial colonization in the airway during late infancy, thus increasing the risk of infantile wheezing. PMID- 28831039 TI - Exit from quiescence displays a memory of cell growth and division. AB - Reactivating quiescent cells to proliferate is critical to tissue repair and homoeostasis. Quiescence exit is highly noisy even for genetically identical cells under the same environmental conditions. Deregulation of quiescence exit is associated with many diseases, but cellular mechanisms underlying the noisy process of exiting quiescence are poorly understood. Here we show that the heterogeneity of quiescence exit reflects a memory of preceding cell growth at quiescence induction and immediate division history before quiescence entry, and that such a memory is reflected in cell size at a coarse scale. The deterministic memory effects of preceding cell cycle, coupled with the stochastic dynamics of an Rb-E2F bistable switch, jointly and quantitatively explain quiescence-exit heterogeneity. As such, quiescence can be defined as a distinct state outside of the cell cycle while displaying a sequential cell order reflecting preceding cell growth and division variations.The quiescence-exit process is noisy even in genetically identical cells under the same environmental conditions. Here the authors show that the heterogeneity of quiescence exit reflects a memory of preceding cell growth at quiescence induction and immediate division history prior to quiescence entry. PMID- 28831040 TI - One-domain CD4 Fused to Human Anti-CD16 Antibody Domain Mediates Effective Killing of HIV-1-Infected Cells. AB - Bispecific killer cells engagers (BiKEs) which can bind to natural killer (NK) cells through the activating receptor CD16A and guide them to cells expressing the HIV-1 envelope glycoprotein (Env) are a promising new weapon for elimination of infected cells and eradication of the virus. Here we report the design, generation and characterization of BiKEs which consist of CD16A binding human antibody domains fused through a flexible linker to an engineered one-domain soluble human CD4. In presence of cells expressing HIV-1 envelope glycoproteins (Envs), these BiKEs activated specifically CD16A-expressing Jurkat T cells, degranulated NK cells, induced cytokine production and killed Env-expressing cells. They also effectively mediated killing of chronically and acutely HIV-1 infected T cells by human peripheral blood mononuclear cells. The presumed ability of these CD4-based BiKEs to bind all HIV-1 isolates, their small size and fully human origin, combined with high efficacy suggest their potential for HIV-1 eradication. PMID- 28831041 TI - Ambient particulate air pollution (PM2.5) is associated with the ratio of type 2 diabetes to obesity. AB - We used county level data for T2D prevalence across the mainland USA and matched this to county level ambient PM2.5. Multiple linear regression was used to determine the relation between prevalence of T2D with PM2.5 after adjustment for confounding factors. PM2.5 explained 6.3% of the spatial variation in obesity, and 17.9% of the spatial variation in T2D. After correcting the T2D prevalence for obesity, race, poverty, education and temperature, PM2.5 still explained 8.3% of the residual variation in males (P < 0.0001) and 11.5% in females (P < 0.0001). The effect on obesity prevalence corrected for poverty, race education and temperature was much lower and hence the ratio of T2D to obesity prevalence was significantly associated with PM2.5 in males (R2 = 11.1%, P < 0.0001) and females (R2 = 16.8%, P < 0.0001). This association was repeated across non African countries (R2 = 14.9%, P < 0.0001). High levels of PM2.5 probably contribute to increased T2D prevalence in the USA, but have a more minor effect on the obesity. Exposure to high environmental levels of PM2.5 (relative to the USA) may explain the disproportional risk of T2D in relation to obesity in Asian populations. PMID- 28831043 TI - The influence of attention and reward on the learning of stimulus-response associations. AB - We can learn new tasks by listening to a teacher, but we can also learn by trial and-error. Here, we investigate the factors that determine how participants learn new stimulus-response mappings by trial-and-error. Does learning in human observers comply with reinforcement learning theories, which describe how subjects learn from rewards and punishments? If yes, what is the influence of selective attention in the learning process? We developed a novel redundant relevant learning paradigm to examine the conjoint influence of attention and reward feedback. We found that subjects only learned stimulus-response mappings for attended shapes, even when unattended shapes were equally informative. Reward magnitude also influenced learning, an effect that was stronger for attended than for non-attended shapes and that carried over to a subsequent visual search task. Our results provide insights into how attention and reward jointly determine how we learn. They support the powerful learning rules that capitalize on the conjoint influence of these two factors on neuronal plasticity. PMID- 28831042 TI - Acoustically actuated ultra-compact NEMS magnetoelectric antennas. AB - State-of-the-art compact antennas rely on electromagnetic wave resonance, which leads to antenna sizes that are comparable to the electromagnetic wavelength. As a result, antennas typically have a size greater than one-tenth of the wavelength, and further miniaturization of antennas has been an open challenge for decades. Here we report on acoustically actuated nanomechanical magnetoelectric (ME) antennas with a suspended ferromagnetic/piezoelectric thin film heterostructure. These ME antennas receive and transmit electromagnetic waves through the ME effect at their acoustic resonance frequencies. The bulk acoustic waves in ME antennas stimulate magnetization oscillations of the ferromagnetic thin film, which results in the radiation of electromagnetic waves. Vice versa, these antennas sense the magnetic fields of electromagnetic waves, giving a piezoelectric voltage output. The ME antennas (with sizes as small as one-thousandth of a wavelength) demonstrates 1-2 orders of magnitude miniaturization over state-of-the-art compact antennas without performance degradation. These ME antennas have potential implications for portable wireless communication systems.The miniaturization of antennas beyond a wavelength is limited by designs which rely on electromagnetic resonances. Here, Nan et al. have developed acoustically actuated antennas that couple the acoustic resonance of the antenna with the electromagnetic wave, reducing the antenna footprint by up to 100. PMID- 28831044 TI - Synthesis of quenchable amorphous diamond. AB - Diamond owes its unique mechanical, thermal, optical, electrical, chemical, and biocompatible materials properties to its complete sp 3-carbon network bonding. Crystallinity is another major controlling factor for materials properties. Although other Group-14 elements silicon and germanium have complementary crystalline and amorphous forms consisting of purely sp 3 bonds, purely sp 3 bonded tetrahedral amorphous carbon has not yet been obtained. In this letter, we combine high pressure and in situ laser heating techniques to convert glassy carbon into "quenchable amorphous diamond", and recover it to ambient conditions. Our X-ray diffraction, high-resolution transmission electron microscopy and electron energy-loss spectroscopy experiments on the recovered sample and computer simulations confirm its tetrahedral amorphous structure and complete sp 3 bonding. This transparent quenchable amorphous diamond has, to our knowledge, the highest density among amorphous carbon materials, and shows incompressibility comparable to crystalline diamond.Diamond's properties are dictated by its crystalline, fully tetrahedrally bonded structure. Here authors synthesize a bulk sp 3-bonded amorphous form of carbon under high pressure and temperature, show that it has bulk modulus comparable to crystalline diamond and that it can be recovered under ambient conditions. PMID- 28831045 TI - Layered van der Waals crystals with hyperbolic light dispersion. AB - Compared to artificially structured hyperbolic metamaterials, whose performance is limited by the finite size of the metallic components, the sparse number of naturally hyperbolic materials recently discovered are promising candidates for the next generation of hyperbolic materials. Using first-principles calculations, we extend the number of known naturally hyperbolic materials to the broad class of layered transition metal dichalcogenides (TMDs). The diverse electronic properties of the transition metal dichalcogenides result in a large variation of the hyperbolic frequency regimes ranging from the near-infrared to the ultraviolet. Combined with the emerging field of van der Waals heterostructuring, we demonstrate how the hyperbolic properties can be further controlled by stacking different two-dimensional crystals opening new perspectives for atomic scale design of photonic metamaterials. As an application, we identify candidates for Purcell factor control of emission from diamond nitrogen-vacancy centers.Natural hyperbolic materials retain the peculiar optical properties of traditional metamaterials whilst not requiring artificial structuring. Here, the authors perform a theoretical screening of a large class of natural materials with hyperbolic dispersion among the family of layered transition metal dichalcogenides. PMID- 28831046 TI - Pulmonary inflammation and cytokine dynamics of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during A(H1N1)pdm09 influenza infection. AB - Asthmatic patients present more rapid progression of respiratory distress after A(H1N1)pdm09 influenza infection than after seasonal infection. Here, we sought to clarify the pathophysiology of early deterioration in asthmatic patients after A(H1N1)pdm09 infection. Cytokine levels and virus titres in bronchoalveolar lavage fluid from mice with and without asthma after A(H1N1)pdm09 or seasonal H1N1 infection were examined. In asthma/A(H1N1)pdm09 mice, IL-6 and TNF-alpha levels peaked at 3 days post-infection and were higher than those in all other groups. IFN-gamma levels in asthma/A(H1N1)pdm09 mice at 3 days post-infection were higher than in all other mice at any time point, whereas at 7 days post infection, the levels were lowest in asthma/A(H1N1)pdm09 mice. Virus titres in asthma/A(H1N1)pdm09 mice were highest at 3 days post-infection, and decreased by 7 days post-infection, although the levels at this time point were still higher than that in any other group. Histopathological examination showed more inflammatory cell infiltration and lung tissue destruction in the asthma/A(H1N1)pdm09 group than in any other group. The distinct cytokine profiles in A(H1N1)pdm09-infected asthmatic mice indicated excessive inflammation and virus replication within a few days after infection. Thus, bronchial asthma could be a more exacerbating factor for pandemic influenza infection than for seasonal influenza infection. PMID- 28831048 TI - Tip-dated phylogeny of whirligig beetles reveals ancient lineage surviving on Madagascar. AB - The temporal origin of Madagascar's extraordinary endemic diversity is debated. A preference for Cenozoic dispersal origins has replaced the classical view of Mesozoic vicariance in the wake of molecular dating. However, evidence of ancient origins is mounting from arthropod groups. Using phylogenetic 'tip-dating' analysis with fossils, we show that a whirligig beetle species, Heterogyrus milloti, inhabiting forest streams in southeastern Madagascar is the last survivor of a once dominant and widespread Mesozoic group. With a Late Triassic to Early Jurassic origin (226-187 Ma) it is the hitherto oldest dated endemic lineage of animal or plant on Madagascar. Island biotas' sensitivity to extinction is well known, but islands can also provide refuge from continental extinction. Heterogyrus milloti is an irreplaceable link to the freshwater biota of the Mesozoic and serves as a reminder of what may be lost without critical conservation efforts on Madagascar. PMID- 28831047 TI - Flow-induced elongation of von Willebrand factor precedes tension-dependent activation. AB - Von Willebrand factor, an ultralarge concatemeric blood protein, must bind to platelet GPIbalpha during bleeding to mediate hemostasis, but not in the normal circulation to avoid thrombosis. Von Willebrand factor is proposed to be mechanically activated by flow, but the mechanism remains unclear. Using microfluidics with single-molecule imaging, we simultaneously monitored reversible Von Willebrand factor extension and binding to GPIbalpha under flow. We show that Von Willebrand factor is activated through a two-step conformational transition: first, elongation from compact to linear form, and subsequently, a tension-dependent local transition to a state with high affinity for GPIbalpha. High-affinity sites develop only in upstream regions of VWF where tension exceeds ~21 pN and depend upon electrostatic interactions. Re-compaction of Von Willebrand factor is accelerated by intramolecular interactions and increases GPIbalpha dissociation rate. This mechanism enables VWF to be locally activated by hydrodynamic force in hemorrhage and rapidly deactivated downstream, providing a paradigm for hierarchical mechano-regulation of receptor-ligand binding.Von Willebrand factor (VWF) is a blood protein involved in clotting and is proposed to be activated by flow, but the mechanism is unknown. Here the authors show that VWF is first converted from a compact to linear form by flow, and is subsequently activated to bind GPIbalpha in a tension-dependent manner. PMID- 28831050 TI - Morph specific foraging behavior by a polymorphic raptor under variable light conditions. AB - Colour polymorphism may be maintained within a population by disruptive selection. One hypothesis proposes that different morphs are adapted to different ambient light conditions, with lighter morphs having a selective advantage in bright conditions and darker morphs having advantages in darker conditions. The mechanism for this advantage is proposed to be through enhanced crypsis via background-matching. We explore this hypothesis in a polymorphic raptor, the black sparrowhawk Accipiter melanoleucus, which exhibits a discrete dark and white-morph. We use GPS-tracking data to contrast the foraging behaviour and habitat selection of morphs. As predicted, we found that light-levels influenced foraging behaviour in different ways for morphs: Dark-morphs showed a decrease in foraging with increasing light-levels; whereas no relationship was found for white-morphs. Furthermore, we found differential-degrees of habitat selection, with dark-morphs selecting more enclosed habitats compared to white-morphs. This suggests that different morphs may be better adapted to foraging under different light-conditions, potentially playing a role in maintaining colour polymorphism in this species. Our results may also help explain why dark-morphs predominate in this study region, which experiences high rainfall and lower light-levels during the breeding-period. This study suggests that avian morphs may allocate/partition foraging activity by weather conditions/habitat, which maximise their concealment from prey. PMID- 28831051 TI - A mobile pathogenicity chromosome in Fusarium oxysporum for infection of multiple cucurbit species. AB - The genome of Fusarium oxysporum (Fo) consists of a set of eleven 'core' chromosomes, shared by most strains and responsible for housekeeping, and one or several accessory chromosomes. We sequenced a strain of Fo f.sp. radicis cucumerinum (Forc) using PacBio SMRT sequencing. All but one of the core chromosomes were assembled into single contigs, and a chromosome that shows all the hallmarks of a pathogenicity chromosome comprised two contigs. A central part of this chromosome contains all identified candidate effector genes, including homologs of SIX6, SIX9, SIX11 and SIX 13. We show that SIX6 contributes to virulence of Forc. Through horizontal chromosome transfer (HCT) to a non pathogenic strain, we also show that the accessory chromosome containing the SIX gene homologs is indeed a pathogenicity chromosome for cucurbit infection. Conversely, complete loss of virulence was observed in Forc016 strains that lost this chromosome. We conclude that also a non-wilt-inducing Fo pathogen relies on effector proteins for successful infection and that the Forc pathogenicity chromosome contains all the information necessary for causing root rot of cucurbits. Three out of nine HCT strains investigated have undergone large-scale chromosome alterations, reflecting the remarkable plasticity of Fo genomes. PMID- 28831049 TI - Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development. AB - Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life. PMID- 28831052 TI - Rapid amplification of four retrotransposon families promoted speciation and genome size expansion in the genus Panax. AB - Genome duplication and repeat multiplication contribute to genome evolution in plants. Our previous work identified a recent allotetraploidization event and five high-copy LTR retrotransposon (LTR-RT) families PgDel, PgTat, PgAthila, PgTork, and PgOryco in Panax ginseng. Here, using whole-genome sequences, we quantified major repeats in five Panax species and investigated their role in genome evolution. The diploids P. japonicus, P. vietnamensis, and P. notoginseng and the tetraploids P. ginseng and P. quinquefolius were analyzed alongside their relative Aralia elata. These species possess 0.8-4.9 Gb haploid genomes. The PgDel, PgTat, PgAthila, and PgTork LTR-RT superfamilies accounted for 39-52% of the Panax species genomes and 17% of the A. elata genome. PgDel included six subfamily members, each with a distinct genome distribution. In particular, the PgDel1 subfamily occupied 23-35% of the Panax genomes and accounted for much of their genome size variation. PgDel1 occupied 22.6% (0.8 Gb of 3.6 Gb) and 34.5% (1.7 Gb of 4.9 Gb) of the P. ginseng and P. quinquefolius genomes, respectively. Our findings indicate that the P. quinquefolius genome may have expanded due to rapid PgDel1 amplification over the last million years as a result of environmental adaptation following migration from Asia to North America. PMID- 28831053 TI - Large Scale Metabolic Profiling identifies Novel Steroids linked to Rheumatoid Arthritis. AB - Recent metabolomics studies of Rheumatoid Arthritis (RA) reported few metabolites that were associated with the disease, either due to small cohort sizes or limited coverage of metabolic pathways. Our objective is to identify metabolites associated with RA and its cofounders using a new untargeted metabolomics platform. Moreover, to investigate the pathomechanism of RA by identifying correlations between RA-associated metabolites. 132 RA patients and 104 controls were analyzed for 927 metabolites. Metabolites were tested for association with RA using linear regression. OPLS-DA was used to discriminate RA patients from controls. Gaussian Graphical Models (GGMs) were used to identify correlated metabolites. 32 metabolites are identified as significantly (Bonferroni) associated with RA, including the previously reported metabolites as DHEAS, cortisol and androstenedione and extending that to a larger set of metabolites in the steroid pathway. RA classification using metabolic profiles shows a sensitivity of 91% and specificity of 88%. Steroid levels show variation among the RA patients according to the corticosteroid treatment; lowest in those taking the treatment at the time of the study, higher in those who never took the treatment, and highest in those who took it in the past. Finally, the GGM reflects metabolite relations from the steroidogenesis pathway. PMID- 28831054 TI - Recovery of hippocampal functions and modulation of muscarinic response by electroacupuncture in young diabetic rats. AB - The muscarinic receptor response to acetylcholine regulates the hippocampal related learning, memory, neural plasticity and the production and processing of the pro-nerve growth factor (proNGF) by hippocampal cells. The development and progression of diabetes generate a mild cognitive impairment reducing the functions of the septo-hippocampal cholinergic circuitry, depressing neural plasticity and inducing proNGF accumulation in the brain. Here we demonstrate, in a rat model of early type-1 diabetes, that a physical therapy, the electroacupuncture, counteracts the diabetes-induced deleterious effects on hippocampal physiology by ameliorating hippocampal-related memory functions; recovering the impaired long-term potentiation at the dentate gyrus (DG-LTP) and the lowered expression of the vesicular glutamate transporter 1; normalizing the activity-dependent release of proNGF in diabetic rat hippocampus. Electroacupuncture exerted its therapeutic effects by regulating the expression and activity of M1- and M2-acetylcholine muscarinic receptors subtypes in the dentate gyrus of hippocampus. Our results suggest that a physical therapy based on repetitive sensory stimulation could promote hippocampal neural activity, neuronal metabolism and functions, and conceivably improve the diabetes-induced cognitive impairment. Our data can support the setup of therapeutic protocols based on a better integration between physical therapies and pharmacology for the cure of diabetes-associated neurodegeneration and possibly for Alzheimer's disease. PMID- 28831055 TI - Horizontal transfer of a beta-1,6-glucanase gene from an ancestral species of fungal endophyte to a cool-season grass host. AB - Molecular characterisation has convincingly demonstrated some types of horizontal gene transfer in eukaryotes, but nuclear gene transfer between distantly related eukaryotic groups appears to have been rare. For angiosperms (flowering plants), nuclear gene transfer events identified to date have been confined to genes originating from prokaryotes or other plant species. In this report, evidence for ancient horizontal transfer of a fungal nuclear gene, encoding a beta-1,6 glucanase enzyme for fungal cell wall degradation, into an angiosperm lineage is presented for the first time. The gene was identified from de novo sequencing and assembly of the genome and transcriptome of perennial ryegrass, a cool-season grass species. Molecular analysis confirmed the presence of the complete gene in the genome of perennial ryegrass. No corresponding sequence was found in other plant species, apart from members of the Poeae sub-tribes Loliinae and Dactylidinae. Evidence suggests that a common ancestor of the two sub-tribes acquired the gene from a species ancestral to contemporary grass-associated fungal endophytes around 9-13 million years ago. This first report of horizontal transfer of a nuclear gene from a taxonomically distant eukaryote to modern flowering plants provides evidence for a novel adaptation mechanism in angiosperms. PMID- 28831056 TI - Discrimination of three types of homopolymers in single-stranded DNA with solid state nanopores through external control of the DNA motion. AB - To achieve DNA sequencing with solid-state nanopores, the speed of the DNA in the nanopore must be controlled to obtain sequence-specific signals. In this study, we fabricated a nanopore-sensing system equipped with a DNA motion controller. DNA strands were immobilized on a Si probe, and approach of this probe to the nanopore vicinity could be controlled using a piezo actuator and stepper motor. The area of the Si probe was larger than the area of the membrane, which meant that the immobilized DNA could enter the nanopore without the need for the probe to scan to determine the location of the nanopore in the membrane. We demonstrated that a single-stranded DNA could be inserted into and removed from a nanopore in our experimental system. The number of different ionic-current levels observed while DNA remained in the nanopore corresponded to the number of different types of homopolymers in the DNA. PMID- 28831057 TI - Seasonal singing of a songbird living near the equator correlates with minimal changes in day length. AB - Behaving in accordance with natural cycles is essential for survival. Birds in the temperate regions use the changes of day length to time their behavior. However, at equatorial latitudes the photoperiod remains almost constant throughout the year, and it is unclear which cues songbirds use to regulate behaviors, such as singing. Here, we investigated the timing of dawn-song of male silver-beaked tanagers in the equatorial lowland Amazonas over two years. In this region, birds experience around nine minutes of annual day length variation, with sunrise times varying by 32 minutes over the year. We show that the seasonal timing of dawn-song was highly regular between years, and was strongly correlated with slight increases in day length. During the singing season the daily dawn song onset was precisely aligned to variations in twilight time. Thus, although photoperiodic changes near the equator are minimal, songbirds can use day length variation to time singing. PMID- 28831058 TI - A method for rapid high-throughput biophysical analysis of proteins. AB - Quantitative determination of protein thermodynamic stability is fundamental to many research areas, both basic and applied. Although chemical-induced denaturation is the gold-standard method, it has been replaced in many settings by semi-quantitative approaches such as thermal stability measurements. The reason for this shift is that chemical denaturation experiments are labour intensive, sample-costly and time-consuming, and it has been assumed that miniaturisation to a high-throughput format would not be possible without concomitantly comprising data quality. Here we exploit current technologies to create a high-throughput label-free chemical denaturation method that is capable of generating replicate datasets on multiple proteins in parallel on a timescale that is at least ten times faster, much more economical on sample, and with the potential for superior data quality, than the conventional methods used in most research labs currently. PMID- 28831059 TI - Modal beam splitter: determination of the transversal components of an electromagnetic light field. AB - The transversal profile of beams can always be defined as a superposition of orthogonal fields, such as optical eigenmodes. Here, we describe a generic method to separate the individual components in a laser beam and map each mode onto its designated detector with low crosstalk. We demonstrate this with the decomposition into Laguerre-Gaussian beams and introduce a distribution over the integer numbers corresponding to the discrete orbital and radial momentum components of the light field. The method is based on determining an eigenmask filter transforming the incident optical eigenmodes to position eigenmodes enabling the detection of the state of the light field using single detectors while minimizing cross talk with respect to the set of filter masks considered. PMID- 28831060 TI - Drug screening of cancer cell lines and human primary tumors using droplet microfluidics. AB - Precision Medicine in Oncology requires tailoring of therapeutic strategies to individual cancer patients. Due to the limited quantity of tumor samples, this proves to be difficult, especially for early stage cancer patients whose tumors are small. In this study, we exploited a 2.4 * 2.4 centimeters polydimethylsiloxane (PDMS) based microfluidic chip which employed droplet microfluidics to conduct drug screens against suspended and adherent cancer cell lines, as well as cells dissociated from primary tumor of human patients. Single cells were dispersed in aqueous droplets and imaged within 24 hours of drug treatment to assess cell viability by ethidium homodimer 1 staining. Our results showed that 5 conditions could be screened for every 80,000 cells in one channel on our chip under current circumstances. Additionally, screening conditions have been adapted to both suspended and adherent cancer cells, giving versatility to potentially all types of cancers. Hence, this study provides a powerful tool for rapid, low-input drug screening of primary cancers within 24 hours after tumor resection from cancer patients. This paves the way for further technological advancement to cutting down sample size and increasing drug screening throughput in advent to personalized cancer therapy. PMID- 28831061 TI - Integrated roles of BclA and DD-carboxypeptidase 1 in Bradyrhizobium differentiation within NCR-producing and NCR-lacking root nodules. AB - Legumes harbor in their symbiotic nodule organs nitrogen fixing rhizobium bacteria called bacteroids. Some legumes produce Nodule-specific Cysteine-Rich (NCR) peptides in the nodule cells to control the intracellular bacterial population. NCR peptides have antimicrobial activity and drive bacteroids toward terminal differentiation. Other legumes do not produce NCR peptides and their bacteroids are not differentiated. Bradyrhizobia, infecting NCR-producing Aeschynomene plants, require the peptide uptake transporter BclA to cope with the NCR peptides as well as a specific peptidoglycan-modifying DD-carboxypeptidase, DD-CPase1. We show that Bradyrhizobium diazoefficiens strain USDA110 forms undifferentiated bacteroids in NCR-lacking soybean nodules. Unexpectedly, in Aeschynomene afraspera nodules the nitrogen fixing USDA110 bacteroids are hardly differentiated despite the fact that this host produces NCR peptides, suggesting that USDA110 is insensitive to the host peptide effectors and that nitrogen fixation can be uncoupled from differentiation. In agreement with the absence of bacteroid differentiation, USDA110 does not require its bclA gene for nitrogen fixing symbiosis with these two host plants. Furthermore, we show that the BclA and DD-CPase1 act independently in the NCR-induced morphological differentiation of bacteroids. Our results suggest that BclA is required to protect the rhizobia against the NCR stress but not to induce the terminal differentiation pathway. PMID- 28831062 TI - Visualization of the internal structure of Didymosphenia geminata frustules using nano X-ray tomography. AB - For the first time, the three-dimensional (3D) internal structure of naturally produced Didymosphenia geminata frustules were nondestructively visualized at sub 100 nm resolution. The well-optimized hierarchical structures of these natural organisms provide insight that is needed to design novel, environmentally friendly functional materials. Diatoms, which are widely distributed in freshwater, seawater and wet soils, are well known for their intricate, siliceous cell walls called 'frustules'. Each type of diatom has a specific morphology with various pores, ribs, minute spines, marginal ridges and elevations. In this paper, the visualization is performed using nondestructive nano X-ray computed tomography (nano-XCT). Arbitrary cross-sections through the frustules, which can be extracted from the nano-XCT 3D data set for each direction, are validated via the destructive focused ion beam (FIB) cross-sectioning of regions of interest (ROIs) and subsequent observation by scanning electron microscopy (SEM). These 3D data are essential for understanding the functionality and potential applications of diatom cells. PMID- 28831064 TI - Expression of CXCR4 on T-cell subsets and Plasma IL-17 Concentrations in Patients with Aplastic Anaemia. AB - Acquired aplastic anaemia (AA) is caused by T-cells migrating to and attacking bone marrow (BM) in response to chemokines (e.g., CXCR4). We investigated CXCR4 expressions on circulating T-cell subsets, plasma IL-17A concentrations, and their correlations with AA manifestations. We enrolled 71 patients with acquired AA (36 severe AA cases [SAA] and 35 non-severe AA cases [NSAA]) and 42 healthy volunteers. We used flow cytometry and ELISA to measure circulating CD4+ and CD8+ T-cells, their CXCR4 expressions, and plasma IL-17A concentrations. Compared to the healthy controls, SAA patients had fewer peripheral CD4+ T-cells, more CD8+ T cells, and a significantly decreased CD4+/CD8+ ratio which was positively correlated with AA manifestations. Patients with SAA or NSAA had higher proportions of CD4+CXCR4+ and CD8+CXCR4+ T-cells, which were negatively correlated with haemoglobin concentrations and absolute neutrophil counts. Patients with SAA or NSAA had higher plasma IL-17A concentrations, which were negatively correlated with AA manifestations and the CD4+/CD8+ ratio. IL-17A concentrations showed a very week correlation with CD4+CXCR4+ T-cells frequencies, and no correlation with CD8+CXCR4+ T-cells frequencies. Aberrant CXCR4 expression may allow circulating T-cells, especially CD8+ T-cells, to infiltrate BM during AA progression. Elevated IL-17A concentrations may contribute to AA progression outside of the CXCR4-SDF-1alpha axis. PMID- 28831063 TI - Sterol targeting drugs reveal life cycle stage-specific differences in trypanosome lipid rafts. AB - Cilia play important roles in cell signaling, facilitated by the unique lipid environment of a ciliary membrane containing high concentrations of sterol-rich lipid rafts. The African trypanosome Trypanosoma brucei is a single-celled eukaryote with a single cilium/flagellum. We tested whether flagellar sterol enrichment results from selective flagellar partitioning of specific sterol species or from general enrichment of all sterols. While all sterols are enriched in the flagellum, cholesterol is especially enriched. T. brucei cycles between its mammalian host (bloodstream cell), in which it scavenges cholesterol, and its tsetse fly host (procyclic cell), in which it both scavenges cholesterol and synthesizes ergosterol. We wondered whether the insect and mammalian life cycle stages possess chemically different lipid rafts due to different sterol utilization. Treatment of bloodstream parasites with cholesterol-specific methyl beta-cyclodextrin disrupts both membrane liquid order and localization of a raft associated ciliary membrane calcium sensor. Treatment with ergosterol-specific amphotericin B does not. The opposite results were observed with ergosterol-rich procyclic cells. Further, these agents have opposite effects on flagellar sterol enrichment and cell metabolism in the two life cycle stages. These findings illuminate differences in the lipid rafts of an organism employing life cycle specific sterols and have implications for treatment. PMID- 28831065 TI - Reactive oxygen species-mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression. AB - Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-kappaB (NF-kappaB), indicating that NF-kappaB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control. PMID- 28831067 TI - The function of the inner nuclear envelope protein SUN1 in mRNA export is regulated by phosphorylation. AB - SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1. It also binds to the NPC through association with the nuclear pore component Nup153, which is involved in mRNA export. The SUN1-NXF1 association is at least partly regulated by a protein kinase C (PKC) which phosphorylates serine 113 (S113) in the N terminal domain leading to reduced interaction. The phosphorylation appears to be important for the SUN1 function in nuclear mRNA export since GFP-SUN1 carrying a S113A mutation was less efficient in restoring mRNA export after SUN1 knockdown as compared to the wild type protein. By contrast, GFP-SUN1-S113D resembling the phosphorylated state allowed very efficient export of poly(A)+RNA. Furthermore, probing a possible role of the LINC complex component Nesprin-2 in this process we observed impaired mRNA export in Nesprin-2 knockdown cells. This effect might be independent of SUN1 as expression of a GFP tagged SUN-domain deficient SUN1, which no longer can interact with Nesprin-2, did not affect mRNA export. PMID- 28831066 TI - Identification of candidate genes involved in isoquinoline alkaloids biosynthesis in Dactylicapnos scandens by transcriptome analysis. AB - Dactylicapnos scandens (D. Don) Hutch (Papaveraceae) is a well-known traditional Chinese herb used for treatment of hypertension, inflammation, bleeding and pain for centuries. Although the major bioactive components in this herb are considered as isoquinoline alkaloids (IQAs), little is known about molecular basis of their biosynthesis. Here, we carried out transcriptomic analysis of roots, leaves and stems of D. scandens, and obtained a total of 96,741 unigenes. Based on gene expression and phylogenetic relationship, we proposed the biosynthetic pathways of isocorydine, corydine, glaucine and sinomenine, and identified 67 unigenes encoding enzymes potentially involved in biosynthesis of IQAs in D. scandens. High performance liquid chromatography analysis demonstrated that while isocorydine is the most abundant IQA in D. scandens, the last O methylation biosynthesis step remains unclear. Further enzyme activity assay, for the first time, characterized a gene encoding O- methyltransferase (DsOMT), which catalyzes O-methylation at C7 of (S)-corytuberine to form isocorydine. We also identified candidate transcription factor genes belonging to WRKY and bHLH families that may be involved in the regulation of IQAs biosynthesis. Taken together, we first provided valuable genetic information for D. scandens, shedding light on candidate genes involved in IQA biosynthesis, which will be critical for further gene functional characterization. PMID- 28831068 TI - Synthesis of Nm-PHB (nanomelanin-polyhydroxy butyrate) nanocomposite film and its protective effect against biofilm-forming multi drug resistant Staphylococcus aureus. AB - Melanin is a dark brown ubiquitous photosynthetic pigment which have many varied and ever expanding applications in fabrication of radio-protective materials, food packaging, cosmetics and in medicine. In this study, melanin production in a Pseudomonas sp. which was isolated from the marine sponge Tetyrina citirna was optimized employing one-factor at a time experiments and characterized for chemical nature and stability. Following sonication nucleated nanomelanin (Nm) particles were formed and evaluated for antibacterial and antioxidant properties. Nanocomposite film was fabricated using combinations (% w/v) of polyhydroxy butyrate-nanomelanin (PHB:Nm) blended with 1% glycerol. The Nm was found to be spherical in shape with a diameter of 100-140 nm and showed strong antimicrobial activity against both Gram positive and Gram negative bacteria. The Nm-PHB nanocomposite film was homogeneous, smooth, without any cracks, and flexible. XRD and DSC data indicated that the film was crystalline in nature, and was thermostable up to 281.87 degrees C. This study represents the first report on the synthesis of Nm and fabrication of Nm-PHB nanocomposite film which show strong protective effect against multidrug resistant Staphyloccoccus aureus. Thus this Nm-PHB nanocomposite film may find utility as packaging material for food products by protecting the food products from oxidation and bacterial contamination. PMID- 28831069 TI - Theoretical Studies of Intracellular Concentration of Micro-organisms' Metabolites. AB - With the rapid growth of micro-organism metabolic networks, acquiring the intracellular concentration of microorganisms' metabolites accurately in large batch is critical to the development of metabolic engineering and synthetic biology. Complementary to the experimental methods, computational methods were used as effective assessing tools for the studies of intracellular concentrations of metabolites. In this study, the dataset of 130 metabolites from E. coli and S. cerevisiae with available experimental concentrations were utilized to develop a SVM model of the negative logarithm of the concentration (-logC). In this statistic model, in addition to common descriptors of molecular properties, two special types of descriptors including metabolic network topologic descriptors and metabolic pathway descriptors were included. All 1997 descriptors were finally reduced into 14 by variable selections including genetic algorithm (GA). The model was evaluated through internal validations by 10-fold and leave-one-out (LOO) cross-validation, as well as external validations by predicting -logC values of the test set. The developed SVM model is robust and has a strong predictive potential (n = 91, m = 14, R2 = 0.744, RMSE = 0.730, Q2 = 0.57; R2p = 0.59, RMSEp = 0.702, Q2p = 0.58). An effective tool could be provided by this analysis for the large-batch prediction of the intracellular concentrations of the micro-organisms' metabolites. PMID- 28831070 TI - Superfluid flow above the critical velocity. AB - Superfluidity and superconductivity have been widely studied since the last century in many different contexts ranging from nuclear matter to atomic quantum gases. The rigidity of these systems with respect to external perturbations results in frictionless motion for superfluids and resistance-free electric current flow in superconductors. This peculiar behaviour is lost when external perturbations overcome a critical threshold, i.e. above a critical magnetic field or a critical current for superconductors. In superfluids, such as liquid helium or ultracold gases, the corresponding quantities are a critical rotation rate and a critical velocity respectively. Enhancing the critical values is of great fundamental and practical value. Here we demonstrate that superfluidity can be completely restored for specific, arbitrarily large flow velocities above the critical velocity through quantum interference-induced resonances providing a nonlinear counterpart of the Ramsauer-Townsend effect occurring in ordinary quantum mechanics. We illustrate the robustness of this phenomenon through a thorough analysis in one dimension and prove its generality by showing the persistence of the effect in non-trivial 2d systems. This has far reaching consequences for the fundamental understanding of superfluidity and superconductivity and opens up new application possibilities in quantum metrology, e.g. in rotation sensing. PMID- 28831071 TI - Stimulation triggers endogenous activity patterns in cultured cortical networks. AB - Cultures of dissociated cortical neurons represent a powerful trade-off between more realistic experimental models and abstract modeling approaches, allowing to investigate mechanisms of synchronized activity generation. These networks spontaneously alternate periods of high activity (i.e. network bursts) with periods of quiescence in a dynamic state which recalls the fluctuation of in vivo UP and DOWN states. Network bursts can also be elicited by external stimulation and their spatial propagation patterns tracked by means of multi-channel micro electrode arrays. In this study, we used rat cortical cultures coupled to micro electrode arrays to investigate the similarity between spontaneous and evoked activity patterns. We performed experiments by applying electrical stimulation to different network locations and demonstrated that the rank orders of electrodes during evoked and spontaneous events are remarkably similar independently from the stimulation source. We linked this result to the capability of stimulation to evoke firing in highly active and "leader" sites of the network, reliably and rapidly recruited within both spontaneous and evoked bursts. Our study provides the first evidence that spontaneous and evoked activity similarity is reliably observed also in dissociated cortical networks. PMID- 28831072 TI - Working memory accuracy for multiple targets is driven by reward expectation and stimulus contrast with different time-courses. AB - The richness of sensory input dictates that the brain must prioritize and select information for further processing and storage in working memory. Stimulus salience and reward expectations influence this prioritization but their relative contributions and underlying mechanisms are poorly understood. Here we investigate how the quality of working memory for multiple stimuli is determined by priority during encoding and later memory phases. Selective attention could, for instance, act as the primary gating mechanism when stimuli are still visible. Alternatively, observers might still be able to shift priorities across memories during maintenance or retrieval. To distinguish between these possibilities, we investigated how and when reward cues determine working memory accuracy and found that they were only effective during memory encoding. Previously learned, but currently non-predictive, color-reward associations had a similar influence, which gradually weakened without reinforcement. Finally, we show that bottom-up salience, manipulated through varying stimulus contrast, influences memory accuracy during encoding with a fundamentally different time-course than top-down reward cues. While reward-based effects required long stimulus presentation, the influence of contrast was strongest with brief presentations. Our results demonstrate how memory resources are distributed over memory targets and implicates selective attention as a main gating mechanism between sensory and memory systems. PMID- 28831073 TI - Biodiversity conservation gaps in the Brazilian protected areas. AB - Although Brazil is a megadiverse country and thus a conservation priority, no study has yet quantified conservation gaps in the Brazilian protected areas (PAs) using extensive empirical data. Here, we evaluate the degree of biodiversity protection and knowledge within all the Brazilian PAs through a gap analysis of vertebrate, arthropod and angiosperm occurrences and phylogenetic data. Our results show that the knowledge on biodiversity in most Brazilian PAs remain scant as 71% of PAs have less than 0.01 species records per km2. Almost 55% of Brazilian species and about 40% of evolutionary lineages are not found in PAs, while most species have less than 30% of their geographic distribution within PAs. Moreover, the current PA network fails to protect the majority of endemic species. Most importantly, these results are similar for all taxonomic groups analysed here. The methods and results of our countrywide assessment are suggested to help design further inventories in order to map and secure the key biodiversity of the Brazilian PAs. In addition, our study illustrates the most common biodiversity knowledge shortfalls in the tropics. PMID- 28831074 TI - Simulation of Quantum Dynamics of Excitonic Systems at Finite Temperature: an efficient method based on Thermo Field Dynamics. AB - Quantum electron-vibrational dynamics in molecular systems at finite temperature is described using an approach based on Thermo Field Dynamics theory. This formulation treats temperature effects in the Hilbert space without introducing the Liouville space. The solution of Thermo Field Dynamics equations with a novel technique for the propagation of Tensor Trains (Matrix Product States) is implemented and discussed. The methodology is applied to the study of the exciton dynamics in the Fenna-Mathews-Olsen complex using a realistic structured spectral density to model the electron-phonon interaction. The results of the simulations highlight the effect of specific vibrational modes on the exciton dynamics and energy transfer process, as well as call for careful modeling of electron-phonon couplings. PMID- 28831075 TI - DEMETER plant DNA demethylase induces antiviral response by interferon signalling in animal cells. AB - DNA methylation is a prominent epigenetic modification in plants and animals regulated by similar mechanisms but the process of DNA demethylation is profoundly different. Unlike vertebrates that require a series of enzymatic conversions of 5-methylcytosine (5mC) into other bases for DNA demethylation, plants utilize the DEMETER (DME) family of 5mC DNA glycosylases to catalyze a direct removal of 5mC from DNA. Here we introduced Arabidopsis DME into human HEK 293T cells to allow direct 5mC excision, and observed that direct DNA demethylation activity was successfully implemented by DME expression. In addition, DME induced diverse cellular responses such as cell proliferation inhibition, cell cycle dysregulation and S phase arrest. Microarray and methylome analyses revealed that DME upregulated a number of genes including cell cycle components, heat shock proteins, and notably, various interferon-stimulated genes. Moreover, DME-mediated DNA demethylation activated endogenous repeat elements, which are likely to form dsRNAs as viral mimics and eventually trigger interferon cascades to establish the antiviral state. This work demonstrates that plant DNA demethylase catalyzes DNA demethylation with a bypass of initial base conversion steps, and the interferon signaling plays a pivotal role to alleviate genotoxic stresses associated with DME-induced DNA demethylation in mammalian cells. PMID- 28831076 TI - Extracellular redox sensitivity of Kv1.2 potassium channels. AB - Kv1.2 is a prominent potassium channel subtype in the nervous system and serves as an important structural template for investigation of ion channel function. However, Kv1.2 voltage-dependence exhibits dramatic cell-to-cell variability due to a gating mode shift that is regulated by an unknown mechanism. We report that this variable behavior is regulated by the extracellular redox environment. Exposure to reducing agents promotes a shift in gating properties towards an 'inhibited' gating mode that resists opening, and causes channels to exhibit pronounced use-dependent activation during trains of repetitive depolarizations. This sensitivity to extracellular redox potential is absent in other Kv1 channels, but is apparent in heteromeric channels containing Kv1.2 subunits, and overlaps with the reported physiological range of extracellular redox couples. Mutagenesis of candidate cysteine residues fails to abolish redox sensitivity. Therefore, we suggest that an extrinsic, redox-sensitive binding partner imparts these properties. PMID- 28831077 TI - Microchannel contacting of crystalline silicon solar cells. AB - There is tremendous interest in reducing losses caused by the metal contacts in silicon photovoltaics, particularly the optical and resistive losses of the front metal grid. One commonly sought-after goal is the creation of high aspect-ratio metal fingers which provide an optically narrow and low resistance pathway to the external circuit. Currently, the most widely used metal contact deposition techniques are limited to widths and aspect-ratios of ~40 MUm and ~0.5, respectively. In this study, we introduce the use of a micropatterned polydimethylsiloxane encapsulation layer to form narrow (~20 MUm) microchannels, with aspect-ratios up to 8, on the surface of solar cells. We demonstrate that low temperature metal pastes, electroless plating and atomic layer deposition can all be used within the microchannels. Further, we fabricate proof-of-concept structures including simple planar silicon heterojunction and homojunction solar cells. While preliminary in both design and efficiency, these results demonstrate the potential of this approach and its compatibility with current solar cell architectures. PMID- 28831078 TI - Analyses of Long Non-Coding RNA and mRNA profiling using RNA sequencing in chicken testis with extreme sperm motility. AB - Sperm motility is the most important indicator in evaluating roosters' fecundity. However, the genetic mechanisms underlying chicken sperm motility is not yet clear. Long non-coding RNA (lncRNA) play epigenetic roles in reproduction. In this study, RNA sequencing was employed to profile the testis transcriptome (lncRNA and mRNA) of six Beijing-you cocks divergent in sperm motility. In total, 2,597 lncRNAs were identified in the chicken testis, including 1,267 lincRNAs, 975 anti-sense lncRNAs, and 355 intronic lncRNAs. They shared similar features with previous studies. Of these lncRNAs, 124 were differentially expressed. Among 17,690 mRNAs detected in this study, 544 were differentially expressed, including a bunch of genes with known functions on sperm motility. GO annotation analysis revealed these genes were involved in ATP binding, cilium assembly, and oxidation reduction processes. Integrating analysis of lncRNA and mRNA profiles predicted 10 lncRNA-gene pairs, including 8 co-regulated and 2 inversely-regulated pairs. To the best of our knowledge, this is the first genome-wide investigation of the lncRNAs in the chicken testis associated with sperm motility. Our results provided a catalog of chicken testis lncRNAs and genes worthy of further studies to understand their roles in cocks' reproductive performance regulation. PMID- 28831079 TI - Fear or food - abundance of red fox in relation to occurrence of lynx and wolf. AB - Apex predators may affect mesopredators through intraguild predation and/or supply of carrion from their prey, causing a trade-off between avoidance and attractiveness. We used wildlife triangle snow-tracking data to investigate the abundance of red fox (Vulpes vulpes) in relation to lynx (Lynx lynx) and wolf (Canis lupus) occurrence as well as land composition and vole (Microtus spp.) density. Data from the Swedish wolf-monitoring system and VHF/GPS-collared wolves were used to study the effect of wolf pack size and time since wolf territory establishment on fox abundance. Bottom-up processes were more influential than top-down effects as the proportion of arable land was the key indicator of fox abundance at the landscape level. At this spatial scale, there was no effect of wolf abundance on fox abundance, whereas lynx abundance had a positive effect. In contrast, at the wolf territory level there was a negative effect of wolves on fox abundance when including detailed information of pack size and time since territory establishment, whereas there was no effect of lynx abundance. This study shows that different apex predator species may affect mesopredator abundance in different ways and that the results may be dependent on the spatiotemporal scale and resolution of the data. PMID- 28831080 TI - Dynamic, heterogeneous endothelial Tie2 expression and capillary blood flow during microvascular remodeling. AB - Microvascular endothelial cell heterogeneity and its relationship to hemodynamics remains poorly understood due to a lack of sufficient methods to examine these parameters in vivo at high resolution throughout an angiogenic network. The availability of surrogate markers for functional vascular proteins, such as green fluorescent protein, enables expression in individual cells to be followed over time using confocal microscopy, while photoacoustic microscopy enables dynamic measurement of blood flow across the network with capillary-level resolution. We combined these two non-invasive imaging modalities in order to spatially and temporally analyze biochemical and biomechanical drivers of angiogenesis in murine corneal neovessels. By stimulating corneal angiogenesis with an alkali burn in Tie2-GFP fluorescent-reporter mice, we evaluated how onset of blood flow and surgically-altered blood flow affects Tie2-GFP expression. Our study establishes a novel platform for analyzing heterogeneous blood flow and fluorescent reporter protein expression across a dynamic microvascular network in an adult mammal. PMID- 28831082 TI - Corrosion resistance and bioactivity enhancement of MAO coated Mg alloy depending on the time of hydrothermal treatment in Ca-EDTA solution. AB - In this study, a two-step surface treatment was developed to restrain the rapid primary degradation of a biodegradable Mg alloy and to improve their biocompatibility. Micro arc oxidation (MAO) coating was performed in alkaline electrolytes such as 1.0 M NaOH with 0.1 M glycerol and 0.1 M Na3PO4. Hydrothermal treatment was performed in 0.1 M Ca-EDTA (C10H12CaN2Na2O8) and 0.5 M NaOH solution at 90 degrees C for different times (6, 12, 24, and 48 h). The film morphology and chemical properties were evaluated by XRD and FE-SEM. The electrochemical and corrosion behaviors were examined in the simulated body fluid, and cytotoxicity was assessed using MC3T3-E1 cells. After MAO coating, an oxide layer containing [Formula: see text] formed on the surface. During the hydrothermal treatment in Ca-EDTA solution, calcium phosphate and Mg(OH)2 were produced via a reaction between [Formula: see text] on the surface and Ca2+ in solution. The layer with ceramics and oxides was grown on the surface with increasing hydrothermal treatment time, and improved the surface corrosion resistance. The 24 h hydrothermal-treated group showed the lowest immersion corrosion rate and high cell viability. Therefore, this treatment was the most favorable surface modification for improving the initial corrosion resistance and bioactivity of the biodegradable Mg alloy. PMID- 28831081 TI - EGFR and PDGFRA co-expression and heterodimerization in glioblastoma tumor sphere lines. AB - Concurrent amplifications of EGFR and PDGFRA have been reported in up to 5% of glioblastoma (GBM) and it remains unclear why such independent amplification events, and associated receptor overexpression, would be adaptive during glioma evolution. Here, we document that EGFR and PDGFRA protein co-expression occurs in 37% of GBM. There is wide cell-to-cell variation in the expressions of these receptor tyrosine kinases (RTKs) in stable tumor sphere lines, frequently defining tumor cell subpopulations with distinct sensitivities to growth factors and RTK inhibitors. We also find evidence for functional transactivation of PDGFRA by EGFR and EGF-induced receptor heterodimerization, both of which are abolished by EGFR inhibitors. These results indicate that GBM growth responses to targeted therapies previously tested in clinical trials are strongly influenced by the balance of EGFR and PDGFRA activation in individual cells, which is heterogeneous at baseline. PMID- 28831083 TI - Increased peripheral blood inflammatory cytokine levels in amyotrophic lateral sclerosis: a meta-analysis study. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with poorly understood etiology. Increasing evidence suggest that inflammation may play a critical role in the pathogenesis of ALS. Several studies have demonstrated altered levels of blood cytokines in ALS, but results were inconsistent. Therefore, we did a systematic review of studies comparing blood inflammatory cytokines between ALS patients and control subjects, and quantitatively combined the clinical data with a meta-analysis. The systematic review of Pubmed and Web of Science identified 25 studies encompassing 812 ALS patients and 639 control subjects. Random-effects meta-analysis demonstrated that blood tumor necrosis factor-alpha (TNF; Hedges' g = 0.655; p = 0.001), TNF receptor 1 (Hedges' g = 0.741; p < 0.001), interleukin 6 (IL-6; Hedges' g = 0.25; p = 0.005), IL-1beta (Hedges' g = 0.296; p = 0.038), IL-8 (Hedges' g = 0.449; p < 0.001) and vascular endothelial growth factor (Hedges' g = 0.891; p = 0.003) levels were significantly elevated in patients with ALS compared with control subjects. These results substantially enhance our knowledge of the inflammatory response in ALS, and peripheral blood inflammatory cytokines may be used as diagnostic biomarkers for ALS in the future. PMID- 28831084 TI - Resistance mechanisms and fitness of Salmonella Typhimurium and Salmonella Enteritidis mutants evolved under selection with ciprofloxacin in vitro. AB - The aim of this study was to investigate the difference in resistance mechanisms and fitness of Salmonella Typhimurium (ST) and Salmonella Enteritidis (SE) mutants selected during the evolution of resistance under exposure to increasing ciprofloxacin concentrations in vitro. Mutations in quinolone target genes were screened by PCR. Phenotypic characterization included susceptibility testing by the broth dilution method, investigation of efflux activity and growth rate, and determination of the invasion of human intestinal epithelium cells in vitro. The two Salmonella serotypes exhibited differences in target gene mutations and efflux pump gene expression during the development of resistance. In the parental strains, ST had a competitive advantage over SE. During the development of resistance, initially, the SE strain was more competitive. However, once ciprofloxacin resistance was acquired, ST once again became the more competitive strain. In the absence of bile salts or at 0.1% bile, the growth rate of SE was initially greater than that of ST, but once ciprofloxacin resistance was acquired, ST had higher growth rates. ST strains showed decreased invasion of epithelial cells in 0.1% bile. These data indicate that ciprofloxacin-resistant ST strains are more competitive than ciprofloxacin-resistant SE strains. PMID- 28831085 TI - Percutaneous Closure of Left Atrial Appendage affects Mid-Term Release of MR proANP. AB - The left atrial appendage (LAA) represents both a predisposing source of thrombus formation and of neuro-humoral haemostasis. This study aims to evaluate changes of biomarker expression before and after successful percutaneous closure of the LAA. Patients with atrial fibrillation and contraindication for oral anticoagulant therapy were enrolled. Blood samples were taken within 24 hours before (T1) and at least 6 months (mid-term) (T2) after successful implantation of LAA occlusion devices. Blood levels of high sensitivity troponin I and T (hsTnI, hsTnT), aminoterminal pro-brain natriuretic peptide (NT-proBNP) and mid regional pro-atrial natriuretic peptide (MR-proANP) were evaluated at both time points. A total of 42 patients with successful percutaneous LAA closure were included. Median mid-term follow-up was of 183 days. HsTnT, hsTnI and NT-proBNP did not show any significant differences over time. Serum levels of MR-proANP increased significantly between immediate pre-intervention (T1: median = 245.7 pmol/l, IQR 155.8-361.3 pmol/l) and at mid-term follow-up (T2: median = 254 pmol/l, IQR 183.4-396.4 pmol/l) (p = 0.037). These results indicate, that percutaneous LAA closure affects neuro-humoral haemostasis by increasing MR proANP serum levels at mid-term follow-up. PMID- 28831086 TI - Potential Use of MALDI-ToF Mass Spectrometry for Rapid Detection of Antifungal Resistance in the Human Pathogen Candida glabrata. AB - The echinocandins are relatively new antifungal drugs that represent, together with the older azoles, the recommended and/or preferred agents to treat candidaemia and other forms of invasive candidiasis in human patients. If "time is of the essence" to reduce the mortality for these infections, the administration of appropriate antifungal therapy could be accelerated by the timely reporting of laboratory test results. In this study, we attempted to validate a MALDI-ToF mass spectrometry-based assay for the antifungal susceptibility testing (AFST) of the potentially multidrug-resistant pathogen Candida glabrata against anidulafungin and fluconazole. The practical applicability of the assay, reported here as MS-AFST, was assessed with a panel of clinical isolates that were selected to represent phenotypically and genotypically/molecularly susceptible or resistant strains. The data show the potential of our assay for rapid detection of antifungal resistance, although the MS-AFST assay performed at 3 h of the in vitro antifungal exposure failed to detect C. glabrata isolates with echinocandin resistance-associated FKS2 mutations. However, cell growth kinetics in the presence of anidulafungin revealed important cues about the in vitro fitness of C. glabrata isolates, which may lead to genotypic or phenotypic antifungal testing in clinical practice. PMID- 28831088 TI - Multiple sources and sinks of dissolved inorganic carbon across Swedish streams, refocusing the lens of stable C isotopes. AB - It is well established that stream dissolved inorganic carbon (DIC) fluxes play a central role in the global C cycle, yet the sources of stream DIC remain to a large extent unresolved. Here, we explore large-scale patterns in delta13C-DIC from streams across Sweden to separate and further quantify the sources and sinks of stream DIC. We found that stream DIC is governed by a variety of sources and sinks including biogenic and geogenic sources, CO2 evasion, as well as in-stream processes. Although soil respiration was the main source of DIC across all streams, a geogenic DIC influence was identified in the northernmost region. All streams were affected by various degrees of atmospheric CO2 evasion, but residual variance in delta13C-DIC also indicated a significant influence of in-stream metabolism and anaerobic processes. Due to those multiple sources and sinks, we emphasize that simply quantifying aquatic DIC fluxes will not be sufficient to characterise their role in the global C cycle. PMID- 28831087 TI - Differential response of rat strains to obesogenic diets underlines the importance of genetic makeup of an individual towards obesity. AB - Obesity, a multifactorial disorder, results from a chronic imbalance of energy intake vs. expenditure. Apart from excessive consumption of high calorie diet, genetic predisposition also seems to be equally important for the development of obesity. However, the role of genetic predisposition in the etiology of obesity has not been clearly delineated. The present study addresses this problem by selecting three rat strains (WNIN, F-344, SD) with different genetic backgrounds and exposing them to high calorie diets. Rat strains were fed HF, HS, and HFS diets and assessed for physical, metabolic, biochemical, inflammatory responses, and mRNA expression. Under these conditions: significant increase in body weight, visceral adiposity, oxidative stress and systemic pro-inflammatory status; the hallmarks of central obesity were noticed only in WNIN. Further, they developed altered glucose and lipid homeostasis by exhibiting insulin resistance, impaired glucose tolerance, dyslipidemia and fatty liver condition. The present study demonstrates that WNIN is more prone to develop obesity and associated co morbidities under high calorie environment. It thus underlines the cumulative role of genetics (nature) and diet (nurture) towards the development of obesity, which is critical for understanding this epidemic and devising new strategies to control and manage this modern malady. PMID- 28831089 TI - Magmatic evolution of a Cordilleran flare-up and its role in the creation of silicic crust. AB - The role of magmatic processes as a significant mechanism for the generation of voluminous silicic crust and the development of Cordilleran plateaus remains a lingering question in part because of the inherent difficulty in quantifying plutonic volumes. Despite this difficulty, a growing body of independently measured plutonic-to-volcanic ratios suggests the volume of plutonic material in the crust related to Cordilleran magmatic systems is much larger than is previously expected. To better examine the role of crustal magmatic processes and its relationship to erupted material in Cordilleran systems, we present a continuous high-resolution crustal seismic velocity model for an ~800 km section of the active South American Cordillera (Puna Plateau). Although the plutonic-to volcanic ratios we estimate vary along the length of the Puna Plateau, all ratios are larger than those previously reported (~30:1 compared to 5:1) implying that a significant volume of intermediate to silicic plutonic material is generated in the crust of the central South American Cordillera. Furthermore, as Cordilleran type margins have been common since the onset of modern plate tectonics, our findings suggest that similar processes may have played a significant role in generating and/or modifying large volumes of continental crust, as observed in the continents today. PMID- 28831090 TI - Accelerating next generation sequencing data analysis with system level optimizations. AB - Next generation sequencing (NGS) data analysis is highly compute intensive. In memory computing, vectorization, bulk data transfer, CPU frequency scaling are some of the hardware features in the modern computing architectures. To get the best execution time and utilize these hardware features, it is necessary to tune the system level parameters before running the application. We studied the GATK HaplotypeCaller which is part of common NGS workflows, that consume more than 43% of the total execution time. Multiple GATK 3.x versions were benchmarked and the execution time of HaplotypeCaller was optimized by various system level parameters which included: (i) tuning the parallel garbage collection and kernel shared memory to simulate in-memory computing, (ii) architecture-specific tuning in the PairHMM library for vectorization, (iii) including Java 1.8 features through GATK source code compilation and building a runtime environment for parallel sorting and bulk data transfer (iv) the default 'on-demand' mode of CPU frequency is over-clocked by using 'performance-mode' to accelerate the Java multi-threads. As a result, the HaplotypeCaller execution time was reduced by 82.66% in GATK 3.3 and 42.61% in GATK 3.7. Overall, the execution time of NGS pipeline was reduced to 70.60% and 34.14% for GATK 3.3 and GATK 3.7 respectively. PMID- 28831091 TI - Low Habitual Dietary Calcium and Linear Growth from Adolescence to Young Adulthood: results from the China Health and Nutrition Survey. AB - Evidences from clinical trials and meta-analyses of calcium supplementation in linear growth have given conflicting results, and few longitudinal studies have investigated the long-term associations between dietary calcium and linear growth, especially in the population with low-calcium plant-based diets. We investigated the prospective associations of low habitual dietary calcium with adult height and height-for-age z-score (HAZ) from adolescence to adulthood among 2019 adolescents from the China Health and Nutrition Survey (CHNS). The average dietary calcium intakes were 426(standard deviation: 158) mg/d in boys and 355(134) mg/d in girls during adolescence. During a median follow-up of 7.0 (interquartile range: 5.9-9.0) years, boys reached an average of 169.0(6.7) cm and girls reached 158.4(5.8) cm in adulthood. After adjusting for other potential confounders, non-linear regression found that boys with dietary calcium intakes below 327 mg/d had shorter adult stature, and those taking over 566 mg/d had faster height growth whether adjusting for physical exercises level or not. No significant associations were found in girls. Our study suggests that in boys with plant-based diets, higher dietary calcium intake during adolescence is associated with faster height growth, but not with adult height; calcium intake below 300 mg/d may result in shorter adult stature. PMID- 28831092 TI - Photo-flocculation of microbial mat extracellular polymeric substances and their transformation into transparent exopolymer particles: Chemical and spectroscopic evidences. AB - Upon exposure to sunlight extracellular polymeric substances (EPS) were partially transformed into transparent exopolymer particles (TEP) and unstable flocs of different sizes without the addition of any precursors. Parallel factor (PARAFAC) modelling of the sample fluorescence spectra identified humic-like and protein like or tyrosine-like components in both untreated and irradiated EPS samples. After 58 hours of solar irradiation, humic-like substances were entirely decomposed, while the regenerated protein-like substance from EPS was the key component in the irradiated samples. Degradation and reformation of EPS occurred which was confirmed by the results of size exclusion chromatography, dissolved organic carbon, total protein and total polysaccharide analyses. Irradiated EPS was composed of -COOH or C = O (amide I band) and -NH and -CN (amide II band), while Fourier transform infrared spectroscopy (FTIR) of TEP revealed more acidic COOH and -C-O groups, indicating typical acidic protein-like TEP. The regenerated protein-like substances could form complexes with free metals originating from degraded EPS in irradiated samples, which could be responsible for the formation of TEP/floc in the aqueous media. These results suggest that TEP/floc formation from EPS could occur by a complexation mechanism between dissolved organic matter and metals, thereby causing ionic charge neutralisation upon sunlight exposure. PMID- 28831093 TI - Hypertriglyceridemia-waist and risk of developing type 2 diabetes: The Rural Chinese Cohort Study. AB - Limited information is available on the effect of hypertriglyceridemia-waist (HTGW) combination and its dynamic status on the risk of type 2 diabetes mellitus (T2DM) in rural China. A cohort of 12,086 participants 18 to 92 years old was retained in this study. Kaplan-Meier analysis yielded the cumulative incidence of T2DM for each phenotype group (based on TG level and waist circumference [WC] at baseline). Cox regression yielded hazard ratios relating HTGW (based on TG level and WC at baseline and follow-up) to risk of developing T2DM. After a median follow-up of 6.0 years (71,432 person-years of follow-up), T2DM developed in 621 participants. For HTGW participants, the incidence of T2DM was 26.4/1000, 20.6/1000, and 21.9/1000 person-years for males, females, and overall, respectively. The adjusted HR for HTGW associated with T2DM was 7.63 (95% CI 4.32 13.49) for males and 7.75 (4.71-12.78) for females. Compared with consistent HTGW, with transformation from baseline HTGW to normal WC and normal triglycerides level at follow-up, the risk of developing T2DM was reduced by 75% and 78% for males and females. HTGW is a major risk factor for T2DM, but the risk could be reduced by improved triglycerides level and WC. PMID- 28831094 TI - Serum and urine 1H NMR-based metabolomics in the diagnosis of selected thyroid diseases. AB - Early detection of nodular thyroid diseases including thyroid cancer is still primarily based on invasive procedures such as fine-needle aspiration biopsy. Therefore, there is a strong need for development of new diagnostic methods that could provide clinically useful information regarding thyroid nodular lesions in a non-invasive way. In this study we investigated 1H NMR based metabolic profiles of paired urine and blood serum samples, that were obtained from healthy individuals and patients with nodular thyroid diseases. Estimation of predictive potential of metabolites was evaluated using chemometric methods and revealed that both urine and serum carry information sufficient to distinguish between patients with nodular lesions and healthy individuals. Data fusion allowed to further improve prediction quality of the models. However, stratification of tumor types and their differentiation in relation to each other was not possible. PMID- 28831095 TI - Discrepancies between leg-to-leg bioelectrical Impedance analysis and computerized tomography in abdominal visceral fat measurement. AB - The aim of this study was to evaluate leg-to-leg bioelectrical impedance analysis (LBIA) using a four-contact electrode system for measuring abdominal visceral fat area (VFA). The present study recruited 381 (240 male and 141 female) Chinese participants to compare VFA measurements estimated by a standing LBIA system (VFALBIA) with computerized tomography (CT) scanned at the L4-L5 vertebrae (VFACT). The total mean body mass index (BMI) was 24.7 +/- 4.2 kg/m2. Correlation analysis, regression analysis, Bland-Altman plot, and paired sample t-tests were used to analyze the accuracy of the VFALBIA. For the total subjects, the regression line was VFALBIA = 0.698 VFACT + 29.521, (correlation coefficient (r) = 0.789, standard estimate of error (SEE) = 24.470 cm2, p < 0.001), Lin's correlation coefficient (CCC) was 0.785; and the limit of agreement (LOA; mean difference +/-2 standard deviation) ranged from -43.950 to 67.951 cm2, LOA% (given as a percentage of mean value measured by the CT) was 48.2%. VFALBIA and VFACT showed significant difference (p < 0.001). Collectively, the current study indicates that LBIA has limited potential to accurately estimate visceral fat in a clinical setting. PMID- 28831096 TI - Inflammatory cytokine-induced changes in neural network activity measured by waveform analysis of high-content calcium imaging in murine cortical neurons. AB - During acute neuroinflammation, increased levels of cytokines within the brain may contribute to synaptic reorganization that results in long-term changes in network hyperexcitability. Indeed, inflammatory cytokines are implicated in synaptic dysfunction in epilepsy and in an array of degenerative and autoimmune diseases of the central nervous system. Current tools for studying the impact of inflammatory factors on neural networks are either insufficiently fast and sensitive or require complicated and costly experimental rigs. Calcium imaging offers a reasonable surrogate for direct measurement of neuronal network activity, but traditional imaging paradigms are confounded by cellular heterogeneity and cannot readily distinguish between glial and neuronal calcium transients. While the establishment of pure neuron cultures is possible, the removal of glial cells ignores physiologically relevant cell-cell interactions that may be critical for circuit level disruptions induced by inflammatory factors. To overcome these issues, we provide techniques and algorithms for image processing and waveform feature extraction using automated analysis of spontaneous and evoked calcium transients in primary murine cortical neuron cultures transduced with an adeno-associated viral vector driving the GCaMP6f reporter behind a synapsin promoter. Using this system, we provide evidence of network perturbations induced by the inflammatory cytokines TNFalpha, IL1beta, and IFNgamma. PMID- 28831097 TI - Taxonomic bias in biodiversity data and societal preferences. AB - Studying and protecting each and every living species on Earth is a major challenge of the 21st century. Yet, most species remain unknown or unstudied, while others attract most of the public, scientific and government attention. Although known to be detrimental, this taxonomic bias continues to be pervasive in the scientific literature, but is still poorly studied and understood. Here, we used 626 million occurrences from the Global Biodiversity Information Facility (GBIF), the biggest biodiversity data portal, to characterize the taxonomic bias in biodiversity data. We also investigated how societal preferences and taxonomic research relate to biodiversity data gathering. For each species belonging to 24 taxonomic classes, we used the number of publications from Web of Science and the number of web pages from Bing searches to approximate research activity and societal preferences. Our results show that societal preferences, rather than research activity, strongly correlate with taxonomic bias, which lead us to assert that scientists should advertise less charismatic species and develop societal initiatives (e.g. citizen science) that specifically target neglected organisms. Ensuring that biodiversity is representatively sampled while this is still possible is an urgent prerequisite for achieving efficient conservation plans and a global understanding of our surrounding environment. PMID- 28831098 TI - RNA-Seq analysis on chicken taste sensory organs: An ideal system to study organogenesis. AB - RNA-Seq is a powerful tool in transcriptomic profiling of cells and tissues. We recently identified many more taste buds than previously appreciated in chickens using molecular markers to stain oral epithelial sheets of the palate, base of oral cavity, and posterior tongue. In this study, RNA-Seq was performed to understand the transcriptomic architecture of chicken gustatory tissues. Interestingly, taste sensation related genes and many more differentially expressed genes (DEGs) were found between the epithelium and mesenchyme in the base of oral cavity as compared to the palate and posterior tongue. Further RNA Seq using specifically defined tissues of the base of oral cavity demonstrated that DEGs between gustatory (GE) and non-gustatory epithelium (NGE), and between GE and the underlying mesenchyme (GM) were enriched in multiple GO terms and KEGG pathways, including many biological processes. Well-known genes for taste sensation were highly expressed in the GE. Moreover, genes of signaling components important in organogenesis (Wnt, TGFbeta/ BMP, FGF, Notch, SHH, Erbb) were differentially expressed between GE and GM. Combined with other features of chicken taste buds, e.g., uniquely patterned array and short turnover cycle, our data suggest that chicken gustatory tissue provides an ideal system for multidisciplinary studies, including organogenesis and regenerative medicine. PMID- 28831100 TI - Reversible inactivation of a peptidoglycan transpeptidase by a beta-lactam antibiotic mediated by beta-lactam-ring recyclization in the enzyme active site. AB - beta-lactam antibiotics act as suicide substrates of transpeptidases responsible for the last cross-linking step of peptidoglycan synthesis in the bacterial cell wall. Nucleophilic attack of the beta-lactam carbonyl by the catalytic residue (Ser or Cys) of transpeptidases results in the opening of the beta-lactam ring and in the formation of a stable acyl-enzyme. The acylation reaction is considered as irreversible due to the strain of the beta-lactam ring. In contradiction with this widely accepted but poorly demonstrated premise, we show here that the acylation of the L,D-transpeptidase Ldtfm from Enterococcus faecium by the beta-lactam nitrocefin is reversible, leading to limited antibacterial activity. Experimentally, two independent methods based on spectrophotometry and mass spectrometry provided evidence that recyclization of the beta-lactam ring within the active site of Ldtfm regenerates native nitrocefin. Ring strain is therefore not sufficient to account for irreversible acylation of peptidoglycan transpeptidases observed for most beta-lactam antibiotics. PMID- 28831099 TI - Unilateral stimulation of the lateral division of the dorsal telencephalon induces synaptic plasticity in the bilateral medial division of zebrafish. AB - This study was aimed to evaluate the synaptic plasticity in projections from the dorsal lateral region (Dl) to the bilateral dorsal medial region (Dm) of the zebrafish telencephalon. The results showed that unilateral electrical stimulation of the Dl evokes a negative field potential (FP) in both the contralateral and ipsilateral side of the Dm. We tested synaptic plasticity, including high-frequency stimulation-induced LTP (HFS-LTP) and low-frequency stimulation-induced LTD (LFS-LTD). We demonstrated that HFS-induced bilateral LTP is NMDAR-dependent by the application of an NMDAR antagonist, DL-AP5 (30 MUM, suprafused for 10 min), which blocked the HFS-induced LTP in both the contralateral and ipsilateral Dm. In addition, LTP was restored after DL-AP5 was washed out by continuous aCSF suprafusion. These results suggested that the potentiation is NMDAR-dependent. Either LFS (1 Hz for 20 min) or applying the mGluR agonist, DHPG (40 MUM, suprafused for 10 min) successfully induced bilateral LTD for at least 1 h. Furthermore, both the contralateral fEPSP and LTP vanished after ablation of the anterior commissure. In conclusion, the results of the present study suggested that the projection between the Dl and contralateral Dm in the telencephalon of zebrafish is via the anterior commissure and possesses synaptic plasticity. PMID- 28831101 TI - Growth differentiation factor 15 promotes blood vessel growth by stimulating cell cycle progression in repair of critical-sized calvarial defect. AB - Repair of large bone defects remains a challenge for surgeons, tissue engineering represents a promising approach. However, the use of this technique is limited by delayed vascularization in central regions of the scaffold. Growth differentiation factor 15(GDF15) has recently been reported to be a potential angiogenic cytokine and has an ability to promote the proliferation of human umbilical vein endothelial cells(HUVECs). Whether it can be applied for promoting vascularized bone regeneration is still unknown. In this study, we demonstrated that GDF15 augmented the expression of cyclins D1 and E, induced Rb phosphorylation and E2F-1 nuclear translocation, as well as increased HUVECs proliferation. Furthermore, we also observed that GDF15 promoted the formation of functional vessels at an artificially-induced angiogenic site, and remarkably improved the healing in the repair of critical-sized calvarial defects. Our results confirm the essential role of GDF15 in angiogenesis and suggest its potential beneficial use in regenerative medicine. PMID- 28831102 TI - Circular RNAs expression profiles in human gastric cancer. AB - Circular RNAs (circRNAs) are implicated in a variety of cancers. However, the roles of circRNAs in gastric cancer (GC) remain largely unknown. In the current study, circRNAs expression profiles were screened in GC, using 5 pairs of GC and matched non-GC tissues with circRNA chip. Preliminary results were verified with quantitative PCR (qRT-PCR). Briefly, total of 713 circRNAs were differentially expressed in GC tissues vs. non-GC tissues (fold change >= 2.0, p < 0.05): 191 were upregulated, whereas 522 were downregulated in GC tissues. qRT-PCR analysis of randomly selected 7 circRNAs from the 713 circRNAs in 50 paired of GC vs. non GC control tissues confirmed the microarray data. Gene ontology (GO) and KEGG pathway analyses showed that many circRNAs are implicated in carcinogenesis. Among differentially expressed circRNAs, hsa_circ_0076304, hsa_circ_0035431, and hsa_circ_0076305 had the highest magnitude of change. These results provided a preliminary landscape of circRNAs expression profile in GC. PMID- 28831103 TI - A novel fluorescent imaging technique for assessment of cerebral vasospasm after experimental subarachnoid hemorrhage. AB - Various techniques have been developed to study changes in the cerebral vasculature in numerous neuropathological processes including subarachnoid hemorrhage (SAH). One of the most widely employed techniques uses India ink gelatin casting, which presents numerous challenges due to its high viscosity, rapid solidification, and its impact on immunohistochemical analysis. To overcome these limitations, we developed a novel technique for assessing cerebral vasospasm using cerebrovascular perfusion with ROX, SE (5-Carboxy-X-Rhodamine, Succinimidyl Ester), a fluorescent labeling dye. We found that ROX SE perfusion achieves excellent delineation of the cerebral vasculature, was qualitatively and quantitatively superior to India ink-gelatin casting for the assessment of cerebral vasospasm, permits outstanding immunohistochemical examination of non vasospasm components of secondary brain injury, and is a more efficient and cost effective experimental technique. ROX SE perfusion is therefore a novel and highly useful technique for studying cerebrovascular pathology following experimental SAH. PMID- 28831104 TI - Chemically imaging bacteria with super-resolution SERS on ultra-thin silver substrates. AB - Plasmonic hotspots generate a blinking Surface Enhanced Raman Spectroscopy (SERS) effect that can be processed using Stochastic Optical Reconstruction Microscopy (STORM) algorithms for super-resolved imaging. Furthermore, by imaging through a diffraction grating, STORM algorithms can be modified to extract a full SERS spectrum, thereby capturing spectral as well as spatial content simultaneously. Here we demonstrate SERS and STORM combined in this way for super-resolved chemical imaging using an ultra-thin silver substrate. Images of gram-positive and gram-negative bacteria taken with this technique show excellent agreement with scanning electron microscope images, high spatial resolution at <50 nm, and spectral SERS content that can be correlated to different regions. This may be used to identify unique chemical signatures of various cells. Finally, because we image through as-deposited, ultra-thin silver films, this technique requires no nanofabrication beyond a single deposition and looks at the cell samples from below. This allows direct imaging of the cell/substrate interface of thick specimens or imaging samples in turbid or opaque liquids since the optical path doesn't pass through the sample. These results show promise that super-resolution chemical imaging may be used to differentiate chemical signatures from cells and could be applied to other biological structures of interest. PMID- 28831105 TI - Emotional over- and under-eating in early childhood are learned not inherited. AB - Emotional overeating (EOE) has been associated with increased obesity risk, while emotional undereating (EUE) may be protective. Interestingly, EOE and EUE tend to correlate positively, but it is unclear whether they reflect different aspects of the same underlying trait, or are distinct behaviours with different aetiologies. Data were from 2054 five-year-old children from the Gemini twin birth cohort, including parental ratings of child EOE and EUE using the Child Eating Behaviour Questionnaire. Genetic and environmental influences on variation and covariation in EUE and EOE were established using a bivariate Twin Model. Variation in both behaviours was largely explained by aspects of the environment completely shared by twin pairs (EOE: C = 90%, 95% CI: 89%-92%; EUE: C = 91%, 95% CI: 90%-92%). Genetic influence was low (EOE: A = 7%, 95% CI: 6%-9%; EUE: A = 7%, 95% CI: 6% 9%). EOE and EUE correlated positively (r = 0.43, p < 0.001), and this association was explained by common shared environmental influences (BivC = 45%, 95% CI: 40%-50%). Many of the shared environmental influences underlying EUE and EOE were the same (rC = 0.50, 95% CI: 0.44, 0.55). Childhood EOE and EUE are etiologically distinct. The tendency to eat more or less in response to emotion is learned rather than inherited. PMID- 28831106 TI - Epidemiological and Clinical Features of Primary Giant Cell Tumors of the Distal Radium: A Multicenter Retrospective Study in China. AB - Giant cell tumors of the distal radius are challenging for surgeons because they are associated with high recurrence rates and poor functional outcomes. Between June 2005 and October 2015, patients with primary giant cell tumors of the distal radius were recruited from seven orthopedic centers in China. The patients' clinical features and demographic characteristics were obtained from medical records and reviewed retrospectively. Overall, 48 cases of giant cell tumors of the distal radius were assessed in this study. These patients were more likely to be between 20 and 40 years of age, to have a Campanacci grade of III, and to undergo a surgical style of resection. The prevalence of pathological fractures was 12.5% overall (20.0% in men and 4.3% in women). The prevalence of local recurrence was 30.0% overall (38.1% in men and 21.1% in women) during the average follow-up period of 62.5 months, with a pulmonary metastasis rate of 5.0%. Giant cell tumors of the distal radius were predominant in men and were more likely to recur locally than around the knee. These findings suggest that it is crucial to evaluate the optimal surgical approach for balancing local recurrence control and functional outcomes to reduce the disease burden. PMID- 28831107 TI - Unraveling the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis: expanding the phenotypic variability of RAX mutations. AB - Ocular coloboma is a common eye malformation arising from incomplete closure of the human optic fissure during development. Multiple genetic mutations contribute to the disease process, showing extensive genetic heterogeneity and complexity of coloboma spectrum diseases. In this study, we aimed to unravel the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis. The subjects were recruited and underwent specialized ophthalmologic clinical examination. A combination of whole exome sequencing (WES), homozygosity mapping, and comprehensive variant analyses was performed to uncover the causative mutation. Only one homozygous mutation (c.113 T > C, p.I38T) in RAX gene survived our strict variant filtering process, consistent with an autosomal recessive inheritance pattern. This mutation segregated perfectly in the family and is located in a highly conserved functional domain. Crystal structure modeling indicated that I38T affected the protein structure. We describe a patient from a consanguineous Chinese family with unusual coloboma, proven to harbor a novel RAX mutation (c.113 T > C, p.I38T, homozygous), expanding the phenotypic variability of ocular coloboma and RAX mutations. PMID- 28831108 TI - Ecological and evolutionary consequences of alternative sex-change pathways in fish. AB - Sequentially hermaphroditic fish change sex from male to female (protandry) or vice versa (protogyny), increasing their fitness by becoming highly fecund females or large dominant males, respectively. These life-history strategies present different social organizations and reproductive modes, from near-random mating in protandry, to aggregate- and harem-spawning in protogyny. Using a combination of theoretical and molecular approaches, we compared variance in reproductive success (V k*) and effective population sizes (N e) in several species of sex-changing fish. We observed that, regardless of the direction of sex change, individuals conform to the same overall strategy, producing more offspring and exhibiting greater V k* in the second sex. However, protogynous species show greater V k*, especially pronounced in haremic species, resulting in an overall reduction of N e compared to protandrous species. Collectively and independently, our results demonstrate that the direction of sex change is a pivotal variable in predicting demographic changes and resilience in sex-changing fish, many of which sustain highly valued and vulnerable fisheries worldwide. PMID- 28831109 TI - Exposure to agricultural pesticide impairs visual lateralization in a larval coral reef fish. AB - Lateralization, i.e. the preferential use of one side of the body, may convey fitness benefits for organisms within rapidly-changing environments, by optimizing separate and parallel processing of different information between the two brain hemispheres. In coral reef-fishes, the movement of larvae from planktonic to reef environments (recruitment) represents a major life-history transition. This transition requires larvae to rapidly identify and respond to sensory cues to select a suitable habitat that facilitates survival and growth. This 'recruitment' is critical for population persistence and resilience. In aquarium experiments, larval Acanthurus triostegus preferentially used their right-eye to investigate a variety of visual stimuli. Despite this, when held in in situ cages with predators, those larvae that previously favored their left-eye exhibited higher survival. These results support the "brain's right-hemisphere" theory, which predicts that the right-eye (i.e. left-hemisphere) is used to categorize stimuli while the left-eye (i.e. right-hemisphere) is used to inspect novel items and initiate rapid behavioral-responses. While these experiments confirm that being highly lateralized is ecologically advantageous, exposure to chlorpyrifos, a pesticide often inadvertently added to coral-reef waters, impaired visual-lateralization. This suggests that chemical pollutants could impair the brain function of larval fishes during a critical life-history transition, potentially impacting recruitment success. PMID- 28831110 TI - Hypoxia regulates RhoA and Wnt/beta-catenin signaling in a context-dependent way to control re-differentiation of chondrocytes. AB - Cartilage tissue is avascular and hypoxic which regulates chondrocyte phenotype via stabilization of HIFs. Here, we investigated the role of hypoxia and HIFs in regulation of Rho and canonical Wnt signaling in chondrocytes. Our data demonstrates that hypoxia controls the expression of RhoA in chondrocytes in a context-dependent manner on the culturing conditions. Within a 3D microenvironment, hypoxia suppresses RhoA on which hypoxia-driven expression of chondrogenic markers depends. Conversely, hypoxia leads to upregulation of RhoA in chondrocytes on 2D with a failure in re-expression of chondrogenic markers. Similarly to RhoA, hypoxic regulation of Wnt/beta-catenin signaling depends on the microenvironment. Hypoxia downregulates beta-catenin within 3D hydrogels whereas it causes a potent increase on 2D. Hypoxia-induced suppression of canonical Wnt signaling in 3D contributes to the promotion of chondrogenic phenotype as induction of Wnt signaling abrogates the hypoxic re-differentiation of chondrocytes. Inhibiting Wnt/beta-catenin signaling via stabilization of Axin2 leads to a synergistic enhancement of hypoxia-induced expression of chondrogenic markers. The effects of hypoxia on Rho and Wnt/beta-catenin signaling are HIF dependent as stabilizing HIFs under normoxia revealed similar effects on chondrocytes. The study reveals important insights on hypoxic signaling of chondrocytes and how hypoxia regulates cellular mechanisms depending on the cellular microenvironment. PMID- 28831111 TI - Maskless X-Ray Writing of Electrical Devices on a Superconducting Oxide with Nanometer Resolution and Online Process Monitoring. AB - X-ray nanofabrication has so far been usually limited to mask methods involving photoresist impression and subsequent etching. Herein we show that an innovative maskless X-ray nanopatterning approach allows writing electrical devices with nanometer feature size. In particular we fabricated a Josephson device on a Bi2Sr2CaCu2O8+delta (Bi-2212) superconducting oxide micro-crystal by drawing two single lines of only 50 nm in width using a 17.4 keV synchrotron nano-beam. A precise control of the fabrication process was achieved by monitoring in situ the variations of the device electrical resistance during X-ray irradiation, thus finely tuning the irradiation time to drive the material into a non superconducting state only in the irradiated regions, without significantly perturbing the crystal structure. Time-dependent finite element model simulations show that a possible microscopic origin of this effect can be related to the instantaneous temperature increase induced by the intense synchrotron picosecond X-ray pulses. These results prove that a conceptually new patterning method for oxide electrical devices, based on the local change of electrical properties, is actually possible with potential advantages in terms of heat dissipation, chemical contamination, miniaturization and high aspect ratio of the devices. PMID- 28831112 TI - Discovery from a large-scaled survey of Trichoderma in soil of China. AB - The first large-scaled survey of soil-inhabiting Trichoderma is conducted in 23 provinces of China. Twenty-three new species belonging to the green-ascospored clades are discovered. Their phylogenetic positions are determined by sequence analyses of the combined partial sequences of translation elongation factor 1 alpha and the second largest RNA polymerase subunit encoding genes. Morphology and culture characteristics are observed, described and illustrated in detail. Distinctions between the new species and their close relatives are compared and discussed. They are named as: T. aggregatum, T. alpinum, T. bannaense, T. breve, T. brevicrassum, T. byssinum, T. chlamydosporicum, T. concentricum, T. ganodermatis, T. hainanense, T. hengshanicum, T. hirsutum, T. hunanense, T. ingratum, T. liberatum, T. linzhiense, T. longisporum, T. polypori, T. pseudodensum, T. simplex, T. solum, T. undatipile and T. zayuense. PMID- 28831113 TI - RNA-Seq reveals MicroRNA expression signature and genetic polymorphism associated with growth and muscle quality traits in rainbow trout. AB - The role of microRNA expression and genetic variation in microRNA-binding sites of target genes on growth and muscle quality traits is poorly characterized. We used RNA-Seq approach to investigate their importance on 5 growth and muscle quality traits: whole body weight (WBW), muscle yield, muscle crude-fat content, muscle shear force and whiteness. Phenotypic data were collected from 471 fish, representing 98 families (~5 fish/family) from a growth-selected line. Muscle microRNAs and mRNAs were sequenced from 22 families showing divergent phenotypes. Ninety microRNAs showed differential expression between families with divergent phenotypes, and their expression was strongly associated with variation in phenotypes. A total of 204 single nucleotide polymorphisms (SNPs) present in 3' UTR of target genes either destroyed or created novel illegitimate microRNA target sites; of them, 78 SNPs explained significant variation in the aforementioned 5 muscle traits. Majority of the phenotype-associated SNPs were present in microRNA-binding sites of genes involved in energy metabolism and muscle structure. These findings suggest that variation in microRNA expression and/or sequence variation in microRNA binding sites in target genes play an important role in mediating differences in fish growth and muscle quality phenotypes. PMID- 28831114 TI - Mast cell activation in the acupoint is important for the electroacupuncture effect against pituitrin-induced bradycardia in rabbits. AB - This research was conducted to verify the structural and functional characteristics of mast cells in the electroacupuncture (EA) effects on bradycardia. First, we examined the mast cell density at PC 6, adjacent acupoint LU 7, and a non-acupoint. We tested the effects of EA at PC 6 on heart rate (HR) and blood pressure (BP) in rabbits with pituitrin-induced bradycardia. We also injected sodium cromolyn (Cro), a mast cell membrane stabilizer, at PC 6 30 min before EA to investigate if it affected the EA effects. The results showed that in both PC 6 and LU 7, the mast cell densities were higher than in the non acupoint (P < 0.05). EA could induce mast cell degranulation at PC 6, which could be suppressed by sodium cromolyn (P < 0.05). EA improved HR, though the change was relatively small in the initial stage with a significant change at 35 min after modelling (P < 0.05). BP significantly improved at 10 min after the onset of pituitrin-induced bradycardia (P < 0.05). The EA effects on both HR and BP were suppressed by sodium cromolyn (P < 0.05). Therefore, we concluded that mast cells in the acupoint are important for the EA effects against pituitrin-induced bradycardia in rabbits. PMID- 28831115 TI - A miR-SNP biomarker linked to an increased lung cancer survival by miRNA-mediated down-regulation of FZD4 expression and Wnt signaling. AB - Through a new hypothesis-driven and microRNA-pathway-based SNP (miR-SNP) association study we identified a novel miR-SNP (rs713065) in the 3'UTR region of FZD4 gene linked with decreased risk of death in early stage NSCLC patients. We determined biological function and mechanism of action of this FZD4-miR-SNP biomarker in a cellular platform. Our data suggest that FZD4-miR-SNP loci may significantly influence overall survival in NSCLC patients by specifically interacting with miR-204 and modulating FZD4 expression and cellular function in the Wnt-signaling-driven tumor progression. Our findings are bridging the gap between the discovery of epidemiological SNP biomarkers and their biological function and will enable us to develop novel therapeutic strategies that specifically target epigenetic markers in the oncogenic Wnt/FZD signaling pathways in NSCLC. PMID- 28831116 TI - Controlling congestion on complex networks: fairness, efficiency and network structure. AB - We consider two elementary (max-flow and uniform-flow) and two realistic (max-min fairness and proportional fairness) congestion control schemes, and analyse how the algorithms and network structure affect throughput, the fairness of flow allocation, and the location of bottleneck edges. The more realistic proportional fairness and max-min fairness algorithms have similar throughput, but path flow allocations are more unequal in scale-free than in random regular networks. Scale free networks have lower throughput than their random regular counterparts in the uniform-flow algorithm, which is favoured in the complex networks literature. We show, however, that this relation is reversed on all other congestion control algorithms for a region of the parameter space given by the degree exponent gamma and average degree . Moreover, the uniform-flow algorithm severely underestimates the network throughput of congested networks, and a rich phenomenology of path flow allocations is only present in the more realistic alpha-fair family of algorithms. Finally, we show that the number of paths passing through an edge characterises the location of a wide range of bottleneck edges in these algorithms. Such identification of bottlenecks could provide a bridge between the two fields of complex networks and congestion control. PMID- 28831117 TI - Abnormal skin in toe webs is a marker for abnormal glucose metabolism. A cross sectional survey among 1,849 adults in Finland. AB - Diabetes is undiagnosed disease and easy screening tools for it are warranted. Because foot complications are usual in diabetes, we aimed to test hypothesis that skin abnormalities are found already from patients who are not aware of having diabetes, by studying the possible association between unhealthy toe web skin and abnormal glucose metabolism. 1,849 cases without previously diagnosed diabetes participated to the 46-year follow-up study of the Northern Finland Birth Cohort. A skin investigation was performed for all, and abnormal skin findings in toe web spaces were taken as explanatory variables. Abnormal glucose tolerance was the main outcome and it was tested with an oral glucose tolerance test (OGTT), glycosylated haemoglobin fraction (HbA1c) Values are numbers (percentages) of sub and fasting blood glucose. The participants who had any abnormal skin findings in toe webs were associated with 2.5-fold (OR 2.5, 95% CI 1.3-4.9) and 6-fold (OR 6.2, 1.4-27.6) increased risk of having previously undiagnosed diabetes detected by a 2-hour OGTT and HbA1c, respectively. The predictive power of toe web findings was comparable with FINDRISC score. Abnormal skin findings in the toe webs show increased risk of occult diabetes, and may, thus serve as an additional sign of undiagnosed diabetes. PMID- 28831118 TI - Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer's disease progression. AB - Olfactory dysfunction is among the earliest features of Alzheimer's disease (AD). Although neuropathological abnormalities have been detected in the olfactory bulb (OB), little is known about its dynamic biology. Here, OB- proteome analysis showed a stage-dependent synaptic proteostasis impairment during AD evolution. In addition to progressive modulation of tau and amyloid precursor protein (APP) interactomes, network-driven proteomics revealed an early disruption of upstream and downstream p38 MAPK pathway and a subsequent impairment of Phosphoinositide dependent protein kinase 1 (PDK1)/Protein kinase C (PKC) signaling axis in the OB from AD subjects. Moreover, a mitochondrial imbalance was evidenced by a depletion of Prohibitin-2 (Phb2) levels and a specific decrease in the phosphorylated isoforms of Phb1 in intermediate and advanced AD stages. Interestingly, olfactory Phb subunits were also deregulated across different types of dementia. Phb2 showed a specific up-regulation in mixed dementia, while Phb1 isoforms were down-regulated in frontotemporal lobar degeneration (FTLD). However, no differences were observed in the olfactory expression of Phb subunits in progressive supranuclear palsy (PSP). To sum up, our data reflect, in part, the missing links in the biochemical understanding of olfactory dysfunction in AD, unveiling Phb complex as a differential driver of neurodegeneration at olfactory level. PMID- 28831119 TI - Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection. AB - Severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-like coronavirus are a potential threat to global health. However, reviews of the long term effects of clinical treatments in SARS patients are lacking. Here a total of 25 recovered SARS patients were recruited 12 years after infection. Clinical questionnaire responses and examination findings indicated that the patients had experienced various diseases, including lung susceptibility to infections, tumors, cardiovascular disorders, and abnormal glucose metabolism. As compared to healthy controls, metabolomic analyses identified significant differences in the serum metabolomes of SARS survivors. The most significant metabolic disruptions were the comprehensive increase of phosphatidylinositol and lysophospha tidylinositol levels in recovered SARS patients, which coincided with the effect of methylprednisolone administration investigated further in the steroid treated non-SARS patients with severe pneumonia. These results suggested that high-dose pulses of methylprednisolone might cause long-term systemic damage associated with serum metabolic alterations. The present study provided information for an improved understanding of coronavirus-associated pathologies, which might permit further optimization of clinical treatments. PMID- 28831120 TI - Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis. AB - IgA nephropathy (IgAN) is the most prevalent among primary glomerular diseases worldwide. Although our understanding of IgAN has advanced significantly, its underlying biology and potential drug targets are still unexplored. We investigated a combinatorial approach for the analysis of IgAN-relevant -omics data, aiming at identification of novel molecular signatures of the disease. Nine published urinary proteomics datasets were collected and the reported differentially expressed proteins in IgAN vs. healthy controls were integrated into known biological pathways. Proteins participating in these pathways were subjected to multi-step assessment, including investigation of IgAN transcriptomics datasets (Nephroseq database), their reported protein-protein interactions (STRING database), kidney tissue expression (Human Protein Atlas) and literature mining. Through this process, from an initial dataset of 232 proteins significantly associated with IgAN, 20 pathways were predicted, yielding 657 proteins for further analysis. Step-wise evaluation highlighted 20 proteins of possibly high relevance to IgAN and/or kidney disease. Experimental validation of 3 predicted relevant proteins, adenylyl cyclase-associated protein 1 (CAP1), SHC-transforming protein 1 (SHC1) and prolylcarboxypeptidase (PRCP) was performed by immunostaining of human kidney sections. Collectively, this study presents an integrative procedure for -omics data exploitation, giving rise to biologically relevant results. PMID- 28831121 TI - The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function. AB - HD-PTP is a tumour suppressor phosphatase that controls endocytosis, down regulation of mitogenic receptors and cell migration. Central to its role is the specific recruitment of critical endosomal sorting complexes required for transport (ESCRTs). However, the molecular mechanisms that enable HD-PTP to regulate ESCRT function are unknown. We have characterised the molecular architecture of the entire ESCRT binding region of HD-PTP using small angle X-ray scattering and hydrodynamic analyses. We show that HD-PTP adopts an open and extended conformation, optimal for concomitant interactions with multiple ESCRTs, which contrasts with the compact conformation of the related ESCRT regulator Alix. We demonstrate that the HD-PTP open conformation is functionally competent for binding cellular protein partners. Our analyses rationalise the functional cooperation of HD-PTP with ESCRT-0, ESCRT-I and ESCRT-III and support a model for regulation of ESCRT function by displacement of ESCRT subunits, which is crucial in determining the fate of ubiquitinated cargo. PMID- 28831122 TI - Naturally acquired antibody response to Plasmodium falciparum describes heterogeneity in transmission on islands in Lake Victoria. AB - As markers of exposure anti-malaria antibody responses can help characterise heterogeneity in malaria transmission. In the present study antibody responses to Plasmodium falciparum AMA-1, MSP-119 and CSP were measured with the aim to describe transmission patterns in meso-endemic settings in Lake Victoria. Two cross-sectional surveys were conducted in Lake Victoria in January and August 2012. The study area comprised of three settings: mainland (Ungoye), large island (Mfangano) and small islands (Takawiri, Kibuogi, Ngodhe). Individuals provided a finger-blood sample to assess malaria infection by microscopy and PCR. Antibody response to P. falciparum was determined in 4,112 individuals by ELISA using eluted dried blood from filter paper. The overall seroprevalence was 64.0% for AMA-1, 39.5% for MSP-119, and 12.9% for CSP. Between settings, seroprevalences for merozoite antigens were similar between Ungoye and Mfangano, but higher when compared to the small islands. For AMA-1, the seroconversion rates (SCRs) ranged from 0.121 (Ngodhe) to 0.202 (Ungoye), and were strongly correlated to parasite prevalence. We observed heterogeneity in serological indices across study sites in Lake Victoria. These data suggest that AMA-1 and MSP-119 sero-epidemiological analysis may provide further evidence in assessing variation in malaria exposure and evaluating malaria control efforts in high endemic area. PMID- 28831123 TI - Liprin-alpha-1 is a novel component of the murine neuromuscular junction and is involved in the organization of the postsynaptic machinery. AB - Neuromuscular junctions (NMJs) are specialized synapses that connect motor neurons to skeletal muscle fibers and orchestrate proper signal transmission from the nervous system to muscles. The efficient formation and maintenance of the postsynaptic machinery that contains acetylcholine receptors (AChR) are indispensable for proper NMJ function. Abnormalities in the organization of synaptic components often cause severe neuromuscular disorders, such as muscular dystrophy. The dystrophin-associated glycoprotein complex (DGC) was shown to play an important role in NMJ development. We recently identified liprin-alpha-1 as a novel binding partner for one of the cytoplasmic DGC components, alpha dystrobrevin-1. In the present study, we performed a detailed analysis of localization and function of liprin-alpha-1 at the murine NMJ. We showed that liprin-alpha-1 localizes to both pre- and postsynaptic compartments at the NMJ, and its synaptic enrichment depends on the presence of the nerve. Using cultured muscle cells, we found that liprin-alpha-1 plays an important role in AChR clustering and the organization of cortical microtubules. Our studies provide novel insights into the function of liprin-alpha-1 at vertebrate neuromuscular synapses. PMID- 28831124 TI - A novel inducible prophage from the mycosphere inhabitant Paraburkholderia terrae BS437. AB - Bacteriophages constitute key gene transfer agents in many bacteria. Specifically, they may confer gene mobility to Paraburkholderia spp. that dwells in soil and the mycosphere. In this study, we first screened mycosphere and bulk soils for phages able to produce plaques, however found these to be below detection. Then, prophage identification methods were applied to the genome sequences of the mycosphere-derived Paraburkholderia terrae strains BS001, BS007, BS110 and BS437, next to P. phytofirmans strains BS455, BIFAS53, J1U5 and PsJN. These analyses revealed all bacterial genomes to contain considerable amounts [up to 13.3%] of prophage-like sequences. One sequence predicted to encode a complete phage was found in the genome of P. terrae BS437. Using the inducing agent mitomycin C, we produced high-titered phage suspensions. These indeed encompassed the progeny of the identified prophage (denoted phi437), as evidenced using phage major capsid gene molecular detection. We obtained the full sequence of phage phi437, which, remarkably, had undergone a reshuffling of two large gene blocks. One predicted moron gene was found, and it is currently analyzed to understand the extent of its ecological significance for the host. PMID- 28831125 TI - Exploration of the Brain in Rest: Resting-State Functional MRI Abnormalities in Patients with Classic Galactosemia. AB - Patients with classic galactosemia, a genetic metabolic disorder, encounter cognitive impairments, including motor (speech), language, and memory deficits. We used functional magnetic resonance imaging to evaluate spontaneous functional connectivity during rest to investigate potential abnormalities in neural networks. We characterized networks using seed-based correlation analysis in 13 adolescent patients and 13 matched controls. Results point towards alterations in several networks, including well-known resting-state networks (e.g. default mode, salience, visual network). Particularly, patients showed alterations in networks encompassing medial prefrontal cortex, parietal lobule and (pre)cuneus, involved in spatial orientation and attention. Furthermore, altered connectivity of networks including the insula and superior frontal gyrus -important for sensory motor integration and motor (speech) planning- was demonstrated. Lastly, abnormalities were found in networks involving occipital regions, linked to visuospatial capacities and working memory. Importantly, across several seeds, altered functional connectivity to the superior frontal cortex, anterior insula, parietal lobule and the (pre)cuneus was observed in patients, suggesting special importance of these brain regions. Moreover, these alterations correlated with neurocognitive test results, supporting a relation with the clinical phenotype. Our findings contribute to improved characterization of brain impairments in classic galactosemia and provide directions for further investigations. PMID- 28831126 TI - Increasing the doping efficiency by surface energy control for ultra-transparent graphene conductors. AB - Graphene's attractiveness in many applications is limited by its high resistance. Extrinsic doping has shown promise to overcome this challenge but graphene's performance remains below industry requirements. This issue is caused by a limited charge transfer efficiency (CTE) between dopant and graphene. Using AuCl3 as a model system, we measure CTE as low as 5% of the expected values due to the geometrical capacitance of small adsorbate clusters. We here demonstrate a strategy for enhancing the CTE by a two-step optimization of graphene's surface energy prior to AuCl3 doping. First, exposure to UV ozone modified the hydrophilicity of graphene and was found to decrease the cluster's geometric capacitance, which had a direct effect on the CTE. Occurrence of lattice defects at high UV exposure, however, deteriorated graphene's transport characteristics and limited the effectiveness of this pretreatment step. Thus, prior to UV exposure, a functionalized polymer layer was introduced that could further enhance graphene's surface energy while protecting it from damage. Combination of these treatment steps were found to increase the AuCl3 charge transfer efficiency to 70% and lower the sheet resistance to 106 Omega/gamma at 97% transmittance which represents the highest reported performance for doped single layer graphene and is on par with commercially available transparent conductors. PMID- 28831127 TI - Spacial Energy Distribution Manipulation with Multi-focus Huygens Metamirror. AB - Huygens metasurface is a planar array of crossed electric and magnetic dipoles, which provide specific surface current to tailor the electromagnetic field distribution. By changing the geometrical parameters of the proposed unit cell, the manipulation range of reflection phase can achieve 2pi, while the amplitude of the reflection coefficient can keep above 0.993. Based on the designed Huygens meta-atoms, a novel multi-focus Huygens metamirror is proposed at microwave range in this paper. Utilizing the meta-atoms with the desired reflection phase distribution as calculated, the incident plane wave can be converged to designated points in any desired fashion including focal number, location and intensity distribution, which exhibits outstanding manipulation capability. Our research on Huygens metamirror provides a fascinating design of multi-focus imaging in microwave region, which makes it potential applications in antenna and imaging systems. PMID- 28831128 TI - Associations between lead concentrations and cardiovascular risk factors in U.S. adolescents. AB - Little is known regarding the effects of environmental lead exposure on cardiovascular risk factors in the adolescent population. We studied 11,662 subjects included in the National Health and Nutrition Examination Survey (NHANES) 1999-2012. Blood lead levels were analysed for their association with cardiovascular risk factors (CVRF). Regression coefficients (Beta) and 95% confidence intervals (CIs) of blood lead in association with CVRF (e.g., total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, fasting glucose, glycohemoglobin, fasting insulin, and blood pressure) were estimated using multivariate and generalized linear regression after adjusting for age, gender, ethnicity, serum cotinine, body mass index (BMI), physical activity, and household income. We identified a strong positive association between blood lead (coefficient = 0.022, 95% CI 0.003, 0.041; P = 0.022) and LDL-cholesterol in adolescents (age 12-19 years). However, no associations with other CVRFs were found in the overall population. In the generalized linear models, participants with the highest lead levels demonstrated a 1.87% (95% CI 0.73%, 3.02%) greater increase in serum LDL-cholesterol (p for trend = 0.031) when compared to participants with the lowest lead levels. These results provide epidemiological evidence that low levels of blood lead are positively associated with LDL cholesterol in the adolescent population. PMID- 28831129 TI - Longitudinal observations of progressive cardiac dysfunction in a cardiomyopathic animal model by self-gated cine imaging based on 11.7-T magnetic resonance imaging. AB - The purpose of this study was to longitudinally assess left ventricular function and wall thickness in a hamster model of cardiomyopathy using 11.7-T magnetic resonance imaging (MRI). MRI were performed for six cardiomyopathic J2N-k hamsters and six J2N-n hamsters at 5, 10, 15, and 20 weeks of age. Echocardiography was also performed at 20 weeks. The ejection fraction (EF) at 15 and 20 weeks of age in J2N-k hamsters showed a significant decrease compared with those in controls. Conversely, the end-systolic and end-diastolic volumes in cardiomyopathic hamsters showed a significant increase compared with those in controls. Moreover, the heart walls of J2N-k hamsters at 15 and 20 weeks were thicker than those of controls at end-systole; however, there were no significant differences at end-diastole. Optical microscopy with Masson's trichrome staining depicted no fibrosis in the control myocardium, although it showed interstitial fibrosis in the 20-week-old J2N-k cardiomyopathic myocardium. There were no differences in EF and the wall thickness observed on MRI and those observed on echocardiography. These results indicate the presence of systolic dysfunction in cardiomyopathic hamsters. Self-gated cine imaging based on 11.7-T MRI can be used for serial measurements of cardiac function and wall thickness in a cardiomyopathic model. PMID- 28831130 TI - A broadband reflective-type half-wave plate employing optical feedbacks. AB - We propose and demonstrate a type of a broadband half-wave plate that operates in the reflective mode. It consists of a metal grating embedded in a dielectric slab and placed on top of a grounded metal surface. We theoretically show that owing to the optical feedback effect which originates from the wave reflections at the air-dielectric interface, the proposed half-wave plate exhibits a broadened and flattened response when comparing to the case where the feedback effect is absent. Such a prediction is validated using both numerical and experimental works carried out on a half-wave plate designed at 10 GHz. Moreover, our theoretical analysis also reveals that the half-wave plate has an interesting feature of broad angular response. Taking advantage of these features, we experimentally demonstrate that the proposed device can function as a freely tunable linear polarization converter with polarization conversion residues less than -20 dB in a wide frequency band, under the condition that the incident angle is as large as 45 degrees. PMID- 28831131 TI - Nm23-H1-stabilized hnRNPA2/B1 promotes internal ribosomal entry site (IRES) mediated translation of Sp1 in the lung cancer progression. AB - Our recent studies have indicated that specificity protein-1 (Sp1) accumulates substantially in the early stage of lung cancer but is partially decreased in the late stages, which is an important factor in the progression of the cancer. In this study, we found that Nm23-H1 and hnRNPA2/B1 could be recruited to the 5'UTR of Sp1 mRNA. In investigating the clinical relevance of Nm23-H1/Sp1 levels, we found a positive correlation between lung cancer patients with poor prognosis and low levels of Sp1 and Nm23-H1, suggesting an association between Nm23-H1/Sp1 levels and survival rate. Knockdown of Nm23-H1 inhibits lung cancer growth but increases lung cancer cell malignancy, which could be rescued by overexpression of Sp1, indicating that Nm23-H1-induced Sp1 expression is critical for lung cancer progression. We also found that Nm23-H1 increases the protein stability of hnRNPA2/B1and is thereby co-recruited to the 5'UTR of Sp1 mRNA to regulate cap independent translational activity. Since the Sp1 level is tightly regulated during lung cancer progression, understanding the molecular mechanisms underlying the regulation by Nm23-H1/hnRNPA2B1 of Sp1 expression in the various stages of lung cancer will be beneficial for lung cancer therapy in the future. PMID- 28831132 TI - Cyclocarya paliurus tea leaves enhances pancreatic beta cell preservation through inhibition of apoptosis. AB - Leaves of Cyclocarya paliurus are a sweet tea traditionally used to treat obesity and diabetes in China. However, its protective mechanisms against hyperglycemia remains unclear. Here, we demonstrate that the extract of C. paliurus leaves significantly decreased body loss, food intake and blood glucose level, and increased blood insulin level, beta-cell number and insulin-producing beta cells in high-fat diet-low dose STZ-induced diabetic mice. In vivo and in vitro studies also showed the extract of C. paliurus leaves significantly inhibited pancreatic beta cell apoptosis by suppressing the expression of caspase 8, caspase 9 and cleaved caspase-3, as well as Bax/Bcl-2 ratio, down-regulating p38, ERK and JNK phosphorylation, and up-regulating Akt phosphorylation. These effects were significantly enhanced by inhibitor p-38 or ERK or JNK, and counteracted by inhibitor of PI3K. In addition, the extract of C. paliurus leaves also significantly improved hepatic steatosis, nephropathy and cardiac hypertrophy of diabetic mice. Taken together, these results provide the insight into the effects of C. paliurus leaves on pancreatic beta cell preservation in standing glucolipotoxicity. Therefore, C. paliurus tea leaves may be used as a new remedy for diabetes through enhancing pancreatic beta cell preservation by inhibiting beta cell apoptosis. PMID- 28831133 TI - Aluminum plasmonic nanoshielding in ultraviolet inactivation of bacteria. AB - Ultraviolet (UV) irradiation is an effective bacterial inactivation technique with broad applications in environmental disinfection. However, biomedical applications are limited due to the low selectivity, undesired inactivation of beneficial bacteria and damage of healthy tissue. New approaches are needed for the protection of biological cells from UV radiation for the development of controlled treatment and improved biosensors. Aluminum plasmonics offers attractive opportunities for the control of light-matter interactions in the UV range, which have not yet been explored in microbiology. Here, we investigate the effects of aluminum nanoparticles (Al NPs) prepared by sonication of aluminum foil on the UVC inactivation of E. coli bacteria and demonstrate a new radiation protection mechanism via plasmonic nanoshielding. We observe direct interaction of the bacterial cells with Al NPs and elucidate the nanoshielding mechanism via UV plasmonic resonance and nanotailing effects. Concentration and wavelength dependence studies reveal the role and range of control parameters for regulating the radiation dosage to achieve effective UVC protection. Our results provide a step towards developing improved radiation-based bacterial treatments. PMID- 28831134 TI - Evaluation of the new Chinese Disseminated Intravascular Coagulation Scoring System in critically ill patients: A multicenter prospective study. AB - Disseminated intravascular coagulation (DIC) is a common life-threatening complication in critically ill patients. The diagnostic scoring systems of DIC enable a more prompt and accurate diagnosis of DIC, such as the International Society on Thrombosis and Haemostasis (ISTH), the Japanese Association for Acute Medicine (JAAM) and the Japanese Ministry of Health and Welfare (JMHW). This study prospectively evaluated the newly proposed Chinese DIC Scoring System (CDSS), which was conducted at 18 centers in China during a one-year period. Receiver operating characteristic (ROC) curves showed that, for diagnosis of DIC and for prediction of the 28-day all-cause mortality, the CDSS had larger areas under the ROC curve (AUCs) than the ISTH and the JAAM in different groups. The CDSS also had larger AUC than the JMHW for the ISTH DIC in non-infectious diseases. All of the AUCs of the CDSS were greater than 0.8, accompanied with both high sensitivity and high specificity. Furthermore, the CDSS score was an independent predictor of mortality (odds ratio, 1.882; p < 0.001), and could reflect the illness severity (p < 0.001 for Spearman's rank correlations with the scores of severity). In conclusion, the CDSS is worthy of promotion with a better diagnostic and prognostic value for DIC. PMID- 28831135 TI - Study on Physio-chemical Properties of plasma polymerization in C2H2/N2 plasma and Their Impact on COL X. AB - Nitrogen-containing plasma polymerization is of considerable interest for tissue engineering due to their properties on cell adhesion and mesenchymal stem cells (MSCs) response. In this study, low-pressure RF plasma of acetylene and nitrogen was used to deposit nitrogen-containing plasma polymerized coatings on several substrates. Deposition kinetics and surface characteristics of coatings were investigated in terms of RF power and gas flow ratio. OES was used to monitor the plasma process and investigate the relation between the film structure and plasma species. Presence of several bonds and low concentration of amine functional groups were determined using FTIR and Colorimetric methods. Contact angle goniometry results indicated about 30% increase in surface hydrophilicity. Stability of coatings in air and two different liquid environments was examined by repeating surface free energy measurements. Deposited films exhibited acceptable stability during the storage duration. Surface roughness measured by AFM was found to decrease with growing concentration of nitrogen. The deposition rate increased with increasing RF power and decreased with growing concentration of nitrogen. Zeta potential measurements of coatings revealed the negative potential on the surface of the thin films. Temporary suppression of collagen X in the presence of plasma coatings was confirmed by RT-PCR results. PMID- 28831136 TI - Multi-factors including Inflammatory/Immune, Hormones, Tumor-related Proteins and Nutrition associated with Chronic Prostatitis NIH IIIa+b and IV based on FAMHES project. AB - Chronic prostatitis (CP) is a complex disease. Fragmentary evidence suggests that factors such as infection and autoimmunity might be associated with CP. To further elucidate potential risk factors, the current study utilized the Fangchenggang Area Male Health and Examination Survey (FAMHES) project; where 22 inflammatory/immune markers, hormone markers, tumor-related proteins, and nutrition-related variables were investigated. We also performed baseline, regression, discriminant, and receiver operating characteristic (ROC) analyses. According to NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), participants were divided into chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS, pain >= 4; divided into IIIa and IIIb sub-groups) and non-CPPS (pain = 0; divided into IV and normal sub-groups). Analyses revealed osteocalcin as a consistent protective factor for CP/CPPS, NIH-IIIb, and NIH-IV prostatitis. Further discriminant analysis revealed that ferritin (p = 0.002) and prostate-specific antigen (PSA) (p = 0.010) were significantly associated with NIH-IIIa and NIH-IV prostatitis, respectively. Moreover, ROC analysis suggested that ferritin was the most valuable independent predictor of NIH-IIIa prostatitis (AUC = 0.639, 95% CI = 0.534-0.745, p = 0.006). Together, our study revealed inflammatory/immune markers [immunoglobulin E, Complement (C3, C4), C-reactive protein, anti-streptolysin, and rheumatoid factors], hormone markers (osteocalcin, testosterone, follicle stimulating hormone, and insulin), tumor-related proteins (carcinoembryonic and PSA), and a nutrition-related variable (ferritin) were significantly associated with CP or one of its subtypes. PMID- 28831137 TI - Immunological memory to blood-stage malaria infection is controlled by the histamine releasing factor (HRF) of the parasite. AB - While most subunit malaria vaccines provide only limited efficacy, pre erythrocytic and erythrocytic genetically attenuated parasites (GAP) have been shown to confer complete sterilizing immunity. We recently generated a Plasmodium berghei (PbNK65) parasite that lacks a secreted factor, the histamine releasing factor (HRF) (PbNK65 hrfDelta), and induces in infected mice a self-resolving blood stage infection accompanied by a long lasting immunity. Here, we explore the immunological mechanisms underlying the anti-parasite protective properties of the mutant PbNK65 hrfDelta and demonstrate that in addition to an up regulation of IL-6 production, CD4+ but not CD8+ T effector lymphocytes are indispensable for the clearance of malaria infection. Maintenance of T cell associated protection is associated with the reduction in CD4+PD-1+ and CD8+PD-1+ T cell numbers. A higher number of central and effector memory B cells in mutant infected mice also plays a pivotal role in protection. Importantly, we also demonstrate that prior infection with WT parasites followed by a drug cure does not prevent the induction of PbNK65 hrfDelta-induced protection, suggesting that such protection in humans may be efficient even in individuals that have been infected and who repeatedly received antimalarial drugs. PMID- 28831139 TI - Research on the control strategy of distributed energy resources inverter based on improved virtual synchronous generator. AB - This paper focus on the power fluctuations of the virtual synchronous generator(VSG) during the transition process. An improved virtual synchronous generator(IVSG) control strategy based on feed-forward compensation is proposed. Adjustable parameter of the compensation section can be modified to achieve the goal of reducing the order of the system. It can effectively suppress the power fluctuations of the VSG in transient process. To verify the effectiveness of the proposed control strategy for distributed energy resources inverter, the simulation model is set up in MATLAB/SIMULINK platform and physical experiment platform is established. Simulation and experiment results demonstrate the effectiveness of the proposed IVSG control strategy. PMID- 28831138 TI - Embryonic hindbrain patterning genes delineate distinct cardio-respiratory and metabolic homeostatic populations in the adult. AB - Previous studies based on mouse genetic mutations suggest that proper partitioning of the hindbrain into transient, genetically-defined segments called rhombomeres is required for normal respiratory development and function in neonates. Less clear is what role these genes and the neurons they define play in adult respiratory circuit organization. Several Cre drivers are used to access and study developmental rhombomeric domains (Eng1 Cre , HoxA2-Cre, Egr2 Cre , HoxB1 Cre , and HoxA4-Cre) in the adult. However, these drivers show cumulative activity beyond the brainstem while being used in intersectional genetic experiments to map central respiratory circuitry. We crossed these drivers to conditional DREADD mouse lines to further characterize the functional contributions of Cre defined populations. In the adult, we show that acute DREADD inhibition of targeted populations results in a variety of not only respiratory phenotypes but also metabolic and temperature changes that likely play a significant role in the observed respiratory alterations. DREADD mediated excitation of targeted domains all resulted in death, with unique differences in the patterns of cardio-respiratory failure. These data add to a growing body of work aimed at understanding the role of early embryonic patterning genes in organizing adult respiratory homeostatic networks that may be perturbed in congenital pathophysiologies. PMID- 28831140 TI - Adult-Onset Vitelliform Macular Dystrophy caused by BEST1 p.Ile38Ser Mutation is a Mild Form of Best Vitelliform Macular Dystrophy. AB - Adult-onset vitelliform macular dystrophy (AVMD) is a common and benign macular degeneration which can be caused by BEST1 mutation. Here, we investigated the clinical characteristics associated with a newly identified BEST1 mutation, p.Ile38Ser and confirmed the associated physiological functional defects. The 51 year-old patient presented bilateral small subretinal yellow deposits. Consistent with AVMD, the corresponding lesions showed hyperautofluorescence, late staining in fluorescein angiography, and subretinal hyper-reflective materials in spectral domain optical coherence tomography. Genetic analysis demonstrated that the patient presented with a heterozygous p.Ile38Ser BEST1 mutation. Surface biotinylation and patch clamp experiments were performed in transfected HEK293T cells. Although, the identified BEST1 mutant maintains normal membrane expression, p.Ile38Ser mutant showed significantly smaller currents than wild type (WT). However, it showed larger currents than other BEST1 mutants, p.Trp93Cys, causing autosomal dominant best vitelliform macular dystrophy (BVMD), and p.Ala195Val, causing autosomal recessive bestrophinopathy (ARB). The cells expressing both WT and each BEST1 mutant showed that the functional defect of p.Ile38ser was milder than that of p.Trp93Cys, whereas combination of p.Ala195Val with WT showed good current. We identified and described the phenotype and in vitro functions of a novel BEST1 mutation causing AVMD. AVMD induced by p.Ile38Ser BEST1 mutation is a mild form of BVMD. PMID- 28831141 TI - GBF3 transcription factor imparts drought tolerance in Arabidopsis thaliana. AB - Drought transcriptome analysis of finger millet (Eleusine coracana) by cDNA subtraction identified drought responsive genes that have a potential role in drought tolerance. Through virus-induced gene silencing (VIGS) in a related crop species, maize (Zea mays), several genes, including a G-BOX BINDING FACTOR 3 (GBF3) were identified as candidate drought stress response genes and the role of GBF3 in drought tolerance was studied in Arabidopsis thaliana. Overexpression of both EcGBF3 and AtGBF3 in A. thaliana resulted in improved tolerance to osmotic stress, salinity and drought stress in addition to conferring insensitivity to ABA. Conversely, loss of function of this gene increased the sensitivity of A. thaliana plants to drought stress. EcGBF3 transgenic A. thaliana results also suggest that drought tolerance of sensitive plants can be improved by transferring genes from far related crops like finger millet. Our results demonstrate the role of GBF3 in imparting drought tolerance in A. thaliana and indicate the conserved role of this gene in drought and other abiotic stress tolerance in several plant species. PMID- 28831142 TI - The complex evolutionary history and phylogeography of Caridina typus (Crustacea: Decapoda): long-distance dispersal and cryptic allopatric species. AB - The evolutionary history of the old, diverse freshwater shrimp genus Caridina is still poorly understood, despite its vast distribution - from Africa to Polynesia. Here, we used nuclear and mitochondrial DNA to infer the phylogeographic and evolutionary history of C. typus, which is one of only four species distributed across the entire range of the genus. Despite this species' potential for high levels of gene flow, questions have been raised regarding its phylogeographic structure and taxonomic status. We identified three distinct lineages that likely diverged in the Miocene. Molecular dating and ancestral range reconstructions are congruent with C. typus' early dispersal to Africa, possibly mediated by the Miocene Indian Ocean Equatorial Jet, followed by back dispersal to Australasia after the Jet's closure. Furthermore, several different species delimitation methods indicate each lineage represents a distinct (cryptic) species, contradicting current morphospecies delimitation of a single C. typus taxon. The evolutionary history of C. typus lineages is complex, in which ancient oceanic current systems and (currently unrecognised) speciation events preceded secondary sympatry of these cryptic species. PMID- 28831143 TI - Genome-wide comparative analysis of H3K4me3 profiles between diploid and allotetraploid cotton to refine genome annotation. AB - Polyploidy is a common evolutionary occurrence in plants. Recently, published genomes of allotetraploid G. hirsutum and its donors G. arboreum and G. raimondii make cotton an accessible polyploid model. This study used chromatin immunoprecipitation with high-throughput sequencing (ChIP-Seq) to investigate the genome-wide distribution of H3K4me3 in G. arboreum and G. hirsutum, and explore the conservation and variation of genome structures between diploid and allotetraploid cotton. Our results showed that H3K4me3 modifications were associated with active transcription in both cottons. The H3K4me3 histone markers appeared mainly in genic regions and were enriched around the transcription start sites (TSSs) of genes. We integrated the ChIP-seq data of H3K4me3 with RNA-seq and ESTs data to refine the genic structure annotation. There were 6,773 and 12,773 new transcripts discovered in G. arboreum and G. hirsutum, respectively. Furthermore, co-expression networks were linked with histone modification and modularized in an attempt to explain differential H3K4me3 enrichment correlated with changes in gene transcription during cotton development and evolution. Taken together, we have combined epigenomic and transcriptomic datasets to systematically discover functional genes and compare them between G. arboreum and G. hirsutum, which may be beneficial for studying diploid and allotetraploid plants with large genomes and complicated evolution. PMID- 28831144 TI - Diabetes mellitus is a significant risk factor for the development of liver cirrhosis in chronic hepatitis C patients. AB - We explored the association between diabetes mellitus (DM) and the risk of hepatitis C virus (HCV)-related liver cirrhosis in Chinese patients with chronic hepatitis C (CHC). To examine the link between DM and liver cirrhosis, we conducted a case-control study of 210 Chinese CHC patients diagnosed with liver cirrhosis, comparing them to an age- and sex-matched control group of 431 CHC patients without liver cirrhosis. We conducted logistic regression analyses adjusting for demographic features and liver cirrhosis risk factors, and found that DM increased the risk of developing liver cirrhosis 2-fold [adjusted odds ratio (AOR), 2.132; 95% confidence interval (CI), 1.344-3.382]. Furthermore, the proportion of liver cirrhosis patients and CHC-only patients with elevated serum triglycerides (>1.8 mmol/L) were 5.2% and 17.4%, respectively, yielding an AOR of 0.264 (95% CI, 0.135-0.517). Multivariate analyses that stratified the risk of developing HCV-related liver cirrhosis in DM patients by gender revealed that the estimated AOR (95% CI) for males was 0.415 (0.178-0.969). In conclusion, DM was associated with an increased risk of developing liver cirrhosis in CHC patients in China. Furthermore, among patients diagnosed with both CHC and DM, females had an increased risk of liver cirrhosis development. PMID- 28831145 TI - Projecting potential distribution of Eucryptorrhynchus scrobiculatus Motschulsky and E. brandti (Harold) under historical climate and RCP 8.5 scenario. AB - Ailanthus altissima (Mill.) Swingle and its variant A. altissima var. Qiantouchun are notorious invasive weeds. Two weevils, Eucryptorrhynchus scrobiculatus (ESC) and E. brandti (EBR) are considered as candidates for biological control of A. altissima. The aim of this study was to model the potential distributions of ESC and EBR using CLIMEX 4.0. The projected potential distributions of ESC and EBR included almost all current distribution areas of A. altissima, except Southeast Asia. Under historical climate, potential distribution area of EBR is larger than that of ESC, 46.67 * 106 km2 and 35.65 * 106 km2, respectively. For both ESC and EBR, climate change expanded the northern boundary of potential distributions northward approximately 600 km by the middle of 21st century, and 1000 km by the end of 21st century under RCP 8.5. However, the suitable range decreased to the south in the Southern Hemisphere because of heat stress. The modelled potential distributions of ESC and EBR in the United States demonstrated that the climate was suitable for both weevils. Therefore, considering only climate suitability, both ESC and EBR can be considered as potential biological control agents against A. altissima with some confidence that climatic conditions are likely suitable. PMID- 28831146 TI - Differential neurophysiological correlates of information processing in Internet gaming disorder and alcohol use disorder measured by event-related potentials. AB - Internet gaming disorder (IGD) shares clinical and neuropsychological features with alcohol use disorder (AUD), but few studies have identified the neurophysiological characteristics of IGD. We investigated the N100 and P300 event-related potentials (ERPs) in patients with IGD to compare them with those of patients with AUD and healthy controls (HCs). Twenty-six patients with IGD, 22 patients with AUD, and 29 HCs participated in this study. ERPs were acquired from young male adults during an auditory oddball task. Between-group differences in N100 and P300 were investigated separately using repeated-measures analysis of variance. Correlations between the ERP values and neurocognitive functioning of each group were examined. Both the IGD and AUD groups showed reduced P300 amplitudes at the midline central and parietal area compared with the HCs. The IGD exhibited reduced N100 amplitudes at the midline frontal area compared with the HCs. The reduced P300 were correlated with a higher spatial span error rate in the IGD. The reduced N100 and P300 were not correlated with Internet addiction severity scores in the IGD. These results indicate that IGD have abnormalities in the P300 comparable to those in AUD. Moreover, the reduction in N100 could be considered a candidate trait marker for IGD. PMID- 28831147 TI - How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study. AB - Janus kinase 2 (JAK2) has been regarded as an essential target for the treatment of myeloproliferative neoplasms (MPNs). BBT594 and CHZ868, Type-II inhibitors of JAK2, illustrate satisfactory efficacy in preclinical MPNs and acute lymphoblastic leukemia (ALL) models. However, the L884P mutation of JAK2 abrogates the suppressive effects of BBT594 and CHZ868. In this study, conventional molecular dynamics (MD) simulations, umbrella sampling (US) simulations and MM/GBSA free energy calculations were employed to explore how the L884P mutation affects the binding of BBT594 and CHZ868 to JAK2 and uncover the resistance mechanism induced by the L884P mutation. The results provided by the US and MD simulations illustrate that the L884P mutation enhances the flexibility of the allosteric pocket and alters their conformations, which amplify the conformational entropy change (-TDeltaS) and weaken the interactions between the inhibitors and target. Additionally, the structural analyses of BBT594 and CHZ868 in complex with the WT JAK2 illustrate that the drug tail with strong electronegativity and small size located in the allosteric pocket of JAK2 may enhance anti-resistance capability. In summary, our results highlight that both of the changes of the conformational entropies and enthalpies contribute to the L884P-induced resistance in the binding of two Type-II inhibitors into JAK2 kinase. PMID- 28831148 TI - Effects of genotype and temperature on accumulation of plant secondary metabolites in Canadian and Australian wheat grown under controlled environments. AB - Predictions of global increased temperature are for 1.8-4 degrees C by 2100. Increased temperature as an abiotic stress may exert a considerable influence on the levels of secondary metabolites in plants. These secondary metabolites may possibly exert biological activities beneficial in prevention or treatment of disorders linked to oxidative stress in human. Wheat secondary compounds in three Canadian and three Australian genotypes grown under controlled environments, in which the only changing parameter was temperature, were investigated. Kennedy and AC Navigator contained the highest amount of total phenolic acids among Australian and Canadian wheat genotypes, respectively. The total phenolic acids and total flavonoid contents of wheat genotypes increased following the increase of the growing temperature. In all the wheat genotypes, regardless of their growing temperatures, linoleic acid (C18:2n6) was measured as the main fatty acid. Significant increases in palmitic acid (C16:0) and oleic acid (C18:1n9) and significant decreases in linoleic acid (C18:2n6) and linolenic acid (C18:3n3) were observed at increased of growing temperature for all wheat genotypes. Growing temperature decreased campesterol content of wheat genotypes. Genotype and growing temperature significantly shifted the production of wheat secondary metabolites. This information might be used as a guide for breeding wheat varieties with higher antioxidant properties. PMID- 28831149 TI - Engineered production and evaluation of 6'-deoxy-tallysomycin H-1 revealing new insights into the structure-activity relationship of the anticancer drug bleomycin. AB - The bleomycins (BLMs), a family of glycopeptide antibiotics, are currently used clinically in combination with a number of other agents for the treatment of malignant tumors. Other members of the BLM family include tallysomycins (TLMs), phleomycins and zorbamycin (ZBM). We previously cloned and characterized the biosynthetic gene clusters for BLMs, TLMs and ZBM. Applications of combinatorial biosynthesis strategies to the three biosynthetic machineries enabled the engineered production of several BLM analogs with unique structural characteristics and varying DNA cleavage activities, thereby providing an outstanding opportunity to study the structure-activity relationship (SAR) for the BLM family of anticancer drugs. We now report the engineered production of a new BLM-TLM-ZBM hybrid metabolite, named 6'-deoxy-TLM H-1, which consists of the 22-desmethyl-BLM aglycone, the TLM A C-terminal amine and the ZBM disaccharide, by heterologous expression of the zbmGL genes from the ZBM biosynthetic gene cluster in the Streptoalloteichus hindustanus DeltatlmH mutant strain SB8005. Evaluation of the DNA cleavage activities of 6'-deoxy-TLM H-1 as a measurement for its potential anticancer activity, in comparison with TLM H-1 and BLM A2, reveals new insight into the SAR of BLM family of anticancer drugs.The Journal of Antibiotics advance online publication, 23 August 2017; doi:10.1038/ja.2017.93. PMID- 28831150 TI - GLP-1/Exendin-4 induces beta-cell proliferation via the epidermal growth factor receptor. AB - Exendin-4 is a long acting glucagon-like peptide 1 (GLP-1) analogue that is an agonist for the GLP-1 receptor, a G-protein coupled receptor (GPCR). Exendin-4 is used to clinically improve glucose tolerance in diabetic patients due to its ability to enhance insulin secretion. In rodents, and possibly in humans, exendin 4 can stimulate beta-cell proliferation. The exact mechanism of action to induce beta-cell proliferation is not well understood. Here, using a beta-cell specific epidermal growth factor receptor (EGFR) null mouse, we show that exendin-4 induced an increase in proliferation and beta-cell mass through EGFR. Thus, our study sheds light on the role of EGFR signaling in the effects of exendin-4 on the control of blood glucose metabolism and beta-cell mass. PMID- 28831151 TI - Magnetic-control multifunctional acoustic metasurface for reflected wave manipulation at deep subwavelength scale. AB - Acoustic metasurfaces, exhibiting superior performance with subwavelength thickness, are ideal alternatives for functionalities such as wavefront modulation and acoustic energy trapping, etc. However, most of the reported acoustic metasurfaces were passive. Here a magnetically tuned mechanism is reported for membrane-type acoustic metamaterials. Harnessing the geometric nonlinearity of membrane structures, the transmission spectrum is both theoretically and experimentally tuned over broadband by an external static magnetic force. Simultaneously, the phase profiles can be readily tailored by the magnetic stimulus. Further, a magnetic-control multifunctional metasurface is proposed for low-frequency wave manipulation. By switching the magnetic force distribution, multi extraordinary phenomena, such as acoustic wave redirecting, focusing, bending, etc., are realized without changing the physical structure. Besides, it is demonstrated the proposed metasurface, at deep subwavelength scale (~1/85lambda), supports anomalous reflected wave manipulation over a wide band. These results open up new degrees of freedom to steer acoustic wave and pave a way for designing active acoustic devices. PMID- 28831152 TI - Different route of hydroxide incorporation and thermal stability of new type of water clathrate: X-ray single crystal and Raman investigation. AB - Chlormayenite Ca12Al14O32[?4Cl2] (?-vacancy) is partially hydrated micro porouss mineral with hydroxide groups situated at various crystallographic sites. There are few mechanisms describing its hydration. The first one assumes Cl- substitution by OH- at the center of the structural cages (W-site). The second one determines the converting a T1O4 tetrahedron to a T1O3(OH)3 octahedron due to the replacement of oxygen at the O2 site by three OH-groups according to the scheme: (O2O2- + W Cl-) -> 3 * O2aOH. The third mechanism, not considered so far in the case of zeolite-like minerals, includes the hydroxide incorporation in form of hydrogarnet defect due to the arrangement of tetrahedral (OH)4 in vacant cages. This yields a strong hydrated phase containing even up to 35% of water more than in any currently known mineral applicable to Portland cement. Moreover, water molecules present in different structural cages are stable up to 355 K while dehydroxylation linked to the gradual loss of only 8% of OH- groups according to 3 O2aOH- -> O2O2- + W OH- + gH2O occurs at temperature range from 355 K to 598 K. PMID- 28831153 TI - Rate of entropy model for irreversible processes in living systems. AB - In living systems, it is crucial to study the exchange of entropy that plays a fundamental role in the understanding of irreversible chemical reactions. However, there are not yet works able to describe in a systematic way the rate of entropy production associated to irreversible processes. Hence, here we develop a theoretical model to compute the rate of entropy in the minimum living system. In particular, we apply the model to the most interesting and relevant case of metabolic network, the glucose catabolism in normal and cancer cells. We show, (i) the rate of internal entropy is mainly due to irreversible chemical reactions, and (ii) the rate of external entropy is mostly correlated to the heat flow towards the intercellular environment. The future applications of our model could be of fundamental importance for a more complete understanding of self renewal and physiopatologic processes and could potentially be a support for cancer detection. PMID- 28831154 TI - Lineage structure of Streptococcus pneumoniae may be driven by immune selection on the groEL heat-shock protein. AB - Populations of Streptococcus pneumoniae (SP) are typically structured into groups of closely related organisms or lineages, but it is not clear whether they are maintained by selection or neutral processes. Here, we attempt to address this question by applying a machine learning technique to SP whole genomes. Our results indicate that lineages evolved through immune selection on the groEL chaperone protein. The groEL protein is part of the groESL operon and enables a large range of proteins to fold correctly within the physical environment of the nasopharynx, thereby explaining why lineage structure is so stable within SP despite high levels of genetic transfer. SP is also antigenically diverse, exhibiting a variety of distinct capsular serotypes. Associations exist between lineage and capsular serotype but these can be easily perturbed, such as by vaccination. Overall, our analyses indicate that the evolution of SP can be conceptualized as the rearrangement of modular functional units occurring on several different timescales under different pressures: some patterns have locked in early (such as the epistatic interactions between groESL and a constellation of other genes) and preserve the differentiation of lineages, while others (such as the associations between capsular serotype and lineage) remain in continuous flux. PMID- 28831155 TI - Transcriptome changes in Arabidopsis thaliana infected with Pseudomonas syringae during drought recovery. AB - Field-grown plants experience cycles of drought stress and recovery due to variation in soil moisture status. Physiological, biochemical and transcriptome responses instigated by recovery are expected to be different from drought stress and non-stressed state. Such responses can further aid or antagonize the plant's interaction with the pathogen. However, at molecular level, not much is known about plant-pathogen interaction during drought recovery. In the present study, we performed a microarray-based global transcriptome profiling and demonstrated the existence of unique transcriptional changes in Arabidopsis thaliana inoculated with Pseudomonas syringae pv. tomato DC3000 at the time of drought recovery (drought recovery pathogen, DRP) when compared to the individual drought (D) or pathogen (P) or drought recovery (DR). Furthermore, the comparison of DRP with D or DR and P transcriptome revealed the presence of a few common genes among three treatments. Notably, a gene encoding proline dehydrogenase (AtProDH1) was found to be commonly up-regulated under drought recovery (DR), DRP and P stresses. We also report an up-regulation of pyrroline-5-carboxylate biosynthesis pathway during recovery. We propose that AtProDH1 influences the defense pathways during DRP. Altogether, this study provides insight into the understanding of defense responses that operate in pathogen-infected plants during drought recovery. PMID- 28831156 TI - The influence of vision on tactile Hebbian learning. AB - NMDA-dependent Hebbian learning drives neuronal plasticity in different cortical areas, and across species. In the primary somatosensory cortex (S-I), Hebbian learning is induced via the persistent low-rate afferent stimulation of a small area of skin. In particular, plasticity is induced in superficial cortical layers II/III of the S-I cortex that represents the stimulated area of skin. Here, we used the model system of NMDA-dependent Hebbian learning to investigate the influence of non-afferent (visual) input on Hebbian plasticity in S-I. We induced Hebbian learning in 48 participants by applying 3 hours of tactile coactivation to the right index fingertip via small loudspeaker membranes. During coactivation, different groups viewed either touches to individual fingers, which is known to activate S-I receptive fields, touches to an object, which should not activate S-I receptive fields, or no touch at all. Our results show that coactivation significantly lowers tactile spatial discrimination thresholds at the stimulated finger post- versus pre-training across groups. However, we did not find evidence for a significant modulatory effect of visual condition on tactile spatial discrimination performance. This suggests that non-afferent (visual) signals do not interact with Hebbian learning in superficial cortical layers of S-I, but may integrate into deeper cortical layers instead. PMID- 28831157 TI - Composition formulas of Fe-based transition metals-metalloid bulk metallic glasses derived from dual-cluster model of binary eutectics. AB - It is known that bulk metallic glasses follow simple composition formulas [cluster](glue atom)1 or 3 with 24 valence electrons within the framework of the cluster-plus-glue-atom model. Though the relevant nearest-neighbor cluster can be readily identified from a devitrification phase, the glue atoms remains poorly defined. The present work is devoted to understanding the composition rule of Fe (B,P,C) based multi-component bulk metallic glasses, by introducing a cluster based eutectic liquid model. This model regards a eutectic liquid to be composed of two stable liquids formulated respectively by cluster formulas for ideal metallic glasses from the two eutectic phases. The dual cluster formulas are first established for binary Fe-(B,C,P) eutectics: [Fe-Fe14]B2Fe + [B-B2Fe8]Fe ~ Fe83.3B16.7 for eutectic Fe83B17, [P-Fe14]P + [P-Fe9]P2Fe~Fe82.8P17.2 for Fe83P17, and [C-Fe6]Fe3 + [C-Fe9]C2Fe ~ Fe82.6C17.4 for Fe82.7C17.3. The second formulas in these dual-cluster formulas, being respectively relevant to devitrification phases Fe2B, Fe3P, and Fe3C, well explain the compositions of existing Fe-based transition metals-metalloid bulk metallic glasses. These formulas also satisfy the 24-electron rule. The proposition of the composition formulas for good glass formers, directly from known eutectic points, constitutes a new route towards understanding and eventual designing metallic glasses of high glass forming abilities. PMID- 28831158 TI - Inhibition of post-transcriptional steps in ribosome biogenesis confers cytoprotection against chemotherapeutic agents in a p53-dependent manner. AB - The p53-mediated nucleolar stress response associated with inhibition of ribosomal RNA transcription was previously shown to potentiate killing of tumor cells. Here, we asked whether targeting of ribosome biogenesis can be used as the basis for selective p53-dependent cytoprotection of nonmalignant cells. Temporary functional inactivation of the 60S ribosome assembly factor Bop1 in a 3T3 cell model markedly increased cell recovery after exposure to camptothecin or methotrexate. This was due, at least in part, to reversible pausing of the cell cycle preventing S phase associated DNA damage. Similar cytoprotective effects were observed after transient shRNA-mediated silencing of Rps19, but not several other tested ribosomal proteins, indicating distinct cellular responses to the inhibition of different steps in ribosome biogenesis. By temporarily inactivating Bop1 function, we further demonstrate selective killing of p53-deficient cells with camptothecin while sparing isogenic p53-positive cells. Thus, combining cytotoxic treatments with inhibition of select post-transcriptional steps of ribosome biogenesis holds potential for therapeutic targeting of cells that have lost p53. PMID- 28831159 TI - Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway. AB - The Phospholipase D (PLD) superfamily is linked to neurological disease, cancer, and fertility, and a recent report correlated a potential loss-of-function PLD2 polymorphism with hypotension. Surprisingly, PLD2 -/- mice exhibit elevated blood pressure accompanied by associated changes in cardiac performance and molecular markers, but do not have findings consistent with the metabolic syndrome. Instead, expression of endothelial nitric oxide synthase (eNOS), which generates the potent vasodilator nitric oxide (NO), is decreased. An eNOS inhibitor phenocopied PLD2 loss and had no further effect on PLD2 -/- mice, confirming the functional relationship. Using a human endothelial cell line, PLD2 loss of function was shown to lower intracellular free cholesterol, causing upregulation of HMG Co-A reductase, the rate-limiting enzyme in cholesterol synthesis. HMG Co A reductase negatively regulates eNOS, and the PLD2-deficiency phenotype of decreased eNOS expression and activity could be rescued by cholesterol supplementation and HMG Co-A reductase inhibition. Together, these findings identify a novel pathway through which the lipid signaling enzyme PLD2 regulates blood pressure, creating implications for on-going therapeutic development of PLD small molecule inhibitors. Finally, we show that the human PLD2 polymorphism does not trigger eNOS loss, but rather creates another effect, suggesting altered functioning for the allele. PMID- 28831160 TI - Genetics of body fat mass and related traits in a pig population selected for leanness. AB - Obesity is characterized as the excessive accumulation of body fat and has a complex genetic foundation in humans including monogenic high-risk mutations and polygenic contributions. Domestic pigs represent a valuable model on an obesity promoting high-caloric diet while constantly evaluated for body characteristics. As such, we investigated the genetics of obesity-related traits, comprising subcutaneous fat thickness, lean mass percentage, and growth rate, in a pig population. We conducted genome-wide association analyses using an integrative approach of single-marker regression models and multi-marker Bayesian analyses. Thus, we identified 30 genomic regions distributed over 14 different chromosomes contributing to the variation in obesity-related traits. In these regions, we validated the association of four candidate genes that are functionally connected to the regulation of appetite, processes of adipogenesis, and extracellular matrix formation. Our findings revealed fundamental genetic factors which deserves closer attention regarding their roles in the etiology of obesity. PMID- 28831161 TI - Computational prediction of new auxetic materials. AB - Auxetics comprise a rare family of materials that manifest negative Poisson's ratio, which causes an expansion instead of contraction under tension. Most known homogeneously auxetic materials are porous foams or artificial macrostructures and there are few examples of inorganic materials that exhibit this behavior as polycrystalline solids. It is now possible to accelerate the discovery of materials with target properties, such as auxetics, using high-throughput computations, open databases, and efficient search algorithms. Candidates exhibiting features correlating with auxetic behavior were chosen from the set of more than 67 000 materials in the Materials Project database. Poisson's ratios were derived from the calculated elastic tensor of each material in this reduced set of compounds. We report that this strategy results in the prediction of three previously unidentified homogeneously auxetic materials as well as a number of compounds with a near-zero homogeneous Poisson's ratio, which are here denoted "anepirretic materials".There are very few inorganic materials with auxetic homogenous Poisson's ratio in polycrystalline form. Here authors develop an approach to screening materials databases for target properties such as negative Poisson's ratio by using stability and structural motifs to predict new instances of homogenous auxetic behavior as well as a number of materials with near-zero Poisson's ratio. PMID- 28831162 TI - Magnetic Nanoparticle Assisted Self-assembly of Cell Penetrating Peptides Oligonucleotides Complexes for Gene Delivery. AB - Magnetic nanoparticles (MNPs, Fe3O4) incorporated into the complexes of cell penetrating peptides (CPPs)-oligonucleotides (ONs) promoted the cell transfection for plasmid transfection, splice correction, and gene silencing efficiencies. Six types of cell penetrating peptides (CPPs; PeptFect220 (denoted PF220), PF221, PF222, PF223, PF224 and PF14) and three types of gene therapeutic agents (plasmid (pGL3), splicing correcting oligonucleotides (SCO), and small interfering RNA (siRNA) were investigated. Magnetic nanoparticles incorporated into the complexes of CPPs-pGL3, CPPs-SCO, and CPPs-siRNA showed high cell biocompatibility and efficiently transfected the investigated cells with pGL3, SCO, and siRNA, respectively. Gene transfer vectors formed among PF14, SCO, and MNPs (PF14-SCO MNPs) showed a superior transfection efficiency (up to 4-fold) compared to the noncovalent PF14-SCO complex, which was previously reported with a higher efficiency compared to commercial vector called LipofectamineTM2000. The high transfection efficiency of the new complexes (CPPs-SCO-MNPs) may be attributed to the morphology, low cytotoxicity, and the synergistic effect of MNPs and CPPs. PF14-pDNA-MNPs is an efficient complex for in vivo gene delivery upon systemic administration. The conjugation of CPPs-ONs with inorganic magnetic nanoparticles (Fe3O4) may open new venues for selective and efficient gene therapy. PMID- 28831163 TI - Five-partite entanglement generation between two optical frequency combs in a quasi-periodic chi (2) nonlinear optical crystal. AB - We theoretically prove five-partite entanglement can be produced among modes of two simultaneously generated optical frequency combs via second-order nonlinear interaction in a designed periodically poled lithium niobat (PPLN) crystal. An extendible model is proposed to analyze the entanglement characteristics of generated comb modes by applying van Loock and Furusawa criteria. Our proposal provides a potential approach for generating multipartite entangled states, the so-called cluster states, which are the key resources for quantum computation. Moreover, simultaneously generation of two entangled combs can provide much higher efficiency to generate cluster states. PMID- 28831164 TI - Dynamics and detection of the Newton-Wigner time delays at interfaces using a swivelling method. AB - Evanescent waves are ubiquitous at interfaces with optical, seismic or acoustic waves, and also with electron, neutron or atom beams. Newton was the first to suspect that both small time delays and spatial shifts exist during total internal reflection. However, these effects are so tiny that the spatial shifts were only observed in 1947 in optics, whereas the time delay values predicted by the Wigner model in the 10-14 s range in optics had to await femtosecond lasers to be detected with difficulty. The spatial shifts have been isolated in many areas but the time delays, though fundamental, generally remain out of reach, particularly with particles. In textbooks usually both quantities are supposed to be simply linked. Here we report, using swivelling detectors, that the spatial and temporal measurements are intimately intermingled, especially in the so called cyclical regime. Indeed, while the spatial shift does not depend on the type of detection, the measured time delay can be positive, negative or zero, but controllable. We also discuss how such intricate measurements of spatial and temporal effects allow crucial time penalties to be eliminated in guided soliton propagation, and should be used to unambiguously identify the Newton-Wigner time delays for particles. PMID- 28831165 TI - Subcellular domain-dependent molecular hierarchy of SFK and FAK in mechanotransduction and cytokine signaling. AB - Focal adhesion kinase (FAK) and Src family kinases (SFK) are known to play critical roles in mechanotransduction and other crucial cell functions. Recent reports indicate that they reside in different microdomains of the plasma membrane. However, little is known about their subcellular domain-dependent roles and responses to extracellular stimuli. Here, we employed fluorescence resonance energy transfer (FRET)-based biosensors in conjunction with collagen-coupled agarose gels to detect subcellular activities of SFK and FAK in three-dimensional (3D) settings. We observed that SFK and FAK in the lipid rafts and nonrafts are differently regulated by fluid flow and pro-inflammatory cytokines. Inhibition of FAK in the lipid rafts blocked SFK response to fluid flow, while inhibition of SFK in the non-rafts blocked FAK activation by the cytokines. Ex-vivo FRET imaging of mouse cartilage explants showed that intermediate level of interstitial fluid flow selectively decreased cytokine-induced SFK/FAK activation. These findings suggest that SFK and FAK exert distinctive molecular hierarchy depending on their subcellular location and extracellular stimuli. PMID- 28831166 TI - Mutation of the Slt2 ortholog from Cryphonectria parasitica results in abnormal cell wall integrity and sectorization with impaired pathogenicity. AB - We assessed the biological function of CpSlt2, an ortholog of the cell wall integrity (CWI) MAPK of Saccharomyces cerevisiae, in the chestnut blight fungus Cryphonectria parasitica. The CpSlt2-null mutant exhibited marked changes in colonial growth, near absence of conidiation and aerial hyphae, and abnormal pigmentation. In addition, the CpSlt2-null mutant exhibited CWI-related phenotypic defects including hypersensitivity to cell wall-disturbing agents and other stresses. Electron microscopy revealed the presence of abnormal hyphae such as intrahyphal hyphae. In addition, virulence assays indicated that the CpSlt2 gene plays an important role in fungal pathogenesis. As cultivation of the mutant strains progressed, the majority of the colonies showed sporadic sectorization and mycelia from the sectored area stably maintained the sectored phenotype. Although mycelial growth was partially recovered, the sectored progeny had dramatically impaired virulence, confirming the CpSlt2 gene has a role in pathogenicity. Compared to a previous mutant of the CpBck1 gene, a MAPKKK gene in CWI pathway, the CpSlt2-null mutant showed similar, although not identical, phenotypic changes and most phenotypic changes were less severe than those of the CpBck1-null mutant. These results suggest that the unique sectorization is CWI pathway-specific, though the components in the same CWI pathway have common and specific functions. PMID- 28831167 TI - Mutant p53 stimulates cell invasion through an interaction with Rad21 in human ovarian cancer cells. AB - Missense mutations of TP53 are extremely common, and mutant p53 accumulation and gain-of-function play crucial roles in human ovarian cancer. Here, we investigated the role of mutant p53 in cell migration and invasion as well as its underlying molecular mechanisms in human ovarian cancer cells. Overexpression of mutant p53 significantly increased migration and invasion in p53-null SKOV3 cells. In contrast, knockdown of mutant p53 significantly compromised mutant p53 induced cell migration and invasion. Microarray analysis revealed that several migration/invasion-related genes, including S1PR1 (Sphingosine-1-phosphate receptor 1) and THBS1 (Thrombospodin 1), were significantly upregulated in SKOV3 cells that overexpressed mutant p53-R248 (SKOV3R248). We found that Rad21 is involved in the transcriptional regulation of the migration/invasion-related genes induced by mutant p53-R248. Knockdown of Rad21 significantly attenuated the mutant p53-R248-induced invasion and the expressions of S1PR1 and THBS1. Moreover, co-immunoprecipitation and chromatin immunoprecipitation assays revealed that mutant p53 interacts with Rad21 and binds to the Rad21-binding elements in the S1PR1 and THBS1 genes. Finally, downregulation of S1PR1 significantly attenuated the invasion driven by mutant p53-R248. These novel findings reveal that mutant p53-R248 maintains gain-of-function activity to stimulate cell invasion and induces the related gene expressions through an interaction with Rad21 in human ovarian cancer cells. PMID- 28831168 TI - Large-Area Nanolattice Film with Enhanced Modulus, Hardness, and Energy Dissipation. AB - We present an engineered nanolattice material with enhanced mechanical properties that can be broadly applied as a thin film over large areas. The nanolattice films consist of ordered, three-dimensional architecture with thin-shell tubular elements, resulting in favorable modulus-density scaling (n ~ 1.1), enhanced energy dissipation, and extremely large material recoverability for strains up to 20% under normal compressive loading. At 95.6% porosity, the nanolattice film has demonstrated modulus of 1.19 GPa and specific energy dissipation of 325.5 kJ/kg, surpassing previously reported values at similar densities. The largest length scale in the reported nanolattice is the 500 nm unit-cell lattice constant, allowing the film to behave more like a continuum material and be visually unobservable. Fabricated using three-dimensional colloidal nanolithography and atomic layer deposition, the process can be scaled for large-area patterning. The proposed nanolattice film can find applications as a robust multifunctional insulating film that can be applied in integrated photonic elements, optoelectronic devices, and microcircuit chips. PMID- 28831169 TI - Direct evidence of correlation between the second harmonic generation anisotropy patterns and the polarization orientation of perovskite ferroelectric. AB - For ferroelectric materials, where the polar state breaks the inversion symmetry, second harmonic generation is a useful tool to prove their ferroelectric properties. However, the correlation between the anisotropy patterns and the polarization orientation of the ferroelectric domains has not been clarified yet. In this work, we systematically investigated this correlation in a typical perovskite oxide ferroelectric, Barium Titanate (BaTiO3) crystal, by second harmonic generation and the piezoresponse force microscopy technique. The evolution of polarization-dependent anisotropy patterns proves that there is a linear relationship between the rotation angle of second harmonic generation anisotropy patterns and the polarization angle of BaTiO3 single crystals. It is a direct evidence illustrating that the polarization of BaTiO3 crystal can be qualitatively identified in 0 degrees -180 degrees by second harmonic generation technology. This work gives a glance at improving a nonintrusive and convenient method to identify the polarization of perovskite ferroelectric materials. PMID- 28831171 TI - Mapping the spatial variability of HIV infection in Sub-Saharan Africa: Effective information for localized HIV prevention and control. AB - Under the premise that in a resource-constrained environment such as Sub-Saharan Africa it is not possible to do everything, to everyone, everywhere, detailed geographical knowledge about the HIV epidemic becomes essential to tailor programmatic responses to specific local needs. However, the design and evaluation of national HIV programs often rely on aggregated national level data. Against this background, here we proposed a model to produce high-resolution maps of intranational estimates of HIV prevalence in Kenya, Malawi, Mozambique and Tanzania based on spatial variables. The HIV prevalence maps generated highlight the stark spatial disparities in the epidemic within a country, and localize areas where both the burden and drivers of the HIV epidemic are concentrated. Under an era focused on optimal allocation of evidence-based interventions for populations at greatest risk in areas of greatest HIV burden, as proposed by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United States President's Emergency Plan for AIDS Relief (PEPFAR), such maps provide essential information that strategically targets geographic areas and populations where resources can achieve the greatest impact. PMID- 28831170 TI - Transcriptome analysis of genes involved in secondary cell wall biosynthesis in developing internodes of Miscanthus lutarioriparius. AB - Miscanthus is a promising lignocellulosic bioenergy crop for bioethanol production. To identify candidate genes and regulation networks involved in secondary cell wall (SCW) development in Miscanthus, we performed de novo transcriptome analysis of a developing internode. According to the histological and in-situ histochemical analysis, an elongating internode of M. lutarioriparius can be divided into three distinct segments, the upper internode (UI), middle internode (MI) and basal internode (BI), each representing a different stage of SCW development. The transcriptome analysis generated approximately 300 million clean reads, which were de novo assembled into 79,705 unigenes. Nearly 65% of unigenes was annotated in seven public databases. Comparative profiling among the UI, MI and BI revealed four distinct clusters. Moreover, detailed expression profiling was analyzed for gene families and transcription factors (TFs) involved in SCW biosynthesis, assembly and modification. Based on the co-expression patterns, putative regulatory networks between TFs and SCW-associated genes were constructed. The work provided the first transcriptome analysis of SCW development in M. lutarioriparius. The results obtained provide novel insights into the biosynthesis and regulation of SCW in Miscanthus. In addition, the genes identified represent good candidates for further functional studies to unravel their roles in SCW biosynthesis and modification. PMID- 28831172 TI - Pioglitazone Enhances Cytosolic Lipolysis, beta-oxidation and Autophagy to Ameliorate Hepatic Steatosis. AB - Non-alcoholic fatty liver disease closely contributes to the development of obesity and insulin resistance. Even though pioglitazone has been reported to effectively lessen hepatic steatosis in human studies, its molecular mechanism remains unclear. This study is designed to investigate the regulation of cytosolic lipolysis, beta-oxidation and autophagy by pioglitazone in a mice model of high fat diet (HFD) and cell model incubated with palmitic acid. Our results revealed hepatic steatosis was apparently induced by HFD and it was significantly reversed by pioglitazone. The serum insulin and hepatic triglyceride content was significantly decreased by co-administered pioglitazone with HFD. Hepatic expression of cytosolic-lipolysis related proteins (ATGL, HSL), beta-oxidation (CPT-1A) and autophagy-related proteins (ATG7, LC3, LAL) was significantly enhanced by pioglitazone. Knockdown PPARalpha/PPARgamma in AML12 cells significantly and proportionally reduced the expressions of ATGL, CPT-1A and LC3II, which was induced by pioglitazone. Furthermore, facilitation of the autophagic flux by pioglitazone was obviously blocked by lysosomal inhibitor, leupeptin, to demonstrate accumulation of the LC3II and intracellular lipid in AML12 cells. Our results demonstrated that pioglitazone attenuating the hepatic steatosis may be mediated by enhancing cytosolic lipolysis, beta-oxidation and autophagy in a PPARalpha and PPARgamma dependent manner. PMID- 28831173 TI - Fungal lifestyle reflected in serine protease repertoire. AB - Fungi are able to switch between different lifestyles in order to adapt to environmental changes. Their ecological strategy is connected to their secretome as fungi obtain nutrients by secreting hydrolytic enzymes to their surrounding and acquiring the digested molecules. We focus on fungal serine proteases (SPs), the phylogenetic distribution of which is barely described so far. In order to collect a complete set of fungal proteases, we searched over 600 fungal proteomes. Obtained results suggest that serine proteases are more ubiquitous than expected. From 54 SP families described in MEROPS Peptidase Database, 21 are present in fungi. Interestingly, 14 of them are also present in Metazoa and Viridiplantae - this suggests that, except one (S64), all fungal SP families evolved before plants and fungi diverged. Most representatives of sequenced eukaryotic lineages encode a set of 13-16 SP families. The number of SPs from each family varies among the analysed taxa. The most abundant are S8 proteases. In order to verify hypotheses linking lifestyle and expansions of particular SP, we performed statistical analyses and revealed previously undescribed associations. Here, we present a comprehensive evolutionary history of fungal SP families in the context of fungal ecology and fungal tree of life. PMID- 28831174 TI - Time-Resolved Spectroscopic Study on the Photoredox Reaction of 2-(p Hydroxymethyl)phenylAnthraquinone. AB - In this work, we report a combined time-resolved spectroscopic and density functional theory computational study on 2-(p-hydroxymethyl)phenylanthraquinone (PPAQ) in which the benzyl alcohol moiety is significantly farther away from the AQ ketone group compared to the compound 2-(1-hydroxyethyl) 9,10-anthraquinone (HEAQ) so as to investigate the photophysical and photochemical reactions of PPAQ in several solvents, especially for the photoredox reaction in a pH 2 aqueous solution. The results here indicate that PPAQ undergoes the photoredox reaction via a two-step pathway and that the low efficiency of the photoredox reaction of PPAQ compared to the related HEAQ molecule is caused by the longer distance between the benzyl alcohol moiety and the AQ ketone moieties. PMID- 28831175 TI - Substrate properties modulate cell membrane roughness by way of actin filaments. AB - Cell membrane roughness has been proposed as a sensitive feature to reflect cellular physiological conditions. In order to know whether membrane roughness is associated with the substrate properties, we employed the non-interferometric wide-field optical profilometry (NIWOP) technique to measure the membrane roughness of living mouse embryonic fibroblasts with different conditions of the culture substrate. By controlling the surface density of fibronectin (FN) coated on the substrate, we found that cells exhibited higher membrane roughness as the FN density increased in company with larger focal adhesion (FA) sizes. The examination of membrane roughness was also confirmed with atomic force microscopy. Using reagents altering actin or microtubule cytoskeletons, we provided evidence that the dynamics of actin filaments rather than that of microtubules plays a crucial role for the regulation of membrane roughness. By changing the substrate rigidity, we further demonstrated that the cells seeded on compliant gels exhibited significantly lower membrane roughness and smaller FAs than the cells on rigid substrate. Taken together, our data suggest that the magnitude of membrane roughness is modulated by way of actin dynamics in cells responding to substrate properties. PMID- 28831176 TI - Genome organization: A vision of 3D chromatin organization. PMID- 28831177 TI - Condition-dependence of pheomelanin-based coloration in nuthatches Sitta europaea suggests a detoxifying function: implications for the evolution of juvenile plumage patterns. AB - Adult-like juvenile plumage patterns often signal genotypic quality to parents. During adulthood, the same patterns often signal quality to mates. This has led to assume that adult-like juvenile plumage is a developmental consequence of sexual selection operating in adults. Many of these patterns are produced by the pigment pheomelanin, whose synthesis may help remove toxic excess cysteine. Excess cysteine is likely to arise under conditions of relatively low stress, such as those experienced by nestling birds. Thus, adult-like plumage may be advantageous for juveniles if produced by pheomelanin. In the Eurasian nuthatch Sitta europaea, juveniles are sexually dichromatic and identical to adults. Nestling nuthatches in poorer condition develop more intense pheomelanin-based feathers, indicating greater pigment production. The same is not observed in adults. This is contrary to a function related to signaling quality and instead suggests that, at least in the Eurasian nuthatch, adult-like juvenile plumage has evolved because of the detoxifying function of pheomelanin-based pigmentation. Given the prevalence of colors typically conferred by pheomelanin in juvenile plumage patterns, the detoxifying capacity of pheomelanin under low stress levels should be considered as an explanation for the evolution of both adult-like and distinctively juvenile plumage patterns. PMID- 28831178 TI - Silicon rich nitride ring resonators for rare - earth doped telecommunications band amplifiers pumped at the O-band. AB - Ring resonators on silicon rich nitride for potential use as rare-earth doped amplifiers pumped at 1310 nm with amplification at telecommunications-band are designed and characterized. The ring resonators are fabricated on 300 nm and 400 nm silicon rich nitride films and characterized at both 1310 nm and 1550 nm. We demonstrate ring resonators exhibiting similar quality factors exceeding 10,000 simultaneously at 1310 nm and 1550 nm. A Dysprosium-Erbium material system exhibiting photoluminescence at 1510 nm when pumped at 1310 nm is experimentally demonstrated. When used together with Dy-Er co-doped particles, these resonators with similar quality factors at 1310 nm and 1550 nm may be used for O-band pumped amplifiers for the telecommunications-band. PMID- 28831179 TI - Global Proteomics-based Identification and Validation of Thymosin Beta-4 X-Linked as a Prognostic Marker for Head and Neck Squamous Cell Carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) represents a major health concern worldwide. We applied the matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to analyze paired normal (N) and tumor (T) samples from head and neck squamous cell carcinoma as well as liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis in HNSCC cell lines to identify tumor-associated biomarkers. Our results showed a number of proteins found to be over-expressed in HNSCC. We identified thymosin beta-4 X linked (TMSB4X) is one of the most significant candidate biomarkers. Higher TMSB4X expression in the tumor was found by N/T-paired HNSCC samples at both RNA and protein level. Overexpression of TMSB4X was found significantly associated with poor prognosis of overall survival (OS, P = 0.006) and recurrence-free survival (RFS, P = 0.013) in HNSCC patients. Silencing of TMSB4X expression in HNSCC cell line reduced the proliferation and invasion ability in vitro, as well as inhibited the cervical lymph node metastasis in vivo. Altogether, our global proteomics analysis identified that TMSB4X is a newly discovered biomarker in HNSCC whose functions resulted in enhanced proliferation and metastasis in vitro and in vivo. TMSB4X may be a potential therapeutic target for treating HNSCC patients. PMID- 28831182 TI - Colorectal cancer: Early MRI imaging predicts regorafenib response. PMID- 28831180 TI - Peritoneal Dialysis Catheter Emplacement by Advanced Laparoscopy: 8-year Experience from a Medical Center of China. AB - Laparoscopic experience and relevant reports about PD catheter emplacement in Chinese patients are seldom. In this study, we described our experience with advanced laparoscopy for PD catheter implantation in Chinese patients. There were one hundred and thirty Chinese patients accepted advanced laparoscopic approach for PD catheter emplacement in this study. Six of 26 patients with prior abdominal operations had abdominal adhesion, while six of 104 patients without prior abdominal surgeries showed abdominal adhesion. Operation time required 10 to 180 minutes. During a mean follow-up time of 26.46 months, the catheter complications were shown as outflow obstruction (n = 6, 4.62%), pericatheter leaking (n = 3, 2.31%), hydrocele of tunica vaginalis (n = 1, 0.77% in all), and umbilical hernia (n = 2, 1.54%). Cumulative revision-free survival probability for catheter loss from mechanical complications at 8 years was 0.95. During the postoperative follow-up ranged between 6 and 106 months, 98 patients (75.38%) were still on CAPD, 17 patients (13.08%) died, 8 patients (6.15%) were transferred to hemodialysis, 6 patients (4.62%) received kidney transplantation, and 1 patient (0.77%) showed improved renal function. These results showed that PD catheter placement with advanced laparoscopy is a safe and effective approach in Chinese patients with or without prior abdominal surgeries. PMID- 28831181 TI - Tibial dyschondroplasia is highly associated with suppression of tibial angiogenesis through regulating the HIF-1alpha/VEGF/VEGFR signaling pathway in chickens. AB - Tibial dyschondroplasia (TD) is an intractable poultry problem that is characterized by the appearance of non-vascularized and non-mineralized cartilage masses in tibial growth plates (TGPs). However, the role of angiogenesis inhibition in the occurrence of TD remains unknown. In this study, we found that, compared to low-altitude Arbor Acres chickens (AACs), high-altitude Tibetan chickens showed higher tibial vascular distributions that were accompanied by up regulation of hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor A (VEGFA) and VEGF receptors. These observations provide insights into hypoxia-induced angiogenesis, which may be related to the absence of TD in high-altitude native Tibetan chickens. Importantly, hypoxia experiments also showed that during hypoxia, tibial angiogenesis was enhanced, which was due to pro-angiogenic factor up-regulation (including VEGFA, VEGFR1, VEGFR2, and IL-8), in AACs. Moreover, we observed that thiram-induced TD could strongly inhibit tibial angiogenesis in the hypertrophic zone through coordinated down-regulation of HIF-1alpha and pro-angiogenic factors, leading to a disruption in the blood supply to the TGP. Taken together, these findings reveal that the occurrence of TD is highly associated with inhibition of tibial angiogenesis through down regulated expression of HIF-1alpha, VEGFA and VEGF receptors, which results in suppression of TGP development. PMID- 28831183 TI - Lower gastrointestinal tract: What are normal bowel movement patterns? PMID- 28831185 TI - Innate immunity: A new way out for lysozyme. PMID- 28831184 TI - Direct-acting antiviral agents for HCV infection affecting people who inject drugs. AB - Globally, 12 million people are estimated to have injected drugs in the past year, 50% of whom have chronic HCV infection, with people who have previously injected drugs presenting an additional large reservoir of infection. The availability of simple and tolerable interferon-free direct-acting antiviral agents (DAAs) for HCV infection, which have a cure rate of >95% represents one of the most exciting advances in clinical medicine in the past few decades. Adherence and response to DAA therapy among people who inject drugs (PWID) receiving opioid substitution therapy (OST) in clinical trials are comparable to populations without a history of injecting drugs. Further data are required among current PWID not receiving OST. Given the potential prevention benefits of treatment, DAAs have enhanced cost-effectiveness among PWID. As HCV therapy is expanded to populations of PWID with high-risk behaviours for re-exposure, acknowledgement that HCV reinfection will occur is crucial, and appropriate strategies must be in place to maximize prevention of reinfection and offer retreatment for reinfection. This Review will also discuss essential components for broadening access to HCV care for PWID as we strive for the global elimination of HCV infection. PMID- 28831187 TI - Coeliac disease: Blood test for diagnosis more effective than biopsy. PMID- 28831186 TI - The IBD interactome: an integrated view of aetiology, pathogenesis and therapy. AB - Crohn's disease and ulcerative colitis are prototypical complex diseases characterized by chronic and heterogeneous manifestations, induced by interacting environmental, genomic, microbial and immunological factors. These interactions result in an overwhelming complexity that cannot be tackled by studying the totality of each pathological component (an '-ome') in isolation without consideration of the interaction among all relevant -omes that yield an overall 'network effect'. The outcome of this effect is the 'IBD interactome', defined as a disease network in which dysregulation of individual -omes causes intestinal inflammation mediated by dysfunctional molecular modules. To define the IBD interactome, new concepts and tools are needed to implement a systems approach; an unbiased data-driven integration strategy that reveals key players of the system, pinpoints the central drivers of inflammation and enables development of targeted therapies. Powerful bioinformatics tools able to query and integrate multiple -omes are available, enabling the integration of genomic, epigenomic, transcriptomic, proteomic, metabolomic and microbiome information to build a comprehensive molecular map of IBD. This approach will enable identification of IBD molecular subtypes, correlations with clinical phenotypes and elucidation of the central hubs of the IBD interactome that will aid discovery of compounds that can specifically target the hubs that control the disease. PMID- 28831188 TI - Freestanding and flexible graphene papers as bioelectrochemical cathode for selective and efficient CO2 conversion. AB - During microbial electrosynthesis (MES) driven CO2 reduction, cathode plays a vital role by donating electrons to microbe. Here, we exploited the advantage of reduced graphene oxide (RGO) paper as novel cathode material to enhance electron transfer between the cathode and microbe, which in turn facilitated CO2 reduction. The acetate production rate of Sporomusa ovata-driven MES reactors was 168.5 +/- 22.4 mmol m-2 d-1 with RGO paper cathodes poised at -690 mV versus standard hydrogen electrode. This rate was approximately 8 fold faster than for carbon paper electrodes of the same dimension. The current density with RGO paper cathodes of 2580 +/- 540 mA m-2 was increased 7 fold compared to carbon paper cathodes. This also corresponded to a better cathodic current response on their cyclic voltammetric curves. The coulombic efficiency for the electrons conversion into acetate was 90.7 +/- 9.3% with RGO paper cathodes and 83.8 +/- 4.2% with carbon paper cathodes, respectively. Furthermore, more intensive cell attachment was observed on RGO paper electrodes than on carbon paper electrodes with confocal laser scanning microscopy and scanning electron microscopy. These results highlight the potential of RGO paper as a promising cathode for MES from CO2. PMID- 28831189 TI - A comparative analysis of longitudinal computed tomography and histopathology for evaluating the potential of mesenchymal stem cells in mitigating radiation induced pulmonary fibrosis. AB - Radiation-induced pulmonary fibrosis (RIPF) is a debilitating side effect that occurs in up to 30% of thoracic irradiations in breast and lung cancer patients. RIPF remains a major limiting factor to dose escalation and an obstacle to applying more promising new treatments for cancer cure. Limited treatment options are available to mitigate RIPF once it occurs, but recently, mesenchymal stem cells (MSCs) and a drug treatment stimulating endogenous stem cells (GM-CSF) have been investigated for their potential in preventing this disease onset. In a pre clinical rat model, we contrasted the application of longitudinal computed tomography (CT) imaging and classical histopathology to quantify RIPF and to evaluate the potential of MSCs in mitigating RIPF. Our results on histology demonstrate promises when MSCs are injected endotracheally (but not intravenously). While our CT analysis highlights the potential of GM-CSF treatment. Advantages and limitations of both analytical methods are contrasted in the context of RIPF. PMID- 28831190 TI - Comparative Genomic and Regulatory Analyses of Natamycin Production of Streptomyces lydicus A02. AB - Streptomyces lydicus A02 is used by industry because it has a higher natamycin producing capacity than the reference strain S. natalensis ATCC 27448. We sequenced the complete genome of A02 using next-generation sequencing platforms, and to achieve better sequence coverage and genome assembly, we utilized single molecule real-time (SMRT) sequencing. The assembled genome comprises a 9,307,519 bp linear chromosome with a GC content of 70.67%, and contained 8,888 predicted genes. Comparative genomics and natamycin biosynthetic gene cluster (BGC) analysis showed that BGC are highly conserved among evolutionarily diverse strains, and they also shared closer genome evolution compared with other Streptomyces species. Forty gene clusters were predicted to involve in the secondary metabolism of A02, and it was richly displayed in two-component signal transduction systems (TCS) in the genome, indicating a complex regulatory systems and high diversity of metabolites. Disruption of the phoP gene of the phoR-phoP TCS and nsdA gene confirmed phosphate sensitivity and global negative regulation of natamycin production. The genome sequence and analyses presented in this study provide an important molecular basis for research on natamycin production in Streptomyces, which could facilitate rational genome modification to improve the industrial use of A02. PMID- 28831191 TI - Red blood cells release microparticles containing human argonaute 2 and miRNAs to target genes of Plasmodium falciparum. AB - Red blood cells (RBCs) are known to function as a refuge for providing food resources and as a shelter against the host's immune system after malaria parasite (Plasmodium) infection. Recent studies have reported significant production of extracellular vesicles (microparticles, MPs) in the circulation of malaria patients. However, it is unclear how these extracellular vesicles are generated and what their biological functions are. In this study, we isolated the MPs from a culture medium of normal RBCs and malaria parasite-infected RBCs (iRBCs), compared their quantity and origins, and profiled their miRNAs by deep sequencing. We found a much larger number of MPs released in the culture of iRBCs than in the culture of normal RBCs. Further investigation indicated that, in these MPs, human argonaute 2 (hAgo2) was found to bind to hundreds of miRNAs. These hAgo2-miRNA complexes were transferred into the parasites, and the expression of an essential malaria antigen, PfEMP1, was downregulated by miR 451/140 through its binding to the A and B subgroups of var genes, a family of genes encoding PfEMP1. Our data suggest for the first time that, through the release of MPs, mature RBCs present an innate resistance to malaria infection. These studies also shed new light on the reason why RBCs' genetic mutation occurs mainly in populations living in intensive malaria endemic areas and on the possibility of using miRNAs as novel medicines for malaria patients. PMID- 28831192 TI - Zika virus infects renal proximal tubular epithelial cells with prolonged persistency and cytopathic effects. AB - Zika virus (ZIKV) infection can cause fetal developmental abnormalities and Guillain-Barre syndrome in adults. Although progress has been made in understanding the link between ZIKV infection and microcephaly, the pathology of ZIKV, particularly the viral reservoirs in human, remains poorly understood. Several studies have shown that compared to serum samples, patients' urine samples often have a longer duration of ZIKV persistency and higher viral load. This finding suggests that an independent viral reservoir may exist in the human urinary system. Despite the clinical observations, the host cells of ZIKV in the human urinary system are poorly characterized. In this study, we demonstrate that ZIKV can infect renal proximal tubular epithelial cells (RPTEpiCs) in immunodeficient mice in vivo and in both immortalized and primary human renal proximal tubular epithelial cells (hRPTEpiCs) in vitro. Importantly, ZIKV infection in mouse kidneys caused caspase-3-mediated apoptosis of renal cells. Similarly, in vitro infection of immortalized and primary hRPTEpiCs resulted in notable cytopathic effects. Consistent with the clinical observations, we found that ZIKV infection can persist with prolonged duration in hRPTEpiCs. RNA-Seq analyses of infected hRPTEpiCs revealed a large number of transcriptional changes in response to ZIKV infection, including type I interferon signaling genes and anti-viral response genes. Our results suggest that hRPTEpiCs are a potential reservoir of ZIKV in the human urinary system, providing a possible explanation for the prolonged persistency of ZIKV in patients' urine. PMID- 28831193 TI - Tuberculosis/cryptococcosis co-infection in China between 1965 and 2016. AB - Cases of tuberculosis/cryptococcosis co-infection are rapidly increasing in China. However, most studies addressing this co-infection have been published in Chinese journals, and this publication strategy has obscured this disease trend for scientists in other parts of the world. Our investigation found that 62.9% of all co-infection cases worldwide were reported in the Chinese population (n=197) between 1965 and 2016, and 56.3% of these Chinese cases were reported after 2010. Nearly all cases originated from the warm and wet monsoon regions of China. HIV positive subjects tended to correlate with more severe manifestations of a tuberculosis/cryptococcosis co-infection than those without HIV. Notablely, dual tubercular/cryptococcal meningitis was the most frequent (54.0%) and most easily misdiagnosed (95.2%, n=40/42) co-infection. We also found that the combined use of cerebrospinal fluid pressure and concentrations of glucose, protein and chlorine might be an inexpensive and effective indicator to differentiate tubercular/cryptococcal co-infection meningitis from tubercular meningitis and cryptococcal meningitis. PMID- 28831194 TI - Origin and invasion of the emerging infectious pathogen Sphaerothecum destruens. AB - Non-native species are often linked to the introduction of novel pathogens with detrimental effects on native biodiversity. Since Sphaerothecum destruens was first discovered as a fish pathogen in the United Kingdom, it has been identified as a potential threat to European fish biodiversity. Despite this parasite's emergence and associated disease risk, there is still a poor understanding of its origin in Europe. Here, we provide the first evidence to support the hypothesis that S. destruens was accidentally introduced to Europe from China along with its reservoir host Pseudorasbora parva via the aquaculture trade. This is the first study to confirm the presence of S. destruens in China, and it has expanded the confirmed range of S. destruens to additional locations in Europe. The demographic analysis of S. destruens and its host P. parva in their native and invasive range further supported the close association of both species. This research has direct significance and management implications for S. destruens in Europe as a non-native parasite. PMID- 28831195 TI - Identification of a natural recombinant transmissible gastroenteritis virus between Purdue and Miller clusters in China. AB - Transmissible gastroenteritis virus (TGEV) is an infective coronavirus (CoV) that causes diarrhea-related morbidity and mortality in piglets. For the first time, a natural recombination strain of a TGEV Anhui Hefei (AHHF) virus between the Purdue and the Miller clusters was isolated from the small intestine content of piglets in China. A phylogenetic tree based on a complete genome sequence placed the TGEV AHHF strain between the Purdue and the Miller clusters. The results of a computational analysis of recombination showed that the TGEV AHHF strain is a natural recombinant strain between these clusters. Two breakpoints located in the open reading frame 1a (ORF1a) and spike (S) genes were identified. The pathogenicity of the TGEV AHHF strain was evaluated in piglets, and the results show that TGEV AHHF is an enteric pathogenic strain. These results provide valuable information about the recombination and evolution of CoVs and will facilitate future investigations of the molecular pathogenesis of TGEV. PMID- 28831196 TI - Assembly of a functional and responsive microstructure by heat bonding of DNA grafted colloidal brick. AB - A micromachine constructed to possess various chemical and mechanical functions is one of the ultimate targets of technology. Conventional lithographic processes can be used to form complicated structures. However, they are basically limited to rigid and static structures with poor surface properties. Here, we demonstrate a novel method for assembling responsive and functional microstructures from diverse particles modified with DNA strands. The DNA strands are designed to form hairpins at room temperature and denature when heated. Structures are assembled through the simultaneous manipulation and heating of particles with "hot" optical tweezers, which incorporates the particles one by one. The flexible connection formed by DNA strands allows the responsive deformation of the structures with local controllability of the structural flexibility. We assembled a microscopic robot arm actuated by an external magnet, a hinge structure with a locally controlled connection flexibility and a three-dimensional double helix structure. The method is simple and can also be applied to build complex biological tissues from cells. PMID- 28831197 TI - A pulsed-air model of blue whale B call vocalizations. AB - Blue whale sound production has been thought to occur by Helmholtz resonance via air flowing from the lungs into the upper respiratory spaces. This implies that the frequency of blue whale vocalizations might be directly proportional to the size of their sound-producing organs. Here we present a sound production mechanism where the fundamental and overtone frequencies of blue whale B calls can be well modeled using a series of short-duration (<1 s) wavelets. We propose that the likely source of these wavelets are pneumatic pulses caused by opening and closing of respiratory valves during air recirculation between the lungs and laryngeal sac. This vocal production model is similar to those proposed for humpback whales, where valve open/closure and vocal fold oscillation is passively driven by airflow between the lungs and upper respiratory spaces, and implies call frequencies could be actively changed by the animal to center fundamental tones at different frequency bands during the call series. PMID- 28831198 TI - Methamphetamine abuse impairs motor cortical plasticity and function. AB - Exposure to addictive drugs triggers synaptic plasticity in reward-related brain regions, such as the midbrain, nucleus accumbens and the prefrontal cortex. Effects of chronic drug exposure on other brain areas have not been fully investigated. Here, we characterize synaptic plasticity in motor cortex after methamphetamine self-administration in rats. We show that this causes a loss of corticostriatal plasticity in rat brain slices and impaired motor learning in the rotarod task. These findings are paralleled by the observation of a lack of transcranial magnetic stimulation-induced potentiation or depression of motor evoked potentials in human patients with addiction, along with poor performance in rotary pursuit task. Taken together, our results suggest that chronic methamphetamine use can affect behavioral performance via drug-evoked synaptic plasticity occluding physiological motor learning. PMID- 28831200 TI - Genetic variation of ANK3 is associated with lower white matter structural integrity in bipolar disorder. PMID- 28831199 TI - Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. AB - Autism spectrum disorder (ASD) represents a set of complex neurodevelopmental disorders with large degrees of heritability and heterogeneity. We sequenced 136 microcephaly or macrocephaly (Mic-Mac)-related genes and 158 possible ASD-risk genes in 536 Chinese ASD probands and detected 22 damaging de novo mutations (DNMs) in 20 genes, including CHD8 and SCN2A, with recurrent events. Nine of the 20 genes were previously reported to harbor DNMs in ASD patients from other populations, while 11 of them were first identified in present study. We combined genetic variations of the 294 sequenced genes from publicly available whole-exome or whole-genome sequencing studies (4167 probands plus 1786 controls) with our Chinese population (536 cases plus 1457 controls) to optimize the power of candidate-gene prioritization. As a result, we prioritized 67 ASD-candidate genes that exhibited significantly higher probabilities of haploinsufficiency and genic intolerance, and significantly interacted and co-expressed with each another, as well as other known ASD-risk genes. Probands with DNMs or rare inherited mutations in the 67 candidate genes exhibited significantly lower intelligence quotients, supporting their strong functional impact. In addition, we prioritized 39 ASD-related Mic-Mac-risk genes, and showed their interaction and co-expression in a functional network that converged on chromatin remodeling, synapse transmission and cell cycle progression. Genes within the three functional subnetworks exhibited distinct and recognizable spatiotemporal-expression patterns in human brains and laminar-expression profiles in the developing neocortex, highlighting their important roles in brain development. Our results indicate some of Mic-Mac-risk genes are involved in ASD. PMID- 28831202 TI - Matrix turnover linked to dietary weight loss. PMID- 28831201 TI - BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/beta catenin signalling. AB - The novel pyrazoline derivative, BHX, has recently been shown to exhibit potent anti-tumour activity by blocking the Wnt/beta-catenin signalling pathway. However, its effect on breast cancer growth and invasion are unknown. Our results show that BHX suppresses MDA-MB-231 cell viability and colony formation in a dose dependent manner, and induces apoptosis and G0/G1 phase arrest. BHX-treated breast cancer cells showed morphological characteristics of cells undergoing apoptosis. Furthermore, BHX inhibited cell migration and invasion, which was associated with increased E-cadherin mRNA and protein expression, and down regulation of SNAIL and vimentin. In addition, BHX induced the generation of intracellular ROS and decreased beta-catenin protein and mRNA expression. We used a mouse xenograft model to investigate the effects of BHX in vivo, where the growth of MDA-MB-231 xenografted tumours was suppressed in nude mice treated continuously with BHX for 21 days. Finally, the rat plasma concentration of BHX was measured by ultra-performance liquid-chromatography tandem mass spectrometry and the pharmacokinetic parameters of BHX were processed by non-compartmental analysis. In conclusion, BHX merits further study as a novel therapeutic small molecule for the treatment of breast cancer. PMID- 28831203 TI - Microtubule nucleation: beyond the template. AB - Microtubules are cytoskeletal filaments central to a wide range of essential cellular functions in eukaryotic cells. Consequently, cells need to exert tight control over when, where and how many microtubules are being made. Whereas the regulation of microtubule dynamics is well studied, the molecular mechanisms of microtubule nucleation are still poorly understood. Next to the established master template of nucleation, the gamma-tubulin ring complex, other microtubule associated proteins that affect microtubule dynamic properties have recently been found to contribute to nucleation. It has begun to emerge that the nucleation efficiency is controlled not only by template activity but also by, either additionally or alternatively, the stabilization of the nascent microtubule 'nucleus'. This suggests a simple conceptual framework for the mechanisms regulating microtubule nucleation in cells. PMID- 28831204 TI - Chromosome biology: Different turfs for cohesin and condensin. PMID- 28831205 TI - Phosphorylated mTOR Expression Profiles in Human Normal and Carcinoma Tissues. AB - Mammalian target of rapamycin (mTOR) is a key controller of cell growth and proliferation in normal tissues and solid tumors. In the present study, an immunohistochemical analysis of the expression pattern of phosphorylated mTOR (p mTOR) was performed in human normal fetal and adult tissues and various carcinoma tissues. p-mTOR expression showed tissue and cell type specificity in normal and cancer tissues. In normal fetal and adult tissues, p-mTOR staining was observed in the intestinal crypt, intrahepatic bile ductule, pancreatic duct, distal nephron of the kidney, umbrella cell of urothelium, mesothelial cell, and choroid plexus. In cancer tissues, p-mTOR expression was higher in adenocarcinoma than in other types of cancers, in metastatic cancer than in primary cancer, and in the forefront of the infiltrating cancer cells. These results suggest that p-mTOR is implicated not only in cell proliferation but also in tubular morphogenesis in normal and cancer tissues. In addition, mTOR activation appears to be associated with cancer cell invasion and migration in solid tumors. PMID- 28831206 TI - Expression and Clinical Significance of ILF2 in Gastric Cancer. AB - The aim of this study is to investigate the expression levels and clinical significance of ILF2 in gastric cancer. The mRNA and protein expression levels of ILF2 were, respectively, examined by quantitative real-time PCR (qRT-PCR) and Western blot from 21 paired fresh frozen GC tissues and corresponding normal gastric tissues. In order to analyze the expression pattern of ILF2 in GC, 60 paired paraffin-embedded GC slides and corresponding normal gastric slides were detected by immunohistochemistry (IHC) assay. The correlation between ILF2 protein expression levels and clinicopathological parameters, overall survival (OS), disease-free survival (DFS), and clinical prognosis were analyzed by statistical methods. Significantly higher levels of ILF2 were detected in GC tissues compared with normal controls at both mRNA and protein level. High expression of ILF2 was tightly correlated with depth of invasion, lymph node metastasis, pathological stage, and histological differentiation. Log-rank test showed that high expression of ILF2 was positively associated with poor clinical prognosis. Multivariate analysis identified that ILF2 was an independent prognostic factor for OS and DFS. Our findings suggest that ILF2 may be a valuable biomarker and a novel potential prognosis predictor for GC patients. PMID- 28831207 TI - Intrathecal Resiniferatoxin Modulates TRPV1 in DRG Neurons and Reduces TNF Induced Pain-Related Behavior. AB - Transient receptor potential vanilloid-1 (TRPV1) is a nonselective cation channel, predominantly expressed in sensory neurons. TRPV1 is known to play an important role in the pathogenesis of inflammatory and neuropathic pain states. Previous studies suggest interactions between tumor necrosis factor- (TNF-) alpha and TRPV1, resulting in a modulation of ion channel function and protein expression in sensory neurons. We examined the effect of intrathecal administration of the ultrapotent TRPV1 agonist resiniferatoxin (RTX) on TNF induced pain-associated behavior of rats using von Frey and hot plate behavioral testing. Intrathecal injection of TNF induces mechanical allodynia (2 and 20 ng/kg) and thermal hyperalgesia (200 ng) 24 h after administration. The additional intrathecal administration of RTX (1.9 MUg/kg) alleviates TNF-induced mechanical allodynia and thermal hyperalgesia 24 h after injection. In addition, TNF increases the TRPV1 protein level and number of TRPV1-expressing neurons. Both effects could be abolished by the administration of RTX. These results suggest that the involvement of TRPV1 in TNF-induced pain offers new TRPV1-based experimental therapeutic approaches and demonstrates the analgesic potential of RTX in inflammatory pain diseases. PMID- 28831208 TI - Evaluation of Inflammatory Markers in a Large Sample of Obstructive Sleep Apnea Patients without Comorbidities. AB - Systemic inflammation is important in obstructive sleep apnea (OSA) pathophysiology and its comorbidity. We aimed to assess the levels of inflammatory biomarkers in a large sample of OSA patients and to investigate any correlation between these biomarkers with clinical and polysomnographic (PSG) parameters. This was a cross-sectional study in which 2983 patients who had undergone a polysomnography for OSA diagnosis were recruited. Patients with known comorbidities were excluded. Included patients (n = 1053) were grouped according to apnea-hypopnea index (AHI) as mild, moderate, and severe. Patients with AHI < 5 served as controls. Demographics, PSG data, and levels of high-sensitivity C reactive protein (hs-CRP), fibrinogen, erythrocyte sedimentation rate (ESR), and uric acid (UA) were measured and compared between groups. A significant difference was found between groups in hs-CRP, fibrinogen, and UA. All biomarkers were independently associated with OSA severity and gender (p < 0.05). Females had increased levels of hs-CRP, fibrinogen, and ESR (p < 0.001) compared to men. In contrast, UA levels were higher in men (p < 0.001). Our results suggest that inflammatory markers significantly increase in patients with OSA without known comorbidities and correlate with OSA severity. These findings may have important implications regarding OSA diagnosis, monitoring, treatment, and prognosis. This trial is registered with ClinicalTrials.gov number NCT03070769. PMID- 28831209 TI - Different Modulatory Effects of IL-17, IL-22, and IL-23 on Osteoblast Differentiation. AB - OBJECTIVES: To examine the expressions of IL-17, IL-22, and IL-23 receptors in four osteoblast models and the effects of IL-17, IL-22, and IL-23 on osteoblasts. METHODS: Gene expression levels of receptors, alkaline phosphatase (ALP), osteocalcin (OCN), and Runt-related transcription factor 2 (Runx-2), were evaluated by RT-PCR and real-time RT-PCR. Proliferative responses and cell cycle analysis were detected by a CCK-8 assay and flow cytometry, respectively. ALP activity and ALP mass were detected by an ALP activity assay and ALP staining, respectively. RESULTS: In primary osteoblasts, only the IL-17 receptor was expressed. In C2C12, MC3T3-E1, and Saos-2 cells, the genes of IL-17, IL-22, and IL-23 receptors were not detectable. None of IL-17, IL-22, and IL-23 had an obvious effect on the proliferation of primary osteoblasts, but IL-17 exhibited an inhibitory effect on the gene expression of ALP, OCN, and Runx-2. The ALP activity and ALP mass of primary osteoblasts were downregulated by IL-17 treatment in a dose-dependent manner, and IL-17 failed to inhibit BMP-2-induced phosphorylation of Smad. CONCLUSION: Primary osteoblasts constitutively express IL-17 receptors, but none of C2C12 cells, MC3T3-E1 cells, and Saos-2 cells express any receptors for IL-17, IL-22, and IL-23. IL-17 inhibits BMP-2-induced osteoblast differentiation via the BMP/Smad-independent pathway. PMID- 28831210 TI - IL-10-Producing B Cells Suppress Effector T Cells Activation and Promote Regulatory T Cells in Crystalline Silica-Induced Inflammatory Response In Vitro. AB - Long-term exposure to crystalline silica leads to silicosis, which is characterized by persistent lung inflammation and lung fibrosis. Multiple immune cells have been demonstrated to participate in crystalline silica-induced immune responses. Our previous study indicated that B10 could control lung inflammation through modulating the Th balance in experimental silicosis in mice. However, the regulatory mechanism of B10 on CD4+ T cells is still unclear. MACS-sorted CD19+ B cells from the three different groups were cultured with CD4+ T cells either with or without transwell insert plates to evaluate the effects of B10 on CD4+ T cells, including Teff and Treg. B10 was eliminated by anti-CD22 application in vivo. Flow cytometry was used to test the frequencies of CD4+ T cells, and the expressions of the related cytokines were detected by real-time PCR and CBA. Insufficient B10 elevated the levels of proinflammatory cytokines and promoted Th responses in a way independent upon cell-cell contact in the Teff and B cell coculture system. B10 could both increase Treg activity and enhance conversion of Teff into Treg. Our findings demonstrated that B10 could affect Th responses by the release of IL-10, enhancing Treg functions and converting Teff into Treg. PMID- 28831211 TI - Screening method for Staphylococcus aureus identification in subclinical bovine mastitis from dairy farms. AB - BACKGROUND: Staphylococcus aureus is one of the most important contagious bacteria causing subclinical bovine mastitis. This bacterial infection is commonly identified by determine the pathogen in bovine milk samples through conventional technique including coagulase test. However, this test has several disadvantages as low sensitivity, risk of biohazard, cost expensive, and limited preparation especially in local area. AIM: Aim of this study was to compare and assess the screening method, Mannitol fermentation test (Mannitol salt agar [MSA]), and deoxyribonuclease (DNase) test, for S. aureus identification in milk samples. MATERIALS AND METHODS: A total of 224 subclinical bovine mastitis milk samples were collected from four provinces of Thailand and determined S. aureus using conventional method and also subjected to the screening test, MSA and DNase test. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) among both tests were analyzed and compared to the tube coagulase test (TCT), as reference method. Immunological test by latex agglutination and molecular assay by determined spa gene were also used to identify and differentiate S. aureus. RESULTS: A total of 130 staphylococci were isolated by selective media, Gram-stain, and catalase test. The number of S. aureus which identified using TCT, MSA and DNase test were 32, 102, and 74 isolates, respectively. All TCT results were correlated to results of latex agglutination and spa gene which were 32 S. aureus. MSA showed 100% sensitivity, 28.57% specificity, 31.37% PPV, and 100% NPV, whereas DNase showed 53.13% sensitivity, 41.84% specificity, 22.97% PPV, and 73.21% NPV. DNase test showed higher specificity value than MSA but the test presented 26.79% false negative results whereas no false-negative result from MSA when comparing to TCT. CONCLUSION: MSA had a tendency to be a good preference for screening S. aureus because of its high sensitivity and NPV. The result from this study will improve a choice to use a screening test to diagnose S. aureus of veterinary field for prompt disease controlling and effective treatment. PMID- 28831212 TI - Performance of broiler chicken fed multicarbohydrases supplemented low energy diet. AB - AIM: Objective of this study was to investigate the effect of multicarbohydrases supplementation on performance of broilers fed low energy diet. MATERIALS AND METHODS: A total of 75 days old chicks were selected and randomly divided into three treatments groups (T1, T2, and T3); each group contained 25 chicks distributed in five replicates of five chicks each. T1 group (positive control) was offered control ration formulated as per Bureau of Indian Standards recommendations. In T2 group (negative control) ration, metabolizable energy (ME) was reduced by 100 kcal/kg diet. T3 group ration was same as that of T2 except that it was supplemented with multicarbohydrases (xylanase at 50 g/ton+mannanase at 50 g/ton+amylase at 40 g/ton). Feed intake and body weight of all experimental birds were recorded weekly. Metabolic trial was conducted for 3 days at the end of experiment to know the retention of nutrients. RESULTS: Significant improvement (p<0.01) was observed in total weight gain, feed conversion efficiency, and performance index in broilers under supplementary group T3 as compared to T1 and T2 groups. Retention of crude protein and ether extract was significantly increased (p<0.05) in T3 group supplemented with multicarbohydrases as compared to other groups. Retention of dry matter, crude fiber, and nitrogen free extract was comparable in all the three groups. Significantly highest dressed weight, eviscerated weight, and drawn weight (% of live body weight) were observed in multicarbohydrases supplemented T3 group, however it was comparable in T1 and T2 groups. CONCLUSION: It was concluded that the supplementation of multicarbohydrases (xylanase at 50 g/ton+mannanase at 50 g/ton+amylase at 40 g/ton) in low energy diet improved overall performance of broilers. PMID- 28831213 TI - Cuticular surface damage of Ascaridia galli adult worms treated with Veitchia merrillii betel nuts extract in vitro. AB - AIM: The objective of this research was to in vitro evaluate the cuticular surface damage of Ascaridia galli adult worms treated with ethanolic extract of betel nuts Veitchia merrillii. MATERIALS AND METHODS: Phytochemical screening was done using FeCl3, Wagner and Dragendorff reagents, NaOH, MgHCl, and Liebermann Burchard reaction test. Amount of 16 worms were segregated into four groups with three replicates. Four worms of each group submerged into phosphate buffered saline, 25 mg/ml, and 75 mg/ml crude ethanolic extract of V. merrillii, and 15 mg/ml albendazole. The effect of these extract was observed 40 h after incubation as soon as worms death. The worms were sectioned transversally and were explored for any cuticular histopathological changes in their body surface under microscope. RESULTS: We found that the ethanolic extract of V. merrillii betel nuts contains tannins, alkaloids, flavonoids, triterpenoids, and saponins. The ethanolic extract of betel nuts V. merrillii induces surface alterations caused cuticular damage of A. galli adult worms. CONCLUSION: We concluded that ethanolic extract of betel nuts V. merrillii possess anthelmintic activity caused cuticular damage of A. galli adult worms. PMID- 28831214 TI - Detection and characterization of pathogenic Pseudomonas aeruginosa from bovine subclinical mastitis in West Bengal, India. AB - AIM: Subclinical mastitis in bovines is mainly responsible for the huge economic loss of the dairy farmers, of which Pseudomonas aeruginosa is one of the causative agents. The study was aimed at a screening of suspected milk samples from different cattle farms of West Bengal for detection and confirmation of P. aeruginosa strains followed by their characterization. MATERIALS AND METHODS: Around 422 milk samples were screened from different dairy farms primarily by on spot bromothymol blue (BTB) test and then in the lab by somatic cell counts (SCC) to finally consider 352 samples for detection of P. aeruginosa. Selective isolation and confirmation of the isolates were done using selective media, viz., cetrimide and Pseudomonas agar followed by confirmation by fluorescent technique. Molecular characterization of the strains was done by polymerase chain reaction for the presence of toxA (enterotoxin A, 352 bp) and exoS (exoenzyme S, 504 bp) genes. RESULTS: Approximately, 371 (87.9%) samples were positive in on-spot BTB test among which 352 (94.8%) samples revealed high SCC values (more than 3 lakh cells/ml) showing infection when screened. Among these, 23 (6.5%) samples yielded typical Pseudomonas sp. isolates out of which only 19 (5.4%) isolates were confirmed to be P. aeruginosa which showed characteristic blue-green fluorescence due to the presence of pigment pyoverdin under ultraviolet light. Out of these 19 isolates, 11 isolates were positive for toxA, 6 isolates for exoS, and 2 for both these pathogenic genes. CONCLUSION: Approximately, 5.4% cases of bovine subclinical mastitis infections in South Bengal were associated with P. aeruginosa which possess pathogenic genes such as toxA (63.2%) and exoS (36.8%). PMID- 28831215 TI - Anti-diarrhea activity of the aqueous root bark extract of Byrsocarpus coccineus on castor oil-induced diarrhea in Wistar rats. AB - AIM: The use of traditional medicine as an alternative source of cure for many ailments has played an important role in health care delivery in both developing and developed countries. Byrsocarpus coccineus Schum and Thonn (Connaraceae) is used in traditional medicine for treatment of various disease conditions, including diarrhea. The anti-diarrhea activity of the root bark aqueous extract of B. coccineus was investigated in this study. MATERIALS AND METHODS: Acute toxicity evaluation of the aqueous extract of B. coccineus root bark was performed in exposed rats. Diarrhea was induced in exposed rats with castor oil, and the effect of the extract on castor oil-induced gastrointestinal motility and enteropooling was consequently investigated. RESULTS: In the acute toxicity study, the extract caused no death in treated rats nor produced signs of delayed toxicity, even at 5000 mg/kg. The aqueous root bark extract of B. coccineus also decreased the distance travelled by activated charcoal in the gastrointestinal tract of treated rats when compared to control rats. Results of castor oil induced enteropooling revealed slight reduction in the weight of intestinal contents of treated rats compared to control rats. There was significant (p<0.05) decrease in the frequency of defecation as well as in the number of unformed feces produced by castor oil-induced diarrhea at 100 mg/kg dose with 74.96% inhibition of defecation. CONCLUSION: The study demonstrated the anti-diarrheic property of the aqueous extract of B. coccineus root bark as currently exploited in our traditional herbal therapy. PMID- 28831216 TI - Noninvasive assessment of gastrointestinal parasites infection in free-ranging wild herbivores and adjoining livestock of Panna Tiger Reserve, Madhya Pradesh, India. AB - AIM: This study was conducted to know the epidemiology of gastrointestinal parasites of free-ranging wild herbivores and adjoining livestock of Panna Tiger Reserve, Madhya Pradesh, India. MATERIALS AND METHODS: A total of 374 fecal samples from wild herbivores (Chital Axis axis - 123, Sambar Rusa unicolor - 94, Nilgai Boselaphus tragocamelus - 86, and Chinkara Gazella bennettii - 71) and 284 fecal samples of domestic herbivores (cattle - 118, buffalo - 78, and goat - 88) were collected from common grazing land and adjoining area of tiger reserve. Detailed coprological examination for the presence of parasitic eggs/oocysts by direct smear examination, standard sedimentation, and floatation techniques was performed. RESULTS: Fecal samples (n=374) of four different species of wild herbivores were screened. Out of which, 55.61% (n=208) were positive for parasitic infection. Among them, 13.10% (n=49) were positive for mixed parasitic infection of two or more parasite and 42.5% (n=159) were found positive for single parasitic infection. A total of 284 fecal samples of domestic animals were screened from adjoining areas of the tiger reserve. Out of which, 66.54% (n=189) were positive for parasitic infections, out of which 19.71% (n=56) were positive for mixed infection of two or more parasites, and 46.83% (n=133) were found positive for single parasitic infection. CONCLUSION: Wild herbivores at Panna Tiger Reserve were exposed to parasites including some that are known to be pathogenic; majority of wild animals had mixed infection of Eimeria spp., Trichuris spp., Moniezia spp., Amphistome, Strongyloides spp., Balantidium spp., and Fasciola spp. PMID- 28831217 TI - Repair of segmental radial defect with autologous bone marrow aspirate and hydroxyapatite in rabbit radius: A clinical and radiographic evaluation. AB - AIM: Finding an ideal bone substitute to treat large bone defects, delayed union and nonunions remain a challenge for orthopedic surgeons and researchers. Several studies have been conducted on bone regeneration; each has its own advantages and disadvantages. The aim of this study was to evaluate the effect of a combination of hydroxyapatite (HA) powder with autologous bone marrow (BM) aspirate on the repair of segmental radial defect in a rabbit model. MATERIALS AND METHODS: A total of 36 male and adult New Zealand rabbit with a mean weight of 2.25 kg were used in this study. Approximately, 5 mm defect was created in the mid-shaft of the radius to be filled with HA powder in the control group "HA" (n=18) and with a combination of HA powder and autologous BM aspirate in the test group "HA+BM" (n=18). Animals were observed daily for healing by inspection of the surgical site, and six rabbits of each group were sacrificed at 30, 60, and 90 post operative days to perform a radiographic evaluation of defect site. RESULTS: Obtained results revealed a better and more rapid bone regeneration in the test group: Since the defect was rapidly and completely filled with mature bone tissue after 90 days. CONCLUSION: Based on these findings, we could infer that adding a BM aspirate to HA is responsible of a better regeneration process leading to a complete filling of the defect. PMID- 28831219 TI - Effects of commonly used chemical fertilizers on development of free-living stages of Haemonchus contortus in experimentally infected pasture. AB - AIM: The effects of N-P-K fertilizers in the form of urea, single super phosphate and muriate of potash on development of free-living stages of Haemonchus contortus were studied. MATERIALS AND METHODS: Five parasite free experimental plots of 1 m*1 m area, each of paddy leaves (15-day-old) and an equal number of Cynodon dactylon grass were infested with about 10*104 eggs/ml phosphate buffer saline along with the application of the calculated amount of fertilizers solution. On the 10th day of posttreatment, the pasture was cut, processed, larvae recovered by Baermann method and counted, which was expressed as number of L3 per kg dry matter (DM) of pasture. RESULTS: The average recovered population of L3 of H. contortus per kg DM varied significantly (p<0.05) between the paddy leaves (5933.57+/-22.718) and Cynodon grass (4861.00+/-22.718). When different doses of chemical fertilizer and their impact on different pasture were analyzed for control (T-1, 0-0-0 kg/ha N-P-K), the mean L3 recovery per kg DM of paddy (19512.7+/-50.80) was more than that of Cynodon grass (16540.9+/-50.80). Larvae recovery per kg DM for different pastures under treatment were in decreasing order as follows: T-2 of paddy (6981.33+/-50.80, 35.77%), T-2 of Cynodon (5545.38+/-50.80, 33.52%), T-3 of paddy (317378+/-50.80, 16.26%), and T-3 of Cynodon (2218.72+/-50.80, 13.41%) which showed significant difference (p<0.05) among the treatments. In T-4 (paddy) and T-5 (Cynodon), the average number of recovery of larvae was nil implying no significant variation (p>0.05). CONCLUSION: This study shown that when N-P-K fertilizers administered at recommended level, significantly reduced larval translation of H. contortus minimizing pasture infectivity for the free range grazing animals. PMID- 28831218 TI - Evaluation of crude larval protein and recombinant somatic protein 26/23 (rHcp26/23) immunization against Haemonchuscontortus in sheep. AB - AIM: The aim of this study was to evaluate the potential possibility of crude larval and recombinant (rHcp26/23) antigens of Haemonchus contortus for immunization to control sheep hemonchosis. MATERIALS AND METHODS: A total of 21 lambs were divided into five groups. Lambs were immunized with larval and recombinant (rHcp26/23) proteins at day 0 and day 14 and after that challenged with 5000 infective larvae of H. contortus on day 42. An unvaccinated positive control group was challenged with L3 in the meantime. An unvaccinated negative control group was not challenged. RESULTS: Fecal egg count reduction taking after challenge for rHcp26/23 and larval antigens was 92.2% and 38.2%, respectively, compared with the positive control group. Vaccine incited protection in rHcp26/23 and larval immunization was reflected in significant (p<0.05) decreases in worm burden; 59.9% and 40.1%, respectively. CONCLUSION: Recombinant rHcp26/23 vaccine induced a partial immune response and had immune-protective effect against sheep hemonchosis. PMID- 28831220 TI - Serotyping, antibiotic susceptibility, and virulence genes screening of Escherichia coli isolates obtained from diarrheic buffalo calves in Egyptian farms. AB - AIM: In Egypt as in many other countries, river water buffalo (Bubalus bubalis) is considered an important source of high-quality milk and meat supply. The objective of this study was to investigate serotypes, virulence genes, and antibiotic resistance determinants profiles of Escherichia coli isolated from buffalo at some places in Egypt; noticibly, this issue was not discussed in the country yet. MATERIALS AND METHODS: A number of 58 rectal samples were collected from diarrheic buffalo calves in different regions in Egypt, and bacteriological investigated for E. coli existence. The E. coli isolates were biochemically, serologicaly identified, tested for antibiotic susceptibility, and polymerase chain reaction (PCR) analyzed for the presence of antibiotic resistance determinants and virulence genes. RESULTS: Overall 14 isolates typed as E. coli (24.1%); 6 were belonged to serogroup O78 (10.3%), followed by O125 (4 isolates, 6.9%), then O158 (3 isolates, 5.2%) and one isolate O8 (1.7%), among them, there were 5 E. coli isolates showed a picture of hemolysis (35.7%). The isolates exhibited a high resistance to beta lactams over 60%, followed by sulfa (50%) and aminoglucoside (42.8%) group, in the same time the isolates were sensitive to quinolone, trimethoprim-sulfamethoxazole, tetracycline (100%), and cephalosporine groups (71.4%). A multiplex PCR was applied to the 14 E. coli isolates revealed that all were carrying at least one gene, as 10 carried blaTEM (71.4%), 8 Sul1 (57.1%), and 6 aadB (42.8%), and 9 isolates could be considered multidrug resistant (MDR) by an incidence of 64.3%. A PCR survey was stratified for the most important E. coli virulence genes, and showed the presence of Shiga toxins in 9 isolates carried either one or the two Stx genes (64.3%), 5 isolates carried hylA gene (35.7%), and eae in 2 isolates only (14.3%), all isolates carried at least one virulence gene except two (85.7%). CONCLUSION: The obtained data displayed that in Egypt, buffalo as well as other ruminants could be a potential source of MDR pathogenic E. coli variants which have a public health importance. PMID- 28831221 TI - Prevalence and antimicrobial resistance pattern of Shiga toxigenic Escherichia coli in diarrheic buffalo calves. AB - AIM: Aim of the study was to investigate the prevalence, virulence gene profiles, and antimicrobial resistance pattern of Shiga toxigenic Escherichia coli (STEC) in diarrheic buffalo calves from Andhra Pradesh and Telangana States. MATERIALS AND METHODS: A total of 375 fecal samples from diarrheic buffalo calves of 1-7, 8 30, 31-60, and 61-90 days age were collected from which STEC were isolated, and virulence genes were detected using multiplex polymerase chain reaction. The antimicrobial resistance of isolates was tested by disk diffusion method. RESULTS: The prevalence of E. coli associated diarrhea in buffalo calves was 85.04%, of which 35.01% was STEC origin. In STEC, the combination of eaeA and, hlyA virulence genes was highest (42.45%) followed by stx1 (16.04%), stx1, stx2 and hlyA (13.21%), stx2 (12.64%), stx1, eae and hlyA (9.43%) and stx1 and hlyA (6.6%) genes were detected. Highest antimicrobial resistance was observed for tetracycline (63.21%) and ampicillin (48.11%), while chloramphenicol, gentamycin (96.33%) and imipenem (99.06%) antibiotics are susceptible. Multidrug resistance was detected in 69.81% of the STEC isolates from diarrheic buffalo calves. CONCLUSION: Higher prevalence of eaeA and hlyA genes carrying isolates of STEC may be a serious zoonotic threat and increased prevalence of multidrug resistance in E. coli may necessitate stringent selection of appropriate antimicrobial agent in treating buffalo calf diarrhea cases. PMID- 28831222 TI - Semen characteristics, extension, and cryopreservation of Rusa deer (Rusa timorensis). AB - AIM: The objective of this research is to report parameters for breeding soundness evaluation, semen extension, and cryopreservation in Rusa timorensis. MATERIALS AND METHODS: Seven healthy stags were chosen for semen collection using an electroejaculator. The collections were performed twice in a breeding season between February and June 2016. Samples were collected between 2 and 3 weeks interval, collected twice for each animal. Semen was evaluated, extended, and cryopreserved using four different extenders; Andromed(r), BioXcell(r), Triladyl(r), and a modified Tris-egg yolk combined with Eurycoma longifolia Jack. RESULTS: R. timorensis semen characteristics according to volume (ml), color, sperm concentration (106/ml), general motility (%), progressive motility (%), and % morphology of normal spermatozoa are 0.86+/-0.18 ml, thin milky to milky, 1194.2+/-346.1 106/ml, 82.9+/-2.8%, 76.1+/-4.8%, and 83.9+/-4.8%, respectively. CONCLUSION: Semen characteristics of R. timorensis collected by electroejaculation is good allowing for cryopreservation and future artificial insemination work. The most suitable extender for Rusa deer semen is Andromed(r). PMID- 28831223 TI - Alterations in lipid profile in neonatal calves affected by diarrhea. AB - AIM: The aim of this study was to determine the alterations in the lipid profile, plasma alkaline phosphatase (ALP) activity, total and direct bilirubin levels of neonatal calves with diarrhea. MATERIALS AND METHODS: A total of 25 calves with diarrhea as experimental group and 10 healthy calves as control group, 1-30 days old, were enrolled in the study. Blood samples were collected from jugular vein in tubes with anticoagulant agent to evaluate the concentration of triglycerides, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), ALP, total and direct bilirubin. Very low-density lipoprotein-cholesterol (VLDL-C) and low density lipoprotein-cholesterol (LDL-C) levels were calculated according to the Friedewald formula. RESULTS: Significant increases in the plasma levels of ALP (p<0.05), total and direct bilirubin, triglycerides, and VLDL-C (p<0.01) were determined, whereas significant decreases in the levels of total cholesterol, HDL C and LDL-C (p<0.01) were observed in neonatal calves with diarrhea. CONCLUSION: According to the findings of this study, liver functions impaired and, therefore, lipid profile is affected negatively in neonatal calves with diarrhea. PMID- 28831224 TI - Phenotypic approach artemisinin resistance in malaria rodent as in vivo model. AB - AIM: The aim of this study is to prove the development of artemisinin resistance phenotypically in malaria rodent as an in vivo resistance development model in humans. MATERIALS AND METHODS: Plasmodium berghei was infected intraperitoneally in mice, then artemisinin was given with "4-day-test" with effective dose (ED) 99% dose for 3 days which begins 48 h after infection (D2, D3, and D4). Parasite development was followed during 5th until 10th days of infection. After parasitemia >2% of red blood cell which contains parasites on 1 mice, that mice were used as donor to be passaged on the new 5 mice. After that, parasitemia was calculated. ED50 and ED90 were examined with parasite clearance time (PCT), recrudescence time (RT), and also morphology development examination of intraerythrocytic cycle of P. berghei with transmission electron microscope. RESULTS: Among the control group compare with the treatment group showed significant differences at alpha=0.05 on 5th day (D5) until 10th day (D10). The control group of 4th passage (K4) with passage treatment group of 4th passage (P4) on the 10th days (D10) post infection showed no significant differences in the alpha=0.05. The average percentage of inhibition growth was decreasing which is started from 5th to 10th day post infection in P1, P2, P3, and P4. On the development of P. berghei stage, which is given repeated artemisinin and repeated passage, there was a formation of dormant and also vacuoles in Plasmodium that exposed to the drug. CONCLUSION: Exposure to artemisinin with repeated passages in mice increased the value of ED50 and ED90, decreased the PCT and RT and also changes in morphology dormant and vacuole formation. PMID- 28831225 TI - Identification of Toxocara spp. eggs in dog hair and associated risk factors. AB - AIM: The aim of the study was to identify the presence of eggs of Toxocaraspp. in dog hair and to identify any risk factors associated with this. MATERIALS AND METHODS: A total of 96 dogs were sampled collecting hair from the head, perianal and hindquarters. Epidemiologic data from each animal were recorded to identify risk factors. The samples of hair were washed with solutions of distilled water, phosphate-buffered saline and Tween 20 detergent. Microscopic analysis was subsequently performed for the identification of eggs. RESULTS: Out of the total dogs, 41.7% were positive for the presence of parasite egg in their hair. Toxocara eggs were found in hair from the head (14.5%), tail (20.8%), and limbs (10.4%). Dogs, younger than 12 months old, showed higher values (4.7%) of egg presence in the perianal area (p<0.05). The principal risk factors for the presence of eggs in hair were not deworming (odds ratio [OR]=3.60, p<0.004) and not brushing (OR=2.26, p<0.12). CONCLUSION: These results show that in the state of Mexico there is a high percentage of dogs contaminated with Toxocara spp. eggs in their hair. This should be seriously considered due to the potential problems of toxocariasis and the risk to public health. PMID- 28831226 TI - Antibiotic and heavy metal resistance of Aeromonas hydrophila and Edwardsiella tarda isolated from red hybrid tilapia (Oreochromis spp.) coinfected with motile aeromonas septicemia and edwardsiellosis. AB - AIM: The aim of this study is to identify antibiogram and heavy metal resistance pattern of Aeromonas hydrophila and Edwardsiella tarda isolated from red hybrid tilapia (Oreochromis spp.) coinfected with motile aeromonas septicemia and edwardsiellosis in four commercial fish farms. MATERIALS AND METHODS: A. hydrophila and E. tarda were isolated using glutamate starch phenol red and xylose lysine deoxycholate (Merck, Germany) as a selective medium, respectively. All the suspected bacterial colonies were identified using conventional biochemical tests and commercial identification kit (BBL Crystal, USA). Susceptibility testing of present bacterial isolates to 16 types of antibiotics (nalidixic acid, oxolinic acid, compound sulfonamides, doxycycline, tetracycline, novobiocin, chloramphenicol, kanamycin, sulfamethoxazole, flumequine, erythromycin, ampicillin, spiramycin, oxytetracycline, amoxicillin, and fosfomycin) and four types of heavy metals (mercury, chromium, copper, and zinc) were carried out using disk diffusion and two-fold agar dilution method, respectively. RESULTS: Three hundred isolates of A. hydrophila and E. tarda were successfully identified by biochemical tests. Antibiotic susceptibility testing results showed that 42.2% of the bacterial isolates were sensitive to compound sulfonamides, sulfamethoxazole, flumequine, oxytetracycline, doxycycline, and oxolinic acid. On the other hand, 41.6% of these isolates were resistant to novobiocin, ampicillin, spiramycin, and chloramphenicol, which resulted for multiple antibiotic resistance index values 0.416. Among tested heavy metals, bacterial isolates exhibited resistant pattern of Zn2+ > Cr6+ > Cu2+ > Hg2+. CONCLUSION: Results from this study indicated that A. hydrophila and E. tarda isolated from coinfected farmed red hybrid tilapia were multi-resistant to antibiotics and heavy metals. These resistant profiles could be useful information to fish farmers to avoid unnecessary use of antimicrobial products in the health management of farmed red hybrid tilapia. PMID- 28831227 TI - Effects of herbal ointment containing the leaf extracts of Madeira vine (Anredera cordifolia (Ten.) Steenis) for burn wound healing process on albino rats. AB - AIM: Skin burn is a health problem that requires fast and accurate treatment. If not well-treated, the burn will cause various damaging conditions for the patient. The leaf extract of Madeira vine (Anredera cordifolia (Ten.) Steenis), or popularly known as Binahong in Indonesia, has been used to treat various diseases. The purpose of this research is to determine the effects of leaf extracts of Madeira vine (A. cordifolia (Ten.) Steenis) on skin burn healing process in rats as an animal model. MATERIALS AND METHODS: In this research, there were four treatment groups: G0, G1, G2, and G3, each consisting of five rats. All these rats were given skin burns, using hot metal plates. Then, sulfadiazine was given to G0, 2.5% leaf extract of Madeira vine was given to G1, 5% extract was given to G2, and 10% extract was given to G3, for straight 14 days topically, 3 times a day. At the end of the treatment period, skin excisions were conducted, and histopathological examination was carried out. RESULT: Microscopic observation on the wound healing process on the collagen deposition, polymorphonuclear infiltration, angiogenesis, and fibrosis showed that G2 had a significant difference with G0, G1, and G3 (p<0.05), while group G0 was significantly different from G1 and G3 (p<0.05). The better burn healing process on G2 allegedly because of the activity of flavonoid, saponin, and tannin, contained in the Madeira vine, which have the antioxidant, anti-inflammatory, and antibacterial effects. CONCLUSION: The ointment from the 5% leaf extract of Madeira vine (A. cordifolia (Ten.) Steenis) has been proven to be effective to be used for topical burn therapy. PMID- 28831228 TI - Characterization of Salmonella Gallinarum isolates from backyard poultry by polymerase chain reaction detection of invasion (invA) and Salmonella plasmid virulence (spvC) genes. AB - AIM: The aim was to characterize Salmonella enterica serovar Gallinarum isolated from backyard poultry by polymerase chain reaction (PCR) detection of virulence genes invasion (invA) and Salmonella plasmid virulence C (spvC). MATERIALS AND METHODS: Two strains of Salmonella serovar Gallinarum isolates used in this study were obtained from an outbreak of fowl typhoid in backyard Vanaraja fowl. PCR technique was used for detection of invA and spvC genes using standard methodology. The invA PCR product from one representative isolate was sequenced and compared with other related Salmonella serovars in GenBank data. RESULTS: Salmonella Gallinarum produced expected amplicons of invA and spvC gene products. Nucleotide sequence of 285 bp invA gene was deposited in GenBank with accession no. KX788214. Sequence analysis of invA gene was found conserved in Salmonella serovars and demonstrated 100% homology with closely related serovars of Salmonella. CONCLUSION: Invasion gene (invA) was found to be highly conserved in Salmonella Gallinarum and highly similar with closely related serovars. The isolates also contained plasmid-mediated spvC gene indicating possession of virulence plasmid. PMID- 28831229 TI - Baseline hematology and serum biochemistry results for Indian leopards (Panthera pardus fusca). AB - AIM: The aim of the study was to establish the baseline hematology and serum biochemistry values for Indian leopards (Panthera pardus fusca), and to assess the possible variations in these parameters based on age and gender. MATERIALS AND METHODS: Hemato-biochemical test reports from a total of 83 healthy leopards, carried out as part of routine health evaluation in Bannerghatta Biological Park and Manikdoh Leopard Rescue Center, were used to establish baseline hematology and serum biochemistry parameters for the subspecies. The hematological parameters considered for the analysis included hemoglobin (Hb), packed cell volume, total erythrocyte count (TEC), total leukocyte count (TLC), mean corpuscular volume (MCV), mean corpuscular Hb (MCH), and MCH concentration. The serum biochemistry parameters considered included total protein (TP), albumin, globulin, aspartate aminotransferase, alanine aminotransferase (ALT), blood urea nitrogen, creatinine, triglycerides, calcium, and phosphorus. RESULTS: Even though few differences were observed in hematologic and biochemistry values between male and female Indian leopards, the differences were statistically not significant. Effects of age, however, were evident in relation to many hematologic and biochemical parameters. Sub-adults had significantly greater values for Hb, TEC, and TLC compared to adults and geriatric group, whereas they had significantly lower MCV and MCH compared to adults and geriatric group. Among, serum biochemistry parameters the sub-adult age group was observed to have significantly lower values for TP and ALT than adult and geriatric leopards. CONCLUSION: The study provides a comprehensive analysis of hematologic and biochemical parameters for Indian leopards. Baselines established here will permit better captive management of the subspecies, serve as a guide to assess the health and physiological status of the free ranging leopards, and may contribute valuable information for making effective management decisions during translocation or rehabilitation process. PMID- 28831230 TI - Probiotic characterization of lactic acid bacteria isolated from swine intestine. AB - AIM: A study was conducted with the objective to isolate probiotic microorganisms from swine intestine. MATERIALS AND METHODS: In this study 63 isolates (24 caeca, 24 colon mucosal scrapings, and 15 rectal swab samples) were collected from Large White Yorkshire pigs. The isolates were inoculated and grown in de Man Rogosa Sharpe broth at 37 degrees C with 5% CO2 for 48 h and subjected to morphological identification. Colonies having Gram-positive rods were selected for further physiological and biochemical identification tests, which were conducted in triplicate in two runs for each of the selected isolates using a standard protocol. Probiotic properties among the identified species were determined through the implementation of several tests related with pH tolerance, bile tolerance, and antimicrobial activity. RESULTS: Morphological identification revealed that only 23 isolates were Gram-positive rods. Physiological tests performed on these 23 isolates further revealed that four of them did not exhibit any growth, at all conditions studied. The rest 19 isolates were, therefore, selected and subjected to biochemical tests. Six isolates were rejected because they were oxidase and nitrate reduction positive. From the 13 isolates subjected to sugar fermentation tests, speciation of only two isolates could be ascertained, one of the isolates showed characteristics for Lactobacillus acidophilus and the other for Lactobacillus plantarum. These two isolates were assessed for the strain possessing maximum probiotic property, and it was inferred that both - L. plantarum and L. acidophilus could tolerate a wide pH range (2-9), a wide bile concentration (0.05-0.3%) and revealed antimicrobial activity toward Escherichia coli, and Enterobacter spp. CONCLUSION: L. plantarum and L. acidophilus were isolated from swine intestine and were found to have good probiotic properties. PMID- 28831231 TI - Serogrouping and antibiotic resistance of Escherichia coli isolated from broiler chicken with colibacillosis in center of Algeria. AB - AIM: Colibacillosis is considered as one of the major bacterial infections in avian pathology. The excessive use of antibiotics reduced their effectiveness, which eventually led to the risk of emergence of antibiotic resistance. The aim of this study was to isolate, identify and serotype the pathogenic Escherichia coli strains and to determine their antibiotic susceptibility. MATERIALS AND METHODS: A total of 180 samples from different organs of broilers with colibacillosis lesions were collected (liver, spleen, lung, and heart) in center of Algeria. The isolation and identification of E. coli were carried out using conventional techniques. Then, these strains were serotyped and tested over 13 antibiotics. RESULTS: A total of 156 strains of E. coli were isolated. Serotyping results showed that 50 strains belong to 3 serotypes (23 for O1, 11 for O2, 16 for O78) which represent 32% of isolates. The antimicrobial susceptibility test, presented high level of resistance to tetracyclines (94.12%), flumequine (91.5%), sulfamethoxazole-trimethoprim (88.89%), enrofloxacin (86.27%), nalidixic acid (85.62%), ampicillin (83.01%) and doxycycline (75.81%), medium level resistance to chloramphenicol (39.22%), and amoxicillin-clavulanic acid (43.13%). All the strains were susceptible to cefotaxime, excepting three, which presented an extended spectrum beta-lactamase (ESBL). In addition, the results of multi resistance showed that all the strains were resistant at the minimum to two antibiotics and 66.66% of strains were resistant to at least seven antibiotics. CONCLUSION: The antibiotic resistance continues to rise at an alarming rate, and the emergence of ESBL is considered as a threat for public health. PMID- 28831232 TI - Effect of paddy straw plus nonforage fiber sources based complete rations with different levels of neutral detergent fiber on hemato-biochemical and mineral profile of lactating dairy cows. AB - AIM: This study was conducted to assess the effect of feeding paddy straw plus nonforage fiber sources based complete rations with different levels of neutral detergent fiber (NDF) on hemato-biochemical and mineral parameters of lactating dairy cows. MATERIALS AND METHODS: The study was conducted for 6 months in 18 lactating dairy cows, divided into three groups of six each, by feeding them on paddy straw plus nonforage fiber sources based complete rations containing different levels of NDF, in two phases of 3 months (90 days) each, being the early and mid lactation phases, respectively. Three isonitrogenous and isocaloric complete rations, T1, T2 and T3 with 25%, 30% and 35% NDF, respectively, were fed to the experimental animals. Blood samples were collected at the beginning and the end of each of the two phases to estimate the different hematological, plasma protein, and mineral parameters to know the overall health status of the animals and standard methods were followed to analyze the samples. RESULTS: There was no significant difference (p>0.05) in various hematological parameters such as hemoglobin, glucose, and blood urea nitrogen (BUN) in blood; plasma protein parameters such as total protein, albumin, globulin and albumin: globulin ratio and mineral parameters such as plasma calcium and phosphorus levels at the beginning and end of Phase I (1st day and 90th day) and Phase II (91st day and 180th day) as well as between the three dietary treatments, with all the values being in the normal range for lactating dairy cows. Even though nonsignificant (p>0.05), the BUN values of animals fed on ration T1, both at the beginning and end of Phase I, were higher than that of animals fed on rations T2 and T3 because the diet T1 with lowest NDF and the highest soluble carbohydrate content underwent rapid fermentation in the rumen, produced more energy, which was utilized by the rumen microbes to degrade the protein in the feed to ammonia, the excess ammonia being transported to the liver and excreted through the blood resulting in a higher BUN content. CONCLUSION: Feeding of paddy straw plus nonforage fiber sources based complete rations with different levels of NDF had no effect on hemato-biochemical and mineral profile as well as overall health status of lactating dairy cows. However, the higher, BUN values found in cows fed on diet T1 with 25% NDF as compared to those fed on T2 and T3 with 30% and 35% NDF, respectively, indicate more wastage of protein in T1 as compared to T2 and T3, in early lactation. PMID- 28831233 TI - Correlation between hand bone mineral density and joint destruction in established rheumatoid arthritis. AB - OBJECTIVE: We aimed to clarify the correlation between bone mineral density (BMD) and the modified total Sharp score of the hand in Japanese patients with established rheumatoid arthritis (RA). METHODS: We examined the hands of 57 patients who had RA for more than 20 years. BMD for the whole hand was measured using dual-energy x-ray absorptiometry. Concurrently, the hands were analyzed using radiography to estimate the van der Heijde-modified total Sharp score (vdH S). RESULTS: The patients were all women with a median age of 69.7 years and RA disease duration of 29.9 years. The correlation coefficients were -0.513 (P < 0.0001) for hand BMD and vdH-S of the hand, -0.576 (P < 0.0001) for hand BMD and the erosion score of the vdH-S, and -0.339 (P < 0.0001) for hand BMD and the joint narrowing score of the vdH-S. CONCLUSIONS: Hand BMD is correlated with the vdH-S in long-established RA. The hand BMD is important for structural assessment of the hand. Additionally, we may be able to predict the vdH-S of the hand on the basis of the hand BMD in long-established RA. PMID- 28831234 TI - Ultrasound guided Needling vs Radial Shockwave Therapy in calcific tendinitis of the shoulder: A prospective randomized trial. AB - PURPOSE: Ultrasound Needling(UN) and Radial Shockwave(RSWT) aim to dissolve deposits in Shoulder Calcific tendinitis. METHODS: RCT in 25 patients to compare short term effectiveness. Outcome measures were pain and functional outcome at 6 weeks and 1 year and decrease of deposits after 6 weeks. RESULTS: UN decreased deposit more than RSWT(P = 0.029). After 6 weeks, Constant, NRS and Oxford improved more in UN. After 1 year, there was no significant difference in NRS(p = 0.45) or Oxford(p = 0.32). CONCLUSION: Compared to RSWT, UN resulted in lower pain and faster resorption of calcifications after 6 weeks. No significant differences were found after 1 year. PMID- 28831235 TI - Benign heart murmurs as a predictor for complications following total joint arthroplasty. AB - BACKGROUND: There is scant literature examining the predictive role of heart murmurs in the absence of suspected structural heart disease on complications of non-cardiac surgery. We hypothesize the detection of heart murmurs in the absence of structural heart disease will help identify patients at risk for complications following total joint arthroplasty (TJA) surgery. METHOD: This was a prospective cohort of patients undergoing TJA over a twenty-month period. The study was performed at a single academic institution with four subspecialty surgeons. Patients undergoing primary TJA who were over eighteen years old, gave informed consent, and had adequate documentation were included in the study. Patients with a preoperative murmur or a newly discovered postoperative murmur were compared against patients with no murmur. Surgery-related complications, performance with physical therapy, and discharge to a non-home facility were measured in each group. FINDINGS: 345 (63%) eligible patients were included. 20 (5.8%) patients had a documented preoperative murmur and 36 (10.4%) patients had a new postoperative murmur. No patient had concern for major structural heart disease. Preoperative murmurs independently predicted development of acute kidney injury (OR 7.729, p < 0.001; RR 1.36). Preoperative murmurs also predicted likelihood to be discharged to a non-home facility (OR 2.97, p = 0.03; RR 1.87). New postoperative murmurs independently correlated with decreased performance with physical therapy (OR 0.466, p = 0.045; RR 0.664). INTERPRETATION: Detection of heart murmurs both preoperatively and postoperatively is a low cost strategy to identify post-TJA surgical patients at risk for postoperative acute kidney injury, decreased physical performance, and discharge to non-home facilities. These patients may benefit from early fluid resuscitation and renally-dosed post operative medications. PMID- 28831236 TI - Prothrombin fragment F1+2 in plasma and urine during total hip arthroplasty. AB - OBJECTIVE: To study the time course and correlation of prothrombin fragment (F1 + 2) in plasma and urine during THA. METHOD: F1 + 2 concentrations were recorded at four time-points during THA. RESULTS: F1 + 2 increased during surgery. In contrast to urine, plasma F1 + 2 was temporarily reduced the first postoperative day. At day six, plasma F1 + 2 was significantly elevated indicating on-going thrombin activation, while urine F1 + 2 was normalized. CONCLUSION: The response in coagulation to operative trauma can be recorded with F1 + 2 both in plasma and urine. We were not able to demonstrate any correlation of F1 + 2 in plasma and urine later in the postoperative period. PMID- 28831237 TI - Knowledge of Human Cytomegalovirus Infection and Prevention in Pregnant Women: A Baseline, Operational Survey. AB - Currently, the only efficient way to prevent human Cytomegalovirus (HCMV) infection in pregnancy is primary prophylaxis through hygienic measures. So, we evaluated knowledge of HCMV and its prevention in a group of pregnant women. An anonymous questionnaire with multiple-choice answers was administered to all pregnant women who were followed up at the Obstetrics and Gynecology Unit of "Pugliese-Ciaccio Hospital," a third-level hospital in Catanzaro (Southern Italy), from November 2015 to March 2016. Previously prescribed serology results for HCMV were also evaluated. Three hundred and fifty women participated in the study and the results clearly demonstrated that knowledge of pregnant women about HCMV is poor. Moreover, prescribed screening procedures need to be optimized, since one out of three pregnant women has not been tested for HCMV or the screening was not performed adequately. For this reason, it is important to implement informative campaign in both pregnant women and providing physicians. PMID- 28831238 TI - Correction to: Environ. Eng. Sci. 2017;34(1):51-61. DOI: 10.1089/ees.2016.0223. AB - [This corrects the article DOI: 10.1089/ees.2016.0223.]. PMID- 28831239 TI - Comparison of Machine Learning Methods for the Arterial Hypertension Diagnostics. AB - The paper presents results of machine learning approach accuracy applied analysis of cardiac activity. The study evaluates the diagnostics possibilities of the arterial hypertension by means of the short-term heart rate variability signals. Two groups were studied: 30 relatively healthy volunteers and 40 patients suffering from the arterial hypertension of II-III degree. The following machine learning approaches were studied: linear and quadratic discriminant analysis, k nearest neighbors, support vector machine with radial basis, decision trees, and naive Bayes classifier. Moreover, in the study, different methods of feature extraction are analyzed: statistical, spectral, wavelet, and multifractal. All in all, 53 features were investigated. Investigation results show that discriminant analysis achieves the highest classification accuracy. The suggested approach of noncorrelated feature set search achieved higher results than data set based on the principal components. PMID- 28831240 TI - Changes in macular parameters in different types of amblyopia: optical coherence tomography study. AB - PURPOSE: The purposes of this study were to investigate the changes in macular parameters (thickness, volume) and peripapillary retinal nerve fiber layer (RNFL) thickness (RNFLT) in different cases of amblyopia versus the normal fellow eyes using optical coherence tomography (OCT) and to estimate the relationship of OCT changes with various defined patients' parameters. DESIGN: This is a prospective, observational, cross-sectional case series. METHODS: The method involved measuring the peripapillary RNFLT, macular thickness, and macular volume via spectral domain (OCT) in different types of amblyopia and comparing with the other fellow eyes. This study was conducted at the Mansoura Ophthalmic Center. RESULTS: A total of 64 patients with different types of amblyopia were included. The mean central macular thickness (CMT) was 196.2+/-50.03 um in the amblyopic eyes versus 167+/-12.76 um in the fellow eyes (P=0.000), the mean average macular thickness was 265.80+/-12.77 um in the amblyopic eyes versus 259.10+/-3.09 um in the fellow eyes (P=0.000), the mean macular volume was 7.59+/-0.32 mm3 in the amblyopic eyes versus 7.34+/-0.071 mm3 in the fellow eyes (P=0.002), and the mean global RNFLT was 97.00+/-11.60 um in the amblyopic eyes versus 78.50+/-13.05 um in the fellow eyes (P=0.029). There was a discrepancy between the different amblyopic types. Age and the axial length were the only independent variables that statistically significantly correlated with the CMT. CONCLUSION: The unilateral amblyopic eyes were prone to have a higher CMT and thicker global RNFL compared to those of the sound fellow eyes. Retinal variations between different types of the amblyopia differ from one type to another. The age could be considered as a predictor of the disease worsening and treatment prognosis. Further studies are required to emphasize these results. PMID- 28831241 TI - Ambulatory blood pressure parameters after canrenone addition to existing treatment regimens with maximum tolerated dose of angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers plus hydrochlorothiazide in uncontrolled hypertensive patients. AB - BACKGROUND: Blockade of the renin-angiotensin-aldosterone system is a cornerstone in cardiovascular disease prevention and hypertension treatment. The relevance of ambulatory blood pressure monitoring (ABPM) has been widely confirmed for both increasing the accuracy of blood pressure (BP) measurements, particularly in pharmacological trials, and focusing on 24 h BP prognostic parameters. The aim of this study was to assess the effects of canrenone addition on ambulatory BP in uncontrolled hypertensive patients already treated with the highest tolerated dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 receptor (AT1R) antagonists plus hydrochlorothiazide (HCT). METHODS: ABPM was performed at baseline and after 3 months of combination therapy in 158 outpatients with stage 1 or 2 hypertension who were randomized to add canrenone (50 or 100 mg) to the pre-existing therapy with ACE inhibitors or AT1R antagonists plus HCT. Twenty-four-hour systolic and diastolic BPs were considered normalized when the values were <130 and <80 mmHg, respectively. RESULTS: The addition of canrenone was associated with a reduction in systolic and diastolic BPs (24 h and daytime and nighttime; P<0.001), mean arterial pressures (P<0.001), and pulse pressures (P<0.01). The Delta 24 h systolic/diastolic BPs were -13.5+/ 11.2/-8+/-8 mmHg and -16.1+/-13.5/-11.2+/-8.3 mmHg (50 and 100 mg/day, respectively). In the 50 mg arm, the 24 h systolic and diastolic BPs were normalized in 67.5% and 74% of the patients, respectively, and in 61.6% and 68.5% of the patients in the 100 mg arm, respectively (P<0.05; P= not significant for 50 vs 100 mg). The percentage of patients whose nocturnal decrease was >10% with respect to diurnal values did not change during combination therapy. CONCLUSION: Canrenone addition to ACE inhibitors or AT1R antagonists plus HCT was associated with a significant reduction of 24 h BP and to an increased number of patients meeting 24 h ABPM targets in a clinical setting of uncontrolled stage 1 or 2 hypertension. PMID- 28831243 TI - Autoinjector preference among patients with multiple sclerosis: results from a national survey. AB - PURPOSE: Autoinjectors are well-established in supporting multiple sclerosis (MS) therapy. This market survey was aimed at investigating patients' rating of three devices for subcutaneous interferon beta formulations: the electronic autoinjectors Betaconnect(r) and RebiSmartTM as well as the mechanical ExtaviProTM device. PATIENTS AND METHODS: Organization and conduction of structured face-to-face interviews in five German cities were managed through an independent external market research company. After questionnaire validation (n=15), 85 participants currently either using the Betaconnect (n=39), the RebiSmart (n=36) or the ExtaviPro injector (n=10) were asked 22 questions in the same order. First, patients named their current device in use, watched the corresponding instruction video, and were queried about their device. Second, patients were asked about their opinion of an ideal autoinjector. Third, instruction videos for the two non-used devices were presented and participants could dummy-inject into a pillow. Last, patients evaluated device features and indicated their preferred autoinjector. RESULTS: Before having been presented the two other autoinjectors not in use, evaluation of patients' satisfaction with their own device revealed that 82% of the Betaconnect users, 67% of the RebiSmart and 60% of the ExtaviPro users were highly satisfied. All patients desired some improvement of their own device particularly concerning optimization of size and handling. Subsequent to testing and watching instruction videos of all devices, the Betaconnect received the best rating regarding different functions. Finally, participants indicated their preferred autoinjector, provided their own medication was suitable for all three devices: 56.5% of the participants (n=48/85) chose the Betaconnect, 36.5% the RebiSmart (n=31/85), and 5% the ExtaviPro device (n=4/85); 2% did not answer (n=2/85). CONCLUSION: In this survey, the Betaconnect device was the preferred autoinjector and may currently best meet patients' needs. As it was closest to participants' opinion of an ideal device, the Betaconnect might contribute to treatment adherence. Our results need to be confirmed in further studies. PMID- 28831242 TI - Modeling the human Nav1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade. AB - Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel's selectivity filters to reach the channel's central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed "state-of-the-art" steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure-property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel. PMID- 28831244 TI - Antibiotic use for pneumonia among children under-five at a pediatric hospital in Dhaka city, Bangladesh. AB - BACKGROUND: Pneumonia has been the leading cause of morbidity and mortality among children under 5 for more than 3 decades, particularly in low-income countries like Bangladesh. The World Health Organization (WHO) developed a pneumonia case management strategy which included the use of antibiotics for both primary and hospital-based care. This study aims to describe antibiotic usage for treating pneumonia in children in a private pediatric teaching hospital in Dhaka, Bangladesh. METHODS: We conducted this cross-sectional study among children <5 years old who were admitted to a private pediatric hospital in Dhaka with a diagnosis of pneumonia in November 2012. RESULTS: We enrolled 80 children during the study period. Among them, 28 (35.4%) were underweight, 14 (17.7%) were moderately underweight, and 13 (16.5%) were severely under-weight. On the basis of WHO classification (2005), 43 children (54%) had severe pneumonia and 37 (46%) had very severe pneumonia, as diagnosed by the research physician. Among the prescribed antibiotics in the hospital, parenteral ceftriaxone was the most common 40 (50%), followed by cefotaxime plus amikacin 14 (17.5%), cefuroxime 7 (8.8%), ceftazidime plus amikacin 6 (7.5%), ceftriaxone plus amikacin 3 (3.8%), meropenem 2 (2.5%), cefepime 2 (2.5%), and cefotaxime 2 (2.5%). CONCLUSION: Despite the WHO pneumonia treatment strategy, the inappropriate use of higher generation cephalosporin and carbapenem was high in the study hospital. The results underscore the noncompliance with the WHO guidelines of antibiotic use and the importance of enforcing regulatory policy of the rational use of antibiotics for treating hospitalized children with pneumonia. Following these guidelines may help prevent increased antimicrobial resistance. PMID- 28831245 TI - Medication adherence has an impact on disease activity in rheumatoid arthritis: a systematic review and meta-analysis. AB - OBJECTIVE: Disease activity of rheumatoid arthritis (RA) patients was often measured by the 28-joint count disease activity score (DAS-28), which consists of 28 swollen and tender joint counts, patient's assessment of disease activity (visual analog scale [VAS]) and erythrocyte sedimentation rate. C-reactive protein was also used to measure disease activity in RA patients. The aim was to explore the impact of medication adherence on disease activity in patients with RA. METHODS: A systematic search was performed in major electronic databases (PubMed, Web of Science, the Cochrane Library, CNKI, VIP and Wan fang) to identify studies reporting medication adherence and disease activity in RA patients. Results were expressed as mean difference (MD) and 95% CI. RESULTS: A total of seven identified studies matched the inclusion criteria, reporting on a total of 1,963 adult RA patients in the analysis. The total score of DAS-28 was significantly lower in adherent patients than in nonadherent subjects (MD =-0.42, 95% CI [-0.80, -0.03], P=0.03). Similarly, a significant difference was observed between medication adherent and nonadherent groups in erythrocyte sedimentation rate (MD =-7.39, 95% CI [-11.69, -3.08], P<0.01) and tender joint count (MD = 1.29, 95% CI [-2.51, -0.06], P=0.04). Interestingly, the results of the meta analysis showed no significant difference between medication adherent and nonadherent patients in swollen joint count (MD =-0.16, 95% CI [-2.13, 1.80], P=0.87), visual analog scale (MD =1.41, 95% CI [-3.68, 6.50], P=0.59) and C reactive protein (MD =0.35, 95% CI [-0.64, 1.34], P=0.49). CONCLUSION: The study suggests that RA patients with higher medication adherence tended to have lower disease activity. PMID- 28831246 TI - General quality of life of patients with acne vulgaris before and after performing selected cosmetological treatments. AB - BACKGROUND: Achieving a satisfying quality of life for a patient by applying individually matched therapy is, simultaneously, a great challenge and a priority for contemporary medicine. Patients with visible dermatological ailments are particularly susceptible to reduction in the general quality of life. Among the dermatological diseases, acne causes considerable reduction in the quality of life and changes in self-perception that lead to the worsening of a patient's mental condition, including depression and suicidal thoughts. As a result, difficulties in contact with loved ones, as well as social and professional problems are observed, which show that acne is not a somatic problem alone. To a large extent, it becomes a part of psychodermatology, becoming an important topic of public health in social medicine practice. Pharmacological treatment of acne is a challenge for a dermatologist and often requires the necessity of cooperating with a cosmetologist. Cosmetological treatments are aimed at improving the condition of the skin and reduction or subsiding of acne skin changes. AIM: The aim of this study was to assess the influence of selected cosmetological treatments on the general quality of life of patients with acne. MATERIALS AND METHODS: The study group consisted of 101 women aged 19-29 years ([Formula: see text] years, SD =2.3 years). All subjects were diagnosed with acne vulgaris of the face. In the study group, the acne changes occurred over the course of 3-15 years ([Formula: see text] years, SD =2.7 years). Selected cosmetological treatments (intensive pulsing light, alpha-hydroxy acids, cavitation peeling, needle-free mesotherapy, diamond microdermabrasion and sonophoresis) were performed in series in the number depending on the particular patient's chosen treatment, after excluding contraindications. General quality of life of the patients was estimated using the Skindex-29 and Dermatology Life Quality Index (DLQI) questionnaires, before and after the cosmetological treatment. RESULTS: Statistical analysis of the data obtained from the Skindex-29 questionnaire in areas (emotions, symptoms and physical functioning) and DLQI questionnaire in areas (daily activities, leisure, work and school, personal relations and treatment) showed great improvement in the general quality of life after applying a series of cosmetological treatments. The results are statistically relevant at P<0.0001. CONCLUSION: The cosmetological treatment significantly improved the general quality of life of patients with acne vulgaris and their skin condition, which was evaluated by the Hellgren-Vincent scale. It was proven that therapy performed in cosmetological clinics may become an integral part of or complete dermatological treatment. PMID- 28831247 TI - Validity of physician-diagnosed COPD in relation to spirometric definitions of COPD in a general population aged 50-64 years - the SCAPIS pilot study. AB - BACKGROUND: In epidemiological studies, items about physician-diagnosed COPD are often used. There is a lack of validation and standardization of these items. MATERIALS AND METHODS: In a general population-based study, 1,050 subjects completed a questionnaire and performed spirometry, including forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) after inhalation of 400 ug of salbutamol. COPD was defined as the ratio of FEV1/FVC <0.7 after bronchodilation. Physician-diagnosed COPD was defined as an affirmative answer to the single item: "Have you ever had COPD diagnosed by a physician?", physician diagnosed COPD/emphysema as an affirmative answer to any of the two single items; "Have you ever had COPD diagnosed by a physician?" or "Have you ever been told by a physician that you have emphysema?", physician-diagnosed chronic bronchitis as an affirmative answer to; "Have you ever been told by a physician that you have chronic bronchitis?" and physician-diagnosed COPD, emphysema or chronic bronchitis was defined as an affirmative answer to either of the three items above. RESULTS: For the single item about physician-diagnosed COPD, the sensitivity was around 0.11 and the specificity was almost 0.99 in relation to COPD. The sensitivity of the combined items about COPD/emphysema in detecting COPD was 0.11 and the specificity was high, 0.985. When the items about physician diagnosed COPD, emphysema or chronic bronchitis were merged as one entity, the sensitivity went up (0.13) and the specificity went down (0.95). CONCLUSION: Items about physician-diagnosed COPD have low sensitivity but a very high specificity, indicating that these items will minimize the proportion of false positives. The low sensitivity will underestimate the total burden of COPD in the general population. Items about physician-diagnosed COPD may be used in studies of risk factors for COPD, but are not recommended in prevalence studies. PMID- 28831248 TI - Hand grip strength and chronic obstructive pulmonary disease in Korea: an analysis in KNHANES VI. AB - BACKGROUND: Muscle mass is known to be associated with mortality in elderly adults. Because hand grip strength (HGS) is known as a simple assessment tool for muscular strength, many researchers have studied the association between HGS and disease. However, empirical evidence for the relationship between chronic obstructive pulmonary disease (COPD) and HGS is still controversial. The aim of this study was to evaluate the association between COPD and HGS, using Korean population data. METHODS: This was a population-based cross-sectional study. Data were obtained from the sixth Korean National Health and Nutrition Examination Survey, which was conducted from 2013 to 2015. To reduce the effects of HGS related factors and potential confounding factors, propensity score matching was used to match subjects with and without COPD. RESULTS: Among 14,930 subjects, 832 were enrolled in each group (non-COPD and COPD) after propensity score matching. COPD subjects did not have lower HGS than non-COPD subjects (non-COPD vs COPD, male, 38.0+/-7.0 vs 38.9+/-7.0 kg, P=0.044, female, 23.8+/-4.6 vs 24.2+/-4.9 kg, P=0.342). Lung function was classified by Global Initiative for Chronic Obstructive Lung Disease stages and was not significantly associated with HGS. For male COPD subjects, there was a significant correlation between HGS and the EuroQol Five-Dimension Questionnaire (EQ5D) utility score index, which is an indicator of quality of life that adjusts for age and body mass index (r=0.201, P<0.001). The correlation was absent for female subjects (r=0.098, P=0.170). CONCLUSION: COPD subjects did not have lower HGS than non-COPD subjects. HGS did not associate with lung function. However, the HGS of male COPD subjects was positively associated with EQ5D utility score index, an indicator of quality of life. HGS may be helpful as an additional method to the evaluation of quality of life in male COPD patients. PMID- 28831249 TI - Multicenter study of the COPD-6 screening device: feasible for early detection of chronic obstructive pulmonary disease in primary care? AB - BACKGROUND AND AIM: Early detection of COPD may reduce the future burden of the disease. We aimed to investigate whether prescreening with a COPD-6 screening device (measuring FEV1 and FEV6) facilitates early detection of COPD in primary care. METHODS: In primary care, individuals at high risk of COPD (ie, age >=35 years, relevant exposure, and at least one respiratory symptom) and no previous diagnosis of obstructive lung disease were examined with a COPD-6 screening device. In prioritized order, the criteria for proceeding to confirmatory spirometry were FEV1/FEV6 <0.7, FEV1 <80%pred, or clinical suspicion of COPD regardless of test result (medical doctor's [MD] decision). Based on spirometry, including bronchodilator (BD) reversibility test, individuals were classified as COPD (post-BD FEV1/FVC <0.70), asthma (DeltaFEV1 >=0.50 L), or no obstructive lung disease. RESULTS: A total of 2,990 subjects (54% men, mean age 59 years, and mean 28 pack-years) were enrolled, of whom 949 (32%) proceeded from COPD-6 screening to confirmative spirometry based on the following criteria: 510 (54%) FEV1/FEV6 <0.70, 382 (40%) FEV1 <80%pred, and 57 (6%) MD decision. Following confirmative spirometry, the 949 individuals were diagnosed as having COPD (51%), asthma (3%), and no obstructive lung disease (45%). COPD was diagnosed in 487 (16%) of the enrolled subjects in whom confirmative spirometry was performed in 69% based on FEV1/FEV6 <0.7 and in 29% based on FEV1 <=80%pred. CONCLUSION: Prescreening with the COPD-6 device showed acceptable specificity for the selection of subjects for diagnostic spirometry and is likely to be a useful alternative to current practice in primary care. PMID- 28831250 TI - An evaluation of activity tolerance, patient-reported outcomes and satisfaction with the effectiveness of pulmonary daoyin on patients with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Pulmonary Daoyin (PD) (evolved from ancient Chinese daoyin skills), is a rehabilitation technology that combines specially designed movements of the arms and body and controlled breathing exercises, to improve the physiological and psychological status of patients with chronic respiratory disease. Pulmonary rehabilitation is effective for patients with chronic obstructive pulmonary disease (COPD), and the efficacy of PD is unknown. The aim of this study is to investigate the effect of a PD program in enhancing activity tolerance, patient-reported outcomes and satisfaction with the effectiveness on patients with COPD. MATERIALS AND METHODS: The multi-center, randomized controlled trial was conducted from November 2011 to June 2012 in local communities in cities of the 11 research centers in China. It included COPD patients (moderate to very severe) who were recruited from an outpatient clinic. A randomized controlled study included 464 COPD patients who were randomly allocated either to the PD group, participating in a 3-month, ten times-weekly supervised PD-based pulmonary rehabilitation program, or to a control group continuing with regular medical treatment alone. Data were gathered using the 6 minute walking distance (6MWD) test, COPD patient-reported outcomes (COPD-PRO) and Effectiveness Satisfaction Questionnaire for COPD (ESQ-COPD), which was filled out at baseline and 3 months post-intervention. SAS 9.2 was used for statistical analysis. RESULTS: Of the 464 patients in the study, 461 were included in the full analysis set (FAS); 429 were in the per-protocol analysis set (PPS). After 3-month intervention, there was a significant difference between the two groups in 6MWD (FAS; P=0.049; PPS; P=0.041), total score and all domains of COPD-PRO (FAS; P=0.014; PPS; P=0.003) and ESQ-COPD (FAS; P=0.038; PPS; P<0.001). CONCLUSIONS: The PD program was able to improve the activity tolerance level and satisfaction of COPD patients because of its effectiveness. PMID- 28831251 TI - PDGF-metronidazole-encapsulated nanofibrous functional layers on collagen membrane promote alveolar ridge regeneration. AB - This study aimed to develop a functionally graded membrane (FGM) to prevent infection and promote tissue regeneration. Poly(l-lactide-co-d,l-lactide) encapsulating platelet-derived growth factor (PDLLA-PDGF) or metronidazole (PDLLA MTZ) was electrospun to form a nanofibrous layer on the inner or outer surface of a clinically available collagen membrane, respectively. The membrane was characterized for the morphology, molecule release profile, in vitro and in vivo biocompatibility, and preclinical efficiency for alveolar ridge regeneration. The PDLLA-MTZ and PDLLA-PDGF nanofibers were 800-900 nm in diameter, and the thicknesses of the functional layers were 20-30 MUm, with sustained molecule release over 28 days. All of the membranes tested were compatible with cell survival in vitro and showed good tissue integration with minimal fibrous capsule formation or inflammation. Cell proliferation was especially prominent on the PDLLA-PDGF layer in vivo. On the alveolar ridge, all FGMs reduced wound dehiscence compared with the control collagen membrane, and the FGM with PDLLA PDGF promoted osteogenesis significantly. In conclusion, the FGMs with PDLLA-PDGF and PDLLA-MTZ showed high biocompatibility and facilitated wound healing compared with conventional membrane, and the FGM with PDLLA-PDGF enhanced alveolar ridge regeneration in vivo. The design represents a beneficial modification, which may be easily adapted for future clinical use. PMID- 28831252 TI - Preparation, characterization, and transfection efficiency of low molecular weight polyethylenimine-based nanoparticles for delivery of the plasmid encoding CD200 gene. AB - Various strategies have been utilized to improve both gene transfer efficiency and cell-induced toxicity of polyethylenimine (PEI), the most extensively investigated cationic polymeric vector. In this study, we sought to enhance transfection efficiency of low molecular weight PEI (LMW PEI) while maintaining its low toxicity by cross-linking LMW PEI via succinic acid linker. These modifications were designed to improve the hydrophilic-hydrophobic balance of the polymer, by enhancing the buffering capacity and maintaining low cytotoxic effects of the final conjugate. Decreased expression of CD200 in the central nervous system has been considered as one of the proposed mechanisms associated with neuroinflammation in multiple sclerosis; therefore, we selected plasmid encoding CD200 gene for transfection using the modified PEI derivatives. Dynamic light scattering experiments demonstrated that the modified PEIs were able to condense plasmid DNA and form polyplexes with a size of approximately 130 nm. The highest level of CD200 expression was achieved at a carrier to plasmid ratio of 8, where the expression level was increased by 1.5 fold in the SH-SY5Y cell line, an in vitro model of neurodegenerative disorders. Furthermore, the results of in vivo imaging of the LMW PEI-based nanoparticles in the mouse model of multiple sclerosis revealed that fluorescently labeled plasmid encoding CD200 was distributed from the injection site to various tissues and organs including lymph nodes, liver, brain, and finally, kidneys. The nanoparticles also showed the ability to cross the blood-brain barrier and enter the periventricular area. PMID- 28831253 TI - Endocytotic uptake of HPMA-based polymers by different cancer cells: impact of extracellular acidosis and hypoxia. AB - BACKGROUND: Polymeric nanoparticles allow to selectively transport chemotherapeutic drugs to the tumor tissue. These nanocarriers have to be taken up into the cells to release the drug. In addition, tumors often show pathological metabolic characteristics (hypoxia and acidosis) which might affect the polymer endocytosis. MATERIALS AND METHODS: Six different N-(2 hydroxypropyl)methacrylamide (HPMA)-based polymer structures (homopolymer as well as random and block copolymers with lauryl methacrylate containing hydrophobic side chains) varying in molecular weight and size were analyzed in two different tumor models. The cellular uptake of fluorescence-labeled polymers was measured under hypoxic (pO2 ~1.5 mmHg) and acidic (pH 6.6) conditions. By using specific inhibitors, different endocytotic routes (macropinocytosis and clathrin-mediated, dynamin-dependent, cholesterol-dependent endocytosis) were analyzed separately. RESULTS: The current results revealed that the polymer uptake depends on the molecular structure, molecular weight and tumor line used. In AT1 cells, the uptake of random copolymer was five times stronger than the homopolymer, whereas in Walker-256 cells, the uptake of all polymers was much stronger, but this was independent of the molecular structure and size. Acidosis increased the uptake of random copolymer in AT1 cells but reduced the intracellular accumulation of homopolymer and block copolymer. Hypoxia reduced the uptake of all polymers in Walker-256 cells. Hydrophilic polymers (homopolymer and block copolymer) were taken up by all endocytotic routes studied, whereas the more lipophilic random copolymer seemed to be taken up preferentially by cholesterol- and dynamin dependent endocytosis. CONCLUSION: The study indicates that numerous parameters of the polymer (structure, size) and of the tumor (perfusion, vascular permeability, pH, pO2) modulate drug delivery, which makes it difficult to select the appropriate polymer for the individual patient. PMID- 28831254 TI - Development of a novel microemulsion for oral absorption enhancement of all-trans retinoic acid. AB - This study was aimed to develop a novel microemulsion that contained oleth-5 as a surfactant to enhance the oral absorption of all-trans retinoic acid (ATRA). The prepared microemulsion was evaluated for its particle size, shape, zeta potential, in vitro release, in vitro intestinal absorption, intestinal membrane cytotoxicity and stability. The obtained microemulsion was spherical in shape with a particle size of <200 nm and a negative surface charge. The in vitro release of the ATRA-loaded microemulsion was best fit with the zero-order model. This microemulsion significantly improved the intestinal absorption of ATRA. Confocal laser scanning microscopy analysis using a fluorescent dye-loaded microemulsion also confirmed the intestinal absorption result. The intestinal membrane cytotoxicity of the ATRA-loaded microemulsion did not differ from an edible oil (fish oil). Stability testing showed that the ATRA-loaded microemulsion was more stable at 25 degrees C than 40 degrees C. PMID- 28831255 TI - Stratum corneum lipid liposome-encapsulated panomycocin: preparation, characterization, and the determination of antimycotic efficacy against Candida spp. isolated from patients with vulvovaginitis in an in vitro human vaginal epithelium tissue model. AB - In this study, a liposomal lyophilized powder formulation of panomycocin was developed for therapeutic purposes against vulvovaginal candidiasis which affects 80% of women worldwide. Panomycocin is a potent antimycotic protein secreted by the yeast Wickerhamomyces anomalus NCYC 434. This study involved the preparation of panomycocin-loaded stratum corneum lipid liposomes (SCLLs), characterization of the SCLLs, and determination of antimycotic efficacy of the formulation against Candida albicans and Candida glabrata clinical vaginal isolates in a human vaginal epithelium tissue model. The encapsulation and loading efficiencies of SCLLs were 73% and 76.8%, respectively. In transmission electron microscopy images, the SCLLs appeared in the submicron size range. Dynamic light scattering analyses showed that the SCLLs had uniform size distribution. Zeta potential measurements revealed stable and positively charged SCLLs. In Fourier transform infrared spectroscopy analyses, no irreversible interactions between the encapsulated panomycocin and the SCLLs were detected. The SCLLs retained >98% of encapsulated panomycocin in aqueous solution up to 12 hours. The formulation was fungicidal at the same minimum fungicidal concentration values for non-formulated pure panomycocin when tested on an in vitro model of vaginal candidiasis. This is the first study in which SCLLs and a protein as an active ingredient have been utilized together in a formulation. The results obtained in this study led us to conduct further preclinical trials of this formulation for the development of an effective topical anti-candidal drug with improved safety. PMID- 28831256 TI - Comorbidity of schizophrenia and social phobia - impact on quality of life, hope, and personality traits: a cross sectional study. AB - OBJECTIVE: The purpose of the study was to explore whether the comorbidity of social phobia affects symptoms severity, positive and negative symptoms, self stigma, hope, and quality of life in patients with schizophrenia spectrum disorders. METHODS: This is a cross-sectional study in which all participants completed the Internalized Stigma of Mental Illness (ISMI) scale, Adult Dispositional Hope Scale (ADHS), Liebowitz Social Anxiety Scale (LSAS), Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), Positive and Negative Syndrome Scale (PANSS), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Temperament and Character Inventory - Revised (TCI-R), and the demographic questionnaire. The disorder severity was assessed both by a psychiatrist (Clinical Global Impression Severity - the objective version [objCGI S] scale) and by the patients (Clinical Global Impression Severity - the subjective version [subjCGI-S] scale). The patients were in a stabilized state that did not require changes in the treatment. Diagnosis of schizophrenia, schizoaffective disorder, or delusional disorder was determined according to the International Classification of Diseases 10th Revision (ICD-10) research criteria. A structured interview by Mini International Neuropsychiatric Interview was used to confirm the diagnosis. RESULTS: The study included 61 patients of both genders. Clinically, the patients with comorbid social phobia had the earlier onset of the illness, more severe current psychopathology, more intense anxiety (general and social), and higher severity of depressive symptoms. The patients with comorbid social phobia showed the significantly lower quality of life compared to the patients without this comorbidity. The patients with comorbid social phobia also had a statistically lower mean level of hope and experienced a higher rate of the self-stigma. They also exhibited higher average scores of personality trait harm avoidance (HA) and a lower score of personality trait self-directedness (SD). CONCLUSION: The study demonstrated differences in demographic factors, the severity of the disorder, self-stigma, hope, HA, and SD between patients with schizophrenia spectrum disorders with and without comorbid social phobia. PMID- 28831257 TI - Encephalitis with reversible splenial and deep cerebral white matter lesions associated with Epstein-Barr virus infection in adults. AB - BACKGROUND: Approximately 200 cases of mild encephalitis with reversible splenial (MERS) and deep cerebral white matter lesions have been reported since MERS was first defined in 2004. MERS occurs more frequently in children; in adults, only ~60 cases have been reported. Until now, only four cases of MERS in adults have been associated with Epstein-Barr virus (EBV). CASE PRESENTATION: We report three adult cases of MERS associated with EBV infection in China. For all three patients, cranial magnetic resonance imaging (MRI) indicated solitary reversible splenial and/or perilateral ventricle white matter lesions with reduced diffusion. In the present report, all patients were adults presenting with high fever, headache, apathy, and confusion, as well as significant signs of meningeal inflammation. These symptoms peaked 10-14 days after disease onset, with serious hyponatremia (112-129 mmol/L), an elevated cerebrospinal fluid white blood cell count (80-380/mm3), and significantly increased protein levels (1,010-1,650 mg/dL). Cranial MRI indicated abnormal signal intensity in the splenium of corpus callosum and symmetrically reversible lesions scattered in the thalamus and deep cerebral white matter. The clinical symptoms tended to improve after ~10-14 days of antiviral treatment. However, these patients recovered more slowly than patients with viral meningitis. CONCLUSION: MERS associated with EBV infection in adults occurs less frequently but with more severe symptoms than in children. EBV infection should be considered for patients with MERS symptoms. MERS has a good prognosis. PMID- 28831259 TI - An observational study of duloxetine versus SSRI monotherapy for the treatment of painful physical symptoms in Japanese patients with major depressive disorder: primary analysis. AB - OBJECTIVE: The objective of this study was to assess the effectiveness of duloxetine monotherapy, in comparison with selective serotonin reuptake inhibitor (SSRI) monotherapy, in the treatment of painful physical symptoms (PPS) in Japanese patients with major depressive disorder (MDD) in real-world clinical settings. METHODS: This was a multicenter, 12-week prospective, observational study. This study enrolled MDD patients with at least moderate PPS, defined as a Brief Pain Inventory-Short Form (BPI-SF) average pain score (item 5) >=3. Patients were treated with duloxetine or SSRIs (escitalopram, sertraline, paroxetine, or fluvoxamine) for 12 weeks, and PPS were assessed by BPI-SF average pain score. The primary outcome was early improvement in the BPI-SF average pain score at 4 weeks post-baseline. RESULTS: A total of 523 patients were evaluated for treatment effectiveness (duloxetine N=273, SSRIs N=250). The difference in BPI-SF average pain score between the two groups was not statistically significant at 4 weeks post-baseline, the primary endpoint (least-squares mean change from baseline [95% confidence interval]: duloxetine, -2.8 [-3.1, -2.6]; SSRIs, -2.5 [-2.8, -2.3]; P=0.166). There was a numerical advantage for duloxetine in improvement from 4 to 12 weeks post-baseline, and the difference was statistically significant at 8 weeks post-baseline (least-squares mean change from baseline [95% confidence interval]: duloxetine, -3.6 [-3.9, -3.3]; SSRIs, 3.1 [-3.4, -2.8]; P=0.023). The 30% and 50% responder rates were significantly higher in patients treated with duloxetine at 4 and 8 weeks post-baseline. There were no serious adverse events experienced by duloxetine-treated patients. The rate of discontinuations due to adverse events was similar for duloxetine and the SSRIs (1.0% and 0.8% of patients, respectively). CONCLUSION: In this observational study, BPI-SF improvement was not significantly different at 4 weeks, the primary endpoint; however, patients treated with duloxetine tended to show better improvement in PPS compared to those treated with SSRIs. PMID- 28831258 TI - Which psychological, psychophysiological, and anthropometric factors are connected with life events, depression, and quality of life in patients with cardiovascular disease. AB - OBJECTIVE: The aim of the study was to determine psychological, psychophysiological, and anthropometric factors connected with life events, level of depression, and quality of life in people at risk for cardiovascular disease and healthy controls. METHODS: This is a cross-sectional study involving arterial hypertension patients and healthy controls. There were several measurements including physical, anthropological, cardiovascular, and psychophysiological measurements and administration of questionnaires. RESULTS: A total of 99 participants were recruited for this study, 54 healthy controls (mean age: 35.59+/-13.39 years) and 45 patients with cardiovascular disease (CVD) (mean age: 46.33+/-12.39 years). The healthy controls and the patients with CVD significantly differed in the mean total score of life events, level of depression, quality of life score, temperature, blood pressure (BP), pulse transit time, heart rate, high-frequency total power, heart rate variability total power, waist-to-height ratio (WHtR), body fat percentage, fat control, pulse wave velocity, and augmentation index. In healthy subjects, the total score of the life events was not correlated with any cardiovascular or anthropometric factor. A score of depression significantly correlated with the WHtR, augmentation index, body fat percentage, and fat control. The quality of life - visual scale correlated with the body temperature, BP, and percentage of body fat. In the group of the patients with CVD, the score of the life events did not correlate with any measured cardiovascular or anthropometric factor. The level of depression correlated with the augmentation index. The quality of life - visual scale significantly correlated with body temperature, WHtR, and fat control. CONCLUSION: The patients with CVD reported higher scores of life events, worse quality of life, and a greater level of depressive symptoms than healthy controls. In healthy controls, a higher mean total score of life events significantly negatively correlated with high-frequency total power, and the degree of depression correlated with being overweight. In patients with CVD, a score of depression was linked to being overweight. PMID- 28831260 TI - An observational study of duloxetine versus SSRI monotherapy in Japanese patients with major depressive disorder: subgroup analyses of treatment effectiveness for pain, depressive symptoms, and quality of life. AB - OBJECTIVE: To examine how clinical and demographic patient baseline characteristics influence effectiveness of duloxetine versus selective serotonin reuptake inhibitor (SSRI) treatment, in real-world Japanese clinical settings of patients with major depressive disorder (MDD) and associated painful physical symptoms (PPS). METHODS: This was a multicenter, 12-week, prospective, observational study in patients with MDD (Quick Inventory of Depressive Symptomatology >=16) and at least moderate PPS (Brief Pain Inventory-Short Form [BPI-SF] average pain >=3). Patients received duloxetine or SSRIs (escitalopram, sertraline, paroxetine, or fluvoxamine). Assessments were made by using BPI-SF average pain, 17-item Hamilton Rating Scale for Depression (HAM-D17), EuroQol 5 dimension questionnaire, Social Adaptation Self-Evaluation Scale, Global Assessment of Functioning, and ability to work. Predefined subgroups included the number of previous episodes of depression (0 vs >=1), baseline BPI-SF average pain score (<=6 vs >6), baseline HAM-D17 total score (<=18 vs >18), baseline HAM D17 retardation (<=7 vs >7) and anxiety somatic subscale scores (<=6 vs >6), and age (<65 vs >=65 years). RESULTS: Treatment effectiveness was evaluated in 523 patients (duloxetine N=273, SSRIs N=250). Treatment with duloxetine was superior to SSRIs on most outcome measures in patients experiencing their first depressive episode, those with higher baseline PPS levels, and in patients with more severe baseline depression. This was also the case for older patients. In patients with less severe depression, SSRI treatment tended to show more improvements in depression and quality of life measures versus duloxetine treatment. CONCLUSION: These preplanned subgroup analyses of data from a prospective observational study suggest that, for Japanese MDD patients with PPS, duloxetine is more effective than SSRIs in patients with a first episode of MDD, with more severe depression, or more severe PPS. PMID- 28831261 TI - Real-world use of PCSK-9 inhibitors by early adopters: cardiovascular risk factors, statin co-treatment, and short-term adherence in routine clinical practice. AB - BACKGROUND: Inconsistency of real-world medication use with labeled indications may affect cost and clinical value of pharmacotherapy. PCSK-9 inhibitors are labeled in the US for use with statins to reduce low-density lipoprotein cholesterol in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH). OBJECTIVE: To assess consistency with labeled indications and treatment persistency for early (first 5 post-launch months) adopters of PCSK-9 inhibitor pharmacotherapy. METHODS: Retrospective analysis of commercially insured cohorts derived from the Truven Health MarketScan(r) database was performed. Subjects were aged 18-64 years, initiated PCSK-9 inhibitor or highest-intensity statin (rosuvastatin 40 mg/day or atorvastatin 80 mg/day) pharmacotherapy from August to December 2015, and were enrolled throughout 2015 and during separate baseline (pre-treatment) periods of 6 and 18 months. Baseline ASCVD, FH, and ASCVD events (myocardial infarction, transient ischemic attack, and cerebrovascular occlusion) were measured. Persistency was measured through December 2015 for subcohorts of patients initiating treatment from August to September 2015. RESULTS: Baseline disease rates were higher for patients treated with PCSK-9 inhibitors (n=390) compared with highest-intensity statins (n=26,306): ASCVD (68.5% vs 33.4%, respectively); FH (39.7% vs 15.5%); both P<0.001. In 18 months pre-treatment, 35.6% of PCSK-9 inhibitor-treated patients had >=1 ASCVD event, and 87.9% had a labeled indication. Rates of 60-day nonpersistency for PCSK-9 inhibitors and highest-intensity statins were 33.3% and 39.8%, respectively (P=0.207). During PCSK-9 inhibitor pharmacotherapy, 33.8% of patients had evidence of statin supply and, of those initiating treatment from August to September, 40.9% filled >=1 statin prescription. Of those with sustained pre-treatment statin use, 34.8% had no statin supply during PCSK-9 inhibitor pharmacotherapy. CONCLUSION: Among early-adopting PCSK-9 inhibitor treated patients, the off-label diagnosis rate was 12%; a majority lacked statin co-treatment; and one third filled prescriptions for <=60 days. Inconsistency with labeled uses may reflect prescriber/patient decisions, health-insurance coverage determinations, or statin intolerance not reported on claims. PMID- 28831262 TI - Predictive value of respiratory symptoms for the diagnosis of pollen-induced seasonal asthma among children and adults in Inner Mongolia. AB - BACKGROUND: The diagnosis of asthma is made on the basis of variable respiratory symptoms and supported by objective evidence of variable airflow limitation. However, spirometry and bronchoprovocation tests may not be routinely available in resource-scarce settings or in the context of large-scale epidemiological studies. There is a gap in knowledge about the predictive value of respiratory symptoms for the diagnosis of pollen-induced asthma. OBJECTIVE: The aim of this study was to investigate the predictive value of self-reported respiratory symptoms for diagnosing pollen-induced asthma. PATIENTS AND METHODS: We recruited 1,161 patients with respiratory symptoms who presented to the respiratory medicine outpatient clinic of two central hospitals in Inner Mongolia during the pollen season of July-September 2015. All patients were interviewed by a respiratory physician and completed a questionnaire survey, lung function tests and skin prick tests for common inhaled allergens. RESULTS: A total of 392 patients (33.8%) were diagnosed with asthma and 292 (25.2%, 160 adults, 132 children) with pollen-induced asthma. Respiratory symptoms of cough, wheezing, dyspnea, chest pain and nocturnal awakenings due to breathlessness were all associated with increased odds of being diagnosed with pollen-induced asthma, with cough being the most common symptom in both adults and children, giving a sensitivity of 90.6% in adults and 88.6% in children. Wheezing was the most specific symptom (78% and 89.5% in adults and children, respectively) compared to other symptoms. Overall, the positive predictive value of respiratory symptoms was poor for diagnosing pollen-induced asthma, with the exception of wheezing in children which had a high positive predictive value of 72.7%. CONCLUSION: Cough was the predominant symptom in adults and children with pollen-induced asthma. Wheezing was a reliable predictor of pollen-induced asthma in children. In adults, respiratory symptoms were not sufficiently reliable for diagnosing pollen induced asthma. PMID- 28831263 TI - Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance. AB - Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment and outcomes of chronic myeloid leukemia (CML). Despite their significant impact on the management of CML, there is growing evidence that TKIs may cause cardiovascular and/or metabolic complications. In this review, we present the current evidence regarding the cardiovascular safety profiles of BCR-ABL TKIs. Methodological challenges of studies that reported the cardiovascular safety of TKIs are discussed. We also propose management strategies for cardiovascular surveillance and risk factor modification during treatment with these agents. PMID- 28831264 TI - microRNA-130a is an oncomir suppressing the expression of CRMP4 in gastric cancer. AB - Gastric cancer is one of the most common causes of death worldwide, although its incidence has steadily declined in recent years. There is strong evidence that aberrantly expressed microRNAs (miRNAs) are involved in gastric cancer tumorigenesis. Furthermore, CRMP4 is closely associated with the occurrence and development of gastric cancer, and our predictions suggest that miR-130a, which can promote gastric cancer tumorigenesis, is a potential CRMP4 regulator. In this study, we investigated the expression of CRMP4 and miR-130a in human gastric cancer cell lines by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) examination and direct interactions between miR 130a and CRMP4 by dual-luciferase reporter assay. We also evaluated the biological roles of miR-130a and CRMP4 in gastric cancer cells by flow cytometry, MTT assay, soft agar colony formation assay, and Transwell tests and confirmed CRMP4 function in vivo, using a tumor xenograft model. Our results demonstrated that CRMP4 expression was significantly decreased at both the gene and protein levels, while miR-130a expression was notably increased, in five human gastric cancer cell lines compared with human gastric epithelial cells. Dual-luciferase reporter assays indicated that CRMP4 was the direct target of miR-130a. Moreover, an inverse regulatory relationship between miR-130a and CRMP4 was verified by qRT PCR and WB, and overexpression of miR-130a in BGC823 cells enhanced apoptosis and cell proliferation, arrested the cell cycle in G0/G1, and facilitated cell colony formation, invasion, migration, and adhesion, while upregulation of CRMP4 had opposite effects. Finally, the growth and weight of transplanted tumors derived from BGC823 cells in which CRMP4 was knocked down were remarkably reduced. These data indicate that miR-130a is an oncomir targeting CRMP4 and could be developed as a potential prognostic factor and a novel therapeutic target in gastric cancer. PMID- 28831265 TI - Clinicopathological and prognostic significance of circulating tumor cells in patients with head and neck cancer: a meta-analysis. AB - BACKGROUND: Many studies have assessed the clinical use of circulating tumor cells (CTCs) in head and neck cancer, but the clinicopathological and prognostic significance of CTCs is still unclear. MATERIALS AND METHODS: Two authors systematically searched the studies independently with keywords in PubMed, MEDLINE, EMBASE, Science Citation Index Expanded and Cochrane Library (from inception to February 2017). The estimated hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were set as effect measures. All analyses were performed by STATA 12.0. RESULTS: A total of 17 studies were included in this meta-analysis. Positive CTCs were significantly associated with poor overall survival (HR =2.80, 95% CI: 1.34-5.86), disease-free survival (HR =3.86, 95% CI: 2.03-7.36) and progression-free survival (HR =3.31, 95% CI: 1.71 6.42). CTC-positive patients tend to have higher recurrence (RR =2.13, 95% CI: 1.26-3.59) and regional lymph node metastasis (RR =1.18, 95% CI: 1.02-1.36) rate and a more advanced tumor stage (RR =1.16, 95% CI: 1.03-1.32). CONCLUSION: Our meta-analysis has confirmed the significant prognostic value of CTCs in head and neck cancer patients. The presence of CTCs could be used as a monitoring tool for tumor status of head and neck cancer, especially for the early detection of the tumor recurrence and progression, advanced disease and the node metastasis. PMID- 28831266 TI - Prognosis of neutrophil-to-lymphocyte ratio in clinical early-stage tongue (cT1/T2N0) cancer. AB - BACKGROUND: Inflammation plays a role in the development of cancer. This study aims to analyze the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and other clinicopathological determinants in early-stage (cT1/T2N0) tongue cancer. MATERIALS AND METHODS: A total of 262 patients were selected from our institute's cancer database between 2004 and 2011. Optimal cutoff value of NLR and lymph node density (LND) were determined statistically using receiver operating characteristic curve analysis for survival prediction. The 5-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) rates were estimated using the Kaplan-Meier method. RESULTS: The results showed that, in this cohort, the optimal cutoff value of NLR was 2.95 and for LND, it was 0.031. Patients with NLR >=2.95 correlated significantly with positive N classification (P=0.011), T2 classification (P=0.007), positive perineural invasion (P<0.001), and a tumor thickness of >5 mm (P=0.005). The 5 year OS among patients with NLR <2.95 was much higher than that in patients with NLR >=2.95 (P<0.001). Similarly, the 5-year DSS among patients with NLR <2.95 was much higher than that in patients with NLR >=2.95 (P=0.002). The 5-year DFS among patients with NLR <2.95 was much higher than that in patients with NLR >=2.95 (P=0.004). The 5-year OS, DSS, and DFS were significantly reduced among patients with LND >0.031 compared to those with LND <0.031, respectively. In multivariate analysis, NLR, LND, and tumor thickness were independent prognostic factors for OS. CONCLUSION: Pretreatment NLR >=2.95 is significantly correlated with a larger tumor, positive neck lymph node metastasis, and positive perineural invasion. Importantly, it indicates reduced survival rate. Therefore, if the NLR >=2.95 in early-stage (cT1/T2N0) tongue cancer is noted preoperatively, it reveals more invasive tumor behavior clinically. Then, aggressive treatments, including elective neck dissection, become necessary. PMID- 28831268 TI - A prospective study of the association between sickle cell disease and hepatobiliary effects in Bahrain. AB - BACKGROUND: Sickle cell disease is a genetic disorder that leads to abnormally high levels of hemoglobin sickling in erythrocytes. Patients suffer debilitating and severe complications that affect multiple organs, though mainly the liver, gallbladder, spleen, bones, and kidneys. It has a significant impact on morbidity and mortality rates and is associated with substantial health care costs. METHODS: For this study, the researchers prospectively reviewed the charts of 154 sickle cell disease patients who had been treated in Salmaniya Medical Complex hospital in Bahrain between September 2013 and December 2014. RESULTS: The results obtained showed that 95% of patients had sickle cell hemoglobin type. Of the sample patients, 80% exhibited bone pain, with all patients exhibiting bone crisis. Biochemical tests revealed reduced hemoglobin concentration, elevated bilirubin, compromised liver function, and lower white blood cell counts. The incidence of hepatitis B and C was very low, at 0% and 9%, respectively. There were a large number of hospital admissions, with 11 days as an average length of stay. The most common ultrasound findings in this study were hepatomegaly, hepatosplenomegaly, cholelithiasis, gallbladder sludge, and splenomegaly. CONCLUSION: Sickle cell disease had profound negative effects on multiple organs, with a particularly large number of complications related to the hepatobiliary system. PMID- 28831267 TI - Bystander signaling via oxidative metabolism. AB - The radiation-induced bystander effect (RIBE) is the initiation of biological end points in cells (bystander cells) that are not directly traversed by an incident radiation track, but are in close proximity to cells that are receiving the radiation. RIBE has been indicted of causing DNA damage via oxidative stress, besides causing direct damage, inducing tumorigenesis, producing micronuclei, and causing apoptosis. RIBE is regulated by signaling proteins that are either endogenous or secreted by cells as a means of communication between cells, and can activate intracellular or intercellular oxidative metabolism that can further trigger signaling pathways of inflammation. Bystander signals can pass through gap junctions in attached cell lines, while the suspended cell lines transmit these signals via hormones and soluble proteins. This review provides the background information on how reactive oxygen species (ROS) act as bystander signals. Although ROS have a very short half-life and have a nanometer-scale sphere of influence, the wide variety of ROS produced via various sources can exert a cumulative effect, not only in forming DNA adducts but also setting up signaling pathways of inflammation, apoptosis, cell-cycle arrest, aging, and even tumorigenesis. This review outlines the sources of the bystander effect linked to ROS in a cell, and provides methods of investigation for researchers who would like to pursue this field of science. PMID- 28831269 TI - Sex differences in complex regional pain syndrome type I (CRPS-I) in mice. AB - BACKGROUND: Sex differences have been increasingly highlighted in complex regional pain syndrome (CRPS) in clinical practice. In CRPS type I (CRPS-I), although inflammation and oxidative stress have been implicated in its pathogenesis, whether pain behavior and the underlying mechanism are sex-specific is unclear. In the present study, we sought to explore whether sex differences have an impact on inflammation, oxidative stress, and pain sensitivity in CRPS-I. METHODS: Chronic post-ischemia pain (CPIP) was established in both male and female mice as an animal model of CRPS-I. Edema and mechanical allodynia of bilateral hind paws were assessed after reperfusion. Blood samples were analyzed for serum levels of oxidative stress markers and inflammatory cytokines. RESULTS: Both male and female mice developed edema. Male mice developed CPIP at day 3 after reperfusion; female mice developed CPIP at day 2 after reperfusion. Female mice displayed significantly earlier and higher mechanical allodynia in the ischemic hind paw, which was associated with higher serum levels of IL-2, TNF alpha, isoprostanes, 8 OhdG, and malondialdehyde at day 2 after reperfusion. Moreover, female mice showed significantly lower SOD and IL-4 compared to male mice at day 2 after reperfusion. CONCLUSION: Our results indicate that sex differences in inflammatory and oxidative stress states may play a central role in the sex-specific nociceptive hypersensitivity in CRPS-I, and offer a new insight into pharmacology treatments to improve pain management with CRPS. PMID- 28831270 TI - Effects of vicarious pain on self-pain perception: investigating the role of awareness. AB - The observation of pain in others may enhance or reduce self-pain, yet the boundary conditions and factors that determine the direction of such effects are poorly understood. The current study set out to show that visual stimulus awareness plays a crucial role in determining whether vicarious pain primarily activates behavioral defense systems that enhance pain sensitivity and stimulate withdrawal or appetitive systems that attenuate pain sensitivity and stimulate approach. We employed a mixed factorial design with the between-subject factors exposure time (subliminal vs optimal) and vicarious pain (pain vs no pain images), and the within-subject factor session (baseline vs trial) to investigate how visual awareness of vicarious pain images affects subsequent self-pain in the cold-pressor test. Self-pain tolerance, intensity and unpleasantness were evaluated in a sample of 77 healthy participants. Results revealed significant interactions of exposure time and vicarious pain in all three dependent measures. In the presence of visual awareness (optimal condition), vicarious pain compared to no-pain elicited overall enhanced self-pain sensitivity, indexed by reduced pain tolerance and enhanced ratings of pain intensity and unpleasantness. Conversely, in the absence of visual awareness (subliminal condition), vicarious pain evoked decreased self-pain intensity and unpleasantness while pain tolerance remained unaffected. These findings suggest that the activation of defense mechanisms by vicarious pain depends on relatively elaborate cognitive processes, while - strikingly - the appetitive system is activated in highly automatic manner independent from stimulus awareness. Such mechanisms may have evolved to facilitate empathic, protective approach responses toward suffering individuals, ensuring survival of the protective social group. PMID- 28831271 TI - A systematic review of sex differences in the placebo and the nocebo effect. AB - OBJECTIVES: The present review investigated whether there are systematic sex differences in the placebo and the nocebo effect. METHODS: A literature search was conducted in multiple electronic databases. Studies were included if the study compared a group or condition where a placebo was administered to a natural history group or similar cohort. RESULTS: Eighteen studies were identified - 12 on placebo effects and 6 on nocebo effects. Chi-square tests revealed that 1) males responded more strongly to placebo treatment, and females responded more strongly to nocebo treatment, and 2) males responded with larger placebo effects induced by verbal information, and females responded with larger nocebo effects induced by conditioning procedures. CONCLUSION: This review indicates that there are sex differences in the placebo and nocebo effects, probably caused by sex differences in stress, anxiety, and the endogenous opioid system. PMID- 28831272 TI - Pain reporting and analgesia management in 270 children with a progressive neurologic, metabolic or chromosomally based condition with impairment of the central nervous system: cross-sectional, baseline results from an observational, longitudinal study. AB - Little is known about the prevalence, characterization and treatment of pain in children with progressive neurologic, metabolic or chromosomal conditions with impairment of the central nervous system. The primary aims of this study were to explore the differences between parental and clinical pain reporting in children with life-limiting conditions at the time of enrollment into an observational, longitudinal study and to determine if differences in pain experiences were associated with patient- or treatment-related factors. Pain was common, under recognized and undertreated among the 270 children who enrolled into the "Charting the Territory" study. Children identified by their parents as experiencing pain (n=149, 55%) were older, had more comorbidities such as dyspnea/feeding difficulties, were less mobile with lower functional skills and used analgesic medications more often, compared to pain-free children. Forty-one percent of children with parent-reported pain (21.8% of all patients) experienced pain most of the time. The majority of clinicians (60%) did not document pain assessment or analgesic treatment in the medical records of patients who were experiencing pain. Documentation of pain in the medical record was positively correlated with children receiving palliative care services and being prescribed analgesics, such as acetaminophen, nonsteroidal anti-inflammatory drugs and opioids, as well as the adjuvant analgesics gabapentin and amitriptyline. PMID- 28831273 TI - Oncological safety and cosmetic outcomes in oncoplastic breast conservation surgery, a review of the best level of evidence literature. AB - Oncoplastic breast conservation surgery (OBCS) is increasingly becoming part of routine breast cancer surgical management. OBCS may be viewed as an extension of standard breast conservation surgery for resecting tumors of larger sizes without compromising on cosmetic outcome, or as an alternative to mastectomy. High quality evidence to support the oncological safety and benefits of OBCS is lacking. This review will focus on the best available level of evidence and address key issues regarding oncological safety in OBCS, such as tumor resection margins and re-excision rates, local recurrence and patient outcome, postoperative complications and adjuvant therapy delivery, and briefly discuss cosmetic outcome in OBCS. Comparative observational studies and systematic review report no poorer outcomes compared with standard breast conservation surgery. More evidence needs to be generated to support the oncological safety and improved aesthetic outcome. Prospective data collection will significantly contribute to the generation of stronger evidence. PMID- 28831274 TI - Biomechanical paradigm and interpretation of female pelvic floor conditions before a treatment. AB - BACKGROUND: Further progress in restoring a woman's health may be possible if a patient with a damaged pelvic floor could undergo medical imaging and biomechanical diagnostic tests. The results of such tests could contribute to the analysis of multiple treatment options and suggest the optimal one for that patient. AIM: To develop a new approach for the biomechanical characterization of vaginal conditions, muscles, and connective tissues in the female pelvic floor. METHODS: Vaginal tactile imaging (VTI) allows biomechanical assessment of the soft tissue along the entire length of the anterior, posterior, and lateral vaginal walls at rest, with manually applied deflection pressures and with muscle contraction, muscle relaxation, and Valsalva maneuver. VTI allows a large body of measurements to evaluate individual variations in tissue elasticity, support defects, as well as pelvic muscle function. Presuming that 1) the female pelvic floor organs are suspended by ligaments against which muscles contract to open or close the outlets and 2) damaged ligaments weaken the support and may reduce the force of muscle contraction, we made an attempt to characterize multiple pelvic floor structures from VTI data. RESULTS: All of the 138 women enrolled in the study were successfully examined with the VTI. The study subjects have had normal pelvic support or pelvic organ prolapse (stages I-IV). The average age of this group of subjects was 60+/-15 years. We transposed a set of 31 VTI parameters into a quantitative characterization of pelvic muscles and ligamentous structures. Interpretation of the acquired VTI data for normal pelvic floor support and prolapse conditions is proposed based on biomechanical assessment of the functional anatomy. CONCLUSION: Vaginal tactile imaging allows biomechanical characterization of female pelvic floor structures and tissues in vivo, which may help to optimize treatment of the diseased conditions such as prolapse, incontinence, atrophy, and some forms of pelvic pain. PMID- 28831275 TI - Beneficiaries of conflict: a qualitative study of people's trust in the private health care system in Mogadishu, Somalia. AB - BACKGROUND: In 2005, the World Health Conference called for all nations to move toward universal health coverage, which is defined as "access to adequate health care for all at an affordable price". Despite this, an estimated 90% of Somalia's largely impoverished population use private health care. Therefore, considering that the private health care system is the dominant health care system in Mogadishu, Somalia, exploring the accessibility to, as well as people's trust in, the private sector is essential to help contribute an equitable and affordable health care system in the country. METHODS: A qualitative study using unstructured interviews was conducted in Mogadishu from August to November of 2016. A purposive sampling approach was used to recruit 23 participants, including seven medical doctors who own private health centers, eight patients, five medical students and three senior officials who work for the Ministry of Health. Data were analyzed using a thematic analysis. RESULTS: Our findings show that the private health care system in Mogadishu is not only unregulated but also expensive, with the cost of health care often unaffordable for the majority of the country's citizens. There is evidence of prescription of inappropriate treatment, tendency to conduct unnecessary laboratory tests, excessive use of higher diagnostic technologies and overcharging - including the widespread practice of further appointments for follow-up - which inflates the costs. The study also found poor patient-provider relationship and widespread distrust of the private health care system. CONCLUSION: The study findings underline the need for the Somali government to develop regulatory mechanisms and guidelines with the potential to guide the private health care sector to provide equitable and affordable health care to people in Mogadishu. The doctor-patient relationship has been - and remains - a keystone of care; thus, there is an urgent need for guidelines for private health care providers to treat their patients with dignity and respect. The education system, particularly the syllabus used by medical faculties, should be reviewed and improved to provide medical students with necessary knowledge, skills and attitudes to maintain patient dignity and rights. PMID- 28831276 TI - Hematologic abnormalities and associated factors among HIV infected children pre- and post-antiretroviral treatment, North West Ethiopia. AB - INTRODUCTION: There are few studies on the hematologic parameters of HIV-infected individuals in Ethiopia; of these, almost all studies researched adults. Our current study is unique in that it mainly focused on the pediatric population and compared both pre- and post-antiretroviral therapy (ART) children. Inference from this study can be used for other developing countries where the burden of HIV disease is high. OBJECTIVE: The aim of this study was to identify hematologic abnormalities in HIV-infected children before and after initiation of ART. METHODOLOGY: A cross-sectional study was conducted on HIV-infected children from June 1 to August 30, 2015. Data were collected using a pretested and structured questionnaire. Statistical analysis was performed using SPSS 20 version. RESULTS: The median age of study subjects was 10 years with an interquartile range (IQR) of (6, 12). Two-thirds (74.3%) of study subjects received ART for >1 year. The median of CD4 count before ART was 490 cells/mm3 with an IQR of (286, 765); this increased to 663 cells mm3 with an IQR of (499, 908) after ART. Likewise, the median of hemoglobin before ART was 11.5 mg/dL with an IQR of (9.9, 13), which increased after ART to 13 mg/dL with an IQR of (11.8, 14). The prevalence of anemia was 42.8% before and 18.9% after ART initiation. The median of absolute neutrophil count before ART was 3*103 with an IQR of (2.1, 4.6) and after ART, it became 3*103 with IQR of (1.9, 4.2). Age <5 years (adjusted odds ratio [AOR]: 2.76; 95% CI: 1.5, 5.0), an advanced stage of AIDS (AOR: 2.8; 95% CI: 1.4, 5.6) and CD4% <25% (AOR: 2.4; 95% CI: 1.2, 4.9) were significantly associated with anemia before ART initiation, while opportunistic infections were associated with anemia after initiation of ART (AOR: 2.3; 95% CI: 1.08, 4.8). CONCLUSION: ART positively or negatively affects the hematologic profile of HIV-infected children. The current study demonstrated a significant reduction of anemia after initiation of ART. PMID- 28831277 TI - Changing opinions about research by Saudi medical students. AB - OBJECTIVE: The objective of this study was to investigate and compare the opinions and attitudes of medical students toward medical research in five Saudi universities and examine the changes observed in these opinions and attitudes in one of these universities over a period of time. METHODS: This is a cross sectional study conducted among medical students in five Saudi universities. This study was based on a survey undertaken in 2015. The survey consisted of five questions inquiring about the opinions and attitudes of medical students toward medical research. The same survey was carried out 8 years earlier in one of these universities (King Abdulaziz University [KAU]), and the results obtained during the two periods (2007 and 2015) were compared. RESULTS: A convenient sample of 924 students was selected from five Saudi universities. Ninety-five (10.3%) of the medical students were not aware of the usefulness and importance scientific research will have on their future careers. A total of 409 (44.3%) stated that they had no knowledge on how to conduct scientific research. On the other hand, a vast majority of medical students (98.1%) expressed a willingness and interest to participate in scientific research if provided with an opportunity. The percentage of students from KAU strongly agreeing to participate in research rose from 33.1% in 2007 to 81.5% in 2015 (P=0.001). Of all the students surveyed, 431 (46.6%) had participated in scientific research as undergraduates. CONCLUSION: Most students in five Saudi universities expressed enthusiasm for participating in a research project, but only a few of them had sufficient knowledge on basic research. There was considerable improvement in students' perception of research in KAU when comparing their responses in 2007 to those in 2015. PMID- 28831278 TI - Opioid Prescribing Practices and Training Needs of Quebec Family Physicians for Chronic Noncancer Pain. AB - AIM: To examine medical practices and training needs of Quebec family physicians with respect to pain management and opioid prescription for chronic noncancer pain (CNCP). METHODOLOGY: An online survey was carried out in 2016. RESULTS: Of 636 respondents (43.0% men; 54.3% >= 50 years old), 15.2% and 70.9% felt very or somewhat confident that they could properly prescribe opioids for CNCP. Concerns related to abuse (72.5% strongly/somewhat agree), dependence (73.2%), and lack of support (75.4%) were the main barriers reported. Only 19.7% always/often screened their patients for risks of abuse and dependence using a screening tool. About two-thirds of participants (65.7%) had recently (last five years) taken part in continuing education programs on opioid use for CNCP and 73.4% on CNCP management. Patient evaluation and differential diagnoses of chronic pain syndromes were rated as a top priority for further training. CONCLUSIONS: This study provides insights into Quebec family physicians' concerns, practices, and needs with respect to the management of CNCP. Physicians' difficulties around the application of strategies to mitigate the problem of opioid abuse and addiction are worrying. The need to better train physicians in the field of pain and addiction cannot be emphasized enough. PMID- 28831279 TI - Setup uncertainties and PTV margins at different anatomical levels in intensity modulated radiotherapy for nasopharyngeal cancer. AB - AIM: To determine the systematic error (?), random error (sigma) and derive PTV margin at different levels of the target volumes in Nasopharyngeal Cancer (NPC). MATERIALS AND METHODS: A retrospective offline review was done for patients who underwent IMRT for NPC from June 2015 to May 2016 at our institution. Alternate day kV images were matched with digitally reconstructed radiographs to know the setup errors. All radiographs were matched at three levels - the clivus, third cervical (C3) and sixth cervical (C6) vertebra. The shifts in positions along the vertical, longitudinal and lateral axes were noted and the ? and sigma at three levels were calculated. PTV margins were derived using van Herk's formula. RESULTS: Twenty patients and 300 pairs of orthogonal portal films were reviewed. The ? for the clivus, C3 and C6 along vertical, longitudinal and lateral directions were 1.6 vs. 1.8 vs. 2 mm; 1.2 vs. 1.4 vs. 1.4 mm and 0.9 vs. 1.6 and 2.3 mm, respectively. Similarly, the random errors were 1.1 vs. 1.4 vs. 1.8 mm; 1.1 vs. 1.2 vs. 1.2 mm and 1.2 vs. 1.3 vs. 1.6 mm. The PTV margin at the clivus was 4.4 mm along the vertical, 4 mm along the longitudinal direction and 3.2 m in the lateral direction. At the C3 level, it was 5.5 mm in the vertical, 5 mm in the lateral direction and 4.4 mm in the longitudinal direction. At the C6 level, it was 6.4 mm in the vertical, 6.9 mm in the lateral direction and 4.4 mm in the longitudinal direction. CONCLUSION: A differential margin along different levels of target may be necessary to adequately cover the target. PMID- 28831280 TI - Malignant pleural mesothelioma - Pleural cavity irradiation after decortication with helical tomotherapy. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive disease that poses a treatment challenge in spite of recent technical developments. The aim of this retrospective analysis is to assess the feasibility of administering intensity-modulated radiotherapy (IMRT) to the pleural cavity using helical tomotherapy in patients who had undergone pleurectomy/decortication (P/D) and also the resulting toxicity levels. PATIENTS AND METHODS: Ten patients who had MPM and had undergone P/D were treated with pleural cavity irradiation that included a median dose of 52.2 Gy using helical tomotherapy. The median age of the patients was 53 years (31-74). In addition to clinical and diagnostic findings from regular follow-up examinations, we evaluated the dose distribution for other organs at risk to assess treatment in relation to toxicity, with special regard for the underlying intact lung. RESULTS: The mean lung dose on the treatment site was 32.8 Gy (+/-6.8). The V20 Gy was 71.7% (+/-17.2). No treatment related toxicity that exceeded grade III according to common toxicity criteria (CTC) was observed. Median progression-free survival (PFS) was 13 months with a median overall survival (OAS) of 19 months. CONCLUSION: The findings of this analysis provide data indicating that sparing the underlying lung in patients with MPM after P/D is not only feasible with helical tomotherapy, but that this treatment also causes reasonably few side effects. PMID- 28831282 TI - Gamma-Glutamyl Transpeptidase-to-Platelet Ratio Predicts Significant Liver Fibrosis of Chronic Hepatitis B Patients in China. AB - BACKGROUND AND AIMS: We want to investigate whether a novel noninvasive marker is suitable for Chinese CHB patients. METHODS: A total of 160 treatment-naive CHB patients who underwent liver biopsy were enrolled in our study, and we assessed the diagnostic accuracies of GPR, aspartate transaminase-to-platelet ratio index (APRI), and the fibrosis index based on 4 factors (FIB-4) in them. RESULTS: Of these 160 CHB patients, the numbers of F0, F1, F2, F3, and F4 are 34 (21.3%), 62 (38.8%), 18 (11.3%), 24 (15%), and 22 (13.8%), respectively. The area under the receiver operating characteristic curves (AUROC) of GPR for fibrosis (0.77 versus 0.70, P = 0.03), significant fibrosis (0.70 versus 0.63, P = 0.02), and extensive fibrosis (0.71 versus 0.64, P = 0.02) were significantly higher than those of APRI. The AUROCs of GPR and Fib-4 for fibrosis (0.77 versus 0.75, P = 0.14), significant fibrosis (0.70 versus 0.70, P = 0.22), extensive fibrosis (0.71 versus 0.68, P = 0.13), and cirrhosis (0.64 versus 0.67, P = 0.24) were comparable. CONCLUSIONS: The GPR can be a routine laboratory marker to stage liver fibrosis in patients with CHB in China. PMID- 28831281 TI - Improving radiation oncology through clinical audits: Introducing the IROCA project. AB - As radiotherapy practice and processes become more complex, the need to assure quality control becomes ever greater. At present, no international consensus exists with regards to the optimal quality control indicators for radiotherapy; moreover, few clinical audits have been conducted in the field of radiotherapy. The present article describes the aims and current status of the international IROCA "Improving Radiation Oncology Through Clinical Audits" project. The project has several important aims, including the selection of key quality indicators, the design and implementation of an international audit, and the harmonization of key aspects of radiotherapy processes among participating institutions. The primary aim is to improve the processes that directly impact clinical outcomes for patients. The experience gained from this initiative may serve as the basis for an internationally accepted clinical audit model for radiotherapy. PMID- 28831283 TI - In Vitro Dissolution Profile of Dapagliflozin: Development, Method Validation, and Analysis of Commercial Tablets. AB - Dapagliflozin was the first of its class (inhibitors of sodium-glucose cotransporter) to be approved in Europe, USA, and Brazil. As the drug was recently approved, there is the need for research on analytical methods, including dissolution studies for the quality evaluation and assurance of tablets. The dissolution methodology was developed with apparatus II (paddle) in 900 mL of medium (simulated gastric fluid, pH 1.2), temperature set at 37 +/- 0.5 degrees C, and stirring speed of 50 rpm. For the quantification, a spectrophotometric (lambda = 224 nm) method was developed and validated. In validation studies, the method proved to be specific and linear in the range from 0.5 to 15 MUg.mL-1 (r2 = 0.998). The precision showed results with RSD values lower than 2%. The recovery of 80.72, 98.47, and 119.41% proved the accuracy of the method. Through a systematic approach by applying Factorial 23, the robustness of the method was confirmed (p > 0.05). The studies of commercial tablets containing 5 or 10 mg demonstrated that they could be considered similar through f1, f2, and dissolution efficiency analyses. Also, the developed method can be used for the quality evaluation of dapagliflozin tablets and can be considered as a scientific basis for future official pharmacopoeial methods. PMID- 28831284 TI - Effect of Isopropyl Alcohol Concentration and Etching Time on Wet Chemical Anisotropic Etching of Low-Resistivity Crystalline Silicon Wafer. AB - A micropyramid structure was formed on the surface of a monocrystalline silicon wafer (100) using a wet chemical anisotropic etching technique. The main objective was to evaluate the performance of the etchant based on the silicon surface reflectance. Different isopropyl alcohol (IPA) volume concentrations (2, 4, 6, 8, and 10%) and different etching times (10, 20, 30, 40, and 50 min) were selected to study the total reflectance of silicon wafers. The other parameters such as NaOH concentration (12% wt.), the temperature of the solution (81.5 degrees C), and range of stirrer speeds (400 rpm) were kept constant for all processes. The surface morphology of the wafer was analyzed by optical microscopy and atomic force microscopy (AFM). The AFM images confirmed a well-uniform pyramidal structure with various average pyramid sizes ranging from 1 to 1.6 MUm. A UV-Vis spectrophotometer with integrating sphere was used to obtain the total reflectivity. The textured silicon wafers show high absorbance in the visible region. The optimum texture-etching parameters were found to be 4-6% vol. IPA and 40 min at which the average total reflectance of the silicon wafer was reduced to 11.22%. PMID- 28831285 TI - Prevalence of Bacterial Vaginosis and Associated Risk Factors among Women Complaining of Genital Tract Infection. AB - BACKGROUND: Bacterial vaginosis is a global concern due to the increased risk of acquisition of sexually transmitted infections. OBJECTIVES: To determine the prevalence of bacterial vaginosis and bacteria causing aerobic vaginitis. METHODS: A cross-sectional study was conducted among 210 patients between September 2015 and July 2016 at St. Paul's Hospital. Gram-stained vaginal swabs were examined microscopically and graded as per Nugent's procedure. Bacteria causing aerobic vaginitis were characterized, and their antimicrobial susceptibility pattern was determined. RESULTS: The overall prevalence of bacterial vaginosis was 48.6%. Bacterial vaginosis was significantly associated with number of pants used per day (p = 0.001) and frequency of vaginal bathing (p = 0.045). Of 151 bacterial isolates, 69.5% were Gram-negative and 30.5% were Gram positive bacteria. The overall drug resistance level of Gram-positive bacteria was high against penicillin, tetracycline, and erythromycin. Cefoxitin and tobramycin were the most active drugs against Gram-positive bacteria. The overall drug resistance level of Gram-negative bacteria was high against tetracycline, ampicillin, and amoxicillin. Amikacin and tobramycin were the most active drugs against Gram-negative bacteria. CONCLUSIONS: The prevalence of bacterial vaginosis was high and was affected by individual hygiene. Routine culture of vaginal samples should be performed on patients with vaginitis and the drug susceptibility pattern of each isolate should be determined. PMID- 28831286 TI - Standardized Kaempferia parviflora Extract Inhibits Intrinsic Aging Process in Human Dermal Fibroblasts and Hairless Mice by Inhibiting Cellular Senescence and Mitochondrial Dysfunction. AB - Intrinsic skin aging is a complex biological phenomenon mainly caused by cellular senescence and mitochondrial dysfunction. This study evaluated the inhibitory effect of Kaempferia parviflora Wall ex. Baker ethanol extract (KPE) on H2O2 stimulated cellular senescence and mitochondrial dysfunction both in vitro and in vivo. KPE significantly increased cell growth and suppressed senescence associated beta-galactosidase activation. KPE inhibited the expression of cell cycle inhibitors (p53, p21, p16, and pRb) and stimulated the expression of cell cycle activators (E2F1 and E2F2). H2O2-induced hyperactivation of the phosphatidylinositol 3-kinase/protein kinase B (AKT) signaling pathway was suppressed by KPE through regulated expression of forkhead box O3a (FoxO3a) and mammalian target of rapamycin (mTOR). KPE attenuated inflammatory mediators (interleukin-6 (IL-6), IL-8, nuclear factor kappa B (NF-kappaB), and cyclooxygenase-2 (COX-2)) and increased the mRNA expression of PGC-1alpha, ERRalpha, NRF1, and Tfam, which modulate mitochondrial biogenesis and function. Consequently, reduced ATP levels and increased ROS level were also reversed by KPE treatment. In hairless mice, KPE inhibited wrinkle formation, skin atrophy, and loss of elasticity by increasing the collagen and elastic fibers. The results indicate that KPE prevents intrinsic aging process in hairless mice by inhibiting cellular senescence and mitochondrial dysfunction, suggesting its potential as a natural antiaging agent. PMID- 28831287 TI - Extracts of Salvia-Nelumbinis Naturalis Ameliorate Nonalcoholic Steatohepatitis via Inhibiting Gut-Derived Endotoxin Mediated TLR4/NF-kappaB Activation. AB - Nonalcoholic steatohepatitis (NASH) is featured by the presence of hepatic steatosis combined with inflammation and hepatocellular injury. Gut-derived endotoxin plays a crucial role in the pathogenesis of NASH. Salvia-Nelumbinis naturalis (SNN), a formula of Traditional Chinese Medicine, has been identified to be effective for NASH, but the mechanisms were not thoroughly explored. In the present study, a NASH model was generated using C57BL/6 mice fed a high fat diet (HFD) supplemented periodically with dextran sulfate sodium (DSS) in drinking water for 12 weeks. Mice fed HFD alone (without DSS) or chow diet were used as controls. The NASH mice were given the SNN extracts in the following 4 weeks, while control mice were provided with saline. Mice fed HFD developed steatosis, and DSS supplementation resulted in NASH. The SNN extracts significantly improved metabolic disorders including obesity, dyslipidemia, and liver steatosis and reduced hepatic inflammation, circulating tumor necrosis factor-alpha (TNF alpha), and lipopolysaccharide (LPS) levels. The beneficial effect of the SNN extracts was associated with restoration of intestinal conditions (microbiota, integrity of intestinal barrier) and inhibition of TLR4/NF-kappaB activation. These results suggest that the SNN extracts ameliorate NASH progression, possibly through blocking endotoxin related TLR4/NF-kappaB activation. PMID- 28831288 TI - Uncertain Associations of Major Bleeding and Concurrent Use of Antiplatelet Agents and Chinese Medications: A Nested Case-Crossover Study. AB - Despite the evidence that some commonly used Chinese medications (CMs) have antiplatelet/anticoagulant effects, many patients still used antiplatelets combined with CMs. We conducted a nested case-crossover study to examine the associations between the concomitant use of antiplatelets and CMs and major bleeding using population-based health database in Taiwan. Among the cohort of 79,463 outpatients prescribed antiplatelets (e.g., aspirin and clopidogrel) continuously, 1,209 patients hospitalized with new occurring bleeding in 2012 and 2013 were included. Those recruited patients served as their own controls to compare different times of exposure to prespecified CMs (e.g., Asian ginseng and dong quai) and antiplatelet agents. The periods of case, control 1, and control 2 were defined as 1-4 weeks, 6-9 weeks, and 13-16 weeks before hospitalization, respectively. Conditional logistic regression analyses found that concurrent use of antiplatelet drugs with any of the prespecified CMs in the case period might not significantly increase the risks of bleeding over that in the control periods (OR = 1.00, 95% CI 0.51 to 1.95 and OR = 1.13, 95% CI 0.65 to 1.97). The study showed no strong relationships between hospitalization for major bleeding events and concurrent use of antiplatelet drugs with the prespecified CMs. PMID- 28831289 TI - Probing for Sparse and Fast Variable Selection with Model-Based Boosting. AB - We present a new variable selection method based on model-based gradient boosting and randomly permuted variables. Model-based boosting is a tool to fit a statistical model while performing variable selection at the same time. A drawback of the fitting lies in the need of multiple model fits on slightly altered data (e.g., cross-validation or bootstrap) to find the optimal number of boosting iterations and prevent overfitting. In our proposed approach, we augment the data set with randomly permuted versions of the true variables, so-called shadow variables, and stop the stepwise fitting as soon as such a variable would be added to the model. This allows variable selection in a single fit of the model without requiring further parameter tuning. We show that our probing approach can compete with state-of-the-art selection methods like stability selection in a high-dimensional classification benchmark and apply it on three gene expression data sets. PMID- 28831290 TI - An Update on Statistical Boosting in Biomedicine. AB - Statistical boosting algorithms have triggered a lot of research during the last decade. They combine a powerful machine learning approach with classical statistical modelling, offering various practical advantages like automated variable selection and implicit regularization of effect estimates. They are extremely flexible, as the underlying base-learners (regression functions defining the type of effect for the explanatory variables) can be combined with any kind of loss function (target function to be optimized, defining the type of regression setting). In this review article, we highlight the most recent methodological developments on statistical boosting regarding variable selection, functional regression, and advanced time-to-event modelling. Additionally, we provide a short overview on relevant applications of statistical boosting in biomedicine. PMID- 28831291 TI - Numerical simulation of a compound capsule in a constricted microchannel. AB - Simulations of the passage of eukaryotic cells through a constricted channel aid in studying the properties of cancer cells and their transport in the bloodstream. Compound capsules, which explicitly model the outer cell membrane and nuclear lamina, have the potential to improve computational model fidelity. However, general simulations of compound capsules transiting a constricted microchannel have not been conducted and the influence of the compound capsule model on computational performance is not well known. In this study, we extend a parallel hemodynamics application to simulate the fluid-structure interaction between compound capsules and fluid. With this framework, we compare the deformation of simple and compound capsules in constricted microchannels, and explore how deformation depends on the capillary number and on the volume fraction of the inner membrane. The computational framework's parallel performance in this setting is evaluated and future development lessons are discussed. PMID- 28831292 TI - Effect of Emodin on Preventing Postoperative Intra-Abdominal Adhesion Formation. AB - BACKGROUND: Postoperative intra-abdominal adhesions are a major complication after abdominal surgery. Although various methods have been used to prevent and treat adhesions, the effects have not been satisfactory. Emodin, a naturally occurring anthraquinone derivative and an active ingredient in traditional Chinese herbs, exhibits a variety of pharmacological effects. In our study, we demonstrated the effect of emodin treatment on preventing postoperative adhesion formation. MATERIALS AND METHODS: A total of 48 rats were divided into six groups. Abdominal adhesions were created by abrasion of the cecum and its opposite abdominal wall. In the experimental groups, the rats were administered daily oral doses of emodin. On the seventh day after operation, the rats were euthanized, and blood and pathological specimens were collected. Abdominal adhesion formation was evaluated by necropsy, pathology, immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay analyses. RESULTS: Abdominal adhesions were markedly reduced by emodin treatment. Compared with the control group, collagen deposition was reduced and the peritoneal mesothelial completeness rate was higher in the emodin-treated groups. Emodin had anti inflammatory effects, reduced oxidative stress, and promoted the movement of the intestinal tract (P < 0.05). CONCLUSION: Emodin significantly reduced intra abdominal adhesion formation in a rat model. PMID- 28831293 TI - 3-Hydroxykynurenine and 3-Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture. AB - Copper is an integral component of various enzymes, necessary for mitochondrial respiration and other biological functions. Excess copper is related with neurodegenerative diseases as Alzheimer and is able to modify cellular redox environment, influencing its functions, signaling, and catabolic pathways. Tryptophan degradation through kynurenine pathway produces some metabolites with redox properties as 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3 HANA). The imbalance in their production is related with some neuropathologies, where the common factors are oxidative stress, inflammation, and cell death. This study evaluated the effect of these kynurenines on the copper toxicity in astrocyte cultures. It assessed the CuSO4 effect, alone and in combination with 3 HK or 3-HANA on MTT reduction, ROS production, mitochondrial membrane potential (MMP), GHS levels, and cell viability in primary cultured astrocytes. Also, the chelating copper effect of 3-HK and 3-HANA was evaluated. The results showed that CuSO4 decreased MTT reduction, MMP, and GSH levels while ROS production and cell death are increasing. Coincubation with 3-HK and 3-HANA enhances the toxic effect of copper in all the markers tested except in ROS production, which was abolished by these kynurenines. Data suggest that 3-HK and 3-HANA increased copper toxicity in an independent manner to ROS production. PMID- 28831295 TI - Corrigendum to "Macroautophagy and Selective Mitophagy Ameliorate Chondrogenic Differentiation Potential in Adipose Stem Cells of Equine Metabolic Syndrome: New Findings in the Field of Progenitor Cells Differentiation". AB - [This corrects the article DOI: 10.1155/2016/3718468.]. PMID- 28831294 TI - Ameliorative Effect of Daidzein on Cisplatin-Induced Nephrotoxicity in Mice via Modulation of Inflammation, Oxidative Stress, and Cell Death. AB - Oxidative stress and inflammation are part and parcel of cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of soy isoflavone constituent, daidzein, in cisplatin-induced renal damage. Cisplatin-induced nephrotoxicity was evident by the histological damage in proximal tubular cells and by the increase in serum neutrophil gelatinase-associated lipocalin (NGAL), blood urea nitrogen (BUN), creatinine, and urinary kidney injury molecule-1 (KIM 1). Cisplatin-induced cell death was shown by TUNEL staining and caspase-3/7 activity. Daidzin treatment reduced all kidney injury markers (NGAL, BUN, creatinine, and KIM-1) and attenuated cell death (apoptotic markers). In cisplatin-induced kidney injury, renal oxidative/nitrative stress was manifested by the increase in lipid peroxidation and protein nitration. Cisplatin induced the reactive oxygen species-generating enzyme NOX-2 and impaired antioxidant defense enzyme activities such as glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities. Cisplatin-induced oxidative/nitrative stress was attenuated by daidzein treatment. Cisplatin induced CD11b-positive macrophages in kidneys and daidzein attenuated CD11b-positive cells. Daidzein attenuated cisplatin-induced inflammatory cytokines tumor necrosis factor alpha (TNFalpha), interleukin 10 (IL-10), interleukin 18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1). Daidzein attenuated cell death in vitro. Our data suggested that daidzein attenuated cisplatin-induced kidney injury through the downregulation of oxidative/nitrative stress, immune cells, inflammatory cytokines, and apoptotic cell death, thus improving kidney regeneration. PMID- 28831296 TI - Histopathological Changes in the Kidney following Congestive Heart Failure by Volume Overload in Rats. AB - BACKGROUND: This study investigated histopathological changes and apoptotic factors that may be involved in the renal damage caused by congestive heart failure in a rat model of infrarenal aortocaval fistula (ACF). METHODS: Heart failure was induced using a modified approach of ACF in male Wistar rats. Sham operated controls and ACF rats were characterized by their morphometric and hemodynamic parameters and investigated for their histopathological, ultrastructural, and apoptotic factor changes in the kidney. RESULTS: ACF-induced heart failure is associated with histopathological signs of congestion and glomerular and tubular atrophy, as well as nuclear and cellular degeneration in the kidney. In parallel, overexpression of proapoptotic Bax protein, release of cytochrome C from the outer mitochondrial membrane into cell cytoplasm, and nuclear transfer of activated caspase 3 indicate apoptotic events. This was confirmed by electron microscopic findings of apoptotic signs in the kidney such as swollen mitochondria and degenerated nuclei in renal tubular cells. CONCLUSIONS: This study provides morphological evidence of renal injury during heart failure which may be due to caspase-mediated apoptosis via overexpression of proapoptotic Bax protein, subsequent mitochondrial cytochrome C release, and final nuclear transfer of activated caspase 3, supporting the notion of a cardiorenal syndrome. PMID- 28831297 TI - Biomarkers of Aging: From Cellular Senescence to Age-Associated Diseases. PMID- 28831298 TI - Nationwide prevalence of Rickettsia felis infections in patients with febrile illness in Bangladesh. AB - From July 2015 to December 2016, the presence of rickettsial pathogens was investigated for 414 patients with unknown fever in eight places in all the divisions of Bangladesh. Rickettsia felis was identified in blood samples from all the regions (overall detection rate, 19.6%), suggesting nationwide prevalence of R. felis infections. PMID- 28831299 TI - West Nile virus meningitis in a patient with human immunodeficiency virus type 1 infection. AB - The emergence of West Nile virus lineage 2 in central Macedonia, Greece, in 2010 resulted in large outbreaks for 5 consecutive years. We report a case of viral meningitis in an individual infected with human immunodeficiency virus type 1, which preceded the recognition of the outbreak and was confirmed retrospectively as West Nile virus neuroinvasive disease. PMID- 28831300 TI - Description of 'Blautia phocaeensis' sp. nov. and 'Lachnoclostridium edouardi' sp. nov., isolated from healthy fresh stools of Saudi Arabia Bedouins by culturomics. AB - We report here the main characteristics of 'Blautia phocaeensis' strain Marseille P3441 sp. nov. and 'Lachnoclostridium edouardi' strain Marseille-P3397 sp. nov., that were isolated from a faecal specimen of a 42-year-old female Saudi Bedouin. We used a bacterial culturomics approach combined with taxono-genomics. PMID- 28831301 TI - 'Olsenella congonensis' sp.nov., identified in human stool sample. AB - We report the main characteristics of 'Olsenella congonensis' strain Marseille P3359T (CSUR P3359), which was isolated from the stool sample of a healthy 47 year-old pygmy female. PMID- 28831303 TI - Pseudoamblyopia in Congenital Cyclotropia. AB - PURPOSE: To study the effect of surgery on amblyopia and suppression associated with congenital cyclovertical strabismus. METHODS: The fixation pattern was investigated with microperimetry before and soon after surgery in ten consecutive children operated for congenital superior oblique palsy at the S. Martino Hospital, Belluno, Italy, between September 2014 and December 2015. Changes in visual performance in terms of best-corrected visual acuity (BCVA) and stereopsis between the day before and one week after surgery were also evaluated. No other amblyopia treatment has been administered during the time study. RESULTS: Surgical correction of the excyclodeviation in congenital SO palsy determined monocular and binocular sensory consequences: monocularly, in the cyclodeviated amblyopic eye, BCVA (0.46-0.03 LogMAR; p < 0.0001) and the fixation pattern improved, as demonstrated by microperimetry examination. Binocularly, stereopsis improved or emerged while suppression at the Worth four-dot test disappeared. CONCLUSIONS: In the absence of further amblyopic factors such as coexisting constant vertical and/or horizontal deviation and anisometropia, the amblyopia encountered in congenital SO palsy may resolve soon after the surgical alignment. Therefore, it may be considered and defined "pseudoamblyopia." PMID- 28831302 TI - Cutaneous infection and bactaeremia caused by Erwinia billingiae: a case report. AB - Cellulitis and erysipelas are common skin infections usually caused by Staphylococcus aureus and streptococci. Gram-negative rods are rarely implicated. We report here a case of dermohypodermitis and bactaeremia caused by Erwinia billingiae, a Gram-negative bacteria usually pathogenic and epiphytic to pome fruit tree. PMID- 28831304 TI - Novel Technique to Overcome the Nonavailability of a Long Needle 9-0 Polypropylene Suture for Sutured Scleral Fixation of the Posterior Chamber Intraocular Lens Using a Single Fisherman's Knot. AB - PURPOSE: To describe a method to overcome the nonavailability of a long needle 9 0 polypropylene suture for sutured scleral fixation of the posterior chamber intraocular lens (PC-IOL) using a single fisherman's knot (SFK). METHODS: First, a 10-0 polypropylene suture was passed from the sclera to the ciliary sulcus using a long needle. A 9-0 suture was tied to the unpassed portion of the 10-0 suture with an SFK. We pulled the 10-0 suture to pass the SFK through the sclera, and then we cut the knot and removed the 10-0 suture. IOL fixation with 9-0 sutures used the conventional techniques used for sutured scleral-fixated IOL. Preoperative and postoperative visual acuity, corneal astigmatism, and endothelial cell count and intraoperative/postoperative complications were evaluated. RESULTS: An SFK joining the two sutures was passed through the sclera without breakage or slippage. A total of 35 eyes from 35 patients who underwent sutured scleral fixation of the IOL. An intraoperative complication (minor intraocular hemorrhage) was recorded in four cases. Knot exposure, IOL dislocation, subluxation, and retinal detachment were not observed. CONCLUSIONS: The SFK offers the opportunity to use 9-0 sutures for the long-term safety and may not require the surgeon to learn any new technique. PMID- 28831305 TI - Changes in Ocular Surface Characteristics after Switching from Benzalkonium Chloride-Preserved Latanoprost to Preservative-Free Tafluprost or Benzalkonium Chloride-Preserved Tafluprost. AB - PURPOSE: The aim of the present study was to examine the effects of switching from Latanoprost ophthalmic solution containing a preservative to preservative free Tafluprost ophthalmic solution or Tafluprost containing a preservative on ocular surfaces. MATERIALS AND METHODS: Forty patients (40 eyes) with glaucoma (mean age: 62.0 +/- 10.9 years) using Latanoprost with preservative for six months or longer were assigned either to a Tafluprost-containing-preservative group (20 eyes) or preservative-free-Tafluprost group (20 eyes). The intraocular pressure, corneal epithelial barrier function (fluorescein uptake concentration with fluorophotometer FL-500), superficial punctate keratopathy (AD classification), and tear film breakup time (TBUT) were assessed before switching and at 12 weeks after switching. RESULTS: No significant differences in intraocular pressure were noted after switching in either group. Corneal epithelial barrier function was improved significantly after switching in both the Tafluprost-containing-preservative and the preservative-free-Tafluprost groups. There were no significant differences in AD scores after switching in the Tafluprost-containing-preservative group, but significant improvements were noted in the preservative-free-Tafluprost group. No significant differences in TBUT were noted in the Tafluprost-containing-preservative or preservative-free Tafluprost groups after switching. CONCLUSION: After switching from preservative Latanoprost to Tafluprost containing-preservative or preservative-free Tafluprost, corneal epithelial barrier function was improved while the intraocular pressure reduction was retained. PMID- 28831306 TI - Polar Value Analysis of Low to Moderate Astigmatism with Wavefront-Guided Sub Bowman Keratomileusis. AB - PURPOSE: To evaluate the astigmatic outcomes of wavefront-guided sub-Bowman keratomileusis (WFG-SBK) for low to moderate myopic astigmatism. METHODS: This study enrolled 100 right eyes from 100 patients who underwent WFG-SBK for the correction of myopia and astigmatism. The polar value method was performed with anterior and posterior corneal astigmatism measured with Scheimpflug camera combined with Placido corneal topography (Sirius, CSO) and refractive astigmatism preoperatively and 1 month, 3 months, and 6 months postoperatively. RESULTS: Similar results for surgically induced astigmatism (SIA) and error of the procedure in both anterior corneal astigmatism (ACA) and total ocular astigmatism (TOA). There was a minor undercorrection of the cylinder in both ACA and TOA. Posterior corneal astigmatism (PCA) showed no significant change. CONCLUSIONS: Wavefront-guided SBK could provide good astigmatic outcomes for the correction of low to moderate myopic astigmatism. The surgical effects were largely attributed to the astigmatic correction of the anterior corneal surface. Posterior corneal astigmatism remained unchanged even after WFG-SBK for myopic astigmatism. Polar value analysis can be used to guide adjustments to the treatment cylinder alongside a nomogram designed to optimize postoperative astigmatic outcomes in myopic WFG-SBK. PMID- 28831308 TI - Effective bioremediation of a petroleum-polluted saline soil by a surfactant producing Pseudomonas aeruginosa consortium. AB - Bacteria able to produce biosurfactants can use petroleum-based hydrocarbons as a carbon source. Herein, four biosurfactant-producing Pseudomonas aeruginosa strains, isolated from oil-contaminated saline soil, were combined to form a bacterial consortium. The inoculation of the consortium to contaminated soil alleviated the adverse effects of salinity on biodegradation and increased the rate of degradation of petroleum hydrocarbon approximately 30% compared to the rate achieved in non-treated soil. In saline condition, treatment of polluted soil with the consortium led to a significant boost in the activity of dehydrogenase (approximately 2-fold). A lettuce seedling bioassay showed that, following the treatment, the soil's level of phytotoxicity was reduced up to 30% compared to non-treated soil. Treatment with an appropriate bacterial consortium can represent an effective means of reducing the adverse effects of salinity on the microbial degradation of petroleum and thus provides enhancement in the efficiency of microbial remediation of oil-contaminated saline soils. PMID- 28831307 TI - Changes in Intraocular Straylight and Visual Acuity with Age in Cataracts of Different Morphologies. AB - PURPOSE: To investigate the significance of difference in straylight of cataract eyes with different morphologies, as a function of age and visual acuity. METHODS: A literature review to collect relevant papers on straylight, age, and visual acuity of three common cataract morphologies leads to including five eligible papers for the analysis. The effect of morphology was incorporated to categorize straylight dependency on the two variables. We also determined the amount of progression in a cataract group using a control group. RESULTS: The mean straylight was 1.22 log units +/- 0.20 (SD) in nuclear (592 eyes), 1.26 log units +/- 0.23 in cortical (776 eyes), and 1.48 log units +/- 0.34 in posterior subcapsular (75 eyes) groups. The slope of straylight-age relationship was 0.009 (R2 = 0.20) in nuclear, 0.012 (R2 = 0.22) in cortical, and 0.014 (R2 = 0.11) in posterior subcapsular groups. The slope of straylight-visual acuity relationship was 0.62 (R2 = 0.25) in nuclear, 0.33 (R2 = 0.13) in cortical, and 1.03 (R2 = 0.34) in posterior subcapsular groups. CONCLUSION: Considering morphology of cataract provides a better insight in assessing visual functions of cataract eyes, in posterior subcapsular cataract, particularly, in spite of notable elevated straylight, visual acuity might not manifest severe loss. PMID- 28831309 TI - Effect of Efavirenz on Endogenous Progesterone Concentrations and Contraceptive Outcomes among Ugandan HIV Infected Women Coadministering Ethinylestradiol/Levonorgestrel. AB - This study assessed the effect of efavirenz mid-dose plasma concentrations on mid luteal endogenous progesterone concentrations and contraceptive outcomes among 49 HIV infected women coadministering ethinylestradiol/levonorgestrel, including 34 HIV positive women on Highly Active Antiretroviral Therapy (HAART) and 15 HAART naive HIV infected women, purposively selected from Mulago Hospital, Uganda. A blood sample was collected once between days 20 and 22 of each woman's menstrual cycle for measuring endogenous progesterone and efavirenz concentrations by electrochemiluminescence technology and High Performance Liquid Chromatography (HPLC), respectively. Descriptive statistical analysis and correlation and logistic regression analysis were done using SPSS v.21 and R3.1. Efavirenz showed a weak positive linear relationship with endogenous progesterone at efavirenz concentrations below 12 MUg/ml. Based on serum endogenous progesterone, the observed hormonal contraceptives failure rate (24.5%) was higher than expected (maximum 8%). A higher proportion of HIV positive women on efavirenz based HAART (26.5%) was at risk of contraceptive failure than their HIV infected HAART naive counterparts (20%) though it was not statistically significant (p = 0.63). Efavirenz mid-dose plasma concentrations seem to have no significant effect on mid-luteal endogenous progesterone concentrations and contraceptive outcomes among HIV infected Ugandan women coadministering ethinylestradiol/levonorgestrel oral pills. PMID- 28831310 TI - Spiritual Struggle in Parents of Children with Cystic Fibrosis Increases Odds of Depression. AB - OBJECTIVE: Spiritual struggle (SS) is associated with poorer health outcomes including depression. The study's main objectives were to characterize change in depression over time, examine longitudinal associations between SS and depression, and determine the extent to which experiencing SS at baseline was predictive of developing depression at follow-up. METHODS: A two-site study collected questionnaire responses of parents (N = 112; 72% female) of children with cystic fibrosis followed longitudinally. Generalized linear mixed effects modeling examined the association between depression and SS over time and assessed potential mediators, moderators, and confounders. RESULTS: Prevalence of depression increased from baseline to follow-up (OR: 3.6, P < 0.0001), regardless of degree of SS. Parents with Moderate/Severe SS were more likely to have depressive symptoms, compared to parents without SS (OR: 15.2, P = 0.0003) and parents who had Mild SS (OR: 10.2, P = 0.0001). Being female and feeling less "at peace" also significantly predicted increased depression (OR: 2.5, P = 0.0397, and OR: 1.15, P = 0.0419, resp.). Experiencing SS at baseline was not predictive of having depression subsequently at follow-up. CONCLUSIONS: Parents experiencing SS were significantly more likely to report depressive symptoms. Interventions to reduce SS have shown efficacy and may be considered. PMID- 28831311 TI - Corrigendum to "Effect of Chronic Morphine Consumption on Synaptic Plasticity of Rat's Hippocampus: A Transmission Electron Microscopy Study". AB - [This corrects the article DOI: 10.1155/2013/290414.]. PMID- 28831312 TI - Comparing Dorsal Tangential and Lateral Views of the Wrist for Detecting Dorsal Screw Penetration after Volar Plating of Distal Radius Fractures. AB - BACKGROUND: The dorsal tangential (DT) view has been shown to improve the detection of dorsal screw perforation during volar distal radius fracture fixation. Here we performed a cadaveric imaging survey study to evaluate if the DT view was uniformly beneficial for all screws. METHODS: Standardized placement of fixed-angle volar distal radius plates was performed on two cadavers. Fluoroscopic images depicting variable screw perforation of each of the four screw holes on the plate were generated. A 46-image survey was distributed at a large academic medical center. Respondents were asked to answer if the screw was perforating through the dorsal cortex in each image. Statistical analysis was performed using Fisher's exact test. A p value < .05 was considered significant. RESULTS: The DT view offered a significantly more reliable determination of dorsal screw penetration than traditional lateral imaging for the radial-most screw at all degrees of perforation and the middle two screws at 2 mm of perforation. Residents and attendings had more accurate screw readings overall using the DT view. CONCLUSIONS: The DT view is superior to traditional lateral imaging in the detection of small amounts of dorsal perforation of the radial most three screws of a fixed-angle volar plate. PMID- 28831314 TI - Surgery Averted Using a Novel, Minimally Invasive Approach to Treat Very Severe Radial Artery Spasm. AB - A 42-year-old male admitted with a non-ST elevation myocardial infarction was referred for invasive angiographic assessment. Based on preprocedural assessment, the right radial artery approach was selected. Despite possessing none of the consensus risk factors for radial artery spasm, in addition to receiving standard arterial spasm prophylaxis and conscious sedation, the patient suffered very severe radial artery spasm with initial catheter placement, resulting in entrapment of a 5 Fr pigtail catheter within the left ventricle. After exhausting traditional methods for resolution of radial artery spasm, surgical intervention appeared to be the only remaining option for removal of the entrapped catheter. Prior to committing to surgery, use of an axillary nerve block to hinder sympathetic vascular tone was suggested and attempted. This intervention resulted in atraumatic catheter removal. We present a case of very severe radial artery spasm refractory to customary interventions, alleviated with a novel, minimally invasive technique, which spared surgical intervention. PMID- 28831315 TI - An Unexpected Case of Black Mamba (Dendroaspis polylepis) Bite in Switzerland. AB - Mambas (genus Dendroaspis) are among the most feared venomous African snakes. Without medical treatment, mamba bites are frequently fatal. First-aid treatment includes lymphatic retardation with the pressure immobilization technique. Medical management comprises continuous monitoring, securing patency of the airway, ensuring adequate ventilation, symptomatic measures, and administration of specific antivenin. We report an unusual case of a snake breeder bitten by a black mamba in Switzerland, report the clinical course, and review the lifesaving emergency management of mamba bites. This case highlights the importance of early antivenin administration and suggests that emergency and critical care physicians as well as first responders all around the world should be familiar with clinical toxinology of exotic snake bites as well as with the logistics to most rapidly make the specific antivenin available. PMID- 28831316 TI - Pravastatin-Induced Eczematous Eruption Mimicking Psoriasis. AB - BACKGROUND: Statins, an example of the most commonly prescribed medications to the elderly, are not without side effects. Dermatologic events are often overlooked as arising from medications, particularly those which are taken chronically. Moreover, elderly patients are prone to pharmacologic interactions due to multiple medications. In this report, we describe a case of a statin induced eczematous dermatitis with a psoriasis-like clinical presentation and review the skin manifestations that may arise from statin therapy. CASE PRESENTATION: An 82-year-old man with gout and hypercholesterolemia presented to dermatology clinic with new onset of pruritic, scaly erythematous plaques bilaterally on the extensor surfaces of his arms. He had never had similar lesions before. Despite various topical and systemic treatments over several months, the rash continued to evolve. The patient was then advised to discontinue his long-term statin, which led to gradual resolution of his symptoms. He was subsequently diagnosed with statin-induced eczematous dermatitis. CONCLUSIONS: This case report describes an adverse cutaneous reaction to statins that is rarely reported in the literature. Medications, including longstanding therapies, should be suspected in cases of refractory dermatologic lesions. PMID- 28831313 TI - Emotion Processing by ERP Combined with Development and Plasticity. AB - Emotions important for survival and social interaction have received wide and deep investigations. The application of the fMRI technique into emotion processing has obtained overwhelming achievements with respect to the localization of emotion processes. The ERP method, which possesses highly temporal resolution compared to fMRI, can be employed to investigate the time course of emotion processing. The emotional modulation of the ERP component has been verified across numerous researches. Emotions, described as dynamically developing along with the growing age, have the possibility to be enhanced through learning (or training) or to be damaged due to disturbances in growth, which is underlain by the neural plasticity of emotion-relevant nervous systems. And mood disorders with typical symptoms of emotion discordance probably have been caused by the dysfunctional neural plasticity. PMID- 28831317 TI - Synchronous Upper Squamous and Lower Adenocarcinoma of the Oesophagus: A Rarely Reported Case Treated with Palliative Chemotherapy and Stenting. AB - Oesophageal cancer is divided into two main subtypes, squamous and adenocarcinoma. It is the eighth most common cancer in the world with squamous more common in the developing world and adenocarcinoma most prevalent in the developed world. Incidences of concomitant squamous carcinoma with adenocarcinoma are exceedingly rare with only a few documented occurrences in the form of case reports existing. Here we report a case of synchronous squamous and adenocarcinoma of the oesophagus occurring in an 81-year-old lady with dysphagia, weight loss, and no identifiable risk factors. PMID- 28831318 TI - An Endoscopic Nasomediastinal Approach to a Mediastinal Abscess Developing after Zenker's Diverticulectomy. AB - Zenker's diverticulum is the most frequent symptomatic diverticulum of the esophagus, but the prevalence is <0.1%. The optimal treatment is surgery. Here, we present a nasomediastinal drainage approach to treatment of a mediastinal abscess, developing in the late postoperative period and attributable to leakage from the staple line. PMID- 28831319 TI - Bilateral Ganglion Cysts of the Ligamentum Flavum in the Cervical Spine Causing a Progressive Cervical Radiculomyelopathy and Literature Review. AB - Here we report a unique case of bilateral ganglion cysts originating from the ligamentum flavum in the cervical spine. Degenerative cysts of the ligamentum flavum are rare lesions, and most had been reported in the lumbar spine. Its occurrence in the cervical spine is extremely rare: only eight have been reported. A 66-year-old male patient presented with progressive paraparesis, pain, and paresthesia in his bilateral T1 dermatomes that had lasted for three weeks. Magnetic resonance imaging of the cervical spine demonstrated a well demarcated cystic lesion in the bilateral dorsolateral aspects of the C7/T1 segment and significant compression of the cervical cord. All case reports of ganglion cysts of the cervical ligamentum flavum including the present one showed characteristic symptoms and signs of myelopathy such as paraparesis or quadriparesis associated with varying degrees of paresthesia or pain in the upper extremities. Ganglion cysts of the cervical ligamentum flavum are considered a cause of cervical radiculomyelopathy due to cervical intraspinal cystic lesions. Bilateral occurrence and associated subluxation of the involved cervical segments again support the degenerative pathogenesis of ganglion cysts of the ligamentum flavum in the cervical spine. PMID- 28831320 TI - Rapid Onset of B12 Deficiency in the Setting of Worsening Multiple Myeloma: Correlations between B12 Deficiency and Multiple Myeloma. AB - A 67-year-old female with a relapse of multiple myeloma after being in remission for approximately 2 years following autologous stem cell transplant presented with worsening pancytopenia, over a three-month period. There were an increase in her monoclonal spike at 3.13 g/dL on serum protein electrophoresis, low serum B12 levels, and positive intrinsic factor antibodies. Three months before, she had normal B12 levels and a significantly lower monoclonal spike of 1.07 g/dL. She was diagnosed with B12 deficiency with pernicious anaemia in the setting of her worsening myeloma. Multiple myeloma (MM) has been linked with B12 deficiency and pernicious anaemia. Several mechanisms have been described regarding the pathogenesis of B12 deficiency in such patients. Increased tumour activity can further perpetuate the development of B12 deficiency in such patients. With regard to our case, the increase in tumour activity and onset of pernicious anaemia could have contributed to the rapid development of B12 deficiency. In contrast to this, rapid development of B12 deficiency could also signify relapse or worsening of the myeloma as seen in our case. Physicians ought to consider B12 deficiency in patients with worsening pancytopenia and myeloma. PMID- 28831321 TI - Cryosurgery as an Option for the Treatment of Vascular Lesions of the Oral Cavity. AB - Cryosurgery is a treatment modality consisting in the destruction of tissue by the application of extremely low temperatures. This causes irreversible damage to cellular metabolism, leading to tissue destruction within minutes, a mechanism that may be beneficial when used in diseased tissues. Because cryosurgery is effective, simple, and easy to perform, it has been used in the treatment of lesions in both medical and dental fields. This technique provides many advantages, such as easy operation, absence of intraoperative bleeding, and low infection rate. We report the case of a patient with a hemangiomatous lesion of the oral cavity who was treated with liquid nitrogen spray cryosurgery, with successful results at 18-month follow-up. PMID- 28831322 TI - Intercostal Artery Laceration: Rare Complication of Thoracentesis and Role of Ultrasound in Early Detection. AB - Hemothorax is a rare but potentially fatal postthoracentesis complication. Early clinical signs may be nonspecific resulting in diagnostic delay. A high index of suspicion is vital for early diagnosis and intervention to avoid further bleeding. Following procedure, early bedside ultrasound findings can be vital for early detection. We report a case of massive hemothorax in a 63-year-old male following therapeutic thoracentesis. Diagnosis was made following highly suggestive sonographic findings prompting thoracotomy and lacerated intercostal artery cauterization. PMID- 28831323 TI - Malrotation Induced Small Intestine Ischemia in an Adolescent. AB - Intestinal malrotation occurs if midgut does not complete or partially completes its 270 degrees counter-clockwise rotation around the superior mesenteric artery during embryologic life. In general, it frequently manifests with vomiting due to duodenal obstruction and volvulus in the initial months of life, and it is very rare to manifest in the adulthood. A 20-year-old male patient who had severe abdominal pain, nausea, vomiting, and distention for one day was evaluated at the emergency department. On abdominal tomography "swirling appearance of structures around the superior mesenteric artery" was reported. CT appearance was considered compatible with a rotational anomaly. Emergency surgery was planned for the patient. In laparotomy, it was observed that an approximately 100 cm long small intestine segment was rotated around a band (Ladd) and ischemia was developed in this segment due to rotation of its mesentery. The rotation of the small intestinal mesentery was corrected by opening the bands. After the warm application to the intestinal mesenteric ischemia for a while, the color and the peristalsis of the intestines became normal. The patient was discharged on postoperative day 2 with suggestions. PMID- 28831324 TI - Use of Diagnostic Laparoscopy for Identification of Bilateral Noncommunicating Hydroceles in an Infant with Right-Sided Abdominoscrotal Mass and Left-Sided Scrotal Mass. AB - Infantile abdominoscrotal hydrocele (ASH) is a rare condition characterized by a dumbbell-shaped cystic mass extending from the scrotum to the abdomen. We present the case of a 4-month-old infant who presented with progressively enlarging bilateral scrotal swelling and a tense, ballotable right-sided abdominal mass with extension into the scrotum. Scrotal ultrasound revealed bilateral hydroceles but exam and ultrasound could not rule out communication. At the time of planned hydrocelectomy, initial diagnostic laparoscopy was used to identify a massive right-sided ASH extending from the internal ring to the umbilicus and a large noncommunicating left-sided hydrocele that was visible with application of pressure to the left side of the scrotum. Following confirmation of anatomy with diagnostic laparoscopy, a scrotal approach to hydrocelectomy was performed as well as bilateral orchidopexy. PMID- 28831325 TI - Prescription of Antibiotics to Treat Gonorrhoea in General Practice in Flanders 2009-2013: A Registry-Based Retrospective Cohort Study. AB - BACKGROUND: General practitioners (GPs) as a group have been identified as playing an important role in gonorrhoea management in Flanders. Belgian guidelines recommended ceftriaxone or alternatively spectinomycin from 2008 onwards and azithromycin combination therapy since 2012. OBJECTIVES: This study investigates to which extent contemporary gonorrhoea treatment guidelines were followed. METHODS: A retrospective cohort study (2009-2013) of antibiotic prescriptions for gonorrhoea cases registered in the Flemish Intego general practice database was carried out. The database is based on electronic health record routine registration by over 90 GPs using the software programme Medidoc. RESULTS: Ninety-one gonorrhoea cases with ten chlamydia and one genital trichomonas coinfections in 90 patients were registered between 2009 and 2013. The proportion of cases with ceftriaxone and/or spectinomycin prescriptions rose from 13% (two of 15 cases) in 2009 to 56% (nine of 16 cases) in 2013. Combination therapy of ceftriaxone and/or spectinomycin together with azithromycin rose from 0 of 15 cases (0%) in 2009 to 7 of 16 cases (44%) in 2013. CONCLUSION: Although numbers are small, the results suggest that gonorrhoea therapy guideline adherence improved between 2009 and 2013. PMID- 28831327 TI - Extraction of Illegal Dyes from Red Chili Peppers with Cholinium-Based Deep Eutectic Solvents. AB - Deep eutectic solvents (DESs) as a new kind of green solvents have been used to extract bioactive compounds but there are few applications in extracting chrysoidine dyes. In this study, we developed an ultrasonic-assisted extraction method with choline chloride/hydrogen bond donor (ChCl/HBD) DES for the extraction of chrysoidine G (COG), astrazon orange G (AOG), and astrazon orange R (AOR) in food samples. Some experimental parameters, such as extraction time, raw material/solvent ratio, and temperature, were evaluated and optimized as follows: the ratio of ChCl/HBD, 1 : 2 (v/v); the ratio of sample/DES, 1 : 10 (g/mL); extraction time, 20 min; extraction temperature, 50 degrees C. Under the optimized conditions, the limits of detection (MUg/mL) were 0.10 for COG and 0.06 for AOG and AOR. The relative standard deviations were in the range of 1.2-2.1%. The recoveries of the three dyes were in the range of 80.2-105.0%. By comparing with other commonly used solvents for extracting chrysoidine dyes, the advantages of DESs proved them to be potential extraction solvents for chrysoidine G, astrazon orange G, and astrazon orange R in foods. PMID- 28831326 TI - Dynamic Changes in the Nigrostriatal Pathway in the MPTP Mouse Model of Parkinson's Disease. AB - The characteristic brain pathology and motor and nonmotor symptoms of Parkinson's disease (PD) are well established. However, the details regarding the causes of the disease and its course are much less clear. Animal models have significantly enriched our current understanding of the progression of this disease. Among various neurotoxin-based models of PD, 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model is the most commonly studied model. Here, we provide an overview of the dynamic changes in the nigrostriatal pathway in the MPTP mouse model of PD. Pathophysiological events, such as reductions in the striatal dopamine (DA) concentrations and levels of the tyrosine hydroxylase (TH) protein, depletion of TH-positive nerve fibers, a decrease in the number of TH positive neurons in the substantia nigra pars compacta (SNpc), and glial activation, are addressed. This article will assist with the development of interventions or therapeutic strategies for PD. PMID- 28831328 TI - A Unique Application of Negative Pressure Wound Therapy Used to Facilitate Patient Engagement in the Amputation Recovery Process. AB - Amputation rates during recent military conflicts were at an all-time high, but medical treatment of those amputations and attitudes of service members to get back to duty are also surging ahead. We present the cases of an active duty rescue C130 pilot with an above-the-knee amputation and a retired army sergeant with a below-the-knee amputation. Successful rehabilitation was augmented in both cases by using negative pressure incorporated in a custom prosthetic socket to accelerate incision closure, improve self-efficacy in wound care, and self management, ultimately leading to faster recovery times, full engagement of the rehabilitation process, and return to active duty. PMID- 28831329 TI - Targeted Muscle Reinnervation to Improve Pain, Prosthetic Tolerance, and Bioprosthetic Outcomes in the Amputee. AB - Scope and Significance: There are ~185,000 amputations each year and nearly 2 million amputees currently living in the United States. Approximately 25% of these amputees will experience chronic pain issues secondary to localized neuroma pain and/or phantom limb pain. Problem: The significant discomfort caused by neuroma and phantom limb pain interferes with prosthesis wear, subjecting amputees to the additional physical and psychological morbidity associated with chronic immobility. Although numerous neuroma treatments are described, none of these methods are consistently effective in eliminating symptoms. Translational Relevance: Targeted muscle reinnervation (TMR) is a surgical technique involving the transfer of residual peripheral nerves to redundant target muscle motor nerves, restoring physiological continuity and encouraging organized nerve regeneration to decrease and potentially prevent the chaotic and misdirected nerve growth, which can contribute to pain experienced within the residual limb. Clinical Relevance: TMR represents one of the more promising treatments for neuroma pain. Prior research into "secondary" TMR performed in a delayed manner after amputation has shown great improvement in treating amputee pain issues because of peripheral nerve dysfunction. "Primary" TMR performed at the time of amputation suggests that it may prevent neuroma formation while avoiding the risks associated with a delayed procedure. In addition, TMR permits the target muscles to act as bioamplifiers to direct bioprosthetic control and function. Summary: TMR has the potential to treat pain from neuromas while enabling amputee patients to return to their activities of daily living and improve prosthetic use and tolerance. Recent research in the areas of secondary (i.e., delayed) and primary TMR aims to optimize efficacy and efficiency and demonstrates great potential for establishing a new standard of care for amputees. PMID- 28831331 TI - Salvage of Infected Nasal Reconstruction with a Polymethyl Methacrylate Spacer. AB - Total nasal reconstruction is a challenging multistage procedure. Infections can destroy the cartilage framework and seriously compromise the result. The use of polymethyl methacrylate with antibiotics as a spacer has been described in the treatment of skeletal infections. Using this same principle, the use of a polymethyl methacrylate with antibiotics spacer for an infected nasal reconstruction is reported in a clinical case. PMID- 28831330 TI - Impact of Traumatic Lower Extremity Injuries Beyond Acute Care: Movement-Based Considerations for Resultant Longer Term Secondary Health Conditions. AB - Significance: Advances in field-based trauma care, surgical techniques, and protective equipment have collectively facilitated the survival of a historically large number of service members (SMs) following combat trauma, although many sustained significant composite tissue injuries to the extremities, including limb loss (LL) and limb salvage (LS). Beyond the acute surgical and rehabilitative efforts that focus primarily on wound care and restoring mobility, traumatic LL and LS are associated with several debilitating longer term secondary health conditions (e.g., low back pain [LBP], osteoarthritis [OA], and cardiovascular disease [CVD]) that can adversely impact physical function and quality of life. Recent Advances: Despite recent advancements in prosthetic and orthotic devices, altered movement and mechanical loading patterns have been identified among persons with LL and salvage, which are purported risk factors for the development of longer term secondary musculoskeletal conditions and may limit functional outcomes and/or concomitantly impact cardiovascular health. Critical Issues: The increased prevalence of and risk for LBP, OA, and CVD among the relatively young cohort of SMs with LL and LS significantly impact physiological and psychological well-being, particularly over the next several decades of their lives. Future Directions: Longitudinal studies are needed to characterize the onset, progression, and recurrence of health conditions secondary to LL and salvage. While not a focus of the current review, detailed characterization of physiological biomarkers throughout the rehabilitation process may provide additional insight into the current understanding of disease processes of the musculoskeletal and cardiovascular systems. PMID- 28831333 TI - Association of Insurance Status with the Use of Immediate Breast Reconstruction in Women with Breast Cancer. AB - : Our group sought to determine the influence of health insurance coverage on use of immediate breast reconstruction for working-age women undergoing mastectomy for breast cancer. METHODS: We used 2 complementary databases, the Texas Cancer Registry-linked Medicaid database and the MarketScan private insurance database, to identify working-age women in Texas from 2000 to 2007 treated with mastectomy for incident breast cancer. Logistic regression tested the association between Medicaid versus private insurance and receipt of immediate breast reconstruction, adjusting for patient, treatment, and socio-demographic covariates. Reimbursement for reconstruction, adjusted for inflation and reported in 2014 dollars, was estimated from claims. RESULTS: Median age was 49.7 years for the Medicaid cohort compared with 50.4 years for the MarketScan cohort (P = 0.02). From 2000 to 2007, use of reconstruction increased significantly for patients in the MarketScan cohort (38.1-53.9%; Ptrend = 0.009) but not those in the Medicaid cohort (10.5 16.6%; Ptrend = 0.24). In total, 15.7% of patients in the Medicaid cohort underwent immediate reconstruction (n = 213/1,360) compared with 50.7% (n = 1,405/2,772) of patients in the MarketScan cohort (adjusted relative risk, 3.09; 95% CI, 2.78-3.40). Reimbursement for reconstruction was $3,167 (95% CI, $2,512 $3,820) for patients in the Medicaid cohort compared with $15,432 (95% CI, $14,030-$16,834) for patients in the MarketScan cohort. CONCLUSIONS: Type of insurance coverage is an important factor associated with receipt of immediate breast reconstruction. We postulate that the marked difference in reimbursement for reconstruction between Medicaid and private insurance creates a relative disincentive for plastic surgeons and hospitals to offer breast reconstruction to patients with Medicaid. PMID- 28831332 TI - Development of a Universal Nutritional Screening Platform for Plastic Surgery Patients. AB - : Plastic surgeons routinely see patients with complex or chronic wounds of all etiology. In a previous study, we found that up to 1 in 4 of these patients is at risk for malnutrition, which may be influencing their ability to heal. The goal of this study was to develop and validate a universal screening protocol that would be fast and accurate and allow for effective intervention and optimization of nutrition before plastic surgery. METHODS: To accomplish these goals, we adopted a 2-part screening algorithm using the Canadian Nutritional Screening Tool (CNST) to triage patients in our outpatient clinics and then further screened those identified as being at risk using the Subjective Global Assessment (SGA) tool and blood work. RESULTS: We screened 111 patients with diagnoses related to breast cancer (n = 10; 9.01%), elective surgery (n = 38; 34.23%), emergency surgery (n = 8; 7.21%), fractures (n = 15; 13.51%), and wounds (n = 40; 36.04%). Of the screened subjects, 15.32% (n = 17) were found to be at nutritional risk using the CNST, and 13 were confirmed to be moderately or severely malnourished using the SGA. Importantly, there were no positive correlations between nutritional status and smoking, diabetes, body mass index, or age, indicating that a universal screening protocol is needed to effectively screen a diverse plastic surgery population for malnutrition. CONCLUSIONS: Screening patients with both the CNST and the SGA is an effective way to identify patients before surgery to improve outcomes. PMID- 28831334 TI - Simultaneous Surgical Treatment for Smile Dysfunction and Lagophthalmos Involving a Dual Latissimus Dorsi Flap. AB - Paralytic lagophthalmos and smile dysfunction are serious complications of facial paralysis and various reconstructive procedures have been developed to treat them. Among these procedures, there is no doubt that dynamic procedures are more effective than static ones. The 1-stage simultaneous surgical treatment of these 2 dysfunctions with a dynamic procedure involving a single muscle would be ideal, but no such methods have been reported. In this article, we present a 1-stage method for the simultaneous surgical treatment involving the use of a dual latissimus dorsi muscle flap. In this method, 2 muscle flaps based on the descending and transverse branches of the thoracodorsal vessels are transferred to the face. The descending and transverse branches of the thoracodorsal nerve are sutured to separate branches of the masseteric nerve. Using this method, complete eyelid closure during strong clenching and voluntary smiling during weak clenching without eyelid closure were achieved. Although our method does not result in spontaneous smiling, we believe that it is a good option for some patients with long-standing facial paralysis. PMID- 28831335 TI - Subcutaneously Placed Breast Implants after a Skin-Sparing Mastectomy: Do We Always Need ADM? AB - : Immediate breast reconstruction is an acceptable treatment option after mastectomy for prophylaxis of early breast cancer. Different options exist for implant placement, incision technique, patient suitability, and institutional experience. This article is a case series exploring the feasibility and outcomes of patients undergoing immediate breast reconstruction using skin-sparing mastectomy without mesh or acellular dermal matrix (ADM) and with a vertical inframammary incision. METHODS: A single-institution retrospective analysis was performed for all patients who underwent immediate single-stage reconstruction with subcutaneous silicon implants without ADM between 2009 and 2014 inclusive. Patient, operative and treatment variables were extracted. All patients with viable mastectomy skin flaps intraoperatively and at least 5 mm of subcutaneous tissue were eligible except for patients who were deemed too slim by the senior surgeon preoperatively and thus at risk of implant visibility or skin rippling. RESULTS: There were 26 patients (bilateral n = 12 and unilateral n = 14) eligible for analysis, with a median long-term follow-up of 51.5 months. The majority of complications were classified as minor affecting 46.2% of the cohort (n = 12). There were 20 episodes of complications overall. The most frequent episodes were contour defects (x = 5), minor seroma (x = 4), and malrotation and minor infection (x = 3). There was 1 episode of capsular contracture. CONCLUSION: Skin sparing mastectomy with immediate subcutaneous silicon implant reconstruction with a vertical incision and without the need for mesh or ADM is an acceptable and safe treatment option. Accurate patient selection and skin flap viability is the key to achieving optimal outcomes with this approach. PMID- 28831336 TI - Recurrence Rates Over 20 Years in the Treatment of Malignant Melanoma: Immediate Versus Delayed Reconstruction. AB - : Wide local excision (WLE) with a safety margin is the standard of treatment for primary head and neck cutaneous malignant melanoma (HNCMM). Studies have demonstrated inconsistency in recurrence rates following immediate versus delayed reconstruction. The objectives of this study were to assess and compare recurrence rates after WLE of HNCMM followed by immediate or delayed reconstruction in determining recurrence-free survival estimates. METHODS: A consecutive, retrospective analysis of 451 patients undergoing WLE of primary HNCMM followed by reconstruction over a period of 20 years was performed. Patients were divided into 2 groups based on timing of reconstruction (immediate versus delayed). Univariate analyses were performed to assess distributions. Kaplan-Meier survival analysis and multivariate Cox proportional hazard analyses were performed to estimate recurrence-free survival. RESULTS: Tumor specimen positive margins were comparable between immediate and delayed reconstruction groups (P = 0.129). Univariate analysis demonstrated comparable local melanoma recurrence after immediate or delayed reconstruction (41.4% versus 53.3%; P = 0.399). After adjusting for prognostic factors, multivariate analysis also failed to demonstrate an association between reconstruction timing and local recurrence free survival (P = 0.167). CONCLUSIONS: In this long-term study, we were not able to demonstrate an association between reconstruction timing and local recurrence free survival after excision WLE of HNCMM, rendering immediate reconstruction a reliable approach. In addition, the presence of ulceration and a positive sentinel lymph node were positively associated with the risk of recurrence. PMID- 28831337 TI - Distraction Osteogenesis for Brachymetatarsia by Using Internal Device. AB - Congenital brachymetatarsia most commonly involves the fourth ray and may be combined with metacarpal shortening. Now, many reports demonstrated the usefulness of distraction osteogenesis for lengthening of the metatarsals by using an external distraction device. In this article, we treated shortening fourth metatarsal by bone lengthening using the internal distraction device. This technique has some advantages over the method of external distraction. PMID- 28831338 TI - Critical Evaluation of Risk Factors of Infection Following 2-Stage Implant-Based Breast Reconstruction. AB - : Infection is a dreaded complication following 2-stage implant-based breast reconstruction that can prolong the reconstructive process and lead to loss of implant. This study aimed to characterize outcomes of reconstructions complicated by infection, identify patient and surgical factors associated with infection, and use these to develop an infection management algorithm. METHODS: We performed a retrospective review of all consecutive implant-based breast reconstructions performed by the senior author (2006-2015) and collected data regarding patient demographics, medical history, operative variables, presence of other complications (necrosis, seroma, hematoma), and infection characteristics. Univariate and multivariate binomial logistic regression analyses were performed to identify independent predictors of infection. RESULTS: We captured 292 patients who underwent 469 breast reconstructions. In total, 14.1% (n = 66) of breasts were complicated by infection, 87.9% (n = 58) of those were admitted and given intravenous antibiotics, 80.3% (n = 53) of all infections were cleared after the first attempt, whereas the remaining recurred at least once. The most common outcome was explantation (40.9%; n = 27), followed by secondary implant insertion (21.2%; n = 14) and operative salvage (18.2%; n = 12). Logistic regression analysis demonstrated that body mass index (P = 0.01), preoperative radiation (P = 0.02), necrosis (P < 0.001), seroma (P < 0.001), and hematoma (P = 0.03) were independent predictors of infection. CONCLUSIONS: We observed an overall infectious complication rate of 14.1%. Heavier patients and patients who received preoperative radiation were more likely to develop infectious complications, suggesting that closer monitoring of high risk patients can potentially minimize infectious complications. Further, more aggressive management may be warranted for patients whose operations are complicated by necrosis, seroma, or hematoma. PMID- 28831339 TI - Microfocused Ultrasound with Visualization and Calcium Hydroxylapatite for Improving Skin Laxity and Cellulite Appearance. AB - : Age-associated skin laxity contributes to worsening of cellulite appearance. This study evaluated the effects of microfocused ultrasound with visualization (MFU-V; Ultherapy) in combination with diluted calcium hydroxylapatite (CaHA; Radiesse) on cellulite appearance and on neocollagenesis. METHODS: Twenty women (18-55 years old) with skin laxity and moderate-to-severe cellulite on the buttocks and thighs were retrospectively enrolled. MFU-V was applied using 4 and 7 MHz transducers (25 lines/transducer/site) and immediately followed by subdermal CaHA injection (1 ml/buttock or thigh). Photographs at baseline and 90 days were assessed by 2 independent, blinded evaluators using a 5-item cellulite severity scale. One subject scheduled for thighplasty received treatment with 6 different CaHA dilutions (0.3 ml/5 cm2) followed by MFU-V. Tissue specimens from each dilution site were examined under polarized light microscopy to assess neocollagenesis. RESULTS: Both evaluators reported statistically significant improvements compared with baseline for each item on the cellulite severity scale (P < 0.001) with a 4.5-point improvement in mean overall score (P < 0.001) after a single MFU-V/CaHA treatment. At 90 days, histologic analysis showed peak neocollagenesis in samples treated with the 1:1 dilution, whether with CaHA alone or in combination with MFU-V. The highest conversion of collagen type III into collagen type I at month 3 occurred in samples injected with 1:1 and 1:0.6 CaHA dilutions without subsequent MFU-V treatment. Both procedures were well tolerated, and subject satisfaction was high. CONCLUSIONS: Combination treatment with MFU-V and diluted CaHA is effective for improving skin laxity and the appearance of cellulite on the buttocks and upper thighs. PMID- 28831341 TI - Wide Awake Open Reduction of Irreducible Metacarpal Phalangeal Joint Dislocations. AB - Supplemental Digital Content is available in the text. PMID- 28831340 TI - The Diagon/Gel Implant: A Preliminary Report of 894 Cases. AB - : The breast has always been perceived as the emblem of femininity. Desire of having an ideal breast form has been of interest for a long time. METHODS: This preliminary article is a retrospective analysis of 894 cases of breast augmentation with Diagon/Gel breast implants covered with a micropolyurethane foam (Microthane). The surgical technique employed is a modified dual plane, which enables us to use a new anatomical implant to move the glandular parenchyma into a higher position. RESULTS: The study extended from January 2010 to September 2015, during which no breast implant developed Baker grade III or IV capsular contracture (CC) and only a few adverse events occurred. Patients reported to be highly satisfied with the final outcome, which was very natural both in the form and movement. CONCLUSIONS: The new concept of Diagon/Gel represents the next step in the evolutionary progress of breast implants and allows the surgeon to perform not only a breast augmentation but also parenchymal elevation, which otherwise would have required a mastopexy, and we have called it breast enhancement. PMID- 28831342 TI - Diagnostic Accuracy of Lymphoscintigraphy for Lymphedema and Analysis of False Negative Tests. AB - : Lymphedema is the chronic enlargement of tissue due to inadequate lymphatic function. Diagnosis is made by history and physical examination and confirmed with lymphoscintigraphy. The purpose of this study was to assess the accuracy of lymphoscintigraphy for the diagnosis of lymphedema and to determine characteristics of patients with false-negative tests. METHODS: Individuals referred to our lymphedema program with "lymphedema" between 2009 and 2016 were analyzed. Subjects were assessed by history, physical examination, and lymphoscintigraphy. Patient age at presentation, duration of lymphedema, location of disease, gender, previous infections, and lymphedema type were analyzed. RESULTS: The study included 227 patients (454 limbs); lymphedema was diagnosed clinically in 169 subjects and confirmed by lymphoscintigraphy in 162 (117 primary, 45 secondary; 96% sensitivity). Fifty-eight patients were thought to have a condition other than lymphedema, and all had negative lymphoscintigrams (100% specificity). A subgroup analysis of the 7 individuals with lymphedema clinically, but normal lymphoscintigrams, showed that all had primary lymphedema; duration of disease and infection history were not different between true positive and false-negative lymphoscintigram results (P = 0.5). Two patients with a false-negative test underwent repeat lymphoscintigraphy, which then showed lymphatic dysfunction consistent with lymphedema. CONCLUSION: Lymphoscintigraphy is very sensitive and specific for lymphedema. All patients with false-negative studies had primary lymphedema. A patient with a high clinical suspicion of lymphedema and a normal lymphoscintigram should be treated conservatively for the disease and undergo repeat lymphoscintigraphy. PMID- 28831343 TI - Biomechanical Properties of First Dorsal Extensor Compartment Regarding Adequacy as a Bone-Ligament-Bone Graft. AB - : Bone-ligament-bone grafts for reconstruction of the scapholunate ligament are a valuable tool to prevent disease progression to carpal collapse. Locally available grafts do not require an additional donor site. The first extensor compartment was evaluated biomechanically regarding its possible use as an autograft. METHODS: Twelve native fresh-frozen, human cadaver specimens were tested by applying axial tension in a Zwick Roell machine. Load to failure, transplant elongation, and bony avulsion were recorded. The load to failure was quantitated in newtons (N) and the displacement in length (millimeters). Parameters were set at distinct points as start of tension, 1 mm stretch and 1.5 mm dissociation, failure and complete tear, and were evaluated under magnified visual control. Although actual failure occurred at higher tension, functional failure was defined at a stretch of 1.5 mm. RESULTS: Mean load at 1 mm elongation was 44.1 +/- 28 N and at 1.5 mm elongation 57.5 +/- 42 N. Failure occurred at 111 +/- 83.1 N. No avulsion of the bony insertion was observed. Half the transplants failed in the central part of the ligament, while the rest failed near the insertion but not at the insertion itself. Analysis of tension strength displayed a wide range from 3.8 to 83.7 N/mm at a mean of 33.4 +/- 28.4 N/mm. CONCLUSIONS: The biomechanical tensile properties of the first dorsal extensor compartment are similar to those of the dorsal part of the scapholunate ligament. A transplant with a larger bone stock and a longer ligament may display an advantage, as insertion is possible in the dorsal, easily accessible part of the carpal bones rather than in the arete-like region adjacent to the insertion of the scapholunate ligament. In this study, 1.5 mm lengthening of the bone-ligament bone transplant was defined as clinical failure, as such elongation will cause severe gapping and is considered as failure of the transplant. PMID- 28831344 TI - Rhinoplasty Setsquare Device: A Novel Instrument to Verify Columellar and Nasal Dorsal Position at the Midsagittal Line. AB - Even a mild degree of postoperative deviation of the nasal dorsum and/or columella from the midsagittal plane could be enough to displease a patient. Postoperative judgment of the nasal dorsum and the columellar positioning on the midsagittal plane is somewhat of a subjective decision determined by the surgeons' naked eye. Most innovations tend to evolve from necessities. The risk and reality of misjudging the positioning for both the nasal dorsum and/or the columella led me to develop a device for the objective measurement of the midsagittal axis of the nose. I have called it the rhinoplasty setsquare device. This device is made from 316 quality stainless chrome. It is completely sterilizable. It consists of 4 main parts. During the finishing touches of the operation, the correct placement of the rhinoplasty setsquare device will provide the surgeon with an objective decision that will help make the positioning of the nasal dorsum and the columella more precise. When I conducted my research on literature and device catalogs for possible devices designed for measurement in rhinoplasty operations, I ran into devices such as the Castroviejo caliper, calibrated lateral crus stabilizer, Joseph measuring rod, and Thorpe Marchac caliper. All of them are unique in their function and design. However, as far as I could see, there is no device similar in form and function to my rhinoplasty setsquare device. I have been using this device for 8 months for all my rhinoplasty patients. I am more confident now in my postoperative results due to its objective measurement of the midsagittal line. PMID- 28831345 TI - Characterization of the Capsule Surrounding Smooth and Textured Tissue Expanders and Correlation with Contracture. AB - : Capsular contracture is a common complication after breast augmentation surgery. This study pathologically evaluated the soft-tissue response to surface modifications in both smooth and textured tissue expander prostheses. METHODS: Smooth tissue expanders and textured tissue expanders in 5 cases each were used for breast reconstruction after mastectomy. Histological samples were harvested from the capsules when the tissue expanders were replaced by silicone implants. Collagen orientation and cellular responses were assessed histologically. Capsular contracture was evaluated using the Baker classification 6 months and 2 years after the removal of the tissue expander. RESULTS: The capsules surrounding the smooth tissue expanders tended to produce more contracture than those surrounding the textured tissue expanders. The collagen architecture of the capsules of the smooth tissue expanders showed random orientation with fragmentation. Conversely, the capsules of the textured tissue expanders showed parallel orientation with collagen bundles of almost normal structure. Significantly more fibrils of elastin and myofibroblasts were found in the capsules surrounding the smooth tissue than in those surrounding the textured ones. CONCLUSIONS: The collagen fibers surrounding the smooth tissue expanders could be cracked during expansion, which may lead to scarring and contracture. Conversely, the collagen orientation surrounding the textured tissue expanders was excellent. Moreover, the increase in elastic fibers and myofibroblasts in the capsules surrounding the smooth tissue expanders may be associated with in vivo contraction patterns. Therefore, the surface type of tissue expanders affects capsular contraction after replacement with definitive implants. PMID- 28831346 TI - Donor-Site Morbidity After DIEAP Flap Breast Reconstruction-A 2-Year Postoperative Computed Tomography Comparison. AB - : The study was undertaken to provide a more complete picture of donor-site morbidity following the deep inferior epigastric artery perforator (DIEAP) flap harvest in breast reconstruction. Most studies evaluating this subject have been performed using ultrasonography. Computed tomography (CT) might provide valuable information. METHODS: In 14 patients who were reconstructed with a DIEAP flap, donor-site morbidity was assessed by comparing routine preoperative CT abdomen with CT abdomen performed 2 years postoperatively. The anteroposterior diameter and transverse diameter (TD) of the rectus muscle were measured bilaterally within 4 standardized zones. Diastasis recti abdominis (DRA) was measured in the same zones. The abdominal wall was assessed for hernias, bulging, and seromas. RESULTS: The operated rectus muscle had a significantly increased anteroposterior diameter in 2 zones and decreased TD in 1 zone compared with preoperative measurements. Comparing the operated and nonoperated rectus muscles, the former had a significantly decreased TD in 1 zone. Supraumbilical DRA was significantly decreased with surgery, whereas infraumbilical DRA was significantly increased. No new hernias or bulging were found. Two patients had seroma formation in the abdominal wall. CONCLUSIONS: Symmetry of the 2 hemiabdomens is well preserved after DIEAP flap harvest; however, significant changes to the rectus muscles and DRA were observed. Hernia formation does not seem to be a postoperative complication of importance. The study indicates that DIEAP flaps result in limited donor-site morbidity, which for most patients does not outweigh the benefits of free perforator flap breast reconstruction. PMID- 28831347 TI - The Visualization of the Functional Role of the Depressor Septi Nasi Muscle by Ultrasound. AB - Supplemental Digital Content is available in the text. PMID- 28831348 TI - Animation Deformity in Postmastectomy Implant-Based Reconstruction. AB - : Despite increasing interest in prepectoral implant-based reconstruction to avoid animation deformity (AD), the prevalence of this deformity and patient attitudes toward it have not been extensively studied. The purpose of this study was to report on AD in the breast reconstruction population and identify those at highest risk. METHODS: A retrospective chart review was completed for patients at least 6 months postoperative from subpectoral, implant-based breast reconstruction using acellular dermal matrix in the lower pole. Patient age, BMI, and implant size were collected. A questionnaire was distributed to the patients. Returned questionnaires were compiled and data were analyzed. RESULTS: Eighty four of 108 patients (77.8%) returned the questionnaire with 62 (75.6%) reporting AD; 75.6% of patients were aware of AD, 14.6% considered it moderate, and 11% considered it severe. No statistically significant differences in age, body mass index, implant size, or athleticism were found between those who noted AD versus those who did not. Forty-one of 79 patients (51.9%) would have been interested in an initial surgical procedure without AD; interest dropped significantly if the alternative surgery involved increased risk, cost, or additional stages of reconstruction. CONCLUSION: The prevalence of AD in subpectoral implant-based breast reconstruction is significantly higher than in subpectoral augmentation. The majority of patients expressed interest in an alternative procedure to avoid AD unless it involved increased risk, cost, or additional surgeries. We found insignificant differences in age, athleticism, BMI, and implant size between patients who note AD and those who do not. Further study is necessary to better define patients at risk for AD to guide patient-centered breast reconstruction. PMID- 28831349 TI - A Limited Submuscular Direct-to-Implant Technique Utilizing AlloMax. AB - : This study evaluates a novel limited submuscular direct-to-implant technique utilizing AlloMax where only the upper few centimeters of the implant is covered by the pectoralis, whereas the majority of the implant including the middle and lower poles are covered by acellular dermal matrix. METHODS: The pectoralis muscle is released off its inferior and inferior-medial origins and allowed to retract superiorly. Two sheets of AlloMax (6 * 16 cm) are sutured together and secured to the inframammary fold, serratus fascia, and the superiorly retracted pectoralis. Thirty-seven breasts in 19 consecutive patients with follow-up at 6 months were reviewed. RESULTS: Nineteen consecutive patients with 37 reconstructed breasts were studied. Average age was 50 years, average BMI was 24.3. Ptosis ranged from grade 0-III, and average cup size was B (range, A-DDD). Early minor complications included 1 seroma, 3 minor postoperative hematomas managed conservatively, and 3 minor wound healing problems. Three breasts experienced mastectomy skin flap necrosis and were managed with local excision. There were no cases of postoperative infection, red breast, grade III/IV capsular contractures, or implant loss. A single patient complained of animation postoperatively. One patient desired fat grafting for rippling. CONCLUSIONS: The limited submuscular direct-to-implant technique utilizing AlloMax appears to be safe with a low complication rate at 6 months. This technique minimizes the action of the pectoralis on the implant, reducing animation deformities but still providing muscle coverage of the upper limit of the implant. Visible rippling is reduced, and a vascularized bed remains for fat grafting of the upper pole if required. PMID- 28831350 TI - Intimal Surface Suture Line (End-Product) Assessment of End-to-Side Microvascular Anastomosis. AB - Microsurgery simulation courses increasingly use assessment methodologies to evaluate the quality of microvascular anastomosis and to provide constructive feedback in competency-based training. Assessment tools evaluating the "journey" of skill acquisition in anastomosis have evolved, including global rating scores, hand motion analysis, and evaluation of the final outcome, that is, "end-product" assessment. Anastomotic patency is the gold standard end-product in clinical microvascular surgery, and in vivo end-to-side anastomosis, which can be confirmed using the Acland-test. Microsurgery simulation training is moving to include nonliving models, where possible, according to the principles of the replacement, reduction, and refinement of the use of animals in research. While a standardized end-product assessment tool for nonliving end-to-end anastomosis exists, there is no similar tool for end-to-side anastomosis. Intimal surface suture line assessment is an error list-based tool, which involves exposing the intimal surface of a vessel and analysis of the quality of suture placement. Errors in end-to side anastomosis were classified according to the potential clinical significance (high, medium, or low) perceived by the senior authors. Intimal surface suture line assessment provides constructive feedback during microsurgery training, helping to minimize technical errors, which are likely to impact on the final outcome in a clinical environment. Intimal surface suture line assessment lends itself to nonliving simulation training courses as an end product self-assessment tool, especially during the early learning curve, to demonstrate progression. It has intraoperative relevance by assessment of the intimal surface suture line as the final sutures are placed in an end-to-side anastomosis to provide objective feedback to trainees in relation to likely physiological anastomotic outcome. PMID- 28831351 TI - An Unusual Presentation of an Osteoid Osteoma in the Lunate Bone. AB - An osteoid osteoma is a rare benign tumor of the carpal bones. It is extremely rarely found in the lunate bone in patients above 30 years of age. We present a case report of a 61-year-old man with an osteoid osteoma of the left wrist, which was masked by degenerative carpal bone disease and a comorbidity of an inflammatory bowel disease. The mainstay of imaging including plain radiographs, computed tomography, magnetic resonance imaging, and bone scintigraphy led to the clinical diagnosis of a lunatomalacia. The tumor was removed by coincidence during removal of the diseased lunate bone. Postoperatively, the patient was immediately free of pain and remained free at his 3 months postoperative follow up. PMID- 28831352 TI - The Supra-Inframammary Fold Approach to Breast Augmentation: Avoiding a Double Bubble. AB - : The inframammary incision for breast augmentation is commonly made at or below the existing inframammary fold (IMF) in an effort to keep the scar in the crease. In recent studies, surgeons inferiorly relocate the IMF, center the implant at nipple level, and attempt to secure the new IMF with sutures. The fascial attachments (also called ligaments) holding the IMF are released, risking a bottoming-out deformity or a double bubble. METHODS: This retrospective study evaluated 160 consecutive women undergoing primary subpectoral breast augmentation. An incision was made 0.5-1.0 cm above the IMF. Dissection proceeded directly to the pectoralis margin, preserving IMF fascial attachments. The pectoralis origin was released from the lower sternum. Surveys were administered to obtain patient-reported outcome data. Ninety-eight patients (61%) participated. RESULTS: Implants often appear high on the chest at early follow-up appointments but gradually settle. One patient (0.6%) developed a double bubble. No reoperations were needed for implant malposition. One patient had a mild animation deformity. There were no cases of symmastia. The mean result rating was 9.1/10. Four percent of surveyed patients found their implants too high; 8% found them too low. Ninety-two patients (94%) reported that their scars were well hidden. Ninety-six women (98%) said that they would redo the surgery. CONCLUSIONS: A supra-IMF approach anticipates the normal descent of implants after augmentation. Scars remain hidden both in standing and supine positions. This method reduces the short-term risk of reoperation for implant malposition or a double bubble. PMID- 28831353 TI - Large Eyelid Defect Repair Using a Free Full-Thickness Eyelid Graft. AB - Large eyelid full-thickness defects are traditionally repaired using flaps with a blood-supplying pedicle, for the reconstruction of the anterior or posterior lamella or both. This is a 2-stage procedure involving occlusion of vision in the affected eye for 4-8 weeks, as the flap pedicle is not divided until vascularization is deemed adequate. However, the importance of using a flap with a pedicle to ensure adequate perfusion of the graft has recently been questioned. PMID- 28831354 TI - Hemostasis and Type 1 Neurofibromatosis. PMID- 28831355 TI - Elizabeth Croll: ASPS Patient of Courage 2016. AB - Mrs. Elizabeth Croll was selected as an American Society of Plastic Surgeons (ASPS) Patient of Courage in 2016. During a boating accident that occurred within 1 month after graduating from Harvard Business School, she was struck by an oncoming boat and suffered severe facial trauma, resulting in an open skull injury with loss of her right eye. She has since undergone multiple reconstructive surgical procedures beginning in 1997 and continuing up to the month before she was awarded the ASPS Patient of Courage. During this time, she got married, started a family, and continued an ambitious business career. Mrs. Croll is the epitome of an individual who has overcome tragedy to further her career, her community, and access to medical care for indigent children. PMID- 28831356 TI - Hypercalcemia Secondary to Silicone Breast Implant Rupture: A Rare Entity to Keep in Mind. PMID- 28831357 TI - Periauricular Keloids on Face-Lift Scars in a Patient with Facial Nerve Paralysis. AB - Keloids are caused by excessive scar formation that leads to scar growth beyond the initial scar boundaries. Keloid formation and progression is promoted by mechanical stress such as skin stretch force. Consequently, keloids rarely occur in paralyzed areas and areas with little skin tension, such as the periauricular region. Therefore, periauricular incision is commonly performed for face lifts. We report a rare case of keloids that arose from face-lift scars in a patient with bilateral facial nerve paralysis. A 51-year-old Japanese man presented with abnormal proliferative skin masses in bilateral periauricular scars. Seventeen years before, he had a cerebral infarction that resulted in permanent bilateral facial nerve paralysis. Three years before presentation, the patient underwent face-lift surgery with periauricular incisions. We diagnosed multiple keloids. We removed the masses surgically, closed the wounds with sutures in the superficial musculoaponeurotic system layer to reduce tension on the wound edges, reconstructed the earlobes with local skin flaps, and provided 2 consecutive days of radiotherapy. The wounds/scars were managed with steroid plasters and injections. Histology confirmed that the lesions were keloids. Ten months after surgery, the lesions did not exhibit marked regrowth. The keloids appeared to be caused by the patient's helmet, worn during his 3-hour daily motorcycle rides, which placed repeated tension on the periauricular area. This rare case illustrates how physical force contributes to auricular and periauricular keloid development and progression. It also shows that when performing surgery with periauricular incisions, care should be taken to eliminate wound/scar stretching. PMID- 28831358 TI - Patient-Reported Outcomes Are Better after Oncoplastic Breast Conservation than after Mastectomy and Autologous Reconstruction. AB - : Oncoplastic breast-conserving surgery (OBCS) avoids mastectomy for larger tumors, but patient-reported outcomes are unknown. METHODS: The BREAST-Q questionnaire was distributed to 333 women following therapeutic mammaplasty or latissimus dorsi (LD) miniflap since 1991 [tumor diameter, 32.5 (5-100) mm). QScore software generated scores/100 for breast appearance, physical, emotional, and sexual wellbeing. Outcomes following therapeutic mammaplasty and LD miniflap were compared and qualitative data analyzed to identify common themes relating to satisfaction. RESULTS: One hundred fifty (45%) women responded [mammaplasty versus LD miniflap, 52% versus 42%; age, 52 (30-83) years; follow-up, 84 (4-281) months). Eighty-nine percent rated OBCS better than mastectomy, > 80% recommending it to others. Mean outcome scores for breast appearance, physical, and emotional wellbeing were high and persisted beyond 15 years. Therapeutic mammaplasty patients were significantly more satisfied than those undergoing LD miniflap with the shape (P < 0.05), the size (P < 0.005), and the natural feel of the treated breast (P = 0.01). They demonstrated similar scores for physical and emotional wellbeing and a lower score for sexual wellbeing than LD miniflap patients. More LD miniflap patients reported back/shoulder symptoms and were more likely to report upper back pain (P < 0.05), but very few (< 5%) were concerned about donor-site appearance. Overall satisfaction with surgical outcomes was high in both OBCS groups (82% "excellent/very good") but greatest after therapeutic mammaplasty (P < 0.005). CONCLUSIONS: Patients report long-lasting satisfaction after OBCS and outcomes that compare very favorably with those reported following mastectomy and immediate autologous reconstruction. PMID- 28831359 TI - Embryonic Stem Cell-Like Population in Dupuytren's Disease Expresses Components of the Renin-Angiotensin System. AB - : The renin-angiotensin system (RAS) mediates cardiac and renal fibrosis. Dupuytren's disease (DD) is a proliferative fibromatosis affecting the hands. This study investigated the expression of the RAS in DD. METHODS: 3,3 Diaminobenzidine (DAB) and immunofluorescent immunohistochemical (IHC) staining for (pro)renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1), and angiotensin II receptor 2 (ATIIR2) was performed on 4 MUm thick formalin-fixed paraffin-embedded sections of DD cords and nodules from 6 patients. Western blotting (WB) and NanoString mRNA analysis were performed to confirm RAS protein expression and transcriptional activation, respectively. RESULTS: IHC staining demonstrated the expression of PRR, ACE, ATIIR1, and ATIIR2 on the ERG+ and CD34+ endothelium of the micro vessels surrounding the DD cords and nodules. PRR was also expressed on the pericyte layer of these microvessels. WB confirmed protein expression of PRR, ACE, and ATIIR2 but not ATIIR1. NanoString analysis confirmed transcriptional activation of PRR, ACE, ATIIR1, but ATIIR2 was below detectable levels. CONCLUSIONS: We demonstrated expression of PRR, ATIIR1, ATIIR2, and ACE on the embryonic stem cell-like cell population on the microvessels surrounding DD nodules and cords by IHC staining, although the expression of ATIIR1 was not confirmed by WB and that of ATIIR2 was below detectable levels on NanoString analysis. These findings suggest the embryonic stem cell-like cell population as a potential therapeutic target for DD, by using RAS modulators. PMID- 28831360 TI - Vismodegib for Locally Advanced Periocular and Orbital Basal Cell Carcinoma: A Review of 15 Consecutive Cases. AB - Basal cell carcinoma (BCC) is the most common periocular skin cancer and can lead to significant morbidity. We assess the effectiveness of vismodegib, a first-in class Hedgehog signaling pathway inhibitor, in the management of periocular and orbital BCCs based on clinical response, tolerability, and orbital content preservation. All patients with periocular or orbital BCCs who met criteria for vismodegib treatment were recruited prospectively between May 2012 and 2014 from 2 hospitals. Patients received oral vismodegib (150 mg daily) until disease progression, unacceptable toxicity, or withdrawal. All patients were followed up monthly. Patient demographics, tumor size, treatment duration including dosing regimen, adverse events, response rate, duration of response, progression-free survival, and disease-free survival were analyzed. All 15 patients had biopsy proven BCCs with no metastatic disease at presentation. The mean age was 74 years and 10 patients (67%) had orbital involvement. The mean lesion longest dimension was 51 mm and 7 cases (47%) represented recurrence following previous surgery and/or radiotherapy. The mean treatment duration was 13 months and mean follow-up duration 36 months. Ten patients (67%) had a complete response, 3 (20%) had a partial response, and 2 had progressive disease following an initial partial response (13%). The partial response of 55% in 1 patient allowed subsequent surgical resection with clear margins. Vismodegib is effective for treating periocular and orbital BCCs with orbital salvage of patients who otherwise would have required exenteration. There is a neoadjuvant role for vismodegib but further studies are required. PMID- 28831361 TI - Reelevating the Mastectomy Flap: A Safe Technique for Improving Nipple-Areolar Complex Malposition after Nipple-Sparing Mastectomy. AB - Nipple-areolar complex (NAC) malposition is one of the most common complications following nipple-sparing mastectomy with implant-based reconstruction. To maximize perfusion to the NAC, traditional methods of correcting NAC malposition limit undermining below the NAC. We demonstrate a series of cases in which improvement of NAC malposition was safely performed by reelevating the NAC and mastectomy flap to allow redraping of the soft tissue envelope over the implant and the overlying capsule. Thirty-four patients were identified in a span over 4 years where 44 NACs were repositioned using this method. There was zero incidence of postoperative ischemia or necrosis of the NAC or mastectomy flaps. There was noticeable improvement in the NAC position on the breast mound. Reelevation of the mastectomy skin flap to correct malposition of the NAC after nipple-sparing mastectomy is a safe and effective option, avoids additional scars, and can be performed more than once to further improve positioning of the NAC. PMID- 28831362 TI - Autologous Latissimus Dorsi Breast Reconstruction Flap Salvage: Microvascular Anastomosis with Serratus Branch. AB - Autologous breast reconstruction has become a standard option during the recovery of breast cancer survivors. Although pedicle damage is a rare complication of this procedure, extensive torsion or tension can lead to partial or total flap failure. We report a case of partial flap salvage after accidental transection of the pedicled blood supply within the intramuscular course of a latissimus dorsi musculocutaneous flap. This salvage technique involved microvascular anastomosis between the remaining vasculature of the latissimus dorsi pedicle and the serratus branch of the thoracodorsal artery and vein. PMID- 28831363 TI - Consultation for Simple Laceration Repair When On-Call in the Emergency Department: Potential Quagmire. AB - What are the forces obligating a plastic surgeon who is on-call for the emergency department to respond to a consultation request for repair of a simple laceration? Although the duties are clear in cases of obvious surgical emergency, ambiguity and subsequent conflict may arise when the true nature of the emergency is less clear. Does the consultant's clinical discretion dictate the obligation in the case of a simple laceration; or is it subservient to either the discretion of the requesting health-care provider or even the patient? Do federal statutes such as the Emergency Medical Treatment and Labor Act, or perhaps more local rules apply, such as the by-laws of the hospital? It would behoove all medical practitioners to familiarize themselves with both the legal and moral implications of these issues. Having legitimate policies in place which actively address those situations where the consultative obligation is unclear is critical to resolve potential conflict. PMID- 28831364 TI - Quilting Sutures, Scarpa Fascia Preservation, and Meta-Analyses of Seroma Rates after Abdominoplasty. PMID- 28831366 TI - Preschool children's physical activity intensity during school time: Influence of school schedule. AB - Chile's Physical Activity Report Card graded the overall index on PA behavior with an F The Ministry of Sports is implementing since 2014 "Jardin Activo" (JA program) which recommends 3 weekly teacher-led PE lessons for preschool children, on half or full day attendance. We determined the effectiveness of the JA program (contribution to MVPA during school time) and assessed if effectiveness varied according to schedule. 596 five y olds, (50% boys) were selected from 66 schools; 52.9% attended half day and 47.1% full day. Children wore accelerometers during school time a day with and one without PE lesson (JA day/non JA day). We compared PA intensity between both these days by gender, using descriptive statistics and t-tests and determined the differential effect on PA intensity, between non JA and JA days by school schedule, using mixed models analyses We compared beta of sedentary and of MVPA by schedule with t-tests. Significant differences were found in PA intensity between both days within each gender. Minutes being sedentary were significantly less during JA days (14 and 15 min in boys and girls respectively); MVPA significantly higher in JA days (11 and 10 min respectively). % time children were sedentary and % they engaged in MVPA differed by schedule. Sedentary minutes were significantly higher (beta - 16.2 vs - 13.2) in half day, while the increase in MVPA was significantly higher (beta 12.5 vs 9.7) in full day. The JA program is effective, especially when children attend school full time. PMID- 28831365 TI - Comparative Study of Prepectoral and Subpectoral Expander-Based Breast Reconstruction and Clavien IIIb Score Outcomes. AB - : Prepectoral breast reconstruction is increasingly popular. This study compares complications between 2 subpectoral and 1 prepectoral breast reconstruction technique. METHODS: Between 2008 and 2015, 294 two-staged expander breast reconstructions in 213 patients were performed with 1 of 3 surgical techniques: (1) Prepectoral, (2) subpectoral with acellular dermal matrix (ADM) sling ("Classic"), or (3) subpectoral/subserratus expander placement without ADM ("No ADM"). Demographics, comorbidities, radiation therapy, and chemotherapy were assessed for correlation with Clavien IIIb score outcomes. Follow-up was a minimum of 6 months. RESULTS: Surgical cohorts (n = 165 Prepectoral; n = 77 Classic; n = 52 No ADM) had comparable demographics except Classic had more cardiac disease (P = 0.03), No ADM had higher body mass index (BMI) (P = 0.01), and the Prepectoral group had more nipple-sparing mastectomies (P < 0.001). Univariate analysis showed higher expander complications with BMI >= 40 (P = 0.05), stage 4 breast cancer (P = 0.01), and contralateral prophylactic mastectomy (P = 0.1), whereas implant complications were associated with prior history of radiation (P < 0.01). There was more skin necrosis (P = 0.05) and overall expander complications (P = 0.01) in the Classic cohort, whereas the No ADM group trended toward the lowest expander complications among the 3. Multivariate analysis showed no difference in overall expander complication rates between the 3 groups matching demographics, mastectomy surgery, risks, and surgical technique. CONCLUSIONS: Prepectoral and subpectoral Classic and No ADM breast reconstructions demonstrated comparable grade IIIb Clavien score complications. BMI > 40, stage 4 cancer, and contralateral prophylactic mastectomy were associated with adverse expander outcomes and a prior history of radiation therapy adversely impacted implant outcomes. Ninety-day follow-up for expander and implant complications may be a better National Surgical Quality Improvement Program measure. PMID- 28831367 TI - Correlates of children's independent outdoor play: Cross-sectional analyses from the Millennium Cohort Study. AB - Time spent outdoors is associated with higher levels of physical activity. To date, correlates of independent outdoor play have not been investigated. This study aimed to identify potential demographic, behavioural, environmental and social correlates of children's independent outdoor play. Data were from the Millennium Cohort Study when children were aged 7 years. Parents reported whether their children played out unsupervised (yes/no) as well as the above mentioned correlates of unsupervised outdoor play. Children's physical activity levels were measured using waist worn accelerometry. Multiple logistic regression was used to examine associations between correlates and odds of independent (unsupervised) outdoor play. Adjusted multiple linear regression was used to estimate associations between independent outdoor play and objective measures of physical activity. Activity was measured as average daily moderate-to-vigorous activity, steps, and sedentary behaviour. 3856 (n = 29%) participants were categorised as engaging in independent outdoor play. Older age, being white British, being in poverty, living in close proximity to both family friends and family, having fewer internalising problems, having more externalising conduct problems and fewer pro-social behaviours were associated with higher odds of independent outdoor play. Independent outdoor play was associated with > 2 additional minutes of moderate-to-vigorous activity (B = 2.21 95% CI, 1.09 to 3.34), > 330 additional steps per day (B = 336.66 95% CI 209.80 to 463.51), and nearly 5 min less time spent sedentary per day (B = - 4.91 95% CI - 7.54, - 2.29) Younger children, those from a higher socio-economic-status, those isolated in location from family friends and family, and those with high levels of prosocial behaviour have lower levels of independent outdoor play. Independent outdoor play was associated with higher levels of physical activity and less time sedentary. Future interventions to promote independent outdoor play should target such populations. PMID- 28831368 TI - Associations between seasonal meteorological conditions and the daily step count of adults in Yokohama, Japan: Results of year-round pedometer measurements in a large population. AB - People's year-round interpersonal step count variations according to meteorological conditions are not fully understood, because complete year-round data from a sufficient sample of the general population are difficult to acquire. This study examined the associations between meteorological conditions and objectively measured step counts using year-round data collected from a large cohort (N = 24,625) in Yokohama, Japan from April 2015 to March 2016. Two-piece linear regression analysis was used to examine the associations between the monthly median daily step count and three meteorological indices (mean values of temperature, temperature-humidity index (THI), and net effective temperature (NET)). The number of steps per day peaked at temperatures between 19.4 and 20.7 degrees C. At lower temperatures, the increase in steps per day was between 46.4 and 52.5 steps per 1 degrees C increase. At temperatures higher than those at which step counts peaked, the decrease in steps per day was between 98.0 and 187.9 per 1 degrees C increase. Furthermore, these effects were more obvious in elderly than non-elderly persons in both sexes. A similar tendency was seen when using THI and NET instead of temperature. Among the three meteorological indices, the highest R2 value with step counts was observed with THI in all four groups. Both high and low meteorological indices discourage people from walking and higher values of the indices adversely affect step count more than lower values, particularly among the elderly. Among the three indices assessed, THI best explains the seasonal fluctuations in step counts. PMID- 28831369 TI - Dimensions of sexual orientation and sleep disturbance among young adults. AB - We examined associations among 3 dimensions of sexual orientation (identity, attraction, and behavior) and sleep disturbance among young adults in the United States. Using Wave IV of the National Longitudinal Study of Adolescent Health (respondents aged 24-32, N = 14,334), we ran multivariate logistic regressions to estimate the probability of reporting trouble falling asleep, trouble staying asleep, and short sleep duration, based on specific sexual orientation categories. Results after controlling for mental health indicate that these categories are more likely to have trouble falling asleep: women who identify as "bisexual" (OR = 1.85, CI: 1.21,2.82), women attracted to "both sexes" (OR = 1.31, CI: 1.00,1.72), women who have had "mostly opposite sex" partners (OR = 1.40, CI: 1.10,1.77), and men who have had "mostly same sex" partners (OR = 2.28, CI: 1.21,4.31). For trouble staying asleep: women who identify as "bisexual" (OR = 1.48, CI: 1.01,2.18), men and women attracted to "both sexes" (OR = 1.81, CI: 1.12,2.91; OR = 1.27, CI: 1.00,1.60), and women who have had "mostly opposite sex partners" (OR = 1.38, CI: 1.13,1.69). For short sleep duration: women who identify as "mostly straight" or "mostly gay" (OR = 1.27, CI: 1.01,1.60; OR = 2.64, CI: 1.36,5.14), men who identify as "bisexual" (OR = 2.56, CI: 1.26,5.18), women attracted only to "same sex" (OR = 2.42, CI: 1.48,3.96), men attracted to "both sexes" (OR = 1.88, CI: 1.21,2.93), and women who have had "mostly same sex" partners (OR = 4.90, CI: 2.10,11.46). Given the variation in findings, it is necessary to analyze each sexual orientation dimension and the categories within each dimension to adequately understand sleep disturbances among sexual minority populations. PMID- 28831370 TI - "Knowledge, recommendation, and beliefs of e-cigarettes among physicians involved in tobacco cessation: A qualitative study". AB - Physicians are rated the most trustworthy source of information for smokers and thus play an increasing role in disseminating information on e-cigarettes to patients. Therefore, it is important to understand what is currently being communicated about e-cigarettes between physicians and patients. This study explored the knowledge, beliefs, communication, and recommendation of e cigarettes among physicians of various specialties. Semi-structured interviews were conducted in early 2016 with 35 physicians across five different specialties. Interviews were transcribed and coded for the following deductive themes: (1) tobacco cessation recommendation practices, (2) knowledge of e cigarettes, (3) communication of e-cigarettes with patients, (4) recommendation of e-cigarettes, and (5) general beliefs about e-cigarettes. Physicians across all specialties reported having conversations with patients about e-cigarettes. Conversations were generally prompted by the patient inquiring about e-cigarettes as a cessation method. Overall, physicians felt there was a lack of information on the efficacy and long term health effects but despite lack of evidence, generally did not discourage patients from trying e-cigarettes as a cessation device. Although physicians did not currently recommend e-cigarettes over traditional cessation methods, they were open to recommending e-cigarettes in the future if adequate data became available suggesting effectiveness. Patients are inquiring about e-cigarettes with physicians across various specialties. Future research should continue to study physicians' perceptions/practices given their potential to impact patient behavior and the possibility that such perceptions may change over time in response to the evidence-base on e-cigarettes. PMID- 28831371 TI - Effect of weather on pedestrian trip count and duration: City-scale evaluations using mobile phone application data. AB - We examined the association between meteorological (weather) conditions in a given locale and pedestrian trips frequency and duration, through the use of locative digital data. These associations were determined for seasonality, urban microclimate, and commuting. We analyzed GPS data from a broadly available activity tracking mobile phone application that automatically recorded 247,814 trips from 5432 unique users in Boston and 257,697 trips from 8256 users in San Francisco over a 50-week period. Generally, we observed increased air temperature and the presence of light cloud cover had a positive association with hourly trip frequency in both cities, regardless of seasonality. Temperature and weather conditions generally showed greater associations with weekend and discretionary travel, than with weekday and required travel. Weather conditions had minimal association with the duration of the trip, once the trip was initiated. The observed associations in some cases differed between the two cities. Our study illustrates the opportunity that emerging technology presents to study active transportation, and exposes new methods to wider consideration in preventive medicine. PMID- 28831372 TI - An unusual case of recurrent chest infections. AB - This case presentation relates to a 53 year old male, cachectic in appearance, who presented with progressively worsening dyspnoea, cough, intermittent haemoptysis and a history of nasal dryness ongoing over five months. The patient had received multiple courses of oral antibiotics for suspected community acquired pneumonia with no significant improvement. He was referred to our Respiratory Department for further evaluation of his symptoms. His HRCT showed right middle lobe consolidation with central cavitations. Furthermore, the transbronchial biopsy had been performed and the cytological examination revealed lipid laden macrophage with interstitial inflammatory changes. With return to the patient over the counter drug history, he described the frequent use of petroleum jelly to alleviate the symptoms of nasal dryness. This is the first report case of exogenous lipoid pneumonia presented with haemoptysis and cavitations in the HRCT. PMID- 28831373 TI - Chronic eosinophilic pneumonia after radiation therapy for squamous cell lung cancer. AB - Reports of chronic eosinophilic pneumonia (CEP) after radiation therapy are limited to breast cancer. We herein describe a case of CEP after radiation therapy for lung cancer. The patient was a 65-year-old man who had asymptomatic peripheral blood eosinophilia but no history of asthma or allergy. One month after completion of radiation therapy, chest CT scan revealed infiltrates inside the irradiated area, leading to the diagnosis of radiation pneumonitis. His condition improved after receiving corticosteroids. However, one months after withdrawal of corticosteroids, he noticed cough and shortness of breath with patchy ground glass opacity in the contralateral lung. The WBC count was 9900/MUl with 17% eosinophils and bronchoalveolar lavage showed eosinophils of 14%, leading to the diagnosis of CEP. His condition improved after receiving corticosteroids and subsequent tapering without recurrence. Asymptomatic peripheral blood eosinophilia at the initial diagnosis of lung cancer might be a trigger for developing CEP. PMID- 28831374 TI - Diffuse pulmonary infiltrates: A guise of adenocarcinoma. AB - Small and non-small cell lung cancer present in a variety of radiologic and clinical patterns, and have been linked to smoking. Primary adenocarcinoma of the lung has been increasingly recognized in females and nonsmokers, often presenting a diagnostic challenge. In the absence of smoking history, these radiographic patterns may be initially misdiagnosed as an infectious or inflammatory condition, often delaying the diagnosis of malignancy. We report two cases of female patients with relatively short or no smoking history presenting with diffuse pulmonary infiltrates not typically seen in primary lung cancer, which created a diagnostic challenge, ultimately diagnosed as primary lung adenocarcinoma. Each case had different subtype patterns of adenocarcinoma. The first case described adenocarcinoma of mostly acinar pattern; while the second case was noted to have adenocarcinoma of micropapillary pattern. Given lung adenocarcinoma's nonspecific presentation, which may mimic infectious and diffuse interstitial lung disease, the above cases highlight the importance of entertaining lung adenocarcinoma as part of the differential diagnosis of such presentations. PMID- 28831375 TI - Airway fibroepithelial polyposis. AB - Fibroepithelial polyps are benign lesions, frequently found in the skin and genitourinary tract. Airway involvement is rare, and few case reports have been published. Our patient was a 79 y.o. male smoker, who was referred to us with a 3 month history of dry cough. At physical examination, the patient looked well, but a chest CT showed a 6-mm polyp lesion in his trachea. A flexible bronchoscopy confirmed this lesion, and forceps biopsies were performed. Argon plasma coagulation was used to completely resect and treat the lesion. Pathological analysis revealed a fibroepithelial polyp (FP). The aim of this manuscript is to report a case of FP with bronchoscopic management and to review the current literature about this condition. PMID- 28831376 TI - Cognitive clustering in schizophrenia patients, their first-degree relatives and healthy subjects is associated with anterior cingulate cortex volume. AB - Cognitive impairments are a core feature in schizophrenia patients (SCZ) and are also observed in first-degree relatives (FR) of SCZ. However, substantial variability in the impairments exists within and among SCZ, FR and healthy controls (HC). A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among SCZ, unaffected FR and HC. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (SCZ, FR and HC), cognitive clustering was performed, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. As expected, there were significant differences in the five BACS subscales among the diagnostic groups. The cluster analytic approach generated three meaningful subgroups: (i) neuropsychologically normal, (ii) intermediate impaired and (iii) widespread impaired. The cognitive subgroups were mainly affected by the clinical diagnosis, and significant differences in all BACS subscales among clusters were found. The effects of the diagnosis and cognitive clusters on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex (ACC) volumes were affected by the additive effects of diagnosis and cognition. Our findings demonstrate a cognitive continuum among SCZ, FR and HC and support the concept of cognitive impairment and the related ACC volumes as intermediate phenotypes in SCZ. PMID- 28831378 TI - Why do nematomorphs leave their hosts? AB - Image 1. PMID- 28831377 TI - Centrality of prefrontal and motor preparation cortices to Tourette Syndrome revealed by meta-analysis of task-based neuroimaging studies. AB - Tourette Syndrome (TS) is a neurodevelopmental condition characterized by chronic multiple tics, which are experienced as compulsive and 'unwilled'. Patients with TS can differ markedly in the frequency, severity, and bodily distribution of tics. Moreover, there are high comorbidity rates with attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), anxiety disorders, and depression. This complex clinical profile may account for apparent variability of findings across neuroimaging studies that connect neural function to cognitive and motor behavior in TS. Here we crystalized information from neuroimaging regarding the functional circuitry of TS, and furthermore, tested specifically for neural determinants of tic severity, by applying activation likelihood estimation (ALE) meta-analyses to neuroimaging (activation) studies of TS. Fourteen task-based studies (13 fMRI and one H2O-PET) met rigorous inclusion criteria. These studies, encompassing 25 experiments and 651 participants, tested for differences between TS participants and healthy controls across cognitive, motor, perceptual and somatosensory domains. Relative to controls, TS participants showed distributed differences in the activation of prefrontal (inferior, middle, and superior frontal gyri), anterior cingulate, and motor preparation cortices (lateral premotor cortex and supplementary motor area; SMA). Differences also extended into sensory (somatosensory cortex and the lingual gyrus; V4); and temporo-parietal association cortices (posterior superior temporal sulcus, supramarginal gyrus, and retrosplenial cortex). Within TS participants, tic severity (reported using the Yale Global Tic Severity Scale; YGTSS) selectively correlated with engagement of SMA, precentral gyrus, and middle frontal gyrus across tasks. The dispersed involvement of multiple cortical regions with differences in functional reactivity may account for heterogeneity in the symptomatic expression of TS and its comorbidities. More specifically for tics and tic severity, the findings reinforce previously proposed contributions of premotor and lateral prefrontal cortices to tic expression. PMID- 28831379 TI - Lousy chicks: Chewing lice from the Imperial Shag, Leucocarbo atriceps. AB - Forty-one imperial shag chicks were sampled for lice during the breeding season of 2014 in Punta Leon, Argentina. We found 2 lice species, Pectinopygus turbinatus infesting the body and Piagetiella caputincisum present in the oral cavity of the birds. This constitutes the first host record for P. turbinatus and the first record for the continental Argentina for P. caputincisum. Ninety-three percent of the chicks were infested by at least one lice species. P. turbinatus was present in all of the lousy chicks, while P. caputincisum infested 84.2% of them. The mean intensity was 29.5 and the range 1-129. There was no difference in prevalence, mean intensity or mean abundance between louse species. However, we found differences among the pattern of infestation of each species. Imperial shag chicks were infested by their parents during their first days of life by P. turbinatus, mainly in nymphal stage and by P. caputincisum as adult lice. Our results showed differences among lice species that could be related to the restrictions that lice from seabirds faced during their life cycle. PMID- 28831380 TI - Draft genome sequence of the halophilic Halobacillus mangrovi KTB 131 isolated from Topan salt of the Jeon-nam in Korea. AB - The draft genome sequence of the halophilic bacterium Halobacillus mangrovi KTB 131, isolated from Topan salt of the Jeon-nam in Korea, was established. The genome comprises 4,151,649 bp, with a G + C content of 41.6%. The strain displays a high number of genes responsible for secondary metabolite biosynthesis, transport, and catabolism compared to other Halobacillus bacterial genus members. Numerous genes responsible for various transport systems, solute accumulation, and aromatic/sulfur decomposition were detected. The first genomic analysis encourages further research on comparative genomics and potential biotechnological applications. The whole draft genome sequence of Halobacillus mangrovi KTB 131 is now available (Bioproject PRJNA380285). PMID- 28831381 TI - Draft genome sequence of a monokaryotic model brown-rot fungus Postia (Rhodonia) placenta SB12. PMID- 28831382 TI - Capnocytophaga canimorsus sepsis in a methotrexate-treated patient with rheumatoid arthritis. AB - Capnocytophaga canimorsus is a gram-negative rod that can be transmitted primarily by dog bites. This life-threatening organism commonly causes sepsis in patients with splenectomy or alcoholism. A 53-year-old rheumatoid arthritis male treated with methotrexate (MTX) for 5 years was admitted for a 4-day history of fever and dyspnea. He had been bitten on a finger by the family dog 4 days before onset. Laboratory tests revealed pancytopenia, acute renal failure, and evidence of disseminated intravascular coagulation, and he subsequently developed acute respiratory distress syndrome. Furthermore, blood cultures grew gram-negative bacilli and despite intensive treatment, he died 5 days after admission. Later, C. canimorsus was identified from his culture samples using a species-specific polymerase chain reaction. C. canimorsus infections should be considered in the differential diagnosis of sepsis for immunocompromised hosts following animal bites. PMID- 28831383 TI - Infective endocarditis caused by Pseudomonas stutzeri in a patient with Marfan syndrome: Case report and brief literature review. AB - Invasive infections due to Pseudomonas stutzeri have rarely been described and mainly occur in immunocompromised individuals. We report a case of infective endocarditis caused by P. stutzeri after previous cardiac surgery in a Lebanese patient with Marfan syndrome. We review the literature and conclude that this pathogen may be of particular medical relevance in the Mediterranean Basin. PMID- 28831384 TI - Emerging role of Actinomyces meyeri in brain abscesses: A case report and literature review. AB - We describe a case of a 29-year-old man from Pakistan who presented with progressive neurologic symptoms over 1 week and was found to have a right parietal cerebral abscess. Neurosurgical drainage cultures showed growth of Actinomyces meyeri, Streptococcus intermedius, and Parvimonas micra. An abscessed molar was identified as the likely port of entry and was extracted. The patient was treated with metronidazole, vancomycin, and doxycycline because of prior anaphylaxis to penicillin. At 6-month follow-up, repeat magnetic resonance imaging showed no signs of residual abscess. Culture-independent identification techniques (e.g., ribosomal sequencing) increasingly identify Actinomyces meyeri as a causative agent and significant pathogen in spontaneous brain abscesses. As understanding about Actinomyces meyeri's prevalence and pathogenesis improves, questions arise about optimal treatment strategy, which we discuss based on a literature review. PMID- 28831385 TI - The prevalence of diseases caused by lysosome-related genes in a cohort of undiagnosed patients. AB - Lysosomal diseases (LD) comprise a group of approximately 60 hereditary conditions caused by progressive accumulation of metabolites due to defects in lysosomal enzymes and degradation pathways, which lead to a wide range of clinical manifestations. The estimated combined incidence of LD is between 1 in 4000 to 1 in 13,000 live births, with recent data from pilot newborn screening studies showing even higher incidence. We aimed to determine the prevalence of the classical LD and other diseases caused by lysosome-related genes in our cohort of diagnostic odyssey patients. The Individualized Medicine Clinic at Mayo Clinic is increasingly utilizing whole exome sequencing (WES) to determine the genetic etiology of undiagnosed Mendelian disease. From September 2012 to April 2017, WES results from 350 patients with unexplained symptoms were reviewed. Disease-causing variants were identified in MYO6, CLN6, LRBA, KCTD7, and ARSB revealing a genetic diagnosis of a LD in 8 individuals from 5 families. Based on our findings, lysosome-related disorders may be collectively common, reaching up to 1.5% prevalence in a cohort of patients with undiagnosed diseases presenting to a genetics clinic. PMID- 28831386 TI - Identification of Australian Aboriginal and Torres Strait Islander Cancer Patients in the Primary Health Care Setting. AB - BACKGROUND: Aboriginal and Torres Strait Islander Australians have poorer cancer outcomes and experience 30% higher mortality rates compared to non-Indigenous Australians. Primary health care (PHC) services are increasingly being recognized as pivotal in improving Indigenous cancer patient outcomes. It is currently unknown whether patient information systems and practices in PHC settings accurately record Indigenous and cancer status. Being able to identify Indigenous cancer patients accessing services in PHC settings is the first step in improving outcomes. METHODS: Aboriginal Medical Centres, mainstream (non-Indigenous specific), and government-operated centers in Queensland were contacted and data were collected by telephone during the period from 2014 to 2016. Participants were asked to (i) identify the number of patients diagnosed with cancer attending the service in the previous year; (ii) identify the Indigenous status of these patients and if this information was available; and (iii) advise how this information was obtained. RESULTS: Ten primary health care centers (PHCCs) across Queensland participated in this study. Four centers were located in regional areas, three in remote areas and three in major cities. All participating centers reported ability to identify Indigenous cancer patients attending their service and utilizing electronic Patient Care Information Systems (PCIS) to manage their records; however, not all centers were able to identify Indigenous cancer patients in this way. Indigenous cancer patients were identified by PHCCs using PCIS (n = 8), searching paper records (n = 1), and combination of PCIS and staff recall (n = 1). Six different types of PCIS were being utilized by participating centers. There was no standardized way to identify Indigenous cancer patients across centers. Health service information systems, search functions and capacities of systems, and staff skill in extracting data using PCIS varied between centers. CONCLUSION: It is crucial to be able to easily identify Indigenous cancer patients accessing health services in the PHC setting to monitor progress, improve and evaluate care, and ultimately improve Indigenous cancer outcomes. It is also important for PHC staff to receive adequate training and support to utilize PCISs efficiently and effectively. PMID- 28831389 TI - Uncover the Underlying Mechanism of Drug-Induced Myopathy by Using Systems Biology Approaches. AB - Drug-induced myopathy (DIM) is a rare side effect; however, the consequence could be fatal. There are few reports to systematically assess the underlying mechanism of DIM. In this study, we curated the comprehensive DIM drug list based on structured labeling products (SPLs) and carried out the analysis based on chemical structure space, drug protein interaction, side effect space, and transcriptomic profiling space. Some key features are enriched from each of analysis. Specifically, the similarity of DIM drugs is more significant than random chance, which shows that the chemical structure could distinguish the DIM positive drugs from negatives. The cytochrome P450 (CYP) was identified to be shared by DIM drugs, which indicated the important role of metabolism in DIM. Three pathways including pathways in cancer, MAPK signaling pathway, and GnRH signaling pathway enriched based on transcriptomic analysis may explain the underlying mechanism of DIM. Although the DIM is the current focus of the study, the proposed approaches could be applied to other toxicity assessments and facilitate the safety evaluation. PMID- 28831388 TI - A New Network-Based Strategy for Predicting the Potential miRNA-mRNA Interactions in Tumorigenesis. AB - MicroRNA (miRNA) plays an important role in the degradation and inhibition of mRNAs and is a kind of essential drug targets for cancer therapy. To facilitate the clinical cancer research, we proposed a network-based strategy to identify the cancer-related miRNAs and to predict their targeted genes based on the gene expression profiles. The strategy was validated by using the data sets of acute myeloid leukemia (AML), breast invasive carcinoma (BRCA), and kidney renal clear cell carcinoma (KIRC). The results showed that in the top 20 miRNAs ranked by their degrees, 90.0% (18/20), 70.0% (14/20), and 70.0% (14/20) miRNAs were found to be associated with the cancers for AML, BRCA, and KIRC, respectively. The KEGG pathways and GO terms enriched with the genes that were predicted as the targets of the cancer-related miRNAs were significantly associated with the biological processes of cancers. In addition, several genes, which were predicted to be regulated by more than three miRNAs, were identified to be the potential drug targets annotated by using the human protein atlas database. Our results demonstrated that the proposed strategy can be helpful for predicting the miRNA mRNA interactions in tumorigenesis and identifying the cancer-related miRNAs as the potential drug targets. PMID- 28831387 TI - Tissue Remodeling in Chronic Eosinophilic Esophageal Inflammation: Parallels in Asthma and Therapeutic Perspectives. AB - Chronic eosinophilic inflammation is associated with tissue remodeling and fibrosis in a number of chronic T-helper 2 (Th2)-mediated diseases including eosinophilic esophagitis (EoE) and asthma. Chronic inflammation results in dysregulated tissue healing, leading to fibrosis and end organ dysfunction, manifesting clinically as irreversible airway obstruction in asthma and as esophageal rigidity, strictures, narrowing, dysmotility, dysphagia, and food impactions in EoE. Current therapies for EoE and asthma center on reducing inflammation-driven tissue remodeling and fibrosis with corticosteroids, coupled with symptomatic control and allergen avoidance. Additional control of Th2 inflammation can be achieved in select asthma patients with biologic therapies such as anti-IL-5 and anti-IL-13 antibodies, which have also been trialed in EoE. Recent molecular analysis suggests an emerging role for structural cell dysfunction, either inherited or acquired, in the pathogenesis and progression of EoE and asthma tissue remodeling. In addition, new data suggest that inflammation independent end organ rigidity can alter structural cell function. Herein, we review emerging data and concepts for the pathogenesis of tissue remodeling and fibrosis primarily in EoE and relevant pathogenetic parallels in asthma, focusing additionally on emerging disease-specific therapies and the ability of these therapies to reduce tissue remodeling in subsets of patients. PMID- 28831390 TI - AQUACEL(r) Ag Surgical Dressing Reduces Surgical Site Infection and Improves Patient Satisfaction in Minimally Invasive Total Knee Arthroplasty: A Prospective, Randomized, Controlled Study. AB - The use of modern surgical dressings to prevent wound complications and surgical site infection (SSI) after minimally invasive total knee arthroplasty (MIS-TKA) is lacking. In a prospective, randomized, controlled study, 240 patients were randomized to receive either AQUACEL Ag Surgical dressing (study group) or a standard dressing (control group) after MIS-TKA. The primary outcome was wound complication (SSI and blister). The secondary outcomes were wear time and number of dressing changes in the hospital and patient satisfaction (pain, comfort, and ease of use). In the intention-to-treat analysis, there was a significant reduction in the incidence of superficial SSI (0.8%, 95% CI? 0.00-2.48) in the study group compared to 8.3% (95% CI? 3.32-13.3) in the control group (p = 0.01). There were no differences in blister and deep/organ-space SSIs between the two groups. Multivariate analysis revealed that AQUACEL Ag Surgical dressing was an independent risk factor for reduction of SSI (odds ratio: 0.07, 95% CI: 0.01 0.58, p = 0.01). The study group had longer wear time (5.2 +/- 0.7 versus 1.7 +/- 0.4 days, p < 0.0001) and lower number of dressing changes (1.0 +/- 0.2 versus 3.6 +/- 1.3 times, p < 0.0001). Increased patient satisfaction (p < 0.0001) was also noted in the study group. AQUACEL Ag Surgical dressing is an ideal dressing to provide wound care efficacy, patient satisfaction, reduction of SSI, and cost effectiveness following MIS-TKA. PMID- 28831391 TI - Corrigendum to "Expression of miRNA-122 Induced by Liver Toxicants in Zebrafish". AB - [This corrects the article DOI: 10.1155/2016/1473578.]. PMID- 28831393 TI - Novel Microbial Diagnostic Methods for Clinical, Environmental, and Food Samples. PMID- 28831392 TI - Pathoanatomic Risk Factors for Instability and Adjacent Segment Disease in Lumbar Spine: How to Use Topping Off? AB - PURPOSE: The goal of this review is to identify criteria indicating implantation of hybrid system into lumbar spine and to evaluate general benefits of use. METHODS: A systematic review of literature was performed using current randomized clinical trials, reviews, and meta-analyses. Data sources included relevant literature of human studies identified through searches of Medline Library until May 2015. RESULTS: Predisposing factors for Adjacent Segment Disease (ASDi) are discussed in literature: laminar horizontalization, insufficiency of fascia thoracolumbalis, facet tropism, and facet sagittalization. Currently there is no evidence for topping off. There are only 12 studies and these have no consistent statements about use of a hybrid system for avoidance of ASDi. CONCLUSION: Hybrid instrumentation of lumbar spine, either with pedicle-based technique or additional spacer, might possibly prevent ASDi from developing in previously damaged segment adjacent to a fusion. Good clinical data proving effectiveness of this new implant technique is as yet unavailable. Thus, currently one must speak of an unevaluated procedure. Various radiological classifications can assist in making a reliable decision as to whether hybrid instrumentation is an appropriate choice of therapy. Pathoanatomical conditions of facet joints and laminae as well as preservation of sagittal balance must also be considered. PMID- 28831394 TI - Arthroscopically Assisted Coracoclavicular Fixation Using a Single Flip Button Device Technique: What Are the Main Factors Affecting the Maintenance of Reduction? AB - BACKGROUND: Among coracoclavicular (CC) fixation techniques, the use of flip button device was demonstrated to have successful outcomes with the advantage of being able to accommodate an arthroscopic procedure. PURPOSE: This study was conducted to investigate the factors associated with loss of fixation after arthroscopically assisted CC fixation using a single flip button device for acromioclavicular (AC) joint dislocations. MATERIALS AND METHODS: We enrolled a total of 47 patients (35 men and 12 women). Plain radiography was performed at a mean of 24 months postoperatively to evaluate the final radiological outcome. The primary outcome measure was a long-term reduction of the AC joint for at least 24 months. RESULTS: We found that 29 patients had a high quality reduction (61.7%) and 18 patients had a low quality reduction (38.3%) in initial postoperative CT findings. Our study showed that the duration (5 days) from injury to treatment and the quality of initial postoperative reduction were significantly associated with the maintenance of reduction at final follow-up. CONCLUSION: Our study showed that maintaining stable reduction after arthroscopically assisted CC fixation using a single flip button device technique is difficult especially in patients who received delayed treatment or whose initial reduction quality was poor. PMID- 28831396 TI - Association between Serum Homocysteine Level and Obstructive Sleep Apnea: A Meta Analysis. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common problem that affects human health. Researches have reported a variety of results with reference to the association between OSA and serum homocysteine (Hcy) level. This meta-analysis is proposed to figure out the association between serum Hcy level and OSA. METHODS: Eligible studies were identified via searching PubMed, Embase, and China National Knowledge Infrastructure (CNKI). Two independent reviewers reviewed studies. The Newcastle-Ottawa Quality Assessment Scale (NOS) was employed for quality assessment of included studies. RevMan (5.1) software and STATA (12.0) software were applied to data analyses. RESULTS: 10 studies containing 839 subjects were included in the present meta-analysis; results revealed that Hcy levels in OSA group were 2.40 MUmol/l higher than that in control group (95% confidence interval: 0.6 to 4.20, P < 0.01; I2 = 96%). Subgroup analysis showed a significant increase of serum Hcy level in OSA patients compared with healthy controls when apnea hyperpnoea index (AHI) >= 30. CONCLUSIONS: Serum Hcy levels and OSA have close-knit and significant association. Analyses demonstrated that patients with OSA had a higher serum Hcy level than healthy controls. In addition, this difference is more significant in moderate or severe OSA patients. PMID- 28831395 TI - Elevated Foxp3/CD8 Ratio in Lung Adenocarcinoma Metastatic Lymph Nodes Resected by Transcervical Extended Mediastinal Lymphadenectomy. AB - A balance between tumor invasion and immune defence system is widely investigated. Objective. The aim of this study was to evaluate lymphocyte phenotype in lymph nodes (LNs) of patients with lung cancer in relation to the presence of metastases. Methods. We investigated 364 LNs resected by transcervical extended mediastinal lymphadenectomy (TEMLA) of 49 patients with squamous cell carcinoma (SCC) or adenocarcinoma (AD) with (A) and without metastases (B). Expression of CD4, CD8, CD25, CTLA-4, and Foxp3 was assessed by immunohistochemical staining. Results. We observed a strong nuclear staining for Foxp3 in lymphocytes and cancer cells and strong membranous/cytoplasmatic reaction for CD4 and CD8, but low for CD25 and CTLA-4. There were significantly higher proportions of CD8+ cells in AD (B) versus AD (A) LNs (80% versus 52.5%, p < 0.05). The Foxp3/CD8 ratio was higher in AD (A) versus AD (B) LNs (0.4 versus 0.25, p < 0.05). No significant differences in the cell markers expression in SCC LNs were found. Conclusion. Significant differences in lymphocyte phenotype in AD may indicate an exceptional biology of this type of lung cancer. TEMLA resected LNs may serve as valuable samples for evaluation of immune status in lung cancer patients. PMID- 28831397 TI - The Reliability and Validity of Using Ice to Measure Cold Pain Threshold. AB - Cold pain threshold (CPT) measures an individual's pain threshold in response to a cold stimulus. CPT is most accurately determined with specialised equipment; however this technology is not readily accessible to clinicians. Instead, ice has been employed to measure CPT. An optimal ice protocol has not yet been identified. The aim of this study was to evaluate the reliability and validity of two CPT protocols using ice in a young, healthy population. Twenty-two participants aged 22.6 (SD 1.81) years underwent CPT measurements over 6 anatomical sites across 3 protocols, which were repeated in 2 sessions. One protocol measured pain (PVAS) following ice applied for a standardised period of 30 seconds; a second protocol measured time to onset of pain, and the reference standard measured CPT using laboratory equipment (TSA-II). The PVAS protocol demonstrated the best reliability (mean ICC 0.783, 95% CI 0.706 to 0.841), but the Timed protocol demonstrated superior validity compared to the reference standard (mean ICC -0.504, 95% CI -0.621 to -0.365). PMID- 28831398 TI - Practice and Barriers towards Provision of Health Promotion Services among Community Pharmacists in Gondar, Northwest Ethiopia. AB - BACKGROUND: Health promotion is now becoming an integral part of community pharmacy practice worldwide. OBJECTIVES: This study was intended to determine the level of involvement of community pharmacists in providing health promotion service and to identify the barriers to the practice. METHODS: A cross-sectional study was conducted on 48 community pharmacists working in Gondar town, Northwest Ethiopia. Data on sociodemographic factors, practice, and barriers to health promotion service were collected and analyzed using SPSS version 20. RESULTS: The majority of respondents were B.Pharm holders (n = 27, 56.3%). Almost all respondents (n = 45, 95.8%) were willing and claimed to be well involved in health promotion services. The top 5 services were related to drug misuse, asthma, diabetes, family planning, and cardiovascular diseases. However, involvement in some types of health promotion services significantly differed based on sex, educational level, and pharmacy ownership of respondents. The main barrier reported was lack of training. CONCLUSION: The community pharmacists in Gondar, Northwest Ethiopia, are engaged in health promotion activities. However lack of training has limited their level of involvement and practice differences were noted based on sex, educational level, and pharmacy ownership status of the respondents. PMID- 28831400 TI - Serum Osteocalcin and Testosterone Concentrations in Adult Males with or without Primary Osteoporosis: A Meta-Analysis. AB - Osteocalcin (Ocn) and testosterone play important roles in male skeleton. However, the concentrations of serum osteocalcin and testosterone have never been systematically compared between populations with and without primary male osteoporosis, a common skeletal disorder in adult males. We searched the PubMed, Embase, and Cochrane Library for relevant studies. A meta-analysis was performed to compare the serum osteocalcin and testosterone concentrations between primary osteoporotic males and age-matched nonosteoporotic (non-OP) males. Five case control studies with 300 adult males were included. We found no significant difference between cases and controls in serum total osteocalcin (TOcn) [95% confidence interval (CI): -1.25, 1.31; p = 0.96] and total testosterone (TT) concentrations [95% CI: -0.88, 4.22; p = 0.20]. The level of evidence of this carefully performed meta-analysis is 3a according to Oxford (UK) CEBM Levels of Evidence. Future well-designed studies with larger sample size and better standardization of Ocn assay are awaited to confirm and update our current findings. PMID- 28831402 TI - Associations of TNFR1 with kidney function outcomes by age, gender, and baseline kidney function status: Data from the Heart and Soul Study. AB - Tumor necrosis factor receptor type 1 (TNFR1) is associated with kidney disease and mortality risk in various populations [1], [2]. We evaluated associations of TNFR1 with mortality and mediators of this relationship in doi: 10.1016/j.atherosclerosis.2017.05.021. Whether or not these associations are influenced by age, gender, or baseline kidney function are not known. We evaluated associations of TNFR1 levels with measures of kidney function stratifying by these variables. Our outcomes included estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, albumin to creatinine ratio (ACR) >30 mg/g, and rapid kidney function loss, defined as a change in eGFR of greater than 3% per year. PMID- 28831399 TI - New Frontiers in Genetics, Gut Microbiota, and Immunity: A Rosetta Stone for the Pathogenesis of Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD), which encompasses ulcerative colitis (UC) and Crohn's disease (CD), is a complicated, uncontrolled, and multifactorial disorder characterized by chronic, relapsing, or progressive inflammatory conditions that may involve the entire gastrointestinal tract. The protracted nature has imposed enormous economic burdens on patients with IBD, and the treatment is far from optimal due to the currently limited comprehension of IBD pathogenesis. In spite of the exact etiology still remaining an enigma, four identified components, including personal genetic susceptibility, external environment, internal gut microbiota, and the host immune response, are responsible for IBD pathogenesis, and compelling evidence has suggested that IBD may be triggered by aberrant and continuing immune responses to gut microbiota in genetically susceptibility individuals. The past decade has witnessed the flourishing of research on genetics, gut microbiota, and immunity in patients with IBD. Therefore, in this review, we will comprehensively exhibit a series of novel findings and update the major advances regarding these three fields. Undoubtedly, these novel findings have opened a new horizon and shed bright light on the causality research of IBD. PMID- 28831401 TI - Global Screening of Antiviral Genes that Suppress Baculovirus Transgene Expression in Mammalian Cells. AB - Although baculovirus has been used as a safe and convenient gene delivery vector in mammalian cells, baculovirus-mediated transgene expression is less effective in various mammalian cell lines. Identification of the negative regulators in host cells is necessary to improve baculovirus-based expression systems. Here, we performed high-throughput shRNA library screening, targeting 176 antiviral innate immune genes, and identified 43 host restriction factor genes in a human A549 lung carcinoma cell line. Among them, suppression of receptor interaction protein kinase 1 (RIP1, also known as RIPK1) significantly increased baculoviral transgene expression without resulting in significant cell death. Silencing of RIP1 did not affect viral entry or cell viability, but it did inhibit nuclear translocation of the IRF3 and NF-kappaB transcription factors. Also, activation of downstream signaling mediators (such as TBK1 and IRF7) was affected, and subsequent interferon and cytokine gene expression levels were abolished. Further, Necrostatin-1 (Nec-1)-an inhibitor of RIP1 kinase activity-dramatically increased baculoviral transgene expression in RIP1-silenced cells. Using baculovirus as a model system, this study presents an initial investigation of large numbers of human cell antiviral innate immune response factors against a "nonadaptive virus." In addition, our study has made baculovirus a more efficient gene transfer vector for some of the most frequently used mammalian cell systems. PMID- 28831403 TI - Long-term climate data description in Ethiopia. AB - This article presents long-term analyzed rainfall and temperature data obtained from the National Metrological Agency (NMA) of Ethiopia. Using tables and graphic trends of analysis, the article shows the low and declining level of average annual rainfall as well as the high inter-annual fluctuations for 18 weather stations located in different agro-climatic zones of the country. The high variation of annual maximum and minimum temperature has been similarly observed for decades in the stations. Ethiopia's average annual temperature has risen between 1955 and 2015 by 1.65 degrees C. The country's agricultural production depends heavily on local temperature and rainfall. The evidence is clear that a slight change in such climatic elements negatively affects the food security condition of both producers and consumers. Although data from the Central Statistical Agency (CSA) show that major cereal crop production has increased at the national level, partly due to the increasing application of fertilizers and modern seeds, Ethiopia's food security condition is deteriorating due to global climatic events caused droughts and rain failure. The rate of food price inflation is thus often higher than the general consumer price inflation rate. PMID- 28831405 TI - Survey data reflecting popular opinions of the causes and mitigation of climate change. AB - The data presented within this manuscript reports the results of a 20-question opinion survey concerning popular beliefs regarding the causes of and possible mitigation of climate change. The results and opinions from 746 survey respondents are presented. The data reflects certain misconceptions of climate change, and is useful for investigators to begin forming opinions of the public's knowledge regarding the potentially inflammatory topics of climate change, greenhouse gases, and geo-engineering. PMID- 28831404 TI - Dataset on the impact of UV, nitric acid and surfactant treatments on low-density polyethylene biodegradation. AB - Present investigation evaluates the LDPE (low-density polyethylene) biodegradation efficiency of polymer degrading bacteria along with UV, nitric acid and surfactant treatments. In current scenario LDPE contamination reported as dominant pollutant in terrestrial and aquatic ecosystem due to its expulsion from commercial and domestic practices. Biodegradation serve as an innovative and effective approach to waste management as compared to land filling and burning processes. The outcomes of UV, nitric acid and surfactant treatments on polymer degradation in addition to bacterial treatment were determined by SEM, FT-IR and electrical conductivity analysis. PMID- 28831406 TI - Data and calculus on isobolographic analysis to determine the antinociceptive interaction between calcium channel blocker and a TRPV1 blocker in acute pain model in mice. AB - Determining antinociceptive interaction between Phalpha1beta toxin (a voltage gated calcium channel blocker) and SB366791 (selective TRPV1 antagonist) may have both clinical and mechanistic implications for the pain management. This data in brief article is associated to the research paper "Synergistic antinociceptive effect of a calcium channel blocker and a TRPV1 blocker in an acute pain model in mice". This material supports the isobolographic analysis performed with the above drugs and shows: data of the dose response curves of the agents given as single drug or combination regimens. Mathematics and statistical processing of dose response curves, proportion of drugs dosage to be used in the combination, calculus of theoretical additive DE20 dose as well as experimentally obtained DE20 are provided. It is also presented details of statistical comparison between theoretical and experimentally obtained DE20. PMID- 28831407 TI - Dataset on electro-optically tunable smart-supercapacitors based on oxygen-excess nanograin tungsten oxide thin film. AB - The dataset presented here is related to the research article entitled "Highly Efficient Electro-optically Tunable Smart-supercapacitors Using an Oxygen-excess Nanograin Tungsten Oxide Thin Film" (Akbar et al., 2017) [9] where we have presented a nanograin WO3 film as a bifunctional electrode for smart supercapacitor devices. In this article we provide additional information concerning nanograin tungsten oxide thin films such as atomic force microscopy, Raman spectroscopy, and X-ray diffraction spectroscopy. Moreover, their electrochemical properties such as cyclic voltammetry, electrochemical supercapacitor properties, and electrochromic properties including coloration efficiency, optical modulation and electrochemical impedance spectroscopy are presented. PMID- 28831408 TI - Shotgun metagenomic data on the human stool samples to characterize shifts of the gut microbial profile after the Helicobacter pylori eradication therapy. AB - The shotgun sequencing data presented in this report are related to the research article named "Gut microbiome shotgun sequencing in assessment of microbial community changes associated with H. pylori eradication therapy" (Khusnutdinova et al., 2016) [1]. Typically, the H. pylori eradication protocol includes a prolonged two-week use of the broad-spectrum antibiotics. The presented data on the whole-genome sequencing of the total DNA from stool samples of patients before the start of the eradication, immediately after eradication and several weeks after the end of treatment could help to profile the gut microbiota both taxonomically and functionally. The presented data together with those described in Glushchenko et al. (2017) [2] allow researchers to characterize the metagenomic profiles in which the use of antibiotics could result in dramatic changes in the intestinal microbiota composition. We perform 15 gut metagenomes from 5 patients with H. pylori infection, obtained through the shotgun sequencing on the SOLiD 5500 W platform. Raw reads are deposited in the ENA under project ID PRJEB21338. PMID- 28831409 TI - The idiosyncratic drug-induced gene expression changes in HepG2 cells. AB - The inflammatory stress has been associated with an increase in susceptibility to idiosyncratic drug-induced liver injury (DILI). However, the molecular mechanisms of this inflammation-associated idiosyncratic drug hepatotoxicity remain unknown. We exposed HepG2 cells with high and low doses of three idiosyncratic (I) and three non-idiosyncratic (N) compounds, in the presence (I+ and N+) or absence (I- and N-) of a cytokine mix for 6, 12 and 24 h. To investigate the genome-wide expression patterns, microarray was performed using the Agilent 4*44K Whole Human Genome chips. The data presented in this DIB include the expression of genes participating in the ceramide metabolism, ER stress, apoptosis and cell survival pathways. The functions of these genes were illustrated in our associated article (Jiang et al., 2017) [1]. Raw and normalized gene expression data are available through NCBI GEO (accession number GSE102006). PMID- 28831410 TI - Dataset of 2-(2-(4-aryloxybenzylidene) hydrazinyl) benzothiazole derivatives for GQSAR of antitubercular agents. AB - Fragment based Quantitative structure activity relationship (QSAR) analysis on reported 25 2-(2-(4-aryloxybenzylidene) hydrazinyl) benzothiazole dataset as antitubercular agents were carried out. Molecules in the current dataset were fragmented into six fragments (R1, R2, R3, R4, R5, R6).Group based QSAR Models were derived using Multiple linear regression (MLR) analysis and selected on the basis of various statistical parameters. Dataset of benzothiazole reveled importance of presence of halogen atoms on is essential requirement. The generated models will provide structural requirements of benzothiazole derivatives which can be used to design and develop potent antitubercular derivatives. PMID- 28831411 TI - Whole transcriptome data of zebrafish exposed to chronic dose of depleted uranium. AB - The concentration of depleted uranium (DU) in the environment is expected to increase due to anthropogenic activities, posing potential risks on ecosystems. The effects of chronic exposure to DU at concentration close to the environmental standards (0.3-30 ug DU/L) are scarcely characterised. Genomic alterations caused by low doses of pollutants can potentially propagate over generations, but how these effects may affect the health of the progeny remain uncertain for the vast majority of toxicants. The present dataset describes the transcriptomic effects of a chronic exposure to 20 ug DU/L during 10 days on adult zebrafish (Danio rerio) organs, the brain, the testis and the ovaries. The potential multigenerational effects of DU were assessed on the progeny of the adult exposed fish at the two-cells stage and after four days of development. We describe in this article the summary statistics of the differential gene expression analysis and focus on key molecular pathways affected by an exposure to a low concentration of DU. The data presented in this study supports the observation made in Armant et al. (2017) [1] (https://doi.org/10.1016/j.dib.2016.05.007) that DU can induce a molecular stress in both adult zebrafish and their progeny. The raw dataset has been deposited at the Gene Expression Omnibus (GEO) repository under the accession number GEO:GSE96603. PMID- 28831412 TI - Enhanced land use datasets and future scenarios of land change for Slovakia. AB - The presented datasets relate to the research article entitled "Land changes in Slovakia: past processes and future directions" [8]. The datasets include the land use and cover (LUC) maps of Slovakia for the years 2006 and 2012 and maps of five future land use scenarios for 2040 developed along the axes of globalisation vs. regionalisation and low vs. high policy intervention (IPCC). Datasets were produced in raster format by combining thematic maps, outputs of models defining particular LUC sector and statistical data taken from European and national predictions of future land change development.The maps have a spatial resolution of 20 m. PMID- 28831413 TI - Cutaneous eruption associated with Streptococcus dysgalactiae (group C Streptococcus) bacteremia. PMID- 28831414 TI - Paraneoplastic atypical scleromyxedema with advanced gastric cancer. PMID- 28831415 TI - Difficult-to-diagnose facial melanomas: Utility of reflectance confocal microscopy in uncovering the diagnosis. PMID- 28831416 TI - The use of QuikClot combat gauze in cervical and vaginal hemorrhage. AB - QuikClot combat gauze is a synthetic hemostatic dressing used for hemorrhage control. There is a paucity of data describing the clinical use and hemostatic results of combat gauze in the obstetric and gynecologic setting. This case series demonstrates the use of combat gauze as an effective hemostatic agent when used as vaginal packing in cervical and vaginal hemorrhage. Hemostasis was achieved rapidly in all cases and further interventions were avoided. The combat gauze remained in place for a mean time of 15 h with no adverse side effects observed. The use of combat gauze as vaginal packing may provide an alternative option in the treatment of cervical and vaginal hemorrhage when other traditional conservative and surgical interventions fail or are unavailable. PMID- 28831417 TI - Dual progestin therapy for fertility-sparing treatment of grade 2 endometrial adenocarcinoma. AB - *A case of grade 2 endometrial adenocarcinoma in a young woman desiring fertility sparing treatment*Successful conservative management of refractory endometrial adenocarcinoma with dual progestin therapy*A brief review of conservative management in endometrial adenocarcinoma. PMID- 28831418 TI - Primary low-grade endometrial stromal sarcoma of the omentum. AB - *Extra-uterine endometrial stromal sarcoma may arise in endometriosis.*Abdominal exploration for extra pelvic endometriosis is warranted.*Representative endometriotic implants should be resected and/or biopsied if clinically suspicious. PMID- 28831419 TI - A Festschrift in Honor of Jane Grant-Kels, M.D. PMID- 28831420 TI - The International Journal of Women's Dermatology is now listed on PubMed Central. PMID- 28831421 TI - Parenting and female dermatologists' perceptions of work-life balance. AB - BACKGROUND: Women in medicine may feel pressure to choose between the competing demands of career goals and being a dedicated spouse and parent. OBJECTIVE: The purpose of this survey study is to report on the current opinions of female dermatologists with regard to family planning, maternity leave, and career success. METHODS: We surveyed 183 members of the Women's Dermatologic Society using a 13-question survey that was approved for distribution by the institutional review board committee of the University of Connecticut Health Center. RESULTS: We found that women were most likely to have children while they were residents (51%), despite the fact that residents were more likely to report barriers to childbearing at this career stage. These barriers included length of maternity leave, appearing less committed to residency responsibilities compared with peers, and inadequate time and privacy to breast feed. Strategies to achieve a work-life balance included hiring in-home help and working part-time. Of note, many women commented on the need for more family planning resources at work. CONCLUSION: Thought should be given to future administrative strategies that can lessen the burden of parents who are dermatologists and have academic ambitions. PMID- 28831423 TI - Breast implant-associated anaplastic large cell lymphoma: A review and assessment of cutaneous manifestations. AB - One newly recognized form of T-cell lymphoma is breast implant-associated anaplastic large cell lymphoma (biALCL), which appears in close proximity to breast implants. The number of reported cases of biALCL is increasing and warrants careful attention by clinicians to more effectively diagnose and treat affected individuals. As pertinent to dermatologists, the objective of this paper is to present the associated cutaneous features of this clinical entity along with the pathogenesis, management, and clinical outcomes. biALCL is a T-cell lymphoma in which malignant T-cells are characterized by large pleomorphic and anaplastic morphology and immunoreactivity for CD30, similar to primary cutaneous anaplastic large cell lymphomas (pcALCL). It has a favorable clinical outcome like nonimplant-associated pcALCL and involves the fibrous capsule around the implant, which creates an immunologically privileged site with a peri-implant effusion (seroma). More rare presentations are of a solitary mass. Appropriate management of biALCL is the complete surgical removal of the implant and total capsulectomy. Dermatologists should be aware of the occurrence of this entity in patients who have breast implants because patients may present specifically for breast-related cutaneous findings or have incidental cutaneous changes noted during a skin examination. The recognition and timely diagnosis of biALCL is critical to prevent progression to more advanced disease, ensure adequate treatment with removal of the implant, and avoid unnecessary aggressive systemic chemotherapy. PMID- 28831422 TI - Laser treatment of medical skin disease in women. AB - Laser treatment is a relatively new and increasingly popular modality for the treatment of many dermatologic conditions. A number of conditions that predominantly occur in women and that have a paucity of effective treatments include rosacea, connective tissue disease, melasma, nevus of Ota, lichen sclerosus (LS), notalgia paresthetica and macular amyloidosis, and syringomas. Laser therapy is an important option for the treatment of patients with these conditions. This article will review the body of literature that exists for the laser treatment of women with these medical conditions. PMID- 28831425 TI - Blue plaque on the chest: A sign of systemic disease. PMID- 28831424 TI - Management of severe acne during pregnancy: A case report and review of the literature. AB - The treatment of acne during pregnancy is often limited by the potential toxicities that are posed to the fetus by the most common and effective acne therapies. As with all dermatoses during pregnancy, the treatment of acne vulgaris in this population requires a thorough understanding of the risks and benefits that are inherent to each treatment. We report on a case of a 30-year old pregnant patient with severe acne conglobata who showed significant improvement with a combination treatment of topical modalities, oral metronidazole, and low dose prednisone during pregnancy. We also review the literature and present an approach for the care of these patients. PMID- 28831426 TI - Warty (follicular) dyskeratoma on the mons pubis. AB - Warty (follicular) dyskeratoma (WD) is a discrete nodular lesion that demonstrates the characteristic histopathologic findings of acantholysis and dyskeratosis. WDs most commonly occur on the head and neck of adults. We present a case of WD that occurred on the mons pubis of a 53-year-old woman. Only a few other cases of WDs occurring on the vulva have been reported. WD most likely represents a tumor of the follicular infundibulum. Despite its name, there is no evidence that WD is caused by a human papillomavirus (HPV) infection. Although occurrences on the vulva are rare, they must be distinguished from HPV-induced squamous tumors when found in this area. PMID- 28831427 TI - Eosinophilic variant of eccrine porocarcinoma of the scalp: Case report and review of the literature. AB - Porocarcinoma is a rare malignant neoplasm of the acrosyringium with metastatic potential that most commonly presents on the acral skin in older adults (mean age = 72 years). We present the case of a 43-year-old woman who developed a rapidly growing de novo porocarcinoma on the scalp with an unusual oncocytic appearance. The tumor consisted of benign eccrine poroma that arose from the epidermis and broad pushing borders with minimal cytological atypia but ample eosinophilic cytoplasm with numerous mitotic figures. Although some tumors may appear deceptively bland, the histologic recognition of pushing/infiltrative borders and mitotic figures are helpful to make the appropriate diagnosis of carcinoma. This lesion was treated with Mohs micrographic surgery and the patient remained free of recurrence after more than 2 years. It is important to recognize the eosinophilic variants of eccrine porocarcinoma because it can histologically mimic a squamous cell carcinoma. PMID- 28831428 TI - Considerations for dermatologists when treating U.S. Military Service Members. AB - Civilian dermatologists sometimes provide care to military service members. This article provides an overview of special considerations that are relevant to the dermatologic treatment of members of the U.S. Armed Forces. We provide a review of the potential implications of certain conditions and treatments for medical retention standards and discuss how service-connected disabilities due to skin conditions are rated and compensated. Understanding service members' circumstances and priorities can help guide discussions and decisions about their care. PMID- 28831429 TI - Differences in dermatology training abroad: A comparative analysis of dermatology training in the United States and in India. AB - Dermatology residency training is not standardized internationally, and each country dictates how training is conducted within its own borders. This article highlights the types of variability in training that can occur from country to country by comparing dermatology residency training programs in the United States and India. This article specifically analyzes the differences that pertain to application and selection, residency program structure, and post-residency opportunities. PMID- 28831430 TI - Analogs of human genetic skin disease in domesticated animals. AB - Genetic skin diseases encompass a vast, complex, and ever expanding field. Recognition of the features of these diseases is important to ascertain a correct diagnosis, initiate treatment, consider genetic counseling, and refer patients to specialists when the disease may impact other areas. Because genodermatoses may present with a vast array of features, it can be bewildering to memorize them. This manuscript will explain and depict some genetic skin diseases that occur in both humans and domestic animals and offer a connection and memorization aid for physicians. In addition, we will explore how animal diseases serve as a model to uncover the mechanisms of human disease. The genetic skin diseases we will review are pigmentary mosaicism, piebaldism, albinism, Griscelli syndrome, ectodermal dysplasias, Waardenburg syndrome, and mucinosis in both humans and domesticated animals. PMID- 28831431 TI - Teledermatology: An updated overview of clinical applications and reimbursement policies. AB - Telemedicine is an emerging field in healthcare that provides services from different medical specialties to patients all around the world. One of the specialties in telemedicine, teledermatology, has grown exponentially as a cost effective way to implement dermatological healthcare to underserved areas and populations. This article reviews the literature that pertains to the cost effectiveness, reliability, public access, patient satisfaction, and reimbursement policies of teledermatology. Teledermatology was found to be cost effective and reliable in reducing in-person visits and time away from work, and allows for the faster delivery of care. However, reimbursement policies for teledermatology services are rather new and vary significantly from state to state. As public interest in and access to teledermatology continue to grow, the future of teledermatology depends on the development of new technology as well as quality improvement strategies and the evolution of sustainable reimbursement policies. PMID- 28831433 TI - The most important decision of your life is.... PMID- 28831432 TI - Clinical trials in dermatology. AB - Clinical trials are the backbone of modern day medicine. Randomized, double blinded, placebo-controlled studies are critical for advancement in medicine and dermatology. Skin conditions such as psoriasis and atopic dermatitis are among the most common health problems in the United States. Clinical trials can provide treatments that not only offer objective improvements in clinical disease status but also subjective improvements in the quality of life of patients who are afflicted with the disease. In this article, we discuss the processes and resources of a clinical trials unit and the challenges that can be encountered during the study process. It is critical to engage in clinical trials to treat patients most effectively with new and innovative therapies that are rooted in trial-validated, evidence-based medicine. PMID- 28831434 TI - Reducing 30-Day Rehospitalization Rates Using a Transition of Care Clinic Model in a Single Medical Center. AB - BACKGROUND: Rehospitalization for medical patients is common. Multiple interventions of varying complexity have been shown to be effective in achieving that goal with variable results in the literature. For medical patients discharged home, no single intervention implemented alone has been shown to have a sustainable effect in preventing rehospitalization. OBJECTIVE: To study the effect of a transition of care clinic model on the 30-day rehospitalization rate in a single medical center. METHODS: Retrospective observational analysis of adult patients discharged home from Memorial Medical Center from September 1, 2014, through December 31, 2014. The primary outcome was to compare hospital readmission rates between patients who followed up with a transition of care (TOC) clinic and those who did not. RESULTS: The study population included 378 patient discharges. A total of 40 patients (10.6%) were readmitted to the hospital within 30 days of discharge. Patients who attended the TOC clinic had a significantly lower 30-day readmission rates (3.8% versus 11.7%). A Cox regression analysis showed that the TOC clinic attendance had a significant negative predication for readmission (HR 0.186, 95% CI 0.038-0.898, P = 0.038). CONCLUSION: Adopting a TOC model after discharging medical patients has reduced the readmission rates in our study. PMID- 28831435 TI - Differences Are Important: Breast Cancer Therapy in Different Ethnic Groups. PMID- 28831436 TI - Developing CSCO Lung Cancer Practice Guidelines Stratified by Resource Availability and Treatment Value. PMID- 28831437 TI - PALOMA-3: Phase III Trial of Fulvestrant With or Without Palbociclib in Premenopausal and Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy-Safety and Efficacy in Asian Patients. AB - PURPOSE: To assess efficacy and safety of palbociclib plus fulvestrant in Asians with endocrine therapy-resistant metastatic breast cancer. PATIENTS AND METHODS: The Palbociclib Ongoing Trials in the Management of Breast Cancer 3 (PALOMA-3) trial, a double-blind phase III study, included 521 patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer with disease progression on endocrine therapy. Patient-reported outcomes (PROs) were assessed on study treatment and at the end of treatment. RESULTS: This preplanned subgroup analysis of the PALOMA-3 study included premenopausal and postmenopausal Asians taking palbociclib plus fulvestrant (n = 71) or placebo plus fulvestrant (n = 31). Palbociclib plus fulvestrant improved progression-free survival (PFS) compared with fulvestrant alone. Median PFS was not reached with palbociclib plus fulvestrant (95% CI, 9.2 months to not reached) but was 5.8 months with placebo plus fulvestrant (95% CI, 3.5 to 9.2 months; hazard ratio, 0.485; 95% CI, 0.270 to 0.869; P = .0065). The most common all cause grade 3 or 4 adverse events in the palbociclib arm were neutropenia (92%) and leukopenia (29%); febrile neutropenia occurred in 4.1% of patients. Within patient mean trough concentration comparisons across subgroups indicated similar palbociclib exposure between Asians and non-Asians. Global quality of life was maintained; no statistically significant changes from baseline were observed for patient-reported outcome scores with palbociclib plus fulvestrant. CONCLUSION: This is the first report, to our knowledge, showing that palbociclib plus fulvestrant improves PFS in asian patients. Palbociclib plus fulvestrant was well tolerated in this study. PMID- 28831438 TI - Decreased Survival With Mastectomy Vis-a-Vis Breast-Conserving Surgery in Stage II and III Breast Cancers: A Comparative Treatment Effectiveness Study. AB - PURPOSE: The primary purpose of hospital-based cancer registries is assessing patient care. Clinical stage-based survival and treatment-based survival are some of the key parameters for such assessment. Because of the challenges in obtaining follow-up parameters, a separate study on patterns of care and survival was undertaken by the Indian National Cancer Registry Program. The results for cancer of the female breast are presented here. PATIENTS AND METHODS: Data abstracted in a standardized patient information form were transmitted online to a central repository. Treatment patterns were assessed for 9,903 patients diagnosed between January 1, 2006, and December 31, 2008, from 13 institutions. Survival analysis was restricted to 7,609 patients from nine institutions wherein follow-up details (as of December 31, 2012) were available for at least 60% of patients. RESULTS: The overall 5-year survival rates with breast-conserving surgery (BCS) and mastectomy (MS) were 94.0% and 85.8%, respectively, for stage II disease (adjusted hazard ratio, 2.40; 95% CI, 1.8 to 3.2) and 87.1% and 69.0%, respectively, for stage III disease (hazard ratio, 2.82; 95% CI, 2.2 to 3.7). Patients who had MS did better with systemic therapy (chemotherapy and/or hormone therapy), whereas patients with BCS required just local radiation therapy to achieve best survival. CONCLUSION: This observational study in the natural setting of care of patients with cancer in India showed significantly decreased survival with MS when compared with BCS. The reasons for lower survival with MS and the biologic or scientific rationale of the necessity of systemic therapy to achieve optimal survival in patients undergoing MS but not in those with BCS need further investigation. PMID- 28831439 TI - Clinical Overestimation of HER2 Positivity in Early Estrogen and Progesterone Receptor-Positive Breast Cancer and the Value of Molecular Subtyping Using BluePrint. AB - PURPOSE: Human epidermal growth factor receptor 2 (HER2) positivity is an important prognostic and predictive indicator in breast cancer. HER2 status is determined by immunohistochemistry and fluorescent in situ hybridization (FISH), which are potentially inaccurate techniques as a result of several technical factors, polysomy of chromosome 17, and amplification or overexpression of CEP17 (centromeric probe for chromosome 17) and/or HER2. In South Africa, HER2-positive tumors are excluded from a MammaPrint (MP; Agendia BV, Amsterdam, Netherlands) pretest algorithm. Clinical HER2 status has been reported to correlate poorly with molecular subtype. The aim of this study was to investigate the correlation of clinical HER2 status with BluePrint (BP) molecular subtyping. METHODS: Clinico pathologic and genomic information was extracted from a prospectively collected central MP database containing records of 256 estrogen receptor-positive and/or progesterone receptor-positive tumors. Twenty-one tumors considered HER2 positive on immunohistochemistry or FISH were identified for this study. RESULTS: The median age of patients was 56 years (range, 34 to 77 years), with a median tumor size of 16 mm (3 to 27 mm). Four (19%) tumors were confirmed HER2-enriched subtype, six (29%) were luminal A, and 11 (52%) were luminal B. The positive predictive values of HER2/CEP17 ratio >= 2 and HER2 copy number >= 6 were only 29% and 40%, respectively. The differences in means for HER2/CEP17 ratio were significant between BP HER2-enriched versus luminal (P = .0249; 95% CI, 0.12 to 1.21) and MP high-risk versus low-risk tumors (P = .0002; 95% CI, 0.40 to 1.06). CONCLUSION: Of the 21 tumors considered clinically HER2 positive, only four were HER2-enriched subtype with BP, indicating an overestimation of HER2 positivity. FISH testing has a poor positive predictive value. PMID- 28831440 TI - Prediagnostic Intervals in Retinoblastoma: Experience at an Oncology Center in Brazil. AB - PURPOSE: Retinoblastoma is the most common intraocular malignancy of childhood. In most cases, parents are the first to notice leukocoria and other symptoms before undergoing a prolonged period of stress before diagnosis. The purpose of this study was to determine prediagnostic intervals of patients with retinoblastoma at an oncology tertiary center (Instituto Nacional de Cancer) in Rio de Janeiro, Brazil, and relate them to stage at diagnosis, eye salvage, and survival. METHODS: Parents or caregivers of children with retinoblastoma registered between January 2006 and September 2013 were interviewed using a semistructured individually applied questionnaire, concerning their trajectory before registration. RESULTS: Out of 76 patients, 39 (51%) were girls, 52 (68%) had unilateral retinoblastoma, and 24 (32%) had bilateral retinoblastoma, totaling 100 affected eyes. The most common stage of diagnosis was the intraocular group, with 63 (83%) patients; nine (12%) were extraocular, and four (5%) had metastatic disease. During the follow-up time of 37 +/- 24.5 months, 10 (13%) patients died and 70 (70%) eyes were enucleated. Mean family interval was 1.6 +/- 2.6 months, mean medical interval was 5.0 +/- 6.2 months, mean referral interval was 0.2 +/- 1.4 months, and mean overall interval was 7.1 +/- 6.9 months. In univariate analysis, age at diagnosis, maternal education, medical interval, and overall interval were significantly related to advanced stage at diagnosis and survival. In multivariate analysis, maternal education and medical interval were significantly related to advanced stage at diagnosis and survival. No variables affected eye salvage. CONCLUSION: Medical interval was responsible for 70% of the overall interval; therefore, programs or campaigns targeting retinoblastoma early diagnosis should focus emphasize in medical awareness. PMID- 28831441 TI - Pain Management and Use of Opioids in Pediatric Oncology in India: A Qualitative Approach. AB - PURPOSE: Consumption of medical opium for pain relief in India is low, despite the country being one of the main world producers of the substance. We investigated obstacles to opioid use and physician perceptions about optimal pain management in pediatric oncology patients in India. METHODS: Semistructured interviews were conducted with oncologists who work in pediatric oncology settings. A mixed sampling strategy was used, including maximum variation and confirmation and disconfirmation of cases, as well as snowball sampling. Key informants were identified. Interviews were audio recorded, transcribed verbatim, and analyzed by thematic analysis methodology. RESULTS: Twenty-three interviews were performed across 20 Indian institutions. The main obstacles identified were lack of financial resources, inadequate education of health care providers on pain management, insufficient human resources (particularly lack of dedicated trained oncology nurses), poor access to opioids, and cultural perceptions about pain. Children from rural areas, treated in public hospitals, and from lower socioeconomic classes appear disadvantaged. A significant equality gap exists between public institutions and private institutions, which provide state-of-the art treatment. CONCLUSION: The study illuminates the complexity of pain management in pediatric oncology in India, where financial constraints, lack of education, and poor access to opioids play a dominant role, but lack of awareness and cultural perceptions about pain management among health care providers and parents emerged as important contributing factors. Urgent interventions are needed to optimize care in this vulnerable population. PMID- 28831442 TI - Cancer Care at Times of Crisis and War: The Syrian Example. AB - PURPOSE: As Syria enters its fifth year of conflict, the number of civilians killed and injured continues to rise sharply. Along with this conflict comes the rapid decline of medical care, specifically cancer care. To determine physician and equipment availability, cancer screening and management, and possible solutions relative to various major cities, a survey was distributed to physicians inside Syria through the help of the humanitarian organization Syrian American Medical Society. METHODS: Online surveys were distributed to both certified oncologists who work in cancer clinics and general physicians who work in rural and mobile clinics inside Syria. Variables assessed were physician specialty, location, population, cost, regional situation (besieged versus government controlled), and resource availability and access. Results were stratified by location and physician specialty. RESULTS: Survey results revealed a large shortage of specialized physicians and inhibited accessibility to screening and management options in besieged areas compared with government controlled regions. Physicians within both government-controlled and besieged cities reported limited or no targeted agents, radiation therapy, clinical trials, bone marrow transplantation, positron emission tomography scans, magnetic resonance imaging, and genetic testing. CONCLUSION: The Syrian civil war has resulted in suboptimal oncology care in the majority of the region. In consideration of specific deficiencies in cancer care, we recommend several solutions that may better the level of care in Syria: patient education on medical documentation and self-examination; online consultation; and cheap, effective screening methods. The implementation of these recommendations may change the course of cancer care in a country that has deteriorated into the worst humanitarian crisis of the century. PMID- 28831443 TI - Survey of Implementation of Antiemetic Prescription Standards in Indian Oncology Practices and Its Adherence to the American Society of Clinical Oncology Antiemetic Clinical Guideline. AB - PURPOSE: Adherence to international antiemetic prophylaxis guidelines like those of ASCO can result in better control of chemotherapy-induced nausea and vomiting; however, the extent of implementation of such guidelines in India is unknown. Therefore, this survey was planned. METHODS: This study was an anonymized cross sectional survey approved by the ethics committee. Survey items were generated from the clinical questions given in the ASCO guidelines. The survey was disseminated through personal contacts at an oncology conference and via e-mail to various community oncology centers across India. The B1, B2, and B3 domains included questions regarding the optimal antiemetic prophylaxis for high, moderate, and low-minimal emetogenic regimens. RESULTS: Sixty-six (62.9%) of 105 responded and 65 centers (98.5%) were aware of the published guidelines. The partial, full, and no implementation scores were 92.5%, 4.5%, and 3.0%, respectively. Full implementation was better for the low-minimal emetogenic regimens (34.8%) than the highly emetogenic regimens (6.1%). The three most frequent reasons for hampered implementation of ASCO guidelines in routine chemotherapy practice cited by centers were a lack of sensitization (26 centers; 39.4%), lack of national guidelines (12 centers; 18.2%), and lack of administrative support (10 centers; 15.2%). CONCLUSION: Awareness regarding ASCO antiemetic guidelines is satisfactory in Indian oncology practices; however, there is a need for sensitization of oncologists toward complete implementation of these guidelines in their clinical practice. PMID- 28831444 TI - Positive PD-L1 Expression Predicts Worse Outcome in Cutaneous Angiosarcoma. AB - PURPOSE: Programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) targeted therapies have shown promising survival outcomes in several human neoplasms. However, it is unclear whether the expression of PD-L1 can be correlated to any clinical and pathologic variables in patients with cutaneous angiosarcoma (CA). The aim of this study was to evaluate the clinicopathological significance of PD L1 expression in CA patients. MATERIALS AND METHODS: Data from 52 patients with CA were retrospectively reviewed. PD-L1 expression, tumor proliferation determined by Ki-67 index, and immunohistochemical evaluation of tumor infiltrating lymphocytes, CD4+ and CD8+, were used to determine correlation with clinicopathological variables. RESULTS: PD-L1 was positively expressed in 40% of all patients. PD-L1 expression was significantly associated with tumor cell proliferation. Multivariate analysis confirmed that high levels of CD8+ tumor infiltrating lymphocytes were a significant predictor in patients with clinical stage I CA and the positive expression of PD-L1 was an independent prognostic factor in predicting worse outcome. CONCLUSION: PD-L1 expression is a novel pathologic marker for predicting worse outcome in patients with CA. PMID- 28831445 TI - Comparison of Symptom Score and Bronchoscopy-Based Assessment With Conventional Computed Tomography-Based Assessment of Response to Chemotherapy in Lung Cancer. AB - PURPOSE: There is a paucity of literature on symptom score (SS) plus fiberoptic bronchoscopy (FOB) -based response evaluation (RE) to chemotherapy for lung cancer. This study aimed to compare the reliability of RE by SS, chest radiograph (CXR), and FOB with computed tomography (CT) -based assessment (Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria) for lung cancer chemotherapy. METHODS: This was a prospective observational study involving treatment-naive patients with lung cancer planned for chemotherapy, with one or more lesions on FOB and CT. Patients underwent assessment twice by SS, CXR, FOB, and CT (at baseline and after chemotherapy). Six symptoms (dyspnea, cough, chest pain, hemoptysis, anorexia, and weight loss) were noted on visual analog scale. Respiratory symptom burden (RSB) and total symptom burden (TSB) were calculated from the first four and all six symptoms, respectively, as the mean of individual SS. Bronchoscopic findings were recorded as per European Respiratory Society classification for tracheobronchial stenosis. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) by each method. For FOB and SS, improvement or worsening by >= 20% was taken as PR or PD, respectively, whereas < 20% change was considered SD. Agreements were tested using Cohen's kappa statistic. RESULTS: All individual SS, RSB, and TSB scores, and the number and distribution of FOB lesions improved significantly after chemotherapy. Individually, CXR and SS had no or minimal agreement with FOB-based and CT-based responses. RECIST and WHO criteria had strong agreement overall (Cohen's kappa = 0.872) and perfect agreement for PD (Cohen's kappa = 1.000). Cohen's kappavalues for FOB-based assessment with RECIST and WHO were 0.324 and 0.349, respectively for overall RE, and 0.462 and 0.501 for differentiating responders (CR and PR) from nonresponders (SD and PD), respectively. Cohen's kappavalues for PD were 0.629 (FOB alone), 0.672 (FOB and RSB), 0.739 (FOB and TSB), and 0.764 (FOB and CXR). CONCLUSION: CT based assessment should remain the reference for objective RE of chemotherapy in lung cancer. A combination of FOB and CXR may be used as a surrogate to diagnose PD if CT is not feasible. PMID- 28831446 TI - Identifying and Prioritizing Gaps in Neuroendocrine Tumor Research: A Modified Delphi Process With Patients and Health Care Providers to Set the Research Action Plan for the Newly Formed Commonwealth Neuroendocrine Tumor Collaboration. AB - PURPOSE: Neuroendocrine tumors (NETs) are a diverse group of malignancies that pose challenges common to all rare tumors. The Commonwealth Neuroendocrine Tumor Collaboration (CommNETS) was established in 2015 to enhance outcomes for patients with NETs in Canada, Australia, and New Zealand. A modified Delphi process was undertaken involving patients, clinicians, and researchers to identify gaps in NETs research to produce a comprehensive and defensible research action plan. METHODS: A three-round modified Delphi process was undertaken with larger representation than usual for medical consensus processes. Patient/advocate and health care provider/researcher expert panels undertook Round 1, which canvassed 17 research priorities and 42 potential topics; in Round 2, these priorities were ranked. Round 3 comprised a face-to-face meeting to generate final consensus rankings and formulate the research action plan. RESULTS: The Delphi groups consisted of 203 participants in Round 1 (64% health care providers/researchers, 36% patient/advocates; 52% Canadian, 32% Australian, and 17% New Zealander), of whom 132 participated in Round 2. The top eight priorities were biomarker development; peptide receptor radionuclide therapy optimization; trials of new agents in advanced NETs; functional imaging; sequencing therapies for metastatic NETs, including development of validated surrogate end points for studies; pathologic classification; early diagnosis; interventional therapeutics; and curative surgery. Two major areas were ranked significantly higher by patients/advocates: early diagnosis and curative surgery. Six CommNETS working parties were established. CONCLUSION: This modified Delphi process resulted in a well-founded set of research priorities for the newly formed CommNETS collaboration by involving a large, diverse group of stakeholders. This approach to setting a research agenda for a new collaborative group should be adopted to ensure that research plans reflect unmet needs and priorities in the field. PMID- 28831447 TI - Presentation, Treatment, and Outcomes of Haitian Women With Breast Cancer in Miami and Haiti: Disparities in Breast Cancer-A Retrospective Cohort Study. AB - PURPOSE: We compared a cohort of Haitian immigrants with residents in Haiti with breast cancer (BC) to evaluate the effects of location on presentation, treatment, and outcomes. PATIENTS AND METHODS: Participants were Haitian women with BC living in Miami who presented to the University of Miami/Jackson Memorial Hospital and women with BC living in Haiti who presented to the Innovating Health International Women's Cancer Center. The primary outcome was the relationship between location, cancer characteristics, and survival. The secondary objective was to compare our results with data extracted from the SEER database. Cox regression was used to compare survival. RESULTS: One hundred two patients from University of Miami/Jackson Memorial Hospital and 94 patients from Innovating Health International were included. The patients in Haiti, compared with the patients in Miami, were younger (mean age, 50.2 v 53.7 years, respectively; P = .042), presented after a longer duration of symptoms (median, 20 v 3 months, respectively; P < .001), had more advanced stage (44.7% v 25.5% with stage III and 27.6% v 18.6% with stage IV BC, respectively), and had more estrogen receptor (ER) -negative tumors (44.9% v 26.5%, respectively; P = .024). The percentage of women who died was 31.9% in Haiti died compared with 17.6% in Miami. Median survival time was 53.7 months for women in Haiti and was not reached in Miami. The risk of death was higher for women in Haiti versus women in Miami (adjusted hazard ratio, 3.09; P = .0024). CONCLUSION: Women with BC in Haiti experience a significantly worse outcome than immigrants in Miami, which seems to be related to a more advanced stage and younger age at diagnosis, more ER-negative tumors, and lack of timely effective treatments. The differences in age and ER status are not a result of access to care and are unexplained. PMID- 28831448 TI - Cervical Precancer Treatment in Low- and Middle-Income Countries: A Technology Overview. AB - Cervical cancer is the fourth leading cause of cancer-related death in women worldwide, with 90% of cases occurring in low- and middle-income countries (LMICs). There has been a global effort to increase access to affordable screening in these settings; however, a corresponding increase in availability of effective and inexpensive treatment modalities for ablating or excising precancerous lesions is also needed to decrease mortality. This article reviews the current landscape of available and developing technologies for treatment of cervical precancer in LMICs. At present, the standard treatment of most precancerous lesions in LMICs is gas-based cryotherapy. This low-cost, effective technology is an expedient treatment in many areas; however, obtaining and transporting gas is often difficult, and unwieldy gas tanks are not conducive to mobile health campaigns. There are several promising ablative technologies in development that are gasless or require less gas than conventional cryotherapy. Although further evaluation of the efficacy and cost-effectiveness is needed, several of these technologies are safe and can now be implemented in LMICs. Nonsurgical therapies, such as therapeutic vaccines, antivirals, and topical applications, are also promising, but most remain in early-stage trials. The establishment of evidence-based standardized protocols for available treatments and the development and introduction of novel technologies are necessary steps in overcoming barriers to treatment in LMICs and decreasing the global burden of cervical cancer. Guidance from WHO on emerging treatment technologies is also needed. PMID- 28831449 TI - American Society of Clinical Oncology Multidisciplinary Cancer Management Course: Connecting Lives, Cancer Care, Education, and Compassion in Zimbabwe-A Pilot for Efforts of Sustainable Benefit? AB - The burden of cancer in low- to middle-income countries is growing and is expected to rise dramatically while resources to manage this disease remain inadequate. All authorities for the management of cancer recommend multidisciplinary care. Educational efforts by international organizations to assist local professionals in caring for their patients tend to have a lasting impact because they empower local professionals and enhance their skills. A multidisciplinary cancer management course was designed by American Society of Clinical Oncology staff and local experts to provide a roadmap for cross specialty interaction and coordination of care in Zimbabwe. The outcome of the course was measured through feedback obtained from participants and impact on local workforce. The cancer management course was relevant to daily practice and fostered long-lasting partnerships and collaborations. Furthermore, it resulted in a more motivated local workforce and strengthened existing multidisciplinary practices. Cancer care is in a critical state in low- to middle-income countries. Educational efforts and collaborative partnerships may provide a cost-effective strategy with sustainable benefits. A multidisciplinary approach to optimize therapy is desirable. Evaluation of the course impact after a period of 6 months to 1 year is needed to determine the sustainability and impact of such efforts. PMID- 28831450 TI - Colonic Mucosa-Associated Lymphoid Tissue Lymphoma Presented as Multiple Polyposis at Colonoscopy in a Nigerian Man: Case Report of a Rare Occurrence and Brief Review of Literature. PMID- 28831451 TI - DNA Repair Defect and RAS Mutation in Two Patients With Schistosoma mansoni Associated Colorectal Cancer: Carcinogenesis Steps or Mere Coincidence? PMID- 28831452 TI - Call for Breast Cancer Risk Factor Education in Countries With Limited Health Care Resources. PMID- 28831453 TI - High Epidermal Growth Factor Receptor Mutation Rates in Peruvian Patients With Non-Small-Cell Lung Cancer: Is It a Matter of Asian Ancestry? PMID- 28831454 TI - Identification of an albumin-like protein in plasma of Atlantic cod (Gadus morhua) and its biomarker potential for PAH contamination. AB - Increased research efforts are currently focusing on Atlantic cod (Gadus morhua) and its significance for monitoring the contaminant situation in marine environments. Polycyclic aromatic hydrocarbons (PAHs) are well known toxic and carcinogenic compounds, thus continuous monitoring is required to ensure ecosystem sustainability and human food safety. A sensitive biomarker of PAH exposure in humans is the detection of PAH metabolites bound to albumin in blood. The potential of a similar PAH-albumin biomarker in Atlantic cod was therefore investigated by a desktop bioinformatic study followed by liquid chromatography mass spectrometry/mass spectrometry analysis of plasma from 16 fish. For the first time, an albumin-like protein in plasma of Atlantic cod is described, and the biomarker potential based on PAH-albumin adduct detection is discussed. Due to the detected low abundance of the albumin-like protein, it was found unlikely to be applicable as a new biomarker tool for evaluation of PAH exposure. PMID- 28831455 TI - Inhibition of p70S6K does not mimic the enhancement of Akt phosphorylation by rapamycin. AB - It has been suggested that the mTOR complex 1 (mTORC1)/p70S6K axis represses upstream PI3K/Akt signaling through phosphorylation of IRS-1 and its subsequent degradation. One potential and current model that explains Akt activation induced by the mTOR inhibitor rapamycin is the relief of mTORC1/p70S6K-mediated feedback inhibition of IRS-1/PI3K/Akt signaling, although this has not been experimentally proven. In this study, we found that chemical inhibition of p70S6K did not increase Akt phosphorylation. Surprisingly, knockdown of p70S6K even substantially inhibited Akt phosphorylation. Hence, p70S6K inhibition clearly does not mimic the activation of Akt by rapamycin. Inhibition or enforced activation of p70S6K did not affect the ability of rapamycin to increase Akt phosphorylation. Moreover, inhibition of mTORC1 with either rapamycin or raptor knockdown did not elevate IRS-1 levels, despite potently increasing Akt phosphorylation. Critically, knockdown or knockout of IRS-1 or IRS-2 failed to abolish the ability of rapamycin to increase Akt phosphorylation. Therefore, IRS 1 and IRS-2 are not essential for mediating rapamycin-induced Akt activation. Collectively, our findings suggest that Akt activation by rapamycin or mTORC1 inhibition is unlikely due to relief of p70S6K-mediated feedback inhibition of IRS-1/PI3K/Akt signaling. PMID- 28831456 TI - Strategies for enzyme saving during saccharification of pretreated lignocellulo starch biomass: effect of enzyme dosage and detoxification chemicals. AB - Two strategies leading to enzyme saving during saccharification of pretreated lignocellulo-starch biomass (LCSB) was investigated which included reducing enzyme dosage by varying their levels in enzyme cocktails and enhancing the fermentable sugar yield in enzyme-reduced systems using detoxification chemicals. Time course release of reducing sugars (RS) during 24-120 h was significantly higher when an enzyme cocktail containing full dose of cellulase (16 FPU/g cellulose) along with half dose each of xylanase (1.5 mg protein/g hemicelluloses) and Stargen (12.5 MUl/g biomass) was used to saccharify conventional dilute sulphuric acid (DSA) pretreated biomass compared to a parallel system where only one-fourth the dose of the latter two enzymes was used. The reduction in RS content in the 120 h saccharified mash to the extent of 3-4 g/L compared to the system saccharified with full complement of the three enzymes could be overcome considerably by supplementing the system (half dose of two enzymes) with detoxification chemical mix incorporating Tween 20, PEG 4000 and sodium borohydride. Microwave (MW)-assisted DSA pretreated biomass on saccharification with enzyme cocktail having full dose of cellulase and half dose of Stargen along with detoxification chemicals gave significantly higher RS yield than DSA pretreated system saccharified using three enzymes. The study showed that xylanase could be eliminated during saccharification of MW-assisted DSA pretreated biomass without affecting RS yield when detoxification chemicals were also supplemented. The Saccharification Efficiency and Overall Conversion Efficiency were also high for the MW-assisted DSA pretreated biomass. Since whole slurry saccharifcation of pretreated biomass is essential to conserve fermentable sugars in LCSB saccharification, detoxification of soluble inhibitors is equally important as channelling out of insoluble lignin remaining in the residue. As one of the major factors contributing to the cost of ethanol production from LCSB is the cost of enzymes, appropriate modification of enzyme cocktail based on the composition of the pretreated biomass coupled with effective detoxification of the slurry would be a promising approach towards cost reduction. PMID- 28831457 TI - Editorial: Use and Misuse of Systemic Antibiotics in Periodontitis Treatment. PMID- 28831458 TI - Cemental Tears: A Report of Four Cases and Literature Review. AB - PURPOSE: To present four different cases with a diagnosed cemental tear. The differences in aetiology, clinical diagnosis and treatment of cemental tears are described and discussed in order to provide guidance for clinical practice. CASES: Four patients of different ages presented with gingival swelling and other different complaints. Clinically, localised deep periodontal pockets and inflammation were noted on affected aspects in four cases. Radiographic examination revealed a prickly or flakey structure and bone loss on the affected side of the involved tooth. Different treatments, such as extraction, traditional periodontal initial therapy, periodontal flap surgery, or no clinical intervention were given based on different extents of tooth mobility and bone loss. In the first two cases, teeth with cemental tear were extracted due to poor prognosis. In case 3, deep pockets recovered to a normal condition, while cemental tears on the distal aspect of tooth 21 had no abnormal sensation or clinical symptoms. In case 4, a periapical radiograph showed distal bone loss was interrupted, and the tooth also recovered normal mobility. Histopathological evaluation of the specimens with H&E staining all resulted in a definitive diagnosis of cemental/cementodentinal tears. CONCLUSIONS: Cementodentinal or cemental tears are unique, localized, tooth-related factors associated with attachment loss. Aging, trauma and occlusal overload are the main aetiological factors. Early diagnosis and appropriate treatment will avoid unnecessary tooth extraction and result in a better prognosis. Detailed clinical and radiographic examinations as well as explorative surgery may help to make a diagnosis of cemental tears, but histopathological analysis is the only method for a definitive diagnosis. PMID- 28831459 TI - Frequency of Application of AmF/NaF/SnCl2 Solution and Its Potential in Inhibiting the Progression of Erosion in Human Dental Enamel - An In Vitro Study. AB - PURPOSE: To evaluate whether increasing the frequency of its use can enhance the protective effect of AmF/NaF/SnCl2 solution against dental erosion. MATERIALS AND METHODS: Sixty human enamel samples were obtained from sound human third molars, and after the formation of incipient erosive lesions (1% citric acid, pH 4.0, for 3 min), they were divided into five treatment groups (n = 12): G1 - deionised water (negative control); G2 - NaF solution (positive control) once a day; G3 - NaF solution (positive control) twice a day; G4 - AmF/NaF/SnCl2 solution once a day; G5 - AmF/NaF/SnCl2 solution twice a day. The samples were then subjected to 5 days of erosive cycling through 6 daily immersions (2 min each) in citric acid solution (0.05 M, pH 2.6). At the end of erosive cycling, surface wear was determined by means of optical profilometry. RESULTS: One-way ANOVA showed that the surface wear was affected by surface treatments (p < 0.001). Tukey's test showed no difference between the groups in which NaF was applied once or twice, but they showed limited reduction in wear compared to the deionised water group (G1). In the groups treated with the AmF/NaF/SnCl2 solution, there was a statistically significant difference between one and two application times (p < 0.001). Although both demonstrated statistically significantly reduced tissue loss, increasing the frequency increased its anti-erosive potential. CONCLUSION: The AmF/NaF/SnCl2 solution proved to be effective in reducing dental enamel surface loss and its use twice a day potentiated its anti-erosive effect. PMID- 28831460 TI - Disease Staging Index for Aggressive Periodontitis. AB - Major advances in the knowledge about the aetiopathogenesis of aggressive periodontitis (AgP) have been achieved. An ever increasing number of scientific articles related to AgP are published every year contributing significantly to the knowledge of this unique and complex disease. AgP has been classified into localised and generalised forms based on their extent and disease progression with distinct clinical and radiological features. A classification of AgP based on severity (mild, moderate and severe) exists; however, it is not easily applicable. Therefore, studies on AgP do not categorise the disease based on severity. A disease staging index for AgP is proposed based on clinical and radiological features, as well as risk factors. Based on the presence or absence of risk factors confirmed by longitudinal studies, cases of AgP can be divided into low risk, medium risk and high risk profiles for disease progression. Clinicians can devise a broad treatment plan for their AgP cases based on this staging. More frequent recall intervals are proposed for patients at medium and high risk for disease progression. Ten cases of AgP with 10-year follow-up were used to validate the staging index by retrospectively assigning prognosis and associating it with tooth loss. The use of this staging by researchers would increase external validity of research on AgP. Long-term analysis of AgP cases are needed to validate this staging index longitudinally. PMID- 28831461 TI - The Impact of Brief Interventions for Tobacco Cessation on Patients' Awareness of Cigarette Smoking as a Risk Factor for Chronic Periodontitis. AB - PURPOSE: To evaluate the awareness of cigarette smoking as a risk factor for chronic periodontitis in patients either undergoing active periodontal treatment (APT) or enrolled in supportive periodontal therapy (SPT). MATERIALS AND METHODS: Comprehensive tobacco use history was collected with a questionnaire in 50 patients before and after APT (test) and in 50 patients (control) enrolled in SPT at the School of Dental Medicine, University of Bern. Carbon monoxide (CO) exhalation levels were measured in both APT and SPT patients. RESULTS: In the test group, 94% (n = 47) completed the study. Before APT, 48% of these (n = 24) knew about the association between smoking and periodontal disease, while 42% (n = 21) assumed a possible association and 10% (n = 5) did not. Following APT, 53% (n = 25) knew about the association, while 34% (n = 17) still assumed a possible association and 10% (n = 5) did not. In the control group, 60% (n = 30) of SPT patients knew about the association of smoking with periodontal disease, while 30% (n = 15) assumed an association and 10% (n = 5) were not aware of any association. In both APT and SPT patients, neither between-group nor baseline to follow-up differences were detected (p > 0.05). CONCLUSIONS: Brief interventions for tobacco cessation during APT or SPT failed to increase periodontal patients' awareness of smoking as a risk factor for chronic periodontitis. In order to both increase awareness and motivation to quit tobacco use, more counseling than conventional brief interventions may be needed. Key words: chronic periodontitis, exhaled carbon monoxide, patient education, risk factor, smoking, smoking cessation. PMID- 28831462 TI - Structural features of monohydrated 2-(4-fluorophenyl)ethylamine: a combined spectroscopic and computational study. AB - A jet-cooled singly hydrated 2-(4-fluorophenyl)ethylamine (4-FPEA-H2O) cluster has been studied by ionization-loss stimulated Raman spectroscopy of the 4-FPEA photofragment and density functional calculations of the parent. Comparison of the measured spectrum of the photofragment to computed scaled harmonic Raman spectra of different conformers of the 4-FPEA-H2O cluster, at the M06-2X/6 311++G(d,p) level of theory, allowed determination of the calculated spectrum that best fits the experimental one. The correlation between them was further supported by the stability of the cluster, as revealed from the calculated energies of the fully optimized geometries of the possible different clusters in the ground electronic state. The corresponding structure consists of a water molecule, which is hydrogen-bonded to the nitrogen lone pair of the folded ethylamino side chain in the most stable gauche conformer of 4-FPEA. The presence of the hydrogen bond and other bonding and non-bonding interactions was also tested by atoms in molecules and noncovalent interaction analyses. The former approach showed no critical points in electron density, while the latter revealed regional topologies of reduced density gradients, indicating the formation of this hydrogen-bond and other attractive and repulsive interactions. The monohydration of 4-FPEA provides an insight into the intra- and inter-molecular interactions that play a role in stabilizing the cluster. PMID- 28831463 TI - A highly luminescent entangled metal-organic framework based on pyridine substituted tetraphenylethene for efficient pesticide detection. AB - A novel pillared-layered entangled luminescent metal-organic framework [Zn2(bpdc)2(BPyTPE)] (1) (BPyTPE = (E)-1,2-diphenyl-1,2-bis(4-(pyridin-4 yl)phenyl)ethene) has been designed and constructed. The solvent-free 1 exhibits strong blue-green emission with an excellent fluorescence quantum yield of 99% and provides a facile and reversible method to sensitively and quantitatively detect trace pesticide of 2,6-dichloro-4-nitroaniline. PMID- 28831464 TI - Metal-free redox active deep eutectic solvents. AB - Metal-free deep eutectic solvents composed of hydrogen bond donors and viologen based ammonium salts exhibit reversible electrochemistry with viologen concentrations of 4.2 M and freezing points near room temperature. Spectroelectrochemistry and simulation of voltammetry indicate poor aggregation of the reduced radical cation. PMID- 28831465 TI - Sisters together: co-sensitization of near-infrared emission of ytterbium(iii) by BODIPY and porphyrin dyes. AB - A ytterbium(iii) acetate complex with a BODIPY and a porphyrin as co-sensitizers emits strongly at 978 nm over a broader excitation window between 450-560 nm. PMID- 28831466 TI - Novel fluorescent cationic benzothiazole dye that responds to G-quadruplex aptamer as a novel K+ sensor. AB - A fluorescent cationic benzothiazole dye that selectively targets a G-quadruplex aptamer was designed and synthesized as a K+ sensor. The K+-driven aptamer sensor is based on the strategy of conformational transition from single-stranded DNA to G-quadruplex structure, leading to an amplified fluorescence signal in the reporter. This fluorescent sensor displayed high selectivity for K+, suggesting great potential for practical applications. PMID- 28831467 TI - Remarkable nonlinear optical response of excess electron compounds: theoretically designed alkali-doped aziridine M-(C2NH5)n. AB - Theoretically designed alkali-doped aziridine M-(C2NH5)n (M = Li, Na and K; n = 1, 2, 3, and 4) are investigated by density functional theory (DFT) and time dependent TD-DFT. The interaction energies at optimized electronic structures indicate that alkali-doped aziridine are quite stable. The natural population analysis of charges on alkali atoms show that all positive and electronic transitions to LUMO orbitals are large, so that the designed compounds not only have electride features, but also have large flexible ligands. This leads to a high-performance nonlinear optical response (NLO) and this remarkable NLO response mainly comes from alkali atoms. By calculating the first hyperpolarizabilities for M-(C2NH5)4 with M@Calix[4]pyrrole for comparison, we demonstrate that enhancements of the NLO response of M-(C2NH5)4 are 10 to 100 times larger than those of M@Calix[4]pyrrole, and in particular, the largest first hyperpolarizability values of Na-(C2NH5)4 is up to 3.4 * 106 (a.u.). PMID- 28831468 TI - Functionalized lignin biomaterials for enhancing optical properties and cellular interactions of dyes. AB - We report a library of functionalized lignins and demonstrate their utility as nanocontainers for organic dyes in biologically relevant applications. Kraft lignin was modified via SN2 reaction at the phenolic -OH group utilizing a mild base, potassium carbonate, and various alkyl halides, several bearing additional functionalities, with dimethylsulfoxide as solvent. The resulting phenoxy ethers were characterized by 1H-NMR and IR spectroscopy, as well as DLS and SEM to evaluate their morphology and supramolecular organization. Lignin modified with long-chain hydrocarbon tails was found to effectively encapsulate DiD, a cyanine dye, decrease aggregation, enhance optical transitions and exert a photoprotective effect. The dye-lignin assemblies were also examined as imaging agents, via confocal microscopy, and found to accumulate intracellularly with no leaching of the dye to hydrophobic subcellular components observed. Lignin functionalized with short chain carboxylic acids interacts with ligands directed at the norepinephrine transporter (NET), suggesting applications in sequestration of neuroactive compounds. PMID- 28831469 TI - Mechanistic insight into selective catalytic combustion of HCN over Cu-BEA: influence of different active center structures. AB - HCN being a highly toxic N-containing volatile organic compound (VOCs) poses great threat to human living environment. Selective catalytic combustion of HCN (HCN-SCC) over metal modified zeolite catalysts has attracted great attention due to related high efficiency and excellent N2 selectivity. In the present work, three types of 24T-Cu-BEA models with different active centers of single [Cu]+, double [Cu]+, and [Cu-O-Cu]2+ were constructed for HCN-SCC mechanism simulations based on density functional theory (DFT). DFT simulation results revealed that HCN-SCC followed an oxidation mechanism over double [Cu]+ through an intermediate of NCO, wherein the synergistic effects of double [Cu]+ active centers were clearly observed, resulting in a significantly lowered energy barrier (1.6 kcal mol-1) during HCN oxidation into NCO. However, an oxidation mechanism (HCN oxidized into NH radical and CO2 through intermediate of HNCO) combining with a hydrolysis mechanism (NH radical hydrolyses into NH3) occurred over single [Cu]+ and [Cu-O-Cu]2+, wherein the NH2 hydrolysis to NH3 step was regarded as the rate determining step with an energy barrier of 72.3 and 74.3 kcal mol-1, respectively. Finally, Mulliken charge transfer (CT) analysis was conducted, based on which the electric properties of different active centers were well illustrated. PMID- 28831470 TI - Benzoquinonoid-bridged dinuclear actinide complexes. AB - We report the coordination chemistry of the tripodal tris[2-amido(2 pyridyl)ethyl]amine ligand, L, with thorium(iv) and uranium(iv). Using a salt metathesis strategy from the potassium salt of this ligand, K3L, new actinide complexes were isolated, namely the dimeric thorium complex [ThCl(L)]2 (1) and the monomeric uranium complex UI(THF)(L) (2); under different crystallisation conditions, the dimeric uranium complex is also isolated, [UI(L)]2 (2-dimer). With the aim of studying electronic phenomena such as magnetic exchange between two actinide ions, we have synthesised the first examples of dinuclear, quinoid bridged actinide complexes from dianionic 2,5-bis[2,6-(diisopropyl)anilide]-1,4 benzoquinone (QDipp) and 2,5-bis[2-(methoxy)anilide]-1,4-benzoquinone (QOMe) ligands. The resulting complexes are [Th(L)]2QDipp (3), [Th(THF)(L)]2QOMe (5) and [U(L)]2QOMe (6). The targeted [U(L)]2QDipp complex (4) could not be isolated. All isolated complexes have been characterised by spectroscopic methods and X-ray crystallography. The uranium(iv) complexes 2-dimer and 6 have been studied by SQUID magnetometry but indicate that there is negligible magnetic exchange between the two uranium(iv) ions. The reduced form of 6, [K(18-c-6)][6-] is unstable and highly sensitive, but X-ray crystallography indicates that it is a novel UIVUIV complex bridged by a quinoid-radical. PMID- 28831471 TI - Rapid and specific luminescence sensing of Cu(ii) ions with a porphyrinic metal organic framework. AB - We herein present a porphyrinic metal-organic framework (MOF) as a highly sensitive fluorescent probe targeting Cu(ii) ions with a fast response. The well isolated nature of porphyrin moieties within the framework greatly enable accessible recognition sites, which leads to an outstanding detection limit performance of 67 nM among MOF-based materials. PMID- 28831472 TI - The fluctuating population of Sm 4f configurations in topological Kondo insulator SmB6 explored with high-resolution X-ray absorption and emission spectra. AB - High-resolution partial-fluorescence-yield X-ray absorption and resonant X-ray emission spectra were used to characterize the temperature dependence of Sm 4f configurations and orbital/charge degree of freedom in SmB6. The variation of Sm 4f configurations responds well to the formed Kondo gap, below 140 K, and an in gap state, below 40 K. The topological in-gap state is correlated with the fluctuating population of Sm 4f configurations that arises via carrier transfer between 3d94f6 and 3d94f5 states; both states are partially delocalized, and the mediating 5d orbital plays the role of a transfer path. Complementary results shown in this work thus manifest the importance of configuration fluctuations and orbital delocalization in the topological surface state of SmB6. PMID- 28831473 TI - Magnetic diversity in three-dimensional two-fold-interpenetrated structures: a story of two compounds. AB - A magnetostructural correlation has been carried out for two newly synthesized two-fold-interpenetrated three-dimensional structures. Compound 1, denoted as [Ni(L1)(L2)].2DMF (where L1 is 1,4-benzene-dicarboxylic acid (BDC), L2 is 4,4 oxybis-(N-(pyridine-4-yl)benzamide), and DMF is N,N'-dimethylformamide), was observed to have a three-dimensional structure with two-fold interpenetration. Compound 2, denoted as [Co(L3)(L2)].2DMF (where L3 is 2,5-thiopehene-dicarboxylic acid (TDC)), was also observed to display a three-dimensional structure with an architecture identical to that of compound 1. Both compounds were well characterised using several techniques including single-crystal X-ray diffraction, powder X-ray diffraction, TGA, and IR. Magnetism and specific heat measurements of compound 1 revealed a canted-antiferromagnetic transition at TN ~ 4 K and a field-induced spin-flop transition at a relatively low field strength. These exotic features were attributed to the low-symmetry space group P(1[combining macron]) and single-ion anisotropy of the Ni2+ sub-lattice. In contrast, compound 2 was found to be weakly antiferromagnetic in nature with a negligible interaction between the magnetic Co2+ ions. PMID- 28831474 TI - Differential capacitance of an electric double layer with asymmetric solvent mediated interactions: mean-field theory and Monte Carlo simulations. AB - The differential capacitance of an electrical double layer is directly affected by properties of the electrolyte solution such as temperature, salt concentration, ionic size, and solvent structure. In the present work, we employ a mean-field approach and Monte Carlo simulations to investigate how the inclusion of asymmetric solvent-mediated ion-ion and ion-surface interactions affects the differential capacitance. We focus on a charged flat electrode immersed in an electrolyte solution of monovalent ions at physiological concentration in a uniform dielectric background. Solvent-mediated anion-anion, anion-cation and cation-cation interactions are modeled on the basis of Yukawa potentials with three independent strengths that add to Coulomb and excluded volume pair-potentials, the latter accounted for through a lattice gas approach. We use the three interaction strengths to produce and analyze asymmetric profiles of the differential capacitance as function of the electrode's surface charge density. While solvent-mediated anion-anion and cation-cation interactions mainly affect the behavior at medium charge densities of the electrode, anion-cation repulsion increases the differential capacitance of a weakly charged electrode. We present a simple phenomenological model to rationalize this finding. Most importantly, because the added solvent-mediated interaction potential is comparatively soft, our mean-field model is able to qualitatively - and in some cases quantitatively - reproduce all Monte Carlo simulation results, even at high surface charge densities of the electrode. PMID- 28831475 TI - Interfacial properties of borophene contacts with two-dimensional semiconductors. AB - The interfacial properties of beta12 phase borophene contacts with other common two-dimensional materials (transition-metal dichalcogenides, group IV-enes and group V-enes) have been systematically studied using a density functional theory (DFT) method. The zero tunneling barrier is found for all of the investigated beta12 phase borophene contacts except for the case of beta12 borophene/graphene. The chemically reactive properties and high work function (4.9 eV) of the stable beta12 borophene lead to the formation of Ohmic contacts with silicene, germanene, stanene, black phosphorene, arsenene and antimonene. The advantage of the zero tunnel barrier remains when changing the borophene from the beta12 phase to the Delta phase. Therefore, a high carrier injection rate is expected in these borophene contacts. Our study provides guidance on borophene for future two dimensional materials based device designs. PMID- 28831476 TI - Phenylarsine oxide (PAO) induces apoptosis in HepG2 cells via ROS-mediated mitochondria and ER-stress dependent signaling pathways. AB - Arsenic trioxide (As2O3) is an old drug that has recently been reintroduced as a therapeutic agent for acute promyelocytic leukemia (APL). Although As2O3 is also applied to treat other types of cancer in vitro and in vivo, it has been reported that single agent As2O3 has poor efficacy against non-hematologic malignant cancers in clinical trials. Recently, a few reports have indicated that organic arsenic compounds can be a possible alternative for the treatment of As2O3 resistant cancers. In this study, we aimed to investigate whether the organic arsenic compound phenylarsine oxide (PAO) has potent cytotoxic effects against human hepatocellular carcinoma (HCC) HepG2 cells. Our results showed that PAO not only had a potent inhibitory effect on the proliferation of HepG2 cells but also activated apoptosis-related proteins (e.g., caspase-3 and -9 and poly-ADP ribose polymerase) in a dose- and time-dependent manner. Furthermore, intracellular ROS were specifically accumulated in the mitochondria and endoplasmic reticulum (ER) after exposure to PAO, implying that they are the target organelles for PAO induced cytotoxicity. Additionally, when the cells were pretreated with antioxidant N-acetylcysteine (NAC), apoptosis and ER-stress were attenuated significantly, suggesting that induction of apoptosis and cell death probably occurs through the ROS-mediated mitochondria and ER-stress dependent signaling pathways. PMID- 28831477 TI - Biotin-tagged platinum(iv) complexes as targeted cytostatic agents against breast cancer cells. AB - A biotin-guided platinumIV complex is highly cytotoxic against breast cancer cells but hypotoxic against mammary epithelial cells. The mono-biotinylated PtIV complex is superior to the di-biotinylated one and hence a promising drug candidate for the targeted therapy of breast cancer. PMID- 28831479 TI - 129Xe NMR-based sensors: biological applications and recent methods. AB - Xenon is a first-rate sensor of biological events owing to its large polarizable electron cloud, which induces significant modifications to NMR parameters in response to slight changes in its local environment. The use of xenon as a sensor is of increasing interest for sensitive magnetic resonance imaging, because its signal can be enhanced by several orders of magnitude, mainly by spin-exchange optical pumping. Furthermore, xenon can be vectorized toward targets of interest by using functionalized host systems, which enables their detection at sub nanomolar concentrations. In association with a new generation of detection methods, this gives rise to a powerful molecular imaging approach, whereby xenon can be delivered systematically several times after the introduction of a functionalized host system. PMID- 28831478 TI - A cancer cell specific targeting nanocomplex for combination of mRNA-responsive photodynamic and chemo-therapy. AB - We have developed a cancer cell specific targeting nanocomplex which combines photodynamic therapy with chemotherapy through precisely responding to the intracellular tumor-related mRNA. The combined treatment of these two modalities showed significantly enhanced therapeutic effects on cancer cells. PMID- 28831480 TI - Performance limitations in thieno[3,4-c]pyrrole-4,6-dione-based polymer:ITIC solar cells. AB - We report a systematic study of the efficiency limitations of non-fullerene organic solar cells that exhibit a small energy loss (Eloss) between the polymer donor and the non-fullerene acceptor. To clarify the impact of Eloss on the performance of the solar cells, three thieno[3,4-c]pyrrole-4,6-dione-based conjugated polymers (PTPD3T, PTPD2T, and PTPDBDT) are employed as the electron donor, which all have complementary absorption spectra compared with the ITIC acceptor. The corresponding photovoltaic devices show that low Eloss (0.54 eV) in PTPDBDT:ITIC leads to a high open-circuit voltage (Voc) of 1.05 V, but also to a small quantum efficiency, and in turn photocurrent. The high Voc or small energy loss in the PTPDBDT-based solar cells is a consequence of less non-radiative recombination, whereas the low quantum efficiency is attributed to the unfavorable micro-phase separation, as confirmed by the steady-state and time resolved photoluminescence experiments, grazing-incidence wide-angle X-ray scattering, and resonant soft X-ray scattering (R-SoXS) measurements. We conclude that to achieve high performance non-fullerene solar cells, it is essential to realize a large Voc with small Eloss while simultaneously maintaining a high quantum efficiency by manipulating the molecular interaction in the bulk heterojunction. PMID- 28831481 TI - A new strategy for inducing dipole moments in charge-transfer complexes: introduction of asymmetry into axially ligated iron phthalocyanines. AB - Introduction of asymmetry into charge-transfer complexes composed of axially ligated iron phthalocyanines was achieved. In the obtained crystals of TPP[FeIII(Pc)(CN)Cl]2, TPP[FeIII(Pc)(CN)Br]2, and TPP[FeIII(Pc)BrCl]2 (TPP = tetraphenylphosphonium and Pc = phthalocyanine), the axial positions of the iron atoms were occupied by 50/50 ratios of the ligands CN/Cl, CN/Br, and Br/Cl, respectively. The crystal structures of the obtained CT complexes were isostructural to those composed of the symmetric analogues of the type [FeIII(Pc)L2] (L = CN, Cl or Br); the [FeIII(Pc)LL'] units formed regular one dimensional chains along the c-axis following the symmetry of the P42/n space group. Despite forming similar regular chains to the symmetric systems, the electrical resistivities and activation energies were enhanced in the obtained CT complexes compared to those in symmetric systems, indicating that the charge ordered states were stabilised by the introduction of asymmetry. More specifically, the dielectric relaxation behaviour of the inhomogeneous disordered TPP[FeIII(Pc)(CN)Cl]2 probably suggests that a dipole moment was induced in this material. PMID- 28831482 TI - Ultrathin TiO2-B nanowires as an anode material for Mg-ion batteries based on a surface Mg storage mechanism. AB - Ultrathin TiO2-B nanowires with a naked (-110) surface were prepared by a hydrothermal process and used as the anode material for Mg-ion batteries. The material delivered a reversible Mg2+ ion capacity of 110 mA h g-1 at the 0.1C rate. Excellent cycling stability was achieved with a small capacity-fading rate of 0.08% per cycle. In addition, a discharge capacity of 34 mA h g-1 was obtained at the 50C rate, demonstrating the material's excellent high rate capability. First-principles calculations showed that Mg2+ ions hardly penetrated into the TiO2-B lattice because of a very large Mg2+ ion diffusion barrier of 0.63 eV. Instead, the Mg2+ ions were stored at the 4-coordinated vacancies of TiO2-B nanowire (-110) surfaces. The adsorbed Mg2+ ions were bonded with unpaired surface oxygen atoms. Meanwhile, a small amount of electrons were transferred from the O-2p state to the Ti-3d state. PMID- 28831483 TI - Monitoring thermally induced structural deformation and framework decomposition of ZIF-8 through in situ temperature dependent measurements. AB - ZIF-8 is an easily synthesized porous material which is widely applied in gas storage/separation, catalysis, and nanoarchitecture fabrication. Thermally induced atomic displacements and the resultant framework deformation/collapse significantly influence the application of ZIF-8, and therefore, in situ temperature dependent FTIR spectroscopy was utilized to study the framework changes during heating in the oxidative environment. The results suggest that ZIF 8 undergoes three transition stages, which are the lattice expansion stage below 200 degrees C, the "reversible" structural deformation stage from 200 to 350 degrees C, and the decomposition/collapse stage over 350 degrees C. Our research indicates that the Zn-N bond breaks at a temperature of 350 degrees C in the oxidant environment, leading to a drastic deformation of the ZIF-8 structure. PMID- 28831484 TI - Protective effects of theasinensin A against carbon tetrachloride-induced liver injury in mice. AB - Theasinensins have been identified as a major group of unique catechin dimers mainly found in oolong tea and black tea. Among several types of theasinensins, theasinensin A (TSA), an epigallocatechin gallate (EGCG) dimer with an R-biphenyl bond, is the most abundant theasinensin prevalent in oolong tea. Previous studies have reported that TSA exhibits antioxidative, anti-inflammatory and anti-cancer activities in vitro and in vivo. However, little is known about the hepatoprotective effect of TSA. Thus, the aim of this study was to investigate the inhibitory effect of TSA on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. After intraperitoneal injection of CCl4 for eight weeks, histological lesions in the liver tissue and elevated serum levels of alanine aminotransferase and alkaline phosphatase were found in mice. Conversely, oral administration of TSA relieved CCl4-induced liver injury as well as ameliorated liver functions. Our immunohistochemical staining results revealed that collagen deposition was profoundly reduced due to supplementation with TSA. In addition, we also found that hepatic alpha-smooth muscle actin (alpha-SMA) and matrix metallopeptidase 9 (MMP-9) expression was suppressed through the inhibition of transforming growth factor beta (TGF-beta). Taken together, our current findings suggest that TSA may serve as a potent bioactive constituent from oolong tea that acts against liver fibrosis through the inhibition of hepatic stellate cell (HSC) activation. PMID- 28831485 TI - An ultrasensitive enzyme-free electrochemical immunosensor based on redox cycling amplification using methylene blue. AB - We report a new enzyme-free electrochemical sensor for ultrasensitive measurements of protein biomarkers in plasma and whole blood samples based on a unique electrochemical-chemical-chemical (ECC) redox cycling signal amplification scheme. This scheme uses methylene blue (MB) as a redox indicator which undergoes an endergonic reaction with Ru(NH3)63+ and a highly exergonic reaction with tris(2-carboxyethyl)phosphine (TCEP). This approach offers improved detection sensitivity and sensor stability compared with enzyme-based ECC redox cycling techniques, while involving a simpler sensor modification process and detection protocol. This redox cycling scheme was combined with a robust immunosandwich assay for quantitative measurements of protein biomarkers. For proof of principle, Plasmodium falciparum histidine-rich protein 2 (PfHRP2) was measured in human plasma and whole blood samples, which could be detected down to 10 fg mL 1 and 18 fg mL-1, respectively. Furthermore, this immunosensor exhibits high selectivity, excellent reproducibility and good stability for up to 2 weeks, making it a promising platform for point-of-care testing, especially for detecting extremely low biomarker concentrations in raw biofluids. PMID- 28831486 TI - Total synthesis and mass spectrometric analysis of a Mycobacterium tuberculosis phosphatidylglycerol featuring a two-step synthesis of (R)-tuberculostearic acid. AB - We report the total synthesis of (R)-tuberculostearic acid-containing Mycobacterium tuberculosis phosphatidylglycerol (PG). The approach features a two step synthesis of (R)-tuberculostearic acid, involving an (S)-citronellyl bromide linchpin, and the phosphoramidite-assisted assembly of the full PG structure. Collision-induced dissociation mass spectrometry of two chemically-synthesized PG acyl regioisomers revealed diagnostic product ions formed by preferential loss of carboxylate at the secondary (sn-2) position. PMID- 28831487 TI - Light intensity field enhancement (LIFE) induced localized edge abrasion of silica-coated silver nanoprisms. AB - Silver nanoprisms (AgNPrs) exhibit localized surface plasmon resonance (LSPR) in the near infrared (NIR) region of the electromagnetic spectrum. LSPR-driven electric field enhancement around AgNPr edges has been investigated in various studies. A coating of dielectric materials such as silica on the surface of the AgNPrs is employed to extend the application of these nanoparticles under biocompatible conditions and to increase the thermal stability. Upon interactions with optical excitation (pulsed laser excitation), the AgNPrs undergo light intensity field enhancement (LIFE) at the corners. In the cases of hybrid hetero structures of AgNPrs with silica coatings (AgNPr@SiO2), LIFE leads to nano structural deformations. In this study, we demonstrate that, depending on the intensity of the light excitation, the medium properties and the geometrical sharpness of the corners of the prisms, LIFE could induce localized damage or abrasion at the edges of the immediate dielectric contact, which in this case was the silica coating. A theoretical study was conducted to establish the influence of the finite radius of curvature (ROC) of the corners on the plasmonic interactions to generate LIFE during optical excitation. Experiments were performed on AgNPr@SiO2 using nanosecond pulsed laser excitation at 900 nm and electron microscopic analysis of the nanostructures revealed the localized edge abrasion of the silica at the prism corners. To further study the effect of the direct plasmonic excitation during LIFE, pulsed laser excitation on ultra-thin graphene oxide (GO) wrapped AgNPr@SiO2 (GO-AgNPr@SiO2) was conducted. Due to the GO wrapping and subsequent changes in light absorption, the extent of the LIFE at the corners diminishes, which leads to structural stability and preservation of the hetero-structure morphology. PMID- 28831488 TI - Synthesis of the octahydronaphthalene core of nahuoic acid A via a B(C6F5)3 catalyzed intramolecular Diels-Alder (IMDA) reaction. AB - Model tetraenal 9b underwent intramolecular Diels-Alder cycloaddition in CH2Cl2 at -10 degrees C under catalysis by the bulky Lewis acid B(C6F5)3 to deliver as major components the cis-fused angularly-methylated octahydronaphthalene products, which are formed through the alternative exo orientations of the reacting moieties. One of these diastereomers features the relative and absolute configuration present in the core of nahuoic acid A, a natural product that acts as a cofactor-competitive inhibitor of the lysine methyl transferase SETD8. By contrast, catalysis of the reaction by Me2AlCl at -40 degrees C selectively afforded the trans-fused isomer resulting from the Re-endo orientation. PMID- 28831489 TI - Phonon-glass electron-crystals in ZnO-multiwalled carbon nanotube nanocomposites. AB - We propose a strategy for enhancing thermoelectric performance through the realization of a 'phonon-glass electron-crystal' (PGEC) by interface control using multiwalled carbon nanotubes (MWCNTs). By the consolidation of undoped ZnO nanoparticles with MWCNTs (0.5, 1, and 2 wt%) using spark plasma sintering, we fabricated the interface-controlled ZnO-MWCNT nanocomposites, in which ZnO grains were surrounded with a MWCNT network. Both single crystal-like charge transport (electron-crystal) and considerably reduced thermal conductivity (phonon-glass) were achieved simultaneously thanks to the beneficial effects of the MWCNT network, and this led to the enhancement of the thermoelectric figure of merit. We discussed these findings on PGECs in the ZnO-MWCNT nanocomposites from the viewpoint of interface control in detail, and our strategy may provide a promising way to the realization of PGEC in other hybrid thermoelectric materials. PMID- 28831490 TI - Strain and electric-field control of magnetism in supercrystalline iron oxide nanoparticle-BaTiO3 composites. AB - The manipulation of the magnetism of self-assembled iron oxide nanoparticle (NP) monolayers on top of BaTiO3 (BTO) single crystals is reported. We observe strain induced magnetoelectric coupling (MEC) as shown by measurements of both the magnetization and magneto-electric AC susceptibility (MEACS). The magnetization, coercivity, remanent magnetization and MEACS signal as a function of temperature show abrupt jumps at the BTO phase transition temperatures. Hereby the jump values are opposite for in-plane and out-of-plane measurements. Grazing incidence small angle X-ray scattering (GISAXS) and scanning electron microscopy (SEM) confirm a hexagonal close-packed supercrystalline order of the NP monolayers. Cross-sectional scanning transmission electron microscopy (STEM) experiments provide information about the layer structure of the sample. This work opens up viable possibilities for fabricating energy-efficient electronic devices by self assembly techniques. PMID- 28831491 TI - A switchable 3D liquid-liquid biconvex lens with enhanced resolution using Dean flow. AB - Liquid-liquid (L2) microlenses have great potential for various applications in imaging and detection systems. Traditional L2 microlenses are almost two dimensional (2D) due to the modulation of flow rates in planer chips. Fundamental difficulties in effective application to cell imaging and analysis arise due to the limitations of 2D profiles. Herein, we demonstrate the feasible design of three-dimensional (3D) L2 biconvex lenses to detect flowing cells. Using the auxiliary curved microchannels, a 3D L2 lens is formed using Dean flow. The shape of the 3D biconvex lens and its focal length can be modulated by tuning the flow rates of the liquids. 3D light focusing was successfully achieved and the focal length could be modulated by around 435 MUm, from 3554 MUm to 3989 MUm, in the experiment. The numerical aperture of the 3D L2 lens was also measured and its range was 0.175-0.198. Compared to a traditional objective lens with the same magnification (4*/0.1), the resolution of the 3D L2 biconvex lenses was improved 1.79-fold due to being completely immersed in liquid. Mouse myeloma cells sp2/0 and acute promyelocytic leukemia cells NB4 were imaged in the contrast experiments. The time response of experimental manipulation was about 2.7 ms. This 3D biconvex lens has great application prospects for cell imaging and analysis systems in lab-on-a-chip settings. PMID- 28831493 TI - Building with ions: towards direct write of platinum nanostructures using in situ liquid cell helium ion microscopy. AB - Direct write with a liquid precursor using an ion beam in situ, allows fabrication of nanostructures with higher purity than using gas phase deposition. Specifically, positively charged helium ions, when compared to electrons, localize the reaction zone to a single-digit nanometer scale. However, to control the interaction of the ion beam with the liquid precursor, as well as enable single digit fabrication, a comprehensive understanding of the radiolytic process, and the role of secondary electrons has to be developed. Here, we demonstrate an approach for directly writing platinum nanostructures from aqueous solution using a helium ion microscope, and discuss possible mechanisms for the beam-induced particle growth in the framework of Born-Oppenheimer and real-time electron dynamics models. We illustrate the nanoparticle nucleation and growth parameters through data analysis of in situ acquired movie data, and correlate these results to a fully encompassing, time-dependent, quantum dynamical simulation that takes into account both quantum and classical interactions. Finally, sub-15 nm resolution platinum structures generated in liquid are demonstrated. PMID- 28831494 TI - [Erratum to: Diagnosis of ischemia and revascularization in patients with ventricular tachyarrhythmia]. PMID- 28831492 TI - Quantitative profiling of innate immune activation by viral infection in single cells. AB - Cells infected by viruses can exhibit diverse patterns of viral and cellular gene expression. The patterns arise in part from the stochastic or noisy reaction kinetics associated with the small number of genomes, enzymes, and other molecules that typically initiate virus replication and activate cellular anti viral defenses. It is not known what features, if any, of the early viral or cellular gene expression correlate with later processes of viral replication or cell survival. Here we used two fluorescent reporters to visualize innate immune activation of human prostate cancer (PC3) cells against infection by vesicular stomatitis virus. The cells were engineered to express green-fluorescent protein under control of the promoter for IFIT2, an interferon-sensitive component of the anti-viral response, while red-fluorescent protein was expressed as a byproduct of virus infection. To isolate and quantitatively analyze single-cells, we used a unique microwell array device and open-source image processing software. Kinetic analysis of viral and cellular reporter profiles from hundreds of cells revealed novel relationships between gene expression and the outcome of infection. Specifically, the relative timing rather than the magnitude of the viral gene expression and innate immune activation correlated with the infection outcome. Earlier viral or anti-viral gene expression favored or hindered virus growth, respectively. Further, analysis of kinetic parameters estimated from these data suggests a trade-off between robust antiviral signaling and cell death, as indicated by a higher rate of detectable cell lysis in infected cells with a detectable immune response. In short, cells that activate an immune response lyse at a higher rate. More broadly, we demonstrate how the intrinsic heterogeneity of individual cell behaviors can be exploited to discover features of viral and host gene expression that correlate with single-cell outcomes, which will ultimately impact whether or not infections spread. PMID- 28831495 TI - 21st Annual SASRO Meeting. PMID- 28831496 TI - [Erratum to: Conservative and surgical ileus treatment]. PMID- 28831498 TI - [The central nervous system as the target organ of general anesthesia]. PMID- 28831499 TI - Erratum to: Efficacy of rasagiline and selegiline in Parkinson's disease: a head to-head 3-year retrospective case-control study. PMID- 28831500 TI - [Tendon pathologies around the ankle]. PMID- 28831501 TI - Non-traumatic hemorrhage is controlled with REBOA in acute phase then mortality increases gradually by non-hemorrhagic causes: DIRECT-IABO registry in Japan. AB - PURPOSE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is now a feasible and less invasive resuscitation procedure. This study aimed to compare the clinical course of trauma and non-trauma patients undergoing REBOA. METHODS: Patient demographics, etiology, bleeding sites, hemodynamic response, length of critical care, and cause of death were recorded. Characteristics and outcomes were compared between non-trauma and trauma patients. Kaplan-Meier survival analysis was then conducted. RESULTS: Between August 2011 and December 2015, 142 (36 non-trauma; 106 trauma) cases were analyzed. Non-traumatic etiologies included gastrointestinal bleeding, obstetrics and gynecology-derived events, visceral aneurysm, abdominal aortic aneurysm, and post-abdominal surgery. The abdomen was a common bleeding site (69%), followed by the pelvis or extra-pelvic retroperitoneum. None of the non-trauma patients had multiple bleeding sites, whereas 45% of trauma patients did (P < 0.001). No non-trauma patients required resuscitative thoracotomy compared with 28% of the trauma patients (P < 0.001). Non-trauma patients presented a lower 24-h mortality than trauma patients (19 vs. 51%, P = 0.001). The non-trauma cases demonstrated a gradual but prolonged increased mortality, whereas survival in trauma cases rapidly declined (P = 0.009) with similar hospital mortality (68 vs. 64%). Non-trauma patients who survived for 24 h had 0 ventilator-free days and 0 ICU-free days vs. a median of 19 and 12, respectively, for trauma patients (P = 0.33 and 0.39, respectively). Non-hemorrhagic death was more common in non-trauma vs. trauma patients (83 vs. 33%, P < 0.001). CONCLUSIONS: Non-traumatic hemorrhagic shock often resulted from a single bleeding site, and resulted in better 24-h survival than traumatic hemorrhage among Japanese patients who underwent REBOA. However, hospital mortality increased steadily in non-trauma patients affected by non-hemorrhagic causes after a longer period of critical care. PMID- 28831503 TI - [Migration of an axillary plexus catheter fragment : A severed catheter tip unnoticed on removal wandered into the central nervous system]. AB - MIGRATION OF AN AXILLARY PLEXUS CATHETER FRAGMENT INTO THE INTRACEREBRAL COMPARTMENT: During removal of an axillary plexus catheter used for pain therapy, the catheter was probably inadvertently and unnoticed severed together with the suture fixation. The error went unnoticed and an approximately 14 cm long catheter fragment remained in the patient. The patient complained of neck pain, nausea and vomiting 2.5 years later. A computed tomography scan of the cranium and neck region revealed a tubular foreign body with a diameter of ca. 1 mm and a length of ca. 14 cm. The foreign body was identified to be the sheared catheter fragment. In the meantime, the fragment had obviously migrated from the axilla into the intracranial compartment. The tip of the catheter was found at the ventral surface of the pons and surgical extraction was not possible. Following a futile intervention by the hospital's liability insurance and despite evidence from an expert opinion for a gross treatment error, the patient took civil legal action against the hospital. A settlement was reached and the accused hospital committed itself to pay a compensation of 200,000 ? plus any additional costs. PMID- 28831505 TI - The Digital Revolution and Its Impact on Interventional Radiology. PMID- 28831504 TI - Cystic fibrosis: the conductance regulator, ceramides, and possible treatments. PMID- 28831506 TI - [Cystic pancreatic tumors: diagnostics and new biomarkers]. AB - Mortality due to pancreatic ductal adenocarcinoma (PDAC) will increase in the near future. The only curative treatment for PDAC is radical resection; however, even small carcinomas exhibit micrometastases leading to early relapse. Accordingly, detection of premalignant precursor lesions is important. In essence, PDAC develops from three precursor lesions: pancreatic intraepithelial lesions (PanIN), intraductal papillary-mucinous neoplasia (IPMN) and mucinous cystic neoplasia (MCN). Together with serous cystic neoplasia (SCN) and solid pseudopapillary neoplasia (SPN), these cystic lesions constitute the most common cystic neoplasms in the pancreas. In the case of IPMN, main and branch duct IPMN have to be differentiated because of a markedly different malignancy potential. While main duct IPMN and MCN have a high malignancy transformation rate, branch duct IPMNs are more variable with respect to malignant transformation. This shows that differential diagnosis of cystic lesions is important; however, this is often very difficult to accomplish using conventional imaging. Novel biomarkers and diagnostic tools based on the molecular differences of cystic pancreatic lesions could be helpful to differentiate these lesions and facilitate early diagnosis. The aim is to distinguish the premalignant cysts from strictly benign cystic lesions and a timely detection of malignant transformation. This article provides an overview on the molecular characteristics of cystic pancreatic lesions as a basis for improved diagnostics and the development of new biomarkers. PMID- 28831507 TI - [Can 12- instead of 4-weekly zoledronic acid ad ministration reduce skeletal events in patients with bone metastases?] PMID- 28831508 TI - [WHO classification and clinical spectrum of cutaneous lymphomas]. AB - BACKGROUND: Cutaneous lymphomas are rare skin cancers with a wide clinical spectrum. OBJECTIVE: To give an overview of the current classification and the clinical spectrum of cutaneous lymphomas. MATERIAL AND METHODS: Analysis and summary of the current literature concerning the different entities of cutaneous lymphomas. RESULTS: A few modifications in the nomenclature of cutaneous lymphoma have been introduced in the revised version of the WHO classification 2016. In the last years new types of lymphomatoid papulosis were described. Moreover, two subgroups of folliculotropic mycosis fungoides are now mentioned. The CD4+ small/medium T-cell lymphoproliferative disorder is no longer classified as an overt lymphoma. As new entities the EBV+ mucocutaneous ulcer, an EBV-associated diffuse large B-cell lymphoma (not otherwise specified) and a primary cutaneous acral CD8+ T-cell (provisional) lymphoma are being considered. CONCLUSION: The classification of cutaneous lymphomas is based on the revised version of the WHO classification (2016). The clinical pathological correlation is an elementary component for correct diagnosis. PMID- 28831509 TI - [Long-term efficacy of multimodal pain therapy for chronic back pain]. AB - BACKGROUND: The day clinic for pain therapy at the Orthopedic Clinic of the University Heidelberg has been in existence since 2001. In the context of multimodal pain therapy patients with chronic and chronically recurring pain of the musculoskeletal system are treated. METHODS: The present prospective long term study investigated the effects of therapy using the following outcome parameters: pain intensity, disability, depression, functional capacity and vitality. For this purpose patients with low back pain (n = 59) were questioned in writing at four measurement times: start of therapy (t0), completion of therapy (t1), 6 months (t2) and 10 years (t3) following therapy. Of the examined patients 78% were in chronification stages I and II, according to the Mainz pain staging system (MPSS) of Gerbershagen. AIM: The main aim of the study was to examine the effects of multimodal pain therapy in the long term. RESULTS: In the short, medium and long term significant differences were found in the outcome parameters with low to high effect sizes (d = 0.36-1.85). There was a continuous improvement of the pain intensity in the long term, and 10 years after pain therapy the effect size for the currently asked pain intensity was d = 1.28. CONCLUSION: Multimodal pain therapy is an effective method for the treatment of chronic back pain. It not only leads to short and medium-term improvements but also proves to be efficient in the long term. This form of pain therapy seems to lead to long-term success, particularly for patients with low-grade chronification. PMID- 28831510 TI - A new Jurassic theropod from China documents a transitional step in the macrostructure of feathers. AB - Genuine fossils with exquisitely preserved plumage from the Late Jurassic and Early Cretaceous of northeastern China have recently revealed that bird-like theropod dinosaurs had long pennaceous feathers along their hindlimbs and may have used their four wings to glide or fly. Thus, it has been postulated that early bird flight might initially have involved four wings (Xu et al. Nature 421:335-340, 2003; Hu et al. Nature 461:640-643, 2009; Han et al. Nat Commun 5:4382, 2014). Here, we describe Serikornis sungei gen. et sp. nov., a new feathered theropod from the Tiaojishan Fm (Late Jurassic) of Liaoning Province, China. Its skeletal morphology suggests a ground-dwelling ecology with no flying adaptations. Our phylogenetic analysis places Serikornis, together with other Late Jurassic paravians from China, as a basal paravians, outside the Eumaniraptora clade. The tail of Serikornis is covered proximally by filaments and distally by slender rectrices. Thin symmetrical remiges lacking barbules are attached along its forelimbs and elongate hindlimb feathers extend up to its toes, suggesting that hindlimb remiges evolved in ground-dwelling maniraptorans before being co-opted to an arboreal lifestyle or flight. PMID- 28831511 TI - Far infrared promotes wound healing through activation of Notch1 signaling. AB - : The Notch signaling pathway is critically involved in cell proliferation, differentiation, development, and homeostasis. Far infrared (FIR) has an effect that promotes wound healing. However, the underlying molecular mechanisms are unclear. In the present study, we employed in vivo and HaCaT (a human skin keratinocyte cell line) models to elucidate the role of Notch1 signaling in FIR promoted wound healing. We found that FIR enhanced keratinocyte migration and proliferation. FIR induced the Notch1 signaling pathway in HaCaT cells and in a microarray dataset from the Gene Expression Omnibus database. We next determined the mRNA levels of NOTCH1 in paired normal and wound skin tissues derived from clinical patients using the microarray dataset and Ingenuity Pathway Analysis software. The result indicated that the Notch1/Twist1 axis plays important roles in wound healing and tissue repair. In addition, inhibiting Notch1 signaling decreased the FIR-enhanced proliferation and migration. In a full-thickness wound model in rats, the wounds healed more rapidly and the scar size was smaller in the FIR group than in the light group. Moreover, FIR could increase Notch1 and Delta1 in skin tissues. The activation of Notch1 signaling may be considered as a possible mechanism for the promoting effect of FIR on wound healing. FIR stimulates keratinocyte migration and proliferation. Notch1 in keratinocytes has an essential role in FIR-induced migration and proliferation. NOTCH1 promotes TWIST1-mediated gene expression to assist wound healing. FIR might promote skin wound healing in a rat model. KEY MESSAGES: FIR stimulates keratinocyte migration and proliferation. Notch1 in keratinocytes has an essential role in FIR-induced migration and proliferation. NOTCH1 promotes TWIST1-mediated gene expression to assist wound healing. FIR might promote skin wound healing in a rat model. PMID- 28831512 TI - [Advance directive of probands in pharmaceutical research : A medical ethics discussion]. AB - In the fourth Act on the amendment of pharmaceutical legal and other regulations in November 2016, the legislature has designated the proband advance directive based on the instrument of patient advance directive to enable group beneficial research with persons not capable of giving consent. This article describes the existing conditional need for group beneficial research and presents the problem of the decisive instrument for advance directives at the center of the considerations. The features of the proband advance directive concluded by the legislature stand in opposition to a successful implementation, particularly due to the necessary concrete clarification content far in advance for informed research participants. This article describes solution possiblities, which refer to the realization of the instrument of a proxy research authorization as well as the consideration of an advance research planning based on the advance care planning. PMID- 28831513 TI - Acidic, neutral and alkaline forest ponds as a landscape element affecting the biodiversity of freshwater snails. AB - In recent years, the number of areas remaining under the influence of acidity has increased. At all levels of ecosystems, biodiversity decreases with acidification, due to the elimination of species that are most sensitive to low pH. Forest ponds belong to a specific group that varied in location, a huge amount of leaf litter, and isolation from other aquatic environments. They are crucial in the industrial landscape with well-developed industry and human activity. The aim was to investigate the relative importance of water chemistry in explaining snail assemblage compositions and species richness in forest ponds of contrasting pH. Patterns in gastropod communities were determined from an analysis in 26 forest ponds with multivariate gradient analysis. Ponds ranged in a base mean pH from 3.0 to 9.0. pH has been found to be an important factor influencing gastropod fauna. Neutral ponds support diverse communities, typical of small water bodies. In two acidic pond types, snail fauna was different. Among the species characteristic for acidic ponds (pH < 6) were Anisus spirorbis and Aplexa hypnorum. The greatest distinct characterised alkaline ponds with the numerous appearance of alien Physa acuta. The most diverse gastropod fauna was found in neutral ponds, whereas the lowest degree of diversity was found in ponds with the lowest pH. Current knowledge of pH-associated changes in aquatic ecosystems is still incomplete because anthropogenic acidification is a recent phenomenon. It is extremely important in forest habitats, since they react more intensively to climatic factors and are often used in landscape management and planning. PMID- 28831514 TI - [Parasomnia and paroxysmal dyskinesia]. AB - Short involuntary paroxysmal movements or behavioral patterns are an important differential diagnosis to epileptic seizures, especially when occurring for the first time. Typically, these attacks are not witnessed by medically trained personnel and the patient anamnesis or observations by a third party are often not specific enough to differentiate between epileptic seizures and the differential diagnoses. This review presents the epidemiology, the clinical presentation, the necessary diagnostic steps and the differential diagnostic approach to parasomnias and dyskinesias. The focus is on the clinical aspects, and therapeutic principles are also briefly described. PMID- 28831515 TI - [Differential diagnosis of epileptic seizures : What is epilepsy and what is not?] PMID- 28831516 TI - [Management of traumatic intestinal injury of mass casualties]. AB - While intestinal injury is relatively rare in blunt abdominal trauma, it is common in penetrating abdominal trauma. Intestinal injury cannot be detected effectively by computed tomography (CT); therefore penetrating abdominal injury or abdominal signs in blunt trauma require liberal indications for explorative laparotomy. In mass casualty situations patients with hemodynamic instability and abdominal signs should be prioritized for surgery. Besides intra-abdominal hemorrhage the major issue is septic complications due to intestinal perforation. The current surgical strategy should reflect the number of injured patients and the individual pattern of injuries. Damage control surgery is not an effective strategy to improve survival rates in severely injured patients or in mass casualty situations. Damage control surgery focuses on lifesaving procedures especially bleeding control and control of contamination. This includes an open abdomen strategy with later definitive repair and abdominal wall closure. PMID- 28831517 TI - [Terrorist attack trauma - an individual entity of polytrauma : A 10-year update]. AB - The incidence of terrorist attacks is increasing worldwide, and they have also become a permanent threat in European cities. Due to its complexity, terrorist attack trauma places high demands on the strategy of surgical treatment. The combination of various mechanisms, explosions and gunshot injuries, with the characteristic pressure (blast) damage and a high proportion of penetrating trauma with simultaneous burns are characteristic features. Unlike in military conflicts, injuries to people of all ages and without ballistic body protection (body armor) are to be expected. The mechanism of the attack and its local conditions are of relevance for the assessment of the situation and the expected injury patterns. Thus, suicide attacks result in several times higher numbers of fatalities and casualties. Explosions on free ground lead to different types of injury than those in closed or semi-enclosed spaces. The treatment principles of the Advanced Trauma Life Support (ATLS(r)) are based on the intrahospital care of casualties as well as damage control strategies with trigger factors. In order to prepare and educate clinics and surgeons in Germany for such scenarios, various course formats of the professional societies, the German Society for General and Visceral Surgery (DGAV) and the German Society for Trauma Surgery (DGU) have now been established. PMID- 28831518 TI - [Viscoelasticity-based treatment of bleeding injuries]. AB - Uncontrolled bleeding is the leading preventable cause of death in patients with multiple injuries. Currently, trauma-induced coagulopathy is seen as an independent disease entity influencing survival. Severely bleeding trauma patients are often treated with classical blood products in predefined ratios (damage control resuscitation). Viscoelasticity-based and target-oriented approaches could possibly be given priority. Viscoelasticity-based diagnostics and therapy enable the qualitative investigation of whole blood and provide therapeutically usable information on initiation, dynamics and sustainability of thrombus formation. Due to the ease of handling and timely results this lends itself as a point-of-care procedure. This article presents the clinical issues with using viscoelastic procedures and current expert recommendations taking the literature into consideration. PMID- 28831519 TI - Interactive effects of water and controlled release urea on nitrogen metabolism, accumulation, translocation, and yield in summer maize. AB - To investigate the interactive effects of water and N from controlled release urea (CRU) on N metabolism, accumulation, translocation, and yield in Zhengdan958 (a summer maize cultivar planted widely in China), three water levels (adequate water W3, mild water stress W2, severe water stress W1) and four amounts of CRU (N) (N0, N1, N2, and N3 were 0, 105, 210, and 315 kg N ha-1, respectively) were carried out under the waterproof shed and soil column conditions. The results showed that yield, N metabolism, accumulation, and translocation were significantly affected by water, CRU, and their interactions after tasseling. Yields showed an increasing trend in response to N rates from 100.2 to 128.8 g plant-1 under severe water stress (W1), from 124.7 to 174.6 g plant-1 under mild water stress (W2), and from 143.7 to 177.0 g plant-1 under adequate water conditions (W3). There was an associated optimum amount of N for each water level. Under W1 and W2, N3 treatments showed significant advantages in three N metabolism enzymes' activities and the N accumulations, and yield and its components were highest. But the nitrogen harvest index (NHI) of N3 had no significant difference with other nitrogen treatments. Under W3, the N translocation efficiency (NTE) and N translocation conversion rate (NTCR) of N2 in stem and leaf were higher than those of N3, but the N metabolism enzymes' activities and yields of N2 and N3 had no significant difference, which indicated that N2 was superior to N3. The N3 treatment under W2 and N2 under W3 increased the N accumulation capacity in maize grain as well as the N translocation to grain that contributed to the increase of 1000-gain weight and grains per ear after tasseling. Under this experimental condition, a CRU rate of 225 kg ha-1 was the best treatment when the soil moisture content was 75 +/- 5% of field capacity, but an N rate of 300 kg ha-1 was superior when soil moisture content was maintained at 55 +/- 5% of field capacity during the entire growing season. PMID- 28831520 TI - Does the evidence support population-wide screening for type 2 diabetes? No. AB - Large-scale, centrally-coordinated screening for undiagnosed type 2 diabetes is an attractive option to reduce the mortality and morbidity resulting from inadequately controlled diabetes. However, there is limited research examining the direct consequences of such screening programmes on outcomes such as cardiovascular disease and death. Two papers published in this edition of Diabetologia (DOIs: 10.1007/s00125-017-4323-2 and 10.1007/s00125-017-4299-y ) examine data from one of the very few trials conducted in this area. Overall, there was little benefit that could be directly related to the screening programme. In part, this was due to the high levels of opportunistic screening in the control group. Thus, when there are high levels of opportunistic screening for type 2 diabetes, there remains no clear evidence of benefit of centrally coordinated screening programmes that approach individuals outside usual healthcare settings. PMID- 28831521 TI - [Redo urethroplasty with buccal mucosa]. AB - Urethral strictures can occur on the basis of trauma, infections, iatrogenic induced or idiopathic and have a great influence on the patient's quality of life. The current prevalence rate of male urethral strictures is 0.6% in industrialized western countries. The favored form of treatment has experienced a transition from less invasive interventions, such as urethrotomy or urethral dilatation, to more complex open surgical reconstruction. Excision and primary end-to-end anastomosis and buccal mucosa graft urethroplasty are the most frequently applied interventions with success rates of more than 80%. Risk factors for stricture recurrence after urethroplasty are penile stricture location, the length of the stricture (>4 cm) and prior repeated endoscopic therapy attempts. Radiation-induced urethral strictures also have a worse outcome. There are various therapy options in the case of stricture recurrence after a failed urethroplasty. In the case of short stricture recurrences, direct vision urethrotomy shows success rates of approximately 60%. In cases of longer or more complex stricture recurrences, redo urethroplasty should be the therapy of choice. Success rates are higher than after urethrotomy and almost comparable to those of primary urethroplasty. Patient satisfaction after redo urethroplasty is high. Primary buccal mucosa grafting involves a certain rate of oral morbidity. In cases of a redo urethroplasty with repeated buccal mucosa grafting, oral complications are only slightly higher. PMID- 28831522 TI - Quantitative trait locus mapping under irrigated and drought treatments based on a novel genetic linkage map in mungbean (Vigna radiata L.). AB - KEY MESSAGE: A novel genetic linkage map was constructed using SSR markers and stable QTLs were identified for six drought tolerance related-traits using single environment analysis under irrigation and drought treatments. Mungbean (Vigna radiata L.) is one of the most important leguminous food crops. However, mungbean production is seriously constrained by drought. Isolation of drought-responsive genetic elements and marker-assisted selection breeding will benefit from the detection of quantitative trait locus (QTLs) for traits related to drought tolerance. In this study, we developed a full-coverage genetic linkage map based on simple sequence repeat (SSR) markers using a recombinant inbred line (RIL) population derived from an intra-specific cross between two drought-resistant varieties. This novel map was anchored with 313 markers. The total map length was 1010.18 cM across 11 linkage groups, covering the entire genome of mungbean with a saturation of one marker every 3.23 cM. We subsequently detected 58 QTLs for plant height (PH), maximum leaf area (MLA), biomass (BM), relative water content, days to first flowering, and seed yield (Yield) and 5 for the drought tolerance index of 3 traits in irrigated and drought environments at 2 locations. Thirty eight of these QTLs were consistently detected two or more times at similar linkage positions. Notably, qPH5A and qMLA2A were consistently identified in marker intervals from GMES5773 to MUS128 in LG05 and from Mchr11-34 to the HAAS_VR_1812 region in LG02 in four environments, contributing 6.40-20.06% and 6.97-7.94% of the observed phenotypic variation, respectively. None of these QTLs shared loci with previously identified drought-related loci from mungbean. The results of these analyses might facilitate the isolation of drought-related genes and help to clarify the mechanism of drought tolerance in mungbean. PMID- 28831523 TI - Should we screen for type 2 diabetes among asymptomatic individuals? Yes. AB - RCTs of whether screening asymptomatic individuals for undiagnosed diabetes results in reduced mortality or has other benefits have been suggestive, but inconclusive. In this issue of Diabetologia, two additional controlled studies (DOIs: 10.1007/s00125-017-4323-2 and 10.1007/s00125-017-4299-y ) that investigated whether screening for type 2 diabetes in asymptomatic individuals is associated with a reduction in mortality are presented. Treating diabetes early, and identifying and treating impaired glucose tolerance, are of benefit, and economic modelling indicates such screening is cost-effective. Now that such screening is already underway in many countries, new data, along with the existing evidence, suggests opportunistic screening is the best way forward. More research is needed, however, on how best to screen and how to improve risk-factor control once dysglycaemia is detected. PMID- 28831524 TI - [Meniscal root lesions: clinical relevance and treatment]. AB - Meniscal roots play an important role in load distribution of the tibiofemoral knee joint. Thus, meniscal root tears are severe injuries of the knee, which significantly expose cartilage to increased stress. Two entities are distinguished: (i) acute root tears that mainly affect the posterolateral root and often occur with ruptures of the anterior cruciate ligament; and (ii) chronic, degenerative root tears that mainly affect the posteromedial root. For diagnosis of both entities, the patient's medical history, a knee examination and especially MRI play key roles. The treatment of choice is in general transtibial fixation of the torn root, which leads to an increased clinical improvement and a decrease of the progression of arthritis. PMID- 28831525 TI - Large correction in opening wedge high tibial osteotomy with resultant joint-line obliquity induces excessive shear stress on the articular cartilage. AB - PURPOSE: The purpose of this study was to analyse the resultant stress induced by joint-line obliquity after HTO for varus knee deformity using a three-dimensional (3D) finite element model analysis. METHODS: The geometrical bone data used in this study were derived from commercially available human bone digital anatomy media. The 3D knee models were developed using 3D computer-aided design software. The articular surface was overlaid with a 2-mm-thick cartilage layer for both femoral and tibial condyles. Ligament structures were simulated based on properties reported in previous anatomical studies. Regarding the loading condition, isolated axial loads of 1200 N with lateral joint-line inclinations of 2.5 degrees , 5 degrees , 7.5 degrees , and 10 degrees in reference to the horizontal axis were applied to the femur to simulate the mechanical environment in a knee with joint-line obliquity. RESULTS: A steep rise of shear stress in the medial compartment was noted in the model with obliquity of 5 degrees or more. This laterally directed shear stress exhibited an incremental increase in accordance with the obliquity angle. The maximum shear stress value in the medial cartilage increased from 1.6 MPa for the normal knee to 3.3, 5.2, and 7.2 MPa in the joint-line obliquity models with 5 degrees , 7.5 degrees , and 10 degrees of obliquity, respectively. CONCLUSIONS: The effects of HTO for varus knee deformity on the amount/distribution of stresses in the articular cartilage were analysed using a 3D finite element model. It was shown that joint-line obliquity of more than 5 degrees induced excessive shear stress in the tibial articular cartilage. A large amount of correction in OWHTO with a resultant joint-line obliquity of 5 degrees or more may induce detrimental stress to the articular cartilage. Double level osteotomy should be considered as a surgical option in this situation. PMID- 28831526 TI - Global invasive Cochliobolus species: cohort of destroyers with implications in food losses and insecurity in the twenty-first century. AB - Matching the global food demand by 2050 and to ensure the stability of food security in over than 99 countries, it is necessary to scale up the production of food such as sorghum, wheat, rice, maize and sugarcane which are however natural hosts of Cochliobolus species. Cochliobolus species major epidemics such as the Great Bengal famine, Southern corn leaf blight, and Northern leaf spot blight were associated with substantial economic losses in the past decades. Thus, there is an urgent need to establish a specific coordinated global surveillance program for the migration of invasive Cochliobolus species, planning contextual control programs engaging all agricultural stakeholders and information sharing in real time for prevention of disastrous Cochliobolus disease outbreak effects. We discuss pertinent outcome of interactions of cash crops with Cochliobolus species having devastating impact on the livelihood of farmers and food security. While post-genomic era elucidated prominent differences among Cochliobolus heterostrophus, C. carbonum, C. victoriae, C. lunatus and C. miyabeanus, their destructive potentials and implications in food losses remained unearthed. Intriguingly, the annual colossal losses caused by Cochliobolus species in the production perspective of sorghum, wheat, rice, maize, cassava and soybean is estimated over 10 billion USD worldwide. This paper provides a comprehensive analysis of the invasive Cochliobolus species distribution and diversity, evolving pathogenicity, persistent diseases, threats and epidemics, consequences on food crops production and increasing global food insecurity issues. PMID- 28831527 TI - Use of antihistamines and risk of ventricular tachyarrhythmia: a nested case control study in five European countries from the ARITMO project. AB - PURPOSE: After regulatory restrictions for terfenadine and astemizole in '90s, only scarce evidence on proarrhythmic potential of antihistamines has been published. We evaluate the risk of ventricular tachyarrhythmia (VA) related to the use of individual antihistamines. METHODS: A matched case-control study nested in a cohort of new users of antihistamines was conducted within the EU funded ARITMO project. Data on 1997-2010 were retrieved from seven healthcare databases: AARHUS (Denmark), GEPARD (Germany), HSD and ERD (Italy), PHARMO and IPCI (Netherlands) and THIN (UK). Cases of VA were selected and up to 100 controls were matched to each case. The odds ratio (OR) of current use for individual antihistamines (AHs) was estimated using conditional logistic regression. RESULTS: For agents largely used to prevent allergic symptoms, such as cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine, we found no VA risk. A statistically significant, increased risk of VA was found only for current use of cyclizine in the pooled analysis (ORadj, 5.3; 3.6-7.6) and in THIN (ORadj, 5.3; 95% CI, 3.7-7.6), for dimetindene in GEPARD (ORadj, 3.9; 1.1-14.7) and for ebastine in GEPARD (ORadj, 3.3; 1.1-10.8) and PHARMO (ORadj, 4.6; 1.3-16.2). CONCLUSIONS: The risk of VA associated with a few specific antihistamines could be ascribable to heterogeneity in pattern of use or in receptor binding profile. PMID- 28831528 TI - Association between infection and severe drug adverse reactions: an analysis using data from the Japanese Adverse Drug Event Report database. AB - PURPOSE: It has been reported recently that immune reactions are involved in the pathogenesis of certain types of adverse drug reactions (ADRs). We aimed to determine the associations between infections and drug-induced interstitial lung disease (DILD), rhabdomyolysis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), or drug-induced liver injury (DILI) using a spontaneous adverse drug event reporting database in Japan. METHODS: The reported cases were classified into three categories (anti-infectious drug group, concomitant infection group, and non-infection group) based on the presence of anti-infectious drugs (either as primary suspected drug or concomitant drug) and infectious disease. We assessed the association between four severe ADRs and the presence and seriousness of infection using logistic regression analysis. RESULTS: We identified 177,649 cases reported in the study period (2009-2013). Logistic regression analysis showed significant positive associations between infection status and onset of SJS/TEN or DILI (SJS/TEN: anti-infectious drug group: odds ratio (OR) 2.04, 95% CI [1.85-2.24], concomitant infection group: OR 2.44, 95% CI [2.21-2.69], DILI: anti-infectious drug group: OR 1.27, 95% CI [1.09 1.49], concomitant infection group: OR 1.25, 95% CI [1.04-1.49]), compared to the non-infection group. By contrast, there were negative or no associations between infection and DILD or rhabdomyolysis. A significantly positive association between infection and SJS/TEN seriousness (OR 1.48, 95% CI [1.10-1.98]) was observed. CONCLUSIONS: This study suggested that infection plays an important role in the development of SJS/TEN and DILI. For the patients with infection and/ or anti-infectious drugs, careful monitoring for severe ADRs, especially SJS/TEN, might be needed. PMID- 28831529 TI - Diagnosis of spinal dural arteriovenous fistula using 3D T2-weighted imaging. AB - PURPOSE: To evaluate spinal MRIs without and with 3D T2W imaging among patients without and with spinal dural arteriovenous fistula (SDAVF) confirmed by spinal digital subtraction angiography (DSA). METHODS: A retrospective case-control study was performed among patients without and with SDAVF who had both spinal MRIs and gold standard spinal DSA. Two neuroradiologists independently reviewed spinal MRIs that were performed with either sagittal T2W turbo spin echo (2D group) or sagittal 3D T2W sampling perfection with application-optimized contrasts using different flip-angle evolutions (SPACE) (3D group) and documented the presence or absence of SDAVF. Using spinal DSA diagnosis as a gold standard, the sensitivity, specificity, and interobserver agreement for the 2D-group and 3D group MRI diagnosis were calculated. RESULTS: The 2D group consisted of 21 patients and the 3D group consisted of 16 patients. For both radiologists, the 2D group demonstrated a sensitivity of 100% and specificity of 100%. Interobserver agreement in the 2D group was perfect (k = 1.0). For both radiologists, the 3D group demonstrated sensitivity of 100.0% and specificity of 92.3%. Interobserver agreement in the 3D group was perfect (k = 1.0). While flow voids were considered more conspicuous, spinal cord signal abnormality was considered less conspicuous with 3D T2W SPACE compared with conventional 2D STIR sequence. CONCLUSION: 3D T2W SPACE should be used in conjunction with 2D T2W sequences to more accurately detect abnormal cord signal and determine when perimedullary flow voids are pathologically abnormal for the radiologic diagnosis of SDAVF. PMID- 28831530 TI - Evolution of Ventricular Energetics in the Different Stages of Palliation of Hypoplastic Left Heart Syndrome: A Retrospective Clinical Study. AB - Hyperplastic left heart syndrome (HLHS) patients are palliated by creating a Fontan-type circulation passing from different surgical stages. The aim of this work is to describe the evolution of ventricular energetics parameters in HLHS patients during the different stages of palliation including the hybrid, the Norwood, the bidirectional Glenn (BDG), and the Fontan procedures. We conducted a retrospective clinical study enrolling all HLHS patients surgically treated with hybrid procedure and/or Norwood and/or BDG and/or Fontan operation from 2011 to 2016 collecting echocardiographic and hemodynamic data. Measured data were used to calculate energetic variables such as ventricular elastances, external and internal work, ventriculo-arterial coupling and cardiac mechanical efficiency. From 2010 to 2016, a total of 29 HLHS patients undergoing cardiac catheterization after hybrid (n = 7) or Norwood (n = 6) or Glenn (n = 8) or Fontan (n = 8) procedure were retrospectively enrolled. Ventricular volumes were significantly higher in the Norwood circulation than in the hybrid circulation (p = 0.03) with a progressive decrement from the first stage to the Fontan completion. Ventricular elastances were lower in the Norwood circulation than in the hybrid circulation and progressively increased passing from the first stage to the Fontan completion. The arterial elastance and Rtot increased in the Fontan circulation. The ventricular work progressively increased. Finally, the ventricular efficiency improves passing from the first to the last stage of palliation. The use of ventricular energetic parameters could lead to a more complete evaluation of such complex patients to better understand their adaptation to different pathophysiological conditions. PMID- 28831531 TI - Brain functional networks: correlation analysis with clinical indexes in patients with diabetic retinopathy. AB - PURPOSE: The relationship between parameters of brain functional networks and clinical indexes is unclear so far in patients with diabetic retinopathy (DR). This paper is to investigate this. METHODS: Twenty-one patients with different grades of DR and 21 age- and sex-matched healthy controls were enrolled from August 2012 to September 2014. The clinical indexes recorded included DR grade, duration of diabetes, HbA1c, diabetic foot screen, fasting plasma glucose, insulin, Homa-beta, Homa-IR, insulin sensitive index (ISI), Mini-Mental State Examination (MMSE), and patient sex and age. Subjects were scanned using 3-T MR with blood-oxygen-level-dependent and 3D-FSPGR sequences. MR data was analyzed via preprocessing and functional network construction, and quantified indexes of network (clustering coefficient, characteristic path length, global efficiency, degree distribution, and small worldness) were evaluated. Statistics consisted of ANOVA and correlation. RESULTS: There were significant differences between patients and controls among clustering coefficient, characteristic path length, degree distribution, and small worldness parameters (P < 0.05). MMSE scores negatively correlated with characteristic path length, and Hb1Ac negatively correlated with small worldness. MMSE, duration of diabetes, diabetic foot screen, fasting plasma glucose, insulin, Homa-beta, Homa-IR, ISI, DR grade, and patient age, except from Hb1Ac, correlated with degree distribution in certain brain areas. CONCLUSION: Brain functional networks are altered, specifically in the areas of visual function and cognition, and these alterations may reflect the severity of visual weakness and cognitive decline in DR patients. Moreover, the brain networks may be affected both by long-standing and instant clinical factors. PMID- 28831532 TI - Orf6 gene encoded glyoxalase involved in mycotoxin citrinin biosynthesis in Monascus purpureus YY-1. AB - As traditional edible fungi, Monascus spp. have been widely used as folk medicine, food colorants, and fermentation starters in East Asian countries for more than a thousand years. However, the presence of citrinin, which has nephrotoxic, hepatotoxic, and carcinogenic activities, raises suspicions about the safety of Monascus products. Citrinin biosynthesis in Monascus is known to occur via a polyketide pathway and a citrinin biosynthesis gene cluster, which include the characterized polyketide synthetase pksCT. A gene, orf6, encodes a protein that shows significant similarity to glyoxalase and is located between ctnE and orf1. This study analyzed orf6 function, and successfully obtained an orf6 disruption strain (Deltaorf6). Citrinin production was significantly greater (3.6-fold) in the Deltaorf6 strain than in the wild-type Monascus purpureus YY-1, and RT-PCR analysis further revealed increased expression of numerous genes of the citrinin biosynthesis gene cluster in Deltaorf6. Therefore, orf6 proved to be a major inhibitor, directly involved in citrinin biosynthesis. Moreover, pigment production in Deltaorf6 was reduced by approximately 30%, while the transcription levels of many genes involved in Monascus pigments (MPs) biosynthesis had increased. This dichotomy indicated that MPs and citrinin yields may be improved simultaneously; however, a portion of the pigments was consumed to protect the cells from oxidative damage in the Deltaorf6 strain. An Deltaorf6 revertant restored the citrinin and pigment yields to normal levels. This study makes a contribution to explore the citrinin biosynthesis pathway and provides some theoretical guidance to improving the safety of Monascus-related products. PMID- 28831533 TI - [Psychotherapy for posttraumatic stress disorder in older adults]. AB - BACKGROUND: In contrast to the high demographic relevance of the older population, relatively little is known about prevalence rates, the typologies/symptom profiles and effective therapeutic approaches for posttraumatic stress disorder (PTSD) in older adults. AIM: The aim of the present article is to provide an overview of prevalence rates, typologies of PTSD and effective treatment approaches for PTSD in the elderly. RESULTS: Compared to younger cohorts, the group of older people has a markedly lower PTSD prevalence in the vast majority of epidemiological studies. There is a comparable structure over all age classes (i. e. classes with low, moderate and high symptoms) with respect to the symptom profile of PTSD. There are currently only a few controlled treatment studies for the cohort of older adults. The published controlled or randomized controlled interventional studies suggest that trauma-focused and narrative approaches seem to be effective in the treatment of PTSD in the elderly. CONCLUSION: Future research should take account of the results so far in order to verify the existing preliminary results and to deal with current limitations. Randomized controlled trials are required, which should include a heterogeneous sample of elderly people and examine different therapeutic approaches in their effectiveness and feasibility in this cohort. PMID- 28831534 TI - Comparison of 18F-FET PET and perfusion-weighted MRI for glioma grading: a hybrid PET/MR study. AB - PURPOSE: Both perfusion-weighted MR imaging (PWI) and O-(2-18F-fluoroethyl)-L tyrosine PET (18F-FET) provide grading information in cerebral gliomas. The aim of this study was to compare the diagnostic value of 18F-FET PET and PWI for tumor grading in a series of patients with newly diagnosed, untreated gliomas using an integrated PET/MR scanner. METHODS: Seventy-two patients with untreated gliomas [22 low-grade gliomas (LGG), and 50 high-grade gliomas (HGG)] were investigated with 18F-FET PET and PWI using a hybrid PET/MR scanner. After visual inspection of PET and PWI maps (rCBV, rCBF, MTT), volumes of interest (VOIs) with a diameter of 16 mm were centered upon the maximum of abnormality in the tumor area in each modality and the contralateral unaffected hemisphere. Mean and maximum tumor-to-brain ratios (TBRmean, TBRmax) were calculated. In addition, Time-to-Peak (TTP) and slopes of time-activity curves were calculated for 18F-FET PET. Diagnostic accuracies of 18F-FET PET and PWI for differentiating low-grade glioma (LGG) from high-grade glioma (HGG) were evaluated by receiver operating characteristic analyses (area under the curve; AUC). RESULTS: The diagnostic accuracy of 18F-FET PET and PWI to discriminate LGG from HGG was similar with highest AUC values for TBRmean and TBRmax of 18F-FET PET uptake (0.80, 0.83) and for TBRmean and TBRmax of rCBV (0.80, 0.81). In case of increased signal in the tumor area with both methods (n = 32), local hot-spots were incongruent in 25 patients (78%) with a mean distance of 10.6 +/- 9.5 mm. Dynamic FET PET and combination of different parameters did not further improve diagnostic accuracy. CONCLUSIONS: Both 18F-FET PET and PWI discriminate LGG from HGG with similar diagnostic performance. Regional abnormalities in the tumor area are usually not congruent indicating that tumor grading by 18F-FET PET and PWI is based on different pathophysiological phenomena. PMID- 28831536 TI - Results with eight and a half years average follow-up on two hundred and eight e Motion FP(r) knee prostheses, fitted using computer navigation for knee osteoarthritis in patients with over ten degrees genu varum. AB - PURPOSE: The aim of this study was to analyse the clinical and radiographic results of 208 e-Motion(r) posterior cruciate-retaining, mobile bearing prostheses (BBraun-Aesculap, Tuttlingen, Germany) fitted using computer navigation, for knee osteoarthritis with a genu varum greater than 10 degrees . METHODS: One hundred ninety-two patients were operated on with 208 e-Motion(r) prostheses fitted, between January 2006 and December 2011, using the OrthoPilot(r) computer navigation system. Average pre-operative IKS score was 70 +/- 27 points (6-143) with a function score of 38 +/- 20.5 (0-90) and a knee score of 32.5 +/- 13 (0-63). Average flexion was 116.5 degrees +/- 13 degrees (65-140 degrees ). Average pre-operative HKA angle was 166 degrees +/- 3 degrees (154-169 degrees ). RESULTS: 2Results are available for 134 patients, with a total of 150 knees operated on (38 lost to follow-up and 20 deceased). Average follow-up was 104.5 months (60-116 months). On last follow-up, the average IKS was 180 +/- 22 points (95-200) with 86.5 +/- 16 points (25-100) for the function score and 93.5 +/- 8 points (55-100) for the knee score. Knee flexion was 116 degrees +/- 10.5 degrees (80-135 degrees ) and average HKA angle was 179 degrees +/- 2 degrees (175-184 degrees ). The pre-operative objective was achieved in 90.5% of knees. CONCLUSION: The e-Motion(r) mobile bearing posterior cruciate-retaining prosthesis, fitted using computer navigation, offers excellent results after an average of 8.5 years follow-up. These results are at least equivalent, even superior, to those of the posterior-stabilised prostheses usually used for this type of deformity. PMID- 28831535 TI - Effect of population screening for type 2 diabetes and cardiovascular risk factors on mortality rate and cardiovascular events: a controlled trial among 1,912,392 Danish adults. AB - AIMS/HYPOTHESIS: Health check programmes for chronic disease have been introduced in a number of countries. However, there are few trials assessing the benefits and harms of these screening programmes at the population level. In a post hoc analysis, we evaluated the effect of population-based screening for type 2 diabetes and cardiovascular risk factors on mortality rates and cardiovascular events. METHODS: This register-based, non-randomised, controlled trial included men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk score questionnaire. Individuals at moderate-to-high risk were invited to visit their GP for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other general practices in Denmark constituted the retrospectively constructed no-screening (control) group. Outcomes were mortality rate and cardiovascular events (cardiovascular disease death, non-fatal ischaemic heart disease or stroke). The analysis was performed according to the intention-to-screen principle. RESULTS: Among the screening group, 27,177 (18%) individuals attended for assessment of diabetes status and cardiovascular risk. Of these, 1,533 were diagnosed with diabetes. During a median follow-up of 9.5 years, there were 11,826 deaths in the screening group and 141,719 in the no-screening group (HR 0.99 [95% CI 0.96, 1.02], p = 0.66). There were 17,941 cardiovascular events in the screening group and 208,476 in the no-screening group (HR 0.99 [0.96, 1.02], p = 0.49). CONCLUSIONS/INTERPRETATION: A population-based stepwise screening programme for type 2 diabetes and cardiovascular risk factors among all middle-aged adults in Denmark was not associated with a reduction in rate of mortality or cardiovascular events between 2001 and 2012. PMID- 28831537 TI - Factors Affecting Public Preferences for Grassland Landscape Heterogeneity in the Great Plains. AB - Agricultural intensification has fragmented rangelands in the Great Plains, which has contributed to uniform and homogeneous landscapes and decreased biodiversity. Alternative land management practices involving fire-grazing interactions can help maintain biodiversity without affecting livestock productivity. A survey was designed to understand the factors that influence preferences among the general population towards grassland landscape heterogeneity. Given the ordinal nature of survey responses, requisite data were analyzed using a generalized ordinal logit model. Results suggested that respondents who valued open space and those who recognized a need for a varying mix of uniform grasses and grasslands preferred landscape heterogeneity. Female respondents were about two times as likely to prefer heterogeneous landscapes compared to male respondents. In contrast, population groups that preferred wildlife habitat did not desire heterogeneous landscapes. Results suggest the need for extension and outreach activities to educate certain segments of the general population regarding benefits of alternative management practices that support landscape heterogeneity in the Great Plains. PMID- 28831538 TI - Screening for type 2 diabetes: do screen-detected cases fare better? AB - AIMS/HYPOTHESIS: We aimed to investigate whether diabetes cases detected through screening have better health outcomes than clinically detected cases in a population-based cohort of adults who were eligible to be screened for diabetes at 10 year intervals. METHODS: The Vasterbotten Intervention Programme is a community- and individual-based public health programme in Vasterbotten County, Sweden. Residents are invited to clinical examinations that include screening for diabetes by OGTTs at age 30, 40, 50 and 60 years (individuals eligible for screening, n = 142,037). Between 1992 and 2013, we identified 1024 screen detected cases and 8642 clinically detected cases of diabetes using registry data. Clinically detected individuals were either prior screening participants (n = 4506) or people who did not participate in screening (non-participants, n = 4136). Study individuals with diabetes were followed from date of detection until end of follow-up, emigration, death or incident cardiovascular disease (CVD), renal disease or retinopathy event, and compared using Cox proportional hazard regression adjusted for calendar time, age at detection, year of detection, sex and socioeconomic status. RESULTS: The average age at diabetes diagnosis was 4.6 years lower for screen-detected individuals compared with clinically detected individuals. Overall, those who were clinically detected had worse health outcomes than those who were screen-detected (HR for all-cause mortality 2.07 [95% CI 1.63, 2.62]). Compared with screen-detected study individuals, all-cause mortality was higher for clinically detected individuals who were screening non participants (HR 2.31 [95% CI 1.82, 2.94]) than for those clinically detected who were prior screening participants (HR 1.70 [95% CI 1.32, 2.18]). Estimates followed a similar pattern for CVD, renal disease and retinopathy. CONCLUSIONS/INTERPRETATION: Individuals with screen-detected diabetes were diagnosed earlier and appeared to fare better than those who were clinically detected with regard to all-cause mortality, CVD, renal disease and retinopathy. How much of these associations can be explained by earlier treatment because of screening rather than healthy user bias, lead time bias and length time bias warrants further investigation. PMID- 28831539 TI - Effect of screening for type 2 diabetes on risk of cardiovascular disease and mortality: a controlled trial among 139,075 individuals diagnosed with diabetes in Denmark between 2001 and 2009. AB - AIMS/HYPOTHESIS: There is continuing debate about the net benefits of population screening for type 2 diabetes. We compared the risk of cardiovascular disease (CVD) and mortality among incident cases of type 2 diabetes in a screened group with those in an unscreened group. METHODS: In this register-based non-randomised controlled trial, eligible individuals were all men and women aged 40-69 years without known diabetes, registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes-risk-score questionnaire. Individuals at moderate-to-high risk were invited to visit their family doctor for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other practices in Denmark constituted the retrospectively constructed no-screening (control) group. In this post hoc analysis, we identified individuals from the screening and no-screening groups who were diagnosed with diabetes between 2001 and 2009 (n = 139,075), and compared risk of CVD and mortality in these groups between 2001 and 2012. RESULTS: In the screening group, 27,177/153,107 (18%) individuals attended for screening, of whom 1533 were diagnosed with diabetes. Between 2001 and 2009, 13,992 people were newly diagnosed with diabetes in the screening group (including those diagnosed by screening) and 125,083 in the no-screening group. Between 2001 and 2012, the risks of CVD and mortality were lower among individuals with diabetes in the screening group compared with individuals with diabetes in the no-screening (control) group (CVD HR 0.84, 95% CI 0.80, 0.89; mortality HR 0.79, 95% CI 0.74, 0.84). CONCLUSIONS/INTERPRETATION: A single round of diabetes screening and cardiovascular risk assessment in middle-aged Danish adults in general practice was associated with a significant reduction in risk of all-cause mortality and CVD events in those diagnosed with diabetes. PMID- 28831540 TI - Rare gene variants in a patient with azathioprine-induced lethal myelosuppression. PMID- 28831541 TI - Durable remission is achievable with localized treatment and reduction of immunosuppression in limited stage EBV-related plasmablastic lymphoma. PMID- 28831542 TI - [Importance of imaging diagnostics and EEG for differential diagnosis of epileptic seizures]. AB - Electroencephalography (EEG) and neuroimaging are the two most crucial diagnostic methods for epilepsy. The EEG represents the only specific method to detect epileptogenicity of a brain lesion. The EEG shows some syndrome-specific alterations, helps to make therapeutic decisions and allows prognosis about the disease. Neuroimaging in epilepsy includes magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Neuroimaging is crucial to clarify the underlying etiology and to localize the epileptogenic zone and has contributed to expanding the spectrum of patients where epilepsy surgery can be provided. Both EEG and neuroimaging are valuable methods in the hands of experienced epileptologists but both can also be misdiagnosed and lead to a wrong diagnosis and treatment decisions. This review discusses the contribution of both methods, their potential role and limitations and shows typical examples of wrong interpretation. PMID- 28831543 TI - A single recent injury is a potent risk factor for the development of accelerated knee osteoarthritis: data from the osteoarthritis initiative. AB - We examined the association between previously reported modifiable risk factors for accelerated knee osteoarthritis (AKOA) at the Osteoarthritis Initiative's (OAI) baseline and 48-month visits among adults who develop AKOA between the 48- and 96-month visits. We conducted a case-control study using data from the OAI baseline to the 96-month visit. Participants had no radiographic knee osteoarthritis (KOA) in the index knee at OAI baseline and 48-month visits [Kellgren-Lawrence (KL) <2]. We classified 2 groups: (1) AKOA: >1 knee developed advance-stage KOA (KL = 3 or 4) between 48- and 96-month visits and (2) No KOA: no KOA and no change in radiographic severity bilaterally over 96 months. We used logistic regression models to evaluate the association between the outcome of AKOA (versus no KOA) and several modifiable risk factors collected at OAI baseline and 48-month visits [body mass index (BMI), systolic blood pressure, comorbidity score, and NSAID use]. We also explored a new injury from baseline to 48 months and from 48- to 96 months. Adults with greater baseline and 48-month BMI were more likely to develop AKOA. Injury was only associated with AKOA onset when it occurred within 4 years of developing AKOA [prior 2 years: odds ratio = 6.21; 95% confidence interval (CI) 3.40, 11.35; 2-4 years prior: odds ratio = 4.42, 95% CI 2.06, 9.50]. BMI may consistently predispose an adult to AKOA, but certain injuries are likely a catalyst for AKOA. PMID- 28831544 TI - [Non-device-based telemonitoring : Toy or tool?] AB - Non-device-based telemedical management can be useful to prevent decompensation and death in patients suffering from easily disequilibrated conditions like diabetes mellitus, chronic obstructive pulmonary disease and heart failure (HF). This article summarizes current knowledge on non-device-based telemedical care for patients with HF. Several parameters (heart rate, heart rate variability, systolic blood pressure, pulse pressure, body weight, physical activity as derived from accelerometry, and occurrence of atrial and ventricular arrhythmias) have been identified as being associated with imminent clinical deterioration of HF patients. Structured telephone-based support and noninvasive telemonitoring with integrated electronic transfer of physiological data have been applied to care for HF patients and have been evaluated in multiple studies. The impact of telemedical care on clinical outcome appears to depend on the applied telemedical configuration and on the disease severity of targeted populations. The exclusive use of an automated telephone response system has not been successful. In patients with optimal medical therapy and relatively low decompensation risk noninvasive telemonitoring did not significantly reduce mortality. Nevertheless meta-analyses of structured telephone support and of noninvasive telemonitoring combining knowledge from available randomized trials suggest that both of these telemedical approaches may reduce the mortality risk of HF patients by 13-20%. The results of the Telemedical Interventional Management in Heart Failure II (TIM HF II) trial on noninvasive telemonitoring versus usual care in 1500 high-risk HF patients are awaited in 2018 and will further clarify the usefulness of telemedical care in this field. PMID- 28831546 TI - Dietary Proteins Rapidly Altered the Microbial Composition in Rat Caecum. AB - Dietary proteins can alter gut microbial diversity. However, little is known about how gut bacteria respond to dietary proteins during short-term feeding. In the present study, PCR-DGGE analysis was performed to compare changes in gut microbial composition in rat caecum after rats were fed proteins from soy, pork, beef, chicken, fish and casein (control) for 2, 7 and 14 days. On day 2, differences were observed in microbial composition between groups of red meat (pork and beef) and white meat (chicken and fish) proteins. For a certain diet group, microbial composition showed a great change with feeding time. Principle component analysis indicated that the soy protein group showed a good separation in microbial composition from the casein and meat protein groups on days 7 and 14. PMID- 28831545 TI - How the humble insect brain became a powerful experimental model system. AB - In the 21st century, neurobiological studies focused on the insect brain are revealing unprecedented insight into the molecular, cellular, developmental, and circuit aspects of brain organization and function, notably in the genetic model system of Drosophila melanogaster. Underlying this accelerating progress in understanding the insect brain is a century-long history of ground breaking experimental investigation, methodological advance, and conceptual insight catalyzed by the integration of two emerging research fields, neuroscience and genetics. This review traces some of the key early steps in this remarkable historical scientific adventure of exploring the brain of "these apparently humble representatives of life". PMID- 28831547 TI - Developmental visual deprivation: long term effects on human cone driven retinal function. AB - PURPOSE: To assess whether infantile visual deprivation induced by developmental cataract may influence the cone-driven retinal function in humans. METHODS: A total of 14 patients with history of bilateral developmental cataract (DC), who had undergone uncomplicated cataract extraction surgery and intraocular lens implant, and 14 healthy subjects (HS) were enrolled. All patients underwent complete ophthalmological and orthoptic evaluations and best-corrected visual acuity measurement. Light-adapted full-field electroretinograms (ERG) and photopic negative responses (PhNR) were recorded to obtain a reliable measurement of the outer/inner retinal function and of the retinal ganglion cells' function, respectively. RESULT: Mean values of light-adapted ERG a- and b-wave implicit times were slightly delayed when compared to HS values. Light-adapted ERG a-wave amplitude mean values showed borderline values (p = 0.001), whereas a-wave amplitude analysis at 5 ms, b-wave and PhNR amplitude mean values showed no significant differences when compared to control values. No significant correlations were found when age at surgery, time elapsed from surgery, duration of the visual deprivation, age at examination, age at first detection of the opacity, BCVA and electrophysiological parameters were plotted together. Coherently with morphological studies, the extremely light bioelectrical impairment of the cone pathway in our cohort of patients describes minimal functional abnormalities of a well-structured retina that is not completely mature. CONCLUSIONS: Our present results, combined to those of our previous work on congenital cataracts, allow us to enhance the comprehension of functional developmental mechanisms of children's retinas and highlight the relevance of the timely treatment of lens opacities during infancy. PMID- 28831548 TI - Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial. AB - Neuromyelitis optica spectrum disorder (NMOSD) often follows a relapsing course. As disability in NMOSD is attack-related, effective treatments are needed. We aimed to compare the efficacy of azathioprine (AZA) and rituximab (RIT) as maintenance therapy in NMOSD patients. An open, randomized clinical trial was conducted during September 2015 to December 2016, in Isfahan, Iran. Initially, 100 NMOSD patients were approached, 86 entered the study, and 68 cases completed the trial. All patients had a relapsing-remitting course with expanded disability extended scale (EDSS) <=7 (median 2.75, range = 0-7). Patients were randomized into two groups, which did not differ according to age, gender distribution, and disease duration. In the AZA group, 35 patients [20 aquaporin-4 (AQP4)-IgG positive] were started on 50 mg/day oral AZA and increased to 2-3 mg/kg/day (with oral prednisolone as adjunctive therapy). In the RIT group, 33 patients (13 aquaporin-4-IgG positive) received 1 g intravenous rituximab and repeated 2 weeks later and then every 6 months. Annualized relapse rate (ARR) was measured as the primary outcome and EDSS as the secondary outcome after 12 months of intervention. The mean ARR [standard deviation (SD)] in the AZA group decreased from 1 (0.38) to 0.51 (0.55) (P value <0.001) and in the RIT group decreased from 1.30 (0.68) to 0.21 (0.42) (P value <0.001). ARR after intervention minus ARR before intervention [mean (SD)] was 1.09 (0.72) in RIT group and 0.49 (0.59) in AZA group (P value <0.001). EDSS after intervention minus EDSS before intervention [mean (SD)] was 0.98 (1.14) in RIT group and 0.44 (0.54) in AZA group (P value <0.001). Nineteen patients (54.3%) in AZA group and 26 patients (78.8%) in RIT group became relapse-free after intervention (P value = 0.033). AZA and RIT can both effectively decrease ARR and EDSS in NMOSD patients. RIT was significantly more effective than AZA treatment. Trial Registration Name of registry: clinicaltrials.gov; ID: NCT03002038; URL: https://clinicaltrials.gov/ct2/show/NCT03002038 . PMID- 28831549 TI - Halobium Salinum sp. nov., Isolated from a Marine Solar Saltern. AB - A halophilic archaeal strain YJ-8-ST was isolated from Yangjiang marine solar saltern, China. Cells from strain YJ-8-ST were pleomorphic, lysed in distilled water, stained Gram-negative, and formed red-pigmented colonies on agar plate. Optimal growth of the strain was obtained at 3.1 M NaCl (range 1.4-4.8 M), 0.1 M MgCl2 (range 0.005-1.0 M), 37 degrees C (range 20-50 degrees C), and pH 7.5 (range 5.5-9.5). The major polar lipids are phosphatidylglycerol (PG), phosphatidylglycerol phosphate methyl ester (PGP-Me), sulfated mannosyl glucosyl diether (S-DGD-1), and mannosyl glucosyl diether (DGD-1). The 16S rRNA gene and rpoB' gene of strain YJ-8-ST were phylogenetically related to the corresponding genes of Halobium palmae (96.9-97.2 and 92.7% similarities, respectively). The DNA G+C content of strain YJ-8-ST was determined to be 68.9 mol%. The phenotypic, chemotaxonomic, and phylogenetic characteristics suggested that strain YJ-8-ST (=CGMCC 1.12553T = JCM 30029T) represents a new species of Halobium, for which the name Halobium salinum sp. nov. is proposed. PMID- 28831550 TI - Persistence to oral disease-modifying therapies in multiple sclerosis patients. AB - Dimethyl fumarate (DMF), fingolimod (FTY) and teriflunomide (TFN) are oral disease-modifying therapies (DMTs) approved for relapsing-remitting multiple sclerosis (RRMS) whose efficacy and tolerability have been separately assessed in phase III trials. Conversely, little evidence exists about their head-to-head comparison. The aim of the study was to evaluate the 1-year persistence to DMF, FTY and TFN in patients with RRMS. Patients affected by RRMS who started treatment with DMF, FTY or TFN were identified. The study end-point was 12-month drug persistence as time to discontinuation and proportion of patients who discontinued medication within 1-year. A total of 307 patients were included (DMF = 114, FTY = 129, TFN = 64). The mean times to discontinuation were 144 (84), 189 (72) and 138 (120) days in the DMF, FTY and TFN cohorts (p = 0.036). At 12-month, the proportion of patients discontinuing medication was lower for subjects taking FTY (9.8%) compared with those starting DMF (21.9%) and TFN (23.6%) (p = 0.020). Compared to FTY cohort, DMF [adjOR = 3.26 (1.38-7.70); p = 0.007] and TFN [adjOR = 2.89 (1.10-7.63); p = 0.032] treated patients were more likely to have discontinued their drug at 1-year since initiation. In patients with RRMS, FTY was associated with a better persistence profile as compared to DMF and TFN. PMID- 28831551 TI - Control of RNA polymerase II-transcribed genes by direct binding of TOR kinase. AB - Under conditions of nutrient limitation and cellular stress, or by addition of rapamycin, the mechanistic target of rapamycin complex 1 (mTORC1) is inhibited. This results in downregulation of genes that encode rRNA and ribosomal proteins. While most of the mTORC1 functions that have been previously characterized at a mechanistic level take place in the cytoplasm, nuclear roles have also been reported, including direct association of TOR kinase with rRNA genes. This review highlights the recent observation that Saccharomyces cerevisiae Tor1p also binds directly to the RNA polymerase II-transcribed gene encoding Hmo1p, a protein that is involved in communicating mTORC1 activity to downstream targets. A reduction in HMO1 mRNA levels in response to DNA damage or addition of rapamycin requires Tor1p, suggesting a role for TOR kinase in control of gene activity by direct binding to target genes. Potential targets for chromatin-bound Tor1p are discussed and the possibility that Tor1p similarly contributes to control of other genes linked to ribosome biogenesis is considered. PMID- 28831552 TI - Safety and efficacy of bi-annual intra-articular LBSA0103 injections in patients with knee osteoarthritis. AB - The objective of this study is to assess the safety and efficacy of repeated intra-articular injection of high molecular weight hyaluronic acid (LBSA0103) at a 26-week interval, in patients with osteoarthritis of the knee. The study was an open-label, single arm, multicentre prospective trial conducted in patients with symptomatic knee osteoarthritis. The intervention consisted of two intra articular injections of LBSA0103, with the second injection performed 26 weeks after the first injection. The primary outcome was the incidence of adverse drug reactions related to each injection. Assessment of efficacy of repeated injections in terms of maintenance of pain relief was a secondary objective of this study. Of the 185 patients screened, 174 patients received the first injection and 153 patients received both injections of LBSA0103. Nine adverse drug reactions occurred in seven patients (4.02%) after the first injection, while only one adverse drug reaction occurred (0.65%) after the second injection. As a secondary outcome measure, the improvements in the efficacy parameters including total WOMAC score and weight-bearing pain were all significant at both week 13 and 39 compared to the baseline value (P < 0.001), and improvements after the second injection were consistent with those after the initial injection of LBSA0103 (between week 26 and week 39, P < 0.001). Repeated intra-articular injection of LBSA0103 at a 26-week interval is safe without increased risk of adverse drug reactions. Additionally, LBSA0103 is effective in reduction of osteoarthritis knee pain and in maintenance of pain reduction for a 39-week period when a second injection is administered. PMID- 28831553 TI - Efficacy and safety of misoprostol, dinoprostone and Cook's balloon for labour induction in women with foetal growth restriction at term. AB - BACKGROUND AND OBJECTIVES: To compare effectiveness and safety of dinoprostone, misoprostol and Cook's balloon as labour-inducing agents in women with intrauterine growth restriction (IUGR) at term. METHODS: Retrospective cohort chart review of women diagnosed with foetal growth restriction at term in Reina Sofia Hospital, Cordoba, Spain from January 2014 to December 2015. Registration of baseline characteristics and method of induction was made. The main outcome was time from induction to delivery. Obstetric and perinatal outcomes were also collected. RESULTS: A total of 99 women were diagnosed with IUGR in the mentioned period. Of them, 21 women were induced with dinoprostone [dinoprostone group (DG)], 20 with misoprostol (MG) and in 58 with Cook's balloon (CG). Groups were homogeneous regarding pre-induction Bishop score and parity. The CG required more time (24.36 vs. 19.23 h; p = 0.02) and more oxytocin dose for conduction of labour from induction to delivery (6.75 vs. 1.24 mUI; p < 0.01) than DG. Moreover, the CG also needed more oxytocin than MG, 6.75 vs. 2.37 mUI (p < 0.001). Caesarean rate was 5, 14.9 and 17.3% in MG, DG and CG, respectively. No differences were observed in rates of uterine tachysystole, non-reassuring foetal status and neonatal adverse events. INTERPRETATION AND CONCLUSIONS: Prostaglandins were more effective than Cook's balloon to induce labour and achieve vaginal birth in this sample of women with IUGR at term, with a similar safety profile. PMID- 28831555 TI - Reply to "Association of HLA-B27 and its subtypes with ankylosing spondylitis and clinical manifestations of ankylosing spondylitis in different HLA-B27 subtypes: comment on the article by Lin et al." PMID- 28831554 TI - The impact of patient-specific instrumentation on unicompartmental knee arthroplasty: a prospective randomised controlled study. AB - PURPOSE: Patient-specific instrumentation (PSI) has been proposed as a means of improving surgical accuracy and ease of implantation during technically challenging procedures such as unicompartmental knee arthroplasty (UKA). The purpose of this prospective randomised controlled trial was to compare the accuracy of implantation and functional outcome of mobile-bearing medial UKAs implanted with and without PSI by experienced UKA surgeons. METHODS: Mobile bearing medial UKAs were implanted in 43 patients using either PSI guides or conventional instrumentation. Intra-operative measurements, meniscal bearing size implanted, and post-operative radiographic analyses were performed to assess component positioning. Functional outcome was determined using the Oxford Knee Score (OKS). RESULTS: PSI guides could not be used in three cases due to concerns regarding accuracy and registration onto native anatomy, particularly on the tibial side. In general, similar component alignment and positioning was achieved using the two systems (n.s. for coronal/sagittal alignment and tibial coverage). The PSI group had greater tibial slope (p = 0.029). The control group had a higher number of optimum size meniscal bearing inserted (95 vs 52%; p = 0.001). There were no differences in OKS improvements (n.s). CONCLUSION: Component positioning for the two groups was similar for the femur but less accurate on the tibial side using PSI, often with some unnecessarily deep resections of the tibial plateau. Although PSI was comparable to conventional instrumentation based on OKS improvements at 12 months, we continue to use conventional instrumentation for UKA at our institution until further improvements to the PSI guides can be demonstrated. LEVEL OF EVIDENCE: Therapeutic, Level I. PMID- 28831556 TI - [Active cardiac implantable electronic devices: What is possible in ambulatory health care in 2017?] AB - Telemonitoring (TM) features are implemented in nearly all cardiac implantable electronic devices (CIEDs) that have recently been released to the market. In combination with pacemakers, defibrillators and systems for cardiac resynchronization it is a safe and efficient method for routine technical aftercare of the devices as well as for monitoring heart failure and arrhythmias. Using TM has the potential to optimize patient care with regard to economic, clinical and safety aspects. Despite the good availability of existing data and clear recommendations of the responsible scientific societies, it is often seen as an isolated solution which is not fully integrated into standard care, although it has its own EBM number for implantable cardioverter-defibrillators and cardiac resynchronization therapy systems. The reasons are not only the unsatisfactory reimbursement of costs, different IT structures and the borders between clinics and medical practices, but also acceptance problems of physicians and legal aspects. The compensation of cardiac pacemakers and 'event recorders' is unsolved. TM provides the prospect for optimal and cross-sectoral patient care. Furthermore it has the potential to become the standard method for the care for patients with a CIED. PMID- 28831557 TI - Modeling shade tree use by beef cattle as a function of black globe temperature and time of day. AB - Increasing temperatures associated with global climate change threaten to disrupt agricultural systems such as beef production, yet relatively little is known about the use of natural tree shade to mitigate the negative effects of heat stress on beef cattle. In this study, we evaluated how temperature and time of day influenced the utilization of tree shade in relation to coloration, orientation, and behavior of beef cattle in a pasture system. Temperatures in shade and direct sunlight were measured using black globe temperature (BGT) data loggers. Time-lapse images from game cameras were used to obtain counts of shade usage, coloration, orientation, and behavior of cattle throughout the daytime hours. In general, we found that shade utilization and most of the predominating orientations and behaviors differed significantly (P < 0.05) by both time of day (Hour) and BGT in direct sunlight (BGTsun), while interactions between these two effects (Hour * BGTsun) were often nonsignificant. The mean percentage of the herd using shade was highest in mid-morning (87-96%) and early afternoon (97%), but also increased with BGTsun regardless of the time of day; these trends were similar for both dark- and light-colored cattle. Lying down was the dominant behavior exhibited in the shade, while foraging was the most prevalent behavior in the sun. When herd shade usage was lowest in mid- to late-afternoon (<1%) we also observed an increase in the use of heat-mitigating orientations in the sun (37-47%). We discuss some practical implications of these results, including the potential use of temperature thresholds to interpret cattle behaviors and shade usage. PMID- 28831558 TI - Importance of adhesiolysis in revision surgery for vibrant soundbridge device failures at the short incus process. AB - The objectives of the study were to report a vibrant soundbridge (VSB) implant revision surgical method involving adhesiolysis at the short incus process under local anesthesia and demonstrate successful hearing performance after surgery. Three cases of VSB surgery, performed in 2016, were enrolled. All cases had diagnoses of device failure. This 'seven-incision line' exposed the floating mass transducer directly, after which the three steps (adhesiolysis, curettage, and hydrocortisone injection) were performed. Upon fitting the VSB, sound fields were evaluated immediately and at 3 months after the revision. During the revisions of surgery, all patients achieved immediate hearing gains and noticed differences in the outer devices with different amplifications. Satisfactory improvements in hearing thresholds and speech recognition abilities were confirmed by improvements of 20-30 dB in hearing loss 3 months after revision surgery. The VSB implant revision surgical method involving adhesiolysis is safe and efficient for patients who experience a VSB device failure. This method will reduce the requirement for surgery under general anesthesia, reduce the overall period of clinical therapy and, therefore, minimize patients' medical costs. Level of Evidence 4. PMID- 28831559 TI - [Ophthalmological health care of the institutionalized elderly : The OVIS study]. AB - BACKGROUND: Due to demographic change and societal transformation the number of elderly persons living in retirement homes is growing in Germany. Access to health care is more complicated in the setting of nursing homes. Different regional studies suggest unmet ophthalmological health care needs in institutionalized elderly people. This study assessed the current ophthalmological health care structure and supply status in nursing homes in Germany. METHODS: This prospective, multicenter cross-sectional study was conducted by 14 study centers in Germany. Elderly people living in 32 nursing homes were included after approval by the local institutional review boards. A standardized examination was performed which included a detailed medical and ocular history, refraction, visual acuity testing, tonometry, biomicroscopy and dilated funduscopy. Unmet ophthalmological health care needs were documented and the data were analyzed descriptively and via logistic regression modelling. RESULTS: A total of 600 participants (434 women and 166 men) aged 50-104 years were examined of which 368 (61%) had ophthalmological conditions requiring treatment. The most prevalent findings were cataracts (315; 53%), disorders of the eyelids (127; 21%), dry eye disease (57; 10%) and posterior capsule opacification (43; 7%). In 63 (11%) of the participants glaucoma was suspected and 55 (9%) of the examined population had a known diagnosis of glaucoma, of whom one third was not on any or on insufficient anti-glaucomatous therapy. 236 (39%) showed signs of age-related macular degeneration (AMD). Only 52% of the examined cohort had been examined by an ophthalmologist within the last 5 years and 39% stated that they would currently not be able to consult an ophthalmologist. Reported barriers were mainly transport and lack of support. CONCLUSION: This study demonstrates considerable unmet ophthalmological health care needs of the institutionalized elderly in Germany. Novel and reformed models of specialist care provision have to be developed. PMID- 28831560 TI - A homofermentative Bacillus sp. BC-001 and its performance as a potential L lactate industrial strain. AB - Bacillus sp. BC-001 was first reported as a potent thermotolerant and homofermentative strain for an industrial-scale L-lactate production. In a flask culture, this isolate fermented both glucose and sucrose to lactate with high yield (0.96 and 0.87 g/g) and productivity (2.8 and 2.6 g/L h), respectively. The higher lactate production performance was obtained in the simultaneous saccharification and fermentation of liquefied starch (150.1 g/L final titer, 0.98 g/g yield, 3.2 g/L h productivity) and the fed-batch glucose fermentation (139.9 g/L final titer, 0.96 g/g yield, 2.9 g/L h productivity). Significant increase in lactate productivity (5.5-6.1 g/L h) was obtained from the high/heavy inoculum seed in the stirred tank fermentor. Both calcium bases and monovalent bases were successfully employed for pH control during lactate fermentation by this isolate resulting in a versatile and simple operation. By the two-phase fermentation using the high/heavy-inoculum seed of BC-001, the fermentation reproducibility was acquired toward the pilot-scale fermentors. PMID- 28831561 TI - Complete Genome Sequence of Sphingobium baderi DE-13, an Alkyl-Substituted Aniline-Mineralizing Bacterium. AB - Alkyl-substituted aniline is an important aniline derivative that may be associated with serious environmental risks. Previously, Sphingobium baderi DE 13, a bacterium that can mineralize alkyl substituted anilines such as 2,6 dimethylaniline, 2,6-diethylaniline, 2-methyl-6-ethylaniline, 2-methylaniline, and 2-ethylaniline, was isolated from active sludge. Here, we report the complete genome sequence of strain DE-13. It contains one circular chromosome and eight circular plasmids with total 4,583,422 bp and GC content of 62.41%. The reported and predicted genes involved in the catabolism of alkyl-substituted anilines are indicated. This study will provide insights into the bacterial catabolism of alkyl substituted anilines. PMID- 28831562 TI - Phylogenetic position of the family Orientocreadiidae within the superfamily Plagiorchioidea (Trematoda) based on partial 28S rDNA sequence. AB - Trematodes of the family Orientocreadiidae are mostly parasites of freshwater fishes. Here, the phylogenetic position of this family is inferred based on the partial 28S rDNA sequence from a representative of the genus Orientocreadium s. str.-O. pseudobagri Yamaguti, 1934. Sequences were analysed by maximum likelihood and Bayesian inference algorithms. Both approaches placed the Orientocreadiidae within a clade corresponding to the superfamily Plagiorchioidea and supported the family Leptophallidae as a sister taxon. PMID- 28831563 TI - Changes in balance coordination and transfer to an unlearned balance task after slackline training: a self-organizing map analysis. AB - How humans maintain balance and change postural control due to age, injury, immobility or training is one of the basic questions in motor control. One of the problems in understanding postural control is the large set of degrees of freedom in the human motor system. Therefore, a self-organizing map (SOM), a type of artificial neural network, was used in the present study to extract and visualize information about high-dimensional balance strategies before and after a 6-week slackline training intervention. Thirteen subjects performed a flamingo and slackline balance task before and after the training while full body kinematics were measured. Range of motion, velocity and frequency of the center of mass and joint angles from the pelvis, trunk and lower leg (45 variables) were calculated and subsequently analyzed with an SOM. Subjects increased their standing time significantly on the flamingo (average +2.93 s, Cohen's d = 1.04) and slackline (+9.55 s, d = 3.28) tasks, but the effect size was more than three times larger in the slackline. The SOM analysis, followed by a k-means clustering and marginal homogeneity test, showed that the balance coordination pattern was significantly different between pre- and post-test for the slackline task only (chi 2 = 82.247; p < 0.001). The shift in balance coordination on the slackline could be characterized by an increase in range of motion and a decrease in velocity and frequency in nearly all degrees of freedom simultaneously. The observation of low transfer of coordination strategies to the flamingo task adds further evidence for the task-specificity principle of balance training, meaning that slackline training alone will be insufficient to increase postural control in other challenging situations. PMID- 28831564 TI - Post-operative Outcomes in Children Undergoing Fontan Palliation in a Regionalized Surgical System. AB - Evidence suggests that outcomes in pediatric cardiac surgery are improved by consolidating care into centers of excellence. Our objective was to determine if outcomes are equivalent in patients across a large regional referral base, or if patients from centers without on-site surgery are at a disadvantage. Since 1996, all pediatric cardiac surgery has been offered at one of two centers within the region assessed, with the majority being performed at Stollery Children's Hospital. All patients who underwent a Fontan between 1996 and 2016 were included. Follow-up data including length of stay (LOS), repeat surgical interventions, and transplant-free survival were acquired for each patient. The association between post-operative outcomes and home center was assessed using Kaplan-Meier survival analysis and Cox proportional Hazards models. 320 children (median age 3.3 years, IQR 2.8-4.0) were included; 120 (37.5%) had the surgical center as their home center. Cardiac anatomy was hypoplastic left heart syndrome in 107 (33.4%) subjects. Median LOS was 11 days (IQR, 8-17), and there were 8 in hospital deaths. There were 17 deaths and 11 transplants over the course of follow-up. Five-year transplant-free survival was 92.5%. There was no difference in hospital re-intervention, late re-intervention, or survival by referral center (all p > 0.05). In multivariable analysis, home center was not predictive of either LOS (R 2 = -0.40, p = 0.87) or transplant-free survival (1.52, 95%CI 0.66, 3.54). In children with complex congenital heart disease, a regionalized surgical care model achieves good outcomes, which do not differ according to a patient's home base. PMID- 28831565 TI - Systemic inflammatory response after hernia repair: a systematic review. AB - PURPOSE: All surgical procedures elicit a complex systemic inflammatory response effectuated and modulated by cytokines. The purpose of this systematic review was to present an overview of the inflammatory response and the serum markers associated with hernia repair and to compare the response between patients treated with and without mesh. METHODS: The review was conducted in line with PRISMA guidelines. The outcomes of interest were serum concentration of leukocytes, cytokines, and acute phase proteins before and after hernia repair with or without mesh reinforcement. The risk of bias was assessed using the Cochrane ROBINS-I tool for non-randomized studies of intervention. RESULTS: A total of 31 studies were included in the systematic review including 1326 patients with a mean age ranging from 33 to 67 years. The studies predominantly included males (95.0% males, 5.0% female) with inguinal hernias (98.5% inguinal hernias, 1.5% incisional hernias). The inflammatory response after hernia repair was characterized by an increase in CRP, IL-6, leukocytes, neutrophils, IL-1, IL 10, fibrinogen, and alpha1-antitrypsin and a decrease in lymphocytes and albumin within the first 24 postoperative hours. The systemic inflammatory response was normalized before or on the seventh postoperative day. A higher CRP and IL-6 serum concentration was found in patients treated with mesh compared with sutured repairs. CONCLUSIONS: Hernia repair elicits a systemic inflammatory response characterized by an increase in CRP, IL-6, leukocytes, neutrophils, IL-1, IL-10, fibrinogen, and alpha1-antitrypsin and a decrease in lymphocytes and albumin. A higher inflammatory response was found after mesh repair compared with non-mesh repair and after open mesh repair compared with laparoscopic mesh repair. PMID- 28831566 TI - A Western diet-induced mouse model reveals a possible mechanism by which metformin decreases obesity. PMID- 28831567 TI - Horse spermatogonial stem cell cryopreservation: feasible protocols and potential biotechnological applications. AB - The establishment of proper conditions for spermatogonial stem cells (SSCs) cryopreservation and storage represents an important biotechnological approach for the preservation of the genetic stock of valuable animals. This study demonstrates the effects of different cryopreservation protocols on the survival rates and phenotypic expression of SSCs in horses. The cells were enzymatically isolated from testes of eight adult horses. After enrichment and characterization of germ cells in the suspension, the feasibility of several cryopreservation protocols were evaluated. Three different cryomedia compositions, associated with three different methods of freezing (vitrification, slow-freezing and fast freezing) were evaluated. Based on the rates of viable SSCs found before and after thawing, as well as the number of recovered cells after cryopreservation, the best results were obtained utilizing the DMSO-based cryomedia associated with the slow-freezing method. In addition, when isolated cells were cultured in vitro, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and immunofluorescence analysis indicated that the cryopreserved cells were as metabolically active as the fresh cells and were also expressing typical SSCs proteins (VASA, NANOS2 and GFRA1). Therefore, our results indicate that equine SSCs can be cryopreserved without impairment of structure, function, or colony forming abilities. PMID- 28831568 TI - Gender differences and the role of parental education, school types and migration on the body mass index of 2930 Austrian school children : A cross-sectional study. AB - BACKGROUND: Austria faces increasing numbers of childhood overweight and obesity. Despite increasing numbers of studies, associations between parental body mass index (BMI) and education and the school type on overweight/obesity in students have not been reported. The objective of this study was to evaluate the influence of these parameters on the genesis of overweight/obesity in a large cohort representative of youth in Upper Austrian. METHODS: A cross-sectional analysis of data from 2930 children and adolescents aged 10, 14 or 17 years from 11 different state school types was conducted. Students and their parents completed a questionnaire and heights and weights were measured. RESULTS: Of the students 16.9% fulfilled the criteria for overweight and 5.6% for obesity, with the highest rates in the 10-year-olds (19.6% and 5.8%, respectively). While no gender differences were present in the youngest age group, the body mass index (BMI) during adolescence remained higher in boys but decreased significantly in girls. Male gender remained a risk factor through all calculations. Boys were overrepresented in schools with lower education levels and more often had BMIs >= 85th and >=95th percentile. Higher parental education levels and lower parental BMIs were associated with lower BMIs of their offspring. Migration was an additional association factor for BMIs >= 85th percentile. CONCLUSION: Low parental education levels, higher parental BMIs and migration background were associated with overweight and obesity in 10-year-olds. In adolescence, male gender and higher parental BMIs remained risk factors. PMID- 28831569 TI - Madarosis: a qualitative study to assess perceptions and experience of Australian patients with early breast cancer treated with taxane-based chemotherapy. AB - PURPOSE: Eyebrow and eyelash loss (madarosis) is a common and distressing side effect of chemotherapy for which no protective strategies have yet been developed. The purpose of this study was to develop an overview of perceptions and experiences of women undergoing taxane-based treatment for early breast cancer. METHODS: A total of 25 women with a diagnosis of invasive early breast cancer participated in a focus group (n = 5), ages ranging from 35 to 64 (median 50), all had completed therapy with a taxane-based chemotherapy treatment. This focus group used targeted questions to explore participants' perceptions and experience of madarosis during and following chemotherapy and identified issues associated with impact of madarosis on quality of life (QoL). Thematic analysis was conducted to identify important issues experienced by participants. RESULTS: Seven themes emerged from the data: (1) timing of regrowth and permanent changes, (2) meaning/importance of eyebrow/eyelashes, (3) preparedness/information given, (4) impact of the hair loss of self, (5) impact of hair loss on others, (6) physiological side effects of loss of eyebrows/eyelashes, and (7) management of loss of eyebrows/eyelashes. In addition, participants noted physical symptoms of eye irritation during their treatment that they attributed to madarosis. CONCLUSION: This study highlights the significant impact of madarosis on patients, providing the first published analysis of patient's attitude and perception of eyelash and eyebrow loss during chemotherapy. Further research in this area is required and will be benefitted from the development of a dedicated instrument/questionnaire that can capture and measure the impact of madarosis on QoL and allow development of clinical trial strategies. PMID- 28831570 TI - Differential Response Pattern of Oropharyngeal Pressure by Bolus and Dry Swallows. AB - The aim of this study was to determine if bolus and dry swallow showed similar pressure changes in the oropharynx using our newly developed device. A unique character of it includes that baropressure can be measured with the sensor being placed in the balloon and can assess the swallowing mechanics in terms of pressure changes in the oropharynx with less influences of direct contacts of boluses and oropharyngeal structures during swallow indirectly. Fifteen healthy subjects swallowed saliva (dry), 15 ml of water, 45 ml of water, and 15 ml of two different types of food in terms of viscosity (potage soup-type and mayonnaise type foods). Suprahyoid muscle activity was recorded simultaneously. Three parameters, area under the curve (AUC), peak amplitude, and duration of pressure, were analyzed from each swallow. Almost all of the bolus swallowing events had biphasic baropressure responses consisting of an early phase and late phase (99%), whereas 90% of the saliva swallowing events had a single phase. AUC, peak, and duration displayed greater effects during the late phase than during the early phase. Baropressure of the early phase, but not of the late phase, significantly increased with increasing volume; however, small but significant viscosity effects on pressure were seen during both phases. Peak pressure of the late phase was preceded by maximum muscle activity, whereas that of the early phase was seen when muscle activity displayed a peak response. These findings indicated that our device with the ability to measure baropressure has the potential to provide additional parameter to assess the swallow physiology, and biphasic baropressure responses in the early and late phases could reflect functional aspects of the swallowing reflexes. PMID- 28831571 TI - The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant. AB - Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science. PMID- 28831572 TI - Fast track and outpatient surgery in total knee arthroplasty: beneficial for patients, doctors and hospitals. PMID- 28831573 TI - Native predators living in invaded areas: responses of terrestrial amphibian species to an Argentine ant invasion. AB - Predator-prey interactions play a key role in the success and impacts of invasive species. However, the effects of invasive preys on native predators have been poorly studied. Here, we first reviewed hypotheses describing potential relationships between native predators and invasive preys. Second, we examined how an invasive prey, the Argentine ant (Linepithema humile), affected a native terrestrial amphibian community. In the field, we looked at the structure of the amphibian community in invaded versus uninvaded areas and characterized amphibian trophic ecology. The amphibian community sampled seemed to show a species dependent response in abundance to invasion: adults of the natterjack toad (Bufo calamita), the species demonstrating the highest degree of ant specialization, were less abundant in invaded areas. Although available ant biomass was significantly greater in invaded than in uninvaded areas (only Argentine ants occurred in the former), amphibians consumed relatively fewer ants in invaded areas. In the lab, we quantified amphibian consumption of Argentine ants versus native ants and assessed whether consumption patterns could have been influenced by prior exposure to the invader. The lab experiments corroborated the field results: amphibians preferred native ants over Argentine ants, and prior exposure did not influence consumption. Differences in preference explained why amphibians consumed fewer Argentine ants in spite of their greater relative availability; they might also explain why the most ant-specialized amphibians seemed to avoid invaded areas. Our results suggest the importance to account for predator feeding capacities and dietary ranges to understand the effects of invasive species at higher trophic levels. PMID- 28831574 TI - Changes in Swallowing-Related Quality of Life After Endoscopic Treatment for Zenker's Diverticulum Using the SWAL-QOL Questionnaire. PMID- 28831575 TI - A simplified and validated ultrasound scoring system to evaluate synovitis of bilateral wrists and hands in patients with rheumatoid arthritis. AB - The objective of this study was to develop and validate an optimal simplified combination of joints for ultrasonographic assessment of synovitis in wrists and hands in patients with rheumatoid arthritis (RA). Twenty-two joints, including bilateral wrists, all proximal interphalangeal (PIP), and metacarpophalangeal (MCP) joints, were evaluated by grey-scale (GS) and power Doppler (PD) ultrasound using semi-quantitative scoring systems in 705 RA patients. Candidate joint sets were then selected by multiple linear regression analysis and the optimal candidate set was eventually validated in 235 RA patients. Through multiple linear regression analysis, the standard coefficient (beta) of MCP2, MCP3, and MCP5 joints in terms of GS was higher than other joints. The adjusted R 2 of the model composed of wrist, MCP2, MCP3, and MCP5 joints was greater than 0.9. Among the sum GS and PD scores of various selected joint combinations, total score-8, including bilateral wrist, MCP2, MCP3, and MCP5 joints, not only showed highest sensitivity and negative predictive value (93.86 and 92.90% for GS; 97.20 and 97.21% for PD, respectively) but also the best correlation with the total score 22 (r = 0.955 and 0.972 for GS and PD). The score-8 was further validated in 235 RA patients. The sensitivity for detecting synovitis by GS and PD was 94.35 and 94.12%, and the negative predictive values were 94.07 and 95.68%, respectively. Total score-8 system, including bilateral wrist, MCP2, MCP3, and MCP5 joints, is simple and efficient to pick up active synovitis of wrists and hands in patients with RA in daily practice. PMID- 28831577 TI - Chest radiographic features of human metapneumovirus infection in pediatric patients. AB - BACKGROUND: Human metapneumovirus (HMPV) was identified in 2001 and is a common cause of acute respiratory illness in young children. The radiologic characteristics of laboratory-confirmed HMPV acute respiratory illness in young children have not been systematically assessed. OBJECTIVE: We systematically evaluated the radiographic characteristics of acute respiratory illness associated with HMPV in a prospective cohort of pediatric patients. MATERIALS AND METHODS: We included chest radiographs from children <5 years old with acute respiratory illness who were enrolled in the prospective New Vaccine Surveillance Network (NVSN) study from 2003 to 2009 and were diagnosed with HMPV by reverse transcription-polymerase chain reaction (RT-PCR). Of 215 HMPV-positive subjects enrolled at our tertiary care children's hospital, 68 had chest radiographs obtained by the treating clinician that were available for review. Two fellowship trained pediatric radiologists, independently and then in consensus, retrospectively evaluated these chest radiographs for their radiographic features. RESULTS: Parahilar opacities were the most commonly observed abnormality, occurring in 87% of children with HMPV. Hyperinflation also occurred frequently (69%). Atelectasis (40%) and consolidation (18%) appeared less frequently. Pleural effusion and pneumothorax were not seen on any radiographs. CONCLUSION: The clinical presentations of HMPV include bronchiolitis, croup and pneumonia. Dominant chest radiographic abnormalities include parahilar opacities and hyperinflation, with occasional consolidation. Recognition of the imaging patterns seen with common viral illnesses like respiratory syncytial virus (RSV) and HMPV might facilitate diagnosis and limit unnecessary antibiotic treatment. PMID- 28831576 TI - Prevention of fracture-related infection: a multidisciplinary care package. AB - Fracture-related infection (FRI) remains a challenging complication. It may result in permanent functional loss or even amputation in otherwise healthy patients. For these reasons, it is important to focus attention on prevention. In treatment algorithms for FRI, antibiotic stewardship programmes have already proved their use by means of a multidisciplinary collaboration between microbiologists, surgeons, pharmacists, infectious disease physicians and nursing staff. A similar approach, however, has not been described for infection prevention. As a first step towards achieving a multidisciplinary care package for infection prevention, this review summarises the most recent guidelines published by the World Health Organization (WHO) and US National Institutes of Health Centers for Disease Control and Prevention (CDC), primarily focusing on the musculoskeletal trauma patient. The implementation of these guidelines, together with close collaboration between infection control physicians, surgeons, anaesthesiologists and nursing staff, can potentially have a beneficial effect on the rate of FRI after musculoskeletal trauma surgery. It must be stated that most evidence presented here in support of these guidelines was not obtained from musculoskeletal trauma research. Although most preventive measures described in these studies can be generalised to the musculoskeletal trauma patient, there are still important differences with nontrauma patients that require further attention. Future research should therefore focus more on this very defined patient population and more specifically on FRI prevention. PMID- 28831578 TI - Predictive Value of the New Zealand Secretion Scale (NZSS) for Pneumonia. AB - Accumulated pharyngo-laryngeal secretions have been associated with aspiration and pneumonia. While traditional secretion scales evaluate location and amount, the eight-point New Zealand Secretion Scale (NZSS) uniquely encompasses a responsiveness subcomponent. This prospective observational study investigated the predictive value of NZSS for aspiration and pneumonia. Consecutive inpatients (N:180) referred for flexible endoscopic evaluation of swallowing (FEES) were recruited (neurological 49%, critical care 31%, structural 15%, other 5% etiologies). Mean age was 63 years (range 18-95 years, S.D. 18). A standardized protocol was completed on 264 FEES (180 first FEES, 84 repeat FEES). Penetration aspiration scale (PAS) (ICC = .89) and NZSS (ICC = .91) were independently scored by two raters. Aspiration of food and/or fluids occurred in 36% of FEES; 24% silently. Median NZSS was 3 (range 0-7); with silent aspiration of secretions in 33% of FEES. There was a significant correlation between NZSS and PAS (R = .37, p < .001). Incidence of pneumonia during admission was 46% and was significantly associated with PAS (p < .001), NZSS (p < .001), age (p < .001), and tracheostomy (p < .001). Of those who developed pneumonia, 33% had both high PAS (>5) and high NZSS (>4). Eleven percent of those who developed pneumonia had an elevated NZSS (>4) in the absence of aspiration (PAS < 6). This large study reports the significant relationship between accumulated secretions, airway responsiveness, and pneumonia. This comprehensive scale is a useful tool when carrying out endoscopic evaluation and has the potential to predict pneumonia in patients irrespective of their aspiration status. PMID- 28831579 TI - Social makes smart: rearing conditions affect learning and social behaviour in jumping spiders. AB - There is a long-standing debate as to whether social or physical environmental aspects drive the evolution and development of cognitive abilities. Surprisingly few studies make use of developmental plasticity to compare the effects of these two domains during development on behaviour later in life. Here, we present rearing effects on the development of learning abilities and social behaviour in the jumping spider Marpissa muscosa. These spiders are ideally suited for this purpose because they possess the ability to learn and can be reared in groups but also in isolation without added stress. This is a critical but rarely met requirement for experimentally varying the social environment to test its impact on cognition. We split broods of spiders and reared them either in a physically or in a socially enriched environment. A third group kept under completely deprived conditions served as a 'no-enrichment' control. We tested the spiders' learning abilities by using a modified T-maze. Social behaviour was investigated by confronting spiders with their own mirror image. Results show that spiders reared in groups outperform their conspecifics from the control, i.e. 'no enrichment', group in both tasks. Physical enrichment did not lead to such an increased performance. We therefore tentatively suggest that growing up in contact with conspecifics induces the development of cognitive abilities in this species. PMID- 28831580 TI - Multiple values of 18F-FDG PET/CT in idiopathic inflammatory myopathy. AB - This study aimed to investigate the multiple values of 18F-FDG PET/CT in detecting malignant tumors, evaluating myopathy, and determining interstitial lung disease in patients with idiopathic inflammatory myopathy (IIM). We retrospectively analyzed the data of 38 patients who were examined by 18F-FDG PET/CT and eventually diagnosed as IIM. We also collected the data of another 22 cases with negative PET/CT as the control. Pulmonary HRCT images were acquired simultaneously with regular 18F-FDG PET/CT imaging for each patient. Image analysis included the presence of malignant lesions, muscular FDG uptake, and interstitial lung disease and its imaging features. IIM was classified into polymyositis (PM), classic dermatomyositis (CDM), and clinical amyopathic dermatomyositis (CADM). All suspected malignant lesions were confirmed by histopathological examination. Interstitial lung disease was diagnosed by HRCT. Rapidly progressive interstitial lung disease (RP-ILD) was determined according to clinical follow-ups. The significance of 18F-FDG PET/CT in the detection of malignancy, observation of activity of myopathy, and determination of interstitial lung disease in IIM patients was explored based on the final clinical diagnosis. In the 38 patients with IIM, 3 cases were classified as PM, 18 as CDM, and 17 as CADM. PET/CT correctly detected 7 cases (18.4%) of malignant tumors, and all of which were found in CDM and PM patients. The muscular FDG uptake in IIM patients was higher than the control population, and it was higher in patients with myopathy (including PM and CDM) than in patients with CADM. The muscular FDG uptake in IIM patients was correlated with elevated serum creatine kinase level (r = 0.332, P = 0.042) and impaired muscle strength (r = -0.605, P < 0.001). Interstitial lung disease was detected by HRCT in 30 patients (78.9%), and 7 of them were eventually confirmed as RP-ILD, according to the clinical outcome. The FDG uptake in lung lesions of RP-ILD patients was higher than those with chronic interstitial lung diseases, even though no significant difference was found between the CT features of RP-ILD and chronic interstitial lung disease. When SUVmax >= 2.4 was employed as the threshold for RP-ILD prediction, the diagnostic efficiency was yield with a sensitivity of 100.0% (7/7), specificity of 87.0% (20/23), and accuracy of 90.0% (27/30), respectively. For IIM patients, 18F-FDG PET/CT has multiple values in identifying malignancies, observing the status of inflammatory myopathy, detecting interstitial lung disease, and predicting the occurrence of RP-ILD. Therefore, it is recommended to use PET/CT in the clinical course of diagnosis and management of IIM. PMID- 28831581 TI - Serum adipokines, adipose tissue measurements and metabolic parameters in patients with advanced radiographic knee osteoarthritis. AB - We conducted the present study to evaluate the serum levels of adipokines (leptin, total and high molecular adiponectin, resistin), a marker of cartilage breakdown (C2C), and ghrelin together with body composition in patients with knee osteoarthritis (OA). Fifty patients and 50 sex-matched healthy subjects (HS) were evaluated. Knee OA was scored according to the Kellgren-Lawrence (KL) grade. Body composition parameters including lean mass and measurements of fat mass (total fat, adiposity, fat in the android and gynoid regions, visceral fat and trunk/legs fat ratio) were obtained using dual energy X-ray absorptiometry. Most of the recruited patients (88%) had advanced knee OA with KL grade 3 or 4. The patients had higher body mass index than HS (p < 0.0001). Serum leptin, high molecular adiponectin, resistin and ghrelin levels did not differ between patients and HS. Total adiponectin was higher in women with OA compared to women from the HS group (p = 0.004). Total fat mass, adiposity and measurements of central adiposity (fat in the android region, trunk/lower limbs fat ratio and visceral fat) were increased in patients with knee OA (all p < 0.05). Total adiponectin was borderline associated with the severity of OA. Our results show that total adiponectin is significantly increased in women with advanced knee OA. Independently of gender, patients with severe knee OA were characterized by a significant excess of fat with a distribution toward the visceral region. This abnormal body composition may contribute to the cardiometabolic profile that is described in patients with knee OA. PMID- 28831582 TI - Asymmetric dimethylarginine and symmetric dimethylarginine prospectively relates to carotid wall thickening in black men: the SABPA study. AB - The relationship of both asymmetric (ADMA) and symmetric (SDMA) dimethylarginine with carotid wall thickness is inconclusive especially among black populations. We aimed to compare carotid intima media thickness (cIMT) and dimethylarginine levels in 75 black and 91 white men at baseline and after a 3-year follow-up, and to investigate associations of percentage change in cIMT with percentage change in dimethylarginine levels (ADMA and SDMA). Plasma levels of ADMA and SDMA were determined with a liquid chromatography mass spectrometry method and B-mode ultrasonography was used to determine the cIMT at baseline and follow-up. In black men, mean cIMT (p = 0.79) and ADMA levels (p = 0.67) remained the same, but SDMA levels were lower (p < 0.001) when comparing baseline and follow-up. In white men, cIMT increased (p < 0.001), but both mean ADMA and SDMA levels decreased (p < 0.001) over time. In black men, percentage change in cIMT was positively associated with percentage change in ADMA (R 2 = 0.49; beta = 0.46; p < 0.001) and percentage change in SDMA (R 2 = 0.46; beta = 0.41; p < 0.001). These associations were absent in the white men. Despite lower mean SDMA and similar ADMA and cIMT in black men, percentage change in cIMT was independently associated with percentage change in ADMA and percentage change in SDMA. These results suggest an important role for ADMA and SDMA lowering strategies to delay carotid wall thickening, especially in black populations prone to the development of cardiovascular disease. PMID- 28831583 TI - 18F-FDG-PET detects complete response to PD1-therapy in melanoma patients two weeks after therapy start. AB - PURPOSE: The aim of the study was to evaluate if 18F-FDG-PET has the potential to detect complete responders to PD1-therapy in patients with unresectable metastasized melanoma two weeks after therapy initiation. METHODS: Between September 2014 and May 2016, ten patients (four females; 65 +/- 12 y) received a whole-body 18F-FDG-PET/MRI examination at three time points: Before therapy start (t0, base-line), two weeks (t1, study examination) and three months after treatment initiation (t2, reference standard). Therapy response was assessed with PET response criteria in solid tumors (PERCIST). Time to progression and overall survival (OS) were obtained for all patients. RESULTS: Three patients with partial metabolic response in PET at t1 turned out to have complete response at t2. No tumor relapse was observed in those patients so far (observation period: 265, 511 and 728 days, respectively). At t2, progressive metabolic disease (PMD) was seen in six patients from whom four showed PMD and two showed stable metabolic disease (SMD) at t1. OS in patients with PMD at t2 varied between 148 and 814 days. SMD at both t1 and t2 was seen in one patient, tumor progress was observed after 308 days. CONCLUSION: Our study indicates that whole-body 18F-FDG PET might be able to reliably identify complete responders to PD1-therapy as early as two weeks after therapy initiation in stage IV melanoma patients. This might help to shorten therapy regimes and avoid unnecessary side effects in the future. PMID- 28831585 TI - Association between AKI and all-cause mortality after EVAR. PMID- 28831584 TI - Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores. AB - After introducing a rituximab-containing chemoimmunotherapy (R-CHOP) for diffuse large B cell lymphoma (DLBCL), a partial response (PR) which is regarded as treatment failure is still observed. To investigate the prognostic factors for the DLBCL patients with a PR to R-CHOP, we retrospectively evaluated 758 newly diagnosed DLBCL patients. After R-CHOP, 88 (11.6%) achieved a PR. Three-year progression-free and overall survival rates measured from the date of PR achievement (PFS2 and OS2) were 57.4 and 67.8%, respectively. The secondary International Prognostic Index (IPI2) scores after R-CHOP were low (0-1) in 68.2% and high (2-3) in 31.8% of the patients. The Deauville scores from 18 fluorodeoxyglucose positron emission tomography after R-CHOP showed low (2-3) in 58.0% and high (4) in 42.0% of the patients. High IPI2 and high Deauville scores were associated with worse PFS2 (P < 0.001 and P = 0.009) and OS2 (P = 0.013 and P = 0.067). The high-risk group defined by the IPI2 and Deauville scores, whose scores were both high, showed significantly lower 3-year PFS2 (P < 0.001) and OS2 (P = 0.006) rates compared with those of the other groups. In multivariate analyses, the IPI score of >= 3 at diagnosis and bone marrow involvement at diagnosis were independent prognostic factors. In addition, high IPI2-Deauville score after R-CHOP was significantly associated with poor PFS2 (P = 0.009) and demonstrated a trend toward inferior OS2. In conclusion, DLBCL patients who partially responded to R-CHOP are still a heterogeneous group, for which IPI2 and Deauville scores should be evaluated for prediction of prognosis. PMID- 28831586 TI - Elevated circulating levels of xenopsin-related peptide-1 are associated with polycystic ovary syndrome. AB - PURPOSE: This study was conducted to compare serum xenopsin-related peptide-1 (XP 1) levels in women with polycystic ovary syndrome (PCOS) and in healthy women and to determine the role of XP-1 levels in PCOS. METHODS: Forty patients with PCOS and 38 healthy women were included in the study and matched with age and body mass index. Fasting blood glucose, insulin, high sensitivity C-reactive protein (hs-CRP), XP-1 and total testosterone levels of all participants were measured. RESULTS: Serum XP-1 levels significantly increased in women with PCOS compared to the control group (6.49 +/- 1.57 vs 5.29 +/- 1.45 ng/ml, p = 0.001). Serum insulin, hs-CRP, HOMA-IR, total testosterone levels and waist circumference were higher in women with PCOS than in control group. High XP-1 levels were associated with PCOS after adjustment for potential confounders. Receiver operating characteristic (ROC) curve analysis confirmed that the area under ROC curves was 0.703 (95% CI 0.588-0.818, p < 0.002) for XP-1 levels. The optimal cut-off value of XP-1 for detecting PCOS was >=5.87 ng/ml. CONCLUSIONS: Our results indicate that increased XP-1 levels were associated with PCOS after adjustment for potential confounders, which has been shown to be effective in the function of the insulin signaling pathway. PMID- 28831587 TI - Usefulness of an access-site hemostasis device in neuroendovascular treatment. AB - BACKGROUND: We examined the safety and efficacy of the access-site hemostasis device Angio-SealTM STS Plus (AS; St. Jude Medical,St. Paul, MN, USA) compared with the method of hemostasis by manual compression (MC) in neuroendovascular therapy. METHOD: We conducted a prospective multicenter registration study enrolling 229 patients who were scheduled to undergo endovascular treatment. RESULTS: Of the 119 and 110 cases assigned to the AS and MC groups, 118 (99.2%) and 105 (95.5%) achieved successful hemostasis, respectively. Six AS patients and 38 MC patients had access-site hematoma (5% vs 34.5%, P < 0.001). Hemostasis time was significantly shorter in the AS group than in the MC group (4.4 min vs 150.7 min, P < 0.001). Puncture-site hematoma was significantly larger in the AS group than the MC group (5.5 cm vs 2.9 cm, P < 0.05). Patients in the AS group had a significantly shorter hospital stay than those in the MC group (8.7 days vs 13.3 days, P < 0.001); they also had a significantly shorter time before they could start to walk (23.9 h vs 52.2 h, P < 0.001). No serious adverse events were noted in either group. Minor adverse events included four cases from the AS group and two cases from the MC group. CONCLUSIONS: Use of an access-site hemostatic device resulted in quick and reliable access-site hemostasis in neuroendovascular therapy. When using AS, it is necessary to be careful when there is a possibility of a hematoma, as the hematomas, though significantly less frequent than in MC, were significantly bigger in that group. PMID- 28831588 TI - Encouraging option of multi-staged gross total resection for a C11orf-RelA fusion positive supratentorial anaplastic ependymoma. AB - Ependymomas are primary neuroepithelial malignancies that mainly occur during childhood, and arise from ependymal cells along the ventricular systems of the CNS. Recently, it was elucidated that two-thirds of supratentorial (ST) ependymomas harbor oncogenic fusions of RELA, whose protein product is the principal effector of canonical NF-kappaB signaling. RELA fusion proteins activate signaling for tumor proliferation and malignant progression, resulting in poorer prognoses in these patients compared to those in patients with other ST ependymomas. In this study, we encountered a case of C11orf-RelA fusion-positive ST anaplastic ependymoma that was diagnosed in first tumor resection surgery of multi-staged gross total resection with molecular evidence. In ependymomas, regardless of tumor location or pathological grade, subtotal resection is associated with higher rates of mortality compared with GTR. Molecular analysis based on the application of recent molecular knowledge for ST ependymomas performs a role in appropriate and individualized treatment strategies. PMID- 28831589 TI - Functional and quality of life outcome after non-operatively managed proximal humeral fractures. AB - BACKGROUND: Fractures of the proximal humerus are common and most often treated non-operatively. However, long-term follow-up studies focusing on functional results and quality of life in patients after this type of fracture are scarce. The primary aim of this study is to report the long-term functional and quality of life outcome in patients with a proximal humeral fracture. MATERIALS AND METHODS: A retrospective analysis of all consecutive patients undergoing non operative treatment for a proximal humeral fracture in a level 2 trauma centre between January 2000 and December 2013 was performed. A database consisting of all relevant demographic, patient and fracture characteristics was created. Subsequently, a questionnaire containing the DASH (Disabilities of the Arm, Shoulder and Hand) score, EuroQol-5D (EQ-5D), VAS (visual analogue scale) score, and subjective questions was sent to all patients. RESULTS: A total of 410 patients (65 male, 345 female) were included for analyses. Average follow-up was 90 +/- 48 months. DASH-scores <15 were considered as good. A median DASH-score of 6.67 [0.83-22.50] was found. A significant lower DASH-score was seen in patients under the age of 65 compared to older patients (p < 0.001). In comparison to an age-matched general Dutch population, Health related Quality of Life (HrQoL) on the EQ-us was not significantly worse in our study population (difference 0.02). Strong (negative) correlation was found between DASH-score and VAS-score, and DASH-score and HrQoL, respectively rho = -0.534 and rho = -0.787. CONCLUSION: Long-term functional and quality of life outcomes are good in most patients after proximal humeral fractures, but negatively correlated to each other. LEVEL OF EVIDENCE: Level III. PMID- 28831590 TI - Limitations of the endonasal endoscopic approach in treating olfactory groove meningiomas. A systematic review. AB - OBJECTIVE: To review current management strategies for olfactory groove meningioma (OGM)s and the recent literature comparing endoscopic endonasal (EEA) with traditional transcranial (TCA) approaches. METHODS: A PubMed search of the recent literature (2011-2016) was performed to examine outcomes following EEA and TCA for OGM. The extent of resection, visual outcome, postoperative complications and recurrence rates were analyzed using percentages and proportions, the Fischer exact test and the Student's t-test using Graphpad PRISM 7.0Aa (San Diego, CA) software. RESULTS: There were 444 patients in the TCA group with a mean diameter of 4.61 (+/-1.17) cm and 101 patients in the EEA group with a mean diameter of 3.55 (+/- 0.58) cm (p = 0.0589). GTR was achieved in 90.9% (404/444) in the TCA group and 70.2% (71/101) in the EEA group (p < 0.0001). Of the patients with preoperative visual disturbances, 80.7% (21/26) of patients in the EEA cohort had an improvement in vision compared to 12.83%(29/226) in the TCA group (p < 0.0001). Olfaction was lost in 61% of TCA and in 100% of EEA patients. CSF leaks and meningitis occurred in 25.7% and 4.95% of EEA patients and 6.3% and 1.12% of TCA patients, respectively (p < 0.0001; p = 0.023). CONCLUSIONS: Our updated literature review demonstrates that despite more experience with endoscopic resection and skull base reconstruction, the literature still supports TCA over EEA with respect to the extent of resection and complications. EEA may be an option in selected cases where visual improvement is the main goal of surgery and postoperative anosmia is acceptable to the patient or in medium-sized tumors with existing preoperative anosmia. Nevertheless, based on our results, it seems more prudent at this time to use TCA for the majority of OGMs. PMID- 28831591 TI - Does the radiologically isolated syndrome exist? A dual-task cost pilot study. AB - Simultaneous performance of motor and cognitive tasks may compete for common brain network resources in aging or patients with some neurological diseases, suggesting the occurrence of a cognitive-motor interference. While this phenomenon has been well described for multiple sclerosis (MS) patients, it never has been tested on asymptomatic subject with magnetic resonance imaging (MRI) findings suggestive of demyelinating disease (i.e., radiologically isolated syndrome: RIS). In this pilot study, 10 RIS subjects and 10 sex/age-matched healthy controls were tested by means of static posturography under eyes opened (single-task trial) and while performing two different cognitive tasks (semantic modified word list generation for first dual-task trial and phonemic semantic modified word list generation for second dual-task trial), to estimate the dual task cost (DTC) of standing balance. In our sample, under cognitive interference (without any substantial differences between semantic and phonemic modified word list generation), the RIS group showed significance differences in CoP (center of pressure) total sway area, ellipse eccentricity, CoP sway path length, CoP median sway velocity along the AP (anteroposterior) axis and along the ML (mediolateral) axis, reflecting a higher negative DTC respect to healthy subjects (which have simply shown a statistical trend, failing to reach a significance, in some trials). The phenomenon of cognitive-motor interference might be unmasked by a dual-task posturography in RIS subjects, too. We hypothesize that this approach could be useful to early reveal the presence of a demyelinating disease and to reach a MS diagnosis in subjects otherwise classified as RIS. PMID- 28831592 TI - A comparative study of intraoperative findings and postoperative outcomes between atypical and typical hemifacial spasms. AB - In most hemifacial spasm cases, the spasm initiates from the orbicularis occuli muscle and gradually spreads downwards to the orbicularis oris and buccinator muscles. Seldomly, the spasm might start from the orbicularis oris and buccinator muscles and develop upwards, which has been called as atypical hemifacial spasm (aHFS). Until now, little is known about its pathogenesis and the efficacy of microvascular decompression (MVD) surgery. We reviewed 1935 HFS cases undergoing MVD between 2007 through 2016. Among them, 15 were diagnosed as aHFS, whom were focused on. Their intraoperative findings and postoperative outcomes were compared with those typical hemifacial spasm (tHFS) cases. In the aHFS group, the conflict site was found in the root exit zone (REZ) in 12 (rostral 9, dorsal 2, and ventral 1) and in the cisternal segment in 3. In the tHFS group, the conflict site was found in the REZ in 1812 (rostral 6, caudal 1734, dorsal 12, and ventral 60) and in the cisternal segment in 108. The rostral REZ seemed to be the most frequent neurovascular conflict site in aHFS compared to the caudal REZ in tHFS (p < 0.05). Postoperatively, the effective rate of MVD was 93.3% in the aHSF group, while 96.3% in the tHSF group (p > 0.05). It was demonstrated that MVD may also lead to a satisfactory outcome for aHFS. Although the caudal REZ of the facial nerve is a frequent conflict site for most of the hemifacial spasm cases, the rostral side or cisternal segment of the facial nerve root should not be ignored while searching for the offending artery. PMID- 28831593 TI - Impact of rapid diagnosis of Staphylococcus aureus bacteremia from positive blood cultures on patient management. AB - We have performed a retrospective, before-after comparison of turnaround time and therapy adjustment parameters before and after the introduction of matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) plus mecA polymerase chain reaction (PCR) for the identification of methicillin-resistant Staphylococcus aureus (MRSA) in positive blood cultures. There were 227 episodes of S. aureus bacteremia during the study periods. The pre-MALDI-TOF and post MALDI-TOF groups included 133 and 94 patients, respectively. The two rapid methods performed sequentially decreased the turnaround time of MRSA identification by nearly 50% (2.06 +/- 1.95 vs. 3.95 +/- 1.70 days). There was no significant reduction in the length of hospitalization (28.27 +/- 32.16 vs. 28.62 +/- 28.75 days). In both groups, the adequacy of the empirical antibacterial therapy was similar (59.49% vs. 51.31%), but the optimization of the therapy was more frequent in the post-MALDI-TOF group. Routine implementation of these techniques provides results earlier than conventional methods and increases the proportion of episodes with adequate change of empirical to directed antimicrobial therapy. PMID- 28831594 TI - Bacterial DNA Detected in Japanese Rice Wines and the Fermentation Starters. AB - As Japanese rice wine (sake) brewing is not done aseptically, bacterial contamination is conceivable during the process of sake production. There are two types of the fermentation starter, sokujo-moto and yamahai-moto (kimoto). We identified bacterial DNA found in various sakes, the sokujo-moto and the yamahai moto making just after sake yeast addition. Each sake has a unique variety of bacterial DNA not observed in other sakes. Although most bacterial DNA sequences detected in the sokujo-moto were found in sakes of different sake breweries, most bacterial DNA sequences detected in the yamahai-moto at the early stage of the starter fermentation were not detected in any sakes. Our findings demonstrate that various bacteria grow and then die during the process of sake brewing, as indicated by the presence of trace levels of bacterial DNA. PMID- 28831595 TI - Juvenile systemic sclerosis: experience from a tertiary care center from India. AB - Juvenile systemic sclerosis (JSSc) is a rare disorder with paucity of information on its treatment and longterm outcome. Herein, we are sharing our experience with this rare entity. Case records of children, diagnosed to have systemic sclerosis attending Pediatric Rheumatology Clinic at All India Institute of Medical Sciences, New Delhi from January 1998 to June 2016 were reviewed. The demographic, clinical, laboratory, treatment and outcome details were recorded. Disease outcome was classified arbitrarily as controlled, partly controlled or non-responsive/progressive based on: (A) ability to perform activities of daily life (ADL) and (B) presence or absence of musculoskeletal symptoms, skin changes (ulceration/progressive digital pitting/gangrene), and visceral organ involvement (dyspahgia, cardiopulmonary symptoms). Controlled: ability to perform ADL and absence of B features for at least 6 months. Partly controlled: inability to perform ADL or any of the B features. Non-responsive/progressive disease: presence of both A and any of B features. Thirty-two children (21, girls) diagnosed as systemic sclerosis for whom follow-up of more than 6 months was available were included for this retrospective analysis. Mean (SD) age at presentation was 112.79 (30.05) months, while the median (IQR) delay in diagnosis was 28.5 (9-47.25) months. Of the 32 children 17 (53.12%) had diffuse systemic sclerosis (dSSc), 5 (15.62%) had limited systemic sclerosis (lSSc) and 10 (31.25%) had sclerosis with overlap syndrome. The common clinical features apart from sclerosis/induration proximal to metacarpophalangeal joint were Raynauds phenomenon (n = 22, 68.7%), skin rash (n = 20, 62%), arthritis or arthralgia (n = 16, 50%), and muscular weakness (n = 10, 31.2%). Among those for whom data regarding investigations were available; ANA was positive in 50% (12/24), whereas Anti Scl70 was positive in one out three cases. Treatment regimen included naproxen, methotrexate, calcium channel blockers with or without steroids. HCQ was added in children with skin rash or in children with partial control. Median (IQR) follow-up period was 19.75 (12-31.75) months. With the above treatment protocol, 19 (59.3%) children achieved disease control on treatment, 8 (26.6%) had partial control while 5 (16.6%) showed no response or progressive disease. Esophageal dysmotility and intertitial lung disease (ILD) were documented in three children each. Complication (cataract and herpes zoster) related to immunosuppressive therapy were observed in two children. There was no mortality during the study period. Juvenile Sclerosis though rare is associated with significant morbidities and lacks a curative treatment but a reasonable quality of life to perform daily activities can be achieved using methotrexate and steroid-based immuosuppressive therapy. PMID- 28831597 TI - Prognostic value of glomerular filtration rate and proteinuria in patients with diabetes mellitus and advanced chronic kidney disease. PMID- 28831596 TI - Proteomic Analysis of Vibrio parahaemolyticus Under Cold Stress. AB - Vibrio parahaemolyticus is a kind of food-borne pathogenic bacterium, which can seriously infect food, especially seafood causing gastroenteritis and other disease. We studied the global proteome responses of V. parahaemolyticus under cold stress by nano-liquid chromatography-tandem mass spectrometry to improve the present understanding of V. parahaemolyticus proteomics events under cold stress. A total of 1151 proteins were identified and 101 proteins were differentially expressed, of which 69 were significantly up-regulated and 32 were downregulated. Functional categorization of these proteins revealed distinct differences between cold-stressed and control cells. These proteins were grouped into 21 functional categories by the clusters of orthologous groups (COG) analysis. The most of up regulated proteins were functionally categorized as nucleotide transport and metabolism, transcription, function unknown, and defense mechanisms. These up regulated proteins play an important role under cold stress. PMID- 28831598 TI - The difference in medical costs between carbapenem-resistant Acinetobacter baumannii and non-resistant groups: a case study from a hospital in Zhejiang province, China. AB - This retrospective study aims to compare differences in the medical costs between inpatients infected/colonised with carbapenem-resistant (CRAB) and carbapenem susceptible (CSAB) Acinetobacter baumannii in a hospital in Zhejiang province, China. Because the patient population was large, we randomly selected 60% of all inpatients with clinical specimens between 2013 and 2015. We classified the A. baumannii cases as CRAB or CSAB based on antibiotic susceptibility testing. Univariate and multivariate analyses were used to identify factors associated with the total medical cost (TMC). Those included in the study totalled 2980 inpatients, 71.3% of whom had CRAB infection/colonisation. Differences in the TMC between the CRAB and CSAB groups were lower by multivariate analyses than the differences obtained by univariate analyses. Carbapenem resistance was significantly associated with an approximately 1.5-fold increase in the TMC after accounting for confounding factors. Our study highlights the heavy financial burden imposed by A. baumannii and carbapenem resistance on the Chinese healthcare system. PMID- 28831599 TI - Efficacy of intermediate-dose cytarabine in central nervous system-relapsed wild type BRAF Erdheim-Chester disease. PMID- 28831600 TI - Encouraging results with the compassionate use of hydralazine/valproate (TRANSKRIPTM) as epigenetic treatment for myelodysplastic syndrome (MDS). AB - The hypomethylating agents azacytidine and decitabine are unaffordable for many patients with MDS. The combination of the DNA methyltransferase inhibitor hydralazine and the histone deacetylase inhibitor valproate has shown preliminary efficacy in MDS. The aim of this study is to evaluate the clinical efficacy and safety of hydralazine/valproate in a case series of MDS patients treated in a compassionate manner. Hydralazine was dosed according to the acetylation genotype of patients (slow acetylators 83 mg daily; fast acetylators 182 mg daily), and valproate was dosed at 30 mg/kg/day. Both drugs were given daily until disease progression. Response and toxicity were evaluated with the International Working Group criteria and CTCAE, version 4, respectively. Survival parameters were estimated with the Kaplan-Meier method. From 2009 to 2012, 14 patients were treated. The median age +/- SD was 55.2 +/- 19.52 (range 23-87) years. According to the IPSS, cases were graded as intermediate-1 (n = 8/14; 57.2%) or intermediate-2 (n = 6/14; 42.8%). Responses were as follows: five (35.7%) complete response, one (7.1%) partial response, and two (14.28%) became transfusion independent. The mean duration of response +/- SD was 60 +/- 35.28 months (range 5-94). Three patients progressed to AML. At a median follow-up of 57 months (range 1-106), the median OS was 27 months. At that point, five patients remained on the treatment, one with partial response and four with complete response. The median OS was not reached in the eight patients who saw a clinical benefit from the treatment, in comparison to an OS of 7 months in the six patients who had no treatment. The combination of hydralazine and valproate is safe and effective in MDS, and its further testing is highly desirable. PMID- 28831601 TI - Endothelin-1, alpha-Klotho, 25(OH) Vit D levels and severity of disease in scleroderma patients. AB - Considering the role of endothelin-1 (ET-1) in tissue remodeling and fibrosis during the development of scleroderma as well as the effect of alpha-Klotho in pathogenesis of calcinosis and/or endothelial cell injury and its correlation with severity of disease, this study aimed to evaluate serum ET-1, alpha-Klotho and 25(OH) vitamin D levels in patients with limited and diffuse scleroderma compared to healthy subjects. In this cross-sectional study, 60 scleroderma patients according to the ACR/EULAR 2013 criteria and 60 age- and sex-matched healthy controls were included. In patients, clinical examination was performed and Medsger severity scale was assessed. Serum ET-1, soluble alpha-Klotho and 25(OH)D3 levels were measured using ELISA kits. The mean +/- SD age of patients and controls was 46.2 +/- 9.6 and 47.2 +/- 7.0 years, respectively. Compared to healthy controls, serum ET-1 was significantly higher in SSc patients (p = 0.001); whilst serum alpha-Klotho and 25(OH)D3 were significantly lower in patients (p = 0.001). The most common organs involved in patients were skin, lung, peripheral vascular and gastrointestinal system and the severity of involvement was mainly mild and/or moderate. There were no significant differences in serum ET-1 and alpha-Klotho levels according to the severity of different organ involvement (p > 0.05). There was no significant correlation between presence or absence of calcinosis and negative or positivity of auto antibodies with ET-1, alpha-Klotho and 25(OH)D3 levels. Although our study revealed higher serum ET-1 and lower serum alpha-Klotho levels in SSc patients compared to healthy controls, there were not any significant correlations between their serum levels with severity of organ involvement. PMID- 28831602 TI - Plaque accumulation on titanium disks with different surface treatments: an in vivo investigation. AB - Implants with rough surfaces are today widely used. It has been speculated that rough surfaces (Ra > 0.2 MUm) provide a better "substrate" for retention and accumulation of plaque in terms of area, thickness and colony-forming unit that can eventually lead to peri mucositis and/or peri-implantitis. The aim of this investigation was to evaluate in vivo the plaque accumulation after 48 h on three implant surfaces with different treatments. For this investigation, we used 21 sterilized titanium disks, with a diameter of 8mm and a thickness of 3 mm, provided by the manufacturer: 7 with machined surface, as smooth control, 7 with HA grit sandblasted RBM surface and 7 with Ca++ incorporated in titanium Xpeed surface. One disk for each surface treatment was characterized at time 0 by SEM and AFM to study, respectively, the surface morphology and roughness. The other 18 disks were mounted randomly on three upper acrylic bites in a buccal lateral position, worn for 48 h by three volunteer students for plaque accumulation. After 48 h each disk was removed and analyzed qualitatively and quantitatively by an independent operator, not involved into the study, in order to avoid bias. Data collected were statistically analyzed by one-way ANOVA. The qualitative analysis showed no differences in terms of total plaque accumulation between the surfaces. Data from quantitative analysis using Anova Test showed no significance between all groups. In this in vivo investigation all the surfaces studied promoted plaque formation. The degree of surface roughness seems not to be a critical factor for plaque accumulation. PMID- 28831604 TI - Distinct taxonomic and functional composition of soil microbiomes along the gradient forest-restinga-mangrove in southeastern Brazil. AB - Soil microorganisms play crucial roles in ecosystem functioning, and the central goal in microbial ecology studies is to elucidate which factors shape community structure. A better understanding of the relationship between microbial diversity, functions and environmental parameters would increase our ability to set conservation priorities. Here, the bacterial and archaeal community structure in Atlantic Forest, restinga and mangrove soils was described and compared based on shotgun metagenomics. We hypothesized that each distinct site would harbor a distinct taxonomic and functional soil community, which is influenced by environmental parameters. Our data showed that the microbiome is shaped by soil properties, with pH, base saturation, boron and iron content significantly correlated to overall community structure. When data of specific phyla were correlated to specific soil properties, we demonstrated that parameters such as boron, copper, sulfur, potassium and aluminum presented significant correlation with the most number of bacterial groups. Mangrove soil was the most distinct site and presented the highest taxonomic and functional diversity in comparison with forest and restinga soils. From the total 34 microbial phyla identified, 14 were overrepresented in mangrove soils, including several archaeal groups. Mangrove soils hosted a high abundance of sequences related to replication, survival and adaptation; forest soils included high numbers of sequences related to the metabolism of nutrients and other composts; while restinga soils included abundant genes related to the metabolism of carbohydrates. Overall, our finds show that the microbial community structure and functional potential were clearly different across the environmental gradient, followed by functional adaptation and both were related to the soil properties. PMID- 28831605 TI - Neural stem cells and epilepsy: functional roles and disease-in-a-dish models. AB - Epilepsy is a disorder of the central nervous system characterized by spontaneous recurrent seizures. Although current therapies exist to control the number and severity of clinical seizures, there are no pharmacological cures or disease modifying treatments available. Use of transgenic mouse models has allowed an understanding of neural stem cells in their relation to epileptogenesis in mesial temporal lobe epilepsy. Further, with the significant discovery of factors necessary to reprogram adult somatic cell types into pluripotent stem cells, it has become possible to study monogenic epilepsy-in-a-dish using patient-derived neurons. This discovery along with some of the newest technological advances in recapitulating brain development in a dish has brought us closer than ever to a platform in which to study and understand the mechanisms of this disease. These technologies will be critical in understanding the mechanism of epileptogenesis and ultimately lead to improved therapies and precision medicine for patients with epilepsy. PMID- 28831603 TI - Functional and morphological outcome in patients with chronic central serous chorioretinopathy treated by subthreshold micropulse laser. AB - BACKGROUND: Chronic central serous chorioretinopathy is a serious therapeutic problem as it may lead to significant visual impairment. The aim of this retrospective study is to evaluate functional and morphological effects, as well as factors influencing visual outcome in patients treated by subthreshold micropulse laser. METHODS: Fifty-one eyes with chronic central serous chorioretinopathy lasting longer than 4 months (18 months on average) underwent up to two sessions of subtreshold micropulse laser treatment. Change in best corrected visual acuity, central retinal thickness, central retinal volume, average central retinal thickness and maximum subretinal fluid height were measured. Relation between the effects of the treatment and the initial retinal morphological and functional parameters was then analyzed. RESULTS: The total resorption of subretinal fluid was achieved in 36 cases (70.6%). There was, however, only a minor improvement in best corrected visual acuity of approximately one line on the Snellen chart. No correlation was observed between the effects of the treatment and the duration of the symptoms, retinal morphology and initial visual acuity. Younger patients responded better to the therapy. CONCLUSION: Subthreshold micropulse laser treatment in chronic serous chorioretinopathy provides good morphological results, however significant improvement of visual acuity is not to be expected. PMID- 28831606 TI - Changes in quality of life from infancy to school age after esophagoesophagostomy for tracheoesophageal fistula: thoracotomy versus thoracoscopy. AB - BACKGROUND: We assessed the quality of life (QOL) of postoperative esophageal atresia (EA) with tracheoesophageal fistula (TEF) cases, comparing open with thoracoscopic repair. METHODS: A retrospective review of consecutive EA/TEF repairs (2001-2014) was performed, excluding cases with birth weight less than 2000 g and severe cardiac/chromosomal anomalies. Of 37 cases, 13 had thoracoscopic repair (TR) and 24 had open repair (OR) according to the operating surgeon's preference. QOL was determined regularly by scoring responses to a standard questionnaire about oral intake, vomiting, bougienage, coughing, growth retardation, learning ability, and thoracic deformity. Lower scores reflected poorer outcome. QOL after TR and OR was compared 1 year postoperatively (POQ) and after starting school (ScQ). RESULTS: Subject demographics were similar. Apart from two anastomotic leaks that resolved spontaneously after TR, there were no intraoperative complications or recurrence of TEF. Laparoscopic fundoplication was required for gastroesophageal reflux in four cases (OR 1; TR 3) (p = ns). QOL scores went from 6.5 -> 11.5 in OR and 4.6 -> 11.3 in TR, respectively. Final ScQ scores were similar, but POQ was significantly higher after OR (p < 0.05). CONCLUSION: Initial QOL scores were significantly lower after TR, but by school age QOL scores were similar. PMID- 28831607 TI - Prognostic impact of hospital volume on familial adenomatous polyposis: a nationwide multicenter study. AB - PURPOSE: Many studies have shown that hospital volume is significantly associated with short- and long-term outcomes in various diseases, including cancer. However, there have been no reports discussing the relationship between hospital volume and familial adenomatous polyposis (FAP). This study aimed to clarify whether hospital volume affects short- and long-term outcomes in FAP patients. METHODS: We established a retrospectively collected database of FAP patients who underwent initial surgical treatment at 23 Japanese institutions during 2000 2012. Factors associated with short- and long-term outcomes were analyzed. RESULTS: The study cohort included 303 FAP patients. These patients were classified into tertile categories according to hospital volume: low (n = 31), middle (n = 72), and high volume (n = 200). The proportion of only adenoma/stage 0 was comparable among tertile categories. The adoption of operative procedure significantly differed among tertile categories; specifically, high-volume institutions preferred handsewn ileal pouch-anal anastomosis without diverting ileostomy (P < 0.001 and < 0.001, respectively). Nevertheless, the frequency of complications with Clavien-Dindo classification grade >= 3 was not significantly different among tertile categories. Functional results were acceptable in every category. Wexner scores were significantly lower in high-volume compared to low volume institutions (P = 0.02). Multivariate analyses showed that UICC stage and hospital volume were significantly associated with overall survival (P = 0.04 and 0.03, respectively). CONCLUSIONS: Hospital volume was significantly associated with short- and long-term outcomes in FAP patients. PMID- 28831608 TI - Infectious and inflammatory diseases of the central nervous system-the spectrum of imaging findings and differential diagnosis. AB - The infectious and inflammatory diseases of the central nervous system (CNS) including the brain and spine can present with a wide spectrum of clinical symptoms, locations, and appearance. The purpose of this exhibit is to review the different patterns of their presentations, to illustrate their imaging characteristics and techniques, and to discuss their clinical features and pathology so that the correct diagnosis can be made and prompt intervention can be initiated on a timely fashion. PMID- 28831610 TI - Microbial taxonomy in the era of OMICS: application of DNA sequences, computational tools and techniques. AB - The current prokaryotic taxonomy classifies phenotypically and genotypically diverse microorganisms using a polyphasic approach. With advances in the next generation sequencing technologies and computational tools for analysis of genomes, the traditional polyphasic method is complemented with genomic data to delineate and classify bacterial genera and species as an alternative to cumbersome and error-prone laboratory tests. This review discusses the applications of sequence-based tools and techniques for bacterial classification and provides a scheme for more robust and reproducible bacterial classification based on genomic data. The present review highlights promising tools and techniques such as ortho-Average Nucleotide Identity, Genome to Genome Distance Calculator and Multi Locus Sequence Analysis, which can be validly employed for characterizing novel microorganisms and assessing phylogenetic relationships. In addition, the review discusses the possibility of employing metagenomic data to assess the phylogenetic associations of uncultured microorganisms. Through this article, we present a review of genomic approaches that can be included in the scheme of taxonomy of bacteria and archaea based on computational and in silico advances to boost the credibility of taxonomic classification in this genomic era. PMID- 28831611 TI - Dementia-specific training for nursing home staff : A systematic literature review. AB - BACKGROUND: For people with dementia high-quality care is vital, since at present dementia cannot be cured. In nursing homes this care is provided by the staff, who therefore require dementia-specific training enabling them to improve the quality of life for people with dementia. OBJECTIVE: This article compares existing dementia-specific training for nursing home staff with recommendations, based on the current state of research, by the Alzheimer's Association and the National Institute for Health and Care Excellence, and discusses the outcome of this training. MATERIAL AND METHODS: A systematic review of the literature was conducted to identify studies addressing dementia-specific training. The electronic databases Embase, Medline, Cochrane, CINAHL, PsychINFO, PSYNDEX, and ScienceDirect were searched. RESULTS: The training topics most commonly considered were person-centered care, communicating with people affected by dementia, and information about dementia. The roles of different social and healthcare professionals, palliative care of people with dementia, and understanding family dynamics are least featured in the training. There are training concepts which focus not only on the transfer of knowledge but also on practical exercises. CONCLUSION: In general, the recommended topics were addressed in dementia-specific training concepts, but there is potential for optimization. Further research is needed to identify success criteria in dementia specific training and identify the successful combination of theoretical knowledge and practical exercise. PMID- 28831609 TI - Behavioral Interventions Targeting Alcohol Use Among People Living with HIV/AIDS: A Systematic Review and Meta-Analysis. AB - Alcohol use is often reported among people living with HIV/AIDS (PLWHA) and is associated with increased sexual risk and poor medication adherence. This meta analysis evaluated the efficacy of behavioral interventions addressing alcohol use among PLWHA. Twenty-one studies (N = 8461 PLWHA) that evaluated an individual level intervention addressing alcohol use alone or as part of a more comprehensive alcohol/HIV intervention, included a control condition, and were available through December 2016 were included. Independent raters coded study, sample, and intervention content. Weighted mean effect sizes, using random effects models, were calculated. Results indicate that interventions reduced alcohol consumption, increased condom use, and improved medication adherence relative to controls (d +s = 0.10-0.24). Plasma viral load was also reduced in intervention versus control participants (d + = 0.14, 95% CI = 0.02, 0.26; k = 7). These findings show that behavioral interventions addressing alcohol use can successfully reduce alcohol consumption and also improve HIV-related outcomes among PLWHA. PMID- 28831612 TI - Blood urea nitrogen to serum creatinine ratio as a prognostic factor in diarrhea associated hemolytic uremic syndrome: a validation study. AB - : Identifying those children with complicated forms of diarrhea-associated hemolytic uremic syndrome (D+HUS) on admission can optimize their management. Recently, the blood urea nitrogen to serum creatinine ratio (BCR) at admission has been proposed as a novel and accurate predictor of complicated clinical outcome in D+HUS; therefore, we performed this retrospective study aimed to validate such observation in a larger series of patients. A complicated course was defined as developing one or more of the following: severe neurological or bowel injury, pancreatitis, cardiac or pulmonary involvement, hemodynamic instability, hemorrhage, and death. Data from 161 children were reviewed, 50 of them with a complicated disease including five deaths. Those with worse evolution presented a lower admission BCR than those with good outcome (22.5 vs. 30.8; p = 0.005). BCR at admission showed a limited ability to identify children at risk of a complicated course, with an AUC of 0.63 (95% CI 0.58-0.71) and an optimal cutoff point of <= 26.7, which achieves a sensitivity of 70% (95% CI 55.2-81.7) and a specificity of 56.7% (95% CI 47-66). CONCLUSION: In this validation study, the BCR at admission provided a limited value to predict severe forms of D+HUS. What is Known: * BCR at admission has been proposed as an accurate predictor of complicated clinical course in children with D+HUS. What is New: * In a larger series of children with D+HUS, we were unable to confirm the usefulness of the admission BCR to early identify those at risk of complicated forms of the disease. * Further research is warranted to improve the optimal detection of these high-risk patients. PMID- 28831613 TI - Sustained intraocular pressure elevation in eyes treated with intravitreal injections of anti-vascular endothelial growth factor for diabetic macular edema in a real-life setting. AB - PURPOSE: The aim of this study was to investigate the sustained intraocular pressure (IOP) elevation after repeated anti-VEGF intravitreal injections (IVI) in patients with diabetic macular edema (DME). METHODS: A retrospective study included 140 eyes without prior glaucoma, treated with at least three anti-VEGF injections for DME between 2012 and 2016. IOP elevation was defined by an increase above baseline IOP by >=6 mmHg. Baseline IOP was defined as the mean of IOP values before treatment initiation. Three groups were differentiated: group 1 without IOP elevation, groups 2 and 3 with IOP elevation and IOP <21 mmHg (group 2) and >=21 mmHg (group 3). Rate and several risk factors of IOP elevation were assessed and compared between the three groups. RESULTS: IOP elevation occurred in ten eyes (7.1%). IOP was <21 mmHg in six eyes and >=21 mmHg in four eyes. Statistically significant associations were found between IOP elevation and the number of injections, and HbA1c level. Two patients required local hypotonic treatment. CONCLUSIONS: In a real-life setting, we confirmed in eyes with center involved DME without prior glaucoma or IOP elevation that repeated anti-VEGF IVI may increase the risk of sustained IOP elevation in about 7% of eyes. PMID- 28831614 TI - Non Invasive Blood Flow Features Estimation in Cerebral Arteries from Uncertain Medical Data. AB - A methodology for non-invasive estimation of the pressure in internal carotid arteries is proposed. It uses data assimilation and Ensemble Kalman filters in order to identify unknown parameters in a mathematical description of the cerebral network. The approach uses patient specific blood flow rates extracted from Magnetic Resonance Angiography and Magnetic Resonance Imaging. This construction is necessary as the simulation of blood flows in complex arterial networks, such as the circle of Willis, is not straightforward because hemodynamic parameters are unknown as well as the boundary conditions necessary to close this complex system with many outlets. For instance, in clinical cases, the values of Windkessel model parameters or the Young's modulus and the thickness of the arteries are not available on per-patient cases. To make the approach computational efficient, a reduced order zero-dimensional compartment model is used for blood flow dynamics. Using this simplified model, the proof-of concept study demonstrates how to use the EnKF as an optimization tool to find parameters and how to make the inverse hemodynamic problem tractable. The predicted blood flow rates in the internal carotid arteries and the predicted systolic and diastolic brachial blood pressures are found to be in good agreement with the clinical measurements. PMID- 28831616 TI - A Randomized Controlled Trial Evaluating Efficacy of Promoting a Home-Based HIV Self-Testing with Online Counseling on Increasing HIV Testing Among Men Who Have Sex with Men. AB - We developed an innovative home-based HIV self-testing (HIVST) service that included mailing of a free HIVST kit, and providing online real-time instructions and pre-test/post-test counseling (HIVST-OIC). The present parallel-group and non blinded randomized controlled trial was conducted to evaluate the efficacy of promoting HIVST-OIC in increasing HIV testing rate among 430 men who have sex with men (MSM), with access to online live-chat applications in Hong Kong. At month 6, as compared to the control group, the intervention group reported significantly higher prevalence of HIV testing of any type (89.8 vs. 50.7%; relative risk (RR): 1.77; p < 0.001). Among those who have taken up any HIV testing in the last six months, significant between-group difference was found in multiple male sex partnerships (34.2 vs. 47.7%, RR: 0.72; p = 0.021). HIVST-OIC has a strong potential in increasing prevalence of HIV testing and reducing sexual risk behaviors. Implementation research is warranted. PMID- 28831615 TI - The evaluation of extraction techniques for Tetranychus urticae (Acari: Tetranychidae) from apple (Malus domestica) and cherry (Prunus avium) leaves. AB - Tetranychus urticae is a widespread polyphagous mite, found on a variety of fruit crops. Tetranychus urticae feeds on the underside of the leaves perforating plant cells and sucking the cell contents. Foliar damage and excess webbing produced by T. urticae can reduce fruit yield. Assessments of T. urticae populations while small provide reliable and accurate ways of targeting control strategies and recording their efficacy against T. urticae. The aim of this study was to evaluate four methods for extracting low levels of T. urticae from leaf samples, representative of developing infestations. These methods were compared to directly counting of mites on leaves under a dissecting microscope. These methods were ethanol washing, a modified paraffin/ethanol meniscus technique, Tullgren funnel extraction and the Henderson and McBurnie mite brushing machine with consideration to: accuracy, precision and simplicity. In addition, two physically different leaf morphologies were compared; Prunus leaves which are glabrous with Malus leaves which are setaceous. Ethanol extraction consistently yielded the highest numbers of mites and was the most rapid method for recovering T. urticae from leaf samples, irrespective of leaf structure. In addition the samples could be processed and stored before final counting. The advantages and disadvantages of each method are discussed in detail. PMID- 28831617 TI - HIV Prevalence Among Hospitalized Patients at the Main Psychiatric Referral Hospital in Botswana. AB - We examined HIV prevalence among patients 18-49 year olds admitted to a psychiatric hospital in Botswana in 2011 and 2012. The retrospective study analyzed females (F) and males (M) separately, comparing proportions with Chi square test and continuous variables with Wilcoxon rank-sum test, assessing significance at the 5% level. HIV seroprevalence among hospitalized psychiatric patients was much more common among females (53%) compared with males (19%) (p < 0.001). These women also appeared more vulnerable to infection compared with females in the general population (29%) (p < 0.017). Among both women and men, HIV-infection appeared most common among patients with organic mental disorders (F:68%, M:41%) and neurotic, stress related and somatoform disorders (F:68%, M:42%). The largest proportion of HIV infections co-occurred among patients diagnosed with schizophrenia, schizotypal and other psychotic disorders (F:48%; M:55%), mood (affective) disorders (F:21%; M:16%) and neurotic, stress-related and somatoform disorders (F:16%; M:20%). Interventions addressing both mental health and HIV among women and men require development. PMID- 28831618 TI - A Pilot Randomized Controlled Trial of an Integrated In-person and Mobile Phone Delivered Counseling and Text Messaging Intervention to Reduce HIV Transmission Risk among Male Sex Workers in Chennai, India. AB - Men who have sex with men (MSM) are at increased risk for HIV infection in India, particularly those who engage in transactional sex with other men (i.e., male sex workers; MSW). Despite the need, HIV prevention efforts for Indian MSW are lacking. As in other settings, MSW in India increasingly rely on the use of mobile phones for sex work solicitation. Integrating mobile phone technology into an HIV prevention intervention for Indian MSW may mitigate some of the challenges associated with face-to face approaches, such as implementation, lack of anonymity, and time consumption, while at the same time proving to be both feasible and useful. This is a pilot randomized controlled trial to examine participant acceptability, feasibility of study procedures, and preliminary efficacy for reducing sexual risk for HIV. MSW (N = 100) were equally randomized to: (1) a behavioral HIV prevention intervention integrating in-person and mobile phone delivered HIV risk reduction counseling, and daily, personalized text or voice messages as motivating "cognitive restructuring" cues for reducing condomless anal sex (CAS); or (2) a standard of care (SOC) comparison condition. Both groups received HIV counseling and testing at baseline and 6-months, and completed ACASI-based, behavioral and psychosocial assessments at baseline, 3, and 6 months. Mixed-effects regression procedures specifying a Poisson distribution and log link with a random intercept and slope for month of follow up was estimated to assess the intervention effect on the primary outcomes: (1) CAS acts with male clients who paid them for sex, and (2) CAS acts with male non paying sexual partners-both outcomes assessed over the past month. The intervention was both feasible (98% retention at 6-months) and acceptable (>96% of all intervention sessions attended); all intervention participants rated the intervention as "acceptable" or "very acceptable." A reduction in the reported number of CAS acts with male clients who paid them for sex in the past month was seen in both study conditions. MSW in the intervention condition reported a faster rate of decline in the number of CAS acts with male clients in the past month from the baseline to both the 3-month (B = -1.20; 95% CI -1.68, -0.73; p < 0.0001) and 6-month (B = -2.44; 95% CI -3.35, -1.53; p < 0.00001) assessment visits compared to the SOC condition. Post-hoc contrasts indicated that, at 3 months, participants in the intervention condition reported 1.43 (SD = 0.29) CAS acts with male clients in the past month compared to 4.85 (SD = 0.87) in the control condition (p = 0.0003). Furthermore, at 6 months, the intervention condition participants reported 0.24 (SD = 0.09) CAS acts with male clients in the past month compared to 2.79 (SD = 0.79) in the control condition (p < 0.0001). Findings are encouraging and provide evidence of feasibility and acceptability, and demonstrate initial efficacy (for reducing sexual risk for HIV) of a behavioral HIV prevention intervention for Indian MSW that combines daily, personalized text or voice messages with mobile phone-delivered sexual risk reduction counseling and skills building. Future testing of the intervention in a fully powered randomized controlled efficacy trial is warranted. PMID- 28831619 TI - Important role of calcium chloride in preventing carbon monoxide generation during desflurane degradation with alkali hydroxide-free carbon dioxide absorbents. AB - We investigated whether calcium chloride (CaCl2), a supplementary additive in carbon dioxide (CO2) absorbents, could affect carbon monoxide (CO) production caused by desflurane degradation, using a Japanese alkali-free CO2 absorbent Yabashi Lime(r)-f (YL-f), its CaCl2-free and 1% CaCl2-added derivatives, and other commercially available alkali-free absorbents with or without CaCl2. The reaction between 1 L of desflurane gas (3-10%) and 20 g of desiccated specimen was performed in an artificial closed-circuit anesthesia system for 3 min at 20 or 40 degrees C. The CO concentration was measured using a gas chromatograph equipped with a semiconductor sensor detector. The systems were validated by detecting dose-dependent CO production with an alkali hydroxide-containing CO2 absorbent, Sodasorb(r). Compared with YL-f, the CaCl2-free derivative caused the production of significantly more CO, while the 1% CaCl2-added derivative caused the production of a comparable amount of CO. These phenomena were confirmed using commercially available absorbents AMSORB(r) PLUS, an alkali-free absorbent with CaCl2, and LoFloSorbTM, an alkali-free absorbent without CaCl2. These results suggest that CaCl2 plays an important role in preventing CO generation caused by desflurane degradation with alkali hydroxide-free CO2 absorbents like YL-f. PMID- 28831620 TI - A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant. AB - Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD50) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant. PMID- 28831621 TI - Studying cognitive functions by means of direct electrical stimulation: a review. AB - In recent years, neurosurgical patients have highly contributed to research in behavioural neurology. This development is in part due to the use of direct electrical stimulation during brain surgery. Indeed, during surgery for a tumour, involving both grey and white matter, it has become a common clinical practice to awaken patients with the aim of investigating the functional role of restricted brain areas. The surgeon can optimize the extent of resection and improve overall survival without causing permanent neurological deficits, owing to individual, specific mapping and preservation of eloquent structures. This type of mapping offers a unique opportunity to investigate the functional connectivity of the brain, permitting real-time anatomo-functional correlations, in awaken patients undergoing surgery. By gathering all cortical and axonal sites in which stimulation produces the same types of error, one can build up a picture of the network underlying the disrupted function. In this review, the main achievements concerning networks involved in some aspects of language, visuo-spatial cognition, calculation and emotion will be highlighted. PMID- 28831622 TI - Evaluation of a photocrosslinkable hydroxyethyl chitosan hydrogel as a potential drug release system for glaucoma surgery. AB - Hydroxyethyl chitosan (HECTS) is a critical derivative of chitosan that has been widely used as biomedical materials due to great water-solubility and excellent biocompatibility. Here, photosensitive hydroxyethyl chitosan was synthesized by introducing azide group on NH2 of HECTS (HECTS-AZ), afterwards FTIR and 1H NMR spectra were detected to confirm the formation of HECTS-AZ. The solution of HECTS AZ can achieve a sol-gel transition through UV irradiation for 30 s. The evaluation of biocompability and biodegradability in vivo was conducted in rats, visual and pathological examinations exhibited the HECTS-AZ has excellent biocompability and degradation time of the hydrogel is more than 14 weeks. Furthermore, HECTS-AZ hydrogel as an ocular drug delivery system loading heparin was prepared to implant under sclera of rabbit after glaucoma filtration surgery (GFS). The experimental results demonstrated the heparin loaded hydrogel can effectively maintain filtration bleb and lowing intraocular pressure (IOP) after GFS for prolonged time. Besides, obvious inflammatory reactions and side effects have not been observed in ocular during the experimental period. In conclusion, the HECTS-AZ hydrogel is a potential drug delivery device for the treatment of glaucoma and other ocular diseases. PMID- 28831623 TI - Structural consequences of mutations associated with idiopathic restrictive cardiomyopathy. AB - Idiopathic restrictive cardiomyopathy (RCM, MIM# 115210) is the least common type of cardiomyopathies, often of genetic origin. Recently we described a spectrum of variants-classified as pathogenic, likely pathogenic and variants of unknown significance-in 24 patients suffering from idiopathic RCM. Pathogenic variants, detected in half of the RCM cases, were found in sarcomeric and cytoskeletal genes that have a predominant role in the development of RCM. Here we have analyzed the structural consequences of these missense variants and predicted their effect on the function of three large groups of domains: intrinsically disordered regions (IDRs), fibronectin-type III (FnIII) domains, and immunoglobulin-like (Ig) domains. Our findings indicate that pathogenic mutations are likely to disrupt interdomain interfaces, interfere with protein interactions, and affect protein stability, potentially destabilizing the multi domain architecture of myofibrils and leading to myocardial stiffness in patients with idiopathic RCM. PMID- 28831624 TI - Vascular parkinsonism or idiopathic NPH? New insights from CSF pressure analysis. AB - Differential diagnosis between vascular parkinsonism (VP) and idiopathic normal pressure hydrocephalus (iNPH) is particularly challenging due to similar clinical and neuroradiological features. The objective of this study is to differentiate VP with radiological evidence of ventricular enlargement (REVE) from iNPH on the basis of cerebrospinal fluid (CSF) hydrodynamics. CSF pressure components were investigated in patients with a clinical diagnosis of VP and REVE. Data of eight patients (seven men; age 76 +/- 3.9 years; disease duration 26.5 +/- 15.6 months) were evaluated. CSF opening pressure values were normal in all patients. Also, mean CSF pressure values during short-term monitoring were normal, except in one patient. Four out of the eight patients had raised values of pulse wave amplitude (PWA) during the opening phase (mean +/- SD 57.1 +/- 19.9 mmH2O), meanwhile during short-term monitoring, seven out of the eight patients showed raised values of mean PWA (76.8 +/- 23 mmH2O). We found that most of patients with clinical characteristics of VP and REVE showed elevated PWA during the short-term monitoring of CSF pressure as observed in iNPH patients. Patients clinically identified as VP may be part of the clinical spectrum of iNPH. PMID- 28831625 TI - Synthesis and biological evaluation of novel aliphatic acid-conjugated antimicrobial peptides as potential agents with anti-tumor, multidrug resistance reversing activity and enhanced stability. AB - Compared with traditional anti-tumor drugs, antimicrobial peptides as novel anti tumor agents have prominent advantages of higher specificity and circumvention of multi-drug resistance. BP100 is a multifunctional membrane-active peptide with high antimicrobial activity. Taking BP100 as a lead peptide, we designed and synthesized a series of aliphatic chain-conjugated peptides through solid-phase synthesis. Biological evaluation revealed that these peptides exhibited better anti-cancer activity than BP100. Further investigations revealed that these peptides could disrupt the cell membrane and trigger the cytochrome C release into cytoplasm, which ultimately resulted in apoptosis. Meanwhile, these peptides also exhibited effective anti-tumor activity against multidrug resistant cells and had multidrug resistance-reversing effect. Additionally, conjugation of aliphatic acid to those peptides could enhance their stability in plasma. In conclusion, aliphatic acid-modified peptides might be promising anti-tumor agents for cancer therapy. PMID- 28831626 TI - Fabrication and characterization of low-cost, bead-free, durable and hydrophobic electrospun membrane for 3D cell culture. AB - This paper reports the fabrication of electrospun polydimethylsiloxane (PDMS) membranes/scaffolds that are suitable for three-dimensional (3D) cell culture. Through modification the ratio between PDMS and polymethylmethacrylate (PMMA) as carrier polymer, we report the possibility of increasing PDMS weight ratio of up to 6 for electrospinning. Increasing the PDMS content increases the fiber diameter, the pore size, and the hydrophobicity. To our best knowledge, this is the first report describing beads-free, durable and portable electrospun membrane with maximum content of PDMS suitable for cell culture applications. To show the proof-of-concept, we successfully cultured epithelial lung cancer cells on these membranes in a static well plate without surface modification. Surprisingly, due to three-dimensional (3D) and hydrophobic nature of the electrospun fibers, cells aggregated into 3D multicellular spheroids. These easily detachable and cost effective scaffolds with controllable thicknesses and high tensile strength are good candidates for cell-stretching devices, organ-on-a-chip devices, tissue engineering and studies of non-adherent mammalian cancer stem cells. PMID- 28831627 TI - Gender differences in keratoconus keratoplasty: a 25-year study in Southern Brazil and global perspective. AB - PURPOSE: To compare the characteristics and outcomes of male and female patients that underwent corneal transplantation for keratoconus (KC) in Southern Brazil and worldwide. METHODS: Retrospective longitudinal study that evaluated medical records of patients who were submitted to keratoplasty between August 1990 and September 2015 in two tertiary hospitals in the state of Rio Grande do Sul (Brazil) and review of the Medline and Embase database international literature. RESULTS: Out of a total of 4026 corneal transplants at that period, 1284 patients (1530 eyes) received preoperative diagnosis of KC (31.8%). A total of 839 men underwent keratoplasty for KC (65.4%) with mean age of 30.3 (+/-12.2) years. The 445 transplanted women (34.6%) had a mean age of 34.5 (+/-14.8) years. Both differences were statistically significant (p < 0.01). Regarding laterality, skin color, recipient and donor cornea trephination diameter, and rejection episodes there was no significant difference between the two groups at baseline (p > 0.05). Females were submitted significantly more to deep anterior lamellar keratoplasty (DALK) in comparison with males (26.5 vs. 15.7%, p < 0.01). We were able to include 57.4% of the original keratoplasties for our follow-up data analysis. Male sex and penetrating keratoplasty (PK) were associated significantly with increased risk for graft failure in KC transplantation at the end of follow-up (p < 0.05). The mean follow-up of transplanted patients was similar in both groups. CONCLUSION: Keratoconus is the most transplanted corneal disease in Southern Brazil and globally. Studies in Africa, Asia, Europe and North America also showed gender differences in KC patients submitted to keratoplasty. We found that men were transplanted in a 1.9 male/female ratio and at an earlier age than women. At final follow-up, male sex and PK were risk factors associated with increased graft failure. It is essential to broaden the hormonal and genetic investigations to elucidate why keratoconic males have undergone more keratoplasties and have more secondary failure than females. PMID- 28831628 TI - Patients' Mental Health Journeys: A Qualitative Case Study with Interactive Computer-Assisted Client Assessment Survey (iCASS). AB - Despite growing concerns about common mental disorders (CMDs), challenges persist in accessing timely and appropriate care, especially for immigrant, refugee, racialized and low-income groups. Partnering with a community health centre serving these populations in Toronto, we examined the Interactive Computer assisted Client Assessment Survey (iCCAS) that screens for CMDs (depression, generalized anxiety, post-traumatic stress, and alcohol overuse) and related social factors. In this case study design with embedded units, we explored the mental health care journeys of patients who screened positive for a CMD. The analysis identified three major pathways of care: (1) early detection of previously unidentified CMDs; (2) detection of comorbid mental health conditions; and (3) prevention of possible relapse and/or management of existing previously recognized mental health condition. These cases indicate iCCAS holds potential to facilitate more open, tailored, and informed collaborations between patients and clinicians regarding mental health care plans. PMID- 28831629 TI - Fluorescence Behavior of Schiff Base-N, N'-bis(salicylidene) Trans 1, 2 Diaminocyclohexane in Proteinous and Micellar Environments. AB - Fluorescence properties of N, N'-bis(salicylidene) trans 1, 2-diaminocyclohexane (H 2 L) is used to probe the anionic (SDS), cationic (CTAB) and nonionic (TX-100) micelles as well as in serum albumins (BSA and HSA) and chicken egg white lysozyme (LYZ) by steady state and picosecond time-resolved fluorescence spectroscopy. The fluorescence band intensity was found to increase with concomitant blue-shift with gradual addition of different surfactants. All the experimental results suggest that the probe molecule resides in the micelle-water interface rather than going into the micellar core. However, the penetration is more towards the micellar hydrocarbon core in nonionic surfactant (TX-100) while comparing with ionic surfactants (SDS and CTAB). Several mean microscopic properties such as critical micelle concentration, polarity parameters and binding constant were calculated in presence of different surfactants. The decrease in nonradiative decay rate constants in micellar environments indicates restricted motion of the probe inside the micellar nanocages with increasing fluorescence emission intensity and quantum yields. Further in this work, we also investigated the interaction behavior of the probe with different proteins at low concentrations under physiological conditions (pH = 7.4). Stern-Volmer analysis of the tryptophan (Trp) fluorescence quenching data in presence of probe reveals Stern-Volmer constant (Ksv) as well as bimolecular quenching rate constant (Kq). The binding constant as well as the number of binding sites of the probe with proteins were also monitored and found to be 1:1 stoichiometry ratio. PMID- 28831630 TI - Hands-free smartphone-based diagnostics for simultaneous detection of Zika, Chikungunya, and Dengue at point-of-care. AB - Infectious diseases remain the world's top contributors to death and disability, and, with recent outbreaks of Zika virus infections there has been an urgency for simple, sensitive and easily translatable point-of-care tests. Here we demonstrate a novel point-of-care platform to diagnose infectious diseases from whole blood samples. A microfluidic platform performs minimal sample processing in a user-friendly diagnostics card followed by real-time reverse-transcription loop-mediated isothermal amplification (RT-LAMP) on the same card with pre-dried primers specific to viral targets. Our point-of-care platform uses a commercial smartphone to acquire real-time images of the amplification reaction and displays a visual read-out of the assay. We apply this system to detect closely related Zika, Dengue (types 1 and 3) and Chikungunya virus infections from whole blood on the same pre-printed chip with high specificity and clinically relevant sensitivity. Limit of detection of 1.56e5 PFU/mL of Zika virus from whole blood was achieved through our platform. With the ability to quantitate the target nucleic acid, this platform can also perform point-of-care patient surveillance for pathogen load or select biomarkers in whole blood. PMID- 28831631 TI - Comparison of the efficacy and feasibility of laser enucleation of bladder tumor versus transurethral resection of bladder tumor: a meta-analysis. AB - The transurethral resection of bladder tumor (TURBT) remains the most widely used method in the surgical treatment of the non-muscle invasive bladder tumor (NMIBT). Despite its popularity, the laser technique has been widely used in urology as an alternative, via the application of transurethral laser enucleation of bladder tumor. The aim of the present study was to compare the efficacy and feasibility between transurethral laser enucleation and transurethral resection of bladder tumor. A systematic search of the following databases was conducted: PubMed, Wed of Science, Cochrane Library, EMBASE, Google scholar, and Medline. The search included studies up to the 1st of January 2017. The outcomes of interest that were used in order to assess the two techniques included operation time, catheterization time, hospitalization time, obturator nerve reflex, bladder perforation, bladder irritation, 24-month-recurrence rate, and the postoperative adjuvant intravesical chemotherapy. A total of 13 trials with 2012 participants were included, of which 975 and 1037 underwent transurethral laser enucleation and transurethral resection of bladder tumor, respectively. No significant difference was noted in the operation time between the two groups, although significant differences were reported for the variables catheterization time, hospitalization time, obturator nerve reflex, bladder perforation, bladder irritation, and 24-month-recurrence rate. In the mitomycin and epirubicin subgroups, no significant differences were observed in the laser enucleation and TURBT methods with regard to the 24-month-recurrence rate. The laser enucleation was superior to TURBT with regard to the parameters obturator nerve reflex, bladder perforation, catheterization time, hospitalization time, and 24-month recurrence rate. Moreover, laser enucleation can offer a more accurate result of the tumor's pathological stage and grade. PMID- 28831632 TI - Utilization of bioimpedance spectroscopy in the prevention of chronic breast cancer-related lymphedema. AB - BACKGROUND: This analysis was performed to assess the impact of early intervention following prospective surveillance using bioimpedance spectroscopy (BIS) to detect and manage breast cancer-related lymphedema (BCRL). METHODS: From 8/2010 to 12/2016, 206 consecutive patients were evaluated with BIS. The protocol included pre-operative assessment with L-Dex as well as post-operative assessments at regular intervals. Patients with L-Dex scores >10 from baseline were considered to have subclinical BCRL and were treated with over-the-counter (OTC) compression sleeve for 4 weeks. High-risk patients were defined as undergoing axillary lymph node dissection (ALND), receiving regional nodal irradiation (RNI), or taxane chemotherapy. Chronic BCRL was defined as the need for complex decongestive physiotherapy (CDP). RESULTS: Median follow-up was 25.9 months. Overall, 17% of patients had one high-risk feature, 8% two, and 7% had three. 9.8% of patients were diagnosed with subclinical BCRL with highest rates seen following ALND (23 vs. 7%, p = 0.01). Development of subclinical BCRL was associated with ALND and receipt of RNI. At last follow-up, no patients (0%) developed chronic, clinically detectable, BCRL. Subset analysis was performed of the 30 patients undergoing ALND. Median number of nodes removed was 18 and median number of positive nodes was 2. 77% received taxane chemotherapy, 62% axillary RT, and 48% had elevated BMI. Overall, 86% of patients had at least one additional high-risk feature, 70% at least two, and 23% had all three. Seven patients (23%) had abnormally elevated L-Dex scores at some point during follow up. To date, none has required CDP. CONCLUSIONS: The results of this study support prospective surveillance utilizing BIS initiated pre-operatively with subsequent post-operative follow-up measurements for the detection of subclinical BCRL. Intervention triggered by subclinical BCRL detection with an elevated L-Dex score was associated with no cases progressing to chronic, clinically detectable BCRL even in very high-risk patients. PMID- 28831634 TI - Using MALDI-TOF MS typing method to decipher outbreak: the case of Staphylococcus saprophyticus causing urinary tract infections (UTIs) in Marseille, France. AB - Staphylococcus saprophyticus is one of the leading causes of urinary tract infections (UTI). In December 2014, our surveillance system identified an abnormal increase in S. saprophyticus causing UTIs in four university hospitals in Marseille, indicating a suspected community S. saprophyticus UTI outbreak. This was detected by our surveillance system BALYSES (Bacterial real-time Laboratory-based Surveillance System). S. saprophyticus/ Escherichia coli UTI ratio increased three-fold from 0.0084 in 2002 to 0.025 in December 2015 in Marseille with an abnormal peak in December 2014, and with an annual estimated ratio trend of 5.10-6 (p-value < 10-3). Matrix-Assisted Laser Desorption Ionisation-Time of Flight Mass Spectrometry (MALDI-TOF MS) spectral analysis of strains was used to analyse strains cluster expansion, comparing strains from Marseille to those from Nice during the same period. MALDI-TOF MS spectral analysis revealed a geographical restricted clonal expansion of the strains clusters in Marseille as compared to Nice. Our finding suggests (i) a geographically restricted expansion of a specific S. saprophyticus strain clusters circulating in Marseille, and (ii) MALDI-TOF MS can be used as a cost effective tool to investigate an outbreak. PMID- 28831633 TI - Characterization of major histocompatibility complex class I, and class II DRB loci of captive and wild Indian leopards (Panthera pardus fusca). AB - The major histocompatibility complex (MHC), in vertebrate animals, is a multi genic protein complex that encodes various receptors. During a disease, MHC interacts with the antigen and triggers a cascade of adaptive immune responses to overcome a disease outbreak. The MHC is very important region from immunological point of view, but it is poorly characterized among Indian leopards. During this investigation, we examined genetic diversity for MHC class I (MHC-I) and MHC class II-DRB (MHC-II) among wild and captive Indian leopards. This study estimated a pool of 9 and 17 alleles for MHC-I and MHC-II, respectively. The wild group of individuals showed higher nucleotide diversity and amino acid polymorphism compared to the captive group. A phylogenetic comparison with other felids revealed a clustering in MHC-I and interspersed presence in MHC-II sequences. A test for selection also revealed a deviation from neutrality at MHC II DRB loci and higher non-synonymous substitution rate (dN) among the individuals from wild group. Further, the wild individuals showed higher dN for both MHC I and II genes compared to the group that was bred under captive conditions. These findings suggest the role of micro-evolutionary forces, such as pathogen-mediated selection, to cause MHC variations among the two groups of Indian leopards, because the two groups have been bred in two different environments for a substantial period of time. Since, MHC diversity is often linked with the quality of immunological health; the results obtained from this study fill the gap of knowledge on disease predisposition among wild and captive Indian leopards. PMID- 28831635 TI - A multicenter, observational, prospective study of self- and parent-reported quality of life in adolescent multiple sclerosis patients self-administering interferon-beta1a using RebiSmartTM-the FUTURE study. AB - Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-beta1a (Rebif; 22 MUg), administered subcutaneously three times weekly using the RebiSmartTM electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being "Emotional functioning." In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p = 0.041). Significant increases were also evident for parent-reported "Psychosocial health summary score" (+ 5.90 points; p = 0.015) and "School functioning" (+ 7.84 points; p = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmartTM for self-administration of Rebif(r) can experience long-term improvements in QL. PMID- 28831636 TI - Survival and level of care among breast cancer patients with brain metastases treated with whole brain radiotherapy. AB - PURPOSE: The benefit of whole brain radiotherapy (WBRT) for late stage breast cancer patients with brain metastases has been questioned. In this study we evaluated survival and level of care (hospital or home) following WBRT in a population-based cohort by personal and tumor characteristics. METHODS: We identified 241 consecutive patients with breast cancer and brain metastases receiving WBRT in Stockholm, Sweden, 1999-2012. Through review of medical records, we collected data on prognostic determinants including level of care before and after WBRT. Survival was estimated using Cox regression, and odds ratios (OR) of not coming home using logistic regression. RESULTS: Median age at WBRT was 58 years (range 30---88 years). Most patients (n = 212, 88%) were treated with 4 Gray * 5. Median survival following WBRT was 2.9 months (interquartile range 1.1-6.6 months), and 57 patients (24%) were never discharged from hospital. Poor performance status and triple-negative tumors were associated with short survival (WHO 3-4 median survival 0.9 months, HR = 5.96 (3.88-9.17) versus WHO 0-1; triple-negative tumors median survival 2.0 months, HR = 1.87 (1.23-2.84) versus Luminal A). Poor performance status and being hospitalized before WBRT were associated with increased ORs of not coming home whereas cohabitation with children at home was protective. CONCLUSION: Survival was short following WBRT, and one in four breast cancer patients with brain metastases could never be discharged from hospital. When deciding about WBRT, WHO score, level of care before WBRT, and the patient's choice of level of care in the end of-life period should be considered. PMID- 28831638 TI - Health Insurance Status and Eligibility Among Patients who Seek Healthcare at a Free Clinic in the Affordable Care Act Era. AB - Free clinics provide care to over 1.8 million people in the United States every year and are a valuable safety net for uninsured and underinsured patients. The Affordable Care Act has resulted in millions of newly insured Americans, yet there is continued demand for healthcare at free clinics. In this study, we assessed health insurance status and eligibility among 489 patients who visited a free clinic in 2016. Eighty-seven percent of patients seen were uninsured, 53.1% of whom were eligible for health insurance (Medicaid or subsidized insurance premiums). The majority of these patients completed health insurance applications at their visit with the help of a navigator. A majority of patients who were not eligible for health insurance lacked citizenship status. This study highlights that a significant number of patients who visit free clinics are eligible for health insurance, and that free clinics are important sites for health insurance navigation programs. PMID- 28831637 TI - In vivo immunological properties research on mesenchymal stem cells based engineering cartilage by a dialyzer pocket model. AB - As the seed cells, the immune properties of the mesenchymal stem cells are important for the tissue engineering restoring effect. But the in vivo research model is lacking. In the study, based on a dialyzer pocket model, changes in immunological properties and the differentiation of seeded mesenchymal stem cells (MSCs) in collagen hydrogel were studied in muscle and articular cavity implantation, respectively. The results showed that collagen hydrogel can induce MSCs to form cartilage tissue, followed by alteration of immunological properties. In muscle implantation, relatively low expression of major histocompatibility complex (MHC) molecules and low level of one-way mixed lymphocyte reactions (MLR) on the seeded MSCs were observed, but only a little cartilage tissue formed. In articular cavity implantation, more cartilage tissue formed, but higher MHC expressions and MLR level were found. Results indicated that the immunomodulation and the cartilage formation of the seeded MSCs will be impacted by the scaffold and the environment of the in vivo implanted site. The dialyzer pocket model can be used for the in vivo research for the MSC-based strategy of the tissue engineering, especially for the optimization of the immunomodulation. PMID- 28831639 TI - Human Exposure to Wild Animals in the Sankuru Province of the Democratic Republic of the Congo. AB - Due to the high level of biological diversity in the Congo Basin and human population dependence on bushmeat, the DRC represents an ideal location for expanding knowledge on wild animal exposures and thus the potential for transmission of zoonotic pathogens. However, limited information exists on patterns and extent of contact with wildlife in such communities. Using a cross sectional study, 14 villages in the Sankuru Province of the DRC were surveyed between August and September 2007. Villagers >= 1 year of age and at home of the time of the survey were eligible and enrolled to describe and assess factors associated with animal exposures (both activity and type of animal). Among respondents, 91% reported exposure to rodents, 89% to duikers, 78% to non-human primates (NHPs), and 32% reported contact with bats in the month prior to the survey. The most frequently reported activities included eating (95%), cooking (70%), and butchering or skinning of animals (55%). The activities and animals to which subjects had contact varied by sex and age. Moreover, we observed a high correlation of the same activities across animal types. In this and other populations that rely on bushmeat, there is a high frequency of exposure to multiple animal species through various modalities. In the event of future zoonotic disease outbreaks, effective public health interventions and campaigns that mitigate the risk of animal contact during outbreaks need to be broad to include various modes of contact and should be directed to both men and women across all age groups. As available information is limited, further studies are necessary to better understand the complex relationships and exposures individuals have with animals. PMID- 28831640 TI - Puerarin and Amlodipine Improvement of D-Galactose-Induced Impairments of Behaviour and Neurogenesis in Mouse Dentate Gyrus: Correlation with Glucocorticoid Receptor Expression. AB - Glucocorticoid receptors (GRs) exert actions on the hippocampus that are important for memory formation. There are correlations between vascular dysfunctions and GR-related gene expression. Both vascular dysfunction and GR gene expression decline occur during the ageing process. Therefore, hypotensors, which have effects on improving vascular dysfunction, may be able to ameliorate GR gene expression decline in ageing mice and improve ageing-mediated memory deficits. In this study, we hypothesized that hypotensors could alleviate the decline of GR gene expression and ameliorate age-induced learning and memory deficits in a D-gal-induced ageing mice model. In line with our hypothesis, we found that chronic D-gal treatment decreased GR and DCX expression in the hippocampus, leading to learning and memory deficits. Amlodipine (AM) and puerarin (PU) treatment improved GR gene expression decline in the hippocampus and ameliorated the learning and memory deficits of D-gal-treated mice. These changes correlated with enhanced DCX expression and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Furthermore, PU treatment conveyed better effects than AM treatment, but combination therapy did not enhance the effects on improving GR expression. However, we did not find evidence of these changes in non-D-gal-treated mice that lacked GR gene expression decline. These results suggest that AM and PU could improve D-gal-induced behavioural deficits in correlation with GR gene expression. PMID- 28831641 TI - The role of triploids in the origin and evolution of polyploids of Turnera sidoides complex (Passifloraceae, Turneroideae). AB - Triploids can play an important role in polyploid evolution. However, their frequent sterility is an obstacle for the origin and establishment of neotetraploids. Here we analyzed the microsporogenesis of triploids (x = 7) and the crossability among cytotypes of Turnera sidoides, aiming to test the impact of triploids on the origin and demographic establishment of tetraploids in natural populations. Triploids of T. sidoides exhibit irregular meiotic behavior. The high frequency of monovalents and of trivalents with non-convergent orientations results in unbalanced and/or non-viable male gametes. In spite of abnormalities in chromosome pairing and unbalanced chromosome segregation, triploids are not completely sterile and yielded up to 67% of viable pollen. Triploids that originated by the fusion of 2n * n gametes of the same taxon showed more regular meiotic behavior and higher fertility than triploids from the contact zone of diploids and tetraploids or triploids of hybrid origin. The reproductive isolation of T. sidoides cytotypes of different ploidy level is not strict and the 'triploid block' may be overcome occasionally. Triploids of T. sidoides produce diploid and triploid progeny suggesting that new generations of polyploids could originate from crosses between triploids or from backcrosses with diploids. The capability of T. sidoides to multiply asexually by rhizomes, would enhance the likelihood that a low frequency of neopolyploids can be originated and maintained in natural populations of T. sidoides. PMID- 28831642 TI - Different prognosis of young breast cancer patients in their 20s and 30s depending on subtype: a nationwide study from the Korean Breast Cancer Society. AB - PURPOSE: Numerous studies have demonstrated that breast cancer in young women (BCY) has unfavorable prognostic features and more unfavorable subtypes. However, few studies have evaluated the effect of subtype disparities on breast cancer prognosis by age, especially for BCY. We analyzed breast cancer mortality stratified by tumor subtype according to age among patients younger than 50 years. METHODS: Data from the Korean Breast Cancer Society Registry for patients diagnosed with invasive breast cancer when aged less than 50 years between 2003 and 2010 were reviewed retrospectively. RESULTS: We identified 30,793 patients with breast cancer who were eligible for analysis. Of these, 793 (2.6%) were aged 20-29 and 8926 (28.8%) were aged 30-39. Median follow-up duration was 84 months. Mean age was 42.4 years. Patients in their 20s were more likely to have cancer of advanced stage and higher nuclear grade, present with lymphovascular invasion, and have unfavorable subtypes. Patients in the 20s group showed worse prognosis. In multivariate analysis for overall survival (OS), the hazard ratio (HR) for patients in the 20s group was higher than that for the 30s and 40s groups, and patients with triple-negative breast cancer (TNBC) showed higher HR than patients with HER-2 or luminal subtype (all p < 0.0001). When stratified by subtype, luminal subtype showed significantly worse prognosis in the 20s group than the 30s and 40s groups, whereas HER-2 and TNBC subtypes showed no significant difference. CONCLUSION: Patients in their 20s with breast cancer had unfavorable characteristics and worse prognosis than patients in their 30s and 40s. When stratified by tumor subtype, patients in their 20s with luminal subtype of breast cancer showed worse prognosis than older patients, whereas HER-2 and TNBC subtypes showed no significant differences. PMID- 28831643 TI - Investigation of NLO Properties of Fluorescent BORICO Dyes: a Comprehensive Experimental and Theoretical Approach. AB - BORICO dyes with N, N-diethyl as a strong donor and BF2 complexed iminocoumarin six member core as strong acceptor are investigated as an efficient non linear optical chromophores. Extended pi-conjugation over iminocoumarin moiety is useful to make ICT character of BORICO dyes more significant and is established on the scale of Generalised Mulliken Hush analysis scale. Bond length alternation and bond order alternation values for three BORICO chromophores estimates the cyanine like framework for optimal non linear optical response. The frontier molecular orbital diagrams obtained from density functional theory calculations shows that there is charge transfer from donor to accepter as well as effective overlap between them making the basis for optimal NLO response of BORICO chromophores. The theoretical values of linear and non linear optical responses for three BORICO NLOphores obtained by using three different functionals B3LYP, CAMB3LYP and BHandHLYP with 6-311+g(d,p) basis set are quite consistent for the values of static dipole moment (MU), linear polarizability (alpha) and first hyperpolarizability (beta). However in case of the gamma values calculation, compare to the similar values obtained by CAMB3LYP and BHandHLYP functionals, B3LYP overestimates the same. The vibrational motions play decisive role in the overall non linear optical properties of BORICO chromophores. PMID- 28831644 TI - Experiences of Genetic Counselors Practicing in Rural Areas. AB - In-person genetic counseling clinics in rural areas are likely to improve access to genetic counseling in underserved regions, but studies have not previously examined how these clinics function or described the experience of practicing in a rural setting. The present mixed-methods study explored the professional experiences of clinical genetic counselors who practice in rural areas, including the benefits and challenges of practicing in these settings and the counselors' motivations for doing so. The authors surveyed 20 genetic counselors who self reported working in rural areas and conducted interviews with six individuals whose workplaces were confirmed as rural per RUCA code. Major obstacles to the provision of genetics services in rural areas included travel distance and low referral rates due to lack of awareness or skepticism. Facilitating factors included relying on resources such as professional networks and prioritizing outreach and education. Participants reported high professional satisfaction and were motivated to work in rural areas by personal experiences and qualities of the job such as being a generalist and having greater professional autonomy. These data demonstrate the feasibility of practicing in rural settings and suggest that in-person rural genetic counseling clinics may complement other strategies such as alternative service delivery models in increasing access for rural residents. PMID- 28831645 TI - Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor-negative breast carcinoma. AB - PURPOSE: The tumor microenvironment plays pivotal roles in promotion of many malignancies. Cancer-associated fibroblasts (CAFs) have been well-known to promote proliferation, angiogenesis, and metastasis but mechanistic understanding of tumor-stroma interactions is not yet complete. Recently, estrogen synthetic enzymes were reported to be upregulated by co-culture with stromal cells in ER positive breast carcinoma (BC) but effects of co-culture on androgen metabolism have not been extensively examined. Therefore, we evaluated roles of CAFs on androgen metabolism in ER-negative AR-positive BC through co-culture with CAFs. METHODS: Concentrations of steroid hormone in supernatant of co-culture of MDA-MB 453 and primary CAFs were measured using GC-MS. Cytokines derived from CAFs were determined using Cytokine Array. Expressions of androgen synthetic enzymes were confirmed using RT-PCR and Western blotting. Correlations between CAFs and androgen synthetic enzymes were analyzed using triple-negative BC (TNBC) patient tissues by immunohistochemistry. RESULTS: CAFs were demonstrated to increase expressions and activities of 17betaHSD2, 17betaHSD5, and 5alpha-Reductase1. IL-6 and HGF that were selected as potential paracrine mediators using cytokine array induced 17betaHSD2, 17betaHSD5, and 5alpha-Reductase1 expression. Underlying mechanisms of IL-6 paracrine regulation of 17betaHSD2 and 17betaHSD5 could be partially dependent on phosphorylated STAT3, while phosphorylated ERK could be involved in HGF-mediated 5alpha-Reductase1 induction. alpha-SMA status was also demonstrated to be significantly correlated with 17betaHSD2 and 17betaHSD5 status in TNBC tissues, especially AR-positive cases. CONCLUSIONS: Results of our present study suggest that both IL-6 and HGF derived from CAFs could contribute to the intratumoral androgen metabolism in ER-negative BC patients. PMID- 28831646 TI - Endometriosis-associated infertility: GDF-9, AMH, and AMHR2 genes polymorphisms. AB - PURPOSE: The purpose of this paper is to determine whether there is a correlation between polymorphisms in the growth differentiation factor-9 (GDF-9) gene and anti-Mullerian hormone (AMH) gene and its receptor, AMHR2, and endometriosis associated infertility. METHODS: This is a case-control study to evaluate whether there is a correlation between polymorphisms in the GDF-9 gene (SNPs determined by direct sequencing), AMH gene, AMHR2 (both SNPs determined by genotyping using TaqMan Allelic Discrimination), and endometriosis-associated infertility. The study included 74 infertile women with endometriosis and 70 fertile women (tubal ligation) as a control group. RESULTS: Patient age and the mean FSH levels were similar between the infertile with endometriosis and fertile without endometriosis groups. The frequency of genotypes between the groups for GDF-9 gene polymorphisms did not show statistical significance, nor did the AMHR2 gene polymorphism. However, the AMH gene polymorphism did show statistical significance, relating the polymorphic allele with infertility in endometriosis. CONCLUSIONS: We demonstrate that an SNP in the AMH gene is associated with infertility in endometriosis, whereas several SNPs in the GDF-9 gene and the - 482A G SNP in the AMHR2 gene were found to be unrelated. PMID- 28831647 TI - Novel biomarkers of metabolic dysfunction is autism spectrum disorder: potential for biological diagnostic markers. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is behaviorally defined by social and communication impairments and restricted interests and repetitive behaviors. There is currently no biomarkers that can help in the diagnosis. Several studies suggest that mitochondrial dysfunction is commonly involved in ASD pathophysiology, but standard mitochondrial biomarkers are thought to be very variable. In the present study we examine a wide variety of plasma biomarkers of mitochondrial metabolism and the related abnormalities of oxidative stress and apoptosis in 41 ASD patients assessed for ASD severity using the Childhood Autism Rating Scales and 41 non-related age and sex matched healthy controls. Our findings confirm previous studies indicating abnormal mitochondrial and related biomarkers in children with ASD including pyruvate, creatine kinase, Complex 1, Glutathione S-Transferase, glutathione and Caspase 7. As a novel finding, we report that lactate dehydrogenase is abnormal in children with ASD. We also identified that only the most severe children demonstrated abnormalities in Complex 1 activity and Glutathione S-Transferase. Additionally, we find that several biomarkers could be candidates for differentiating children with ASD and typically developing children, including Caspase 7, gluthatione and Glutathione S Transferase by themselves and lactate dehydrogenase and Complex I when added to other biomarkers in combination. Caspase 7 was the most discriminating biomarker between ASD patients and healthy controls suggesting its potential use as diagnostic marker for the early recognition of ASD pathophysiology. This study confirms that several mitochondrial biomarkers are abnormal in children with ASD and suggest that certain mitochondrial biomarkers can differentiate between ASD and typically developing children, making them possibly useful as a tool to diagnosis ASD and identify ASD subgroups. PMID- 28831648 TI - Analytical Techniques Used to Detect DNA Binding Modes of Ruthenium(II) Complexes with Extended Phenanthroline Ring. AB - This review describes the analytical techniques used to detect DNA-probes such as Ru(II) complexes with hetero cyclic imidazo phenanthroline (IP) ligands. Studies on drug-DNA interactions are useful biochemical techniques for visualization of DNA both in vitro and in vivo. The interactions of small molecules that binds to DNA are mainly classified into two major classes, one involving covalent binding and another non-covalent binding. Covalent binding in DNA can be irreversible and may leads to inhibition of all DNA processes which subsequently leads to cell death. Usually, covalent interactions leads to permanent changes in the structure of nucleic acids. The non-covalent interaction of molecules with DNA can be due to electrostatic interaction, intercalation and groove binding. These interactions of DNA probes can be explored by various spectroscopic techniques viz. UV-visible, emission, emission quenching spectroscopy, viscosity and thermal denaturation measurements. PMID- 28831650 TI - Modifiable health-related factors (smoking, physical activity and body mass index) and health care use and costs among adult cancer survivors. AB - OBJECTIVE: To examine the associations between modifiable health-related factors, such as smoking, low physical activity and higher body mass index (BMI), and annual health care visits and expenditures among adult cancer survivors in the United States. METHODS: Using data from the 2010-2014 Medical Expenditures Panel Survey, we identified 4920 cancer survivors (aged 18-64 years) and a matched comparison group. Our outcomes were number of annual health care visits [i.e., outpatient/office-based, hospital discharges and emergency department (ED) visits] and total health care expenditures. We examined health-related factors, demographics, insurance and health status (i.e., comorbidity and mental distress). Bivariate and multivariable analyses examined the associations between outcomes and health-related factors. RESULTS: Of survivors, approximately 21% were current smokers, 52% reported low physical activity and 35% were obese, vs. 19.6, 49.5 and 36.7%, respectively, of the comparison group. These factors were associated with greater comorbidity and mental distress in both groups. Current smokers among survivors were less likely to have outpatient visits [marginal effect on the number of visits (ME) = -3.44, 95% confidence interval (CI) -5.02 to -1.86, P < 0.001] but more likely to have ED visits (ME = 0.11, 95% CI 0.05 0.18, P = 0.001) than non-smokers. Physically active individuals in both groups had fewer ED visits, and lower total expenditures than those who reported low physical activity. CONCLUSION: Regular assessments of health-related factors should be incorporated in survivorship care to reduce the burden of cancer. Modification of survivors' health-related factors (e.g., low physical activity) may help improve their health outcomes and reduce financial burden. PMID- 28831649 TI - Imaging Markers of Post-Stroke Depression and Apathy: a Systematic Review and Meta-Analysis. AB - Several brain imaging markers have been studied in the development of post-stroke depression (PSD) and post-stroke apathy (PSA), but inconsistent associations have been reported. This systematic review and meta-analysis aims to provide a comprehensive and up-to-date evaluation of imaging markers associated with PSD and PSA. Databases (Medline, Embase, PsycINFO, CINAHL, and Cochrane Database of Systematic Reviews) were searched from inception to July 21, 2016. Observational studies describing imaging markers of PSD and PSA were included. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to examine the association between PSD or PSA and stroke lesion laterality, type, and location, also stratified by study phase (acute, post-acute, chronic). Other imaging markers were reviewed qualitatively. The search retrieved 4502 studies, of which 149 studies were included in the review and 86 studies in the meta-analyses. PSD in the post-acute stroke phase was significantly associated with frontal (OR 1.72, 95% CI 1.34-2.19) and basal ganglia lesions (OR 2.25, 95% CI 1.33-3.84). Hemorrhagic stroke related to higher odds for PSA in the acute phase (OR 2.58, 95% CI 1.18-5.65), whereas ischemic stroke related to higher odds for PSA in the post-acute phase (OR 0.20, 95% CI 0.06-0.69). Frequency of PSD and PSA is modestly associated with stroke type and location and is dependent on stroke phase. These findings have to be taken into consideration for stroke rehabilitation programs, as this could prevent stroke patients from developing PSD and PSA, resulting in better clinical outcome. PMID- 28831651 TI - Treatment of stable slipped capital femoral epiphysis: systematic review and exploratory patient level analysis. AB - BACKGROUND: Several aspects of slipped capital femoral epiphysis (SCFE) treatment remain controversial. Loder's work has been instrumental in changing our understanding and approach to the management of the condition when he introduced the concept of "slip instability" and showed that avascular necrosis (AVN) developed in 47% of unstable slips but none of the stable slips. As the two types of SCFE behave differently in terms of presentation, progress and complications, we approached them as two different conditions to highlight these differences. This paper focuses on treatments of stable SCFE. MATERIALS AND METHODS: An extensive literature search was carried out from multiple databases. One thousand six hundred and twenty-three citations were screened. Three hundred and sixteen full publications were obtained for further scrutiny. Fifty-eight studies (2262 hips) were included in the review. These studies evaluated 6 interventions. AVN was chosen as a surrogate for bad outcome. Secondary outcomes were chondrolysis (CL), femoro-acetabular impingement (FAI), osteoarthritis (OA) and patients' reported outcomes. The latter were pooled when they met our predefined criteria. RESULTS: The type of surgical intervention was an important risk factor. Pinning in situ (PIS) was associated with the lowest AVN rate (1.4%). Moreover, the CL, FAI and OA rates were relatively low in patients who underwent PIS. These were not translated into high patient satisfaction rates among these patients, with only 47% reporting an "excellent" outcome. In contrast, 87% of patients who underwent Ganz surgical dislocation reported an "excellent" outcome. The Ganz surgical dislocation was associated with an AVN rate of 3.3%; double that observed in pinning in situ. CONCLUSION: Pinning in situ is the best treatment for mild and moderate stable slip. Ganz surgical dislocation gives higher patient satisfaction for severe stable slip but the risk of AVN is doubled compared with pinning in situ. Devices that allow continued growth may be better than standard screws. LEVEL OF EVIDENCE: Level III. PMID- 28831652 TI - Cross-Cultural Adaptation and Validation of the SWAL-QoL Questionnaire in Greek. AB - The purpose of this study was to translate and adapt the 44-item SWAL-QoL into Greek and examine its internal consistency, test-retest reliability, external construct validity, and discriminant validity in order to provide a validated dysphagia-specific QoL instrument in the Greek language. The instrument was translated into Greek using the back translation to ensure linguistic validity and was culturally adapted resulting in the SWAL-QoL-GR. Two groups of participants were included: a patient group of 86 adults (48 males; age range: 18 87 years) diagnosed with oropharyngeal dysphagia, and an age-matched healthy control group (39 adults; 19 males; age range: 18-84 years). The Greek 30-item version of the WHOQOL-BREF was used for assessment of construct validity. Overall, the questionnaire achieved good to excellent psychometric values. Internal consistency of all 10 subscales and the physical symptoms scale of the SWAL-QoL-GR assessed by Cronbach's alpha was good to excellent (0.811 < alpha < 0.940). Test-retest validity was found to be good to excellent as well. In addition, moderate to strong correlations were found between seven of the ten subscales of the SWAL-QoL-GR with limited items of the WHOQOmicronL-BREF (0.401 < rho < 0.65), supporting good construct validity of the SWAL-QoL-GR. The SWAL-QoL GR also correctly differentiated between patients with dysphagia and age-matched healthy controls (p < 0.001) on all 11 scales, further indicating excellent discriminant validity. Finally, no significant differences were found between the two sexes. This cultural adaptation and validation allows the use of this tool in Greece, further enhancing our clinical and scientific efforts to increase the evidence-based practice resources for dysphagia rehabilitation in Greece. PMID- 28831653 TI - A Delphi Survey and Analysis of Expert Perspectives on One Health in Australia. AB - One Health (OH) is an interdisciplinary approach aiming to achieve optimal health for humans, animals and their environments. Case reports and systematic reviews of success are emerging; however, discussion of barriers and enablers of cross sectoral collaboration are rare. A four-phase mixed-method Delphi survey of Australian human and animal health practitioners and policymakers (n = 52) explored areas of consensus and disagreement over: (1) the operational definition of OH; (2) potential for cross-sectoral collaboration; and (3) key priorities for shaping the development of an OH response to significantly elevated zoonotic disease risk. Participants agreed OH is essential for effective infectious disease prevention and control, and on key priorities for outbreak responses, but disagreed over definitions and the relative priority of animal health and welfare and economic considerations. Strong support emerged among Australian experts for an OH approach. There was also recognition of the need to ensure cross-sectoral differences are addressed. PMID- 28831654 TI - Redox potentials of ubiquinone, menaquinone, phylloquinone, and plastoquinone in aqueous solution. AB - Quinones serve as redox active cofactors in bacterial photosynthetic reaction centers: photosystem I, photosystem II, cytochrome bc 1, and cytochrome b 6 f. In particular, ubiquinone is ubiquitous in animals and most bacteria and plays a key role in several cellular processes, e.g., mitochondrial electron transport. Their experimentally measured redox potential values for one-electron reduction E m(Q/Q.-) were already reported in dimethylformamide (DMF) versus saturated calomel electrode but not in water versus normal hydrogen electrode (NHE). We calculated E m(Q/Q.-) of 1,4-quinones using a quantum chemical approach. The calculated energy differences of reduction of Q to Q.- in DMF and water for 1,4 quinone derivatives correlated highly with the experimentally measured E m(Q/Q.-) in DMF and water, respectively. E m(Q/Q.-) were calculated to be -163 mV for ubiquinone, -260 mV for menaquinone and phylloquinone, and -154 mV for plastoquinone in water versus NHE. PMID- 28831655 TI - Spread of Dermacentor reticulatus is associated with the loss of forest area. AB - Changes in tick distribution and abundance are among the main drivers of the (re)emergence of transmitted pathogens. We aimed to uncover the reasons of the reported spread of Dermacentor reticulatus in Poland using a variety of proxies of environmental features, ground-measured temperature and remotely-sensed data of temperature and vegetation. Ground-measured temperature was recorded in 2013 2014, in sites where D. reticulatus presence (n = 16) or absence (n = 16) was confirmed. We specifically aimed to test whether changes in phenology of vegetation and the length of the growing season were correlated with field derived data regarding the presence/absence of D. reticulatus. We also used categorical descriptions of the habitat to capture the vegetation patterns that might delineate the distribution of the tick. We demonstrated that temperature, phenology of vegetation and length of growing season have no correlation with the occurrence of D. reticulatus in Poland. There is, however, a clear association between the trends of the loss of forests and the presence of the tick. This parameter was two times higher at sites colonized by D. reticulatus in comparison to the sites where the population of the tick is not yet established. A spatial analysis demonstrated that the preferred territories for D. reticulatus are those of a highly fragmented landscape within a large patch of homogeneous vegetation, in the vicinity of permanent water courses or reservoirs. PMID- 28831656 TI - Comparative study of the formation of brominated disinfection byproducts in UV/persulfate and UV/H2O2 oxidation processes in the presence of bromide. AB - The objective of this research was to compare the transformation of Br- and formation of brominated byproducts in UV/persulfate (PS) and UV/H2O2 processes. It was revealed that Br- was efficiently transformed to free bromine which reacted with humic acid (HA) or dihydroxybenzoic acid resulting in the formation of brominated byproducts such as bromoacetic acids (BAAs) in UV/PS system. In contrast, no free bromine and brominated byproducts could be detected in UV/H2O2 system, although the oxidization of Br- was evident. We presumed that the oxidation of Br- by hydroxyl radicals led to the formation of bromine radicals. However, the bromine radical species could be immediately reduced back to Br- by H2O2 before coupling to each other to form free bromine, which explains the undetection of free bromine and BAAs in UV/H2O2. In addition to free bromine, we found that the phenolic functionalities in HA molecules, which served as the principal reactive sites for free chlorine attack, could be in situ generated when HA was exposed to free radicals. This study demonstrates that UV/H2O2 is more suitable than UV/PS for the treatment of environmental matrices containing Br-. Graphical abstract Graphical abstract. PMID- 28831658 TI - Magnetic treatment of microalgae for enhanced product formation. AB - Static or modulated magnetic fields (MF) may interact with the biological system and affect the metabolism of microorganisms, such as their photosynthetic capacity or synthesis of carbohydrates. Their effects on microorganisms, which can be classified into inhibiting, stimulating and null, may be interpreted as the result of stress that cells undergo, thus, leading to responses through the same mechanisms. Biological effects of exposure to magnetic forces depend on magnetic intensity, frequency and exposure time. Modifications in these parameters may enhance product formation. Effects differ according to the form and application of MF characteristic parameters. Magnetic treatments have the advantages of being convenient and non-toxic, having low running cost, emitting no secondary pollution, enabling wide application and being easily shielded. MF application to the cultivation of microalgae, to improve the production of finished biomolecules, is a simple, inexpensive and powerful process. However, bioeffects of MF on microalgae need to be further investigated because there have currently been very few available reports in the literature. Thus, studies which aim at optimizing parameters involved in MF application must be developed in order to obtain the best conditions for the production of molecules with high economic potential. PMID- 28831657 TI - Performance of HADDOCK and a simple contact-based protein-ligand binding affinity predictor in the D3R Grand Challenge 2. AB - We present the performance of HADDOCK, our information-driven docking software, in the second edition of the D3R Grand Challenge. In this blind experiment, participants were requested to predict the structures and binding affinities of complexes between the Farnesoid X nuclear receptor and 102 different ligands. The models obtained in Stage1 with HADDOCK and ligand-specific protocol show an average ligand RMSD of 5.1 A from the crystal structure. Only 6/35 targets were within 2.5 A RMSD from the reference, which prompted us to investigate the limiting factors and revise our protocol for Stage2. The choice of the receptor conformation appeared to have the strongest influence on the results. Our Stage2 models were of higher quality (13 out of 35 were within 2.5 A), with an average RMSD of 4.1 A. The docking protocol was applied to all 102 ligands to generate poses for binding affinity prediction. We developed a modified version of our contact-based binding affinity predictor PRODIGY, using the number of interatomic contacts classified by their type and the intermolecular electrostatic energy. This simple structure-based binding affinity predictor shows a Kendall's Tau correlation of 0.37 in ranking the ligands (7th best out of 77 methods, 5th/25 groups). Those results were obtained from the average prediction over the top10 poses, irrespective of their similarity/correctness, underscoring the robustness of our simple predictor. This results in an enrichment factor of 2.5 compared to a random predictor for ranking ligands within the top 25%, making it a promising approach to identify lead compounds in virtual screening. PMID- 28831659 TI - Digestibility of Quinoa (Chenopodium quinoa Willd.) Protein Concentrate and Its Potential to Inhibit Lipid Peroxidation in the Zebrafish Larvae Model. AB - Quinoa protein concentrate (QPC) was extracted and digested under in vitro gastrointestinal conditions. The protein content of QPC was in the range between 52.40 and 65.01% depending on the assay used. Quinoa proteins were almost completely hydrolyzed by pepsin at pH of 1.2, 2.0, and 3.2. At high pH, only partial hydrolysis was observed. During the duodenal phase, no intact proteins were visible, indicating their susceptibility to the in vitro simulated digestive conditions. Zebrafish larvae model was used to evaluate the in vivo ability of gastrointestinal digests to inhibit lipid peroxidation. Gastric digestion at pH 1.2 showed the highest lipid peroxidation inhibition percentage (75.15%). The lipid peroxidation activity increased after the duodenal phase. The digest obtained at the end of the digestive process showed an inhibition percentage of 82.10%, comparable to that showed when using BHT as positive control (87.13%). PMID- 28831661 TI - Bariatric Surgery Is Gaining Ground as Treatment of Obesity After Heart Transplantation: Report of Two Cases. AB - Experience with bariatric surgery in patients after orthotopic heart transplantation (OHT) is still limited. We performed a retrospective review of patients who underwent bariatric surgery after OHT from January 1, 2010 to December 31, 2016. Two post-OHT patients with BMI of 37.5 and 36.2 kg/m2 underwent laparoscopic robotic-assisted Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy, respectively. Quality of life substantially improved for both patients. Bariatric surgery is safe and feasible in OHT patients, despite numerous risk factors. Careful selection of patients is required with proper preoperative management and overall care. Due to the complexity of treatment and perioperative care in this specific population, these operations should be done in high-volume centers with multidisciplinary teams composed of bariatric, cardiac transplant surgeons and critical care physicians. Bariatric surgery can be highly effective for treatment of obesity after OHT. PMID- 28831662 TI - Pituitary apoplexy and rivaroxaban. AB - Pituitary apoplexy (PA), defined by the occurrence of a massive hemorrhagic necrotic rearrangement within a pituitary adenoma, is rare. Its occurrence can be associated with certain risk factors, including anticoagulation. We report the first case of PA with rivaroxaban which is one of the new oral anticoagulants: a 73 year-old patient presenting with severe headache and visual field deterioration. Surgery was performed. Radiotherapy treatment was decided three months after surgery because of tumor residue. PMID- 28831663 TI - "It's Not Like Therapy": Patient-Inmate Perspectives on Jail Psychiatric Services. AB - Jails may serve an important public health function by treating individuals with psychiatric problems. However, scholars debate the service qualities that can best achieve this aim. Some suggest the possibility of comprehensive psychiatric services in jails, while others recommend a narrower focus on basic elements of care (assessments, medication management, and crisis intervention). To date, this debate remains uninformed by service recipients. This qualitative study addresses this gap by illuminating patient-inmate perspectives on jail psychiatric services. Patient-inmate experiences indicate that the jail environment is incongruent with the provision of comprehensive psychiatric services. Thus, program administrators would best serve patient-inmates by strengthening basic services and connections to community-based providers who can provide comprehensive and effective care. PMID- 28831660 TI - Distribution of polybrominated diphenyl ethers in breast milk, cord blood and placentas: a systematic review. AB - Polybrominated diphenyl ethers (PBDEs) have been extensively used as flame retardants in consumer products. PBDEs rapidly bioaccumulate in the environment, food, wild animals and humans. In this review, we investigated the harmful effects of PBDEs on humans, especially in early life, and summarised the levels of PBDEs in human biological samples (breast milk, cord blood and placentas). In addition, we described the spatiotemporal distribution of PBDEs in this review. PBDE levels in breast milk, cord blood and placentas were generally higher in North America than in other regions, such as Asia, Europe, Oceania and Africa. However, high levels of PBDEs in human biological samples were detected at e waste recycling sites in South China, East China and South Korea. This finding suggests that newborns living in e-waste regions are exposed to high levels of PBDEs during prenatal and postnatal periods. The time trends of PBDE concentration differed according to the region. Few studies have investigated PBDE levels in humans from 1967 to 2000, but they increased rapidly after 2000. PBDE concentration peaked at approximately 2006 globally. Compared with other PBDE congeners, BDE-47, BDE-153 and BDE-209 were the major components, but the detection rate of BDE-209 was lower than those of others. Future studies should focus on determining the BDE-209 concentration, which requires the implementation of different analytical approaches. Additionally, the levels of PBDEs in human samples and the environment should be monitored, especially in e-waste recycling regions. Graphical abstract The figures described the spatial distribution of the lowest (Fig. a1) and highest concentration of ?PBDE (Fig. a2) in different countries by 2006 and described the spatial distribution of the lowest (Fig. b1) and highest concentration of ?PBDE (Fig. b2) in different countries from 2007 to 2015. All the figures indicated that the levels of PBDEs in North America were substantially higher than those in many regions of Europe, Asia, Oceania, or Africa. Comparing Fig. a1-b1 or Fig. a2-b2, increasing trends were observed in some countries, especially in some regions in China, Korea and Canada. PMID- 28831665 TI - Persistence of MS-2 Bacteriophage Within Eastern Oysters. AB - Male-specific bacteriophages have been proposed as human enteric virus indicators for shellfish. In this study, Eastern oysters (Crassostrea virginica) were individually exposed to 5.6 * 1010 PFU of MS-2 for 48 h at 15 degrees C followed by collective maintenance in continuously UV-sterilized seawater for 0-6 weeks at either 7, 15, or 24 degrees C. Initial contamination levels of MS-2 were >6 log PFU. Assessment of weekly declines of viable MS-2 indicated that cooler temperatures dramatically enhanced the persistence of MS-2 within oyster tissues. At 3 weeks, the average log PFU reductions for MS-2 within oysters were 2.28, 2.90, and 4.57 for oysters held at 7, 15, and 24 degrees C, respectively. Fitting temporal survival data with linear and nonlinear Weibull models indicated that the Weibull model best fit the observed reductions. In total, these data can serve as a guideline for regulatory agencies regarding the influence of water temperature on indicator phage after episodic sewage exposure. PMID- 28831666 TI - An Unusual Case of Infertility: Urethral Coitus Due to Cribriform Hymen. AB - Urethral coitus is a rare type of sexual practice, usually due to vaginal agenesis or hymeneal anomalies. We report a case of urethral coitus in a healthy couple who were evaluated for infertility. The female partner had cribriform hymen and dilated urethral orifice but did not report any problems except infertility and her genital anatomy was normal. The male partner reported concerns over his penile size but was otherwise healthy. After incision of hymen, they were able to have vaginal coitus and successfully conceived. While urethral coitus is rare, it should be suspected in women presenting with infertility and a dilated urethral orifice. PMID- 28831667 TI - Nutcracker Syndrome Secondary to Bariatric Surgery. PMID- 28831664 TI - Low-temperature stress: is phytohormones application a remedy? AB - Among the various abiotic stresses, low temperature is one of the major environmental constraints that limit the plant development and crop productivity. Plants are able to adapt to low-temperature stress through the changes in membrane composition and activation of reactive oxygen scavenging systems. The genetic pathway induced due to temperature downshift is based on C-repeat-binding factors (CBF) which activate promoters through the C-repeat (CRT) cis-element. Calcium entry is a major signalling event occurring immediately after a downshift in temperature. The increase in the level of cytosolic calcium activates many enzymes, such as phospholipases and calcium dependent-protein kinases. MAP-kinase module has been shown to be involved in the cold response. Ultimately, the activation of these signalling pathways leads to changes in the transcriptome. Several phytohormones, such as abscisic acid, brassinosteroids, auxin, salicylic acid, gibberellic acid, cytokinins and jasmonic acid, have been shown to play key roles in regulating the plant development under low-temperature stress. These phytohormones modulate important events involved in tolerance to low-temperature stress in plants. Better understanding of these events and genes controlling these could open new strategies for improving tolerance mediated by phytohormones. PMID- 28831668 TI - Fish Collagen Hydrolysates Modulate Cartilage Metabolism. AB - Osteoarthritis is a degenerative joint disease in which interleukin-1beta plays a major role in the inflammatory process. Administration of collagen hydrolysate was an optional treatment of osteoarthritis. Fish has become an interesting source of collagen hydrolysate because of religious reason and there is no risk from mad cow disease. However, the effects of different sizes of fish collagen hydrolysate on cartilage and chondrocyte metabolism have not been well studied yet. This study examined the effect of different sizes of fish collagen hydrolysate on cartilage metabolism. Three different sizes of fish collagen hydrolysate were prepared by size exclusion using centrifugation, which composed of small fraction (<3 kDa), medium fraction (3-10 kDa) and large fraction (>10 kDa). Using porcine cartilage explant, in physiological condition, all the three fractions had no effect on cartilage metabolism, but they could induce pro-MMP3 and pro-MMP13 secretions through activation of p-ERK and p-p38. In pathological condition induced by interleukin-1beta and oncostatin-M, small and medium fractions showed additive effect with interleukin-1beta and oncostatin-M on cartilage degradation, whereas large size had no effect. In addition, the effect of small size occurred through further activation of p-p65, which resulted in further induction of active-MMP13, while medium size had a different mechanism. In conclusion, all three fractions fish collagen hydrolysate had no effect on cartilage metabolism in physiological condition, but small and medium fractions had adverse effect on cartilage in pathological condition. Taken together, various sizes of fish collagen hydrolysate showed different effects on cartilage metabolism. Therefore, different sizes of fish collagen hydrolysates play different roles on cartilage metabolism, especially in the pathological condition. PMID- 28831669 TI - Implementation of a Novel Medical School Multidisciplinary and Interprofessional Oncology Curriculum: a Mixed Method Study. AB - As the population of patients with cancer and survivors grows, physician knowledge of oncology clinical care and research is increasingly important. Despite this patient population growth, medical students and non-oncology physicians report insufficient oncologic and survivorship care training. First year students at a single US medical school completing a summer research experience were invited to participate in integrated Scholars in Oncology Associated Research (SOAR) program. SOAR seeks to broaden students' understanding of multidisciplinary and interprofessional oncology clinical care and research. SOAR consists of three components: structured didactics, multidisciplinary tumor board attendance, and interprofessional shadowing. A mixed-methods approach investigated whether student knowledge improved after SOAR. Thirty-three students enrolled in SOAR (20 in 2015, 13 in 2016) and completed pre-assessments. Twenty five (75.8%) students completed SOAR and post-assessments. Self-reported understanding of clinical (2[2, 3] vs. 4[4], p < 0.01) and research oncology (2[2, 3] vs. 4[4], p < 0.01) improved after SOAR. Understanding of individual disciplines also significantly improved. When describing clinical oncology, responses written post-SOAR were more comprehensive, averaging 3.7 themes per response vs. 2.8 on pre-assessments (p = 0.03). There were more references to "survivorship" as a component of oncology on post-assessments (0[0.0%] vs. 7[28.0%], p < 0.01) and "screening/prevention" (2[6.1%] vs. 7[28.0%], p = 0.03). Additionally, students more often described cancer care as a continuum on post assessments (4[12.1%] vs. 11[44.0%], p = 0.01). A structured didactic and experiential introduction to oncology, SOAR, was successfully piloted. SOAR improved participant understanding of oncology and its distinct clinical and research disciplines. Future work will focus on expanding SOAR into a longitudinal oncology curriculum. PMID- 28831670 TI - Thrombocytosis as a prognostic factor in inflammatory breast cancer. AB - PURPOSE: Platelets are essential components of hemostasis and also play an important role in the tumor microenvironment. The purposes of our research were to examine the role of thrombocytosis in inflammatory breast cancer (IBC) and to know which cytokine drives thrombocytosis. METHODS: We reviewed the medical records of 3654 patients with stage I-III breast cancer treated between 1998 and 2013, including 230 patients (6%) with IBC. We used Chi-squared test or Fisher's exact test to compare the variables between patients with and without thrombocytosis. Multivariate Cox regression models were used to determine the association of thrombocytosis with overall survival. We also examined baseline serum cytokine levels in 81 patients with primary IBC to determine the association of inflammatory cytokines with thrombocytosis. RESULTS: We found that thrombocytosis was the only variable that predicted prognosis. Fifty-five patients (1.5%) had thrombocytosis. Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC (3.4% vs. 1.4%, p = 0.015). In patients with IBC, thrombocytosis was associated with worse overall survival [hazard ratio 2.38, 95% confidence interval (CI) 1.05-5.4, p = 0.0378]. Circulating levels of growth-regulated oncogene (GRO) (odds ratio 1.003, 95% CI 1.001-1.005, p = 0.0019) and transforming growth factor beta (TGF-beta) (odds ratio 1.3, 95% CI 1.128-1.499, p = 0.0003) were associated with thrombocytosis. CONCLUSIONS: Thrombocytosis was more prevalent in patients with IBC than in those with non-IBC and it was associated with poor prognosis. GRO and TGF-beta were associated with thrombocytosis in IBC. PMID- 28831671 TI - Opportunistic Invasive Mycoses in AIDS: Cryptococcosis, Histoplasmosis, Coccidiodomycosis, and Talaromycosis. AB - PURPOSE OF REVIEW: The goal of this review is to provide an update on the epidemiology, diagnosis, and treatment of opportunistic fungal infections in patients with human immunodeficiency virus (HIV) infection including Cryptococcus spp., Histoplasma spp., Coccidioides spp., and Talaromyces marneffei, formerly Penicillium marneffei. RECENT FINDINGS: In many settings, despite increasing roll out of antiretroviral therapy (ART), opportunistic invasive mycoses produce a substantial burden of disease. The prevalence of specific fungal pathogens depends on their endemicity. Viral suppression achieved by greater access to ART and increased the availability of point-of-care testing with rapid diagnostic tests (RDTs) aid to curtail the associated fungi morbidity. RDTs allow earlier screening to preemptively initiate treatment of opportunistic fungal pathogens. Identifying asymptomatic cryptococcal infection before starting ART is crucial in reducing the risk of the immune reconstitution inflammatory syndrome (IRIS). There is an urgent need to decrease the burden of opportunistic invasive fungal infections in individuals with HIV/AIDS through different interventions: (a) continue to expand the deployment of ART to the most affected populations to achieve viral suppression; (b) ensure early diagnosis of fungal pathogen with point-of-care testing; PMID- 28831672 TI - Update on Mental Health of Infants and Children of Parents Affected With Mental Health Issues. AB - This paper highlights the most recent publications, in the field of psychiatry, on offspring of patients with psychiatric illnesses such as schizophrenia and bipolar disorder, and then summarizes what we know about the progeny of adults with mood disorders, the most prevalent of parental disorders. Studies examining personality disorders and contextual factors such as stress and trauma are examined with a focus on the crucial question of development and attachment status in children. Findings converge to reveal that offspring of parents (generally mothers) with most major psychiatric disorders present a higher risk for all mental disorders, and a wide range of disorders are also found in children, adolescent, and finally adult offspring of mothers with mood and anxiety disorders. Developmental psychopathology and infant and child psychiatry have focused on early relationship formation through social interaction and attachment patterns as pathways affected by vulnerability or resilience factors. First year of life longitudinal studies following mothers and infants has shown that maternal psychopathology is positively correlated with higher risk of attachment issues. It would seem that pathology appears when adaptation to real life contexts becomes difficult in association with an accumulation of negative individual characteristics and environmental circumstances. We suggest that in order to move forward psychiatry should embrace a developmental cascade model, which posits a cumulative pathway for the emergence of psychopathology in the developing child. We propose that we have sufficient knowledge today to start implementing multilevel approaches to enhance the health and mental health of the next generation. PMID- 28831673 TI - Measurement of MBF by PET is ready for prime time as an integral part of clinical reports in diagnosis and risk assessment of patients with known or suspected CAD PRO. PMID- 28831674 TI - Performance characteristics of specimen radiography for margin assessment for ductal carcinoma in situ: a systematic review. AB - BACKGROUND: Reducing positive margin rate (PMR) and reoperation rate in breast conserving operations remains a challenge, mainly regarding ductal carcinoma in situ (DCIS). Intra-operative margin assessment tools have emerged to reduce PMR over the last decades, including specimen radiography (SR). No consensus has been reached on the reliability and efficacy of SR in DCIS. OBJECTIVE: We performed a systematic literature review to assess the performance characteristics of SR for margin assessment of breast lesions with pure DCIS and invasive cancers with DCIS components. METHODS: A literature search was conducted for diagnostic studies up to April 2017 concerning SR for intra-operative margin assessment of breast lesions with pure DCIS or with DCIS components. Studies reporting sensitivity and specificity calculated using final pathology report as reference test were included. Due to improved imaging technology, studies published more than 15 years ago were excluded. Methodological quality was assessed using quality assessment of diagnostic accuracy studies-2 checklist. Due to clinical and methodological diversity, meta-analysis was considered not useful. RESULTS: Of 235 citations identified, 9 met predefined inclusion criteria and documented diagnostic efficacy data. Sensitivity ranged from 22 to 77% and specificity ranged from 51 to 100%. Positive predictive value and negative predictive value ranged from 53 to 100% and 32 to 95%, respectively. High or unclear risk of bias was found in reference standard in 5 of 9 studies. High concerns regarding applicability of index test were found in 6 of 9 studies. CONCLUSIONS: The present results do not support the routine use of intra-operative specimen radiography to reduce the rate of positive margins in patients undergoing breast conserving surgery for pure DCIS or the DCIS component in invasive cancer. Future studies need to differentiate between initial and final specimen margin involvement. This could provide surgeons with a number needed to treat for a more applicable outcome. PMID- 28831675 TI - Comparison between absorption and biological activity on the efficiency of the biotrickling filtration of gaseous streams containing ammonia. AB - Polluted air streams can be purified using biological treatments such as biotrickling filtration, which is one of the most widely accepted techniques successfully tuned to treat a wide variety of exhausted gaseous streams coming from a series of industrial sectors such as food processing, flavor manufacturers, rendering, and composting. Since the degradation of a pollutant occurs at standard pressure and temperature, biotrickling filtration, whether compared with other more energy-demanding chemical-physical processes of abatement (such as scrubbing, catalytic oxidation, regenerative adsorption, incineration, advanced oxidation processes, etc.), represents a very high energy efficient technology. Moreover, as an additional advantage, biodegradation offers the possibility of a complete mineralization of the polluting agents. In this work, biotrickling filtration has been considered in order to explore its efficiency with respect to the abatement of ammonia (which is a highly water soluble compound). Moreover, a complete mathematical model has been developed in order to describe the dynamics of both absorption and biological activities which are the two dominant phenomena occurring into these systems. The results obtained in this work have shown that the absorption phenomenon is very important in order to define the global removal efficiency of ammonia from the gaseous stream (particularly, 44% of the ammonia is abated by water absorption). Moreover, it has been demonstrated (through the comparison between experimental results and theoretical simulations) that the action of bacteria, which enhance the rate of ammonia transfer to the liquid phase, can be modeled through a simple Michaelis Menten relationship. PMID- 28831676 TI - Effects of scarcity, aesthetics and ecology on wildlife auction prices of large African mammals. AB - For successful integration of biological conservation into economic markets, economic processes need to capture ecological values. South African wildlife ranching is a tourist-based activity that generates unique information on the economic value of wildlife species. We used public data from South African wildlife auctions to evaluate if annual prices 1991-2012 related to species characteristics associated with scarcity, aesthetics and ecology of South African carnivores and ungulates. While none of the species characteristics influenced carnivore prices, ungulate prices were related to characteristics associated with novelty and aesthetics, which relative importance had increased over time. We raise both ecological and economic concerns for this apparent focus. Our results also suggest a potential importance of non-species-related factors, such as market and buyer characteristics. We encourage further evaluation of the relative influences of species characteristics versus factors that are intrinsically linked to economic processes on price variations in South African wildlife. PMID- 28831677 TI - The autopsy evaluation of "straightforward" fire deaths. PMID- 28831678 TI - Evaluation of allergic sensitization in Lebanese patients with allergic conjunctivitis. AB - PURPOSE: To describe the profile of patients with allergic conjunctivitis (AC) regarding their demographics, symptomatology and specific allergen sensitization, in a Lebanese tertiary hospital. METHODS: Cross-sectional study conducted at the Hotel-Dieu de France hospital (Beirut, Lebanon) during a period of 18 months. Patients with seasonal or perennial AC presenting for ophthalmic consultation had measurements of total and specific IgE. A matching group of patients with AC seen at the allergist office during the same period underwent skin prick tests (SPTs). RESULTS: Forty-four patients were enrolled for blood work by their ophthalmologists. Seasonal and perennial forms were almost equivalent. In total, 56.8% had positive specific IgE, with higher prevalence in patients with seasonal AC (p = 0.002), other associated allergies particularly allergic rhinitis (p = 0.002) or a family history of allergy (p = 0.005). Ocular surface severity scales were not shown as predictors. High levels of total IgE were commonly detected in those with positive specific IgE. Thirty-eight patients were assessed with SPT, and all had a positive result for at least one allergen. Dust mites were found to be the most frequent allergens based upon both specific IgE (72%) and SPT (92%), followed by Parietaria and other pollens. CONCLUSION: In our study, dust mites mono- or co-sensitization is present in the majority of patients with AC, with odds of positivity being higher using SPT than specific IgE. The latter are found more readily in seasonal AC and in the presence of personal and family history of allergy. PMID- 28831679 TI - Update on the role of bone biopsy in the management of patients with CKD-MBD. AB - Patients with chronic kidney disease (CKD) are at increased risk of fractures. The fracture risk steadily increases along with the progression of renal disease to become several-fold higher in end-stage renal disease (ESRD) patients as compared to age and sex-matched controls. Renal osteodystrophy (ROD) is a heterogeneous group of metabolic bone diseases complicating progressive chronic kidney disease. Bone biomarkers and bone imaging techniques may help to assess bone health and predict fractures in CKD, but do have important inherent limitations. The gold standard for the diagnosis and specific classification of renal osteodystrophy (ROD) remains the (quantitative) histomorphometric analysis of the bone biopsy. By informing on bone turnover and mineralization, a bone biopsy may help guide prevention and treatment of ROD and its consequences. This review aims to present an update on epidemiological and procedural aspects, clinical indications, and histomorphometric analysis of bone biopsies and to define the role of bone biopsy in current CKD-MBD care. PMID- 28831681 TI - NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase eta in response to oxidative DNA damage. AB - NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 (NEDD8) and the roles of NEDDylation involved in the DNA damage response (DDR) are largely unknown. Translesion synthesis (TLS) is a damage-tolerance mechanism, in which RAD18/RAD6-mediated monoubiquitinated proliferating cell nuclear antigen (PCNA) promotes recruitment of polymerase eta (poleta) to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination. In addition, NEDP1 acts as the deNEDDylase of PCNA, and NEDP1 deletion enhances PCNA NEDDylation but reduces its ubiquitination. In response to H2O2 stimulation, NEDP1 disassociates from PCNA and RAD18-dependent PCNA NEDDylation increases markedly after its ubiquitination. Impairment of NEDDylation by Ubc12 knockout enhances PCNA ubiquitination and promotes PCNA-poleta interaction, while up-regulation of NEDDylation by NEDD8 overexpression or NEDP1 deletion reduces the excessive accumulation of ubiquitinated PCNA, thus inhibits PCNA-poleta interaction and blocks poleta foci formation. Moreover, Ubc12 knockout decreases cell sensitivity to H2O2-induced oxidative stress, but NEDP1 deletion aggravates this sensitivity. Collectively, our study elucidates the important role of NEDDylation in the DDR as a modulator of PCNA monoubiquitination and poleta recruitment. PMID- 28831682 TI - Differences in grip force control between young and late middle-aged adults. AB - Grip force control is a crucial function for human to guarantee the quality of life. To examine the effects of age on grip force control, 10 young adults and 11 late middle-aged adults participated in visually guided tracking tasks using different target force levels (25, 50, and 75% of the subject's maximal grip force). Multiple measures were used to evaluate the tracking performance during force rising phase and force maintenance phase. The measurements include the rise time, fuzzy entropy, mean force percentage, coefficient of variation, and target deviation ratio. The results show that the maximal grip force was significantly lower in the late middle-aged adults than in the young adults. The time of rising phase was systematically longer among late middle-aged adults. The fuzzy entropy is a useful indicator for quantitating the force variability of the grip force signal at higher force levels. These results suggest that the late middle-aged adults applied a compensatory strategy that allow allows for sufficient time to reach the required grip force and reduce the impact of the early and subtle degenerative changes in hand motor function. PMID- 28831680 TI - Olfactory Dysfunction as an Early Biomarker in Parkinson's Disease. AB - Olfactory dysfunction is common in Parkinson's disease (PD) and often predates the diagnosis by years, reflecting early deposition of Lewy pathology, the histologic hallmark of PD, in the olfactory bulb. Clinical tests are available that allow for the rapid characterization of olfactory dysfunction, including tests of odor identification, discrimination, detection, and recognition thresholds, memory, and tests assessing the build-up of odor intensity across increasing suprathreshold stimulus concentrations. The high prevalence of olfactory impairment, along with the ease and low cost of assessment, has fostered great interest in olfaction as a potential biomarker for PD. Hyposmia may help differentiate PD from other causes of parkinsonism, and may also aid in the identification of "pre-motor" PD due to the early pathologic involvement of olfactory pathways. Olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline. In this article, we summarize the existing literature on olfaction in PD, focusing on the potential for olfaction as a biomarker for early or differential diagnosis and prognosis. PMID- 28831684 TI - Distinct and Untamed: Articulating Bulimic Identities. AB - Bulimia nervosa and anorexia nervosa are inextricably linked, with substantial clinical and epidemiological overlaps. Yet, while anorexia has been analyzed extensively in medical anthropology, bulimia remains under-theorized. This is, perhaps, because, compared to self-starvation, binge eating presents a logic of practice that is difficult to reconcile with culturally reified notions of self control, transcendence, and hard work. Thus, although anthropologists have analyzed anorexic subjectivities as imbued with a sense of cleanliness and purity, moral superiority, and heroics, similar analyses have not been extended to bulimic subjectivities; instead, bulimia has been subsumed, as a tangential disorder, into analyses of anorexia. In this paper, I aim to move bulimic identities from the margins to the centre of anthropological analysis. Based on participant narratives, I analyze bulimic identity as articulated by six Israeli women who identified as bulimic and received treatment for bulimia. The women's narratives show that bulimic identity is aligned with concepts of distinct selfhood. For these women, to be bulimic was to be framed as 'abnormal'; but this 'abnormality', albeit a source of social stigma and shame, held meanings that went beyond pathology. Through the claiming of bulimic identity, the women positioned themselves as untamed, non-conforming subjects, who acted against gendered and classed expectations-and even against the limitations of the body. Their constructions of bulimic distinction highlight the need for anthropological work that situates bulimia not as a footnote to anorexia, but as a structurally and culturally meaningful condition in its own right. PMID- 28831683 TI - Oligopeptide Transport in Rat Lung Alveolar Epithelial Cells is Mediated by Pept2. AB - PURPOSE: Studies were conducted in primary cultured rat alveolar epithelial cell monolayers to characterize peptide transporter expression and function. METHODS: Freshly isolated rat lung alveolar epithelial cells were purified and cultured on permeable support with and without keratinocyte growth factor (KGF). Messenger RNA and protein expression of Pept1 and Pept2 in alveolar epithelial type I- and type II-like cell monolayers (+/-KGF, resp.) were examined by RT-PCR and Western blotting. 3H-Glycyl-sarcosine (3H-gly-sar) transmonolayer flux and intracellular accumulation were evaluated in both cell types. RESULTS: RT-PCR showed expression of Pept2, but not Pept1, mRNA in both cell types. Western blot analysis revealed presence of Pept2 protein in type II-like cells, and less in type I-like cells. Bi-directional transmonolayer 3H-gly-sar flux lacked asymmetry in transport in both types of cells. Uptake of 3H-gly-sar from apical fluid of type II-like cells was 7-fold greater than that from basolateral fluid, while no significant differences were observed from apical vs. basolateral fluid of type I-like cells. CONCLUSIONS: This study confirms the absence of Pept1 from rat lung alveolar epithelium in vitro. Functional Pept2 expression in type II-like cell monolayers suggests its involvement in oligopeptide lung disposition, and offers rationale for therapeutic development of di/tripeptides, peptidomimetics employing pulmonary drug delivery. PMID- 28831685 TI - Platypnea-orthodeoxia syndrome: additive value of three-dimensional echocardiography. PMID- 28831687 TI - A Longitudinal Analysis of the Influence of a Peer Run Warm Line Phone Service on Psychiatric Recovery. AB - This article focuses on the impact of a peer run warm line as part of the psychiatric recovery process. It utilized data including the Recovery Assessment Scale, community integration measures and crisis service usage. Longitudinal statistical analysis was completed on 48 sets of data from 2011, 2012, and 2013. Although no statistically significant differences were observed for the RAS score, community integration data showed increases in visits to primary care doctors, leisure/recreation activities and socialization with others. This study highlights the complexity of psychiatric recovery and that nonclinical peer services like peer run warm lines may be critical to the process. PMID- 28831686 TI - Food Versus Pharmacy: Assessment of Nutritional and Pharmacological Strategies to Improve Bone Health in Energy-Deficient Exercising Women. AB - PURPOSE OF REVIEW: The review aims to summarize our current knowledge surrounding treatment strategies aimed at recovery of bone mass in energy-deficient women suffering from the Female Athlete Triad. RECENT FINDINGS: The independent and interactive contributions of energy status versus estrogen status on bone density, geometry, and strength have recently been reported, highlighting the importance of addressing both energy and estrogen in treatment strategies for bone health. This is supported by reports that have identified energy-related features (low body weight and BMI) and estrogen-related features (late age of menarche, oligo/amenorrhea) to be significant risk factors for low bone mineral density and bone stress injury in female athletes and exercising women. Nutritional therapy is the recommended first line of treatment to recover bone mass in energy-deficient female athletes and exercising women. If nutritional therapy fails after 12 months or if fractures or significant worsening in BMD occurs, pharmacological therapy may be considered in the form of transdermal estradiol with cyclic oral progestin (not COC). PMID- 28831688 TI - Socio-demographic, Marital, and Psychosocial Factors Associated with Condom Use Negotiation Self-Efficacy Among Mozambican Women at Risk for HIV Infection. AB - PURPOSE: In Mozambique, women are the most affected by HIV/AIDS. Self-efficacy is one of the main predictors of effective use of a condom. Therefore, it is essential to identify the factors that influence condom-use negotiation self efficacy in vulnerable women. The aim of this paper is to identify socio demographic, marital, and psychosocial factors associated with condom-use negotiation self-efficacy among Mozambican women at risk for HIV infection. METHODS: Participants were women (173) who were patients at the Gynecology Department of the Central Hospital of Beira, Mozambique, and at risk for HIV infection. Women completed measures of condom-use negotiation self-efficacy, HIV prevention knowledge, and perceived barriers against safer sex. RESULTS: The results showed that demographic and marital variables are associated with condom use negotiation self-efficacy, namely, those having more than 9 years of education, who are younger and not living with a partner, and who talk about AIDS with partners report higher condom-use negotiation self-efficacy. Regarding psychosocial factors, higher HIV prevention knowledge and fewer perceived barriers to safer sex predict higher condom-use negotiation self-efficacy. CONCLUSION: These results can contribute to sexual health promotion and HIV/AIDS prevention in Mozambican women because they identify at-risk groups and marital and psychosocial malleable factors that can be targeted in AIDS prevention among at-risk Mozambican women. PMID- 28831689 TI - Balancing the Need for Personalization of QT Correction and Generalization of Study Results: Going Beyond Thorough QT Studies. PMID- 28831691 TI - Parvovirus B19 infection associated with hemolytic anemia and cranial polyneuropathy. AB - Parvovirus B19 (PB19) is a common, widespread, small, single-stranded DNA virus which has been linked with a broad spectrum of clinical illnesses, including a variety of neurological complications such as encephalitis, meningitis, myelitis, stroke, cerebellar ataxia, and neuropathy. The authors describe a case of PB19 infection associated with hemolytic anemia and cranial polyneuropathy involving the second and third cranial nerves in a 23-year-old immunocompetent woman. The diagnosis of acute PB19 infection was established with detection of positive DNA and anti-PB19 IgM antibodies in blood samples. Antiganglioside antibody studies were performed and serum anti-GD1b IgG was strongly positive. Further investigation was normal or negative, excluding other infectious or autoimmune disorders. The patient was initially treated with a 5-day course of intravenous immunoglobulin (IGIV). Because of incomplete neurological recovery, methylprednisolone was also administered 7 days after IGIV therapy initiation. Complete resolution of clinical symptoms was observed 3 months after disease onset at follow-up visit, despite the persistence of PB19 DNA and anti-PB19 IgM antibodies in serum 5 months after the initial presentation. Our report provides evidence that PB19 could affect both the central and peripheral nervous system, possibly by triggering an autoimmune mechanism that leads to autoantibody production. PMID- 28831690 TI - Effects of risk factors for and components of metabolic syndrome on the quality of life of patients with systemic lupus erythematosus: a structural equation modeling approach. AB - PURPOSE: This study assessed the relationships among the risk factors for and components of metabolic syndrome (MetS) and health-related quality of life (HRQOL) in a hypothesized causal model using structural equation modeling (SEM) in patients with systemic lupus erythematosus (SLE). METHODS: Of the 505 SLE patients enrolled in the Korean Lupus Network (KORNET registry), 244 had sufficient data to assess the components of MetS at enrollment. Education level, monthly income, corticosteroid dose, Systemic Lupus Erythematosus Disease Activity Index, Physicians' Global Assessment, Beck Depression Inventory, MetS components, and the Short Form-36 at the time of cohort entry were determined. SEM was used to test the causal relationship based on the Analysis of Moment Structure. RESULTS: The average age of the 244 patients was 40.7 +/- 11.8 years. The SEM results supported the good fit of the model (chi 2 = 71.629, p = 0.078, RMSEA 0.034, CFI 0.972). The final model showed a direct negative effect of higher socioeconomic status and a positive indirect effect of higher disease activity on MetS, the latter through corticosteroid dose. MetS did not directly impact HRQOL but had an indirect negative impact on it, through depression. CONCLUSIONS: In our causal model, MetS risk factors were related to MetS components. The latter had a negative indirect impact on HRQOL, through depression. Clinicians should consider socioeconomic status and medication and seek to modify disease activity, MetS, and depression to improve the HRQOL of SLE patients. PMID- 28831692 TI - Cold-Inducible Protein RBM3 Protects UV Irradiation-Induced Apoptosis in Neuroblastoma Cells by Affecting p38 and JNK Pathways and Bcl2 Family Proteins. AB - Induced by hypothermia, cold-inducible protein RBM3 (RNA-binding protein motif 3), has been implicated in neuroprotection against various toxic insults such as hypoxia and ischemia. However, whether mild hypothermia and RBM3 prevent neural cells from UV irradiation-elicited apoptosis is unclear. In the present study, human neuroblastoma cell line SH-SY5Y was used as a cell model for neural cell death, and it was demonstrated that mild hypothermia protects SH-SY5Y cells from UV irradiation-induced apoptosis. However, the protective effect of mild hypothermia was abrogated when RBM3 was silenced. Conversely, the overexpression of RBM3 rescued SH-SY5Y cells from UV-induced apoptosis, as indicated by the decreased levels of cleaved caspase-3 and PARP, and increased cell survival. The analysis on the mechanism underlying RBM3-mediated neuroprotection against UV insult showed that RBM3 could substantially block the activation of p38 and JNK signaling pathways. In addition, the overexpression of RBM3 reduced the expression of pro-apoptotic proteins Bax and Bad, leaving the pro-survival protein Bcl-2 unaffected. In conclusion, RBM3 is the key mediator of mild hypothermia-related protection against UV in neuroblastoma cells, and the neuroprotective effect might be exerted through interfering with pro-apoptotic signaling pathways p38 and JNK and regulating pro-apoptotic proteins Bax and Bad. PMID- 28831693 TI - Febrile Child. AB - Fever without focus (FWF) is a common symptom in children for which parents seek health care consultation. It can be secondary to benign or serious causes. A pediatrician should be able to discriminate the benign from the serious causes by identifying the red flag signs. A systematic approach using detailed history, careful examination and laboratory tests is essential for early recognition, timely management and prompt referral to any emergency department. At the same time, benign cases require parental reassurance, symptomatic treatment and appropriate follow-up advice, taking care to avoid unnecessary investigations and antimicrobials. PMID- 28831694 TI - Increased Plasma Galectin-3 Preceding the Development of Delayed Cerebral Infarction and Eventual Poor Outcome in Non-Severe Aneurysmal Subarachnoid Hemorrhage. AB - A matricellular protein galectin-3 is involved in tissue injury and inflammation, but the role of galectin-3 remains unclear in aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to assess whether acute-stage galectin-3 levels were associated with the subsequent development of neurovascular events and outcome after SAH. This study included 83 consecutive patients diagnosed with aneurysmal SAH of resuscitated World Federation of Neurological Surgeons (WFNS) grades 1-3. Plasma galectin-3 levels were once measured on days 1-3 (the day after clipping or coiling). Fifteen patients had poor outcomes, which were associated with increasing age, female, pre-onset morbidity, worse WFNS grade, modified Fisher computed tomography scale, acute hydrocephalus, and higher galectin-3 levels compared with good outcomes. Multivariate analyses revealed that plasma galectin-3 was an independent determinant for poor outcome (odds ratio, 3.08; 95% confidence interval, 1.58-6.00; p = 0.001). Among post-SAH neurovascular events occurring on day 4 and thereafter, delayed cerebral ischemia and infarction, but not angiographic vasospasm and shunt-dependent hydrocephalus, showed significantly higher plasma galectin-3 levels on days 1-3. The receiver operating characteristic curve indicated that plasma galectin-3 with a cutoff value of 3.30 or 3.48 ng/ml predicted delayed cerebral infarction development or poor outcome (specificity, 62.5%, 70.6%; sensitivity, 90.9%, 73.3%, respectively). The findings suggest that plasma galectin-3 levels on days 1-3 would be a useful biomarker for predicting subsequent development of delayed cerebral infarction and eventual poor outcome and provide a new candidate, which may mediate between post-SAH early brain injury or inflammation and delayed cerebral infarction without vasospasm. PMID- 28831695 TI - Evaluation of pharmacokinetic model designs for subcutaneous infusion of insulin aspart. AB - Effective mathematical modelling of continuous subcutaneous infusion pharmacokinetics should aid understanding and control in insulin therapy. Thorough analysis of candidate model performance is important for selecting the appropriate models. Eight candidate models for insulin pharmacokinetics included a range of modelled behaviours, parameters and complexity. The models were compared using clinical data from subjects with type 1 diabetes with continuous subcutaneous insulin infusion. Performance of the models was compared through several analyses: R2 for goodness of fit; the Akaike Information Criterion; a bootstrap analysis for practical identifiability; a simulation exercise for predictability. The simplest model fit poorly to the data (R2 = 0.53), had the highest Akaike score, and worst prediction. Goodness of fit improved with increasing model complexity (R2 = 0.85-0.92) but Akaike scores were similar for these models. Complexity increased practical non-identifiability, where small changes in the dataset caused large variation (CV > 10%) in identified parameters in the most complex models. Best prediction was achieved in a relatively simple model. Some model complexity was necessary to achieve good data fit but further complexity introduced practical non-identifiability and worsened prediction capability. The best model used two linear subcutaneous compartments, an interstitial and plasma compartment, and two identified variables for interstitial clearance and subcutaneous transfer rate. This model had optimal performance trade-off with reasonable fit (R2 = 0.85) and parameterisation, and best prediction and practical identifiability (CV < 2%). PMID- 28831697 TI - Cheminformatic characterization of natural products from Panama. AB - In this work, we discuss the characterization and diversity analysis of 354 natural products (NPs) from Panama, systematically analyzed for the first time. The in-house database was compared to NPs from Brazil, compounds from Traditional Chinese Medicine, natural and semisynthetic collections used in high-throughput screening, and compounds from ChEMBL. An analysis of the "global diversity" was conducted using molecular properties of pharmaceutical interest, three molecular fingerprints of different design, molecular scaffolds, and molecular complexity. The global diversity was visualized using consensus diversity plots that revealed that the secondary metabolites in the Panamanian flora have a large scaffold diversity as compared to other composite databases and also have several unique scaffolds. The large scaffold diversity is in agreement with the broad range of biological activities that this collection of NPs from Panama has shown. This study also provided further quantitative evidence of the large structural complexity of NPs. The results obtained in this study support that NPs from Panama are promising candidates to identify selective molecules and are suitable sources of compounds for virtual screening campaigns. PMID- 28831696 TI - BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD. AB - PURPOSE: The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. METHODS: A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. RESULTS: Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0-9.0) in the BRCA group as a whole, 6.5 (IQR 4.0-8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5-9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0-11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). CONCLUSIONS: Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve. PMID- 28831698 TI - Utility of Appendiceal Calcifications Detected on Computed Tomography as a Predictor for an Underlying Appendiceal Epithelial Neoplasm. AB - BACKGROUND: Mucinous appendiceal neoplasms can contain radiopaque calcifications. Whether appendiceal radiographic calcifications indicate the presence of an appendiceal epithelial neoplasm is unknown. This study aimed to determine whether appendiceal calcifications detected by computed tomography (CT) correlate with the presence of appendiceal epithelial neoplasms. METHODS: From prospective appendiceal and pathology databases, 332 cases of appendiceal neoplasm and 136 cases of control appendectomy were identified, respectively. Only cases with preoperative CT scans available for review were included in the study. Images were reviewed by two abdominal radiologists. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated, and the kappa statistic was used to determine agreement between the radiologists' interpretations. RESULTS: Interobserver agreement between the radiologists was substantial, with a kappa of 0.74. Appendiceal mural calcifications were identified on CT scans in 106 appendiceal neoplasm cases (32%) and in 1 control case (1%) (P = 0.0001). In the appendiceal neoplasm subgroup, the presence of radiographic calcifications was associated with mucinous histology (35% vs 17%; P = 0.006; odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18-0.78) and with well-differentiated histologic grade (40% vs 24%; P = 0.002; OR, 0.47; 95% CI, 0.29-0.76). The findings showed a sensitivity of 31.9% (95% CI, 26.9-37.2%), a specificity of 99.3% (95% CI, 96-100%), a PPV of 99.1% (95% CI, 94.9-100%), and an NPV of 37.4% (95% CI, 32.4-42.6%). CONCLUSION: This case-control study showed that appendiceal mural calcifications detected on CT are associated with underlying appendiceal epithelial neoplasms and that the identification of incidental mural appendiceal calcifications may have an impact on decisions regarding surgical intervention. PMID- 28831699 TI - Comparison of cumulative dissipated energy delivered by active-fluidic pressure control phacoemulsification system versus gravity-fluidics. AB - PURPOSE: To compare the cumulative dissipated energy (CDE), aspiration time and estimated aspiration fluid utilized during phacoemulsification cataract surgery using two phacoemulsification systems . METHODS: A total of 164 consecutive eyes of 164 patients undergoing cataract surgery, 82 in the active-fluidics group and 82 in the gravity-fluidics group were enrolled in this study. Cataracts graded NII to NIII using LOCS II were included. Each subject was randomly assigned to one of the two platforms with a specific configuration: the active-fluidics Centurion (r) phacoemulsification system or the gravity-fluidics Infiniti (r) Vision System. CDE, aspiration time (AT) and the mean estimated aspiration fluid (EAF) were registered and compared. RESULTS: A mean age of 68.3 +/- 9.8 years was found (range 57-92 years), and no significant difference was evident between both groups. A positive correlation between the CDE values obtained by both platforms was verified (r = 0.271, R 2 = 0.073, P = 0.013). Similarly, a significant correlation was evidenced for the EAF (r = 0.334, R 2 = 0.112, P = 0.046) and AT values (r = 0.156, R 2 = 0.024, P = 0.161). A statistically significantly lower CDE count, aspiration time and estimated fluid were obtained using the active fluidics configuration when compared to the gravity-fluidics configuration by 19.29, 12.10 and 9.29%, respectively (P = 0.001, P < 0.0001 and P = 0.001). CONCLUSIONS: The active-fluidics Centurion (r) phacoemulsification system achieved higher surgical efficiency than the gravity-fluidics Infiniti (r) IP system for NII and NIII cataracts. PMID- 28831700 TI - Screening of genetic variants in ADCYAP1R1, MME and 14q21 in a Swedish cluster headache cohort. AB - BACKGROUND: We have genotyped a Swedish cluster headache case-control population for three genetic variants representing the most significant markers identified in a recently published genome wide association study on cluster headache. The genetic variants were two common polymorphisms; rs12668955 in ADCYAP1R1 (adenylate cyclase activating polypeptide 1 receptor type 1), rs1006417, an intergenic variant on chromosome 14q21 and one rare mutation, rs147564881, in MME (membrane metalloendopeptidase). RESULTS: We screened 542 cluster headache patients and 581 controls using TaqMan real-time PCR on a 7500 fast cycler, and pyrosequencing on a PSQ 96 System. Statistical analysis for genotype and allele association showed that neither of the two common variants, rs12668955 and rs1006417 were associated with cluster headache. The MME mutation was investigated with pyrosequencing in patients, of whom all were wild type. CONCLUSION: In conclusion rs12668955 and rs1006417 do not impact the risk of developing cluster headache in the Swedish population. Also, rs147564881 does not seem to be enriched within the Swedish cluster headache patient group. PMID- 28831701 TI - Lethal and sublethal effects, and incomplete clearance of ingested imidacloprid in honey bees (Apis mellifera). AB - A previous study claimed a differential behavioural resilience between spring or summer honey bees (Apis mellifera) and bumble bees (Bombus terrestris) after exposure to syrup contaminated with 125 ug L-1 imidacloprid for 8 days. The authors of that study based their assertion on the lack of body residues and toxic effects in honey bees, whereas bumble bees showed body residues of imidacloprid and impaired locomotion during the exposure. We have reproduced their experiment using winter honey bees subject to the same protocol. After exposure to syrup contaminated with 125 ug L-1 imidacloprid, honey bees experienced high mortality rates (up to 45%), had body residues of imidacloprid in the range 2.7-5.7 ng g-1 and exhibited abnormal behaviours (restless, apathetic, trembling and falling over) that were significantly different from the controls. There was incomplete clearance of the insecticide during the 10-day exposure period. Our results contrast with the findings reported in the previous study for spring or summer honey bees, but are consistent with the results reported for the other bee species. PMID- 28831702 TI - Microbial community composition and electricity generation in cattle manure slurry treatment using microbial fuel cells: effects of inoculum addition. AB - Microbial fuel cell (MFC) is a sustainable technology to treat cattle manure slurry (CMS) for converting chemical energy to bioelectricity. In this work, two types of allochthonous inoculum including activated sludge (AS) and domestic sewage (DS) were added into the MFC systems to enhance anode biofilm formation and electricity generation. Results indicated that MFCs (AS + CMS) obtained the maximum electricity output with voltage approaching 577 +/- 7 mV (~ 196 h), followed by MFCs (DS + CMS) (520 +/- 21 mV, ~ 236 h) and then MFCs with autochthonous inoculum (429 +/- 62 mV, ~ 263.5 h). Though the raw cattle manure slurry (RCMS) could facilitate electricity production in MFCs, the addition of allochthonous inoculum (AS/DS) significantly reduced the startup time and enhanced the output voltage. Moreover, the maximum power (1.259 +/- 0.015 W/m2) and the highest COD removal (84.72 +/- 0.48%) were obtained in MFCs (AS + CMS). With regard to microbial community, Illumina HiSeq of the 16S rRNA gene was employed in this work and the exoelectrogens (Geobacter and Shewanella) were identified as the dominant members on all anode biofilms in MFCs. For anode microbial diversity, the MFCs (AS + CMS) outperformed MFCs (DS + CMS) and MFCs (RCMS), allowing the occurrence of the fermentative (e.g., Bacteroides) and nitrogen fixation bacteria (e.g., Azoarcus and Sterolibacterium) which enabled the efficient degradation of the slurry. This study provided a feasible strategy to analyze the anode biofilm formation by adding allochthonous inoculum and some implications for quick startup of MFC reactors for CMS treatment. PMID- 28831704 TI - First report of molecular characterization and phylogenetic analysis of RoTat 1.2 VSG of Trypanosoma evansi from equine isolate. AB - Rotat 1.2 variant surface glycoprotein (VSG) is considered to be an important VSG expressed in most of the isolates of Trypanosoma evansi. This makes the molecule an important candidate for both molecular- and serological-based detection of surra. There are ample reports of existence of this gene in isolates from cattle, buffalo, and camel across the world. Of late, there are reports of its absence from a fewer isolates of T. evansi of murine and wildlife origin. Search of literature revealed no reports from horses. The present communication presents the first report of molecular cloning and characterization of Rotat 1.2 VSG from horse isolate of T. evansi from semi-arid region of India. Alongside, the gene was compared with various other isolates across the world. Interestingly, the isolate was found to be closer to camel isolates from Egypt than the other known isolates from India and Kenya. PMID- 28831703 TI - The role played by modified bioinspired surfaces in interfacial properties of biomaterials. AB - The success of a biomaterial relies on an appropriate interaction between the surface of that biomaterial and the surrounding environment; more specifically, the success of a biomaterial depends on how fluids, proteins, and cells interact with the foreign material. For this reason, the surface properties of biomaterial, such as composition, charge, wettability, and roughness, must be optimized for a desired application to be achieved. In this review we highlight different bioinspired approaches that are used to manipulate and fine-tune the interfacial properties of biomaterials. Inspired by noteworthy natural processes, researchers have developed materials with a functional anatomy that range from hierarchical hybrid structures to self-cleaning interfaces. In this review we focus on (1) the creation of particles and modified surfaces inspired by the structure and composition of biogenic mineralized tissues, (2) the development of biofunctional coatings, (3) materials inspired by biomembranes and proteins, and (4) the design of superwettable materials. Our intention is to point out different bioinspired methodologies that have been used to design materials for biomedical applications and to discuss how interfacial properties modified by manipulation of these materials determine their final biological response. Our objective is to present future research directions and to highlight the potential of bioinspired materials. We hope this review will provide an understanding of the interplay between interfacial properties and biological response so that successful biomaterials can be achieved. PMID- 28831705 TI - Predictors of first ischemic lower limb ulcer in dialysis patients: an observational cohort study. AB - BACKGROUND: Lower limb ischemia affects the quality of life, physical activity and life expectancy of dialysis patients. The aim of this study was to investigate the risk factors associated with ischemic foot ulcers considering clinical, laboratory and therapeutic domains. METHODS: This observational cohort study was based on data from the Nephrology and Dialysis Department database of Alessandro Manzoni Hospital, Lecco (Italy). All of the incident patients who started dialysis between 1 January 1999 and 29 February 2012 were enrolled, excluding temporary guests, patients with acute renal failure and patients with previous limb ischemia or amputation. Multivariate Cox regression analysis identified the predictors in each domain, which were matched in the final model. A time-dependent approach was used to take into account the evolution of some of the prognostic covariates. RESULTS: Of the 526 incident dialysis patients, 120 developed a lower limb ischemic lesion after a median of 13 months. The incidence of new ulcers was constant during the study period (6 per 100 person-years), but higher in the diabetics with a relative rate of 4.5. The variables significantly related to an increased risk of lower limb ulcers were age, male gender, diabetes, ischemic heart disease, treatment with proton pump inhibitors, iron, anticoagulants and calcium-based binders, and blood levels of phosphorus, triglycerides and C-reactive protein. CONCLUSION: The incidence of lower limb ulcers was highest during the early dialysis follow-up and was associated with, in addition to diabetes, modifiable laboratory and therapeutic predictors such as anticoagulants, proton pump inhibitors, calcium-containing binders, calcimimetics and iron. PMID- 28831706 TI - Microbial diversity in solar greenhouse soils in Round-Bohai Bay-Region, China: The influence of cultivation year and environmental condition. AB - Round-Bohai Bay (RBB)-Region is an important crop production area in China, where vegetables are mainly produced in solar greenhouses. However, excessive fertilization and monoculture have caused serious deterioration of soil quality in this region. Soil microbial communities play pivotal roles in many ecosystem processes and are recognized as integrative components of soil quality. Therefore, in this study, we investigated bacterial and fungal diversity in solar greenhouse soils covering a wide range of cultivation year (CY) and sampling site (SS), by using pyrosequencing technology. Surprisingly, CY and SS had little influence on bacterial and fungal relative abundance and diversity. However, environmental factors (EF) and soil available potassium (K) in particular made a significant contribution to the variation of soil bacterial and fungal communities. Specifically, K showed significant (P < 0.05) correlations with dominant bacterial phyla Bacteroidetes, Acidobacteria, Chloroflexi, and Planctomycetes and fungal phyla Ascomycota and Basidiomycota. These results suggested that soil EF appeared more important than CY and SS in shaping the compositions of bacterial and fungal communities. In addition, since fertilizer K has been in the long-term abused in RBB-Region, future vegetable production should pay more attention to K input to reduce the negative effect on soil microbial communities. PMID- 28831707 TI - Aggressive angiomyxoma of the liver: a case report and literature review. AB - BACKGROUND: Aggressive angiomyxoma (AAM) is a rare mesenchymal tumor that occurs almost exclusively in the soft tissue of the pelvis and perineum. AAM has both locally infiltrative and recurrent characteristics. Very few cases of AAM occurring outside of the pelvis and perineum have been reported. Here, we report a case of AAM originating in the liver of a 33-year-old female patient. CASE PRESENTATION: A 33-year-old woman underwent S8 subsegmentectomy after clinical diagnosis of a mucinous cystic neoplasm of the liver. Histological analysis revealed a tumor composed of spindle-shaped cells with vascular proliferation in a myxoid stroma. Immunohistochemically, the tumor cells stained positively for CD34, estrogen receptor (ER), and progesterone receptor (PgR) and negatively for S-100, EMA, CK19, CD99, HMB45, and alpha-smooth muscle actin. The tumor was diagnosed as AAM originating from the liver. The patient received no adjuvant chemotherapy. No sign of recurrence or distant metastasis has been noted for 10 months after the surgery. CONCLUSIONS: We here report a second case of AAM originating from the liver, which is an uncommon location for this particular tumor. PMID- 28831709 TI - Predictive Validation and the Re-Analysis of Cost-Effectiveness: Do We Dare to Tread? PMID- 28831708 TI - Assessing Spatial Relationships between Race, Inequality, Crime, and Gonorrhea and Chlamydia in the United States. AB - Incidence rates of chlamydia and gonorrhea reached unprecedented levels in 2015 and are concentrated in southern counties of the USA. Using incidence data from the Center for Disease Control, Moran's I analyses assessed the data for statistically significant clusters of chlamydia and gonorrhea at the county level in 46 states of the USA. Lagrange multiplier diagnostics justified selection of the spatial Durbin regression model for chlamydia and the spatial error model for gonorrhea. Rates of chlamydia (Moran's I = .37, p < .001) and gonorrhea (Moran's I = .38, p < .001) were highly clustered particularly in the southern region of the USA. Logged percent in poverty (B = .49, p < .001 and B = .48, p < .001) and racial composition of African-Americans (B = .16, p < .001 and B = .40, p < .001); Native Americans (B = .12, p < .001 and B = .20, p < .001); and Asians (B = .14, p < .001 and B = .09, p < .001) were significantly associated with greater rates of chlamydia and gonorrhea, respectively, after accounting for spatial dependence in the data. Logged rates of rates violent crimes were associated with chlamydia (B = .053, p < .001) and gonorrhea (B = .10, p < .001). Logged rates of drug crimes (.052, p < .001) were only associated with chlamydia. Metropolitan census designation was associated with logged rates of chlamydia (B = .12, p < .001) and gonorrhea (B = .24, p < .001). Spatial heterogeneity in the distribution of rates of chlamydia and gonorrhea provide important insights for strategic public health interventions in the USA and inform the allocation of limited resources for the prevention of chlamydia and gonorrhea. PMID- 28831710 TI - Intervention for patient reported urinary symptoms in prostate cancer survivors: Systematic review. AB - PURPOSE: Prostate cancer survivors can experience poor quality of life (QoL) due to urinary symptoms. Accordingly, studies on the effects of various symptom management methods for improving subjective urinary symptoms and the QoL of prostate cancer survivors have been actively conducted. This study aimed to evaluate the effects of subjective measurement of symptom management interventions for patients with prostate cancer receiving treatment. METHODS: We used PubMed, EMBASE, CINAHL, PsycInfo, and Cochrane Library CENTRAL to systematically search for randomized controlled trials published in English, through January 2017. RESULTS: We found and systematically reviewed 14 studies for symptom management intervention content, mode of delivery, session, and provider. We then conducted a meta-analysis of seven randomized controlled trials involving 846 participants, comparing symptom management with usual care. There was a small but statistically significant improvement in subjective urinary symptoms (d = -0.32, 95% CI [-0.47, -0.19], p < 0.001, I 2 = 30.3%), but QoL was not statistically significant. A subgroup analysis by intervention type and start time found statistically significant effects on subjective urinary symptoms. CONCLUSIONS: Symptom management interventions had small but statistically significant effects on urinary symptoms. However, the present findings should be interpreted with caution considering the number of studies with limited conclusions. IMPLICATIONS FOR CANCER SURVIVORS: Pre-/post-prostatectomy symptom management intervention may be recommended as a nursing intervention to improve symptom management in prostate cancer survivors. However, more research should be conducted to identify the most effective symptom management intervention. PMID- 28831711 TI - Altered insula-default mode network connectivity in fibromyalgia: a resting-state magnetoencephalographic study. AB - BACKGROUND: Fibromyalgia (FM) is a disabling chronic pain syndrome with unknown pathophysiology. Functional magnetic resonance imaging studies on FM have suggested altered brain connectivity between the insula and the default mode network (DMN). However, this connectivity change has not been characterized through direct neural signals for exploring the embedded spectrotemporal features and the pertinent clinical relevance. METHODS: We recorded the resting-state magnetoencephalographic activities of 28 patients with FM and 28 age- and sex matched controls, and analyzed the source-based functional connectivity between the insula and the DMN at 1-40 Hz by using the minimum norm estimates and imaginary coherence methods. We also measured the connectivity between the DMN and the primary visual (V1) and somatosensory (S1) cortices as intrapatient negative controls. Connectivity measurement was further correlated with the clinical parameters of FM. RESULTS: Compared with the controls, patients with FM reported more tender points (15.2+/-2.0 vs. 5.9+/-3.7) and higher total tenderness score (TTS; 29.1+/-7.0 vs. 7.7+/-5.5; both p < 0.001); they also had decreased insula-DMN connectivity at the theta band (4-8 Hz; left, p = 0.007; right, p = 0.035), but displayed unchanged V1-DMN and S1-DMN connectivity (p > 0.05). When patients with FM and the controls were combined together, the insula DMN theta connectivity was negatively correlated with the number of tender points (left insula, r = -0.428, p = 0.001; right insula, r = -0.4, p = 0.002) and TTS score (left insula, r = -0.429, p = 0.001; right insula, r = -0.389, p = 0.003). Furthermore, in patients with FM, the right insula-DMN connectivity at the beta band (13-25 Hz) was negatively correlated with the number of tender points (r = 0.532, p = 0.004) and TTS (r = -0.428, p = 0.023), and the bilateral insula-DMN connectivity at the delta band (1-4 Hz) was negatively correlated with FM Symptom Severity (left: r = -0.423, p = 0.025; right: r = -0.437, p = 0.020) and functional disability (Fibromyalgia Impact Questionnaire; left: r = -0.415, p = 0.028; right: r = -0.374, p = 0.050). CONCLUSIONS: We confirmed the frequency specific reorganization of the insula-DMN connectivity in FM. The clinical relevance of this connectivity change may warrant future studies to elucidate its causal relationship and potential as a neurological signature for FM. PMID- 28831713 TI - Improving the Crossing-SIBTEST Statistic for Detecting Non-uniform DIF. AB - This paper demonstrates that, after applying a simple modification to Li and Stout's (Psychometrika 61(4):647-677, 1996) CSIBTEST statistic, an improved variant of the statistic could be realized. It is shown that this modified version of CSIBTEST has a more direct association with the SIBTEST statistic presented by Shealy and Stout (Psychometrika 58(2):159-194, 1993). In particular, the asymptotic sampling distributions and general interpretation of the effect size estimates are the same for SIBTEST and the new CSIBTEST. Given the more natural connection to SIBTEST, it is shown that Li and Stout's hypothesis testing approach is insufficient for CSIBTEST; thus, an improved hypothesis testing procedure is required. Based on the presented arguments, a new chi-squared-based hypothesis testing approach is proposed for the modified CSIBTEST statistic. Positive results from a modest Monte Carlo simulation study strongly suggest the original CSIBTEST procedure and randomization hypothesis testing approach should be replaced by the modified statistic and hypothesis testing method. PMID- 28831712 TI - Treatment with Biologicals in Rheumatoid Arthritis: An Overview. AB - Management and therapy of rheumatoid arthritis (RA) has been revolutionized by the development and approval of the first biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumor necrosis factor (TNF) alpha at the end of the last century. Today, numerous efficacious agents with different modes of action are available and achievement of clinical remission or, at least, low disease activity is the target of therapy. Early therapeutic interventions aiming at a defined goal of therapy (treat to target) are supposed to halt inflammation, improving symptoms and signs, and preserving structural integrity of the joints in RA. Up to now, bDMARDs approved for therapy in RA include agents with five different modes of action: TNF inhibition, T cell co-stimulation blockade, IL-6 receptor inhibition, B cell depletion, and interleukin 1 inhibition. Furthermore, targeted synthetic DMARDs (tsDMARDs) inhibiting Janus kinase (JAK) and biosimilars also are approved for RA. The present review focuses on bDMARDs and tsDMARDS regarding similarities and possible drug-specific advantages in the treatment of RA. Furthermore, compounds not yet approved in RA and biosimilars are discussed. Following the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) recommendations, specific treatment of the disease will be discussed with respect to safety and efficacy. In particular, we discuss the question of favoring specific bDMARDs or tsDMARDs in the two settings of insufficient response to methotrexate and to the first bDMARD, respectively. PMID- 28831715 TI - Influence of fruit age of the Brazilian Green Dwarf coconut on the relationship between Aceria guerreronis population density and percentage of fruit damage. AB - The coconut mite, Aceria guerreronis Keifer (Acari: Eriophyidae), is one of the main coconut pests in the American, African and parts of the Asian continents, reaching densities of several thousand mites per fruit. Diagrammatic scales have been developed to standardize the estimation of the population densities of A. guerreronis according to the estimated percentage of damage, but these have not taken into account the possible effect of fruit age, although previous studies have already reported the variation in mite numbers with fruit age. The objective of this study was to re-construct the relation between damage and mite density at different fruit ages collected in an urban coconut plantation containing the green dwarf variety ranging from the beginning to nearly the end of the infestation, as regularly seen under field conditions in northeast Brazil, in order to improve future estimates with diagrammatic scales. The percentage of damage was estimated with two diagrammatic scales on a total of 470 fruits from 1 to 5 months old, from a field at Ilheus, Bahia, Brazil, determining the respective number of mites on each fruit. The results suggested that in estimates with diagrammatic scales: (1) fruit age has a major effect on the estimation of A. guerreronis densities, (2) fruits of different ages should be analyzed separately, and (3) regular evaluation of infestation levels should be done preferably on fruits of about 3-4 months old, which show the highest densities. PMID- 28831716 TI - Ultrasound assisted intensification of enzyme activity and its properties: a mini review. AB - Over the last decade, ultrasound technique has emerged as the potential technology which shows large applications in food and biotechnology processes. Earlier, ultrasound has been employed as a method of enzyme inactivation but recently, it has been found that ultrasound does not inactivate all enzymes, particularly, under mild conditions. It has been shown that the use of ultrasonic treatment at appropriate frequencies and intensity levels can lead to enhanced enzyme activity due to favourable conformational changes in protein molecules without altering its structural integrity. The present review article gives an overview of influence of ultrasound irradiation parameters (intensity, duty cycle and frequency) and enzyme related factors (enzyme concentration, temperature and pH) on the catalytic activity of enzyme during ultrasound treatment. Also, it includes the effect of ultrasound on thermal kinetic parameters and Michaelis Menten kinetic parameters (km and Vmax) of enzymes. Further, in this review, the physical and chemical effects of ultrasound on enzyme have been correlated with thermodynamic parameters (enthalpy and entropy). Various techniques used for investigating the conformation changes in enzyme after sonication have been highlighted. At the end, different techniques of immobilization for ultrasound treated enzyme have been summarized. PMID- 28831717 TI - A Randomized Trial of Brief Versus Extended Seizure Prophylaxis After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Seizures occur in 10-20% of patients with subarachnoid hemorrhage (SAH), predominantly in the acute phase. However, anticonvulsant prophylaxis remains controversial, with studies suggesting a brief course may be adequate and longer exposure may be associated with worse outcomes. Nonetheless, in the absence of controlled trials to inform practice, patients continue to receive variable chemoprophylaxis. The objective of this study was to compare brief versus extended seizure prophylaxis after aneurysmal SAH. METHODS: We performed a prospective, single-center, randomized, open-label trial of a brief (3-day) course of levetiracetam (LEV) versus extended treatment (until hospital discharge). The primary outcome was in-hospital seizure. Secondary outcomes included drug discontinuation and functional outcome. RESULTS: Eighty-four SAH patients had been randomized when the trial was terminated due to slow enrollment. In-hospital seizures occurred in three (9%) of 35 in the brief LEV group versus one (2%) of 49 in the extended group (p = 0.2). Ten (20%) of the extended group discontinued LEV prematurely, primarily due to sedation. Four of five seizures (including one pre-randomization) occurred in patients with early brain injury (EBI) on computed tomography (CT) scans (adjusted OR 12.5, 95% CI 1.2-122, p = 0.03). Good functional outcome (mRS 0-2) was more likely in the brief LEV group (83 vs. 61%, p = 0.04). CONCLUSIONS: This study was underpowered to demonstrate superiority of extended LEV for seizure prophylaxis, although a trend to benefit was seen. Seizures primarily occurred in those with radiographic EBI, suggesting targeted prophylaxis may be preferable. Larger trials are required to evaluate optimal chemoprophylaxis in SAH, especially in light of worse outcomes in those receiving extended treatment. PMID- 28831718 TI - Effects of river-lake interactions in water and sediment on phosphorus in Dongting Lake, China. AB - As a large river connected lake, Dongting Lake is influenced by anthropogenic activities and the discharge from its upstream tributaries in the lake basin and by the water recharge via a connection to the Yangtze River (YR) outside the basin. This makes the lake phosphorous cycle more complex than that in other disconnected lakes. Here, we calculated section fluxes and ran a hydrodynamic model to investigate the phosphorus (P) variations in response to the changing interactions in the water and sediment between the YR, four tributaries, and the lake. Results show that particulate P was the dominant form with a significant linear relationship with suspended sediment (r 2 = 0.906). The sediment input reduction from the YR through three water inlets, which is closely related to the Three Gorges Reservoir operation since 2003, led to a decrease in the total P (TP) concentration in the western Dongting Lake. However, the impact and range of this decrease were fairly limited. Compared with the limited effect of the YR, the raised TP flux from the Yuanjiang tributary controlled the TP concentration at the outlet of the western Dongting Lake. Apart from the influence of the YR and the tributaries, anthropogenic activities (sand dredging) in the eastern Dongting Lake also contributed to a high TP concentration around the S10 area through sediment resuspension. We suggest that, compared with the reduction in TP flux and sediment load from the connected Yangtze River outside the basin, the elements within the basin (increased TP input from tributaries and sand dredging) have a greater effect on the variations of TP in Dongting Lake. PMID- 28831719 TI - Petersen's hernia after living donor liver transplantation. AB - BACKGROUND: Hepaticojejunostomy may be used for biliary reconstruction in certain cases of liver transplantation. In this occasion, Roux-en-Y biliary reconstruction is predominantly performed. Petersen's hernia is an internal hernia that can occur after Roux-en-Y reconstruction, and it may lead to extensive ischemic changes affecting incarcerated portions of the small bowel or Roux limb resulting in severe complications with a poor prognosis. CASE PRESENTATION: The present case was a 44-year-old male who underwent living donor liver transplantation (LDLT) for familial amyloid polyneuropathy and in whom biliary reconstruction was performed with Roux-en-Y hepaticojejunostomy. Two years after liver transplantation, symptomatic bowel strangulation was diagnosed by CT examination and emergent surgery was performed accordingly. On exploration, an ischemic limb associated with Petersen's hernia was observed. Although repositioning of the incarcerated bowel loop gradually improved the color of the limb, the limb failed to completely recover to a normal color. To allow accurate evaluation for the viability of the limb, we decided to perform a second-look operation after 48 h. On re-exploration, the surface of the limb remained a dark color; however, intraoperative endoscopic findings revealed only partial necrosis of the mucosa. Next, we resected the portion of ischemic damaged limb only following side-to-side jejunojejunostomy. Consequently, redoing of biliary reconstruction could be avoided and the original hepaticojejunostomy site was preserved. Although the stricture of the remnant Roux limb occurred 1 month thereafter, it was successfully managed by balloon dilation via percutaneous transhepatic biliary drainage route. CONCLUSIONS: The occurrence of Petersen's hernia should always be considered in cases of liver transplantation with Roux-en Y biliary reconstruction. On the basis of an accurate assessment of the extent of jejunal limb injury, reanastomosis of the hepaticojejunostomy, a potentially high risk surgical procedure, can be avoided in emergent situations. PMID- 28831720 TI - The Role of the Vice Chair for Education in Departments of Psychiatry. PMID- 28831714 TI - Omega-3 fatty acid levels in red blood cell membranes and physical decline over 3 years: longitudinal data from the MAPT study. AB - Studies have shown that omega-3 polyunsaturated fatty acids (PUFAs) are associated with brain, cardiovascular, and immune function, as well as physical performance and bone health in older adults. So far, few studies have investigated the associations between PUFA status and performance-based tests of physical function. The objective of this study was to investigate the associations between the omega-3 PUFA levels (eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)) in red blood cell (RBC) membranes and physical performance, in a sample of community-dwelling older adults. This is a longitudinal observational study using data from the Multidomain Alzheimer's Disease Trial (MAPT), a randomized, placebo-controlled trial. Four hundred participants from MAPT placebo group with available PUFA data were included. Omega-3 PUFA levels in RBC membranes were measured at baseline, and their percentage of total RBC membrane fatty acid content was calculated. We dichotomized the standardized omega-3 PUFA levels in RBC membranes as low (lowest quartile) vs. high (three upper quartiles). Gait speed (in m/s) and short physical performance battery (SPPB) score (range from 0 to 12, higher is better) were used to assess physical performance at baseline and after 6, 12, 24, and 36 months. Participants were 75.2 (+/- 4.3) years old and 68% were female. Bivariate analyses found that the characteristic of the participants in the lowest quartile of omega-3 PUFA levels (Q1) and those in the three upper quartiles (Q2-Q4) was not different at baseline; only those in Q1 were slightly older. In an unadjusted model, the difference in gait speed after 3 years of follow-up was significant (- 0.09 +/- 0.03 m/s; p = 0.008) between participants in Q1 and those in Q2-Q4. In a model adjusted for age, gender, educational level, cognitive function, depressive status, body mass index, physical activity, grip strength, and their time interaction, this difference remained clinically relevant (- 0.07 +/- 0.04 m/s; p = 0.075). No difference between the two groups was found for the SPPB score development over 3 years. Older adults with subjective memory complaints and in the lower quartile of omega-3 have a faster decline on gait speed compared to people in the three upper quartiles. Other longitudinal studies are needed to explore this association and to examine mechanisms. PMID- 28831722 TI - Reduced motor competence in children with obesity is associated with structural differences in the cerebellar peduncles. AB - Previous studies have suggested that neurological factors partly explain the reduced motor competence found in many children with obesity. Accordingly, the aim of this study was to compare motor competence and white matter organization of important pathways for motor control (cerebellar peduncles) in children with and without obesity. Nineteen children with obesity and 25 children with a healthy weight, aged 7-11 years old, were included. Anthropometric measurements were taken and the level of motor competence was assessed using the Movement Assessment Battery for Children (2nd Edition). Children's brain was scanned using diffusion weighted imaging preceded by a standard anatomical scan. Fractional anisotropy and mean diffusivity were extracted from the cerebellar peduncles. Obese children's level of motor competence was significantly lower than that in healthy weight peers (p < 0.05). Additionally, significant group differences (p < 0.05) were found for values of fractional anisotropy, but not for mean diffusivity. Further analyses revealed that lower values of fractional anisotropy in the inferior (p = 0.040) and superior (p = 0.007) cerebellar peduncles were present in children with obesity compared to children with a healthy weight. After controlling for multiple comparisons (p < 0.0167), only significant differences in the superior cerebellar peduncle remained significant. Our results showed that childhood obesity is accompanied by reduced motor competence and alterations in white matter organization. This suggests that the motor difficulties of children with obesity are not solely due to carrying excess weight, which may have implications for prevention and intervention programs. PMID- 28831724 TI - Flat Epithelial Atypia on Core Biopsy and Upgrade to Cancer: a Systematic Review and Meta-Analysis. AB - BACKGROUND: No consensus exists on whether flat epithelial atypia (FEA) diagnosed percutaneously should be surgically excised. A systematic review and meta analysis of the frequency of upgrade to cancer or an atypical ductal hyperplasia (ADH) at surgical excision of FEA was performed. METHODS: Embase, MEDLINE, Scopus, and Web of Science databases from January 2003 to November 2015 were searched. The inclusion criteria required a manuscript in English with original data on FEA diagnosed percutaneously, data including the presence or absence of other concurrent high-risk lesions, and data including outcome of cancer at surgical excision. Studies were assessed for quality, and two reviewers extracted data. Random-effects meta-analysis was used to pool estimates. The impact of study-level characteristics was assessed by stratified meta-analysis and meta regression. RESULTS: The inclusion criteria was met by 32 studies. A total of 1966 core needle biopsies showed pure FEA, and 1517 (77%) showed surgical excision. The proportions of patients with upgrade to cancer varied from 0 to 42%, with an overall pooled estimate of 11.1%. Heterogeneity was observed, with the greatest impact based on whether a study included cases of FEA diagnosed before 2003. With restriction of the investigation to 16 higher-quality studies, the cancer upgrade pooled estimate was 7.5% (95% confidence interval [CI], 5.4 10.4%), and the rate of invasive cancer was 3% (95% CI 1.9-4.5%). For upgrade to ADH, data from 22 studies including 937 patients were analyzed. The proportion of patients upgraded to ADH ranged from 0 to 60%, with a pooled estimate of 17.9% overall and 18.6% among high-quality studies. CONCLUSIONS: With patient management change potential for approximately 25% of patients, this analysis supports a general recommendation for surgical excision of FEA diagnosed by core biopsy. PMID- 28831725 TI - Pyruvate Carboxylase Deficiency Mimicking Diabetic Ketoacidosis. PMID- 28831723 TI - Functional MRI for Surgery of Gliomas. AB - PURPOSE OF REVIEW: Advanced neuroimaging techniques such as functional MRI (fMRI) and diffusion MR tractography have been increasingly used at every stage of the surgical management of brain gliomas, as a means to improve tumor resection while preserving brain functions. This review provides an overview of the last advancements in the field of functional MRI techniques, with a particular focus on their current clinical use and reliability in the preoperative and intraoperative setting, as well as their future perspectives for personalized multimodal management of patients with gliomas. RECENT FINDINGS: fMRI and diffusion MR tractography give relevant insights on the anatomo-functional organization of eloquent cortical areas and subcortical connections near or inside a tumor. Task-based fMRI and diffusion tensor imaging (DTI) tractography have proven to be valid and highly sensitive tools for localizing the distinct eloquent cortical and subcortical areas before surgery in glioma patients; they also show good accuracy when compared with intraoperative stimulation mapping data. Resting-state fMRI functional connectivity as well as new advanced HARDI (high angular resolution diffusion imaging) tractography methods are improving and reshaping the role of functional MRI for surgery of gliomas, with potential benefit for personalized treatment strategies. Noninvasive functional MRI techniques may offer the opportunity to perform a multimodal assessment in brain tumors, to be integrated with intraoperative mapping and clinical data for improving surgical management and oncological and functional outcome in patients affected by gliomas. PMID- 28831726 TI - Potential utility of anti-gravity treadmills in the realm of cardiovascular stress testing. PMID- 28831727 TI - Approaches for Establishing Clinically Relevant Dissolution Specifications for Immediate Release Solid Oral Dosage Forms. AB - This manuscript represents the perspective of the Dissolution Analytical Working Group of the IQ Consortium. The intent of this manuscript is to highlight the challenges of, and to provide a recommendation on, the development of clinically relevant dissolution specifications (CRS) for immediate release (IR) solid oral dosage forms. A roadmap toward the development of CRS for IR products containing active ingredients with a non-narrow therapeutic window is discussed, within the context of mechanistic dissolution understanding, supported by in-human pharmacokinetic (PK) data. Two case studies present potential outcomes of following the CRS roadmap and setting dissolution specifications. These cases reveal some benefits and challenges of pursuing CRS with additional PK data, in light of current regulatory positions, including that of the US Food and Drug Administration (FDA), who generally favor this approach, but with the understanding that both industry and regulatory agency perspectives are still evolving in this relatively new field. The CRS roadmap discussed in this manuscript also describes a way to develop clinically relevant dissolution specifications based primarily on dissolution data for batches used in pivotal clinical studies, acknowledging that not all IR product development efforts need to be supported by additional PK studies, albeit with the associated risk of potentially unnecessarily tight manufacturing controls. Recommendations are provided on what stages during the life cycle investment into in vivo studies may be valuable. Finally, the opportunities for CRS within the context of post approval changes, Modeling and Simulation (M&S), and the application of biowaivers, are briefly discussed. PMID- 28831728 TI - Robotic radical prostatectomy with concomitant repair of inguinal hernia: is it safe? AB - Robotic radical prostatectomy (RARP) is well established as a safe and effective treatment for prostate cancer. According to published studies, patients undergoing RARP are at increased risk of being diagnosed with an inguinal hernia after RARP and are four times more likely to have an inguinal hernia repair (IHR) following RARP. Several studies have demonstrated the effectiveness and safety of IHR during RARP. Overall, it has been observed that IHR adds on average, 12-15 min in total surgical time and there were no significant differences between RARP with or without IHR with respect to postoperative complications. This study analyzes a large series of patients undergoing RARP (1100) and compares them to a group that underwent RARP with IHR (39). Between December 2008 and January 2015, 1139 patients underwent RARP at Florida Hospital in Celebration, FL. Of the total patients, 39 underwent concomitant IHR. All procedures were performed by the same surgeons (urologist and general surgeon), using the same techniques of RARP and TAPP inguinal hernia repair. After 30 days, the differences were evaluated between groups regarding surgical time, EBL and postoperative complications. The average age of patients undergoing the procedure was 61.65 years. The mean procedure time was approximately 120 min (min), with an additional period of 68 min for IHR (mean = 188; p = 0.0001). There was a significant difference in BMI between the groups, 28.3 kg/m2 for patients undergoing RARP and 26.8 kg/m2 for those who underwent RARP and IHR (p = 0.028). The EBL averaged 110.87 mL, with no significant difference between groups (p = 0371). There was no significant association between clinical stage of the patient and the type of procedure performed (p = 12:35). There was no significant difference in the presence of comorbidities and the operation preformed. There were 61 events recorded postoperatively, 57 (5.2%) among patients who underwent only RARP and 4 (10.26%) among those who had both. Taken together, the small amounts of complications in both groups prevent statistical significance. This study compared two groups of patients undergoing RARP: those with IHR and those without. Our study demonstrated an increase in surgical time; however, there was no increase in postoperative complications. From the data presented, we suggest that the performance of both procedures concomitantly is feasible and safe. PMID- 28831730 TI - Re-examining the procedure for simulating polymer Tg using molecular dynamics. AB - In this work, the poly(ethylene oxide) bulk as one example has been iteratively heated and cooled back using MD simulations to examine the effects of thermal history on the resulting Tg. It is demonstrated that, after the system is equilibrated once at the high temperatures, the simulated Tg does not exhibit a systematical shift with the thermal history, and the averaged Tg compares well with that for the single procedure, that is, adequately equilibrating at the highest temperature and cooling with the same rate to the lowest temperature. Additionally, the continuous and stepwise processes lead to almost identical Tg, density and volumetric expansive coefficients at both the glassy and rubbery states at 300 K and 1 atm. However, these results would somewhat vary with what (volume or density) are used and how to yield them. Furthermore, the stepwise processes allow one to obtain the time-dependent dynamical Tg values from the reorientation functions of the monomer vectors, which suggest greater differences within longer observation time. This work rationalizes the "golden standard" procedure to simulate polymer Tg using the MD method, and provides some key clues to obtain the reliable results (specially for comparisons). Graphical abstract The extensive molecular dynamics simulations show that the glass transition temperature (Tg) values obtained from volumetric (vol.) or density (den.) data do not exhibit a systematic shift with the thermal history (Proc.) whereas the Tg values obtained from dynamical (dyn.) data decrease and exhibit greater difference with increasing the observation time (t*). PMID- 28831729 TI - Diagnosis of Allergy to Mammals and Fish: Cross-Reactive vs. Specific Markers. AB - PURPOSE OF REVIEW: Allergen extracts are still widely used in allergy diagnosis as they are regarded as sensitive screening tools despite the fact that they may lack some minor allergens. Another drawback of extracts is their low specificity, which is due to the presence of cross-reactive allergens. Progress in allergen identification has disclosed a number of allergenic molecules of homologous sequence and structure which are present in different animal species. This review summarizes recent advances in mammalian and fish allergen identification and focuses on their clinical relevance. RECENT FINDINGS: Serum albumins and parvalbumins are well-known animal panallergens. More recently several members of the lipocalin family were found to be cross-reactive between furry animals whereas in fish, additional allergens, enolase, aldolase and collagen, were found to be important and cross-reactive allergens. New epidemiological studies have analysed the prevalence and clinical relevance of mammalian and fish components. Primary sensitization can be distinguished from cross-sensitization by using marker allergens. Although substantial progress has been made in allergen identification, only few markers are commercially available for routine clinical practice. PMID- 28831731 TI - Cost of Treatment of Febrile Acute Respiratory Infection (FARI) Among Under-Five Children Attending Health Facilities of Ballabgarh, Haryana. AB - OBJECTIVE: To estimate the expenditure incurred towards treatment of an episode of respiratory infection among under-fives in outpatient and inpatient departments of primary and secondary level health facilities. METHODS: During March 2011 - September 2012, under-five children presenting with febrile acute respiratory infection (FARI) in the outpatient (OPD) and inpatient (IPD) departments of public and private health facilities of Ballabgarh, Haryana were enrolled in the study. Children who were free from co-morbidities and whose contact number or proper address were available, were enrolled and followed up over telephone or by house visits till recovery. Information was collected on expenditure incurred towards treatment of FARI. Work loss of each day was valued as per capita national income per day. Cost of service in public facilities were supplemented by WHO-CHOICE estimates. The cost of respiratory episode in different settings are expressed in median and inter quartile range (IQR). RESULTS: One hundred fourteen children from OPD and 75 from IPD were enrolled and followed up till recovery. Among eligible children 40% and 20% in OPD and IPD were excluded respectively as they could not provide address or contact number. The median costs of an episode treated in OPD and IPD were INR 447(IQR: INR 294 669) and INR 7506.06 (IQR: INR 3765-10,406) respectively. CONCLUSIONS: Respiratory infections are responsible for substantial economic burden, especially with huge proportion of out-of-pocket expenditure. Total cost of a respiratory episode that required hospitalization was 1.5 times the per capita monthly income of an Indian. PMID- 28831732 TI - Erratum to: An MR-Conditional High-Torque Pneumatic Stepper Motor for MRI-Guided and Robot-Assisted Intervention. PMID- 28831733 TI - Pre-surgical Pulmonary Rehabilitation in Asthma Patients Undergoing Bariatric Surgery. AB - This pilot study was performed to investigate the feasibility of pre-surgical pulmonary rehabilitation (PR) in morbidly obese patients with uncontrolled asthma, undergoing bariatric surgery. Four morbidly obese female patients with asthma participated in a 12-week PR program (exercise, diet, and psychological intervention) before undergoing bariatric surgery, and the outcomes were compared to a matched group of seven female controls (bariatric surgery only). In patients who participated in PR, asthma control and asthma quality of life improved dramatically after 3 months of PR. Besides, asthma control was better at the moment of surgery. The results of this pilot study show that PR is feasible in morbidly obese asthmatics and should be considered for a selected group of patients with uncontrolled asthma before undergoing bariatric surgery. PMID- 28831734 TI - Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons. AB - Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5 hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or MU-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; alpha1 adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation. PMID- 28831735 TI - Identification, heterologous expression and characterization of a dye decolorizing peroxidase of Pleurotus sapidus. AB - The coding sequence of a peroxidase from the secretome of Pleurotus sapidus was cloned from a cDNA library. Bioinformatic analyses revealed an open reading frame of 1551 bp corresponding to a primary translation product of 516 amino acids. The DyP-type peroxidase was heterologously produced in Trichoderma reesei with an activity of 55,000 U L-1. The enzyme was purified from the culture supernatant, biochemically characterized and the kinetic parameters were determined. The enzyme has an N-terminal signal peptide composed of 62 amino acids. Analysis by Blue Native PAGE and activity staining with ABTS, as well as gel filtration chromatography showed the native dimeric state of the enzyme (115 kDa). Analysis of the substrate range revealed that the recombinant enzyme catalyzes, in addition to the conversion of some classic peroxidase substrates such as 2,2' azino-bis(3-ethylthiazoline-6-sulfonate) and substituted phenols like 2,6 dimethoxyphenol, also the decolorization of the anthraquinonic dye Reactive Blue 5. The enzyme also catalyzes bleaching of natural colorants such as beta-carotene and annatto. Surprisingly, beta-carotene was transformed in the presence and absence of H2O2 by rPsaDyP, however enzyme activity was increased by the addition of H2O2. This indicates that the rPsaDyP has an oxidase function in addition to a peroxidase activity. As a consequence of the high affinity to the characteristic substrate Reactive Blue 5 the rPsaDyP belongs functionally to the dyp-type peroxidase family. PMID- 28831736 TI - Intravascular Lymphoma in the CNS: Options for Treatment. AB - Purpose of review The purpose of this review was to discuss therapeutic manipulations and effective current interventions available to treat intravascular lymphoma in the central nervous system. Recent findings Patients experienced resolution and remission of disease for 14 months and up to 2 years after eight cycles of R-CHOP and four courses of intrathecal therapy with MTX, cytarabine, and prednisolone. Intravascular use of unfractionated heparin during therapy may contribute to better outcome. Summary Series of therapeutic avenues were analyzed and compared. The effective current treatment of intravascular lymphoma in the CNS is considered to be a combinational intrathecal methotrexate based chemotherapy with rituximab. Since intrathecal administration bypasses the blood-brain barrier, lower doses can be given, which thereby minimizes systemic toxicity. Practical use of intrathecal chemotherapy is also justified for prophylaxis in intravascular lymphoma-diagnosed patients without CNS involvement. PMID- 28831737 TI - Adjuvant Chemoradiotherapy for Non-Pretreated Gastric Cancer. AB - BACKGROUND: While the curative approach to gastric cancer includes perioperative regimens in several countries, a substantial proportion of patients may not receive treatment prior to surgery. This study examines the adjuvant provision of chemoradiotherapy (CRT) for non-pretreated patients with cancer of the stomach including the gastric cardia. METHODS: All surgically treated patients with primary adenocarcinoma of the stomach and gastric cardia diagnosed between January 2004-December 2013 were selected from the Netherlands Cancer Registry. Patients who did not receive neoadjuvant treatment were included. Early gastric cancers (cT1), postoperative deaths within 90 days, patients with metastatic disease (M1), patients who received adjuvant chemotherapy and patients with macroscopic tumor after surgery (R2) were excluded. RESULTS: Some 3277 patients underwent surgery, and 99 patients (3%) received adjuvant CRT. Treatment was more often administered in patients with a younger age (<65 years) and a high socioeconomic status (SES), in case of non-cardia cancer, positive lymph nodes, and positive resection margins (R1). Median survival time was 28 months (95% CI 17-39), compared to 35 months (95% CI 33-38) in CRT-naive patients. After adjustment for confounders, a small net benefit for adjuvant CRT was found (hazard ratio, HR: 0.75, 95% CI 0.58-0.96). In subgroup analyses, benefit was most pronounced for patients with seven or more lymph metastases. CONCLUSIONS: Marginal survival benefit was observed for adjuvant CRT in gastric cancer patients who did not receive neoadjuvant treatment. Treatment could be considered for patients with disease involving nodal invasion and those left with microscopic residual disease after surgery. PMID- 28831738 TI - Epidemiology from Tweets: Estimating Misuse of Prescription Opioids in the USA from Social Media. AB - BACKGROUND: The misuse of prescription opioids (MUPO) is a leading public health concern. Social media are playing an expanded role in public health research, but there are few methods for estimating established epidemiological metrics from social media. The purpose of this study was to demonstrate that the geographic variation of social media posts mentioning prescription opioid misuse strongly correlates with government estimates of MUPO in the last month. METHODS: We wrote software to acquire publicly available tweets from Twitter from 2012 to 2014 that contained at least one keyword related to prescription opioid use (n = 3,611,528). A medical toxicologist and emergency physician curated the list of keywords. We used the semantic distance (SemD) to automatically quantify the similarity of meaning between tweets and identify tweets that mentioned MUPO. We defined the SemD between two words as the shortest distance between the two corresponding word-centroids. Each word-centroid represented all recognized meanings of a word. We validated this automatic identification with manual curation. We used Twitter metadata to estimate the location of each tweet. We compared our estimated geographic distribution with the 2013-2015 National Surveys on Drug Usage and Health (NSDUH). RESULTS: Tweets that mentioned MUPO formed a distinct cluster far away from semantically unrelated tweets. The state by-state correlation between Twitter and NSDUH was highly significant across all NSDUH survey years. The correlation was strongest between Twitter and NSDUH data from those aged 18-25 (r = 0.94, p < 0.01 for 2012; r = 0.94, p < 0.01 for 2013; r = 0.71, p = 0.02 for 2014). The correlation was driven by discussions of opioid use, even after controlling for geographic variation in Twitter usage. CONCLUSIONS: Mentions of MUPO on Twitter correlate strongly with state-by-state NSDUH estimates of MUPO. We have also demonstrated that a natural language processing can be used to analyze social media to provide insights for syndromic toxicosurveillance. PMID- 28831739 TI - Patterns of uptake of prostate-specific membrane antigen (PSMA)-targeted 18F DCFPyL in peripheral ganglia. AB - OBJECTIVE: Radiotracers targeting prostate-specific membrane antigen (PSMA) have increasingly been recognized as showing uptake in a number of normal structures, anatomic variants, and non-prostate-cancer pathologies. We aimed to explore the frequency and degree of uptake in peripheral ganglia in patients undergoing PET with the PSMA-targeted agent 18F-DCFPyL. METHODS: A total of 98 patients who underwent 18F-DCFPyL PET/CT imaging were retrospectively analyzed. This included 76 men with prostate cancer (PCa) and 22 patients with renal cell carcinoma (RCC; 13 men, 9 women). Scans were evaluated for uptake in the cervical, stellate, celiac, lumbar and sacral ganglia. Maximum standardized uptake value corrected to body weight (SUVmax), and maximum standardized uptake value corrected to lean body mass (SULmax) were recorded for all ganglia with visible uptake above background. Ganglia-to-background ratios were calculated by dividing the SUVmax and SULmax values by the mean uptake in the ascending aorta (Aortamean) and the right gluteus muscle (Gluteusmean). RESULTS: Overall, 95 of 98 (96.9%) patients demonstrated uptake in at least one of the evaluated peripheral ganglia. With regard to the PCa cohort, the most frequent sites of radiotracer accumulation were lumbar ganglia (55/76, 72.4%), followed by the cervical ganglia (51/76, 67.1%). Bilateral uptake was found in the majority of cases [lumbar 44/55 (80%) and cervical 30/51 (58.8%)]. Additionally, discernible radiotracer uptake was recorded in 50/76 (65.8%) of the analyzed stellate ganglia and in 45/76 (59.2%) of the celiac ganglia, whereas only 5/76 (6.6%) of the sacral ganglia demonstrated 18F-DCFPyL accumulation. Similar findings were observed for patients with RCC, with the most frequent locations of radiotracer uptake in both the lumbar (20/22, 90.9%) and cervical ganglia (19/22, 86.4%). No laterality preference was found in mean PSMA-ligand uptake for either the PCa or RCC cohorts. CONCLUSION: As PSMA-targeted agents become more widely disseminated, the patterns of uptake in structures that are not directly relevant to patients' cancers must be understood. This is the first systematic evaluation of the uptake of 18F-DCFPyL in ganglia demonstrating a general trend with a descending frequency of radiotracer accumulation in lumbar, cervical, stellate, celiac, and sacral ganglia. The underlying biology that leads to variability of PSMA-targeted radiotracers in peripheral ganglia is not currently understood, but may provide opportunities for future research. PMID- 28831740 TI - Expression of miR-155 associated with Toll-like receptors 3, 7, and 9 transcription in the olfactory bulbs of cattle naturally infected with BHV5. AB - Bovine herpesvirus 5 (BHV5) infection of young cattle is frequently associated with fatal neurological disease and, as such, represents an attractive model for studying the pathogenesis of viral-induced meningoencephalitis. Following replication in the nasal mucosa, BHV5 invades the central nervous system (CNS) mainly through the olfactory pathway. The innate immune response triggered by the host face to virus replication through the olfactory route is poorly understood. Recently, an upregulation of conserved pathogen-associated molecular pattern, as Toll-like receptors (TLRs), has been demonstrated in the CNS of BHV5 experimentally infected cows. A new perspective to understand host-pathogen interactions has emerged elucidating microRNAs (miRNAs) network that interact with innate immune response during neurotropic viral infections. In this study, we demonstrated a link between the expression of TLRs 3, 7, and 9 and miR-155 transcription in the olfactory bulbs (OB) of 16 cows suffering from acute BHV5 induced neurological disease. The OBs were analyzed for viral antigens and genome, miR-155 and TLR 3, 7, and 9 expression considering three major regions: olfactory receptor neurons (ORNs), glomerular layer (GL), and mitral cell layer (ML). BHV5 antigens and viral genomes, corresponding to glycol-C gene, were detected in all OBs regions by fluorescent antibody assay (FA) and PCR, respectively. TLR 3, 7, and 9 transcripts were upregulated in ORNs and ML, yet only ORN layers revealed a positive correlation between TLR3 and miR-155 transcription. In ML, miR-155 correlated positively with all TLRs studied. Herein, our results evidence miR-155 transcription in BHV5 infected OB tissue associated to TLRs expression specifically ORNs which may be a new window for further studies. PMID- 28831741 TI - American perspective: Comparing the AHA/ACC and ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. PMID- 28831742 TI - Prevalence of sexual dysfunctions and other sexual disorders in adults with attention-deficit/hyperactivity disorder compared to the general population. AB - Attention-deficit/hyperactivity disorder (ADHD) is characterized by symptoms of inattention and/or hyperactivity and impulsivity that lead to dysfunctioning in daily life. One of the affected areas of life that has so far not been studied in ADHD is sexual functioning. The goal of this study was to assess prevalence of sexual dysfunctions and other sexual disorders among adults with ADHD. A total of n = 136 adult patients treated in a Dutch outpatient ADHD clinic filled out two questionnaires to screen for sexual dysfunctions and other sexual disorders. We compared the prevalence of sexual dysfunctions and other sexual disorders in our ADHD patient population to results from two large surveys among the general Dutch population. We found that 39% of the male and 43% of the female ADHD patients had symptoms of a sexual dysfunction, and 17% of the male and 5% of the female ADHD patients had symptoms of any other sexual disorder. Only one male patient had received a diagnosis of a sexual disorder at this clinic prior to study participation. In conclusion, sexual dysfunctions and other sexual disorders are highly prevalent in adults with ADHD. Screening for sexual disorders should be therefore standard procedure during diagnostic assessment. PMID- 28831743 TI - Recurrent establishment of de novo centromeres in the pericentromeric region of maize chromosome 3. AB - Centromeres can arise de novo from non-centromeric regions, which are often called "neocentromeres." Neocentromere formation provides the best evidence for the concept that centromere function is not determined by the underlying DNA sequences, but controlled by poorly understood epigenetic mechanisms. Numerous neocentromeres have been reported in several plant and animal species. However, it has been elusive how and why a specific chromosomal region is chosen to be a new centromere during the neocentromere activation events. We report recurrent establishment of neocentromeres in a pericentromeric region of chromosome 3 in maize (Zea mays). This latent region is located in the short arm and is only 2 Mb away from the centromere (Cen3) of chromosome 3. At least three independent neocentromere activation events, which were likely induced by different mechanisms, occurred within this latent region. We mapped the binding domains of CENH3, the centromere-specific H3 histone variant, of the three neocentromeres and analyzed the genomic and epigenomic features associated with Cen3, the de novo centromeres and an inactivated centromere derived from an ancestral chromosome. Our results indicate that lack of genes and transcription and a relatively high level of DNA methylation in this pericentromeric region may provide a favorable chromatin environment for neocentromere activation. PMID- 28831744 TI - Structural Analysis of Unsaturated Glycosphingolipids Using Shotgun Ozone-Induced Dissociation Mass Spectrometry. AB - Glycosphingolipids are essential biomolecules widely distributed across biological kingdoms yet remain relatively underexplored owing to both compositional and structural complexity. While the glycan head group has been the subject of most studies, there is paucity of reports on the lipid moiety, particularly the location of unsaturation. In this paper, ozone-induced dissociation mass spectrometry (OzID-MS) implemented in a traveling wave-based quadrupole time-of-flight (Q-ToF) mass spectrometer was applied to study unsaturated glycosphingolipids using shotgun approach. Resulting high resolution mass spectra facilitated the unambiguous identification of diagnostic OzID product ions. Using [M+Na]+ adducts of authentic standards, we observed that the long chain base and fatty acyl unsaturation had distinct reactivity with ozone. The reactivity of unsaturation in the fatty acyl chain was about 8-fold higher than that in the long chain base, which enables their straightforward differentiation. Influence of the head group, fatty acyl hydroxylation, and length of fatty acyl chain on the oxidative cleavage of double bonds was also observed. Application of this technique to bovine brain galactocerebrosides revealed co-isolated isobaric and regioisomeric species, which otherwise would be incompletely identified using contemporary collision-induced dissociation (CID) alone. These results highlight the potential of OzID-MS in glycosphingolipids research, which not only provides complementary structural information to existing CID technique but also facilitates de novo structural determination of these complex biomolecules. Graphical Abstract ?. PMID- 28831745 TI - The Ball is in Your Court: Agenda for Research to Advance the Science of Patient Preferences in the Regulatory Review of Medical Devices in the United States. PMID- 28831747 TI - Prospective evaluation of the SD BIOLINE Dengue Duo rapid test during a dengue virus epidemic. AB - Dengue virus is endemic in French Guiana with occurrence of cyclical outbreaks. There is a need for rapid tests allowing dengue laboratory diagnosis in healthcare centers scattered throughout this wide Amazonian territory. Our objective was to evaluate the real-life performance of the SD BIOLINE Dengue Duo (IgG/IgM + NS1 Ag) rapid test (RDT) during the 2012-2013 dengue epidemics. The RDT was evaluated in parallel with routine laboratory tests, PlateliaTM Dengue NS1 Ag and Focus Diagnostics Dengue Fever Virus IgM Capture DxSelect. A total of 3,347 patients with suspected dengue acute infection were evaluated. The diagnostic performances of the SD BIOLINE NS1 Ag were equivalent to Platelia NS1, 471 patients (14.1%) were NS1 Ag positive with the RDT and 14.2% with Platelia. The Cohen's Kappa coefficient was 0.86 [95%CI: 0.83-0.88], indicating an almost perfect agreement. Moreover, the sensitivity of SD BIOLINE NS1 Ag relative to the RT-PCR method was 87% [95%CI: 80-93%] and the specificity was 92% [95% CI: 87 97%]. However, the SD BIOLINE IgM test was found positive in 6.3% of the samples in comparison to 10.7% with Dx Select IgM. The Cohen's Kappa coefficient was 0.53 [95%CI: 0.47-0.58] indicating a moderate agreement. This raised concern about the SD BIOLINE IgM for the diagnostic of dengue in endemic areas. When considering only NS1 Ag results and not IgM, the RDT could be a viable solution to manage dengue outbreaks in healthcare centers where no laboratory services are available, in the early phase of the disease. PMID- 28831746 TI - The KATP channel in migraine pathophysiology: a novel therapeutic target for migraine. AB - BACKGROUND: To review the distribution and function of KATP channels, describe the use of KATP channels openers in clinical trials and make the case that these channels may play a role in headache and migraine. DISCUSSION: KATP channels are widely present in the trigeminovascular system and play an important role in the regulation of tone in cerebral and meningeal arteries. Clinical trials using synthetic KATP channel openers report headache as a prevalent-side effect in non migraine sufferers, indicating that KATP channel opening may cause headache, possibly due to vascular mechanisms. Whether KATP channel openers can provoke migraine in migraine sufferers is not known. CONCLUSION: We suggest that KATP channels may play an important role in migraine pathogenesis and could be a potential novel therapeutic anti-migraine target. PMID- 28831748 TI - Attitudes Toward Spirituality and Spiritual Care among Iranian Nurses and Nursing Students: A Cross-Sectional Study. AB - Addressing spiritual needs is taken into account as an integral part of holistic health care and also an important component of nursing practice. The aim of present study is to evaluate attitudes toward spirituality and spiritual care among nurses and nursing students at Semnan University of Medical Sciences in Iran. In this cross-sectional study, all nurses (n = 180) working in the teaching hospitals affiliated to Semnan University of Medical Sciences as well as senior nursing students (n = 50) selected by the census method. Finally, 168 individuals meeting the inclusion criteria were evaluated as the study sample. The data collection instrument was the Spirituality and Spiritual Care Rating Scale. The mean and standard deviation scores of attitudes toward spirituality and spiritual care among nurses and nursing students were 59 +/- 10.9, and the scores obtained by the majority of study population (64.3%) ranged between 32 and 62 which were at a moderate and relatively desirable level. Nurses and nursing students working in aforementioned hospitals reported positive attitudes to spirituality and spiritual care. Given the importance of spiritual care and also the moderate level of spirituality and spiritual care among nurses and nursing students in this study, institutionalization of the concept of spirituality, provision of an appropriate context to deliver such care, and also implementation of interventions in order to improve spiritual care along with other nursing skills were assumed of utmost importance. PMID- 28831749 TI - PML-IRIS in an HIV-2-infected patient presenting as Bell's palsy. AB - We present the case of an HIV-2-infected patient who developed progressive multifocal leukoencephalopathy (PML) in the setting of immune reconstitution inflammatory syndrome (IRIS) presenting as Bell's palsy. The brain MRI showed a single lesion in the facial colliculus considered initially to be ischemic in nature. This case report should alert clinicians that PML can occur in the setting of HIV-2 infection. It also illustrates the difficulty of establishing the diagnosis of PML. PMID- 28831750 TI - Imbalanced expression of polycistronic miRNA in acute myeloid leukemia. AB - miR-1 and miR-133 are clustered on the same chromosomal loci and are transcribed together as a single transcript that is positively regulated by ecotropic virus integration site-1 (EVI1). Previously, we described how miR-133 has anti tumorigenic potential through repression of EVI1 expression. It has also been reported that miR-1 is oncogenic in the case of acute myeloid leukemia (AML). Here, we show that expression of miR-1 and miR-133, which have distinct functions, is differentially regulated between AML cell lines. Interestingly, the expression of miR-1 and EVI1, which binds to the promoter of the miR-1/miR-133 cluster, is correlative. The expression levels of TDP-43, an RNA-binding protein that has been reported to increase the expression, but inhibits the activity, of miR-1, were not correlated with expression levels of miR-1 in AML cells. Taken together, our observations raise the possibility that the balance of polycistronic miRNAs is regulated post-transcriptionally in a hierarchical manner possibly involving EVI1, suggesting that the deregulation of this balance may play some role in AML cells with high EVI1 expression. PMID- 28831751 TI - Discontinuation of Biologic Therapy in Rheumatoid Arthritis: Analysis from the Corrona RA Registry. AB - INTRODUCTION: Despite the availability of multiple effective therapies, discontinuation/switching of treatment is common for many patients with rheumatoid arthritis (RA). This study was designed to examine initiation of biologic disease-modifying anti-rheumatic drugs (bDMARDs) within the Consortium of Rheumatology Researchers of North America (Corrona) RA Registry, and characterize reasons for discontinuation. METHODS: Inclusion criteria were: Corrona-registered adults (>=18 years) with RA (2002-2011); age of RA onset: >=16 years; >=6 months' follow-up after initiation of first/subsequent bDMARD. Patients receiving both tumor necrosis factor antagonists and non-TNF antagonists were included. Treatment discontinuation was defined as first report of stopping initial therapy or initiation of new bDMARD at/between visits, using a follow-up physician questionnaire. RESULTS: Overall, 6209 patients met inclusion criteria and 80.7% received TNF antagonists. Median time to discontinuation/change of therapy was 25.1 months (26.5 months with TNF antagonists vs. 20.5 months with non-TNF antagonists; log-rank p < 0.0001); 82.2, 67.3, and 51.1% of patients remained on therapy at 6, 12, and 24 months, respectively. Reasons for discontinuation were captured for 49.2% of patients, including: loss of efficacy (35.8%); physician preference (27.8%); safety (20.1%); patient preference (17.9%); and no access to treatment (9.0%). Baseline factors with greatest correlation to discontinuation were modified Health Assessment Questionnaire scores, patient-reported anxiety/depression, initiation of bDMARD treatment in 2007-2010 versus 2002-2003, and Clinical Disease Activity Index scores. CONCLUSIONS: Almost one-third of patients in the US discontinue currently available bDMARD therapies for RA by 12 months and almost half by 24 months, most commonly due to loss of efficacy. FUNDING: Corrona LLC and MedImmune. PMID- 28831752 TI - Longitudinal Assessment of the Effect of Atrasentan on Thoracic Bioimpedance in Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. OBJECTIVE: We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. METHODS: Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. RESULTS: Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). CONCLUSIONS: We conclude that thoracic bioimpedance did not reflect changes in weight gain or edema with atrasentan treatment in this study. However, the sample size was small, and it may be of interest to explore the use of thoracic bioimpedance in a larger population to understand its potential clinical use in monitoring fluid retention in patients with chronic kidney disease who receive ET receptor antagonists. PMID- 28831754 TI - Comparative therapeutic effect of steroidal and non-steroidal anti-inflammatory drugs on pro-inflammatory cytokine production in water buffalo calves (Bubalus bubalis) naturally infected with bronchopneumonia: a randomized clinical trial. AB - In the current study, we compared the therapeutic effects of a non-steroidal and a steroidal anti-inflammatory drug on the production of pro-inflammatory cytokines, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-12p40 (IL-12p40), interferon gamma (IFNgamma), and tumor necrosis factor alpha (TNF alpha) in the blood of water buffalo (Bubalus bubalis) calves naturally infected by bronchopneumonia. Twenty-seven buffalo calves (7 +/- 2-month-old, 163 +/- 12 kg) reared in smallholder farms in El-Dakahlia province in Egypt were identified to have bronchopneumonia and randomly allocated into three equal groups. Ten clinically healthy buffalo calves with negative bronchoalveolar lavage results were served as negative control. Diseased calves were treated with tulathromycin alone, a combination of tulathromycin with dexamethasone (steroidal anti inflammatory drug) or tulathromycin with flunixin meglumine (non-steroidal anti inflammatory drug). The results revealed significant elevations (P < 0.05) in the production of selected cytokines in all diseased calves in comparison with healthy animals. Six days post-treatment, a significant inhibition (P < 0.05) in the production of all assessed cytokines was observed in the blood of all treated calves. Interestingly, the serum concentrations of IL-1beta and IL-12p40 were returned to the normal levels in pneumonic calves treated with the combination therapy of tulathromycin and flunixin meglumine. A strong significant positive correlation (P < 0.05) was detected between clinical sum scoring and IL-12p40 and TNF-alpha concentrations. The obtained results indicate the selectively potent anti-inflammatory effect of flunixin meglumine on the production of pro inflammatory cytokines in pneumonic buffalo calves and highlight the efficacy of flunixin meglumine in the treatment of bronchopneumonia in buffalo calves when used in combination with tulathromycin. PMID- 28831753 TI - Pharmacological Management of Restless Legs Syndrome and Periodic Limb Movement Disorder in Children. AB - Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are under recognized sleep disorders in children and adolescents. Several recent epidemiological studies have shown that RLS and PLMD are common in the pediatric population, and if left untreated, may lead to cardiovascular and neurocognitive consequences. Therefore, early diagnosis and intervention may help preventing long-term consequences. The management of RLS and PLMD in children involves both non-pharmacologic and pharmacologic approaches. Although there is emerging literature supporting medical therapy in children with RLS and PLMD, the overall experiences with these medications remain limited. Most children and adolescents with RLS and PLMD have low iron storage; therefore, iron therapy should be considered as the first line of treatment in children. Currently, there is no FDA approved medication for RLS and PLMD in children. There is increasing evidence on the effectiveness of dopaminergic medications in children but the data are quite limited. Other medications such as alpha2delta-1 ligands, benzodiazepine, and clonidine are frequently used, but have not been adequately investigated in children. Further studies are needed to evaluate the safety and efficacy of pharmacologic therapy for RLS and PLMD in children. PMID- 28831755 TI - A model of natural degradation of 17-alpha-ethinylestradiol in surface water and identification of degradation products by GC-MS. AB - Over the past decade, the environment has been polluted by a wide spectrum of exogenous chemicals and environmental analysis has become one of the most progressive parts of analytical research. The aim of this work was to determine the kinetics of natural degradation, and to identify the degradation products of the massively used estrogenic drug, 17-alpha-ethinylestradiol. The photodegradation, oxidation and thermostability conditions were selected according to ICH requirements for pharmaceutical stability testing. A simple 72-h photodegradation study in purified water exhibited significant first-order kinetics with the kinetic constant k = 0.0303 h-1, and degradation halftime 22.8 h. The basic halftime could be reduced to 17.1 h by the addition of sea salt, and increase in temperature. Monohydroxy, dihydroxy and dehydrogenated derivatives of ethinylestradiol with intact steroidal structure were identified as major degradation products resulting from simple photodegradation. The addition of an oxidative agent significantly accelerated the degradation rate; combined with higher temperature, the degradation halftime was reduced to 1.1 h with the first order kinetic constant k = 0.632 h-1. TOC analysis showed a notable decrease of organic mass (18% in 3 days) during oxidation experiments, and confirmed the degradation of steroidal structure. PMID- 28831756 TI - The efficacy of transcranial magnetic stimulation on migraine: a meta-analysis of randomized controlled trails. AB - OBJECTIVES: As a non-invasive therapy, whether transcranial magnetic stimulation (TMS) is effective on migraine. This article was aimed to assess the efficacy of TMS on migraine based on randomized controlled trails (RCTs). METHODS: We searched PubMed, Embase and Cochrane Library electronic databases for published studies which compared TMS group with sham group, conducted a meta-analysis of all RCTs. RESULTS: Five studies, consisting of 313 migraine patients, were identified. Single-pulse transcranial magnetic stimulation is effective for the acute treatment of migraine with aura after the first attack (p = 0.02). And, the efficacy of TMS on chronic migraine was not significant (OR 2.93; 95% CI 0.71 12.15; p = 0.14). CONCLUSIONS: TMS is effective for migraine based on the studies included in the article. PMID- 28831757 TI - Development of a circulation direct sampling and monitoring system for O2 and CO2 concentrations in the gas-liquid phases of shake-flask systems during microbial cell culture. AB - Monitoring the environmental factors during shake-flask culture of microorganisms can help to optimise the initial steps of bioprocess development. Herein, we developed a circulation direct monitoring and sampling system (CDMSS) that can monitor the behaviour of CO2 and O2 in the gas-liquid phases and obtain a sample without interrupting the shaking of the culture in Erlenmeyer flasks capped with breathable culture plugs. Shake-flask culturing of Escherichia coli using this set-up indicated that a high concentration of CO2 accumulated not only in the headspace (maximum ~100 mg/L) but also in the culture broth (maximum ~85 mg/L) during the logarithmic phase (4.5-9.0 h). By packing a CO2 absorbent in the gas circulation unit of CDMSS, a specialised shake-flask culture was developed to remove CO2 from the headspace. It was posited that removing CO2 from the headspace would suppress increases in the dissolved CO2 concentration in the culture broth (maximum ~15 mg/L). Furthermore, the logarithmic growth phase (4.5 12.0 h) was extended, the U.O.D.580 and pH value increased, and acetic acid concentration was reduced, compared with the control. To our knowledge, this is the first report of a method aimed at improving the growth of E. coli cells without changing the composition of the medium, temperature, and shaking conditions. PMID- 28831758 TI - Inter-partner and Temporal Variations in the Perception of Sexual Risk for HIV. AB - This study uses longitudinal qualitative methods to examine how gay and bisexual men perceive sexual risk across both a variety of partners and across time. Over ten weeks, participants completed three quantitative personal relationship diaries (PRD) describing sexual encounters during that time period. Participants then completed a timeline-based individual in-depth interview to unpack the PRD data. Participants used multiple factors to determine their own sexual risk (e.g., type of sex, partner concurrency, emotional connections), which often resulted in inconsistencies in defining sexual risk and determining the level of risk both within and across partners and across time. These findings can inform HIV prevention messages and programming. PMID- 28831759 TI - Evidence of Concussion Signs in National Rugby League Match Play: a Video Review and Validation Study. AB - BACKGROUND: Many professional sports have introduced sideline video review to help recognise concussions. The reliability and validity of identifying clinical and observable signs of concussion using video analysis has not been extensively explored. This study examined the reliability and validity of clinical signs of concussion using video analysis in the National Rugby League (NRL). METHODS: All 201 professional NRL matches from the 2014 season were reviewed to document six signs of possible concussion (unresponsiveness, slow to get up, clutching/shaking head, gait ataxia, vacant stare, and seizure). RESULTS: A total of 127,062 tackles were reviewed. Getting up slowly was the most common observable sign (2240 times in the season, 1.8% of all tackles) but only 223 times where it appeared to be a possible concussion (0.2% of all tackles and 10.0% of the times it occurred). Additionally, clutching/shaking the head occurred 361 times (on 212 occasions this sign appeared to be due to a possible concussion), gait ataxia was observed 102 times, a vacant stare was noted 98 times, unresponsiveness 52 times, and a possible seizure 4 times. On 383 occasions, one or more of the observable signs were identified and deemed associated with a possible concussion. There were 175 incidences in which a player appeared to demonstrate two or more concussion signs, and 54 incidences where a player appeared to demonstrate three or more concussion signs. A total of 60 diagnosed concussions occurred, and the concussion interchange rule was activated 167 times. Intra-rater reliability (kappa = 0.65-1.00) was moderate to perfect for all six video signs; however, the inter-rater reliability was not as strong (kappa = 0.22-0.76). Most of the signs had relatively low sensitivity (0.18-0.75), but high specificity (0.85-1.00). CONCLUSIONS: Using video replay, observable signs of concussion appear to be sensitive to concussion diagnoses when reviewing known injuries among professional rugby league players. When reviewing an entire season, however, certain signs occur very commonly and did not identify concussion. Thus, the implementation of video review in the NRL is challenging, but can provide a useful addition to sideline concussion identification and removal from play decisions. PMID- 28831760 TI - Tracheoesophageal fistula after total resection of gastric conduit for gastro aortic fistula due to gastric ulcer. AB - BACKGROUND: Tracheoesophageal fistula (TEF) is a rare but life-threatening complication after esophagectomy. It has a high mortality rate and often leads to severe aspiration pneumonia. Various types of surgical repair procedures have been reported, but the optimal management of TEF is challenging and controversial. Treatment should be individualized to each patient. CASE PRESENTATION: A 66-year-old female underwent transthoracic esophagectomy with gastric tube reconstruction and an intrathoracic anastomosis for esophageal cancer. Three years later, she had hematemesis and was diagnosed with a gastro aortic fistula due to a gastric ulcer. She underwent endovascular aortic repair urgently at another hospital. Two days later, she underwent total resection of the gastric tube, during which time an injury to the trachea occurred; it was repaired by patching the stump of the esophagus to the injury site. Two months later, descending aortic replacement was performed due to infection of the stent graft. Six months after the first operation, a TEF developed. The patient was referred to our hospital for further treatment. The fistula was ligated and divided via a cervical approach, and a pectoralis major muscle flap was used to cover the defect. Esophageal reconstruction with the pedunculated jejunum was performed via a subcutaneous route. The postoperative course was uneventful. The patient was discharged after 6 months of physical and dysphagia rehabilitation. CONCLUSION: A TEF located near the cervicothoracic border was successfully treated with a pectoralis major muscle flap through a cervical approach. Total resection of a gastric conduit in the posterior mediastinum carries a risk of tracheobronchial injury; however, if such an injury occurs, surgeons should be able to repair the injury using a suitable flap depending on the injury site. PMID- 28831761 TI - Laparoscopic repair of parahiatal hernia after esophagectomy: a case report. AB - BACKGROUND: Diaphragmatic hernia is a potential complication of esophagectomy, which usually occurs as a hiatal hernia and more frequently after minimally invasive esophagectomy. Parahiatal hernia is a rare form of diaphragmatic hernia, and to the best of our knowledge, parahiatal hernia after esophagectomy has not been previously reported. Here, we report a case of parahiatal hernia after esophagectomy that was successfully managed laparoscopically. CASE PRESENTATION: A 73-year-old man underwent thoracoscopic esophagectomy for esophageal cancer with gastric tube reconstruction via the posterior mediastinum. Postoperative morbidity was ileus, which required conservative treatment, and intestinal obstruction for which operation with laparotomy was necessary. He was admitted with abdominal pain and vomiting at 15 months after esophagectomy. Abdominal X ray revealed colon gas in the intrathoracic space. A barium enema examination showed a transverse colon incarcerated in the intrathoracic space. The patient was preoperatively diagnosed with hiatal hernia after esophagectomy, and laparoscopic hernia repair was performed. During the surgery, the hiatus was found to be intact, and the defect was clearly separated from the left crus of the diaphragm. Parahiatal hernia was the operative diagnosis. The incarcerated colon was repositioned in the abdominal cavity, and the defect was repaired using a composite mesh. CONCLUSIONS: Laparoscopic surgery was found to be effective for the diagnosis and repair of parahiatal hernia. PMID- 28831762 TI - Survey of methanotrophic diversity in various ecosystems by degenerate methane monooxygenase gene primers. AB - Methane is the second most important greenhouse gas contributing to about 20% of global warming. Its mitigation is conducted by methane oxidizing bacteria that act as a biofilter using methane as their energy and carbon source. Since their first discovery in 1906, methanotrophs have been studied using a complementary array of methods. One of the most used molecular methods involves PCR amplification of the functional gene marker for the diagnostic of copper and iron containing particulate methane monooxygenase. To investigate the diversity of methanotrophs and to extend their possible molecular detection, we designed a new set of degenerate methane monooxygenase primers to target an 850 nucleotide long sequence stretch from pmoC to pmoA. The primers were based on all available full genomic pmoCAB operons. The newly designed primers were tested on various pure cultures, enrichment cultures and environmental samples using PCR. The results demonstrated that this primer set has the ability to correctly amplify the about 850 nucleotide long pmoCA product from Alphaproteobacteria, Gammaproteobacteria, Verrucomicrobia and the NC10 phyla methanotrophs. The new primer set will thus be a valuable tool to screen ecosystems and can be applied in conjunction with previously used pmoA primers to extend the diversity of currently known methane oxidizing bacteria. PMID- 28831763 TI - Relationship between magnetic resonance imaging findings, radiological grading, psychological distress and pain in patients with symptomatic knee osteoarthritis. AB - BACKGROUND: Synovial hypertrophy, synovial effusions, and abnormalities in the subchondral bone play a key role in the pathogenesis of osteoarthritis (OA) and are associated with pain. Understanding and careful clinical assessment together with better imaging such as magnetic resonance imaging (MRI) of the knee may improve treatment strategies. The aim of this cross-sectional study was to investigate the associations between the structural findings on MRI (bone marrow lesions [BMLs], synovitis, cartilage defects, meniscal lesions), X-ray examination (Kellgren and Lawrence [K/L] grade), and psychological aspects with pain in patients with knee osteoarthritis (KOA). METHODS: In this study, patients with symptomatic KOA were included. Knee radiographs were acquired and scored according to the K/L score. MRI was performed with a 1.5 T whole-body scanner; the presence of the following alterations was collected: BMLs, infrapatellar fat pad (IFP) synovitis, condral defects, and meniscal tears. Knee pain was assessed with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. The Mental Component Summary Scale Score (MCS) of the Medical Outcomes Study Short-Form 36 Health Survey (SF-36) questionnaire was used to evaluate psychological impact. RESULTS: BMLs were detected in 57 (38.3%) subjects of 149 participants (aged 51-81 years, female 75.8%). Cartilage defects were found in 91.9% of patients, IFP synovitis in 37.5%, meniscal lesions in 34.9%. In multiple regression analyses, WOMAC knee pain was significantly associated with the volume of the BMLs (p = 0.0001), IFP synovitis (p = 0.0036), and SF-36 MCS (p = 0.0001), but not with K/L grades, meniscal lesion score, cartilage defect, sex, age, educational level, disease duration and BMI. CONCLUSION: In symptomatic KOA patients, MRI features, such as larger BMLs, IFP synovitis, and high levels of psychological distress, are associated with greater knee pain. Confirmation of these findings in the prospective studies of KOA is needed. PMID- 28831764 TI - Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns. AB - BACKGROUND: In Parkinson's disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [18F]FDG-PET (to demonstrate brain metabolism in awake animals), [18F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model. RESULTS: We found unilateral nigro striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [18F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation. CONCLUSIONS: Our results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated. PMID- 28831765 TI - Validation of transpulmonary thermodilution variables in hemodynamically stable patients with heart diseases. AB - BACKGROUND: Transpulmonary thermodilution is recommended in the treatment of critically ill patients presenting with complex shock. However, so far it has not been validated in hemodynamically stable patients with heart disease. METHODS: We assessed the validity of cardiac output, global end-diastolic volume index (GEDVI), an established marker of preload thought to reflect the volume of all four heart chambers, global ejection fraction (GEF) and cardiac function index (CFI) as variables of cardiac function, and extravascular lung water index (EVLWI) as indicator of pulmonary edema in 29 patients undergoing elective left and right heart catheterization including left ventricular angiography with stable coronary heart disease and normal cardiac function (controls, n = 11), moderate-to-severe aortic valve stenosis (AS, n = 10), or dilated cardiomyopathy (DCM, n = 8). RESULTS: Cardiac output was similar in controls, AS, and DCM, with good correlation between transpulmonary thermodilution and pulmonary artery catheter using the Fick method (r = 0.69, p < 0.0001). Left ventricular end diastolic volume was normal in controls and AS, but significantly higher in DCM (104 +/- 37 vs 135 +/- 63 vs 234 +/- 24 ml, p < 0.01). GEDVI did not differentiate between patients with normal and patients with enlarged left ventricular end-diastolic volume (848 +/- 128 vs 882 +/- 213 ml m-2, p = 0.60). No difference in GEF and CFI was found between patients with normal and patients with reduced left ventricular ejection fraction. Patients with AS but not DCM had higher EVLWI than controls (9 +/- 2 vs 12 +/- 4 vs 11 +/- 3 ml kg-1, p = 0.04), while there was only a trend in pulmonary artery occlusion pressure (8 +/- 3 vs 10 +/- 5 vs 14 +/- 7 mmHg, p = 0.05). CONCLUSIONS: Cardiac output measurement by transpulmonary thermodilution is unaffected by differences in ventricular size and outflow obstruction. However, GEDVI did not identify markedly enlarged left ventricular end-diastolic volumes, and neither GEF nor CFI reflected the increased heart chamber volumes and markedly impaired left ventricular function in patients with DCM. In contrast, EVLWI is probably a sensitive marker of subclinical pulmonary edema particularly in patients with elevated left ventricular-filling pressure irrespective of differences in left ventricular function. PMID- 28831766 TI - NMR resonance assignments of the EVH1 domain of neurofibromin's recruitment factor Spred1. AB - Neurofibromin and Sprouty-related EVH1 domain-containing protein 1 (Spred1) both act as negative regulators of the mitogen-activated protein kinase pathway and are associated with the rare diseases Neurofibromatosis type 1 and Legius syndrome, respectively. Spred1 recruits the major GTPase activating protein (GAP) neurofibromin from the cytosol to the membrane in order to inactivate the small G protein Ras. These functions are dependent on the N-terminal EVH1 domain and the C-terminal Sprouty domain of Spred1 whereas the former specifically recognizes the GAP related domain of neurofibromin and the latter is responsible for membrane targeting. Within the GAP domain, Spred1 binding depends on the GAPex portion which is dispensable for Ras inactivation. In a first step towards the characterization of the Neurofibromin Spred1 interface in solution we assigned backbone and side chain 1H, 13C, and 15N chemical shifts of the Spred1 derived EVH1 domain. Our chemical shift data analysis indicate seven consecutive beta strands followed by a C-terminal alpha-helix which is in agreement with the previously reported crystal structure of Spred1(EVH1). Our data provide a framework for further analysis of the function of patient-derived mutations associated with rare diseases. PMID- 28831767 TI - The combination of indocyanine green clearance test and model for end-stage liver disease score predicts early graft outcome after liver transplantation. AB - Early allograft dysfunction (EAD) and early postoperative complications are two important clinical endpoints when evaluating clinical outcomes of liver transplantation (LT). We developed and validated two ICGR15-MELD models in 87 liver transplant recipients for predicting EAD and early postoperative complications after LT by incorporating the quantitative liver function tests (ICGR15) into the MELD score. Eighty seven consecutive patients who underwent LT were collected and divided into a training cohort (n = 61) and an internal validation cohort (n = 26). For predicting EAD after LT, the area under curve (AUC) for ICGR15-MELD score was 0.876, with a sensitivity of 92.0% and a specificity of 75.0%, which is better than MELD score or ICGR15 alone. The recipients with a ICGR15-MELD score >=0.243 have a higher incidence of EAD than those with a ICGR15-MELD score <0.243 (P <0.001). For predicting early postoperative complications, the AUC of ICGR15-MELD score was 0.832, with a sensitivity of 90.9% and a specificity of 71.0%. Those recipients with an ICGR15 MELD score >=0.098 have a higher incidence of early postoperative complications than those with an ICGR15-MELD score <0.098 (P < 0.001). Finally, application of the two ICGR15-MELD models in the validation cohort still gave good accuracy (AUC, 0.835 and 0.826, respectively) in predicting EAD and early postoperative complications after LT. The combination of quantitative liver function tests (ICGR15) and the preoperative MELD score is a reliable and effective predictor of EAD and early postoperative complications after LT, which is better than MELD score or ICGR15 alone. PMID- 28831768 TI - JCPyV microRNA in plasma inversely correlates with JCPyV seropositivity among long-term natalizumab-treated relapsing-remitting multiple sclerosis patients. AB - Sensitive biomarkers are needed to better manage multiple sclerosis (MS) patients for natalizumab (NTZ)-associated risk of progressive multifocal leukoencephalopathy (PML). A currently used risk stratification algorithm, mainly based on JC polyomavirus (JCPyV) serology, has not led to a reduction of PML incidence. Therefore, this study was designed to evaluate the presence and prevalence of JCPyV miRNAs in plasma of NTZ-treated MS patients, and to explore their biomarker potential for NTZ-associated PML risk assessment. Altogether, 102 plasma samples from 49 NTZ-treated and 28 interferon-beta (IFN-beta)-treated relapsing-remitting MS patients, and 25 healthy controls (HCs) were analyzed for jcv-miR-J1-5p (5p miRNA) and jcv-miR-J1-3p (3p miRNA) expression. The overall detection rate of 5p miRNA was 84% (41/49) among NTZ-treated patients, 75% (21/28) among IFN-beta-treated patients, and 92% (23/25) in HCs. Relative 5p miRNA expression levels were lower in NTZ-treated patients as compared to patients treated with IFN-beta (p = 0.027) but not to HCs. Moreover, 5p miRNA expression inversely correlated with anti-JCPyV antibody index among JCPyV seropositive long-term NTZ-treated patients (r = -0.756; p = 0.002). The overall detection rate of 3p miRNA was low. Our results suggest that JCPyV miRNA in plasma may be linked to the reactivation of persistent JCPyV, to enhanced virus replication, and eventually to the risk of developing PML among NTZ-treated MS patients. However, further study is warranted in a larger data set including samples from PML patients to confirm the clinical relevance of JCPyV miRNA as a sign of/in viral reactivation, and to identify its potential to predict developing PML risk. PMID- 28831769 TI - A two-stage temperature control strategy enhances extracellular secretion of recombinant alpha-cyclodextrin glucosyltransferase in Escherichia coli. AB - The effects of temperature on extracellular secretion of the alpha-cyclodextrin glucosyltransferase (alpha-CGTase) from Paenibacillus macerans JFB05-01 by Escherichia coli were investigated. When protein expression was induced at constant temperature, the greatest amount of extracellular recombinant alpha CGTase was produced at 25 degrees C. Higher or lower induction temperatures were not conducive to extracellular secretion of recombinant alpha-CGTase. To enhance extracellular secretion of alpha-CGTase by E. coli, a two-stage temperature control strategy was adopted. When expression was induced at 25 degrees C for 32 h, and then the temperature was shifted to 30 degrees C, the extracellular alpha CGTase activity at 90 h was 45% higher than that observed when induction was performed at a constant temperature of 25 degrees C. Further experiments suggested that raising the induction temperature can benefit the transport of recombinant enzyme and compensate for the decreased rate of recombinant enzyme synthesis during the later stage of expression. This report provides a new method of optimizing the secretory expression of recombinant enzymes by E. coli. PMID- 28831770 TI - Distribution of Species of Dermatophyte Among Patients at a Dermatology Centre of Nghean Province, Vietnam, 2015-2016. AB - INTRODUCTION: Vietnam is a tropical country so fungal diseases including dermatophytosis may be prevalent, but epidemiological profiles of agents responsible for the infection have rarely been reported. OBJECTIVE: To find out the distribution of dermatophytes among patients living in a central province of Vietnam. METHODS: We examined dermatophyte infections in patients with lesions suspected of dermatophytosis referred to the Nghean provincial leprosy and dermatology centre from August 2015 to August 2016. The speciation of dermatophyte was performed by conventional and molecular approaches. RESULTS: One hundred and thirty-six patients (90 males and 46 females) were included. Those aged from 11 to 30 contribute 59.1%. The most common agent found was Trichophyton rubrum (66.9%), followed by T. interdigitale (12.5%), T. tonsurans (9.6%), Microsporum incurvatum (8.1%), and the less frequent species were M. canis (2.2%) and T. violaceum (0.7%). Epidermophyton floccosum was not reported. T. rubrum were more common in men (74.4%) than in women (52.2%), while T. interdigitale and M. incurvatum were more common in women (21.7 and 15.2%) than in men (7.8 and 4.4%). Patients infected with Microsporum spp. had small-sized lesions for only 3 months, while those affected by Trichophyton spp. had large-sized lesions with longer duration. CONCLUSION: Trichophyton species are the predominant agents of infection in Nghean province, while Epidermophyton species is absent. Additional investigations are required to clarify the epidemiological profile of dermatophytes in Vietnam. PMID- 28831772 TI - From visualizing nerves to visualizing blocks: a natural trend? PMID- 28831771 TI - Role of illumination intensity in microcystin development using Microcystis aeruginosa as the model algae. AB - Microcystis aeruginosa (M. aeruginosa) is one of the most common genera of cyanobacteria in algal blooms. In the present work, the impact of the illumination intensity on the growth of M. aeruginosa has been studied and a grinding method for the extraction of intracellular microcystins (MCs) was developed. The variations of algal density, pH, total phosphorus (TP), and total nitrogen (TN) have been investigated during MCs' culturing period. Results showed that the extraction efficiency of MC-YR by the grinding method was 275% higher than the sonication method, and the extraction efficiencies of MC-RR and MC-LR by the grinding method were similar to the sonication method. The optimal illumination intensity for M. aeruginosa was found to be 19-38 MUmol m-2 s-1 with suitable pH range of 7.5-10.5. Active release of extracellular MCs was not significantly observed when illumination intensities were <= 38 MUmol m-2 s-1. Furthermore, the intracellular MC yields under different illumination intensities were found to be a relatively stable level. However, excess illumination intensity (>= 47 MUmol m-2 s-1) led to the lysis of algal cell and increased the concentrations of extracellular MCs, with MC-RR as the dominant compound. The calculated intracellular/extracellular MCs ratios for MC-RR, MC-LR, and MC-YR were 2.38 (N = 100, SD = 2.44), 2.68 (N = 64, SD = 3.48), and 1.25 (N = 30, SD = 1.64), respectively. Strong illumination intensity and cell lysis were found to be the two major factors influencing the release of extracellular MCs. PMID- 28831773 TI - Improved Treatment and Utilization of Rice Straw by Coprinopsis cinerea. AB - As one of the most abundant renewable resources, rice straw is an attractive lignocellulosic material for animal feeding or for the production of biochemical. An appropriate pre-treatment technique is essential for converting rice straw to rich fodder or biofuel. Based on previous work, Coprinopsis cinerea can grow on rice straw medium and therefore it is useful for the treatment of rice straw. However, little is known regarding its degradation systems and nutrition values. In this study, we firstly found that C. cinerea could grow rapidly on rice straw without any additives by the production of a series of enzymes (laccase, cellulase, and xylanase) and that the microstructure and contents of rice straw changed significantly after being treated by C. cinerea. We propose that a possible underlying mechanism exists in the degradation. Moreover, C. cinerea has a high nutrition value (23.5% crude protein and 22.2% total amino acids). Hence, fermented rice straw with mycelium could be a good animal feedstuff resource instead of expensive forage. The direct usage of C. cinerea treatment is expected to be a practical, cost-effective, and environmental-friendly approach for enhancing the nutritive value and digestibility of rice straw. PMID- 28831774 TI - Humanized mice: models for evaluating NeuroHIV and cure strategies. AB - While the human immunodeficiency virus (HIV) epidemic was initially characterized by a high prevalence of severe and widespread neurological pathologies, the development of better treatments to suppress viremia over years and even decades has mitigated many of the severe neurological pathologies previously observed. Despite effective treatment, mild neurocognitive impairment and premature cognitive aging are observed in HIV-infected individuals, suggesting a changing but ongoing role of HIV infection in the central nervous system (CNS). Although current therapies are effective in suppressing viremia, they are not curative and patients must remain on life-long treatment or risk recrudescence of virus. Important for the development and evaluation of a cure for HIV will be animal models that recapitulate critical aspects of infection in vivo. In the following, we seek to summarize some of the recent developments in humanized mouse models and their usefulness in modeling HIV infection of the CNS and HIV cure strategies. PMID- 28831775 TI - Erratum to: Assessment of kidney function in children by enzymatic determination of 2-h or 24-h creatinine clearance: comparison with inulin clearance. PMID- 28831777 TI - Counterpoint: Should Radiation Therapy After Surgery for Ductal Carcinoma In Situ Be Standard Practice? RT Should Not Be Standard Practice After Surgery for DCIS. PMID- 28831776 TI - Persistent post-traumatic headache vs. migraine: an MRI study demonstrating differences in brain structure. AB - BACKGROUND: The majority of individuals with post-traumatic headache have symptoms that are indistinguishable from migraine. The overlap in symptoms amongst these individuals raises the question as to whether post-traumatic headache has a unique pathophysiology or if head trauma triggers migraine. The objective of this study was to compare brain structure in individuals with persistent post-traumatic headache (i.e. headache lasting at least 3 months following a traumatic brain injury) attributed to mild traumatic brain injury to that of individuals with migraine. METHODS: Twenty-eight individuals with persistent post-traumatic headache attributed to mild traumatic brain injury and 28 individuals with migraine underwent brain magnetic resonance imaging on a 3 T scanner. Regional volumes, cortical thickness, surface area and curvature measurements were calculated from T1-weighted sequences and compared between subject groups using ANCOVA. MRI data from 28 healthy control subjects were used to interpret the differences in brain structure between migraine and persistent post-traumatic headache. RESULTS: Differences in regional volumes, cortical thickness, surface area and brain curvature were identified when comparing the group of individuals with persistent post-traumatic headache to the group with migraine. Structure was different between groups for regions within the right lateral orbitofrontal lobe, left caudal middle frontal lobe, left superior frontal lobe, left precuneus and right supramarginal gyrus (p < .05). Considering these regions only, there were differences between individuals with persistent post-traumatic headache and healthy controls within the right lateral orbitofrontal lobe, right supramarginal gyrus, and left superior frontal lobe and no differences when comparing the migraine cohort to healthy controls. CONCLUSIONS: In conclusion, persistent post-traumatic headache and migraine are associated with differences in brain structure, perhaps suggesting differences in their underlying pathophysiology. Additional studies are needed to further delineate similarities and differences in brain structure and function that are associated with post-traumatic headache and migraine and to determine their specificity for each of the headache types. PMID- 28831778 TI - Very late stent thrombosis in everolimus-eluting stent with predisposing mechanical factors: Differential features. AB - no abstract. PMID- 28831779 TI - Double left anterior descending artery: Congenital anomaly or normal variant of coronary arteries? PMID- 28831780 TI - Intrapericardial paraganglioma: The role of integrated advanced multi-modality cardiac imaging for the assessment and management of rare primary cardiac tumors. AB - N/A. PMID- 28831781 TI - A huge left atrial mass "not a myxoma". AB - N/A. PMID- 28831782 TI - Percutaneous closure of the inadvertent subclavian artery cannulation during pacemaker implantation. AB - N/A. PMID- 28831783 TI - Baloon atrial septostomy in pulmonary arterial hypertension: Atrial flow regulator - New therapeutic option. PMID- 28831784 TI - Response to the comment on the article entitled "Balloon atrial septostomy in pulmonary arterial hypertension: A beneficial effect on the control of rhythm abnormalities". PMID- 28831785 TI - Clinical, Pathologic, and Genetic Features of Collagen VI-Related Myopathy in Korea. AB - BACKGROUND AND PURPOSE: Mutations in collagen VI-related genes (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). These were previously believed to be separate disease entities, but they are now both classified as collagen VI-related myopathies, which cover a broad clinical spectrum. We aimed to analyze the clinical, pathologic, and genetic characteristics of patients with collagen VI-related myopathy in Korea. METHODS: We reviewed the clinical, pathologic, and genetic features in 22 patients with collagen VI-related myopathy from 13 families, as confirmed by genetic analysis of collagen VI-related genes. RESULTS: The mean ages of the 22 patients at first symptom presentation and diagnosis were 4.5 and 24.9 years, respectively. Four patients in 4 families showed the phenotype of intermediate collagen VI-related myopathies (IM), 16 patients in 7 families had the BM phenotype, and 2 patients in 2 families presented with the typical UCMD phenotype. Based on genetic analysis, five patients (five families) comprising four with IM and one with typical UCMD had missense mutations in the triple-helical domain of COL6A1, and ten patients (four families) with BM showed exon-14-skipping mutations. Additionally, we found two novel mutations: c.956A>G (p.K319R) in COL6A1 and c.6221G>T (p.G2074V) in COL6A3. CONCLUSIONS: Missense mutations in the triple helical domain of COL6A1 are the most common mutations related to collagen VI related myopathy in Korea. Patients with these mutations have a tendency toward an earlier disease onset and more severe progression compared to patients with other mutations. PMID- 28831787 TI - Seasonal Variation in the Incidence of Transient Global Amnesia in South Korea. PMID- 28831789 TI - Hemiatrophy of the Tongue with Contralateral Hemiparesis in a Patient with Multifocal Acquired Demyelinating Sensory and Motor Neuropathy. PMID- 28831788 TI - Isolated Trochlear Palsy Due to Pilocytic Astrocytoma Involving the Pineal Gland. PMID- 28831786 TI - Abnormal Sleep Delta Rhythm and Interregional Phase Synchrony in Patients with Restless Legs Syndrome and Their Reversal by Dopamine Agonist Treatment. AB - BACKGROUND AND PURPOSE: The purpose of this study was to characterize abnormal cortical activity during sleep in restless legs syndrome (RLS) patients and to determine the effects of treatment with a dopamine agonist. Based on whole-brain electroencephalograms, we attempted to verify alterations in the functional network as well as the spectral power of neural activities during sleep in RLS patients and to determine whether the changes are reversed by treatment with pramipexole. METHODS: Twelve drug-naive RLS patients participated in the study. Overnight polysomnography was performed before and after treatment: the first recording was made immediately prior to administering the first dose of pramipexole, and the second recording was made 12-16 weeks after commencing pramipexole administration. Sixteen age-matched healthy participants served as a control group. The spectral power and interregional phase synchrony were analyzed in 30-s epochs. The functional characteristics of the cortical network were quantified using graph-theory measures. RESULTS: The delta-band power was significantly increased and the small-world network characteristics in the delta band were disrupted in RLS patients compared to the healthy controls. These abnormalities were successfully treated by dopaminergic medication. The delta band power was significantly correlated with the RLS severity score in the RLS patients prior to treatment. CONCLUSIONS: Our findings suggest that the spectral and functional network characteristics of neural activities during sleep become abnormal in RLS patients, and these abnormalities can be successfully treated by a dopamine agonist. PMID- 28831790 TI - Reversible Dementia with Middle Cerebellar Peduncle Hyperintensity: 1-Year Follow Up of HIV-Negative Neurosyphilis. PMID- 28831791 TI - Anaphylaxis after Idarucizumab Infusion. PMID- 28831792 TI - Feasibility of spatial frequency-domain imaging for monitoring palpable breast lesions. AB - In breast cancer diagnosis and therapy monitoring, there is a need for frequent, noninvasive disease progression evaluation. Breast tumors differ from healthy tissue in mechanical stiffness as well as optical properties, which allows optical methods to detect and monitor breast lesions noninvasively. Spatial frequency-domain imaging (SFDI) is a reflectance-based diffuse optical method that can yield two-dimensional images of absolute optical properties of tissue with an inexpensive and portable system, although depth penetration is limited. Since the absorption coefficient of breast tissue is relatively low and the tissue is quite flexible, there is an opportunity for compression of tissue to bring stiff, palpable breast lesions within the detection range of SFDI. Sixteen breast tissue-mimicking phantoms were fabricated containing stiffer, more highly absorbing tumor-mimicking inclusions of varying absorption contrast and depth. These phantoms were imaged with an SFDI system at five levels of compression. An increase in absorption contrast was observed with compression, and reliable detection of each inclusion was achieved when compression was sufficient to bring the inclusion center within ~12 mm of the phantom surface. At highest compression level, contrasts achieved with this system were comparable to those measured with single source-detector near-infrared spectroscopy. PMID- 28831794 TI - Simultaneous en-face imaging of multiple layers with multiple reference optical coherence tomography. AB - A technique based on multiple reference optical coherence tomography (MR-OCT) is proposed for simultaneous imaging at multiple depths. The technique has been validated by imaging a reference sample and a fingerprint in-vivo. The principle of scanning multiple selected layers is shown by imaging a partial fingerprint with 200*200*200 voxels of 3*3*0.5 mm size and obtaining an arbitrary amount of layers merely by digital processing. The spacing among the layers can be adjusted arbitrarily, and the SNR roll-off is shown for three different spacings. At a mirror scan frequency of 1 kHz and an A-line rate of 2 kHz, the acquisition time was 20 s for one volume. The results show the feasibility of the application of layer scanning MR-OCT that uses a partial mirror in the reference arm of the Michelson interferometer. The reduced scan range required for layer scanning allows even higher scan rates that are limited only by the voice coil design and the mass-spring system, e.g., mirror mass, spring constant, and damping. PMID- 28831793 TI - Reflectance confocal microscopy-guided laser ablation of basal cell carcinomas: initial clinical experience. AB - Laser ablation offers a procedure for precise, fast, and minimally invasive removal of superficial and early nodular basal cell carcinomas (BCCs). However, the lack of histopathological confirmation has been a limitation toward widespread use in the clinic. A reflectance confocal microscopy (RCM) imaging guided approach offers cellular-level histopathology-like feedback directly on the patient, which may then guide and help improve the efficacy of the ablation procedure. Following an ex vivo benchtop study (reported in our earlier papers), we performed an initial study on 44 BCCs on 21 patients in vivo, using a pulsed erbium:ytterbium aluminum garnet laser and a contrast agent (aluminum chloride). In 10 lesions on six patients, the RCM imaging-guided detection of either presence of residual tumor or complete clearance was immediately confirmed with histopathology. Additionally, 34 BCCs on 15 patients were treated with RCM imaging-guided laser ablation, with immediate confirmation for clearance of tumor (no histopathology), followed by longer-term monitoring, currently in progress, with follow-up imaging (again, no histopathology) at 3, 6, and 18 months. Thus far, the imaging resolution appears to be sufficient and consistent for monitoring efficacy of ablation in the wound, both immediately postablation and subsequently during recovery. The efficacy results appear to be promising, with observed clearance in 19 cases of 22 cases with follow-ups ranging from 6 to 21 months. An additional 12 cases with 1 to 3 months of follow-ups has shown clearance of tumor but a longer follow-up time is required to establish conclusive results. Further instrumentation development will be necessary to cover larger areas with a more automatically controlled instrument for more uniform, faster, and deeper imaging of margins. PMID- 28831795 TI - Covalent Organic Framework Material Bearing Phloroglucinol Building Units as a Potent Anticancer Agent. AB - Covalent organic frameworks (COFs) having periodicity in pores of nanoscale dimensions can be suitably designed for the organic building units bearing reactive functional groups at their surfaces. Thus, they are an attractive option as an anticancer agent to overcome the limitations of chemotherapy. Herein, we first report a new porous biodegradable nitrogen containing COF material, EDTFP-1 (ethylenedianiline-triformyl phloroglucinol), synthesized using 4,4' ethylenedianiline and 2,4,6-triformylphloroglucinol via Schiff base condensation reaction. EDTFP-1 exhibited 3D-hexagonal porous structure with average pores of ca. 1.5 nm dimension. Here, we have explored the anticancer potentiality of EDTFP 1. Result demonstrated an enhanced cytotoxicity was observed against four cancer cells HCT 116, HepG2, A549, and MIA-Paca2 with significant lower IC50 on HCT116 cells. Additionally, EDTFP-1-induced cell death was associated with the characteristic apoptotic changes like cell membrane blebbing, nuclear DNA fragmentation, externalization of phosphatidylserine from the cell membrane followed by a loss of mitochondrial membrane potential as well as modulation of pro and antiapoptotic proteins. Further, the result depicted a direct correlation between the generations of ROS with mitochondrial-dependent apoptosis through the involvement of p53 phosphorylation upon EDTFP-1 induction, suggesting this COF material is a novel chemotherapeutic agent for cancer treatment. PMID- 28831796 TI - One-Pot Synthesis of Spirocyclic or Fused Pyrazoles from Cyclic Ketones: Calcium Carbide as the Carbon Source in Ring Expansion. AB - N-Tosylhydrazones generated in situ from cyclic ketones smoothly underwent a [3 + 2] cycloaddition to afford saturated spirocyclic pyrazoles and further transformed to the fused analogues via a ring expansion in certain cases. An inexpensive and renewable resource, calcium carbide, was utilized as the carbon source in the ring expansion. The salient features of this reaction include widely available starting materials, convenient one-pot/two-step procedure, great efficiency, and high regioselectivity. Remarkably, this reaction underwent a [1,5]-sigmatropic rearrangement process, which was supported by deuterium labeling experiments. PMID- 28831797 TI - Cytochalasins from an Australian Marine Sediment-Derived Phomopsis sp. (CMB M0042F): Acid-Mediated Intramolecular Cycloadditions Enhance Chemical Diversity. AB - Chemical analysis of an Australian coastal marine sediment-derived fungus, Phomopsis sp. (CMB-M0042F), yielded the known cytochalasins J (1) and H (2), together with five new analogues, cytochalasins J1-J3 (3-5) and H1 and H2 (6 and 7). Structures of 1-7 were assigned on the basis of detailed spectroscopic analysis, chemical interconversion, and biosynthetic and mechanistic considerations. Of note, 1 and 2 proved to be highly sensitive to acid-mediated transformation, with 1 affording 3-5 and 2 affording 6 and 7. Whereas 1, 2, 4, and 5 were detected as natural products in crude culture extracts, 3, 6, and 7 were designated as acid-mediated handling artifacts. We propose novel stereo- and regiospecific intramolecular cycloadditions, under tight functional group control, that facilitate selective conversion of 1 and 2 to the rare 5/6/6/7/5- and 5/6/5/8-fused heterocycles 5 and 7, respectively. Knowledge of acid sensitivity within the cytochalasin family provides a valuable cautionary lesson that has the potential to inform our analysis of past and future investigations into this structure class and inspire novel biomimetic transformations leading to new chemical diversity. PMID- 28831798 TI - Cross-Linked Polyelectrolyte for Improved Selectivity and Processability of Iontronic Systems. AB - On-demand local release of biomolecules enables fine-tuned stimulation for the next generation of neuromodulation therapies. Such chemical stimulation is achievable using iontronic devices based on microfabricated, highly selective ion exchange membranes (IEMs). Current limitations in processability and performance of thin film IEMs hamper future developments of this technology. Here we address this limitation by developing a cationic IEM with excellent processability and ionic selectivity: poly(4-styrenesulfonic acid-co-maleic acid) (PSS-co-MA) cross linked with polyethylene glycol (PEG). This enables new design opportunities and provides enhanced compatibility with in vitro cell studies. PSSA-co-MA/PEG is shown to out-perform the cation selectivity of the previously used iontronic material. PMID- 28831799 TI - Preparation of Some Homologous TEMPO Nitroxides and Oxoammonium Salts; Notes on the NMR Spectroscopy of Nitroxide Free Radicals; Observed Radical Nature of Oxoammonium Salt Solutions Containing Trace Amounts of Corresponding Nitroxides in an Equilibrium Relationship. AB - Three new homologous TEMPO oxoammonium salts and three homologous nitroxide radicals have been prepared and characterized. The oxidation properties of the salts have been explored. The direct 13C NMR and EPR spectra of the nitroxide free radicals and the oxoammonium salts, along with TEMPO and its oxoammonium salt, have been successfully measured with little peak broadening of the NMR signals. In the spectra of all ten compounds (nitroxides and corresponding oxoammonium salts), the carbons in the 2,2,6,6-tetramethylpiperidine core do not appear, implying paramagnetic properties. This unpredicted overall paramagnetism in the oxoammonium salt solutions is explained by a redox equilibrium as shown between oxoammonium salts and trace amounts of corresponding nitroxide. This equilibrium is confirmed by electron interchange reactions between nitroxides with an N-acetyl substituent and oxoammonium salts with longer acyl side chains. PMID- 28831800 TI - Copper-Catalyzed Oxidative Alkylation (Methylation) of Phosphonamides and Phosphinamides Using Dicumyl Peroxide. AB - An effective and practical CuI-catalyzed methodology toward N-alkyl or N-methyl phosphonamides and phosphinamides was herein demonstrated. The transformation took place readily under the oxidative conditions, and plenty of N-alkylated (methylated) amides (30 examples) were successfully furnished in high efficiency (up to 92% yields). Dicumyl peroxide was considered to act either as the oxidant for the alkylation reaction or as methyl donator for the methylation protocol. PMID- 28831801 TI - Kinetically Trapped Liquid-State Conformers of a Sodiated Model Peptide Observed in the Gas Phase. AB - We investigate the peptide AcPheAla5LysH+, a model system for studying helix formation in the gas phase, in order to fully understand the forces that stabilize the helical structure. In particular, we address the question of whether the local fixation of the positive charge at the peptide's C-terminus is a prerequisite for forming helices by replacing the protonated C-terminal Lys residue by Ala and a sodium cation. The combination of gas-phase vibrational spectroscopy of cryogenically cooled ions with molecular simulations based on density-functional theory (DFT) allows for detailed structure elucidation. For sodiated AcPheAla6, we find globular rather than helical structures, as the mobile positive charge strongly interacts with the peptide backbone and disrupts secondary structure formation. Interestingly, the global minimum structure from simulation is not present in the experiment. We interpret that this is due to high barriers involved in rearranging the peptide-cation interaction that ultimately result in kinetically trapped structures being observed in the experiment. PMID- 28831802 TI - Fabrication of Calcium Phosphate Microflowers and Their Extended Application in Bone Regeneration. AB - The structure of materials is known to play an important role in material function. Nowadays, flowerlike structures have gained attention for studies not only in analytical chemistry, but also in biomaterial design. In this study, flowerlike structures were applied in bone regeneration in the form of calcium phosphate microflowers. The material was synthesized by a simple and environmentally friendly method. We characterized the structure and properties of the microflower using various methods. Cytotoxicity and osteogenesis-related gene regulations of the microflower were investigated in vitro. Cell uptake was observed by immunofluorescence. Rat calvarial critical-size defect models were successfully established to further confirm the enhanced bone regeneration ability of this material. We expect that this novel study will be of practical importance for the extended application of flowerlike materials and will provide new insights into the optimization of the morphology of calcium phosphate materials. PMID- 28831803 TI - Conformal Electronics Wrapped Around Daily Life Objects Using an Original Method: Water Transfer Printing. AB - The water transfer printing method is used to transfer patterned films on random three-dimensional objects. This industrially viable technology has been demonstrated to intimately wrap metallic and polymeric films around different materials. This method avoids the use of rigid substrate during the transfer step. Patterns can be transferred to objects without folds even when holed, addressing a challenging issue in the field of conformal electronics. This technique allows high film bending properties to be reached. This promising method enables us to integrate large-area films onto daily life objects. A bent capacitive touchpad is fabricated showing the potential applications of this technology. PMID- 28831804 TI - Mobile Phone Sensing of Cocaine in a Lateral Flow Assay Combined with a Biomimetic Material. AB - Lateral flow assays (LFAs) are an ideal choice for drug abuse testing favored by their practicability, portability, and rapidity. LFA based on-site rapid screening devices provide positive/negative judgment in a short response time. The conventionally applied competitive assay format used for small molecule analysis such as abused drugs restricts the quantitation ability of LFA strips. We report herein, for the first time, a new strategy using the noncompetitive assay format via a biomimetic material, namely, poly(p-phenylene) beta cyclodextrin poly(ethylene glycol) (PPP-CD-g-PEG) combined with gold nanoparticle (AuNP) conjugates as the labeling agent to recognize the target cocaine molecule in the test zone. The intensities of the visualized red color in the test line indicate that the cocaine concentrations were analyzed via a smartphone application. Significantly, a combination of this platform with a smartphone application provides quantitative data on the cocaine amount, making it a very inventive and attractive approach especially for on-site applications at critical points such as traffic stops and the workplace. PMID- 28831805 TI - Highly Sensitive and Selective Sensing of Free Bilirubin Using Metal-Organic Frameworks-Based Energy Transfer Process. AB - Free bilirubin, a key biomarker for jaundice, was detected with a newly designed fluorescent postsynthetically modified metal organic framework (MOF) (UIO-66-PSM) sensor. UiO-66-PSM was prepared based on the aldimine condensation reaction of UiO-66-NH2 with 2,3,4-trihydroxybenzaldehyde. The fluorescence of UIO-66-PSM could be effectively quenched by free bilirubin via a fluorescent resonant energy transfer process, thus achieving its recognition of free bilirubin. It was the first attempt to design a MOF-based fluorescent probe for sensing free bilirubin. The probe exhibited fast response time, low detection limit, wide linear range, and high selectivity toward free bilirubin. The sensing system enabled the monitor of free bilirubin in real human serum. Hence, the reported free bilirubin sensing platform has potential applications for clinical diagnosis of jaundice. PMID- 28831806 TI - Mixed Self-Assembly of Polyethylene Glycol and Aptamer on Polydopamine Surface for Highly Sensitive and Low-Fouling Detection of Adenosine Triphosphate in Complex Media. AB - Detection of disease biomarkers within complex biological media is a substantial outstanding challenge because of severe biofouling and nonspecific adsorptions. Herein, a reliable strategy for sensitive and low-fouling detection of a biomarker, adenosine triphosphate (ATP) in biological samples was developed through the formation of a mixed self-assembled sensing interface, which was constructed by simultaneously self-assembling polyethylene glycol (PEG) and ATP aptamer onto the self-polymerized polydopamine-modified electrode surface. The developed aptasensor exhibited high selectivity and sensitivity toward the detection of ATP, and the linear range was 0.1-1000 pM, with a detection limit down to 0.1 pM. Moreover, owing to the presence of PEG within the sensing interface, the aptasensor was capable of sensing ATP in complex biological media such as human plasma with significantly reduced nonspecific adsorption effect. Assaying ATP in real biological samples including breast cancer cell lysates further proved the feasibility of this biosensor for practical application. PMID- 28831807 TI - Terahertz Spectroscopic Probe of Hot Electron and Hole Transfer from Colloidal CsPbBr3 Perovskite Nanocrystals. AB - Colloidal all inorganic CsPbX3 (X = Cl, Br, I) nanocrystals (NCs) have emerged to be an excellent material for applications in light emission, photovoltaics, and photocatalysis. Efficient interfacial transfer of photogenerated electrons and holes are essential for a good photovoltaic and photocatalytic material. Using time-resolved terahertz spectroscopy, we have measured the kinetics of photogenerated electron and hole transfer processes in CsPbBr3 NCs in the presence of benzoquinone and phenothiazine molecules as electron and hole acceptors, respectively. Efficient hot electron/hole transfer with a sub-300 fs time scale is the major channel of carrier transfer thus overcomes the problem related to Auger recombination. A secondary transfer of thermalized carriers also takes place with time scales of 20-50 ps for electrons and 137-166 ps for holes. This work suggests that suitable interfaces of CsPbX3 NCs with electron and hole transport layers would harvest hot carriers, increasing the photovoltaic and photocatalytic efficiencies. PMID- 28831808 TI - Reply: Intravenous Ferumoxytol in Pediatric Patients With Iron-Deficiency Anemia. AB - Iron Deficiency in children is common problem. Its mechanism could be nutritional or due to lack of iron absorption. Several conditions are associated with IDA. Presence of inflammation further complicate attempts to make a definitive diagnoses or accurately quantify reponse to therapy. PMID- 28831809 TI - Effectiveness of a treatment guideline for schizophrenia in adolescents: Lessons from a middle-income country. AB - INTRODUCTION: Treatment guidelines for schizophrenia represent a standard way to manage patients, especially in countries with limited staff resources. However, they have not been compared on their efficacy with treatment as usual, despite adult studies suggesting they can be more effective. METHODS: Inpatient and outpatient adolescents with schizophrenia were randomly allocated to be either treated according to a guideline-based treatment ( n = 43) or treatment as usual ( n = 44). The effects on symptoms, psychosocial functioning and cognition were compared in a 6-month follow-up. RESULTS: There were no differences between groups in the pharmacological treatment, reduction in symptom severity or cognition. The guideline-based treatment group showed a better functioning at months 3 and 6. CONCLUSION: The guideline-based treatment had a greater effect than the treatment as usual in the psychosocial functioning of adolescent patients ( www.clinicaltrials.gov ; II3/02/0811). PMID- 28831810 TI - A new type of crime: Pseudo-amok and the Internet as amplifier. PMID- 28831811 TI - Prospective associations between personality and bullying among Australian adolescents. AB - OBJECTIVE: This study aimed to examine whether high-risk personality dimensions increased susceptibility to bullying victimisation and perpetration among Australian adolescents. METHOD: Longitudinal cohort study of 527 secondary school students in Australia (baseline average age = 13 years, 67% female and 93% Australian-born). Bullying was measured using an amended version of the Revised Olweus Bully/Victim Scale. Personality was measured using the Substance Use Risk Profile Scale. The data were analysed using mixed models, examining the association between baseline personality scores and frequency of victimisation/perpetration 12 months later. RESULTS: Baseline hopelessness and baseline impulsivity were positively associated with frequency of victimisation 12 months later. Baseline anxiety sensitivity was negatively associated with victimisation 12 months later for males. There was a positive association between baseline impulsivity and frequency of bullying perpetration 12 months later. CONCLUSION: High-risk personality dimensions predicted later bullying victimisation and bullying perpetration among Australian adolescents. This indicates that adding a personality-focused intervention for high-risk adolescents to existing universal bullying prevention approaches may be effective in improving the prevention of bullying among adolescents, as well as reducing other associated emotional and behavioural problems. PMID- 28831812 TI - Thromboembolic and Major Bleeding Events With Rivaroxaban Versus Warfarin Use in a Real-World Setting. AB - BACKGROUND: Although randomized trials demonstrate the noninferiority of rivaroxaban compared with warfarin in the context of nonvalvular atrial fibrillation (AF), little is known about how these drugs compare in practice. OBJECTIVE: To assess the relative effectiveness and safety of rivaroxaban versus warfarin in a large health system and to evaluate this association by time in therapeutic range (TTR). METHODS: We conducted a retrospective cohort study with propensity matching in the Cleveland Clinic Health System. The study included patients initiated on warfarin or rivaroxaban for thromboembolic prevention in nonvalvular AF between January 2012 and July 2016. The main outcomes were thromboembolic events and major bleeds. Analyses were stratified by warfarin patients' TTR. RESULTS: The cohort consisted of 472 propensity-matched pairs. The mean age was 73.6 years (SD = 11.7), and the mean CHADS2 score was 1.8. The median TTR for warfarin patients was 64%. In the propensity-matched analysis, there was no significant difference in thromboembolic or major bleeding events between groups. Among warfarin patients with a TTR <64% and their matched rivaroxaban pairs, there was also no significant difference in thromboembolic or major bleeding events. CONCLUSIONS: Under real-world conditions, warfarin and rivaroxaban were associated with similar safety and effectiveness, even among those with suboptimal therapeutic control. Individualized decision making, taking into account the nontherapeutic tradeoffs associated with these medications (eg, monitoring, half-life, cost) is warranted. PMID- 28831813 TI - The Emerging Role of PD-1/PD-L1-Targeting Immunotherapy in the Treatment of Metastatic Urothelial Carcinoma. AB - OBJECTIVE: To summarize and evaluate immunotherapy agents targeting programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) recently approved for the treatment of metastatic urothelial carcinomas (UC). DATA SOURCES: A literature review was performed using PubMed (2012 to June 2017), the American Society of Clinical Oncology abstract databases (2012 to June 2017 Annual Meetings/symposia), and the America Association for Cancer Research symposia (2012 to June 2017). A search using clinicaltrials.gov was conducted to identify studies for atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. STUDY SELECTION AND DATA EXTRACTION: English language phase I to III studies assessing PD-1 and PD-L1 in UC were incorporated. DATA SYNTHESIS: Atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab have demonstrated clinical efficacy with tolerable toxicities in patients with metastatic UC with disease progression following platinum-based chemotherapy. Anti-PD-1/PD-L1 therapies may provide overall survival advantage; these are currently being evaluated in ongoing phase 3 studies. Greater objective response rates seem to be observed in PD-L1-positive patients versus PD-L1-negative patients, but methodologies in this assessment differ among clinical trials. The identification of biomarkers that provide greater insight into patients who positively respond to PD-1/PD-L1 therapies are needed. CONCLUSIONS: Treatment options for metastatic UC have expanded to include PD-1/PD-L1 therapies. These agents should be strongly considered as second-line therapy over single-agent chemotherapy for patients who fail or progress after platinum-based treatment. PMID- 28831814 TI - Translational delivery of Cool Little Kids to prevent child internalising problems: Randomised controlled trial. AB - OBJECTIVE: To determine whether a population-delivered parenting programme assists in preventing internalising problems at school entry for preschool children at-risk with temperamental inhibition. METHODS: Design: a randomised controlled trial was used. SETTING: the setting was 307 preschool services across eight socioeconomically diverse government areas in Melbourne, Australia. PARTICIPANTS: a total of 545 parents of inhibited 4-year-old children: 498 retained at 1-year follow up. Early intervention: Cool Little Kids parenting group programme was implemented. Primary outcomes: the primary outcomes were child DSM-IV anxiety disorders (assessor blind) and internalising problems. SECONDARY OUTCOMES: the secondary outcomes were parenting practices and parent mental health. RESULTS: At 1-year follow up (mean (standard deviation) age = 5.8 (0.4) years), there was little difference in anxiety disorders between the intervention and control arms (44.2% vs 50.2%; adjusted odds ratio = 0.86, 95% confidence interval = [0.60, 1.25], p = 0.427). Internalising problems were reduced in the intervention arm (Strengths and Difficulties Questionnaire: abnormal - 24.2% vs 33.0%; adjusted odds ratio = 0.56, 95% confidence interval = [0.35, 0.89], p = 0.014; symptoms - mean (standard deviation) = 2.5 (2.0) vs 2.9 (2.2); adjusted mean difference = -0.47, 95% confidence interval = [-0.81, 0.13], p = 0.006). Parents' participation in the intervention was modest (29.4% attended most groups, 20.5% used skills most of the time during the year). A priori interaction tests suggested that for children with anxious parents, the intervention reduced anxiety disorders and internalising symptoms after 1 year. CONCLUSION: Offering Cool Little Kids across the population for inhibited preschoolers does not impact population outcomes after 1 year. Effects may be emerging for inhibited children at highest risk with parent anxiety. Trial outcomes will continue into mid-childhood. PMID- 28831815 TI - Commentary on Jeffrey Voigt et al.'s Article, "Private Rooms in Low Acuity Settings: A Systematic Review of Literature". PMID- 28831816 TI - Finding positives in caregiving: The unique experiences of Chinese spousal caregivers of persons with young-onset dementia. AB - The experience of taking care of spouses with young-onset dementia has been identified as unique and merits considerations. However, current knowledge about this area in Chinese spousal caregivers is scarce. A qualitative descriptive study was therefore conducted to explore the experience of spousal caregivers of persons with young-onset dementia in Hong Kong. A total of six spousal caregivers of persons diagnosed with dementia before the age of 65 participated in this study. Three major categories were identified: coming to terms with an unexpected diagnosis; multiple unanticipated and 'early' losses and finding positives and meaning. This study has highlighted the influence of sociocultural values on the spousal caregiving experience in young-onset dementia caregiving. The findings also have significant implications for the development of interventions to facilitate the spousal caregivers to accept and sustain their caregiving role. PMID- 28831817 TI - Biomarkers, imaging and multifocality in intraductal papillary mucinous neoplasms: relevant for decision making? PMID- 28831818 TI - Clinical pharmacokinetic study for the effect of glimepiride matrix tablets developed by quality by design concept. AB - OBJECTIVE: Implementation of a new pharmaceutical technique to improve aqueous solubility and thus dissolution, enhancement of drug permeation, and finally formulation of a controlled release tablet loaded with glimepiride (GLMP). SIGNIFICANCE: Improve GLMP bioavailability and pharmacokinetics in type II diabetic patients. METHODS: Different polymers were used to enhance aqueous GLMP solubility of which a saturated polymeric drug solution was prepared and physically adsorbed onto silica. An experimental design was employed to optimize the formulation parameters affecting the preparation of GLMP matrix tablets. A compatibility study was conducted to study components interactions. Scanning electron microscope (SEM) was performed before and after the tablets were placed in the dissolution medium. An in vivo study in human volunteers was performed with the optimized GLMP tablets, which were compared to pure and marketed drug products. RESULTS: Enhancement of GLMP aqueous solubility, using the polymeric drug solution technique, by more than 6-7 times when compared with the binary system. All the studied formulation factors significantly affected the studied variables. No significant interaction was detected among components. SEM illustrated the surface and inner tablet structure, and confirmed the drug release which was attributed to diffusion mechanism. The volunteer group administered the optimized GLMP tablet exhibited higher drug plasma concentration (147.4 ng/mL), longer time to reach maximum plasma concentration (4 h) and longer t1/2 (7.236 h) compared to other groups. CONCLUSIONS: Matrix tablet loaded with a physically modified drug form could represent a key solution for drugs with inconsistent dissolution and absorption profiles. PMID- 28831819 TI - Private Rooms in Low Acuity Settings: A Systematic Review of the Literature. AB - OBJECTIVES: Determine if the peer-reviewed evidence supports single-patient ward bedrooms in low-acuity care settings within a hospital. BACKGROUND: New evidence exists since the 2006 Facility Guideline Institute guideline recommended single bedded rooms (SBRs) in low-acuity care settings. Additionally, prior studies evaluated high-acuity care settings (e.g., critical care) in their recommendations on SBRs. There is a need to reevaluate the evidence. METHODS: A systematic review of the literature was completed including electronic and hand searches of references. A data extraction form was utilized. Two reviewers evaluated the studies independently. Studies that were included examined the effect of single-patient rooms on medical surgical ward beds only. Each study was graded using accepted clinical evidence grading instruments. RESULTS: Over 1,400 records were identified. After excluding studies, a total of 49 records were graded. The highest quality evidence identified (Center for Evidence-Based Medicine [CEBM]: 2a, 2b, and Grading of Recommendations, Assessment, Development, and Evaluation [GRADE] C) did not support the use of single-patient rooms for reducing infections, for minimizing patient falls, for reducing medication errors, or for patient satisfaction. Operational efficiencies were improved with SBRs but only addressed the maternity ward. The lowest quality evidence (CEBM: 4/5 and GRADE D) supported the use of single-patient rooms. CONCLUSIONS: Based on CEBM and GRADE assessments, there is a lack of high-quality data supporting the use of low-acuity SBRs throughout the entire hospital. Furthermore, it is recommended that more research be conducted on the effect of SBRs, so higher quality evidence is developed. PMID- 28831820 TI - Juvenile Corrections in the Era of Reform: A Meta-Synthesis of Qualitative Studies. AB - In this article, the authors synthesize knowledge from select qualitative studies examining rehabilitation-oriented juvenile residential corrections and aftercare programs. Using meta-synthesis methodology, the authors extracted and coded content from 10 research studies conducted by five authors across criminology, sociology, and social welfare disciplines. The total number of published works based on those studies analyzed was 18. Collectively, these studies offer insight into three major components of the juvenile correctional experience: therapeutic treatment and evidence-based practices, the shaping of identities and masculinities, and preparation for reentry. This analysis is particularly important as the United States is currently in an era of reform during which policymakers are increasingly espousing the benefits of rehabilitation for youth offenders over punishment. These studies took place before, during, and after this era of reform, and yet, the findings are surprisingly consistent over time, raising key questions about the effectiveness of the reform strategies. PMID- 28831821 TI - Long-term outcomes of over 8,000 medial Oxford Phase 3 Unicompartmental Knees-a systematic review. AB - Background and purpose - There is debate as to the relative merits of unicompartmental and total knee arthroplasty (UKA, TKA). Although the designer surgeons have achieved good results with the Oxford UKA there is concern over the reproducibility of these outcomes. Therefore, we evaluated published long-term outcomes of the Oxford Phase 3 UKA. Patients and methods - We searched databases to identify studies reporting >=10 year outcomes of the medial Oxford Phase 3 UKA. Revision, non-revision, and re-operation rates were calculated per 100 component years (% pa). Results - 15 studies with 8,658 knees were included. The annual revision rate was 0.74% pa (95% CI 0.67-0.81, n = 8,406) corresponding to a 10-year survival of 93% and 15-year survival of 89%. The non-revision re operation rate was 0.19% pa (95% CI 0.13-0.25, n = 3,482). The re-operation rate was 0.89% pa (95% CI 0.77-1.02, n = 3,482). The most common causes of revision were lateral disease progression (1.42%), aseptic loosening (1.25%), bearing dislocation (0.58%), and pain (0.57%) (n = 8,658). Average OKS scores were 40 at 10 years (n = 3,417). The incidence of medical complications was 0.83% (n = 1,443). Interpretation - Very good outcomes were achieved by both designer and non-designer surgeons. The PROMs, medical complication rate, and non-revision re operation rate were better than those found in meta-analyses and publications for TKA but the revision rate was higher. However, if failure is considered to be all re-operations and not just revisions, then the failure rate of UKA was less than that of TKA. PMID- 28831823 TI - Mutation rates for 20 STR loci in a population from Sao Paulo state, Southeast, Brazil. AB - Short tandem repeats (STRs) are genetic markers largely employed in forensic analysis and paternity investigation cases. When an inconsistency between the parent and child is considered as a possible mutation, the mutation rate should be incorporated into paternity index calculations to give a robust result and to reduce the chance of misinterpretation. The aim of this study was to estimate the mutation rates of 20 autosomal STRs loci used for paternity tests. In these loci we analysed 29,831 parent-child allelic transfers from 929 duo or trio paternity tests carried out during 2012?2016 from Sao Paulo State, Brazil. We identified 35 mutations in 16 loci, and they were more frequent in the paternal germline compared to the maternal germline. The loci with the highest rate were vWA and FGA and the ones with the lowest rate were PENTA E, PENTA D, D21S11, D7S820 and D6S1043. We did not identified any mutation in D2S1338, TH01, TPOX and D16S539 loci. All mutations consisted of losses or gains of one repeat unit. Mutation rates found in the Sao Paulo population have peculiarities, which justifies the use of regional databases in laboratories. PMID- 28831822 TI - Effect of zolpidem on functional recovery in a rat model of ischemic stroke. AB - Objective To evaluate the effects of zolpidem on functional recovery in a rat model of acute ischemic stroke. Methods Following ischemic stroke procedures, 42 rats (six in each group) were randomly assigned to receive zolpidem (0.1, 0.25, 0.5, 1.0, 2.0 or 4.0 mg/kg) or normal saline administer intraperitoneally once daily for two weeks. Motor behavioural index (MBI) scores, radial 8-arm maze (RAM) test times and brain MRI scans were obtained 24 hours (Day 1) and two weeks (Day 14) post-procedure. Immunohistochemistry was performed on Day 14. Results By comparison with the normal saline group, the 0.5 and 1.0 mg/kg zolpidem groups showed statistically significant improvements in MBI scores and increased numbers of brain-derived neurotrophic factor (BDNF) stained cells over the two week dosing period. By contrast, the 4.0 mg/kg zolpidem group had statistically significantly impaired MBI scores compared with the control group. No differences among groups were found in RAM times or infarction volumes. Conclusions This study in a rat model showed that 0.5-1.0 mg/kg of zolpidem had beneficial effects on behavioural recovery by enhancing neural plasticity without causing any memory impairment in acute ischemic stroke. PMID- 28831824 TI - VEGF as a potential target in lung cancer. AB - Introduction The vascular endothelial growth factor A (VEGF) is the main mediator of angiogenesis. In addition, VEGF contributes to cancer growth and metastasis directly targeting tumor cells. VEGF overexpression and/or high VEGF serum levels have been reported in lung cancer. Areas covered We searched Pubmed for relevant preclinical studies with the terms 'lung cancer' 'VEGF' and 'in vivo'. We also searched the Clinicaltrials.gov database, the FDA and the EMA websites for the most recent updates on clinical development of anti-VEGF agents. Expert opinion VEGF plays an important role in sustaining the development and progression of lung cancer and it might represent an attractive target for therapeutic strategies. Nevertheless, clinical trials failed to attend the promising expectations deriving from preclinical studies with anti-VEGF agents. To improve the efficacy of anti-VEGF therapies in lung cancer, potential strategies might be the employment of combinatory therapies with immune checkpoint inhibitors or agents that inhibit signaling pathways and proangiogenic factors activated in response to VEGF blockade, and the identification of novel targets in the VEGF cascade. Finally, the identification of predictive markers might help to select patients who are more likely to respond to anti-angiogenic drugs. PMID- 28831825 TI - PDL-1/PD1 inhibitors: antibody or antinobody? PMID- 28831827 TI - Women in Prison With Traumatic Brain Injury: Prevalence, Mechanism, and Impact on Mental Health. AB - Relatively little is known about the characteristics of female offenders. Here, we studied the prevalence of traumatic brain injury (TBI) and mental health issues in an exclusively female prison population in New Zealand. Participants ( N = 38) were recruited from all security levels at Christchurch Women's Prison. Measures for depression, anxiety, and stress, sleep, and a history of TBI were administered; 94.7% (36/38) of participants presented with a history of TBI. Younger age at first injury was associated with an increased risk of mental health problems. The study concludes that TBI is highly prevalent among female offenders and may be linked to increased mental health problems. TBI should be considered as an important factor in offender pathways and treatment programs. PMID- 28831826 TI - Factors related to the recurrence of benign thyroid nodules after thermal ablation. PMID- 28831828 TI - Contextualizing Informal Labeling Effect on Adolescent Recidivism in South Korea. AB - Symbolic interactionism argues that the effect of informal labeling by general others, such as family and friends, on behavior depends on the social context under which labeling takes place. Despite abundant research on informal labeling, little effort has been made to contextualize its impact on adolescent reoffending. Also, compared with other theories, only a few studies have been conducted among youths in Asian population. Using three consecutive waves of self reported survey data from a nationally representative sample of 2,406 Korean adolescents, this study examined an interactional model for the informal labeling effect. Findings suggest that informal labeling, as well as school commitment and delinquent peer association, has an independent effect on delinquency. Also supported is the symbolic interactionist hypothesis that adolescents with greater involvement in delinquent subcultures were less susceptible to informal labeling. Implications of the findings are discussed. PMID- 28831829 TI - Prescription patterns and adequacy of blood pressure control among adult hypertensive patients in Kenya; findings and implications. AB - BACKGROUND: Hypertension is a major cause of global morbidity and mortality, with high prevalence rates in Africa including Kenya. Consequently, it is imperative to understand current treatment approaches and their effectiveness in practice. Currently, there is paucity of such data in Kenya, which is a concern. The aim is to describe prescribing patterns and adequacy of blood pressure (BP) control in adult hypertensive patients to guide future practice. METHOD: Retrospective study of patients attending a sub-county outpatient clinic combined with qualitative interviews. RESULTS: 247 hypertensive patients, predominantly female, mean age 55.8 years on antihypertensive therapy for 1-5 years, were analyzed. ACEIs and thiazide diuretics were the most commonly prescribed drugs, mainly as combination therapy. Treatment typically complied with guidelines, mainly for stage 2 hypertension (75%). BP control was observed in 46% of patients, with a significant reduction in mean systolic (155 to 144 mmHg) and diastolic (91 to 83 mmHg) BP (P < 0.001). Patients on >=2 antihypertensive drugs were more likely to have uncontrolled BP (OR:1.9, p = 0.021). CONCLUSION: Encouragingly good adherence to guidelines was helped by training. Poor blood pressure control in the majority needs to be addressed. Additional training of prescribers and follow up of measures to improve BP control will be introduced and followed up. PMID- 28831830 TI - Biological treatment of the knee with platelet-rich plasma or bone marrow aspirate concentrates. AB - - Knee pathologies including focal cartilage injuries, osteoarthritis (OA), and ligament injuries are common. The poor regeneration and healing potential of cartilage has led to the search for other treatment modalities with improved healing capacity. Furthermore, with an increasing elderly population that desires to remain active, the burden of knee pathologies is expected to increase. Increased sports participation and the desire to return to activities faster is also demanding more effective and minimally invasive treatment options. Thus, the use of biologic agents in the treatment of knee pathologies has emerged as a potential option. Despite the increasing use of biologic agents for knee pathology, there are conflicting results on the efficacy of these products. Furthermore, strong data supporting the optimal preparation methods and composition for widely used biologic agents, such as platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), largely remain absent from the literature. This review presents the literature on the most commonly employed biologic agents for the different knee pathologies. PMID- 28831831 TI - Commentary on Private Rooms in Low-Acuity Settings: A Systematic Review of the Literature. PMID- 28831832 TI - Do all aromatase inhibitors have similar efficacy and safety? PMID- 28831833 TI - Postoperative Nasal Septal Abscess Following Use of 2-Octylcyanoacrylate and Polydioxanone Plate in Open Septorhinoplasty: A Case Series. AB - BACKGROUND: The employment of 2-octylcyanoacrylate adhesive (Dermabond) to assist graft placement in open septorhinoplasty has been increasingly used to stabilize cartilage grafts. Literature regarding this application has been mixed, with some showing the possibility of increased rates of inflammation, if not infection. We present an original comparative case series involving postoperative septal abscess formation adjacent to caudal strut grafting where both Dermabond and an absorbable polydioxanone (PDS) plate were used. OBJECTIVE: To report an original comparative case series of patients who developed a postoperative septal abscess following open septorhinoplasty in the context of Dermabond application to affix cartilage to a PDS plate to facilitate caudal septal strut grafting. DESIGN: Retrospective comparative series with relevant clinical photographs, culture studies, and surgical figures. SETTING: Tertiary medical treatment facility. RESULTS: Two patients underwent primary open septorhinoplasty with placement of an autologous caudal septal extension graft, which was stabilized using a PDS plate and secured into position using both Dermabond and PDS suture. Postoperatively, both patients presented a nasal septal abscess at an average of 8 weeks that required serial drainage and subsequent removal of the PDS plate in 1 of the patients. Cultures demonstrated mixed flora as well as Proteus mirabilis, previously unreported in the nasal septal abscess literature. In comparison to 8 patients who underwent reconstruction with PDS plate alone (without Dermabond application), this represents a relative risk of 15 ( P value = .053) for a septal abscess complication when Dermabond is employed . CONCLUSIONS: We present an original case series on our limited, though impactful experience with PDS plate reconstruction using Dermabond to facilitate caudal septal graft placement in open septorhinoplasty. In conjunction with previously reported case series, which demonstrated elevated risk of prolonged inflammation and infection, we would recommend avoidance of subcutaneous Dermabond as an adjunct, particularly in combination with PDS plate utilization. PMID- 28831834 TI - Does Snoring Time Always Reflect the Severity of Obstructive Sleep Apnea? AB - OBJECTIVES: Although it is commonly believed that the degree of snoring reflects the severity of obstructive sleep apnea (OSA), there is often a mismatch between the improvement in OSA and the decrease of snoring time following OSA treatment. The aim of this study was to determine the relationship between OSA severity and snoring time. METHODS: A total of 280 subjects who complained of snoring were divided by apnea-hypopnea index (AHI) into 5 groups. The snoring rate (the amount of sleep time spent snoring divided by the total sleep time) and the clinical data including polysomnographic findings were compared and analyzed. RESULTS: There was no significant correlation between AHI and snoring rate (r = -0.038, P = .524). The snoring rate in the control group was significantly lower than that in the moderate ( P < .001) and severe ( P = .003) groups. The snoring rate in the very severe group was significantly lower than those in the mild ( P < .001), moderate ( P < .001), and severe ( P < .001) groups. However, there was no significant difference between snoring rates in the control group and the very severe group ( P = .832). CONCLUSIONS: The change in snoring rate according to the severity of AHI showed an inverted U-shaped pattern, with a peak in the moderate OSA group. PMID- 28831835 TI - Bone Pain in a Preadolescent Girl. PMID- 28831836 TI - Long-term outcome of Epstein-Barr virus DNAemia and PTLD with the use of preemptive rituximab following allogeneic HSCT. AB - We studied retrospectively the outcome of Epstein-Barr virus (EBV)-related disease with EBV monitoring and preemptive rituximab to prevent post-transplant lymphoproliferative disorder (PTLD) in 319 consecutive allogeneic stem cell transplantations 2004-2012. Patients who received anti-thymocyte globulin (ATG) or alemtuzumab were regarded as high-risk for PTLD (n = 214). EBV DNAemia >=1000 copies/mL plasma was observed in 50 (23%) of the high-risk patients. Thirty-three of the high-risk (15%) and one of the low-risk (1%) patients received rituximab, in combination with reduction of immunosuppression (n = 24) or chemotherapy (n = 4). Although rituximab was initiated only 5 d after first EBV load >=1000 copies/mL, 85% of the rituximab-treated patients developed symptoms (lymphadenopathy 50%, fever 76%, and encephalitis/meningitis 12%). Response-rate to EBV treatment was 88%. Overall survival at 1- and 5-year was 71 and 52% for rituximab-treated patients, which was not inferior to all other patients post transplant. In conclusion, rituximab therapy for EBV DNAemia does not affect long term survival negatively. PMID- 28831837 TI - Racial disparities in the management of acne: evidence from the National Ambulatory Medical Care Survey, 2005-2014. AB - PURPOSE: Racial health disparities are widespread in the United States, but little is known about racial disparities in the management of dermatological conditions. MATERIALS AND METHODS: Nationally representative data on the management of acne vulgaris were gathered from the National Ambulatory Medical Care Survey (NAMCS) for the years 2005-2014. Visits to any specialist were included. Rao-Scott chi-square tests and multivariate adjusted logistic regressions were used to identify differences in patient demographics, visit characteristics and acne medications across races. RESULTS: Black patients are less likely than white patients to visit a dermatologist (adjusted odds ratio (aOR) 0.48, p = 0.001), receive any acne medication (aOR 0.64, p = 0.01), receive a combination acne medication (aOR 0.52, p = 0.007) or receive isotretinoin (aOR 0.46, p = 0.03). Adjusting for management by a dermatologist eliminated the association between race and the prescription of any acne medication as well as between race and the prescription of isotretinoin. CONCLUSION: Among outpatient visits for acne in the United States, racial disparities exist in the likelihood of seeing a dermatologist and receiving treatment. Treatment disparities are less common when care is provided by a dermatologist. More research is needed to better understand the causes of disparities in acne management and other dermatological conditions. PMID- 28831838 TI - Synthesis of Applied Behavior Analytic Interventions for Packing in Pediatric Feeding Disorders. AB - Packing, which consists of holding food in the mouth for an extended time during meals, is a form of disordered feeding associated with pediatric feeding disorders. The behavior can disrupt the pace and completion of a meal and lead to increased risk of choking, inadequate food and liquid intake, and elevated caregiver stress associated with mealtimes. Applied behavior analysis research has developed and evaluated behavioral interventions to improve feeding by reducing packing. This systematic review extends prior research by synthesizing characteristics of the packing intervention literature, evaluating the certainty of the evidence provided by studies, identifying potential directions for future research, and discussing the results in the context of evidence-based practice. PMID- 28831839 TI - Customized Versus Noncustomized Sound Therapy for Treatment of Tinnitus: A Randomized Crossover Clinical Trial. AB - OBJECTIVES: To determine the effectiveness of a customized sound therapy and compare its effectiveness to that of masking with broadband noise. METHODS: Subjects were randomized to receive either customized sound therapy or broadband noise for 2 hours per day for 3 months and then switched to the other treatment after a washout period. The outcome variables were tinnitus loudness (scored 0 10), Tinnitus Handicap Inventory (THI), Beck Anxiety Inventory (BAI), minimum masking levels (MML), and residual inhibition (RI). RESULTS: Eighteen subjects completed the study. Mean age was 53 +/- 11 years, and mean tinnitus duration was 118 +/- 99 months. With customized sound therapy, mean loudness decreased from 6.4 +/- 2.0 to 4.9 +/- 1.9 ( P = .001), mean THI decreased from 42.8 +/- 21.6 to 31.5 +/- 20.3 ( P < .001), mean BAI decreased from 10.6 +/- 10.9 to 8.3 +/- 9.9 ( P = .01), and MML decreased from 22.3 +/- 11.6 dB SL to 17.2 +/- 10.6 dB SL ( P = .005). After 3 months of broadband noise therapy, only BAI and, to a lesser degree, MML decreased ( P = .003 and .04, respectively). CONCLUSIONS: Customized sound therapy can decrease the loudness and THI scores of tinnitus patients, and the results may be superior to broadband noise. PMID- 28831840 TI - Crystal engineering of lactose using electrospray technology: carrier for pulmonary drug delivery. AB - CONTEXT: Dry powder inhalers (DPIs) consisting of a powder mixture containing coarse carrier particles (generally lactose) and micronized drug particles are used for lung drug delivery. The effective drug delivery to the lungs depends on size and shape of carrier particles. Thus, various methods have been proposed for engineering lactose particles to enhance drug delivery to lungs. OBJECTIVE: The objective of current work was to assess suitability of electrospray technology toward crystal engineering of lactose. Further, utility of the prepared lactose particles as a carrier in DPI was evaluated. MATERIALS AND METHODS: Saturated lactose solutions were electrosprayed to obtain electrosprayed lactose (EL) particles. The polymorphic form of EL was determined using Fourier transform infrared spectroscopy, powder X-ray diffractometry, and differential scanning calorimetry. In addition, morphological, surface textural, and flow properties of EL were determined using scanning electron microscopy and Carr's index, respectively. The aerosolization properties of EL were determined using twin stage impinger and compared with commercial lactose particles [Respitose(r) (SV003, Goch, Germany)] used in DPI formulations. RESULTS AND DISCUSSION: EL was found to contain both isomers (alpha and beta) of lactose having flow properties comparable to Respitose(r) (SV003). In addition, the aerosolization properties of EL were found to be significantly improved when compared to Respitose(r) (SV003) which could be attributed to morphological (high elongation ratio) and surface characteristic (smooth surface) alterations induced by electrospray technology. CONCLUSION: Electrospray technology can serve as an alternative technique for continuous manufacturing of engineered lactose particles which can be used as a carrier in DPI formulations. PMID- 28831841 TI - Ethics and Issues of Secondary Prevention Efforts in Child Sexual Abuse. AB - This article discusses the ethical, practical, and moral issues surrounding secondary prevention efforts of child sexual abuse from a professional and practice-based perspective. Transcripts of a semistructured consultation event with n = 15 international experts on the secondary prevention of child sexual abuse were analysed using thematic qualitative analysis. The research identified four main critical areas linked to secondary prevention efforts, including, the psychology of self-reporting and disclosure; the interaction with and within existing legal, social, and professional frameworks; the scale and type of an appropriate response; and potential hurdles (i.e., within media, public, politics). The article outlines these areas, highlighting participant perspectives on risk-enhancing and mitigating factors for each domain. PMID- 28831842 TI - Transdermal agomelatine microemulsion gel: pyramidal screening, statistical optimization and in vivo bioavailability. AB - Agomelatine is a new antidepressant having very low oral drug bioavailability less than 5% due to being liable to extensive hepatic 1st pass effect. This study aimed to deliver agomelatine by transdermal route through formulation and optimization of microemulsion gel. Pyramidal screening was performed to select the most suitable ingredients combinations and then, the design expert software was utilized to optimize the microemulsion formulations. The independent variables of the employed mixture design were the percentages of capryol 90 as an oily phase (X1), Cremophor RH40 and Transcutol HP in a ratio of (1:2) as surfactant/cosurfactant mixture 'Smix' (X2) and water (X3). The dependent variables were globule size, optical clarity, cumulative amount permeated after 1 and 24 h, respectively (Q1 and Q24) and enhancement ratio (ER). The optimized formula was composed of 5% oil, 45% Smix and 50% water. The optimized microemulsion formula was converted into carbopol-based gel to improve its retention on the skin. It enhanced the drug permeation through rat skin with an enhancement ratio of 37.30 when compared to the drug hydrogel. The optimum ME gel formula was found to have significantly higher Cmax, AUC 0-24 h and AUC0-infinity than that of the reference agomelatine hydrogel and oral solution. This could reveal the prosperity of the optimized microemulsion gel formula to augment the transdermal bioavailability of agomelatine. PMID- 28831843 TI - Self-care behavior and related factors in older patients with uncontrolled hypertension. AB - BACKGROUND: Effective self-care behavior can help reduce hypertension complications, but the rate of engagement in self-care behavior is relatively low among elderly patients. OBJECTIVES: To examine levels of self-care and factors affecting self-care among elderly patients with uncontrolled hypertension compared with those with controlled hypertension. DESIGN: Cross-sectional survey. METHODS: A total of 255 elderly patients were selected to measure hypertensive patients' self-care behavior and self-efficacy, knowledge of hypertension management, family support, and perceived severity of hypertension as well as their depression levels. RESULTS: The uncontrolled hypertension group showed lower scores for self-care behavior and self-efficacy than the controlled hypertension group. Only self-efficacy significantly affected self-care behavior in the latter group, whereas self-efficacy, education level, and family support affected self-care behavior in the former group. CONCLUSIONS: The study results indicated that strategies for uncontrolled hypertension elderly patients should consider patients' educational, family support, and self-efficacy levels in order to improve their self-regulation. PMID- 28831844 TI - Ethics Regulation in Social Computing Research: Examining the Role of Institutional Review Boards. AB - The parallel rise of pervasive data collection platforms and computational methods for collecting, analyzing, and drawing inferences from large quantities of user data has advanced social computing research, investigating digital traces to understand mediated behaviors of individuals, groups, and societies. At the same time, methods employed to access these data have raised questions about ethical research practices. This article provides insights into U.S. institutional review boards' (IRBs) attitudes and practices regulating social computing research. Through descriptive and inferential analysis of survey data from staff at 59 IRBs at research universities, we examine how IRBs evaluate the growing variety of studies using pervasive digital data. Findings unpack the difficulties IRB staff face evaluating increasingly technical research proposals while highlighting the belief in their ability to surmount these difficulties. They also indicate a lack of consensus among IRB staff about what should be reviewed and a willingness to work closely with researchers. PMID- 28831845 TI - Examining school-day dietary intakes among Canadian children. AB - Understanding how dietary intakes vary over the course of the school day can help inform targeted school-based interventions, but little is known about the distribution or determinants of school-day dietary intakes in Canada. This study examined differences between school-hour and non-school-hour dietary intakes and assessed demographic and socioeconomic correlates of school-hour diet quality among Canadian children. Nationally representative data from the Canadian Community Health Survey were analyzed using 24-h dietary recalls falling on school days in 2004 (n = 4827). Differences in nutrient and food-group densities during and outside of school hours and differences in School Heathy Eating Index (School-HEI) scores across sociodemographic characteristics were examined using survey-weighted, linear regression models. Children reported consuming, on average, 746 kcal during school hours (one-third of their daily energy intakes). Vitamins A, D, B12, calcium, and dairy products densities were at least 20% lower during school hours compared with non-school hours. Differences in School-HEI scores were poorly explained by sociodemographic factors, although age and province of residence emerged as significant correlates. The school context provides an important opportunity to promote healthy eating, particularly among adolescents who have the poorest school-hour dietary practices. The nutritional profile of foods consumed at school could be potentially improved with increased intake of dairy products, thereby increasing intakes of protein, vitamin A, vitamin D, calcium, and magnesium. PMID- 28831846 TI - Isolation, structural identification and biological characterization of two conopeptides from the Conus pennaceus venom. AB - A novel anti-mollusk conopeptide pn4c was isolated from the Conus pennaceus venom by repeated HPLC fractionation based on the activity against freshwater snails. The primary structure of pn4c was determined by the mass spectrometric de novo sequencing analysis. In addition, pn3a was isolated from the same fraction containing pn4c, as a peptide with unknown functions. PMID- 28831847 TI - How to use a corticosteroid nasal spray. AB - Rationale and key points This article outlines the appropriate and effective technique for using a corticosteroid nasal spray. If these sprays are used inappropriately, they will be ineffective and might reduce the patient's adherence to the treatment. Nurses can use the information in this article to advise patients on the appropriate technique for using a corticosteroid nasal spray. " Topical corticosteroid nasal sprays are commonly used to treat seasonal and persistent allergic rhinitis, which cause inflammation inside the nose and can lead to nasal blockage. Where inflammation inside the nose is the predominant symptom of nonallergic rhinitis, corticosteroid nasal sprays can also be used as a treatment modality. " Corticosteroid nasal sprays do not reduce inflammation immediately and can take up to two weeks before the patient experiences the benefits of using the spray. Patients should be made aware that a corticosteroid nasal spray does not work immediately and requires daily use to become effective. " Preparing the nose through cleansing, for example by performing nasal douching, is recommended as an adjunctive treatment. Reflective activity 'How to' articles can help update your practice and ensure it remains evidence based. Apply this article to your practice. Reflect on and write a short account of: " How you think this article will change your practice. " How you could use this information to educate your patients and colleagues on the appropriate technique for using a corticosteroid nasal spray. PMID- 28831848 TI - Action and inaction in multi-behaviour recommendations: a meta-analysis of lifestyle interventions. AB - This meta-analysis examined theoretical predictions about the effects of different combinations of action (e.g., start an exercise regime) and of inaction (e.g., reduce screen time, rest in between weight lifting series) recommendations in smoking, diet, and physical activity multiple-domain interventions. The synthesis included 150 research reports of interventions promoting multiple behaviour domain change and measuring change at the most immediate follow-up. The main outcome measure was an indicator of overall change that combined behavioural and clinical effects. There were two main findings. First, as predicted, interventions produced the highest level of change when they included a predominance of recommendations along one behavioural dimension (i.e., predominantly inaction or predominantly action). Unexpectedly, within interventions with predominant action or inaction recommendations, those including predominantly inaction recommendations had greater efficacy than those including predominantly action recommendations. This effect, however, was limited to interventions in the diet and exercise domains, but reversed (greater efficacy for interventions with predominant action vs. inaction recommendations) in the smoking domain. These findings provide important insights on how to best combine recommendations when interventions target clusters of health behaviours. PMID- 28831849 TI - Launching Successful Beginnings for Early Career Faculty Researchers. AB - Junior faculty follow a research path replete with challenges as they strive to create knowledge in their area of interest while balancing new responsibilities. Unlike graduate school, where students focus inward on personal development, junior faculty must add responsibilities in ways that hold them accountable as members of a university. This special article deals with three themes of interest to new junior faulty launching research programs: personal development, collaboration and team development within university settings, and funding advice. Strategies in these areas provide guidance on navigating early careers and finding success in the academic setting. PMID- 28831850 TI - Characterization of lignocellulose particles during lignocellulose solubilization by Clostridium thermocellum. AB - Clostridium thermocellum is a candidate bacterium for lignocellulose utilization due to its efficient lignocellulose solubilization ability. It has been reported that C. thermocellum efficiently degrades purified cellulose substrates, but cannot completely degrade milled lignocellulose powders. Evaluation of cellulose and hemicellulose contents in a lignocellulose residue after the cultivation of C. thermocellum indicated that C. thermocellum degraded cellulose and hemicellulose equally. Microscopic observations demonstrated that C. thermocellum significantly degraded small-sized lignocellulose particles, but it only partially degraded the larger sized particles. The lignin content of the large sized particles was higher than that of the small particles. The remained large sized particles included vascular tissues. These results suggest that the lignified structures such as vascular tissues in milled lignocellulose were less susceptible to bacterial lignocellulose solubilization. PMID- 28831851 TI - An attributional life cycle assessment for an Italian residential multifamily building. AB - The study describes an attributional life cycle assessment carried out according to the ISO standards and focused on an Italian multifamily residential building. The aim was developing an exhaustive and reliable inventory of high-quality primary data, comparing the environmental impacts along the three stages of the building life cycle. The pre-use phase takes into account the production of all the construction materials, transportation, and on-site assembling. The use phase quantifies the resource consumptions for 50 years of the building utilization and ordinary maintenance. The end-of-life phase includes the building demolition and the management of generated wastes. The results quantify how the design criteria affect the environmental performances of the residential building along its life cycle. The role of the pre-use phase appears remarkable for global warming potential (GWP), due to the huge impacts of steel and concrete production processes. The use phase gives the largest contributions, which reach 77% and 84% of the total, for the categories of global warming and non-renewable energy. The end-of-life phase provides limited avoided impacts. A comparative analysis quantifies the improvements achievable with an alternative type of partitions and external walls. Acronyms: AC: air conditioning; C&DW: construction and demolition waste; CFL: compact fluorescent lamp; DHW: domestic hot water; EC: European Commission; EU: European Union; GDP: gross domestic product; GHG: greenhouse gases; GWP: global warming potential; LCA: life cycle assessment; LCI: life cycle inventory; LCIA: life cycle impact assessment; MFA: material flow analysis; NREP: non-renewable energy potential; RINP: respiratory inorganics potential; WFD: Waste Framework Directive. PMID- 28831852 TI - Perspectives on power relations in human health and well-being. PMID- 28831853 TI - Defining active progressive multiple sclerosis. AB - BACKGROUND: It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). OBJECTIVE: To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. METHODS: Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24). RESULTS: Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. CONCLUSION: Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression. PMID- 28831854 TI - Impact of the economic crisis on health-related behaviors in Italy. AB - BACKGROUND: Evidence exists supporting the impact of the Great Recession on health-related behaviors internationally, though few studies are available concerning the Italian population. AIM: To assess the impact of the late 2000s economic crisis on health-related behaviors linked to population mental health in Italy. METHODS: Descriptive study. Health indicators came from the Italian Institute of Statistics database (years 2000-2015). Statistics performed by means of linear regression models. RESULTS: Increased smokers (beta = 1.68, p = .03), heavy smokers, that is, people smoking 11-20 cigarettes per day (beta = 2.18, p = .04) or more than 20 cigarettes per day (beta = 1.04, p < .01) and mean number of smoked cigarettes per day (beta = 0.56, p = .02) were noticeable. Also, prevalence of overweight increased (beta = 0.91, p = .04), while the Italian families' expenditure for alcoholic beverages decreased (beta = -812.80, p = .01). Alcohol consumption decreased (beta = -0.60, p < .01), especially in men (beta = -0.95, p < .01); binge drinking increased in years 2009-2010. No change was noticeable in the diet indicators collected. CONCLUSION: The economic crisis may have increased smoking, overweight and binge drinking in Italy (though data on the latter phenomenon are not conclusive), and reduced overall alcohol consumption. PMID- 28831855 TI - Social support perceptions of Turkish people with schizophrenia: What helps and what doesn't help. AB - BACKGROUND: Social support is an important facilitator of the quality of life for people with schizophrenia. This study examines what is perceived as helpful and unhelpful support from the members of the natural social networks by 32 Turkish people with schizophrenia. MATERIAL: Semi-structured interviews and thematic analysis were used to examine what is perceived as helpful and unhelpful support. DISCUSSION AND CONCLUSION: The findings suggested that instrumental, emotional and socialization supports were the general categories that capture the perceptions of support. Intrusion and belittling/rejection appeared as unhelpful. It is important to take these perceptions into account in providing psychoeducation to families and in designing psychosocial intervention programs. PMID- 28831856 TI - The impact of medial cuneiform bone variant measures on the severity of hallux valgus: A radiological study. AB - PURPOSE: The aetiology of hallux valgus (HV) is multifactorial in nature. The first metatarsocuneiform joint obliquity is a well-known factor in the development of the deformity. The purpose of this study is to assess the correlation of different medial cuneiform radiological measures on the severity of HV. METHODS: Full weight-bearing anteroposterior views of 152 feet with different clinical severity are divided into four groups: without deformity and with mild, moderate and severe deformities. Three medial cuneiform angles were assessed, namely, the first metatarsocuneiform angle (MCA), the first metatarsocuneiform slope angle (MCSA) and the medial cuneiform lateral tilt angle (MCLTA). RESULTS: The first MCA average values of groups 1, 2, 3 and 4 were (25.16 +/- 5.74 degrees , 27.38 +/- 6.14 degrees , 30.27 +/- 5.62 degrees and 34.28 +/- 6.81 degrees ), respectively. Statistical differences were detected between groups (1, 3) and (1, 4) with p values of 0.034 and 0.001, respectively. The average values of the first MCSA of groups 1, 2, 3 and 4 were 19.26 +/- 4.97 degrees , 22.54 +/- 5.62 degrees , 26.13 +/- 6.36 degrees and 32.17 +/- 5.85 degrees , respectively. Significant differences were detected between groups (1, 3) and (1, 4) with p values of 0.04 and 0.023, respectively. Average values of the MCLTA of groups 1, 2, 3 and 4 were 80.85 +/- 4.49 degrees , 74.56 +/- 5.28 degrees , 62.38 +/- 6.34 degrees and 58.78 +/- 6.25 degrees , respectively. Statistical significances were detected between groups (1, 2), (1, 3) and (1, 4) with p values of 0.026, 0.018 and 0.001, respectively. CONCLUSIONS: Increasing the medial cuneiform lateral tilt increases the first metatarsocuneiform articulation obliquity demonstrated by the increase in the first MCSA which in term enhances the progression of varus deformity of the first metatarsal bone explained by the increase in the first MCA. PMID- 28831857 TI - Paranasal Sinus Disease in Children With Headache. AB - BACKGROUND: Sinus headache is one of the most frequent misdiagnosis given to children with headache. The objective of this study is to evaluate the frequency of sinus disease in children with headache that do not fulfill the criteria for headache attributed to disorder of the nose or paranasal sinuses. METHODS: This is a prospective study conducted at the authors' pediatric neurology clinic. Data from children with headache was evaluated and compared with a disease control group composed of children without history of headache. All patients underwent neuroimaging assessment. Patients with diagnosis of acute infectious sinus disease were excluded from the analysis. The type of headache was classified according to the International Headache Society. Statistical analysis was performed using the Fisher exact test, with a level of significance of .05. RESULTS: A total of 62 patients with headache were evaluated; 24 boys, 38 girls, ages ranging from 3 to 18 years (mean = 9.7 years). Of the patients, 29 had migraine without aura, 4 had frequent episodic tension type headache, 3 had both migraine without aura and frequent episodic tension type headache, 3 had migraine with brainstem aura, 2 had episodic tension type headache, 1 had migraine with aura. In 20 patients the type of headache could not be established. The disease control group had 41 patients; 25 boys, 16 girls, ages ranging from 3 to 17 years (mean = 7.3 years). Sinus abnormalities detected by neuroimaging were present in 12 patients in the headache group and in 11 patients in the disease control group ( P = .469). CONCLUSION: The authors conclude that sinus abnormalities are a common finding in neuroimaging tests of children with or without headache. Sinus disease disclosed by neuroimaging evaluation should not preclude the diagnosis of migraine or other types of primary headache. PMID- 28831858 TI - Intuition in Clinical Decision Making: Differences Among Practicing Nurses. AB - PURPOSE: To examine the relationships and differences in the use of intuition among three categories of practicing nurses from various clinical units at a medical center in the Midwest. DESIGN: Descriptive, correlational, cross sectional, prospective design. METHOD: Three categories of nurses were based on the clinical unit: medical/surgical nurses ( n = 42), step-down/progressive care nurses ( n = 32), and critical care nurses ( n = 24). Participants were e-mailed the Rew Intuitive Judgment Scale (RIJS) via their employee e-mail to measure intuition in clinical practice. Participants were also asked to rate themselves according to Benner's (novice to expert) proficiency levels. FINDINGS: Nurses practicing at higher self-reported proficiency levels, as defined by Benner, scored higher on the RIJS. More years of clinical experience were associated with higher self-reported levels of nursing proficiency and higher scores on the RIJS. There were no differences in intuition scores among the three categories of nurses. CONCLUSION: Nurses have many options, such as the nursing process, evidence-based clinical decision-making pathways, protocols, and intuition to aid them in the clinical decision-making process. Nurse educators and development professionals have a responsibility to recognize and embrace the multiple thought processes used by the nurse to better the nursing profession and positively affect patient outcomes. PMID- 28831859 TI - Fabrication of dopamine modified polylactide-poly(ethylene glycol) scaffolds with adjustable properties. AB - Bio-based polymers have been widely used to be as scaffolds for repairing the bone defects. However, the polymer scaffolds are generally lack of bioactivity and cell recognition site. Seeking effective ways to improve the bioactivity and interaction between materials and tissue or cells is clinically important for long-term performance of bone repair materials. In this work, polylactide-b poly(ethylene glycol)-b-polylactide (PLA-PEG-PLA, PLEL) tri-block copolymers were firstly synthesized by ring-opening polymerization of lactide using PEG with various molecular weights. Inspired by excellent adhesion of dopamine (DA), a facile and effective method was developed to fabricate polydopamine (PDA) and polydopamine/nano-hydroxyapatite (PDA/n-HA) modified PLEL scaffolds by deposition of PDA and PDA/n-HA coating. The surface structure, degradation rates and mineralization of the modified PLEL scaffolds were investigated, and obviously improved after immobilization of PDA and PDA/n-HA coatings. Moreover, the biocompatible results showed a significant increase in cells viability and adhesion. Therefore, the surface modification with PDA and PDA/n-HA could not only adjust the properties of scaffolds, but also reinforce the interfacial adhesion between the PLEL and cells. PMID- 28831861 TI - The impact of temporal variability of excess sludge characteristics on the effects obtained in the process of its ultrasonic disintegration. AB - This paper aimed to indicate the characteristics of excess sludge, which have the greatest impact on the effects obtained during its ultrasonic disintegration (UD). The direct and technological effects observed after sludge disintegration and anaerobic digestion (AD) depend on the factors affecting the quality of its matrix and simply on the parameters of a disintegrator. Sludge samples originate from a Central Waste Water Treatment Plant in Gliwice, and were collected after mechanical thickening by a monthly period. This approach allowed to observe the temporal changes of sludge characteristics, in a continuous manner. To evaluate the achieved disintegration effects, the following indicators were used: degree of disintegration (DDCOD) and the author's indicators describing the direct and technological effects of UD (IDi, ITi, ITd), based on the changes in the sludge characteristics. Disintegration was carried out by means of an ultrasonic device equipped with a thin sonotrode. AD was conducted under mesophilic conditions for 20 days. Statistical analysis confirmed that the most important parameters of sludge, which determine obtained effects, were total and volatile solids, capillary suction time, concentration of chemical oxygen demand and pH value. The investigations have also showed that the increase in sludge temperature during its disintegration has a significant impact on the magnitude of other effects obtained in the process. PMID- 28831860 TI - Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy. AB - INTRODUCTION: In several observational studies, statin use has been associated with reduced risk of progression and mortality in men with prostate cancer (PCa). The study aim was to investigate the association between statin use at time of PCa diagnosis and time to PCa progression in men with advanced or metastatic PCa receiving androgen deprivation therapy (ADT) as primary treatment. PATIENTS AND METHODS: The study population consisted of all men receiving ADT as primary therapy at two Danish Urological Departments in 2007-2013. The primary outcome was time to progression defined as castration-resistant PCa (CRPC) or PCa death. Survival analyses were conducted with Kaplan-Meier analyses, cause specific Cox proportional hazards models, and competing risk analyses. RESULTS: A total of 537 men were included, of whom 141 were statin users at time of diagnosis. The median follow-up time was 5.7 years (95% CI: 5.1-6.2). No significant difference in progression-free survival between statin users and non-statin users was observed at 5 years; 29% for statin users (95% CI: 19-40%) and 28% (95% CI: 23-34%) for non-statin users, p = 0.31. In multivariable Cox analyses, there was no significant association between statin use and risk of progression, HR 0.98 (95% CI: 0.72-1.32). In competing risk analyses the 5-year cumulative incidence of progression was 55% (95% CI: 46-64%) for statin users and 62% (95% CI: 57-67%) for non-statin users, p = 0.11. CONCLUSION: In the current study, statin use at time of PCa diagnosis was unrelated to time to progression in men primarily treated with ADT. PMID- 28831862 TI - Prunus mume extract exerts antioxidant activities and suppressive effect of melanogenesis under the stimulation by alpha-melanocyte stimulating hormone in B16-F10 melanoma cells. AB - In the current study, we examined the antioxidant and skin-whitening properties of Prunus mume extract (PME). The ability of PME to scavenge 2,2-diphenyl-1 picrylhydrazyl (DPPH) radicals was investigated in vitro. At a concentration of 1000 MUg/mL, PME neutralized >45% free radical activity. Cell viability assessment with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that at concentrations <1500 MUg/mL, PME does not exert cytotoxic effects on murine B16 melanoma (B16) cells. Morphological analysis disclosed that melanin production is inhibited in B16 cells treated with 250 nM alpha-melanocyte-stimulating hormone (alpha-MSH) and PME. We conclude that fruit extracts of P. mume exert a skin-whitening effect by inhibiting melanin production via regulation of melanogenesis-associated protein expression in melanocytes. PMID- 28831863 TI - Emodin extends lifespan of Caenorhabditis elegans through insulin/IGF-1 signaling pathway depending on DAF-16 and SIR-2.1. AB - The naturally occurring anthraquinone emodin has been serving primarily as an anti-bacterial and anti-inflammatory agent. However, little is known about its potential on anti-aging. This investigation examined the effect of emodin on lifespan and focused on its physiological molecular mechanisms in vivo. Using Caenorhabditis elegans (C. elegans) as an animal model, we found emodin could extend lifespan of worms and improve their antioxidant capacity. Our mechanistic studies revealed that emodin might function via insulin/IGF-1 signaling (IIS) pathway involving, specifically the core transcription factor DAF-16. Quantitative RT-PCR results illustrated that emodin up-regulated transcription of DAF-16 target genes which express antioxidants to promote antioxidant capacity and lifespan of worms. In addition, attenuated effect in sir-2.1 mutants suggests that emodin likely functioned in a SIR-2.1-dependent manner. Our study uncovers a novel role of emodin in prolonging lifespan and supports the understanding of emodin being a beneficial dietary supplement. PMID- 28831866 TI - Letter. AB - How about a Think Drink campaign for nurses working in the wards? They are often dehydrated themselves. PMID- 28831865 TI - Bribes and plasters won't do. AB - I disagree with Graham Scott's editorial (9 August). We should not be bribing men into nursing, we should be fighting to reinstate the bursary for all healthcare students and be looking at the issues around gender stereotyping and perceptions relating to occupations. PMID- 28831867 TI - 'Nothing ventured, nothing gained'. AB - Winifred Oluchukwu Eboh qualified as a registered general nurse in 1984 and as a midwife 18 months later. She moved into higher education 17 years ago, completing a PhD in public health in 2004, and is now lecturer in adult nursing at the University of Essex. PMID- 28831869 TI - Poor sleep patterns are detrimental to waistlines and metabolic health. AB - Adults in the UK who have poor sleep patterns are more likely to be overweight and obese and have poorer metabolic health, study findings have found. PMID- 28831868 TI - Hydration benefits everyone. AB - I welcome the Think Drink hydration campaign (online news, 11 August). PMID- 28831870 TI - The nurses who risk their safety. AB - Prisons are overcrowded and understaffed, leading to nurses being subjected to increasing danger, the RCN says. There have been reports of nurses being held hostage, and a nurse manager was blinded in one eye last year after being punched by an inmate at a young offenders' institution in Kent. PMID- 28831871 TI - First Macmillan bereavement nurse starts work. AB - A hospital in Essex has appointed the UK's first dedicated Macmillan bereavement nurse. PMID- 28831864 TI - Aging, Health, and Quality of Life for Older People Living With HIV in Sub Saharan Africa: A Review and Proposed Conceptual Framework. AB - OBJECTIVE: The number of people living with HIV (PLWH) over 50 years old in sub Saharan Africa is predicted to triple in the coming decades, to 6-10 million. Yet, there is a paucity of data on the determinants of health and quality of life for older PLWH in the region. METHODS: A review was undertaken to describe the impact of HIV infection on aging for PLWH in sub-Saharan Africa. RESULTS: We (a) summarize the pathophysiology and epidemiology of aging with HIV in resource-rich settings, and (b) describe how these relationships might differ in sub-Saharan Africa, (c) propose a conceptual framework to describe determinants of quality of life for older PLWH, and (d) suggest priority research areas needed to ensure long-term gains in quality of life for PLWH in the region. CONCLUSIONS: Differences in traditional, lifestyle, and envirnomental risk factors, as well as unique features of HIV epidemiology and care delivery appear to substantially alter the contribution of HIV to aging in sub-Saharan Africa. Meanwhile, unique preferences and conceptualizations of quality of life will require novel measurement and intervention tools. An expanded research and public health infrastructure is needed to ensure that gains made in HIV prevention and treamtent are translated into long-term benefits in this region. PMID- 28831872 TI - Female genital mutilation. AB - Essential facts Female genital mutilation (FGM) is any procedure that removes all or part of the female genital organs for cultural or any other non-therapeutic reasons. FGM is a form of child abuse and gender violence against women. About 137,000 females in England and Wales have undergone it. PMID- 28831873 TI - More training places made available through clearing. AB - Extra nurse training places promised by the government have been made available for students receiving their A-level results. Universities were told early last week that they will have additional capacity on their nursing degree courses, which begin within weeks. PMID- 28831875 TI - 'My nurse helped me believe I could recover - and that I deserved to'. AB - Before nurse Sarah Moody started working with me 18 months ago, I'd been an inpatient of eating disorder services for 11 years, and had been under the care of intense mental health services since I was 13. PMID- 28831876 TI - Chief nurse to lead NHS London region. AB - England's chief nursing officer (CNO) Jane Cummings will take charge of the NHS England London region until a permanent regional director has been recruited. PMID- 28831878 TI - Mental health nurses needed for Grenfell team. AB - Nurses with backgrounds in mental health services or experience of providing psychological therapies are needed to join a team supporting the community affected by the Grenfell Tower fire. PMID- 28831879 TI - 'Politics first, strategy later' fails in workforce planning. AB - The government's shambolic approach to planning the nursing workforce in England has been laid bare again, although this time a positive spin can be put on its ham-fisted attempt to address the crisis. PMID- 28831880 TI - Don't make an expensive mistake with tuition fees and loans. AB - What will student tuition fees mean for nurses? From August, new nursing and midwifery students - and those entering most allied healthcare professions - no longer receive NHS bursaries and will have to pay tuition fees for their courses at English universities. They will have access to the student loans system available to other students. With yearly tuition costs of up to L9,250, plus means-tested maintenance loans, many nurses will start their careers with debts of L40,000 or more. PMID- 28831881 TI - Routine HIV tests at GPs shown to be cost-effective. AB - Offering routine HIV tests to people registering with a new GP surgery in high risk areas is cost-effective and could save lives, a study has shown. PMID- 28831882 TI - Tai chi improves balance and reduces the risk of falls. AB - Doing tai chi may help prevent falls in older and at-risk adults, an analysis of research has found. PMID- 28831883 TI - Nursing in blood and transplant services. AB - In April, NHS Blood and Transplant Services (NHSBT) launched its nursing strategy, setting out its vision up to 2020. PMID- 28831884 TI - Readers' panel - Would bringing back nurses' homes improve recruitment? AB - Our experts consider a hot topic of the day. PMID- 28831885 TI - Please don't make me ask 'How did I do?' AB - Here I am, gaunt, twitching with stress and bug-eyed. Just another nurse revalidation, in other words. PMID- 28831886 TI - Benefits of reminiscence therapy. AB - During my second placement in my first year of training, I was working in a community hospital where I helped to care for an older male patient, who I will call Ben. PMID- 28831887 TI - Sir Ian McKellen joins healthcare assistants at Wigan's Pride parade. AB - Healthcare assistants had a brush with stardom when they marched with Sir Ian McKellen at Pride, pictured above. PMID- 28831890 TI - Reducing health inequalities. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article outlined the health inequalities that people with serious mental illness (SMI) may experience. It acknowledged the barriers they often encounter in accessing healthcare services, and discussed how lifestyle behaviours, symptoms of mental illness and the side effects of medication can contribute to reduced life expectancy. PMID- 28831891 TI - Will the money tree grow another branch for us? AB - It would be churlish in the extreme to appear unimpressed by the government's announcement of plans to increase staffing numbers in mental health services. PMID- 28831892 TI - Supporting safe sexual and intimate expression among older people in care homes. AB - This article outlines how care home staff can support safe sexual and intimate expression among older people. Older people may continue to engage in sexual and intimate acts in a residential setting; however, because of the stigma associated with sexual and intimate expression among older people, many care homes prohibit such intimacy. It is essential that care home staff adopt a person-centred approach to care that recognises the importance of maintaining the dignity and autonomy of residents while considering the potential for harm associated with sexual and intimate expression. This article discusses the issues associated with managing sexual and intimate expression among older people in care homes and uses a case study example to assist care homes in developing sexual health policies. PMID- 28831893 TI - Student life - A tool for healing the planet. AB - Climate change and sustainability could be embedded in nursing degree curricula thanks to a pioneering scheme involving universities across Europe. PMID- 28831894 TI - Should patients complete the course? AB - In a recent article in the British Medical Journal (BMJ), a group of experts including infectious disease specialists and microbiologists discussed whether patients should stop taking antibiotics when they feel better. PMID- 28831895 TI - Healthcare assistant fined for accessing medical records of friends and colleagues. AB - NHS staff are being reminded of the potentially serious consequences of prying into patients' records without a valid reason after a healthcare assistant (HCA) secretly accessed medical information on 29 people. PMID- 28831896 TI - How to make it go your way on the day. AB - Finally, your big day has come. As you wake up on 'interview day' you will likely feel a mixture of nervous anticipation and excitement. A new job can open doors to the next chapter in your life, so this is only natural, but first you must be offered the post. PMID- 28831897 TI - We need to rethink global spending priorities. AB - The Alma-Ata declaration, signed by 134 countries in 1978, was a landmark for public health. It recognised that the 'attainment of health by people in one country directly concerns and benefits every other country', and that economic and social development, alongside improved access to primary healthcare, is critical to attaining health for all. PMID- 28831898 TI - Recognising and responding to care erosion: part 2. AB - This article is the second in a two-part series discussing a gradual decline in standards of care, termed 'care erosion'. The first part of this article used cognitive dissonance theory to discuss the psychosocial mechanisms involved in care erosion and focused on the nurse's role in identifying and preventing declining standards in care. This article, part two, explores the wider involvement of individuals, organisations and nurse education in preventing care erosion, with a particular focus on reflection; mastery of nursing skills and care; supporting nursing values; and addressing denial and trivialisation of, and justifications for, substandard care. PMID- 28831903 TI - Think Drink campaign gets national attention. AB - A hospital's award-winning scheme - which helps patients recover faster from surgery side effects by keeping them hydrated pre-operation - is being shared nationwide. PMID- 28831904 TI - Good care cannot help all. AB - Thank you for the thoughtful article 'Nurse backs challenge to law on assisted dying' (analysis, 26 July). It was well balanced, but I feel I must challenge some statements in it. PMID- 28831907 TI - Study challenges advice to always complete antibiotic courses. AB - Patients may not need to complete a course of antibiotics as previously recommended by medical advice, researchers have argued. PMID- 28831905 TI - Letter. AB - The news of expanding nurse training places is yet another announcement by the government devoid of any attempt to take any accountability for their role in the destruction of our profession. PMID- 28831908 TI - A scheme off to a slow start. AB - Just 30 nurse apprentices are due to begin university courses in September, a figure that falls far short of the 1,000 a year predicted by the government once the scheme is fully established. PMID- 28831909 TI - We must speak of hope as well as catastrophe. AB - Al Gore, the former US vice-president and now campaigner on climate change, has just released a follow-up to his groundbreaking 2006 documentary An Inconvenient Truth. Gore's first film won an Oscar and grossed $49 million - astonishing for a documentary. PMID- 28831910 TI - Delirium in advanced cancer may have link to lower survival rate. AB - Patients with advanced cancer who present at emergency departments (EDs) with delirium are prone to an earlier death, a study has found. PMID- 28831911 TI - Nanoparticle-Based Drugs: A Potential Armamentarium of Effective Anti-Cancer Therapies. AB - BACKGROUND: Cancer is a foremost cause of mortality worldwide. Available treatments are non-specific and cannot cross biological barriers, which have restricted their usages. Furthermore, the side effects of existing treatments have promoted the exploration of nanotechnological approaches to achieve site specific drug delivery. The diminutive sizes of nanoparticles, and hence, their large surface to volume ratios, means they are inherently more efficient at delivering drugs to specific tumor sites. This review highlights different approaches to cancer therapy, and the importance of nanoparticles in cancer therapy. Applications and limitations of different types of nanomedicines used for cancer imaging and treatment are discussed. METHODS: We undertook extensive literature search of bibliographic databases (e.g. PubMed, Google Scholar, Medline, Web of Science etc.) using different keywords and combination of keywords to retrieve the relevant information. RESULTS: This review provides overview of cancer and need for nanoparticle-based therapies for their treatment, and deliberates the different types of nanomaterials used as nanomedicines for cancer imaging and treatment in addition to their applications and limitations. Furthermore, applications of nanoparticles in modern cancer therapies and research strategies have been explored to overcome cancer. CONCLUSION: Nanotechnology has provided a lot of novel therapeutics for the diagnosis and treatment of different cancers over the last 2-3 decades. However, there are few limitations of nanotechnological based anti-cancer therapies. Nanotechnology is enabling novel, specialized treatments for cancer; this will be a high-impact area of nanomedicine yielding more medical advancements with the next 10 years. PMID- 28831912 TI - Clinical, Prognostic and Therapeutic Significance of Heat Shock Proteins in Cancer. AB - BACKGROUND: Heat Shock Proteins (HSPs) constitute a group of proteins that play a crucial role in the process of protein folding. HSPs are also known to modulate a number of key apoptotic factors. High expression of these proteins is reported in an array of cancers, such as breast, prostate, colorectal, lung, ovarian, gastric, oral and esophageal cancer. Ample amount of investigations were carried out on a variety of cancers suggesting HSPs as a promising hallmark in cancers. Their expression profile in several tumors elucidates that they help in proliferation, invasion, metastasis and death of cancerous cells. Detection of the levels of heat shock proteins and their specific antibodies in the sera of diseased individuals can play an important role in cancer diagnosis. OBJECTIVES: This review will present and summarize latest research being carried out on heat shock proteins. It will also highlight the clinical and prognostic features of HSP27, HSP60, HSP70, HSP90 and HSP110, and will discuss future implications of HSPs in the diagnosis and prognosis of cancer. Furthermore, the role of heat shock proteins as a therapeutic target in cancer will be discussed. In addition, the review article will report various studies, where HSPs have been targeted for their therapeutic potential. CONCLUSION: In summary, multiple experimental investigations have been successful in suggesting the role of heat shock protein as a clinical biomarker and therapeutic target in cancer. HSPs are associated with a number of cancer hallmarks such as cell proliferation, invasion and metastasis. Inhibition of HSPs has resulted in successful therapeutic outcome in cancer. It has served as a novel anti-cancer therapy for the treatment of several cancer forms. However, more experimental studies are required to elucidate the reliability and efficacy of heat shock proteins in combination with other conventional markers for cancer diagnosis and prognosis. Novel and effective interventions through HSP inhibition are expected to decrease the burden of cancer in the near future. PMID- 28831913 TI - Pharmacology and Perioperative Considerations for Psychiatric Medications. AB - BACKGROUND: Psychotropic medications are being used increasingly as analgesics and for other off-label indications for patients with and without psychiatric conditions. While the pharmacology of most of these drugs is now known, their interaction with anesthetic drugs and implications of regular use are still relatively unclear. OBJECTIVE: We discuss the pharmacology, side effects, and potential medication interactions with anesthetic agents of various commonly prescribed psychotropic medications and the current recommendations regarding the continuation of these medications during the patients' perioperative care. METHOD: A review of the current literature present on PubMed and Medline was conducted between the years 2000-2016. The reference lists of each selected article were also reviewed for additional sources of information. CONCLUSION: Psychotropic medications can be broadly divided into classes, which include antidepressants, antipsychotics, anxiolytics, mood stabilizers, and stimulants. Although most evidence suggests the continuation of these medications in the perioperative period, it is still important to determine how psychotropic medications interact with routinely used anesthetic agents and which medications should be continued and which should not be continued on an individualized basis for each patient. PMID- 28831914 TI - Enhancement in Biological Activity of L-Asparginase by its Conjugation on Silica Nanoparticles. AB - BACKGROUND: L-asparaginase is a drug of choice in the treatment of Hodgkin's lymphoma and acute lymphoblastic leukemia. Production of its bioconjugates can increase its half-life, stability and decrease its immunogenicity. OBJECTIVE: The aim of the present study was to immobilize this drug on silica nanoparticles by two different cross-linking agents. METHOD: The drug was conjugated to nanoparticles by two cross-linking agents; 1-ethyl-3-(3- dimethylaminopropyl) carboiimide HCl (EDC) or glutaraldehyde. The effect of the drug to the nanoparticles ratio, the amount of cross-linking agents and the time of conjugation were optimized according to the zeta potential, size particle and the enzyme immobilization efficiency. Conjugation of L-asparaginase to nanoparticles was confirmed by FT-IR and TEM. The activity, kinetic profiles, stability against pH changes, thermal and storage stability of the native and immobilized drug were compared. RESULTS: The results showed significant increase in pH range of the stability and decrease in the km value of the drug after immobilization; indicating an increase in the enzyme tendency for the substrate. The Time of stability of the drug increased after immobilization in plasma and phosphate buffer saline which can increase its half-life of circulation. CONCLUSION: The activity and stability of immobilized drug by EDC were better than glutaraldehyde. PMID- 28831915 TI - Translating the Potential of Stem Cells for Diabetes Mellitus: Challenges and Opportunities. AB - BACKGROUND: Diabetes mellitus, the widely prevalent disease of pancreas, is a metabolic disorder caused by autoimmune destruction of beta cells or insulin insufficiency or insulin resistance. Replacement of damaged beta cells by cell therapy can mitigate the condition and re-establish normal metabolic control. This has opened up new horizons for research, such as stem cells, cellular reprogramming and beta cell regeneration. OBJECTIVE: The goal of the study was to summarize the available literature on the use of stem cells for the regeneration of pancreatic beta cells and treatment of diabetes mellitus. RESULTS AND CONCLUSION: Stem cells are exceptional having the potential to self renew and differentiate in many lineages. Stem cells hold tremendous potential to regenerate beta cells and treat diabetes mellitus but many milestones on the way are yet to be achieved. But researchers do believe that stem cells and regenerative medicines will be widely used in clinical practices and possibly new effective methodology would be designed for even cure, mitigate and reduce the social burden of diabetes mellitus. PMID- 28831916 TI - Discovery and Development of Natural Products and their Derivatives as Photosensitizers for Photodynamic Therapy. AB - Photodynamic therapy (PDT) has been developed as an alternative modality for the management of neoplastic and nonneoplastic diseases. It is a minimally invasive treatment that involves the interaction of a non-toxic photosensitizer (PS), light and molecular oxygen to generate reactive oxygen species (ROS), resulting in the destruction of unwanted cells and tissues. Discovery and development of new PSs with optimized properties are much crucial for achieving a desirable therapeutic efficacy. This review describes the photochemical and photobiological mechanisms of PDT, and outlines the recent progress in discovery and development of natural products and their derivatives as phototherapeutic drugs. The potential limitations and future perspectives of PDT in clinical application are also presented and discussed. PMID- 28831917 TI - Diversity and Functionality of Mycobacterial Mycolic Acids in Relation to Host pathogen Interactions. AB - BACKGROUND: The complex architecture of the mycobacterial cell wall is responsible for many physiological and infection-associated properties of these pathogens. Long chain mycolic acids with chiral functional groups constitute a major lipid envelope component, and therefore play a crucial role in determining the permeability and fluidity of the cell wall. Varying proportions of the different mycolate types are present in various mycobacteria. This serves to designate a specific mycolic acid profile, allowing the differentiation of species and subspecies. OBJECTIVE: In this review, we explore the diversity in mycolic acid chemical structure, its influence on cell wall permeability and consequences for virulence, and present how they might be exploited as research targets in diagnosis and chemotherapy. METHODS: The search of bibliographic databases for adequate, informative and valuable peerreviewed literature was undertaken. The proper papers were identified by the hand and electronic searching through the relevant to the topic-leading journals, key words, named authors, reference scanning, etc. RESULTS: The review is based on the ninety two carefully selected articles that allow this review to provide up-to-date information. Twenty nine papers were published within last 5 years, including 10 showed up in 2016-2017. CONCLUSION: The revision of the relevant literature showed that mycolic acids played a crucial role in host-pathogen interactions and thus might serve as a promising tool for differentiation of mycobacterial species and discovering novel tuberculocidal therapeutic strategies. PMID- 28831919 TI - Editorial: Natural Compounds and Their Derivatives as a Source of Promising Drugs for Diabetes and Insulin Resistance. PMID- 28831920 TI - Editorial: Drug Targets and Biomarkers for Obstetric/Gynecologic/Reproductive Diseases. PMID- 28831918 TI - A Therapeutic Connection between Dietary Phytochemicals and ATP Synthase. AB - For centuries, phytochemicals have been used to prevent and cure multiple health ailments. Phytochemicals have been reported to have antioxidant, antidiabetic, antitussive, antiparasitic, anticancer, and antimicrobial properties. Generally, the therapeutic use of phytochemicals is based on tradition or word of mouth with few evidence-based studies. Moreover, molecular level interactions or molecular targets for the majority of phytochemicals are unknown. In recent years, antibiotic resistance by microbes has become a major healthcare concern. As such, the use of phytochemicals with antimicrobial properties has become pertinent. Natural compounds from plants, vegetables, herbs, and spices with strong antimicrobial properties present an excellent opportunity for preventing and combating antibiotic resistant microbial infections. ATP synthase is the fundamental means of cellular energy. Inhibition of ATP synthase may deprive cells of required energy leading to cell death, and a variety of dietary phytochemicals are known to inhibit ATP synthase. Structural modifications of phytochemicals have been shown to increase the inhibitory potency and extent of inhibition. Sitedirected mutagenic analysis has elucidated the binding site(s) for some phytochemicals on ATP synthase. Amino acid variations in and around the phytochemical binding sites can result in selective binding and inhibition of microbial ATP synthase. In this review, the therapeutic connection between dietary phytochemicals and ATP synthase is summarized based on the inhibition of ATP synthase by dietary phytochemicals. Research suggests selective targeting of ATP synthase is a valuable alternative molecular level approach to combat antibiotic resistant microbial infections. PMID- 28831922 TI - Editorial: New Potential Targets for the Treatment of Biliary Diseases. PMID- 28831923 TI - The Food and Drug Addiction Epidemic: Targeting Dopamine Homeostasis. AB - Obesity is damaging the lives of more than 300 million people worldwide and maintaining a healthy weight using popular weight loss tactics remains a very difficult undertaking. Managing the obesity problem seems within reach, as better understanding develops, of the function of our genome in drug/nutrient responses. Strategies indicated by this understanding of nutriepigenomics and neurogenetics in the treatment and prevention of metabolic syndrome and obesity include moderation of mRNA expression by DNA methylation, and inhibition of histone deacetylation. Based on an individual's genetic makeup, deficient metabolic pathways can be targeted epigenetically by, for example, the provision of dietary supplementation that includes phytochemicals, vitamins, and importantly functional amino acids. Also, the chromatin structure of imprinted genes that control nutrients during fetal development can be modified. Pathways affecting dopamine signaling, molecular transport and nervous system development are implicated in these strategies. Obesity is a subtype of Reward Deficiency Syndrome (RDS) and these new strategies in the treatment and prevention of obesity target improved dopamine function. It is not merely a matter of gastrointestinal signaling linked to hypothalamic peptides, but alternatively, finding novel ways to improve ventral tegmental area (VTA) dopaminergic function and homeostasis. PMID- 28831924 TI - Management of Antiepileptic Treatment After Epilepsy Surgery - Practices and Problems. AB - BACKGROUND: Although epilepsy surgery is a recognized treatment option for drug resistant epilepsies since several decades, the management of antiepileptic drugs (AEDs) after successful surgery still remains one of the most difficult and unsolved therapeutic challenges. Indeed, no systematic controlled trials have been specifically conducted so far and no consensus or standardized guidelines regarding postsurgical drug discontinuation policy and procedures are available. METHODS: In this paper, we aim to provide an updated overview on the present knowledge on this topic, which is based mainly on retrospective studies reporting practices used in individual centers. RESULTS: Currently available data suggest that: 1) rate of seizure recurrence appears to be higher in patients undergoing early (before 6 months or 9 months according to different studies) AED withdrawal; 2) seizures that recur during AED tapering are easier to control than unprovoked postoperative seizure relapses; 3) there is no evidence to support negative long-term implications on seizure outcomes in patients who attempted AED withdrawal. In the pediatric age group, shorter intervals from surgery to AED reduction and to complete AED discontinuation predict seizure relapse during or after AED reduction/withdrawal. However, this does not correlate with the chances of regaining seizure freedom after drug reintroduction. CONCLUSION: Carefully conducted prospective longitudinal studies and randomized controlled trials are warranted to establish the correct post-surgical pharmacologic treatment and to identify the best candidates for AEDs discontinuation. PMID- 28831921 TI - In Silico Studies in Drug Research Against Neurodegenerative Diseases. AB - BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease (PD), spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective degeneration of neurons and axons in the central nervous system (CNS) and constitute one of the major challenges of modern medicine. Computeraided or in silico drug design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays. METHODS: In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches. RESULTS: Detailed analysis of the recently reported case studies revealed that the majority of them use a sequential combination of ligand and structure-based virtual screening techniques, with particular focus on pharmacophore models and the docking approach. CONCLUSION: Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future. PMID- 28831925 TI - Diabetes Mellitus and Male Aging: Pharmacotherapeutics and Clinical Implications. AB - Andropause or male menopause is defined as androgen decline and onset of hypogonadism in the aging male. Testosterone deficiency in adult male is associated with diabetes mellitus, coronary artery disease, and heart failure. Type 2 diabetic male patients aged above 30 years showed low testosterone levels which is common in diabetic men and had symptoms of hypogonadism. Male sexual dysfunction among diabetic patients can include disorders of libido, ejaculatory problems, and erectile dysfunctions are common among people with diabetes, particularly in older men who had diabetes for years. Older diabetics tend to have both impaired insulin release as well as insulin resistance. There is growing evidence indicating the pathophysiological connections among the mechanisms of oxidative damage by disruption of the oxidative balance, increased levels of enzymatic glycation products in testicular region and glucose transporters, obesity and proinflammatory cytokines in male infertile patients with diabetes. Epidemiological studies suggest that many clinical findings in diabetics are linked to low testosterone levels. This article reviews pathophysiological mechanisms, observational studies, and clinical implications of testosterone therapy in type 2 diabetes mellitus. PMID- 28831926 TI - [Organ donation following physician-hastened death at home]. AB - Patients considering physician-hastened death (PHD) increasingly express a wish to donate organs after death. This fairly unique proposition stems from patients' desire to do something good with (parts of) the same diseased body that has prompted them to request physician-hastened death. In this article we describe a patient with amyotrophic lateral sclerosis (ALS) who expressed this wish. In March 2017 a national guideline on 'Organ donation following physician-hastened death' (ODP) was presented to the Minister of Health, Welfare and Sport of the Netherlands. From the development of this guideline it emerged that, for PHD patients, being forced to experience their final conscious moments in hospital - in order to facilitate organ donation - was a key reason for not choosing ODP. Together with an anaesthesiologist-intensivist, the GP of the ALS patient developed a domestic ODP, thereby overcoming the hurdle of experiencing death in hospital and maintaining the possible option of organ donation. The applied solution is an 'anaesthesia bridge' which separates the experience of farewells, and losing consciousness under pre-medication at home, from biological death and organ donation in hospital. PMID- 28831927 TI - [Necrotic toes in a female patient using interferon]. AB - BACKGROUND: Interferon has an important role in treatment of viral hepatitis, multiple sclerosis and solid and non-solid tumours. Ischaemia and necrosis of the extremities are relatively little-known adverse effects of treatment with interferon. CASE DESCRIPTION: A 44-year-old woman was treated with interferon beta for relapsing-remitting multiple sclerosis. She developed ischaemia and necrosis of the right lower extremity. Extensive laboratory and imaging investigations offered no clear diagnosis, leading to suspicion of a connexion with interferon-beta treatment. Discontinuation of interferon lead to rapid healing, clearly suggesting a relationship between interferon and the vascular complications. CONCLUSION: Vascular complications during treatment with interferon seem to arise fairly frequently, and can even occur many years after commencing therapy. When vascular symptoms similar to Raynaud's syndrome develop, careful monitoring of the disease course and treatment with vasodilators if required is important. If this is insufficiently effective, interferon should be discontinued. Prompt recognition can prevent significant morbidity in these patients. PMID- 28831928 TI - [Driving status of syncope patients is not part of standard advice]. AB - OBJECTIVE: Some medical problems, such as syncope, have direct consequences for fitness to drive. Our objective was to discover if patients had been informed about their driving status after a syncopal episode by their physician, and if this advice was in line with current legislation. DESIGN: Cross-sectional study. METHOD: By means of a structured questionnaire, 150 patients referred to the syncope clinic at the Academic Medical Centre, Amsterdam, were asked about the advice they had received concerning their driving status during previous consultations with their general practitioner or specialists. A syncope expert then assessed the driving status of all patients in the light of the existing and new ruling. RESULTS: In 121 of the 150 patients (81%), a certain or highly-likely cause for their loss of consciousness was determined: 68 patients had reflex syncope, 25 patients orthostatic hypotension, 20 patients psychogenic pseudosyncope, three patients cardiac syncope, three patients had epilepsy and two patients another diagnosis. Seven patients had experienced an episode while driving. Only 26/150 patients (17%) reported that the consequences of their episodes for their driving status had been discussed with them at earlier consultations. If driving was discussed, in only 31% had the current Dutch legislation on driving been followed. Over a third (38%) of the patients felt they should no longer drive. CONCLUSION: Fewer than one in five patients reported that driving status was discussed by a physician after a syncope episode. If advice had been given, it was often not in line with current legislation. PMID- 28831929 TI - [A man with a swelling of the forehead]. AB - A 39-year-old male was admitted to the emergency room with a swelling of the forehead. He had a fever since 5 days and increasing pain on his forehead. He was diagnosed with Pott's puffy tumour, a complication of sinusitis. PMID- 28831930 TI - [Pulmonary embolism response teams: what is the added value for patients with acute pulmonary embolism?] AB - Adequate triaging of patients presenting with acute pulmonary embolism (PE) is essential for appropriate treatment, especially for patients with severe PE. Optimal treatment for this latter group of patients includes pharmaco-mechanical reperfusion treatment for the minority of patients who present with haemodynamic instability, and standard anticoagulation and close monitoring on the ward for the intermediate-high risk patient. In the USA, pulmonary embolism response teams (PERT) have been introduced to coordinate triaging of these patients. We discuss the potential role of PERT teams in Dutch hospitals. The main advantage of PERT could be a uniform management strategy that is supported by a multidisciplinary team including all key specialists in the treatment of severe PE. PMID- 28831931 TI - ? AB - OBJECTIVE To evaluate the effect of an ice-lolly on acute postoperative pain.DESIGN Randomised prospective intervention study.METHOD A total of 100 patients scheduled for an elective laparoscopic cholecystectomy were recruited to participate in the study. Patients were randomised to receive either an ice lolly or no treatment after arrival at the post-anaesthesia care unit. The analgesic requirements (opioid and non-opioid), pain scores, and the presence of nausea and vomiting were registered on the post- anaesthesia care unit and ward during the first 24 hours after surgery. This study is registered in the Nederlands Trial Register under number NTR5335. RESULTS In the post anaesthesia care unit, pain scores did not differ between patients who received an ice-lolly and those who did not. The opioid requirements of patients who had consumed an ice-lolly were significantly lower than those of the patients who had not (cumulative piritramide dose: 4.9 (SD 4.2) with ice-lolly vs. 6.6 (SD 4.0) without ice-lolly mg; P = 0.04). Furthermore, patients who did not receive an ice lolly required more additional pain relief with non-opioid analgesics than patients who had been given an ice- lolly (31% vs. 10%; P = 0.01). Combining all administered opioid and non-opioid analgesics into one analgesic composite score showed that patients who received an ice-lolly required significantly fewer analgesics in the post-anaesthesia care unit than patients who had not been given an ice-lolly (2.2 (SD 1.7) vs. 2.9 (SD 1.8); P = 0.03). No differences between the groups in pain scores or use of analgesics were observed on the ward in the first 24 hours postoperatively. CONCLUSION The postoperative consumption of an ice-lolly reduces postoperative opioid and non-opioid analgesic requirements in the post- anaesthesia care unit. Conflict of interest and financial support: none declared. PMID- 28831932 TI - [A rare cause of insufficiency fractures]. AB - A 41-year-old male with a history of cutaneous sarcoidosis presented with sudden onset pain in his left foot. An X-ray showed cystic lesions in the proximal phalanges of the foot with two insufficiency fractures. The lace-like pattern of these lesions is exemplary for osseous sarcoidosis. PMID- 28831933 TI - [Initiating patients on home mechanical ventilation]. AB - More and more patients with chronic respiratory insufficiency are eligible for home mechanical ventilation. As a result, medical doctors are increasingly confronted with said patients. The treatment goal of this supporting therapy is to improve quality of life and possibly life extension. Centres for home mechanical ventilation decide on the indication, whereas the clinical setup of the ventilator takes place in a hospital setting. Staff in the Dutch Gelderse Vallei hospital have been initiating - both non-invasive and invasive - home mechanical ventilation for various patient groups for the last 4 years. This is a labour-intensive process during which numerous issues can occur. Experience and expertise is necessary for a successful process. A multidisciplinary approach and accessible consultation between stakeholders is of great importance when setting up home mechanical ventilation for these patients. PMID- 28831935 TI - [Acute dyspnoea during brachial plexus blockade]. AB - A 73-year-old woman was scheduled for brachial shunt surgery. She received regional anaesthesia of the right brachial plexus via a supraclavicular approach. During surgery we noticed acute dyspnoea with a saturation reduction. A postoperative chest X-ray showed a high position of the right diaphragm, which was caused by a phrenic nerve blockade due to the anaesthesia. This completely disappeared within 24 hours. PMID- 28831934 TI - [Functional abdominal symptoms in children: the role of the abdominal X-ray and measurement of colon transit time]. AB - Functional constipation and functional non-retentive faecal incontinence are common problems in childhood; these functional defaecation disorders are diagnosed according to the Rome IV criteria. Here we describe the role of an abdominal X-ray in diagnosing functional defaecation disorders, and address the limited additional value of a plain abdominal X-ray. In limited cases it may be helpful to determine colonic transit time using an abdominal X-ray to differentiate between functional constipation and functional non-retentive faecal incontinence. The diagnostic value of abdominal X-rays in children with functional abdominal pain will be discussed. The aims of this article are to explore ways of reducing unnecessary use of abdominal X-rays and reducing unnecessary radiation exposure in children with functional defaecation disorders and functional abdominal pain. PMID- 28831936 TI - [The acutely ill oncological patient: admit to ICU or not?] AB - - 5-10% of all oncological patients will be admitted to ICU at some point.- Medical oncological patients are usually admitted due to respiratory insufficiency or sepsis.- Mortality among medical-oncological ICU patients has decreased to an average of 40%, with a wide spread per tumour type.- The main prognostic factors for ICU survival are: clinical condition, severity of the acute condition, tumour type, and some specific oncological conditions.- This article describes directive ICU admission criteria, subdivided into three categories of medical oncological patients. Although not validated, these criteria give guidance to clinicians in deciding whether ICU admission is a responsible course of action.- In patients with an uncertain prognosis an ICU trial can be useful.- ICU admission criteria are largely based on expert opinion, as sufficient scientific evidence is lacking. A multidisciplinary decision process is therefore important.- Ideally, decision-making about ICU treatment should take place at an early stage in primary health care or outpatient clinic; this is called Advance Care Planning. PMID- 28831937 TI - [Pain reduction during vaccination of young children]. AB - - Children have the right to pain mitigation during vaccination.- There are several simple, non-costly and safe interventions to effectively reduce pain during vaccination.- To improve the Dutch vaccination praxis, it is essential to train professionals in the use of these interventions.- Using the vaccination technique described in the guideline of the Dutch National Immunisation Programme results in pain reduction.- As a pain-reducing intervention at every vaccination procedure, the healthcare professional can give the child and parents a feeling of being in control by explaining about the vaccination procedure, pain and pain reduction and by vaccinating in calm, low-stimulus surroundings.- Other effective interventions include distracting the child, having it sit in the lap of a parent, giving it something to suck on, feeding it or having it drink a sugary solution, and using a topical anaesthetic cream. The healthcare professional should implement these interventions in consultation with, and attuned to, both the child and its parents. PMID- 28831938 TI - [A pregnant woman with increasing constipation]. AB - A 29-year-old gravida 2 para 1 presented with symptoms of increasing constipation in the first trimester of pregnancy. Shortly before this pregnancy, she was suspected of a retroperitoneal cyst. In the analysis of the increased constipation combined with this recent medical history, MRI was performed, which showed an anterior sacral meningocele. PMID- 28831939 TI - [Was the Q fever outbreak in the Netherlands surprising?] AB - The world's largest outbreak of Q fever swept the Netherlands between 2007 and 2010. The disease seemed to take us by surprise. Thousands of people fell ill, dozens of people died and patients continue to suffer from chronic Q fever even today. Eventually, tens of thousands of pregnant dairy goats were killed to prevent the causative agent of Q fever, Coxiella burnetii, to spread. The outbreak and its consequences still resonate in court cases, regional politics and reports by the National Ombudsman. How could this have happened? The most common explanation is that collaboration between veterinarians and physicians was not good enough. But is this the right analysis? Historical research provides a different perspective. PMID- 28831940 TI - Temperature-related parasite infection dynamics: the case of proliferative kidney disease of brown trout. AB - Climate change, in particular rising temperature, is suspected to be a major driver for the emergence of many wildlife diseases. Proliferative kidney disease of salmonids, caused by the myxozoan Tetracapsuloides bryosalmonae, was used to evaluate how temperature dependence of host-parasite interactions modulates disease emergence. Brown trout (Salmo trutta fario) kept at 12 and 15 degrees C, were experimentally infected with T. bryosalmonae. Parasite development in the fish host and release of spores were quantified simultaneously to unravel parasite transmission potential from the vertebrate to the invertebrate host. A change to a stable plateau in infection intensity of the kidney coincided with a threshold at which spore shedding commenced. This onset of parasite release was delayed at the low temperature in accordance with reaching this infection intensity threshold, but the amount of spores released was irrespective of temperature. The production of parasite transmission stages declined with time. In conclusion, elevated temperature modifies the parasite transmission opportunities by increasing the duration of transmission stage production, which may affect the spread and establishment of the parasite in a wider range of rivers. PMID- 28831941 TI - Leishmania infection in bats from a non-endemic region of Leishmaniasis in Brazil. AB - Leishmaniasis is a complex of zoonotic diseases caused by parasites of the genus Leishmania, which can develop in domestic as well as wild animals and humans throughout the world. Currently, this disease is spreading in rural and urban areas of non-endemic regions in Brazil. Recently, bats have gained epidemiological significance in leishmaniasis due to its close relationship with human settlements. In this study, we investigated the presence of Leishmania spp. DNA in blood samples from 448 bats belonging to four families representing 20 species that were captured in the Triangulo Mineiro and Alto Paranaiba areas of Minas Gerais State (non-endemic areas for leishmaniasis), Brazil. Leishmania spp. DNA was detected in 8.0% of the blood samples, 41.6% of which were Leishmania infantum, 38.9% Leishmania amazonensis and 19.4% Leishmania braziliensis. No positive correlation was found between Leishmania spp. and bat food source. The species with more infection rates were the insectivorous bats Eumops perotis; 22.2% (4/18) of which tested positive for Leishmania DNA. The presence of Leishmania in the bat blood samples, as observed in this study, represents epidemiological importance due to the absence of Leishmaniasis cases in the region. PMID- 28831942 TI - PRICING, REIMBURSEMENT, AND HEALTH TECHNOLOGY ASSESSMENT OF MEDICINAL PRODUCTS IN BULGARIA. AB - OBJECTIVES: The aim of this study was to investigate the analysis, discussion, and challenges of the price and reimbursement process of medicinal products in Bulgaria in the period 2000-15 and health technology assessment (HTA) role in these processes. METHODS: The dynamics of the reform, with respect to the healthcare and pharmaceutical sectors, are tracked by documentary review of regulations, articles, and reports in the European Union (EU), as well as analytical and historical analysis. RESULTS: Pricing and reimbursement processes have passed through a variety of committees between 2003 and 2012. Separate units for pricing and reimbursement of medicinal products were established in Bulgaria for the first time, in 2013, when an independent body, the National Council at Prices and Reimbursement of Medicinal Products, was set up to approve medicinal products with new international nonproprietary names (INN) for reimbursement in Bulgaria. Over the course of 2 years (2013-14), thirty-three new INNs were approved for reimbursement. In December 2015, a new HTA body was introduced, and assigned to the National Centre for Public Health and Analyses. CONCLUSIONS: Although Bulgaria has current legislation on pricing and reimbursement which is in accordance with the EU rules, there is no mechanism for reporting and monitoring these processes or the financial resources annually, so as to provide an overall objective assessment and analysis by year. Therefore, this financial assessment should become a national policy objective for the future. PMID- 28831943 TI - Necrotizing Teflon Granuloma After Microvascular Decompression and Gamma Knife. PMID- 28831945 TI - Studies in vitro on infectivity and sensitivity to antileishmanial drugs in New World Leishmania species transfected with the green fluorescent protein [pIR3(-) eGFP]. AB - Current chemotherapeutic agents for leishmaniasis have several disadvantages interfering with the effective treatment and therefore more and better antileishmanial drugs are needed. Discovery of candidates for leishmaniasis treatment requires not only accurate and precise methodologies but also well known biological system to measure infectivity of parasites and antileishmanial activity of the new compounds. Significant variation in the in vitro and in vivo infectivity and sensitivity to established and experimental drugs in Leishmania strains are reported. This work reports the in vitro biological behavior and antileishmanial drugs sensitivity of different green fluorescent protein transfectant Leishmanias strains. The in vitro growth kinetic and infectivity to U937 cells vary slightly in the Leishmania transfectant strains in comparison with their correspondant wild-type. However, the insertion of the pIR3(-)-eGFP may affect the sensitivity of the parasites to meglumine antimoniate (MA) and miltefosine but not to amphotericin B (AMB) and pentamidine isethionate. In consequence, AMB or pentamidine isethionate but not MA or miltefosine should be used as antileishmanial control drugs during in vitro assays of antileishmanial activity. Furthermore, is recommended to test compounds against more than one Leishmania strain in order to verify that the antileihmanial activity of these compound is similar among species. PMID- 28831946 TI - Long-term Recovery From Hurricane Sandy: Evidence From a Survey in New York City. AB - OBJECTIVES: This study aimed to examine a range of factors influencing the long term recovery of New York City residents affected by Hurricane Sandy. METHODS: In a series of logistic regressions, we analyzed data from a survey of New York City residents to assess self-reported recovery status from Hurricane Sandy. RESULTS: General health, displacement from home, and household income had substantial influences on recovery. Individuals with excellent or fair health were more likely to have recovered than were individuals with poor health. Those with high and middle income were more likely to have recovered than were those with low income. Also, individuals who had not experienced a decrease in household income following Hurricane Sandy had higher odds of recovery than the odds for those with decreased income. Additionally, displacement from the home decreased the odds of recovery. Individuals who applied for assistance from the Build it Back program and the Federal Emergency Management Agency had lower odds of recovering than did those who did not apply. CONCLUSIONS: The study outlines the critical importance of health and socioeconomic factors in long-term disaster recovery and highlights the need for increased consideration of those factors in post-disaster interventions and recovery monitoring. More research is needed to assess the effectiveness of state and federal assistance programs, particularly among disadvantaged populations. (Disaster Med Public Health Preparedness. 2018;12:172 175). PMID- 28831944 TI - Biological factors that impinge on Chagas disease drug development. AB - Chagas disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi, and is the most important parasitic infection in Latin America. The current drugs, benznidazole and nifurtimox, are characterized by limited efficacy and toxic side-effects, and treatment failures are frequently observed. The urgent need for new therapeutic approaches is being met by a combined effort from the academic and commercial sectors, together with major input from not-for-profit drug development consortia. With the disappointing outcomes of recent clinical trials against chronic Chagas disease, it has become clear that an incomplete understanding of parasite biology and disease pathogenesis is impacting negatively on the development of more effective drugs. In addition, technical issues, including difficulties in establishing parasitological cure in both human patients and animal models, have greatly complicated the assessment of drug efficacy. Here, we outline the major questions that need to be addressed and discuss technical innovations that can be exploited to accelerate the drug development pipeline. PMID- 28831947 TI - An Inter-regional US Blood Supply Simulation Model to Evaluate Blood Availability to Support Planning for Emergency Preparedness and Medical Countermeasures. AB - OBJECTIVES: Planning for a response to threats like pandemics or mass casualty events is a national priority. The US blood supply system can be particularly vulnerable to such events. It is important to understand the impacts of emergency situations on blood availability and the resiliency of the US blood supply system. METHODS: On the basis of the Stock-and-Flow simulation model of the US blood supply system, we developed an inter-regional blood transfer system representing the action of multiple blood collectors and distributors to enable effective planning of strategies to minimize collection and donation disruptions to the blood supply system in the event of a national emergency. RESULTS: We simulated a pandemic or mass casualty event on both a national and an inter regional blood supply system. Differences in the estimated impacts demonstrated the importance of incorporating spatial and temporal variations of blood collection and utilization across US regions. The absence of blood shortage in both emergency scenarios highlighted the resilience of the inter-regional system to meet the potential associated blood demand. CONCLUSIONS: Our inter-regional model considered complex factors and can be a valuable tool to assist regulatory decision-making and strategic planning for emergency preparedness to avoid and mitigate associated adverse health consequences. (Disaster Med Public Health Preparedness. 2018;12:201-210). PMID- 28831948 TI - Social and psychological consequences of not crying: possible associations with psychopathology and therapeutic relevance. AB - OBJECTIVE: Emotional crying is hypothesized to serve intra- and interpersonal functions. Intrapersonal functions are assumed to facilitate the capacity to recover from emotional distress, thus promoting well-being. Interpersonal functions are postulated to have a major impact on social functioning. We hypothesized that non-criers would have lower well-being and poorer social functioning than criers. METHODS: Study participants included 475 people who reportedly lost the capacity to cry and 179 "normal" control criers. Applied measures assessed crying, well-being, empathy, attachment, social support, and connection with others. Prevalence estimates of not crying by gender were obtained from a panel survey of 2,000 Dutch households. RESULTS: In the main survey, tearless cases had less connection with others, less empathy, and experienced less social support, but were equal in terms of well-being. They also reported being less moved by emotional stimuli and had a more avoidant and less anxious attachment style. In multivariate analyses, being male, having an avoidant attachment style, and lacking empathy were independent predictors of tearlessness. Some 46.1% felt that not being able to cry affected them negatively; however, despite these findings, only 2.9% had sought any kind of professional help. Loss of the capacity to cry occurred in 8.6% of the men and 6.5% of the women in the large panel survey. CONCLUSIONS: Despite reduced empathy, less connection with others, and a more avoidant/less anxious attachment type, well-being is maintained in tearless people. Additional clinical and therapeutic investigations of tearlessness may lead to clarification of bidirectional associations between psychiatric disorders (e.g., alexithymia, posttraumatic stress disorder, psychopathy) and tearlessness. PMID- 28831949 TI - The opioid crisis: A case for shifting from tertiary to primary prevention. PMID- 28831950 TI - Post-Traumatic Stress Disorder Symptoms Among Children of Kathmandu 1 Year After the 2015 Earthquake in Nepal. AB - OBJECTIVE: The 2015 earthquake in Nepal affected the country in terms of economy, and by causing damage and stress reactions. This study aimed to estimate the prevalence and determine individual child- and family-level predictors of post traumatic stress disorder (PTSD) symptoms. METHODS: A community-based cross sectional study was carried out in Kathmandu district 15 months after the earthquake. Multistage cluster sampling was adopted to collect 800 earthquake affected children aged 7-16 years and a face-to-face interview was conducted. Trauma exposure questionnaire and Child PTSD Symptoms Scale were used for assessment of the level of exposure and PTSD symptoms. Multilevel generalized linear regression analysis was used to explore individual and family-level predictors. RESULTS: Among the children, 51% had moderate-to-severe PTSD symptoms. Children of school age (adjusted odds ratio=2.83 [1.45-5.49]), those attending lower-secondary school (2.26 [1.21-4.21]), those having a higher exposure to the severity of the earthquake, and those with low psychosocial acuity [1.70 (1.10-2.60)] were more likely to have more severe PTSD symptoms compared with those who were adolescents and in higher-secondary school, whereas children from a family living in an urban (0.33 [0.19-0.59]) setting and following Hindu religion (0.31 [0.16-0.60]) were less likely to have PTSD symptoms compared with children from suburban areas and those following Buddhist religion. CONCLUSION: PTSD symptoms were prevalent among children of Nepal more than a year following the earthquake. Family-level indicators cannot be excluded when studying children's trauma reactions. (Disaster Med Public Health Preparedness. 2018;12:486-492). PMID- 28831951 TI - Protein ingestion preserves proteasome activity during intense aseptic inflammation and facilitates skeletal muscle recovery in humans. AB - The ubiquitin-proteasome system (UPS) is the main cellular proteolytic system responsible for the degradation of normal and abnormal (e.g. oxidised) proteins. Under catabolic conditions characterised by chronic inflammation, the UPS is activated resulting in proteolysis, muscle wasting and impaired muscle function. Milk proteins provide sulphur-containing amino acid and have been proposed to affect muscle inflammation. However, the response of the UPS to aseptic inflammation and protein supplementation is largely unknown. The aim of this study was to investigate how milk protein supplementation affects UPS activity and skeletal muscle function under conditions of aseptic injury induced by intense, eccentric exercise. In a double-blind, cross-over, repeated measures design, eleven men received either placebo (PLA) or milk protein concentrate (PRO, 4*20 g on exercise day and 20 g/d for the following 8 days), following an acute bout of eccentric exercise (twenty sets of fifteen eccentric contractions at 30 degrees /s) on an isokinetic dynamometer. In each trial, muscle biopsies were obtained from the vastus lateralis muscle at baseline, as well as at 2 and 8 d post exercise, whereas blood samples were collected before exercise and at 6 h, 1 d, 2 d and 8 d post exercise. Muscle strength and soreness were assessed before exercise, 6 h post exercise and then daily for 8 consecutive days. PRO preserved chymotrypsin-like activity and attenuated the decrease of strength, facilitating its recovery. PRO also prevented the increase of NF-kappaB phosphorylation and HSP70 expression throughout recovery. We conclude that milk PRO supplementation following exercise-induced muscle trauma preserves proteasome activity and attenuates strength decline during the pro-inflammatory phase. PMID- 28831952 TI - Genomics of lactation: role of nutrigenomics and nutrigenetics in the fatty acid composition of human milk. AB - Human milk covers the infant's nutrient requirements during the first 6 months of life. The composition of human milk progressively changes during lactation and it is influenced by maternal nutritional factors. Nowadays, it is well known that nutrients have the ability to interact with genes and modulate molecular mechanisms impacting physiological functions. This has led to a growing interest among researchers in exploring nutrition at a molecular level and to the development of two fields of study: nutrigenomics, which evaluates the influence of nutrients on gene expression, and nutrigenetics, which evaluates the heterogeneous individual response to nutrients due to genetic variation. Fatty acids are one of the nutrients most studied in relation to lactation given their biologically important roles during early postnatal life. Fatty acids modulate transcription factors involved in the regulation of lipid metabolism, which in turn causes a variation in the proportion of lipids in milk. This review focuses on understanding, on the one hand, the gene transcription mechanisms activated by maternal dietary fatty acids and, on the other hand, the interaction between dietary fatty acids and genetic variation in genes involved in lipid metabolism. Both of these mechanisms affect the fatty acid composition of human milk. PMID- 28831953 TI - A cluster randomised control trial of a multi-component weight management programme for adults with intellectual disabilities and obesity. AB - There have been few published controlled studies of multi-component weight management programmes that include an energy deficit diet (EDD), for adults with intellectual disabilities and obesity. The objective of this study was to conduct a single-blind, cluster randomised controlled trial comparing a multi-component weight management programme to a health education programme. Participants were randomised to either TAKE 5, which included an EDD or Waist Winners Too (WWToo), based on health education principles. Outcomes measured at baseline, 6 months (after a weight loss phase) and 12 months (after a 6-month weight maintenance phase), by a researcher blinded to treatment allocation, included: weight; BMI; waist circumference; physical activity; sedentary behaviour and health-related quality of life. The recruitment strategy was effective with fifty participants successfully recruited. Both programmes were acceptable to adults with intellectual disabilities, evidenced by high retention rates (90 %). Exploratory efficacy analysis revealed that at 12 months there was a trend for more participants in TAKE 5 (50.0 %) to achieve a clinically important weight loss of 5-10 %, in comparison to WWToo (20.8 %) (OR 3.76; 95 % CI 0.92, 15.30; 0.064). This study found that a multi-component weight management programme that included an EDD, is feasible and an acceptable approach to weight loss when tailored to meet the needs of adults with intellectual disabilities and obesity. PMID- 28831954 TI - Effects of different dietary DHA:EPA ratios on gonadal steroidogenesis in the marine teleost, tongue sole (Cynoglossus semilaevis). AB - The present study was conducted to investigate the effects of dietary DHA and EPA on gonadal steroidogenesis in mature females and males, with a feeding trial on tongue sole, a typical marine teleost with sexual dimorphism. Three experimental diets differing basically in DHA:EPA ratio, that is, 0.68 (diet D:E-0.68), 1.09 (D:E-1.09) and 2.05 (D:E-2.05), were randomly assigned to nine tanks of 3-year old tongue sole (ten females and fifteen males in each tank). The feeding trail lasted for 90 d before and during the spawning season. Fish were reared in a flowing seawater system and fed to apparent satiation twice daily. Compared with diet D:E-0.68, diet D:E-1.09 significantly enhanced the oestradiol production in females, whereas diet D:E-2.05 significantly enhanced the testosterone production in males. In ovaries, diet D:E-1.09 induced highest mRNA expression of follicle stimulating hormone receptor (FSHR), steroidogenic acute regulatory protein, 17alpha-hydroxylase (P450c17) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In testes, diet 2.05 resulted in highest mRNA expression of FSHR, cholesterol side-chain cleavage enzyme, P450c17 and 3beta-HSD. Fatty acid profiles in fish tissues reflected closely those of diets. Female fish had more gonadal EPA content but less DHA content than male fish, whereas there was a reverse observation in liver. In conclusion, the dietary DHA:EPA ratio, possibly combined with the dietary EPA:arachidonic acid ratio, differentially regulated sex steroid hormone synthesis in mature female and male tongue soles. Females seemed to require more EPA but less DHA for the gonadal steroidogenesis than males. The results are beneficial to sex-specific nutritive strategies in domestic teleost. PMID- 28831955 TI - Alternate Healthy Eating Index 2010, Dietary Inflammatory Index and risk of mortality: results from the Whitehall II cohort study and meta-analysis of previous Dietary Inflammatory Index and mortality studies. AB - We aimed to examine the association between the Alternative Healthy Eating Index updated in 2010 (AHEI-2010), the Dietary Inflammatory Index (DIITM) and risk of mortality in the Whitehall II study. We also conducted a meta-analysis on the DII based results from previous studies to summarise the overall evidence. Data on dietary behaviour assessed by self-administered repeated FFQ and on mortality status were available for 7627 participants from the Whitehall II cohort. Cox proportional hazards regression models were performed to assess the association between cumulative average of AHEI-2010 and DII scores and mortality risk. During 22 years of follow-up, 1001 participants died (450 from cancer, 264 from CVD). Both AHEI-2010 (mean=48.7 (sd 10.0)) and DII (mean=0.37 (sd 1.41)) were associated with all-cause mortality. The fully adjusted hazard ratio (HR) per sd, were 0.82; 95 % CI 0.76, 0.88 for AHEI-2010 and 1.18; 95 % CI 1.08, 1.29 for DII. Significant associations were also observed with cardiovascular and cancer mortality risk. For DII, a meta-analysis (using fixed effects) from this and four previous studies showed a positive association of DII score with all-cause (HR=1.04; 95 % CI 1.03, 1.05, 28 891deaths), cardiovascular (HR=1.05; 95 % CI 1.03, 1.07, 10 424 deaths) and cancer mortality (HR=1.05; 95 % CI 1.03, 1.07, n 8269).The present study confirms the validity to assess overall diet through AHEI 2010 and DII in the Whitehall II cohort and highlights the importance of considering diet indices related to inflammation when evaluating all-cause, cardiovascular and cancer mortality risk. PMID- 28831956 TI - Effect of acid whey-fortified breads on caecal fermentation processes and blood lipid profile in rats. AB - Two types of diet - standard and atherogenic - were used to study the effect of wheat or wheat-rye breads supplemented with 20 % acid whey concentrate after ultrafiltration on the physiological response of growing rats. The acid whey concentrate after ultrafiltration used in rat diets caused reduced weight gain (for atherogenic diet with wheat bread); growth of caecum tissue and digesta weight; a decrease in the pH of caecum digesta (for atherogenic diet); reduced activity of bacterial glycolytic enzymes; and a significant increase in total SCFA for both types of diet with wheat-rye breads containing acid whey concentrate. For wheat bread with acid whey, in standard diet, a statistically significant increase was found in the population of bifidobacteria. The results showed that the acid whey concentrates could be used as a valuable food ingredient. PMID- 28831957 TI - Favourable nutrient intake and displacement with long-term walnut supplementation among elderly: results of a randomised trial. AB - Older adults tend to require fewer energy content and higher levels of nutrients to promote and maintain optimal health. Regrettably, dietary variety and quality are known to decline with advancing age. We conducted a 2-year prospective, randomised, dietary intervention trial where we asked free-living elderly subjects (63-79 years) on self-selected habitual diets to incorporate walnuts daily into their diet (15 % energy). We then compared their nutrient intake with that of a similar group of concurrent participants on self-selected habitual diets but abstaining from walnut consumption (control). No recipes or advice on use of nuts were provided. Dietary intake was assessed by multiple unannounced 24 h telephone dietary recalls. On average, walnut supplement consumption was 43 g/d or 1171.5 kJ (281 kcal). The mean daily energy intake was 954 kJ (228 kcal) higher in the walnut group than in the control group (P<0.001). Compared with control, participants in the walnut group reported significantly higher intake of total protein, vegetable protein, total PUFA and n-3 and n-6 PUFA; and significantly lower intake of total carbohydrate, animal protein, SFA, and Na. An estimated 19 % of total energy and 25 % of total fat from other food sources was displaced. Displacement of MUFA and total PUFA was 21 and 16 %, respectively. Thus adding a daily supplement of walnuts to an ad libitum diet of older adults can induce favourable modifications to the nutrient profile in a way that addresses declining nutrient intake associated with aging. PMID- 28831959 TI - Stage-dependent behavioural changes but early castration induced by the acanthocephalan parasite Polymorphus minutus in its Gammarus pulex intermediate host. AB - Multidimensionality in parasite-induced phenotypic alterations (PIPA) has been observed in a large number of host-parasite associations, particularly in parasites with complex life cycles. However, it is still unclear whether such a syndrome is due to the successive activation of independent PIPAs, or results from the synchronous disruption of a single mechanism. The aim of the present study was to investigate the onset and progression of two PIPAs (a behavioural alteration: reversion of geotaxis, and castration) occurring in the crustacean amphipod Gammarus pulex infected with the acanthocephalan Polymorphus minutus, at different parasite developmental stages. Modifications of geotaxis in hosts differed according to the parasite developmental stage. Whereas the cystacanth stage induced a negative geotaxis (exposing the gammarid to predation by birds, the definitive hosts), the acanthella stage, not yet infective for the definitive host, induced a stronger positive geotaxis (presumably protecting gammarids from bird predation). In contrast, castration was almost total at the acanthella stage, with no significant variation in the intensity according to parasite maturation. Finally, no significant correlation was found between the intensity of behavioural changes and the intensity of castration. We discuss our results in relation with current views on the evolution of multidimensionality in PIPA. PMID- 28831958 TI - Processed red meat contribution to dietary patterns and the associated cardio metabolic outcomes. AB - Evidence suggests that processed red meat consumption is a risk factor for CVD and type 2 diabetes (T2D). This analysis investigates the association between dietary patterns, their processed red meat contributions, and association with blood biomarkers of CVD and T2D, in 786 Irish adults (18-90 years) using cross sectional data from a 2011 national food consumption survey. All meat-containing foods consumed were assigned to four food groups (n 502) on the basis of whether they contained red or white meat and whether they were processed or unprocessed. The remaining foods (n 2050) were assigned to twenty-nine food groups. Two-step and k-means cluster analyses were applied to derive dietary patterns. Nutrient intakes, plasma fatty acids and biomarkers of CVD and T2D were assessed. A total of four dietary patterns were derived. In comparison with the pattern with lower contributions from processed red meat, the dietary pattern with greater processed red meat intakes presented a poorer Alternate Healthy Eating Index (21.2 (sd 7.7)), a greater proportion of smokers (29 %) and lower plasma EPA (1.34 (sd 0.72) %) and DHA (2.21 (sd 0.84) %) levels (P<0.001). There were no differences in classical biomarkers of CVD and T2D, including serum cholesterol and insulin, across dietary patterns. This suggests that the consideration of processed red meat consumption as a risk factor for CVD and T2D may need to be re-assessed. PMID- 28831960 TI - Parasitic nematodes of the genus Syphacia Seurat, 1916 infecting Muridae in the British Isles, and the peculiar case of Syphacia frederici. AB - Syphacia stroma (von Linstow, 1884) Morgan, 1932 and Syphacia frederici Roman, 1945 are oxyurid nematodes that parasitize two murid rodents, Apodemus sylvaticus and Apodemus flavicollis, on the European mainland. Only S. stroma has been recorded previously in Apodemus spp. from the British Isles. Despite the paucity of earlier reports, we identified S. frederici in four disparate British sites, two in Nottinghamshire, one each in Berkshire and Anglesey, Wales. Identification was based on their site in the host (caecum and not small intestine), on key morphological criteria that differentiate this species from S. stroma (in particular the tail of female worms) and by sequencing two genetic loci (cytochrome C oxidase 1 gene and a section of ribosomal DNA). Sequences derived from both genetic loci of putative British S. frederici isolates formed a tight clade with sequences from continental worms known to be S. frederici, clearly distinguishing these isolates from S. stroma which formed a tight clade of its own, distinct from clades representative of Syphacia obvelata from Mus and S. muris from Rattus. The data in this paper therefore constitute the first record of S. frederici from British wood mice, and confirm the status of this species as distinct from both S. obvelata and S. stroma. PMID- 28831961 TI - Efficient milking hygiene reduces bacterial spore contamination in milk. AB - Clostridia in the milk can lead to late blowing, a cheese defect. Clostridia are ubiquitous, deriving from both the farm environment and the feed ingested by the cows, and are transferred into the milk through faecal contamination. Our aim was to investigate the effect of different in-parlour practices on the content of anaerobic spore-forming bacteria in milk, and to monitor the variation in spore content in the feed and environment. The experiment, conducted in an experimental dairy during autumn, was repeated in exactly the same way for two consecutive years. The experimental design applied three different milking routines in three consecutive 7-d periods: forestripping alone (F); forestripping and post-dipping (F+Post); pre-dipping, wiping, forestripping and post-dipping (Pre+F+Post). Teat skin swabs and samples of feed, faeces, bedding materials and milk were collected for microbiological analyses. The dietary forage of the lactating cows included maize silage, which, in both years, was found to have the highest level of clostridial spore contamination. Pre-dipping with a detergent/emollient solution, and drying with a disposable paper towel, proved much more efficient in reducing spore contamination than forestripping alone, both on the teats (1.30 vs. 2.20 log10 MPN/swab; P < 0.001) and in the milk (1.82 vs. 2.47 log10 MPN/L, P < 0.02), while post-dipping had little influence on spore count. The standard plate count in milk was significantly lower with Pre+F+Post treatment than with F (3.80 vs. 4.51 log10 CFU/mL, P < 0.01). The teat preparation procedure did not influence the lactic acid bacterial levels in the milk, which is very positive in that decreased lactic acid bacterial content can lessen raw milk cheese quality. PMID- 28831962 TI - Effects of feed delivery frequency in different environmental conditions on time budget of lactating dairy cows. AB - This study aimed to examine the influence of feed delivery frequency and environmental conditions on daily time budget of lactating dairy cows. The study was carried out in two commercial dairy farms with Holstein herds. Fifty lactating dairy cows milked in automatic milking units (AMS farm) and 96 primiparous lactating dairy cows milked in a conventional milking parlour (conventional farm) were exposed to different frequencies of feed delivery replicated in different periods of the year (warm and mild) that were characterized by different temperature-humidity indices (THI). On each farm, feeding treatments consisted of two different feed delivery frequencies (1* and 2* on the AMS farm; 2* and 3* on the conventional farm). All behaviours of the cows were monitored for the last 8 d of each treatment period using continuous video recording. The two data sets from different farm systems were considered separately for analysis. On both farms, environmental conditions expressed as THI affected time budgets and the pattern of the behavioural indices throughout the day. The variation in the frequency of feed delivery seems to affect the cow's time budget only in a limited way. Standing time of cows on the conventional farm and the time spent by cows in the milking waiting area on the AMS farm both increased in response to increased feeding frequency. Although feed delivery frequency showed limited influence on cow's time budget, the effect on standing time could be carefully considered, especially on farms equipped with AMS where the type of cow traffic system (e.g., milking first) might amplify the negative consequences of more frequent feed delivery. Further investigations are required to evaluate the effect of THI and feed delivery frequency on other aspects of behavioural activity. PMID- 28831963 TI - A predictive model to evaluate the impact of the cooling profile on growth of psychrotrophic bacteria in raw milk from conventional and robotic milking. AB - This Research Communication explores the usefulness of predictive modelling to explain bacterial behaviour during cooling. A simple dynamic lag phase model was developed and validated. The model takes into account the effect of the cooling profile on the lag phase and growth in bulk tank milk. The time before the start of cooling was the most critical and should not exceed 1 h. The cooling rate between 30 and approximately 10 degrees C was the second most critical period. Cooling from 30 to 10 degrees C within 2 h ensured minimal growth of psychrotrophic bacteria in the milk. The cooling rate between 10 and 4 degrees C (the slowest phase of cooling) was of surprisingly little importance. Given a normal cooling profile to 10 degrees C, several hours of prolonged cooling time made practically no difference in psychrotrophic counts. This behaviour can be explained by the time/temperature dependence of the work needed by the bacteria to complete the lag phase at low temperature. For milk quality advisors, it is important to know that slow cooling below 10 degrees C does not result in high total counts of bacteria. In practice, slow cooling is occasionally found at farms with robotic milking. However, when comparing psychrotrophic growth in bulk milk tanks designed for robotic milking or conventional milking, the model predicted less growth for robotic milking for identical cooling profiles. It is proposed that due to the different rates of milk entering the tank, fewer bacteria will exit the lag phase during robotic milking and they will be more diluted than in conventional milking systems. At present, there is no international standard that specifies the cooling profile in robotic systems. The information on the insignificant effect of the cooling rate below 10 degrees C may be useful in the development of a standard. PMID- 28831964 TI - Biological activity of the non-microbial fraction of kefir: antagonism against intestinal pathogens. AB - Kefir is a fermented milk obtained by the activity of kefir grains which are composed of lactic and acetic acid bacteria, and yeasts. Many beneficial health effects have been associated with kefir consumption such as stimulation of the immune system and inhibition of pathogenic microorganisms. The biological activity of kefir may be attributed to the presence of a complex microbiota as well as the microbial metabolites that are released during fermentation. The aim of this work was to characterise the non-microbial fraction of kefir and to study its antagonism against Escherichia coli, Salmonella spp. and Bacillus cereus. During milk fermentation there was a production of organic acids, mainly lactic and acetic acid, with a consequent decrease in pH and lactose content. The non microbial fraction of kefir added to nutrient broth at concentrations above 75% v/v induced a complete inhibition of pathogenic growth that could be ascribed to the presence of un-dissociated lactic acid. In vitro assays using an intestinal epithelial cell model indicated that pre-incubation of cells with the non microbial fraction of kefir did not modify the association/invasion of Salmonella whereas pre-incubation of Salmonella with this fraction under conditions that did not affect their viability significantly decreased the pathogen's ability to invade epithelial cells. Lactate exerted a protective effect against Salmonella in a mouse model, demonstrating the relevance of metabolites present in the non microbial fraction of kefir produced during milk fermentation. PMID- 28831965 TI - A comparative analysis of vehicle-related greenhouse gas emissions between organic and conventional dairy production. AB - Agricultural industrialisation and globalisation have steadily increased the transportation of food across the world. In efforts to promote sustainability and self-sufficiency, organic milk producers in Sweden are required to produce a higher level of cattle feed on-farm in the hope that increased self-sufficiency will reduce reliance on external inputs and reduce transport-related greenhouse gas emissions. Using data collected from 20 conventional and 20 organic milk producers in Sweden this paper aims to assess the global warming impact of farmyard vehicles and the transportation of feed produced 'off-farm' in order to compare the impact of vehicle-related emissions from the different production methods. The findings show organic and conventional production methods have different vehicle-related emission outputs that vary according to a reliance on either road transportation or increased farmyard machinery use. Mechanical weeding is more fuel demanding than conventional agrichemical sprayers. However, artificial fertilising is one of the highest farmyard vehicle-related emitters. The general findings show organic milk production emits higher levels of farm vehicle-related emissions that fail to be offset by reduced emissions occurring from international transport emissions. This paper does not propose to cover a comprehensive supply chain carbon footprint for milk production or attempt to determine which method of production has the largest climatic impact. However, it does demonstrate that Sweden's legal requirements for organic producers to produce more feed on-farm to reduce transport emissions have brought emissions back within Sweden's greenhouse gas inventory and raises questions around the effectiveness of policies to reduce vehicle-related emissions. Further research is needed into the effectiveness of climate change mitigation on food production policies, in particular looking at various trade-offs that affects the entire food supply chain. PMID- 28831966 TI - Editorial: We need to bring the calves back to the dairy cows. PMID- 28831967 TI - Replacing wheat with canola meal and maize grain in the diet of lactating dairy cows: Feed intake, milk production and cow condition responses. AB - This research paper describes the effect of partially replacing wheat with maize grain and canola meal on milk production and body condition changes in early lactation Holstein-Friesian dairy cows consuming a grass silage-based diet over an 83-d period. Two groups of 39 cows were stratified for age, parity, historical milk yield and days in milk (DIM), and offered one of two treatment diets. The first treatment (CON) reflected a typical diet used by Western Australian dairy producers in summer and comprised (kg DM/cow per d); 8 kg of annual ryegrass silage, 6 kg of crushed wheat (provided once daily in a mixed ration), 3.6 kg of crushed lupins (provided in the milking parlour in two daily portions) and ad libitum lucerne haylage. The second treatment diet (COMP) was identical except the 6 kg of crushed wheat was replaced by 6 kg of a more complex concentrate mix (27% crushed wheat, 34% maize grain and 37% canola meal). Lucerne haylage was provided independently in the paddock to all cows, and no pasture was available throughout the experiment. The COMP group had a greater mean overall daily intake (22.5 vs 20.4 kg DM/cow) and a higher energy corrected milk (ECM) yield (29.2 vs 27.1 kg/cow; P = 0.047) than the CON cows. The difference in overall intake was caused by a higher daily intake of lucerne haylage in COMP cows (4.5 vs 2.3 kg DM/cow). The CON group had a higher concentration of milk fat (42.1 vs 39.3 g/kg; P = 0.029) than COMP cows. Milk protein yield was greater in COMP cows (P < 0.021); however, milk fat yield was unaffected by treatment. It is concluded that partially replacing wheat with canola meal and maize grain in a grass silage based diet increases voluntary DMI of conserved forage and consequently yields of ECM and milk protein. PMID- 28831968 TI - Mammary gland and milk fatty acid composition of two dairy goat breeds under feed restriction. AB - Goat dairy products are an important source of animal protein in the tropics. During the dry season, pasture scarcity leads animals to lose up to 40% of their body weight, a condition known as Seasonal Weight Loss (SWL) that is one of the major constraints in ruminant production. Breeds with high tolerance to SWL are relevant to understand the physiological responses to pasture scarcity so they could be used in programs for animal breeding. In the Canary Islands there are two dairy goat breeds with different levels of tolerance to SWL: the Palmera, susceptible to SWL; and the Majorera, tolerant to SWL. Fat is one of the milk components most affected by environmental and physiological conditions. This study hypothesises that feed-restriction affects Majorera and Palmera breeds differently, leading to different fatty acid profiles in the mammary gland and milk. An interaction between breed and feed-restriction was observed in the mammary gland. Feed-restriction was associated with an increase in oleic acid and a decrease in palmitic acid percentage in the Palmera breed whereas no differences were observed in the Majorera breed. Palmitic and oleic acids together constituted around 60% of the total fatty acids identified, which suggests that Palmera breed is more susceptible to SWL. In milk, feed-restriction affected both breeds similarly. Regarding the interaction of the breed with the treatment, we also observed similar responses in both breeds, but this influence affects only around 2% of the total fatty acids. In general, Majorera breed is more tolerant to feed-restriction. PMID- 28831969 TI - Statistical properties of proportional residual energy intake as a new measure of energetic efficiency. AB - Traditional ratio measures of efficiency, including feed conversion ratio (FCR), gross milk efficiency (GME), gross energy efficiency (GEE) and net energy efficiency (NEE) may have some statistical problems including high correlations with milk yield. Residual energy intake (REI) or residual feed intake (RFI) is another criterion, proposed to overcome the problems attributed to the traditional ratio criteria, but it does not account for production or intake levels. For example, the same REI value could be considerable for low producing and negligible for high producing cows. The aim of this study was to propose a new measure of efficiency to overcome the problems attributed to the previous criteria. A total of 1478 monthly records of 268 lactating Holstein cows were used for this study. In addition to FCR, GME, GEE, NEE and REI, a new criterion called proportional residual energy intake (PREI) was calculated as REI to net energy intake ratio and defined as proportion of net energy intake lost as REI. The PREI had an average of -0.02 and range of -0.36 to 0.27, meaning that the least efficient cow lost 0.27 of her net energy intake as REI, while the most efficient animal saved 0.36 of her net energy intake as less REI. Traditional ratio criteria (FCR, GME, GEE and NEE) had high correlations with milk and fat corrected milk yields (absolute values from 0.469 to 0.816), while the REI and PREI had low correlations (0.000 to 0.069) with milk production. The results showed that the traditional ratio criteria (FCR, GME, GEE and NEE) are highly influenced by production traits, while the REI and PREI are independent of production level. Moreover, the PREI adjusts the REI magnitude for intake level. It seems that the PREI could be considered as a worthwhile measure of efficiency for future studies. PMID- 28831970 TI - Characterisation of gene expression related to milk fat synthesis in the mammary tissue of lactating yaks. AB - This research communication describes the profile of gene expression related to the synthesis of yak milk as determined via quantitative reverse transcription polymerase chain reaction (RT-qPCR). Significant up-regulation during lactation were observed in genes related to fatty acid (FA) uptake from blood (LPL, CD36), intracellular FA transport (FABP3), intracellular FA activation of long- and short-chain FAs (ACSS1, ACSS2, ACSL1), de novo synthesis (ACACA), desaturation (SCD), triacyglycerol (TAG) synthesis (AGPAT6, GPAM, LPIN1), lipid droplet formation (PLIN2, BTN1A1, XDH), ketone body utilisation (BDH1, OXCT1), and transcription regulation (THRSP, PPARGC1A). In particular, intracellular de novo FA synthesis (ACSS2, ACACA, and FABP3) and TAG synthesis (GPAM, AGPAT6, and LPIN1), whose regulation might be orchestrated as part of the gene network under the control of SERBF1 in the milk fat synthesis process, were more activated compared to levels in dairy cows. However, the genes involved in lipid droplet formation (PLIN2, XDH, and BTN1A1) were expressed at lower levels compared to those in dairy cows, where these genes are mainly controlled by the PPARG regulator. PMID- 28831971 TI - Capacity of milk composition to identify the feeding system used to feed dairy cows. AB - This Research Paper addresses the hypothesis that is possible to identify the type of feed used for dairy cows by means of the analysis of milk composition and the fatty acid profile of milk fat. Sixteen dairy farms were monitored during 1 year with quarterly visits between summer 2014 and spring 2015. Rations varied throughout the year due to annual dynamic change of forage production, forage rotation, variation of nutrient requirements according to physiological state of the animal, etc. The ingredients of the rations were analysed by cluster identifying five feeding systems based on the main ingredient of the diet: grazing, maize silage, grass silage, dry forage and concentrate. Milk composition could explain up to 91.3% of the total variability among feeding systems, while fatty acid profile could explain only up to 61.2% of total variability. However, when the sum of types of fatty acids and their ratios are taken, up to 93.5% of total variability could be explained. The maize silage system had the greatest milk yield, protein, solid non-fat and urea proportions, as well as the highest proportion of saturated fatty acid and lowest concentration of trans11 18 : 1, cis9 18 : 1 and 18 : 3 n3. Principal component analysis distinguishes the maize silage system from other feeding systems, both from milk composition and milk fatty acid profile. Concentrate system overlapped partially with the grazing, grass silage and dry forage systems. The latter systems had the highest concentrations of cis9 18 : 1, trans11 18 : 1 and 18 : 3, but there was no clear differentiation among them. PMID- 28831972 TI - Influence of milk processing temperature on growth performance, nitrogen retention, and hindgut's inflammatory status and bacterial populations in a calf model. AB - This research communication describes a study aimed at evaluating the effects of heat treatment of milk on growth performance, N retention, and hindgut's inflammatory status and bacterial populations using young dairy calves as a model. Twenty-one Holstein calves were randomly allocated to one of three treatments: raw milk (RM), pasteurised milk (PAST), or UHT milk (UHT). Calves were submitted to a N balance study, and a biopsy from the distal colon and a faecal sample were obtained from 5 animals per treatment to determine expression of several genes and potential changes in the hindgut's bacterial population. Milk furosine content was 33-fold greater in UHT than in RM and PAST milks. Calves receiving RM grew more than those fed UHT, and urinary N excretion was greatest in calves fed UHT. Quantification of Lactobacillus was lower in calves consuming PAST or UHT, and Gram negative bacteria were greater in UHT than in PAST calves. The expression of IL-8 in the hindgut's mucosa was lowest and that of IL-10 tended to be lowest in RM calves, and expression of claudin-4 tended to be greatest in UHT calves. In conclusion, the nutritional value of UHT-treated milk may be hampered because it compromises growth and increases N excretion in young calves and may have deleterious effects on the gut's bacterial population and inflammation status. PMID- 28831973 TI - Analysis of microsatellite markers in a Cuban water buffalo breed. AB - The aim of this Regional Research Communication was to validate a panel of 30 microsatellite markers recommended by FAO/ISAG for studies of biodiversity in cattle to improve the characterisation of Cuban buffalo populations. The water buffalo (Bubalus bubalis) is an economically important livestock species. Therefore, research focused on the study of the genetic relationships among water buffalo populations is useful to support conservation decisions and to design breeding schemes. Twenty-eight of the 30 tested regions were amplified, one of which (ETH10) turned out to be monomorphic. A total of 143 alleles were observed in the Cuban water buffalo population. The average number of alleles per locus was 5.04. The number of alleles per polymorphic locus ranged from two (INRA 63 and MM12) to nine (ETH185). The observed and expected heterozygosity ranged from 0.108 (HAUT24) to 0.851 (CSSM66) and 0.104 (MM12) to 0.829(INRA32), respectively. The polymorphic information content (PIC) ranged from 0.097 (MM12) to 0.806 (INRA32), and the overall value for these markers was 0.482. Within the population, inbreeding estimates (F IS) was positive in 14 of the 30 loci analysed. This study thus highlights the usefulness of heterologous bovine microsatellite markers to assess the genetic variability in Cuban water buffalo breeds. Furthermore, the results can be utilised for future breeding strategies and conservation. PMID- 28831974 TI - Expression profiles of miRNAs from bovine mammary glands in response to Streptococcus agalactiae-induced mastitis. AB - This study aimed to describe the expression profiles of microRNAs (miRNAs) from mammary gland tissues collected from dairy cows with Streptococcus agalactiae induced mastitis and to identify differentially expressed miRNAs related to mastitis. The mammary glands of Chinese Holstein cows were challenged with Streptococcus agalactiae to induce mastitis. Small RNAs were isolated from the mammary tissues of the test and control groups and then sequenced using the Solexa sequencing technology to construct two small RNA libraries. Potential target genes of these differentially expressed miRNAs were predicted using the RNAhybrid software, and KEGG pathways associated with these genes were analysed. A total of 18 555 913 and 20 847 000 effective reads were obtained from the test and control groups, respectively. In total, 373 known and 399 novel miRNAs were detected in the test group, and 358 known and 232 novel miRNAs were uncovered in the control group. A total of 35 differentially expressed miRNAs were identified in the test group compared to the control group, including 10 up-regulated miRNAs and 25 down-regulated miRNAs. Of these miRNAs, miR-223 exhibited the highest degree of up-regulation with an approximately 3-fold increase in expression, whereas miR-26a exhibited the most decreased expression level (more than 2-fold). The RNAhybrid software predicted 18 801 genes as potential targets of these 35 miRNAs. Furthermore, several immune response and signal transduction pathways, including the RIG-I-like receptor signalling pathway, cytosolic DNA sensing pathway and Notch signal pathway, were enriched in these predicted targets. In summary, this study provided experimental evidence for the mechanism underlying the regulation of bovine mastitis by miRNAs and showed that miRNAs might be involved in signal pathways during S. agalactiae-induced mastitis. PMID- 28831976 TI - Department of Error. PMID- 28831975 TI - Detailed fatty acid profile of milk, cheese, ricotta and by products, from cows grazing summer highland pastures. AB - In this research two-dimensional GC was used to analyse, for the first time, the detailed fatty acid (FA) profiles of 11 dairy matrices: raw milk (evening whole, evening partially skimmed, morning whole, and vat milk), cream, fresh cheese, whey, ricotta, scotta, 6- and 12-month-ripened cheeses, obtained across artisanal cheese- and ricotta-making trials carried out during the summer period while cows were on highland pastures. Samples were collected during 7 cheese- and ricotta making procedures carried out at 2-week intervals from bulk milk to study possible differences in the transfer and modification of FA. Compared with morning milk, evening milk had fewer de novo synthetised FA. The detailed FA profile of partially skimmed milk differed little from that of evening whole milk before skimming, but the cream obtained differed from partially skimmed milk and from fresh cheese in about half the FA, due mainly to higher contents of all de novo FA, and lower contents of n-3 and n-6 FA. Fresh cheese and whey had similar FA profiles. The ricotta manufacturing process affected the partition of FA between ricotta and scotta, the FA profile of the latter differing in terms of groups and individual FA from the former, whereas ricotta and fresh cheese had similar composition of FA. In general, there was an increase in medium-chain saturated FA, and a decrease in many polyunsaturated FA during the first 6 months of ripening, but not during the second 6 months. Two-dimensional GC yielded a very detailed and informative FA profile on all the 11 dairy products and by products analysed. PMID- 28831977 TI - Department of Error. PMID- 28831978 TI - 40 years of percutaneous coronary intervention: where next? PMID- 28831979 TI - The rising north-south divide in health in the UK. PMID- 28831980 TI - Nicotine addiction, reduction, and smoking cessation. PMID- 28831981 TI - Intravenous fibrinolytics in STEMI: a 25-year perspective. PMID- 28831982 TI - Expansion of the treatment toolbox for mitral regurgitation. PMID- 28831983 TI - Hunting hidden parasites: Trypanosoma cruzi. PMID- 28831984 TI - The cost of complacency-black lung in Australia. PMID- 28831985 TI - Jeroen Bax: inspiring the next generation of cardiologists. PMID- 28831986 TI - China, Africa, and US academia join hands to advance global health. PMID- 28831987 TI - Global health: generation men. PMID- 28831988 TI - PubMed should raise the bar for journal inclusion. PMID- 28831989 TI - The BLISTER study: possible overestimation of tetracycline efficacy. PMID- 28831990 TI - The BLISTER study: possible overestimation of tetracycline efficacy - Authors' reply. PMID- 28831991 TI - Forgotten episodes of euthanasia in the 19th century. PMID- 28831992 TI - Comparative efficacy and safety of reperfusion therapy with fibrinolytic agents in patients with ST-segment elevation myocardial infarction: a systematic review and network meta-analysis. AB - BACKGROUND: Fibrinolytic therapy offers an alternative to mechanical reperfusion for ST-segment elevation myocardial infarction (STEMI) in settings where health care resources are scarce. Comprehensive evidence comparing different agents is still unavailable. In this study, we examined the effects of various fibrinolytic drugs on clinical outcomes. METHODS: We did a network meta-analysis based on a systematic review of randomised controlled trials comparing fibrinolytic drugs in patients with STEMI. Several databases were searched from inception up to Feb 28, 2017. We included only randomised controlled trials that compared fibrinolytic agents as a reperfusion therapy in adult patients with STEMI, whether given alone or in combination with adjunctive antithrombotic therapy, against other fibrinolytic agents, a placebo, or no treatment. Only trials investigating agents with an approved indication of reperfusion therapy in STEMI (streptokinase, tenecteplase, alteplase, and reteplase) were included. The primary efficacy outcome was all-cause mortality within 30-35 days and the primary safety outcome was major bleeding. This study is registered with PROSPERO (CRD42016042131). FINDINGS: A total of 40 eligible studies involving 128 071 patients treated with 12 different fibrinolytic regimens were assessed. Compared with accelerated infusion of alteplase with parenteral anticoagulants as background therapy, streptokinase and non-accelerated infusion of alteplase were significantly associated with an increased risk of all-cause mortality (risk ratio [RR] 1.14 [95% CI 1.05-1.24] for streptokinase plus parenteral anticoagulants; RR 1.26 [1.10-1.45] for non-accelerated alteplase plus parenteral anticoagulants). No significant difference in mortality risk was recorded between accelerated infusion of alteplase, tenecteplase, and reteplase with parenteral anticoagulants as background therapy. For major bleeding, a tenecteplase-based regimen tended to be associated with lower risk of bleeding compared with other regimens (RR 0.79 [95% CI 0.63-1.00]). The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy increased the risk of major bleeding by 1.27-8.82-times compared with accelerated infusion alteplase plus parenteral anticoagulants (RR 1.47 [95% CI 1.10-1.98] for tenecteplase plus parenteral anticoagulants plus glycoprotein inhibitors; RR 1.88 [1.24-2.86] for reteplase plus parenteral anticoagulants plus glycoprotein inhibitors). INTERPRETATION: Significant differences exist among various fibrinolytic regimens as reperfusion therapy in STEMI and alteplase (accelerated infusion), tenecteplase, and reteplase should be considered over streptokinase and non-accelerated infusion of alteplase. The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy should be discouraged. FUNDING: None. PMID- 28831993 TI - Compassionate use of the PASCAL transcatheter mitral valve repair system for patients with severe mitral regurgitation: a multicentre, prospective, observational, first-in-man study. AB - BACKGROUND: Severe mitral regurgitation is associated with impaired prognosis if left untreated. Using the devices currently available, transcatheter mitral valve repair (TMVr) remains challenging in complex anatomical situations. We report the procedural and 30-day results of the first-in-man study of the Edwards PASCAL TMVr system. METHODS: In this multicentre, prospective, observational, first-in man study, we collected data from seven tertiary care hospitals in five countries that had a compassionate use programme in which patients underwent transcatheter mitral valve repair using the Edwards PASCAL TMVr system. Eligible patients were those with symptomatic, severe functional, degenerative, or mixed mitral regurgitation deemed at high risk or inoperable. Safety and efficacy of the procedure were prospectively assessed at device implantation, discharge, and 30 days after device implantation. The key study endpoints were technical success assessed at the end of the procedure and device success 30 days after implantation using the Mitral Valve Academic Research Consortium definitions. FINDINGS: Between Sept 1, 2016, and March 31, 2017, 23 patients (median age 75 years [IQR 61-82]) had treatment for moderate-to-severe (grade 3+) or severe (grade 4+) mitral regurgitation using the Edwards PASCAL TMVr system. At baseline, the median EuroScore II score was 7.1% (IQR 3.6-12.8) and the median Society of Thoracic Surgeons predicted risk of mortality for mitral valve repair was 4.8% (2.1-9.0) and 6.8% (2.9-10.1) for mitral valve replacement. 22 (96%) of 23 patients were New York Heart Association (NYHA) class III or IV at baseline. The implantation of at least one device was successful in all patients, resulting in procedural residual mitral regurgitation of grade 2+ or less in 22 (96%) patients. Six (26%) of 23 patients had two implants. Periprocedural complications occurred in two (9%) of 23 patients (one minor bleeding event and one transient ischaemic attack). Despite the anatomical complexity of mitral regurgitation in the patients in this compassionate use cohort, technical success was achieved in 22 (96%) of 23 patients, and device success at 30 days was achieved in 18 (78%) patients. Three patients (13%) died during the 30 day follow-up. 19 (95%) of 20 patients alive 30 days after implantation were NYHA class I or II. INTERPRETATION: This study establishes feasibility of the Edwards PASCAL TMVr system with a high rate of technical success and reduction of mitral regurgitation severity. Further research is needed on procedural and long-term clinical outcomes. FUNDING: None. PMID- 28831994 TI - Coronary balloon angioplasty, stents, and scaffolds. AB - Since the first coronary angioplasty on Sept 16, 1977, the field of percutaneous coronary intervention has evolved rapidly. Now marking its 40th anniversary, percutaneous coronary intervention has become one of the most common medical procedures worldwide. Much of this progress has been due to the iteration and improvement of angioplasty technologies. Balloon angioplasty was limited by unpredictable procedural outcomes due to vessel dissection and recoil, and a high rate of restenosis. The introduction of stents resulted in more stable early results and lower rates of restenosis, although early stent thrombosis and neointimal hyperplasia causing vessel renarrowing were key limitations. Drug eluting stents delivering antiproliferative agents significantly lowered the rates of restenosis, permitting widespread use of percutaneous coronary intervention in more advanced and complex disease. Although fully bioresorbable scaffolds have the potential to further improve long-term outcomes, they have not yet achieved results equivalent to those of conventional metallic drug-eluting stents in the early years after implantation. Progress in catheter technology did not occur in isolation, and the success of percutaneous coronary intervention is also due to important advances in intracoronary imaging, and adjunct pharmacotherapy-each of which is reviewed in other papers in this Series. PMID- 28831995 TI - Intravascular imaging in coronary artery disease. AB - Although it is the method used by most interventional cardiologists to assess the severity of coronary artery disease and guide treatment, coronary angiography has many known limitations, particularly the fact that it is a lumenogram depicting foreshortened, shadowgraph, planar projections of the contrast-filled lumen rather than imaging the diseased vessel itself. Intravascular imaging intravascular ultrasound and more recently optical coherence tomography-provide a tomographical or cross-sectional image of the coronary arteries. These techniques are clinically useful to answer questions such as whether the stenosis is clinically relevant; the identification of the culprit lesion; or whether the plaque (or patient) is at high risk of future adverse events. They can also be used to optimise stent implantation to minimise stent-related adverse events, provide answers to the likelihood of distal embolisation or peri-procedural myocardial infarction during stent implantation, and provide reasons for stent thrombosis or restenosis. This review considers the usefulness of intravascular imaging in day-to-day practice. PMID- 28831996 TI - Update on antithrombotic therapy after percutaneous coronary revascularisation. AB - For relief of coronary obstruction, percutaneous coronary intervention has become a standard-of-care procedure over the past 40 years. Nonetheless, optimal outcomes after coronary stenting require careful attention to antithrombotic therapy. This review aims to summarise the current available evidence and discusses how to integrate scientific knowledge into clinical decisions. In recent years, improvement and modifications of drugs and devices have changed the field tremendously, and substantially benefitted patient outcomes. The key challenge of how to provide optimal protection against thrombotic events without excessive increases in bleeding risk has remained the same for decades. Alternative strategies with new drugs, both antiplatelet and anticoagulant agents, and new coronary stents will continue the journey to achieve this ultimate goal. PMID- 28831997 TI - Department of Error. PMID- 28831998 TI - Department of Error. PMID- 28831999 TI - Department of Error. PMID- 28832000 TI - Department of Error. PMID- 28832001 TI - Acquired epileptic opercular syndrome related to a heterozygous deleterious substitution in GRIN2A. AB - Epileptic encephalopathies with continuous spike-and-waves during sleep (CSWS) are characterized by cognitive or language impairment, and are occasionally associated with pathogenic variants of the GRIN2A gene. In these disorders, speech dysfunction could be either related to cerebral dysfunction caused by the GRIN2A deleterious variant or intense interictal epileptic activity. Here, we present a patient with apraxia of speech, clearly linked to severity of epilepsy, carrying a GRIN2A variant. A 6-year-old boy developed acute regression of expressive language following epileptic seizures, leading to complete mutism, at which time EEG revealed CSWS. MEG showed bilateral superior parietal and opercular independent CSWS onsets and PET with fluorodeoxyglucose demonstrated significant increase in relative glucose metabolism in bilateral superior parietal regions. Corticosteroids induced a regression of CSWS together with impressive improvement in speech abilities. This case supports the hypothesis of a triggering role for epileptic discharges in speech deterioration observed in children carrying a deleterious variant of GRIN2A. When classic antiepileptic drugs fail to control epileptic activity, corticosteroids should be considered. Multimodal functional neuroimaging suggests a role for opercular and superior parietal areas in acquired epileptic opercular syndrome. [Published with video sequences on www.epilepticdisorders.com]. PMID- 28832002 TI - Pointed rhythmic theta waves: a unique EEG pattern in KCNQ2-related neonatal epileptic encephalopathy. AB - We report the case of an infant with KCNQ2-related neonatal epileptic encephalopathy presenting with intractable seizures beginning on the second day of life, which were resistant to multiple antiepileptic drugs. Continuous EEG recordings starting on the sixth day of life demonstrated a unique pattern of inter-and postictal focal rhythmic pointed theta waves of lambdoid morphology in the immediate postictal period, localizing to the side of the antecedent seizure. Interictal EEG exhibited discontinuous background, including patterns of burst suppression and multifocal discharges, predominantly in the centrotemporal regions, which were aggravated during sleep. MRI demonstrated T1 signal abnormalities in the basal ganglia, bilaterally. Genetic testing revealed a de novo missense mutation in KCNQ2 at position c.545 T>G, encoding a previously unreported substitution (p.Val182Gly). Seizure control was achieved immediately after starting a lidocaine infusion at age 4 weeks. The patient remained largely seizure-free following add-on oral carbamazepine for maintenance therapy and weaning off lidocaine. This is the first report of a patient with KCNQ2-related neonatal epileptic encephalopathy and therapy-refractory seizures aborted by lidocaine, demonstrating a unique EEG pattern of inter- and postictal focal rhythmic pointed theta waves. Whether this pattern could be an early EEG marker for this disorder remains to be confirmed. [Published with video sequences on www.epilepticdisorders.com]. PMID- 28832003 TI - Atonic seizures in children with surgically remediable epilepsy: a motor system seizure phenotype? AB - Atonic seizures are common in some epileptic syndromes beginning in infancy or early childhood but they are rarely described in epilepsy with focal seizures of structural aetiology. We aimed to characterize the electroclinical features of atonic seizures in surgically remediable paediatric patients and to study the spatiotemporal organization of the underlying epileptogenic networks. We retrospectively analysed two consecutive, longitudinally evaluated and surgically treated paediatric patients presenting with atonic seizures as a manifestation of pharmacoresistant epilepsy of structural aetiology, evidenced by scalp- and stereotactic intracerebral video-EEG-recordings. A quantitative analysis of the epileptogenic zone organization was performed using the "epileptogenicity index". Long-lasting generalized ictal atonia, occurring in infancy, was a predominant clinical feature in both patients, with some hints of focal origin present in one case. The seizure phenotype evolved at later age into subtle segmental atonia, associated with prominent positive motor signs. The epileptogenic zone was localized within the dorsolateral or mesiolateral premotor region. Its spatial organization was focal, matching the lesional cortex in one and distributed involving several lesional and non-lesional structures in the other case. The emergence of atonic semiology temporally correlated with involvement of both lateral and mesial premotor, as well as primary motor areas. We hypothesize that atonic seizures may be considered as a motor system seizure phenotype in the setting of structural epilepsy. Complete removal of the epileptogenic area provided excellent seizure control. PMID- 28832004 TI - Outcome of vagus nerve stimulation for drug-resistant epilepsy: the first three years of a prospective Japanese registry. AB - Vagus nerve stimulation (VNS) is an established option of adjunctive treatment for patients with drug-resistant epilepsy, however, evidence for long-term efficacy is still limited. Studies on clinical outcomes of VNS in Asia are also limited. We report the overall outcome of a national, prospective registry that included all patients implanted in Japan. The registry included patients of all ages with all seizure types who underwent VNS implantation for drug-resistant epilepsy in the first three years after approval of VNS in 2010. The registry excluded patients who were expected to benefit from resective surgery. Efficacy analysis was assessed based on the change in frequency of all seizure types and the rate of responders. Changes in cognitive, behavioural and social status, quality of life (QOL), antiepileptic drug (AED) use, and overall AED burden were analysed as other efficacy indices. A total of 385 patients were initially registered. Efficacy analyses included data from 362 patients. Age range at the time of VNS implantation was 12 months to 72 years; 21.5% of patients were under 12 years of age and 49.7% had prior epilepsy surgery. Follow-up rate was >90%, even at 36 months. Seizure control improved over time with median seizure reduction of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2%, and responder rates of 38.9%, 46.8%, 55.8%, 57.7%, and 58.8% at three, six, 12, 24, and 36 months of VNS therapy, respectively. There were no substantial changes in other indices throughout the three years of the study, except for self/family-accessed QOL which improved over time. No new safety issues were identified. Although this was not a controlled comparative study, this prospective national registry of Japanese patients with drug-resistant epilepsy, with >90% follow-up rate, indicates long-term efficacy of VNS therapy which increased over time, over a period of up to three years. The limits of such trials, in terms of AED modifications and during follow-up and difficulties in seizure counting are also discussed. PMID- 28832005 TI - The use of single bipolar scalp derivation for the detection of ictal events during long-term EEG monitoring. AB - Epilepsy is difficult to diagnose using routine EEG recordings of short duration in patients who have low seizure frequency. Long-term EEG may be useful but is impractical in an out-of-hospital setting. We investigated whether single-channel scalp EEG placed behind the earlobe is suitable for seizure identification during prolonged EEG monitoring. Scalp EEG samples were selected from subjects over 15 years of age, and comprised two segments of either background followed by seizure or background followed by background. Bipolar EEG derivations in three directions (F8-T8, C4-T8 and T8-P8) were evaluated for the presence of a seizure by two experienced reviewers. For each EEG segment containing a seizure, one pair of electrodes was oriented towards the suspected region of seizure onset, while two pairs of electrodes were oriented elsewhere. The EEG data contained five frontally localized seizures, five parietal, five temporal, two occipital, and four primary or secondary generalized seizures. The sensitivity and specificity for recognition of seizures was 86% and 95% for Reviewer 1, and 79% and 99% for Reviewer 2, respectively. When identifying a seizure with the lead orientation towards the region of seizure onset, both reviewers identified 20 out of 21 seizures (95%). When the lead was not oriented towards the region of seizure onset, the reviewers identified 34 and 30 out of 42 ictal records correctly, respectively. These results suggest that it is possible to identify epileptic seizures by bipolar EEG derivation using only two scalp electrodes. Lead orientation towards the suspected region of seizure onset is important for optimal detection sensitivity. PMID- 28832006 TI - Megakaryocytic Emperipolesis Associated with Thrombocytopenia: Causative or Coincidence? PMID- 28832007 TI - Leishmaniasis: Bone Marrow Aspirate Smear and Rapid Antibody Test. PMID- 28832008 TI - First Observation of Hemoglobin San Diego, a High Oxygen Affinity Hemoglobin Variant, in Turkey. PMID- 28832009 TI - Frequency and Risk Factors for Secondary Malignancies in Patients with Mycosis Fungoides. PMID- 28832010 TI - The Scope of Kidney Affection in Monoclonal Gammopathies at All Levels of Clinical Significance. AB - Multiple myeloma (MM) is one of the most important clonal malignant plasma cell disorders and renal involvement is associated with poor prognosis. Although there are several reasons for renal impairment in MM, the main cause is the toxic effects of monoclonal proteins. Although cast nephropathy is the best known and unchallenged diagnosis for hematologists and pathologists, the renal effects of monoclonal gammopathy can be various. Monoclonal gammopathy of renal significance was proposed by the International Kidney and Monoclonal Gammopathy Research Group for renal lesions in monoclonal gammopathy in recent years. Renal lesions in monoclonal gammopathy can be grouped as follows: light chain (cast) nephropathy, acute tubular injury/necrosis, tubulointerstitial nephritis, amyloidosis, monoclonal Ig deposition diseases, immunotactoid glomerulopathy, type I cryoglobulinemia, proliferative glomerulonephritis with monoclonal IgG deposits, C3 glomerulopathy with monoclonal gammopathy, and crystal-storing histiocytosis, considering the previous and new terminology. In this study, renal involvement of monoclonal gammopathies, in terms of previous and new terminology, was reviewed. PMID- 28832011 TI - A Myopathy, Lactic Acidosis, Sideroblastic Anemia (MLASA) Case Due to a Novel PUS1 Mutation. PMID- 28832012 TI - Receiver Operating Characteristic Curve Analysis May be Helpful to Study the Prognostic Value of miR-155 in B-Cell Non-Hodgkin Lymphoma. PMID- 28832013 TI - Model and experiments to optimize co-adaptation in a simplified myoelectric control system. AB - OBJECTIVE: To compensate for a limb lost in an amputation, myoelectric prostheses use surface electromyography (EMG) from the remaining muscles to control the prosthesis. Despite considerable progress, myoelectric controls remain markedly different from the way we normally control movements, and require intense user adaptation. To overcome this, our goal is to explore concurrent machine co adaptation techniques that are developed in the field of brain-machine interface, and that are beginning to be used in myoelectric controls. APPROACH: We combined a simplified myoelectric control with a perturbation for which human adaptation is well characterized and modeled, in order to explore co-adaptation settings in a principled manner. RESULTS: First, we reproduced results obtained in a classical visuomotor rotation paradigm in our simplified myoelectric context, where we rotate the muscle pulling vectors used to reconstruct wrist force from EMG. Then, a model of human adaptation in response to directional error was used to simulate various co-adaptation settings, where perturbations and machine co adaptation are both applied on muscle pulling vectors. These simulations established that a relatively low gain of machine co-adaptation that minimizes final errors generates slow and incomplete adaptation, while higher gains increase adaptation rate but also errors by amplifying noise. After experimental verification on real subjects, we tested a variable gain that cumulates the advantages of both, and implemented it with directionally tuned neurons similar to those used to model human adaptation. This enables machine co-adaptation to locally improve myoelectric control, and to absorb more challenging perturbations. SIGNIFICANCE: The simplified context used here enabled to explore co-adaptation settings in both simulations and experiments, and to raise important considerations such as the need for a variable gain encoded locally. The benefits and limits of extending this approach to more complex and functional myoelectric contexts are discussed. PMID- 28832014 TI - Terahertz-infrared electrodynamics of single-wall carbon nanotube films. AB - Broad-band (4-20 000 cm-1) spectra of real and imaginary conductance of a set of high-quality pristine and AuCl3-doped single-walled carbon nanotube (SWCNT) films with different transparency are systematically measured. It is shown that while the high-energy (>=1 eV) response is determined by well-known interband transitions, the lower-energy electrodynamic properties of the films are fully dominated by unbound charge carriers. Their main spectral effect is seen as the free-carrier Drude-type contribution. Partial localization of these carriers leads to a weak plasmon resonance around 100 cm-1. At the lowest frequencies, below 10 cm-1, a gap-like feature is detected whose origin is associated with the energy barrier experienced by the carriers at the intersections between SWCNTs. It is assumed that these three mechanisms are universal and determine the low frequency terahertz-infrared electrodynamics of SWCNT wafer-scale films. PMID- 28832015 TI - Effect of Mo on the phase stability and elastic mechanical properties of Ti-Mo random alloys from ab initio calculations. AB - Ti-Mo alloys are promising materials for shape memory alloys and biomedical materials. Whereas, the appearance of metastable omega phase can cause embrittlement and destroy the shape memory effect. In order to avoid the omega phase, the effect of Mo on the temperature dependent lattice parameters, phase stability and elastic mechanical properties of beta, alpha, and omega Ti1-x Mo x (x = 0-2.0) random alloys was systematically investigated by using the exact muffin-tin orbitals method in combination with the coherent potential approximation. The theoretical predictions for the lattice parameters are in good agreement with the available experiments. Results show that beta Ti0.96Mo0.04 can almost transform to omega phase without lattice deformation and volume change, which suggests that the athermal omega phase is easier to precipitate and grow near 4 at.% Mo content in the beta Ti1-x Mo x alloys. The critical content of Mo for the competed stabilization of beta phase at T = 300 K is ~11.2 at.%. Its valence electron concentration of 4.224 is viewed as a necessary criterion for the competed phase stability. The calculations of formation energy are used to explain successfully why the partitioning of Mo can be found in Ti0.91Mo0.09 alloy after annealing. Through the analysis of formation energy, both Mo addition and increasing temperature can stabilize the beta phase. The calculated Cauchy pressure, Pugh's ratio, Poisson ratio, and Young's modulus suggests that omega phase is intrinsically brittle and has large Young's modulus compared with beta and alpha phases. PMID- 28832016 TI - Role of vacancy sites and UV-ozone treatment on few layered MoS2 nanoflakes for toxic gas detection. AB - Various issues like global warming and environmental pollutions have led to the research of toxic gas detection worldwide. In this work, we have tried to develop a molybdenum disulfide (MoS2) based gas sensor to detect toxic gases like ammonia and NO. MoS2, an inorganic analog of graphene, has attracted lots of attention for many different applications recently. This paper reports the use of liquid exfoliated MoS2 nanoflakes as the sensing layer in a handheld, resistive toxic gas sensor. The nanoflakes were exfoliated from MoS2 bulk powder using a sonication based exfoliation technique at room temperature. The successful exfoliation of the nanoflakes was characterized using different techniques e.g., optical microscopy, atomic force microscopy, field emission scanning electron microscopy, high resolution transmission electron microscopy, x-ray diffraction, Raman spectroscopy, x-ray photoelectron spectroscopy and ultraviolet-visible spectrophotometry. The characterization results showed that few-layered nanoflakes have successfully been exfoliated. The MoS2 nanoflakes showed reasonable sensing towards ammonia and NO. In order to explore the effect of particle size on ammonia sensing, the MoS2 flakes were also exfoliated using different sonication times. We also observed that various factors like presence of vacancy sites, ambient oxygen, humidity, different contact electrodes have significant effect on the sensing characteristics. In fact, the response of the sensing layer against 400 ppm of ammonia increased from 54.1% to ~80% when it was UV-ozone treated. This work holds promises to developing cost-effective, reliable and highly sensitive MoS2 based ammonia sensors. PMID- 28832017 TI - Probing of free and localized excitons and trions in atomically thin WSe2, WS2, MoSe2 and MoS2 in photoluminescence and reflectivity experiments. AB - We report on detailed temperature dependent (T = 7-295 K) optical spectroscopy studies of WSe2, WS2, MoSe2 and MoS2 monolayers exfoliated onto the same SiO2/Si substrate. In the high energy region of absorption type (reflectivity contrast RC) and emission (photo-luminescence-PL) spectra of all the monolayers resonances related to the neutral and charged excitons (X and T) are detected in the entire measured temperature range. The optical amplitudes of excitons and trions strongly depend on the temperature and two dimensional carrier gas (2DCG) concentration. In the low energy PL spectra of WSe2 and WS2 we detect a group of lines (L) which dominates the spectra at low temperatures but rapidly quenches with the increase in the temperature. Interestingly, in the same energy range of the RC spectra recorded for WS2, we observe an additional line (L 0), which behaves in the same way as the L lines in the PL spectra. The optical amplitude of L 0 and T resonances in the RC spectra strongly increases with the growth of the 2DCG concentration. On the base of these observations we identify the L 0 resonance in the RC spectra as arising from the fine structure of the trion. We also propose that the line interpreted previously in PL spectra of WSe2 and WS2 as related to the biexciton emission is a superposition of the biexciton, trion and localized exciton emission. We find that with the temperature increase from 7 295 K the total PL intensity decreases moderately in WSe2 and WS2, strongly in MoS2 and dramatically in MoSe2. PMID- 28832018 TI - Optical properties and band alignments in ZnTe nanoparticles/MoS2 layer hetero interface using SE and KPFM studies. AB - Integration of a layered two-dimensional (2D) material with a non-2D material provides a platform where one can modulate and achieve the properties desired for various next-generation electronic and opto-electronic applications. Here, we investigated ZnTe nanoparticles/MoS2 hetero-interfaces with the thickness of the MoS2 varying from few to multilayer. High-resolution transmission electron microscopy was used to observe the crystalline behaviour of the ZnTe nanoparticles, while the number of MoS2 layers was investigated using Raman measurements. Spectroscopic ellipsometry (SE) analysis based on the five-layer fitting model was used to analyse the optical behaviour of the heterojunction, where the excitonic features corresponding to the MoS2 layers and absorption features due to the ZnTe nanoparticles are observed. From the Kelvin probe force microscopy (KPFM) measurements, the surface potential (SP) of the ZnTe nanoparticles/MoS2 is found to be different in comparison with the SP of the ZnTe nanoparticles and MoS2, which is indicative of the charge transfer at the ZnTe nanoparticles/MoS2 hetero-interface. Various parameters obtained using SE and KPFM measurements were used to propose energy band alignments at the ZnTe nanoparticles/MoS2 hetero-interface. In addition, an interface photovoltage of 193 mV was obtained by carrying out KPFM measurements under illuminating condition. PMID- 28832019 TI - Anisotropic electrical transport of flexible tungsten carbide nanostructures: towards nanoscale interconnects and electron emitters. AB - Due to the coexistence of metal- and ionic-bonds in a hexagonal tungsten carbide (WC) lattice, disparate electron behaviors were found in the basal plane and along the c-axial direction, which may create an interesting anisotropic mechanical and electrical performance. To demonstrate this, low-dimensional nanostructures such as nanowires and nanosheets are suitable for investigation because they usually grow in single crystals with special orientations. Herein, we report the experimental research regarding the anisotropic conductivity of [0001] grown WC nanowires and basal plane-expanded nanosheets, which resulted in a conductivity of 7.86 * 103 Omega-1 . m-1 and 7.68 * 104 Omega-1 . m-1 respectively. This conforms to the fact that the highly localized W d state aligns along the c direction, while there is little intraplanar directional bonding in the W planes. With advanced micro-manipulation technology, the conductivity of a nanowire was tested to be approximately constant, even under a considerable bending state. Moreover, the field electron emission of WC was evaluated based on large area emission and single nanowire (nanosheet) emission. A single nanowire exhibits a stable electron emission performance, which can output emission currents >3 uA before fusing. These results provide useful references to assess low-dimensional WC nanostructures as electronic materials in flexible devices, such as nanoscale interconnects and electron emitters. PMID- 28832020 TI - Abstracts from the XI National Congress and VIII International of the Spanish Society of Conservative Dentistry May 19-21, 2016, Granada, Spain - Meeting Abstract. PMID- 28832022 TI - Prevalence of somatic mutations in patients with aplastic anemia using peripheral blood cfDNA as compared with BM. PMID- 28832021 TI - Failure to Inactivate Nuclear GSK3beta by Ser389-Phosphorylation Leads to Focal Neuronal Death and Prolonged Fear Response. AB - GSK3beta plays an essential role in promoting cell death and is emerging as a potential target for neurological diseases. Understanding the mechanisms that control neuronal GSK3beta is critical. A ubiquitous mechanism to repress GSK3beta involves Akt-mediated phosphorylation of Ser9. Here we show that phosphorylation of GSK3beta on Ser389 mediated by p38 MAPK specifically inactivates nuclear GSK3beta in the cortex and hippocampus. Using GSK3beta Ser389 to Ala mutant mice, we show that failure to inactivate nuclear GSK3beta by Ser389 phosphorylation causes neuronal cell death in subregions of the hippocampus and cortex. Although this focal neuronal death does not impact anxiety/depression-like behavior or hippocampal-dependent spatial learning, it leads to an amplified and prolonged fear response. This phenotype is consistent with some aspects of post-traumatic stress disorder (PTSD). Our studies indicate that inactivation of nuclear GSK3beta by Ser389 phosphorylation plays a key role in fear response, revealing new potential therapeutic approaches to target PTSD. PMID- 28832023 TI - Oncolytic reovirus sensitizes multiple myeloma cells to anti-PD-L1 therapy. PMID- 28832024 TI - Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma. AB - Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL. PMID- 28832025 TI - Corrigendum: Whole genome analysis of a schistosomiasis-transmitting freshwater snail. AB - This corrects the article DOI: 10.1038/ncomms15451. PMID- 28832026 TI - TGF-beta1 alters esophageal epithelial barrier function by attenuation of claudin 7 in eosinophilic esophagitis. AB - Barrier dysfunction has been implicated in the pathophysiology of eosinophilic esophagitis (EoE). Transforming growth factor-beta1 (TGF-beta1), a potent pleiotropic molecule, is increased in EoE; however, no study has evaluated its influence on esophageal epithelial barrier. We hypothesized that TGF-beta1 regulates barrier dysfunction in EoE. We aimed to determine the role of TGF-beta1 in the epithelial barrier in models of EoE. To examine the impact of TGF-beta1 on esophageal barrier, immortalized human esophageal epithelial (EPC2-hTERT) cells were exposed to TGF-beta1 during the three-dimensional air-liquid interface (3D ALI) model in vitro. TGF-beta1 exposure diminished EPC2-hTERT barrier function as measured by transepithelial electrical resistance (TEER) and 3 kDa Fluorescein isothiocyanate dextran paracellular flux (FITC Flux), and hematoxylin and eosin (H&E) assessment revealed prominent cellular separation. In analysis of epithelial barrier molecules, TGF-beta1 led to the specific reduction in expression of the tight-junction molecule, claudin-7 (CLDN7), and this was prevented by TGF-beta-receptor I inhibitor. Short hairpin ribonucleic acid (shRNA)-mediated CLDN7 knockdown diminished epithelial barrier function, whereas CLDN7 overexpression resulted in protection from TGF-beta1-mediated barrier dysfunction. In pediatric EoE biopsies CLDN7 expression was decreased and altered localization was observed with immunofluorescence analysis, and the TGF-beta1 downstream transcription factor, phosphorylated SMAD2/3 (pSMAD2/3), was increased. Our data suggest that TGF-beta1 participates in esophageal epithelial barrier dysfunction through CLDN7 dysregulation. PMID- 28832028 TI - Assessment of correlation between vitamin D level and prevalence of preterm births in the population of pregnant women in Poland. AB - OBJECTIVES: Aim of this project is determination of the correlation between the level of vitamin D in blood serum and duration of pregnancy in population in central Poland. MATERIAL AND METHODS: 25-Hydroxyvitamin D (25(OH)D) level was determined in blood serum, using enzyme-linked immunosorbent assay (ELISA). Standardized history of each patient was recorded. The history included: general medical history, data regarding the course of pregnancy and information about health-related behavior that could influence vitamin D concentration. Two hundred and-one Caucasian women at childbirth were qualified into the study. The study group was divided into 2 parts: 100 patients who had a spontaneous premature birth and 101 patients who had birth at full term. RESULTS: Vitamin D deficiency (< 30 ng/ml) was very common for both groups (69.6% of patients in the premature group and 72% - in the control group). Patients who had a premature birth had severe vitamin D deficiency (less than 10 ng/ml) more often than in the control group (34% vs. 14.2%, p = 0.001). Severe vitamin D deficiency increased the risk of premature birth but the association was not statistically significant in the multivariate regression model (odds ratio (OR) = 2.47, 95% confidence interval (CI): 0.86-7.15, p = 0.094). CONCLUSIONS: Severe vitamin D deficiency (< 10 ng/ml) may be the factor increasing the risk of preterm birth. Int J Occup Med Environ Health 2017;30(6):933-941. PMID- 28832029 TI - Poisoning deaths in Poland: Types and frequencies reported in Lodz, Krakow, Sosnowiec, Gdansk, Wroclaw and Poznan during 2009-2013. AB - OBJECTIVES: The aim of this study has been to assess the characteristics of acute poisoning deaths in Poland over a period of time 2009-2013. MATERIAL AND METHODS: The analysis was based on the data obtained from the patient records stored in toxicology departments in 6 cities - Lodz, Krakow, Sosnowiec, Gdansk, Wroclaw and Poznan. Toxicological analyses were routinely performed in blood and/or urine. Major toxic substances were classified to one of the following categories: pharmaceuticals, alcohol group poisonings (ethanol and other alcohols), gases, solvents, drugs of abuse, pesticides, metals, mushrooms, others. Cases were analyzed according to the following criteria: year, age and gender of analyzed patients, toxic substance category and type of poisoning. The recorded fatal poisonings were classified according to the International Classification of Diseases. RESULTS: The record of 261 deaths were retrospectively reviewed. There were 187 males (71.64%) and 74 females (28.36%) and the male to female ratio was 2.52. Alcohol group poisonings were more frequently responsible for deaths in men compared to all poisonings, 91.1% vs. 71.6%, respectively (p < 0.05), and pharmaceutical agents were more frequently responsible for deaths in women, 47.4% vs. 28.4%, (p < 0.05). Methanol was the most common agent in the alcohol group poisonings, accounting for 43.75% (N = 49), followed by ethylene glycol, 39.29% (N = 44), and ethanol, 16.96% (N = 19). CONCLUSIONS: Epidemiological profile data from investigation of poisoning deaths in Poland may be very useful for the development of preventive programs. Int J Occup Med Environ Health 2017;30(6):897 908. PMID- 28832027 TI - Protein kinase C-delta (PKCdelta), a marker of inflammation and tuberculosis disease progression in humans, is important for optimal macrophage killing effector functions and survival in mice. AB - We previously demonstrated that protein kinase C-delta (PKCdelta) is critical for immunity against Listeria monocytogenes, Leishmania major, and Candida albicans infection in mice. However, the functional relevance of PKCdelta during Mycobacterium tuberculosis (Mtb) infection is unknown. PKCdelta was significantly upregulated in whole blood of patients with active tuberculosis (TB) disease. Lung proteomics further revealed that PKCdelta was highly abundant in the necrotic and cavitory regions of TB granulomas in multidrug-resistant human participants. In murine Mtb infection studies, PKCdelta-/- mice were highly susceptible to tuberculosis with increased mortality, weight loss, exacerbated lung pathology, uncontrolled proinflammatory cytokine responses, and increased mycobacterial burdens. Moreover, these mice displayed a significant reduction in alveolar macrophages, dendritic cells, and decreased accumulation of lipid bodies (lungs and macrophages) and serum fatty acids. Furthermore, a peptide inhibitor of PKCdelta in wild-type mice mirrored lung inflammation identical to infected PKCdelta-/- mice. Mechanistically, increased bacterial growth in macrophages from PKCdelta-/- mice was associated with a decline in killing effector functions independent of phagosome maturation and autophagy. Taken together, these data suggest that PKCdelta is a marker of inflammation during active TB disease in humans and required for optimal macrophage killing effector functions and host protection during Mtb infection in mice. PMID- 28832030 TI - Did legal regulations change the reporting frequency of sharp injuries of medical personnel? Study from 36 hospitals in Lodz Province, Poland. AB - OBJECTIVES: The aim of the study has been to analyze the epidemiological data on sharp injuries among health care workers before and after the implementation of regulations related to the conduct of the register of sharp injuries. MATERIAL AND METHODS: We hypothesized that the introduction of legislation would change the existing low reportability of sharp injuries and reporting incidents would increase. In Poland the binding regulations, dating back to 2013, require the employer to keep a record of sharp injuries. Therefore, we compared the data from before and after the entry regulations. Data was collected from the records of occupational exposure/accidents at work in hospitals in the Lodz Province during 2010-2014. The feedback came from 36 hospitals (return index = 51.5%), representing a total annual average of 13 211 medical workers. RESULTS: The incidence of injuries did not change significantly over the period 2010-2014, and the number of reported injuries in 2014 (the year when the Regulation had already been effective) was even lower than in the previous years. The average annual injury index was 12.31 injuries per 1000 employees (95% confidence interval: 11.48-13.16/1000). The incidence of injuries among nurses was significantly higher than in other groups of medical professionals (p < 0.05). These injuries most often occur while using needles (p < 0.05). CONCLUSIONS: The obligation to record occupational exposures set forth in current regulations is not likely to improve the reliability of reporting the incidents actually taking place. Further research should focus on identifying barriers to reporting cases of exposure to potentially infectious material. Action should be taken to raise awareness of medical personnel about the possible effects of exposure to infectious material, in particular, the benefits of the implementation of early post-exposure procedures. Perhaps it will increase the reporting frequency of sharp injuries of medical personnel. Int J Occup Med Environ Health 2018;31(1):37-46. PMID- 28832031 TI - Activation of C-H bonds by rare-earth metallocene-butyl complexes. AB - The stable metallocene-butyl complexes [(CpMe)2M(nBu)]2 (M = Y, Dy) were synthesized and their reactivity towards to ferrocene and bulky N-heterocyclic carbenes investigated. Selective mono-deprotonation of ferrocene and a benzylic methyl group of IMes were observed, whereas a control reaction of (CpMe)3M with IMes resulted in a normal-to-abnormal NHC rearrangement. PMID- 28832032 TI - Exploiting the high oxidation potential of carisoprodol on a boron-doped diamond electrode: an improved method for its simultaneous determination with acetaminophen and caffeine. AB - A boron-doped diamond electrode (BDDE) was employed for the first time in the development of a voltammetric method for the simultaneous determination of acetaminophen (ACT), caffeine (CAF) and carisoprodol (CAR). CAR presents a high oxidation potential (2.0 V) and this electrode is suitable for this purpose due to its wide electrochemical potential window. The anodic peak potentials of ACT, CAF and CAR oxidation on the BDDE were found to be 0.980 V, 1.50 V and 2.03 V (vs. Ag/AgCl (3.0 mol L-1 KCl)), respectively, by cyclic voltammetry. After optimization of the analytical conditions employing BDDE at pH 6.0 in a Britton Robinson buffer solution, square-wave voltammetry (SWV) was applied to the simultaneous determination, by which the peak currents for the three molecules were found to vary linearly with their concentrations in the range of 2.99-283 MUmol L-1 for ACT, 2.99-84.8 MUmol L-1 for CAF and 19.9-207 MUmol L-1 for CAR, with detection limits of 0.768 MUmol L-1, 0.771 MUmol L-1, and 3.11 MUmol L-1, respectively. The proposed method was employed for the simultaneous determination of the three molecules in pharmaceutical formulations and the results were successfully validated with a comparative spectrophotometric method. The use of BDDE showed advantages such as low cost, suitable linearity for simultaneous quantification in real samples, no adsorption problems, and possessing rapidity and excellent reproducibility. This electrode represents a suitable electrochemical sensor for the routine analysis of these drugs. PMID- 28832033 TI - A biomass derived N/C-catalyst for the electrochemical production of hydrogen peroxide. AB - Pomelo peel, a waste biomass, was used as an all-in-one (carbon source, self template, and heteroatom) precursor to develop a nanoporous N/C-electrocatalyst for highly selective and energy-saving H2O2 production, in which disordered carbonous defects and five-membered rings (pyrrolic-N) played vital roles. PMID- 28832034 TI - Surface-modified polymers for cardiac tissue engineering. AB - Cardiovascular disease (CVD), leading to myocardial infarction and heart failure, is one of the major causes of death worldwide. The physiological system cannot significantly regenerate the capabilities of a damaged heart. The current treatment involves pharmacological and surgical interventions; however, less invasive and more cost-effective approaches are sought. Such new approaches are developed to induce tissue regeneration following injury. Hence, regenerative medicine plays a key role in treating CVD. Recently, the extrinsic stimulation of cardiac regeneration has involved the use of potential polymers to stimulate stem cells toward the differentiation of cardiomyocytes as a new therapeutic intervention in cardiac tissue engineering (CTE). The therapeutic potentiality of natural or synthetic polymers and cell surface interactive factors/polymer surface modifications for cardiac repair has been demonstrated in vitro and in vivo. This review will discuss the recent advances in CTE using polymers and cell surface interactive factors that interact strongly with stem cells to trigger the molecular aspects of the differentiation or formulation of cardiomyocytes for the functional repair of heart injuries or cardiac defects. PMID- 28832035 TI - Gelatin gels as multi-element calibration standards in LA-ICP-MS bioimaging: fabrication of homogeneous standards and microhomogeneity testing. AB - Highly homogeneous multi-element gelatin calibration standards were fabricated for quantitative LA-ICP-MS bioimaging. Heterogeneity issues caused by the so called "coffee-stain" and/or "Marangoni" effects were found to be element dependent but could be circumvented by careful selection of drying/setting conditions. A micro-homogeneity test was developed for certification of the standards. PMID- 28832036 TI - Label-free, high content screening using Raman microspectroscopy: the toxicological response of different cell lines to amine-modified polystyrene nanoparticles (PS-NH2). AB - Nanotoxicology has become an established area of science due to growing concerns over the production and potential use of nanomaterials in a wide-range of areas from pharmaceutics to nanomedicine. Although different cytotoxicity assays have been developed and are widely used to determine the toxicity of nanomaterials, the production of multi-parametric information in a rapid and non-invasive way is still challenging, when the amount and diversity of physicochemical properties of nanomaterials are considered. High content screening can provide such analysis, but is often prohibitive in terms of capital and recurrent costs in academic environments. As a label-free technique, the applicability of Raman microspectroscopy for the analysis of cells, tissues and bodily fluids has been extensively demonstrated. The multi-parametric information in the fingerprint region has also been used for the determination of nanoparticle localisation and toxicity. In this study, the applicability of Raman microspectroscopy as a 'high content nanotoxicological screening technique' is demonstrated, with the aid of multivariate analysis, on non-cancerous (immortalized human bronchial epithelium) and cancerous cell-lines (human lung carcinoma and human lung epidermoid cells). Aminated polystyrene nanoparticles are chosen as model nanoparticles due to their well-established toxic properties and cells were exposed to the nanoparticles for periods from 24-72 hours. Spectral markers of cellular responses such as oxidative stress, cytoplasmic RNA aberrations and liposomal rupture are identified and cell-line dependent systematic variations in these spectral markers, as a function of the exposure time, are observed using Raman microspectroscopy, and are correlated with cellular assays and imaging techniques. PMID- 28832037 TI - Increasing the lifetimes of charge separated states in porphyrin-fullerene polyads. AB - Two linear polyads were designed using zinc(ii)porphyrin, [ZnP], and N-methyl-2 phenyl-3,4-fullero-pyrrolidine (C60) where C60 is dangling either at the terminal position of [ZnP]-C6H4-[triple bond, length as m-dash]-C6H4-[ZnP]-C60 (1) or at the central position of [ZnP]-C6H4-[triple bond, length as m-dash]-C6H4 [ZnP(C60)]-C6H4-[triple bond, length as m-dash]-C6H4-[ZnP] (2) in order to test whether the fact of having one or two side electron donors influences the rate of electron transfer, ket. These polyads were studied using cyclic voltammograms, DFT computations, steady state and time-resolved fluorescence spectroscopy, and femtosecond transient absorption spectroscopy (fs-TAS). Photo-induced electron transfer confirmed by the detection of the charge separated state [ZnP+]/C60- from fs-TAS occurs with rates (ket) of 3-4 * 1010 s-1 whereas the charge recombinations (CRs) are found to produce the [ZnP] ground state via two pathways (central [ZnP+]/C60- (ps) and terminal central [ZnP+]/C60- (ns) producing [1ZnP] (ground state) and [3ZnP*]). The formation of the T1 species is more predominant for 2. PMID- 28832038 TI - An organocatalytic cis-selective approach to bicyclic delta-lactones. AB - A new, cis-selective, approach for the synthesis of bicyclic delta-lactones bearing a fused cyclohex-2-en-1-one moiety is described. The strategy utilizes a cascade reactivity of cyclic 1,3-diketones and 3-arylidenefuran-2(3H)-ones with the butenolide-ring-opening reaction enabling the construction of the delta lactone framework. It benefits from broad scope, high enantioselectivity and excellent cis-diastereoselectivity. PMID- 28832039 TI - Self-assembly of a nanotube from a black phosphorus nanoribbon on a string of fullerenes at low temperature. AB - A string of fullerenes is used for generating a nanotube by self-assembly of a black phosphorus (BP) nanoribbon at a temperature of 8 K. Among the fullerenes in the string, there are at least two fixed fullerenes placed along the edge of the BP ribbon for keeping its configuration stability during winding. By way of molecular dynamics simulations, it is found that successful generation of a BP nanotube depends on the bending stiffness of the ribbon and the attraction between the fullerenes and the ribbon. When the attraction is strong enough, the two edges (along the zigzag direction) of the BP ribbon will be able to bond covalently to form a nanotube. By the molecular dynamics approach, the maximum width of the BP ribbon capable of forming a nanotube with a perfect length is investigated in three typical models. The maximum width of the BP ribbon becomes larger with the string containing more fullerenes. This finding reveals a way to control the width of the BP ribbon which forms a nanotube. It provides guidance for fabricating a BP nanotube with a specified length, the same as to the width of the ribbon. PMID- 28832040 TI - Hollow AuxAg/Au core/shell nanospheres as efficient catalysts for electrooxidation of liquid fuels. AB - One plausible approach to endow nanocrystals with both enhanced catalytic activity and stability for the electrooxidation of liquid fuels is to chemically control the crystal structures of nanoparticles. To date, core-shell and alloy structures have been demonstrated to offer generally two precious opportunities to design highly efficient nanocatalysts for the electrooxidation reaction of organic molecules. We herein combine these two advantages and develop a general method to successfully synthesize hollow AuxAg/Au core/shell nanospheres with a high yield approaching 100% via a combined seed mediated and galvanic replacement method. The results from the electrochemical measurements have revealed that this as-obtained hollow AuxAg/Au core/shell nanosphere exhibited considerably high electrocatalytic performance towards ethylene glycol and glycerol oxidation with mass activity of 4585 and 3486 mA mgAu-1, which were 5.3- and 5.8-fold higher than that of pure Au. We trust this strategy may be extended to the syntheses of other multimetallic nanocatalysts with such fascinating nanostructures and the as obtained hollow AuxAg/Au core/shell nanospheres can be well applied to serve as highly desirable anode catalysts for the electrooxidation of ethylene glycol and glycerol. PMID- 28832041 TI - Highly controllable direct femtosecond laser writing of gold nanostructures on titanium dioxide surfaces. AB - A highly reproducible and controllable deposition procedure for gold nanostructures on a titanium dioxide (TiO2) surface using femtosecond laser light has been demonstrated. This is realized by precisely focusing onto the TiO2 surface in the presence of a pure gold ion solution. The deposition is demonstrated both in dot arrays and line structures. Thanks to the multi-photon excitation, we observe that the deposition area of the nanostructures can be confined to a degree far greater than the diffraction limited focal spot. Finally, we demonstrate that catalytic activity with visible light irradiation is enhanced, proving the applicability of our new deposition technique to the catalytic field. PMID- 28832042 TI - A flexible metallic actuator using reduced graphene oxide as a multifunctional component. AB - Flexible actuators are widely in demand for many real-life applications. Considering that existing actuators based on polymers, low-dimensional materials and pore-rich materials are mostly limited by slow response rate, high driving voltage and poor stability, we report here a novel metal based flexible actuator which is fabricated simply through partial oxidation and nano-function of copper foil with the assistance of reduced graphene oxide. The obtained asymmetric metallic actuator is (electric-)thermally driven and exhibits fast response rate (~2 s) and large curvature (2.4 cm-1) under a low voltage (~1 V) with a sustainable operation of up to ~50 000 cycles. The actuator can also be triggered by infrared irradiation and direct-heating under various conditions including air, water, and vacuum. PMID- 28832043 TI - Plasmonic heating from indium nanoparticles on a floating microporous membrane for enhanced solar seawater desalination. AB - Passive solar evaporation represents a promising and environmentally benign method of water purification/desalination. Plasmonic nanoparticles have been demonstrated as an effective approach for enhancing solar steam generation through a plasmonic heating effect, nonetheless the efficiency is constrained by unnecessary bulk heating of the entire liquid volume, while the noble metals commonly used are not cost-effective in terms of availability and their sophisticated preparation. Herein, a paper-like plasmonic device consisting of a microporous membrane and indium nanoparticles (In NPs/MPM) is fabricated through a simple thermal evaporation method. Due to the light-weight and porous nature of the device, the broadband light absorption properties, and theoretically the excellent plasmonic heating effect from In NP which could be even higher than gold, silver and aluminium nanoparticles, our device can effectively enhance solar water evaporation by floating on the water surface and its utility has been demonstrated in the solar desalination of a real seawater sample. The durability of the device in solar seawater desalination has also been investigated over multiple cycles with stable performances. This portable device could provide a solution for individuals to do water/seawater purification in under-developed areas with limited/no access to electricity or a centralized drinking water supply. PMID- 28832044 TI - Hard templating ultrathin polycrystalline hematite nanosheets: effect of nano dimension on CO2 to CO conversion via the reverse water-gas shift reaction. AB - Understanding how nano-dimensionality impacts iron oxide based catalysis is central to a wide range of applications. Here, we focus on hematite nanosheets, nanowires and nanoparticles as applied to catalyze the reverse water gas shift (RWGS) probe reaction. We introduce a novel approach to synthesize ultrathin (4-7 nm) hematite nanosheets using copper oxide nanosheets as a hard template and propose a reaction mechanism based on density functional theory (DFT) calculations. Hematite nanowires and nanoparticles were also synthesized and characterized. H2 temperature programmed reduction (H2-TPR) and RWGS reactions were performed to glean insights into the mechanism of CO2 conversion to CO over the iron oxide nanomaterials and were compared to H2 binding energy calculations based on density functional theory. While the nanosheets did exhibit high CO2 conversion, 28% at 510 degrees C, we found that the iron oxide nanowires had the highest CO2 conversion, reaching 50% at 750 degrees C under atmospheric pressure. No products besides CO and H2O were detected. PMID- 28832045 TI - Multifunctional carbon dots for highly luminescent orange-emissive cellulose based composite phosphor construction and plant tissue imaging. AB - A new class of carbon dot (CD) grafted cellulose hybrid phosphors has been prepared in a facile and fast process. The reddish-orange emissive CDs can be effectively dispersed in cellulose matrices through hydrogen binding, and thus highly efficient orange-emissive CD-based phosphors were successfully obtained with a quantum yield of 44%. Moreover, the affinity of CDs for binding cellulose provides them the feasibility for fluorescence mapping of cellulosic plant cell walls. Several model plant tissues have been employed to investigate the pathway of CDs. Confocal analysis demonstrated that plant tissues can readily absorb CDs from aqueous solutions and bind them with cellulose-rich structures. These studies may open up new avenues for the exploration of CDs in long-wavelength emissive solid-state lighting and plant tissue imaging. PMID- 28832046 TI - Surface oxidation and thermoelectric properties of indium-doped tin telluride nanowires. AB - The recent discovery of excellent thermoelectric properties and topological surface states in SnTe-based compounds has attracted extensive attention in various research areas. Indium doped SnTe is of particular interest because, depending on the doping level, it can either generate resonant states in the bulk valence band leading to enhanced thermoelectric properties, or induce superconductivity that coexists with topological states. Here we report on the vapor deposition of In-doped SnTe nanowires and the study of their surface oxidation and thermoelectric properties. The nanowire growth is assisted by Au catalysts, and their morphologies vary as a function of substrate position and temperature. Transmission electron microscopy characterization reveals the formation of an amorphous surface in single crystalline nanowires. X-ray photoelectron spectroscopy studies suggest that the nanowire surface is composed of In2O3, SnO2, Te and TeO2 which can be readily removed by argon ion sputtering. Exposure of the cleaned nanowires to atmosphere leads to rapid oxidation of the surface within only one minute. Characterization of electrical conductivity sigma, thermopower S, and thermal conductivity kappa was performed on the same In doped nanowire which shows suppressed sigma and kappa but enhanced S yielding an improved thermoelectric figure of merit ZT compared to the undoped SnTe. PMID- 28832047 TI - Self-assembly based plasmonic nanoparticle array coupling with hexagonal boron nitride nanosheets. AB - Investigation of hexagonal boron nitride nanosheet (BNNS)/plasmonic nanoparticle (NP) composites is of crucial importance for developing plasmaron-based nanodevices. In this study, a simple and effective way for depicting the fabrication of BNNS/Au NP nanocomposites is reported. Diblock copolymer-based NP arrays exhibiting high hexagonal ordering and offering easy control of particle size are utilized to produce Au NP arrays by directly bonding them to BNNSs on a large scale, allowing to investigate the underlying physics of the metal/BNNS interface. The coupling between BNNSs and plasmonic Au NP arrays, work function, charge transfer and surface-enhanced Raman scattering (SERS) of BNNS phonon modes are explored. It is revealed that local surface plasmon resonance (LSPR) of Au NPs induces an electromagnetic mechanism responsible for enhanced Raman results of BNNSs when placing them below Au NPs. In contrast, essential contribution of chemical enhancement from charge transfer induced by energy realignment at the metal/BNNS interface is manifested in hybrid systems of Au NPs and encapsulated BNNS. This work is the first demonstration on evolution of plasmon resonance and charge-based interactions dependent on metal/BNNS interface, thus providing straightforward implications to further develop BNNS-based plasmonics, optoelectronics, and electronics. PMID- 28832048 TI - A bioinspired poly(N-isopropylacrylamide)/silver nanocomposite as a photonic crystal with both optical and thermal responses. AB - Responsive photonic crystals (PCs) would exhibit reversible changes in reflectance wavelength under external stimuli. Generally, external stimuli are applied, which would result in the variation of the photonic band gap. Internal stimuli would be more attractive for not destroying the hierarchical structures. Herein, we report a straightforward way to fabricate an optically induced thermo responsive PC for the first time by coating butterfly wing scales with thermo sensitive poly(N-isopropylacrylamide) (PNIPAm) with Ag nanoparticles formed in situ. As optic-thermo converters, Ag nanoparticles can convert light into thermal energy because of their surface plasmon resonance properties. The increase in temperature resulted in the phase transition of the PNIPAm coating on the wing scales, leading to the change of the bioinspired PC structure. Correspondingly, a blue shift in reflectance wavelength was detected for the obtained PC. Interestingly, a reversible optical thermo-responsive performance was observed through controlling the light source. This strategy is believed to be applied in other internal stimuli-responsive PCs with attractive properties, with the combination of various noble particles and a wide range of hierarchical photonic structures in nature. PMID- 28832050 TI - One-flask synthesis of pyrazolone thioethers involving catalyzed and uncatalyzed thioetherification pathways of pyrazolones. AB - A one-flask thioetherification of pyrazolones has been demonstrated by transforming several pyrazolones to their corresponding 4-mercaptopyrazolone derivatives and employing them towards cross-coupling with various aromatic and heteroaromatic iodides by applying Pd(OAc)2/xantphos as the catalytic system. The coupling ability of these thiol intermediates with 2,3-dichloropyrazine through an aromatic SN2 pathway has also been established. This methodology provides the use of inexpensive starting materials along with a short reaction time. PMID- 28832049 TI - An enzymatic strategy to asymmetrically branched N-glycans. AB - An enzymatic strategy was developed to generate asymmetrically branched N-glycans from natural sources by using a panel of glycosidases and glycosyltransferases. Briefly, LacZ beta-galactosidase was employed to selectively trim symmetrically branched N-glycans isolated from bovine fetuin. The yielding structures were then converted to asymmetrically branched core structures by robust glycosyltransferase for further extension. PMID- 28832051 TI - Insight into the deprotonation at the half-equivalence point of (thio)amido benzimidazoles in the presence of anions. AB - Three crystallographic structures highlight the acid-base half-equivalence point of hydrogen-bond donor (thio)amido-benzimidazoles induced by fluoride or benzoate salts with concomitant hydrogen-bonding and deprotonation as a merged synergic process. PMID- 28832052 TI - Comprehensive benchmarking of density matrix functional approximations. AB - The energy usually serves as a yardstick in assessing the performance of approximate methods in computational chemistry. After all, these methods are mostly used for the calculation of the electronic energy of chemical systems. However, computational methods should be also aimed at reproducing other properties, such strategy leading to more robust approximations with a wider range of applicability. In this study, we suggest a battery of ten tests with the aim to analyze density matrix functional approximations (DMFAs), including several properties that the exact functional should satisfy. The tests are performed on a model system with varying electron correlation, carrying a very small computational effort. Our results not only put forward a complete and exhaustive benchmark test for DMFAs, currently lacking, but also reveal serious deficiencies of existing approximations that lead to important clues in the construction of more robust DMFAs. PMID- 28832053 TI - Synthesis and investigation of neptunium zirconium phosphate, a member of the NZP family: crystal structure, thermal behaviour and Mossbauer spectroscopy studies. AB - A new double neptunium zirconium phosphate of the type MxZr2(PO4)3 (M = Np), crystallizing in the structure type NaZr2(PO4)3 (NZP, NASICON), was synthesized by solid state reactions at high temperatures and characterized by X-ray diffraction, infrared spectroscopy and Mossbauer spectroscopy. The Rietveld refinement of the XRD pattern together with the analysis of the IR spectra of the sample confirmed the space group P3[combining macron]c, the same as that for the lanthanide analogues Ln0.33Zr2(PO4)3. However, Mossbauer studies revealed the presence of neptunium in the two oxidation states +3 and +4, indicating a two phase NZP system with different crystallographic environments of the neptunium atoms. The thermal behaviour of the sample was followed up to 1400 degrees C by thermogravimetric analysis. PMID- 28832057 TI - Physicomechanical properties of spark plasma sintered carbon nanotube-containing ceramic matrix nanocomposites. AB - Recently, a wide variety of research works have focused on carbon nanotube (CNT) ceramic matrix nanocomposites. In many cases, these novel materials are produced through conventional powder metallurgy methods including hot pressing, conventional sintering, and hot isostatic pressing. However, spark plasma sintering (SPS) as a novel and efficient consolidation technique is exploited for the full densification of high-temperature ceramic systems. In these binary nanocomposites, CNTs are added to ceramic matrices to noticeably modify their inferior properties and SPS is employed to produce fully dense compacts. In this review, a broad overview of these systems is provided and the potential influences of CNTs on their functional and structural properties are addressed. The technical challenges are then mentioned and the ongoing debates over overcoming these drawbacks are fully highlighted. The structural classification used is material-oriented. It helps the readers to easily find the material systems of interest. The SPSed CNT-containing ceramic matrix nanocomposites are generally categorized into four main classes: CNT-oxide systems; CNT-nitride systems, CNT-carbide systems, and CNT-boride systems. A large number of original curves and bubble maps are provided to fully summarize the experimental results reported in the literature. They pave the way for obviously selecting the ceramic systems required for each industrial application. The properties in consideration include the relative density, hardness, yield strength, fracture toughness, electrical and thermal conductivities, modulus, and flexural strength. These unique graphs facilitate the comparison between reported results and help the reader to easily distinguish the best method for producing the ceramic systems of interest and the optimal conditions under which the superior properties can be reached. The authors have concentrated on the microstructure evolution physicomechanical property relationship and tried to relate each property to pertinent microstructural phenomena and address why the properties are degraded or enhanced with the variation of SPS conditions or material parameters. PMID- 28832059 TI - Electronic, magnetic and photophysical properties of MOFs and COFs: general discussion. PMID- 28832060 TI - Rational design of an orthogonal noncovalent interaction system at the MUPP1 PDZ11 complex interface with CaMKIIalpha-derived peptides in human fertilization. AB - The recognition and association between the Ca2+/calmodulin-activated protein kinase II-alpha (CaMKIIalpha) and the multi-PDZ domain protein 1 (MUPP1) plays an important role in the sperm acrosome reaction and human fertilization. Previously, we have demonstrated that the MUPP1 PDZ11 domain is the primary binding partner of the CaMKIIalpha C-terminal tail, which can be targeted by a rationally designed sia peptide with nanomolar affinity. Here, we further introduced an orthogonal noncovalent interaction (ONI) system between a native hydrogen bond and a designed halogen bond across the complex interface of the PDZ11 domain with the sia [Asn-1Phe] peptide mutant, where the halogen bond was formed by substituting the o-hydrogen atom of the benzene ring of the peptide Phe 1 residue with a halogen atom (F, Cl, Br or I). Molecular dynamics simulations and high-level theoretical calculations suggested that bromine (Br) is a good compromise between the halogen-bonding strength and steric hindrance effect due to introduction of a bulkier halogen atom into the tightly packed complex interface. Fluorescence spectroscopy assays revealed that the resulting o-Br substituted peptide (Kd = 18 nM) exhibited an ~7.6-fold affinity increase relative to its native counterpart (Kd = 137 nM). In contrast, the p-Br substituted peptide, a negative control that is unable to establish the ONI according to structure-based analysis, has decreased affinity (Kd = 210 nM) upon halogenation. PMID- 28832062 TI - Antioxidant and anti-inflammatory effects of cauliflower leaf powder-enriched diet against LPS induced toxicity in rabbits. AB - Brassica phytochemicals exert a broad spectrum of health-promoting activities. The aim of this study was to investigate the possible beneficial effects of a cauliflower leaf powder (CLP)-enriched diet to prevent inflammation and oxidative stress resulting from injection of lipopolysaccharide (LPS) into rabbits. Animals (24 rabbits) were randomly divided into two groups and fed with a standard diet (SD) or a standard diet supplemented with a 100 g kg-1 diet of CLP. After 60 days, six rabbits of both groups received a LPS injection (100 MUg per kg body weight). Serum samples collected after 90 min of LPS injection were assessed for their content of both inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and matrix-metalloproteinases (MMP-2 and MMP-9) and oxidative stress biomarkers such as thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). LPS increased the levels of TNF-alpha, IL-6, and TBARS as well as MMP-2 and MMP-9 activities, whereas it decreased the GSH levels and SOD and CAT activities. In conclusion, preventive supplementation with CLP can protect rabbits from the inflammation and oxidative stress induced by LPS. PMID- 28832063 TI - Formation of crystalline nanoparticles by iron binding to pentapeptide (Asp-His Thr-Lys-Glu) from egg white hydrolysates. AB - A novel peptide from egg white, Asp-His-Thr-Lys-Glu (DHTKE), contains specific amino acids associated with iron binding. The present study aims to better understand the molecular basis of interactions between the DHTKE peptide and iron ions. The ultraviolet-visible and fluorescence spectra indicate an interaction between the DHTKE peptide and iron ions, which leads to the formation of a DHTKE iron complex. Notably, Asp, Glu, His, and Lys in the DHTKE peptide play crucial roles in the formation of the DHTKE-iron complex, and the iron-binding site of the DHTKE peptide corresponds primarily to the amide and carboxyl groups. The DHTKE peptide can bind iron ions in a 1 : 2 ratio with a binding constant of 1.312 * 105 M-1. Moreover, the DHTKE-iron complex belongs to thermodynamically stable nanoparticles that are present in the crystalline structure, which might be attributed to peptide folding induced by iron binding. Meanwhile, the DHTKE iron complex exhibits a relatively high iron-releasing percentage and exerts excellent solubility in the human gastrointestinal tract in vitro. This suggests a potential application of peptides containing Asp, Glu, His, or Lys residues as potential iron supplements. PMID- 28832064 TI - Catalysis in MOFs: general discussion. PMID- 28832065 TI - A microfluidic platform for the high-throughput study of pathological cardiac hypertrophy. AB - Current in vitro models fall short in deciphering the mechanisms of cardiac hypertrophy induced by volume overload. We developed a pneumatic microfluidic platform for high-throughput studies of cardiac hypertrophy that enables repetitive (hundreds of thousands of times) and robust (over several weeks) manipulation of cardiac MUtissues. The platform is reusable for stable and reproducible mechanical stimulation of cardiac MUtissues (each containing only 5000 cells). Heterotypic and homotypic MUtissues produced in the device were pneumatically loaded in a range of regimes, with real-time on-chip analysis of tissue phenotypes. Concentrated loading of the three-dimensional cardiac tissue faithfully recapitulated the pathology of volume overload seen in native heart tissue. Sustained volume overload of MUtissues was sufficient to induce pathological cardiac remodeling associated with upregulation of the fetal gene program, in a dose-dependent manner. PMID- 28832066 TI - The structural landscape in 14-vertex clusters of silicon, M@Si14: when two bonding paradigms collide. AB - The structural chemistry of the title clusters has been the source of controversy in the computational literature because the identity of the most stable structure appears to be pathologically dependent on the chosen theoretical model. The candidate structures include a D3h-symmetric 'fullerene-like' isomer with 3 connected vertices (A), an 'arachno' architecture (B) and an octahedral isomer with high vertex connectivities typical of 'closo' electron-deficient clusters (C). The key to understanding these apparently very different structures is the fact that they make use of the limited electron density available from the endohedral metal in very different ways. Early in the transition series the favoured structure is the one that maximises transfer of electron density from the electropositive metal to the cage whereas for later metals it is the one that minimises repulsions with the increasingly core-like d electrons. The varying role of the d electrons across the transition series leads directly to strong functional dependency, and hence to the controversy in the literature. PMID- 28832061 TI - Point-of-care diagnostics to improve maternal and neonatal health in low-resource settings. AB - Each day, approximately 830 women and 7400 newborns die from complications during pregnancy and childbirth. Improving maternal and neonatal health will require bringing rapid diagnosis and treatment to the point of care in low-resource settings. However, to date there are few diagnostic tools available that can be used at the point of care to detect the leading causes of maternal and neonatal mortality in low-resource settings. Here we review both commercially available diagnostics and technologies that are currently in development to detect the leading causes of maternal and neonatal mortality, highlighting key gaps in development where innovative design could increase access to technology and enable rapid diagnosis at the bedside. PMID- 28832067 TI - Comparison of Overridden Medication-related Clinical Decision Support in the Intensive Care Unit between a Commercial System and a Legacy System. AB - BACKGROUND: Electronic health records (EHRs) with clinical decision support (CDS) have shown to be effective at improving patient safety. Despite this, alerts delivered as part of CDS are overridden frequently, which is of concern in the critical care population as this group may have an increased risk of harm. Our organization recently transitioned from an internally-developed EHR to a commercial system. Data comparing various EHR systems, especially after transitions between EHRs, are needed to identify areas for improvement. OBJECTIVES: To compare the two systems and identify areas for potential improvement with the new commercial system at a single institution. METHODS: Overridden medication-related CDS alerts were included from October to December of the systems' respective years (legacy, 2011; commercial, 2015), restricted to three intensive care units. The two systems were compared with regards to CDS presentation and override rates for four types of CDS: drug-allergy, drug-drug interaction (DDI), geriatric and renal alerts. A post hoc analysis to evaluate for adverse drug events (ADEs) potentially resulting from overridden alerts was performed for 'contraindicated' DDIs via chart review. RESULTS: There was a significant increase in provider exposure to alerts and alert overrides in the commercial system (commercial: n=5,535; legacy: n=1,030). Rates of overrides were higher for the allergy and DDI alerts (p<0.001) in the commercial system. Geriatric and renal alerts were significantly different in incidence and presentation between the two systems. No ADEs were identified in an analysis of 43 overridden contraindicated DDI alerts. CONCLUSIONS: The vendor system had much higher rates of both alerts and overrides, although we did not find evidence of harm in a review of DDIs which were overridden. We propose recommendations for improving our current system which may be helpful to other similar institutions; improving both alert presentation and the underlying knowledge base appear important. PMID- 28832068 TI - The Emerging Role of the Chief Research Informatics Officer in Academic Health Centers. AB - BACKGROUND: The role of the Chief Research Informatics Officer (CRIO) is emerging in academic health centers to address the challenges clinical researchers face in the increasingly digitalized, data-intensive healthcare system. Most current CRIOs are the first officers in their institutions to hold that role. To date there is very little published information about this role and the individuals who serve it. OBJECTIVE: To increase our understanding of the CRIO role, the leaders who serve it, and the factors associated with their success in their organizations. METHODS: The Clinical Research Informatics Working Group of the American Medical Informatics Association (AMIA) conducted a national survey of CRIOs in the United States and convened an expert panel of CRIOs to discuss their experience during the 2016 AMIA Annual Symposium. RESULTS: CRIOs come from diverse academic backgrounds. Most have advance training and extensive experience in biomedical informatics but the majority have been CRIOs for less than three years. CRIOs identify funding, data governance, and advancing data analytics as their major challenges. CONCLUSION: CRIOs play an important role in helping shape the future of clinical research, innovation, and data analytics in healthcare in their organizations. They share many of the same challenges and see the same opportunities for the future of the field. Better understanding the background and experience of current CRIOs can help define and develop the role in other organizations and enhance their influence in the field of research informatics. PMID- 28832069 TI - Comment Topic Evolution on a Cancer Institution's Facebook Page. AB - OBJECTIVES: Our goal was to identify and track the evolution of the topics discussed in free-text comments on a cancer institution's social media page. METHODS: We utilized the Latent Dirichlet Allocation model to extract ten topics from free-text comments on a cancer research institution's FacebookTM page between January 1, 2009, and June 30, 2014. We calculated Pearson correlation coefficients between the comment categories to demonstrate topic intensity evolution. RESULTS: A total of 4,335 comments were included in this study, from which ten topics were identified: greetings (17.3%), comments about the cancer institution (16.7%), blessings (10.9%), time (10.7%), treatment (9.3%), expressions of optimism (7.9%), tumor (7.5%), father figure (6.3%), and other family members & friends (8.2%), leaving 5.1% of comments unclassified. The comment distributions reveal an overall increasing trend during the study period. We discovered a strong positive correlation between greetings and other family members & friends (r=0.88; p<0.001), a positive correlation between blessings and the cancer institution (r=0.65; p<0.05), and a negative correlation between blessings and greetings (r=-0.70; p<0.05). CONCLUSIONS: A cancer institution's social media platform can provide emotional support to patients and family members. Topic analysis may help institutions better identify and support the needs (emotional, instrumental, and social) of their community and influence their social media strategy. PMID- 28832070 TI - Panel of Villin, Pro-Ex-C, Estrogen Receptor and Progesterone Receptor Expressions Could Help in Differentiation Between Endocervical and Endometrioid Adenocarcinoma. AB - OBJECTIVE: Endocervical and endometrioid adenocarcinoma have marked overlapping features and the differentiation between them is important for their accurate management. Villin is an actin-binding protein which has an important role in the maintenance of microvilli in epithelial cells and epithelial cell-specific anti apoptotic protein processes. Pro-Ex-C is a marker for higher-risk human papilloma virus (HPV) which targets the cell cycle proteins causing their overexpression. The aim of the study was to clarify the diagnostic and predictive role of villin, Pro-Ex-C, estrogen receptor (ER) and progesterone receptor (PR) expression in endocervical and endometrioid adenocarcinoma. MATERIAL AND METHOD: We evaluated villin, Pro-Ex-C, ER and PR expressions in 15 cases of endocervical adenocarcinoma and 30 cases of endometrioid adenocarcinoma. We analyzed the diagnostic and predictive role of that panel in both carcinoma subtypes. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. RESULTS: Positive villin and Pro-Ex-C expressions were positively correlated with the presence and pattern of cervical stromal invasion (p < 0.05). ER was positive in all cases of endometrioid adenocarcinoma. PR was detected in most cases of endometrioid adenocarcinoma. The differences of villin, Pro-Ex-C, ER and PR expression in endocervical and endometrioid adenocarcinoma was statistically significant (p < 0.05). This methodology for distinguishing endocervical and endometrioid adenocarcinoma had a sensitivity of 100%, a specificity of 100% and a significant prognostic and predictive role. CONCLUSION: In conclusion, villin, Pro-Ex-C, ER and PR expressions have diagnostic and predictive roles in endocervical and endometrioid adenocarcinoma. PMID- 28832071 TI - Prognostic Value of Twist-1, E-cadherin and EZH2 in Prostate Cancer: An Immunohistochemical Study. AB - OBJECTIVE: There is an urgent need to identify molecular biomarkers rather than clinical markers to distinguish aggressive prostate cancer from the indolent majority for proper treatment and accurate prediction of prognosis. We aimed to investigate the immunohistochemical expression of epithelial-mesenchymal transition (EMT)-related molecules (Twist-1 and E-cadherin) and the stem cell marker EZH2 in prostate cancer and to assess their ability to identify the high risk patients, in a trial to explore their prognostic implications. MATERIAL AND METHOD: Immunohistochemical expression of Twist-1, E-cadherin and EZH2 in 50 specimens of prostate cancer and 20 cases of benign prostatic hyperplasia were studied. The relationship between their expression and the clinicopathological variables, biochemical recurrence, and biochemical progression-free survival were investigated. RESULTS: Our results revealed that high Twist-1, as well as high EZH2 expression, was strongly associated with higher pre-treatment PSA level, Gleason score >=7, advanced tumor stage, lymph node involvement, distant metastasis and biochemical progression. Aberrant E-cadherin expression was significantly associated with higher pre-treatment PSA level, Gleason score >=7, advanced tumor stage, lymph node involvement, and distant metastasis. A significant positive correlation between Twist-1 and EZH2 expression was found (p < 0.001), while E-cadherin expression showed a negative correlation with both markers (p < 0.001). A significant association was found between high Twist-1, high EZH2& aberrant E-cadherin expression, and shorter biochemical progression free survival. CONCLUSION: The high Twist-1 expression, aberrant E-cadherin and high EZH2 expression in primary prostate cancer are considered as adverse prognostic markers of an aggressive tumor with high metastatic potential. Assessment of their expression level would contribute to the accurate prediction of biochemical progression. PMID- 28832072 TI - Can Cutting-Needle Biopsy Be an Alternative to Excisional Biopsy in Lymph Node Pathologies? AB - OBJECTIVE: We aimed to compare cutting-needle biopsy (CNB) diagnoses with excisional biopsy diagnoses of enlarging lymph nodes and to determine the diagnostic value of CNB. MATERIAL AND METHOD: Out of the 291 cases that underwent CNB from lymph nodes between 2010 and 2016, 60 were included in the study in which pathological lymph nodes were excised after CNB. Demographic information, pathology and imaging reports, the diameters of the lymph nodes and the length of the CNBs of these cases were obtained from the hospital registry system. Diagnoses of the CNBs and excisional biopsies were then compared. RESULTS: According to the excisional biopsy diagnosis, 7 of the 60 cases (11.7%) were benign and 53 of them (88.3%) were malignant. 28 (53%) of the malignant cases were diagnosed as Hodgkin's lymphoma while the others (47%) got a non-Hodgkin's lymphoma diagnosis. In the 8 non-diagnostic CNBs, 3(37%) of them were found to be benign/reactive, while 5 (63%) were diagnosed as malign lymphoma in excisional biopsy. Similarly, 7(64%) of the 11 cases diagnosed as benign/reactive in CNB, were found to be malignant with excisional biopsy. When CNB and excisional biopsy were compared, sensitivity and specificity were 90% and 100%; positive predictive value (PPV) and negative predictive value (NPV) were 100% and 0%, respectively, and the diagnostic accuracy rate (DV) was 86.5%. The mean diameter of the benign lymph nodes was 26.1 mm and the mean diameter of the malignant ones was 35.6 mm. There was no significant difference between malignant and benign lymph node size (p > 0.05). There was also no statistically significant difference between CNB length and correct diagnosis (p=0.233). CONCLUSION: CNB is a non-invasive procedure. It is an alternative to excisional biopsy because of its low morbidity and low cost. However, the sensitivity of CNB is lower than its specificity, and we recommend the surgical excision of lymph nodes with a clinically strong neoplasm suspicion because of the presence of false negatives in 7 cases. PMID- 28832073 TI - Poster Colours: Pocket-Friendly Alternative to Tissue Marking Dyes. PMID- 28832074 TI - Programmed Death Ligand 1 (PD-L1) Expression in Malignant Mesenchymal Tumors. AB - OBJECTIVE: Programmed death ligand 1 (PD-L1) found on tumor cells has recently been reported to have a key role in the development and dissemination of many tumors, such as lung and breast carcinomas. In this study, we retrospectively analyzed PD-L1 expression among different types of sarcomas. MATERIAL AND METHOD: Tissue microarrays of 3-4 mm diameter were composed from paraffin blocks of 222 various sarcomas. Slides prepared from microarrays were stained for PD-L1 antibody (Cell Signaling, E1L3N(r)) using Leica Bond Autostainer. Any membranous staining over 5% of the cells was regarded as positive. Quantitative real-time PCR with TaqMan gene expression assays for PDL1 was performed using whole sections from FFPE tissue of PD-L1 positive cases, by normalizing absolute values to beta-actin. Relative expression level of mRNA of PDL1 was calculated and scored using Log102(threshold cycle of b-actin - threshold cycle of PDL1). RESULTS: Immunohistochemically, PD-L1 expression was present in 34 of 222 (15%) sarcomas. 5/13 (39%) undifferentiated pleomorphic sarcomas, 6/18 (33%) malignant peripheral nerve sheath tumors, 5/16 (31%) dedifferentiated liposarcomas, 4/19 (21%) rhabdomyosarcomas, 2/16 (13%) epithelioid sarcomas, 2/15 (13%) leiomyosarcomas, 3/26 (12%) synovial sarcomas, 1/18 (6%) myxoid liposarcoma, 1/2 (50%) extraskeletal myxoid chondrosarcoma, 1/3 (33%) alveolar soft part sarcoma, 1/3 (33%) parachordoma/myoepithelioma, 1/5 (20%) pleomorphic liposarcoma, 1/7 (14%) angiosarcoma, 1/8 (13%) Ewing sarcoma showed PD-L1 expression. Cases of solitary fibrous tumor/hemangiopericytoma (18), desmoplastic round cell tumor (14), Ewing-like sarcoma (6), epithelioid hemangioendothelioma (5), clear cell sarcoma (4), myxofibrosarcoma (4), low grade fibromyxoid sarcoma (2) were all negative. Tumor-infiltrating hematopoietic cells were positive for PD-L1 in 32 cases (15%) with only 2 cases overlapping with PD-L1 staining in tumoral cells. Sixteen of 34 (47%) immunohistochemically PD-L1 positive cases showed significant but low-level PD-L1 mRNA overexpression. CONCLUSION: We have shown PD-L1 expression in a subset of sarcomas, both at the protein and mRNA level. High grade pleomorphic sarcomas tend to show more frequent PD-L1 expression. Clinical trials are necessary to further assess the effect of anti PD-L1 drugs on sarcomas showing PD-L1 expression. PMID- 28832075 TI - Prognostic Significance of Programmed Cell Death Ligand 1 (PD-L1), CD8+ Tumor Infiltrating Lymphocytes and p53 in Non-Small Cell Lung Cancer: An Immunohistochemical Study. AB - OBJECTIVE: Programmed cell death ligand-1 interacts with the immune receptors on the surface of CD8+ tumor infiltrating lymphocytes and PD-1, thereby blocking its anti-tumor activity. Therapeutics suppression of this interaction will show a promise in the treatment of non-small cell lung cancer by restoring the functional anti-tumor T-cell activity. We aimed to evaluate the association between the immunohistochemical expression of PD-L1, stromal CD8+ tumor infiltrating lymphocytes and p53 with the clinicopathological characteristics, response to chemotherapy, progression-free-survival, and overall survival. MATERIAL AND METHOD: We examined the immunohistochemical expression of PD-L1, stromal CD8+ TILs, and p53 expression in 50 patients with advanced stage (III&IV) non-small cell lung cancer. RESULTS: PD-L1 was expressed in 56% of the studied cases. PD-L1 expression was related to unfavorable response to the therapy without significant difference. PD-L1 expression was significantly associated with disease progression, poor progression-free-survival & overall survival. CD8+ TILs were high in 32% of the cases. Tumors with high CD8+ TILs showed a partial response to therapy and had a better progression-free-survival and overall survival. p53 expressed in 82% of the studied cases. There was a significant negative association between PD-L1 and CD8+ TILs (p=0.009), while a non significant association was found between p53 and PD-L1 (p=0.183). CONCLUSION: PD L1 overexpression is an unfavorable prognostic marker, while the high CD8 + TILs is a good prognostic marker in non-small cell lung cancer. PD-L1 immunohistochemical assessment may be used for the selection of patients legible for treatment with anti-PD-L1 therapy. PMID- 28832076 TI - Collision of Malignant Melanoma and Squamous Cell Carcinoma in Rectum: First Report of a Rare Tumor. AB - The term collision tumor is used to describe two neoplasms occurring in the same anatomic location with juxtaposition of different tumor elements. Such a coexistence of tumors anywhere in the body is relatively rare. We report a case of 32-year-old female with collision tumor of rectum. The tumor showed two distinct histological patterns with predominant component consisting of malignant melanoma and a minor component of squamous cell carcinoma. The morphological picture of collision was further confirmed by specific immunohistochemical profile of the two tumors. Collision tumors of rectum are uncommon with most of the reported cases comprising adenocarcinoma and neuroendocrine tumors. To the best of our knowledge this is the first case of collision tumor of malignant melanoma and squamous cell carcinoma in the rectum. PMID- 28832077 TI - Diagnostic and Treatment Reproducibility of Cervical Intraepithelial Neoplasia / Squamous Intraepithelial Lesion and Factors Affecting the Diagnosis. AB - OBJECTIVE: Inter-observer differences in the diagnosis of HPV related cervical lesions are problematic and response of gynecologists to these diagnostic entities is non-standardized. This study evaluated the diagnostic reproducibility of "cervical intraepithelial neoplasia" (CIN) and "squamous intraepithelial lesion" (SIL) diagnoses. MATERIAL AND METHOD: 19 pathologists evaluated 66 cases once using H&E slides and once with immunohistochemical studies (p16, Ki-67 and Pro-ExC). Management response to diagnoses was evaluated amongst 12 gynecologists. Pathologists and gynecologists were also given a questionnaire about how additional information like smear results and age modify diagnosis and management. RESULTS: We show moderate interobserver diagnostic reproducibility amongst pathologists. The overall kappa value was 0.50 and 0.59 using the CIN and SIL classifications respectively. Impact of immunohistochemical evaluation on interpretation of cases differed and there was lack of statistically significant improvement of interobserver diagnostic reproducibility with the addition of immunohistochemistry. We saw that choice of treatment methods amongst gynecologists varied and overall concordance was only fair to moderate. The CIN2 diagnostic category was seen to have the lowest percentage agreement amongst both pathologists and gynecologists. We showed that pathologists had diagnostic "styles" and gynecologists had management "styles". CONCLUSION: In summary each pathologist had different diagnostic tendencies which were affected not only by histopathology and marker studies, but also by the patient management tendencies of the gynecologist that the pathologist worked with. The two-tiered modified Bethesda system improved diagnostic agreement. We concluded that immunohistochemistry should be used only to resolve problems in select cases and not for every case. PMID- 28832078 TI - The Role of CD34 and D2-40 in the Differentiation of Dermatofibroma and Dermatofibrosarcoma Protuberans. AB - OBJECTIVE: Dermatofibroma (DF) is a benign fibrohistiocytic tumor whereas dermatofibrosarcoma protuberans (DFSP) has intermediate malignant potential. CD34 is the most commonly used antibody in differentiating these tumors. Various studies have stated the rates of D2-40 expression as 0-50% in DFSPs and 86-100% in DFs. Our aim in this study was to determine the expression of CD34 and D2-40 in DFs and DFSPs and the possible use of D2-40 in the differential diagnosis of these lesions. MATERIAL AND METHOD: This is a retrospective study including 30 DF and 15 DFSP cases which were reevaluated for epidermal changes, the presence of a transmission zone (Grenz zone), infiltration of soft tissues, infiltration pattern and histologic subtypes in addition to cellular pleomorphism, nuclear atypia, and necrosis. A manual immunohistochemistry procedure was performed with D2-40 and CD 34 antibodies using a representative paraffin block. RESULTS: The average age was 37.36 and 42.86 years in the DF and DFSP cases. The average diameter was 0.9 and 5.03 cm, respectively, for the DFs and DFSPs. There was a significant correlation between the two entities for sex, localization and diameter of the lesion. A significant difference was found between the positivity of CD34 and D2-40 in DFs and DFSPs. CONCLUSION: Additional immunohistochemical markers may be needed in DFs with CD34 positivity. Our results showed the additional helpful role of this marker in problematic cases. PMID- 28832079 TI - Are CD68 and Factor VIII-RA Expression Different in Central and Peripheral Giant Cell Granuloma of Jaw: An Immunohistochemical Comparative Study. AB - OBJECTIVE: Central giant cell granuloma and peripheral giant cell granuloma of the jaw and oral cavity are identical in histopathologic features, although they are different in pathogenesis and clinical behavior. The aim of present study was to compare CD 68 and factor VIII related antigen (VIII-RA ) immunoreactivity in central giant cell granuloma and peripheral giant cell granuloma to determine the biologic nature and clinical behavior of these lesions which may lead to a better or new treatment modality. MATERIAL AND METHOD: CD68 and factor VIII-RA expression were examined immunohistochemically in 22 cases of central giant cell granuloma (10 aggressive and 12 non- aggressive ) and 19 cases of peripheral giant cell granuloma. The Kruskal-Wallis test followed by the Dunn test was used for data analysis. RESULTS: CD68 expression was observed in approximately 100% of multinucleated giant cells and 50% of mononuclear cells. Overexpression of factor VIII-RA in the endothelial cells of capillary like vessels in the periphery of the lesions was prominent. A statistical significant difference for CD68 intensity score in mononuclear cells among three groups (P=0.016) was observed. Indeed, factor VIII-RA intensity score in the endothelial cells of central giant cell granuloma and peripheral giant cell granuloma showed significant difference (P=0.004). CONCLUSION: These findings support the histiocyte/macrophage nature of multinucleated giant cells and mononuclear cells. Overexpression and high intensity score of CD68 in mononuclear cells and the high intensity score of factor VIII-RA in endothelial cells represent less aggressive behavior in central giant cell granuloma. PMID- 28832081 TI - Primary Splenic Pregnancy- A Rare but Imperative Cause of Hemoperitoneum - Case Report and Review of Literature. AB - Primary splenic pregnancy is an extremely rare form of extratubal ectopic pregnancy. These cases often cause splenic rupture in very early course of their gestation thereby presenting with hemoperitoneum in emergencies. Owing to the higher risk of exsanguination and death caused by hemoperitoneum, it is essential to diagnose these cases for proper management and better prognosis of the patients. We present the case of a 23-year-old female, gravida 2, para 1, live issue 1 presenting to the emergency outpatient department with acute abdomen and hemoperitoneum. There was no history of trauma. The patient had a positive urine pregnancy test and raised beta HCG levels. Emergency laparotomy revealed an otherwise unremarkable fallopian tube and ovary with a hemoperitoneum of 2.5 liters. A tiny splenic laceration was considered to be the source of bleeding and splenectomy was performed. Microscopy was suggestive of a primary ectopic pregnancy, spleen. Since hemoperitoneum in pregnancy is a rare but potentially fatal condition with a high risk of mortality, an accurate preoperative diagnosis is crucial in the management of such patients. The possibility of a ruptured extratubal ectopic pregnancy must be considered as one of the differential diagnoses of acute abdomen with hemoperitoneum in women of childbearing age. PMID- 28832082 TI - Synchronous Cervical Minimal Deviation Adenocarcinoma, Gastric Type Adenocarcinoma and Lobular Endocervical Glandular Hyperplasia Along with STIL in Peutz-Jeghers Syndrome: Eliciting Oncogenesis Pathways. AB - We describe an unusual case of a Peutz-Jeghers syndrome associated with a composite synchronous cervical neoplasia comprising precursor "lobular endocervical glandular hyperplasia (LEGH)", "minimal deviation adenocarcinoma (MDA)" and "gastric-type adenocarcinoma (GTA)" along with a serous tubal intraepithelial lesion (STIL) in the right fallopian tube. A 24-year-old woman presented with a white mucoid discharge and bleeding per vaginum for one year. Histopathological evaluation showed MDA & GTA in FIGO grade III with pelvic lymph node metastasis despite a deceptively bland tumour morphology and low Ki-67 index, indicating an aggressive tumour course and poor prognosis. Diagnostic marker profile in the cervix showed gastric type mucin and positive expression of CK-7, CK-20 (patchy), CEA, and negative CDX-2, p16, ER and PR. Further an attempt at eliciting the oncogenesis pathway in view of the p16 and HPV negative nature of the gastric type cervical adenocarcinoma showed negativity for p53 but activation of cyclin D1. Growth factors including Her2 and EGFR were negative while VEGFR was over-expressed. She was treated by radical hysterectomy and pelvic radiation. She was free from recurrence at the 12-month follow-up. This is a first-time report of a STIL in the fallopian tube which was validated by a unilateral mutant type p53 expression and increased Ki67 index, associated with synchronous gastric type adenocarcinoma of the cervix in all stages of evolution. PMID- 28832084 TI - Water-Clear Cell Adenoma of the Mediastinal Parathyroid Gland. AB - Water-clear cell adenoma of the parathyroid gland is a rare neoplasm that consists of cells with abundant clear-pink cytoplasm. There have only been 19 cases reported in the English literature. Here we report a case of water-clear cell adenoma of the mediastinal parathyroid gland. A 70-year-old male patient presented to the hospital with back pain and a mediastinal mass 6 cm in size was detected. After excision and microscopic evaluation, uniform, large clear cells with fine cytoplasmic vacuolization, without nuclear atypia, and arranged in solid and acinar patterns were revealed. The cells formed nests that were separated by fine fibrovascular septae and stained positively with anti parathyroid hormone. To the best of our knowledge, this has not been previously reported in this location. In the differential diagnosis of clear cell lesions of the mediastinum, water-clear cell parathyroid adenoma should be considered. PMID- 28832085 TI - Suitability of foramen magnum measurements in sex determination and their clinical significance. AB - BACKGROUND: The foramen magnum provides a transition between fossa cranii posterior and canalis vertebralis. Medulla oblongata, arteria vertebralis and nervus accessorius spinal part pass through the foramen magnum. In this study, we aimed to make the morphometric measurements of the foramen magnum on computed tomography (CT) and to determine the feasibility of sex determination based on these measurements. Besides sex determination, from a clinical aspect, it is important to know the measurements of the foramen magnum in the normal population in terms of diseases characterised by displacement of the posterior fossa structures through foramen magnum to upper cervical spinal canal such as Chiari malformations and syringomyelia. MATERIALS AND METHODS: All the data for our study was obtained retrospectively from 100 patients (50 males, 50 females) who had a CT scan of the head and neck region in Adnan Menderes University Hospital, Department of Radiology. To examine the foramen magnum in each and every occipital bone, we measured the foramen magnum's anteroposterior diameter, transverse diameter, the area of the foramen magnum and its circumference. RESULTS: We found that men have a higher average value than women in our study. According to Student's t-test results; in all measured parameters, there is significant difference between the genders (p < 0.05). When multivariate discriminant function test is performed for all four measurements, the discrimination rate is 64% for all women, 70% for all men and 67% for both genders. CONCLUSIONS: As a result of our study, the metric data we obtained will be useful in cases where the skeletons' sex could not be determined by any other methods. We believe that, our study may be useful for other studies in determining of sex from foramen magnum. Our measurements could give some information of the normal ranges of the foramen magnum in normal population, so that this can contribute to the diagnosis process of some diseases by imaging. (Folia Morphol 2018; 77, 1: 99-104). PMID- 28832086 TI - Assessment of the orbit morphometry on West Anatolian dry skulls. AB - The orbit is very frequently damaged by traumas which result in not only bone deficits, but also functional deformities if reconstruction is not appropriate. Anatomical exposure of the bony orbit is of importance for both anatomists and surgeons who perform operation on this area. The current study evaluated the group of morphometrical parameters on 74 adult West Anatolian dry skulls and stereological surface area on the dry skull orbits while describing the clinical importance. Surface areas on the orbital base of the skulls were also evaluated using stereological method, bilaterally. Anthropological assessment of orbital base (in terms of width and height) revealed no significant difference between right and left sides. Both width and height of the optic foramen were significantly higher on the right side compared to left. The distances between the margins (medial, lateral, superior, inferior) of the orbital base and the optic foramen were longer on the right side compared to left, except the distances between the lateral margins. There was no significant difference among the subjects between right and left sides with respect to the orbital base in terms of stereological area calculation. The results are significant because there are no recorded anatomical data on West Anatolian skulls at previous researches. (Folia Morphol 2018; 77, 1: 105-109). PMID- 28832087 TI - The effect of anatomic differences on the relationship between renal artery and diaphragmatic crus. AB - BACKGROUND: The aim of this study is to investigate the effect of anatomic differences on the relationship between renal artery and diaphragmatic crus via the touch of two structures. MATERIALS AND METHODS: The study included dynamic computed tomography (CT) scans of 308 patients performed mainly for characterisation of liver and renal masses. Anatomic differences including the thickness of the diaphragmatic crus, the localisation of renal artery ostium at the wall of aorta, the level of renal artery origin with respect to superior mesenteric artery were evaluated. Statistical relationships between renal artery diaphragmatic crus contact and the anatomic differences were assessed. RESULTS: Thickness of the diaphragmatic crus at the level of renal artery origin exhibited a statistically significant relationship to renal artery-diaphragmatic crus contact at the left (p < 0.001) and right side (p < 0.001). There was a statistically significant relationship between high renal artery origin and renal artery- -diaphragmatic crus contact at the left (p < 0.001) and right side (p = 0.01). The localisation of renal artery ostium at the wall of aorta (right side, p = 0.436, left side, p = 0.681) did not demonstrate a relationship to renal artery-diaphragmatic crus contact. CONCLUSIONS: Thickness of the diaphragmatic crus and high renal artery origin with respect to superior mesenteric artery are crucial anatomic differences determining the relationship of renal artery and diaphragmatic crus. (Folia Morphol 2018; 77, 1: 22-28). PMID- 28832088 TI - Ponticulus posticus in a cohort of orthodontic children and adolescent patients with different sagittal skeletal anomalies: a comparative cone beam computed tomography investigation. AB - BACKGROUND: The objective of this study was to evaluate the prevalence and characteristics of ponticulus posticus (PP) in groups with sagittal skeletal anomalies in a Turkish population using cone beam computed tomography (CBCT). MATERIALS AND METHODS: A total of 181 CBCT images were evaluated according to gender, side and characteristics of PP in the three different sagittal skeletal groups. RESULTS: The average age of the patients was 13.88 +/- 2.99 years (ranging 8-18 years). The study population consisted of 104 (57.5%) females and 77 (42.5%) males. PP was detected in 66 (36.5%) patients. Unilateral and bilateral PP was identified in 29 (43.9%) and 37 (56.1%) patients, respectively. The prevalence of PP in the atlas vertebrae was found to be higher in males than in females and this was statistically significant (p <= 0.05). PP was most frequently detected in class III patients (25, 13.8%). Statistically significant differences between the different sagittal skeletal groups were observed (p <= 0.05). CONCLUSIONS: Ponticulus posticus is a common anomaly in Turkish populations and is associated with different sagittal skeletal patterns. The highest frequency of PP was found in angle class III patients. (Folia Morphol 2018; 77, 1: 65-71). PMID- 28832089 TI - Cone beam computed tomography evaluation of ponticulus posticus in patients with cleft lip and palate: a retrospective radio-anatomic study. AB - BACKGROUND: Ponticulus posticus (PP) is an abnormal bony bridge on the atlas. It plays a significant role in patients undergoing C1 lateral mass screw procedure. Patients with cleft lip and palate (CLP) have higher risk than patients in general population for the appearance of cervical vertebral anomalies. The purpose of the this study was twofold: to determine the prevalence and characteristics of PP in patients with CLP, and to compare the findings with patients in general population using cone beam computed tomography. MATERIALS AND METHODS: Cone beam computed tomography images from 54 individuals who had undergone surgical repair of cleft lip and/or palate were analysed as the study group. For comparison purposes a control group was randomly selected from 108 patients and matched with the CLP subjects. RESULTS: Although 12 of the 54 (22.3%) patients with surgically repaired cleft lip and/or palate in the study group were identified to have PP, only 10 of the 108 (9.2%) patients in the control group had PP. The distribution of the presence of PP between the groups was statistically significant. CONCLUSIONS: Ponticulus posticus is an important anomaly and the presence of PP is important for patients. PP can have clinical significance in cervical spine surgery as this study has indicated that the likelihood of encountering PP is higher in patients with CLP. We suggest that PP should be taken into account prior to cervical vertebral surgery in patients with CLP. (Folia Morphol 2018; 77, 1: 72-78). PMID- 28832090 TI - Successful combined surgical approach in a rare case of retrotracheal goitre in a patient with anatomical impediments. AB - Diving goitres can descend the cervical region expanding directly into the thoracic cavity. In most cases, diving goitres extend into the anterosuperior compartment, but they may also extend behind the trachea. We herein present a case of a male patient with retrotracheal goitre and history of left thyroid lobectomy and median sternotomy for thoracic aortic aneurysm repair with graft placement. After detailed preoperative evaluation, the patient underwent surgical resection of the mass through a combined approach; the existing cervical incision and a right posterolateral mini-thoracotomy. The postoperative course of the patient was uncomplicated. One year after surgery, the patient is asymptomatic and disease-free. (Folia Morphol 2018; 77, 1: 166-169). PMID- 28832091 TI - Co-existence of the double inferior vena cava with complex interiliac venous communication and aberrant common hepatic artery arising from superior mesenteric artery: a case report. AB - Variations of the arterial and venous system of the abdomen and pelvis have important clinical significance in hepatobiliary surgery, abdominal laparoscopy, and radiological intervention. A case of double inferior vena cava (IVC) with complex interiliac communication and variation of the common hepatic artery (CHA) arising from superior mesenteric artery (SMA) in a 79-year-old male cadaver is presented. Both IVCs ascended on either side of the abdominal aorta. The left sided IVC crossed anterior to the aorta at the level of the left renal vein. The union of both IVCs was at the level just above the right renal vein. The diameter of right-sided IVC, left-sided IVC and the common IVC were 16.73 mm, 21.57 mm and 28.75 mm, respectively. In the pelvic cavity, the right common iliac vein was formed by a union of right external and internal iliac veins while the formation of left common iliac vein was from the external iliac vein and two internal iliac veins. An interiliac vein ran from right internal iliac vein to left common iliac vein with an additional communicating vein running from the middle of this interiliac vein to the right common iliac vein. Another co-existence variation in this case was the origin of the CHA arising from the SMA with a suprapancreatic retroportal course. Clinical importance of double IVC are observed in retroperitoneal surgery, whole organ transplantation or radical nephrectomy, surgical ligation of the IVC or the placement of an IVC filter for thromboembolic disease. The variation of CHA has an important clinical significance in liver transplantation, abdominal laparoscopy and radiological abdominal intervention. (Folia Morphol 2018; 77, 1: 151-155). PMID- 28832092 TI - A symptomatic pelvic rib. AB - Pelvic rib is a rare anomaly where ectopic rib is found in a pelvic region. It is usually found occasionally in asymptomatic patients. We report a case of 15-year old male, diagnosed with a symptomatic pelvic rib. It had an unusual presentation creating a pseudotumour associated with pain and reduced range of motion in the hip joint. Patient was operated on with good result and final diagnosis was confirmed in pathological examination. (Folia Morphol 2018; 77, 2: 406-408). PMID- 28832093 TI - "Heart without smoke" educational campaign - the role of patient education in secondary prevention of cardiovascular disease. AB - BACKGROUND: Nicotine addiction is the strongest factor in the increase of the risk of recurrent ischaemic events. AIM: The aim of the study was to analyse the effectiveness of a smoking cessation educational programme in a population of patients hospitalised with acute myocardial infarction within the "Heart without smoke" campaign. METHODS: In this study, we included 100 consecutive patients, active smokers, hospitalised with acute myocardial infarction (STEMI or NSTEMI) at the Centre for Invasive Cardiology, Angiology, and Electrotherapy in Pinczow, Poland in the period from January to December 2015 (12 months). Patients were participants in the educational campaign about tobacco addiction "Heart without smoke". RESULTS: At one-month follow-up observation: 61 patients had quit smoking and an additional 35 had decreased the number of cigarettes smoked per day. During six-month follow-up interview: 51 patients did not smoke cigarettes (13 had returned to smoking, three had additionally stopped smoking, one person had died). There were no statistically significant correlations between smoking cessation and gender (p = 0.4; p = 0.2), age (p = 0.8; p = 0.8) and length of prior smoking habit (p = 0.8; p = 0.5) and daily cigarette consumption before myocardial infarctions (p = 0.3; p = 0.3), one month, and six months after hospital discharge, respectively. CONCLUSIONS: Constant education of patients after myocardial infarction was an effective method for smoking cessation in over 50% of smokers six months after myocardial infarction. PMID- 28832094 TI - Initial experience of catheter ablation for cardiac arrhythmias in children and adolescents at a newly built ablation centre. AB - BACKGROUND: Catheter ablation (CA) therapy is the first-choice treatment in adults with heart rhythm disturbances. Arrhythmias in adults are mainly conditioned by coronary artery disease. Aetiology of arrhythmias in children is mostly associated with inherited heart disorders. According to the current guidelines, CA is widely used in children, indicating the need to make it more achievable in the paediatric population. AIM: To assess the efficacy and safety of CA in children with different types of arrhythmias on the initial learning curve at a newly built Ablation Centre in the Independent Paediatric Hospital of the Medical University of Warsaw, Poland. METHODS: The study population comprised 32 children with supraventricular tachycardias, asymptomatic pre-excitation syndrome, or ventricular ectopic beats undergoing CA. The mean age of the study population was 14.1 +/- 2.4 years. In all patients, electrophysiological study (EPS) and CA were performed. Analysis with respect to procedure duration, fluoroscopy exposure duration, location of accessory pathways (AP), success rate, recurrences, and complications was performed. RESULTS: The mean procedure duration was 105.4 +/- 41.4 min (range 40-175 min). The mean fluoroscopy duration was 8:34 +/- 5:01 min (range 1:28-21:01). The mean exposure to ionising radiation was 4.7 +/- 3.2 mcG/kg. EPS revealed signifi!cantly more frequent presence of AP in the left side (57.1%). The radiofrequency ablation procedure was successful in 26 of 32 (81.3%) children, and cryoablation was successful in two of four patients. In two (6.3%) children minor complications occurred. CONCLUSIONS: Catheter ablation may be effectively performed without major complications in the initial phase of the learning curve if a reasonable approach with a gradual increase of the procedural complexity is taken. PMID- 28832095 TI - The relationship between exposure to hepatitis B virus and increased atherosclerosis-associated morbidity - a meta-analysis. AB - BACKGROUND AND AIM: The relationship between exposure to hepatitis B virus (HBV) and atherosclerosis-associated disease morbidity has not been clearly elucidated. We performed a meta-analysis to explore whether exposure to HBV is a risk factor for atherosclerosis-associated diseases. METHODS: We searched the PubMed, Web of Science, Cochrane Library, Embase, and Scopus databases for related studies. We then chose the eligible studies for meta-analysis and assessed quality assessment and risk of bias. RESULTS: The meta-analysis of the included studies showed that exposure to HBV tends to increase atherosclerosis-associated disease morbidity, but this increase was not statistically significant. CONCLUSIONS: Hepatitis B virus may not be a risk factor for atherosclerosis-associated diseases, but further studies that employ more sensitive clinical parameters are needed to verify this result. PMID- 28832096 TI - The endothelial nitric oxide synthase cofactor tetrahydrobiopterin shields the remote myocardium from apoptosis after experimental myocardial infarction in vivo. AB - BACKGROUND: Following myocardial infarction (MI), apoptosis occurs early in the remote myocardium and contributes to the processes of myocardial remodelling. Increased nitrosative stress is a well-known and potent inductor of myocardial apopto!sis. Excess activation of endothelial nitric oxide synthase (eNOS) increases its uncoupling potential and results in nitrosative stress via formation of peroxynitrite. However, the pathophysiological role of eNOS signalling in the remote myocardium after MI is as yet undefined. AIM: The impact of eNOS activation on pro- and anti-apoptotic signalling in the remote myocardium and the influence of pretreatment with the eNOS cofactor tetrahydrobiopterin (BH4) on eNOS activation, nitrosative stress level, and apoptosis induction and execution were studied in a rat MI model in vivo. RESULTS: Twenty-four hours after anterior MI, eNOS activity in animals treated with left anterior descending coronary artery ligation (LIG) significantly increased in the posterior left ventricular (LV) myocardium as did protein nitrosylation when com!pared to sham treatment. This was paralleled by induction of apoptosis via the extrinsic and intrinsic pathways. Moreover, anti-apoptotic signalling via protein kinase B/Akt and glycogen synthase-kinase 3 beta was suppressed. Notably, pretreatment with the eNOS cofactor BH4 reduced eNOS activation, prevented excess protein nitrosylation, blunted apoptosis induction, facilitated anti-apoptotic signalling, and eventually prevented apoptosis execution. CONCLUSIONS: Here we showed that 24 h after experimental MI in rats in vivo, apoptosis was induced in the posterior non-in!farcted LV wall. Evidence is presented that pretreatment with the eNOS cofactor BH4 resulted in less nitrosative stress and weakened apoptotic processes, although the stabilisers contained did participate in this phenomenon. Because apoptosis is a crucial component of myocardial remodelling, influencing eNOS signalling might be an interesting pharmacological target for the development of novel anti-remodelling therapies. PMID- 28832097 TI - Effect of tandem lesions on haemodynamic parameters: an experimental study. AB - BACKGROUND: The morphology and extensity of the stenotic lesion is crucial as well as the obstruction ratio. It is well known that the complexity of lesions has a direct impact on endovascular treatment (PTCA/stent); however, the arrangement of the lesions is underestimated and not well studied. AIM: We sought to evaluate the haemodynamic effects of different stenotic lesion models and arrangements in vitro. METHODS: Vascular circulation was simulated in vitro. Oxygenator, tubing set, polytetrahidroflouroethylene synthetic graft, pressure and flow rate, sensors were used to build the simulation model. Measurements of isolated short, isolated long, identical stenotic tandem short, identical stenotic tandem long, sub-critical long, and critical short lesion combinations were performed and haemodynamic parameters were recorded. RESULTS: Tandem lesions were more likely to result in critical stenosis comparing single lesions with the same obstruction ratio. This difference became more significant as the obstruction ratio was raised. Tandem long lesions also resulted in more critical stenosis than tandem short lesions. It can be claimed that tandem lesions can result in more flow restriction with reference to single lesions with the same stenotic ratio. Contrary to expectations, tandem short lesions were found to be more stenotic compared with the same degree long individual lesions. CONCLUSIONS: It is effortless to give the decision for simple, discrete and individual lesions, while the ideal decision for long and complicated lesions may remain unclear. Even if these "grey zone" lesions are considered non-critical while investigating them one by one, it must be kept in mind that the overall stenotic effect of these lesions may lead to more haemodynamic impairment. PMID- 28832098 TI - Insulins in Diabetes Care - Consensus & Recommendations from Tenth National Insulin Summit. PMID- 28832099 TI - Consensus on Insulin Dose Modification During Fasting in Type 2 Diabetes. AB - INTRODUCTION: Fasting for patients with type 2 diabetes mellitus (T2DM) carries a risk of an assortment of complications. The decision of T2DM patient to fast should be made after sufficient discussion with physician regarding the risks involved. The current consensus is developed to help physicians manage T2DM patients during fasting. OBJECTIVE: To provide simple and easily implementable guidelines on insulin dose modification during fasting in T2DM patients. METHODS: The expert group committee discussed and proposed six recommendations for the use of insulin regimens during fasting. The recommendations were proposed on diet, exercise and categorization of risks during fast, breaking fast, dose modification of basal insulins, premix insulins and prandial insulins. All these recommendations were based on established guidelines and published scientific literature. These evidences were then factored into the national context based on the expert committee representative's patient-physician experience in their clinical practice and common therapeutic practices followed in India to successfully achieve optimal glucose control. The final consensus-based recommendations were proposed and collectively recorded for each insulin regimen. RESULTS: Recommendations based on insulin dose modification during fasting in T2DM patients has been developed. Patients with diabetes, who fast are recommended to keep themselves hydrated, consume low glycaemic and high fibre food but, avoid sugary and caffeinated drinks along with fried foods. The main goal of insulin therapy during fasting is to provide adequate insulin to prevent post meal hyperglycaemia and prevent hypoglycaemia during fast. CONCLUSIONS: We hope that the consensus based recommendations mentioned in this paper will be a useful reference tool for health care practitioners to initiate and intensify insulin therapy in T2DM patients in order to successfully complete fasting without much complication. PMID- 28832100 TI - Consensus on Use of Insulins in Gestational Diabetes. AB - INTRODUCTION: Gestational Diabetes Mellitus (GDM), diabetes diagnosed during pregnancy is associated with maternal (caesarean delivery, hypoglycaemia, hyperbilirubinaemia, shoulder dystocia, pre-term delivery and birth trauma) and fetal (Hyperbilirubinaemia in offspring, Neonatal hypoglycaemia, Macrosomia) complications. Despite, insulin being the standard treatment for GDM cases, there is no existing comprehensive consensus update on use of insulin in Indian patients with GDM. OBJECTIVE: To provide simple and easily implementable guidelines to healthcare physicians on use of insulin in GDM. METHODS: Each consensus based on indications, choice of insulin regimen , titration and insulin therapy during intrapartum and postpartum was presented based on established guidelines and published scientific literature. These evaluations were then factored into the national context based on the expert committee representatives' patient-physician experience in their clinical practice and common therapeutic practices followed in India for successful GDM management. RESULTS: Recommendations based on use of insulin in GDM has been developed. The key recommendations are:to monitor fasting plasma glucose (FPG) and 2-hour post prandial glucose PPG levels and the glycaemic targets are: FPG < 95 mg/dL and 2 hour PPG < 120 mg/dL, short-and intermediate acting human insulin are the first choice of insulin regimens, rapid-acting (Insulin Aspart or Lispro) may be considered, use basal/intermediate acting insulin at bedtime, if FPG>110 mg/dL. During intrapartum, start IV insulin infusion with hourly glucose monitoring. Those women who require insulin < 20 U over 24 hours prior to labor may not need interpartum use of insulin infusion and Insulin dosing is stopped after birth and capillary glucose monitoring for 24-48 hours. CONCLUSIONS: We hope that the consensus based recommendations mentioned in this paper will be a useful reference tool for healthcare practitioners to achieve glycaemic targets in GDM patients. PMID- 28832101 TI - Consensus on Bridges for Barriers to Insulin Therapy. AB - INTRODUCTION: Insulin is an effective, safe and well-tolerated drug for glycaemic control. However, there are significant barriers to its use. OBJECTIVE: This consensus statement aims to define these barriers and suggest bridges to overcome them. METHODS: The consensus statements are based upon deliberations of a meeting held at New Delhi, India on 20 August 2016. The expert group committee reviewed various barriers to insulin use and categorized them into various categories: patient/community-related, physician-related and drug-related. The committee further proposed recommendations, based on published literature and their clinical experience, to address each of these barriers. RESULTS: Barriers (and bridges) can be classified as patient/community, physician/provider, and drug/device. Patient and physician barriers can further be categorized as those related to perceived inadequacy, perceived high cost, and perceived lack of benefit. Drug and device barriers can similarly be classified as those linked with perceived inadequacy, perceived high cost, and perceived lack of tolerability. Such a classification allows diabetes care providers to build appropriate bridges, which in turn facilitate timely insulin usage. Patient related barriers can be bridged by education, support and counselling. Use of modern insulin regimes and social marketing can address barriers related to perceived cost and lack of benefit. Physician related barriers can be resolved by training on various aspects of diabetes care. This will also help to break drug and device barriers, by ensuring appropriate choice of regimes, preparations and delivery devices. CONCLUSIONS: The consensus statements provide an easily understandable taxonomic structure of barriers to insulin use. By using a reader friendly rubric, and by focusing on bridges (rather than barriers alone), it promotes a proactive and positive approach to diabetes management. The consensus statement should serve as a useful pedagogic and clinical tool for diabetes care professionals, and facilitate good diabetes care across the world. PMID- 28832103 TI - Metal-Organic-Framework-Derived Yolk-Shell-Structured Cobalt-Based Bimetallic Oxide Polyhedron with High Activity for Electrocatalytic Oxygen Evolution. AB - The development of inexpensive, efficient, and environmentally friendly catalysts for oxygen evolution reaction (OER) is of great significant for green energy utilization. Herein, binary metal oxides (MxCo3-xO4, M = Zn, Ni, and Cu) with yolk-shell polyhedron (YSP) structure were fabricated by facile pyrolysis of bimetallic zeolitic imidazolate frameworks (MCo-ZIFs). Benefiting from the synergistic effects of metal ions and the unique yolk-shell structure, MxCo3-xO4 YSP displays good OER catalytic activity in alkaline media. Impressively, ZnxCo3 xO4 YSP shows a comparable overpotential of 337 mV at 10 mA cm-2 to commercial RuO2 and exhibits superior long-term durability. The high activity and good stability reveals its promising application. PMID- 28832104 TI - Hybrid Triazine-Boron Two-Dimensional Covalent Organic Frameworks: Synthesis, Characterization, and DFT Approach to Layer Interaction Energies. AB - The conversion of 2,4,6-tris(4'-bromophenyl)-1,3,5-triazine to the respective triboronic acid was successfully accomplished by a simple triple Br/Li exchange followed by boronation. Further dehydrative condensation reactions with 2,3,6,7,10,11-hexahydroxytriphenylene or 2,3,6,7-tetrahydroxy-9,10 dilalkylanthracenes (R = Me, Et) resulted in materials featuring good porosity and sorption properties with the nitrogen uptake exceeding 500 cm3/g (STP) and SBET up to 1267 m2/g (T = 77.2 K). In addition, simple dehydration of this compound was employed for the preparation of a hybrid 2D COF composed of triazine, boroxine, and benzene rings. The formation of materials was confirmed by the IR analysis and NMR studies on water-decomposed samples. All obtained COFs exhibit high thermal stability with decomposition temperatures in the range of 400-600 degrees C. They also show quite different morphology ranging from regular 0.5-4 MUm spherical and ellipsoidal clusters to 5-12 MUm bent rodlike particles. The PXRD studies supported by periodic DFT modeling in Crystal09 package revealed the formation of crystalline 2D honeycomb-type lattices with eclipsed stacking models. In addition, the differences between boroxine-triazine material and related COF-1 and CTF-1 structures were investigated by comparing layer interaction energies, work function values as well as atomic charges and electrostatic potential maps plotted on the electron density surfaces. It demonstrates that the interactions between layers are enhanced by the stacking of triazine and boroxine rings. Finally, we have investigated the upper limit to space accessible volume using a procrystal electron density approach. PMID- 28832105 TI - Precise Composition Tailoring of Mixed-Cation Hybrid Perovskites for Efficient Solar Cells by Mixture Design Methods. AB - Mixed anion/cation perovskites absorber has been recently implemented to construct highly efficient single junction solar cells and tandem devices. However, considerable efforts are still required to map the composition-property relationship of the mixed perovskites absorber, which is essential to facilitate device design. Here we report the intensive exploration of mixed-cation perovskites in their compositional space with the assistance of a rational mixture design (MD) methods. Different from the previous linear search of the cation ratios, it is found that by employing the MD methods, the ternary composition can be tuned simultaneously following simplex lattice designs or simplex-centroid designs, which enable significantly reduced experiment/sampling size to unveil the composition-property relationship for mixed perovskite materials and to boost the resultant device efficiency. We illustrated the composition-property relationship of the mixed perovskites in multidimension and achieved an optimized power conversion efficiency of 20.99% in the corresponding device. Moreover, the method is demonstrated to be feasible to help adjust the bandgap through rational materials design, which can be further extended to other materials systems, not limited in polycrystalline perovskites films for photovoltaic applications only. PMID- 28832106 TI - Nanosecond Dynamics at Protein Metal Sites: An Application of Perturbed Angular Correlation (PAC) of gamma-Rays Spectroscopy. AB - Metalloproteins are essential to numerous reactions in nature, and constitute approximately one-third of all known proteins. Molecular dynamics of proteins has been elucidated with great success both by experimental and theoretical methods, revealing atomic level details of function involving the organic constituents on a broad spectrum of time scales. However, the characterization of dynamics at biomolecular metal sites on nanosecond time scales is scarce in the literature. The aqua ions of many biologically relevant metal ions exhibit exchange of water molecules on the nanosecond time scale or faster, often defining their reactivity in aqueous solution, and this is presumably also a relevant time scale for the making and breaking of coordination bonds between metal ions and ligands at protein metal sites. Ligand exchange dynamics is critical for a variety of elementary steps of reactions in metallobiochemistry, for example, association and dissociation of metal bound water, association of substrate and dissociation of product in the catalytic cycle of metalloenzymes, at regulatory metal sites which require binding and dissociation of metal ions, as well as in the transport of metal ions across cell membranes or between proteins involved in metal ion homeostasis. In Perturbed Angular Correlation of gamma-rays (PAC) spectroscopy, the correlation in time and space of two gamma-rays emitted successively in a nuclear decay is recorded, reflecting the hyperfine interactions of the PAC probe nucleus with the surroundings. This allows for characterization of molecular and electronic structure as well as nanosecond dynamics at the PAC probe binding site. Herein, selected examples describing the application of PAC spectroscopy in probing the dynamics at protein metal sites are presented, including (1) exchange of Cd2+ bound water in de novo designed synthetic proteins, and the effect of remote mutations on metal site dynamics; (2) dynamics at the beta-lactamase active site, where the metal ion appears to jump between the two adjacent sites; (3) structural relaxation in small blue copper proteins upon 111Ag+ to 111Cd2+ transformation in radioactive nuclear decay; (4) metal ion transfer between two HAH1 proteins with change in coordination number; and (5) metal ion sensor proteins with two coexisting metal site structures. With this Account, we hope to make our modest contribution to the field and perhaps spur additional interest in dynamics at protein metal sites, which we consider to be severely underexplored. Relatively little is known about detailed atomic motions at metal sites, for example, how ligand exchange processes affect protein function, and how the amino acid composition of the protein may control this facet of metal site characteristics. We also aim to provide the reader with a qualitative impression of the possibilities offered by PAC spectroscopy in bioinorganic chemistry, especially when elucidating dynamics at protein metal sites, and finally present data that may serve as benchmarks on a relevant time scale for development and tests of theoretical molecular dynamics methods applied to biomolecular metal sites. PMID- 28832107 TI - Deposition and Adhesion of Polydopamine on the Surfaces of Varying Wettability. AB - Mussel-inspired chemistry, particularly the versatile coating capability of polydopamine (PDA), has received much research interest as a promising strategy for fabricating functional coatings in numerous fields. However, the understanding of deposition mechanisms and adhesion behaviors of PDA on different substrates still remains incomplete, significantly limiting the related fundamental research and its practical applications. In this work, a colloidal probe atomic force spectroscopy technique was employed to quantify the interaction forces and adhesion between the PDA coatings and the substrate surfaces with different wettabilities. The surface force measurements and thermodynamic analysis of interaction energy indicate that the surface wettability has a significant influence on the adhesion, deposition behaviors, and morphologies of PDA coatings. Compared with the hydrophilic surfaces, the hydrophobic surfaces exhibit stronger adhesion with the PDA coatings. Furthermore, for the first time, this work demonstrates that ethanol has the capability of effectively displacing the trapped air/vapor layer or the so-called "hydrophobic depletion layer" on the hydrophobic substrate to allow the intimate contact between PDA and the substrate, thus enhancing the adhesion and facilitating the PDA deposition. This work provides new insights into the fundamental PDA deposition mechanism as well as the design and development of versatile mussel-inspired coatings on the substrates of varying hydrophobicity. PMID- 28832108 TI - Low-Cost Fabrication of Printed Electronics Devices through Continuous Wave Laser Induced Forward Transfer. AB - Laser-induced forward transfer (LIFT) is a direct-writing technique that allows printing inks from a liquid film in a similar way to inkjet printing but with fewer limitations concerning ink viscosity and loading particle size. In this work, we prove that liquid inks can be printed through LIFT by using continuous wave (CW) instead of pulsed lasers, which allows a substantial reduction in the cost of the printing system. Through the fabrication of a functional circuit on both rigid and flexible substrates (plastic and paper), we provide a proof-of concept that demonstrates the versatility of the technique for printed electronics applications. PMID- 28832109 TI - Sensitive Surface-Enhanced Raman Scattering Detection Using On-Demand Postassembled Particle-on-Film Structure. AB - Highly sensitive and low-cost surface-enhanced Raman scattering (SERS) substrates are essential for practical applications of SERS. In this work, we report an extremely simple but effective approach to achieve sensitive SERS detection of molecules (down to 10-10 M) by using a particle/molecule/film sandwich configuration. Compared to conventional SERS substrates which are preprepared to absorb analyte molecules for detection, the proposed sandwich configuration is achieved by postassembling a flexible transparent gel tape embedded with plasmonic nanoparticles onto an Au film decorated with to-be-detected analyte molecules. In such a configuration, the individual plasmonic gel tape and Au film have low or no SERS activity but the final assembled sandwich structure shows strong SERS signal due to the formation of numerous hot spots at the particle film interface, where the analyte molecules themselves serve as both spacer and signal probes. Because of its simple configuration, we demonstrate that the proposed SERS substrate can be obtained over a large area with extremely low cost. Particularly, because of the on-demand nature and the flexibility, such a postassembly strategy provides an ideal solution to detect the pesticide residue on fruit surfaces with significantly enhanced sensitivity. PMID- 28832110 TI - Sequence-Specific Detection of MicroRNAs Related to Clear Cell Renal Cell Carcinoma at fM Concentration by an Electroosmotically Driven Nanopore-Based Device. AB - MicroRNAs (miRs) are small noncoding RNAs that play a critical role in gene regulation. Recently, traces of cancer-related miRs have been identified in body fluids, which make them remarkable noninvasive biomarkers. In this study, a new nanopore-based detection scheme utilizing a borosilicate micropipette and an assay of complementary gamma-peptide nucleic acid (gamma-PNA) probes conjugated to polystyrene beads have been reported for the detection of miR-204 and miR-210 related to the clear cell Renal Cell Carcinoma (ccRCC). Electroosmotic flow (EOF) is induced as the driving force to transport PNA-beads harboring target miRs to the tip of the pore (sensing zone), which results in pore blockades with unique and easily distinguishable serrated shape electrical signals. The concentration detection limit is investigated to be 1 and 10 fM for miR-204 and miR-210, respectively. The EOF transport mechanism enables highly sensitive detection of molecules with low surface charge density with 97.6% detection accuracy compared to the conventional electrophoretically driven methods. Furthermore, resistive pulse experiments are conducted to study the correlation of the particles' surface charge density with their translocation time and verify the detection principle. PMID- 28832111 TI - Promoting Charge Separation and Injection by Optimizing the Interfaces of GaN:ZnO Photoanode for Efficient Solar Water Oxidation. AB - Photoelectrochemical water splitting provides an attractive way to store solar energy in molecular hydrogen as a kind of sustainable fuel. To achieve high solar conversion efficiency, the most stringent criteria are effective charge separation and injection in electrodes. Herein, efficient photoelectrochemical water oxidation is realized by optimizing charge separation and surface charge transfer of GaN:ZnO photoanode. The charge separation can be greatly improved through modified moisture-assisted nitridation and HCl acid treatment, by which the interfaces in GaN:ZnO solid solution particles are optimized and recombination centers existing at the interfaces are depressed in GaN:ZnO photoanode. Moreover, a multimetal phosphide of NiCoFeP was employed as water oxidation cocatalyst to improve the charge injection at the photoanode/electrolyte interface. Consequently, it significantly decreases the overpotential and brings the photocurrent to a benchmark of 3.9 mA cm-2 at 1.23 V vs RHE and a solar conversion efficiency over 1% was obtained. PMID- 28832112 TI - Simultaneous Profiling of DNA Mutation and Methylation by Melting Analysis Using Magnetoresistive Biosensor Array. AB - Epigenetic modifications, in particular DNA methylation, are gaining increasing interest as complementary information to DNA mutations for cancer diagnostics and prognostics. We introduce a method to simultaneously profile DNA mutation and methylation events for an array of sites with single site specificity. Genomic (mutation) or bisulphite-treated (methylation) DNA is amplified using nondiscriminatory primers, and the amplicons are then hybridized to a giant magnetoresistive (GMR) biosensor array followed by melting curve measurements. The GMR biosensor platform offers scalable multiplexed detection of DNA hybridization, which is insensitive to temperature variation. The melting curve approach further enhances the assay specificity and tolerance to variations in probe length. We demonstrate the utility of this method by simultaneously profiling five mutation and four methylation sites in human melanoma cell lines. The method correctly identified all mutation and methylation events and further provided quantitative assessment of methylation density validated by bisulphite pyrosequencing. PMID- 28832113 TI - A Sliding-Mode Triboelectric Nanogenerator with Chemical Group Grated Structure by Shadow Mask Reactive Ion Etching. AB - The sliding-mode triboelectric nanogenerator (S-TENG) with grated structure has important applications in energy harvest and active sensors; however its concavo convex structure leads to large frictional resistance and abrasion. Here, we developed a S-TENG with a chemical group grated structure (S-TENG-CGG), in which the triboelectric layer's triboelectric potential has a positive-negative alternating charged structure. The triboelectric layer of the S-TENG-CGG was fabricated through a reactive ion etching process with a metal shadow mask with grated structure. In the etched region, the nylon film, originally positively charged as in friction with stainless steel, gained opposite triboelectric potential and became negatively charged because of the change of surface functional groups. The output signals of the S-TENG-CGG are alternating and the frequency is determined by both the segment numbers and the moving speed. The applications of the S-TENG-CGG in the charging capacitor and driving calculator are demonstrated. In the S-TENG-CGG, since there is no concavo-convex structure, the frictional resistance and abrasion are largely reduced, which enhances its performances in better stability and longer working time. PMID- 28832114 TI - Co3O4@(Fe-Doped)Co(OH)2 Microfibers: Facile Synthesis, Oriented-Assembly, Formation Mechanism, and High Electrocatalytic Activity. AB - Cobalt oxide or hydroxide nanoarchitectures, often synthesized via solvothermal or electrodeposition or templated approaches, have wide technological applications owing to their inherent electrochemical activity and unique magnetic responsive properties. Herein, by revisiting the well-studied aqueous system of Co/NaBH4 at room temperature, the chainlike assembly of Co3O4 nanoparticles is attained with the assistance of an external magnetic field; more importantly, a one-dimensional hierarchical array consisting of perpendicularly oriented and interconnected Co(OH)2 thin nanosheets could be constructed upon such well aligned Co3O4 assembly, generating biphasic core-shell-structured Co3O4@Co(OH)2 microfibers with permanent structural integrity even upon the removal of the external magnetic field; isomorphous doping was also introduced to produce Co3O4@Fe-Co(OH)2 microfibers with similar structural merits. The cobalt-chemistry in such a Co/NaBH4 aqueous system was illustrated to reveal the compositional and morphological evolutions of the cobalt species and the formation mechanism of the microfibers. Owing to the presence of Co3O4 as the core, such anisotropic Co3O4@(Fe-doped)Co(OH)2 microfibers demonstrated interesting magnetic-responsive behaviors, which could undergo macro-scale oriented-assembly in response to a magnetic stimulus; and with the presence of a hierarchical array of weakly crystallized thin (Fe-doped) Co(OH)2 nanosheets with polycrystallinity as the shell, such microfibers demonstrated remarkable electrocatalytic activity toward oxygen evolution reactions in alkaline conditions. PMID- 28832115 TI - Grafting of Ring-Opened Cyclopropylamine Thin Films on Silicon (100) Hydride via UV Photoionization. AB - The grafting of cyclopropylamine onto a silicon (100) hydride (Si-H) surface via a ring-opening mechanism using UV photoionization is described here. In brief, radicals generated from the Si-H surface upon UV irradiation were found to behave in classical hydrogen abstraction theory manner by which the distal amine group was first hydrogen abstracted and the radical propagated down to the cyclopropane moiety. This subsequently liberated the strained bonds of the cyclopropane group and initiated the surface grafting process, producing a thin film approximately 10-15 nm in height. Contact angle measurements also showed that such photoionization irradiation had yielded an extremely hydrophilic surface (~21.3 degrees ) and X-ray photoelectron spectroscopy also confirmed the coupling was through the Si-C linkage. However, when the surface underwent high-temperature hydrosilylation (>160 degrees C), the reaction proceeded predominantly through the nucleophilic NH2 group to form a Si-N linkage to the surface. This rendered the surface hydrophobic and hence suggested that the Si-H homolysis model may not be the main process. To the best of our knowledge, this was the first attempt reported in the literature to use photoionization to directly graft cyclopropylamine onto a silicon surface and in due course generate a highly rich NH-terminated surface that was found to be highly bioactive in promoting cell viability on the basis of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide studies. PMID- 28832116 TI - Chemically Sumoylated Histone H4 Stimulates Intranucleosomal Demethylation by the LSD1-CoREST Complex. AB - Lysine-specific demethylase 1 (LSD1) downregulates eukaryotic gene activity by demethylating mono- and dimethylated Lys4 in histone H3. Elucidating the biochemical crosstalk of LSD1 with histone post-translational modifications (PTMs) is essential for developing LSD1-targeted therapeutics in human cancers. We interrogated the small ubiquitin-like modifier (SUMO)-driven regulation of LSD1 activity with semisynthetic nucleosomes containing site-specifically methylated and sumoylated histones. We discovered that nucleosomes containing sumoylated histone H4 (suH4), a modification associated with gene repression, stimulate LSD1 activity by a mechanism dependent upon the SUMO-interaction motif in CoREST. Furthermore, the stimulatory effect of suH4 was spatially limited and did not extend to the demethylation of adjacent nonsumoylated nucleosomes. Thus, we have identified histone modification by SUMO as the first PTM that stimulates intranucleosomal demethylation by the developmentally critical LSD1-CoREST complex. PMID- 28832117 TI - Miniprotein Design: Past, Present, and Prospects. AB - The design and study of miniproteins, that is, polypeptide chains <40 amino acids in length that adopt defined and stable 3D structures, is resurgent. Miniproteins offer possibilities for reducing the complexity of larger proteins and so present new routes to studying sequence-to-structure and sequence-to-stability relationships in proteins generally. They also provide modules for protein design by pieces and, with this, prospects for building more-complex or even entirely new protein structures. In addition, miniproteins are useful scaffolds for templating functional domains, for example, those involved in protein-protein interactions, catalysis, and biomolecular binding, leading to potential applications in biotechnology and medicine. Here we select examples from almost four decades of miniprotein design, development, and dissection. Simply because of the word limit for this Account, we focus on miniproteins that are cooperatively folded monomers in solution and not stabilized by cross-linking or metal binding. In these cases, the optimization of noncovalent interactions is even more critical for the maintenance of the folded states than in larger proteins. Our chronology and catalogue highlights themes in miniproteins, which we explore further and begin to put on a firmer footing through an analysis of the miniprotein structures that have been deposited in the Protein Data Bank (PDB) thus far. Specifically, and compared with larger proteins, miniproteins generally have a lower proportion of residues in regular secondary structure elements (alpha helices, beta strands, and polyproline-II helices) and, concomitantly, more residues in well-structured loops. This allows distortions of the backbone enabling mini-hydrophobic cores to be made. This also contrasts with larger proteins, which can achieve hydrophobic cores through tertiary contacts between distant regions of sequence. On average, miniproteins have a higher proportion of aromatic residues than larger proteins, and specifically electron rich Trp and Tyr, which are often found in combination with Pro and Arg to render networks of CH-pi or cation-pi interactions. Miniproteins also have a higher proportion of the long-chain charged amino acids (Arg, Glu, and Lys), which presumably reflects salt-bridge formation and their greater surface area-to volume ratio. Together, these amino-acid preferences appear to support greater densities of noncovalent interactions in miniproteins compared with larger proteins. We anticipate that with recent developments such as parametric protein design, it will become increasingly routine to use computation to generate and evaluate models for miniproteins in silico ahead of experimental studies. This could include accessing new structures comprising secondary structure elements linked in previously unseen configurations. The improved understanding of the noncovalent interactions that stabilize the folded states of such miniproteins that we are witnessing through both in-depth bioinformatics analyses and experimental testing will feed these computational protein designs. With this in mind, we can expect a new and exciting era for miniprotein design, study, and application. PMID- 28832118 TI - Sub-10 nm Tunable Hybrid Dielectric Engineering on MoS2 for Two-Dimensional Material-Based Devices. AB - The successful realization of high-performance 2D-materials-based nanoelectronics requires integration of high-quality dielectric films as a gate insulator. In this work, we explore the integration of organic and inorganic hybrid dielectrics on MoS2 and study the chemical and electrical properties of these hybrid films. Our atomic force microscopy, X-ray photoelectron spectroscopy (XPS), Raman, and photoluminescence results show that, aside from the excellent film uniformity and thickness scalability down to 2.5 nm, the molecular layer deposition of octenyltrichlorosilane (OTS) and Al2O3 hybrid films preserves the chemical and structural integrity of the MoS2 surface. The XPS band alignment analysis and electrical characterization reveal that through the inclusion of an organic layer in the dielectric film, the band gap and dielectric constant can be tuned from ~7.00 to 6.09 eV and ~9.0 to 4.5, respectively. Furthermore, the hybrid films show promising dielectric properties, including a high breakdown field of ~7.8 MV/cm, a low leakage current density of ~1 * 10-6 A/cm2 at 1 MV/cm, a small hysteresis of ~50 mV, and a top-gate subthreshold voltage swing of ~79 mV/dec. Our experimental findings provide a facile way of fabricating scalable hybrid gate dielectrics on transition metal dichalcogenides for 2D-material-based flexible electronics applications. PMID- 28832119 TI - Superior Selective CO2 Adsorption of C3N Pores: GCMC and DFT Simulations. AB - Development of high-performance sorbents is extremely significant for CO2 capture due to its increasing atmospheric concentration and impact on environmental degradation. In this work, we develop a new model of C3N pores based on GCMC calculations to describe its CO2 adsorption capacity and selectivity. Remarkably, it exhibits an outstanding CO2 adsorption capacity and selectivity. For example, at 0.15 bar it shows exceptionally high CO2 uptakes of 3.99 and 2.07 mmol/g with good CO2/CO, CO2/H2, and CO2/CH4 selectivity at 300 and 350 K, separately. More importantly, this adsorbent also shows better water stability. Specifically, its CO2 uptakes are 3.80 and 5.91 mmol/g for and 0.15 and 1 bar at 300 K with a higher water content. Furthermore, DFT calculations demonstrate that the strong interactions between C3N pores and CO2 molecules contribute to its impressive CO2 uptake and selectivity, indicating that C3N pores can be an extremely promising candidate for CO2 capture. PMID- 28832120 TI - Single Continuous Near-Infrared Laser-Triggered Photodynamic and Photothermal Ablation of Antibiotic-Resistant Bacteria Using Effective Targeted Copper Sulfide Nanoclusters. AB - The emergence of antibiotic-resistant bacterial strains has made conventional antibiotic therapies less efficient. The development of a novel nanoantibiotic approach for efficiently ablating such bacterial infections is becoming crucial. Herein, a collection of poly(5-(2-ethyl acrylate)-4-methylthiazole-g butyl)/copper sulfide nanoclusters (PATA-C4@CuS) was synthesized for efficient capture and effective ablation of levofloxacin-resistant Gram-negative and Gram positive bacteria upon tissue-penetrable near-infrared (NIR) laser irradiation. In this work, we took advantage of the excellent photothermal and photodynamic properties of copper sulfide nanoparticles (CuSNPs) upon NIR laser irradiation and thiazole derivative as a membrane-targeting cationic ligand toward bacteria. The conjugated nanoclusters could anchor the bacteria to trigger the bacterial aggregation quickly and efficiently kill them. These conjugated nanoclusters could significantly inhibit levofloxacin-resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Bacillus amyloliquefaciens at 5.5 MUg/mL under NIR laser irradiation (980 nm, 1.5 W cm-2, 5 min), which suggested that the heat and reactive oxygen species (ROS) generated from the irradiated CuSNPs attached to bacteria were effective in eliminating and preventing the regrowth of the bacteria. Importantly, the conjugated nanoclusters could promote healing in bacteria-infected rat wounds without nonspecific damage to normal tissue. These findings highlight the promise of the highly versatile multifunctional nanoantibiotics in bacterial infection. PMID- 28832121 TI - Critical Interface States Controlling Rectification of Ultrathin NiO-ZnO p-n Heterojunctions. AB - Herein, we consider the heterojunction formation of two prototypical metal oxides: p-type NiO and n-type ZnO. Elementally abundant, low-cost metal oxide/oxide' heterojunctions are of interest for UV optical sensing, gas sensing, photocatalysis, charge confinement layers, piezoelectric nanogenerators, and flash memory devices. These heterojunctions can also be used as current rectifiers and potentially as recombination layers in tandem photovoltaic stacks by making the two oxide layers ultrathin. In the ultrathin geometry, understanding and control of interface electronic structure and chemical reactions at the oxide/oxide' interface are critical to functionality, as oxygen atoms are shared at the interface of the dissimilar materials. In the studies presented here the extent of chemical reactions and interface band bending is monitored using X-ray and ultraviolet photoelectron spectroscopies. Interface reactivity is controlled by varying the near surface composition of nickel oxide, nickel hydroxide, and nickel oxyhydroxide using standard surface-treatment procedures. A direct correlation between relative percentage of interface hydroxyl chemistry (and hence surface Lewis basicity) and the local band edge alignment for ultrathin p-n junctions (6 nm NiO/30 nm ZnO) is observed. We propose an acid-base formulism to explain these results: the stronger the acid base reaction, the greater the fraction of interfacial electronic states which lower the band offset between the ZnO conduction band and the NiO valence band. Increased interfacial gap states result in larger reverse bias current of the p-n junction and lower rectification ratios. The acid-base formulism could serve as a future design principle for oxide/oxide' and other heterojunctions based on dissimilar materials. PMID- 28832122 TI - Structural and Electrochemical Consequences of [Cp*] Ligand Protonation. AB - There are few examples of the isolation of analogous metal complexes bearing [eta5-Cp*] and [eta4-Cp*H] (Cp* = pentamethylcyclopentadienyl) complexes within the same metal/ligand framework, despite the relevance of such structures to catalytic applications. Recently, protonation of Cp*Rh(bpy) (bpy = 2,2' bipyridyl) has been shown to yield a complex bearing the uncommon [eta4-Cp*H] ligand, rather than generating a [RhIII-H] complex. We now report the purification and isolation of this protonated species, as well as characterization of analogous complexes of 1,10-phenanthroline (phen). Specifically, reaction of Cp*Rh(bpy) or Cp*Rh(phen) with 1 equiv of Et3NH+Br- affords rhodium compounds bearing endo-eta4-pentamethylcyclopentadiene (eta4 Cp*H) as a ligand. NMR spectroscopy and single-crystal X-ray diffraction studies confirm protonation of the Cp* ligand, rather than formation of metal hydride complexes. Analysis of new structural data and electronic spectra suggests that phen is significantly reduced in Cp*Rh(phen), similar to the case of Cp*Rh(bpy). Backbonding interactions with olefinic motifs are activated by formation of [eta4 Cp*H]; protonation of [Cp*] stabilizes the low-valent metal center and results in loss of reduced character on the diimine ligands. In accord with these changes in electronic structure, electrochemical studies reveal a distinct manifold of redox processes that are accessible in the [Cp*H] complexes in comparison with their [Cp*] analogues; these processes suggest new applications in catalysis for the complexes bearing endo-eta4-Cp*H. PMID- 28832123 TI - In Vitro Isothermal Nucleic Acid Amplification Assisted Surface-Enhanced Raman Spectroscopic for Ultrasensitive Detection of Vibrio parahaemolyticus. AB - Detection of pathogenic microorganisms is of great importance for public health and food safety. Traditional protocols can hardly meet the continuously increasing demand in sensitivity and specificity of pathogen detections. In this study, we adopted Vibrio parahaemolyticus (V. parahaemolyticus, Vp) as the model analyte, and developed an antibody-Vp-aptamer heterosandwich-based surface enhanced Raman scattering (SERS) method in conjunction with in vitro isothermal amplification for sensitive detection of V. parahaemolyticus. The rolling circular amplification (RCA) products provided enormous sites for assembling the Au@Ag nanoparticles and forming excess "hot-spot" sites for Raman measurement. By using this enhanced Raman signal strategy in the detection, a limit of detection (LOD) as low as 1 cfu/mL was successfully achieved for ultrasensitive detection of V. parahaemolyticus. In addition, we have applied this method to artificially contaminated food samples. The detection data indicated that this method is able to determine the concentrations of V. parahaemolyticus in the spiked food samples with satisfactory sensitivity and specificity and, thus, this developed ultrasensitive SERS scheme is well suited for the urgent need in pathogen detection and demonstrated great potential in food safety, environment monitoring, and a clinical setting. PMID- 28832124 TI - Optically Active Ultrafine Au-Ag Alloy Nanoparticles Used for Colorimetric Chiral Recognition and Circular Dichroism Sensing of Enantiomers. AB - Despite a significant surge in the number of investigations into chirality at the nanoscale, especially thiolated chiral molecules capping gold clusters, only limited knowledge is currently available to elaborate the alloying effect on chiroptical behavior of bimetallic nanoparticles (NPs). Also, few successful cases as to the efforts toward the development of chirality-dependent applications on the optically active nanomaterial have been made. Herein, as a positive test case for chiral alloy nanoparticle synthesis, the stable and large chiroptical ultrafine Au-Ag alloy NPs were prepared by reduction of different molar fractions of HAuCl4 and AgNO3 with NaBH4 in the presence of d/l penicillamine (d/l-Pen). Compared with those of monometallic Au and Ag counterparts with comparable size, the Au-Ag alloy NPs (Ag mole fraction, 70%) obviously displayed the largest optical activities with the maximum g-factors of ~1.6 * 10-3. Impressively, the Pen-mediated synthesis of chiral Au-Ag alloy NPs possesses a colorimetric self-recognition function and can be used as an incisive circular dichroism (CD) probe toward d- and l-Pen enantiomers. The plasmonic CD signal amplification (DeltaICD) shows good linearity with the amount of Pen over the range of 5.0-80.0 MUM with a detection limit (3sigma) of 1.7 MUM for l-Pen and 1.5 MUM for d-Pen, respectively. In addition, the sensing system exhibits good selectivity toward d- and l-Pen in the presence of other enantiomers; therefore, it is highly expected that the approach described here would open new opportunities for design of more novel enantioselective analyses of important species related to biological processes. PMID- 28832125 TI - Tetrametallic Thorium Compounds with Th4E4 (E = S, Se) Cubane Cores. AB - Tetrametallic thorium compounds with a Th4E4 core (E = S, Se) having a distorted cubane structure can be prepared by ligand-based reductions of elemental E with thorium chalcogenolates, prepared by in situ oxidation of Th metal with a 3:1 mixture of PhEEPh and F5C6EEC6F5. Four compounds, (py)8Th4S4(MU2-SPh)4(SC6F5)4, (py)8Th4S4(MU2-SPh)4(SeC6F5)4, (py)8Th4Se4(MU2-SePh)4(SeC6F5)4, and (py)8Th4Se4(MU2-SePh)4(SC6F5)4, were isolated and characterized by NMR spectroscopy and X-ray diffraction. These compounds clearly demonstrate the chemical impact of ring fluorination, with the less-nucleophilic EC6F5 ligands occupying the terminal binding sites and the EPh ligands bridging two metal centers. For this series of compounds, crystal packing and intermolecular pi...pi and H-bonding interactions result in a consistent motif and crystallization in a body-centered tetragonal unit cell. Solution-state 77Se NMR spectroscopy reveals that the solid-state structures are maintained in pyridine. PMID- 28832126 TI - A Series of Lanthanide-Germanate Oxo Clusters Decorated by 1,10-Phenanthroline Chromophores. AB - A series of lanthanide-germanate oxo clusters, [Ln8(phen)2Ge12(MU3 O)24T12(H2O)16].2H2O [Ln = Dy (1a) and Er (1b); T = -CH2CH2COO- group; phen = 1,10-phenanthroline], [Ln8(phen)2Ge12(MU3-O)24T12(H2O)16].2phen.16H2O [Ln = Sm (2a), Eu (2b), and Gd (2c)], and [Ho8(phen)2Ge12(MU3-O)24T12(H2O)14].2phen.13H2O (3), have been hydrothermally synthesized from the reactions of bis(carboxyethylgermanium sesquioxide) and Ln2O3 with auxiliary phen chromophores. Compounds 1a and 1b consist of cage clusters [Ln8(phen)2Ge12(MU3 O)24T12(H2O)16] and free H2O molecules, where cage clusters are arranged in a CsCl type, while compounds 2a-2c consist of cage clusters [Ln8(phen)2Ge12(MU3 O)24T12(H2O)16], free phen, and free H2O molecules, where cage clusters are arranged in a NaCl type. Compound 3 consists of the one-dimensional neutral chain [Ho8(phen)2Ge12(MU3-O)24T12(H2O)14]n and free H2O molecules. These compounds provide the first examples of p-f heterometallic [Ge-O-Ln] oxo clusters decorated by phen chromophores. The photoluminescent and magnetic properties of all compounds have been investigated. PMID- 28832127 TI - Templated Self-Assembly of Dynamic Peptide Nucleic Acids. AB - Template-directed macromolecule synthesis is a hallmark of living systems. Inspired by this natural process, several fundamentally novel mechanisms for template-directed assembly of nucleic acid analogues have been developed. Although these approaches have broad significance, including potential applications in biotechnology and implications for the origins of life, there are unresolved challenges in how to characterize in detail the complex assembly equilibria associated with dynamic templated reactions. Here we describe mechanistic studies of template-directed dynamic assembly for thioester peptide nucleic acid (tPNA), an informational polymer that responds to selection pressures under enzyme-free conditions. To overcome some of the inherent challenges of mechanistic studies of dynamic oligomers, we designed, synthesized, and implemented tPNA-DNA conjugates. The DNA primer region affords a high level of control over the location and register of the tPNA backbone in relation to the template strand. We characterized the degree and kinetics of dynamic nucleobase mismatch correction at defined backbone positions. Furthermore, we report the fidelity of dynamic assembly in tPNA as a function of position along the peptide backbone. Finally, we present theoretical studies that explore the level of fidelity that can be expected for an oligomer having a given hybridization affinity in dynamic templated reactions and provide guidance for the future development of sequence self-editing polymers and materials. As our results demonstrate, the use of molecular conjugates of constitutionally static and dynamic polymers establishes a new methodology for expediting the characterization of the complex chemical equilibria that underlie the assembly of dynamic informational polymers. PMID- 28832128 TI - Paper Spray Chemical Ionization: Highly Sensitive Ambient Ionization Method for Low- and Nonpolar Aromatic Compounds. AB - Sensitivity is an important factor determining successful mass spectrometry (MS) analysis of metabolome, protein, drugs, and environmental samples. Currently, nanoelectrospray ionization (ESI) is widely used as a sensitive ionization method. However, application of nano-ESI is limited to polar molecules and there is no atmospheric pressure ionization technique developed that can be used for MS analysis of low- and nonpolar compounds with sensitivity that can match with nano ESI. Herein, we propose paper spray chemical ionization (PSCI) as an ionization technique that can be used to analyze low- and nonpolar aromatic compounds with high sensitivity. PSCI is based on paper spray ionization utilizing corona discharge phenomenon. PSCI can sensitively and quantitatively detect down to picogram (or femtomole) levels of low- and nonpolar aromatic compounds. PMID- 28832130 TI - New Adamantane-like Silicophosphate Cage and Its Reactivity toward Tris(pentafluorophenyl)borane. AB - The condensation reaction between Ph2Si(OC(O)CH3)2 and OP(OSiMe3)3 leads to elimination of CH3C(O)OSiMe3 and the formation of the new silicophosphate cage molecule Ph12Si6P4O16 (1) with an adamantane-like core possessing four terminal P?O moieties and six O-SiPh2-O bridging groups. Compound 1 was further reacted with the Lewis acid B(C6F5)3. We observed adduct formation by coordination through the P?O->B bonds and isolated and structurally characterized two new molecules. In the first of them, the adamantane-like cage is preserved and three phosphoryl oxygen atoms coordinate to boranes, forming Ph12Si6O16P4.3B(C6F5)3 (2); the remaining P?O group is inverted toward the cage center pointing along a C3 molecular axis. The molecule is chiral, and the compound 2 crystallizes as a conglomerate of homochiral crystals. Enantiomers 2M and 2P were both structurally characterized. The second adduct resulted from an unexpected reorganization of the Si-O-P linkages in the adamantane cage during the reaction of 1 with 4 equiv of B(C6F5)3. The bis-adduct Ph6Si3O8P2.2B(C6F5)3 (3) was formed with an inorganic core representing half of the parent molecule 1. PMID- 28832129 TI - The Conformational Flexibility of the Acyltransferase from the Disorazole Polyketide Synthase Is Revealed by an X-ray Free-Electron Laser Using a Room Temperature Sample Delivery Method for Serial Crystallography. AB - The crystal structure of the trans-acyltransferase (AT) from the disorazole polyketide synthase (PKS) was determined at room temperature to a resolution of 2.5 A using a new method for the direct delivery of the sample into an X-ray free electron laser. A novel sample extractor efficiently delivered limited quantities of microcrystals directly from the native crystallization solution into the X-ray beam at room temperature. The AT structure revealed important catalytic features of this core PKS enzyme, including the occurrence of conformational changes around the active site. The implications of these conformational changes for polyketide synthase reaction dynamics are discussed. PMID- 28832131 TI - Vacuum Referred Binding Energy (VRBE)-Guided Design of Orange Persistent Ca3Si2O7:Eu2+ Phosphors. AB - Orange persistent phosphors of Ca3Si2O7 (CSO) doped with Eu2+ were strategically developed by codoping Sm3+ or Tm3+. First, a vacuum referred binding energy, VRBE, diagram of Ca3Si2O7 (CSO) was constructed from the measured spectroscopic data. By the zigzag curve of the divalent lanthanide ions in the VRBE diagram, Sm3+ and Tm3+ ions were predicted to be a suitable electron trap for the persistent luminescence. The initial persistent luminance of CSO:Eu2+-Sm3+ and CSO:Eu2+-Tm3+ was found to be 290 times and 9300 times stronger, respectively, compared with CSO:Eu2+. By optimizing Eu2+ and Tm3+ concentrations, the persistent luminescence duration on 0.32 mcd/m2 reached approximately 50 min in CSO:Eu2+-Tm3+. From the VRBE diagram and the persistent luminescence properties, we discuss the persistent mechanism including the charging process, detrapping process, and electron trapping centers. PMID- 28832132 TI - Short Arginine Motifs Drive Protein Stickiness in the Escherichia coli Cytoplasm. AB - Although essential to numerous biotech applications, knowledge of molecular recognition by arginine-rich motifs in live cells remains limited. 1H,15N HSQC and 19F NMR spectroscopies were used to investigate the effects of C-terminal GRn (n = 1-5) motifs on GB1 interactions in Escherichia coli cells and cell extracts. While the "biologically inert" GB1 yields high-quality in-cell spectra, the -GRn fusions with n = 4 or 5 were undetectable. This result suggests that a tetra-arginine motif is sufficient to drive interactions between a test protein and macromolecules in the E. coli cytoplasm. The inclusion of a 12 residue flexible linker between GB1 and the -GR5 motif did not improve detection of the "inert" domain. In contrast, all of the constructs were detectable in cell lysates and extracts, suggesting that the arginine-mediated complexes were weak. Together these data reveal the significance of weak interactions between short arginine-rich motifs and the E. coli cytoplasm and demonstrate the potential of such motifs to modify protein interactions in living cells. These interactions must be considered in the design of (in vivo) nanoscale assemblies that rely on arginine-rich sequences. PMID- 28832134 TI - Transcriptomic Response of Arabidopsis thaliana Exposed to CuO Nanoparticles, Bulk Material, and Ionic Copper. AB - Engineered nanoparticles (ENPs) exhibit unique properties advantageous in a number of applications, but they also represent potential health and environmental risks. In this study, we investigated the phytotoxic mechanism of CuO ENPs using transcriptomic analysis and compared this response with the response to CuO bulk particles and ionic Cu2+. Ionic Cu2+ at the concentration of 0.16 mg L-1 changed transcription of 2692 genes (p value of <0.001, fold change of >=2) after 7 days of exposure, whereas CuO ENPs and bulk particles (both in the concentration of 10 mg L-1) altered the expression of 922 and 482 genes in Arabidopsis thaliana roots, respectively. The similarity between transcription profiles of plants exposed to ENPs and ionic Cu2+ indicated that the main factor in phytotoxicity was the release of Cu2+ ions from CuO ENPs after 7 days of exposure. The effect of Cu2+ ions was evident in all treatments, as indicated by the down-regulation of genes involved in metal homeostasis and transport and the up-regulation of oxidative stress response genes. ENPs were more soluble than bulk particles, resulting in the up-regulation of metallochaperone-like genes or the down-regulation of aquaporins and metal transmembrane transporters that was also characteristic for ionic Cu2+ exposure. PMID- 28832133 TI - The Mechanism of Regulation of Pantothenate Biosynthesis by the PanD-PanZ.AcCoA Complex Reveals an Additional Mode of Action for the Antimetabolite N-Pentyl Pantothenamide (N5-Pan). AB - The antimetabolite pentyl pantothenamide has broad spectrum antibiotic activity but exhibits enhanced activity against Escherichia coli. The PanDZ complex has been proposed to regulate the pantothenate biosynthetic pathway in E. coli by limiting the supply of beta-alanine in response to coenzyme A concentration. We show that formation of such a complex between activated aspartate decarboxylase (PanD) and PanZ leads to sequestration of the pyruvoyl cofactor as a ketone hydrate and demonstrate that both PanZ overexpression-linked beta-alanine auxotrophy and pentyl pantothenamide toxicity are due to formation of this complex. This both demonstrates that the PanDZ complex regulates pantothenate biosynthesis in a cellular context and validates the complex as a target for antibiotic development. PMID- 28832135 TI - Response of Aerobic Granular Sludge to the Long-Term Presence of CuO NPs in A/O/A SBRs: Nitrogen and Phosphorus Removal, Enzymatic Activity, and the Microbial Community. AB - The increasing use of cupric oxide nanoparticles (CuO NPs) has raised concerns about their potential environmental toxicity. Aerobic granular sludge (AGS) is a special form of microbial aggregates. In this study, the removal efficiencies of nitrogen and phosphorus, enzyme activities and microbial community of AGS under long-term exposure to CuO NPs (at concentrations of 5, 20, 50 mg/L) in aerobic/oxic/anoxic (A/O/A) sequencing batch reactors (SBRs) were investigated. The results showed the chronic toxicity caused by different concentrations of CuO NPs (5, 20, 50 mg/L) resulted in increases in the production of ROS of 110.37%, 178.64%, and 188.93% and in the release of lactate dehydrogenase (LDH) of 108.33%, 297.05%, 335.94%, respectively, compared to the control. Besides, CuO NPs decreased the activities of polyphosphate kinase (PPK) and exophosphatase (PPX), leading to lower phosphorus removal efficiency. However, the NH4+-N removal rates remained stable, and the removal efficiencies of TN increased due to the synthesis of nitrite and nitrous oxide (N2O) reductases. In addition, CuO NPs at concentrations of 0, 5, 20 mg/L increased the secretion of protein (PN) to 90, 91, 105 mg/gVSS, respectively, which could alleviate the toxicity of CuO NPs. High-throughput sequencing showed that CuO NPs increased the abundance of nitrogen-removal bacteria and reduced the abundance of phosphorus-removal bacteria, which is consistent with the results of pollutant removal upon long term exposure to CuO NPs. PMID- 28832136 TI - Design of a Binuclear Ni(II) Complex with Large Ising-type Anisotropy and Weak Anti-Ferromagnetic Coupling. AB - The preparation of a binuclear Ni(II) complex with a pentacoordinate environment using a cryptand organic ligand and the imidazolate bridge is reported. The coordination sphere is close to trigonal bipyramidal (tbp) for one Ni(II) and to square pyramidal (spy) for the other. The use of the imidazolate bridge that undergoes pi-pi stacking with two benzene rings of the chelating ligand induces steric hindrance that stabilizes the pentacoordinate environment. Magnetic measurements together with theoretical studies of the spin states energy levels allow fitting the data and reveal a large Ising-type anisotropy and a weak anti ferromagnetic exchange coupling between the metal ions. The magnitude and the nature of the magnetic anisotropy and the difference in anisotropy between the two metal ions are rationalized using wave-function-based calculations. We show that a slight distortion of the coordination sphere of Ni(II) from spy to tbp leads to an Ising-type anisotropy. Broken-symmetry density functional calculations rationalize the weak anti-ferromagnetic exchange coupling through the imidazolate bridge. PMID- 28832138 TI - Mechanism and Origin of Chemical Selectivity in Oxaziridine-Based Methionine Modification: A Computational Study. AB - Oxaziridine-based redox sulfur imidation provides a breakthrough strategy for selective modification at methionine in proteins. The chemoselectivity of imidization (N-transfer) over oxidation (O-transfer) of the thioether functionality of methionine, and the modification selectivity of methionine over other amino acids, are the key features of this strategy. To elucidate the detailed reaction mechanism and the origin of the reported chemoselectivity, a theoretical investigation on the oxaziridine-based methionine modification reaction is reported. It is found that both the N-transfer and O-transfer pathways occur in a concerted mechanism. Distortion/interaction-activation strain model analysis indicates that the N-transfer chemoselectivity is mainly controlled by the interaction energy. Orbital and charge analysis further supports that the interaction energy resulting from the orbital interaction favors the N-transfer pathway at the early stage of the reaction. The calculated reactivity of eight potential amino acid competitors with the oxaziridine shows excellent selectivity for methionine modification, consistent with the experimental observations. The scarcity of active species in neutral aqueous solution leads to the weak reactivity of tyrosine, lysine, and arginine. The stronger charge-transfer interactions between methionine and the oxaziridine compared with that for the other amino acids also play vital roles in the modification selectivity. PMID- 28832139 TI - Enantioselective C-H Functionalization-Addition Sequence Delivers Densely Substituted 3-Azabicyclo[3.1.0]hexanes. AB - An enantioselective C-H functionalization route to perfluoroalkyl-containing 3 azabicyclo[3.1.0]hexanes is disclosed. A modular and bench-stable diazaphospholane ligand enables highly enantioselective Pd(0)-catalyzed cyclopropane C-H functionalization using trifluoroacetimidoyl chlorides as electrophilic partners. In turn, the resulting cyclic ketimine products react smoothly with a broad variety of nucleophiles in one-pot processes enabling the rapid and modular construction of heavily substituted pyrrolidines. PMID- 28832137 TI - Late-Stage C-H Alkylation of Heterocycles and 1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines. AB - Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a Csp3-centered radical that can engage in the C-H alkylation of heterocyclic bases and 1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C-H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears. PMID- 28832140 TI - Multimodal Generally Recognized as Safe ZnO/Nanocopper Composite: A Novel Antimicrobial Material for the Management of Citrus Phytopathogens. AB - Copper (Cu) bactericides/fungicides are used extensively for crop protection in agriculture. Concerns for Cu accumulation in soil, Cu leaching into the surrounding ecosystem, and development of Cu resistance in phytopathogenic bacteria are evident. While there is no suitable alternative to Cu available to date for agricultural uses, it is possible to reduce Cu per application by supplementing with Zn and improving Cu bioavailability using nanotechnology. We have prepared a non-phytotoxic composite material consisting of generally recognized as safe ZnO 800 particles and nanocopper-loaded silica gel (ZnO nCuSi). The morphology of the ZnO-nCuSi material was characterized using scanning electron microscopy, showing ZnO particles dispersed in the silica gel matrix. ZnO-nCuSi demonstrated strong in vitro antimicrobial properties against several model plant bacterial species. Two consecutive year field efficacy results showed that agri-grade ZnO-nCuSi was effective in controlling citrus canker disease at less than half the metallic rate of the commercial cuprous oxide/zinc oxide pesticide. PMID- 28832141 TI - Isothermal Titration Calorimetry to Probe the Coil-to-Globule Transition of Thermoresponsive Polymers. AB - Isothermal titration calorimetry (ITC) is introduced as a new way to study the effect of cosolutes on the coil-to-globule transition of thermoresponsive polymers. From isothermal titrations, critical cosolute concentrations can be identified, at which a coil-to-globule transition occurs. The concept of a temperature-dependent critical cosolute concentration is proven employing different isomers of dihydroxybenzene (DHB) and one isomer of hydroxy benzaldehyde (mHBA) in solutions of two thermoreversible polymer, namely poly(N isopropylacrylamide) (PNiPAM) and poly(N,N-diethylacrylamide) (PDEAM). It is shown that the temperature-dependent critical cosolute concentration, determined by ITC, and the cosolute concentration-dependent critical temperature, probed via differential scanning calorimetry (DSC), yield the same phase diagram. The advantage of employing ITC is the ability to probe even critical concentrations at very low temperatures, whereas the corresponding critical temperatures are not easily accessible in DSC. In addition, kinetic information about the coil-to globule transition in different systems is obtained, and the effect of the DHB isomers on the transition temperature is found to scale as ortho > para > meta. PMID- 28832142 TI - Study of the Synchrotron Photoionization Oxidation of 2-Methylfuran Initiated by O(3P) under Low-Temperature Conditions at 550 and 650 K. AB - The O-(3P)-initiated oxidation of 2-methylfuran (2-MF) was investigated using vacuum-ultraviolet synchrotron radiation from the Advanced Light Source at Lawrence Berkeley National Laboratory. Reaction species were studied by multiplexed photoionization mass spectrometry at 550 and 650 K. The oxygen addition pathway is favored in this reaction, forming four triplet diradicals that undergo intersystem crossing into singlet epoxide species that lead to the formation of products at m/z 30 (formaldehyde), 42 (propene), 54 (1-butyne, 1,3 butadiene, and 2-butyne), and 70 (2-butenal, methyl vinyl ketone, and 3-butenal). Mass-to-charge ratios, photoionization spectra, and adiabatic ionization energies for each primary reaction species were obtained and used to characterize their identities. In addition, by means of electronic structure calculations, potential energy surface scans of the different species produced throughout the oxidation were examined to further validate the primary chemistry occurring. Branching fractions for the formation of the primary products were calculated at the two temperatures and contribute 81.0 +/- 21.4% at 550 K and 92.1 +/- 25.5% at 650 K. PMID- 28832143 TI - Supramolecular Multiblock Copolymers Featuring Complex Secondary Structures. AB - This contribution introduces main-chain supramolecular ABC and ABB'A block copolymers sustained by orthogonal metal coordination and hydrogen bonding between telechelic polymers that feature distinct secondary structure motifs. Controlled polymerization techniques in combination with supramolecular assembly are used to engineer heterotelechelic pi-sheets that undergo high-fidelity association with both helical and coil-forming synthetic polymers. Our design features multiple advances to achieve our targeted structures, in particular, those emulating sheet-like structural aspects using poly(p-phenylenevinylene)s (PPVs). To engineer heterotelechelic PPVs in a sheet-like design, we engineer an iterative one-pot cross metathesis-ring-opening metathesis polymerization (CM ROMP) strategy that affords functionalized Grubbs-II initiators that subsequently polymerize a paracyclophanediene. Supramolecular assembly of two heterotelechelic PPVs is used to realize a parallel pi-sheet, wherein further orthogonal assembly with helical motifs is possible. We also construct an antiparallel pi-sheet, wherein terminal PPV blocks are adjacent to a flexible coil-like poly(norbornene) (PNB). The PNB is designed, through supramolecular chain collapse, to expose benzene and perfluorobenzene motifs that promote a hairpin turn via charge transfer-aided folding. We demonstrate that targeted helix-(pi-sheet)-helix and helix-(pi-sheet)-coil assemblies occur without compromising intrinsic helicity, while both parallel and antiparallel beta-sheet-like structures are realized. Our main-chain orthogonal assembly approach allows the engineering of multiblock copolymer scaffolds featuring diverse secondary structures via the directional assembly of telechelic building blocks. The targeted assemblies, a mix of sequence-defined helix-sheet-coil and helix-sheet-helix architectures, are Nature inspired synthetic mimics that expose alpha/beta and alpha+beta protein classes via de novo design and cooperative assembly strategies. PMID- 28832144 TI - Effect of Imidazole on the Electrochemistry of Zinc Porphyrins: An Electrochemical and Computational Study. AB - In this study, the electrochemical behavior of zinc meso-substituted porphyrins in the presence of imidazole is examined by using both cyclic voltammetry (CV) and density functional theory (DFT) methods. The results show that the first half wave oxidation potentials (1st E1/2) of zinc porphyrins complexed with imidazole all move to the negative side, while the second ones (2nd E1/2) move to the positive side, resulting in larger half-wave oxidation potential splittings of the two oxidation states (DeltaE = second E1/2 - first E1/2) comparing with the zinc porphyrins. By employing DFT calculations, we have found that both sterically controlled inter pi-conjugation between porphyrin rings and meso substituted phenyl groups and deformation of porphyrin rings do play important roles in contributing to the half-wave oxidation potentials. Imidazole exhibits strong effects on the deformation of porphyrin rings which is dominant in determining the first E1/2 while the inter pi-conjugation between porphyrin rings and meso-substituted phenyl groups mainly contributes to the second E1/2. Without imidazole, the inter pi-conjugation between porphyrin rings and meso-substituted phenyl groups is the only important criterion which effects both first E1/2 and second E1/2 of zinc porphyrins. PMID- 28832145 TI - Quantum Chemical Prediction of Equilibrium Acidities of Ureas, Deltamides, Squaramides, and Croconamides. AB - Robust quantum chemical methods are employed to predict the pKa's of several families of dual hydrogen-bonding organocatalysts/anion receptors, including deltamides and croconamides as well as their thio derivatives. The average accuracy of these predictions is ~1 pKa unit and allows for a comparison of the acidity between classes of receptors and for quantitative studies of substituent effects. These computational insights further explain the relationship between pKa and chloride anion affinity of these receptors that will be important for designing future anion receptors and organocatalysts. PMID- 28832146 TI - Structural Differentiation between Layered Single (Ni) and Double Metal Hydroxides (Ni-Al LDHs) Using Wavelet Transformation. AB - Layered double hydroxides (LDHs) are anionic clays important in disciplines such as environmental chemistry, geochemistry, and materials science. Developments in signal processing of extended X-ray absorption fine structure (EXAFS) data, such as wavelet transformation (WT), have been used to identify transition metals and Al present in the hydroxide sheets of LDHs. The WT plots of LDHs should be distinct from those of isostructural single metal hydroxides. However, no direct comparison of these minerals appears in the literature using WT. This work systematically analyzes a suite of Ni-rich mineral standards, including Ni-Al LDHs, single metal Ni hydroxides, and Ni-rich silicates using WT. The results illustrate that the WT plots for alpha-Ni(OH)2 and Ni-Al LDHs are often indistinguishable from each other, with similar two-component plots for the different mineral types. This demonstrates that the WT of the first metal shell often cannot be used to differentiate an LDH from a single metal hydroxide. Interlayer anions adsorbed to the hydroxide sheet of alpha-Ni(OH)2 affect the EXAFS spectra and are not visible in the FT but are clearly resolved and discrete in the WT. PMID- 28832147 TI - Flavonoid and Galloyl Glycosides Isolated from Saxifraga spinulosa and Their Antioxidative and Inhibitory Activities against Species That Cause Piroplasmosis. AB - Eight new flavonoid-based 3'-O-beta-d-glucopyranosides (1-8) and three new galloyl glucosides (9, 11, 12), were isolated from the aerial parts of Saxifraga spinulosa, along with 25 known compounds. The structures of the new compounds were elucidated by spectroscopic methods. Most of the isolated compounds exhibited potent DPPH radical-scavenging activities. Further, their inhibitory activities were evaluated against Babesia bovis, Babesia bigemina, Babesia caballi, and Theileria equi, protozoan parasites that cause piroplasmosis in livestock. The results indicated that several of these compounds showed growth inhibitory effects on such organisms that cause piroplasmosis. PMID- 28832148 TI - Benchmarks and Dielectric Constants for Reparametrized OPLS and Polarizable Force Field Models of Chlorinated Hydrocarbons. AB - The knowledge of dielectric response properties of the environment is of paramount importance in many theoretical embedding methods and studies of solutes and of catalytic sites and processes in condensed phases. In particular, the realistic embedding of active sites into solid/liquid and liquid/liquid interfaces is a crucial point in the context of modeling energy conversion (e.g., electrochemical, photochemical, power-to-X) processes. Recently, the finding that the dielectric permeability of liquids near solid/liquid interfaces is far from being constant but deviates strongly from the bulk value within several nanometers from the interface has raised the interest in a more fundamental understanding of the response properties near interfaces. As these questions are hard to study experimentally, reliable theoretical models are required. Here we describe a careful first-principles based reparametrization of nonpolarizable molecular mechanics force fields for a class of technological relevant organic chlorinated hydrocarbon solvents which are immiscible with water. For the solvent 1,2-dichloroethane (1,2-DCE) we also present a new polarizable force field based on the Drude oscillator model. Its parametrization needs particular attention to avoid unphysical couplings between the internal torsional degree of freedom and the Drude oscillators, which could severely skew the response properties. The performance of this new set of force fields is critically assessed based on a comprehensive molecular dynamics study. PMID- 28832149 TI - Decomposition of Methanol on Mixed CuO-CuWO4 Surfaces. AB - Mixed CuO(2 * 1)-CuWO4 layers on a Cu(110) surface have been prepared by the on surface reaction of the CuO(2 * 1) surface oxide with adsorbed (WO3)3 clusters. The adsorption and decomposition of methanol on these well-defined CuO-CuWO4 surfaces has been followed by high-resolution X-ray photoelectron spectroscopy (XPS), high-resolution electron energy loss spectroscopy (HREELS), and temperature-programmed desorption (TPD) to assess the molecular surface species and their concentration, while the state of the surface oxide phases before and after methanol decomposition has been characterized by scanning tunneling microscopy (STM), low energy electron diffraction (LEED), and XPS. Surface methoxy species form the primary methanol decomposition products, which desorb partly by recombination as methanol at 200-300 K or decompose into CHx and possibly CO. The most reactive surfaces are mixed CuO-CuWO4 phase, with CuWO4 coverages 0.5-0.8 monolayer, thus pointing at the importance of oxide phase boundary sites. In a minority reaction channel, a small amount of formaldehyde is detected on the CuWO4 surface. The CuWO4 oxide phase becomes modified as a result of reduction and a morphology transition triggered by the methanol decomposition, but the pristine surface state can be recovered by a postoxidation treatment with oxygen. PMID- 28832150 TI - From Colloidal Monodisperse Nickel Nanoparticles to Well-Defined Ni/Al2O3 Model Catalysts. AB - In the past few decades, advances in colloidal nanoparticle synthesis have created new possibilities for the preparation of supported model catalysts. However, effective removal of surfactants is a prerequisite to evaluate the catalytic properties of these catalysts in any reaction of interest. Here we report on the colloidal preparation of surfactant-free Ni/Al2O3 model catalysts. Monodisperse Ni nanoparticles (NPs) with mean particle size ranging from 4 to 9 nm were synthesized via thermal decomposition of a zerovalent precursor in the presence of oleic acid. Five weight percent Ni/Al2O3 catalysts were produced by direct deposition of the presynthesized NPs on an alumina support, followed by thermal activation (oxidation-reduction cycle) for complete surfactant removal and surface cleaning. Structural and morphological characteristics of the nanoscale catalysts are described in detail following the propagation of the bulk and surface Ni species at the different treatment stages. Powder X-ray diffraction, electron microscopy, and temperature-programmed reduction experiments as well as infrared spectroscopy of CO adsorption and magnetic measurements were conducted. The applied thermal treatments are proven to be fully adequate for complete surfactant removal while preserving the metal particle size and the size distribution at the level attained by the colloidal synthesis. Compared with standard impregnated Ni/Al2O3 catalysts, the current model materials display narrowed Ni particle size distributions and increased reducibility with a higher fraction of the metallic nickel atoms exposed at the catalyst surface. PMID- 28832151 TI - Modeling of Polyelectrolyte Adsorption from Micellar Solutions onto Biomimetic Substrates. AB - Depositing cationic polyelectrolytes (PEs) from micellar solutions that include surfactants (SU) onto surfaces is a rich, complex, highly relevant, and challenging topic that covers a broad field of practical applications (e.g., from industrial to personal care). The role of the molecular architecture of the constituents of the PEs are often overruled, or at least and either, underestimated in regard to the surface properties. In this work, we aim to evaluate the effect of a model biomimetic surface that shares the key characteristics of the extreme surface of hair and its concomitant chemo- and physisorbed properties onto the deposition of a complex PEs:SU system. To tackle out the effect of the molecular architecture of the PEs, we consider (i) a purely linear and hydrophilic PE (P100) and (ii) a PE with lateral amphiphilic chains (PegPE). Using numerical self-consistent field calculations, we show that the architecture of the constituents interfere with the surface properties in a nonintuitive way such that, depending on the amphiphilicity and hydrophilicity of the PEs and the hydrophobicity of the surface, a re-entrant adsorbing transition can be observed, the lipid coverage of the model hair surface being the unique control parameter. Such a behavior is rationalized by the anticooperative associative properties of the coacervate micelles in solution, which is also controlled by the architecture of the PEs and SU. We now expect that PEs adsorption, as a rule, is governed by the molecular details of the species in solution as well as the surface specificities. We emphasize that molecular realistic modeling is essential to rationalize and optimize the adsorption process of, for example, polymer conditioning agents in water-rinsed cosmetic or textile applications. PMID- 28832152 TI - Photoluminescence from Radiative Surface States and Excitons in Methylammonium Lead Bromide Perovskites. AB - In view of its band gap of 2.2 eV and its stability, methylammonium lead bromide (MAPbBr3) is a possible candidate to serve as a light absorber in a subcell of a multijunction solar cell. Using complementary temperature-dependent time-resolved microwave conductance (TRMC) and photoluminescence (TRPL) measurements, we demonstrate that the exciton yield increases with lower temperature at the expense of the charge carrier generation yield. The low-energy emission at around 580 nm in the cubic phase and the second broad emission peak at 622 nm in the orthorhombic phase originate from radiative recombination of charges trapped in defects with mobile countercharges. We present a kinetic model describing both the decay in conductance as well as the slow ingrowth of the TRPL. Knowledge of defect states at the surface of various crystal phases is of interest to reach higher open-circuit voltages in MAPbBr3-based cells. PMID- 28832153 TI - Impact of Surface Active Ionic Liquids on the Cloud Points of Nonionic Surfactants and the Formation of Aqueous Micellar Two-Phase Systems. AB - Aqueous micellar two-phase systems (AMTPS) hold a large potential for cloud point extraction of biomolecules but are yet poorly studied and characterized, with few phase diagrams reported for these systems, hence limiting their use in extraction processes. This work reports a systematic investigation of the effect of different surface-active ionic liquids (SAILs)-covering a wide range of molecular properties-upon the clouding behavior of three nonionic Tergitol surfactants. Two different effects of the SAILs on the cloud points and mixed micelle size have been observed: ILs with a more hydrophilic character and lower critical packing parameter (CPP < 1/2) lead to the formation of smaller micelles and concomitantly increase the cloud points; in contrast, ILs with a more hydrophobic character and higher CPP (CPP >= 1) induce significant micellar growth and a decrease in the cloud points. The latter effect is particularly interesting and unusual for it was accepted that cloud point reduction is only induced by inorganic salts. The effects of nonionic surfactant concentration, SAIL concentration, pH, and micelle zeta potential are also studied and rationalized. PMID- 28832154 TI - Simulating Bilayers of Nonionic Surfactants with the GROMOS-Compatible 2016H66 Force Field. AB - Polyoxyethylene glycol alkyl ether amphiphiles (CiEj) are important nonionic surfactants, often used for biophysical and membrane protein studies. In this work, we extensively test the GROMOS-compatible 2016H66 force field in molecular dynamics simulations involving the lamellar phase of a series of CiEj surfactants, namely C12E2, C12E3, C12E4, C12E5, and C14E4. The simulations reproduce qualitatively well the monitored structural properties and their experimental trends along the surfactant series, although some discrepancies remain, in particular in terms of the area per surfactant, the equilibrium phase of C12E5, and the order parameters of C12E3, C12E4, and C12E5. The polar head of the CiEj surfactants is highly hydrated, almost like a single polyethyleneoxide (PEO) molecule at full hydration, resulting in very compact conformations. Within the bilayer, all CiEj surfactants flip-flop spontaneously within tens of nanoseconds. Water-permeation is facilitated, and the bending rigidity is 4 to 5 times lower than that of typical phospholipid bilayers. In line with another recent theoretical study, the simulations show that the lamellar phase of CiEj contains large hydrophilic pores. These pores should be abundant in order to reproduce the comparatively low NMR order parameters. We show that their contour length is directly correlated to the order parameters, and we estimate that they should occupy approximately 7-10% of the total membrane area. Due to their highly dynamic nature (rapid flip-flops, high water permeability, observed pore formation), CiEj surfactant bilayers are found to represent surprisingly challenging systems in terms of modeling. Given this difficulty, the results presented here show that the 2016H66 parameters, optimized independently considering pure-liquid as well as polar and nonpolar solvation properties of small organic molecules, represent a good starting point for simulating these systems. PMID- 28832155 TI - Pseudomonas aeruginosa Proteome under Hypoxic Stress Conditions Mimicking the Cystic Fibrosis Lung. AB - Pseudomonas aeruginosa is a ubiquitous Gram-negative pathogen known to inhabit hypoxic mucus plugs of cystic fibrosis (CF) patient lungs. Despite the high prevalence and related patient mortality, the protein machinery enabling the bacterium to adapt to low oxygen environment remains to be fully elucidated. We investigated this by performing both SWATH mass spectrometry and data-dependent SPS-MS3 of TMT-labeled peptides to profile the proteomes of two P. aeruginosa CF isolates, PASS2 and PASS3, and a laboratory reference strain, PAO1, grown under hypoxic stress (O2 < 1%) in media that mimic the nutrient components of the CF lung. Quantitated across all three strains were 3967 P. aeruginosa proteins, reflecting approximately 71% of predicted ORFs in PAO1 and representing the most comprehensive proteome of clinically relevant P. aeruginosa to date. Comparative analysis revealed 735, 640, and 364 proteins were altered by 2-fold or more when comparing low oxygen to aerobic growth in PAO1, PASS2, and PASS3, respectively. Strikingly, under hypoxic stress, all strains showed concurrent increased abundance of proteins required for both aerobic (cbb3-1 and cbb3-2 terminal oxidases) and anaerobic denitrification and arginine fermentation, with the two clinical isolates showing higher relative expression of proteins in these pathways. Additionally, functional annotation revealed that clinical strains portray a unique expression profile of replication, membrane biogenesis, and virulence proteins during hypoxia which may endow these bacteria with a survival advantage. These protein profiles illuminate the diversity of P. aeruginosa mechanisms to adapt to low oxygen and shows that CF isolates initiate a robust molecular response to persist under these conditions. PMID- 28832156 TI - Silver-Free Direct Synthesis of Alkynylphosphine Oxides via spC-H/P(O)-H Dehydrogenative Coupling Catalyzed by Palladium. AB - A silver-free palladium-catalyzed dehydrogenative phosphorylation of terminal alkynes with hydrogen phosphine oxides has been developed. Both aromatic and aliphatic terminal alkynes including those bearing functional groups coupled readily with hydrogen phosphine oxides, producing the corresponding value-added alkynylphosphine oxides in good to excellent yields. This reaction could be easily conducted at gram scales (10 mmol) without any decrease of the reaction efficiency, showing highly potential synthetic value in organic synthesis. A plausible Pd(0)/Pd(II) mechanism is proposed. PMID- 28832157 TI - Reaction Discovery Using Neopentylene-Tethered Coupling Partners: Cycloisomerization/Oxidation of Electron-Deficient Dienynes. AB - A rhodium-catalyzed cycloisomerization and oxidation of tethered dienynes for the synthesis of indanes is described. An auxiliary fragmentation/olefination method (also described herein) provides novel access to tethered alkyne-dienoate substrates. The reported method circumvents current limitations in and expands the scope of inverse-demand Diels-Alder-type cycloadditions. Traditional discovery substrates involving malonate-, ether-, and sulfonamide-based tethers are problematic in the current methodology, underscoring the unique virtue of neopentylene-tethered substrates for reaction discovery. PMID- 28832159 TI - 3-Acylindoles Synthesis: Ruthenium-Catalyzed Carbonylative Coupling of Indoles and Aryl Iodides. AB - A novel and convenient procedure for the synthesis of 3-acylindoles from simple indoles and aryl iodides has been established. Through ruthenium-catalyzed carbonylative C-H functionalization of indoles, with Mo(CO)6 as the solid CO source, the desired indol-3-yl aryl ketones were isolated in moderate to good yields. Not only N-alkylindoles but also N-H indoles can be applied here. PMID- 28832160 TI - Phainanolide A, Highly Modified and Oxygenated Triterpenoid from Phyllanthus hainanensis. AB - Phainanolide A (1), a highly modified triterpenoid incorporating an unprecedented 6/9/6 heterotricyclic system and a highly oxygenated 5,5-spirocyclic ketal lactone, along with three new triterpenoids 2-4 were isolated from Phyllanthus hainanensis. Their structures were completely elucidated by a combination of diverse methods including 2D NMR, quantum chemical NMR and ECD calculations, and NMR data analogy with model compounds. Compounds 1-4 exhibited both remarkable cytotoxic and immunosuppressive activities. PMID- 28832161 TI - Synthesis of Silicon and Germanium-Containing Heterosumanenes via Rhodium Catalyzed Cyclodehydrogenation of Silicon/Germanium-Hydrogen and Carbon-Hydrogen Bonds. AB - A three-step synthesis of C3-symmetric trisilasumanene and trigermasumanene, heteroanalogues of the pi-bowl sumanene, was achieved using a threefold rhodium catalyzed cyclodehydrogenation of Si/Ge-H and C-H bonds as the key step. Trigermasumanene was proven to adopt a planar geometry by single crystal X-ray diffraction for the first time. The optical properties were also investigated by UV-vis and fluorescence spectroscopy. PMID- 28832158 TI - Strain-Mediated Interlayer Coupling Effects on the Excitonic Behaviors in an Epitaxially Grown MoS2/WS2 van der Waals Heterobilayer. AB - van der Waals heterostructures composed of two different monolayer crystals have recently attracted attention as a powerful and versatile platform for studying fundamental physics, as well as having great potential in future functional devices because of the diversity in the band alignments and the unique interlayer coupling that occurs at the heterojunction interface. However, despite these attractive features, a fundamental understanding of the underlying physics accounting for the effect of interlayer coupling on the interactions between electrons, photons, and phonons in the stacked heterobilayer is still lacking. Here, we demonstrate a detailed analysis of the strain-dependent excitonic behavior of an epitaxially grown MoS2/WS2 vertical heterostructure under uniaxial tensile and compressive strain that enables the interlayer interactions to be modulated along with the electronic band structure. We find that the strain modulated interlayer coupling directly affects the characteristic combined vibrational and excitonic properties of each monolayer in the heterobilayer. It is further revealed that the relative photoluminescence intensity ratio of WS2 to MoS2 in our heterobilayer increases monotonically with tensile strain and decreases with compressive strain. We attribute the strain-dependent emission behavior of the heterobilayer to the modulation of the band structure for each monolayer, which is dictated by the alterations in the band gap transitions. These findings present an important pathway toward designing heterostructures and flexible devices. PMID- 28832162 TI - Ruthenium-Catalyzed Synthesis of 2H-Azirines from Isoxazolinones. AB - 2H-Azirines are synthetically versatile, highly strained, three-membered heterocycles containing an imino double bond. We report their efficient Ru catalyzed synthesis using low catalyst loadings under neutral conditions from isoxazolinone substrates, which are readily accessible from beta-ketoesters. The azirines were shown to be efficient precursors for functionalized pyridine, indole, dihydropyrrole, and pyrrolidine heterocycles. PMID- 28832163 TI - Phosphinoyl Radical-Initiated alpha,beta-Aminophosphinoylation of Alkenes. AB - A new double functionalization reaction of alkenes through AgNO3-mediated phosphinoyl radical addition followed by Cu(II)-catalyzed amination is introduced. This one-pot, three-component reaction is performed under mild conditions to afford alpha,beta-aminophosphinoylation products. PMID- 28832165 TI - Iodine-Catalyzed Oxidative Coupling To Construct C-O Bonds for the Synthesis of 2,3-Dihydrooxepines. AB - The iodine-catalyzed catalytic formal [3 + 3 + 1] cycloaddition for the preparation of a seven-membered O-heterocyclic ring is presented, which is an achievement of methyl and carbonyl group reactivity of 3-methyl-5-pyrazolones to forge the Csp3-O bond. This novel protocol provides a straightforward and efficient access to structurally diverse fused O-heterocycles through an iodine catalyzed iodination/Kornblum oxidation/oxidative coupling/C-O bond formation cascade reaction. This approach demonstrates the unprecedented concurrent realization of the unique reactivity among the methyl, methylene, and carbonyl groups in 3-methyl-5-pyrazolones for the construction of 2,3-dihydrooxepine rings. Moreover, a broad substrate scope displays a graceful diversity-oriented synthetic approach. PMID- 28832164 TI - Tumor-Targeting Micelles Based on Linear-Dendritic PEG-PTX8 Conjugate for Triple Negative Breast Cancer Therapy. AB - Most small molecular chemotherapeutics have poor water solubility and unexpected pharmacokinetics and toxicity to normal tissues. A series of nano drug delivery systems have been developed to solve the problems, among which a micelle based on linear-dendritic polymer-drug conjugates (LDPDCs) is a promising strategy to deliver hydrophobic chemotherapeutics due to its small size, fine stability in blood circulation, and high drug loading capacity. In this work we synthesized a novel amphiphilic linear-dendritic PEG-PTX8 conjugate which can also encapsulate extra free PTX and self-assemble into uniform ultrasmall micelles with a hydrated diameter of 25.50 +/- 0.27 nm. To realize efficient drug delivery to tumor sites, a cyclic tumor homing and penetrating peptide iNGR was linked to the PEG-PTX8 conjugate. The biological evaluation was performed on a human triple negative breast cancer model. PTX accumulation in tumor at 24 h of the TNBC-bearing mice treated with iNGR-PEG-PTX8/PTX micelles was significantly enhanced (P < 0.001, two-way ANOVA) compared to that of Taxol and untargeted MeO-PEG-PTX8/PTX micelles. Furthermore, iNGR-PEG-PTX8/PTX micelles showed an obvious strong antitumor effect, and the median survival time of TNBC bearing mice treated with iNGR-modified micelles was significantly extended compared to Taxol. Therefore, this smart micelle system may be a favorable platform for effective TNBC therapy. PMID- 28832166 TI - Photoisomers of Azobenzene Star with a Flat Core: Theoretical Insights into Multiple States from DFT and MD Perspective. AB - This study focuses on comparing physical properties of photoisomers of an azobenzene star with benzene-1,3,5-tricarboxamide core. Three azobenzene arms of the molecule undergo a reversible trans-cis isomerization upon UV-vis light illumination giving rise to multiple states from the planar all-trans one, via two mixed states to the kinked all-cis isomer. Employing density functional theory, we characterize the structural and photophysical properties of each state indicating a role the planar core plays in the coupling between azobenzene chromophores. To characterize the light-triggered switching of solvophilicity/solvophobicity of the star, the difference in solvation free energy is calculated for the transfer of an azobenzene star from its gas phase to implicit or explicit solvents. For the latter case, classical all-atom molecular dynamics simulations of aqueous solutions of azobenzene star are performed employing the polymer consistent force field to shed light on the thermodynamics of explicit hydration as a function of the isomerization state and on the structuring of water around the star. From the analysis of two contributions to the free energy of hydration, the nonpolar van der Waals and the electrostatic terms, it is concluded that isomerization specificity largely determines the polarity of the molecule and the solute-solvent electrostatic interactions. This convertible hydrophilicity/hydrophobicity together with readjustable occupied volume and the surface area accessible to water, affects the self assembly/disassembly of the azobenzene star with a flat core triggered by light. PMID- 28832167 TI - Structured Ionomer Thin Films at Water Interface: Molecular Dynamics Simulation Insight. AB - Controlling the structure and dynamics of thin films of ionizable polymers at water interfaces is critical to their many applications. As the chemical diversity within one polymer is increased, controlling the structure and dynamics of the polymer, which is a key to their use, becomes a challenge. Here molecular dynamics simulations (MD) are used to obtain molecular insight into the structure and dynamics of thin films of one such macromolecule at the interface with water. The polymer consists of an ABCBA topology with randomly sulfonated polystyrene (C), tethered symmetrically to flexible poly(ethylene-r-propylene) blocks (B), and end-capped by a poly(t-butylstyrene) block (A). The compositions of the interfacial and bulk regions of thin films of the ABCBA polymers are followed as a function of exposure time to water. We find that interfacial rearrangements take place where buried ionic segments migrate toward the water interface. The hydrophobic blocks collapse and rearrange to minimize their exposure to water. The water that initially drives interfacial reengagements breaks the ionic clusters within the film, forming a dynamic hydrophilic internal network within the hydrophobic segments. PMID- 28832168 TI - Distinct Effects of Multivalent Macroion and Simple Ion on the Structure and Local Electric Environment of a Weak Polyelectrolyte in Aqueous Solution. AB - Adding ionic species can critically affect the structure of weak polyelectrolyte (PE) chains, whose charge density in aqueous solution can be greatly regulated by bathing solution conditions such as pH and added ions. Distinct from simple ions that can be treated as point charges, multivalent macroions of finite size, including many charged nanoparticles and biopolymers, could show strong electrostatic coupling with PEs and effectively modify the conformation and assembly of PEs in aqueous solution. In this work, we have compared the effects of hydrophilic multivalent macroion of finite size and simple divalent ion on the conformational transition of a model weak polybase, poly(2-vinylpyridine) (P2VP), in dilute aqueous solution. By using fluorescence correlation spectroscopy combined with photon counting histogram analysis, we have examined the swollen-to collapsed conformational transition and local electric potential of a P2VP chain in ionic aqueous solution at a single-molecule level. Adding inorganic polytungstate ([W12]) macroion bearing eight negative charges per [W12] of ~0.8 nm in diameter at increased concentration from 10-9 to 10-5 mM can lead to a shift of the critical conformational transition pH, pHcr, of P2VP to lower pH values, in an opposite trend to the previously reported effect of adding simple monovalent anion. Conversely, adding simple divalent sulfate anion can lead to a nonmonotonic change of pHcr when increasing its concentration from 0.03 to 15 mM. Additionally, at pH < pHcr where P2VP is highly protonated and adopts a swollen conformation, a monotonic decrease of P2VP size is observed with increased sulfate ionic concentration, exhibiting the typical ionic screening effect. In contrast, the size of the P2VP chain shows little change with increasing [W12] concentration before the precipitation of P2VP from water. To investigate the distinct effects of multivalent ion and macroion on the conformational transition of P2VP in aqueous solution, we have also measured the local proton concentration in the vicinity to a P2VP chain by an attached pH-sensitive fluorescence probe. In both cases, we have observed the monotonic reduction of the local electric potential of a swollen P2VP chain with increased ionic concentration, despite the increased protonation degree of P2VP. The results suggest that counterion condensation of multivalent ion and macroion can modify the effective net charge density of P2VP chains in dilute aqueous solution. However, possibly due to its high multivalency and finite size, multivalent [W12] macroion is much more effective in modifying the local electric environment and structure of P2VP chains at 3-7 orders of magnitude lower concentrations than simple sulfate counterion. PMID- 28832169 TI - Synthesis of Tribenzo[b,e,g]phosphindole Oxides via Radical Bicyclization Cascades of o-Arylalkynylanilines. AB - A new DTBP/Mg(NO3)2-mediated bicyclization cascade of o-arylalkynylanilines with secondary arylphosphine oxides has been developed, enabling dual C(sp2)-H functionalization along with the cleavage of the C-N bond. The combination between regioselective P-centered radical-triggered [3 + 2] cyclization and C centered radical-induced cross-coupling in a one-pot manner delivered 27 examples of tribenzo[b,e,g]phosphindole oxides with generally high regioselectivity. A reasonable mechanism for forming such products involving radical addition cyclization cascade is proposed. PMID- 28832170 TI - [Novel Findings in Follicular Lymphoma Pathogenesis and the Concepts of Targeted Therapy]. AB - The molecular pathogenesis of follicular lymphoma (FL) was partially revealed by the discovery of BCL2 translocations to the region encoding the immunoglobulin heavy chain, which accompany the vast majority of cases. This aberration leads to the ectopic and constitutive expression of anti-apoptotic BCL2 protein in B cells. Nevertheless, the aberration alone is not sufficient for FL development, which suggests necessity of further genetic aberrations acquisition for neoplastic transformation to FL. Their discovery has been enabled by recent progress in the field of massive parallel sequencing (next generation sequencing), which revealed high number of genetic aberrations connected with onset and progression of FL. The occurrence of many of these aberrations in the early stages of the disease, and the fact that they are shared by the majority of patients with FL, fundamentally changed our former understanding of the disease onset. Furthermore, in a large fraction of patients, FL undergoes histological transformation to a more aggressive lymphoma, which is also associated with specific genetic alterations. In this review, we summarize the current knowledge of molecular pathways connected with FL biology and discuss their role in the context of normal B-cell development. Understanding of FL biology is essential for the development of new targeted therapies and the stratification of patients, and potentially also for the selection of treatment for specific patients who share the same genetic aberrations.Key words: follicular lymphoma - mutation - aberration - apoptosis - epigenetic regulators - microRNA This research was carried out under the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustain ability Programme II. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 28. 1. 2017Accepted: 5. 3. 2017. PMID- 28832171 TI - [Confocal Laser Endomicroscopy in the Diagnostics of Malignancy of the Gastrointestinal Tract]. AB - In confocal laser endomicroscopy (CLE), a type of optical microscope that uses a laser beam as its light source and processes the acquired image by processor unit is used. Although the principle behind the device has been known since 1957, its use in clinical practice has only recently been enabled by technical developments, and it is therefore a relatively new modality in differential diagnosis. CLE enables real-time microscopic imaging of the tissue under investigation and in fact non-invasive in vivo biopsy. First experiences with CLE have primarily been obtained in the field of endoscopy, in particular in the pathology of the esophagus, stomach, bile duct, pancreas, and colon. Further to its use in endoscopy, CLE was recently developed for perioperative use, with the most experience gained in neurological, breast, and prostate surgery. Numerous prospective randomized trials have confirmed the benefits of CLE in tumor screening, differential diagnosis of tumors or inflammatory diseases, earlier diagnostics of diseases, and reducing the number of required endoscopic examinations. In addition, CLE is associated with minimal side effects. A known possible side effect is allergy to the fluorescein used to stain tissues during the examination. Extending of endoscopic examination or surgery is minimal in the hands of trained personnel. Current limiting factors of CLE include insufficient clinical experience, the price of the CLE device and probes, and the subjectivity inherent in the evaluation of microscopic images by the endoscopist or surgeon. This article summarizes published studies of CLE in the diagnostics of oncological diseases of the gastrointestinal tract.Key words: confocal microscopy - gastrointestinal tract - neoplasms The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 9. 2. 2017Accepted: 26. 2. 2017. PMID- 28832172 TI - [Metastatic Pituitary Disorders]. AB - BACKGROUND: Pituitary metastases are a rare complication of generalized cancer. Metastases to the pituitary gland occur in only 1% of patients operated on for sellar tumor. The most common presenting symptom in patients with pituitary metastases is diabetes insipidus, whereas this is rare in those with pituitary adenoma. MATERIAL AND METHODS: This publication presents the cases of two patients with pituitary metastases and a systematic review of the literature. English-language publications related to pituitary metastases and published from 1957 to 2016 were identified using the PubMed database. RESULTS: A total of 131 publications containing information about 259 patients (121 female and 138 male; mean age, 57.3 years) were identified. The most often metastasized breast carcinoma (24.6%) and lung carcinoma (23.8%), followed by thyroid carcinoma (11.3%), renal cell carcinoma (7.8%), hepatocellular carcinoma (4.3%), colorectal carcinoma (3.5%), and malignant melanoma (3.5%). The most frequent initial symptoms were manifestations of diabetes insipidus (39.6%), anterior pituitary deficiency (44.9%), perimeter disorders (51.6%), headache (37.6%), cranial nerve palsy (33.5%), and pseudoprolactinemia (16.7%). Radiotherapy (67.8%) and surgical treatment (63.9%) were the most frequently used treatment. CONCLUSION: The average survival time from the onset of metastatic disease was 11.8 months. Surgical therapy alone or in combination with radiation therapy does not prolong survival, but alleviates symptoms and improves quality of life.Key words: pituitary metastasis - diabetes insipidus - hypopituitarism - transsphenoidal surgery The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 13. 1. 2017Accepted: 4. 4. 2017. PMID- 28832173 TI - [Radiation Necrosis in the Upper Cervical Spinal Cord in a Patient Treated with Proton Therapy after Radical Resection of the Fourth Ventricle Ependymoma]. AB - BACKGROUND: Radiation necrosis in eloquent areas of the central nervous system (CNS) is one of the most serious forms of toxicity from radiation therapy. The occurrence of radiation necrosis in the CNS is described in a wide range of 3 months to 13 years after radiation therapy. The incidence of this complication covers a wide range of 3-47%. The potential advantage of proton therapy is the ability to reduce dose to normal tissue and escalate tumor dose. Proton beams enter and pass through the tissue with minimal dose deposition until they reach the end of their paths, where the peak of dose, known as the Bragg peak, occurs. Thereafter, a steep dose fall-off is evident. Such a precisely-distributed dose should reduce the toxicity of the treatment. PATIENT: A 23 year-old female patient underwent radical microsurgical resection of anaplastic ependymoma that originated from the floor of the fourth ventricle. The tumor was growing into the foramen magnum dorsally from the medulla oblongata. Taking into account the age of the patient, the localization of the tumor and the required dose of 60 Gy, proton therapy was chosen due to the lower risk of damage to the brain stem. Radiation therapy was performed using pencil beam scanning and one dorsal field. Following this course of treatment, radiation necrosis of the medulla oblongata and the upper cervical spinal cord occurred with fatal clinical impact on the patient. The article analyses possible causes of this complication and a review of the current literature is given. CONCLUSION: Despite the theoretical advantages of proton therapy, no clinical benefit in CNS tumors has yet been proven in comparison with modern methods of photon therapy. Proton therapy is accompanied by many uncertainties which can cause unpredictable complications, such as radiation necrosis at the edges of the target volume. Following proton therapy, there is not only a higher incidence of radiation necrosis but it occurs both sooner and to a higher degree. In cases of high anatomical complexity, the neurosurgeon should cooperate in the creation of the radiation treatment planning to ensure its optimization.Key words: brain tumors - ependymoma - radiation therapy - proton therapy - necrosis - radiation necrosis This work was partially supported by research project MH CZ - DRO (Faculty Hospital in Pilsen - FNPl, 00669806). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 29. 6. 2017Accepted: 25. 7. 2017. PMID- 28832174 TI - [Intensity Modulated Hyperfractionated Accelerated Radiotherapy to Treat Advanced Head and Neck Cancer - Predictive Factors of Overall Survival]. AB - AIM: The aim of this study was to evaluate overall survival (OS) and prognostic factors in patients ineligible for chemotherapy who were treated with a hyperfractionated accelerated schedule with simultaneous integrated boost. MATERIAL AND METHODS: From May, 2008, to April, 2013, 122 patients with locally advanced nonmetastatic squamous laryngeal (14%), hypopharyngeal (30%), oropharyngeal (30%), and oral cavity (27%) cancer were treated at our institution. The median age, Karnofsky Performance Status (KPS), and gross tumor volume (GTV) of the patients were 63 years (range, 46-87 years), 80% (range, 50 100%), and 46 ml (range, 5-250 ml), resp. The median total dose of radiotherapy was 72.6 Gy (range, 62-77 Gy) at 1.4-1.5 Gy per fraction, and 55 Gy at 1.1 Gy per fraction was delivered for GTV (primary and lymphadenopathy) with a margin of 0.7 cm and regional lymphatic areas with a margin of 0.3 cm. The dose was delivered 2* a day, with a 6-8 hour interval between doses, via a 6 MeV linear accelerator. OS was estimated using the Kaplan-Meier method, and predictors of OS were analyzed using Cox proportional hazards regression. RESULTS: The median duration of the radiotherapy series was 37 days (range, 32-45 days). The incidence of grade 3 acute toxicity was 62% for mucosa (oral cavity and/or pharynx) and 0% for skin. Confluent mucositis cleared in all cases within 21 days. No grade 4 or 5 toxicities were recorded. PEG was introduced before treatment in 55 patients (45%). The 1-and 2-year OS was 65% and 32%, resp. KPS less than 80% (RR 2.4, 95% CI 1.3-4.2; p = 0.004), cancers other than oropharyngeal or laryngeal cancer (RR 2.0, 95% CI 1.1-3.5; p = 0.016), and capacity of high GTV (RR 1.006, 95% CI 1.001 1.011; p = 0.017) were found to be negative prognostic factors for OS. CONCLUSION: More than 30% of patients with poor prognosis survived for longer than 2 years. KPS before treatment was the strongest prognostic factor for better OS.Key words: head and neck cancer - radiotherapy dose fractionation - survival analysis - acceleration - hyperfractionation This work was supported by RVO FNOs/2016 (HPV status as predictive and prognostic factor for primary and secondary head and neck cancer). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 9. 3. 2017Accepted: 19. 4. 2017. PMID- 28832175 TI - [Docetaxel-Cabazitaxel-Enzalutamide Versus Docetaxel-Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer]. AB - AIM: The aim of this retrospective study was to compare the efficacy of the sequence docetaxel-cabazitaxel-enzalutamide vs. docetaxel-enzalutamide in patients with metastatic castration-resistant prostate cancer. PATIENTS AND METHODS: Of the cohort of 35 patients, 11 were treated with the sequence docetaxel-cabazitaxel-enzalutamide and 24 were treated with the sequence docetaxel-enzalutamide. The doses were as follows: docetaxel, 75 mg/m2; cabazitaxel, 25 mg/m2; and enzalutamide, 160 mg/day. Overall survival (OS) was defined as the interval between the initial dose of docetaxel and death or the date of the last control for survivors (censored). OS was assessed using the Kaplan-Meier method, and the two arms were compared using the log-rank test. The significance level for all statistical tests was set at alpha = 0.05. RESULTS: The median OS of patients treated with the sequence docetaxel-cabazitaxel enzalutamide was 28.8 months, vs. 24.4 months in patients treated with the sequence docetaxel-enzalutamide. No statistically significance differences in OS were found between the two arms (HR 0.678, 95% CI 0.264-1.744; p = 0.418). Grade 3-4 toxicity was observed for each drug, as follows: docetaxel: fatigue and peripheral neuropathy in six patients, nausea in three patients, and diarrhea and neutropenia in one patient; cabazitaxel: anemia in two patients and neutropenia in one patient; and enzalutamide: anemia in six patients, thrombocytopenia in two patients, and cerebral hemorrhage in one patient. CONCLUSION: No statistically significant differences in OS were found between the sequences docetaxel cabazitaxel-enzalutamide and docetaxel-enzalutamide.Key words: prostate cancer - metastasis - chemotherapy - targeted hormonal treatment The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 13. 2. 2017Accepted: 20. 3. 2017. PMID- 28832176 TI - [Reactive Lymphoid Hyperplasia of the Liver]. AB - CASE: Here, we present the case of a 50-year-old woman diagnosed with stage I hormone-dependent breast cancer. The patient underwent partial mastectomy followed by adjuvant radiotherapy and hormone treatment with tamoxifen. Three years later, she presented with a solitary liver lesion on MRI, which was highly suspicious of malignancy. However, several fine needle biopsies were performed, and histopathological examination revealed no signs of neoplasia. As a result of these alarming discrepancies, the multidisciplinary board recommended a diag nostic laparotomy, which yielded a finding consistent with reactive lymphoid hyperplasia, a pseudolymphoma of the liver, on a background of incipient steatohepatitis. This rare condition is characterized by proliferation of non neoplastic lymphocytes in extranodular sites, and is usually an incidental finding on imaging modalities in clinically asymptomatic patients, predominantly women. Lesions share some radiologic features with primary malignant liver diseases such as hepatocellular carcinoma or cholangiocarcinoma. Although the etiology remains unclear, reactive lymphoid hyperplasia is believed to be associated with some malignancies, including breast cancer, or inflammatory and autoimmune disorders. Reactive lymphoid hyperplasia usually progresses slowly, with some cases of spontaneous regression described in the literature. To the best of our knowledge, only 50 cases of hepatic reactive lymphoid hyperplasia have been reported so far.Key words: pseudolymphoma - hyperplasia - liver - lymphatic tissue The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 20. 3. 2017Accepted: 10. 4. 2017. PMID- 28832177 TI - The Chest Wall Tumor as a Rare Clinical Presentation of Hepatocellular Carcinoma Metastasis. AB - BACKGROUND: Extrahepatic metastatic spread of hepatocellular carcinoma is present at the time of diagnosis in 5-15% of hepatocellular carcinoma patients. The most common site of metastastic spread is the lungs, bones, lymph nodes. Isolated chest wall localization is extremely rare. CASE: We report a 58-year-old patient with large, synchronous chest wall hepatocellular carcinoma metastasis with solitary primary hepatocellular carcinoma. He underwent a radical, surgical en bloc metastasectomy and subsequent anatomic liver resection. Removal of this metastasis further led to aggressive dissemination to different sites during the course of the disease and subsequently the patient was treated with antiangiogenic therapy and, after failure, with systemic chemotherapy. Combined multimodality treatment in this case led to overall survival of 22-months. We suggest that the initial huge presentation of chest wall metastasis and consecutive aggressive dissemination after surgical removal could be explained by the biological process called "tumor self-seeding" by circulating tumor cells. CONCLUSION: The chest wall hepatocellular carcinoma metastasis is a rare entity associated with poor prognosis. Radical surgical approach is limited to a minority of patients and may be justified for the treatment of extrahepatic metastases on a case by case basis.Key words: hepatocellular carcinoma - chest wall metastasis - metastasectomy - ciculating tumor cells. PMID- 28832178 TI - [Radiotherapy of Lung Tumours in Idiopathic Pulmonary Fibrosis]. AB - BACKGROUND: This article is a joint statement of the Czech Pneumological and Physiological Society and the Czech Society for Radiation Oncology, Biology and Physics, and reviews current opinions on radiotherapy in patients with idiopathic pulmonary fibrosis (IPF). In general, radiotherapy of lung tumours is associated with risk of radiation pneumonitis (RP); moreover, IPF may be complicated by acute exacerbations (AE-IPF). Both complications may immediately threaten patients lives. MATERIAL AND METHODS: Assessment of individual radiotherapy modalities has shown that conventional radiotherapy is not appropriate, especially in large tumours. Up to 30% of patients are at risk of developing AE IPF. As a result, as many as 83% of patients die within 3 months of initiation of lung cancer treatment. Fatal RP is most commonly observed within 2 months of radiotherapy. In IPF accompanied by early-stage non-small cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) may be considered. NSCLC should be treated with chemotherapy. Several cases report severe exacerbations of subclinical IPF after SBRT even with minimal signs of previous interstitial involvement. Grade 2 RP has been reported in up to 50% of cases with any level of interstitial change detected by lung CT prior to radiotherapy. In palliative radiotherapy, external radiation may be considered as an exception if the main bronchi are involved. Similarly, brachytherapy may be indicated for certain cases of bronchial stenosis. RESULTS: The presence of any level of interstitial change suggests a risk for fatal RP and AE-IPF. This is also supported by the fact that, at the present time, there are no dose limitations for radiation therapy of lung cancer in IPF, irrespective of whether conventional fractionated radiotherapy or SBRT is used. Moreover, there are no reliable predictive factors for lung involvement. In some studies, RP was more frequently associated with high CRP and LDH levels, PS 2 and interstitial changes of 10% or more. Treatment depends on the severity of the involvement. In more severe forms, corticosteroids, antibiotics and oxygen therapy should be administered. Ventilation support is often needed. CONCLUSION: Radiotherapy for patients with IPF and lung cancer or other chest tumours requires an individual approach depending on the local findings, the patients lung function and general condition, and the prognosis of the primary disease. Decision-making should take into consideration potential benefits and risks, and be carried out by a multidisciplinary team comprising a pulmonologist and clinical and radiation oncologists. Treatment should always be thoroughly discussed with the patient signing an informed consent form.Key words: idiopathic pulmonary fibrosis - chest radiotherapy - indications - radiation pneumonitis - acute exacerbation of idiopathic pulmonary fibrosis - treatment This work was supported by grant AZV 16-32-318 A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 4. 5. 2017Accepted: 18. 5. 2017. PMID- 28832179 TI - Self-care educational intervention to reduce hospitalisations in heart failure: A randomised controlled trial. AB - BACKGROUND: A variety of educational interventions have been implemented to assist patients with heart failure to maintain their own health, develop self care behaviours and decrease readmissions. AIMS: The purpose of this study was to determine the effectiveness of a multimedia educational intervention for patients with heart failure in reducing unplanned hospital readmissions. METHODS: The study, a randomised controlled trial in a large tertiary referral hospital in Australia, recruited 200 patients. Patients diagnosed with heart failure were randomly allocated 1:1 to usual education or a multimedia educational intervention. The multimedia approach began with an individual needs assessment to develop an educational plan. The educational intervention included viewing a DVD, and verbal discussion supported by a written manual with a teach-back evaluation strategy. The primary outcome was all-cause unplanned hospital readmission at 28 days, three months and 12 months post-recruitment. The secondary outcomes were changes in knowledge and self-care behaviours at three months and 12 months post-recruitment. RESULTS: At 12 months, data on 171 participants were analysed. There were 24 participants who had an unplanned hospital readmission in the intervention group compared to 44 participants in the control group ( p=0.005). The self-care educational intervention reduced the risk of readmission at 12 months by 30% (relative risk: 0.703; 95% confidence interval: 0.548-0.903). CONCLUSION: A targeted multimedia educational intervention can be effective in reducing all-cause unplanned readmissions for people with heart failure. PMID- 28832180 TI - Effect of POU5F1 Expression Level in Clonal Subpopulations of Bovine Fibroblasts Used as Nuclear Donors for Somatic Cell Nuclear Transfer. AB - Somatic cell nuclear transfer (SCNT) success is partially hindered by the low epigenetic reprogramming efficiency of the donor cell. Previous studies suggest cellular heterogeneity among donor nuclei in regard to reprogramming potential, which precludes comparison among different strategies to increase cloning success. In this context, we evaluated the effect of using clonal cell populations (CPs) of bovine adult fibroblasts established by single-cell plating in SCNT. Different CPs were evaluated in regard to proliferation rate, senescence level, and chromosome stability, as well as for POU5F1 (POU class 5 homeobox 1) mRNA expression levels. In total, 9 of 24 CPs (37.5%) were successfully expanded in vitro up to the fourth passage and shown to proliferate following cryopreservation, at which time cell analyses were performed. The use of a CP with low senescence level, normal karyotype, and highest POU5F1 expression levels did not improve embryo development rates or quality following SCNT. As previously suggested, this study supports the notion that levels of POU5F1 expression in the donor nucleus do not impact the SCNT results. Notably, the single-cell seeding approach used herein to isolate CPs may be extended to the evaluation of additional predictor markers of reprogrammability success for SCNT in future experiments. PMID- 28832181 TI - Treatment of Pediatric Acute-Onset Neuropsychiatric Disorder in a Large Survey Population. AB - OBJECTIVE: The goal of this study was to investigate treatment histories and outcomes in a large community sample of youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), and, where appropriate, to examine the impact of immune deficiency on treatment outcomes. METHODS: A comprehensive internet based survey was completed by parents or guardians of youth who had received physician diagnoses of PANS, or by young adults (age 18+) who had themselves been diagnosed by a physician (N = 698). Data regarding the treatment histories of these patients, including the variety of medical and psychological treatments employed and the caregiver- or self-reported response to each, are presented. RESULTS: The PANS patients in this study had commonly been treated with antibiotic (N = 675), anti-inflammatory (N = 437), and/or psychotropic therapy (N = 378). Response to antibiotic treatment was best when treatment was relatively aggressive, with broad-spectrum antibiotics and courses of >30 days generally producing the best results (i.e., up to 52% of patients achieving a "very effective" response). For immune-deficient patients (caregiver-reported laboratory studies below normal limits; N = 108), use of broad-spectrum antibiotics appeared to be particularly desirable. Anti-inflammatory therapies, including over-the-counter medications such as ibuprofen, were at least "somewhat effective" for most patients. Intravenous immunoglobulin (IVIG) had been used to treat PANS in 193 (28%) of the patients and was at least "somewhat effective" for 89%, although for 18% of these, the effect was not sustained. The highest rate of sustained response to IVIG treatment was seen in immune-deficient patients who received doses of at least 0.8 g/kg IVIG on a regular basis. Psychotropic medications, most commonly SSRIs (38% reported a trial), were commonly employed, but were often ineffective (e.g., 44% found SSRIs "somewhat" to "very effective"). Many patients (N = 473) had received some form of psychotherapy with some benefit, with cognitive behavioral therapy found to be at least somewhat effective in a majority of those treated with this modality. CONCLUSION: Among the PANS patients represented in this study, relatively aggressive treatment courses targeted at eradicating infection and modulating the inflammatory response appeared to provide the best caregiver-reported therapeutic results, and to be generally well tolerated. Given its relative efficacy and tolerability, treatment targeting the inflammatory response may represent an underutilized approach in this population. The results of this study should be considered in light of the limitations inherent in a self-selected and administered online survey. PMID- 28832182 TI - New Universal Nomenclature in Auriculotherapy. AB - OBJECTIVES: To propose at the auriculotherapists a New Universal Nomenclature of Auriculotherapy, able to receive any mapping whatsoever. DESIGN: We built this proposition by using electronic database search to find the different formulations of Auricular Acupuncture Points (AAPs), by studying neuroradiology methods describing reliable and reproducible marks able to adapt to all brain morphologies, by studying the analysis of brain dissections, showed us the internal organization of the brain; and after having proved the neurophysiological correlations between auricular displays and their brain correspondences. RESULTS: Since the 1950s, the study of Auriculotherapy by Paul Nogier and his students regularly progressed. The World Health Organization recognized it in 1987 and developed the First International Nomenclature in 1990. The number of therapeutic zones of the ear, in proportion to the constant progress in neurophysiology, never stops growing. This growth presents a major problem: all the first classifications became inappropriate and unfit. We propose a Universal Nomenclature of Auriculotherapy which is a biomathematical model of the brain anatomic organization, with 189 areas on the lateral ear and 89 areas on the medial ear. CONCLUSION: The Universal Auriculotherapy Nomenclature we proposed to the World Federation of Chinese Medicine Societies and which approved it at its International Convention in September 2011 in London, gives accurate Cartesian Marks and is able to receive any mapping whatsoever. Dispatching around 57 countries (Europe, America, China, Russia and Africa) and 195 Acupuncture Societies, it will facilitate the work of auriculotherapists and allow a scientific progress of the subject worldwide. This progress will allow the largest number of people to have a common tool for education, research, and publications of the discipline. PMID- 28832183 TI - Breastfeeding, Infant Formula, and Introduction to Complementary Foods-Comparing Data Obtained by Questionnaires and Health Visitors' Reports to Weekly Short Message Service Text Messages. AB - BACKGROUND: Studies on prevalence and effects of breastfeeding call for reliable and precise data collection to optimize infant nutrition, growth, and health. Data on breastfeeding and infant nutrition are at risk of, for example, recall bias or social desirability bias. OBJECTIVE: The aim of the present analysis was to compare data on infant nutrition, that is, breastfeeding, use of infant formula, and introduction to complementary foods, obtained by four different methods. We assumed that weekly short message service (SMS) questions were the most reliable method, to which the other methods were compared. DESIGN: The study population was part of the Odense Child Cohort. The four methods used were: (a) self-administered questionnaire 3 months postpartum, (b) self-administered questionnaire 18 months postpartum, (c) registrations from health visitors visiting the families several times within the first year of life, and (d) weekly SMS questions introduced shortly after birth. RESULTS: In total, 639 singleton mothers with data from all four methods were included. The proportion of mothers initiating breastfeeding varied from 86% to 97%, the mean duration of exclusive breastfeeding from 12 to 19 weeks, and the mean age when introduced to complementary foods from 19 to 21 weeks. The mean duration of any breastfeeding was 33 weeks across methods. CONCLUSIONS: Compared with the weekly SMS questions, the self-administered questionnaires and the health visitors' reports resulted in a greater proportion of mothers with an unknown breastfeeding status, a longer duration of exclusive breastfeeding and later introduction to complementary foods, while the duration of any breastfeeding did not differ. PMID- 28832184 TI - Type 1 Diabetes at High Altitude: Performance of Personal Insulin Pumps and Patient Metabolic Control. AB - High-altitude trekking can expose people to extreme environmental conditions, like low temperatures and hypobaric hypoxia. Such extreme conditions make it more difficult for people with type 1 diabetes mellitus (T1DM) to maintain glycemic control. Intensive blood glucose monitoring using either glucose meters or continuous systems is imperative in these cases. In this observational study, we report metabolic control of T1DM patients and the performance of various insulin pumps at high altitude. All 19 patients with T1DM included in this study participated in the final step of the "5000 meters above sugar level" initiative, which involved trekking Damavand Mountain to an altitude of 5670 meters above sea level. We found that all pump models worked well without any disruption and no cases of diabetes decompensation or severe hypoglycemia occurred. Therefore, healthy, physically fit, and experienced individuals with T1DM should not be discouraged from participating in mountain trekking activities, as modern personal insulin pumps work well at high altitudes. PMID- 28832186 TI - The need for sex-specific precision biomarkers for antiplatelet therapies. PMID- 28832185 TI - Long Noncoding RNA HOXA11-AS Functions as miRNA Sponge to Promote the Glioma Tumorigenesis Through Targeting miR-140-5p. AB - Long noncoding RNAs (lncRNAs) have been proved as important regulators in many diseases, including cancers. HOXA11 antisense RNA (HOXA11-AS) is a novel identified lncRNA associated with cancer progression. However, the role of HOXA11 AS in glioma remains poorly understood and needs to be elucidated. The purpose of this study is to investigate the role and regulating mechanism of HOXA11-AS on gliomagenesis. Expression of HOXA11-AS was significantly upregulated in glioma tissue and cell lines compared with the adjacent normal tissue and cells. Moreover, patients with high HOXA11-AS expression had a shorter survival and poorer prognosis than that of lower expression. Loss-of-function experiments revealed that HOXA11-AS knockdown inhibited the proliferation, induced cell cycle arrest at G0/G1 phase, and enhanced the apoptosis. Bioinformatics prediction forecast that miR-140-5p directly targeted HOXA11-AS at 3'-UTR, which was confirmed by luciferase reporter assay. In vitro rescue experiment assays, miR 140-5p inhibitor transfection, could reverse the function of HOXA11-AS knockdown on the proliferation, cell cycle arrest, and apoptosis. Taken together, the present study illustrates that the pathway of HOXA11-AS sponging miR-140-5p might play a vital regulating role in the development and progression of glioma. PMID- 28832187 TI - Race and atrial flutter: a needed update to understand the atrial fibrillation race paradox. PMID- 28832188 TI - Dual/multitargeted xanthone derivatives for Alzheimer's disease: where do we stand? AB - To date, the current therapy for Alzheimer's disease (AD) based on acetylcholinesterase inhibitors is only symptomatic, being its efficacy limited. Hence, the recent research has been focused in the development of different pharmacological approaches. Here we discuss the potential of xanthone derivatives as new anti-Alzheimer agents. The interference of xanthone derivatives with acetylcholinesterase and other molecular targets and cellular mechanisms associated with AD have been recently systematically reported. Therefore, we report xanthones with anticholinesterase, monoamine oxidase and amyloid beta aggregation inhibitory activities as well as antioxidant properties, emphasizing xanthone derivatives with dual/multitarget activity as potential agents to treat AD. We also propose the structural features for these activities that may guide the design of new, more effective xanthone derivatives. [Formula: see text]. PMID- 28832189 TI - The Association Between XPG Gene Polymorphism and Gastric Cancer Risk. AB - PURPOSE: Studies exploring the association between the Xeroderma pigmentosum group G (XPG) gene polymorphisms and gastric cancer (GC) risk provide conflicting findings. Thus, this meta-analysis was performed. MATERIALS AND METHODS: The PubMed and EMBASE databases were comprehensively searched to identify studies for the inclusion in the meta-analysis. The strength of the association was evaluated by calculating pooled odds ratios and 95% confidence intervals. RESULTS: Nine case-control studies involving 3540 cases and 3953 controls were included in the meta-analysis, which revealed that the XPG rs751402 polymorphism is positively associated with GC risk and could be viewed as a risk factor of GC in three genetic models. CONCLUSION: The XPG gene rs751402 polymorphism is associated with an increased risk of GC in Chinese Han populations. This finding should be verified by larger studies that include additional ethnic groups. PMID- 28832190 TI - Corrigendum. PMID- 28832191 TI - If there were a vaccine against acute myocardial infarction, would you use it? PMID- 28832192 TI - Trends in the Surgical Treatment for Cubital Tunnel Syndrome: A Survey of Members of the American Society for Surgery of the Hand. AB - BACKGROUND: Cubital tunnel syndrome is the second most common compression neuropathy affecting the upper extremity. The aim of this study was to determine the preferred surgical treatment for cubital tunnel syndrome by members of the American Society for Surgery of the Hand (ASSH). METHODS: We invited members of the ASSH research mailing list to complete our online survey. They were presented with 6 hypothetical cases and asked to choose their preferred treatment from the following options: open in situ decompression, endoscopic decompression, submuscular transposition, subcutaneous transposition, medial epicondylectomy, and conservative management. This was assessed independently and anonymously through an online survey (SurveyMonkey). RESULTS: 1069 responses were received. Seventy-three percent of the respondents preferred to continue conservative management when a patient presented with occasional paresthesias for greater than 6 months with a normal electromyogram (EMG) or nerve conduction velocity (NCV). Sixty-five percent picked open in situ decompression if paresthesias, weakness of intrinsics, and EMG/NCV reports of mild to moderate ulnar nerve entrapment was present. More than 50% of respondents picked open in situ decompression, as their preferred treatment when sensory loss of two-point discrimination of less than 5 or more than 10 was present in addition to the findings mentioned above. Seventy nine percent of the respondents said their treatment algorithm would change if ulnar nerve subluxation was present. CONCLUSIONS: Our survey results indicate that open in situ decompression is the preferred operative procedure, if there is no ulnar nerve subluxation, among hand surgeons for cubital tunnel syndrome. PMID- 28832193 TI - Salicylic acid derivatives and phenylspirodrimanes from the sponge-associated fungus Hansfordia sinuosae. AB - Three new salicylic acid derivatives (1-3) and a known one, 6-(3'-hydroxypropyl) 2-hydroxybenzoic acid (4), together with seven known phenylspirodrimanes (5-11), were isolated from the sponge-associated fungus Hansfordia sinuosae, collected from the South China Sea. HRESIMS, FT-IR Spectroscopy, and NMR techniques including COSY, HSQC, and HMBC were used to elucidate the structures of these compounds. The inhibitory effects of the isolated compounds (1-11) against HIV-1 virus were evaluated, and most of the phenylspirodrimanes (5, 8-11) showed varying degrees of anti-HIV activity. PMID- 28832194 TI - The role of cardiovascular ultrasound in diagnosis and management of pulmonary embolism. AB - The diagnosis of acute pulmonary embolism (PE) is one of the most important problems in medical emergencies. Commonly accepted criterion for diagnosis of deep venous thrombosis is the lack of vein compressibility assessed by Compression UltraSonography. Echocardiography represents an easily available and reliable imaging technique in the clinical setting of hemodynamic instability and in the direct visualization of thromboembolic masses in the right heart chambers. Moreover, echocardiography is useful for prognostic stratification after acute PE as right ventricular dysfunction is the most important predictor of mortality in this context. This review aims to highlight usefulness, potentialities and perspectives of standard and advanced echocardiography in evaluating patients affected by PE. PMID- 28832195 TI - Update on the significance of postprocedural aortic regurgitation after transcatheter aortic valve replacement on postprocedural prognosis. AB - Transcatheter aortic valve replacement (TAVR) is an established therapy for patients with aortic stenosis and a high surgical risk. Recent data on intermediate-risk patients will probably enlarge the indication for TAVR. In the beginning of the TAVR era, relevant (>mild) aortic regurgitation (AR) was a common finding after TAVR; it was associated with worse outcome compared with patients without significant AR. To date, several improvements in imaging, grading of severity and treatment have been done and will be discussed in this article. AR after TAVR still is a strong and independent predictor of 1-year mortality and every effort should be made to prohibit its development. PMID- 28832196 TI - Salvage of Failed Achilles Tendon Interposition Arthroplasty for DRUJ Instability After Ulnar Head Resection With Aptis Prosthesis. AB - BACKGROUND: Historically, failed conservative treatment for irreparably damaged distal radioulnar joints (DRUJs) is treated via distal ulnar resection or DRUJ fusion; complications include disabling painful convergence of the radius and ulnar stump during lifting Various treatments for radioulnar impingement include distal radioulnar Achilles tendon allograft interpositional arthroplasty. This technique does not adequately prevent radioulnar impingement and we explore an alternative treatment. METHODS: We report 7 adult patients who failed Achilles tendon interposition, subsequently treated with Aptis total DRUJ prostheses (mean follow-up, 26 months; range, 7-40). RESULTS: Revision to Aptis prosthesis produced clinically stable DRUJ, improved grip strength and painless lifting capabilities, high patient satisfaction, and no major complications. All returned to daily activities and even recreational sports. CONCLUSIONS: Tendon lacks biomechanical features key to the shock-absorbing function of cartilage-features it cannot deliver when used to prevent radioulnar convergence. We report Aptis DRUJ prosthesis as an alternative to the tendon allograft technique. PMID- 28832198 TI - Joint Space Narrowing in Patients With Pisotriquetral Osteoarthritis. AB - BACKGROUND: Patients with suspected pisotriquetral osteoarthritis may show joint space narrowing. However, the extent of joint space narrowing and its deviation from the joint space width (JSW) in normal anatomy is unknown. In this pathoanatomic study, we therefore compared the JSW in the pisotriquetral joint between osteoarthritic patient wrists and healthy wrists. METHODS: We reviewed preoperative computed tomography (CT) scans of 8 wrists of patients with ulnar sided wrist pain who underwent a pisiformectomy with confirmed pisotriquetral osteoarthritis at surgery. We also reviewed CT scans of 20 normal wrists from healthy volunteers serving as control group. Three-dimensional CT models of the pisiform and triquetrum were obtained from both affected and normal wrists, after which the minimum JSW was calculated in an automated fashion. RESULTS: In the patient group, the median (interquartile range) of the minimum JSW was 0.1 mm (0.0-0.2), and in the control group, 0.8 mm (0.3-0.9) ( P = .007). CONCLUSIONS: We showed that the pisotriquetral joint space in osteoarthritic patient wrists was significantly narrowed compared with healthy wrists. These results suggest that JSW evaluation has a potential diagnostic value in the work-up of patients with suspected pisotriquetral osteoarthritis. This is an interesting area for future clinical research, especially because no gold standard for diagnosing pisotriquetral osteoarthritis has been established yet. PMID- 28832197 TI - Does a Comparison View Improve the Reliability of Staging Wrist Osteoarthritis? AB - BACKGROUND: Radiological grading of wrist osteoarthritis associated with scaphoid nonunion advanced collapse (SNAC) can be difficult. A comparison radiograph of the contralateral healthy wrist and an educational training in the various SNAC stages may improve reliability. Our purposes were to evaluate the difference in the reliability: (1) between observers who rate SNAC wrists with and without a comparison radiograph; and (2) between observers who receive training prior to ratings and those who do not. METHODS: In this cross-sectional survey study, 82 fully trained orthopedic or hand surgeons rated anteroposterior radiographs of 19 patient wrists following a scaphoid nonunion based on SNAC stages 0 to 4. Observers were randomized online in 4 groups: one group rated unilateral views without training, a second group unilateral views with training, a third group bilateral views without training, and a fourth group bilateral views with training. Training included a 1-page clarification of the SNAC stages. Interobserver agreement was calculated using kappa statistics. RESULTS: There was no significant difference between agreement between observers who rated unilateral radiographs (kappa = 0.55) and who rated bilateral radiographs (kappa = 0.58) ( P = .14), nor between agreement between observers who received training (kappa = 0.59) and who did not (kappa = 0.54) ( P = .058). CONCLUSIONS: The use of an additional comparison view and/or training does not seem to be clinically relevant in SNAC staging. There is room for improvement in the way we assess patients with SNAC wrists. PMID- 28832199 TI - Acute Calcific Tendinitis of the Index Finger in a Child. AB - BACKGROUND: Calcific tendinitis is characterized by calcium hydroxyapatite crystal deposition within tendons and is a common cause of musculoskeletal pain in adults. Its clinical manifestations may be acute, chronic, or asymptomatic. Acute calcific tendinitis is self-resolving condition that is rarely reported in the pediatric population and may be overlooked for more common processes, leading to unnecessary treatment. METHODS: A chart reivew was performed of a single case of acute calcific tendonitis of the index finger in a child. RESULTS: We describe a case of calcific tendinitis of the index finger in a 9-year-old boy who was referred to us for a second opinion after surgical exploration of an acutely inflamed digit was recommended based on his initial presentation. The calcifications and symptoms resolved over time without operative management. CONCLUSIONS: Although rare in children, acute calcific tendinitis can present similar to an infection. However, appropriate managment is non-operative as the symptoms and radiographic findings resolve over time. PMID- 28832200 TI - Use of Particulated Juvenile Articular Cartilage Allograft for Osteochondral Lesions of the Wrist. AB - BACKGROUND: Articular cartilage injuries are a common injury among young, active patients, and the most appropriate treatment for these injuries remains controversial. A promising new technology in the treatment of high-grade cartilage injuries is particulated juvenile articular cartilage (PJAC) allograft (DeNovo NT, Zimmer, Warsaw, Indiana). This has been shown to be successful in multiple joints including the knee, talus, and elbow. No studies or case reports exist in supporting or discouraging its use in injuries of the wrist, in specific, the scaphoid. METHODS: The use of PJAC allograft is described for the treatment of an active 21-year-old male with an Outerbridge Grade IV chondral lesion on the proximal pole of his right scaphoid and right distal radius scaphoid facet who had failed conservative management. The patient was followed clinically and radiographically for 21 months. RESULTS: The patient had return to full sport (jujutsu) and full range-of-motion, both of which represented an improvement from his preoperative exam. Radiographically, the chondral lucency seen had decreased in size and was almost completely absent on radiographs after 21 months. CONCLUSIONS: The results of this case suggest that PJAC can be used safely and effectively in the wrist thereby potentially broadening the indications for its use. PMID- 28832201 TI - Coronal Hamate Fracture Associated With Carpometacarpal Dislocations of All of the Fingers: Review of the Literature and Case Report. AB - BACKGROUND: Dislocation of all 5 carpometacarpal (CMC) joints of a single hand is a rare injury. METHODS: The literature regarding CMC fracture-dislocations was reviewed and a case was presented. RESULTS: The relevant literature was consolidated to clinically relevant categories including 'Clinical Presentation and Diagnosis,' 'Management of CMC Fracture Dislocation and Hamate Fractures,' and 'Outcomes.' CONCLUSIONS: The mechanism associated with this injury is often high energy that causes multiple simultaneous life- or limb-threatening injuries that could distract the examiner from identifying this injury. The case we present involves an axial dislocation of the carpus that resulted in dorsal dislocations of all CMC joints, dislocation of the hamate-capitate articulation, as well as fractures of the first metacarpal and the hamate. PMID- 28832202 TI - Radial Plate Fixation: A Novel Technique for Distal Radius Fractures. AB - BACKGROUND: Distal radius fractures represent a common fracture pattern frequently treated with volar locked plating for fixation. However, other methods may provide equivalent outcomes and minimize risks associated with the volar approach and hardware placement. One such method is the radial plate. METHODS: After confirmation of institutional board review, we retrospectively reviewed data from 7 patients with our primary functional outcomes measured by Mayo wrist and Disabilities of the Arm, Shoulder and Hand (QuickDASH) scores. The most recent radiographic and motion parameters were recorded. RESULTS: Mean age at time of injury was 49 years (range, 19-68 years) with clinical follow-up of 81.6 months (range, 43.5-95.5 months). Five patients had good to excellent outcomes with a mean QuickDASH score of 0.92 for those patients. The mean QuickDASH score for all patients was 18.5. Mean radial height, inclination, and volar tilt were within 5% of the contralateral side. Standard deviation values for radiographic measures and clinical range of motion indicate significant variability in our data set. CONCLUSIONS: Although the results are mixed, our small cohort indicates radial plate fixation could provide a viable alternative to volar plate fixation of distal radius fractures. Further prospective investigation is warranted to better describe long-term outcomes using this technique. PMID- 28832203 TI - The Fourth Extensor Compartment Artery Vascularized Bone Graft of the Distal Radius for CMC Fusion in the Treatment of Carpal Boss: A Case Report. AB - BACKGROUND: Carpometacarpal joints can be affected by traumatic or degenerative pathology. Although different techniques have been described to treat these conditions, most authors agree that arthrodesis is an effective treatment modality. Vascularized bone grafts of the distal radius have been used to treat carpal conditions, such as scaphoid nonunion or Kienbock disease, and they have been shown to have several advantages over nonvascularized bone grafts. METHODS: We report a case of a carpal boss in a female patient treated with an arthrodesis of the second and third carpometacarpal joints by using the fourth extensor compartment artery vascularized bone graft. RESULTS: At 6 weeks postoperative bone union was achieved. At 2 years follow-up the patient was able to perform daily life activities without pain. CONCLUSIONS: The fourth ECA VBG with reverse blood flow from the dorsal intercarpal arch allowed the graft to reach the CMC. A solid fusion was obtained at 6 weeks due to the biological advantage of the VBG. PMID- 28832204 TI - Wrong-Bone Excision in Hand Surgery. AB - BACKGROUND: The incidence of wrong-bone excision in hand surgery is not known. The wrist offers a unique challenge in that a single surgical incision yields access to multiple potential surgical sites, thus rendering site marking less effective. Mistaken identification of structures in the wrist is a real and potentially troublesome phenomenon. This study is designed to evaluate the occurrence of wrong-bone excision and to identify any risk factors and preventative measures that may help to prevent this complication in the future. METHODS: We designed an anonymous online survey to determine the occurrence, risk factors, medicolegal outcomes, and preventative measures of wrong-bone excision. We distributed the survey to 777 hand surgeons via email. RESULTS: Ninety-nine surgeons responded to our survey. Twenty-three respondents had participated in an excision of the incorrect bone in the wrist. The most common error was partial or complete excision of the scaphoid during a planned excision of the trapezium. Respondents indicated that inadequate visualization, inadequate localization, and teaching of a resident or fellow contributed to the error. There was only 1 case of legal action. CONCLUSIONS: The results of our survey indicate that there exists a non-zero incidence of wrong-bone excision in hand surgery. The most common mistake is incorrect excision of the scaphoid during a planned trapeziectomy. Most surgeons feel that their patients were pleased with their outcome despite this complication, and legal action is rare. Deliberate identification of known landmarks was identified as the most useful strategy in preventing wrong-bone excision. PMID- 28832205 TI - Endoscopic Fascia Release for Forearm Chronic Exertional Compartment Syndrome: Case Report and Surgical Technique. AB - BACKGROUND: Chronic exertional compartment syndrome (CECS) of the forearm is traditionally treated with open compartment release requiring large incisions that can result in less than optimal esthetic results. The purpose of this study is to describe a case report of 2 professional motocross patients with forearm CECS treated endoscopically using a minimally invasive technique. METHODS: Two professional motocross racers presented with a history of chronic proximal volar forearm pain when motocross riding. Other symptoms included paresthesia and weakness, which, at times, led to an inability to continue riding. Both failed conservative management. Compartment pressure measurements were performed before and after provocative exercises to confirm diagnosis of CECS. Release of both the volar and dorsal compartments was performed endoscopically through a single incision. RESULTS: Symptoms resolved after surgery. The first patient resumed riding at 1 week, competing at 3 weeks, and continues to ride competitively without symptoms at 3 years postoperative. The second patient began riding at 1 week and won second place in the National Supercross finals 5 weeks after simultaneous bilateral release. CONCLUSIONS: This technique is simple and effective. The cannula used protects the superficial nerves while allowing release through a small, cosmetically pleasing incision. PMID- 28832206 TI - Closed Partial Flexor Digitorum Profundus Rupture: An Unusual Cause of Pediatric Trigger Finger. AB - BACKGROUND: Trigger finger is a common condition, causing impaired gliding of the digital flexor tendons. Chronic inflammation is the usual cause, but acute trigger finger following partial tendon laceration has also been described. METHODS: We describe the case of a four year old girl who presented with inability to flex her index finger. Operative exploration revealed a closed partial rupture of the flexor digitorum profundus tendon, catching on the A2 pulley and preventing normal tendon gliding. RESULTS: Excision of the damaged section of tendon allowed normal gliding motion, and once the wound had healed the patient regained full painless motion. CONCLUSION: Acute trigger finger caused by partial flexor tendon injury is an uncommon but well-documented presentation. Surgical exploration not only confirms the diagnosis, but allows for excision of the damaged segment to return normal movement without compromising strength. PMID- 28832207 TI - Predictors of Nerve Injury After Gunshot Wounds to the Upper Extremity. AB - BACKGROUND: The purpose of this study is to examine the incidence of nerve injury, clinical variables associated with nerve palsy, and predictive factors of nerve laceration after gunshot wounds to the upper extremity. METHODS: Forty-one patients from a level I trauma center with gunshot wounds to the upper extremity who underwent surgical exploration between 2007 and 2014 were identified retrospectively. Patients with proximal ipsilateral injuries, inadequate documentation, imaging, or with a pre-existing neurologic deficit were excluded. Patient demographics, clinical sensory and motor examination, the presence of retained bullet fragments, fracture, vascular injury, and compartment syndrome were recorded. Univariate analysis was performed to determine significant predictors of intraoperative nerve laceration. Significance was set at P < .05. RESULTS: Fifty-nine nerves were explored in 41 patients. There were higher frequencies of fractures, retained fragments, vascular injury, and compartment syndrome in patients with nerve palsies, although none were associated with nerve laceration. Patients with palsies on presentation were significantly more likely to have a nerve laceration found intraoperatively. CONCLUSIONS: Gunshot wounds to the upper extremity with focal nerve deficits remain a difficult problem for orthopedic surgeons. The present study provides evidence that may help guide operative decision making in treatment of these injuries. PMID- 28832208 TI - Aneurysmal Bone Cyst Involving the Pisiform: A Case Report. AB - BACKGROUND: Aneurysmal bone cysts are an uncommon form of benign primary bone tumors; affection of the hand is very rare. METHODS: A rigorous review of the literature showed that this type of tumor has not previously been described in the pisiform. In this article, we report the occurrence of an aneurysmal bone tumor in the pisiform of the left hand of a 19-year-old male. RESULTS: This tumor was successfully treated through surgical excision with an uneventful recovery. We describe the process behind the diagnosis of the lesion and the subsequent treatment in an attempt to highlight the rare but possible occurrence of aneurysmal bone cysts in the pisiform. CONCLUSION: Appropriate treatment of aneurysmal bone cysts in this location is required, due to the anatomical nature of the pisiform itself with the risks of pathologic fracture and ulnar nerve compression. PMID- 28832209 TI - Triceps Tendon Ruptures: A Systematic Review. AB - BACKGROUND: Triceps tendon ruptures (TTR) are an uncommon injury. The aim of this systematic review was to classify diagnostic signs, report outcomes and rerupture rates, and identify potential predisposing risk factors in all reported cases of surgical treated TTR. METHODS: A literature search collecting surgical treated cases of TTR was performed, identifying 175 articles, 40 of which met inclusion criteria, accounting for 262 patients. Data were pooled and analyzed focusing on medical comorbidities, presence of a fleck fracture on the preoperative lateral elbow x-ray film (Dunn-Kusnezov Sign [DKS]), outcomes, and rerupture rates. RESULTS: The average age of injury was 45.6 years. The average time from injury to day of surgery was 24 days while 10 patients had a delay in diagnosis of more than 1 month. Renal disease (10%) and anabolic steroid use (7%) were the 2 most common medical comorbidities. The DKS was present in 61% to 88% of cases on the lateral x-ray film. Postoperatively, 89% of patients returned to preinjury level of activity, and there was a 6% rerupture rate at an average follow-up of 34.6 months. The vast majority (81%) of the patients in this review underwent repair via suture fixation. CONCLUSIONS: TTR is an uncommon injury. Risks factors for rupture include renal disease and anabolic steroid use. Lateral elbow radiographs should be scrutinized for the DKS in patients with extension weakness. Outcomes are excellent following repair, and rates of rerupture are low. PMID- 28832210 TI - QuickDASH Score Is Associated With Treatment Choice in Patients With Trapeziometacarpal Arthrosis. AB - BACKGROUND: Trapeziometacarpal (TMC) arthrosis has a variety of treatment options, including nonoperative (eg, education, splint, injection) and operative management. Symptoms and limitations vary greatly among patients. The purpose of this study was to determine an association of symptoms and limitations, quantified using the Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, with treatment choice in patients newly diagnosed with TMC arthrosis. We also addressed the association of the QuickDASH score with radiographic severity and sought factors associated with higher QuickDASH scores. METHODS: As part of the routine new patient intake paperwork, all new patients completed a QuickDASH form. We included 81 new patients with newly diagnosed TMC arthrosis visiting the office of 1 of 5 orthopedic hand surgeons between March 1, 2015, and November 30, 2015. Eight patients were excluded because of incomplete QuickDASH forms. RESULTS: Based on QuickDASH tertiles, patients with a low QuickDASH score were more likely to choose education alone than patients with intermediate and high QuickDASH scores; no patients in the lowest QuickDASH tertile chose injection or surgery. Patients who chose education alone also had a lower mean QuickDASH score than patients who chose splint or surgery. Radiographic severity and other patient-related factors were not associated with greater symptoms and limitations. CONCLUSIONS: More adaptive patients (lower QuickDASH) are less likely to choose injection or surgery, irrespective of disease severity. The psychosocial factors known to correlate with greater symptoms and limitations might lead patients to feel they have fewer options or to choose more interventional options than they would if they were more at ease. In other words, inadequate attention to psychosocial factors may increase the risk of misdiagnosis of patient preferences. PMID- 28832211 TI - Ischemic Hand Complications From Intra-Arterial Injection of Sublingual Buprenorphine/Naloxone Among Patients With Opioid Dependency. AB - BACKGROUND: Sublingual buprenorphine/naloxone, a common treatment for opioid dependence, is frequently abused by intravenous injection. Inadvertent intra arterial injection of buprenorphine/naloxone can produce acute ischemic insult to the hand due to gelatin embolism. Our purpose was to review a series of these patients in order to describe the clinical entity, review the outcomes, and propose a rational treatment algorithm. METHODS: Clinical records of all patients evaluated by the hand surgery team between 2011 and 2015 for ischemia of the hand after buprenorphine/naloxone injection were reviewed. Treatment, complications, and amount of tissue loss were recorded. Patients presenting within 48 hours of the injection were treated with intravenous heparin for 5 days, followed by oral aspirin and clopidogrel for 30 days. Those presenting after 48 hours were treated with aspirin and clopidogrel only. RESULTS: Ten patients presented during the review period. Average follow-up time was 13 weeks. Eight had ischemia of the radial side of the hand, 1 of the ulnar side, and 1 had bilateral ischemia. Three patients were treated with intravenous heparin and 5 with oral agents. Two presented with dry gangrene and did not receive anticoagulation. All patients experienced tissue loss. There was no difference in outcome regardless of treatment. CONCLUSIONS: With the increasing use of sublingual buprenorphine/naloxone in opioid dependency, ischemic hand injuries will be seen with greater frequency. Whereas outcomes did not vary with treatment modality in this series, further study is needed to determine the most effective treatment of these injuries. PMID- 28832212 TI - What Factors Influence the Outcome of Surgically Treated Soft Tissue Sarcomas of the Hand and Wrist? AB - BACKGROUND: Soft tissue sarcomas (STS) of the hand are exceedingly rare. The aim of this study was to review our institution's experience with STS of the hand to identify factors affecting outcomes and survivorship. METHODS: We retrospectively reviewed the records of 46 hand STS treated with definitive surgery at our institution between 1992 and 2013. Pertinent demographics as well as information regarding the surgical procedure, and disease status at latest follow-up were reviewed. Mean age at diagnosis was 38 years with a mean follow-up of 5 years. RESULTS: The most common tumor subtypes were epithelioid (n = 10) and synovial sarcoma (n = 8). Sixty-one percent were superficial in location. Thirty-three patients had had a nononcologic resection prior to definitive surgical treatment at our institution. Ultimately, negative margins were obtained in all cases. Local recurrence was observed in 5 patients and distant metastases in 14 patients. Tumor sizes >=2 cm, American Joint Committee on Cancer (AJCC) grade, and depth of the tumor were found to adversely affect the outcome in terms of disease-free and overall survival. Reexcision of an inadvertently excised tumor at an outside institution did not adversely affect the outcome. The 10-year overall and disease-free survival was 72% and 63%. CONCLUSIONS: Local recurrence after a wide excision was observed infrequently; however, distant disease was relatively common. Tumors with a size >=2 cm were associated with a worse disease free and overall survival, highlighting the aggressive nature of these tumors. PMID- 28832213 TI - Combined Perihamate Peripisiform and Peritrapezium Open Axial Carpal Dislocation: Description of a New Pattern of Crush Injury. AB - BACKGROUND: Axial carpal dislocations and fracture-dislocations remain difficult to understand and to treat. The outcome is directly related to the injury pattern and long-term results are not good in most cases. METHODS: 39-year-old male admitted to our emergency department after his left hand was caught between 2 rollers for 10 minutes. He was diagnosed of an open axial carpal dislocation type B (perihamate peripisiform) and type E (peritrapezium) of Garcia-Elias. An extensive debridement, reduction of the carpometacarpal dislocations and stabilization with Kirschner wires was performed requiring a full thickness skin graft 14 days after the trauma. RESULTS: At 4-year follow-up, he had 70 degrees of wrist extension, and 78 degrees of wrist flexion, grip strength of 65% compared to the healthy side and x-ray showed mild signs of osteoarthritis. He was satisfied and returned to the same job. CONCLUSIONS: Axial carpal dislocations continue to be difficult injuries to address but also to classify. Since the prognosis depends on the injury pattern and other associated lesions, we believe that adding a type G which include the association of different patterns to the classification of Garcia-Elias could be useful not in changing the treatment but probably indicating a worse prognosis. PMID- 28832214 TI - Painful Pseudotendon of the Flexor Carpi Radialis Tendon: A Literature Review and Case Report. AB - BACKGROUND: Flexor tendon ruptures in the wrist are uncommon. Flexor carpi radialis (FCR) tendon rupture can occur in rheumatoid patients, following cortisone injection for tenosynovitis, and following trauma. Following tendon rupture, tethering of the ruptured FCR tendon, or pseudotendon, can form which may or may not be symptomatic. METHODS: A literature review was done reviewing treatment and outcomes of FCR tendon lesions. A case report of painful FCR pseudotendon following a fall is presented. The patient presented 4 months after injury with a tender lump 6 cm proximal to the wrist joint with pain and weakness aggravated with wrist motion and gripping. RESULTS: The literature review reveals operative excision of a symptomatic FCR pseudotendon lesion results in great patient satisfaction with no morbidity. In this case report, in spite of conservative measures including cortisone injection and activity modification, the patient had persistent symptoms. The patient proceeded with surgery for complete excision of both the painful pseudotendon and retracted FCR tendon stump. Post-operatively, his wrist motion and grip strength returned to normal, and his Disabilities of the Arm, Shoulder, and Hand (DASH) score was significantly improved from 72 to 9. CONCLUSIONS: FCR pseudotendon is an uncommon condition and can be seen following trauma. Majority of FCR tendon ruptures resolve with non-operative treatment. Based on the excellent outcomes following complete FCR tendon harvest for thumb carpometacarpal (CMC) joint reconstruction, complete excision of a symptomatic pseudotendon results in excellent relief of symptoms with no long-term morbidity. PMID- 28832215 TI - A Clinical Study of the Modified Thread Carpal Tunnel Release. AB - BACKGROUND: Previous studies have indicated that the thread carpal tunnel release (TCTR) is a safe and effective technique. Through a study on 11 cadaveric wrists, the TCTR procedure was modified and the needle control accuracy was improved to 0.15 to 0.2 mm, which is precise enough to preserve superficial palmar aponeurosis (SupPA), Berrettini branch, and common digital nerves. The aim of the present study was to verify the modified TCTR clinically. METHODS: The modified TCTR was performed on 159 hands of 116 patients. The Boston Carpal Tunnel Syndrome Questionnaire was used for assessing the outcomes. Statistical analyses were used to compare the outcomes with the available data from the literature for the open and endoscopic techniques. RESULTS: TCTR led to significant improvement in the short-term results, and the outcomes were better in long-term results compared with the open or endoscopic release. The SupPA, Berrettini branch, and common digital nerves were protected. There was no neurovascular complication for any case. Significant relief of symptoms was observed 3 to 5 hours post procedure. Most patients used their hands on the day of the procedure for simple daily activity. Patients reported their sleep quality was improved on the surgical day. Most patients with office jobs were able to return to work on postoperative day 1, and those with repetitive jobs returned to work in about 2 weeks. The statistical evidence proves that the modified TCTR procedure results in improved clinical outcomes as compared with open carpal tunnel release (CTR) and endoscopic CTR. CONCLUSIONS: The TCTR procedure has been shown to be a safe and effective technique for CTR. The modified TCTR procedure minimizes postoperative complications, such as pillar pain, scar tenderness, or functional weakness, by avoiding unnecessary injuries to the surrounding structures around the transverse carpal ligament during the procedure. PMID- 28832216 TI - Advances in 3D Modeling: Preoperative Templating for Revision Wrist Surgery. AB - BACKGROUND: Three-dimensional (3D) printing is a computer-directed process leading to the layered synthesis of scaled models. The popularity and availability of the technique has exponentially increased over the last decade, and as such is seeing a greater number of medical and surgical applications. METHODS: We report 3 cases involving the use of 3D printing as an aid to operative planning in the revision of wrist surgery. RESULTS: All patients underwent successful operative interventions with a L34 average cost of model creation. CONCLUSIONS: A growing number of reports are emerging in reconstructive surgical specialities including maxillofacial, orthopedic, and plastic surgery; from our experience, we advocate the economically viable use of 3D printing for preoperative templating. PMID- 28832217 TI - The Effect of Priming With Questionnaire Content on Grip Strength in Patients With Hand and Upper Extremity Illness. AB - BACKGROUND: Grip strength is a performance-based measure of upper extremity function that might be influenced by priming (the influence of a response to a stimulus by exposure to another stimulus). This study addressed the influence of questionnaire content on performance measurements such as grip strength between patients who complete the standard Pain Catastrophizing Scale (PCS) compared with patients who complete a positively adjusted PCS. METHODS: Between June 2015 and August 2015, we enrolled 122 patients who presented to 3 hand surgeons at 3 outpatient offices. They were randomized to 2 groups: the control group, which completed the PCS, and the intervention group, which completed a positively phrased version of the PCS. Before and after completion of the questionnaire, we measured each patient's grip strength 3 times by alternating between hands. Two patients were excluded after participation. We calculated both the preintervention and postintervention mean and maximum grip strengths. RESULTS: There was no significant difference between groups on mean or maximum grip strength before completion of the questionnaires. There was a greater improvement in mean grip strength of both hands in the intervention group compared with the PCS group. This improvement was statistically significant in the affected hand. The maximum grip strength showed a statistically significant greater improvement in both hands in the positive PCS group compared with the control group. CONCLUSIONS: Positive priming through a questionnaire leads to an increase in mean and maximum grip strength when compared with the standard questionnaire that uses negative terms rather than positive. PMID- 28832218 TI - Emerging interleukin receptor antagonists for the treatment of asthma. AB - INTRODUCTION: Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. Most patients with asthma can be well-controlled with inhaled corticosteroids and, if necessary, the addition of a long-acting beta agonist. Despite these therapies, 5% to 10% of patients with asthma have severe, uncontrolled asthma. Selecting patients based on peripheral eosinophil counts and a history of exacerbations has led to significant decreases in exacerbations and an improvement in asthma control with medications that target IL-4, IL-5 and IL 13/. Areas covered: This review will cover the definition of severe asthma, existing treatment options, biomarkers, and the emerging role of interleukin antagonists in the treatment of severe asthma. Expert opinion: IL antagonists are novel drugs targeting important inflammatory cytokines in asthma. Anti-IL-5 drugs provide the most promise as they have obtained regulatory approval and are available for use. Anti-IL-4 drug results are also promising. There is, however, uncertainty regarding the success of anti-IL-13 drugs development at this point. An ongoing focus of research is to significantly increase our understanding of the biology of asthma, and in particular severe asthma, making more and better targeted therapies. There may also be potential in the future to use these new drugs earlier in the development of asthma, as disease-modifying interventions that might be associated with remission or even cure. PMID- 28832219 TI - Estimated reductions in hospitalizations and deaths from childhood diarrhea following implementation of rotavirus vaccination in Africa. AB - INTRODUCTION: Rotavirus is the leading cause of hospitalizations and deaths from diarrhea. 33 African countries had introduced rotavirus vaccines by 2016. We estimate reductions in rotavirus hospitalizations and deaths for countries using rotavirus vaccination in national immunization programs and the potential of vaccine introduction across the continent. Areas covered: Regional rotavirus burden data were reviewed to calculate hospitalization rates, and applied to under-5 population to estimate baseline hospitalizations. Rotavirus mortality was based on 2013 WHO estimates. Regional pre-licensure vaccine efficacy and post introduction vaccine effectiveness studies were used to estimate summary effectiveness, and vaccine coverage was applied to calculate prevented hospitalizations and deaths. Uncertainties around input parameters were propagated using boot-strapping simulations. In 29 African countries that introduced rotavirus vaccination prior to end 2014, 134,714 (IQR 112,321-154,654) hospitalizations and 20,986 (IQR 18,924-22,822) deaths were prevented in 2016. If all African countries had introduced rotavirus vaccines at benchmark immunization coverage, 273,619 (47%) (IQR 227,260-318,102) hospitalizations and 47,741 (39%) (IQR 42,822-52,462) deaths would have been prevented. Expert commentary: Rotavirus vaccination has substantially reduced hospitalizations and deaths in Africa; further reductions are anticipated as additional countries implement vaccination. These estimates bolster wider introduction and continued support of rotavirus vaccination programs. PMID- 28832221 TI - Editorial. PMID- 28832222 TI - Natalizumab in the treatment of Crohn's disease patients. AB - INTRODUCTION: Amongst the available therapies for moderate to severe Crohn's disease (CD) patients who are refractory to conventional therapy, anti-TNF blockers are the most effective biological treatment option. However, many patients experience a primary or secondary non-response to anti-TNF therapy, creating the need for alternative biological drugs that target different mechanisms of action and inflammatory pathways. Natalizumab, the first non-anti TNF biological drug to be approved for treatment of CD patients, is a recombinant humanized antibody that targets the alpha4-subunit of both alpha4beta1 and alpha4beta7 integrins, thus preventing activated leukocyte homing to the intestinal mucosa. Areas covered: This article summarizes the pathophysiological background and the efficacy and safety data of natalizumab, as well as the regulatory issues surrounding it. Expert opinion: Natalizumab represents an effective therapy for refractory CD patients. However, the rare but serious event of progressive multifocal leukoencephalopathy occurrence has compromised its widespread use. The subsequent advent of more specific anti-integrin drugs (i.e. vedolizumab) that carry a more favorable safety profile further reduces the clinical indications for natalizumab. The regulatory process for natalizumab distribution and monitoring in the US may provide a forum for discussion on how to optimally manage use of drugs that offer clinical benefits to patients, while minimizing associated risks. PMID- 28832223 TI - Local bone loss in patients with anti-citrullinated peptide antibody and arthralgia, evaluated with high-resolution peripheral quantitative computed tomography. AB - OBJECTIVE: To investigate bone changes in the metacarpophalangeal (MCP) joints of anti-citrullinated peptide antibody (ACPA)-positive patients with arthralgia, but not arthritis, compared to healthy controls. METHOD: Using a cross-sectional study design, patients were recruited from hospitals and private care rheumatologists, and controls from a test subject website. All subjects underwent medical history interview, clinical examination, and biochemical screening including ACPA. Patients with positive ACPA, arthralgia, and no rheumatic disease were included. Controls without a history or signs of rheumatological disease or positive ACPA were included. A 2.7-cm-long region around the second and third MCP joints was evaluated using high-resolution peripheral quantitative computed tomography with a voxel size of 82 um. RESULTS: Twenty-nine ACPA-positive patients and 29 healthy controls were evaluated. Trabecular volumetric bone mineral density and bone volume fraction did not differ between the groups. In addition, the cortical bone was not affected in patients, as we found no difference in average cortical thickness and cortical bone area between the groups. In contrast, the trabeculae were significantly (p < 0.05) thinner in both second and third MCP heads compared with controls, whereas trabecular number and trabecular separation did not differ between the groups. No erosions were demonstrated and the number of non-specific breaks did not differ between the groups. CONCLUSION: Trabecular bone changes were observed in ACPA-positive patients with arthralgia compared with healthy controls. The results may reflect inflammatory up-regulated trabecular bone resorption leading to early bone loss before the onset of clinical arthritis. PMID- 28832224 TI - Effect of Kollidon VA(r)64 particle size and morphology as directly compressible excipient on tablet compression properties. AB - The study evaluates use of Kollidon VA(r)64 and a combination of Kollidon VA(r)64 with Kollidon VA(r)64 Fine as excipient in direct compression process of tablets. The combination of the two grades of material is evaluated for capping, lamination and excessive friability. Inter particulate void space is higher for such excipient due to the hollow structure of the Kollidon VA(r)64 particles. During tablet compression air remains trapped in the blend exhibiting poor compression with compromised physical properties of the tablets. Composition of Kollidon VA(r)64 and Kollidon VA(r)64 Fine is evaluated by design of experiment (DoE). A scanning electron microscopy (SEM) of two grades of Kollidon VA(r)64 exhibits morphological differences between coarse and fine grade. The tablet compression process is evaluated with a mix consisting of entirely Kollidon VA(r)64 and two mixes containing Kollidon VA(r)64 and Kollidon VA(r)64 Fine in ratio of 77:23 and 65:35. A statistical modeling on the results from the DoE trials resulted in the optimum composition for direct tablet compression as combination of Kollidon VA(r)64 and Kollidon VA(r)64 Fine in ratio of 77:23. This combination compressed with the predicted parameters based on the statistical modeling and applying main compression force between 5 and 15 kN, pre-compression force between 2 and 3 kN, feeder speed fixed at 25 rpm and compression range of 45-49 rpm produced tablets with hardness ranging between 19 and 21 kp, with no friability, capping, or lamination issue. PMID- 28832225 TI - MUC1 aptamer-conjugated mesoporous silica nanoparticles effectively target breast cancer cells. AB - In the present study, we developed aptamer (Apt) conjugated mesoporous silica nanoparticles (MSNs) for specific delivery of epirubicin (EPI) to breast cancer cells. MSNs were synthesized and functionalized with 3 mercaptopropyltrimethoxysilane (3-MPTMS), followed by MUC1 aptamer conjugation through disulfide bonds. The nanoparticles were analyzed by transmission electron microscopy (TEM), particle size analyzer, zeta potential, elemental analysis (CHNS), aptamer conjugation efficiency, drug loading efficiency, and drug release profile. Cell uptake and in vitro cytotoxicity of different formulations were performed. The results of MSNs characterization confirmed spherical nanoparticles with thiol functional groups. Particle size of obtained nanoparticles was 163 nm in deionized water. After conjugation of MUC1 aptamer and EPI loading (MSN-MUC1 EPI), particle size increased to 258 nm. The aptamer conjugation to MSNs with disulfide bonds were confirmed using gel retardation assay. Cellular uptake studies revealed better cell uptake of MSN-MUC1-EPI compared to MSN-EPI. Moreover, cytotoxicity study results in MCF7 cell lines showed improved cytotoxicity of MSN-MUC1-EPI in comparison with MSN-EPI or EPI at the same concentration of drug. These results exhibited that MSN-MUC1-EPI has the potential for targeted drug delivery into MUC1 positive breast cancer cells to improve drug efficacy and alleviate side effects. PMID- 28832227 TI - Interactional Alarms: Experts' Framing of Health Risks in Live Broadcast News Interviews. AB - This study examined how experts frame health risks in real-time interactions with journalists. Though there is evidence that experts influence media framing of health risks, the ways they respond to journalists' agendas in real-time interactions have yet to be explored. This paper examines instances of risk assessment extracted from a corpus of news interviews to determine how expert assessments were requested and provided. The analysis reveals that experts rarely deliver their assessments neutrally but rather treat these exchanges as opportunities for framing or reframing the topic. Their framing is shown to be responsive to journalistic agendas and to those who experts understand to be accountable when their assessment is elicited. These findings suggest ways in which news interviews can be useful in health communication. The implications for experts, journalists, and public information officers who plan to use interviews for this purpose are discussed. PMID- 28832226 TI - Effects of the hydroalcoholic extract of Rosa damascena on learning and memory in male rats consuming a high-fat diet. AB - CONTEXT: High-fat diet (HFD) can cause deficits in learning and memory through oxidative stress and increase Alzheimer disease risk. Rosa damascena Mill. (Rosaceae) extract possesses potent antioxidant properties. OBJECTIVE: This study investigated the effects of the hydroalcoholic extracts of petals of R. damascena on learning and memory in male rats consuming an HFD. MATERIALS AND METHODS: Forty male Wistar rats (200-250 g) were randomly assigned to four groups: control, R. damascena extract, HFD and HFD + extract. The extract (1 g/kg bw daily) was administered by oral gavage for 1 month. Animals were allowed free access to high-fat chow for 3 months. The Morris water maze and the passive avoidance learning tests were used to assess learning and memory. RESULTS: In the passive avoidance learning test, the step-through latencies in the retention test (STLr) of the extract (147.4 +/- 23.3) and HFD (150.3 +/- 25.2) groups were significantly lower than those of the control group (270.4 +/- 10.5) (respectively, p < 0.001 and p < 0.01). STLr was significantly higher in the HFD + extract group (265.3 +/- 10.6) than in the HFD group (150.3 +/- 25.2) (p < 0.01). Time spent in the dark compartment (TDC) in the HFD + extract group (5.3 +/- 2.6) was significantly lower than that in the HFD group (85.8 +/- 19.1) (p < 0.05). DISCUSSION AND CONCLUSION: Our results indicate that, while HFD or R. damascena extract alone leads to memory deficits, R. damascena extract exerted a positive effect on HFD-induced memory deficits. We hypothesize that the observed effects of R. damascena extract are likely due to its strong antioxidant properties. PMID- 28832228 TI - Caffeic acid methyl and ethyl esters exert potential antidiabetic effects on glucose and lipid metabolism in cultured murine insulin-sensitive cells through mechanisms implicating activation of AMPK. AB - CONTEXT: Caffeic acid methyl (CAME) and ethyl (CAEE) esters stimulate glucose uptake and AMP-activated protein kinase (AMPK) in C2C12 myocytes (ATCC(r) CRL 1772TM). OBJECTIVE: Effects of CAME and CAEE were now assessed on myocyte glucose transporter GLUT4 activity and expression, on hepatic gluconeogenesis and on adipogenesis as well as major underlying signaling pathways. MATERIALS AND METHODS: GLUT4 protein translocation was studied in L6 GLUT4myc cells, glucose-6 phospatase (G6Pase) in H4IIE hepatocytes and adipogenesis in 3T3-L1 adipocytes. Key modulators were measured using western immunoblot. Cells were treated for 18 h with either CAME or CAEE at various concentrations (12.5-100 MUM). RESULTS: Myocyte glucose uptake rose from 10.1 +/- 0.5 to 18.7 +/- 0.8 and 21.9 +/- 1.0 pmol/min/mg protein in DMSO-, CAME- and CAEE-stimulated cells, respectively, similar to insulin (17.7 +/- 1.2 pmol/min/mg protein), while GLUT4myc translocation increased significantly by 1.70 +/- 0.18, by 1.73 +/- 0.18- and by 1.95 +/- 0.30-fold (relative to DMSO), following insulin, CAME and CAEE stimulation, respectively. CAME and CAEE suppressed hepatocyte G6Pase by 62.0 +/- 6.9% and 62.7 +/- 6.0% with IC50 of 45.93 and 22.64 MUM, respectively, comparable to insulin (70.7 +/- 2.3% inhibition). Finally, CAME and CAEE almost abrogated adipogenesis (83.3 +/- 7.2% and 97.3 +/- 3.0% at 100 MUM; IC50 of 13.8 and 12.9 MUM, respectively). The compounds inhibited adipogenic factors C/EBP-beta and PPAR-gamma and stimulated AMPK activity in the three cell-lines. DISCUSSION AND CONCLUSIONS: CAME and CAEE exerted antidiabetic activities in insulin-responsive cells through insulin-independent mechanisms involving AMPK and adipogenic factors. PMID- 28832230 TI - Professor Ruth Duncan: a pioneer in the field of polymer therapeutics. PMID- 28832229 TI - Effects of polysaccharide from Physalis alkekengi var. francheti on liver injury and intestinal microflora in type-2 diabetic mice. AB - CONTEXT: Diabetic liver injury is a serious diabetic complication. The alterations of intestinal microbiota play an important role in induction and promotion of liver injury progression. Physalis alkekengi L. var. francheti (Mast.) Makino (Solanaceae) has been used as a water decoction for treating diabetes. OBJECTIVE: To study the effects of a polysaccharide (PPSB) from Physalis alkekengi var. francheti on liver injury and intestinal microflora in type-2 diabetic mice. MATERIALS AND METHODS: Streptozotocin (160 mg/kg) was injected i.p. for 3 days to build model. The diabetic mice were randomly divided into four groups together with control group (10 mice in each group). The doses of PPSB were 50 and 100 mg/kg, respectively. After 5 weeks administration, level of blood glucose, ALT and AST were measured. Alterations of intestinal microflora, and protein expression of TGF-beta1, TNF-alpha and DCN were detected. RESULTS: Level of blood glucose decreased from (25.38 +/- 2.21) mmol/L to (18.01 +/- 2.53) mmol/L, ALT and AST decreased to (24.67 +/- 4.86) U/L and (30.84 +/- 7.50) U/L in PPSB-H group. Lactobacillus, Clostridium butyricum, and Bacteroides increased remarkably with increasing concentration of PPSB, but Enterobacter was inhibited. The relative expression of TGF-beta1 and TNF-alpha decreased to (0.70 +/- 0.17) and (0.39 +/- 0.06), and the expression of DCN increased to (0.65 +/- 0.13). DISCUSSION AND CONCLUSIONS: Probiotics have been promoted by PPSB, and protein expressions have been modulated in the progression of liver injury. PPSB could be used as a natural agent for treating diabetic liver injury and intestinal microflora imbalance. PMID- 28832231 TI - Unruptured intracranial aneurysms: management strategy and current endovascular treatment options. AB - INTRODUCTION: Unruptured intracranial aneurysms (UIA) have a high prevalence (3.2%) and are increasingly diagnosed with modern imaging tools. The main risk of UIA is their rupture associated with intracranial bleeding with often severe clinical consequences. Areas covered: This review discusses the management strategy of UIAs, based on the large series of the literature (ISUIA, ATENA, UCAS, ...), knowing that no randomized controlled trial is available to compare different strategies. The different endovascular treatments are described. Expert commentary: Due to the relatively scarce data regarding the risk of rupture of UIAs, the strategy of management is often difficult to define. It has to be multidisciplinary and has to take into account several factors related to the patient and the aneurysm. Beside the surgical approach, several endovascular tools are available to treat UIAs, that includes standard coiling, balloon assisted coiling, stent-assisted coiling, flow diversion, and flow disruption. PMID- 28832233 TI - Bioactivity-guided isolation and identification of anti-adipogenic compounds from Sanguisorba officinalis. AB - CONTEXT: Sanguisorba officinalis Linne (Rosaceae) is a medicinal plant used traditionally for the treatment of inflammatory and metabolic diseases in Korea, China, and Japan. In our previous study, a 50% ethanol extract inhibited fat accumulation in 3T3-L1 adipocytes. OBJECTIVE: This study investigates bioassay guided fractionation, isolation, and identification of anti-adipogenic bioactive compounds in S. officinalis. MATERIALS AND METHODS: The bioassay-guided fractionation was conducted using effective differentiation of 3T3-L1 cells into adipocytes (with 50 MUg/mL test material for 8 days) to isolate the inhibitory compounds from ethyl acetate fraction of S. officinalis 50% ethanol extract. The cytotoxicity of each fraction and isolated compound was tested using MTT assay (with 25-300 MUg/mL test material). Structures of the isolated active compounds were elucidated using 1H NMR, 13 C NMR, HSQC, HMBC, FT-IR, and MS. RESULTS: An active ethyl acetate fraction obtained with solvent partition of the extract inhibited lipid accumulation (44.84%) on 3T3-L1 cells without cytotoxicity (102.3%) at the concentration of 50 MUg/mL. The ethyl acetate fraction was determined to be mainly composed by isorhamnetin-3-O-d-glucuronide (1) and ellagic acid (2). Pure isorhamnetin-3-O-d-glucuronide (IC30 is 18.43 MUM) and ellagic acid (IC30 is 19.32 MUM) showed lipid accumulation inhibition on 3T3-L1 cells without cytotoxicity (117.5% and 104.3%) at the concentration of 20 MUM, respectively. DISCUSSION AND CONCLUSIONS: These results suggested that S. officinalis is a potential natural ingredient for the prevention of obesity, which may due to bioactive compounds such as isorhamnetin-3-O-d-glucuronide and ellagic acid. PMID- 28832232 TI - Anti-inflammatory effect of pomegranate flower in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages. AB - CONTEXT: Punica granatum L (Punicaceae) flower is an important diabetes treatment in oriental herbal medicine. OBJECTIVE: This study investigates the inflammation effects of pomegranate flower (PFE) ethanol extract in LPS-induced RAW264.7 cells. MATERIALS AND METHODS: PFE (10, 25, 50, 100 MUg/mL) was applied to 1 MUg/mL LPS-induced RAW 264.7 macrophages in vitro. Levels of nitric oxide (NO), prostaglandin E2 (PGE2) and pro-inflammatory cytokines interleukin (IL)-1beta (IL 1beta), interleukin (IL)-6 (IL-6) and tumor necrosis factor (TNF-alpha) in the supernatant fraction were determined using enzyme-linked immunosorbent assay (ELISA). Expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), phosphorylation of mitogen-activated protein kinase (MAPK) subgroups extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and P38, as well as nuclear factor-kappaB (NF-kappaB) activation in extracts were detected via Western blot. RESULTS: 10-100 MUg/mL PFE decreased the production of NO (IC50 value = 31.8 MUg/mL), PGE2 (IC50 value = 54.5 MUg/mL), IL 6 (IC50 value = 48.7 MUg/mL), IL-1beta (IC50 value = 71.3 MUg/mL) and TNF-alpha (IC50 value = 62.5 MUg/mL) in LPS-stimulated RAW 264.7 cells significantly. A mechanism-based study showed that phosphorylation of ERK1/2, p38, JNK and translocation of the NF-B p65 subunit into nuclei were inhibited by the PFE treatment. DISCUSSION AND CONCLUSION: These results show that PFE produced potential anti-inflammatory effect through modulating the synthesis of several mediators and cytokines involved in the inflammatory process. PMID- 28832234 TI - Deferring the Decision Point: Treatment Assertions in Neurology Outpatient Consultations. AB - Recommendations can be implied by asserting some generalisation about a treatment's benefit without overtly directing the patient to take it. Focusing on a collection of assertions in UK neurology consultations, this paper shows that these are overwhelmingly receipted as "merely" doing informing and argues that this is made possible by their ambiguous design: their relatively depersonalised formats convey that the neurologist is simply telling the patient what's available, but the link made between the treatment and the patient's condition implies that it will be of benefit. Thus, assertions, while stopping short of telling the patient what to do, are hearable as recommendation relevant. This delicates balance leaves it up to the patient to respond either to the implied or on-record action (recommending vs. informing). When treated as "merely" doing informing, assertions defer the decision point until the neurologist has done something more. Three main interactional functions of this are identified as follows: (i) indicating the existence of a solution to a concern, without making a decision relevant next; (ii) orienting to the patient's right to choose; and (iii) making "cautious" recommendations. PMID- 28832235 TI - Anti-inflammatory effect of torilidis fructus ethanol extract through inhibition of Src. AB - CONTEXT: Torilidis fructus, fruits of Torilis japonica Decadolle (Umbelliferae), is a medicinal herb traditionally used as a pesticide, an astrictive, or a medicine for various inflammatory diseases. OBJECTIVES: Due to the lack of pharmacological studies on this herbal medicine, we explored the inhibitory activity of torilidis fructus on the macrophage-mediated inflammatory response using its ethanol extract (Tf-EE). MATERIAL AND METHODS: The Griess assay and prostaglandin (PGE2) ELISA assay were conducted with Tf-EE (0-75 ug/mL) and LPS (1 ug/mL) treated RAW264.7 cells in cultured media. Tf-EE pretreated RAW264.7 cells were incubated with LPS for 6 h and semi-quantitative PCR was performed. Reporter gene assays, overexpression of target enzymes and immunoblotting were performed on macrophages to determine the molecular targets of Tf-EE. RESULTS: Tf EE markedly suppressed the inflammatory response of macrophages, such as lipopolysaccharide (LPS)-induced nitric oxide (NO) and PGE2 production with IC50 values of 35.66 and 62.47 ug/mL, respectively. It was also found that Tf-EE reduced the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 by 80%. Nuclear translocation and activation of nuclear factor (NF)-kappaB (p65 and p50) were declined by 60% and 30% respectively, and their regulatory events including the phosphorylation of AKT, IkappaBalpha, Src, and the formation of complexes between Src and p-p85 were also recognized to be diminished. CONCLUSIONS: The signalling events managed by Src and p85 complex seemed to be critically involved in Tf-EE-mediated anti-inflammatory response. This might suggest that Tf-EE exhibited anti-inflammatory effects through Src-targeted inhibition of NF-kappaB. PMID- 28832236 TI - ICUS/CCUS/CHIP: basics & beyond. AB - INTRODUCTION: Patients presenting with idiopathic cytopenia with non-diagnostic marrow morphology and a normal karyotype pose a diagnostic and therapeutic challenge. Additional diagnostic information from mutation analysis could provide important clinical insights. However, one has to be cautious during such diagnostic interpretations in view of the recent documentation of clonal somatic mutations in healthy elder individuals. Whether to regard clonality synonymous with malignant proliferation or a manifestation of ageing process is to be judged carefully. Areas covered: The review covers defining criteria and diagnostic work up for Idiopathic cytopenia of undetermined significance (ICUS), Clonal cytopenia of undetermined significance (CCUS), Clonal hematopoiesis of indeterminate potential (CHIP). It also presents the results from previous reports on this subject. In addition the evolution and potential impact of these entities is discussed. Expert commentary: Current evidence does not support the use of somatic mutations as presumptive evidence of myelodysplastic syndrome (MDS). Including CCUS under the category of MDS requires further insight on natural disease course. Longitudinal follow up study on ICUS, CCUS, CHIP may eventually identify the pathological significance of the clonal mutations. An absence of mutation however may still be useful as good predictor of not having MDS. PMID- 28832237 TI - A review of economic evaluations for beneficial health outcomes of micronutrient and long-chain omega-3 fatty acid supplementation. AB - A comprehensive review of the literature identified 13 papers exploring economic evaluations of supplementation with micronutrients or long-chain omega-3 fatty acids in developed countries. Evidence of efficacy included single-study-based estimates and estimates based on published meta-analyses or data synthesis. Results suggest that supplementation with specific micronutrients or long-chain omega-3 fatty acids for specific health outcomes, and targeted at particular population groups, may be cost-effective or deliver cost savings for health care providers. While the quality of the analyses was variable and some authors reported considerable uncertainty of the results, the approaches adopted were in the main conservative. This suggests that investigating the potential economic impact of supplementation, particularly where there is good evidence of efficacy and predicted clinical benefit, is informative. Economic evaluations may also be useful to assess whether further nutritional research into particular health outcomes is a good investment of funds. PMID- 28832238 TI - Which Abortion Patients Have Had a Prior Abortion? Findings from the 2014 U.S. Abortion Patient Survey. AB - BACKGROUND: Updated information about abortion patients who have had a prior abortion could inform patient-centered practices that help women avoid unintended pregnancies in the future. MATERIALS AND METHODS: Data come from a national sample of 8,380 nonhospital U.S. abortion patients accessing services at 87 facilities. The dependent variable was a self-reported measure of prior abortion. Bivariate and multivariable analyses were used to assess associations between a range of demographic and circumstantial characteristics and reports of obtaining a prior abortion. RESULTS: We found that 45% of patients reported having one or more prior abortions. Age was most strongly associated with this outcome, and patients aged 30 and older had more than two times the odds of having had a prior abortion compared with those aged 20-24. Other characteristics associated with an increased likelihood of prior abortion included having one or more children, being black, relying on insurance or financial assistance to pay for the procedure, and exposure to disruptive events in the last 12 months. Characteristics associated with a decreased likelihood of having a prior abortion included having a college degree and living 25 or more miles from the facility where the current abortion was obtained. CONCLUSIONS: Age is the biggest risk factor for having had a prior abortion; the longer a woman has been alive, the longer she is at risk of unintended pregnancy. Some characteristics associated with prior abortion were beyond the control of the individuals experiencing them. PMID- 28832239 TI - Pre-transplant histology does not improve prediction of 5-year kidney allograft outcomes above and beyond clinical parameters. AB - Pre-implant kidney biopsy is used to determine suitability of marginal donor kidneys for transplantation. However, there is limited data examining the utility of pre-implant histology in predicting medium term graft outcome. This retrospective study examined kidney transplants over a 10-year period at a single center to determine if pre-implant histology can identify cases of eGFR <=35 ml/min/1.73m2 at 5 year follow up beyond a clinical predictive logistic regression model. We also compared outcomes of dual kidney transplants with standard single kidney transplants. Of 1195 transplants, 171 received a pre implant kidney biopsy and 15 were dual transplants. There was no significant difference in graft and patient survival rates. Median eGFR was lower in recipients of biopsied kidneys compared with standard kidney transplants (44 vs. 54 ml/min/1.73m2, p < .001). Median eGFR of dual transplant and standard kidney transplants were similar (58 vs. 54 ml/min/1.73m2, p = .64). Glomerular sclerosis (p = .05) and Karpinski Score (p = .03) were significant predictors of eGFR at 5 years in multivariate analysis but did not improve discrimination of eGFR <=35 ml/min/1.73m2 at 5-years beyond a clinical prediction model comprising donor age, donor hypertension and terminal donor creatinine (C-statistic 0.67 vs. 0.66; p = .647). Pre-implant histology did not improve prediction of medium-term graft outcomes beyond clinical predictors alone. Allograft function of dual transplant kidneys was similar to standard transplants, suggesting that there is scope to increase utilization of kidneys considered marginal based on histology. PMID- 28832240 TI - 'Was it worth it?' Intrathecal analgesia for cancer pain: A qualitative study exploring the views of family carers. AB - BACKGROUND: Intrathecal drug delivery is known to reduce pain in patients where conventional systemic analgesia has been ineffective or intolerable. However, there is little information regarding the effects of intrathecal drug delivery on quality of life and function in those with advanced, incurable cancer. AIM: Retrospective exploration of the views of bereaved carers regarding the physical and psychosocial effects of external tunnelled intrathecal drug delivery in patients with advanced incurable cancer. DESIGN: Thematic analysis of qualitative interviews with carers of deceased individuals who received percutaneous external tunnelled intrathecal drug delivery as part of their pain management, within two UK centres. SETTING: A total of 11 carers were recruited from two UK Palliative Care centres. Family carers of adult patients who had received external tunnelled intrathecal drug delivery analgesia for cancer pain and had died between 6 and 48 months prior to contact were included. Carer relatives who were considered likely to be too vulnerable or who had lodged a complaint about treatment within the recruiting department or who had been treated directly by the interviewer were excluded. RESULTS: In total, 11 interviews took place. The emerging themes were (1) making the decision to have the intrathecal - relatives described desperate situations with severe pain and/or sedation, meaning that the individual would try anything; (2) timing and knowing they were having the best - an increased access to pain and palliative care services, meant carers felt everything possible was being done, making the situation more bearable; (3) was it worth it? - the success of the external tunnelled intrathecal drug delivery was judged on its ability to enable the individual to be themselves through their final illness. Side effects were often considered acceptable, if the external tunnelled intrathecal drug delivery enabled improvements in quality of life. CONCLUSION: Carers perceived external tunnelled intrathecal drug delivery as most valuable when it improved quality of life towards the end of life, by reducing pain and side effects of conventional systemic analgesia to enable individuals 'to be themselves'. Under these circumstances, the carers judged significant side effects to be acceptable. PMID- 28832241 TI - Gender Differences and Socioeconomic Factors Related to Osteoporosis: A Cross Sectional Analysis of Nationally Representative Data. AB - BACKGROUND: Osteoporosis has been considered a disease that primarily affects women, but recently male osteoporosis is also attracting attention. This study aims to comparatively analyze socioeconomic and other factors that are related to the prevalence of osteoporosis in both men and women. MATERIALS AND METHODS: This study used data from the Korean Community Health Survey conducted in 2013. To determine factors related to osteoporosis prevalence, researchers applied a binary logistic regression model, first for all research participants, then separately for male and female participants. RESULTS: Women were more likely than men to have osteoporosis (odds ratio 12.33, 95% confidence interval 11.55-13.17). Factors related to osteoporosis prevalence included age, education level, region, economic activity, alcohol consumption, salt intake, depression, and body mass index in both genders. Low education and income levels were more highly associated with osteoporosis prevalence in women than in men. CONCLUSIONS: Most of the factors were not gender specific, but some socioeconomic determinants varied by gender. Future studies that will focus on the effects of socioeconomic factors on osteoporosis, as well as gender-related differences in prevention and control of osteoporosis, are needed. PMID- 28832243 TI - A systematic review of portable electronic technology for health education in resource-limited settings. AB - OBJECTIVE: The objective of this study is to conduct a systematic review of the literature of how portable electronic technologies with offline functionality are perceived and used to provide health education in resource-limited settings. METHODS: Three reviewers evaluated articles and performed a bibliography search to identify studies describing health education delivered by portable electronic device with offline functionality in low- or middle-income countries. Data extracted included: study population; study design and type of analysis; type of technology used; method of use; setting of technology use; impact on caregivers, patients, or overall health outcomes; and reported limitations. RESULTS: Searches yielded 5514 unique titles. Out of 75 critically reviewed full-text articles, 10 met inclusion criteria. Study locations included Botswana, Peru, Kenya, Thailand, Nigeria, India, Ghana, and Tanzania. Topics addressed included: development of healthcare worker training modules, clinical decision support tools, patient education tools, perceptions and usability of portable electronic technology, and comparisons of technologies and/or mobile applications. Studies primarily looked at the assessment of developed educational modules on trainee health knowledge, perceptions and usability of technology, and comparisons of technologies. Overall, studies reported positive results for portable electronic device-based health education, frequently reporting increased provider/patient knowledge, improved patient outcomes in both quality of care and management, increased provider comfort level with technology, and an environment characterized by increased levels of technology-based, informal learning situations. Negative assessments included high investment costs, lack of technical support, and fear of device theft. CONCLUSIONS: While the research is limited, portable electronic educational resources present promising avenues to increase access to effective health education in resource-limited settings, contingent on the development of culturally adapted and functional materials to be used on such devices. PMID- 28832242 TI - Expression and Functional Analysis of Tumor-Related Factor S100A4 in Antler Stem Cells. AB - Annual antler renewal is a stem cell-based epimorphic process driven by antler stem cells (ASCs) resident in antlerogenic periosteum (AP). Antlerogenic periosteal cells express a high level of S100A4, a metastasis-associated protein, which intrigued us to explore what role S100A4 could play in antler regeneration. The present study set out to investigate expression and effects of S100A4 in the ASCs and their progeny. The results showed that not only did cells from the AP express a high level of S100A4, but also the pedicle periosteum and the antler growth center. In the antler growth center, we found S100A4-positive cells were specifically located in blood vessel walls and in vascularized areas. In vitro, recombinant deer S100A4 protein stimulated the proliferation of the AP cells, promoted proliferation, migration and tube formation of human vascular endothelial cells, and enhanced migration of Hela cells, but not AP cells. These findings demonstrated that S100A4 in the ASCs may play a significant role in stimulating angiogenesis, proliferation, but not motility, of ASCs. Deer antlers offer a unique model to explore how rapid cell proliferation with a high level of S100A4 expression is elegantly regulated without becoming cancerous. PMID- 28832244 TI - Development and pretest of key visual imagery in a campaign for the prevention of child maltreatment. AB - INTRODUCTION: This article discusses the development and pretesting of key visual imagery in a promotional campaign developed in Quebec, Canada. This campaign is the media-based component of a broader prevention strategy involving the use of the Triple P program (Sanders, 1999). OBJECTIVES: The purpose was to pretest with parents the preliminary version of a poster that uses the campaign's key visual imagery prior to final production. METHOD: In total, 26 parents from the regions of Quebec City and Montreal participated in four focus groups. RESULTS: Two general themes emerged from the focus groups: (i) emotions and reactions arising from the key visual imagery; and (ii) comprehension of the message being conveyed. CONCLUSION: Based on this information, recommendations were made to the marketing agency, which then modified the campaign's key visual imagery and proposed a final layout. PMID- 28832245 TI - Health promotion and sustainability programmes in Australia: barriers and enablers to evaluation. AB - In an era characterised by the adverse impacts of climate change and environmental degradation, health promotion programmes are beginning to actively link human health with environmental sustainability imperatives. This paper draws on a study of health promotion and sustainability programmes in Australia, providing insights to evaluation approaches being used and barriers and enablers to these evaluations. The study was based on a multi-strategy research involving both quantitative and qualitative methods. Health promotion practitioners explained through surveys and semi-structured interviews that they focused on five overarching health and sustainability programme types (healthy and sustainable food, active transport, energy efficiency, contact with nature, and capacity building). Various evaluation methods and indicators (health, social, environmental, economic and demographic) were identified as being valuable for monitoring and evaluating health and sustainability programmes. Findings identified several evaluation enablers such as successful community engagement, knowledge of health and sustainability issues and programme champions, whereas barriers included resource constraints and competing interests. This paper highlights the need for ecological models and evaluation tools to support the design and monitoring of health promotion and sustainability programmes. PMID- 28832246 TI - Decreasing Surgical Site Infections after Ventral Hernia Repair: A Quality Improvement Initiative. AB - BACKGROUND: Surgical site infections (SSIs) remain prevalent after ventral hernia repair (VHR). In 2013-2014, a safety-net academic hospital initiated a two pronged quality-improvement (QI) project: (1) Development and implementation of evidence-based guidelines; and (2) creation of a specialized hernia clinic to manage challenging patients and complex ventral hernias. Our objective was to decrease SSI rates after elective VHR. METHODS: The primary outcome was SSI 30 days post-operatively, which was assessed in aggregate and with a stratified analysis based on case complexity using the chi2 test. RESULTS: A total of 399 patients in the pre-QI period and 390 patients in post-QI period (178 patients in general surgery clinics; 212 patients in the specialty hernia clinic) underwent VHR. Patients treated in the post-QI period were less likely to experience an SSI (13.5% vs. 1.5%; p < 0.001). On subgroup analysis of the post-QI clinics, specialty hernia clinic patients had an even lower risk of SSI than those in general surgery clinics (1.4% versus 1.7%). CONCLUSIONS: The QI initiatives of evidence-based guidelines and the specialty hernia clinic were associated with lower SSI rates. Differences in peri-operative management included differences in patient selection and pre-operative preparation and increased use of synthetic mesh and laparoscopy. Future studies must investigate the long-term outcomes of these initiatives. PMID- 28832247 TI - miRNA profiling for diagnosis, prognosis and stratification of cancer treatment in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a lethal malignancy originating from the biliary tract epithelium. Most patients are diagnosed at an advanced stage. Even after resection with curative intent, prognosis remains poor. Previous studies have reported the evolving role of miRNAs as novel biomarkers in cancer diagnosis, prognostication and chemotherapy response. Various miRNAs, such as miR-21, miR 26, miR-122 and miR-150, have been identified as possible blood-based biomarkers for noninvasive diagnosis of CCA. Moreover, epithelial-mesenchymal transition (EMT)- and angiogenesis-associated miRNAs have been implicated in tumor cell dissemination and are able to determine clinical outcome. In fact, miRNAs involved in cell survival might even determine chemotherapy response. This review provides an overview of known miRNAs as CCA-specific biomarkers. PMID- 28832248 TI - Pre-injury assessment of everyday executive function in moderate to severe traumatic brain injury. AB - Executive dysfunction is frequently observed in moderate to severe traumatic brain injury (TBI) and is commonly assessed with objective measures or subjective rating scales. Given the variability in executive function in the normal population, a reliable measure of pre-injury executive function would be of considerable value. In this study we examined pre-injury self and collateral (relative or friend) ratings on the Frontal Systems Behavior Rating Scale (FrSBe). Fifty-one persons with moderate to severe TBI and their collaterals provided before- and after-TBI ratings at 3 months post injury. A subset of 36 dyads were retested at 6 and 12 months; 26 neurologically intact controls and their collaterals also provided FrSBe ratings. At 3 months post injury, the difference between patient and collateral ratings of current status was larger than the difference relating to premorbid status, suggesting that patients were able to rate themselves from a pre-injury perspective. However, pre-injury ratings from collaterals were more reliable over time compared with patients' self-ratings. For all sets of ratings - before injury, after injury, and status of healthy controls - collateral ratings indicated more abnormality, overall, than comparable self-ratings. Evaluating one's own executive behaviour may be a difficult task even without TBI, with the difficulty exacerbated by the effects of injury. PMID- 28832250 TI - Prevalence and correlates of resistance training skill competence in adolescents. AB - The aim of this study is to examine the prevalence and correlates of adolescents' resistance training (RT) skill competence. Participants were 548 adolescents (14.1 +/- 0.5 years) from 16 schools in New South Wales, Australia. RT skills were assessed using the Resistance Training Skills Battery. Demographics, BMI, muscular fitness, perceived strength, RT self-efficacy, and motivation for RT were also assessed. The proportion demonstrating "competence" and "near competence" in each of the six RT skills were calculated and sex differences explored. Associations between the combined RT skill score and potential correlates were examined using multi-level linear mixed models. Overall, the prevalence of competence was low (range = 3.3% to 27.9%). Females outperformed males on the squat, lunge and overhead press, whereas males performed better on the push-up (p < .05). Significant associations were seen for a number of correlates, which largely differed by sex. Muscular fitness was moderately and positively associated with RT skills among both males (beta = 0.34, 95%CIs = 0.23 to 0.46) and females (beta = 0.36, 95%CIs = 0.23 to 0.48). Our findings support a link between RT skills and muscular fitness. Other associations were statistically significant but small in magnitude, and should therefore be interpreted cautiously. PMID- 28832251 TI - DNA binding to folic acid-chitosan nanoconjugates. PMID- 28832249 TI - Diet-induced vitamin D deficiency has no effect on acute post-stroke outcomes in young male mice. AB - Recent observational studies have reported that patients with low circulating levels of vitamin D experience larger infarct volumes and worse functional outcomes after ischemic stroke compared to those with sufficient levels. However, it is unknown whether a causal relationship exists between low vitamin D levels and poor stroke outcome. This study aimed to assess the effect of vitamin D deficiency on acute outcomes post-stroke. Male C57Bl6 mice (six week old) were assigned to either a control or vitamin D deficient diet for four weeks prior to stroke. Stroke was induced by 1 h middle cerebral artery occlusion (MCAO) with reperfusion. At 24 h, we assessed functional outcomes, infarct volume, quantified immune cells in the brain by immunofluorescence and examined susceptibility to lung infection. ELISAs showed that the plasma level of hydroxyvitamin D3 was 85% lower in mice fed the vitamin D-deficient diet compared with the control group. Despite this, vitamin D deficiency had no impact on functional outcomes or infarct volume after stroke. Further, there were no differences in the numbers of infiltrating immune cells or bacterial load within the lungs. These data suggest that diet-induced vitamin D deficiency has no effect on acute post-stroke outcomes. PMID- 28832252 TI - Personality, Income, and Compensatory Consumption: Low-Income Extraverts Spend More on Status. PMID- 28832253 TI - Suicides by drowning in Greece: Findings from a 10-year sample (2006-2015). AB - We studied a sample of suicide victims from Greece's main port of Piraeus area (population: approx. 700,000 individuals) and investigated all suicides for the 10-year period 2006-2015, collecting data from the victims' forensic records at the Piraeus Department of Forensic Medicine. Sixty-nine (15.9%) out of 435 suicides were due to drowning, 51 (73.9%) males and 18 (26.1%) females. Drowning was the third most common suicide method with most in the sea (92.8%), fewer in wells (7.2%). Median age: males 52.2 years (standard deviation (SD): 20.3, range: 27-89) and females 58.8 years (SD: 15.2, range: 32-84). Psychiatric medications: antidepressants (6 cases, 8.9%), benzodiazepines (6 cases, 8.9%) and antipsychotics (1 case, 1.5%). Other substances: alcohol (14 cases, 20.9%), cocaine (1 case, 1.5%) and opioids (1 case, 1.5%). No seasonal effect was observed for suicides by drowning. Greece, being a country with an embracing coastline, could provide a field of study for suicide by drowning. PMID- 28832254 TI - The relationship between press release and newspaper coverage of tobacco-related issues in South Korea. AB - This study investigates an association between press release and news media response on tobacco-related issues in South Korea. We retrieved 231 tobacco related newspaper articles from all major dailies throughout the year 2005. In total, 37 press releases on tobacco-related issues and policies published by the Korea Ministry of Health and Welfare were obtained from the Ministry website. Content analysis and appropriate statistical tests were performed. Results from our content analysis suggest that producing more press releases on tobacco related issues may result in a greater volume of newspaper articles, and that a press release on a new topical issue may effect more intense media coverage. Findings also show that when Korean newspaper articles overall held less favorable views of tobacco-related policies and programs in 2005, taxation was the most frequent theme with a non-positive opinion. Findings from our multivariate logistic regression models imply that a newspaper article with a source press release-especially about a new topical issue-is more likely than an article without a source press release to discuss tobacco-related issues more positively. Our findings suggest that a press release may serve as an effective media strategy for reaching out to the public by disseminating tobacco-control efforts and policies. PMID- 28832255 TI - The Pharmacogenetics Laboratory of the Department of Pharmacology and Toxicology at the American University of Beirut Faculty of Medicine. AB - The pharmacogenetics (PGx) laboratory at the Department of Pharmacology and Toxicology at the American University of Beirut Faculty of Medicine was established in October 2007. Several projects on the genetic polymorphisms of drug metabolizing enzymes and transporters with treatment of noncommunicable diseases such as cardiac diseases and cancers are ongoing. We have been applying the 'candidate gene' PGx approach, and recently started using higher throughput analyses. The more recent research projects are geared towards performing more extensive genotyping and including bigger and more representative population samples such as by developing research registries and prospectively following up patients. Furthermore, many technologies and research applications, such as next generation sequencing and pharmacoepigenetics that complement and enhance PGx research and applications, are being actively pursued. PMID- 28832256 TI - 3D Tendon Strain Estimation Using High-frequency Volumetric Ultrasound Images: A Feasibility Study. AB - Estimation of strain in tendons for tendinopathy assessment is a hot topic within the sports medicine community. It is believed that, if accurately estimated, existing treatment and rehabilitation protocols can be improved and presymptomatic abnormalities can be detected earlier. State-of-the-art studies present inaccurate and highly variable strain estimates, leaving this problem without solution. Out-of-plane motion, present when acquiring two-dimensional (2D) ultrasound (US) images, is a known problem and may be responsible for such errors. This work investigates the benefit of high-frequency, three-dimensional (3D) US imaging to reduce errors in tendon strain estimation. Volumetric US images were acquired in silico, in vitro, and ex vivo using an innovative acquisition approach that combines the acquisition of 2D high-frequency US images with a mechanical guided system. An affine image registration method was used to estimate global strain. 3D strain estimates were then compared with ground-truth values and with 2D strain estimates. The obtained results for in silico data showed a mean absolute error (MAE) of 0.07%, 0.05%, and 0.27% for 3D estimates along axial, lateral direction, and elevation direction and a respective MAE of 0.21% and 0.29% for 2D strain estimates. Although 3D could outperform 2D, this does not occur in in vitro and ex vivo settings, likely due to 3D acquisition artifacts. Comparison against the state-of-the-art methods showed competitive results. The proposed work shows that 3D strain estimates are more accurate than 2D estimates but acquisition of appropriate 3D US images remains a challenge. PMID- 28832257 TI - Survey of the Occurrence and Human Infective Potential of Giardia duodenalis and Cryptosporidium spp. in Wastewater and Different Surface Water Sources of Western Romania. AB - From the group of parasitic protozoa, Giardia and Cryptosporidium are the most common pathogens spread in surface water sources, representing a continuous threat to public health and water authorities. The aim of this survey was to assess the occurrence and human infective potential of these pathogens in treated wastewaters and different surface water sources. A total of 76 western Romanian water bodies in four counties (Arad, Bihor, Caras-Severin and Timis) were investigated, including the effluents of wastewater treatment plants (n = 11) and brooks (n = 19), irrigation channels (n = 8), lakes (n = 16), and ponds (n = 22). Water samples were collected through polyester microfiber filtration. Giardia cysts and Cryptosporidium oocysts were isolated using immunomagnetic separation, according to the US EPA 1623 method, followed by their identification and counting by immunofluorescence (IF) microscopy. All samples were screened through PCR-based techniques targeting the gdh gene for Giardia spp. and the 18S rRNA gene for Cryptosporidium spp., followed by sequencing of the positive results. Cryptosporidium-positive samples were subtyped based on sequence analysis of the GP60 gene. Giardia spp. was found in all tested water types with a cumulative detection rate of 90.1% in wastewaters, 26.3% in brooks, 37.5% in irrigation channels, 31.2% in lakes, and 36.4% in ponds. Except for ponds, all monitored water bodies harbored the Giardia duodenalis AII subassemblage with human infective potential. In addition, the ruminant origin assemblage E was widely distributed, and the domestic/wild canid-specific assemblage D was also recorded in a pond. Three (27.3%) wastewater samples were Cryptosporidium positive, and the identified species was the zoonotic Cryptosporidium parvum, with IIaA15G2R1 (n = 2) and IIdA18G1 subtypes. The results highlight that this threat to the public health must be brought to the attention of epidemiologists, health officials, and water authorities. PMID- 28832258 TI - Comprehensive evaluation of ecological security in mining area based on PSR-ANP GRAY. AB - With the large exploitation of mineral resources, a series of problems have appeared in the ecological environment of the mining area. Therefore, evaluating the ecological security of mining area is of great significance to promote its healthy development. In this paper, the evaluation index system of ecological security in mining area was constructed from three dimensions of nature, society and economy, combined with Pressure-State-Response framework model. Then network analytic hierarchy process and GRAY relational analysis method were used to evaluate the ecological security of the region, and the weighted correlation degree of ecological security was calculated through the index data of a coal mine from 2012 to 2016 in China. The results show that the ecological security in the coal mine area is on the rise as a whole, though it alternatively rose and dropped from 2012 to 2016. Among them, the ecological security of the study mining area is at the general security level from 2012 to 2015, and at a relatively safe level in 2016. It shows that the ecological environment of the study mining area can basically meet the requirement of the survival and development of the enterprises. PMID- 28832259 TI - A Snapshot Avian Surveillance Reveals West Nile Virus and Evidence of Wild Birds Participating in Toscana Virus Circulation. AB - INTRODUCTION: Birds are involved in the epidemiology of several vector-borne viruses, as amplification hosts for viruses, dissemination vehicles for the vectors, and sources of emerging strains in cross-species transmission. Turkey provides diverse habitats for a variety of wild birds and is located along major bird migration routes. This study was undertaken to provide a cross-sectional screening of avian specimens for a spectrum of vector-borne viruses. MATERIALS AND METHODS: The specimens were collected in Hatay province, in the Mediterranean coast of the Anatolian peninsula, located in the convergence zone of the known migration routes. Generic PCR assays were used for the detection of members of Nairovirus, Flavivirus, and Phlebovirus genera of Flaviviridae and Bunyaviridae families. The circulating viruses were characterized via sequencing and selected specimens were inoculated onto Vero cell lines for virus isolation. RESULTS AND DISCUSSION: Specimens from 72 wild birds belonging in 8 orders and 14 species were collected. A total of 158 specimens that comprise 32 sera (20.3%) from 7 species and 126 tissues (79.7%) from 14 species were screened. Eight specimens (8/158, 5%), obtained from 4 individuals (4/72, 5.5%), were positive. West Nile virus (WNV) lineage 1 sequences were characterized in the spleen, heart, and kidney tissues from a lesser spotted eagle (Clanga pomarina), which distinctly clustered from sequences previously identified in Turkey. Toscana virus (TOSV) genotype A and B sequences were identified in brain and kidney tissues from a greater flamingo (Phoenicopterus roseus), a great white pelican (Pelecanus onocrotalus), and a black stork (Ciconia nigra), without successful virus isolation. Partial amino acid sequences of the viral nucleocapsid protein revealed previously unreported substitutions. This study documents the involvement of avians in WNV dispersion in Anatolia as well in TOSV life cycle. PMID- 28832260 TI - Development of chitosan/gelatin/keratin composite containing hydrocortisone sodium succinate as a buccal mucoadhesive patch to treat desquamative gingivitis. AB - The aim of this research was to develop chitosan/gelatin/keratin composite containing hydrocortisone sodium succinate as a buccal mucoadhesive patch to treat desquamative gingivitis, which was fabricated through an environmental friendly process. Mucoadhesive films increase the advantage of higher efficiency and drug localization in the affected region. In this research, mucoadhesive films, for the release of hydrocortisone sodium succinate, were prepared using different ratios of chitosan, gelatin and keratin. In the first step, chitosan and gelatin proportions were optimized after evaluating the mechanical properties, swelling capacity, water uptake, stability, and biodegradation of the films. Then, keratin was added at different percentages to the optimum composite of chitosan and gelatin together with the drug. The results of surface pH showed that none of the samples were harmful to the buccal cavity. FTIR analysis confirmed the influence of keratin on the structure of the composite. The presence of a higher amount of keratin in the composite films resulted in high mechanical, mucoadhesive properties and stability, low water uptake and biodegradation in phosphate buffer saline (pH = 7.4) containing 104 U/ml lysozyme. The release profile of the films ascertained that keratin is a rate controller in the release of the hydrocortisone sodium succinate. Finally, chitosan/gelatin/keratin composite containing hydrocortisone sodium succinate can be employed in dental applications. PMID- 28832261 TI - Prospects and progress of immunotherapy for bladder cancer. AB - INTRODUCTION: With recent advances in immunooncology and the introduction of checkpoint inhibitors into clinical practice for many cancers, the treatment landscape of urothelial carcinoma has changed dramatically and will continue to change further. Currently, a number of compounds and combinations are under investigation in numerous clinical trials and various clinical scenarios for bladder cancer. Areas covered: In this review, the authors provide an overview of the history and rationale for immunotherapy in bladder cancer. They also provide the currently available data evaluating checkpoint inhibitors for bladder cancer, and discuss ongoing trials and future perspectives for urothelial carcinoma treatment. Expert opinion: The introduction of checkpoint inhibitors into the management of bladder cancer marks a significant milestone for this disease. Checkpoint inhibitors have the potential to impact patients across multiple disease states from non-muscle-invasive disease to metastatic tumors refractory to conventional treatment. That being said, validated biomarkers, including genetic signatures, to accurately predict response, and the establishment of optimal sequencing and combination of these immunotherapeutic agents with chemo/radiotherapy are urgently needed. PMID- 28832262 TI - Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications. AB - INTRODUCTION: Long-acting injectable (LAI) antipsychotics are a useful but underutilized option in the management of schizophrenia. Areas covered: This is a narrative review of newer LAI antipsychotics approved by the US Food and Drug Administration and is an update to a previously published review from 2013. Emphasized are new indications and new dosing intervals. Expert commentary: Ensuring that persons receiving oral antipsychotics are aware that LAI antipsychotics are available is important. The use of LAI antipsychotics can decrease the risk of relapse in both first-episode and chronic schizophrenia. Available treatments differ in terms of specific indications, approved injection sites, needle gauge, injection volume, injection interval, requirements for oral supplementation, availability of pre-filled syringes, storage needs, and post injection observation period, as well as potential drug-drug interactions and commonly encountered adverse reactions. Approved indications have expanded beyond schizophrenia to also include bipolar maintenance (risperidone microspheres and aripiprazole monohydrate) and schizoaffective disorder (paliperidone palmitate monthly). Intervals between injections can be longer than one month (six-week or two-month aripiprazole lauroxil, and three-month paliperidone palmitate). After a review of the evidence-base, guidance is offered on the appropriate selection among the LAI formulations of both first and second-generation antipsychotics. PMID- 28832264 TI - Challenges in Developing Evidence-Based Practice in High-Performance Sport. PMID- 28832263 TI - Vasorelaxant properties of Vernonia amygdalina ethanol extract and its possible mechanism. AB - CONTEXT: Vernonia amygdalina Del. (VA) (Asteraceae) is commonly used to treat hypertension in Malaysia. OBJECTIVE: This study investigates the vasorelaxant mechanism of VA ethanol extract (VAE) and analyzes its tri-step FTIR spectroscopy fingerprint. MATERIALS AND METHODS: Dried VA leaves were extracted with ethanol through maceration and concentrated using rotary evaporator before freeze-dried. The vasorelaxant activity and the underlying mechanisms of VAE using the cumulative concentration (0.01-2.55 mg/mL at 20-min intervals) were evaluated on aortic rings isolated from Sprague Dawley rats in the presence of antagonists. RESULTS: The tri-step FTIR spectroscopy showed that VAE contains alkaloids, flavonoids, and saponins. VAE caused the relaxation of pre-contracted aortic rings in the presence and absence of endothelium with EC50 of 0.057 +/- 0.006 and 0.430 +/- 0.196 mg/mL, respectively. In the presence of Nomega-nitro-l-arginine methyl ester (EC50 0.971 +/- 0.459 mg/mL), methylene blue (EC50 1.203 +/- 0.426 mg/mL), indomethacin (EC50 2.128 +/- 1.218 mg/mL), atropine (EC50 0.470 +/- 0.325 mg/mL), and propranolol (EC50 0.314 +/- 0.032 mg/mL), relaxation stimulated by VAE was significantly reduced. VAE acted on potassium channels, with its vasorelaxation effects significantly reduced by tetraethylammonium, 4 aminopyridine, barium chloride, and glibenclamide (EC50 0.548 +/- 0.184, 0.158 +/ 0.012, 0.847 +/- 0.342, and 0.304 +/- 0.075 mg/mL, respectively). VAE was also found to be active in reducing Ca2+ released from the sarcoplasmic reticulum and blocking calcium channels. CONCLUSIONS: The vasorelaxation effect of VAE involves upregulation of NO/cGMP and PGI2 signalling pathways, and modulation of calcium/potassium channels, and muscarinic and beta2-adrenergic receptor levels. PMID- 28832266 TI - The value of the participatory network mapping tool to facilitate and evaluate coordinated action in health promotion networks: two Dutch case studies. AB - INTRODUCTION: Facilitating processes for coordinated action in the field of health promotion is a challenge. Poorthuis and Bijl's (2006) Participatory Network Mapping Tool (PNMT) uses visualization and discussion to map the positions and roles of network actors, stimulate learning processes, and elicit actionable knowledge. This article describes the results from the application of the PNMT in networks of two Dutch health promotion programmes (Health Race and BeweegKuur) with the aim of determining the value of the PNMT to partners in health promotions networks. METHODS: A qualitative secondary analysis (QSA) was conducted to clarify positions and roles, learning processes, and actionable knowledge of network actors in existing data sets including five group interviews of the Health Race programme and 16 individual interviews and 15 group interviews of the BeweegKuur programme. RESULTS: The PNMT maps both positions and roles of (missing) actors and makes successes (e.g. knowing each other) and challenges (e.g. implementing new activities) visible. Thus, the PNMT provides a starting point for discussion and reflection and eliciting actionable knowledge such as involving new actors and target populations in the programme. CONCLUSION: The PNMT contributes to the facilitation of coordinated action in health promotion networks by making positions and roles of network partners visible. In combination with dialogue and reflection the PNMT helps to elucidate factors influencing coordinated action and outcomes. The PNMT is valuable in grasping intangible aspects between actors by stimulating collective learning. These insights can be used by researchers and network actors to achieve more successful coordinated action for health promotion. PMID- 28832265 TI - Access to and Satisfaction with Prenatal Care Among Pregnant Women with Physical Disabilities: Findings from a National Survey. AB - BACKGROUND: Previous qualitative studies suggest that women with physical disabilities face disability-specific barriers and challenges related to prenatal care accessibility and quality. This study aims to examine the pregnancy and prenatal care experiences and needs of U.S. mothers with physical disabilities and their perceptions of their interactions with their maternity care clinicians. MATERIALS AND METHODS: We conducted the first survey of maternity care access and experiences of women with physical disabilities from 37 states. The survey was disseminated in partnership with disability community agencies and via social media and targeted U.S. women with a range of physical disabilities who had given birth in the past 10 years. The survey included questions regarding prenatal care quality and childbirth and labor experiences. RESULTS: A total of 126 women with various physical disability types from 37 states completed the survey. Almost half of the respondents (53.2%) reported that their physical disability was a big factor in their selection of a maternity care provider and 40.3% of women reported that their prenatal care provider knew little or nothing about the impact of their physical disability on their pregnancy. Controlling for maternal demographic characteristics and use of mobility equipment, women who reported that their prenatal care provider lacked knowledge of disability and those who felt they were not given adequate information were more likely to report unmet needs for prenatal care. CONCLUSIONS: The findings from this study suggest the need for training and education for clinicians regarding the prenatal care needs of women with physical disabilities. PMID- 28832267 TI - The Severity and Impact of Pelvic Girdle Pain and Low-Back Pain in Pregnancy: A Multinational Study. AB - BACKGROUND: Pelvic girdle pain (PGP) and low-back pain (LBP) are the most common musculoskeletal disorders experienced during pregnancy, yet they are not familiar to healthcare providers in some countries. The objective was to compare prevalence, severity, and impact of PGP and LBP among pregnant women in the United States, the United Kingdom, Norway, and Sweden. Women's desires for, access to, and experience of treatment were also examined. MATERIALS AND METHODS: This is a cross-sectional self-reported questionnaire study of pregnant women, recruited at maternity care units in gestational weeks 30-38. Main outcome measures were presence and impact of PGP and/or LBP. RESULTS: A total of 869 pregnant women from the United States (n = 214), the United Kingdom (n = 220), Norway (n = 220), and Sweden (n = 215) were included. PGP and/or LBP were reported by 70%-86%, with lowest prevalence in Scandinavia. Severity and impact differed significantly across countries (p < 0.001), with U.K. women reporting the highest pain intensity (Numeric Rating Scale [NRS] 7/10) and highest mean total score on the Pelvic Girdle Questionnaire (PGQ) (46/100). U.S. women were significantly less afflicted, with mean PGQ total score 35/100 (p <= 0.001). The countries differed regarding concern about PGP and/or LBP (p < 0.001), with U.K. women being most affected (NRS 5/10). Norwegian women were most likely to receive treatment (53%) and U.S. women least likely (24%) (p < 0.001). Among women receiving treatment, 68%-87% reported a positive effect. CONCLUSIONS: PGP and/or LBP during pregnancy are common in the United States, the United Kingdom, Norway, and Sweden. Severity, concern, and treatment experiences differed across countries. The majority of women who received treatment reported a positive effect. PMID- 28832268 TI - DNA methylation profiling opens a new phase in the search of targeted therapy against Ewing sarcoma. PMID- 28832269 TI - Commentary on "Surgical Site Infection Research Opportunities". PMID- 28832270 TI - Evaluation of a Short Course of Antimicrobial Therapy for Complicated Intra Abdominal Infections in Critically Ill Surgical Patients. AB - BACKGROUND: The optimal duration of antimicrobial therapy for treatment of complicated intra-abdominal infections (cIAI) in critically ill surgical patients is unknown. Recent evidence suggests that a short (four-day) course of therapy may be effective, however data in severely critically ill patients are limited. PATIENTS AND METHODS: A single-center, retrospective, cohort study was conducted at a tertiary academic medical center. Adult patients admitted to the surgical intensive care unit (SICU) with cIAI between December 2011 and July 2015 were enrolled. Patients undergoing transplantation and those with less than 24 h in the SICU were excluded. Patients were divided into two groups, short (<= 7 d) and long (> 7 d) antimicrobial therapy. The primary outcome was treatment failure, which was defined as a composite of recurrent cIAI, secondary extra-abdominal infection, and/or in-hospital mortality from any cause. Categorical and continuous data were analyzed with chi2 and Mann-Whitney U tests, respectively. Binary logistic regression was performed to determine factors associated with treatment failure and mortality. RESULTS: Of 1,679 patients screened, 240 were included, 103 in the short and 137 in the long group. Patients in the short and long groups received a median of 5 and 14 d of therapy, respectively (p < 0.001). Treatment failure occurred less frequently with a short duration of therapy (39% versus 63%, p < 0.001) and it occurred two days sooner after source control in patients receiving the shorter courses of antimicrobial therapy (short, median 6 d, interquartile range [IQR] 3-9; long, 8 d, IQR 6-14; p < 0.001). Logistic regression demonstrated that a long duration of therapy was associated with treatment failure (odds ratio [OR] 2.186, 95% confidence interval [CI] 1.251 3.820, p = 0.006), but not with mortality (OR 0.738, 95% CI 0.329-1.655, p = 0.461). CONCLUSIONS: In critically ill surgical patients with cIAI, a short duration of antimicrobial therapy after source control resulted in similar outcomes to previously published studies, providing support for the safety of this approach in critically ill patients. PMID- 28832272 TI - Response to Arenal et al.: "Commentary on 'Surgical Site Infection Research Opportunities'". PMID- 28832273 TI - Test-retest reliability and practice effects for the ANAM General Neuropsychological Screening battery. AB - OBJECTIVE: As the use of computer-based neurocognitive assessment is rapidly expanding, the need to systematically study and document key psychometric properties of these measures has become increasingly more salient. To meet this aim, this study examined test-retest reliability and practice effects for the Automated Neuropsychological Assessment Metrics General Neuropsychological Screening battery (ANAM GNS) in a sample of 94 community dwelling adults. METHOD: ANAM GNS was administered and then repeated (alternate form) after 30 days. Test retest reliability, practice effects, and the standard error of measurement were calculated. Using these estimates, reliable change indices were calculated to determine degree of performance change needed to exceed chance and measurement error (with 90% confidence interval). RESULTS: The test-retest reliability for the ANAM composite score was .91. Performance significantly improved upon retest, but the effect size was small consistent with minimal practice effects. The threshold indicating change beyond chance or measurement error with 90% certainty was .9 (z-score). CONCLUSIONS: Findings suggest that the ANAM GNS has excellent test-retest reliability upon retest at 30 days. Small practice effects can be expected. Change greater than .9 standard deviations in the ANAM composite score is likely to represent meaningful clinical change. This paper presents initial psychometric data from the ANAM GNS and supports its use as a reliable measure of cognition. PMID- 28832274 TI - Male and Female Single-Victim Sexual Homicide Offenders: Distinguishing the Types of Weapons Used in Killing Their Victims. AB - Most studies have focused on male sexual homicide offenders (SHOs) without testing whether sex differences exist. Accordingly, little is known about the distinctions between male and female SHOs, particularly with respect to their use of weapons in killing their victims. This study used a sample of 3,160 single victim sexual homicide cases (3,009 male and 151 female offenders) from the U.S. Supplementary Homicide Reports database to explore sex differences in the types of murder weapons used by offenders in killing victims over the 37-year period 1976 to 2012. Findings indicated that significantly more male SHOs used personal weapons (43%) and more female SHOs used firearms (63%) in their offense commission. In general, female offenders predominantly used weapons that were physically less demanding (e.g., firearms and edged and other weapons; 89%). Different trends in the murder weapons used by male and female SHOs from different age groups were observed. Interestingly, findings showed that the type of weapon used by SHOs was in part influenced by the victims and their characteristics. PMID- 28832271 TI - Prolonged Operative Duration Increases Risk of Surgical Site Infections: A Systematic Review. AB - BACKGROUND: The incidence of surgical site infection (SSI) across surgical procedures, specialties, and conditions is reported to vary from 0.1% to 50%. Operative duration is often cited as an independent and potentially modifiable risk factor for SSI. The objective of this systematic review was to provide an in depth understanding of the relation between operating time and SSI. PATIENTS AND METHODS: This review included 81 prospective and retrospective studies. Along with study design, likelihood of SSI, mean operative times, time thresholds, effect measures, confidence intervals, and p values were extracted. Three meta analyses were conducted, whereby odds ratios were pooled by hourly operative time thresholds, increments of increasing operative time, and surgical specialty. RESULTS: Pooled analyses demonstrated that the association between extended operative time and SSI typically remained statistically significant, with close to twice the likelihood of SSI observed across various time thresholds. The likelihood of SSI increased with increasing time increments; for example, a 13%, 17%, and 37% increased likelihood for every 15 min, 30 min, and 60 min of surgery, respectively. On average, across various procedures, the mean operative time was approximately 30 min longer in patients with SSIs compared with those patients without. CONCLUSIONS: Prolonged operative time can increase the risk of SSI. Given the importance of SSIs on patient outcomes and health care economics, hospitals should focus efforts to reduce operative time. PMID- 28832275 TI - Association Between Obesity and Chronic Kidney Disease, Defined by Both Glomerular Filtration Rate and Albuminuria, in Korean Adults. AB - BACKGROUND: Chronic kidney disease (CKD) has often been defined based on glomerular filtration rate (GFR) alone. The Kidney Disease: Improving Global Outcomes guideline highlights albuminuria in the CKD definition. Thus, we investigated the association between obesity and CKD, as defined by both GFR and albuminuria, in Korean adults. METHODS: We used Korea National Health and Nutrition Examination Survey 2011-2014 data (N = 19,331, >=19 years old) representing the national Korean population. CKD was classified by (1) estimated GFR (eGFR) < 60 mL/min/1.73 m2 (CKDGFR); (2) albumin-to-creatinine ratio (ACR) >=30 mg/gram (CKDACR); and (3) eGFR < 60 mL/min/1.73 m2 or ACR >=30 mg/gram (CKDRisk). Associations between obesity and each CKD category were evaluated using multivariate logistic regression analysis. RESULTS: The prevalence rates of CKDGFR, CKDACR, and CKDRisk were 2.2%, 6.7%, and 8.1%, respectively. Compared with the normal body mass index (BMI; 18.5-22.9 kg/m2) group, men with BMI >= 25 kg/m2 had 1.88 times greater risk of CKDGFR in the adjusted model [95% confidence interval (CI), 1.26-2.80; P = 0.002]; BMI was not significantly associated with CKDGFR in women. In contrast, both men and women with BMI >= 25 kg/m2 had 1.58 and 1.40 times higher risk of CKDACR (95% CI, 1.21-2.07 and 1.08-1.81, respectively, both P < 0.01). Obese men and women had 1.65 and 1.38 times higher risk of CKDRisk (95% CI, 1.29-2.12 and 1.09-1.75, respectively, both P < 0.01). CONCLUSIONS: Obesity was significantly associated with an increased ACR-based CKD risk. Longitudinal studies are needed to investigate the role of overweight and obesity in the development and progression of CKD. PMID- 28832276 TI - Combining Single Nucleotide Polymorphism Genotyping Array with Bulked Segregant Analysis to Map a Gene Controlling Adult Plant Resistance to Stripe Rust in Wheat Line 03031-1-5 H62. AB - Stripe rust, caused by Puccinia striiformis f. sp. tritici, is one of the most devastating diseases of wheat worldwide. Growing resistant cultivars is considered the best approach to manage this disease. In order to identify the resistance gene(s) in wheat line 03031-1-5 H62, which displayed high resistance to stripe rust at adult plant stage, a cross was made between 03031-1-5 H62 and susceptible cultivar Avocet S. The mapping population was tested with Chinese P. striiformis f. sp. tritici race CYR32 through artificial inoculation in a field in Yangling, Shaanxi Province and under natural infection in Tianshui, Gansu Province. The segregation ratios indicated that the resistance was conferred by a single dominant gene, temporarily designated as YrH62. A combination of bulked segregant analysis (BSA) with wheat 90K single nucleotide polymorphism (SNP) array was used to identify molecular markers linked to YrH62. A total of 376 polymorphic SNP loci identified from the BSA analysis were located on chromosome 1B, from which 35 kompetitive allele-specific PCR (KASP) markers selected together with 84 simple sequence repeat (SSR) markers on 1B were used to screen polymorphism and a chromosome region associated with rust resistance was identified. To saturate the chromosomal region covering the YrH62 locus, a 660K SNP array was used to identify more SNP markers. To develop tightly linked markers for marker-assisted selection of YrH62 in wheat breeding, 18 SNPs were converted into KASP markers. A final linkage map consisting of 15 KASP and 3 SSR markers was constructed with KASP markers AX-109352427 and AX-109862469 flanking the YrH62 locus in a 1.0 cM interval. YrH62 explained 63.8 and 69.3% of the phenotypic variation for disease severity and infection type, respectively. YrH62 was located near the centromeric region of chromosome 1BS based on the positions of the SSR markers in 1B deletion bins. Based on the origin, responses to P. striiformis f. sp. tritici races, and marker distances, YrH62 is likely different from the other reported stripe rust resistance genes/quantitative trait loci on 1B. The gene and tightly linked KASP markers will be useful for breeding wheat cultivars with resistance to stripe rust. PMID- 28832278 TI - Corrigendum. PMID- 28832277 TI - Condom Communication: Reports of Sexually Active Young Adults' Recent Messages With New Partners. AB - The incidence of sexually transmitted infections is high, with recent estimates suggesting 110 million cases (CDC, 2013b). A key method to reducing the risk for sexually transmitted infections is the use of a condom. Consequently, this inquiry aimed to describe the content of and reactions to condom communication. Results revealed the following condom conversation strategies: condom possession, condom exploration, condom demand, and health concerns. Results both support and challenge previous condom studies, therefore extending and informing this line of research. Data further describe reactions to condom conversations and reasons for not having a condom conversation. Findings provide tangible evidence to be used in the training of sexually active young adults. PMID- 28832279 TI - Gender differences in substance use and psychiatric distress among medical students: A comprehensive statewide evaluation. AB - BACKGROUND: Medical student wellness has emerged as an important issue in medical education. The purpose of the present study was to obtain a comprehensive assessment of substance use, psychological distress, and help-seeking among male and female medical students in order to identify targets for continued intervention efforts. METHODS: Medical students from all 9 medical schools in the state of Florida were invited via e-mail and/or announcements to complete an anonymous online questionnaire assessing their well-being. Of 5053 matriculating medical students, 1137 (57.1% female) responded to the questionnaire. Descriptive statistics, t tests, and chi-square analyses were computed using SPSS 20. RESULTS: Over 70% of students acknowledged binge drinking, with men reporting higher frequency than women (chi2 = 13.90, P = .003), and 22.7% (n = 201) reported marijuana use during medical school, with higher rates (chi2 = 9.50, P = .02) among men (27.0%, n = 99) than women (18.9%, n = 93). A significant minority of students reported nonmedical use of prescription stimulants and prescription opioids. In addition, 3.3% of male students (n = 12) compared with 0.6% of female students (n = 3) reported problematic drug use. Further, almost 2/3 of respondents reported decreased psychological health since beginning medical school, with women noting greater reductions (chi2 = 12.39, P = .05) and higher levels of stress (chi2 = 16.30, P = .003). Over 10% of students (n = 102) endorsed "thoughts of committing suicide" during medical school, and 70.1% felt they would benefit from mental healthcare (79.3% of women vs. 59.6% of men; chi2 = 41.94, P < .001), although only 39.8% accessed help. CONCLUSIONS: Despite efforts to address medical student wellness, students continue to report concerning levels of psychological distress, suicidal ideation, and substance use. More work is needed to effectively address medical student mental health and well-being. PMID- 28832280 TI - Using surrogate vaccines to assess feasibility and acceptability of future HIV vaccine trials in men: a randomised trial in inner-city Johannesburg, South Africa. AB - BACKGROUND: Developing an effective HIV vaccine is the overriding priority for HIV prevention research. Enrolling and maintaining cohorts of men into HIV vaccine efficacy trials is a necessary prerequisite for the development and licensure of a safe and efficacious vaccine. METHODS: One hundred-fifty consenting HIV-negative men were enrolled into a pilot 1:1 randomised controlled trial of immediate vaccination with a three-dose hepatitis B vaccine compared to deferred vaccination (at 12 months) to investigate feasibility and acceptability of a future HIV vaccine trial in this population. Adverse events, changes in risk behaviour, acceptability of trial procedures and motivations for participation in future trials were assessed. RESULTS: Men were a median 25 years old (inter quartile range = 23-29), 53% were employed, 90% secondary school educated and 67% uncircumcised. Of the 900 scheduled study visits, 90% were completed in the immediate vaccination arm (405/450) and 88% (396/450) in the delayed arm (P = 0.338). Acceptability of trial procedures and services was very high overall. However, only 65% of the deferred group strongly liked being randomised compared to 90% in the immediate group (P = 0.001). Informed consent processes were viewed favourably by 92% of the delayed and 82% of the immediate group (P = 0.080). Good quality health services, especially if provided by a male nurse, were rated highly. Even though almost all participants had some concern about the safety of a future HIV vaccine (98%), the majority were willing to participate in a future trial. Future trial participation would be motivated mainly by the potential for accessing an effective vaccine (81%) and altruism (75%), rather than by reimbursement incentives (2%). CONCLUSIONS: Recruitment and retention of men into vaccine trials is feasible and acceptable in our setting. Findings from this surrogate vaccine trial show a high willingness to participate in future HIV vaccine trials. While access to potentially effective vaccines is important, quality health services are an equally compelling incentive for enrolment. PMID- 28832281 TI - Analysing local-level responses to migration and urban health in Hillbrow: the Johannesburg Migrant Health Forum. AB - Johannesburg is home to a diverse migrant population and a range of urban health challenges. Locally informed and implemented responses to migration and health that are sensitive to the particular needs of diverse migrant groups are urgently required. In the absence of a coordinated response to migration and health in the city, the Johannesburg Migrant Health Forum (MHF) - an unfunded informal working group of civil society actors - was established in 2008. We assess the impact, contributions and challenges of the MHF on the development of local-level responses to migration and urban health in Johannesburg to date. In this Commentary, we draw on data from participant observation in MHF meetings and activities, a review of core MHF documents, and semi-structured interviews conducted with 15 MHF members.The MHF is contributing to the development of local level migration and health responses in Johannesburg in three key ways: (1) tracking poor quality or denial of public services to migrants; (2) diverse organisational membership linking the policy process with community experiences; and (3) improving service delivery to migrant clients through participation of diverse service providers and civil society organisations in the Forum. Our findings indicate that the MHF has a vital role to play in supporting the development of appropriate local responses to migration and health in a context of continued - and increasing - migration, and against the backdrop of rising anti-immigrant sentiments. PMID- 28832282 TI - From fear to resilience: adolescents' experiences of violence in inner-city Johannesburg, South Africa. AB - BACKGROUND: For adolescents growing up in poor urban South African settings, violence is often a part of daily life and has lasting effects on physical and mental health outcomes in adulthood. We conducted a qualitative study to document and understand the forms of interpersonal violence experienced by adolescents living in Hillbrow, Johannesburg. In this article, we explore how violence is experienced differently by adolescent boys and girls, how they conceptualise 'dangerous' and 'safe' spaces in their neighbourhood and what gaps exist in available services for youth in Hillbrow. METHODS: The article draws on data collected in the formative phase of the 'Wellbeing of Adolescents in Vulnerable Environments' (WAVE) Study of challenges faced by adolescents (15-19 years) growing up in impoverished parts of five cities. This article reports on analysis using only data from the Johannesburg site. Using both purposive and snowball sampling to select participants, we conducted in-depth interviews (n = 20) and community mapping exercises with female (n = 19) and male (n = 20) adolescents living in Hillbrow, as well as key informant interviews with representatives of residential shelters, CBOs, and NGOs working with youth (n = 17). Transcripts were coded manually and analysed using an inductive thematic analysis approach. RESULTS: Both girls and boys reported high exposure to witnessing violence and crime. For girls, the threat of sexual harassment and violence was pervasive, while boys feared local gangs, the threat of physical violence, and being drawn into substance-abuse. Home was largely a safe haven for boys, whereas for girls it was often a space of sexual violence, abuse and neglect. Some adolescents developed coping mechanisms, such as actively seeking out community theatres, churches and other places of sanctuary from violence. Community-based services and shelters that support adolescents reported a lack of resources, overall instability and difficulties networking effectively. CONCLUSIONS: Adolescents in Hillbrow commonly witnessed and had direct experience of many forms of violence in their environment, and these experiences differed markedly by gender. Interventions that build young peoples' social capital and resilience are essential for reducing violence-related trauma and long-term health and social consequences for adolescents in this community. PMID- 28832284 TI - Attendance at antenatal clinics in inner-city Johannesburg, South Africa and its associations with birth outcomes: analysis of data from birth registers at three facilities. AB - BACKGROUND: Antenatal care (ANC) clinics serve as key gateways to screening and treatment interventions that improve pregnancy outcomes, and are especially important for HIV-infected women. By disaggregating data on access to ANC, we aimed to identify variation in ANC attendance by level of care and across vulnerable groups in inner-city Johannesburg, and document the impact of non attendance on birth outcomes. METHODS: This record review of routine health service data involved manual extraction of 2 years of data from birth registers at a primary-, secondary- and tertiary-level facility within inner-city Johannesburg. Information was gathered on ANC attendance, HIV testing and status, pregnancy duration, delivery mode and birth outcomes. Women with an unknown attendance status were considered as not having attended clinic, but effects of this assumption were tested in sensitivity analyses. Multiple logistic regression was used to identify associations between ANC attendance and birth outcomes. RESULTS: Of 31,179 women who delivered, 88.7% (27,651) had attended ANC (95% CI = 88.3-89.0). Attendance was only 77% at primary care (5813/7543), compared to 89% at secondary (3661/4113) and 93% at tertiary level (18,177/19,523). Adolescents had lower ANC attendance than adults (85%, 1951/2295 versus 89%, 22,039/24,771). Only 37% of women not attending ANC had an HIV test (1308/3528), compared with 93% of ANC attenders (25,756/27,651). Caesarean section rates were considerably higher in women who had attended ANC (40%, 10,866/27,344) than non-attenders (13%, 422/3360). Compared to those who had attended ANC, non-attenders were 1.6 fold more likely to have a preterm delivery (95% CI adjusted odds ratio [aOR] = 1.4-1.8) and 1.4 fold more likely to have a stillbirth (aOR 95% CI = 1.1-1.9). Similar results were seen in analyses where missing data on ANC attendance was classified in different ways. CONCLUSION: Inner-city Johannesburg has an almost 5% lower ANC attendance rate than national levels. Attendance is particularly concerning in the primary care clinic that serves a predominantly migrant population. Adolescents had especially low rates, perhaps owing to stigma when seeking care. Interventions to raise ANC attendance, especially among adolescents, may help improve birth outcomes and HIV testing rates, bringing the country closer to achieving maternal and child health targets and eliminating HIV in children. PMID- 28832283 TI - Alcohol use and sexual risk behaviour among men and women in inner-city Johannesburg, South Africa. AB - BACKGROUND: Alcohol misuse is a key factor underlying the remarkable vulnerability to HIV infection among men and women in sub-Saharan Africa, especially within urban settings. Its effects, however, vary by type of drinking, population group and are modified by socio-cultural co-factors. METHODS: We interviewed a random sample of 1465 men living in single-sex hostels and 1008 women in adjacent informal settlements in inner-city, Johannesburg, South Africa. Being drunk in the past week was used as an indicator of heavy episodic drinking, and frequency of drinking and number of alcohol units/week used as measures of volume. Associations between dimensions of alcohol use (current drinking, volume of alcohol consumed and heavy episodic drinking patterns) and sexual behaviours were assessed using multivariate logistic regression. RESULTS: Most participants were internal migrants from KwaZulu Natal province. About half of men were current drinkers, as were 13% of women. Of current male drinkers, 18% drank daily and 23% were drunk in the past week (women: 14% and 29% respectively). Among men, associations between heavy episodic drinking and sexual behaviour were especially pronounced. Compared with non-drinkers, episodic ones were 2.6 fold more likely to have transactional sex (95%CI = 1.7-4.1) and 2.2 fold more likely to have a concurrent partner (95%CI = 1.5-3.2). Alcohol use in men, regardless of measure, was strongly associated with having used physical force to have sex. Overall effects of alcohol on sexual behaviour were larger in women than men, and associations were detected between all alcohol measures in women, and concurrency, transactional sex and having been forced to have sex. CONCLUSIONS: Alcohol use and sexual behaviours are strongly linked among male and female migrant populations in inner-city Johannesburg. More rigorous interventions at both local and macro level are needed to alleviate alcohol harms and mitigate the alcohol-HIV nexus, especially among already vulnerable groups. These should target the specific dimensions of alcohol use that are harmful, assist women who drink to do so more safely and address the linkages between alcohol and sexual violence. PMID- 28832285 TI - Prevalence of anogenital HPV infection, related disease and risk factors among HIV-infected men in inner-city Johannesburg, South Africa: baseline findings from a cohort study. AB - BACKGROUND: Persistent high-risk human papillomavirus (HR-HPV) infection is associated with the development of anogenital cancers, particularly in men living with HIV (MLWH). We describe the prevalence of anogenital HPV infection, abnormal anal cytology and anogenital warts (AGWs) in MLWH in Johannesburg, and explore whether HPV infection and receipt of antiretroviral treatment is associated with detection of abnormal anal cytology and AGWs. METHODS: We enrolled a cohort of 304 sexually-active MLWH >=18 years, who completed a questionnaire and physical examination. Genital swabs were collected from all men and intra-anal swabs from 250 (82%). Swabs were tested for HPV DNA and genotypes, and anal smears graded using the Bethesda classification. Factors associated with anogenital disease were assessed by logistic regression models. RESULTS: Two thirds were receiving antiretroviral treatment, for a median 33 months (IQR = 15-58) and 54% were HIV virologically suppressed. Only 5% reported ever having sex with men. Among 283 genital swabs with valid results, 79% had any HPV, 52% had HR-HPV and 27% had >1 HR-HPV infection. By comparison, 39% of the 227 valid intra-anal swabs had detectable HPV, 25% had any HR-HPV and 7% >1 HR infection. While most anal smears were normal (51%), 20% had ASCUS and 29% were LSIL. No cases had HSIL or cancer. Infection with >1 HR type (adjusted OR [aOR] = 2.39; 95%CI = 1.02-5.58) and alpha 9 types (aOR = 3.98; 95%CI = 1.42-11.16) were associated with having abnormal cytology. Prevalence of AGWs was 12%. Infection with any LR type (aOR = 41.28; 95%CI = 13.57-125.62), >1 LR type (aOR = 4.14; 95%CI = 1.60-10.69), being <6 months on antiretroviral treatment (aOR = 6.90; 95%CI = 1.63-29.20) and having a CD4+ count <200 cells/MUL (aOR = 5.48; 95%CI: 1.60-18.78) were associated with having AGWs. CONCLUSIONS: In this population, anogenital HR-HPV infection and associated low-grade disease is common, but severe anal dysplasia was not detected. Findings reinforce the need for HPV vaccination in men for preventing both AGWs and HR-HPV infection. Given the absence of anal HSILs, however, the findings do not support the use of anal screening programmes in this population. PMID- 28832286 TI - Intersections between polyvictimisation and mental health among adolescents in five urban disadvantaged settings: the role of gender. AB - BACKGROUND: Polyvictimisation (PV) - exposure to violence across multiple contexts - causes considerable morbidity and mortality among adolescents. Despite high levels of violence in urban disadvantaged settings, gender differences in associations between PV and mental health have not been well established. METHODS: We analysed data from a survey with 2393 adolescents aged 15-19 years, recruited using respondent-driven sampling from urban disadvantaged settings in Baltimore (USA), Delhi (India), Ibadan (Nigeria), Johannesburg (South Africa) and Shanghai (China). PV was defined as exposure to two or more types of violence in the past 12 months with family, peers, in the community, or from intimate partners and non-partner sexual violence. Weighted logistic regression models are presented by gender to evaluate whether PV is associated with posttraumatic stress, depression, suicidal thoughts and perceived health status. RESULTS: PV was extremely common overall, but ranged widely, from 74.5% of boys and 82.0% of girls in Johannesburg, to 25.8 and 23.9% respectively in Shanghai. Community violence was the predominant violence type, affecting 72.8-93.7% across the sites. More than half of girls (53.7%) and 45.9% of boys had at least one adverse mental health outcome. Compared to those that did not report violence, boys exposed to PV had 11.4 higher odds of having a negative perception of health (95%CI adjusted OR = 2.45-53.2), whilst this figure was 2.58 times in girls (95%CI = 1.62-4.12). Among girls, PV was associated with suicidal thoughts (adjusted OR = 4.68; 95%CI = 2.29-9.54), posttraumatic stress (aOR = 4.53; 95%CI = 2.44-8.41) and depression (aOR = 2.65; 95%CI = 1.25-5.63). Among boys, an association was only detected between PV and depression (aOR = 1.82; 95%CI = 1.00 3.33). CONCLUSION: The findings demonstrate that PV is common among both sexes in urban disadvantaged settings across the world, and that it is associated with poor mental health outcomes in girls, and with poor health status in both girls and boys. Clearly, prevention interventions are failing to address violence exposure across multiple contexts, but especially within community settings and in Johannesburg. Interventions are needed to identify adolescents exposed to PV and link them to care, with services targeting a range of mental health conditions among girls and perhaps focusing on depression among boys. PMID- 28832287 TI - "Honey, Milk and Bile": a social history of Hillbrow, 1894-2016. AB - This commentary constructs a social history of Hillbrow, an inner-city suburb in Johannesburg, South Africa, based on a review of relevant published historical, anthropological and sociological texts. We highlight the significant continuities in the social structure of the suburb, despite the radical transformations that have occurred over the last 120 years.Originally envisaged as a healthy residential area, distinct from the industrial activity of early Johannesburg, Hillbrow was a prime location for health infrastructure to serve the city. By the late 1960s, the suburb had been transformed by the rapid construction of high rise office and apartment buildings, providing temporary low cost accommodation for young people, migrants and immigrants. In the 1980s, Hillbrow defied the apartheid state policy of racial separation of residential areas, and earned the reputation of a liberated zone of tolerance and inclusion. By the 1990s, affected by inner-city decay and the collapse of services for many apartment buildings, the suburb became associated with crime, sex work, and ungovernability. More recently, the revitalisation of the Hillbrow Health Precinct has created a more optimistic narrative of the suburb as a site for research and interventions that has the potential to have a positive impact on the health of its residents.The concentration of innovative public health interventions in Hillbrow today, particularly in the high quality health services and multidisciplinary research of the Hillbrow Health Precinct, creates the possibility for renewal of this troubled inner-city suburb. PMID- 28832289 TI - At the Heart of the Problem: Health in Johannesburg's Inner-City. PMID- 28832288 TI - Is laboratory screening prior to antiretroviral treatment useful in Johannesburg, South Africa? Baseline findings of a clinical trial. AB - BACKGROUND: Screening for renal, hepatic and haematological disorders complicates the initiation of current first-line antiretroviral therapy (ART). Each additional test done adds substantial costs, both through direct laboratory expenses, but also by increasing the burden on health workers and patients. Evaluating the prevalence of clinically relevant abnormalities in different population groups could guide decisions about what tests to recommend in national guidelines, or in local adaptations of these. METHODS: As part of enrolment procedures in a clinical trial, 771 HIV-positive adults, predominantly from inner city primary health care clinics, underwent laboratory screening prior to ART. Participants had to be eligible for ART, based on the then CD4 eligibility threshold of 350 cells/MUL, antiretroviral naive and have no symptoms of peripheral neuropathy. RESULTS: Participants were mostly female (57%) and a mean 34 years old. Creatinine clearance rates were almost all above 50 mL/min (99%), although 5% had microalbuminuria. Hepatitis B antigenaemia was common (8% of participants), of whom 40% had a raised AST/ALT, though only 2 had transaminase levels above 200 IU/L. Only 2% of participants had severe anaemia (haemoglobin <8 g/dl) and 1% neutropaenia (neutrophils <0.75 * 10^9/L). Costs per case detected of hepatitis B infection was USD135, but more than USD800 for a raised creatinine. CONCLUSIONS: Hepatitis B continues to be a common co-infection in HIV infected adults, and adds complexity to management of ART switches involving tenofovir. Routine renal and haematological screening prior to ART detected few abnormalities. The use of these screening tests should be assessed among patients with higher CD4 counts, who may even have fewer abnormalities. Formal evaluation of cost-effectiveness of laboratory screening prior to ART is warranted. PMID- 28832290 TI - Sexual and reproductive health outcomes among female sex workers in Johannesburg and Pretoria, South Africa: Recommendations for public health programmes. AB - BACKGROUND: The sexual and reproductive health (SRH) status of female sex workers is influenced by a wide range of demographic, behavioural and structural factors. These factors vary considerably across and even within settings. Adopting an overly standardised approach to sex worker programmes may compromise its impact on some sub-groups in local areas. METHODS: Records of female sex workers attending clinic-, community-, or hotel-based health services in Johannesburg (n = 1422 women) and Pretoria (n = 408 women), South Africa were analysed. We describe the population's characteristics and identified factors associated with sexual and reproductive health outcomes, namely HIV status; previous symptomatic sexually transmitted infection (STI); modern contraceptive use and number of child dependents. RESULTS: The women in Johannesburg were less likely than those in Pretoria to have HIV (42.2% vs 52.9%), or previous symptomatic STIs (44.3% vs. 8.3%), and were 1.4 fold less likely to have child dependents (20.1% vs. 15.3%). About 43% of women in Johannesburg were Zimbabwean and 40% in Pretoria. Of concern, only about 15% of women in both sites were using modern contraceptives. Johannesburg women were also more likely to access health services at a hotel (85.0% vs. 80.6%) or clinic (5.7% vs. 0.5%), to have completed secondary education (57.1% vs. 36.0%), and moved house more than twice during the past year (19.6 vs. 2.0%). In both cities, risk of HIV rose rapidly with age (23.8%-58.2% vs. 22.0%-64.8%). Of interest, HIV prevalence was considerably higher in those with consistent condom use with one's main partner than inconsistent users. CONCLUSIONS: Sex worker populations are heterogeneous. Local health programmes must prioritise services that reflect the variety and complexity of sex worker needs and behaviours, and should be designed in consultation with sex workers. Segmenting sex worker populations according to age, country of origin and place of service delivery, and training healthcare providers accordingly, could help prevent new HIV infections, improve adherence to antiretroviral treatment and increase uptake of SRH services. PMID- 28832291 TI - [Increased mortality in metal-on-metal versus non-metal-on-metal primary total hip arthroplasty at 10 years and longer follow-up: a systematic review and meta analysis]. AB - OBJECTIVE: To determine the mortality and the morbidity in patients with metal-on metal articulations (MOM THA) when compared to patients with non-metal-on-metal articulations (non-MOM THA) after primary total hip arthroplasty. DESIGN: Systematic review, meta-analyses and meta-regression (registration: PROSPERO 2014:CRD42014007417). METHOD: Search of PubMed, MEDLINE, EMBASE, Web of Science, Cochrane, CINAHL, AcademicSearchPremier, ScienceDirect, Wiley and clinical trial registers. We included randomised controlled trials and observational studies of primary total hip arthroplasty comparing MOM THA with non-MOM THA. We used meta regression to identify and evaluate potential modifying variables such as follow up duration. RESULTS: Forty-seven studies were included, comprising over 4,000 THA in randomised trials and over 500,000 THA in observational studies. For mortality, random effects analysis revealed a higher pooled risk difference (RD) of 0.7% (95%-CI: 0.0-2.3%; I-square 42%); the heterogeneity was explained by differences in follow-up. When restricted to studies with long term follow-up (i.e. 10 years or more), the RD for mortality was 8,5% (95%-CI: 5,8-11,2). Further subgroup analyses and meta-regression random effects models revealed no evidence for other modifying variables (study level covariates, e.g. resurfacing vs. non-resurfacing MOM) than follow-up duration. CONCLUSION: Meta-analysis suggests there may be an increased long-term risk of mortality associated with MOM THA compared to patients with non-MOM THA. PMID- 28832292 TI - [Intensive follow-on care does not prevent a repeat compulsory admission; a prospective cohort study with a 5-year follow-up]. AB - OBJECTIVE: To explore the relationship between psychiatric care consumption after a compulsory admission and the probability of a repeat compulsory admission. DESIGN: Prospective cohort study with a 5-year follow-up. METHOD: Mental health care consumption was registered for 460 patients admitted compulsorily under the Dutch Psychiatric Care (Compulsory Admissions) Act by the Amsterdam Emergency Psychiatry service between 15 September 2004 and 14 September 2006, with socio demographic and clinical data as independent variables. RESULTS: There was no repeat compulsory admission in 63% of the cohort. The odds ratio for repeat compulsory admission only decreased in the fourth year (odds ratio (OR) 0.64; 95% CI 0.45-0.92). Repeat compulsory admission was associated with high treatment continuity (chi2 p <= 0.001) and a high level of care consumption during the follow-up period (chi2 p <= 0.001). Compulsory admission was predicted on the basis of: high care consumption in the five years prior to inclusion (OR 2.61; 1.44-4.73), aged younger than 35 years at outset (OR 1.65; 1.08-2.52), living alone at the time of inclusion (OR 1.68; 1.22-2.33), and a history of compulsory admission (OR 1.56; 1.03-2.35). CONCLUSION: Two-thirds of the patients were not re-admitted compulsorily. The probability of a repeat admission of this kind fell only after four years. Patients who underwent a repeat compulsory admission proved to be the ones who had been treated most intensively, yet this intense treatment did not prevent a higher probability of readmission. When not taking the quality and nature of care and social integration of patients into account, attempts to reduce treatment dropout on the one hand and more intense treatments on the other may not have an effect on reducing the probability of a repeat compulsory admission. PMID- 28832293 TI - [Myosotis in children with flu; a rare complication of influenza]. AB - Influenza is a common viral infection, which occurs in yearly endemics during the winter period. Complications are mostly seen amongst the elderly, but may also be seen in previously healthy children; the airways and central nervous system, in particular, may be affected. Another complication of influenza, first described in 1957 and only sporadically discussed, is influenza associated myositis (IAM). In this article we describe three patients with IAM. IAM is mainly seen in children, and boys are more often affected than girls. It is most commonly seen in influenza type B. The pathogenesis is largely unknown, but the clinical presentation and laboratory results for IAM are quite typical. Clinical presentation may be very severe, and when the clinical symptoms are not recognized, invasive tests will often follow. Most cases of IAM are self limiting, but a minority of the patients might experience life-threatening complications. PMID- 28832294 TI - [Acute flaccid myelitis after a respiratory tract infection; first Dutch case related to enterovirus type D68 infection]. AB - BACKGROUND: Acute flaccid myelitis (AFM) is a relatively rare disorder affecting the anterior horn of the spinal cord and brain stem. It is characterised by rapid progressive weakness of the limbs and respiratory muscles, often combined with cranial nerve dysfunction. This used to be seen in infections with the polio virus, but in recent years, AFM has been mainly associated with enterovirus D68 infection. CASE DESCRIPTION: A boy of nearly 4 years-old developed rapidly progressive weakness and respiratory failure after an upper airway infection. Initially, Guillain-Barre syndrome was suspected, but after further investigations enterovirus D68 was detected in the nasopharyngeal aspirate and the diagnosis of AFM was made. CONCLUSION: Progressive weakness after a respiratory tract infection should raise the suspicion of enterovirus-associated AFM. This syndrome can be distinguished from Guillain-Barre syndrome by its more rapid progression, asymmetrical weakness and greater involvement of the upper limbs. The diagnosis can be confirmed by typical findings on MRI and electromyography of the spinal cord and brain stem, combined with the detection of enterovirus D68 in nasopharyngeal specimens. PMID- 28832295 TI - [A painful knee that cannot bend]. AB - A 59-year-old woman was seen at the ER with a painful right knee locked in extension. This was caused by unloaded hyperextension in bed. Interlocking patellofemoral osteophytes and a superior patella dislocation tilted away from the femur were seen on the X-ray, which are both pathognomonic signs of a superior dislocation of the patella. PMID- 28832296 TI - [Continued anticoagulation for unprovoked venous thromboembolism: guidance through the maze of recent studies]. AB - Recent American, European and Dutch guidelines recommend indefinite anticoagulation after a diagnosis of unprovoked venous thromboembolism in the absence of a high bleeding risk. The recommended approach would be to only stop anticoagulant therapy after three months in patients with one or more untreatable risk factors for bleeding such as prior major bleeding, uncorrectable hypertension or deep thrombocytopenia. Vitamin K-antagonists and direct oral anticoagulants (DOACs) were found to protect against recurrent venous thromboembolism at cost of major bleedings, although at a lower frequency than the number of prevented thrombotic events. Due to the lower risk of major bleeding than associated with vitamin K-antagonists, DOACs are the preferred treatment option for the long term treatment of unprovoked venous thromboembolism. Apixaban is available in a reduced dose for long-term treatment, and rivaroxaban in a reduced dose was recently shown to be more effective than aspirin. PMID- 28832297 TI - [Practicing medicine at the end of life: use clear language]. AB - Up to thirty years ago, in the Netherlands the word 'stervensbegeleiding' [literally, dying-guidance] was used to refer to care for people in the last days of life. After Cicely Saunders had developed a multidisciplinary and multidimensional approach for care for the dying, the wording changed, until the word 'palliative care' was adopted. This care gradually developed from care for the dying to care for all people with life-threatening illness, as illustrated in the WHO definition. This shift in focus of care raises the question of when palliative care starts. The surprise question is regarded as a useful tool for marking this shift in focus of care. However, answering the surprise question does not inform us about palliative care needs. Nevertheless, when people enter the dying phase, a fundamental change in the nature of care is needed. The word 'stervensbegeleiding' marks this change of care. PMID- 28832298 TI - [Enterovirus type D68 and acute flaccid paralysis: a new duo?] AB - Following a case of acute flaccid paralysis after infection with enterovirus type D68, we highlight current understanding of the causal role of enterovirus infection in this neurological syndrome. Acute flaccid paralysis is a rare complication of enterovirus infections. Such viruses have become a more common cause of severe respiratory-tract infections, especially in children with underlying lung disease such as asthma. PMID- 28832299 TI - [Economic insights into promoting healthy behaviour: the pros and cons of a financial incentive]. AB - Recent studies have shown that financial incentives help to promote a healthier lifestyle; these include better adherence to medication, taking more exercise and quitting smoking. Although this is in accordance with economic theory, it also raises objections. Firstly, it may be considered too paternalistic, secondly it raises health care costs, and thirdly it creates ethical dilemmas. In this commentary I argue that it may still be worthwhile to implement these incentives. Moreover, I use insights from behavioural economics to provide a number of recommendations on promoting healthy behaviour in a more cost-effective way, while taking into account the resulting ethical issues. PMID- 28832300 TI - Subliminal and supraliminal processing of reward-related stimuli in anorexia nervosa. AB - BACKGROUND: Previous studies have highlighted the role of the brain reward and cognitive control systems in the etiology of anorexia nervosa (AN). In an attempt to disentangle the relative contribution of these systems to the disorder, we used functional magnetic resonance imaging (fMRI) to investigate hemodynamic responses to reward-related stimuli presented both subliminally and supraliminally in acutely underweight AN patients and age-matched healthy controls (HC). METHODS: fMRI data were collected from a total of 35 AN patients and 35 HC, while they passively viewed subliminally and supraliminally presented streams of food, positive social, and neutral stimuli. Activation patterns of the group * stimulation condition * stimulus type interaction were interrogated to investigate potential group differences in processing different stimulus types under the two stimulation conditions. Moreover, changes in functional connectivity were investigated using generalized psychophysiological interaction analysis. RESULTS: AN patients showed a generally increased response to supraliminally presented stimuli in the inferior frontal junction (IFJ), but no alterations within the reward system. Increased activation during supraliminal stimulation with food stimuli was observed in the AN group in visual regions including superior occipital gyrus and the fusiform gyrus/parahippocampal gyrus. No group difference was found with respect to the subliminal stimulation condition and functional connectivity. CONCLUSION: Increased IFJ activation in AN during supraliminal stimulation may indicate hyperactive cognitive control, which resonates with clinical presentation of excessive self-control in AN patients. Increased activation to food stimuli in visual regions may be interpreted in light of an attentional food bias in AN. PMID- 28832301 TI - Prostate Cancer: Has Patience Paid Off? PMID- 28832302 TI - Legends in Urology. PMID- 28832304 TI - MRI-targeted biopsy: is systematic biopsy obsolete? AB - INTRODUCTION: Although prostate cancer is the most common non-cutaneous cancer in men, it is traditionally diagnosed with a non-targeted, systematic transrectal ultrasound prostate biopsy (TRUS-Bx). This technique has been demonstrated to both under-detect clinically significant (CS) cancer and over-detect clinically insignificant cancer, and performs poorly in patients with a prior negative biopsy. With recent advances in MRI technology, most prominently the advent of multiparametric MRI, MRI-targeted prostate biopsy (MRI-TB) has been gaining favor as a more accurate alternative to TRUS-Bx. In this review, we attempt to summarize the current literature on MRI-TB and to determine if there is evidence supporting the use of MRI-TB alone. MATERIALS AND METHODS: The literature was reviewed for articles pertaining to MRI-TB and its performance compared to systematic biopsy. RESULTS: Most studies support the increased sensitivity of MRI TB (0.90, 95% CI 0.85-0.94) compared to TRUS-Bx (0.79, 95% CI 0.68-0.87) for the detection of CS prostate cancer, as MRI-TB can detect up to 30% more high risk and 17% fewer low risk cancers. MRI-TB also tends to perform better than TRUS-Bx in patients with prior negative biopsy, as TRUS-Bx may miss up to half of CS cancers detected by MRI-TB, and in those with lesions at atypical locations. However, as the technology for imaging and image-guided biopsies continues to develop, there is still a role for TRUS-Bx in the management of patients with prostate cancer. CONCLUSIONS: Our analysis of the literature suggests that although MRI-TB is superior to TRUS-Bx, there is still a role for traditional systematic biopsy. PMID- 28832305 TI - Procedural povidone iodine rectal preparation reduces bacteriuria and bacteremia following prostate needle biopsy. AB - INTRODUCTION: To determine if a povidone iodine rectal preparation (PIRP) reduces rates of bacteriuria and bacteremia following transrectal ultrasound guided prostate needle biopsy (TRUS PNB). MATERIALS AND METHODS: Men undergoing TRUS PNB were prospectively enrolled in a study comparing the impact of PIRP versus standard of care (two pills of ciprofloxacin 500 mg). Urine, blood, and rectal cultures were obtained 30 minutes post-procedure with colony forming units (CFUs) determined after 48 hours. Patients were called 7 and 30 days post-procedure to evaluate for infections. RESULTS: A total of 150 men were accrued into this study including 95 receiving PIRP and 55 the standard of care. Two-thirds of patients were undergoing an initial biopsy, 19% used antibiotics within the previous 6 months, and median number of biopsy cores was 14. There were no differences between the two cohorts with respect to baseline or biopsy characteristics. In the PIRP cohort, rectal cultures before and after PIRP administration noted a 97.2% reduction in microorganism colonies (2.4 x 10 5 CFU/mL versus 6.7 x 103CFU/mL, p < 0.001). Mean urine bacterial counts following TRUS PNB were 1 CFU/mL for PIRP versus 7 CFU/mL for standard cohort (p < 0.001). Mean serum bacterial counts following TRUS PNB were 0 CFU/mL for PIRP versus 3 CFU/mL for standard of care (p = 0.01). One patient in the PIRP cohort (1.1%) developed post biopsy sepsis while 3 (5.5%) in the standard cohort had an infectious complication (1 UTI, 2 sepsis). CONCLUSION: A PIRP regimen reduced bacteruria and bacteremia following TRUS PNB. PMID- 28832306 TI - Clinical use of patient decision-making aids for stone patients. AB - INTRODUCTION: Patient decision-making aids (PDMAs) help patients make informed healthcare decisions and improve patient satisfaction. The utility of PDMAs for patients considering treatments for urolithiasis has not yet been published. We report our experience using PDMAs developed at our institution in the outpatient clinical setting in patients considering a variety of treatment options for stones. MATERIALS AND METHODS: Patients with radiographically confirmed urolithiasis were given PDMAs regarding treatment options for their stone(s) based on their clinical profile. We assessed patients' satisfaction, involvedness, and feeling of making a more informed decision with utilization of the PDMAs using a Likert Scale Questionnaire. Information was also collected regarding previous stone passage, history and type of surgical intervention for urolithiasis, and level of education. RESULTS: Patients (n = 43; 18 males, 23 females and two unknown) 53 +/- 14years old were included. Patients reported that they understood the advantages and disadvantages outlined in the PDMAs (97%), that the PDMAs helped them make a more informed decision (83%) and felt more involved in the decision making process (88%). Patients reported that the aids were presented in a balanced manner and used up-to-date scientific information (100%, 84% respectively). Finally, a majority of the patients prefer an expert's opinion when making a treatment decision (98%) with 73% of patients preferring to form their own opinion based on available information. Previous stone surgery was associated with patients feeling more involved with the decision making process (p = 0.0465). CONCLUSIONS: PDMAs have a promising role in shared decision-making in the setting of treatment options for nephrolithiasis. PMID- 28832307 TI - Preoperative immunonutrition prior to radical cystectomy: a pilot study. AB - INTRODUCTION: To investigate the use of a high-arginine immunonutrient supplement prior to radical cystectomy for bladder cancer. MATERIALS AND METHODS: We recruited 40 patients to consume a total of four high-arginine immunonutrient shakes per day for 5 days prior to radical cystectomy. The primary outcome measures were safety, tolerability and adherence to the supplementation regimen. Ninety-day postoperative outcomes were also compared between supplemented patients and a cohort of 104 prospectively identified non-supplemented radical cystectomy patients. Multivariable logistic regression models were used to compare overall complications, infectious complications, and readmission rates between groups. RESULTS: There were no serious adverse events during supplementation. Four patients (10%) stopped supplementation due to nausea (n = 2) and bloating (n = 2). Thirty-three patients (83%) consumed all prescribed shakes. Immunonutrient supplementation was not significantly associated with overall complications (adjusted odds ratio [OR] 1.08; 95% confidence interval [CI] 0.50-2.33), infectious complications (OR 1.23; 95% CI 0.49-3.07), or readmissions (OR 1.48; 95% CI 0.62-3.51) on multivariable analyses. CONCLUSIONS: Preoperative supplementation with a high-arginine immunonutrient shake was safe and well tolerated prior to radical cystectomy. Contrary to prior reports, immunonutrient supplementation was not associated with lower postoperative infectious complications in this cohort, perhaps owing to the 5 day supplementation period. Further study is needed to identify the optimal immunonutrient supplement regimen for radical cystectomy patients. PMID- 28832308 TI - Value of nutrition supplementation prior to cystectomy. PMID- 28832309 TI - Preoperative symptoms predict continence after post-radiation transurethral resection of prostate. AB - INTRODUCTION: Lower urinary tract symptoms and retention are known complications of radiation for prostate cancer and traditionally transurethral resection of the prostate (TURP) has been avoided in these patients because of the risk of incontinence. The purpose of this study was to evaluate the incidence and predictors of post-TURP incontinence in previously radiated patients. MATERIALS AND METHODS: One-hundred and eleven patients who underwent brachytherapy or external beam radiotherapy for prostate cancer with subsequent TURP performed between 1992 and 2012 at a single institution were identified. We tested for associations between post-TURP continence status and pre-TURP predictors including age, preoperative urinary symptoms and type and timing of radiation therapy. RESULTS: New-onset incontinence developed in 27% (95% CI 17%, 39%) of patients after first post-radiation TURP and 32% (95% CI 23%, 42%) of patients after any TURP, including repeat TURPs. Forty-three percent of patients had resolution of incontinence with first TURP (95% CI 25%, 63%); only 25% (95% CI 7%, 52%) of patients had resolution following repeat TURPs. Age was significantly associated with incontinence (OR per 10 years 2.02, 95% CI 1.10, 3.74, p = 0.024). Post-TURP incontinence was more common in men with pre-TURP urgency. CONCLUSIONS: Rates of post-TURP incontinence were higher in men who were older or had pre-TURP urinary urgency. Assessment of preoperative symptoms would allow for better patient selection. Further research should determine whether this results in better outcomes, including decreased incidence of new onset incontinence and increase in resolution of incontinence. PMID- 28832310 TI - A decision aid versus shared decision making for prostate cancer screening: results of a randomized, controlled trial. AB - INTRODUCTION: Shared decision making (SDM) is widely encouraged by both the American Urological Association and Choosing Wisely for prostate cancer screening. Implementation of SDM is challenging secondary to time constraints and competing patient priorities. One strategy to mitigate the difficulties in implementing SDM is to utilize a decision aid (DA). Here we evaluate whether a DA improves a patient's prostate cancer knowledge and affects prostate-specific antigen (PSA) screening rates. MATERIALS AND METHODS: Patients were randomized to usual care (UC), DA, or DA + SDM. Perception of quality of care was measured using the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. Outcomes were stratified by long term provider relationship (LTPR, > 3 years) versus short term provider relationship (STPR, < 3 years). Knowledge of prostate cancer screening and the decision regarding screening were assessed. Groups were compared using ANOVA and logistic regression models. RESULTS: A total of 329 patients were randomized. Patients in the DA + SDM arm were significantly more likely to report discussing the implication of screening (33% DA + SDM, 22% UC, 16% DA, p = 0.0292) and answered significantly more knowledge questions correctly compared to the UC arm (5.03 versus 4.46, p = 0.046). However, those in the DA arm were significantly less likely to report that they always felt encouraged to discuss all health concerns (72% DA, 78% DA + SDM, 87% UC, p = 0.0285). Interestingly, STPR patients in the DA arm were significantly more likely to undergo PSA-based prostate cancer screening (41%) than the UC arm (8%, p = 0.019). This effect was not observed in the LTPR group. CONCLUSIONS: Providing patients a DA without a personal interaction resulted in a greater chance of undergoing PSA-based screening without improving knowledge about screening or understanding of the consequences of this decision. This effect was exacerbated by a shorter term provider relationship. With complex issues such as the decision to pursue PSA-based prostate cancer screening, tools cannot substitute for direct interaction with a trusted provider. PMID- 28832311 TI - Surgical technique for removal of tined lead for InterStim. AB - INTRODUCTION: We aimed to introduce our technique describing the removal of a chronic implanted tined-lead in patients with a sacral neuromodulator implant. MATERIALS AND METHODS: We performed a retrospective review of patients who had chronic sacral neuromodulator (InterStim) implanted by a single surgeon from 2001 through 2015. This simple surgical technique was developed and successfully performed to remove the leads. Primary reasons for removal were elective due to poor symptoms control and failure to maintain response or lead migration. Patient demographics, indication for implantation, as well as installation and removal complications were recorded and analyzed. RESULTS: Twenty-five patients were included [mean age: 60.4 years (32-86), 17 females]. Primary indications for sacral nerve stimulation were overactive bladder in 16 (64%), mixed incontinence in 6 (24%), urinary retention in 2 (8%), and interstitial cystitis 3 (12%). Mean implant duration was 24.2 (0.5-90) months. The existing tined lead was removed and replaced in 11 (44%) patients while the remaining 14 (56%) underwent complete removal of the unit without subsequent replacement. Successful lead removal without complications was achieved in 24 (96%) patients. CONCLUSIONS: This minimally invasive technique is a simple, safe, and effective method of removing chronic implanted tined leads en bloc. PMID- 28832312 TI - Surgical technique for removal of InterStim leads. PMID- 28832313 TI - 180W-LBO GreenLight XPS laser vaporization for benign prostatic hyperplasia: our experience with current markers of surgical proficiency for durable and reproducible outcomes. AB - INTRODUCTION: This study aims at analyzing the impact of reaching current markers of proficiency on intra and postoperative clinical outcomes of laser vaporization with 180W GreenLight XPS in the treatment of benign prostatic hyperplasia. MATERIALS AND METHODS: A retrospective analysis was conducted on a prospectively collected database of 328 consecutive patients who underwent photoselective vaporization of the prostate (PVP) using Greenlight XPS performed by a single experienced laser surgeon. A logarithmic model was used to evaluate the case number to attain benchmark criteria for durable treatment. We compared clinical outcomes before and after current markers of proficiency, defined as either an energy density of 4kJ/cm3 or a 6 month prostate-specific antigen (PSA) drop of = 50%, were attained. RESULTS: Energy delivered per prostate volume increased significantly with experience. The published benchmark values of 4kJ/cm3 and 6 month PSA drop of 50% were attained after 190 and 155 cases, respectively. There were no significant differences between groups in intraoperative complications or postoperative functional outcomes. However, the number of Clavien-Dindo category I adverse events significantly decreased with experience. Sub-analysis evaluating prostate volumes <= 80 cm3 and > 80 cm3 demonstrated comparable clinical outcomes before and after technical proficiency. CONCLUSION: In our experience, the case volume required to achieve consistent reference values related to durable clinical outcomes and surgical proficiency was > 150 cases. However, desirable clinical outcomes were attained before reaching current markers of proficiency, regardless of preoperative prostate size. This suggests that current thresholds of technical proficiency may not be a good predictor of satisfying clinical outcomes. PMID- 28832314 TI - A case of emphysematous cystitis caused by Klebsiella pneumoniae. AB - Emphysematous cystitis is a rare type of urinary tract infection that is characterized by air pockets within the bladder wall and lumen, which come from gas that is mainly produced by gram-negative bacteria, notably Escherichia coli. This infection is more common in older women with poorly controlled diabetes. An abdominal computerized tomography (CT) scan is the gold standard method to make the diagnosis. The infection can be life-threatening, so prompt treatment is essential. We present a case of a 39-year-old woman with poorly controlled type 2 diabetes who developed emphysematous cystitis after a bilateral adrenalectomy. The infection was diagnosed by a CT scan that revealed gas in the bladder wall. A urine culture revealed 106 colonies/mL of Klebsiella pneumoniae. After a month of treatment with intravenous antibiotics (vancomycin plus meropenem plus colistin), bladder drainage, and strict glycemic control, the patient had a good outcome. PMID- 28832315 TI - Amyloidosis and acute hemorrhage of the kidney, ureter, and bladder. AB - Gross hematuria is a common occurrence in adults. The differential diagnosis is extensive, including: malignancy, trauma, inflammation of the urinary tract, and stones. While, urinary tract amyloidosis represents only a small percentage of causative gross hematuria, it is concerning because of its superficial resemblance to malignant processes. We report the case of an 82-year-old male with concurrent primary amyloidosis of the kidney, ureter and bladder in the setting of acute hemorrhage. Histopathological examination of several biopsied samples confirmed our diagnosis. A nephroureterectomy with bladder cuff was successfully performed without complication along with watchful waiting for the bladder amyloidosis. PMID- 28832316 TI - How I do it: Balloon tamponade of prostatic fossa following Aquablation. AB - Since its first report in the 1870s, control of bleeding after transurethral resection of the prostate (TURP) has remained a concern. Foley's initial report of a urinary catheter involved placement of the balloon into the prostatic fossa following TURP. Removal of prostate tissue with a high-velocity saline stream (Aquablation) is a recently reported alternative to TURP. As Aquablation is heat free, alternatives to non-thermal hemostasis were sought to optimize the procedure. We report use of a balloon catheter in the prostatic fossa after Aquablation as a post-resection hemostatic method. PMID- 28832317 TI - Cryptorchidism: experience and reason. AB - INTRODUCTION: To characterize our contemporary clinical experience with cryptorchidism. MATERIALS AND METHODS: The records of boys referred for cryptorchidism were reviewed from 2001 to 2011. Data regarding the incidence of retractile testes, testicular ascent, surgical approach and outcomes were tabulated. Follow up was both early (< 12 weeks) and late (> 12 weeks). RESULTS: A total of 1885 patients, or 2593 testes, were identified. Eight hundred and forty-one children (45%) or 1204 testes (46%) were retractile on initial exam-57% bilateral; 187 testes (7%) later 'ascended' on re-examination and underwent surgery--15% bilateral; 1340 (85%) testes were palpable in the inguinal canal and underwent inguinal orchidopexy--98% were successful; 69 (4%) of initially palpable testes were found to be atrophic and removed; 167 (11%) testes were non palpable and underwent laparoscopy-46 were atrophic and removed; 31 were vanishing; 33 were brought down using an inguinal approach at the same sitting with 97% success; 47 underwent staged Fowler-Stephens orchidopexy (FSO) and 10 underwent non-staged FSO, with 82% and 78% success respectively. All second stages were performed open. CONCLUSIONS: Almost half of children referred for cryptorchidism had retractile testes. Surgery for later ascent was required in 16% of testes judged to be retractile at a median age of 8 years, emphasizing the need for repeat examination. High success rates with inguinal orchidopexy were achieved, even in non-palpable testes. Testes requiring FSO were uncommonly encountered-approximately 5 testes/year or 4% of testes undergoing surgery-and success was achieved in approximately 80%. PMID- 28832318 TI - Abstracts of the Mid-Atlantic Section of the American Urological Association Annual Meeting. September 14 - 17, 2016. PMID- 28832319 TI - Uncertainty exposure causes behavioural sensitization and increases risky decision-making in male rats: toward modelling gambling disorder. AB - BACKGROUND: An animal model of gambling disorder, previously known as pathological gambling, could advance our understanding of the disorder and help with treatment development. We hypothesized that repeated exposure to uncertainty during gambling induces behavioural and dopamine (DA) sensitization - similar to chronic exposure to drugs of abuse. Uncertainty exposure (UE) may also increase risky decision-making in an animal model of gambling disorder. METHODS: Male Sprague Dawley rats received 56 UE sessions, during which animals responded for saccharin according to an unpredictable, variable ratio schedule of reinforcement (VR group). Control animals responded on a predictable, fixed ratio schedule (FR group). Rats yoked to receive unpredictable reward were also included (Y group). Animals were then tested on the Rat Gambling Task (rGT), an analogue of the Iowa Gambling Task, to measure decision-making. RESULTS: Compared with the FR group, the VR and Y groups experienced a greater locomotor response following administration of amphetamine. On the rGT, the FR and Y groups preferred the advantageous options over the risky, disadvantageous options throughout testing (40 sessions). However, rats in the VR group did not have a significant preference for the advantageous options during sessions 20-40. Amphetamine had a small, but significant, effect on decision-making only in the VR group. After rGT testing, only the VR group showed greater hyperactivity following administration of amphetamine compared with the FR group. LIMITATIONS: Reward uncertainty was the only gambling feature modelled. CONCLUSION: Actively responding for uncertain reward likely sensitized the DA system and impaired the ability to make optimal decisions, modelling some aspects of gambling disorder. PMID- 28832320 TI - Refinement by integration: aggregated effects of multimodal imaging markers on adult ADHD. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is biologically heterogeneous, with different biological predispositions - mediated through developmental processes - converging upon a common clinical phenotype. Brain imaging studies have variably shown altered brain structure, activity and connectivity in children and adults with ADHD. Recent methodological developments allow for the integration of information across imaging modalities, potentially yielding a more coherent view regarding the biology underlying the disorder. METHODS: We analyzed a sample of adults with persistent ADHD and healthy controls using an advanced multimodal linked independent component analysis approach. Diffusion and structural MRI data were fused to form imaging markers reflecting independent components that explain variation across modalities. We included these markers as predictors into logistic regression models on adult ADHD and put those into context with predictions of estimated intelligence, age and sex. RESULTS: We included 87 adults with ADHD and 93 controls in our analysis. Participants' courses associated with all imaging markers explained 27.86% of the variance in adult ADHD. No single imaging modality dominated this result. Instead, it was explained by aggregation of relatively small effects across several modalities and markers. One of the top markers for adult ADHD was multimodal and linked to morphological and microstructural effects within anterior temporal brain regions; another was linked to cortical thickness. Several markers were also influenced by estimated intelligence, age and/or sex. LIMITATIONS: Although complex analytical approaches, such as the one applied here, provide insight into otherwise hidden mechanisms, they also increase the complexity of interpretations. CONCLUSION: No dominant imaging modality or marker characterizes structural brain phenotypes in adults with ADHD, but we can refine our characterization of the disorder by the integration of small effects across modalities. PMID- 28832321 TI - Structural alterations in patients with obsessive-compulsive disorder: a surface based analysis of cortical volume, surface area and thickness. AB - BACKGROUND: Mounting evidence indicates the presence of structural brain alterations in individuals with obsessive-compulsive disorder (OCD). Findings are, however, rather heterogeneous, which may be partly because of differences in methodological approaches or clinical sample characteristics. The aim of the present study was to analyze the whole brain cortical volume, surface area and thickness in a large sample of patients with OCD compared with age- and sex matched healthy controls. METHODS: We conducted whole brain surface-based analyses of grey matter measures using the automated FreeSurfer software in patients with OCD and matched controls. Group analyses were performed and corrected for multiple testing using Monte Carlo simulations (p < 0.05). Altered brain regions and their average morphological values were associated to symptom severity and type (Yale-Brown Obsessive Compulsive Scale scores). RESULTS: We included 75 patients and 75 controls in our analyses. Patients with OCD showed decreases in both volume and surface area compared with healthy controls in inferior-superior parieto-occipital regions. In addition, the precuneus, posterior cingulate areas, middle frontal and orbitofrontal areas, and middle inferior temporal areas extending to the fusiform gyrus were characterized by a reduced surface area only. There were no differences in grey matter thickness between the groups. LIMITATIONS: The presence of comorbidities, medication usage and the multisymptomatic feature of OCD could have influenced our results to a certain degree. CONCLUSION: Our results suggest decreased grey matter volume and surface area in several key regions in patients with OCD. Parietal regions showed reductions in both volume and surface area, which underlines the potential relevance of these regions for the pathophysiology of the disorder. PMID- 28832323 TI - Prevalence of Epidermal Growth Factor Receptor Mutations in Patients with Non Small Cell Lung Cancer in Turkish Population. AB - AIMS: Epidermal growth factor receptor mutation analysis in non-small cell lung cancer is important for selecting patients who will receive treatment with tyrosine kinase inhibitors. In this study, we aimed to investigate the prevalence of epidermal growth factor receptor mutations and mutation patterns in the Turkish population. METHODS: We retrospectively reviewed molecular pathology reports of 959 cases with lung cancer analysed for epidermal growth factor receptor mutations. We analysed all four epidermal growth factor receptor exon mutations using a real-time polymerase chain reaction platform. RESULTS: In this study, the epidermal growth factor receptor mutation rate in the Turkish population was 16.7% (160 of 959). The epidermal growth factor receptor mutation frequency was significantly higher in women (37.1%, n=96) than in men (9.1%, n=64) (p<0.001). In addition, the epidermal growth factor receptor mutation rate was higher in the adenocarcinoma histologic type (p<0.001). Patients with mutations were older than those without mutations (p=0.003). The most frequent mutations were exon 19 deletions (48.8%, 78/160) and exon 21 L858R point mutations (38.1.1%, 61/160). We also detected compound mutation patterns in three cases (1.9%). CONCLUSION: The prevalence of epidermal growth factor receptor mutations in the Turkish population was slightly higher than that in the Caucasian population and lower than that in the East Asian population. The results of this study may provide guidance in personalized therapy of non-small cell lung cancer in the Turkish population. PMID- 28832326 TI - Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon M-F. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood. 1973;41(4):489-496. PMID- 28832324 TI - The Morphological Anatomy of the Menisci of the Knee Joint in Human Fetuses. AB - BACKGROUND: Development of the foetal period of the meniscus has been reported in different studies. AIMS: Evaluation of lateral and medial meniscus development, typing and the relationship of the tibia during the foetal period. STUDY DESIGN: Anatomical dissection. METHODS: We evaluated 210 knee menisci obtained from 105 human foetuses ranging in age from 9 to 40 weeks' gestation. Foetuses were divided into four groups, and the intra-articular structure was exposed. We subsequently acquired images (Samsung WB 100 26X Optical Zoom Wide, Beijing, China) of the intra-articular structures with the aid of a millimetric ruler. The images were digitized for morphometric analyses and analysed by using Netcad 5.1 Software (Ak Muhendislik, Ankara, Turkey). RESULTS: The lateral and medial meniscal areas as well as the lateral and the medial articular surface areas of the tibia increased throughout gestation. We found that the medial articular surface areas were larger than the lateral articular surface areas, and the difference was statistically significant. The ratios of the mean lateral and medial meniscal areas to the lateral and medial articular surface areas, respectively, of the tibia decreased gradually from the first trimester to full term. The most common shape of the medial meniscus was crescentic (50%), and that of the lateral meniscus was C-shaped (61%). CONCLUSION: This study reveals the development of morphological changes and morphometric measurements of the menisci. PMID- 28832325 TI - The Change of Perinatal Mortality Over Three Decades in a Reference Centre in the Aegean Region: Neonatal Mortality has decreased but Foetal Mortality Remains Unchanged. AB - BACKGROUND: Perinatal, foetal and neonatal mortality statistics are important to show the development of a health care system in a country. However, in our country there are very few national and regional data about the changing pattern of perinatal neonatal mortality along with the development of new technologies in this area. AIMS: Evaluation of the changes in mortality rates and the causes of perinatal and neonatal deaths within years in a perinatal reference centre which serves a high-risk population. STUDY DESIGN: Cross-sectional retrospective study. METHODS: The perinatal, neonatal and foetal mortality rates in the years 1979 1980 (1st time point) and 1988-1989 (2nd time point) were compared with the year 2008 (3rd time point). The causes of mortality were assessed by Wigglesworth classification and death reports. The neonatal mortality in the neonatal intensive care unit was also calculated. RESULTS: Foetal mortality rates were 44/1000, 31.4/1000 and 41.75/1000 births, perinatal mortality rates were 35.6/1000, 18.8/1000 and 9/1000 births, and neonatal mortality rates were 35.6/1000, 18.8/1000 and 9/1000 live births for the three study time points, respectively. The mortality rate in neonatal intensive care unit decreased consistently from 33%, to 22.6% and 10%, respectively, together with decreasing neonatal mortality rates. The causes of perinatal deaths were foetal death 85%, immaturity 4%, and lethal congenital malformations 8% according to Wigglesworth classification in 2008, showing the high impact of foetal deaths on this high perinatal mortality rate. Infectious causes of neonatal deaths decreased but congenital anomalies increased in the last decades. CONCLUSION: Although neonatal mortality rate decreased significantly; foetal mortality rate has stayed unchanged since the late eighties. In order to decrease foetal and perinatal mortality rates more efficiently, reducing consanguineous marriages and providing better antenatal care for high risk pregnancies are needed. PMID- 28832322 TI - A chemical screen in zebrafish embryonic cells establishes that Akt activation is required for neural crest development. AB - The neural crest is a dynamic progenitor cell population that arises at the border of neural and non-neural ectoderm. The inductive roles of FGF, Wnt, and BMP at the neural plate border are well established, but the signals required for subsequent neural crest development remain poorly characterized. Here, we conducted a screen in primary zebrafish embryo cultures for chemicals that disrupt neural crest development, as read out by crestin:EGFP expression. We found that the natural product caffeic acid phenethyl ester (CAPE) disrupts neural crest gene expression, migration, and melanocytic differentiation by reducing Sox10 activity. CAPE inhibits FGF-stimulated PI3K/Akt signaling, and neural crest defects in CAPE-treated embryos are suppressed by constitutively active Akt1. Inhibition of Akt activity by constitutively active PTEN similarly decreases crestin expression and Sox10 activity. Our study has identified Akt as a novel intracellular pathway required for neural crest differentiation. PMID- 28832327 TI - B cells, PF4/heparin complexes, and complement. PMID- 28832328 TI - Combined therapy in MCL: less may be more? PMID- 28832329 TI - Thrombosis in AML? Yes, but when to worry? PMID- 28832330 TI - The bottom (central) line in pediatric DVT. PMID- 28832331 TI - Adding some muscle to blood coagulation. PMID- 28832332 TI - Parathyroid hormone-related protein-producing cyclin D3-positive blastoid variant of mantle cell lymphoma with hypercalcemia. PMID- 28832333 TI - CD5-/SOX-11- mantle cell lymphoma with concomitant monotypic plasmacytic differentiation. PMID- 28832334 TI - Beyond the margin recipe: the probability of correct target dosage and tumor control in the presence of a dose limiting structure. AB - In the past, hypothetical spherical target volumes and ideally conformal dose distributions were analyzed to establish the safety of planning target volume (PTV) margins. In this work we extended these models to estimate how alternative methods of shaping dose distributions could lead to clinical improvements. Based on a spherical clinical target volume (CTV) and Gaussian distributions of systematic and random geometrical uncertainties, idealized 3D dose distributions were optimized to exhibit specific stochastic properties. A nearby spherical organ at risk (OAR) was introduced to explore the benefit of non-spherical dose distributions. Optimizing for the same minimum dose safety criterion as implied by the generally accepted use of a PTV, the extent of the high dose region in one direction could be reduced by half provided that dose in other directions is sufficiently compensated. Further reduction of this unilateral dosimetric margin decreased the target dose confidence, however the actual minimum CTV dose at 90% confidence typically exceeded the minimum PTV dose by 20% of prescription. Incorporation of smooth dose-effect relations within the optimization led to more concentrated dose distributions compared to the use of a PTV, with an improved balance between the probability of tumor cell kill and the risk of geometrical miss, and lower dose to surrounding tissues. Tumor control rate improvements in excess of 20% were found to be common for equal integral dose, while at the same time evading a nearby OAR. These results were robust against uncertainties in dose-effect relations and target heterogeneity, and did not depend on 'shoulders' or 'horns' in the dose distributions. PMID- 28832335 TI - Cubic-phase zirconia nano-island growth using atomic layer deposition and application in low-power charge-trapping nonvolatile-memory devices. AB - The manipulation of matter at the nanoscale enables the generation of properties in a material that would otherwise be challenging or impossible to realize in the bulk state. Here, we demonstrate growth of zirconia nano-islands using atomic layer deposition on different substrate terminations. Transmission electron microscopy and Raman measurements indicate that the nano-islands consist of nano crystallites of the cubic-crystalline phase, which results in a higher dielectric constant (kappa ~ 35) than the amorphous phase case (kappa ~ 20). X-ray photoelectron spectroscopy measurements show that a deep quantum well is formed in the Al2O3/ZrO2/Al2O3 system, which is substantially different to that in the bulk state of zirconia and is more favorable for memory application. Finally, a memory device with a ZrO2 nano-island charge-trapping layer is fabricated, and a wide memory window of 4.5 V is obtained at a low programming voltage of 5 V due to the large dielectric constant of the islands in addition to excellent endurance and retention characteristics. PMID- 28832336 TI - Improving image quality for digital breast tomosynthesis: an automated detection and diffusion-based method for metal artifact reduction. AB - In digital breast tomosynthesis (DBT), the high-attenuation metallic clips marking a previous biopsy site in the breast cause errors in the estimation of attenuation along the ray paths intersecting the markers during reconstruction, which result in interplane and inplane artifacts obscuring the visibility of subtle lesions. We proposed a new metal artifact reduction (MAR) method to improve image quality. Our method uses automatic detection and segmentation to generate a marker location map for each projection (PV). A voting technique based on the geometric correlation among different PVs is designed to reduce false positives (FPs) and to label the pixels on the PVs and the voxels in the imaged volume that represent the location and shape of the markers. An iterative diffusion method replaces the labeled pixels on the PVs with estimated tissue intensity from the neighboring regions while preserving the original pixel values in the neighboring regions. The inpainted PVs are then used for DBT reconstruction. The markers are repainted on the reconstructed DBT slices for radiologists' information. The MAR method is independent of reconstruction techniques or acquisition geometry. For the training set, the method achieved 100% success rate with one FP in 19 views. For the test set, the success rate by view was 97.2% for core biopsy microclips and 66.7% for clusters of large post lumpectomy markers with a total of 10 FPs in 58 views. All FPs were large dense benign calcifications that also generated artifacts if they were not corrected by MAR. For the views with successful detection, the metal artifacts were reduced to a level that was not visually apparent in the reconstructed slices. The visibility of breast lesions obscured by the reconstruction artifacts from the metallic markers was restored. PMID- 28832337 TI - Study on dependence of dose enhancement on cluster morphology of gold nanoparticles in radiation therapy using a body-centred cubic model. AB - Gold nanoparticles (GNPs) injected in a body for dose enhancement in radiation therapy are known to form clusters. We investigated the dependence of dose enhancement on the GNP morphology using Monte-Carlo simulations and compared the model predictions with experimental data. The cluster morphology was approximated as a body-centred cubic (BCC) structure by placing GNPs at the 8 corners and the centre of a cube with an edge length of 0.22-1.03 um in a 4 * 4 * 4 um3 water filled phantom. We computed the dose enhancement ratio (DER) for 50 and 260 kVp photons as a function of the distance from the cube centre for 12 different cube sizes. A 10 nm-wide concentric shell shaped detector was placed up to 100 nm away from a GNP at the cube centre. For model validation, simulations based on BCC and nanoparticle random distribution (NRD) models were performed using parameters that corresponded to the experimental conditions, which measured increases in the relative biological effect due to GNPs. We employed the linear quadratic model to compute cell surviving fraction (SF) and sensitizer enhancement ratio (SER). The DER is inversely proportional to the distance to the GNPs. The largest DERs were 1.97 and 1.80 for 50 kVp and 260 kVp photons, respectively. The SF predicted by the BCC model agreed with the experimental value within 10%, up to a 5 Gy dose, while the NRD model showed a deviation larger than 10%. The SERs were 1.21 +/- 0.13, 1.16 +/- 0.11, and 1.08 +/- 0.11 according to the experiment, BCC, and NRD models, respectively. We most accurately predicted the GNP radiosensitization effect using the BCC approximation and suggest that the BCC model is effective for use in nanoparticle dosimetry. PMID- 28832338 TI - Nanoscale electromechanical and electronic properties of free-standing ZnO nano- and microstructured platelets. AB - The piezoelectric response, conductivity and surface potential of individual grains and grain boundaries in free-standing polycrystalline ZnO nano- and microstructured platelets is studied using scanning probe based techniques on the nanoscale. We find that applied dc electric fields can alter the piezoresponse in individual grains, as well as the local nanoscale conductivity, and invert the relative surface potential at grain boundaries. This can be attributed to defect accumulation at the grain surfaces and at grain boundaries and the associated density of carriers. Together with recently observed below-bandgap photoconductivity at grain boundaries, the presented observation opens new venues for potential nanoelectronic applications that rely on grain and grain boundary engineering and functionality in a wide-bandgap transparent material. PMID- 28832339 TI - Coherent normalization for in vivo measurements of gadolinium in bone. AB - OBJECTIVE: Recent evidence of gadolinium (Gd) deposition in bones of healthy individuals who have previously received Gd-based contrast agents (GBCAs) for MRI has led to a demand for in vivo measurement techniques. The technique of x-ray fluorescence provides a low risk and painless method to assess Gd deposition in bone, and has the potential to be a useful clinical tool. However, interpatient variability creates a challenge while performing in vivo measurements. APPROACH: We explored the use of coherent normalization, which involves normalizing the Gd K x-rays to the coherent scattered gamma-ray from the excitation source, for bone Gd measurements through a series of phantom-based experiments and Monte Carlo simulations. MAIN RESULTS: We found coherent normalization is able to correct for variation in overlying tissue thickness over a wide range (0-12.2 mm). The Gd signal to coherent signal ratio is independent of tissue thickness for both experiments and Monte Carlo simulations. SIGNIFICANCE: Coherent normalization has been demonstrated to be used in practice with normal healthy adults to improve in vivo bone Gd measurements. PMID- 28832340 TI - Overcoming the drawback of lower sense margin in tunnel FET based dynamic memory along with enhanced charge retention and scalability. AB - The work reports on the use of a planar tri-gate tunnel field effect transistor (TFET) to operate as dynamic memory at 85 degrees C with an enhanced sense margin (SM). Two symmetric gates (G1) aligned to the source at a partial region of intrinsic film result into better electrostatic control that regulates the read mechanism based on band-to-band tunneling, while the other gate (G2), positioned adjacent to the first front gate is responsible for charge storage and sustenance. The proposed architecture results in an enhanced SM of ~1.2 MUA MUm-1 along with a longer retention time (RT) of ~1.8 s at 85 degrees C, for a total length of 600 nm. The double gate architecture towards the source increases the tunneling current and also reduces short channel effects, enhancing SM and scalability, thereby overcoming the critical bottleneck faced by TFET based dynamic memories. The work also discusses the impact of overlap/underlap and interface charges on the performance of TFET based dynamic memory. Insights into device operation demonstrate that the choice of appropriate architecture and biases not only limit the trade-off between SM and RT, but also result in improved scalability with drain voltage and total length being scaled down to 0.8 V and 115 nm, respectively. PMID- 28832342 TI - Designing hybrid gate dielectric for fully printing high-performance carbon nanotube thin film transistors. AB - The electrical characteristics of carbon nanotube (CNT) thin-film transistors (TFTs) strongly depend on the properties of the gate dielectric that is in direct contact with the semiconducting CNT channel materials. Here, we systematically investigated the dielectric effects on the electrical characteristics of fully printed semiconducting CNT-TFTs by introducing the organic dielectrics of poly(methyl methacrylate) (PMMA) and octadecyltrichlorosilane (OTS) to modify SiO2 dielectric. The results showed that the organic-modified SiO2 dielectric formed a favorable interface for the efficient charge transport in s-SWCNT-TFTs. Compared to single-layer SiO2 dielectric, the use of organic-inorganic hybrid bilayer dielectrics dramatically improved the performances of SWCNT-TFTs such as mobility, threshold voltage, hysteresis and on/off ratio due to the suppress of charge scattering, gate leakage current and charge trapping. The transport mechanism is related that the dielectric with few charge trapping provided efficient percolation pathways for charge carriers, while reduced the charge scattering. High density of charge traps which could directly act as physical transport barriers and significantly restrict the charge carrier transport and, thus, result in decreased mobile carriers and low device performance. Moreover, the gate leakage phenomenon is caused by conduction through charge traps. So, as a component of TFTs, the gate dielectric is of crucial importance to the manufacture of high quality TFTs from the aspects of affecting the gate leakage current and device operation voltage, as well as the charge carrier transport. Interestingly, the OTS-modified SiO2 allows to directly print horizontally aligned CNT film, and the corresponding devices exhibited a higher mobility than that of the devices with the hybrid PMMA/SiO2 dielectric although the thickness of OTS layer is only ~2.5 nm. Our present result may provide key guidance for the further development of printed nanomaterial electronics. PMID- 28832344 TI - Strain controlled switching effects in phosphorene and GeS. AB - By performing first principles calculations within the combined approach of density functional theory and nonequilibrium Green's function technique, we have designed some nanoelectronic devices to explore the ferroelastic switching of phosphorene and phosphorene analogs GeS. With the structure swapping along the zigzag direction and armchair direction, band gap transformed at different states due to their anisotropic phosphorene-like structure. From the initial state to the middle state, the band gap becomes progressively smaller, after that, it becomes wide. By analyzing transmission coefficients, it is found that the transport properties of phosphorene and GeS can be controlled by a uniaxial strain. The results also manifest that GeS has great potential to fabricate ferroic nonvolatile memory devices, because its relatively high on/off transmission coefficient ratio (~1000) between the two stable ferroelastic states. PMID- 28832343 TI - A new formalism for modelling parameters alpha and beta of the linear-quadratic model of cell survival for hadron therapy. AB - We propose a new formalism for calculating parameters alpha and beta of the linear-quadratic model of cell survival. This formalism, primarily intended for calculating relative biological effectiveness (RBE) for treatment planning in hadron therapy, is based on a recently proposed microdosimetric revision of the single-target multi-hit model. The main advantage of our formalism is that it reliably produces alpha and beta that have correct general properties with respect to their dependence on physical properties of the beam, including the asymptotic behavior for very low and high linear energy transfer (LET) beams. For example, in the case of monoenergetic beams, our formalism predicts that, as a function of LET, (a) alpha has a maximum and (b) the alpha/beta ratio increases monotonically with increasing LET. No prior models reviewed in this study predict both properties (a) and (b) correctly, and therefore, these prior models are valid only within a limited LET range. We first present our formalism in a general form, for polyenergetic beams. A significant new result in this general case is that parameter beta is represented as an average over the joint distribution of energies E 1 and E 2 of two particles in the beam. This result is consistent with the role of the quadratic term in the linear-quadratic model. It accounts for the two-track mechanism of cell kill, in which two particles, one after another, damage the same site in the cell nucleus. We then present simplified versions of the formalism, and discuss predicted properties of alpha and beta. Finally, to demonstrate consistency of our formalism with experimental data, we apply it to fit two sets of experimental data: (1) alpha for heavy ions, covering a broad range of LETs, and (2) beta for protons. In both cases, good agreement is achieved. PMID- 28832345 TI - Biomimetic surface functionalization of clinically relevant metals used as orthopaedic and dental implants. AB - Titanium and its alloys or tantalum (Ta) are materials used in orthopaedic and dental implants due to their excellent mechanical properties and biocompatibility. However, their bioactivity and osteoconductivity is low. With a view to improving the bioactivity of these materials we hypothesised that the surface of Ta and TiAl6V4 can be functionalised with biomimetic, amorphous nano sized calcium phosphate (CaP) apatite-like deposits, instead of creating uniform coatings, which can lead to flaking, delamination and poor adherence. We used Ta and TiAl6V4 metal discs with smooth and rough surfaces. Amorphous CaP apatite like particles were deposited on the different surfaces by a biomimetic rapid two step soaking method using concentrated simulated body fluid (SBF) solutions without a pre-treatment of the metal surfaces to induce CaP deposition. Immersion times in the second SBF solution of 48 and 18 h for Ta and TiAl6V4 respectively produced CaP deposits composed of amorphous globular nano-sized particles that also contained Mg, C and O. Longer immersion times produced more uniform coatings as well as an undesired calcite mineral phase. Prediction of in vivo behaviour by immersion in regular SBF showed that the obtained CaP deposits would act as a catalyst to rapidly form a Ca deficient CaP layer that also incorporates Mg. The amorphous CaP apatite-like deposits promoted initial attachment, proliferation and osteogenic differentiation of bone marrow derived mesenchymal stem cells. Finally, we used our method to functionalise 3D porous structures of titanium alloy made by selective laser sintering. Our study uses a novel and cost effective approach to functionalise clinically relevant metal surfaces in order to increase the bioactivity of these materials, which could improve their clinical performance. PMID- 28832346 TI - Team Approach: Single-Event Multilevel Surgery in Ambulatory Patients with Cerebral Palsy. PMID- 28832347 TI - Perioperative Smoking Cessation and Clinical Care Pathway for Orthopaedic Surgery. PMID- 28832348 TI - Evidence-Based Management of the Knee in Hemophilia. PMID- 28832349 TI - Inclusion body myositis: advancements in diagnosis, pathomechanisms, and treatment. AB - PURPOSE OF REVIEW: To review new advances in inclusion body myositis (IBM) and discuss them in light of current knowledge on diagnosis, pathomechanisms, and treatment perspectives. RECENT FINDINGS: IBM is a treatment refractory inflammatory myopathy in middle-aged patients that leads to a slow, relentlessly progressive muscle weakness, and atrophy. Recent data collections suggest that mortality in IBM patients is somewhat elevated compared with the general population. One major risk factor for death is severe dysphagia, which can now be determined by a novel real-time MRI technique. Recently, proposed diagnostic criteria with a combination of clinical and histopathological features have improved sensitivity and specificity. cytosolic 5'-nucleotidase 1A antibodies have been characterized in IBM patients and their pathophysiologic role has recently been studied. New inflammatory pathomechanisms have been identified in IBM muscle and may help to design novel treatment strategies. A broad spectrum of immunosuppressive and immunomodulatory trials have been conducted, but - so far- no effective treatment is available. Current therapeutic attempts aim to block the myostatin pathway or restore the protein homeostasis. SUMMARY: The expanding knowledge of the complex disease, the refinement of diagnostic criteria, and developments in diagnostic procedures are expected to foster the much needed design of new treatment approaches for future clinical trials. PMID- 28832351 TI - Characterizing the Age and Stimulus Frequency Interaction for Ocular Vestibular Evoked Myogenic Potentials. AB - OBJECTIVES: The normal process of aging is mostly associated with global decline in almost all sensory aspects of the human body. While aging affects the 500-Hz tone burst-evoked ocular vestibular-evoked myogenic potentials (oVEMPs) by reducing the amplitudes and prolonging the latencies, its interaction with oVEMP responses at other frequencies has not been studied. Therefore, the present study aimed at investigating the impact of advancing age on the frequency tuning of oVEMP. DESIGN: Using a cross-sectional research design, oVEMPs were recorded for tone burst frequencies of 250, 500, 750, 1000, 1500, and 2000 Hz from 270 healthy individuals divided into six age groups (10-20, 20-30, 30-40, 40-50, 50-60, and >60 years). RESULTS: The results revealed significantly lower response rates and amplitudes in age groups above 50 years of age than all the other groups at nearly all the frequencies (p < 0.05). Further, the frequency tuning was obtained at 500 or 750 Hz in majority of individuals below 60 years of age and at >=1000 Hz in most of the individuals above 60 years of age (p < 0.05). Thus, there was a significant shift in frequency tuning of oVEMP from 500 or 750 Hz in the younger and the middle-aged adults to >=1000 Hz in older adults, especially above 60 years of age. CONCLUSIONS: The results of the study showed significantly higher prevalence of frequency tuning at 1000 Hz in older adults above 60 years of age. Because the shift in frequency tuning to >=1000 Hz is frequently used for identification of Meniere's disease, it is suggested that age-related correction be used for the diagnosis of Meniere's disease when using frequency tuning of oVEMP. PMID- 28832352 TI - Prognostic Evaluation of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Endometrial Cancer: A Retrospective Study. AB - OBJECTIVE: This study aims to ascertain if semiquantitative measurements derived from F-fluorodeoxyglucose positron emission tomography/computed tomography can be used as prognostic markers in patients with newly diagnosed endometrial cancer. MATERIALS AND METHODS: Patients with endometrial cancer and a preoperative F fluorodeoxyglucose positron emission tomography/computed tomography before curatively intended treatment were included. The scans were evaluated using standard uptake values [maximum standard uptake value (SUVmax) and partial volume corrected (c) mean standardized uptake value (SUVmean)] and whole-body total lesion glycolysis (cTLG). All measurements were analyzed as prognostic factors in relation to overall survival (OS). Receiver operating characteristic curves were performed on all 3 positron emission tomography measurements to find the optimal cut-off for predicting OS. Multivariate Cox proportional regression models were used for prognostic evaluation. RESULTS: Eighty-three patients (median age, 69.9 y; range, 26.8-91.1) with primarily high-risk endometrial cancer or suspected high The International Federation of Gynecology and Obstetrics stage were included. Mean follow-up time was 3.48 years (range, 0.31-6.87), and 24 patients died during follow-up. In multivariate analyses with adjustment for other known prognostic factors, a SUVmax of greater than or equal to 14.3 g/mL and cSUVmean of greater than or equal to 12.7 g/mL of the primary tumor yielded a hazard ratio for OS of 3.18 (1.19-8.49) and 1.93 (0.80-4.68), respectively. Whole-body cTLG of greater than or equal to 176.1 g yielded a hazard ratio of 5.70 (1.94-16.78) for OS in a multivariate analysis. CONCLUSIONS: Preoperative SUVmax and cTLG showed potential as independent prognostic markers of OS in patients with primarily high risk endometrial cancer. Thus, SUVmax and cTLG might help identify patients who could benefit from a more aggressive treatment strategy or closer surveillance. PMID- 28832350 TI - Which nonautoimmune myopathies are most frequently misdiagnosed as myositis? AB - PURPOSE OF REVIEW: To discuss the spectrum of nonautoimmune myopathies that may be misdiagnosed as autoimmune myopathy. RECENT FINDINGS: Inherited myopathies, such as dysferlinopathy, calpainopathy, and facioscapulohumeral dystrophy may be misdiagnosed as autoimmune myopathy, especially when they have inflammatory muscle biopsies. Inclusion body myositis is frequently misdiagnosed as polymyositis when rimmed vacuoles are absent on muscle biopsy, and a careful neuromuscular evaluation is not performed. Hypothyroid myopathy can be misdiagnosed as immune-mediated necrotizing myopathy if thyroid function tests, including a T4 level, are not obtained. Self-limited statin myopathy can be distinguished from statin-associated autoimmune myopathy because patients with the former do not have autoantibodies recognizing 3-hydroxy-3-methylglutaryl coenzyme A reductase. SUMMARY: Autoimmune myopathies can usually be distinguished from nonautoimmune myopathies based on a combination of the patient history, neuromuscular exam, laboratory findings, and/or muscle biopsy features. PMID- 28832353 TI - Allogeneic stem-cell transplantation for myelofibrosis. AB - PURPOSE OF REVIEW: Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative therapy for myelofibrosis. The number of HSCTs performed for this indication has been steadily increasing over the past years, even after the approval of the Janus kinase (JAK) inhibitor, ruxolitinib. This increase may be attributed to improved patient selection based on new prognostic molecular markers, more frequent use of matched unrelated donors, secondary to better (high-resolution) human leukocyte antigen typing and supportive care. Ruxolitinib approval raises new questions regarding the role of JAK inhibitors in the transplant setting. RECENT FINDINGS: The current review summarizes recent updates on HSCT in myelofibrosis. Predictors for transplant outcomes, and specific considerations related to myelofibrosis patient selection for HSCT (e.g. molecular risk stratification) are reviewed. In addition, this review will consider management of myelofibrosis patients in the peritransplant period, including the role of ruxolitinib in the pretransplant period, pre and posttransplant splenomegaly, transplant protocols, posttransplant follow-up of minimal residual disease and interventions in the event of poor engraftment. SUMMARY: HSCT remains a highly relevant treatment option for myelofibrosis in the era of JAK inhibitors. Recent advances may contribute to a refined definition of HSCT eligibility and identification of the optimal transplantation time, conditioning protocols and posttransplant management. PMID- 28832354 TI - Autologous hematopoietic cell transplantation of mantle cell lymphoma: emerging trends. AB - PURPOSE OF REVIEW: The management of mantle cell lymphoma has changed significantly with the adoption of immunochemotherapy and dose intensive treatment strategies in specific patient populations. Randomized controlled trials have established the role of rituximab-based treatments and autologous stem cell transplantation as standards of care. Novel therapeutics are also being integrated into these treatment strategies. RECENT FINDINGS: Rituximab-based primary treatment has been shown to significantly improve complete remission rates. The addition of autologous stem cell transplantation has also improved progression-free survival (PFS) although data regarding potential overall survival (OS) benefits are not clear. Complete remission and minimal residual disease (MRD) negative disease states are predictive of outcome. Rituximab maintenance post SCT has also been shown to significantly improves PFS and OS. SUMMARY: Current therapeutic standards in mantle cell lymphoma have clearly improved patient outcomes with improvements in remission rates, PFS, and OS. Autologous stem cell transplant (ASCT) as a consolidation strategy of primary treatment has improved outcomes, and the incorporation of novel drugs into frontline therapy may further improve the efficacy of the treatment. MRD-driven strategies may ultimately define appropriate patient subsets towards ASCT or alternative approaches. PMID- 28832355 TI - Prehospital hemostatic resuscitation to achieve zero preventable deaths after traumatic injury. AB - PURPOSE OF REVIEW: To describe how hemostatic resuscitation can be used in the prehospital phase of resuscitation to reduce preventable deaths after traumatic injury. RECENT FINDINGS: Hemorrhagic shock is the leading cause of death that is preventable after injury. The National Academy of Sciences, recently, recommended that achievement of zero preventable deaths after traumatic injury should be the goal of a national trauma system. In the United States, there are an estimated 25 000 preventable deaths per year in the prehospital phase of resuscitation because of traumatic hemorrhagic shock. Therefore, to achieve the goal of zero preventable deaths after injury, both shock and hemostatic dysfunction need to be addressed rapidly in the prehospital phase of resuscitation. This review will highlight the epidemiology and outcomes of traumatic hemorrhagic shock, and explore potential solutions such as group O whole blood and platelets stored at 2 6 degrees C. Trauma research receives the lowest funding relative to the burden of morbidity and mortality it creates when compared with all other diseases. Increased resources are required to achieve zero preventable deaths after injury. SUMMARY: Prehospital hemostatic resuscitation has the potential to significantly reduce preventable death from hemorrhage. PMID- 28832356 TI - Blood pressure in hemodialysis: targets? AB - PURPOSE OF REVIEW: In the absence of 'hard' clinical-trial evidence to define optimal blood pressure (BP) targets and validate different BP measurement techniques, management of hypertension in hemodialysis is based on expert opinions. In this review, we provide a comparative evaluation of out-of-dialysis BP monitoring versus dialysis-unit BP recordings in diagnosing hypertension, guiding its management and prognosticating mortality risk. RECENT FINDINGS: Owing to their high variability and poor reproducibility, predialysis and postdialysis BP recordings provide inaccurate reflection of the actual BP load outside of dialysis. Contrary to the reverse association of peridialytic BP with mortality, elevated home and ambulatory BP provides a direct mortality signal. Out-of dialysis BP monitoring, even when done in the clinic, is a reliable approach to manage hypertension in the dialysis unit. Whenever none of these measures are available, median intradialytic SBP can provide a better estimate of interdialytic BP levels compared with peridialytic BP measurements. SUMMARY: Although out-of-dialysis BP monitoring have better diagnostic accuracy and prognostic validity, randomized trials are needed to ascertain BP targets for managing hypertension in hemodialysis patients. PMID- 28832357 TI - Recurrent glomerular disease after kidney transplantation. AB - PURPOSE OF REVIEW: With improving short-term kidney transplant outcomes, recurrent glomerular disease is being increasingly recognized as an important cause of chronic allograft failure. Further understanding of the risks and pathogenesis of recurrent glomerular disease enable informed transplant decisions, along with the development of preventive and treatment strategies. RECENT FINDINGS: Multiple observational studies have highlighted differences in rates and outcomes for various recurrent glomerular diseases, although these rates have not markedly improved over the last decade. Emerging evidence supports use of rituximab to treat recurrent primary membranous nephropathy and possibly focal segmental glomerulosclerosis (FSGS), whereas eculizumab is effective in glomerular diseases associated with complement dysregulation [C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS)]. SUMMARY: Despite the potential for recurrence in the allograft, transplant remains the optimal therapy for patients with advanced chronic kidney disease (CKD) secondary to primary glomerular disease. Biomarkers and therapeutic options necessitate accurate pretransplant diagnoses with opportunities for improved surveillance and treatment of recurrent glomerular disease posttransplant. PMID- 28832358 TI - Doubly Robust Additive Hazards Models to Estimate Effects of a Continuous Exposure on Survival. AB - BACKGROUND: The effect of an exposure on survival can be biased when the regression model is misspecified. Hazard difference is easier to use in risk assessment than hazard ratio and has a clearer interpretation in the assessment of effect modifications. METHODS: We proposed two doubly robust additive hazards models to estimate the causal hazard difference of a continuous exposure on survival. The first model is an inverse probability-weighted additive hazards regression. The second model is an extension of the doubly robust estimator for binary exposures by categorizing the continuous exposure. We compared these with the marginal structural model and outcome regression with correct and incorrect model specifications using simulations. We applied doubly robust additive hazard models to the estimation of hazard difference of long-term exposure to PM2.5 (particulate matter with an aerodynamic diameter less than or equal to 2.5 microns) on survival using a large cohort of 13 million older adults residing in seven states of the Southeastern United States. RESULTS: We showed that the proposed approaches are doubly robust. We found that each 1 MUg m increase in annual PM2.5 exposure was associated with a causal hazard difference in mortality of 8.0 * 10 (95% confidence interval 7.4 * 10, 8.7 * 10), which was modified by age, medical history, socioeconomic status, and urbanicity. The overall hazard difference translates to approximately 5.5 (5.1, 6.0) thousand deaths per year in the study population. CONCLUSIONS: The proposed approaches improve the robustness of the additive hazards model and produce a novel additive causal estimate of PM2.5 on survival and several additive effect modifications, including social inequality. PMID- 28832359 TI - Functional dyspepsia and gastroparesis. AB - PURPOSE OF REVIEW: This review summarizes recent progress in the epidemiology, pathophysiology and treatment of functional dyspepsia and gastroparesis. RECENT FINDINGS: The definition of functional dyspepsia and its subgroups has been revised in the recent Rome IV consensus. In gastroparesis, the symptom pattern and its similarities and differences from functional dyspepsia have been a focus of recent research. In functional dyspepsia, pathophysiological research continued to evaluate gastric sensorimotor dysfunctions, but low-grade inflammatory changes and loss of mucosal integrity in the duodenum is a new topic of intense research. Treatment advances include new prokinetics such as acotiamide and the ghrelin receptor agonist relamorelin. The efficacy of tricyclic antidepressants was recently reviewed and mirtazapine is a new agent used in the treatment of functional dyspepsia and gastroparesis. In gastroparesis, research has focused on the role of macrophages in loss of interstitial cells of Cajal, and on the role of pyloric resistance as a target for therapy, using botulinum toxin injection and gastric per-endoscopic pyloric myotomy. SUMMARY: The functional dyspepsia definition and subgrouping were updated in the Rome IV consensus. Research focuses on duodenal mucosal alterations in functional dyspepsia and pyloric resistance in gastroparesis. New treatments include novel prokinetics and pylorus-directed interventions. PMID- 28832360 TI - Gastric interventional endoscopy. AB - PURPOSE OF REVIEW: To review new advances in gastric interventional endoscopy. RECENT FINDINGS: Implementation of gastric endoscopy as a therapeutic option in obesity, gastric cancer, and gastroparesis. SUMMARY: Less invasive new gastric endoscopic procedures can potentially replace currently offered laparoscopic approaches in many fields. In this article, we will review the use of endoscopic sleeve gastroplasty as a weight loss procedure, endoscopic submucosal dissection in treatment of early gastric cancer, and gastric per-oral endoscopic myotomy in treatment of refractory gastroparesis. These procedures can increase access to bariatric weigh loss procedures, provide an organ-saving curative option for early gastric cancer, and offer a new modality to improve refractory gastroparesis. PMID- 28832361 TI - Stomach and duodenum. PMID- 28832362 TI - Do Children and Adolescents With Inflammatory Bowel Disease Complete Clinical Disease Indices Similar to Physicians? AB - OBJECTIVES: The degree to which children and adolescents with inflammatory bowel disease (IBD) complete clinical disease activity indices in accordance with their physician is indefinite. Therefore, we investigated the agreement between patient and physician-based clinical indices in children and adolescents with a previous diagnosis of IBD. METHODS: In this cross-sectional study, IBD patients (8-18 years) were included prospectively. Patients completed a patient-based short Pediatric Crohn's Disease Activity Index (shPCDAI) for Crohn disease or the Pediatric Ulcerative Colitis Activity Index (PUCAI) for ulcerative or indeterminate colitis. Physicians completed the original physician-based shPCDAI or PUCAI. Agreement was calculated with linear weighted kappa. RESULTS: In total, 154 pairs of clinical indices were collected: 89 pairs of shPCDAI's (median age at assessment 15.6 years, 61% men) and 55 pairs of PUCAI's (median age at assessment 14.0 years, 44% men). The shPCDAI disease activity category only fairly agreed between patient- and physician-based indices (kappa: 0.40 [95% confidence interval 0.24-0.55], P < 0.001), with perfect agreement in 58% of pairs. In the majority of disagreement (81%), patients scored in a higher shPCDAI disease activity category. The PUCAI disease activity category substantially agreed between patient- and physician-based indices (kappa: 0.64 [95% confidence interval 0.45-0.83], P < 0.001), with perfect agreement in 78% of pairs. In the majority of disagreement (75%), patients scored in a higher PUCAI disease activity category. CONCLUSIONS: Patient- and physician-based shPCDAI and PUCAI do not always agree, particularly the shPCDAI, and therefore, should not be interpreted equivalently in management and research on children and adolescents with IBD. PMID- 28832363 TI - Intranasal vaccination against angiotensin II type 1 receptor and pneumococcal surface protein A attenuates hypertension and pneumococcal infection in rodents. AB - OBJECTIVES: To combat global increases in the prevalence of lifestyle-related diseases and concomitant infectious diseases, we aimed to develop an innovative intranasal vaccine that simultaneously targets both hypertension and pneumonia, is not given by invasive injection, and offers prolonged therapeutic effect and reduced frequency of administration. METHODS: Angiotensin II type 1 receptor pneumococcal surface protein A (AT1R-PspA) vaccine, consisting of a cationic nanometer-sized hydrogel incorporating AT1R partial peptide conjugated with PspA and cyclic diguanylate monophosphate adjuvant, was created and given intranasally to spontaneously hypertensive rats (SHRs). Antigen-specific antibodies and blood pressure were examined to evaluate immune responses and the antihypertensive effect of the vaccine. To examine the protective effect of antibodies induced by vaccination on pneumococcal infection, sera obtained from immunized SHRs were incubated with a lethal dose of Streptococcus pneumoniae and then administered to mice. RESULTS: Five doses of AT1R-PspA nasal-vaccine-induced AT1R-specific serum IgG antibody production and attenuated the development of hypertension in SHRs in the long term. Both in-vitro and in-vivo studies revealed that responses to angiotensin II were suppressed in vaccinated rats. Mice passively immunized with sera obtained from AT1R-PspA-vaccinated SHRs were protected from lethal pneumococcal infection. CONCLUSION: Intranasal immunization with AT1R-PspA vaccine has the potential to simultaneously attenuate the development of hypertension and protect from lethal pneumococcal infection. PMID- 28832364 TI - Screening of primary aldosteronism by clinical features and daily laboratory tests: combination of urine pH, sex, and serum K. AB - OBJECTIVE: To develop and validate a scoring system for selection of patients who should proceed to endocrinologic examinations of primary aldosteronism in newly diagnosed hypertensive patients. METHODS: A multivariate logistic regression analysis for primary aldosteronism was undertaken by use of seven possible primary aldosteronism markers, age less than 40 years, female sex, moderate-to severe hypertension, hypokalemia, serum Na minus Cl at least 40 mmol/l, serum uric acid 237.92 MUmol/l or less (4.0 mg/dl), and urine pH (U-pH) at least 7.0, in consecutive outpatients newly diagnosed with hypertension. The diagnostic criteria of primary aldosteronism were plasma aldosterone concentration-to-plasma renin activity ratio [ARR, (ng/dl)/(ng/ml per h)] at least 20 and at least one positive result in four types of challenge tests. RESULTS: Of 130 patients, 24 were diagnosed with primary aldosteronism. The area under the receiver operating characteristic curve (AUC) for a logistic model incorporating all possible primary aldosteronism markers was 0.73 [95% confidence interval (CI): 0.61-0.85]. Removing high U-pH, female sex, and hypokalemia from the full model decreased the AUC by 0.059, 0.035, and 0.011, respectively. We devised pH of urine, female sex, low serum K (PFK) score, in which one point each was assigned to high U-pH, female sex, and hypokalemia. The prevalences of primary aldosteronism in patients with 0, 1, 2, and 3 points were 11, 14, 42, and 60%, respectively. In external validation datasets (n = 106), AUC of PFK score was significantly higher than that of hypokalemia alone (0.73, 95% CI: 0.63-0.83 vs. 0.53, 95% CI: 0.44-0.63, P < 0.01). CONCLUSION: PFK score may be a better parameter than hypokalemia alone for identifying patients with a high probability of having primary aldosteronism. PMID- 28832365 TI - Achieving target SBP for lowering the risk of major adverse cardiovascular events in persons with diabetes mellitus. AB - AIM: To test the efficacy of achieving target SBP less than 120 mmHg, or less than 140 mmHg, for lowering the risk of major adverse cardiovascular events (MACE) in persons with diabetes mellitus. METHOD: The study comprised 4732 [mean +/- SD age: 63 +/- 7 years; 2258 (48%) women] persons with advanced diabetes mellitus. Participants randomly assigned to achieve intensive (<120 mmHg) or standard (<140 mmHg) SBP control were grouped according to whether or not they achieved their respective SBP goal. MACE consisted of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes. RESULTS: During a median 5.0 (interquartile range: 4.2-5.7) years, 1939 (82%) and 2038 (86%) persons achieved SBP targets less than 120 and less than 140 mmHg in each treatment arm, respectively. Overall, 208 (9%) and 237 (10%) persons in the intensive and standard treatment arms experienced MACE. In the intensive treatment arm, multivariable Cox regression revealed no significant reduction in risk of MACE for those who achieved a target SBP less than 120 mmHg. In the standard treatment arm, those who achieved a target SBP less than 140 mmHg displayed a substantial reduction in risk of MACE (hazard ratio = 0.65, P = 0.005), all-cause death (hazard ratio = 0.64, P = 0.02), and nonfatal stroke (hazard ratio = 0.47, P = 0.02) as compared with those whose achieved SBP was 140 mmHg or higher. CONCLUSION: Achieving a standard SBP goal between 120 and 140 mmHg may prove useful for lowering cardiovascular risk in persons with diabetes mellitus. Achieving a target SBP less than 120 mmHg does not appear to mitigate risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT00000620 (https://clinicaltrials.gov/ct2/results?term=NCT00000620&Search=Search). PMID- 28832366 TI - HIV and myocarditis. AB - PURPOSE OF REVIEW: The purpose of this article is to review the literature on HIV and myocarditis and HIV-associated heart failure. RECENT FINDINGS: Currently, 17 million people are receiving antiretroviral therapy (ART) globally. There is a decrease in mortality from HIV in the last decade with increased survival in those receiving ART. HIV-associated cardiac failure is on the increase, with more cases of diastolic dysfunction reported in the ART era. The pathophysiology of HIV-associated myocarditis is multifactorial. Cardiovascular magnetic resonance (CMR), through tissue characterization, demonstrates increased native T1 values which reflect both increased myocardial inflammation and fibrosis in HIV infection. SUMMARY: HIV-associated myocarditis is common and may be an important cause of HIV-associated cardiac failure. CMR is an important imaging modality for the study of myocardial inflammation. PMID- 28832368 TI - Are we successfully managing cardiovascular disease in people living with HIV? AB - PURPOSE OF REVIEW: The aim of this study was to discuss the most recent research in the management of cardiovascular disease (CVD) in people living with HIV (PLWHIV) with a focus on screening, primary and secondary prevention. RECENT FINDINGS: The cause of CVD in PLWHIV is complex and multifactorial and creates a demand for a multifaceted approach to screening and prevention. Current screening and management of CVD risk factors in PLWHIV is suboptimal, reasons for this are not clear and the data are still scarce both in the primary and secondary preventive setting. There are no optimal routine risk screening tools available to accurately detect early and subclinical disease; PLWHIV are undertreated with preventive drugs such as statins and aspirin and antihypertensives; there are still no programmes that have been shown significantly efficient over time with regards to improved smoking cessation, increased physical activity and optimal diet, and recent reports call for intensified focus on HIV-positive women as a particularly vulnerable subgroup. SUMMARY: There is a need for further studies investigating barriers to optimal CVD risk factor management in PLWHIV and an increased focus of CVD prevention in HIV-positive women. PMID- 28832367 TI - Cardiovascular disease risk among women living with HIV in North America and Europe. AB - PURPOSE OF REVIEW: To examine the epidemiology and mechanistic underpinnings of heightened cardiovascular disease (CVD) risk among women living with HIV (WLHIV) in North America and Europe. RECENT FINDINGS: WLHIV in North America and Europe exhibit high CVD incidence rates, which are at par with those of compatriot men living with HIV. Compared with uninfected women, WLHIV in these regions face a 2 4-fold increased relative risk for myocardial infarction, stroke, and heart failure. HIV-associated CVD risk is fuelled by a negative synergy of traditional cardiometabolic risk factors and heightened systemic immune activation/inflammation. Among WLHIV, female sex and endogenous sex hormone production influence both traditional cardiometabolic risk factors and patterns of systemic immune activation/inflammation. WLHIV in North America and Europe may also experience heightened CVD risk in relation to a relatively increased prevalence of behavioral and psychosocial CVD risk factors, coupled with suboptimal therapeutic targeting of known traditional cardiometabolic risk factors. SUMMARY: Additional research on sex-specific mechanisms of HIV associated CVD - based not only out of North America and Europe but also and especially out of Africa, Asia, and South America - will inform the development of CVD prediction algorithms and prevention guidelines clinically relevant to the approximately 17 million women aging with HIV globally. PMID- 28832369 TI - Trial designs for statin muscle intolerance. AB - PURPOSE OF REVIEW: This article aims to review the spectrum of statin-associated muscle symptoms (SAMS), the consequences of downtitration of statin therapy on cardiovascular events, the published trials of nonstatin therapy in patients who report SAMS, and to provide a framework for future trials in SAMS patients. RECENT FINDINGS: SAMS is reported in 10-25% of patients prescribed statin therapy; however, the few patients enrolled in randomized, double-blind, controlled clinical trials (RCTs) discontinue statin therapy due to adverse events. Several possible reasons for this discrepancy in clinical practice versus RCTs may results from patient selection in clinical trials that excludes patients with characteristics that increase the risk of SAMS, widespread use of higher intensity statins in low-risk populations that evaluated in nearly all RCTs, and perceptions concerning harm of statin therapy. Clinical trials of nonstatin therapy have shown that most patients tolerate statin therapy upon repeat challenge, and thus better tools are needed to more accurately identify SAMS patients and enroll these patients in RCTs of nonstatin therapy. SUMMARY: Clinical trials in patients who report SAMS have shown better tolerability of certain classes of nonstatin therapy. Low rates of recurrent SAMS in double-blind rechallenge have led some to challenge the concept of statin muscle intolerance. However, patients with perceived SAMS downtitrate their statin therapy and suffer more cardiovascular events. A revised paradigm for evaluation of SAMS is proposed. PMID- 28832370 TI - Dietary nitrate as modulator of physical performance and cardiovascular health. AB - PURPOSE OF REVIEW: Early interventional trials reported improvements in cardiac and exercise outcomes with inorganic nitrate ingestion. The current review aims to provide a brief update of recent evidence regarding ergogenic and cardiovascular effects of dietary nitrate and practical recommendations. RECENT FINDINGS: Recent evidence has been inconsistent and questions remain regarding effective dose, duration, and source of nitrate and cohorts likely to benefit. Dietary nitrate may be most relevant to those with vascular/metabolic impairments, those engaging in short-term, intense exercise, deconditioned individuals, and those with a low dietary nitrate intake. SUMMARY: The evidence for cardiovascular/exercise benefit is plausible but inconsistent. However, dietary nitrate, in contrast to pharmacological nitrate, has a high benefit-risk ratio. Although nitrate supplementation has grown in popularity, it is suggested that increased green vegetables consumption may provide similar/superior benefits to nitrate supplementation in a cheaper, safer, and potentially tastier context. PMID- 28832371 TI - Dietary factors in the etiology and therapy of attention deficit/hyperactivity disorder. AB - PURPOSE OF REVIEW: The purpose of this study is to discuss the role of dietary factors in the etiology and therapy of attention deficit/hyperactivity disorder (ADHD). Relevant literature published from January 2016 to January 2017 was included in this review. RECENT FINDINGS: Unhealthy prenatal diet may be associated with ADHD in the offspring through an increase in epigenetic changes. The few-foods diet may have some efficacy, but requires further investigation before firm conclusions can be drawn. The efficacy of the supplementation of polyunsaturated fatty acids in the therapy of ADHD is probably small and may be confined to patient subgroups. It is unclear whether vitamin deficiency plays a role in the etiology of ADHD. SUMMARY: There is no clear evidence supporting a role of food or nutrient-based intervention strategies in the etiology and therapy of ADHD. The investigation of the inter-relationship between diet and other lifestyle interventions may be a promising approach. PMID- 28832372 TI - Nutrient modulation in the management of disease-induced muscle wasting: evidence from human studies. AB - PURPOSE OF REVIEW: In addition to being essential for movement, skeletal muscles act as both a store and source of key macronutrients. As such, muscle is an important tissue for whole body homeostasis, undergoing muscle wasting in times of starvation, disease, and stress, for example, to provide energy substrates for other tissues. Yet, muscle wasting is also associated with disability, comorbidities, and mortality. As nutrition is so crucial to maintaining muscle homeostasis 'in health', it has been postulated that muscle wasting in cachexia syndromes may be alleviated by nutritional interventions. This review will highlight recent work in this area in relation to muscle kinetics, the acute metabolic (e.g. dietary protein), and longer-term effects of dietary interventions. RECENT FINDINGS: Whole body and skeletal muscle protein synthesis invariably exhibit deranged kinetics (favouring catabolism) in wasting states; further, many of these conditions harbour blunted anabolic responses to protein nutrition compared with healthy controls. These derangements underlie muscle wasting. Recent trials of essential amino acid and protein-based nutrition have shown some potential for therapeutic benefit. SUMMARY: Nutritional modulation, particularly of dietary amino acids, may have benefits to prevent or attenuate disease-induced muscle wasting. Nonetheless, there remains a lack of recent studies exploring these key concepts to make conclusive recommendations. PMID- 28832373 TI - Pregnancy in Patients With Congenital Heart Disease: A Contemporary Challenge. AB - The majority of female patients with congenital heart disease (CHD) survives into childbearing age and require evidence-based counseling regarding pregnancy options. Even though most of them will have an uneventful pregnancy, they may be at high risk of cardiac, obstetric, and fetal complications. Predictive factors for these complications have been previously identified in numerous studies and with the use of specific scores [CARdiac disease in PREGnancy, Zwangerschap bij Aangeboren HARtAfwijkingen, and World Health Organization (WHO) risk stratification.] Importantly, the subtype of CHD is of vital importance for the pregnancy outcome. Considering the above, the multidisciplinary management of these pregnant patients by experts in the field of CHD is imperative. PMID- 28832374 TI - Chronic Thromboembolic Pulmonary Hypertension: Epidemiology, Diagnosis, and Management. AB - Chronic thromboembolic pulmonary hypertension (CTEPH), classified as World Health Organization (WHO) group 4 pulmonary hypertension (PH), is an interesting and rare pulmonary vascular disorder secondary to mechanical obstruction of the pulmonary vasculature from thromboembolism resulting in PH. The pathophysiology is complex, beginning with mechanical obstruction of the pulmonary arteries, which eventually leads to arteriopathic changes and vascular remodeling in the nonoccluded arteries and in the distal segments of the occluded arteries mediated by thrombus nonresolution, abnormal angiogenesis, endothelial dysfunction, and various local growth factors. Based on available data, CTEPH is a rare disease entity occurring in a small proportion (0.5-3%) of patients after acute pulmonary embolism with an annual incidence ranging anywhere between 1 and 7 cases per million population. It is often underdiagnosed or misdiagnosed as idiopathic pulmonary arterial hypertension due to a lack of clinical suspicion or the under utilization of radionuclide ventilation/perfusion scan. Although the current standard remains planar ventilation/perfusion scintigraphy as the initial imaging study to screen for CTEPH, and invasive pulmonary angiography with right heart catheterization as confirmatory modalities, they are likely to be replaced by modalities that can provide both anatomic and functional data while minimizing radiation exposure. Surgery is the gold standard treatment and offers better improvements in clinical and hemodynamic parameters compared with medical therapy. The management of CTEPH requires a multidisciplinary team, operability assessment, experienced surgical center, and the consideration of medical PH directed therapies in patients who have inoperable disease, in addition to supportive therapies. Although, balloon pulmonary angioplasty is gaining interest to improve pulmonary hemodynamics and symptoms in CTEPH patients not amenable to surgery, further investigative randomized studies are needed to validate its use. It is very important for the present-day physician to be familiar with the disease entity and its appropriate evaluation to facilitate early diagnosis and appropriate management. PMID- 28832375 TI - Contemporary Diagnosis and Management of Atrial Flutter: A Continuum of Atrial Fibrillation and Vice Versa? AB - Atrial flutter (AFlu) is usually a fast (>240 bpm) and regular right atrial macroreentrant tachycardia, with a constrained critical region of the reentry circuit located at the cavotricuspid isthmus (CTI; typical CTI-dependent AFlu). However, a variety of right and left atrial tachycardias, resulting from different mechanisms, can also present as AFlu (atypical non-CTI-dependent AFlu). The electrocardiogram can provide clues to its origin and location; however, additional entrainment and more sophisticated electroanatomical mapping techniques may be required to identify its mechanism, location, and target area for a successful ablation. Although atrial fibrillation and AFlu are 2 separate arrhythmias, they often coexist before and after drug and/or ablation therapies. Indeed, there appears to be a close interrelationship between these 2 arrhythmias, and one may "transform" into the other. These issues are discussed in this overview, and practical algorithms are proposed to guide AFlu localization and illustrate the AFlu and atrial fibrillation continuum. PMID- 28832376 TI - Low-Dose Radioactive Iodine Ablation Is Sufficient in Patients With Small Papillary Thyroid Cancer Having Minor Extrathyroidal Extension and Central Lymph Node Metastasis (T3 N1a). AB - PURPOSE: The aim of this study was to evaluate the effectiveness of low-dose radioactive iodine (RAI) ablation in patients with small papillary thyroid cancer (PTC) exhibiting microscopic extrathyroidal extension (mETE) and central lymph node (CLN) metastasis. METHODS: Among patients who underwent RAI ablation between March 2007 and February 2014, those who had small PTCs (<=2 cm), as well as mETE and CLN metastasis (T3 N1a M0), were enrolled. Response to ablation and long-term outcomes were assessed and compared according to the administered RAI dose. Factors associated with unsuccessful ablation were also determined. RESULTS: A total of 180 patients were included in the study. Eighty-eight patients had been treated with 1110 MBq (low-dose group) and 92 with 2960 MBq (high-dose group) of RAI. There were no significant differences in the responses to ablation (P = 0.810) and long-term outcomes (P = 0.663) between both groups. Among all patients enrolled, 13 did not achieve successful ablation at long-term follow-up. Logistic regression found that a high ratio of metastatic nodes was a significant factor for predicting unsuccessful ablation. CONCLUSIONS: Low-dose RAI ablation did not produce significantly different responses or long-term outcomes in patients with small PTCs exhibiting mETE and CLN metastasis. These findings suggest that low dose ablation may be sufficient in this specific group of intermediate-risk patients, although careful selection is required for patients with a high ratio of metastatic nodes. PMID- 28832379 TI - Lumps and Clumps. PMID- 28832377 TI - Safety and Effectiveness of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy After Regional Hepatic Embolization in Patients With Somatostatin-Expressing Neuroendocrine Tumors. AB - PURPOSE: Peptide receptor radionuclide therapy (PRRT) with Lu-DOTATATE is shown to be an effective therapeutic option for somatostatin-expressing neuroendocrine neoplasms. Some concerns are raised over safety of this modality in patients with a history of regional chemoembolization and radionuclide hepatic embolization (CRHE) and is cause of reluctance among some physicians for suggesting Lu DOTATATE in this patient population. METHODS: We retrospectively reviewed 143 patients with somatostatin-expressing neuroendocrine tumors who underwent Lu DOTATATE PRRT. Statistical analysis was performed on effect of Lu-DOTATATE in patients with and without prior CRHE using resampling procedures and correlation coefficient (r). RESULTS: Proportion of toxicity in patients with and without CRHE was comparable (P = 0.246). No statistically significant correlation (r) found between any toxicity and prior CRHE (r = -0.3 to -0.03) or time elapsed between embolization and the first cycle of PRRT (r = -0.59 to 0.17). Following PRRT, 76.5% of patients with CRHE experienced benefit (partial response + stable disease), whereas 23.4% experienced progressive disease. Patients with CRHE showed more stable disease (P = 0.048) and less progressive disease (P = 0.046) following PRRT compared with no CRHE. The CRHE and no-CRHE status shared same probability for developing partial response/complete response following PRRT (P = 0.50). CONCLUSIONS: Treatment with Lu-DOTATATE did not show clinically or statistically significant toxicity in CRHE patients regardless of frequency of embolization or time interval between embolization and first PRRT. Results suggested a statistically significant higher response rate in patients with a history of CRHE. A prior history of CRHE is not a contraindication to subsequent PRRT. PMID- 28832380 TI - Improvement in the Axial Symptoms and Magnetic Resonance Imaging Findings With Apremilast in Psoriatic Arthritis. PMID- 28832381 TI - A Rare Case of Lupus Pancreatitis Disguised as Gallstone Pancreatitis. PMID- 28832382 TI - Flip or Flop: Post-Traumatic Charcot Arthropathy of the Right Hip from Acrobatics. PMID- 28832383 TI - Could Anticoagulation or Antiaggregation Treatment Be Ceased in Patients With Primary Antiphospholipid Syndrome When Antiphospholipid Antibodies Become Persistently Negative? PMID- 28832384 TI - The Evolving Role of Tumor Treating Fields in Managing Glioblastoma: Guide for Oncologists. AB - Glioblastoma (GBM) is a devastating brain tumor with poor prognosis despite advances in surgery, radiation, and chemotherapy. Survival of patients with glioblastoma remains poor, with only 1 in 4 patients alive at 2 years, and a 5 year survival rate of about 5%. Recurrence is nearly universal and, after recurrence, prognosis is poor with very short progression-free survival and overall survival (OS). Various salvage chemotherapy strategies have been applied with limited success. Tumor Treating Fields (TTFields) are a novel treatment modality approved for treatment of either newly diagnosed or recurrent GBM. TTFields therapy involves a medical device and transducer arrays to provide targeted delivery of low intensity, intermediate frequency, alternating electric fields to produce antimitotic effects selective for rapidly dividing tumor cells with limited toxicity. In the phase 3 EF-14 trial, TTFields plus temozolomide provided significantly longer progression-free survival and OS compared with temozolomide alone in patients with newly diagnosed GBM after initial chemoradiotherapy. The addition of TTFields to standard therapy improved median OS from 15.6 to 20.5 months (P=0.04). In the phase 3 EF-11 trial, for recurrent GBM, TTFields provided comparable efficacy as investigator's choice systemic therapy, with improved patient-reported quality of life and a lower incidence of serious adverse events. Primary toxicity associated with TTFields is skin irritation generally managed with array relocation and topical treatments including antibiotics and steroids. TTFields therapy has demonstrated proven efficacy in management of GBM, including improvement in OS for patients with newly diagnosed GBM, and is under current investigation in other brain and extracranial tumors. PMID- 28832386 TI - Marfanoid habitus is a nonspecific feature of Perrault syndrome. AB - The objective of this study was to report the clinical and biological characteristics of two Perrault syndrome cases in a Moroccan family with homozygous variant c.1565C>A in the LARS2 gene and to establish genotype phenotype correlation of patients with the same mutation by review of the literature. Whole-exome sequencing was performed. Data analysis was carried out and confirmed by Sanger sequencing and segregation. The affected siblings were diagnosed as having Perrault syndrome with sensorineural hearing loss at low frequencies; the female proband had primary amenorrhea and ovarian dysgenesis. Both affected individuals had a marfanoid habitus and no neurological features. Both patients carried the homozygous variant c.1565C>A; p.Thr522Asn in exon 13 of the LARS2 gene. This variant has already been reported as a homozygous variant in three other Perrault syndrome families. Both affected siblings of a Moroccan consanguineous family with LARS2 variants had low-frequency sensorineural hearing loss, marfanoid habitus, and primary ovarian insufficiency in the affected girl. According to the literature, this variant, c.1565C>A; p.Thr522Asn, can be correlated with low-frequency hearing loss. However, marfanoid habitus was been considered a nonspecific feature in Perrault syndrome, but we believe that it may be more specific than considered previously. This diagnosis allowed us to provide appropriate management to the patients and to provide more accurate genetic counseling to this family. PMID- 28832387 TI - Letter from the Editor. PMID- 28832388 TI - General Health Status After Nonoperative Versus Operative Treatment for Acute, Complete Acromioclavicular Joint Dislocation: Results of a Multicenter Randomized Clinical Trial. AB - OBJECTIVE: To assess the general health status of patients after nonoperative (Non-op) versus operative (OP) treatment for acromioclavicular (AC) joint dislocations. DESIGN: Multicenter randomized controlled clinical trial conducted in 11 Canadian trauma centers. A total of 83 patients with acute (<=28 days old), complete (Rockwood grades III, IV, or V) dislocations of the AC joint were included in this study. INTERVENTION: Participants were randomized to Non-op treatment or OP treatment with hook plate fixation. MAIN OUTCOME MEASURES: Physical and mental health were evaluated using the Short Form-36 version 2 survey at baseline, 6 weeks, 3 months, 6 months, 1 year, and 2 years. RESULTS: In the Non-op group, 33 patients had grade III injuries, 3 patients had grade IV injuries, 5 patients had grade V injuries, and the injury grade was unknown for 2 patients. In the OP group, 37 patients had grade III injuries and 3 patients had grade V injuries (no difference in Type IV and V Non-op vs. OP, P = 0.12). Fifty eight percent of patients in the Non-op group and 63% of patients in the OP group completed the 2-year follow-up. The Non-op group had better physical health scores than the OP group at 3 months after treatment (52.13 vs. 45.75, P < 0.001). There were no significant differences between the physical health scores of the 2 groups at any other point (6 weeks, 45.81 vs. 41.21, P = 0.03; 6 months, 54.50 vs. 51.61, P = 0.02; 1 year, 55.10 vs. 53.96, P = 0.37; 2 years, 55.24 vs. 57.13, P = 0.17). Mental health scores were similar between the Non-op and OP groups at each follow-up interval (6 weeks, 49.29 vs. 51.27, P = 0.49; 3 months, 52.24 vs. 55.84, P = 0.13; 6 months, 54.89 vs. 55.05, P = 0.93; 1 year, 55.35 vs. 56.72, P = 0.35; 2 years, 56.41 vs. 55.43, P = 0.56). In both treatment groups, the preinjury physical and mental health scores were better than published population norms before declining to a level equal to or below the norm after dislocation. Physical health recovered to a level above the norm at 6 months in the Non-op group and 2 years in the OP group. Mental health recovered at 3 months in the OP group and 6 months in the Non-op group. CONCLUSIONS: Hook plate fixation does not lead to improved general health status compared with Non-op treatment. Presently, there is no definitive evidence that hook plate fixation is superior to Non-op treatment for acute complete AC joint dislocations. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28832389 TI - Prospective Evaluation of Posttraumatic Stress Disorder and Depression in Orthopaedic Injury Patients With and Without Concomitant Traumatic Brain Injury. AB - OBJECTIVES: Psychological morbidities after injury [eg, posttraumatic stress disorder (PTSD) and depression] are increasingly recognized as a significant determinant of overall outcome. Traumatic brain injury (TBI) negatively impacts outcomes of patients with orthopaedic injury, but the association of concurrent TBI, orthopaedic injury, and symptoms of PTSD and depression has not been examined. This study's objective was to examine symptoms of PTSD and depression in patients with orthopaedic trauma with and without TBI. DESIGN: Longitudinal prospective cohort study. SETTING: Urban Level I Trauma Center in the Southwest United States. PATIENTS/PARTICIPANTS: Orthopaedic trauma patients older than 18 years admitted for >=24 hours. MAIN OUTCOME MEASUREMENTS: Questionnaires examining demographics, injury-related variables, PTSD, and depression were administered during hospitalization and 3, 6, and 12 months later. Orthopaedic injury and TBI were determined based on ICD-9 codes. Generalized linear models determined whether PTSD and depression at follow-up were associated with TBI. RESULTS: Of the total sample (N = 214), 44 (21%) sustained a TBI. Those with TBI had higher rates of PTSD symptoms, 12 months postinjury (P = 0.04). The TBI group also had higher rates of depressive symptoms, 6 months postinjury (P = 0.038). CONCLUSIONS: Having a TBI in addition to orthopaedic injury was associated with significantly higher rates of PTSD at 12 months and depression at 6 months postinjury. This suggests that sustaining a TBI in addition to orthopaedic injury places patients at a higher risk for negative psychological outcomes. The findings of this study may help clinicians to identify patients who are in need for psychological screening and could potentially benefit from intervention. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28832390 TI - Re: Vertically Oriented Femoral Neck Fractures: A Biomechanical Comparison of 3 Fixation Constructs. PMID- 28832391 TI - Reply re: Vertically Oriented Femoral Neck Fractures: A Biomechanical Comparison of 3 Fixation Constructs. PMID- 28832392 TI - Ischemic Preconditioning Blunts Muscle Damage Responses Induced by Eccentric Exercise. AB - PURPOSE: Ischemic preconditioning (IPC) is known to reduce muscle damage induced by ischemia and reperfusion injury during surgery. Because of similarities between the pathophysiological formation of ischemia and reperfusion injury and eccentric exercise-induced muscle damage (EIMD), as characterized by an intracellular accumulation of Ca, an increased production of reactive oxygen species, and increased proinflammatory signaling, the purpose of the present study was to investigate whether IPC performed before eccentric exercise may also protect against EIMD. METHODS: Nineteen healthy men were matched to an eccentric only (ECC; n = 9) or eccentric proceeded by IPC group (IPC + ECC; n = 10). The exercise protocol consisted of bilateral biceps curls (3 * 10 repetitions at 80% of the concentric one-repetition maximum). In IPC + ECC, IPC was applied bilaterally at the upper arms by a tourniquet (200 mm Hg) immediately before the exercise (3 * 5 min of occlusion, separated by 5 min of reperfusion). Creatine kinase (CK), arm circumference, subjective pain (visual analog scale score), and radial displacement (tensiomyography, maximal radial displacement) were assessed before IPC, preexercise, postexercise, and 20 min, 2 h, 24 h, 48 h, and 72 h postexercise. RESULTS: CK differed from baseline only in ECC at 48 h (P < 0.001) and 72 h (P < 0.001) postexercise. After 24, 48, and 72 h, CK was increased in ECC compared with IPC + ECC (between groups: 24 h, P = 0.004; 48 h, P < 0.001; 72 h, P < 0.001). The visual analog scale score was significantly higher in ECC at 24-72 h postexercise when compared with IPC + ECC (between groups: all P values < 0.001). The maximal radial displacement was decreased on all postexercise days in ECC (all P values < 0.001) but remained statistically unchanged in IPC + ECC (between groups: P < 0.01). CONCLUSIONS: These findings indicate that IPC performed before a bout of eccentric exercise of the elbow flexors blunts EIMD and exercise-induced pain while maintaining the contractile properties of the muscle. PMID- 28832393 TI - Caffeine Increases Work Done above Critical Power, but Not Anaerobic Work. AB - PURPOSE: The assumption that the curvature constant (W') of the power-duration relationship represents anaerobic work capacity is a controversial, unresolved question. We investigated if caffeine ingestion could increase total work done above critical power (CP), and if this would be accompanied by greater anaerobic energy expenditure and by an enhanced maintenance of maximal oxidative metabolic rate. METHODS: Nine men (26.6 +/- 5.3 yr, VO2max 40.6 +/- 5.8 mL.kg.min) cycled until exhaustion at different exercise intensities on different days to determine the CP and W'. On separated days, participants cycled until exhaustion in the severe-intensity domain (136% +/- 7% of CP) after ingesting either caffeine (5 mg.kg body mass) or a placebo. RESULTS: Time to exhaustion was 34% longer with caffeine compared with placebo, and this was accompanied by a greater work done above CP (23.7 +/- 5.7 vs 17.5 +/- 3.6 kJ; 130% +/- 30% vs 95% +/- 14% of W', P < 0.01). Caffeine increased the aerobic energy expenditure (296.4 +/- 91.0 vs 210.2 +/- 71.9 kJ, P < 0.01), but not anaerobic lactic, anaerobic alactic, and total anaerobic (lactic + alactic) energy expenditure. The end values of heart rate and ventilation were higher with caffeine, but the VO2 end was similar between conditions and was not different from VO2max. Caffeine did not change time to reach VO2max but increased time maintained at VO2max (199.3 +/- 105.9 vs 111.9 +/ 87.1 s, P < 0.05). CONCLUSIONS: Caffeine increased total work done above CP, but this was not associated with greater anaerobic work. Rather, this was associated with a higher tolerance to maintain exercise at maximal oxidative metabolic rate. PMID- 28832394 TI - Nocebo Effect in Meniere's Disease: A Meta-analysis of Placebo-controlled Randomized Controlled Trials. AB - OBJECTIVE: To estimate the frequency and strength of nocebo effects in trials for Meniere disease (MD). DATA SOURCES: A literature search was conducted in PUBMED. The search terms we used were " Meniere or Meniere's," "treatment," and "placebo." Limitations included article type to be Clinical Trial or Randomized Controlled Trial, text availability to be Full text, Species to be Humans and Language to be English. STUDY SELECTION: We included placebo-controlled pharmaceutical RCTs that referred specifically to MD and recruited at least 10 adults in each arm. We excluded those studies with JADAD score <=3. DATA EXTRACTION: Thirty-six articles were screened identifying 12 eligible studies. Studies were included after consensus of both authors. DATA SYNTHESIS: The meta analysis was conducted using the RevMan programme as suggested by the Cochrane Collaboration Group. Data were analyzed using a random effects model. CONCLUSION: Nocebo is an important confounding factor of the reported AEs in RCTs for treatment of MD and subsequently in the clinical practice. The pooled estimate of the percentage of placebo-treated patients with at least one AE was 42.3% (95% CI 8.1% to 16.3%), in comparison to 53.8% (95% CI 48.0% to 59.5%) for active drug treated patients. Reporting of RCTs in MD is suboptimal and we recommend authors to endorse the CONSORT checklist. PMID- 28832397 TI - Discovery of endogenous opioid systems: what it has meant for the clinician's understanding of pain and its treatment. AB - Before the discovery of the endogenous opioid system in the 1970s, opioids were understood only through the lens of opioid drug effects. Opium produced sleep, pain relief, and addiction. Once a variety of opioids had been extracted from opium, and still others synthesized chemically, it became clear that there must be endogenous receptors to explain differential drug effects. So, the search was on to identify the receptors, and subsequently their endogenous ligands. Even then, the consequential ways in which the endogenous opioid system influences the way we respond to the environment and survive took time to unravel. Today's understanding extends far beyond simply accepting pain relief and addiction as separate processes, to the realization that the endogenous opioid system achieves constant adjustments between punishment (pain) and reward in communicating areas of the brain previously thought to subserve separate functions. The system also plays a crucial role in socialization. Taken together, these 2 lines of research have led to new insights into why the endogenous opioid system is so important in terms of evolution, individual survival and day-to-day function, and how important it is to consider opioid medications within the context of these critical natural functions. PMID- 28832396 TI - Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model. AB - Neuroplasticity in the amygdala, a brain center for emotions, leads to increased neuronal activity and output that can generate emotional-affective behaviors and modulate nocifensive responses. Mechanisms of increased activity in the amygdala output region (central nucleus, CeA) include increased reactive oxygen species, and so we explored beneficial effects of monomethyl fumarate (MMF), which can have neuroprotective effects through the nuclear factor (erythroid-derived 2) like 2 (Nrf2) antioxidant response pathway. Systemic (intraperitoneal) MMF dose dependently inhibited vocalizations and mechanosensitivity (hindlimb withdrawal reflexes) of rats in an arthritis pain model (kaolin-carrageenan-induced monoarthritis in the knee). Stereotaxic administration of MMF into the CeA by microdialysis also inhibited vocalizations but had a limited effect on mechanosensitivity, suggesting a differential contribution to emotional-affective vs sensory pain aspects. Extracellular single-unit recordings of CeA neurons in anesthetized rats showed that stereotaxic administration of MMF into the CeA by microdialysis inhibited background activity and responses of CeA neurons to knee joint stimulation in the arthritis pain model. Monomethyl fumarate had no effect on behaviors and neuronal activity under normal conditions. The results suggest that MMF can inhibit emotional-affective responses in an arthritis pain model through an action that involves the amygdala (CeA). PMID- 28832395 TI - Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain. AB - Gabapentin (GBP) is a first-line therapy for neuropathic pain, but its mechanisms and sites of action remain uncertain. We investigated GBP-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal GBP reversed evoked mechanical hypersensitivity and produced conditioned place preference (CPP) and dopamine (DA) release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal GBP also significantly inhibited dorsal horn wide-dynamic-range neuronal responses to a range of evoked stimuli in SNL rats. By contrast, GBP microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP, and elicited NAc DA release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on wide dynamic-range neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous GBP-induced CPP and NAc DA release but failed to block its inhibition of tactile allodynia. Gabapentin, therefore, can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity, and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from nonopioid analgesics, GBP requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain-motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of GBP's analgesic effects in patients. PMID- 28832398 TI - Hypoalgesic placebo effects can occur with transparent disclosures. PMID- 28832399 TI - Editor's Introduction. PMID- 28832400 TI - Predicting Adverse Neonatal Outcome Especially When Gestational Age Is Uncertain: Utility of Sonographic Measurement of Fetal Abdominal Wall Thickness. AB - Early and accurate prenatal diagnosis of intrauterine growth restriction is important. Commonly used biometric parameters have limited specificity and require accurate dating. Fetal abdominal wall thickness (AWT) could be a useful supplemental parameter. We performed a retrospective study of 100 third trimester ultrasound exams and compared the sensitivity and specificity of AWT to those of weight percentile (WP) in predicting adverse perinatal outcome.There is a statistically significant difference between the AWT of patients with normal perinatal outcome and that of patients with adverse outcome (P < 0.01). When compared with WP across the entire range of the receiver operating characteristics curve, AWT [area under the curve (AUC), 0.76] has an efficacy similar to that of WP (AUC, 0.72; P = 0.30). However, AWT has superior performance over WP (AUC, 0.72 vs AUC, 0.61, respectively, P = 0.04) in the high specificity range (70%-100%) of the receiver operating characteristics curve, where the consequences of a false negative greatly outweigh those of a false positive. In our study population, with a cutoff value of 4 mm, AWT was a useful and more specific predictor of adverse perinatal outcome than WP. Abdominal wall thickness may be more useful in situations when dating is uncertain. PMID- 28832405 TI - Applying the PDSA Framework to Examine the Use of the Clinical Nurse Leader to Evaluate Pressure Ulcer Reporting. PMID- 28832401 TI - Advantages of Routine Ultrasound Combined With Contrast-Enhanced Ultrasound in Diagnosing Papillary Thyroid Carcinoma. AB - This study aimed to evaluate the advantages of routine ultrasound (US), contrast enhanced US (CEUS), and the combination of these 2 methods in diagnosing papillary thyroid carcinoma (PTC). We subjected 89 patients with calcified thyroid nodules to conventional US and CEUS and then retrospectively analyzed the US and CEUS features of 89 patients with single, solid PTC. On this basis, we then evaluated the ability of US, CEUS, and their combination to diagnose PTC. In the 89 patients with thyroid nodules, US findings differed significantly from CEUS findings (P < 0.05). In the US group, the diagnostic sensitivity, specificity, and accuracy were 87.5%, 78.8%, and 88.0%, respectively; in the CEUS group, these values were 92.9% (P < 0.05), 87.9% (P < 0.05), and 92.9% (P < 0.05), respectively; and when the methods were combined, the diagnostic sensitivity, specificity, and accuracy were 96.7%, 92.7%, and 94.9%, respectively. A typical PTC nodule can be definitively diagnosed using US and CEUS; more specifically, the features of slow progression, late enhancement, and low enhancement were highly associated with a diagnosis of PTC. When these features were combined, they exhibited higher diagnostic performance than any individual method. PMID- 28832406 TI - Racial differences in calculated bioavailable vitamin D with vitamin D/calcium supplementation. AB - OBJECTIVES: Some studies suggest that bioavailable 25-dihydroxyvitamin D [25 (OH)D] is more accurate than total 25-(OH)D as an assessment of vitamin D (VitD) status in black individuals. We hypothesized that increases in bioavailable 25 (OH)D would correlate better with improvement in bone outcomes among black HIV infected adults. DESIGN: This is a secondary analysis of AIDS Clinical Trials Group A5280, a randomized, double-blind study of VitD3 and calcium supplementation in HIV-infected participants initiating antiretroviral therapy. METHODS: Effect of VitD/calcium on total and calculated bioavailable 25-(OH)D, parathyroid hormone, bone turnover markers, and bone mineral density in black and nonblack participants were evaluated at 48 weeks. Wilcoxon signed-rank tests and Wilcoxon rank sum tests assessed within and between-race differences. RESULTS: Of 165 participants enrolled, 129 (40 black and 89 nonblack) had complete data. At baseline, black participants had lower total 25-(OH)D [median (Q1,Q3) 22.6 (15.8, 26.9) vs. 31.1 (23.1, 38.8) ng/ml, P < 0.001] but higher bioavailable 25-(OH)D [2.9 (1.5, 5.2) vs. 2.0 (1.5, 3.0) ng/ml, P = 0.022] than nonblack participants. After 48 weeks of VitD/calcium supplementation, bioavailable 25-(OH)D increased more in black than nonblack participants, but there were no between-race differences change in bone turnover markers or bone mineral density. The associations between increases in 25-(OH)D levels and change in bone outcomes appeared similar for both total and bioavailable 25-(OH)D. CONCLUSION: Baseline and change in bioavailable 25-(OH)D were higher among black adults initiating antiretroviral therapy with VitD/calcium; however, associations between 25-(OH)D and bone outcomes appeared similar for total and bioavailable 25-(OH)D. The assessment of total 25-(OH)D may be sufficient for evaluation of VitD status in black HIV-infected individuals. TRIAL REGISTRATION NUMBER: NCT01403051. PMID- 28832407 TI - Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches. AB - OBJECTIVES: HIV-1 subtypes A1 and D cocirculate in a rural community in Mbarara, Uganda. This study examines HIV-1 intersubtype recombination in this community under a full-genome sequencing context. We aim to estimate prevalence, examine time trends, and test for clinical correlates and outcomes associated with intersubtype recombinants. METHODS: Near-full-genome HIV-1 Sanger sequence data were collected from plasma samples of 504 treatment-naive individuals, who then received protease inhibitor or nonnucleoside reverse transcriptase inhibitor containing regimens and were monitored for up to 7.5 years. Subtypes were inferred by Los Alamos Recombinant Identification Program (RIP) 3.0 and compared with Sanger/REGA and MiSeq/RIP. 'Nonrecombinants' and 'recombinants' infections were compared in terms of pretherapy viral load, CD4 cell count, posttherapy time to virologic suppression, virologic rebound, first CD4 rise above baseline and sustained CD4 recovery. RESULTS: Prevalence of intersubtype recombinants varied depending on the genomic region examined: gag (15%), prrt (11%), int (8%), vif (10%), vpr (2%), vpu (9%), GP120 (8%), GP41 (18%), and nef (4%). Of the 200 patients with near-full-genome data, prevalence of intersubtype recombination was 46%; the most frequently observed recombinant was A1-D (25%). Sanger/REGA and MiSeq/RIP yielded generally consistent results. Phylogenetic tree revealed most recombinants did not share common ancestors. No temporal trend was observed (all P > 0.1). Subsequent subtype switches were detected in 27 of 143 (19%) study participants with follow-up sequences. Nonrecombinant versus recombinants infections were not significantly different in any pre nor posttherapy clinical correlates examined (all P > 0.2). CONCLUSION: Intersubtype recombination was highly prevalent (46%) in Uganda if the entire HIV genome was considered, but was neither associated with clinical correlates nor therapy outcomes. PMID- 28832408 TI - Reproductive coercion among women living with HIV: an unexplored risk factor for negative sexual and mental health outcomes. AB - BACKGROUND: Unintended pregnancy is prevalent among women living with HIV, and is associated with poor health outcomes for women and babies. Reproductive coercion may be one unexplored mechanism for this elevated risk. METHODS: Past-year reproductive coercion data were obtained via self-reported survey from a sample of women receiving HIV specialty care in Baltimore, Maryland, USA. RESULTS: In total, 11 of the 67 women (16.4%) included in the sample reported past-year reproductive coercion. Almost two-thirds (64%) of women reporting reproductive coercion were also positive for recent post-traumatic stress disorder symptoms compared with 27% of women who did not report reproductive coercion (Fisher's exact P = 0.033). DISCUSSION: The prevalence of reproductive coercion among our sample of in care women living with HIV suggests that attention should be paid to the impact of partner influence and coercive behaviors regarding pregnancy intentions. Because of the many potential negative consequences of unintended pregnancy for women living with HIV, it is important that providers be aware of such abuse and steps that can be taken to identify and support patients who are experiencing reproductive coercion. PMID- 28832409 TI - Comparative effectiveness of dual vs. single-action antidepressants on HIV clinical outcomes in HIV-infected people with depression. AB - OBJECTIVE: Depression is highly prevalent among people living with HIV/AIDS (PLWHA) and has deleterious effects on HIV clinical outcomes. We examined changes in depression symptoms, viral suppression, and CD4 T cells/MUl among PLWHA diagnosed with depression who initiated antidepressant treatment during routine care, and compared the effectiveness of dual-action and single-action antidepressants for improving those outcomes. DESIGN: Comparative effectiveness study of new user dual-action or single-action antidepressant treatment episodes occurring from 2004 to 2014 obtained from the Center for AIDS Research Network of Integrated Clinical Systems. METHODS: We identified new user treatment episodes with no antidepressant use in the preceding 90 days. We completed intent-to-treat and per protocol evaluations for the main analysis. Primary outcomes, were viral suppression (HIV viral load <200 copies/ml) and CD4 T cells/MUl. In a secondary analysis, we used the Patient Health Questionnaire-9 (PHQ-9) to evaluate changes in depression symptoms and remission (PHQ <5). Generalized estimating equations with inverse probability of treatment weights were fitted to estimate treatment effects. RESULTS: In weighted intent-to-treat analyses, the probability of viral suppression increased 16% after initiating antidepressants [95% confidence interval = (1.12, 1.20)]. We observed an increase of 39 CD4T cells/MUl after initiating antidepressants (30, 48). Both the frequency of remission from depression and PHQ-9 scores improved after antidepressant initiation. Comparative effectiveness estimates were null in all models. CONCLUSION: Initiating antidepressant treatment was associated with improvements in depression, viral suppression, and CD4 T cells/MUl, highlighting the health benefits of treating depression in PLWHA. Dual and single-action antidepressants had comparable effectiveness. PMID- 28832410 TI - Visceral fat reduction with tesamorelin is associated with improved liver enzymes in HIV. AB - OBJECTIVE: Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). DESIGN AND METHODS: We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period. RESULTS: At baseline, VAT was positively associated with ALT (P = 0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30 U/l, VAT responders experienced greater reductions in ALT (-8.9 +/- 22.6 vs. 1.4 +/- 34.7 U/l, P = 0.004) and AST (-3.8 +/- 12.9 vs. 0.4 +/- 22.4 U/l, P = 0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT. CONCLUSION: A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV infected patients with abdominal obesity and elevated baseline transaminases. PMID- 28832411 TI - Hair levels of preexposure prophylaxis drugs measure adherence and are associated with renal decline among men/transwomen. AB - OBJECTIVE: The US preexposure prophylaxis (PrEP) Demonstration Project (U.S. Demo) evaluated MSM on PrEP postmarketing and found low seroconversion rates. The objective of this study is to examine hair levels as an adherence measure to PrEP. DESIGN: Using an 'opt-in' design, participants of PrEP Demo were invited to enroll into a substudy where hair was collected quarterly. METHODS: Tenofovir concentrations were measured in hair by liquid chromatography/tandem mass spectrometry. Hair levels consistent with >=4 doses/week (protective in other studies) defined adequate adherence. Mixed effects multivariate logistic regression models examined factors associated with >=4 doses/week. Separate mixed effects models evaluated the relationship between hair PrEP levels and changes in creatinine clearance (CrCl) over time. RESULTS: Overall, 58% of U.S. Demo participants enrolled into this opt-in study; reasons for nonparticipation included insufficient hair (61%) and concerns about hairstyle (27%). Hair and dried blood spots levels consistent with >=4 doses/week were highly concordant (84%). Hair levels showed adequate adherence in 87% of 875 person-visits (among 280 participants). Factors associated with adequate adherence in multivariate models were amphetamine use [adjusted odds ratio (aOR) 2.59 (0.97-6.9, P 0.06)], condomless receptive anal sex [aOR 2.28 (1.19-4.40, P 0.01)], and stable housing [aOR 2.63 (1.03-6.67), P 0.04]. Hair levels of tenofovir showed a monotonic relationship with decline in CrCl (P 0.01 for trend). CONCLUSION: In this substudy of the U.S. PrEP demonstration project, hair and dried blood spots levels were highly concordant and hair concentrations demonstrated adequate adherence 87% of the time, with stable housing and high-risk behavior associated with higher adherence. Daily PrEP drug taking is associated with modest declines in CrCl. PMID- 28832412 TI - The HIV-1 integrase E157Q polymorphism per se does not alter susceptibility to raltegravir and dolutegravir in vitro. AB - : The HIV-1 integrase E157Q natural polymorphism has been reported to cause one case of raltegravir (RAL) and dolutegravir (DTG) failure. Six recombinant viruses were constructed containing integrase from clinical HIV-1 isolates found to harbour E157Q as the only integrase strand inhibitor (INSTI) resistance-related mutation. Phenotypic analysis showed that E157Q results in minimal changes in RAL and DTG susceptibility. Together with data retrieved from the Stanford HIV database, our results indicate that E157Q is not a relevant INSTI resistance mutation per se. The previously reported case of E157Q-based resistance must have resulted from combined as yet unidentified integrase polymorphisms. PMID- 28832413 TI - Paradigm Shift in Lung Cancer Therapy: Imaging and Clinical Implications. PMID- 28832414 TI - Lung Cancer: Postoperative Imaging and Complications. AB - In patients with early-stage lung cancer, surgical resection is the treatment of choice. Knowledge of the expected postsurgical changes and awareness of the temporal evolution of these findings as well as potential complications are important in avoiding misinterpretation. We review the surgical techniques used for lung cancer resection, expected postoperative radiologic manifestations, as well as potential early and late postoperative complications in order to improve diagnostic interpretation and optimize patient management. PMID- 28832415 TI - Lung Cancer: Posttreatment Imaging: Radiation Therapy and Imaging Findings. AB - Over the last few decades, advances in radiation therapy technology have markedly improved radiation delivery. Advancements in treatment planning with the development of image-guided radiotherapy and techniques such as proton therapy, allow precise delivery of high doses of radiation conformed to the tumor. These advancements result in improved locoregional control while reducing radiation dose to surrounding normal tissue. The radiologic manifestations of these techniques can differ from radiation induced lung disease seen with traditional radiation therapy. Awareness of these radiologic manifestations and correlation with radiation treatment plans are important to differentiate expected radiation induced lung injury from recurrence, infection and drug toxicity. PMID- 28832416 TI - Targeted Therapy and Imaging Findings. AB - Non-small cell lung cancer (NSCLC) is usually diagnosed when it is not amenable to curative surgery or radiation. Many of these patients are candidates for systemic therapy. Median survival is only approximately 10 months, and, accordingly, treatment in advanced NSCLC is evolving toward a more personalized approach with the identification of genetic abnormalities based on biomarkers. For example, gene mutations in EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) lead to a cascade of pathways resulting in uncontrolled growth, proliferation, and survival of tumor cells. Targeted therapies are aimed at the products of these mutated genes and include agents such as erlotinib and gefitinib (in EGFR-mutant NSCLC) or crizotinib (in ALK positive NSCLC). Antiangiogenesis agents such as bevacizumab are another category of targeted therapy that inhibits vascular endothelial growth factors. The imaging characteristics of advanced NSCLC with genetic abnormalities, the evolution of targeted therapies and their imaging manifestations will be discussed. PMID- 28832417 TI - 2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: A report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. AB - The Society of Cardiovascular Computed Tomography (SCCT) and the Society of Thoracic Radiology (STR) have jointly produced this document. Experts in this subject have been selected from both organizations to examine subject specific data and write this guideline in partnership. A formal literature review, weighing the strength of evidence has been performed. When available, information from studies on cost was considered. Computed tomography (CT) acquisition, CAC scoring methodologies and clinical outcomes are the primary basis for the recommendations in this guideline. This guideline is intended to assist healthcare providers in clinical decision making. The recommendations reflect a consensus after a thorough review of the best available current scientific evidence and practice patterns of experts in the field and are intended to improve patient care while acknowledging that situations arise where additional information may be needed to better inform patient care. PMID- 28832418 TI - Pain evaluation in the ED: A review. PMID- 28832419 TI - Early identification of idiopathic sudden sensorineural hearing loss. PMID- 28832420 TI - A post-master's advanced certificate in gerontology for NPs. PMID- 28832421 TI - Bacterial sepsis in the neonate. AB - Neonatal bacterial infections leading to sepsis occur frequently in the first few days or weeks of life. NPs must be able to recognize the early signs of sepsis and understand the need for rapid evaluation and treatment. This article discusses antibiotic treatments for various types and locations of bacterial infections and sepsis in the neonate. PMID- 28832422 TI - Secondary amenorrhea: Diagnostic approach and treatment considerations. AB - Disruptions in the menstrual cycle are a common complaint in primary care and women's health. Irregular or absent menstrual periods should trigger an evaluation to identify the root cause. This article discusses secondary amenorrhea and provides a systematic approach to its diagnostic evaluation, with referral considerations. PMID- 28832423 TI - Clarithromycin-nifedipine-induced acute kidney injury. PMID- 28832425 TI - Transitioning Florida NPs to opioid prescribing. AB - Prior to statutory changes in prescriptive authority for controlled substances, this study examined the knowledge gaps and prescribing limitations of Florida advanced registered nurse practitioners regarding opioids. Study results revealed statistically significant knowledge gaps in the areas of federal and state guidelines; opioid classes and proper doses; risk assessment skills; monitoring of treatment; and confidence in dealing with challenges of opioid prescribing. PMID- 28832426 TI - Different features of the histopathological subtypes of ovarian tumors in pre- and postmenopausal women. AB - OBJECTIVE: To date, epidemiological evidence has consistently supported a link between ovarian cancer risk and menopause. However, little is known about how menopause status affects the risk of specific histological subtypes of ovarian tumors. We aimed to analyze the differences in various histopathological subtypes of ovarian tumors between pre- and postmenopausal women. METHODS: We reviewed the medical records of women who underwent surgery for ovarian tumors and received histopathological confirmation at the Busan Paik Hospital between January 1997 and October 2016. Pathological findings were regrouped according to 2014 World Health Organization (WHO) classification and subdivided into the following five main categories: epithelial, germ cell, sex cord-stromal, tumor-like lesions, and secondary tumors. RESULTS: A total of 4,683 cases (3,404 premenopausal and 1,279 postmenopausal) were included in this study. Among the 4,683 neoplasms, epithelial tumors accounted for 52.6%, germ cell tumors for 27.1%, sex cord stromal tumors (SCSTs) for 4.1%, tumor-like lesions for 14.0%, and secondary tumors for 0.8%. Among the epithelial tumors, malignant epithelial tumors were significantly associated with postmenopausal women (5.4% vs 22.1%, P < 0.0001), whereas benign epithelial tumors were significantly associated with premenopausal women (40.5% vs 31.9%, P < 0.0001). Among the 1,271 cases of germ cell tumors, most (97.6%) were benign mature teratoma and 2.4% were malignant germ cell tumors. Germ cell tumors were noted more frequently in premenopausal women than in postmenopausal women (31.3% vs 16.1%, P < 0.0001). Among the 194 cases of SCSTs, fibrothecoma was the most common (71.6%) followed by adult granulosa cell tumor (12.9%). The majority of SCSTs occurred in postmenopausal women (2.1% vs 9.5%, P < 0.0001). Among the 656 cases of tumor-like ovarian lesions, corpus luteum cyst was the most common (31.9%) followed by tubo-ovarian abscess (27.6%). Tumor-like ovarian lesions were significantly associated with premenopausal women (15.2% vs 10.7%, P = 0.0001). Among the 36 cases of secondary tumors, 66.7% of the metastatic ovarian tumors were Krukenberg tumors. There was no significant difference in the incidence of secondary tumors between the groups. CONCLUSIONS: We demonstrated the differences in diverse histological subtypes of ovarian tumors according to the menopause status based on the new WHO classification for Korean women. PMID- 28832427 TI - Resistance training reduces inflammation and fatigue and improves physical function in older breast cancer survivors. AB - OBJECTIVE: Resistance training (RT) reduces fatigue and improves physical function and quality of life (QOL) in breast cancer survivors (BCS). This may be related to reductions in systemic and tissue-specific inflammation. This pilot study examines the hypothesis that RT induces changes in systemic and tissue specific inflammation that contribute to improvements in physical and behavioral function in postmenopausal BCS. METHODS: Eleven BCS (60 +/- 2 years old, body mass index 30 +/- 1 kg/m, mean +/- SEM) underwent assessments of fatigue (Piper Fatigue Scale), physical function, QOL (SF-36), glucose and lipid metabolism, and systemic, skeletal muscle, and adipose tissue inflammation (n = 9) before and after 16 weeks of moderate-intensity whole-body RT. RESULTS: Muscle strength improved by 25% to 30% (P < 0.01), QOL by 10% (P = 0.04), chair stand time by 15% (P = 0.01), 6-minute walk distance by 4% (P = 0.03), and fatigue decreased by 58% (P < 0.01), fasting insulin by 18% (P = 0.04), and diastolic and systolic blood pressure by approximately 5% (P = 0.04) after RT. BCS with the worst fatigue and QOL demonstrated the greatest improvements (absolute change vs baseline: fatigue: r = -0.95, P < 0.01; QOL: r = -0.82, P < 0.01). RT was associated with an approximately 25% to 35% relative reduction in plasma and adipose tissue protein levels of proinflammatory interleukin (IL)-6sR, serum amyloid A, and tumor necrosis factor-alpha, and 75% relative increase in muscle pro-proliferative, angiogenic IL-8 protein content by 75% (all P < 0.05). BCS with the highest baseline proinflammatory cytokine levels had the greatest absolute reductions, and the change in muscle IL-8 correlated directly with improvements in leg press strength (r = 0.53, P = 0.04). CONCLUSIONS: These preliminary results suggest that a progressive RT program effectively lowers plasma and tissue-specific inflammation, and that these changes are associated with reductions in fatigue and improved physical and behavioral function in postmenopausal BCS. PMID- 28832428 TI - Functional capacity depends on lower limb muscle strength rather than on abdominal obesity in active postmenopausal women. AB - OBJECTIVE: An association has been found between abdominal obesity and functional capacity (FC) in the literature where waist circumference has been used to infer abdominal obesity. However, most studies focused on evaluating predictors of FC and functional disabilities only in sedentary people. This study aimed to examine whether abdominal obesity is associated with FC in physically active postmenopausal women. METHODS: Forty-four active (>7,500 steps/d) postmenopausal women were recruited. Body composition and distribution (DXA), FC (chair stand/alternate-step/one-leg-stance), handgrip strength and knee extensor strength (dynamometry), steps/d (accelerometer), and cardiorespiratory function (spirometry/VO2max) were measured. The cohort was divided into groups based on a FC score (1-4 scale using quartiles). Pearson's correlation, t test, and linear regression were applied using SPSS (17.0). RESULTS: There was no correlation for body composition or BMI with FC score. However, waist circumference (r = -0.34, P = 0.024), handgrip (r = 0.32, P = 0.036), knee extensor strength (r = 0.43, P = 0.003), and VO2max (r = 0.41, P = 0.006) were significantly correlated with FC score. In addition, when the highest quartile group was compared with the lowest one, a significant difference was observed for knee extensor strength (P = 0.003), which was also the only variable inserted into the FC prediction equation derived from the stepwise regression model (r = 0.19, F = 9.582, P = 0.003). CONCLUSIONS: Our results demonstrate an association between abdominal obesity and FC in active postmenopausal women and that the strongest association and the best predictor of FC was lower limb muscle strength. Thus, active postmenopausal women with abdominal obesity may not necessarily have a reduced FC if lower limb muscle strength is preserved. PMID- 28832429 TI - Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). AB - OBJECTIVE: This study determined whether two different formulations of hormone therapy (HT): oral conjugated equine estrogens (o-CEE; 0.45 mg/d, n = 209), transdermal 17beta-estradiol (t-E2; 50 MUg/d, n = 201) plus cyclic progesterone (Prometrium, 200 mg) or placebo (PBO, n = 243) affected sleep domains in participants of the Kronos Early Estrogen Prevention Study. METHODS: Participants completed the Pittsburgh Sleep Quality Index at baseline and during the intervention at 6, 18, 36, and 48 months. Global sleep quality and individual sleep domain scores were compared between treatments using analysis of covariance, and correlated with vasomotor symptom (VMS) scores using Spearman correlation coefficients. RESULTS: Global Pittsburgh Sleep Quality Index scores (mean 6.3; 24% with score >8) were similar across groups at baseline and were reduced (improved sleep quality) by both HT (average change -1.27 [o-CEE] and 1.32 [t-E2]) when compared with PBO (-0.60; P = 0.001 [o-CEE vs PBO] and P = 0.002 [t-E2 vs PBO]). Domain scores for sleep satisfaction and latency improved with both HT. The domain score for sleep disturbances improved more with t-E2 than o-CEE or PBO. Global sleep scores significantly correlated with VMS severity (rs = 0.170, P < 0.001 for hot flashes; rs = 0.177, P < 0.001 for night sweats). Change in scores for all domains except sleep latency and sleep efficiency correlated with change in severity of VMS. CONCLUSIONS: Poor sleep quality is common in recently menopausal women. Sleep quality improved with both HT formulations. The relationship of VMS with domains of sleep suggests that assessing severity of symptoms and domains of sleep may help direct therapy to improve sleep for postmenopausal women. PMID- 28832431 TI - Perceived Need Versus Current Spending: Gaps in Providing Foundational Public Health Services in Communities. AB - OBJECTIVE: Our objective was to estimate the gap between the costs for local health jurisdictions (LHJs) to provide foundational public health services (FPHS) and actual spending on FPHS and to examine factors associated with that gap. DESIGN: We employed resource-based cost estimation methods for this observational study and conducted multivariate analyses with measures derived from secondary administrative data. We used primary data collected from LHJ leaders that depicted 2014 spending and perceived need. We also included secondary administrative data depicting annual 2000-2013 expenditures organized into categories containing key elements of FPHS areas. SETTING: We included primary data from a representative sample of 10 LHJs in Washington State and secondary data for all 35 LHJs in Washington. PARTICIPANTS: Participants were public health practice leaders from each sample LHJ. MAIN OUTCOME MEASURE: Our main outcome of interest was the gap identified between current spending and the perceived spending needed to provide FPHS in a jurisdiction. RESULTS: Actual FPHS spending was approximately 65% of spending needed to provide overall FPHS for our sample LHJs, but the size of the gap varied substantially by program. Some gaps also varied widely by LHJ, with spending gaps widest among rural and high poverty communities. Percent poverty and the metropolitan nature of a jurisdiction were factors significantly related to FPHS spending in our multivariate analyses. CONCLUSIONS: Actual spending lags far behind local officials' estimates of spending needed to provide FPHS and is likely influenced by local conditions. Major apparent gaps between spending and need, particularly in areas such as costly Business Competencies, underscore the need for cross-cutting capabilities to support public health system responsiveness and for attention to be paid to local conditions. PMID- 28832430 TI - Local Boards of Health Characteristics Influencing Support for Health Department Accreditation. AB - BACKGROUND: Local boards of health (LBoHs) serve as the governance body for 71% of local health departments (LHDs). PURPOSE: To assess the impact of LBoH governance functions and other characteristics on the level of LBoH support of LHD accreditation. METHODS: Data from 394 LHDs that participated in the 2015 Local Boards of Health Survey were used for computing summative scores for LBoHs for domains of taxonomy and performing logistic regression analyses in 2016. RESULTS: Increased odds of an LBoH directing, encouraging, or supporting LHD accreditation activities were significantly associated with (a) a higher overall combined score measuring performance of governance functions and presence of other LBoH characteristics (adjusted odds ratio [AOR] = 1.05; P < .001); (b) a higher combined score for the Governance Functions subscale (AOR = 1.06; P < .01); (c) the "continuous improvement" governance function (AOR = 1.15; P < .001); and (d) characteristics and strengths such as board composition (eg, LBoH size, type of training, elected vs nonelected members), community engagement and input, and the absence of an elected official on the board (AOR = 1.14; P = .02). CONCLUSIONS: LBoHs are evenly split by thirds in their attention to Public Health Accreditation Board accreditation among the following categories: (a) encouraged or supported, (b) discussed but made no recommendations, and (c) did not discuss. This split might indicate that they are depending on the professional leadership of the LHD to make the decision or that there is a lack of awareness. The study findings have policy implications for both LBoHs and initiatives aimed at strengthening efforts to promote LHD accreditation. PMID- 28832432 TI - Elevating Oral Health Interprofessional Practice Among Pediatricians Through a Statewide Quality Improvement Learning Collaborative. AB - CONTEXT: Because of persistent effects of early childhood caries and impacts of dental health professional shortages areas, the integration of oral health in primary care settings is a public health priority. In this study, we explored oral health interprofessional practice (OHIP) as an integrative pathway to reduce oral health disparities. OHIP can include performing oral health risk assessments, describing the importance of fluoride in the drinking water, implementing fluoride varnish application, and referring patients to a dental home. OBJECTIVE: To conduct a formative evaluation of how 15 pediatric primary care practices implemented the adoption of OHIP in their clinical settings. DESIGN: Using an ecological framework, we conducted a qualitative process evaluation to measure the factors that inhibited and facilitated OHIP adoption into pediatric settings. Document review analysis and qualitative interviews were conducted with pediatric practices to contextualize challenges and facilitators to OHIP adoption. SETTING AND PARTICIPANTS: A total of 15 Children's Health Insurance Program Reauthorization Act pediatric practices located in 13 South Carolina counties participated in this study. MAIN OUTCOME MEASURES: Outcomes of interest were the facilitators and challenges of OHIP adoption into pediatric primary care practices. RESULTS: Thematic analysis revealed challenges for OHIP adoption including limited resources and capacity, role delineation for clinical and administrative staff, communication, and family receptiveness. OHIP training for clinical practitioners and staff and responsiveness from clinical staff and local dentists were facilitators of OHIP adoption. Twelve key recommendations emerged on the basis of participant experiences within OHIP, with developing an active dental referral network and encouraging buy-in from clinical staff for OHIP adoption as primary recommendations. CONCLUSION: We demonstrated the effectiveness of a learning collaborative meeting among pediatric primary care providers to adopt OHIPs. This work reveals an actionable pathway to support oral health equity advancement for children through an additional access point of preventive oral care, reinforcement of positive oral health behaviors, and interaction between parent and child for overall health and wellness of the family. PMID- 28832433 TI - A Content Analysis of Nonprofit Hospital Community Health Needs Assessments and Community Benefit Implementation Strategies in Philadelphia. AB - CONTEXT: Nonprofit hospitals are mandated to perform a community health needs assessment, develop an implementation strategy to address community needs, and invest in improving community health through community benefit investments in order to maintain the tax exemptions afforded nonprofit hospitals. OBJECTIVE: We sought to describe the regional health needs identified across community health needs assessments and the portfolio of implementation strategies reported to address those needs. DESIGN: The study provides a content analysis of community health needs assessments and implementation strategies for nonprofit hospitals in one urban region. SETTING: The study focused on nonprofit hospitals in Philadelphia, Pennsylvania. MAIN OUTCOME MEASURES: Community benefit documents were coded to characterize health needs and intervention activities using the 4 health factor categories of the County Health Rankings framework: clinical care, health behaviors, social and economic factors, and physical environment. RESULTS: Hospitals predominantly identified health needs related to access to care, especially mental health and dental care, and insurance coverage and costs of care. In many instances, there is little alignment between needs identified through the community health needs assessments and the reported implementation strategies. Specifically, dental care, behavioral health, substance abuse, social factors, and health care and prescription drug costs were all cited as important community needs but were infrequently targeted by implementation strategies. CONCLUSIONS: Nonprofit hospital community health needs assessments in Philadelphia predominantly identify needs related to access to care and to some extent health behaviors. There is incomplete alignment between the needs identified in hospital assessments and the needs targeted in implementation strategies, underscoring a need for regional coordination in community benefit investments. Improved regional coordination between hospitals serving the region may offer the opportunity to eliminate duplicative efforts and increase the amount of funds available to address unmet needs. PMID- 28832434 TI - Perceived Facilitators and Barriers to Local Health Department Workers' Participation in Infectious Disease Emergency Responses. AB - CONTEXT: Local health departments play a key role in emergency preparedness and respond to a wide range of threats including infectious diseases such as seasonal influenza, tuberculosis, H1N1, Ebola virus disease, and Zika virus disease. To successfully respond to an infectious disease outbreak, local health departments depend upon the participation of their workforce; yet, studies indicate that sizable numbers of workers would not participate in such a response. The reasons why local health department workers participate, or fail to participate, in infectious disease responses are not well understood. OBJECTIVE: To understand why local health department workers are willing, or not willing, to report to work during an infectious disease response. DESIGN: From April 2015 to January 2016, we conducted 28 semistructured interviews with local health department directors, preparedness staff, and nonpreparedness staff. SETTING: Interviews were conducted with individuals throughout the United States. PARTICIPANTS: We interviewed 28 individuals across 3 groups: local health department directors (n = 8), preparedness staff (n = 10), and nonpreparedness staff (n = 10). MAIN OUTCOME MEASURES: Individuals' descriptions of why local health department workers are willing, or not willing, to report to work during an infectious disease response. RESULTS: Factors that facilitate willingness to respond to an infectious disease emergency included availability of vaccines and personal protective equipment; flexible work schedule and childcare arrangements; information sharing via local health department trainings; and perceived commitments to one's job and community. Factors that hinder willingness to respond to an infectious disease emergency included potential disease exposure for oneself and one's family; logistical considerations for care of children, the elderly, and pets; and perceptions about one's role during an infectious disease response. CONCLUSION: Our findings highlight opportunities for local health departments to revisit their internal policies and engage in strategies likely to promote willingness to respond among their staff. As LHDs face the persistent threat of infectious diseases, they must account for response willingness when planning for and fielding emergency responses. Our findings highlight opportunities for local health departments to revisit their internal policies and engage in strategies likely to promote response willingness to infectious disease emergencies among their staff. PMID- 28832435 TI - Never Quit Trying: Reengaging Tobacco Users in Statewide Cessation Services. AB - CONTEXT: Tobacco dependence is well established as a chronic condition typically requiring numerous quit attempts. Tobacco users are unlikely to return to the same cessation program on their own. OBJECTIVE: This program evaluation examined the effectiveness of using multiple outreach methods to reengage tobacco users in a statewide cessation program at varying time points after their initial program enrollment. DESIGN: Participants were randomized to receive or not receive reengagement outreach. We conducted outreach via phone, e-mail, and/or text (based on methods participants agreed to receive) at 1, 2, or 3 months post initial engagement. Participants were offered the opportunity to reenroll in QUITPLAN Services. SETTING: Minnesota's QUITPLAN Services PARTICIPANTS:: A total of 3020 tobacco users who enrolled in Minnesota's QUITPLAN Services and either received a 2-week starter kit of nicotine replacement therapy or completed 0-1 QUITPLAN Helpline calls. MAIN OUTCOME MEASURES: We explored group differences in the odds of reengagement (defined as enrolling in a phone cessation program or selecting 2 or more of nicotine replacement therapy starter kit, text messaging, e-mail program, or print materials), contributors to reengagement, and costs. RESULTS: 14.7% in the Reengagement Outreach (RO) group and 3.4% in the Comparison (no outreach) group reengaged. The majority (71%) reengaged during phone outreach. There were no significant differences in reengagement rates by follow up time period (1, 2, or 3 months). Cost per reengagement was $546, mostly due to one-time setup costs; scaling to 10 000 tobacco users would cost approximately $101 per reengagement. CONCLUSIONS: Conducting proactive outreach through state funded quitlines is an effective approach to reengaging tobacco users, yielding a 5-fold greater odds of reengagement compared with no outreach. Since most costs were for initial setup, the cost per reengagement would decrease as the outreach population size increases. Such outreach has the potential to foster treatment utilization and quit attempts. PMID- 28832437 TI - Identifying Overweight and Obesity in Brazilian Schoolchildren, 2014. AB - CONTEXT: For any intervention in a population, we need to understand population characteristics and needs. The School Health Program (PSE) is a Brazilian national proposal for the improvement of schoolchildren's quality of life by integrating health and education areas to address vulnerabilities that affect the development of students from public schools. OBJECTIVE: To describe the prevalence of overweight and obesity in school-aged children and adolescents and to expound methods to evaluate the nutritional status deviation. DESIGN: Cross sectional study. SETTING: Schools in Itatiba, Sao Paulo, Brazil, participating in PSE. PARTICIPANTS: A total of 6829 schoolchildren aged 6 month to 15 years. MAIN OUTCOME MEASURES: Nutritional status and standard percentile curves for body mass index (BMI) for gender. RESULTS: In children younger than 5 years, the prevalence of being overweight was 13.9%; for those between 5 years or older and younger than 10 years, it was 33.9%; and for those 10 years or older, it was 34.0%. In males, obesity and severe obesity were more present (10.7% and 3.7%, respectively) than in girls (9.5% and 1.9%, respectively). Regarding location, it was found that the region with the highest income showed a higher prevalence of overweight children. Compared with the World Health Organization reference BMI curves, our reference percentile curve showed a higher standard for the cutoff points between normal range and overweight. CONCLUSION: From our results, we found that age and measures of weight and height in schoolchildren could contribute, in a cheap and simple way, to the assessment of nutritional status in a region. This is helpful in providing health monitoring and assisting in making public health decisions, as well as serving in comparison with other scientific studies. Partnership between education and health systems can facilitate and improve the quality of health management among schoolchildren. PMID- 28832438 TI - Evacuation Decision Making and Expanded Roles of Adult Daycare Services in the Great East Japan Earthquake: Qualitative Analysis Using Semistructured Interviews. AB - CONTEXT: The roles of adult daycare services during disaster evacuations in the relationships with community resilience are unknown. The initial 72 hours after a disaster are crucial because people in the disaster area depend on their own efforts or the resources available at the moment until the arrival of external support. OBJECTIVE: To clarify the evacuation-related decision making of the administrators of adult daycare services within 72 hours after the Great East Japan Earthquake and to describe the roles of adult daycare services during the month following the earthquake. DESIGN: Qualitative study using semistructured interviews. The transcribed interviews were analyzed anonymously through an inductive qualitative content analysis using ATLAS.ti. SETTING: Kesennuma City, Miyagi Prefecture. PARTICIPANTS: Eleven key informants (3 primary care providers and 8 administrators) from 8 institutions. RESULTS: Immediately after the disaster, 6 institutions implemented shelter-in-place. The evacuation behaviors of the adult daycare institutions were diverse, but each institution was transformed repeatedly within 72 hours. With respect to evacuation decision making, the primary issues involved whether to go to mandatory evacuation sites. However, after 3 days, the institutions relocated from these sites to other places. During a period of approximately 1 month, 7 institutions managed the evacuation of service users and care providers. The expanded institutional roles were as follows: "confirming the safety of the users' families," "substituting residential facilities," and "imposing leadership during the evacuation." CONCLUSIONS: If institutions choose to shelter-in-place, it should be sustained for as long as possible. Sufficiently planned stores of food and water to accommodate daytime users are needed. Institutions that employ shelter-in-place as an evacuation plan should maintain close contact with local governments. Furthermore, local governments should predetermine how to manage these institutions in the event of a disaster. To build community resilience for disasters, developing linkage with private organizations' resilience is beneficial. PMID- 28832436 TI - Using Obesity Research to Shape Obesity Policy in Minnesota: Stakeholder Insights and Feasibility of Recommendations. AB - OBJECTIVE: Preventing childhood obesity requires innovative, evidence-based policy approaches. This study examines the use of research evidence by obesity policy stakeholders in Minnesota and develops pilot tools for communicating timely evidence to policymakers. DESIGN, SETTING, AND PARTICIPANTS: From November 2012 to January 2013, semistructured interviews were conducted with 51 Minnesota stakeholders in childhood obesity prevention. Interviewees included 16 state legislators and staff; 16 personnel from the Minnesota Department of Education, Minnesota Department of Health, and Minnesota Department of Transportation; and 19 advocates for and against childhood obesity prevention legislation (response rate = 71%). MAIN OUTCOME MEASURES: Participants were asked their views on 3 themes: (1) Whether and how they used research evidence in their current decision making processes; (2) barriers to using research evidence for policymaking; and (3) suggestions for improving the evidence translation process. All interviews were audio-recorded and transcribed. A team approach to qualitative analysis was used to summarize themes, compare findings across interviewees' professional roles, and highlight unexpected findings, areas of tension, or illuminating quotes. RESULTS: Stakeholders used research evidence to support policy decisions, educate the public, and overcome value-based arguments. Common challenges included the amount and complexity of research produced and limited relationships between researchers and decision makers. Responding to interviewee recommendations, we developed and assessed 2 pilot tools: a directory of research experts and a series of research webinars on topics related to childhood obesity. Stakeholders found these materials relevant and high-quality but expressed uncertainty about using them in making policy decisions. CONCLUSIONS: Stakeholders believe that research evidence should inform the design of programs and policies for childhood obesity prevention; however, many lack the time and resources to consult research consistently. Future efforts to facilitate evidence informed policymaking should emphasize approaches to designing and presenting research that better meets the needs of policy and programmatic decision makers. PMID- 28832440 TI - A Profile of Low Back Pain: Treatment and Costs Associated With Patients Referred to Orthopedic Specialists in Sweden. AB - STUDY DESIGN: Analysis of Swedish national and regional register data. OBJECTIVES: The aim of this study was to characterize healthcare resource utilization, productivity loss, and costs of patients with low back pain (LBP) with or without leg pain, who have been referred from primary care settings to orthopedic specialist care. SUMMARY OF BACKGROUND DATA: Register data on outpatient and inpatient care, work absence, drug prescriptions, socioeconomics, and mortality were extracted for patients visiting orthopedic specialists for LBP in the Swedish region Vastra Gotaland (1.6 million inhabitants in 2015) in 2008 to 2011 (4 years). METHODS: Patients were followed with regard to resource use and costs during "LBP episodes," defined as the time period from the first visit to an orthopedic specialist ("index-point") until the last observed resource use registered with an LBP diagnosis. Patients were also followed during fixed time periods of 2 years before and 2 years after the index-point. RESULTS: In total, 16,329 LBP episodes were identified (13,931 unique patients), in six diagnosis groups. Mean societal cost per LBP episode was estimated at &OV0556;6466 (SD 21,884), where indirect cost constituted 74% and half of the 26% remaining direct costs were owing to hospital inpatient care. Patients underwent surgery in 10% of the episodes (n = 1583). Cost per LBP episode varied between diagnosis groups, with a range of &OV0556;18,668 to &OV0556;40,774 in episodes with surgery and &OV0556;978 to &OV0556;10,379 in episodes without surgery. Assessment of the fixed time period of 2 years before and after index-point showed that costs increased gradually during the year before in all groups and declined the year after in all groups. CONCLUSION: The marked decline in total costs the year after referral to an orthopaedic specialist indicates that the treatment provided, regardless of treatment, has an effect and also likely improves the quality of life for the patient. LEVEL OF EVIDENCE: 4. PMID- 28832441 TI - Explaining How Cognitive Behavioral Approaches Work for Low Back Pain: Mediation Analysis of the Back Skills Training Trial. AB - STUDY DESIGN: This is secondary research examining the longitudinal mediation effect within a structural equation model. OBJECTIVE: To identify possible mechanisms that mediate the effects of a cognitive behavioral approach upon disability and pain in low back pain patients. SUMMARY OF BACKGROUND DATA: Cognitive behavioral interventions (CBIs) can improve pain and disability in low back pain (LBP) but the mechanisms of action are unclear. We used data from a large randomized controlled trial to investigate mediators of the treatment effect of CBI. METHODS: Pain self-efficacy, fear avoidance, and physical and mental functioning were selected as candidate mediators based on the theoretical rationale of the intervention. The primary treatment outcomes were the Roland Morris Questionnaire (RMDQ) and the modified Von Korff scale (MVK pain and disability) at 12 months. We used structural equation models to estimate the contribution of mediators. All models were tested for goodness-of-fit using chi , Root Mean Square Error of Approximation, Adjusted Goodness of Fit Index, and Bentler Comparative Fit Index. RESULTS: We included 701 adults with LBP. The average RMDQ score at baseline for those on the intervention arm was 8.8 (Standard Deviation 5.0). The intervention was effective in reducing disability and pain at 12 months. Change in mental functioning was not a significant mediator. Changes to pain self-efficacy, fear avoidance, and physical functioning were causal mediators of the treatment effect at 12 months (RMDQ b= -0.149, P < 0.001; MVK-pain b = -0.181, P < 0.001 and MVK-disability b = -0.180, P < 0.001). Overall, the SEM model exceeded the threshold for acceptable goodness-of-fit. CONCLUSION: Fear avoidance and self-efficacy were important causal mediators of the cognitive behavioral treatment effect. Self-assessed change in physical function was a causal mediator but mental functioning was not. This suggests people need to experience meaningful change in physical function and beliefs but not in mental functioning associated with LBP, to achieve a treatment benefit. LEVEL OF EVIDENCE: 2. PMID- 28832442 TI - Correspondence. PMID- 28832443 TI - Organ Procurement and Transplantation in Belgium. PMID- 28832445 TI - Alone Again, Naturally: B Cells Encountering Antigen Without T cells. PMID- 28832446 TI - Tools for Predicting Kidney Transplant Outcomes. PMID- 28832447 TI - Megan Sykes, MD: Michael J. Friedlander Professor of Medicine and Professor of Microbiology & Immunology and Surgical Sciences (in Surgery) and Director of Columbia Center for Translational Immunology Columbia University, New York City, NY. PMID- 28832448 TI - Alan Ting, PhD, 1943-2017. PMID- 28832449 TI - mTOR Inhibition to Prevent Posttransplant Malignancies-Don't Stop Believin'. PMID- 28832450 TI - HLA Population Genetics in Solid Organ Transplantation. AB - HLAs are fundamental to the adaptive immune response and play critical roles in the cellular and humoral response in solid organ transplantation. The genes encoding HLA proteins are the most polymorphic within the human genome, with thousands of different allelic variants known within the population. Application of the principles of population genetics to the HLA genes has resulted in the development of a numeric metric, the calculated panel-reactive antibody (CPRA) that predicts the likelihood of a positive crossmatch as a function of a transplant candidate's unacceptable HLA antigens. The CPRA is an indispensible measure of access to transplantation for sensitized candidates and is used as the official measure of sensitization for allocation of points in the US Kidney Allocation System and Eurotransplant. Here, we review HLA population genetics and detail the mathematical basis of the CPRA. An understanding of these principles by transplant clinicians will lay the foundation for continued innovation in the care of sensitized patients. PMID- 28832451 TI - Induction Therapy, Rejection, and Graft Outcomes in Pediatric and Adolescent Kidney Transplant Recipients. AB - BACKGROUND: Although the clinical benefit of interleukin-2-receptor antibody (IL 2RAb) induction in reducing the risk of acute rejection in adult kidney transplant recipients is well established, a similar benefit in pediatric recipients remains controversial. The aim of this study is to evaluate the efficacy of IL-2RAb in reducing acute rejection in pediatric and adolescent recipients aged 21 years or younger using Australia and New Zealand Dialysis and Transplant registry. METHODS: The association between IL-2RAb induction and risk of acute rejection was examined using adjusted logistic regression and propensity score analyses, whereby the associations between induction, graft loss, and incident cancer were examined using adjusted Cox regression analysis. RESULTS: There were 658 recipients followed up for a median of 5.5 years between 2001 and 2012. The use of IL-2RAb induction was associated with adjusted odds ratios of 0.61 (95% confidence interval [CI], 0.41-0.91; P = 0.007) for any rejection and 0.57 (95% CI, 0.35-0.92; P = 0.020) for early rejection occurring in the first 6 months after transplant. These associations were attenuated in the propensity score analysis but remained statistically significant with adjusted odds ratio of 0.65 (95% CI, 0.49-0.87) for any rejection and 0.64 (95% CI, 0.44-0.93) for early rejection. There were no associations between induction, graft loss, and incident cancer. CONCLUSIONS: Induction treatment of IL-2RAb in pediatric and adolescent kidney transplant recipients is associated with at least a 40% reduction in the odds of acute rejection, independent of age, era, immunological status, and initial immunosuppression. PMID- 28832452 TI - The Authors' Reply. PMID- 28832453 TI - Quality and Safety Education for Nurses: Looking Forward. PMID- 28832454 TI - 2017 National Quality and Safety Education for Nurses Faculty Survey Results. AB - The Quality and Safety Education for Nurses (QSEN) national initiative, started in 2005, has supported the adoption and integration of updated quality and safety competencies in nursing education. However, faculty needs regarding QSEN competency integration, and the degree to which QSEN competencies are reflected in current nursing curricula, have not been assessed nationally. This study (N = 2037) reports the findings of the 2017 National QSEN Faculty Survey and discusses implications for nurse educators and programs of nursing education. PMID- 28832455 TI - Quality and Safety Education for Nurses Implementation: Is It Sustainable? AB - Is the Quality and Safety Education for Nurses (QSEN) initiative still advancing in prelicensure nursing education? The purpose of this article is to report a 2 part evaluation regarding QSEN within the curricula. The evaluation included an online survey and conference for faculty in the San Francisco Bay Area (SFBA). This article discusses survey results and the ideas and suggestions of SFBA faculty that were made at the conference. The results were positive. Most schools continue to advance QSEN into their curricula. Ten ways to strengthen integration of QSEN in the curriculum and barriers are identified. PMID- 28832456 TI - Implementation Science: New Approaches to Integrating Quality and Safety Education for Nurses Competencies in Nursing Education. AB - Although quality and safety competencies were developed and disseminated nearly a decade ago by the Quality and Safety Education for Nurses (QSEN) project, the uptake in schools of nursing has been slow. The use of implementation science methods may be useful to accelerate quality and safety competency integration in nursing education. The article includes a definition and description of implementation science methods and practical implementation strategies for nurse educators to consider when integrating the QSEN competencies into nursing curriculum. PMID- 28832457 TI - Implementing Quality and Safety Education for Nurses in Postclinical Conferences: Transforming the Design of Clinical Nursing Education. AB - Postclinical conferences are an essential component of clinical nursing education. Numerous constraints including the rapidly changing clinical teaching environment and the struggle to secure clinical placements are affecting the use and purpose of postclinical conferences. This article describes 1 faculty member's approach in designing and implementing a teaching strategy to integrate Quality and Safety Education for Nurses and concepts from a concept-based curriculum into a unique clinical seminar format. PMID- 28832458 TI - Teaching Informatics to Prelicensure, RN-to-BSN, and Graduate Level Students. AB - Teaching nursing informatics to students in associate, baccalaureate, RN-BSN, and graduate nursing programs poses challenges for curriculum design, as well as developing appropriate instruction and assessment methods. The current state of nursing informatics education provides opportunities for unique instructional design and assessment techniques. Key course content is provided with suggestions for teaching informatics that focus on leveling for prelicensure, RN-BSN, and graduate nursing programs. PMID- 28832459 TI - Learning to Overcome Hierarchical Pressures to Achieve Safer Patient Care: An Interprofessional Simulation for Nursing, Medical, and Physician Assistant Students. AB - To positively impact patient safety, the Institute of Medicine, as well as the Quality and Safety Education for Nurses initiative, has recommended clinician training in structured communication techniques. Such techniques are particularly useful in overcoming hierarchical barriers in health care settings. This article describes an interprofessional simulation program to teach structured communication techniques to preprofessional nursing, medical, and physician assistant students. The teaching and evaluation plans are described to aid replication. PMID- 28832460 TI - Impact of Simulation-Enhanced Pharmacology Education in Prelicensure Nursing Education. AB - Student and novice nurses are susceptible to committing medication errors related to lack of experience. To address medication safety, a quasi-experimental design (N = 120) was used to test the effect of adding simulation to an undergraduate nursing pharmacology course on students' confidence and competence, medication adverse events, and observed medication administration practices. Students who received simulation-enhanced pharmacology demonstrated important improvements in medication administration safety. Implementing simulation in nursing pharmacology curriculum is consistent with recommendations to implement Quality and Safety Education for Nurses competencies into nursing education. PMID- 28832461 TI - Rapid Health Care Improvement Science Curriculum Integration Across Programs in a School of Nursing. AB - This article describes the systematic efforts undertaken by a school of nursing in the Northeastern United States to foster innovation in health professions education. We present an application of modified team coaching and plan-do-study act improvement methods in an educational context to rapidly integrate a quality and safety curriculum across programs. We discuss applications in generalist, advanced practice, doctoral, residency, and advanced fellowship programs and provide examples of each. PMID- 28832462 TI - Quality and Safety Education for Nurses Competencies in Doctor of Nursing Practice Education: Exemplars From Education and Practice. AB - Graduate level Quality and Safety Education for Nurses (QSEN) competencies were created to facilitate preparation of the Doctor of Nursing Practice (DNP) graduate to have an impact on health care system changes, advance nursing practice, and improve the health of populations. Although there is agreement that QSEN competencies are important to DNP education, little is known about implementation of the competencies. This article describes the importance of QSEN competencies in DNP education and provides exemplars of QSEN competencies in DNP education and practice. PMID- 28832463 TI - Integration of Quality and Safety Education for Nurses Into Practice: Academic Practice Partnership's Role. AB - There is a trend to adopt the Quality and Safety Education for Nurses (QSEN) competencies into nursing practice's organizational activities. Incorporating the competencies has created unique challenges for the practice setting. The purpose of this article is to identify the different types of academic-practice partnerships that promote quality and safety, including a specific focus on how the QSEN competencies are being incorporated into practice settings. PMID- 28832464 TI - Association of Maternal Obesity With Maternal and Neonatal Outcomes in Cases of Uterine Rupture. PMID- 28832465 TI - In Reply. PMID- 28832466 TI - Outcomes of Twin Pregnancies in Women 45 Years of Age or Older. PMID- 28832467 TI - In Reply. PMID- 28832468 TI - Fetoscopic Open Neural Tube Defect Repair: Development and Refinement of a Two Port, Carbon Dioxide Insufflation Technique. PMID- 28832469 TI - In Reply. PMID- 28832470 TI - Obstetrics and Gynecology Resident Interest and Participation in Global Health. PMID- 28832471 TI - In Reply. PMID- 28832475 TI - Practice Bulletin No. 182 Summary: Hereditary Breast and Ovarian Cancer Syndrome. AB - Hereditary breast and ovarian cancer syndrome is an inherited cancer susceptibility syndrome characterized by multiple family members with breast cancer, ovarian cancer, or both. Based on the contemporary understanding of the origins and management of ovarian cancer and for simplicity in this document, ovarian cancer also refers to fallopian tube cancer and primary peritoneal cancer. Clinical genetic testing for gene mutations allows more precise identification of those women who are at an increased risk of inherited breast cancer and ovarian cancer. For these individuals, screening and prevention strategies can be instituted to reduce their risks. Obstetrician-gynecologists play an important role in the identification and management of women with hereditary breast and ovarian cancer syndrome. If an obstetrician-gynecologist or other gynecologic care provider does not have the necessary knowledge or expertise in cancer genetics to counsel a patient appropriately, referral to a genetic counselor, gynecologic or medical oncologist, or other genetics specialist should be considered (1). More genes are being discovered that impart varying risks of breast cancer, ovarian cancer, and other types of cancer, and new technologies are being developed for genetic testing. This Practice Bulletin focuses on the primary genetic mutations associated with hereditary breast and ovarian cancer syndrome, BRCA1 and BRCA2, but also will briefly discuss some of the other genes that have been implicated. PMID- 28832476 TI - Committee Opinion No. 714 Summary: Obesity in Adolescents. AB - Rates of obesity among adolescents in the United States have increased at a dramatic rate along with the prevalence of weight-related diseases. Between the 1980s and 2014, the prevalence of obesity among adolescent females in the United States increased from approximately 10% to 21%. Although the steep increase in the prevalence of obesity in children (2-11 years) has slowed, the prevalence of obesity in adolescents (12-19 years) continues to increase. Because the obese female adolescent faces medical, psychologic, and reproductive health challenges, early intervention is imperative in preventing short-term and long-term morbidity. The obstetrician-gynecologist who is knowledgeable about the behavioral and environmental factors that influence obesity may be better able to educate parents, guardians, and adolescents and advocate for programs that increase physical activity and improve nutrition. The obstetrician-gynecologist should be able to identify obese adolescents, particularly those at risk of comorbid conditions. They may have the opportunity to initiate behavioral counseling, participate in multidisciplinary teams that care for overweight and obese adolescents, and advocate for community programs to prevent obesity. PMID- 28832477 TI - Committee Opinion No. 715 Summary: Social Etiquette for Program Directors and Faculty. AB - Educators in obstetrics and gynecology work within a changing clinical learning environment. Ethnic, cultural, and social diversity among colleagues and learners have increased, and MUethods of communication have expanded in ever more novel ways. Clerkship, residency, and fellowship directors, in partnership with chairs and senior faculty, are urged to take the lead in setting the tone for workplace etiquette, communication, and social behavior of faculty and trainees to promote a high standard of civility and citizenship. The Council on Resident Education in Obstetrics and Gynecology (CREOG) Education Committee has promulgated recommendations that can be used to help address professional relationships, professional appearance, and social media usage. These recommendations also address communications pertinent to educational processes such as interviewing, teaching, evaluation, and mentoring. PMID- 28832478 TI - Committee Opinion No. 716 Summary: The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer in Women at Average Risk. AB - Ovarian cancer is the second most common type of female reproductive cancer, and more women die from ovarian cancer than from cervical cancer and uterine cancer combined. Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality. Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer. Women with a strong family history of ovarian, breast, or colon cancer may have hereditary breast and ovarian cancer syndrome (BRCA mutation) or hereditary nonpolyposis colorectal cancer (Lynch syndrome), and these women are at increased risk of developing ovarian cancer. Women with these conditions should be referred for formal genetic counseling to better assess their cancer risk, including their risk of ovarian cancer. If appropriate, these women may be offered additional testing for early detection of ovarian cancer. The use of transvaginal ultrasonography and tumor markers (such as cancer antigen 125), alone or in combination, for the early detection of ovarian cancer in average risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (eg, surgery) resulting from false-positive test results. The patient and her obstetrician-gynecologist should maintain an appropriate level of suspicion when potentially relevant signs and symptoms of ovarian cancer are present. PMID- 28832480 TI - Committee Opinion No. 718 Summary: Update on Immunization and Pregnancy: Tetanus, Diphtheria, and Pertussis Vaccination. AB - The overwhelming majority of morbidity and mortality attributable to pertussis infection occurs in infants who are 3 months and younger. Infants do not begin their own vaccine series against pertussis until approximately 2 months of age. This leaves a window of significant vulnerability for newborns, many of whom contract serious pertussis infections from family members and caregivers, especially their mothers, or older siblings, or both. In 2013, the Advisory Committee on Immunization Practices published its updated recommendation that a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) should be administered during each pregnancy, irrespective of the prior history of receiving Tdap. The recommended timing for maternal Tdap vaccination is between 27 weeks and 36 weeks of gestation. To maximize the maternal antibody response and passive antibody transfer and levels in the newborn, vaccination as early as possible in the 27-36-weeks-of-gestation window is recommended. However, the Tdap vaccine may be safely given at any time during pregnancy if needed for wound management, pertussis outbreaks, or other extenuating circumstances. There is no evidence of adverse fetal effects from vaccinating pregnant women with an inactivated virus or bacterial vaccine or toxoid, and a growing body of robust data demonstrate safety of such use. Adolescent and adult family members and caregivers who previously have not received the Tdap vaccine and who have or anticipate having close contact with an infant younger than 12 months should receive a single dose of Tdap to protect against pertussis. Given the rapid evolution of data surrounding this topic, immunization guidelines are likely to change over time, and the American College of Obstetricians and Gynecologists will continue to issue updates accordingly. PMID- 28832479 TI - Committee Opinion No. 717 Summary: Sulfonamides, Nitrofurantoin, and Risk of Birth Defects. AB - The evidence regarding an association between the nitrofuran and sulfonamide classes of antibiotics and birth defects is mixed. As with all patients, antibiotics should be prescribed for pregnant women only for appropriate indications and for the shortest effective duration. During the second and third trimesters, sulfonamides and nitrofurantoins may continue to be used as first line agents for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms. Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available. Pregnant women should not be denied appropriate treatment for infections because untreated infections can commonly lead to serious maternal and fetal complications. PMID- 28832481 TI - Committee Opinion No. 719 Summary: Multifetal Pregnancy Reduction. AB - Although not all multifetal pregnancies occur after the use of assisted reproductive technology, fertility treatments have contributed significantly to the increase in multifetal pregnancies. In almost all cases, it is preferable to avoid the risk of higher-order multifetal pregnancy by limiting the number of embryos to be transferred or by cancelling a gonadotropin cycle when the ovarian response suggests a high risk of a multifetal pregnancy. When multifetal pregnancies do occur, incorporating the ethical framework presented in this Committee Opinion will help obstetrician-gynecologists counsel and guide patients as they make decisions regarding continuing or reducing their multifetal pregnancies. PMID- 28832482 TI - Committee Opinion No. 720 Summary: Maternal-Fetal Surgery for Myelomeningocele. AB - Myelomeningocele, a severe form of spina bifida, occurs in approximately 1 in 3,000 live births in the United States. The extent of disability is generally related to the level of the myelomeningocele defect, with a higher upper level of lesion generally corresponding to greater deficits. Open maternal-fetal surgery for myelomeningocele repair is a major procedure for the woman and her affected fetus. Although there is demonstrated potential for fetal and pediatric benefit, there are significant maternal implications and complications that may occur acutely, postoperatively, for the duration of the pregnancy, and in subsequent pregnancies. Women with pregnancies complicated by fetal myelomeningocele who meet established criteria for in utero repair should be counseled in a nondirective fashion regarding all management options, including the possibility of open maternal-fetal surgery. Maternal-fetal surgery for myelomeningocele repair should be offered only to carefully selected patients at facilities with an appropriate level of personnel and resources. PMID- 28832483 TI - Clinical Updates in Women's Health Care Summary: Mood and Anxiety Disorders: Primary and Preventive Care Review. AB - The management of psychiatric disorders in women is complicated by reproductive life cycle events. Psychiatric disorders can be initiated or exacerbated during times of hormonal change (such as menarche, the premenstrual period, the postpartum period, and perimenopause), and during the childbearing years, treatment is complicated by pregnancy and breastfeeding. These issues make determining the appropriate psychiatric medications to use in the treatment of mood and anxiety disorders in women complex. This monograph addresses practical approaches in the provision of thorough and individualized care for women with mood or anxiety disorders. PMID- 28832484 TI - Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome. AB - Hereditary breast and ovarian cancer syndrome is an inherited cancer susceptibility syndrome characterized by multiple family members with breast cancer, ovarian cancer, or both. Based on the contemporary understanding of the origins and management of ovarian cancer and for simplicity in this document, ovarian cancer also refers to fallopian tube cancer and primary peritoneal cancer. Clinical genetic testing for gene mutations allows more precise identification of those women who are at an increased risk of inherited breast cancer and ovarian cancer. For these individuals, screening and prevention strategies can be instituted to reduce their risks. Obstetrician-gynecologists play an important role in the identification and management of women with hereditary breast and ovarian cancer syndrome. If an obstetrician-gynecologist or other gynecologic care provider does not have the necessary knowledge or expertise in cancer genetics to counsel a patient appropriately, referral to a genetic counselor, gynecologic or medical oncologist, or other genetics specialist should be considered (1). More genes are being discovered that impart varying risks of breast cancer, ovarian cancer, and other types of cancer, and new technologies are being developed for genetic testing. This Practice Bulletin focuses on the primary genetic mutations associated with hereditary breast and ovarian cancer syndrome, BRCA1 and BRCA2, but also will briefly discuss some of the other genes that have been implicated. PMID- 28832485 TI - Committee Opinion No. 714: Obesity in Adolescents. AB - Rates of obesity among adolescents in the United States have increased at a dramatic rate along with the prevalence of weight-related diseases. Between the 1980s and 2014, the prevalence of obesity among adolescent females in the United States increased from approximately 10% to 21%. Although the steep increase in the prevalence of obesity in children (2-11 years) has slowed, the prevalence of obesity in adolescents (12-19 years) continues to increase. Because the obese female adolescent faces medical, psychologic, and reproductive health challenges, early intervention is imperative in preventing short-term and long-term morbidity. The obstetrician-gynecologist who is knowledgeable about the behavioral and environmental factors that influence obesity may be better able to educate parents, guardians, and adolescents and advocate for programs that increase physical activity and improve nutrition. The obstetrician-gynecologist should be able to identify obese adolescents, particularly those at risk of comorbid conditions. They may have the opportunity to initiate behavioral counseling, participate in multidisciplinary teams that care for overweight and obese adolescents, and advocate for community programs to prevent obesity. PMID- 28832486 TI - Committee Opinion No. 715: Social Etiquette for Program Directors and Faculty. AB - Educators in obstetrics and gynecology work within a changing clinical learning environment. Ethnic, cultural, and social diversity among colleagues and learners have increased, and methods of communication have expanded in ever more novel ways. Clerkship, residency, and fellowship directors, in partnership with chairs and senior faculty, are urged to take the lead in setting the tone for workplace etiquette, communication, and social behavior of faculty and trainees to promote a high standard of civility and citizenship. The Council on Resident Education in Obstetrics and Gynecology (CREOG) Education Committee has promulgated recommendations that can be used to help address professional relationships, professional appearance, and social media usage. These recommendations also address communications pertinent to educational processes such as interviewing, teaching, evaluation, and mentoring. PMID- 28832487 TI - Committee Opinion No. 716: The Role of the Obstetrician-Gynecologist in the Early Detection of Epithelial Ovarian Cancer in Women at Average Risk. AB - Ovarian cancer is the second most common type of female reproductive cancer, and more women die from ovarian cancer than from cervical cancer and uterine cancer combined. Currently, there is no strategy for early detection of ovarian cancer that reduces ovarian cancer mortality. Taking a detailed personal and family history for breast, gynecologic, and colon cancer facilitates categorizing women based on their risk (average risk or high risk) of developing epithelial ovarian cancer. Women with a strong family history of ovarian, breast, or colon cancer may have hereditary breast and ovarian cancer syndrome (BRCA mutation) or hereditary nonpolyposis colorectal cancer (Lynch syndrome), and these women are at increased risk of developing ovarian cancer. Women with these conditions should be referred for formal genetic counseling to better assess their cancer risk, including their risk of ovarian cancer. If appropriate, these women may be offered additional testing for early detection of ovarian cancer. The use of transvaginal ultrasonography and tumor markers (such as cancer antigen 125), alone or in combination, for the early detection of ovarian cancer in average risk women have not been proved to reduce mortality, and harms exist from invasive diagnostic testing (eg, surgery) resulting from false-positive test results. The patient and her obstetrician-gynecologist should maintain an appropriate level of suspicion when potentially relevant signs and symptoms of ovarian cancer are present. PMID- 28832488 TI - Committee Opinion No. 717: Sulfonamides, Nitrofurantoin, and Risk of Birth Defects. AB - The evidence regarding an association between the nitrofuran and sulfonamide classes of antibiotics and birth defects is mixed. As with all patients, antibiotics should be prescribed for pregnant women only for appropriate indications and for the shortest effective duration. During the second and third trimesters, sulfonamides and nitrofurantoins may continue to be used as first line agents for the treatment and prevention of urinary tract infections and other infections caused by susceptible organisms. Prescribing sulfonamides or nitrofurantoin in the first trimester is still considered appropriate when no other suitable alternative antibiotics are available. Pregnant women should not be denied appropriate treatment for infections because untreated infections can commonly lead to serious maternal and fetal complications. PMID- 28832489 TI - Committee Opinion No. 718: Update on Immunization and Pregnancy: Tetanus, Diphtheria, and Pertussis Vaccination. AB - The overwhelming majority of morbidity and mortality attributable to pertussis infection occurs in infants who are 3 months and younger. Infants do not begin their own vaccine series against pertussis until approximately 2 months of age. This leaves a window of significant vulnerability for newborns, many of whom contract serious pertussis infections from family members and caregivers, especially their mothers, or older siblings, or both. In 2013, the Advisory Committee on Immunization Practices published its updated recommendation that a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) should be administered during each pregnancy, irrespective of the prior history of receiving Tdap. The recommended timing for maternal Tdap vaccination is between 27 weeks and 36 weeks of gestation. To maximize the maternal antibody response and passive antibody transfer and levels in the newborn, vaccination as early as possible in the 27-36-weeks-ofgestation window is recommended. However, the Tdap vaccine may be safely given at any time during pregnancy if needed for wound management, pertussis outbreaks, or other extenuating circumstances. There is no evidence of adverse fetal effects from vaccinating pregnant women with an inactivated virus or bacterial vaccine or toxoid, and a growing body of robust data demonstrate safety of such use. Adolescent and adult family members and caregivers who previously have not received the Tdap vaccine and who have or anticipate having close contact with an infant younger than 12 months should receive a single dose of Tdap to protect against pertussis. Given the rapid evolution of data surrounding this topic, immunization guidelines are likely to change over time, and the American College of Obstetricians and Gynecologists will continue to issue updates accordingly. PMID- 28832490 TI - Committee Opinion No. 719: Multifetal Pregnancy Reduction. AB - Although not all multifetal pregnancies occur after the use of assisted reproductive technology, fertility treatments have contributed significantly to the increase in multifetal pregnancies. In almost all cases, it is preferable to avoid the risk of higher-order multifetal pregnancy by limiting the number of embryos to be transferred or by cancelling a gonadotropin cycle when the ovarian response suggests a high risk of a multifetal pregnancy. When multifetal pregnancies do occur, incorporating the ethical framework presented in this Committee Opinion will help obstetrician-gynecologists counsel and guide patients as they make decisions regarding continuing or reducing their multifetal pregnancies. PMID- 28832491 TI - Committee Opinion No. 720: Maternal-Fetal Surgery for Myelomeningocele. AB - Myelomeningocele, a severe form of spina bifida, occurs in approximately 1 in 3,000 live births in the United States. The extent of disability is generally related to the level of the myelomeningocele defect, with a higher upper level of lesion generally corresponding to greater deficits. Open maternal-fetal surgery for myelomeningocele repair is a major procedure for the woman and her affected fetus. Although there is demonstrated potential for fetal and pediatric benefit, there are significant maternal implications and complications that may occur acutely, postoperatively, for the duration of the pregnancy, and in subsequent pregnancies. Women with pregnancies complicated by fetal myelomeningocele who meet established criteria for in utero repair should be counseled in a nondirective fashion regarding all management options, including the possibility of open maternal-fetal surgery. Maternal-fetal surgery for myelomeningocele repair should be offered only to carefully selected patients at facilities with an appropriate level of personnel and resources. PMID- 28832492 TI - Implications of infection and trends of antibiotic prescribing in hospitalized patients diagnosed with serious mental illness. AB - Hospital-acquired infections have been recognized as a significant factor in increased morbidity and mortality across our health system. Unique to infections associated with inpatient psychiatric hospitalization is the additional hypothesized association of the role that antipsychotic agents and/or underlying disease may play in an increased risk for infection. In this paper, we explore the types of infections diagnosed in an inpatient psychiatric hospital, the demographics of the patients infected, and whether or not the patient was on antipsychotic agents at the time of infection. PMID- 28832493 TI - Modulation of Gut Microbiota of Overweight Mice by Agavins and Their Association with Body Weight Loss. AB - Agavins consumption has led to accelerated body weight loss in mice. We investigated the changes on cecal microbiota and short-chain fatty acids (SCFA) associated with body weight loss in overweight mice. Firstly, mice were fed with standard (ST5) or high-fat (HF5) diet for five weeks. Secondly, overweight mice were shifted to standard diet alone (HF-ST10) or supplemented with agavins (HF-ST + A10) or oligofructose (HF-ST + O10), for five more weeks. Cecal contents were collected before and after supplementation to determine microbiota and SCFA concentrations. At the end of first phase, HF5 mice showed a significant increase of body weight, which was associated with reduction of cecal microbiota diversity (PD whole tree; non-parametric t test, p < 0.05), increased Firmicutes/Bacteroidetes ratio and reduced SCFA concentrations (t test, p < 0.05). After diet shifting, HF-ST10 normalized its microbiota, increased its diversity, and SCFA levels, whereas agavins (HF-ST + A10) or oligofructose (HF-ST + O10) led to partial microbiota restoration, with normalization of the Firmicutes/Bacteroides ratio, as well as higher SCFA levels (p < 0.1). Moreover, agavins noticeably enriched Klebsiella and Citrobacter (LDA > 3.0); this enrichment has not been reported previously under a prebiotic treatment. In conclusion, agavins or oligofructose modulated cecal microbiota composition, reduced the extent of diversity, and increased SCFA. Furthermore, identification of bacteria enriched by agavins opens opportunities to explore new probiotics. PMID- 28832495 TI - A Fair Contention Access Scheme for Low-Priority Traffic in Wireless Body Area Networks. AB - Recently, wireless body area networks (WBANs) have attracted significant consideration in ubiquitous healthcare. A number of medium access control (MAC) protocols, primarily derived from the superframe structure of the IEEE 802.15.4, have been proposed in literature. These MAC protocols aim to provide quality of service (QoS) by prioritizing different traffic types in WBANs. A contention access period (CAP)with high contention in priority-based MAC protocols can result in higher number of collisions and retransmissions. During CAP, traffic classes with higher priority are dominant over low-priority traffic; this has led to starvation of low-priority traffic, thus adversely affecting WBAN throughput, delay, and energy consumption. Hence, this paper proposes a traffic-adaptive priority-based superframe structure that is able to reduce contention in the CAP period, and provides a fair chance for low-priority traffic. Simulation results in ns-3 demonstrate that the proposed MAC protocol, called traffic- adaptive priority-based MAC (TAP-MAC), achieves low energy consumption, high throughput, and low latency compared to the IEEE 802.15.4 standard, and the most recent priority-based MAC protocol, called priority-based MAC protocol (PA-MAC). PMID- 28832496 TI - iTRAQ-Based Quantitative Proteomics Analysis on Rice Anther Responding to High Temperature. AB - As one of the most important crops, rice provides the major food for more than half of the world population. However, its production is limited by many environmental factors, among which high temperature stress (HS) frequently occurs during anthesis and reduces its spikelet fertility. To explore the mechanism of HS tolerance in rice, we conducted a comparative proteomics analysis on the anthers between HS resistant and sensitive cultivars under different levels of high temperature. Under the same HS treatment, the resistant cultivar showed much higher spikelet fertility than the sensitive cultivar. Proteomic data showed that HS lead to the degradation of ribosomal proteins in the sensitive cultivar but not in the resistant one, which might result in the injury of protein biosynthetic machinery. In contrast, HS induced the increase of sHSP, beta expansins and lipid transfer proteins in the resistant cultivar, which might contribute to its ability to tolerate HS. The results provide some new insights into the mechanism of rice HS response. PMID- 28832494 TI - Integrins as Therapeutic Targets: Successes and Cancers. AB - Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFbeta, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of alpha4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments. PMID- 28832497 TI - Dexmedetomidine Prevents Lipopolysaccharide-Induced MicroRNA Expression in the Adult Rat Brain. AB - During surgery or infection, peripheral inflammation can lead to neuroinflammation, which is associated with cognitive impairment, neurodegeneration, and several neurodegenerative diseases. Dexmedetomidine, an alpha-2-adrenoceptor agonist, is known to exert anti-inflammatory and neuroprotective properties and reduces the incidence of postoperative cognitive impairments. However, on the whole the molecular mechanisms are poorly understood. This study aims to explore whether dexmedetomidine influences microRNAs (miRNAs) in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Adult Wistar rats were injected with 1 mg/kg LPS intraperitoneal (i.p.) in the presence or absence of 5 ug/kg dexmedetomidine. After 6 h, 24 h, and 7 days, gene expressions of interleukin 1-beta (IL1-beta), tumor necrosis factor-alpha (TNF-alpha), and microRNA expressions of miR 124, 132, 134, and 155 were measured in the hippocampus, cortex, and plasma. Dexmedetomidine decreased the LPS-induced neuroinflammation in the hippocampus and cortex via significant reduction of the IL1-beta and TNF-alpha gene expressions after 24 h. Moreover, the LPS-mediated increased expressions of miR 124, 132, 134, and 155 were significantly decreased after dexmedetomidine treatment in both brain regions. In plasma, dexmedetomidine significantly reduced LPS-induced miR 155 after 6 h. Furthermore, there is evidence that miR 132 and 134 may be suitable as potential biomarkers for the detection of neuroinflammation. PMID- 28832498 TI - Corneal Fibroblasts as Sentinel Cells and Local Immune Modulators in Infectious Keratitis. AB - The cornea serves as a barrier to protect the eye against external insults including microbial pathogens and antigens. Bacterial infection of the cornea often results in corneal melting and scarring that can lead to severe visual impairment. Not only live bacteria but also their components such as lipopolysaccharide (LPS) of Gram-negative bacteria contribute to the development of inflammation and subsequent corneal damage in infectious keratitis. We describe the important role played by corneal stromal fibroblasts (activated keratocytes) as sentinel cells, immune modulators, and effector cells in infectious keratitis. Corneal fibroblasts sense bacterial infection through Toll like receptor (TLR)-mediated detection of a complex of LPS with soluble cluster of differentiation 14 (CD14) and LPS binding protein present in tear fluid. The cells then initiate innate immune responses including the expression of chemokines and adhesion molecules that promote the recruitment of inflammatory cells necessary for elimination of the infecting bacteria. Infiltrated neutrophils are activated by corneal stromal collagen and release mediators that stimulate the production of pro-matrix metalloproteinases by corneal fibroblasts. Elastase produced by Pseudomonas aeruginosa (P. aeruginosa) activates these released metalloproteinases, resulting in the degradation of stromal collagen. The modulation of corneal fibroblast activation and of the interaction of these cells with inflammatory cells and bacteria is thus important to minimize corneal scarring during treatment of infectious keratitis. Pharmacological agents that are able to restrain such activities of corneal fibroblasts without allowing bacterial growth represent a potential novel treatment option for prevention of excessive scarring and tissue destruction in the cornea. PMID- 28832499 TI - A Molecular Modeling Study of the Hydroxyflutamide Resistance Mechanism Induced by Androgen Receptor Mutations. AB - Hydroxyflutamide (HF), an active metabolite of the first generation antiandrogen flutamide, was used in clinic to treat prostate cancer targeting androgen receptor (AR). However, a drug resistance problem appears after about one year's treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot. In this study, molecular dynamics (MD) simulations combined with the molecular mechanics generalized Born surface area (MM-GBSA) method have been carried out to analyze the interaction mechanism between HF and wild-type (WT)/mutant ARs. The obtained results indicate that AR helix 12 (H12) plays a pivotal role in the resistance of HF. It can affect the coactivator binding site at the activation function 2 domain (AF2, surrounded by H3, H4, and H12). When H12 closes to the AR ligand binding domain (LBD) like a lid, the coactivator binding site can be formed to promote transcription. However, once H12 is opened to expose LBD, the coactivator binding site will be distorted, leading to invalid transcription. Moreover, per residue free energy decomposition analyses indicate that N705, T877, and M895 are vital residues in the agonist/antagonist mechanism of HF. PMID- 28832501 TI - Line-Constrained Camera Location Estimation in Multi-Image Stereomatching. AB - Stereomatching is an effective way of acquiring dense depth information from a scene when active measurements are not possible. So-called lightfield methods take a snapshot from many camera locations along a defined trajectory (usually uniformly linear or on a regular grid-we will assume a linear trajectory) and use this information to compute accurate depth estimates. However, they require the locations for each of the snapshots to be known: the disparity of an object between images is related to both the distance of the camera to the object and the distance between the camera positions for both images. Existing solutions use sparse feature matching for camera location estimation. In this paper, we propose a novel method that uses dense correspondences to do the same, leveraging an existing depth estimation framework to also yield the camera locations along the line. We illustrate the effectiveness of the proposed technique for camera location estimation both visually for the rectification of epipolar plane images and quantitatively with its effect on the resulting depth estimation. Our proposed approach yields a valid alternative for sparse techniques, while still being executed in a reasonable time on a graphics card due to its highly parallelizable nature. PMID- 28832500 TI - miR-145-5p Suppresses Tumor Cell Migration, Invasion and Epithelial to Mesenchymal Transition by Regulating the Sp1/NF-kappaB Signaling Pathway in Esophageal Squamous Cell Carcinoma. AB - MicroRNAs (miRNAs) play important roles in the progression of human cancer. Although previous reports have shown that miR-145-5p is down-regulated in esophageal squamous cell carcinoma (ESCC), the roles and mechanisms of down regulation of miR-145-5p in ESCC are still largely unknown. Using microRNA microarray and Gene Expression Omnibus (GEO) datasets, we confirmed that miR-145 5p was down-regulated in ESCC tissues. In vitro assays revealed that ectopic miR 145-5p expression repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT). miR-145-5p also reduced the expressions of cell cycle genes including cyclin A2 (CCNA2), cyclin D1 (CCND1) and cyclin E1 (CCNE1), the EMT-associated transcription factor Slug, and matrix metalloproteinases (MMPs) including MMP2, MMP7 and MMP13. Furthermore, miR-145-5p mimics reduced candidate target gene specificity protein 1 (Sp1) and nuclear factor kappa B (NF-kappaB) (p65) both in mRNA and protein levels. Knockdown of Sp1 phenocopied the effects of miR-145-5p overexpression on cell cycle regulators, EMT and the expression of NF-kappaB (p65). Importantly, inhibition of the NF-kappaB signaling pathway or knockdown of NF-kappaB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells. In conclusion, our results suggested that miR-145-5p plays tumor-suppressive roles by inhibiting esophageal cancer cell migration, invasion and EMT through regulating the Sp1/NF-kappaB signaling pathway. PMID- 28832504 TI - Bi-Component Nanostructured Arrays of Co Dots Embedded in Ni80Fe20 Antidot Matrix: Synthesis by Self-Assembling of Polystyrene Nanospheres and Magnetic Properties. AB - A bi-component nanostructured system composed by a Co dot array embedded in a Ni80Fe20 antidot matrix has been prepared by means of the self-assembling polystyrene nanospheres lithography technique. Reference samples constituted by the sole Co dots or Ni80Fe20 antidots have also been prepared, in order to compare their properties with those of the bi-component material. The coupling between the two ferromagnetic elements has been studied by means of magnetic and magneto-transport measurements. The Ni80Fe20 matrix turned out to affect the vortex nucleation field of the Co dots, which in turn modifies the magneto resistance behaviour of the system and its spinwave properties. PMID- 28832502 TI - Reduced Mortality in Maintenance Haemodialysis Patients on High versus Low Dialysate Magnesium: A Pilot Study. AB - BACKGROUND: Although low magnesium levels have been associated with an increased mortality in dialysis patients, they are kept low by routinely-used dialysates containing 0.50 mmol/L magnesium. Thus, we investigated the impact of a higher dialysate magnesium concentration on mortality. METHODS: 25 patients on high dialysate magnesium (HDM) of 0.75 mmol/L were 1:2 matched to 50 patients on low dialysate magnesium (LDM) of 0.50 mmol/L and followed up for 3 years with regards to all-cause and cardiovascular mortality. Patients were matched according to age, gender, a modified version of the Charlson Comorbidity Index (CCI), and smoking status. RESULTS: During the follow-up period, five patients died in the HDM and 18 patients in the LDM group. Patients in the HDM group had significantly higher ionized serum magnesium levels than matched controls (0.64 +/- 0.12 mmol/L vs. 0.57 +/- 0.10 mmol/L, p = 0.034). Log rank test showed no difference between treatment groups for all-cause mortality. After adjustment for age and CCI, Cox proportional hazards regression showed that HDM independently predicted a 65% risk reduction for all-cause mortality (hazard ratio 0.35, 95% confidence interval [CI]: 0.13, 0.97). Estimated 3-year probability of death from a cardiovascular event was 14.5% (95% CI: 7.9, 25.8) in the LDM group vs. 0% in the HDM group. Log rank test found a significant group difference for cardiovascular mortality (chi2 = 4.15, p = 0.042). CONCLUSIONS: Our data suggests that there might be a beneficial effect of an increased dialysate magnesium on cardiovascular mortality in chronic dialysis patients. PMID- 28832503 TI - Genetic Divergence and Chemotype Diversity in the Fusarium Head Blight Pathogen Fusarium poae. AB - Fusarium head blight is a disease caused by a complex of Fusarium species. F. poae is omnipresent throughout Europe in spite of its low virulence. In this study, we assessed a geographically diverse collection of F. poae isolates for its genetic diversity using AFLP (Amplified Fragment Length Polymorphism). Furthermore, studying the mating type locus and chromosomal insertions, we identified hallmarks of both sexual recombination and clonal spread of successful genotypes in the population. Despite the large genetic variation found, all F. poae isolates possess the nivalenol chemotype based on Tri7 sequence analysis. Nevertheless, Tri gene clusters showed two layers of genetic variability. Firstly, the Tri1 locus was highly variable with mostly synonymous mutations and mutations in introns pointing to a strong purifying selection pressure. Secondly, in a subset of isolates, the main trichothecene gene cluster was invaded by a transposable element between Tri5 and Tri6. To investigate the impact of these variations on the phenotypic chemotype, mycotoxin production was assessed on artificial medium. Complex blends of type A and type B trichothecenes were produced but neither genetic variability in the Tri genes nor variability in the genome or geography accounted for the divergence in trichothecene production. In view of its complex chemotype, it will be of utmost interest to uncover the role of trichothecenes in virulence, spread and survival of F. poae. PMID- 28832505 TI - Mn2+-ZnSe/ZnS@SiO2 Nanoparticles for Turn-on Luminescence Thiol Detection. AB - Biological thiols are antioxidants essential for the prevention of disease. For example, low levels of the tripeptide glutathione are associated with heart disease, cancer, and dementia. Mn2+-doped wide bandgap semiconductor nanocrystals exhibit luminescence and magnetic properties that make them attractive for bimodal imaging. We found that these nanocrystals and silica-encapsulated nanoparticle derivatives exhibit enhanced luminescence in the presence of thiols in both organic solvent and aqueous solution. The key to using these nanocrystals as sensors is control over their surfaces. The addition of a ZnS barrier layer or shell produces more stable nanocrystals that are isolated from their surroundings, and luminescence enhancement is only observed with thinner, intermediate shells. Tunability is demonstrated with dodecanethiol and sensitivities decrease with thin, medium, and thick shells. Turn-on nanoprobe luminescence is also generated by several biological thiols, including glutathione, N-acetylcysteine, cysteine, and dithiothreitol. Nanoparticles prepared with different ZnS shell thicknesses demonstrated varying sensitivity to glutathione, which allows for the tuning of particle sensitivity without optimization. The small photoluminescence response to control amino acids and salts indicates selectivity for thiols. Preliminary magnetic measurements highlight the challenge of optimizing sensors for different imaging modalities. In this work, we assess the prospects of using these nanoparticles as luminescent turn-on thiol sensors and for MRI. PMID- 28832506 TI - Determination and Visualization of Peimine and Peiminine Content in Fritillaria thunbergii Bulbi Treated by Sulfur Fumigation Using Hyperspectral Imaging with Chemometrics. AB - Rapid, non-destructive, and accurate quantitative determination of the effective components in traditional Chinese medicine (TCM) is required by industries, planters, and regulators. In this study, near-infrared hyperspectral imaging was applied for determining the peimine and peiminine content in Fritillaria thunbergii bulbi under sulfur fumigation. Spectral data were extracted from the hyperspectral images. High-performance liquid chromatography (HPLC) was conducted to determine the reference peimine and peiminine content. The successive projection algorithm (SPA), weighted regression coefficient (Bw), competitive adaptive reweighted sampling (CARS), and random frog (RF) were used to select optimal wavelengths, while the partial least squares (PLS), least-square support vector machine (LS-SVM) and extreme learning machine (ELM) were used to build regression models. Regression models using the full spectra and optimal wavelengths obtained satisfactory results with the correlation coefficient of calibration (rc), cross-validation (rcv) and prediction (rp) of most models being over 0.8. Prediction maps of peimine and peiminine content in Fritillaria thunbergii bulbi were formed by applying regression models to the hyperspectral images. The overall results indicated that hyperspectral imaging combined with regression models and optimal wavelength selection methods were effective in determining peimine and peiminine content in Fritillaria thunbergii bulbi, which will help in the development of an online detection system for real-world quality control of Fritillaria thunbergii bulbi under sulfur fumigation. PMID- 28832507 TI - A Biological Signal-Based Stress Monitoring Framework for Children Using Wearable Devices. AB - The safety of children has always been an important issue, and several studies have been conducted to determine the stress state of a child to ensure the safety. Audio signals and biological signals including heart rate are known to be effective for stress state detection. However, collecting those data requires specialized equipment, which is not appropriate for the constant monitoring of children, and advanced data analysis is required for accurate detection. In this regard, we propose a stress state detection framework which utilizes both audio signal and heart rate collected from wearable devices, and adopted machine learning methods for the detection. Experiments using real-world data were conducted to compare detection performances across various machine learning methods and noise levels of audio signal. Adopting the proposed framework in the real-world will contribute to the enhancement of child safety. PMID- 28832508 TI - Highly Efficient and Stable Organic Solar Cells via Interface Engineering with a Nanostructured ITR-GO/PFN Bilayer Cathode Interlayer. AB - An innovative bilayer cathode interlayer (CIL) with a nanostructure consisting of in situ thermal reduced graphene oxide (ITR-GO) and poly[(9,9-bis(3'-(N,N dimethylamion)propyl)-2,7-fluorene)-alt-2,7-(9,9-dioctyl) fluorene] (PFN) has been fabricated for inverted organic solar cells (OSCs). An approach to prepare a CIL of high electronic quality by using ITR-GO as a template to modulate the morphology of the interface between the active layer and electrode and to further reduce the work function of the electrode has also been realized. This bilayer ITR-GO/PFN CIL is processed by a spray-coating method with facile in situ thermal reduction. Meanwhile, the CIL shows a good charge transport efficiency and less charge recombination, which leads to a significant enhancement of the power conversion efficiency from 6.47% to 8.34% for Poly({4,8-bis[(2 ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl}{3-fluoro-2-[(2 ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl} (PTB7):[6,6]-phenyl-C71-butyric acid methyl ester (PC71BM)-based OSCs. In addition, the long-term stability of the OSC is improved by using the ITR-GO/PFN CIL when compared with the pristine device. These results indicate that the bilayer ITR-GO/PFN CIL is a promising way to realize high-efficiency and stable OSCs by using water-soluble conjugated polymer electrolytes such as PFN. PMID- 28832509 TI - Statistical-QoS Guaranteed Energy Efficiency Optimization for Energy Harvesting Wireless Sensor Networks. AB - Energy harvesting, which offers a never-ending energy supply, has emerged as a prominent technology to prolong the lifetime and reduce costs for the battery powered wireless sensor networks. However, how to improve the energy efficiency while guaranteeing the quality of service (QoS) for energy harvesting based wireless sensor networks is still an open problem. In this paper, we develop statistical delay-bounded QoS-driven power control policies to maximize the effective energy efficiency (EEE), which is defined as the spectrum efficiency under given specified QoS constraints per unit harvested energy, for energy harvesting based wireless sensor networks. For the battery-infinite wireless sensor networks, our developed QoS-driven power control policy converges to the Energy harvesting Water Filling (E-WF) scheme and the Energy harvesting Channel Inversion (E-CI) scheme under the very loose and stringent QoS constraints, respectively. For the battery-finite wireless sensor networks, our developed QoS driven power control policy becomes the Truncated energy harvesting Water Filling (T-WF) scheme and the Truncated energy harvesting Channel Inversion (T-CI) scheme under the very loose and stringent QoS constraints, respectively. Furthermore, we evaluate the outage probabilities to theoretically analyze the performance of our developed QoS-driven power control policies. The obtained numerical results validate our analysis and show that our developed optimal power control policies can optimize the EEE over energy harvesting based wireless sensor networks. PMID- 28832510 TI - Virtual Sensor for Kinematic Estimation of Flexible Links in Parallel Robots. AB - The control of flexible link parallel manipulators is still an open area of research, endpoint trajectory tracking being one of the main challenges in this type of robot. The flexibility and deformations of the limbs make the estimation of the Tool Centre Point (TCP) position a challenging one. Authors have proposed different approaches to estimate this deformation and deduce the location of the TCP. However, most of these approaches require expensive measurement systems or the use of high computational cost integration methods. This work presents a novel approach based on a virtual sensor which can not only precisely estimate the deformation of the flexible links in control applications (less than 2% error), but also its derivatives (less than 6% error in velocity and 13% error in acceleration) according to simulation results. The validity of the proposed Virtual Sensor is tested in a Delta Robot, where the position of the TCP is estimated based on the Virtual Sensor measurements with less than a 0.03% of error in comparison with the flexible approach developed in ADAMS Multibody Software. PMID- 28832511 TI - Benchmarking Foot Trajectory Estimation Methods for Mobile Gait Analysis. AB - Mobile gait analysis systems based on inertial sensing on the shoe are applied in a wide range of applications. Especially for medical applications, they can give new insights into motor impairment in, e.g., neurodegenerative disease and help objectify patient assessment. One key component in these systems is the reconstruction of the foot trajectories from inertial data. In literature, various methods for this task have been proposed. However, performance is evaluated on a variety of datasets due to the lack of large, generally accepted benchmark datasets. This hinders a fair comparison of methods. In this work, we implement three orientation estimation and three double integration schemes for use in a foot trajectory estimation pipeline. All methods are drawn from literature and evaluated against a marker-based motion capture reference. We provide a fair comparison on the same dataset consisting of 735 strides from 16 healthy subjects. As a result, the implemented methods are ranked and we identify the most suitable processing pipeline for foot trajectory estimation in the context of mobile gait analysis. PMID- 28832512 TI - Cross-Reactive Plasmonic Aptasensors for Controlled Substance Identification. AB - In this work, we developed an assay to determine if an arbitrary white powder is a controlled substance, given the plasmonic response of aptamer-gold nanoparticle conjugates (Apt-AuNPs). Toward this end, we designed Apt-AuNPs with specific a response to common controlled substances without cross reactivity to chemicals typically used as fillers in street formulations. Plasmonic sensor variation was shown to produce unique data fingerprints for each chemical analyzed, supporting the application of multivariate statistical techniques to annotate unknown samples by chemical similarity. Importantly, the assay takes less than fifteen minutes to run, and requires only a few micrograms of the material, making the proposed assay easily deployable in field operations. PMID- 28832513 TI - EEG-Based Brain-Computer Interface for Decoding Motor Imagery Tasks within the Same Hand Using Choi-Williams Time-Frequency Distribution. AB - This paper presents an EEG-based brain-computer interface system for classifying eleven motor imagery (MI) tasks within the same hand. The proposed system utilizes the Choi-Williams time-frequency distribution (CWD) to construct a time frequency representation (TFR) of the EEG signals. The constructed TFR is used to extract five categories of time-frequency features (TFFs). The TFFs are processed using a hierarchical classification model to identify the MI task encapsulated within the EEG signals. To evaluate the performance of the proposed approach, EEG data were recorded for eighteen intact subjects and four amputated subjects while imagining to perform each of the eleven hand MI tasks. Two performance evaluation analyses, namely channel- and TFF-based analyses, are conducted to identify the best subset of EEG channels and the TFFs category, respectively, that enable the highest classification accuracy between the MI tasks. In each evaluation analysis, the hierarchical classification model is trained using two training procedures, namely subject-dependent and subject-independent procedures. These two training procedures quantify the capability of the proposed approach to capture both intra- and inter-personal variations in the EEG signals for different MI tasks within the same hand. The results demonstrate the efficacy of the approach for classifying the MI tasks within the same hand. In particular, the classification accuracies obtained for the intact and amputated subjects are as high as 88 . 8 % and 90 . 2 % , respectively, for the subject-dependent training procedure, and 80 . 8 % and 87 . 8 % , respectively, for the subject independent training procedure. These results suggest the feasibility of applying the proposed approach to control dexterous prosthetic hands, which can be of great benefit for individuals suffering from hand amputations. PMID- 28832514 TI - Avocado Consumption Increases Macular Pigment Density in Older Adults: A Randomized, Controlled Trial. AB - Lutein is selectively incorporated into the macula and brain. Lutein levels in the macula (macular pigment; MP) and the brain are related to better cognition. MP density (MPD) is a biomarker of brain lutein. Avocados are a bioavailable source of lutein. This study tests the effects of the intake of avocado on cognition. This was a six-month, randomized, controlled trial. Healthy subjects consumed one avocado (n = 20, 0.5 mg/day lutein, AV) vs. one potato or one cup of chickpeas (n = 20, 0 mg/day lutein, C). Serum lutein, MPD, and cognition were assessed at zero, three, and six months. Primary analyses were conducted according to intent-to-treat principles, with repeated-measures analysis. At six months, AV increased serum lutein levels by 25% from baseline (p = 0.001). C increased by 15% (p = 0.030). At six months, there was an increase in MPD from baseline in AV (p = 0.001) and no increase in C. For both groups, there was an improvement in memory and spatial working memory (p = 0.001; p = 0.032, respectively). For AV only there was improved sustained attention (p = 0.033), and the MPD increase was related to improved working memory and efficiency in approaching a problem (p = 0.036). Dietary recommendations including avocados may be an effective strategy for cognitive health. PMID- 28832515 TI - Exposure Modelling of Extremely Low-Frequency Magnetic Fields from Overhead Power Lines and Its Validation by Measurements. AB - A three-dimensional model for calculating long term exposure to extremely low frequency magnetic fields from high-voltage overhead power lines is presented, as well as its validation by measurements. For the validation, the model was applied to two different high-voltage overhead power lines in Iffwil and Wiler (Switzerland). In order to capture the daily and seasonal variations, each measurement was taken for 48 h and the measurements were carried out six times at each site, at intervals of approximately two months, between January and December 2015. During each measurement, a lateral transect of the magnetic flux density was determined in the middle of a span from nine measurement points in the range of +/-80 m. The technical data of both the lines as well as the load flow data during the measurement periods were provided by the grid operators. These data were used to calculate 48 h averages of the absolute value of the magnetic flux density and compared with modelled values. The highest 48 h average was 1.66 uT (centre of the line in Iffwil); the lowest 48 h average was 22 nT (80 m distance from the centre line in Iffwil). On average, the magnetic flux density was overestimated by 2% (standard deviation: 9%) in Iffwil and underestimated by 1% (8%) in Wiler. Sensitivity analyses showed that the uncertainty is mainly driven by errors in the coordinates and height data. In particular, for predictions near the centre of the line, an accurate digital terrain model is critical. PMID- 28832516 TI - Reply: Diabetogenic Potential of Ancestral and Modern Wheat Landraces, Nutrients 2017, 9, 816. AB - Our "diabetogenic diet" composition [1] was indeed based on the one described by Funda et al. [2] with regards to dietary requirements.[...]. PMID- 28832518 TI - Basic Simulation Environment for Highly Customized Connected and Autonomous Vehicle Kinematic Scenarios. AB - To enhance the reality of Connected and Autonomous Vehicles (CAVs) kinematic simulation scenarios and to guarantee the accuracy and reliability of the verification, a four-layer CAVs kinematic simulation framework, which is composed with road network layer, vehicle operating layer, uncertainties modelling layer and demonstrating layer, is proposed in this paper. Properties of the intersections are defined to describe the road network. A target position based vehicle position updating method is designed to simulate such vehicle behaviors as lane changing and turning. Vehicle kinematic models are implemented to maintain the status of the vehicles when they are moving towards the target position. Priorities for individual vehicle control are authorized for different layers. Operation mechanisms of CAVs uncertainties, which are defined as position error and communication delay in this paper, are implemented in the simulation to enhance the reality of the simulation. A simulation platform is developed based on the proposed methodology. A comparison of simulated and theoretical vehicle delay has been analyzed to prove the validity and the creditability of the platform. The scenario of rear-end collision avoidance is conducted to verify the uncertainties operating mechanisms, and a slot-based intersections (SIs) control strategy is realized and verified in the simulation platform to show the supports of the platform to CAVs kinematic simulation and verification. PMID- 28832517 TI - Therapeutic Potential of Amino Acids in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD), which includes both ulcerative colitis and Crohn's disease, is a chronic relapsing inflammation of the gastrointestinal tract, and is difficult to treat. The pathophysiology of IBD is multifactorial and not completely understood, but genetic components, dysregulated immune responses, oxidative stress, and inflammatory mediators are known to be involved. Animal models of IBD can be chemically induced, and are used to study etiology and to evaluate potential treatments of IBD. Currently available IBD treatments can decrease the duration of active disease but because of their adverse effects, the search for novel therapeutic strategies that can restore intestinal homeostasis continues. This review summarizes and discusses what is currently known of the effects of amino acids on the reduction of inflammation, oxidative stress, and cell death in the gut when IBD is present. Recent studies in animal models have identified dietary amino acids that improve IBD, but amino acid supplementation may not be adequate to replace conventional therapy. The animal models used in dietary amino acid research in IBD are described. PMID- 28832519 TI - The Enigmatic Origin of Papillomavirus Protein Domains. AB - Almost a century has passed since the discovery of papillomaviruses. A few decades of research have given a wealth of information on the molecular biology of papillomaviruses. Several excellent studies have been performed looking at the long- and short-term evolution of these viruses. However, when and how papillomaviruses originate is still a mystery. In this study, we systematically searched the (sequenced) biosphere to find distant homologs of papillomaviral protein domains. Our data show that, even including structural information, which allows us to find deeper evolutionary relationships compared to sequence-only based methods, only half of the protein domains in papillomaviruses have relatives in the rest of the biosphere. We show that the major capsid protein L1 and the replication protein E1 have relatives in several viral families, sharing three protein domains with Polyomaviridae and Parvoviridae. However, only the E1 replication protein has connections with cellular organisms. Most likely, the papillomavirus ancestor is of marine origin, a biotope that is not very well sequenced at the present time. Nevertheless, there is no evidence as to how papillomaviruses originated and how they became vertebrate and epithelium specific. PMID- 28832520 TI - Real-Time Motion Tracking for Indoor Moving Sphere Objects with a LiDAR Sensor. AB - Object tracking is a crucial research subfield in computer vision and it has wide applications in navigation, robotics and military applications and so on. In this paper, the real-time visualization of 3D point clouds data based on the VLP-16 3D Light Detection and Ranging (LiDAR) sensor is achieved, and on the basis of preprocessing, fast ground segmentation, Euclidean clustering segmentation for outliers, View Feature Histogram (VFH) feature extraction, establishing object models and searching matching a moving spherical target, the Kalman filter and adaptive particle filter are used to estimate in real-time the position of a moving spherical target. The experimental results show that the Kalman filter has the advantages of high efficiency while adaptive particle filter has the advantages of high robustness and high precision when tested and validated on three kinds of scenes under the condition of target partial occlusion and interference, different moving speed and different trajectories. The research can be applied in the natural environment of fruit identification and tracking, robot navigation and control and other fields. PMID- 28832522 TI - A FPGA-Based, Granularity-Variable Neuromorphic Processor and Its Application in a MIMO Real-Time Control System. AB - Artificial Neural Networks (ANNs), including Deep Neural Networks (DNNs), have become the state-of-the-art methods in machine learning and achieved amazing success in speech recognition, visual object recognition, and many other domains. There are several hardware platforms for developing accelerated implementation of ANN models. Since Field Programmable Gate Array (FPGA) architectures are flexible and can provide high performance per watt of power consumption, they have drawn a number of applications from scientists. In this paper, we propose a FPGA-based, granularity-variable neuromorphic processor (FBGVNP). The traits of FBGVNP can be summarized as granularity variability, scalability, integrated computing, and addressing ability: first, the number of neurons is variable rather than constant in one core; second, the multi-core network scale can be extended in various forms; third, the neuron addressing and computing processes are executed simultaneously. These make the processor more flexible and better suited for different applications. Moreover, a neural network-based controller is mapped to FBGVNP and applied in a multi-input, multi-output, (MIMO) real-time, temperature sensing and control system. Experiments validate the effectiveness of the neuromorphic processor. The FBGVNP provides a new scheme for building ANNs, which is flexible, highly energy-efficient, and can be applied in many areas. PMID- 28832521 TI - Opposite Roles of RNase and Kinase Activities of Inositol-Requiring Enzyme 1 (IRE1) on HSV-1 Replication. AB - In response to the endoplasmic reticulum (ER) stress induced by herpes simplex virus type 1 (HSV-1) infection, host cells activate the unfolded protein response (UPR) to reduce the protein-folding burden in the ER. The regulation of UPR upon HSV-1 infection is complex, and the downstream effectors can be detrimental to viral replication. Therefore, HSV-1 copes with the UPR to create a beneficial environment for its replication. UPR has three branches, including protein kinase RNA (PKR)-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activated transcription factor 6 (ATF6). IRE1alpha is the most conserved branch of UPR which has both RNase and kinase activities. Previous studies have shown that IRE1alpha RNase activity was inactivated during HSV-1 infection. However, the effect of the two activities of IRE1alpha on HSV-1 replication remains unknown. Results in this study showed that IRE1alpha expression was up-regulated during HSV-1 infection. We found that in HEC-1-A cells, increasing RNase activity, or inhibiting kinase activity of IRE1alpha led to viral suppression, indicating that the kinase activity of IRE1alpha was beneficial, while the RNase activity was detrimental to viral replication. Further evidence showed that the kinase activity of IRE1alpha leads to the activation of the JNK (c-Jun N-terminal kinases) pathway, which enhances viral replication. Taken together, our evidence suggests that IRE1alpha is involved in HSV-1 replication, and its RNase and kinase activities play differential roles during viral infection. PMID- 28832523 TI - A Biosensor-CMOS Platform and Integrated Readout Circuit in 0.18-MUm CMOS Technology for Cancer Biomarker Detection. AB - This paper presents a biosensor-CMOS platform for measuring the capacitive coupling of biorecognition elements. The biosensor is designed, fabricated, and tested for the detection and quantification of a protein that reveals the presence of early-stage cancer. For the first time, the spermidine/spermine N1 acetyltransferase (SSAT) enzyme has been screened and quantified on the surface of a capacitive sensor. The sensor surface is treated to immobilize antibodies, and the baseline capacitance of the biosensor is reduced by connecting an array of capacitors in series for fixed exposure area to the analyte. A large sensing area with small baseline capacitance is implemented to achieve a high sensitivity to SSAT enzyme concentrations. The sensed capacitance value is digitized by using a 12-bit highly digital successive-approximation capacitance-to-digital converter that is implemented in a 0.18 MUm CMOS technology. The readout circuit operates in the near-subthreshold regime and provides power and area efficient operation. The capacitance range is 16.137 pF with a 4.5 fF absolute resolution, which adequately covers the concentrations of 10 mg/L, 5 mg/L, 2.5 mg/L, and 1.25 mg/L of the SSAT enzyme. The concentrations were selected as a pilot study, and the platform was shown to demonstrate high sensitivity for SSAT enzymes on the surface of the capacitive sensor. The tested prototype demonstrated 42.5 MUS of measurement time and a total power consumption of 2.1 MUW. PMID- 28832524 TI - Understanding Insulin Endocrinology in Decapod Crustacea: Molecular Modelling Characterization of an Insulin-Binding Protein and Insulin-Like Peptides in the Eastern Spiny Lobster, Sagmariasus verreauxi. AB - The insulin signalling system is one of the most conserved endocrine systems of Animalia from mollusc to man. In decapod Crustacea, such as the Eastern spiny lobster, Sagmariasus verreauxi (Sv) and the red-claw crayfish, Cherax quadricarinatus (Cq), insulin endocrinology governs male sexual differentiation through the action of a male-specific, insulin-like androgenic gland peptide (IAG). To understand the bioactivity of IAG it is necessary to consider its bio regulators such as the insulin-like growth factor binding protein (IGFBP). This work has employed various molecular modelling approaches to represent S. verreauxi IGFBP and IAG, along with additional Sv-ILP ligands, in order to characterise their binding interactions. Firstly, we present Sv- and Cq-ILP2: neuroendocrine factors that share closest homology with Drosophila ILP8 (Dilp8). We then describe the binding interaction of the N-terminal domain of Sv-IGFBP and each ILP through a synergy of computational analyses. In-depth interaction mapping and computational alanine scanning of IGFBP_N' highlight the conserved involvement of the hotspot residues Q67, G70, D71, S72, G91, G92, T93 and D94. The significance of the negatively charged residues D71 and D94 was then further exemplified by structural electrostatics. The functional importance of the negative surface charge of IGFBP is exemplified in the complementary electropositive charge on the reciprocal binding interface of all three ILP ligands. When examined, this electrostatic complementarity is the inverse of vertebrate homologues; such physicochemical divergences elucidate towards ligand binding specificity between Phyla. PMID- 28832526 TI - Identification of Upper and Lower Level Yield Strength in Materials. AB - This work evaluates the possibility of identifying mechanical parameters, especially upper and lower yield points, by the analytical processing of specific elements of the topography of surfaces generated with abrasive waterjet technology. We developed a new system of equations, which are connected with each other in such a way that the result of a calculation is a comprehensive mathematical-physical model, which describes numerically as well as graphically the deformation process of material cutting using an abrasive waterjet. The results of our model have been successfully checked against those obtained by means of a tensile test. The main prospect for future applications of the method presented in this article concerns the identification of mechanical parameters associated with the prediction of material behavior. The findings of this study can contribute to a more detailed understanding of the relationships: material properties-tool properties-deformation properties. PMID- 28832527 TI - Numerical and Experimental Studies on the Explosive Welding of Tungsten Foil to Copper. AB - This work verifies that the W foil could be successfully welded on Cu through conventional explosive welding, without any cracks. The microstructure was observed through scanning electron microscopy (SEM), optical microscopy and energy-dispersive X-ray spectrometry (EDS). The W/Cu interface exhibited a wavy morphology, and no intermetallic or transition layer was observed. The wavy interface formation, as well as the distributions of temperature, pressure and plastic strain at the interface were studied through numerical simulation with Smoothed Particle Hydrodynamics (SPH). The welding mechanism of W/Cu was analyzed according to the numerical results and experimental observation, which was in accordance with the indentation mechanism proposed by Bahrani. PMID- 28832525 TI - The Epidemiology of African Swine Fever in "Nonendemic" Regions of Zambia (1989 2015): Implications for Disease Prevention and Control. AB - African swine fever (ASF) is a highly contagious and deadly viral hemorrhagic disease of swine. In Zambia, ASF was first reported in 1912 in Eastern Province and is currently believed to be endemic in that province only. Strict quarantine measures implemented at the Luangwa River Bridge, the only surface outlet from Eastern Province, appeared to be successful in restricting the disease. However, in 1989, an outbreak occurred for the first time outside the endemic province. Sporadic outbreaks have since occurred almost throughout the country. These events have brought into acute focus our limited understanding of the epidemiology of ASF in Zambia. Here, we review the epidemiology of the disease in areas considered nonendemic from 1989 to 2015. Comprehensive sequence analysis conducted on genetic data of ASF viruses (ASFVs) detected in domestic pigs revealed that p72 genotypes I, II, VIII and XIV have been involved in causing ASF outbreaks in swine during the study period. With the exception of the 1989 outbreak, we found no concrete evidence of dissemination of ASFVs from Eastern Province to other parts of the country. Our analyses revealed a complex epidemiology of the disease with a possibility of sylvatic cycle involvement. Trade and/or movement of pigs and their products, both within and across international borders, appear to have been the major factor in ASFV dissemination. Since ASFVs with the potential to cause countrywide and possibly regional outbreaks, could emerge from "nonendemic regions", the current ASF control policy in Zambia requires a dramatic shift to ensure a more sustainable pig industry. PMID- 28832528 TI - Time-Dependent Density Functional Computations of the Spectrochemical Properties of Dithiolodithiole and Thiophene Electrochromic Systems. AB - The importance of organic electrochromic materials has grown considerably in recent decades due to their application in smart window, automotive, and aircraft technologies. Theoretical prediction of the optical properties should contribute to their better characterization and help the explanation of the experimental data. By using various exchange-correlation functionals, we show how density functional theory (DFT) and the related time-dependent formulation (TDDFT) are able to correctly reproduce the spectrochemical properties of dithiolodithiole and thiophene organic electrochromic systems. PMID- 28832529 TI - Assessment of Autophagy in Neurons and Brain Tissue. AB - Autophagy is a complex process that controls the transport of cytoplasmic components into lysosomes for degradation. This highly conserved proteolytic system involves dynamic and complex processes, using similar molecular elements and machinery from yeast to humans. Moreover, autophagic dysfunction may contribute to a broad spectrum of mammalian diseases. Indeed, in adult tissues, where the capacity for regeneration or cell division is low or absent (e.g., in the mammalian brain), the accumulation of proteins/peptides that would otherwise be recycled or destroyed may have pathological implications. Indeed, such changes are hallmarks of pathologies, like Alzheimer's, Prion or Parkinson's disease, known as proteinopathies. However, it is still unclear whether such dysfunction is a cause or an effect in these conditions. One advantage when analysing autophagy in the mammalian brain is that almost all the markers described in different cell lineages and systems appear to be present in the brain, and even in neurons. By contrast, the mixture of cell types present in the brain and the differentiation stage of such neurons, when compared with neurons in culture, make translating basic research to the clinic less straightforward. Thus, the purpose of this review is to describe and discuss the methods available to monitor autophagy in neurons and in the mammalian brain, a process that is not yet fully understood, focusing primarily on mammalian macroautophagy. We will describe some general features of neuronal autophagy that point to our focus on neuropathologies in which macroautophagy may be altered. Indeed, we centre this review around the hypothesis that enhanced autophagy may be able to provide therapeutic benefits in some brain pathologies, like Alzheimer's disease, considering this pathology as one of the most prevalent proteinopathies. PMID- 28832530 TI - The Response of Heterotrophic Prokaryote and Viral Communities to Labile Organic Carbon Inputs Is Controlled by the Predator Food Chain Structure. AB - Factors controlling the community composition of marine heterotrophic prokaryotes include organic-C, mineral nutrients, predation, and viral lysis. Two mesocosm experiments, performed at an Arctic location and bottom-up manipulated with organic-C, had very different results in community composition for both prokaryotes and viruses. Previously, we showed how a simple mathematical model could reproduce food web level dynamics observed in these mesocosms, demonstrating strong top-down control through the predator chain from copepods via ciliates and heterotrophic nanoflagellates. Here, we use a steady-state analysis to connect ciliate biomass to bacterial carbon demand. This gives a coupling of top-down and bottom-up factors whereby low initial densities of ciliates are associated with mineral nutrient-limited heterotrophic prokaryotes that do not respond to external supply of labile organic-C. In contrast, high initial densities of ciliates give carbon-limited growth and high responsiveness to organic-C. The differences observed in ciliate abundance, and in prokaryote abundance and community composition in the two experiments were in accordance with these predictions. Responsiveness in the viral community followed a pattern similar to that of prokaryotes. Our study provides a unique link between the structure of the predator chain in the microbial food web and viral abundance and diversity. PMID- 28832531 TI - The Association between Air Pollution and Population Health Risk for Respiratory Infection: A Case Study of Shenzhen, China. AB - Nowadays, most of the research on air pollution and its adverse effects on public health in China has focused on megacities and heavily-polluted regions. Fewer studies have focused on cities that are slightly polluted. Shenzhen used to have a favorable air environment, but its air quality has deteriorated gradually as a result of development in recent years. So far, no systematic investigations have been conducted on the adverse effects of air pollution on public health in Shenzhen. This research has applied a time series analysis model to study the possible association between different types of air pollution and respiratory hospital admission in Shenzhen in 2013. Respiratory hospital admission was divided into two categories for comparison analysis among various population groups: acute upper respiratory infection and acute lower respiratory infection. The results showed that short-term exposure to ambient air pollution was significantly associated with acute respiratory infection hospital admission in Shenzhen in 2013. Children under 14 years old were the main susceptible population of acute respiratory infection due to air pollution. PM10, PM2.5 and NO2 were the primary air pollutants threatening respiratory health in Shenzhen. Though air pollution level is generally relatively low in Shenzhen, it will benefit public health to control the pollution of particulate matter as well as other gaseous pollutants. PMID- 28832532 TI - The Potential of Targeting Brain Pathology with Ascl1/Mash1. AB - The proneural factor Achaete-scute complex-like 1 (Ascl1/Mash1) acts as a pioneering transcription factor that initializes neuronal reprogramming. It drives neural progenitors and non-neuronal cells to exit the cell cycle, and promotes neuronal differentiation by activating neuronal target genes, even those that are normally repressed. Importantly, force-expression of Ascl1 was shown to drive proliferative reactive astroglia formed during stroke and glioblastoma stem cells towards neuronal differentiation, and this could potentially diminish CNS damage resulting from their proliferation. As a pro-neural factor, Ascl1 also has the general effect of enhancing neurite growth by damaged or surviving neurons. Here, a hypothesis that brain pathologies associated with traumatic/ischemic injury and malignancy could be targeted with pro-neural factors that drives neuronal differentiation is formulated and explored. Although a good number of caveats exist, exogenous over-expression of Ascl1, alone or in combination with other factors, may be worth further consideration as a therapeutic approach in brain injury and cancer. PMID- 28832533 TI - Determination of Coenzyme A and Acetyl-Coenzyme A in Biological Samples Using HPLC with UV Detection. AB - Coenzyme A (CoA) and acetyl-coenzyme A (acetyl-CoA) play essential roles in cell energy metabolism. Dysregulation of the biosynthesis and functioning of both compounds may contribute to various pathological conditions. We describe here a simple and sensitive HPLC-UV based method for simultaneous determination of CoA and acetyl-CoA in a variety of biological samples, including cells in culture, mouse cortex, and rat plasma, liver, kidney, and brain tissues. The limits of detection for CoA and acetyl-CoA are >10-fold lower than those obtained by previously described HPLC procedures, with coefficients of variation <1% for standard solutions, and 1-3% for deproteinized biological samples. Recovery is 95 97% for liver extracts spiked with Co-A and acetyl-CoA. Many factors may influence the tissue concentrations of CoA and acetyl-CoA (e.g., age, fed, or fasted state). Nevertheless, the values obtained by the present HPLC method for the concentration of CoA and acetyl-CoA in selected rodent tissues are in reasonable agreement with literature values. The concentrations of CoA and acetyl CoA were found to be very low in rat plasma, but easily measurable by the present HPLC method. The method should be useful for studying cellular energy metabolism under normal and pathological conditions, and during targeted drug therapy treatment. PMID- 28832534 TI - Transcriptional Analysis Allows Genome Reannotation and Reveals that Cryptococcus gattii VGII Undergoes Nutrient Restriction during Infection. AB - Cryptococcus gattii is a human and animal pathogen that infects healthy hosts and caused the Pacific Northwest outbreak of cryptococcosis. The inhalation of infectious propagules can lead to internalization of cryptococcal cells by alveolar macrophages, a niche in which C. gattii cells can survive and proliferate. Although the nutrient composition of macrophages is relatively unknown, the high induction of amino acid transporter genes inside the phagosome indicates a preference for amino acid uptake instead of synthesis. However, the presence of countable errors in the R265 genome annotation indicates significant inhibition of transcriptomic analysis in this hypervirulent strain. Thus, we analyzed RNA-Seq data from in vivo and in vitro cultures of C. gattii R265 to perform the reannotation of the genome. In addition, based on in vivo transcriptomic data, we identified highly expressed genes and pathways of amino acid metabolism that would enable C. gattii to survive and proliferate in vivo. Importantly, we identified high expression in three APC amino acid transporters as well as the GABA permease. The use of amino acids as carbon and nitrogen sources, releasing ammonium and generating carbohydrate metabolism intermediaries, also explains the high expression of components of several degradative pathways, since glucose starvation is an important host defense mechanism. PMID- 28832537 TI - High Boron-loaded DNA-Oligomers as Potential Boron Neutron Capture Therapy and Antisense Oligonucleotide Dual-Action Anticancer Agents. AB - Boron cluster-modified therapeutic nucleic acids with improved properties are of interest in gene therapy and in cancer boron neutron capture therapy (BNCT). High metallacarborane-loaded antisense oligonucleotides (ASOs) targeting epidermal growth factor receptor (EGFR) were synthesized through post-synthetic Cu (I) assisted "click" conjugation of alkyne-modified DNA-oligonucleotides with a boron cluster alkyl azide component. The obtained oligomers exhibited increased lipophilicity compared to their non-modified precursors, while their binding affinity to complementary DNA and RNA strands was slightly decreased. Multiple metallacarborane residues present in the oligonucleotide chain, each containing 18 B-H groups, enabled the use of IR spectroscopy as a convenient analytical method for these oligomers based on the diagnostic B-H signal at 2400-2650 cm-1. The silencing activity of boron cluster-modified ASOs used at higher concentrations was similar to that of unmodified oligonucleotides. The screened ASOs, when used in low concentrations (up to 50 MUM), exhibited pro-oxidative properties by inducing ROS production and an increase in mitochondrial activities in HeLa cells. In contrast, when used at higher concentrations, the ASOs exhibited anti-oxidative properties by lowering ROS species levels. In the HeLa cells (tested in the MTT assay) treated (without lipofectamine) or transfected with the screened compounds, the mitochondrial activity remained equal to the control level or only slightly changed (+/-30%). These findings may be useful in the design of dual-action boron cluster-modified therapeutic nucleic acids with combined antisense and anti-oxidant properties. PMID- 28832536 TI - Chemical and Antimicrobial Analyses of Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood, an Endemic of the Western Balkan. AB - A comprehensive study on essential oil and different solvent extracts of Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood (Lamiaceae) from Montenegro is reported. The gas chromatography-mass spectrometry analysis of the essential oil revealed a total of 43 components with bicyclogermacrene (23.8%), germacrene D (8%), (E)-caryophyllene (7.9%) and spathulenol (5.5%) as the major ones. Sesquiterpenoid group was found to be the most dominant one (64.8%), with 19.9% of the oxygenated forms. In the crude methanol extract of the investigated plant, obtained by Sohhlet exraction, the total phenol content was 14.7 +/- 0.4 mg of GA/g, the total flavonoids were 0.29 +/- 0.03% expressed as hyperoside percentage, whereas the total tannins content was 0.22 +/- 0.04% expressed as pyrogallol percentage. For the antimicrobial activity determination, the following microorganisms have been used: methicillin-susceptible Staphylococcus aureus (MSSA (American Type Culture Collection (ATCC) 29213)) and methicillin resistant S. aureus (MRSA (clinical strain)), Escherichia coli (ATCC 25922), carbapenem-susceptible Klebsiella pneumoniae (clinical strain), carbapenem resistant K. pneumoniae (clinical strain) and Candida albicans (ATCC 14053). The essential oil showed high potency against MSSA and MRSA, both at high (~5 * 105 CFU/mL) and low (~5 * 103 CFU/mL) inoculum. With respect to MSSA, the minimal inhibitory concentration (MIC) value was 0.307 mg/mL, with bactericidal activity obtained at 0.615 mg/mL, while, in the case of MRSA, the MIC and minimal bactericidal concentration (MBC) values were 0.076 and 0.153 mg/mL, respectively. Regarding anti-Candida albicans activity, the MIC value was 2.46 mg/mL without reaching fungicidal activity. In addition to the observed essential oil efficacy, different solvent extracts were analyzed for their antimicrobial activity. Similarly to the essential oil, thehighest efficacy was observed against both MSSA and MRSA strains, at high and low inoculums, in the case of the 1,2 dichloroethane and methanol extracts. A potent fungicidal activity has been also found for the n-hexane and 1,2-dichloroethane extracts. It can be concluded that Sideritis romana L. subsp. purpurea (Tal. ex Benth.) Heywood provides a wide range of application in different fields such as phytochemistry, pharmacology, toxicology or pharmacognosy. PMID- 28832538 TI - Research and Development of Electrostatic Accelerometers for Space Science Missions at HUST. AB - High-precision electrostatic accelerometers have achieved remarkable success in satellite Earth gravity field recovery missions. Ultralow-noise inertial sensors play important roles in space gravitational wave detection missions such as the Laser Interferometer Space Antenna (LISA) mission, and key technologies have been verified in the LISA Pathfinder mission. Meanwhile, at Huazhong University of Science and Technology (HUST, China), a space accelerometer and inertial sensor based on capacitive sensors and the electrostatic control technique have also been studied and developed independently for more than 16 years. In this paper, we review the operational principle, application, and requirements of the electrostatic accelerometer and inertial sensor in different space missions. The development and progress of a space electrostatic accelerometer at HUST, including ground investigation and space verification are presented. PMID- 28832535 TI - Dendrimers as Nanocarriers for Nucleic Acid and Drug Delivery in Cancer Therapy. AB - Dendrimers are highly branched polymers with easily modifiable surfaces. This makes them promising structures for functionalization and also for conjugation with drugs and DNA/RNA. Their architecture, which can be controlled by different synthesis processes, allows the control of characteristics such as shape, size, charge, and solubility. Dendrimers have the ability to increase the solubility and bioavailability of hydrophobic drugs. The drugs can be entrapped in the intramolecular cavity of the dendrimers or conjugated to their functional groups at their surface. Nucleic acids usually form complexes with the positively charged surface of most cationic dendrimers and this approach has been extensively employed. The presence of functional groups in the dendrimer's exterior also permits the addition of other moieties that can actively target certain diseases and improve delivery, for instance, with folate and antibodies, now widely used as tumor targeting strategies. Dendrimers have been investigated extensively in the medical field, and cancer treatment is one of the greatest areas where they have been most used. This review will consider the main types of dendrimer currently being explored and how they can be utilized as drug and gene carriers and functionalized to improve the delivery of cancer therapy. PMID- 28832540 TI - In Vitro Effectiveness of Microspheres Based on Silk Sericin and Chlorella vulgaris or Arthrospira platensis for Wound Healing Applications. AB - Some natural compounds have recently been widely employed in wound healing applications due to their biological properties. One such compound is sericin, which is produced by Bombix mori, while active polyphenols, polysaccharides and proteins are synthetized by Chlorella vulgaris and Arthrospira platensis microalgae. Our hypothesis was that sericin, as an optimal bioactive polymeric carrier for microencapsulation process, could also improve the regenerative effect of the microalgae. A solvent-free extraction method and spray drying technique were combined to obtain five formulations, based on algal extracts (C. vulgaris and A. platensis, Chl and Art, respectively) or silk sericin (Ser) or their mixtures (Chl-Ser and Art-Ser). The spray drying was a suitable method to produce microspheres with similar dimensions, characterized by collapsed morphology with a rough surface. Art and Art-Ser showed higher antioxidant properties than other formulations. All microspheres resulted in cytocompatibility on fibroblasts until 1.25 mg/mL and promoted cell migration and the complete wound closure; this positive effect was further highlighted after treatment with Art and Art-Ser. To our surprize the combination of sericin to Art did not improve the microalgae extract efficacy, at least in our experimental conditions. PMID- 28832541 TI - Aflatoxin B1 Contamination in Chicken Livers and Gizzards from Industrial and Small Abattoirs, Measured by ELISA Technique in Maputo, Mozambique. AB - Aflatoxins are the most toxic and carcinogenic mycotoxins produced by Aspergillus species. Aflatoxin B1 (AFB1) contamination in industrial and local chicken livers and gizzards in Maputo was investigated. One hundred boiler livers and 80 boiler gizzards were collected from industrial and local cutting poultry production sectors. The samples were analyzed by the ELISA method (MaxSignal(r), Bioo Scientific Corporation). AFB1 was found in 39% of liver samples and 13.8% of gizzards, with mean levels of 1.73 ug/kg and 1.07 ug/kg, respectively. The frequency of contamination and AFB1 levels in samples from local sector producers was not significantly higher than those from industrial sector producers (p > 0.05). No correlation was found (p = 0.493; r2 = 0.013) between AFB1 levels in livers and hepatic weights. The AFB1 levels were lower than the allowed limits, suggesting that these products do not pose high risk to consumers. Notwithstanding, there is a need to implement aflatoxin residue monitoring and controls in all chicken meat products; this economic and efficient technique appears to be valuable for improved food safety in Mozambique. PMID- 28832539 TI - Fighting Cancer with Mathematics and Viruses. AB - After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex antitumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these research fields to increase the value of the preclinical development and the therapeutic efficacy of the resulting treatments. PMID- 28832543 TI - Covalent Porphyrin Hybrids Linked with Dipyrrin, Bidipyrrin or Thiacorrole. AB - Novel meso-meso directly linked porphyrin hybrids were successfully targeted and synthesized, with porphyrin units linked with dipyrrin, bidipyrrin or thiacorrole, expanding the ranges of dipyrrin derivatives and showing diverse metal coordinations and further influencing the chemical shift of pyrrole units. The porphyrinyl dipyrrin nickel complex 3 was successfully obtained in a high yield by the oxidation of porphyrinyl dipyrromethane 2 and subsequent coordination. Further oxidative coupling reactions of 3 afforded por-bidipyrrin por hybrid 4. Interestingly, an unexpected methoxy por-bidipyrrin-por hybrid 6 was generated by treating 4 with FeCl3 in CH2Cl2/MeOH and subsequent coordination. In addition to open chain hybrids, an aromatic scaffold hybrid por thiacorrole-por 8 was synthesized by treating porphyrinyl dibromo-dipyrrin nickel complex 7 with Na2S.9H2O. A series of porphyrin hybrids offers a new approach for pi-conjugated molecules. PMID- 28832542 TI - Solution NMR Spectroscopy in Target-Based Drug Discovery. AB - Solution NMR spectroscopy is a powerful tool to study protein structures and dynamics under physiological conditions. This technique is particularly useful in target-based drug discovery projects as it provides protein-ligand binding information in solution. Accumulated studies have shown that NMR will play more and more important roles in multiple steps of the drug discovery process. In a fragment-based drug discovery process, ligand-observed and protein-observed NMR spectroscopy can be applied to screen fragments with low binding affinities. The screened fragments can be further optimized into drug-like molecules. In combination with other biophysical techniques, NMR will guide structure-based drug discovery. In this review, we describe the possible roles of NMR spectroscopy in drug discovery. We also illustrate the challenges encountered in the drug discovery process. We include several examples demonstrating the roles of NMR in target-based drug discoveries such as hit identification, ranking ligand binding affinities, and mapping the ligand binding site. We also speculate the possible roles of NMR in target engagement based on recent processes in in cell NMR spectroscopy. PMID- 28832544 TI - Genome-Wide Identification and Characterization of the GmSnRK2 Family in Soybean. AB - Sucrose non-fermenting-1 (SNF1)-related protein kinase 2s (SnRK2s) that were reported to be involved in the transduction of abscisic acid (ABA) signaling, play important roles in response to biotic and abiotic stresses in plants. Compared to the systemic investigation of SnRK2s in Arabidopsisthaliana and Oryza sativa, little is known regarding SnRK2s in soybean, which is one of the most important oil and protein crops. In the present study, we performed genome-wide identification and characterization of GmSnRK2s in soybean. In summary, 22 GmSnRK2s were identified and clustered into four groups. Phylogenetic analysis indicated the expansion of SnRK2 gene family during the evolution of soybean. Various cis-acting elements such as ABA Response Elements (ABREs) were identified and analyzed in the promoter regions of GmSnRK2s. The results of RNA sequencing (RNA-Seq) data for different soybean tissues showed that GmSnRK2s exhibited spatio-temporally specific expression patterns during soybean growth and development. Certain GmSnRK2s could respond to the treatments including salinity, ABA and strigolactones. Our results provide a foundation for the further elucidation of the function of GmSnRK2 genes in soybean. PMID- 28832545 TI - The Marine Natural Product Pseudopterosin Blocks Cytokine Release of Triple Negative Breast Cancer and Monocytic Leukemia Cells by Inhibiting NF-kappaB Signaling. AB - Pseudopterosins are a group of marine diterpene glycosides which possess an array of biological activities including anti-inflammatory effects. However, despite the striking in vivo anti-inflammatory potential, the underlying in vitro molecular mode of action remains elusive. To date, few studies have examined pseudopterosin effects on cancer cells. However, to our knowledge, no studies have explored their ability to block cytokine release in breast cancer cells and the respective bidirectional communication with associated immune cells. The present work demonstrates that pseudopterosins have the ability to block the key inflammatory signaling pathway nuclear factor kappaB (NF-kappaB) by inhibiting the phosphorylation of p65 and IkappaB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor) in leukemia and in breast cancer cells, respectively. Blockade of NF-kappaB leads to subsequent reduction of the production of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha) and monocyte chemotactic protein 1 (MCP-1). Furthermore, pseudopterosin treatment reduces cytokine expression induced by conditioned media in both cell lines investigated. Interestingly, the presence of pseudopterosins induces a nuclear translocation of the glucocorticoid receptor. When knocking down the glucocorticoid receptor, the natural product loses the ability to block cytokine expression. Thus, we hypothesize that pseudopterosins inhibit NF-kappaB through activation of the glucocorticoid receptor in triple negative breast cancer. PMID- 28832546 TI - Self-Rated Health Status and Cardiorespiratory Fitness in a Sample of Schoolchildren from Bogota, Colombia. The FUPRECOL Study. AB - To evaluate the relationship between Self-Rated Health (SRH) and cardiorespiratory fitness (CRF) in a sample of children and adolescents enrolled in official schools in Bogota, Colombia. A cross-sectional study was performed with 7402 children and adolescents between 9 and 17 years of age. Participants were asked to rate their health based on eight validated questions, addressing the participants propensity for headache, stomach-ache, backache, feeling-low, irritability/bad mood, nervousness, sleeping-difficulties, and dizziness. The choices were "rarely or never", "almost every month", "almost every week", and "more than once a week/about every day". Participants performed the international course-navette shuttle run test to estimate CRF, and cut-off points for age and gender were used to categorize the healthy/unhealthy fitness zone according to the FITNESSGRAM(r) criteria. Overall, 16.4% of those surveyed reported a perception of irritability/bad mood "more than once a week/about every day", followed by feeling-low and nervousness (both with 9.9%). Dizziness had the lowest prevalence with a percentage of 6.9%. Unhealthy CRF in boys increased the likelihood of headaches by 1.20 times, stomach aches by 1.31 times, feeling-low by 1.29 times, nervousness by 1.24 times, and dizziness by 1.29 times. In girls, unhealthy CRF increased the likelihood of headaches by 1.19 times, backache by 1.26 times, feeling-low by 1.28 times, irritability/bad mood by 1.17 times, sleeping-difficulties by 1.20 times, and dizziness by 1.27 times. SRH was associated with CRF in both genders. Early identification of children and adolescents with low CRF levels will permit interventions to promote healthy behaviors and prevent future diseases during adulthood. PMID- 28832547 TI - Fabrication of Innovative Silk/Alginate Microcarriers for Mesenchymal Stem Cell Delivery and Tissue Regeneration. AB - The aim of this study was to exploit silk fibroin's properties to develop innovative composite microcarriers for mesenchymal stem cell (MSCs) adhesion and proliferation. Alginate microcarriers were prepared, added to silk fibroin solution, and then treated with ethanol to induce silk conformational transition. Microcarriers were characterized for size distribution, coating stability and homogeneity. Finally, in vitro cytocompatibility and suitability as delivery systems for MSCs were investigated. Results indicated that our manufacturing process is consistent and reproducible: silk/alginate microcarriers were stable, with spherical geometry, about 400 MUm in average diameter, and fibroin homogeneously coated the surface. MSCs were able to adhere rapidly onto the microcarrier surface and to cover the surface of the microcarrier within three days of culture; moreover, on this innovative 3D culture system, stem cells preserved their metabolic activity and their multi-lineage differentiation potential. In conclusion, silk/alginate microcarriers represent a suitable support for MSCs culture and expansion. Since it is able to preserve MSCs multipotency, the developed 3D system can be intended for cell delivery, for advanced therapy and regenerative medicine applications. PMID- 28832548 TI - Nypa fruticans Wurmb. Vinegar's Aqueous Extract Stimulates Insulin Secretion and Exerts Hepatoprotective Effect on STZ-Induced Diabetic Rats. AB - BACKGROUND: An aqueous extract (AE) of vinegar made from Nypa fruticans Wurmb. can improve postprandial glucose levels in normoglycaemic rats. The aim of this study was to evaluate its antihyperglycaemic activity further using in vivo and in vitro approaches. METHODS: AE was administered to streptozotocin (STZ)-induced diabetic rats twice daily at three doses (1000, 500, and 250 mg/kg b.w.) for 12 days p.o. Several biochemical analyses and a histological study of the pancreas and liver were performed, accompanied by a cell culture assay. RESULTS: As compared to diabetic control (DC), AE at the doses of 500 and 1000 mg/kg b.w. caused significant reduction (p < 0.05) of blood glucose, total cholesterol and triglycerides levels, with positive improvement of serum insulin levels. Interestingly, immunohistochemical staining of the pancreas suggested no beta cell regeneration, despite significant increase in insulin production. AE-treated groups, however, showed overall restoration of the hepatic histoarchitecture of STZ-induced liver damage, suggesting a possible hepatoprotective effect. The pancreatic effect of AE was further studied through RIN-5F cell culture, which revealed a positive stimulatory effect on insulin release at a basal glucose concentration (1.1 mM). CONCLUSION: Nypa fruticans Wurmb. vinegar's aqueous extract exerts its antihyperglycaemic activity, at least in part, through insulin stimulatory and hepatoprotective effects. PMID- 28832549 TI - Consumption of a High Quantity and a Wide Variety of Vegetables Are Predicted by Different Food Choice Motives in Older Adults from France, Italy and the UK. AB - BACKGROUND: Consumption of a high quantity and wide variety of vegetables is currently recommended for health. Dietary variety can be low, however, particularly for older adults. This study investigated the affective factors associated with the quantity and variety of vegetables consumed by older adults in France, Italy and the UK. METHODS: Adults aged 65 years plus completed questionnaires on self-reported vegetable intake (quantity and variety), liking for vegetables, attitudes towards intake, and demographic variables. RESULTS: In 497 older adults (France, n = 187, Italy, n = 152, UK, n = 158), higher quantities of vegetables consumed were associated with a higher age, affluence score and liking for vegetables, and a lower importance in consumption of familiarity (smallest beta = 0.11, p = 0.03). Greater variety was associated with a higher liking and importance of health benefits, and a lower importance of familiarity (smallest beta = -0.11, p < 0.01). Higher quantity and variety combined (quantity * variety) was associated with a higher age, liking and importance of health benefits, and a lower importance of familiarity (smallest beta = 0.14, p = 0.02). Country-specific effects were also found (smallest beta = 0.20, p < 0.01). CONCLUSIONS: These findings demonstrate a role for liking and a lower concern for eating familiar foods in vegetable consumption, and a particular role for concern for health benefits in the consumption of a greater variety of vegetables. PMID- 28832550 TI - Spectral EMG Changes in Cervical Dystonia Patients and the Influence of Botulinum Toxin Treatment. AB - Botulinum toxin (BoNT) injections in the dystonic muscles is the preferred treatment for Cervical Dystonia (CD), but the proper identification of the dystonic muscles remains a challenge. Previous studies showed decreased 8-14 Hz autospectral power in the electromyography (EMG) of splenius muscles in CD patients. Cumulative distribution functions (CDF's) of dystonic muscles showed increased CDF10 values, representing increased autospectral powers between 3 and 10 Hz, relative to power between 3 and 32 Hz. In this study, we evaluated both methods and investigated the effects of botulinum toxin. Intramuscular EMG recordings were obtained from the splenius, semispinalis, and sternocleidomastoid muscles during standardized isometric tasks in 4 BoNT-naive CD patients, 12 BoNT treated patients, and 8 healthy controls. BoNT-treated patients were measured 4-7 weeks after their last BoNT injections and again after 11-15 weeks. We found significantly decreased 8-14 Hz autospectral power in splenius muscles, but not in the semispinalis and sternocleidomastoid muscles of CD patients when compared to healthy controls. CDF10 analysis was superior in demonstrating subtle autospectral changes, and showed increased CDF10 values in all studied muscles of CD patients. These results did not change significantly after BoNT injections. Further studies are needed to investigate the origin of these autospectral changes in dystonia patients, and to assess their potential in muscle selection for BoNT treatment. PMID- 28832551 TI - Preparation and Structural Analysis of Nano-Silver Loaded Poly(styrene-co-acrylic acid) Core-Shell Nanospheres with Defined Shape and Composition. AB - A systematic study for the preparation and structural analysis of poly(styrene-co acrylic acid) composite nanospheres (PSA) and silver nanoparticles loaded poly(styrene-co-acrylic acid) composite nanospheres (nAg@PSA) is reported. Poly(styrene-co-acrylic acid) nanospheres were synthesized by soap-free emulsion polymerization of styrene (St) and acrylic acid (AA) in water. Ag nanoparticles (Ag-NPs) were well-dispersed on the surfaces of poly(styrene-co-acrylic acid) composite nanospheres by in situ chemical reduction of AgNO3 using NaBH4 as a reducing agent in water. The particle size of PSA nanospheres was uniform. The surfaces of PSA nanospheres were distributed by highly uniform half-sphere arrays. Those half-sphere protruded more with the increase of the feeding amount of AA or the feed ratios of AA and St. The carboxyl groups content of nanospheres was directly proportional to the nanosphere surface area. This relationship and X ray photoelectron spectroscopy and transmission electron microscopy images of the PSA nanospheres indicate that the acrylic acid was mainly distributed on the surface of the polystyrene spheres with unnegligible thickness. The number of Ag NPs depends on immobilized carboxyl groups on the surface of PSA, according to thermogravimetry, ultraviolet-visible, X-ray diffraction and transmission electron microscopy results. PMID- 28832553 TI - Radiolytic Synthesis of Pt-Particle/ABS Catalysts for H2O2 Decomposition in Contact Lens Cleaning. AB - A container used in contact lens cleaning requires a Pt plating weight of 1.5 mg for H2O2 decomposition although Pt is an expensive material. Techniques that decrease the amount of Pt are therefore needed. In this study, Pt nanoparticles instead of Pt plating film were supported on a substrate of acrylonitrile butadiene-styrene copolymer (ABS). This was achieved by the reduction of Pt ions in an aqueous solution containing the ABS substrate using high-energy electron beam irradiation. Pt nanoparticles supported on the ABS substrate (Pt particle/ABS) had a size of 4-10 nm. The amount of Pt required for Pt particle/ABS was 250 times less than that required for an ABS substrate covered with Pt plating film (Pt-film/ABS). The catalytic activity for H2O2 decomposition was estimated by measuring the residual H2O2 concentration after immersing the catalyst for 360 min. The Pt-particle/ABS catalyst had a considerably higher specific catalytic activity for H2O2 decomposition than the Pt-film/ABS catalyst. In addition, sterilization performance was estimated from the initial rate of H2O2 decomposition over 60 min. The Pt-particle/ABS catalyst demonstrated a better sterilization performance than the Pt-film/ABS catalyst. The difference between Pt-particle/ABS and Pt-film/ABS was shown to reflect the size of the O2 bubbles formed during H2O2 decomposition. PMID- 28832552 TI - Does Physical Activity Mediate the Associations Between Local-Area Descriptive Norms, Built Environment Walkability, and Glycosylated Hemoglobin? AB - Associations between local-area residential features and glycosylated hemoglobin (HbA1c) may be mediated by individual-level health behaviors. Such indirect effects have rarely been tested. This study assessed whether individual-level self-reported physical activity mediated the influence of local-area descriptive norms and objectively expressed walkability on 10-year change in HbA1c. HbA1c was assessed three times for adults in a 10-year population-based biomedical cohort (n = 4056). Local-area norms specific to each participant were calculated, aggregating responses from a separate statewide surveillance survey for 1600 m road-network buffers centered on participant addresses (local prevalence of overweight/obesity (body mass index >=25 kg/m2) and physical inactivity (<150 min/week)). Separate latent growth models estimated direct and indirect (through physical activity) effects of local-area exposures on change in HbA1c, accounting for spatial clustering and covariates (individual-level age, sex, smoking status, marital status, employment and education, and area-level median household income). HbA1c worsened over time. Local-area norms directly and indirectly predicted worsening HbA1c trajectories. Walkability was directly and indirectly protective of worsening HbA1c. Local-area descriptive norms and walkability influence cardiometabolic risk trajectory through individual-level physical activity. Efforts to reduce population cardiometabolic risk should consider the extent of local-area unhealthful behavioral norms and walkability in tailoring strategies to improve physical activity. PMID- 28832554 TI - Contribution of Intrinsic Lactate to Maintenance of Seizure Activity in Neocortical Slices from Patients with Temporal Lobe Epilepsy and in Rat Entorhinal Cortex. AB - Neuronal lactate uptake supports energy metabolism associated with synaptic signaling and recovery of extracellular ion gradients following neuronal activation. Altered expression of the monocarboxylate transporters (MCT) in temporal lobe epilepsy (TLE) hampers lactate removal into the bloodstream. The resulting increase in parenchymal lactate levels might exert both, anti- and pro ictogen effects, by causing acidosis and by supplementing energy metabolism, respectively. Hence, we assessed the contribution of lactate to the maintenance of transmembrane potassium gradients, synaptic signaling and pathological network activity in chronic epileptic human tissue. Stimulus induced and spontaneous field potentials and extracellular potassium concentration changes (?[K+]O) were recorded in parallel with tissue pO2 and pH in slices from TLE patients while blocking MCTs by alpha-cyano-4-hydroxycinnamic acid (4-CIN) or d-lactate. Intrinsic lactate contributed to the oxidative energy metabolism in chronic epileptic tissue as revealed by the changes in pO2 following blockade of lactate uptake. However, unlike the results in rat hippocampus, ?[K+]O recovery kinetics and field potential amplitude did not depend on the presence of lactate. Remarkably, inhibition of lactate uptake exerted pH-independent anti-seizure effects both in healthy rat and chronic epileptic tissue and this effect was partly mediated via adenosine 1 receptor activation following decreased oxidative metabolism. PMID- 28832555 TI - Impact of Soil Warming on the Plant Metabolome of Icelandic Grasslands. AB - Climate change is stronger at high than at temperate and tropical latitudes. The natural geothermal conditions in southern Iceland provide an opportunity to study the impact of warming on plants, because of the geothermal bedrock channels that induce stable gradients of soil temperature. We studied two valleys, one where such gradients have been present for centuries (long-term treatment), and another where new gradients were created in 2008 after a shallow crustal earthquake (short-term treatment). We studied the impact of soil warming (0 to +15 degrees C) on the foliar metabolomes of two common plant species of high northern latitudes: Agrostis capillaris, a monocotyledon grass; and Ranunculus acris, a dicotyledonous herb, and evaluated the dependence of shifts in their metabolomes on the length of the warming treatment. The two species responded differently to warming, depending on the length of exposure. The grass metabolome clearly shifted at the site of long-term warming, but the herb metabolome did not. The main up-regulated compounds at the highest temperatures at the long-term site were saccharides and amino acids, both involved in heat-shock metabolic pathways. Moreover, some secondary metabolites, such as phenolic acids and terpenes, associated with a wide array of stresses, were also up-regulated. Most current climatic models predict an increase in annual average temperature between 2-8 degrees C over land masses in the Arctic towards the end of this century. The metabolomes of A. capillaris and R. acris shifted abruptly and nonlinearly to soil warming >5 degrees C above the control temperature for the coming decades. These results thus suggest that a slight warming increase may not imply substantial changes in plant function, but if the temperature rises more than 5 degrees C, warming may end up triggering metabolic pathways associated with heat stress in some plant species currently dominant in this region. PMID- 28832556 TI - An Appetite for Modernizing the Regulatory Framework for Protein Content Claims in Canada. AB - The need for protein-rich plant-based foods continues as dietary guidelines emphasize their contribution to healthy dietary patterns that prevent chronic disease and promote environmental sustainability. However, the Canadian Food and Drug Regulations provide a regulatory framework that can prevent Canadian consumers from identifying protein-rich plant-based foods. In Canada, protein nutrient content claims are based on the protein efficiency ratio (PER) and protein rating method, which is based on a rat growth bioassay. PERs are not additive, and the protein rating of a food is underpinned by its Reasonable Daily Intake. The restrictive nature of Canada's requirements for supporting protein claims therefore presents challenges for Canadian consumers to adapt to a rapidly changing food environment. This commentary will present two options for modernizing the regulatory framework for protein content claims in Canada. The first and preferred option advocates that protein quality not be considered in the determination of the eligibility of a food for protein content claims. The second and less preferred option, an interim solution, is a framework for adopting the protein digestibility corrected amino acid score as the official method for supporting protein content and quality claims and harmonizes Canada's regulatory framework with that of the USA. PMID- 28832558 TI - Saving life and limb. PMID- 28832557 TI - Effectiveness of an Intervention to Promote Self-Efficacy on Quality of Life of Patients with Nasopharyngeal Carcinoma of the Zhuang Tribe Minority in Guangxi, China: A Prospective Study. AB - BACKGROUND Nasopharyngeal carcinoma (NPC) is endemic in China and patient self management is poor. Minorities may suffer from psychological problems during treatments for NPC. This study aimed to implement an intervention to promote self efficacy of minority patients (Zhuang tribe, Guangxi, China) with NPC to improve their quality of life (QOL). MATERIAL AND METHODS This was a prospective study of 120 patients with NPC treated at the First Affiliated Hospital of Guangxi Medical University (Guangxi, China), randomized to conventional care (n=60, controls) or conventional care plus self-efficacy interventions based on health education, behavior therapy, and psychological intervention (n=60, self-efficacy group). Self-efficacy was evaluated using the general self-efficacy scale, and QOL using the EORTC QLQ-C30. The questionnaires were completed at discharge, at 6 months, and at 1 and 2 years. The primary outcome was QOL. RESULTS There was no difference in QOL at baseline. From study start to hospital discharge, overall QOL scores decreased in both groups, but this decrease was more important in the control group (controls: -39.31 vs. self-efficacy: -27.04, P<0.05). After discharge, each functional field QOL scores and overall QOL increased with time in the 2 groups, and they were significantly higher in the self-efficacy group. CONCLUSIONS This intervention promoting self-efficacy could increase patients' own potential and initiative, enhance their confidence and ability to solve health problems, improve their coping with adverse effects of treatments, and have positive effects on their QOL. Self-efficacy theory-based interventions could be worth popularization during the treatment and recovery of minority patients with NPC. PMID- 28832559 TI - Critical limb ischaemia: artery repair. PMID- 28832561 TI - Stent-based delivery of adeno-associated viral vectors with sustained vascular transduction and iNOS-mediated inhibition of in-stent restenosis. AB - In-stent restenosis remains an important clinical problem in the era of drug eluting stents. Development of clinical gene therapy protocols for the prevention and treatment of in-stent restenosis is hampered by the lack of adequate local delivery systems. Herein we describe a novel stent-based gene delivery platform capable of providing local arterial gene transfer with adeno-associated viral (AAV) vectors. This system exploits the natural affinity of protein G (PrG) to bind to the Fc region of mammalian IgG, making PrG a universal adaptor for surface immobilization of vector-capturing antibodies (Ab). Our results: 1) demonstrate the feasibility of reversible immobilization of AAV2 vectors using vector tethering by AAV2-specific Ab appended to the stent surface through covalently attached PrG, 2) show sustained release kinetics of PrG/Ab-immobilized AAV2 vector particles into simulated physiological medium in vitro and site specific transduction of cultured cells, 3) provide evidence of long-term (12 weeks) arterial expression of luciferase with PrG/Ab-tethered AAV2Luc, and 4) show anti-proliferative activity and anti-restenotic efficacy of stent immobilized AAV2iNOS in the rat carotid artery model of stent angioplasty. PMID- 28832562 TI - A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data. AB - Rapid identification of clinically significant variants is key to the successful application of next generation sequencing technologies in clinical practice. The Melbourne Genomics Health Alliance (MGHA) variant prioritization framework employs a gene prioritization index based on clinician-generated a priori gene lists, and a variant prioritization index (VPI) based on rarity, conservation and protein effect. We used data from 80 patients who underwent singleton whole exome sequencing (WES) to test the ability of the framework to rank causative variants highly, and compared it against the performance of other gene and variant prioritization tools. Causative variants were identified in 59 of the patients. Using the MGHA prioritization framework the average rank of the causative variant was 2.24, with 76% ranked as the top priority variant, and 90% ranked within the top five. Using clinician-generated gene lists resulted in ranking causative variants an average of 8.2 positions higher than prioritization based on variant properties alone. This clinically driven prioritization approach significantly outperformed purely computational tools, placing a greater proportion of causative variants top or in the top 5 (permutation P-value=0.001). Clinicians included 40 of the 49 WES diagnoses in their a priori list of differential diagnoses (81%). The lists generated by PhenoTips and Phenomizer contained 14 (29%) and 18 (37%) of these diagnoses respectively. These results highlight the benefits of clinically led variant prioritization in increasing the efficiency of singleton WES data analysis and have important implications for developing models for the funding and delivery of genomic services. PMID- 28832563 TI - Participation in interdisciplinary meetings on genetic diagnostics (NGS). AB - Diagnostics using next generation sequencing (NGS) requires high-quality interdisciplinary collaboration. In order to gain insight into this crucial collaborative process, we made video recordings of a new multidisciplinary team at work in the clinical genetics department of the University Medical Centre Groningen. Conversation Analysis was used to investigate the ways in which the team members deal with the disciplinary boundaries between them. We found that the team established different 'participation frames' in which to discuss recurring topics. Patients were discussed only by the medical doctors, whereas results of genetic tests were discussed by doctors, molecular biologists and genetic laboratory technicians. Information technology (IT) aspects were discussed by biologists, genetics analysts and bio-informaticians, but not doctors. We then interviewed team members who said they believed that the division of labour embodied in these participation frames contributes to achieving their team's goals. PMID- 28832564 TI - Haplotype-based stratification of Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD. PMID- 28832565 TI - Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias. AB - Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness that can be complicated by other neurological or non-neurological signs. Despite a high genetic heterogeneity (>60 causative genes), 40-70% of the families remain without a molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the most frequent diagnoses. We have now explored 98 unsolved families from this series using custom next generation sequencing panels analyzing up to 70 candidate HSP genes. We identified the likely disease-causing variant in 20 of the 98 families with KIF5A being the most frequently mutated gene. We also found 52 variants of unknown significance (VUS) in 38% of the cases. These new diagnoses resulted in 42% of solved cases in the full Portuguese cohort (81/193). Segregation of the variants was not always compatible with the presumed inheritance, indicating that the analysis of all HSP genes regardless of the inheritance mode can help to explain some cases. Our results show that there is still a large set of unknown genes responsible for HSP and most likely novel mechanisms or inheritance modes leading to the disease to be uncovered, but this will require international collaborative efforts, particularly for the analysis of VUS. PMID- 28832566 TI - Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome. AB - Microcephalic primordial dwarfism (MPD) is a group of autosomal recessive inherited single-gene disorders with intrauterine and postnatal global growth failure. Seckel syndrome is the most common form of the MPD. Ten genes are known with Seckel syndrome. Using genome-wide SNP genotyping and homozygosity mapping we mapped a Seckel syndrome gene to chromosomal region 4q28.1-q28.3 in a Turkish family. Direct sequencing of PLK4 (polo-like kinase 4) revealed a homozygous splicing acceptor site transition (c.31-3 A>G) that results in a premature translation termination (p.[=,Asp11Profs*14]) causing deletion of all known functional domains of the protein. PLK4 is a master regulator of centriole biogenesis and its deficiency has recently been associated with Seckel syndrome. However, the role of PLK4 in genomic stability and the DNA damage response is unclear. Evaluation of the PLK4-Seckel fibroblasts obtained from patient revealed the expected impaired centriole biogenesis, disrupted mitotic morphology, G2/M delay, and extended cell doubling time. Analysis of the PLK4-Seckel cells indicated that PLK4 is also essential for genomic stability and DNA damage response. These findings provide mechanistic insight into the pathogenesis of the severe growth failure associated with PLK4-deficiency. PMID- 28832567 TI - Third party interpretation of raw genetic data: an ethical exploration. AB - In the wake of recent regulations targeting direct-to-consumer genetic testing (DTC-GT), an increasing number of websites have emerged that offer consumers alternative means to derive health information from their DTC-GT raw data. While the ethical concerns associated with DTC-GT have been extensively discussed in the literature, the implications of third party interpretation (TPI) websites have remained largely unexplored. Here we sought to describe these services and elucidate their ethical implications in the context of the current DTC-GT debate. We reviewed five popular TPI websites that use SNP-based genomic data to report health-related information: Promethease, Interpretome, LiveWello, Codegen.eu, and Enlis Personal. We found that many of the ethical concerns previously described in DTC-GT also applied to TPI websites, including inadequate informed consent, questionable clinical validity and utility, and lack of medical supervision. However, some concerns about data usage and privacy reported in DTC-GT were less prominent in the five TPI websites we studied: none of them sold or shared user data, and 3/5 sites did not retain data in the long term. In addition, while exaggerated claims and inaccurate advertising have been frequently problematic in DTC-GT, advertising was minimal in the TPI sites we assessed, and 4/5 made no claims of health benefits. Overall, TPI adds a new dimension to the ethical debate surrounding DTC-GT, and awareness of these services will become increasingly important as personal genomics continues to expand. This study constitutes the first detailed ethical analysis of these services, and presents a starting point for further research and ethical reflection. PMID- 28832568 TI - Uptake of genetic testing by the children of Lynch syndrome variant carriers across three generations. AB - Many Lynch syndrome (LS) carriers remain unidentified, thus missing early cancer detection and prevention opportunities. Tested probands should inform their relatives about cancer risk and options for genetic counselling and predictive gene testing, but many fail to undergo testing. To assess predictive testing uptake and demographic factors influencing this decision in LS families, a cross sectional registry-based cohort study utilizing the Finnish Lynch syndrome registry was undertaken. Tested LS variant probands (1184) had 2068 children divided among three generations: 660 parents and 1324 children (first), 445 and 667 (second), and 79 and 77 (third). Of children aged >18 years, 801 (67.4%), 146 (43.2%), and 5 (23.8%), respectively, were genetically tested. Together, 539 first-generation LS variant carriers had 2068 children and grandchildren (3.84 per carrier). Of the 1548 (2.87 per carrier) eligible children, 952 (61.5%) were tested (1.77 per carrier). In multivariate models, age (OR 1.08 per year; 95% CI 1.06-1.10), family gene (OR 2.83; 1.75-4.57 for MLH1 and 2.59; 1.47-4.56 for MSH2 compared with MSH6), one or more tested siblings (OR 6.60; 4.82-9.03), no siblings (OR 4.63; 2.64-8.10), and parent under endoscopic surveillance (OR 5.22; 2.41-11.31) were independent predictors of having genetic testing. Examples of parental adherence to regular surveillance and genetically tested siblings strongly influenced children at 50% risk of LS to undergo predictive gene testing. High numbers of untested, adult at-risk individuals exist even among well-established cohorts of known LS families with good adherence to endoscopic surveillance. PMID- 28832569 TI - SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population. AB - Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set. PMID- 28832570 TI - Accurate and comprehensive analysis of single nucleotide variants and large deletions of the human mitochondrial genome in DNA and single cells. AB - Massive parallel sequencing (MPS) can accurately quantify mitochondrial DNA (mtDNA) single nucleotide variants (SNVs), but no MPS methods are currently validated to simultaneously and accurately establish the breakpoints and frequency of large deletions at low heteroplasmic loads. Here we present the thorough validation of an MPS protocol to quantify the load of very low frequency, large mtDNA deletions in bulk DNA and single cells, along with SNV calling by standard methods. We used a set of well-characterized DNA samples, DNA mixes and single cells to thoroughly control the study. We developed a custom script for the detection of mtDNA rearrangements that proved to be more accurate in detecting and quantifying deletions than pre-existing tools. We also show that PCR conditions and primersets must be carefully chosen to avoid biases in the retrieved variants and an increase in background noise, and established a lower detection limit of 0.5% heteroplasmic load for large deletions, and 1.5 and 2% for SNVs, for bulk DNA and single cells, respectively. Finally, the analysis of different single cells provided novel insights into mtDNA cellular mosaicism. PMID- 28832571 TI - The effect of inflammation on serum zinc concentrations and the prevalence estimates of population-level zinc status among Congolese children aged 6-59 months. AB - BACKGROUND/OBJECTIVES: Zinc is a negative acute-phase reactant; hence, its concentration decreases in the presence of inflammation. There is no current consensus on how to control for the effect of inflammation on serum zinc, which has implications for accurate estimates of population-level zinc status. We aimed to measure the association between inflammation and serum zinc concentrations and to compare the means and the prevalence of zinc deficiency using unadjusted and inflammation-adjusted serum zinc concentrations among Congolese children. SUBJECTS/METHODS: Non-fasting blood was collected in the afternoon in trace element-free vacutainers from 744 apparently healthy children aged 6-59 months in the Democratic Republic of the Congo. Serum was analyzed for zinc, C-reactive protein (CRP) and alpha-1 acid glycoprotein (AGP) for 665 children with complete data for all three biomarkers. Linear regression was used to generate correction factors (CFs) based on three stages of inflammation: incubation (CRP >5 mg/l and normal AGP), early convalescence (CRP >5 mg/l and AGP >1 g/l) and late convalescence (AGP >1 g/l and normal CRP), relative to no inflammation. RESULTS: Overall unadjusted mean+/-s.d. serum zinc concentration was 9.4+/-2.1 MUmol/l. Study-generated CFs (95% confidence interval) for incubation, early and late convalescence were 1.01 (0.88, 1.14), 1.15 (1.11, 1.21) and 1.07 (1.03, 1.11), respectively. After applying the CFs, overall adjusted mean+/-s.d. serum zinc concentration was 10.1+/-2.2 MUmol/l, and prevalence of zinc deficiency (<8.7 MUmol/l) decreased from 35% (n=234/665) to 24% (n=160/665). CONCLUSIONS: Adjustment of zinc concentrations for inflammation is warranted when assessing population-level zinc status.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.127. PMID- 28832572 TI - Mediterranean diet and prognosis of first-diagnosed Acute Coronary Syndrome patients according to heart failure phenotype: Hellenic Heart Failure Study. AB - BACKGROUND/OBJECTIVES: Nutrition in secondary prevention of Acute Coronary Syndrome (ACS) is inadequately investigated. We sought to evaluate the role of Mediterranean diet in prognosis of first-diagnosed ACS patients, according to heart failure type. SUBJECTS/METHODS: in 2006-2009, 1000 consecutive patients hospitalized at First Cardiology Clinic of Athens with ACS diagnosis were enrolled in the study. In 2016, 10-year follow-up was performed (75% participation rate). Only n=690 (69%) first-diagnosed ACS patients were included. Adherence to Mediterranean diet was assessed through MedDietScore (range 0-55). Heart failure phenotypes were reduced, mid-range and preserved ejection fraction (that is, HFrEF, HFmrEF and HFpEF, respectively). RESULTS: Ranking from first to third MedDietScore tertile, fewer 1, 2 and 10-year fatal/non-fatal ACS events were observed. Multivariate logistic regression analysis highlighted a significantly inverse association between MedDietScore and long-term ACS prognosis in 1 year (odds ratio (OR)=0.84, 95% confidence interval (CI) (0.71, 1.00), P=0.05), 2 year (OR=0.91, 95% CI (0.82, 1.00), P=0.04) and 10 year (OR=0.93, 95% CI (0.85, 1.00), P=0.05) follow-up. Further analysis revealed that MedDietScore differentially affected patients' prognosis according to heart failure phenotype, with short-term impact in HFrEF and HFmrEF patients yet longer positive outcomes in HFpEF and C-reactive protein potentially mediated these relations. CONCLUSIONS: Mediterranean diet seemed to protect against recurrent cardiac episodes in coronary patients with major ACS complications. Results were more encouraging with regard to patients with preserved left ventricle function. Such findings may possess a cost-effective, supplementary-to-medical, treatment approach in this patient category where evidence concerning their management are inconclusive.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.122. PMID- 28832573 TI - Effects of L-carnitine supplementation on biomarkers of oxidative stress, antioxidant capacity and lipid profile, in patients with pemphigus vulgaris: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND/OBJECTIVES: Pemphigus vulgaris (PV), as an autoimmune disease including mucosa and the skin, is associated with several complications and comorbidities. The present study planned to determine the effect of L-carnitine (LC) supplementation on biomarkers of oxidative stress (OS), antioxidant capacity and lipid profile in PV patients.Subjects/MethodsFifty two control and patients with PV, participated in the current randomized, double-blind, placebo-controlled clinical trial. The patients were allocated randomly to receive 2 g per day LC tartrate subdivided into two equal doses of 1 g before breakfast and dinner (n=26) or placebo (n=26) for 8 weeks. Anthropometric, lipid profile and OS values were determined at baseline and end of intervention period. RESULTS: LC intake significantly reduced serum levels of triglycerides, total-, LDL- cholesterol and oxidative stress index (OSI; P<0.05). In addition, supplementation with LC resulted to a meaningful increase in levels of total antioxidant capacity (TAC) (P=0.05) and serum carnitine (P<0.001). LC intake revealed non-significant change in serum total oxidant capacity (P=0.15) and HDL- cholesterol (P=0.06) in comparison to the placebo. CONCLUSIONS: LC consumption may have favorable results on TAC, OSI and lipid profiles in patients with PV. The results were in line with the idea that LC supplementation can be associated with positive effects on metabolic status and OS of patients with PV.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.131. PMID- 28832574 TI - Hot infusions and risk of colorectal cancer in Uruguay: a case-control study. AB - BACKGROUND/OBJECTIVES: The evidence of possible roles for the most common hot infusions intake (tea and coffee) in the risk of colorectal cancer (CRC) needs additional data. Regarding 'mate' intake (infusion of Ilex paraguariensis herb), a previous multi-site study reported lack of association for its highest intake on CRC risk. The present study was conducted to better understand the associations between the intake of this and other infusions and CRC risk. SUBJECTS/METHODS: Patients (611 CRC incident cases and 2394 controls, all belonging to public hospitals) were interviewed through a questionnaire, including socio-demographic, reproductive and lifestyle variables, and a food frequency questionnaire of 64 items, analyzing tea, 'mate' and coffee intake (consumer status, daily intake, age at start and at quit). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated through unconditional logistic regression, adjusting for relevant potential confounders. RESULTS: Tea and coffee intake displayed significant and inverse associations with CRC risk, mainly among men (OR=0.54, 95% CI 0.38-0.76 for tea and OR=0.59, 95% CI 0.41-0.85 for coffee). Mate intake showed a significant inverse association among women (OR=0.50, 95% CI 0.33-0.77), with a marginal heterogeneity between sexes (P=0.07). Concerning age strata, tea intake displayed inverse associations in all ages, whereas 'mate' and coffee intake showed stronger inverse associations for age ?70, suggesting a gradient along time. CONCLUSIONS: We found evidence of different significant inverse associations for tea, 'mate' and coffee intake and CRC risk. To our knowledge, this is the first epidemiologic study reporting inverse results on 'mate' intake and CRC, which are explained by a stronger association among women.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.130. PMID- 28832575 TI - Using judgement analysis to identify dietitians' referral prioritisation for assessment in adult acute services. AB - BACKGROUND/OBJECTIVES: Dietitians need to prioritise referrals in order to manage their work load. Novice dietitians may not receive training on prioritisation and could be helped with an evidence-based, effective decision-making training tool. To develop such a tool, it is necessary to understand how experts make prioritisation decisions. This study aimed to model expert decision-making policy for prioritising dietetic referrals in adult acute-care services. METHODS/SUBJECTS: Social judgement theory was used to model expert decision making policy. Informational cues and cue levels were identified. A set of case scenarios that replicated dietetic referrals in adult acute services were developed using fractional factorial design approach. Experienced dietitians were asked to make prioritisation decisions on case scenarios. A model was derived using multiple regression analysis to elicit the weighting given to cues and cue levels by the experts when making prioritisation decisions. RESULTS: Six cues and 21 cue levels were identified, and 60 unique case scenarios were created. Fifty experienced dietitians made decisions on these case scenarios. The 'reason for referral' and 'biochemistry picture' were the two most influential cues, and 'weight history' was the least significant. 'Nutritional status', 'presenting complaint' and 'previous food intake' had similar weightings. In all, 95.7% of the variability in the experts' average judgement (adjusted R2=0.93) was predicted by the 6 cues. CONCLUSIONS: A model for referral prioritisation in adult acute services described experienced dietitians' decision-making policy. This can be used to develop training materials that may increase the effectiveness and quality of prioritisation judgements.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.123. PMID- 28832576 TI - Longitudinal assessment of body composition in healthy Swedish children from 1 week until 4 years of age. AB - BACKGROUND/OBJECTIVES: Knowledge of longitudinal body composition development is required to identify the mechanisms behind childhood overweight and obesity and to prevent these conditions. However, accurate data on this development in early childhood are lacking. Our aim was to describe the longitudinal body composition development in healthy young Swedish children. SUBJECTS/METHODS: Body size and composition were assessed in 26 children using air-displacement plethysmography (1 and 12 weeks and 4.4 years of age) and isotope dilution (1.5 and 3 years of age) and compared with available reference data. RESULTS: Body fat (%) for boys (n=16) was 12.8+/-3.9 (1 week), 25.6+/-4.8 (12 weeks), 28.2+/-3.8 (1.5 years), 27.3+/-5.1 (3 years) and 26.1+/-3.5 (4.4 years). For girls (n=10) these values were 15.3+/-2.9, 25.7+/-3.9, 27.9+/-3.3, 26.3+/-7.2 and 26.0+/-5.3, respectively. These values were above the Fomon reference values at 1.5 years of age and later and higher than the Butte reference (P<0.05) for boys at 1.5 years of age. At all ages the coefficients of variation were higher for body fat (%) (12-30%) than for BMI (4-11%). CONCLUSIONS: At 4 years of age our children had more body fat than indicated by reference data. This high level may have already been established at 1.5 years of age but our small sample and the lack of appropriate reference data limit the possibility of drawing firm conclusions. Our results demonstrate the limitations of BMI when investigating overweight and obesity in early life and highlight the need for appropriate reference body composition data in infants and young children.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.125. PMID- 28832578 TI - A two-locus model of selection in autotetraploids: Chromosomal gametic disequilibrium and selection for an adaptive epistatic gene combination. AB - In this paper, we present a two-locus model of selection for an autotetraploid population. We also investigate a measure of disequilibrium that occurs between homologous chromosomes in the diploid gametes of autotetraploids, namely chromosomal gametic disequilibrium. We apply the model and measure of disequilibrium to compare how an adaptive epistatic gene combination is inherited and selected for in an autotetraploid versus diploid population. Autotetraploids are expected to have higher genomic mutation and recombination rates relative to diploids, due to a greater ploidy level. These two processes can work in opposition in terms of selection for adaptive epistatic gene combinations. While a higher genomic mutation rate can generate the alleles that confer an epistatic combination more quickly, a higher recombination rate is expected to break the combination down more quickly. We show that chromosomal gametic disequilibrium in autotetraploids can potentially compensate for less linkage disequilibrium in autotetraploids. We also explore how double reduction affects the inheritance of and selection for an epistatic gene combination. Over all, our analysis provides theoretical evidence that adaptive epistatic combinations can be selected for more efficiently in autotetraploids versus diploids. This may provide insight into empirical work that finds epistasis has a role in causing population differentiation between autotetraploid plant populations. PMID- 28832577 TI - Heritable gene expression differences between lake and stream stickleback include both parallel and antiparallel components. AB - The repeated phenotypic patterns that characterize populations undergoing parallel evolution provide support for a deterministic role of adaptation by natural selection. Determining the level of parallelism also at the genetic level is thus central to our understanding of how natural selection works. Many studies have looked for repeated genomic patterns in natural populations, but work on gene expression is less common. The studies that have examined gene expression have found some support for parallelism, but those studies almost always used samples collected from the wild that potentially confounds the effects of plasticity with heritable differences. Here we use two independent pairs of lake and stream threespine stickleback (Gasterosteus aculeatus) raised in common garden conditions to assess both parallel and antiparallel (that is, similar versus different directions of lake-stream expression divergence in the two watersheds) heritable gene expression differences as measured by total RNA sequencing. We find that more genes than expected by chance show either parallel (22 genes, 0.18% of expressed genes) or antiparallel (24 genes, 0.20% of expressed genes) lake-stream expression differences. These results correspond well with previous genomic studies in stickleback ecotype pairs that found similar levels of parallelism. We suggest that parallelism might be similarly constrained at the genomic and transcriptomic levels. PMID- 28832579 TI - Extreme polyandry aids the establishment of invasive populations of a social insect. AB - Although monandry is believed to have facilitated the evolution of eusociality, many highly eusocial insects have since evolved extreme polyandry. The transition to extreme polyandry was likely driven by the benefits of within-colony genetic variance to task specialization and/or disease resistance, but the extent to which it confers secondary benefits, once evolved, is unclear. Here we investigate the consequences of extreme polyandry on the invasive potential of the Asian honey bee, Apis cerana. In honey bees and other Hymenoptera, small newly founded invasive populations must overcome the genetic constraint of their sex determination system that requires heterozygosity at a sex-determining locus to produce viable females. We find A. cerana queens in an invasive population mate with an average of 27 males (range 16-42) that would result in the founding queen/s carrying 75% of their source population's sex alleles in stored sperm. This mating frequency is similar to native-range Chinese A. cerana (mean 29 males, range 19-46). Simulations reveal that extreme polyandry reduces the risk, relative to monandry or moderate polyandry, that colonies produce a high incidence of inviable brood in populations that have experienced a founder event, that is, when sex allele diversity is low and/or allele frequencies are unequal. Thus, extreme polyandry aids the invasiveness of A. cerana in two ways: (1) by increasing the sex locus allelic richness carried to new populations with each founder, thereby increasing sex locus heterozygosity; and (2) by reducing the population variance in colony fitness following a founder event. PMID- 28832580 TI - Loss of CD73-mediated extracellular adenosine production exacerbates inflammation and abnormal alveolar development in newborn mice exposed to prolonged hyperoxia. AB - BackgroundHyperoxic lung injury is characterized by cellular damage from high oxygen concentrations that lead to an inflammatory response and it disrupts normal alveolarization in the developing newborn lung. Adenosine is a signaling molecule that is generated extracellularly by ecto-5'-nucleotidase (CD73) in response to injury. Extracellular adenosine signals through cell surface receptors and has been found to have a protective role in acute injury situations; however, chronic elevations have been associated with detrimental changes in chronic lung diseases. We hypothesized that hyperoxia-induced lung injury leads to CD73-mediated increases in extracellular adenosine, which are detrimental to the newborn lung.MethodsC57Bl/6 and CD73-/- mice were exposed to 95% oxygen, 70% oxygen, or room air. Adenosine concentration and markers of pulmonary inflammation and lung development were measured.ResultsExposure to hyperoxia caused pulmonary inflammation and disrupted normal alveolar development in association with increased pulmonary adenosine levels. Loss of CD73-mediated extracellular adenosine production led to decreased survival with exposure to 95% oxygen, and exacerbated pulmonary inflammation and worsened lung development with 70% oxygen exposure.ConclusionExposure to hyperoxia causes lung injury associated with an increase in adenosine concentration, and loss of CD73-mediated adenosine production leads to worsening of hyperoxic lung injury.Pediatric Research advance online publication, 23 August 2017; doi:10.1038/pr.2017.176. PMID- 28832581 TI - Understanding and overcoming antibiotic resistance. PMID- 28832582 TI - Cardiomyocyte oxidants production may signal to T. cruzi intracellular development. AB - Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, presents a variable clinical course, varying from asymptomatic to serious debilitating pathologies with cardiac, digestive or cardio-digestive impairment. Previous studies using two clonal T. cruzi populations, Col1.7G2 (T. cruzi I) and JG (T. cruzi II) demonstrated that there was a differential tissue distribution of these parasites during infection in BALB/c mice, with predominance of JG in the heart. To date little is known about the mechanisms that determine this tissue selection. Upon infection, host cells respond producing several factors, such as reactive oxygen species (ROS), cytokines, among others. Herein and in agreement with previous data from the literature we show that JG presents a higher intracellular multiplication rate when compared to Col1.7G2. We also showed that upon infection cardiomyocytes in culture may increase the production of oxidative species and its levels are higher in cultures infected with JG, which expresses lower levels of antioxidant enzymes. Interestingly, inhibition of oxidative stress severely interferes with the intracellular multiplication rate of JG. Additionally, upon H2O2-treatment increase in intracellular Ca2+ and oxidants were observed only in JG epimastigotes. Data presented herein suggests that JG and Col1.7G2 may sense extracellular oxidants in a distinct manner, which would then interfere differently with their intracellular development in cardiomyocytes. PMID- 28832583 TI - Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity. AB - The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo )antigen presentation in infectious diseases and cancer. Here, by exploiting co occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal distant modulation of the binding specificity at P2 for some HLA-I alleles by residues in the HLA-I binding site but outside of the B-pocket and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays. PMID- 28832584 TI - Losing its ground: A case study of fast declining populations of a 'least concern' species, the bonnet macaque (Macaca radiata). AB - The populations of many species that are widespread and commensal with humans have been drastically declining during the past few decades, but little attention has been paid to their conservation. Here, we report the status of the bonnet macaque, a species that is considered 'least-concern' for conservation. We show that the widely ranging rhesus macaque is expanding its range into the distributional range of the bonnet macaque, a species endemic only to southern India. Bonnet macaques have very low abundance in forests of all types indicating that it is not a typically forest dwelling species. The traditionally preferred habitats of bonnet macaques have been Hindu temples/ tourist spots but our data reveal that nearly 50% population of bonnet macaques has disappeared from such previously occupied spots. Another preferred habitat of bonnet macaques has been roadsides with abundant Ficus trees adjoining croplands. We found that between 2003 and 2015, the roadsides have drastically changed where vegetation has been replaced with barren lands and urbanization. Consequently, the populations of bonnet macaques have declined by more than 65% over the past 25 years, and by more than 50% between 2003 and 2015 alone. We, therefore, conclude that this 'least-concern' species is actually facing serious conservation challenges. We also identify a few places such as small hillocks with natural vegetation and a few temples/tourist spots which are likely to remain stable and thus can serve as 'bonnet macaque conservation reserves'. Since the bonnet macaque shares many traits with several other commensal and 'low-risk' species, it can serve as a model for the development of long-term conservation strategies for most such species. PMID- 28832585 TI - Choice of measure matters: A study of the relationship between socioeconomic status and psychosocial resources in a middle-aged normal population. AB - Psychosocial resources may serve as an important link to explain socioeconomic differences in health. Earlier studies have demonstrated that education, income and occupational status cannot be used interchangeably as indicators of a hypothetical latent social dimension. In the same manner, it is important to disentangle the effect of measuring different constructs of psychosocial resources. The aim of this study was therefore to analyse if associations between socioeconomic status (SES) and psychosocial resources differ depending on the measures used. A cross-sectional population-based study of a random sample (n = 1007) of middle-aged individuals (45-69 years old, 50% women) in Sweden was performed using questionnaire and register data. SES was measured as education, occupation, household income and self-rated economy. Psychosocial resources were measured as social integration, social support, mastery, self-esteem, sense of coherence (SOC) and trust. Logistic regression models were applied to analyse the relationships controlling for the effects of possible confounders. The measures of SES were low or moderately correlated to each other as were the measures of psychosocial resources. After controlling for age, sex, country of birth and employment status, household income and self-rated economy were associated with all six psychosocial resources; occupation was associated with three (social integration, self-esteem and trust) and education with two (social integration and self-esteem). Social integration and self-esteem showed a significant and graded relationship with all SES measures; trust was associated with all SES measures except education, whereas SOC and mastery were only associated with household income and self-rated economy. After controlling for other SES measures, no associations with psychosocial resources remained for education or occupation. In conclusion, associations between SES and psychosocial resources did differ depending on the measures used. The findings illustrate the importance of the choice of measure when investigating SES as well as psychosocial resources. PMID- 28832586 TI - Local environmental and meteorological conditions influencing the invasive mosquito Ae. albopictus and arbovirus transmission risk in New York City. AB - Ae. albopictus, an invasive mosquito vector now endemic to much of the northeastern US, is a significant public health threat both as a nuisance biter and vector of disease (e.g. chikungunya virus). Here, we aim to quantify the relationships between local environmental and meteorological conditions and the abundance of Ae. albopictus mosquitoes in New York City. Using statistical modeling, we create a fine-scale spatially explicit risk map of Ae. albopictus abundance and validate the accuracy of spatiotemporal model predictions using observational data from 2016. We find that the spatial variability of annual Ae. albopictus abundance is greater than its temporal variability in New York City but that both local environmental and meteorological conditions are associated with Ae. albopictus numbers. Specifically, key land use characteristics, including open spaces, residential areas, and vacant lots, and spring and early summer meteorological conditions are associated with annual Ae. albopictus abundance. In addition, we investigate the distribution of imported chikungunya cases during 2014 and use these data to delineate areas with the highest rates of arboviral importation. We show that the spatial distribution of imported arboviral cases has been mostly discordant with mosquito production and thus, to date, has provided a check on local arboviral transmission in New York City. We do, however, find concordant areas where high Ae. albopictus abundance and chikungunya importation co-occur. Public health and vector control officials should prioritize control efforts to these areas and thus more cost effectively reduce the risk of local arboviral transmission. The methods applied here can be used to monitor and identify areas of risk for other imported vector-borne diseases. PMID- 28832587 TI - Social venue range and referral chain impact: Implications for the sampling of hidden communities. AB - BACKGROUND: It has been argued that the success of respondent-driven sampling (RDS) in generating unbiased estimates for epidemiologic outcomes depends on participants' abilities to generate long referral chains. While this is thought to depend on the number of people participants know in the target population, this idea is rarely tested. Furthermore, little attention has been paid to the role of other aspects of social connectedness in recruitment, such as participants' involvement in local clubs and venues. METHODS: We examine whether the recruitment potential of young Black men who have sex with men (YBMSM) depends on (1) their social network size and (2) their affiliations with a variety of sex venues across geographic areas. We analyze data from a 2014 RDS study of 598 YBMSM on the south side of Chicago. RESULTS: Both a participant's personal network size and the number of different types of sex venues with which he was affiliated were significantly positively associated with (1) the total number of recruits in the participant's prospective referral chains and (2) the lengths of those chains. However, only venue affiliation remain significantly associated with recruitment potential in the multivariate model. CONCLUSIONS: The success of RDS in generating valid samples may depend more on recruiting participants who are involved in multiple venues within the community (i.e., their affiliation networks) than on recruiting those who have large personal social networks. PMID- 28832588 TI - Diagnostic accuracy and acceptability of rapid HIV oral testing among adults attending an urban public health facility in Kampala, Uganda. AB - BACKGROUND: The prevalence of HIV in Uganda is 7.3%, and yet nearly 40% of people living with HIV are unaware of their status. The current HIV testing policy which is strictly blood-based poses several challenges including: a need for high level laboratory skills, stringent waste disposal needs, and painful sample collection. It is envisaged that introduction of a rapid, painless HIV oral fluid test as a potential alternative is likely to increase the number of people testing. The aim of this study was to determine the diagnostic accuracy and acceptability of rapid HIV oral testing among adults attending Kisenyi Health Centre IV in Kampala. METHODS AND FINDINGS: We conducted a cross-sectional study among 440 adults recruited consecutively at Kisenyi Health Centre IV from January to March 2016. The diagnostic accuracy of the HIV oral test was assessed by comparing to the national HIV serial testing algorithm. We also assessed for acceptability among patients and health care workers (HCWs) by triangulating responses from a structured questionnaire, three focus group discussions and seven key informant interviews. Acceptability was defined as willingness to take the test at the time of the study and intention for future use of the test if it was availed. The prevalence of HIV infection among study participants was 14.8%. The HIV oral fluid test was highly accurate with sensitivity of 100% (95% CI; 94.5-100.0), specificity of 100% (95% CI; 99.0-100.0), positive predictive value (PPV) of 100% (95% CI; 94.5-100.0) and negative predictive value (NPV) of 100% (95% CI; 99.0 100.0). Acceptability of HIV oral testing was also high at 87.0% (95% CI; 83.6 89.9). Participants preferred HIV oral testing because it was: pain free (91%, n = 399) and did not require blood draw (82%, n = 360). CONCLUSION: The HIV oral fluid test has high diagnostic accuracy and acceptability. HIV oral testing is a suitable addition to the national HIV testing strategies with the potential of increasing access to HIV testing services in Uganda. PMID- 28832589 TI - A counseling program on nuisance bleeding improves quality of life in patients on dual antiplatelet therapy: A randomized controlled trial. AB - BACKGROUND: Nuisance bleeding is a major determinant of quality of life and drug discontinuation in patients on dual antiplatelet therapy (DAPT). However, no randomized trial has been focused on the impact of nuisance bleeding on quality of life. METHODS: BATMAN is an investigator-driven, randomized, controlled, single-center, open trial (NCT02554006). Four hundred and forty-eight consecutive patients with indication to at least 6 months of DAPT were randomized to: i) multimodal counseling program focused on nuisance bleedings (interventional arm); ii) usual discharge process (control arm). The primary endpoint was the one-month health-related quality of life assessed by the EuroQol-5 Dimension (EQ-5D) visual analog scale (VAS) score. Secondary endpoints were EQ-5D at 1 and 6 months, EQ-5D VAS at 6 months, DAPT withdrawal, need of information regarding DAPT and/or nuisance bleedings, 6-month ischemic and bleeding adverse events. RESULTS: The EQ5D-VAS was significantly higher in the interventional arm compared to the control arm at 1 and 6 months (81[74-88] vs. 73[64-80], p < 0.001 at 1 month; 82[76-88] vs. 74[65-81], p < 0.001 at 6 months). Patients in the interventional arm had also significantly lower pain/discomfort and anxiety/depression at the EQ 5D both at 1 and 6 months. Patients in the control arm withdrew DAPT significantly more (7 (3%) vs. 1 (0.4%), p = 0.03) and looked for information regarding DAPT and/or about nuisance bleeding more frequently than those in the interventional arm (178 (79%) vs.19 (8%), p < 0.001). CONCLUSIONS: The systematic utilization of a multimodal counseling program improved quality of life and reduced the DAPT withdrawal rate in patients on DAPT. PMID- 28832590 TI - Does higher education hone cognitive functioning and learning efficacy? Findings from a large and diverse sample. AB - Attending school is a multifaceted experience. Students are not only exposed to new knowledge but are also immersed in a structured environment in which they need to respond flexibly in accordance with changing task goals, keep relevant information in mind, and constantly tackle novel problems. To quantify the cumulative effect of this experience, we examined retrospectively and prospectively, the relationships between educational attainment and both cognitive performance and learning. We analyzed data from 196,388 subscribers to an online cognitive training program. These subscribers, ages 15-60, had completed eight behavioral assessments of executive functioning and reasoning at least once. Controlling for multiple demographic and engagement variables, we found that higher levels of education predicted better performance across the full age range, and modulated performance in some cognitive domains more than others (e.g., reasoning vs. processing speed). Differences were moderate for Bachelor's degree vs. High School (d = 0.51), and large between Ph.D. vs. Some High School (d = 0.80). Further, the ages of peak cognitive performance for each educational category closely followed the typical range of ages at graduation. This result is consistent with a cumulative effect of recent educational experiences, as well as a decrement in performance as completion of schooling becomes more distant. To begin to characterize the directionality of the relationship between educational attainment and cognitive performance, we conducted a prospective longitudinal analysis. For a subset of 69,202 subscribers who had completed 100 days of cognitive training, we tested whether the degree of novel learning was associated with their level of education. Higher educational attainment predicted bigger gains, but the differences were small (d = 0.04 0.37). Altogether, these results point to the long-lasting trace of an effect of prior cognitive challenges but suggest that new learning opportunities can reduce performance gaps related to one's educational history. PMID- 28832591 TI - A deterministic mathematical model for bidirectional excluded flow with Langmuir kinetics. AB - In many important cellular processes, including mRNA translation, gene transcription, phosphotransfer, and intracellular transport, biological "particles" move along some kind of "tracks". The motion of these particles can be modeled as a one-dimensional movement along an ordered sequence of sites. The biological particles (e.g., ribosomes or RNAPs) have volume and cannot surpass one another. In some cases, there is a preferred direction of movement along the track, but in general the movement may be bidirectional, and furthermore the particles may attach or detach from various regions along the tracks. We derive a new deterministic mathematical model for such transport phenomena that may be interpreted as a dynamic mean-field approximation of an important model from mechanical statistics called the asymmetric simple exclusion process (ASEP) with Langmuir kinetics. Using tools from the theory of monotone dynamical systems and contraction theory we show that the model admits a unique steady-state, and that every solution converges to this steady-state. Furthermore, we show that the model entrains (or phase locks) to periodic excitations in any of its forward, backward, attachment, or detachment rates. We demonstrate an application of this phenomenological transport model for analyzing ribosome drop off in mRNA translation. PMID- 28832592 TI - Air blast injuries killed the crew of the submarine H.L. Hunley. AB - The submarine H.L. Hunley was the first submarine to sink an enemy ship during combat; however, the cause of its sinking has been a mystery for over 150 years. The Hunley set off a 61.2 kg (135 lb) black powder torpedo at a distance less than 5 m (16 ft) off its bow. Scaled experiments were performed that measured black powder and shock tube explosions underwater and propagation of blasts through a model ship hull. This propagation data was used in combination with archival experimental data to evaluate the risk to the crew from their own torpedo. The blast produced likely caused flexion of the ship hull to transmit the blast wave; the secondary wave transmitted inside the crew compartment was of sufficient magnitude that the calculated chances of survival were less than 16% for each crew member. The submarine drifted to its resting place after the crew died of air blast trauma within the hull. PMID- 28832593 TI - Prediction of BMI at age 11 in a longitudinal sample of the Ulm Birth Cohort Study. AB - Obesity is one of the greatest public health challenges in the world with childhood prevalence rates between 20-26% and numerous associated health risks. The aim of the current study was to analyze the 11-year follow-up data of the Ulm Birth Cohort Study (UBCS), to identify whether abnormal eating behavior patterns, especially restrained eating, predict body mass index (BMI) at 11 years of age and to explore other factors known to be longitudinally associated with it. Of the original UBCS, n = 422 children (~ 40% of the original sample) and their parents participated in the 11-year follow-up. BMI at age 8 and 11 as well as information on restrained eating, psychological problems, depressive symptoms, lifestyle, and IQ at age 8 were assessed. Partial Least Squares Structural Equation Modeling (PLS-SEM) was used to predict children's BMI scores at age 11. PLS-SEM explained 68% of the variance of BMI at age 11, with BMI at age 8 being the most important predictor. Restrained eating, via BMI at age 8 as well as parental BMI, had further weak associations with BMI at age 11; no other predictor was statistically significant. Since established overweight at age 8 already predicts BMI scores at age 11 longitudinally, obesity interventions should be implemented in early childhood. PMID- 28832594 TI - Social isolation, loneliness and their relationships with depressive symptoms: A population-based study. AB - OBJECTIVES: To assess the relationship between various social isolation indicators and loneliness, and to examine the differential associations that social isolation indicators, loneliness have with depressive symptoms. METHODS: Baseline data for 1,919 adults (aged 21 years and above) from a representative health survey in the Central region of Singapore was used for this study. The association between social isolation indicators (marital status, living arrangement, social connectedness with relatives and friends) and loneliness (the three-item UCLA Loneliness) were assessed, and their differential associations with depressive symptoms (the Patient Health Questionnaire-9) were examined using multiple linear regression, controling for relevant covariates. RESULTS: There was significant overlap between loneliness and social isolation. Social connectedness with relatives and friends were mildly correlated with loneliness score (|r| = 0.14~0.16). Social isolation in terms of weak connectedness with relatives and with friends and loneliness were associated with depressive symptoms even after controling for age, gender, employment status and other covariates. The association of loneliness with depressive symptoms (beta = 0.33) was independent of and stronger than that of any social isolation indicators (|beta| = 0.00~0.07). CONCLUSIONS: The results of the study establishes a significant and unique association of different social isolation indicators and loneliness with depressive symptoms in community-dwelling adults aged 21 and above. PMID- 28832595 TI - Verbal monitoring in Parkinson's disease: A comparison between internal and external monitoring. AB - Patients with Parkinson's disease (PD) display a variety of impairments in motor and non-motor language processes; speech is decreased on motor aspects such as amplitude, prosody and speed and on linguistic aspects including grammar and fluency. Here we investigated whether verbal monitoring is impaired and what the relative contributions of the internal and external monitoring route are on verbal monitoring in patients with PD relative to controls. Furthermore, the data were used to investigate whether internal monitoring performance could be predicted by internal speech perception tasks, as perception based monitoring theories assume. Performance of 18 patients with Parkinson's disease was measured on two cognitive performance tasks and a battery of 11 linguistic tasks, including tasks that measured performance on internal and external monitoring. Results were compared with those of 16 age-matched healthy controls. PD patients and controls generally performed similarly on the linguistic and monitoring measures. However, we observed qualitative differences in the effects of noise masking on monitoring and disfluencies and in the extent to which the linguistic tasks predicted monitoring behavior. We suggest that the patients differ from healthy subjects in their recruitment of monitoring channels. PMID- 28832596 TI - Femicide in Turkey between 2000 and 2010. AB - Although intimate partner violence (IPV) is an important problem that threatens women's health, very few studies focus on the victim-perpetrator relationship or examine this relationship across Turkey. The aim of this study is to contribute to a better understanding of femicide cases in Turkey and to describe the socio demographic, clinical, forensic, and criminological characteristics of femicide victims and offenders. This study analysed 162 femicide cases that occurred in 12 cities in Turkey from 1 January 2000 to 31 December 2010. Eighty women were killed by their partners (classified as intimate partner femicide, IPF), and 81 women were killed by one of their relatives, friends, or strangers (classified as non-intimate partner femicide, non-IPF). According to our results, the typical IPF victim is of child-bearing age, does not have a paid job, is married or divorced, is killed in a domestic setting due to injuries to the thorax or abdomen produced by an edged/pointed weapon or firearm, and is possibly a victim of overkill. The typical IPF perpetrator is close to his victim's age, has a paid job, has no mental disability, owns a gun, and has threatened his partner or ex partner previously because of jealousy/infidelity/honour or separation. The typical non-IPF victim is very similar to the IPF victim; however, her marital status can be single, married or divorced, and she is commonly killed by a relative. The surveillance and screening of femicide and IPV is an important step when analysing and attempting to prevent femicide. Second, the training and sensitization of health professionals are important. Moreover, health staff should be encouraged to participate in advocacy interventions. Third, gun ownership must be brought under control. PMID- 28832597 TI - Decadal-scale variation in diet forecasts persistently poor breeding under ocean warming in a tropical seabird. AB - Climate change effects on population dynamics of natural populations are well documented at higher latitudes, where relatively rapid warming illuminates cause effect relationships, but not in the tropics and especially the marine tropics, where warming has been slow. Here we forecast the indirect effect of ocean warming on a top predator, Nazca boobies in the equatorial Galapagos Islands, where rising water temperature is expected to exceed the upper thermal tolerance of a key prey item in the future, severely reducing its availability within the boobies' foraging envelope. From 1983 to 1997 boobies ate mostly sardines, a densely aggregated, highly nutritious food. From 1997 until the present, flying fish, a lower quality food, replaced sardines. Breeding success under the poor diet fell dramatically, causing the population growth rate to fall below 1, indicating a shrinking population. Population growth may not recover: rapid future warming is predicted around Galapagos, usually exceeding the upper lethal temperature and maximum spawning temperature of sardines within 100 years, displacing them permanently from the boobies' island-constrained foraging range. This provides rare evidence of the effect of ocean warming on a tropical marine vertebrate. PMID- 28832598 TI - Netlang: A software for the linguistic analysis of corpora by means of complex networks. AB - To date there is no software that directly connects the linguistic analysis of a conversation to a network program. Networks programs are able to extract statistical information from data basis with information about systems of interacting elements. Language has also been conceived and studied as a complex system. However, most proposals do not analyze language according to linguistic theory, but use instead computational systems that should save time at the price of leaving aside many crucial aspects for linguistic theory. Some approaches to network studies on language do apply precise linguistic analyses, made by a linguist. The problem until now has been the lack of interface between the analysis of a sentence and its integration into the network that could be managed by a linguist and that could save the analysis of any language. Previous works have used old software that was not created for these purposes and that often produced problems with some idiosyncrasies of the target language. The desired interface should be able to deal with the syntactic peculiarities of a particular language, the options of linguistic theory preferred by the user and the preservation of morpho-syntactic information (lexical categories and syntactic relations between items). Netlang is the first program able to do that. Recently, a new kind of linguistic analysis has been developed, which is able to extract a complexity pattern from the speaker's linguistic production which is depicted as a network where words are inside nodes, and these nodes connect each other by means of edges or links (the information inside the edge can be syntactic, semantic, etc.). The Netlang software has become the bridge between rough linguistic data and the network program. Netlang has integrated and improved the functions of programs used in the past, namely the DGA annotator and two scripts (ToXML.pl and Xml2Pairs.py) used for transforming and pruning data. Netlang allows the researcher to make accurate linguistic analysis by means of syntactic dependency relations between words, while tracking record of the nature of such syntactic relationships (subject, object, etc). The Netlang software is presented as a new tool that solve many problems detected in the past. The most important improvement is that Netlang integrates three past applications into one program, and is able to produce a series of file formats that can be read by a network program. Through the Netlang software, the linguistic network analysis based on syntactic analyses, characterized for its low cost and the completely non invasive procedure aims to evolve into a sufficiently fine grained tool for clinical diagnosis in potential cases of language disorders. PMID- 28832599 TI - Temporal and spatial correlation patterns of air pollutants in Chinese cities. AB - As a huge threat to the public health, China's air pollution has attracted extensive attention and continues to grow in tandem with the economy. Although the real-time air quality report can be utilized to update our knowledge on air quality, questions about how pollutants evolve across time and how pollutants are spatially correlated still remain a puzzle. In view of this point, we adopt the PMFG network method to analyze the six pollutants' hourly data in 350 Chinese cities in an attempt to find out how these pollutants are correlated temporally and spatially. In terms of time dimension, the results indicate that, except for O3, the pollutants have a common feature of the strong intraday patterns of which the daily variations are composed of two contraction periods and two expansion periods. Besides, all the time series of the six pollutants possess strong long term correlations, and this temporal memory effect helps to explain why smoggy days are always followed by one after another. In terms of space dimension, the correlation structure shows that O3 is characterized by the highest spatial connections. The PMFGs reveal the relationship between this spatial correlation and provincial administrative divisions by filtering the hierarchical structure in the correlation matrix and refining the cliques as the tinny spatial clusters. Finally, we check the stability of the correlation structure and conclude that, except for PM10 and O3, the other pollutants have an overall stable correlation, and all pollutants have a slight trend to become more divergent in space. These results not only enhance our understanding of the air pollutants' evolutionary process, but also shed lights on the application of complex network methods into geographic issues. PMID- 28832600 TI - HPN-07, a free radical spin trapping agent, protects against functional, cellular and electrophysiological changes in the cochlea induced by acute acoustic trauma. AB - Oxidative stress is considered a major cause of the structural and functional changes associated with auditory pathologies induced by exposure to acute acoustic trauma AAT). In the present study, we examined the otoprotective effects of 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07), a nitrone-based free radical trap, on the physiological and cellular changes in the auditory system of chinchilla following a six-hour exposure to 4 kHz octave band noise at 105 dB SPL. HPN-07 has been shown to suppress oxidative stress in biological models of a variety of disorders. Our results show that administration of HPN-07 beginning four hours after acoustic trauma accelerated and enhanced auditory/cochlear functional recovery, as measured by auditory brainstem responses (ABR), distortion product otoacoustic emissions (DPOAE), compound action potentials (CAP), and cochlear microphonics (CM). The normally tight correlation between the endocochlear potential (EP) and evoked potentials of CAP and CM were persistently disrupted after noise trauma in untreated animals but returned to homeostatic conditions in HPN-07 treated animals. Histological analyses revealed several therapeutic advantages associated with HPN-07 treatment following AAT, including reductions in inner and outer hair cell loss; reductions in AAT-induced loss of calretinin-positive afferent nerve fibers in the spiral lamina; and reductions in fibrocyte loss within the spiral ligament. These findings support the conclusion that early intervention with HPN-07 following an AAT efficiently blocks the propagative ototoxic effects of oxidative stress, thereby preserving the homeostatic and functional integrity of the cochlea. PMID- 28832601 TI - Educational expansion and inequalities in mortality-A fixed-effects analysis using longitudinal data from 18 European populations. AB - OBJECTIVE: The aim of this paper is to empirically evaluate whether widening educational inequalities in mortality are related to the substantive shifts that have occurred in the educational distribution. MATERIALS AND METHODS: Data on education and mortality from 18 European populations across several decades were collected and harmonized as part of the Demetriq project. Using a fixed-effects approach to account for time trends and national variation in mortality, we formally test whether the magnitude of relative inequalities in mortality by education is associated with the gender and age-group specific proportion of high and low educated respectively. RESULTS: The results suggest that in populations with larger proportions of high educated and smaller proportions of low educated, the excess mortality among intermediate and low educated is larger, all other things being equal. CONCLUSION: We conclude that the widening educational inequalities in mortality being observed in recent decades may in part be attributed to educational expansion. PMID- 28832602 TI - Do individualism and collectivism on three levels (country, individual, and situation) influence theory-of-mind efficiency? A cross-country study. AB - This study investigated whether individualism and collectivism (IC) at country, individual, and situational level influence how quickly and accurately people can infer mental states (i.e. theory of mind, or ToM), indexed by accuracy and reaction time in a ToM task. We hypothesized that collectivism (having an interdependent self and valuing group concerns), compared to individualism (having an independent self and valuing personal concerns), is associated with greater accuracy and speed in recognizing and understanding the thoughts and feelings of others. Students (N = 207) from individualism-representative (the Netherlands) and collectivism-representative (Vietnam) countries (Country IC) answered an individualism-collectivism questionnaire (Individual IC) and were randomly assigned to an individualism-primed, collectivism-primed, or no-prime task (Situational IC) before performing a ToM task. The data showed vast differences between the Dutch and Vietnamese groups that might not be attributable to experimental manipulation. Therefore, we analyzed the data for the groups separately and found that Individual IC did not predict ToM accuracy or reaction time performance. Regarding Situational IC, when primed with individualism, the accuracy performance of Vietnamese participants in affective ToM trials decreased compared to when primed with collectivism and when no prime was used. However, an interesting pattern emerged: Dutch participants were least accurate in affective ToM trials, while Vietnamese participants were quickest in affective ToM trials. Our research also highlights a dilemma faced by cross cultural researchers who use hard-to-reach populations but face the challenge of disentangling experimental effects from biases that might emerge due to an interaction between cultural differences and experimental settings. We propose suggestions for overcoming such challenges. PMID- 28832603 TI - Social media and colorectal cancer: A systematic review of available resources. AB - AIM: Social media (SM) can provide information and medical knowledge to patients. Our aim was to review the literature and web-based content on SM that is used by Colorectal Cancer (CRC) patients, as well as surgeons' interaction with SM. METHOD: Studies published between 2006 and 2016 were assessed. We also assessed the impact of several hashtags on Twitter with a freeware (Symplur). RESULTS: Nine studies were included assessing Twitter (78%), Forums/Cancer-survivor networks (33%), and Facebook (22%). Aims included use of SM by CRC patients (67%), cancer-specific usage of SM with different types of cancer (44%), content credibility (33%), and influence in CRC awareness (33%). Prevention was the most common information that CRC patients looked for, followed by treatment side effects. Only 2% of CRC SM users are doctors. SM use by colorectal consultants was suboptimal. Only 38% of surgeons had a LinkedIn account (most with less than 50 connections), and 3% used Twitter. A steep increase of tweets was observed for searched Hashtags over time, which was more marked for #ColonCancer (+67%vs+38%, #Coloncancer vs #RectalCancer). Participants engaged with colon cancer increased by 85%, whereas rectal cancer ones increased by 29%. The hashtag '#RectalCancer' was mostly tweeted by colorectal surgeons. The official twitter account of American Society of Colorectal Surgeons (@fascrs_updates) was the most active account. CONCLUSION: CRC patients and relatives are increasingly engaging with SM. CRC surgeons' participation is poor, but we confirm a trend toward a greater involvement. Most SM lack of authoritative validation and the quality of shared content still is largely anecdotic and not scientifically evidenced-based. However, SM may offer several advantages over conventional information sharing sources for CRC patients and surgeons, and create connections with mutual enrichment. PMID- 28832604 TI - Soil iron and aluminium concentrations and feet hygiene as possible predictors of Podoconiosis occurrence in Kenya. AB - BACKGROUND: Podoconiosis (mossy foot) is a neglected non-filarial elephantiasis considered to be caused by predisposition to cumulative contact of uncovered feet to irritative red clay soil of volcanic origins in the tropical regions. Data from structured observational studies on occurrence of Podoconiosis and related factors are not available in Kenya. METHODOLOGY/PRINCIPAL FINDINGS: To establish the occurrence and aspects associated with Podoconiosis, a cross-sectional survey was implemented in an area located within 30 km from the foot of volcanic Mount Longonot in the Great Rift Valley in Kenya. Five villages and 385 households were selected using multistage and systematic random sampling procedures respectively during the survey. Podoconiosis was determined by triangulating (1) the clinical diagnosis, (2) molecular assaying of sputum samples to rule out Wuchereria bancrofti microfilaria and (3) determining the concentration of six elements and properties in the soil known to be associated with Podoconiosis. A structured questionnaire was used to identify possible risk factors. Univariable and multivariable Poisson regression analyses were carried out to determine factors associated with Podoconiosis. Thirteen participants were clinically positive for Podoconiosis giving an overall prevalence of 3.4%. The prevalence ranged between 0% and 18.8% across the five villages. Molecular assay for W. bancrofti test turned negative in the 13 samples. The following factors were positively associated with the Podoconiosis prevalence (P<0.1) in the univariable analyses: (i) age, (ii) gender, (iii) education level, (iv) frequency of washing legs, (v) frequency of wearing shoes, (vi) soil pH, and (vii) village. Unexpectedly, the concentration of soil minerals previously thought to be associated with Podoconiosis was found to be negatively associated with the Podoconiosis prevalence (P<0.1). In the multivariable analyses, only frequency of wearing shoes and village turned out significant (P<=0.05). By modeling the different soil mineral concentrations and pH while adjusting for the variable frequency of wearing shoes, only iron concentration was significant and in the negative dimension (P<=0.05). However, controlling for Iron, Aluminum concentrations turned significant. CONCLUSION/SIGNIFICANCE: This study has pointed to a hitherto unreported occurrence of Podoconiosis cases and has contributed to the baseline knowledge on the occurrence of Podoconiosis in Kenya. Consistent with many studies, wearing shoes remain an important risk factor for the occurrence of the disease. However, our findings are inconsistent with some of the hitherto postulations that associate Podoconiosis prevalence with certain minerals in the soil in other regions in Africa. These findings provide new beginnings for the cross-disciplinary research of Podoconiosis in environmental health, socio ecology and ecological niche and geo-spatial modeling and prediction. PMID- 28832605 TI - Dosimetric evaluation of MobiusFX in the RapidArc delivery quality assurance comparing with 3DVH. AB - The dosimetric characteristics of MobiusFX, which uses the treatment machine log file to calculate the dose inside the patient body, were analyzed for use in the RapidArc delivery quality assurance (DQA) process. The accuracy and usefulness of MobiusFX in clinical cases was evaluated by comparing the dose calculated by MobiusFX with that calculated by the conventional measurement dose based program, 3DVH. The results of gamma evaluation with three different criteria (3%-3 mm, 4% 3 mm, 5%-3 mm) were analyzed, and the dose changes were calculated while simulating variable position errors (6 mm, 3 mm) and dosimetric output increases (6%, 3%). Although the doses calculated by each tool were not identical due to differences in the calculation algorithms, the doses calculated by MobiusFX were generally similar to those calculated by 3DVH. Based on these results, MobiusFX exhibited the required accuracy for clinical application. However, it could not determine the dosimetric output variation. It should therefore be considered a supplementary DQA tool that can verify the error in the daily treatment process, but not an ideal DQA tool that can replace conventional measurement based DQA methods. PMID- 28832606 TI - Mentalizing skills do not differentiate believers from non-believers, but credibility enhancing displays do. AB - The ability to mentalize has been marked as an important cognitive mechanism enabling belief in supernatural agents. In five studies we cross-culturally investigated the relationship between mentalizing and belief in supernatural agents with large sample sizes (over 67,000 participants in total) and different operationalizations of mentalizing. The relative importance of mentalizing for endorsing supernatural beliefs was directly compared with credibility enhancing displays-the extent to which people observed credible religious acts during their upbringing. We also compared autistic with neurotypical adolescents. The empathy quotient and the autism-spectrum quotient were not predictive of belief in supernatural agents in all countries (i.e., The Netherlands, Switzerland and the United States), although we did observe a curvilinear effect in the United States. We further observed a strong influence of credibility enhancing displays on belief in supernatural agents. These findings highlight the importance of cultural learning for acquiring supernatural beliefs and ask for reconsiderations of the importance of mentalizing. PMID- 28832607 TI - Dread of uncertain pain: An event-related potential study. AB - Humans experience more stress about uncertain situations than certain situations. However, the neural mechanism underlying the uncertainty of a negative stimulus has not been determined. In the present study, event-related potential was recorded to examine neural responses during the dread of unpredictable pain. We used a cueing paradigm in which predictable cues were always followed by electric shocks, unpredictable cues by electric shocks at a 50/50 ratio and safe cues by no electric shock. Visual analogue scales following electric shocks were presented to quantify subjective anxiety levels. The behavioral results showed that unpredictable cues evoked high-level anxiety compared with predictable cues in both painful and unpainful stimulation conditions. More importantly, the ERPs results revealed that unpredictable cues elicited a larger P200 at parietal sites than predictable cues. In addition, unpredictable cues evoked larger P200 compared with safe cues at frontal electrodes and compared with predictable cues at parietal electrodes. In addition, larger P3b and LPP were observed during perception of safe cues compared with predictable cues at frontal and central electrodes. The similar P3b effect was also revealed in the left sites. The present study underlined that the uncertain dread of pain was associated with threat appraisal process in pain system. These findings on early event-related potentials were significant for a neural marker and development of therapeutic interventions. PMID- 28832608 TI - When the firm prevents the crash: Avoiding market collapse with partial control. AB - Market collapse is one of the most dramatic events in economics. Such a catastrophic event can emerge from the nonlinear interactions between the economic agents at the micro level of the economy. Transient chaos might be a good description of how a collapsing market behaves. In this work, we apply a new control method, the partial control method, with the goal of avoiding this disastrous event. Contrary to common control methods that try to influence the system from the outside, here the market is controlled from the bottom up by one of the most basic components of the market-the firm. This is the first time that the partial control method is applied on a strictly economical system in which we also introduce external disturbances. We show how the firm is capable of controlling the system avoiding the collapse by only adjusting the selling price of the product or the quantity of production in accordance to the market circumstances. Additionally, we demonstrate how a firm with a large market share is capable of influencing the demand achieving price stability across the retail and wholesale markets. Furthermore, we prove that the control applied in both cases is much smaller than the external disturbances. PMID- 28832610 TI - First fossil of an oestroid fly (Diptera: Calyptratae: Oestroidea) and the dating of oestroid divergences. AB - Calyptrate flies include about 22,000 extant species currently classified into Hippoboscoidea (tsetse, louse, and bat flies), the muscoid grade (house flies and relatives) and the Oestroidea (blow flies, bot flies, flesh flies, and relatives). Calyptrates are abundant in nearly all terrestrial ecosystems, often playing key roles as decomposers, parasites, parasitoids, vectors of pathogens, and pollinators. For oestroids, the most diverse group within calyptrates, definitive fossils have been lacking. The first unambiguous fossil of Oestroidea is described based on a specimen discovered in amber from the Dominican Republic. The specimen was identified through digital dissection by CT scans, which provided morphological data for a cladistic analysis of its phylogenetic position among extant oestroids. The few known calyptrate fossils were used as calibration points for a molecular phylogeny (16S, 28S, CAD) to estimate the timing of major diversification events among the Oestroidea. Results indicate that: (a) the fossil belongs to the family Mesembrinellidae, and it is identified and described as Mesembrinella caenozoica sp. nov.; (b) the mesembrinellids form a sister clade to the Australian endemic Ulurumyia macalpinei (Ulurumyiidae) (McAlpine's fly), which in turn is sister to all remaining oestroids; (c) the most recent common ancestor of extant Calyptratae lived just before the K-Pg boundary (ca. 70 mya); and (d) the radiation of oestroids began in the Eocene (ca. 50 mya), with the origin of the family Mesembrinellidae dated at ca. 40 mya. These results provide new insight into the timing and rate of oestroid diversification and highlight the rapid radiation of some of the most diverse and ecologically important families of flies. ZooBank accession number-urn:lsid:zoobank.org:pub:0DC5170B 1D16-407A-889E-56EED3FE3627. PMID- 28832609 TI - Distinct aging profiles of CD8+ T cells in blood versus gastrointestinal mucosal compartments. AB - A hallmark of human immunosenescence is the accumulation of late-differentiated memory CD8+ T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, enhanced activation, and increased secretion of inflammatory cytokines. Importantly, oligoclonal expansions of these cells are associated with increased morbidity and mortality risk in elderly humans. Currently, most information on the adaptive immune system is derived from studies using peripheral blood, which contains approximately only 2% of total body lymphocytes. However, most lymphocytes reside in tissues. It is not clear how representative blood changes are of the total immune status. This is especially relevant with regard to the human gastrointestinal tract (GALT), a major reservoir of total body lymphocytes (approximately 60%) and an anatomical region of high antigenic exposure. To assess how peripheral blood T cells relate to those in other locations, we compare CD8+ T cells from peripheral blood and the GALT, specifically rectosigmoid colon, in young/middle age, healthy donors, focusing on phenotypic and functional alterations previously linked to senescence in peripheral blood. Overall, our results indicate that gut CD8+ T cells show profiles suggestive of greater differentiation and activation than those in peripheral blood. Specifically, compared to blood from the same individual, the gut contains significantly greater proportions of CD8+ T cells that are CD45RA- (memory), CD28 , CD45RA-CD28+ (early memory), CD45RA-CD28- (late memory), CD25-, HLA-DR+CD38+ (activated) and Ki-67+ (proliferating); ex vivo CD3+ telomerase activity levels are greater in the gut as well. However, gut CD8+ T cells may not necessarily be more senescent, since they expressed significantly lower levels of CD57 and PD-1 on CD45RO+ memory cells, and had in vitro proliferative dynamics similar to that of blood cells. Compartment-specific age-effects in this cohort were evident as well. Blood cells showed a significant increase with age in proportion of HLA DR+38+, Ki-67+ and CD25+ CD8+ T cells; and an increase in total CD3+ ex-vivo telomerase activity that approached significance. By contrast, the only age effect seen in the gut was a significant increase in CD45RA- (memory) and concurrent decrease in CD45RA+CD28+ (naive) CD8+ T cells. Overall, these results indicate dynamics of peripheral blood immune senescence may not hold true in the gut mucosa, underscoring the importance for further study of this immunologically important tissue in evaluating the human immune system, especially in the context of chronic disease and aging. PMID- 28832611 TI - A degradation debt? Large-scale shifts in community composition and loss of biomass in a tropical forest fragment after 40 years of isolation. AB - Habitat loss and fragmentation are among the biggest threats to tropical biodiversity and associated ecosystem services. We examined forest dynamics in a mid-elevation 365-ha fragment in southern Costa Rica. The fragment was isolated in the mid-1970s and belongs to the Las Cruces Biological Station. A 2.25-ha permanent plot was established in the center of the old-growth forest (>400 m to nearest edge boundary) and all plants >5 cm DBH were censused, mapped, and identified to species in two surveys taken ~5-6 years apart (>3,000 stems/survey). Although the reserve maintains high species richness (>200 spp.), with many rare species represented by only one individual, we document a strong shift in composition with a two-fold increase in the number of soft-wooded pioneer individuals. The dominant late-successional understory tree species, Chrysochlamys glauca (Clusiaceae), and most species in the Lauraceae, declined dramatically. Turnover was high: 22.9% of stems in the first survey were lost, and 27.8% of stems in the second survey represented new recruits. Mean tree diameter decreased significantly and there was a 10% decrease in overall biomass. Such alteration has been documented previously but only in smaller fragments or within ~100 m of an edge boundary. Further penetration into this fragment was perhaps driven by a progressive invasion of disturbance-adapted species into the fragment's core over time; the loss of once-dominant late successional species could be a contributing factor. The pattern found is of particular concern given that such fragments represent a substantial portion of today's remaining tropical habitat; further studies in similar-sized fragments that have been isolated for similar prolonged periods are called for. PMID- 28832612 TI - Neck/shoulder discomfort due to visually demanding experimental near work is influenced by previous neck pain, task duration, astigmatism, internal eye discomfort and accommodation. AB - Visually demanding near work can cause eye discomfort, and eye and neck/shoulder discomfort during, e.g., computer work are associated. To investigate direct effects of experimental near work on eye and neck/shoulder discomfort, 33 individuals with chronic neck pain and 33 healthy control subjects performed a visual task four times using four different trial lenses (referred to as four different viewing conditions), and they rated eye and neck/shoulder discomfort at baseline and after each task. Since symptoms of eye discomfort may differ depending on the underlying cause, two categories were used; internal eye discomfort, such as ache and strain, that may be caused by accommodative or vergence stress; and external eye discomfort, such as burning and smarting, that may be caused by dry-eye disorders. The cumulative performance time (reflected in the temporal order of the tasks), astigmatism, accommodation response and concurrent symptoms of internal eye discomfort all aggravated neck/shoulder discomfort, but there was no significant effect of external eye discomfort. There was also an interaction effect between the temporal order and internal eye discomfort: participants with a greater mean increase in internal eye discomfort also developed more neck/shoulder discomfort with time. Since moderate musculoskeletal symptoms are a risk factor for more severe symptoms, it is important to ensure a good visual environment in occupations involving visually demanding near work. PMID- 28832613 TI - Structural and immunochemical relatedness suggests a conserved pathogenicity motif for secondary cell wall polysaccharides in Bacillus anthracis and infection associated Bacillus cereus. AB - Bacillus anthracis (Ba) and human infection-associated Bacillus cereus (Bc) strains Bc G9241 and Bc 03BB87 have secondary cell wall polysaccharides (SCWPs) comprising an aminoglycosyl trisaccharide repeat: ->4)-beta-d-ManpNAc-(1->4)-beta d-GlcpNAc-(1->6)-alpha-d-GlcpNAc-(1->, substituted at GlcNAc residues with both alpha- and beta-Galp. In Bc G9241 and Bc 03BB87, an additional alpha-Galp is attached to O-3 of ManNAc. Using NMR spectroscopy, mass spectrometry and immunochemical methods, we compared these structures to SCWPs from Bc biovar anthracis strains isolated from great apes displaying "anthrax-like" symptoms in Cameroon (Bc CA) and Cote d'Ivoire (Bc CI). The SCWPs of Bc CA/CI contained the identical HexNAc trisaccharide backbone and Gal modifications found in Ba, together with the alpha-Gal-(1->3) substitution observed previously at ManNAc residues only in Bc G9241/03BB87. Interestingly, the great ape derived strains displayed a unique alpha-Gal-(1->3)-alpha-Gal-(1->3) disaccharide substitution at some ManNAc residues, a modification not found in any previously examined Ba or Bc strain. Immuno-analysis with specific polyclonal anti-Ba SCWP antiserum demonstrated a reactivity hierarchy: high reactivity with SCWPs from Ba 7702 and Ba Sterne 34F2, and Bc G9241 and Bc 03BB87; intermediate reactivity with SCWPs from Bc CI/CA; and low reactivity with the SCWPs from structurally distinct Ba CDC684 (a unique strain producing an SCWP lacking all Gal substitutions) and non infection-associated Bc ATCC10987 and Bc 14579 SCWPs. Ba-specific monoclonal antibody EAII-6G6-2-3 demonstrated a 10-20 fold reduced reactivity to Bc G9241 and Bc 03BB87 SCWPs compared to Ba 7702/34F2, and low/undetectable reactivity to SCWPs from Bc CI, Bc CA, Ba CDC684, and non-infection-associated Bc strains. Our data indicate that the HexNAc motif is conserved among infection-associated Ba and Bc isolates (regardless of human or great ape origin), and that the number, positions and structures of Gal substitutions confer unique antigenic properties. The conservation of this structural motif could open a new diagnostic route in detection of pathogenic Bc strains. PMID- 28832614 TI - Estradiol modulates neural response to conspecific and heterospecific song in female house sparrows: An in vivo positron emission tomography study. AB - Although there is growing evidence that estradiol modulates female perception of male sexual signals, relatively little research has focused on female auditory processing. We used in vivo 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging to examine the neuronal effects of estradiol and conspecific song in female house sparrows (Passer domesticus). We assessed brain glucose metabolism, a measure of neuronal activity, in females with empty implants, estradiol implants, and empty implants ~1 month after estradiol implant removal. Females were exposed to conspecific or heterospecific songs immediately prior to imaging. The activity of brain regions involved in auditory perception did not differ between females with empty implants exposed to conspecific vs. heterospecific song, but neuronal activity was significantly reduced in females with estradiol implants exposed to heterospecific song. Furthermore, our within individual design revealed that changes in brain activity due to high estradiol were actually greater several weeks after peak hormone exposure. Overall, this study demonstrates that PET imaging is a powerful tool for assessing large-scale changes in brain activity in living songbirds, and suggests that after breeding is done, specific environmental and physiological cues are necessary for estradiol-stimulated females to lose the selectivity they display in neural response to conspecific song. PMID- 28832615 TI - Comorbidities in pulmonary tuberculosis cases in Puducherry and Tamil Nadu, India: Opportunities for intervention. AB - BACKGROUND: We aimed to define characteristics of TB patients in Puducherry and two districts of Tamil Nadu, India and calculate the population attributable fractions (PAF) of TB from malnutrition and alcohol. METHODS: New smear-positive TB cases were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT India) cohort. Census and National Family Health Survey data were used for comparisons. RESULTS: Data were analyzed for 409 participants enrolled between May 2014-June 2016; 307 (75.1%) were male, 60.2% were malnourished (body mass index [BMI] <18.5 kg/m2), and 29.1% severely malnourished (BMI <16). "Hazardous" alcohol use (based on AUDIT-C score) was reported by 155/305 (50.8%) of males. Tuberculosis cases were more likely than the Puducherry population to be malnourished (62.6% v 10.2% males and 71.7% v 11.3% of females; both p<0.001), and male cases were more likely to use alcohol than male non-cases (84.4% v 41%; p < .001). The PAF of malnutrition was 57.4% in males and 61.5% in females; the PAF for alcohol use was 73.8% in males and 1.7% in females. CONCLUSIONS: Alcohol use in men and malnutrition are helping drive the TB epidemic in Southern India. Reducing the TB burden in this population will require efforts to mitigate these risk factors. PMID- 28832616 TI - Low 25(OH)-vitamin D concentrations are associated with emotional and behavioral problems in German children and adolescents. AB - BACKGROUND: Evidence has accumulated for the association between low vitamin D serum concentrations and mental health disorders in both children and adults. We performed a cross-sectional analysis in a population-based sample of children and adolescents to detect associations between 25(OH)-vitamin D serum [25(OH)D] concentrations and scores of the five Strengths and Difficulties Questionnaire (SDQ) subscales and the total difficulties score in different age groups (age >=3 <12 years and >=12-<18 years). METHODS: 9068 participants of the population based, nation-wide German Health Interview and Examination Survey for Children and Adolescents (KIGGS) with information on mental health status assessed by the SDQ and 25(OH)D levels were included in the analysis. For statistical analysis we used linear regression models stratified by gender based on different adjustment sets. For the younger subsample the analysis was additionally adjusted for the frequency of playing outside. We compared the associations based on parent- and self-ratings of the SDQ for children and adolescents aged >=12-<18 years. RESULTS: We found inverse associations between 25(OH)D concentrations and the subscales emotional problems, peer relationship problems and the total difficulties score in both genders after adjustment for potential confounders. The strongest associations were observed in the older subsample for parent ratings in boys and self-ratings in girls. In the younger subsample the associations were less strong and no longer evident after adjustment for potential confounders such as migration background, socioeconomic status and frequency of playing outside. CONCLUSION: Based on the large-scale cross sectional study in a German population-based sample of children and adolescents we detected inverse associations between 25(OH)D concentrations and both parent- and self-rated SDQ scores of the total difficulties scale and different subscales with the strongest association in the subsample aged >=12-<18 years for both genders. Migration background and socioeconomic status were detected as relevant confounders. Further studies-particularly in countries with comparatively low mean 25(OH)D concentrations-in childhood and adolescence are warranted. Longitudinal studies are also necessary to infer direction of effects. Finally, RCTs in children and adolescents are required to determine whether Vitamin D is beneficial for mental health. PMID- 28832617 TI - Molluscicidal activities of curcumin-nisin polylactic acid nanoparticle on Biomphalaria pfeifferi. AB - BACKGROUND: Snail intermediate host control is a widely canvassed strategy for schistosomiasis control in endemic countries. While there have been increasing studies on the search for potent molluscicides in the past years, the use of nanoparticulate agents as molluscicides is yet to gain wide attention. The aim of this study was to assess the molluscicidal potential of curcumin-nisin poly lactic acid (PLA) entrapped nanoparticle (CurNisNp) against Biomphalaria pfeifferi, a snail intermediate host for Schistosoma mansoni. METHODOLOGY/PRINCIPAL FINDINGS: CurNisNp formulated by double emulsion method was tested against the young adults, < 1 week, 1-2-week old juveniles, 1 day (blastula) and 7 day-old (hippo-stage) egg masses of B. pfeifferi. Mortality in the different stages was determined after 96-h of exposure at varying concentrations (350, 175, 87.5, 43.75 and 21.88 ppm). The sub-lethal effects of CurNisNp on the hatchability of the 7-day-old egg masses and egg laying capacity of the young adult snails were determined. The CurNisNp diameter, polydispersity index (PDI), zeta potential and drug entrapment efficiency were 284.0 +/- 17.9 nm, 0.166 +/- 0.03, -16.6 +/- 2.45 mV and 35.0% respectively. The < 1 week old juveniles and the 1-day-old egg stage (blastula) of B. pfeifferi with LC50 277.9 ppm and 4279.5 ppm were the most susceptible and resistant stages to the drug respectively. CurNisNp was also observed to cause significant reductions (P<0.05) in egg hatchability and egg laying capacity with strong negative correlation between egg laying capacity and concentration (r = -0.928; P<0.05). CONCLUSION/SIGNIFICANCE: This study showed that CurNisNp has molluscicidal activities on different developmental stages of B. pfeifferi. It is therefore recommended that the formulation be more optimised to give a nanoparticle with a narrow range monodispersed PDI for better drug distribution and eventual greater molluscicidal activities. PMID- 28832618 TI - Characterization of host plant resistance to zebra chip disease from species derived potato genotypes and the identification of new sources of zebra chip resistance. AB - 'Candidatus Liberibacter solanacearum' (Lso), an uncultivable phloem-limited phytopathogenic bacteria, is known to be associated with Zebra Chip disease (ZC), which represents a major threat to potato production in the US and elsewhere. This pathogen is transmitted by the phloem-feeding potato psyllid, Bactericera cockerelli Sulc (Hem. Triozidae). Currently, there are no reports of resistance to ZC in cultivated potatoes. This greenhouse study was conducted to evaluate Lso transmission success and the susceptibility of 11 potato breeding clones, representing diverge genetic background, to ZC, in relation to a susceptible commercial cultivar, Russet Burbank. Individual plants were exposed to two Lso positive potato psyllids for 48 hours. The percentage of successful Lso transmission varied across the evaluated genotypes ranging between 7 and 57%. Freshly-cut and fried tubers showed significant variation in ZC symptom severity among the breeding clones, with several genotypes expressing relative tolerance when compared to Russet Burbank. None of the evaluated clones showed statistically lower Lso titers than Russet Burbank with the exception of one genotype in the second year of the study. However, the presence of a non significant relationship between average symptom severity and Lso titer indicated variations in phenotypic responses (i.e. tolerance) to Lso existed among evaluated breeding lines. Breeding clones A07781-3LB, A07781-4LB and A07781-10LB had relatively lower Lso titer (low susceptibility) and tuber symptom expression (high tolerance) among the tested genotypes. As these three clones represent full siblings, the observed effects could be indicative of the presence of a genetic basis for resistance/tolerance to ZC. Findings provide a better understanding of resistance/tolerance to ZC, and contribute to continued efforts in breeding for resistance to this disease. PMID- 28832620 TI - A novel splice site mutation of myosin VI in mice leads to stereociliary fusion caused by disruption of actin networks in the apical region of inner ear hair cells. AB - An unconventional myosin encoded by the myosin VI gene (MYO6) contributes to hearing loss in humans. Homozygous mutations of MYO6 result in nonsyndromic profound congenital hearing loss, DFNB37. Kumamoto shaker/waltzer (ksv) mice harbor spontaneous mutations, and homozygous mutants exhibit congenital defects in balance and hearing caused by fusion of the stereocilia. We identified a Myo6c.1381G>A mutation that was found to be a p.E461K mutation leading to alternative splicing errors in Myo6 mRNA in ksv mutants. An analysis of the mRNA and protein expression in animals harboring this mutation suggested that most of the abnormal alternatively spliced isoforms of MYO6 are degraded in ksv mice. In the hair cells of ksv/ksv homozygotes, the MYO6 protein levels were significantly decreased in the cytoplasm, including in the cuticular plates. MYO6 and stereociliary taper-specific proteins were mislocalized along the entire length of the stereocilia of ksv/ksv mice, thus suggesting that MYO6 attached to taper specific proteins at the stereociliary base. Histological analysis of the cochlear hair cells showed that the stereociliary fusion in the ksv/ksv mutants, developed through fusion between stereociliary bundles, raised cuticular plate membranes in the cochlear hair cells and resulted in incorporation of the bundles into the sheaths of the cuticular plates. Interestingly, the expression of the stereociliary rootlet-specific TRIO and F-actin binding protein (TRIOBP) was altered in ksv/ksv mice. The abnormal expression of TRIOBP suggested that the rootlets in the hair cells of ksv/ksv mice had excessive growth. Hence, these data indicated that decreased MYO6 levels in ksv/ksv mutants disrupt actin networks in the apical region of hair cells, thereby maintaining the normal structure of the cuticular plates and rootlets, and additionally provided a cellular basis for stereociliary fusion in Myo6 mutants. PMID- 28832621 TI - A prospective examination of online social network dynamics and smoking cessation. AB - INTRODUCTION: Use of online social networks for smoking cessation has been associated with abstinence. Little is known about the mechanisms through which the formation of social ties in an online network may influence smoking behavior. Using dynamic social network analysis, we investigated how temporal changes of an individual's number of social network ties are prospectively related to abstinence in an online social network for cessation. In a network where quitting is normative and is the focus of communications among members, we predicted that an increasing number of ties would be positively associated with abstinence. METHOD: Participants were N = 2,657 adult smokers recruited to a randomized cessation treatment trial following enrollment on BecomeAnEX.org, a longstanding Internet cessation program with a large and mature online social network. At 3 months post-randomization, 30-day point prevalence abstinence was assessed and website engagement metrics were extracted. The social network was constructed with clickstream data to capture the flow of information among members. Two network centrality metrics were calculated at weekly intervals over 3 months: 1) in-degree, defined as the number of members whose posts a participant read; and 2) out-degree-aware, defined as the number of members who read a participant's post and commented, which was subsequently viewed by the participant. Three groups of users were identified based on social network engagement patterns: non users (N = 1,362), passive users (N = 812), and active users (N = 483). Logistic regression modeled 3-month abstinence by group as a function of baseline variables, website utilization, and network centrality metrics. RESULTS: Abstinence rates varied by group (non-users = 7.7%, passive users = 10.7%, active users = 20.7%). Significant baseline predictors of abstinence were age, nicotine dependence, confidence to quit, and smoking temptations in social situations among passive users (ps < .05); age and confidence to quit among active users. Among centrality metrics, positive associations with abstinence were observed for in-degree increases from Week 2 to Week 12 among passive and active users, and for out-degree-aware increases from Week 2 to Week 12 among active users (ps < .05). CONCLUSIONS: This study is the first to demonstrate that increased tie formation among members of an online social network for smoking cessation is prospectively associated with abstinence. It also highlights the value of using individuals' activities in online social networks to predict their offline health behaviors. PMID- 28832622 TI - The 'Feline Five': An exploration of personality in pet cats (Felis catus). AB - The idea of animals possessing personalities was once dismissed by the scientific community, but has since gained traction with evidence for potential application to improve captive animal management and welfare. Although domestic cats are popular companion animals, research has tended to overlook the value of personality assessment for management and care of pet cats. The aim of this study was to investigate personality in a large sample of pet cats with a view to understanding practical implications for pet cats in the home. Personality of 2,802 pet cats, from South Australia and New Zealand, was rated by their owners utilising a survey measuring 52 personality traits. Five reliable personality factors were found using principal axis factor analysis: Neuroticism, Extraversion, Dominance, Impulsiveness and Agreeableness. Implications for the 'Feline Five' are discussed in relation to their potential application to improving the management and welfare of pet cats. Highly Impulsive cats for example, may be reacting to something stressful in their environment, whereas cats with low Agreeableness scores, showing irritability may indicate underlying pain or illness. Thus, the need for a systematic and holistic approach to personality that includes both the individual pet cat and its environment is recommended, and opens the door to future interdisciplinary intervention. PMID- 28832619 TI - Correction: Genome-wide physical activity interactions in adiposity - A meta analysis of 200,452 adults. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006528.]. PMID- 28832623 TI - Variants of sequence family B Thermococcus kodakaraensis DNA polymerase with increased mismatch extension selectivity. AB - Fidelity and selectivity of DNA polymerases are critical determinants for the biology of life, as well as important tools for biotechnological applications. DNA polymerases catalyze the formation of DNA strands by adding deoxynucleotides to a primer, which is complementarily bound to a template. To ensure the integrity of the genome, DNA polymerases select the correct nucleotide and further extend the nascent DNA strand. Thus, DNA polymerase fidelity is pivotal for ensuring that cells can replicate their genome with minimal error. DNA polymerases are, however, further optimized for more specific biotechnological or diagnostic applications. Here we report on the semi-rational design of mutant libraries derived by saturation mutagenesis at single sites of a 3'-5' exonuclease deficient variant of Thermococcus kodakaraensis DNA polymerase (KOD pol) and the discovery for variants with enhanced mismatch extension selectivity by screening. Sites of potential interest for saturation mutagenesis were selected by their proximity to primer or template strands. The resulting libraries were screened via quantitative real-time PCR. We identified three variants with single amino acid exchanges-R501C, R606Q, and R606W-which exhibited increased mismatch extension selectivity. These variants were further characterized towards their potential in mismatch discrimination. Additionally, the identified enzymes were also able to differentiate between cytosine and 5 methylcytosine. Our results demonstrate the potential in characterizing and developing DNA polymerases for specific PCR based applications in DNA biotechnology and diagnostics. PMID- 28832624 TI - Pediatric cryptosporidiosis: An evaluation of health care and societal costs in Peru, Bangladesh and Kenya. AB - Cryptosporidium is a leading cause of pediatric diarrhea in resource-limited settings; yet, few studies report the health care costs or societal impacts of this protozoan parasite. Our study examined direct and indirect costs associated with symptomatic cryptosporidiosis in infants younger than 12 months in Kenya, Peru and Bangladesh. Inputs to the economic burden model, such as disease incidence, population size, health care seeking behaviour, hospital costs, travel costs, were extracted from peer-reviewed literature, government documents, and internationally validated statistical tools for each country. Indirect losses (i.e. caregiver income loss, mortality, and growth faltering) were also estimated. Our findings suggest that direct treatment costs per symptomatic cryptosporidiosis episode were highest in Kenya ($59.01), followed by Peru ($23.32), and Bangladesh ($7.62). The total annual economic impacts for the 0-11 month cohorts were highest in Peru ($41.5M; range $0.88-$599.3M), followed by Kenya ($37.4M; range $1.6-$804.5M) and Bangladesh ($9.6M, range $0.28-$91.5M). For all scenarios, indirect societal costs far outweighed direct treatment costs. These results highlight the critical need for innovative improvements to current prevention, diagnostic and treatment strategies available in resource poor settings, as well as the need for solutions that span multiple disciplines including food and water safety, sanitation and livestock production. PMID- 28832625 TI - Adjuvant treatment with monosialoganglioside may improve neurological outcomes in neonatal hypoxic-ischemic encephalopathy: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Ganglioside has a neuroprotective role in neonatal hypoxic-ischemic encephalopathy (HIE). This study aimed to evaluate the neurological outcomes of monosialoganglioside as adjuvant treatment for neonatal HIE by conducting a meta analysis. METHODS: A comprehensive literature search was made in the Pubmed, EMBASE, Cochrane Library, Wanfang, CNKI, VIP databases through October 2016. Randomized controlled trials comparing monosialoganglioside with the usual treatment for newborns having HIE deemed eligible. Weighted mean difference (WMD) and risk ratio (RR) with 95% confidence interval (CI) were calculated for continuous and dichotomous data, respectively. RESULTS: Ten trials consisting of 787 neonates were included. Adjuvant treatment with monosialoganglioside significantly reduced major neurodevelopmental disabilities (RR = 0.35; 95% CI = 0.21-0.57), cerebral palsy (RR = 0.32; 95% CI = 0.12-0.87), mental retardation (RR = 0.31; 95% CI = 0.11-0.88) as well as improved the mental (WMD = 14.95; 95% CI = 7.44-22.46) and psychomotive (WMD = 13.40; 95% CI = 6.69-20.11) development index during the follow-up. Also, monosialoganglioside significantly improved Neonatal Behavioral Neurological Assessment scores (WMD = 2.91; 95% CI = 2.05 3.78) compared with the usual treatment. However, adverse effects associated with monosialoganglioside were poorly reported in the included trials. CONCLUSION: Adjuvant treatment with monosialoganglioside had beneficial effects in improving neurological outcomes in neonatal HIE. However, these findings should be interpreted with caution because of methodological flaws in the included trials. Furthermore, safety of monosialoganglioside use should also be further evaluated. PMID- 28832626 TI - The effect of Bacopa monnieri on gene expression levels in SH-SY5Y human neuroblastoma cells. AB - Bacopa monnieri is a plant used as a nootropic in Ayurveda, a 5000-year-old system of traditional Indian medicine. Although both animal and clinical studies supported its role as a memory enhancer, the molecular and cellular mechanism underlying Bacopa's nootropic action are not understood. In this study, we used deep sequencing (RNA-Seq) to identify the transcriptome changes upon Bacopa treatment on SH-SY5Y human neuroblastoma cells. We identified several genes whose expression levels were regulated by Bacopa. Biostatistical analysis of the RNA Seq data identified biological pathways and molecular functions that were regulated by Bacopa, including regulation of mRNA translation and transmembrane transport, responses to oxidative stress and protein misfolding. Pathway analysis using the Ingenuity platform suggested that Bacopa may protect against brain damage and improve brain development. These newly identified molecular and cellular determinants may contribute to the nootropic action of Bacopa and open up a new direction of investigation into its mechanism of action. PMID- 28832627 TI - Analysis of repetitive amino acid motifs reveals the essential features of spider dragline silk proteins. AB - The extraordinary mechanical properties of spider dragline silk are dependent on the highly repetitive sequences of the component proteins, major ampullate spidroin 1 and 2 (MaSp2 and MaSp2). MaSp sequences are dominated by repetitive modules composed of short amino acid motifs; however, the patterns of motif conservation through evolution and their relevance to silk characteristics are not well understood. We performed a systematic analysis of MaSp sequences encompassing infraorder Araneomorphae based on the conservation of explicitly defined motifs, with the aim of elucidating the essential elements of MaSp1 and MaSp2. The results show that the GGY motif is nearly ubiquitous in the two types of MaSp, while MaSp2 is invariably associated with GP and di-glutamine (QQ) motifs. Further analysis revealed an extended MaSp2 consensus sequence in family Araneidae, with implications for the classification of the archetypal spidroins ADF3 and ADF4. Additionally, the analysis of RNA-seq data showed the expression of a set of distinct MaSp-like variants in genus Tetragnatha. Finally, an apparent association was uncovered between web architecture and the abundance of GP, QQ, and GGY motifs in MaSp2, which suggests a co-expansion of these motifs in response to the evolution of spiders' prey capture strategy. PMID- 28832629 TI - Analysis of topological relationships and network properties in the interactions of human beings. AB - In the animal world, various kinds of collective motions have been found and proven to be efficient ways of carrying out some activities such as searching for food and avoiding predators. Many scholars research the interactions of collective behaviors of human beings according to the rules of collective behaviors of animals. Based on the Lennard-Jones potential function and a self organization process, our paper proposes a topological communication model to simulate the collective behaviors of human beings. In the results of simulations, we find various types of collective behavior and fission behavior and discover the threshold for the emergence of collective behavior, which is the range five to seven for the number of topology K. According to the analysis of network properties of the model, the in-degree of individuals is always equal to the number of topology. In the stable state, the out-degrees of individuals distribute around the value of the number of topology K, except that the out degree of a single individual is approximately double the out-degrees of the other individuals. In addition, under different initial conditions, some features of different kinds of networks emerge from the model. We also find the leader and herd mentality effects in the characteristics of the behaviors of human beings in our model. Thus, this work could be used to discover how to promote the emergence of beneficial group behaviors and prevent the emergence of harmful behaviors. PMID- 28832628 TI - Multi-tissue RNA-seq and transcriptome characterisation of the spiny dogfish shark (Squalus acanthias) provides a molecular tool for biological research and reveals new genes involved in osmoregulation. AB - The spiny dogfish shark (Squalus acanthias) is one of the most commonly used cartilaginous fishes in biological research, especially in the fields of nitrogen metabolism, ion transporters and osmoregulation. Nonetheless, transcriptomic data for this organism is scarce. In the present study, a multi-tissue RNA-seq experiment and de novo transcriptome assembly was performed in four different spiny dogfish tissues (brain, liver, kidney and ovary), providing an annotated sequence resource. The characterization of the transcriptome greatly increases the scarce sequence information for shark species. Reads were assembled with the Trinity de novo assembler both within each tissue and across all tissues combined resulting in 362,690 transcripts in the combined assembly which represent 289,515 Trinity genes. BUSCO analysis determined a level of 87% completeness for the combined transcriptome. In total, 123,110 proteins were predicted of which 78,679 and 83,164 had significant hits against the SwissProt and Uniref90 protein databases, respectively. Additionally, 61,215 proteins aligned to known protein domains, 7,208 carried a signal peptide and 15,971 possessed at least one transmembrane region. Based on the annotation, 81,582 transcripts were assigned to gene ontology terms and 42,078 belong to known clusters of orthologous groups (eggNOG). To demonstrate the value of our molecular resource, we show that the improved transcriptome data enhances the current possibilities of osmoregulation research in spiny dogfish by utilizing the novel gene and protein annotations to investigate a set of genes involved in urea synthesis and urea, ammonia and water transport, all of them crucial in osmoregulation. We describe the presence of different gene copies and isoforms of key enzymes involved in this process, including arginases and transporters of urea and ammonia, for which sequence information is currently absent in the databases for this model species. The transcriptome assemblies and the derived annotations generated in this study will support the ongoing research for this particular animal model and provides a new molecular tool to assist biological research in cartilaginous fishes. PMID- 28832630 TI - Long-term treatment with budesonide/formoterol attenuates circulating CRP levels in chronic obstructive pulmonary disease patients of group D. AB - BACKGROUND: The systemic inflammation is associated with clinical outcome and mortality in chronic obstructive pulmonary disease (COPD) patients. To investigate the effects of tiotropium (Tio) and/or budesonide/formoterol (Bud/Form) on systemic inflammation biomarkers in stable COPD patients of group D, a randomized, open-label clinical trial was conducted. METHODS: Eligible participants (n = 324) were randomized and received either Tio 18ug once daily (group I), Bud/Form 160/4.5ug twice daily (group II), Bud/Form 320/9ug twice daily (group III), or Tio 18ug once daily with Bud/Form 160/4.5ug twice daily (group IV) for 6 months. Systemic inflammation biomarkers were measured before randomization and during the treatment, including C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-8 (IL-8), serum amyloid A (SAA), tumor necrosis factor-alpha (TNF-alpha), fibrinogen (Fib), and white blood cell (WBC). RESULTS: After 6-month treatment, CRP levels in group II, group III and group IV changed by a median (interquartile range) of -1.25 (-3.29, 1.18) mg/L, -1.13 (-2.55, 0.77) mg/L, and -1.56 (-4.64, 0.22) mg/L respectively, all of which with statistical differences compared with group I. In addition, there were no treatment differences in terms of IL-8, SAA, TNF-alpha, Fib and WBC levels. CONCLUSIONS: A long-term treatment with Bud/Form alone or together with Tio can attenuate circulating CRP levels in COPD patients of group D, compared with Tio alone. PMID- 28832631 TI - DNA strand breaks and TDP-43 mislocation are absent in the murine hSOD1G93A model of amyotrophic lateral sclerosis in vivo and in vitro. AB - Mutations in the human Cu/Zn superoxide dismutase type-1 (hSOD1) gene are common in familial amyotrophic lateral sclerosis (fALS). The pathophysiology has been linked to, e.g., organelle dysfunction, RNA metabolism and oxidative DNA damage conferred by SOD1 malfunction. However, apart from metabolically evoked DNA oxidation, it is unclear whether severe genotoxicity including DNA single-strand breaks (SSBs) and double-strand breaks (DSBs), originates from loss of function of nuclear SOD1 enzyme. Factors that endogenously interfere with DNA integrity and repair complexes in hSOD1-mediated fALS remain similarly unexplored. In this regard, uncontrolled activation of transposable elements (TEs) might contribute to DNA disintegration and neurodegeneration. The aim of this study was to elucidate the role of the fALS-causing hSOD1G93A mutation in the generation of severe DNA damage beyond well-characterized DNA base oxidation. Therefore, DNA damage was assessed in spinal tissue of hSOD1G93A-overexpressing mice and in corresponding motor neuron-enriched cell cultures in vitro. Overexpression of the hSOD1G93A locus did not change the threshold for severe DNA damage per se. We found that levels of SSBs and DSBs were unaltered between hSOD1G93A and control conditions, as demonstrated in post-mitotic motor neurons and in astrocytes susceptible to replication-dependent DNA breakage. Analogously, parameters indicative of DNA damage response processes were not activated in vivo or in vitro. Evidence for a mutation-related elevation in TE activation was not detected, in accordance with the absence of TAR DNA binding protein 43 (TDP-43) proteinopathy in terms of cytoplasmic mislocation or nuclear loss, as nuclear TDP 43 is supposed to silence TEs physiologically. Conclusively, the superoxide dismutase function of SOD1 might not be required to preserve DNA integrity in motor neurons, at least when the function of TDP-43 is unaltered. Our data establish a foundation for further investigations addressing functional TDP-43 interaction with ALS-relevant genetic mutations. PMID- 28832632 TI - Transetherification of 2,4-dimethoxynitrobenzene by aromatic nucleophilic substitution. AB - In view of the few reports concerning aromatic nucleophilic substitution reactions featuring an alkoxy group as a leaving group, the aromatic nucleophilic substitution of 2,4-dimethoxynitrobenzene was investigated with a bulky t butoxide nucleophile under microwave irradiation. The transetherification of 2,4 dimethoxynitrobenezene with sodium t-butoxide under specific conditions, namely for 20 min at 110 degrees C in 10% dimethoxyethane in toluene, afforded the desired product in 87% yield with exclusive ortho-selectivity. A variety of reaction conditions were screened to obtain the maximum yield. The aromatic nucleophilic substitution of 2,4-dimethoxynitrobenzene with t-butoxide should be carried out under controlled conditions in order to avoid the formation of byproducts, unlike that of dihalogenated activated benzenes. Among the formed byproducts, a major compound was elucidated as 2,4-dimethoxy-N-(5-methoxy-2 nitrophenyl)aniline by X-ray crystallography. PMID- 28832633 TI - Can facts trump unconditional trust? Evidence-based information halves the influence of physicians' non-evidence-based cancer screening recommendations. AB - Informed decision making in medicine, defined as basing one's decision on the best current medical evidence, requires both informed physicians and informed patients. In cancer screening, however, studies document that these prerequisites are not yet met. Many physicians do not know or understand the medical evidence behind screening tests, do not adequately counsel (asymptomatic) people on screening, and make recommendations that conflict with existing guidelines on informed choice. Consistent with this situation, nation-wide studies showed that the general public misperceives the contribution of cancer screening but that understanding considerably improves when evidence-based information is provided. However, can evidence-based patient information about cancer screening make people also less likely to simply follow a physician's non-evidence-based advice? A national sample of 897 German citizens, surveyed in face-to-face computer assisted personal interviews, received either evidence-based (e.g., absolute risks on benefits and harms; n = 451) or non-evidence-based (e.g., relative risks on benefits only; n = 446) patient information about a cancer screening test and were then asked to make their initial cancer screening choice. Thereafter, participants received a hypothetical physician's recommendation, which was non evidence-based in terms of existing guidelines on informed decision making (i.e., reporting either benefits or harms but not both; no provision of numbers). When provided with non-evidence-based patient information (n = 446), a mean of 33.1% of 235 participants whose initial screening choice contradicted the hypothetical physician's non-evidence-based recommendation adjusted their choice in deference to that recommendation (95% CI: 27.4 to 39.4%), whereas with evidence-based patient information (n = 451), only half as many, a mean of 16.0% of 225 (95% CI: 11.8 to 21.4%), modified their choice. Thus, evidence-based patient information makes people less likely to simply follow non-evidence-based recommendations of physicians and supports people in making evidence-based decisions even when not adequately counseled on cancer screening. PMID- 28832634 TI - Expression and potential roles of sodium-potassium ATPase and E-cadherin in human gastric adenocarcinoma. AB - BACKGROUND: Gastric adenocarcinoma originates from an abnormal epithelium. The aim of this study was to investigate the expression of sodium-potassium ATPase (NKA), a transmembrane protein located in the epithelium for Na+ and K+ transportation, and E-cadherin, which are both crucial for the epithelium and adherens junction, as potential gastric cancer biomarkers. METHODS: 45 patients diagnosed with gastric adenocarcinoma were recruited. Immunohistochemistry and immunofluorescence were conducted to for localization of NKA alpha1-, beta1 isoform, and E-cadherin. NKA enzyme activity was determined by NADH-linked methods and immunoblotting of NKA alpha1-, beta1-isoform, and E-cadherin were performed to evaluate protein expression. RESULTS: Immunostaining revealed that NKA was co-localized with E-cadherin in the glands of the gastric epithelium. Both NKA activity and alpha1-isoform protein expression were reduced in the study group (P < 0.05), indicating impaired NKA functions. In the adherens junctions, the NKA beta1-isoform and E-cadherin were significantly reduced in the study groups (P < 0.05), indicating the adhesion force between cells may have been weakened. CONCLUSIONS: A significant decrease in NKA function (protein and activity) and E-cadherin in tumor lesions appear promising biomarker for gastric adenocarcinoma. Therefore, developing screening methods for detecting NKA function may be beneficial for the early diagnosis of gastric cancer. In our knowledge, this study was the first to investigate the NKA and E-cadherin expression in the relation of gastric adenocarcinoma in human patients. PMID- 28832635 TI - Expression of the angiogenic mediator, angiopoietin-like 4, in the eyes of patients with proliferative sickle retinopathy. AB - The recent success of therapies directly targeting the angiogenic mediator, vascular endothelial growth factor (VEGF), for the treatment of proliferative diabetic retinopathy has encouraged clinicians to extend the use of anti-VEGF therapies for the treatment of another ischemic retinal vascular disease, proliferative sickle cell retinopathy (PSR), the most common cause of irreversible blindness in patients with sickle cell disease. However, results from case reports evaluating anti-VEGF therapies for PSR have been mixed. This highlights the need to identify alternative therapeutic targets for the treatment of retinal neovascularization in sickle cell patients. In this regard, angiopoietin-like 4 (ANGPTL4) is a novel angiogenic factor regulated by the transcription factor, hypoxia-inducible factor 1, the master regulator of angiogenic mediators (including VEGF) in ischemic retinal disease. In an effort to identify alternative targets for the treatment of sickle cell retinopathy, we have explored the expression of ANGPTL4 in the eyes of patients with PSR. To this end, we examined expression and localization of ANGPTL4 by immunohistochemistry in autopsy eyes from patients with known PSR (n = 5 patients). Complementary studies were performed using enzyme-linked immunosorbent assays in aqueous (n = 8; 7 patients, 2 samples from one eye of same patient) and vitreous (n = 3 patients) samples from a second group of patients with active PSR. We detected expression of ANGPTL4 in neovascular tissue and in the ischemic inner retina in PSR, but not control, eyes. We further observed elevated expression of ANGPTL4 in the aqueous and vitreous of PSR patients compared to controls. These results suggest that ANGPTL4 could contribute to the development of retinal neovascularization in sickle cell patients and could therefore be a therapeutic target for the treatment of PSR. PMID- 28832636 TI - Effects of explicit cueing and ambiguity on the anticipation and experience of a painful thermal stimulus. AB - Many factors can influence the way in which we perceive painful events and noxious stimuli, but less is known about how pain perception is altered by explicit knowledge about the impending sensation. This study aimed to investigate the impact of explicit cueing on anxiety, arousal, and pain experience during the anticipation and delivery of noxious thermal heat stimulations. Fifty-two healthy volunteers were randomised to receive explicit instructions about visual cue stimulus temperature pairings, or no explicit instructions about the cue-stimulus pairs. A pain anxiety task was used to investigate the effects of explicit cueing on anticipatory anxiety, pain experience and electrophysiological responses. Participants who received explicit instructions about the cue-stimulus pairs (i.e., the relationship between the colour of the cue and the temperature of the associated stimuli) reported significantly higher subjective anxiety prior to the delivery of the thermal heat stimuli (p = .025, partial eta squared = .10). There were no effects of explicit cueing on subsequent pain intensity, unpleasantness, or the electrophysiological response to stimulus delivery. The perceived intensity and unpleasantness of the stimuli decreased across the blocks of the paradigm. In both groups anticipating the ambiguous cue elicited the largest change in electrophysiological arousal, indicating that not knowing the impending stimulus temperature led to increased arousal, compared to being certain of receiving a high temperature thermal stimulus (both p < .001). Perceived stimulus intensity varied between ambiguous and non-ambiguous cues, depending on the temperature of the stimulus. Together these findings highlight the impact and importance of explicit cueing and uncertainty in experimental pain studies, and how these factors influence the way healthy individuals perceive and react to noxious and innocuous thermal stimuli. PMID- 28832637 TI - A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction. AB - Metformin improves cardiovascular prognosis in patients with diabetes mellitus, compared to alternative glucose-lowering drugs, despite similar glycemic control. Direct cardiovascular protective properties have therefore been proposed, and studied in preclinical models of myocardial infarction. We now aim to critically assess the quality and outcome of these studies. We present a systematic review, quality assessment and meta-analysis of the effect of metformin in animal studies of experimental myocardial infarction. Through a comprehensive search in Pubmed and EMBASE, we identified 27 studies, 11 reporting on ex vivo experiments and 18 reporting on in vivo experiments. The primary endpoint infarct size as percentage of area at risk was significantly reduced by metformin in vivo (MD -18.11[-24.09, 12.14]) and ex vivo (MD -18.70[-25.39, -12.02]). Metformin improved the secondary endpoints left ventricular ejection fraction (LVEF) and left ventricular end systolic diameter. A borderline significant effect on mortality was observed, and there was no overall effect on cardiac hypertrophy. Subgroup analyses could be performed for comorbidity and timing of treatment (infarct size and mortality) and species and duration of ischemia (LVEF), but none of these variables accounted for significant amounts of heterogeneity. Reporting of possible sources of bias was extremely poor, including randomization (reported in 63%), blinding (33%), and sample size calculation (0%). As a result, risk of bias (assessed using SYRCLE's risk of bias tool) was unclear in the vast majority of studies. We conclude that metformin limits infarct-size and improves cardiac function in animal models of myocardial infarction, but our confidence in the evidence is lowered by the unclear risk of bias and residual unexplained heterogeneity. We recommend an adequately powered, high quality confirmatory animal study to precede a randomized controlled trial of acute administration of metformin in patients undergoing reperfusion for acute myocardial infarction. PMID- 28832638 TI - The potential impact of new Andean dams on Amazon fluvial ecosystems. AB - Increased energy demand has led to plans for building many new dams in the western Amazon, mostly in the Andean region. Historical data and mechanistic scenarios are used to examine potential impacts above and below six of the largest dams planned for the region, including reductions in downstream sediment and nutrient supplies, changes in downstream flood pulse, changes in upstream and downstream fish yields, reservoir siltation, greenhouse gas emissions and mercury contamination. Together, these six dams are predicted to reduce the supply of sediments, phosphorus and nitrogen from the Andean region by 69, 67 and 57% and to the entire Amazon basin by 64, 51 and 23%, respectively. These large reductions in sediment and nutrient supplies will have major impacts on channel geomorphology, floodplain fertility and aquatic productivity. These effects will be greatest near the dams and extend to the lowland floodplains. Attenuation of the downstream flood pulse is expected to alter the survival, phenology and growth of floodplain vegetation and reduce fish yields below the dams. Reservoir filling times due to siltation are predicted to vary from 106-6240 years, affecting the storage performance of some dams. Total CO2 equivalent carbon emission from 4 Andean dams was expected to average 10 Tg y-1 during the first 30 years of operation, resulting in a MegaWatt weighted Carbon Emission Factor of 0.139 tons C MWhr-1. Mercury contamination in fish and local human populations is expected to increase both above and below the dams creating significant health risks. Reservoir fish yields will compensate some downstream losses, but increased mercury contamination could offset these benefits. PMID- 28832639 TI - Single neuron recordings of bilinguals performing in a continuous recognition memory task. AB - We report the results of a bilingual continuous recognition memory task during which single- and multi-neuron activity was recorded in human subjects with intracranial microwire implants. Subjects (n = 5) were right-handed Spanish English bilinguals who were undergoing evaluation prior to surgery for severe epilepsy. Subjects were presented with Spanish and English words and the task was to determine whether any given word had been seen earlier in the testing session, irrespective of the language in which it had appeared. Recordings in the left and right hippocampus revealed notable laterality, whereby both Spanish and English items that had been seen previously in the other language (switch trials) triggered increased neural firing in the left hippocampus. Items that had been seen previously in the same language (repeat trials) triggered increased neural firings in the right hippocampus. These results are consistent with theories that propose roles of both the left- and right-hemisphere in real-time linguistic processing. Importantly, this experiment presents the first instance of intracranial recordings in bilinguals performing a task with switching demands. PMID- 28832640 TI - Restored nitric oxide bioavailability reduces the severity of acute-to-chronic transition in a mouse model of aristolochic acid nephropathy. AB - Aristolochic Acid (AA) nephropathy (AAN) is a progressive tubulointerstitial nephritis characterized by an early phase of acute kidney injury (AKI) leading to chronic kidney disease (CKD). The reduced nitric oxide (NO) bioavailability reported in AAN might contribute to renal function impairment and progression of the disease. We previously demonstrated that L-arginine (L-Arg) supplementation is protective in AA-induced AKI. Since the severity of AKI may be considered a strong predictor of progression to CKD, the present study aims to assess the potential benefit of L-Arg supplementation during the transition from the acute phase to the chronic phase of AAN. C57BL/6J male mice were randomly subjected to daily i.p. injections of vehicle or AA for 4 days. To determine whether renal AA induced injuries were linked to reduced NO production, L-Arg was added to drinking water from 7 days before starting i.p. injections, until the end of the protocol. Mice were euthanized 5, 10 and 20 days after vehicle or AA administration. AA-treated mice displayed marked renal injury and reduced NO bioavailability, while histopathological features of AAN were reproduced, including interstitial cell infiltration and tubulointerstitial fibrosis. L-Arg treatment restored renal NO bioavailability and reduced the severity of AA induced injury, inflammation and fibrosis. We concluded that reduced renal NO bioavailability contributes to the processes underlying AAN. Furthermore, L-Arg shows nephroprotective effects by decreasing the severity of acute-to-chronic transition in experimental AAN and might represent a potential therapeutic tool in the future. PMID- 28832641 TI - Departure time influences foraging associations in little penguins. AB - Recent studies have documented that little penguins (Eudyptula minor) associate at sea, displaying synchronised diving behaviour throughout a foraging trip. However, previous observations were limited to a single foraging trip where only a small number of individuals were simultaneously tracked. Consequently, it is not known whether coordinated behaviour is consistent over time, or what factors influence it. In the present study, breeding adults were concurrently instrumented with GPS and dive behaviour data loggers for at least 2 consecutive foraging trips during guard and post-guard stage at two breeding colonies (London Bridge and Gabo Island, south-eastern Australia) of contrasting population size (approximately 100 and 30,000-40,000, respectively). At both colonies, individuals were sampled in areas of comparable nesting density and spatial area. At London Bridge, where individuals use a short (23 m) common pathway from their nests to the shoreline, > 90% (n = 42) of birds displayed foraging associations and 53-60% (n = 20) maintained temporally consistent associations with the same conspecifics. Neither intrinsic (sex, size or body condition) nor extrinsic (nest proximity) factors were found to influence foraging associations. However, individuals that departed from the colony at a similar time were more likely to associate during a foraging trip. At Gabo Island, where individuals use a longer (116 m) pathway with numerous tributaries to reach the shoreline, few individuals (< 31%; n = 13) from neighbouring nests associated at sea and only 1% (n = 1) maintained associations over subsequent trips. However, data from animal-borne video cameras indicated individuals at this colony displayed foraging associations of similar group size to those at London Bridge. This study reveals that group foraging behaviour occurs at multiple colonies and the pathways these individuals traverse with conspecifics may facilitate opportunistic group formation and resulting in foraging associations irrespective of nesting proximity and other factors. PMID- 28832642 TI - The remnant of the European rabbit (Oryctolagus cuniculus) IgD gene. AB - Although IgD first appeared, along with IgM, in the cartilaginous fishes and has been retained throughout subsequent vertebrate evolution, it has been lost in a diverse group of vertebrate species. We previously showed that, unlike vertebrates that express IgD, the rabbit lacks an IgD (Cdelta) gene within 13.5 kb downstream of the IgM gene. We report here that, by conducting BLAST searches of rabbit Ig heavy chain genomic DNA with known mammalian IgD exons, we identified the remnant of the rabbit Cdelta gene approximately 21 kb downstream of the IgM gene. The remnant Cdelta locus lacks the deltaCH1 and hinge exons, but contains truncated deltaCH2 and deltaCH3 exons, as well as largely intact, but non-functional, secretory and transmembrane exons. In addition, we report that the Cdelta gene probably became non-functional in leporids at least prior to the divergence of rabbits and hares ~12 million years ago. PMID- 28832643 TI - Effect of naringin on gp120-induced injury mediated by P2X7 receptors in rat primary cultured microglia. AB - Human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein 120 has been shown to activate microglia, causing release of inflammatory and toxic factors. The P2X7 receptor, primarily expressed on microglia, is closely associated with inflammation. Naringin, a plant bioflavonoid, has anti-inflammatory and anti oxidative properties. We hypothesized that P2X7 receptor mediated gp120-induced injury in primary cultured microglia, and that naringin would have a protective effect. We showed that HIV-1 gp120 peptide (V3 loop, fragment 308-331) appeared to induce apoptosis of primary cultured microglia. However, there was a decrease of microglia apoptosis in gp120+naringin group compared with gp120 group. Using qPCR, Western blot, and immunofluorescence, we showed that gp120 stimulated expression of P2X7 mRNA and receptor protein, and this stimulation was inhibited by naringin. Treatment with gp120 increased concentrations of eATP, TNFalpha and IL-1beta, and these effects were inhibited by naringin. Taken together, these results suggested that gp120 contributed to microglial cell injury and neurotoxic activity by up-regulating expression of P2X7, in a naringin-protective manner. PMID- 28832644 TI - 3-O-trans-p-coumaroyl-alphitolic acid, a triterpenoid from Zizyphus jujuba, leads to apoptotic cell death in human leukemia cells through reactive oxygen species production and activation of the unfolded protein response. AB - 3-O-trans-p-coumaroyl-alphitolic acid (3OTPCA), a triterpenoid isolated from the plant Zizyphus jujuba (ZJ), is known to be cytotoxic to cancer cells; however, the molecular mechanism underlying 3OTPCA-induced cell death remains unknown. Here, we provide novel evidence that 3OTPCA induces apoptotic cell death in human leukemia cells. We found that 3OPTCA induces DNA fragmentation within 24 h after treatment in U937 cells, which was also observed in other leukemia cell lines, including Molt-4 and Jurkat cells. We then investigated other parameters involved in apoptosis, including phosphatidylserine externalization and caspase-3 cleavage in U937 cells treated with 3OTPCA. 3OTPCA caused significant DNA fragmentation, annexin-V binding, and caspase-3 cleavage, indicating that 3OTPCA exerts cytotoxicity through apoptosis induction. RNA-seq analysis revealed that the expression of transcripts associated with the unfolded protein response (UPR), such as spliced XBP-1 and CHOP, were up-regulated by 3OTPCA treatment. 3OTPCA induced UPR activation may be due to endoplasmic reticulum (ER) stress because both 3OTPCA and thapsigargin, an endoplasmic Ca2+ transport ATPase inhibitor, increased intracellular calcium levels. 3OTPCA down-regulated the expression of Bcl-2, a target of CHOP, and led to the loss of the mitochondrial membrane, indicating that the intrinsic (mitochondrial) apoptotic pathway was triggered by 3OTPCA, likely through UPR activation. Furthermore, we found that 3OTPCA induced superoxide anion generation and, following p38 MAPK phosphorylation, caspase-8 cleavage without affecting Fas expression. It also induced subsequent Bid cleavage, which may enhance the apoptosis triggered by the intrinsic pathway. These findings reveal for the first time that 3OTPCA induces apoptotic cell death through the generation of reactive oxygen species and activation of UPR. PMID- 28832645 TI - Microparticle and anti-influenza activity in human respiratory secretion. AB - Respiratory secretions, such as saliva and bronchoalveolar fluid, contain anti influenza activity. Multiple soluble factors have been described that exert anti influenza activity and are believed to be responsible for the anti-influenza activity in respiratory secretions. It was previously shown that a bronchial epithelial cell culture could produce exosome-like particles with anti-influenza activity. Whether such extracellular vesicles in respiratory secretions have anti influenza activity is unknown. Therefore, we characterized bronchoalveolar lavage fluid and found microparticles, which mostly stained positive for epithelial cell markers and both alpha2,3- and alpha2,6-linked sialic acid. Microparticles were purified from bronchoalveolar lavage fluid and shown to exhibit anti-influenza activity by a hemagglutination inhibition (HI) assay and a neutralization (NT) assay. In addition, physical binding between influenza virions and microparticles was demonstrated by electron microscopy. These findings indicate that respiratory microparticles containing viral receptors can exert anti-viral activity by probably trapping viral particles. This innate mechanism may play an important role in the defense against respiratory viruses. PMID- 28832646 TI - Serological and molecular tools to diagnose visceral leishmaniasis: 2-years' experience of a single center in Northern Italy. AB - The diagnosis of visceral leishmaniasis (VL) remains challenging, due to the limited sensitivity of microscopy, the poor performance of serological methods in immunocompromised patients and the lack of standardization of molecular tests. The aim of this study was to implement a combined diagnostic workflow by integrating serological and molecular tests with standardized clinical criteria. Between July 2013 and June 2015, the proposed workflow was applied to specimens obtained from 94 in-patients with clinical suspicion of VL in the Emilia-Romagna region, Northern Italy. Serological tests and molecular techniques were employed. Twenty-one adult patients (22%) had a confirmed diagnosis of VL by clinical criteria, serology and/or real-time polymerase chain reaction; 4 of these patients were HIV-positive. Molecular tests exhibited higher sensitivity than serological tests for the diagnosis of VL. In our experience, the rK39 immunochromatographic test was insufficiently sensitive for use as a screening test for the diagnosis of VL caused by L. infantum in Italy. However, as molecular tests are yet not standardized, further studies are required to identify an optimal screening test for Mediterranean VL. PMID- 28832647 TI - Transcriptional responses of ecologically diverse Drosophila species to larval diets differing in relative sugar and protein ratios. AB - We utilized three ecologically diverse Drosophila species to explore the influence of ecological adaptation on transcriptomic responses to isocaloric diets differing in their relative proportions of protein to sugar. Drosophila melanogaster, a cosmopolitan species that breeds in decaying fruit, exemplifies individuals long exposed to a Western diet higher in sugar, while the natural diet of the cactophilic D. mojavensis, is much lower in carbohydrates. Drosophila arizonae, the sister species of D. mojavensis, is largely cactophilic, but also utilizes rotting fruits that are higher in sugars than cacti. We exposed third instar larvae for 24 hours to diets either (1) high in protein relative to sugar, (2) diets with equal amounts of protein and sugar, and (3) diets low in protein but high in sugar. As we predicted, based upon earlier interspecific studies of development and metabolism, the most extreme differences in gene expression under different dietary conditions were found in D. mojavensis followed by D. arizonae. No differential expression among diets was observed for D. melanogaster, a species that survives well under all three conditions, with little impact on its metabolism. We suggest that these three species together provide a model to examine individual and population differences in vulnerability to lifestyle associated health problems such as metabolic syndrome and diabetes. PMID- 28832648 TI - Matrix metalloproteinases operate redundantly in Arabidopsis immunity against necrotrophic and biotrophic fungal pathogens. AB - Matrix metalloproteinases (MMPs) are evolutionarily conserved and multifunctional effector molecules playing pivotal roles in development and homeostasis. In this study we explored the involvement of the five Arabidopsis thaliana At-MMPs in plant defence against microbial pathogens. Expression of At2-MMP was most responsive to inoculation with fungi and a bacterial pathogen followed by At3-MMP and At5-MMP, while At1-MMP and At4-MMP were non-responsive to these biotic stresses. Loss-of-function mutants for all tested At-MMPs displayed increased susceptibility to the necrotrophic fungus Botrytis cinerea and double mutant at2,3-mmp and triple mutant at2,3,5-mmp plants developed even stronger symptoms. Consistent with this, transgenic Arabidopsis plants that expressed At2-MMP constitutively under the Cauliflower mosaic virus 35S promoter showed enhanced resistance to the necrotrophic pathogen. Similarly, resistance to the biotrophic Arabidopsis powdery mildew fungus Golovinomyces orontii was also compromised particularly in the at2,3-mmp / at2,3,5-mmp multiplex mutants, and increased in At2-MMP overexpressor plants. The degree of disease resistance of at-mmp mutants and At2-MMP overexpressor plants also correlated positively with the degree of MAMP-triggered callose deposition in response to the bacterial flagellin peptide flg22, suggesting that matrix metalloproteinases contribute to pattern-triggered immunity (PTI) in interactions of Arabidopsis with necrotrophic and biotrophic pathogens. PMID- 28832649 TI - How genetic data improve the interpretation of results of faecal glucocorticoid metabolite measurements in a free-living population. AB - Measurement of glucocorticoid metabolites (GCM) in faeces has become a widely used and effective tool for evaluating the amount of stress experienced by animals. However, the potential sampling bias resulting from an oversampling of individuals when collecting "anonymous" (unknown sex or individual) faeces has rarely been investigated. We used non-invasive genetic sampling (NIGS) to investigate potential interpretation errors of GCM measurements in a free-living population of mountain hares during the mating and post-reproductive periods. Genetic data improved the interpretation of results of faecal GCM measurements. In general GCM concentrations were influenced by season. However, genetic information revealed that it was sex-dependent. Within the mating period, females had higher GCM levels than males, but individual differences were more expressed in males. In the post-reproductive period, GCM concentrations were neither influenced by sex nor individual. We also identified potential pitfalls in the interpretation of anonymous faecal samples by individual differences in GCM concentrations and resampling rates. Our study showed that sex- and individual dependent GCM levels led to a misinterpretation of GCM values when collecting "anonymous" faeces. To accurately evaluate the amount of stress experienced by free-living animals using faecal GCM measurements, we recommend documenting individuals and their sex of the sampled population. In stress-sensitive and elusive species, such documentation can be achieved by using NIGS and for diurnal animals with sexual and individual variation in appearance or marked individuals, it can be provided by a detailed field protocol. PMID- 28832650 TI - Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice. AB - Acetaminophen (APAP) is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp) 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet) on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v) fructose in water (or regular water) for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes) was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold) higher basal glutathione levels and (~2 fold) lower basal (mRNA and activity) levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased alpha-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota. PMID- 28832651 TI - Inhibition of the bioavailability of heavy metals in sewage sludge biochar by adding two stabilizers. AB - Agricultural application of sewage sludge (SS) after carbonization is a plausible way for disposal. Despite its benefits of improving soil fertility and C sequestration, heavy metals contained in sewage sludge biochars (SSB) are still a concern. In this study, two types of heavy metal stabilizers were chosen: fulvic acid (FA) and phosphogypsum (with CaSO4, CS, as the main component). The two stabilizers were incorporated into SS prior to 350 degrees C carbonization for 1 h at the rates of 1%, 2%, or 4%. The obtained SSBs were then analyzed by Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). Total and available concentrations of four heavy metals, i.e., Zn, Pb, Cd, and Ni, in the SSBs were determined. In addition, a series of pot soil culture experiments was conducted to investigate the effects of stabilizers incorporation into SSB on heavy metal bioavailability and the uptake by plants (corn as an indicator) and plant biomass yield, with SS and SSB (no stabilizers) as controls. The results showed that incorporation of both FA and CS increased functional groups such as carboxyl, phenol, hydroxyl, amine and quinine groups in the SSBs. The percentage of heavy metals in sulfuric and oxidizable state and residual state of SSBs were significantly increased after carbonization, and hence the mobility of the heavy metals in SSBs was decreased. The introduction of the stabilizers (i.e., FA or CS) significantly lowered the total and available concentrations of Zn, Pb, Cd, and Ni. The reduction in available heavy metal concentration increased with incorporation rate of the stabilizers from 1% to 4%. In the treatments with FA or CS incorporated SSB, less heavy metals were taken up by plants and more plant biomass yields were obtained. The mitigating effects were more pronounced at higher rates of FA or CS stabilizer. These findings provide a way to lower bioavailability of heavy metals in SS or SSB for land application or horticulture as a peat substitute. PMID- 28832652 TI - Impact of post-dialysis calcium level on ex vivo rat aortic wall calcification. AB - OBJECTIVES: Vascular calcification is a frequent complication in chronic haemodialysis patients and is associated with adverse outcomes. Serum calcium and phosphate levels and imbalances in calcification regulators are thought to contribute to the process. In this regard, the dialysate calcium concentration is a modifiable tool for modulating the risk of vascular calcification. We explored pre- and post-dialysis phosphate and calcium concentrations in stable chronic haemodialysis patients treated by dialysis with the KDIGO-suggested 1.5 mmol/L calcium dialysate to investigate the effects on ex vivo calcification of rat aortic rings. APPROACH AND RESULTS: At the end of haemodialysis, mean serum calcium levels were increased in 88% of paired pre-/post-dialysis samples, while mean serum phosphate and parathyroid hormone levels were decreased. Rat aortic ring cultures grown at the same calcium and phosphate concentrations revealed that pre- and post-dialysis resulted in a similar degree of calcification. By contrast, haemodialysis with unchanged serum calcium resulted in a 5-fold reduction in calcium deposition. CONCLUSION: Dialysis with the widely prescribed 1.5 mmol/L calcium dose results in persistent high serum calcification potential in a sizable proportion of patients, driven by increased post-dialysis calcium concentration. This could potentially be mitigated by individualising dialysate calcium dosage based on pre-dialysis serum calcium levels. PMID- 28832653 TI - Association of physical activity with cardiovascular and renal outcomes and quality of life in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) are more readily prone to have impaired physical activity than the general population. The aim of this study is to examine the relationship between physical activity and adverse clinical outcomes and quality of life (QOL) in CKD. One hundred and sixty-one patients with CKD stages 1-5 was enrolled from February 2013 to September 2013 and followed up until June 2016. Physical activity was measured using high handgrip strength, 30-second chair stand, and 2-minute step. The QOL was assessed using the Taiwan version of the World Health Organization Quality of Life-BREF. Clinical outcomes included commencing dialysis, major adverse cardiovascular events (MACEs), and first hospitalization. Of all participants, 1 kgf increase in handgrip strength was significantly associated with 0.13 score increase in total scores of QOL and 0.05 score increase in physical domain of QOL in adjusted analysis. One time increase in 30-second chair stand was significantly correlated with 0.14 score increase in psychological domain of QOL. Over a mean follow-up period of 29.1+/-11.2 months, 37 (23.0%) reached commencing dialysis, 11(6.8%) had MACEs, and 50(31.1%) had first hospitalization. High handgrip strength (hazard ratio (HR): 0.89, 95% CI: 0.84-0.96) and high 2-minute step (HR: 0.04, 95% CI: 0.01-0.95) were significantly associated with decreased risk for commencing dialysis in multivariate analysis. Thirty-second chair-stand was negatively associated with MACEs (HR: 0.65, 95%CI: 0.47-0.89) and first hospitalization (HR: 0.84, 95%CI: 0.74-0.95). In conclusion, physical activity is a potential predictor of QOL and adverse clinical outcomes in patients with CKD. PMID- 28832654 TI - The bereavement experience of adolescents and early young adults with cancer: Peer and parental loss due to death is associated with increased risk of adverse psychological outcomes. AB - BACKGROUND: Adolescents commonly experience loss due to death, and perceived closeness to the deceased can often increase the intensity of bereavement. Adolescents and early young adult (AeYA) oncology patients may recall previous losses or experience new losses, possibly of other children with cancer, while coping with their own increased risk of mortality. The bereavement experiences of AeYA patients are not well described in the literature. METHODS AND FINDINGS: This analysis of bereavement sought to describe the prevalence and types of losses, the support following a death, and the impact of loss on AeYAs aged 13-21 years with malignant disease (or a hematologic disorder requiring allogeneic transplant). Participants were receiving active oncologic therapy or had completed therapy within the past 3 years. Participants completed a bereavement questionnaire and inventories on depression, anxiety, and somatization. The cross sectional study enrolled 153 AeYAs (95% participation), most (88%) of whom had experienced a loss due to death. The most commonly reported losses were of a grandparent (58%) or friend (37%). Peer deaths were predominantly cancer related (66%). Many participants (39%) self-identified a loss as "very significant." As loss significance increased, AeYAs were more likely to report that it had changed their life "a lot/enormously" (P<0.0001), that they were grieving "slowly or never got over it" (P<0.0001), and that they felt a need for more professional help (P = 0.026). Peer loss was associated with increased risk of adverse psychological outcomes (P = 0.029), as was parental loss (P = 0.018). CONCLUSIONS: Most AeYAs with serious illness experience the grief process as slow or ongoing. Peer or parental loss was associated with increased risk of negative mental health outcomes. Given the high prevalence of peer loss, screening for bereavement problems is warranted in AeYAs with cancer, and further research on grief and bereavement is needed in AeYAs with serious illness. PMID- 28832655 TI - Complement inhibition attenuates acute kidney injury after ischemia-reperfusion and limits progression to renal fibrosis in mice. AB - The complement system is an essential component of innate immunity and plays a major role in the pathogenesis of ischemia-reperfusion injury (IRI). In this study, we investigated the impact of human C1-inhibitor (C1INH) on the early inflammatory response to IRI and the subsequent progression to fibrosis in mice. We evaluated structural damage, renal function, acute inflammatory response, progression to fibrosis and overall survival at 90-days post-injury. Animals receiving C1INH prior to reperfusion had a significant improvement in survival rate along with superior renal function when compared to vehicle (PBS) treated counterparts. Pre-treatment with C1INH also prevented acute IL-6, CXCL1 and MCP-1 up-regulation, C5a release, C3b deposition and infiltration by neutrophils and macrophages into renal tissue. This anti-inflammatory effect correlated with a significant reduction in the expression of markers of fibrosis alpha smooth muscle actin, desmin and picrosirius red at 30 and 90 days post-IRI and reduced renal levels of TGF-beta1 when compared to untreated controls. Our findings indicate that intravenous delivery of C1INH prior to ischemic injury protects kidneys from inflammatory injury and subsequent progression to fibrosis. We conclude that early complement blockade in the context of IRI constitutes an effective strategy in the prevention of fibrosis after ischemic acute kidney injury. PMID- 28832656 TI - Involvement of insulin resistance in D-galactose-induced age-related dementia in rats: Protective role of metformin and saxagliptin. AB - Age-related dementia is one of the most devastating disorders affecting the elderly. Recently, emerging data suggest that impaired insulin signaling is the major contributor in the development of Alzheimer's dementia (AD), which is the most common type of senile dementia. In the present study, we investigated the potential therapeutic effects of metformin (Met) and saxagliptin (Saxa), as insulin sensitizing agents, in a rat model of brain aging and AD using D galactose (D-gal, 150 mg/kg/day, s.c. for 90 successive days). Six groups of adult male Wistar rats were used: normal, D-gal, Met (500 mg/kg/day, p.o), and Saxa (1 mg/kg/day, p.o) control groups, as well as D-gal/Met and D-gal/Sax treated groups. Impaired learning and memory function was observed in rats treated with D-gal using Morris water maze test. Biochemical and histopathological findings also revealed some characteristic changes of AD in the brain that include the increased content of acetylcholine, glutamate, and phosphorelated tau, as well as deposition of amyloid plaques and neurofibrillary tangles. Induction of insulin resistance in experimentally aged rats was evidenced by increased blood glycated hemoglobin, brain contents of insulin and receptors for advanced glycated end-products, as well as decreased brain insulin receptor level. Elevation of oxidative stress markers and TNF-alpha brain content was also demonstrated. Met and Saxa, with a preference to Met, restored the normal memory and learning functions in rats, improved D-gal-induced state of insulin resistance, oxidative stress and inflammation, and ameliorated the AD biochemical and histopathological alterations in brain tissues. Our findings suggest that D-gal model of aging results in a diminishing of learning and memory function by producing a state of impaired insulin signaling that causes a cascade of deleterious events like oxidative stress, inflammation, and tau hyper phosphorylation. Reversing of these harmful effects by the use of insulin sensitizing drugs like Met and Saxa suggests their involvement in alleviation insulin resistance as the underlying pathology of AD and hence their potential use as anti-dementia drugs. PMID- 28832657 TI - Inheritance analysis and mapping of quantitative trait loci (QTL) controlling individual anthocyanin compounds in purple barley (Hordeum vulgare L.) grains. AB - Anthocyanin-rich barley can have great potential in promoting human health and in developing nutraceuticals and functional foods. As different anthocyanin compounds have different antioxidant activities, breeding cultivars with pre designed anthocyanin compositions could be highly desirable. Working toward this possibility, we assessed and reported for the first time the genetic control of individual anthocyanin compounds in barley. Of the ten anthocyanins assessed, two, peonidin-3-glucoside (P3G) and cyanidin-3-glucoside (C3G), were major components in the purple pericarp barley genotype RUSSIA68. Quantitative trait locus (QTL) mapping showed that both anthocyanin compounds were the interactive products of two loci, one located on chromosome arm 2HL and the other on 7HS. However, the two different anthocyanin components seem to be controlled by different interactions between the two loci. The effects of the 7HS locus on P3G and C3G were difficult to detect without removing the effect of the 2HL locus. At least one copy of the 2HL alleles from the purple pericarp parent was required for the synthesis of P3G. This does not seem to be the case for the production of C3G which was produced in each of all the different allele combinations between the two loci. Typical maternal effect was also observed in the inheritance of purple pericarp grains in barley. The varied values of different compounds, coupled with their different genetic controls, highlight the need for targeting individual anthocyanins in crop breeding and food processing. PMID- 28832658 TI - Effects of equol on multiple K+ channels stably expressed in HEK 293 cells. AB - The present study investigated the effects of equol on cardiovascular K+ channel currents. The cardiovascular K+ channel currents were determined in HEK 293 cells stably expressing cloned differential cardiovascular K+ channels with conventional whole-cell patch voltage-clamp technique. We found that equol inhibited hKv1.5 (IC50: 15.3 MUM), hKv4.3 (IC50: 29.2 MUM and 11.9 MUM for hKv4.3 peak current and charge area, respectively), IKs (IC50: 24.7 MUM) and IhERG (IC50: 31.6 and 56.5 MUM for IhERG.tail and IhERG.step, respectively), but not hKir2.1 current, in a concentration-dependent manner. Interestingly, equol increased BKCa current with an EC50 of 0.1 MUM. It had no significant effect on guinea pig ventricular action potentials at concentrations of <=3 MUM. These results demonstrate that equol inhibits several cardiac K+ currents at relatively high concentrations, whereas it increases BKCa current at very low concentrations, suggesting that equol is a safe drug candidate for treating patients with cerebral vascular disorders. PMID- 28832659 TI - Racial disparities in cancer-related survival in patients with squamous cell carcinoma of the esophagus in the US between 1973 and 2013. AB - BACKGROUND: Esophageal cancer makes up approximately 1% of all diagnosed cancers in the US. There is a persistent disparity in incidence and cancer-related mortality rates among different races for esophageal squamous cell carcinoma (SCC). Most previous studies investigated racial disparities between black and white patients, occasionally examining disparities for Hispanic patients. Studies including Asians/Pacific Islanders (API) as a subgroup are rare. Our objective was to determine whether there is an association between race and cancer-related survival in patients with esophageal SCC. METHODS AND FINDINGS: This was a retrospective cohort study using the National Cancer Institute's Surveillance, Epidemiology, and End Result (SEER) database. The SEER registry is a national database that collects information on all incident cancer cases in 13 states of the United States and covers nearly 26% of the US population Patients aged 18 and over of White, Black, or Asian/Pacific Islander (API) race with diagnosed esophageal SCC from 1973 to 2013 were included (n = 13,857). To examine overall survival, Kaplan-Meier curves were estimated for each race and the log-rank test was used to compare survival distributions. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios with 95% confidence intervals. The final adjusted model controlled for sex, marital status, age at diagnosis, decade of diagnosis, ethnicity, stage at diagnosis, and form of treatment. Additional analyses stratified by decade of diagnosis were conducted to explore possible changes in survival disparities over time. After adjustment for potential confounders, black patients had a statistically significantly higher hazard ratio compared to white patients (HR 1.08; 95% confidence interval (CI) 1.03-1.13). However, API patients did not show a statistically significant difference in survival compared with white patients (HR 1.00; 95% CI 0.93-1.07). Patients diagnosed between 1973 and 1979 had twice the hazard of death compared to those diagnosed between 2000 and 2013 (HR 2.05, 95% CI 1.93-2.19). Patients diagnosed in 1980-1989 and 1990-1999 had had HRs of 1.59 (95% CI 1.51-1.68) and 1.33 (95% CI 1.26-1.41), respectively. After stratification according to decade of diagnosis, the HR for black patients compared with white patients was 1.14 (95% CI 1.02-1.29) in 1973-1979 and 1.12 (95% CI 1.03-1.23) in 1980-1989. These disparities were not observed after 1990; the HR for black patients compared with white patients was 1.03 (95% CI 0.93-1.13) in 1990-1999 and 1.05 (95% CI 0.96 1.15) in 2000-2013. CONCLUSIONS: Black patients with esophageal SCC were found to have a higher hazard of death compared to white and API patients. Survival disparities between races appear to have decreased over time. Future research that takes insurance status and other social determinants of health into account should be conducted to further explore possible disparities by race. PMID- 28832660 TI - A cross-sectional study of hepatitis C among people living with HIV in Cambodia: Prevalence, risk factors, and potential for targeted screening. AB - The epidemiology of hepatitis C in Cambodia is not well-known. We evaluated the prevalence of hepatitis C virus (HCV) and risk factors in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh to strengthen the evidence for suitable HCV testing strategies among people living with HIV (PLWH) in Cambodia. All consenting adult PLWH without a history of HCV treatment were tested for HCV between November 2014 and May 2016 according to the CDC algorithm (HCV antibody II electro-chemiluminescence immunoassay, followed by COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HCV PCR and INNO-LIA(r) HCV Score immunoblot end-testing). Genotyping was performed using the line probe assay Versant HCV genotype 2.0(r). The study enrolled a total of 3045 patients (43% males, median age: 42.5 years, <1% high risk). HCV antibodies were detected in 230 (7.6%; 95% confidence interval [CI] 6.6-8.5). Upon further testing, HCV antibodies were confirmed in 157 (5.2%; 95% CI 4.4-6.0) and active HCV in 106 (3.5%; 95% CI 2.8-4.2). Viremic prevalence peaked among men aged 50-55 years (7.3%) and women aged >55 years (11.2%). Genotype 1b (45%) and 6 (41%) were predominant. Coinfected patients had a higher aspartate-to-platelet ratio index, lower platelets, a lower HBsAg positivity rate and more frequent diabetes. Based on logistic regression, blood transfusion antecedents (adjusted odds ratio 2.9; 95% CI 1.7-4.9), unsafe medical injections (2.0; 1.3-3.2), and partner (3.4; 1.5-7.6) or household member (2.4; 1.3-3.2) with liver disease were independently associated with HCV in women. However, having a tattoo/scarification (1.9; 1.1-3.4) and household member (3.1; 1.3-7.3) with liver disease were associated with HCV in men. Thus, our study found intermediate endemicity of active hepatitis C in a large Cambodian HIV cohort and provides initial arguments for targeted HCV screening (>50 years, partner/household member with liver disease, diabetes, increased aspartate-to platelet ratio index) as efficient way forward. PMID- 28832661 TI - Graphettes: Constant-time determination of graphlet and orbit identity including (possibly disconnected) graphlets up to size 8. AB - Graphlets are small connected induced subgraphs of a larger graph G. Graphlets are now commonly used to quantify local and global topology of networks in the field. Methods exist to exhaustively enumerate all graphlets (and their orbits) in large networks as efficiently as possible using orbit counting equations. However, the number of graphlets in G is exponential in both the number of nodes and edges in G. Enumerating them all is already unacceptably expensive on existing large networks, and the problem will only get worse as networks continue to grow in size and density. Here we introduce an efficient method designed to aid statistical sampling of graphlets up to size k = 8 from a large network. We define graphettes as the generalization of graphlets allowing for disconnected graphlets. Given a particular (undirected) graphette g, we introduce the idea of the canonical graphette [Formula: see text] as a representative member of the isomorphism group Iso(g) of g. We compute the mapping [Formula: see text], in the form of a lookup table, from all 2k(k - 1)/2 undirected graphettes g of size k <= 8 to their canonical representatives [Formula: see text], as well as the permutation that transforms g to [Formula: see text]. We also compute all automorphism orbits for each canonical graphette. Thus, given any k <= 8 nodes in a graph G, we can in constant time infer which graphette it is, as well as which orbit each of the k nodes belongs to. Sampling a large number N of such k-sets of nodes provides an approximation of both the distribution of graphlets and orbits across G, and the orbit degree vector at each node. PMID- 28832662 TI - Oxygen-dependent regulation of tumor growth and metastasis in human breast cancer xenografts. AB - BACKGROUND: Tumor hypoxia is relevant for tumor growth, metabolism, resistance to chemotherapy and metastasis. We have previously shown that hyperoxia, using hyperbaric oxygen treatment (HBOT), attenuates tumor growth and shifts the phenotype from mesenchymal to epithelial (MET) in the DMBA-induced mammary tumor model. This study describes the effect of HBOT on tumor growth, angiogenesis, chemotherapy efficacy and metastasis in a triple negative MDA-MB-231 breast cancer model, and evaluates tumor growth using a triple positive BT-474 breast cancer model. MATERIALS AND METHODS: 5 x 105 cancer cells were injected s.c. in the groin area of NOD/SCID female mice. The BT-474 group was supplied with Progesterone and Estradiol pellets 2-days prior to tumor cell injection. Mice were divided into controls (1 bar, pO2 = 0.2 bar) or HBOT (2.5 bar, pO2 = 2.5 bar, 90 min, every third day until termination of the experiments). Treatment effects were determined by assessment of tumor growth, proliferation (Ki67 staining), angiogenesis (CD31-staining), metastasis (immunostaining), EMT markers (western blot), stromal components collagen type I, Itgb1 and FSP1 (immunostaining) and chemotherapeutic efficacy (5FU). RESULTS: HBOT significantly suppressed tumor growth in both the triple positive and negative tumors, and both MDA-MB-231 and BT-474 showed a decrease in proliferation after HBOT. No differences were found in angiogenesis or 5FU efficacy between HBOT and controls. Nevertheless, HBOT significantly reduced both numbers and total area of the metastastatic lesions, as well as reduced expression of N-cadherin, Axl and collagen type I measured in the MDA-MB-231 model. No change in stromal Itgb1 and FSP1 was found in either tumor model. CONCLUSION: Despite the fact that behavior and prognosis of the triple positive and negative subtypes of cancer are different, the HBOT had a similar suppressive effect on tumor growth, indicating that they share a common oxygen dependent anti-tumor mechanism. Furthermore, HBOT significantly reduced the number and area of metastatic lesions in the triple negative model as well as a significant reduction in the EMT markers N-cadherin, Axl and density of collagen type I. PMID- 28832663 TI - Effects of the hippocampus on the motor expression of augmented breaths. AB - Augmented breaths, also known as sighs, constitute the normal repertoire of breathing in freely behaving humans and animals. The breaths are believed to be generated by neurones in the preBotzinger complex but under modulatory influence from higher brain centres, particularly in the limbic system due to the strong correlations between the expression of emotional behaviours such as anxiety and the occurrence of augmented breaths. The current study examines the role of the hippocampus in the motor expression of augmented breaths, and also examines the characteristics of eupneic breaths surrounding a sigh before and after stimulating the hippocampus in urethane anaesthetised Sprague-Dawley rats. Neurochemical microstimulation using the excitatory amino acid, D,L-Homocysteic acid, was used to locate areas in the hippocampus with the potential to modulated the motor expression of augmented breaths. The CA1 neurone cluster of the ventral hippocampus was found to completely suppress the expression of augmented breaths without affecting the intrinsic properties of the breaths. A similar neurone cluster, but in the dorsal field of the hippocampus, was also investigated and found to have no effects over the expression of augmented breaths. The data supports the hypothesis that there is a structural or functional relationship between neurones of the ventral hippocampus and brainstem nuclei that control augmented breaths. The implications of these findings in the context of behaviours are discussed but with due consideration of experimental conditions. PMID- 28832664 TI - Neogene sharks and rays from the Brazilian 'Blue Amazon'. AB - The lower Miocene Pirabas Formation in the North of Brazil was deposited under influence of the proto-Amazon River and is characterized by large changes in the ecological niches from the early Miocene onwards. To evaluate these ecological changes, the elasmobranch fauna of the fully marine, carbonate-rich beds was investigated. A diverse fauna with 24 taxa of sharks and rays was identified with the dominant groups being carcharhiniforms and myliobatiforms. This faunal composition is similar to other early Miocene assemblages from the proto Carribbean bioprovince. However, the Pirabas Formation has unique features compared to the other localities; being the only Neogene fossil fish assemblage described from the Atlantic coast of Tropical Americas. Phosphate oxygen isotope composition of elasmobranch teeth served as proxies for paleotemperatures and paleoecology. The data are compatible with a predominantly tropical marine setting with recognized inshore and offshore habitats with some probable depth preferences (e.g., Aetomylaeus groups). Paleohabitat of taxa particularly found in the Neogene of the Americas (?Carcharhinus ackermannii, ?Aetomylaeus cubensis) are estimated to have been principally coastal and shallow waters. Larger variation among the few analyzed modern selachians reflects a larger range for the isotopic composition of recent seawater compared to the early Miocene. This probably links to an increased influence of the Amazon River in the coastal regions during the Holocene. PMID- 28832665 TI - Severe maternal morbidity in Zanzibar's referral hospital: Measuring the impact of in-hospital care. AB - OBJECTIVE: to analyse the impact of in-hospital care on severe maternal morbidity using WHO's near-miss approach in the low-resource, high mortality setting of Zanzibar's referral hospital. SETTING: Mnazi Mmoja Hospital, a tertiary care facility, in Zanzibar, Tanzania. METHODS: We identified all cases of morbidity and mortality in women admitted within 42 days after the end of pregnancy at Mnazi Mmoja Hospital in the period from April to October 2016. The severity of complications was classified using WHO's near-miss approach definitions: potentially life-threatening condition (PLTC), maternal near-miss (MNM) or maternal death (MD). Quality of in-hospital care was assessed using the mortality index (MI) defined as ratio between mortality and severe maternal outcome (SMO) where SMO = MD + MNM, cause-specific case facility rates and comparison with predicted mortality based on the Maternal Severity Index model. MAIN OUTCOMES: 5551 women were included. 569 (10.3%) had a potentially life-threatening condition and 65 (1.2%) a severe maternal outcome (SMO): 37 maternal near-miss cases and 28 maternal deaths. The mortality index was high at 0.43 and similar for women who developed a SMO within 12 hours of admission and women who developed a SMO after 12 hours. A standardized mortality ratio of 6.03 was found; six times higher than that expected in moderate maternal mortality settings given the same severity of cases. Obstetric haemorrhage was found to be the main cause of SMO. Ruptured uterus and admission to ICU had the highest case-fatality rates. Maternal death cases seemed to have received essential interventions less often. CONCLUSIONS: WHO's near-miss approach can be used in this setting. The high mortality index observed shows that in-hospital care is not preventing progression of disease adequately once a severe complication occurs. Almost one in two women experiencing life-threatening complications will die. This is six times higher than in moderate mortality settings. PMID- 28832666 TI - Cannabis use in male and female first episode of non-affective psychosis patients: Long-term clinical, neuropsychological and functional differences. AB - BACKGROUND: Numerous studies show the existence of a high prevalence of cannabis use among patients with psychosis. However, the differences between men and women who debut with a first episode of psychosis (FEP) regarding cannabis use have not been largely explored. The aim of this study was to identify the specific sex factors and differences in clinical evolution associated with cannabis use. METHOD: Sociodemographic characteristics at baseline were considered in our sample of FEP patients to find differences depending on sex and the use of cannabis. Clinical, functional and neurocognitive variables at baseline, 1-year, and 3-years follow-up were also explored. RESULTS: A total of 549 patients, of whom 43% (N = 236) were cannabis users, 79% (N = 186) male and 21% (N = 50) female, were included in the study. There was a clear relationship between being male and being a user of cannabis (OR = 5.6). Cannabis users were younger at illness onset. Longitudinal analysis showed that women significantly improved in all three dimensions of psychotic symptoms, both in the subgroup of cannabis users and in the non-users subgroup. Conversely, subgroups of men did not show improvement in the negative dimension. In cognitive function, only men presented a significant time by group interaction in processing speed, showing a greater improvement in the subgroup of cannabis users. CONCLUSION: Despite knowing that there is a relationship between cannabis use and psychosis, due to the high prevalence of cannabis use among male FEP patients, the results showed that there were very few differences in clinical and neurocognitive outcomes between men and women who used cannabis at the start of treatment compared to those who did not. PMID- 28832667 TI - Secretory expression and purification of Bacillus licheniformis keratinase in insect cells. AB - The keratinase (kerA) gene from Bacillus licheniformis PWD-1 was expressed and purified in insect cells. First, the sequence encoding Ker-His-Flag was designed based on the amino acid sequence of the protein and peptide and codon optimization in order to ensure the high expression in insect cells. In the next step, the synthetic DNA was inserted into the pUC57 vector and then sub-cloned in the pFastBacTM-1 donor vector by BamHI/HindIII restriction sites. The constructed vector was transformed to E. coli DH10BacTM cell to generate recombinant bacmid carrying Ker-His-Flag. Recombinant viruses were produced by infecting insect Spodoptera frugiperda (Sf9) cells with bacmid DNA and used for proteins production. Target proteins were purified from the cell supernatants by Ni2+-NTA affinity chromatography and evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. The purified product contained two peptides with molecular weights of 38 kDa and 30 kDa and had an optimal pH and temperature at 8.0 and 45 degrees C for keratinolytic activity, respectively. The final product had a specific activity of about 635 U/mg. In summary, we have demonstrated that the open reading frame containing recombinant Ker-His-Flag was expressed and secreted by leader peptide of mellittin from Apis mellitera in insect cells and affinity purification through 8His-Flag tag. It presents an alternative technology for producing keratinases. To our knowledge, it was the first report on the expression of functional keratinase from Bacillus licheniformis in insect cells system. PMID- 28832668 TI - Context-dependent medicinal effects of anabasine and infection-dependent toxicity in bumble bees. AB - BACKGROUND: Floral phytochemicals are ubiquitous in nature, and can function both as antimicrobials and as insecticides. Although many phytochemicals act as toxins and deterrents to consumers, the same chemicals may counteract disease and be preferred by infected individuals. The roles of nectar and pollen phytochemicals in pollinator ecology and conservation are complex, with evidence for both toxicity and medicinal effects against parasites. However, it remains unclear how consistent the effects of phytochemicals are across different parasite lineages and environmental conditions, and whether pollinators actively self-medicate with these compounds when infected. APPROACH: Here, we test effects of the nectar alkaloid anabasine, found in Nicotiana, on infection intensity, dietary preference, and survival and performance of bumble bees (Bombus impatiens). We examined variation in the effects of anabasine on infection with different lineages of the intestinal parasite Crithidia under pollen-fed and pollen-starved conditions. RESULTS: We found that anabasine did not reduce infection intensity in individual bees infected with any of four Crithidia lineages that were tested in parallel, nor did anabasine reduce infection intensity in microcolonies of queenless workers. In addition, neither anabasine nor its isomer, nicotine, was preferred by infected bees in choice experiments, and infected bees consumed less anabasine than did uninfected bees under no-choice conditions. Furthermore, anabasine exacerbated the negative effects of infection on bee survival and microcolony performance. Anabasine reduced infection in only one experiment, in which bees were deprived of pollen and post-pupal contact with nestmates. In this experiment, anabasine had antiparasitic effects in bees from only two of four colonies, and infected bees exhibited reduced-rather than increased-phytochemical consumption relative to uninfected bees. CONCLUSIONS: Variation in the effect of anabasine on infection suggests potential modulation of tritrophic interactions by both host genotype and environmental variables. Overall, our results demonstrate that Bombus impatiens prefer diets without nicotine and anabasine, and suggest that the medicinal effects and toxicity of anabasine may be context dependent. Future research should identify the specific environmental and genotypic factors that determine whether nectar phytochemicals have medicinal or deleterious effects on pollinators. PMID- 28832669 TI - TGC repeat expansion in the TCF4 gene increases the risk of Fuchs' endothelial corneal dystrophy in Australian cases. AB - Fuchs' endothelial corneal dystrophy (FECD) is a progressive, vision impairing disease. Common single nucleotide polymorphisms (SNPs) and a trinucleotide repeat polymorphism, thymine-guanine-cytosine (TGC), in the TCF4 gene have been associated with the risk of FECD in some populations. We previously reported association of SNPs in TCF4 with FECD risk in the Australian population. The aim of this study was to determine whether TGC repeat polymorphism in TCF4 is associated with FECD in the Australian population. In 189 unrelated Australian cases with advanced late-onset FECD and 183 matched controls, the TGC repeat polymorphism located in intron 3 of TCF4 was genotyped using a short tandem repeat (STR) assay. The repeat length was verified by direct sequencing in selected homozygous carriers. We found significant association between the expanded TGC repeat (>= 40 repeats) in TCF4 and advanced FECD (P = 2.58 * 10-22; OR = 15.66 (95% CI: 7.79-31.49)). Genotypic analysis showed that 51% of cases (97) compared to 5% of controls (9) were heterozygous or homozygous for the expanded repeat allele. Furthermore, the repeat expansion showed stronger association than the most significantly associated SNP, rs613872, in TCF4, with the disease in the Australian cohort. This and haplotype analysis of both the polymorphisms suggest that considering both the polymorphisms together rather than either of the two alone would better predict susceptibility to FECD in the Australian population. This is the first study to report association of the TGC trinucleotide repeat expansion in TCF4 with advanced FECD in the Australian population. PMID- 28832670 TI - Peripapillary retinal splitting visualized on OCT in glaucoma and glaucoma suspect patients. AB - PURPOSE: To identify the risk factors for development of peripapillary retinal splitting (schisis) in patients with glaucoma or suspicion of glaucoma. SETTING: Glaucoma Clinic, Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL. METHODS: In this institutional cross-sectional study, 495 patients (990 eyes) who had undergone spectral-domain optical coherence tomography (OCT Spectralis HRA-OCT, Heidelberg Engineering) optic nerve head (ONH) imaging and did not have identifiable optic nerve pits, pseudopits or coloboma were included. OCT scans were reviewed by two observers. MAIN OUTCOME MEASURES: Presence of peripapillary retinal splitting identified on OCT raster scans. RESULTS: Eleven of 990 glaucoma and glaucoma suspect eyes (1.1%) of 7 patients (2 females, 5 males, mean age 64.5 +/- 9.2 years) had peripapillary retinal splitting. Two of these 11 eyes had extension of the splitting into the macula but none to the fovea. Of these 11 patients, 2 (28.6%) were glaucoma suspects, 3 (42.9%) had primary open-angle glaucoma, 1 (14.3%) had chronic angle closure glaucoma and 1 (14.3%) had pigmentary glaucoma. 7/11 (63.6%) eyes had vitreous traction to the disc visualized on OCT and 6/11 eyes (54.5%) had beta zone peripapillary atrophy. CONCLUSIONS: We observed peripapillary retinal splitting in 1.1% of a series of 990 glaucoma and glaucoma-suspect eyes. Evidence of adherent vitreous with traction and peripapillary atrophy was found in a majority of the involved eyes. A comparison to an age and axial length matched cohort is required to determine if this is a condition that is associated with glaucoma. PMID- 28832671 TI - Pseudomonas aeruginosa ExlA and Serratia marcescens ShlA trigger cadherin cleavage by promoting calcium influx and ADAM10 activation. AB - Pore-forming toxins are potent virulence factors secreted by a large array of bacteria. Here, we deciphered the action of ExlA from Pseudomonas aeruginosa and ShlA from Serratia marcescens on host cell-cell junctions. ExlA and ShlA are two members of a unique family of pore-forming toxins secreted by a two-component secretion system. Bacteria secreting either toxin induced an ExlA- or ShlA dependent rapid cleavage of E-cadherin and VE-cadherin in epithelial and endothelial cells, respectively. Cadherin proteolysis was executed by ADAM10, a host cell transmembrane metalloprotease. ADAM10 activation is controlled in the host cell by cytosolic Ca2+ concentration. We show that Ca2+ influx, induced by ExlA or ShlA pore formation in the plasma membrane, triggered ADAM10 activation, thereby leading to cadherin cleavage. Our data suggest that ADAM10 is not a cellular receptor for ExlA and ShlA, further confirming that ADAM10 activation occurred via Ca2+ signalling. In conclusion, ExlA- and ShlA-secreting bacteria subvert a regulation mechanism of ADAM10 to activate cadherin shedding, inducing intercellular junction rupture, cell rounding and loss of tissue barrier integrity. PMID- 28832672 TI - White noise speech illusion and psychosis expression: An experimental investigation of psychosis liability. AB - BACKGROUND: An association between white noise speech illusion and psychotic symptoms has been reported in patients and their relatives. This supports the theory that bottom-up and top-down perceptual processes are involved in the mechanisms underlying perceptual abnormalities. However, findings in nonclinical populations have been conflicting. OBJECTIVES: The aim of this study was to examine the association between white noise speech illusion and subclinical expression of psychotic symptoms in a nonclinical sample. Findings were compared to previous results to investigate potential methodology dependent differences. METHODS: In a general population adolescent and young adult twin sample (n = 704), the association between white noise speech illusion and subclinical psychotic experiences, using the Structured Interview for Schizotypy-Revised (SIS R) and the Community Assessment of Psychic Experiences (CAPE), was analyzed using multilevel logistic regression analyses. RESULTS: Perception of any white noise speech illusion was not associated with either positive or negative schizotypy in the general population twin sample, using the method by Galdos et al. (2011) (positive: ORadjusted: 0.82, 95% CI: 0.6-1.12, p = 0.217; negative: ORadjusted: 0.75, 95% CI: 0.56-1.02, p = 0.065) and the method by Catalan et al. (2014) (positive: ORadjusted: 1.11, 95% CI: 0.79-1.57, p = 0.557). No association was found between CAPE scores and speech illusion (ORadjusted: 1.25, 95% CI: 0.88 1.79, p = 0.220). For the Catalan et al. (2014) but not the Galdos et al. (2011) method, a negative association was apparent between positive schizotypy and speech illusion with positive or negative affective valence (ORadjusted: 0.44, 95% CI: 0.24-0.81, p = 0.008). CONCLUSION: Contrary to findings in clinical populations, white noise speech illusion may not be associated with psychosis proneness in nonclinical populations. PMID- 28832673 TI - Consumption and direct costs of dental care for patients with head and neck cancer: A 16-year cohort study. AB - Patients with head and neck (H&N) cancer are commonly treated with surgery and/or radiotherapy, which can increase the risk of oral infection, dental caries, and periodontal disease. The present study investigated dental care consumption and costs in patient with H&N cancer before and after the cancer diagnosis. Data from Swedish regional and national registers were used to follow up dental care utilization and dental procedure costs. The analysis included 2,754 patients who had been diagnosed with H&N cancer (exposed cohort) in Stockholm County, Sweden, during 2000-2012 and 13,036 matched persons without cancer (unexposed cohort). The exposed cohort was sub-grouped into irradiated and non-irradiated patients for analysis. The exposed cohort underwent a moderately higher number of dental procedures per year than the unexposed cohort in both the year of the cancer diagnosis and the year after cancer diagnosis; in addition, these numbers were higher in the irradiated than in the non-irradiated subgroup of the exposed cohort. Dental care consumption and costs in the exposed cohort declined over time but remained at a slightly higher level than in the unexposed cohort over the long term (more than two years). Examinations and preventive procedures accounted for most of the higher consumption in the short term (2 years) and at the longer term follow-up. Swedish national insurance subsidized costs for dental treatment, which were highest in the irradiated subgroup and lowest in the unexposed cohort. Direct costs to the patient, however, were similar among the groups. Swedish national health insurance protects patients with H&N cancer from high dental expenditures. Further studies on the cost-effectiveness of preventive dental care for patients are needed. PMID- 28832674 TI - The aggressiveness of neurotrauma practitioners and the influence of the IMPACT prognostic calculator. AB - Published guidelines have helped to standardize the care of patients with traumatic brain injury; however, there remains substantial variation in the decision to pursue or withhold aggressive care. The International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic calculator offers the opportunity to study and decrease variability in physician aggressiveness. The authors wish to understand how IMPACT's prognostic calculations currently influence patient care and to better understand physician aggressiveness. The authors conducted an anonymous international, multidisciplinary survey of practitioners who provide care to patients with traumatic brain injury. Questions were designed to determine current use rates of the IMPACT prognostic calculator and thresholds of age and risk for death or poor outcome that might cause practitioners to consider withholding aggressive care. Correlations between physician aggressiveness, putative predictors of aggressiveness, and demographics were examined. One hundred fifty-four responses were received, half of which were from physicians who were familiar with the IMPACT calculator. The most frequent use of the calculator was to improve communication with patients and their families. On average, respondents indicated that in patients older than 76 years or those with a >85% chance of death or poor outcome it might be reasonable to pursue non-aggressive care. These thresholds were robust and were not influenced by provider or institutional characteristics. This study demonstrates the need to educate physicians about the IMPACT prognostic calculator. The consensus values for age and prognosis identified in our study may be explored in future studies aimed at reducing variability in physician aggressiveness and should not serve as a basis for withdrawing care. PMID- 28832675 TI - Time-course global proteome analyses reveal an inverse correlation between Abeta burden and immunoglobulin M levels in the APPNL-F mouse model of Alzheimer disease. AB - Alzheimer disease (AD) stands out amongst highly prevalent diseases because there is no effective treatment nor can the disease be reliably diagnosed at an early stage. A hallmark of AD is the accumulation of aggregation-prone amyloid beta peptides (Abeta), the main constituent of amyloid plaques. To identify Abeta dependent changes to the global proteome we used the recently introduced APPNL-F mouse model of AD, which faithfully recapitulates the Abeta pathology of the disease, and a workflow that interrogated the brain proteome of these mice by quantitative mass spectrometry at three different ages. The elevated Abeta burden in these mice was observed to cause almost no changes to steady-state protein levels of the most abundant >2,500 brain proteins, including 12 proteins encoded by well-confirmed AD risk loci. The notable exception was a striking reduction in immunoglobulin heavy mu chain (IGHM) protein levels in homozygote APPNL-F/NL-F mice, relative to APPNL-F/wt littermates. Follow-up experiments revealed that IGHM levels generally increase with age in this model. Although discovered with brain samples, the relative IGHM depletion in APPNL-F/NL-F mice was validated to manifest systemically in the blood, and did not extend to other blood proteins, including immunoglobulin G. Results presented are consistent with a cause-effect relationship between the excessive accumulation of Abeta and the selective depletion of IGHM levels, which may be of relevance for understanding the etiology of the disease and ongoing efforts to devise blood-based AD diagnostics. PMID- 28832677 TI - Fish oil mitigates myosteatosis and improves chemotherapy efficacy in a preclinical model of colon cancer. AB - BACKGROUND: This study aimed to assess whether feeding a diet containing fish oil was efficacious in reducing tumor- and subsequent chemotherapy-associated myosteatosis, and improving tumor response to treatment. METHODS: Female Fischer 344 rats were fed either a control diet for the entire study (control), or switched to a diet containing fish oil (2.0 g /100 g of diet) one week prior to tumor implantation (long term fish oil) or at the start of chemotherapy (adjuvant fish oil). Chemotherapy (irinotecan plus 5-fluorouracil) was initiated 2 weeks after tumor implantation (cycle-1) and 1 week thereafter (cycle-2). Reference animals received no tumor or treatment and only consumed the control diet. All skeletal muscle measures were conducted in the gastrocnemius. To assess myosteatosis, lipids were assessed histologically by Oil Red O staining and total triglyceride content was quantified by gas chromatography. Expression of adipogenic transcription factors were assessed at the mRNA level by real-time RT PCR. RESULTS: Feeding a diet containing fish oil significantly reduced tumor- and subsequent chemotherapy-associated increases in skeletal muscle neutral lipid (p<0.001) and total triglyceride content (p<0.03), and expression of adipogenic transcription factors (p<0.01) compared with control diet fed animals. The adjuvant fish oil diet was as effective as the long term fish oil diet in mitigating chemotherapy-associated skeletal muscle fat content, and in reducing tumor volume during chemotherapy compared with control fed animals (p<0.01). CONCLUSION: Long term and adjuvant fish oil diets are equally efficacious in reducing chemotherapy-associated myosteatosis that may be occurring by reducing expression of transcription factors involved in adipogenesis/lipogenesis, and improving tumor-response to chemotherapy in a neoplastic model. PMID- 28832676 TI - Genome-wide discovery of novel M1T1 group A streptococcal determinants important for fitness and virulence during soft-tissue infection. AB - The Group A Streptococcus remains a significant human pathogen causing a wide array of disease ranging from self-limiting to life-threatening invasive infections. Epithelium (skin or throat) colonization with progression to the subepithelial tissues is the common step in all GAS infections. Here, we used transposon-sequencing (Tn-seq) to define the GAS 5448 genetic requirements for in vivo fitness in subepithelial tissue. A near-saturation transposon library of the M1T1 GAS 5448 strain was injected subcutaneously into mice, producing suppurative inflammation at 24 h that progressed to prominent abscesses with tissue necrosis at 48 h. The library composition was monitored en masse by Tn-seq and ratios of mutant abundance comparing the output (12, 24 and 48 h) versus input (T0) mutant pools were calculated for each gene. We identified a total of 273 subcutaneous fitness (scf) genes with 147 genes (55 of unknown function) critical for the M1T1 GAS 5448 fitness in vivo; and 126 genes (53 of unknown function) potentially linked to in vivo fitness advantage. Selected scf genes were validated in competitive subcutaneous infection with parental 5448. Two uncharacterized genes, scfA and scfB, encoding putative membrane-associated proteins and conserved among Gram-positive pathogens, were further characterized. Defined scfAB mutants in GAS were outcompeted by wild type 5448 in vivo, attenuated for lesion formation in the soft tissue infection model and dissemination to the bloodstream. We hypothesize that scfAB play an integral role in enhancing adaptation and fitness of GAS during localized skin infection, and potentially in propagation to other deeper host environments. PMID- 28832678 TI - Recurrent triple-negative breast cancer (TNBC) tissues contain a higher amount of phosphatidylcholine (32:1) than non-recurrent TNBC tissues. AB - Triple-negative breast cancer (TNBC) is one of the breast cancer subtype that displays a high risk of early recurrence and short overall survival. Improvement of the prognosis of patients with TNBC requires identifying a predictive factor of recurrence, which would make it possible to provide beneficial personalized treatment. However, no clinically reliable predictive factor is currently known. In this study, we investigated the predictive factor of recurrence in TNBC using matrix-assisted laser desorption/ionization-imaging mass spectrometry for lipid profiling of breast cancer specimens obtained from three and six patients with recurrent and non-recurrent TNBC, respectively. The signal for phosphatidylcholine (PC) (32:1) at m/z 732.5 was significantly higher in the recurrence group compared to the non-recurrence group (P = 0.024). PC (32:1) was more abundant in the cancer epithelial area than it was in the surrounding stroma, suggesting that abnormal lipid metabolism was associated with malignant transformation. Our results indicate PC (32:1) as a candidate predictive factor of TNBC recurrence. A future prospective study investigating whether personalized therapy based on PC (32:1) intensity improves the prognosis of patients with TNBC is recommended. PMID- 28832679 TI - A comprehensive simulation study on classification of RNA-Seq data. AB - RNA sequencing (RNA-Seq) is a powerful technique for the gene-expression profiling of organisms that uses the capabilities of next-generation sequencing technologies. Developing gene-expression-based classification algorithms is an emerging powerful method for diagnosis, disease classification and monitoring at molecular level, as well as providing potential markers of diseases. Most of the statistical methods proposed for the classification of gene-expression data are either based on a continuous scale (eg. microarray data) or require a normal distribution assumption. Hence, these methods cannot be directly applied to RNA Seq data since they violate both data structure and distributional assumptions. However, it is possible to apply these algorithms with appropriate modifications to RNA-Seq data. One way is to develop count-based classifiers, such as Poisson linear discriminant analysis and negative binomial linear discriminant analysis. Another way is to bring the data closer to microarrays and apply microarray-based classifiers. In this study, we compared several classifiers including PLDA with and without power transformation, NBLDA, single SVM, bagging SVM (bagSVM), classification and regression trees (CART), and random forests (RF). We also examined the effect of several parameters such as overdispersion, sample size, number of genes, number of classes, differential-expression rate, and the transformation method on model performances. A comprehensive simulation study is conducted and the results are compared with the results of two miRNA and two mRNA experimental datasets. The results revealed that increasing the sample size, differential-expression rate and decreasing the dispersion parameter and number of groups lead to an increase in classification accuracy. Similar with differential-expression studies, the classification of RNA-Seq data requires careful attention when handling data overdispersion. We conclude that, as a count based classifier, the power transformed PLDA and, as a microarray-based classifier, vst or rlog transformed RF and SVM classifiers may be a good choice for classification. An R/BIOCONDUCTOR package, MLSeq, is freely available at https://www.bioconductor.org/packages/release/bioc/html/MLSeq.html. PMID- 28832680 TI - Predicting the length of hospital stay of post-acute care patients in Taiwan using the Chinese version of the continuity assessment record and evaluation item set. AB - BACKGROUND: The Chinese version of the Continuity Assessment Record and Evaluation (CARE-C) item set was developed to facilitate the assessment of post acute care (PAC) patients in Taiwan. Considering that the length of hospital stay (LOS) has a significant effect on the total healthcare cost, determining whether the CARE-C scores could predict the LOS of PAC patients is of great interest to the PAC providers. METHODS: This prospective trial included PAC patients with stroke or central nervous system injuries. The demographic data and CARE-C scores were collected after admission and before discharge. A multivariable stepwise linear regression model was used to identify the predictors of the LOS using age, sex, tube placement status, CARE-C component scores at admission, and score differences between admission and discharge as independent variables. RESULTS: This study included 178 patients (66 women and 112 men), with a mean age of 61.9 +/- 15.6 years. Indwelling urinary catheter placement status at admission (beta = 0.241, p = 0.002) was a positive predictor of the LOS, whereas age (beta = 0.189, p = 0.010), core transfer subscale score at admission (beta = -0.176, p = 0.020), and difference in continence subscale score (beta = -0.203, p = 0.008) were negative predictors of the LOS. The model explained 14% of the total variance. CONCLUSIONS: Indwelling urinary catheter placement status at admission, age, core transfer subscale score at admission, and difference in the CARE-C continence subscale score were identified as predictors of the LOS. The explanatory power of these predictors might be limited due to the regulations of Taiwan's National Health Insurance. PMID- 28832681 TI - The MHC class II antigen presentation pathway in human monocytes differs by subset and is regulated by cytokines. AB - Monocytes play a critical role in the innate and adaptive immune systems, performing phagocytosis, presenting antigen, and producing cytokines. They are a heterogeneous population that has been divided in humans into classical, intermediate, and non-classical subsets, but the roles of these subsets are incompletely understood. In this study, we investigated the expression patterns of MHC class II (MHCII) and associated molecules and find that the intermediate monocytes express the highest levels of the MHC molecules, HLA-DR (tested in n = 30 samples), HLA-DP (n = 30), and HLA-DQ (n = 10). HLA-DM (n = 30), which catalyzes the peptide exchange on the MHC molecules, is also expressed at the highest levels in intermediate monocytes. To measure HLA-DM function, we measured levels of MHCII-bound CLIP (class II invariant chain peptide, n = 23), which is exchanged for other peptides by HLA-DM. We calculated CLIP:MHCII ratios to normalize CLIP levels to MHCII levels, and found that intermediate monocytes have the lowest CLIP:MHCII ratio. We isolated the different monocyte subsets (in a total of 7 samples) and analyzed their responses to selected cytokines as model of monocyte activation: two M1-polarizing cytokines (IFNgamma, GM-CSF), an M2 polarizing cytokine (IL-4) and IL-10. Classical monocytes exhibit the largest increases in class II pathway expression in response to stimulatory cytokines (IFNgamma, GM-CSF, IL-4). All three subsets decrease HLA-DR levels after IL-10 exposure. Our findings argue that intermediate monocytes are the most efficient constitutive antigen presenting subset, that classical monocytes are recruited into an antigen presentation role during inflammatory responses and that IL-10 negatively regulates this function across all subsets. PMID- 28832683 TI - Sex-specific rejection in mate-guarding pair formation in the intertidal copepod, Tigriopus californicus. AB - Securing a potential mate is one of the most important processes in sexual reproduction of animals. Intertidal copepods of the genus Tigriopus show mate guarding behavior where a male captures a female and continues to clasp her for up to two weeks prior to copulation. Although these copepods form a mate-guarding pair between a male and a female with high accuracy, interactions between the sexes in pair formation have not been well described and the mechanism allowing successful male-female pair formation is not yet understood. In this study, we performed experiments with Tigriopus californicus to analyze the behavior of both a capturer (male) and a captured individual (female or male) in formation of a guarding pair. While capturer males were attracted by both females and males, capture of virgin males was terminated in a significantly shorter time than that of virgin females. However, when presented freshly killed females or males, regardless of the sex of the body, capturer males continued to clasp the body for a comparable time as in an attempt on a living female. Our results suggest that a sex-specific rejection signal actively sent by captured males prevents male-male pair formation. Experiments also suggest that mated females reject an attempt of pair formation. To our knowledge, this is the first study to suggest involvement of active rejection by a captured individual in facilitation of reproductively successful male-female guarding pair formation in the genus Tigriopus. PMID- 28832682 TI - Ancestry as a potential modifier of gene expression in breast tumors from Colombian women. AB - BACKGROUND: Hispanic/Latino populations are a genetically admixed and heterogeneous group, with variable fractions of European, Indigenous American and African ancestries. The molecular profile of breast cancer has been widely described in non-Hispanic Whites but equivalent knowledge is lacking in Hispanic/Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian women was Luminal B as defined by St. Gallen 2013 criteria. In this study we explored ancestry-associated differences in molecular profiles of Luminal B tumors among these highly admixed women. METHODS: We performed whole-transcriptome RNA-seq analysis in 42 Luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to Luminal subtype and to the proportion of European and Indigenous American ancestry and performed differential expression analysis comparing Luminal B against Luminal A tumors according to the assigned ancestry groups. RESULTS: We found 5 genes potentially modulated by genetic ancestry: ERBB2 (log2FC = 2.367, padj<0.01), GRB7 (log2FC = 2.327, padj<0.01), GSDMB (log2FC = 1.723, padj<0.01, MIEN1 (log2FC = 2.195, padj<0.01 and ONECUT2 (log2FC = 2.204, padj<0.01). In the replication set we found a statistical significant association between ERBB2 expression with Indigenous American ancestry (p = 0.02, B = 3.11). This association was not biased by the distribution of HER2+ tumors among the groups analyzed. CONCLUSIONS: Our results suggest that genetic ancestry in Hispanic/Latina women might modify ERBB2 gene expression in Luminal tumors. Further analyses are needed to confirm these findings and explore their prognostic value. PMID- 28832684 TI - Relationship between serum calprotectin (S100A8/9) and clinical, laboratory and ultrasound parameters of disease activity in rheumatoid arthritis: A large cohort study. AB - BACKGROUND: Calprotectin may be a sensitive biomarker of rheumatoid arthritis (RA) disease activity. OBJECTIVES: In the current study, we investigated whether calprotectin is a better biomarker than CRP for predicting clinical activity and ultrasound parameters in patients with RA. METHODS: A total of 160 patients with RA underwent clinical (swollen joint count-SJC, tender joint count-TJC, Disease Activity Score-DAS28, Clinical Disease Activity Index-CDAI, and simplified Disease Activity Index-SDAI) and ultrasound (German US7) examination. Clinical and laboratory measures were correlated with ultrasound findings using Spearman's correlation coefficient. Differences in serum calprotectin levels in patients with variable disease activity according to the DAS28-ESR and CDAI scores were assessed using ANOVA. Multivariate regression analysis was used to determine the predictive values of calprotectin, CRP and SJC for CDAI and PD US synovitis scores. RESULTS: Serum calprotectin was significantly associated with DAS28-ESR (r = 0.321, p<0.001), DAS28-CRP (r = 0.346, p<0.001), SDAI (r = 0.305, p<0.001), CDAI (r = 0.279, p<0.001) scores and CRP levels (r = 0.556, p<0.001). Moreover, calprotectin was significantly correlated with GS (r = 0.379, p<0.001) and PD synovitis scores (r = 0.419, p<0.001). The multivariate regression analysis showed that calprotectin is a better predictor of the CDAI score and PD US synovitis than CRP. CONCLUSIONS: The results of this study support an additional role of calprotectin in assessing inflammatory activity in patients with RA. PMID- 28832685 TI - Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival. AB - BACKGROUND: Type 1 diabetes is an autoimmune disease that destroys insulin producing beta cells in the pancreas. Pancreatic islet transplantation could be an effective treatment option for type 1 diabetes once several issues are resolved, including donor shortage, prevention of islet necrosis and loss in pre- and post-transplantation, and optimization of immunosuppression. This study seeks to determine the cause of necrotic loss of isolated islets to improve transplant efficiency. METHODOLOGY: The oxygen tension inside isolated human islets of different sizes was simulated under varying oxygen environments using a computational in silico model. In vitro human islet viability was also assessed after culturing in different oxygen conditions. Correlation between simulation data and experimentally measured islet viability was examined. Using these in vitro viability data of human islets, the effect of islet diameter and oxygen tension of the culture environment on islet viability was also analyzed using a logistic regression model. PRINCIPAL FINDINGS: Computational simulation clearly revealed the oxygen gradient inside the islet structure. We found that oxygen tension in the islet core was greatly lower (hypoxic) than that on the islet surface due to the oxygen consumption by the cells. The hypoxic core was expanded in the larger islets or in lower oxygen cultures. These findings were consistent with results from in vitro islet viability assays that measured central necrosis in the islet core, indicating that hypoxia is one of the major causes of central necrosis. The logistic regression analysis revealed a negative effect of large islet and low oxygen culture on islet survival. CONCLUSIONS/SIGNIFICANCE: Hypoxic core conditions, induced by the oxygen gradient inside islets, contribute to the development of central necrosis of human isolated islets. Supplying sufficient oxygen during culture could be an effective and reasonable method to maintain isolated islets viable. PMID- 28832686 TI - Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma. AB - To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1+/-1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7+/-1.8) in control subjects. The patients with GRS>=12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP>=22mmHg) compared with all patients. The IOP related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation. PMID- 28832687 TI - Nuclear envelope-distributed CD147 interacts with and inhibits the transcriptional function of RING1 and promotes melanoma cell motility. AB - Melanoma accounts for nearly 80% of all deaths associated with skin cancer.CD147 plays a very important role in melanoma progression and the expression level may correlate with tumor malignancy. RING1 can bind DNA and act as a transcriptional repressor, play an important role in the aggressive phenotype in melanoma. The interactions between CD147 and RING1 were identified with a yeast two-hybrid and RING1 interacted with CD147 through the transmembrane domain. RING1 inhibits CD147's capability promoting melanoma cell migration. In conclusion, the study identified novel interactions between CD147 and RING1, recovered CD147 nuclear envelope distribution in melanoma cells, and suggested a new mechanism underlying how cytoplasmic CD147 promotes melanoma development. PMID- 28832688 TI - Evaluation of changes to the Rickettsia rickettsii transcriptome during mammalian infection. AB - The lifecycle of Rickettsia rickettsii includes infection of both mammalian and arthropod hosts, with each environment presenting distinct challenges to survival. As such, these pathogens likely have distinctive transcriptional strategies for infection of each host. Herein, we report the utilization of next generation sequencing (RNAseq) and bioinformatic analysis techniques to examine the global transcriptional profile of R. rickettsii within an infected animal, and to compare that data to transcription in tissue culture. The results demonstrate substantial R. rickettsii transcriptional alteration in vivo, such that the bacteria are considerably altered from cell culture. Identification of significant transcriptional changes and validation of RNAseq by quantitative PCR are described with particular emphasis on known antigens and suspected virulence factors. Together, these results suggest that transcriptional regulation of a distinct cohort of genes may contribute to successful mammalian infection. PMID- 28832689 TI - Incidence and severity of acute mountain sickness and associated symptoms in children trekking on Xue Mountain, Taiwan. AB - BACKGROUND: Acute mountain sickness (AMS) occurs in non-acclimatized people after an acute ascent to an altitude of 2,500 m or higher. The aim of this study was to examine the incidence and severity of AMS and associated symptoms in children. METHODS: The prospective observational study included 197 healthy, non acclimatized 11 and 12-year-old children trekking the round-trip from the trailhead to the summit of Xue Mountain, Taiwan (2,179 m to 3,886 m) over 3 days. AMS was evaluated at Qika Hut (2,460 m) on Day 1, at Sanliujiu Hut on Day 2 (3,100 m), and at the same altitude (3,100 m) after reaching the summit on Day 3. We used the Lake Louise Score (LLS) to diagnose AMS and record daily AMS associated symptoms. We gave acetazolamide to children with mild to moderate AMS. Dexamethasone was reserved for individuals suffering from severe AMS. Acetaminophen was administrated to children with headache, and metoclopramide for those with nausea or vomiting. RESULTS: There were 197 subjects eligible for analysis. The overall incidence of AMS was 40.6%, which was higher in males and in subjects with a higher body mass index (BMI) (p < 0.05). The prevalence of AMS on Day 1 was 5.6%, which was significantly lower than that on Day 2 (29.4%) and Day 3 (23.4%). The mean LLS of all subjects was 1.77 +/- 2.08. The overall incidence of severe AMS (LLS >= 5) was 12.5%. The mean LLS of the AMS group (3.02 +/- 2.46) was significantly higher than that of the non-AMS group (0.92 +/- 1.16, p < 0.001). Among the AMS group, the mean LLS was 1.00 +/- 1.55 on Day 1, 4.09 +/ 1.97 on Day 2, and 3.98 +/- 2.42 on Day 3. The most common symptom was sleep disturbance followed by dizziness, and headache. The prevalence of headache was 46.2% on Day 2 at 3,100 m, and 31.3% on Day 3 at the same altitude after climbing the summit (3,886 m). Males experienced significantly more headache and fatigue than females (p < 0.05). The LLS and prevalence of all AMS symptoms were significantly higher in the AMS than the non-AMS group (p < 0.05). CONCLUSIONS: The AMS incidence among children trekking to Xue Mountain was 40.6%. AMS is common and mostly manifests as mild symptoms. Gender (male) and a higher BMI could be considered two independent risk factors of higher AMS incidence. Sleep disturbance is the most common symptom, and the lower prevalence of headache on Day 3 may be due to the effects of medication and/or acclimatization. PMID- 28832690 TI - Development of a fluorescent reporter system for monitoring ER stress in Chinese hamster ovary cells and its application for therapeutic protein production. AB - Mammalian cell expression systems have become a workhorse for the production of biotherapeutic proteins. As such, there is an ever increasing demand for higher productivity from these expression platforms to reduce manufacturing costs. While great advances have been made in the optimization of culture conditions and cell line selection to improve productivity, protein mis-folding remains a common limitation to high levels of production of therapeutic proteins. Accumulation of mis- and unfolded protein in the endoplasmic reticulum (ER) causes ER stress and initiates the unfolded protein response (UPR) that results in an activation of protein folding machinery, translation attenuation in an effort to proper folding of the newly synthesized peptides or may even lead to apoptosis if the correct folding is not restored. As a result, UPR associated apoptosis often results in lower protein expression. To better understand the molecular mechanisms in these pathways, we developed a reporter construct that detects Inositol-requiring enzyme 1 (IRE1)-alpha mediated splicing of X-box binding protein 1 (XBP1) to monitor the course of UPR activation in cell lines expressing monoclonal antibodies. Using this reporter we observed a clear activation of UPR in cells treated with known ER stress causing pharmacological agents, such as Tunicamycin (Tm) and Thapsigargin (Tg), as well as in stable IgG expressing cells during fed batch cultures. Furthermore, we developed a stress metric that we term as ER stress index (ERSI) to gauge basal ER stress in cells which we used as a predictive tool for isolation of high IgG expressing cell lines. This reporter system, with its ability to monitor the stress involved in recombinant protein expression, has utility to assist in devising engineering strategies for improved production of biotherapeutic drugs. PMID- 28832691 TI - Synthesis of borasiloxanes by oxidative hydrolysis of silanes and pinacolborane using Cu3(BTC)2 as a solid catalyst. AB - A convenient method for the synthesis of borasiloxanes from silanes and pinacolboranes using Cu3(BTC)2 as a heterogeneous catalyst in acetonitrile at 70 degrees C is reported. This procedure is more convenient than Ru and Pd based homogeneous catalysts because it avoids the use of noble metals, easy handling of starting materials and the catalyst can be reused. PMID- 28832693 TI - Artificial hagfish protein fibers with ultra-high and tunable stiffness. AB - Stiff fibers are used as reinforcing phases in a wide range of high-performance composite materials. Silk is one of the most widely studied bio-fibers, but alternative materials with specific advantages are also being explored. Among these, native hagfish (Eptatretus stoutii) slime thread is an attractive protein based polymer. These threads consist of coiled-coil intermediate filaments (IFs) as nano-scale building blocks, which can be transformed into extended beta-sheet containing chains upon draw-processing, resulting in fibers with impressive mechanical performance. Here, we report artificial hagfish threads produced by recombinant protein expression, which were subsequently self-assembled into coiled-coil nanofilaments, concentrated, and processed into beta-sheet-rich fibers by a "picking-up" method. These artificial fibers experienced mechanical performance enhancement during draw-processing. We exploited the lysine content to covalently cross-link the draw-processed fibers and obtained moduli values (E) in tension as high as ~20 GPa, which is stiffer than most reported artificial proteinaceous materials. PMID- 28832692 TI - Microfluidics for exosome isolation and analysis: enabling liquid biopsy for personalized medicine. AB - Exosomes, the smallest sized extracellular vesicles (?30-150 nm) packaged with lipids, proteins, functional messenger RNAs and microRNAs, and double-stranded DNA from their cells of origin, have emerged as key players in intercellular communication. Their presence in bodily fluids, where they protect their cargo from degradation, makes them attractive candidates for clinical application as innovative diagnostic and therapeutic tools. But routine isolation and analysis of high purity exosomes in clinical settings is challenging, with conventional methods facing a number of drawbacks including low yield and/or purity, long processing times, high cost, and difficulties in standardization. Here we review a promising solution, microfluidic-based technologies that have incorporated a host of separation and sensing capabilities for exosome isolation, detection, and analysis, with emphasis on point-of-care and clinical applications. These new capabilities promise to advance fundamental research while paving the way toward routine exosome-based liquid biopsy for personalized medicine. PMID- 28832694 TI - MOFs modeling and theory: general discussion. PMID- 28832695 TI - Effects of flexibility and electrostatic interactions on the coupled binding folding mechanisms of Chz.core and H2A.z-H2B. AB - The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. Although there are several studies on the binding process of Chz.core, the detailed coupled binding-folding processes are still elusive. In this study, we explored the coupled binding-folding mechanism and the effect of flexibility by continuously monitoring the flexibility degree of Chz.core. We applied an all-atom structure based model (SBM), which takes advantage of providing both backbone and sidechain information about the conformational changes of Chz.core during binding. We presented a somewhat different "fly-casting" picture that the long IDP can undergo a tertiary stretching and bending with larger capture radii than ordered proteins. Our results suggest that the higher flexibility of Chz.core contributes to the shorter times for capturing events, leading to higher recognition efficiencies. In addition, compared to the ordered proteins, the high flexibility of the intrinsically disordered protein enables Chz.core to have a lower binding barrier and a faster association rate, which are favorable for the binding process to its partner H2A.z-H2B. PMID- 28832696 TI - Sigmatropic proton shifts: a quantum chemical study. AB - A quantum chemical study of [1,j] sigmatropic proton shifts in polyenyl anions and related conjugated systems has been performed. We found that the Woodward Hoffmann rules can be applied to understand the stereochemical outcome of these sigmatropic rearrangements, showing that [1,j] sigmatropic proton shift occurs antarafacially when j = 4n + 2, while suprafacial proton shift is symmetry allowed when j = 4n. The activation barriers for [1,j] proton shifts in polyenyl anions CjHj+3- are 48.2 (j = 2), 32.8 (j = 4), 21.0 (j = 6), 40.5 (j = 8), and 49.1 (j = 10) kcal mol-1, respectively. This trend can be explained by the trade off between stereoelectronic requirement and ring strain in the proton shift transition structure. Among these reactions, only the [1,6] proton shift with the lowest activation barrier can occur intramolecularly under mild reaction conditions. The others are unlikely to take place in a direct manner. Consequently, proton shuttles are generally required to facilitate these sigmatropic proton shifts through a protonation/deprotonation mechanism. PMID- 28832697 TI - New directions in gas sorption and separation with MOFs: general discussion. PMID- 28832698 TI - Theoretical study on the reaction mechanism of hydrogenation of furfural to furfuryl alcohol on Lewis acidic BEA zeolites: effects of defect structure and tetravalent metals substitution. AB - Furfural acquired from agricultural sources is receiving extensive attention in the petrochemical industry as it offers an alternative route to generate more valuable hydrocarbon compounds. Herein, we investigate the furfural hydrogenation to furfuryl alcohol catalyzed by Lewis acidic BEA zeolites at the molecular level by means of the M06-L density functional theory. The mechanistic pictures in the catalytic procedure are revealed. The possible reaction pathways are considered to proceed via either concerted or stepwise mechanisms. With the contribution of zeolite oxygen bridging for the H-H splitting, the rate determining step activation barrier for the stepwise mechanism is 14.7 kcal mol-1 lower than that for the concerted mechanism. The stepwise reaction therefore seems to be favored compared to the concerted one. The catalytic effect of the defect zeolite framework on the stepwise mechanism is also investigated. The activation energy for the stepwise rate-determining step over this site is significantly lower than the corresponding step over the perfect one by 14.1 kcal mol-1. Finally, the catalytic activity of tetravalent metal centers (Sn, Ge, Zr and Hf) substituted in BEA is also preliminarily compared and it is found to follow the order of Hf > Zr > Sn > Ge based on activation energies and the reaction rate. The difference in the activation energy can be traced back to the difference in the charge transfer from the catalytic site to the adsorbed molecules. PMID- 28832707 TI - ERRATUM. AB - [This corrects the article doi: 10.5935/0101-2800.20170022]. PMID- 28832708 TI - Resilience of the health team in caring for people with mental disorders in a psychiatric hospital. AB - OBJECTIVE: Evaluating and understanding the resilience process of the health team in caring for people with mental disorders in a psychiatric hospital. METHOD: A mixed-method study with concomitant triangulation of data from a cross-sectional study, with health professionals, and Grounded Theory in the data. Quantitative data were collected using the Resilience Scale and analyzed using descriptive and inferential statistics. Qualitative data were obtained from interviews and analyzed using initial and focused coding. RESULTS: 40 health professionals participated in the study. Mean responses of the participants in the resilience scale were 99.80 +/- 12.86 points, with a minimum of 35 and a maximum of 114 points. From the qualitative data, we can highlight the professionals' commitment in developing competencies in caring for people with mental disorders; valorization of teamwork and positive impact on work for the re-signification of the meaning of life. CONCLUSION: Understanding this process of resilience enables developing strategies to improve the quality of life of workers in psychiatric hospitals. OBJETIVO: Avaliar e compreender o processo de resiliencia da equipe de saude no cuidado a pessoas com transtornos mentais em um hospital psiquiatrico. METODO: Estudo de metodo misto com triangulacao concomitante de dados de um estudo transversal, com profissionais de saude, e uma Teoria Fundamentada nos Dados. Os dados quantitativos foram coletados a partir da Escala de Resiliencia e analisados por meio de estatistica descritiva e inferencial. Os dados qualitativos foram obtidos a partir de entrevistas e analisados mediante codificacao inicial e focalizada. Resultados:: Participaram da pesquisa 40 profissionais de saude. Na escala de resiliencia, a media das respostas dos participantes foi 99,80+/-12,86 pontos, o minimo foi de 35 e o maximo de 114 pontos. Nos dados qualitativos, destacaram-se o empenho dos profissionais para o desenvolvimento de competencias para o cuidado de pessoas com transtornos mentais, a valorizacao do trabalho em equipe e o impacto positivo no trabalho para a ressignificacao do sentido da vida. Conclusao: O entendimento desse processo de resiliencia possibilita o desenvolvimento de estrategias para a melhoria da qualidade de vida dos trabalhadores que atuam em hospitais psiquiatricos. PMID- 28832706 TI - Behavior of lung ultrasound findings during spontaneous breathing trial. AB - OBJECTIVE: We aimed to investigate a potential association between B-lines and weaning failure. METHODS: Fifty-seven subjects eligible for ventilation liberation were enrolled. Patients with tracheostomy were excluded. Lung ultrasound assessments of six thoracic zones were performed immediately before and at the exnd of the spontaneous breathing trial. B-predominance was defined as any profile with anterior bilateral B-pattern. Patients were followed up to 48 hours after extubation. RESULTS: Thirty-eight individuals were successfully extubated; 11 failed the spontaneous breathing trial and 8 needed reintubation within 48 hours of extubation. At the beginning of the T-piece trial, B-pattern or consolidation was already found at the lower and posterior lung regions in more than half of the individuals and remained non-aerated at the end of the trial. A trend toward loss of lung aeration during spontaneous breathing trials was observed only in the spontaneous breathing trial-failure group (p = 0.07), and there was higher B-predominance at the end of the trial (p = 0.01). CONCLUSION: A loss of lung aeration during the spontaneous breathing trial in non dependent lung zones was demonstrated in subjects who failed to wean. PMID- 28832709 TI - Human capital in the nursing management of hospitals. AB - OBJECTIVE: To analyze how the components of human capital are used in the nursing management of hospital organizations. METHOD: This was an exploratory and qualitative study. Data collection took place between October 2014 and May 2015 using semi-structured interviews. The data were analyzed according to content analysis. RESULTS: Twelve nurse managers participated. The components of human capital used by the nurses in personnel management were: during the hiring process, when requiring specialized education in the field and prior professional experience; when retaining talents with promotion strategies; in building capacities of professionals through support and training; and in collective work to construct processes and outcome assessment. CONCLUSION: The components of human capital need to be managed strategically with a focus on professional skills and development, with the aim of transforming individual and collective knowledge into new technology. OBJETIVO: Analisar como os componentes do capital humano sao utilizados na gestao de enfermeiras em organizacoes hospitalares. METODO: Estudo exploratorio, com abordagem qualitativa. A coleta de dados ocorreu de outubro de 2014 a maio de 2015 com a utilizacao de entrevistas semiestruturadas. Os dados foram analisados segundo a analise de conteudo. RESULTADOS: Participaram 12 gestoras de enfermagem. Os componentes do capital humano utilizados pelas enfermeiras na gestao de pessoas foram: no processo admissional ao utilizar como criterios para contratacao a exigencia de especializacao na area e experiencia profissional previa; na manutencao de talentos com estrategias de promocao; na capacitacao de profissionais com apoio e treinamento; e no trabalho coletivo para a construcao dos processos e avaliacao dos resultados. CONCLUSAO: Os componentes do capital humano precisam ser gerenciados estrategicamente com foco nas competencias e no desenvolvimento do profissional, visando transformar os conhecimentos individuais e coletivos em novas tecnologias. PMID- 28832710 TI - Erratum. AB - [This corrects the article doi: 10.1590/s1806-37562016000000354]. PMID- 28832711 TI - Horizontal gaze palsy and progressive scoliosis: magnetic resonance imaging features and surgical treatment. PMID- 28832713 TI - Comparing depth-dependent curing radiant exposure and time of curing of regular and flow bulk-fill composites. AB - The effect of restoration depth on the curing time of a conventional and two bulk fill composite resins by measuring microhardness and the respective radiosity of the bottom surface of the specimen was investigated. 1-, 3- and 5-mm thick washers were filled with Surefil SDR Flow-U (SDR), Tetric EvoCeram Bulk Fill-IVA (TEC) or Esthet-X HD-B1 (EHD), and cured with Bluephase(r) G2 for 40s. Additional 1-mm washers were filled with SDR, TEC or EHD, placed above the light sensor of MARC(r), stacked with pre-cured 1-, 3- or 5-mm washer of respective material, and cured for 2.5~60s to mimic 2-, 4- and 6-mm thick composite curing. The sensor measured the radiosity (EB) at the bottom of specimen stacks. Vickers hardness (VH) was measured immediately at 5 locations with triplicate specimens. Nonlinear regression of VH vs EB by VH=alpha[1-exp(-EB/beta)] with all thickness shows that the values of alpha, maximum hardness, are 21.6+/-1.0 kg/mm2 for SDR, 38.3+/-0.6 kg/mm2 for TEC and 45.3+/-2.6 kg/mm2 for EHD, and the values of beta, rate parameter, are 0.40+/-0.06 J/cm2 for SDR, 0.77+/-0.04 J/cm2 for TEC and 0.58+/ 0.09 J/cm2 for EHD. The radiosity of the bottom surface was calculated when the bottom surface of each material attained 80% of alpha of each material. The curing times for each material are in agreement with manufacturer recommendation for thickness. It is possible to estimate time needed to cure composite resin of known depth adequately by the radiosity and microhardness of the bottom surface. PMID- 28832712 TI - Different engagement of TLR2 and TLR4 in Porphyromonas gingivalis vs. ligature induced periodontal bone loss. AB - This study was conducted to investigate the roles of different Toll-like receptor (TLR) signaling in Porphyromonas gingivalis (P. gingivalis)-induced and ligature induced experimental periodontal bone resorption in mice. Wild-type (WT), TLR2 knockout (KO), TLR4KO, and TLR2&4 KO mice with C57/BL6 background were divided into three groups: control, P. gingivalis infection, and ligation. Live P. gingivalis or silk ligatures were placed in the sulcus around maxillary second molars over a 2-week period. Images were captured by digital stereomicroscopy, and the bone resorption area was measured with ImageJ software. The protein expression level of gingival RANKL was measured by ELISA. The gingival mRNA levels of RANKL, IL-1beta, TNF-alpha, and IL-10 were detected by RT-qPCR. The results showed that P. gingivalis induced significant periodontal bone resorption in WT mice and TLR2 KO mice but not in TLR4 KO mice or TLR2&4 KO mice. For all four types of mice, ligation induced significant bone loss compared with that in control groups, and this bone loss was significantly higher than that in the P. gingivalis infection group. RANKL protein expression was significantly increased in the ligation group compared with that in the control group for all four types of mice, and in the P. gingivalis infection group of WT, TLR2 KO, and TLR4 KO mice. Expression patterns of RANKL, IL-1beta, TNF-alpha, and IL-10 mRNA were different in the P. gingivalis infection group and the ligation group in different types of mice. In summary, P. gingivalis-induced periodontal bone resorption is TLR4-dependent, whereas ligation-induced periodontal bone resorption is neither TLR2- nor TLR4-dependent. PMID- 28832714 TI - Ki-67 protein predicts survival in oral squamous carcinoma cells: an immunohistochemical study. AB - The aim of this study was to identify the expression of Ki-67 and MCM3 in oral squamous cell carcinoma (OSCC) as well as to address the correlation with patient survival and clinical features. Samples were collected from 51 patients with OSCC who presented for follow-up. Immunohistochemical expression of Ki-67 and MCM3 in all groups was performed. The scoring system was previous published by Tsurutani in 2005. We used Kappa index to evaluate observers agreement degree. The associations between protein expression and clinical variables were examined for statistical significance using the chi-squared test. The overall survival rates were estimated by the Kaplan-Meier method and the relationship between protein expression and survival was compared using the log-rank test (p < 0.05). The overall survival time for a patient with positive immunostaining for Ki-67 is shorter than for a patient with negative immunostaining, (log-rank test, p = 0.00882). Patients with tumor size T3 and T4 showed a statistically significant relationship with Ki-67 immunoexpression (log-rank test, p = 0.0174). The relationship between Ki-67 expression and the relation between age, gender, smoking, tumor site, lymph node metastasis and disease stage was not significant. The examiners agreement degree by Kappa presented p value < 0.05. There was not a significant correlation when we evaluated MCM3 expression regarding clinical characteristics and survival rate. From these results, the present study suggests that positive Ki-67 expression found in OSCC patients may contribute to predict the survival in OSCC samples, as well as the relation between the protein and the tumor size. PMID- 28832715 TI - Characterization and coating stability evaluation of nickel-titanium orthodontic esthetic wires: an in vivo study. AB - The objective of this study was to compare coating dimensions and surface characteristics of two different esthetic covered nickel-titanium orthodontic rectangular archwires, as-received from the manufacturer and after oral exposure. The study was designed for comparative purposes. Both archwires, as-received from the manufacturer, were observed using a stereomicroscope to measure coating thickness and inner metallic dimensions. The wires were also exposed to oral environment in 11 orthodontic active patients for 21 days. After removing the samples, stereomicroscopy images were captured, coating loss was measured and its percentage was calculated. Three segments of each wire (one as-received and two after oral exposure) were observed using scanning electron microscopy for a qualitative analysis of the labial surface of the wires. The Lilliefors test and independent t-test were applied to verify normality of data and statistical differences between wires, respectively. The significance level adopted was 0.05. The results showed that the differences between the wires while comparing inner height and thickness were statistically significant (p < 0.0001). In average, the most recently launched wire presented a coating thickness twice that of the control wire, which was also a statistically significant difference. The coating loss percentage was also statistically different (p = 0.0346) when the latest launched wire (13.27%) was compared to the control (29.63%). In conclusion, the coating of the most recent wire was thicker and more uniform, whereas the control had a thinner coating on the edges. After oral exposure, both tested wires presented coating loss, but the most recently launched wire exhibited better results. PMID- 28832716 TI - Risk factors for implant failure: a retrospective study in an educational institution using GEE analyses. AB - This study aimed to evaluate dental implant outcomes and to identify risk factors associated with implant failure over 12 years via dental records of patients attending an educational institution. Dental records of 202 patients receiving 774 dental implants from 2002 to 2014 were analyzed by adopting a more reliable statistical method to evaluate risk factors with patients as the unit [generalized estimating equation (GEE)]. Information regarding patient age at implantation, sex, use of tobacco, and history of systemic diseases was collected. Information about implant location in the arch region and implant length, diameter, and placement in a grafted area was evaluated after 2 years under load. Systemic and local risk factors for early and late implant failure were studied. A total of 18 patients experienced 25 implant failures, resulting in an overall survival rate of 96.8% (2.84% and 0.38% early and late implant failures, respectively). The patient-based survival rate was 91.8%. GEE univariate and multivariate analyses revealed that a significant risk factor for implant failure was the maxillary implant (p = 0.006 and p = 0.014, respectively). Bone grafting appeared to be a risk factor for implant failure (p = 0.054). According to GEE analyses, maxillary implants had significantly worse outcomes in this population and were considered to be a risk factor for implant failure. Our results suggested that implants placed in a bone augmentation area had a tendency to fail. PMID- 28832717 TI - Longitudinal impact of clinical and socioenvironmental variables on oral health related quality of life in adolescents. AB - The aim of the present study was to investigate the impact of oral diseases, socioeconomic status, and family environmental factors on changes in the perception of oral health-related quality of life (OHRQoL) in adolescents. A prospective cohort study was conducted in Juiz de Fora, Minas Gerais, Brazil, with a sample of 286 twelve-year-old adolescents from public and private schools, selected by means of multistage random sampling. The adolescents were clinically examined for dental caries experience (number of decayed, missing, and filled teeth - DMFT index), presence of bleeding, and orthodontic treatment needs. They were asked to complete the Brazilian version of the Child Perceptions Questionnaire (CPQ11-14). In addition, parents answered a questionnaire about their socioeconomic status and family environmental characteristics. After 3 years, the adolescents were contacted again to participate in the research. Logistic regression models, with explanatory variables assessed both individually and jointly, were used to determine which independent variables impacted longitudinally on OHRQoL. The final result demonstrated that only DMFT explained part of the response variability in CPQ11-14 scores. In conclusion, caries experience was an important predictor of OHRQoL in adolescents followed up for 3 years. PMID- 28832718 TI - Evaluation of the physicochemical properties of silicone- and epoxy resin-based root canal sealers. AB - To assess the physicochemical properties of AH Plus, GuttaFlow 2, GuttaFlow BioSeal, and MM Seal, five samples of each root canal sealer were evaluated to determine their setting time (ST), dimensional change (DC), solubility (SL), flow (FL), and radiopacity (RD) according to American National Standards Institute/American Dental Association (ANSI/ADA) Specification 57. The distilled and deionized water obtained from the SL test were subjected to atomic absorption spectrometry to observe the presence of Ca2+, K+, and Na+ ions. Statistical analysis was performed by using one-way ANOVA and Tukey-Kramer tests (p < 0.05). The following results were obtained: ST (min) (AH Plus 463.6 +/- 13.22; GuttaFlow 2 24.35 +/- 2.78; GuttaFlow Bioseal 17.4 +/- 0.55; MM Seal 47.60 +/- 4.39), DC (%) (AH Plus 0.06 +/- 0.12; GuttaFlow 2 -26.06 +/- 1.24; GuttaFlow Bioseal 2.10 +/- 1.47; MM Seal 8.47 +/- 2.41), SL (%) (AH Plus 0.41 +/- 0.21; GuttaFlow 2 5.13 +/- 4.11; GuttaFlow Bioseal 3.03 +/- 1.05; MM Seal 0.94 +/- 0.17), FL (mm) (AH Plus 36.42 +/- 0.40; GuttaFlow 2 36.44 +/- 0.05; GuttaFlow Bioseal 35.4 +/- 0.03; MM Seal 52.75 +/- 0.60), and RD (mmAl) (AH Plus 7.52 +/- 1.59; GuttaFlow 2 6.85 +/- 0.14; GuttaFlow Bioseal 7.02 +/- 0.18; MM Seal 3.32 +/- 0.90). ST, DC, SL, FL, and RD showed statistical differences among the root canal sealers (p < 0.05). As AH Plus showed the lowest DC and SL values (p < 0.05), the findings indicate that this sample is the only sealer conforming to ANSI/ADA standards. PMID- 28832719 TI - Spider species richness and sampling effort at Cracraft'S Belem Area of Endemism. AB - A list of spider species is presented for the Belem Area of Endemism, the most threatened region in the Amazon Basin, comprising portions of eastern State of Para and western State of Maranhao, Brazil. The data are based both on records from the taxonomic and biodiversity survey literature and on scientific collection databases. A total of 319 identified species were recorded, with 318 occurring in Para and only 22 in Maranhao. About 80% of species are recorded at the vicinities of the city of Belem, indicating that sampling effort have been strongly biased. To identify potentially high-diversity areas, discounting the effect of variations in sampling effort, the residues of a linear regression between the number of records and number of species mapped in each 0.25 degrees grid cells were analyzed. One grid, representing the Alto Turiacu Indigenous land, had the highest deviation from the expected from the linear regression, indicating high expected species richness. Several other grid cells showed intermediate values of the regression residuals, indicating species richness moderately above to the expected from the model. PMID- 28832720 TI - Sodium reduction in margarine using NaCl substitutes. AB - Sodium chloride is traditionally used as a food additive in food processing. However, because of its high sodium content, NaCl has been associated with chronic diseases. Margarine is a popular product that is used in several preparations, but it includes high sodium content; therefore, it is among the products whose sodium content should be reduced. Thus, the objective of this study was to produce margarines with reduced sodium content prepared using a salt mixture. The following 4 margarine formulations were prepared: Formulation A (control - 0% sodium reduction), Formulation B (20.8% less sodium), Formulation C (33.0% less sodium) and Formulation D (47.4% less sodium). The low sodium formulations were produced using a salt mixture consisting of NaCl, KCl, and monosodium glutamate at different concentrations. The margarines were evaluated using an acceptance test and descriptive tests: time-intensity and temporal dominance of sensations. The mixture used is a good alternative for preparing low sodium margarine because the low sodium formulations feature equal salinity and do not produce a strange or bad taste. Furthermore, it may be possible to prepare margarines with up to 47.4% less sodium and that are acceptable to consumers. PMID- 28832721 TI - Development and evaluation of an inhalation chamber for in vivo tests. AB - The bioavailability, toxicity, and therapeutic efficacy of a drug is directly related to its administration route. The pulmonary route can be accessed by inhalation after fumigation, vaporization or nebulization. Thus, pharmacological and toxicological evaluation accessed by an apparatus specifically designed and validated for this type of administration is extremely important. Based on pre existing models, an inhalation chamber was developed. This presents a central structure with five animal holders. The nebulized air passes directly and continuously through these holders and subsequently to an outlet. Evaluation of its operation was performed using clove essential oil, a nebulizer, and a flow meter. The air within the chamber was collected by static headspace and analyzed by gas chromatography with a flame ionization detector. For this purpose, a 2.5 minutes chromatographic method was developed. The air flow in each of the five outputs was 0.92 liters per minute. During the first minute, the chamber became saturated with the nebulized material. Homogeneous and continuous operation of the chamber was observed without accumulation of volatile material inside it for 25 minutes. The inhalation chamber works satisfactorily for in vivo tests with medicines designed to be administrated by inhalation. PMID- 28832722 TI - Palisadegrass effects on N fertilizer dynamic in intercropping systems with corn. AB - Corn grain yield, nitrogen (N) fertilizer efficiency and distribution to corn alone and three forms of corn and palisadegrass (Urochloa spp.) intercropping implantation was investigated. A field experiment with 15N labeling fertilizer was performed in randomized block design. No form of palisadegrass intercropping implantation affected corn grain yield, total N accumulation and N use efficiency (NUE), which were 8.7 t ha-1, 205 kg ha-1 and 37% respectively. The palisadegrass produced on average 1.9 t of dry mass, absorbing a maximum of 6 kg ha-1 or 5.5% of N fertilizer during corn growing. Furthermore, the palisadegrass did not affect N fertilizer distribution in soil-plant system, in which 28.2% was recovered in the soil and 40.4% in the plants (corn + palisadegrass). The results show that for the three intercropping implantation methods the palisadegrass did not compete with corn for N fertilizer. PMID- 28832723 TI - Is Forced Swimming Immobility a Good Endpoint for Modeling Negative Symptoms of Schizophrenia? - Study of Sub-Anesthetic Ketamine Repeated Administration Effects. AB - Immobility time in the forced swimming has been described as analogous to emotional blunting or apathy and has been used for characterizing schizophrenia animal models. Several clinical studies support the use of NMDA receptor antagonists to model schizophrenia in rodents. Some works describe the effects of ketamine on immobility behavior but there is variability in the experimental design used leading to controversial results. In this study, we evaluated the effects of repeated administration of ketamine sub-anesthetic doses in forced swimming, locomotion in response to novelty and novel object recognition, aiming a broader evaluation of the usefulness of this experimental approach for modeling schizophrenia in mice. Ketamine (30 mg/kg/day i.p. for 14 days) induced a not persistent decrease in immobility time, detected 24h but not 72h after treatment. This same administration protocol induced a deficit in novel object recognition. No change was observed in mice locomotion. Our results confirm that repeated administration of sub-anesthetic doses of ketamine is useful in modeling schizophrenia-related behavioral changes in mice. However, the immobility time during forced swimming does not seem to be a good endpoint to evaluate the modeling of negative symptoms in NMDAR antagonist animal models of schizophrenia. PMID- 28832724 TI - Selection of alfalfa genotypes for resistance to the foliar pathogen Curvularia geniculata. AB - Foliar diseases impose severe restrictions on the persistence and productivity of Medicago sativa, both of which may be increased by developing disease resistant and more competitive genotypes that can improve pasture quality. We found Curvularia geniculata as the principal alfalfa foliar pathogen in the Brazilian state of Rio Grande do Sul (RS). Growth chamber experiments evaluated the resistance of alfalfa genotypes 'E1C4', 'CPPSul', 'ABT 805' and 'CUF-101' to C. geniculata as compared the control 'Crioula' genotype. These genotypes were also evaluated in field trials at a sea level site in Eldorado do Sul in central RS and at two sites L200 m above sea level, one in Bage municipality in south west RS and the other at a farm near the town of Alto Feliz in north east RS. Plants were spray-inoculated with 1.6 x 106 ml-1 of C. geniculata spores and visually evaluated for leaf damage 14 days later. The C. geniculata infection rates varied from zero to 100%. Alfalfa persistence and forage mean dry mass (DM) production at the Eldorado site were measured during different seasons from November 2013 to January 2015 by calculating the incidence of invasive plants and morphologically separating leaves from stems and calculating both leaf and stem DM. Data were analysed using mixed statistical models. The best results for persistence and forage DM were shown by the 'CPPSul' genotypes (DM = 16,600 kg ha-1) and 'Crioula' (DM = 15,750 kg ha-1). These two genotypes will be used for subsequent investigations and selection cycles. PMID- 28832725 TI - The quantification of testicular cells during the postnatal development in two Caviomorph rodents: the guinea pig (Cavia porcellus) and the cutia (Dasyprocta agouti). AB - The germinative, Sertoli and Leydig cells of two caviomorph rodents (Cavia porcellus and Dasyprocta agouti) were counted as well as the estimation of the total volume of the testis and the total volume of seminiferous tubules and interstitium in prepubertal, pubertal and adult animals. The number of spermatogonia, spermatocytes and spermatids cells increased during the pubertal phase in both rodents, notably the spermatid cells. The spermatocyte and spermatid slightly decreased in the adult of both rodents, but the increment in spermatogonia cells number was seen, mainly in cutias. The number of Sertoli cells increased in pubertal rodents, but in the adult the number reduced. Substantial number of Leydig cells was counted in pubertal and adult guinea pigs. In cutias, the number of Leydig cells increased in pubertal phase and decline in adults. The design-based stereological method has proven to be unbiased and reliable to be applied in reproduction studies. PMID- 28832726 TI - A new name for Agromyza flava Sousa & Couri (Diptera: Agromyzidae). AB - A new name Agromyza pauciflava nom. nov. is proposed for Agromyza flava Sousa & Couri. PMID- 28832727 TI - Occurrence of arbuscular mycorrhizal fungi on King George Island, South Shetland Islands, Antarctica. AB - Arbuscular mycorrhizal fungi make up an important ecological niche in ecosystems, and knowledge of their diversity in extreme environments is still incipient. The objective of this work was to evaluate the density and diversity of arbuscular mycorrhizal fungi in the soil of King George Island in the South Shetland Islands archipelago, Antarctica. For that, soil and roots of Deschampsia antarctica were collected at the brazilian research station in Antarctica. The spore density, species diversity and mycorrhizal colonization in the roots were evaluated. There was a low density of spores (27.4 +/- 17.7) and root mycorrhizal colonization (6 +/- 5.1%), which did not present statistical difference. Four species of arbuscular mycorrhizal fungi were identified, distributed in two genera: three species of the genus Glomus (Glomus sp1, Glomus sp2 and Glomus sp3) and one of the genus Acaulospora, which was identified at species level (Acaulospora mellea). Greater soil diversity was verified with pH 5.9 and phosphorus concentration of 111 mg dm-3, occurring two species of genus Glomus and A. mellea. Based on literature data, this may be the first record of this species of Acaulospora mellea in Antarctic soils, colonizing D. antarctica plants. PMID- 28832728 TI - Mercury content in the fur of jaguars (Panthera onca) from two areas under different levels of gold mining impact in the Brazilian Pantanal. AB - The Pantanal is the largest inland wetland in the world and is under increasing anthropogenic threats, including long-term regionally intensive gold mining practices. Gold mining activities are known to cause the release of harmful pollutants such as mercury (Hg) to the surrounding environment. Jaguars (Panthera onca (Linnaeus, 1758)) are apex predators, and therefore show great potential to accumulate Hg by biomagnification. We hypothesize that total Hg content in the fur of jaguars from two sites within the Brazilian Pantanal would be significantly different as a function of distance from active gold mining operations. The Hg content was determined by fluorescence spectrometry. The mean +/- SD Hg content in jaguars from the study site influenced by gold mining (SB) was compared to jaguars sampled in the area free of gold mining activities (CA) using a one-way ANOVA. The mean Hg content in jaguars from SB (673.0 +/- 916.8 ug g-1) is significantly different from jaguars sampled in CA (29.7 +/- 23.3 ug g 1), p = 0.03. The maximum recorded content of Hg was 2,010.4 +/- 150.5 ug g-1, highest level ever recorded in a wild animal. The data indicate that Hg is an important threat to jaguars within at-risk regions of the Pantanal. PMID- 28832729 TI - The reasons for evisceration after penetrating keratoplasty between 1995 and 2015. AB - PURPOSE: The purpose of this study was to determine the indications and frequency of evisceration after penetrating keratoplasty (PK). METHODS: The medical records of all patients who underwent evisceration after PK between January 1, 1995 and December 31, 2015 at Ankara Training and Research Hospital were reviewed. Patient demographics and the surgical indications for PK, diagnosis for evisceration, frequency of evisceration, and the length of time between PK and evisceration were recorded. RESULTS: The frequency of evisceration was 0.95% (16 of 1684), and the mean age of the patients who underwent evisceration was 56.31 +/- 14.82 years. The most common indication for PK that resulted in evisceration was keratoconus (37.5%), and the most common underlying cause leading to evisceration was endophthalmitis (56.25%). The interval between PK and evisceration ranged from 9 to 78 months. CONCLUSIONS: Although keratoplasty is one of the most successful types of surgery among tissue transplantations, our findings show that it is associated with a possible risk of evisceration. PMID- 28832730 TI - Successful treatment of fungal endophthalmitis using intravitreal caspofungin. AB - Fungal endophthalmitis is a rare condition often associated with poor prognosis. We present a case of postoperative acute fungal endophthalmitis caused by the yeast-like fungus Stephanoascus ciferrii (Candida ciferrii). The fungus was resistant to fluconazole, voriconazole, and amphotericin B but susceptible to caspofungin. Because the degree of vitreal penetration of caspofungin after its intravenous administration is unclear, we performed multiple intravitreal injections, first with 50 ug/0.1 ml and then with 250 ug/0.1 ml caspofungin. Despite the recurrence of symptoms, intravitreal injection of caspofungin finally abolished the inflammation and achieved ambulatory vision that persisted until 1 year of follow-up. To our knowledge, this is the first report of S. ciferrii endophthalmitis and its successful treatment with intravitreal caspofungin. PMID- 28832731 TI - Photoreceptor assessment using adaptive optics in resolved central serous chorioretinopathy. AB - We present a case of a patient with resolved central serous chorioretinopathy (CSC) in the left eye with persistent mild visual alterations 4 years after the resolution of the disease. Left eye exam revealed a best corrected visual acuity of 20/25 and a slight change of macular pigmentation. Optical coherence tomography revealed only minor irregularities in the topography of retinal pigment epithelium and Bruch's membrane. Adaptive optics (AO) optics demonstrated lower density, spacing, and changes in the photoreceptor mosaic pattern in the left eye than in the right eye, suggesting that CSC may cause damage to cones after clinical recovery. We conclude that AO can provide additional information to assist in the treatment and follow-up of patients with CSC or other macular pathologies. PMID- 28832732 TI - Vision status, ophthalmic assessment, and quality of life in the very old. AB - PURPOSE: To determine the vision status, ophthalmic findings, and quality of life among the very elderly. METHODS: This was a cross-sectional observational study of individuals aged 80 years and above. A comprehensive ophthalmic exam was performed with mea surement of both the presenting (PVA) and best-corrected visual acuity. The Quality of Life Short Form-36 (SF-36) and the Visual Function Questionnaire (VFQ-25) were also administered. RESULTS: A total of 150 non institutionalized participants were assigned to three age groups: 80-89 years (n=70), 90-99 years (n=50), and 100 years and older (n=30). PVA and best corrected visual acuity were normal (>=20/30) in 20 (13.3%) and 37 participants (24.7%), respectively. Regarding PVA, mild visual impairment (<20/30 to >=20/60) was found in in 53 (35.4%), moderate visual impairment (<20/60 to >=20/200) in 50 (33.3%), severe visual impairment (<20/200 to >=20/400) in 8 (5.3%), and blindness (<20/400) in 19 (12.7%) participants. Regarding best-corrected visual acuity, mild, moderate, and severe visual impairments were present in 55 (36.7%), 38 (25.3%), and 5 (3.3%) participants, respectively, and blindness was present in 15 (10%). The main causes of visual impairment/blindness were cataract (43.8%), refractive errors (21.5%), age-related macular degeneration (17.7%), and myopic degeneration (3.8%). SF-36 scores were worse in those with low visual acuity, while VFQ-25 domain scores were poorer in those with vision impairment/blindness. CONCLUSION: Vision impairment and blindness was present in three-quarters of this sample, but it was notable that adequate correction with spectacles improved visual acuity. This reinforces the need for regular ophthalmic care in elderly patients to improve their quality of life by optimizing vision. PMID- 28832733 TI - Blinding trachoma among Maku Indians of the upper Rio Negro: a neglected public health problem. PMID- 28832734 TI - Corneal properties and glaucoma: a review of the literature and meta-analysis. AB - PURPOSE: Studies have suggested that corneal biomechanical properties influence intraocular pressure (IOP) measurements, namely central corneal thickness (CCT) and corneal hysteresis (CH). The present study aimed to investigate the associations of CH and CCT with glaucoma development. METHODS: We performed a review of the literature and meta-analysis of observational studies (2006-2016) that included both adult glaucoma patients and controls and reported CCT and CH as outcomes. Nineteen studies were conside red eligible, and the mean difference (MD) between groups (patient and control) for both variables was used for statistical analyses. RESULTS: A total of 1,213 glaucoma and 1,055 healthy eyes were studied. Quan titative analysis suggested that CH was significantly lower in the glaucoma group than in the control group (MD=-1.54 mmHg, 95% CI [-1.68, 1.41], P<0.0001). Additionally, CCT was significantly lower in the glaucoma group than in the control group (MD=-8.49 um, 95% CI [-11.36, -5.62], P<0.001). CONCLUSION: Corneal properties appear to differ between glaucoma patients and healthy controls. Our results emphasize the importance of corneal biomechanical properties in IOP interpretation and should support further studies on the influence of CH and CCT in glaucoma screening and diagnosis. PMID- 28832735 TI - Safety and efficacy of intracameral moxifloxacin injection for prophylaxis of endophthalmitis after phacoemulsification. AB - PURPOSE: To evaluate the safety and efficacy of 0.05 mL intracameral injection of moxifloxacin in patients who underwent phacoemulsification and intraocular lens (IOL) implant. METHODS: Retrospective study comprising patients who underwent phacoemulsification and IOL implant between January 2009 and December 2013. Patients were divided into two groups. Group A followed standard endophthalmitis prevention protocol and group B followed the same protocol plus intracameral injection of 0.05 mL of moxifloxacin hydrochloride at 5.45 mg/mL, immediately after IOL implant. RESULTS: Medical records from 7,195 eyes of 3,751 patients (median age: 67.8 +/- 8.96, range: 48-83 years, 53.8% female) were evaluated. Group A included 3,515 eyes of 1,838 patients and group B included 3,680 eyes of 1,913 patients. The incidence of endophthalmitis in group A was 0.22% (8:3,515 eyes) and in group B was 0.03% (1:3,680 eyes, p=0.0198, Fischer's exact test). No toxicity or inflammation related to the use of moxifloxacin was observed. CONCLUSIONS: There was a 7.3-fold lower ratio of endophthalmitis in the group that received moxifloxacin intracameral injection. This study provides further evidence that moxifloxacin is an effective intracameral prophylactic antibiotic. PMID- 28832736 TI - Effects of obesity on retrobulbar flow hemodynamics: color Doppler ultrasound evaluation. AB - PURPOSE: To evaluate intraocular pressure (IOP) and extraocular orbital vessels with color Doppler ultrasound (CDU) and investigate the effects of obesity on retrobulbar blood flow. METHODS: Fifty-nine patients were included in this prospective study. Patients were divided into two groups according to body mass index: Group 1 (31 obese patients) and Group 2 (28 non-obese patients). IOP was measured with a Goldmann applanation tonometer, and CDU was used to evaluate the retrobulbar vessels. RESULTS: The mean IOP was 18 +/- 6.68 mmHg in the obese group and 13.71 +/- 1.60 mmHg in the control group (p<0.001). When the CDU values for the central retinal artery were compared between the groups, the pulsatility index was found to be significantly lower in the obese group than in the control group (p<0.001). When the CDU values for the ophthalmic artery (OA) were compared between the groups, the peak systolic velocity (p<0.001) and end-diastolic velocity (p=0.002) values were found to be significantly lower in the obese group than in the control group. CONCLUSIONS: Obese patients have a higher mean IOP and lower flow velocity than non-obese patients. Increased IOP together with decreased retrobulbar blood flow, particularly in obese individuals, may increase the risk of glaucoma development. PMID- 28832737 TI - Corneal backscatter in insulin-dependent and non-insulin-dependent diabetes mellitus patients: a pilot study. AB - PURPOSE: To compare central corneal backscatter obtained from Scheimpflug images between patients with insulin-dependent and non-insulin-dependent diabetes mellitus (IDDM and NIDDM, respectively) and healthy controls. METHODS: Seven patients with IDDM (7 eyes), eleven patients with NIDDM (11 eyes), and sixteen healthy subjects (16 eyes) were included in this pilot study. Scheimpflug imaging system (Pentacam, Oculus Inc., Germany) was used to obtain optical sections of the cornea. Seven meridians were analyzed for each eye, oriented from 70 degrees to 110 degrees . Optical density values for the central 3-mm and 5-mm zones of the cornea were obtained by image analysis using external software. RESULTS: Corneal backscatter was significantly higher in the diabetic patients than in the controls for the central 3-mm (p=0.016) and 5-mm (p=0.014) zones. No significant differences in corneal backscatter were found between the IDDM and NIDDM groups for either zone (both p>0.05). In the NIDDM group, significant correlations were observed for both central zones between corneal backscatter and age (3 mm: r=0.604, p=0.025; 5 mm: r=0.614, p=0.022) and central corneal thickness (3 mm: r=0.641, p=0.017; 5 mm: r=0.671, p=0.012); this was not found in the IDDM group (p>0.05). The presence of diabetes showed a significant effect on central corneal backscatter (Kruskal-Wallis test, p<0.001). CONCLUSIONS: Diabetic patients showed higher values of corneal light backscatter than healthy subjects. Corneal optical density analysis may be a useful tool for monitoring and assessing the ocular changes caused by diabetes. PMID- 28832738 TI - Multimodal assessment of patients with chronic central serous chorioretinopathy. AB - PURPOSE: To examine differences between fluorescein angiography (FA) and indocyanine green angiography (ICG) findings in patients with chronic central serous chorioretinopathy (CSC), comparing these with optical coherence tomography (OCT) findings. METHODS: Ten consecutive patients with chronic CSC (19 eyes; 7 men; mean age, 50.7 +/- 8.4 years) underwent multimodal evaluation that included FA, ICG, and OCT (Spectralis HRA-OCT, Heidelberg Engineering, Heidelberg, Germany). Changes such as hyperfluorescence (caused by increased transmission of the normal choroidal fluorescence, staining, or "pooling") and hypofluorescence (caused by a blockage or vascular filling defect) were evaluated in the early (4 min), middle (4-8 min) and late (>8 min) angiography phases and compared to OCT findings. RESULTS: Bilateral disease was present in nine of the 10 patients. Areas of discontinuation or attenuation of the hyporeflective layer of the retinal pigment epithelium (RPE) on OCT were observed at the same locations as hyperfluorescent angiography window defects on FA and ICG within examination phases. In areas of serous or RPE detachment, the hyperfluorescence pattern was similar on FA and ICG. However, ICG demonstrated areas of hyperfluorescence secondary to choriocapillaris hyperpermeability, with no corresponding change on FA in 12 (70%) of the 19 eyes. This finding was more evident in the middle and late phases of the examinations and there was no evident change in retinal architecture on OCT in these hyperpermeable choroidal regions. CONCLUSION: In patients with chronic CSC, ICG may reveal choroidal abnormalities that are not evident on FA. This finding may help optimize the monitoring and treatment of CSC. PMID- 28832739 TI - Tacrolimus eye drops as monotherapy for vernal keratoconjunctivitis: a randomized controlled trial. AB - PURPOSE: To assess the efficacy of monotherapy using tacrolimus eye drops versus sodium cromoglycate for the treatment of vernal keratoconjunctivitis (VKC). METHODS: Randomized double-masked controlled trial comparing the efficacy of tacrolimus 0.03% eye drops t.i.d. (Group 1) with sodium cromoglycate 4% eye drops t.i.d. (Group 2) for the symptomatic control of VKC at days 0, 15, 30, 45, and 90 of follow-up. Visual acuity, intraocular pressure, and other complications were evaluated to assess safety and side effects. RESULTS: In total, 16 patients were included, with 8 enrolled in each group. Two patients from Group 2 were excluded from the analysis at days 45 and 90 because of corticosteroid use. Most patients were male (81.8%) and presented with limbal VKC (56.3%). There were statistically significant differences in favor of tacrolimus in the following severity scores: itching at day 90 (p=0.001); foreign body sensation at day 15 (p=0.042); photophobia at day 30 (p=0.041); keratitis at day 30 (p=0.048); and limbal activity at days 15 (p=0.011), 30 (p=0.007), and 45 (p=0.015). No relevant adverse effects were reported, except for a burning sensation with tacrolimus, though this did not compromise treatment compliance. CONCLUSION: Treatment with tacrolimus was superior to sodium cromoglycate when comparing severity scores for symptoms of itching, foreign body sensation, and photophobia, as well as for signs of limbal inflammatory activity and keratitis. PMID- 28832740 TI - Solitary fibrous tumor of the lacrimal gland mimicking pleomorphic adenoma. AB - Solitary fibrous tumor (SFT) is a rare mesenchymal spindle-cell neoplasm commonly found in the pleura; it is rare in the orbit and extremely rare in the lacrimal gland. We herein report a case of SFT of the lacrimal gland that mimicked a pleo morphic adenoma. We discuss the clinical, radiological, histopathological, and immunohistochemical findings that provided insight and rationale to accurately diagnose this case. PMID- 28832741 TI - Supratarsal injection of triamcinolone for severe vernal keratoconjunctivitis in children. AB - PURPOSE: To evaluate the use of supratarsal injection of triamcinolone acetonide in severe vernal keratoconjunctivitis (VKC) in children. METHODS: Patients included in this open clinical trial were those with severe VKC-associated with keratitis, gelatinous limbal infiltrates, and/or giant papillae, with a history of recurrence and resistance to conventional topical antiallergic agents. Patients were treated with a supratarsal injection of 20 mg triamcinolone acetonide. RESULTS: Analysis included 27 injections in 23 eyes of 17 patients with severe allergic keratoconjunctivitis. Mean age was 12.3 (range: 7-19) years. Mean follow-up time was 39.3 months (SD=19.21). In the 17 patients, the disease was successfully controlled for an average of 3.6 months (range: 1-16), during which allergy symptoms and signs were significantly improved, with complete resolution of lid edema and conjunctival chemosis, significant decline of pannus and keratitis, and reduction of giant papillae size. CONCLUSION: Treatment of severe, acute VKC in children with supratarsal injection of 20 mg triamcinolone acetonide showed satisfactory results and was well tolerated by patients; it may therefore constitute a safe option for severe and challenging cases. While full disease remission was not achieved, a significant improvement was found in ocular allergy symptoms and signs, with a reduction in the frequency of acute recurrences. PMID- 28832742 TI - Ultrasound parameters of normal lacrimal sac and chronic dacryocystitis. AB - PURPOSE: To compared the ultrasound findings of the lacrimal sac between subjects with normal lacrimal systems those with chronic dacryocystitis. METHODS: A retrospective study of 10 subjects with a normal lacrimal system (Group 1) and 10 with chronic dacryocystitis (Group 2) diagnosed according to B-mode ultrasound with a 10-MHz transducer and the direct-contact technique (AVISO, Quantel Medical) for lacrimal sac assessment. We analyzed the dimensions, features, and content of the sacs. Characteristics of the population: female: 6, Group 1; 8, Group 2; mean age 48.4 years (SD=19.9; range, 22-80 years), Group 1; 50.5 years (SD=15.5; range, 25-75 years), Group 2. RESULTS: The dimensions of the lacrimal sac were as follows: anteroposterior 1.86 and 10.99 mm in Groups 1 and 2, respectively, p<0.0001; vertical 9.79 and 14.13 mm in Groups 1 and 2, respectively, p=0.049. Qualitative evaluation of the lacrimal sac contents showed hypoechogenic content in Group 1 (10, 100%) and hyperechogenic punctiform content in Group 2 (10, 100%) with partial filling in seven cases (70%). CONCLUSIONS: Ultrasonography can differentiate normal lacrimal sacs from sacs compromised by chronic dacryocystitis, thus being useful as an adjunct to clinical examination and surgical planning. PMID- 28832743 TI - Effects of hemodialysis on corneal and anterior chamber morphometry and intraocular pressure in patients with end-stage renal disease. AB - PURPOSE: To evaluate the effects of hemodialysis (HD) on corneal and anterior chamber morphometry, as well as intraocular pressure (IOP) in patients with end stage renal disease. METHODS: Fifty right eyes were examined 30 minutes before and after HD. IOP was measured with a Goldmann applanation tonometer, and Ehlers' formula was used to calculate the corrected IOP values. The central corneal thickness (CCT), corneal volume (CV), keratometric values, anterior chamber depth (ACD), aqueous depth (AQD), anterior chamber volume (ACV), and anterior chamber angle (ACA) in the nasal and temporal quadrants were measured with a Sirius anterior segment analysis system. Blood urea nitrogen levels, body mass, and systolic and diastolic arterial pressure were also measured before and after HD. RESULTS: The mean age was 60.80 +/- 13.38 (range: 35-80) years. The mean uncorrected and corrected IOP values decreased from 18.06 +/- 3.91 and 18.31 +/- 4.83 mmHg to 16.94 +/- 3.87 and 16.95 +/- 4.74 mmHg after HD, respectively (p=0.011 and p=0.003, respectively). The mean CCT decreased from 536.38 +/- 24.73 to 533.18 +/- 27.25 um (p=0.002), and the mean CV decreased from 57.52 +/- 3.15 to 55.68 +/- 3.55 mm3 (p<0.001) after HD. There were no significant changes in ACD, AQD, ACV, ACA, or the keratometric values (p>0.05 for all values). There were no significant correlations between the ocular and systemic parameters (p>0.05 for all correlations). CONCLUSIONS: Uncorrected IOP, corrected IOP, CCT, and CV values decreased after HD, whereas the anterior chamber morphometry values remained similar between the measurements performed before and after HD. PMID- 28832744 TI - Posterior argentinean flag-like sign during primary posterior continuous curvilinear capsulorhexis. AB - We describe a unique complication during primary posterior continuous curvilinear capsulorhexis (PCCC) in a patient with megalocornea scheduled for phacoemulsification with toric multifocal intraocular lens (IOL) implantation. After nucleus emulsification and cortex removal, the capsular bag was filled with cohesive viscoelastic in preparation for PCCC to achieve reverse optic capture of the IOL, thus ensuring stability. However, as soon as the initial puncture was made using a 27-gauge needle to start the capsulotomy, the posterior capsule opening extended peripherally from 0o-180o. This capsule extension was similar to the Argentinean-flag sign in hypermature cataracts, and both are caused by excessive intracapsular pressure. Careful bimanual manipulation was performed to implant the IOL on the desired axis, which occurred uneventfully. At a postoperative visit, the patient exhibited excellent uncorrected visual acuity with a well-aligned IOL. PMID- 28832745 TI - Predictors of Mediastinitis Risk after Coronary Artery Bypass Surgery: Applicability of Score in 1.322 Cases. AB - BACKGROUND: Mediastinitis is a severe surgical complication of low incidence, but high lethality. Scores used in the preoperative period to stratify the risk of postoperative mediastinitis may contribute to improve the results. OBJECTIVE: To test the applicability of the MagedanzSCORE in predicting the risk factors for mediastinitis in patients undergoing coronary artery bypass grafting at a cardiology reference hospital. METHODS: Historical cohort study with adult patients who underwent coronary artery bypass grafting. The analyzed variables were contemplated in the MagedanzSCORE: reoperation, chronic obstructive pulmonary disease (COPD), obesity, class IV unstable angina, polytransfusion therapy, mediastinitis and death as outcome variables. RESULTS: Of the 1.322 patients examined, 56 (4.2%) developed mediastinitis. Of these, 26 (46.4%) were classified as high risk for mediastinitis and 15 (26.8%) at very high risk for mediastinitis. Three of the five variables of the Magendanz Score showed statistically significant differences: reoperation, COPD and obesity. Class IV unstable angina and postoperative polytransfusion were not associated with mediastinitis after coronary artery by-pass grafting. The area under the ROC curve was 0.80 (CI 95% 0.73 - 0.86), indicating the model's satisfactory ability to predict the occurrence of mediastinitis. CONCLUSION: The tool was useful in the preoperative assessment demonstrating the risk for mediastinitis in this population of intensive care patients. (Arq Bras Cardiol. 2017; [online].ahead print, PP.0-0). PMID- 28832746 TI - Evaluation of Quality of Life in Patients with and without Heart Failure in Primary Care. AB - BACKGROUND: Heart failure (HF) is a major public health issue with implications on health-related quality of life (HRQL). OBJECTIVE: To compare HRQL, estimated by the Short-Form Health Survey (SF-36), in patients with and without HF in the community. METHODS: Cross-sectional study including 633 consecutive individuals aged 45 years or older, registered in primary care. The subjects were selected from a random sample representative of the population studied. They were divided into two groups: group I, HF patients (n = 59); and group II, patients without HF (n = 574). The HF group was divided into HF with preserved ejection fraction (HFpEF - n = 35) and HF with reduced ejection fraction (HFrEF - n = 24). RESULTS: Patients without HF had a mean SF-36 score significantly greater than those with HF (499.8 +/- 139.1 vs 445.4 +/- 123.8; p = 0.008). Functional capacity - ability and difficulty to perform common activities of everyday life - was significantly worse (p < 0.0001) in patients with HF independently of sex and age. There was no difference between HFpEF and HFrEF. CONCLUSION: Patients with HF had low quality of life regardless of the syndrome presentation (HFpEF or HFrEF phenotype). Quality of life evaluation in primary care could help identify patients who would benefit from a proactive care program with more emphasis on multidisciplinary and social support. (Arq Bras Cardiol. 2017; [online].ahead print, PP.0-0). PMID- 28832747 TI - Pre-Participation Physical Fitness does not Influence Adherence to a Supervised Exercise Program. AB - BACKGROUND: Exercise-based cardiac rehabilitation tends to reduce mortality. However, it requires medium/long-term adherence to regular physical exercise. It is relevant to identify the variables that affect adherence to an supervised exercise program (SEP). OBJECTIVE: To evaluate the influence of pre-participation levels of aerobic and non-aerobic physical fitness components in medium-term adherence to SEP. METHODS: A total of 567 SEP participants (65 +/- 12 years) (68% men) were studied. Participants adherent to the program for less than 6 months (48%) (non-adherent - NAD) were compared with 52% of participants who were adherent for 6 months or more (adherents - AD). In the non-aerobic fitness, flexibility (FLX) (Flexitest) and muscle power (MPW)/body weight in standing rowing (watts/kg) were evaluated while aerobic fitness was obtained by direct measure of VO2max/body weight (VO2). These measurements were normatized for sex and age based on percentiles (P) (P-FLX/P-MPW) of reference data or percentages of predicted (P-VO2). Additionally, AD and NAD with extreme results (tertiles) were simultaneously compared for the three variables. RESULTS: There was no difference between AD and NAD for non-aerobic results, in median [P25-P75], P FLX: 30 [13-56] and 31 [9-52], respectively, (p = 0.69) and P-MPW: 34 [17-58] and 36 [16-62], respectively (p = 0.96), and for aerobic results (mean +/- standard error) P-VO2 (75.9 +/- 1.3% and 75.0 +/- 1.3%, respectively) (p = 0.83). When comparing extreme tertiles, a difference was found for P-MPW in the lower tertile only, with a slight advantage of AD over NAD- 9 [5-16] versus 4 [1-11] (p = 0.04). CONCLUSION: Although awareness of the pre-participation levels of aerobic and non-aerobic physical fitness components is useful for individualized exercise prescription, these variables do not seem to influence medium-term adherence to SEP. PMID- 28832748 TI - Prevalence, clinical correlates and maternal psychopathology of deliberate self harm in children and early adolescents: results from a large community study. AB - OBJECTIVES: Little is known about the prevalence and correlates of deliberate self-harm (DSH) in children from low- and middle-income countries. We investigated the prevalence of DSH and its clinical and maternal psychopathological associations in Brazilian children (n=2,508, ages 6-14y) in a community-based study. METHODS: Participants of the High Risk Cohort Study for the Development of Childhood Psychiatric Disorders (HRC) and their mothers were assessed in structured interviews. Current (last month) and lifetime DSH were estimated, including analysis stratified by age groups. Logistic regressions were performed to investigate the role of the children's clinical diagnoses and maternal psychopathology on DSH prevalence estimates, adjusting for potential confounding factors. RESULTS: The prevalence of current DSH was 0.8% (children 0.6%, adolescents 1%) and lifetime DSH was 1.6% (1.8% and 1.5%, respectively). Current and lifetime DSH were more frequent in children with depression, attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), even in multiple models accounting for demographic variables and co occurring psychiatric disorders. Maternal anxiety disorder was strongly associated with current and lifetime DSH in offspring; whereas current DSH, specifically in young children, was associated with maternal mood disorder. CONCLUSION: Diagnoses of depression, ADHD and ODD were consistently associated with DSH, as was having a mother with anxiety disorder. PMID- 28832749 TI - Schizophrenia and work: aspects related to job acquisition in a follow-up study. AB - OBJECTIVE: Work is considered one of the main forms of social organization; however, few individuals with schizophrenia find work opportunities. The purpose of this study was to evaluate the relationship between schizophrenia symptoms and job acquisition. METHOD: Fifty-three individuals diagnosed with schizophrenia from an outpatient treatment facility were included in an 18-month follow-up study. After enrollment, they participated in a prevocational training group. At the end of training (baseline) and 18 months later, sociodemographic, clinical data and occupational history were collected. Positive and negative symptoms (Positive and Negative Syndrome Scale - PANSS), depression (Calgary Depression Scale), disease severity (Clinical Global Impression - CGI), functionality (Global Assessment of Functioning - GAF), personal and social performance (Personal and Social Performance - PSP) and cognitive functions (Measurement and Treatment Research to Improve Cognition in Schizophrenia - MATRICS battery) were applied at baseline and at the end of the study. RESULTS: Those with some previous work experience (n=19) presented lower scores on the PANSS, Calgary, GAF, CGI and PSP scales (p < 0.05) than those who did not work. Among those who worked, there was a slight worsening in positive symptoms (positive PANSS). CONCLUSIONS: Individuals with less severe symptoms were more able to find employment. Positive symptom changes do not seem to affect participation at work; however, this calls for discussion about the importance of employment support. PMID- 28832750 TI - Effectiveness evaluation of mood disorder treatment algorithms in Brazilian public healthcare patients. AB - OBJECTIVE: To assess the effectiveness of three mood disorder treatment algorithms in a sample of patients seeking care in the Brazilian public healthcare system. METHODS: A randomized pragmatic trial was conducted with an algorithm developed for treating episodes of major depressive disorder (MDD), bipolar depressive episodes and mixed episodes of bipolar disorder (BD). RESULTS: The sample consisted of 259 subjects diagnosed with BD or MDD (DSM-IV-TR). After the onset of symptoms, the first treatment occurred ~6 years and the use of mood stabilizers began ~12 years. All proposed algorithms were effective, with response rates around 80%. The majority of the subjects took 20 weeks to obtain a therapeutic response. CONCLUSIONS: The algorithms were effective with the medications available through the Brazilian Unified Health System. Because therapeutic response was achieved in most subjects by 20 weeks, a follow-up period longer than 12 weeks may be required to confirm adequate response to treatment. Remission of symptoms is still the main desired outcome. Subjects who achieved remission recovered more rapidly and remained more stable over time. CLINICAL TRIAL REGISTRATION: NCT02901249, NCT02870283, NCT02918097. PMID- 28832751 TI - Analysis of suicide mortality in Brazil: spatial distribution and socioeconomic context. AB - OBJECTIVE: To perform a spatial analysis of suicide mortality and its correlation with socioeconomic indicators in Brazilian municipalities. METHODS: This is an ecological study with Brazilian municipalities as a unit of analysis. Data on deaths from suicide and contextual variables were analyzed. The spatial distribution, intensity and significance of the clusters were analyzed with the global Moran index, MoranMap and local indicators of spatial association (LISA), seeking to identify patterns through geostatistical analysis. RESULTS: A total of 50,664 deaths from suicide were registered in Brazil between 2010 and 2014. The average suicide mortality rate in Brazil was 5.23/100,000 population. The Brazilian municipalities presenting the highest rates were Taipas do Tocantins, state of Tocantins (79.68 deaths per 100,000 population), Itapora, state of Mato Grosso do Sul (75.15 deaths per 100,000 population), Mampituba, state of Rio Grande do Sul (52.98 deaths per 100,000 population), Paranhos, state of Mato Grosso do Sul (52.41 deaths per 100,000 population), and Monjolos, state of Minas Gerais (52.08 deaths per 100,000 population). Although weak spatial autocorrelation was observed for suicide mortality (I = 0.2608), there was a formation of clusters in the South. In the bivariate spatial and classical analysis, no correlation was observed between suicide mortality and contextual variables. CONCLUSION: Suicide mortality in Brazil presents a weak spatial correlation and low or no spatial relationship with socioeconomic factors. PMID- 28832752 TI - Analysis of the spatial distribution of dengue cases in the city of Rio de Janeiro, 2011 and 2012. AB - OBJECTIVE: Analyze the spatial distribution of classical dengue and severe dengue cases in the city of Rio de Janeiro. METHODS: Exploratory study, considering cases of classical dengue and severe dengue with laboratory confirmation of the infection in the city of Rio de Janeiro during the years 2011/2012. The georeferencing technique was applied for the cases notified in the Notification Increase Information System in the period of 2011 and 2012. For this process, the fields "street" and "number" were used. The ArcGis10 program's Geocoding tool's automatic process was performed. The spatial analysis was done through the kernel density estimator. RESULTS: Kernel density pointed out hotspots for classic dengue that did not coincide geographically with severe dengue and were in or near favelas. The kernel ratio did not show a notable change in the spatial distribution pattern observed in the kernel density analysis. The georeferencing process showed a loss of 41% of classic dengue registries and 17% of severe dengue registries due to the address in the Notification Increase Information System form. CONCLUSIONS: The hotspots near the favelas suggest that the social vulnerability of these localities can be an influencing factor for the occurrence of this aggravation since there is a deficiency of the supply and access to essential goods and services for the population. To reduce this vulnerability, interventions must be related to macroeconomic policies. OBJETIVO: Analisar a distribuicao espacial dos casos de dengue classico e dengue grave no municipio do Rio de Janeiro. METODOS: Estudo exploratorio, considerando casos de dengue classico e de dengue grave com comprovacao laboratorial da infeccao, ocorridos no municipio do Rio de Janeiro nos anos de 2011/2012. Foi aplicada a tecnica de georreferenciamento dos casos notificados no Sistema de Informacao de Agravos de Notificacao, no periodo de 2011 e 2012. Para esse processo, utilizaram-se os campos "logradouro" e "numero". Foi realizado o processo automatico da ferramenta Geocoding do programa ArcGis10. A analise espacial foi feita a partir do estimador de densidade Kernel. RESULTADOS: A densidade de Kernel apontou areas quentes para dengue classico nao coincidente geograficamente a dengue grave, estando localizadas dentro ou proximas de favelas. O calculo da razao de Kernel nao apresentou modificacao significativa no padrao de distribuicao espacial observados na analise da densidade de Kernel. O processo de georreferenciamento mostrou perda de 41% dos registros de dengue classico e 17% de dengue grave devido ao enderecamento da ficha do Sistema de Informacao de Agravos de Notificacao. CONCLUSOES: As areas quentes proximas as favelas sugerem que a vulnerabilidade social existente nessas localidades pode ser um fator de influencia para a ocorrencia desse agravo, uma vez que ha deficiencia da oferta e acesso a bens e servicos essenciais para a populacao. Para diminuir essa vulnerabilidade, as intervencoes devem estar relacionadas a politicas macroeconomicas. PMID- 28832753 TI - Recent illicit drug use among psychiatric patients in Brazil: a national representative study. AB - OBJECTIVE: To estimate factors associated to illicit drug use among patients with mental illness in Brazil according to gender. METHODS: A cross-sectional representative sample of psychiatric patients (2,475 individuals) was randomly selected from 11 hospitals and 15 public mental health outpatient clinics. Data on self-reported illicit drug use and sociodemographic, clinical and behavioral characteristics were obtained from face-to-face interviews. Logistic regression was used to estimate associations with recent illicit drug use. RESULTS: The prevalence of any recent illicit drug use was 11.4%. Men had higher prevalence than women for all substances (17.5% and 5.6%, respectively). Lower education, history of physical violence, and history of homelessness were associated with drug use among men only; not professing a religion was associated with drug use in women only. For both men and women, younger age, current hospitalization, alcohol and tobacco use, history of incarceration, younger age at sexual debut, and more than one sexual partner were statistically associated with illicit drug use. CONCLUSIONS: Recent illicit drug use among psychiatric patients is higher than among the general Brazilian population and it is associated with multiple factors including markers of psychiatric severity. Our data indicate the need for the development of gender-based drug-use interventions among psychiatric patients in Brazil. Integration of substance use treatment strategies with mental health treatment should be a priority. PMID- 28832754 TI - Estimated costs of advanced lung cancer care in a public reference hospital. AB - OBJECTIVE: To estimate the direct medical costs of advanced non-small cell lung cancer care. METHODS: We assessed a cohort of 277 patients treated in the Brazilian National Cancer Institute in 2011. The costs were estimated from the perspective of the hospital as a service provider of reference for the Brazilian Unified Health System. The materials and procedures used were identified and quantified, per patient, and we assigned to them monetary values, consolidated in phases of the assistance defined. The analyses had a descriptive character with costs in Real (R$). RESULTS: Overall, the cohort represented a cost of R$2,473,559.91, being 71.5% related to outpatient care and 28.5% to hospitalizations. In the outpatient care, costs with radiotherapy (34%) and chemotherapy (22%) predominated. The results pointed to lower costs in the initial phase of treatment (7.2%) and very high costs in the maintenance phase (61.6%). Finally, we identified statistically significant differences of average cost by age groups, education levels, physical performance, and histological type. CONCLUSIONS: This study provides a current, useful, and relevant picture of the costs of patients with non-small cell lung cancer treated in a public hospital of reference and it provides information on the magnitude of the problem of cancer in the context of public health. The results confirm the importance of radiation treatment and hospitalizations as the main components of the cost of treatment. Despite some losses of follow-up, we assess that, for approximately 80% of the patients included in the study, the estimates presented herein are satisfactory for the care of the disease, from the perspective of a service provider of reference of the Brazilian Unified Health System, as it provides elements for the management of the service, as well as for studies that result in more rational forms of resource allocation. OBJETIVO: Estimar os custos medicos diretos da assistencia ao cancer de pulmao nao pequenas celulas avancado. METODOS: Foi avaliada uma coorte de 277 pacientes matriculados no Instituto Nacional do Cancer em 2011. Os custos foram estimados sob a perspectiva do hospital como prestador de servicos de referencia para o SUS. Insumos e procedimentos utilizados foram identificados e quantificados, por paciente, sendo a eles atribuidos valores monetarios, consolidados por fases da assistencia definidas. As analises tiveram carater descritivo com custos em reais (R$). RESULTADOS: Em termos globais, a coorte representou um custo de R$2.473.559,91, sendo 71,5% relacionados a atencao ambulatorial e 28,5% as internacoes. Na atencao ambulatorial, predominaram os custos com radioterapia (34%) e quimioterapia (22%). Os resultados apontaram para custos menores na fase inicial de tratamento (7,2%) e custos muito elevados na fase de manutencao (61,6%). Por fim, identificaram-se diferencas estatisticamente significativas das medias dos custos por faixas etarias, niveis de escolaridade, desempenho fisico e tipo histologico. CONCLUSOES: Este estudo fornece um retrato atual, util e relevante sobre os custos de pacientes com cancer de pulmao nao pequenas celulas assistidos em um hospital publico de referencia e prove elementos sobre a magnitude do problema do cancer no ambito da saude publica. Os resultados ratificam a importancia do tratamento radioterapico e das internacoes como principais componentes de custo do tratamento. Apesar de algumas perdas de seguimento avalia se que, para cerca de 80% dos pacientes incluidos no estudo, as estimativas aqui apresentadas sejam satisfatoriamente fidedignas ao cuidado da doenca, sob a perspectiva de um prestador de referencia do SUS, fornecendo elementos para a gestao do servico, bem como para estudos que redundem em formas mais racionais de alocacao de recursos. PMID- 28832755 TI - Assessment in the primary care of the State of Sao Paulo, Brazil: incipient actions in sexual and reproductive health. AB - OBJECTIVE: The objective of this study is to assess performance in sexual and reproductive health of primary health care services of the Brazilian Unified Health System, in the State of Sao Paulo, Brazil. METHODS: An evaluative framework was built for sexual and reproductive health with the categorization of 99 indicators in three domains: sexual and reproductive health promotion (25), sexually transmitted infections/AIDS prevention and care (43), and reproductive health care (31). This framework was applied to assess the services responses to the questionnaire of Quality Evaluation of Primary Health Care in the Municipalities of Sao Paulo State (QualiAB), in 2010. Percentages were calculated for positive responses to indicators and performance in the sexual and reproductive health dimension, according to domains, and their contribution to the overall score in sexual and reproductive health (Friedman), relative participation (Dunn), and correlation (Spearman) was verified. RESULTS: Overall, 2,735 services participated in the study. They were located in 586 municipalities (distributed throughout the 17 regional health departments of Sao Paulo), of which 70.6% had fewer than 100,000 inhabitants. The overall average performance of these services for sexual and reproductive health is 56.8%. The actions are characterized by: prenatal with adequate beginning and exams, better organization for immediate rather than for late postnatal care, and selective reproductive planning for some contraceptives; prevention based on specific protection, limitations in the prevention of congenital syphilis, in the treatment of sexually transmitted infections, and in the screening of cervical and breast cancer; specific educational activities, with a restricted vulnerability approach, focus on sexuality over reproduction. The domain of reproductive health has greater participation in the overall score, followed by prevention/care and promotion. The three domains are correlated; the domain of prevention/care has the highest correlation with the other ones. CONCLUSIONS: The implementation of sexual and reproductive health in primary health care in the services studied is incipient. The revision of the purpose of the work, the dissemination of technologies, and the investing in permanent education are needed. The evaluative framework built can be used by the sexual and reproductive health program services and management in primary health care, thereby contributing to their actions. OBJETIVO: Avaliar o desempenho em saude sexual e reprodutiva de servicos de atencao primaria a saude do Sistema Unico de Saude, no estado de Sao Paulo. METODOS: Construiu-se quadro avaliativo para a saude sexual e reprodutiva com a categorizacao de 99 indicadores em tres dominios: promocao a saude sexual e reprodutiva (25), prevencao e assistencia as doencas sexualmente transmissiveis/aids (43), e atencao a saude reprodutiva (31). Esse quadro foi aplicado para avaliar as respostas dos servicos ao questionario Avaliacao da Qualidade da Atencao Basica em Municipios de Sao Paulo (QualiAB), em 2010. Calcularam-se as porcentagens de respostas positivas aos indicadores e o desempenho na dimensao saude sexual e reprodutiva, segundo os dominios; e verificou-se sua contribuicao para o escore geral em saude sexual e reprodutiva (Friedman), participacao relativa (Dunn) e correlacao (Spearman). RESULTADOS: Participaram 2.735 servicos, localizados em 586 municipios (distribuidos nos 17 departamentos regionais de saude paulistas), dos quais 70,6% municipios com menos de 100.000 habitantes. A media geral do desempenho desses servicos para saude sexual e reprodutiva e 56,8%. As acoes sao caracterizadas por: pre-natal com inicio e exames adequados, melhor organizacao para puerperio imediato do que tardio, e planejamento reprodutivo seletivo para alguns contraceptivos; prevencao baseada em protecao especifica, limites na prevencao da sifilis congenita, no tratamento de doencas sexualmente transmissiveis, no rastreamento do cancer cervical e mamario; atividades educativas pontuais, com restrita abordagem das vulnerabilidades, predominio do enfoque da sexualidade centrado na reproducao. O dominio saude reprodutiva tem maior participacao no escore geral, seguido de prevencao/assistencia e promocao. Os tres dominios estao correlacionados; o dominio prevencao/assistencia apresenta as maiores correlacoes com os demais. CONCLUSOES: A implementacao da saude sexual e reprodutiva na atencao primaria a saude nos servicos estudados e incipiente. E necessario rever finalidades do trabalho, disseminar tecnologias e investir em educacao permanente. O quadro avaliativo construido pode ser utilizado pelos servicos e pela gestao do programa de saude sexual e reprodutiva na atencao primaria a saude e contribuir para suas acoes. PMID- 28832756 TI - Multinomial model and zero-inflated gamma model to study time spent on leisure time physical activity: an example of ELSA-Brasil. AB - OBJECTIVE: To compare two methodological approaches: the multinomial model and the zero-inflated gamma model, evaluating the factors associated with the practice and amount of time spent on leisure time physical activity. METHODS: Data collected from 14,823 baseline participants in the Longitudinal Study of Adult Health (ELSA-Brasil - Estudo Longitudinal de Saude do Adulto ) have been analysed. Regular leisure time physical activity has been measured using the leisure time physical activity module of the International Physical Activity Questionnaire. The explanatory variables considered were gender, age, education level, and annual per capita family income. RESULTS: The main advantage of the zero-inflated gamma model over the multinomial model is that it estimates mean time (minutes per week) spent on leisure time physical activity. For example, on average, men spent 28 minutes/week longer on leisure time physical activity than women did. The most sedentary groups were young women with low education level and income. CONCLUSIONS: The zero-inflated gamma model, which is rarely used in epidemiological studies, can give more appropriate answers in several situations. In our case, we have obtained important information on the main determinants of the duration of leisure time physical activity. This information can help guide efforts towards the most vulnerable groups since physical inactivity is associated with different diseases and even premature death. PMID- 28832757 TI - Structure and work process in primary care and hospitalizations for sensitive conditions. AB - OBJECTIVE: The objective of this study is to investigate whether the characteristics of the structure of primary health units and the work process of primary care teams are associated with the number of hospitalizations for primary care sensitive conditions. METHODS: In this ecological study, we have analyzed data of Brazilian municipalities related to sociodemographic characteristics, coverage of care programs, structure of primary health units, and work process of primary care teams. We have obtained the data from the first cycle of the Brazilian Program for Improving Access and Quality of the Primary Care, of the Department of Information Technology of the Brazilian Unified Health System, the Brazilian Institute of Geography and Statistics, and the United Nations Development Programme. The associations have been estimated using negative binomial regression coefficients (beta) and respective 95% confidence intervals, with a hierarchical approach in three levels (alpha = 5%). RESULTS: In the adjusted analysis for the outcome in 2013, in the distal level, the coverage of the Bolsa Familia Program (beta = -0.001) and private insurance (beta = -0.01) had a negative association, and the human development index (beta = 1.13), the proportion of older adults (beta = 0.05) and children under the age of five (beta = 0.05), and the coverage of the Community Health Agent Strategy (beta = 0.002) showed positive association with hospitalizations for primary care sensitive conditions. In the intermediate level, minimum hours (beta = -0.14) and availability of vaccines (beta = -0.16) showed a negative association, and availability of medications showed a positive association (beta = 0.16). In the proximal level, only the variable of matrix support (beta = 0.10) showed a positive association. The variables in the adjusted analysis of the number of hospitalizations for primary care sensitive conditions in 2014 presented the same association as in 2013. CONCLUSIONS: The characteristics of the structure of primary health units and the work process of the primary care teams impact the number of hospitalizations for primary care sensitive conditions in Brazilian municipalities. OBJETIVO: Investigar se caracteristicas da estrutura das unidades basicas de saude e do processo de trabalho das equipes de atencao basica estao associadas ao numero de internacoes por condicoes sensiveis a atencao primaria. METODOS: Neste estudo ecologico, foram analisados dados de municipios brasileiros relativos a caracteristicas sociodemograficas, de cobertura de programas assistenciais, de estrutura das unidades basicas de saude e processo de trabalho das equipes de atencao basica. Os dados foram obtidos do primeiro ciclo do Programa de Melhoria do Acesso e Qualidade da Atencao Basica, do Departamento de Informatica do Sistema Unico de Saude, do Instituto Brasileiro de Geografia e Estatistica e do Programa das Nacoes Unidas. Estimaram-se as associacoes por meio de coeficientes de regressao binomial negativa (beta) e respectivos intervalos de confianca a 95%, com abordagem hierarquizada em tres blocos (alpha = 5%). RESULTADOS: Na analise ajustada, para o desfecho em 2013, no bloco distal, a cobertura do Programa Bolsa Familia (beta = -0,001) e de plano privado (beta = 0,01) apresentaram associacao negativa; e o indice de desenvolvimento humano (beta = 1,13), a proporcao de pessoa idosa (beta = 0,05) e de menor de cinco anos (beta = 0,05) e a cobertura da Estrategia de Agentes Comunitarios de Saude (beta = 0,002) mostraram associacao positiva com internacoes por condicoes sensiveis a atencao primaria. No bloco intermediario, apresentaram associacao negativa o horario minimo (beta = -0,14) e a disponibilidade de vacina (beta = -0,16); e associacao positiva, a disponibilidade de medicamentos (beta = 0,16). No bloco proximal, apenas a variavel apoio matricial (beta = 0,10) mostrou associacao positiva. Na analise ajustada do numero de internacoes por condicoes sensiveis a atencao primaria em 2014, as variaveis apresentaram o mesmo sentido de associacao de 2013. CONCLUSOES: Caracteristicas da estrutura das unidades basicas de saude e do processo de trabalho das equipes de atencao basica impactam no numero de internacoes por condicoes sensiveis a atencao primaria nos municipios brasileiros. PMID- 28832758 TI - Risk factors for syphilis in women: case-control study. AB - OBJECTIVE: To determine the sociodemographic, behavioral, and health care factors related to the occurrence of syphilis in women treated at public maternity hospitals. METHODS: This is a case-control study (239 cases and 322 controls) with women admitted to seven maternity hospitals in the municipality of Recife, Brazil, from July 2013 to July 2014. Eligible women were recruited after the result of the VDRL (Venereal Disease Research Laboratory) under any titration. The selection of cases and controls was based on the result of the serology for syphilis using ELISA (enzyme-linked immunosorbent assay). The independent variables were grouped into: sociodemographic, behavioral, clinical and obstetric history, and health care in prenatal care and maternity hospital. Information was obtained by interview, during hospitalization, with the application of a questionnaire. Odds ratios and 95% confidence intervals were estimated using logistic regression to identify the predicting factors of the variable to be explained. RESULTS: The logistic regression analysis identified as determinant factors for gestational syphilis: education level of incomplete basic education or illiterate (OR = 2.02), lack of access to telephone (OR = 2.4), catholic religion (OR = 1.70 ), four or more pregnancies (OR = 2.2), three or more sexual partners in the last year (OR = 3.1), use of illicit drugs before the age of 18 (OR = 3.0), and use of illicit drugs by the current partner (OR = 1.7). Only one to three prenatal appointments (OR = 3.5) and a previous history of sexually transmitted infection (OR = 9.7) were also identified as determinant factors. CONCLUSIONS: Sociodemographic, behavioral, and health care factors are associated with the occurrence of syphilis in women and should be taken into account in the elaboration of universal strategies aimed at the prevention and control of syphilis, but with a focus on situations of greater vulnerability. OBJETIVO: Determinar os fatores sociodemograficos, comportamentais e de assistencia a saude relacionados a ocorrencia de sifilis em mulheres atendidas em maternidades publicas. METODOS: Trata-se de um estudo caso-controle (239 casos e 322 controles) com mulheres admitidas em sete maternidades do municipio do Recife, no periodo de julho de 2013 a julho de 2014. As mulheres elegiveis foram recrutadas apos o resultado do VDRL (Venereal Disease Research Laboratory) sob qualquer titulacao. A selecao dos casos e controles considerou o resultado da sorologia por ELISA (enzyme-linked immunosorbent assay), variavel dependente utilizada como diagnostico para sifilis neste estudo. As variaveis independentes foram agrupadas em: sociodemograficas; comportamentais; e antecedentes clinicos e obstetricos; e assistencia a saude no pre-natal e na maternidade. As informacoes foram obtidas por meio de entrevista, durante o internamento, por aplicacao de um questionario. Foi calculado odds ratio (OR), intervalo de confianca de 95% e realizada analise de regressao logistica para identificar os fatores preditores da variavel a ser explicada. RESULTADOS: A analise de regressao logistica identificou como fatores determinantes para a sifilis gestacional: nivel de escolaridade fundamental incompleto ou analfabeta (OR = 2,02), ausencia de acesso a telefone (OR = 2,4), religiao catolica (OR = 1,70), quatro ou mais gestacoes (OR = 2,2), tres ou mais parceiros sexuais no ultimo ano (OR = 3,1), uso de drogas ilicitas antes dos 18 anos (OR = 3,0) e uso de drogas ilicitas por parte do atual companheiro (OR = 1,7). Alem desses, foram observadas a ocorrencia de apenas uma a tres consultas ao pre-natal (OR = 3,5) e historia anterior de infeccao sexualmente transmissivel (OR = 9,7). CONCLUSOES: Fatores sociodemograficos, comportamentais e de assistencia a saude estao associados a ocorrencia de sifilis em mulheres e devem ser levados em consideracao na elaboracao de estrategias universais direcionadas a prevencao e controle da sifilis, porem com foco em situacoes de maior vulnerabilidade. PMID- 28832759 TI - Spatial patterns of preventable perinatal mortality in Salvador, Bahia, Brazil. AB - OBJECTIVE: To identify the spatial distribution patterns and areas of higher risk of preventable perinatal mortality in the city of Salvador, State of Bahia, Brazil. METHODS: We carried out a spatial aggregated study in 2007, considering the weighting areas (census tracts contiguous sets) of Salvador, of which the center and north present low life conditions. Data were obtained from national vital statistics systems and the 2010 Census. Addresses of live births and stillbirths were geocoded by weighting area. The spatial distribution of the perinatal mortality rate was analyzed from thematic maps. Spatial dependence was evaluated by the Global and Local Geary's and Moran's Indexes. RESULTS: Crude and smoothed perinatal mortality rates were high in areas situated to the north, west, and in center of Salvador. The smoothed rates in weighting areas ranged from 4.9/1,000 to 22.3/1,000 births. Of all perinatal deaths, 92.1% could have been prevented. We identified spatial dependence for preventable perinatal mortality for care in pregnancy, with neighboring areas with high risk in the north of the city. CONCLUSIONS: The preventability potential of perinatal mortality was high in Salvador, in 2007. The spatial distribution pattern with higher rates in disadvantaged areas of the city suggests the existence of social inequalities in health. The characteristics of the process of urban development of Salvador, which has inadequate prenatal care, possibly influenced the magnitude and spatial distribution pattern of this mortality. PMID- 28832760 TI - Meta-analysis of the association between PADI4 -92C/G polymorphism and rheumatoid arthritis in the Chinese population. AB - Many studies have evaluated the correlation between peptidylarginine deiminase 4 (PADI4) -92C/G polymorphism and rheumatoid arthritis (RA), but the results remain inconclusive. Therefore, we performed a meta-analysis in the Chinese population to provide comprehensive data on the association between PADI4 -92C/G polymorphism and RA. Eligible studies published before May 2016 were identified in PubMed and Chinese databases. The strengths of these associations were assessed by pooled odds ratios (OR) and 95% confidence interval (CI). Eight studies documenting a total of 1351 RA cases and 1585 controls were included in this meta-analysis. In the overall analysis, a significant association between the PADI4 -92C/G polymorphism and RA was found in the Chinese population (G vs C: OR=1.32, 95%CI=1.02-1.71; GG+CG vs CC: OR=1.75, 95%CI=1.20-2.53). The subgroup analyses stratified by geographic area(s) and source of controls revealed significant results in South China, in hospital-based studies and population based studies. In summary, this meta-analysis suggested that PADI4 -92C/G polymorphism may be associated with the RA incidence in the Chinese population, especially for South China. Further studies conducted on other ethnic groups are required for definite conclusions. PMID- 28832761 TI - Salinomycin enhances doxorubicin sensitivity through reversing the epithelial mesenchymal transition of cholangiocarcinoma cells by regulating ARK5. AB - Chemotherapy response rates in patients with cholangiocarcinoma remain low, primarily due to the development of drug resistance. Epithelial-mesenchymal transition (EMT) of cancer cells is widely accepted to be important for metastasis and progression, but it has also been linked to the development of chemoresistance. Salinomycin (an antibiotic) has shown some potential as a chemotherapeutic agent as it selectively kills cancer stem cells, and has been hypothesized to block the EMT process. In this study, we investigated whether salinomycin could reverse the chemoresistance of cholangiocarcinoma cells to the chemotherapy drug doxorubicin. We found that combined salinomycin with doxorubicin treatment resulted in a significant decrease in cell viability compared with doxorubicin or salinomycin treatment alone in two cholangiocarcinoma cell lines (RBE and Huh-28). The dosages of both drugs that were required to produce a cytotoxic effect decreased, indicating that these two drugs have a synergistic effect. In terms of mechanism, salinomycin reversed doxorubicin-induced EMT of cholangiocarcinoma cells, as shown morphologically and through the detection of EMT markers. Moreover, we showed that salinomycin treatment downregulated the AMP-activated protein kinase family member 5 (ARK5) expression, which regulates the EMT process of cholangiocarcinoma. Our results indicated that salinomycin reversed the EMT process in cholangiocarcinoma cells by inhibiting ARK5 expression and enhanced the chemosensitivity of cholangiocarcinoma cells to doxorubicin. Therefore, a combined treatment of salinomycin with doxorubicin could be used to enhance doxorubicin sensitivity in patients with cholangiocarcinoma. PMID- 28832762 TI - Antidepressant effects of Kai-Xin-San in fluoxetine-resistant depression rats. AB - This study aimed to investigate the antidepressant effect and the mechanism of action of Kai-Xin-San (KXS) in fluoxetine-resistant depressive (FRD) rats. Two hundred male Wistar rats weighing 200+/-10 g were exposed to chronic and unpredictable mild stresses (CUMS) for 4 weeks and given fluoxetine treatment simultaneously. The rats that did not show significant improvement in behavioral indexes were chosen as the FRD model rats. These rats were randomly divided into four groups: FRD model control; oral fluoxetine and aspirin; oral KXS at a dose of 338 mg.kg-1.day-1; and oral KXS at a dose of 676 mg.kg-1.day-1. Rats continued to be exposed to CUMS and underwent treatment once a day for 3 weeks, then cytokine (COX-2, IFN-gamma, IL-1beta, IL-2, IL-4, IL-6, IL-10, TGF-beta, and TNF alpha) levels in the hippocampus and serum, and organ coefficients were measured. Both doses of KXS improved the crossing and rearing frequencies, sucrose preference index, and body weight in FRD rats. KXS at a dose of 338 mg.kg-1.day 1reduced COX-2, IL-2, IL-6, TNF-alpha levels, increased IL-10 level in the hippocampus, and reduced IL-2 and TNF-alpha levels in serum. KXS at a dose of 676 mg.kg-1.day-1reduced TNF-alpha level in the hippocampus, reduced IL-2 and TNF alpha levels in serum, and increased IFN-gamma and IL-10 levels in the hippocampus and serum. There were no significant differences in organ coefficients of the spleen among and between groups. The results suggested that oral administration of KXS in FRD rats was effective in improving behavior disorders by influencing various inflammatory pathways. PMID- 28832763 TI - Methotrexate associated to lipid core nanoparticles improves cardiac allograft vasculopathy and the inflammatory profile in a rabbit heart graft model. AB - Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and has no effective treatment. A lipid nanoemulsion (LDE) can carry chemotherapeutic agents in the circulation and concentrates them in the heart graft. The aim of the study was to investigate the effects of methotrexate (MTX) associated to LDE. Rabbits fed a 0.5% cholesterol diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg.kg-1.day-1 orally) and allocated to treatment with intravenous LDE-MTX (4 mg/kg, weekly, n=10) or with weekly intravenous saline solution (control group, n=10), beginning on the day of surgery. Animals were euthanized 6 weeks later. Compared to controls, grafts of LDE-MTX treated rabbits showed 20% reduction of coronary stenosis, with a four-fold increase in vessel lumen and 80% reduction of macrophage staining in grafts. Necrosis was attenuated by LDE-MTX. Native hearts of both LDE-MTX and Control groups were apparently normal. Gene expression of lipoprotein receptors was significantly greater in grafts compared to native hearts. In LDE-MTX group, gene expression of the pro-inflammatory factors tumor necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-18, vascular cell adhesion molecule-1, and matrix metalloproteinase-12 was strongly diminished whereas expression of anti inflammatory interleukin-10 increased. LDE-MTX promoted improvement of the cardiac allograft vasculopathy and diminished inflammation in heart grafts. PMID- 28832764 TI - Proliferation and osteogenic activity of fibroblasts induced with fibronectin. AB - The aim of this study was to determine the proliferation and osteogenic activity of fibroblasts induced with fibronectin and their possible dose-dependent relationship. The fibroblasts obtained by tissue explants adherent method were induced with fibronectin at different concentrations of 0, 10, 20, 40, 60, and 80 MUg/mL for 14 days. The 3H-thymidine and 3H-proline incorporation test was used to evaluate the synthesis of DNA and collagen by fibroblasts, respectively. The mineralized nodules and osteocalcin secretion, as vital osteogenic indicators, were detected with tetracycline labeling and 125I-labeled competitive immunoassay, respectively. Fibronectin significantly increased the synthesis of DNA and collagen by fibroblasts, especially at the concentration of 40 MUg/mL (P<0.05). The increased secretion of osteocalcin in the supernatant was also statistically significant at the concentration of 40 MUg/mL (P<0.05). The mineralized nodules with trabecula-like structure derived from induced fibroblasts were positive for tetracycline labeling. The granulation tissue derived fibroblasts induced with fibronectin exhibited increased proliferative, functional and osteogenic potential. Fibroblasts are considered a possible in situ stem cell in tissue engineering. PMID- 28832765 TI - Is endobronchial ultrasound-guided transbronchial needle aspiration with a stylet necessary for lymph node screening in lung cancer patients? AB - During endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA), a needle is commonly used with a stylet, although recently the stylet has been omitted. This prospective study aimed to compare the quality of specimens obtained by EBUS-TBNA performed with and without a stylet. Between November 2013 and November 2014, 131 patients with lung cancer underwent EBUS-TBNA, with a total of 148 mediastinal or hilar lymph nodes sampled both with and without an inner-stylet, yielding 296 cytological specimens. Specimens were scored cytologically using five parameters: background blood or clot, amount of cellular material, degree of cellular degeneration, degree of cellular trauma, and retention of appropriate architecture. The procedure with a stylet required significantly longer operation time than without a stylet (14.5+/-0.8 vs 12.7+/ 1.1 min, P<0.001). Excellent specimens were obtained in 261/296 and 260/296 samples in the procedures with and without a stylet, respectively (P=0.9), while the remaining 35 and 36 samples, respectively, were adequate. The diagnosing and staging of lung cancer using EBUS-TBNA did not differ significantly between the groups. In conclusion, specimen collection by EBUS-TBNA without a stylet is easier and faster than the procedure using a stylet and absence of a stylet did not alter specimen quality or diagnostic accuracy. PMID- 28832766 TI - Potential benefit of (-)-epigallocatechin-3-gallate for macrovascular complications in diabetes. AB - Vascular problems are the most common complications in diabetes. Substantial evidence from epidemiological and pathophysiological studies show that hyperglycemia is a major risk factor for macrovascular complications in patients with diabetes. (-)-Epigallocatechin-3-gallate (EGCG), the major catechin derived from green tea, is known to exert a variety of cardiovascular beneficial effects. The protective effects of EGCG in diabetes are also evident. However, whether EGCG is beneficial against macrovascular complications that occur in diabetes remains unknown. Our previous studies demonstrated that treatment of EGCG inhibits high glucose-induced vascular smooth muscle cell proliferation and suppresses high glucose-mediated vascular inflammation in human umbilical vein endothelial cells. Therefore, we hypothesize that EGCG might be an effective potential candidate to reduce the macrovascular complications in diabetes. PMID- 28832767 TI - Antiviral activity of shikonin ester derivative PMM-034 against enterovirus 71 in vitro. AB - Human enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD), particularly in infants and children below 4 years of age. Shikonin is a bioactive compound with anti-inflammatory, antiviral, and antibacterial activities derived from the roots of the Chinese medicinal herb Lithospermum erythrorhizon. This study aimed to examine the antiviral activity of PMM-034, a shikonin ester derivative, against EV71 in rhabdomyosarcoma (RD) cells. Cytotoxicity of PMM-034 on RD cells was determined using WST-1 assay. Dose and time-dependent effects of PMM-034 on EV71 replication in RD cells were determined using plaque reduction assay. mRNA expression levels of EV71/VP1 and pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, and TNF-alpha) were determined by real-time RT-PCR, and EV71/VP1 and phospho-p65 protein expressions were determined by western blot analysis. PMM-034 exhibited only weak cytotoxicity against RD cells. However, PMM-034 exhibited significant antiviral activity against EV71 in RD cells with 50% inhibitory concentration of 2.31 MUg/mL. The VP1 mRNA and protein levels were significantly reduced in cells treated with PMM 034. Furthermore, relative mRNA expression levels of IL-1beta, IL-6, IL-8, and TNF-alpha significantly decreased in the cells treated with PMM-034, while the phospho-p65 protein expression was also significantly lower in the treated cells. These results indicated that PMM-034 suppressed the expressions of pro inflammatory cytokines in RD cells, exhibiting antiviral activity against EV71, as evidenced by the reduced VP1 mRNA and protein levels in PMM-034-treated cells. Thus, PMM-034 is a promising candidate for further development as an EV71 inhibitor. PMID- 28832769 TI - Welfarism and extra-welfarism: a critical overview. AB - Rules and principles for guiding decision-making in the health care sector have been debated for decades. Here, we present a critical appraisal of the two most important paradigms in this respect: welfarism and extra-welfarism. While the former deals with the maximization of the overall sum of individual utilities as its primary outcome, the latter has been focusing on the maximization of the overall health status. We argue that welfarism has three main problems: (1) its central idea of overall sum of individual utilities does not capture societal values decisively relevant in the context of health; (2) the use of the Potential Pareto Improvement brings an unresolvable separation between efficiency and equity; and (3) individual utility may not be a good measure in the health sector, given that individuals might value things that diminish their overall health. In turn, the extra-welfarist approach is criticized regarding four main limitations: (1) the advocated expansion of the evaluative space, moving from utility to health, may have represented in reality a narrowing of it; (2) it operates using non-explicit considerations of equity; (3) it still holds the issue of "inability to desire" of unprivileged people being considered the best judges of weighing the criteria used to building the health measures; and (4) there is controversial empirical evidence about society members' values that support its assumptions. Overall, both paradigms show significant weaknesses, but the debate has still been within the realm of welfare economics, and even the new approaches to resource allocation in health care systems appear to be unable to escape from these boundaries. PMID- 28832768 TI - Application of data mining techniques to explore predictors of upper urinary tract damage in patients with neurogenic bladder. AB - This study proposed a decision tree model to screen upper urinary tract damage (UUTD) for patients with neurogenic bladder (NGB). Thirty-four NGB patients with UUTD were recruited in the case group, while 78 without UUTD were included in the control group. A decision tree method, classification and regression tree (CART), was then applied to develop the model in which UUTD was used as a dependent variable and history of urinary tract infections, bladder management, conservative treatment, and urodynamic findings were used as independent variables. The urethra function factor was found to be the primary screening information of patients and treated as the root node of the tree; Pabd max (maximum abdominal pressure, >14 cmH2O), Pves max (maximum intravesical pressure, <=89 cmH2O), and gender (female) were also variables associated with UUTD. The accuracy of the proposed model was 84.8%, and the area under curve was 0.901 (95%CI=0.844-0.958), suggesting that the decision tree model might provide a new and convenient way to screen UUTD for NGB patients in both undeveloped and developing areas. PMID- 28832770 TI - [Micro-death and life of Severina? Preemptive risk communication]. AB - This essay problematizes the dominant approach to health risk communication. It thus consults and analyzes authors that present themselves as experts in risk communication and passages from mainstream audiovisual media broadcasts. While risk communication appears as an area of mediation between experts and the lay public, with the potential to generate technological innovation and potentially consumable merchandise, health risk communication occupies a biopolitical place that reinforces blaming individuals and individualizing risk avoidance proposals. The effacement of the contexts in which risk exposures occur feeds and is fed by the current neoliberal context. In addition to attempts at mediation that are often problematic, the rational and individual risk management perspective, no matter how fully equipped with innovative technologies, fails to ameliorate the contextual precariousness in which health risks are produced. Paradoxically, the belief in risk management (the dominant approach in health risk communication) ends up producing moralization, anxiety, and malaise. PMID- 28832771 TI - [Indicators of physical and social neighborhood attributes measured by the Systematic Social Observation method]. AB - Place of residence is heavily shaped by social position, indicating that neighborhood characteristics can be important contributing factors to health iniquities. The objectives were to construct indicators of the physical and social environment in an urban context based on variables obtained with the Systematic Social Observation method (SSO) and to analyze them according to the Health Vulnerability Index (HVI). The instrument was developed to determine the characteristics of the physical and social neighborhood in two health districts in Belo Horizonte, Minas Gerais State, Brazil. Data were collected from April to June 2011. To develop the simple indicators, ratios were calculated for the number of observed items per residence in each segment. Composite indicators were built using principal components analysis via covariance matrix. The final sample consisted of 1,295 street segments nested in 147 neighborhoods. Indicators referring to street conditions and transit items, mobility, appearance, housing and property, physical disorder, safety/security, and services showed a dose response behavior in relation to HVI (p < 0.05). Indicators pertaining to place to practice physical activity and leisure did not show significant differences. The indicators displayed coherent behavior towards different HVI strata and proved adequate within each respective domain and subdomain. PMID- 28832773 TI - [Optimistic perspectives in communicating difficult news on fetal development]. AB - Communicating diagnostic news in health contexts is a potentially difficult event for all parties involved. However, despite this task's presence in the physician patient context, it is rarely addressed during clinical training. The current study thus aimed to describe and evaluate how difficult news can be toned down during genetic counseling sessions involving cases of fetal syndromes and/or malformations. The study analyzed 33 naturalistic interactions (i.e. real situations), taped and transcribed, according to the theoretical and methodological perspective of Conversation Analysis, with an ethnomethodological basis. These interactions consisted of sessions in clinical genetics with pregnant women seen at the fetal medicine service of a reference hospital for maternal and child health in the Brazilian Unified National Health System (SUS). The analysis showed that communicating difficult news can be accompanied by optimistic perspectives that are scaled-up according to each situation's severity. In the absence of a positive diagnosis, the appointments can conclude with positive aspects such as recommendations for palliative care, so that the patient always leaves the appointment with some kind of recommendation. This study proposes to innovate and expand the scope of studies on communicating difficult news in the physician-patient relationship in Brazil, precisely by developing an analysis of real interactions in genetic counseling and thus providing interactional backing for training health professionals that deal with this challenge in their routine work. PMID- 28832772 TI - [Structural typology of Brazilian primary healthcare units: the 5 Rs]. AB - The structural typology of Brazil's 38,812 primary healthcare units (UBS) was elaborated on the basis of the results from a survey in cycle 1 of the National Program for Improvement in Access and Quality of Primary Care. Type of team, range of professionals, shifts open to the public, available services, and installations and inputs were the sub-dimensions used. For each sub-dimension, a reference standard was defined and a standardized score was calculated, with 1 as the best. The final score was calculated by factor analysis. The final mean score of Brazilian UBS was 0.732. The sub-dimension with the worst score was "installations and inputs" and the best was "shifts open to the public". The primary healthcare units were classified according to their final score in five groups, from best to worst: A, B, C, D, and E. Only 4.8% of the Brazilian UBS attained the maximum score. The typology showed specific characteristics and a regional distribution pattern: units D and/or E accounted for nearly one-third of the units in the North, and two-thirds of units A were situated in the South and Southeast of Brazil. Based on the typology, primary healthcare units were classified according to their infrastructure conditions and possible strategies for intervention, as follows: failed, rudimentary, limited, fair, and reference (benchmark). The lack of equipment and inputs in all the units except for type A limits their scope of action and case-resolution capacity, thus restricting their ability to respond to health problems. The typology presented here can be a useful tool for temporal and spatial monitoring of the quality of infrastructure in UBS in Brazil. PMID- 28832774 TI - [The medical community's perceptions of management of the layoff process]. AB - The definition and process of layoff are evolving rapidly. This study focuses on the perceptions of physicians in Catalonia, Spain, concerning layoff and the identification of strategies and proposals that allow more satisfactory adjustment to the process. A qualitative approach was used with 16 in-depth interviews with key persons in the healthcare setting (phase 1) and 6 focus groups with 72 persons, according to sampling criteria (phase 2). The analysis was interpretative, based on Grounded Theory. Comparison and triangulation of the results generated by the different techniques and researchers revealed the social representation of the current healthcare organization (immersed in a new public management model) on the medical community and the layoff process. In this sense, retirement is seen as a personal issue, separate from human resources policies, which are more interested in staff turnover at a lower "cost". Given this situation, the article proposes alternatives that value physicians' experience and expertise before they leave the healthcare organization. PMID- 28832775 TI - To privatize or not to privatize: that is the question. But the only question? Reediting the liberal agenda for drinking water supply and sanitation in Brazil. PMID- 28832776 TI - [Latent tuberculosis infection in persons with HIV/AIDS, associated factors, and progression to active disease in a city in southern Brazil]. AB - The study proposed to identify the prevalence of latent tuberculosis infection (LTBI) in persons living with HIV/AIDS (PLWHA), associated factors, and progression to active tuberculosis among the identified cases. This was an epidemiological and descriptive study. The study population consisted of PLWHA seen from 2003 and 2014 in a reference center for HIV/AIDS. Data were collected from patient files and the Brazilian Information System for Notifiable Diseases (SINAN). Bivariate statistical analysis used the chi-square test in which variables with p < 0.2 were selected to enter the multiple regression model. Type I error was set at 5% (p < 0.05) for all the tests. In the study, 690 cases were analyzed, and 66 (9.4%) had a diagnosis of LTBI, with a prevalence of 7.5 cases per 100 patients. Of the 53 cases (80.3%) of LTBI who were prescribed treatment with isoniazid, only 26 (39.4%) concluded treatment, and 10 (15.1%) dropped out. Male gender (adjusted OR = 1.8; 95%CI: 1.1-3.3), current incarceration (adjusted OR = 7.6; 95%CI: 2.35-24.9), and high lymphocyte count were associated with LTBI diagnosis (adjusted OR = 1.1; 95%CI: 1.1-1.2). Forty-seven (6.7%) of LTBI cases progressed to active TB. Diagnosis and treatment of LTBI in PLWHA were not prioritized, which contributed to the development of active disease among cases. The study contributed to knowledge on LTBI in PLWHA, demonstrating crucial aspects in the management of PLWHA and the importance of detecting LTBI and early initiation of isoniazid, aimed at improved quality of life and prognosis for PLWHA. PMID- 28832777 TI - [Validity of self-perceived dental caries as a diagnostic test and associated factors in adults]. AB - This study aimed to analyze the validity of self-perceived dental caries and associated factors in a sample of 795 adults (35-44 years). The dependent variable was self-perceived dental caries, and the independent variables were combined in blocks. Three logistic models were performed: (1) all adults; (2) adults with a formal diagnosis of caries; and (3) adults without such caries. Self-perceived dental caries showed 77.7% sensitivity, 58% specificity, 65% accuracy, 52% positive predictive value, and 81% negative predictive value. In Model 1, self-perceived dental caries was associated with time of use of dental services, access to information, flossing, formal diagnosis of caries, self perceived need for treatment, toothache, and dissatisfaction with oral health and general health. In Model 2, self-perceived dental caries was associated with time of use of dental services, self-perceived need for treatment, and dissatisfaction with oral health and general health. In Model 3, self-perceived dental caries was associated with time of use of dental services, access to information, flossing, self-perceived need for treatment, and dissatisfaction with oral health. Self perceived dental caries showed limited utility as a diagnostic method. PMID- 28832778 TI - [Needs for dental prostheses and their use in elderly Brazilians according to the National Oral Health Survey (SBBrazil 2010): prevalence rates and associated factors]. AB - The objectives of this study were to evaluate the use of and need for dental prostheses among elderly Brazilians (65-74 years of age) and to verify associated factors. Data were analyzed from 7,496 elderly participants in the National Oral Health Survey in 2010 (SBBrazil 2010). Use of and need for dental prosthesis were the outcomes. The exposure variables included demographic and socioeconomic characteristics, dental services use, and self-rated oral health. Descriptive, bivariate, and multivariate analyses were performed. Prevalence rates for use of and need for dental prostheses were 78.2% and 68.7%, respectively. The Southeast Region had the highest prevalence of use (71.3%) and the greatest need for dental prostheses (82.9%). Multivariate Poisson regression analyses showed greater use of dental prostheses by women, individuals with 5 to 7 years of schooling, and users of private dental services, and lower use by black individuals and those with self-reported need for dental prostheses. Less need for dental prostheses was seen in women and in users of private services, and greater need in those with self-reported need for dental prostheses. Regional differences were seen in the distribution of use and need for dental prostheses. Still, the findings showed high prevalence rates for both outcomes in all regions of Brazil. Socioeconomic and demographic variables and use of dental services influenced the use of and need for dental prostheses. PMID- 28832780 TI - [Preferences for work in primary care among medical students in Minas Gerais State, Brazil: evidence from a discrete choice experiment]. AB - This article presents the results of a discrete choice experiment (DCE) conducted in 2012 with 277 final-year medical students from Minas Gerais State, Brazil. The experiment tested students' preferences concerning future work as physicians in primary health care, based on hypothetical job scenarios aimed at measuring the likelihood of placement in areas with a shortage of doctors. Application of DCE involved (i) a qualitative stage to define the attributes and their respective levels to comprise the job scenarios, (ii) construction and application of the instrument, and (iii) analysis with application of multinomial logit with conditional probability to estimate the weight of attributes and to construct scenarios for choice probability. The results indicate that the job attribute that most impacted students' choice was location, followed by job conditions, pay, access to medical residency, type of employment relationship, and workload. Students from private medical schools, with higher family income, and females were generally more likely to resist job assignments in unsafe urban areas and remote areas of the countryside. The job scenarios that proved most plausible in terms of public intervention were those that combined middle-level wages, good working conditions, and 10 to 20 bonus points on medical residency exams. PMID- 28832779 TI - Can neck circumference predict insulin resistance in older people? A cross sectional study at primary care in Brazil. AB - This study focused on the correlation between neck circumference and other anthropometric measurements and cardiovascular risk factors and insulin resistance in the elderly in Niteroi, Rio de Janeiro State, Brazil. This was a cross-sectional study in 411 patients seen in primary care. Anthropometric measurements including neck circumference, body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) were recorded. Bioelectrical impedance analysis (BIA) estimated the percentage of total body fat (%TBF). Insulin resistance was estimated by HOMA-IR (homeostasis model assessment IR index). The data were analyzed by the Mann-Whitney test and the correlation between numerical variables by Spearman's test. Receiver operating characteristic (ROC) was used to assess the anthropometric measurements' predictive capacity to diagnosis insulin resistance. Neck circumference was positively correlated with WC, BMI, WHR, %TBF, and HOMA-IR in both sexes. In women, neck circumference showed higher AUC (area under the curve) for insulin resistance. In men, WC showed higher AUC, followed by BMI and neck circumference. The current study in Southeast Brazil suggests that neck circumference can predict insulin resistance, an important marker of cardiovascular risk in the elderly population treated in primary care. PMID- 28832781 TI - Health transition in Brazil: regional variations and divergence/convergence in mortality. AB - This study analyzes the main characteristics of the health transition in Brazil and its five major regions, using a framework that accounts for regional inequalities in mortality trends. The regional mortality divergence/convergence process is described and discussed by considering the specific contributions of age groups and causes of death in life expectancy variations. Results show that mortality change in Brazil has follow the epidemiologic transition theory to some extent during the period under analysis - for instance, the sharp decline in infant mortality in all regions (first from infectious and parasitic diseases and then from causes associated with the perinatal period) and the increase in the participation of chronic and degenerative diseases as the main cause of death. However, some features of Brazilian transition have not followed the linear and unidirectional pattern proposed by the epidemiologic transition theory, which helps to understand the periods of regional divergence in life expectancy, despite the long-term trends showing reducing regional inequalities. The emergence of HIV/AIDS, the persistence of relatively high levels of other infections and parasitic diseases, the regional differences in the unexpected mortality improvements from cardiovascular diseases, and the rapid and strong variations in mortality from external causes are some of the examples. PMID- 28832782 TI - [Contradictions and the cost-effectiveness threshold]. PMID- 28832783 TI - [The authors reply]. PMID- 28832784 TI - CSP: a common good in Public Health. PMID- 28832785 TI - Prevalence of physical intimate partner violence in the first six months after childbirth in the city of Rio de Janeiro, Brazil. AB - The aim of the study was to estimate the prevalence of physical intimate partner violence in the first six months after childbirth among women attending primary care clinics (UBS) for the infant's follow-up in Rio de Janeiro, Brazil. This is the first study on the theme using a representative sample of primary care clinics in the city of Rio de Janeiro. The study used a cross-sectional design from June to September 2007 and included 927 mothers/infants seen at 27 UBS, selected by complex sampling, geographically representative of the city. The information was collected in face-to-face interviews by a previously trained team, using a structured questionnaire. History of physical intimate partner violence from the child's birth to the date of the interview was obtained with the Brazilian version of the Revised Conflict Tactics Scales (CTS2). Thirty percent (95%CI: 26.2-33.8) of mothers reported having experienced some form of physical intimate partner violence in the postpartum and 14% (95%CI: 11.0-17.0) reported severe physical violence. The physical abuse occurred especially among black teenage mothres, in unfavorable socioeconomic situation, that did not live with the partner and that had received inadequate or no prenatal care and reported difficulties in breastfeeding and use of healthcare services. The widespread occurrence of physical intimate partner violence emphasizes the urgent need to deal with the problem. Primary healthcare services must be linked to other support networks and health professionals need to be prepared to deal with the problem. PMID- 28832786 TI - [Food consumption and anthropometry related to the frailty syndrome in low-income community-living elderly in a large city]. AB - The aim of this study was to describe anthropometric and food intake data related to the frailty syndrome in the elderly. This was a cross-sectional study in individuals >= 60 years of age in a household survey in the Manguinhos neighborhood of Rio de Janeiro, Brazil (n = 137). Frailty syndrome was diagnosed according to Fried et al., anthropometric measures were taken, and a food frequency questionnaire was applied and the results compared to Brazilian Ministry of Health guidelines. In the pre-frail and frail groups, body mass index and measures of central adiposity showed higher levels, while lean muscle parameters showed lower values, proportional to the syndrome's gradation. Frail elderly consumed higher amounts of grains and lower amounts of beans and fruit; pre-frail elderly consumed more vegetables, dairy products, and high-sugar and high-fat foods; the two groups consumed similar amounts of meat. Thus, diagnosis of the syndrome, anthropometric evaluation, and dietary assessment should be included in health policies for the elderly, since they assist in early identification of risk and favor interventions for disease prevention and health and nutritional promotion. PMID- 28832787 TI - [Essential tremor in endemic disease control agents exposed to pesticides: a case control study]. AB - Tremor is the most frequent movement disorder in the population and can be associated with pesticide exposure. The aim was to assess the odds of essential tremor in 442 endemic disease control agents in Rio de Janeiro State, Brazil, exposed to pesticides. Fifty-one cases and 204 controls were selected (1:4). All participants answered a questionnaire on socio-demographic, occupational, and toxicological items. The influence of pesticide exposure on the development of tremor was estimated by non-conditional logistic regression, adjusted for selected covariables. Mean age of the study population was 49 (SD = 7) years, and the difference between cases (mean = 50.8; SD = 6.9) and controls (mean = 48.5; SD = 6.9) was statistically significant (p = 0.03). Those with 16 to 16.9 years of pesticide use showed the highest odds of essential tremor (adjusted OR = 4.60; 95%CI: 1.29-16.41). Our results suggest that 16 to 16.9 years of pesticide exposure had a major impact on the development of essential tremor. PMID- 28832788 TI - [How much does the backlog on drug patents cost for health in Brazil?] AB - The backlog in processing patent applications in Brazil has persisted since the enactment of Law 9,279/1996, when the country resumed granting patents on drugs. The agencies responsible for granting such patents, namely the Brazilian National Patent and Trademark Office (INPI) and the Brazilian National Health Surveillance Agency (Anvisa) cite technical and administrative reasons for the backlog. However, little research has focused on the economic impacts for health due to the inefficiency of the Brazilian patent system. The current study thus proposes a methodology to estimate the extent to which government procurement of medicines is burdened by the backlog in drug patent applications. According to the results, a total of more than BRL 14 million (USD 4.5 million) is spent unnecessarily per year by the Federal Government on just one antiretroviral drug due to the extension of the respective patent's life. Measures to resolve this situation are urgently needed in the three branches of government. These include hiring more staff for the INPI, analysis of bills of law under review in the two houses of the Brazilian Congress to amend the Industrial Property Law, and ruling on direct class action claims of unconstitutionality to suppress the legal mechanisms that allow extending the life of patents. PMID- 28832789 TI - Education: The Key of SBCCV. Performance of BJCVS, The Facts. PMID- 28832790 TI - Thirtieth Anniversary of the Brazilian Journal of Cardiovascular Surgery. And Devising the Next Decades. PMID- 28832791 TI - Techniques, Timing & Prognosis of Post Infarct Ventricular Septal Repair: a Re look at Old Dogmas. AB - Objective:: The study aimed to identify the factors affecting the prognosis of post myocardial infarction (MI) ventricular septal rupture (VSR) and to develop a protocol for its management. Methods:: This was a single center, retrospective prospective study (2009-2014), involving 55 patients with post MI VSR. The strengths of association between risk factors and prognosis were assessed using multivariate logistic regression analysis. The UNM Post MI VSR management and prognosis scoring systems (UPMS & UPPS) were developed. Results:: Thirty-day mortality was 52.5% (35% in the last 3 years). Twenty-eight (70%) patients underwent concomitant coronary artery bypass grafting. Residual ventricular septal defect was found in 3 (7.5%) patients. The multivariate analysis showed low mean blood pressure with intra-aortic balloon pump (OR 11.43, P=0.001), higher EuroSCORE II (OR 7.47, P=0.006), higher Killip class (OR 27.95, P=0.00), and shorter intervals between MI and VSR (OR 7.90, P=0.005) as well as VSR and Surgery (OR 5.76, P=0.016) to be strong predictors of mortality. Concomitant coronary artery bypass grafting (P=0.17) and location (P=0.25) of VSR did not affect the outcome. Mean follow-up was 635.8+/-472.5 days and 17 out of 19 discharged patients were in NYHA class I-II. Conclusion:: The UNM Post-MI VSR Scoring Systems (UPMS & UPPS) help in management and prognosis, respectively. They divide patients into 3 groups: 1) Immediate Surgery - Patients with scores of <25 require immediate surgery, preferably with extracorporeal membrane oxygenation support, and have poor prognosis; 2) Those with scores of 25-75 should be managed with "Optimal Delay" and they have intermediate outcomes; 3) Patients with scores of >75 can undergo Elective Repair and they are likely to have good outcomes. PMID- 28832792 TI - A New Experimental Device for Transapical Access of the Aortic and Mitral Valves as well as the Aorta in its Various Segments. AB - Objective:: To present the results of a new experimental device developed to facilitate the transapical access in endovascular treatment of structural heart diseases. It aims to reduce the risk of bleeding and complications in this type of access and demonstrate the device as a safe, fast and effective alternative. Methods:: CorPoint is composed of three parts: introducer, base with coiled spring, and closing capsule. By rotating movements, the spring is introduced into the myocardium and progressively approaches the base to the surface of the heart. Guidewires and catheters are inserted through the hollow central part and, at the end of the procedure, the capsule is screwed over the base, therefore stopping any bleeding. Results:: The device was implanted in 15 pigs, weighing 60 kg each, through an anterolateral thoracotomy, while catheters were introduced and guided by fluoroscopy. All animals had minimal bleeding; introducers with diameter up to 22 Fr were used and various catheters and guidewires were easily handled. After finishing the procedure, the closing capsule was attached and no bleeding was observed at the site. Conclusion:: This new device has proved effective, fast and secure for the transapical access. This shows great potential for use, especially by ensuring an easier and direct access to the mitral and aortic valves; the shortest distance to be traveled by catheters; access to the ascending and descending aorta; decreased bleeding complications; decreased surgical time; and the possibility of allowing the technique to evolve and become totally percutaneous. PMID- 28832793 TI - Quality of Life, Depression, Anxiety and Coping Strategies after Heart Transplantation. AB - Introduction:: Heart transplantation is the therapeutic procedure indicated to increase the survival of patients with refractory heart failure. Improvement in overall functioning and quality of life are expected factors in the postoperative period. Objective:: To identify and evaluate mental disorders and symptoms, such as depression and anxiety, quality of life and coping strategies in the post surgical situation of heart transplantation. Methods:: A cross-sectional, quantitative study with patients who have undergone heart transplantation. Participants answered to the Sociodemographic Questionnaire, Beck Depression Inventory (BDI-II), Beck Anxiety Inventory (BAI), MINI International Neuropsychiatric Interview, Escala Modos de Enfrentamento de Problemas (Ways of Coping Scale) (EMEP) and World Health Organization Quality of Life-BREF (WHOQOL BREF). For data analysis, the significance level was considered P<=0.05. Results:: A total of 33 patients participated in the study. The BDI-II results indicated that 91% (n=30) of the patients presented a minimal level. In BAI, 94% (n=31) of the patients demonstrated minimal level of anxiety symptoms. WHOQOL BREF showed a perception of quality of life considered good in all domains. The EMEP data have registered a problem-focused coping strategy. According to MINI, a single case of major depressive episode, current and recurrent was recorded. Conclusion:: Although most participants in the sample had symptoms of depression and anxiety, only one patient was identified with moderate symptoms in both domains. The most used strategy was coping focused on the problem. Patients have classified the perceptions of quality of life as 'good', pointing out satisfaction with their health. PMID- 28832794 TI - Coronary Perfusion Pressure during Antegrade Cardioplegia in On-Pump CABG Patients. AB - Objective:: The aim of this study was to investigate whether aortic tension estimated by palpation and cardioplegia infusion line pressure provide results equivalent to those obtained with direct aortic intraluminal pressure measurement. Methods:: Sixty consecutive patients who underwent coronary artery bypass graft surgeries with extracorporeal circulation were analyzed. Sanguineous cardioplegic solution in a ratio of 4:1 was administered using a triple lumen antegrade cannula. After crossclamping, cardioplegia was infused and aortic root pressure was recorded by surgeon (A) considering the aortic tension he felt in his fingertips. At the same time, another surgeon (B) recorded his results for the same measurement. Concomitantly, the anesthesiologist recorded intraluminal pressure in the aortic root and the perfusionist recorded delta pressure in cardioplegia infusion line. None of the participants involved in these measurements was allowed to be informed about the values provided by the other examiners. Results:: The Bland-Altman test showed that a considerable variation between aortic wall tension was found as measured by palpation and by intraluminal pressure, with a bias of -9.911+/-18.75% (95% limits of agreement: 46.7 to 26.9). No strong correlation was observed between intraluminal pressure and cardioplegia line pressure (Spearman's r=0.61, 95% confidence interval 0.5 0.7; P<0.0001). Conclusion:: These findings reinforce that cardioplegia infusion should be controlled by measuring intraluminal pressure, and that palpation and cardioplegia line pressure are inaccurate methods, the latter should always be used to complement intraluminal measurement to ensure greater safety in handling the cardioplegia circuit. PMID- 28832795 TI - Cardiopulmonary Resuscitation in an Average Brazilian Intensive Care Unit: Should We Perform Less or Better? AB - Introduction:: Few data can be found about cardiac arrest in the intensive care unit outside reference centers in third world countries. Objective:: To study epidemiology and prognostic factors associated with cardiac arrest in the intensive care unit (ICU) in an average Brazilian center. Methods:: Between June 2011 and July 2014, 302 cases of cardiac arrest in the intensive care unit were prospectively evaluated in 273 patients (age: 68.9 +/- 15 years) admitted in three mixed units. Data regarding cardiac arrest and cardiopulmonary resuscitation were collected in an "Utstein style" form and epidemiologic data was prospectively obtained. Factors associated with do not resuscitate orders, return of spontaneous circulation and survival were studied using binary logistic regression. Statistical package software used was SPSS 19.0 (IBM Inc., USA). Results:: Among 302 cardiac arrests, 230 (76.3%) had their initial rhythm recorded and 141 (61.3%) was in asystole, 62 (27%) in pulseless electric activity (PEA) and 27 had a shockable rhythm (11.7%). In 109 (36.1%) cases, cardiac arrest had a suspected reversible cause. Most frequent suspected cardiac arrest causes were hypotension (n=98; 32.5%), multiple (19.2%) and hypoxemia (17.5%). Sixty (19.9%) cardiac arrests had do not resuscitate orders. Prior left ventricle dysfunction was the only predictor of do not resuscitate order (OR: 3.1 [CI=1.03 9.4]; P=0.04). Among patients that received cardiopulmonary resuscitation, 59 (24.4%) achieved return of spontaneous circulation and 12 survived to discharge (5.6%). Initial shockable rhythm was the only return of spontaneous circulation predictor (OR: 24.9 (2.4-257); P=0.007) and survival (OR: 4.6 (1.4-15); P=0.01). Conclusion:: Cardiopulmonary resuscitation rate was high considering ICU patients, so was mortality. Prior left ventricular dysfunction was a predictor of do not resuscitate order. Initial shockable rhythm was a predictor of return of spontaneous circulation and survival. PMID- 28832796 TI - Transverse Sternal Split: a Safe Mini-invasive Approach for Perventricular Device Closure of Ventricular Septal Defect. AB - Objective:: Perventricular device closure of ventricular septal defect through midline sternotomy avoids the cardiopulmonary bypass, however, lacks the cosmetic advantage. Perventricular device closure of ventricular septal defect with transverse split sternotomy was performed to add the cosmetic advantage of mini invasive technique. Methods:: Thirty-six pediatric patients with mean age 7.14+/ 3.24 months and weight 5.00+/-0.88 kg were operated for perventricular device closure of ventricular septal defect through transverse split sternotomy in 4th intercostal space under transesophageal echocardiography guidance. In case of failure or complication, surgical closure of ventricular septal defect was performed through the same incision with cervical cannulation of common carotid artery and internal jugular vein for commencement of cardiopulmonary bypass. All the patients were postoperatively followed, and then discharged from hospital due to their surgical outcome, morbidity and mortality. Results:: Procedure was successful in 35 patients. Two patients developed transient heart block. Surgical closure of ventricular septal defect was required in one patient. Mean duration of ventilation was 11.83+/-3.63 hours. Mean intensive care unit and hospital stay were 1.88+/-0.74 days and 6.58+/-1.38 days, respectively. There was no in hospital mortality. A patient died one day after hospital discharge due to arrhythmia. No patients developed wound related, vascular or neurological complication. In a mean follow-up period of 23.3+/-18.45 months, all 35 patients were doing well without residual defect with regression of pulmonary artery hypertension as seen on transthoracic echocardiography. Conclusion:: Transverse split sternotomy incision is a safe and effective alternative to a median sternotomy for perventricular device closure of ventricular septal defect with combined advantage of better cosmetic outcomes and avoidance of cardiopulmonary bypass. PMID- 28832797 TI - Are the Early Postoperative Outcomes of Coronary Artery Bypass Grafting Surgery in Elderly Women Worse Compared to Men's? AB - Objective:: To investigate the impact of gender difference in early postoperative outcomes in elderly patients (aged 70 or older) undergoing coronary artery bypass grafting surgery. Methods:: Between October 2009 and December 2013, a total of 223 elderly patients (aged 70 or older) undergoing isolated primary coronary artery bypass grafting surgery were included in this retrospective observational cohort study. Patients were divided into two groups according to their gender. The patients' medical records were collected, their baseline preoperative characteristics, operative data, and postoperative outcomes were retrospectively reviewed, and the effect of gender difference in the early postoperative outcomes was analyzed. Results:: Group 1 (female patients) and Group 2 (male patients) consisted of 71 and 152 patients, respectively. Mean age of patients was 74.4+/ 3.6 years (range: 70-84 years). The level of EuroSCORE I, the incidence of hypertension and hyperlipidemia were significantly higher in Group 1, while the rate of smoking was significantly higher in Group 2. Mean postoperative intubation time, length of intensive care unit and hospital stay were longer in female patients than in male patients, but these differences were not statistically significant. No statistically significant difference between two groups in terms of the transfusion of blood products was observed. The rates of in-hospital mortality and major postoperative complications were statistically similar between the two groups. Conclusion:: In conclusion, the female gender was not associated with worse early postoperative outcomes in elderly patients undergoing coronary artery bypass grafting surgery. PMID- 28832798 TI - Avoiding Liver Injury with Papaverine and Ascorbic Acid Due to Infrarenal Cross Clamping: an Experimental Study. AB - Objective:: Ischemia-reperfusion injury after acute ischemia treatment is a serious condition with high mortality and morbidity. Ischemia-reperfusion injury may result in organ failure particularly in kidney, lung, liver, and heart. In our study, we investigated the effects of papaverine and vitamin C on ischemia reperfusion injury developed in the rat liver after occlusion-reperfusion of rat aorta. Methods:: 32 Sprague-Dawley female rats were randomized into four groups (n=8). Ischemia was induced with infrarenal aortic cross-clamping for 60 minutes; then the clamp was removed and reperfusion was allowed for 120 minutes. While the control group and the ischemia-reperfusion group did not receive any supplementary agent, two other groups received vitamin C and papaverine hydrochloride (papaverine HCL). Liver tissues were evaluated under the light microscope. Histopathological examination was assessed by Suzuki's criteria and results were compared between groups. Results:: In ischemia-reperfusion group, severe congestion, severe cytoplasmic vacuolization, and parenchymal necrosis over 60% (score 4) were observed. In vitamin C group, mild congestion, mild cytoplasmic vacuolization and parenchymal necrosis below 30% (score 2) were found. In papaverine group, moderate congestion, moderate cytoplasmic vacuolization and parenchymal necrosis below 60% (score 3) were observed. Conclusion:: An ischemia of 60 minutes induced on lower extremities causes damaging effects on hepatic tissue. Vitamin C and papaverine are helpful in reducing liver injury after acute ischemia reperfusion and may partially avoid related negative conditions. PMID- 28832800 TI - Modified Hybrid Procedure in Hypoplastic Left Heart Syndrome: Initial Experience of a Center in Northeastern Brazil. AB - Introduction:: Although it only corresponds to 2.5% of congenital heart defects, hypoplastic left heart syndrome (HLHS) is responsible for more than 25% of cardiac deaths in the first week of life. Palliative surgery performed after the second week of life is considered an important risk factor in the treatment of HLHS. Objective:: The aim of this study is to describe the initial experience of a medical center in Northeastern Brazil with a modified off-pump hybrid approach for palliation of HLHS. Methods:: From November 2012 through November 2015, the medical records of 8 patients with HLHS undergoing hybrid procedure were retrospectively evaluated in a tertiary private hospital in Northeastern Brazil. The modified off-pump hybrid palliation consisted of stenting of the ductus arteriosus guided by fluoroscopy without contrast and banding of the main pulmonary artery branches. Demographic and clinical variables were recorded for descriptive analysis. Results:: Eight patients were included in this study, of whom 37.5% were female. The median age and weight at the time of the procedure was 2 days (p25% and p75% = 2 and 4.5 days, respectively) and 3150 g (p25% and p75% = 3077.5 g and 3400 g, respectively), respectively. The median length in intensive care unit stay was 6 days (p25% and p75% = 3.5% and 8 days, respectively). There were no in-hospital deaths. Four patients have undergone to the second stage of the surgical treatment of HLHS. Conclusion:: In this series, the initial experience with the modified off-pump hybrid procedure showed to be safe, allowing a low early mortality rate among children presenting HLHS. PMID- 28832799 TI - Surgical Treatment of Atrial Fibrillation in Patients with Rheumatic Valve Disease. AB - Objective:: To assess heart rhythm and predictive factors associated with sinus rhythm after one year in patients with rheumatic valve disease undergoing concomitant surgical treatment of atrial fibrillation. Operative mortality, survival and occurrence of stroke after one year were also evaluated. Methods:: Retrospective longitudinal observational study of 103 patients undergoing rheumatic mitral valve surgery and ablation of atrial fibrillation using uni- or bipolar radiofrequency between January 2013 and December 2014. Age, gender, functional class (NYHA), type of atrial fibrillation, EuroSCORE, duration of atrial fibrillation, stroke, left atrial size, left ventricular ejection fraction, cardiopulmonary bypass time, myocardial ischemia time and type of radiofrequency were investigated. Results:: After one year, 66.3% of patients were in sinus rhythm. Sinus rhythm at hospital discharge, lower left atrial size in the preoperative period and bipolar radiofrequency were associated with a greater chance of sinus rhythm after one year. Operative mortality was 7.7%. Survival rate after one year was 92.3% and occurrence of stroke was 1%. Conclusion:: Atrial fibrillation ablation surgery with surgical approach of rheumatic mitral valve resulted in 63.1% patients in sinus rhythm after one year. Discharge from hospital in sinus rhythm was a predictor of maintenance of this rhythm. Increased left atrium and use of unipolar radiofrequency were associated with lower chance of sinus rhythm. Operative mortality rate of 7.7% and survival and stroke-free survival contribute to excellent care results for this approach. PMID- 28832802 TI - Occult Metastatic Melanoma Presenting as an Acute Coronary Syndrome. AB - Melanoma is a tumor that virtually involves any tissue and commonly metastasizes to the heart. It is usually not diagnosed because of the absent/nonspecific cardiac signs and symptoms. Herein, we present a case of a 41-year-old man without any cardiovascular risk factor, admitted to the emergency room with chest pain, diagnosed with a myocardial infarction. Due to the presence of a mass adjacent to the mitral valve on the cardiac ultrasound examination, causing mitral regurgitation, the patient was referred to surgery. Pathological analysis of the excised specimens diagnosed the melanoma. The chemotherapy was started and achieved a partial response. Cardiac metastases usually affect the myocardium, leaving the valves unaffected. In this case, the acute coronary syndrome was the first manifestation of the malignant melanoma. We highlight the high level of suspicion needed in these cases. PMID- 28832803 TI - Left Atrial Myxoma Following Coronary Artery Bypass Grafting with Patient Coronary Arterial Grafts: a Rarity. AB - The development of left atrial myxoma after coronary artery bypass graft surgery is a rare entity. A 60-year-old man with previous off-pump coronary artery bypass grafting four years ago with patent coronary grafts was diagnosed with left atrial mass. The patient underwent successful resection of the same through minimally invasive right anterolateral thoracotomy. Histopathology of the atrial mass confirmed the diagnosis of atrial myxoma. PMID- 28832801 TI - MicroRNAs and Current Concepts on the Pathogenesis of Abdominal Aortic Aneurysm. AB - OBJECTIVE: Abdominal aortic aneurysm is an important cause of morbidity and mortality in the elderly. Currently, the only way to prevent rupture and death related to abdominal aortic aneurysms is through surgical intervention. Endovascular treatment is associated with less morbidity than conventional treatment. The formation of an aneurysm is a complex multifactorial process, involving destructive remodeling of the connective tissue around the affected segment of the aorta wall. MicroRNAs are small sequences of non-coding RNAs that control diverse cellular functions by promoting degradation or inhibition of translation of specific mRNAs. A profile aberrant expression of miRNAs has been linked to human diseases, including cardiovascular dysfunction. PMID- 28832804 TI - Complex karyotype including ring chromosome 11 in a patient with acute myeloid leukemia: case report. AB - CONTEXT: Complex karyotypes in acute myeloid leukemia (AML) are characterized by an overall low response rate with frequent relapses after clinical treatment. CASE REPORT: Here, we describe the case of a 61-year-old obese female with clinically diagnosed AML who presented a complex karyotype involving an uncommon abnormality: ring chromosome 11. Immunophenotypic analysis confirmed the diagnosis. Classical and molecular cytogenetic analyses, using GTG banding and FISH (fluorescence in situ hybridization), revealed the presence of complex structural rearrangement involving r(11), add(12)(p13), der(5) and der(13). CONCLUSIONS: Molecular cytogenetic analysis is suitable for better identification and characterization of chromosomal rearrangements in AML. Case reports like this, as well as population-based studies, are necessary for understanding the karyotypic changes that occur in humans. PMID- 28832806 TI - A psychotic experience during adolescence: reasoning about differential diagnosis. Case report. AB - CONTEXT:: The aim of the present clinical review was to illustrate the diagnostic difficulty associated with psychotic experiences during adolescence, in the light of the multiplicity of circumstances interplaying during this period. It was also intended to illustrate the observation that not all hallucinations occur in the context of a declared psychotic disorder. CASE REPORT:: The patient was a 16-year old adolescent girl who came to the Emergency Department of Coimbra Pediatric Hospital. On admission, she displayed mood and sensory perception disorders, with a bizarre gait abnormality. A diagnosis of conversion disorder was finally suggested, in accordance with the International Classification of Diseases, 10th edition. CONCLUSIONS:: Conversive hallucinations are rare in the psychiatric literature. This diagnostic hypothesis only gained consistency over a long period of follow-up within a child and adolescent psychiatry outpatient service, which was fundamental for appropriate diagnostic clarification. The authors discuss psychotic experiences that can arise from a neurotic setting and share the reasoning that was constructed in relation to the differential diagnosis. The psychogenesis and phenomenology of this young patient's conversive hallucinations and the therapeutic strategies adopted over the course of the follow-up are also discussed. PMID- 28832805 TI - Clinical and epidemiological profile of tuberculosis in an urban area with high human development index in southeastern Brazil. Time series study. AB - CONTEXT AND OBJECTIVE: In the twenty-first century, tuberculosis remains a serious public health problem in Brazil. The aim here was to characterize tuberculosis in a municipality with a high human development index (HDI), based on clinical and epidemiological variables. DESIGN AND SETTING: Epidemiological study with analysis of incidence that included 533 new cases of tuberculosis in the municipality of Araraquara, Sao Paulo, reported to the Brazilian Notifiable Diseases Information System (SINAN) between 2002 and 2011. METHODS: To identify trends, this period was divided into two five-year periods (2002-2006 and 2007 2011). The incidence rates were compared using ratios and confidence intervals. RESULTS: The incidence of tuberculosis was 26.82 cases per 100,000 inhabitants, and decreased by 22% between the two periods, which was statistically significant. Cases were more prevalent among men (72.61%) and among adults between 30 and 59 years of age with non-specialized professions and low education levels. There was a statistically significant reduction in cases among individuals over 50. The age group with highest incidence was 50-59 years in the first period and 30-39 years in the second. Total recovery occurred in more than 70%. There was a reduction in the number of diagnoses made within primary care and an increase within public hospital care between the two periods. The most common coinfections were AIDS and hepatitis C. CONCLUSIONS: The incidence of tuberculosis in this municipality was lower than the national incidence, with a declining trend and a high cure rate, and the main coinfections were AIDS and hepatitis C. PMID- 28832807 TI - Methicillin-resistant Staphylococcus aureus in cystic fibrosis patients: do we need to care? A cohort study. AB - CONTEXT AND OBJECTIVE: The prevalence of a variety of potentially pathogenic microorganisms in cystic fibrosis patients, such as methicillin-resistant Staphylococcus aureus (MRSA), has increased over the past decade. Given the increasing prevalence of MRSA and the few data available in the literature, better understanding of the clinical repercussions of colonization by this bacterium in cystic fibrosis patients becomes essential. This study aimed to evaluate the repercussions of chronic colonization by MRSA in cystic fibrosis patients. DESIGN AND SETTING: Retrospective cohort study from January 2004 to December 2013 in a cystic fibrosis reference center. METHODS: Each patient with cystic fibrosis was evaluated for nutritional status (body mass index, BMI, and BMI percentile), pulmonary function and tomographic abnormalities (modified Bhalla scores) at the time of chronic colonization by MRSA or methicillin susceptible Staphylococcus aureus (MSSA) and throughout the study period. RESULTS: Twenty pairs of patients were included. There were no significant differences between the groups regarding nutritional characteristics. Spirometric data showed a trend towards greater obstruction of the airways in patients with MRSA. Patients with MRSA presented greater structural damage to their lungs, demonstrated not only by the total Bhalla score but also by its parameters individually. CONCLUSIONS: Patients colonized by MRSA presented greater functional and structural respiratory impairment at the time of chronic colonization. Disease progression was also faster in patients chronically colonized by MRSA than in those with MSSA. This was shown through comparisons that avoided possible confounding variables. PMID- 28832808 TI - Prolonged survival after surgical resection of cerebral metastasis from melanoma with multisystemic metastasis already present: a case report and literature review. AB - CONTEXT: Malignant melanoma is the third most common cause of cerebral metastases after breast and lung cancer. Despite advances in therapeutic options, the prognosis for patients with cerebral metastases from melanoma remains poor, with a median survival time of six months after diagnosis. CASE REPORT: A 65-year-old woman was diagnosed with a malignant melanoma on the third toe of her left foot.The tumorous spot was excised surgically. However, the melanoma reappeared after one year and skin biopsy confirmed recurrence of malignant melanoma. Investigations showed metastasis to the left pelvic region, left lobe of the liver and right lobe of the lung.The patient then received chemotherapy. Subsequently, the patient was brought to the emergency department with an altered level of consciousness (Glasgow coma scale: 9) and hemiplegia on the right side of her body. Computed tomography scans of the brain revealed hemorrhagic lesions in the parieto-occipital lobes of the brain. Urgent surgical evacuation was done to remove the lesion, following which the patient showed improvement in her score on the Glasgow coma scale and a concomitant decrease in weakness. She was discharged from hospital with full consciousness.The patient died of acute renal failure 14 months after the brain surgery and approximately 4 years after the initial presentation of the case. CONCLUSION: This case outcome is rare and shows the effectiveness of surgery to treat cerebral metastasis from malignant melanoma in a situation with multisystem metastasis already present. PMID- 28832809 TI - Relationship between total and segmental bone mineral density and different domains of physical activity among children and adolescents: cross-sectional study. AB - BACKGROUND: This study aimed to investigate the relationship between total and segmental bone mineral density (BDM) and physical activity (PA) in different domains (school, leisure and sports) among adolescents and children. DESIGN AND SETTING: Cross-sectional study in the Universidade Estadual Paulista Julio de Mesquita Filho (UNESP). METHODS: The study sample consisted of 173 children and adolescents (10.31 +/- 1.87 years). The BMDs for the whole body (WB) and the regions of the trunk and legs were measured using dual energy X-ray absorptiometry (DXA). PA was measured using the Baecke questionnaire. A regression model was used to analyze the relationship between all the BMDs and the different domains of PA. RESULTS: 41.5% of the adolescents had high percentages of body fat. Regarding the comparison between physically active and insufficiently active adolescents, there were no statistically significant differences in any BMD variables (P > 0.05). The BMD of the legs showed positive relationships with the total PA (beta = 0.009; P = 0.013) and sports PA (beta = 0.010; P = 0.049) after insertion of the confounders. Similarly, the WB BMD showed the same relationships (total PA: beta = 0.005; P = 0.045; and sports PA: beta = 0.008; P = 0.049). No relationship was found between leisure and school PA and any of the BMDs (P > 0.05). CONCLUSION: The results indicated that practice of sport was related to higher BMD values, independent of sex, age and body fatness. PMID- 28832810 TI - Spontaneous rupture of right gastroepiploic artery aneurysm: a rare cause of hemorrhagic shock. Case report. AB - CONTEXT:: Aneurysms of the gastroepiploic arteries are seen only rarely. They are usually diagnosed during autopsy or laparotomy in patients with hemodynamic instability. Although the operation to treat this condition is relatively easy, delay in making the diagnosis affects the course of the disease. CASE REPORT:: A 57-year-old woman was admitted to the emergency department with abdominal pain and unconsciousness. A computed tomography scan showed extravasation of contrast agent at the headcorpus junction of the pancreas, and the patient underwent exploratory laparotomy under general anesthesia. During laparotomy, aneurysmatic rupture of the right gastroepiploic artery was detected. Control over bleeding was achieved by ligating the right gastroepiploic artery at its origin. The aneurysm was also resected and sent for pathological examination. CONCLUSION:: Especially in cases of unidentified shock, splanchnic artery aneurysms should be kept in mind. Moreover, in the light of the data in the literature, the possibility of death should be taken into account seriously and, if feasible, prophylactic aneurysmectomy should be performed. PMID- 28832811 TI - Unethical research trend: shadow libraries. PMID- 28832812 TI - Relation between arithmetic performance and phonological working memory in children. AB - Purpose: To compare the results of Loop Phonological Working Memory (LPWM) in children without global learning alterations, with lower and average/higher arithmetic performance. Methods: The study was conducted with 30 children, between the ages of seven and nine years old, who attended the second or third grade of elementary school in the public network. Exclusion criteria were children with suggestive signs of hearing loss, neurological disorders, poor performance in the reading comprehension test or in speech therapy. The children included in the study were submitted to the subtest of arithmetic of Academic Achievement Test for division into two groups (G1 and G2). The G1 was composed of children with low performance in arithmetic and G2 for children with average/higher performance in arithmetic. All children were submitted to PWM assessment through the repetition of pseudowords test. Statistical analysis was performed using the Mann-Whitney test and a p-value <0.05 was considered significant. Results: The study included 20 girls and 10 boys, mean age 8.7 years. The G1 was composed of 17 children and G2 of 13 children. There was a statistically significant difference between the groups studied for the repetition of pseudowords with three and four syllables. Conclusion: The results of this study provide support for the hypothesis that changes in phonological working memory are related to difficulties in arithmetic tests. PMID- 28832813 TI - Language in Frontotemporal Dementia: an analysis in light of Enunciative Discursive Neurolinguistics. AB - The aim of this case study was to perform a cross-sectional analysis of spontaneous speech of a patient with Frontotemporal Dementia (FTD). For this purpose, four speech and language therapy episodes, from 2012 to 2014, were selected, transcribed and analyzed in light of Enunciative-Discursive Neurolinguistics. The analysis showed, as the patient's FTD status progressed, that he used different semiotic strategies, e.g., use of repetition and gesture during speech production. It also highlighted the importance of the interlocutor's role of prompting the patient to express verbal meaning. Thus, it can be concluded that the recognition of the strategies used by the patient in favor of his role as a speaker, during interactions, is what enables and legitimates his role. PMID- 28832814 TI - Screening tool for oropharyngeal dysphagia in stroke - Part I: evidence of validity based on the content and response processes. AB - Purpose: The aim of the present study was to identify the evidence of validity based on the content and response process of the Rastreamento de Disfagia Orofaringea no Acidente Vascular Encefalico (RADAVE; "Screening Tool for Oropharyngeal Dysphagia in Stroke"). Methods: The criteria used to elaborate the questions were based on a literature review. A group of judges consisting of 19 different health professionals evaluated the relevance and representativeness of the questions, and the results were analyzed using the Content Validity Index. In order to evidence validity based on the response processes, 23 health professionals administered the screening tool and analyzed the questions using a structured scale and cognitive interview. Results: The RADAVE structured to be applied in two stages. The first version consisted of 18 questions in stage I and 11 questions in stage II. Eight questions in stage I and four in stage II did not reach the minimum Content Validity Index, requiring reformulation by the authors. The cognitive interview demonstrated some misconceptions. New adjustments were made and the final version was produced with 12 questions in stage I and six questions in stage II. Conclusion: It was possible to develop a screening tool for dysphagia in stroke with adequate evidence of validity based on content and response processes. Both validity evidences obtained so far allowed to adjust the screening tool in relation to its construct. The next studies will analyze the other evidences of validity and the measures of accuracy. PMID- 28832815 TI - [Medical anthropologies in Europe]. PMID- 28832816 TI - "They fear us because we are Other": attitudes towards disabled people in today's Russia. AB - Although the number of disabled people in post-Soviet Russia exceeds 13 million, research regarding many processes occurring within this large segment of the society remains scant. The objective of this article was to examine the different notions and stereotypes dealing with impairments. Using the qualitative approach of oral history, in-depth interviews with 11 men and 16 women with disabilities were carried out in three regions of Russia, as were interviews with six experts in Moscow and Nizhny Novgorod. In addition, accounts of disability experience published in online journals were examined. The analysis of these sources shows that the perception of disabled people and disability in general is ambivalent and impacts the perception of disability and self-identification of disabled people who are also a part of Russian society. PMID- 28832817 TI - [Medical education and medical anthropology in Europe: the cases of Italy and Spain]. AB - The aim of this article is to compare the development of health education in Italy and Spain from the point of view of the role played by medical anthropology in both countries. The context is provided by the changes in the concept of health education advocated by the UN technical agencies, especially the World Health Organization and Unesco, during the second half of the twentieth century. Despite their many similarities, Italy and Spain underwent different political evolutions over the last century. Therefore, it is interesting to compare both cases and the influence the social sciences had in health education initiatives. In order to assess the role of medical anthropology, the 1958 launch and the development of the Centro Sperimentale per l'Educazione Sanitaria (Perugia, Italy), which was at the forefront of health education in Europe until the 1990s, was reconstructed through oral sources. After a brief description of the scant initiatives regarding health education existing in the Spain of the dictatorship, the influence of the Perusine anthropologists on Spanish health education during the democratic transition is evaluated. PMID- 28832818 TI - [Sex workers and public health: intersections, vulnerabilities and resistance]. AB - Since the 19th century with syphilis and most recently with AIDS, sex workers have been seen as a means for disease transmission and a public health problem that requires intervention. However, researchers have shown that in Western countries, HIV rates in people involved in commercial sex are low, except for in specific groups, such as intravenous drug users. Moreover, the risks faced by sex workers due to stigmatization and other forms of violence have been put into evidence. Based on an urban ethnography with street sex workers carried out in Porto (Portugal), between 2004 and 2005, this article discusses the social, labor, and legal vulnerabilities affecting people involved in commercial sex and how these interfere with their health. Focus is placed on the strategies used by sex workers to minimize health risks and their discourses of resistance in fighting vulnerabilities. PMID- 28832819 TI - [The meaning of the diagnosis in the illness trajectory of a person with rheumatic disease: From the uncertainty to biographical disruption]. AB - This article seeks to analyze the meaning of the medical diagnosis in the biographies of people who suffer from a rheumatic disease. Based in the ethnographic method, in-depth interviews were carried out among fifteen informants affected by different rheumatic conditions from the City of Barcelona. These interviews make it possible to see how the symptoms, dysfunctions or limitations experienced up until the definitive diagnosis can be reinterpreted in the presence of a model that explains the condition and gives it a name, attributing new meaning to the symptoms and establishing certain care and coping strategies. After a period of uncertainty, this definitive medical diagnosis allows for an enigmatic chronic condition from which the person is suffering to be deciphered, representing a turning point in the care trajectory that is understood as a biographical disruption redefining the past and future of the subject. However, it is often necessary for those affected to undergo a complex, erratic and uncertain itinerary to reach the final diagnosis, which is then identified retrospectively as a milestone in the illness experience. PMID- 28832820 TI - [Toxic bodies: perceived risk of internal contamination by chemical compounds in Spain]. AB - This article analyses the social perception of human exposure to chemical compounds and discourses and practices regarding bodily boundaries when faced with internal contamination. Based on qualitative and interdisciplinary research carried out in Catalonia, the social meanings attributed to the environmental and food dangers and risks related to chemical compounds that affect human health, and the place that the body takes in the production of these discourses, were explored. In order to do so, between June and November 2011, 43 semi-structured interviews with workers with some awareness of chemical contaminants were carried out, emphasizing how these people (re)interpret the different existing discourses about internal contamination as well as their perceptions regarding the introduction of chemical compounds into the body and the dangers that these substances pose to health. PMID- 28832821 TI - Narrative medicine in the framework of empirical social research: the Russian context. AB - This article contains the results of the empirical analysis carried out in 2012 2016 which sought to examine whether patients' narratives of their illness were present in doctor-patient communication and whether this subjective story was significant to both sides of the medical communication in Russian somatic disease medicine. The research was carried out in four stages and combined qualitative and quantitative methods, analyzing the perspectives of patients, doctors and medical students through surveys and interviews as well as looking at online doctor-patient communication in health forums. In all four stages, the results of the research showed that little value was placed on the subjective experience of disease in doctor-patient interactions. The topic of narrative medicine is new to Russian social studies, making the results of this research an important contribution to the establishment of narrative medicine as a global idea advocating the universal therapeutic and ethical value of patients' stories of illness in the "remission society," in which chronic pathologies dominate. PMID- 28832822 TI - [Contributions to a feminist anthropology of health: the study of the menstrual cycle]. AB - Medical or Health Anthropology focused on the study of women continues to be a main area of anthropological study in Spain. The contributions of two referential figures in feminist health anthropology, Marcia Inhorn and Mari Luz Esteban, are applied to review the findings of a qualitative research study on the menstrual cycle carried out through 20 interviews with women between the ages of 16 and 44 years, between 2013 and 2014, in the municipality of Madrid. The analysis shows that menstruation is a clear example of the reproductive essentialization of women, of biological reductionism, of the medicalization of women's bodies and, above all, of the standardization of bodies. The visibilization and questioning of these assumptions through the voices of the women interviewed highlight the importance of this field within medical anthropology. PMID- 28832823 TI - [Less well-established forms of knowledge: new positionings in the field of collective mental health]. AB - Collective health is a paradigm with a long history in Latin America. Similarly, collective mental health has had an interesting development in certain Latin American countries, even acting to stimulate psychiatric reform. However, both paradigms appear to be encapsulated in specific times and places, among other reasons because of a hegemonic global-scale epistemology that, by imposing a naturalized model of truth, denies other forms of knowledge the opportunity to question not only already-established disease categories, treatment protocols and health policies, but the established order itself. In this article, we reflect on the power of ethnography, as both a form of knowledge and a social relation in itself, to broaden the space available for a possible field of collective health in a context where it is still incipient: Europe. The ethnographic point of view allows us to rethink that which is already accepted, creating permeability in entrenched practices and opening up surprising new possibilities. PMID- 28832824 TI - [Literary, biographic and autoethnographic contributions in Spanish medical anthropology: the case of Catalonia]. AB - The autoethnographic method has been an important contribution to the development of medical anthropology in Spain. This article first reviews and explores documents published before 1980 that are usually classified as literature and autobiography and are linked to the health-disease-care process, a paradigmatic example of which is Ramona Via's diary Com neixen els Catalans [How Catalans are born] published in 1972. The second part of the article is focused on contributions carried out since the 1980s using the concept of autoethnography, which have as their object the body, health and illness based on a subjective ethnographic experience. This period, unlike the first, is characterized by the emergence of anthropologist authors who have promoted the development of this method, legitimized by the Tarragona School and substantialized in the first Spanish conference of autoethnography in 2015. PMID- 28832825 TI - [Food education: health and social cohesion]. AB - Using a theoretical-reflexive approach, this article connects the results of various qualitative studies in social conflict and medical anthropology, in order to investigate how food can be a tool for social transformation in terms of health but also in terms of the dialogue, respect and coexistence among people, groups and communities. In this sense the article presents a first approximation to a new theoretical and methodological approach to food education. In this approach, food adopts a political, sociocultural and participatory perspective that brings us closer to an innovative understanding of the phenomenon of food: not only as an analytic and diagnostic tool, but also as an instrument for health education interventions toward conflict resolution and the promotion of healthier societies overall - nutritionally, but also in terms of equality and social cohesion. PMID- 28832826 TI - [Study of perceptions regarding health in people who use bicycles as a means of transport]. AB - In recent years, the development of specific promotion policies in some Spanish cities has led to increased use of bicycles as a means of transport. In the case of the city of Seville, bicycle commuting within the metropolitan area has gone from being quantitatively insignificant to amounting to more than 6% of the modal share. Based in ethnographic research carried out in the region of Andalucia between 2013 and 2015, implementing interviews, focus groups and participatory forums in which 320 adults took part, this article analyzes from a sociocultural point of view perceptions about the health of those who use bicycles as a means of transportation and evidences some challenges that need to be faced in promoting bicycle transportation in the city. Among the effects reported by users, those relating to the perception of improvements in their state of health and emotional well-being can be highlighted. The article concludes by problematizating the analysis of the relationship between health and physical exercise in the city from a socio-anthropological perspective. PMID- 28832827 TI - [Associations and dissociations: agents, discourses and controversies surrounding child hyperactivity]. AB - Attention deficit hyperactivity disorder (ADHD) generates debates and confrontations among diverse social agents with different conceptions of normality, health, the individual and the social. In this scenario of controversy, parents have tried to improve the living conditions of their children through a number of models of social participation in health. Using a qualitative ethnographic approach, fieldwork was carried out from 2013 to 2015 with the purpose of analyzing the universe of organizations regarding ADHD in Spain as well as other individual parenting initiatives with collective repercussions. The work seeks to identify the different relationships with expert knowledge in existence and the models of knowledge circulation that take place within those relationships, focusing on the way they configure discursive stances, establish collective dynamics, and develop actions. The disputed character of ADHD is evidenced in models more complex than that of the expert/layperson duality, as well as in new strategies of production and collectivization of knowledge facilitated by the Internet. PMID- 28832828 TI - [Long-term informal care in Spain: challenges, views and solutions]. AB - Caring for chronic illnesses at all ages represents a growing social and public health problem. Due to insufficient public coverage in Spain, around 80% of long term care is provided by the sick person's social network. Based in ethnographic research on chronicity carried out between 2009 and 2013 in Spain, this article analyzes the problem of long-term informal care for middle-aged adults with chronic diseases. The results highlight the factors that condition, enhance or limit informal care: the personal, domestic and family situation of the sick person; the cyclical course of chronic diseases; and the social response to illness. The limitations of the informal care model suggest the need to listen to the voices of those affected in order to understand their real needs and adapt official programs oriented towards chronicity accordingly. PMID- 28832829 TI - Variation in the isotopic composition of striped weakfish Cynoscion guatucupa of the Southwest Atlantic Ocean in response to dietary shifts. AB - The aim of this study was to analyze the isotopic composition in muscle of striped weakfish Cynoscion guatucupa from Southwest Atlantic Ocean in order to evaluate a possible variation in delta13C and delta15N in response to dietary shifts that occur as animals grow. We also explored for isotopic evidence of differences between sample locations. The results showed an agreement between isotope analysis and previous conventional studies. Differences in the isotope composition between sampling location were not observed. A positive relation exists between isotope values and total body length of the animals. The Cluster analysis defined three groups of size classes, validated by the MDS. Differences in the relative consumption of prey species in each size class were also observed performing isotope mixing models (SIAR). Variation in delta15N among size classes would be associated with the consumption of a different type of prey as animals grow. Small striped weakfish feed on small crustaceans and progressively increase their consumption of fish (anchovy, Engraulis anchoita), increasing by this way their isotope values. On the other hand, differences in delta13C values seemed to be related to age-class specific spatial distribution patterns. Therefore, large and small striped weakfish remain specialized but feeding on different prey at different trophic levels. These results contribute to the study of the diet of striped weakfish, improve the isotopic ecology models and highlight on the importance of accounting for variation in the isotopic composition in response to dietary shifts with the size of one of the most important fishery resources in the region. PMID- 28832830 TI - Using in situ flow cytometry images of ciliates and dinoflagellates for aquatic system monitoring. AB - Short-period variability in plankton communities is poorly documented, especially for variations occurring in specific groups in the assemblage because traditional analysis is laborious and time-consuming. Moreover, it does not allow the high sampling frequency required for decision making. To overcome this limitation, we tested the submersible CytoSub flow cytometer. This device was anchored at a distance of approximately 10 metres from the low tide line at a depth of 1.5 metres for 12 hours to monitor the plankton at a site in the biological reserve of Barra da Tijuca beach, Rio de Janeiro. Data analysis was performed with two dimensional scatter plots, individual pulse shapes and micro images acquisition. High-frequency monitoring results of two interesting groups are shown. The abundance and carbon biomass of ciliates were relatively stable, whereas those from dinoflagellates were highly variable along the day. The linear regression of biovolume measures between classical microscopy and in situ flow cytometry demonstrate high degree of adjustment. Despite the success of the trial and the promising results obtained, the large volume of images generated by the method also creates a need to develop pattern recognition models for automatic classification of in situ cytometric images. PMID- 28832831 TI - Assessment of the antibacterial, cytotoxic and antioxidant activities of Morus nigra L. (Moraceae). AB - This study was carried out to assess the antibacterial, cytotoxic and antioxidant activities of extracts of Morus nigra L. HPLC was used to determine the fingerprint chromatogram of the crude ethanolic extract (Mn-EtOH). The antibacterial effect was assessed through the method of microdilution. The cytotoxicity was tested against human tumour cell lines using the 3-(4,5-dimethyl 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The total phenolic and flavonoid contents were also assessed through the Folin-Ciocalteu and aluminum chloride methods, respectively. Antioxidant activities of the extracts were evaluated by using 2,2-diphenyl-1-picrylhydrazil (DPPH) radical scavenging and beta-carotene-linoleic acid bleaching methods. The presence of phenolic compounds in Mn-EtOH was confirmed using HPLC. The extracts showed activity against most microorganisms tested. The extracts did not show any expressive antiproliferative effect in the assessment of cytotoxicity. The most significant total phenolic content was 153.00 +/- 11.34 mg of gallic acid equivalent/g to the ethyl acetate extract (AcOEt). The total flavonoid content was 292.50 +/- 70.34 mg of catechin equivalent/g to the AcOEt extract, which presented the best antioxidant activity (IC50 50.40 +/- 1.16 MUg/mL) for DPPH scavenging. We can conclude that this species shows strong antibacterial and antioxidant activities, as well as weak cytotoxic effects. PMID- 28832832 TI - Reproductive cycle of Mytella guyanensis (Lamarck, 1819) in a Marine Reserve (RESEX Bay of Iguape), Bahia, Brazil. AB - Mytella guyanensis, consumed and commercialized in coastal regions of Brazil, is one of several bivalve species of socioeconomic interest for coastal communities. Besides serving as a source of income and subsistence for these communities, it also contributes to their food security as it is a source of proteins and micronutrients. Thus, the reproductive cycle of this species was studied aiming to contribute to food security and its preservation. Samples were collected monthly, between March 2014 and March 2015, in a natural stock (12 degrees 38'50"S; 38 degrees 51'43"W) in a Marine Reserve (RESEX Bay of Iguape) (community Engenho da Ponte), Bahia, Brazil. Mytella guyanensis is collected by women on site, where the artisanal fishing of this resource is performed without following any specific handling procedure. Also, empirical evidence indicates overexploitation. The specimens collected were measured along the anterior posterior axis (length), and after macroscopic analysis they were fixed in Davidson solution, processed by routine histology techniques and stained with Harris haematoxylin and eosin (H&E). The macroscopic analysis showed sexual dimorphism, with the male and female gonads presenting a milky-white and orange colour, respectively. A 1:1 sex ratio (M: F) was observed and reproduction of the species was continuous all year round. March, April, July and August were the months with highest values of gamete elimination. We suggest that a M. guyanensis management plan should restrict capture during these months, in order to sustainably regulate exploitation of this food resource in this reserve. PMID- 28832833 TI - Characterization of digestive enzymes from captive Brazilian flounder Paralichthys orbignyanus. AB - Knowledge of specific enzyme activity, along with animal habits and digestive capacity is essential in formulating an appropriate diet for any species. In this study, we evaluated and characterized the activity of digestive enzymes present in the liver, intestine, and stomach of Paralichthys orbignyanus. The effects of pH and temperature on enzyme activity were also evaluated via the use of specific substrates. The use of specific substrates and inhibitors showed strong evidence of the presence of trypsin (BApNA= 0.51 +/- 0.2 mU mg-1), chimotrypsin (SApNA= 2.62 +/- 1.8 mU mg-1), and aminopeptidases (Leu-p-Nan =0.9709 +/- 0.83 mU mg-1) in the intestine. Optimum pH for the activity of trypsin, chemotrypsin, leucino aminopeptidase, amilase, and pepsin were 9.5, 9.0, 8.0, 7.5, and 3.5, respectively, while optimum temperatures were 50, 50, 50, 40, and 45 degrees C, respectively. These results provide additional information regarding the biology of Brazilian flounder and can be used as a basis for further studies regarding fish feeding physiology. PMID- 28832834 TI - Perkinsus beihaiensis (Perkinsozoa) in oysters of Bahia State, Brazil. AB - This study reports the pathogen Perkinsus beihaiensis in oysters of the genus Crassostrea on the coast of the State of Bahia (Brazil), its prevalence, infection intensity and correlation with salinity. Oysters (n = 240) were collected between October and December 2014 at eight sampling stations between latitudes 13 degrees 55'S and 15 degrees 42'S. The laboratory procedures included macroscopic analysis, histology, culture in Ray's fluid thioglycollate medium (RFTM), Polymerase Chain Reaction (PCR) and DNA sequencing. PCR and sequencing have been used for the genetic identification of oysters as well. Two species of oysters have been identified: Crassostrea rhizophorae and C. brasiliana. In both oyster species P. beihaiensis was the only Perkinsus species detected. In C. rhizophorae, the average prevalence was 82.8% by histology and 65.2% by RFTM. In C. brasiliana, the prevalences were 70.5% and 35.7%, respectively. The higher prevalence of P. beihaiensis in C. rhizophorae was probably influenced by salinity, with which was positively correlated (r> 0.8). In both oysters, P. beihaiensis was located mainly in the gastric epithelium. The infection was generally mild or moderate, without apparent harm to the hosts, but in cases of severe infection, there was hemocytical reaction and tissue disorganization. The generally high prevalence in the region suggests that oysters should be monitored with respect to this pathogen, especially in growing areas. PMID- 28832835 TI - Toxicity of synthetic flavorings, nature identical and artificial, to hematopoietic tissue cells of rodents. AB - The goal of this study was to analyze cytotoxicity, genotoxicity and mutagenicity to bone marrow cells of mice of nature identical synthetic flavorings, passion fruit and strawberry, and artificial synthetic flavorings, vanilla, chocolate, tutti-frutti and cookie, at doses 0.5; 1.0; 2.0; 5.0 and 10.0 mL/kg. The additives were given to the animals by gavage in a single daily application for seven days. Data were subjected to analysis of variance (ANOVA) followed by post Tukey's post hoc test, p <0.05. Animals treated with 2.0; 5.0 and 10.0 mL/Kg of flavorings chocolate, strawberry and cookie, and 5.0 and 10.0 mL/Kg of flavorings vanilla and passion fruit died on the fifth and sixth day of the experiment, respectively. The doses 0.5 and 1.0 mL/Kg of the six additives significantly reduced erythropoiesis in the examined tissue. Also, treatments 0.5 and 1.0 mL/Kg of chocolate, and 1.0 mL/Kg of strawberry and biscuit induced the formation of micronuclei in the bone marrow erythrocytes, at a significant frequency. Therefore, under the study conditions, the six microingredients analyzed were cytotoxic and genotoxic, and additives strawberry, chocolate and cookie were also mutagenic in at least one of the evaluated doses. PMID- 28832836 TI - Microencapsulation of essential thyme oil by spray drying and its antimicrobial evaluation against Vibrio alginolyticus and Vibrio parahaemolyticus. AB - The aims of this research were first, to evaluate the antibacterial potential of commercial thyme essential oil against V. alginolyticus and V. parahaemolyticys and second, using the spray drying technique to produce microcapsules. chemical compounds of thyme oil and microcapsules were identified and quantified being thymol the chemical component present at the highest concentration. Oil-in-water (O/W) emulsions were prepared and the microcapsules were obtained with a spray dryer using maltodextrin as wall material (ratio 1:4). Thyme oil and the microcapsules exhibited antimicrobial activity against V. parahaemolyticus and V. alginolyticus. The spray drying process did not affect the antimicrobial activity of thyme essentialoil. PMID- 28832837 TI - Analysis of the landscape complexity and heterogeneity of the Pantanal wetland. AB - This is the first report on analysis of habitat complexity and heterogeneity of the Pantanal wetland. The Pantanal encompasses a peculiar mosaic of environments, being important to evaluate and monitor this area concerning conservation of biodiversity. Our objective was to indirectly measure the habitat complexity and heterogeneity of the mosaic forming the sub-regions of the Pantanal, by means of remote sensing. We obtained free images of Normalized Difference Vegetation Index (NDVI) from the sensor MODIS and calculated the mean value (complexity) and standard deviation (heterogeneity) for each sub-region in the years 2000, 2008 and 2015. The sub-regions of Pocone, Canoeira, Paraguai and Aquidauana presented the highest values of complexity (mean NDVI), between 0.69 and 0.64 in the evaluated years. The highest horizontal heterogeneity (NDVI standard deviation) was observed in the sub-region of Tuiuiu, with values of 0.19 in the years 2000 and 2015, and 0.21 in the year 2008. We concluded that the use of NDVI to estimate landscape parameters is an efficient tool for assessment and monitoring of the complexity and heterogeneity of the Pantanal habitats, applicable in other regions. PMID- 28832838 TI - Phenology of Guarea macrophylla Vahl (Meliaceae) in subtropical riparian forest in southern Brazil. AB - Climate is one of the main factors that affect plant behavior. The phenology of Guarea macrophylla Vahl, which is a small tree used for reforestation of degraded areas, was monitored for 18 months in a riparian forest at the Schmidt Stream, Campo Bom, in the state of Rio Grande do Sul, southern Brazil. Vegetative (leaf fall and leaf flushing) and reproductive events were observed, with the latter divided into flowering (flower buds and anthesis) and fruiting (unripe, ripening and ripe fruit). Phenological events were related to temperature, photoperiod and precipitation and their seasonality was verified by circular statistical analysis. Vegetative phenophases were continuous; they were not related to climate factors and presented low intensity, emphasizing the perennial aspect of the species. Flowering occurred during spring and summer. Both flower buds and anthesis were related to temperature and photoperiod. Fruiting was constant and went through all stages of development. Unripe fruits developed during the months with the lowest photoperiod and ripen more intensely in winter, on colder days. Ripe fruit became available for dispersal in spring, in times of longer photoperiod and higher temperatures. Except for leaf fall, all other phenological events showed seasonality in their manifestation. The one-month difference between the onsets of the flowering phases observed in this study indicated that local climate changes induced the early occurrence of this phenophase. PMID- 28832839 TI - Condition factor variations over time and trophic position among four species of Characidae from Amazonian floodplain lakes: effects of an anomalous drought. AB - The effects of extreme droughts on freshwater fish remain unknown worldwide. In this paper, we estimated the condition factor, a measure of relative fitness based on the relationship of body weight to length, in four fish species representing two trophic levels (omnivores and piscivores) from Amazonian floodplain lakes for three consecutive years: 2004, 2005 (an anomalous drought year), and 2006. The two omnivores, Colossoma macropomum and Mylossoma duriventre, exhibited trends consistent with their life cycles in 2004 and 2006: high values during the hydrologic seasons of high water, receding water, and low water, with a drop following reproduction following the onset of rising water. However during the drought year of 2005 the condition factor was much lower than normal during receding and low water seasons, probably as a result of an abnormal reduction in resource availability in a reduced habitat. The two piscivorous piranhas, Serrasalmus spilopleura and S. elongatus, maintained relatively stable values of condition factor over the hydrologic cycles of all three years, with no apparent effect of the drought, probably because the reduction in habitat is counterbalanced by the resulting increase in relative prey density. We suggest that if predictions of increasing drought in the Amazon are correct, predatory species may benefit, at least in the short run, while omnivores may be negatively affected. PMID- 28832841 TI - First report of the alien species Trichopodus trichopterus (Pallas, 1770) in the state of Ceara, Brazil. PMID- 28832840 TI - Biomarkers and bioindicators of the environmental condition using a fish species (Pimelodus maculatus Lacepede, 1803) in a tropical reservoir in Southeastern Brazil. AB - The Funil Reservoir receives a large amount of xenobiotics from the Paraiba do Sul River (PSR) from large number of industries and municipalities in the watershed. This study aimed to assess environmental quality along the longitudinal profile of the Paraiba do Sul River-Funil Reservoir system, by using biomarkers and bioindicators in a selected fish species. The raised hypothesis is that Funil Reservoir acts as a filter for the xenobiotics of the PSR waters, improving river water quality downstream the dam. Two biomarkers, the ethoxyresorufin-O-deethylase activity (EROD), measured as fluorimetricly in S9 hepatic fraction, and the micronuclei frequency (MN), observed in erythrocytes of the cytoplasm, and three bioindicators, the hepatosomatic index (HSI), gonadosomatic index (GSI) and condition factor (CF) were used in Pimelodus maculatus, a fish species widely distributed in the system. Four zones were searched through a longitudinal gradient: 1, river upstream from the reservoir; 2, upper reservoir; 3, lower reservoir; 4, river downstream of the reservoir. EROD activity and HSI and GSI had significant differences among the zones (P<0.05). The upper reservoir had the lowest EROD activity and HSI, whereas the river downstream of the reservoir had the highest EROD and lowest GSI. The river upstream from the reservoir showed the highest HSI and GSI. It is suggested that the lowest environmental condition occur at the river downstream of the reservoir, where it seems to occur more influence of xenobiotics, which could be associated with hydroelectric plant operation. The hypothesis that Funil reservoir acts as a filter decanting pollution from the Paraiba do Sul River waters was rejected. These results are novel information on this subject for a native fish species and could be useful for future comparisons with other environments. PMID- 28832842 TI - Estimation of peacock bass (Cichla spp.) mortality rate during catch-release fishing employing different post-capture procedures. AB - The effect of catch-and-release fishing on the survival of peacock bass (Cichla spp.) was evaluated by comparing two types of artificial bait (jig and shallow diver plugs) and two types of post-catch confinement. Two experiments were conducted during the periods January-February and October-November 2012 in the Unini River, a right-bank tributary of the Negro River. In total, 191 peacock bass were captured. Both groups of fish were subjected to experimental confinement (collective and individual) for three days. Additionally, 11 fish were tagged with radio transmitters for telemetry monitoring. Mortality rate was estimated as the percentage of dead individuals for each type of bait and confinement. For peacock bass caught with jig baits, mortality was zero. The corresponding figure for shallow-diver bait was 1.66% for fish in collective containment, 18.18% for fish monitored by telemetry and 0% for individuals confined individually. Our results show low post-release mortality rates for peacock bass. Furthermore, neither the type of confinement nor the type of bait had a statistically significant influence on mortality rates. While future studies could include other factors in the analysis, our results show that catch and-release fishing results in low mortality rates. PMID- 28832843 TI - Air pollution and low birth weight in an industrialized city in Southeastern Brazil, 2003-2006. AB - Introduction:: Birth weight is an important indicator of several conditions that manifest earlier (as fetal and neonatal mortality and morbidity, inhibited growth and cognitive development) and later in life such as chronic diseases. Air pollution has been associated with adverse pregnancy outcomes. Objective:: Retrospective cohort study investigated the association between low birth weight (LBW) and maternal exposure to air pollutants in Volta Redonda city, Rio de Janeiro, Brazil, from 2003 to 2006. Methods:: Birth data was obtained from Brazilian Information System. Exposure information (O3, PM10, temperature and humidity) was provided by Governmental Air Quality Monitoring System. Linear and Logistic models, adjusted for sex, type of pregnancy, prenatal care, place of birth, maternal age, parity, education, congenital anomalies and weather variables were employed. Results:: Low birth weight (LBW) represented 9.1% of all newborns (13,660). For an interquartile range increase in PM10 it was found OR2 ndTrimester = 1.06 (95%CI 1.02 - 1.10), OR3 rdTrimester = 1.06 (95%CI 1.02 - 1.10) and, in O3 it was found OR2 ndTrimester = 1.03 (95%CI 1.01 - 1.04), OR3 rdTrimester = 1.03 (95%CI 1.02 - 1.04). The dose-response relationship and a reduction in birth weight of 31.11 g (95%CI -56.64 - -5.58) was observed in the third trimester of pregnancy due to an interquartile increase of O3. Conclusion:: This study suggests that exposures to PM10 and O3, even being below the Brazilian air quality standards, contribute to risks of low birth weight. PMID- 28832844 TI - Capturing deaths not informed to the Ministry of Health: proactive search of deaths in Brazilian municipalities. AB - Introduction:: The proactive search of deaths is a strategy for capturing events that were not informed to the Mortality Information System of Ministry of Health. Its importance to reduce underreporting of deaths and to evaluate the operation of the information system is widely known. Objective:: To describe the methodology and main findings of the Proactive Search of Deaths, 2013, establishing the contribution of different information sources. Methods:: The research was carried out in 79 Brazilian municipalities. We investigated several official and unofficial sources of information about deaths of municipality residents. Every information source investigated and all cases found in each source were typed in an on-line panel. The second stage of the research was the confirmation of cases to verify information of year and residence and to complete missing information. For all confirmed cases, we estimated the completeness of death registration and correction factors according to the adequacy level of mortality information. Results:: We found 2,265 deaths that were not informed to the Mortality Information System. From those, 49.3% were found in unofficial sources, cemeteries and funeral homes. In some rural municipalities, precarious burial conditions were found in cemeteries in the middle of the forest and no registration of the deceased. Correction factors were inversely associated to the adequacy level of mortality information. Conclusion:: The findings confirm the association between level of information adequacy and completeness of death registration, and indicate that the application of the proactive search is an effective method to capture deaths not informed to the Ministry of Health. PMID- 28832845 TI - Emotional and motor symptoms in riverside dwellers exposed to mercury in the Amazon. AB - Introduction:: The investigation of clinical and neurological impactations associated with exposure to mercury levels in exposed populations is necessary in the Amazon. Objective:: To analyze emotional and motor symptoms of riverside dwellers exposed by diet in the municipalities of Itaituba and Acara, in Para, Brazil. Methods:: Hair samples were collected to assess the total mercury (HgT). Demographic data as well as emotional (depression, anxiety and insomnia) and motor (paresthesia, muscle weakness, loss of balance when walking, tremors, limb pain and dysarthria) symptomatology data were obtained. Results:: Mean levels of HgT in Itaituba were significantly higher (p < 0.0001) than in Acara. Emotional symptoms were identified in 26 (26.5%) participants from Itaituba and in 24 (52.2%) from Acara. Specific motor complaints in Itaituba occurred in 63 (64.3%) volunteers; the most frequently mentioned afflictions were limb pain (36.7%), paresthesia (32.6%) and muscle weakness (27.5%). In Acara, 33 (71.7%) participants had motor symptoms, the majority of which complained of paresthesia (54.3%), limb pain (52.2%) and tremors (34.8%). Average HgT levels in Itaituba in those with emotional and motor symptoms were above the tolerable levels (6 ug/g) determined by the World Health Organization. Conclusion:: Results showed that mercury levels in emotional and motor symptoms in Itaituba are higher than in riverside dwellers in Acara. Further studies, including the application of specific qualitative and/or quantitative standard tests, as well as the investigation of other clinical signs are necessary. PMID- 28832846 TI - Feminicides in Porto Alegre: How many? Who are they? AB - Objective:: To quantify and typify the feminicides occurred in the city of Porto Alegre from 2006 to 2010. Methods:: Cross-sectional study that examines the sociodemographic characteristics of victims and perpetrators and the circumstances of feminicides obtained in police investigations of women murdered in the city of Porto Alegre. Statistical analyses were performed using the SPSS software, version 20.0, with the chi2 test; p <0.05 was considered as significant. Results:: Of the 89 surveys analyzed, we categorized 64 deaths (72%) as feminicides. Most victims were young, poorly educated and exercised socially undervalued occupations. They had a history of violence perpetrated by an intimate partner and one quarter of them had registered a police report. Conclusion:: These data indicate the magnitude of this crime and the need to identify risk situations and prevent lethal outcomes. PMID- 28832847 TI - Satisfaction with mental health community services among patients' relatives. AB - Objective:: This study aims to assess the satisfaction of family members of patients of mental health community services through a tested, validated and previously applied scale in order to allow comparison of results. Methods:: The results were obtained by applying the scale SATIS-BR to 1242 relatives of patients of 40 mental health community services in Brazil. The average scores of the three subscales of the SATIS-BR scale were compared using the Wilcoxon test. To measure statistical significance for each item of the scale, the Friedman test was applied, considering significant p-value < 0.05. Results:: The average overall satisfaction score was 4.35 with a standard deviation (SD) of 0.44, with a range varying from 1 to 5. The subscale with the highest score refers to the "Results of Treatment", what presents scores of 4.54 with SD of 0.66. As for the other subscales, which refer to "Reception and Staff Competence" and "Service Privacy and Confidentiality" had scores of 4.25 (SD: 0.51) and 4.17 (SD: 0.51). Conclusion:: The high level of satisfaction with the service among families of patients highlights the potential of these services and their contribution to the advance of a model of mental health community care, as it seems to be the global trend. The different results between the scales further suggest that the family distinguishes different aspects of the service and evaluates separately, providing a good reference for evaluation studies. PMID- 28832848 TI - Risk and protective factors for noncommunicable chronic diseases in adolescents by race/skin color: National Adolescent School-Based Health Survey. AB - Introduction:: The race/skin color is an important predictor of health status of the population, as well as a marker of social inequalities. Objective:: The aim of this paper was to describe the prevalence of the main risks and the protective factors for chronic diseases in schoolchildren, according to race/skin color differences. Methods:: Data from the National Adolescent School-Based Health Survey (2012) were used. This is a cross-sectional study carried out in public and private schools. Prevalences were calculated according to the distribution by race/skin color. Prevalence ratios adjusted for age and maternal schooling were analyzed. Results:: White adolescents were younger, studied more frequently in private schools and had mothers with higher levels of education in comparison to the other students. Consumption of beans and fruits was higher among black, brown, and indigenous participants. Physical activity was more frequent among indigenous people. Experimentation with alcohol was higher among white adolescents. Indigenous students reported greater physical violence. Asian and black adolescents reported experiencing greater bullying. Conclusion:: Minimizing racial and ethnic disparities in health is necessary to disease prevention and health promotion among adolescents. PMID- 28832849 TI - Overweight and associated factors in adolescents from a brazilian capital. AB - Objective:: To evaluate the prevalence of overweight in adolescents and its associated factors. Methods:: A cross-sectional study in public and private schools in Goiania, Brazil. Socioeconomic status, family history of obesity, lifestyle, blood pressure and Body Mass Index were studied in a sample of 1,169 Brazilian youth aged 12 - 18 years, who attended public and private schools. Data were obtained from a questionnaire and anthropometric measurements previously tested in a pilot study. Poisson regression was used to estimate the prevalence of overweight, prevalence ratios and associations with the other factors. Results:: The prevalence of overweight was 21.2%, with a significant difference between boys and girls (26.3 and 16.8% respectively). Regression analysis showed that maternal obesity was associated with a higher prevalence of overweight in boys (PR = 1.86; p = 0.004), and boys aged 15 - 18 years had a lower prevalence of overweight than boys aged 12 - 14 years (PR = 0.70; p = 0.021). Among the girls, the presence of obese parents was associated with higher prevalence of overweight (PR = 2.42; p < 0.001), and the girls from a C class socioeconomic position were negatively associated with overweight (PR = 0.67; p = 0.035). Conclusions:: Overweight in adolescence is associated with gender, obesity family history, and socioeconomic position. These data should be considered when planning intervention programs. PMID- 28832850 TI - Changes in commuting to work and physical activity in the population of three municipalities in the Sao Paulo region in 2000 and 2010. AB - Objective:: To evaluate the changes in commuting to work and physical activity (PA) in the population of three municipalities in the Sao Paulo region in 2000 and 2010. Methods:: Cross-sectional study with a representative sample of 602 adults (62.3% men) carried out in the municipalities of Santo Andre, Sao Bernardo do Campo and Sao Caetano do Sul in 2000 (n = 304; 66.1% men) and 2010 (n = 298; 58.4% men). Physical activity was assessed by the International Physical Activity Questionnaire and participants were classified into active (>= 150 min/week) and insufficiently active (< 150 min/week). The commuting to work was classified in active transport (walking and cycling), private (bike, car, vans and buses) and public (buses, vans, train or subway). Results:: Average (min/week) PA walk (229.4 versus 190.6), moderate (449.1 versus 347.4), vigorous (354.4 versus 317.4) and total (552.3 versus 442.5) shows the participants were greater in 2010 than in 2000. The prevalence assets increased from 62.2 to 78.2%, respectively. A negative relationship was found between active transport and public with socioeconomic status; active transport and education level; public transport and age. Positive relationship was found only among private transport and socioeconomic status. The average of the total PA (min/week) was higher (p = 0.024; 32.2%) in 2010 than in 2000 for active transport. Conclusions:: Surveillance data in full PA in the three municipalities of Sao Paulo indicate that the average active commuting to work increased after ten years, while public transport has decreased. PMID- 28832851 TI - Perceived stress among Primary Health Care Professionals in Brazil. AB - Objective:: To evaluate the perceived stress (PS) of professionals in Primary Health Care and its association with the characteristics of the teams in the Family Health Program (FHP). The association between PS and self-referred morbidity was also investigated. Methods:: This is a cross-sectional study conducted with 450 employees from 60 teams in 12 Basic Health Units (BHUs) in a region of Sao Paulo. The differences in the total score in the Perceived Stress Scale were evaluated through multiple linear regression models. Results:: Higher levels of PS were observed in those who had been working for one year or more in the same team, in the categories of doctors, nurses and community health workers, females, non-religious, and in BHU professionals in incomplete teams (absence of a physician). Lower perceived stress was found in widowers. It was observed that individuals with higher levels of PS have higher chances of reporting chronic health problems. Conclusion:: It can be concluded that the perception of stress in this population is associated with individual, professional factors, and the composition of teams in healthcare units. PMID- 28832852 TI - Trends of self-rated health in relation to overweight in the adult population in Brazilian Midwest capitals. AB - Objective:: To estimate the trends of self-rated health in relation to overweight in the adult population of the capitals of the Brazilian Midwest region and the Federal District. Methods:: Cross-sectional study with a population aged 20 to 59 years, using data from the Telephone-based Surveillance of Risk and Protective Factors for Chronic Diseases (VIGITEL), performed between 2008 and 2014. The estimates using the complex sampling design were made using simple linear regression, trend graphs and Boxplot. Results:: The categories "poor" and "very poor" didn't increase in the analyzed period. There was an average increase of 0.5 percentage point per year in the categories "fair" and "good" and an average decrease of 1.0 percentage point in the category "very good". The trend analysis of mean body mass index found there was a progressive growth in all cities. The worst health perceptions showed higher values of body mass index in both sexes. We observed the existence of obese people assessing their health positively. Conclusion:: Self-rated health remained relatively constant whereas the body mass index continued to grow between 2008 and 2014. The self-rated health of individuals with high body mass index (>30 kg/m2) does not seem to be directly related to their weight. Therefore, it is important to analyze the association of these two variables controlling for morbidity, health behaviors (smoking and alcohol consumption, physical activity and diet), and sociodemographic factors. PMID- 28832853 TI - Assessment of Pharmaceutical Services in a Southern Brazilian City. AB - Introduction:: Well-planned and executed pharmaceutical services (PS) are important for proper treatment of the population's health needs, thus enabling the access to essential drugs and promoting their rational use. Objective:: To assess the situation of PS in the city of Uruguaiana (State of Rio Grande do Sul), Brazil. Methods:: This cross-sectional study was applied to 650 interviews between June and September of 2013 in 11 Basic Health Units (UBS) and in the Main Pharmacy of the city. The indicators of prescription, of patient's care, and of service, were assessed according to the recommendations of the World Health Organization (WHO).The Instrument of Self-Assessment for Pharmaceutical Services Planning (IAPAF) from the Brazilian Department of Health was used to assess the management and planning capacity of the PS, which was then applied in the Main Pharmacy and in the medicine stockroom. Results:: The number of drugs per prescription varied from 1 to 10 (mean = 1.7). The percentages of prescribed drugs by generic name, and included in the City List of Essential Drugs (REMUME) were, respectively, 75.5 and 67.7%; antibiotics were prescribed in 9.7% of the medical appointments. The average time of medical appointment was 6 minutes; 51.4% of the users obtained their prescription; only 18.9% of the patients completely understood their prescriptions. Of the 24 items analyzed in the IAPAF, 12 were found in stage 1 (worst rating), 12 in stage 2, and none in stage 3 (ideal situation). Conclusion:: Results seem to show the lack of PS in Uruguaiana with regard to planning, management, and patient's care. The absence of effective management may result in waste and incorrect use of drugs. PMID- 28832854 TI - Agreement between different recall periods in drug utilization studies. AB - Objective:: To assess the agreement between three recall periods for self reported drug use using a 24-hour recall period as reference. Methods:: Participants were allocated into three groups with different recall periods of 7, 14 and 30 days and were interviewed at two different times. A 24-hour recall questionnaire was answered during the first interview, and a questionnaire on drug use over the different recall periods tested was answered during the second interview. The agreement between the questionnaires was evaluated using percent agreement and kappa. Results:: For continuous drugs, percent agreement varied between 92 and 99% and kappa varied between 0.71 and 0.97 for three periods tested. For drugs of occasional use, percent agreement varied between 63 and 81% and kappa varied between 0.27 and 0.52. The prevalence of drugs, particularly those of occasional use, increases with time. Conclusions:: The high level of agreement between the three recall periods suggests that all of them are valid for the investigation of drugs of continuous use. PMID- 28832855 TI - Polypharmacy among the elderly: a population-based study. AB - Objective:: To investigate polypharmacy among the elderly living in the urban area of Florianopolis, in the state of Santa Catarina, Brazil, estimating the prevalence and associated factors. Methods:: This is a cross-sectional population based study with a sample of 1,705 individuals aged 60 years old or older, between 2009 and 2010. The dependent variable was polypharmacy (defined as "use of five or more medications"). The following exploratory variables were utilized: sociodemographic data, use of health services and self-rated health status. Prevalence ratios (PR) were estimated by multivariate analysis using the Poisson regression. Results:: The mean for the medications used by the elderly population was 3.8 (ranging from 0 to 28). The prevalence of polypharmacy was 32%, with 95% confidence interval (95% CI) 29.8 - 34.3. The characteristics presenting a positive association with polypharmacy were: female gender (PR = 1.27; 95%CI 1.03 - 1.57), increasing age (PR = 1.38; 95% CI 1.08 - 1.77), negative self-rated health status (PR = 1.99; 95% CI 1.59 - 2.48) and medical appointments in the 3 months prior to the interview (PR = 1.89; 95% CI 1.53 - 2.32). The groups of medication most utilized by the elderly individuals in polypharmacy were those indicated for the cardiovascular system, digestive tract and metabolism, as well as the nervous system. Conclusion:: The pattern of medication use among this elderly population is within the national average. The prevalence of polypharmacy and the characteristics associated with it were similar to those found in other regions of Brazil. PMID- 28832856 TI - Hospitalizations for primary care-sensitive conditions in Pelotas, Brazil: 1998 to 2012. AB - Objective:: To verify the hospitalization trend for primary care sensitive conditions in Pelotas, Rio Grande do Sul, Brazil from 1998 to 2012. Methods:: An ecological study compared hospitalizations rates of the city of Pelotas with the rest of state of Rio Grande do Sul. Analysis was conducted using direct standardization of rates, coefficients were stratified by sex and the Poisson regression was used. Results:: Hospitalizations for sensitive conditions decreased in Pelotas and Rio Grande do Sul. In Pelotas, a 63.8% decrease was detected in the period observed, and there was a 43.1% decrease in the state of Rio Grande do Sul. Poisson regression coefficients showed a decrease of 7% in Pelotas and of 4% in the rest of Rio Grande do Sul each year. Conclusion:: During the study period, several changes were introduced in the Brazilian Unified Health System ("Sistema Unico de Saude") that may have influenced the results, including changes in administration, health funding, and a complete reworking of primary care through the creation of the Family Health Strategy program ("Estrategia Saude da Familia"). PMID- 28832858 TI - Pharmacists as Integral Members of the Cardiovascular Team-Reply. PMID- 28832857 TI - Association between demographic and socioeconomic conditions with exercise practice and physical fitness in community projects participants aged 50 years or more in Ribeirao Preto, Sao Paulo. AB - Objective:: To investigate the association between both demographic and socioeconomic conditions with physical fitness and regular practice of physical exercises in participants of community projects, supervised by a physical education teacher. This enabled to investigate whether the adoption of an active lifestyle depends only on the personal choice or has any influence of socioeconomic factors. Methods:: 213 individuals aged over 50 years joined the study, and provided information about their socioeconomic status (age, gender, education/years of study, and income); usual level of physical activity (ULPA); and physical fitness, by a physical battery tests which allowed the calculation of general functional fitness index (GFFI). Results:: The generalized linear model showed that participants ranked in the highest GFFI groups (good and very good) had more years of study and higher income (p < 0.05). The multiple linear regression model complements the previous analysis, demonstrating the magnitude of the change in the GFFI in association with the years of study (group > 15), income (all groups) and age (p < 0.05). By means of analysis of variance, a difference between the groups was verified and longer practice of exercises (> 6 months) were also associated with education and income (p < 0.05); among the groups with exercise practice whether greater than or equal to six months, that supervised showed better results in the GFFI (p < 0.05). Conclusion:: The association between variables strengthens the hypothesis that adherence and maintenance of physical exercise might not be only dependent of individual's choice, but also the socioeconomic factors, which can influence the choice for any active lifestyle. PMID- 28832859 TI - Pregnancy and the Surgeon-Too Many Opinions, Too Little Evidence. PMID- 28832860 TI - Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy-Breakthrough in Low-Density Lipoprotein Cholesterol Lowering, Breakdown in Value. PMID- 28832861 TI - Pharmacists as Integral Members of the Cardiovascular Team. PMID- 28832862 TI - Paraesophageal Hernia Repair Outcomes Using Minimally Invasive Approaches. PMID- 28832863 TI - An Elderly Man With a Pacemaker and a Recent Fall. PMID- 28832864 TI - Questions and Answers. PMID- 28832865 TI - Drivers of Payment Variation in 90-Day Coronary Artery Bypass Grafting Episodes. AB - Importance: Coronary artery bypass grafting (CABG) is scheduled to become a mandatory Medicare bundled payment program in January 2018. A contemporary understanding of 90-day CABG episode payments and their drivers is necessary to inform health policy, hospital strategy, and clinical quality improvement activities. Furthermore, insight into current CABG payments and their variation is important for understanding the potential effects of bundled payment models in cardiac care. Objective: To examine CABG payment variation and its drivers. Design, Setting, and Participants: This retrospective cohort study used Medicare and private payer claims to identify patients who underwent nonemergent CABG surgery from January 1, 2012, through October 31, 2015. Ninety-day price standardized, risk-adjusted, total episode payments were calculated for each patient, and hospitals were divided into quartiles based on the mean total episode payments of their patients. Payments were then subdivided into 4 components (index hospitalization, professional, postacute care, and readmission payments) and compared across hospital quartiles. Seventy-six hospitals in Michigan representing a diverse set of geographies and practice environments were included. Main Outcomes and Measures: Ninety-day CABG episode payments. Results: A total of 5910 patients undergoing nonemergent CABG surgery were identified at 33 of the 76 hospitals; of these, 4344 (73.5%) were men and mean (SD) age was 68.0 (9.3) years. At the patient level, risk-adjusted, 90-day total episode payments for CABG varied from $11 723 to $356 850. At the hospital level, the highest payment quartile of hospitals had a mean total episode payment of $54 399 compared with $45 487 for the lowest payment quartile (16.4% difference, P < .001). The highest payment quartile hospitals compared with the lowest payment quartile hospitals had 14.6% higher index hospitalization payments ($34 992 vs $30 531, P < .001), 33.9% higher professional payments ($8060 vs $6021, P < .001), 29.6% higher postacute care payments ($7663 vs $5912, P < .001), and 35.1% higher readmission payments ($3576 vs $2646, P = .06). The drivers of this variation are diagnosis related group distribution, increased inpatient evaluation and management services, higher utilization of inpatient rehabilitation, and patients with multiple readmissions. Conclusions and Relevance: Wide variation exists in 90-day CABG episode payments for Medicare and private payer patients in Michigan. Hospitals and clinicians entering bundled payment programs for CABG should work to understand local sources of variation, with a focus on patients with multiple readmissions, inpatient evaluation and management services, and postdischarge outpatient rehabilitation care. PMID- 28832866 TI - Association of Fluid Administration With Morbidity in Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy. AB - Importance: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal cancers can be associated with significant complications. Randomized trials have demonstrated increased morbidity with liberal fluid regimens in abdominal surgery. Objective: To investigate the association of intraoperative fluid administration and morbidity in patients undergoing CRS/HIPEC. Design, Setting, and Participants: A retrospective analysis of information from a prospectively collected institutional database was conducted at a National Cancer Institute-designated comprehensive cancer center. A total of 133 patients from April 15, 2009, to June 23, 2016, with primary or secondary peritoneal cancers were included. Exposures: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Main Outcomes and Measures: Morbidity associated with intraoperative fluid management calculated by the comprehensive complication index, which uses a formula combining all perioperative complications and their severities into a continuous variable from 0 to 100 in each patient. Results: Of the 133 patients identified, 38% and 37% had diagnoses of metastatic appendiceal and colorectal cancers, respectively. Mean age was 54 (interquartile range [IQR], 47-64) years, and mean peritoneal cancer index was 13 (IQR, 7-18). Mitomycin and platinum-based chemotherapeutic agents were used in 96 (72.2%) and 37 (27.8%) of the patients, respectively. Mean intraoperative fluid (IOF) rate was 15.7 (IQR, 11.3-18.7) mL/kg/h. Mean comprehensive complication index (CCI) was 26.0 (IQR, 8.7-36.2). On multivariate analysis, age (coefficient, 0.32; 95% CI, 0.01-0.64; P = .04), IOF rate (coefficient, 0.97; 95% CI, 0.19 1.75; P = .02), and estimated blood loss (coefficient, 0.02; 95% CI, 0.01-0.03; P = .002) were independent predictors of increased CCI. In particular, patients who received greater than the mean IOF rate experienced a 43% increase in the CCI compared with patients who received less than the mean IOF rate (31.5 vs 22.0; P = .02). Conclusions and Relevance: Intraoperative fluid administration is associated with a significant increase in perioperative morbidity in patients undergoing CRS/HIPEC. Fluid administration protocols that include standardized restrictive fluid rates can potentially help to mitigate morbidity in patients undergoing CRS/HIPEC. PMID- 28832868 TI - Error on X-axes in Figure 2. PMID- 28832869 TI - Episode Payment Model for Coronary Artery Bypass Grafting-Opportunities and Challenges. PMID- 28832867 TI - Cost-effectiveness of Evolocumab Therapy for Reducing Cardiovascular Events in Patients With Atherosclerotic Cardiovascular Disease. AB - Importance: The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab has been demonstrated to reduce the composite of myocardial infarction, stroke, or cardiovascular death in patients with established atherosclerotic cardiovascular disease. To our knowledge, long-term cost effectiveness of this therapy has not been evaluated using clinical trial efficacy data. Objective: To evaluate the cost-effectiveness of evolocumab in patients with atherosclerotic cardiovascular disease when added to standard background therapy. Design, Setting, and Participants: A Markov cohort state transition model was used, integrating US population-specific demographics, risk factors, background therapy, and event rates along with trial-based event risk reduction. Costs, including price of drug, utilities, and transitional probabilities, were included from published sources. Exposures: Addition of evolocumab to standard background therapy including statins. Main Outcomes and Measures: Cardiovascular events including myocardial infarction, ischemic stroke and cardiovascular death, quality-adjusted life-year (QALY), incremental cost effectiveness ratio (ICER), and net value-based price. Results: In the base case, using US clinical practice patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol levels of at least 70 mg/dL (to convert to millimoles per liter, multiply by 0.0259) and an annual events rate of 6.4 per 100 patient-years, evolocumab was associated with increased cost and improved QALY: incremental cost, $105 398; incremental QALY, 0.39, with an ICER of $268 637 per QALY gained ($165 689 with discounted price of $10 311 based on mean rebate of 29% for branded pharmaceuticals). Sensitivity and scenario analyses demonstrated ICERs ranging from $100 193 to $488 642 per QALY, with ICER of $413 579 per QALY for trial patient characteristics and event rate of 4.2 per 100 patient-years ($270 192 with discounted price of $10 311) and $483 800 if no cardiovascular mortality reduction emerges. Evolocumab treatment exceeded $150 000 per QALY in most scenarios but would meet this threshold at an annual net price of $9669 ($6780 for the trial participants) or with the discounted net price of $10 311 in patients with low-density lipoprotein cholesterol levels of at least 80 mg/dL. Conclusions and Relevance: At its current list price of $14 523, the addition of evolocumab to standard background therapy in patients with atherosclerotic cardiovascular disease exceeds generally accepted cost effectiveness thresholds. To achieve an ICER of $150 000 per QALY, the annual net price would need to be substantially lower ($9669 for US clinical practice and $6780 for trial participants), or a higher-risk population would need to be treated. PMID- 28832870 TI - New Hope for a Gonorrhea Vaccine. PMID- 28832871 TI - Reframing the Opioid Epidemic as a National Emergency. PMID- 28832872 TI - Noninvasive Testing for Nonalcoholic Steatohepatitis and Hepatic Fibrosis in Patients With Psoriasis Receiving Long-term Methotrexate Sodium Therapy. AB - Importance: The long-term implications of hepatotoxic effects in patients with psoriasis remains uncharacterized, and a method is needed for the noninvasive monitoring of the development and progression of hepatic fibrosis in patients with psoriasis receiving long-term methotrexate therapy. Objective: To evaluate if NASH FibroSure, a noninvasive test for nonalcoholic steatohepatitis (NASH) and hepatic fibrosis, can be used for patients with psoriasis to aid in determining eligibility for methotrexate sodium (MTX) therapy, monitor for the development of MTX-induced hepatotoxic effects, and monitor for worsening of hepatic fibrosis scores during MTX therapy. Design, Setting, and Participants: A retrospective descriptive analysis was conducted among a cohort of patients with psoriasis treated with MTX who underwent NASH FibroSure testing between January 1, 2007, and December 31, 2013, at a dermatology referral center at a single institution. Data analysis was performed from January 1 to December 31, 2014. Main Outcomes and Measures: NASH FibroSure risk scores suggesting the development and progression of hepatic fibrosis in patients with psoriasis receiving long-term MTX therapy. Results: Included in the institutional experience portion of the study were 129 patients with psoriasis undergoing treatment with MTX, while 107 patients (57 women and 50 men; mean [SD] age, 83.3 [13.5] years) underwent NASH FibroSure testing during MTX therapy and were eligible for correlation analysis. Of the 129 patients with psoriasis undergoing treatment with MTX, 69 (53.5%) underwent NASH FibroSure testing prior to starting MTX; 19 of those patients (27.5%) had elevated fibrosis scores, and 54 (78.3%) had elevated steatosis scores. Among the 107 patients who underwent NASH FibroSure testing during MTX therapy, the cumulative MTX dose corresponded to a statistically significant association of a higher NASH FibroSure hepatic fibrosis score in women (Spearman rho = 0.21; P = .02) but not in men (Spearman rho = 0.17; P = .11). All patients in the cohort except 1 were managed without a liver biopsy. Conclusions and Relevance: The patients with psoriasis in this study had a high prevalence of elevated hepatic steatosis scores. The NASH FibroSure test can be used to monitor changes in fibrosis score in patients with psoriasis receiving MTX. In a single institution cohort, these results suggest that NASH FibroSure may be used, especially among female patients, to help monitor for risk of worsening fibrosis during MTX therapy. PMID- 28832873 TI - Acute Neck Swelling and Chest Pain After Forceful Coughing. PMID- 28832874 TI - US Medical Licensing Examination Step 2 Clinical Knowledge Score in Dermatology Resident Selection. PMID- 28832875 TI - Could Lithium in Drinking Water Reduce the Incidence of Dementia? PMID- 28832876 TI - Addiction Potential of Cigarettes With Reduced Nicotine Content in Populations With Psychiatric Disorders and Other Vulnerabilities to Tobacco Addiction. AB - Importance: A national policy is under consideration to reduce the nicotine content of cigarettes to lower nicotine addiction potential in the United States. Objective: To examine how smokers with psychiatric disorders and other vulnerabilities to tobacco addiction respond to cigarettes with reduced nicotine content. Design, Setting, and Participants: A multisite, double-blind, within participant assessment of acute response to research cigarettes with nicotine content ranging from levels below a hypothesized addiction threshold to those representative of commercial cigarettes (0.4, 2.3, 5.2, and 15.8 mg/g of tobacco) at 3 academic sites included 169 daily smokers from the following 3 vulnerable populations: individuals with affective disorders (n = 56) or opioid dependence (n = 60) and socioeconomically disadvantaged women (n = 53). Data were collected from March 23, 2015, through April 25, 2016. Interventions: After a brief smoking abstinence, participants were exposed to the cigarettes with varying nicotine doses across fourteen 2- to 4-hour outpatient sessions. Main Outcomes and Measures: Addiction potential of the cigarettes was assessed using concurrent choice testing, the Cigarette Purchase Task (CPT), and validated measures of subjective effects, such as the Minnesota Nicotine Withdrawal Scale. Results: Among the 169 daily smokers included in the analysis (120 women [71.0%] and 49 men [29.0%]; mean [SD] age, 35.6 [11.4] years), reducing the nicotine content of cigarettes decreased the relative reinforcing effects of smoking in all 3 populations. Across populations, the 0.4-mg/g dose was chosen significantly less than the 15.8-mg/g dose in concurrent choice testing (mean [SEM] 30% [0.04%] vs 70% [0.04%]; Cohen d = 0.40; P < .001) and generated lower demand in the CPT (alpha = .027 [95% CI, 0.023-0.031] vs alpha = .019 [95% CI, 0.016-0.022]; Cohen d = 1.17; P < .001). Preference for higher over lower nicotine content cigarettes could be reversed by increasing the response cost necessary to obtain the higher dose (mean [SEM], 61% [0.02%] vs 39% [0.02%]; Cohen d = 0.40; P < .001). All doses reduced Minnesota Nicotine Withdrawal Scale total scores (range of mean decreases, 0.10-0.50; Cohen d range, 0.21-1.05; P < .001 for all), although duration of withdrawal symptoms was greater at higher doses (eta2 = 0.008; dose by-time interaction, P = .002). Conclusions and Relevance: Reducing the nicotine content of cigarettes may decrease their addiction potential in populations that are highly vulnerable to tobacco addiction. Smokers with psychiatric conditions and socioeconomic disadvantage are more addicted and less likely to quit and experience greater adverse health impacts. Policies to reduce these disparities are needed; reducing the nicotine content in cigarettes should be a policy focus. PMID- 28832879 TI - Progressive Annular Plaques in a Toddler. PMID- 28832880 TI - Association of Vitamin D Receptor Polymorphisms With the Risk of Nonmelanoma Skin Cancer in Adults. AB - Importance: Protective effects of UV-B radiation against nonmelanoma skin cancer (NMSC) are exerted via signaling mechanisms involving the vitamin D receptor (VDR). Recent studies have examined single-nucleotide polymorphisms (SNPs) in the VDR, resulting in contradictory findings as to whether these polymorphisms increase a person's risk for NMSC. Objective: To examine whether the polymorphisms in the VDR gene are associated with the development of NMSC and the demographic characteristics of the participants. Design, Setting, and Participants: This case-control study recruited 100 individuals who received a diagnosis of and were being treated for basal cell carcinoma or squamous cell carcinoma (cases) and 100 individuals who were receiving treatment of a condition other than skin cancer (controls) at the dermatology clinics at the Kirklin Clinic of the University of Alabama at Birmingham Hospital between January 1, 2012, and December 31, 2014. All participants completed a questionnaire that solicited information on skin, hair, and eye color; skin cancer family history; and sun exposure history, such as tanning ability and number of severe sunburns experienced throughout life. Blood samples for DNA genotyping were collected from all participants. Main Outcomes and Measures: Polymorphisms in the VDR gene (ApaI, BsmI, and TaqI) were assessed to determine the association of polymorphisms with NMSC development and demographic characteristics. chi2 Analysis was used to determine whether genotype frequencies deviated significantly from Hardy-Weinberg equilibrium. Logistic regression was used to calculate odds ratios (ORs) and associated 95% CIs for the identification of factors associated with NMSC diagnosis. A model was created to predict NMSC diagnoses using known risk factors and, potentially, VDR SNPs. Results: A total of 97 cases and 100 controls were included. Of the 97 cases, 68 (70%) were men and 29 (30%) were women, with a mean (SD) age of 70 (11) years. Of the 100 controls, 46 (46%) were men and 54 (54%) were women, with a mean (SD) age of 63 (9) years. All participants self-identified as non-Hispanic white. A model including age, sex, and skin color was created to most effectively predict the incidence of skin cancer. Risk factors that significantly increased the odds of an NMSC diagnosis were light skin color (OR, 5.79 [95% CI, 2.79-11.99]), greater number of severe sunburns (OR, 2.59 [95% CI, 1.31-5.10]), light eye color (OR, 2.47 [95% CI, 1.30-4.67]), and less of an ability to tan (OR, 2.35 [95% CI, 1.23 4.48]). The risk factors of family history of NMSC (OR, 1.66 [95% CI, 0.90-3.07]) and light hair color (OR, 1.17 [95% CI, 0.51-2.71]) did not reach statistical significance. Participants with the BsmI SNP were twice as likely to develop NMSC than participants with no mutation (OR, 2.04 [95% CI, 1.02-4.08]; P = .045). Conclusions and Relevance: The results of this study are especially useful in the early treatment and prevention of NMSC with chemopreventive agents (for those with the BsmI SNP). A screening for the BsmI SNP may emphasize the importance of sun protection and facilitate skin cancer prevention and, therefore, decrease the skin cancer burden. PMID- 28832881 TI - Influence of Linguistic and Nonlinguistic Variables on Generalization and Maintenance Following Phonomotor Treatment for Aphasia. AB - Purpose: Although phonomotor treatment shows promise as an effective intervention for anomia in people with aphasia, responses to this treatment are not consistent across individuals. To better understand this variability, we examined the influence of 5 participant characteristics-age, time postonset, aphasia severity, naming impairment, and error profile-on generalization and maintenance of confrontation naming and discourse abilities following phonomotor treatment. Method: Using retrospective data from 26 participants with aphasia who completed a 6-week phonomotor treatment program, we examined the relationships between participant characteristics of interest and change scores on confrontation naming and discourse tasks, measured pretreatment, immediately following treatment, and 3 months following treatment. Results: Although the participant characteristics of aphasia severity and error profile appeared to predict generalization to improved confrontation naming of untrained items and discourse performance, a post hoc analysis revealed that no one characteristic predicted generalization across participants at 3 months posttreatment. Conclusions: Response to phonomotor treatment does not appear to be influenced by aphasia and anomia severity level, error profile, participant age, or time postonset. Other factors, however, may influence response to intensive aphasia treatment and are worthy of continued exploration. PMID- 28832882 TI - Cutaneous Pseudolymphoma Arising as Wolf's Post-Herpetic Isotopic Response. PMID- 28832878 TI - Development of Phase Locking and Frequency Representation in the Infant Frequency Following Response. AB - Purpose: This study investigates the development of phase locking and frequency representation in infants using the frequency-following response to consonant vowel syllables. Method: The frequency-following response was recorded in 56 infants and 15 young adults to 2 speech syllables (/ba/ and /ga/), which were presented in randomized order to the right ear. Signal-to-noise ratio and Fsp analyses were used to verify that individual responses were present above the noise floor. Thirty-six and 39 infants met these criteria for the /ba/ or /ga/ syllables, respectively, and 31 infants met the criteria for both syllables. Data were analyzed to obtain measures of phase-locking strength and spectral magnitudes. Results: Phase-locking strength to the fine structure in the consonant-vowel transition was higher in young adults than in infants, but phase locking was equivalent at the fundamental frequency between infants and adults. However, frequency representation of the fundamental frequency was higher in older infants than in either the younger infants or adults. Conclusion: Although spectral amplitudes changed during the first year of life, no changes were found with respect to phase locking to the stimulus envelope. These findings demonstrate the feasibility of obtaining these measures of phase locking and fundamental pitch strength in infants as young as 2 months of age. PMID- 28832877 TI - Association of Lithium in Drinking Water With the Incidence of Dementia. AB - Importance: Results from animal and human studies suggest that lithium in therapeutic doses may improve learning and memory and modify the risk of developing dementia. Additional preliminary studies suggest that subtherapeutic levels, including microlevels of lithium, may influence human cognition. Objective: To investigate whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water. Design, Setting, and Participants: This Danish nationwide, population based, nested case-control study examined longitudinal, individual geographic data on municipality of residence and data from drinking water measurements combined with time-specific data from all patients aged 50 to 90 years with a hospital contact with a diagnosis of dementia from January 1, 1970, through December 31, 2013, and 10 age- and sex-matched control individuals from the Danish population. The mean lithium exposure in drinking water since 1986 was estimated for all study individuals. Data analysis was performed from January 1, 1995, through December 31, 2013. Main Outcomes and Measures: A diagnosis of dementia in a hospital inpatient or outpatient contact. Diagnoses of Alzheimer disease and vascular dementia were secondary outcome measures. In primary analyses, distribution of lithium exposure was compared between patients with dementia and controls. Results: A total of 73 731 patients with dementia and 733 653 controls (median age, 80.3 years; interquartile range, 74.9-84.6 years; 44 760 female [60.7%] and 28 971 male [39.3%]) were included in the study. Lithium exposure was statistically significantly different between patients with a diagnosis of dementia (median, 11.5 ug/L; interquartile range, 6.5-14.9 ug/L) and controls (median, 12.2 ug/L; interquartile range, 7.3-16.0 ug/L; P < .001). A nonlinear association was observed. Compared with individuals exposed to 2.0 to 5.0 ug/L, the incidence rate ratio (IRR) of dementia was decreased in those exposed to more than 15.0 ug/L (IRR, 0.83; 95% CI, 0.81-0.85; P < .001) and 10.1 to 15.0 ug/L (IRR, 0.98; 95% CI, 0.96-1.01; P = .17) and increased with 5.1 to 10.0 ug/L (IRR, 1.22; 95% CI, 1.19-1.25; P < .001). Similar patterns were found with Alzheimer disease and vascular dementia as outcomes. Conclusions and Relevance: Long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia in a nonlinear way; however, confounding from other factors associated with municipality of residence cannot be excluded. PMID- 28832883 TI - Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders. AB - Importance: Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored. Objective: To assess what impact mitochondrial lineages encompassing ancient mtDNA functional polymorphisms, termed haplogroups, have on ASD risk. Design, Setting, and Participants: In this cohort study, individuals with autism and their families were studied using the Autism Genetic Resource Exchange cohort genome-wide association studies data previously generated at the Children's Hospital of Philadelphia. From October 2010 to January 2017, we analyzed the data and used the mtDNA single-nucleotide polymorphisms interrogated by the Illumina HumanHap 550 chip to determine the mtDNA haplogroups of the individuals. Taking into account the familial structure of the Autism Genetic Resource Exchange data, we then determined whether the mtDNA haplogroups correlate with ASD risk. Main Outcomes and Measures: Odds ratios of mitochondrial haplogroup as predictors of ASD risk. Results: Of 1624 patients with autism included in this study, 1299 were boys (80%) and 325 were girls (20%). Families in the Autism Genetic Resource Exchange collection (933 families, encompassing 4041 individuals: 1624 patients with ASD and 2417 healthy parents and siblings) had been previously recruited in the United States with no restrictions on age, sex, race/ethnicity, or socioeconomic status. Relative to the most common European haplogroup HHV, European haplogroups I, J, K, O-X, T, and U were associated with increased risk of ASD, as were Asian and Native American haplogroups A and M, with odds ratios ranging from 1.55 (95% CI, 1.16-2.06) to 2.18 (95% CI, 1.59-3) (adjusted P < .04). Hence, mtDNA haplogroup variation is an important risk factor for ASD. Conclusions and Relevance: Because haplogroups I, J, K, O-X, T, and U encompass 55% of the European population, mtDNA lineages must make a significant contribution to overall ASD risk. PMID- 28832884 TI - "Whatdunit?" Sentence Comprehension Abilities of Children With SLI: Sensitivity to Word Order in Canonical and Noncanonical Structures. AB - Purpose: With Aim 1, we compared the comprehension of and sensitivity to canonical and noncanonical word order structures in school-age children with specific language impairment (SLI) and same-age typically developing (TD) children. Aim 2 centered on the developmental improvement of sentence comprehension in the groups. With Aim 3, we compared the comprehension error patterns of the groups. Method: Using a "Whatdunit" agent selection task, 117 children with SLI and 117 TD children (ages 7:0-11:11, years:months) propensity matched on age, gender, mother's education, and family income pointed to the picture that best represented the agent in semantically implausible canonical structures (subject-verb-object, subject relative) and noncanonical structures (passive, object relative). Results: The SLI group performed worse than the TD group across sentence types. TD children demonstrated developmental improvement across each sentence type, but children with SLI showed improvement only for canonical sentences. Both groups chose the object noun as agent significantly more often than the noun appearing in a prepositional phrase. Conclusions: In the absence of semantic-pragmatic cues, comprehension of canonical and noncanonical sentences by children with SLI is limited, with noncanonical sentence comprehension being disproportionately limited. The children's ability to make proper semantic role assignments to the noun arguments in sentences, especially noncanonical, is significantly hindered. PMID- 28832885 TI - A Comparison of Early Adolescent Behavioral Health Risks Among Urban American Indians/Alaska Natives and their Peers. AB - We sought to examine behavioral health indicators for an early adolescent population of American Indians/Alaska Natives (AI/AN) within an urban setting in Washington State. We conducted secondary data analyses from a randomized clinical trial implemented in local middle schools that compared AI/ANs (n = 43), non Hispanic Whites (n = 620), and other racial/ethnic minority youth (n = 527) across a variety of behavioral health risks. AI/AN youth reported significantly more depressive symptoms than other racial/ethnic minorities as well as non Hispanic Whites. They also reported more discrimination, more generalized anxiety, and were more likely to have initiated substance use, in comparison to non-Hispanic Whites. Psychosocial screening and early intervention are critically needed for AI/AN youth. PMID- 28832886 TI - Obesogenic Behaviors, Self-Efficacy, and Depressive Symptoms in American Indian Children. AB - BACKGROUND: American Indian (AI) children suffer from high rates of obesity, obesity-related disease, obesogenic behaviors, and depressive symptoms. OBJECTIVE: Study was designed to determine the associations between depressive symptoms and obesogenic behaviors in school-aged AI children in Oklahoma. METHODS: Study design was cross-sectional. Depressive symptoms, beverage intake, fruit and vegetable intake, meal frequency, physical activity, and screen time were self-reported. RESULTS: Mean participant age was 10.5 +/- 1.6 years (n = 121); 64% were overweight/obese. Depressive symptoms were associated with dieting and screen time. CONCLUSION: AI chronic disease prevention efforts will benefit by including measures for depression and associations of obesogenic behaviors and depressive symptoms in treatment planning. PMID- 28832887 TI - The Association Between Positive Relationships with Adults and Suicide-Attempt Resilience in American Indian Youth in New Mexico. AB - This study examined the 2013 New Mexico Youth Risk and Resiliency Survey (NM YRRS) to determine whether cultural connectedness and positive relationships with adults protected against suicide attempts among American Indian and Alaska Native (AI/AN) youth and whether these relationships differed by gender. The sample included 2,794 AI/AN students in grades 9 to 12 who answered the question about past-year suicide attempts. Protective factor variables tested included relationships with adults at home, school, and the community. The language spoken at home was used as a proxy measure for cultural connectedness. Positive relationships with adults were negatively associated with the prevalence of past year suicide attempts in bivariate analysis. However, language spoken at home was not associated with the prevalence of suicide attempts. Multivariate analysis showed that among girls, relationships with adults at home, at school, and in the community were independently associated with lower suicide-attempt prevalence. Among boys, only relationships with adults at home showed such an association. These results have important implications for the direction of future research about protective factors associated with AI/AN youth suicide risk as well as in the design of suicide intervention and prevention programs. PMID- 28832888 TI - American Indian and White Adoptees: Are There Mental Health Differences? AB - Adult adoptees are at increased risk for mental health problems compared to nonadoptees. However, little is known about subsets of adoptees that may be more or less vulnerable to mental health problems. The purpose of this study was to explore the presence of mental health problems of American Indian (AI) persons compared to White persons who were separated from their birth families during childhood by foster care and/or adoption. Family systems theory guided the study. AI adoptees reported higher percentages of problems than White adoptees on all mental health problems measures (e.g., substance abuse, mental health, self injury, and suicide). Data analysis included a series of chi-square statistics and logistic regression models. AI adoptees were more likely to report mental health problems, including alcohol addiction, alcohol recovery, drug recovery, self-assessed eating disorder, eating disorder diagnosis, self-harm, and suicidal ideation than were whites. PMID- 28832889 TI - Stressful Life Events and Self-Reported Postpartum Depressive Symptoms 13-24 Months After Live Birth Among Non-Hispanic American Indian/Alaska Native Mothers in Oregon: Results from a Population-Based Survey. AB - OBJECTIVES: We explored the association between stressful life events and postpartum depressive symptoms among non-Hispanic American Indian and Alaska Native (AI/AN) mothers. METHODS: We analyzed self-reports of stressful life events and depressive symptoms from 298 AI/AN respondents and conducted logistic regression to examine their association. RESULTS: Of the AI/AN mothers who responded, 29.7% reported depressive symptoms during their second postpartum year. Partner-related and traumatic stressful life events were significantly associated with increased risk of postpartum depressive symptoms. CONCLUSIONS: AI/AN women should receive intensive screening for depression through the second postpartum year. Programs that address stressful life events may be part of a plan to decrease postpartum depression. PMID- 28832890 TI - The Gulf War era multiple sclerosis cohort: 3. Early clinical features. AB - OBJECTIVES: To present clinical features at diagnosis for a large nationwide incident cohort of multiple sclerosis (MS) among those serving in the US military during the Gulf War era (GWE). MATERIALS & METHODS: Medical records and databases from the Department of Veterans Affairs (VA) for cases of MS with onset in or after 1990, active duty between 1990 and 2007 and service connection by the VA, were reviewed for diagnosis and demographic variables. Neurological involvement was summarized by the Kurtzke Disability Status Scale (DSS) and the Multiple Sclerosis Severity Score (MSSS). RESULTS: Among 1919 cases of clinically definite MS, 94% had a relapsing-remitting course and 6% were primary progressive at diagnosis. More males of all races and blacks of both sexes were progressive. At diagnosis, functional system involvement was pyramidal 69%, cerebellar 58%, sensory 55%, brainstem 45%, bowel/bladder 23%, cerebral 23%, visual 18%, and other 5%. Mean DSS scores were: white males, females 2.9, 2.7; black males, females 3.3, 2.8; and other-race males, females 3.2, 2.6. Mean and median MSSS were marginally greater in black males and other males compared to the other sex race groups. CONCLUSIONS: In this incident cohort, males and blacks had significantly higher proportions of primary progressive MS. DSS at diagnosis was significantly more severe in blacks and significantly less so in whites and in women vs men, but MSSS was only marginally greater in black males and other-race males. This morbidity assessment early in the course of MS provides population based data for diagnosis, management, and prognosis. PMID- 28832891 TI - Outcome of cancer-related seizures in patients treated with lacosamide. AB - OBJECTIVES: Lacosamide is an antiepileptic drug (AED), which has proven to be effective to control seizures, including acute conditions such as status epilepticus. The aim of this study is to describe the clinical experience with lacosamide in neuro-oncological patients. MATERIALS AND METHODS: Multicenter retrospective study in patients with cancer-related seizures, who received lacosamide as an add-on therapy. RESULTS: Forty-eight patients with benign and malignant tumors, including primary brain tumors, lymphomas, systemic cancer with central nervous system involvement, or paraneoplastic encephalitis, were included. Lacosamide was effective in the control of chronic seizures in patients with either benign or malignant tumors. The success rate was greater in malignant tumors, and drug-resistant epilepsies were more likely associated with benign tumors. Adverse events occurred in nearly 70% of patients, particularly in acute conditions and associated with the concomitant use of radio-/chemotherapy. Lacosamide-related adverse events were more likely somnolence and dizziness, which usually resolved after dose adjustment. After starting lacosamide, nearly half of the patients discontinued one of the baseline AEDs and decreased or discontinued dexamethasone. Fifteen patients with status epilepticus were treated with intravenous lacosamide, and 73% of them had their condition resolved without serious drug-related adverse events. CONCLUSION: Lacosamide is an AED to consider in cases of cancer-related seizures. Lacosamide pharmacodynamics and pharmacokinetics allow the achievement of responder rates over 50% with no serious adverse effects, amelioration of side effects from other AEDs or radio /chemotherapy, and no significant drug interactions. Furthermore, the intravenous formulation shows clear benefits in acute conditions such as status epilepticus. PMID- 28832892 TI - Bronchial wheezing predicts inflammation and respiratory failure in fire smoke victims. AB - BACKGROUND: Acute fire smoke inhalation injury involves inflammatory mediators whose roles are poorly understood. We carried out a prospective observational study of fire smoke victims to identify clinical and biochemical markers that may predict pulmonary dysfunction and investigated possible correlations between dysfunction and cytokines in bronchoalveolar lavage (BAL) fluid and blood. METHODS: Forty patients with respiratory and/or neurological symptoms following acute fire smoke inhalation had pulmonary function tests and blood gas analyses performed on admission, at discharge, and after 3 months. Cytokines were measured using BioPlex/XMap technology. RESULTS: On admission, 30 (75%) patients had dyspnea. Patients presenting with bronchial wheezing (n = 14) had significantly lower PEF (201 l/min, 82-360) than non-wheezing patients (406 l/min, 100-683) (n = 16, P = 0.03). Bronchial wheezing predicted need for ICU treatment with OR = 93.3 at 95% CI (P < 0.001) and was associated with gas exchange impairment, with mean pa O2 /FiO2 ratio 34.4 (11.8-49.8) kPa on admission and 21.3 (8.3-44.5) kPa 48 h later. Blood HbCO also predicted ICU treatment, with OR = 1.58 at 95% CI (P < 0.001). Serum CRP, IL-6, IL-8, and MCP-1 were significantly higher in wheezing patients after 12-24 h compared with non-wheezing patients and study controls. Cytokine levels were still elevated after 3 months. BAL fluid had significantly higher levels of IL-8, MCP-1, IL-1beta, and G-CSF compared with healthy controls. CONCLUSION: In victims of fire smoke inhalation, pulmonary wheezing predicts inflammation, pulmonary dysfunction, respiratory failure, and need for intensive care. PMID- 28832893 TI - Cognitive complaint in early Parkinson's disease: A pilot study. AB - BACKGROUND: Subjective cognitive complaint (SCC) is a criterion recommended by the Movement Disorder Society (MDS) task force for the diagnosis of mild cognitive impairment (MCI). Until now there were few specific tools for detecting SCC in PD. We sought to develop a new tool to assess SCC specifically dedicated for PD. MATERIALS AND METHODS: We set a group of experts in movements disorders and neurocognition to develop an easy-to-use tool based on a visual analogue scale (VAS) for five cognitive domains: memory, executive functions, spatial orientation, attention, and language. We use it to assess SCC twice (at a one month interval) in PD patients with disease duration of less than 5 years. Comprehensibility of the VAS was assessed. Controls were assessed with the same VAS. Patients with PD also underwent neuropsychological testing. RESULTS: VAS was easily understandable by the 70 patients with PD. We found significant SCC for the patients with PD vs controls in three cognitive domains: executive functions (1.7 +/- 1.9 vs 0.8 +/- 1.1; P < .001), language (2.3 +/- 2.5 vs 1.0 +/- 1.3, P < .001), and attention (2.1 +/- 2.2 vs 1.2 +/- 1.2; P < .01). Reproducibility between the two evaluations of patients with PD was good. There was no relationship between SCC and the results of neuropsychological testing. CONCLUSIONS: SCC seems to appear early in PD, in three cognitive domains (executive functions, language, and attention), and VAS might be a good way to detect SCC in PD, but need to be validated. PMID- 28832894 TI - Ultrasound-guided regional blockade for lipoma excision: a new approach to an old technique. AB - BACKGROUND: Local anesthesia for lipoma excision can be feasible with anesthetic injection in the fascial plane between the lipoma and the surrounding soft tissues under real-time ultrasonography [ultrasound- guided lipoma plane (ULP) block]. The advantage of targeting a single anesthetic injection plane under ultrasound guidance may allow for technically easier block placement and long term analgesic effects. METHODS: Forty-eight patients were randomly assigned to receive ULP block, group A (n = 24) or traditional block, group B (n = 24). Primary outcome measure was the number of needle passes required to perform the blockade. The level of procedure pain and the time to first request of analgesia were assessed. RESULTS: Median (interquartile range) needle passes required to complete the blockade was significantly less in the group A 1(1, 1) in comparison with the group B 3 (2.5, 3); P = 0.0001. Group A required fewer needle redirections 1.5 (1, 2) than group B 2 (2, 2.5); P = 0.001. Group A showed significantly less procedure-related pain 2 (2, 3) when compared with group B 4 (3, 4); P = 0.0001. The time to first rescue analgesic was significantly longer in group A (21.3 +/- 4.7 h) in comparison with group B (4.4 +/- 1.2 h); P = 0.001. CONCLUSION: Ultrasound-guided lipoma plane blockade reduces the number of needle passes required to complete the block and provides less procedure pain and longer pain relief compared with the traditional block in patients undergoing lipoma excision. PMID- 28832895 TI - Is the incidence of recurrent pregnancy loss increasing? A retrospective register based study in Sweden. AB - INTRODUCTION: The aim of this study was to estimate the incidence of recurrent pregnancy loss (RPL). The prevalence of RPL defined as three or more consecutive miscarriages before gestation week 22, is often stated to be 1%. To our knowledge no study has estimated the incidence of RPL, which might be more informative and clinically relevant than the prevalence. MATERIAL AND METHODS: This retrospective register-based study was conducted from 2003 until 2012 in Sweden with data provided by the Swedish National Board of Health and Welfare. In all, 6852 women were registered with the diagnoses of RPL in the National Patient Register. The incidence of RPL is the number of new women receiving the RPL diagnosis per year in the numerator and population at risk in the denominator. RESULTS: For each year, from 2003 to 2012, the incidence was calculated in two different risk populations: [1] all women aged 18-42 years, and [2] all women registered as being pregnant (deliveries or miscarriages). The average incidence in the study period was 53 per 100 000 (0.05%) in women aged 18-42 years and 650 per 100 000 (0.65%) in women who had achieved pregnancy in the period. The incidence of RPL in the two risk populations increased by 74 and 58%, respectively, during the study period. CONCLUSION: This study suggests that the incidence of RPL increased during the 10-year period studied. Causes can only be speculated upon in this study design, but might be associated with environmental changes, as the increase was fairly rapid. PMID- 28832896 TI - End-tidal control vs. manually controlled minimal-flow anesthesia: a prospective comparative trial. AB - BACKGROUND: To ensure safe general anesthesia, manually controlled anesthesia requires constant monitoring and numerous manual adjustments of the gas dosage, especially for low- and minimal-flow anesthesia. Oxygen flow-rate and administration of volatile anesthetics can also be controlled automatically by anesthesia machines using the end-tidal control technique, which ensures constant end-tidal concentrations of oxygen and anesthetic gas via feedback and continuous adjustment mechanisms. We investigated the hypothesis that end-tidal control is superior to manually controlled minimal-flow anesthesia (0.5 l/min). METHODS: In this prospective trial, we included 64 patients undergoing elective surgery under general anesthesia. We analyzed the precision of maintenance of the sevoflurane concentration (1.2-1.4%) and expiratory oxygen (35-40%) and the number of necessary adjustments. RESULTS: Target-concentrations of sevoflurane and oxygen were maintained at more stable levels with the use of end-tidal control (during the first 15 min 28% vs. 51% and from 15 to 60 min 1% vs. 19% deviation from sevoflurane target, P < 0.0001; 45% vs. 86% and 5% vs. 15% deviation from O2 target, P < 0.01, respectively), while manual controlled minimal-flow anesthesia required more interventions to maintain the defined target ranges of sevoflurane (8, IQR 6-12) and end-tidal oxygen (5, IQR 3-6). The target-concentrations were reached earlier with the use of end-tidal compared with manual controlled minimal flow anesthesia but required slightly greater use of anesthetic agents (6.9 vs. 6.0 ml/h). CONCLUSIONS: End-tidal control is a superior technique for setting and maintaining oxygen and anesthetic gas concentrations in a stable and rapid manner compared with manual control. Consequently, end-tidal control can effectively support the anesthetist. PMID- 28832897 TI - Reliability of an Online Geriatric Assessment Procedure Using the interRAI Acute Care Assessment System. AB - OBJECTIVES: To determine whether geriatric triage decisions made using a comprehensive geriatric assessment (CGA) performed online are less reliable than face-to-face (FTF) decisions. DESIGN: Multisite noninferiority prospective cohort study. Two specialist geriatricians assessed individuals sequentially referred for an acute care geriatric consultation. Participants were allocated to one FTF assessment and an additional assessment (FTF or online (OL)), creating two groups two FTF (FTF-FTF, n = 81) or online and FTF (OL-FTF, n = 85). SETTING: Three acute care public hospitals in two Australian states. PARTICIPANTS: Admitted individuals referred for CGA. INTERVENTION: Nurse-administered CGA, based on the interRAI Acute Care assessment system accessed online and other online clinical data such as pathology results and imaging enabling geriatricians to review participants' information and provide input into their care from a distance. MEASUREMENTS: The primary decision subjected to this analysis was referral for permanent residential care. Geriatricians also recorded recommendations for referrals and variations for medication management and judgment regarding prognosis at discharge and after 3 months. RESULTS: Overall percentage agreement was 88% (n = 71) for the FTF-FTF group and 91% (n = 77) for the OL-FTF group. The difference in agreement between the FTF-FTF and OL-FTF groups was -3%, indicating that there was no difference between the methods of assessment. Judgements made regarding diagnoses of geriatric syndromes, medication management, and prognosis (with regard to hospital outcome and location at 3 months) were found to be equally reliable in each mode of consultation. CONCLUSION: Geriatric assessment performed online using a nurse-administered structured CGA system was no less reliable than conventional assessment in making clinical triage decisions. PMID- 28832898 TI - Spontaneous breathing trials after prolonged mechanical ventilation monitored by electrical impedance tomography: an observational study. AB - BACKGROUND: The study objective was to examine the correlation between regional ventilation distribution measured with electrical impedance tomography (EIT) and weaning outcomes during spontaneous breathing trial (SBT). METHODS: Fifteen patients received 100% automatic tube compensation (ATC) during the first and 70% during the second hour. Another 15 patients received external continuous positive airway pressure (CPAP) of 5 and 7.5 cmH2 O during the first and second hours, respectively. Regional ventilation distributions were monitored with EIT. RESULTS: Tidal volume and tidal variation of impedance correlated significantly during assist-control ventilation and ATC in all patients (r2 = 0.80 +/- 0.18, P < 0.001). Higher support levels resulted in similar ventilation distribution and tidal volume, but higher end-expiratory lung impedance (EELI) (P < 0.05). Analysis of regional intratidal gas distribution revealed a redistribution of ventilation towards dorsal regions with lower support level in 13 of 30 patients. These patients had a higher weaning success rate (only 1 of 13 patients failed). Eight of 17 other patient failed (P < 0.05). The number of SBT days needed for weaning was significantly lower in the former group of 13 patients (13.1 +/- 4.0 vs. 20.9 +/- 11.2 days, P < 0.05). CONCLUSIONS: Regional ventilation distribution patterns during inspiration were associated with weaning outcomes, and they may be used to predict the success of extubation. PMID- 28832899 TI - Declining prevalence of cytological squamous intraepithelial lesions of the cervix among women living with well-controlled HIV - Most women living with HIV do not need annual PAP smear screening. AB - INTRODUCTION: Cervical screening by means of annual Papanicolaou (PAP) smears has been recommended for all women living with HIV. We analysed the results of our annual PAP smear screening program to identify low-risk subgroups for less rigorous screening. MATERIAL AND METHODS: The study comprised 369 women followed at the Helsinki University Hospital 2002-2013, with a total of 2033 PAP smear results. We analyzed the temporal changes in PAP smear findings. Logistic regression analysis for binominal dependent variables was used for assessing risk factors for ever having cytological squamous intraepithelial lesions (hereafter referred as SIL) using generalized estimating equations taking into account multiple observations of each patient. RESULTS: Most women had well-controlled HIV, especially towards the end of the study. PAP smear results improved substantially. At the time of each individual's last PAP smear, 90.0% of the findings displayed normal results. Conversely, the rate of SIL decreased from 16.8% to 4.6% from 2002 to 2013. In multivariate analysis the risk of SIL was significantly lower in women with consecutive normal PAP smear findings during the first two years of follow up [odds ratio (OR) 0.21, 95% confidence interval (CI) 0.10-0.45, p < 0.001] and with CD4 counts >500 cells/MUL (OR 0.11, 95% CI 0.05-0.26, p < 0.001). CONCLUSIONS: Widespread use of combination antiretroviral therapy (cART) and systematic cervical screening has reduced the rate of abnormal PAP smears. It seems feasible to identify low-risk women by combining HIV-related information and PAP smear results. Screening low-risk women living with HIV at three-year intervals similar to HIV-negative women appears justified. PMID- 28832900 TI - Comment on: Quality of Life, Perceptions, and Health Satisfaction of Older Adults with End-Stage Renal Disease. PMID- 28832901 TI - Focused cardiac ultrasound is feasible in parturients; a prospective observational study. AB - BACKGROUND: In pregnancy, the major causes of morbidity and mortality include diseases that affect circulation profoundly and restoration of normal circulation is a key objective. Focused cardiac ultrasound provides information on the individual determinants of circulation and has a significant impact on patient management. This study aimed to determine the feasibility of focused cardiac ultrasound in term parturients. METHODS: Forty parturients underwent focused cardiac ultrasound. Parasternal long-axis, parasternal short-axis, 4-chamber and subcostal views were performed in the left-lateral position and the supine position by a novice operator. All images were graded on the following scale: 1 = no image; 2 = poor and insufficient image; 3 = sufficient image quality; 4 = good image quality; 5 = perfect image quality. A cut-off grade of three signified images sufficient for clinical decision-making. RESULTS: Images sufficient for clinical decision-making were obtained in all patients when including all imaging views. 37/40 (93 %) patients presented images of grade >= 4, whereas 10/40 (25%) patients had images of grade 5. Image grades were higher in the left lateral position (all P < 0.001). Parturients with a body mass index <= 30 kg/m2 did not present different image grades than parturients with a higher body mass index (P = 0.753). Subcostal views could not be obtained. CONCLUSION: Focused cardiac ultrasound is feasible in the obstetric population and images of sufficient quality for clinical decision-making were obtained in all parturients by an operator with limited experience. PMID- 28832902 TI - Development of an instrument for the evaluation of advanced life support performance. AB - BACKGROUND: Assessing advanced life support (ALS) competence requires validated instruments. Existing instruments include aspects of technical skills (TS), non technical skills (NTS) or both, but one instrument for detailed assessment that suits all resuscitation situations is lacking. This study aimed to develop an instrument for the evaluation of the overall ALS performance of the whole team. METHODS: This instrument development study had four phases. First, we reviewed literature and resuscitation guidelines to explore items to include in the instrument. Thereafter, we interviewed resuscitation team professionals (n = 66), using the critical incident technique, to determine possible additional aspects associated with the performance of ALS. Second, we developed an instrument based on the findings. Third, we used an expert panel (n = 20) to assess the validity of the developed instrument. Finally, we revised the instrument based on the experts' comments and tested it with six experts who evaluated 22 video recorded resuscitations. RESULTS: The final version of the developed instrument had 69 items divided into adherence to guidelines (28 items), clinical decision-making (5 items), workload management (12 items), team behaviour (8 items), information management (6 items), patient integrity and consideration of laymen (4 items) and work routines (6 items). The Cronbach's alpha values were good, and strong correlations between the overall performance and the instrument were observed. CONCLUSION: The instrument may be useful for detailed assessment of the team's overall performance, but the numerous items make the use demanding. The instrument is still under development, and more research is needed to determine its psychometric properties. PMID- 28832903 TI - Drug-eluting stents versus bare-metal stents for acute coronary syndrome. AB - BACKGROUND: Approximately 3.7 million people died from acute coronary syndrome worldwide in 2012. Acute coronary syndrome, also known as myocardial infarction or unstable angina pectoris, is caused by a sudden blockage of the blood supplied to the heart muscle. Percutaneous coronary intervention is often used for acute coronary syndrome, but previous systematic reviews on the effects of drug-eluting stents compared with bare-metal stents have shown conflicting results with regard to myocardial infarction; have not fully taken account of the risk of random and systematic errors; and have not included all relevant randomised clinical trials. OBJECTIVES: To assess the benefits and harms of drug-eluting stents versus bare metal stents in people with acute coronary syndrome. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, SCI-EXPANDED, and BIOSIS from their inception to January 2017. We also searched two clinical trials registers, the European Medicines Agency and the US Food and Drug Administration databases, and pharmaceutical company websites. In addition, we searched the reference lists of review articles and relevant trials. SELECTION CRITERIA: Randomised clinical trials assessing the effects of drug eluting stents versus bare-metal stents for acute coronary syndrome. We included trials irrespective of publication type, status, date, or language. DATA COLLECTION AND ANALYSIS: We followed our published protocol and the methodological recommendations of Cochrane. Two review authors independently extracted data. We assessed the risks of systematic error by bias domains. We conducted Trial Sequential Analyses to control the risks of random errors. Our primary outcomes were all-cause mortality, major cardiovascular events, serious adverse events, and quality of life. Our secondary outcomes were angina, cardiovascular mortality, and myocardial infarction. Our primary assessment time point was at maximum follow-up. We assessed the quality of the evidence by the GRADE approach. MAIN RESULTS: We included 25 trials randomising a total of 12,503 participants. All trials were at high risk of bias, and the quality of evidence according to GRADE was low to very low. We included 22 trials where the participants presented with ST-elevation myocardial infarction, 1 trial where participants presented with non-ST-elevation myocardial infarction, and 2 trials where participants presented with a mix of acute coronary syndromes.Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug eluting stents with bare-metal stents on the risk of all-cause mortality or major cardiovascular events. The absolute risk of death was 6.97% in the drug-eluting stents group compared with 7.74% in the bare-metal stents group based on the risk ratio (RR) of 0.90 (95% confidence interval (CI) 0.78 to 1.03, 11,250 participants, 21 trials/22 comparisons, low-quality evidence). The absolute risk of a major cardiovascular event was 6.36% in the drug-eluting stents group compared with 6.63% in the bare-metal stents group based on the RR of 0.96 (95% CI 0.83 to 1.11, 10,939 participants, 19 trials/20 comparisons, very low-quality evidence). The results of Trial Sequential Analysis showed that we did not have sufficient information to confirm or reject our anticipated risk ratio reduction of 10% on either all-cause mortality or major cardiovascular events at maximum follow-up.Meta-analyses at maximum follow-up showed evidence of a benefit when comparing drug-eluting stents with bare-metal stents on the risk of a serious adverse event. The absolute risk of a serious adverse event was 18.04% in the drug-eluting stents group compared with 23.01% in the bare-metal stents group based on the RR of 0.80 (95% CI 0.74 to 0.86, 11,724 participants, 22 trials/23 comparisons, low-quality evidence), and Trial Sequential Analysis confirmed this result. When assessing each specific type of adverse event included in the serious adverse event outcome separately, the majority of the events were target vessel revascularisation. When target vessel revascularisation was analysed separately, meta-analysis showed evidence of a benefit of drug-eluting stents, and Trial Sequential Analysis confirmed this result.Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug-eluting stents with bare-metal stents on the risk of cardiovascular mortality (RR 0.91, 95% CI 0.76 to 1.09, 9248 participants, 14 trials/15 comparisons, very low-quality evidence) or myocardial infarction (RR 0.98, 95% CI 0.82 to 1.18, 10,217 participants, 18 trials/19 comparisons, very low-quality evidence). The results of the Trial Sequential Analysis showed that we had insufficient information to confirm or reject our anticipated risk ratio reduction of 10% on cardiovascular mortality and myocardial infarction.No trials reported results on quality of life or angina. AUTHORS' CONCLUSIONS: The current evidence suggests that drug-eluting stents may lead to fewer serious adverse events compared with bare-metal stents without increasing the risk of all-cause mortality or major cardiovascular events. However, our Trial Sequential Analysis showed that there currently was not enough information to assess a risk ratio reduction of 10% for all-cause mortality, major cardiovascular events, cardiovascular mortality, or myocardial infarction, and there were no data on quality of life or angina. The evidence in this review was of low to very low quality, and the true result may depart substantially from the results presented in this review.More randomised clinical trials with low risk of bias and low risks of random errors are needed if the benefits and harms of drug-eluting stents for acute coronary syndrome are to be assessed properly. More data are needed on the outcomes all-cause mortality, major cardiovascular events, quality of life, and angina to reduce the risk of random error. PMID- 28832904 TI - Infectious and immunogenetic factors in bipolar disorder. AB - OBJECTIVE: Despite the evidence supporting the association between infection and bipolar disorder (BD), the genetic vulnerability that mediates its effects has yet to be clarified. A genetic origin for the immune imbalance observed in BD, possibly involved in the mechanisms of pathogen escape, has, however, been suggested in recent studies. METHOD: Here, we present a critical review based on a systematic literature search of articles published until December 2016 on the association between BD and infectious/immunogenetic factors. RESULTS: We provide evidence suggesting that infectious insults could act as triggers of maladaptive immune responses in BD and that immunogenetic vulnerability may amplify the effects of such environmental risk factors, increasing susceptibility to subsequent environmental encounters. Quality of evidence was generally impaired by scarce attempt of replication, small sample sizes and lack of high-quality environmental measures. CONCLUSION: Infection has emerged as a potential preventable cause of morbidity in BD, urging the need to better investigate components of the host-pathogen interaction in patients and at-risk subjects, and thus opening the way to novel therapeutic opportunities. PMID- 28832905 TI - Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE. AB - BACKGROUND: Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of people with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether people with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that people received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier, potentially curative stage could avoid the risk of cancer progression and thus lead to improvements in cancer-related mortality and morbidity. This is an update of a review first published in 2015. OBJECTIVES: To determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT of the lower limb or PE) is effective in reducing cancer and VTE-related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (16 February 2017). In addition, the CIS searched the Cochrane Register of Studies CENTRAL (2017, Issue 1). We searched trials registries (February 2017) and checked the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised trials in which people with an unprovoked VTE were allocated to receive specific tests for cancer or clinically indicated tests only were eligible for inclusion in this review. Primary outcomes included all cause mortality, cancer-related mortality and VTE-related mortality. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed quality and extracted data. We resolved any disagreements by discussion. MAIN RESULTS: Four studies with 1644 participants met the inclusion criteria (two studies in the original review and two in this update). Two studies assessed the effect of extensive tests versus tests at the physician's discretion) while the other two studies assessed the effect of standard testing plus positron emission tomography (PET)/computed tomography (CT) scanning versus standard testing alone. For extensive tests versus tests at the physician's discretion, the quality of the evidence was low due to risk of bias (early termination of the studies). When comparing standard testing plus PET/CT scanning versus standard testing alone, the quality of evidence was moderate due to a risk of detection bias. The quality of the evidence was downgraded further when detection bias was present in one study with a low number of events.When comparing extensive tests versus tests at the physician's discretion, pooled analysis on two studies showed that testing for cancer was consistent with either a benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.15 to 1.67; 396 participants; 2 studies; P = 0.26; low quality evidence). One study (201 participants) showed that, overall, malignancies were less advanced in extensively tested participants than in participants in the control group. In total, 9/13 participants diagnosed with cancer in the extensively tested group had a T1 or T2 stage malignancy compared to 2/10 participants diagnosed with cancer in the control group (OR 5.00, 95% CI 1.05 to 23.76; P = 0.04; low quality evidence). There was no clear difference in detection of advanced stages between extensive tests versus tests at the physician's discretion: one participant in the extensively tested group had stage T3 compared with four participants in the control group (OR 0.25, 95% CI 0.03 to 2.28; P = 0.22; low quality evidence). In addition, extensively tested participants were diagnosed earlier than control group (mean: 1 month with extensive tests versus 11.6 months with tests at physician's discretion to cancer diagnosis from the time of diagnosis of VTE). Extensive testing did not increase the frequency of an underlying cancer diagnosis (OR 1.32, 95% CI 0.59 to 2.93; 396 participants; 2 studies; P = 0.50; low quality evidence). Neither study measured all-cause mortality, VTE-related morbidity and mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life.When comparing standard testing plus PET/CT screening versus standard testing alone, standard testing plus PET/CT screening was consistent with either a benefit or no benefit on all cause mortality (OR 1.22, 95% CI 0.49 to 3.04; 1248 participants; 2 studies; P = 0.66; moderate quality evidence), cancer-related mortality (OR 0.55, 95% CI 0.20 to 1.52; 1248 participants; 2 studies; P = 0.25; moderate quality evidence) or VTE-related morbidity (OR 1.02, 95% CI 0.48 to 2.17; 854 participants; 1 study; P = 0.96; moderate quality evidence). With regards to stage of cancer, there was no clear difference for detection of early (OR 1.78, 95% 0.51 to 6.17; 394 participants; 1 study; P = 0.37; low quality evidence) or advanced (OR 1.00, 95% CI 0.14 to 7.17; 394 participants; 1 study; P = 1.00; low quality evidence) stages of cancer. There was also no clear difference in the frequency of an underlying cancer diagnosis (OR 1.71, 95% CI 0.91 to 3.20; 1248 participants; 2 studies; P = 0.09; moderate quality evidence). Time to cancer diagnosis was 4.2 months in the standard testing group and 4.0 months in the standard testing plus PET/CT group (P = 0.88). Neither study measured VTE-related mortality, complications of anticoagulation, adverse effects of cancer tests, participant satisfaction or quality of life. AUTHORS' CONCLUSIONS: Testing for cancer in people with unprovoked VTE may lead to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer and VTE-related morbidity and mortality. The results could be consistent with either benefit or no benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made. PMID- 28832906 TI - Thrombocalc: implementation and uptake of personalized postpartum venous thromboembolism risk assessment in a high-throughput obstetric environment. AB - INTRODUCTION: Venous thromboembolism risk assessment (VTERA) is recommended in all pregnant and postpartum women. Our objective was to develop, pilot and implement a user-friendly electronic VTERA tool. MATERIAL AND METHODS: We developed "Thrombocalc", an electronic VTERA tool using Microsoft EXCELTM . Thrombocalc was designed as a score-based tool to facilitate rapid assessment of all women after childbirth. Calculation of a total score estimated risk of venous thromboembolism in line with consensus guidelines. Recommendations for thromboprophylaxis were included in the VTERA output. Implementation was phased. Uptake of the VTERA tool was assessed prospectively by monitoring the proportion of women who gave birth in our institution and had a completed risk assessment. Factors affecting completion and accuracy of risk assessments were also assessed. RESULTS: Thrombocalc was used prospectively to risk-assess 8380 women between September 2014 and December 2015. Compliance with this tool increased dramatically throughout the study period; over 92% of women were risk-assessed in the last quarter of data collection. Compliance was not adversely affected if delivery took place out of working hours [adjusted odds ratio (aOR) 1.03, 95% confidence interval (CI) 0.93-1.14]. Risk assessment was less likely in the case of cesarean deliveries (aOR 0.66, 95% CI 0.60-0.73) and stillborn infants (aOR 0.48, 95% CI 0.29-0.79). Misclassification of risk factors led to approximately 207 (2.5%) inaccurate thromboprophylaxis recommendations. CONCLUSIONS: Our electronic, score-based VTERA tool provides a highly effective mechanism for rapid assessment of individual postpartum venous thromboembolism risk in a high throughput environment. PMID- 28832907 TI - Complications in operative hysteroscopy - is prevention possible? AB - Operative hysteroscopy in a hospital setting has revolutionized surgical treatment of benign uterine disorders. It is minimally invasive, cost- and time effective, and may spare patients major surgical interventions. Operative hysteroscopy in a day-case hospital setting is regarded as a safe and well tolerated procedure with low complication rates. However, prevention of adverse events is crucial in daily practice to optimize patient care. Complications in operative hysteroscopy can be divided into early complications, including bleeding, uterine perforation, infection and fluid overload, or late complications and suboptimal outcomes, such as incomplete resection and intrauterine adhesions. Awareness and knowledge of management of adverse events as well as the use of possible preventative measures will increase the quality and safety of hysteroscopic surgery. The present commentary focuses on these issues as an up-to-date basis for everyday clinical practice. PMID- 28832909 TI - Longitudinal transvaginal ultrasound evaluation of cesarean scar niche incidence and depth in the first two years after single- or double-layer uterotomy closure: a randomized controlled trial. AB - INTRODUCTION: Cesarean deliveries are the most common abdominal surgery procedure globally, and the optimal way to suture the hysterotomy remains a matter of debate. The aim of this study was to assess the incidence of cesarean scar niches and the depth after single- or double-layer uterine closure. MATERIAL AND METHODS: We performed a randomized controlled trial in which women were allocated to three uterotomy suture techniques: continuous single-layer unlocked, continuous locked single-layer, or double-layer sutures. Transvaginal ultrasound was performed six weeks and 6-24 months after cesarean delivery [Clinicaltrials.gov (NCT02338388)]. RESULTS: The study included 435 women. Six weeks after delivery, the incidence of niche was not significantly different between the groups (p = 0.52): 40% for single-layer unlocked, 32% for single layer locked and 43% for double-layer sutures. The mean +/- SD niche depths were 3.0 +/- 1.4 mm for single-layer unlocked, 3.6 +/- 1.7 mm for single-layer locked and 3.3 +/- 1.3 mm for double-layer sutures (p = 1.0). There were no significant differences (p = 0.58) in niche incidence between the three groups at the second ultrasound follow up: 30% for single-layer unlocked, 23% for single-layer locked and 29% for double-layer sutures. The mean +/- SD niche depth was 3.1 +/- 1.5 mm after single-layer unlocked, 2.8 +/- 1.5 mm after single-layer locked and 2.5 +/- 1.2 mm after double-layer sutures (p = 0.61). There was a trend (p = 0.06) for the residual myometrium thickness to be thicker after double-layer repair at the long-term follow up. CONCLUSIONS: The incidence of cesarean scar niche formation and the niche depth was independent of the hysterotomy closure technique. PMID- 28832910 TI - Some Concerns About Diagnostic Test Accuracy for Infections. PMID- 28832911 TI - Different strategies for diagnosing gestational diabetes to improve maternal and infant health. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is carbohydrate intolerance resulting in hyperglycaemia with onset or first recognition during pregnancy. If untreated, perinatal morbidity and mortality may be increased. Accurate diagnosis allows appropriate treatment. Use of different tests and different criteria will influence which women are diagnosed with GDM. This is an update of a review published in 2011 and 2015. OBJECTIVES: To evaluate and compare different testing strategies for diagnosis of gestational diabetes mellitus to improve maternal and infant health while assessing their impact on healthcare service costs. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (9 January 2017) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised trials if they evaluated tests carried out to diagnose GDM. We excluded studies that used a quasi-random model, cluster-randomised or cross over trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included a total of seven small trials, with 1420 women. One trial including 726 women was identified by this update and examined the two step versus one step approach. These trials were assessed as having varying risk of bias, with few outcomes reported. We prespecified six outcomes to be assessed for quality using the GRADE approach for one comparison: 75 g oral glucose tolerance test (OGTT) versus 100 g OGTT; data for only one outcome (diagnosis of gestational diabetes) were available for assessment. One trial compared three different methods of delivering glucose: a candy bar (39 women), a 50 g glucose polymer drink (40 women) and a 50 g glucose monomer drink (43 women). We have included the results reported by this trial as separate comparisons. No trial reported on measures of costs of health services.We examined six main comparisons. 75 g OGTT versus 100 g OGTT (1 trial, 248 women): women who received 75 g OGTT had a higher relative risk of being diagnosed with GDM (risk ratio (RR) 2.55, 95% confidence interval (CI) 0.96 to 6.75; very-low quality evidence). No data were reported for the following additional outcomes prespecified for GRADE assessment: caesarean section, macrosomia > 4.5 kg or however defined in the trial, long-term type 2 diabetes maternal, long-term type 2 diabetes infant and economic costs. Candy bar versus 50 g glucose monomer drink (1 trial, 60 women): more women receiving the candy bar, rather than glucose monomer, preferred the taste of the candy bar (RR 0.60, 95% CI 0.42 to 0.86) and 1-hour glucose was less with the candy bar. There were no differences in the other outcomes reported (maternal side effects). No infant outcomes were reported or any review primary outcomes. 50 g glucose polymer drink versus 50 g glucose monomer drink (3 trials, 239 women): mean difference (MD) in gestation at birth was -0.80 weeks (1 trial, 100 women; 95% CI -1.69 to 0.09). Total side effects were less common with the glucose polymer drink (1 trial, 63 women; RR 0.21, 95% CI 0.07 to 0.59), and no clear difference in taste acceptability was reported (1 trial, 63 women; RR 0.99, 95% CI 0.76 to 1.29). Fewer women reported nausea following the 50 g glucose polymer drink compared with the 50 g glucose monomer drink (1 trial, 66 women; RR 0.29, 95% CI 0.11 to 0.78). No other measures of maternal morbidity or outcomes for the infant were reported. 50 g glucose food versus 50 g glucose drink (1 trial, 30 women): women receiving glucose in their food, rather than as a drink, reported fewer side effects (RR 0.08, 95% CI 0.01 to 0.56). No clear difference was noted in the number of women requiring further testing (RR 0.14, 95% CI 0.01 to 2.55). No other measures of maternal morbidity or outcome were reported for the infant or review primary outcomes. 75 g OGTT World Health Organization (WHO) criteria versus 75 g OGTT American Diabetes Association (ADA) criteria (1 trial, 116 women): no clear differences in included outcomes were observed between women who received the 75 g OGTT and were diagnosed using criteria based on WHO (1999) recommendations and women who received the 75 g OGTT and were diagnosed using criteria recommended by the ADA (1979). Outcomes measured included diagnosis of gestational diabetes (RR 1.47, 95% CI 0.66 to 3.25), caesarean section (RR 1.07, 95% CI 0.85 to 1.35), macrosomia defined as > 90th percentile by ultrasound or birthweight equal to or exceeding 4000 g (RR 0.73, 95% CI 0.19 to 2.79), stillbirth (RR 0.49, 95% CI 0.02 to 11.68) and instrumental birth (RR 0.21, 95% CI 0.01 to 3.94). No other secondary outcomes were reported. Two-step approach (50 g oral glucose challenge test followed by selective 100 g OGTT Carpenter and Coustan criteria) versus one-step approach (universal 75 g OGTT ADA criteria) (1 trial, 726 women): women allocated the two-step approach had a lower risk of being diagnosed with GDM at 11 to 14 weeks' gestation compared to women allocated the one-step approach (RR 0.51, 95% CI 0.28 to 0.95). No other primary or secondary outcomes were reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to suggest which strategy is best for diagnosing GDM. Large randomised trials are required to establish the best strategy for correctly identifying women with GDM. PMID- 28832912 TI - Screening for late-onset Pompe disease in western Denmark. AB - OBJECTIVE: Late-onset Pompe disease (LOPD) is a rare autosomal recessively inherited metabolic myopathy caused by reduced activity of the lysosomal enzyme alpha-glucosidase. In a previous screening study at two large neuromuscular university clinics in Denmark, three patients with LOPD were identified out of 103 patients screened. No systematic screening has been performed at the other neurological departments in the western part of Denmark. Thus, patients with a diagnosis of unspecified myopathy were screened for LOPD. MATERIALS AND METHODS: At seven neurological departments in the western part of Denmark, medical records were evaluated for all patients registered with myopathy diagnosis codes (ICD 10 codes: G 71.0-71.9 and G 72.0-72.9) during the period January 1, 2002, to December 31, 2012. If no specific diagnosis has been reached, patients were invited for screening. Dried blood spot (DBS) test was used to analyze the activity of the enzyme alpha-glucosidase. RESULT: A total of 654 patients were identified. From the medical records, information was obtained concerning symptoms, family history, electromyography, muscle biopsy results and creatine kinase levels. Eighty-seven patients (13.3%) (males 61%) at a mean age of 53.3 years (SD 16.5) fulfilled the criteria for screening. A DBS test was performed in 47 (54%) patients. In all patients, the enzyme activity was within reference values. CONCLUSION: None of the screened patients had a reduced activity of the enzyme alpha-glucosidase. Although the cohort studied was small, our findings do not suggest that LOPD is underdiagnosed in patients with unspecified myopathy in western Denmark. PMID- 28832908 TI - Pain Assessment in INTensive care (PAINT): an observational study of physician documented pain assessment in 45 intensive care units in the United Kingdom. AB - Pain is a common and distressing symptom experienced by intensive care patients. Assessing pain in this environment is challenging, and published guidelines have been inconsistently implemented. The Pain Assessment in INTensive care (PAINT) study aimed to evaluate the frequency and type of physician pain assessments with respect to published guidelines. This observational service evaluation considered all pain and analgesia-related entries in patients' records over a 24-h period, in 45 adult intensive care units (ICUs) in London and the South-East of England. Data were collected from 750 patients, reflecting the practice of 362 physicians. Nearly two-thirds of patients (n = 475, 64.5%, 95%CI 60.9-67.8%) received no physician-documented pain assessment during the 24-h study period. Just under one third (n = 215, 28.6%, 95%CI 25.5-32.0%) received no nursing-documented pain assessment, and over one-fifth (n = 159, 21.2%, 95%CI 19.2-23.4)% received neither a doctor nor a nursing pain assessment. Two of the 45 ICUs used validated behavioural pain assessment tools. The likelihood of receiving a physician pain assessment was affected by the following factors: the number of nursing assessments performed; whether the patient was admitted as a surgical patient; the presence of tracheal tube or tracheostomy; and the length of stay in ICU. Physician-documented pain assessments in the majority of participating ICUs were infrequent and did not utilise recommended behavioural pain assessment tools. Further research to identify factors influencing physician pain assessment behaviour in ICU, such as human factors or cultural attitudes, is urgently needed. PMID- 28832914 TI - Comparing the accuracy of maternal, clinical, and ultrasound estimations to predict birthweight: a meta-analysis. AB - INTRODUCTION: Accurate prediction of birthweight prior to delivery is necessary to establish periconceptional strategies to reduce the rates of adverse pregnancy outcomes. This study was performed to determine whether maternal, clinical, or ultrasound estimation provides the best predictor of birthweight. MATERIAL AND METHODS: Meta-analysis was performed to summarize the relative ratios of the rate of one of maternal, clinical, and ultrasound estimation within 10% of actual birthweight to that of each of the others within the same range and the difference in correlation coefficient of actual birthweight between clinical and ultrasound estimations. Study quality was assessed with regard to the representativeness of participants, verification bias, and review bias. Publication bias was assessed using Egger's test. RESULTS: Thirty-seven relatively good quality studies were included in the analysis. There was no significant difference in the rates of estimates within 10% of actual birthweight between clinical and maternal estimations (n = 8 and p = 0.491) or between ultrasound and maternal estimations (n = 6 and p = 0.568), or in the correlation coefficient of actual birthweight with ultrasound estimation compared with clinical estimation (n = 5 and p = 0.621). However, the rate of ultrasound estimations within 10% of actual birthweight was significantly higher than that of clinical estimations (n = 18 and p = 0.033). The data showed no publication bias (p = 0.058-0.854). CONCLUSIONS: Ultrasound estimation may be the best predictor of birthweight. PMID- 28832913 TI - First-aid training in school: amount, content and hindrances. AB - BACKGROUND: To increase knowledge and competence about first aid in the population, first-aid instruction is included in primary and secondary school curricula. This study aimed to establish how much time is spent on first-aid training, which first-aid measures are taught, and which factors prevent teachers from providing the quantity and quality of first-aid training that they wish to give. METHODS: A questionnaire was distributed to teachers in physical education in primary and secondary schools and to teachers in vocational subjects in higher secondary schools. RESULTS: The teachers taught a median of two lessons in first aid per year. Cardiopulmonary resuscitation (CPR) was taught by 64% of teachers, free airway and recovery position by 69% and stopping severe bleeding by 51%. Recognising heart attack and stroke was taught by 25% and 23%, respectively. The main factors that the teachers perceived as limiting the amount and quality of first-aid training were insufficient learning objective specifications in the curriculum, too many other competence aims, lack of CPR mannequins and lack of training as first-aid instructors. DISCUSSION: Norwegian teachers provide an appreciable amount of first-aid training to their students. However, several potential life-saving measures are poorly covered. The curriculum needs to contain first aid but also should specify what first-aid measures to be taught. First-aid training of teachers should adequately prepare them to be first-aid instructors. PMID- 28832915 TI - Mortality and causes of death among women with a history of placental abruption. AB - INTRODUCTION: Women with a history of placental abruption have an increased later morbidity, but not much is known of the later mortality. MATERIAL AND METHODS: Data on women with placental abruption (index cohort) between 1969 and 2005 (n = 7805) were collected from the Finnish Hospital Discharge Register and the Finnish Medical Birth Register. A matched reference cohort consisted of women without placental abruption (n = 23 523). The causes of death were retrieved from the Cause-of-Death Register. Cause-specific mortality was compared by hazard ratios (HR). Standardized mortality ratios were calculated to compare both cohorts with the general female population. The main outcome measure was subsequent mortality. RESULTS: By the end of 2013 there were 395 deaths in the index cohort and 863 deaths in the reference cohort. The overall mortality was increased in the index cohort compared with the reference cohort [HR 1.39, 95% confidence interval (CI) 1.24-1.57]. The index cohort had an increased risk of death from respiratory tract malignancies (HR 1.72, 95% CI 1.05-2.82), alcohol-related causes (HR 1.84, 95% CI 1.25-2.72), and external causes (HR 1.63, 95% CI 1.19-2.22), especially suicide (HR 1.71, 95% CI 1.07-2.74). The mortality from cardiovascular diseases did not differ. The standardized mortality ratio was increased in the index cohort compared with the general Finnish female population (HR 1.13, 95% CI 1.02 1.24), especially for respiratory tract malignancies (HR 1.79, 95% CI 1.16-2.64). The index cohort women tended to die younger than referent women (p < 0.001). CONCLUSIONS: Overall mortality among women with a history of placental abruption is increased. These women tend to die younger than referent women do. PMID- 28832916 TI - Reduced incidence of neonatal early-onset group B streptococcal infection after promulgation of guidelines for risk-based intrapartum antibiotic prophylaxis in Sweden: analysis of a national population-based cohort. AB - INTRODUCTION: This study aimed to investigate the incidence of neonatal early onset group B streptococcal (GBS) infection in Sweden after promulgation of guidelines (2008) for risk factor-based intrapartum antibiotic prophylaxis, and evaluate the presence of risk factors and obstetric management in mothers. MATERIAL AND METHODS: National registers were searched for infants with early onset GBS infection during 2006-2011. Medical records of cases and case mothers were abstracted. Verified cases of sepsis/meningitis and cases with clinical sepsis/pneumonia were documented, as well as risk factors in case mothers and timeliness of intrapartum antibiotic prophylaxis administration. RESULTS: There were 227 cases with verified infection, with an incidence of 0.340/00 of live births during the whole period. There was a significant decrease after promulgation of guidelines, from 0.40 to 0.300/00 [odds ratio (OR) 0.75, 95% confidence interval (CI) 0.57-0.99]. A significant decrease in the number of cases with clinical GBS sepsis/pneumonia was also observed. In parturients with one or more risk factors, the incidence of any GBS infection was reduced by approximately 50% (OR 0.47, 95% CI 0.35-0.64), although there were many cases where the opportunity for timely administration of intrapartum antibiotic prophylaxis was missed. In infants of mothers without risk factor(s) there was no reduction in early-onset GBS morbidity. The mortality in verified cases was 4.8% (95% CI 2.1-7.6). CONCLUSIONS: The introduction of national guidelines for risk based intrapartum antibiotic prophylaxis coincided with a significant 50% risk reduction of neonatal early-onset GBS infection in infants of parturients presenting with one or more risk factors. A stricter adherence to guidelines could probably have reduced the infant morbidity further. PMID- 28832917 TI - Propensity score method for analyzing the effect of labor induction in prolonged pregnancy. AB - INTRODUCTION: There is an ongoing debate on the optimal time of labor induction to reduce the risks associated with prolonged pregnancy. MATERIAL AND METHODS: Registry-based study of 212 716 term, singleton cephalic deliveries between 2006 and 2012 in Finland comparing the outcomes of labor induction with those of expectant management in five, three-day gestational age periods between 40 and 42 weeks (group 1: 40+0 -40+2 ; group 2: 40+3 -40+5 ; group 3: 40+6 -41+1 ; group 4: 41+2 -41+4 ; group 5: 41+5 -42+0 ). Using Poisson regression, induced deliveries in each of the gestational age periods were compared with all ongoing pregnancies. Propensity score matching was applied to reduce confounding by indication. RESULTS: In the gestational age groups 1 and 2, labor induction significantly decreased the risk of meconium aspiration syndrome [relative risk (RR) 0.40, 95% confidence interval (CI) 0.18-0.91 (group 1), RR 0.44, 95% CI 0.21 0.91 (group 2)] but increased the risk for prolonged hospitalization of a neonate [RR 1.30, 95% CI 1.10-1.54 (group 1) and RR 1.23, 95% CI 1.03-1.47 (group 2)]. In groups 3 and 4, labor induction significantly increased the risk for emergency cesarean section [RR 1.17, 95% CI 1.06-1.28 (group 3) and RR 1.19, 95% CI 1.09 1.29 (group 4)] but still reduced the risk for meconium aspiration syndrome. In group 5, labor induction did not affect the risk for any of the studied outcomes (operative delivery, obstetric trauma, neonatal mortality, respirator treatment, Apgar <7). CONCLUSIONS: Propensity score matching is a novel approach to studying the effect of labor induction. It highlighted the conflicting maternal and neonatal risks and benefits of the intervention, and supported expectant management as a valid option, at least until close to 42 weeks. PMID- 28832919 TI - Infective dermatitis associated with human T-lymphotropic virus type 1 infection in Adelaide, South Australia. PMID- 28832918 TI - Predictors of insubordinate aggression among captive female rhesus macaques. AB - OBJECTIVES: Cercopithicine primates tend to have nepotistic hierarchies characterized by predictable, kinship-based dominance. Although aggression is typically directed down the hierarchy, insubordinate aggression does occur. Insubordination is important to understand because it can precipitate social upheaval and undermine group stability; however, the factors underlying it are not well understood. We test whether key social and demographic variables predict insubordination among captive female rhesus macaques. MATERIALS AND METHODS: To identify factors influencing insubordination, multivariate analyses of 10,821 dyadic conflicts among rhesus macaque females were conducted, using data from six captive groups. A segmented regression analysis was used to identify dyads with insubordination. Negative binomial regression analyses and an information theoretic approach were used to assess predictors of insubordination among dyads. RESULTS: In the best models, weight difference (w = 1.0; IRR = 0.930), age (dominant: w = 1.0, IRR = 0.681; subordinate: w = 1.0, IRR = 1.069), the subordinate's total number of allies (w = 0.727, IRR = 1.060) or non-kin allies (w = 0.273, IRR = 1.165), the interaction of the dominant's kin allies and weight difference (w = 0.938, IRR = 1.046), violation of youngest ascendancy (w = 1.0; IRR = 2.727), and the subordinate's maternal support (w = 1.0; IRR = 2.928), are important predictors of insubordination. DISCUSSION: These results show that both intrinsic and social factors influence insubordinate behavior. This adds to evidence of the importance of intrinsic factors and flexibility in a social structure thought to be rigid and predetermined by external factors. Further, because insubordination can precipitate social overthrow, determining predictors of insubordination will shed light on mechanisms underlying stability in nepotistic societies. PMID- 28832921 TI - That's What Doctors Do, Right? PMID- 28832920 TI - Effect of New Oral Anticoagulants on Prescribing Practices for Atrial Fibrillation in Older Adults. AB - OBJECTIVES: To determine the effect of new oral anticoagulants (NOACs) on prescribing practices in older adults with atrial fibrillation (AF). DESIGN: Retrospective observational cohort study. SETTING: Academic medical center in St. Louis, Missouri. PARTICIPANTS: Individuals aged 75 and older with AF admitted to the hospital from October 2010 through September 2015 (N = 6,568, 50% female, 15% non-white). MEASUREMENTS: Information on NOACs and warfarin prescribed at discharge was obtained from hospital discharge summaries, and linear regression was used to examine quarterly trends in their use. Multivariable logistic regression was used to assess independent predictors of anticoagulant use. RESULTS: NOAC use increased over time (correlation coefficient (r) = 0.87, P < .001), warfarin use did not change (r = -0.16, P = .50), and overall anticoagulant use (NOACs and warfarin) increased (r = 0.68, P = .001). NOAC use increased over time in all age groups (75-79, 80-84, 85-89) except aged 90 and older, but increasing age attenuated the rate of NOAC uptake. There was no consistent relationship between age and warfarin or overall anticoagulant use, except that individuals aged 90 and older had consistently lower use. Overall, fewer than 45% of participants were prescribed an anticoagulant. In multivariable analysis, younger age, white race, female sex, higher hemoglobin, higher creatinine clearance, being on a medical service, hypertension, stroke or transient ischemic attack, no history of intracranial hemorrhage, and a modified HAS-BLED score of less than 3 increased the likelihood of receiving NOACs. CONCLUSION: Prescription of anticoagulants for AF increased in older adults primarily because of an increase in the use of NOACs. Nonetheless, fewer than 45% of participants were prescribed an anticoagulant. Additional research is needed to optimize prescribing practices for older adults with AF. PMID- 28832922 TI - Heritability and genetic integration of tooth size in the South Carolina Gullah. AB - OBJECTIVES: This article provides estimates of narrow-sense heritability and genetic pleiotropy for mesiodistal tooth dimensions for a sample of 20th century African American individuals. Results inform biological distance analysis and offer insights into patterns of integration in the human dentition. MATERIALS AND METHODS: Maximum mesiodistal crown dimensions were measured using Hillson FitzGerald calipers on 469 stone dental casts from the Menegaz-Bock Collection. Narrow-sense heritability estimates and genetic and phenotypic correlations were estimated using SOLAR 8.1.1 with covariate screening for age, sex, age*sex interaction, and birth year. RESULTS: Heritability estimates were moderate (~0.10 - 0.90; h2 mean = 0.51) for most measured variables with sex as the only significant covariate. Patterns of genetic correlation indicate strong integration across tooth classes, except molars. Comparison of these results to previously published work suggests lower overall heritability relative to other human populations and much stronger genetic integration across tooth classes than obtained from nonhuman primate genetic pleiotropy estimates. CONCLUSIONS: These results suggest that the high heritabilities previously published may reflect overestimates inherent in previous study designs; as such the standard estimate of 0.55 used in biodistance analyses may not be appropriate. For the Gullah, isolation and endogamy coupled with elevated levels of physiological and economic stress may suppress narrow-sense heritability estimates. Pleiotropy analyses suggest a more highly integrated dentition in humans than in other mammals. PMID- 28832923 TI - Vitamin D-mentia: Is Vitamin D Optional or Essential for Preventing Late-Life Cognitive Decline? PMID- 28832924 TI - The effect of acetazolamide on intra-ocular pressure after Trendelenburg positioning - a randomised double-blind crossover trial in volunteers. AB - Recent evidence suggests Trendelenburg positioning can produce a significant rise in intra-ocular pressure. Peri-operative vision loss in patients undergoing laparoscopic colorectal surgery has been reported with the rise in intra-ocular pressure suggested as a possible factor. Acetazolamide decreases intra-ocular pressure by reducing the formation of aqueous humour, so we aimed to investigate if it could attenuate the intra-ocular pressure rise that can occur in the Trendelenburg position. Nine healthy volunteers were recruited and randomly assigned to a double-blind crossover comparison of placebo or acetazolamide with a minimal 4 days' washout period before the second study day. One and a half hours after taking the medication, volunteers lay head-down at 17 degrees for 4 h. Intraocular pressure measurements were repeated in both eyes every 30 min over a 4-h period. There were two males and seven female volunteers, with a mean (SD) age of 54.3 (18.5) years. The mean (SD) increase in intra-ocular pressure following 4 h in the Trendelenburg position was 3.17 (4.63) mmHg after the placebo, and 0.02 (4.01) mmHg (p = 0.02) after acetazolamide. We have shown than acetazolamide can attenuate the rise that occurs in intra-ocular pressure when in the Trendelenburg position. PMID- 28832925 TI - Reply to: Function but not Multimorbidity at the Cornerstone of Geriatric Medicine. PMID- 28832926 TI - Thoracic Kyphosis and Physical Function: The Framingham Study. AB - OBJECTIVE: To evaluate the association between thoracic kyphosis and physical function. DESIGN: Prospective cohort. SETTING: Framingham, Massachusetts. PARTICIPANTS: Framingham Heart Study Offspring and Third Generation cohort members who had computed tomography (CT) performed between 2002 and 2005 and physical function assessed a mean 3.4 years later (N = 1,100; mean age 61 +/- 8, range 50-85). MEASUREMENTS: Thoracic kyphosis (Cobb angle, T4-T12) was measured in degrees using supine CT scout images. Participants were categorized according to Cobb angle to compare those in the highest quartile (Q4, most-severe kyphosis) with those in the lowest quartiles (Q1-Q3). Quick walking speed (m/s), chair stand time (seconds), grip strength (kg), and self-reported impairments were assessed using standardized procedures. Analyses were adjusted for age, height, weight, smoking, follow-up time, vertebral fractures, and prevalent spinal degeneration. RESULTS: Thoracic kyphosis was not associated with physical function in women or men, and these results were consistent in those younger than 65 and those aged 65 and older. For example, walking speed was similar in adults younger than 65 with and without severe kyphosis (women, Q4: 1.38 m/s, Q1-Q3: 1.40 m/s, P = .69; men, Q4: 1.65 m/s, Q1-Q3: 1.60 m/s; P = .39). CONCLUSION: In healthy relatively high-functioning women and men, kyphosis severity was not associated with subsequent physical function. Individuals at risk of functional decline cannot be targeted based on supine CT thoracic curvature measures alone. PMID- 28832927 TI - Innovation in a Learning Health Care System: Veteran-Directed Home- and Community Based Services. AB - A path-breaking example of the interplay between geriatrics and learning healthcare systems is the Veterans Health Administration's (VHA's) planned roll out of a program for providing participant-directed home- and community-based services to veterans with cognitive and functional limitations. We describe the design of a large-scale, stepped-wedge, cluster-randomized trial of the Veteran Directed Home- and Community-Based Services (VD-HCBS) program. From March 2017 through December 2019, up to 77 Veterans Affairs Medical Centers will be randomized to times to begin offering VD-HCBS to veterans at risk of nursing home placement. Services will be provided to community-dwelling participants with support from Aging and Disability Network Agencies. The VHA Partnered Evidence based Policy Resource Center (PEPReC) is coordinating the evaluation, which includes collaboration from operational stakeholders from the VHA and Administration for Community Living and interdisciplinary researchers from the Center of Innovation in Long-Term Services and Supports and the Center for Health Services Research in Primary Care. For older veterans with functional limitations who are eligible for VD-HCBS, we will evaluate health outcomes (hospitalizations, emergency department visits, nursing home admissions, days at home) and healthcare costs associated with VD-HCBS availability. Learning healthcare systems facilitate diffusion of innovation while enabling rigorous evaluation of effects on patient outcomes. The VHA's randomized rollout of VD-HCBS to veterans at risk of nursing home placement is an example of how to achieve these goals simultaneously. PEPReC's experience designing an evaluation with researchers and operations stakeholders may serve as a framework for others seeking to develop rapid, rigorous, large-scale evaluations of delivery system innovations targeted to older adults. PMID- 28832928 TI - Variation in human gape cycle kinematics and occlusal topography. AB - OBJECTIVES: This study tested hypotheses relating intraspecific variation in occlusal morphology and intraspecific variation in jaw movements during feeding. Gape cycle kinematic variation was hypothesized to correlate with gape cycle number within a chewing sequence as well as with food toughness and stiffness. Gape cycle kinematic variation was also hypothesized to correlate with variation in occlusal area, slope, and volume. METHODS AND MATERIALS: Twenty-six adult human subjects chewed four foods with varying material properties while their jaw movements were recorded using three-dimensional coordinates of facial markers captured with a Vicon camera system. Post-canine occlusal morphology of each subject was quantified in ArcGIS using dental topographic analysis of dental casts. RESULTS: Gape cycle duration did not vary with gape cycle number, food toughness, or food stiffness. Gape cycle vertical and lateral displacement correlated negatively with gape cycle number, while foods with higher toughness and Young's modulus had greater jaw vertical and lateral displacement. Subjects with steeper occlusal slopes had longer gape cycle durations and greater amounts of vertical displacement during the slow closing phase of the gape cycle. DISCUSSION: The results suggest that gape cycle durations are relatively consistent despite changes in food properties and gape cycle number, while occlusal slope affects gape cycle duration and vertical displacement during inferred occlusal contact. However, gape cycle number and bolus properties explain greater amounts of kinematic variation than does occlusal morphology. PMID- 28832929 TI - A test of the optimal iron hypothesis among breastfeeding Ariaal mothers in northern Kenya. AB - OBJECTIVE: The optimal iron hypothesis posits a trade-off in iron nutrition-iron deficiency restricts iron available to infectious agents, protecting against severe infection, but also compromises immune defense-such that mild-to-moderate iron deficiency may be more adaptive than either iron-replete or severe deficiency in environments with high infectious disease load. This hypothesis has not been tested among adults. MATERIALS AND METHODS: A secondary analysis of data and specimens from 220 lactating mothers in northern Kenya was conducted. Elevated serum C-reactive protein (CRP > 2 or >5 mg/l) was utilized to identify prevalent subclinical infection/inflammation. Iron deficiency was identified with transferrin receptor in archived dried blood spots (TfR > 5.0 mg/l). The absence of iron deficiency or anemia (Hemoglobin < 12 g/l) defined the iron replete state. Iron-deficient erythropoiesis (IDE, mild-to-moderate iron deficiency) was defined as iron deficiency without anemia; iron deficiency anemia (IDA, severe iron deficiency) as iron deficiency with anemia; and noniron-deficiency anemia (NIDA) as anemia without iron deficiency. RESULTS: The prevalence of elevated inflammation (subclinical infection) was lowest in IDE. In logistic regression, IDE was inversely associated with inflammation (for CRP > 2 mg/l: adjusted odds ratio, aOR = 0.30; p = 0.02; for CRP > 5 mg/l: aOR = 0.27; p = 0.10), compared to the iron replete state. The protective effect of IDE differed in the presence of vitamin A deficiency or underweight. CONCLUSIONS: We interpret these patterns as tentative support for the optimal iron hypothesis in breastfeeding women in the infectious disease ecology of northern Kenya. Iron deficiency may interact in important ways with other forms of malnutrition that are known to affect immune protection. PMID- 28832930 TI - Function But Not Multimorbidity at The Cornerstone of Geriatric Medicine. PMID- 28832931 TI - The characteristic mid-shaft cross-sectional shape of the ulna in Jomon hunter gatherers. AB - OBJECTIVES: The Jomon people were hunter-gatherers who inhabited the Japanese archipelago between 10,000 BC and 300 BC. Here, we focus on the mid-shaft cross sectional shape of the ulna in the Jomon population and compare it with modern Japanese people. MATERIALS AND METHODS: Jomon specimens, including 32 males and 22 females, were excavated from shell mound sites in the Pacific and Seto inland coastal area of Honshu island in the Japanese archipelago dated to the Late-to Final Jomon phase (between 2,000 BC and 300 BC). Mid-shaft ulna cross-sectional shapes were compared with modern Japanese specimens (25 males, 21 females) using standard linear measurements and elliptic Fourier analysis (EFA). Differences from both sides of this element were compared using predicted handedness. RESULTS: Linear measurements and EFA results show that ulna shape of both sexes within the Jomon population are relatively larger in the antero-posterior direction and have more developed posterior borders than modern Japanese males and females. No significant differences were observed between Jomon sexes based on the predicted dominant side, but differences were evident in the predicted nondominant side. At the same time, bilateral differences were recognized in Jomon females, because of a lower level of posterior border development in the predicted nondominant side compared to the dominant side. DISCUSSION: Shape differences between Jomon people and modern Japanese can be explained by variation in the habitual loading of the ulna. Sexual dimorphism in ulna shape within the Jomon population suggests division of labor differences. PMID- 28832932 TI - Reply to Comment on: Quality of Life, Perceptions, and Health Satisfaction of Older Adults with End-Stage Renal Disease. PMID- 28832933 TI - Synthesis and gelation of copolypept(o)ides with random and block structure. AB - Copolypept(o)ides of polysarcosine (PSar) and poly(N-isopropyl-L-glutamine) (PIGA) with random and block sequence structures were synthesized by ring-opening polymerization (ROP) of sarcosine N-carboxyanhydrides (Sar-NCA) and gamma-benzyl l-glutamate N-carboxyanhydrides (BLG-NCA) and post modification. With different distribution of Sar along the main chain, H-bonding pattern and secondary structure of polypeptides were turned, as well as aggregation and gelation behavior. Both copolypept(o)ides formed hydrogels above their critical gelation concentrations (CGCs) without thermo-sensitivity, which was normally reserved for PEG copolypeptides (eg, PEG-b-PIGA). In particular, a different mechanism from previously reported micellar percolation or fibrillar entanglement was suggested for gelation of the random copolypept(o)ide. Therefore, hydrogels from copolymers of PSar and PIGA represented a new approach to construct easy-handling, biocompatible, biodegradable and thermo-stable gels that could potentially be applied in biomedical fields. PMID- 28832935 TI - The view from the top. Is it worth recording for posterity? PMID- 28832934 TI - Relative tooth size at birth in primates: Life history correlates. AB - OBJECTIVES: Dental eruption schedules have been closely linked to life history variables. Here we examine a sample of 50 perinatal primates (28 species) to determine whether life history traits correlate with relative tooth size at birth. MATERIALS AND METHODS: Newborn primates were studied using serial histological sectioning. Volumes of deciduous premolars (dp2 -dp4 ), replacement teeth (if any), and permanent molars (M1-2/3 ) of the upper jaw were measured and residuals from cranial length were calculated with least squares regressions to obtain relative dental volumes (RDVs). RESULTS: Relative dental volumes of deciduous or permanent teeth have an unclear relationship with relative neonatal mass in all primates. Relative palatal length (RPL), used as a proxy for midfacial size, is significantly, positively correlated with larger deciduous and permanent postcanine teeth. However, when strepsirrhines alone are examined, larger RPL is correlated with smaller RDV of permanent teeth. In the full sample, RDVs of deciduous premolars are significantly negatively correlated with relative gestation length (RGL), but have no clear relationship with relative weaning age. RDVs of molars lack a clear relationship with RGL; later weaning is associated with larger molar RDV, although correlations are not significant. When strepsirrhines alone are analyzed, clearer trends are present: longer gestations or later weaning are associated with smaller deciduous and larger permanent postcanine teeth (only gestational length correlations are significant). DISCUSSION: Our results indicate a broad trend that primates with the shortest RGLs precociously develop deciduous teeth; in strepsirrhines, the opposite trend is seen for permanent molars. Anthropoids delay growth of permanent teeth, while strepsirrhines with short RGLs are growing replacement teeth concurrently. A comparison of neonatal volumes with existing information on extent of cusp mineralization indicates that growth of tooth germs and cusp mineralization may be selected for independently. PMID- 28832936 TI - Chlamydia testing and diagnosis following initiation of long-acting reversible contraception: A retrospective cohort study. AB - BACKGROUND: Long-acting reversible contraception (LARC) effectively protects against pregnancy but provides no protection against sexually transmitted infections (STIs). AIM: To compare rates of chlamydia testing and diagnosis for women initiating long-acting versus oral contraception. MATERIALS AND METHODS: Retrospective cohort study involving data collection for 6160 women initiating post-abortion contraception at a large New Zealand regional public hospital abortion clinic (2009-2012), with chlamydia testing data obtained from the local laboratory during two-year follow up. Negative binomial regression modelling examined the effect of contraceptive method on two outcome measures: chlamydia testing and chlamydia diagnosis (adjusting for potential covariates of age, ethnicity, past chlamydia infection, pregnancy history) in year one and two of follow up. RESULTS: Two thousand seven hundred and twenty nine women (44%) received a LARC and 1764 (28.6%) were prescribed oral contraception. Adjusted testing rates differed by contraceptive method only in year one (P < 0.01): with higher rates among copper intrauterine device users (relative risk (RR) 1.2, 95% CI 1.06-1.35), and lower rates for implant users (RR 0.84, 95% CI 0.72-0.99) compared with oral contraceptive users (reference group). No significant differences were observed in chlamydia diagnosis rates by contraceptive method (P > 0.05). Younger age, past chlamydia infection, Maori and Pacific ethnicity were associated with higher rates of chlamydia diagnosis (P < 0.01). CONCLUSIONS: Known STI-related risk factors (age, ethnicity, past infection) but not contraceptive method were independently related to rates of subsequent chlamydia diagnosis. This suggests that increased LARC uptake would not occur at the expense of chlamydia control. Regular screening and risk reduction advice (including condom use) are important chlamydia control measures for at-risk groups. PMID- 28832938 TI - Energetic cost of walking in fossil hominins. AB - OBJECTIVE: Many biomechanical studies consistently show that a broader pelvis increases the reaction forces and bending moments across the femoral shaft, increasing the energetic costs of unloaded locomotion. However, a biomechanical model does not provide the real amount of metabolic energy expended in walking. The aim of this study is to test the influence of pelvis breadth on locomotion cost and to evaluate the locomotion efficiency of extinct Pleistocene hominins. MATERIAL AND METHODS: The current study measures in vivo the influence of pelvis width on the caloric cost of locomotion, integrating anthropometry, body composition and indirect calorimetry protocols in a sample of 46 subjects of both sexes. RESULTS: We show that a broader false pelvis is substantially more efficient for locomotion than a narrower one and that the influence of false pelvis width on the energetic cost is similar to the influence of leg length. Two models integrating body mass, femur length and bi-iliac breadth are used to estimate the net and gross energetic costs of locomotion in a number of extinct hominins. The results presented here show that the locomotion of Homo was not energetically more efficient than that of Australopithecus and that the locomotion of extinct Homo species was not less efficient than that of modern Homo sapiens. DISCUSSION: The changes in the anatomy of the pelvis and lower limb observed with the appearance of Homo ergaster probably did not fully offset the increased expenditure resulting from a larger body mass. Moreover, the narrow pelvis in modern humans does not contribute to greater efficiency of locomotion. PMID- 28832939 TI - Reply to: Some Concerns About Diagnostic Test Accuracy for Infections. PMID- 28832937 TI - Systematic Review of Sex-Specific Reporting of Data: Cholinesterase Inhibitor Example. AB - OBJECTIVES: To improve the value of research for older adults, we examine sex specific reporting of data from drug trials for the management of dementia. These data are important because they may influence considerations ranging from the health of populations to shared decision-making by individual patient and caregiver about the risk and benefit of a drug therapy. METHODS: Randomized controlled trials of cholinesterase inhibitors (i.e., donepezil, rivastigmine, or galantamine) with clinical outcomes were identified from searches of MEDLINE, EMBASE, and the Cochrane Library. Sex-specific data were extracted from nine sections (title, abstract, introduction, methods, outcomes, results, discussion, limitations, and conclusion). Among the donepezil trials only, more detailed harms data were obtained. FINDINGS: Thirty-three randomized controlled trials were identified evaluating 15,971 participants (9,103 (57%) female). Trials were highly cited (median citations 158, interquartile range 62-441) and published in high impact journals (median impact factor 7.4, interquartile range 3.4-8.2). Sex was not mentioned in the title, introduction, limitations, or conclusion section of any trial. Only three trials (9%) mentioned sex in the abstract (all as a demographic characteristic), and 8 (24%) in the methods. Almost all (32 (97%)) trials mentioned sex in the results as a demographic variable. One trial reported a sex difference for a secondary outcome. Among the 16 trials studying donepezil, adverse events were frequently reported and often dose-related. No trial provided sex-specific reporting of adverse events. CONCLUSIONS: There is an almost complete lack of sex-specific reporting of data in clinical trials for dementia drug therapies, and no sex-specific reporting of adverse events. Sex-specific reporting of data should be required in drug trials to increase research value and ultimately inform more tailored prescribing for older adults. PMID- 28832940 TI - Is there a role for minimal residual disease monitoring in the management of patients with hairy-cell leukaemia? PMID- 28832941 TI - Major trauma in older people: implications for anaesthesia and intensive care medicine. PMID- 28832942 TI - Kinetics based reaction optimization of enzyme catalyzed reduction of formaldehyde to methanol with synchronous cofactor regeneration. AB - Enzymatic reduction of carbon dioxide (CO2 ) to methanol (CH3 OH) can be accomplished using a designed set-up of three oxidoreductases utilizing reduced pyridine nucleotide (NADH) as cofactor for the reducing equivalents electron supply. For this enzyme system to function efficiently a balanced regeneration of the reducing equivalents during reaction is required. Herein, we report the optimization of the enzymatic conversion of formaldehyde (CHOH) to CH3 OH by alcohol dehydrogenase, the final step of the enzymatic redox reaction of CO2 to CH3 OH, with kinetically synchronous enzymatic cofactor regeneration using either glucose dehydrogenase (System I) or xylose dehydrogenase (System II). A mathematical model of the enzyme kinetics was employed to identify the best reaction set-up for attaining optimal cofactor recycling rate and enzyme utilization efficiency. Targeted process optimization experiments were conducted to verify the kinetically modeled results. Repetitive reaction cycles were shown to enhance the yield of CH3 OH, increase the total turnover number (TTN) and the biocatalytic productivity rate (BPR) value for both system I and II whilst minimizing the exposure of the enzymes to high concentrations of CHOH. System II was found to be superior to System I with a yield of 8 mM CH3 OH, a TTN of 160 and BPR of 24 MUmol CH3 OH/U . h during 6 hr of reaction. The study demonstrates that an optimal reaction set-up could be designed from rational kinetics modeling to maximize the yield of CH3 OH, whilst simultaneously optimizing cofactor recycling and enzyme utilization efficiency. PMID- 28832944 TI - Biometrics, JABES and the International Biometric Society. PMID- 28832943 TI - CRISPRi repression of nonhomologous end-joining for enhanced genome engineering via homologous recombination in Yarrowia lipolytica. AB - In many organisms of biotechnological importance precise genome editing is limited by inherently low homologous recombination (HR) efficiencies. A number of strategies exist to increase the effectiveness of this native DNA repair pathway; however, most strategies rely on permanently disabling competing repair pathways, thus reducing an organism's capacity to repair naturally occurring double strand breaks. Here, we describe a CRISPR interference (CRISPRi) system for gene repression in the oleochemical-producing yeast Yarrowia lipolytica. By using a multiplexed sgRNA targeting strategy, we demonstrate efficient repression of eight out of nine targeted genes to enhance HR. Strains with nonhomologous end joining repressed were shown to have increased rates of HR when transformed with a linear DNA fragment with homology to a genomic locus. With multiplexed targeting of KU70 and KU80, and enhanced repression with Mxi1 fused to deactivated Cas9 (dCas9), rates of HR as high as 90% were achieved. The developed CRISPRi system enables enhanced HR in Y. lipolytica without permanent genetic knockouts and promises to be a potent tool for other metabolic engineering, synthetic biology, and functional genomics studies. PMID- 28832945 TI - Occurrence of osteon banding in adult human cortical bone. AB - OBJECTIVES: Differentiating human from nonhuman fragmented bone is often accomplished using histological methods if the observation of gross morphology proves insufficient. Linearly oriented primary and/or secondary osteonal systems, commonly referred to as osteon bands, are described as a strong indicator of nonhuman bone, particularly the occurrence of multiple bands. This phenomenon has been conventionally documented using two-dimensional (2D) histology, but such analyses are destructive and typically limited to a single cross-section. Progressive developments in high-resolution X-ray imaging, however, allow for the nondestructive three-dimensional (3D) visualization of bone microarchitecture. The primary objective of the current research was to visualize and document the occurrence of osteon banding in adult human cortical bone using high-resolution synchrotron radiation-based micro-Computed Tomography (SR micro-CT). MATERIALS AND METHODS: Synchrotron radiation-based micro-CT scanning was carried out at the Canadian Light Source (CLS) national synchrotron facility. The presence or absence of osteon banding was visualized in human skeletal elements from three adult males with representative samples from all regions of the skeleton (n = 129). If present, osteon banding was described and quantified. RESULTS: Results indicated that 23 of 129 human cortical bone specimens exhibited osteon banding, representing 18% of the sample. Linear arrangements of primary and/or secondary osteons were observed in the following skeletal elements: temporal, parietal, frontal, occipital, clavicle, mandible, femur, tibia, ulna, second metatarsal, and sacrum. DISCUSSION: The present work represents the first 3D examination of inter-element variation in osteon banding in adult human cortical bone. Findings indicate that the presence of multiple osteon bands in a single specimen is not diagnostic of nonhuman bone. As such, osteon banding categorically should not be taken as evidence of nonhuman bone in forensic and archaeological contexts. PMID- 28832946 TI - Codelivery of anti-cancer agents via double-walled polymeric microparticles/injectable hydrogel: A promising approach for treatment of triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is an aggressive sub-type of breast cancer that rarely responds to conventional chemotherapy. Therefore, novel agents or new routes need to be developed to improve treatment efficacy and diminish severe side-effects of anti-cancer agents in TNBC patients. This study explores a novel localized co-delivery platform with potential application against TNBC. Uniform core-shell microparticles encapsulating cisplatin (Cis-DDP) and paclitaxel (PTX) are fabricated using coaxial electrohydrodynamic atomization technique and subsequently are embedded into an injectable hydrogel. The hydrogel provides an additional diffusion barrier against Cis-DDP and confines premature release of drugs. In addition, the hydrogel can provide a versatile tool for retaining particles in the tumor resected cavity during the injection following debulking surgery and prevent surgical site infection due to its inherent antibacterial properties. The combination of Cis-DDP and PTX demonstrates a synergistic effect against MDA-MB-231 cell line assigned to three different mechanisms of action, including denaturation of DNA strands, stabilization of microtubules, and amplification of intracellular reactive oxygen species (ROS) and activation of caspase-3 pathways. The results show a significant accumulation of mitochondrial ROS insults in cells upon treatment that consequently causes programmed cells death. The performance of microparticles/hydrogel carrier is evaluated against three-dimensional MDA-MB-231 (breast cancer) 3D spheroids, where a superior efficacy and a greater reduction in spheroid growth are observed over 14 days, as compared with free-drug treatment. Overall, drug-loaded core-shell microparticles embedded into injectable hydrogel provides a promising strategy to treat aggressive cancers and a modular platform for a broad range of localized multidrug therapies customizable to the cancer type. PMID- 28832947 TI - The significance of serum immunoglobulin paraprotein in diffuse large B-cell lymphoma. PMID- 28832948 TI - Diagnosis of CLL revisited: increased specificity by a modified five-marker scoring system including CD200. AB - The modified Matutes score has been the basis for the diagnosis of chronic lymphocytic leukaemia (CLL) by flow cytometry for the past 15 years. To increase the specificity of the current score we systematically evaluated the diagnostic value of established as well as novel markers, such as CD200, in a large cohort of patients with untreated B-cell malignancies (n = 370). Double positivity for CD5 and CD23 was of very high value to differentiate between CLL and non-CLL cases. In addition, lack of FMC7 expression as well as CD79b expression intensity showed high sensitivity (90.4% and 92.3%) with acceptable specificity (74.4% and 76.9%). For surface IgM, low or absent expression displayed poor specificity in distinguishing CLL from non-CLL cases (51,3%; sensitivity 83,7%). Finally, CD200 positivity showed high sensitivity and specificity. Therefore, CD5/CD23, FMC7, CD79b and CD200 were included in our new CLLflow score, which retained high sensitivity (97.1% vs. 98.6% for the Matutes score, P = 0.38), but showed markedly increased specificity (87.2% vs. 53.8%, P < 0.001). These results were confirmed in our validation cohort (sensitivity 97.0% vs. 100%, P = not applicable; specificity 86.4% vs. 59.1%, P = 0.03). Our data support the use of our new CLLflow score for the diagnosis of CLL with significantly higher specificity. PMID- 28832949 TI - A metabolic engineering strategy for producing free fatty acids by the Yarrowia lipolytica yeast based on impairment of glycerol metabolism. AB - In recent years, bio-based production of free fatty acids from renewable resources has attracted attention for their potential as precursors for the production of biofuels and biochemicals. In this study, the oleaginous yeast Yarrowia lipolytica was engineered to produce free fatty acids by eliminating glycerol metabolism. Free fatty acid production was monitored under lipogenic conditions with glycerol as a limiting factor. Firstly, the strain W29 (Deltagpd1), which is deficient in glycerol synthesis, was obtained. However, W29 (Deltagpd1) showed decreased biomass accumulation and glucose consumption in lipogenic medium containing a limiting supply of glycerol. Analysis of substrate utilization from a mixture of glucose and glycerol by the parental strain W29 revealed that glycerol was metabolized first and glucose utilization was suppressed. Thus, the Deltagpd1Deltagut2 double mutant, which is deficient also in glycerol catabolism, was constructed. In this genetic background, growth was repressed by glycerol. Oleate toxicity was observed in the Deltagpd1Deltagut2Deltapex10 triple mutant strain which is deficient additionally in peroxisome biogenesis. Consequently, two consecutive rounds of selection of spontaneous mutants were performed. A mutant released from growth repression by glycerol was able to produce 136.8 mg L-1 of free fatty acids in a test tube, whereas the wild type accumulated only 30.2 mg L-1 . Next, an isolated oleate resistant strain produced 382.8 mg L-1 of free fatty acids. Finely, acyl-CoA carboxylase gene (ACC1) over-expression resulted to production of 1436.7 mg L-1 of free fatty acids. The addition of dodecane promoted free fatty acid secretion and enhanced the level of free fatty acids up to 2033.8 mg L-1 during test tube cultivation. PMID- 28832950 TI - Engineered T cells towards TNFRSF13C (BAFFR): a novel strategy to efficiently target B-cell acute lymphoblastic leukaemia. PMID- 28832951 TI - Comparative analysis of plant-produced, recombinant dimeric IgA against cell wall beta-glucan of pathogenic fungi. AB - Immunoglobulins A (IgA) are crucially involved in protection of human mucosal surfaces from microbial pathogens. In this work, we devised and expressed in plants recombinant chimeric antifungal antibodies (Abs) of isotype A (IgA1, IgA2, and scFvFcA1), derived from a murine mAb directed to the fungal cell wall polysaccharide beta-glucan which had proven able to confer protection against multiple pathogenic fungi. All recombinant IgA (rIgA) were expressed and correctly assembled in dimeric form in plants and evaluated for yield, antigen binding efficiency and antifungal properties in vitro, in comparison with a chimeric IgG1 version. Production yields and binding efficiency to purified beta glucans showed significant variations not only between Abs of different isotypes but also between the different IgA formats. Moreover, only the dimeric IgA1 was able to strongly bind cells of the fungal pathogen Candida albicans and to restrain its adhesion to human epithelial cells. Our data indicate that IgG to IgA switch and differences in molecular structure among different rIgA formats can impact expression in plant and biological activity of anti-beta-glucans Abs and provide new insights for the design of recombinant IgA as anti-infective immunotherapeutics, whose potential is still poorly investigated. PMID- 28832952 TI - Optical transfer diagnosis differentiating benign and malignant pigmented lesions in a simulated primary care practice. AB - BACKGROUND: The detection of melanoma poses a substantial challenge, particularly for primary care providers (PCPs) who may have limited training in discriminating between suspicious and benign melanocytic lesions. The noninvasive optical transfer diagnosis (OTD) method was designed to be used by PCPs in their decision making process. OBJECTIVES: To assess the potential of the OTD method by developing, training and validating an OTD indication algorithm for automated discrimination between benign melanocytic lesions and malignant lesions, based on a set of 712 lesions. METHODS: The authors performed in vivoOTD capture and subsequent analysis of 712 pigmented lesions. Of the lesions, 415 were clinically and dermoscopically benign and 297 were dermoscopically suspicious or equivocal. After image capture, all suspicious or equivocal lesions were biopsied and examined histopathologically. RESULTS: Of the 297 suspicious or equivocal lesions, histopathological findings revealed 80 to be malignant (64 melanomas, 13 basal cell carcinomas and 3 squamous cell carcinomas). OTD misdiagnosed one of the 80 malignant lesions as benign (sensitivity, 99%). OTD specificity was 93% for the dermoscopically benign lesions, 73% for all lesions included in the study and 36% for the clinically suspicious but histopathologically benign lesions. CONCLUSIONS: High sensitivity and specificity, as provided by OTD in this preliminary study, would help PCPs reduce the number of referrals for dermatology consultation, excision or biopsy. Further studies are planned for screening patients in a primary care setting, with comparisons of OTD results with biopsy or dermoscopy results. PMID- 28832953 TI - Colchicine: an ancient drug with novel applications. AB - Colchicine is a treatment for gout that has been used for more than a millennium. It is the treatment of choice for familial Mediterranean fever and its associated complication, amyloidosis. The 2009 U.S. Food and Drug Administration approval of colchicine as a new drug had research consequences. Recent investigations with large cohorts of patients with gout who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology. Some emerging dermatological uses include the treatment of epidermolysis bullosa acquisita, leucocytoclastic vasculitis, aphthous stomatitis and others. In this work we relate the history and the new horizon of this ancient medicine. PMID- 28832954 TI - Triradial and quadriradial chromosomes detected in a case of B-cell prolymphocytic leukaemia. PMID- 28832955 TI - Cutaneous lupus erythematosus: quality of life and related factors in a cohort of 260 patients from A Coruna, Spain. PMID- 28832956 TI - Early-stage Hodgkin lymphoma outcomes after combined modality therapy according to the post-chemotherapy 5-point score: can residual pet-positive disease be cured with radiotherapy alone? AB - Early-stage classical Hodgkin lymphoma (HL) patients are evaluated by an end-of chemotherapy positron emission tomography-computed tomography (eoc-PET-CT) after doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and before radiation therapy (RT). We determined freedom from progression (FFP) in patients treated with ABVD and RT according to the eoc-PET-CT 5-point score (5PS). Secondarily, we assessed whether patients with a positive eoc-PET-CT (5PS of 4-5) can be cured with RT alone. The cohort comprised 174 patients treated for stage I-II HL with ABVD and RT alone. ABVD was given with a median of four cycles and RT with a median dose of 30.6 Gy. Five-year FFP was 97%. Five-year FFP was 100% (0 relapses/98 patients) for patients with a 5PS of 1-2, 97% (2/65) for a 5PS of 3, 83% (1/8) for a 5PS of 4, and 67% (1/3) for a 5PS of 5 (P < 0.001). Patients with positive eoc-PET-CT scans who were selected for salvage RT alone had experienced a very good partial response to ABVD. Risk factors for recurrence in this subgroup included a small reduction in tumour size and a 'bounce' in >=1 PET-CT parameter (reduction then rise from interim to final scan). Thus, a positive eoc PET-CT is associated with inferior FFP; however, appropriately selected patients can be cured with RT alone. PMID- 28832958 TI - The role of heparin in sepsis: much more than just an anticoagulant. AB - Despite progress in antibiotic treatment, mechanical ventilation, fluid resuscitation and blood glucose maintenance, sepsis remains a cause of high mortality in the intensive care unit to date, there are no proven treatment strategies for the routine management of septic patients. The extensive interaction between inflammation and coagulation contributes to the basic pathophysiology of sepsis. Thus, the agents that attenuate the activation of both inflammation and coagulation may improve the outcome in sepsis. Apart from the well-known anticoagulant effects of heparin, it also possesses various immunomodulatory properties and protects glycocalyx from shedding. Hence, heparin seems to be such an agent. Immunothrombosis plays an important role in early host defence against bacterial dissemination, thus the proper timing for anticoagulant therapy should be determined. We review the available experimental and clinical data supporting the use of heparin in sepsis. At this time the use of heparin in the treatment of sepsis is conflicting. Future trials of heparin therapy for sepsis should concentrate on the very severely ill patients, in whom benefit is most likely to be demonstrated. PMID- 28832957 TI - Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies. AB - Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18.6, 12.8 and 25.0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non-blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0-1, non-bulky disease and non-blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease. PMID- 28832959 TI - Real world data of the impact of first cycle daratumumab on multiple myeloma and AL amyloidosis services. PMID- 28832960 TI - Comparison of pyoderma gangrenosum and Martorell hypertensive ischaemic leg ulcer in a Swiss cohort. PMID- 28832961 TI - Risk of death from breast cancer after treatment for ductal carcinoma in situ. AB - BACKGROUND: Studies to date have failed to demonstrate any survival benefit from preventing local recurrence after treatment for ductal breast carcinoma in situ (DCIS). Patient- and tumour-related risk factors for death from breast cancer in women with a primary DCIS were analysed here in a large case-control study. METHODS: A nested case-control study was conducted in a population-based cohort of women with primary DCIS between 1992 and 2012. Women who later died from breast cancer were identified. Four controls per case were selected randomly by incidence density sampling. Medical records and pathology reports were retrieved. Conditional logistic regression was used to calculate odds ratios (ORs) and 95 per cent confidence intervals for risk of death from breast cancer. RESULTS: From a cohort of 6964 women, 96 who died from breast cancer were identified and these were compared with a group of 318 controls. Tumour size over 25 mm or multifocal DCIS (OR 2.55, 95 per cent c.i. 1.53 to 4.25), a positive or uncertain margin status (OR 3.91, 1.59 to 9.61) and detection outside the screening programme (OR 2.12, 1.16 to 3.86) increased the risk of death from breast cancer. The risks were not affected by age or type of treatment. In the multivariable analysis, tumour size (OR 1.95, 1.06 to 3.67) and margin status (OR 2.69, 1.15 to 7.11) remained significant. CONCLUSION: In the present study, large tumour size and positive or uncertain margin status were associated with a higher risk of death from breast cancer after treatment for primary DCIS. More extensive treatment was not associated with lower risk, which may be due to confounding by indication, or indicate that some DCIS has an inherent potential for metastatic spread. PMID- 28832962 TI - Rubiarbonone C inhibits platelet-derived growth factor-induced proliferation and migration of vascular smooth muscle cells through the focal adhesion kinase, MAPK and STAT3 Tyr705 signalling pathways. AB - BACKGROUND AND PURPOSE: The proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor (PDGF) are important steps in cardiovascular diseases, including neointimal lesion formation, myocardial infarction and atherosclerosis. Here, we evaluated the rubiarbonone C mediated signalling pathways that regulate PDGF-induced VSMC proliferation and migration. EXPERIMENTAL APPROACH: Cell proliferation and migration were measured in cells treated with rubiarbonone C followed by PDGF BB using the MTT assay, [3 H]-thymidine incorporation, flow cytometry and wound-healing migration assay, MMP gelatin zymography, a fluorescence assay for F-actin. Western blotting of molecules including MAPK, focal adhesion kinase (FAK) and STAT3 and an immunofluorescence assay using anti-PCNA and -STAT3 antibodies were performed to evaluate rubiarbonone C signalling pathway(s). The medial thickness of the carotid artery was evaluated using a mouse carotid ligation model. KEY RESULTS: Rubiarbonone C inhibited PDGF-induced VSMC proliferation and migration and diminished the ligation-induced increase in medial thickness of the carotid artery. In PDGF-stimulated VSMCs rubiarbonone C decreased the following: (i) levels of cyclin-dependent kinases, cyclins, PCNA and hyperphosphorylated retinoblastoma protein; (ii) levels and activity of MMP2 and MMP9; (iii) activation of MAPK; (iv) F-actin reorganization, by reducing FAK activation; (v) activation of STAT3. CONCLUSIONS AND IMPLICATIONS: These findings suggest that rubiarbonone C inhibits the proliferation and migration of VSMCs by inhibiting the FAK, MAPK and STAT3 signalling pathways. Therefore, rubiarbonone C could be a good candidate for the treatment of cardiovascular disease. PMID- 28832964 TI - Nationwide outcomes in patients undergoing surgical exploration without resection for pancreatic cancer. AB - BACKGROUND: Despite improvements in diagnostic imaging and staging, unresectable pancreatic cancer is still encountered during surgical exploration with curative intent. This nationwide study investigated outcomes in patients with unresectable pancreatic cancer found during surgical exploration. METHODS: All patients diagnosed with primary pancreatic (adeno)carcinoma (2009-2013) in the Netherlands Cancer Registry were included. Predictors of unresectability, 30-day mortality and poor survival were evaluated using logistic and Cox proportional hazards regression analysis. RESULTS: There were 10 595 patients with pancreatic cancer during the study interval. The proportion of patients undergoing surgical exploration increased from 19.9 to 27.0 per cent (P < 0.001). Among 2356 patients who underwent surgical exploration, the proportion of patients with tumour resection increased from 61.6 per cent in 2009 to 71.3 per cent in 2013 (P < 0.001), whereas the contribution of M1 disease (18.5 per cent overall) remained stable. Patients who had exploration only had an increased 30-day mortality rate compared with those who underwent tumour resection (7.8 versus 3.8 per cent; P < 0.001). In the non-resected group, among those with M0 (383 patients) and M1 (435) disease at surgical exploration, the 30-day mortality rate was 4.7 and 10.6 per cent (P = 0.002), median survival was 7.2 and 4.4 months (P < 0.001), and 1 year survival rates were 28.0 and 12.9 per cent, respectively. Among other factors, low hospital volume (0-20 resections per year) was an independent predictor for not undergoing tumour resection, but also for 30-day mortality and poor survival among patients without tumour resection. CONCLUSION: Exploration and resection rates increased, but one-third of patients who had surgical exploration for pancreatic cancer did not undergo resection. Non-resectional surgery doubled the 30-day mortality rate compared with that in patients undergoing tumour resection. PMID- 28832965 TI - Self-Construals and Social Adjustment in Immigrant and Nonimmigrant Early Adolescents: The Moderating Role of Executive Functioning. AB - This study examined whether executive functions (EFs) moderate the association between independent and interdependent self-construals and social adjustment in 488 Moroccan, Romanian, and Italian preadolescents (ages 11-13) in Italy. Participants were assessed using self-report questionnaires and standardized EF tasks. Better working memory was related to increased social competence across all groups. High levels of inhibitory control were found to enhance the positive relation between interdependence and prosocial behavior for native Italian youth, and between interdependence and social competence for Moroccan preadolescents. High levels of cognitive flexibility boosted the interdependence-social competence link for the immigrant groups, whereas among native Italian preadolescents, the interdependence-social competence link was significant at low levels of flexibility. Implications for developmental theory and practice are discussed. PMID- 28832963 TI - The role of the red blood cell in host defence against falciparum malaria: an expanding repertoire of evolutionary alterations. AB - The malaria parasite has co-evolved with its human host as each organism struggles for resources and survival. The scars of this war are carried in the human genome in the form of polymorphisms that confer innate resistance to malaria. Clinical, epidemiological and genome-wide association studies have identified multiple polymorphisms in red blood cell (RBC) proteins that attenuate malaria pathogenesis. These include well-known polymorphisms in haemoglobin, intracellular enzymes, RBC channels, RBC surface markers, and proteins impacting the RBC cytoskeleton and RBC morphology. A better understanding of how changes in RBC physiology impact malaria pathogenesis may uncover new strategies to combat the disease. PMID- 28832966 TI - Magnetic resonance imaging in acaeruloplasminaemia - a rare differential diagnosis of microcytic anaemia with iron overload. PMID- 28832967 TI - Making the grade: The newest US Preventive Services Task Force prostate cancer screening recommendation. PMID- 28832968 TI - Motives of corporate political donations: industry regulation, subjective judgement and the origins of pragmatic and ideological corporations. AB - What motivates corporate political action? Are corporations motivated by their own narrow economic self-interest; are they committed to pursuing larger class interests; or are corporations instruments for status groups to pursue their own agendas? Sociologists have been divided over this question for much of the last century. This paper introduces a novel case - that of Australia - and an extensive dataset of over 1,500 corporations and 7,500 directors. The paper attempts to understand the motives of corporate political action by examining patterns of corporate political donations. Using statistical modelling, supported by qualitative evidence, the paper argues that, in the Australian case, corporate political action is largely motivated by the narrow economic self-interest of individual corporations. Firms' interests are, consistent with regulatory environment theory, defined by the nature of government regulation in their industry: those in highly regulated industries (such as banking) and those dependent on government support (such as defence) tend to adopt a strategy of hedging their political support, and make bipartisan donations (to both major parties). In contrast, firms facing hostile regulation (such as timber or mining), and those without strong dependence on state support (such as small companies) tend to adopt a strategy of conservative partisanship, and make conservative-only donations. This paper argues that regulatory environment theory needs to be modified to incorporate greater emphasis on the subjective political judgements of corporations facing hostile regulation: a corporation's adoption of conservative partisanship or hedging is not just a product of the objective regulation they face, but also whether corporate leaders judge such regulation as politically inevitable or something that can be resisted. Such a judgement is highly subjective, introducing a dynamic and unpredictable dimension to corporate political action. PMID- 28832969 TI - Little Evidence That Socioeconomic Status Modifies Heritability of Literacy and Numeracy in Australia. AB - Socioeconomic status (SES) has been found to moderate the influence of genes and the environment on cognitive ability, such that genetic influence is greater when SES is higher, and the shared environment is greater when SES is lower, but not in all Western countries. The effects of both family and school SES on the heritability of literacy and numeracy in Australian twins aged 8, 10, 12, and 14 years with 1,307, 1,235, 1,076, and 930 pairs at each age, respectively, were tested. Shared environmental influences on Grade 3 literacy were greater with low family SES, and no other moderating effects of SES were significant. These findings are contrasted with results from the United States and the United Kingdom. PMID- 28832970 TI - Differential binding of tetrodotoxin and its derivatives to voltage-sensitive sodium channel subtypes (Nav 1.1 to Nav 1.7). AB - BACKGROUND AND PURPOSE: The development of subtype-selective ligands to inhibit voltage-sensitive sodium channels (VSSCs) has been attempted with the aim of developing therapeutic compounds. Tetrodotoxin (TTX) is a toxin from pufferfish that strongly inhibits VSSCs. Many TTX analogues have been identified from marine and terrestrial sources, although their specificity for particular VSSC subtypes has not been investigated. Herein, we describe the binding of 11 TTX analogues to human VSSC subtypes Nav 1.1-Nav 1.7. EXPERIMENTAL APPROACH: Each VSSC subtype was transiently expressed in HEK293T cells. The inhibitory effects of TTX analogues on each subtype were assessed using whole-cell patch-clamp recordings. KEY RESULTS: The inhibitory effects of TTX on Nav 1.1-Nav 1.7 were observed in accordance with those reported in the literature; however, the 5-deoxy-10,7 lactone-type analogues and 4,9-anhydro-type analogues did not cause inhibition. Chiriquitoxin showed less binding to Nav 1.7 compared to the other TTX-sensitive subtypes. Two amino acid residues in the TTX binding site of Nav 1.7, Thr1425 and Ile1426 were mutated to Met and Asp, respectively, because these residues were found at the same positions in other subtypes. The two mutants, Nav 1.7 T1425M and Nav 1.7 I1426D, had a 16-fold and 5-fold increase in binding affinity for chiriquitoxin, respectively. CONCLUSIONS AND IMPLICATIONS: The reduced binding of chiriquitoxin to Nav 1.7 was attributed to its C11-OH and/or C12-NH2 , based on reported models for the TTX-VSSC complex. Chiriquitoxin is a useful tool for probing the configuration of the TTX binding site until a crystal structure for the mammalian VSSC is solved. PMID- 28832972 TI - On assessing the effect of breast cancer screening schemes. PMID- 28832971 TI - Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar-to-ductal metaplasia. AB - BACKGROUND AND PURPOSE: Pancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. EXPERIMENTAL APPROACH: We analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS 275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants. KEY RESULTS: HDAC expression and activity were up regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly disrupted macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell autonomous manner by impeding the EGF receptor signalling axis. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease. PMID- 28832974 TI - Role of mitochondrial membrane permeabilization and depolarization in platelet apoptosis. PMID- 28832973 TI - Longitudinal Trajectories of Family Functioning Among Recent Immigrant Adolescents and Parents: Links With Adolescent and Parent Cultural Stress, Emotional Well-Being, and Behavioral Health. AB - This study examined longitudinal effects of adolescent and parent cultural stress on adolescent and parent emotional well-being and health behaviors via trajectories of adolescent and parent family functioning. Recent immigrant Latino adolescents (Mage = 14.51) and parents (Mage = 41.09; N = 302) completed measures of these constructs. Latent growth modeling indicated that adolescent and parent family functioning remained stable over time. Early levels of family functioning predicted adolescent and parent outcomes. Baseline adolescent cultural stress predicted lower positive adolescent and parent family functioning. Latent class growth analyses produced a two-class solution for family functioning. Adolescents and parents in the low family functioning class reported low family functioning over time. Adolescents and parents in the high family functioning class experienced increases in family functioning. PMID- 28832977 TI - "Wealth Makes Many Friends": Children Expect More Giving From Resource-Rich Than Resource-Poor Individuals. AB - Young children show social preferences for resource-rich individuals, although few studies have explored the causes underlying such preferences. We evaluate the viability of one candidate cause: Children believe that resource wealth relates to behavior, such that they expect the resource rich to be more likely to materially benefit others (including themselves) than the resource poor. In Studies 1 and 2 (ages 4-10), American children from predominantly middle-income families (n = 94) and Indian children from lower income families (n = 30) predicted that the resource rich would be likelier to share with others than the resource poor. In Study 3, American children (n = 66) made similar predictions in an incentivized decision-making task. The possibility that children's expectations regarding giving contribute to prowealth preferences is discussed. PMID- 28832975 TI - Close Friendship Strength and Broader Peer Group Desirability as Differential Predictors of Adult Mental Health. AB - Middle adolescents' close friendship strength and the degree to which their broader peer group expressed a preference to affiliate with them were examined as predictors of relative change in depressive symptoms, self-worth, and social anxiety symptoms from ages 15 to 25 using multimethod, longitudinal data from 169 adolescents. Close friendship strength in midadolescence predicted relative increases in self-worth and decreases in anxiety and depressive symptoms by early adulthood. Affiliation preference by the broader peer group, in contrast, predicted higher social anxiety by early adulthood. Results are interpreted as suggesting that adolescents who prioritize forming close friendships are better situated to manage key social developmental tasks going forward than adolescents who prioritize attaining preference with many others in their peer milieu. PMID- 28832976 TI - A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma. AB - BACKGROUND: ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1. METHODS: A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m2 ) and nab-paclitaxel (125 mg/m2 ) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m2 weekly (cohort 1) or at 36 mg/m2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine. RESULTS: Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached). CONCLUSIONS: ADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017;123:4556-4565. (c) 2017 American Cancer Society. PMID- 28832980 TI - Nationwide skin cancer screening in Germany: Evaluation of the training program. AB - BACKGROUND: In July 2008, the German statutory health insurance introduced a nationwide skin cancer screening program. Before the introduction, eligible physicians had to qualify to perform the screening test and counsel their patients on skin cancer screening. To educate physicians, a curriculum and training materials were developed. Since 2015 a revised curriculum and training materials have been used. The purpose of this paper is to provide information about the curriculum and to evaluate the revised training program. METHODS: A total of 573 completed pre- and posttests were analyzed with regard to changes in the identification of skin cancer, diagnostic accuracy, knowledge, and physicians' self-assessed-confidence. For statistical analysis, Mann-Whitney U test, Cohen's d, and chi-square test were used. RESULTS: General practitioners (GPs) diagnosed 7.45 of 12 skin lesions correctly before and 9.26 after the training course (P < 0.001). Compared to GPs, dermatologists' accuracy was higher at pre- and posttest (pre: 10.03, post: 10.21, P = 0.160). The mean of correctly answered questions increased significantly in knowledge on screening and early detection (4.46-5.14, P < 0.001) as well as skin cancer and skin cancer screening (5.51-6.39, P < 0.001). CONCLUSION: Participating physicians got a comprehensive understanding of skin cancer screening and counseling through the training and increased their diagnostic skills. In particular, GPs identified and diagnosed significantly more skin lesions correctly after the training compared to before the training, while dermatologists' diagnostic skills were high at both times, before and after. PMID- 28832981 TI - Interim FDG-PET has no value in selecting patients who require treatment modification in both early- and advanced-stage Hodgkin lymphoma: response to Adams and Kwee. PMID- 28832978 TI - Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer. AB - BACKGROUND: Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab. METHODS: Eligible patients with metastatic RCC who had previously received 1 to 4 prior lines of therapy, including VEGF-targeted agents, were randomized 1:1 to receive bevacizumab 10 mg/kg intravenously every 2 weeks (arm A) or the same plus TRC105 10 mg/kg intravenously every 2 weeks (arm B). The primary endpoint was progression-free survival (PFS) at 12 and 24 weeks. Correlative studies included serum transforming growth factor beta (TGFbeta) and CD105 levels as well as tissue immunostaining for TGFbeta receptors. RESULTS: Fifty-nine patients were enrolled (28 on arm A and 31 on arm B), and 1 patient on each arm had a confirmed partial response. The median PFS for bevacizumab alone was 4.6 months compared with 2.8 for bevacizumab plus TRC105 (P = .09). Grade >= 3 toxicities occurred in 16 patients (57%) who received bevacizumab compared with 19 (61%) who received bevacizumab plus TRC105 (P = .9). Baseline serum TGFbeta levels below the median (<10.6 ng/mL) were associated with longer median PFS (5.6 vs 2.1 months; P = .014). CONCLUSIONS: TRC105 failed to improve PFS when added to bevacizumab. TGFbeta warrants further study as a biomarker in RCC. Cancer 2017;123:4566-4573. (c) 2017 American Cancer Society. PMID- 28832979 TI - Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation. AB - BACKGROUND: The immune profile of sarcomatoid renal cell carcinoma (sRCC), including the programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) status, has not been well characterized. METHODS: An immunohistochemical digital analysis of PD-L1, PD-1, CD4, and CD8 was performed on nephrectomy specimens from 118 sRCC patients and 92 nonsarcomatoid clear cell renal cell carcinoma (ccRCC) patients. The clinical characteristics of the population were compared between sRCC and ccRCC. Overall survival was estimated, and comparisons were made between PD-L1-positive and PD-L1-negative groups as well as tumor infiltrating lymphocyte (TIL)-high and TIL-low groups. RESULTS: The PD-L1 H-score of sRCC (mean, 3.7; range, 0-192.1) was significantly higher than the score of grade 4 ccRCC (P = .001), and 41.3% of sRCC cases showed a PD-L1 H-score >= 10. The PD-1-positive cell density was significantly higher in sRCC versus ccRCC within the tumor and at the invasive front. The intratumoral CD8-positive cell density was significantly higher in sRCC versus ccRCC. Forty-one percent in the sarcomatoid component of sRCC and 8% in the epithelioid component of sRCC had an adaptive immune resistance phenotype (PD-L1-positive and TIL-positive), whereas only 1% in ccRCC had the type I phenotype. CONCLUSIONS: sRCC showed higher PD-L1 expression and higher PD-1- and CD8-positive cell density than grade 4 ccRCC. The results indicate a notable immunosuppressive environment in sRCC. Despite advances in the treatment of advanced-stage renal cell carcinoma, sRCC still has a poor prognosis. This work describes highly immunosuppressive characteristics of sRCC in comparison with an appropriate ccRCC control. The results suggest PD-1/PD L1 blockade therapy as a potential therapeutic approach for sRCC. Cancer 2017;123:4823-31. (c) 2017 American Cancer Society. PMID- 28832982 TI - Mothers' Physiological and Affective Responding to Infant Distress: Unique Antecedents of Avoidant and Resistant Attachments. AB - In a sample of 127 mother-infant dyads, this study examined the predictive significance of mothers' physiological and observed emotional responding within distressing and nondistressing caregiving contexts at 6 months for infant attachment assessed with Fraley and Spieker's (2003) dimensional approach and the categorical approach at 12 months. Findings revealed that a lesser degree of maternal respiratory sinus arrhythmia withdrawal and higher levels of maternal neutral (vs. positive) affect within distressing (vs. nondistressing) caregiving contexts were distinctive antecedents of avoidance versus resistance assessed dimensionally (but not categorically), independent of maternal sensitivity. Discussion focuses on the usefulness of examining mothers' physiological and affective responding, considering the caregiving context, and employing the dimensional approach to attachment in identifying unique antecedents of patterns of attachment insecurity. PMID- 28832983 TI - Comparison of recommendations for screening mammography using CISNET models. AB - BACKGROUND: Currently, there are several different recommendations for screening mammography from major national health care organizations, including: 1) annual screening at ages 40 to 84 years; 2) screening annually at ages 45 to 54 years, then biennially at ages 55 to 79 years; and 3) biennial screening at ages 50 to 74 years. METHODS: Mean values of six Cancer Intervention and Surveillance Modeling Network (CISNET) models were used to compare these three screening mammography recommendations in terms of benefits and risks. RESULTS: Mean mortality reduction was greatest with the recommendation of annual screening at ages 40 to 84 years (39.6%), compared with the hybrid recommendation of screening annually at ages 45 to 54 years, then biennially at ages 55 to 79 years (30.8%), and the recommendation of biennial screening at ages 50 to 74 years (23.2%). For a single-year cohort of US women aged 40 years, assuming 100% compliance, more breast cancers deaths would be averted over their lifetime with annual screening starting at age 40 (29,369) than with the hybrid recommendation (22,829) or biennial screening ages 50-74 (17,153 based on 2009 CISNET estimates, 15,599 based on 2016 CISNET estimates). To achieve the greatest mortality benefit, this single-year cohort of women would have the greatest total number of screening mammograms, benign recalls, and benign biopsies performed over the course of screening by following annual screening starting at age 40 years (90.2 million, 6.8 million, and 481,269, respectively) than by following the hybrid recommendation (49.0 million, 4.1 million, and 286,288, respectively) or biennial screening at ages 50 to 74 years (27.3 million, 2.3 million, and 162,885, respectively). CONCLUSION: CISNET models demonstrate that the greatest mortality reduction is achieved with annual screening of women starting at age 40 years. Cancer 2017;123:3673-3680. (c) 2017 American Cancer Society. PMID- 28832985 TI - Aggressive digital papillary adenocarcinoma: treatment with Mohs micrographic surgery and an update of the literature. AB - BACKGROUND: Aggressive digital papillary adenocarcinoma (ADPA) is a rare adenocarcinoma of the sweat glands. AIMS: We wish to report the treatment of two cases of ADPA with Mohs micrographic surgery and review the presentation, management, and prognosis of this rare malignancy. MATERIALS & METHODS: Cases of ADPA were identified from recent surgery logs. Demographic, tumor, and treatment characteristics were extracted. A PubMed database search for English language full-text articles of aggressive digital papillary adenocarcinoma was performed, and relevant articles were summarized. RESULTS: Two cases of ADPA were identified. A 53-year-old man presented with ADPA on his right third fingernail, and a 65-year-old man presented with ADPA on his right thumb. Both patients underwent Mohs micrographic surgery and negative sentinel lymph node biopsy, remaining recurrence free at 34 and 9 months, respectively. DISCUSSION: ADPA frequently presents as a solitary mass on the digit. Treatment of ADPA with local excision or amputation has historically been fraught with high recurrence rates. Regional lymph node spread and distant metastasis have been reported. Mohs micrographic surgery may be an alternative treatment for ADPA. CONCLUSION: Mohs micrographic surgery is a viable option for ADPA and warrants further exploration. Long-term follow-up is important, and additional studies will need to identify the role of sentinel lymph node biopsy. PMID- 28832984 TI - Receipt of definitive therapy in elderly patients with unfavorable-risk prostate cancer. AB - BACKGROUND: Conservative management of aggressive prostate cancer in the elderly without definitive therapy has been associated with a 10-year prostate cancer specific mortality of approximately 50%. The authors examined the prevalence of definitive therapy in elderly patients with intermediate-risk or high-risk disease. METHODS: 411,343 patients who were diagnosed from 2004 through 2012 with intermediate-risk or high-risk prostate cancer were identified in the National Cancer Database. Multivariable logistic regression adjusting for sociodemographic characteristics and comorbidity was used to examine the association between age and receipt of definitive therapy, defined as radical prostatectomy or radiotherapy, and of primary androgen deprivation therapy (ADT) among patients who did not receive definitive therapy. RESULTS: In total, 87.1% of high-risk patients and 91.9% of intermediate-risk patients received definitive therapy. When stratified by age, 93.7%, 92.1%, 90.8%, 87.6%, 80.9%, and 55.2% of high-risk patients and 96.1%, 94.7%, 93.4%, 89.7%, 82.7%, and 62.8% of intermediate-risk patients ages <60, 60 to 64, 65 to 69, 70 to 74, 75 to 79, and >=80 years received definitive therapy, respectively. For both high-risk and intermediate risk patients, increasing age was significantly associated with a decreased likelihood of receiving definitive therapy overall (both P < .001) and a greater likelihood of receiving primary ADT among those who did not receive definitive therapy (both P < .001). CONCLUSIONS: Older age was significantly associated with a decreased likelihood of receiving definitive therapy and an increased likelihood of receiving primary ADT in this national cohort of patients with intermediate-risk or high-risk prostate cancer. Notably, approximately 40% to 45% of patients aged >=80 years did not receive definitive therapy. These findings are alarming given the dismal outcomes of conservatively managed unfavorable-risk prostate cancer. Cancer 2017;123:4832-40. (c) 2017 American Cancer Society. PMID- 28832986 TI - Results of a prospective phase 2 study of pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma. AB - BACKGROUND: This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma. METHODS: Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression free rate (PFR) at 12 weeks (PFR12). RESULTS: Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy. CONCLUSIONS: The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. (c) 2017 American Cancer Society. PMID- 28832987 TI - Neural substrate and clinical significance of general movements: an update. AB - : General movements are present from early fetal life to 3 to 5 months corrected age. Atypical general movements, especially in the last, so-called fidgety general movement phase, are predictive of cerebral palsy (CP). This review updates knowledge on the neural substrate and clinical significance of typical and atypical general movements. Typical general movements are primarily characterized by complexity and variation. Presumably these core characteristics are initially induced by modulating activity of the cortical subplate. When the subplate gradually dissolves between 3 months before term and 3 months corrected age the cortical plate takes over. This coincides with the fidgety general movement phase. Conceivably, fidgety activity reflects 'sparsification', i.e. fragmentation of cortical network activity. The quintessential feature of atypical general movements is reduced complexity and variation. This is attributed to impaired integrity of extensive cortical-subcortical networks, in which the subplate and periventricular white matter play a prominent role. The most serious forms of network impairment are associated with absent fidgety movements. WHAT THIS PAPER ADDS: The emergence of fidgety movements reflects a developmental transition from widespread to fragmented cortical network activity. Atypical general movements characterized by reduced complexity and variation are attributed to impaired integrity of extensive cortical-subcortical networks. PMID- 28832988 TI - Interrater reliability of two gait performance measures in children with neuromotor disorders across two different settings. AB - AIM: To examine the interrater agreement of the two gait performance measures - the Functional Mobility Scale (FMS) and Gillette Functional Assessment Questionnaire - walking scale (FAQ) - within health professionals and parents in children with neuromotor disorders, measured in an inpatient setting and at home. METHOD: Seventy-one children with a neuromotor diagnosis (44 males, 27 females; median age 12y 11mo [interquartile range 4y-10mo]) were consecutively recruited when starting an inpatient active gait rehabilitation programme. Physiotherapists and nurses independently scored the level of children's gait performance with the FMS and the FAQ, while parents' scores regarding the children's gait performance at home were obtained by interview or telephone call at the same measurement points. RESULTS: Linear weighted kappa coefficients were substantial to almost perfect for all comparisons. Kappa coefficients ranged from 0.62 to 0.85 for the FMS-5, from 0.79 to 0.92 for the FMS-50, from 0.83 to 0.90 for the FMS-500, and from 0.69 to 0.77 for the FAQ. Friedman tests did not reveal significant differences between the different rater groups. INTERPRETATION: The unexpectedly high level of interrater agreement between parents, physiotherapists, and nurses demonstrates that the FMS and FAQ can reliably assess gait performance in an inpatient setting. Inpatient scores correspond well to the children's performance in their usual environment. WHAT THIS PAPER ADDS: The Functional Mobility Scale and Gillette Functional Assessment Questionnaire - walking scale measure gait performance reliably at home and in an inpatient setting. Physiotherapists, nurses, and parents reliably score gait performance. Inpatient gait performance scores correspond well to children's performance at home. Physiotherapists and nurses in an inpatient setting can reliably estimate gait performance at home. PMID- 28832989 TI - A case of Netherton syndrome with intestinal atresia, a novel SPINK5 mutation, and a fatal course. PMID- 28832990 TI - Why Most Children Think Well of Themselves. AB - This research aimed to examine whether and why children hold favorable self conceptions (total N = 882 Dutch children, ages 8-12). Surveys (Studies 1-2) showed that children report strongly favorable self-conceptions. For example, when describing themselves on an open-ended measure, children mainly provided positive self-conceptions-about four times more than neutral self-conceptions, and about 11 times more than negative self-conceptions. Experiments (Studies 3-4) demonstrated that children report favorable self-conceptions, in part, to live up to social norms idealizing such self-conceptions, and to avoid seeing or presenting themselves negatively. These findings advance understanding of the developing self-concept and its valence: In middle and late childhood, children's self-conceptions are robustly favorable and influenced by both external (social norms) and internal (self-motives) forces. PMID- 28832991 TI - Emergency department visits for children with cerebral palsy: what triggers the call for help? PMID- 28832992 TI - Measuring communicative participation in population-based samples of children with speech and language difficulties. PMID- 28832993 TI - What's new in dermoscopy of Bowen's disease: two new dermoscopic signs and its differential diagnosis. AB - BACKGROUND: Clinical and dermoscopic features of Bowen's disease (BD) show great diversity. Some lesions of BD are often difficult to be differentiated from seborrheic keratosis, actinic keratosis, lichen planus-like keratosis, etc. It is necessary to fully describe the dermoscopic features of the disease, considering differential diagnosis. OBJECTIVE: To describe the dermoscopic feautres of Bowen's disease and summarize the dermoscopic differential diagnosis of the disease. PATIENTS AND METHODS: Altogether 146 lesions with a histopathological diagnosis of Bowen's disease were consecutively included in this study. All the lesions were imaged with dermoscopy and analyzed for dermoscopic features. RESULTS: A total of 146 lesions were analyzed. The dermoscopic features most frequently observed in our series of lesions were scales (78.8%), glomerular vessels (69.2%), yellow crusts (56.8%), focal hemorrhage (55.5%), focal/multifocal hypopigmentation (44.5%), and linear irregular vessels (42.5%). Besides, we found two new dermoscopic signs in BD: the double-edge sign (30.1%) and the clusters of brown structureless areas (38.4%). CONCLUSION: Bowen's disease presents a variety of dermoscopic features. The recognition of two new dermoscopic signs of BD and fully understanding its dermoscopic features will help us in differential diagnosis. PMID- 28832995 TI - Physical activity interventions for children and young people with cerebral palsy. PMID- 28832994 TI - C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease. AB - Complement C4 genes are linked to paediatric inflammatory bowel disease (PIBD), but the mechanisms have remained unclear. We examined the influence of C4B gene number on intestinal microbiota and in-vitro serum complement activation by intestinal microbes in PIBD patients. Complement C4A and C4B gene numbers were determined by genomic reverse transcription-polymerase chain reaction (RT-PCR) from 64 patients with PIBD (Crohn's disease or ulcerative colitis). The severity of the disease course was determined from faecal calprotectin levels. Intestinal microbiota was assessed using the HITChip microarray. Complement reactivity in patients was analysed by incubating their sera with Yersinia pseudotuberculosis and Akkermansia muciniphila and determining the levels of C3a and soluble terminal complement complex (SC5b-9) using enzyme immunoassays. The microbiota diversity was wider in patients with no C4B genes than in those with one or two C4B genes, irrespective of intestinal inflammation. C4B and total C4 gene numbers correlated positively with soluble terminal complement complex (TCC, SC5b-9) levels when patient serum samples were stimulated with bacteria. Our results suggest that the C4B gene number associates positively with inflammation in patients with PIBD. Multiple copies of the C4B gene may thus aggravate the IBD associated dysbiosis through escalated complement reactivity towards the microbiota. PMID- 28832996 TI - Motion Perception and Form Discrimination in Extremely Preterm School-Aged Children. AB - This population-based study evaluated motion and form perception in 71 children born extreme premature (EPT; < 27 gestational weeks), aged 6.5 years, as compared to a matched group of 79 control children born at term. Motion and form perception were evaluated by motion coherence and form coherence tests. The EPT group showed a poorer performance on both tasks as compared to the control group. However, after controlling for IQ and visual acuity, the EPT group showed only a significant deficit in motion perception. No association was found between motion perception accuracy and gestational age, previous retinopathy of prematurity, or previous intraventricular hemorrhage in the EPT group. The results highlight the long-term motion perception deficits in children born EPT. PMID- 28832997 TI - When Peer Performance Matters: Effects of Expertise and Traits on Children's Self Evaluations After Social Comparison. AB - The present research examined the influence of peer characteristics on children's reactions to upward social comparisons. In Experiment 1, one hundred twenty-six 5 , 8-, and 10-year-olds were told that they were outperformed by an expert or novice peer. Older children reported higher self-evaluations after comparisons with an expert rather than a novice, whereas 5-year-olds reported high self evaluations broadly. In Experiment 2, ninety-eight 5- to 6-year-olds and 9- to 10 year-olds were told that the peer possessed a positive or negative trait that was task relevant (i.e., intelligence) or task irrelevant (i.e., athleticism). Older children reported higher self-evaluations after hearing about positive rather than negative traits, irrespective of relevance. Younger children reported high self-evaluations indiscriminately. Results inform the understanding of social comparison development in childhood. PMID- 28832999 TI - Psychosocial function following pediatric stroke: at 1 year and 5 years on. PMID- 28832998 TI - Dynamic monitoring of p53 translocation to mitochondria for the analysis of specific inhibitors using luciferase-fragment complementation. AB - Intracellular protein translocation plays a pivotal role in regulating complex biological processes, including cell death. The tumor suppressor p53 is a transcription factor activated by DNA damage and oxidative stress that also translocates from the cytosol into the mitochondrial matrix to facilitate necrotic cell death. However, specific inhibitors of p53 mitochondrial translocation are largely unknown. To explore the inhibitors of p53, we developed a bioluminescent probe to monitor p53 translocation from cytosol to mitochondria using luciferase fragment complementation assays. The probe is composed of a novel pair of luciferase fragments, the N-terminus of green click beetle luciferase CBG68 (CBGN) and multiple-complement luciferase fragment (McLuc1). The combination of luciferase fragments showed significant luminescence intensity and high signal-to-background ratio. When the p53 connected with McLuc1 translocates from cytosol into mitochondrial matrix, CBGN in mitochondrial matrix enables to complement with McLuc1, resulting in the restoration of the luminescence. The luminescence intensity was significantly increased under hydrogen peroxide induced oxidative stress following the complementation of CBGN and McLuc1. Pifithrin-MU, a selective inhibitor of p53 mitochondrial translocation, prevented the mitochondrial translocation of the p53 probe in a concentration-dependent manner. Furthermore, the high luminescence intensity made it easier to visualize the p53 translocation at a single cell level under a bioluminescence microscope. This p53 mitochondrial translocation assay is a new tool for high-throughput screening to identify novel p53 inhibitors, which could be developed as drugs to treat diseases in which necrotic cell death is a major contributor. PMID- 28833000 TI - School-age children's neural sensitivity to horizontal orientation energy in faces. AB - Face processing mechanisms are tuned to specific low-level features including mid range spatial frequencies and horizontal orientation energy. Behaviorally, adult observers are more effective at face recognition tasks when these information channels are available. Neural responses to face images also reflect these information biases: Face-sensitive ERP components respond preferentially to face images that contain horizontal orientation energy. How does neural tuning of face representations to horizontal information develop? Behavioral results show that this information bias increases over time such that younger children have a reduced bias favoring horizontally-filtered faces that increases with age. In the present study, we chose to investigate how neural sensitivity to these low-level features develops in the same age range, using ERP as a means of studying children and adults. Specifically, we examined how both face-sensitive ERP components (the P100 and N170) changed their responses to faces and non-faces as a function of age and orientation energy. Briefly, we found that the latency of the P100 and N170 component across age groups was consistent with the gradual emergence of a bias favoring horizontal orientation energy during middle childhood. The amplitude of the N170 component, however, exhibited a more complicated developmental profile that does not easily map onto previous behavioral results obtained from children in the same age ranges. PMID- 28833001 TI - Dermoscopy of borderline tuberculoid leprosy. AB - INTRODUCTION: Leprosy is a chronic granulomatous condition caused by Mycobacterium leprae, and borderline tuberculoid (BT) leprosy is the most common type of leprosy and presents with large, well- to ill-defined hypopigmented patches. It is known for atypical presentations. Dermoscopy of granulomatous conditions is well documented. However, there is no description of dermoscopy of BT leprosy in the literature. Authors evaluated the dermoscopic patterns of BT leprosy. CASE REPORT: Patients with BT leprosy were studied for dermoscopic patterns. A total of 12 patients (8 male, 4 female) with a median age of 25 years were present. Mean duration of disease was 6 months. The most frequent pattern was white areas (100%) followed by decreased density of hairs. Yellow globules were observed in 8 (66.66%) patients. Decreased white dots (represent sweat duct openings) and branching vessels were noted in 6 (50%) and 4 (33.33%) patients, respectively. CONCLUSION: This is the first report of dermoscopy of BT leprosy in the literature, and new dermoscopic observations were made by the authors. Dermoscopy of BT leprosy shows characteristic patterns, thus it adds valuable information for the diagnosis of BT leprosy. PMID- 28833002 TI - Corpus callosum and bilateral motor performance after unilateral neonatal arterial ischemic stroke. PMID- 28833005 TI - Ustekinumab for severe atopic dermatitis: an important negative study. PMID- 28833006 TI - Image Gallery: Folliculitis keloidalis on white-skinned scalp vertex. PMID- 28833007 TI - Drug survival of methotrexate in psoriasis. PMID- 28833008 TI - Patient-centred health care for people with chronic skin conditions. PMID- 28833009 TI - Cover Image: Invasion of a cutaneous melanoma tumour. PMID- 28833010 TI - Keratinocyte skin cancers in the spotlight. PMID- 28833012 TI - Psoralen-ultraviolet A maintenance in mycosis fungoides: the underlying question. PMID- 28833013 TI - Lifting the biofilm lid on the antibacterial and antibiofilm effects of sodium hypochlorite against Staphylococcus aureus in atopic dermatitis. PMID- 28833014 TI - Image Gallery: Haemorrhagic shock due to a cutaneous pyogenic granuloma. PMID- 28833015 TI - Switching expensive drugs with frequently diminishing value. PMID- 28833016 TI - HSP90 inhibition in angiosarcoma. PMID- 28833017 TI - Expanding mutation landscape and phenotypic spectrum of autosomal recessive congenital ichthyosis. PMID- 28833018 TI - Interests and their conflicts. PMID- 28833019 TI - Fatigue and psoriasis. PMID- 28833020 TI - Alopecia in Cronkhite-Canada syndrome. PMID- 28833021 TI - Genetic prediction of treatment response in psoriasis is still a work in progress. PMID- 28833022 TI - Maintenance therapy with psoralen-ultraviolet A for mycosis fungoides: in the absence of evidence sitting on the fence is appropriate. PMID- 28833023 TI - Image Gallery: Secondary cutaneous involvement of the ear with systemic small lymphocytic lymphoma: a rare manifestation. PMID- 28833024 TI - The role of access to care in acral lentiginous melanoma survival. PMID- 28833025 TI - Image Gallery: Dermoscopy as an auxiliary tool in exogenous ochronosis. PMID- 28833027 TI - Nivolumab improves survival for patients with advanced lung cancer. PMID- 28833026 TI - Image Gallery: A case of cutaneous giant angiosarcoma treated successfully with electrochemotherapy. PMID- 28833028 TI - Second primary cancers deadlier for younger patients. PMID- 28833029 TI - First person: Rudiger Hehlmann: The professor of medicine and founder of the European LeukemiaNet builds on his hard-won legacy of improving the survival rates of patients with leukemia. PMID- 28833030 TI - Corrigendum. PMID- 28833031 TI - A20 deletion in T cells modulates acute graft-versus-host disease in mice. AB - The NF-kappaB regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4+ and CD8+ donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-gamma and systemic inflammation was elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20+/+ T cells. Still, A20-deficient T cells, activated either through T cell receptor dependent or -independent mechanisms, were less viable than control A20+/+ T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell mediated inflammatory diseases like GVHD. PMID- 28833032 TI - Bearded versus thorny: the fireworm Hermodice carunculata preys on the sea urchin Paracentrotus lividus. PMID- 28833033 TI - Gaps contribute tree diversity to a tropical floodplain forest. AB - Treefall gaps have long been a central feature of discussions about the maintenance of tree diversity in both temperate and tropical forests. Gaps expose parts of the forest floor to direct sunlight and create a distinctive microenvironment that can favor the recruitment into the community of so-called gap pioneers. This traditional view enjoys strong empirical support, yet has been cast into doubt by a much-cited article claiming that gaps are inherently "neutral" in their contribution to forest dynamics. We present concurrent data on seedfall and sapling recruitment into gaps vs. under a vertically structured canopy in an Amazonian floodplain forest in Peru. Our results strongly uphold the view of gaps as important generators of tree diversity. Our methods differed significantly from those employed by the neutralist group and can explain the contrasting outcomes. We found that seedfall into gaps differs both quantitatively and qualitatively from that falling under a multi-tiered canopy, being greatly enriched in wind-dispersed and autochorus species and sharply deficient in all types of zoochorous seeds. Despite a reduced input of zoochorous seeds, zoochorous species made up 79% of saplings recruiting into gaps, whereas wind-dispersed species made up only 1%. Cohorts of saplings recruiting into gaps are less diverse than those recruiting under a closed canopy (Fisher's alpha = 40 vs. 100) and compositionally distinct, containing many light-demanding species that rarely, if ever, recruit under shaded conditions. Saplings recruiting into gaps appear to represent a variable mix of shade-tolerant survivors of the initiating treefall and sun-demanding species that germinate subsequently. PMID- 28833034 TI - Rheumatoid arthritis fibroblast-like synoviocytes co-cultured with PBMC increased peripheral CD4+ CXCR5+ ICOS+ T cell numbers. AB - 'Circulating' T follicular helper cells (Tfh), characterized by their surface phenotypes CD4+ chemokine receptor 5 (CXCR5)+ inducible co-stimulatory molecule (ICOS)+ , have been identified as the CD4+ T cell subset specialized in supporting the activation, expansion and differentiation of B cells. Fibroblast like synoviocytes (FLS) are critical in promoting inflammation and cartilage destruction in rheumatoid arthritis (RA), and the interaction between FLS and T cells is considered to facilitate FLS activation and T cell recruitment. However, it remains unknown whether RA-FLS co-cultured with activated peripheral blood mononuclear cells (PBMC) has immunoregulatory effects on peripheral Tfh. In the present study, we co-cultured RA-FLS with or without anti-CD3/CD28-stimulated PBMC. The results showed that RA-FLS co-cultured with stimulated PBMC could increase the numbers of CD4+ CXCR5+ ICOS+ T cells of RA PBMC possibly via the production of interleukin (IL)-6, a critical cytokine involved in the differentiation of Tfh cells. We also observed increased reactive oxygen species (ROS) levels in the co-culture system of RA-FLS and PBMC. The percentage of CD4+ CXCR5+ ICOS+ T cells was decreased when ROS production was inhibited by N-acetyl L-cysteine (NAC), a specific inhibitor which can decrease ROS production. In addition, we showed that the higher levels of tumour necrosis factor (TNF)-alpha and IL-1beta in the co-culture system and the blocking of TNF receptor 2 (TNF-R2) and IL-1beta receptor (IL-1betaR) both decreased the numbers of CD4+ CXCR5+ ICOS+ T cells. Our study reveals a novel mechanistic insight into how the interaction of RA-FLS and PBMC participates in the RA pathogenesis, and also provides support for the biologicals application for RA. PMID- 28833035 TI - Prenatal programming of postnatal plasticity for externalizing behavior: Testing an integrated developmental model of genetic and temperamental sensitivity to the environment. AB - Although both gene- and temperament-environment interactions contribute to the development of youth externalizing problems, it is unclear how these factors jointly affect environmental sensitivity over time. In a 7-year longitudinal study of 232 children (aged 5-10) with and without ADHD, we employed moderated mediation to test a developmentally sensitive mechanistic model of genetic and temperamental sensitivity to prenatal and postnatal environmental factors. Birth weight, a global measure of the prenatal environment, moderated predictions of child negative emotionality from a composite of dopaminergic polymorphisms (i.e., DRD4 and DAT1), such that birth weight inversely predicted negative emotionality only for children with genetic plasticity. Negative emotionality, in turn, predicted externalizing behavior 4-5 years later, beyond genetic and postnatal parenting effects. Finally, birth weight moderated the indirect effect of dopaminergic genotypes on externalizing problems through negative emotionality, partially supporting a prenatal programming model. We discuss theoretical and empirical implications for models of environmental sensitivity. PMID- 28833036 TI - Treatment with lacosamide impedes generalized seizures in a rodent model of cortical dysplasia. AB - OBJECTIVE: Epilepsy is a common neurologic disorder resulting in spontaneous, recurrent seizures. About 30-40% of patients are not responsive to pharmacologic therapies. This may be due to the differences between individual patients such as etiology, underlying pathophysiology, and seizure focus, and it highlights the importance of new drug discovery and testing in this field. Our goal was to determine the efficacy of lacosamide (LCM), a drug approved for the treatment of focal seizures, in a model of generalized epilepsy with cortical dysplasia (CD). We sought to compare LCM to levetiracetam (LEV), a drug that is currently used for the treatment of both partial and generalized epilepsy and to test its proficiency. METHODS: Pregnant rats were irradiated to produce pups with malformed cortices in a model of CD, which will be referred to as the "first hit." Adult animals, developed normally (NL) and irradiated (XRT), were surgically implanted with electroencephalography (EEG) electrodes. Baseline EEG was recorded on all rats prior to pretreatments with either LCM, LEV, or placebo (PBO). After 30 min, all rats were injected with a subconvulsive dose of pentylenetetrazole (PTZ), a gamma-aminobutyric acid receptor A (GABAA ) antagonist used to provoke generalized seizures as a "second hit." RESULTS: LCM and LEV were both effective against seizures induced by PTZ. XRT rats had a higher seizure incidence with longer and more severe seizures than NL rats. Seizure duration was decreased with both LCM and LEV in all animals. In XRT rats, there was a significant reduction in acute seizure incidence and severity with both LCM and LEV after PTZ injection. SIGNIFICANCE: Our results suggest that LCM could be used as a potential treatment option for generalized epilepsy with CD as the underlying pathology. PMID- 28833037 TI - Peristomal skin complications: what dermatologists need to know. AB - A stoma is an artificial opening to the skin formed when a part of the gastrointestinal tract is resected and opened to the skin in order to divert the bowel content to the skin surface. The incidence of stomal and peristomal complication varies from 30 to 67% with a significant negative impact on patient quality of life. Despite their prevalence, care providers tend to show insufficient awareness of peristomal skin complications, and research-based evidence related to peristomal skin complication and management options particularly in dermatology literature is sparse. This article will present a comprehensive review of peristomal skin complications in classification, clinical presentation, causes, prevention, and management aiming at increasing knowledge about this topic. PMID- 28833038 TI - LCE: leaf carbon exchange data set for tropical, temperate, and boreal species of North and Central America. AB - Leaf canopy carbon exchange processes, such as photosynthesis and respiration, are substantial components of the global carbon cycle. Climate models base their simulations of photosynthesis and respiration on an empirical understanding of the underlying biochemical processes, and the responses of those processes to environmental drivers. As such, data spanning large spatial scales are needed to evaluate and parameterize these models. Here, we present data on four important biochemical parameters defining leaf carbon exchange processes from 626 individuals of 98 species at 12 North and Central American sites spanning ~53 degrees of latitude. The four parameters are the maximum rate of Rubisco carboxylation (Vcmax ), the maximum rate of electron transport for the regeneration of Ribulose-1,5,-bisphosphate (Jmax ), the maximum rate of phosphoenolpyruvate carboxylase carboxylation (Vpmax ), and leaf dark respiration (Rd ). The raw net photosynthesis by intercellular CO2 (A/Ci ) data used to calculate Vcmax , Jmax , and Vpmax rates are also presented. Data were gathered on the same leaf of each individual (one leaf per individual), allowing for the examination of each parameter relative to others. Additionally, the data set contains a number of covariates for the plants measured. Covariate data include (1) leaf-level traits (leaf mass, leaf area, leaf nitrogen and carbon content, predawn leaf water potential), (2) plant-level traits (plant height for herbaceous individuals and diameter at breast height for trees), (3) soil moisture at the time of measurement, (4) air temperature from nearby weather stations for the day of measurement and each of the 90 d prior to measurement, and (5) climate data (growing season mean temperature, precipitation, photosynthetically active radiation, vapor pressure deficit, and aridity index). We hope that the data will be useful for obtaining greater understanding of the abiotic and biotic determinants of these important biochemical parameters and for evaluating and improving large-scale models of leaf carbon exchange. PMID- 28833039 TI - Minimally manipulated murine regulatory T cells purified by reversible Fab Multimers are potent suppressors for adoptive T-cell therapy. AB - The transfer of regulatory T cells, either freshly isolated, or modified, represents a promising therapeutic approach to dampen misdirected immune responses, like autoimmune diseases, chronic inflammatory syndromes and graft versus host disease. Clinical isolation of highly pure regulatory T cell (Treg) populations is still challenging and labeling reagents can influence their viability and functionality, potentially altering the potency of isolated Treg cell products. Here we show that reversible Fab multimer-based Treg purification can prevent conventional antibody label-induced interferences in vitro and in vivo. Remaining isolation reagents negatively interfere with Treg engraftment efficacy in C57BL/6 wild-type mice due to Fcgamma-receptor- as well as IL-2 receptor-mediated mechanisms. Using a preclinical model for acute GvHD, we further show that purified 'label-freed' Tregs are protective at substantially lower cell numbers as compared to conventional nonreversible antibody staining, translating into significantly improved survival of mice treated with minimally manipulated Tregs. These findings have important clinical relevance for future Treg-based cell therapies. PMID- 28833040 TI - Demographic drivers of functional composition dynamics. AB - Mechanisms of community assembly and ecosystem function are often analyzed using community-weighted mean trait values (CWMs). We present a novel conceptual framework to quantify the contribution of demographic processes (i.e., growth, recruitment, and mortality) to temporal changes in CWMs. We used this framework to analyze mechanisms of secondary succession in wet tropical forests in Mexico. Seed size increased over time, reflecting a trade-off between colonization by small seeds early in succession, to establishment by large seeds later in succession. Specific leaf area (SLA) and leaf phosphorus content decreased over time, reflecting a trade-off between fast growth early in succession vs. high survival late in succession. On average, CWM shifts were driven mainly (70%) by growth of surviving trees that comprise the bulk of standing biomass, then mortality (25%), and weakly by recruitment (5%). Trait shifts of growing and recruiting trees mirrored the CWM trait shifts, and traits of dying trees did not change during succession, indicating that these traits are important for recruitment and growth, but not for mortality, during the first 30 yr of succession. Identifying the demographic drivers of functional composition change links population dynamics to community change, and enhances insights into mechanisms of succession. PMID- 28833041 TI - The intersensory redundancy hypothesis: Extending the principle of unimodal facilitation to prenatal development. AB - Selective attention to different properties of stimulation provides the foundation for perception, learning, and memory. The Intersensory Redundancy Hypothesis (IRH) proposes that early in development information presented redundantly across two or more modalities (multimodal) selectively recruits attention to and enhances perceptual learning of amodal properties, whereas information presented to a single sense modality (unimodal) enhances perceptual learning of modality-specific properties. The present study is the first to assess this principle of unimodal facilitation in non-human animals in prenatal development. We assessed bobwhite quail embryos' prenatal detection of pitch, a modality-specific property, under conditions of unimodal and bimodal (synchronous or asynchronous) exposure. Chicks exposed to prenatal unimodal auditory stimulation or asynchronous bimodal (audiovisual) stimulation preferred the familiarized maternal call over a novel pitch-modified maternal call following hatching, whereas chicks exposed to redundant (synchronous) audiovisual stimulation failed to prefer the familiar call over the pitch-modified call. These results provide further evidence that selective attention is recruited to specific stimulus properties of events in early development and that these biases are evident even during the prenatal period. PMID- 28833042 TI - "What" and "where" was when? Memory for the temporal order of episodic events in children. AB - In the past, researchers have shown that the individual components of episodic memory (i.e "what," "where," and "when") may emerge at different points in development. Specifically, while children as young as three can accurately report the "what" and "where" of an event, they struggle to accurately report when the event occurred. One explanation for children's difficulty in reporting when an event took place is a rudimentary understanding, and ability to use, temporal terms. In the current experiment, we employed a physical timeline to aid children's reporting of the order in which a series of episodic events occurred. Overall, while 4-, 5-, and 6-year olds performed above chance, 3-year olds did not. Our findings suggest that 3-year olds' limited ability to produce temporal terms may not be the rate-limiting step preventing them from identifying when events occurred in their recent past. PMID- 28833043 TI - Simultaneous monitoring of maternal and fetal heart rate variability during labor in relation with fetal gender. AB - Male gender is considered a risk factor for several adverse perinatal outcomes. Fetal gender effect on fetal heart rate (FHR) has been subject of several studies with contradictory results. The importance of maternal heart rate (MHR) monitoring during labor has also been investigated, but less is known about the effect of fetal gender on MHR. The aim of this study is to simultaneously assess maternal and FHR variability during labor in relation with fetal gender. Simultaneous MHR and FHR recordings were obtained from 44 singleton term pregnancies during the last 2 hr of labor (H1, H2 ). Heart rate tracings were analyzed using linear (time- and frequency-domain) and nonlinear indices. Both linear and nonlinear components were considered in assessing FHR and MHR interaction, including cross-sample entropy (cross-SampEn). Mothers carrying male fetuses (n = 22) had significantly higher values for linear indices related with MHR average and variability and sympatho-vagal balance, while the opposite occurred in the high-frequency component and most nonlinear indices. Significant differences in FHR were only observed in H1 with higher entropy values in female fetuses. Assessing the differences between FHR and MHR, statistically significant differences were obtained in most nonlinear indices between genders. A significantly higher cross-SampEn was observed in mothers carrying female fetuses (n = 22), denoting lower synchrony or similarity between MHR and FHR. The variability of MHR and the synchrony/similarity between MHR and FHR vary with respect to fetal gender during labor. These findings suggest that fetal gender needs to be taken into account when simultaneously monitoring MHR and FHR. PMID- 28833044 TI - Back to Hegel? On Gillian Rose's critique of sociological reason. AB - Thirty-five years ago, Gillian Rose articulated a significant critique of classical sociological reason, emphasizing its relationship to its philosophical forebears. In a series of works, but most significantly in her Hegel contra Sociology, Rose worked to specify the implications of sociology's failure, both in its critical Marxist and its 'scientific' forms, to move beyond Kant and to fully come to terms with the thought of Hegel. In this article, I unpack and explain the substance of her criticisms, developing the necessary Hegelian philosophical background on which she founded them. I argue that Rose's attempted recuperation of 'speculative reason' for social theory remains little understood, despite its continued relevance to contemporary debates concerning the nature and scope of sociological reason. As an illustration, I employ Rose to critique Chernilo's recent call for a more philosophically sophisticated sociology. From the vantage point of Rose, this particular account of a 'philosophical sociology' remains abstract and rooted in the neo-Kantian contradictions that continue to characterize sociology. PMID- 28833045 TI - Pharmacokinetic variability of valproate in women of childbearing age. AB - The purpose was to investigate pharmacokinetic variability of valproic acid (VPA) in women of childbearing age by therapeutic drug monitoring (TDM) data to elucidate the variable relationship between dose and serum concentrations with the ultimate aim of facilitating safer use of VPA. Anonymized retrospective data from the TDM database (2006-2015) at the National Center for Epilepsy in Norway were used. Trough total concentrations of VPA at assumed steady state in women aged 14-46 years were analyzed. Data from 643 nonpregnant women of childbearing age (mean age = 27 years) were included. Mean dose and serum concentration of VPA were 968 (standard deviation [SD] = 453) mg/day and 411 (SD = 138) MUmol/L, respectively, and 59% used polytherapy. The pharmacokinetic variability in serum concentration/dose (C/D) ratios between women was extensive. For doses <700 mg/day (n = 202; 32%; 150-625 mg/day), mean serum concentration was 336 MUmol/L and variability in C/D ratio was 10-fold. The variability decreased with increasing dose to eightfold (>=700 to <1,500 mg/day, n = 358) and fourfold (>=1,500 mg/day, n = 96). This study demonstrates the extensive pharmacokinetic variability of VPA among women of childbearing age, which is most pronounced at low doses. In future studies, serum concentrations of VPA, rather than dosage, should be used as a guide for exposure of VPA and possible risks of teratogenicity to evaluate safety aspects of VPA in women. PMID- 28833047 TI - Clinical practice guidelines for neonatal arterial ischaemic stroke. PMID- 28833046 TI - AhR activation increases IL-2 production by alloreactive CD4+ T cells initiating the differentiation of mucosal-homing Tim3+ Lag3+ Tr1 cells. AB - Activation of the aryl hydrocarbon receptor (AhR) by immunosuppressive ligands promotes the development of regulatory T (Treg) cells. Although AhR-induced Foxp3+ Treg cells have been well studied, much less is known about the development and fate of AhR-induced Type 1 Treg (AhR-Tr1) cells. In the current study, we identified the unique transcriptional and functional changes in murine CD4+ T cells that accompany the differentiation of AhR-Tr1 cells during the CD4+ T-cell-dependent phase of an allospecific cytotoxic T lymphocyte (allo-CTL) response. AhR activation increased the expression of genes involved in T-cell activation, immune regulation and chemotaxis, as well as a global downregulation of genes involved in cell cycling. Increased IL-2 production was responsible for the early AhR-Tr1 activation phenotype previously characterized as CD25+ CTLA4+ GITR+ on day 2. The AhR-Tr1 phenotype was further defined by the coexpression of the immunoregulatory receptors Lag3 and Tim3 and non-overlapping expression of CCR4 and CCR9. Consistent with the increased expression of CCR9, real-time imaging showed enhanced migration of AhR-Tr1 cells to the lamina propria of the small intestine and colon. The discovery of mucosal imprinting of AhR-Tr1 cells provides an additional mechanism by which therapeutic AhR ligands can control immunopathology. PMID- 28833048 TI - Progressive intellectual and neurological disorders: can surveillance lead to improved outcomes? PMID- 28833049 TI - Raised intracranial pressure and retinal haemorrhages in childhood encephalopathies: reply to the commentary by Squier. PMID- 28833050 TI - Dare Greatly: Enter the Arena. PMID- 28833051 TI - The end of spasticity? PMID- 28833052 TI - Neonatal arterial ischemic stroke: evidence required for future guidelines. PMID- 28833053 TI - A distinct clinicopathological variant of focal cortical dysplasia IIId characterized by loss of layer 4 in the occipital lobe in 12 children with remote hypoxic-ischemic injury. AB - OBJECTIVE: In 2011, the International League Against Epilepsy (ILAE) proposed a consensus classification system of focal cortical dysplasia (FCD) to distinguish clinicopathological subtypes, for example, "isolated" FCD type Ia-c and IIa-b, versus "associated" FCD type IIIa-d. The histopathological differentiation of FCD type I and III variants remains, however, a challenging issue in everyday practice. We present a unique histopathological pattern in patients with difficult-to-diagnose FCD, which highlights this dilemma, but also helps to refine the current ILAE classification scheme of FCD. METHODS: We present a retrospective series of 11 male and one female patient with early onset pharmacoresistant epilepsy of the posterior quadrant (mean age at seizure onset = 4.6 years). All surgical specimens were reviewed. Clinical histories were retrieved and extracted from archival patient files. RESULTS: Microscopic inspection revealed abnormalities in cortical architecture with complete loss of layer 4 in all surgical samples of the occipital lobe, as confirmed by semiquantitative measurements (p < 0.01). Clinical history reported early transient hypoxic condition in nine patients (75%). Magnetic resonance imaging (MRI) revealed abnormal signals in the occipital lobe in all patients, and signal changes suggestive of subcortical encephalomalacia were found in seven patients. Surgical treatment achieved favorable seizure control (Engel class I and II) in seven patients with an available follow-up period of 6.1 years. SIGNIFICANCE: Prominent disorganization of cortical layering and lack of any other microscopically visible principle lesion in the surgical specimen would result in this neuropathological pattern hitherto being classified as FCD ILAE type Ib. However, perinatal hypoxia with distinctive MRI changes suggested primarily a hypoxemic lesion and acquired pathomechanism of neuronal cell loss in the occipital lobe of our patient series. We propose, therefore, classifying this distinctive clinicopathological pattern as a separate variant of FCD ILAE type IIId. PMID- 28833054 TI - Psychological distress associated with cancer screening: A systematic review. AB - BACKGROUND: Current national cancer screening recommendations include the potential risk of psychological harm related to screening. However, data on the relation of psychological distress to cancer screening is limited. The authors conducted a systematic review to assess psychological distress associated with cancer screening procedures. METHODS: Studies that administered measures of psychological distress between 2 weeks before and 1 month after the screening procedure were included. RESULTS: In total, 22 eligible studies met criteria for review, including 13 observational trials and 9 randomized controlled trials. Eligible studies used a broad range of validated and unvalidated measures. Anxiety was the most commonly assessed construct and was measured using the State Trait Anxiety Inventory. Studies included breast, colorectal, prostate, lung, and cervical screening procedures. Distress was low across procedures, with the exception of colorectal screening. Distress did not vary according to the time at which distress was measured. None of the studies were conducted exclusively with the intention of assessing distress at the time of screening. CONCLUSIONS: Evidence of low distress during the time of cancer screening suggests that distress might not be a widespread barrier to screening among adults who undergo screening. However, more studies are needed using validated measures of distress to further understand the extent to which screening may elicit psychological distress and impede adherence to national screening recommendations. Cancer 2017;123:3882-94. (c) 2017 American Cancer Society. PMID- 28833056 TI - Never surprise a patient with scurvy. PMID- 28833055 TI - Impact of portal vein infiltration and type of venous reconstruction in surgery for borderline resectable pancreatic cancer. AB - BACKGROUND: The International Study Group of Pancreatic Surgery (ISGPS) recommends operative exploration and resection of pancreatic cancers in the presence of reconstructable mesentericoportal axis involvement. However, there is no consensus on the ideal method of vascular reconstruction. The effect of depth of tumour invasion of the vessel wall on outcome is also unknown. METHODS: This was a retrospective cohort study of pancreaticoduodenectomy with vein resection for T3 adenocarcinoma of the head of the pancreas across nine centres. Outcome measures were overall survival based on the impact of the depth of tumour infiltration of the vessel wall, and morbidity, in-hospital mortality and overall survival between types of venous reconstruction: primary closure, end-to-end anastomosis and interposition graft. RESULTS: A total of 229 patients underwent portal vein resection; 129 (56.3 per cent) underwent primary closure, 64 (27.9 per cent) had an end-to-end anastomosis and 36 (15.7 per cent) an interposition graft. There was no difference in overall morbidity (26 (20.2 per cent), 14 (22 per cent) and 9 (25 per cent) respectively; P = 0.817) or in-hospital mortality (6 (4.7 per cent), 2 (3 per cent) and 2 (6 per cent); P = 0.826) between the three groups. One hundred and six patients (47.5 per cent) had histological evidence of vein involvement; 59 (26.5 per cent) had superficial invasion (tunica adventitia) and 47 (21.1 per cent) had deep invasion (tunica media or intima). Median survival was 18.8 months for patients who had primary closure, 27.6 months for those with an end-to-end anastomosis and 13.0 months among patients with an interposition graft. There was no significant difference in median survival between patients with superficial, deep or no histological vein involvement (20.8, 21.3 and 13.3 months respectively; P = 0.111). Venous tumour infiltration was not associated with decreased overall survival on multivariable analysis. CONCLUSION: In this study, there was no difference in morbidity between the three modes of venous reconstruction, and overall survival was similar regardless of tumour infiltration of the vein. PMID- 28833058 TI - The Experience of Prisoners' Parents: A Meta-Synthesis of Qualitative Studies. AB - The parents of prisoners have long drawn the attention of researchers, due to their role in the etiology of criminality as well as the importance of their support of their offspring during and after incarceration. However, although studies have shown that the parents of prisoners experience high levels of distress, burden, and social stigma, research into their experience is only now beginning to emerge. This metasynthesis examined the limited body of qualitative research on the experience of prisoners' parents, as an exploratory step toward advancing the understanding of their experience. Relevant terms were used to systematically search key databases. Ten small-scale studies, which varied in focus, location, and disciplinary orientation, met the inclusion criteria. The synthesis produced four core themes, reflecting findings regarding parents' (primarily mothers') experience of their offspring's incarceration: parenting from a distance; the burden of care; troubled parental identity; and social reaction. Furthermore, the findings suggested a number of possible mediating factors of this experience, such as parents' social capital and their cognitive appraisal of their offspring's criminality. These themes imply a possible experience of "imprisonment by association" among the parents of inmates and illuminate features that may be unique to them. Given the inherent limitations regarding generalizability of a metasynthesis and the heterogeneity of the experiences of the parents represented by the articles reviewed, the findings call for future large-scale quantitative studies to explore the challenges and therapeutic needs of parents of prisoners regarding the themes identified. PMID- 28833057 TI - Rank acquisition in rhesus macaque yearlings following permanent maternal separation: The importance of the social and physical environment. AB - Rank acquisition is a developmental milestone for young primates, but the processes by which primate yearlings attain social rank in the absence of the mother remain unclear. We studied 18 maternally reared yearling rhesus macaques (Macaca mulatta) that differed in their social and physical rearing environments. We found that early social experience and maternal rank, but not individual traits (weight, sex, age), predicted dominance acquisition in the new peer-only social group. Yearlings also used coalitions to reinforce the hierarchy, and social affiliation (play and grooming) was likely a product, rather than a determinant, of rank acquisition. Following relocation to a familiar environment, significant rank changes occurred indicating that familiarity with a physical environment was salient in rank acquisition. Our results add to the growing body of literature emphasizing the role of the social and physical environment on behavioral development, namely social asymmetries among peers. PMID- 28833059 TI - Parental depression and parent and child stress physiology: Moderation by parental hostility. AB - This study examined the moderating role of parental hostility on the associations between parental depression and the cortisol awakening response (CAR) and morning cortisol levels of both parents and children. 148 parents and 148 preschool-aged children provided salivary cortisol samples at waking, 30 and 45 min post-waking on two consecutive days. Parental depression was assessed using a clinical interview, and parental hostility was assessed using an observational parent child interaction task. Results indicated that the combination of parental lifetime depression and high parental hostility was associated with lower morning cortisol levels in both parents and children. This interactive effect was present in children regardless of their exposure to parental depression. In addition, the combination of higher levels of parents' current depressive symptoms and parental hostility was associated with lower parent CAR. Lastly, parents' and children's lower morning cortisol levels were associated with parent-reported child externalizing symptoms. Findings demonstrate that parents and children have similar stress system functioning related to parental depression and the parenting context, as well as children's behavioral problems, which may play a role in the intergenerational transmission of risk for psychopathology. PMID- 28833060 TI - TCR signalling network organization at the immunological synapses of murine regulatory T cells. AB - Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation status notably discriminates Treg cells from Tconv cells. Overall, this study identified 121 Treg cell-specific phosphorylations. Short-term triggering of T cell subsets via CD3 and CD28 widely harmonized these variations with the exception of eleven TCR signalling components that mainly regulate cytoskeleton dynamics and molecular transport. Accordingly, conjugation with B cells indeed caused variant cellular morphology and revealed a Treg cell-specific recruitment of TCR signalling components such as PKCtheta, PLCgamma1 and ZAP70 as well as B cell-derived CD86 into the IS. Together, results from this study support the existence of a Treg cell-specific IS and suggest Treg cell-specific cytoskeleton dynamics as a novel determinant for the unique functional properties of Treg cells. PMID- 28833061 TI - Supratrochlear Neuralgia: A Prospective Case Series of 15 Patients. AB - OBJECTIVE: The aim of this study was to describe clinical features unique to supratrochlear neuralgia. BACKGROUND: The supratrochlear nerve supplies the medial aspect of the forehead. Due to the intricate relationship between supraorbital and supratrochlear nerves, neuralgic pain in this region has been traditionally attributed to supraorbital neuralgia. No cases of supratrochlear neuralgia have been reported so far. METHODS: From 2009 through 2016, we prospectively recruited patients with pain confined to the territory of the supratrochlear nerve. RESULTS: Fifteen patients (13 women, 2 men; mean age 51.4 years, standard deviation 14.9) presented with pain in the lower paramedian forehead, extending to the eyebrow in two patients and to the internal angle of the orbit in another. Pain was unilateral in 11 patients (six on the right, five on the left), and bilateral in four. Six patients had continuous pain and nine described intermittent pain. Palpation of the supratrochlear nerve at the medial third of the supraorbital rim resulted in hypersensitivity in all cases. All but one patient exhibited sensory disturbances within the painful area. Fourteen patients underwent anesthetic blockades of the supratrochlear nerve, with immediate relief in all cases and long-term remission in three. Six of them had received unsuccessful anesthetic blocks of the supraorbital nerve. Five patients were treated successfully with oral drugs and one patient was treated with radiofrequency. CONCLUSIONS: Supratrochlear neuralgia is an uncommon disorder causing pain in the medial region of the forehead. It may be differentiated from supraorbital neuralgia and other similar headaches and neuralgias based on the topography of the pain and the response to anesthetic blockade. PMID- 28833062 TI - Zinc and its transporter ZIP6 are key mediators of breast cancer cell survival under high glucose conditions. AB - Recent studies have shown that hyperglycaemia is related to breast cancer progression; however, the mechanisms underlying the relationship between hyperglycaemia and breast cancer cell survival remain unknown. Here, we demonstrate that as compared to physiological glucose conditions, high glucose conditions promote a significant increase in MCF-7 cell survival under hypoxia. High glucose levels inhibit apoptosis and induce epithelial-to-mesenchymal transition, resulting in increased cell viability under hypoxic conditions. Moreover, high glucose-treated cells display significant increases in intracellular Zn2+ levels and reduction in mRNA expression of the zinc (Zn) transporter Zrt- and Irt-like protein 6 (ZIP6) in hypoxia. ZIP6 deficiency disturbs intracellular Zn2+ homeostasis, leading to increased cell survival in hypoxia and reduced E-cadherin expression, indicating that decreased ZIP6 expression is strongly associated with resistance to hypoxia. PMID- 28833063 TI - Metabolism and functions of docosahexaenoic acid-containing membrane glycerophospholipids. AB - Omega-3 (omega-3) fatty acids (FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to have important roles in human health and disease. Besides being utilized as fuel, omega-3 FAs have specific functions based on their structural characteristics. These functions include serving as ligands for several receptors, precursors of lipid mediators, and components of membrane glycerophospholipids (GPLs). Since omega-3 FAs (especially DHA) are highly flexible, the levels of DHA in GPLs may affect membrane biophysical properties such as fluidity, flexibility, and thickness. Here, we summarize some of the cellular mechanisms for incorporating DHA into membrane GPLs and propose biological effects and functions of DHA-containing membranes of several cell and tissue types. PMID- 28833064 TI - Patterns of protective associations differ for antibodies to P. falciparum infected erythrocytes and merozoites in immunity against malaria in children. AB - Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity. PMID- 28833066 TI - Critical Issues and Optimized Practices in Quantification of Protein Abundance Level to Determine Interindividual Variability in DMET Proteins by LC-MS/MS Proteomics. AB - Protein quantification data on drug metabolizing enzymes and transporters (collectively referred as DMET proteins) in human tissues are useful in predicting interindividual variability in drug disposition. While targeted proteomics is an emerging technique for quantification of DMET proteins, the methodology involves significant technical challenges especially when multiple samples are analyzed in a single study over a long period of time. Therefore, it is important to thoroughly address the critical variables that could affect DMET protein quantification. PMID- 28833065 TI - Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3+ regulatory T cells. AB - Intestinal regulatory T cells (Tregs) are fundamental in peripheral tolerance toward commensals and food-borne antigens. Accordingly, gut-draining mesenteric lymph nodes (mLNs) represent a site of efficient peripheral de novo Treg induction when compared to skin-draining peripheral LNs (pLNs), and we had recently shown that LN stromal cells substantially contribute to this process. Here, we aimed to unravel the underlying molecular mechanisms and generated immortalized fibroblastic reticular cell lines (iFRCs) from mLNs and pLNs, allowing unlimited investigation of this rare stromal cell subset. In line with our previous findings, mLN-iFRCs showed a higher Treg-inducing capacity when compared to pLN-iFRCs. RNA-seq analysis focusing on secreted molecules revealed a more tolerogenic phenotype of mLN- as compared to pLN-iFRCs. Remarkably, mLN iFRCs produced substantial numbers of microvesicles (MVs) that carried elevated levels of TGF-beta when compared to pLN-iFRC-derived MVs, and these novel players of intercellular communication were shown to be responsible for the tolerogenic properties of mLN-iFRCs. Thus, stromal cells originating from mLNs contribute to peripheral tolerance by fostering de novo Treg induction using TGF-beta-carrying MVs. This finding provides novel insights into the subcellular/molecular mechanisms of de novo Treg induction and might serve as promising tool for future therapeutic applications to treat inflammatory disorders. PMID- 28833067 TI - Estimation of Population Average Treatment Effects in the FIRST Trial: Application of a Propensity Score-Based Stratification Approach. AB - OBJECTIVE/STUDY QUESTION: To estimate and compare sample average treatment effects (SATE) and population average treatment effects (PATE) of a resident duty hour policy change on patient and resident outcomes using data from the Flexibility in Duty Hour Requirements for Surgical Trainees Trial ("FIRST Trial"). DATA SOURCES/STUDY SETTING: Secondary data from the National Surgical Quality Improvement Program and the FIRST Trial (2014-2015). STUDY DESIGN: The FIRST Trial was a cluster-randomized pragmatic noninferiority trial designed to evaluate the effects of a resident work hour policy change to permit greater flexibility in scheduling on patient and resident outcomes. We estimated hierarchical logistic regression models to estimate the SATE of a policy change on outcomes within an intent-to-treat framework. Propensity score-based poststratification was used to estimate PATE. DATA COLLECTION/EXTRACTION METHODS: This study was a secondary analysis of previously collected data. PRINCIPAL FINDINGS: Although SATE estimates suggested noninferiority of outcomes under flexible duty hour policy versus standard policy, the noninferiority of a policy change was inconclusively noninferior based on PATE estimates due to imprecision. CONCLUSIONS: Propensity score-based poststratification can be valuable tools to address trial generalizability but may yield imprecise estimates of PATE when sparse strata exist. PMID- 28833068 TI - Pervasive gene expression responses to a fluctuating diet in Drosophila melanogaster: The importance of measuring multiple traits to decouple potential mediators of life span and reproduction. AB - Phenotypic plasticity is an important concept in life-history evolution, and most organisms, including Drosophila melanogaster, show a plastic life-history response to diet. However, little is known about how these life-history responses are mediated. In this study, we compared adult female flies fed an alternating diet (yoyo flies) with flies fed a constant low (CL) or high (CH) diet and tested how whole genome expression was affected by these diet regimes and how the transcriptional responses related to different life-history traits. We showed that flies were able to respond quickly to diet fluctuations throughout life span by drastically changing their transcription. Importantly, by measuring the response of multiple life-history traits we were able to decouple groups of genes associated with life span or reproduction, life-history traits that often covary with a diet change. A coexpression network analysis uncovered which genes underpin the separate and shared regulation of these life-history traits. Our study provides essential insights to help unravel the genetic architecture mediating life-history responses to diet, and it shows that the flies' whole genome transcription response is highly plastic. PMID- 28833070 TI - Application of Groundwater Vulnerability Overlay and Index Methods to the Jijel Plain Area (Algeria). AB - Today, scientists are deeply concerned by the vulnerability of groundwater reservoirs to pollution. Relatively simple overlay and index methods can be used to produce groundwater vulnerability maps in geographic information system. In addition, this study deals with contamination from nonpoint sources. In this study, two such models, DRASTIC and GOD, were applied in the Jijel Plain area of northeast Algeria and compared with measured groundwater nitrate concentrations. This showed that results from DRASTIC were better than GOD, 69% correlation with nitrate compared to 56%. DRASTIC was better able to identify vulnerable zones along the river valleys. The DRASTIC model was then modified using the nitrate concentrations to optimize the rating score given within each parameter range and sensitivity analysis to change the weighting given for each parameter. These combined changes gave a final Pearson's correlation of 83% with nitrate. This showed that recharge, aquifer type, and topography were the key factors in controlling vulnerability to nitrate pollution. PMID- 28833071 TI - Emerging mechanisms regulating mitotic synchrony during animal embryogenesis. AB - The basic mechanisms controlling mitosis are highly conserved in animals regardless of cell types and developmental stages. However, an exceptional aspect of mitosis is seen during early animal embryogenesis in which a large fertilized egg is quickly divided into smaller blastomeres according to the reproducible spatiotemporal pattern that does not rely on the cell-cycle arrest or growth. This mitosis, referred to as cleavage, overlaps in the timeframe with the specification of cell fate. The precise spatiotemporal regulation of cleavages is therefore essential to the creation of the appropriate cell number and to the morphology of an embryo. To achieve the reproducibility of cleavage during embryogenesis, the relative timing of mitosis between cells, which we refer to as synchrony, must be properly regulated. Studies in model organisms have begun to reveal how the synchrony of mitosis is regulated by the developmental modulation of cell-cycle machineries. In this review, we focus on three such mechanisms: biochemical switches that achieve the synchrony of mitosis, the nucleo cytoplasmic ratio that provokes the asynchrony of mitosis, and the transcriptional mechanisms coupled with cell fate control that reestablish the synchrony of mitosis in each fate-restricted compartment. Our review is an attempt to understand the temporal patterns of cleavages in animal embryos created by the combinations of these three mechanisms. PMID- 28833069 TI - RNA-editing enzymes ADAR1 and ADAR2 coordinately regulate the editing and expression of Ctn RNA. AB - Adenosine deaminases acting on RNA (ADARs) are proteins that catalyse widespread A-to-I editing within RNA sequences. We recently reported that ADAR2 edits and stabilizes nuclear-retained Cat2 transcribed nuclear RNA (Ctn RNA). Here, we report that ADAR1 coordinates with ADAR2 to regulate editing and stability of Ctn RNA. We observe an RNA-dependent interaction between ADAR1 and ADAR2. Furthermore, ADAR1 negatively regulates interaction of Ctn RNA with RNA destabilizing proteins. We also show that breast cancer (BC) cells display elevated ADAR1 but not ADAR2 levels, compared to nontumourigenic cells. Additionally, BC patients with elevated levels of ADAR1 show low survival. Our findings provide insights into overlapping substrate preferences of ADARs and potential involvement of ADAR1 in BC. PMID- 28833072 TI - Cutaneous metastasis: experience from a tertiary healthcare institution in Singapore. PMID- 28833073 TI - Cheating and resistance to cheating in natural populations of the bacterium Pseudomonas fluorescens. AB - Bacteria perform cooperative behaviors that are exploitable by noncooperative cheats, and cheats frequently arise and coexist with cooperators in laboratory microcosms. However, evidence of competitive dynamics between cooperators and cheats in nature remains limited. Using the production of pyoverdine, an iron scavenging molecule, and natural soil populations of Pseudomonas fluorescens, we found that (1) nonproducers are present in the population; (2) they co-occur (<1cm3 ) with pyoverdine producers; (3) they retain functional pyoverdine receptors; and (4) they can use the pyoverdine of on average 52% of producers. This suggests nonproducers can potentially act as social cheats in soil: utilizing the pyoverdine of others while producing little or none themselves. However, we found considerable variation in the extent to which nonproducers can exploit producers, as some isolates appear to produce exclusive forms of pyoverdine or kill nonproducers with toxins. We examined the consequences of this variation using theoretical modeling. We found variance in exploitability leads to some cheats gaining increased fitness benefits and others decreased benefits. However, the absolute gain in fitness from high exploitation is lower than the drop in fitness from low exploitation, decreasing the mean fitness of cheats and subsequently lowering the proportion of cheats maintained in the population. Our results suggest that although cooperator-cheat dynamics can occur in soil, a range of mechanisms can prevent nonproducers from exploiting producers. PMID- 28833075 TI - Accuracy of 50-g glucose challenge test to detect International Association of Diabetes and Pregnancy Study Groups criteria-defined hyperglycemia. AB - OBJECTIVES: To determine the accuracy of the 50-g glucose challenge test (GCT) in detecting hyperglycemia in pregnancy (HIP) across a range of glucose thresholds relative to the International Association of Diabetes and Pregnancy Study Groups diagnostic criteria, and to determine the accuracy of the 50-g GCT among patients with different risk status. METHODS: The present prospective cohort study included women aged 18-45 years at 24-31+6 weeks of pregnancy who presented at the Mother and Child Hospital, Akure, Nigeria, between September 1, 2015, and February 29, 2016. Patients underwent the 50-g GCT followed by the 75-g oral glucose tolerance test (OGTT). The accuracy of different 50-g GCT thresholds in diagnosing HIP was assessed based on International Association of Diabetes and Pregnancy Study Groups diagnostic criteria, with the 75-g OGTT used as a clinical reference standard. RESULTS: Of 280 patients enrolled, 46 (16.4%) had HIP. The sensitivity of the 50-g GCT to detect HIP decreased from 47.8% (95% confidence interval [CI], 32.9-63.1) at a 7.2-mmol/L threshold to 32.6% (95% CI, 19.5-48.0) at a 8.0-mmol/L threshold; the specificity improved from 84.2% (95% CI, 78.9 88.6) to 95.3% (95% CI, 91.7-97.6), respectively. CONCLUSION: The 50-g GCT performed poorly compared with the 75-g OGTT for detecting HIP. It appears to be an unsuitable replacement for the 75-g OGTT. PMID- 28833074 TI - Methodological considerations for disentangling a risk factor's influence on disease incidence versus postdiagnosis survival: The example of obesity and breast and colorectal cancer mortality in the Women's Health Initiative. AB - Often, studies modeling an exposure's influence on time to disease-specific death from study enrollment are incorrectly interpreted as if based on time to death from disease diagnosis. We studied 151,996 postmenopausal women without breast or colorectal cancer in the Women's Health Initiative with weight and height measured at enrollment (1993-1998). Using Cox regression models, we contrast hazard ratios (HR) from two time-scales and corresponding study subpopulations: time to cancer death after enrollment among all women and time to cancer death after diagnosis among only cancer survivors. Median follow-up from enrollment to diagnosis/censoring was 13 years for both breast (7,633 cases) and colorectal cancer (2,290 cases). Median follow-up from diagnosis to death/censoring was 7 years for breast and 5 years for colorectal cancer. In analyses of time from enrollment to death, body mass index (BMI) >= 35 kg/m2 versus 18.5-<25 kg/m2 was associated with higher rates of cancer mortality: HR = 1.99; 95% CI: 1.54, 2.56 for breast cancer (p trend <0.001) and HR = 1.40; 95% CI: 1.04, 1.88 for colorectal cancer (p trend = 0.05). However, in analyses of time from diagnosis to cancer death, trends indicated no significant association (for BMI >= 35 kg/m2 , HR = 1.25; 95% CI: 0.94, 1.67 for breast [p trend = 0.33] and HR = 1.18; 95% CI: 0.84, 1.86 for colorectal cancer [p trend = 0.39]). We conclude that a risk factor that increases disease incidence will increase disease-specific mortality. Yet, its influence on postdiagnosis survival can vary, and requires consideration of additional design and analysis issues such as selection bias. Quantitative tools allow joint modeling to compare an exposure's influence on time from enrollment to disease incidence and time from diagnosis to death. PMID- 28833076 TI - The immune system prevents recurrence of transplanted but not autochthonous antigenic tumors after oncogene inactivation therapy. AB - Targeted oncogene inactivation by small molecule inhibitors can be very effective but tumor recurrence is a frequent problem in the clinic. Therapy by inactivation of the cancer-driving oncogene in transplanted tumors was shown to be augmented in the presence of T cells. However, these experiments did not take into account the long-term, usually tolerogenic, interaction of de novo malignancies with the immune system. Here, we employed mice, in which SV40 large T (Tag) and firefly luciferase (Luc) as fusion protein (TagLuc) could be regulated with the Tet-on system and upon activation resulted in tumors after a long latency. TagLuc inactivation induced profound tumor regression, demonstrating sustained oncogene addiction. While tumor relapse after TagLuc inactivation was prevented in immunocompetent mice bearing transplanted tumors, autochthonous tumors relapsed or recurred after therapy discontinuation indicating that the immune system that coevolved with the malignancy over an extended period of time lost the potency to mount an efficient anti-tumor immune response. By contrast, adoptively transferred CD8+ T cells targeting the cancer-driving oncogene eradicated recurrent autochthonous tumors, highlighting a suitable therapy option in a clinically relevant model. PMID- 28833077 TI - Sexually antagonistic evolution caused by male-male competition in the pistil. AB - Although sexual selection and sexual conflict are important evolutionary forces in animals, their significance in plants is uncertain. In hermaphroditic organisms, such as many plants, sexual conflict may occur both between mating partners (interlocus conflict) and between male and female sex roles within an individual (intralocus conflict). We performed experimental evolution, involving lines that were crossed with either one or two pollen donors (monogamous or polyandrous lines), in the hermaphroditic plant (Collinsia heterophylla) where early fertilizations are associated with female fitness costs (reduced seed set). Artificial polyandry for four generations resulted in enhanced pollen performance and increased female fitness costs compared to the monogamous and source (starting material) lines. Female fitness was also reduced in the monogamous line, indicating a possible trade-off between sex roles, resulting from early pollination. We performed a second experiment to investigate a potential harming effect of pollen performance on seed set. We found that high siring success of early arriving pollen competing with later-arriving pollen was associated with high female fitness costs, consistent with an interlocus sexual conflict. Our study provides evidence for the importance of sexual selection in shaping evolution of plant reproductive strategies, but also pinpoints the complexity of sexual conflict in hermaphroditic species. PMID- 28833078 TI - Case report of induced medical abortion following depot administration of medroxyprogesterone acetate. PMID- 28833079 TI - Cancer-associated fecal microbial markers in colorectal cancer detection. AB - Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harboring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a "high-risk" microbial pattern to other further diagnostic procedures such as colonoscopy. PMID- 28833080 TI - Non-invasive monitoring of the cardiac effects of continuous intravenous oxytocin infusion during cesarean delivery. PMID- 28833082 TI - Use of bulldog vascular clamps to reduce intraoperative bleeding during cesarean hysterectomy for placenta percreta. PMID- 28833081 TI - Transcriptional repressor Blimp1 regulates follicular regulatory T-cell homeostasis and function. AB - The B-lymphocyte-induced maturation protein 1 (Blimp1) regulates T-cell homeostasis and function. Loss of Blimp1 could double the proportion of follicular regulatory T (Tfr) cells. However, the effects that Blimp1 may have on the function of Tfr cells remain unknown. Here we document the function for Blimp1 in Tfr cells in vitro and in vivo. Data presented in this study demonstrate that Tfr cells indirectly inhibit the activation and differentiation of B cells by negatively regulating follicular helper T cells, so lowering the secretion of antibody. Lack of Blimp1 makes the immune suppression function of Tfr cells impaired in vitro. In the in vivo study, adoptive transfer of Tfr cells could reduce immune responses in germinal centres and relieve the muscle weakness symptoms of mice with experimental autoimmune myasthenia gravis. Blimp1 deficiency resulted in reduced suppressive ability of Tfr cells. This study identifies that Tfr cells are potent suppressors of immunity and are controlled by Blimp1. PMID- 28833083 TI - Why are some plant-pollinator networks more nested than others? AB - Empirical studies have found that the mutualistic interactions forming the structure of plant-pollinator networks are typically more nested than expected by chance alone. Additionally, theoretical studies have shown a positive association between the nested structure of mutualistic networks and community persistence. Yet, it has been shown that some plant-pollinator networks may be more nested than others, raising the interesting question of which factors are responsible for such enhanced nested structure. It has been argued that ordered network structures may increase the persistence of ecological communities under less predictable environments. This suggests that nested structures of plant pollinator networks could be more advantageous under highly seasonal environments. While several studies have investigated the link between nestedness and various environmental variables, unfortunately, there has been no unified answer to validate these predictions. Here, we move from the problem of describing network structures to the problem of comparing network structures. We develop comparative statistics, and apply them to investigate the association between the nested structure of 59 plant-pollinator networks and the temperature seasonality present in their locations. We demonstrate that higher levels of nestedness are associated with a higher temperature seasonality. We show that the previous lack of agreement came from an extended practice of using standardized measures of nestedness that cannot be compared across different networks. Importantly, our observations complement theory showing that more nested network structures can increase the range of environmental conditions compatible with species coexistence in mutualistic systems, also known as structural stability. This increase in nestedness should be more advantageous and occur more often in locations subject to random environmental perturbations, which could be driven by highly changing or seasonal environments. This synthesis of theory and observations could prove relevant for a better understanding of the ecological processes driving the assembly and persistence of ecological communities. PMID- 28833084 TI - Pregnancy outcomes among patients with prior bladder exstrophy. PMID- 28833085 TI - Development of a strategy and computational application to select candidate protein analogues with reduced HLA binding and immunogenicity. AB - Unwanted immune responses against protein therapeutics can reduce efficacy or lead to adverse reactions. T-cell responses are key in the development of such responses, and are directed against immunodominant regions within the protein sequence, often associated with binding to several allelic variants of HLA class II molecules (promiscuous binders). Herein, we report a novel computational strategy to predict 'de-immunized' peptides, based on previous studies of erythropoietin protein immunogenicity. This algorithm (or method) first predicts promiscuous binding regions within the target protein sequence and then identifies residue substitutions predicted to reduce HLA binding. Further, this method anticipates the effect of any given substitution on flanking peptides, thereby circumventing the creation of nascent HLA-binding regions. As a proof-of principle, the algorithm was applied to Vatreptacog alpha, an engineered Factor VII molecule associated with unintended immunogenicity. The algorithm correctly predicted the two immunogenic peptides containing the engineered residues. As a further validation, we selected and evaluated the immunogenicity of seven substitutions predicted to simultaneously reduce HLA binding for both peptides, five control substitutions with no predicted reduction in HLA-binding capacity, and additional flanking region controls. In vitro immunogenicity was detected in 21.4% of the cultures of peptides predicted to have reduced HLA binding and 11.4% of the flanking regions, compared with 46% for the cultures of the peptides predicted to be immunogenic. This method has been implemented as an interactive application, freely available online at http://tools.iedb.org/deimmunization/. PMID- 28833088 TI - Abstracts of the 105th , FDI World Dental Congress, September 2017. PMID- 28833086 TI - The alpha1beta1 region is crucial for biofilm enhancement activity of MTC28 in Mycobacterium smegmatis. AB - We show here that MTC28, a secretory antigen of 28 kDa from Mycobacterium tuberculosis, is involved in biofilm formation. The exogenous addition of MTC28 to the culture medium as well its expression in Mycobacterium smegmatis mc2 155 shows an enhancement in biofilm formation, which leads to drug resistance. Structural analysis of MTC28 followed by mutational studies confirms the role of its alpha1beta1 region in the biofilm enhancement activity. Confocal and flow cytometry studies show that the alpha1beta1 region of MTC28 is crucial for binding to the M. smegmatis cell wall. The enhancement in biofilm formation due to MTC28 is also observed in M. tuberculosis H37Ra. This is the first report on the structure-function relationship of MTC28. PMID- 28833087 TI - Menstrual pain and risk of epithelial ovarian cancer: Results from the Ovarian Cancer Association Consortium. AB - Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR = 1.07, 95% CI: 1.01 1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR = 1.48, 95% CI: 1.10 1.99) and serous borderline (OR = 1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed. PMID- 28833089 TI - Life stage and species identity affect whether habitat subsidies enhance or simply redistribute consumer biomass. AB - Quantifying the response of mobile consumers to changes in habitat availability is essential for determining the degree to which population-level productivity is habitat limited rather than regulated by other, potentially density-independent factors. Over landscape scales, this can be explored by monitoring changes in density and foraging as habitat availability varies. As habitat availability increases, densities may: (1) decrease (unit-area production decreases; weak habitat limitation); (2) remain stable (unit-area production remains stable; habitat limitation) or (3) increase (unit-area production increases; strong habitat limitation). We tested the response of mobile estuarine consumers over 5 months to changes in habitat availability in situ by comparing densities and feeding rates on artificial reefs that were or were not adjacent to neighbouring artificial reefs or nearby natural reefs. Using either constructed or natural reefs to manipulate habitat availability, we documented threefold density decreases among juvenile stone crabs as habitat increased (i.e. weak habitat imitation). However, for adult stone crabs, density remained stable across treatments, demonstrating that habitat limitation presents a bottleneck in this species' later life history. Oyster toadfish densities also did not change with increasing habitat availability (i.e. habitat limitation), but densities of other cryptic fishes decreased as habitat availability increased (i.e. weak limitation). Feeding and abundance data suggested that some mobile fishes experience habitat limitation, or, potentially in one case, strong limitation across our habitat manipulations. These findings of significant, community-level habitat limitation provide insight into how global declines in structurally complex estuarine habitats may have reduced the fishery production of coastal ecosystems. PMID- 28833091 TI - Invasive earthworms erode soil biodiversity: A meta-analysis. AB - Biological invasions pose a serious threat to biodiversity and ecosystem functioning across ecosystems. Invasions by ecosystem engineers, in particular, have been shown to have dramatic effects in recipient ecosystems. For instance, invasion by earthworms, a below-ground invertebrate ecosystem engineer, in previously earthworm-free ecosystems alters the physico-chemical characteristics of the soil. Studies have shown that such alterations in the soil can have far reaching impacts on soil organisms, which form a major portion of terrestrial biodiversity. Here, we present the first quantitative synthesis of earthworm invasion effects on soil micro-organisms and soil invertebrates based on 430 observations from 30 independent studies. Our meta-analysis shows a significant decline of the diversity and density of soil invertebrates in response to earthworm invasion with anecic and endogeic earthworms causing the strongest effects. Earthworm invasion effects on soil micro-organisms were context dependent, such as depending on functional group richness of invasive earthworms and soil depth. Microbial biomass and diversity increased in mineral soil layers, with a weak negative effect in organic soil layers, indicating that the mixing of soil layers by earthworms (bioturbation) may homogenize microbial communities across soil layers. Our meta-analysis provides a compelling evidence for negative effects of a common invasive below-ground ecosystem engineer on below-ground biodiversity of recipient ecosystems, which could potentially alter the ecosystem functions and services linked to soil biota. PMID- 28833092 TI - Leaving the placenta in situ versus conservative and radical surgery in the treatment of placenta accreta spectrum disorders. AB - OBJECTIVE: To compare different treatment methods in the management of placenta accreta spectrum (PAS) disorders. METHODS: In a retrospective cohort study, medical records were retrieved for patients who underwent elective surgery at 24 weeks of pregnancy or more after a diagnosis of PAS disorder (creta, increta, or percreta) at a center in Turkey between May 2, 2010, and August 10, 2016. The final analysis included patients whose diagnosis was confirmed intraoperatively and for whom complete data were available. Patients were divided into three groups: group 1 included those who underwent hysterectomy without placental removal, group 2 included patients whose placenta was left in situ, and group 3 included those who underwent placental removal and conservative surgery. RESULTS: Among 79 included patients (33 creta, 18 increta, 28 percreta), 27 (34%) were in group 1, 15 (19%) in group 2, and 37 (47%) in group 3. Total blood loss and the amounts of blood products transfused were lowest in group 2; significant differences between groups were noted (all P <= 0.001). Surgical complication rates were similar between groups (4/27 [15%], 1/15 [7%], and 11/37 [30%], respectively; P=0.119). Overall uterine preservation rates were not significantly different between groups 2 and 3 (14/15 [93%] vs 33/37 [89%]; P>0.99). CONCLUSION: Leaving the placenta in situ could become the treatment of choice for PAS disorders. PMID- 28833090 TI - Development of the LYVE-1 gene with an acidic-amino-acid-rich (AAAR) domain in evolution is associated with acquisition of lymph nodes and efficient adaptive immunity. AB - CRSBP-1 (mammalian LYVE-1) is a membrane glycoprotein highly expressed in lymphatic endothelial cells (LECs). It has multiple ligands, including hyaluronic acid (HA) and growth factors/cytokines (e.g., PDGF-BB and VEGF-A) containing CRS motifs (clusters of basic amino-acid residues). The ligand binding activities are mediated by Link module and acidic-amino-acid-rich (AAAR) domains, respectively. These CRSBP-1/LYVE-1 ligands have been shown to induce opening of lymphatic intercellular junctions in LEC monolayers and in lymphatic vessels in wild-type mice. We hypothesize that CRSBP-1/LYVE-1 ligands, particularly CRS-containing growth factors/cytokines, are secreted by immune and cancer cells for lymphatic entry during adaptive immune responses and lymphatic metastasis. We have looked into the origin of the Link module and AAAR domain of LYVE-1 in evolution and its association with the development of lymph nodes and efficient adaptive immunity. Lymph nodes represent the only major recent innovation of the adaptive immune systems in evolution particularly to mammals and bird. Here we demonstrate that the development of the LYVE-1 gene with the AAAR domain in evolution is associated with acquisition of lymph nodes and adaptive immunity. LYVE-1 from other species, which have no lymph nodes, lack the AAAR domain and efficient adaptive immunity. Synthetic CRSBP-1 ligands PDGF and VEGF peptides, which contain the CRS motifs of PDGF-BB and VEGF-A, respectively, specifically bind to CRSBP-1 but do not interact with either PDGFbetaR or VEGFR2. These peptides function as adjuvants by enhancing adaptive immunity of pseudorabies virus (PRV) vaccine in pigs. These results support the notion that LYVE-1 is involved in adaptive immunity in mammals. PMID- 28833093 TI - Multifaceted role of IL-21 in rheumatoid arthritis: Current understanding and future perspectives. AB - Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder designated with hyperplastic synovium, bone destruction and cartilage degradation. Current therapies involve targeting major cytokines and inflammatory mediators involved in RA to alleviate the pain and provide a temporary relief. Interleukin 21 (IL-21), a recently identified cytokine is known to possess a versatile role in modulating the cells of the RA synovium. Over the past decade, the pleiotropic role of IL-21 in RA pathogenesis has been implicated in several aspects. T helper 17 (Th17) and follicular T helper cells (Tfh), being the key immunomodulators of the RA synovium secrete high amounts of IL-21 during disease progression. Several studies have provided experimental evidences elucidating the multifaceted role of IL-21 in RA disease progression. IL-21 has the potential to activate T cells, B cells, monocytes/macrophages and synovial fibroblasts in RA pathogenesis through activation of JAK-STAT, MAPK and PI3K/Akt signaling pathways. Till date, therapies targeting Th17 cells and its inflammatory cytokines have been under investigation and are subjected to various clinical trials. This review showcases the role of IL-21 in RA pathogenesis and recent reports implicating its function in various immune cells, major signaling pathways, and in promoting osteoclastogenesis. PMID- 28833094 TI - Progress and prospects of circular RNAs in Hepatocellular carcinoma: Novel insights into their function. AB - Hepatocellular carcinoma (HCC) is one of the most predominant subjects of liver malignancies, which arouses global concern in the recent years. Advanced studies have found that Circular RNAs (circRNAs) are differentially expressed in HCC, with its regulatory capacity in HCC pathogenesis and metastasis. However, the underlying mechanism remains largely unknown. In this review, we summarized the functions and mechanisms of those aberrantly expressed circRNAs in HCC tissues. We hope to enlighten more comprehensive studies on the detailed mechanisms of circRNAs and explore their potential values in clinic applications. It revealed that hsa_circ_0004018 can be used as a potential biomarker in HCC diagnosis, with its superior sensitivity to alpha-fetoprotein (AFP). Notably, the correlation of circRNA abundance in the proliferation of liver regeneration (LR) has recently been clarified and different circRNA profiles served as candidates for nonalcoholic steatohepatitis (NASH) diagnosis also be discussed. Therefore, the improved understanding of circRNAs in HCC pathogenesis and metastasis proposed a novel basis for the early diagnosis in HCC patients, which provides a useful resource to explore the pathogenesis of HCC. PMID- 28833095 TI - 3-D range of motion envelopes reveal interacting degrees of freedom in avian hind limb joints. AB - Measuring range of motion (ROM) is a valuable technique that can link bone morphology to joint function in both extant and extinct taxa. ROM results are commonly presented as tables or graphs of maxima and minima for each rotational degree of freedom. We investigate the interactions among three degrees of freedom using X-ray reconstruction of moving morphology (XROMM) to measure ROM of the main hind limb joints of Helmeted Guineafowl (Numida meleagris). By plotting each rotation on an axis, we generate three-dimensional ROM volumes or envelopes composed of hundreds of extreme joint positions for the hip, knee, and intertarsal joints. We find that the shapes of ROM volumes can be quite complex, and that the contribution of long-axis rotation is often substantial. Plotting in vivo poses from individual birds executing different behaviors shows varying use of potential rotational combinations within their ROM envelopes. XROMM can provide unprecedented high-resolution data on the spatial relationship of skeletal elements and thereby illuminate/elucidate the complex ways in which soft and hard tissues interact to produce functional joints. In joints with three rotational degrees of freedom, two-dimensional representations of ROM (flexion/extension and abduction/adduction) are incomplete. PMID- 28833096 TI - Heparan sulfate proteoglycan deficiency up-regulates the intracellular production of nitric oxide in Chinese hamster ovary cell lines. AB - We investigated the role of glycosaminoglycans (GAGs) in the regulation of endothelial nitric oxide synthase (eNOS) activity in wild-type CHO-K1 cells and in xylosyltransferase-deficient CHO-745 cells. GAGs inhibit the integrin/FAK/PI3K/AKT signaling pathway in CHO-K1 cells, decreasing the phosphorylation of eNOS at Ser1177. Furthermore, in CHO-K1 cells, eNOS and PKCalpha are localized at sphingolipid- and cholesterol-rich domains in the plasma membrane called caveolae. At caveolae, PKCalpha activation stimulates the phosphorylation of eNOS on Thr495, resulting in further inhibition of NO production in these cells. In our data, CHO-745 cells generate approximately 12 fold more NO than CHO-K1 cells. Increased NO production in CHO-745 cells promotes higher rates of protein S-nitrosylation and protein tyrosine nitration. Regarding reactive oxygen species (ROS) production, CHO-745 cells show lower basal levels of superoxide (O2- ) than CHO-K1 cells. In addition, CHO-745 cells express higher levels of GPx, Trx1, and catalase than CHO-K1 cells, suggesting that CHO-745 cells are in a constitutive nitrosative/oxidative stress condition. Accordingly, we showed that CHO-745 cells are more sensitive to oxidant-induced cell death than CHO-K1 cells. The high concentration of NO and reactive oxygen species generated by CHO-745 cells can induce simultaneous mitochondrial biogenesis and antioxidant gene expression. These observations led us to propose that GAGs are part of a regulatory mechanism that participates in eNOS activation and consequently regulates nitrosative/oxidative stress in CHO cells. PMID- 28833097 TI - Retrospective surveys of obstetric red cell transfusion practice in the UK and USA. AB - OBJECTIVE: To examine whether professional guidance promoting a policy of restrictive blood transfusion is being followed. METHODS: A retrospective analysis of post-delivery transfusion data from 17 maternity units in the UK (1988-2000) was undertaken. Additionally, an audit was performed of women receiving one or two units of red cells 6-24 hours after delivery at three centers in the UK and USA in 2013-2016. RESULTS: Between 1988 and 2000, 4700 women received one or two transfusions: 303 (6.4%) received one unit and 4397 (93.6%) received two. Median estimated blood loss (EBL) was similar in both groups (600 mL [IQR 400-1000] vs 700 mL [IQR 400-1000], respectively; P=0.862]. Between 2013 and 2016, 41, 22, and 64 women received one or two units during transfusion at centers A, B, and C, respectively. Two units were transfused for 40 (97.6%) of the women in center A, 21 (95.5%) at center B, and 58 (90.6%) at center C. Median EBL was similar, irrespective of whether one or two units were given. CONCLUSION: Current transfusion practice deviates from evidence-based guidelines. Either by default or longstanding tradition, more women receive two rather than one unit despite similar EBL. PMID- 28833099 TI - Simvastatin induces G1 arrest by up-regulating GSK3beta and down-regulating CDK4/cyclin D1 and CDK2/cyclin E1 in human primary colorectal cancer cells. AB - Simvastatin (SIM), a widely used cholesterol-lowering drug, also exhibits tumor suppressive potentials in several types of malignancy. Colorectal cancer (CRC), the third most common malignant neoplasm, accounts for the second most leading cause of cancer-related deaths worldwide. In the present study, we investigated the anticancer effects of SIM on CRC using primary cancer cells lines (CPs: CP1 to CP5) isolated from five Taiwanese colorectal cancer patients as a model for colorectal cancer. We treated all five CPs with SIM for 24-72 hr and observed the respective cell viability by an MTT assay. SIM increased DNA content of the G1 phase, but did not induce apoptosis/necrosis in CPs as shown by flow cytometry with propidium iodide (PI)/annexin V double staining and PI staining. The expression of G1 phase-related proteins was analyzed by RT-PCR and Western blotting. SIM suppressed cell growth and induced cell cycle G1 -arrest by suppressing the expression of CDK4/cyclin D1 and CDK2/cyclin E1, but elevating the expression of glycogen synthase kinase 3beta in CPs. Our findings indicate that SIM may have antitumor activity in established colorectal cancer. PMID- 28833098 TI - Caffeine May Reduce Perceived Sweet Taste in Humans, Supporting Evidence That Adenosine Receptors Modulate Taste. AB - Multiple recent reports have detailed the presence of adenosine receptors in sweet sensitive taste cells of mice. These receptors are activated by endogenous adenosine in the plasma to enhance sweet signals within the taste bud, before reporting to the primary afferent. As we commonly consume caffeine, a powerful antagonist for such receptors, in our daily lives, an intriguing question we sought to answer was whether the caffeine we habitually consume in coffee can inhibit the perception of sweet taste in humans. 107 panelists were randomly assigned to 2 groups, sampling decaffeinated coffee supplemented with either 200 mg of caffeine, about the level found in a strong cup of coffee, or an equally bitter concentration of quinine. Participants subsequently performed sensory testing, with the session repeated in the alternative condition in a second session on a separate day. Panelists rated both the sweetened coffee itself and subsequent sucrose solutions as less sweet in the caffeine condition, despite the treatment having no effect on bitter, sour, salty, or umami perception. Panelists were also unable to discern whether they had consumed the caffeinated or noncaffeinated coffee, with ratings of alertness increased equally, but no significant improvement in reaction times, highlighting coffee's powerful placebo effect. This work validates earlier observations in rodents in a human population. PMID- 28833100 TI - Language impairment and comorbid vulnerabilities among young people in custody. AB - BACKGROUND: While the prevalence of language and communication difficulties among young people in custody is well established, holistic understanding of the complexity and co-occurrence of additional vulnerabilities among this population are rare. METHODS: Ninety-three young people in a young offenders institution in England were assessed using the Comprehensive Health Assessment Tool, the Test of Word Knowledge, and a range of additional assessments of communication, cognition, and neurodevelopmental difficulties. RESULTS: Forty-seven percent of the young people demonstrated an aspect of language skills significantly below the population average, with more than one in four identified as having impairment. Only one in four of those with an impairment had previously accessed speech and language services. Language needs were associated with difficulties with social communication and nonverbal cognition, as well as higher risk of self harm and substance misuse. CONCLUSIONS: Earlier identification of language difficulties requires routine assessment of young people at risk of engagement in offending behavior. Where language difficulties are identified, holistic assessments of needs should be undertaken. There is a need for speech and language therapy provision within youth justice services, as well as in other services accessed by young people at risk of engagement in offending. PMID- 28833101 TI - Nurses' perceptions of health beliefs and impact on teaching and practice: a Q sort study. AB - AIM: To understand Chinese nurses' perceptions of health beliefs, their content, origin and the influence of sociocultural factors, as a basis of their evidence based practice. This study contributes to a larger study to establish the health beliefs of Japanese, Australian, Chinese, South Korean and Thai nurses. BACKGROUND: Registered nurses teach patients and students about maintaining or attaining health are subject to the same range of influences and their health beliefs may be antithetical to current health evidence. METHODS: Q-method design using q-sort and interview was used to explore the perspectives on a range of health beliefs of 60 nurses in four cities in China. FINDINGS: Three factors arose from the perceptions of the participants about health and accounted for 50.2% of the total variance: (1) social impact, (2) 'the importance of evidence', and (3) beliefs rooted in culture. DISCUSSION: Influence on nurses' health beliefs was explored in terms of the internalized and frequently unconscious beliefs, values and norms tying them to their communities, reflecting the need for nurses to be aware of their health beliefs and behaviours. CONCLUSIONS: Education for nurses in practice needs to acknowledge that individual practitioners' beliefs strongly influence health teaching for patients and families. In order to implement evidenced-based practice and teach in line with current evidence nurses need to critically examine and reflect on the impact of culture, society and the media on their own health beliefs. IMPLICATIONS FOR NURSING POLICY AND HEALTH POLICY: Education policy needs to consider that culture and societal pressures affect nurses' health beliefs and practice. Critical thinking, reflective and evidence-based practice need to be emphasized in clinical training and nurse education. China also needs to develop policies to allow nurses to be able to assess the reliability of health information on the Internet and to make quality health research more available. PMID- 28833102 TI - Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells. AB - Homocysteine (Hcy) causes endothelial dysfunction by inducing oxidative stress in most neurodegenerative disorders. This dysfunction is highly correlated with mitochondrial dynamics such as fusion and fission. However, there are no strategies to prevent Hcy-induced mitochondrial remodeling. Tetrahydrocurcumin (THC) is an anti-inflammatory and anti-oxidant compound. We hypothesized that THC may ameliorates Hcy-induced mitochondria remodeling in mouse brain endothelial cells (bEnd3) cells. bEnd3 cells were exposed to Hcy treatment in the presence or absence of THC. Cell viability and autophagic cell death were measured with MTT and MDC staining assay. Reactive oxygen species (ROS) production was determined using DCFH-DA staining by confocal microscopy. Autophagy flux was assessed using a conventional GFP-microtubule-associated protein 1 light chain 3 (LC3) dot assay. Interaction of phagophore marker LC-3 with mitochondrial receptor NIX was observed by confocal imaging. Mitochondrial fusion and fission were evaluated by western blot and RT-PCR. Our results demonstrated that Hcy resulted in cell toxicity in a dose-dependent manner and supplementation of THC prevented the detrimental effects of Hcy on cell survival. Furthermore, Hcy also upregulated fission marker (DRP-1), fusion marker (Mfn2), and autophagy marker (LC-3). Finally, we observed that Hcy activated mitochondrial specific phagophore marker (LC-3) and co-localized with the mitochondrial receptor NIX, as viewed by confocal microscopy. Pretreatment of bEnd3 with THC (15 MUM) ameliorated Hcy induced oxidative damage, mitochondrial fission/fusion, and mitophagy. Our studies strongly suggest that THC has beneficial effects on mitochondrial remodeling and could be developed as a potential therapeutic agent against hyperhomocysteinemia (HHcy) induced mitochondrial dysfunction. PMID- 28833103 TI - Mouse acidic mammalian chitinase exhibits transglycosylation activity at somatic tissue pH. AB - Mouse acidic mammalian chitinase (AMCase) degrades chitin with highest efficiency at pH 2.0 and is active up to pH 8.0. Here, we report that mouse AMCase also exhibits transglycosylation activity under neutral conditions. We incubated natural and artificial chitin substrates with mouse AMCase at pH 2.0 or 7.0 and analyzed the resulting oligomers using an improved method of fluorescence assisted carbohydrate electrophoresis. Mouse AMCase produces primarily dimers of N-acetyl-d-glucosamine [(GlcNAc)2 ] under both pH conditions while generating transglycosylated (GlcNAc)3 primarily at pH 7.0 and at lower levels at pH 2.0. These results indicate that mouse AMCase catalyzes hydrolysis as well as transglycosylation and suggest that this enzyme can play a novel role under physiological conditions in peripheral tissues, such as the lungs. PMID- 28833104 TI - Low folate metabolic stress reprograms DNA methylation-activated sonic hedgehog signaling to mediate cancer stem cell-like signatures and invasive tumour stage specific malignancy of human colorectal cancers. AB - The mechanistic role of colonic low folate metabolic stress (LFMS) in colorectal cancer (CRC) malignancy development remains unknown. Folate analysis on the 99 paired human CRC tissues localized LFMS to the deep invasive T3/T4 staged tumours with hypo-methylated sonic hedgehog (Shh) promoter region and amplified expressions of Shh ligand and Gli1 effector, which coincided with deregulated expressions of the epithelial-mesenchymal transition (EMT) mediators. Colonic folate levels of CRC were inversely correlated with pluripotent expressions of the SOX2, NANOG and OCT4 markers (p < 0.05). Exposure of human colon adenocarcinoma cells to LFMS microenvironment significantly hypomethylated Shh promoter region, activated Shh signaling, induced transcript and protein expressions of the pluripotent markers, promoted trans-differentiation as EMT by deregulation of Snail mediator and epithelial marker E-cadherin, increased MMP2/MMP9 enzymatic digestion on matrix protein for invasion, and promoted self renewal capability of anchorage-independent tumor-spheroid formation. LFMS induced cancer stem cell (CSC) signature and CRC invasion is synergized with inhibition of DNA methylation by 5-Aza-2-deoxycytidine (5AZA) in rewiring EMT genotypes, which can be blockade by the Shh inhibitor (cyclopamine). The in vivo and in vitro data corroboratively identify CSC-like molecular targets specific to the LFMS-predisposed invasive CRC through reprogramming DNA methylation-activated Shh signaling. The study highlights CSC targets specific to LFMS-predisposed invasive CRC in optimizing folate co-chemotherapy to minimize tumour metastasis potential of CRC patients. PMID- 28833105 TI - Bactericidal Efficacy of Hydrogen Peroxide-Based Disinfectants Against Gram Positive and Gram-Negative Bacteria on Stainless Steel Surfaces. AB - : In order to develop disinfectant formulations that leverage the effectiveness of hydrogen peroxide (H2 O2 ), this study evaluated the bactericidal efficacy of hydrogen peroxide-based disinfectants against Gram-positive and Gram-negative bacteria on stainless steel surfaces. Low concentration of hydrogen peroxide as 0.5% with a cationic polymer, ethoxylated fatty alcohol, and ethyl alcohol had bactericidal efficacy (reductions >= 4 log10 CFU/mL) against Escherichia coli, Staphylococcus aureus, Enterococcus hirae, and Pseudomonas aeruginosa. Hydrogen peroxide-based disinfectants were more effective against E. hirae and P. aeruginosa than to S. aureus. However, the efficacy of hydrogen peroxide against catalase positive bacteria such as S. aureus was increased when this compound was formulated with low concentrations of benzalkonium chloride or ethyl alcohol, lactic acid, sodium benzoate, cationic polymer, and salicylic acid. This study demonstrates that the use of hydrogen peroxide with other antimicrobial products, in adequate concentrations, had bactericidal efficacy in Gram-positive and Gram negative bacteria on stainless steel surfaces, enabling to reduce the effective concentration of hydrogen peroxide. In the same way, the use of hydrogen peroxide based disinfectants could reduce the concentrations of traditional disinfectants as quaternary ammonium compounds and therefore a reduction of their chemical residues in the environment after being used. PRACTICAL APPLICATION: The study of the bactericidal properties of environmentally nontoxic disinfectants such as hydrogen peroxide, sole or in formulations with other disinfectants against Gram positive and Gram-negative bacteria can enhance the efficacy of various commonly used disinfectant formulations with the hygiene benefits that it entails. Also, the use of hydrogen peroxide formulations can reduce the concentration levels of products that generate environmental residues. PMID- 28833106 TI - Simultaneous Detection of Escherichia coli O157:H7, Salmonella enteritidis, and Listeria monocytogenes at a Very Low Level Using Simultaneous Enrichment Broth and Multichannel SPR Biosensor. AB - : Detection of foodborne pathogens at very low levels is still a challenge. A custom-built multichannel surface plasmon resonance (SPR) biosensor and simultaneous enrichment broth (SEB) were used to develop a simultaneous detection method for 3 important foodborne pathogens, Escherichia coli O157:H7 (O157:H7), Salmonella enteritidis, and Listeria monocytogenes, at a very low level. These 3 foodborne pathogens at a very low level (14, 6, and 28 CFU/25 g (mL) for O157:H7, S. enteritidis, and L. monocytogenes, respectively) were inoculated in SEB and incubated at 37 C for 24 h. Sample prepared from the simultaneous enrichment culture was analyzed using the multichannel SPR biosensor and sensor chip immobilized with polyclonal antibodies specific to each of the target pathogens. O157:H7, S. enteritidis, and L. monocytogenes in chicken were detected simultaneously at an inoculum dose of 14, 6, and 28 CFU/25 g, respectively. Our method using a custom-built multichannel SPR biosensor and enrichment in SEB is expected as a rapid and simultaneous detection method for low levels of O157:H7, S. enteritidis, and L. monocytogenes in food. PRACTICAL APPLICATION: Our method is expected as a rapid and simultaneous detection method for pathogens at very low levels. It has great potential for safety control of food and microbiological detection applications. PMID- 28833107 TI - Clinical Characteristics of Fatal Methamphetamine-related Stroke: A National Study. AB - The study aimed to determine the clinical characteristics of fatal methamphetamine-related stroke in Australia, 2009-2015. There were 38 cases, 60.5% male, with a mean age of 40.3 years. In no case was there evidence that this was the first time methamphetamine had been used by the decedent, and 52.6% had known histories of injecting drug use. The stroke was hemorrhagic in 37 of 38 cases. In 21.1% of cases, the stroke was purely parenchymal and, in 18.4%, involved purely the subarachnoid space. A ruptured berry aneurysm was present in 31.6% and in 68.8% of initial subarachnoid hemorrhages. There was evidence of systemic hypertension in 8 of 25 cases in which full autopsy findings were available. With increased use of methamphetamine, there is a high probability of increased hemorrhagic stroke incidence among young people. In cases of fatal hemorrhagic stroke among young cases presenting to autopsy, the possibility of methamphetamine use should be borne in mind. PMID- 28833108 TI - Composition and Nutrient Value Proposition of Brewers Spent Grain. AB - Brewer's spent grain (BSG), a major brewing industry byproduct, is generated in large quantities annually. This review summarizes research into the composition and preservation of BSG, different extraction techniques for BSG proteins and phenolic acids, and the bioactivities of these phenolic components. Moreover, this article also highlights BSG integration into foodstuff for human consumption and animal feed supplements. BSG is considered a rich source of fiber, protein, and phenolic compounds. The phenolic acids present in BSG are hydroxycinnamic acids (ferulic, p-coumaric, and caffeic acids), which have many biofunctions, such as antioxidant, anticarcinogenic, antiatherogenic, and antiinflammatory activities. Previously, attempts have been made to integrate BSG into human food, such as ready-to-eat snacks, cookies and bread, to increase fiber and protein contents. The addition of BSG to animal feed leads to increased milk yields, higher fat contents in milk, and is a good source of essential amino acids. Therefore, many studies have concluded that integrating the biofunctional compounds in BSG into human food and animal feed has various health benefits. PMID- 28833109 TI - Analysis of liquid suspensions using scanning electron microscopy in transmission: estimation of the water film thickness using Monte-Carlo simulations. AB - Environmental scanning electron microscopy (ESEM) allows the observation of liquids under specific conditions of pressure and temperature. Moreover, when working in the transmission mode, that is in scanning transmission electron microscopy (STEM), nano-objects can be analysed inside a liquid. The contrast in the images is mass-thickness dependent as in STEM-in-TEM (transmission electron microscopy) using closed cells. However, in STEM-in-ESEM, as the liquid-vapour equilibrium is kept dynamically, the thickness of the water droplet remains unknown. In this paper, the contrasts measured in the experimental images are compared with calculations using Monte-Carlo simulations in order to estimate the thickness of water. Two examples are given. On gold nanoparticles, the thickness of a thick film can be estimated thanks to a contrast inversion. On core-shell latex particles, the grey level of the shell compared with those of the core and of the water film gives a relatively precise measurement of the water film thickness. PMID- 28833110 TI - An Objective Measure of Splitting in Parental Alienation: The Parental Acceptance Rejection Questionnaire. AB - Both clinicians and forensic practitioners should distinguish parental alienation (rejection of a parent without legitimate justification) from other reasons for contact refusal. Alienated children-who were not abused-often engage in splitting and lack ambivalence with respect to the rejected parent; children who were maltreated usually perceive the abusive parent in an ambivalent manner. The purpose of this study was to assess the usefulness of the Parental Acceptance Rejection Questionnaire (PARQ) in identifying and quantifying the degree of splitting, which may assist in diagnosing parental alienation. Results showed that severely alienated children engaged in a high level of splitting, by perceiving the preferred parent in extremely positive terms and the rejected parent in extremely negative terms. Splitting was not manifested by the children in other family groups. The PARQ may be useful for both clinicians and forensic practitioners in evaluating children of divorced parents when there is a concern about the possible diagnosis of parental alienation. PMID- 28833111 TI - The effects of receptive and expressive instructional sequences on varied conditional discriminations. AB - Many Early Intensive Behavioral Intervention (EIBI) curricula recommend teaching receptive responding before targeting expressive responding (Leaf & McEachin, 1999; Lovaas, 2003). However, a small literature base suggests that teaching expressive responses first may be more efficient when teaching children with ASD and other developmental disabilities (Petursdottir & Carr, 2011). The present study employed an alternating treatments design to compare the effects of three instructional sequences to teach feature, function, and class to three children diagnosed with ASD: (a) receptive-expressive, (b) expressive-receptive, and (c) mixed. The results suggested that expressive-receptive was the most efficient training sequence for all three participants. Additionally, greater emergent responding was observed with the expressive-receptive training sequence. PMID- 28833112 TI - The Difficult Task of Diagnosing Prostate Cancer Metastases on Dry Bone. AB - The interpretation of pathology on skeletal remains is mandatory for implementing the biological profile and for disease recognition. Prostate cancer is one of the most common tumors, with a high preference for the skeleton as a primary site of metastasis. Its diagnosis on bone is however still ambiguous, due to its "osteoblastic" and resorptive manifestation. This study investigates distribution and appearance of prostate cancer metastases on dry bone on six known cases (selected from the Milano Cemetery Skeletal Collection) and one healthy individual. A macroscopic inspection was performed highlighting the abnormalities observed, describing location, shape, dimension, and aspect. A great amount of proliferative and mixed lesions was noticed, but also cases of pure lytic lesions were displayed. The multiple appearances of the manifestations observed display the difficulty in correctly identifying such a pathology, but also the potential and advantages provided by investigating a study sample with known antemortem history. PMID- 28833113 TI - Dorsal and Ventral Parts of Thalamic Nucleus Submedius Project to Different Areas of Rat Orbitofrontal Cortex: A Single Neuron-Tracing Study Using Virus Vectors. AB - The rodent orbitofrontal cortex is involved in a variety of cognitive and behavioral functions that require thalamic input to be successfully expressed. Although the thalamic nucleus submedius (Sm) is a major source of afferents to the orbitofrontal cortex, thalamocortical projection from the Sm has not been fully elucidated. In the present study, we first divided the rat Sm into dorsal and ventral parts according to the distribution of vesicular glutamate transporter 2-immunoreactive varicosities, which were somatosensory afferents from the brain stem. Subsequently we investigated dendritic and axonal arborizations of individual dorsal and ventral Sm neurons by visualizing the processes with Sindbis virus vectors expressing membrane-targeted fluorescent proteins. The number of dendritic processes of ventral Sm neurons was greater than that of dorsal Sm neurons. In the cerebral cortex, all the reconstructed Sm neurons sent axons primarily to layers 2-5. Interestingly, dorsal Sm neurons formed a single axon arbor exclusively within the ventrolateral orbital area, whereas ventral Sm neurons made two axon arbors in the lateral orbital and ventral orbital areas simultaneously. The spread of each axon arbor was 500-1000 um in diameter in the direction tangential to the cortical surface. These results indicate that the dorsal and ventral Sm comprise two distinct thalamocortical pathways. The dorsal Sm pathway relay somatosensory information to the ventrolateral orbital area and may be involved in emotional and aversive aspects of nociceptive information processing, whereas the ventral Sm pathway seems to co activate distant orbitofrontal cortical areas, and may link their functions under certain circumstances. This article is protected by copyright. All rights reserved. PMID- 28833114 TI - Estimating Biological Characteristics With Virtual Laser Data. AB - Laser scanning technology is increasingly being used in forensic anthropological research to obtain virtual data for archival purposes and post hoc measurement collection. This research compared the measurement accuracy of two laser scanners the FARO Focus3D 330X and the FARO Freestyle3D -against traditionally obtained (i.e., by hand) control data (N = 454). Skeletal data were collected to address a novel question: the ability of laser scanning technology to produce measurements useful for biological characteristic estimation, such as sex and stature. Results indicate that both devices produced measurements very similar to control (c. 3-mm average absolute error), but also illuminate a tendency to under-measure. Despite these findings, the virtual data produced sex and stature estimates that varied little from control-produced estimates, signifying the usefulness of virtual data for preliminary biological identification when the skeletal elements are no longer available for physical analysis. PMID- 28833115 TI - Validation of a One-Step Method for Extracting Fatty Acids from Salmon, Chicken and Beef Samples. AB - : Fatty acid extraction methods are time-consuming and expensive because they involve multiple steps and copious amounts of extraction solvents. In an effort to streamline the fatty acid extraction process, this study compared the standard Folch lipid extraction method to a one-step method involving a column that selectively elutes the lipid phase. The methods were tested on raw beef, salmon, and chicken. Compared to the standard Folch method, the one-step extraction process generally yielded statistically insignificant differences in chicken and salmon fatty acid concentrations, percent composition and weight percent. Initial testing showed that beef stearic, oleic and total fatty acid concentrations were significantly lower by 9-11% with the one-step method as compared to the Folch method, but retesting on a different batch of samples showed a significant 4-8% increase in several omega-3 and omega-6 fatty acid concentrations with the one step method relative to the Folch. Overall, the findings reflect the utility of a one-step extraction method for routine and rapid monitoring of fatty acids in chicken and salmon. Inconsistencies in beef concentrations, although minor (within 11%), may be due to matrix effects. PRACTICAL APPLICATION: A one-step fatty acid extraction method has broad applications for rapidly and routinely monitoring fatty acids in the food supply and formulating controlled dietary interventions. PMID- 28833116 TI - Fatal Myocarditis Following Treatment with the PD-1 Inhibitor Nivolumab. AB - Therapeutic antibodies targeting the programmed cell death protein 1 (PD-1) pathway function as immune checkpoint inhibitors, allowing the immune system to recognize tumors which otherwise escape immune surveillance. However, these agents can also elicit an autoimmune response by inhibiting the ability of non neoplastic tissues and regulatory cells to suppress the immune system. Here we present a fatal case of active myocarditis in a 55-year-old man with non-small cell lung cancer which occurred following monotherapy with the PD-1 inhibitor nivolumab (Opdivo). He presented with acute right-sided heart failure and died 1 day after admission. Postmortem examination revealed multiple gelatinous lesions in the myocardium of the interventricular septum and the bilateral atria and ventricles which had microscopic features diagnostic of myocarditis. Subsequent studies failed to identify an infectious cause. Immune checkpoint inhibitors are an increasingly common addition to anticancer regimens and they should be considered in the evaluation of acute myocarditis. PMID- 28833117 TI - An Evidence-Based Forensic Taxonomy of Windows Phone Communication Apps. AB - Communication apps can be an important source of evidence in a forensic investigation (e.g., in the investigation of a drug trafficking or terrorism case where the communications apps were used by the accused persons during the transactions or planning activities). This study presents the first evidence based forensic taxonomy of Windows Phone communication apps, using an existing two-dimensional Android forensic taxonomy as a baseline. Specifically, 30 Windows Phone communication apps, including Instant Messaging (IM) and Voice over IP (VoIP) apps, are examined. Artifacts extracted using physical acquisition are analyzed, and seven digital evidence objects of forensic interest are identified, namely: Call Log, Chats, Contacts, Locations, Installed Applications, SMSs and User Accounts. Findings from this study would help to facilitate timely and effective forensic investigations involving Windows Phone communication apps. PMID- 28833118 TI - Maternal smoking during pregnancy and offspring personality in childhood and adulthood. AB - OBJECTIVE: Maternal smoking during pregnancy (MSDP) has been associated with offspring internalizing and externalizing disorders. The purpose of this research is to examine whether MSDP is also associated with variations in normal personality traits in childhood and adulthood. METHOD: This study uses four independent samples (total N = 16,323) to examine whether there are mean-level differences in offspring personality traits by MSDP, controlling for relevant sociodemographic factors. Two samples are of children (Ns = 3,782 and 3,841) and two samples are of adults (Ns = 1,786 and 6,914). RESULTS: A meta-analysis across the four samples indicated that offspring of mothers who did smoke during pregnancy scored higher in Neuroticism (p = .000) and Extraversion (p = .003) and lower in Conscientiousness (p = .002) than offspring of mothers who did not smoke during pregnancy. The association between MSDP and Neuroticism and Conscientiousness held across both childhood and adulthood and when propensity score matching was used, whereas the association with Extraversion was only apparent in adulthood and did not hold with propensity scores. CONCLUSIONS: These results suggest that MSDP is associated with individual differences in psychological traits in childhood and adulthood and may be one prenatal factor that contributes to trait Neuroticism and Conscientiousness. PMID- 28833120 TI - Cover Image, Volume 232, Number 12, December 2017. AB - Cover: The cover image, by Michaela R. Reagan et al., is based on the Perspective A Perspective on Malignancy in the Marrow, DOI 10.1002/jcp.25860. PMID- 28833119 TI - The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta-analysis of efficacy and safety. AB - The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment-related adverse event rate, overall survival (OS), and progression-free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open-label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03-2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78-0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72-1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03-2.19, p = 0.036) than that of monotherapy. This meta-analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab-ipilimumab-sargramostim combination should be investigated further. PMID- 28833121 TI - Anthocyanins of Jambolao (Syzygium cumini): Extraction and pH-Dependent Color Changes. AB - : Jambolao fruits are promising sources of anthocyanins, and in this study, the jambolao fruit from the Brazilian Amazonian region was characterized and the efficiency of six ethanol-based solutions to extract anthocyanins was determined. Moreover, the color changes of anthocyanin extracts, as influenced by different pH conditions (pH from 1.0 to 8.0), were evaluated. The fruits exhibited high contents of total anthocyanins (296 mg/100 g) and the CIELAB parameters characterized jambolao as a purple-red colored fruit (a* = 20.30, b* = -4.17, and hab?= 348.39). Among the six different ethanol-based solutions, ethanol 95% with 1% of HCl (v/v) was the most efficient solution to extract anthocyanins from jambolao fruits. Furthermore, the CIELAB parameters were characterized as useful tool to monitor the color changes of anthocyanins of jambolao over the tested pH range. Therefore, jambolao fruits from Amazonian region have technological potential for the application by food, pharmaceutical, and cosmetic industries. PRACTICAL APPLICATION: Jambolao fruits are great source of anthocyanins and the incorporation of these natural pigments as food colorants is not only valuable to improve overall appearance, but it is also beneficial to human health. The production of natural extracts with high levels of anthocyanins from jambolao can be considered a very useful approach to the food, pharmaceutical and cosmetic industries. PMID- 28833122 TI - Establishment of a cell line with high transfection efficiency from zebrafish Danio rerio embryos and its susceptibility to fish viruses. AB - A cell line ZBE3 isolated from a continuous cell culture derived from zebrafish Danio rerio blastomeres by clonal growth was characterized. ZBE3 cells had been subcultured for >120 passages since the initial primary culture of the blastomeres. The ZBE3 cells grow stably at temperature from 20 to 32 degrees C with an optimum temperature of 28 degrees C in ESM2 or ESM4 medium with 15% foetal bovine serum (FBS). The optimum FBS concentration for ZBE3 cell growth ranged from 15 to 20%. Cytogenetical analysis indicated that the modal chromosome number of ZBE3 cells was 50, the same as the diploid chromosome number of D. rerio. Significant cytopathic effect was observed in ZBE3 cells after infection with redspotted grouper nervous necrosis virus, Singapore grouper iridovirus and grass carp reovirus, and the viral replication in the cells was confirmed by real time quantitative PCR and transmission electron microscopy, indicating the susceptibility of ZBE3 cells to the three fish viruses. After transfected with pEGFP-N3 plasmid, ZBE3 cells showed a transfection efficiency of about 40% which was indicated by the percentage of cells expressing green fluorescence protein. The stable growth, susceptibility to fish viruses as well as high transfection efficiency make ZBE3 cells be a useful tool in transgenic manipulation, fish virus-host cell interaction and immune response in fish. PMID- 28833124 TI - Needs assessment for patients food intake monitoring among Indonesian healthcare professionals. AB - AIM: The aim of this study was to provide a needs assessment related to the current practice of food intake monitoring for hospitalized adult patients among healthcare professionals and obtain feedback for the development of a new dietary assessment tool. BACKGROUND: Continuous effort has been made to identify patients at high risk of malnutrition, but monitoring and documentation of nutritional intake are relative less emphasized upon. METHODS: A needs assessment through a cross-sectional study design was carried out at six hospitals in Yogyakarta, Indonesia. A self-administered semi-structured questionnaire was filled out by 111 respondents recruited from three different professions (nurses, dietitians and serving assistants) in the wards. RESULTS: Seventy per cent of the respondents perceived that the current dietary assessment tool used to record patients' food intake was simple; however, the disadvantage of this tool was its tedious process of computing nutritional values of food consumed. Furthermore, more than half respondents encountered problems in conducting food intake record of patients, primarily due to limited number of human resources, followed by time constraints and perception that such dietary assessment as not part of their job scope. DISCUSSION: This study has revealed important information in developing a simple, valid and reliable dietary assessment tool for monitoring food intake of hospitalized patients to be applied by interdisciplinary hospital professionals. CONCLUSIONS: Awareness of the important on monitoring nutrient intake of patients should be emphasized among healthcare professionals. The current dietary assessment tool requires modification due to lengthy time taken to complete the task and poor accuracy in intake estimation. IMPLICATION FOR NURSING AND HEALTH POLICY: Hospitals should provide protocols and guidelines of cooperation among interdisciplinary professionals, including nurses, which includes a simple dietary assessment tool to assist nutritional management of hospitalized patients. PMID- 28833123 TI - Telomere length variation in tumor cells and cancer-associated fibroblasts: potential biomarker for hepatocellular carcinoma. AB - The role of telomere dysfunction and aberrant telomerase activities in hepatocellular carcinoma (HCC) has been overlooked for many years. This study aimed to delineate the variation and prognostic value of telomere length in HCC. Telomere-specific fluorescence in situ hybridization (FISH) and qPCR were used to evaluate telomere length in HCC cell lines, tumor tissues, and isolated non-tumor cells within the tumor. Significant telomere attrition was found in tumor cells and cancer-associated fibroblasts (CAFs) compared to their normal counterparts, but not in intratumor leukocytes or bile duct epithelial cells. Clinical relevance and prognostic value of telomere length were investigated on tissue microarrays of 257 surgically treated HCC patients. Reduced intensity of telomere signals in tumor cells or CAFs correlated with larger tumor size and the presence of vascular invasion (p < 0.05). Shortened telomeres in tumor cells or CAFs associated with reduced survival and increased recurrence, and were identified as independent prognosticators for HCC patients (p < 0.05). These findings were validated in an independent HCC cohort of 371 HCC patients from The Cancer Genome Atlas (TCGA) database, confirming telomere attrition and its prognostic value in HCC. We also showed that telomerase reverse transcriptase promoter (TERTp) mutation correlated with telomere shortening in HCC. Telomere variation in tumor cells and non-tumor cells within the tumor microenvironment of HCC was a valuable prognostic biomarker for this fatal malignancy. (c) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 28833125 TI - Marginal distribution and high heterozygosity of asexual Caloglossa vieillardii (Delesseriaceae, Rhodophyta) along the Australian coasts. AB - In animals and land plants, many asexual species originate through inter- or intraspecific crosses, and such heterozygous asexuals frequently are more abundant than their sexual relatives in marginal habitats. Although asexual species have been reported in various macroalgal taxa, detailed information regarding their distribution, heterozygosity, and origin is limited. Because many asexual tetrasporophyte strains of Caloglossa vieillardii have been isolated from South Australia, far from their core tropical habitats, we re-examined the distribution range of asexual C. vieillardii and genotyped these and other western Pacific strains using an actin gene marker. We confirmed the marginal distribution of the asexuals; however, a small patch of sexual thalli was newly discovered 450 km further west from asexual populations in South Australia. Three heterozygous genotypes and one homozygous genotypes were detected from nine asexual populations; 21 heterozygous strains were obligately asexual, but one homozygous strain suddenly produced sexual gametophytes after several years of culture. We hypothesized that the most abundant heterozygous genotype (defined as type 3/4) in asexual populations occurred by a cross between type 3 and type 4 allele gametophytes, both of which were isolated from the Australian coasts. In the crossing experiments, certain combinations between type 3 females and type 4 males produced tetrasporophytes, which recycled successive tetrasporophytes. In the culture experiments, whereas both sexual and asexual strains successfully produced tetraspores at 12 degrees C, no sexual strains released carpospores below 14 degrees C. However, it is uncertain whether this slight difference of maturation temperature was related to the marginal distribution of asexual C. vieillardii. PMID- 28833127 TI - Effects of the Maillard Reaction on the Immunoreactivity of Amandin in Food Matrices. AB - : Amandin is the major storage protein and allergen in almond seeds. Foods, containing almonds, subjected to thermal processing typically experience Maillard browning reaction. The resulting destruction of amino groups, protein glycation, and/or denaturation may alter amandin immunoreactivity. Amandin immunoreactivity of variously processed almond containing foods was therefore the focus of the current investigation. Commercial and laboratory prepared foods, including those likely to have been subjected to Maillard browning, were objectively assessed by determining Hunter L* , a* , b* values. The L* values for the tested samples were in the range of 31.75 to 85.28 consistent with Maillard browning. Three murine monoclonal antibodies, 4C10, 4F10, and 2A3, were used to determine the immunoreactivity of the targeted samples using immunoassays (ELISA, Western blot, dot blot). The tested foods did not exhibit cross-reactivity indicating that the immunoassays were amandin specific. For sandwich ELISAs, ratio (R) of sample immunoreactivity to reference immunoreactivity was calculated. The ranges of R values were 0.67 to 15.19 (4C10), 1.00 to 11.83 (4F10), and 0.77 to 23.30 (2A3). The results of dot blot and Western blot were consistent with those of ELISAs. Results of these investigations demonstrate that amandin is a stable marker protein for almond detection regardless of the degree of amandin denaturation and/or destruction as a consequence of Maillard reaction encountered under the tested processing conditions. PRACTICAL APPLICATION: Foods containing almond are often subjected to processing prior to consumption. Amandin, the major allergen in almond, may experience Maillard reaction. Understanding the change in amandin immunoreactivity as a result of Maillard reaction is important for amandin detection and production of hypoallergenic food products. PMID- 28833126 TI - Visuo-manual tracking: does intermittent control with aperiodic sampling explain linear power and non-linear remnant without sensorimotor noise? AB - KEY POINTS: A human controlling an external system is described most easily and conventionally as linearly and continuously translating sensory input to motor output, with the inevitable output remnant, non-linearly related to the input, attributed to sensorimotor noise. Recent experiments show sustained manual tracking involves repeated refractoriness (insensitivity to sensory information for a certain duration), with the temporary 200-500 ms periods of irresponsiveness to sensory input making the control process intrinsically non linear. This evidence calls for re-examination of the extent to which random sensorimotor noise is required to explain the non-linear remnant. This investigation of manual tracking shows how the full motor output (linear component and remnant) can be explained mechanistically by aperiodic sampling triggered by prediction error thresholds. Whereas broadband physiological noise is general to all processes, aperiodic sampling is associated with sensorimotor decision making within specific frontal, striatal and parietal networks; we conclude that manual tracking utilises such slow serial decision making pathways up to several times per second. ABSTRACT: The human operator is described adequately by linear translation of sensory input to motor output. Motor output also always includes a non-linear remnant resulting from random sensorimotor noise from multiple sources, and non-linear input transformations, for example thresholds or refractory periods. Recent evidence showed that manual tracking incurs substantial, serial, refractoriness (insensitivity to sensory information of 350 and 550 ms for 1st and 2nd order systems respectively). Our two questions are: (i) What are the comparative merits of explaining the non-linear remnant using noise or non-linear transformations? (ii) Can non-linear transformations represent serial motor decision making within the sensorimotor feedback loop intrinsic to tracking? Twelve participants (instructed to act in three prescribed ways) manually controlled two systems (1st and 2nd order) subject to a periodic multi-sine disturbance. Joystick power was analysed using three models, continuous-linear-control (CC), continuous-linear-control with calculated noise spectrum (CCN), and intermittent control with aperiodic sampling triggered by prediction error thresholds (IC). Unlike the linear mechanism, the intermittent control mechanism explained the majority of total power (linear and remnant) (77 87% vs. 8-48%, IC vs. CC). Between conditions, IC used thresholds and distributions of open loop intervals consistent with, respectively, instructions and previous measured, model independent values; whereas CCN required changes in noise spectrum deviating from broadband, signal dependent noise. We conclude that manual tracking uses open loop predictive control with aperiodic sampling. Because aperiodic sampling is inherent to serial decision making within previously identified, specific frontal, striatal and parietal networks we suggest that these structures are intimately involved in visuo-manual tracking. PMID- 28833128 TI - Extraversion and life satisfaction: A cross-cultural examination of student and nationally representative samples. AB - OBJECTIVE: Previous research on Extraversion and life satisfaction suggests that extraverted individuals are more satisfied with their lives. However, existing studies provide inflated effect sizes, as they were based on simple correlations. In five studies, the authors provide better estimates of the relationship between Extraversion and life satisfaction. METHOD: The current study examined student and nationally representative samples from Canada, the United States, the United Kingdom, Germany, and Japan (Study 1, N = 1,460; Study 2, N = 5,882; Study 3, N = 18,683; Study 4, N = 13,443; Study 5, Japan N = 952 and U.S. N = 891). The relationship between Extraversion and life satisfaction was examined using structural equation modeling by regressing life satisfaction on the Big Five traits. RESULTS: Extraversion was a unique predictor of life satisfaction in the North American student and nationally representative samples (Study 1, beta = .232; Study 2, beta = .225; Study 5, beta = .217), but the effect size was weaker or absent in other non-North American samples (Germany, United Kingdom, and Japan). CONCLUSIONS: The findings attest to the moderating role of culture on Extraversion and life satisfaction and the importance of controlling for shared method variance. PMID- 28833129 TI - Volume loading augments cutaneous vasodilatation and cardiac output of heat stressed older adults. AB - KEY POINTS: Age-related changes in cutaneous microvascular and cardiac functions limit the extent of cutaneous vasodilatation and the increase in cardiac output that healthy older adults can achieve during passive heat stress. However, it is unclear if these age-related changes in microvascular and cardiac functions maximally restrain the levels of cutaneous vasodilatation and cardiac output that healthy older adults can achieve during heat stress. We observed that rapid volume loading, performed during passive heat stress, augments both cutaneous vasodilatation and cardiac output in healthy older humans. These findings demonstrate that the microcirculation of healthy aged skin can further dilate during passive heat exposure, despite peripheral limitations to vasodilatation. Furthermore, healthy older humans can augment cardiac output when cardiac pre load is increased during heat stress. ABSTRACT: Primary ageing markedly attenuates cutaneous vasodilatation and the increase in cardiac output during passive heating. However, it remains unclear if these responses are maximally restrained by age-related changes in cutaneous microvascular and cardiac functions. We hypothesized that rapid volume loading performed during heat stress would increase cardiac output in older adults without parallel increases in cutaneous vasodilatation. Twelve young (Y: 26 +/- 5 years) and ten older (O: 69 +/- 3 years) healthy adults were passively heated until core temperature increased by 1.5 degrees C. Cardiac output (thermodilution), forearm vascular conductance (FVC, venous occlusion plethysmography) and cutaneous vascular conductance (CVC, laser-Doppler) were measured before and after rapid infusion of warmed saline (15 mL kg-1 , ~7 min). While heat stressed, but prior to saline infusion, cardiac output (O: 6.8 +/- 0.4 vs. Y: 9.4 +/- 0.6 L min-1 ), FVC (O: 0.08 +/- 0.01 vs. Y: 0.17 +/- 0.02 mL (100 mL min-1 mmHg-1 )-1 ), and CVC (O: 1.29 +/- 0.34 vs. Y: 1.93 +/- 0.30 units mmHg-1 ) were lower in older adults (all P < 0.01). Rapid saline infusion increased cardiac output (O: +1.9 +/- 0.3, Y: +1.8 +/- 0.7 L min-1 ), FVC (O: +0.015 +/- 0.007, Y: +0.048 +/- 0.013 mL (100 mL min-1 mmHg-1 )-1 ), and CVC (O: +0.28 +/- 0.10, Y: +0.29 +/- 0.16 units mmHg-1 ) in both groups (all P < 0.01). The absolute increase in cardiac output and CVC were similar between groups, whereas FVC increased to a greater extent in young adults (P < 0.01). These results demonstrate that healthy older adults can achieve greater levels of cutaneous vasodilatation and cardiac output during passive heating. PMID- 28833131 TI - The core planar cell polarity gene, Vangl2, maintains apical-basal organisation of the corneal epithelium. AB - The role of the core planar cell polarity (PCP) pathway protein, Vangl2, was investigated in the corneal epithelium of the mammalian eye, a paradigm anatomical model of planar cell migration. The gene was conditionally knocked out in vivo and knocked down by siRNA, followed by immunohistochemical, behavioural and morphological analysis of corneal epithelial cells. The primary defects observed in vivo were of apical-basal organisation of the corneal epithelium, with abnormal stratification throughout life, mislocalisation of the cell membrane protein, Scribble, to the basal side of cells, and partial loss of the epithelial basement membrane. Planar defects in migration after wounding and in the presence of an applied electric field were noted. However, knockdown of Vangl2 also retarded cell migration in individual cells that had no contact with their neighbours, which precluded a classic PCP mechanism. It is concluded that some of the planar polarity phenotypes in PCP mutants may arise from disruption of apical-basal polarity. PMID- 28833130 TI - Inducible satellite cell depletion attenuates skeletal muscle regrowth following a scald-burn injury. AB - KEY POINTS: Severe burns result in significant skeletal muscle cachexia that impedes recovery. Activity of satellite cells, skeletal muscle stem cells, is altered following a burn injury and likely hinders regrowth of muscle. Severe burn injury induces satellite cell proliferation and fusion into myofibres with greater activity in muscles proximal to the injury site. Conditional depletion of satellite cells attenuates recovery of myofibre area and volume following a scald burn injury in mice. Skeletal muscle regrowth following a burn injury requires satellite cell activity, underscoring the therapeutic potential of satellite cells in the prevention of prolonged frailty in burn survivors. ABSTRACT: Severe burns result in profound skeletal muscle atrophy; persistent muscle atrophy and weakness are major complications that hamper recovery from burn injury. Many factors contribute to the erosion of muscle mass following burn trauma, and we have previously shown concurrent activation and apoptosis of muscle satellite cells following a burn injury in paediatric patients. To determine the necessity of satellite cells during muscle recovery following a burn injury, we utilized a genetically modified mouse model (Pax7CreER -DTA) that allows for the conditional depletion of satellite cells in skeletal muscle. Additionally, mice were provided 5-ethynyl-2'-deoxyuridine to determine satellite cell proliferation, activation and fusion. Juvenile satellite cell-wild-type (SC-WT) and satellite cell-depleted (SC-Dep) mice (8 weeks of age) were randomized to sham or burn injury consisting of a dorsal scald burn injury covering 30% of total body surface area. Both hindlimb and dorsal muscles were studied at 7, 14 and 21 days post-burn. SC-Dep mice had >93% depletion of satellite cells compared to SC-WT (P < 0.05). Burn injury induced robust atrophy in muscles located both proximal and distal to the injury site (~30% decrease in fibre cross-sectional area, P < 0.05). Additionally, burn injury induced skeletal muscle regeneration, satellite cell proliferation and fusion. Depletion of satellite cells impaired post-burn recovery of both muscle fibre cross-sectional area and volume (P < 0.05). These findings support an integral role for satellite cells in the aetiology of lean tissue recovery following a severe burn injury. PMID- 28833132 TI - Foraging traits modulate stingless bee community disassembly under forest loss. AB - Anthropogenic land use change is an important driver of impacts to biological communities and the ecosystem services they provide. Pollination is one ecosystem service that may be threatened by community disassembly. Relatively little is known about changes in bee community composition in the tropics, where pollination limitation is most severe and land use change is rapid. Understanding how anthropogenic changes alter community composition and functioning has been hampered by high variability in responses of individual species. Trait-based approaches, however, are emerging as a potential method for understanding responses of ecologically similar species to global change. We studied how communities of tropical, eusocial stingless bees (Apidae: Meliponini) disassemble when forest is lost. These bees are vital tropical pollinators that exhibit high trait diversity, but are under considerable threat from human activities. We compared functional traits of stingless bee species found in pastures surrounded by differing amounts of forest in an extensively deforested landscape in southern Costa Rica. Our results suggest that foraging traits modulate competitive interactions that underlie community disassembly patterns. In contrast to both theoretical predictions and temperate bee communities, we found that stingless bee species with the widest diet breadths were less likely to persist in sites with less forest. These wide-diet-breadth species also tend to be solitary foragers, and are competitively subordinate to group-foraging stingless bee species. Thus, displacement by dominant, group-foraging species may make subordinate species more dependent on the larger or more diversified resource pool that natural habitats offer. We also found that traits that may reduce reliance on trees-nesting in the ground or inside nests of other species correlated with persistence in highly deforested landscapes. The functional trait perspective we employed enabled capturing community processes in analyses and suggests that land use change may disassemble bee communities via different mechanisms in temperate and tropical areas. Our results further suggest that community processes, such as competition, can be important regulators of community disassembly under land use change. A better understanding of community disassembly processes is critical for conserving and restoring pollinator communities and the ecosystem services and functions they provide. PMID- 28833133 TI - Exercise and oestrogens: aerobic high-intensity exercise promotes leg vascular and skeletal muscle mitochondrial adaptations in early postmenopause. PMID- 28833134 TI - Changes in shoulder muscle activity pattern on surface electromyography after breast cancer surgery. AB - BACKGROUND AND OBJECTIVES: Alterations in muscle activation and restricted shoulder mobility, which are common in breast cancer patients, have been found to affect upper limb function. The purpose of this study was to determine muscle activity patterns, and to compare the prevalence of abnormal patterns among the type of breast surgery. METHODS: In total, 274 breast cancer patients were recruited after surgery. Type of breast surgery was divided into mastectomy without reconstruction (Mastectomy), reconstruction with tissue expander/implant (TEI), latissimus dorsi (LD) flap, or transverse rectus abdominis flap (TRAM). Activities of shoulder muscles were measured using surface electromyography. Experimental analysis was conducted using a Gaussian filter smoothing method with regression. RESULTS: Patients demonstrated different patterns of muscle activation, such as normal, lower muscle electrical activity, and tightness. After adjusting for BMI and breast surgery, the odds of lower muscle electrical activity and tightness in the TRAM are 40.2% and 38.4% less than in the Mastectomy only group. The prevalence of abnormal patterns was significantly greater in the ALND than SLNB in all except TRAM. CONCLUSIONS: Alterations in muscle activity patterns differed by breast surgery and reconstruction type. For breast cancer patients with ALND, TRAM may be the best choice for maintaining upper limb function. PMID- 28833135 TI - Sleep awakens active expiration. PMID- 28833136 TI - A Study on the Estimation of Postmortem Interval Based on Environmental Temperature and Concentrations of Substance in Vitreous Humor. AB - A method to determine postmortem interval (PMI) based on environmental temperature and the concentrations of vitreous humor (VH) molecules were explored. Rabbit carcasses were placed in a chamber at 5, 15, 25, or 35 degrees C, and 80-100 MUL of VH was collected with the double-eye alternating micro sampling method every 12 h. A Roche DPPI biochemical analyzer was used to measure the concentrations of six substances in VH samples. The interpolation function model and mixed-effect model were employed for data fitting to establish equations for PMI estimation. The concentrations of K+ , P, Mg2+ , creatinine (CRE), and urea nitrogen (UN) exhibited an upward trend with increasing PMI in all temperature groups, while the concentration of Ca2+ showed a downward trend. Validation results using K+ and Mg2+ ions revealed that the mixed-effect model provided a better estimation than the interpolation function model using the data from our experiment. However, both models were able to estimate PMI using temperature and VH molecule concentrations. PMID- 28833137 TI - Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma. AB - Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the known involvement of TERT and EZH2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia-telangiectasia-mutated (ATM) phosphorylation levels. Conversely, diminished TERT and FASN levels upon siRNA-mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition-mediated decrease in FASN and EZH2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT-EZH2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non-canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma. PMID- 28833138 TI - Molecular and morphological delimitation and generic classification of the family Oocystaceae (Trebouxiophyceae, Chlorophyta). AB - The family Oocystaceae (Chlorophyta) is a group of morphologically and ultrastructurally distinct green algae that constitute a well-supported clade in the class Trebouxiophyceae. Despite the family's clear delimitation, which is based on specific cell wall features, only a few members of the Oocystaceae have been examined using data other than morphological. In previous studies of Trebouxiophyceae, after the establishment of molecular phylogeny, the taxonomic status of the family was called into question. The genus Oocystis proved to be paraphyletic and some species were excluded from Oocystaceae, while a few other species were newly redefined as members of this family. We investigated 54 strains assigned to the Oocystaceae using morphological, ultrastructural and molecular data (SSU rRNA and rbcL genes) to clarify the monophyly of and diversity within Oocystaceae. Oonephris obesa and Nephrocytium agardhianum clustered within the Chlorophyceae and thus are no longer members of the Oocystaceae. On the other hand, we transferred the coenobial Willea vilhelmii to the Oocystaceae. Our findings combined with those of previous studies resulted in the most robust definition of the family to date. The division of the family into three subfamilies and five morphological clades was suggested. Taxonomical adjustments in the genera Neglectella, Oocystidium, Oocystis, and Ooplanctella were established based on congruent molecular and morphological data. We expect further taxonomical changes in the genera Crucigeniella, Eremosphaera, Franceia, Lagerheimia, Oocystis, and Willea in the future. PMID- 28833139 TI - Identification of Potent ACE Inhibitory Peptides from Wild Almond Proteins. AB - : In this study, the production, fractionation, purification and identification of ACE (angiotensin-I-converting enzyme) inhibitory peptides from wild almond (Amygdalus scoparia) proteins were investigated. Wild almond proteins were hydrolyzed using 5 different enzymes (pepsin, trypsin, chymotrypsin, alcalase and flavourzyme) and assayed for their ACE inhibitory activities. The degree of ACE inhibiting activity obtained after hydrolysis was found to be in the following order: alcalase > chymotrypsin > trypsin/pepsin > flavourzyme. The hydrolysates obtained from alcalase (IC50 = 0.8 mg/mL) were fractionated by sequential ultrafiltration at 10 and 3 kDa cutoff values and the most active fraction (<3 kDa) was further separated using reversed phase high-performance liquid chromatography (RP-HPLC). Peptide sequence identifications were carried out on highly potential fractions obtained from RP-HPLC by means of liquid chromatography coupled to electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS). Sequencing of ACE inhibitory peptides present in the fraction 26 of RP-HPLC resulted in the identification of 3 peptide sequences (VVNE, VVTR, and VVGVD) not reported previously in the literature. Sequence identification of fractions 40 and 42 from RP-HPLC, which showed the highest ACE inhibitory activities (84.1% and 86.9%, respectively), resulted in the identification of more than 40 potential ACE inhibitory sequences. The results indicate that wild almond protein is a rich source of potential antihypertensive peptides and can be suggested for applications in functional foods and drinks with respect to hindrance and mitigation of hypertension after in vivo assessment. PRACTICAL APPLICATION: This study has shown the potential of wild almond proteins as good sources for producing ACE-inhibitory active peptides. According to this finding, peptides with higher ACE inhibitory activities could be released during the gastrointestinal digestion and contribute to the health- promoting activities of this natural protein source. PMID- 28833140 TI - Characterization of steryl glycosides in marine microalgae by gas chromatography triple quadrupole mass spectrometry (GC-QQQ-MS). AB - BACKGROUND: Steryl glycosides (SGs) are sterol conjugates found in various plants, especially in those making up human diets. It has been demonstrated that SGs have potential health benefits, and they could be used as food supplements in a variety of food matrixes. Marine microalgae are a potential resource for human food and ingredients. In this study, gas chromatography-triple quadrupole mass spectrometry (GC-QQQ-MS) was used to characterize unknown SGs in eight microalgae belonging to different classes (Isochrysis galbana 3011, Pavlova viridis, Platymonas helgolandica, Conticribra weissflogii, Thalassiosira pseudonana, Nitzschia closterium, Gymnodinium sp., and Karlodinum veneficum). RESULTS: The SGs were first extracted from lyophilized algae with chloroform-methanol, purified by solid-phase extraction and analyzed as trimethylsilyl derivatives. Nine SGs have been identified. In particular, new SGs like occelasteryl glycoside and stellasteryl glycoside were found in Gymnodinium sp., 24-methylene cholesteryl glycoside was detected in P. helgolandica, and 4,24-dimethylcholestan 3-yl glycoside was identified as the main constituent of microalga K. veneficum. The results also showed that the compositions of SGs in different microalgae varied, with a range of 5.234 to 0.036 g kg-1 , and microalga P. viridis contained the most abundant SGs. CONCLUSION: GC-QQQ-MS is a powerful tool to detect SGs with different structures from a variety of microalgae. The compositions of SGs in different microalgae varied greatly. Microalgae are a good source of highly valued SGs. (c) 2017 Society of Chemical Industry. PMID- 28833141 TI - Transcriptional profiling of human neural precursors post alcohol exposure reveals impaired neurogenesis via dysregulation of ERK signaling and miR-145. AB - Gestational alcohol exposure causes a range of neuropsychological disorders by modulating neurodevelopmental genes and proteins. The extent of damage depends on the stage of the embryo as well as dosage, duration and frequency of exposure. Here, we investigated the neurotoxic effects of alcohol using human embryonic stem cells. Multiple read-outs were engaged to assess the proliferation and differentiation capacity of neural precursor cells upon exposure to 100 mM ethanol for 48 h corresponding to the blood alcohol levels for binge drinkers. Whole-genome analysis revealed a spatiotemporal dysregulation of neuronal- and glial-specific gene expression that play critical roles in central nervous system (CNS) development. Alterations observed in the transcriptome may be attributed to epigenetic constitution witnessed by differential histone H3 Lys-4/Lys-27 modifications and acetylation status. In-depth mRNA and protein expression studies revealed abrogated extracellular signal-regulated kinases signaling in alcohol-treated cells. Consistent with this finding, ingenuity pathway analysis and micro-RNA profiling demonstrated up-regulation of miR-145 by targeting the neural specifier Sox-2. We also show that the neurite branching complexity of tubulin, beta 3 class III+ neurons was greatly reduced in response to alcohol. Finally, in vivo studies using zebrafish embryos reconfirmed the in vitro findings. Employing molecular endpoints in a human model, this report indicates for the first time that acute alcohol exposure could lead to impaired brain development via perturbation of extracellular signal-regulated kinases pathway and miR-145. However, it still needs to be addressed whether these modulations sustain throughout development, compromising the ability of the individual during adulthood and aging. PMID- 28833142 TI - Leaf odour cues enable non-random foraging by mammalian herbivores. AB - Searching for food is the first critical stage of foraging, and search efficiency is enhanced when foragers use cues from foods they seek. Yet we know little about food cues used by one major group of mammals, the herbivores, a highly interactive component of most ecosystems. How herbivores forage and what disrupts this process, both have significant ecological and evolutionary consequences beyond the animals themselves. Our aim was to investigate how free-ranging mammalian herbivores exploit leaf odour cues to find food plants amongst a natural and complex vegetation community. Our study system comprised the native "deer equivalent" of eastern Australian forests, the swamp wallaby Wallabia bicolor, and seedlings of Eucalyptus, the foundation tree genus in these ecosystems. We quantified how foraging wallabies responded to odour cues from plants manipulated in several ways: varying the quantity of visually concealed leaves, comparing damaged vs. undamaged leaves, and whole plants vs. those with suppressed cues. The rate of discovery of leaves by wallabies increased with odour cue magnitude, yet animals were extremely sensitive to even a tiny odour source of just a few leaves. Whole seedlings were discovered faster if their leaves were damaged. Wallabies found whole seedlings and those with suppressed visual cues equally rapidly, day and night. Seedlings with very little odour were discovered mainly by day, as nocturnal foraging success was severely disrupted. This study shows how leaf odour attracts mammalian herbivores to food plants, enabling non-random search for even tiny odour sources. As damaged leaves enhanced discovery, we suggest that the benefit of attracting natural enemies to invertebrate herbivores feeding on plants (potential "cry for help") may be offset by a cost-increased browsing by mammalian herbivores. This cost should be incorporated into multi-trophic plant-animal studies. Finally, the breakdown in capacity to find plants at night suggests substantial but unrecognized foraging costs to herbivores when abiotic factors, such as cold temperatures or pollution, reduce or degrade plant odour cues. We predict that an increasingly polluted world will alter the foraging success of mammalian herbivores, with significant ecological ramifications given that browsing can shape ecosystems. PMID- 28833143 TI - Antioxidant properties and chemical characterization of Spanish Opuntia ficus indica Mill. cladodes and fruits. AB - BACKGROUND: Recent studies have demonstrated that consumption of Opuntia ficus indica Mill. has an important positive health benefit, mainly due to antioxidant properties, which justifies this research. This study examined antioxidant activity, organic acid and sugar profile, total phenolic, and physicochemical characteristics of six O. ficus-indica cultivars growing in the Spanish Mediterranean. It should be noted that, in this study, both cladodes (young and adult) and fruits (peel and pulp) were analyzed. RESULTS: The antioxidant activity (2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl 1-picrylhydrazyl methods) was higher in fruit peel than in cladodes. The young cladodes presented an important antioxidant activity by the ferric-reducing ability of plasma method as well as a higher total phenolic content (18.90 g gallic acid equivalent per kilogram). High-performance liquid chromatography (HPLC) with diode-array detector analysis revealed the absence of sucrose and the presence of glucose and fructose, which the values were higher in pulp fruits. HPLC with refractive index detector analysis showed that citric, malic, and succinic acids were the main organic acids in all cultivars, with a significant higher content in old cladodes. CONCLUSION: These investigations valorize O. ficus-indica fruits in comparison with cladodes. In general, this plant can be considered as an ingredient for the production of health-promoting food, highlighting mainly in the antioxidant activity and total polyphenols content found in young cladodes and peel fruits. (c) 2017 Society of Chemical Industry. PMID- 28833144 TI - Retraction Statement: Anti-inflammatory properties of tianeptine on lipopolysaccharide-induced changes in microglial cells involve toll-like receptor related pathways. AB - 'Anti-inflammatory properties of tianeptine on lipopolysaccharide-induced changes in microglial cells involve toll-like receptor-related pathways' by Slusarczyk, J., Trojan, E., Glombik, K., Piotrowska, A., Budziszewska, B., Kubera, M., Popiolek-Barczyk, K., Lason, W., Mika, J. and Basta-Kaim, A. The above article from the Journal of Neurochemistry published on 14 February 2016 on Wiley Online Library ( www.onlinelibrary.com), and in Volume 136, pp. 958-970, is being retracted by agreement between the corresponding author Agnieszka Basta-Kaim, the Journal's Editor-in-Chief Jorg Schulz, and John Wiley & Sons Ltd. The Editorial Office was alerted by a science journalist that the same Western Blot lane had been used to represent two different proteins. The Western Blot signal of iNOS in Fig. 4a was supposedly identical to the Western Blot signal of phospho-JNK in Fig. 6b. The corresponding author stated that "on the final step of figure 6 preparation the first author made, by mistake, an incorrect attachment of representative p-JNK blots." A corrected Fig. 6b is enclosed below. The second concern reaching the Editorial Office was that the same Western Blot signal appeared to have been used to represent two different experimental conditions: the iNOS control signal (-/- LPS/TIA Fig. 4a) appears as a horizontal and vertical mirror image of the last signal in this line (+/10 LPS/TIA Fig. 4a). The raw membrane which was used to produce Fig. 4a is enclosed on the next page and highlights the steps that were undertaken during figure preparation. Although the initial concern was not proven, concerns remained regarding the question how an inadvertent flipping of the first Western blot lane could happen. A corrected Fig. 4a prepared by the corresponding author from the raw image of iNOS western blot depicted above, without flipped first lane, is presented below: Although the corresponding author provided a large amount of evidence to explain disparities in the presentation of Western Blot images, due to the number of inconsistencies that were revealed during review of the provided evidence and the inability to confirm the nature of the steps that led to them, it was felt that the above mentioned Western Blot images presented in this publication were not reliable, even if the conclusions may still be valid. The first author would like to apologize to the readers, reviewers and editors of Journal of Neurochemistry for the errors. Reference Slusarczyk J., Trojan E., Glombik K., Piotrowska A., Budziszewska B., Kubera M., Popiolek-Barczyk K., Lason W., Mika J. and Basta-Kaim A. (2016) Anti-inflammatory properties of tianeptine on lipopolysaccharide induced changes in microglial cells involve toll-like receptor-related pathways. J. Neurochem. 136, 958-970. https://doi.org/10.1111/jnc.13452. PMID- 28833145 TI - Extrusion modifies some physicochemical properties of milk protein concentrate for improved performance in high-protein nutrition bars. AB - BACKGROUND: Extruded and ground milk protein concentrate powders, specifically those with 800 g kg-1 protein (i.e. MPC80), imparted softness, cohesion and textural stability to high-protein nutrition (HPN) bars. The present study evaluated some physicochemical properties of extruded and conventionally produced (i.e. spray-dried) MPC80 to explain these improvements. Protein chemical changes and aggregations within MPC80-formulated HPN bars during storage were characterized. RESULTS: Extruded MPC80 powders had broader particle size distribution (P < 0.05) and smaller volume-weighted mean diameter (P < 0.05) than the spray-dried control. Loose, tapped and particle densities increased (P < 0.05) and correspondingly occluded and interstitial air volumes decreased (P < 0.05) after extruding and milling MPC80. Extrusion decreased water holding capacity (P < 0.05) and solubility (P < 0.05), yet improved the wettability (P < 0.05) of MPC80. MPC80 free sulfhydryl (P < 0.05) and free amine (P < 0.05) concentrations decreased after extrusion. Sulfhydryl and amine concentrations changed (P < 0.05) and disulfide-linked and, more prominently, Maillard-induced aggregates developed during HPN bar storage. CONCLUSION: Extrusion and milling together changed the physicochemical properties of MPC80. Chemical changes and protein aggregations occurred in HPN bars prepared with either type of MPC80. Thus, the physicochemical properties of the formulating powder require consideration for desired HPN bar texture and stability. (c) 2017 Society of Chemical Industry. PMID- 28833147 TI - What's interpersonal in interpersonal perception? The role of target's attachment in the accuracy of perception. AB - OBJECTIVE: We examined the influence of attachment orientation on the accuracy of perception of negative affect in close relationships. We hypothesized that tracking accuracy of perceiving negative affect (a) would be lower among perceivers and targets with higher attachment avoidance and (b) would be lowest when both the target and perceiver were high on attachment avoidance. Tracking accuracy would be (c) higher among perceivers and targets with higher attachment anxiety and (d) highest when both the target and perceiver were high on attachment anxiety. METHOD: We collected data from 92 couples who reported their negative affect and perception of their partner's negative affect in interactions with each other on 20 days. RESULTS: Results supported the hypotheses for attachment avoidance and tracking accuracy. Tracking accuracy of perceived negative affect was low when the target was high on attachment avoidance; accuracy was lowest when both the target and the perceiver were high on attachment avoidance. CONCLUSIONS: Lower "readability" of high avoidantly attached targets' emotions may inhibit intimacy and sensitive responding, which thereby may contribute to poor relationship outcomes. PMID- 28833146 TI - Trismus surgical release and free flap reconstruction after radiation therapy in oral and oropharyngeal squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVES: This study aims to review our experience in trismus release followed by free flap reconstruction after radiotherapy in oral and oropharyngeal cancer, describe the results obtained in long-term follow-up and identify possible predictors of outcome. METHODS: Patients' demographics, tumor characteristics and treatment where retrieved. Surgical release and reconstructive procedures were detailed. Interincisor distances (IIDs) where measured preoperatively (PO-IID), intraoperatively after release (IO-IID) and in the last follow-up (FU-IID). Potential predictors of outcome in terms of interincisor long-term gain (LT-gain) and postoperative loss (PO-loss) were analyzed. RESULTS: Twenty-eight patients were included in our study. The mean LT gain was 8.9 +/- 7.0 mm, and the PO-loss was 22.14 +/- 7.27 mm. Patients with a PO-IID of 10 mm or less had a significant higher LT-gain (P = 0.038). Predictors of worse outcome included having received a previous maxillectomy during tumor ablation (lower LT-gain, P = 0.035), and previous buccal mucosa resection (higher PO-loss, P = 0.044). CONCLUSIONS: Trismus release and free flap reconstruction after radiotherapy in oral and oropharyngeal cancer patients seems to be associated with modest long term results and a high incidence of trismus recurrence, particularly in cases of prior buccal resections or maxillectomy. Patients should be adequately informed and carefully selected before indicating the procedure. PMID- 28833148 TI - Effect of microwave freeze drying on quality and energy supply in drying of barley grass. AB - BACKGROUND: Young barley grass leaves are well-known for containing the antioxidant substances flavonoid and chlorophyll. However, low product quality and energy efficiency exist with respect to the dehydration of barley grass leaves. To improve energy supply and the quality of barley grass, microwave heating instead of contact heat was applied for the freeze drying of barley grass at a pilot scale at 1, 1.5 and 2 W g-1 , respectively; After drying, energy supply and quality parameters of color, moisture content, chlorophyll, flavonoids, odors of dried barley grass were determined to evaluate the feasibility of the study. RESULTS: Microwave freeze drying (MFD) allowed a low energy supply and high contents of chlorophyll and flavonoids. A lightness value of 60.0, a green value of -11.5 and an energy supply of 0.61 kW h-1 g-1 were observed in 1.5 W g-1 MFD; whereas drying time (7 h) decreased by 42% compared to contact heating. Maximum content of flavonoid and chlorophyll was 11.7 and 12.8 g kg-1 barley grass. Microwave heating leads to an odor change larger than that for contact heating observed for the freeze drying of barley grass. CONCLUSION: MFD retains chlorophyll and flavonoids, as well as colors and odors of samples, and also decreases energy consumption in the freeze drying of barley grass. (c) 2017 Society of Chemical Industry. PMID- 28833149 TI - Lignin composition is more important than content for maize stem cell wall degradation. AB - BACKGROUND: The relationship between the chemical and molecular properties - in particular the (acid detergent) lignin (ADL) content and composition expressed as the ratio between syringyl and guaiacyl compounds (S:G ratio) - of maize stems and in vitro gas production was studied in order to determine which is more important in the degradability of maize stem cell walls in the rumen of ruminants. Different internodes from two contrasting maize cultivars (Ambrosini and Aastar) were harvested during the growing season. RESULTS: The ADL content decreased with greater internode number within the stem, whereas the ADL content fluctuated during the season for both cultivars. The S:G ratio was lower in younger tissue (greater internode number or earlier harvest date) in both cultivars. For the gas produced between 3 and 20 h, representing the fermentation of cell walls in rumen fluid, a stronger correlation (R2 = 0.80) was found with the S:G ratio than with the ADL content (R2 = 0.68). The relationship between ADL content or S:G ratio and 72-h gas production, representing total organic matter degradation, was weaker than that with gas produced between 3 and 20 h. CONCLUSION: The S:G ratio plays a more dominant role than ADL content in maize stem cell wall degradation. (c) 2017 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28833150 TI - Extra-virgin olive oil: are consumers provided with the sensory quality they want? A hedonic price model with sensory attributes. AB - BACKGROUND: Over the years, niche-differentiation strategies and food policies have pushed quality standards of European extra-virgin olive oil towards a product that has a sensory profile consisting of fruity, bitter and pungent notes, with such oils having excellent healthy features. However, it is unclear whether typical consumers are ready for a richer and more complex sensory profile than the neutral one historically found on the market. This potential discrepancy is investigated in the present study aiiming to determine whether current demand is able to appreciate this path of quality enhancement. Implicit prices for each and every attribute of extra-virgin olive oil with a focus on sensory characteristics were investigated using a hedonic price model. RESULTS: Although confirming the importance of origin and terroir for extra-virgin olive oil, the results of the present study strongly confirm the discrepancy between what is currently valued on the market and what novel supply trends are trying to achieve in terms of the sensory properties of such products. CONCLUSION: Increasing consumer awareness about the direct link between the health quality of oils and their sensory profile appears to be necessary to make quality enhancement programs more successful on the market and hence more effective for companies. (c) 2017 Society of Chemical Industry. PMID- 28833151 TI - Effects of Polysaccharides in Lycium Barbarum Berries from Different Regions of China on Macrophages Function and their Correlation to the Glycosidic Linkages. AB - : Berries of Lycium barbarum L. are not only used for traditional Chinese medicine, but also for raw materials in many health foods. Polysaccharides are major components of L. barbarum berries, which possess a variety of biological activities. In this study, effects of water-soluble polysaccharides, in 8 typical batches of L. barbarum berries collected from different producing areas of China, on macrophage function were evaluated in vitro. Furthermore, to better understand the structure-activity relationship of the polysaccharides in L. barbarum berries, the activity of typical polysaccharides and their partial acid and enzymatic hydrolysates were also investigated and compared. The results showed that the effects of polysaccharides of different regions are similar, which should be correlated to their similar chemical properties. However, their promotion effects on macrophage function are different in degree, this might be caused by their different content of active polysaccharides. Moreover, the alpha 1,4-d-galactosiduronic and alpha-1,5-arabinosidic linkages, especially the former one was discovered to significantly affect the promotion effect on macrophage function induced by the polysaccharides in L. barbarum berries. These results were beneficial to improve the pharmacological activity-based quality control of polysaccharides in L. barbarum berries and their products. PRACTICAL APPLICATION: The results showed that immunomodulation effects of polysaccharides in L. barbarum berries (LBPs) from different regions are similar, but different in degree, this might be caused by their different content of bioactive polysaccharides. Moreover, an enzymatic digestion method was used to investigate the structure-bioactivity relationship of polysaccharides from LBPs. The result indicated that alpha-1,4-d-galactosiduronic and alpha-1,5-arabinosidic linkages, especially the former one was significantly affect the immunomodulation effects of LBPs. The results were beneficial to the improvement of pharmacological activity-based quality control of LBPs and future development of related unique functional and health products. PMID- 28833152 TI - Is acupuncture an effective complementary tool within otolaryngological perioperative care? PMID- 28833153 TI - Rollout Strategy to Implement Interoperable Traceability in the Seafood Industry. AB - Verifying the accuracy and rigor of data exchanged within and between businesses for the purposes of traceability rests on the existence of effective and efficient interoperable information systems that meet users' needs. Interoperability, particularly given the complexities intrinsic to the seafood industry, requires that the systems used by businesses operating along the supply chain share a common technology architecture that is robust, resilient, and evolves as industry needs change. Technology architectures are developed through engaging industry stakeholders in understanding why an architecture is required, the benefits provided to the industry and individual businesses and supply chains, and how the architecture will translate into practical results. This article begins by reiterating the benefits that the global seafood industry can capture by implementing interoperable chain-length traceability and the reason for basing the architecture on a peer-to-peer networked database concept versus more traditional centralized or linear approaches. A summary of capabilities that already exist within the seafood industry that the proposed architecture uses is discussed; and a strategy for implementing the architecture is presented. The 6 step strategy is presented in the form of a critical path. PMID- 28833154 TI - The Expanding Role of Traceability in Seafood: Tools and Key Initiatives. AB - In the last decade, a range of drivers within the seafood sector have incentivized the application of traceability to issues beyond food safety and inventory management. Some of the issues motivating the expanded use of traceability within the global seafood sector include: increased media attention on the legal and social risks within some seafood supply chains, governmental traceability requirements, private-sector sustainability commitments, and others. This article begins with an overview of these topics in the seafood industry, and why many nongovernment organizations (NGOs), companies, and government actors have turned to traceability as a tool to address them. We discuss how traceability connects to key requirements of environmental sustainability and social responsibility. Later, we review the range of traceability services, tools, software solutions, and the due diligence measures that are currently being leveraged within the seafood sector. The paper concludes with a discussion of several NGO- and industry-led traceability initiatives that are examples of seafood traceability improvements. PMID- 28833155 TI - Implementing Interoperability in the Seafood Industry: Learning from Experiences in Other Sectors. AB - Interoperability of communication and information technologies within and between businesses operating along supply chains is being pursued and implemented in numerous industries worldwide to increase the efficiency and effectiveness of operations. The desire for greater interoperability is also driven by the need to reduce business risk through more informed management decisions. Interoperability is achieved by the development of a technology architecture that guides the design and implementation of communication systems existing within individual businesses and between businesses comprising the supply chain. Technology architectures are developed through a purposeful dialogue about why the architecture is required, the benefits and opportunities that the architecture offers the industry, and how the architecture will translate into practical results. An assessment of how the finance, travel, and health industries and a sector of the food industry-fresh produce-have implemented interoperability was conducted to identify lessons learned that can aid the development of interoperability in the seafood industry. The findings include identification of the need for strong, effective governance during the establishment and operation of an interoperability initiative to ensure the existence of common protocols and standards. The resulting insights were distilled into a series of principles for enabling syntactic and semantic interoperability in any industry, which we summarize in this article. Categorized as "structural," "operational," and "integrative," the principles describe requirements and solutions that are pivotal to enabling businesses to create and capture value from full chain interoperability. The principles are also fundamental to allowing governments and advocacy groups to use traceability for public good. PMID- 28833157 TI - Introduction. PMID- 28833156 TI - Current Barriers to Large-scale Interoperability of Traceability Technology in the Seafood Sector. AB - Interoperability is a critical component of full-chain digital traceability, but is almost nonexistent in the seafood industry. Using both quantitative and qualitative methodology, this study explores the barriers impeding progress toward large-scale interoperability among digital traceability systems in the seafood sector from the perspectives of seafood companies, technology vendors, and supply chains as a whole. We highlight lessons from recent research and field work focused on implementing traceability across full supply chains and make some recommendations for next steps in terms of overcoming challenges and scaling current efforts. PMID- 28833158 TI - Plant growth-promoting bacteria elevate the nutritional and functional properties of black cumin and flaxseed fixed oil. AB - BACKGROUND: In order to study the influence of plant growth-promoting bacteria (PGPB) belonging to Streptomyces sp., Paenibacillus sp., and Hymenobacter sp. on fixed oil content of flaxseed and black cumin, 2-year field experiments were conducted. PGPB was applied during seedtime of plants. The extraction of oil from seeds was performed using supercritical CO2 . RESULTS: The addition of PGPB significantly increases the content of C18:1 (from 16.06 +/- 0.03% to 16.97 +/- 0.03%) and C18:3 (from 42.97 +/- 0.2% to 45.42 +/- 0.5%) in flaxseed oil and C18:2 (from 52.68 +/- 0.50% to 57.11 +/- 0.40%) and C20:2 (from 4.34 +/- 0.02% to 4.54 +/- 0.03%) in black cumin seed oil. The contents of total polyphenols, flavonoids, and carotenoids, as well as antioxidant activity measured by ferric reducing ability of plasma assay, were found to be greater in the oil from the seeds of plants treated with the PGPB, compared with the respective non-treated samples. CONCLUSION: The use of PGPB enhances plant nutritive properties; these represent a great source for obtaining valuable functional food ingredients. (c) 2017 Society of Chemical Industry. PMID- 28833159 TI - Best practices for multidisciplinary integration of a DCIS genomic assay into clinical practice. AB - Most newly diagnosed ductal carcinoma in situ (DCIS) is treated with breast conserving surgery (BCS) +/- radiation therapy (RT). A key challenge is deciding whether or not to include RT with BCS. This decision is often determined by the degree of risk associated with disease recurrence. However, methods for risk assessment have not kept pace with diagnostic advances. The DCIS Score is an independent predictor and quantifier of individualized recurrence risk in patients with DCIS. Although the test is the only available genomic classifier for DCIS, the degree of adoption is varied, and it has not yet been fully accepted as standard practice. Recognizing the importance of individualizing recurrence assessment in patients with DCIS, the authors convened to review relevant clinical data, share best practices, and establish recommendations regarding how the assay should be incorporated into the decision-making process. Based on their clinical experiences, the authors concluded that effective integration of the DCIS Score should involve shared decision-making between surgeons and other specialties (radiation oncologists, pathologists, patient navigators, and physician assistants), with the patient's preference being a primary consideration. This manuscript aims to provide easy-to-use, clear-cut, and practical guidance to help physicians utilize the DCIS Score to improve risk assessment and inform treatment decisions for their patients with DCIS, including how to understand, run, interpret, and communicate the actionable results to patients. PMID- 28833160 TI - The role of exercise in mitigating subcortical ischemic vascular cognitive impairment. AB - Subcortical ischemic vascular cognitive impairment (SIVCI) is the most preventable form of cognitive dysfunction. There is converging evidence from animal and human studies that indicate vascular injury as the primary cause of SIVCI. Currently, there are no curative pharmaceutical treatments for vascular dementia; however, exercise may be a promising strategy to combat SIVCI. This review will focus on the role of exercise as a strategy to prevent or slow the progression of SIVCI, with particular emphasis on the mechanisms by which exercise may improve cerebrovascular function. We propose that exercise may be an effective strategy to combat SIVCI by improving cognitive function, increasing the bioavailability of neurotrophins, stimulating endothelial function, and controlling vascular risk factors. This article is part of the Special Issue "Vascular Dementia". PMID- 28833161 TI - Rare Death Via Histamine Poisoning Following Crab Consumption: A Case Report. AB - Histamine poisoning (scombroid food poisoning) is a toxicity syndrome that results from eating spoiled fish. To date, however, few poisoning (or mortality) cases have been reported in relation to crab consumption. Here, we describe a very uncommon case in which a 37-year-old woman and her 14-year-old son ate cooked crabs (Scylla serrata), resulting in the death of the female. Samples of vomitus, food residue, liver tissue, gastric content, intestinal content, and cardiac blood were analyzed by high-performance liquid chromatography. Toxicological analysis revealed that histamine concentrations were very high in the cooked crab (47.08 mg/100 g) and intestinal content (22.54 mg/100 g). Comparing our toxicological results, police investigations, and family member statements, it can be assumed that the decedent ingested spoiled crabs, and by excluding other causes of death, lethal intoxication with histamine poisoning was confirmed. PMID- 28833162 TI - The kindlin-2 double act. PMID- 28833163 TI - Control of Native Spoilage Yeast on Dealcoholized Red Wine by Preservatives Alone and in Binary Mixtures. AB - In order to preserve a commercial dealcoholized red wine (DRW), a study with 4 preservatives and binary mixtures of them were performed against 2 native spoilage yeasts: Rhodotorula mucilaginosa and Saccharomyces cerevisiae. Minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) for potassium sorbate, sodium benzoate, sodium metabisulfite and dimethyl dicarbonate (DMDC) were evaluated in DRW stored at 25 degrees C. MICs of potassium sorbate and sodium metabisulfite were 250 and 60 mg/kg, respectively for both target strains. However for sodium benzoate, differences between yeasts were found; R. mucilaginosa was inhibited at 125 mg/kg, while S. cerevisiae at 250 mg/kg. Regarding MFC, differences between strains were only found for sodium metabisulfite obtaining a MFC of 500 mg/kg for R. mucilaginosa and a MFC of 250 mg/kg for S. cerevisiae. Potassium sorbate and sodium benzoate showed the MFC at 1000 mg/kg and DMDC at 200 mg/kg. Regarding the effect of binary mixtures the Fractional Fungicidal Concentration Index (FFCi ) methodology showed that binary mixtures of 100 mg/kg DMDC/200 mg/kg potassium sorbate (FFCi = 0.7) and 50 mg/kg DMDC / 400 mg/kg sodium benzoate (FFCi = 0.65) have both synergistic effect against the 2 target strains. These binary mixtures can control the growth of spoilage yeasts in DRW without metabisulfite addition. The results of this work may be important in preserving the health of DRW consumers by eliminating the use of metabisulfite and reducing the risk of growth of R. mucilagosa, recently recognized as an emerging pathogen. PMID- 28833164 TI - A case-control evaluation of fungiform papillae density in burning mouth syndrome. AB - HYPOTHESIS: It has been hypothesized that high fungiform papillae density may be a risk factor for developing the taste and pain alterations characteristic of burning mouth syndrome. OBJECTIVE: Evaluate whether fungiform papillae density, taste sensitivity, and mechanical pain sensitivity differ between burning mouth syndrome cases and controls. STUDY DESIGN: This case-control study compared cases diagnosed with primary burning mouth syndrome with pain-free controls. METHODS: Participants (17 female cases and 23 female controls) rated the intensity of sucrose, sodium chloride, citric acid, and quinine applied separately to each side of the anterior tongue and sampled whole mouth. Mechanical pain sensitivity was assessed separately for each side of the tongue using weighted pins. Digital photographs of participants' tongues were used to count fungiform papillae. RESULTS: Burning mouth syndrome cases had increased whole mouth taste intensity. Cases also had increased sensitivity to quinine on the anterior tongue, as well as increased mechanical pain sensitivity on the anterior tongue. Fungiform papillae density did not differ significantly between cases and controls. Fungiform papillae density on the left and right sides of the tongue were correlated in controls; however, there was no left/right side correlation in cases. CONCLUSION: Cases had increased pain and taste perception on the anterior tongue. The lack of correlation between left and right fungiform papillae density in cases may be an indication of asymmetrical lingual innervation in these patients. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:841-846, 2018. PMID- 28833165 TI - Volumetric analysis of olfactory neuroblastoma skull base laterality and implications on neck disease. AB - OBJECTIVE: To determine if the laterality of primary tumors in patients with olfactory neuroblastoma (ONB) influenced the pattern and development of neck disease. METHODS: Using a retrospective cohort study design from 1994 to 2015, the primary tumors of patients who either presented with or developed neck disease were volumetrically analyzed using iPlan software (version 3.0.0, BrainLAB, Feldkirchen, Germany) by two independent observers. Agreement of volume derived sidedness was assessed with a kappa statistic, whereas agreement in volume-derived degree of tumor laterality was evaluated with an intraclass correlation coefficient. A one-sample t test was used to assess the difference in dominant percentage between the two observers. RESULTS: Sixty-one patients with histological diagnosis and treatment of ONB at our institution were identified. Twenty-four patients exhibited neck involvement, 13 of whom could be volumetrically analyzed. Tumors that were greater than 75% eccentric to one side all exhibited contralateral disease, whereas the majority of unilateral neck disease was associated with relatively midline masses. Within the entire cohort, ipsilateral level 2 lymph nodes displayed the highest involvement (83%, 20 of 24), followed by ipsilateral level 1 (54%, 13 of 24), contralateral level 2 (46%, 11 of 24), contralateral level 1 (21%, 5 of 24), and ipsilateral level 3 (21%, 5 of 24). CONCLUSION: Ipsilateral neck involvement frequently was observed; however, the degree of ONB primary site laterality did not appear to have implications on the development of contralateral neck disease. Therefore, when considering elective therapy to the neck, ONB laterality should not be used to justify unilateral neck treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:864 870, 2018. PMID- 28833166 TI - Gastric dilation-volvulus in dogs attending UK emergency-care veterinary practices: prevalence, risk factors and survival. AB - OBJECTIVE: To report prevalence, risk factors and clinical outcomes for presumptive gastric dilation-volvulus diagnosed among an emergency-care population of UK dogs. METHODS: The study used a cross-sectional design using emergency-care veterinary clinical records from the VetCompass Programme spanning September 1, 2012 to February 28, 2014 and risk factor analysis using multivariable logistic regression modelling. RESULTS: The study population comprised 77,088 dogs attending 50 Vets Now clinics. Overall, 492 dogs had presumptive gastric dilation-volvulus diagnoses, giving a prevalence of 0.64% (95% Confidence interval: 0.58 to 0.70%). Compared with cross-bred dogs, breeds with the highest odds ratios for the diagnosis of presumptive gastric dilation volvulus were the great Dane (odds ratio: 114.3, 95% Confidence interval 55.1 to 237.1, P<0.001), akita (odds ratio: 84.4, 95% Confidence interval 33.6 to 211.9, P<0.001) and dogue de Bordeaux (odds ratio: 82.9, 95% Confidence interval 39.0 to 176.3, P<0.001). Odds increased as dogs aged up to 12 years and neutered male dogs had 1.3 (95% Confidence interval 1.0 to 1.8, P=0.041) times the odds compared with entire females. Of the cases that were presented alive, 49.7% survived to discharge overall, but 79.3% of surgical cases survived to discharge. CLINICAL SIGNIFICANCE: Approximately 80% of surgically managed cases survived to discharge. Certain large breeds were highly predisposed. PMID- 28833167 TI - Co-ordination of the upper and lower limbs for vestibular control of balance. AB - KEY POINTS: When standing and holding an earth-fixed object, galvanic vestibular stimulation (GVS) can evoke upper limb responses to maintain balance. In the present study, we determined how these responses are affected by grip context (no contact, light grip and firm grip), as well as how they are co-ordinated with the lower limbs to maintain balance. When GVS was applied during firm grip, hand and ground reaction forces were generated. The directions of these force vectors were co-ordinated such that the overall body sway response was always aligned with the inter-aural axis (i.e. craniocentric). When GVS was applied during light grip (< 1 N), hand forces were secondary to body movement, suggesting that the arm performed a mostly passive role. These results demonstrate that a minimum level of grip is required before the upper limb becomes active in balance control and also that the upper and lower limbs co-ordinate for an appropriate whole-body sway response. ABSTRACT: Vestibular stimulation can evoke responses in the arm when it is used for balance. In the present study, we determined how these responses are affected by grip context, as well as how they are co-ordinated with the rest of the body. Galvanic vestibular stimulation (GVS) was used to evoke balance responses under three conditions of manual contact with an earth-fixed object: no contact, light grip (< 1 N) (LG) and firm grip (FG). As grip progressed along this continuum, we observed an increase in GVS-evoked hand force, with a simultaneous reduction in ground reaction force (GRF) through the feet. During LG, hand force was secondary to the GVS-evoked body sway response, indicating that the arm performed a mostly passive role. By contrast, during FG, the arm became actively involved in driving body sway, as revealed by an early force impulse in the opposite direction to that seen in LG. We then examined how the direction of this active hand vector was co-ordinated with the lower limbs. Consistent with previous findings on sway anisotropy, FG skewed the direction of the GVS-evoked GRF vector towards the axis of baseline postural instability. However, this was effectively cancelled by the hand force vector, such that the whole-body sway response remained aligned with the inter-aural axis, maintaining the craniocentric principle. These results show that a minimum level of grip is necessary before the upper limb plays an active role in vestibular-evoked balance responses. Furthermore, they demonstrate that upper and lower-limb forces are co ordinated to produce an appropriate whole-body sway response. PMID- 28833168 TI - Effector-mediated discovery of a novel resistance gene against Bremia lactucae in a nonhost lettuce species. AB - Candidate effectors from lettuce downy mildew (Bremia lactucae) enable high throughput germplasm screening for the presence of resistance (R) genes. The nonhost species Lactuca saligna comprises a source of B. lactucae R genes that has hardly been exploited in lettuce breeding. Its cross-compatibility with the host species L. sativa enables the study of inheritance of nonhost resistance (NHR). We performed transient expression of candidate RXLR effector genes from B. lactucae in a diverse Lactuca germplasm set. Responses to two candidate effectors (BLR31 and BLN08) were genetically mapped and tested for co-segregation with disease resistance. BLN08 induced a hypersensitive response (HR) in 55% of the L. saligna accessions, but responsiveness did not co-segregate with resistance to Bl:24. BLR31 triggered an HR in 5% of the L. saligna accessions, and revealed a novel R gene providing complete B. lactucae race Bl:24 resistance. Resistant hybrid plants that were BLR31 nonresponsive indicated other unlinked R genes and/or nonhost QTLs. We have identified a candidate avirulence effector of B. lactucae (BLR31) and its cognate R gene in L. saligna. Concurrently, our results suggest that R genes are not required for NHR of L. saligna. PMID- 28833169 TI - Intraosseous mucoepidermoid carcinoma: Outcome review. AB - OBJECTIVE: Identify the effect of patient characteristics, disease traits, and treatment modality on patient outcomes in the rare disease process of intraosseous mucoepidermoid carcinoma. STUDY DESIGN: Retrospective review of institutional case records and literature. METHODS: This study includes one case report, a literature review of the MEDLINE database from 1950 through June 2017 using keywords "intraosseous" and "mucoepidermoid," and a query of the University of California, Los Angeles, Department of Pathology database for all documented cases of intraosseous mucoepidermoid carcinoma of the head and neck. RESULTS: Indicators of poorer prognosis were male gender (P = 0.0071) and higher histological grade (P = 0.0095). Lesion site, size, association with odontogenic cyst, and treatment type did not have a statistically significant correlation with patient outcomes. There also was no statistically significant correlation observed between treatment modality and recurrent or progressive disease when stratified by histological grade of the cancer. CONCLUSION: This study identified male gender and high histological tumor grade as poor prognostic indicators; however, it did not reveal a statistically significant relationship between treatment modality and patient outcomes. Data regarding patient outcomes following treatment was limited due to loss to follow-up, suggesting that further investigation is required. Based on this review, decisions regarding treatment should be clinically guided and individually tailored to the patient's baseline health, disease severity, and the patient's treatment goals. A multi-disciplinary conference, as was utilized in the presented case report, may be the best approach to treatment planning for these patients at this time. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1083-1092, 2018. PMID- 28833170 TI - New Perspectives on an Old Issue: A Comparative MS-CASPT2 and OM2-MRCI Study of Polyenes and Protonated Schiff Bases. AB - Polyenic systems are involved in light perception of numerous living organisms. Although a pi-conjugated backbone is a common feature of all polyenes, their photophysics may vary. We provide a comparative quantum mechanical study of low lying S1 and S2 excited states in short (3-5 double bonds) symmetric all-trans linear polyenes and corresponding protonated Schiff bases. In our investigation, we use the well-established ab initio multireference CASPT2 approach and benchmark the efficient semiempirical OM2-MRCI approach against it. For all protonated Schiff bases, MS-CASPT2 results in two distinct S1 minima with inverted and noninverted bond length pattern, respectively. We find that OM2-MRCI is a computationally affordable and reliable alternative to MS-CASPT2 for investigations of polyenic systems, particularly when highly demanding calculations (e.g. excited-state dynamics) need to be performed. PMID- 28833171 TI - Facile Synthesis of BiOI Nanoparticles at Room Temperature and Evaluation of their Photoactivity Under Sunlight Irradiation. AB - In this study, highly photoactive BiOI nanoparticles (NPs) under sunlight irradiation were synthesized by a facile precipitation method using polyvinylpyrrolidone (PVP) at room temperature. The as-prepared catalysts were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transition electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared (FTIR) and UV-vis diffuse reflectance spectra (UV-vis DRS). The results of XRD showed that PVP did not have any significant effect on tetragonal crystalline structure of BiOI. Also, using different amounts of PVP in the synthesis led to different morphologies and sizes of BiOI particles. It was found that using 0.2 g of PVP in the synthesis method changed morphology from 1 MUm platelets to NPs with size under 10 nm. In addition, the photocatalytic performance of prepared photocatalysts was evaluated in the photodegradation of reactive blue 19 (RB19) dye under sunlight irradiation. The BiOI synthesized using 0.2 g PVP (BiOI0.2) showed higher degradation efficiency compared to BiOI prepared without any additive. Excellent visible light photocatalytic properties of nano-scaled BiOI0.2 samples compared to BiOI platelets could be attributed to higher surface-to-volume ratio and narrow band-gap energy of as-prepared BiOI0.2 NPs. PMID- 28833172 TI - Response of the plant hormone network to boron deficiency. AB - Plant hormones (PH) adjust plant growth to environmental conditions such as nutrient availability. Although responses of individual PHs to growth-determining nutrient supplies have been reported, little is known about simultaneous dynamics in the metabolism of different PH species. Brassica napus seedlings were grown under increasing supply of B, and LC-MS/MS was used to characterize bioactive forms of different PH species together with several of their precursors, storage and inactivated forms. Increasing shoot B concentrations in response to B supply were accompanied by decreasing concentrations of abscisic acid (ABA) and indole-3 acetic acid (IAA), which appeared to be synthesized under B deficiency mainly via indole-3-acetonitrile (IAN). By contrast, shoot B concentrations correlated closely with cytokinins, and the B-dependent growth response appeared to be triggered primarily by de-novo synthesis of cytokinins and by re-routing less active towards highly active forms of cytokinin. Also gibberellin biosynthesis strongly increased with B supply, in particular gibberellin species from the non 13-hydroxylation pathway. The brassinosteroid castasterone appeared to support shoot growth primarily at suboptimal B nutrition. These results indicate that a variable B nutritional status causes coordinated changes in PH metabolism as prerequisite for an adjusted growth response. PMID- 28833173 TI - Disruption of stomatal lineage signaling or transcriptional regulators has differential effects on mesophyll development, but maintains coordination of gas exchange. AB - Stomata are simultaneously tasked with permitting the uptake of carbon dioxide for photosynthesis while limiting water loss from the plant. This process is mainly regulated by guard cell control of the stomatal aperture, but recent advancements have highlighted the importance of several genes that control stomatal development. Using targeted genetic manipulations of the stomatal lineage and a combination of gas exchange and microscopy techniques, we show that changes in stomatal development of the epidermal layer lead to coupled changes in the underlying mesophyll tissues. This coordinated response tends to match leaf photosynthetic potential (Vcmax ) with gas-exchange capacity (gsmax ), and hence the uptake of carbon dioxide for water lost. We found that different genetic regulators systematically altered tissue coordination in separate ways: the transcription factor SPEECHLESS (SPCH) primarily affected leaf size and thickness, whereas peptides in the EPIDERMAL PATTERNING FACTOR (EPF) family altered cell density in the mesophyll. It was also determined that interlayer coordination required the cell-surface receptor TOO MANY MOUTHS (TMM). These results demonstrate that stomata-specific regulators can alter mesophyll properties, which provides insight into how molecular pathways can organize leaf tissues to coordinate gas exchange and suggests new strategies for improving plant water-use efficiency. PMID- 28833174 TI - Enhanced motivation to alcohol in transgenic mice expressing human alpha synuclein. AB - alpha-Synuclein (alphaSYN) is the neuropathological hallmark protein of Parkinson's disease (PD) and related neurodegenerative disorders. Moreover, the gene encoding alphaSYN (SNCA) is a major genetic contributor to PD. Interestingly, independent genome-wide association studies also identified SNCA as the most important candidate gene for alcoholism. Furthermore, single nucleotide-polymorphisms have been associated with alcohol-craving behavior and alcohol-craving patients showed augmented alphaSYN expression in blood. To investigate the effect of alphaSYN on the addictive properties of chronic alcohol use, we examined consumption, motivation, and seeking responses induced by environmental stimuli and relapse behavior in transgenic mice expressing the human mutant [A30P]alphaSYN throughout the brain. The primary reinforcing effects of alcohol under operant self-administration conditions were increased, while consumption and the alcohol deprivation effect were not altered in the transgenic mice. The same mice were subjected to immunohistochemical measurements of immediate-early gene inductions in brain regions involved in addiction-related behaviors. Acute ethanol injection enhanced immunostaining for the phosphorylated form of cAMP response element binding protein in both amygdala and nucleus accumbens of alphaSYN transgenic mice, while in wild-type mice no effect was visible. However, at the same time, levels of cFos remain unchanged in both genotypes. These results provide experimental confirmation of SNCA as a candidate gene for alcoholism in addition to its known link to PD. PMID- 28833175 TI - Mst-1 deficiency promotes post-traumatic spinal motor neuron survival via enhancement of autophagy flux. AB - The mammalian Ste20-like kinase 1 (Mst-1) is a serine-threonine kinase and a component of the Hippo tumor suppressor pathway, which reacts to pathologically relevant stress and regulates cell death. However, little is known about its role in spinal cord injury. Here, we found that p-Mst-1, the activated form of Mst-1, was induced in the post-traumatic spinal motor neurons. In vivo evidence demonstrated that Mst-1 deficiency promoted post-traumatic spinal motor neuron survival, Basso mouse scale scores, and synapse survival. Moreover, we found that autophagosome formation and autolysosome degradation enhanced by Mst-1 deficiency were crucial to attenuate the death of injured spinal motor neurons. Taken together, our findings demonstrate that Mst-1 deficiency promotes post-traumatic spinal motor neuron survival via enhancement of autophagy flux. PMID- 28833176 TI - Cerebral amyloid angiopathy as a cause of neurodegeneration. AB - Sporadic, age-related cerebral amyloid angiopathy (CAA) is most commonly recognized clinically as a cause of hemorrhagic stroke and transient focal neurological episodes in older persons. But a growing body of research in the last 5 years shows that the pathophysiology of CAA is much more complex than previously believed, leading to many different types of brain injury. CAA has now been linked with brain atrophy in regions remote from those directly affected by intracerebral hematomas, and with risk for progressive cognitive decline in the absence of new hemorrhagic strokes. Therefore, CAA is associated with features - brain atrophy and progressive cognitive decline - that are typically considered hallmarks of neurodegenerative disease. Although CAA is usually accompanied by some degree of Alzheimer's disease pathology, the profiles of cortical thinning and cognitive impairment do not fully overlap with those seen in Alzheimer's disease, suggesting that there are CAA-specific pathways of neurodegeneration. CAA-related brain ischemia may be an important mechanism that leads to brain injury, cortical disconnection, and cognitive impairment. This article is part of the Special Issue "Vascular Dementia". PMID- 28833177 TI - A worthy self is a caring self: Examining the developmental relations between self-esteem and self-compassion in adolescents. AB - OBJECTIVE: Self-compassion has been framed as a healthy alternative to self esteem, as it is nonevaluative. However, rather than being alternatives, it may be that the two constructs develop in a mutually reinforcing way. The present study tested this possibility among adolescents. METHOD: A large adolescent sample (N = 2,809; 49.8% female) reported levels of trait self-esteem and self compassion annually for 4 years. Autoregressive cross-lagged structural equation models were used to estimate the reciprocal longitudinal relations between the two constructs. RESULTS: Self-esteem consistently predicted changes in self compassion across the 4 years of the study, but not vice versa. CONCLUSIONS: Self esteem appears to be an important antecedent of the development of self compassion, perhaps because the capacity to extend compassion toward the self depends on one's appraisals of worthiness. These findings add important insights to our theoretical understanding of the development of self-compassion. PMID- 28833178 TI - Expediting red blood cell transfusions by syringing causes significant hemolysis. AB - BACKGROUND: Techniques commonly used to expedite blood transfusions include pneumatically pressurizing red blood cell (RBC) bags or manual syringing its contents. We compared these techniques on RBC hemolysis using a simulated transfusion model. STUDY DESIGN AND METHODS: Fifteen warmed RBC units that were 12.3 +/- 4.3 (95% confidence interval [CI], 10.1-14.5) days old were each subjected to two experimental rapid transfusion techniques. RBCs from each technique were directed through 18- and 22-gauge cannulas attached to blood administration sets. One technique involved RBC bag pressurization to 300 mmHg. The other employed a 20-mL syringe to effect forceful, manual aspiration from the RBC bag followed by forceful, manual RBC injection. The control group was gravity driven without cannulas. Free hemoglobin (Hb) concentrations were measured and percent hemolysis was calculated. RESULTS: Free Hb concentrations and percent hemolysis (median [95% CI]) were similar in the control (0.05 [0.03-0.08] g/dL and 0.13% [0.09%-0.17%], respectively) and pressurized experiments (0.06 [0.05 0.09] g/dL; 0.14% [0.12%-0.22%]), respectively. Syringing resulted in 10-fold higher free Hb concentrations (0.55 [0.38-0.92] g/dL) and percent hemolysis (1.28% [1.03%-2.15%]) than when employing the control (p < 0.0001) or pressurization (p < 0.0001) techniques. Cannula sizes studied did not affect hemolysis. CONCLUSION: Forceful manual syringing caused significant hemolysis and high free Hb concentrations. Pressurizing RBC bags induced no more hemolysis than after gravity-facilitated transfusions. Syringing to expedite RBC transfusions should be avoided in favor of pneumatic RBC bag pressurization. PMID- 28833179 TI - The Chlamydomonas CO2 -concentrating mechanism and its potential for engineering photosynthesis in plants. AB - Contents Summary I. Introduction 54 II. Recent advances in our understanding of the Chlamydomonas CCM 55 III. Current gaps in our understanding of the Chlamydomonas CCM 58 IV. Approaches to rapidly advance our understanding of the Chlamydomonas CCM 58 V. Engineering a CCM into higher plants 58 VI. Conclusion and outlook 59 Acknowledgements 60 References 60 SUMMARY: To meet the food demands of a rising global population, innovative strategies are required to increase crop yields. Improvements in plant photosynthesis by genetic engineering show considerable potential towards this goal. One prospective approach is to introduce a CO2 -concentrating mechanism into crop plants to increase carbon fixation by supplying the central carbon-fixing enzyme, Rubisco, with a higher concentration of its substrate, CO2 . A promising donor organism for the molecular machinery of this mechanism is the eukaryotic alga Chlamydomonas reinhardtii. This review summarizes the recent advances in our understanding of carbon concentration in Chlamydomonas, outlines the most pressing gaps in our knowledge and discusses strategies to transfer a CO2 -concentrating mechanism into higher plants to increase photosynthetic performance. PMID- 28833180 TI - Body language reading of emotion in schizophrenia: Associations with symptoms and functional outcome. AB - Our aim was to explore how body language reading of emotion relates to neurocognition, symptoms and functional outcome in schizophrenia. Fifty-four individuals with schizophrenia and eighty-four healthy controls participated in the study. Emotion perception was assessed with a point-light display (PLD) task, the Emotion in Biological Motion (EmoBio) test, neurocognition was measured with the MATRICS Consensus Cognitive Battery (MCCB), and functioning was indexed by one measure of functional capacity and by one self-report questionnaire. Clinical symptoms were assessed with a five factor Positive and Negative Syndrome Scale (PANSS) symptoms model. Participants with schizophrenia had impaired body language reading of emotions compared to healthy controls (Cohen's d = 0.69). In participants with schizophrenia, emotion perception was associated with neurocognition (r = 0.42), functional capacity (r = 0.27) and disorganization symptoms (r = -0.27). Mediation analyses showed that disorganization symptoms mediated the effects of emotion perception and neurocognition, respectively, on social functional capacity. These results suggest that in individuals with schizophrenia, reduced emotion perception from body movements has negative consequences for functional outcome, but that the effect is mediated through disorganization symptoms. PMID- 28833181 TI - The effect of inferior turbinate surgery on ear symptoms. AB - OBJECTIVE: The aim of this placebo-controlled study was to evaluate the effect of various inferior turbinate surgery techniques on Eustachian tube dysfunction related symptoms. STUDY DESIGN: Outcomes were evaluated using the Eustachian Tube Dysfunction Questionnaire (ETDQ-7) and tympanometry results. METHODS: A total of 72 consecutively blinded and randomized adult patients with enlarged inferior turbinates due to persistent year-round rhinitis underwent either a radiofrequency ablation, diode laser, microdebrider-assisted inferior turbinoplasty, or sham surgery procedure. Assessments were conducted prior to surgery and 3 months subsequent to the surgery. RESULTS: In the evaluation of all patients, radiofrequency ablation, microdebrider-assisted inferior turbinoplasty, and sham surgery procedures decreased the ETDQ-7 total score significantly. In a three-way analysis of covariance, there were no significant differences in the results between sham surgery and any of the active treatment procedures. Allergic sensitization, sex, and age also had no effect on the results. There were no significant changes in the pre- and postoperative amounts of abnormal tympanometry curves or in the pre- and postoperative tympanometric peak pressure values in the actively treated patients or in the sham surgery group. CONCLUSION: The improvement of Eustachian tube dysfunction-related symptoms due to surgery of the anterior half of the inferior turbinate was found to be equal to placebo. The findings of this study do not support the use of reduction of the anterior half of the inferior turbinate as a sole procedure intended to treat the ear symptoms assessed by the ETDQ-7 questionnaire. LEVEL OF EVIDENCE: 1b. Laryngoscope, 128:568-572, 2018. PMID- 28833182 TI - Cost-effectiveness analysis of two caries prevention methods in the first permanent molar in children. AB - BACKGROUND: Evidence supports two methods for preventing dental caries lesions in children: pit and fissure sealants (PFS) and fluoride varnishes (FV). The aim of this study was to compare the cost-effectiveness of these two strategies in preventing dental caries lesions on the occlusal surface of the first permanent molar in children. METHODS: A Markov model was used to simulate the progression of dental caries on the occlusal surface of the first permanent molar in a hypothetical cohort of children over a 9-year period. Transition probabilities were extracted from the published literature and costs were calculated from a payer's perspective. Two scenarios were evaluated based on the probability of replacing a failed PFS. Sensitivity analysis was performed to test the robustness of the model. RESULTS: Over the 9-year study period PFS were less expensive and more effective than FV in preventing occlusal dental caries lesions. For the base case scenario the probability of replacing a failed PFS was 100 percent and the Incremental Cost-Effectiveness Ratio (ICER) for PFS was $156.87 per first episode of caries lesion averted. For the second scenario, the probability of replacing a failed PFS was lowered to 50 percent. Here, the ICER dropped to $113.00 per first episode of caries lesion averted and remained the dominant strategy. CONCLUSION: PFS should be the preferred method for the prevention of dental caries lesion on the occlusal surface of the first permanent molar, especially in children who are at high risk and have barriers of access to dental care. PMID- 28833183 TI - Fresh-Squeezed Orange Juice Properties Before and During In Vitro Digestion as Influenced by Orange Variety and Processing Method. AB - : This study aims to analyze the influence of processing and orange variety on initial quality, antioxidant activity, total polyphenol content (TPC), and ascorbic acid content of fresh-squeezed orange juice during in vitro digestion. Fresh-squeezed orange juice was made from Fukumoto Navel, Lane Late Navel, Olinda Nucellar Valencia, and Campbell Valencia oranges, and was processed thermally and nonthermally. Antioxidant activity (FRAP and ABTS assays), TPC (Folin-Ciocalteu method), and ascorbic acid were analyzed before and after gastrointestinal digestion. Bioaccessibility was calculated by comparing the measured values after digestion with the initial value for each juice. Orange variety significantly influenced pH, acidity, and total soluble solids (P < 0.0001). Antioxidant activity by FRAP was significantly higher (P < 0.0001) in Fukumoto Navel orange juice (16.0 +/- 0.4 mM Trolox) than the other juices (range: 9.1 to 10 mM Trolox). TPC was significantly influenced by orange variety (P < 0.0001) and ranged from 521 +/- 6 (Campbell Valencia) to 800 +/- 11 mg gallic acid/L (Lane Late Navel). Processing method did not influence antioxidant and polyphenol bioaccessibility (P > 0.05). However, antioxidant activity by ABTS and ascorbic acid bioaccessibility were significantly influenced by orange variety (P < 0.0001). These results indicate that fruit variety and nutrient bioaccessibility should be considered to optimize processing and formulation parameters. PRACTICAL APPLICATION: Processing method and variety of fruit during beverage manufacturing may influence its nutrient bioaccessibility. We present a detailed examination of the influence of orange variety, harvest time, and processing method on initial quality parameters and antioxidant bioaccessibility. It is recommended that nutritional analysis of beverages take into consideration both the bioaccessibility of nutrients and the initial nutrient content of the beverage. These results can be used for juice processors to take into consideration the harvest season and produce variety to manufacture beverages with higher nutritional quality. PMID- 28833184 TI - Effect of postoperative radiotherapy in pT1pN1cM0 and pT2p/cN0cM0 oropharyngeal squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Consulting of patients with oropharyngeal carcinoma, classified as pT1pN1cM0 and pT2p/cN0cM0, about postoperative radiotherapy is a precarious task as data are lacking. The aim of this study was to evaluate the effects of postoperative radiotherapy for patients with intermediate-stage oropharyngeal carcinoma. STUDY DESIGN: Multicentric retrospective study. METHODS: This analysis was conducted at seven Austrian institutions and included data of patients treated between 2000 and 2012. A total of 81 patients with oropharyngeal squamous cell carcinoma were included, of whom 33 patients received postoperative radiotherapy. p16 status determined by immunohistochemistry was available in 68 patients. RESULTS: Median follow-up was 47.9 months. Postoperative radiotherapy showed no benefits in regard to overall survival (P = .701). In contrast, disease free survival was significantly shortened in all patients without postoperative radiotherapy (P = .001). When dividing the cohort in dependence of p16, p16 positive patients did not benefit from postoperative radiotherapy regarding overall and disease-free survival (P = .934 and P = .102), whereas p16-negative patients showed improved disease-free survival after postoperative radiotherapy (P = .007). Multivariate analysis showed that outcome of postoperative radiotherapy is dependent on p16 status. CONCLUSIONS: In terms of disease-free survival, patients with p16-negative tumors may benefit from postoperative radiotherapy, whereas survival of p16-positive patients is good regardless of additional treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1075-1082, 2018. PMID- 28833186 TI - Identity development in cultural context: The role of deviating from master narratives. AB - OBJECTIVE: The great majority of research on identity and personality development has focused on individual processes of development, to the relative neglect of the cultural context of development. We employ a recently articulated framework for the examination of identity development in context, centered on the construct of master narratives, or culturally shared stories. METHOD: Across four studies, we asked emerging and midlife adults (N = 512) to narrate personal experiences of deviations from these master narratives. RESULTS: Across three quantitative studies, we show that (a) those who elaborated their deviation experiences were more likely to be in structurally marginalized positions in society (e.g., ethnic or sexual minorities); (b) those who elaborated an empowering alternative to the master narrative were more likely to be engaged in identity processes; and (c) master narratives maintain their rigidity by the frequency of their use. In study 4, using qualitative analyses, we illustrate the rigidity of master narratives, as well as the degree to which they take shape in social and group experiences. CONCLUSIONS: These studies emphasize the importance of cultural context in considering personality and identity development. PMID- 28833185 TI - Expiratory muscle strength training for radiation-associated aspiration after head and neck cancer: A case series. AB - OBJECTIVE/HYPOTHESIS: Expiratory muscle strength training (EMST) is a simple, inexpensive, device-driven exercise therapy. Therapeutic potential of EMST was examined among head and neck cancer survivors with chronic radiation-associated aspiration. STUDY DESIGN: Retrospective case series. METHODS: Maximum expiratory pressures (MEPs) were examined among n = 64 radiation-associated aspirators (per penetration-aspiration scale score >= 6 on modified barium swallow). Pre-post EMST outcomes were examined in a nested subgroup of patients (n = 26) who enrolled in 8 weeks of EMST (25 repetitions, 5 days/week, 75% load). Nonparametric analyses examined effects of EMST on the primary endpoint MEPs. Secondary measures included swallowing safety (Dynamic Imaging Grade of Swallowing Toxicity [DIGEST]), perceived dysphagia (M.D. Anderson Dysphagia Inventory [MDADI]), and diet (performance status scale for head and neck cancer patients [PSSHN]). RESULTS: Compared to sex-matched published normative data, MEPs were reduced in 91% (58 of 64) of aspirators (mean +/- standard deviation: 89 +/- 37). Twenty-six patients enrolled in EMST and three patients withdrew. MEPs improved on average 57% (87 +/- 29 to 137 +/- 44 cm H2 O, P < 0.001) among 23 who completed EMST. Swallowing safety (per DIGEST) improved significantly (P = 0.03). Composite MDADI scores improved post-EMST (pre-EMST: 59.9 +/- 17.1, post EMST: 62.7 +/- 13.9, P = 0.13). PSSHN diet scores did not significantly change. CONCLUSION: MEPs were reduced in chronic radiation-associated aspirators relative to normative data, suggesting that expiratory strengthening could be a novel therapeutic target to improve airway protection in this population. Similar to findings in neurogenic populations, these data also suggest improved expiratory pressure-generating capabilities after EMST and translation to functional improvements in swallowing safety in chronic radiation-associated aspirators. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1044-1051, 2018. PMID- 28833187 TI - RHD genotype and zygosity analysis in the Chinese Southern Han D+, D- and D variant donors using the multiplex ligation-dependent probe amplification assay. AB - BACKGROUND AND OBJECTIVES: Several comprehensive genotyping platforms for determining red blood cell (RBC) antigens have been established and validated for use in the Caucasian and Black populations, but not for the Chinese. The multiplex ligation-dependent probe amplification (MLPA) assay was validated for RHD genotyping in the Chinese. MATERIALS AND METHODS: The blood samples of 200 D+, 200 D- and 62 D variant Chinese donors were collected. RhD antigen was routinely typed by serological method. D variant phenotype was determined by an anti-D panel (D-Screen), when RBCs were available. The RHD genotype and its zygosity were analysed with the RH-MLPA technique. When the MLPA was unable to identify a RHD variant, direct sequencing of all exons of the RHD gene was performed. RESULTS: In 200 D+ donors, DD (168/200, 84%), D (12/200, 6%), DDD genotype (1/200) and D variant allele carriers (19/200, 9.5%) were found. In 200 D- donors, six reported RHD alleles, RHD*01EL.01, RHD*01N.03, RHD*01N.05, RHD*01N.16, RHD*DFR2 and RHD*weak partial 15 and one novel RHD*1154T allele were identified in 36.5% (73/200) of them. In 62 D variant donors, three novel RHD alleles, RHD*79_81delCTC, RHD*710T and RHD*689A, and twelve reported alleles, RHD*DVI.3, RHD*weak partial 15, RHD*DVI.4, RHD*01EL.01, RHD*01N.03, RHD*DLO, RHD*DV.5, RHD*D-CE(2-10), RHD*730C, RHD*weak D type 25, 33 and 72, were identified, either alone or in combination. CONCLUSION: The RH-MLPA assay correctly identified the common RHD variant alleles in the Chinese population. However, DNA sequencing was required to identify certain alleles; probes to detect these alleles should be added into the assay. PMID- 28833188 TI - Low hepatitis E virus RNA prevalence in a large-scale survey of United States source plasma donors. AB - BACKGROUND: Hepatitis E virus (HEV) is a small, nonenveloped, single-stranded, RNA virus of emerging concern in industrialized countries. HEV transmission through transfusion of blood components has been reported, but not via plasma derived medicinal products (PDMPs) manufactured with virus inactivation and/or removal steps. This study aimed to determine the prevalence of HEV among US source plasma donors. STUDY DESIGN AND METHODS: Samples were collected from US source plasma donors at centers across the United States and were initially screened for HEV RNA in 96-sample minipools using the Roche cobas HEV test on the cobas 8800 system. Assuming a sensitivity of 18.6 IU/mL, the minipool screening strategy allowed for reliable detection of individual donations with HEV RNA titers of more than 2 * 103 IU/mL. Reactive minipools were resolved to individual donations, which were further analyzed to quantify viral RNA concentration, determine HEV genotype, and immunoglobulin (Ig)G and IgM HEV antibody status. RESULTS: A total of 128,020 samples were collected from 96 CSL Plasma centers in the United States, representing 27 states. The prevalence of HEV RNA-positive samples was 0.002% with three unique HEV-positive donors identified, all HEV Subgenotype 3a. Virus titers of HEV-positive samples were relatively low (103 104 IU HEV RNA/mL). One positive donation was HEV IgG seropositive. CONCLUSION: Routine screening of US source plasma donations for HEV would not substantially improve the safety of most PDMPs. The low prevalence and potential viral load of HEV, together with effective virus reduction steps in manufacturing processes, results in a low residual risk and acceptable safety margins for PDMPs derived from US plasma donors. PMID- 28833189 TI - Musical training modulates the early but not the late stage of rhythmic syntactic processing. AB - Syntactic processing is essential for musical understanding. Although the processing of harmonic syntax has been well studied, very little is known about the neural mechanisms underlying rhythmic syntactic processing. The present study investigated the neural processing of rhythmic syntax and whether and to what extent long-term musical training impacts such processing. Fourteen musicians and 14 nonmusicians listened to syntactic-regular or syntactic-irregular rhythmic sequences and judged the completeness of these sequences. Nonmusicians, as well as musicians, showed a P600 effect to syntactic-irregular endings, indicating that musical exposure and perceptual learning of music are sufficient to enable nonmusicians to process rhythmic syntax at the late stage. However, musicians, but not nonmusicians, also exhibited an early right anterior negativity (ERAN) response to syntactic-irregular endings, which suggests that musical training only modulates the early but not the late stage of rhythmic syntactic processing. These findings revealed for the first time the neural mechanisms underlying the processing of rhythmic syntax in music, which has important implications for theories of hierarchically organized music cognition and comparative studies of syntactic processing in music and language. PMID- 28833190 TI - Cardiorespiratory effects of epidural anesthesia using lidocaine with morphine or dexmedetomidine in capuchin monkeys (Sapajus sp.) undergoing bilateral tubal ligation surgery, anesthetized with isoflurane. AB - BACKGROUND: Epidural anesthesia is indicated to decrease other anesthetic requirements, prolong analgesia, and reduce side effects. In primates, its use has been scarcely described. The aim was to evaluate the cardiorespiratory effects of epidural anesthesia with lidocaine and dexmedetomidine (DEX) or morphine (MOR). METHODS: Ten female capuchin monkeys (Sapajus sp.) received epidural anesthesia with lidocaine and DEX or MOR under general anesthesia. RESULTS: There was a significant decrease in heart rate with DEX and in blood pressure in all groups, with no changes in SpO2 . There was a significant reduction in rectal temperature over time. A stable cardiac rhythm was observed; however, there was a prolonged QT interval with DEX. CONCLUSIONS: Epidural anesthesia with access to the lumbosacral space was safe and easy to perform. DEX decreased heart rate. All groups promoted a decrease in rectal temperature with respiratory and cardiac rhythm stability; however, hypotension should be considered. PMID- 28833191 TI - Exploring spatially varying relationships between children's lead poisoning and environmental factors. AB - Children's lead poisoning continues to compromise children's health and development, particularly in the inner cities of the United States. We applied a global Poisson model, a Poisson with random effects model, and a geographically weighted Poisson regression (GWPR) model to deal with the spatial dependence and heterogeneity of the number of children's lead poisoning cases in Syracuse, New York. We used three environmental factors-the building year (i.e., the year of construction) of houses, the town taxable value of houses, and the soil lead concentration-averaged at the census block level to explore the spatially varying relationships between children's lead poisoning and environmental factors. The results indicated that GWPR not only produced better model fitting and reduced the spatial dependence and heterogeneity in the model residuals but also improved the model predictions for the spatial clusters, or hot spots, of children's lead poisoning across inner city neighborhoods. Furthermore, the spatially varying model coefficients and their associated statistical tests were visualized using geographical information system maps to show the high-risk areas for the impacts of the environmental factors on the response variable. This information can provide valuable insights for public health agencies to make better decisions on lead hazard intervention, mitigation, and control programs. PMID- 28833192 TI - Effect of Agomelatine and Fluoxetine on HAM-D Score, Serum Brain-Derived Neurotrophic Factor, and Tumor Necrosis Factor-alpha Level in Patients With Major Depressive Disorder With Severe Depression. AB - Evidence suggests that neurotrophic factors, inflammatory markers, and circadian rhythm dysfunctions could be involved in pathophysiology of major depressive disorder. This study evaluated the efficacy and tolerability of agomelatine, a melatonergic drug, and fluoxetine (positive comparator) and their effect on serum brain-derived neurotrophic factor (BDNF) and tumor necrosis factor (TNF)-alpha level in patients having major depressive disorder with severe depression. In the present study, we chose TNF-alpha and BDNF because reduction of TNF-alpha and rise in BDNF levels are linked with improvement in major depressive disorder. Patients with Hamilton Rating Scale for Depression (HAM-D) score >=25 were treated with agomelatine or fluoxetine and followed up for 12 weeks. In the agomelatine group, the HAM-D score, BDNF level, and TNF-alpha level at the start of treatment were 31.1 +/- 1.88 ng/mL, 2.44 +/- 0.38 ng/mL, and 512.5 +/- 86.2 pg/mL, respectively, which significantly changed to 13.67 +/- 2.22 ng/mL, 2.87 +/ 0.44 ng/mL, and 391.64 +/- 104.8 pg/mL, respectively (P < .05 for all 3 measures), at 12 weeks. In the fluoxetine group, the HAM-D score, BDNF level, and TNF-alpha level at the start of treatment were 30.83 +/- 2.60 ng/mL, 2.54 +/- 0.37 ng/mL, and 554.14 +/- 46.8 pg/mL, respectively, which significantly changed to 13.67 +/- 1.79 ng/mL, 3.07 +/- 0.33 ng/mL, and 484.15 +/- 49.9 pg/mL, respectively (P < .05 for all 3 measures) at 12 weeks. The BDNF level was significantly increased posttreatment with both drugs, and TNF-alpha level fell significantly more with agomelatine compared to fluoxetine. Thus, chronic neuroinflammatory biomarkers contribute to circuitry dysregulation in depression. Trophic factors repair dysfunctional circuits in depression. Both treatments were found to be safe and well tolerated. PMID- 28833193 TI - Coagulation and fibrinolysis in gastric cancer. AB - Coagulation is a highly conserved process occurring after an injury to a blood vessel and resulting in hemostasis. In the thrombus microenvironment, finely orchestrated events restore vessel integrity through platelet activation, adhesion, and aggregation (primary hemostasis), followed by the coagulation cascades, thrombin generation, and fibrin clot deposition (secondary hemostasis). Several studies on cancer have provided insight into dramatic changes to coagulation-related events (i.e., fibrin clot deposition, fibrinolysis) during tumor pathogenesis, progression, and metastasis, in addition to a tumor-driven systemic activation of hemostasis and thrombosis (Trousseau's syndrome). Diverse molecular and cellular effectors participate in the cross talk between hemostasis and tumors. Here, we focus on some aspects of the interconnection between cancer biology and hemostatic components, with particular attention to some key coagulation-related proteins (e.g., tissue factor, thrombin, fibrinogen, and D dimers) in the particular case of gastric cancer (GC). Recent advances in deciphering the complex molecular link between GC and the coagulation system are described, showing their important roles in better management of patients affected by GC. PMID- 28833195 TI - Dietary vitamin E dosage and source affects meat quality parameters in light weight lambs. AB - BACKGROUND: Supra-nutritional vitamin E supplementation is a commonly used approach to delay lipid oxidation and colour deterioration in lamb and beef meat marketed under modified atmosphere packaging. However, these applications lack a precise calibration of dose for the desired effect and, in addition, limited information is available regarding the use of natural vitamin E for this purpose. RESULTS: Three hundred and sixty Rasa Aragonesa lambs were fed diets supplemented with all-rac-alpha-tocopheryl acetate (250, 500, 1000 and 2000 mg kg-1 compound feed), RRR-alpha-tocopheryl acetate (125, 250, 500 and 1000 mg kg-1 compound feed) and a basal diet without vitamin E supplementation for 14 days before slaughter at 25.8 +/- 1.67 kg body weight. Vitamin E supplementation had no effect (P > 0.05) on average daily weight gain, feed intake and feed efficiency. Display time had larger effects on lipid oxidation, colour stability, myoglobin forms and meat discolouration parameters compared to vitamin E supplementation. However, vitamin E source and dosage significantly extended meat shelf-life as indicated by lipid oxidation, redness, hue angle, metmyoglobin formation, deoxymyoglobin formation, A580-630 and ISO2 . CONCLUSION: The quantification of these effects demonstrated that the biological activity value of 1.36 used to distinguish both vitamin E sources is not appropriate for meat quality enhancing properties. (c) 2017 Society of Chemical Industry. PMID- 28833196 TI - Comparison of risk factors and complications in patients by stratified mastectomy weight: An institutional review of 1041 consecutive cases. AB - BACKGROUND AND OBJECTIVES: This study aims to investigate the specific complication rates, reconstructive differences, and delineate the pertinent independent risk factors in patients with different mastectomy weights. METHODS: A retrospective chart review of consecutive patients undergoing mastectomy between 2010 and 2015 was performed. Patient demographics, comorbidities, and intraoperative and postoperative outcomes were collected. Patients were divided into three groups: those with mastectomy weight <500, 500-1000, and >1000 g. RESULTS: During the study period, a total of 704 consecutive patients and 1041 total mastectomy surgeries had complete mastectomy specimen weight data. Of these, 437 breasts were in the <500 g specimen group, 425 were included in the 500-1000 g group and 179 in the >1000g group. The rate of overall complications between the three mastectomy weight groups (<500, 500-1000, and >1000 g) was statistically significant (14.0%, 17.6%, and 25.7%; P = 0.002, respectively) and were higher with increased mastectomy weights. Notably, in patients with breast mastectomy weight >1000 g, autologous reconstruction had significantly reduced rates of overall complications (AOR = 0.512, P = 0.048). CONCLUSION: Complication rates were lower in women with larger breast weights undergoing autologous reconstruction, warranting potential use of autologous free flap breast reconstruction in women with large mastectomy specimen weights when possible. PMID- 28833197 TI - Recurrence patterns and associated factors of locoregional failure following neoadjuvant chemoradiation and surgery for esophageal cancer. AB - BACKGROUND: Despite neoadjuvant chemoradiation (nCRT) followed by esophagectomy for locally advanced esophageal cancer, locoregional recurrence (LRR) is common and factors associated with LRR have not been clearly identified. METHODS: Patients were identified from a single institution, prospectively maintained database (1996-2013). Patterns of recurrence were described and associated factors of LRR were analyzed using competing risks regression models. RESULTS: Of the 456 patients treated with nCRT and surgery, 167 patients developed recurrence. Locoregional and distant recurrences were observed in 69 (15.1%) and 140 (30.9%) patients, respectively. Time to recurrence (13.6 vs 10.4 months, P = 0.20) and median overall survival (29.3 vs 19.1 months, P = 0.12) were no different among the 27 patients (6%) who developed a solitary LRR compared to patients who developed distant recurrence. Univariable analysis identified lymphovascular invasion (HR 1.46, P = 0.07), lymph node ratio >0.5 (HR 2.16, P = 0.02), positive margin (HR 1.95, P = 0.05), lack of response to neoadjuvant therapy (HR 1.99, P < 0.01), clinical T stage (HR 2.62, P < 0.01) and final T3/4 stage (HR 2.06, P < 0.01) as factors significantly associated with LRR. Clinical T stage and response to neoadjuvant treatment were independently associated with LRR on multivariable analysis. CONCLUSIONS: Although aggressive tumor biology plays a significant role in LRR, optimizing neoadjuvant treatments to obtain a complete pathologic response may lead to improved locoregional control. PMID- 28833194 TI - Mechanobiology of limb musculoskeletal development. AB - While there has been considerable progress in identifying molecular regulators of musculoskeletal development, the role of physical forces in regulating induction, differentiation, and patterning events is less well understood. Here, we highlight recent findings in this area, focusing primarily on model systems that test the mechanical regulation of skeletal and tendon development in the limb. We also discuss a few of the key signaling pathways and mechanisms that have been implicated in mechanotransduction and highlight current gaps in knowledge and opportunities for further research in the field. PMID- 28833198 TI - Constructing a patient-specific computer model of the upper airway in sleep apnea patients. AB - OBJECTIVE: The use of computer simulation to develop a high-fidelity model has been proposed as a novel and cost-effective alternative to help guide therapeutic intervention in sleep apnea surgery. We describe a computer model based on patient-specific anatomy of obstructive sleep apnea (OSA) subjects wherein the percentage and sites of upper airway collapse are compared to findings on drug induced sleep endoscopy (DISE). STUDY DESIGN: Basic science computer model generation. METHODS: Three-dimensional finite element techniques were undertaken for model development in a pilot study of four OSA patients. Magnetic resonance imaging was used to capture patient anatomy and software employed to outline critical anatomical structures. A finite-element mesh was applied to the volume enclosed by each structure. Linear and hyperelastic soft-tissue properties for various subsites (tonsils, uvula, soft palate, and tongue base) were derived using an inverse finite-element technique from surgical specimens. Each model underwent computer simulation to determine the degree of displacement on various structures within the upper airway, and these findings were compared to DISE exams performed on the four study patients. RESULTS: Computer simulation predictions for percentage of airway collapse and site of maximal collapse show agreement with observed results seen on endoscopic visualization. CONCLUSION: Modeling the upper airway in OSA patients is feasible and holds promise in aiding patient-specific surgical treatment. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:277 282, 2018. PMID- 28833199 TI - Questioning the unconscious. AB - In this piece, I outline a brief history of the development of concepts of the unconscious and then suggest ways of bringing understanding to various sides of the discussion. PMID- 28833200 TI - Vertebral heart size in chinchillas (Chinchilla lanigera) usingradiography and CT. AB - OBJECTIVE: To determine the vertebral heart size in chinchillas using right and left lateral radiographic views and CT images. To evaluate the agreement between radiographic and CT modalities. METHODS: Twenty-one clinically healthy chinchillas and seven chinchillas with cardiovascular abnormalities underwent cardiovascular examination before thoracic radiographs and thoracic CT obtained under dexmedetomidine-ketamine anaesthesia. Two observers calculated vertebral heart size for radiographic and CT studies. Reference intervals were calculated with the robust method. Agreement between radiographic and CT-derived vertebral heart size was evaluated with Bland-Altman plots and Deming regression. RESULTS: Mean +/-sd vertebral heart size for lateral radiographs was 8.9 +/-0.62 (reference interval: 7.5 to 10.2) and for CT-derived vertebral heart size was 8.2 +/-0.55 (reference interval: 7.1 to 9.4). CT significantly underestimated the radiographic vertebral heart size by 0.66 vertebrae. There was no significant difference between vertebral heart size for right and left lateral radiographic views, or between female and male chinchillas. CLINICAL SIGNIFICANCE: Radiographic vertebral heart size for chinchillas is larger than that reported for similar rodents. Vertebral heart size can be calculated using radiography or CT in chinchillas, but these techniques are not interchangeable. PMID- 28833201 TI - Dynamics of regulatory T cells (Tregs ) in patients with oral squamous cell carcinoma. AB - BACKGROUND AND OBJECTIVES: The immune dysfunction in oral squamous cell carcinoma (OSCC) patients is one of the major factors for growth and dissemination of tumor affecting disease-free survival. METHODS: The phenotypic and functional characteristics of Regulatory T (Treg ) CD4+ CD25+ FoxP3+ subsets in OSCC patients were assessed by multicolor flow cytometry and its effector component (TGF-beta) by Western blot and qRT-PCR. RESULTS: An increased (P < 0.05) prevalence of Treg phenotypes (CD4+ CD25+ , CD4+ FoxP3+ , CD8+ FoxP3+ , CD4+ CD25+ FoxP3+ ) was observed in the peripheral circulation of OSCC patients that positively correlated with clinicopathological features. The increased frequency of CD4+ CD8+ CD25+ FoxP3+ , a unique T cell subset, CTLA-4+ , GITR+ , NrP1+ , HLA DR+ , CD127+ , Tbet+ , TGF-beta+ , and granzyme B+ (GzmB) Tregs also showed a significantly higher prevalence in OSCC patients. Functionally, CD4+ FoxP3+ Tregs showed skewed expression of IL-2, IL-10, and IL-35 in patients as compared with the normal controls. Further, enhanced expression of CCR5 and CCR7 on Tregs with up regulation of their ligands (CCL5, CCL19, and CCL21) in tumor cells indicates efficient recruitment and trafficking of Tregs to the tumor site. CONCLUSION: It seems reasonable to assume that modulation of functional dynamics of selective Treg subsets may be useful in developing immunotherapeutic strategy for OSCC patients. PMID- 28833202 TI - Molecular composition and heterogeneity of the LRRC8-containing swelling activated osmolyte channels in primary rat astrocytes. AB - KEY POINTS: The volume-regulated anion channel (VRAC) is a swelling-activated chloride channel that is permeable to inorganic anions and a variety of small organic molecules. VRAC is formed via heteromerization of LRRC8 proteins, among which LRRC8A is essential, while LRRC8B/C/D/E serve as exchangeable complementary partners. We used an RNAi approach and radiotracer assays to explore which LRRC8 isoforms contribute to swelling-activated release of diverse organic osmolytes in rat astrocytes. Efflux of uncharged osmolytes (myo-inositol and taurine) was suppressed by deletion of LRRC8A or LRRC8D, but not by deletion of LRRC8C+LRRC8E. Conversely, release of charged osmolytes (d-aspartate) was strongly reduced by deletion of LRRC8A or LRRC8C+LRRC8E, but largely unaffected by downregulation of LRRC8D. Our findings point to the existence of multiple heteromeric VRACs in the same cell type: LRRC8A/D-containing heteromers appear to dominate release of uncharged osmolytes, while LRRC8A/C/E, with the additional contribution of LRRC8D, creates a conduit for movement of charged molecules. ABSTRACT: The volume regulated anion channel (VRAC) is the ubiquitously expressed vertebrate Cl- /anion channel that is composed of proteins belonging to the LRRC8 family and activated by cell swelling. In the brain, VRAC contributes to physiological and pathological release of a variety of small organic molecules, including the amino acid neurotransmitters glutamate, aspartate and taurine. In the present work, we explored the role of all five LRRC8 family members in the release of organic osmolytes from primary rat astrocytes. Expression of LRRC8 proteins was modified using an RNAi approach, and amino acid fluxes via VRAC were quantified by radiotracer assays in cells challenged with hypoosmotic medium (30% reduction in osmolarity). Consistent with our prior work, knockdown of LRRC8A potently and equally suppressed the release of radiolabelled d-[14 C]aspartate and [3 H]taurine. Among other LRRC8 subunits, downregulation of LRRC8D strongly inhibited release of the uncharged osmolytes [3 H]taurine and myo-[3 H]inositol, without major impact on the simultaneously measured efflux of the charged d-[14 C]aspartate. In contrast, the release of d-[14 C]aspartate was preferentially sensitive to deletion of LRRC8C+LRRC8E, but unaffected by downregulation of LRRC8D. Finally, siRNA knockdown of LRRC8C+LRRC8D strongly inhibited the release of all osmolytes. Overall, our findings suggest the existence of at least two distinct heteromeric VRACs in astroglial cells. The LRRC8A/D-containing permeability pathway appears to dominate the release of uncharged osmolytes, while an alternative channel (or channels) is composed of LRRC8A/C/D/E and responsible for the loss of charged molecules. PMID- 28833203 TI - Urban environment: a risk factor for canine immune-mediated disease? AB - OBJECTIVES: To investigate whether dogs living in urban areas are more likely to develop immune-mediated disease than those in rural areas. MATERIALS AND METHODS: A case-control study comparing the prevalence of urban home location between dogs with immune-mediated disease and matched controls. Dogs diagnosed with immune mediated haemolytic anaemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis or meningoencephalomyelitis of unknown origin were identified by case record searches. Breed-matched dogs presenting to the same hospital during the same year as cases were randomly selected as controls. Home locations were classified as rural or urban using the population density of the relevant census tract and conditional logistic regression was used to examine association between home location and immune-mediated disease. RESULTS: In the 137 cases and 137 breed-matched controls, the odds ratio for any immune-mediated disease for dogs living in urban (versus rural) areas was 0.94 (95% confidence interval 0.58 to 1.55, P=0.80). Odds ratios for development of immune-mediated haematological diseases, immune-mediated polyarthritis or meningoencephalomyelitis of unknown origin were also not significantly different from the null value. Multivariable analysis including age, gender and season of presentation did not suggest confounding of effect of home location by these additional variables. CLINICAL SIGNIFICANCE: This study does not support an association between urban environment and immune-mediated disease in dogs. PMID- 28833204 TI - Simultaneous evaluation of the effects of geographic, environmental and temporal isolation in ecotypic populations of Solidago virgaurea. AB - Early stages of ecological speciation can create populations with an ecology and reproduction timing distinct from those of related populations. Landscape genetic models incorporating environmental heterogeneity and population-specific reproductive traits enable the processes of population genetic differentiation to be inferred. We investigated genome-wide genetic variation in ecotypic populations of Solidago virgaurea sensu lato, a herbaceous plant inhabiting a wide range of habitats (woodlands, serpentine barrens and alpine grasslands) and displaying remarkable variation in flowering time. Simultaneous evaluation of environmental factors revealed an overwhelming effect of soil type differences on neutral genetic differentiation, compared with elevational differences. This result probably reflects the abrupt environmental changes generated by geological boundaries, whereas mountain slopes exhibit clinal changes, facilitating gene exchange between neighbouring populations. Temporal isolation was positively associated with genetic differentiation, with some early-flowering serpentine populations having allele frequencies distinct from adjacent nonserpentine populations. Overall, this study highlights the importance of ecological processes and of evolution of flowering time to promote genetic differentiation of S. virgaurea populations in a complex landscape. PMID- 28833205 TI - Preoperative management of colorectal cancer-induced iron deficiency anemia in clinical practice: data from a large observational cohort. AB - BACKGROUND: Preoperative anemia prevalence among colorectal cancer (CRC) patients is high and may adversely influence postoperative outcome. This study assesses the efficacy of a preoperative anemia managing protocol in CRC. STUDY DESIGN AND METHODS: This was a retrospective analysis of consecutive CRC resections at two Spanish centers (January 2012 to December 2013). Preoperative anemia was defined as a hemoglobin (Hb) level of less than 13 g/dL and treated with intravenous iron (IVI) or standard care (oral iron or no iron). Red blood cell transfusion (RBCT) requirements was the primary outcome variable. Postoperative infection rate and length of hospital stay (LOS) were secondary outcome variables. Patients were managed with a restrictive transfusion trigger (Hb < 8 g/dL). Infection was diagnosed clinically and confirmed by laboratory, microbiologic, and/or radiologic evidence. RESULTS: Overall, 322 of 571 patients (56%) presented with anemia: 232 received IVI and 90 standard care. There were differences in RBCT rate between no anemia and anemia (2% vs. 16%; p < 0.01), but not in postoperative infections (19% vs. 22%; p = NS) or LOS. Compared to those on standard care, anemic patients on IVI presented with lower Hb (10.8 g/dL vs. 12.0 g/dL; p < 0.001) at baseline, but similar Hb on day of surgery and Postoperative Day 30. There were no between-group differences in RBCT rates (16% vs. 17%; p = NS), but infection rates were lower among IVI-treated patients (18% vs. 29%; p < 0.05). No relevant IVI-related side effects were recorded. CONCLUSION: Compared to standard care, IVI was more effective in treating preoperative anemia in CRC patients and appeared to reduce infection rate, although it did not reduce postoperative RBCT. PMID- 28833206 TI - Sonographic differentiation between lymphatic and metastatic diseases in cervical lymphadenopathy. AB - OBJECTIVES/HYPOTHESIS: The spectrum of differential diagnosis in cervical lymphadenopathy is extremely broad. In lymphoma and inflammatory diseases, surgical approaches are restricted to diagnostic lymph extirpation, whereas metastatic outgrowth into regional lymph nodes usually requires neck dissection. Lymph node surgery has to manage the balancing act between sufficient radicality and preservation of functional structures. The current study, therefore, aimed to identify parameters to differentiate between lymph nodes of lymphatic and metastatic origin. STUDY DESIGN: Single-center, retrospective cohort study. METHODS: Clinical and sonographic parameters from all patients who underwent diagnostic cervical lymphadenectomy from 2010 to 2015 (N = 262) were included in this retrospective analysis. Parameters with significant differences between the two subgroups were utilized to create a clinical algorithm to distinguish between cervical lymphadenopathy of lymphatic and metastatic genesis. RESULTS: Statistically significant differences between the two subgroups could be shown for clinical (gender, age, nicotine/alcohol abuse, B symptoms, history of cutaneous melanoma, or lymphoma) and ultrasonographic parameters (string-of-beads confirmation, bilaterality, homogenous echostructure, localization in level I, long-to-short axis ratio, and hilar vascularity). The proposed algorithm yielded a sensitivity of 92.4% for metastatic disease. CONCLUSIONS: The implemented algorithm based on ultrasonographic and clinical criteria contributes to one-step surgical approaches that guarantee a sufficient radicality with a minimum of functional loss. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:859-863, 2018. PMID- 28833207 TI - Semicircular canal dehiscence among idiopathic intracranial hypertension patients. AB - OBJECTIVES/HYPOTHESIS: The cause of superior semicircular canal dehiscence (SSCD) is unknown. Because of a demonstrated association with tegmental defects and obesity, some have suggested idiopathic intracranial hypertension (IIH) could contribute by eroding the bone over the canal and resulting in SSCD. However, an association between IIH and SSCD has not previously been evaluated. Our objective was to evaluate an association between IIH and SSCD. STUDY DESIGN: Retrospective cohort. METHODS: A retrospective study was performed of opening pressures for consecutive patients presenting at a lumbar puncture clinic between August 2012 and October 2015. Imaging for patients who also had thin-sectioned computed tomography (CT) imaging was reviewed for the presence of radiographic SSCD. Association between IIH and SSCD was evaluated using the Student t test and multivariate logistic regression. RESULTS: One hundred twenty-one patients had both a lumbar puncture performed and thin-sectioned CT imaging available, of which 24 patients (19.8%) met the criteria for IIH with an opening pressure >25 cm H2 O. The remaining 97 patients (80.2%) did not have elevated opening pressures and served as the control cohort. None of the 24 patients with IIH had radiographic SSCD, whereas eight of the 97 patients (8.2%) without IIH had radiographic SSCD. The average opening pressure in patients without radiographic SSCD was 20.2 cm H2 O compared to 19.3 cm H2 O in patients with radiographic SSCD (P = .521). In multivariate logistic regression controlling for age, body mass index, gender, and comorbidities (hypertension, diabetes, hyperlipidemia), opening pressure was not a significant predictor of radiographic SSCD. CONCLUSIONS: The results of this retrospective pilot study do not suggest an association between IIH and SSCD. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:1196 1199, 2018. PMID- 28833208 TI - Accounting for job satisfaction: Examining the interplay of person and situation. AB - In the present study, we investigate the interplay of personality traits (i.e., person) in frontline care staff in nursing homes and the way they relate to the residents (i.e., situation) to account for their job satisfaction. Participants completed a survey including Mini-IPIP tapping the five-factor model of personality, Individualized Care Inventory tapping four aspects of person centered care and job satisfaction. The results revealed that staff scoring high on neuroticism experienced less job satisfaction. This relationship was partly accounted for by resident autonomy, suggesting that part of the adverse influence of neuroticism on job satisfaction may be mitigated by organizations providing a supportive care environment. In contrast, staff scoring high on agreeableness experienced higher job satisfaction. This relationship was accounted for by another aspect of person-centered care, that is, knowing the person. This suggests that agreeableness in a sense facilitated adjustment of acts of care toward the unique needs and preferences of residents and this partly explained why the more agreeable the staff was the more they felt satisfied at work. In sum, effects of personality traits on job satisfaction in care staff are partially mediated by the perception of working conditions and care policy and to the extent that a certain personality trait affects whether the staff have a positive or negative perception of the way they relate to the residents, they will experience, respectively, higher or a lower job satisfaction. This finding has implications for how to combine a focus on delivering person-centered care with improving personal job satisfaction. PMID- 28833209 TI - A study of 853 high grade osteosarcomas from a single institution-Are outcomes in Indian patients different? AB - AIMS: To review outcomes of 853 patients of primary high grade osteosarcoma operated with curative intent between January 2006 to December 2013. METHODS: All patients underwent appropriate surgical resection after preoperative chemotherapy (non methotrexate based). Excised specimen was analyzed for margins and response to chemotherapy. We analysed various factors (sex, age, size, site, type of surgery, pathologic fractures, margin status, and chemotherapy induced necrosis) for their impact on outcomes. RESULTS: Five year overall survival (OS) for entire cohort was 49% and event free survival (EFS) was 42%. Seventy hundred thirty eight non metastatic patients had OS of 53% and EFS of 47% at 5 years. The 3 year OS and EFS of the metastatic patients was 22% and 9%, respectively. Analysis of 738 non metastatic patients demonstrated that chemotherapy induced necrosis, size of tumor (< / >8 cms), type of surgery (limb salvage vs amputation) significantly affected overall survival. Local recurrence was 9%. Site of tumor (long bone vs pelvis), type of surgery and chemotherapy induced necrosis influenced local recurrence. CONCLUSIONS: Our patients appeared to have poorer survival compared to most Western data, possibly attributable to large tumors. In contrast to existing data, males (71%) were predominantly affected and only patients with 100% necrosis qualified as good responders regarding OS. PMID- 28833210 TI - Status and progress of treatment methods for root caries in the last decade: a literature review. AB - The aim of this literature review is to explore the treatment methods for root caries in laboratory and clinical research in the last decade. A systematic search of publications in PubMed and Web of Science databases was performed. The timespan was limited to the last 10 years and English language. Further retrieval was conducted using the search terms of specific therapies or treatments. Eighty two articles were included in this systematic review and full texts were retrieved. Types of studies included laboratory studies and clinical trials. Therapeutic approaches for root caries without risk of pulp exposure can be categorized into non-invasive and restorative treatment. Non-invasive treatments which targeted different causative factors of root caries have been developed in the last decade. Accordingly, several artificial caries model systems have been proposed for the study of root caries in the laboratory. Carious tissue excavation techniques and restorative materials and procedures have been modified to improve the prognosis of invasive treatment. It is of importance to determine the most appropriate therapy for root caries and further clinical trials are needed to draw firm conclusions concerning the efficacy and consistency of the various treatment methods proposed. PMID- 28833211 TI - Leishmania tarentolae expressing CXCL-10 as an efficient immunotherapy approach against Leishmania major-infected BALB/c mice. AB - Recent findings have demonstrated the suitability of interferon-gamma-induced protein 10 (IP-10) or CXCL-10 as an immunotherapy tool in treatment of leishmaniasis. This chemokine can overcome Leishmania (L.) infection through inducing nitric oxide (NO) production for parasite elimination. This study was undertaken to investigate the therapeutic effects of recombinant Leishmania tarentolae expressing CXCL-10 and an expression vector encoding CXCL-10 (pcDNA CXCL-10-EGFP) in a model of BALB/c mice susceptible to infection by Leishmania major. The outcome of intervention was examined at 3 weeks post-treatment by evaluating the parameters of parasite burden (PB), arginase activity, NO and various cytokines such as IFN-gamma, IL-4, IL-6 and IL-10. The results have shown that despite the efficacy of CXCL-10 expression vector as gene therapy, the live therapy strategy using L. tarentolae expressing CXCL-10 was more effective in terms of decreasing PB. Nitric oxide production increased, especially in the live therapy approaches. Arginase activity also decreased in all regimens, which demonstrates the potency of the treatment. The overall cytokine production shifted in favour of Th1 responses in the treated mice. Altogether, recombinant L. tarentolae expressing CXCL-10 represents a promising therapeutic strategy to improve treatment of cutaneous leishmaniasis. PMID- 28833212 TI - Review of triazine antiprotozoal drugs used in veterinary medicine. AB - Triazines are relatively new antiprotozoal drugs that have successfully controlled coccidiosis and equine protozoal myeloencephalitis. These drugs have favorably treated other protozoal diseases such as neosporosis and toxoplasmosis. In this article, we discuss the pharmacological characteristics of five triazines, toltrazuril, ponazuril, clazuril, diclazuril, and nitromezuril which are used in veterinary medicine to control protozoal diseases which include coccidiosis, equine protozoal myeloencephalitis, neosporosis, and toxoplasmosis. PMID- 28833213 TI - The clinical impact of bedside fiberoptic laryngoscopic recording on a tertiary consult service. AB - OBJECTIVES/HYPOTHESIS: Fiberoptic laryngoscopy is dependent on accurate descriptions of examination findings. Traditional recording methods can be impractical for inpatient consults. Therefore, we aim to determine the utility of a smartphone-coupled portable recording system with flexible laryngoscopy for transmitting information between resident and attending physicians in a real-time setting. STUDY DESIGN: Pilot prospective study in a tertiary academic hospital. METHODS: This is a prospective study of inpatient consultations in a tertiary referral hospital over a 3-month period from April 2015 to June 2015. Flexible laryngoscopy was performed by a resident physician, and mobile recordings were relayed to an attending physician. Concordance of laryngoscopy interpretations between resident and attending physicians as well as changes in management were documented. RESULTS: Seventy-nine fiberoptic examinations were recorded and compared. Each consult was categorized as follows: airway evaluation (AE) (43%, 34/79), voice evaluation (VE) (3.7%, 3/79), dysphagia (D) (24%, 19/79), and aerodigestive tract mass/pathology (ADM) (29.1%, 23/79). Nine examinations showed discordance between resident and attending interpretations. Inter-rater agreement was good, with a kappa value of 0.747 (95% confidence interval: 0.643-0.851). The frequency of discordant exams within each group was as follows: AE (15%, 5/34), VE (33%, 1/3), D (11%, 2/19), and ADM (4.3%, 1/23). In five patients, changes in laryngoscopy interpretation changed clinical management. Seven nondiscordant exams had a change in management after attending review. Of the 79 exams, only one required repeat flexible laryngoscopy by the attending physician. CONCLUSIONS: Portable recording of flexible laryngoscopy is an effective tool for timely management of inpatient consultations. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:818-822, 2018. PMID- 28833214 TI - Pharmacokinetics of cefquinome in red-eared slider turtles (Trachemys scripta elegans) after single intravenous and intramuscular injections. AB - The purpose of this study was to evaluate the pharmacokinetics of cefquinome (CFQ) following single intravenous (IV) or intramuscular (IM) injections of 2 mg/kg body weight in red-eared slider turtles. Plasma concentrations of CFQ were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. The pharmacokinetic parameters following IV injection were as follows: elimination half-life (t1/2lambdaz ) 21.73 +/- 4.95 hr, volume of distribution at steady-state (Vdss ) 0.37 +/- 0.11 L/kg, area under the plasma concentration-time curve (AUC0-infinity ) 163 +/- 32 MUg hr-1 ml-1 , and total body clearance (ClT ) 12.66 +/- 2.51 ml hr-1 kg-1 . The pharmacokinetic parameters after IM injection were as follows: peak plasma concentration (Cmax ) 3.94 +/- 0.84 MUg/ml, time to peak concentration (Tmax ) 3 hr, t1/2lambdaz 26.90 +/- 4.33 hr, and AUC0-infinity 145 +/- 48 MUg hr-1 ml-1 . The bioavailability after IM injection was 88%. Data suggest that CFQ has a favorable pharmacokinetic profile with a long half-life and a high bioavailability in red-eared slider turtles. Further studies are needed to establish a multiple dosage regimen and evaluate clinical efficacy. PMID- 28833215 TI - Facilitating donor compliance with strategies to prevent vasovagal reactions: comparison of web-based and in-center approaches. AB - BACKGROUND: Research has documented beneficial effects of water loading (WL) and applied muscle tension (AMT) on reducing self-reported vasovagal reactions (VVRs) in whole blood (WB) donors. However, the optimal approach to reducing VVRs using these strategies in routine blood collection practice is not known. This study evaluated the effectiveness of embedding newly developed web-based and on-site donor education materials to increase the use of these two prevention techniques during blood collection. STUDY DESIGN AND METHODS: Two studies were conducted with WB donors. In Study 1, donors (n = 375) were randomly allocated to evaluate one of three forms of educational materials (video, webpage, card) in an online questionnaire. In Study 2, donors (n = 598) were randomly assigned to view either off-site web-based or in-center educational materials and were surveyed after donation to assess compliance to the VVR prevention procedure and to self-report VVR. RESULTS: In Study 1, donors rated the video as having the highest message appeal and indicated greater likelihood to use AMT compared to the webpage and card. No differences were found in likelihood to use WL. In contrast, in Study 2, greater adherence to VVR prevention strategies was observed in donors who received the in-center instruction card in comparison to those who received the web-based materials. Examination of viewing data indicated that only a small number of donors had seen the web-based materials. No significant effects of the techniques were found on self-reported VVRs. CONCLUSION: Providing on-site instructions is the most effective method to increase donor compliance to VVR prevention techniques. PMID- 28833216 TI - Managing risk and patient involvement in choosing treatment for cancer: an analysis of two communication practices. AB - Drawing on conversation analyses of oncology consultations collected in Italy, the article examines the communication practices used to recommend treatments. We found that the oncologist formulates the treatment recommendation (TR) for high risk patients in terms of a 'mandatory' choice and for low-risk patients as an 'optional' type of decision. In the first case the doctor presses to reach a decision during the visit while in the second case leaves the decision open ended. Results show that high-risk patients have less time to decide, are pressured towards choosing an option, but have more opportunities for involvement in TR during the visit. Low-risk patients instead have more time and autonomy to make a choice, but they are also less involved in the decision-making in the visit time. Moreover, we document that TR is organised through sequential activities in which the oncologist informs the patient of alternative therapeutic options while at the same time building a case for the kind of treatment she/he believes to be best for the patient's health. We suggest that in this field risk plays a key role in decision-making which should be better understood with further studies and taken into account in the debate on shared decision-making and patient-centred communication. PMID- 28833217 TI - Adjuvant chemoradiation does not improve survival in elderly patients with high risk resected head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: Randomized trials have demonstrated that adjuvant chemoradiotherapy (CRT) confers an overall survival (OS) benefit over adjuvant radiation therapy (RT) alone in patients with resected head and neck squamous cell carcinoma (HNSCC) with adverse pathologic features (positive surgical margins [SM+] and/or extracapsular extension [ECE]). Whether this OS benefit exists in an elderly population remains unknown. STUDY DESIGN: Retrospective database study. METHODS: Using the National Cancer Database, we identified 1,686 elderly patients (age >=70 years) with resected HNSCC with SM+ and/or ECE, who received adjuvant CRT (491 patients, 29%) or adjuvant RT alone (1,195 patients, 71%) between 1998 and 2011. Three-year survival rates were estimated using the Kaplan-Meier method both before and after propensity score matching (PSM). Crude and adjusted hazard ratios (HR) with 95% confidence intervals (CI) were computed using Cox regression modeling. RESULTS: Median follow-up was 23.5 and 42.8 months for all and surviving patients, respectively. Three-year OS was 50.7% and 44.4% among patients receiving adjuvant CRT and RT alone, respectively (P = .002). On multivariate analysis, there was no significant improvement in OS with adjuvant CRT relative to adjuvant RT alone (HR: 0.88, 95% CI: 0.73-1.06). Similarly, a PSM cohort showed no significant difference in the 3-year OS for patients receiving adjuvant CRT versus adjuvant RT alone (48.8% and 50.9%, respectively; P = .839). CONCLUSIONS: Although the addition of chemotherapy to adjuvant RT has been proven effective in randomized trials of patients with resected HNSCC with SM+ or ECE, it may be less efficacious in an elderly patient population treated outside of a controlled trial setting. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:831-840, 2018. PMID- 28833220 TI - What is the role of imaging in the evaluation of the patient presenting with unilateral facial paralysis? PMID- 28833218 TI - Arabidopsis FNRL protein is an NADPH-dependent chloroplast oxidoreductase resembling bacterial ferredoxin-NADP+ reductases. AB - Plastidic ferredoxin-NADP+ oxidoreductases (FNRs; EC:1.18.1.2) together with bacterial type FNRs (FPRs) form the plant-type FNR family. Members of this group contain a two-domain scaffold that forms the basis of an extended superfamily of flavin adenine dinucleotide (FAD) dependent oxidoreductases. In this study, we show that the Arabidopsis thaliana At1g15140 [Ferredoxin-NADP+ oxidoreductase like (FNRL)] is an FAD-containing NADPH dependent oxidoreductase present in the chloroplast stroma. Determination of the kinetic parameters using the DCPIP NADPH dependent diaphorase assay revealed that the reaction catalysed by a recombinant FNRL protein followed a saturation Michaelis-Menten profile on the NADPH concentration with kcat = 3.2 +/- 0.2 s-1 , KmNADPH = 1.6 +/- 0.3 MUM and kcat /KmNADPH = 2.0 +/- 0.4 MUM-1 s-1 . Biochemical assays suggested that FNRL is not likely to interact with Arabidopsis ferredoxin 1, which is supported by the sequence analysis implying that the known Fd-binding residues in plastidic FNRs differ from those of FNRL. In addition, based on structural modelling FNRL has an FAD-binding N-terminal domain built from a six-stranded beta-sheet and one alpha helix, and a C-terminal NADP+ -binding alpha/beta domain with a five-stranded beta-sheet with a pair of alpha-helices on each side. The FAD-binding site is highly hydrophobic and predicted to bind FAD in a bent conformation typically seen in bacterial FPRs. PMID- 28833219 TI - Prevention of transfusion-associated graft-versus-host disease with pathogen reduced platelets with amotosalen and ultraviolet A light: a review. AB - BACKGROUND AND OBJECTIVES: Transfusion-associated graft-versus-host disease (TA GVHD) is a serious complication of blood component transfusion therapy, caused by donor T lymphocytes. gamma-Irradiation or pathogen inactivation methods, capable of inactivating proliferating T cells in blood components, should be selected to prevent TA-GVHD. This review summarizes the published evidence to support the use of pathogen-reduced platelets with amotosalen (150 MUm) and ultraviolet A light (UVA, 320-400 nm, 3 J/cm2 ) for preventing TA-GVHD. MATERIALS AND METHODS: Available literature on the use of pathogen-reduced platelets to prevent TA-GVHD was reviewed. RESULTS: Observational studies, animal models, in vitro studies and mechanistic studies of pathogen-reduced platelets with amotosalen and UVA light showed that inactivation of T cells are equal or even superior to gamma irradiation. CONCLUSION: Pathogen-reduced platelets with amotosalen and UVA light can be used as a measure to prevent TA-GVHD. PMID- 28833221 TI - Gastrostomy in the era of minimally invasive head and neck cancer surgery. AB - OBJECTIVE: Minimally invasive transoral robotic surgery (TORS) is less likely to necessitate gastrostomy tube (GT) following resection of head and neck lesions versus conventional open procedures. However, the incidence of and indications for GT after TORS have not been reported in detail. This study defines the incidence of intra- and postoperative gastrostomy following robotic resection of advanced head and neck disease. It seeks to clarify the relevance of GT after TORS. STUDY DESIGN: Adult patients undergoing TORS and neck dissection from 2008 to 2014 were identified in the New York Statewide Planning and Research Cooperative System all-payer administrative database. METHODS: Demographic data and timing of GT in relation to surgery were recorded. Emergency department (ED) visits and inpatient readmissions were compared with multivariable logistic analysis. RESULTS: Of the 441 included patients, immediate, delayed, and total GT incidence within the first postoperative year was 9.5%, 11.6%, and 21.1%, respectively. Gastrostomy tube complications resulted in 4.5% of 30-day ED visits, 3.3% of 30-day readmissions, and 3.5% of 90-day readmissions. Thirty-nine percent of 90-day readmissions were linked to poor postoperative oral intake. Delayed GT status was associated with an increase in 30-day ED visits, and 30- or 90-day readmissions attributable to poor oral intake (P = 0.10, P < 0.0001, 0.002, respectively). CONCLUSION: Even in the era of minimally invasive TORS, impaired oral intake is a significant postoperative burden to head and neck cancer patients with advanced disease. Attention to patient risk factors combined with a complicated hospital course may identify patients benefiting from early GT. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:847-851, 2018. PMID- 28833222 TI - Retraction: 'Prevention of nausea and vomiting after middle ear surgery: Granisetron versus ramosetron' by Dr Yoshitaka Fujii. PMID- 28833223 TI - Retraction: 'Granisetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting after thyroidectomy' by Dr Yoshitaka Fujii. PMID- 28833224 TI - Retraction: 'Prevention of vomiting after tonsillectomy in children: Granisetron versus ramosetron' by Dr Yoshitaka Fujii. PMID- 28833225 TI - The Glycine Receptor-A Functionally Important Primary Brain Target of Ethanol. AB - Identification of ethanol's (EtOH) primary molecular brain targets and determination of their functional role is an ongoing, important quest. Pentameric ligand-gated ion channels, that is, the nicotinic acetylcholine receptor, the gamma-aminobutyric acid type A receptor, the 5-hydroxytryptamine3 , and the glycine receptor (GlyR), are such targets. Here, aspects of the structure and function of these receptors and EtOH's interaction with them are briefly reviewed, with special emphasis on the GlyR and the importance of this receptor and its ligands for EtOH pharmacology. It is suggested that GlyRs are involved in (i) the dopamine-activating effect of EtOH, (ii) regulating EtOH intake, and (iii) the relapse preventing effect of acamprosate. Exploration of the GlyR subtypes involved and efforts to develop subtype specific agonists or antagonists may offer new pharmacotherapies for alcohol use disorders. PMID- 28833226 TI - In response to Is esophagoscopy necessary during panendoscopy? PMID- 28833227 TI - Physiological and psychological effects of imagery techniques on health anxiety. AB - Previous research has shown that intrusions are part of the psychopathology of mental disorders. Imagery techniques seem to be an effective treatment of negative intrusions. Since negative mental imagery is part of health anxiety, the present study investigated the impact of imagery techniques on health anxiety. A total of 159 students with elevated scores in a health anxiety questionnaire watched an aversive film concerning a cancer patient and were randomly allocated to one of three interventions (positive imagery, imagery reexperiencing, imagery rescripting) or the control group. The intervention lasted 9 min. Physiological data (heart rate and cortisol) as well as psychological measures, such as mood ratings, health anxiety scores, and intrusions, were assessed during the appointment, while psychological measures were assessed over a period of 1 week after the intervention. Cortisol levels changed over time depending on the intervention. Heart rate changed during the 9-min interventions as well, with the fastest decrease during imagery rescripting. Moreover, negative mood and distress decreased after the intervention, while intrusions were reduced 1 week after the intervention in all groups equally. The results suggest that imagery rescripting is a promising technique that seems to activate a process of deep elaboration. Therefore, it might be an adequate way to target health anxiety symptoms such as anxiety, intrusions, and avoidance or safety-seeking behavior. Further studies should focus on imagery rescripting in clinical samples with health anxiety and target individual intrusive images to increase effectiveness. Nevertheless, the development of a long-term explanatory model of rescripting is needed. PMID- 28833228 TI - Trouble articulating the right words: Evidence for a response-exclusion account of distraction during semantic fluency. AB - It is widely held that single-word lexical access is a competitive process, a view based largely on the observation that naming a picture is slowed in the presence of a distractor-word. However, problematic for this view is that a low frequency distractor-word slows the naming of a picture more than does a high frequency word. This supports an alternative, response-exclusion, account in which a distractor-word interferes because it must be excluded from an articulatory output buffer before the right word can be articulated (the picture name): A high, compared to low, frequency word accesses the buffer more quickly and, as such, can also be excluded more quickly. Here we studied the respective roles of competition and response-exclusion for the first time in the context of semantic verbal fluency, a setting requiring the accessing of, and production of, multiple words from long-term memory in response to a single semantic cue. We show that disruption to semantic fluency by a sequence of to-be-ignored spoken distractors is also greater when those distractors are low in frequency, thereby extending the explanatory compass of the response-exclusion account to a multiple word production setting and casting further doubt on the lexical-selection-by competition view. The results can be understood as reflecting the contribution of speech output processes to semantic fluency. PMID- 28833229 TI - Hepatitis E virus RNA in Australian blood donors: prevalence and risk assessment. AB - BACKGROUND AND OBJECTIVES: Hepatitis E virus (HEV) is a known transfusion transmissible agent. HEV infection has increased in prevalence in many developed nations with RNA detection in donors as high as 1 in 600. A high proportion of HEV infections are asymptomatic and therefore not interdicted by donor exclusion criteria. To manage the HEV transfusion-transmission (TT) risk some developed nations have implemented HEV RNA screening. In Australia, HEV is rarely notified; although locally acquired infections have been reported, and the burden of disease is unknown. The purpose of this study was to determine the frequency of HEV infection in Australian donors and associated TT risk. MATERIALS AND METHODS: Plasma samples (n = 74 131) were collected from whole blood donors during 2016 and screened for HEV RNA by transcription-mediated amplification (TMA) in pools of six. Individual TMA reactive samples were confirmed by RT-PCR and, if positive, viral load determined. Prevalence data from the study were used to model the HEV-TT risk. RESULTS: One sample in 74 131 (95% CI: 1 in 1 481 781 to 1 in 15 031) was confirmed positive for HEV RNA, with an estimated viral load of 180 IU/ml, which is below that typically associated with TT. Using a transmission risk model, we estimated the risk of an adverse outcome associated with TT-HEV of approximately 1 in 3.5 million components transfused. CONCLUSION: Hepatitis E virus viremia is rare in Australia and lower than the published RNA prevalence estimates of other developed countries. The risk of TT-HEV adverse outcomes is negligible, and HEV RNA donor screening is not currently indicated. PMID- 28833230 TI - Efficacy and rebound rates in propranolol-treated subglottic hemangioma: A literature review. AB - OBJECTIVE: Propranolol has recently become the treatment of choice for management of subglottic and airway hemangiomas. This literature review aimed to determine the success rate of propranolol for managing these lesions as well as the rate of rebound growth following propranolol treatment cessation. STUDY DESIGN: Literature search involving MEDLINE and Scopus to identify English-language articles. METHODS: Studies were identified using hemangioma, subglottic or airway, and propranolol for search terms. Studies were eligible for inclusion if they reported the treatment used, individual deidentified patient data, and contained patients without medical or surgical treatment prior to propranolol therapy RESULTS: Initial review included 107 abstracts. Twenty-four articles including case reports and case series met inclusion criteria and were included in the qualitative analysis. Forty-nine patients were included. Twenty-eight (57%) were treated with propranolol alone, and 20 (41%) were treated with a combination of propranolol and a corticosteroid. Thirty-seven (76%) of patients were treated with a dose of 2 mg/kg/d of propranolol. The initial treatment was successful in 43 (88%) of patients. Rebound growth occurred in four (9%) patients. Overall, six (12%) patients underwent surgical resection. CONCLUSIONS: Propranolol is efficacious for treating subglottic hemangiomas. Rebound growth does occur in a small subset of patients during the propranolol wean. Close observation for children during weaning of propranolol therapy for subglottic hemangioma is essential. Adjunctive management strategies need to be used in patients with rebound growth. Laryngoscope, 127:2665-2672, 2017. PMID- 28833231 TI - Can dispersal investment explain why tall plant species achieve longer dispersal distances than short plant species? AB - Tall plant species disperse further distances than do short species, within and across dispersal syndromes, yet the driver underpinning this relationship is unclear. The ability of taller plants to invest more in dispersal structures may explain the positive relationship between plant height and dispersal distance. Here, we quantify the cross-species relationships between presence of dispersal structures, dispersal investment plant height and dispersal distance. Plant height, dispersal syndrome and dispersal investment data were collated for 1613 species from the literature, with dispersal distance data collated for 114 species. We find that species with high dispersal investment disperse further than do species with low dispersal investment. Tall species have a greater probability of having dispersal structures on their seeds compared with short species. For species with dispersal structures on their seeds, plant height is very weakly related to dispersal investment. Our results provide the first global confirmation of the dispersal investment-distance hypothesis, and show dispersal investment can be used for predicting species dispersal distances. However, our results and those of previous studies indicate plant height is still the best proxy for estimating species dispersal distances due to it being such a readily available plant trait. PMID- 28833232 TI - Persistent respiratory effort after adenotonsillectomy in children with sleep disordered breathing. AB - OBJECTIVES: Adenotonsillectomy (AT) markedly improves but does not necessarily normalize polysomnographic findings in children with adenotonsillar hypertrophy and related sleep-disordered breathing (SDB). Adenotonsillectomy efficacy should be evaluated by follow-up polysomnography (PSG), but this method may underestimate persistent respiratory effort (RE). Mandibular movement (MMas) monitoring is an innovative measurement that readily identifies RE during upper airway obstruction. We hypothesized that MMas indices would decrease in parallel of PSG indices and that children with persistent RE more reliably could be identified with MMas. METHODS: Twenty-five children (3-12 years of age) with SDB were enrolled in this individual prospective-cohort study. Polysomnography was supplemented with a midsagittal movement magnetic sensor that measured MMas during each respiratory cycle before and > 3 months after AT. RESULTS: Adenotonsillectomy significantly improved PSG indices, except for RE-related arousals (RERA). Mandibular movement index changes after AT significantly were correlated with corresponding decreases in sleep apnea-hypopnea index (AHI) and O2 desaturation index (ODI) (Spearman's rho = 0.978 and 0.922, respectively), whereas changes in MMas duration significantly were associated with both RERA duration (rho = 0.475, P = 0.017) and index (rho = 0.564, P = 0.003). Conditional multivariate analysis showed that both AHI and RERA significantly contributed to the variance of MMas index after AT (P = 0.0003 and 0.0005, respectively), whereas MMas duration consistently was related to the duration of RERA regardless of AT. CONCLUSION: Adenotonsillectomy significantly reduced AHI. However, persistent RERA were apparent in a significant proportion of children, and this was reflected by the remaining abnormal MMas pattern. Follow-up of children after AT can be recommended and readily achieved by monitoring MMas to identify persistent RE. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1230-1237, 2018. PMID- 28833233 TI - Health utilities for controlled and uncontrolled chronic hand eczema in healthcare employees. AB - BACKGROUND: Health utilities provide a universally applicable method for measuring the relative preferences or values of specific health states. Health economic studies use health utilities to estimate disease burden and the cost effectiveness of interventions. Chronic hand eczema (CHE) affects many individuals and adversely affects work productivity. Health utilities for CHE from the perspective of healthcare professionals are lacking. OBJECTIVES: To assess health utilities for CHE from the perspectives of employees in the healthcare sector and affected patients. METHODS: A cross-sectional study with volunteers from the healthcare sector (n = 126) and patients (n = 32) was conducted to establish health utilities (ranging from 1 = perfect health to 0 = death) for mild and severe CHE. RESULTS: The median health utilities of the healthy volunteers derived with the time trade-off method were 0.97 (mean: 0.92) for mild CHE and 0.77 (mean: 0.75) for severe CHE. The median health utilities for mild and severe CHE from the perspective of affected patients were 0.98 (mean: 0.91) and 0.82 (mean: 0.77), respectively. Differences in health utilities between the two study groups were not significant. CONCLUSION: CHE constitutes a considerable burden from the perspective of healthcare employees. Effective control of CHE constitutes an important public health goal. PMID- 28833234 TI - Mannose and fructose metabolism in red blood cells during cold storage in SAGM. AB - BACKGROUND: Alternate sugar metabolism during red blood cell (RBC) storage is not well understood. Here we report fructose and mannose metabolism in RBCs during cold storage in SAGM and the impact that these monosaccharides have on metabolic biomarkers of RBC storage lesion. STUDY DESIGN AND METHODS: RBCs were stored in SAGM containing uniformly labeled 13 C-fructose or 13 C-mannose at 9 or 18 mmol/L concentration for 25 days. RBCs and media were sampled at 14 time points during storage and analyzed using ultraperformance liquid chromatography-mass spectrometry. Blood banking quality assurance measurements were performed. RESULTS: Red blood cells incorporated fructose and mannose during cold storage in the presence of glucose. Mannose was metabolized in preference to glucose via glycolysis. Fructose lowered adenosine triphosphate (ATP) levels and contributed little to ATP maintenance when added to SAGM. Both monosaccharides form the advanced glycation end product glycerate. Mannose activates enzymes in the RBC that take part in glycan synthesis. CONCLUSIONS: Fructose or mannose addition to RBC SAGM concentrates may not offset the shift in metabolism of RBCs that occurs after 10 days of storage. Fructose and mannose metabolism at 4 degrees C in SAGM reflects their metabolism at physiologic temperature. Glycerate excretion is a measure of protein deglycosylation activity in stored RBCs. No cytoprotective effect was observed upon the addition of either fructose or mannose to SAGM. PMID- 28833236 TI - Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I. AB - INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018. PMID- 28833237 TI - Dynamic optimization of stimulation frequency to reduce isometric muscle fatigue using a modified Hill-Huxley model. AB - INTRODUCTION: Optimal frequency modulation during functional electrical stimulation (FES) may minimize or delay the onset of FES-induced muscle fatigue. METHODS: An offline dynamic optimization method, constrained to a modified Hill Huxley model, was used to determine the minimum number of pulses that would maintain a constant desired isometric contraction force. RESULTS: Six able-bodied participants were recruited for the experiments, and their quadriceps muscles were stimulated while they sat on a leg extension machine. The force-time (F-T) integrals and peak forces after the pulse train was delivered were found to be statistically significantly greater than the force-time integrals and peak forces obtained after a constant frequency train was delivered. DISCUSSION: Experimental results indicated that the optimized pulse trains induced lower levels of muscle fatigue compared with constant frequency pulse trains. This could have a potential advantage over current FES methods that often choose a constant frequency stimulation train. Muscle Nerve 57: 634-641, 2018. PMID- 28833239 TI - Relationship of personality with integration and confrontation in internal dialogues. AB - Interest in confrontational and integrative internal dialogues (IDs) has been growing, as they perform numerous important functions. This study aimed to identify the personality-related determinants of integration and confrontation processes in ID that simulates social relationships. The test group comprised 125 students (62 men). Participants were given a description of a fictional problem facing a young married couple and they were to imagine a dialogue between the characters. Additionally three instruments were administered: the NEO Five Factor Inventory, the Experiences in Close Relationships - Revised Questionnaire and the Integration-Confrontation Questionnaire. Using canonical correlation analysis it was found that intense neuroticism and anxious or avoidant attachments, combined with low openness, conscientiousness and agreeableness, are conducive to confrontational attitude in the author of a dialogue, whereas the opposite combination of personality characteristics is associated with integrative attitudes in both parties to the dialogue. PMID- 28833238 TI - CRF1 Receptor-Dependent Increases in Irritability-Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure. AB - BACKGROUND: In humans, emotional and physical signs of withdrawal from ethanol are commonly seen. Many of these symptoms, including anxiety-like and depression like behavior, have been characterized in animal models of ethanol dependence. One issue with several current behavioral tests that measure withdrawal in animal models is that they are often not repeatable within subjects over time. Additionally, irritability, one of the most common symptoms of ethanol withdrawal in humans, has not been well characterized in animal models. The corticotropin releasing factor (CRF)-CRF1 receptor system has been suggested to be critical for the emergence of anxiety-like behavior in ethanol dependence, but the role of this system in irritability-like behavior has not been characterized. METHODS: The present study compared the effects of chronic intermittent ethanol (CIE) vapor exposure-induced ethanol dependence on irritability-like behavior in rats using the bottle-brush test during acute withdrawal and protracted abstinence. Rats were trained to self-administer ethanol in operant chambers and then either left in a nondependent state or made dependent via CIE. Naive, nondependent, and dependent rats were tested for irritability-like behavior in the bottle-brush test 8 hours and 2 weeks into abstinence from ethanol. Separate cohorts of dependent and nondependent rats were used to examine the effect of the specific CRF1 receptor antagonist R121919 on irritability-like behavior. RESULTS: Dependent rats exhibited escalated ethanol intake compared with their own pre-CIE baseline and nondependent rats. At both time points of abstinence, ethanol dependent rats exhibited increased aggressive-like responses compared with naive and nondependent rats. R121919 reduced irritability-like behavior in both dependent and nondependent rats, but dependent rats were more sensitive to R121919. CONCLUSIONS: Irritability-like behavior is a clinically relevant and reliable measure of negative emotional states that is partially mediated by activation of the CRF-CRF1 system and remains elevated during protracted abstinence in ethanol-dependent rats. PMID- 28833240 TI - Estimation of the Power of the Food Effect on QTc to Show Assay Sensitivity. AB - The most recent International Conference on Harmonisation E14 Q&A document states that a separate positive control would not be necessary provided sufficiently high exposures are achieved in the early-phase studies. Realistically, a phase 1 study is unlikely to include a pharmacological positive control, and in cases in which plasma levels of the drug exceeding therapeutic levels are not achieved, the lack of a positive control can constitute a limitation when excluding an effect of regulatory concern. It has been proposed to use the effect of a standardized meal on the estimate of the diurnal time course of QTc to show assay sensitivity. We conducted simulations by subsampling subjects from a 3 different studies and could show that the effect on food on QTc can be reliably prove assay sensitivity for sample sizes as low as 3 * 6 subjects with a power greater than 80%. PMID- 28833241 TI - Messenger RNA profiling of rabbit quadriceps femoris after repeat injections of botulinum toxin: Evidence for a dynamic pattern without further structural alterations. AB - INTRODUCTION: Onabotulinum toxin type A (BoNT-A) is widely used clinically, but it may cause adverse effects. Earlier studies showed repeat BoNT-A injections did not cause progressive atrophy or function loss. The purpose of this study was to assess the influence of repeat BoNT-A injections into rabbit muscle on subsequent molecular alterations. METHODS: Twenty-two rabbits received 0, 1, 2, or 3 BoNT-A injections in the quadriceps femoris muscle at 3-month intervals and were euthanized 6 months after the last injection. Aliquots of both injected and contralateral muscle were frozen, and the total RNA quantified. RESULTS: Total RNA per illigram wet weight tissue was significantly elevated compared with control after 1, 2, or 3 BoNT-A injections. Analysis of mRNA levels for inflammatory molecules, proteinases, adipokines, and mesenchymal stem cells were elevated with increasing BoNT-A injections in injected leg and contralateral leg. DISCUSSION: Future studies should focus on the safety and possible complications of repeat BoNT-A treatments. Muscle Nerve 57: 487-493, 2018. PMID- 28833242 TI - Online dose reconstruction for tracked volumetric arc therapy: Real-time implementation and offline quality assurance for prostate SBRT. AB - PURPOSE: Firstly, this study provides a real-time implementation of online dose reconstruction for tracked volumetric arc therapy (VMAT). Secondly, this study describes a novel offline quality assurance tool, based on commercial dose calculation algorithms. METHODS: Online dose reconstruction for VMAT is a computationally challenging task in terms of computer memory usage and calculation speed. To potentially reduce the amount of memory used, we analyzed the impact of beam angle sampling for dose calculation on the accuracy of the dose distribution. To establish the performance of the method, we planned two single-arc VMAT prostate stereotactic body radiation therapy cases for delivery with dynamic MLC tracking. For quality assurance of our online dose reconstruction method we have also developed a stand-alone offline dose reconstruction tool, which utilizes the RayStation treatment planning system to calculate dose. RESULTS: For the online reconstructed dose distributions of the tracked deliveries, we could establish strong resemblance for 72 and 36 beam co planar equidistant beam samples with less than 1.2% deviation for the assessed dose-volume indicators (clinical target volume D98 and D2, and rectum D2). We could achieve average runtimes of 28-31 ms per reported MLC aperture for both dose computation and accumulation, meeting our real-time requirement. To cross validate the offline tool, we have compared the planned dose to the offline reconstructed dose for static deliveries and found excellent agreement (3%/3 mm global gamma passing rates of 99.8%-100%). CONCLUSION: Being able to reconstruct dose during delivery enables online quality assurance and online replanning strategies for VMAT. The offline quality assurance tool provides the means to validate novel online dose reconstruction applications using a commercial dose calculation engine. PMID- 28833243 TI - A novel homozygous frameshift mutation in Exon 7 of the ADAMTS13 gene in a patient with congenital thrombotic thrombocytopenic purpura from India: a case report. AB - BACKGROUND: Thrombotic thrombocytopenia purpura (TTP) is a rare and life threatening thrombotic microangiopathy characterized by thrombocytopenia and microangiopathic hemolytic anemia. It is caused by deficiency of ADAMTS13 metalloprotease, which cleaves ultra-large von Willebrand factor into smaller functional units. TTP may be congenital or acquired, and the congenital form is caused by inherited mutations in the ADAMTS13 gene, leading to deficiency of protein or reduced protein activity. CASE REPORT: We report a 5-year-old male patient who manifested with thrombocytopenia and microangiopathic hemolytic anemia at the age of 1 year. CONCLUSION: ADAMTS13 activity in the patient was below 5%, and ADAMTS13 antibody was absent. Subsequent genetic analysis of the ADAMTS13 gene revealed a novel homozygous mutation (i.e., frameshift insertion mutation A237GfsX153 [c.708_709insG] in Exon 7 of ADAMTS13). Both parents were heterozygous for this mutation. PMID- 28833244 TI - Anti-human neutrophil antigen-1a, -1b, and -2 antibodies in neonates and children with immune neutropenias analyzed by extracted granulocyte antigen immunofluorescence assay. AB - BACKGROUND: Anti-human neutrophil antigen (HNA) antibodies have been implicated in the development of neonatal alloimmune neutropenia (NAN) and autoimmune neutropenia (AIN). There are many conventional assay methods that detect anti-HNA antibodies. However, a method to measure multiple samples and detect several anti HNA antibodies simultaneously is needed. STUDY DESIGN AND METHODS: We developed a new method, the extracted granulocyte antigen immunofluorescence assay (EGIFA), to analyze anti-HNA-1a, -1b, and -2 antibodies in sera. The results obtained by EGIFA were evaluated in comparison with those from several standard assay methods. Anti-HNA antibodies in serum samples from nine familial cases with suspected NAN (n = 19) and children with suspected AIN (n = 88) were also measured by EGIFA. RESULTS: The evaluation of nine serum samples with anti-HNA antibodies suggested that EGIFA demonstrated equivalent specificity and superior sensitivity to monoclonal antibody-specific immobilization of granulocyte antigens and had comparable sensitivity to the granulocyte indirect immunofluorescence test. EGIFA successfully detected anti-HNA-1a or -1b antibodies in seven of nine familial cases with suspected NAN. EGIFA detected anti-HNA antibodies in 40.9% of children with suspected AIN. Among them, isolated anti-HNA-1a or -1b antibody was detected in 4.5 or 12.5% of children, respectively, and anti-HNA-2 antibody was identified in 3.4% of children. The 30.8% (16 of 52) of children negative for anti-HNA antibody by EGIFA were positive for anti-HLA antibody. CONCLUSION: EGIFA facilitated the measurement of anti-HNA-1a, -1b, and/or -2 antibodies in sera. The prompt measurement of anti HNA antibodies will improve the diagnosis and clinical management of patients with suspected NAN or AIN. PMID- 28833245 TI - The psychometric properties of the Portuguese version of the Personality Inventory for DSM-5. AB - The DSM-5 Section III proposes a hybrid dimensional-categorical model of conceptualizing personality and its disorders that includes assessment of impairments in personality functioning (criterion A) and maladaptive personality traits (criterion B). The Personality Inventory for the DSM-5 is a new dimensional tool, composed of 220 items organized into 25 facets that delineate five higher order domains of clinically relevant personality differences, and was developed to operationalize the DSM-5 model of pathological personality traits. The current studies address the internal consistency (study 1), the test-retest reliability (study 2) and the criterion validity (studies 3 and 4) of the Portuguese version of the PID-5 in samples of native speaking psychology students. Results indicated good internal consistency reliabilities and good temporal stability reliabilities for the majority of the PID-5 traits. The correlational pattern of the PID-5 traits with two measures of personality was in accordance with theoretical expectations and showed its concurrent validity. PMID- 28833246 TI - Increased contribution of wheat nocturnal transpiration to daily water use under drought. AB - Increasing evidence suggests that in crops, nocturnal water use could represent 30% of daytime water consumption, particularly in semi-arid and arid areas. This raises the questions of whether nocturnal transpiration rates (TRN ) are (1) less influenced by drought than daytime TR (TRD ), (2) increased by higher nocturnal vapor pressure deficit (VPDN ), which prevails in such environments and (3) involved in crop drought tolerance. In this investigation, we addressed those questions by subjecting two wheat genotypes differing in drought tolerance to progressive soil drying under two long-term VPDN regimes imposed under naturally fluctuating conditions. A first goal was to characterize the response curves of whole-plant TRN and TRN /TRD ratios to progressive soil drying. A second goal was to examine the effect of VPDN increase on TRN response to soil drying and on 13 other developmental traits. The study revealed that under drought, TRN was not responsive to progressive soil drying and - intriguingly - that TRN seemingly increased with drought under high VPDN consistently for the drought-sensitive genotype. Because TRD was concomitantly decreasing with progressive drought, this resulted in TRN representing up to 70% of TRD at the end of the drydown. In addition, under drought, VPDN increase was found not to influence traits such as leaf area or stomata density. Overall, those findings indicate that TRN contribution to daily water use under drought might be much higher than previously thought, that it is controlled by specific mechanisms and that decreasing TRN under drought might be a valuable trait for improving drought tolerance. PMID- 28833247 TI - Effect of dasatinib in a xenograft mouse model of canine histiocytic sarcoma and in vitro expression status of its potential target EPHA2. AB - Canine histiocytic sarcoma (HS) is an aggressive and highly metastatic tumor. Previously, the kinase inhibitor dasatinib was shown to have potent growth inhibitory activity against HS cells in vitro, possibly via targeting the EPHA2 receptor. Here, the in vivo effect of dasatinib in HS cells was investigated using a xenograft mouse model. Moreover, the expression status of EPHA2 was examined in six HS cell lines, ranging from insensitive to highly sensitive to dasatinib. In the HS xenograft mouse model, dasatinib significantly suppressed tumor growth, as illustrated by a decrease in mitotic and Ki67 indices and an increase in apoptotic index in tumor tissues. On Western blot analysis, EPHA2 was only weakly detected in all HS cell lines, regardless of sensitivity to dasatinib. Dasatinib likely results in the inhibition of xenograft tumor growth via a mechanism other than targeting EPHA2. The findings of this study suggest that dasatinib is a targeted therapy drug worthy of further exploration for the treatment of canine HS. PMID- 28833248 TI - Real-time respiratory phase matching between 2D fluoroscopic images and 3D CT images for precise percutaneous lung biopsy. AB - PURPOSE: A 3D CT image is used along with real-time 2D fluoroscopic images in the state-of-the-art cone-beam CT system to guide percutaneous lung biopsy (PLB). To improve the guiding accuracy by compensating for respiratory motion, we propose an algorithm for real-time matching of 2D fluoroscopic images to multiple 3D CT images of different respiratory phases that is robust to the small movement and deformation due to cardiac motion. METHODS: Based on the transformations obtained from nonrigid registration between two 3D CT images acquired at expiratory and inspiratory phases, we first generate sequential 3D CT images (or a 4D CT image) and the corresponding 2D digitally reconstructed radiographs (DRRs) of vessels. We then determine 3D CT images corresponding to each real-time 2D fluoroscopic image, by matching the 2D fluoroscopic image to a 2D DRR. RESULTS: Quantitative evaluations performed with 20 clinical datasets show that registration errors of anatomical features between a 2D fluoroscopic image and its matched 2D DRR are less than 3 mm on average. Registration errors of a target lesion are determined to be roughly 3 mm on average for 10 datasets. CONCLUSIONS: We propose a real time matching algorithm to compensate for respiratory motion between a 2D fluoroscopic image and 3D CT images of the lung, regardless of cardiac motion, based on a newly improved matching measure. The proposed algorithm can improve the accuracy of a guiding system for the PLB by providing 3D images precisely registered to 2D fluoroscopic images in real-time, without time-consuming respiratory-gated or cardiac-gated CT images. PMID- 28833249 TI - In response to Does mutational analysis influence the management of differentiated thyroid cancers? PMID- 28833250 TI - How do we perform and bill for blood bank physician consultative services? AB - Transfusion medicine (TM) physicians provide medical services that benefit all patients such as providing 24-hour laboratory coverage, advising health care providers on test interpretation and selection, validating new methods, and supervising technical personnel. These services ensure delivery of accurate, reliable, and timely laboratory test results and blood products. TM physicians also provide consultations to individual patients by 1) interpreting and determining the clinical significance of test results (e.g., alloantibodies, direct antiglobulin tests), 2) recommending appropriate component therapy and approving deviations from laboratory policy, and 3) evaluating and recommending treatment of suspected transfusion reactions. The potential benefits of consultations are improved quality and cost of health care, enhanced provider education, and decreased inappropriate testing and product utilization. When physician services are delivered to individual patients, are appropriately requested, provide a diagnosis or recommendation, and are properly documented, TM physicians can receive professional reimbursement. While many TM physicians provide medical direction and oversight of apheresis procedures, billing in this area is sufficiently complex to be reviewed elsewhere. The objective of this article is for educational purposes to describe the 1) benefits of a consultative TM service, 2) development of reimbursement systems in the United States for professional component services and the current regulatory requirements, 3) current procedural terminology codes commonly used for TM physician services, and 4) examples of consultation documentation and daily workflow at tertiary care teaching hospitals. The information provided should help guide physicians to deliver and bill for these services. PMID- 28833251 TI - Identification of a novel B allele with a missense mutation (c.721C>G) in a Korean family with a weak B phenotype. PMID- 28833252 TI - The role of alcohol in identity construction among LGBT people: a qualitative study. AB - Research suggests that alcohol use and misuse are higher among lesbian, gay and bisexual than heterosexual populations, yet the social context of drinking in sexual minority communities has rarely been examined. To explore lesbian, gay, bisexual and transgender (LGBT) people's relationship with alcohol, we conducted seven focus groups (N = 33) with pre-existing groups of friends and work colleagues (18 to 52 years) in Scotland, UK. We identified and analysed patterns in our data using thematic analysis. Respondents perceived heavy drinking as central to the commercial gay scene. Choice of drink and drinking vessel was an important part of identity construction. Respondents discussed the perception that gay men would drink alcopops and cocktails while lesbians would drink pints of beer. Even when stereotypes were dismissed as inaccurate, they were still thought to pressure people to drink 'appropriately'. Respondents who did not identify as male or female, and those who used drag, were particularly aware of their choice of drink as a means to express identity or to challenge people's preconceptions about gender. Researchers developing interventions to reduce alcohol-related harm in sexual minority populations need to take account of the central role of identity construction in LGBT drinking practices. PMID- 28833253 TI - The Case for Insurance Reimbursement of Couple Therapy. AB - A case is made for why it may now be in the best interest of insurance companies to reimburse for marital therapy to treat marital distress. Relevant literature is reviewed with a considerable focus on the reasons that insurance companies would benefit from reimbursing marital therapy - the high costs of marital distress, the growing link between marital distress and a host of related physical and mental health problems, as well as the availability of empirically supported treatments for marital distress. This is followed by a focus on the major reasons insurance companies cite for not reimbursing marital therapy, along with a discussion of advances in several growing bodies of research to address these concerns. Main arguments include the direct medical offset costs of couple and family therapy (including for high utilizers of health insurance), and the fact that insurance companies already find it cost effective to reimburse for prevention of other health and psychological problems. This is followed by implications for practitioners and researchers. PMID- 28833254 TI - Temporal dissociation of salience and prediction error responses to appetitive and aversive taste. AB - The feedback-related negativity (FRN), a frontocentral ERP occurring 200-350 ms after emotionally valued outcomes, has been posited as the neural correlate of reward prediction error, a key component of associative learning. Recent evidence challenged this interpretation and has led to the suggestion that this ERP expresses salience instead. Here, we distinguish between utility prediction error and salience by delivering or withholding hedonistically matched appetitive and aversive tastes, and measure ERPs to cues signaling each taste. We observed a typical FRN (computed as the loss-minus-gain difference wave) to appetitive taste, but a reverse FRN to aversive taste. When tested axiomatically, frontocentral ERPs showed a salience response across tastes, with a particularly early response to outcome delivery, supporting recent propositions of a fast, unsigned, and unspecific response to salient stimuli. ERPs also expressed aversive prediction error peaking at 285 ms, which conformed to the logic of an axiomatic model of prediction error. With stimuli that most resemble those used in animal models, we did not detect any frontocentral ERP signal for utility prediction error, in contrast with dominant views of the functional role of the FRN ERP. We link the animal and human literature and present a challenge for current perspectives on associative learning research using ERPs. PMID- 28833255 TI - A megaporous material harbouring a peptide ligand for affinity IgG purification. AB - Common limitations of Protein A affinity chromatography include high adsorbent costs, ligand instability and possible ligand leakage. In this study, a short peptide with affinity for IgG was synthesized chemically and subsequently immobilized on a megaporous support. The support was prepared utilising the cryogel technique while the peptide-ligand was covalently immobilised via thiol epoxy click chemistry. The cryogel support was chemically grafted to increase the number of reaction sites. This adsorbent was designated as "MP-Pep". Adsorption isotherms were employed to evaluate protein binding capacity. A maximum static binding capacity within the range of 30-60 mg/mL was observed for T hIgG. This parameter compares well with other commercial and non-commercial adsorbents, as reported in the literature. As a control material, a Protein A grafted megaporous cryogel was synthesized. Dynamic binding capacity values were obtained by breakthrough analysis. The peptide cryogel showed a dynamic capacity value 9.0 mg/mL in comparison to 9.7 mg/mL in the case of the Protein A based adsorbent. The ratio of dynamic binding capacity to static binding capacity was 20%, indicating suboptimal product capture. However, the advantage of MP-Pep lies in its cost-effective preparations while maintaining a reasonable binding capacity for the targeted product. The presence of cooperative effects during protein binding could also represent an advantage during the processing of a feedstock containing a product in high concentration. PMID- 28833256 TI - Noncovalent interactions between cisplatin and graphene prototypes. AB - Cisplatin (CP) has been widely used as an anticancer drug for more than 30 years despite severe side effects due to its low bioavailability and poor specificity. For this reason, it is paramount to study and design novel nanomaterials to be used as vectors capable to effectively deliver the drug to the biological target. The CP square-planar geometry, together with its low water solubility, suggests that it could be possibly easily adsorbed on 2D graphene nanostructures through the interaction with the related highly conjugated pi-electron system. In this work, pyrene has been first selected as the minimum approximation to the graphene plane, which allows to properly study the noncovalent interactions determining the CP adsorption. In particular, electronic structure calculations at the MP2C and DFT-SAPT levels of theory have allowed to obtain benchmark interaction energies for some limiting configurations of the CP-pyrene complex, as well as to assess the role of the different contributions to the total interaction: it has been found that the parallel configurations of the aggregate are mainly stabilized around the minimum region by dispersion, in a similar way as for complexes bonded through pi-pi interactions. Then, the benchmark interaction energies have been used to test corresponding estimations obtained within the less expensive DFT to validate an optimal exchange-correlation functional which includes corrections to take properly into account for the dispersion contribution. Reliable DFT interaction energies have been therefore obtained for CP adsorbed on graphene prototypes of increasing size, ranging from coronene, ovalene, and up to C150 H30 . Finally, DFT geometry optimizations and frequency calculations have also allowed a reliable estimation of the adsorption enthalpy of CP on graphene, which is found particularly favorable (about -20 kcal/mol at 298 K and 1 bar) being twice that estimated for the corresponding benzene adsorption. (c) 2017 Wiley Periodicals, Inc. PMID- 28833257 TI - Canonical orbital contributions to the magnetic fields induced by global and local diatropic and paratropic ring currents. AB - The induced magnetic field (IMF) of naphthalene, biphenyl, biphenylene, benzocyclobutadiene, and pentalene is dissected to contributions from the total pi system, canonical pi-molecular orbitals (CMO), and HOMO->pi* excitations, to evaluate and interpret relative global and local diatropicity and paratropicity. Maps of the IMF of the total pi system reveal its relative strength and topology that corresponds to global and local diatropic and paratropic ring currents. The total pi magnetic response is determined by this of canonical HOMOs and particularly by paratropic contributions of rotational excitations from HOMOs to unoccupied pi* orbitals. Low energy excitations and similar nodal structure of HOMO and pi* induce strong paratropic fields that dominate on antiaromatic rings. High energy excitations and different nodal structures lead to weak paratropic contributions of canonical HOMOs, which are overwhelmed by diatropic response of lower energy canonical orbitals in aromatic rings. CMO-IMF analysis is found in agreement with ring current analysis. (c) 2017 Wiley Periodicals, Inc. PMID- 28833258 TI - The antioxidant capacity of erythrocyte concentrates is increased during the first week of storage and correlated with the uric acid level. AB - BACKGROUND AND OBJECTIVES: Red blood cells (RBCs) suffer from lesions during cold storage, depending in part on their ability to counterbalance oxidative stress by activating their antioxidant defence. The aim of this study was to monitor the antioxidant power (AOP) in erythrocyte concentrates (ECs) during cold storage. MATERIALS AND METHODS: Six ECs were prepared in saline-adenine-glucose-mannitol (SAGM) additive solution and followed during 43 days. The AOP was quantified electrochemically using disposable electrode strips and compared with results obtained from a colorimetric assay. Haematological data, data on haemolysis and the extracellular concentration of uric acid were also recorded. Additionally, a kinetic model was developed to extract quantitative kinetic data on the AOP behaviour. RESULTS: The AOP of total ECs and their extracellular samples attained a maximum after 1 week of storage prior to decaying and reaching a plateau, as shown by the electrochemical measurements. The observed trend was confirmed with a colorimetric assay. Uric acid had a major contribution to the extracellular AOP. Interestingly, the AOP and uric acid levels were linked to the sex of the donors. CONCLUSION: The marked increase in AOP during the first week of storage suggests that RBCs are impacted early by the modification of their environment. The AOP behaviour reflects the changes in metabolism activity following the adjustment of the extracellular uric acid level. Knowing the origin, interdonor variability and the effects of the AOP on the RBCs could be beneficial for the storage quality, which will have to be further studied. PMID- 28833259 TI - Stem photosynthesis and hydraulics are coordinated in desert plant species. AB - Coordination between stem photosynthesis and hydraulics in green-stemmed desert plants is important for understanding the physiology of stem photosynthesis and possible drought responses. Plants with photosynthetic stems have extra carbon gain that can help cope with the detrimental effects of drought. We studied photosynthetic, hydraulic and functional traits of 11 plant species with photosynthetic stems from three California desert locations. We compared relationships among traits between wet and dry seasons to test the effect of seasonality on these relationships. Finally, we compared stem trait relationships with analogous relationships in the leaf economics spectrum. We found that photosynthetic and hydraulic traits are coordinated in photosynthetic stems. The slope or intercept of all trait relationships was mediated by seasonality. The relationship between mass-based stem photosynthetic CO2 assimilation rate (Amass ) and specific stem area (SSA; stem surface area to dry mass ratio) was statistically indistinguishable from the leaf economics spectrum. Our results indicate that photosynthetic stems behave like leaves in the coordination of multiple traits related to carbon gain, water movement and water loss. Because of the similarity of the stem Amass -SSA relationship to the leaf Amass -specific leaf area relationship, we suggest the existence of a photosynthetic stem economic spectrum. PMID- 28833260 TI - Instanton rate constant calculations close to and above the crossover temperature. AB - Canonical instanton theory is known to overestimate the rate constant close to a system-dependent crossover temperature and is inapplicable above that temperature. We compare the accuracy of the reaction rate constants calculated using recent semi-classical rate expressions to those from canonical instanton theory. We show that rate constants calculated purely from solving the stability matrix for the action in degrees of freedom orthogonal to the instanton path is not applicable at arbitrarily low temperatures and use two methods to overcome this. Furthermore, as a by-product of the developed methods, we derive a simple correction to canonical instanton theory that can alleviate this known overestimation of rate constants close to the crossover temperature. The combined methods accurately reproduce the rate constants of the canonical theory along the whole temperature range without the spurious overestimation near the crossover temperature. We calculate and compare rate constants on three different reactions: H in the Muller-Brown potential, methylhydroxycarbene -> acetaldehyde and H2 + OH -> H + H2 O. (c) 2017 Wiley Periodicals, Inc. PMID- 28833262 TI - Blood donor show behaviour after an invitation to donate: The influence of collection site factors. AB - BACKGROUND AND OBJECTIVES: Show behaviour after invitation to donate varies considerably across donors. More insight into this variation is important for blood banks in achieving stable stocks. This study examined individual factors determining intended show behaviour. Most importantly, however, this study is the first study to account for variation in donor behaviour across different collection sites. MATERIALS AND METHODS: We applied a multilevel approach to data from Donor InSight, including 11 889 donors from 257 fixed and mobile collection sites in the Netherlands. The aim of the multilevel models was to account for variance at two levels, that is donors and collection sites. We estimated the likelihood of showing after invitation based on individual predictors, including demographics, donation history and attitude. At the collection site level, we included satisfaction with the blood bank aggregated from individual responses by donors who donate at this site, opening hours and collection site type, that is fixed/mobile. RESULTS: Most importantly, show behaviour varied considerably across collection sites and depended on characteristics of these sites. Moreover, women, older and more experienced donors had higher odds of showing after invitation than men, younger and less experienced donors. Donors higher on warm glow, self-efficacy and donor identity more likely showed after an invitation. Higher aggregate satisfaction and donating at fixed collection sites increased the odds of show. CONCLUSION: In addition to individual factors, collection site characteristics are important in explaining variation in donor show behaviour, thus presenting clues for blood bank policies and interventions to improve donor show. PMID- 28833263 TI - Quantitative analysis of clofazimine (Lamprene(r)), an antileprosy agent, in human dried blood spots using liquid chromatography-tandem mass spectrometry. AB - An LC-MS/MS method was developed and validated for bioanalysis of clofazimine in human dried blood spot (DBS) samples in support of a clinical study on multidrug resistant tuberculosis in developing countries. The validated assay dynamic range was from 10.0 to 2000 ng/mL using a 1/8 inch DBS punch. The accuracy and precision of the assay were +/-11.0% (bias) and <=13.5% (CV) for the LLOQs (10.0 ng/mL) and +/-15% (bias) and <=15% (CV) for all other QC levels. The assay was proved to be free from the possible impact owing to spot size and storage temperature (e.g. at 60 degrees C, <= - 60 degrees C). The validated assay is well suited for the intended clinical study where conventional pharmacokinetic sample collection is not feasible. PMID- 28833264 TI - Neuromuscular complications of radiation therapy. AB - Neuromuscular late effects of radiation therapy (RT) result from radiation fibrosis (RF) of the treated tissues. The clinical manifestations of this dysfunction have been termed radiation fibrosis syndrome (RFS). Any segment of the central and/or peripheral nervous system can be involved, including the brain, spinal cord, nerve roots, plexus, peripheral nerves, and muscles. Often, multiple levels are damaged, resulting in a constellation of findings named for the affected structures (i.e., radiculo-plexo-neuro-myopathy). Accurately diagnosing RFS requires the clinician to understand the basics of how radiation is and has been delivered. Key parameters of RT delivery include total dose, dose per fraction, and the radiation field treated. This article describes the basic principles of RT delivery, the pathophysiology of radiation injury, and how to identify and evaluate neuromuscular late effects of radiation in cancer survivors. Muscle Nerve 56: 1031-1040, 2017. PMID- 28833265 TI - Local allergic rhinitis is an independent rhinitis phenotype: The results of a 10 year follow-up study. AB - BACKGROUND: The knowledge about the natural history of local allergic rhinitis (LAR) is limited. One unmet question is to demonstrate whether LAR should be considered the first step in the development of allergic rhinitis (AR) or an independent phenotype. The aim of this study was to prospectively evaluate the natural history of a population with LAR, the potential conversion to AR with systemic atopy and the development of asthma during 10 years. METHODS: This is the second phase of a 10-year follow-up study of a cohort of 176 patients with LAR of recent onset and 115 age- and sex-matched healthy controls prospectively evaluated from 2005 to 2016. Clinical-demographic questionnaire, spirometry, skin prick test and specific IgE were evaluated yearly. Nasal allergen provocation tests (NAPT) with Dermatophagoides pteronyssinus, Alternaria alternata, Olea europaea and grass pollen were performed at baseline, and after 5 and 10 years. RESULTS: After 10-year LAR, patients experienced a significant and clinically relevant worsening of the rhinitis, with increase in emergency assistance, development of asthma, loss of allergen tolerance and impairment of the quality of life. This worsening became significant after 5 years and progressed throughout 10 years. A similar rate of development of AR with systemic atopy was detected in patients and controls (9.7% vs 7.8%, log-rank P=.623). In 5 patients, conversion to systemic atopy occurred >10 years (3%). CONCLUSIONS: LAR is a well differentiated clinical entity with a low rate of development of systemic atopy, a natural evolution towards worsening and a risk factor for suffering asthma. PMID- 28833266 TI - Home monitoring after ambulatory implanted primary cardiac implantable electronic devices: The home ambulance pilot study. AB - BACKGROUND: The Home Monitoring (HM) system of cardiac implantable electronic devices (CIEDs) permits early detection of arrhythmias or device system failures. The aim of this pilot study was to examine how the safety and efficacy of the HM system in patients after ambulatory implanted primary CIEDs compare to patients with a standard procedure and hospitalization. HYPOTHESIS: We hypothesized that HM and their modifications would be a useful extension of the present concepts for ambulatory implanted CIEDs. METHODS: This retrospective analysis evaluates telemetric data obtained from 364 patients in an ambulatory single center over 6 years. Patients were assigned to an active group (n = 217), consisting of those who were discharged early on the day of implantation of the primary CIED, or to a control group (n = 147), consisting of those discharged and followed up with the HM system according to usual medical practices. RESULTS: The mean duration of hospitalization was 73.2% shorter in the active group than in the control group, corresponding to 20.5 +/- 13 fewer hours (95% confidence interval [CI]: 6.3-29.5; P < 0.01) spent in the hospital (7.5 +/- 1.5 vs 28 +/- 4.5 h). This shorter mean hospital stay was attributable to a 78.8% shorter postoperative period in the active group. The proportion of patients with treatment-related adverse events was 11% (n = 23) in the active group and 17% (n = 25) in the control group (95% CI: 5.5-8.3; P = 0.061). This 6% absolute risk reduction (95% CI: 3.3-9.1; P = 0.789) confirmed the noninferiority of the ambulatory implanted CIED when compared with standard management of these patients. CONCLUSIONS: Early discharge with the HM system after ambulatory CIED implantation was safe and not inferior to the classic medical procedure. Thus, together with lower costs, HM and its modifications would be a useful extension of the present concepts for ambulatory implanted CIEDs. PMID- 28833267 TI - Affinity chromatography on monolithic supports for simultaneous and high throughput isolation of immunoglobulins from human serum. AB - Posttranslational modifications of immunoglobulins have been a topic of great interest and have been repeatedly reported as a major factor in disease pathology. Cost-effective, reproducible, and high-throughput (HTP) isolation of immunoglobulins from human serum is vital for studying the changes in protein structure and the following understanding of disease development. Although there are many methods for the isolation of specific immunoglobulin classes, only a few of them are applicable for isolation of all subtypes and variants. Here, we present the development of a scheme for fast and simultaneous affinity purification of alpha (A), gamma (G), and MU (M) immunoglobulins from human serum through affinity monolith chromatography. Affinity-based monolithic columns with immobilized protein A, G, or L were used for antibody isolation. Monolithic stationary phases have a high surface accessibility of binding sites, large flow through channels, and can be operated at high flow rates, making them the ideal supports for HTP isolation of biopolymers. The presented method can be used for HTP screening of human serum in order to simultaneously isolate all three above mentioned immunoglobulins and determine their concentration and changes in their glycosylation pattern as potential prognostic and diagnostic disease biomarkers. PMID- 28833268 TI - Application of HPLC-LTQ Orbitrap MS for metabolic profiles of Polygonum multiflora extract in rats. AB - The root of Polygonum multiflorum (PM) is an important Chinese herbal medicine for treatment of various diseases. Extensive pharmacological studies have been conducted and demonstrated that it shows a wide range of bioactivities. Meanwhile, a considerable number of hepatotoxicity cases owing to oral administration of PM have been reported and have attracted great attention. However, the limited knowledge regarding the metabolism of PM restricts the deeper studies on its pharmacological/toxicological mechanism and therapeutic material basis. The present study aimed to develop a high-performance liquid chromatography coupled with a linear ion trap-Orbitrap hybrid mass spectrometry method for separation and identification of metabolites in rat urine and plasma after oral administration of PM. Based on the proposed strategy, metabolism profiles of PM in rats were proposed for the first time and 43 metabolites were characterized or tentatively identified. Phase II metabolism, such as glucuronidation and sulfation, are the principal pathways of the main components. These findings will be beneficial to further understanding of the pharmacological mechanism and pharmacodynamic material basis of PM. PMID- 28833269 TI - Indoor and outdoor winter activity of Culicoides biting midges, vectors of bluetongue virus, in Italy. AB - Indoor and outdoor winter activity of Culicoides spp. (Diptera: Ceratopogonidae) in central Italy was investigated in order to evaluate whether indoor activity might account for the overwintering of bluetongue virus, as has been hypothesized by some authors. Weekly Culicoides collections were performed at three farms over three consecutive winter seasons. At each farm, two black-light traps were operated simultaneously, indoors and outdoors. Culicoides were identified using both morphological and molecular means. The Culicoides obsoletus group accounted for 98.2% of sampled specimens. Within this group, C. obsoletus s.s. accounted for 56.8% and Culicoides scoticus for 43.2% of samples. Nulliparous, parous and engorged females were caught throughout the entire winter, both indoors and outdoors. At times, indoor catch sizes outnumbered outdoor collections. A significant inverse correlation was found between minimum temperature and the proportion of indoor Culicoides of the total midge catch, thus indicating that lower outdoor temperatures drive Culicoides midges indoors. High rates of engorged females were recorded indoors, possibly as the result of the propensity of C. obsoletus females to feed indoors. Higher proportions of parous females were found in indoor than in outdoor catches, indicating higher survival rates indoors and, consequently, higher vectorial capacities of midges sheltering indoors compared with those remaining outdoors. PMID- 28833270 TI - Tailoring an Alcohol Intervention for American Indian Alaska Native Women of Childbearing Age: Listening to the Community. AB - BACKGROUND: Reduction of risky drinking in women of childbearing age is 1 strategy that may be employed to prevent fetal alcohol spectrum disorder, a sequela of prenatal alcohol exposure. Communities differ in risk and protective factors, necessitating culturally informed interventions for maximal efficacy. This article describes the modification of an existing web-based screening, brief intervention, and referral to treatment intervention to reduce risky drinking among American Indian Alaska Native (AIAN) women of childbearing age in Southern California into a peer-to-peer-based intervention using motivational interviewing (MI). METHODS: The modification process was iterative and included various community focus groups, interviews, and a final review. RESULTS: Intervention modification was required for cultural congruence. Components of the peer-to-peer intervention designed by this project included a flip chart used to guide the motivational interviewing, charts of the financial and physical costs of alcohol consumption, revised baseline and follow-up questionnaires, and guidance regarding the application of MI techniques. CONCLUSIONS: This study may inform the modification of future interventions among AIAN communities. PMID- 28833272 TI - Frontal alpha asymmetry and callous-unemotional traits in imprisoned violent offenders: A pilot study. AB - Based on the approach-withdrawal model of hemispheric asymmetry, anger and aggression have been linked to an approach-related pattern, characterized by stronger relative left-hemispheric anterior cortical activity. Recent work suggests that also in individuals with extremely violent tendencies, such as imprisoned offenders, approach-related asymmetry may be associated with self reported trait anger and aggression. A putative association between alpha asymmetry and further characteristics relevant for aggression, such as callous unemotional (CU) traits, remains to be explored. CU traits may increase the probability of aggressive behavior; nevertheless, they may also enable individuals to inhibit and postpone the overt display of aggression until circumstances grant its strongest impact. In the current exploratory study, we measured trait aggression, CU traits, and resting-state EEG asymmetry in the alpha band (8-13 Hz) in imprisoned violent offenders in a German high security prison. Results revealed that particularly trait callousness was associated with stronger relative right-hemispheric anterior cortical activity (i.e., a withdrawal-related pattern). An association between alpha asymmetry and aggression was not replicated. These preliminary findings suggest that, due to the involved emotional and interpersonal detachment, callousness might be withdrawal related, despite its potential to bring about aggressive behavior. They also imply that the identification of putative clinical subtypes in prisoners is required, as varying psychopathology might undermine an association between alpha asymmetry and aggression. PMID- 28833273 TI - Reinforcement of barrier function and scalp homeostasis by Senkyunolide A to fight against dandruff. AB - OBJECTIVE: Senkyunolide-A (SENKY) can be isolated from Apium graveolens seed oil obtained using supercritical CO2 extraction. SENKY and its parent compounds, the N-butyl phthalides, have been demonstrated to protect cells from CO poisoning, to prevent diabetes mellitus and to decrease cancer cell proliferation. This study was undertaken to evaluate in vitro and in vivo the effect of SENKY on epidermal function improvement, Malassezia effect control, scalp soothing and dandruff reduction via skin protection-related pathways. METHODS: DNA-array and proteomic studies were performed on human keratinocytes, sebocytes and skin explants to demonstrate SENKY activities. Two clinical evaluations were performed under dermatologist control on 106 volunteers, with greasy or dry scalp, experiencing dandruff, itching and redness. Volunteers tested a shampoo followed, or not, by a leave-on, containing SENKY, or their placebos. Dandruff severity and redness were scored on the scalp. Moisturization and sebum release were recorded using relevant measuring apparatus. Itching and scratching evaluations came from volunteers' self-declarations. RESULTS: DNA-array studies on keratinocytes showed a clear regulation of skin barrier functions and epidermis defence pathways. Upregulation of epidermal differentiation complex genes was observed. These preliminary observations were reinforced by immunocytochemistry and immunohistochemistry studies showing a significant increase of involucrin, filaggrin, loricrin, SPRR, LC3B and ceramide 2 productions. Tight-junctions and corneodesmosomes were significantly reinforced both in keratinocyte cultures (corneodesmosin, claudin, ZO-1) and in skin explants (desmoglein). DNA-array studies also demonstrated upregulation of genes involved in detoxification and anti-inflammation pathways. Proteomic studies revealed that hBD2 production was increased in keratinocytes in contact with SENKY, whereas IL-8, PGE-2 and TLR-9 releases were repressed as well as sebocyte lipid production. Clinical evaluations confirmed that after 3 weeks, SENKY significantly reduced dandruff intensity, redness, itching and scalp histamine content compared to placebo and beginning of treatment. CONCLUSION: For the first time, SENKY has been shown to promote scalp homoeostasis by reinforcing barrier and defence functions at both gene and protein levels. It reduces irritation and redness in promoting detoxification and anti-inflammation pathways while controlling the niche of Malassezia. Applied on scalp, SENKY significantly reduces the formation of dandruff and soothes the scalp. PMID- 28833274 TI - Phonon spectra, electronic, and thermodynamic properties of WS2 nanotubes. AB - Hybrid density functional theory calculations are performed for the first time on the phonon dispersion and thermodynamic properties of WS2 -based single-wall nanotubes. Symmetry analysis is presented for phonon modes in nanotubes using the standard (crystallographic) factorization for line groups. Symmetry and the number of infra-red and Raman active modes in achiral WS2 nanotubes are given for armchair and zigzag chiralities. It is demonstrated that a number of infrared and Raman active modes is independent on the nanotube diameter. The zone-folding approach is applied to find out an impact of curvature on electron and phonon band structure of nanotubes rolled up from the monolayer. Phonon frequencies obtained both for layers and nanotubes are used to compute the thermal contributions to their thermodynamic functions. The temperature dependences of energy, entropy, and heat capacity of nanotubes are estimated with respect to those of the monolayer. The role of phonons in the stability estimation of nanotubes is discussed based on Helmholtz free energy calculations. (c) 2017 Wiley Periodicals, Inc. PMID- 28833276 TI - Analysis of the Association of Nonsynonymous Polymorphisms in ADH Genes with Hazardous Drinking in HIV-1-Positive Individuals. AB - BACKGROUND: Hazardous drinking (HD) is a serious health problem in people infected with human immunodeficiency virus type 1 (HIV-1). Single nucleotide polymorphisms (SNPs) in alcohol dehydrogenase (ADH) genes have been associated with HD in different populations, but there were no data about this in HIV-1 positive individuals. This study investigated the association of 4 nonsynonymous SNPs in ADH genes (Arg48His and Arg370Cys in ADH1B gene; Arg272Gln and Ile350Val in ADH1C gene) with HD in people living with HIV-1. METHODS: This case-control study included 365 HIV-1-positive individuals (121 with HD and 244 without HD). Sociodemographic variables were collected with a standardized individual questionnaire. HD (score >=8) and binge drinking (BD) (drinks on the same occasion >=5) were detected with the Alcohol Use Disorders Identification Test. The 4 SNPs were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. The Bonferroni correction was used (considering the 4 SNPs studied). RESULTS: There were no significant differences in the frequencies of Arg370Cys, Arg272Gln, and Ile350Val polymorphisms between HD cases and controls. Otherwise, Arg/His genotype (rs1229984) in ADH1B gene showed a protective effect against HD (aOR = 0.36; 95% CI: 0.14 to 0.90) and BD (aOR = 0.49; 95% CI: 0.21 to 0.95). Nevertheless, these differences were no longer significant after Bonferroni correction. CONCLUSIONS: The results of this study suggest a possible effect of the Arg48His genotype on the protection against HD in HIV-1-positive individuals. PMID- 28833277 TI - Axial or Helical? Considerations for wide collimation CT scanners capable of volumetric imaging in both modes. AB - PURPOSE: To determine whether axial or helical mode is more appropriate for a 16 cm collimation CT scanner capable of step-and-shoot volumetric axial coverage, in terms of radiation dose, image quality, and scan duration. METHODS: All scans were performed with a Revolution CT (GE Healthcare) operating at 120 kV and 100 mAs. Using calibrated optically stimulated luminescence detectors, radiation dose along the axial scan profile was evaluated at the isocenter, including the overlap region between two axial sections. This overlap region measures 3 cm in the z-axis at the isocenter and is required to obtain sufficient projection data from the relatively large cone-beam angles. Using an image quality phantom (Gammex Model 464), spatial resolution, CT number uniformity, image noise, and low contrast detectability (LCD) were evaluated under five different conditions: in the middle of a helical acquisition, in the middle of a 16 cm axial section, at both ends of an axial section and in the overlap region between two axial sections. Scan durations and dose length products (DLP) were recorded for prescribed scan lengths of 2.5-100 cm. RESULTS: The overlap region between two axial sections received a dose 83% higher than the single-exposure region at the isocenter. Within a single axial section, the dose at the anode end was 37% less than at the cathode end due to the anode heel effect. Image noise ranged from a low of 13 HU for the cathode end of an axial section up to 14.7 HU for the anode end (P < 0.001). The LCD was at lower at the anode end of the axial section compared to both the cathode end (P < 0.05) and the overlap location (P < 0.02). The spatial resolution and CT number uniformity were consistent among all conditions. Scan durations were shorter (0.28 s) for the axial mode compared to the helical mode at scan lengths <= 16 cm, and longer at scan lengths >= 16 cm where more than one table position was required, up to a difference of 13.9 s for a the 100 cm scan length (3.8 s for helical compared to 17.6 s for axial). DLPs were consistent between scan modes; slightly lower in axial mode at shorter scan lengths due to helical overranging, and slightly higher in axial mode at longer scan lengths due to the axial overlap regions. CONCLUSIONS: To ensure the most consistent radiation dose and image quality along the scan length, we recommend helical mode for scans longer than the 16 cm coverage of a single axial section. For scan lengths <= 16 cm, axial scanning is the most practical option, with a shorter scan duration and higher dose efficiency. PMID- 28833278 TI - Whole genome sequencing identifies etiology of recurrent male intrauterine fetal death. AB - OBJECTIVE: To identify the underlying genetic cause for recurrent intrauterine fetal death (IUFD) of males. METHODS: Whole genome sequencing was performed on DNA from five healthy obligatory carrier females and an unaffected male offspring of a multigenerational pedigree with recurrent second-trimester IUFD of males (n = 19). When documented, all deaths occurred at <=20 weeks of gestation. Hydrops fetalis was diagnosed at death in the most recent case. RESULTS: Following variant filtering based on a recessive X-linked inheritance pattern, a rare FOXP3 frameshift mutation (p.D303fs*87) that results in a premature truncation of the protein was discovered. Sanger sequencing confirmed the mutation in the affected fetus. The FOXP3 gene encodes for a transcriptional regulator critical to the function of regulatory T cells. FOXP3 mutations are associated with immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome which exclusively affects males and may present with a potentially life threatening complex autoimmune disorder in early childhood. CONCLUSIONS: Here, we demonstrate the utility of whole genome sequencing-based pedigree analysis to identify the genetic cause for recurrent IUFD when chromosome studies, including microarray analysis, are normal. Further studies are needed to determine the prevalence of FOXP3-mediated IUFD in males. (c) 2017 John Wiley & Sons, Ltd. PMID- 28833279 TI - Don't worry, be happy: The role of positive emotionality and adaptive emotion regulation strategies for youth depressive symptoms. AB - OBJECTIVES: Low positive emotionality (PE) represents a temperamental vulnerability to depression in youth. Until now, little research has examined the mechanisms linking PE to depressive symptoms. Starting from integrated cognitive affective models of depression, we aimed to study adaptive emotion regulation (ER) as a key underlying mechanism in the temperament-depression relationship. METHODS: This study investigated whether adaptive ER strategies mediate the association between PE and depressive symptoms in a large community-based sample of youth, using a cross-sectional design. Participants were 1,655 youth (54% girls; 7-16 years, M = 11.41, SD = 1.88) who filled out a set of questionnaires assessing temperament, adaptive ER strategies, and depressive symptoms. RESULTS: Results revealed that low PE was significantly related to higher depressive symptoms among youth and that a lack of total adaptive ER abilities mediated this relationship. More specifically, the infrequent use of problem-solving appeared to be of significant importance. Problems in positive refocusing and a deficient use of forgetting mediated the relationships between low PE and high negative emotionality (NE) in predicting depressive symptoms. Reappraisal and distraction were not significant mediators. CONCLUSION: Results highlight the need to account for temperamental PE and adaptive ER strategies when studying youth depression. The findings contribute to a more nuanced understanding on the differential role of temperamental risk factors for developing depressive symptoms at an early stage and advocate for greater attention to adaptive ER strategies. PRACTITIONER POINTS: Clinical interventions for youth depression may be improved by incorporating adaptive emotion regulation (ER) strategies and enhancing positive emotions. Youth low in positive emotionality (PE) may especially benefit from learning adaptive ER skills. Clinical practitioners should focus on alleviating negative emotions and enhancing positive emotions, especially among youth low in PE. PMID- 28833280 TI - Acaricidal activity of essential oil of Syzygium aromaticum, hydrolate and eugenol formulated or free on larvae and engorged females of Rhipicephalus microplus. AB - The cattle tick, Rhipicephalus microplus (Canestrini, 1888) (Ixodida: Ixodidae), is the most important ectoparasite in cattle-breeding areas and is responsible for severe economic losses. Synthetic acaricides have been used to control this parasite. However, the need for safer products has stimulated the search for new acaricides, such as those to be obtained from medicinal plants. The essential oil of Syzygium aromaticum (clove) has many biological properties and shows great potential for use in veterinary applications. In the context of the need for new agents, this study investigated the in vitro properties of the hydrolate, essential oil and the main constituent of S. aromaticum, eugenol, in formulated and free applications against larvae and females of R. microplus. Eugenol and the essential oil caused 100% mortality in larvae at starting applications of 2.5 mg/mL and 5.0 mg/mL, respectively. The hydrolate showed no activity. Both eugenol and essential oil had good efficacy in adult immersion tests at 50 mg/mL and achieved 100% efficacy at a concentration of 100 mg/mL. The results of these tests reaffirm the important potential of clove essential oil and eugenol. PMID- 28833281 TI - A vascularized preputial free flap for labial reconstruction in a dog. AB - OBJECTIVE: To describe the clinical application of a vascularized preputial free flap in the reconstruction of a large facial-labial defect. STUDY DESIGN: Case report. ANIMALS: An adult neutered male mongrel dog with a large left facial labial defect. METHODS: A preputial free flap was created by elevating the cranial part of the prepuce, using the ipsilateral caudal superficial epigastric vessels as a vascular pedicle. The flap was transferred to the facial-labial defect and the donor vessels anastomosed to the sublingual artery and vein, using standard microvascular technique. RESULTS: The free flap survived, leading to good cosmetic and functional outcomes. No major complications were encountered at either the donor or recipient sites after 2 years of follow-up. CONCLUSION: Vascularized preputial free flaps can be used to manage composite facial and oral cavity defects involving large areas of skin and mucosa. PMID- 28833282 TI - Palatal perforation and chemical ulcers of the tongue in a blind patient. AB - We report a unique case of a potassium aluminum sulfate oral dissolution leading to palatal chemical necrosis and extensive chemical ulcers on the tongue. The patient, a 47-year-old white, blind male, denied using cocaine or other illegal drugs that could cause such lesions. His self-medication started as a treatment for a traumatic ulcerative lesion on the hard palate. After palatal perforation, he started another self-medication routine, mixing corticoid cream and tandrilax tablets with a gauze obturator. Our treatment comprised the removal of all chemical factors, a surgical debridement, and a prosthetic obturator to resolve the communication. The 1-year follow-up showed no complications. PMID- 28833283 TI - MicroRNA-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation. AB - : Transcriptional networks control the differentiation of the hepatocyte and cholangiocyte lineages from embryonic liver progenitor cells and their subsequent maturation to the adult phenotype. However, how relative levels of hepatocyte and cholangiocyte gene expression are determined during differentiation remains poorly understood. Here, we identify microRNA (miR)-337-3p as a regulator of liver development. miR-337-3p stimulates expression of cholangiocyte genes and represses hepatocyte genes in undifferentiated progenitor cells in vitro and in embryonic mouse livers. Beyond the stage of lineage segregation, miR-337-3p controls the transcriptional network dynamics of developing hepatocytes and balances both cholangiocyte populations that constitute the ductal plate. miR-337 3p requires Notch and transforming growth factor-beta signaling and exerts a biphasic control on the hepatocyte transcription factor hepatocyte nuclear factor 4alpha by modulating its activation and repression. With the help of an experimentally validated mathematical model, we show that this biphasic control results from an incoherent feedforward loop between miR-337-3p and hepatocyte nuclear factor 4alpha. CONCLUSION: Our results identify miR-337-3p as a regulator of liver development and highlight how tight quantitative control of hepatic cell differentiation is exerted through specific gene regulatory network motifs. (Hepatology 2018;67:313-327). PMID- 28833285 TI - A novel jig arm to measure tibial plateau angle during tibial plateau leveling osteotomy. AB - OBJECTIVE: To determine the ability of a novel device attached to the proximal tibial plateau leveling osteotomy (TPLO) jig pin to accurately predict intraoperative change in tibial plateau angle (TPA). STUDY DESIGN: In vitro cadaveric study. SAMPLE POPULATION: Left hindlimbs of adult dogs (n = 9). METHODS: A modified Slocum tibial plateau leveling (TPL) jig with the Rotational Osteotomy Measuring Arm (ROMA) was placed on the tibia and a radial TPLO osteotomy was performed. Based on preoperative radiographic TPA measurements, the proximal segment was rotated using the traditional method of marking points on the osteotomy a specified distance apart. After rotation, the predicted TPA was recorded based on the ROMA. Postoperative TPA was measured on radiographs. The ability of the ROMA to predict postoperative TPA was compared to that of the traditional method. RESULTS: The average final TPA achieved with the traditional method was 6.4 degrees (range, 3.0-10.0 degrees ). The ROMA predicted a final TPA of 5.8 degrees (range, 3.8-10.1 degrees ). No significant difference was found between the TPA predicted based on the traditional method and ROMA method. CONCLUSION: The ROMA may be an alternative to the traditional method of measuring proximal segment rotation during TPLO procedure. CLINICAL RELEVANCE: Performing a TPLO with the ROMA may accurately predict the postoperative TPA while eliminating the need for measuring chord length, making reference marks, or referencing TPA charts for various osteotomy blade sizes. PMID- 28833284 TI - Symptom clusters in adults with inflammatory bowel disease. AB - Symptoms (pain, fatigue, sleep disturbance, depression, and anxiety) in inflammatory bowel disease (IBD) are associated with reduced quality of life. Understanding how IBD symptoms cluster and the clinical and demographic factors associated with symptom clusters will enable focused development of symptom management interventions. The study purposes were to (i) identify symptom cluster membership among adults with IBD and (ii) examine associations between demographic (age, gender, race/ethnicity, and education) and clinical factors (smoking status, time since diagnosis, medication type, IBD type, disease activity), and membership in specific symptom cluster groups. We conducted a retrospective study of data from the Crohn's and Colitis Foundation of America's (CCFA) Partners Cohort and used Patient Reported Outcome Measurement Information System (PROMIS) measures to measure pain interference, fatigue, sleep disturbance, anxiety, and depression. The sample included 5,296 participants with IBD (mean age 44, 72% female). In latent class analysis (LCA), four groups of participants were identified based on symptoms: "low symptom burden" (26% of sample), "high symptom burden" (38%), "physical symptoms" (22%), and "psychological symptoms" (14%). In multinomial regression, female gender, smoking, corticosteroids, Crohn's disease, and active disease state were associated with membership in the high symptom burden group. Additional research is needed to test interventions that may be effective at reducing symptom burden for individuals with IBD. PMID- 28833286 TI - Charting the transcriptional regulatory changes in mouse liver during fasting. PMID- 28833287 TI - Changes in medical management and colectomy rates: a population-based cohort study on the epidemiology and natural history of ulcerative colitis in Orebro, Sweden, 1963-2010. AB - BACKGROUND: Whether the epidemiology of ulcerative colitis (UC) has changed during recent decades is partly unknown. AIM: To depict temporal trends in the epidemiology and medical treatment of UC as well as the long-term risk of progression in disease extent and colectomy, during 1963-2010. METHODS: Patients were identified by evaluation of all medical records in the archive of the Colitis Clinic, Orebro University Hospital. Comparisons were made between three time periods, 1963-1975, 1976-1990 and 1991-2005. RESULTS: The annual age standardised incidence increased from 3.5 to 18.5 per 100 000 during the study period (P < .01). Correspondingly, the prevalence increased from 44 to 474 per 100 000 between 1965 and 2010. A higher proportion of males than females had extensive colitis at diagnosis (odds ratio: 1.55; 95% CI 1.17-2.05; P < .01). The risk for progression in disease extent was 34.5% and 18.5% at 10 years, for patients with proctitis and left-sided colitis, respectively (P < .01). The use of 5-aminosalicylates, within 10 years, rise from 79% to 92% between 1963-1975 and 1976-1990 (P < .01). Thiopurine use increased from 7% in 1976-1990 to 34% during 1991-2005 (P < .01). The colectomy rate at 10 years was 13.5% (95% CI 11.1%-15.8%), and the risk was lower among patients diagnosed in 1991-2005 compared to 1963-1975 (adjusted hazard ratio: 0.61; 95% CI 0.39-0.94; P = .02). CONCLUSION: The incidence and prevalence of UC increased over time, and the observed prevalence in 2010 is among the highest reported. In parallel, a decrease in colectomy rates was observed during the most recent decades, potentially reflecting improved medical treatment. PMID- 28833288 TI - Insurance, Public Assistance, and Household Flood Risk Reduction: A Comparative Study of Austria, England, and Romania. AB - In light of increasing losses from floods, many researchers and policymakers are looking for ways to encourage flood risk reduction among communities, business, and households. In this study, we investigate risk-reduction behavior at the household level in three European Union Member States with fundamentally different insurance and compensation schemes. We try to understand if and how insurance and public assistance influence private risk-reduction behavior. Data were collected using a telephone survey (n = 1,849) of household decisionmakers in flood-prone areas. We show that insurance overall is positively associated with private risk-reduction behavior. Warranties, premium discounts, and information provision with respect to risk reduction may be an explanation for this positive relationship in the case of structural measures. Public incentives for risk-reduction measures by means of financial and in-kind support, and particularly through the provision of information, are also associated with enhancing risk reduction. In this study, public compensation is not negatively associated with private risk-reduction behavior. This does not disprove such a relationship, but the negative effect may be mitigated by factors related to respondents' capacity to implement measures or social norms that were not included in the analysis. The data suggest that large-scale flood protection infrastructure creates a sense of security that is associated with a lower level of preparedness. Across the board there is ample room to improve both public and private policies to provide effective incentives for household-level risk reduction. PMID- 28833289 TI - Pharmacokinetics of tigecycline in turkeys following different routes of administration. AB - The aim of this research had been to determine the pharmacokinetics of tigecycline (TIG) in turkey after intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.), and oral (p.o.) administration at a dose of 10 mg/kg. TIG concentrations in plasma were determined using high-performance liquid chromatography with tandem mass spectrometry. Mean concentrations of TIG in turkey plasma in the i.v. group were significantly higher than concentrations of this drug obtained after using the other administration routes. No significant differences were demonstrated in respect to the concentrations achieved after i.m. and s.c. administration. The bioavailability of TIG after i.m., s.c., and p.o. administration was 32.59 +/- 5.99%, 34.91 +/- 9.62%, and 0.97 +/- 0.57%, respectively. Values of half-life in the elimination phase were 23.49 +/- 6.51 hr, 25.42 +/- 4.42 hr, and 26.62 +/- 5.19 hr in i.v., i.m., and s.c. groups, respectively, values of mean residence time were 7.92 +/- 1.41 hr, 19.62 +/- 2.82 hr, and 17.55 +/- 2.59 hr in i.v., i.m., and s.c. groups, respectively, whereas the volume of distribution was 14.85 +/- 5.71 L/kg, 14.68 +/- 2.56 L/kg, and 15.37 +/- 3.00 L/kg in i.v., i.m., and s.c. groups, respectively. Because TIG is not absorbed from the gastrointestinal tract in turkeys to a clinically significant degree, this drug given p.o. could find application in commercial turkey farms only to treat gastrointestinal tract infections. PMID- 28833290 TI - Work-related mortality in the US fishing industry during 2000-2014: New findings based on improved workforce exposure estimates. AB - BACKGROUND: Commercial fishing is a global industry that has been frequently classified as high-risk. The use of detailed surveillance data is critical in identifying hazards. METHODS: The purpose of this study was to provide updated statistics for the entire US fishing industry during 2010-2014, generate fleet specific fatality rates using a revised calculation of full-time equivalent estimates, and examine changes in the patterns of fatalities and in risk over a 15-year period (2000-2014). RESULTS: During 2010-2014, 188 commercial fishing fatalities occurred in the United States. Vessel disasters and falls overboard remain leading contributors to commercial fishing deaths. The Atlantic scallop fleet stands out for achieving substantial declines in the risk of fatalities over the 15-year study period. However, fatality rates ranged from 21 to 147 deaths per 100 000 FTEs, many times higher than the rate for all US workers. CONCLUSIONS: Although the number of fatalities among commercial fishermen in the United States has generally declined since 2000, commercial fishing continues to have one of the highest occupational fatality rates in the United States. The sustainable seafood movement could assist in improving the health and safety of fishing industry workers if worker well-being was integrated into the definition of sustainable seafood. PMID- 28833291 TI - Association between modifiable lifestyle and the prevalence of atrial fibrillation in a Chinese population: Based on the cardiovascular health score. AB - BACKGROUND: The Cardiovascular Health (CVH) Score was comprised of a series of modifiable lifestyle and health factors, which was published by American Heart Association in 2010. Its relationship with atrial fibrillation (AF) remains unclear. HYPOTHESIS: Individuals with a higher CVH Score had a lower risk of AF. METHODS: Participants >=40 years of age were recruited from the Jidong community. Information regarding the following 7 CVH metrics, including smoking, body mass index, diet, physical activity, total cholesterol, and fasting blood glucose, were collected. AF was confirmed with a standard 12-lead electrocardiography or based on the patients' medical histories. A multivariable logistic regression model was used to evaluate the relationship between ideal CVH and AF prevalence. RESULTS: This study included 4477 individuals, among whom 48 had AF (1.07%). Overall, participants with higher ideal components scores had a lower risk of AF (odds ratio [OR]: 0.78; 95% confidence intervals [CI]: 0.62-0.97; P trend = 0.024). Subgroup analyses showed that the trend was consistent in the male participants ages 40 to 60 years. Moreover, patients with 5 to 7 ideal components or 3 to 4 ideal components were associated with 57% and 59% reduced risks for AF, respectively. We also detected a significant association between ideal health factors and the prevalence of AF (OR: 0.79; 95% CI: 0.68-0.93; P = 0.004). CONCLUSIONS: Ideal health behavior and factors are associated with lower prevalence of AF in a community-based population. Improving healthy behavior and these factors may be beneficial to decrease the prevalence of AF. PMID- 28833292 TI - Muscle compression improves reliability of ultrasound echo intensity. AB - INTRODUCTION: Muscle echo intensity has been shown to correlate with disease status in muscle disorders, including Duchenne muscular dystrophy (DMD). We report the effect of sonographer-applied load on measurements of muscle echo intensity. METHODS: Quadriceps ultrasound scans were performed on 22 healthy boys and 16 boys with DMD between the ages of 2.2 and 15.3 years. Transducer contact force was increased linearly from 1.5 to 10 N, and echo intensity was measured throughout. RESULTS: Echo intensity increased linearly with strain at a rate of 42 (95% confidence interval [CI]: 21-63) and 74 (95% CI: 49-98) in the healthy and DMD populations, respectively. Echo intensity reliability was moderate at low strain (intraclass correlation coefficient [ICC] = 0.82) and was improved at high strain (ICC = 0.92). DISCUSSION: Sonographer-applied load introduces error in measurements of echo intensity, but it can be minimized by measuring echo intensity at near-maximal levels of compression. Muscle Nerve 57: 423-429, 2018. PMID- 28833294 TI - The work-related stressors and coping strategies of group-employed rural health care practitioners: A qualitative study. AB - BACKGROUND: Escalating demands on practitioners, stagnating/dwindling resources, and diminishing autonomy have heightened patient-care work-related stress. Using qualitative content/thematic analysis of responses to open-ended survey questions, plus spontaneous comments, we sought to identify rural clinicians' subjective perceptions of their workplace stressors and typical adaptive/coping strategies. METHODS: Within a hybrid inductive-deductive approach, we framed empirical themes (derived by consensus, corroborated with text segments, and extant literature) into theory-based coding templates by which we analyzed the data. RESULTS: Of 308 (65.1% of) recipients completing questionnaires, 290 (94%) answered open-ended questions and/or provided comments. Categorizing stressors by socio-ecology, they cited four themes: Organizational, practitioner/staff related, patient-related, and third party-induced stressors. Organizational stressors were referenced most conspicuously. How respondents described their coping fitted the Stress, Appraisal and Coping. [Lazarus and Folkman (1984): New York, NY: Springer Publishing Company, Inc] model. Emotion-focused were referenced more than problem-focused approaches. Themes scarcely differed by demographics, except for marital status. CONCLUSIONS: Findings highlight needs for resilience coaching, rekindling work meaningfulness, mentorship in work-home balance/limit-setting, supportive peer networks, and deeper teamwork. PMID- 28833293 TI - Evaluating electronic structure methods for accurate calculation of 19 F chemical shifts in fluorinated amino acids. AB - The ability of electronic structure methods (11 density functionals, HF, and MP2 calculations; two basis sets and two solvation models) to accurately calculate the 19 F chemical shifts of 31 structures of fluorinated amino acids and analogues with known experimental 19 F NMR spectra has been evaluated. For this task, BHandHLYP, omegaB97X, and Hartree-Fock with scaling factors (provided within) are most accurate. Additionally, the accuracy of methods to calculate relative changes in fluorine shielding across 23 sets of structural variants, such as zwitterionic amino acids versus side chains only, was also determined. This latter criterion may be a better indicator of reliable methods for the ultimate goal of assigning and interpreting chemical shifts of fluorinated amino acids in proteins. It was found that MP2 and M062X calculations most accurately assess changes in shielding among analogues. These results serve as a guide for computational developments to calculate 19 F chemical shifts in biomolecular environments. (c) 2017 Wiley Periodicals, Inc. PMID- 28833295 TI - Employment of modified Fe3 O4 nanoparticles using thermo-sensitive polymer for extraction and pre-concentration of cefexime in biological samples. AB - Cefexime is a useful antibiotic that can be prescribed to treat bacterial infections. Nanoparticles have been widely marketed as a universal solution among scientists. Many studies have been performed to modify nanoparticles to make them functional as extraction and pre-concentration agents and drug carriers. Temperature-sensitive polymers belong to a group of substances that undergo a major change in their physical features in response to temperature. Recently developed polymers can be used in many different areas, including modification of nanoparticles. In order to modify this nanoparticle, grafting copolymerization of Fe3 O4 nanoparticles was performed using poly (N-vinylcaprolactam) and 3-allyloxy 1,2-propanediol. The optimum conditions for pre-concentration of cefexime were studied. Under these optimum conditions, extraction recovery of biological samples in the range of 71-89% was obtained. The limit of detection and precision of proposed method were 4.5 * 10-4 MUg mL-1 and <4.11% (relative standard deviation), respectively. Based on the results from analysis of cefexime, in biological samples using the proposed method, the ability of this method to extract and pre-concentrate cefexime was confirmed. Also, satisfactory results from an in vitro study on drug release in simulated intestine media were obtained. PMID- 28833296 TI - EXPANDING INFANT MENTAL HEALTH TREATMENT SERVICES TO AT-RISK PRESCHOOLERS AND THEIR FAMILIES THROUGH THE INTEGRATION OF RELATIONAL PLAY THERAPY. AB - The expansion of infant mental health (IMH) to at-risk preschoolers and their families has contributed to the integration of relational play therapy (RPT) into IMH treatment services for this population. Integrating RPT allows access to specialized play and expressive techniques specific to preschool and family development, which improves the clinical ability to meet the multiple and complex needs of at-risk parent-child dyads and their families. This article will examine the RPT literature and explore the similarities and differences between IMH and RPT. In addition, two case studies will highlight a five-phase, integrative clinical-treatment process and provide insight into how IMH clinicians are integrating RPT models and maintaining adherence to the IMH treatment approach. PMID- 28833297 TI - Re: Transcutaneous temperature controlled radiofrequency for orgasmic dysfunction. Lasers in Surgery and Medicine 2016;48(7): 641-645. PMID- 28833299 TI - Re: "2017 ELECTRONIC POSTERS (ePosters)," Lasers in Surgery and Medicine, 2017;49(4):417-467. PMID- 28833300 TI - Pencil graphite leads as simple amperometric sensors for microchip electrophoresis. AB - In this work we demonstrate, for the first time, the use of inexpensive commercial pencil graphite leads as simple amperometric sensors for microchip electrophoresis. A PDMS support containing one channel was fabricated through soft lithography and sanded pencil graphite leads were inserted into this channel to be used as working electrodes. The electrochemical and morphological characterization of the sensor was carried out. The graphite electrode was coupled to PDMS microchips in end-channel configuration and electrophoretic experiments were performed using nitrite and ascorbate as probe analytes. The analytes were successfully separated and detected in well-defined peaks with satisfactory resolution using the microfluidic platform proposed. The repeatability of the pencil graphite electrode was satisfactory (RSD values of 1.6% for nitrite and 12.3% for ascorbate, regarding the peak currents) and its lifetime was estimated to be ca. 700 electrophoretic runs over a cost of ca. $ 0.05 per electrode. The limits of detection achieved with this system were 2.8 MUM for nitrite and 5.7 MUM for ascorbate. For proof of principle, the pencil graphite electrode was employed for the real analysis of well water samples and nitrite was successfully quantified at levels below its maximum contaminant level established in Brazil and US. PMID- 28833301 TI - Level-2 perspectives computed quickly and spontaneously: Evidence from eight- to 9.5-year-old children. AB - It has been widely assumed that computing how a scene looks from another perspective (level-2 perspective taking, PT) is an effortful process, as opposed to the automatic capacity of tracking visual access to objects (level-1 PT). Recently, adults have been found to compute both forms of visual perspectives in a quick but context-sensitive way, indicating that the two functions share more features than previously assumed. However, the developmental literature still shows the dissociation between automatic level-1 and effortful level-2 PT. In the current paper, we report an experiment showing that in a minimally social situation, participating in a number verification task with an adult confederate, eight- to 9.5-year-old children demonstrate similar online level-2 PT capacities as adults. Future studies need to address whether online PT shows selectivity in children as well and develop paradigms that are adequate to test preschoolers' online level-2 PT abilities. Statement of Contribution What is already known on this subject? Adults can access how objects appear to others (level-2 perspective) spontaneously and online Online level-1, but not level-2 perspective taking (PT) has been documented in school-aged children What the present study adds? Eight- to 9.5-year-olds performed a number verification task with a confederate who had the same task Children showed similar perspective interference as adults, indicating spontaneous level-2 PT Not only agent-object relations but also object appearances are computed online by eight- to 9.5-year olds. PMID- 28833302 TI - Patient experience with early discharge after total knee arthroplasty: a focus group study. AB - BACKGROUND: Total knee arthroplasty is experienced as a painful procedure, and pain after surgery seems to be the most limiting factor for early mobilisation. Physical exercise is of utter importance for avoiding complications such as persistent pain and functional limitations. A fast-track pathway aims at improving patient outcome, and patients are now discharged 2-3 days after surgery. Little is known about how the patients cope with pain, exercise or daily activities at home. AIM: To explore the experience of patients undergoing total knee arthroplasty in a fast-track pathway during the first 2 weeks after surgery. DESIGN: Qualitative design. METHODS: Three focus group interviews, including 13 patients from two different units of an orthopaedic department in central Norway, were conducted from May to June 2015. The interviews were analysed using Malteruds' method of systematic text condensation. FINDINGS: The main finding was the patients' determination and ability to cope at home. The fast-track pathway seemed to enable patients to take an active role in own self-care. The patient's coping capacity was strengthened by education, knowledge and predictability. Four main areas related to coping emerged after discharge. First, the majority of patients expressed that it was good to come home and take responsibility for their own rehabilitation. Second, prerequisites for feeling secure after returning home were highlighted. Third, the patients seemed empowered by sharing experiences with others. Fourth, postoperative pain was prevalent in many patients after discharge, but the patients seemed prepared by information provided in the fast-track pathway. CONCLUSION: The fast-track pathway released coping skills and resources among the patients. The expectation of, and preparation for early discharge made the patients feel confident when discharged few days after surgery. The patients expected to take great responsibility for their own rehabilitation process. PMID- 28833303 TI - Mortality in asbestos cement workers in Pavia, Italy: A cohort study. AB - BACKGROUND: The aim of this study was to describe the mortality of a cohort of asbestos-cement workers in the largest plant in the most industrialized Italian region (Lombardy). METHODS: A cohort study was carried out on 1818 subjects, corresponding to 47 536.1 person-years of observation. Standardized mortality ratios (SMRs) were computed for the major causes of death. RESULTS: Increased SMRs were observed for pleural, peritoneal and lung cancers, and for asbestosis (SMR 26.73, 95% Confidence Interval (CI) 20.99-33.55; 9.15, 95%CI 5.00-15.34; 1.48, 95%CI 1.27-1.72; and 368.05, 95%CI 214.40-589.29, respectively). No excess in mortality for laryngeal cancer was observed (SMR 0.70, 95%CI 0.30-1.39). An increased mortality for ovarian cancer (SMR 3.64, 95%CI 0.99-9.33) was observed, although it was not statistically significant. Among men, mortality for pleural malignant mesothelioma was observed to be related to the duration of exposure, though not to latency. CONCLUSIONS: The results of this study are generally consistent with present knowledge. Conversely, our results do not support the hypothesis that pleural malignant mesothelioma risk indefinitely increases after exposure, suggesting instead that the alternative hypothesis of a risk plateau or decrease after a time since first exposure of more than 40 years is more consistent with the observed data. PMID- 28833304 TI - Survival trees for interval-censored survival data. AB - Interval-censored data, in which the event time is only known to lie in some time interval, arise commonly in practice, for example, in a medical study in which patients visit clinics or hospitals at prescheduled times and the events of interest occur between visits. Such data are appropriately analyzed using methods that account for this uncertainty in event time measurement. In this paper, we propose a survival tree method for interval-censored data based on the conditional inference framework. Using Monte Carlo simulations, we find that the tree is effective in uncovering underlying tree structure, performs similarly to an interval-censored Cox proportional hazards model fit when the true relationship is linear, and performs at least as well as (and in the presence of right-censoring outperforms) the Cox model when the true relationship is not linear. Further, the interval-censored tree outperforms survival trees based on imputing the event time as an endpoint or the midpoint of the censoring interval. We illustrate the application of the method on tooth emergence data. PMID- 28833305 TI - Factors associated with second-line triplet therapy in routine care in relapsed/refractory multiple myeloma. AB - WHAT IS KNOWN AND OBJECTIVE: Second-line therapy (SLT) trials in relapsed/refractory multiple myeloma (RRMM) report superior outcomes with triplet combinations. We sought to determine factors associated with triplet SLT in routine practice. METHODS: A retrospective cohort with claims for MM between 01/01/2008 and 03/31/2015 was grouped by 1-2 ("doublet") or 3+ ("triplet") agent therapy. Charlson comorbidity index (CCI) and disability status; CRAB symptoms (hypercalcaemia, renal/bone disease, anaemia); and relapse risk were determined. RESULTS: Among 623 patients, the triplet group (n=146 [23%]) was younger (65.2 vs 69.8 years) and more likely to have high-risk relapse (67% vs 50%), CRAB symptoms (94.5% vs 81.1%), triplet first-line treatment (75% vs 51%) and frontline stem cell transplant (38% vs 20%) (P<0.001 for all). In multivariate analyses, CRAB symptoms (OR: 3.22, 95% CI: 1.47, 7.10), high-risk relapse (OR: 1.71, 95% CI: 1.12, 2.62) and prior triplet therapy (OR: 2.16, 95% CI: 1.38, 3.40), but neither CCI nor disability, were associated with triplet SLT. A trend towards triplets among younger patients (<65 vs >75 years, OR: 1.73, 95% CI: 0.99, 3.04) was observed. WHAT IS NEW AND CONCLUSION: The majority of patients did not receive triplet regimens. Treatment selection with triplet therapy for RRMM should carefully consider comorbidities and patient-specific characteristics. PMID- 28833306 TI - Pulsed electromagnetic fields promote the proliferation and differentiation of osteoblasts by reinforcing intracellular calcium transients. AB - Pulsed electromagnetic fields (PEMF) can be used to treat bone-related diseases, but the underlying mechanism remains unclear, especially the process by which PEMFs initiate biological effects. In this study, we demonstrated the effects of PEMF on proliferation and differentiation of osteoblasts using the model of calcium transients induced by high extracellular calcium. Our results showed that PEMF can increase both the percentage of responding cells and amplitude of intracellular calcium transients induced by high extracellular calcium stimulation. Compared with corresponding extracellular calcium levels, PEMF stimulation increased proliferation and differentiation of osteoblasts and related gene expressions, such as insulin-like growth factor 1 (IGF-1), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and osteocalcin (OCN), which can be completely abolished by BAPTA-AM. Moreover, PEMF did not affect proliferation and differentiation of osteoblasts if no intracellular calcium transient was present in osteoblasts during PEMF exposure. Our results revealed that PEMF affects osteoblast proliferation and differentiation through enhanced intracellular calcium transients, which provided a cue to treat bone related diseases with PEMF. Bioelectromagnetics. 38:541-549, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28833307 TI - A synthetic estimator for the efficacy of clinical trials with all-or-nothing compliance. AB - A critical issue in the analysis of clinical trials is patients' noncompliance to assigned treatments. In the context of a binary treatment with all or nothing compliance, the intent-to-treat analysis is a straightforward approach to estimating the effectiveness of the trial. In contrast, there exist 3 commonly used estimators with varying statistical properties for the efficacy of the trial, formally known as the complier-average causal effect. The instrumental variable estimator may be unbiased but can be extremely variable in many settings. The as treated and per protocol estimators are usually more efficient than the instrumental variable estimator, but they may suffer from selection bias. We propose a synthetic approach that incorporates all 3 estimators in a data-driven manner. The synthetic estimator is a linear convex combination of the instrumental variable, per protocol, and as treated estimators, resembling the popular model-averaging approach in the statistical literature. However, our synthetic approach is nonparametric; thus, it is applicable to a variety of outcome types without specific distributional assumptions. We also discuss the construction of the synthetic estimator using an analytic form derived from a simple normal mixture distribution. We apply the synthetic approach to a clinical trial for post-traumatic stress disorder. PMID- 28833308 TI - The underlying structure of visuospatial working memory in children with mathematical learning disability. AB - This study examined visual, spatial-sequential, and spatial-simultaneous working memory (WM) performance in children with mathematical learning disability (MLD) and low mathematics achievement (LMA) compared with typically developing (TD) children. Groups were matched on reading decoding performance and verbal intelligence. Besides statistical significance testing, we used bootstrap confidence interval estimation and computed effect sizes. Children were individually tested with six computerized tasks, two for each visuospatial WM subcomponent. We found that both MLD and LMA children had low visuospatial WM function in both spatial-simultaneous and spatial-sequential WM tasks. The WM deficit was most expressed in MLD children and less in LMA children. This suggests that WM scores are distributed along a continuum with TD children achieving top scores and MLD children achieving low scores. The theoretical and practical significance of findings is discussed. Statement of Contribution What is already known on this subject? Working memory plays an important role in mathematical achievement. Children with mathematical learning disability (MLD) usually have low working memory resources. Conflicting results have been reported concerning the role of VSWM in individuals with MLD. What the present study adds? Children with different degree of impairment in math achievement and typically developing children were tested. Visual, spatial-sequential, and spatial simultaneous working memory tasks were examined. Only spatial-sequential and spatial-simultaneous working memory tasks discriminated the two impairments groups. PMID- 28833309 TI - Attitudes towards care robots among Finnish home care personnel - a comparison of two approaches. AB - STUDY'S RATIONALE: The significance of care robotics has been highlighted in recent years. AIMS AND OBJECTIVE: The article examines the adoption of care robots in home care settings, and in particular Finnish home care personnel's attitudes towards robots. The study compares the importance of the Negative Attitudes towards Robots Scale advanced by Nomura and specific positive attitudes related to the usefulness of care robots for different tasks in the home care. METHODOLOGICAL DESIGN: A cross-sectional study conducted by questionnaire. The research data were gathered from a survey of Finnish home care personnel (n = 200). RESEARCH METHODS: Exploratory factor analysis, Pearson's correlation coefficient and linear regression analysis. MEASURES: The Negative Attitudes towards Robots Scale (NARS), by Nomura, with a specific behavioural intention scale based on Ajzen's theory of planned behaviour, and a measure of positive attitudes towards the usefulness of care robots for different tasks in home care and the promotion of independent living of older persons. RESULTS: The study shows that NARS helps to explain psychological resistance related to the introduction of care robots, although the scale is susceptible to cultural differences. Care personnel's behavioural intentions related to the introduction of robot applications are influenced also by the perception of the usefulness of care robots. STUDY LIMITATIONS: The study is based only on a Finnish sample, and the response rate of the study was relatively small (18.2%), which limits the generalisability of the results. CONCLUSIONS: The study shows that the examination of home care personnel's attitudes towards robots is not justified to focus only on one aspect, but a better explanation is achieved by combining the perspectives of societal attitudes, attitudes related to psychological reactions and the practical care and promotion of the independent living of older people. PMID- 28833311 TI - Simultaneous determination of morphine-6-d-glucuronide, morphine-3-d-glucuronide and morphine in human plasma and urine by ultra-performance liquid chromatography tandem mass spectrometry: Application to M6G injection pharmacokinetic study. AB - A robust ultra-performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) method for the determination of morphine-6-d-glucuronide (M6G), morphine-3 d-glucuronide (M3G) and morphine (MOR) in human plasma and urine has been developed and validated. The analytes of interest were extracted from plasma by protein precipitation. The urine sample was prepared by dilution. Both plasma and urine samples were chromatographed on an Acquity UPLC HSS T3 column using gradient elution. Detection was performed on a Xevo TQ-S tandem mass spectrometer in multiple reaction monitoring mode using positive electrospray ionization. Matrix interferences were not observed at the retention time of the analytes and internal standard, naloxone-D5. The lower limits of quantitation of plasma and urine were 2/0.5/0.5 and 20/4/2 ng/mL for M6G/M3G/MOR, respectively. Calibration curves were linear over the concentration ranges of 2-2000/0.5-500/0.5-500 and 20 20,000/4-4000/2-2000 ng/mL for M6G/M3G/MOR in plasma and urine samples, respectively. The precision was <7.14% and the accuracy was within 85-115%. Furthermore, stability of the analytes at various conditions, dilution integrity, extraction recovery and matrix effect were assessed. Finally, this quantitative method was successfully applied to the pharmacokinetic study of M6G injection in Chinese noncancer pain patients. PMID- 28833310 TI - Transplacental treatment of fetal tachycardia: A systematic review and meta analysis. AB - OBJECTIVE: Multiple transplacental medications can be used to treat fetal tachycardia. We sought to perform a systematic review and meta-analysis to determine whether digoxin, flecainide, or sotalol was the most efficacious therapy for converting fetal tachycardia to sinus rhythm. METHOD: We performed a systematic review and meta-analysis to compare digoxin, flecainide, or sotalol as first-line therapy for fetal tachycardia. Studies were identified by a search of PubMed (Medline), Web of Science, and Scopus. RESULTS: There were 21 studies included. Flecainide (OR: 1.4, 95% CI: 1.1-2.0, I2 = 60%, P = 0.03) and sotalol (OR:1.4, 95% CI:1.1-2.0, I2 = 30%, P = 0.02) were superior to digoxin for conversion of fetal tachycardia to sinus rhythm. In those with hydrops, the benefit over digoxin was more notable for both flecainide (OR: 5.0, 95% CI: 2.5 10.0, I2 = 0%, P < 0.001) and sotalol (OR: 2.5, 95% CI: 1.7-5.0, I2 = 0%, P < 0.001). When limited to atrioventricular reentrant tachycardia, flecainide was superior to digoxin (OR:1.7, 95% CI:1.1-3.3, I2 = 62%, P = 0.03) and sotalol (OR:1.3, 95% CI:1.1-1.7, I2 = 0%, P = 0.01). CONCLUSION: Digoxin should not be first-line therapy for fetal tachycardia, particularly in the presence of hydrops fetalis. Flecainide should be the first-line therapy of choice in atrioventricular reentrant tachycardia. Further study may identify further sub populations responding differently. PMID- 28833312 TI - Complete degradation of dimethyl phthalate by a Comamonas testosterone strain. AB - A Comamonas testosterone bacterial strain, named as DB-7, capable of utilizing dimethyl phthalate (DMP) as sole carbon source and energy for growth was isolated from soil with plastic film mulching by an enrichment culture technique. This bacterium was identified as C. testosterone by 16S rRNA sequence analysis and phospholipid fatty acid profile. DB-7 could degrade more than 99% of 450 mg L-1 DMP within 14 hours, and degraded DMP of different concentrations rapidly. The optimal degradation temperature and pH were 30-35 degrees C and pH 9.0, respectively. The degradation rate of DMP was positively related to inoculum volume of the bacterium. The result of HPLC and LC/MS analysis of metabolic products indicated that the major degrading intermediates were mono-methyl phthalate (MMP) and phthalic acid (PA) during the degradation of DMP by DB-7. Partial sequences of three genes involved in PA metabolism were detected in DB-7, and the expression of phthalate 4, 5-dioxygenase was drastically induced in the presence of DMP and PA. DB-7 is promising to be applied to DMP bioremediation because of its high degrading efficiency. PMID- 28833313 TI - Ecology and identification of environmental fungi and metabolic processes involved in the biodeterioration of Brazilian soapstone historical monuments. AB - : This study aimed to evaluate the action of organic acids produced by the fungal population associated with the biodeterioration process of the Twelve Prophets of Aleijadinho, a set of soapstone sculptures in Congonhas, state of Minas Gerais, Brazil. For this, samples of fungi were obtained from the surface of each of the 12 outdoor stone sculptures that comprise the set of Prophets. The identification of the colonizing filamentous fungi was performed by classical microbiology and molecular methods. Some species of filamentous fungi-dependent cultivation were detected, and the presence of species Aspergillus versicolor, Curvularia lunata, Epicoccum nigrum, Penicillium citrinum and Pseudocercospora norchiensis indicated a connection with the excretion of organic acids. The acids produced by each of these fungal species were analysed quantitatively by chromatographic methods, revealing potential biodeterioration by the action of acidic metabolites excreted in the stone. SIGNIFICANCE AND IMPACT OF THE STUDY: Minas Gerais, Brazil, is vulnerable to the activities of mineral extraction industries, posing an imminent risk to United Nations Educational, Scientific and Cultural Organization (UNESCO) recognized cities, e.g. Congonhas. Many of these municipalities hold many soapstone religious sculptures and historical monuments. Consequently, soapstone is susceptible to filamentous fungi attack causing irreversible biodeterioration. Despite the concern related to nondestructive sampling of 18th century sculptures, in this study, we have discussed the factors that lead to biodeterioration of soapstone due to organic acid excretion by the fungi that damage the stone, thereby providing an insight in conserving and preserving the soapstone monuments. PMID- 28833314 TI - Rapid improvements in emotion regulation predict intensive treatment outcome for patients with bulimia nervosa and purging disorder. AB - OBJECTIVE: Rapid and substantial behavior change (RSBC) early in cognitive behavior therapy (CBT) for eating disorders is the strongest known predictor of treatment outcome. Rapid change in other clinically relevant variables may also be important. This study examined whether rapid change in emotion regulation predicted treatment outcomes, beyond the effects of RSBC. METHOD: Participants were diagnosed with bulimia nervosa or purging disorder (N = 104) and completed >=6 weeks of CBT-based intensive treatment. Hierarchical regression models were used to test whether rapid change in emotion regulation variables predicted posttreatment outcomes, defined in three ways: (a) binge/purge abstinence; (b) cognitive eating disorder psychopathology; and (c) depression symptoms. Baseline psychopathology and emotion regulation difficulties and RSBC were controlled for. RESULTS: After controlling for baseline variables and RSBC, rapid improvement in access to emotion regulation strategies made significant unique contributions to the prediction of posttreatment binge/purge abstinence, cognitive psychopathology of eating disorders, and depression symptoms. DISCUSSION: Individuals with eating disorders who rapidly improve their belief that they can effectively modulate negative emotions are more likely to achieve a variety of good treatment outcomes. This supports the formal inclusion of emotion regulation skills early in CBT, and encouraging patient beliefs that these strategies are helpful. PMID- 28833315 TI - Experiences of being a family member to an older person with diabetes receiving home care services. AB - AIM: To describe family members' experiences of attending to an old person with diabetes receiving home care services, including their interaction with the formal caregivers. METHODS AND RESULTS: The study has a qualitative descriptive design. From May to August 2015, eight family members were interviewed. Interviews were analysed using qualitative content analysis. To describe family members' experiences, the following four themes were identified: Security through patients' self-management skills and diabetes knowledge; Perceived burden due to the old persons' deteriorated health; Security through competent home care services; and Doubt due to personnel's inadequate approach and interaction. CONCLUSION: It is important for personnel in home care services to consider patients' self-management skills and the family members' diabetes knowledge as key aspects in order to limit experiences of burden when the older person with diabetes has deteriorating health. The findings underscore that interaction with home care personnel skilled in managing diabetes helps family members feel secure. PMID- 28833316 TI - Attitudes of mental health professionals towards service user involvement. AB - Patient-centred care and user involvement in healthcare services are much emphasised globally. This study was the first step in a multicentre research project in Finland to improve service users' and carers' opportunities to be more involved in mental health services. The aim of the study was to assess attitudes of professionals towards service user involvement. The data were collected via an online questionnaire from 1069 mental health professionals in four hospital districts. Altogether, 351 professionals responded. Data were analysed using appropriate statistical methods. According to the results, attitudes of healthcare professionals were more positive towards service users' involvement in their own treatment than in other levels of services. There were also differences in gender, age groups, working places and experiences in the attitudes of professionals concerning service users' involvement in their own treatment. These should be taken into account in the future when planning education for mental health professionals. In spite of governmental guidance on service user involvement and the growing body of knowledge of the benefits associated with it, change in attitudes towards user involvement is slow. Special attention should be paid to the attitudes of professionals working in inpatient care and of those with less working experience. PMID- 28833317 TI - Effects of propolis, caffeic acid phenethyl ester, and pollen on renal injury in hypertensive rat: An experimental and theoretical approach. AB - The objective of this study was to evaluate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE; active compound in propolis), and pollen on biochemical oxidative stress biomarkers in rat kidney tissue inhibited by Nomega nitro-L-arginine methyl ester (L-NAME). The biomarkers evaluated were paraoxonase (PON1), oxidative stress index (OSI), total antioxidant status (TAS), total oxidant status (TOS), asymmetric dimethylarginine (ADMA), and nuclear factor kappa B (NF-kappaB). TAS levels and PON1 activity were significantly decreased in kidney tissue samples in the L-NAME-treated group (P < 0.05). The levels of TAS and PONI were higher in the L-NAME plus propolis, CAPE, and pollen groups compared with the L-NAME-treated group. TOS, ADMA, and NF-kappaB levels were significantly increased in the kidney tissue samples of the L-NAME-treated group (P < 0.05). However, these parameters were significantly lower in the L-NAME plus propolis, CAPE, and pollen groups (P < 0.05) compared with rats administered L NAME alone (P < 0.05). Furthermore, the binding energy of CAPE within catalytic domain of glutathione reductase (GR) enzyme as well as its inhibitory mechanism was determined using molecular modeling approaches. In conclusion, experimental and theoretical data suggested that oxidative alterations occurring in the kidney tissue of chronic hypertensive rats may be prevented via active compound of propolis, CAPE administration. PMID- 28833319 TI - Informing Ex Ante Event Studies with Macro-Econometric Evidence on the Structural and Policy Impacts of Terrorism. AB - Economic consequence analysis is one of many inputs to terrorism contingency planning. Computable general equilibrium (CGE) models are being used more frequently in these analyses, in part because of their capacity to accommodate high levels of event-specific detail. In modeling the potential economic effects of a hypothetical terrorist event, two broad sets of shocks are required: (1) physical impacts on observable variables (e.g., asset damage); (2) behavioral impacts on unobservable variables (e.g., investor uncertainty). Assembling shocks describing the physical impacts of a terrorist incident is relatively straightforward, since estimates are either readily available or plausibly inferred. However, assembling shocks describing behavioral impacts is more difficult. Values for behavioral variables (e.g., required rates of return) are typically inferred or estimated by indirect means. Generally, this has been achieved via reference to extraneous literature or ex ante surveys. This article explores a new method. We elucidate the magnitude of CGE-relevant structural shifts implicit in econometric evidence on terrorist incidents, with a view to informing future ex ante event assessments. Ex post econometric studies of terrorism by Blomberg et al. yield macro econometric equations that describe the response of observable economic variables (e.g., GDP growth) to terrorist incidents. We use these equations to determine estimates for relevant (unobservable) structural and policy variables impacted by terrorist incidents, using a CGE model of the United States. This allows us to: (i) compare values for these shifts with input assumptions in earlier ex ante CGE studies; and (ii) discuss how future ex ante studies can be informed by our analysis. PMID- 28833320 TI - Investigation of pharmacokinetics, tissue distribution and excretion of schisandrin B in rats by HPLC-MS/MS. AB - Schisandrin B has received much attention owing to its various biological activities. The present study was aimed at the formulation development of schisandrin B and investigation of the pharmacokinetic profiles, distribution and excretion of schisandrin B in Sprague-Dawley rats. In this study, micronized schisandrin B particles with particle size of 10-20 MUm were chosen as the research object. Chromatographic separation was carried out on a BDS Hypersil C18 column (50 * 2.1 mm, i.d. 3.5 MUm). Schisandrin B and deoxyschizandrin (internal standard) were detected without interference in the multiple reaction monitoring mode with positive electrospray ionization. The pharmacokinetic parameters were calculated by a noncompartmental method. The area under concentration-time curve and the maximum concentration showed a significant difference in gender. The calculated absolute oral bioavailability of schisandrin B was ~55.0% for female rat and 19.3% for male rat. Schisandrin B exhibited linear pharmacokinetics properties within the range of the tested oral dose (10, 20 and 40 mg/kg). After oral administration of schisandrin B, it was extensively distributed in ovary and adipose tissue. The result also showed very low urinary, biliary and fecal excretion of schisandrin B implying that schisandrin B was excreted mainly in the forms of metabolites. PMID- 28833321 TI - Population pharmacokinetic meta-analysis of ramucirumab in cancer patients. AB - AIMS: Ramucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks binding of VEGF-A, VEGF-C and VEGF-D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach. METHODS: A total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2 and 3 clinical trials in patients with various cancer indications were included in the analysis. Ramucirumab was administered as an intravenous infusion over 1 h at 8 mg kg-1 every 2 weeks or 10 mg kg-1 every 3 weeks. A series of pharmacostatistical models were developed to describe the concentration data. The best model was used to evaluate patient factors for their effect on ramucirumab pharmacokinetics. RESULTS: The pharmacokinetics of ramucirumab were well characterized by a two-compartment model. Mean population estimates of clearance, volume of distribution and half-life for a typical 68-kg patient were 0.0148 l h-1 , 5.30 l and 13.4 days, respectively. A modest relationship was observed between body weight and ramucirumab disposition; clearance and central compartment volume increased with body weight. No other patient characteristics were shown to influence the disposition of ramucirumab in this patient population. CONCLUSIONS: The final model adequately described the concentration time profile of ramucirumab in patients with a range of cancer indications. The model confirmed that a weight-normalized dosing regimen is appropriate for ramucirumab therapy. Dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment. PMID- 28833322 TI - MATERNAL TRAUMA AFFECTS PRENATAL MENTAL HEALTH AND INFANT STRESS REGULATION AMONG PALESTINIAN DYADS. AB - We examined how diverse and cumulated traumatic experiences predicted maternal prenatal mental health and infant stress regulation in war conditions and whether maternal mental health mediated the association between trauma and infant stress regulation. Participants were 511 Palestinian mothers from the Gaza Strip who reported exposure to current war trauma (WT), past childhood emotional (CEA) and physical abuse, socioeconomic status (SES), prenatal mental health problems (posttraumatic stress disorder and depression symptoms), and perceived stress during their secondtrimester of pregnancy as well as infant stress regulation at 4 months. While all trauma types were associated with high levels of prenatal symptoms, CEA had the most wide-ranging effects and was uniquely associated with depression symptoms. Concerning infant stress regulation, mothers' CEA predicted negative affectivity, but only among mothers with low WT. Against hypothesis, the effects of maternal trauma on infant stress regulation were not mediated by mental health symptoms. Mothers' higher SES was associated with better infant stress regulation whereas infant prematurity and male sex predisposed for difficulties. Our findings suggest that maternal childhood abuse, especially CEA, should be a central treatment target among war-exposed families. Cumulated psychosocial stressors might increase the risk for transgenerational problems. PMID- 28833323 TI - Transporter genes ABCG2 rs2231142 and ABCB1 rs1128503 polymorphisms and atorvastatin response in Chilean subjects. AB - WHAT IS KNOWN AND OBJECTIVE: Statins are first-line therapy for reducing high cholesterol levels. However, response to these drugs shows high interindividual variability. We aimed to investigate the influence of two single nucleotide polymorphisms (SNP) (ABCB1 rs1128503 and ABCG2 rs2231142) in the ABC transporter genes on response to short-term low-dose atorvastatin in Chilean hypercholesterolaemic patients. METHODS: We studied 127 Chilean hypercholesterolaemic patients treated with 10 mg/d atorvastatin for 4 weeks. The lipid profile was determined before and after drug administration. Genotyping of the rs1128503 and rs2231142 variants was performed using TaqMan(r) Drug Metabolism Genotyping Assays. RESULTS AND DISCUSSION: Genotype distribution for all polymorphisms investigated was consistent with the Hardy-Weinberg equilibrium. Atorvastatin reduced TC, LDL-C and TG concentrations (P<.05), whereas HDL-C levels were found to be increased (P<.05). Minor allele frequencies for rs1128503 and rs2231142 variants were 0.453 and 0.075, respectively. In this study, patients prescribed with short-term low-dose atorvastatin and carrying ABCB1 (rs1128503) or ABCG2 (rs2231142) SNPs did not show differences in LDL-C response (P>.05). WHAT IS NEW AND CONCLUSION: The ABCB1 SNP was not associated with response to atorvastatin in Chilean subjects. The few ABCG2 421A homozygotes did not allow meaningful inferences to be made for this polymorphism. PMID- 28833324 TI - Antibacterials dispensed in the community comprise 85%-95% of total human antibacterial consumption. AB - WHAT IS KNOWN AND OBJECTIVE: Interventions intended to slow the emergence and spread of antibacterial resistance through enhanced antimicrobial stewardship will be more effective if informed by an accurate knowledge of current patterns of antibacterial consumption. For example, knowledge of the relative magnitude of community antibacterial consumption in relation to hospital antibacterial consumption within each nation or region should help guide decisions about the relative importance of community and hospital antimicrobial stewardship programmes. It is commonly stated that community antibacterial consumption comprises approximately 80% of total national antibacterial consumption. We aimed to determine this proportion across a large range of nations. METHODS: We measured community and hospital antibacterial consumption in New Zealand during 2015, from both reimbursement and purchase data, and compared the New Zealand data with those reported from a large range of other nations during similar time periods. RESULTS AND DISCUSSION: Community antibacterial consumption comprised approximately 85%-95% of total antibacterial consumption in all nations for which data were available, and in New Zealand comprised a higher proportion than in any other nation. The proportion of total antibacterial consumption comprised by community consumption was significantly higher in countries with relatively high levels of total antibacterial consumption than in countries with relatively low levels of total antibacterial consumption. WHAT IS NEW AND CONCLUSION: The high proportion of total antibacterial consumption comprised by community antibacterial consumption suggests devoting particular attention to improved community antimicrobial stewardship. These results suggest that improving antimicrobial stewardship in the community may provide greater overall benefits in combating antibacterial resistance than improving antimicrobial stewardship in hospitals. PMID- 28833325 TI - Facilitating the transition from a nursing student to a Registered Nurse in the final clinical practicum: a scoping literature review. AB - BACKGROUND: Transition from a nursing student to a Registered Nurse is a stressful and challenging process. Different postgraduate residency and orientation programmes have been developed to ease the first year of employment, but less attention has been paid to pregraduate programmes and how the final clinical practicum of nursing education should be conducted to facilitate this transition. AIM: To review the empirical studies concerning interventions that aim to facilitate the transition from nursing student to Registered Nurse in the final clinical practicum of nursing education. The aim was to scrutinise the structures and contents of the interventions and factors connected with the facilitated transition. METHOD: A scoping literature review was conducted with systematic searches in three electronic databases: CINAHL, MEDLINE and ERIC. The searches were limited to studies that were written in English, had available abstract and were published between 2005 and 2016. Two researchers assessed the studies regarding their eligibility with reference to the inclusion and exclusion criteria, and 17 articles were included in this review. Inductive content analysis was used to categorise the contents of studies. RESULTS: The structures of the interventions described included: the participation, learning environment, amount of clinical work, supervisor criteria and supervision methods. The contents of the interventions included supervisor support, transition supportive learning activities and the student's practicum duties. The factors that were connected with facilitated transition were the quality of the supervision, adjusting to a professional nurse's role, achieved comfort and confidence and achieved competence. CONCLUSION: This scoping review offers insight into the diversity of interventions facilitating transition implemented in the final clinical practicum of nursing education. In order to unify these practices and determine the elements necessary to include, studies with stronger designs need to be conducted. PMID- 28833326 TI - Projected increase in obesity and non-alcoholic-steatohepatitis-related liver transplantation waitlist additions in the United States. AB - : Nonalcoholic steatohepatitis (NASH) cirrhosis is the fastest growing indication for liver transplantation (LT) in the United States. We aimed to determine the temporal trend behind the rise in obesity and NASH-related additions to the LT waitlist in the United States and make projections for future NASH burden on the LT waitlist. We used data from the Organ Procurement and Transplantation Network database from 2000 to 2014 to obtain the number of NASH-related LT waitlist additions. The obese population in the United States from 2000 to 2014 was estimated using data from the U.S. Census Bureau and the National Health and Nutrition Examination Survey. Based on obesity trends, we established a time lag between obesity prevalence and NASH-related waitlist additions. We used data from the U.S. Census Bureau on population projections from 2016 to 2030 to forecast obesity estimates and NASH-related LT waitlist additions. From 2000 to 2014, the proportion of obese individuals significantly increased 44.9% and the number of NASH-related annual waitlist additions increased from 391 to 1,605. Increase in obesity prevalence was strongly associated with LT waitlist additions 9 years later in derivation and validation cohorts (R2 = 0.9). Based on these data, annual NASH-related waitlist additions are anticipated to increase by 55.4% (1,354-2,104) between 2016 and 2030. There is significant regional variation in obesity rates and in the anticipated increase in NASH-related waitlist additions (P < 0.01). CONCLUSION: We project a marked increase in demand for LT for NASH given population obesity trends. Continued public health efforts to curb obesity prevalence are needed to reduce the projected future burden of NASH. (Hepatology 2017). PMID- 28833327 TI - Does the "script" need a rewrite? Is medication advice in television medical dramas appropriate? AB - WHAT IS KNOWN AND OBJECTIVE: Television medical dramas depict the healthcare industry and draw considerable interest from the public, while pharmacists play an integral part in providing medication-related advice to the public and other health practitioners in real life. The main objective of this retrospective, observational study was to assess the appropriateness of medication advice given in televised medical dramas and how frequently pharmacists were involved in providing the medication advice. METHODS: Show selection was based on fictional series with a medical drama theme and having the highest viewership. Approximately 100 randomly selected hours of five medical television dramas (House, Grey's Anatomy, Nurse Jackie, Doc Martin and Royal Pains) were assessed for the appropriateness of advice given based on the medication indicated, number of safety checks performed, and the level of adherence to standard clinical guidelines. The appropriateness of medication advice was assessed as appropriate, mostly appropriate, partially appropriate and inappropriate using a piloted, 0-6 point scale. Other parameters recorded included patient demographics, health professionals involved, and the categories of medicines. RESULTS AND DISCUSSIONS: Medications were mentioned on 424 occasions (on average four times per hour), including 239 occasions where medication advice was given. A pharmacist was involved in giving medication advice only 16 times (7%). Using the assessment tool, overall, medication advice was deemed to be appropriate 24% of the time, mostly appropriate 34%, partially appropriate 13% and inappropriate 7%. Although the medication advice given was often for the correct indication and the advice somewhat followed clinical guidelines, it frequently omitted adequate safety checks. Doc Martin had the highest mean appropriateness score, whereas House and Grey's Anatomy had the lowest. WHAT IS NEW AND CONCLUSIONS: Medication was often used for the correct indication in television medical dramas; however, key safety checks were frequently omitted and other medication-related advice, including dose, was less reliable and accurate. Pharmacists were rarely involved in providing medication advice. Viewers should not base medication-related decisions solely on what they see in television medical dramas, and any medication-related advice should be interpreted with extreme caution. PMID- 28833328 TI - Peptide Mimetics: Fast-Forward Look. PMID- 28833329 TI - Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in Chinese liver transplant patients. AB - WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling. METHODS: A total of 47 sets of rich-time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients. The pathophysiological data of these patients were recorded. CYP3A5*3 and ABCB1 genotypes were determined for each patient. The PPK model for TAC was established by nonlinear mixed-effects modelling (nonmem). The impact of pathophysiology and genotype on PPK parameters was evaluated. Bayesian estimators for the area under concentration-time curve (AUC) of TAC were validated. RESULTS: A two-compartment model with lag time was found to be the most suitable model for the pooled full PK and TDM data for Chinese liver transplant patients. The CL/F, V2 /F, Q/F, V3 /F, Ka and lag time were 17.4+/-0.81 L/h, 165+/-44.1 L, 54.9+/-25.8L/h, 594+/ 87.5 L, 0.51+/-0.095 L/h and 1.57+/-0.34 h. Post-operative day (POD), creatinine clearance (CLcr) and ABCB1 C3435T genotypes were found to have significant influences on CL/F (P<.01). ABCB1 C3435T genotypes showed a significant correlation with V2 /F (P<.01). C0 -C2 and C0 -C2 -C4 were shown to be suitable for the estimation of AUC in Chinese liver transplant patients. WHAT IS NEW AND CONCLUSION: A PPK model for TAC was established successfully in Chinese liver transplant patients. POD, CLcr and ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The AUC of TAC in Chinese liver transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed. PMID- 28833330 TI - Patients' intention to consume prescribed and non-prescribed medicines: A study based on the theory of planned behaviour in selected European countries. AB - WHAT IS KNOWN AND OBJECTIVE: Polypharmacy has a significant impact on patients' health with overall expenditure on over-the-counter (OTC) medicines representing a substantial burden in terms of cost of treatment. The aim of this study, which was conducted within the framework of a European Project funded by the European Union under the Seventh Framework Programme and was entitled OTC-SOCIOMED, was to report on possible determinants of patient behaviour regarding the consumption of medicines, and particularly OTCs, in the context of primary care. METHODS: A multicentre, cross-sectional study was designed and implemented in well-defined primary healthcare settings in Cyprus, the Czech Republic, France, Greece, Malta and Turkey. Patients completed a questionnaire constructed on the basis of the theory of planned behaviour (TPB), which was administered via face-to-face interviews. RESULTS AND DISCUSSION: The percentage of patients who had consumed prescribed medicines over a 6-month period was consistently high, ranging from 79% in the Czech Republic and 82% in Turkey to 97% in Malta and 100% in Cyprus. Reported non-prescribed medicine consumption ranged from 33% in Turkey to 92% in the Czech Republic and 97% in Cyprus. TPB behavioural antecedents explained 43% of the variability of patients' intention to consume medicines in Malta and 24% in Greece, but only 3% in Turkey. Subjective norm was a significant predictor of the intention to consume medicines in all three countries (Greece, Malta and Turkey), whereas attitude towards consumption was a significant predictor of the expectation to consume medicines, if needed. WHAT IS NEW AND CONCLUSION: This study shows that parameters such as patients' beliefs and influence from family and friends could be determining factors in explaining the high rates of medicine consumption. Factors that affect patients' behavioural intention towards medicine consumption may assist in the formulation of evidence-based policy proposals and inform initiatives and interventions aimed at increasing the appropriate use of medicines. PMID- 28833332 TI - Pharmacotherapeutic Management of Gastrointestinal Bleeding in Patients with Continuous-Flow Left Ventricular Assist Devices. AB - Continuous-flow left ventricular assist devices (CF-LVADs) have become an integral component of the management in patients with advanced heart failure, serving as destination therapy or as a bridge to heart transplantation. Despite significant advances in the design and longevity of the device, the ongoing risk for bleeding remains a significant concern. The genesis of gastrointestinal bleeding (GIB) in patients with CF-LVADs is likely multifactorial and may include components of acquired von Willebrand disease, angiodysplasia, and gastrointestinal arteriovenous malformations, as well as additional risk factors such as history of GIB and increased age. Several pharmacotherapy options have been used, but the data surrounding their overall efficacy remain sparse. The necessity for larger prospective studies is essential to further advance the management of this devastating complication. Within this review, we discuss the known pathophysiologic process of CF-LVAD-related GIB and highlight the therapeutic options discussed within the literature. In addition, we discuss potential therapeutic options based on mechanisms of action as they correlate to known pathophysiologic processes of CF-LVAD-related GIB. Finally, we provide recommendations for constructing drug therapy regimens in patients with CF-LVADs who develop GIB. PMID- 28833333 TI - Hepatic function of FcRn revealed: Implications for overcoming drug-mediated hepatotoxicity. PMID- 28833331 TI - A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. AB - : The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C?C chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) >=4, and LF (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was >=2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by >=1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent-to-treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. CONCLUSION: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754-1767). PMID- 28833334 TI - Parents' voices: "Our process of advocating for our child with autism." A meta synthesis of parents' perspectives. AB - BACKGROUND: Advocacy has been described by parents of children with autism as an important coping strategy, enabling them to move forward by redirecting emotions into actions. A key factor in the development of collaborative and constructive partnerships between service providers and parents is having an understanding of how parents engage in advocacy and the support needed to do so. This meta synthesis was undertaken to consolidate in-depth qualitative data from parents' perspectives of the process that they use to advocate for their children with autism. METHODS: A qualitative meta-synthesis was conducted, whereby 15 databases were systematically searched. Thirty-one studies were identified and appraised using an adapted version of the Critical Appraisal Skills Programme tool. Data were synthesized into themes through the steps of review, meta-aggregation, integration, and interpretation. RESULTS: The voices of 1,662 parents are presented describing the process of advocacy in the stages of seeking a diagnosis, seeking self-education, and taking action. Taking action includes 2 subthemes: seeking, access, and use of support services and community engagement and educating others. CONCLUSIONS: Results highlight the significant impact that positive experiences with first-line professionals have during the diagnosis process and how these experiences lay the foundation for all future relationships with other service providers. Important implications arise from this meta synthesis for service providers in supporting parents' advocacy and hence building constructive relationships with families with a child with autism. PMID- 28833335 TI - Effect of genetic European taurine ancestry on milk yield of Ankole-Holstein crossbred dairy cattle in mixed smallholders system of Burundi highlands. AB - Different breeding systems associated with specific bovine genetic resources have coexisted in Burundi. To prepare for the development of a national action plan for the improvement of bovine genetic resources in Burundi, we aimed at performing genetic characterization of Ankole and Ankole * European crossbred individuals and assessing the effect of European ancestry on milk productivity of cows kept under the mixed crops livestock system. To that end, we genotyped 37 Ankole and 138 crossbred individuals on 42 636 SNPs and combined these genotypes with those from 21 cattle breeds, representative of the bovine genetic diversity. We also measured milk yield not suckled and estimated suckled milk. Given the results, we confirmed the indicine * African taurine admixed origin of the Ankole in Burundi and showed that crossbred individuals present a high proportion of European ancestry (i.e. 57% on average). As the proportion of European ancestry increased, milk yield increased by 0.03 +/- 0.01 l/day, at a lower extent than expected. We also observed that breeders were unable to correctly evaluate the European proportion in their livestock. Our results may provide useful information for objective dairy breeding in Burundi. As an example, an ex-situ conservation program of Ankole within the framework of value chains is proposed as an accompanying strategy to improve the sustainability of the crossbreeding program. PMID- 28833336 TI - Evaluation of nasal and nasopharyngeal swab collection for the detection of Epstein-Barr virus in nasopharyngeal carcinoma. AB - Epstein-Barr virus detection using nasopharyngeal swabs has been suggested as a potential screening test that could improve the specificity of current EBV-based serological assays. However, application requires insertion of the swab deep into the nasopharynx, a procedure not amenable to non-clinic screening. We reasoned that swabbing the more easily accessible nasal cavity might provide an appealing alternative for NPC detection. Patients > 18 years of age diagnosed with histologically confirmed NPC were recruited from the Otolaryngology Department at the National Taiwan University Hospital. ENT clinicians collected both nasal and nasopharyngeal swabs. EBV DNA and cellular beta-globulin DNA were quantified using quantitative PCR targeting a highly-conserved region of the BKRF1 gene. EBV DNA was detectable (non-zero) in all 34 nasopharyngeal swabs and above the positivity threshold of 1666 EBV copies in 30 (88.2%) patients. EBV DNA was detectable in 50% of 34 nasal swabs and above the positivity threshold in four (11.8%) patients. Average EBV DNA levels were >3-fold higher (P < 0.001) in nasopharyngeal compared to nasal swabs. Among the 17 NPC patients with detectable EBV DNA in both swab types, we observed correlation (P < 0.01) between EBV DNA measurements. Our data represent the first evaluation of EBV DNA collected from nasal swabs. Given current EBV DNA amplification techniques, nasopharyngeal swabs remain more sensitive than nasal swabs for NPC detection. PMID- 28833337 TI - Maternal Body Mass Index and Regional Anaesthesia Use at Term: Prevalence and Complications. AB - BACKGROUND: There is an evidence gap regarding the use of regional anaesthesia (epidural, spinal, or combined epidural/spinal anaesthesia) and associated complications by maternal body mass index (BMI). We examine associations between regional anaesthesia, mode of delivery, and regional anaesthesia complications by pre-pregnancy BMI categories among term deliveries. METHODS: Retrospective cohort study of births in California, 2007-2010, utilizing linked birth certificate data and patient discharge data. Outcomes were mode of delivery (among laboured deliveries) and select regional anaesthesia complications. Multivariable Poisson regression was used to adjust for maternal characteristics. RESULTS: In women undergoing labour (i.e. laboured delivery), women with higher BMI categories were more likely to receive regional analgesia in a dose-response fashion (adjusted risk ratio [RR] 1.10, 95% confidence interval [CI] 1.10, 1.11 for primiparous women with category I obesity), and in those receiving regional anaesthesia, were less likely to deliver vaginally (e.g. RR 0.85, 95% CI 0.84, 0.85 for the same category of women). Regional anaesthesia complications displayed a complex relationship with maternal BMI, with women in intermediate obesity categories having decreased odds as compared to normal-weight women, and women in the highest BMI category having a twofold increased risk of complications (RR 2.34, 95% CI 1.37, 4.02 for primiparous women). CONCLUSION: Labouring women in higher BMI categories were more likely to receive regional anaesthesia and more likely to deliver via caesarean compared to normal weight women and women without regional anaesthesia. Rates of anaesthesia complications were highest among women in the highest BMI category. PMID- 28833338 TI - Reptin regulates insulin-stimulated Akt phosphorylation in hepatocellular carcinoma via the regulation of SHP-1/PTPN6. AB - Hepatocellular carcinoma (HCC) is the main primary cancer of the liver. Many studies have shown that insulin resistance is a risk factor for HCC. We previously discovered the overexpression and oncogenic role of the Reptin/RUVBL2 ATPase in HCC. Here, we found that Reptin silencing enhanced insulin sensitivity in 2 HCC cell lines, as shown by a large potentiation of insulin-induced AKT phosphorylation on Ser473 and Thr308, and of downstream signalling. Reptin silencing did not affect the tyrosine phosphorylation of the insulin receptor nor of IRS1, but it enhanced the tyrosine phosphorylation of the p85 subunit of PI3K. The expression of the SHP-1/PTPN6 phosphatase, which dephosphorylates p85, was reduced after Reptin depletion. Forced expression of SHP-1 restored a normal AKT phosphorylation after insulin treatment in cells where Reptin was silenced, demonstrating that the downregulation of SHP1 is mechanistically linked to increased Akt phosphorylation. In conclusion, we have uncovered a new function for Reptin in regulating insulin signalling in HCC cells via the regulation of SHP-1 expression. We suggest that the regulation of insulin sensitivity by Reptin contributes to its oncogenic action in the liver. PMID- 28833339 TI - An ethnographic investigation of healthcare providers' approaches to facilitating person-centredness in group-based diabetes education. AB - AIM: To investigate approaches among healthcare providers (HCPs) that support or hinder person-centredness in group-based diabetes education programmes targeting persons with type 2 diabetes. METHODS: Ethnographic fieldwork in a municipal and a hospital setting in Denmark. The two programmes included 21 participants and 10 HCPs and were observed over 5 weeks. Additionally, 10 in-depth semi-structured interviews were conducted with patients (n = 7) and HCPs (n = 3). Data were analysed using systematic text condensation. RESULTS: Hindering approaches included a teacher-centred focus on delivering disease-specific information. Communication was dialog based, but HCPs primarily asked closed-ended questions with one correct answer. Additional hindering approaches included ignoring participants with suboptimal health behaviours and a tendency to moralize that resulted in feelings of guilt among participants. Supporting approaches included letting participants set the agenda using broad, open-ended questions. DISCUSSION: Healthcare providers are often socialized into a biomedical approach and trained to be experts. However, person-centredness involves redefined roles and responsibilities. Applying person-centredness in practice requires continuous training and supervision, but HCPs often have minimum support for developing person-centred communication skills. Techniques based on motivational communication, psychosocial methods and facilitating group processes are effective person-centred approaches in a group context. CONCLUSION: Teacher centredness undermined person-centredness because HCPs primarily delivered disease-specific recommendations, leading to biomedical information overload for participants. PMID- 28833340 TI - Emergency Department Recognition of Mental Disorders and Short-Term Risk of Repeat Self-Harm Among Young People Enrolled in Medicaid. AB - Previous studies of adults have shown protective associations between clinical recognition of a mental disorder in the emergency department and short-term risk of repeat self-harm. Similar studies of young self-harm patients are lacking. We conducted a retrospective longitudinal cohort analysis of national Medicaid claims data in patients aged 10-19 years with self-harm who were discharged from emergency departments to the community (N = 2,703). Emergency department mental disorder recognition was not associated with a significant change in repeat self harm visits during the 30-day follow-up period. Future studies should assess whether other aspects of emergency care influence short-term risk of repeat self harm. PMID- 28833341 TI - Gene and environment interactions in autism risk: Reflections on the carnitine deficiency hypothesis by Beaudet (Comment on DOI 10.1002/bies.201700012). PMID- 28833342 TI - The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China. AIM: To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage. METHODS: Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre defined criteria. RESULTS: One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis. CONCLUSIONS: HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes. PMID- 28833343 TI - Correlates of androgens in wild male Barbary macaques: Testing the challenge hypothesis. AB - Investigating causes and consequences of variation in hormonal expression is a key focus in behavioral ecology. Many studies have explored patterns of secretion of the androgen testosterone in male vertebrates, using the challenge hypothesis (Wingfield, Hegner, Dufty, & Ball, 1990; The American Naturalist, 136(6), 829 846) as a theoretical framework. Rather than the classic association of testosterone with male sexual behavior, this hypothesis predicts that high levels of testosterone are associated with male-male reproductive competition but also inhibit paternal care. The hypothesis was originally developed for birds, and subsequently tested in other vertebrate taxa, including primates. Such studies have explored the link between testosterone and reproductive aggression as well as other measures of mating competition, or between testosterone and aspects of male behavior related to the presence of infants. Very few studies have simultaneously investigated the links between testosterone and male aggression, other aspects of mating competition and infant-related behavior. We tested predictions derived from the challenge hypothesis in wild male Barbary macaques (Macaca sylvanus), a species with marked breeding seasonality and high levels of male-infant affiliation, providing a powerful test of this theoretical framework. Over 11 months, 251 hr of behavioral observations and 296 fecal samples were collected from seven adult males in the Middle Atlas Mountains, Morocco. Fecal androgen levels rose before the onset of the mating season, during a period of rank instability, and were positively related to group mating activity across the mating season. Androgen levels were unrelated to rates of male-male aggression in any period, but higher ranked males had higher levels in both the mating season and in the period of rank instability. Lower androgen levels were associated with increased rates of male-infant grooming during the mating and unstable periods. Our results generally support the challenge hypothesis and highlight the importance of considering individual species' behavioral ecology when testing this framework. PMID- 28833344 TI - Radioembolization for hepatocellular carcinoma: Statistical confirmation of improved survival in responders by landmark analyses. AB - : Does imaging response predict survival in hepatocellular carcinoma (HCC)? We studied the ability of posttherapeutic imaging response to predict overall survival. Over 14 years, 948 patients with HCC were treated with radioembolization. Patients with baseline metastases, vascular invasion, multifocal disease, Child-Pugh > B7, and transplanted/resected were excluded. This created our homogeneous study cohort of 134 patients with Child-Pugh <= B7 and solitary HCC. Response (using European Association for Study of the Liver [EASL] and Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1] criteria) was associated with survival using Landmark and risk-of-death methodologies after reviewing 960 scans. In a subanalysis, survival times of responders were compared to those of patients with stable disease (SD) and progressive disease (PD). Uni/multivariate survival analyses were performed at each Landmark. At the 3-month Landmark, responders survived longer than nonresponders by EASL (hazard ratio [HR], 0.46; confidence interval [CI], 0.26 0.82; P = 0.002) but not RECIST 1.1 criteria (HR, 0.70; CI, 0.37-1.32; P = 0.32). At the 6-month Landmark, responders survived longer than nonresponders by EASL (HR, 0.32; CI, 0.15-0.77; P < 0.001) and RECIST 1.1 criteria (HR, 0.50; CI, 0.29 0.87; P = 0.021). At the 12-month Landmark, responders survived longer than nonresponders by EASL (HR, 0.34; CI, 0.15-0.77; P < 0.001) and RECIST 1.1 criteria (HR, 0.52; CI 0.27-0.98; P = 0.049). At 6 months, risk of death was lower for responders by EASL (P < 0.001) and RECIST 1.1 (P = 0.0445). In subanalyses, responders lived longer than patients with SD or PD. EASL response was a significant predictor of survival at 3-, 6-, and 12-month Landmarks on uni/multivariate analyses. CONCLUSION: Response to radioembolization in patients with solitary HCC can prognosticate improved survival. EASL necrosis criteria outperformed RECIST 1.1 size criteria in predicting survival. The therapeutic objective of radioembolization should be radiologic response and not solely to prevent progression. (Hepatology 2018;67:873-883). PMID- 28833345 TI - Contemporary Time Trends in Use of Antiplatelet Agents Among Patients with Acute Coronary Syndrome and Comorbid Diabetes Mellitus or Chronic Kidney Disease. AB - STUDY OBJECTIVE: To describe contemporary trends of P2Y12 inhibitor use in patients with acute coronary syndrome (ACS) and comorbid diabetes mellitus (DM) and/or chronic kidney disease (CKD) who have a higher risk of recurring ACS and may benefit from treatment with higher efficacy third-generation agents (prasugrel and ticagrelor). DESIGN: Observational cohort study. SETTING: A large U.S. commercial insurance program (2009-2015). PATIENTS: P2Y12 inhibitor initiated within 2 weeks after an ACS event. MEASUREMENTS AND MAIN RESULTS: We identified 98,649 P2Y12 inhibitor initiators, of whom 24.5% had comorbid DM (no CKD), 10.5% had CKD (no DM), and 12.6% had DM and CKD. Overall, 85.2% of patients initiated clopidogrel, followed by prasugrel (11.6%) and ticagrelor (3.2%). Prasugrel use decreased over time irrespective of preexisting DM and/or CKD; ticagrelor use increased. In logistic regression models accounting for patient demographics and clinical covariates, preexisting DM alone was not associated with prasugrel or ticagrelor versus clopidogrel treatment initiation; however, having CKD with or without DM significantly reduced the likelihood of receiving prasugrel versus clopidogrel (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.74-0.88 for CKD alone; OR 0.91, 95% CI 0.83-0.98 for DM and CKD). Comorbid DM and CKD reduced the odds of initiating ticagrelor versus clopidogrel (OR 0.80, 95% CI 0.70-0.92). PRINCIPAL CONCLUSIONS: We observed lower or similar use of prasugrel and ticagrelor compared with clopidogrel in patients with ACS and comorbid DM and/or CKD. Given the potential for worse clinical outcomes with clopidogrel in these patients, our findings highlight the need to investigate the implications of these trends on recurrent ACS and bleeding events. PMID- 28833346 TI - Repurposing Valproate, Enteral Clonidine, and Phenobarbital for Comfort in Adult ICU Patients: A Literature Review with Practical Considerations. AB - Provision of adequate sedation is a fundamental part of caring for critically ill patients. Propofol, dexmedetomidine, and benzodiazepines are the most commonly administered sedative medications for adult patients in the intensive care unit (ICU). These agents are limited by adverse effects, need for a monitored environment for safe administration, and lack of universal effectiveness. Increased interest has recently been expressed about repurposing older pharmacologic agents for patient comfort in the ICU. Valproate, enteral clonidine, and phenobarbital are three agents with increasing evidence supporting their use. Potential benefits associated with their utilization are cost minimization and safe administration after transition out of the ICU. This literature review describes the historical context, pharmacologic characteristics, supportive data, and practical considerations associated with the administration of these agents for comfort in critically ill adult patients. PMID- 28833347 TI - A semiparametric joint model for terminal trend of quality of life and survival in palliative care research. AB - Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients' diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial despite potentially beneficial treatment. Often longitudinal QOL and survival data are highly correlated which, in the face of censoring, makes it challenging to properly analyze and interpret terminal QOL trend. To address these issues, we propose a novel semiparametric statistical approach to jointly model the terminal trend of QOL and survival data. There are two sub-models in our approach: a semiparametric mixed effects model for longitudinal QOL and a Cox model for survival. We use regression splines method to estimate the nonparametric curves and AIC to select knots. We assess the model performance through simulation to establish a novel modeling approach that could be used in future palliative care research trials. Application of our approach in a recently completed palliative care clinical trial is also presented. PMID- 28833348 TI - A modification to improve the reliability of [11 C]CN- production in the GE radiochemistry system. AB - We report herein a modification to a component of the GE radiochemistry system that increases the yield and reliability of [11 C]CN- production from [11 C]carbon dioxide. PMID- 28833349 TI - A mixed-methods analysis of logging injuries in Montana and Idaho. AB - BACKGROUND: Despite advances in mechanization, logging continues to be one of the most dangerous occupations in the United States. Logging in the Intermountain West region (Montana and Idaho) is especially hazardous due to steep terrain, extreme weather, and remote work locations. METHODS: We implemented a mixed methods approach combining analyses of workers' compensation claims and focus groups to identify factors associated with injuries and fatalities in the logging industry. RESULTS: Inexperienced workers (>6 months experience) accounted for over 25% of claims. Sprain/strain injuries were the most common, accounting for 36% of claims, while fatalities had the highest median claim cost ($274 411). Focus groups identified job tasks involving felling trees, skidding, and truck driving as having highest risk. CONCLUSIONS: Injury prevention efforts should focus on training related to safe work methods (especially for inexperienced workers), the development of a safety culture and safety leadership, as well as implementation of engineering controls. PMID- 28833351 TI - User participation in a Municipal Acute Ward in Norway: dilemmas in the interface between policy ideals and work conditions. AB - User participation has become an increasingly important principle in health care over the last few decades. Healthcare professionals are expected to involve patients in treatment decisions. Clear guidance as to what this should entail for professionals in clinical work is not accounted for in legislation. In this study, we explore how healthcare professionals in a Municipal Acute Ward perceived, experienced and performed user participation. The ward represents a new short-time service model for emergency assistance in Norway. We focused on the challenges the professionals faced in clinical work and how they dealt with these. Data were drawn from qualitative interviews with 11 healthcare professionals and from 10 observations in relation to previsits and physician's rounds in the ward. Transcripts of interviews and observations were analysed using a method for systematic text condensation. In the analysis, we applied Lipsky's perspective on dilemmas of street-level bureaucrats. The results show that that the professionals perceived user participation as an important and natural part of their work. They experienced difficulties related to collaboration with patients, caregivers, and professionals in other services, and with framework conditions that caused conflicting expectations, responsibility, and priorities. The professionals seemed to take a pragmatic approach to user participation, managing it within narrow perspectives. Our study indicates that the participants dealt with the dilemmas at the cost of user participation. The results demonstrate that there is a gap between the outlined health policy and the professionals' opportunities to fulfil this policy in clinical work regarding user participation. The policy decision-makers should recognise the balancing work required of healthcare professionals to deal with difficulties in clinical work. The knowledge that professionals possess as performers of services and the need for valuing in policy processes should be acknowledged. PMID- 28833350 TI - Hypothalamic CRF1 receptor mechanisms are not sufficient to account for binge like palatable food consumption in female rats. AB - OBJECTIVE: The present study evaluated the effect of systemic injection of the CRF1 receptor antagonist R121919, the corticosterone synthesis inhibitor metyrapone and central amygdala (CeA) injections of the nonselective CRF antagonist D-Phe-CRF(12-41) in rats in which binge eating was evoked by stress and cycles of food restriction. METHOD: Female rats were subjected or not to repeated cycles of regular chow food restriction/ad libitum feeding during which they were also given limited access (2 h) to palatable food. On the test day, rats were either exposed or not to the sight of the palatable food for 15 min without allowing access, before assessing food consumption. RESULTS: Systemic injections of R121919, but not of the metyrapone, blocked binge-like eating behavior. Restricted and stressed rats showed up-regulation of crh1 receptor mRNA signal in the bed nucleus of the stria terminalis and CeA but not in basolateral amygdala (BLA) or in the paraventricular nucleus. Injection D-Phe-CRF(12-41) in CeA but not in the BLA-blocked binge-like eating behavior. DISCUSSION: These findings demonstrate that extra-hypothalamic CRF1 receptors, rather than those involved in endocrine functions, are involved in binge eating and the crucial role of CRF receptors in CeA. CRF1 receptor antagonism may represent a novel pharmacological treatment for binge-related eating disorders. PMID- 28833352 TI - Colorectal cancer in Taiwan: A case-control retrospective analysis of the impact of a case management programme on refusal and discontinuation of treatment. AB - AIMS: The purposes of this study were to identify the impact of a case management programme on the related factors of refusing treatment or discontinuing treatment in Taiwanese colorectal cancer patients. BACKGROUND: Side effects of anti-cancer treatments are associated with refusing treatment and discontinuing treatment. DESIGN: This case-control study, longitudinal database and secondary analysis of population-based data was conducted from 2009-2012. METHODS: Logistic regression was used to reveal the factors related to refusing or discontinuing treatment. RESULTS: Of the 68 patients who refused treatment, the top reasons for refusing treatment were patients or their family considered the patients poor physical condition, difficulty in enduring any condition likely to cause physical discomfort from the disease treatment, selected complementary and alternative medicine, patients or their families or friends experienced negative treatment effects and worried about the side effects of treatment, older age, poor family support and lost contact. Of the 278 patients who discontinued treatment, the most common reasons for discontinuing treatment were patients or their families or friends experienced negative treatment effects and worried about the side effects of treatment, inconvenient transportation, patients or their family considered the patients poor physical condition, difficulty in enduring any condition likely to cause physical discomfort from the disease treatment, poor treatment effect and selected complementary and alternative medicine. CONCLUSION: Case managers can provide positive communication and available resources in relation to cancer treatment. A case management programme can help patients cope with the difficulties encountered during the treatment period. PMID- 28833353 TI - Assessment of an Extended Interval Fondaparinux Dosing Regimen for Venous Thromboembolism Prophylaxis in Critically Ill Patients with Severe Renal Dysfunction Using Antifactor Xa Levels. AB - OBJECTIVE: Pharmacologic options for venous thromboembolism (VTE) prophylaxis are often limited in critically ill patients due to thrombocytopenia and multisystem organ dysfunction. Fondaparinux offers potential advantages in the critically ill; however, it is currently contraindicated in severe renal dysfunction (SRD). We evaluated anti-factor Xa levels in critically ill patients with SRD who were receiving an extended interval dosing regimen of fondaparinux for VTE prophylaxis. METHODS: A prospective, single-arm, interventional study was conducted at two academic hospitals of the Detroit Medical Center. Eligible patients were in the intensive care unit, had an estimated creatinine clearance of less than 30 ml/minute, and had either acute kidney injury or end-stage renal disease; several patients were taking renal replacement therapy. Fondaparinux was administered at an extended interval dosing regimen of 2.5 mg subcutaneously every 48 hours. Fondaparinux peak and trough anti-factor Xa levels were obtained. Lower extremity venous duplex studies were performed at baseline and study completion to assess for deep vein thrombosis (DVT), and patients were monitored for bleeding complications. RESULTS: Thirty-two patients were enrolled. Patients received a median of four doses (interquartile range two to five) of fondaparinux. Fondaparinux peak (n=98) and trough (n=86) anti-factor Xa levels were 0.36 +/- 0.18 mg/L and 0.17 +/- 0.11 mg/L (mean +/- SD), respectively, and were similar to levels reported in patients with normal renal function receiving conventional once-daily dosing. No lower extremity DVTs or suspected VTE events occurred. Two (6%) patients had significant bleeding events. CONCLUSIONS: In critically ill patients with SRD, an extended interval fondaparinux dosing regimen of 2.5 mg every 48 hours for VTE prophylaxis achieved peak and trough anti-factor Xa levels similar to those reported in noncritically ill patients with normal renal function receiving once-daily fondaparinux. This regimen offers an alternative for patients with SRD when heparinoids must be avoided. PMID- 28833354 TI - Immunohistochemical expression of cereblon and MUM1 as potential predictive markers of response to lenalidomide in extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma). AB - Lenalidomide is an active agent for the treatment of MALT lymphoma. Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide. However, there are no data on CRBN and MUM1 expression in MALT lymphoma. In the current study, we have systematically investigated a potential correlation of CRBN/MUM1 immunohistochemical expression and response to lenalidomide-based therapy in a series of 46 patients with MALT lymphoma treated at the Medical University Vienna 2009 to 2014. In total, 28% (13/46) of biopsy specimens derived from gastric tissues, while 72% (33/46) originated from extragastric MALT lymphoma. In terms of CRBN, 54% showed high expression (CRBN+, >=50% positive cells); the remaining 46% were classified as low expression (CRBN-). In contrast to other reports, there was a non-significant trend towards worse response rates in CRBN+ (68% versus 86%, P = 0.161). Relapse rates (P = 0.592) and PFS (P = 0.306) did not differ between CRBN+/CRBN-, but all 3 patients progressing on lenalidomide were CRBN+ and both patients completely lacking CRBN expression responded to treatment. Concerning MUM1, 62% were MUM1-negative (MUM1-) and 38% positive (MUM1+). There was no difference in response to lenalidomide by MUM1-status (MUM1+ 71% versus MUM1- 79%, P = 0.546) and also relapse rates (P = 0.828) and PFS (P = 0.681) did not differ. Interestingly, a subgroup analysis of gastric lymphoma revealed a significantly better PFS for CRBN- and MUM1- patients, respectively (both P < 0.05). To conclude, there was no significant difference in response to lenalidomide between patients with low or high expression of CRBN/MUM1 in a general population of MALT lymphoma, and immunohistochemical CRBN/MUM1 assessment cannot be recommended in the clinical routine. PMID- 28833355 TI - Serum chemerin levels are inversely associated with renal function in a general population. AB - OBJECTIVE: Chemerin has been found to be highly expressed in the kidneys of rodents and has been suggested to affect metabolic syndrome (MetS)-related phenotypes which are in turn related to kidney damage. Only few clinical studies have addressed the relation between circulating chemerin and renal function in humans, and no population-based analyses have yet been performed. The potential influence of MetS-related phenotypes on the assumed association has been largely neglected. We aimed to investigate the association of serum chemerin with renal function in a general population with special regard to possible interactions between chemerin and metabolic phenotypes. DESIGN, PATIENTS AND MEASUREMENTS: Linear and logistic regression models were applied to analyse data from 4082 subjects of the German Study of Health in Pomerania. Main outcomes included estimated glomerular filtration rate (eGFR), serum creatinine and cystatin C and chronic kidney disease. RESULTS: Inverse associations of chemerin with eGFR were observed. The components of the MetS emerged as modulating factors in this relation and enhanced the association. Logistic regression models confirmed the relation between chemerin and eGFR and revealed that each increase in chemerin per 25 ng/mL was associated with an about threefold higher odds of chronic kidney disease [odds ratio 2.72 (95% confidence interval 2.26-3.29)]. CONCLUSIONS: Our results demonstrate a strong inverse association between serum chemerin levels and renal function. This association might be explained by MetS-related phenotypes, which lead to renal damage and are associated with increased chemerin levels and/or an impaired renal elimination of chemerin by diseased kidneys. PMID- 28833356 TI - Clinical evaluation of a new pressure ulcer risk assessment instrument, the Pressure Ulcer Risk Primary or Secondary Evaluation Tool (PURPOSE T). AB - AIM: To test the psychometric properties and clinical usability of a new Pressure Ulcer Risk Assessment Instrument including inter-rater and test-retest reliability, convergent validity and data completeness. BACKGROUND: Methodological and practical limitations associated with traditional Pressure Ulcer Risk Assessment Instruments, prompted a programme to work to develop a new instrument, as part of the National Institute for Health Research funded, Pressure UlceR Programme Of reSEarch (RP-PG-0407-10056). DESIGN: Observational field test. METHOD: For this clinical evaluation 230 patients were purposefully sampled across four broad levels of pressure ulcer risk with representation from four secondary care and four community NHS Trusts in England. Blinded and simultaneous paired (ward/community nurse and expert nurse) PURPOSE-T assessments were undertaken. Follow-up retest was undertaken by the expert nurse. Field notes of PURPOSE-T use were collected. Data were collected October 2012-January 2013. RESULTS: The clinical evaluation demonstrated "very good" (kappa) inter-rater and test-retest agreement for PURPOSE-T assessment decision overall. The percentage agreement for "problem/no problem" was over 75% for the main risk factors. Convergent validity demonstrated moderate to high associations with other measures of similar constructs. CONCLUSION: The PURPOSE-T evaluation facilitated the initial validation and clinical usability of the instrument and demonstrated that PURPOSE-T is suitable of use in clinical practice. Further study is needed to evaluate the impact of using the instrument on care processes and outcomes. PMID- 28833357 TI - Prothrombin Complex Concentrate Reduces Blood Product Utilization in Heart Transplantation. AB - BACKGROUND: Current practices for the reversal of warfarin before cardiac surgery include the use of vitamin K and fresh frozen plasma (FFP) to reduce the risk of bleeding. Although the 2010 International Society of Heart and Lung Transplantation guidelines acknowledge the use of prothrombin complex concentrate (PCC), there is no clear consensus on its efficacy. The objective of this study was to assess the efficacy of four-factor (4-F) PCC administration in patients requiring warfarin reversal before heart transplantation by determining blood product utilization perioperatively. METHODS: Twenty-one patients who received 4 F PCC for warfarin reversal before heart transplantation were compared to a similar cohort of 39 patients who did not receive 4-F PCC, from January 2011 to July 2015. Blood product utilization was collected retrospectively for the 24 hour preoperative, intraoperative, and 48-hour postoperative periods. RESULTS: Patients receiving 4-F PCC required fewer blood products in all three time periods. In the 24-hour preoperative period, 22 (56%) patients in the control group and 2 (10%) patients in the 4-F PCC groups received blood products (p<0.001). Intraoperatively, all patients received blood products. The 4-F PCC group required fewer units of packed red blood cells (median 3 vs 7 units, p<0.001) and FFP (median 4 vs 9 units, p<0.001). In the 48-hour postoperative period, 20 (51%) patients in the control group and 5 (24%) patients in the 4-F PCC group received blood products (p=0.04). CONCLUSIONS: 4-F PCC is associated with reduced blood product utilization 24 hours preoperatively and intraoperatively. Historically, the majority of patients require FFP for warfarin reversal preoperatively. In this single-center study, a significant reduction in the need for FFP was demonstrated with the use of 4-F PCC. PMID- 28833358 TI - Syntheses of isotope-labeled SGLT2 inhibitor canagliflozin (JNJ-28431754). AB - Canagliflozin (Invokana, JNJ-28431754) is an orally bioavailable and selective SGLT2 (subtype 2 sodium-glucose transport protein) inhibitor approved for the treatment of type 2 diabetes. Herein, we report the synthesis of 13 C and 14 C labeled canagliflozin. Stable isotope-labeled [13 C6 ]canagliflozin was synthesized in 4 steps starting from [13 C6 ]-labeled glucose. The [14 C]-Labeled canagliflozin was synthesized by incorporation of [14 C] into the benzylic position between the thiophene and benzene rings of the compound. Detailed synthesis of the isotope-labeled compounds is reported. PMID- 28833359 TI - PATERNAL AND MATERNAL REFLECTIVE FUNCTIONING IN THE WESTERN AUSTRALIAN PEEL CHILD HEALTH STUDY. AB - While past research on the care of infants has been mostly with mothers, in recent times there has been a renewed attention to the father-infant relationship. This study examined differences between mother and father parental reflective functioning (PRF) or parental mentalizing; that is, the parental capacity to reason about their own and their children's behaviors by taking into consideration intentional mental states. Data were collected from 120 couples with a 1-year-old child who were participants in the West Australian Peel Child Health Study. Parental mentalizing was assessed using the Parental Reflective Functioning Questionnaire (PRFQ; Luyten, Mayes, Nijssens, & Fonagy, ). Results showed that mother and father mentalizing with their children was independent and that mothers scored slightly higher levels of mentalizing than did fathers. Paternal mentalizing was weakly associated with family income and father education, and was more strongly associated with family functioning than with maternal mentalizing. Implications for theorizing on PRF and fatherhood more generally are discussed. PMID- 28833360 TI - Understanding the impact of simulated patients on health care learners' communication skills: a systematic review. AB - CONTEXT: Effective communication skills are at the core of good health care. Simulated patients (SPs) are increasingly engaged as an interactive means of teaching, applying and practising communication skills with immediate feedback. There is a large body of research into the use of manikin-based simulation but a gap exists in the body of research on the effectiveness of SP-based education to teach communication skills that impact patient outcomes. The aim of this systematic review was to critically analyse the existing research, investigating whether SP-based communication skills training improves learner-patient communication, how communication skill improvement is measured, and who measures these improvements. METHODS: The databases Medline, ProQuest (Health & Medical Complete, Nursing and Allied Health Source) and CINAHL (EBSCOhost) Education Resources Information Centre (ERIC) were searched for articles that investigated the effects of SP-based education on the communication skills of medical, nursing and allied health learners. RESULTS: There were 60 studies included in the review. Only two studies reported direct patient outcomes, one reporting some negative impact, and no studies included an economic analysis. Many studies reported statistically significant third-party ratings of improved communication effectiveness following SP-based education; however, studies were unable to be pooled for meta-analysis because of the outcome collection methods. There were a small number of studies comparing SP with no training at all and there were no differences between communication skills, contradicting the results from studies reporting benefits. Of the 60 studies included for analysis, 54 (90%) met the minimum quality score of 7/11, with four articles (7%) scoring 11/11. CONCLUSION: SP-based education is widely accepted as a valuable and effective means of teaching communication skills but there is limited evidence of how this translates to patient outcomes and no indication of economic benefit for this type of training over another method. PMID- 28833362 TI - Evaluation of Progesterone Utilization and Birth Outcomes in a State Medicaid Plan. AB - OBJECTIVES: Progesterone (hydroxyprogesterone caproate injection and vaginal progesterone) has been shown to reduce preterm birth (PTB) rates by a third among pregnant women at high risk. The purpose of this analysis is to report birth outcomes and medication adherence among Massachusetts Medicaid (MassHealth) members receiving progesterone, evaluate the association between member characteristics and birth outcomes and medication adherence, and compare cost of care with a prior preterm pregnancy. METHODS: This retrospective cohort study used medical claims, pharmacy claims, and prior authorization (PA) request data for MassHealth members who had a PA submitted for progesterone between January 1, 2011, and March 31, 2015. Members were excluded due to breaks in coverage, progesterone was not indicated for prevention of PTB, and if current gestational week or date of delivery was unavailable. MAIN RESULTS: A total of 418 members were screened for inclusion of whom 190 met criteria and 169 filled progesterone. Mean age was 29.2 years (SD = 5.23), and clinical comorbidities were identified in 90.5% of members. Consistent with clinical trials on progesterone effectiveness, 62.1% of members had a term delivery (37 wks of gestation). Among members with prior gestational age at delivery available, the average difference in gestational age between pregnancies was 8.25 weeks (SD = 6.11). In addition, 66.3% of members were adherent to progesterone based on proportion of days covered (PDC) of 0.8 or higher. The overall mean PDC was 0.79 (SD = 0.26). CONCLUSION: Despite similar birth outcomes in clinical trials and national trends, medication adherence is low in this state Medicaid program. Therefore, members may benefit from adherence support. PMID- 28833361 TI - Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B. AB - Hepatitis B virus (HBV) infection represents a significant public health burden worldwide. Although current therapeutics manage to control the disease progression, lifelong treatment and surveillance are required because drug resistance develops during treatment and reactivations frequently occur following medication cessation. Thus, the occurrence of hepatocellular carcinoma is decreased, but not eliminated. One major reason for failure of HBV treatment is the inability to eradicate or inactivate the viral covalently closed circular DNA (cccDNA), which is a stable episomal form of the viral genome decorated with host histones and nonhistone proteins. Accumulating evidence suggests that epigenetic modifications of cccDNA contribute to viral replication and the outcome of chronic HBV infection. Here, we summarize current progress on HBV epigenetics research and the therapeutic implications for chronic HBV infection by learning from the epigenetic therapies for cancer and other viral diseases, which may open a new venue to cure chronic hepatitis B. (Hepatology 2017;66:2066-2077). PMID- 28833363 TI - Shame and HIV: Strategies for addressing the negative impact shame has on public health and diagnosis and treatment of HIV. AB - There are five ways in which shame might negatively impact upon our attempts to combat and treat HIV. Shame can prevent an individual from disclosing all the relevant facts about their sexual history to the clinician. Shame can be a motivational factor in people living with HIV not engaging with or being retained in care. Shame can prevent individuals from presenting at clinics for STI and HIV testing. Shame can prevent an individual from disclosing their HIV (or STI) status to new sexual partners. Shame can serve to psychologically imprison people, it makes the task of living with HIV a far more negative experience than it should, or needs to, be. Drawing on recent philosophical work on shame, and more broadly on work in the philosophy and psychology of emotion, we (a.) propose a framework for understanding how shame operates upon those who experience the emotion, (b.) propose a strategy for combatting the negative role shame plays in the fight against HIV, and (c) suggest further study so as to identify the tactics that might be employed in pursuing the strategy here proposed. PMID- 28833364 TI - Eosinophilia secondary to lenalidomide therapy. AB - WHAT IS KNOWN AND OBJECTIVE: Limited data are available on eosinophilia as a drug adverse event. We describe a case of eosinophilia from lenalidomide therapy. CASE DESCRIPTION: A 50-year-old woman received lenalidomide, dexamethasone and cyclophosphamide as POEMS syndrome treatment. Eosinophil count rose during lenalidomide treatment and decreased in the periods off treatment. Naranjo nomogram suggested a probable association between the use of lenalidomide and eosinophilia. WHAT IS NEW AND CONCLUSION: Eosinophilia has rarely been described with lenalidomide. This case shows a clear temporal relationship between lenalidomide and eosinophilia. PMID- 28833365 TI - Magnetic resonance imaging findings of the proximal metacarpus in Quarter Horses used for cutting: Retrospective analysis of 32 horses 2009-2012. AB - BACKGROUND: Injury to the proximal suspensory ligament is a common cause of lameness in cutting horses. Radiographic and ultrasonographic imaging of lesions responsible for lameness can provide ambiguous results. MRI provides the most comprehensive diagnostic imaging evaluation of lesions specifically affecting cutting horses. OBJECTIVES: To describe the distribution and severity of bone and soft tissue lesions present in the proximal metacarpus of Quarter Horse cutting horses and to assess the impact of these lesions on return to competition. STUDY DESIGN: Retrospective case series. METHODS: Retrospective analysis of 32 cutting horses referred for MRI of the proximal metacarpus between 2009 and 2012 with a 2 year follow-up period. MRI studies were evaluated by a board-certified veterinary radiologist; the severity of lesions was graded from 0 (absent) to 3 (severe). RESULTS: A total of 20 right and 24 left forelimbs (12 bilateral studies) of 32 horses were evaluated. The most common findings were: third metacarpal (McIII) sclerosis at the proximal suspensory ligament (PSL) origin (42/44), McIII resorption at the PSL origin (32/44), PSL dorsal margin fibre irregularity (30/44) and McIII bone contusion (22/39). Of the 30 horses, 22 horses successfully returned to competition, irrespective of severity of injury. Strong correlation exists between the degree of resorption in the palmar cortex of proximal McIII, degree of McIII sclerosis and severity of dorsal margin fibre irregularity. MAIN LIMITATIONS: Statistical significance was limited by small study population. Further analysis of prognosis was limited by availability of comprehensive medical records. CONCLUSIONS: Cutting horses with proximal metacarpal pain have significant pathological change within the proximal suspensory ligament and its enthesis on the palmar cortex of McIII. Severity of lesions and degree of lameness at the time of diagnosis does not influence return to performance. Accurate diagnosis of proximal metacarpal lesions based on MRI offers clinicians the capacity to select treatment protocols targeted to each disease process. PMID- 28833366 TI - The validity and reliability of the type 2 diabetes and health promotion scale Turkish version: a methodological study. AB - OBJECTIVE: A healthy promotion is important for maintaining health and preventing complications in patients with type 2 diabetes. AIM: The aim of the present study was to examine the psychometrics of a recently developed tool that can be used to screen for a health-promoting lifestyle in patients with type 2 diabetes. METHOD: Data were collected from outpatients attending diabetes clinics. The Type 2 Diabetes and Health Promotion Scale (T2DHPS) and a demographic questionnaire were administered to 295 participants. Forward-backward translation of the original English version was used to develop a Turkish version. Internal consistency of the scale was assessed by Cronbach's alpha. An explanatory factor analysis and confirmatory factor analysis used validity of the Type 2 Diabetes and Health Promotion Scale - Turkish version. RESULTS: Kaiser-Meyer-Olkin (KMO) and Bartlett's sphericity tests showed that the sample met the criteria required for factor analysis. The reliability coefficient for the total scale was 0.84, and alpha coefficients for the subscales ranged from 0.57 to 0.92. A six-factor solution was obtained that explained 59.3% of the total variance. The ratio of chi-square statistics to degrees of freedom (chi2 /df) 3.30 (chi2 = 1157.48/SD = 350); error of root mean square approximation (RMSEA) 0.061; GFI value of 0.91 and comparative fit index (CFI) value was obtained as 0.91. CONCLUSIONS: Turkish version of The T2DHPS is a valid and reliable tool that can be used to assess patients' health-promoting lifestyle behaviours. Validity and reliability studies in different cultures and regions are recommended. PMID- 28833368 TI - Green tea consumption: A potential chemopreventive measure for hepatocellular carcinoma? PMID- 28833367 TI - Iron metabolism in patients with Graves' hyperthyroidism. AB - OBJECTIVES: Graves' hyperthyroidism (GH) interferes with iron metabolism and elevates ferritin. The precise mechanisms remain unclear. The influence of thyroid hormones on the synthesis/regulation of hepcidin, an important regulator of iron metabolism, remains uncharacterized. DESIGN: Prospective observational study. PATIENTS: We included patients (n = 31) with new-onset and untreated GH. MEASUREMENTS: Laboratory parameters indicative of iron metabolism (ferritin, transferrin, hepcidin), inflammatory markers/cytokines and smoking status were assessed at the diagnosis of GH (T0) and at euthyroidism (T1) in the same patients using multivariable analyses. Hepcidin was measured by mass spectrometry (hepcidinMS ) and ELISA (hepcidinEL ). The impact of T3 on hepatic hepcidin expression was studied in a cell culture model using HepG2 cells. RESULTS: Median ferritin levels were significantly lower and transferrin significantly higher at T1 than at T0. HepcidinMS levels were lower in males and females at T1 (statistically significant in males only). No statistically significant difference in hepcidinEL was detected between T0 and T1. Plasma levels of inflammatory markers (high-sensitive CRP, procalcitonin) and cytokines (interleukin 6, interleukin 1beta, tumour necrosis factor alpha) were not different between T0 and T1. Smokers tended to have lower fT3 and fT4 at T0 than nonsmoking GH patients. T3 significantly induced hepcidin mRNA expression in HepG2 cells. CONCLUSIONS: Iron metabolism in patients with GH undergoes dynamic changes in patients with GH that resemble an acute-phase reaction. Inflammatory parameters and cytokines were unaffected by thyroid status. Gender and smoking status had an impact on ferritin, hepcidin and thyroid hormones. PMID- 28833369 TI - Clinical and genetic features of 64 young male paediatric patients with congenital hypogonadotropic hypogonadism. AB - CONTEXT: The diagnosis of congenital hypogonadotropic hypogonadism (CHH) in prepuberty has always been challenging. Here, we aimed at studying the clinical and genetic features of paediatric CHH, especially the phenotype of hypospadias and dual defects (patients showing hypothalamic and/or pituitary defects and testicular hypoplasia), so as to have a better understanding of CHH. DESIGN: The clinical and genetic features of patients with CHH were analysed, and the relationships between hypospadias, dual defects and genetics were investigated. PATIENTS: Patients who visited Beijing Children's Hospital and were positively diagnosed with CHH. MEASUREMENTS: The collected data included sex hormones, MRI of the olfactory bulb, human chorionic gonadotrophin (hCG) test and genetic testing. We analysed clinical features and genetic results, especially hypospadias and dual defects, and compared the stimulated testosterone (T) levels in patients with and without cryptorchidism. RESULTS: Sixty-four patients were positively diagnosed, and forty-seven (73.4%) had Kallmann syndrome (KS). Four patients (6.3%) had hypospadias, including 2 KS. Micropenis combined with cryptorchidism was the most common phenotype (39%). Approximately two-third of patients showed a poor response to hCG; 15 cases were diagnosed with dual defects, and there were no significant differences between those with and without cryptorchidism. Twenty-six cases (51%) of 51 patients were identified as having classical HH mutations, affecting 10 different genes, with oligogenic mutations in 5 cases (9.8%). The most common mutations were in PROKR2 (17.6%), FGFR1 (13.7%) and CHD7 (7.8%). The frequency of PROKR2 mutations was higher in dual HH when compared to other HH cases (6/15 vs 3/36, P = .021). CONCLUSIONS: Micropenis and/or cryptorchidism can serve as important signs for the diagnosis of HH in paediatrics, and the coexistence of hypospadias does not exclude the diagnosis of CHH, including KS or normosmic isolated HH (nHH). Testicular function may be impaired earlier than expected, and PROKR2 mutations need to be evaluated to identify presumed dual defects. PMID- 28833370 TI - Considerations on POEMS associated optic neuropathy. PMID- 28833371 TI - Nurses' perceptions of pain assessment and management practices in neonates: a cross-sectional survey. AB - AIMS: This study aimed to describe pain assessment and management practices for neonates based on nurses' perceptions in neonatal intensive care units (NICUs). DESIGN: A descriptive cross-sectional survey was conducted in Finland. METHODS: Of all nurses (N = 422) working in the NICUs in the country's five university hospitals, 294 responded to a questionnaire. The data were analysed by statistical methods. RESULTS: Nurses agreed that pain assessment is important, but over half of them reported being able to assess pain in a reliable way without using pain assessment scales. Physiological parameters and changes in neonate's behaviour were reported as routinely observed, but many specific facial expressions indicative of pain were less often observed. Only a few pain assessment scales were known, and they were not routinely used in clinical practice. Most nurses reported using physical methods and giving oral sucrose along with non-nutritive sucking. Counselling parents to continue breastfeeding or guiding them to use skin-to-skin care or music was rarely reported as used to alleviate infants' pain. CONCLUSIONS: Educational interventions for nurses are needed to improve pain assessment and management practices in the NICUs. In addition, there is a need for national guidelines in order to ensure the equal treatment to all neonates. PMID- 28833372 TI - Axonal components of nerves innervating the human arm. AB - OBJECTIVE: Axons traveling within the brachial plexus are responsible for the dexterous control of human arm and hand movements. Despite comprehensive knowledge on the topographical anatomy of nerves innervating the human upper limbs, the definite quantity of sensory and motor axons within this neural network remains elusive. Our aim was to perform a quantitative analysis of the axonal components of human upper limb nerves based on highly specific molecular features from spinal cord level to the terminal nerves at wrist level. METHODS: Nerve specimen harvest at predefined harvesting sites (plexus roots and cords as well as major nerves originating from the brachial plexus innervating the arm and hand) was performed in 9 human heart-beating organ donors. Double immunofluorescence staining using antibodies against choline-acetyltransferase and neurofilament was performed to differentiate motor and sensory axons on nerve cross sections. RESULTS: Three hundred fifty thousand axons emerge from the spinal cord to innervate the human upper limb, of which 10% are motor neurons. In all nerves studied, sensory axons outnumber motor axons by a ratio of at least 9:1. The sensory axon contribution increases when moving distally, whereas only 1,700 motor axons reach the hand to innervate the intrinsic musculature. INTERPRETATION: Our results suggest that upper limb motor execution, and particularly dexterous coordination of hand movement, require an unexpectedly low number of motor neurons, with a large convergence of afferent input for feedback control. Ann Neurol 2017;82:396-408. PMID- 28833373 TI - A comment on 'An assessment of the variation in the concentrations of acetylcysteine in infusions for the treatment of paracetamol overdose'. PMID- 28833374 TI - Sensitive phosphoprotein detection in SDS-PAGE via Anthracene Chrome Red A stain. AB - Protein phosphorylation, one of the most important post-translational modifications, plays critical roles in many biological processes. Thus, it is necessary to precisely detect, identify and understand the phosphoproteins from protein mixture for the study of cell biology. We introduce a sensitive and specific detection method for phosphoproteins in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Anthracene Chrome Red A (ACRA) combined with the trivalent metal ion (Al3+ ) is converted to fluorescent complex and the fluorescence is sharply increased by a change of pH environment. Phosphoproteins and non-phosphoproteins can be easily distinguished by the fluorescence quenching due to the structural change of ACRA-Al3+ -phosphoprotein complex, unlike non-phosphoprotein complex. The method using ACRA is a negative staining based on the fluorescence quenching and has a high sensitivity comparable to Pro-Q Diamond stain. ACRA stain can detect 1-2 ng of alpha-casein and beta-casein, 8-16 ng of ovalbumin (OVA) and kappa-casein within 130 min. Moreover, the ACRA stain showed similar linear dynamic ranges and RSD to Pro-Q stain. The linear dynamic ranges of ACRA and the values of correlation coefficient were for OVA (8-500 ng, correlation coefficient r = 0.999), alpha casein (4-500 ng, r = 0.992), beta-casein (4-500 ng, r = 0.996), and kappa-casein (8-500 ng, 0.998), respectively. On the other hand, the values of the relative standard deviations (RSD) ranged from 2.33 to 3.56% for ACRA. The method is sensitive, specific, simple, rapid and compatible with total protein stain such as SYPRO Ruby stain. Therefore, ACRA stain can be an advanced method for phosphoprotein detection in gels. PMID- 28833375 TI - Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion. AB - AIMS: Clear cell sarcoma of the kidney (CCSK) is a rare paediatric renal malignant tumour. The majority of CCSKs have internal tandem duplications (ITDs) of the BCOR gene, whereas a minority have the YWHAE-NUTM2 gene fusion. A third 'double-negative' (DN) category comprises CCSKs with neither BCOR ITDs nor YWHAE NUTM2 fusion. The aim of this study was to characterise 11 histologically diagnosed CCSKs immunohistochemically (with CCND1, BCOR and CCNB3 stains) and genetically. METHODS AND RESULTS: By next-generation sequencing, 10 cases (90.9%) had BCOR exon 15 ITDs, with positive BCOR immunoreactivity being found in four (36%) or eight (72%) cases, depending on the antibody clone. By reverse transcription polymerase chain reaction, none had the YWHAE-NUTM2 fusion. The DN case had a BCOR-CCNB3 fusion and strong nuclear CCNB3 and BCOR immunoreactivity. Quantitative polymerase chain reaction showed markedly elevated BCOR expression in this case, whereas BCOR ITD cases had lower levels of elevated BCOR expression. CONCLUSIONS: The majority of the CCSKs in our cohort had BCOR ITDs, and none had the YWHAE-NUTM2 fusion. We verified the strong, diffuse cyclin D1 (CCND1) immunoreactivity in CCSKs described in recent reports. BCOR immunoreactivity was not consistently positive in all CCSKs with BCOR ITDs, and therefore cannot be used as a diagnostic immunohistochemical stain to identify BCOR ITD cases. The DN case was a BCOR-CCNB3 fusion sarcoma. BCOR-CCNB3 sarcoma is typically a primary bone sarcoma affecting male adolescents, and this is the first report of it presenting in a kidney of a young child as a CCSK. The full spectrum of DN CCSKs awaits more comprehensive characterisation. PMID- 28833376 TI - Development and clinical evaluation of a new sensor design for buccal pulse oximetry in horses. AB - BACKGROUND: The use of pulse oximetry in horses is limited due to inadequate readings with conventional transmission sensor probes. OBJECTIVES: The objectives of this study were to 1) develop an improved sensor design for horses to be used at an appropriate anatomical site, and 2) evaluate this design in an experimental study. STUDY DESIGN: In vivo experiment. METHODS: A new sensor design for reflectance pulse oximetry at the buccal mucosa was developed. A conventional Nonin 2000SL sensor for transmission pulse oximetry was included into this design. Three different prototypes (N1, N2a, N2b) were constructed and used with the Nonin 2500A Vet pulse oximetry monitor. Thirteen anaesthetised warmblood horses were included into a desaturation protocol (100-70% SaO2 ). SpO2 and pulse frequency values were recorded, using SaO2 calculated from blood gas analysis and invasive pulse frequency measurements as reference methods. Bias and precision were evaluated by calculations of the root mean square deviation (Arms ). The agreement of the methods was tested with Bland-Altman analysis. RESULTS: The quality of the pulse frequency readings determined the quality of the SpO2 readings. Good pulse signal strength resulted in a SpO2 -accuracy comparable to that of the original sensor (Nonin 2000SL: Arms = 3%; N1: Arms = 3.60%; N2b: Arms = 3.46%). Especially at heart rates <=30 bpm, pulse rate readings that were about twice as high as the reference value occurred. Their exclusion from the dataset resulted in a pulse rate accuracy similar to that of the original sensor. Bland Altman plots showed limits of agreement typical of pulse oximeters. MAIN LIMITATIONS: The pulse frequency accuracy requires further improvement. The usability in clinical cases needs to be tested. CONCLUSIONS: The new sensor design has been shown to be suitable for buccal pulse oximetry in horses. PMID- 28833377 TI - T1-/T2-weighted ratio differs in demyelinated cortex in multiple sclerosis. AB - Detecting cortical demyelination in patients with multiple sclerosis (MS) is difficult. Using magnetic resonance imaging (MRI), ratio maps of T1-weighted (T1w) and T2-weighted (T2w) images may be sensitive to cortical myelin levels. In this MRI-histological study, postmortem in situ scans were acquired from 6 cadavers with MS on a 3T MRI machine. Immunocytochemistry was used to correlate myelin status and cortical T1w/T2w measures. The results showed that the T1w/T2w values significantly differed between demyelinated and myelinated cortex (p < 0.001). The T1w/T2w ratio maps may be a relatively simple, clinically feasible method to assess cortical demyelination. Ann Neurol 2017;82:635-639. PMID- 28833378 TI - Race, Offense Type, and Suicide Ideation: Tests of the Interpersonal Psychological Theory in Juvenile Offenders. AB - This study evaluated the synergy hypothesis of the Interpersonal-Psychological Theory of Suicide (IPTS), which argues thwarted belongingness and perceived burdensomeness are positively interactive in their association with suicide ideation, in a group of juvenile offenders. It also examined whether this prediction is differentially applicable across race/ethnicity or offense type. Participants included 590 adjudicated and confined male juveniles. Regression was used to test the association between suicide ideation and thwarted belongingness, perceived burdensomeness, and their interaction term. Subsequent analyses included tests of group interactions related to race/ethnicity and offense type. No interaction between thwarted belongingness and perceived burdensomeness was observed, despite adequate power. No significant group interactions were observed for race/ethnicity or offense type. However, results did show significant linear relationships between thwarted belongingness, perceived burdensomeness, and ideation, highlighting their potential utility as intervention targets in this at risk population. Thus, although the current results are the first to show the basic IPTS risk factors generalize across race/ethnicity and offense type, they also failed to support that those factors were interactive, a primary IPTS claim. The absence of an interaction between thwarted belongingness and perceived burdensomeness suggests their role in suicide ideation for juvenile offenders may be more parsimonious than the IPTS proposes. PMID- 28833379 TI - Parents' experiences of their child being admitted to a paediatric intensive care unit: a qualitative study-like being in another world. AB - BACKGROUND: There is very little research on the parent's experiences of having a child admitted to a paediatric intensive care unit. Identifying and describing 'such experiences' could facilitate better parental support from the paediatric intensive care team and help the parents manage a stressful situation. AIMS: This study aimed to describe parents' experiences of having their child admitted to a paediatric intensive care unit. METHODS: Interviews were conducted with 12 parents whose children had been admitted to a paediatric intensive care unit. A qualitative design was used, and the interviews were analysed based on content analysis. RESULT: The analysis revealed two categories: 'being involved' and 'being informed' with seven subcategories: 'caring for the parents', 'security and trust', 'altering the parental role', 'stress and fear', 'the importance of knowing', 'interaction in the care process' and 'being prepared'. An overarching theme emerged: the experience was 'like being in another world'. The study concludes that a child's admission to a paediatric intensive care unit is a stressful situation, and for the parents to be able to handle the anxiety and stress, they need to be informed of and involved in their child's care. CONCLUSIONS: The parents' experience when their child is admitted to a paediatric intensive care unit is fraught with a range of emotion and fear. There are indications that things such as good information, involvement and a positive experience of the transfer to the paediatric ward reduce the stress and anxiety associated with paediatric intensive care admission. The result of this study could be used as a basis for a post-paediatric intensive care follow-up service for the children and their families. PMID- 28833380 TI - Population pharmacokinetics of the MEK inhibitor selumetinib and its active N desmethyl metabolite: data from 10 phase I trials. AB - AIMS: The aims of the study were to characterize the pharmacokinetics (PK) of selumetinib (AZD6244; ARRY-142886), a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor in clinical development for various indications, and its N desmethyl metabolite in healthy volunteers, and evaluate clinically important covariates. METHODS: A pooled-population PK analysis was performed using a nonlinear mixed-effects approach with plasma concentration data from 346 subjects who received single oral doses of selumetinib 20-75 mg across 10 phase I studies. Absolute bioavailability was determined using intravenous [14 C] selumetinib. RESULTS: A two-compartment linear model with sequential zero-first order absorption and a lag time for the zero-order process was described for selumetinib PK. N-desmethyl metabolite disposition was described by a single compartment with linear elimination, without back transformation. The parent-only and joint models generally described pooled data adequately. For the median subject, not taking interacting drugs, estimates for clearance (CL) and central volume of distribution (V2) for selumetinib in the final joint model were 12.7 l h-1 and 35.6 l, respectively. Food effects, comedication with itraconazole [a cytochrome P450 (CYP) 3A4 inhibitor], fluconazole (a CYP2C19 inhibitor) and rifampicin (a CYP3A4 inducer) and formulation effects were incorporated into the base model a priori. Race and hepatic function were also influential in the PK model. Additional covariates affecting selumetinib disposition identified from covariate analysis were age on V2, bilirubin on CL, and weight on CL and V2. CONCLUSIONS: Analysis confirmed previous clinical pharmacology study findings of drug-drug interactions and food effects, with additional covariates that influence selumetinib and N-desmethyl selumetinib PK identified. Dose modifications based on these additional covariates were not considered necessary. PMID- 28833381 TI - Proteomic assessment of the role of N-acyl homoserine lactone in Shewanella putrefaciens spoilage. AB - : Shewanella spp. are the common spoilage organisms found in aquatic food products stored at low temperature and their spoilage mechanism has been reported to be mediated by quorum sensing (QS). However, the specifically expressed proteins responding to N-acyl homoserine-lactone (AHLs) were seldom reported. This study aims to evaluate the effects of different AHL signal molecules on Shewanella putrefaciens Z4 isolated from refrigerated turbot (Scophthalmus maximus) at the proteome level. The results revealed that exogenous AHLs were utilized as QS signal molecules by S. putrefaciens Z4, and AHLs were not degraded by intracellular or extracellular enzymes secreted by S. putrefaciens Z4. Twenty three differently expressed spots upon the addition of AHLs were selected and identified by liquid chromatography-mass spectrometry (LC-MS). The results indicated that proteins involving in growth and metabolism (i.e. citrate synthase, succinate semialdehyde dehydrogenase), environment adaptation and regulators (i.e. polysaccharide deacetylases, transaldolase) were down-regulated upon three kinds of AHLs (C4-HSL, C6-HSL and O-C6-HSL), whereas the abundance of stress response protein and DNA ligase were elevated by the addition of exogenous AHLs. Moreover, the effects of exogenous C6-HSL and O-C6-HSLwere prominent. These results provide evidence that AHL-based QS signal molecules affected some important metabolic properties of S. putrefaciens. SIGNIFICANCE AND IMPACT OF THE STUDY: N-acyl homoserine lactone (AHLs)-based quorum sensing signal molecules involving in the behavior regulation in most of the Gram-negative bacteria have widely been reported. This study aims to evaluate the effect of AHLs on Shewanella putrefaciens Z4 at the proteome level. It provides the theoretic basis for elucidating the spoilage mechanism of Shewanella spp., the common spoilage micro-organism in refrigerated marine aquatic food products. PMID- 28833382 TI - Bayesian hierarchical joint modeling of repeatedly measured continuous and ordinal markers of disease severity: Application to Ugandan diabetes data. AB - Modeling of correlated biomarkers jointly has been shown to improve the efficiency of parameter estimates, leading to better clinical decisions. In this paper, we employ a joint modeling approach to a unique diabetes dataset, where blood glucose (continuous) and urine glucose (ordinal) measures of disease severity for diabetes are known to be correlated. The postulated joint model assumes that the outcomes are from distributions that are in the exponential family and hence modeled as multivariate generalized linear mixed effects model associated through correlated and/or shared random effects. The Markov chain Monte Carlo Bayesian approach is used to approximate posterior distribution and draw inference on the parameters. This proposed methodology provides a flexible framework to account for the hierarchical structure of the highly unbalanced data as well as the association between the 2 outcomes. The results indicate improved efficiency of parameter estimates when blood glucose and urine glucose are modeled jointly. Moreover, the simulation studies show that estimates obtained from the joint model are consistently less biased and more efficient than those in the separate models. PMID- 28833383 TI - Oxidative stress induced by glyphosate-based herbicide on freshwater turtles. AB - Freshwater ecosystems face very strong anthropogenic pressures, among which overexploitation, habitat degradation, flow modification, species invasion, and water pollution lead to growing threats on biodiversity. Urbanization through wastewater treatment, industry through the release of inorganic and organic chemicals, and agriculture through the use of pesticides and herbicides are the main factors involved in water pollution. In France, more precisely in the Pyrenees-Orientales department, the poor quality of the watercourses is attributable overall to the use of glyphosate-based herbicides in agricultural activities. Because these chemicals can impact individuals, populations, and biodiversity, we investigated, under experimental conditions, the physiological response of animals facing abiotic contaminants. We selected as a model, juveniles of the freshwater turtle Trachemys scripta elegans. We measured the gene expression and activity of the catalase and superoxide dismutase enzymes as well as the levels of lipid peroxidation, which are all oxidative stress biomarkers, in turtles challenged with high concentrations of glyphosate-based herbicides, on the one hand, and with degraded waters collected from a local watercourse, on the other. We also measured the acetylcholinesterase activity across the same animals. We showed through variations in gene expression and enzyme activity that a glyphosate commercial formulation induced a stress in turtles. A similar outcome was obtained when turtles faced degraded waters. The results indicated that the poor quality of regional waters could be a real threat for animal health. Because turtles are globally less sensitive to contaminants than amphibians, which are lacking in the degraded waters of the Pyrenees Orientales department, they could constitute an excellent model to follow the evolution of water quality through the study of oxidative stress biomarkers. Environ Toxicol Chem 2017;36:3343-3350. (c) 2017 SETAC. PMID- 28833384 TI - Primary hyperparathyroidism in Chinese children and adolescents: A single-centre experience at Peking Union Medical College Hospital. AB - OBJECTIVE: Primary hyperparathyroidism (PHPT) in children is thought to be extremely rare. Our study aimed to summarize the clinical characteristics and the molecular genetics in patients with paediatric PHPT in China. DESIGN: Retrospective observational study. METHODS: A total of 59 paediatric PHPT patients (onset age <18 years) admitted to Peking Union Medical College Hospital from 1975 to 2015 were retrospectively identified. A group of 118 adult PHPT patients who presented during the same period were selected for comparing clinical characteristics between the two groups. Germline mutation analyses of the MEN1, CDC73, RET, CDKN1B and CaSR genes were performed in 24 patients. RESULTS: Only one paediatric patient (1.7%) with PHPT was asymptomatic. Bone involvement, urolithiasis, acute pancreatitis and hypercalcaemic crisis were present in 86.4%, 39.0%, 6.8% and 10.2% of cases, respectively. Paediatric PHPT presented more commonly with rickets/osteomalacia compared to adult PHPT. Fifty seven paediatric patients underwent surgery. Adenoma, hyperplasia, atypical adenoma and carcinoma occurred in 80.7%, 10.5%, 7.0% and 1.8% of cases, respectively. Of the 24 paediatric patients screened for genetic mutations, two patients were found to carry MEN1 mutations and six were found to carry CDC73 mutations. The mutation rate was 22.2% (4/18) in sporadic patients. CONCLUSION: Unlike adults with PHPT, most paediatric PHPT were symptomatic. Rickets/osteomalacia was more common in paediatric patients than in their adult counterparts. Paediatric PHPT patients can be treated successfully with surgical intervention. Genetic screening of the MEN1 and CDC73 genes for mutations should be recommended in paediatric patients due to a relatively high mutation rate. PMID- 28833385 TI - Empirical Vancomycin Dosing in Pediatric Patients with Congenital Heart Disease and the Impact of Cardiopulmonary Bypass on Trough Concentrations. AB - OBJECTIVES: To determine the optimal vancomycin dosing regimen to achieve empirical goal trough concentrations in pediatric patients with congenital heart disease and to examine the impact of cardiopulmonary bypass on vancomycin dosing requirements. METHODS: Patients younger than 18 years admitted to the pediatric cardiovascular intensive care unit (CVICU) at our institution from October 1, 2012-December 31, 2014, who received at least one dose of vancomycin, were reviewed retrospectively. Included patients had a steady-state vancomycin trough concentration drawn during the study period. The first steady-state vancomycin trough drawn after being initiated on empirical vancomycin therapy was analyzed for each patient. Excluded patients were those who received mechanical circulatory support, any form of renal replacement therapy, or had a serum creatinine result greater than 1.0 mg/dl on the day of vancomycin initiation. RESULTS: Overall, 77 patients met inclusion criteria, of which 57.1% had undergone cardiopulmonary bypass (CPB) before CVICU admission. Median age was 62 days (interquartile range [IQR] 8.3-176 days). Median daily vancomycin dose was 36.25 mg/kg/day (IQR 29-40 mg/kg/day), resulting in a median steady-state trough of 10.0 MUg/ml (IQR 6.3-12.9 MUg/ml). Therapeutic troughs occurred in 50.6% of patients; supratherapeutic and subtherapeutic concentrations were attained in 18.2% and 31.2% of patients, respectively. A subgroup analysis of patients who were post-CPB revealed that the only additional variable to affect vancomycin trough concentrations was aortic cross-clamp time (median 56 min, IQR 0-123.3 min, p=0.02). CONCLUSIONS: Empirical vancomycin dosing to achieve troughs of 8-15 MUg/dl in patients with congenital heart disease without evidence of significant acute kidney injury should be 30 mg/kg/day for neonates, 35-40 mg/kg/day for infants, and 45 mg/kg/day in children, with adjustments required for patients with elevated creatinine or significant aortic cross-clamp time. The receipt and duration of CPB did not affect total daily vancomycin dose requirements. PMID- 28833386 TI - Radioiodination and biological evaluation of nizatidine as a new highly selective radiotracer for peptic ulcer disorder detection. AB - Nizatidine has been labeled using [125 I] with chloramine-T as oxidizing agent. Factors such as the amount of oxidizing agent, amount of substrate, pH, reaction temperature, and reaction time have been systematically studied to optimize the iodination. Biodistribution studies indicate the suitability of radioiodinated nizatidine as a novel tracer to image stomach ulcer. Radioiodinated nizatidine may be considered a highly selective radiotracer for peptic ulcer imaging. PMID- 28833387 TI - Characterization of an anti-varicella-zoster virus compound that targets the portal protein encoded by ORF54. AB - An anti-varicella-zoster virus compound, a 5-chlorobenzo[b]thiophen derivative (45B5), was characterized. Its 50% effective concentration against the cell-free vaccine Oka strain and 50% cytotoxic concentration in human fibroblasts were 16.9 uM and more than 100 uM, respectively. Treatment with 45B5 decreased viral DNA synthesis and IE62 expression weakly but significantly. All 45B5-resistant viral clones isolated were found to have at least one mutation in ORF54 that encodes the portal protein. There were no effects on interaction between the portal and scaffold proteins. Thus, 45B5 may inhibit nuclear delivery of viral DNA. PMID- 28833388 TI - Residents' perceptions of the most positive and negative aspects of the housing situation for people with psychiatric disabilities. AB - The major aim of the present study was to explore what people with psychiatric disabilities, living in two different types of housing, consider to be the best and the worst in their housing situation. A secondary aim was to explore to what extent additional questions to a questionnaire with a free-response format can provide complementary information to the previous knowledge in the field. The content analysis revealed that the physical attributes were of great significance for the residents in ordinary housing, while both psychosocial aspects and physical attributes were important for those living in supported housing. When providing good housing solutions for people with psychiatric disabilities, attention needs to be given to these aspects by politicians, policymakers as well as by nursing staff. PMID- 28833389 TI - Morphological spectrum of renal cell carcinoma, unclassified: an analysis of 136 cases. AB - AIMS: Renal cell carcinoma, unclassified (RCCU) is a category that includes a morphologically and biologically heterogeneous group of tumours that are unable to be diagnosed as other well-defined entities. We aim to describe the morphological findings of tumours within this category and to determine the most frequent morphological features leading to classification difficulty. METHODS AND RESULTS: One hundred and thirty-six cases of RCCU were examined. Patients ranged in age from 23 to 87 years. Seventy-seven patients were men and 59 were women. International Society of Urological Pathology (ISUP) grade was most commonly 3 (n = 66), followed by 2 (n = 42) and 4 (n = 28). Tumour size ranged from 0.6 to 24.9 cm. The American Joint Committee on Cancer (AJCC) pathological T categories included pT1a (n = 50), pT1b (n = 14), pT2a (n = 7), pT2b (n = 4), pT3a (n = 50) and pT4 (n = 9). Forty-four cases included lymph node(s), 41% of which (n = 18) had metastases. Tumours were assessed for a variety of histological features and assigned to the following morphological groups: predominantly oncocytoma/chromophobe RCC-like; clear cell RCC-like; papillary RCC-like; collecting duct-like; and pure sarcomatoid differentiation. The majority of the oncocytoma/chromophobe and clear cell RCC-like phenotypes were low stage (pT1 or pT2). The papillary RCC-like, collecting duct-like and pure sarcomatoid phenotypes were mainly high stage (pT3 or pT4). CONCLUSIONS: Renal cell carcinoma, unclassified is a term that encompasses tumours with a variety of morphological features and a wide biological spectrum. The most common source of diagnostic difficulty was tumours composed of predominantly eosinophilic cells. PMID- 28833390 TI - Morphological Studies of the Tongue of the Egyptian Water Buffalo (Bubalus bubalis) and Their Lingual Papillae Adaptation for Its Feeding Habits. AB - This work was conducted to describe the morphological characters of the tongue of Egyptian water buffalo (Bubalus bubalis). The lingual root and the dorsal middle region of apex and body in addition to the dorsal and ventral surface of lingual tip were devoided from any fungiform papillae. The lingual tip contains conical papillae only. The ventral surface of lingual apex was divided into two portions by the U-shaped fungiform line into papillary and non-papillary region. Histological investigation on the lingual surface epithelium and lamina propria submucosa reflects differences in these layers in different parts of the tongue. By SEM, there are two subtypes of filiform papillae: caudally directed papillae on dorsal surface and rostrally directed papillae on the lateral region of ventral surface of lingual apex. There are two subtypes of conical papillae: small slightly rostrally directed papillae on dorsal and ventral surface of lingual tip and large posteromedially directed papillae on dorsal surface of lingual root. The rounded circumvallate papillae consisted of round bulb surrounded by deep circular groove, which surrounded by circular pad. Higher magnification of filiform papillae indicates the presence of microcrests separated by microgrooves, and these microgrooves consisted of microrodes. The fungiform surface having micropores on the tip of elevated tubercle for taste buds pores. All these observed structures (microcrests, microgrooves, microrodes, tubercles, microridges) in a higher magnification allow animals to transport food particles through the oral cavity and help in the defensive behaviour. There are strong correlations between the tongue anatomical characteristics and its functions. PMID- 28833391 TI - Identification of stable fly attractant compounds in vinasse, a byproduct of sugarcane-ethanol distillation. AB - The stable fly, Stomoxys calcitrans (Diptera: Muscidae), is a worldwide pest of livestock. Recent outbreaks of stable flies in sugarcane fields in Brazil have become a serious problem for livestock producers. Larvae and pupae found inside sugarcane stems after harvesting may indicate that stable flies use these stems as potential oviposition or larval development sites. Field observations suggest that outbreaks of stable flies are associated with the vinasse and filter cake derived from biomass distillation in sugarcane ethanol production that are used as fertilizers in sugarcane fields. Adult stable flies are attracted to vinasse, which appears to present an ideal larval development site. The primary goal of the present study is to demonstrate the role of vinasse in influencing the sensory physiological and behavioural responses of stable flies, and to identify its associated volatile attractant compounds. Both laboratory and field studies showed that vinasse is extremely attractive to adult stable flies. Chemical analyses of volatiles collected revealed a wide range of carboxylic acids, alcohols, phenols and aldehydes as potential attractant compounds. These newly identified attractants could be used to develop a tool for the attractant-baited mass trapping of stable flies in order to reduce infestations. PMID- 28833392 TI - H3K27me3 immunostaining for sex determination in the context of presumed tissue misidentification. PMID- 28833393 TI - Aggressive Behaviors and Suicide Ideation in Inpatient Adolescents: The Moderating Roles of Internalizing Symptoms and Stress. AB - The present study examined a conceptual model in which the association between aggressive behaviors and suicide ideation is moderated by internalizing symptoms and ongoing stress. Participants were 304 psychiatric inpatient adolescents (65.8% girls) ranging in age from 12 to 17 years (Mean age = 14.69). The association between aggressive behaviors and suicide ideation was significantly moderated by internalizing symptoms and ongoing stress; the association was positive in adolescents low in internalizing symptoms or high in ongoing stress, but negative in adolescents high in internalizing symptoms or low in ongoing stress. The three-way interaction between aggressive behaviors, internalizing symptoms, and ongoing stress was not statistically significant. The current findings indicate that in adolescents who display high levels of aggressive behaviors, the presence of high ongoing stress provides a more useful indicator of levels of suicide ideation than the presence of high internalizing symptoms. Implications for case identification and prevention are discussed. PMID- 28833394 TI - High molecular weight caldesmon expression in ovarian adult granulosa cell tumour and fibrothecoma. PMID- 28833395 TI - Depression Mediates the Relationship Between Distress Tolerance and Nonsuicidal Self-Injury Among Adolescents: One-Year Follow-Up. AB - Through a one-year follow-up design, this study examined whether distress tolerance would increase the risk for nonsuicidal self-injury (NSSI), mediated through depression in a representative sample of adolescents. Participants (N = 2,170) were recruited from senior high schools throughout Taiwan using both stratified and cluster sampling in time 1 (T1), and 1,832 students were followed up one year later (T2). Structure equation modeling results revealed that after controlling NSSI measured at T1, NSSI (T2) was significantly predicted by distress tolerance (T1) and fully mediated through depression (T2). The mediating role of depression in the relationship between distress tolerance and NSSI are discussed. PMID- 28833396 TI - A microRNA-7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma. AB - : Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient, and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TYRO3-AXL-MER family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC; however, its role in SR is unknown. In this study, we generated two functionally distinct sorafenib-resistant human Huh-7 HCC cell lines in order to identify new mechanisms to abrogate acquired SR as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA (miR), miR-7-5p (miR 7), in both in vitro and in vivo preclinical models of human HCC and identified miR-7 as a potent tumor suppressor of human HCC. We identified TYRO3 as a new functional target of miR-7, which regulates proliferation, migration, and invasion of Huh-7 cells through the phosphoinositide 3-kinase/protein kinase B pathway and is markedly elevated with acquisition of SR. Furthermore, miR-7 effectively silenced TYRO3 expression in both sorafenib-sensitive and sorafenib resistant Huh-7 cells, inhibiting TYRO3/growth arrest specific 6-mediated cancer cell migration and invasion. CONCLUSION: We identified a mechanism for acquiring SR in HCC that is through the aberrant expression of the TYRO3/phosphoinositide 3 kinase/protein kinase B signal transduction pathway, and that can be overcome by miR-7 overexpression. Taken together, these data suggest a potential role for miR 7 as an RNA-based therapeutic to treat refractory and drug-resistant HCC. (Hepatology 2018;67:216-231). PMID- 28833398 TI - Assessment of time to glucose peak during an oral glucose tolerance test. PMID- 28833399 TI - Work organization, health, and obesity in urban transit operators: A qualitative study. AB - BACKGROUND: Urban transit operators have high rates of obesity, hypertension, and other cardiovascular risk-factors compared to other occupations. There have been few qualitative studies exploring the interrelationships between the organization of transit work, stress, and health including obesity, from the perspective of operators. METHODS: Five focus groups were conducted at five Divisions in a transit authority in Southern California and included 65 bus and rail operators. RESULTS: Operators reported a great deal of stress related to their work, including 1) time pressures and lack of recovery time; 2) long work shifts and overtime; 3) feeling unsafe when dealing with the public; 4) lack of respect from supervisors and management. Operators believed stressful working conditions negatively impacted their health and weight. CONCLUSION: This qualitative study yielded new as well as confirmatory data about stress and transit work organization, health, and weight in operators. This study will add to future survey research and interventions in this population. PMID- 28833400 TI - How Cross-Linguistic Differences in the Grammaticalization of Future Time Reference Influence Intertemporal Choices. AB - According to Chen's (2013) Linguistic Savings Hypothesis (LSH), our native language affects our economic behavior. We present three studies investigating how cross-linguistic differences in the grammaticalization of future-time reference (FTR) affect intertemporal choices. In a series of decision scenarios about finance and health issues, we let speakers of altogether five languages that represent FTR with increasing strength, that is, Chinese, German, Danish, Spanish, and English, choose between hypothetical sooner-smaller and later-larger reward options. While the LSH predicts a present-bias that increases with FTR strength, our decision makers preferred later-larger options and this future-bias increased with FTR-strength. In multiple regressions, the FTR-strength effect persisted when controlled for socioeconomic and cultural differences. We discuss why our findings deviate from the LSH and ask in how far the FTR-strength effect represents a habitual constitution of linguistic relativity or an instance of online decision framing. PMID- 28833402 TI - Good supervision: Every PhD student wants it, but it's not wise simply to expect it.... PMID- 28833401 TI - A novel approach based on low-field NMR for the detection of the pathological components of sputum in cystic fibrosis patients. AB - PURPOSE: Development of a reliable, simple method to monitor lung condition in cystic fibrosis (CF) patients. Lung functionality assessment in CF patients is relevant, as most of them still die of respiratory failure. In lung mucus (sputum) of CF patients, components such as proteins, biopolymers, DNA, bacteria, and mucin are pathologically increased. As lung functionality is related to the amount of the pathological components in the sputum, their determination can help clinicians in monitoring lung condition and planning therapy. METHODS: Low-field NMR was used to evaluate the variation of the relaxation time (T2m ) of the water hydrogens present in CF sputum in relation to the amounts of the pathological components. Low-field NMR was tested in artificial samples (mucin or alginates), then in conditional sputum (saliva from healthy volunteers, added by different amounts of the pathological components), and finally in 12 patients' sputums, in which T2m was correlated to a commonly used lung monitoring test (i.e., forced expiratory volume in the first second). RESULTS: T2m significantly (P < 0.05) differed between samples with and without pathological components and between healthy and CF patients (P < 0.05), in which T2m correlated (r = 0.87) with FEV1 . CONCLUSIONS: The presented method can potentially become a valuable lung monitoring tool in CF patients. Magn Reson Med 79:2323-2331, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833403 TI - Cancer: Towards a general theory of the target: All successful cancer therapies, actual or potential, are reducible to either (or both) of two fundamental strategies. AB - General theories (GT) are reductionist explications of apparently independent facts. Here, in reviewing the literature, I develop a GT to simplify the cluttered landscape of cancer therapy targets by revealing they cluster parsimoniously according to only a few underlying principles. The first principle is that targets can be only exploited by either or both of two fundamentally different approaches: causality-inhibition, and 'acausal' recognition of some marker or signature. Nonetheless, each approach must achieve both of two separate goals, efficacy (reduction in cancer burden) and selectivity (sparing of normal cells); if the mechanisms are known, this provides a definition of rational treatment. The second principle is target fragmentation, whereby the target may perform up to three categoric functions (cytoreduction, modulation, cytoprotection), potentially mediated by physically different target molecules, even on different cell types, or circulating freely. This GT remains incomplete until the minimal requirements for cure, or alternatively, proof that cure is impossible, become predictable. PMID- 28833404 TI - Suppression of c-Myc enhances p21WAF1/CIP1 -mediated G1 cell cycle arrest through the modulation of ERK phosphorylation by ascochlorin. AB - Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, other genes such as the proto-oncogene c-Myc are promising targets for anticancer therapy. In the present study, we provide evidence that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 cell cycle arrest and p21WAF1/CIP1 expression by downregulating of c Myc protein expression. Ascochlorin promoted the G1 arrest, upregulated p53 and p21WAF1/CIP1 , and downregulated c-Myc in HCT116 cells. In p53-deficient cells, ascochlorin enhanced the expression of G1 arrest-related genes except p53. Small interfering RNA (siRNA) mediated c-Myc silencing indicated that the transcriptional repression of c-Myc was related to ascochlorin-mediated modulation of p21WAF1/CIP1 expression. Ascochlorin suppressed the stabilization of the c-Myc protein by inhibiting ERK and P70S6K/4EBP1 phosphorylation, whereas it had no effect on c-Myc degradation mediated by PI3K/Akt/GSK3beta. The ERK inhibitor PD98059 and siRNA-mediated ERK silencing induced G1 arrest and p21WAF1/CIP1 expression by downregulating c-Myc in p53-deficient cells. These results indicated that ascochlorin-induced G1 arrest is associated with the repression of ERK phosphorylation and c-Myc expression. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for ERK/c-Myc. PMID- 28833405 TI - Synthesis and evaluation of novel 18 F-labeled quinazoline derivatives with low lipophilicity for tumor PET imaging. AB - Four novel 18 F-labeled quinazoline derivatives with low lipophilicity, [18 F]4 (2-fluoroethoxy)-6,7-dimethoxyquinazoline ([18 F]I), [18 F]4-(3-((4-(2 fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([18 F]II), [18 F]4 (2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([18 F]III), and [18 F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([18 F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose dependent manner. The EGFR-TK autophosphorylation IC50 values of [18 F]I, [18 F]II, [18 F]III, and [18 F]IV were 7.732, 0.4698, 0.1174, and 0.1176 MUM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [18 F]I and [18 F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80 +/- 3.42%ID/mg protein and 27.31 +/- 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [18 F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [18 F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives. PMID- 28833406 TI - Effect of age and dietary carbohydrate profiles on glucose and insulin dynamics in horses. AB - BACKGROUND: Glucose and insulin dynamics may be different in adult and aged horses. OBJECTIVES: To determine the effects of age and dietary carbohydrates on glucose and insulin dynamics in healthy horses. STUDY DESIGN: Balanced Latin square with four isocaloric diets: CONTROL (hay plus restricted-starch-and-sugar fortified pellets), STARCH (control plus kibbled corn), FIBER (control plus unmolassed sugar beet pulp/soybean hull pellets) and SUGAR (control plus dextrose powder). METHODS: A total of 16 healthy Thoroughbreds and Standardbreds divided into two age groups: ADULT (8.8 +/- 2.9 years; n = 8) and AGED (20.6 +/- 2.1 years; n = 8). Following dietary adaptation, horses underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT), modified oral sugar test (OST) and dietary meal challenge. Outcome variables included: insulin sensitivity (SI), disposition index (DI), glucose effectiveness (Sg) and acute insulin response to glucose (AIRg) from the FSIGTT; peak glucose, peak insulin, time to peak, area under the curve for glucose (AUCg) and insulin (AUCi) from the OST and dietary meal challenge. Data were analyzed using multivariable linear mixed regression modelling. RESULTS: AIRg was higher in AGED (mean [95% confidence interval]; 582.0 [455.0-709.0]) vs. ADULT (358.0 [224.0-491.0]; P = 0.03). ADULT and AGED horses had a higher SI on STARCH (adult: 3.3 [2.3-4.2]; aged: 2.8 [1.9-3.7]) and SUGAR (adult: 3.4 [2.5-4.3]; aged: 4.0 [3.1-4.9]) diets compared with CONTROL (adult: 2.0 [1.1-2.9], P = 0.029 (starch), P = 0.009 (sugar); aged: 1.4 [0.5-2.2], P = 0.009 (starch), P < 0.001 (sugar)). Feeding a STARCH (adult: 21581.0 [15029.0-28133.0]; aged: 35205.0 [29194.0-41216.0]) or SUGAR (adult: 26050.0 [19885.0-32215.0]; aged: 25720.0 [19770.0-31670.0]) meal resulted in postprandial hyperinsulinaemia (AUCi). MAIN LIMITATIONS: Study cohort contained two insulin-sensitive breeds and no insulin-resistant breeds. CONCLUSIONS: Age and diet should be considered when evaluating glucose and insulin dynamics. PMID- 28833408 TI - Suicide Crisis Syndrome Mediates the Relationship Between Long-term Risk Factors and Lifetime Suicidal Phenomena. AB - In recent years, there has been growing attention to the distinction between acute and long-term suicidal risk factors. We have previously characterized an acute, negative affect state, termed the suicide crisis syndrome (SCS), as a marker of near-term suicidal risk. Here, we test whether documented long-term risk factors (i.e., trait vulnerabilities), including perfectionism, impulsivity, chronic substance abuse, insecure attachment, poor social support, and childhood trauma, associate to suicidal phenomena through a pathway of the SCS. A sample of 207 psychiatric inpatients were administered a battery of eight scales, including the Suicide Trigger Scale (STS-3) as a measure of the SCS. While both STS-3 and all trait vulnerabilities were associated with lifetime suicidal ideation and attempts, only STS-3 was related to pre-admission suicide attempts. The STS-3 significantly mediated the effect of each trait vulnerability on lifetime suicidal phenomena (combining ideation and behavior), with the proportion of mediating effect ranging from .29 to .56. Reverse mediation analyses were only significant for insecure attachment, supporting a largely unidirectional mediation effect. The SCS appears to serve as an acute risk factor for suicidal behavior in psychiatric inpatients and may act as a mechanism by which long-term risk factors increase suicidal risk. PMID- 28833407 TI - Fully phase-encoded MRI near metallic implants using ultrashort echo times and broadband excitation. AB - PURPOSE: To develop a fully phase-encoded MRI method for distortion-free imaging near metallic implants, in clinically feasible acquisition times. THEORY AND METHODS: An accelerated 3D fully phase-encoded acquisition with broadband excitation and ultrashort echo times is presented, which uses a broadband radiofrequency pulse to excite the entire off-resonance induced by the metallic implant. Furthermore, fully phase-encoded imaging is used to prevent distortions caused by frequency encoding, and to obtain ultrashort echo times for rapidly decaying signal. RESULTS: Phantom and in vivo acquisitions were used to describe the relationship among excitation bandwidth, signal loss near metallic implants, and T1 weighting. Shorter radiofrequency pulses captured signal closer to the implant by improving spectral coverage and allowing shorter echo times, whereas longer pulses improved T1 weighting through larger maximum attainable flip angles. Comparisons of fully phase-encoded acquisition with broadband excitation and ultrashort echo times to T1 -weighted multi-acquisition with variable resonance image combination selective were performed in phantoms and subjects with metallic knee and hip prostheses. These acquisitions had similar contrast and acquisition efficiency. CONCLUSIONS: Accelerated fully phase-encoded acquisitions with ultrashort echo times and broadband excitation can generate distortion free images near metallic implants in clinically feasible acquisition times. Magn Reson Med 79:2156-2163, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833409 TI - Contact dermatitis is an unrecognized problem in the construction industry: Comparison of four different assessment methods. AB - BACKGROUND: A high contact dermatitis symptoms prevalence has been observed in Dutch construction workers. METHODS: Contact dermatitis was diagnosed by an expert panel using questionnaire data and photographs of 751 subjects' hands. A subset was evaluated by two occupational physicians. Their diagnoses were compared to those of the expert panel. In addition, two self-reported questionnaire-based assessment methods were compared to the expert panel evaluation. Associations between contact dermatitis and determinants were assessed using log-binomial regression analysis. RESULTS: Contact dermatitis prevalence was high: 61.4% (expert panel's diagnosis) and 32.9% (self-reported). Agreement between occupational physicians and the expert panel was low but increased after training. Washing hands with solvents and performing job-related tasks at home were related to contact dermatitis. CONCLUSIONS: Contact dermatitis prevalence among construction workers is high. Recognition of contact dermatitis by occupational physicians is poor but can be improved by training. Awareness of skin disorders should be raised. PMID- 28833410 TI - Direct comparison of in vivo versus postmortem second-order motion-compensated cardiac diffusion tensor imaging. AB - PURPOSE: To directly compare in vivo versus postmortem second-order motion compensated spin-echo diffusion tensor imaging of the porcine heart. METHODS: Second-order motion-compensated spin-echo cardiac diffusion tensor imaging was performed during systolic contraction in vivo and repeated upon cardiac arrest by bariumchloride without repositioning of the study animal or replaning of imaging slices. In vivo and postmortem reproducibility was assessed by repeat measurements. Comparison of helix, transverse, and sheet (E2A) angulation as well as mean diffusivity and fractional anisotropy was performed. RESULTS: Intraclass correlation coefficients for repeated measurements (postmortem/in vivo) were 0.95/0.96 for helix, 0.70/0.66 for transverse, and 0.79/0.72 for E2A angulation; 0.83/0.72 for mean diffusivity; and 0.78/0.76 for fractional anisotropy. The corresponding 95% levels of agreement across the left ventricle were: helix 14 to 18 degrees /12 to 15 degrees , transverse 9 to 10 degrees /10 to 11 degrees , E2A 15 to 20 degrees /16 to 18 degrees . The 95% levels of agreement across the left ventricle for the comparison of postmortem versus in vivo were 20 to 22 degrees for helix, 13 to 19 degrees for transverse, and 24 to 31 degrees for E2A angulation. CONCLUSIONS: Parameters derived from in vivo second-order motion compensated spin-echo diffusion tensor imaging agreed well with postmortem imaging, indicating sufficient suppression of motion-induced signal distortions of in vivo cardiac diffusion tensor imaging. Magn Reson Med 79:2265-2276, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833411 TI - Improved prediction of direction-dependent, acute axonal injury in piglets. AB - To guide development of safety equipment that reduces sports-related head injuries, we sought to enhance predictive relationships between head movement and acute axonal injury severity. The severity of traumatic brain injury (TBI) is influenced by the magnitude and direction of head kinematics. Previous studies have demonstrated correlation between rotational head kinematics and symptom severity in the adult. More recent studies have demonstrated brain injury age- and direction-dependence, relating head kinematics to white matter tract-oriented strains. We have recently developed and assessed novel rotational head kinematic parameters as predictors of white matter damage in the female immature piglet. We show that many previously published rotational kinematic injury predictor metrics poorly predict acute axonal pathology induced by rapid, non-impact head rotations and that inclusion of cerebral moments of inertia (MOI) in rotational head injury metrics refines prediction of diffuse axonal injury following rapid head rotations for two immature age groups. Rotational Work (RotWork) was the best significant predictor of traumatic axonal injury in both newborn and pre adolescent piglets following head rotations in the axial, coronal, and sagittal planes. An improvement over current metrics, we find that RotWork, which incorporates head rotation rate, direction, and brain shape, significantly enhanced acute traumatic axonal injury prediction. For similar injury extent, the RotWork threshold is lower for the newborn piglet than the pre-adolescent. PMID- 28833412 TI - A comparison of group prediction approaches in longitudinal discriminant analysis. AB - Longitudinal discriminant analysis (LoDA) can be used to classify patients into prognostic groups based on their clinical history, which often involves longitudinal measurements of various clinically relevant markers. Patients' longitudinal data is first modelled using multivariate generalised linear mixed models, allowing markers of different types (e.g. continuous, binary, counts) to be modelled simultaneously. We describe three approaches to calculating a patient's posterior group membership probabilities which have been outlined in previous studies, based on the marginal distribution of the longitudinal markers, conditional distribution and distribution of the random effects. Here we compare the three approaches, first using data from the Mayo Primary Biliary Cirrhosis study and then by way of simulation study to explore in which situations each of the three approaches is expected to give the best prediction. We demonstrate situations in which the marginal or random-effects approach perform well, but find that the conditional approach offers little extra information to the random effects and marginal approaches. PMID- 28833414 TI - Introducing the nurse practitioner into the surgical ward: an ethnographic study of interprofessional teamwork practice. AB - AIM: The first nurse practitioners in surgical care were introduced into Swedish surgical wards in 2014. Internationally, organisations that have adopted nurse practitioners into care teams are reported to have maintained or improved the quality of care. However, close qualitative descriptions of teamwork practice may add to existing knowledge of interprofessional collaboration when introducing nurse practitioners into new clinical areas. The aim was to report on an empirical study describing how interprofessional teamwork practice was enacted by nurse practitioners when introduced into surgical ward teams. METHODS AND RESULTS: The study had a qualitative, ethnographic research design, drawing on a sociomaterial conceptual framework. The study was based on 170 hours of ward based participant observations of interprofessional teamwork practice that included nurse practitioners. Data were gathered from 2014 to 2015 across four surgical sites in Sweden, including 60 interprofessional rounds. The data were analysed with an iterative reflexive procedure involving inductive and theory-led approaches. The study was approved by a Swedish regional ethics committee (Ref. No.: 2014/229-31). The interprofessional teamwork practice enacted by the nurse practitioners that emerged from the analysis comprised a combination of the following characteristic role components: clinical leader, bridging team colleague and ever-present tutor. These role components were enacted at all the sites and were prominent during interprofessional teamwork practice. CONCLUSION: The participant nurse practitioners utilised the interprofessional teamwork practice arrangements to enact a role that may be described in terms of a quality guarantee, thereby contributing to the overall quality and care flow offered by the entire surgical ward team. PMID- 28833413 TI - An improved vitrification protocol for equine immature oocytes, resulting in a first live foal. AB - BACKGROUND: The success rate for vitrification of immature equine oocytes is low. Although vitrified-warmed oocytes are able to mature, further embryonic development appears to be compromised. OBJECTIVES: The aim of this study was to compare two vitrification protocols, and to examine the effect of the number of layers of cumulus cells surrounding the oocyte during vitrification of immature equine oocytes. STUDY DESIGN: Experimental in vitro and in vivo trials. METHODS: Immature equine oocytes were vitrified after a short exposure to high concentrations of cryoprotective agents (CPAs), or a long exposure to lower concentrations of CPAs. In Experiment 1, the maturation of oocytes surrounded by multiple layers of cumulus cells (CC oocytes) and oocytes surrounded by only corona radiata (CR oocytes) was investigated. In Experiment 2, spindle configuration was determined for CR oocytes vitrified using the two vitrification protocols. In Experiment 3, further embryonic development was studied after fertilisation and culture. Embryo transfer was performed in a standard manner. RESULTS: Similar nuclear maturation rates were observed for CR oocytes vitrified using the long exposure and nonvitrified controls. Furthermore, a lower maturation rate was obtained for CC oocytes vitrified with the short exposure compared to control CR oocytes (P = 0.001). Both vitrification protocols resulted in significantly higher rates of aberrant spindle configuration than the control groups (P<0.05). Blastocyst development only occurred in CR oocytes vitrified using the short vitrification protocol, and even though blastocyst rates were significantly lower than in the control group (P<0.001), transfer of five embryos resulted in one healthy foal. MAIN LIMITATIONS: The relatively low number of equine oocytes and embryo transfer procedures performed. CONCLUSIONS: For vitrification of immature equine oocytes, the use of 1) CR oocytes, 2) a high concentration of CPAs, and 3) a short exposure time may be key factors for maintaining developmental competence. PMID- 28833415 TI - Two kinds of physician-assisted death. AB - I argue that the concept 'physician-assisted suicide' covers two procedures that should be distinguished: giving someone access to humane means to end his own life, and taking co-responsibility for the safe and effective execution of that plan. In the first section I explain the distinction, in the following sections I show why it is important. To begin with I argue that we should expect the laws that permit these two kinds of 'assistance' to be different in their justificatory structure. Laws that permit giving access only presuppose that the right to self-determination implies a right to suicide, but laws that permit doctors to take co-responsibility may have to appeal to a principle of mercy or beneficence. Actually this difference in justificatory structure can to some extent be found in existing regulatory systems, though far from consistently. Finally I argue that if one recognizes a right to suicide, as Oregon and other American states implicitly do, and as the European Court of Human Rights has recently done explicitly, one is committed to permit the first kind of 'assistance' under some conditions. PMID- 28833416 TI - The acute toxicity of major ion salts to Ceriodaphnia dubia. III. Mathematical models for mixture toxicity. AB - Based on previous research on the acute toxicity of major ions (Na+ , K+ , Ca2+ , Mg2+ , Cl- , SO42- , and HCO3- /CO32- ) to Ceriodaphnia dubia, a mathematical model was developed for predicting the median lethal concentration (LC50) for any ion mixture, excepting those dominated by K-specific toxicity. One component of the model describes a mechanism of general ion toxicity to which all ions contribute and predicts LC50s as a function of osmolarity and Ca activity. The other component describes Mg/Ca-specific toxicity to apply when such toxicity exceeds the general ion toxicity and predicts LC50s as a function of Mg and Ca activities. This model not only tracks well the observed LC50s from past research used for model development but also successfully predicts LC50s from new toxicity tests on synthetic mixtures of ions emulating chemistries of various ion-enriched effluents and receiving waters. It also performs better than a previously published model for major ion toxicity. Because of the complexities of estimating chemical activities and osmolarity, a simplified model based directly on ion concentrations was also developed and found to provide useful predictions. Environ Toxicol Chem 2018;37:247-259. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28833418 TI - Conflicting rationales: leader's experienced ethical challenges in community health care for older people. AB - BACKGROUND: Ethical challenges arise in all types of care, and leaders need to be aware of how to resolve these challenges. Healthcare systems tend to be organised around medical conditions, and the patient is often faced with a series of uncoordinated visits to multiple specialties. Ideally, care should be organised around the patient's needs. AIM: The purpose of this article was to highlight some ethical challenges perceived by leaders with responsibility for management and service distribution, finance and ensuring quality of community health services for older people. METHOD: This study had a qualitative design with a qualitative content analysis of one focus group with six leaders that met four times in total. Leaders from the community healthcare sector in one Norwegian municipality were included, representing both nursing homes and home-based health care. The study followed the intentions of the Declaration of Helsinki and standard ethical principles. The Norwegian Social Science Data Services approved the study. All participants voluntarily gave written informed consent. FINDINGS: The main theme that emerged from this study was the ethical challenge leaders felt in the form of an inherent conflict between a caring rationale versus economic or technological rationales. Four categories emerged: (i) Management: quality versus economy; (ii) Prioritisation: fair distribution of healthcare services; (iii) Responsibility: considering individuals' needs versus the needs of the whole community; and (iv) Welfare technology: possibilities and challenges. CONCLUSION: Leaders' responsibilities in community health care for older people need to strike a balance between ethical principles in the management of limited resources. PMID- 28833417 TI - Comprehensive evaluation of the revised international staging system in multiple myeloma patients treated with novel agents as a primary therapy. AB - The revised International Staging System (R-ISS) has recently been developed to improve the risk stratification of multiple myeloma (MM) patients over the ISS. We assessed the R-ISS in MM patients who were treated with novel agents as a primary therapy and evaluated its discriminative power and ability to reclassify patients from the ISS. A total of 514 newly diagnosed MM patients treated with novel agents including thalidomide, bortezomib, and lenalidomide as a primary therapy were included in this retrospective analysis. With a median follow-up duration of 42.3 months (range, 40.5-44.1), the median overall survival (OS) was 61.0 months. There was a significant difference in median OS (not reached, 60.9, and 50.1 months for stages 1, 2, and 3, respectively, P < 0.001) among the three stages of R-ISS. The C-statistic was significantly greater for R-ISS than for ISS (0.769 vs. 0.696, P < 0.001). The event NRI was -0.08 (95% confidence interval [CI], -0.18-0.01) and the non-event NRI was 0.05 (95% CI, -0.03-0.10), resulting in a total NRI of -0.03 (95% CI, -0.14-0.08, P = 0.602). The R-ISS performs well and has significantly better discriminative power than the ISS in MM patients treated with novel agents as a primary therapy. However, it does not better reclassify patients from the ISS, suggesting that there is still room to improve the staging system. Moreover, new statistical measures for assessing and quantifying the risk prediction of new prognostic models are necessary in future studies. PMID- 28833419 TI - Multislice spiral CT angiography for evaluation of acute aortic syndrome. AB - OBJECTIVE: To discuss the diagnostic value of multislice CT angiography (MSCTA) in acute aortic syndrome (AAS). MATERIALS AND METHODS: The clinical and imaging data of 36 cases diagnosed as AAS by MSCTA were collected. The manifestations of the MSCTA images were reviewed retrospectively, and the average x-ray dose was calculated. RESULTS: Among 36 AAS cases, 16 cases had aortic dissection (AD), 8 cases had penetrating atherosclerotic ulcer (PAU), 7 cases had intramural hematoma (IMH), and 5 cases had unstable thoracic aneurysm (UTA). Of 16 cases with AD, type A and type B accounted for 43.7% (7/16) and 56.3% (9/16), respectively. Of 7 cases with IMH, type A and type B accounted for 42.9% (3/7) and 57.1% (4/7), respectively. CONCLUSION: In spite of the x-ray radiation, MSCTA proves to be a rapid and noninvasive imaging technique for the diagnosis of AAS. PMID- 28833420 TI - Problematising standards in an era of increasing transparency. PMID- 28833422 TI - Judgement of risk in practice. PMID- 28833423 TI - Can continuing professional development mitigate adverse patient outcomes? PMID- 28833424 TI - In defence of efficient medical education. PMID- 28833425 TI - Response to: 'Patients of doctors further from medical school graduation have poorer outcomes'. PMID- 28833426 TI - 'Playing the game': How do surgical trainees seek feedback using workplace-based assessment? AB - OBJECTIVES: Although trainees and trainers find feedback interactions beneficial, difficulties in giving and receiving feedback are reported. Few studies have explored what drives trainees to seek feedback. This study explores how workplace based assessments (WBAs) influence the ways surgical trainees seek feedback and feedback interactions. METHODS: Utilising a template analysis approach, we conducted 10 focus groups with 42 surgical trainees from four regions across the UK. Data were independently coded by three researchers, incorporating three a priori themes identified from a previous quantitative study. Further themes emerged from exploration of these data. The final template, agreed by the three researchers, was applied to all focus group transcripts. The themes were linked in a diagrammatical form to allow critical exploration of the data. RESULTS: Trainees' perceptions of the purpose of WBA for learning or an assessment of learning, and their relationship with their trainer impacted upon how trainees chose to use WBA. Perceiving WBA as a test led trainees to 'play the game': seek positive and avoid negative feedback through WBA. Perceiving WBA as a chance to learn led trainees to seek negative feedback. Some trainees sought negative feedback outside WBA. Negative feedback was more important for changing practice compared with positive feedback, which enabled trainees to 'look good' but had less of an effect on changing clinical practice. The timing of feedback relative to WBA was also important, with immediate feedback being more beneficial for learning; however, delayed feedback was still sought using WBA. DISCUSSION: Trainees' perceptions of the purpose of WBA and their relationship with their trainer informed when they chose to seek feedback. Trainees who perceived WBA as a test were led to 'play the game' by seeking positive and avoiding negative feedback. Outside of WBA, trainees sought negative feedback, which was most important for change in practice. PMID- 28833427 TI - Managing risks and benefits: key issues in entrustment decisions. PMID- 28833428 TI - Tensions in post-examination feedback: information for learning versus potential for harm. AB - OBJECTIVE: Self-regulation is recognised as being a requisite skill for professional practice This study is part of a programme of research designed to explore efficient methods of feedback that improve medical students' ability to self-regulate their learning. Our aim was to clarify how students respond to different forms and content of written feedback and to explore the impact on study behaviour and knowledge acquisition. METHODS: Year 2 students in a 4-year graduate entry medical programme completing four formative progress tests during the academic year were randomised into three groups receiving different feedback reports. All reports included proportion correct overall and by clinical rotation. One group received feedback reports including lists of clinical presentations relating to questions answered correctly and incorrectly; another group received reports containing this same information in combination with response certitude. The final group received reports involving normative comparisons. Baseline progress test performance quartile groupings (a proxy for academic ability) were determined by results on the first progress test. A mixed method approach with triangulation of research findings was used to interpret results. Outcomes of interest included progress test scores, summative examination results and measures derived from study diaries, questionnaires and semi-structured interviews. RESULTS: Of the three types of feedback provided in this experiment, feedback containing normative comparisons resulted in inferior test performance for students in the lowest performance quartile group. This type of feedback appeared to stimulate general rather than examination-focused study. CONCLUSIONS: Medical students are often considered relatively homogenous and high achieving, yet the results of this study suggest caution when providing them with normative feedback indicating poorer performance relative to their peers. There is much need for further work to explore efficient methods of providing written feedback that improves medical students' ability to self-regulate their learning, particularly when giving feedback to those students who have the most room for improvement. PMID- 28833429 TI - Response to letters for Doctors further from Medical School Graduation. PMID- 28833430 TI - A good habit, well-practised, flowers into a virtue. PMID- 28833431 TI - Reply to "Converse well-being of locked-in patients and caregivers". PMID- 28833432 TI - Elasticity of ascending aorta and left ventricular myocardial functions in children with bicuspid aortic valve. AB - BACKGROUND: The aim of the study was to determine the aortic elasticity parameters (EPs) and myocardial function in children with bicuspid aortic valve (BAV). Additionally, we evaluated the effect of aortic leaflet phenotype (ALP) and aortic dilatation on elasticity parameters. METHODS: Sixty-two children diagnosed with isolated BAV (mean age 9.3 years old; patient group) and 63 healthy children (control group) have been evaluated for this study. Patient group was divided into three age subgroups: between 0-6, 7-11 and 12-17 age intervals. Distensibility (DI) and stiffness index (SI) of ascending aorta were calculated by M-mode echocardiographic data. The myocardial functions were evaluated by tissue Doppler echocardiography. RESULTS: Patient group exhibited significantly lower DI and higher SI than control group (SI: 3.8 +/- 1.7 vs 2.4 +/- 0.8, P < .0001). The aortic elasticity indexes in patient group with different age subgroups were different from those in control subgroups. Patient group had significantly lower E' velocity at mitral lateral annulus and septum than control group (P < .017 and P < .001). There was no statistically significant correlation between E' velocities and DI/SI values. We, however, found a weak correlation between septal E' velocities and strain values (r = .255, P = .046). EP did not show statistically significant difference with regard to ALP and presence of aortic dilatation. CONCLUSION: Abnormality of aortic elasticity and myocardial functions can be detected in children with BAV from infantile to adolescent. Myocardial functions are not related to SI and DI. We considered the possibility of intrinsic aortic wall abnormality in children with BAV. PMID- 28833433 TI - Cortical pathology in multiple sclerosis detected by the T1/T2-weighted ratio from routine magnetic resonance imaging. AB - OBJECTIVE: In multiple sclerosis, neuropathological studies have shown widespread changes in the cerebral cortex. In vivo imaging is critical, because the histopathological substrate of most measurements is unknown. METHODS: Using a novel magnetic resonance imaging analysis technique, based on the ratio of T1- and T2-weighted signal intensities, we studied the cerebral cortex of a large cohort of patients in early stages of multiple sclerosis. A total of 168 patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis (Expanded Disability Status Scale: median = 1, range = 0-3.5) and 80 age- and sex matched healthy controls were investigated. We also searched for the histopathological substrate of the T1/T2-weighted ratio by combining postmortem imaging and histopathology in 9 multiple sclerosis brain donors. RESULTS: Patients showed lower T1/T2-weighted ratio values in parietal and occipital areas. The 4 most significant clusters appeared in the medial occipital and posterior cingulate cortex (each left and right). The decrease of the T1/T2 weighted ratio in the posterior cingulate was related to performance in attention. Analysis of the T1/T2-weighted ratio values of postmortem imaging yielded a strong correlation with dendrite density but none of the other parameters including myelin. INTERPRETATION: The T1/T2-weighted ratio decreases in early stages of multiple sclerosis in a widespread manner, with a preponderance of posterior areas and with a contribution to attentional performance; it seems to reflect dendrite pathology. As the method is broadly available and applicable to available clinical scans, we believe that it is a promising candidate for studying and monitoring cortical pathology or therapeutic effects in multiple sclerosis. Ann Neurol 2017;82:519-529. PMID- 28833434 TI - Evaluating the effects of pH, hardness, and dissolved organic carbon on the toxicity of aluminum to freshwater aquatic organisms under circumneutral conditions. AB - Although it is well known that increasing water hardness and dissolved organic carbon (DOC) concentrations mitigate the toxicity of aluminum (Al) to freshwater organisms in acidic water (i.e., pH < 6), these effects are less well characterized in natural waters at circumneutral pHs for which most aquatic life regulatory protection criteria apply (i.e., pH 6-8). The evaluation of Al toxicity under varying pH conditions may also be confounded by the presence of Al hydroxides and freshly precipitated Al in newly prepared test solutions. Aging and filtration of test solutions were found to greatly reduce toxicity, suggesting that toxicity from transient forms of Al could be minimized and that precipitated Al hydroxides contribute significantly to Al toxicity under circumneutral conditions, rather than dissolved or monomeric forms. Increasing pH, hardness, and DOC were found to have a protective effect against Al toxicity for fish (Pimephales promelas) and invertebrates (Ceriodaphnia dubia, Daphnia magna). For algae (Pseudokirchneriella subcapitata), the protective effects of increased hardness were only apparent at pH 6, less so at pH 7, and at pH 8, increased hardness appeared to increase the sensitivity of algae to Al. The results support the need for water quality-based aquatic life protection criteria for Al, rather than fixed value criteria, as being a more accurate predictor of Al toxicity in natural waters. Environ Toxicol Chem 2018;37:49-60. (c) 2017 SETAC. PMID- 28833435 TI - Modelling two cause-specific hazards of competing risks in one cumulative proportional odds model? AB - Competing risks extend standard survival analysis to considering time-to-first event and type-of-first-event, where the event types are called competing risks. The competing risks process is completely described by all cause-specific hazards, ie, the hazard marked by the event type. Separate Cox models for each cause-specific hazard are the standard approach to regression modelling, but they come with the interpretational challenge that there are as many regression coefficients as there are competing risks. An alternative approach is to directly model the cumulative event probabilities, but again, there will be as many models as there are competing risks. The aim of this paper is to investigate the usefulness of a third alternative. Proportional odds modelling of all cause specific hazards summarizes the effect of one covariate on "opposing" competing outcomes in one regression coefficient. For instance, if the competing outcomes are hospital death and alive discharge from hospital, the modelling assumption is that a covariate affects both outcomes in opposing directions, but the effect size is of the same absolute magnitude. We will investigate the interpretational aspects of the approach analysing a data set on intensive care unit patients using parametric methods. PMID- 28833436 TI - Fast 3D magnetic resonance fingerprinting for a whole-brain coverage. AB - PURPOSE: The purpose of this study was to accelerate the acquisition and reconstruction time of 3D magnetic resonance fingerprinting scans. METHODS: A 3D magnetic resonance fingerprinting scan was accelerated by using a single-shot spiral trajectory with an undersampling factor of 48 in the x-y plane, and an interleaved sampling pattern with an undersampling factor of 3 through plane. Further acceleration came from reducing the waiting time between neighboring partitions. The reconstruction time was accelerated by applying singular value decomposition compression in k-space. Finally, a 3D premeasured B1 map was used to correct for the B1 inhomogeneity. RESULTS: The T1 and T2 values of the International Society for Magnetic Resonance in Medicine/National Institute of Standards and Technology MRI phantom showed a good agreement with the standard values, with an average concordance correlation coefficient of 0.99, and coefficient of variation of 7% in the repeatability scans. The results from in vivo scans also showed high image quality in both transverse and coronal views. CONCLUSIONS: This study applied a fast acquisition scheme for a fully quantitative 3D magnetic resonance fingerprinting scan with a total acceleration factor of 144 as compared with the Nyquist rate, such that 3D T1 , T2 , and proton density maps can be acquired with whole-brain coverage at clinical resolution in less than 5 min. Magn Reson Med 79:2190-2197, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833437 TI - Increased N200 and P300 latencies in cognitively impaired elderly carrying ApoE epsilon-4 allele. AB - OBJECTIVE: To compare the results of neuropsychological tests, evoked potentials N200 and P300 and polymorphisms of ApoE and BDNF rs6265 between patients with normal cognition and those with mild cognitive impairment (MCI) and Alzheimer's dementia (AD). METHODS: This is a cross-sectional study of elderly individuals with normal cognition and those with MCI and AD, who were submitted to evoked potential tests (N200 and P300) by means of hearing stimuli based on the auditory oddball paradigm. Genotyping was obtained by using the real-time PCR technique. RESULTS: Sixty-five patients were evaluated as follows: 14 controls, 34 with MCI and 17 with AD. N200 latency and P300 latency and amplitude were not associated with MCI and AD diagnosis. Patients with cognitive impairment (MCI or AD) showed increase in the latencies of P300 and N200. BNDF gene was not associated with cognitive impairment. CONCLUSION: Latencies of N200 and P300 increased in cognitively impaired patients with the presence of ApoE epsilon-4 allele. PMID- 28833438 TI - Mononuclear cell collection for extracorporeal photopheresis: Concentrate characteristics for off-line UV-A irradiation procedure. AB - BACKGROUND AND OBJECTIVE: Extracorporeal photopheresis (ECP) is the most represented cell therapy for treatment of cutaneous T-cell lymphoma, graft-versus host disease and organ rejection. We analyzed our experience in ECP using 2 cell separators (Cobe Spectra and Spectra Optia) focusing on leukapheretic product characteristics, UV-A irradiation procedure and entire ECP process. MATERIALS AND METHODS: We collected data of patients undergoing ECP between January 2012 and February 2015 in order to evaluate collection procedures performed using Cobe Spectra and Spectra Optia, mononuclear cell product, UV-A photoirradiation procedure by Pit System. RESULTS: We performed 484 ECP procedures in 27 patients. Cobe-derived mononuclear cell products were characterized by higher cell yields while Optia-derived mononuclear cell products were characterized by smaller volume, comparable mononuclear cell content but lower erythrocytes, granulocytes, and platelets contamination. CONCLUSION: Our study confirms good results for both cell separators. Blood volume processed being equal, Cobe collects a number of total nucleated cells significantly higher than Optia. Optia, collecting only target cells without significant erythrocytes, granulocytes and platelets contamination, is able to collect a leukapheretic product particularly suitable for ECP. PMID- 28833439 TI - Converse well-being of locked-in patients and caregivers. PMID- 28833440 TI - Magnetization-prepared shells trajectory with automated gradient waveform design. AB - PURPOSE: To develop a fully automated trajectory and gradient waveform design for the non-Cartesian shells acquisition, and to develop a magnetization-prepared (MP) shells acquisition to achieve an efficient three-dimensional acquisition with improved gray-to-white brain matter contrast. METHODS: After reviewing the shells k-space trajectory, a novel, fully automated trajectory design is developed that allows for gradient waveforms to be automatically generated for specified acquisition parameters. Designs for two types of shells are introduced, including fully sampled and undersampled/accelerated shells. Using those designs, an MP-Shells acquisition is developed by adjusting the acquisition order of shells interleaves to synchronize the center of k-space sampling with the peak of desired gray-to-white matter contrast. The feasibility of the proposed design and MP-Shells is demonstrated using simulation, phantom, and volunteer subject experiments, and the performance of MP-Shells is compared with a clinical Cartesian magnetization-prepared rapid gradient echo acquisition. RESULTS: Initial experiments show that MP-Shells produces excellent image quality with higher data acquisition efficiency and improved gray-to-white matter contrast-to noise ratio (by 36%) compared with the conventional Cartesian magnetization prepared rapid gradient echo acquisition. CONCLUSION: We demonstrated the feasibility of a three-dimensional MP-Shells acquisition and an automated trajectory design to achieve an efficient acquisition with improved gray-to-white matter contrast. Magn Reson Med 79:2024-2035, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833441 TI - "I don't know what I was expecting": Home visits by neonatology fellows for infants discharged from the NICU. AB - BACKGROUND: When families transition from the neonatal intensive care unit (NICU) to the home, they become responsible for their infant's daily medical needs. Though neonatology physicians prepare families for hospital discharge, it is unclear how much clinicians understand about how their teaching and instructions translate into home care. The goal of this study was to evaluate the influence of a home visiting program on neonatology fellows' understanding of family needs soon after hospital discharge. METHODS: Neonatology fellows conducted a home visit for an infant recently discharged. Before the visit, fellows reviewed their original discharge instructions, along with information about the family's neighborhood. During the home visit, fellows reviewed their discharge planning with families and discussed any challenges experienced. Afterwards, fellows completed a semi-structured interview; these transcriptions were manually coded for themes. RESULTS: Fellows identified several common women/family discharge challenges. These challenges fall into four domains: (1) inadequate discharge preparation, (2) medicalization of the home, (3) family adjustment to new "normal," and (4) the relevance of social context to discharge planning. Most (90%) fellows reported the home visit experience would affect their future NICU discharge practices and all agreed that home visits should be a part of neonatology training. CONCLUSIONS: Home visits allowed neonatology fellows to examine how their discharge preparation did, or did not, meet the family's needs. Incorporating home visits into neonatology training could help fellows learn about the relevance of social and community factors that are difficult to assess in the inpatient setting. PMID- 28833442 TI - The importance of maintenance conditions of Daphnia magna Straus as a test organism for ecotoxicological analysis. AB - Insufficient attention to the standardization of conditions for test organisms can lead to a distortion of bioassay results by changing the characteristics of the culture. The present study deals with the influence of abiotic factors (temperature of cultivated water, its chemical composition, season of the year) and biotic factors (seeding density) on the culture of Daphnia magna Straus. The natural mortality of D. magna is described by the Gompertz equation. One of the parameters of the equation related to daily increase of mortality is very stable, and we suggest monitoring its constancy as a sign of the health of D. magna culture. Seeding density of crustaceans affects both the fertility of species and their mortality. We observed a high degree of compensation for the natural death of adults with increasing fertility for groups of 10 and 25 species living in 1 L of water; the current population density of D. magna regulates the birth rate of juveniles. If the density is 50 individuals/L, the compensatory effect is reduced. Keeping Daphnia in small groups (for example, 10 individuals) and an increase in temperature from 20 to 25 degrees C reduces the average life expectancy. Therefore, when choosing a test protocol to determine chronic toxicity, it is important to pay attention to the seeding density of Daphnia, the optimal value being approximately 25 individuals/L. Sensitivity of D. magna depends on the season: it is maximal in winter and minimal in spring and summer. In addition, crustaceans' sensitivity increases when they are kept in water with low content of natural salts. Environ Toxicol Chem 2018;37:376-384. (c) 2017 SETAC. PMID- 28833443 TI - Psychometric testing of the revised "Families' Importance in Nursing Care-Nurses' Attitudes instrument". AB - BACKGROUND: The validity of instruments is crucial in ensuring that data collected are sound and that these data represent what the instrument claims to measure. When an instrument is revised or used in a different population, it is useful to re-examine its construct validity. AIM: To test the psychometrics properties of an instrument-the revised Families' Importance In Nursing Care Nurses' Attitudes, designed to measure nurse' attitudes towards involving family in nursing care in an adult acute care setting. DESIGN AND METHODOLOGY: A cross sectional survey design was used in April-May 2016 with a sample of Enrolled and Registered Nurses (N = 212) to test the factor structure of the revised Families' Importance In Nursing-Nurses' Attitudes instrument. The instrument had 26 items with a five-point Likert response scale. Principle components analysis and exploratory factor analysis were performed with oblique rotations to assess the internal structure of the instrument. SETTING: A regional referral hospital in Queensland, Australia. RESULTS: Using Principal Components Analysis and Principal Axis Factoring, we obtained the same factor structure to that originally identified for the instrument. Our results suggested the removal of six items to refine the instrument and achieve simple structure. CONCLUSION: The removal of several items, relabeling of factors and residual cross-loading issues suggest that further revisions to the instrument are needed. PMID- 28833444 TI - Energy-efficient neural information processing in individual neurons and neuronal networks. AB - Brains are composed of networks of an enormous number of neurons interconnected with synapses. Neural information is carried by the electrical signals within neurons and the chemical signals among neurons. Generating these electrical and chemical signals is metabolically expensive. The fundamental issue raised here is whether brains have evolved efficient ways of developing an energy-efficient neural code from the molecular level to the circuit level. Here, we summarize the factors and biophysical mechanisms that could contribute to the energy-efficient neural code for processing input signals. The factors range from ion channel kinetics, body temperature, axonal propagation of action potentials, low probability release of synaptic neurotransmitters, optimal input and noise, the size of neurons and neuronal clusters, excitation/inhibition balance, coding strategy, cortical wiring, and the organization of functional connectivity. Both experimental and computational evidence suggests that neural systems may use these factors to maximize the efficiency of energy consumption in processing neural signals. Studies indicate that efficient energy utilization may be universal in neuronal systems as an evolutionary consequence of the pressure of limited energy. As a result, neuronal connections may be wired in a highly economical manner to lower energy costs and space. Individual neurons within a network may encode independent stimulus components to allow a minimal number of neurons to represent whole stimulus characteristics efficiently. This basic principle may fundamentally change our view of how billions of neurons organize themselves into complex circuits to operate and generate the most powerful intelligent cognition in nature. (c) 2017 Wiley Periodicals, Inc. PMID- 28833445 TI - In silico mapping of allosteric ligand binding sites in type-1 cannabinoid receptor. AB - The recent resolution of the crystal structure of type-1 cannabinoid receptor (CB1 ) and the discovery of novel modulators for this target open the way to the possibility of elucidating the structural requirements for CB1 binding, and thereby facilitate a rational drug design. Compounds that target the orthosteric site of CB1 in some cases have shown side effects. Allosteric modulators could potentially avoid these side effects by influencing binding and/or efficacy of orthosteric ligands. Here, we summarize and compare previous data on different putative allosteric binding sites observed in CB1 homology models with an in silico docking study of the recently published crystal structure of the same receptor on endogenous and natural hydrophobic ligands that act as positive allosteric modulators and negative allosteric modulators of CB1 . In particular, a lipid-exposed pocket targeted by most of the tested molecules is reported and discussed. PMID- 28833446 TI - Necrotic cell death occur via JNK pathway with the activity of transcription factor c-Jun by 4-MC in INS-1 cell line. AB - In this study, it was aimed to determine the doses of 4-methylcatechol causing cell death in rat insulinoma beta-cells (INS-1), to find out the type of cellular death at these doses, and to investigate the molecular mechanism of cellular death occurring. More necrotic cells were observed than apoptosis with the administration of 350, 400, and 450 MUM 4-methylcatechol. Lactate dehydrogenase levels, reactive oxygen species, mitochondrial potential loss, ATP, and GTP losses increased at these doses. The JNK and ERK cellular pathway were screened. We observed an increase in p-RAF1 activity, the active JNK amount, the total c Jun amount, while a decrease in p-RAF1 expression, the total JNK amount, JNK expression, ATF2 expression, active ERK, and its expression and Elk1 expression. It was concluded that cells perform necrotic death by the following options: i) phosphorylated RAF1 activates the JNK pathway with the activity of transcription factor c-Jun; ii) Hsp 70 and Hsp 90 do not show a change inside the cell, rendering the JNK pathway active. PMID- 28833447 TI - Psoriasis or not? Review of 51 clinically confirmed cases reveals an expanded histopathologic spectrum of psoriasis. AB - BACKGROUND: Psoriasis is usually diagnosed clinically, so only non-classic or refractory cases tend to be biopsied. Diagnostic uncertainty persists when dermatopathologists encounter features regarded as non-classic for psoriasis. OBJECTIVE: Define and document classic and non-classic histologic features in skin biopsies from patients with clinically confirmed psoriasis. METHODS: Minimal clinical diagnostic criteria were informally validated and applied to a consecutive series of biopsies histologically consistent with psoriasis. Clinical confirmation required 2 of the following criteria: (1) classic morphology, (2) classic distribution, (3) nail pitting, and (4) family history, with #1 and/or #2 as 1 criterion in every case RESULTS: Fifty-one biopsies from 46 patients were examined. Classic features of psoriasis included hypogranulosis (96%), club shaped rete ridges (96%), dermal papilla capillary ectasia (90%), Munro microabscess (78%), suprapapillary plate thinning (63%), spongiform pustules (53%), and regular acanthosis (14%). Non-classic features included irregular acanthosis (84%), junctional vacuolar alteration (76%), spongiosis (76%), dermal neutrophils (69%), necrotic keratinocytes (67%), hypergranulosis (65%), neutrophilic spongiosis (61%), dermal eosinophils (49%), compact orthokeratosis (37%), papillary dermal fibrosis (35%), lichenoid infiltrate (25%), plasma cells (16%), and eosinophilic spongiosis (8%). CONCLUSIONS: Psoriasis exhibits a broader histopathologic spectrum. The presence of some non-classic features does not necessarily exclude the possibility of psoriasis. PMID- 28833448 TI - A chemical shift encoding (CSE) approach for spectral selection in fluorine-19 MRI. AB - PURPOSE: To develop a chemical shift encoding (CSE) approach for fluorine-19 MRI of perfluorocarbons in the presence of multiple known fluorinated chemical species. THEORY AND METHODS: A multi-echo CSE technique is applied for spectral separation of the perfluorocarbon perfluoro-15-crown-5-ether (PFCE) and isoflurane (ISO) based on their chemical shifts at 4.7 T. Cramer-Rao lower bound analysis is used to identify echo combinations with optimal signal-to-noise performance. Signal contributions are fit with a multispectral fluorine signal model using a non-linear least squares estimation reconstruction directly from k space data. This CSE approach is tested in fluorine-19 phantoms and in a mouse with a 2D and 3D spoiled gradient-echo acquisition using multiple echo times determined from Cramer-Rao lower bound analysis. RESULTS: Cramer-Rao lower bound analysis for PFCE and ISO separation shows signal-to-noise performance is maximized with a 0.33 ms echo separation. A linear behavior (R2 = 0.987) between PFCE signal and known relative PFCE volume is observed in CSE reconstructed images using a mixed PFCE/ISO phantom. Effective spatial and spectral separation of PFCE and ISO is shown in phantoms and in vivo. CONCLUSION: Feasibility of a gradient-echo CSE acquisition and image reconstruction approach with optimized noise performance is demonstrated through fluorine-19 MRI of PFCE with effective removal of ISO signal contributions. Magn Reson Med 79:2183-2189, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833449 TI - microRNA-145 downregulates SIP1-expression but differentially regulates proliferation, migration, invasion and Wnt signaling in SW480 and SW620 cells. AB - microRNA-145 (miR-145) has been shown to act as a tumor suppressor in colorectal cancer but its role in the regulation of epithelial-mesenchymal transition (EMT) is unclear. Ectopic expression of miR-145 suppressed the proliferation, migration and invasion in SW480 but surprisingly enhanced these traits in its metastatic counterpart, SW620 cells, while, antimiR-145 reversed the effects of miR-145 in both of these human colorectal cancer cells. In SW480 and SW620 cells, SMAD interacting protein 1 (SIP1), was identified as a target of miR-145, and its expression was suppressed both at mRNA and protein levels, and siRNA-SIP1 mimicked the effects of miR-145. Further, re-introduction of SIP1 alone or its co expression with miR-145, rescued SW480 and SW620 cells from the effects of miR 145, indicating that the distinct functions of miR-145 might be mediated, in part, through SIP1. Since Wnt signaling plays an essential role in EMT in CRC progression, the effects of miR-145 on the expression of Wnt signaling intermediates and EMT markers were studied. Re-expression of miR-145 was found to downregulate the expression of CTNNB1, TCF4, CCND1, VIM, and SNAI, but, upregulated CDH1 expression in SW480 cells. On the other hand, miR-145 exhibited an oncogenic potential in SW620 cells by actuating Wnt signaling and the expression of EMT-relevant markers. These results strongly hint that the paradoxical functions of miR-145 in the regulation of proliferation, migration and invasion might be mediated through downregulation of SIP1, and differential tuning of Wnt signaling and EMT-mediators. PMID- 28833450 TI - Interoceptive Deficits, Nonsuicidal Self-Injury, and Suicide Attempts Among Women with Eating Disorders. AB - People with eating disorders (EDs) have an elevated risk for both nonsuicidal self-injury (NSSI) and suicide compared to the general population. This study tests two theoretically derived models examining interoceptive deficits as a risk factor for NSSI, and examining interoceptive deficits, NSSI, fearlessness about death, and pain tolerance as risk factors for suicide. Ninety-six adult, treatment-seeking women with EDs completed self-report questionnaires at a single time point. Interoceptive deficits were significantly associated with NSSI, and NSSI was in turn associated with both pain tolerance and fearlessness about death. Further, pain tolerance was in turn associated with past suicide attempts, although fearlessness about death was not associated with suicide attempts. Interoceptive deficits had a direct association with fearlessness about death but not pain tolerance. Results regarding the relation between interoceptive deficits and suicide attempts were mixed, yet overall suggest that interoceptive deficits are related to suicide attempts largely indirectly, through the effects of mediating variables such as NSSI, fearlessness about death, and pain tolerance. Results suggest that interoceptive deficits and pain tolerance merit further investigation as potential risk factors for fatal and nonfatal self-harm among individuals with EDs. PMID- 28833451 TI - Infantile retinal haemorrhages in the absence of brain and bodily injury. PMID- 28833453 TI - It is not ethical to save an infant's life just because we can, without due regard to outcome. PMID- 28833454 TI - Radiofrequency saturation induced bias in aqueductal cerebrospinal fluid flow quantification obtained using two-dimensional cine phase contrast magnetic resonance imaging. AB - PURPOSE: To explore the extent of bias in cerebrospinal fluid flow estimates due to radiofrequency saturation, and its possible impact on the use of two dimensional cine phase contrast magnetic resonance imaging in the diagnosis and characterization of normal pressure hydrocephalus in patients. THEORY AND METHODS: Theoretical signal equations were generated to describe saturation dependence on velocity. An experimental set of phase contrast magnetic resonance imaging scans with two different flip angles was used to show bias in flow estimates in a flow phantom, and in six different healthy volunteers. The cerebral aqueduct was targeted as the flow region of interest. RESULTS: Data from a constant flow phantom showed a spatial distribution of voxels with significant bias in flow at the periphery of the flow region. The velocity difference (bias) maps of the cerebral aqueduct correlated with the spatial velocity gradients around peak systole and peak diastole, and high correlation with temporal velocity gradients during transition between systole and diastole. The aqueductal stroke volume for theta = 30 degrees were found to be significantly higher than for theta = 10 degrees using a Wilcoxon signed rank test. CONCLUSION: This work shows the extent of bias in cerebrospinal fluid flow quantification due to radiofrequency saturation effects. This clinical relevance of this error was presented with respect to shunt responsiveness among normal pressure hydrocephalus patients. Magn Reson Med 79:2067-2076, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833452 TI - Boys have better short-term and long-term survival rates after intensive care admissions than girls. AB - AIM: We investigated possible gender differences in paediatric intensive care morbidity-adjusted mortality. METHODS: In this study, data on all 21 972 paediatric intensive care admissions in Sweden between 2008 and 2015 were analysed regarding morbidity-adjusted survival, using Cox regression, with age, gender and estimated mortality ratio as dependent variables and using the standardised mortality ratio at 90 days after admission. The data were obtained from the Swedish Intensive Care Registry. RESULTS: We found that boys had better overall survival than girls (hazard ratio 0.91 for boys, p = 0.035). In addition, the 90-day survival was also better for boys (standardised mortality ratio 0.85 for boys versus 1.02 for girls, p = 0.0014). The survival advantage was most evident in children less than a year old and for nonsurgical patients. The male advantage was also seen in children admitted with respiratory insufficiency and seizures and was furthermore independent of any concurrent cardiac condition. We did not find any gender difference in the intensity of care or length of stay when corrected for morbidity. CONCLUSION: This study showed that boys have better outcomes than girls after intensive care admissions. The difference does not seem to be based on inequality of care. PMID- 28833455 TI - The vial kit formulation for preparation of no-carrier-added 131 I-MIBG. AB - We have developed a new set of lyophilized kits, composed of 3 different kits, for the instant preparation of no-carrier-added 131 I-MIBG in the clinic. We here discussed the formulation of the kits, optimization of radiolabelling, quality control of radiolabeled 131 I-MIBG, and studies of animal biodistribution. The no carrier-added (nca) 131 I-MIBG injection could be prepared within 30 minutes in the clinic with the help of the lyophilized kits. The radiochemical purity and specific activity (SA) could achieve above 98% and 6700 MBq/mg, respectively. PMID- 28833456 TI - Bivalirudin versus heparin in patients undergoing percutaneous transcatheter aortic valve interventions: A systematic review and meta-analysis. AB - BACKGROUND: Bivalirudin may be an effective anticoagulation alternative to heparin as anticoagulant agent in percutaneous transcatheter aortic valve interventions (PAVI). We aimed to compare safety and efficacy of bivalirudin versus heparin as the procedural anticoagulant agent in patients undergoing PAVI. METHODS: We conducted an electronic database search of all published data. The primary efficacy endpoints were all-cause mortality, cardiovascular mortality, myocardial infarction, and stroke. Safety endpoints include major and life threatening bleed according to VARC and BARC bleeding, blood transfusion, vascular complications, and acute kidney injury. Odds ratios (OR) and 95% confidence intervals (CI) computed using the Mantel-Haenszel method. RESULTS: Three studies (n = 1690 patients) were included, one randomized trial and two observational studies. There was a significant difference favoring bivalirudin over heparin for myocardial infarction (OR 0.41, 95%CI 0.20-0.87). There was no significant difference in all-cause mortality at 30 days (OR 0.97, 95%CI 0.62 1.52), cardiovascular mortality (OR 1.03, 95%CI 0.52-2.05), stroke (OR 1.23, 95%CI 0.62-2.46), vascular complications (OR 0.96, 95%CI 0.70-1.32), acute kidney injury (OR 1.03, 95%CI 0.53-2.00), blood transfusion (OR 0.67, 95% CI 0.45-1.01), major and life-threatening bleed (OR 0.74, 95%CI 0.37-1.49), and BARC bleeding (OR 0.52, 95%CI 0.23-1.18). CONCLUSIONS: In patient undergoing aortic valve interventions, no difference was seen between the use of bivalirudin and heparin as the procedural anticoagulant agent, except for a significant lower myocardial infarction events when bivalirudin was used. Further large randomized trials are needed to confirm current results. PMID- 28833458 TI - A novel echocardiographic hemodynamic classification of heart failure based on stroke volume index and left atrial pressure. AB - BACKGROUND AND AIM: Dividing patients with heart failure (HF) based solely on ejection fraction (EF) may over simplify the hemodynamic states of these patients. We describe a novel echo-derived hemodynamic HF model based on flow (stroke volume index [SVI]) and left atrial pressure (E:E') correlates. METHODS: A retrospective analysis of patients admitted with HF with both reduced (HFrEF) and preserved EF (HFpEF). Patients were subdivided into four hemodynamic groups based on echocardiographic SVI (< or >=35 mL/m2 ) and E/E' (>= or <15). Group A: normal flow and normal filling pressure, Group B: normal flow but high filling pressure, Group C: low flow and low filling pressure, and Group D: low flow and high filling pressure. RESULTS: A total of 176 patients were enrolled, 123 patients had HFrEF and 53 patients had HFpEF. Baseline characteristics were not statistically significant in both groups. In HFrEF, most patients were in group D compared to a heterogeneous distribution in HFpEF (P<.0001). In HFrEF, there was a trend toward an increase in B-type natriuretic peptide levels with a decrease in SVI and increase in E/E' (P=.05) but not in HFpEF. There was no difference in death, major adverse cardiac events, but a higher readmissions rate in the HFpEF group at 30 days and 18 months. CONCLUSIONS: Hemodynamic subgroups differ between HFrEF and HFpEF. There is no difference in major adverse cardiovascular events between both groups with increased readmissions in HPpEF patients. Larger studies may help assess the impact of echo-derived hemodynamic state on clinical outcome. PMID- 28833459 TI - Persistent seizure control in epileptic mice transplanted with gamma-aminobutyric acid progenitors. AB - OBJECTIVE: A significant proportion of the more than 50 million people worldwide currently suffering with epilepsy are resistant to antiepileptic drugs (AEDs). As an alternative to AEDs, novel therapies based on cell transplantation offer an opportunity for long-lasting modification of epileptic circuits. To develop such a treatment requires careful preclinical studies in a chronic epilepsy model featuring unprovoked seizures, hippocampal histopathology, and behavioral comorbidities. METHODS: Transplantation of progenitor cells from embryonic medial or caudal ganglionic eminence (MGE, CGE) were made in a well-characterized mouse model of status epilepticus-induced epilepsy (systemic pilocarpine). Behavioral testing (handling and open field), continuous video-electroencephalographic (vEEG) monitoring, and slice electrophysiology outcomes were obtained up to 270 days after transplantation (DAT). Post-hoc immunohistochemistry was used to confirm cell identity. RESULTS: MGE progenitors transplanted into the hippocampus of epileptic mice rescued handling and open field deficits starting at 60 DAT. In these same mice, an 84% to 88% reduction in seizure activity was observed between 180 and 210 DAT. Inhibitory postsynaptic current frequency, measured on pyramidal neurons in acute hippocampal slices at 270 DAT, was reduced in epileptic mice but restored to naive levels in epileptic mice receiving MGE transplants. No reduction in seizure activity was observed in epileptic mice receiving intrahippocampal CGE progenitors. INTERPRETATION: Our findings demonstrate that transplanted MGE progenitors enhance functional GABA-mediated inhibition, reduce spontaneous seizure frequency, and rescue behavioral deficits in a chronic epileptic animal model more than 6 months after treatment. Ann Neurol 2017;82:530 542. PMID- 28833460 TI - Genomic damage induced by 1-MHz ultrasound in vitro. AB - Genotoxic effects of therapeutic ultrasound are poorly documented, when compared with the wide use of this physical agent. The aim of this work was to investigate the clastogenic and aneugenic potential of 1 MHz ultrasound, employing intensities (200 and 300 mW/cm2 ) above the cavitational threshold, but in the range of those normally used in therapeutics. Both normal fibroblasts (AG01522) and tumoral cells (MCF-7) were sonicated. While no effects on viability were noted, significant increases of CREST-negative micronuclei (indicative of clastogenesis) and CREST-positive micronuclei (indicative of aneuploidy) were detected. Clastogenesis was confirmed by increases of gamma-H2AX foci, while increases of spindle anomalies confirmed the induction of aneuploidy. Our results confirm previous works that showed ultrasound-induced DNA breakage. Moreover, our experiments show that the known effect of ultrasound-induced damage to microtubules is also able to damage the mitotic spindle and induce aneuploidy. On the overall, this work highlights the importance to further investigate the potential risks related to therapeutics US. Environ. Mol. Mutagen. 59:60-68, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28833462 TI - The impact of pollen consumption on honey bee (Apis mellifera) digestive physiology and carbohydrate metabolism. AB - Carbohydrate-active enzymes play an important role in the honey bee (Apis mellifera) due to its dietary specialization on plant-based nutrition. Secretory glycoside hydrolases (GHs) produced in worker head glands aid in the processing of floral nectar into honey and are expressed in accordance with age-based division of labor. Pollen utilization by the honey bee has been investigated in considerable detail, but little is known about the metabolic fate of indigestible carbohydrates and glycosides in pollen biomass. Here, we demonstrate that pollen consumption stimulates the hydrolysis of sugars that are toxic to the bee (xylose, arabinose, mannose). GHs produced in the head accumulate in the midgut and persist in the hindgut that harbors a core microbial community composed of approximately 108 bacterial cells. Pollen consumption significantly impacted total and specific bacterial abundance in the digestive tract. Bacterial isolates representing major fermentative gut phylotypes exhibited primarily membrane-bound GH activities that may function in tandem with soluble host enzymes retained in the hindgut. Additionally, we found that plant-originating beta-galactosidase activity in pollen may be sufficient, in some cases, for probable physiological activity in the gut. These findings emphasize the potential relative contributions of host, bacteria, and pollen enzyme activities to carbohydrate breakdown, which may be tied to gut microbiome dynamics and associated host nutrition. PMID- 28833461 TI - Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat. AB - Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction in mitochondrial membrane potential and metabolic rate, independent of concentration (20-100 MUmol/L). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100 MUmol/L). These effects were prevented by co-treatment with 1 MUmol/L melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1 MUmol/L melatonin of either the breast cancer cell line MCF-7 or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel-induced painful peripheral neuropathy, pretreatment with oral melatonin (5/10/50 mg/kg), given as a daily bolus dose, was protective, dose-dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10 mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2 alpha levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction in C-fibre activity dependent slowing (by 64%). Notably, melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively), and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment. PMID- 28833463 TI - An easy-to-use scoring index to determine severity of mitral regurgitation by 2D echocardiography in clinical practice. AB - PURPOSE: Mitral regurgitation (MR) grading by two-dimensional transthoracic echocardiography is challenging, but important to determine the best treatment strategy in patients with MR. Current guidelines advocate an integrative approach, although no recommendation is provided on how to do so. An easy-to-use index will be helpful for standardized and reproducible MR grading. METHODS: Eleven echocardiographic parameters were retrospectively evaluated in 145 patients with moderate or severe MR. Parameters were scored positive or negative for severe MR, where expert panel consensus reading was considered as the reference standard. Logistic regression was performed, and adjusted coefficients were used to create a risk score for severe MR per patient (ROSE-index). The best cutoff with corresponding predictive values was determined. RESULTS: Eighty-two percent of all parameters could be determined. Multivariable analysis revealed five parameters that remained significant predictors for severe MR: morphology, jet characteristics, vena contracta, systolic reversal, and left ventricular dimensions. With different weighing, a total score of 8 could be obtained. Median total ROSE-index score for moderate (2.0) and severe MR (5.0) did significantly differ. The cutoff score (>=4) revealed sensitivity 0.84 and specificity 0.83 to diagnose severe MR. Negative predictive value was 100% for score 0 and 1; score 6 8 showed a 100% positive predictive value. Inter- and intra-observer agreements were excellent (K-values >0.80). CONCLUSION: Here, we propose an easy-to-use tool for integrated analysis of guideline parameters to assess MR severity. Using this so-called ROSE-index revealed reliable and reproducible assessment of severe MR (cutoff>=4) that may be helpful for clinical decision making. PMID- 28833465 TI - Barrier-free communication in maternity care of allophone migrants: BRIDGE study protocol. AB - AIM: To describe communication and access barriers encountered by allophone women of different migration backgrounds in the Swiss maternity care services, from the perspective of users, healthcare professionals and intercultural interpreters. BACKGROUND: In addition to the challenges of maternal adjustment, pregnant migrant women must also deal with an unfamiliar health service system. Some must overcome language barriers and the stress of uncertain residence status. Limited access to maternity care increases perinatal morbidity and mortality. Almost 10% of foreigners speak none of Switzerland's official languages. Factors that facilitate or hinder communication between migrant women and perinatal healthcare professionals are under-studied and must be understood if we are to overcome those barriers in clinical practice. DESIGN: Qualitative exploratory study with quantitative sub-study. METHODS: Participants will be drawn from German to speaking regions of Switzerland. We will conduct focus group discussions and semi structured interviews with users in their own language (Albanian and Tigrinya) and with healthcare professionals and intercultural interpreters (March-June 2016), then perform Thematic Analysis on the data. In the sub-study, midwives will report their experience of using a telephone interpreting service during postnatal home visits in a questionnaire (October 2013-March 2016). Data will be analysed with descriptive statistics. DISCUSSION: Our study will reveal patterns in communications between allophone migrant women and healthcare providers and communication barriers. By incorporating multiple perspectives, we will describe the challenges all parties face. Our results will inform those who draft recommendations to improve provision of maternity care to allophone women and their families. TRIAL REGISTRATION: ClinicalTrials.gov ID: BernUAS NCT02695316. PMID- 28833466 TI - Clinical and laboratory findings associated with sleep disordered breathing in sickle cell disease. PMID- 28833464 TI - Inhibiting persistent inward sodium currents prevents myotonia. AB - OBJECTIVE: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC-1 current. METHODS: In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita. RESULTS: Intracellular recordings revealed a slow afterdepolarization (AfD) that triggers myotonic action potentials. The AfD is well explained by a tetrodotoxin-sensitive and voltage-dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC. INTERPRETATION: This work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na+ current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na+ current. Ann Neurol 2017;82:385-395. PMID- 28833467 TI - Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. AB - OBJECTIVE: To determine the usefulness of dopamine transporter (DAT) imaging to identify idiopathic rapid eye movement sleep behavior disorder (IRBD) patients at risk for short-term development of clinically defined synucleinopathy. METHODS: Eighty-seven patients with polysomnography-confirmed IRBD underwent 123 I-FP-CIT DAT-SPECT. Results were compared to 20 matched controls without RBD who underwent DAT-SPECT. In patients, FP-CIT uptake was considered abnormal when values were two standard deviations below controls' mean uptake. After DAT-SPECT, patients were followed up during 5.7 +/- 2.2 (range, 2.6-9.9) years. RESULTS: Baseline DAT deficit was found in 51 (58.6%) patients. During follow-up, 25 (28.7%) subjects developed clinically defined synucleinopathy (Parkinson's disease in 11, dementia with Lewy bodies in 13, and multiple system atrophy in 1) with mean latency of 3.2 +/- 1.9 years from imaging. Kaplan-Meier survival analysis showed increased risk of incident synucleinopathy in patients with abnormal DAT-SPECT than with normal DAT-SPECT (20% vs 6% at 3 years, 33% vs 18% at 5 years; log rank test, p = 0.006). Receiver operating characteristics curve revealed that reduction of FP CIT uptake in putamen greater than 25% discriminated patients with DAT deficit who developed synucleinopathy from patients with DAT deficit that remained disease free after 3 years of follow-up. At 5-year follow-up, DAT-SPECT had 75% sensitivity, 51% specificity, 44% positive predictive value, 80% negative predictive value, and likelihood ratio 1.54 to predict synucleinopathy. INTERPRETATION: DAT-SPECT identifies IRBD patients at short-term risk for synucleinopathy. Decreased FP-CIT putamen uptake greater than 25% predicts synucleinopathy after 3 years' follow-up. These observations may be useful to select candidates for disease modification trials in IRBD. Ann Neurol 2017;82:419 428. PMID- 28833468 TI - Scabies in babies. AB - The clinical manifestations of scabies infestation vary according to age, making the diagnosis challenging, particularly for primary care providers and dermatologists who do not routinely care for young children. We present seven cases of newborns and infants who developed inflammatory burrows and nodules early in the course, which is not typical of the eruption seen in older children and adults. We review the cutaneous features, differential diagnosis, and treatment recommendations for scabies in different age groups. PMID- 28833470 TI - Towards unbiased and more versatile NMR-based structure elucidation: A powerful combination of CASE algorithms and DFT calculations. AB - Computer-assisted structure elucidation (CASE) is composed of two steps: (a) generation of all possible structural isomers for a given molecular formula and 2D NMR data (COSY, HSQC, and HMBC) and (b) selection of the correct isomer based on empirical chemical shift predictions. This method has been very successful in solving structural problems of small organic molecules and natural products. However, CASE applications are generally limited to structural isomer problems and can sometimes be inconclusive due to insufficient accuracy of empirical shift predictions. Here, we report a synergistic combination of a CASE algorithm and density functional theory calculations that broadens the range of amenable structural problems to encompass proton-deficient molecules, molecules with heavy elements (e.g., halogens), conformationally flexible molecules, and configurational isomers. PMID- 28833469 TI - Clinicopathologic Features and Magnetic Resonance Imaging Findings in 24 Cats With Histopathologically Confirmed Neurologic Feline Infectious Peritonitis. AB - BACKGROUND: Feline infectious peritonitis (FIP) is the most common infectious central nervous system (CNS) disease in the cat and is invariably fatal. Improved means of antemortem diagnosis is required to facilitate clinical decision making. Information regarding the magnetic resonance imaging (MRI) findings of neurologic FIP currently is limited, resulting in the need for better descriptions to optimize its use as a diagnostic tool. OBJECTIVE: To describe the clinicopathologic features and MRI findings in cases of confirmed neurologic FIP. ANIMALS: Twenty-four client-owned cats with histopathologic confirmation of neurologic FIP. METHODS: Archived records from 5 institutions were retrospectively reviewed to identify cases with confirmed neurologic FIP that had undergone antemortem MRI of the CNS. Signalment, clinicopathologic, MRI, and histopathologic findings were evaluated. RESULTS: Three distinct clinical syndromes were identified: T3-L3 myelopathy (3), central vestibular syndrome (7), and multifocal CNS disease (14). Magnetic resonance imaging abnormalities were detected in all cases, including meningeal contrast enhancement (22), ependymal contrast enhancement (20), ventriculomegaly (20), syringomyelia (17), and foramen magnum herniation (14). Cerebrospinal fluid was analysed in 11 cases; all demonstrated a marked increase in total protein concentration and total nucleated cell count. All 24 cats were euthanized with a median survival time of 14 days (range, 2-115) from onset of clinical signs. Histopathologic analysis identified perivascular pyogranulomatous infiltrates, lymphoplasmacytic infiltrates, or both affecting the leptomeninges (16), choroid plexuses (16), and periventricular parenchyma (13). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnetic resonance imaging is a sensitive means of detecting neurologic FIP, particularly in combination with a compatible signalment, clinical presentation, and CSF analysis. PMID- 28833471 TI - Perceived barriers to and drivers of community participation in protected-area governance. AB - Protected areas (PAs) are a frequently used conservation strategy, yet their socioeconomic impacts on local communities remain contentious. A shift toward increased participation by local communities in PA governance seeks to deliver benefits for human well-being and biodiversity. Although participation is considered critical to the success of PAs, few researchers have investigated individuals' decisions to participate and what this means for how local people experience the costs and benefits of conservation. We explored who participates in PA governance associations and why; the perceived benefits and costs to participation; and how costs and benefits are distributed within and between communities. Methods included 3 focus groups, 37 interviews, and 217 questionnaire surveys conducted in 3 communities and other stakeholders (e.g., employees of a nongovernmental organization and government officials) in PA governance in Madagascar. Our study design was grounded in the theory of planned behavior (TPB), the most commonly applied behavior model in social psychology. Participation in PA governance was limited by miscommunication and lack of knowledge about who could get involved and how. Respondents perceived limited benefits and high costs and uneven distribution of these within and between communities. Men, poorer households, and people in remote villages reported the highest costs. Our findings illustrate challenges related to comanagement of PAs: understanding the heterogeneous nature of communities; ensuring all households are represented in governance participation; understanding differences in the meaning of forest protection; and targeting interventions to reach households most in need to avoid elite capture. PMID- 28833472 TI - Youth Suicide Deaths: Investigation of Clinical Predictors in a Statewide Sample. AB - Death by suicide is a significant cause of mortality among youth. However, there is limited information on the demographic and clinical factors associated with youth suicide deaths. The objective of this study was to link large statewide databases to describe demographic, clinical, and cause of death characteristics among youth who died by suicide. We examined 1,218 decedents under age 26 who died by suicie between 2000 and 2014. Eighteen died before age 12, 53 died between ages 12 and 14, 292 died between ages 15 and 18, and 855 died between ages 19 and 25. Most were male (83%), and firearm was most common cause of death; 28% previously attempted suicide, 31% had a mental health diagnosis, and 17% were prescribed psychotropic medication. Younger children died by hanging/smothering (89% of all 7- to 11-year olds), and overdose/poisoning increased progressively with age. Adolescents had a higher proportion of females than young adults (23% vs. 14%, p = .002). Combining data from the medical examiner and large hospital systems allows examination of youth suicide from a developmental perspective. Differences between age groups included gender, method, diagnosed mental illness, and diagnosis of attention deficit hyperactivity disorder. These data point to missed opportunities for effective interventions for specific developmental stages. PMID- 28833473 TI - Exploring Initiative as a Signal of Knowledge Co-Construction During Collaborative Problem Solving. AB - Peer interaction has been found to be conducive to learning in many settings. Knowledge co-construction (KCC) has been proposed as one explanatory mechanism. However, KCC is a theoretical construct that is too abstract to guide the development of instructional software that can support peer interaction. In this study, we present an extensive analysis of a corpus of peer dialogs that we collected in the domain of introductory Computer Science. We show that the notion of task initiative shifts correlates with both KCC and learning. Speakers take task initiative when they contribute new content that advances problem solving and that is not invited by their partner; if initiative shifts between the partners, it indicates they both contribute to problem solving. We found that task initiative shifts occur more frequently within KCC episodes than outside. In addition, task initiative shifts within KCC episodes correlate with learning for low pre-testers, and total task initiative shifts correlate with learning for high pre-testers. As recognizing task initiative shifts does not require as much deep knowledge as recognizing KCC, task initiative shifts as an indicator of productive collaboration are potentially easier to model in instructional software that simulates a peer. PMID- 28833474 TI - Short-term side effects and attitudes towards second donation: A comparison of related and unrelated haematopoietic stem cell donors. AB - The Nordic Register of Haematopoietic Stem Cell Donors (NRHSD) has registered related and unrelated donors from 10 transplant centres in Sweden, Norway, Finland and Denmark since 1998. We present a prospective, observational study of 1,957 donors, focusing mainly on the differences between related and unrelated donors. Related donors are reported to have more comorbidities, but similar side effects compared with unrelated donors. Side effects after BM or PBSC donation are generally of short duration and in this study no deaths, myocardial infarctions, splenic ruptures, or thromboembolic events are reported. Interestingly, related donors express more hesitancy towards donating again when asked 1 month after donation. PMID- 28833475 TI - Do low-serum vitamin E levels increase the risk of Alzheimer disease in older people? Evidence from a meta-analysis of case-control studies. AB - OBJECTIVE: Whether low-serum vitamin E increases the risk of Alzheimer disease (AD) in older people remains inconclusive. This meta-analysis aims to synthesize evidence-based case-control studies to evaluate the association between serum vitamin E and the risk of AD. METHODS: Potentially relevant studies were selected through PubMed, Embase, Wanfang, Chongqing VIP, and China National Knowledge Infrastructure databases by using the core terms Vitamin E/alpha-tocopherol and Alzheime's disease/senile dementia/AD in the titles, abstracts, and keywords of the articles. The association between serum vitamin E levels and AD was estimated by using the weighted mean difference (WMD) and 95% confidence interval by adopting a random effects model. Heterogeneity was assessed by using Cochran Q test and I2 statistic. Forest plot was used to present the results graphically from meta-analysis. Publication bias was evaluated by using funnel plots and Egger test. RESULTS: We identified 17 studies that met the eligibility criteria. The studies included 2057 subjects with 904 AD patients and 1153 controls. The results indicated that AD patients had a lower concentration of serum vitamin E compared with healthy controls among older people (WMD = -6.811 MUmol/L, 95% confidence interval -8.998 to -4.625; Z = -6.105, P < .001). Publication bias was not detected and sensitivity analysis performed by omitting each study, and calculating the pooled WMD again for the remaining studies indicated the results stable. CONCLUSIONS: Alzheimer disease is associated with a low concentration of serum vitamin E in older people. However, necessary prospective cohort studies should be conducted to determine the risk of serum vitamin E for AD in the future. PMID- 28833477 TI - Salivary cortisol circadian rhythm in infants at psychosocial risk showed more variations than previous studies of healthy full-term infants. PMID- 28833476 TI - Angiotensin-converting enzyme 2-Angiotensin 1-7/1-9 system: novel promising targets for heart failure treatment. AB - Cardiac remodeling (cardiac hypertrophy and fibrosis) is a hallmark of heart failure (HF). It can be induced by the abnormal elevation of several endogenous factors including angiotensin II (Ang II), which is generated from its precursor angiotensin I (Ang I) by the action of angiotensin-converting enzyme. The inhibition of this enzyme or the blockade of the Ang II receptors demonstrated a high clinical value against the progression of HF. Ang I and Ang II may also be converted into angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9), respectively, by the action of angiotensin-converting enzyme 2. Both derivatives demonstrated a promising anticardiac remodeling activity especially against the detrimental effects of Ang II. This manuscript thoroughly reviews the available in vitro and in vivo data on Ang 1-7 and Ang 1-9 in the context of the treatment of HF and discusses the associated molecular mechanisms and the trials to clinically utilize Ang 1-7 mimetics for the treatment of that disease. PMID- 28833478 TI - Melatonin improves the fertilization capacity and developmental ability of bovine oocytes by regulating cytoplasmic maturation events. AB - Melatonin is a well-characterized antioxidant that has been successfully used to protect oocytes from reactive oxygen species during in vitro maturation (IVM), resulting in improved fertilization capacity and development ability. However, the mechanism via which melatonin improves oocyte fertilization capacity and development ability remains to be determined. Here, we studied the effects of melatonin on cytoplasmic maturation of bovine oocytes. In the present study, bovine oocytes were cultured in IVM medium supplemented with 0, 10-7 , 10-9 , and 10-11 mol/L melatonin, and the cytoplasmic maturation parameters of MII oocytes after IVM were investigated, including redistribution of organelles (mitochondria, cortical granules [CGs], and endoplasmic reticulum [ER]), intracellular glutathione (GSH) and ATP levels, expression of endogenous antioxidant genes (Cat, Sod1, and GPx), and fertilization-related events (IP3R1 distribution and expression of CD9 and Juno). Our results showed that melatonin significantly improved the cytoplasmic maturation of bovine oocytes by improving the normal distribution of organelles, increasing intracellular GSH and ATP levels, enhancing antioxidant gene expression levels, and modulating fertilization-related events, all of which resulted in increased fertilization capacity and developmental ability. Meanwhile, melatonin also increased the mRNA and protein expression levels of the Tet1 gene and decreased the Dnmt1 gene mRNA and protein levels in bovine oocytes, indicating that melatonin regulates the expression of the detected genes via demethylation. These findings shed insights into the potential mechanisms by which melatonin improves oocyte quality during IVM. PMID- 28833479 TI - Immune roles of dendritic cells in stem cell transplantation. AB - Dendritic cells (DCs) are professional antigen-presenting cells and initial stimulators for immune response. DCs can shape their functions based on their immune states, which are crucial for the balance of immunity and tolerance to preserve homeostasis. In the immune response involved in stem cell transplantation, DCs also play important roles in inducing immune tolerance and antitumor immunity. After the rapid development of stem cell transplantation technology in recent years, the risks of graft rejection, tumor recurrence, and tumorigenicity are still present after stem cell transplantation. It is important to understand the mechanisms of DC-mediated immune tolerance and stimulation during stem cell transplantation. In this review, we will summarize and analyze the regulatory mechanisms of DCs in stem cell transplantation and their application in clinical settings. It may help to promote the innovation in basic theories and therapeutic approaches of stem cell transplantation. PMID- 28833480 TI - Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues. AB - Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2*- ). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2-C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes pi-pi interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through pi-interactions is important for inhibiting NOX activity. PMID- 28833482 TI - Validity of Single Question for Screening Intimate Partner Violence among Urban Latina Women. AB - OBJECTIVE: The purpose of this study was to test the validity of a single violence question compared with revised Conflict Tactics Scales (CTS2) as an initial tool which can be easily used in community-based health care settings to detect IPV in Latina women. DESIGN AND SAMPLE: The study was conducted using secondary analyses of the baseline data from a culturally tailored HIV risk prevention project SEPA. A total of 657 Mexican and Puerto-Rican women aged 18 40, who reported sexual activities were interviewed. MEASURES: We used data regarding sociodemographic factors, Latino acculturation, a single violence question of "Did your partner hit or hurt you in any way?" and the CTS2 measuring intimate partner violence. RESULTS: Using the CTS2 as a gold standard, the sensitivity and specificity of a single question for screening partner physical violence was 45.9% and 94.7%, respectively. The positive likelihood ratio of a single question for physical violence was 8.59. The sensitivity, specificity, and likelihood ratio of a single question for screening psychological aggression were 17.9%, 98.5%, and 11.89, respectively. CONCLUSION: While a single question used in our study needs further improvement for desirable sensitivity, it may be usable as an initial question for detecting IPV. PMID- 28833483 TI - Neuromyelitis optica broke my heart too. PMID- 28833481 TI - Exploring residual risk for diabetes and microvascular disease in the Diabetes Prevention Program Outcomes Study (DPPOS). AB - AIM: Approximately half of the participants in the Diabetes Prevention Outcomes Study (DPPOS) had diabetes after 15 years of follow-up, whereas nearly all the others remained with pre-diabetes. We examined whether formerly unexplored factors in the DPPOS coexisted with known risk factors that posed additional risk for, or protection from, diabetes as well as microvascular disease. METHODS: Cox proportional hazard models were used to examine predictors of diabetes. Sequential modelling procedures considered known and formerly unexplored factors. We also constructed models to determine whether the same unexplored factors that associated with progression to diabetes also predicted the prevalence of microvascular disease. Hazard ratios (HR) are per standard deviation change in the variable. RESULTS: In models adjusted for demographics and known diabetes risk factors, two formerly unknown factors were associated with risk for both diabetes and microvascular disease: number of medications taken (HR = 1.07, 95% confidence intervals (95% CI) 1.03 to 1.12 for diabetes; odds ratio (OR) = 1.10, 95% CI 1.04 to 1.16 for microvascular disease) and variability in HbA1c (HR = 1.02, 95% CI 1.01 to 1.03 for diabetes; OR = 1.06, 95% CI 1.04 to 1.09 for microvascular disease per sd). Total comorbidities increased risk for diabetes (HR = 1.10, 95% CI 1.04 to 1.16), whereas higher systolic (OR = 1.22, 95% CI 1.13 to 1.31) and diastolic (OR = 1.14, 95% CI 1.05 to 1.22) blood pressure, as well as the use of anti-hypertensives (OR = 1.41, 95% CI 1.23 to 1.62), increased risk of microvascular disease. CONCLUSIONS: Several formerly unexplored factors in the DPPOS predicted additional risk for diabetes and/or microvascular disease - particularly hypertension and the use of anti-hypertensive medications - helping to explain some of the residual disease risk in participants of the DPPOS. PMID- 28833484 TI - Microbial production of mannitol by Lactobacillus brevis 3-A5 from concentrated extract of Jerusalem artichoke tubers. AB - In the present study, the conversion of the extract of Jerusalem artichoke tubers for mannitol production by Lactobacillus brevis 3-A5 was investigated. When the bacterium utilized enzymatic hydrolysates of Jerusalem artichoke extract as the main substrates in batch fermentation, the significant decrease in mannitol productivity was observed when the initial concentration of reducing sugar increased. Then, a strategy of continuous fed-batch fermentation was adopted for improving mannitol production with enzymatic hydrolysates of Jerusalem artichoke extract as main substrates. Although the concentration of mannitol could reach 199.86 g/L at the end of the fermentation, the productivity for the overall process of the fermentation was only 1.67 g/L/H. To improve the mannitol productivity with both higher yield and concentration, the simultaneous enzymatic saccharification and fermentation (SSF) was studied. In SSF, the mannitol production reached 176.50 g/L in 28 H with a productivity of 6.30 g/L/H and a yield of 0.68 g/g total sugar. Our study provides a cost-effective and eco friendly method for mannitol production from a cheap biomass. PMID- 28833485 TI - Enantioselective resolution of 4-chloromandelic acid by liquid-liquid extraction using 2-chloro-N-carbobenzyloxy-L-amino acid. AB - A liquid-liquid extraction resolution of 4-chloro-mandelic acid (4-ClMA) was studied by using 2-chloro-N-carbobenzyloxy-L-amino acid (2-Cl-Z-AA) as a chiral extractant. Important factors affecting the extraction efficiency were investigated, including the type of chiral extractant, pH value of aqueous phase, initial concentration of chiral extractant in organic phase, initial concentration of 4-ClMA in aqueous phase, and resolution temperature. It was observed that the concentration of (R)-4-ClMA was much higher than that of (S)-4 ClMA in organic phase due to a higher stability of the complex formed between (R) 4-ClMA and 2-Cl-Z-AA. A separation factor (alpha) of 3.05 was obtained at 0.02 mol/L 2-Cl-Z-Valine dissolved in dichloromethane, pH of 2.0, concentration of 4 ClMA of 0.11 mmol/Land T of 296.7K. PMID- 28833486 TI - Impaired periodontium and temporomandibular joints in tumour necrosis factor alpha transgenic mice. AB - AIM: Tumour necrosis factor (TNF)-alpha is a pathological factor causing the characteristic symptoms of periodontal disease and rheumatoid arthritis. In this study, we describe the phenotypes of human TNF-alpha transgenic mice (hTNFtg) with respect to their periodontium and the temporomandibular joint (TMJ). MATERIAL AND METHODS: Periodontal structures, TMJ and skull shape of hTNFtg mice and wild-type (WT) littermates were assessed by microcomputed tomography, automated segmentation, geometric morphometrics and histologic ground sections. RESULTS: We show that hTNFtg mice have an eroded lamina dura and reduced periodontal ligament space compared to (WT) littermates. Transgenic mice further exhibit severe destruction of the TMJ. Geometric morphometrics revealed that hTNFtg mice have a more laterally positioned TMJ with a concomitantly enlarged zygomatic process. Mandibular and maxillary teeth occluded properly. CONCLUSIONS: Our findings suggest that chronic inflammation in hTNFtg mice causes destructive changes of the periodontium and the TMJ. PMID- 28833487 TI - Absolute configuration of an axially chiral sulfonate determined from its optical rotatory dispersion, electronic circular dichroism, and vibrational circular dichroism spectra. AB - The absolute configuration (AC) of an axially chiral sulfonate (aCSO), 3,5 dimethyl-2-(naphthalen-1-yl)-6-(naphthalen-1-yl)benzenesulfonate (labeled as aCSO5), was investigated using optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectroscopies. All three methods led to the same conclusion and the AC of aCSO5 is reliably determined to be (-)-(aR, aR), or conversely (+)-(aS, aS). PMID- 28833488 TI - The association of antidepressant treatment with COPD maintenance medication use and adherence in a comorbid Medicare population: A longitudinal cohort study. AB - : The effect of treating comorbid depression to achieve optimal management of chronic obstructive pulmonary disease (COPD) has not yet empirically tested. We examined the association between antidepressant treatment and use of and adherence to COPD maintenance medications among patients with new-onset COPD and comorbid depression. METHODS: Using 2006-2012 Medicare data, this retrospective cohort study identified patients with newly diagnosed COPD and new-onset major depression. Two exposures-antidepressant use (versus non-use) and adherence measured by proportion of days covered (PDC) (PDC >=0.8 versus <0.8)-were assessed quarterly. We used marginal structural models to estimate the effects of prior antidepressant use and adherence on subsequent COPD maintenance inhaler use and adherence outcomes, accounting for time-varying confounders. RESULTS: A total of 25 458 COPD-depression patients, 82% with antidepressant treatment, were followed for a median of 2.5 years. Nearly half (48%) used at least 1 COPD maintenance inhaler in any given quarter; among users, 3 in 5 (61%) had a PDC of <0.8. Compared to patients with no antidepressant treatment, those with antidepressant use were more likely to use (relative ratio [RR] = 1.15, 95% confidence interval [CI] = 1.12- 1.17) and adhere to (RR = 1.08, 95% = 1.03-1.14) their COPD maintenance inhalers. Patients who adhered to antidepressant treatment were more likely to use and adhere to COPD maintenance inhalers. CONCLUSION: Regularly treated depression may increase use of and adherence to necessary maintenance medications for COPD. Antidepressant treatment may be a key determinant to improving medication-taking behaviors among COPD patients comorbid with depression. PMID- 28833489 TI - Coronary revascularization for acute myocardial infarction in the HIV population. AB - OBJECTIVE: To analyze trends in management and outcomes of patients infected with the human immunodeficiency virus (HIV) undergoing percutaneous coronary intervention (PCI) for an acute myocardial infarction (AMI) in the United States. BACKGROUND: Infection with HIV is an independent risk factor for accelerated atherosclerosis associated with higher rates of AMI. Current trends and outcomes of HIV-infected individuals presenting with AMI in the United States remain unknown. METHODS: Using the Healthcare Cost and Utilization Project National Inpatient Sample database we identified HIV-infected individuals who underwent PCI for an AMI from 2002 to 2013. Multivariable logistic regression and propensity-score matching were performed to analyze outcomes. RESULTS: We identified a total of 59 194 patients of which 7841 underwent PCI during index hospitalization (13.3%). Most patients were men (71%), >=50 years of age (82%), and white (74%). ST-elevation myocardial infarction was present in 21% of cases. Charlson comorbidity index (CCI) was 5.67 +/- 0.4. Predictors of post-procedural complications included female sex, black race, higher CCI, and placement of a bare metal stent, whereas predictors of mortality included occurrence of a complication, ST-elevation myocardial infarction, age >=70 years, and higher CCI. Conversely, placement of a drug-eluting stent was associated with a reduced risk of complications and mortality. After propensity-score matching, HIV-infected individuals were less likely to undergo PCI and receive a drug-eluting stent, while having longer length of stay, higher hospitalization costs, and higher in hospital mortality when compared to non-infected individuals. CONCLUSION: Significant disparities continue to affect HIV-infected individuals undergoing PCI for AMI in the United States. PMID- 28833490 TI - How do insect herbivores cope with the extreme oxidative stress of phototoxic host plants? AB - Plants of the Asteraceae and Hypericaceae possess secondary compounds that induce photooxidation in insect herbivores that consume them. One of the well established modes of action of these substances is peroxidation of membrane lipids. Some herbivores counteract these defences by avoidance of light and tissues rich in phototoxins or the ability to detoxify these secondary substances. The cytochrome P-450 polysubstrate monooxygenase systems involved, the metabolic products, and a new putative toxin pump have been described. Dietary antioxidants (beta-carotene, vitamin E, ascorbate) are additional defences against phototoxicity. They reduce mortality in herbivores exposed to phototoxins and some specialist herbivores have high constitutive levels. Adapted specialist insects also have higher constitutive levels of superoxide dismutase (SOD) and respond to phototoxins in their diet by the induction of catalase (CAT), glutathione reductase (GR), and increased levels of reduced glutathione (GSH). Artificial inhibition of the enzymes SOD and CAT had little effect on phototoxicity but inhibition of GSH synthesis in herbivores enhanced photooxidative effects of administered phototoxins on lipid peroxidation. While insects have many mechanisms to overcome plant photooxidants, the Asteraceae appear to have adopted a strategy of counterattack. We suggest and provide preliminary evidence that a second group of secondary substances, the sesquiterpene lactones, occurring in the Asteraceae can attack key antioxidant defences to synergise phototoxins. (c) 1995 Wiley-Liss, Inc. PMID- 28833491 TI - Plant defenses against oxidative stress. AB - Many reactive oxygen species such as ozone, singlet oxygen, hydroxyl radical, and organic oxyradicals have been implicated in damage to plant organs and biopolymers such as chloroplasts, cell membranes, proteins, and DNA. The principal defenses against these reactive molecules and free radicals in plants include detoxifying enzymes (catalase, superoxide dismutase, etc.) and also lower molecular weight secondary products with antioxidant activity. These latter compounds include a great variety of phenolic compounds, carotenoids, nitrogenous, and sulfur-containing materials. Some of the more important mechanisms of action of the secondary compounds will be discussed, with emphasis on the use of structural and kinetic data to identify the most effective antioxidants against peroxy radical-induced damage, which is perhaps the most important of the oxidative stresses present in the usual environment of plants. (c) 1995 Wiley-Liss, Inc. PMID- 28833492 TI - Preface. PMID- 28833493 TI - The relation between insulin-like growth factor 1 levels and risk of depression in ischemic stroke. AB - BACKGROUND: The aim of this study is to evaluate whether lower serum levels of insulin-like growth factor 1 (IGF-1) in the acute phase of ischemic stroke are associated with higher risk of post-stroke depression (PSD) over a 1-year period. METHODS: The subjects were first-ever acute ischemic stroke (AIS) patients who were hospitalized from July 1, 2014 to August 31, 2015. The study also included 120 age-matched and sex-matched healthy controls from the same geographical area. Fasting blood samples were collected within 24 hours of admission for IGF-I measurement. Neurological and neuropsychological evaluations were conducted at a 1-year follow-up. RESULTS: Two-hundred twenty-five patients were observed for a 1 year follow-up, and 74 of these patients (32.9%, 95%CI: 26.8%-39.0%) were diagnosed with PSD. The depression distribution across the IGF-1 quartiles ranged between 61.4% (first quartile) and 8.9% (fourth quartile). In a multivariate model using the first quartiles of the IGF-1 versus quartiles 2 through 4, together with the significant clinical variables, the marker displayed prognostic information, and the odds ratio (OR) for first quartile was 3.35 [95% CI, 1.88 6.79; P = 0.001]. CONCLUSION: The data showed that low serum IGF-1 levels at admission are associated with a high risk of developing PSD, suggesting that these alterations might be involved in the pathophysiology of depression symptoms in stroke patients. PMID- 28833494 TI - Echocardiographic evaluation of patients presenting with acutely decompensated heart failure in the setting of dietary or medication noncompliance-Is there a role? AB - BACKGROUND: Reevaluating patients who are admitted with heart failure (HF) exacerbation using echocardiogram is a common and appropriate indication. However, it is unknown whether it is appropriate to reevaluate such patients when the exacerbation is attributed to patients' noncompliance with self-care behaviors, where the presumption is that the underlying HF biology is stable. METHODS: Echocardiograms on all patients hospitalized for HF exacerbation attributed to dietary or medication noncompliance were retrospectively assessed for the presence of significant changes from prior echocardiogram. RESULTS: A total of 559 charts of patients admitted with heart failure exacerbation were reviewed, of which 125 patients (22%) were thought to have dietary or medication noncompliance as the etiology. Fifty-three patients (42%) had a follow-up echocardiogram performed during the index admission. The likelihood of being reevaluated by an echocardiogram during admission was not affected by the clinical service that the patient was admitted to, the patient's gender, or age. Eighty percent of echocardiograms performed within a year of prior study and 78% of echocardiograms performed >1 year revealed at least one significant change. The most common changes identified were an increase in left atrium diameter, worsening of pulmonary artery systolic pressure and worsening ejection fraction. There was no correlation between the time interval of between echocardiograms and the likelihood of a significant change. CONCLUSIONS: Repeat echocardiograms in patients admitted with HF exacerbation due to noncompliance revealed significant changes in the majority of patients studied. The changes may reflect worsening in cardiac function in addition to the presumed etiology of noncompliance. PMID- 28833495 TI - Decreases in left atrial compliance during early-stage exercise are related to exercise intolerance in asymptomatic significant mitral stenosis. AB - BACKGROUND: Doppler-driven net atrioventricular compliance (Cn ), which represents left atrial (LA) compliance, is an important determinant of pulmonary hypertension in mitral stenosis (MS). HYPOTHESIS: We hypothesized that decreases in Cn during early-stage exercise underlie exercise intolerance in patients with MS. METHODS: Thirty-three asymptomatic patients with significant MS (valve area 1.24 +/- 0.16 cm2 ) underwent resting and bicycle exercise echocardiography. LA compliance and conventional parameters were assessed at each workload. The patients were classified into two groups based on whether they developed dyspnea during exercise: an exercise-intolerance group (n = 22) and an exercise-tolerance group (n = 11). Moreover, "50 W" was defined as an early exercise stage. RESULTS: Although the groups had similar resting characteristics, there were striking differences in their echocardiographic parameters from the early stages of exercise. The relative Cn decrease at 50 W (expressed as a percentage of the resting Cn ) was significantly greater in the exercise-intolerance group (70.3 +/ 15.4% vs 49.7 +/- 9.7%, P < .001). The overall decrease in relative Cn was significantly greater in the exercise-intolerance group (P = .0005). Furthermore, differences in the trends in this parameter were observed between the two groups (P < .0001 for interaction). Multivariate analysis revealed that the relative Cn decrease at 50 W was an independent predictor of exercise intolerance (adjusted OR 1.105, 95% CI 1.030-1.184) after adjustment for other conventional parameters. CONCLUSIONS: Decreases in Cn during early-stage exercise are an important mechanism underlying exercise intolerance in MS. PMID- 28833496 TI - Expression of nestin in embryonic tissues and its effects on clinicopathological characteristics of patients with placenta previa. AB - In this study, we examined expression of nestin in the spinal cord, lung, kidney, stomach, colon, and intestine tissues at different stages of embryos in patients with placenta previa. Fetuses of 75 patients with placenta previa were assigned to case group and 80 fetuses from healthy pregnant women with normal placenta who voluntarily terminated pregnancy to control group. Clinical data of pregnant women were collected at the time of admission. Blood from elbow vein was collected to determine expression of serum nestin. Tissues from spinal cord, lung, kidney, stomach, colon, and intestine in 3-7 months fetuses of the two groups were extracted. Expression of nestin in tissues was detected by immunohistochemistry, Western blotting and RT-qPCR. The mRNA expression of nestin in the case group was increased. Nestin expression was correlated with the gestational age, age of foetus, and type of placenta previa in patients with placenta previa. Positive nestin expression was detected in the spinal cord, lung, kidney, stomach, intestine, and colon tissues in normal and placenta previa embryo at Stage I. The positive cell density and nestin expression decreased at Stage II, and further decreased at Stage III. The case group had higher nestin mRNA and protein levels throughout human fetal development. Findings of this study suggested that, nestin, as a specific marker of neural precursor cells, was expressed in various tissues of the embryo in patients with placenta previa and nestin expression was lower with increased maturation of the embryo. PMID- 28833497 TI - Biomechanical testing of the calcified metacarpal articular surface and its association with subchondral bone microstructure in Thoroughbred racehorses. AB - BACKGROUND: Palmar/plantar osteochondral disease (POD) and third metacarpal/ tarsal condylar fractures are considered fatigue injuries of subchondral bone (SCB) and calcified cartilage due to repetitive high loads in racehorses. In combination with adaptive changes in SCB in response to race training, the accumulation of SCB fatigue is likely to result in changes of joint surface mechanical properties. OBJECTIVES: To determine the spatial relationship and correlation of calcified articular surface biomechanical properties with SCB microstructure and training history in the distal palmar metacarpal condyle of Thoroughbred racehorses. STUDY DESIGN: Cross-sectional study. METHODS: Third metacarpal condyles were examined from 31 Thoroughbred horses with micro-computed tomography (microCT). Hyaline cartilage was removed and reference point indentation (RPI) mechanical testing of the calcified articular surface was performed. Training histories were obtained from trainers. The association among indentation distance increase (IDI, an inverse RPI measure of toughness), and microCT and training variables was assessed using a mixed-effects generalised linear model. RESULTS: Untrained horses had higher IDI than horses that had commenced training (P<0.001). Death as a result of musculoskeletal bone fatigue injury (P = 0.044) and presence of POD (P = 0.05) were associated with higher IDI. The microCT variables connectivity density and trabecular pattern factor were positively (P = 0.002) and negatively (P<0.001) correlated with IDI respectively. MAIN LIMITATIONS: The application of RPI to the calcified articular surface is novel and there is a potential for measurement variability with surface unevenness. CONCLUSION: Commencement of race training is associated with altered material properties of the calcified articular surface in horses. Reduced articular surface material properties can also be detected in horses that have fatigue injuries of the distal metacarpus and at other sites in the skeleton. Measures of SCB connectivity and trabecular surface shape may be more important determinants of resistance to failure of the calcified articular surface than traditional measures such as SCB volume and density. PMID- 28833498 TI - Generation and selection of naive Fab library for parasitic antigen: Anti-BmSXP antibodies for lymphatic filariasis. AB - Phage display has been applied successfully as a tool for the generation of monoclonal antibodies (mAbs). Naive antibody libraries are unique as they are able to overcome several limitations associated with conventional mAb generation methods like the hybridoma technology. Here, we performed an in vitro selection and generation of Fab antibodies against Brugia malayi SXP protein (BmSXP), a recombinant antigen for the detection of lymphatic filariasis. We developed a naive multi ethnic Fab antibody library with an estimated diversity of 2.99 * 109 . The antibody library was used to screen for mAbs against BmSXP recombinant antigen. Soluble monoclonal Fab antibodies against BmSXP were successfully isolated from the naive library. The Fab antibodies obtained were expressed and analyzed to show its binding capability. The diversity obtained from a pool of donors from various ethnic groups allowed for a diverse antibody library to be generated. The mAbs obtained were also functional in soluble form, which makes it useful for further downstream applications. We believe that the Fab mAbs are valuable for further studies and could also contribute to improvements in the diagnosis of filariasis. PMID- 28833499 TI - Manifestation of atopic dermatitis-like skin in TNCB-induced NC/Nga mice is ameliorated by topical treatment of substance P, possibly through blockade of allergic inflammation. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus and eczematous lesion. In this study, topically applied substance P (SP) significantly alleviated AD-like clinical symptoms in 2, 4, 6 trinitrochlorobenzene (TNCB)-induced dermatitis in NC/Nga mice. This effect was nullified by pretreatment of the neurokinin-1 receptor (NK-1R) antagonist CP99994. SP treatment significantly reduced the infiltration of mast cells and CD3-positive T cells as well as inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and thymic stromal lymphopoietin (TSLP), in AD-like skin lesions and decreased the levels of IgE and thymus and activation-regulated chemokine in serum. This SP-induced alleviation of allergic inflammatory responses was also confirmed as reduced activation in the axillary lymph nodes (aLN) and spleen, suggesting the systemic effect of SP on immune responses in TNCB-induced NC/Nga mice. Furthermore, SP-mediated TSLP reduction was confirmed in human keratinocyte culture under pro-inflammatory TNF-alpha stimulation. Taken together, these results suggest that topically administered SP may have potential as a medication for atopic dermatitis. PMID- 28833500 TI - Primary stability of a cementless acetabular cup in a cohort of patient-specific finite element models. AB - The primary stability achieved during total hip arthroplasty determines the long term success of cementless acetabular cups. Pre-clinical finite element testing of cups typically use a model of a single patient and assume the results can be extrapolated to the general population. This study explored the variability in predicted primary stability of a Pinnacle(r) cementless acetabular cup in 103 patient-specific finite element models of the hemipelvis and examined the association between patient-related factors and the observed variability. Cups were inserted by displacement-control into the FE models and then a loading configuration simulating a complete level gait cycle was applied. The cohort showed a range of polar gap of 284-1112 MUm and 95th percentile composite peak micromotion (CPM) of 18-624 MUm. Regression analysis was not conclusive on the relationship between patient-related factors and primary stability. No relationship was found between polar gap and micromotion. However, when the patient-related factors were categorised into quartile groups, trends suggested higher polar gaps occurred in subjects with small and shallow acetabular geometries and cup motion during gait was affected most by low elastic modulus and high bodyweight. The variation in primary stability in the cohort for an acetabular cup with a proven clinical track record may provide benchmark data when evaluating new cup designs. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1012-1023, 2018. PMID- 28833501 TI - Editorial. PMID- 28833502 TI - Tumor-derived exosomes: Potential biomarker or therapeutic target in breast cancer? AB - Exosomes are released by normal and tumour cells, including those involved in breast cancer, and provide a means of intercellular communications. Exosomes with diameters ranging between 30-150 nm are involved in transferring biological information, via various lipids, proteins, different forms of RNAs, and DNA from one cell to another, and this can result in reprogramming of recipient cell functions. These vesicles are present in all body fluids, for example, blood plasma/serum, semen, saliva, cerebrospinal fluid, breast milk, and urine. It has been recently reported that these particles are involved in the development and progression of different tumor types, including breast cancer. Furthermore, it has been suggested that exosomes have the potential to be used as drug transporters, or as biomarkers. This review highlights the potential roles of exosomes in normal and breast cancer cells and their potential applications as biomarkers with special focus on their potential applications in treatment of breast cancer. PMID- 28833503 TI - Persistent acute kidney injury following transcatheter aortic valve replacement. AB - BACKGROUND: Acute kidney injury (AKI) and its severity after transcatheter aortic valve replacement (TAVR) have been associated with worse outcomes. Studies have shown that AKI duration (transient or persistent) affects outcomes independently of AKI severity. This study was undertaken to determine the association, risk factors, and outcomes associated with persistent AKI (pAKI) after TAVR. METHODS: Adult patients undergoing TAVR at Mayo Clinic between January 1, 2008 and June 30, 2014 were enrolled. pAKI was defined as an increased serum creatinine at hospital discharge (>=0.3 mg/dL or >=50% from baseline). Risk factors associated with pAKI were identified with multivariate logistic regression. RESULTS: A total of 386 patients met the inclusion criteria. Fifty patients (13%) had pAKI. Independent risk factors for pAKI on multivariate analysis included diabetes mellitus (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.29-4.66), prior percutaneous coronary intervention (PCI) (OR, 2.39; 95%CI, 1.24-4.80), intra aortic balloon pump (IABP) use (OR, 8.14; 95%CI, 1.60-45.78), and blood transfusion (OR, 2.22; 95%CI, 1.15-4.27). Protective factors for pAKI included a higher baseline estimated glomerular filtration rate (eGFR) (OR, 0.83 per 10 mL/min/1.73 m2 increase in eGFR; 95%CI, 0.71-0.99). After adjusting for the Society of Thoracic Surgeons cardiac surgery risk score, pAKI occurrence remained significantly associated with increased 2-year mortality among hospital survivors (hazard ratio, 2.65; 95%CI, 1.51-4.41). CONCLUSION: pAKI was significantly associated with higher mortality risk following TAVR. Baseline eGFR, diabetes mellitus, previous PCI, IABP, and blood transfusion were risk factors for post procedural pAKI. PMID- 28833504 TI - Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages. AB - Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD-L1 and chemokines by CD163+ CD206+ M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD-L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD-L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T-cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients. PMID- 28833505 TI - Aberrant levels of SUV39H1 and SUV39H2 methyltransferase are associated with genomic instability in chronic lymphocytic leukemia. AB - Chromosomal alterations are commonly detected in patients with chronic lymphocytic leukemia (CLL) and impact disease pathogenesis, prognosis, and progression. Telomerase expression (hTERT), its activity and the telomere length are other important predictors of survival and multiple outcomes in CLL. SUV39H and SUV420H enzymes are histone methyltransferases (HMTases) involved in several cellular processes, including regulation of telomere length, heterochromatin organization, and genome stability. Here, we investigated whether SUV39H1, SUV39H2, SUV420H1, SUV420H2, and hTERT are associated with genomic instability of CLL. SUV39H (1/2), SUV420H (1/2), and hTERT expression was determined in 59 CLL samples by real time PCR. In addition, ZAP-70 protein expression was evaluated by Flow Cytometry and patients' karyotype was defined by Cytogenetic Analysis. Low expression of SUV39H1 was associated with the acquisition of altered and complex karyotypes. Conversely, high expression of SUV39H2 correlated with cytogenetic abnormalities in CLL patients. The pattern of karyotypic alterations differed in samples with detectable or undetectable hTERT expression. Furthermore, hTERT expression in CLL showed a correlation with transcript levels of SUV39H2, which, in part, can explain the association between SUV39H2 expression and cytogenetic abnormalities. Moreover, SUV39H1 correlated with SUV420H1 expression while SUV420H2 was associated with all other investigated HMTases. Our data show that the differential expression of SUV39H1 and SUV39H2 is associated with genomic instability and that the modulation of these HMTases can be an attractive approach to prevent CLL evolution. Environ. Mol. Mutagen. 58:654-661, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28833506 TI - A case of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome with lipoatrophy as an important clinical manifestation. AB - Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome is a PIK3CA-related overgrowth spectrum presenting with congenital, asymmetric, disproportionate overgrowth associated with dysregulated adipose tissue, enlarged bony structures, and mixed primarily truncal vascular malformations. We present this case to raise awareness that very thin body habitus (lipoatrophy) contrasting with areas of overgrowth can be an important clinical feature of this syndrome and, if not recognized, can lead to unnecessary investigations. PMID- 28833507 TI - Usefulness of shear wave elastography as a quantitative diagnosis of chronic pancreatitis. AB - BACKGROUND AND AIM: Chronic pancreatitis (CP) is sometimes diagnosed at the progressed stage. For the early diagnosis of CP, endoscopic ultrasonography (EUS) may be a useful method, but its diagnostic criteria is based on subjective judgment. Shear wave elastography (SW-EG) using transabdominal ultrasonography, which quantifies tissue elasticity as an absolute value, may be an objective and noninvasive method for the diagnosis of CP. METHODS: Eighty-five patients with known or suspected CP who underwent both EUS and SW-EG from October 2012 to July 2016 were included in this study. Patients were categorized into four stages using Rosemont classification and into three stages using Japan Pancreas Society clinical diagnostic criteria 2009 that was EUS-based criteria for the diagnosis of CP. SW-EG was measured five times in the pancreatic parenchyma, and the median value was defined as the pancreatic elastic modulus (PEM). RESULTS: Pancreatic elastic modulus was significantly positively correlated with Rosemont classification stage (rs = 0.54), Japan Pancreas Society stage (rs = 0.41), and the number of EUS features (rs = 0.47). Area under the receiver operating characteristic curve for the accuracy of SW-EG (consistent with CP and suggestive of CP vs normal and indeterminate for CP) was 0.77 (sensitivity 77.1%, specificity 64.9%). In a multivariate linear regression analysis including various EUS features related to PEM, hyperechoic foci with shadowing and lobularity with honeycombing were independent features related to PEM. CONCLUSIONS: Chronic pancreatitis may be diagnosed noninvasively and objectively using SW-EG without performing EUS. PMID- 28833508 TI - In-hospital and long-term outcomes of percutaneous balloon aortic valvuloplasty with concomitant percutaneous coronary intervention in patients with severe aortic stenosis. AB - BACKGROUND: Severe aortic stenosis (AS) often coexists with significant coronary artery disease. OBJECTIVE: To evaluate procedural complications and long-term outcomes of patients with severe AS undergoing balloon aortic valvuloplasty (BAV) and percutaneous coronary intervention (PCI). METHODS: A total of 97 patients with severe AS underwent 104 BAVs as palliative procedure, bridge to definitive treatment, or before urgent non-cardiac surgery. Patients were followed-up for at least 12 months. RESULTS: Of the 97 patients, 34 (35.0%) underwent standalone BAV, 45 (46.4%) underwent BAV with coronary angiography, and 18 (18.6%) BAV with PCI. There were no differences in baseline characteristics and indications for BAV among the groups (P > 0.05). No higher risk of complications after BAV performed with concomitant coronary angiography/PCI was observed. Transcatheter aortic valve implantation was performed after BAV in 13 (13.4%) patients and surgical aortic valve replacement in three (3.1%) patients. In spite of no difference in in-hospital mortality (5.6% vs. 8.9%; P = 0.76), patients with BAV and concomitant PCI had lower long-term mortality than patients with BAV and concomitant coronary angiography (28.5% vs. 51.0%; P = 0.03). In multivariable Cox analysis adjusted for age, sex, and body mass index, the Society of Thoracic Surgeons Predicted Risk of Mortality score was identified as the only independent predictor of long-term mortality for all patients (HR: 1.09, 95%CI: 1.04-1.15, P = 0.0006). CONCLUSIONS: Concomitant PCI or coronary angiography performed with BAV may not increase the risk of major and vascular complications. Patients with BAV and concomitant PCI may have better survival than patients with BAV and concomitant coronary angiography. PMID- 28833509 TI - Ultrastructural, Sensory and Functional Anatomy of the Northern Elephant Seal (Mirounga angustirostris) Facial Vibrissae. AB - Vibrissae (whiskers) play a key role in underwater orientation in foraging phocids through vibrotactile sensation processing. Our aim was to evaluate the structure of northern elephant seal (NES) vibrissae by means of light (LM) and transmission electron microscopy (TEM), in order to elucidate their function. Vibrissal follicles were processed using standardized laboratory methods and LM/TEM techniques. Individual follicular axonal numbers were counted and axonal diameter measured and averaged. NES have mystacial, rhinal, supraorbital and labial vibrissae. The vibrissal follicles are histologically subdivided into a ring, upper and lower cavernous sinuses (LCS). Each vibrissa is innervated by the deep vibrissal nerve. The average number of axons per large mystacial vibrissa is 1804 (+/-123), rhinal 985 (+/-241), supraorbital 1,064 (+/-204) and 374 (+/-65) in labial vibrissa. The entire vibrissal system carries an estimated 148 573 axons, and mystacial vibrissae alone have 125 323 axons. Axonal conduction velocity for each vibrissal type is 55.26 m/s for labial, 56.58 m/s for rhinal and 35.88 m/s for mystacial vibrissae. TEM and LM revealed a plethora of mechanoreceptors within the vibrissal follicles: Merkel cell-neurite complexes, lanceolate and pilo-Ruffini end organs. A vast number of sensory axons projecting from the entire vibrissal system indicate that the vibrissal sensory area takes up a large proportion of phocids' somatosensory cortex. In conclusion, NES has highly sensitive and finely tuned vibrotactile vibrissal sense organs. PMID- 28833510 TI - A new method to quantify the health risks from sources of perfluoroalkyl substances, combined with positive matrix factorization and risk assessment models. AB - A hybrid model based on the positive matrix factorization (PMF) model and the health risk assessment model for assessing risks associated with sources of perfluoroalkyl substances (PFASs) in water was established and applied at Dianchi Lake to test its applicability. The new method contains 2 stages: 1) the sources of PFASs were apportioned by the PMF model and 2) the contribution of health risks from each source was calculated by the new hybrid model. Two factors were extracted by PMF, with factor 1 identified as aqueous fire-fighting foams source and factor 2 as fluoropolymer manufacturing and processing and perfluorooctanoic acid production source. The health risk of PFASs in the water assessed by the health risk assessment model was 9.54 * 10-7 a-1 on average, showing no obvious adverse effects to human health. The 2 sources' risks estimated by the new hybrid model ranged from 2.95 * 10-10 to 6.60 * 10-6 a-1 and from 1.64 * 10-7 to 1.62 * 10-6 a-1 , respectively. The new hybrid model can provide useful information on the health risks of PFAS sources, which is helpful for pollution control and environmental management. Environ Toxicol Chem 2018;37:107-115. (c) 2017 SETAC. PMID- 28833511 TI - Detection and care practices for postpartum depressive symptoms in public-sector obstetric units in Mexico: Qualitative results from a resource-constrained setting. AB - BACKGROUND: Postpartum depression (PPD) is amenable to detection and treatment, but effectively addressing it is contingent on policies, practices, and health care providers working together to address the issue. The aim of this study is to describe a sample of health care providers' existing practices in public-sector obstetric units in Mexico related to detecting and offering care to women with depressive symptomology. METHODS: Semi-structured interviews with 40 health care providers (16 physicians, 13 nurses, three social workers, and eight psychologists) from one tertiary-level and two secondary-level, public-sector obstetric units, were conducted by members of a trained research team from May to July 2012. Qualitative data were analyzed in Spanish according to Grounded Theory, using Nvivo 10 software. RESULTS: Lack of hospital guidelines, training, and time constraints are reasons given for not detecting PPD symptoms among women. Providers reported that their role is cursory and limited to giving women anticipatory guidance for what to expect emotionally after childbirth or providing a trusting atmosphere for women to express their feelings. Care is fragmented and inadequate, in part because of the lack of protocols that define who makes mental health referrals and where. Providers indicated PPD is important but not prioritized in health care for pregnant and postpartum women. CONCLUSION: Critical needs in obstetric units include formal mental health care detection and care protocols during the perinatal period, strategies to address mental health needs despite short hospital stays, and training for providers on how to implement detection and care protocols and strategies. PMID- 28833512 TI - Intrapartum obstetric care in the United States military: Comparison of military and civilian care systems within TRICARE. AB - BACKGROUND: Expectant mothers who are beneficiaries of TRICARE (universal insurance to United States Armed Services members and their dependents) can choose to receive care within direct (salary-based) or purchased (fee-for service) care systems. We sought to compare frequency of intrapartum obstetric procedures and outcomes such as severe acute maternal morbidity (SAMM) and common postpartum complications between direct and purchased care systems within TRICARE. METHODS: TRICARE (2006-2010) claims data were used to identify deliveries. Patient demographics, frequency of types of delivery (noninstrumental vaginal, cesarean, and instrumental vaginal), comorbid conditions, SAMM, and common postpartum complications were compared between the two systems of care. Multivariable models adjusted for patient clinical/demographic factors determined the odds of common complications and SAMM complications in purchased care compared with direct care. RESULTS: A total of 440 138 deliveries were identified. Compared with direct care, purchased care had higher frequency (30.9% vs 25.8%, P<.001) and higher adjusted odds (aOR 1.37 [CI 1.34-1.38]) of cesarean delivery. In stratified analysis by mode of delivery, purchased care had lower odds of common complications for all modes of delivery (aOR[CI]:noninstrumental vaginal: 0.72 [0.71-0.74], cesarean: 0.71 [0.68-0.75], instrumental vaginal: 0.64 [0.60-0.68]) than direct care. However, purchased care had higher odds of SAMM complications for cesarean delivery (aOR 1.31 [CI 1.19-1.44]) compared with direct care. CONCLUSION: Direct care has a higher vaginal delivery rate but also a higher rate of common complications compared with purchased care. Study of direct and purchased care systems in TRICARE may have potential use as a surrogate for comparing obstetric care between salary-based systems and fee-for service systems in the United States. PMID- 28833513 TI - Application of an enhanced device to transluminal retrieval of malappositioned coronary stents: An experimental study. AB - OBJECTIVES: This study investigated the application of a novel enhanced device to retrieval of deployed stents in a porcine coronary model. BACKGROUND: Recurrence of in-stent restenosis and stent thrombosis still remains to be resolved. Under these conditions, it is sometimes necessary to retrieve malfunctional stents responsible for thrombosis. However, few data exist regarding the feasibility and safety of retrieval device use in previously deployed coronary stents. METHODS: We have developed an enhanced device consisting of an asymmetric forceps, conducting shaft (1.6 mm diameter, 150 cm length), and control handle. Bare-metal stents (3 mm diameter) were implanted in four pigs to create a malapposition model. Coronary artery injury was evaluated by intravascular ultrasound (IVUS) and histological imaging on the first and 14th days. RESULTS: The device was delivered to the coronary artery using the existing catheter (7 Fr). After opening the forceps, the blade was forced into the space between the vessel wall and the stent, and the stent struts were then grasped with the forceps. This was then pulled back into the catheter, still grasping the stent struts with the forceps. All stents were successfully retrieved by this method (n = 4). On the first day, no apparent vessel wall injury was detectable by IVUS, although histological findings revealed damage to endothelial monolayer on retrieval of deployed stent. On the 14th day, mild intimal thickening was observed by IVUS and histology. CONCLUSIONS: These results demonstrate that the present device can be applied to transluminal retrieval of acquired malappositioned coronary stents. PMID- 28833514 TI - Tissue oxygenation mapping by combined chemical shift and T1 magnetic resonance imaging. AB - PURPOSE: To propose a method for determining tissue oxygenation via the measurement of fat T1 . The method is based on a 2D fat/water chemical shift encoded and T1 -weighted acquisition. THEORY AND METHODS: A 2D data set was acquired with a fast spin echo sequence with several echo asymmetries and repetition times, wherein one dimension is related to the fat/water phase modulation and the other to the T1 saturation recovery. A joint magnitude-based process of phase modulation and T1 evolution allowed for the collection of the fat fraction and T1 maps with resolved fat or water dominance ambiguity while avoiding the phased error problem. RESULTS: In vitro imaging allowed for the attribution of fat content for different water/oil emulsions that demonstrated longitudinal relaxation rate (R1 ) sensitivity to the oxygenated emulsion environment. The fat R1 values were subsequently compared to reference values, which were measured using low receiver bandwidth acquisition to enhance water and fat signal separations. In vivo feasibility of tissue oxygenation assessment was demonstrated by investigating interscapular brown adipose tissue modifications during an air/carbogen challenge in rats. CONCLUSION: The proposed method offers a precise and robust estimate of tissue oxygenation illustrated by the method's ability to detect-brown adipose tissue oxygenation modifications. Magn Reson Med 79:1981-1991, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833515 TI - Staff perceptions of challenging parent-staff interactions and beneficial strategies in the Neonatal Intensive Care Unit. AB - AIM: To characterise neonatal intensive care unit (NICU) staff perceptions regarding factors which may lead to more challenging staff-parent interactions, and beneficial strategies for working with families with whom such interactions occur. METHODS: A survey of 168 physician and nursing staff at two NICUs in American teaching hospitals inquired about their perceptions of challenging parent-staff interactions and situations in which such interactions were likely to occur. RESULTS: From a medical perspective, staff perceptions of challenging interactions were noted when infants had recent decompensation, high medical complexity, malformations or long duration of stay in the NICU. From a psychological/social perspective, a high likelihood of challenging interactions was noted with parents who were suspicious, interfere with equipment, or parents who hover in the NICU, express paranoid or delusional thoughts, repeat questions, perceive the staff as inaccessible, are managing addictions, or who require child protective services involvement. Frequent family meetings, grieving opportunities, education of parents, social work referrals, clearly defined rules, partnering in daily care and support groups were perceived as the most beneficial strategies for improving difficult interactions. CONCLUSION: This study delineates what staff perceive as challenging interactions and provides support for an educational and interventional role that incorporates mental health professionals. PMID- 28833516 TI - Severe neonatal hyperbilirubinaemia is frequently associated with long hospitalisation for emergency care in Nigeria. AB - AIM: This study investigated the frequency and predictors of a long hospital stay (LHS) for severe neonatal hyperbilirubinaemia in Nigeria. METHODS: Length of stay (LOS) for severe hyperbilirubinaemia was examined among neonates consecutively admitted to the emergency department of a children's hospital in Lagos from January 2013 to December 2014. The median LOS was used as the cut-off for LHS. Multivariate logistic regression determined the independent predictors of LHS based on demographic and clinical factors significantly associated with the log transformed LOS in the bivariate analyses. RESULTS: We enrolled 622 hyperbilirubinaemic infants with a median age of four days (interquartile range 2 6 days) and 276 (44.4%) had LHS based on the median LOS of five days. Regardless of their birth place, infants were significantly more likely to have LHS if they were admitted in the first two days of life (p = 0.008) - especially with birth asphyxia - or had acute bilirubin encephalopathy (p = 0.001) and required one (p = 0.020) or repeat (p = 0.022) exchange transfusions. Infants who required repeat exchange transfusions had the highest odds for LHS (odds ratio 4.98, 95% confidence interval 1.26-19.76). CONCLUSION: Severe hyperbilirubinaemia was frequently associated with long hospitalisation in Nigeria, especially if neonates had birth asphyxia or required exchange transfusions. PMID- 28833517 TI - Multiple linear regression models for predicting chronic aluminum toxicity to freshwater aquatic organisms and developing water quality guidelines. AB - The bioavailability of aluminum (Al) to freshwater aquatic organisms varies as a function of several water chemistry parameters, including pH, dissolved organic carbon (DOC), and water hardness. We evaluated the ability of multiple linear regression (MLR) models to predict chronic Al toxicity to a green alga (Pseudokirchneriella subcapitata), a cladoceran (Ceriodaphnia dubia), and a fish (Pimephales promelas) as a function of varying DOC, pH, and hardness conditions. The MLR models predicted toxicity values that were within a factor of 2 of observed values in 100% of the cases for P. subcapitata (10 and 20% effective concentrations [EC10s and EC20s]), 91% of the cases for C. dubia (EC10s and EC20s), and 95% (EC10s) and 91% (EC20s) of the cases for P. promelas. The MLR models were then applied to all species with Al toxicity data to derive species and genus sensitivity distributions that could be adjusted as a function of varying DOC, pH, and hardness conditions (the P. subcapitata model was applied to algae and macrophytes, the C. dubia model was applied to invertebrates, and the P. promelas model was applied to fish). Hazardous concentrations to 5% of the species or genera were then derived in 2 ways: 1) fitting a log-normal distribution to species-mean EC10s for all species (following the European Union methodology), and 2) fitting a triangular distribution to genus-mean EC20s for animals only (following the US Environmental Protection Agency methodology). Overall, MLR-based models provide a viable approach for deriving Al water quality guidelines that vary as a function of DOC, pH, and hardness conditions and are a significant improvement over bioavailability corrections based on single parameters. Environ Toxicol Chem 2018;37:80-90. (c) 2017 SETAC. PMID- 28833518 TI - Post-sternotomy mediastinitis in the modern era. AB - BACKGROUND: Post-sternotomy mediastinitis is associated with significant mortality and morbidity. Despite surgical advances in cardiac surgery and improvements in perioperative care, mediastinitis remains a devastating post operative complication. This study provides a comprehension review of post sternotomy mediastinitis in the modern era, and discusses the incidence, risk factors, microbiology, prevention, and management of this complication. METHODS: This review was based on a PubMed/MEDLINE literature search up until 9th March 2017 for publications relevant to mediastinitis post-cardiac surgery. RESULTS: The incidence of mediastinitis post-cardiac surgery varies between 0.3 and 3.4%, and is associated with an in-hospital mortality ranging from from 1.1 to 19%. The risk of developing post-operative mediastinitis is dependent on the patients' co morbidities (diabetes, obesity, smoking, renal failure) and surgical techniques (bilateral pedicled internal mammary harvest, excessive cautery, long duration of surgery). Preventative measures including skin and nasal decontamination, antibiotic prophylaxis, strict glycemic control, and meticulous surgical techniques are crucial in reducing the risk. Treatment of post-operative mediastinitis include culture-directed antibiotic therapy, early wound exploration, and debridement followed by sternal reconstruction/closure. Vacuum assisted therapy can be used as a single line therapy or as a bridge to eventual sternal reconstruction/closure. CONCLUSION: Post-sternotomy mediastinitis remains a potentially fatal complication of cardiac surgery despite the advancements in the perioperative care in the modern era. Management on preventative measures, prompt diagnosis, and managements are crucial in reducing associated mortality and morbidity. PMID- 28833520 TI - Introduction to Intradialytic Hypotension: Perspectives in Contemporary Practice. PMID- 28833522 TI - Unusually high prevalence of classical Kaposi's sarcoma in Druze Muslims of Northern Israel. PMID- 28833519 TI - Echocardiography-quantified myocardial strain-a marker of global and regional infarct size that stratifies likelihood of left ventricular thrombus. AB - BACKGROUND: Myocardial strain provides a novel means of quantifying subtle alterations in contractile function; incremental utility post-MI is unknown. OBJECTIVES: To test longitudinal-quantified by postprocessing routine echo-for assessment of MI size measured by cardiac magnetic resonance (CMR) and conventional methods, and assess regional and global strain (GLS) as markers of LV thrombus. METHODS: The population comprised of patients with anterior ST segment MI who underwent echo and CMR prospectively. Preexisting echoes were retrieved, re-analyzed for strain, and compared to conventional MI markers as well as CMR-evidenced MI, function, and thrombus. RESULTS: Seventy-four patients underwent echo and CMR 4 +/- 1 weeks post-MI; 72% had abnormal GLS. CMR quantified MI size was 2.5-fold larger and EF lower among patients with abnormal GLS, paralleling 2.6-3.1 fold differences in Q-wave size and CPK (all P <= .002). GLS correlated with CMR-quantified MI (r = .66), CPK (r = .52) and Q-wave area (r = .44; all P <= .001): Regional strain was lower in the base, mid, and apical LV among patients with CMR-defined transmural MI in each territory (P < .05) and correlated with cine-CMR regional EF (r = .53-.71; P < .001) and echo wall motion (r = .45-.71; P < .001). GLS and apical strain were ~2-fold lower among patients with LV thrombus (P <= .002): Apical strain yielded higher diagnostic performance for thrombus (AUC: 0.83 [0.72-0.93], P = .001) than wall motion (0.73 [0.58 0.88], P = .02), as did global strain (0.78 [0.65-0.90], P = .005) compared to LVEF (0.58 [0.45-0.72], P = .41). CONCLUSIONS: Echo-quantified longitudinal strain provides a marker of MI size and improves stratification for post-MI LV thrombus beyond conventional indices. PMID- 28833521 TI - The effect of peer support groups on family adaptation from the perspective of wives of war veterans with posttraumatic stress disorder. AB - OBJECTIVE: The aim of this study was to examine the effect of peer group support on family adaptation of wives of war veterans suffering from post-traumatic stress disorder (PTSD). DESIGN AND SAMPLE: In this randomized controlled trial, 80 wives of war veterans with PTSD were incorporated, and selected participants were randomly assigned into intervention and control groups (n = 40 per group). The intervention group was divided into four subgroups, with each participating in eight weekly based 1.5-hr peer support group sessions and the control group received no intervention. MEASURES: Demographics form and Family Adaptation Scale (FAS) developed by Antonovsky and Sourani (1988) were applied. RESULTS: The total mean scores of family adaptation increased significantly more in the intervention group than in the control group (p = .033). Furthermore, the time * group interaction effects were significant for internal family fit (p = .013) and a combination of both family fit and family community fit (p = .020) dimensions. Nonetheless family fit dimensions mean scores had no significant increase in the intervention group than the control group over time (p = .948). CONCLUSIONS: Peer support group can be a useful tool for health care professionals to enhance family adaptation in spouses of war veterans with PTSD. PMID- 28833523 TI - Modeling of coarctation of aorta in human fetuses using 3D/4D fetal echocardiography and computational fluid dynamics. AB - OBJECTIVES: We sought to develop a hemodynamic model of aortic and ductal arches using computational fluid dynamics (CFD) and 3D/4D spatio-temporal image correlation (STIC) fetal echocardiography and to investigate the hemodynamics of coarctation of aorta (CoA) in human fetuses using this approach. METHODS: We obtained 3D/4D STIC fetal echocardiographic images of the aortic and ductal arches (DA) in five normal fetuses. Based on these images, we simulated the hemodynamics in the two arches using CFD. Subsequently, we reduced the dimensions of aortic isthmus from 100% to 85%, 70%, 55%, 40%, and 25% of the original dimension digitally. Numerical simulation was repeated in each condition, and flow profile, velocity, pressure, and wall shear stress (WSS) were compared with those of the baseline normal aortic and ductal arches. RESULTS: With the progressive narrowing in the aortic isthmus, there were alterations in the flow profile, velocity, pressure, and WSS. The downstream vortexes disappeared, and the double helix profile became single helix. When the aortic isthmus reduced by 55% in dimension, there was an exponential increase in velocity and WSS and decrease in pressure. CONCLUSIONS: The aortic and ductal arch geometry and flow lead to the alterations in flow profile, velocity, pressure, and WSS in the aortic isthmus in normal and CoA models, which are conductive of ductal issue migration into these areas. A 55% reduction in the dimension of aortic isthmus is associated with exponential change in velocity, pressure, and WSS, a probable threshold for hemodynamically significant CoA. PMID- 28833524 TI - Trichothiodystrophy, complementation group A complicated with squamous cell carcinoma. PMID- 28833525 TI - DNA damage in kidney transplant patients. Role of organ origin. AB - Chronic kidney disease (CKD) patients are characterized by elevated levels of genomic damage. This damage increases when kidney function decreases being maximum in hemodialysis patients. As kidney transplantation improves renal function, and it is related with better survival, the aim of our study was to evaluate potential changes in DNA damage levels after kidney transplantation, and comparing living donor recipients with cadaveric donor recipients. The alkaline comet assay was used to determine DNA breaks and oxidative damaged DNA; and the micronucleus assay was used to determine chromosomal breakage and/or aneuploidy. Fifty CKD patients were followed up after 6 and 12 months of their kidney transplantation. All patients increased their genomic damage levels after 6 and 12 months of renal transplantation, compared with those observed before transplantation, despite of the improvement of their metabolic functions. Donor advanced age correlated positively with higher DNA damage. Genomic damage was lower in living donor transplants with respect to cadaveric donor transplants. Our conclusion is that DNA damage increased in kidney transplantation patients, whereas their renal function improved. Higher levels of DNA damage were found in cadaveric donor transplants when compared to living donor transplants. Environ. Mol. Mutagen. 58:712-718, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28833527 TI - Hip Fracture, Comorbidity, and the Risk of Myocardial Infarction and Stroke: A Danish Nationwide Cohort Study, 1995-2015. AB - We evaluated risks of MI and stroke in elderly patients with hip fracture compared with the general population. We also examined the interaction between hip fracture and comorbidity with respect to risks of MI or stroke, defined as excess of risk explained by combining risks of hip fracture and comorbidity. We conducted a population-based cohort study using Danish health registries, in 1995 to 2015 including 110,563 hip fracture patients and 552,774 members of the comparison cohort from the general population. Thirty-day cumulative incidences of MI were 1.15% among patients with hip fracture and 0.09% in the general population (adjusted hazard ratio [aHR] = 12.97; 95% confidence interval [CI], 11.56 to 14.55). Thirty-day cumulative incidences of stroke were 2.16% for hip fracture patients and 0.21% in the general population (aHR = 9.42; 95% CI, 8.71 to 10.19). During the 31 to 365 days following hip fracture, the aHR for MI was 1.05 (95% CI, 0.97 to 1.14) and remained at this level during the remainder of follow-up (maximum of 20 years). The aHR for stroke was 1.29 (95% CI, 1.22 to 1.35) during the 31 to 365 days following hip fracture, remained elevated for up to 10 years, and then decreased to the general population level. The aHRs for MI and stroke were increased for both men and women, and in all age and comorbidity groups. During the first 30 days, up to 76% of MI and stroke risk was attributable to interaction between hip fracture and comorbidity. Patients with hip fracture are at increased risk of both MI and stroke up to 1 year following the fracture. Risk of stroke, but not of MI, was elevated during up to 10 years postfracture. Although the absolute risks were low, our finding underscores the importance of targeting multimorbidity, including prevention and adequate treatment, to improve the prognosis of hip fracture patients. (c) 2017 American Society for Bone and Mineral Research. PMID- 28833526 TI - Perinatal lead (Pb) exposure results in sex and tissue-dependent adult DNA methylation alterations in murine IAP transposons. AB - Epidemiological and animal data suggest that adult chronic disease is influenced by early-life exposure-induced changes to the epigenome. Previously, we observed that perinatal lead (Pb) exposure results in persistent murine metabolic- and activity-related effects. Using phylogenetic and DNA methylation analysis, we have also identified novel intracisternal A particle (IAP) retrotransposons exhibiting regions of variable methylation as candidate loci for environmental effects on the epigenome. Here, we now evaluate brain and kidney DNA methylation profiles of four representative IAPs in adult mice exposed to human physiologically relevant levels of Pb two weeks prior to mating through lactation. When IAPs across the genome were evaluated globally, average (sd) methylation levels were 92.84% (3.74) differing by tissue (P < 0.001), but not sex or dose. By contrast, the four individual IAPs displayed tissue-specific Pb and sex effects. Medium Pb-exposed mice had 3.86% less brain methylation at IAP 110 (P < 0.01), while high Pb-exposed mice had 2.83% less brain methylation at IAP 236 (P = 0.01) and 1.77% less at IAP 506 (P = 0.05). Individual IAP DNA methylation differed by sex for IAP 110 in the brain and kidney, IAP 236 in the kidney, and IAP 1259 in the kidney. Using Tomtom, we identified three binding motifs that matched to each of our novel IAPs impacted by Pb, one of which (HMGA2) has been linked to metabolic-related conditions in both mice and humans. Thus, these recently identified IAPs display tissue-specific environmental lability as well as sex-specific differences supporting an epigenetic link between early exposure to Pb and later-in-life health outcomes. Environ. Mol. Mutagen. 58:540-550, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28833528 TI - Intraoperative assessment of transient and persistent regional left ventricular wall motion abnormalities in patients undergoing coronary revascularization surgery using real time three-dimensional transesophageal echocardiography: A prospective observational study. AB - OBJECTIVE: To evaluate the feasibility of intraoperative real time three dimensional echocardiography (RT3DE) for identification and quantification of transient and persistent regional wall motion abnormalities (RWMAs) in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting (CABG). DESIGN: A prospective observational study SETTING: Single-center study in an academic tertiary care hospital PARTICIPANTS: A series of 42 patients undergoing elective CABG over a 2-year period were included. INTERVENTION: After induction of anesthesia, a comprehensive transesophageal echocardiography (TEE) examination was performed to evaluate regional wall motion using two-dimensional wall motion score index (WMSI) and RT3D echocardiographic parameters at three specific time points during the operative phase. MEASUREMENTS AND MAIN RESULTS: The 3D assessment of LV function was based on the quantification of change in LV chamber volume over time from each segment excursion. Patients were divided into two groups and subgroups based on TEE findings. There was significant mechanical dyssynchrony in patients with RWMAs (WMSI > 1; systolic dyssynchrony index [SDI] = 7.0 +/- 3.66) as compared to the patients having normal wall motion (WMSI = 1; SDI = 2.0 +/- 0.95; P = .001). Patients with contractile dysfunction were found to have low values of segmental excursion and high values of negative excursion on parametric imaging. Persistent RWMAs due to hibernating myocardium showed significant resolution of mechanical dyssynchrony after revascularization. Parametric imaging could detect transient RWMAs due to stunning and graft dysfunction. Early activating segments (EAS) on "timing bull's-eye" may represent hypercontractile segments and may influence inotrope administration. CONCLUSION: The RT3DE is a valuable modality for precise quantification of regional wall motion during revascularization procedure. PMID- 28833529 TI - Distress and unmet needs during treatment and quality of life in early cancer survivorship: A longitudinal study of haematological cancer patients. AB - OBJECTIVE: To examine the influence of anxiety, depression and unmet supportive care needs on future quality of life (QoL) in multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) patients. METHODS: Multiple myeloma and DLBCL patients recruited through the population-based Victorian Cancer Registry. Data were collected through two telephone interviews: (T1) on average 7 months postdiagnosis, (T2) average 8 months later. QoL was examined at T2 using the Functional Assessment of Cancer Therapy (FACT-G) scale. The Hospital Anxiety and Depression Scale measured anxiety and depression, and the Supportive Care Needs Survey measured unmet needs at T1. Multivariate linear regression examined associations between QoL subscales (physical, emotional, social and functional well-being and overall QoL) and T1 anxiety, depression and unmet needs. RESULTS: Except physical well-being, all other QoL subscales and overall QoL were significantly associated with T1 anxiety. All QoL subscales and overall QoL were significantly associated with T1 depression. Only patient care needs were associated with physical and social well-being and overall QoL. CONCLUSION: Anxiety, depression and patient care unmet needs during treatment are associated with diminished physical and emotional well-being in the following months. Psychological distress and unmet supportive care needs experienced during treatment should be addressed to maximise future QoL. PMID- 28833530 TI - Planning for Publication. PMID- 28833531 TI - Insufficient sleep: Enhanced risk-seeking relates to low local sleep intensity. AB - OBJECTIVES: Chronic sleep restriction is highly prevalent in modern society and is, in its clinical form, insufficient sleep syndrome, one of the most prevalent diagnoses in clinical sleep laboratories, with substantial negative impact on health and community burden. It reflects every-day sleep loss better than acute sleep deprivation, but its effects and particularly the underlying mechanisms remain largely unknown for a variety of critical cognitive domains, as, for example, risky decision making. METHODS: We assessed financial risk-taking behavior after 7 consecutive nights of sleep restriction and after 1 night of acute sleep deprivation compared to a regular sleep condition in a within-subject design. We further investigated potential underlying mechanisms of sleep-loss induced changes in behavior by high-density electroencephalography recordings during restricted sleep. RESULTS: We show that chronic sleep restriction increases risk-seeking, whereas this was not observed after acute sleep deprivation. This increase was subjectively not noticed and was related to locally lower values of slow-wave energy during preceding sleep, an electrophysiological marker of sleep intensity and restoration, in electrodes over the right prefrontal cortex. INTERPRETATION: This study provides, for the first time, evidence that insufficient sleep restoration over circumscribed cortical areas leads to aberrant behavior. In chronically sleep restricted subjects, low slow-wave sleep intensity over the right prefrontal cortex-which has been shown to be linked to risk behavior-may lead to increased and subjectively unnoticed risk-seeking. Ann Neurol 2017;82:409-418. PMID- 28833533 TI - The thoracic duct and the Fontan patient. AB - BACKGROUND: Ultrasound imaging of adults with heart failure and increased central venous pressure (CVP) has shown significant thoracic duct (TD) dilation from impedance in lymphatic drainage. Elevated CVP and abnormal lymphatic drainage are implicated in severe Fontan complications, including protein losing enteropathy (PLE) and plastic bronchitis (PB). Systematic studies of TD and lymphatic circulation in children are limited, and their cervical TD normative values have not been established. METHODS: Thoracic duct imaging was attempted prospectively during routine echocardiograms performed 7/2014-9/2016 in children 5-21 years old with normal cardiovascular physiology and Fontan palliation. TD insertion to the central venous system (lympho-venous junction) was assessed with an S12-4 MHz transducer. For the first 34 patients, only TD ostia were measured, but ostium shape variability at the lympho-venous junction led to including the TD arch 5-10 mm proximal to the ostium for the remaining cohort. RESULTS: Seventy-nine total subjects were studied: 58 controls, 13 Fontan patients with normal systemic ventricular ejection fraction (EF) (>50%), and 8 Fontan patients with decreased EF (<=50%). Combined Fontan subjects had larger TD ostial diameters compared to controls when normalized by body surface area (median 2.6 mm/m2 vs. 2 mm/m2 ) (P=.04). CONCLUSION: To our knowledge, this is the first systematic study of ultrasonographic TD imaging in children. Fontan patients have larger TD diameters, reflecting the impaired lymphatic circulation in patients with this physiology. Further research may provide important associations between sonographic TD features with the functional status of patients with Fontan circulation. PMID- 28833534 TI - Vastly accelerated linear least-squares fitting with numerical optimization for dual-input delay-compensated quantitative liver perfusion mapping. AB - PURPOSE: To propose an efficient algorithm to perform dual input compartment modeling for generating perfusion maps in the liver. METHODS: We implemented whole field-of-view linear least squares (LLS) to fit a delay-compensated dual input single-compartment model to very high temporal resolution (four frames per second) contrast-enhanced 3D liver data, to calculate kinetic parameter maps. Using simulated data and experimental data in healthy subjects and patients, whole-field LLS was compared with the conventional voxel-wise nonlinear least squares (NLLS) approach in terms of accuracy, performance, and computation time. RESULTS: Simulations showed good agreement between LLS and NLLS for a range of kinetic parameters. The whole-field LLS method allowed generating liver perfusion maps approximately 160-fold faster than voxel-wise NLLS, while obtaining similar perfusion parameters. CONCLUSIONS: Delay-compensated dual-input liver perfusion analysis using whole-field LLS allows generating perfusion maps with a considerable speedup compared with conventional voxel-wise NLLS fitting. Magn Reson Med 79:2415-2421, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833532 TI - The Relationship between Brachycephalic Head Features in Modern Persian Cats and Dysmorphologies of the Skull and Internal Hydrocephalus. AB - BACKGROUND: Cat breeders observed a frequent occurrence of internal hydrocephalus in Persian cats with extreme brachycephalic head morphology. OBJECTIVE: To investigate a possible relationship among the grade of brachycephaly, ventricular dilatation, and skull dysmorphologies in Persian cats. ANIMALS: 92 Persian-, 10 Domestic shorthair cats. METHODS: The grade of brachycephaly was determined on skull models based on CT datasets. Cranial measurements were examined with regard to a possible correlation with relative ventricular volume, and cranial capacity. Persians with high (peke-face Persians) and lower grades of brachycephaly (doll face Persians) were investigated for the presence of skull dysmorphologies. RESULTS: The mean cranial index of the peke-face Persians (0.97 +/- 0.14) was significantly higher than the mean cranial index of doll-face Persians (0.66 +/- 0.04; P < 0.001). Peke-face Persians had a lower relative nasal bone length (0.15 +/- 0.04) compared to doll-face (0.29 +/- 0.08; P < 0.001). The endocranial volume was significantly lower in doll-face than peke-face Persians (89.6 +/- 1.27% versus 91.76 +/- 2.07%; P < 0.001). The cranial index was significantly correlated with this variable (Spearman's r: 0.7; P < 0.0001). Mean ventricle: Brain ratio of the peke-face group (0.159 +/- 0.14) was significantly higher compared to doll-face Persians (0.015 +/- 0.01; P < 0.001). CONCLUSION AND CLINICAL RELEVANCE: High grades of brachycephaly are also associated with malformations of the calvarial and facial bones as well as dental malformations. As these dysmorphologies can affect animal welfare, the selection for extreme forms of brachycephaly in Persian cats should be reconsidered. PMID- 28833535 TI - HbA1c variability is associated with increased mortality and earlier hospital admission in people with Type 1 diabetes. AB - AIM: Despite evidence of morbidity, no evidence exists on the relationship between HbA1c variability and mortality in Type 1 diabetes. We performed an observational study to investigate whether the association between HbA1c variability and mortality exists in a population of people with Type 1 diabetes. As a secondary outcome, we compared onset of first hospital admission between groups. METHODS: People with Type 1 diabetes were identified for inclusion from the Scottish Care Information - Diabetes data set. This database includes data of all people known to have diabetes who live within Scotland. A survival analysis was carried out over a 47-month period comparing two groups; group 1 with a HbA1c coefficient of variation (CV) above the median CV value, and group 2 with a CV below the median value. Time to death or first admission was also analysed. A Cox proportional hazard model was used to compare time to death, adjusting for appropriate covariables. RESULTS: Some 6048 individuals with Type 1 diabetes were included in the analysis. Median HbA1c CV was 7.9. The hazard ratio (HR) for mortality for those with an HbA1c CV above the median value is 1.5 over 47 months of follow-up (P < 0.001). HR for survival to either the first admission to hospital or death for those with an HbA1c CV above the median value was 1.35 (95% confidence interval 1.25-1.45) over 730 days of follow-up (P < 0.001). CONCLUSION: Our results show that people with greater HbA1c variability have a higher rate of mortality and earlier hospital admission in Type 1 diabetes. PMID- 28833536 TI - Outcome of second kidney transplantation in patients with previous post transplantation Kaposi's sarcoma: A French retrospective study. AB - This retrospective study concerned 8 patients with post-transplantation Kaposi's sarcoma (pt-KS) after a first kidney transplant who later had a second kidney transplantation. Pt-KS was widespread, with lymph node or visceral involvement in 7 cases. Complete remission was observed in 6 cases and partial remission in 2. After the second kidney transplantation, only 2 cases showed recurrence of skin KS, one with previous complete remission of KS and one with partial remission. The mean delay between stability or complete remission of KS and retransplantation was 2.0 and 7.3 years in patients with and without relapse, respectively. Both recurrent cases showed complete KS remission after tapering immunosuppression therapy and/or switching a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. We compared these 8 cases to 24 controls who had undergone 2 kidney transplantations but did not have KS, matching on sex, age and phototype. Cases and controls did not differ in graft function or survival. A second kidney transplantation may be possible after pt-KS and has acceptable risk, especially after a long complete remission of pt-KS. PMID- 28833538 TI - Predicting the helix-helix interactions from correlated residue mutations. AB - Helix-helix interactions are crucial in the structure assembly, stability and function of helix-rich proteins including many membrane proteins. In spite of remarkable progresses over the past decades, the accuracy of predicting protein structures from their amino acid sequences is still far from satisfaction. In this work, we focused on a simpler problem, the prediction of helix-helix interactions, the results of which could facilitate practical protein structure prediction by constraining the sampling space. Specifically, we started from the noisy 2D residue contact maps derived from correlated residue mutations, and utilized ridge detection to identify the characteristic residue contact patterns for helix-helix interactions. The ridge information as well as a few additional features were then fed into a machine learning model HHConPred to predict interactions between helix pairs. In an independent test, our method achieved an F-measure of ~60% for predicting helix-helix interactions. Moreover, although the model was trained mainly using soluble proteins, it could be extended to membrane proteins with at least comparable performance relatively to previous approaches that were generated purely using membrane proteins. All data and source codes are available at http://166.111.152.91/Downloads.html or https://github.com/dpxiong/HHConPred. PMID- 28833537 TI - GM2 Gangliosidosis in Shiba Inu Dogs with an In-Frame Deletion in HEXB. AB - Consistent with a tentative diagnosis of neuronal ceroid lipofuscinosis (NCL), autofluorescent cytoplasmic storage bodies were found in neurons from the brains of 2 related Shiba Inu dogs with a young-adult onset, progressive neurodegenerative disease. Unexpectedly, no potentially causal NCL-related variants were identified in a whole-genome sequence generated with DNA from 1 of the affected dogs. Instead, the whole-genome sequence contained a homozygous 3 base pair (bp) deletion in a coding region of HEXB. The other affected dog also was homozygous for this 3-bp deletion. Mutations in the human HEXB ortholog cause Sandhoff disease, a type of GM2 gangliosidosis. Thin-layer chromatography confirmed that GM2 ganglioside had accumulated in an affected Shiba Inu brain. Enzymatic analysis confirmed that the GM2 gangliosidosis resulted from a deficiency in the HEXB encoded protein and not from a deficiency in products from HEXA or GM2A, which are known alternative causes of GM2 gangliosidosis. We conclude that the homozygous 3-bp deletion in HEXB is the likely cause of the Shiba Inu neurodegenerative disease and that whole-genome sequencing can lead to the early identification of potentially disease-causing DNA variants thereby refocusing subsequent diagnostic analyses toward confirming or refuting candidate variant causality. PMID- 28833541 TI - Serum levels of omentin-1 are increased after weight loss and are particularly associated with increases in obese children with metabolic syndrome. AB - AIM: There have been very few paediatric studies on omentin-1, an anti inflammatory adipokine that provides a link between adiposity, insulin resistance and metabolic syndrome. This Chinese study evaluated the association between omentin-1 and metabolic syndrome and analysed the effect of a six-month lifestyle intervention on the levels in obese children. METHODS: We recruited 119 obese outpatients (75% boys) aged 7-18 years from the Second Affiliated Hospital of Xi'an Jiaotong University, who underwent a six- month lifestyle intervention. Our controls were 55 matched children with normal weight. Anthropometric parameters, biochemical data and circulating omentin-1 levels were measured at baseline and after six months. RESULTS: Of the 119 obese children, 32 (27%) had metabolic syndrome. The obese children, particularly those with metabolic syndrome, had significantly lower serum omentin-1 levels at baseline than the controls. We also found that the omentin-1 levels were negatively associated with their body mass index, waist circumference and homoeostasis model assessment of insulin resistance. After the six-month lifestyle intervention, the obese children showed significant weight loss and their omentin-1 levels increased. CONCLUSION: Serum omentin-1 was regulated by weight and seemed to be associated with children's metabolic disorders. A six-month lifestyle intervention significantly increased serum omentin-1 levels. PMID- 28833543 TI - Echocardiographic assessment of the right ventricle in the current era: Application in clinical practice. AB - The right ventricle has unique structural and functional characteristics. It is now well recognized that the so-called forgotten ventricle is a key player in cardiovascular physiology. Furthermore, there is accumulating evidence that demonstrates right ventricular dysfunction as an important marker of morbidity and mortality in several commonly encountered clinical situations such as heart failure, pulmonary hypertension, pulmonary embolism, right ventricular myocardial infarction, and adult congenital heart disease. In contrast to the left ventricle, echocardiographic assessment of right ventricular function is more challenging as volume estimations are not possible without the use of three dimensional (3D) echocardiography. Guidelines on chamber quantification provide a standardized approach to assessment of the right ventricle. The technique and limitations of each of the parameters for RV size and function need to be fully understood. In this era of multimodality imaging, echocardiography continues to remain a useful tool for the initial assessment and follow-up of patients with right heart pathology. Several novel approaches such as 3D and strain imaging of the right ventricle have expanded the usefulness of this indispensable modality. PMID- 28833542 TI - Echo-planar spectroscopic imaging with dual-readout alternated gradients (DRAG EPSI) at 7 T: Application for 2-hydroxyglutarate imaging in glioma patients. AB - PURPOSE: To develop echo-planar spectroscopic imaging (EPSI) with large spectral width and accomplish high-resolution imaging of 2-hydroxyglutarate (2HG) at 7 T. METHODS: We designed a new EPSI readout scheme at 7 T. Data were recorded with dual-readout alternated gradients and combined according to the gradient polarity. Following validation of its performance in phantoms, the new readout scheme, together with previously reported 2HG-optimized magnetic resonance spectroscopy (point-resolved spectroscopy echo time of 78 ms), was used for time efficient and high-resolution imaging of 2HG and other metabolites in five glioma patients before treatment. Unsuppressed water, acquired with EPSI, was used as reference for multichannel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house calculated basis sets. RESULTS: Using a readout gradient strength of 9.5 mT/m and slew rate of 90 mT/m/ms, dual-readout alternated gradients EPSI permitted 1638-Hz spectral width with 6 * 6 mm2 in-plane resolution at 7 T. Phantom data indicated that dual-readout alternated gradients EPSI provides proper metabolite signals and induces much less frequency drifts than conventional EPSI. For a spatial resolution of 0.5 mL, 2HG was detected in tumors with precision (Cramer-Rao lower bound < 10%). The 2HG was estimated to be 2.3 to 3.3 mM in tumors of three patients with biopsy-proven isocitrate dehydrogenase (IDH) mutant gliomas. The 2HG was undetectable in an IDH wild-type glioblastoma. For a radiographically suggested glioma, the estimated 2HG of 2.3 +/- 0.2 mM (Cramer-Rao lower bound < 10%) indicated that the lesion may be an IDH mutant glioma. CONCLUSIONS: The data indicated that the dual-readout alternated gradients EPSI can provide reliable high-resolution imaging of 2HG in glioma patients at 7 T in vivo. Magn Reson Med 79:1851-1861, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28833544 TI - Hierarchical Graphene Foam for Efficient Omnidirectional Solar-Thermal Energy Conversion. AB - Efficient solar-thermal energy conversion is essential for the harvesting and transformation of abundant solar energy, leading to the exploration and design of efficient solar-thermal materials. Carbon-based materials, especially graphene, have the advantages of broadband absorption and excellent photothermal properties, and hold promise for solar-thermal energy conversion. However, to date, graphene-based solar-thermal materials with superior omnidirectional light harvesting performances remain elusive. Herein, hierarchical graphene foam (h-G foam) with continuous porosity grown via plasma-enhanced chemical vapor deposition is reported, showing dramatic enhancement of broadband and omnidirectional absorption of sunlight, which thereby can enable a considerable elevation of temperature. Used as a heating material, the external solar-thermal energy conversion efficiency of the h-G foam impressively reaches up to ~93.4%, and the solar-vapor conversion efficiency exceeds 90% for seawater desalination with high endurance. PMID- 28833545 TI - Conjugated Microporous Polymer Nanosheets for Overall Water Splitting Using Visible Light. AB - Direct water splitting into H2 and O2 using photocatalysts by harnessing sunlight is very appealing to produce storable chemical fuels. Conjugated polymers, which have tunable molecular structures and optoelectronic properties, are promising alternatives to inorganic semiconductors for water splitting. Unfortunately, conjugated polymers that are able to efficiently split pure water under visible light (400 nm) via a four-electron pathway have not been previously reported. This study demonstrates that 1,3-diyne-linked conjugated microporous polymer nanosheets (CMPNs) prepared by oxidative coupling of terminal alkynes such as 1,3,5-tris-(4-ethynylphenyl)-benzene (TEPB) and 1,3,5-triethynylbenzene (TEB) can act as highly efficient photocatalysts for splitting pure water (pH ~ 7) into stoichiometric amounts of H2 and O2 under visible light. The apparent quantum efficiencies at 420 nm are 10.3% and 7.6% for CMPNs synthesized from TEPB and TEB, respectively; the measured solar-to-hydrogen conversion efficiency using the full solar spectrum can reach 0.6%, surpassing photosynthetic plants in converting solar energy to biomass (globally average ~0.10%). First-principles calculations reveal that photocatalytic H2 and O2 evolution reactions are energetically feasible for CMPNs under visible light irradiation. The findings suggest that organic polymers hold great potential for stable and scalable solar fuel generation. PMID- 28833546 TI - Metal Thio- and Selenophosphates as Multifunctional van der Waals Layered Materials. AB - Since the discovery of Dirac physics in graphene, research in 2D materials has exploded with the aim of finding new materials and harnessing their unique and tunable electronic and optical properties. The follow-on work on 2D dielectrics and semiconductors has led to the emergence and development of hexagonal boron nitride, black phosphorus, and transition metal disulfides. However, the spectrum of good insulating materials is still very narrow. Likewise, 2D materials exhibiting correlated phenomena such as superconductivity, magnetism, and ferroelectricity have yet to be developed or discovered. These properties will significantly enrich the spectrum of functional 2D materials, particularly in the case of high phase-transition temperatures. They will also advance a fascinating fundamental frontier of size and proximity effects on correlated ground states. Here, a broad family of layered metal thio(seleno)phosphate materials that are moderate- to wide-bandgap semiconductors with incipient ionic conductivity and a host of ferroic properties are reviewed. It is argued that this material class has the potential to merge the sought-after properties of complex oxides with electronic functions of 2D and quasi-2D electronic materials, as well as to create new avenues for both applied and fundamental materials research in structural and magnetic correlations. PMID- 28833547 TI - Using smartphones with suitable apps can be safe and even useful if they are not misused or overused. PMID- 28833548 TI - Evaluation of Gastric pH and Serum Gastrin Concentrations in Cats with Chronic Kidney Disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a highly prevalent condition in cats. Advanced CKD is associated with hyporexia and vomiting, which typically are attributed to uremic toxins and gastric hyperacidity. However, gastric pH studies have not been performed in cats with CKD. HYPOTHESIS/OBJECTIVES: To determine if cats with CKD have decreased gastric pH compared to age-matched, healthy cats. Based on previous work demonstrating an association of hypergastrinemia and CKD, we hypothesized that cats with CKD would have decreased gastric pH compared to healthy, age-matched control cats. ANIMALS: 10 CKD cats; 9 healthy control cats. METHODS: All cats with concurrent disease were excluded on the basis of history, physical examination, CBC, plasma biochemistry profile, urinalysis, urine culture, serum total thyroxine concentration, and serum symmetric dimethylarginine concentration (controls only) obtained within 24 hours of pH monitoring and assessment of serum gastrin concentrations. Serum for gastrin determination was collected, and 12-hour continuous gastric pH monitoring was performed in all cats. Serum gastrin concentration, mean pH, and percentage time that gastric pH was strongly acidic (pH <1 and <2) were compared between groups. RESULTS: No significant differences in serum gastrin concentrations were observed between groups (medians [range]: CKD, 18.7 ng/dL [<10-659.0]; healthy, 54.6 ng/dL [<10-98.0]; P-value = 0.713) or of any pH parameters including mean +/- SD gastric pH (CKD, 1.8 +/- 0.5; healthy, 1.6 +/- 0.3; P-value = 0.23). CONCLUSIONS AND CLINICAL IMPORTANCE: These findings suggest that cats with CKD may not have gastric hyperacidity compared to healthy cats and, therefore, may not need acid suppression. Thus, further studies to determine if there is a benefit to acid suppression in cats with CKD are warranted. PMID- 28833549 TI - Regression of diffuse B-cell lymphoma of the leg with intralesional gentian violet. AB - In this case report, a patient of primary cutaneous diffuse B-cell lymphoma, leg type was treated with intralesional gentian violet as she was judged to be too medically fragile for conventional chemotherapy due to advanced age and multiple serious comorbidities. Gentian violet (crystal violet/hexamethyl pararosaniline) is a triphenylmethane dye. It has been shown to have an inhibitory effect on NADPH oxidase, an enzyme family which is found in abundance in reactive oxygen driven tumors such as melanoma and lymphoma. We hypothesize that intralesional gentian violet treatment caused signalling changes in the lymphoma which allowed for immune clearance of the lymphoma. Complete resolution of the patient's lesion was noted on a follow-up visit. PMID- 28833550 TI - Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Galpha11 Mutation. AB - G-protein subunit alpha-11 (Galpha11 ) couples the calcium-sensing receptor (CaSR) to phospholipase C (PLC)-mediated intracellular calcium (Ca2+i ) and mitogen-activated protein kinase (MAPK) signaling, which in the parathyroid glands and kidneys regulates parathyroid hormone release and urinary calcium excretion, respectively. Heterozygous germline loss-of-function Galpha11 mutations cause familial hypocalciuric hypercalcemia type 2 (FHH2), for which effective therapies are currently not available. Here, we report a novel heterozygous Galpha11 germline mutation, Phe220Ser, which was associated with hypercalcemia in a family with FHH2. Homology modeling showed the wild-type (WT) Phe220 nonpolar residue to form part of a cluster of hydrophobic residues within a highly conserved cleft region of Galpha11 , which binds to and activates PLC; and predicted that substitution of Phe220 with the mutant Ser220 polar hydrophilic residue would disrupt PLC-mediated signaling. In vitro studies involving transient transfection of WT and mutant Galpha11 proteins into HEK293 cells, which express the CaSR, showed the mutant Ser220 Galpha11 protein to impair CaSR-mediated Ca2+i and extracellular signal-regulated kinase 1/2 (ERK) MAPK signaling, consistent with diminished activation of PLC. Furthermore, engineered mutagenesis studies demonstrated that loss of hydrophobicity within the Galpha11 cleft region also impaired signaling by PLC. The loss-of-function associated with the Ser220 Galpha11 mutant was rectified by treatment of cells with cinacalcet, which is a CaSR-positive allosteric modulator. Furthermore, in vivo administration of cinacalcet to the proband harboring the Phe220Ser Galpha11 mutation, normalized serum ionized calcium concentrations. Thus, our studies, which report a novel Galpha11 germline mutation (Phe220Ser) in a family with FHH2, reveal the importance of the Galpha11 hydrophobic cleft region for CaSR mediated activation of PLC, and show that allosteric CaSR modulation can rectify the loss-of-function Phe220Ser mutation and ameliorate the hypercalcemia associated with FHH2. (c) 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. PMID- 28833552 TI - A rare complication of mechanical aortic valve replacement: Separation in the region of the mitral-aortic intervalvular fibrosa. AB - A 28-year-old man was admitted to our emergency service with a shortness of breath and palpitation. On admission, his blood pressure was high and he was in hypertensive pulmonary edema. His physical examination showed rales in both lungs and pansystolic murmur at mitral focus. His medical history included aortic valve replacement (AVR) because of native aortic valve infective endocarditis. Transthoracic echocardiography (TTE) showed normal functional aortic valve. Color flow imaging demonstrated severe mitral regurgitation with posterior eccentric jet. To examine in detail, transesophageal echocardiography (TEE) and three dimensional (3D) echocardiography were performed. TEE disclosed a separation in the subaortic curtain leading to severe mitral regurgitation from the left ventricle to the left atrium. In addition to severe mitral regurgitation with posterior eccentric jet, 26-mm-long pouch was seen in mitral-aortic intervalvular fibrosa (MAIVF) at 120 degrees TEE view. This pouch was separated from the mitral anterior leaflet junction releasing the mitral anterior leaflet and causing prolapse and chorda rupture in the A2 scallop of the mitral anterior leaflet. The MAIVF connects the anterior mitral leaflet to the posterior portion of the aortic annulus. The separation of the MAIVF represents a complication of the aortic valve replacement. PMID- 28833555 TI - Dysfunctional breathing in children and adolescents. PMID- 28833554 TI - Unrecognized subvalvular aortic stenosis: Lessons, insights, and solutions. PMID- 28833556 TI - Overexpression of p53 explains isotretinoin's teratogenicity. AB - The precise molecular basis of retinoid embryopathy is yet unknown. This hypothesis predicts that isotretinoin (13-cis retinoic acid), the prodrug of all trans retinoic acid (ATRA), exaggerates neural crest cell (NCC) apoptosis via upregulation of the pro-apoptotic transcription factor p53, the guardian of the genome. Increased p53 signalling is associated with Treacher Collins-, CHARGE- and fetal alcohol syndrome, which exhibit dysmorphic craniofacial features resembling retinoid embryopathy. In addition, developmental studies of NCC homeostasis in the zebrafish support the pivotal role of p53. Translational evidence implies that isotretinoin-stimulated overactivation of p53 during embryogenesis represents the molecular basis of isotretinoin's teratogenicity. PMID- 28833557 TI - Enhancing recombinant interleukin-6 production yield by fermentation optimization, two-step denaturing, and one-step purification. AB - Interleukin-6 a pleiotropic cytokine involved in a wide range of biological activities. So the large-scale production of biologically active recombinant human interleukin-6 is important for its structural and functional studies. Here, we report an optimized method for shake flask fermentation and a simplified high yield purification procedure for the recombinant interleukin-6. This high-yield expression method not only involves the optimization of the fermentation condition but also the single step purification method as well as a two-step denaturing and one-step refolding process. This approach replaces the more conventional procedure of protein solubilization and refolding. Through applying these strategies, the final cell density and overall product yield of the recombinant human interleukin-6 were obtained as 20.4 g as cell biomass and 150 mg as purified active protein from the I-L of the culture. The purified protein was characterized by HPLC and SDS-PAGE. The results of the current work demonstrate that the described method may be used to develop the process for industrial-scale production of the biologically active recombinant interleukin-6 protein. PMID- 28833558 TI - A highly reproducible cervical cuff technique for rat-to-mouse heterotopic heart xenotransplantation. AB - Xenotransplantation is an effective way to solve the problem of donor shortage in clinical transplantation. However, clinical use of xenotransplantation is currently limited due to immunological challenges such as acute vascular rejection and cell-mediated rejection. To finally surpass this immunological barrier, more preclinical research is needed into the molecular mechanisms of rejection and the possible effects of new immunosuppressants. Our aim was to create a refined, highly reproducible protocol to establish the most suitable rat to-mouse heterotopic heart transplantation model using the cuff technique. PMID- 28833559 TI - Chiroptical properties of dithia[3.3]cyclophanes composed of anthracene and pyridine/pyridinium moieties: A combined experimental and theoretical study. AB - Circular dichroisms (CDs) of neutral and protonated [3.3]anthracenopyridinophane (1 and 1-H+ ) were investigated experimentally and theoretically. Introducing an anthracene moiety with extended conjugation affected the cyclophane structure with the bent angles being appreciably reduced from those of parent [3.3]pyridinophane. The Cotton effects (CEs) observed at the 1 Bb band for both 1 and 1-H+ were fairly strong and apparently bisignate, which, however, turned out not to be a simple exciton couplet but to be composed of multiple transitions. In contrast, the CEs were much weaker in the 1 La band region. The spectral changes upon protonation were less significant compared with the parent pyridinophane, being dominated by the local transitions of anthracene. Nevertheless, the CD spectra of 1 and 1-H+ were well reproduced by theoretical calculations to allow us an unambiguous absolute configuration determination of the first high performance liquid chromatography (HPLC) elute (from Chiralcel IB column) as Sp . The transannular interactions between the anthracene and pyridine/pyridinium units were examined by UV-vis and fluorescence spectroscopy to reveal a charge transfer (CT) band in the low-energy region, particularly for 1-H+ . Despite the comparable CT interactions, the CE at the CT band was much stronger for the anthracenopyridinophane than for the parent pyridinophane, affording an anisotropy (g) factor as large as 4 * 10-3 . PMID- 28833560 TI - The aim of iron chelation therapy in thalassaemia. PMID- 28833561 TI - Development of a Multivariate Predictive Model to Estimate Ionized Calcium Concentration from Serum Biochemical Profile Results in Dogs. AB - BACKGROUND: Ionized calcium concentration is the gold standard to assess calcium status in dogs, but measurement is not always available. OBJECTIVES: (1) To predict ionized calcium concentration from biochemical results and compare the diagnostic performance of predicted ionized calcium concentration (piCa) to those of total calcium concentration (tCa) and 2 corrected tCa formulas; and (2) to study the relationship between biochemical results and variation of measured ionized calcium concentration (miCa). ANIMALS: A total of 1,719 dogs with both miCa and biochemical profile results available. METHODS: Cross-sectional study. Using 1,200 dogs, piCa was determined using a multivariate adaptive regression splines model. Its accuracy and performance were tested on the remaining 519 dogs. RESULTS: The final model included creatinine, albumin, tCa, phosphorus, sodium, potassium, chloride, alkaline phosphatase, triglycerides, and age, with tCa, albumin, and chloride having the highest impact on miCa variation. Measured ionized calcium concentration was better correlated with piCa than with tCa and corrected tCa and had higher overall diagnostic accuracy to diagnose hypocalcemia and hypercalcemia, but not significantly for hypercalcemia. For hypercalcemia, piCa was as sensitive (64%) but more specific (99.6%) than tCa and corrected tCa. For hypocalcemia, piCa was more sensitive (21.8%) and as specific (98.4%) as tCa. Positive and negative predictive values of piCa were high for both hypercalcemia (90% and 98%, respectively) and hypocalcemia (70.8% and 87.7%, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Predicted ionized calcium concentration can be obtained from readily available biochemical and patient results and seems more useful than tCa and corrected tCa to assess calcium disorders in dogs when miCa is unavailable. Validation on external data, however, is warranted. PMID- 28833562 TI - Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3). AB - BACKGROUND: The treatment of levodopa-induced dyskinesia in Parkinson's disease (PD) is an unmet need with no approved drug therapy. OBJECTIVE: The purpose of this study was to investigate the efficacy and safety of 274 mg ADS-5102 (amantadine) extended-release capsules (equivalent to 340-mg amantadine HCl) for levodopa-induced dyskinesia in a randomized controlled trial. METHODS: PD patients with >=1 hour of troublesome dyskinesia and at least mild functional impact were randomized to placebo or ADS-5102 once daily at bedtime for 13 weeks. The primary efficacy analysis was based on change from baseline to week 12 on the Unified Dyskinesia Rating Scale total score in the modified intent-to-treat population. OFF time was a key secondary measure. RESULTS: At week 12, least squares mean change in the Unified Dyskinesia Rating Scale was -20.7 (standard error 2.2) for ADS-5102 (n = 37) and -6.3 (standard error 2.1) for placebo (n = 38; treatment difference -14.4, 95% confidence interval -20.4 to -8.3, P < .0001), indicating improvement in levodopa-induced dyskinesia. OFF time decreased 0.5 hours (standard error 0.3) for ADS-5102 from a baseline mean of 2.6 hours and increased 0.6 hours (standard error 0.3) for placebo from a baseline mean of 2.0 hours (treatment difference -1.1 hours, 95% confidence interval -2.0 to -0.2, P = .0199). The most common adverse events (ADS-5102 versus placebo) included dry mouth (13.5% versus 2.6%), nausea (13.5% versus 2.6%), decreased appetite (10.8% versus 0%), insomnia (10.8% versus 0%), orthostatic hypotension (10.8% versus 0%), constipation (8.1% versus 0%), falls (8.1% versus 5.3%), and visual hallucinations (8.1% versus 5.3%). Adverse events led to treatment discontinuation in 19% versus 8%, respectively. CONCLUSION: ADS-5102 274 mg is an oral pharmacotherapy demonstrating a significant decrease in levodopa-induced dyskinesia and improving OFF time. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28833563 TI - Assessment of model accuracy estimations in CASP12. AB - The record high 42 model accuracy estimation methods were tested in CASP12. The paper presents results of the assessment of these methods in the whole-model and per-residue accuracy modes. Scores from four different model evaluation packages were used as the "ground truth" for assessing accuracy of methods' estimates. They include a rigid-body score-GDT_TS, and three local-structure based scores LDDT, CAD and SphereGrinder. The ability of methods to identify best models from among several available, predict model's absolute accuracy score, distinguish between good and bad models, predict accuracy of the coordinate error self estimates, and discriminate between reliable and unreliable regions in the models was assessed. Single-model methods advanced to the point where they are better than clustering methods in picking the best models from decoy sets. On the other hand, consensus methods, taking advantage of the availability of large number of models for the same target protein, are still better in distinguishing between good and bad models and predicting local accuracy of models. The best accuracy estimation methods were shown to perform better with respect to the frozen in time reference clustering method and the results of the best method in the corresponding class of methods from the previous CASP. Top performing single model methods were shown to do better than all but three CASP12 tertiary structure predictors when evaluated as model selectors. PMID- 28833564 TI - Why haven't the documented benefits of probiotics on preterm babies led to their wider acceptance and use? PMID- 28833565 TI - Side-viewing duodenoscope retroflexion method for bile duct cannulation and sphincterotomy in patient with Billroth II anatomy. PMID- 28833566 TI - High expression of B lymphocyte stimulator in lesional keratinocytes of patients with cutaneous lupus erythematosus. AB - Belimumab, an anti-B lymphocyte stimulator (BLyS) monoclonal antibody, is approved for systemic lupus erythematosus; however, it is unclear if it can be used to treat specific skin lesions in this disease. In this analysis, we investigated the expression of BLyS and its receptors in skin lesions of different subtypes of cutaneous lupus erythematosus (CLE) using immunohistochemistry and gene expression analyses. Compared to healthy controls, the expression of BLyS was significantly higher in skin lesions of all included CLE subtypes. Similar results were seen for the BLyS receptors BAFF-R and BCMA. Moreover, CLE-typical pro-inflammatory mediators (immunostimulatory DNAs) significantly enhanced the BLyS expression of keratinocytes in vitro. This study suggests a potential role for BLyS as therapeutic target in the treatment of CLE skin lesions. PMID- 28833568 TI - Polymer Microstructures through Two-Photon Crosslinking. AB - Two-photon crosslinking of polymers (2PC) is proposed as a novel method for the fabrication of freestanding microstructures via two-photon lithography. During this process in the confocal volume, two-photon absorption leads to (formal) C,H insertion reactions, and consequently to a strictly localized crosslinking of the polymer. To achieve this, the polymer is coated as a solvent-free (glassy) film onto an appropriate substrate, and the desired microstructure is written by 2PC into this glass. In all regions outside of the focal volume where no two-photon process occurs, the polymer remains uncrosslinked and can be washed away during a developing process. Using a self-assembled monolayer containing the same photoreactive group allows covalent attachment of the forming freestanding structures to the substrate, and thus guarantees an improved stability of these structures against shear-induced detachment. As the two photon process is carried out in the glassy state, in a simple way, multilayer structures can be used to write structures having a varying chemical composition perpendicular to the surface. As an example, the 2PC process is used to build a structure from both protein-repellent and protein-adsorbing polymers so that the resulting 3D structure exhibits spatially controlled protein adsorption. PMID- 28833569 TI - In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases. AB - Pemphigoid diseases (PD) are a subgroup of rare acute or chronic autoimmune skin disorders characterized and caused by autoantibodies directed against distinct structural components of the dermal-epidermal junction. Binding of autoantibodies to their targets leads to the formation of blisters and erosions in patients. PDs comprise eight disorders for which the molecular target antigens have been identified. First, we review the available in vitro and ex vivo models for analysis of distinct aspects of the pathogenesis of PDs. This includes the binding of autoantibodies to skin sections, the analysis of blister formation capability and skin complement activation as well as investigation of neutrophil and keratinocyte activation. In addition to this, several animal models of PD have been developed during the last decades. These animal models have greatly contributed to our current understanding of the pathogenesis of PDs. We summarize spontaneously arising PD in animals and the induction of PD by transfer of (auto)antibodies, transfer of (auto)-antigen-specific lymphocytes and by immunization. In combined use, these models allow dissecting all aspects of PD pathogenesis, for example loss of tolerance, autoantibody production and inflammatory skin processes that lead to blister formation. Overall, we aimed to foster translational biomedical research, to deepen our understanding of PD pathogenesis and to develop novel treatments for patients suffering from these life-threatening and difficult-to-treat autoimmune diseases. PMID- 28833570 TI - Neural breathing pattern in newborn infants pre- and postextubation. AB - AIM: To describe the neural breathing pattern before and after extubation in newborn infants. METHODS: Prospective, observational study. In infants deemed ready for extubation, the diaphragm electrical activity (EAdi) was continuously recorded from 30 minute before to two hours after extubation. RESULTS: Total of 25 neonates underwent 29 extubations; 10 extubations resulted in re-intubation within 72 hours. Postextubation, there was an increase in peak EAdi (EAdi-max) and EAdi-delta (peak minus minimum EAdi) in both groups. The pre- to postextubation change in EAdi-max (8.9-11.1 MUv) and EAdi-delta (6-8 MUv) was less in the failure group in comparison with the change in EAdi-max (10.2-13.4 MUv) and EAdi-delta (6.3-10.6 MUv) in the success group, (p = 0.02 and 0.01, respectively). CONCLUSION: In our neonatal cohort, extubation failure was associated with a smaller increase in peak and delta EAdi after extubation. If confirmed, these findings indicate an important cause of extubation failure in preterm infants. PMID- 28833571 TI - Down-regulation of aquaporin 5-mediated epithelial-mesenchymal transition and anti-metastatic effect by natural product Cairicoside E in colorectal cancer. AB - Epithelial-mesenchymal transition (EMT) has emerged as an important determinant role in colorectal cancer (CRC) metastasis. It has been reported that aquaporin 5 (AQP5) is closely linked to CRC metastasis. However, the effect of AQP5 on the EMT process of CRC remains unknown. The current study showed that overexpression of AQP5 activated EMT in CRC cells. Cairicoside E (CE), a natural resin glycoside compound isolated from Ipomoea cairica, showed promising cytotoxic activity in our previous report. Further investigation found that CE inhibited the expression of AQP5 and the EMT process. Moreover, the inhibitory effect of CE on EMT was reversed by overexpression of AQP5. Importantly, CE also suppressed the EMT and p Smad2/3 induced by TGF-beta1. On the other hand, overexpression of AQP5 up regulated the p-Smad2/3, which resulted in the activation of EMT. After silencing of AQP5, CE had no significant effect on EMT markers and p-Smad2/3 induced by TGF beta1, indicating that CE inhibited the EMT through down-regulation of AQP5 and suppression of p-Smad2/3. CE also inhibited the AQP5 expression in the lung metastatic nodules of HCT-116 cells in vivo. Our findings suggested that CE may serve as a promising drug for the treatment of CRC metastasis. PMID- 28833567 TI - Guided bone regeneration: materials and biological mechanisms revisited. AB - Guided bone regeneration (GBR) is commonly used in combination with the installment of titanium implants. The application of a membrane to exclude non osteogenic tissues from interfering with bone regeneration is a key principle of GBR. Membrane materials possess a number of properties which are amenable to modification. A large number of membranes have been introduced for experimental and clinical verification. This prompts the need for an update on membrane properties and the biological outcomes, as well as a critical assessment of the biological mechanisms governing bone regeneration in defects covered by membranes. The relevant literature for this narrative review was assessed after a MEDLINE/PubMed database search. Experimental data suggest that different modifications of the physicochemical and mechanical properties of membranes may promote bone regeneration. Nevertheless, the precise role of membrane porosities for the barrier function of GBR membranes still awaits elucidation. Novel experimental findings also suggest an active role of the membrane compartment per se in promoting the regenerative processes in the underlying defect during GBR, instead of being purely a passive barrier. The optimization of membrane materials by systematically addressing both the barrier and the bioactive properties is an important strategy in this field of research. PMID- 28833572 TI - Correlation between RUST assessments of fracture healing to structural and biomechanical properties. AB - Radiographic Union Score for Tibia (RUST) and modified RUST (mRUST) are radiographic tools for quantitatively evaluating fracture healing using a cortical scoring system. This tool has high intra-class correlation coefficients (ICCs); however, little evidence has evaluated the scores against the physical properties of bone healing. Closed, stabilized fractures were made in the femora of C3H/HeJ male mice (8-12 week-old) of two dietary groups: A control and a phosphate restricted diet group. Micro-computed tomography (uCT) and torsion testing were carried out at post-operative days (POD) 14, 21, 35, and 42 (n = 10 16) per group time-point. Anteroposterior and lateral radiographic views were constructed from the uCT scans and scored by five raters. The raters also indicated if the fracture were healed. ICCs were 0.71 (mRUST) and 0.63 (RUST). Both RUST scores were positively correlated with callus bone mineral density (BMD) (r = 0.85 and 0.80, p < 0.001) and bone volume fraction (BV/TV) (r = 0.86 and 0.80, p < 0.001). Both RUST scores positively correlated with callus strength (r = 0.35 and 0.26, p < 0.012) and rigidity (r = 0.50 and 0.39, p < 0.001). Radiographically healed calluses had a mRUST >=13 and a RUST >=10 and had excellent relationship to structural and biomechanical metrics. Effect of delayed healing due to phosphate dietary restrictions was found at later time points with all mechanical properties (p < 0.011), however no differences found in the RUST scores (p > 0.318). Clinical relevance of this study is both RUST scores showed high correlation to physical properties of healing and generally distinguished healed vs. non-healed fractures. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:945-953, 2018. PMID- 28833574 TI - The effect of botulinum neurotoxin A in patients with plaque psoriasis - an exploratory trial. PMID- 28833573 TI - Factors Associated with Colostrum Quality and Effects on Serum Gamma Globulin Concentrations of Calves in Swiss Dairy Herds. AB - BACKGROUND: Previous studies have shown a high prevalence of failure of passive transfer of immunity (FPT) in Swiss dairy calves. OBJECTIVES: To investigate risk factors associated with poor colostrum quality and FPT on Swiss dairy farms. ANIMALS: Colostrum and serum samples from 373 dam-calf pairs at 141 farms. METHODS: The gamma globulin (Gg) concentrations of the dams' colostrum and the calves' serum samples were determined by electrophoresis. Potential risk factors were assessed by logistic regression of questionnaire data. RESULTS: Prevalence values of 15.5% (95% confidence interval [CI], 12.0-19.6%) for low-quality colostrum (<50 g Gg/L) in cows and 43.5% (95% CI, 38.4-48.8%) for FPT (serum Gg < 10 g/L) in calves were estimated. The main factors associated with low colostrum quality included colostrum leakage before or during parturition and a time lag > 6 hours between parturition and first milking. The results confirm that the occurrence of FPT in calves primarily was influenced by the quality of colostrum, the amount of ingested colostrum, and the time between birth and first feeding. CONCLUSIONS AND CLINICAL IMPORTANCE: These results confirm a large potential for improvement in colostrum harvesting and colostrum feeding procedures in the study herds. Control for colostrum leaking intra-partum, early colostrum milking, and ensuring that the calves ingest a sufficient volume of colostrum within the first hours of life are measures that can be readily implemented by farmers to decrease the incidence of FPT without additional workload. PMID- 28833576 TI - Towards the development of a RNAi-based topical treatment for psoriasis: Proof-of concept in a 3D psoriasis skin model. AB - RNA interference has emerged as a powerful tool for therapeutic gene silencing, as it offers the possibility to silence virtually any known pathology-causing gene. However, in vivo delivery of RNAi molecules is hampered by their unfavourable physicochemical characteristics and susceptibility to degradation by endogenous enzymes. To overcome these limitations, we recently developed an elastic liposomal formulation, called DDC642, as topical delivery system of therapeutic RNAi molecules for skin disorders. In this study, we validated the therapeutic efficacy of DDC642-encapsulated RNAi molecules in the treatment of psoriasis using 3 different in vitro models: a standardized keratinocyte monolayer culture, psoriasis-induced keratinocytes and a psoriasis-reconstructed skin model. Four genes (IL22RA1, KRT17, DEFB4 and TSLP), known to be upregulated in psoriatic lesions, and thereby key players in psoriasis pathogenesis were selected. Moreover, the possibility of using a combined siRNA therapy in the topical treatment of psoriasis was explored. Results indicate a successful gene silencing of each different target, both at mRNA and protein levels. Additionally, siRNA-DDC642 treatment resulted in a reduced expression of specific psoriasis markers, indicating their potential in future therapeutic approach. The examined siRNA combination (ie simultaneous knockdown of KRT17, DEFB4 and TSLP) showed an enhanced reduction in TSLP expression, whereas the decrease in K17 protein expression was impaired in psoriatic keratinocytes. Although the here examined siRNA combination could still be further improved, our study proved already in vitro the clinical potential of targeting multiple genes at once, each playing a different role in a complex disease such as psoriasis. PMID- 28833575 TI - In vivo pig-a and micronucleus study of the prototypical aneugen vinblastine sulfate. AB - The Pig-a assay is being used in regulatory studies to evaluate the potential of agents to induce somatic cell gene mutations and an OECD test guideline is under development. A working group involved with establishing the guideline recently noted that representative aneugenic agents had not been evaluated, and to help fill this data gap Pig-a mutant phenotype and micronucleated reticulocyte frequencies were measured in an integrated study design to assess the mutagenic and cytogenetic damage responses to vinblastine sulfate exposure. Male Sprague Dawley rats were treated for twenty-eight consecutive days with vinblastine dose levels from 0.0156 to 0.125 mg/kg/day. Micronucleated reticulocyte frequencies in peripheral blood were determined at Days 4 and 29, and mutant cell frequencies were determined at Days -4, 15, 29, and 46. Vinblastine affected reticulocyte frequencies, with reductions noted during the treatment phase and increases observed following cessation of treatment. Micronucleated reticulocyte frequencies were significantly elevated at Day 4 in the high dose group. Although a statistically significant increase in mutant reticulocyte frequencies were found for one dose group at a single time point (Day 46), it was not deemed biologically relevant because there was no analogous finding in mutant RBCs, it occurred at the lowest dose tested, and only 1 rat exceeded an upper bound tolerance interval established with historical negative control rats. Therefore, whereas micronucleus induction reflects vinblastine's well-established aneugenic effect on hematopoietic cells, the lack of a Pig-a response indicates that this tubulin-binding agent does not cause appreciable mutagenicity in this same cell type. Environ. Mol. Mutagen. 59:30-37, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28833577 TI - The Pitt Bacteremia Score, Charlson Comorbidity Index and Chronic Disease Score are useful tools for the prediction of mortality in patients with Candida bloodstream infection. AB - Candida bloodstream infection (CBI) is associated with high mortality. The aim of this study was to compare the utility of the combined use of the Pitt Bacteremia Score (PBS) and Charlson Comorbidity Index (CCI) or Chronic Disease Score (CDS) to predict mortality among patients with CBI. Thereby, all consecutive patients with CBI at our institution between 2010 and 2014 were included. The PBS was used to evaluate CBI severity and the CCI and CDS were used to assess comorbidities of patients with CBI. Logistic regression analysis was used to estimate odds ratios for 30-day mortality in models including the PBS and CCI or CDS. A total of 189 CBI episodes were identified. Logistic regression models including the PBS and either CCI or CDS showed that the combined use of a comorbidity score and a severity score significantly predicted 30-day mortality. The performance of the different models was similar. Aggregated scores of comorbidity (CCI and CDS) and disease severity (PBS) are useful for the prediction of 30-day mortality risk in patients with CBI. Their use may facilitate the analysis of risk factors for poorer outcome and the development of an index for CBI mortality. PMID- 28833578 TI - Loss-of-function mutations in filaggrin gene and malignant melanoma: a case control study. AB - BACKGROUND: Loss-of-function mutations in filaggrin gene (FLG) have been suggested to increase the susceptibility of skin malignancies due to reduced levels of epidermal filaggrin and its degradation products, urocanic acid, which may be protective against ultraviolet irradiation. OBJECTIVE: We aimed to investigate the association between FLG mutation status and the occurrence of malignant melanoma (MM) in Danish adults. METHODS: The prevalence of FLG mutations in a sample of MM biopsies was compared with a FLG-genotyped cohort from two general population studies. Pearson's chi-squared and Fisher's exact tests were used to compare the two groups. RESULTS: A total of 867 MM biopsies and 9965 general population controls were genotyped, respectively. In the MM sample, two (0.23%) individuals were homozygous and 80 (9.4%) were heterozygous mutation carriers. In the general population controls, the prevalence of FLG mutations was 18 (0.18%) and 835 (8.4%) for homozygous and heterozygous mutations, respectively. Fisher's exact test and Pearson's chi-squared test yielded non-significant P-values when the groups were compared. CONCLUSION: FLG mutation was not associated with MM in the studied populations. This finding indicates that epidermal deficiency of filaggrin and its degradation products does not influence the risk of MM significantly. PMID- 28833579 TI - Effect of a 12-methacryloyloxy-dodecyl-pyridinium-bromide-containing adhesive with different post types on the long-term bond strength to dentin. AB - The use of matrix metalloproteinase (MMPs) inhibitors, such as 12-methacryloyloxy dodecyl-pyridinium-bromide (MDPB), might improve the adhesion of glass-fiber (GF) and polyfiber (PF) posts to root dentine. This study assessed the effect of an MDPB-containing adhesive on the long-term bond strength of GF or PF posts to bovine dentine. Bovine endodontically treated roots were randomly divided into six groups, according to the post type and adhesive system used, as follows: GF serrated post + MDBP-free adhesive; GF serrated post + MDPB-containing adhesive; GF smooth post + MDBP-free adhesive; GF smooth post + MDPB-containing adhesive; PF post + MDBP-free adhesive; PF post + MDPB-containing adhesive. Specimens were stored in water for 6 months, thermocycled (500 cycles wk-1 ), and submitted to the pull-out test and failure pattern analysis. The cement-dentin interface was evaluated using scanning electron microscopy. The pull-out data were analyzed using anova and Tukey's test (alpha = 0.05). No significant interaction between the type of post and the adhesive system was found. Polyfiber posts showed lower bond strength than GF posts, whether serrated or smooth, and the bond strength of the serrated and smooth GF posts was not significantly different. Adhesive failures were predominant in all groups. The type of retainer influenced the bond strength, and MDPB-containing adhesive did not improve the long-term bond strength of posts to dentine. PMID- 28833581 TI - Community mental health teams for older people in England: Variations in ways of working. AB - OBJECTIVE: Integrated community mental health teams (CMHTs) are a key component of specialist old age psychiatry services internationally. However, in England, significant shifts in policy, including a focus on dementia and age inclusive services, have influenced provision. This study portrays teams in 2009 against which subsequent service provision may be compared. METHODS: A bespoke national postal survey of CMHT managers collected data on teams' structure, composition, organisation, working practices, case management, and liaison activities. RESULTS: A total of 376 CMHTs (88%) responded. Teams comprised a widespread of disciplines. However, just 28% contained the full complement of professionals recommended by government policy. Over 93% of teams had a single point of access, but some GPs bypassed this, and 40% of teams did not accept direct referrals from care homes. Initial assessments were undertaken by multiple disciplines, and 71% of teams used common assessment documentation. Nevertheless, many social workers maintained both NHS and local authority records. In 92% of teams, nominated care coordinators oversaw the support provided by other team members. However, inter agency care coordination was less prevalent. Few teams offered the range of outreach/liaison activities anticipated in the national dementia strategy. CONCLUSIONS: Compared with previous studies, teams had grown and changed, with a clear increase in non-medical practitioners, particularly support workers. Measures to facilitate integrated care within CMHTs (eg, common access and documentation) were widespread, but integration across health and social care/primary and secondary services was less developed. Consideration of barriers to further integration, and the impact of current reforms is potentially fruitful. PMID- 28833580 TI - Oxygenated VOCs, aqueous chemistry, and potential impacts on residential indoor air composition. AB - Dampness affects a substantial percentage of homes and is associated with increased risk of respiratory ailments; yet, the effects of dampness on indoor chemistry are largely unknown. We hypothesize that the presence of water-soluble gases and their aqueous processing alters the chemical composition of indoor air and thereby affects inhalation and dermal exposures in damp homes. Herein, we use the existing literature and new measurements to examine the plausibility of this hypothesis, summarize existing evidence, and identify key knowledge gaps. While measurements of indoor volatile organic compounds (VOCs) are abundant, measurements of water-soluble organic gases (WSOGs) are not. We found that concentrations of total WSOGs were, on average, 15 times higher inside homes than immediately outside (N = 13). We provide insights into WSOG compounds likely to be present indoors using peer-reviewed literature and insights from atmospheric chemistry. Finally, we discuss types of aqueous chemistry that may occur on indoor surfaces and speculate how this chemistry could affect indoor exposures. Liquid water quantities, identities of water-soluble compounds, the dominant chemistry, and fate of aqueous products are poorly understood. These limitations hamper our ability to determine the effects of aqueous indoor chemistry on dermal and inhalation exposures in damp homes. PMID- 28833582 TI - A Retrospective Study on the Safety and Efficacy of Leflunomide in Dogs. AB - BACKGROUND: Little clinical information is available concerning the use of leflunomide in dogs with immune-mediated diseases. OBJECTIVES: To report the safety and efficacy of leflunomide for the treatment of naturally occurring immune-mediated diseases in dogs. ANIMALS: Ninety-two dogs treated with leflunomide for management of suspected immune-mediated diseases. METHODS: Retrospective medical record review from Jan 1995 to Dec 2014. Data that were extracted from the medical records included signalment, body weight, underlying indication for leflunomide, dosage of leflunomide, treatment duration, concurrent medications, treatment response, and adverse events. RESULTS: Adverse events that could be related to leflunomide administration included diarrhea (3 of 92, 3.3%), lethargy (2 of 92, 2.2%), unexplained hemorrhage (3 of 92, 3.3%), thrombocytopenia (2 of 31, 6.5%), and increased liver enzyme activities (1 of 16, 6.3%). Significant dose differences between dogs with adverse events (n = 11; median, 2.9 mg/kg/d; range, 1.8-3.6 mg/kg/d) and dogs without adverse events (n = 81; median, 1.6 mg/kg/d; range, 0.8-4.3 mg/kg/d) were found (P < 0.001). Treatment response could be evaluated in 17 dogs. Of these 17 dogs, 12 dogs (70.5%) had an apparent positive response to the use of leflunomide. There was no significant difference (P = 0.22) in dosages between dogs that responded to leflunomide (n = 12; median, 1.9 mg/kg/d; range, 1.0-3.5 mg/kg/d) and those that did not respond (n = 5; median, 1.7 mg/kg/d; range, 1.0-2.0 mg/kg/d). CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that the starting dosage of leflunomide should be 2 mg/kg/d rather than the currently suggested dosage of 3-4 mg/kg/d. PMID- 28833583 TI - Cell-Free DNA and DNase Activity in Dogs with Immune-Mediated Hemolytic Anemia. AB - BACKGROUND: Immune-mediated hemolytic anemia (IMHA) in dogs has a high risk of thrombosis and is associated with marked neutrophilia and necrosis. Cell death and release of neutrophil extracellular traps contribute to increased serum concentrations of cell-free DNA, and in human autoimmune disease reduced DNase activity further increases cell-free DNA. Free DNA in blood has prothrombotic properties and could contribute to hypercoagulability in IMHA. HYPOTHESIS: Cell free DNA is elevated and DNase activity reduced in dogs with IMHA compared to healthy dogs. ANIMALS: Dogs presenting to two referral hospitals with IMHA (n = 28) and healthy controls (n = 20). METHODS: Prospective observational study. Blood was collected and death and thrombotic events occurring in the first 14 days after hospitalization recorded. DNA was extracted from plasma with a commercial kit and quantified by PicoGreen fluorescence. DNase activity of serum was measured by radial diffusion assay. RESULTS: Cell-free DNA was significantly higher in cases (median: 45 ng/mL, range: 10-2334 ng/mL) than controls (26 ng/mL, range 1-151 ng/mL, P = 0.0084). DNase activity was not different between cases and controls (P = 0.36). Four cases died and there were five suspected or confirmed thrombotic events. Cell-free DNA concentration was associated with death (odds ratio for upper quartile versus lower 3 quartiles: 15; 95% confidence interval 1.62-201; P = 0.03) but not thrombosis (P = 0.57). CONCLUSIONS AND CLINICAL IMPORTANCE: Cell-free DNA is elevated in dogs with IMHA and likely reflects increased release rather than impaired degradation of DNA. Cell-free DNA concentration is potentially associated with death and might be a prognostic indicator, but this requires confirmation in a larger population. PMID- 28833584 TI - Binding Mode and Selectivity of a Scorpiand-Like Polyamine Ligand to Single- and Double-Stranded DNA and RNA: Metal- and pH-Driven Modulation. AB - The interaction of a polyazacyclophane ligand having an ethylamine pendant arm functionalized with an anthryl group (L), with the single-stranded polynucleotides polyA, polyG, polyU, and polyC as well as with the double stranded polynucleotides polyA-polyU, poly(dAT)2 , and poly(dGC)2 has been followed by UV/Vis titration, steady state fluorescence spectroscopy, and thermal denaturation measurements. In the case of the single-stranded polynucleotides, the UV/Vis and fluorescence titrations permit to distinguish between sequences containing purine and pyrimidine bases. For the double-stranded polynucleotides the UV/Vis measurements show for all of them hypochromicity and bathochromic shifts. However, the fluorescence studies reveal that both polyA-polyU and poly(dAT)2 induce a twofold increase in the fluorescence, whereas interaction of poly(dGC)2 with the ligand L induces a quenching of the fluorescence. Cu2+ modulates the interaction with the double-stranded polynucleotides due to the conformation changes that its coordination induces in compound L. In general, the spectroscopic studies show that intercalation seems to be blocked by the formation of the metal complex. All these features suggest the possibility of using compound L as a sequence-selective fluorescence probe. PMID- 28833586 TI - Melanoma and chronic exposure to contraceptives containing microdoses of ethinylestradiol in young women: a retrospective study from the Research on Adverse Drug Events and Reports (RADAR) project comprising a large Midwestern U.S. patient population. PMID- 28833585 TI - Protein structure model refinement in CASP12 using short and long molecular dynamics simulations in implicit solvent. AB - Protein structure prediction has matured over years, particularly those which use structure templates for building a model. It can build a model with correct overall conformation in cases where appropriate templates are available. Models with the correct topology can be practically useful for limited purposes that need residue-level accuracy, but further improvement of the models can allow the models to be used in tasks that need detailed structures, such as molecular replacement in X-ray crystallography or structure-based drug screening. Thus, model refinement is an important final step in protein structure prediction to bridge predictions to real-life applications. Model refinement is one of the categories in recent rounds of critical assessment of techniques in protein structure prediction (CASP) and has recently been drawing more attention due to its realized importance. Here we report our group's performance in the refinement category in CASP12. Our method is based on inexpensive short molecular dynamics (MD) simulations in implicit solvent. Our performance in CASP12 was among the top, which was consistent with the previous round, CASP11. Our method with short MD runs achieved comparable performance with other methods that used longer simulations. Detailed analyses found that improvements typically occurred in entire regions of a structure rather than only in flexible loop regions. The remaining challenge in the structure refinement includes large conformational refinement which involves substantial motions of secondary structure elements or domains. PMID- 28833587 TI - Cutaneous disseminated sporotrichosis: clinical experience of 24 cases. PMID- 28833588 TI - Large nose angiosarcoma treated effectively with oral cyclophosphamide combined with propranolol. PMID- 28833589 TI - Catalyzed Radical Termination in the Presence of Tellanyl Radicals. AB - The decomposition of the diazo initiator dimethyl 2,2'-azobis(isobutyrate) (V 601), generating the Me2 C. (CO2 Me) radical, affords essentially the same fraction of disproportionation and combination in media with a large range of viscosity (C6 D6 , [D6 ]DMSO, and PEG 200) in the 25-100 degrees C range. This is in stark contrast to recent results by Yamago et al. on the same radical generated from Me2 C(TeMe)(CO2 Me) and on other X-TeR systems (X=polymer chain or unimer model; R=Me, Ph). The discrepancy is rationalized on the basis of an unprecedented RTe. -catalyzed radical disproportionation, with support from DFT calculations and photochemicaL V-601 decomposition in the presence of Te2 Ph2 . PMID- 28833590 TI - Moderate to severe hidradenitis suppurativa patients do not have an altered bacterial composition in peripheral blood compared to healthy controls. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease defined by recurrent nodules, tunnels and scarring involving the intertriginous skin. Patients with HS often report an array of systemic symptoms such as fatigue and malaise. The aetiology of these symptoms remains unclear. Previously, various bacteria have been associated with mature HS lesions, and bacteraemia has been reported in patients with HS using traditional culturing methods. Thus, we hypothesized that a low-grade bacteraemia contributes to the symptomatology in patients with HS. OBJECTIVE: To explore the potential presence of bacteraemia in patients with HS and healthy controls. METHOD: A case-control study. Compositions of bacteria in the blood of 27 moderate to severe HS patients and 26 healthy controls were investigated using next-generation 16S ribosomal RNA gene sequencing (NGS) and routine anaerobic and aerobic blood culturing. None of the participants received any antibiotics (systemic or topical therapy) within 1 month prior to the study. HS patients with a recent flare were randomly selected by consecutive recruitment of eligible patients from the Department of Dermatology, Zealand University Hospital, Denmark. Healthy controls were recruited from the University of Copenhagen as well as from the healthcare staff. RESULTS: The different bacterial compositions were investigated using NGS and traditional anaerobic and aerobic blood culturing. Our NGS analysis provided a previously unreported characterization of the bacterial composition in peripheral blood from patients with HS and healthy controls. Overall, our data demonstrated that patients with HS do not have a different bacterial composition in their peripheral blood than healthy controls. CONCLUSION: The study suggests that the self-reported symptoms in HS such as malaise and fatigue may not be linked to bacteraemia. PMID- 28833591 TI - Evaluation of potential long-term changes in endothelial functions and basic echocardiographic parameters in unilateral nephrectomy patients. AB - AIM: Decreased nephron count may result in lower glomerular filtration rate (GFR) and cardiorenal injury in the absence of compensatory hyperfunction. In this study, we aimed to evaluate long-term effects of 50% nephron loss on endothelial functions and cardiac morphology in nondonor nephrectomy patients. METHODS: This study comprised 26 patients (median age: 44 [37.5-50] years, male: 14) with unilateral nephrectomy and 25 healthy controls (median age: 47 [42-50] years, male: 9). Echocardiography was performed in all patients. Endothelial function was examined by measuring ischemia-induced flow-mediated dilation (FMD) of the brachial artery. RESULTS: The mean nephrectomy time was 12.5 (8.75-23.25) years. Estimated glomerular filtration rate (eGFR [CKD-EPI]) was significantly lower in the patient group than controls (85.54+/-16.27 vs 96.35+/-11.68 mL/min, P=0.009). Uric acid levels were significantly higher in the patient group than controls (5.7+/-1.3 vs 4.5+/-0.8, P<0.001). Percentage of FMD was significantly lower in the unilateral nephrectomy patients than the control group (11.6+/-6.2 vs 16.1%+/ 7.9%; P=0.029). Left ventricular posterior wall thickness (LVPWT) (P<0.001), interventricular septal thickness (IVST) (P<0.001), left ventricular (LV) mass (P=0.014), and left ventricular mass index (P=0.014) were significantly higher in the patient group. CONCLUSION: In conclusion, 50% decrease in nephron mass due to unilateral nephrectomy may result in decreased eGFR, impaired endothelial functions and cardiac hypertrophy. What triggers endothelial dysfunction and cardiac hypertrophy in the event of mild decrease in GFR when creatinine has not been elevated yet remains unclear, but uric acid may be playing a role in this process necessitating large-scaled studies. PMID- 28833592 TI - Launching Phonon Polaritons by Natural Boron Nitride Wrinkles with Modifiable Dispersion by Dielectric Environments. AB - Interference-free hyperbolic phonon polaritons (HPPs) excited by natural wrinkles in a hexagonal boron nitride (hBN) microcrystal are reported both experimentally and theoretically. Although their geometries are off-resonant with the excitation wavelength, the wrinkles compensate for the large momentum mismatch between photon and phonon polariton, and launch the HPPs without interference. The spatial feature of wrinkles is about 200 nm, which is an order of magnitude smaller than resonant metal antennas at the same excitation wavelength. Compared with phonon polaritons launched by an atomic force microscopy tip, the phonon polaritons launched by wrinkles are interference-free, independent of the launcher geometry, and exhibit a smaller damping rate (gamma ~ 0.028). On the same hBN microcrystal, in situ nanoinfrared imaging of HPPs launched by different mechanisms is performed. In addition, the dispersion of HPPs is modified by changing the dielectric environments of hBN crystals. The wavelength of HPPs is compressed twofold when the substrate is changed from SiO2 to gold. The findings provide insights into the intrinsic properties of hBN-HPPs and demonstrate a new way to launch and control polaritons in van der Waals materials. PMID- 28833593 TI - Implications of SNP weighting on single-step genomic predictions for different reference population sizes. AB - We investigated the importance of SNP weighting in populations with 2,000 to 25,000 genotyped animals. Populations were simulated with two effective sizes (20 or 100) and three numbers of QTL (10, 50 or 500). Pedigree information was available for six generations; phenotypes were recorded for the four middle generations. Animals from the last three generations were genotyped for 45,000 SNP. Single-step genomic BLUP (ssGBLUP) and weighted ssGBLUP (WssGBLUP) were used to estimate genomic EBV using a genomic relationship matrix (G). The WssGBLUP performed better in small genotyped populations; however, any advantage for WssGBLUP was reduced or eliminated when more animals were genotyped. WssGBLUP had greater resolution for genome-wide association (GWA) as did increasing the number of genotyped animals. For few QTL, accuracy was greater for WssGBLUP than ssGBLUP; however, for many QTL, accuracy was the same for both methods. The largest genotyped set was used to assess the dimensionality of genomic information (number of effective SNP). The number of effective SNP was considerably less in weighted G than in unweighted G. Once the number of independent SNP is well represented in the genotyped population, the impact of SNP weighting becomes less important. PMID- 28833594 TI - Perceval valve-in-valve implant for full root xenograft failure. AB - Aortic root replacement with a biological conduit results in excellent hemodynamics but has limited durability. We report a series of six patients who underwent successful Perceval-S surgical aortic valve implantation following surgical deterioration of a biological valve composite conduit and discuss the technical details and the importance of appropriate valve sizing for this procedure. PMID- 28833596 TI - Room Temperature Electrochemical Sintering of Zn Microparticles and Its Use in Printable Conducting Inks for Bioresorbable Electronics. AB - This study describes a conductive ink formulation that exploits electrochemical sintering of Zn microparticles in aqueous solutions at room temperature. This material system has relevance to emerging classes of biologically and environmentally degradable electronic devices. The sintering process involves dissolution of a surface passivation layer of zinc oxide in CH3 COOH/H2 O and subsequent self-exchange of Zn and Zn2+ at the Zn/H2 O interface. The chemical specificity associated with the Zn metal and the CH3 COOH/H2 O solution is critically important, as revealed by studies of other material combinations. The resulting electrochemistry establishes the basis for a remarkably simple procedure for printing highly conductive (3 * 105 S m-1 ) features in degradable materials at ambient conditions over large areas, with key advantages over strategies based on liquid phase (fusion) sintering that requires both oxide-free metal surfaces and high temperature conditions. Demonstrations include printed magnetic loop antennas for near-field communication devices. PMID- 28833597 TI - Artepillin C as a targeting survivin molecule in oral squamous cell carcinoma cells in vitro: A preliminary study. AB - BACKGROUND: Survivin, a member of the inhibitor of apoptosis family, is overexpressed in most human tumors, but undetectable in normal adult tissues. It is a promising target molecule in cancer treatment, as interference in its function promotes apoptosis. Artepillin C, a major, biologically active ingredient of Brazilian propolis, possesses anticancer activity against several cancer cells with different tissue origins. However, little is known about its bioactivity on oral squamous cell carcinoma cells or its effect on survivin expression. The aim of this study was to investigate the cytotoxic and antisurvivin activities of artepillin C in oral squamous cell carcinoma cells. METHODS: HSC-3 human oral squamous cell carcinoma cells were treated with varying doses of artepillin C for up to 72 hours. Cell viability was measured by WST-1, and the cytotoxic effects of artepillin C on HSC-3 cells were quantified with flow cytometry. The survivin levels were determined by ELISA. RESULTS: Artepillin C exhibited dose- and time-dependent cytotoxic effects on HSC-3 cells. Flow cytometric analysis showed that 22% of untreated HSC-3 cells underwent spontaneous cell death, whereas 77.32% of the cells were killed in response to the highest dose of artepillin C at 72 hours. Survivin expression was reduced in treated cells. CONCLUSIONS: HSC-3 cells are vulnerable to artepillin C in a dose- and time-dependent manner. HSC-3 cell death induced by artepillin C, at least in part, was a result of a decrease in survivin levels. PMID- 28833595 TI - Topical ionic contra-viral therapy comprised of digoxin and furosemide as a potential novel treatment approach for common warts. AB - BACKGROUND: DNA viruses such as HPV rely on K+ influx for replication. Both digoxin and furosemide inhibit the K+ influx by interacting with cell membrane ion co-transporters (Na+ /K+ -ATPase and Na+ -K+ -2Cl- co-transporter-1, respectively). We therefore hypothesized that these two compounds in a topical formulation may be valuable in the treatment of HPV-induced warts. This new approach is called Ionic Contra-Viral Therapy (ICVT). OBJECTIVE: To evaluate systemic exposure, safety and tolerability of ICVT with a combination of furosemide and digoxin after repeated topical application in subjects with common warts. Furthermore, we aimed to evaluate pharmacodynamics effects of ICVT. METHODS: Twelve healthy subjects with at least four common warts on their hands were included in the study and treated with a fixed dose of 980 mg topical gel containing 0.125% (w/w) digoxin and 0.125% (w/w) furosemide for 7 consecutive days on their lower back to assess safety and systemic exposure. Two warts were treated with 10 mg each and two served as negative controls to obtain preliminary evidence of treatment effect. RESULTS: ICVT was well tolerated topically, and there was no evidence of systemic exposure of digoxin or furosemide. There were no clinical relevant safety findings and no serious adverse events (SAEs). A rapid and statistically significant reduction in diameter, height and volume of the warts was already observed at day 14. CONCLUSION: ICVT was found to be safe for administration to humans and 7 days of active treatment showed a statistical significant wart reduction compared to untreated control lesions, clearly indicating pharmacological activity. PMID- 28833598 TI - Carbon-Nanotube-Confined Vertical Heterostructures with Asymmetric Contacts. AB - Van der Waals (vdW) heterostructures have received intense attention for their efficient stacking methodology with 2D nanomaterials in vertical dimension. However, it is still a challenge to scale down the lateral size of vdW heterostructures to the nanometer and make proper contacts to achieve optimized performances. Here, a carbon-nanotube-confined vertical heterostructure (CCVH) is employed to address this challenge, in which 2D semiconductors are asymmetrically sandwiched by an individual metallic single-walled carbon nanotube (SWCNT) and a metal electrode. By using WSe2 and MoS2 , the CCVH can be made into p-type and n type field effect transistors with high on/off ratios even when the channel length is 3.3 nm. A complementary inverter was further built with them, indicating their potential in logic circuits with a high integration level. Furthermore, the Fermi level of SWCNTs can be efficiently modulated by the gate voltage, making it competent for both electron and hole injection in the CCVHs. This unique property is shown by the transition of WSe2 CCVH from unipolar to bipolar, and the transition of WSe2 /MoS2 from p-n junction to n-n junction under proper source-drain biases and gate voltages. Therefore, the CCVH, as a member of 1D/2D mixed heterostructures, shows great potentials in future nanoelectronics and nano-optoelectronics. PMID- 28833599 TI - Effect of patent foramen ovale closure for prevention on recurrent stroke or transient ischemic attack in selected patients with cryptogenic stroke. AB - OBJECTIVES: This study was sought to evaluate the effectiveness of patent foramen ovale (PFO) closure in selected patients (PFO shunt grade more than moderate) with cryptogenic stroke (CS). BACKGROUND: Whether closure of PFO is an effective treatment for prevention of CS is still unclear. METHODS: Consecutive 158 patients (mean age: 49.9 years old, closure group: 67 patients, medication group: 91 patients) were enrolled. The primary end point was a composite of recurrent stroke and transient ischemic attack. RESULTS: Baseline characteristics were similar between the two groups, except age which was younger in the closure group (47.7 +/- 10.8 vs 51.9 +/- 9.9, P = 0.013), and the presence of shunt at rest was more common in the closure group (35.8% vs 10.4%, P = 0.000). Procedural success was 94.0%. Over a mean follow-up of 27.8 months, a total of six primary end point, all of which were strokes, occurred only in the medication group (6.6% vs 0%, P = 0.039). Stroke-free survival rate was significantly higher in the closure group (P = 0.026) CONCLUSIONS: Our study showed that PFO closure may be an effective treatment strategy to prevent recurrent stroke or TIA for patients with CS if it is conducted in selective patients who have PFO shunt more than moderate grade. PMID- 28833600 TI - Clinicopathologic features and pathogenesis of melanocytic colonization in atypical meningioma. AB - Only two prior cases of benign dendritic melanocytes colonizing a meningioma have been reported. We add a third case, describe clinicopathologic features shared by the three, and elucidate the risk factors for this very rare phenomenon. A 29 year-old Hispanic woman presented with headache and hydrocephalus. MRI showed a lobulated enhancing pineal region mass measuring 41 mm in greatest dimension. Subtotal resection of the mass demonstrated an atypical meningioma, WHO grade II, and the patient subsequently underwent radiotherapy. She presented 4 years later with diplopia, and MRI showed an enhancing extra-axial mass measuring 47 mm in greatest dimension and centered on the tentorial incisura. Subtotal resection showed a brain-invasive atypical meningioma with melanocytic colonization. The previous two cases in the literature were atypical meningiomas, one of which was also brain invasive. Atypical meningiomas may be at particular risk for melanocytic colonization as they upregulate molecules known to be chemoattractants for melanocytes. We detected c-Kit expression in a minority of the melanocytes as well as stem cell factor and basic fibroblast growth factor in the meningioma cells, suggesting that mechanisms implicated in normal melanocyte migration may be involved. In some cases, brain invasion with disruption of the leptomeningeal barrier may also facilitate migration from the subarachnoid space into the tumor. Whether there is low-level proliferation of the dendritic melanocytes is unclear. Given that all three patients were non-Caucasian, meningiomas in persons and/or brain regions with increased dendritic melanocytes may predispose to colonization. The age range spanned from 6 years old to 70 years old. All three patients were female. The role of gender and estrogen in the pathogenesis of this entity remains to be clarified. Whether melanocytic colonization may also occur in the more common Grade I meningiomas awaits identification of additional cases. PMID- 28833601 TI - Multimodality imaging of a huge subaortic left ventricular aneurysm in a child. AB - A subannular left ventricular aneurysm is very rare, and is mostly considered to be a congenital anomaly. A subannular left ventricular aneurysm is classified based on the type of its own orifice-submitral or subaortic. Subaortic left ventricular aneurysm occurs less frequently compared with a submitral type of subannular aneurysm. We hereby describe a rare case of a huge bilobed subaortic aneurysm, in which the orifice was located just below the left coronary cusp diagnosed with multimodality imaging in a child. PMID- 28833602 TI - Langerhans cell: exciting developments in health and disease. AB - Langerhans cells (LCs) have been the subject of much research since their discovery in 1868. LCs belong to the subset of leucocytes called dendritic cells. They are present in the epidermis and the pilosebaceous apparatus and monitor the cutaneous environment for changes in homeostasis. During embryogenesis, a wave of yolk sac macrophages seed the fetal skin. Then, fetal liver monocytes largely replace the yolk sac macrophages and comprise the majority of adult LCs. In the presence of skin irritation, LCs process antigen and travel to regional lymph nodes to present antigen to reactive T lymphocytes. Changes in LCs' surface markers during the journey occur under the influence of cytokines. The difference in expression of surface markers and the ability to resist radiation have allowed researchers to differentiate LCs from the murine Langerin-positive dermal dendritic cells. Exciting discoveries have been made recently regarding their role in inflammatory skin diseases, cancer and HIV. New research has shown that antibodies blocking CD1a appear to mitigate inflammation in contact hypersensitivity reactions and psoriasis. While it has been established that LCs have the potential to induce effector cells of the adaptive immune system to counter oncogenesis, recent studies have demonstrated that LCs coordinate with natural killer cells to impair development of squamous cell carcinoma caused by chemical carcinogens. However, LCs may also physiologically suppress T cells and permit keratinocyte transformation and tumorigenesis. Although long known to play a primary role in the progression of HIV infection, it is now understood that LCs also possess the ability to restrict the progression of the disease. There is a pressing need to discover more about how these cells affect various aspects of health and disease; new information gathered thus far seems promising and exciting. PMID- 28833603 TI - Metformin incombination with curcumin inhibits the growth, metastasis, and angiogenesis of hepatocellular carcinoma in vitro and in vivo. AB - Hepatocellular carcinoma (HCC) has poor prognosis due to the advanced disease stages by the time it is diagnosed, high recurrence rates and metastasis. In the present study, we investigated the effects of metformin (a safe anti-diabetic drug) and curcumin (a turmeric polyphenol extracted from rhizome of Curcuma longa Linn.) on proliferation, apoptosis, invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. It was found that co-treatment of metformin and curcumin could not only induce tumor cells into apoptosis through activating the mitochondria pathways, but also suppress the invasion, metastasis of HCC cells and angiogenesis of HUVECs. These effects were associated with downregulation of the expression of MMP2/9, VEGF, and VEGFR-2, up-regulation of PTEN, P53 and suppression of PI3K/Akt/mTOR/NF-kappaB and EGFR/STAT3 signaling. Co administration of metformin and curcumin significantly inhibited HCC tumor growth than administration with metformin or curcumin alone in a xenograft mouse model. Thus, metformin and curcumin in combination showed a better anti-tumor effects in hepatoma cells than either metformin or curcumin presence alone and might represent an effective therapeutic strategy for HCC treatment. PMID- 28833604 TI - Smart Bioinspired Nanochannels and their Applications in Energy-Conversion Systems. AB - Smart bioinspired nanochannels exhibiting ion-transport properties similar to biological ion channels have attracted extensive attention. Like ion channels in nature, smart bioinspired nanochannels can respond to various stimuli, which lays a solid foundation for mass transport and energy conversion. Fundamental research into smart bioinspired nanochannels not only furthers understanding of life processes in living bodies, but also inspires researchers to construct smart nanodevices to meet the increasing demand for the use of renewable resources. Here, a brief summary of recent research progress regarding the design and preparation of smart bioinspired nanochannels is presented. Moreover, representative applications of smart bioinspired nanochannels in energy conversion systems are also summarized. Finally, an outlook for future challenges in this field is given. PMID- 28833605 TI - Si Complies with GaN to Overcome Thermal Mismatches for the Heteroepitaxy of Thick GaN on Si. AB - Heteroepitaxial growth of lattice mismatched materials has advanced through the epitaxy of thin coherently strained layers, the strain sharing in virtual and nanoscale substrates, and the growth of thick films with intermediate strain relaxed buffer layers. However, the thermal mismatch is not completely resolved in highly mismatched systems such as in GaN-on-Si. Here, geometrical effects and surface faceting to dilate thermal stresses at the surface of selectively grown epitaxial GaN layers on Si are exploited. The growth of thick (19 um), crack free, and pure GaN layers on Si with the lowest threading dislocation density of 1.1 * 107 cm-2 achieved to date in GaN-on-Si is demonstrated. With these advances, the first vertical GaN metal-insulator-semiconductor field-effect transistors on Si substrates with low leakage currents and high on/off ratios paving the way for a cost-effective high power device paradigm on an Si CMOS platform are demonstrated. PMID- 28833606 TI - DNA methylation profiles between airway epithelium and proxy tissues in children. AB - AIM: Epidemiological studies of deoxyribonucleic acid (DNA) methylation in airway disease have largely been conducted using blood or buccal samples. However, given tissue specificity of DNA methylation, these surrogate tissues may not allow reliable inferences about methylation in the lung. We sought to compare the pattern of DNA methylation in blood, buccal and nasal epithelial cells to that in airway epithelial cells from children. METHODS: Samples of blood, and buccal, nasal and airway epithelium were obtained from six children undergoing elective anaesthesia for adenotonsillectomy. DNA methylation was assessed at 450 000 5'-C phosphate-G-3' (CpG) sites using the Illumina HumanMethylation450 array. RESULTS: Eighteen samples from all sites were suitable for analysis. Hierarchical clustering demonstrated that the methylation profile in nasal epithelium was most representative of that in airway epithelium; the profile in buccal cells was moderately similar and that in blood was least similar. CONCLUSION: DNA methylation in blood poorly reflects methylation in airway epithelium. Future epidemiological studies of DNA methylation and airway diseases should consider measurement of methylation either in buccal cells or, preferably, in nasal epithelial cells. PMID- 28833607 TI - Ultrafine Silver Nanoparticles for Seeded Lithium Deposition toward Stable Lithium Metal Anode. AB - To exploit the high energy density of the lithium (Li) metal battery, it is imperative to address the dendrite growth and interface instability of the anode. 3D hosts for Li metal are expected to suppress the growth of Li dendrites. Heterogeneous seeds are effective in guiding Li deposition and realizing spatial control over Li nucleation. Herein, this study shows that ultrafine silver (Ag) nanoparticles, which are synthesized via a novel rapid Joule heating method, can serve as nanoseeds to direct the deposition of Li within the 3D host materials, resolving the problems of the Li metal anode. By optimizing the Joule heating method, ultrafine Ag nanoparticles (~40 nm) are homogeneously anchored on carbon nanofibers. The Ag nanoseeds effectively reduce the nucleation overpotential of Li and guide the Li deposition in the 3D carbon matrix uniformly, free from the dendrites. A stable and reversible Li metal anode is achieved in virtue of the Ag nanoseeds in the 3D substrate, showing a low overpotential (~0.025 V) for a long cycle life. The ultrafine nanoseeds achieved by rapid Joule heating render uniform deposition of Li metal anode in 3D hosts, promising a safe and long-life Li metal battery for high-energy applications. PMID- 28833608 TI - Cherchez l'Electron. AB - Who wouldn't want to have a drug that is activated only in the target cell? Prodrugs that are metabolically triggered inside the pathogen but not in the host are an attractive concept in antimicrobial chemotherapy. Of particular interest are bioreductive prodrugs such as nitro compounds or quinones that can initiate cytotoxic redox cascades and release active metabolites. The critical points for the selectivity of such molecules are, what is the source of the electrons that activate the prodrug, and which are the enzymes that catalyze the reduction? Meredith et al. conceive an elegant approach to answer these questions, making use of reverse genetics in Trypanosoma brucei. By overexpression of key reductase genes, they engineer trypanosomal indicator lines that are hypersensitive to particular bioreductive prodrugs and allow to discriminate between one-electron and two-electron transfer activation mechanisms. Indicator lines that are also defective in DNA repair further indicate whether the resultant metabolites interfere with the parasite's genome. This set of T. brucei indicator lines provides a tool for the deconvolution of the mechanisms of prodrug activation and drug action that will facilitate the rational development of bioreductive prodrugs for parasite chemotherapy. PMID- 28833609 TI - Magnetic resonance imaging of the tensor vastus intermedius: A topographic study based on anatomical dissections. AB - The tensor of the vastus intermedius (TVI) is a newly described component of the extensor apparatus of the knee joint. The objective of this study was to evaluate the appearance of the TVI on magnetic resonance (MR) imaging and its association with the adjacent vastus lateralis (VL) and vastus intermedius (VI) muscles and to compare these findings with the corresponding anatomy. MR images were analyzed from a cadaveric thigh where the TVI, as part of the extensor apparatus of the knee joint, had been dissected. The course of the TVI in relation to the adjacent VL and VI was studied. The anatomic dissection and MR imaging revealed a multilayered organization of the lateral extensor apparatus of the knee joint. The TVI is an intervening muscle between the VL and VI that combined into a broad flat aponeurosis in the midthigh and merged into the quadriceps tendon. Dorsally, the muscle fibers of the TVI joined those of the VL and VI and blended into the attachment at the lateral lip of the linea aspera. In this area, distinguishing between these three muscles was not possible macroscopically or virtually by MR imaging. In the dorsal aspect, the onion-like muscle layers of the VL, TVI, and VI fuse to a hardly separable muscle mass indicating that these muscles work in conjunction to produce knee extension torque when knee joint action is performed. Clin. Anat. 30:1096-1102, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28833610 TI - Proof of Concept Studies Directed Towards Designed Molecular Wires: Property Driven Synthesis of Air and Moisture-Stable Polystannanes. AB - Polystannanes with azobenzene moieties designed to protect the Sn-Sn backbone from light- and moisture-induced degradation are described. The azo-stannyl precursor 3 (70 %) is converted in good yields (88-91 %) to the mono- (4), and dichlorostannanes (5), by sequential chlorination, followed by further reduction of 5 to the dihydride (6) using NaBH4 (78 %). All stannanes were characterised by NMR (1 H, 13 C, 119 Sn) spectroscopy and HRMS; in addition, 3, 4 and 5 were structurally elucidated using X-ray diffraction analysis. Metal-free dehydrocoupling of 6 at RT leads exclusively to homopolymer (7-i) displaying an initial solution 119 Sn NMR signal (delta=-196 ppm) that migrates to -235 ppm after 10 days (7-f). In contrast, metal-catalyzed dehydrocoupling of 6 in toluene at RT leads directly 7-f. Random co-polymers formed from 6 and (nBu)2 SnH2 at 4:1 (8 a) and 1:1 (8 b) ratios were compared to the alternating polystannane (9) prepared by the reaction of 6 with (nBu)2 Sn(NEt2 )2 . DFT calculations of 3-6 indicate that hypercoordination at Sn is influenced by substituents and by solvation. Homopolymer 7 was found to have unprecedented moisture and light stability in the solid state for >6 months. PMID- 28833611 TI - Conducting Polymer Microcups for Organic Bioelectronics and Drug Delivery Applications. AB - An ideal neural device enables long-term, sensitive, and selective communication with the nervous system. To accomplish this task, the material interface should mimic the biophysical and the biochemical properties of neural tissue. By contrast, microfabricated neural probes utilize hard metallic conductors, which hinder their long-term performance because these materials are not intrinsically similar to soft neural tissue. This study reports a method for the fabrication of monodisperse conducting polymer microcups. It is demonstrated that the physical surface properties of conducting polymer microcups can be precisely modulated to control electrical properties and drug-loading/release characteristics. PMID- 28833612 TI - A 1D Vanadium Dioxide Nanochannel Constructed via Electric-Field-Induced Ion Transport and its Superior Metal-Insulator Transition. AB - Nanoscale manipulation of materials' physicochemical properties offers distinguished possibility to the development of novel electronic devices with ultrasmall dimension, fast operation speed, and low energy consumption characteristics. This is especially important as the present semiconductor manufacturing technique is approaching the end of miniaturization campaign in the near future. Here, a superior metal-insulator transition (MIT) of a 1D VO2 nanochannel constructed through an electric-field-induced oxygen ion migration process in V2 O5 thin film is reported for the first time. A sharp and reliable MIT transition with a steep turn-on voltage slope of <0.5 mV dec-1 , fast switching speed of 17 ns, low energy consumption of 8 pJ, and low variability of <4.3% is demonstrated in the VO2 nanochannel device. High-resolution transmission electron microscopy observation and theoretical computation verify that the superior electrical properties of the present device can be ascribed to the electroformation of nanoscale VO2 nanochannel in V2 O5 thin films. More importantly, the incorporation of the present device into a Pt/HfO2 /Pt/VO2 /Pt 1S1R unit can ensure the correct reading of the HfO2 memory continuously for 107 cycles, therefore demonstrating its great possibility as a reliable selector in high-density crossbar memory arrays. PMID- 28833613 TI - The role of immediate provisional restorations on implants with a hydrophilic surface: A randomised, single-blind controlled clinical trial. AB - OBJECTIVES: To compare the radiographic bone changes, clinical parameters and aesthetic outcomes of immediately provisionalised and conventionally restored implants at 12- and 24-months post-implant placement. MATERIAL AND METHODS: In 24 patients, 24 bone level implants with a hydrophilic (SLActive) surface were placed in healed sites and they were either immediately provisionalised with a non-occluding temporary crown (test group) or left without a crown (control group). In both groups, the definitive restoration was placed 16 weeks after implant placement. Clinical and radiographic parameters were calculated at 12- and 24-months post-implant placement, together with implant success/survival rates according to three different sets of criteria. The aesthetic outcome was evaluated through the Papilla Fill Index and the Pink Aesthetic Score. RESULTS: The mean marginal bone loss at 1 year was -0.73 mm (SD 0.83 mm) in the test group and -0.22 mm (SD 0.46 mm) in the control group (p > .05). Whilst 100% survival rate and positive aesthetic outcomes were recorded in both groups, three patients of the test group did not fulfil all success criteria. CONCLUSIONS: Immediate provisionalisation may represent a viable option for the replacement of single missing teeth, with radiographic, clinical and aesthetic results comparable to those of conventionally loaded implants at 2 years of follow-up. PMID- 28833614 TI - Globularity-Selected Large Molecules for a New Generation of Multication Perovskites. AB - Perovskite solar cells (PSCs) use perovskites with an APbX3 structure, where A is a monovalent cation and X is a halide such as Cl, Br, and/or I. Currently, the cations for high-efficiency PSCs are Rb, Cs, methylammonium (MA), and/or formamidinium (FA). Molecules larger than FA, such as ethylammonium (EA), guanidinium (GA), and imidazolium (IA), are usually incompatible with photoactive "black"-phase perovskites. Here, novel molecular descriptors for larger molecular cations are introduced using a "globularity factor", i.e., the discrepancy of the molecular shape and an ideal sphere. These cationic radii differ significantly from previous reports, showing that especially ethylammonium (EA) is only slightly larger than FA. This makes EA a suitable candidate for multication 3D perovskites that have potential for unexpected and beneficial properties (suppressing halide segregation, stability). This approach is tested experimentally showing that surprisingly large quantities of EA get incorporated, in contrast to most previous reports where only small quantities of larger molecular cations can be tolerated as "additives". MA/EA perovskites are characterized experimentally with a band gap ranging from 1.59 to 2.78 eV, demonstrating some of the most blue-shifted PSCs reported to date. Furthermore, one of the compositions, MA0.5 EA0.5 PbBr3 , shows an open circuit voltage of 1.58 V, which is the highest to date with a conventional PSC architecture. PMID- 28833615 TI - Participation of cyclooxygenase-2 in lip carcinogenesis. PMID- 28833616 TI - A Novel Bulky Heteroaromatic-Substituted Methanide Mimicking NacNac: Bis(4,6-tert butylbenzoxazol-2-yl)methanide in s-Block Metal Coordination. AB - A novel bulky bis(4,6-tBu-benzoxazol-2-yl)methane ligand was synthesized in a straightforward three-step synthesis. The corresponding complexes [Li{(4,6-tBu NCOC6 H2 )2 CH}THF], [K{eta5 -(4,6-tBu-NCOC6 H2 )2 CH}]infinity , and [MgCl{(4,6 tBu-NCOC6 H2 )2 CH}(THF)2 ] were obtained upon metalation with alkaline or alkaline-earth-metal reagents. Reduction of [MgCl{(4,6-tBu-NCOC6 H2 )2 CH}(THF)2 ] with potassium metal or KC8 led to the formation of the homoleptic compound [Mg{(4,6-tBu-NCOC6 H2 )2 CH}2 ]. All compounds were fully characterized. Their solid-state structures as well as their behavior in solution, which was analyzed with the help of advanced NMR spectroscopic techniques, are discussed in detail. PMID- 28833617 TI - Multishelled CaO Microspheres Stabilized by Atomic Layer Deposition of Al2 O3 for Enhanced CO2 Capture Performance. AB - CO2 capture and storage is a promising concept to reduce anthropogenic CO2 emissions. The most established technology for capturing CO2 relies on amine scrubbing that is, however, associated with high costs. Technoeconomic studies show that using CaO as a high-temperature CO2 sorbent can significantly reduce the costs of CO2 capture. A serious disadvantage of CaO derived from earth abundant precursors, e.g., limestone, is the rapid, sintering-induced decay of its cyclic CO2 uptake. Here, a template-assisted hydrothermal approach to develop CaO-based sorbents exhibiting a very high and cyclically stable CO2 uptake is exploited. The morphological characteristics of these sorbents, i.e., a porous shell comprised of CaO nanoparticles coated by a thin layer of Al2 O3 (<3 nm) containing a central void, ensure (i) minimal diffusion limitations, (ii) space to accompany the substantial volumetric changes during CO2 capture and release, and (iii) a minimal quantity of Al2 O3 for structural stabilization, thus maximizing the fraction of CO2 -capture-active CaO. PMID- 28833618 TI - Intra-operative predictors of postoperative Takotsubo syndrome in liver transplant recipients-An exploratory case-control study. AB - INTRODUCTION: Takotsubo syndrome (TTS), also known as Takotsubo cardiomyopathy or stress-induced cardiomyopathy, has been described following a variety of surgeries and disease states. The relationship between intra-operative anesthesia management and the development of this syndrome has never been fully elucidated. OBJECTIVES: The primary objective of this study was to determine the relationship of multiple intra-operative factors on the pathogenesis of TTS. METHODS: A single center retrospective review of all liver transplants performed at Mayo Clinic Florida from January 2005 to December 2014. Patients developing left ventricular dilation and a concomitant decrease in ejection fraction, a negative cardiac catheterization, or stress test within 30 days of transplantation were identified. Cases were matched 2:1 to controls with respect to MELD, age, sex, and indication for transplantation. Our evaluation included liver graft characteristics, intra-operative medications, and intra-operative hemodynamic measurements. RESULTS: We identified 24 cases of TTS from a pool of 1752 transplants, for an incidence of 1.4%. No statistically significant differences in intra-operative measures between the two groups were identified (all P >= .08). CONCLUSION: Our exploratory, single-center retrospective review evaluating 46 intra-operative characteristics found no association with the development of TTS. PMID- 28833619 TI - Cost-effective options for the prevention and management of gastrointestinal and liver disease in the Asia-Pacific region. AB - The Asia-Pacific region contains more than half of the world's population and is markedly heterogeneous in relation to income levels and the provision of public and private health services. For low-income countries, the major health priorities are child and maternal health. In contrast, priorities for high-income countries include vascular disease, cancer, diabetes, dementia, and mental health disorders as well as chronic inflammatory disorders such as hepatitis B and hepatitis C. Cost-effectiveness analyses are methods for assessing the gains in health relative to the costs of different health interventions. Methods for measuring health outcomes include years of life saved (or lost), quality-adjusted life years, and disability-adjusted life years. The incremental cost effectiveness ratio measures the cost (usually in US dollars) per life year saved, quality-adjusted life year gained, or disability-adjusted life year averted of one intervention relative to another. In low-income countries, approximately 50% of infant deaths (< 5 years) are caused by gastroenteritis, the major pathogen being rotavirus infection. Rotavirus vaccines appear to be cost effective but, thus far, have not been widely adopted. In contrast, infant vaccination for hepatitis B is promoted in most countries with a striking reduction in the prevalence of infection in vaccinated individuals. Cost effectiveness analyses have also been applied to newer and more expensive drugs for hepatitis B and C and to government-sponsored programs for the early detection of hepatocellular, gastric, and colorectal cancer. Most of these studies reveal that newer drugs and surveillance programs for cancer are only marginally cost-effective in the setting of a high-income country. PMID- 28833620 TI - Eosinophils as putative therapeutic targets in bullous pemphigoid. AB - Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering skin disease and is characterized by the presence of autoantibodies directed against the hemidesmosomal proteins BP180 and BP230 that can be detected in the skin and serum of BP patients. Histologically, the dermal infiltration of eosinophils is obvious. The objective of this review was to present evidence that eosinophils play a key role in the pathogenesis of BP. Eosinophils, together with cytokines and chemokines regulating their production, recruitment and activation, are abundantly present in lesional skin, in blisters and in peripheral blood of patients with BP. Recently, using a cryosection model, eosinophils were demonstrated to induce dermal-epidermal separation in the presence of BP antibodies. Thus, eosinophils and their products, as well as mediators regulating their function, present promising targets for the treatment of BP. PMID- 28833621 TI - Persistence and adherence to overactive bladder medications in Japan: A large nationwide real-world analysis. AB - OBJECTIVES: To evaluate persistence and adherence to mirabegron and antimuscarinics in Japan using data from two administrative databases. METHODS: The present retrospective study evaluated insurance claims for employees and dependents aged <=75 years, and pharmacy claims for outpatients. From October 2012 to September 2014, new users of mirabegron or five individual antimuscarinics indicated for overactive bladder in Japan (fesoterodine, imidafenacin, propiverine, solifenacin and tolterodine) were identified and followed for 1 year. Persistence with mirabegron and antimuscarinics were evaluated using Kaplan-Meier methods. Any associations between baseline characteristics (age, sex and previous medication use) and persistence were explored. Adherence was assessed using the medication possession ratio. RESULTS: In total, 3970 and 16 648 patients were included from the insurance and pharmacy claims databases, respectively. Mirabegron treatment was associated with longer median persistence compared with antimuscarinics (insurance claims: 44 [95% confidence intervals 37-56] vs 21 [14-28] to 30 [30-33] days, pharmacy claims: 105 [96-113] vs 62 [56-77] to 84 [77-86] days). The results were consistent when patients were stratified by age, sex and previous medication. Persistence rate at 1 year was higher for mirabegron (insurance claims: 14.0% [11.5-16.8%] vs 5.4% [4.1-7.0%] to 9.1% [5.3-14.2%], pharmacy claims: 25.9% [24.6-27.3%] vs 16.3% [14.0-18.6%] to 21.3% [20.2-22.4%]). Compared with each antimuscarinic, a higher proportion of mirabegron-treated patients had medication possession ratios >=0.8. CONCLUSIONS: This large nationwide Japanese study shows that persistence and adherence are greater with mirabegron compared with five antimuscarinics. PMID- 28833622 TI - A Simple Method for Synthesis of High-Quality Millimeter-Scale 1T' Transition Metal Telluride and Near-Field Nanooptical Properties. AB - The controlled synthesis of MoTe2 and WTe2 is crucial for their fundamental research and potential electronic applications. Here, a simplified ambient pressure chemical vapor deposition (CVD) strategy is developed to synthesize high quality and large-scale monolayer and few-layer 1T'-phase MoTe2 (length ~ 1 mm) and WTe2 (length ~ 350 um) crystals by using ordinary salts (KCl or NaCl) as the growth promoter combining with low-cost (NH4 )6 Mo7 O24 .4H2 O and hydrate (NH4 )10 W12 O41 .xH2 O as the Mo and W sources, respectively. Atomic force microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and transmission electron microscopy confirm the high-quality nature and the atomic structure of the as-grown 1T' MoTe2 and WTe2 flakes. Variable-temperature transport measurements exhibit their semimetal properties. Furthermore, near field nanooptical imaging studies are performed on the 1T' MoTe2 and WTe2 flakes for the first time. The sub-wavelength effects of 1T'-phase MoTe2 (lambdap ~ 140 nm) and WTe2 (lambdap ~ 100 nm) are obtained. This approach paves the way for the growth of special transition-metal dichalcogenides materials and boosts the future polaritonic research of 2D telluride compounds. PMID- 28833623 TI - Structural investigation into the C-terminal extension of the ene-reductase from Ralstonia (Cupriavidus) metallidurans. AB - Ene-reductases (ERs), or Old Yellow Enzymes, catalyze the asymmetric reduction of various activated alkenes. This class of biocatalysts is considered an attractive alternative to current chemical technologies for hydrogenation due to their high selectivity and specificity. Here the X-ray crystal structure of RmER, a "thermophilic"-like ER from Ralstonia (Cupriavidus) metallidurans, is reported. Unlike other members of this class of ERs, RmER is monomeric in solution which we previously related to its atypical elongated C-terminus. A typical dimer interface was however observed in our crystal structure, with the conserved Arg "finger" forming part of the adjacent monomer's active site and the elongated C terminus extending into the active site through contacting the "capping" domain. This dimerization also resulted in the loss of one FMN cofactor from each dimer pair. This potential transient dimerization and dissociation of FMN could conceivably explain the rapid rates previously observed when an FMN light-driven cofactor regeneration system was used during catalysis with RmER. PMID- 28833624 TI - Strategies for Improving the Functionality of Zeolitic Imidazolate Frameworks: Tailoring Nanoarchitectures for Functional Applications. AB - Zeolitic imidazolate frameworks (ZIFs), a subclass of metal-organic frameworks (MOFs) built with tetrahedral metal ions and imidazolates, offer permanent porosity and high thermal and chemical stabilities. While ZIFs possess some attractive physical and chemical properties, it remains important to enhance their functionality for practical application. Here, an overview of the extensive strategies which have been developed to improve the functionality of ZIFs is provided, including linker modifications, functional hybridization of ZIFs via the encapsulation of guest species (such as metal and metal oxide nanoparticles and biomolecules) into ZIFs, and hybridization with polymeric matrices to form mixed matrix membranes for industrial gas and liquid separations. Furthermore, the developed strategies for achieving size and shape control of ZIF nanocrystals are considered, which are important for optimizing the textural characteristics as well as the functional performance of ZIFs and their derived materials/hybrids. Moreover, the recent trends of using ZIFs as templates for the derivation of nanoporous hybrid materials, including carbon/metal, carbon/oxide, carbon/sulfide, and carbon/phosphide hybrids, are discussed. Finally, some perspectives on the potential future research directions and applications for ZIFs and ZIF-derived materials are offered. PMID- 28833625 TI - Physical activity, cardiorespiratory fitness, and metabolic outcomes in monozygotic twin pairs discordant for body mass index. AB - This study aims to investigate (i) how monozygotic (MZ) twin pairs who are discordant for body mass index (BMI) differ for objectively and subjectively measured physical activity (PA) and cardiorespiratory fitness (VO2 max) and (ii) associations of PA and VO2 max with adiposity and measures of metabolic health, in individual twins and independent of genetic and shared environmental effects within twin pairs. We examined 27 BMI-discordant and 14 BMI-concordant MZ twin pairs. Fat and fat-free mass (ffm) were measured by dual-energy X-ray absorptiometry and VO2 max by spiroergometry. PA was measured objectively by accelerometers using ActiGraph GT1M for daytime activity and Actiwatch AW7 for 24 h/d. Self-reported PA was obtained through the Baecke and IPAQ long-form questionnaires. Objectively measured moderate-to-vigorous PA (MVPA, min/d), steps/d, and VO2 max/kg were significantly lower, by 30%, 21%, and 14%, respectively, in the heavier compared with the leaner co-twins of the BMI discordant twin pairs. There were no significant differences in self-reported PA or VO2 max/ffm. As expected, PA and VO2 max/ffm were similar in the BMI concordant co-twins. Furthermore, the 24-h recording of activity suggested that the heavier co-twins had more restless sleep during the night, whereas the leaner co-twins were more active during the day. Within all twin pairs, higher MVPA and steps per day were associated with lower fat percentage and improved metabolic health measures. Objectively, but not subjectively measured PA is associated with lower fat percentage and better metabolic health, independent of genetic and shared environmental factors. PMID- 28833626 TI - Cardiac imaging to detect coronary artery disease in athletes aged 35 years and older. A scoping review. AB - Sudden cardiac death (SCD) is a devastating event in athletes. Screening efforts that were first directed at athletes younger than 35 years are now focusing on the rapidly growing group of older sportspersons. Athletes aged >=35 years have a 10-fold increased risk of exercise-related cardiac arrest, mostly due to coronary artery disease (CAD). Although cardiac imaging is pivotal in identifying CAD, the role of imaging modalities in screening asymptomatic older sportspersons remains unclear. We performed a scoping review to identify the role of cardiac imaging to detect CAD in older sportspersons and to identify gaps in the existing literature. We searched MEDLINE, EMBASE and the Cochrane library for studies reporting data on cardiac imaging of CAD in sportspersons >=35 years. The systematic search yielded 1737 articles, and 14 were included in this scoping review. Imaging modalities included two echocardiography, one unenhanced computed tomography (CT) for coronary artery calcium scoring (CACS), three CACS and contrast-enhanced CT angiography (CCTA), two CACS and cardiac magnetic resonance (CMR), one CCTA with CMR and echocardiography, two CCTA, two CMR, and one myocardial perfusion imaging article. The low number of relevant articles and the selection bias introduced by studying specific groups, like veteran marathon runners, indicate the need for future research. Cardiac CT (CACS and CCTA) probably has the highest potential for pre-participation screening, with high diagnostic value to detect CAD and low radiation dose. However, currently there is insufficient evidence for incorporating routine cardiac imaging in the pre participation screening of asymptomatic sportspersons over 35 years. PMID- 28833627 TI - Deconstructing Quinoline-Class Antimalarials to Identify Fundamental Physicochemical Properties of Beta-Hematin Crystal Growth Inhibitors. AB - A versatile approach to control crystallization involves the use of modifiers, which are additives that interact with crystal surfaces and alter their growth rates. Elucidating a modifier's binding specificity to anisotropic crystal surfaces is a ubiquitous challenge that is critical to their design. In this study, we select hematin, a byproduct of malaria parasites, as a model system to examine the complementarity of modifiers (i.e., antimalarial drugs) to beta hematin crystal surfaces. We divide two antimalarials, chloroquine and amodiaquine, into segments consisting of a quinoline base, common to both drugs, and side chains that differentiate their modes of action. Using a combination of scanning probe microscopy, bulk crystallization, and analytical techniques, we show that the base and side chain work synergistically to reduce the rate of hematin crystallization. In contrast to general observations that modifiers retain their function upon segmentation, we show that the constituents do not act as modifiers. A systematic study of quinoline isomers and analogues shows how subtle rearrangement and removal of functional moieties can create effective constituents from previously ineffective modifiers, along with tuning their inhibitory modes of action. These findings highlight the importance of specific functional moieties in drug compounds, leading to an improved understanding of modifier-crystal interactions that could prove to be applicable to the design of new antimalarials. PMID- 28833629 TI - Olfactory bulb drives respiration-coupled beta oscillations in the rat hippocampus. AB - The synchronization of neuronal oscillations has been suggested as a mechanism to coordinate information flow between distant brain regions. In particular, the olfactory bulb (OB) and the hippocampus (HPC) have been shown to exhibit oscillations in the beta frequency range (10-20 Hz) that are likely to support communication between these structures. Here, we further characterize features of beta oscillations in OB and HPC of rats anesthetized with urethane. We find that beta oscillations simultaneously appear in HPC and OB and phase-lock across structures. Moreover, Granger causality analysis reveals that OB beta activity drives HPC beta. The laminar voltage profile of beta in HPC shows the maximum amplitude in the dentate gyrus (DG), spatially coinciding with olfactory inputs to this region. Finally, we also find that the respiratory cycle and respiration coupled field potential rhythms (1-2 Hz)-but not theta oscillations (3-5 Hz) modulate beta amplitude in OB and HPC. In all, our results support the hypothesis that beta activity mediates the communication between olfactory and hippocampal circuits in the rodent brain. PMID- 28833628 TI - Neural androgen receptor overexpression affects cell number in the spinal nucleus of the bulbocavernosus. AB - The spinal nucleus of the bulbocavernosus (SNB) is a sexually dimorphic neuromuscular system in which the masculinisation of cell number is assumed to depend on the action of perinatal androgen in non-neural targets, whereas the masculinisation of cell size is assumed to depend primarily on the action of adult androgen on SNB cells themselves. To test these hypotheses, we characterised the SNB of Cre/loxP transgenic mice that overexpress androgen receptor (AR) throughout the body (CMV-AR) or in neural tissue only (Nestin-AR). Additionally, we examined the effects of androgen manipulation in male mutants and wild-type (WT) controls. We reproduced the expected sex differences in both motoneurone number and size, as well as the expected adult androgen dependence of SNB size. We found effects of genotype such that both Nestin-AR and CMV-AR have more SNB motoneurones than WT littermates and also that CMV-AR females have larger SNB motoneurones than Nes-AR or WT females. These results raise the possibility that AR can act in neurones and/or glia to rescue SNB motoneurones, as well as on non-neural AR to increase SNB cell size. PMID- 28833630 TI - Potentially malignant disorders-The case for intervention. AB - Potentially malignant disorders (PMD) are recognisable mucosal conditions preceding invasive squamous carcinoma development. Established oral cancer remains a lethal and deforming disease, with a rising incidence. Management techniques for identifiable oral precursor lesions have traditionally been polarised between observational and interventional surgical techniques. By defining salient management goals for treating potentially malignant disease, and examining the evidence supporting the efficacy of treatment intervention, this paper presents the case for interventional laser surgery as a definitive diagnostic and treatment modality. PMID- 28833631 TI - The use of the radial artery following transradial catheterization-A word of caution. PMID- 28833632 TI - Left ventricular strain in aortic stenosis-A more sensitive predictor for earlier aortic valve replacement? PMID- 28833633 TI - Staged open repair for a complex adult aortic coarctation. AB - We describe a two-stage open repair for a complex aortic coarctation in an adult. A total arch replacement with an elephant trunk was performed via a median sternotomy followed in 10 days by a replacement of the descending aorta through a left thoracotomy. PMID- 28833634 TI - Long-term endothelial dysfunction after trans-radial catheterization: A meta analytic approach. AB - BACKGROUND: Following cardiac catheterization using radial artery (RA) access, persistent endothelial dysfunction may limit the use of RA as a conduit during coronary artery bypass graft (CABG) surgery. We reviewed published literature to investigate the effects of transradial coronary catheterization on RA endothelial function. METHODS: We searched PubMed from inception to April 2017 for published studies assessing RA endothelial function late (>=1 month) after coronary catheterization. A total of 12 eligible published studies (n = 490 patients) were included in the final quantitative synthesis. Statistical heterogeneity among studies was assessed by the I2 . A random effects model was used to calculate the pooled estimate for standardized mean difference (SMD). Meta-regression analysis was used to explore predictors of change in RA endothelial function following catheterization. RESULTS: In all studies, a significant reduction in endothelium dependent response was observed post-catheterization (SMD = -0.53, 95% confidence interval [CI]: -0.93 to -0.13, P = 0.01) and a marginal, non-significant, reduction in endothelium independent response (SMD = -0.38, 95%CI: -0.77, 0.01, P < 0.059). In controlled studies, using the contralateral RA as a control, a significant impairment in endothelial function was confirmed (SMD = -6.26, 95%CI: -9.71 to -2.81, P < 0.0001), while the change in endothelium-independent response was not significant (SMD = -4.46, 95%CI: -13.3 to 4.37, P = 0.32). In meta regression analysis male gender (z = 2.36, P = 0.018) and increasing time following catheterization (z = 2.62, P = 0.009) were associated with less RA endothelial dysfunction. CONCLUSIONS: Transradial catheterization impairs endothelium dependent vasodilatory properties of the cannulated RA, which do not recover even several months post-catheterization. Non-recovery of vasomotor function of cannulated RAs may limit their use as arterial grafts during CABG surgery. PMID- 28833635 TI - Management of atrial thrombus formation following surgical closure of an atrial septal defect. AB - Acute thrombus formation on pericardial patches used to close atrial septal defects (ASDs) is uncommon. We present two patients with thrombus formation on native pericardial patches following ASD closure and discuss the management of this complication. PMID- 28833637 TI - Concomitant transfemoral transcatheter aortic and mitral valve-in-valve replacement. AB - The valve-in-valve (viv) procedure has been shown to be effective in treating patients with a degenerated bioprosthesis who are also considered high risk or inoperable for a reoperation. We describe a case of concomitant transfemoral transcatheter viv aortic and mitral valve replacements. PMID- 28833636 TI - Heterogeneity of systolic dysfunction in patients with severe aortic stenosis and preserved ejection fraction. AB - BACKGROUND AND AIM: Left ventricular (LV) systolic strain has been shown to be an early marker of LV dysfunction in patients with severe aortic stenosis (AS) despite preserved ejection fraction (EF). Echocardiography has provided useful data on regional LV strain patterns, but is not as sensitive as magnetic resonance imaging (MRI). No prior studies have used MRI-based strain analysis to characterize regional three-dimensional strain in patients with severe AS. METHODS: Twelve patients with severe AS and preserved EF underwent MRI-based multiparametric strain analysis. Circumferential and longitudinal strain values were calculated at individual points throughout the LV and analyzed in 12 discrete regions. Strain values were compared to a database of normal controls. RESULTS: Compared to control patients, circumferential strain in AS patients was significantly reduced at the base (P = 0.002), mid (P = 0.042), and inferior walls (P < 0.001). Longitudinal strain was significantly reduced at the base (P < 0.001), mid (P < 0.001), anterior (P < 0.001), and septal (P < 0.001) walls. Among patients with AS, there was heterogeneity in the location and severity of abnormalities in circumferential and longitudinal strains despite the presence of a preserved EF and lack of prior myocardial infarction. CONCLUSIONS: LV systolic strain is significantly impaired in patients with AS and preserved EF compared to healthy volunteers. Abnormalities in circumferential and longitudinal strains were heterogeneously distributed across the LV of patients with AS, allowing us to identify sentinel regions that may reflect the earliest signs of developing LV dysfunction. PMID- 28833638 TI - Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition. AB - Brequinar, a potent dihydroorotate dehydrogenase (DHODH) inhibitor, has been evaluated in multiple clinical trials as a potential treatment for cancer. To further understand brequinar-based DHODH inhibition and DHODH's therapeutic relevance in cancer, we have developed novel brequinar-based probes. We disclose a 16-step convergent synthesis of the first brequinar-PROTAC and a four-step approach towards the first mitochondrial-directed brequinar probe. A PROTAC and mitochondria-directed probe of brequinar both possess cytotoxicity that is superior to brequinar in a colony formation assay. PMID- 28833639 TI - Expression and significance of Pim-3 kinase in adult T-cell leukemia. AB - BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Viral Tax protein plays a major role in ATL development. Pim family of serine/threonine kinases is composed of Pim-1, -2, and -3. The potential of Pim family as a target in ATL was analyzed. METHODS: RT-PCR and Western blotting were used to determine the expression of Pim kinases, Tax, and intracellular signal molecules. Knockdown of Pim-3 and RelA was performed using small interfering RNA. The effects on cell proliferation, viability, cell cycle, and apoptosis were analyzed by WST-8, propidium iodide, and APO2.7 assay. NF kappaB DNA binding activity was investigated by electrophoretic mobility shift assay. RESULTS: Pim-3 expression was restricted to HTLV-1-infected T-cell lines. Tax induced Pim-3 expression through NF-kappaB. Knockdown of Pim-3 showed growth inhibition of HTLV-1-infected T cells. NJC97-NH, a novel inhibitor of the Pim-1/3 kinases, inhibited cell viability. NJC97-NH induced G2/M cell cycle arrest associated with downregulation of cyclin A and cyclin B1 expression, as well as apoptosis accompanied with downregulation of XIAP and Mcl-1 expression through inhibition of NF-kappaB pathway, mediated through decrease in IkappaBalpha and RelA phosphorylation. CONCLUSION: Pim-3 is a potentially suitable target for the development of novel therapeutic agents against ATL. PMID- 28833640 TI - Flexible Electrodes for Sodium-Ion Batteries: Recent Progress and Perspectives. AB - Sodium-ion batteries (SIBs) are considered as promising alternatives to lithium ion batteries (LIBs) for large-scale electrical-energy-storage applications due to the wide availability and the low cost of Na resources. Along with the avenues of research on flexible LIBs, flexible SIBs are now being actively developed as one of the most promising power sources for the emerging field of flexible and wearable electronic devices. Here, the recent progress on flexible electrodes based on metal substrates, carbonaceous substrates (i.e., graphene, carbon cloth, and carbon nanofibers), and other materials, as well as their applications in flexible SIBs, are summarized. Also, some future research directions for constructing flexible SIBs are proposed, with the aim of providing inspiration to the further development of advanced flexible SIBs. PMID- 28833641 TI - Transition-Metal-Controlled Inorganic Ligand-Supported Non-Precious Metal Catalysts for the Aerobic Oxidation of Amines to Imines. AB - Most state-of-art transition-metal catalysts usually require organic ligands, which are essential for controlling the reactivity and selectivity of reactions catalyzed by transition metals. However, organic ligands often suffer from severe problems including cost, toxicity, air/moisture sensitivity, and being commercially unavailable. Herein, we show a simple, mild, and efficient aerobic oxidation procedure of amines using inorganic ligand-supported non-precious metal catalysts 1, (NH4 )n [MMo6 O18 (OH)6 ] (M=Cu2+ ; Fe3+ ; Co3+ ; Ni2+ ; Zn2+ , n=3 or 4), synthesized by a simple one-step method in water at 100 degrees C, demonstrating that the catalytic activity and selectivity can be significantly improved by changing the central metal atom. In the presence of these catalysts, the catalytic oxidation of primary and secondary amines, as well as the coupling of alcohols and amines, can smoothly proceed to afford various imines with O2 (1 atm) as the sole oxidant. In particular, the catalysts 1 have transition-metal ion core, and the planar arrangement of the six MoVI centers at their highest oxidation states around the central heterometal can greatly enhance the Lewis acidity of catalytically active sites, and also enable the electrons in the center to delocalize onto the six edge-sharing MO6 units, in the same way as ligands in traditional organometallic complexes. The versatility of this methodology maybe opens a path to catalytic oxidation through inorganic ligand coordinated metal catalysis. PMID- 28833642 TI - Organocatalytic Asymmetric Synthesis of trans-gamma-Lactams. AB - An N-heterocyclic carbene (NHC)-catalyzed highly diastereo- and enantioselective formal [3+2] reaction of o-hydroxy aromatic aldimines and cinnamaldehydes for the preparation of enantioenriched trans-gamma-lactams was developed. An internal hydrogen bond between the o-hydroxy and the imine function was crucial for the reactivity and chemical selectivity. Trans-gamma-lactam 3 d was easily oxidized to multifunctional 1,4-benzoquinone 8, which could further be transformed to biaryl 9 in the presence of a phosphoric acid. Finally, preliminary results for a kinetic resolution of (+/-)-trans-gamma-lactam 3 d under asymmetric NHC catalysis are reported. PMID- 28833643 TI - 1D Coordination Polymer Nanofibers for Low-Temperature Photothermal Therapy. AB - Near-infrared (NIR)-light-triggered photothermal therapy (PTT) usually requires hyperthermia to >50 degrees C for effective tumor ablation, which can potentially induce inflammatory disease and heating damage of normal organs nearby, while tumor lesions without sufficient heating (e.g., the internal part) may survive after treatment. Achieving effective tumor killing under relatively low temperatures is thus critical toward successful clinical use of PTT. Herein, we design a simple strategy to fabricate poly(ethylene glycol) (PEG)-modified one dimensional nanoscale coordination polymers (1D-NCPs) with intrinsic biodegradability, large surface area, pH-responsive behaviors, and versatile theranostic functions. With NCPs consisting of Mn2+/indocyanine green (ICG) as the example, Mn-ICG@pHis-PEG display efficient pH-responsive tumor retention after systemic administration and then load Gambogic acid (GA), a natural inhibitor of heat-shock protein 90 (Hsp90) that plays an essential role for cells to resist heating-induced damage. Such Mn-ICG@pHis-PEG/GA under a mild NIR triggered heating is able to induce effective apoptosis of tumor cells, realizing low-temperature PTT (~43 degrees C) with excellent tumor destruction efficacy. This work not only develops a facile approach to fabricate PEGylated 1D-NCPs with tumor-specific pH responsiveness and theranostic functionalities, but also presents a unique low-temperature PTT strategy to kill cancer in a highly effective and minimally invasive manner. PMID- 28833644 TI - Ultrathin Quantum Dot Display Integrated with Wearable Electronics. AB - An ultrathin skin-attachable display is a critical component for an information output port in next-generation wearable electronics. In this regard, quantum dot (QD) light-emitting diodes (QLEDs) offer unique and attractive characteristics for future displays, including high color purity with narrow bandwidths, high electroluminescence (EL) brightness at low operating voltages, and easy processability. Here, ultrathin QLED displays that utilize a passive matrix to address individual pixels are reported. The ultrathin thickness (~5.5 um) of the QLED display enables its conformal contact with the wearer's skin and prevents its failure under vigorous mechanical deformation. QDs with relatively thick shells are employed to improve EL characteristics (brightness up to 44 719 cd m-2 at 9 V, which is the record highest among wearable LEDs reported to date) by suppressing the nonradiative recombination. Various patterns, including letters, numbers, and symbols can be successfully visualized on the skin-mounted QLED display. Furthermore, the combination of the ultrathin QLED display with flexible driving circuits and wearable sensors results in a fully integrated QLED display that can directly show sensor data. PMID- 28833645 TI - Swiss S1 guideline for the treatment of rosacea. AB - Rosacea (in German sometimes called 'Kupferfinne', in French 'Couperose' and in Italian 'Copparosa') is a chronic and frequently relapsing inflammatory skin disease primarily affecting the central areas of the face. Its geographic prevalence varies from 1% to 22%. The differential diagnosis is wide, and the treatment is sometimes difficult and varies by stage of rosacea. For erythematous lesions and telangiectasia, intense pulsed light (IPL) therapy and lasers are popular treatment option. In addition, a vasoconstrictor agent, brimonidine, has recently been developed. For papulopustular rosacea, topical antibiotics, topical and systemic retinoids, as well as systemic antibiotics are used. A topical acaricidal agent, ivermectin, has undergone clinical development and is now on the market. In the later stages, hyperplasia of the sebaceous glands develops, resulting in phymatous growths such as the frequently observed bulbous nose or rhinophyma. Ablative laser treatments have largely replaced classical abrasive tools. Here, we reviewed the current evidence on the treatment of rosacea, provide a guideline (S1 level) and discuss the differential diagnosis of rosacea. PMID- 28833646 TI - Synthesis of Sialic Acids, Their Derivatives, and Analogs by Using a Whole-Cell Catalyst. AB - Sialic acids (Sias) are important constituents of cell surface glycans. Ready access to Sias in large quantities would facilitate the development of carbohydrate-based vaccines and small-molecule drugs. We now present a facile method for synthesizing various natural forms and non-natural derivatives or analogs of Sias by using a whole-cell catalyst, which is constructed by adding a plasmid containing necessary enzyme genes into a metabolically engineered strain of Escherichia coli. The flexible substrate tolerance of incorporated enzymes (N acetylglucosamine 2-epimerase and N-acetylneuraminic acid aldolase) allows the cellular catalyst to convert a wide range of simple and inexpensive sugars into various Sia-related compounds through an easily scalable fermentation process. Further, syntheses using this whole-cell biotransformation in combination with three conventional enzymatic reactions provide a series of complex Sia-containing glycans (sialyloligosaccharides) and their derivatives bearing different substituents. The processes described herein should permit the large-scale and economical production of both Sias and sialyloligosaccharides, and may complement existing chemical and enzymatic strategies. PMID- 28833647 TI - Rheumatoid arthritis in review: Clinical, anatomical, cellular and molecular points of view. AB - Rheumatoid arthritis (RA) is the most common chronic autoimmune disease of the joints affecting close to 0.5-1.0% of the general population. Although the etiopathogenesis of RA remains elusive, the involvement of dendritic cells and type 17 T-helper cells appears to be pivotal in maintaining a state of chronic inflammation. RA is generally characterized by small joint involvement. A chronic inflammatory process leads to joint destruction and to tendon and ligament laxity and disintegration. These processes result in an imbalance of forces acting on the joints causing joint deformities including swan neck deformity, boutonniere deformity of the hands, flexion deformity of the wrist, lesser toe deformities, and others. In some instances, bony erosions subsequent to the RA disease process can result in life-threatening events including, for example, atlanto-axial subluxation, which can cause myelopathy and paralysis; and basilar invagination, which can cause brain stem injury and imminent death. Although less commonly involved, larger joints are not spared, as evidenced by the involvement of the elbow, hip, and shoulder joints in a sizable proportion of RA patients. The progression and prognosis of this disease entity are variable, guarded and dependent on the efficacy and response to treatment modalities employed. Inadequate management results in disease progression, which ultimately leads to joint erosion, destruction, deformities and substantial decrease in the functional quality of life. Clin. Anat. 31:216-223, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28833648 TI - The impact of atopic dermatitis on work life - a systematic review. AB - Atopic dermatitis (AD) has considerable multidimensional personal and societal costs. However, the extend to which the patient's work life is affected due to AD is more sparsely described in the literature. The objective of this review was to examine the impact on work life for patients with AD, with a specific focus on choice of education and occupation, sick leave, social compensations and change of job due to AD. A systematic literature search was performed in PubMed, EMBASE and Web og Science up to 7 February 2017 for articles on the impact on work life for patients with AD. Results were summarized taking several measures of study quality into account. The search identified twenty-three articles, whereof five studies assessed the influence of AD on educational or job choice, without any consistent conslusion, while eight of nine studies with respect to sick leave and two on disability pensions found AD to have a negative impact. Studies of change or loss of job and AD showed more diverse results, as not all studies documented a negative effect of AD on work life. Atopic dermatitis imposes a burden extending beyond personal, emotional and financial costs. This review strongly implies that AD affects sick leave, and though not fully clarified, possible also job choice, change or loss of job and even disability pensions for the more severe cases. PMID- 28833649 TI - ADAR1 splicing mutation leading to dyschromatosis hereditaria in a Caucasian patient. PMID- 28833650 TI - Anion-Functionalized Pillararenes for Efficient Sulfur Dioxide Capture: Significant Effect of the Anion and the Cavity. AB - A series of anion-functionalized pillararenes were prepared and applied in the capture of SO2 through incorporating an anion with different basicity into pillararenes. A high SO2 absorption capacity up to 15.9 mmol g-1 and excellent reversibility were achieved by tuning the basicity of the anion and the size of the cavity. Spectroscopic investigations and DFT calculations indicated that high SO2 capacity originated from multiple sites interaction between SO2 and the anion, where SO2 chemical absorption was significant strengthened by the cavity, because the anion was confined in the window of the cavity and the window was electron-deficient. Interestingly, a phase transition occurred during absorption and desorption process. The method proposed in this work provided an efficient strategy for improving gas absorption through a simple functionalization of the supermolecule, which was also very important for some other fields such as polymers and materials. PMID- 28833651 TI - Fetal major cardiac defects and placental dysfunction at 11-13 weeks' gestation. AB - OBJECTIVE: To investigate the relationship between fetal major cardiac defects and markers of placental perfusion and function. METHODS: This was a prospective screening study in singleton pregnancies at 11-13 weeks' gestation. Uterine artery pulsatility index (UtA-PI), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were measured and the values were converted into multiples of the normal median (MoM). Median MoM values in fetuses with isolated major cardiac defects were compared with those in fetuses without major defects. RESULTS: The 50 094 singleton pregnancies fulfilling the entry criteria included 49 898 pregnancies with normal cardiac anatomy and 196 (0.39%) with major congenital cardiac defects: 73 (37.2%) with conotruncal defects, 63 (32.1%) with left ventricular outflow tract defects and 60 (30.6%) with valvular defects. In the group with cardiac defects, compared with controls, there was lower median PAPP-A MoM (0.81 vs 1.00, P < 0.0001) and PlGF MoM (0.78 vs 1.00, P < 0.0001) but no significant difference in UtA-PI MoM (1.01 vs 1.00, P = 0.162). CONCLUSION: In pregnancies with isolated fetal major cardiac defects, there is evidence of placental dysfunction in the absence of impaired placental perfusion. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28833653 TI - Spatial and Temporal Modulation of Thermal Emission. AB - Precise control of a material's emissivity is critical for thermal-engineering applications. Metamaterials, which derive their optical properties from sub wavelength structures, have emerged as a promising way to tune emissivity over a wide parameter space. However, metamaterial designs have not yet achieved simultaneous spatial and temporal control of emissivity, which is important for advanced engineering applications such as adaptive thermal management and reconfigurable infrared camouflage. Here, spatiotemporal emissivity control is demonstrated by designing and fabricating a large-area, infrared metamaterial that is modulated with ultraviolet (UV) light. The UV light generates free carriers in a photosensitive ZnO spacer layer, which changes the metamaterial optical properties and causes a localized increase in emissivity. Thermal imaging of the metamaterial during UV illumination reveals an apparent temperature increase as a result of the emissivity change. The imaged temperature fluctuation is recorded under exposure from a temporally modulated and spatially patterned UV illumination source to characterize both the temporal response and spatial resolution of the emissivity change. The results of this work demonstrate new capabilities for thermal metamaterials that could bring about the next generation of thermal-engineering devices. PMID- 28833652 TI - Bateman purpura (dermatoporosis): a localized scurvy treated by topical vitamin C - double-blind randomized placebo-controlled clinical trial. AB - BACKGROUND: Bateman purpura is characterized by diffuse senile skin atrophy, senile purpura and spontaneous stellar pseudocicatrices. Cutaneous changes in the course of ageing have been related to lower levels of ascorbic acid into the dermis of elderly people. OBJECTIVE: In this study, we postulate that senile purpura could be linked to dermal vitamin C deficiency and could be corrected by topical administration of this vitamin. METHODS: A 12-weeks, hemi-member (forearm or leg), randomized double-blind comparative study was conducted in 18 patients with Bateman purpura aged over than 60 years. At each visit, clinical assessment and biometrological measurements were performed. Clinical examination and scoring by experts showed a significant improvement on the vitamin C-treated side compared with the control, with reduction of haemorrhage areas, increase of dermal thickness. RESULTS: Twice-daily application of 5% topical vitamin C led to a clinically apparent improvement of the skin symptoms and allows beneficial effects on skin elasticity and thickness. Bateman purpura, a classical sign of photoaging whose origin has not clearly been recognized could be improved by vitamin C applied on to the skin. CONCLUSION: These results confirm the hypothesis of the underlying role of vitamin C deficiency in the determinism of Bateman purpura. PMID- 28833654 TI - Localized argyria: troublesome side-effect of acupuncture. PMID- 28833655 TI - Validity and reliability of the COHIP-SF in Australian children with orofacial cleft. AB - AIM: To measure the validity and reliability of the Child Oral Health Impact Profile-Short Form (COHIP-SF) in Australian children with orofacial cleft (OFC) and to evaluate the need for a proxy report. DESIGN: Children with OFC and their proxy completed a COHIP-SF questionnaire. Items were divided into oral health, functional and socio-emotional subscales, and scores on all subscales were compared between and within groups. RESULTS: A total of 222 children (average age 11.3, SD = 3.5, range 8.0-14.0) and 215 proxies completed the COHIP-SF, with similar mean scores of 50.8 (SD = 13.7) and 48.1 (SD = 14.0). Excellent internal consistency reliability (Cronbach's alpha 0.9) and convergent validity was evident (P < 0.001); however, discriminant validity was weaker. There was strong correlation between child and proxy reports (Pearson's r = 0.7), and intraclass correlation coefficients were high indicating good child/proxy agreement. Older children had poor socio-emotional well-being (P < 0.004), and children with bilateral cleft lip and palate (CL/P) and velopharyngeal insufficiency/submucous cleft (VPI/SMC) had poor functional well-being. Those with private health insurance reported better oral health-related quality of life (OHRQoL) (P < 0.05). CONCLUSION: The COHIP-SF is a valid and reliable measure for measuring OHRQoL in Australian children with OFC. Proxy reports did not add further information regarding a child's OHRQoL. PMID- 28833656 TI - The in vitro antibacterial activity of incomplete iron salt of polyacrylic acid against Pseudomonas aeruginosa, meticillin-resistant Staphylococcus pseudintermedius and meticillin-resistant S. aureus. AB - BACKGROUND: The incomplete iron salt of polyacrylic acid (IIS-PAA) has been used for its haemostatic, wound healing and antibacterial properties in human patients. IIS-PAA is a water-soluble, acidic, hydrophilic polymer that is active at pH 2.9-4.0. HYPOTHESES/OBJECTIVES: To evaluate the antibacterial effect of IIS PAA against Pseudomonas aeruginosa, meticillin-resistant Staphylococcus pseudintermedius (MRSP) and meticillin-resistant S. aureus (MRSA). METHODS: This was a prospective, nonblinded in vitro study. Sixty canine isolates of P. aeruginosa, MRSP and MRSA were included. Minimum inhibitory concentrations (MICs) of IIS-PAA were determined by agar dilution on Mueller-Hinton agar using testing concentrations ranging from 0.0625-0.4% (raw material 100%) and based on Clinical and Laboratory Standards Institute guidelines. RESULTS: The median MIC for P. aeruginosa was 0.2% (range 0.2-0.3%), mean 0.2% and standard deviation (SD) of 0.018%. The median MIC for MRSP was 0.05% (0.025-0.1%), mean 0.058% and SD 0.022%, and the median MIC for MRSA was 0.1% (0.00625-0.4%), mean 0.126% and SD 0.080%. There were significant differences in MICs between the three bacteria types with MICs highest for Pseudomonas and lowest for MRSP (all P < 0.0001). CONCLUSIONS: IIS-PAA had in vitro antibacterial activity against three important bacterial pathogens. Further studies of IIS-PAA are indicated to assess the potential clinical benefit and in vitro studies to investigate the spectrum of anti-bacterial activity and mode of action. PMID- 28833657 TI - Bridging Coordination of Vinylarenes to Pd3 - or Pd4 Cluster Sites. AB - Though the M3 - or M4 face of palladium clusters may serve as the active binding site of substrates, it has been difficult to elucidate their substrate binding modes in solution. Here, it was proved that a soluble Pd3 - or Pd4 sheet cluster accommodates vinylarenes at its bridging coordination site in an unusual mode in palladium chemistry; that is, for the former, the coordination of the arene moiety precedes that of olefin moiety; for the latter, vinylarene coordinates to a distorted Pd4 sheet through oxidative pi-addition of its styrene moiety. PMID- 28833659 TI - Robust Macroscopic 3D Sponges of Manganese Oxide Molecular Sieves. AB - The construction of macroscopic 3D sponges is of great technological importance for various applications. An outstanding challenge is the facile fabrication of sponges with the desirable combination of good stability, high electrical conductivity, and absorption ability. Here free-standing 3D OMS-2 sponges are demonstrated, with various densities, which possess a combination of desirable physical properties including high porosity, robustness, permeability, recyclability, high electrical conductivity, and selective water absorption in preference to oil. Some of these properties have systematic trends with various densities. The stress of the OMS-2 sponge, made by nanowire-based freeze-drying process, is four orders of magnitude higher than that made by calcination-related process. These new materials should find practical applications in environmental, catalysis, sensing, absorption, and energy storage, particularly in the removal of water spill cleanup, and beyond. PMID- 28833658 TI - Valproic Acid-Functionalized Cyclometalated Iridium(III) Complexes as Mitochondria-Targeting Anticancer Agents. AB - Valproic acid (VPA) is a short-chain, fatty acid type histone deacetylase inhibitor (HDACi), which can cause growth arrest and induce differentiation of transformed cells. Phosphorescent cyclometalated IrIII complexes have emerged as potential anticancer agents. By conjugation of VPA to IrIII complexes through an ester bond, VPA-functionalized cyclometalated iridium(III) complexes 1 a-3 a were designed and synthesized. These complexes display excellent two-photon properties, which are favorable for live-cell imaging. The ester bonds in 1 a-3 a can be hydrolyzed quickly by esterase and display similar inhibition of HDAC activity to VPA. Notably, 1 a-3 a can overcome cisplatin resistance effectively and are about 54.5-89.7 times more cytotoxic than cisplatin against cisplatin resistant human lung carcinoma (A549R) cells. Mechanistic studies indicate that 1 a-3 a can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, accumulate in mitochondria, and induce a series of cell-death related events mediated by mitochondria. This study gives insights into the design and anticancer mechanisms of multifunctional anticancer agents. PMID- 28833660 TI - Manganese-Mediated Linkage of Perchlorate to Aminotetrazoles Produces Twice the Energy Density of the Unmetalated Salt. AB - New regimes of energy density in energetic materials may be achieved by replacement of oxidizing nitro groups with stronger oxidants such as oxychlorine species. We report the energetic material 1,3-di-tert-butyltetrazolium-5 imidoperchloratomanganese(II) 2, which crystallizes as an oligomeric cubane cluster. Bomb calorimetry on the amorphous, solvent-free phase gives an energy density of at least 40+/-3 MJ L- , higher than hydrocarbon combustion in air, more than twice that of traditional energetic nitramines, and ~70 % higher than that of the unmetalated tetrazolium perchlorate salt without metal linkage. The effects of solid-state structure, charge, and lattice energy on the energy of 2 are discussed. PMID- 28833661 TI - Significant Performance Enhancement of Polymer Resins by Bioinspired Dynamic Bonding. AB - Marine mussels use catechol-rich interfacial mussel foot proteins (mfps) as primers that attach to mineral surfaces via hydrogen, metal coordination, electrostatic, ionic, or hydrophobic bonds, creating a secondary surface that promotes bonding to the bulk mfps. Inspired by this biological adhesive primer, it is shown that a ~1 nm thick catecholic single-molecule priming layer increases the adhesion strength of crosslinked polymethacrylate resin on mineral surfaces by up to an order of magnitude when compared with conventional primers such as noncatecholic silane- and phosphate-based grafts. Molecular dynamics simulations confirm that catechol groups anchor to a variety of mineral surfaces and shed light on the binding mode of each molecule. Here, a ~50% toughness enhancement is achieved in a stiff load-bearing polymer network, demonstrating the utility of mussel-inspired bonding for processing a wide range of polymeric interfaces, including structural, load-bearing materials. PMID- 28833662 TI - Survival after lung transplantation in recipients with alpha-1-antitrypsin deficiency compared to other forms of chronic obstructive pulmonary disease: a national cohort study. AB - Alpha-1-antitrypsin deficiency (AATD) is grouped with chronic obstructive pulmonary disease (COPD); however, this may not be appropriate. This study assessed whether AATD confers a different prognosis than COPD following lung transplantation. We employed the United Network for Organ Sharing (UNOS) database, grouping patients by diagnoses of AATD or COPD. Kaplan-Meier methods and Cox modeling were performed to determine the association of diagnosis and overall survival. Of 9569 patients, 1394 (14.6%) had a diagnosis of AATD. Patients with AATD who received a single-lung transplant had reduced 1-year survival [adjusted hazard ratio (AHR): 1.68, 95% CI: 1.26, 2.23]. Among patients who received a bilateral lung transplant, there was no significant difference in survival by diagnosis (AHR for AATD as compared to COPD: 0.96, 95% CI: 0.82, 1.12). After the implementation of the lung allocation score (LAS), there was no significant difference in survival among patients who received a single (AHR: 1.15, 95% CI: 0.69, 1.95) or bilateral (AHR: 0.99, 95% CI: 0.73, 1.34) lung transplant by diagnosis. Lung transplantation is increasingly employed in the care of the patient with COPD. Although recipients undergoing LTX for AATD are at increased risk of both acute rejection and airway dehiscence post-transplant, in the post-LAS era, survival rates are similar for recipients with AATD in comparison with COPD. PMID- 28833663 TI - Redox cycling induces spermptosis and necrosis in stallion spermatozoa while the hydroxyl radical (OH*) only induces spermptosis. AB - Oxidative stress is a major factor explaining sperm dysfunction of spermatozoa surviving freezing and thawing and is also considered a major inducer of a special form of apoptosis, visible after thawing, in cryopreserved spermatozoa. To obtain further insights into the link between oxidative stress and the induction of apoptotic changes, stallion spermatozoa were induced to oxidative stress through redox cycling after exposure to 2-methyl-1,4-naphthoquinone (menadione), or hydroxyl radical formation after FeSO4 exposure. Either exposure induced significant increases (p < 0.05) in two markers of lipid peroxidation: 8 iso-PGF2alpha and 4-hydroxynonenal (4-HNE). While both treatments induced changes indicative of spermptosis (caspase-3 activation and decreased mitochondrial membrane potential) (p < 0.01), menadione induced sperm necrosis and a dramatic reduction in motility and thiol content in stallion spermatozoa. Thus, we provided evidence that oxidative stress underlies spermptosis, and thiol content is a key factor for stallion sperm function. PMID- 28833664 TI - Compound-specific amino acid delta15 N values in archaeological shell: Assessing diagenetic integrity and potential for isotopic baseline reconstruction. AB - RATIONALE: Reconstructing stable isotope (SI) ratios at the base of paleo-food webs is often challenging. For coastal systems, the SI ratios of organic matter in archeological shell represents a possible solution, providing a direct record of primary consumer SI ratios in the littoral zone. However, shell is often porous, with organic compounds susceptible to diagenetic alteration or contamination. If molecular isotopic information is well preserved, compound specific amino acid isotope analysis (CSI-AA) has the potential to provide direct proxies for baseline SI ratios, bypassing many contamination issues, and to allow assessment of the diagenetic state. METHODS: We collected shell from both archeological middens and nearby littoral zones in coastal Alaska, and used a simple organic extraction approach based on decalcification with sequential weak HCl additions to liberate organic material. We measured CSI-AA patterns, molar AA distributions, and the CSI-AA degradation parameter (SigmaV), in the context of bulk SI ratios in fossil shell, modern shell, and soft tissue from five common taxa (urchin, limpet, mussel, periwinkle, chiton). RESULTS: CSI-AA patterns in both soft tissue and shell were consistent with primary consumers, and were indistinguishable in most modern and fossil shell pairs, showing that amino acid delta15 N values can be well preserved in archeological shell. AA molar distributions were also similar, although most fossil shell was enriched in Asx and Gly. Comparison between CSI-AA results from modern specimens confirmed that the source AA group (tracking isotopic baselines) are transferred without substantial modification into the shell record. In contrast, the Trophic AA group had elevated delta15 N values in shell versus soft tissue for all taxa examined, suggesting that a correction factor will be required for any CSI-AA proxies using these AAs. CONCLUSIONS: Overall, this new data indicates that the CSI-AA analysis of fossil shell represents a promising new approach to determining isotopic baselines in coastal paleo-ecosystems. PMID- 28833665 TI - Predictors of smoking relapse after percutaneous coronary intervention in Chinese patients. AB - AIMS AND OBJECTIVES: To evaluate the prevalence and predictors of smoking relapse after percutaneous coronary intervention in Chinese patients. BACKGROUND: Smoking is considered a vital risk factor for coronary heart disease. Although smoking cessation could decrease the risks of adverse cardiac outcomes, many patients resume smoking following a short period of abstinence. However, little is known about smoking resumption in patients who have undergone percutaneous coronary intervention. DESIGN AND METHODS: A longitudinal study was conducted among Chinese patients who underwent percutaneous coronary intervention. Predictive variables were assessed at baseline through medical records and interviews with questionnaires including the Fagerstrom Test for Nicotine Dependence, Center for Epidemiologic Studies-Depression scale and Smoking Self-Efficacy Questionnaire. Smoking relapses were recorded at three, six, nine and 12 months by the self reporting through telephone or at routine visits to the cardiology outpatient clinics. RESULTS: A total of 221 patients who quit smoking immediately after percutaneous coronary intervention completed the whole study. Overall, 51.1%(n = 113) of the patients relapsed within 12 months after percutaneous coronary intervention. The prevalence showed a particular rise (49.6%, n = 56) in the first 3 months and a more gradual increase in the following months. The patients who were employed and had higher nicotine dependence, worse depressive symptoms and lower level of smoking self-efficacy were more vulnerable to relapse to cigarettes. CONCLUSION: The prevalence of smoking relapse is high in the patients who stop smoking in the hospital due to percutaneous coronary intervention. The predictors of smoking relapse are employment, nicotine dependence, depression and smoking self-efficacy in the post- percutaneous coronary intervention patients. RELEVANCE TO CLINICAL PRACTICE: This study may prompt the healthcare providers to focus on the issue of smoking relapse and provide some instructions for identification of the patients with a high-risk of relapse after percutaneous coronary intervention. PMID- 28833666 TI - High Areal Capacity and Lithium Utilization in Anodes Made of Covalently Connected Graphite Microtubes. AB - Lithium metal is an attractive anode material for rechargeable batteries because of its high theoretical specific capacity of 3860 mA h g-1 and the lowest negative electrochemical potential of -3.040 V versus standard hydrogen electrode. Despite extensive research efforts on tackling the safety concern raised by Li dendrites, inhibited Li dendrite growth is accompanied with decreased areal capacity and Li utilization, which are still lower than expectation for practical use. A scaffold made of covalently connected graphite microtubes is reported, which provides a firm and conductive framework with moderate specific surface area to accommodate Li metal for anodes of Li batteries. The anode presents an areal capacity of 10 mA h cm-2 (practical gravimetric capacity of 913 mA h g-1 ) at a current density of 10 mA cm-2 , with Li utilization of 91%, Coulombic efficiencies of ~97%, and long lifespan of up to 3000 h. The analysis of structure evolution during charge/discharge shows inhibited lithium dendrite growth and a reversible electrode volume change of ~9%. It is suggested that an optimized microstructure with moderate electrode/electrolyte interface area is critical to accommodate volume change and inhibit the risks of irreversible Li consumption by side reactions and Li dendrite growth for high-performance Li-metal anodes. PMID- 28833667 TI - Dual-Nuclide Radiopharmaceuticals for Positron Emission Tomography Based Dosimetry in Radiotherapy. AB - Improvement of the accuracy of dosimetry in radionuclide therapy has the potential to increase patient safety and therapeutic outcomes. Although positron emission tomography (PET) is ideally suited for acquisition of dosimetric data because PET is inherently quantitative and offers high sensitivity and spatial resolution, it is not directly applicable for this purpose because common therapeutic radionuclides lack the necessary positron emission. This work reports on the synthesis of dual-nuclide labeled radiopharmaceuticals with therapeutic and PET functionality, which are based on common and widely available metal radionuclides. Dual-chelator conjugates, featuring interlinked cyclen- and triazacyclononane-based polyphosphinates DOTPI and TRAP, allow for strictly regioselective complexation of therapeutic (e.g., 177 Lu, 90 Y, or 213 Bi) and PET (e.g., 68 Ga) radiometals in the same molecular framework by exploiting the orthogonal metal ion selectivity of these chelators (DOTPI: large cations, such as lanthanide(III) ions; TRAP: small trivalent ions, such as GaIII ). Such DOTPI TRAP conjugates were decorated with 3 Gly-urea-Lys (KuE) motifs for targeting prostate-specific membrane antigen (PSMA), employing Cu-catalyzed (CuAAC) as well as strain-promoted (SPAAC) click chemistry. These were labeled with 177 Lu or 213 Bi and 68 Ga and used for in vivo imaging of LNCaP (human prostate carcinoma) tumor xenografts in SCID mice by PET, thus proving practical applicability of the concept. PMID- 28833668 TI - Isotopic analysis on nanogram quantities of carbon from dissolved insect cuticle: a method for paleoenvironmental inferences. AB - RATIONALE: Carbon isotope (delta13 C ) data from arthropod cuticles provide invaluable information on past and present biogeochemical processes. However, such analyses typically require large sample sizes that may mask important variation in delta13 C values within or among species. METHODS: We have evaluated a spooling-wire microcombustion (SWiM) device and isotope ratio mass spectrometry (IRMS) to measure the delta13 C values of carbon dissolved from the cuticle of chitinous aquatic zooplankton. The effects of temperature, pH, and reaction time on the delta13 C values of acid-dissolved bulk cuticle and purified chitin fractions obtained from a single species of chironomid from four commercial suppliers were assessed. These results were compared with baseline delta13 C values obtained on solid cuticle using conventional EA (elemental analyzer)/IRMS. RESULTS: The results indicate differential, time-dependent dissolution of chitin, lipid and protein fractions of cuticle concomitant with slow depolymerization and deacetylation of chitin. Isotopic offsets between dissolved bulk head capsules and a purified chitin fraction suggest the contributions of other isotopically lighter components of the bulk head capsules to bulk chitin extracts. The SWiM/IRMS delta13 C results obtained on dissolved cuticle using a treatment of 4 N HCl at 25 degrees C for 24 h produced generally stable delta13 C values, large sample/blank CO2 yields and a positive correlation with conventional EA/IRMS results on unprocessed cuticle. CONCLUSIONS: The SWiM/IRMS system offers a reliable method to determine delta13 C values on nanogram quantities of carbon from dissolved insect cuticle, thus reducing sample size requirements and providing new opportunities to use delta13 C variation among/within species for reconstructing paleo-biogeochemical processes. PMID- 28833669 TI - A Tumor-Specific Cascade Amplification Drug Release Nanoparticle for Overcoming Multidrug Resistance in Cancers. AB - A cascade amplification release nanoparticle (CARN) is constructed by the coencapsulation of beta-lapachone and a reactive-oxygen-species (ROS)-responsive doxorubicin (DOX) prodrug, BDOX, in polymeric nanoparticles. Releasing beta lapachone first from the CARNs selectively increases the ROS level in cancer cells via NAD(P)H:quinone oxidoreductase-1 (NQO1) catalysis, which induces the cascade amplification release of DOX and overcomes multidrug resistance (MDR) in cancer cells, producing a remarkably improved therapeutic efficacy against MDR tumors with minimal side effects. PMID- 28833670 TI - Profiling cancer risk in oral potentially malignant disorders-A patient cohort study. AB - BACKGROUND: Oral potentially malignant disorders harbour variable and unpredictable risk for squamous carcinoma development. Whilst current management strategies utilise histopathological diagnoses, dysplasia grading and targeted intervention for "high-risk" lesions, clinicians are unable to predict malignant potential. METHODS: Detailed, retrospective clinico-pathological analysis of potentially malignant lesions undergoing malignant transformation, from a 590 patient cohort treated by interventional laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was documented at study census date (31 December 2014). RESULTS: A total of 99 patients (16.8%) developed cancer: 71 (12%) seen "unexpectedly" upon excision and 28 (4.8%) progressing to malignancy at a median of 87.3 months post-surgery. Thirty "unexpected" excisions were micro invasive (42.3%) arising primarily in severely dysplastic precursors (75%) at ventro-lateral tongue and floor of mouth sites (54.5%); 1 patient (1.4%) had a cancer-related death, whilst 58 (81.7%) were disease free. A total of 19 of 28 "progressive" cancers (67.9%) arose at new sites, with erythroleukoplakia a significant predictor of malignancy (P = .0019). Nine (32.1%) developed at the same precursor site, with 6 (77.7%) on the ventro-lateral tongue and floor of mouth. Three (10.7%) were micro-invasive, 9 patients (32.1%) died from metastatic disease and 12 (42.9%) were disease free (P < .001). CONCLUSION: Squamous carcinoma may arise at the site of a precursor lesion as transformation or new site development via field cancerisation. Whilst interventional surgery facilitates early diagnosis and treatment of occult disease, thus reducing risk from same-site transformation, new-site cancer is a significant long-term risk for patients with potentially malignant disorder. PMID- 28833671 TI - Targeted conservative formation of cointegrates between two DNA molecules containing IS26 occurs via strand exchange at either IS end. AB - We recently proposed a model for targeted, conservative cointegrate formation between DNA molecules each containing a copy of IS26, that involves Tnp26 catalyzed strand exchange occurring at either the two left ends or the two right ends of the IS. Here, this model was validated by altering the bases at the outer left terminus, right terminus or both termini of one IS26. The correct bases at both ends were required in the untargeted replicative mode. However, when only one end was altered in one participating IS the frequency of targeted, conservative cointegrate formation was not reduced. The distribution of the altered bases in the cointegrates confirmed that the reaction occurred at the end where the terminal bases of both IS were correct, and cointegrates were not formed when both ends of the same IS were altered. The terminal bases of the active IS26 were also required to support deletion of the aphA1a translocatable unit (TU) from Tn4352B. The choices made by an incoming TU with a wild-type IS26 when the target plasmid included one wild-type IS26 and one with a frameshift in tnp26 demonstrated that Tnp26 exhibits a strong preference for cis action. PMID- 28833672 TI - A large-scale expression strategy for multimeric extracellular protein complexes using Drosophila S2 cells and its application to the recombinant expression of heterodimeric ligand-binding domains of taste receptor. AB - Many of the extracellular proteins or extracellular domains of plasma membrane proteins exist or function as homo- or heteromeric multimer protein complexes. Successful recombinant production of such proteins is often achieved by co expression of the components using eukaryotic cells via the secretory pathway. Here we report a strategy addressing large-scale expression of hetero-multimeric extracellular domains of plasma membrane proteins and its application to the extracellular domains of a taste receptor. The target receptor consists of a heterodimer of T1r2 and T1r3 proteins, and their extracellular ligand binding domains (LBDs) are responsible for the perception of major taste substances. However, despite the functional importance, recombinant production of the heterodimeric proteins has so far been unsuccessful. We achieved the successful preparation of the heterodimeric LBD by use of Drosophila S2 cells, which have a high secretory capacity, and by the establishment of a stable high-expression clone producing both subunits at a comparable level. The method overcame the problems encountered in the conventional transient expression of the receptor protein in insect cells using baculovirus or vector lipofection, which failed in the proper heterodimer production because of the biased expression of T1r3LBD over T1r2LBD. The large-scale expression methodology reported here may serve as one of the considerable strategies for the preparation of multimeric extracellular protein complexes. PMID- 28833673 TI - Wearable Microfluidic Diaphragm Pressure Sensor for Health and Tactile Touch Monitoring. AB - Flexible pressure sensors have many potential applications in wearable electronics, robotics, health monitoring, and more. In particular, liquid-metal based sensors are especially promising as they can undergo strains of over 200% without failure. However, current liquid-metal-based strain sensors are incapable of resolving small pressure changes in the few kPa range, making them unsuitable for applications such as heart-rate monitoring, which require a much lower pressure detection resolution. In this paper, a microfluidic tactile diaphragm pressure sensor based on embedded Galinstan microchannels (70 um width * 70 um height) capable of resolving sub-50 Pa changes in pressure with sub-100 Pa detection limits and a response time of 90 ms is demonstrated. An embedded equivalent Wheatstone bridge circuit makes the most of tangential and radial strain fields, leading to high sensitivities of a 0.0835 kPa-1 change in output voltage. The Wheatstone bridge also provides temperature self-compensation, allowing for operation in the range of 20-50 degrees C. As examples of potential applications, a polydimethylsiloxane (PDMS) wristband with an embedded microfluidic diaphragm pressure sensor capable of real-time pulse monitoring and a PDMS glove with multiple embedded sensors to provide comprehensive tactile feedback of a human hand when touching or holding objects are demonstrated. PMID- 28833674 TI - C-H Cyanation of 6-Ring N-Containing Heteroaromatics. AB - Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C-H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures. PMID- 28833675 TI - Efficacy of oral brush biopsy in potentially malignant disorder management. AB - BACKGROUND: Oral potentially malignant disorders (PMD) harbour unpredictable risk for squamous cell carcinoma development. Current management requires tissue biopsy for histopathology characterisation, dysplasia grading and targeted intervention to "high-risk" lesions, although evidence-based guidelines are limited and diagnoses subjective. This study investigated the use of adjunctive oral brush biopsy techniques during the management of PMD in a UK hospital population. METHODS: Retrospective review of a 310 PMD patient cohort presenting to Maxillofacial Surgery in Newcastle upon Tyne with new, single-site lesions between December 2009 and May 2014. Patients underwent Orcellex(r) brush biopsy and liquid-based cytology examination in addition to conventional biopsy techniques, with management proceeding along established care pathways. Patient demographics, cytology data, most significant histopathology diagnoses and clinical outcome were all documented at the study census date (31.12.15). RESULTS: A total of 170 male & 140 female patients (age range 18-91 years), exhibiting primarily leukoplakia (86.5%) at floor of mouth and ventrolateral tongue sites (44.9%), were identified. Management comprised: observation (49.7%), laser surgery (44.9%), antifungal treatment (3.5%) and Head & Neck clinic referral following cancer diagnosis (1.9%). Clinical outcomes were as follows: disease free (51.3%), persistent PMD (42.3%) and malignant transformation (6.4%). Histology and cytology diagnoses strongly correlated (r = .305). Treatment modality, lesion site, histology and cytology diagnoses were the best predictors of clinical outcome. CONCLUSIONS: Orcellex(r) brush cytology provides reliable diagnoses consistent with conventional histopathology and offers less invasive, adjunctive assessment appropriate for long-term monitoring of patients in specialist clinics. PMID- 28833676 TI - The subthalamic nucleus-external globus pallidus loop biases exploratory decisions towards known alternatives: a neuro-computational study. AB - Theories and models of the basal ganglia have mainly focused on the role of three different corticothalamic pathways: direct, indirect and hyperdirect. Although the indirect and the hyperdirect pathways are linked through the bidirectional connections between the subthalamic nucleus (STN) and the external globus pallidus (GPe), the role of their interactions has been mainly discussed in the context of a dysfunction (abnormal oscillations in Parkinson's disease) and not of its function. We here propose a novel role for the loop formed by the STN and the GPe. We show, through a neuro-computational model, that this loop can bias the selection of actions during the exploratory period after a change in the environmental conditions towards alternative responses. Testing well-known alternative solutions before completely random actions can reduce the time required for the search of a new response after a rule change. Our simulations further show that the knowledge acquired by the indirect pathway can be transferred into a stable memory via learning in the hyperdirect pathway to establish the blocking of unwanted responses. After a rule switch, first the indirect pathway learns to inhibit the previously correct actions. Once the new correct association is learned, the inhibition is transferred to the hyperdirect pathway through synaptic plasticity. PMID- 28833677 TI - The quality improvement attitude survey: Development and preliminary psychometric characteristics. AB - AIMS AND OBJECTIVES: To report the development of a tool to measure nurse's attitudes about quality improvement in their practice setting and to examine preliminary psychometric characteristics of the Quality Improvement Nursing Attitude Scale. BACKGROUND: Human factors such as nursing attitudes of complacency have been identified as root causes of sentinel events. Attitudes of nurses concerning use of Quality and Safety Education for nurse's competencies can be most challenging to teach and to change. No tool has been developed measuring attitudes of nurses concerning their role in quality improvement. DESIGN: A descriptive study design with preliminary psychometric evaluation was used to examine the preliminary psychometric characteristics of the Quality Improvement Nursing Attitude Scale. Registered bedside clinical nurses comprised the sample for the study (n = 57). METHODS: Quantitative data were analysed using descriptive statistics and Cronbach's alpha reliability. Total score and individual item statistics were evaluated. Two open-ended items were used to collect statements about nurses' feelings regarding their experience in quality improvement efforts. RESULTS: Strong support for the internal consistency reliability and face validity of the Quality Improvement Nursing Attitude Scale was found. Total scale scores were high indicating nurse participants valued Quality and Safety Education for Nurse competencies in practice. However, item level statistics indicated nurses felt powerless when other nurses deviate from care standards. Additionally, the sample indicated they did not consistently report patient safety issues and did not have a feeling of value in efforts to improve care. CONCLUSIONS: Findings suggested organisational culture fosters nurses' reporting safety issues and feeling valued in efforts to improve care. Participants' narrative comments and item analysis revealed the need to generate new items for the Quality Improvement Nursing Attitude Scale focused on nurses' perception of their importance in quality and safety and their power to enact principles. RELEVANCE TO THE PRACTICE: The Quality Improvement Nursing Attitude Scale-Revised edition was designed to help in understanding nurses' attitudes and values. It can be used to further explore broad concepts of quality improvement efforts. PMID- 28833678 TI - Nudix-type RNA pyrophosphohydrolase provides homeostasis of virulence factor pyocyanin and functions as a global regulator in Pseudomonas aeruginosa. AB - The PA0336 protein from Pseudomonas aeruginosa belongs to the family of widely distributed Nudix pyrophosphohydrolases, which catalyze the hydrolysis of pyrophosphate bonds in a variety of nucleoside diphosphate derivatives. The amino acid sequence of the PA0336 protein is highly similar to that of the RppH Nudix RNA pyrophosphohydrolase from Escherichia coli, which removes pyrophosphate from 5'-end of triphosphorylated RNA transcripts. Trans-complementation experiments showed that the P. aeruginosa enzyme can functionally substitute for RppH in E. coli cells indicating that, similar to RppH, the Pseudomonas hydrolase mediates RNA turnover in vivo. In order to elucidate the biological significance of the PA0336 protein in Pseudomonas cells, a PA0336 mutant strain was constructed. The mutated strain considerably increased level of the virulence factor pyocyanin compared to wild type, suggesting that PA0336 could be involved in downregulation of P. aeruginosa pathogenicity. This phenotype was reversed by complementation with the wild type but not catalytically inactive PA0336, indicating that the catalytic activity was indispensable for its biological function. Pathogenesis tests in Caenorhabditis elegans showed that the PA0336 mutant of P. aeruginosa was significantly more virulent than the parental strain, confirming further that the P. aeruginosa RNA pyrophosphohydrolase PA0336 modulates bacterial pathogenesis by down-regulating production of virulence-associated factors. To study the role of PA0336 further, transcriptomes of the PA0336 mutant and the wild-type strain were compared using RNA sequencing. The level of 537 transcripts coding for proteins involved in a variety of cellular processes such as replication, transcription, translation, central metabolism and pathogenesis, was affected by the lack of PA0336. These results indicate that the PA0336 RNA pyrophosphohydrolase functions as a global regulator that influences many of transcripts including those involved in P. aeruginosa virulence. PMID- 28833679 TI - Self-Templated Fabrication of MoNi4 /MoO3-x Nanorod Arrays with Dual Active Components for Highly Efficient Hydrogen Evolution. AB - A binder-free efficient MoNi4 /MoO3-x nanorod array electrode with 3D open structure is developed by using Ni foam as both scaffold and Ni source to form NiMoO4 precursor, followed by subsequent annealing in a reduction atmosphere. It is discovered that the self-templated conversion of NiMoO4 into MoNi4 nanocrystals and MoO3-x as dual active components dramatically boosts the hydrogen evolution reaction (HER) performance. Benefiting from high intrinsic activity, high electrochemical surface area, 3D open network, and improved electron transport, the resulting MoNi4 /MoO3-x electrode exhibits a remarkable HER activity with extremely low overpotentials of 17 mV at 10 mA cm-2 and 114 mV at 500 mA cm-2 , as well as a superior durability in alkaline medium. The water alkali electrolyzer using MoNi4 /MoO3-x as cathode achieves stable overall water splitting with a small cell voltage of 1.6 V at 30 mA cm-2 . These findings may inspire the exploration of cost-effective and efficient electrodes by in situ integrating multiple highly active components on 3D platform with open conductive network for practical hydrogen production. PMID- 28833680 TI - Toxicological Effects of Glycyrrhiza glabra (Licorice): A Review. AB - Licorice (Glycyrrhiza glabra) has been considered as an herbal drug since ancient time. Nowadays, it is a well-known spice that possesses worth pharmacological effects. However, some relevant articles have revealed negative impacts of licorice in health. By considering the great wishes in using herbal medicine, it is important to show adverse effects of herbal medicine in health. At present, there are misunderstandings toward the safety of herbal medicines. Herein, we gathered scientific research projects on the toxicity effects of licorice and glycyrrhizin to highlight their safety. In this regards, we categorized our findings about the toxicity effects of licorice and glycyrrhizin in acute, sub acute, sub-chronic, and chronic states. Besides, we discussed on the cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of licorice and glycyrrhizin as well as their developmental toxicity. This review disclosed that G. glabra and glycyrrhizin salts are moderately toxic. They need to be used with caution during pregnancy. G. glabra and glycyrrhizin possess selective cytotoxic effects on cancerous cells. The most important side effects of licorice and glycyrrhizin are hypertension and hypokalemic-induced secondary disorders. Licorice side effects are increased by hypokalemia, prolonged gastrointestinal transient time, decreased type 2 11-beta-hydroxysteroid dehydrogenase activities, hypertension, anorexia nervosa, old age, and female sex. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28833681 TI - Freeze Casting for Assembling Bioinspired Structural Materials. AB - Nature is very successful in designing strong and tough, lightweight materials. Examples include seashells, bone, teeth, fish scales, wood, bamboo, silk, and many others. A distinctive feature of all these materials is that their properties are far superior to those of their constituent phases. Many of these natural materials are lamellar or layered in nature. With its "brick and mortar" structure, nacre is an example of a layered material that exhibits extraordinary physical properties. Finding inspiration in living organisms to create bioinspired materials is the subject of intensive research. Several processing techniques have been proposed to design materials mimicking natural materials, such as layer-by-layer deposition, self-assembly, electrophoretic deposition, hydrogel casting, doctor blading, and many others. Freeze casting, also known as ice-templating, is a technique that has received considerable attention in recent years to produce bioinspired bulk materials. Here, recent advances in the freeze casting technique are reviewed for fabricating lamellar scaffolds by assembling different dimensional building blocks, including nanoparticles, polymer chains, nanofibers, and nanosheets. These lamellar scaffolds are often infiltrated by a second phase, typically a soft polymer matrix, a hard ceramic matrix, or a metal matrix. The unique architecture of the resultant bioinspired structural materials displays excellent mechanical properties. The challenges of the current research in using the freeze-casting technique to create materials large enough to be useful are also discussed, and the technique's promise for fabricating high performance nacre-inspired structural materials in the future is reviewed. PMID- 28833682 TI - Preliminary report: Measurement of apixaban and rivaroxaban in plasma from bleeding patients. AB - OBJECTIVES: The direct oral anticoagulants (DOACs), apixaban and rivaroxaban, are used for anticoagulation treatment. Although biochemical monitoring is not required, severe bleedings caused by DOAC have been reported. We therefore evaluated the chromogenic assay Biophen DiXaI(r) (Biophen) using plasma from non bleeding patients in treatment with DOAC and on spiked plasma from patients with ongoing bleeding. METHODS: The Biophen method was compared with an in-house reference method; liquid chromatography-tandem mass spectrometry (LC-MS/MS) using plasma spiked with the compounds ranging from 20 to 1500 MUg/L. Furthermore, the methods were compared using plasma from non-bleeding patients in treatment with DOAC (n = 106). In addition, plasma was collected from patients not treated with DOAC, but with ongoing bleeding and tested in spiking experiments (n = 14). RESULTS: Analysis of plasma from 106 patients receiving rivaroxaban (n = 91) or apixaban (n = 15) showed agreement and correlation between the methods. Measurement in spiked plasma from patients with active bleeding, however, revealed a 26% overestimation by the assay. CONCLUSIONS: Our findings show that Biophen is suitable for measuring apixaban and rivaroxaban concentrations in plasma. However, our results in patients with active bleeding show an overestimation of 26%. This should be taken into account when assessing possible intoxication with apixaban and rivaroxaban in patients presenting with bleeding. PMID- 28833683 TI - Self-Assembly of Heterogeneously Shaped Nanoparticles into Plasmonic Metamolecules on DNA Origami. AB - Fabrication of plasmonic metamolecules (PMs) with rationally designed complexity is one of the major goals of nanotechnology. Most self-assembled PMs, however, have been constructed using single-component systems. The corresponding plasmonic assemblies still suffer from the lack of complexity, which is required to achieve a high degree of functionality. Here, we report a general applicable strategy that can realize a series of high-ordered hetero-PMs using bottom-up DNA self assembly. DNA-functionalized differently shaped nanoparticles were deliberately arranged in prescribed positions on 3D triangular DNA origami frames to form various hetero-PMs. Importantly, we showed that the optical properties of assembled PMs could be facially tuned by selectively regulating the position of each component. This method provides a promising pathway for manufacturing more complex and advanced materials by integrating diverse nanocomponents with particular properties. PMID- 28833684 TI - Metal-Mediated Base Pairs: From Characterization to Application. AB - The investigation of metal-mediated base pairs and the development of their applications represent a prominent area of research at the border of bioinorganic chemistry and supramolecular coordination chemistry. In metal-mediated base pairs, the complementary nucleobases in a nucleic acid duplex are connected by coordinate bonds to an embedded metal ion rather than by hydrogen bonds. Because metal-mediated base pairs facilitate a site-specific introduction of metal-based functionality into nucleic acids, they are ideally suited for use in DNA nanotechnology. This minireview gives an overview of the general requirements that need to be considered when devising a new metal-mediated base pair, both from a conceptual and from an experimental point of view. In addition, it presents selected recent applications of metal-modified nucleic acids to indicate the scope of metal-mediated base pairing. PMID- 28833685 TI - Drebrin E regulates neuroblast proliferation and chain migration in the adult brain. AB - F-actin-binding protein drebrin has two major isoforms: drebrin A and drebrin E. Drebrin A is the major isoform in the adult brain and is highly concentrated in dendritic spines, regulating spine morphology and synaptic plasticity. Conversely, drebrin E is the major isoform in the embryonic brain and regulates neuronal morphological differentiation, but it is also expressed in neurogenic regions of the adult brain. The subventricular zone (SVZ) is one of the brain regions where adult neurogenesis occurs. Neuroblasts migrate to the olfactory bulb (OB) and integrate into existing neuronal networks, after which drebrin expression changes from E to A, suggesting that drebrin E plays a specific role in neuroblasts in the adult brain. Therefore, to understand the role of drebrin E in the adult brain, we immunohistochemically analyzed adult neurogenesis using drebrin-null-mutant (DXKO) mice. In DXKO mice, the number of neuroblasts and cell proliferation decreased, although cell death remained unchanged. These results suggest that drebrin E regulates cell proliferation in the adult SVZ. Surprisingly, the decreased number of neuroblasts in the SVZ did not result in less neurons in the OB. This was because the survival rate of newly generated neurons in the OB increased in DXKO mice. Additionally, when neuroblasts reached the OB, the change in the migratory pathway from tangential to radial was partly disturbed in DXKO mice. These results suggest that drebrin E is involved in a chain migration of neuroblasts. PMID- 28833686 TI - A New, Practical One-Pot Synthesis of Unprotected Sulfonimidamides by Transfer of Electrophilic NH to Sulfinamides. AB - Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one-pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol under convenient conditions. A wide range of functional groups are tolerated and initial results indicate that the NH transfer is stereospecific. A small molecule X-ray analysis of NH sulfonimidamide 2 a and its behavior in selected in vitro assays in comparison to the matched sulfonamide are also reported. This new reaction provides a safe, short and efficient approach to sulfonimidamides, which have been the subject of recent, growing interest in the life sciences. PMID- 28833687 TI - beta-Acrolein-Substituted Corroles: A Route to the Preparation of Functionalized Polyacrolein Microspheres for Chemical Sensor Applications. AB - An efficient beta-functionalization of [5,10,15-tris-(4 methylphenyl)corrolato]cobalt derivatives through a Vilsmeier-type reaction allows the introduction of an acrolein substituent, which is subsequently copolymerized with pure acrolein. The obtained hybrid microspheres are exploited as nanogravimetric chemical sensors. The sensing properties of the developed sensors are tested through exposure to different volatile organic compounds chosen as model analytes. The results show improved sensor sensitivity of the resulting devices for all the tested analytes with respect to sensors functionalized with either corrole or polyacrolein. The enhanced properties are attributed to the accurate and tunable merging of the properties of both exploited materials. PMID- 28833688 TI - Effects of high alcohol intake, alcohol-related symptoms and smoking on mortality. AB - BACKGROUND AND AIMS: Both high alcohol intake and alcohol dependence increase mortality, and both are associated with smoking. We aimed to compare the associations of quantity of alcohol, number of alcohol-related symptoms and smoking history with all-cause mortality, and to assess symptom count and smoking history as confounders or mediators of the effects of high alcohol intake. DESIGN: Survival was analysed by Cox regression with sex, body mass index, alcohol intake (overall and by beverage), maximum drinks on any day, alcohol symptom count and smoking status as potential predictors of age at death. SETTING: Australia. PARTICIPANTS: Participants were apparently healthy volunteers consisting of 33 593 Australian adult twins and their relatives who completed questionnaires or interviews between 1979 and 2005. MEASUREMENTS: Data on alcohol use, smoking and occurrence of symptoms related to alcohol use disorders and death records from the Australian National Death Index. FINDINGS: A total of 3764 participants were matched with deaths occurring within Australia up to July 2014. Individually, alcohol intake [hazard ratio (HR) = 1.0082, 95% confidence interval (CI) = 1.0063-1.0102, per drink per week], beer intake (HR = 1.0159, 95% CI = 1.0123-1.0195, per drink per week), life-time maximum number of drinks in 1 day (HR = 1.0176, 95% CI = 1.0130-1.0221, per drink), symptom count (HR = 1.0867, 95% CI = 1.0633-1.1106, per symptom) and smoking status (HR = 2.82, 95% CI = 2.52 3.16 for smokers of 10+ cigarettes/day versus never-smokers) were each significant predictors of all-cause mortality. After adjustment for the independently significant predictors alcohol symptom count and smoking status, alcohol intake was no longer significant (adjusted HR = 1.0012 per drink per week, 95% CI = 0.9979-1.0145). CONCLUSIONS: Number of symptoms related to high alcohol intake and tobacco smoking appear to account for the positive association between alcohol consumption and premature mortality. PMID- 28833689 TI - Cold water immersion: kill or cure? AB - NEW FINDINGS: What is the topic of this review? This is the first review to look across the broad field of 'cold water immersion' and to determine the threats and benefits associated with it as both a hazard and a treatment. What advances does it highlight? The level of evidence supporting each of the areas reviewed is assessed. Like other environmental constituents, such as pressure, heat and oxygen, cold water can be either good or bad, threat or treatment, depending on circumstance. Given the current increase in the popularly of open cold water swimming, it is timely to review the various human responses to cold water immersion (CWI) and consider the strength of the claims made for the effects of CWI. As a consequence, in this review we look at the history of CWI and examine CWI as a precursor to drowning, cardiac arrest and hypothermia. We also assess its role in prolonged survival underwater, extending exercise time in the heat and treating hyperthermic casualties. More recent uses, such as in the prevention of inflammation and treatment of inflammation-related conditions, are also considered. It is concluded that the evidence base for the different claims made for CWI are varied, and although in most instances there seems to be a credible rationale for the benefits or otherwise of CWI, in some instances the supporting data remain at the level of anecdotal speculation. Clear directions and requirements for future research are indicated by this review. PMID- 28833691 TI - Switching of Reaction Pathway from C-C Rollover to C-N Ring-Extension Annulation. AB - This work discloses that a simple change in the anion of a copper(II) reagent along with the reaction solvent can dramatically alter the course of a Cp*RhIII catalyzed C-H activation-annulation reaction leading to completely switchable chemoselective products. The nature of the anion in terms of its coordinating ability and basicity, and also the polarity of the solvent have been found to be the crucial factors in the observed divergence. PMID- 28833690 TI - Changes in structure and perfusion of grey matter tissues during recovery from Ischaemic subcortical stroke: a longitudinal MRI study. AB - Stroke recovery with changes in volume and perfusion of grey matter (GM) tissues remains largely unknown. We hypothesized that GM atrophy co-existed with GM plasticity presenting with increased volume and perfusion in specific regions in the period of post-stroke recovery. Twelve well-recovered stroke patients with pure subcortical lesions in the middle cerebral artery-perfused zone were included. All of them underwent structural and perfusion magnetic resonance imaging (MRI) examinations at admission and a mean of 6 months after stroke onset. Differences in GM volume (GMV) on structural images and cerebral blood flow (CBF) derived from perfusion images between two examinations were compared using voxel-based morphometry. The associations between changes in GMV and CBF with clinical scores were analysed. Decreased GMV was found in post-central gyrus, pre-central gyrus, precuneus, angular gyrus, insula, thalamus and cerebellum, and increased GMV was found in hippocampus, orbital gyrus and lingual gyrus (all corrected P < 0.05) at the follow-up examination. Increased CBF was found in subcallosal cingulate gyrus, hippocampus and lingual gyrus (all corrected P < 0.05) at the follow-up examination. Only decreased GMV in the anterior lobe of cerebellum was negatively associated with improvement of Barthel index (beta = -0.683, P = 0.014). Our study provides the imaging evidence of GM atrophy co-existing with GM plasticity involving in increased volume and perfusion in specific regions (including cognition, vision and emotion) in well recovered stroke patients, which advances our understanding of neurobiology of stroke recovery. PMID- 28833692 TI - Central angiotensin-(1-7) increases osmotic thirst. AB - NEW FINDINGS: What is the central question of this study? The central goal of this study was to understand the effects of central angiotensin-(1-7) on basal and osmotically stimulated water intake in rats. What is the main finding and its importance? This study demonstrated that central administration of angiotensin-(1 7) did not induce thirst in basal conditions but increased water intake after osmotic stimulation, such as water deprivation and salt loading. These results indicate a new function for this peptide, which, in turn, allows for future research on the mechanisms through which angiotensin-(1-7) influences osmotic thirst. Angiotensin-(1-7) [Ang-(1-7)] is generated by type 2 angiotensin converting enzyme (ACE2) and binds to the MAS receptor. Although it is well known that Ang-(1-7) functionally antagonizes the effects of the classical renin angiotensin system in several situations, the role of Ang-(1-7) in hydromineral homeostasis is not clear. The aim of this study was to assess the role of Ang-(1 7) on neuroendocrine responses to hyperosmolality in rats. Male Wistar rats were divided into the following three groups: control; 24 h of water deprivation (WD); and 24 h of salt loading (SL; 1.8% NaCl). Intracerebroventricular (i.c.v.) injections of Ang-(1-7) or vehicle were given to assess water intake and plasma concentration of vasopressin. Additionally, the brains from control and WD groups were collected to evaluate gene expression in the subfornical organ (SFO), paraventricular nucleus (PVN) and supraoptic nucleus (SON). It was found that i.c.v. Ang-(1-7) did not change water and salt intake in control rats; however, Ang-(1-7) increased water intake after WD and SL, with no change in salt intake. Plasma vasopressin was not changed by i.c.v. Ang-(1-7) in control or WD rats. Moreover, WD increased Mas gene expression in the SON and PVN, with no changes in Ace2 mRNA levels. In conclusion, Ang-(1-7) increases thirst after osmotic stimuli, indicating that a previous sensitization to its action is necessary. This finding is consistent with the increased Mas gene expression in the PVN and SON after water deprivation. PMID- 28833694 TI - Editorial Comment to Evidenced-based clinical practice guideline for prostate cancer (summary: Japanese Urological Association, 2016 edition). PMID- 28833693 TI - Fibrotic scar model and TGF-beta1 differently modulate action potential firing and voltage-dependent ion currents in hippocampal neurons in primary culture. AB - Traumatic injury of the central nervous system is accompanied by various functional and morphological changes. Animal models of traumatic brain injury are commonly used to investigate changes in behaviour, morphology, in the expression of various proteins around the site of the injury, or the expression of diagnostically important biomarkers. Excitability of a single neuron at, or close to, the site of injury was rarely investigated. Several in vitro models were developed which allow such investigation. In the present work, we employed a fibrotic scar model according to Kimura-Kuroda and coauthors to analyse altered excitability of rat hippocampal neurons under the conditions mimicking traumatic brain injury. Hippocampal neurons from newborn rats were cultured either on a fibrotic scar model or in the presence of TGF-beta1, a cytokine secreted at a brain injury site that may have both neuroprotective and neurodegenerative function. Fibrotic scar facilitated ability of neonatal hippocampal neurons to fire action potential series by increasing the density of voltage activated sodium and potassium currents. Chondroitin sulphate proteoglycans played substantial role in these effects, as proven by their full reversion after administration of Chondroitinase ABC. In contrast, TGF-beta1 did not contribute to them. An application of TGF-beta1 itself attenuated generation of action potentials, inhibited sodium current and potentiated potassium currents. Main alteration of electrophysiological parameters of neonatal hippocampal neurons caused by a fibrotic scar model is enhanced excitability. TGF-beta1 may have predominantly neuroprotective role in injured rat hippocampus. PMID- 28833695 TI - Locally Excited State-Charge Transfer State Coupled Dyes as Optically Responsive Neuron Firing Probes. AB - A selection of NIR-optically responsive neuron probes was produced comprising of a donor julolidyl group connected to a BODIPY core and several different styryl and vinylpyridinyl derived acceptor moieties. The strength of the donor-acceptor interaction was systematically modulated by altering the electron withdrawing nature of the aryl unit. The fluorescence quantum yield was observed to decrease as the electron withdrawing effect of the aryl subunit increased in line with changes of the Hammett parameter. The effectiveness of these fluorophores as optically responsive dyes for neuronal imaging was assessed by measuring the toxicity and signal-to-noise ratio (SNR) of each dye. A great improvement of SNR was obtained when compared to the first-generation BODIPY-based voltage sensitive dyes with concomitant toxicity decrease. The mechanism for the optical response is disparate from conventional cyanine-based dyes, opening up a new way to produce effective voltage sensitive dyes that respond well into the NIR region. PMID- 28833696 TI - Shared evolutionary origin of major histocompatibility complex polymorphism in sympatric lemurs. AB - Genes of the major histocompatibility complex (MHC) play a central role in adaptive immune responses of vertebrates. They exhibit remarkable polymorphism, often crossing species boundaries with similar alleles or allelic motifs shared across species. This pattern may reflect parallel parasite-mediated selective pressures, either favouring the long maintenance of ancestral MHC allelic lineages across successive speciation events by balancing selection ("trans species polymorphism"), or alternatively favouring the independent emergence of functionally similar alleles post-speciation via convergent evolution. Here, we investigate the origins of MHC similarity across several species of dwarf and mouse lemurs (Cheirogaleidae). We examined MHC class II variation in two highly polymorphic loci (DRB, DQB) and evaluated the overlap of gut-parasite communities in four sympatric lemurs. We tested for parasite-MHC associations across species to determine whether similar parasite pressures may select for similar MHC alleles in different species. Next, we integrated our MHC data with those previously obtained from other Cheirogaleidae to investigate the relative contribution of convergent evolution and co-ancestry to shared MHC polymorphism by contrasting patterns of codon usage at functional vs. neutral sites. Our results indicate that parasites shared across species may select for functionally similar MHC alleles, implying that the dynamics of MHC-parasite co-evolution should be envisaged at the community level. We further show that balancing selection maintaining trans-species polymorphism, rather than convergent evolution, is the primary mechanism explaining shared MHC sequence motifs between species that diverged up to 30 million years ago. PMID- 28833698 TI - Noninvasive penetration of 5 nm hyaluronic acid molecules across the epidermal barrier (in vitro) and its interaction with human skin cells. AB - OBJECTIVE: Hyaluronic acid represents one of the major components of the extracellular environment. The main challenge remains in the ability to deliver these molecules noninvasively across the skin barrier, which can be overcome by the reduction in size to an extent that allows these molecules to pass across the skin barrier. The aim of this study was to measure the penetration and bioavailability of low molecular weight hyaluronic acid to cross an epidermal barrier model. METHODS: Determining the quantity of hyaluronic acid in the test solutions was carried with method of photocolorimetry analysis. Investigation of the interaction of cells with LMWHA was studied with a confocal microscope. RESULTS: The study showed that LMWHA is able to cross the epidermis. Most effective penetration level is during the first 6 hours reaching 75%, and then the concentration started to decline and reached the equilibrium state within the following 2 hours. Confocal laser microscopy demonstrated different distribution and behavior of these molecules among the keratinocytes and fibroblasts. CONCLUSION: Reducing the size of hyaluronic acid to 5 nm enhance their transport across the epidermal layer. The concentration of hyaluronic acid molecules was higher on the fibroblast surface in comparison to their extracellular environment. PMID- 28833699 TI - Impaired polymorphonuclear neutrophils in the oral cavity of edentulous individuals. AB - Oral health is characterized by functional oral polymorphonuclear neutrophils (oPMNs). Edentulism might be associated with a loss of oPMNs because these cells enter the oral cavity primarily through the gingival crevices. The main aim of this study was to investigate the numbers of oPMNs in rinse samples obtained from edentulous (n = 21) and dentate (n = 20) subjects. A second study aim was to investigate possible differences between oPMNs and peripheral blood polymorphonuclear neutrophils (cPMNs). Apoptosis/necrosis and cell-activation markers (CD11b, CD63 and CD66b) were analyzed using flow cytometry. Reactive oxygen species (ROS) production was determined either without stimulation (constitutive) or in response to 10 MUM phorbol myristate acetate or Fusobacterium nucleatum. The edentulous subjects presented with lower oPMN counts and higher percentages of apoptotic/necrotic oPMNs compared with dentate subjects. Furthermore, oPMNs from edentulous donors expressed low levels of all three activation markers and low constitutive ROS. In contrast, oPMNs from dentate subjects expressed high levels of all three activation markers and a higher level of constitutive ROS than cPMNs. When challenged, oPMNs from edentulous subjects showed no upregulation in ROS production, whereas oPMNs from dentate subjects retained their ability to respond to stimulation. The functional characteristics of cPMNs were comparable between edentulous and dentate subjects. This study demonstrates that despite having functional cPMNs, edentulous subjects have low oPMN numbers that are functionally impaired. PMID- 28833701 TI - Microvascular imaging of thick placenta with fetal growth restriction. PMID- 28833697 TI - Effect of Intravenously Administered Crystalloid Solutions on Acid-Base Balance in Domestic Animals. AB - Intravenous fluid therapy can alter plasma acid-base balance. The Stewart approach to acid-base balance is uniquely suited to identify and quantify the effects of the cationic and anionic constituents of crystalloid solutions on plasma pH. The plasma strong ion difference (SID) and weak acid concentrations are similar to those of the administered fluid, more so at higher administration rates and with larger volumes. A crystalloid's in vivo effects on plasma pH are described by 3 general rules: SID > [HCO3-] increases plasma pH (alkalosis); SID < [HCO3-] decreases plasma pH (alkalosis); and SID = [HCO3-] yields no change in plasma pH. The in vitro pH of commercially prepared crystalloid solutions has little to no effect on plasma pH because of their low titratable acidity. Appreciation of IV fluid composition and an understanding of basic physicochemical principles provide therapeutically valuable insights about how and why fluid therapy can produce and correct alterations of plasma acid-base equilibrium. The ideal balanced crystalloid should (1) contain species-specific concentrations of key electrolytes (Na+ , Cl- , K+ , Ca++ , Mg++ ), particularly Na+ and Cl- ; (2) maintain or normalize acid-base balance (provide an appropriate SID); and (3) be isosmotic and isotonic (not induce inappropriate fluid shifts) with normal plasma. PMID- 28833702 TI - Benign Synthesis of Black Microspheres of Anatase TiO2 with Paramagnetic Oxygen Vacancies through NH3 Treatment. AB - Coloured TiO2 is coveted for its ability to extract energy from the visible region of electromagnetic spectrum. Here a facile synthesis of black anatase titania microspheres (B-TiO2 ) through a two-step process is reported. In the first step, amorphous white TiO2 microspheres (W-TiO2 ) are obtained by hydrolysing titanium tetraisopropoxide by ammonia vapours in ethanol. In the second step, the W-TiO2 is thermally annealed at 500 degrees C to obtain B-TiO2 . The diffuse reflectance analysis showed that B-TiO2 absorbs across visible spectrum with absorption extending well into NIR region. Raman scattering together with EPR analysis showed compelling evidence of the existence of oxygen deficiency within the crystal in B-TiO2 that induces black colouration in the sample. The defects present in the black anatase sample were confirmed to be single-electron-trapped (or paramagnetic) oxygen vacancies (Vo ?) by XPS and EPR studies. The magnetic susceptibility studies showed existence of antiferromagnetic interactions between these unpaired electron spins. PMID- 28833700 TI - Essential role of endogenous calcitonin gene-related peptide in pain-associated plasticity in the central amygdala. AB - The role of the neuropeptide calcitonin gene-related peptide (CGRP) is well established in nociceptive behaviors. CGRP is highly expressed in the projection pathway from the parabrachial nucleus to the laterocapsular region of the central amygdala (CeC), which plays a critical role in relaying nociceptive information. The CeC is a key structure in pain behavior because it integrates and modulates nociceptive information along with other sensory signals. Previous studies have demonstrated that blockade of the amygdalar CGRP-signaling cascade attenuates nociceptive behaviors in pain models, while CGRP application facilitates amygdalar synaptic transmission and induces pain behaviors. Despite these lines of evidence, it remains unclear whether endogenous CGRP is involved in the development of nociceptive behaviors accompanied with amygdalar plasticity in a peripheral inflammation model in vivo. To directly address this, we utilized a previously generated CGRP knockout (KO) mouse to longitudinally study formalin induced plasticity and nociceptive behavior. We found that synaptic potentiation in the right PB-CeC pathway that was observed in wild-type mice was drastically attenuated in the CGRP KO mice 6 h post-inflammation, when acute nociceptive behavior was no longer observed. Furthermore, the bilateral tactile allodynia 6 h post-inflammation was significantly decreased in the CGRP KO mice. In contrast, the acute nociceptive behavior immediately after the formalin injection was reduced only at 20-25 min post-injection in the CGRP KO mice. These results suggest that endogenous CGRP contributes to peripheral inflammation-induced synaptic plasticity in the amygdala, and this plasticity may underlie the exaggerated nociception-emotion linkage in pain chronification. PMID- 28833703 TI - Non-steroidal anti-inflammatory drugs increase the risk of mucosal injuries but not of overt small bowel bleeding. PMID- 28833705 TI - Silylene-Functionalized N-Heterocyclic Carbene (Si-NHC). AB - The synthesis, structure, and reactivity of the first silylene-functionalized N heterocyclic carbene (Si-NHC), {(L1 )Si}(L2 ), (3) (L1 =PhC(NtBu)2 , L2 =CCH(CNAr)2 C:, Ar=2,6-diisopropylphenyl) are reported. The ditopic carbanionic NHC (dc-NHC), [Li(L2 )]infinity (1) reacts with the monochlorosilylene (L1 )SiCl (2) to afford 3. The HOMO of 3 is the silylene lone-pair orbital, whereas the HOMO-1 is located at the carbene carbon atom. Both SiII and CII functionalities of 3 undergo reactions with chalcogens to give heavier ketone derivatives {(L1 )Si(E)}L2 (E) (E=S, 4; Se, 5; and Te, 6). Compounds 4-6 feature a highly polarized Sidelta+ -Edelta- bond with a formal charge of -0.72 (4), -0.64 (5), and -0.50 e (6) on the E atom. The Wiberg bond indices of 1.64 (4), 1.66 (5), and 1.63 (6) for the Si-E bond however indicate a moderate ppi -ppi interaction between Si and E atoms. Compound 3 functions as a reducing agent and induces disproportionation of Si2 Cl6 to yield the silyl-functionalized NHC, {(L1 )SiCl2 }(L2 ) (7). Treatment of 3 with HSiCl3 leads to the formation of the silyl functionalized imidazolium salt [{(L1 )SiCl2 }(L2 H)]Cl (8). The silylene moiety of 3 readily forms the iridium-silylene complex [{(L2 )(L1 )Si}Ir(cod)Cl] (9) featuring a free NHC ligand on treatment with [Ir(cod)(MU-Cl)]2 . PMID- 28833706 TI - Diversity-Oriented Syntheses by Combining CuAAC and Stereoselective INCIC Reactions with Peptides. AB - Cascade reactions proceeding through peptide-derived N-carbamoyl iminium ions are reported. Two new reactions of N-carbamoyl iminium ions are described, including a stereoselective double cyclization generating N,N'-aminals and an acid-promoted auto-oxidation. Mechanistic investigations revealed that the N,N'-aminal formation is reversible under strongly acidic conditions. Both of these new reactions proved to be completely orthogonal to subsequent CuAAC chemistry. The reactions were performed in solution and on solid support. The robustness and high stereoselectivity of the methodology holds great promise for applications in parallel diversity-oriented synthesis and in combinatorial synthesis for drug screening. PMID- 28833707 TI - Wide QRS tachycardia with RR alternans and QRS alternans. PMID- 28833704 TI - Lipopolysaccharide suppresses IgE-mast cell-mediated reactions. AB - BACKGROUND: Clinical and experimental analyses have identified a central role for IgE/FcepsilonRI/mast cells in promoting IgE-mediated anaphylaxis. Recent data from human studies suggest that bacterial infections can alter susceptibility to anaphylaxis. OBJECTIVE: We examined the effect of LPS exposure on the induction of IgE-mast cell (MC) mediated reactions in mice. METHODS: C57BL/6 WT, tlr4-/- and IL10-/- mice were exposed to LPS, and serum cytokines (TNF and IL-10) were measured. Mice were subsequently treated with anti-IgE, and the symptoms of passive IgE-mediated anaphylaxis, MC activation, Ca2+ -mobilization and the expression of FcepsilonRI on peritoneal MCs were quantitated. RESULTS: We show that LPS exposure of C57BL/6 WT mice constraints IgE-MC-mediated reactions. LPS induced suppression of IgE-MC-mediated responses was TLR-4-dependent and associated with increased systemic IL-10 levels, decreased surface expression of FcepsilonRI on MCs and loss of sensitivity to IgE activation. Notably, LPS induced desensitization of MCs was short term with MC sensitivity to IgE reconstituted within 48 hours, which was associated with recapitulation of FcepsilonRI expression on the MCs. Mechanistic analyses revealed a requirement for IL-10 in LPS-mediated decrease in MC FcepsilonRI surface expression. CONCLUSIONS & CLINICAL RELEVANCE: Collectively, these studies suggest that LPS induced IL-10 promotes the down-regulation of MC surface FcepsilonRI expression and leads to desensitization of mice to IgE-mediated reactions. These studies indicate that targeting of the LPS-TLR-4-IL-10 pathway may be used as a therapeutic approach to prevent adverse IgE-mediated reactions. PMID- 28833708 TI - Asymmetric Aminalization via Cation-Binding Catalysis. AB - Asymmetric cation-binding catalysis, in principle, can generate "chiral" anionic nucleophiles, where the counter cations are coordinated within chiral environments. Nitrogen nucleophiles are intrinsically basic, therefore, its use as nucleophiles is often challenging and limiting the scope of the reaction. Particularly, a formation of configurationally labile aminal centers with alkyl substituents has been a formidable challenge due to the enamine/imine equilibrium of electrophilic substrates. Herein, we report enantioselective nucleophilic addition reactions of potassium phthalimides to Boc-protected alkyl- and aryl substituted alpha-amido sulfones. In situ generated imines smoothly reacted with the nitrogen nucleophiles to corresponding aminals with good to excellent enantioselectivitiy under mild reaction conditions. In addition, transformation of aminal products gave biologically relevant pyrrolidinone-fused hexahydropyrimidine scaffold with excellent stereoselectivity and good yield. PMID- 28833709 TI - Grain-scale stable carbon and oxygen isotopic variations of the international reference calcite, IAEA-603. AB - RATIONALE: The new international reference material IAEA-603 (calcite) for stable carbon and oxygen isotopes (delta13 C and delta18 O values) was released in 2016 to replace the previous reference material, NBS19 (exhausted). We examined the grain-scale isotopic variations in IAEA-603 for application to microscale isotopic analysis of carbonate samples. METHODS: Individual grains of IAEA-603 were analyzed with an IsoPrime100 isotope ratio mass spectrometer with a customized continuous-flow gas preparation system (MICAL3c). The individual grains of IAEA-603 were observed by optical and scanning electron microscopy, and their observational characteristics (grain color and size) were compared with their stable isotope compositions. RESULTS: Translucent grains (main component of IAEA-603; grain weight, 4-132 MUg) had homogeneous isotopic ratios, comparable with the grain-scale isotopic homogeneity of NBS 19. Their average delta13 C and delta18 O values were the same as the recommended values determined by the IAEA. Opaque (whitish) grains (1-2 per 100 grains; grain weight, 8-63 MUg) were significantly more depleted in 13 C and 18 O than the translucent grains. CONCLUSIONS: Low-abundance opaque grains (1-2 grains out of 100 grains) have lower delta13 C and delta18 O values, suggesting that these grains should be eliminated when using IAEA-603 for single-grain (microscale) isotope analysis. PMID- 28833710 TI - Factors associated with self-medication in Spain: a cross-sectional study in different age groups. AB - OBJECTIVE: The identification of factors which may influence a patient's decision to self-medicate. METHODS: Descriptive, cross-sectional study of the adult population (at least 16 years old), using data from the 2009 European Health Interview Survey in Spain, which included 22 188 subjects. Logistic regression models enabled us to estimate the effect of each analysed variable on self medication. KEY FINDINGS: In total, 14 863 (67%) individuals reported using medication (prescribed and non-prescribed) and 3274 (22.0%) of them self medicated. Using logistic regression and stratifying by age, four different models have been constructed. Our results include different variables in each of the models to explain self-medication, but the one that appears on all four models is education level. Age is the other important factor which influences self-medication. Self-medication is strongly associated with factors related to socio-demographic, such as sex, educational level or age, as well as several health factors such as long-standing illness or physical activity. CONCLUSIONS: When our data are compared to those from previous Spanish surveys carried out in 2003 and 2006, we can conclude that self-medication is increasing in Spain. PMID- 28833712 TI - Cell-free fetal DNA analysis in maternal plasma as screening test for trisomies 21, 18 and 13 in twin pregnancy. AB - OBJECTIVES: To evaluate in twin pregnancy the utility of non-invasive prenatal testing using circulating cell-free fetal DNA (cfDNA) in screening for the three main autosomal fetal trisomies. METHODS: cfDNA testing was offered to 492 patients with a twin pregnancy without ultrasound anomaly as a first-line screening test or after routine serum screening. Data were collected prospectively and a retrospective analysis was performed. cfDNA analysis was performed by massively parallel sequencing. The fetal-fraction threshold used for test evaluation was 8%. Regression analysis was performed to investigate the effect on the test failure rate of maternal and pregnancy characteristics, and the performance of the test was also reported. RESULTS: cfDNA analysis was performed as a first-line test (after the first-trimester scan) in 377 patients and following serum screening in 115. Of the 420 pregnancies for which outcome was available and cfDNA screening was assessed, 78.7% were dichorionic diamniotic. The test failed on the first attempt in 12 (2.9%) pregnancies, and regression analysis demonstrated that only maternal weight was a significant independent predictor of test failure. A result was subsequently achieved in the 10 cases for which a second sample was obtained. cfDNA analysis identified all three cases of trisomy 21 and the only case of trisomy 18. For trisomy 21, the specificity was 99.8% (95% CI, 98.7-100.0%). When considering pregnancies according to whether they were conceived spontaneously or after assisted reproductive technology, there were no significant differences in terms of maternal weight or no-result rate for cfDNA screening between these two groups. CONCLUSIONS: In twin pregnancy without fetal ultrasound abnormality, cfDNA screening for trisomies 21, 18 and 13 had a high success rate and good performance. Therefore, in routine practice, cfDNA analysis could be considered as a first- or second-line screening test. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28833711 TI - Hydrogen Bonding: Regulator for Nucleophilic Fluorination. AB - The recent advances in nucleophilic fluorination, regulated through hydrogen bonding interactions are summarized. Two main categories of fluorine nucleophiles are discussed. Alkali-metal fluorides are widely used in various fluorination transformations because they are inexpensive and safe nucleophilic fluorine sources. But the non-controllable nucleophilicity and strong basicity of some of them cause undesired side reactions, which led to the introduction of hydrogen bonding to fine tune their nucleophilicity and basicity. In contrast, an HF-based fluorine nucleophile, HF/DMPU, is in some aspects superior to the conventional HF/pyridine (Olah's reagent) or HF/Et3 N because of the higher hydrogen bond basicity of DMPU. It has been used in several nucleophilic fluorinations such as fluorination of alkynes, fluoro-Prins reaction and fluorination of aziridines. PMID- 28833713 TI - Self-Assembled Vesicle-Carbon Nanotube Conjugate Formation through a Boronate Diol Covalent Linkage. AB - A vesicle-single walled carbon nanotube (CNT) conjugate was developed by a boronic acid-diol covalent linkage between a self-assembled vesicle and dispersed CNT. Trimesic acid based phenylboronic acid appended triple-tailed amphiphiles (T1 and T1S) were synthesized that formed monolayered vesicles through H aggregation in DMSO-water (2:1 v/v) and pure water, respectively. Aqueous CNT dispersion was prepared with cholesterol-based glucose-functionalized amphiphile (D1). These two supramolecular self-assemblies were covalently linked by using a boronic acid-diol interaction between a phenylboronic acid based T1S vesicle and 1,2-diol moieties of glucose tethered dispersing agent (D1) to develop a vesicle CNT conjugate. Lewis acid-base chemistry was exploited to form this boronate-diol adduct between two supramolecular self-assemblies. The formation of vesicles, CNT dispersion, and the vesicle-CNT conjugate was characterized by microscopic and spectroscopic techniques. Anticancer drug doxorubicin was encapsulated within this T1S-vesicle-D1-CNT conjugate with a higher loading capacity compared to the individual cargo carrier (vesicle or CNT). This cytocompatible T1S-vesicle-D1-CNT conjugate successfully delivered loaded doxorubicin within a B16F10 melanoma cell and also exhibited better cellular transportation ability compared to the drug loaded vesicle or CNT. This was further reflected in an enhanced killing efficiency of the cancer cells by the vesicle-CNT conjugate compared to the drug loaded vesicle or CNT. PMID- 28833714 TI - Conversion from twice-daily to once-daily tacrolimus formulation in pediatric liver transplant recipients - a long-term prospective study. AB - To assess the safety and efficacy of conversion from twice-daily tacrolimus to once-daily tacrolimus in pediatric liver transplant recipients. Conversion from twice-daily to once-daily tacrolimus was made in stable pediatric liver transplant recipients. Doses and serum levels of tacrolimus, liver, and renal function were recorded on the day before the conversion and at days 5, 30, 90, and 180 postconversion. Patients were controlled every 2-3 months thereafter. Fifty-five patients were enrolled in the study. The mean age at conversion was 10.2 +/- 3.6 years. The mean tacrolimus trough level was 4.7 +/- 1.9 ng/dl preconversion, followed by a significant decline to 4.2 +/- 1.7 30 days after the switch (P < 0.004). Mean daily tacrolimus dose was 0.09 +/- 0.046 mg/Kg preconversion with a significant increase to 0.11 +/- 0.060 3 months postconversion (P < 0.001). Fifteen patients with calculated glomerular filtration rate between 60 to 80 ml/min/m2 preconversion showed a significant improvement one and 3 years after the switch (73 +/- 4.1, 83 +/- 4.3 and 90.3 +/- 7.3 ml/min/m2 , respectively (P < 0.001). The mean follow-up was 5.2 +/- 2.4 years. Conversion to once-daily tacrolimus is safe and effective in a cohort of stable pediatric liver transplant patients. PMID- 28833715 TI - Exploring the association between genetic and environmental factors and molar incisor hypomineralization: evidence from a twin study. AB - BACKGROUND: The etiology of molar-incisor hypomineralization (MIH) remains unknown. Studies indicate that it is multifactorial, and that genetic and environmental factors are involved. Research with twins provides important subsidy to investigate the Influence of genetics and environmental factors that act during pregnancy on the etiology of alterations. AIM: This cross-sectional study evaluated the agreement of molar incisor hypomineralization (MIH) between monozygotic and dizygotic twin pairs and the association with environmental factors. DESIGN: The sample consisted of 167 pairs of twins (8-15 years old), 94 monozygotic and 73 dizygotic. The parents answered a questionnaire on sociodemographic data and pre-, peri-, and postnatal health. A dental examination was performed by two calibrated examiners (Kappa >=0.88) for MIH diagnosis, following the criteria proposed by the European Academy of Pediatric Dentistry in 2003. RESULTS: The prevalence of MIH was 29.3%. There was greater concordance of MIH between monozygotic twins for affected first molars and permanent incisors (P = 0.0012) and pairs of twins assessed (P = 0.0211). The presence of MIH was associated with family income between one and two wages (P = 0.009, prevalence ratio [PR] = 3.82, confidence interval [CI 95%] 1.40-10.44), above two wages (P = 0.007, PR = 4.60, 95% CI: 1.51-14.05), and gestational hemorrhage (P = 0.032, PR = 5.70, 95% CI: 1.16-28.14). CONCLUSIONS: The greater concordance in the diagnosis of MIH among monozygotic twins indicates a genetic influence, although environmental factors, such as family income and hemorrhage during pregnancy, are also associated with the occurrence of MIH. PMID- 28833716 TI - Genomic estimation of additive and dominance effects and impact of accounting for dominance on accuracy of genomic evaluation in sheep populations. AB - The objectives of this study were to estimate the additive and dominance variance component of several weight and ultrasound scanned body composition traits in purebred and combined cross-bred sheep populations based on single nucleotide polymorphism (SNP) marker genotypes and then to investigate the effect of fitting additive and dominance effects on accuracy of genomic evaluation. Additive and dominance variance components were estimated in a mixed model equation based on "average information restricted maximum likelihood" using additive and dominance (co)variances between animals calculated from 48,599 SNP marker genotypes. Genomic prediction was based on genomic best linear unbiased prediction (GBLUP), and the accuracy of prediction was assessed based on a random 10-fold cross validation. Across different weight and scanned body composition traits, dominance variance ranged from 0.0% to 7.3% of the phenotypic variance in the purebred population and from 7.1% to 19.2% in the combined cross-bred population. In the combined cross-bred population, the range of dominance variance decreased to 3.1% and 9.9% after accounting for heterosis effects. Accounting for dominance effects significantly improved the likelihood of the fitting model in the combined cross-bred population. This study showed a substantial dominance genetic variance for weight and ultrasound scanned body composition traits particularly in cross-bred population; however, improvement in the accuracy of genomic breeding values was small and statistically not significant. Dominance variance estimates in combined cross-bred population could be overestimated if heterosis is not fitted in the model. PMID- 28833717 TI - Incorporating an Inert Polymer into the Interlayer Passivates Surface Defects in Methylammonium Lead Halide Perovskite Solar Cells. AB - The hysteresis effect and instability are important concerns in hybrid perovskite photovoltaic devices that hold great promise in energy conversion applications. In this study, we show that the power conversion efficiency (PCE), hysteresis, and device lifetime can be simultaneously improved for methylammoniumlead halide (CH3 NH3 PbI3-x Clx ) solar cells after incorporating poly(methyl methacrylate) (PMMA) into the PC61 BM electron extraction layer (EEL). By choosing appropriate molecular weights of PMMA, we obtain a 30 % enhancement of PCE along with effectively lowered hysteresis and device degradation, adopting inverted planar device structure. Through the combinatorial study using Kelvin probe force microscopy, diode mobility measurements, and irradiation-dependent solar cell characterization, we attribute the enhanced device parameters (fill factor and open circuit voltage) to the surface passivation of CH3 NH3 PbI3-x Clx , leading to mitigating charge trapping at the cathode interface and resultant Shockley Read-Hall charge recombination. Beneficially, modified by inert PMMA, CH3 NH3 PbI3-x Clx solar cells display a pronounced retardation in performance degradation, resulting from improved film quality in the PC61 BM layer incorporating PMMA which increases the protection for underneath perovskite films. This work enables a versatile and effective interface approach to deal with essential concerns for solution-processed perovskite solar cells by air stable and widely accessible materials. PMID- 28833718 TI - Bovine pericardium for multiple artery reconstruction in kidney transplantation. PMID- 28833719 TI - Integrating medication samples into the traditional community pharmacy supply chain: a feasibility study. AB - OBJECTIVE: To assess the feasibility of a medication sampling program involving community pharmacists. METHODS: A community pharmacy dispensed samples after receiving a voucher given to patients by prescribers. Surveys explored prescribers' and patients' views about sampling and patients' experiences with the program. KEY FINDINGS: Half of prescribers reported providing samples, yet 15 patients redeemed 18 vouchers over 1 year. Patients expressed favourable views towards sampling and pharmacist involvement, despite more than half (n = 8/15, 53%) feeling that visiting the pharmacy was less convenient. CONCLUSION: A voucher-based medication sampling program based in a community pharmacy is a model integrating pharmacist care. PMID- 28833720 TI - Near-field impedance accurately distinguishes among pericardial, intracavitary, and anterior mediastinal position. AB - INTRODUCTION: Epicardial catheter ablation is increasingly used to treat arrhythmias with an epicardial component. Nevertheless, percutaneous epicardial access remains associated with a significant risk of major complications. Developing a technology capable of confirming proper placement within the pericardial space could decrease complication rates. The purpose of this study was to examine differences in bioimpedance among the pericardial space, anterior mediastinum, and right ventricle. METHODS: An ovine model (n = 3) was used in this proof-of-concept study. A decapolar catheter was used to collect bipolar impedance readings; data were collected between each of five electrode pairs of varying distances. Data were collected from three test regions: the pericardial space, anterior mediastinum, and right ventricle. A control region in the inferior vena cava was used to normalize the data from the test regions. Analysis of variance was used to test for differences among regions. RESULTS: A total of 10 impedance values were collected in each animal between each of the five electrode pairs in the three test regions (n = 340) and the control region (n = 145). The average normalized impedance values were significantly different among the pericardial space (1.760 +/- 0.370), anterior mediastinum (3.209 +/- 0.227), and right ventricle (1.024 +/- 0.207; P < 0.0001). In post hoc testing, the differences between each pair of regions were significant, as well (P < 0.001 for all). CONCLUSION: Impedance values are significantly different among these three anatomical compartments. Therefore, impedance can be potentially used as a means to guide percutaneous epicardial access. PMID- 28833721 TI - From a Diphosphanegermylene to Nickel, Palladium, and Platinum Complexes Containing Germyl PGeP Pincer Ligands. AB - The PGeP pincer-type germylene Ge(NCH2 PtBu2 )C6 H4 (1) has been used to prepare a family of group 10 metal complexes, namely, [MCl{kappa3 P,Ge,P-GeCl(NCH2 PtBu2 )2 C6 H4 }] (M=Ni (2Ni ), Pd (2Pd ), Pt (2Pt )), featuring a chloridogermyl PGeP pincer ligand and a Cl-Ge-M-Cl bond sequence. Their reactivity is not initially centered on the metal atom but on their Ge atom. Complexes 2Ni and 2Pd easily led to the hydrolyzed products [Ni2 Cl2 {MU-(kappa3 P,Ge,P-Ge(NCH2 PtBu2 )2 C6 H4 )2 O}], which features a Cl-Ni-Ge-O-Ge-Ni-Cl bond sequence, and [PdCl{kappa3 P,Ge,P Ge(OH)(NCH2 PtBu2 )2 C6 H4 }], which contains a hydroxidogermyl PGeP pincer ligand (2Pt is reluctant to undergo hydrolysis). Simple chloride exchange reactions led to the methoxidogermyl, methylgermyl, and phenylgermyl derivatives [MCl{kappa3 P,Ge,P-GeR(NCH2 PtBu2 )2 C6 H4 }] (M=Pd, Pt; R=OMe, Me, Ph). Whereas the palladium complexes [PdCl{kappa3 P,Ge,P-GeR(NCH2 PtBu2 )2 C6 H4 }] (R=Me, Ph) reacted with more MeLi or PhLi to give palladium black and GeR2 (NCH2 PtBu2 )2 C6 H4 (R=Me, Ph), similar reactions with the analogous platinum complexes afforded the transmetalation derivatives [PtR{kappa3 P,Ge,P-GeR(NCH2 PtBu2 )2 C6 H4 }] (R=Me, Ph). The short length of the CH2 PtBu2 arms of the PGeP pincer ligands forces the metal atoms of all these complexes to be in a very distorted square planar ligand environment. The reactivity results have been rationalized with theoretical calculations. PMID- 28833722 TI - Killing two birds with one stone: response to pembrolizumab in a patient with metastatic melanoma and B-cell chronic lymphocytic leukaemia. PMID- 28833723 TI - Prevalence of malnutrition among older people in medical and surgical wards in hospital and quality of nutritional care: A multicenter, cross-sectional study. AB - AIMS AND OBJECTIVES: To determine and compare the prevalence of malnutrition in medical and surgical hospital units; to assess quality of nutritional care and patients' perception about quality of food and nutritional care. BACKGROUND: Hospital malnutrition in older people leads to increased mortality, length of stay, risk of infections and pressure ulcers. Several studies show that malnutrition is often caused by hospitalisation and related to poor nutritional care. Few studies report data on surgical older patients. DESIGN: A cross sectional, multicenter study was conducted in 12 hospitals in northern Italy. METHODS: Malnutrition prevalence was determined according to the Mini Nutritional Assessment full-version. Head nurses were interviewed in 80 units, through a validated questionnaire regarding quality of nutritional care. Semi-structured interviews were administered to a sample of patients, to investigate their perception about quality of food and nutritional care. RESULTS: Two hundred twenty-eight patients of 1,066 were malnourished (21.4%). Medical patients were at higher risk, so were women, patients aged 85 or more, with impaired autonomy, pressure ulcers or taking more than three drugs. The lack of personnel impacts on quality of care: in 55% of the units, no nutritional screening is performed; nutritional history is investigated in 48% only. No protocols for nutritional problems exist in 70% of the wards; hardly ever the intake is measured. Patients are mostly satisfied, even though they report that food has no taste and is not well presented. They remark the need for more personnel. CONCLUSION: Prevalence was high, as found in other studies. Medical patients were at higher risk. Nutritional care was inadequate, and often no measures were adopted to prevent malnutrition. Staffing should be increased during meals. RELEVANCE TO CLINICAL PRACTICE: These findings will provide indications on the strategies needed to overcome such barriers. PMID- 28833724 TI - Construction and characterization of mutated LEA peptides in Escherichia coli to develop an efficient protein expression system. AB - To develop an efficient protein expression system, we designed a late embryogenesis abundant (LEA) peptide by mutating the LEA peptide constructed in our previous study (LEA-I). The peptide is based on the repeating units of an 11mer motif characteristic of LEA proteins from Polypedilum vanderplanki larvae. In the amino acid sequence of the 13mer LEA peptide, glycine at the 6th and 12th positions was replaced with other amino acids via point mutations. Glutamic acid, lysine, leucine, and asparagine in the LEA peptide at the 6th and 12th positions increased green fluorescence protein (GFP) expression. The GFP expression of the mutated LEA peptide was 1.5 to 2.0 times higher than that without LEA peptide. In contrast, the serine-containing mutated LEA peptide has low GFP expression levels. We hypothesize that the position of amino acids and the nature of amino acid in LEA peptide are important for our coexpression system. These data suggest that the size, structure, and charge of amino acids in the LEA peptide improve the protection and expression of the target protein. The amino acid balance also plays an important role in the expression of the target protein. PMID- 28833725 TI - Nutritional intake and growth velocity in preterm extremely low-birthweight infants in Asia: Are we doing enough? AB - AIM: To describe nutritional practices among preterm extremely low-birthweight (ELBW) infants and their impact on growth and to compare differences in nutritional intervention and comorbidities between those with limited growth velocity (GV < 25th percentile) and those with GV > 25th percentile. METHODS: A prospective cohort study was conducted to assess total protein and energy intake for week 1, days 14, 21 and 28 of life. Post-natal growth was calculated by measuring GV using an exponential model. Univariable analysis was applied to identify the potential risk factors associated with poor GV at day 28 and at discharge from hospital. RESULTS: The median GV from birth to day 28 was 9.84 g/kg/day and 11.87 g/kg/day for GV from birth to discharge. Increased protein and energy intake was associated with higher GV at discharge. Hypotension needing inotropes, necrotising enterocolitis (NEC), patent ductus arteriosus and chronic lung disease were significantly associated with reduced GV at discharge. Infants with NEC, hypotension needing inotropes and sepsis took a significantly longer time to achieve full enteral nutrition. A longer time to attain full enteral feeds was associated with slower GV at discharge. Small-for-gestational-age babies increased from 22% at birth to 66.6% at discharge. CONCLUSIONS: GV at discharge was positively correlated with increasing protein and energy intake in the first 28 days and adversely affected by the presence of neonatal morbidities. There was strong evidence of extra-uterine growth restriction, with the majority of preterm ELBW infants having lower z scores at discharge compared to at birth. PMID- 28833727 TI - Viking Helmet Corroles: Activating Inert Oxidometal Corroles. AB - Chemically inert oxidometal(V) corrols of molybdenum and rhenium undergo clean ligand-exchange reactions upon the action of SiCl4 . The resulting dichlorido complexes show trigonal prismatic coordination of the metal ion with the chlorine atoms residing in a cis configuration, and were studied by optical and resonance spectroscopy as well as DFT calculations. In situ reactivity studies with carbon nucleophiles indicate high reactivity for chlorine replacement. Treatment with sodium cyclopentadienide paves the way to robust molybdenum corrolocene half sandwich complexes. These organometallic compounds are the first corrole species that stabilize an air-stable and diamagnetic low spin d2 -MoIV center. Structural, spectroelectrochemical, and chemical investigations prove a reversible MoIV /MoV redox couple close to the Fc/Fc+ potential for these systems. The high stability of the compounds in both redox states calls for future applications in catalysis and as redox switch. PMID- 28833726 TI - Performance of 1,3-beta-D-glucan for diagnosing invasive fungal diseases in children. AB - Plasma 1,3-beta-D-glucan (BDG) is indicated as a tool for early diagnosis of invasive fungal diseases (IFD). However, data on its diagnostic value are scarce in children. Therefore, definition of BDG test performance in paediatrics is needed. BDG was evaluated in children admitted to "Istituto Giannina Gaslini," Genoa, Italy, who developed clinical conditions at risk for IFD. Results were analysed for sensitivity, specificity, predictive values, likelihood ratios, accuracy, informedness and probability of missing one case by a negative test. A total of 1577 BDG determinations were performed on 255 patients (49% males, median age 5.4 years). Overall 46 IFD were diagnosed, 72% proven/probable. The test performance was evaluated for 80 pg/mL, 120 pg/mL, 200 pg/mL, 350 pg/mL, 400 pg/mL cut offs. Sensitivity was always <0.80 and specificity > 0.90 only for cut offs >=200 pg/mL. Negative predictive value was >=0.90 for all the cut offs evaluated, while positive predictive value resulted barely 0.50 (8% IFD prevalence). Accuracy was never >0.90, and informedness was at best 0.50. The risk of missing one IFD by a negative result was < 10%. Analyses in haemato oncological or newborn patients did not show major differences. Detection of serum BDG does not appear a valuable adjunctive diagnostic tool for IFD in paediatrics. PMID- 28833728 TI - The culture contributing to interruptions in the nursing work environment: An ethnography. AB - AIMS AND OBJECTIVES: To understand the occurrence of interruptions within the culture of the medical nursing unit work environment. BACKGROUND: Interruptions may lead to errors in nursing work. Little is known about how the culture of the nursing work environment contributes to interruptions. DESIGN: A micro-focused ethnographic study was conducted. METHOD: Data collection involved extensive observation of a nursing unit, 1:1 observations of nurses and follow-up interviews with the nurses. Data were analysed from unstructured field notes and interview transcripts. The definitions of interruption and culture guided coding, categorising and identification of themes. RESULTS: A framework was developed that describes the medical nursing unit as a complex culture full of unpredictable, nonlinear changes that affect the entire interconnected system, often in the form of an interruption. The cultural elements contributing to interruptions included (i) the value placed on excellence in patient care and meeting personal needs, (ii) the beliefs that the nurses had to do everything by themselves and that every phone call was important, (iii) the patterns of changing patients, patient transport and coordination of resources and (iv) the normative practices of communicating and adapting. CONCLUSIONS: Interruptions are an integral part of the culture of a medical nursing unit. Uniformly decreasing interruptions may disrupt current practices, such as communication to coordinate care, that are central to nursing work. In future research, the nursing work environment must be looked at through the lens of a complex system. RELEVANCE TO CLINICAL PRACTICE: Interventions to minimise the negative impact of interruptions must take into account the culture of the nursing as a complex adaptive system. Nurses should be educated on their own contribution to interruptions and issues addressed at a system level, rather than isolating the interruption as the central issue. PMID- 28833729 TI - A CRY-BIC negative-feedback circuitry regulating blue light sensitivity of Arabidopsis. AB - Cryptochromes are blue light receptors that regulate various light responses in plants. Arabidopsis cryptochrome 1 (CRY1) and cryptochrome 2 (CRY2) mediate blue light inhibition of hypocotyl elongation and long-day (LD) promotion of floral initiation. It has been reported recently that two negative regulators of Arabidopsis cryptochromes, Blue light Inhibitors of Cryptochromes 1 and 2 (BIC1 and BIC2), inhibit cryptochrome function by blocking blue light-dependent cryptochrome dimerization. However, it remained unclear how cryptochromes regulate the BIC gene activity. Here we show that cryptochromes mediate light activation of transcription of the BIC genes, by suppressing the activity of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), resulting in activation of the transcription activator ELONGATED HYPOCOTYL 5 (HY5) that is associated with chromatins of the BIC promoters. These results demonstrate a CRY-BIC negative feedback circuitry that regulates the activity of each other. Surprisingly, phytochromes also mediate light activation of BIC transcription, suggesting a novel photoreceptor co-action mechanism to sustain blue light sensitivity of plants under the broad spectra of solar radiation in nature. PMID- 28833730 TI - Use of a commercial qPCR assay in 52 high risk shelter cats for disease identification of dermatophytosis and mycological cure. AB - BACKGROUND: qPCR is used to test for dermatophytosis. OBJECTIVES: To determine the clinical usefulness of a commercial qPCR for confirming dermatophytosis in lesional cats, and the clinical usefulness of the qPCR Microsporum spp. and/or M. canis assay for confirming mycological cure. ANIMALS: Fifty two shelter cats with skin lesions. METHODS: qPCR testing of toothbrush fungal culture samples of lesions. RESULTS: qPCR and fungal culture (FC) matched in 49 of 52 cats. The qPCR correctly identified 45 of 46 and two of four cats with M. canis and Trichophyton spp. infections, respectively. qPCR correctly identified two cats as not infected. No evidence of cross reactivity was noted. The Microsporum spp. qPCR assay was positive in 45 of 46 (97.8%) of infected cats. Results were positive on both Microsporum spp. and M. canis assays in 29 of 45 cats. No cat had a positive qPCR result for M. canis alone. Mycological cure was defined as two negative fungal cultures. There were 92 negative FC from the 46 treated cats and qPCR assay for Microsporum spp. and M. canis was negative in 68 of 92 (73.1%) and 79 of 92 (85.9%) samples, respectively. The number of cats correctly identified with mycological cure via qPCR was 30 of 46 (65.2%) and 39 of 46 (84.8%) cats for the Microsporum spp. and M. canis assays, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: The commercial qPCR assay was a reliable test for confirming disease. The qPCR Microsporum spp. assay was more useful for initial disease confirmation; while the qPCR M. canis assay was more useful for determining mycological cure. PMID- 28833731 TI - Potassium (De-)insertion Processes in Prussian Blue Particles: Ensemble versus Single Nanoparticle Behaviour. AB - Potassium (de-)insertion from Prussian blue (PB) is investigated at the single and multi-particle scale. The electrochemical behaviour is found to differ between the two measurement types. At the single particle level, oxidation of the PB nanoparticles with concomitant K+ deinsertion occurs more readily than the associated reduction, relating to K+ insertion. In contrast, the cyclic voltammetry of PB in a composite electrode containing conductive additives and polymeric binder suggests the opposite behaviour. Implications for assessing battery materials are discussed. PMID- 28833733 TI - Combining Two Methods of Sequence Definition in a Convergent Approach: Scalable Synthesis of Highly Defined and Multifunctionalized Macromolecules. AB - The straightforward convergent synthesis of sequence-defined and multifunctionalized macromolecules is described herein. The first combination of two efficient approaches for the synthesis of sequence-defined macromolecules is reported: thiolactone chemistry and the Passerini three-component reaction (P 3CR). The thiolactone moiety was used as protecting group for the thiol, allowing the synthesis of a library of sequence-defined alpha,omega-functionalized building blocks. These building blocks were subsequently efficiently coupled to oligomers with carboxylic acid functionalities in a P-3CR. Thus, larger oligomers with molecular weights of up to 4629.73 g mol-1 were obtained in gram quantities in a convergent approach along with the introduction of independently selectable side chains (up to 15), thus clearly demonstrating the high versatility and the efficiency of the reported approach. PMID- 28833732 TI - Grey matter volume in adolescents with anorexia nervosa and associated eating disorder symptoms. AB - Anorexia nervosa (AN) is a mental health disorder of complex aetiology. Previous neuroimaging studies have found consistent global reductions in global grey matter volume of underweight girls with AN; however, differences in regional grey matter volumes are less consistent. The aims of this study were to investigate grey matter regional volumes of adolescent girls with AN before and after weight recovery and the relationship of any changes with clinical characteristics. We collected high-resolution T1-weighted images from 26 underweight girls with AN before weight gain and 20 healthy control volunteers. Clinical features were assessed using the Eating Disorder Examination Questionnaire. AN subjects displayed reduced grey matter volumes in the insula, amygdala, prefrontal, hippocampal and cingulate cortices and the precuneus, relative to healthy controls. In a subset of 10 AN subjects who were followed after weight recovery, grey matter volumes increased to near-control levels in the orbito- and medial prefrontal, insular, left hippocampal and mid- and posterior cingulate cortices and precuneus. The recovery of the right anterior thalamus and the left orbitofrontal cortex was correlated with improvements in eating concerns and shape concerns, respectively. However, large parts of the anterior cingulate cortex, caudate nuclei and right hippocampus did not display any grey matter recovery following a short-term of treatment. These results show that in adolescents with AN, some brain regions display marked recovery in grey matter volume following weight recovery, whereas others do not, considering grey mater recovery possibly linked to symptom improvement. PMID- 28833734 TI - Modulation of Multiscale 3D Lattices through Conformational Control: Painting Silk Inverse Opals with Water and Light. AB - Structural proteins from naturally occurring materials are an inspiring template for material design and synthesis at multiple scales. The ability to control the assembly and conformation of such materials offers the opportunity to define fabrication approaches that recapitulate the dimensional hierarchy and structure function relationships found in nature. A simple and versatile directed assembly method of silk fibroin, which allows the design of structures across multiple dimensional scales by generating and tuning structural color in large-scale, macro defect-free colloidally assembled 3D nanostructures in the form of silk inverse opals (SIOs) is reported. This approach effectively combines bottom-up and top-down techniques to obtain control on the nanoscale (through silk conformational changes), microscale (through patterning), and macroscale (through colloidal assembly), ultimately resulting in a controllable photonic lattice with predefined spectral behavior, with a resulting palette spanning almost the entire visible range. As a demonstration of the approach, examples of "multispectral" SIOs, paired with theoretical calculations and analysis of their response as a function of changes of lattice constants and refractive index contrast are illustrated. PMID- 28833735 TI - Renal denervation decreases susceptibility of the heart to ventricular fibrillation in a canine model of chronic kidney disease. AB - NEW FINDINGS: What is the central question of this study? Renal denervation (RDN) has been shown to be effective and safe, resulting in better control of blood pressure and an improvement in left ventricular hypertrophy in chronic kidney disease (CKD) patients. Ventricular arrhythmias and sudden cardiac death are common causes of death in CKD patients, but previous studies pay almost no attention to the effects of RDN on the risk of ventricular fibrillation associated with CKD. What is the main finding and its importance? Renal denervation could decrease susceptibility of the heart to ventricular fibrillation in a canine CKD model. Improvement of left ventricular hypertrophy, sympathetic activation and inflammation by RDN may be responsible for its beneficial effects. Renal denervation (RDN) has been shown to have therapeutic value in patients with chronic kidney disease (CKD). The aim of this study was to investigate whether RDN could decrease the susceptibility of the heart to ventricular fibrillation in a canine model of CKD. Twenty-one dogs were used. Chronic kidney disease was produced by subtotal nephrectomy in 16 dogs with RDN treatment (CKD + RDN group, n = 8) or sham RDN (CKD group, n = 8). Another five dogs underwent sham operation and sham RDN to serve as controls (CTR group). Parameters of renal function, blood pressure, echocardiography, ECG, noradrenaline and inflammation were measured at baseline and 6 weeks after the surgical procedure. The ventricular fibrillation threshold (VFT) was determined at the end of the study. Subtotal nephrectomy successfully induced a canine CKD model. When compared with the CTR group, subtotal nephrectomy in the CKD group significantly elevated blood pressure; increased the left ventricular mass, end diastolic left ventricular internal dimension, left ventricular end-diastolic posterior wall thickness and end-diastolic interventricular septum thickness; prolonged the QT interval, corrected QT interval, the interval from the peak to the end of the T wave (Tp-e) and the corrected Tp-e interval; and increased the QT dispersion and the Tp-e/QT ratio; decreased the VFT; and increased the serum concentrations of noradrenaline, C-reactive protein and interleukin-6. Renal denervation significantly attenuated these changes induced by CKD. The study demonstrated that RDN could decrease the susceptibility of the heart to ventricular fibrillation in this CKD model. Improvement of left ventricular hypertrophy, sympathetic activation and inflammation by RDN may be responsible for its beneficial effects. PMID- 28833736 TI - New cancer cases in France in 2015 attributable to different levels of alcohol consumption. AB - BACKGROUND AND AIMS: Alcohol consumption increases the risk of cancer. Thus, to inform policy decisions, this study estimated the number of new cancer cases in France in 2015 attributable to alcohol consumption generally and to light (< 20 g per day (g/day) among women; < 40 g/day among men), moderate (20 to < 40 g/day among women; 40 to < 60 g/day among men) and heavy drinking (>= 40 g/day among women; >= 60 g/day among men), and the number of cancer cases that would have been prevented assuming a previous 10% decrease in alcohol consumption. DESIGN: New cancer cases attributable to alcohol were estimated using a population attributable fraction methodology, assuming a 10-year latency period between exposure and diagnosis. SETTING AND PARTICIPANTS: Population of France, 2015. MEASUREMENTS: Alcohol consumption was estimated by coordinating data from the Barometre sante 2005, a national representative survey (n = 30 455), with data from the Global Information System on Alcohol and Health. Relative risks were obtained from meta-analyses. Cancer data were estimated based on data from the French Cancer Registries Network. Uncertainty intervals (UI) were estimated using a Monte Carlo procedure. FINDINGS: In France in 2015, an estimated 27 894 (95% UI = 24 287-30 996) or 7.9% of all new cancer cases were attributable to alcohol. The number of alcohol-attributable new cancer cases was similar for both men and women, with oesophageal squamous cell carcinomas having the largest attributable fraction (57.7%). Light, moderate, heavy and former alcohol drinking were responsible for 1.5, 1.3, 4.4 and 0.6% of all new cancer cases, respectively. Lastly, if there had been a previous 10% reduction in alcohol consumption, 2178 (95% UI = 1687-2601) new cancer cases would have been prevented. CONCLUSIONS: Alcohol consumption in France appears to cause almost 8% of new cancer cases, with light and moderate drinking contributing appreciably to this burden. A 10% drop in drinking in France would have prevented more than 2000 (estimated) new cancer cases in 2015. PMID- 28833737 TI - Factors influencing the implementation of evidence in Chinese nursing practice. AB - AIMS AND OBJECTIVES: To explore the influencing factors from staff nurses, nurse managers, nursing directors and a physician involved in nursing evidence implementation in Mainland China. BACKGROUND: Although the need for evidence based nursing is well recognised, continuous efforts are needed to strive for closing the gap from evidence to action. Previous studies have explored influencing factors from individual and organisational perspectives in Western countries. However, it remains unclear what the influences (i.e., context and culture) in the developing countries as China. DESIGN: A grounded theory design using in-depth individual interviews was conducted. METHODS: Interviews with 56 participants from 24 evidence-based nursing implementation projects were conducted in Mainland China. Constant comparative analysis was used to discover the concepts describing the influencing factors during the implementation process. RESULTS: Factors that influenced implementation of evidence-based practice in the Chinese context were identified. These included the leaders of the projects, the nature of the evidence, practising nurses, patients involved in the projects, the system where the projects were implemented, as well as the influence from outside of the system. CONCLUSIONS: A variety of factors influencing evidence implementation in Chinese nursing context were identified and further explored from the perspective of different project leaders and culture influence. There is apparently a strong demand for a supportive system, targeted strategies to facilitate various evidence implementations and integrated core elements of evidence-based practice at the point care. RELEVANCE TO CLINICAL PRACTICE: The blurred boundaries and complexity of influencing factors call for a systematic and dynamic perspective during implementation. The competitive priorities emphasise the importance of integration between clinical nursing care and evidence-based practice. PMID- 28833738 TI - Socio-economic differentials in cannabis use trends in Australia. AB - AIM: To test if the degree of change in cannabis use between 2001 and 2013 differed according to socio-economic status. DESIGN: Repeated cross-sectional household surveys that were nationally representative. SETTING: Australia. PARTICIPANTS: Adult samples from the 2001 and 2013 National Drug Strategy Household Surveys (n = 23 642 in 2001 and n = 21 353 in 2013), the largest nationally representative survey on drug use in Australia. MEASUREMENTS: Frequency of cannabis use coded as daily use, weekly use, less than weekly use and non-current use; socio-economic status (SES) as measured by personal income and educational level. FINDING: There were significant differences in changes to levels of cannabis use between SES groups. Among participants who completed high school, the probability of daily use decreased from 0.014 to 0.009 (P < 0.001), and the probability of weekly use decreased from 0.025 to 0.017 (P < 0.001). These probabilities remained stable for participants who did not complete high school. The probability of weekly cannabis use decreased from 0.032 to 0.023 among participants with middle level income (P = 0.004), and from 0.021 to 0.013 among those with high income (P = 0.005). There were no significant changes in these probabilities among those with low income (0.026 in 2001 and 0.032 in 2013; P = 0.203). CONCLUSION: The decline in cannabis use in Australia from 2001 to 2013 occurred largely among higher socio-economic status groups. For people with lower income and/or lower education, rates of frequent cannabis use remained unchanged. PMID- 28833739 TI - Two-Photon In Vivo Imaging with Porous Silicon Nanoparticles. AB - A major obstacle in luminescence imaging is the limited penetration of visible light into tissues and interference associated with light scattering and autofluorescence. Near-infrared (NIR) emitters that can also be excited with NIR radiation via two-photon processes can mitigate these factors somewhat because they operate at wavelengths of 650-1000 nm where tissues are more transparent, light scattering is less efficient, and endogenous fluorophores are less likely to absorb. This study presents photolytically stable, NIR photoluminescent, porous silicon nanoparticles with a relatively high two-photon-absorption cross section and a large emission quantum yield. Their ability to be targeted to tumor tissues in vivo using the iRGD targeting peptide is demonstrated, and the distribution of the nanoparticles with high spatial resolution is visualized. PMID- 28833740 TI - Valuing Metal-Organic Frameworks for Postcombustion Carbon Capture: A Benchmark Study for Evaluating Physical Adsorbents. AB - The development of practical solutions for the energy-efficient capture of carbon dioxide is of prime importance and continues to attract intensive research interest. Conceivably, the implementation of adsorption-based processes using different cycling modes, e.g., pressure-swing adsorption or temperature-swing adsorption, offers great prospects to address this challenge. Practically, the successful deployment of practical adsorption-based technologies depends on the development of made-to-order adsorbents expressing mutually two compulsory requisites: i) high selectivity/affinity for CO2 and ii) excellent chemical stability in the presence of impurities. This study presents a new comprehensive experimental protocol apposite for assessing the prospects of a given physical adsorbent for carbon capture under flue gas stream conditions. The protocol permits: i) the baseline performance of commercial adsorbents such as zeolite 13X, activated carbon versus liquid amine scrubbing to be ascertained, and ii) a standardized evaluation of the best reported metal-organic framework (MOF) materials for carbon dioxide capture from flue gas to be undertaken. This extensive study corroborates the exceptional CO2 capture performance of the recently isolated second-generation fluorinated MOF material, NbOFFIVE-1-Ni, concomitant with an impressive chemical stability and a low energy for regeneration. Essentially, the NbOFFIVE-1-Ni adsorbent presents the best compromise by satisfying all the required metrics for efficient CO2 scrubbing. PMID- 28833741 TI - Entropy as a Gene-Like Performance Indicator Promoting Thermoelectric Materials. AB - High-throughput explorations of novel thermoelectric materials based on the Materials Genome Initiative paradigm only focus on digging into the structure property space using nonglobal indicators to design materials with tunable electrical and thermal transport properties. As the genomic units, following the biogene tradition, such indicators include localized crystal structural blocks in real space or band degeneracy at certain points in reciprocal space. However, this nonglobal approach does not consider how real materials differentiate from others. Here, this study successfully develops a strategy of using entropy as the global gene-like performance indicator that shows how multicomponent thermoelectric materials with high entropy can be designed via a high-throughput screening method. Optimizing entropy works as an effective guide to greatly improve the thermoelectric performance through either a significantly depressed lattice thermal conductivity down to its theoretical minimum value and/or via enhancing the crystal structure symmetry to yield large Seebeck coefficients. The entropy engineering using multicomponent crystal structures or other possible techniques provides a new avenue for an improvement of the thermoelectric performance beyond the current methods and approaches. PMID- 28833742 TI - Application of a novel reference material in an international round robin test on material emissions testing. AB - Emission testing of products is currently a rapidly increasing field of measurement activity. Labeling procedures for construction products are based on such emission test chamber measurements, and hence, measurement performance should be verified. One possible route is to conduct testing of one material in different laboratories within a round robin test (RRT), ideally using homogeneous reference materials, which can be used within interlaboratory studies or as part of the quality management system to ensure comparable results. The applicability of a lacquer system with nine added VOCs (hexanal, styrene, n-decane, limonene, 2 ethyl-1-hexanol, N-methyl-alpha-pyrrolidone, 2-ethylhexyl acrylate, dimethyl phthalate, and n-hexadecane) was evaluated in an international RRT with 55 participating laboratories. An intralaboratory quality check confirmed the homogeneity and reproducibility of the lacquer material for most of the compounds (RSD 5%-6%), which was confirmed in the RRT. However, emissions varied for the polar compound N-methyl-alpha-pyrrolidone and the higher boiling compounds 1,2 dimethyl phthalate, and n-hexadecane which could be traced back to analytical issues. In the RRT, the interlaboratory relative standard deviations (RSDs) ranged from 30% to 65% for all participants but for reference laboratories the range was between 20% and 45%. PMID- 28833743 TI - Paroxysmal nocturnal haemoglobinuria testing in blood transfusion laboratories: do they go with the flow? AB - Paroxysmal nocturnal haemoglobinuria (PNH) is a rare stem cell disorder causing, in untreated patients, symptoms that include renal damage, thrombosis and increased mortality. When correctly diagnosed and treated, patients have reduced symptoms and normal life expectancies. Historically PNH testing resided within blood transfusion laboratories using techniques that were insensitive, for example, the Ham test. However, technology has evolved and flow cytometry is now regarded as the gold standard methodology. Given the clinical importance of diagnosing PNH correctly, we undertook a study to examine PNH testing procedures in blood transfusion laboratories within the UK and Ireland to determine implementation of best practices. An online survey was issued to 386 blood transfusion laboratories in the UK and Ireland requesting details of their current PNH testing practices and procedures. There were 143 responses, representing a 37% response rate. Of these, we identified seven laboratories undertaking PNH testing using obsolete methodologies. Furthermore, multiple centres did not refer samples for confirmatory testing by national PNH reference centres and inclusion on the national PNH disease registry. Staff handling requests for PNH testing should ensure that all samples are tested in accordance with current best practices using only flow cytometry. PMID- 28833745 TI - Pharmacoepidemiology of testosterone: Curbing off-label prescribing. AB - OBJECTIVES: To estimate the impact of the first year of new Pharmaceutical Benefits Scheme (PBS) prescribing criteria that dictate eligibility for national health scheme subsidy of testosterone prescribing. DESIGN: Analysis of cumulative PBS data. SETTING: Retrospective analysis of testosterone prescribing from PBS data. PARTICIPANTS: Nil MAIN OUTCOME MEASURES: PBS expenditure analysed by total expenditure, by state, and by product type as well as the age, indication, and prescriber type for new testosterone treatment. RESULTS: Total PBS expenditure continued to exceed $20 million in 2014 before declining from 2015 with changes that were uniform by state and product type. Prior to 2015, over 80% were for men aged over 40 years of age for low circulating testosterone in the absence of reproductive system disorders ("Low T") initiated by GPs. From 2015, these features were markedly reduced without changing the numbers of new prescriptions for pathological reproductive disorders or specialist initiations. CONCLUSIONS: The short-term impact of 2015 PBS criteria showed highly effective and well targeted curbing of off-label testosterone prescribing. The findings indicate that the main driver for the recent upsurge in testosterone prescribing was treatment of middle-aged men for "Low T" initiated by GPs. PMID- 28833744 TI - Examination of associations between early life victimisation and alcohol's harm from others. AB - INTRODUCTION AND AIMS: Study aims were to examine: (i) how physical and sexual victimisation in early life are associated with alcohol's harm from others; and (ii) whether respondents' current drinking is a mediator of the association between early life victimisation and alcohol's harm from others among men and women. DESIGN AND METHODS: Data were from national computer-assisted telephone interviews, using the landline sample (3335 men and 3520 women ages >=18) from the 2010 US National Alcohol Survey. Harms from someone else's drinking included family/marital problems, financial troubles, assault and vandalism in the past 12 months. Victimisation was measured with severe physical abuse or sexual assault before age 18. RESULTS: Severe physical or sexual victimisation before age 18 was reported by 3.4% of men and 8.1% of women. Significantly more men (5.2%) than women (2.4%) reported assault by other drinkers, and significantly more women reported family/marital (5.3%) and financial problems (2.8%) than did men (2.6 and 1% respectively). Severe early life victimisation was robustly associated with a greater likelihood of experiencing past-year harms from other drinkers for both men and women. Men's drinking partially mediated associations between early life victimisation and recent assaults and vandalism by other drinkers. DISCUSSION AND CONCLUSIONS: Early life victimisation may increase risk of harms from someone else's drinking. Health services and interventions that screen for histories of victimisation may help decrease risk of later harms from others' drinking. Reductions in drinking among men with histories of victimisation also could help reduce their exposure to such harms. [Kaplan LM, Greenfield TK, Karriker-Jaffe KJ. Examination of associations between early life victimisation and alcohol's harm from others. PMID- 28833746 TI - A tug of war: antagonistic effective connectivity patterns over the motor cortex and the severity of motor symptoms in Gilles de la Tourette syndrome. AB - We tested the hypothesis that Gilles de la Tourette syndrome (GTS) is characterized by perturbed connectivity within cortico-subcortical motor networks. To this end, we performed a dynamic causal modelling (DCM) analysis of fMRI data collected during a finger opposition task in 24 normal controls and 24 GTS patients. The DCM analysis allowed us to assess whether any GTS-specific patterns of brain activity were related to intrinsic and/or to task-dependent connectivity. While no abnormalities were found for task-dependent connectivity, intrinsic connectivity was abnormally increased in the premotor network, with stronger connections from the supplementary motor area (SMA), from the dorsolateral premotor cortex and from the putamen to the right superior frontal gyrus, an area where GTS showed over-activation in a previous univariate analysis. We also found a positive correlation between the connectivity strength from the right basal ganglia to the right primary motor cortex (M1) and disease severity measured by the Yale Global Tic Severity Scale (YGTSS). This pattern was mirrored by a negative correlation between the connection strength from the right SMA to the right area M1 and the YGTSS score. These two reverse correlation effects showed a specific relationship with individual disease severity: the greater the imbalance between subcortical and premotor connectivity towards area M1, the higher the YGTSS score. These results reveal the existence of perturbed intrinsic connectivity patterns in the motor networks of GTS patients with two competing forces operating in a tug of war-like mechanism: aberrant subcortical afferents to M1, compensated for by inputs from the premotor cortex. PMID- 28833747 TI - A C(sp2 )-H Dehydrogenation of Heteroarenes and Arenes by a Functionalized Aluminum Hydride. AB - The 2-aminophenylaluminum dihydride (2-TMP-C6 H4 )AlH2 (2) has been prepared and characterized for the first time. Compound 2 features an intramolecular N???Al donor-acceptor bond. 2 reacted with N-methylpyrrole and N-methylindole (both at 50 degrees C) by means of the elusive AlH C(sp2 )-H dehydroalumination to aluminum heteroaryls (3 and 4). Moreover, 2 reacted with PhCCSiMe3 (at room temperature) and Ph2 CCNR (R=iPr or 2,6-iPr2 C6 H3 , at -30 to 20 degrees C ) to yield aluminaindene heterocycle (8) and alumina-aza-naphthalene heterocycle (9 and 10), respectively. These reactions underwent hydroalumination followed by AlH C(sp2 )-H dehydroalumination. The reaction mechanism has been studied by combining experiment and quantum chemical calculations, with the result that the key heteroarene or arene C(sp2 )-H bond activation is involved under cooperative interaction by the inherent N/Al donor/acceptor pair. The reported reactions open a straightforward route to heteroaryl and unique heterocyclic aluminum compounds. PMID- 28833748 TI - The coping experiences of spouses of persons with dementia. AB - AIMS AND OBJECTIVES: To explore how spouses who are caregivers to persons with dementia experience everyday life 6-12 months after participation in the intervention condition in the Norwegian Cognitive Behavioural Therapy for Early Dementia (N-CORDIAL) study. BACKGROUND: There is no current medical curative treatment for cognitive impairment and dementia-associated conditions. These conditions will lead to an increased need for daily assistance and care, as well as greater stress for caregivers. The Norwegian CORDIAL Study is a manual-based randomised controlled trial based on the German CORDIAL study (cognitive rehabilitation and cognitive behavioural treatment for early dementia in Alzheimer's disease), consisting of cognitive rehabilitation, cognitive behavioural therapy and life review methods. DESIGN AND METHODS: A descriptive exploratory study with qualitative semi-structured in-depth interviews with six spouses of persons with dementia who had participated in the Norwegian CORDIAL study. The transcribed text was analysed by systematic text condensation. RESULT: The main theme identified, "An everyday search for meaning," referred to the stress experienced by the caregivers and their coping strategies in everyday life. CONCLUSION: The caregivers had gained increased awareness of coping strategies in everyday life 6-12 months after the intervention. Caregivers who experienced fewer neuropsychiatric symptoms in their spouses with dementia benefitted most from the intervention. RELEVANCE TO CLINICAL PRACTICE: The study is relevant to clinical practice as interventions focusing on how to improve coping strategies may reduce caregiver stress and contribute to postponement of nursing home placement. PMID- 28833750 TI - First-trimester detection of abnormally invasive placenta in high-risk women: systematic review and meta-analysis. AB - OBJECTIVES: The primary aim of this systematic review was to ascertain whether ultrasound signs suggestive of abnormally invasive placenta (AIP) are present in the first trimester of pregnancy. Secondary aims were to ascertain the strength of association and the predictive accuracy of such signs in detecting AIP in the first trimester. METHODS: An electronic search of MEDLINE, EMBASE, CINAHL and Cochrane databases (2000-2016) was performed. Only studies reporting on first trimester diagnosis of AIP that was subsequently confirmed in the third trimester either during operative delivery or by pathological examination were included. Meta-analysis of proportions, random-effects meta-analysis and hierarchical summary receiver-operating characteristics curve analysis were used to analyze the data. RESULTS: Seven studies, involving 551 pregnancies at high risk of AIP, were included. At least one ultrasound sign suggestive of AIP was detected in 91.4% (95% CI, 85.8-95.7%) of cases with confirmed AIP. The most common ultrasound feature in the first trimester of pregnancy was low implantation of the gestational sac close to a previous uterine scar, which was observed in 82.4% (95% CI, 46.6-99.8%) of cases. Anechoic spaces within the placental mass (lacunae) were observed in 46.0% (95% CI, 10.9-83.7%) and a reduced myometrial thickness in 66.8% (95% CI, 45.2-85.2%) of cases affected by AIP. Pregnancies with a low implantation of the gestational sac had a significantly higher risk of AIP (odds ratio, 19.6 (95% CI, 6.7-57.3)), with a sensitivity and specificity of 44.4% (95% CI, 21.5-69.2%) and 93.4% (95% CI, 90.5-95.7%), respectively. CONCLUSIONS: Ultrasound signs of AIP can be present during the first trimester of pregnancy, even before 11 weeks' gestation. Low anterior implantation of the placenta/gestational sac close to or within the scar was the most commonly seen early ultrasound sign suggestive of AIP, although its individual predictive accuracy was not high. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28833751 TI - A proteomic analysis of contextual fear conditioned rats reveals dynamic modifications in neuron and oligodendrocyte protein expression in the dentate gyrus. AB - Contextual memory is an intricate process involving synaptic plasticity and network rearrangement. Both are governed by many molecular processes including phosphorylation and modulation of protein expression. However, little is known about the molecules involved in it. Here, we exploited the advantages of a quantitative proteomic approach to identify a great number of molecules in the rat dentate gyrus after a contextual fear conditioning session. Our results allowed us to highlight protein expression patterns, not only related to neuroplasticity, but also to myelin structure, such as myelin basic protein and myelin proteolipid protein showing a decrease in expression. Validation of the modification in protein expression reveals a dynamic profile during the 48 h following the fear conditioning session. The expression of proteins involved in neurite outgrowth, such as BASP-1 and calcineurin B1, and in synaptic structure and function, VAMP2 and RAB3C, was increased in the dentate gyrus of rats submitted to fear conditioning compared to controls. We showed that the increase in BASP-1 protein was specific to fear conditioning learning as it was not present in immediate-shock rats, neither in rats exposed to a novel environment without being shocked. As myelin is known to stabilise synaptic network, the decrease in myelin proteins suggests a neuroglia interactive process taking place in the dentate gyrus in the 24 h following contextual fear learning, which has never been demonstrated before. These results therefore open the way to the study of new plasticity mechanisms underlying learning and memory. PMID- 28833752 TI - Comparative Study of Different Acorus Species in Potentiating Neuronal Differentiation in Cultured PC12 Cells. AB - Acori Tatarinowii Rhizoma (ATR), the rhizome of Acorus tatarinowii Schott, is a common traditional Chinese medicine being used clinically for mental disorder. However, other Acorus species herbs are all having the same Chinese name 'Chang Pu', making the confusion in herbal market. Acori Graminei Rhizoma (AGR) and Acori Calami Rhizoma (ACR) are common adulterants of ATR. Here, we aim to provide a comparative analysis between ATR, AGR, and ACR in potentiating neuronal differentiation. Volatile oil, derived from Acorus species, was applied onto cultured PC12 cells, and various parameters were determined: (i) transcriptional activation of neurofilament promoters was determined by the promoter-driven luciferase activity assay; (ii) the neurite outgrowth of PC12 cells was captured and measured; and (iii) the neurofilament expression and its underlying mechanism were analyzed by western blotting. The co-treatment of ATR, AGR, or ACR volatile oil with low concentration of nerve growth factor (NGF) could potentiate the NGF induced neuronal differentiation in cultured PC12 cells. In addition, application of protein kinase A inhibitor H89 in cultures blocked the induction of neurofilament. Among these three Acorus species, ATR volatile oil showed the highest NGF-induced induction in neurite outgrowth and neurofilament expression, as compared with that of AGR and ACR. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28833753 TI - Lactoferrin induces tropoelastin expression by activating the lipoprotein receptor-related protein 1-mediated phosphatidylinositol 3-kinase/Akt pathway in human dermal fibroblasts. AB - Dermal fibroblasts generate the extracellular matrix component elastin, which is synthesized as tropoelastin (TE) and play a critical role in maintaining skin elasticity. Lactoferrin (Lf), an 80-kDa iron-binding glycoprotein, has biological functions such as anti-bacterial, -inflammatory, and -cancer activities. We previously reported that bovine Lf increases TE mRNA expression in human dermal fibroblasts. However, it remains unclear how Lf up-regulates TE expression. Here, we investigated molecular mechanisms underlying this effect. Lf promoted the phosphorylation of Akt1 and extracellular signal-regulated protein kinase (ERK)1/2. As expected, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the MAPK inhibitor U0126 inhibited Lf-induced phosphorylation of Akt1 and ERK1/2, respectively. In contrast, LY294002, but not U0126, inhibited Lf induced TE expression. Human dermal fibroblasts expressed lipoprotein receptor related protein 1 (LRP-1) mRNA, and the LRP1 inhibitor receptor-associated protein attenuated Lf-induced increases in TE expression. Furthermore, siRNA mediated knockdown of LRP-1 significantly suppressed Lf-increased TE expression and Lf-induced Akt1 phosphorylation. Iron-saturated Lf (holo-Lf) increased TE expression and promoted Akt1 phosphorylation, when compared to those parameters in cells treated with iron-free Lf (apo-Lf). Transforming growth factor (TGF) beta1 also increased TE expression. LY294002 inhibited TGF-beta1-mediated TE upregulation, whereas TGF-beta1 activated Akt2, but not Akt1, phosphorylation. These results indicate that holo-Lf, but not apo-Lf, increases TE expression through LRP-1 in human dermal fibroblasts and suggest that holo-Lf and TGF-beta1 enhance TE expression by activating the PI3K/Akt1 and PI3K/Akt2 pathways, respectively. PMID- 28833754 TI - Trait impulsiveness is related to smaller post-commissural putamen volumes in males but not females. AB - Impulsivity is considered a vulnerability trait for addiction. Recently, we found trait non-planning impulsiveness measured with the Karolinska Scales of Personality was negatively correlated with dopamine D2/3 receptor availability in the ventral striatum of healthy humans. While also observed in rodents, human studies have failed to find this association with other measures of trait impulsivity. We explored whether another rodent finding, reduced ventral striatum volume with greater impulsivity, could also be observed in humans using this scale. Non-planning impulsiveness was measured in 52 healthy subjects (21 female; mean age: 33.06 +/- 9.69) using the Karolinska Scales of Personality. Striatal subregion volumes, including the globus pallidus, were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Although failing to support our a priori hypothesis, there was a significant sex interaction in the post-commissural putamen with impulsiveness. Exploratory analyses revealed impulsiveness was negatively correlated with post-commissural putamen volumes in males, but positively correlated in females. We replicated this finding in males in an increased sample (including all 52 previous subjects) who provided impulsiveness measured by the Temperament and Character Inventory (n = 73; 32 female; mean age: 33.48 +/- 9.75). These correlations by sex were statistically different from one another, the main finding with the Kasolinksa Scales of Personality surviving correction for multiple comparisons. While impulsivity may be related to reduced ventral striatal D2/3 receptors across sexes, males but not females may show significant reductions in post-commissural putamen volume. These findings have important implications for understanding biological markers underlying sex differences in drug addiction vulnerability. PMID- 28833749 TI - Amyloidogenesis of Tau protein. AB - The role of microtubule-associated protein Tau in neurodegeneration has been extensively investigated since the discovery of Tau amyloid aggregates in the brains of patients with Alzheimer's disease (AD). The process of formation of amyloid fibrils is known as amyloidogenesis and attracts much attention as a potential target in the prevention and treatment of neurodegenerative conditions linked to protein aggregation. Cerebral deposition of amyloid aggregates of Tau is observed not only in AD but also in numerous other tauopathies and prion diseases. Amyloidogenesis of intrinsically unstructured monomers of Tau can be triggered by mutations in the Tau gene, post-translational modifications, or interactions with polyanionic molecules and aggregation-prone proteins/peptides. The self-assembly of amyloid fibrils of Tau shares a number of characteristic features with amyloidogenesis of other proteins involved in neurodegenerative diseases. For example, in vitro experiments have demonstrated that the nucleation phase, which is the rate-limiting stage of Tau amyloidogenesis, is shortened in the presence of fragmented preformed Tau fibrils acting as aggregation templates ("seeds"). Accordingly, Tau aggregates released by tauopathy-affected neurons can spread the neurodegenerative process in the brain through a prion-like mechanism, originally described for the pathogenic form of prion protein. Moreover, Tau has been shown to form amyloid strains-structurally diverse self-propagating aggregates of potentially various pathological effects, resembling in this respect prion strains. Here, we review the current literature on Tau aggregation and discuss mechanisms of propagation of Tau amyloid in the light of the prion like paradigm. PMID- 28833755 TI - Tacrolimus regulates endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation: In vitro and collagen-induced arthritis mouse model. AB - Tacrolimus is an immunosuppressive drug that inhibits the release of inflammatory cytokines involved in rheumatoid arthritis development by blocking T cell activation. "Endoplasmic reticulum stress," an imbalance between protein folding load and capacity leading to the accumulation of unfolded proteins in the endoplasmic reticulum lumen, has been implicated in rheumatoid arthritis and other inflammatory and metabolic diseases. We aimed to investigate the effect of tacrolimus on endoplasmic reticulum stress-mediated osteoclastogenesis and inflammation and elucidate the underlying mechanisms. In vitro studies were performed using mouse bone marrow cells that were cultured with or without interleukin-1beta, thapsigargin, or tacrolimus to induce osteoclast differentiation. A mouse model of arthritis was established by immunizing mice with bovine type II collagen. Tacrolimus was orally administered to mice from day 20 to 45 following the initial immunization, and histopathological changes and expression of specific biomarkers of endoplasmic reticulum stress-mediated inflammatory signaling pathways were examined. In vitro, tacrolimus inhibited receptor activator of nuclear factor-kappaB ligand-mediated osteoclast formation augmented by interleukin-1beta, thapsigargin, or both. Furthermore, tacrolimus inhibited glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 (IRE 1), and activating transcription factor 6 (ATF6) augmented by interleukin-1beta, thapsigargin, or both. Tacrolimus significantly ameliorated osteolysis and endoplasmic reticulum stress intensity in mice. Simultaneously, it reduced inflammatory cell infiltration, osteoclastogenesis, and inflammatory responses by inhibiting GRP78, IRE 1, and ATF6. These findings suggest that tacrolimus exhibits an anti inflammation effect in rheumatoid arthritis and might inhibit joint damage progression by inhibiting endoplasmic reticulum stress. PMID- 28833758 TI - Arsenic-Mediated C-C Coupling of Cyanides Leading to Cyanido Arsazolide [AsC4 N4 ]. AB - The chemistry of arsenic cyanides has been investigated and is found to be completely different to the chemistry of the heavier analogs antimony and bismuth as well as phosphorus. The reaction of As(CN)3 with cyanide salts resulted in the formation of an unknown cyanido arsazolide heterocycle, which represents a structure isomer of the desired [As(CN)4 ]- . The structure, bonding, and formation of this unusual heterocycle is discussed featuring an arsenic mediated C-C coupling of cyanides. [AsC4 N4 ]- salts with different counterions such as [PPh4 ]+ , [PPN]+ =[Ph3 P-N-PPh3 ]+ , Ag+ , and [BMIm]+ are reported with [BMIm][AsC4 N4 ] being a low-temperature ionic liquid (Tm =-62 degrees C). PMID- 28833757 TI - The sawtooth EKG pattern of typical atrial flutter is not related to slow conduction velocity at the cavotricuspid isthmus. AB - INTRODUCTION: We hypothesized that very high-density mapping of typical atrial flutter (AFL) would facilitate a more complete understanding of its circuit. Such very high-density mapping was performed with the RhythmiaTM (Boston Scientific) mapping system using its 64 electrode basket catheter. METHODS AND RESULTS: Data were acquired from 13 patients in AFL. Functional anatomy of the right atrium (RA) was readily identified during mapping including the Crista Terminalis and Eustachian ridge. The leading edge of the activation wavefront was identified without interruption and its conduction velocity (CV) was calculated. CV was not different at the cavotricuspid isthmus (CTI) compared to the remainder of the RA (1.02 vs. 1.03 m/s, P = 0.93). The sawtooth pattern of the surface electrocardiogram (EKG) flutter waves was compared to the position of the dominant wavefront. The downslope of the surface EKG flutter waves represented on average 73% +/- 9% of the total flutter cycle length. During the downslope, the activation wavefront traveled significantly further than during the upslope (182 +/- 21 milliseconds vs. 68 +/- 29 milliseconds, P < 0.0001) with no change in CV between the two phases (0.88 vs. 0.91 m/s, P = 0.79). CONCLUSION: CV at the CTI is not slower than other RA regions during typical AFL. The gradual downslope of the sawtooth EKG is not due to slow conduction at the CTI suggesting that success of ablation at this site relates to anatomical properties rather than the presence of a "slow isthmus." PMID- 28833756 TI - Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia? AB - Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy-associated malformations including focal cortical dysplasia type II (FCDII) and low-grade epilepsy associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi-gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre-operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPdelta) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro glial cell type showing aberrant maturation. PMID- 28833759 TI - Can rapid negative exclusion of blood cultures by a molecular method, enzyme template generation and amplification technique (Cognitor(r) Minus), aid antimicrobial stewardship? AB - OBJECTIVES: Antimicrobial review is an important part of antimicrobial stewardship. A novel enzyme template generation and amplification technique (ETGA), the Cognitor(r) Minus (Momentum Bioscience, Long Hanborough, UK) test, has a 99.5% negative predictive value for bacteraemia and fungaemia. This observational study asked two questions: (1) Does a negative ETGA, indicating no bacteraemia or fungaemia, aid antimicrobial review within 48 h of admission; (2) In this real-life clinical setting, does a negative ETGA mean no bacteraemia or fungaemia? METHODS: Consecutive blood cultures in patients with clinical infection were tested by ETGA. Negative results indicating an absence of bacteraemia or fungaemia were reviewed by the clinical infection team. Antibiotics were reviewed in these patients, and the role of the ETGA result in antibiotic change was recorded. Patients were followed up for a week. KEY FINDINGS: A total of 197 of 246 samples gave a negative result by ETGA. This led to a positive stewardship outcome (antimicrobials changed) in 145 (73.6%) and negative stewardship outcome (empirical antimicrobials continued) in 47 (23.9%). Of the positive stewardship outcomes, the ETGA result supported the decision not to start antimicrobials in 21 (10.7%) patients, to stop antimicrobials in 21 (10.7%), to switch from IV to oral antimicrobials in 103 (52.2%) or to discharge or leave the patient at home in 58 cases (29.4%). CONCLUSIONS: Enzyme template generation and amplification supports antimicrobial stewardship decisions and may have cost advantages in reducing unnecessary empirical antibiotics and antifungal agents and in discharging patients from hospital earlier. ETGA result was consistent with blood culture findings and gave an earlier negative result. PMID- 28833760 TI - Distinct patterns of discrimination and orienting for temporal processing of speech and nonspeech in Chinese children with autism: an event-related potential study. AB - Although many studies have reported domain-general impaired duration perception for speech and nonspeech sounds in children with autism, it remained unclear whether this phenomenon is universally applicable regardless of language background. In some languages such as Finnish and Japanese, vowel duration serves a phonemic role that can signify semantic distinction, and in others (e.g., Mandarin Chinese), vowel duration does not carry this phonemic function. The present event-related potential study investigated neural sensitivity to duration contrasts in speech and nonspeech contexts in Mandarin-speaking children with autism and a control group of age-matched typically developing (TD) children. A passive oddball paradigm was adopted to elicit the mismatch negativity (MMN) and involuntary orienting response (P3a) for change detection. A pure tone condition and a vowel condition were used. The MMN results showed that the autism group had diminished response amplitude and delayed latency in the pure tone condition compared to the TD group, whereas no group difference was found in the vowel condition. The P3a results showed no significant between-group MMN difference in the pure tone condition. In the vowel condition, the autism group had smaller P3a than the TD group. Together, the distinct patterns of discrimination and orienting responses for duration contrasts in pure tones and vowels are consistent with the 'allophonic perception' theory for autism, which may reflect a compromised perceptual weighting system for speech learning. PMID- 28833761 TI - Generalized papillomatosis in three horses associated with a novel equine papillomavirus (EcPV8). AB - BACKGROUND: Currently, seven equine papillomaviruses (PV) are known and are associated with one of three different and distinct clinical presentations. HYPOTHESIS/OBJECTIVES: To report the clinical, histopathological and immunohistochemical findings in horses with generalized papillomatosis associated with a novel equine PV, Equus caballus papillomavirus 8 (EcPV8). ANIMALS: Three client-owned quarter horses. METHODS: Case report, retrospective. RESULTS: Dozens to thousands of papillomas involved the axilla, inguinal area and proximal limbs as well as the ventral and lateral neck, thorax and abdomen. Lesions were sometimes confluent in ventral areas. Fewer lesions were on the face, ears, distal limbs and genitalia. Plaque-type papillomas were small, 0.5 to 1.5 cm in diameter and hyperkeratotic. Histologically, plaque-type papillomas prominently involved follicular infundibula. Immunohistochemical findings demonstrated PV antigen in superficial keratinocyte nuclei. PCR using degenerate primers for the PV L1 gene and sequencing of amplicons revealed PV DNA sequences that were 98% identical for all three cases, but shared <70% identity to other PVs. Horses were otherwise healthy; serum immunoglobulin levels and peripheral blood lymphocyte phenotyping did not identify a known immunodeficiency syndrome. Lesions nearly completely resolved after 1.5 years in one horse and persisted for two years in another, despite intralesional human IFN-alpha treatment. The oldest horse was lost to follow-up. CONCLUSION AND CLINICAL IMPORTANCE: A novel equine papillomavirus (EcPV8) is associated with a distinct, plaque-type, generalized papillomatosis. Papillomas persisted for months to years, with or without treatment. PMID- 28833762 TI - Forming Sticky Droplets from Slippery Polymer Zwitterions. AB - Polymer zwitterions are generally regarded as hydrophilic and repellant or "slippery" materials. Here, a case is described in which the polymer zwitterion structure is tailored to decrease water solubility, stabilize emulsion droplets, and promote interdroplet adhesion. Harnessing the upper critical solution temperature of sulfonium- and ammonium-based polymer zwitterions in water, adhesive droplets are prepared by adding organic solvent to an aqueous polymer solution at elevated temperature, followed by agitation to induce emulsification. Droplet aggregation is observed as the mixture cools. Variation of salt concentration, temperature, polymer concentration, and polymer structure modulates these interdroplet interactions, resulting in distinct changes in emulsion stability and fluidity. Under attractive conditions, emulsions encapsulating 50-75% oil undergo gelation. By contrast, emulsions prepared under conditions where droplets are nonadhesive remain fluid and, for oil fractions exceeding 0.6, coalescence is observed. The uniquely reactive nature of the selected zwitterions allows their in situ modification and affords a route to chemically trigger deaggregation and droplet dispersion. Finally, experiments performed in a microfluidic device, in which droplets are formed under conditions that either promote or suppress adhesion, confirm the salt-responsive character of these emulsions and the persistence of adhesive interdroplet interactions under flow. PMID- 28833763 TI - Effect of Firing Temperature at the Porcelain-Metal Alloy Interface in Porcelain Fused-to-Metal Restorations. A SEM/EDS Study. AB - PURPOSE: To probe in greater detail the changes at the ceramometal interface induced by heat energy absorption, using energy diffraction X-ray spectroscopy (EDS) and scanning electron microscopy (SEM) and correlate these changes with the shear bond strength of porcelain to nickel chromium alloy. MATERIALS AND METHODS: Seventy-five strips of nickel-chromium alloy (20 mm long, 5 mm wide, 3 mm thick) were prepared and layered with porcelain, conforming to ANSI/ADA specification no. 38 (for Metal-Ceramic Dental Restorative Systems: 2010). These test specimens were divided equally into three groups. Specimens of each group (25) were fired to a specific temperature range, that is 700 degrees C, 900 degrees C, and 960 degrees C. SEM and EDS were performed on all specimens, at the metal alloy/ceramic interface. Bonding of the ceramic layer to the metal alloy was evaluated by a shear bond strength test as per ANSI/ADA specification no. 38. The data were recorded and analyzed using one-way ANOVA and post hoc Tukey HSD test. RESULTS: SEM images of the porcelain/metal alloy interface revealed roughness of the metal alloy surface adjacent to the ceramic layer. EDS study revealed that an oxygen depletion zone was formed at the interface region, facilitating the formation of intermetallic compounds. The mean shear bond strength showed an upward trend until 900 degrees C and decreased thereafter. CONCLUSION: Formation of intermetallic compounds at the interface, in the presence of an oxygen depletion zone, was the prime factor in bonding of porcelain to metal alloy. This provides a new concept of ceramometal bonding. PMID- 28833764 TI - Ganglionated plexi as neuromodulation targets for atrial fibrillation. AB - The autonomic nervous system plays an important role in the genesis of atrial fibrillation and is one of the candidate targets for atrial fibrillation therapy. This review focuses on the role of the autonomic nervous system in atrial fibrillation development and discusses the results of the ganglionated plexi catheter and surgical ablation in preclinical and clinical studies. The heart is innervated by the extrinsic and intrinsic autonomic nervous systems. The intrinsic autonomic nervous system consists of multiple ganglionated plexi and axons, which innervate the neighboring atrial myocardium and control their electrophysiological properties. Abnormal autonomic innervation has been observed in an animal model of atrial fibrillation and in humans. Direct recordings of autonomic nerve activity in canine models showed that atrial tachyarrhythmia episodes were invariably preceded by intrinsic cardiac autonomic nerve activity, thus supporting the importance of intrinsic cardiac autonomic nerve activity as the triggers for atrial tachyarrhythmia. Targeting ganglionated plexi with catheter ablation improves the outcomes of paroxysmal atrial fibrillation ablation in addition to pulmonary vein antrum isolation. Ablation of ganglionated plexi alone without pulmonary vein isolation is also useful in controlling paroxysmal atrial fibrillation in some patients. However, surgical ganglionated plexi ablation in patients with a large left atrium, persistent atrial fibrillation, and/or a history of prior catheter ablation does not result in additional benefits. These different outcomes suggest that ganglionated plexi ablation is effective in managing patients with paroxysmal atrial fibrillation, but its effects in patients with persistent atrial fibrillation and advanced atrial diseases might be limited. PMID- 28833766 TI - Conformational heterogeneity in the Hsp70 chaperone-substrate ensemble identified from analysis of NMR-detected titration data. AB - The Hsp70 chaperone system plays a critical role in cellular homeostasis by binding to client protein molecules. We have recently shown by methyl-TROSY NMR methods that the Escherichia coli Hsp70, DnaK, can form multiple bound complexes with a small client protein, hTRF1. In an effort to characterize the interactions further we report here the results of an NMR-based titration study of hTRF1 and DnaK, where both molecular components are monitored simultaneously, leading to a binding model. A central finding is the formation of a previously undetected 3:1 hTRF1-DnaK complex, suggesting that under heat shock conditions, DnaK might be able to protect cytosolic proteins whose net concentrations would exceed that of the chaperone. Moreover, these results provide new insight into the heterogeneous ensemble of complexes formed by DnaK chaperones and further emphasize the unique role of NMR spectroscopy in obtaining information about individual events in a complex binding scheme by exploiting a large number of probes that report uniquely on distinct binding processes. PMID- 28833765 TI - Development and application of an economic model (EQUIPTMOD) to assess the impact of smoking cessation. AB - BACKGROUND AND AIMS: Although clear benefits are associated with reducing smoking, there is increasing pressure on public health providers to justify investment in tobacco control measures. Decision-makers need tools to assess the Return on Investment (ROI)/cost-effectiveness of programmes. The EQUIPT project adapted an ROI tool for England to four European countries (Germany, the Netherlands, Spain and Hungary). EQUIPTMOD, the economic model at the core of the ROI tool, is designed to assess the efficiency of packages of smoking cessation interventions. The objective of this paper is to describe the methods for EQUIPTMOD and identify key outcomes associated with continued and cessation of smoking. METHODS: EQUIPTMOD uses a Markov model to estimate life-time costs, quality-adjusted life years (QALYs) and life years associated with a current and former smoker. It uses population data on smoking prevalence, disease prevalence, mortality and the impact of smoking combined with associated costs and utility effects of disease. To illustrate the tool's potential, costs, QALYs and life expectancy were estimated for the average current smoker for five countries based on the assumptions that they continue and that they cease smoking over the next 12 months. Costs and effects were discounted at country-specific rates. RESULTS: For illustration, over a life-time horizon, not quitting smoking within the next 12 months in England will reduce life expectancy by 0.66, reduce QALYs by 1.09 and result in L4961 higher disease-related health care costs than if the smoker ceased smoking in the next 12 months. For all age-sex categories, costs were lower and QALYs higher for those who quit smoking in the 12 months than those who continued. CONCLUSIONS: EQUIPTMOD facilitates assessment of the cost effectiveness of smoking cessation strategies. The demonstrated results indicate large potential benefits from smoking cessation at both an individual and population level. PMID- 28833767 TI - The roles of mucus-forming mucins, peritrophins and peritrophins with mucin domains in the insect midgut. AB - Most insects have a gut lined with a peritrophic membrane (PM) consisting of chitin and proteins, mainly peritrophins that have chitin-binding domains. The PM is proposed to originate from mucus-forming mucins (Mf-mucins), which acquired a chitin-binding domain that interlocked with chitin, replacing mucus in function. We evaluated the expression of Mf-mucins and peritrophins by RNA-sequencing (RNA seq) throughout the midgut of four distantly related insects. Mf-mucins were identified as proteins with high o-glycosylation and a series of uninterrupted Pro/Thr/Ser residues. The results demonstrate that the mucus layer is widespread in insects, and suggest that insect Mf-mucins are derived from those found in other animals by the loss of the cysteine knot and von Willebrand domains. The data also support a role of Mf-mucins in protecting the middle midgut of Musca domestica against acidic buffers. Mf-mucins may also produce a jelly-like material associated with the PM that immobilizes digestive enzymes in Spodoptera frugiperda. Peritrophins with a domain similar to Mf-mucins may be close to the ancestor of peritrophins. Expression data of peritrophins and chitin synthase genes throughout the midgut of M. domestica, S. frugiperda and Tenebrio molitor indicated that peritrophins were incorporated along the PM, according to their preferential sites of formation. Finally, the data support the view that mucus has functions distinct from the PM. PMID- 28833768 TI - Metastatic efficiency of tumour cells can be impaired by intraoperative cell salvage process: truth or conjecture? AB - The use of salvaged blood in oncological surgery has been a matter of controversy over the years. This is due to the concern of systemic dissemination of reinfused tumour cells. Recent literature, across disciplines, has shed considerable light on its safety in terms of tumour recurrence, progression and overall survival rates. This clinical safety demonstrates the apparent metastatic inefficiency of reinfused tumour cells. The proof of this concept comes from various studies that have shown that salvaged blood has no tumour cells, or has a significantly lower count as compared to the patient's original circulatory tumour load. Recently, we took a step further and found that the tumour cells in the salvaged blood lose the capacity to replicate. In this review, we revisited the safety of salvaged blood from the point of view of metastatic potential. We have presented basic and applied science evidence regarding the innocuous nature of tumour cells that have been subjected to the cell salvage process. The understanding of the metastatic efficiency or the lack of it in tumour cells subjected to salvage process is key to allay the concerns conventionally associated with the use of salvaged blood in tumour surgery. Based on the available literature, we surmise that the prevalent apprehensions on the usage of salvaged blood are ill-founded and further substantiate why tumour cells in the salvaged blood could be regarded as cells with non-metastatic potential. PMID- 28833769 TI - Sensitivity of an oral health-related quality-of-life questionnaire in detecting oral health impairment in preschool children. AB - AIM: This two-year cohort study evaluated whether the Early Childhood Oral Health Impact Scale (ECOHIS) is responsive to detect changes related to dental caries. DESIGN: Preschool children were examined in 2010 regarding dental caries, and their parents responded to the ECOHIS. After 2 years, 352 children (response rate = 73.6%) were re-examined and a new ECOHIS was responded. Children were categorized according to caries increment (no new caries, 1-3 surfaces with new lesions, and four or more decayed surfaces). The outcome variables were related to the decline of quality of life as determined via ECOHIS: decline, severe decline, and differences between baseline and follow-up scores. Effect sizes (ES) were calculated, and the associations were evaluated through Poisson regression. RESULTS: ES was small for children with 1-3 new lesions (ES = 0.19) and moderate for children with four or more new carious lesions (ES = 0.61). Children who developed 1-3 new lesions were significantly associated with all outcome variables compared to children with no new lesions, but the associations were stronger for children with four or more new carious lesions. CONCLUSIONS: The ECOHIS is sensitive to the deterioration of quality of life due to caries increments in preschool children. PMID- 28833770 TI - No geographic variation in thermoregulatory colour plasticity and limited variation in heat-avoidance behaviour in Battus philenor caterpillars. AB - Phenotypic plasticity can help organisms cope with variation in their current environment, including temperature variation, but not all environments are equally variable. In the least variable or extreme environments, plasticity may no longer be used. In this case, the plasticity could be lost altogether, or it could persist with either the same or an altered reaction norm, depending on factors such as the plasticity's costs. In the pipevine swallowtail caterpillar (Battus philenor), I tested for changes in two forms of heat-avoidance plasticity, colour change and refuge-seeking behaviour, across the species' range in the United states, including the cooler eastern parts of its range where colour change has not been observed and is unlikely to be needed. I found that both heat-avoidance behaviour and colour change persisted in all surveyed populations. Indeed, the reaction norm for colour change remained nearly unaltered, whereas the threshold for refuge-seeking only changed slightly across populations. These results suggest that the costs of these plastic traits are low enough for them to be maintained by whatever minimal gene flow the population receives. I show that plasticity can be maintained unaltered in populations where it is not used and discuss the potential consequences of this persistence for both the ecology and evolution of plasticity. PMID- 28833771 TI - Gene copy number variations in adaptive evolution: The genomic distribution of gene copy number variations revealed by genetic mapping and their adaptive role in an undomesticated species, white spruce (Picea glauca). AB - Gene copy number variation (CNV) has been associated with phenotypic variability in animals and plants, but a genomewide understanding of their impacts on phenotypes is largely restricted to human and agricultural systems. As such, CNVs have rarely been considered in investigations of the genomic architecture of adaptation in wild species. Here, we report on the genetic mapping of gene CNVs in white spruce, which lacks a contiguous assembly of its large genome (~20 Gb), and their relationships with adaptive phenotypic variation. We detected 3,911 gene CNVs including de novo structural variations using comparative genome hybridization on arrays (aCGH) in a large progeny set. We inferred the heterozygosity at CNV loci within parents by comparing haploid and diploid tissues and genetically mapped 82 gene CNVs. Our analysis showed that CNVs were distributed over 10 linkage groups and identified four CNV hotspots that we predict to occur in other species of the Pinaceae. Significant relationships were found between 29 of the gene CNVs and adaptive traits based on regression analyses with timings of bud set and bud flush, and height growth, suggesting a role for CNVs in climate adaptation. The importance of CNVs in adaptive evolution of white spruce was also indicated by functional gene annotations and the clustering of 31% of the mapped adaptive gene CNVs in CNV hotspots. Taken together, these results illustrate the feasibility of studying CNVs in undomesticated species and represent a major step towards a better understanding of the roles of CNVs in adaptive evolution. PMID- 28833773 TI - Morbihan disease: successful treatment with slow-releasing doxycycline monohydrate. PMID- 28833772 TI - Mismatch negativity to pitch pattern deviants in schizophrenia. AB - Simple mismatch negativity (MMN) to infrequent pitch deviants is impaired in individuals with long-term schizophrenia (Sz). The complex MMN elicited by pattern deviance often manifes is cut from here]->ts later after deviant onset than simple MMN and can ascertain deficits in abstracting relationships between stimuli. Sz exhibit reduced complex MMN, but so far this has only been measured when deviance detection relies on a grouping rule. We measured MMN to deviants in pitch-based rules to see whether MMN is also abnormal in Sz under these conditions. Three experiments were conducted. Twenty-seven Sz and 28 healthy matched controls (HC) participated in Experiments 1 and 2, and 24 Sz and 26 HC participated in Experiment 3. Experiment 1 was a standard pitch MMN task, and Sz showed the expected MMN reduction (~ 115 ms) in the simple pitch deviant compared to HC. Experiment 2 comprised standard groups of six tones that ascended in pitch, and deviant groups where the last tone descended in pitch. Complex MMN was late (~ 510 ms) and significantly blunted in Sz. Experiment 3 comprised standard groups of 12 tones (six tones ascending in pitch followed by six tones descending in pitch, like a scale), and deviant groups containing two repetitions of six ascending tones (the scale restarted midstream). Complex MMN was also late (~ 460 ms) and significantly blunted in Sz. These results identify a late pitch pattern deviance-related MMN that is deficient in schizophrenia. This suggests specific deficits in later more complex deviance detection in schizophrenia for abstract patterns. PMID- 28833774 TI - Corticosteroid and long-acting beta-agonist therapy reduces epithelial goblet cell metaplasia. AB - BACKGROUND: Bronchial epithelial goblet cell metaplasia (GCM) with hyperplasia is a prominent feature of asthma, but the effects of treatment with corticosteroids alone or in combination with a long-acting beta2 -adrenergic receptor agonist (LABA) on GCM in the bronchial epithelium are unknown. OBJECTIVES: To determine whether corticosteroid alone or in combination with a LABA alters protein and gene expression pathways associated with IL-13-induced goblet cell metaplasia. RESULTS: We evaluated the effects of fluticasone propionate (FP) and of salmeterol (SM), on the response of well-differentiated cultured bronchial epithelial cells to interleukin-13 (IL-13). Outcome measures included gene expression of SPDEF/FOXa2, gene expression and protein production of MUC5AC/MUC5B and morphologic appearance of cultured epithelial cell sheets. We additionally analysed expression of these genes in bronchial epithelial brushings from healthy, steroid-naive asthmatic and steroid-treated asthmatic subjects. In cultured airway epithelial cells, FP treatment inhibited IL-13-induced suppression of FOXa2 gene expression and up-regulation of SPDEF, alterations in gene and protein measures of MUC5AC and MUC5B and induction of GCM. The addition of SM synergistically modified the effects of FP modestly-only for gel-forming mucin MUC5AC. In bronchial epithelial cells recovered from asthmatic vs healthy human subjects, we found FOXa2 and MUC5B gene expression to be reduced and SPDEF and MUC5AC gene expression to be increased; these alterations were not observed in bronchial epithelial cells recovered after treatment with inhaled corticosteroids. CONCLUSION AND CLINICAL RELEVANCE: Corticosteroid treatment inhibits IL-13-induced GCM of the airways in asthma, possibly through its effects on SPDEF and FOXa2 regulation of mucin gene expression. These effects are modestly augmented by the addition of a long-acting beta-agonist. As we found evidence for drug treatment counteracting the effects of IL-13 on the epithelium, we conclude that further exploration into the mechanisms by which corticosteroids and long-acting beta2 -adrenergic agonists confer protection against pathologic airway changes is warranted. PMID- 28833776 TI - Adjuvant radiotherapy versus observation following lumpectomy in ductal carcinoma in-situ: A meta-analysis of randomized controlled trials. AB - The role of adjuvant radiotherapy (RT) following lumpectomy for ductal carcinoma in-situ (DCIS) was addressed in four major randomized controlled trials (RCTs) which were conducted two to three decades ago. Initial results of these trials suggested the protective role of RT in reducing the ipsilateral breast recurrences. Long-term results of all these four trials, based on more than 10 years follow-up data, have recently been published. A meta-analysis of four published RCTs which have addressed the role of adjuvant RT following lumpectomy for DCIS was conducted. Review manager (Cochrane Collaboration's software) version RevMan 5.2 was used for analysis. Evaluated events were ipsilateral breast recurrences (both DCIS and invasive), regional recurrences, contralateral breast events, distant recurrences, and overall mortality. The events were entered as dichotomous variable. The present meta-analysis included four RCTs and a total of 3680 patients - 1710 received adjuvant RT following lumpectomy while 1970 patients did not receive any adjuvant treatment. Patients who received RT had almost half of risk of ipsilateral breast recurrence (RR = 0.53, 95% CI = 0.45-0.62) and regional recurrence (RR = 0.54, 95% CI = 0.32-0.91) compared to those who did not receive adjuvant treatment - there was absolute risk reduction in 15% (95% CI = 12%-17%) for ipsilateral breast recurrences in adjuvant RT treated patients. There was no significant difference in distant recurrence (RR = 1.06, 95% CI = 0.74-1.53), contralateral breast events (RR = 1.22, 95% CI = 0.98 1.52) and overall mortality (RR = 0.93, 95% CI = 0.79-1.09). Though addition of postoperative RT to lumpectomy does not reduce overall mortality, the present meta-analysis confirms that it decreases the ipsilateral breast and regional recurrence by almost half. PMID- 28833777 TI - Peptide Macrocycles Developed from Precisely Regulated Multiple Cyclization of Unprotected Peptides. AB - Peptide macrocycles have been attractive scaffolds for the development of ligands and inhibitors to proteins, which have the potential of being developed as potent drugs. Novel strategies for peptide macrocyclization should be of particular interest to peptide drug design and discovery. Herein, an efficient strategy for designing and synthesizing macrocyclic peptides, which relies on the precisely regulated and efficient one-pot cyclization of unprotected peptides with 2,3,5,6 tetrafluoroterephthalonitrile (4F-2CN), is reported. The peptide bicycles can be considered as novel structurally hyperconstrained peptide macrocycles constrained with a rigidifying ring-closing moiety, consisting of an N-terminal 6-membered ring and C-terminal 13-membered ring fused with the benzene ring of 4F-2CN. These novel macrocyclic peptide scaffolds would be intriguing and promising scaffolds for developing macrocyclic peptide inhibitors and targeting ligands for many proteins. PMID- 28833775 TI - Glucagon-like peptide-1 cleavage product GLP-1 (9-36) amide enhances hippocampal long-term synaptic plasticity in correlation with suppression of Kv4.2 expression and eEF2 phosphorylation. AB - Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), used to be considered a "bio-inactive" metabolite mainly because of its lack of insulinotropic effects and low affinity for GLP-1 receptors, possesses unique properties such as anti-oxidant and cardiovascular protection. Little is known about the role of GLP-1 (9-36) in central nervous system. Here we report that chronic, systemic application of GLP-1 (9-36) in adult mice facilitated both the induction and maintenance phases of hippocampal long-term potentiation (LTP), a major form of synaptic plasticity. In contrast, spatial learning and memory, as assessed by the Morris water maze test, was not altered by GLP-1 (9-36) administration. At the molecular level, GLP-1 (9-36) reduced protein levels of the potassium channel Kv4.2 in hippocampus, which is linked to elevated dendritic membrane excitability. Moreover, GLP-1(9-36) treatment inhibited phosphorylation of mRNA translational factor eEF2, which is associated with increased capacity for de novo protein synthesis. Finally, we showed that the LTP-enhancing effects by GLP-1 (9-36) treatment in vivo were blunted by application of exendin(9-39)amide [EX(9-39)], the GLP-1 receptor (GLP 1R) antagonist, suggesting its role as a GLP-1R agonist. These findings demonstrate that GLP-1 (9-36), which was considered a "bio-inactive" peptide, clearly exerts physiological effects on neuronal plasticity in the hippocampus, a brain region critical for learning and memory. PMID- 28833778 TI - Two New Preyssler-Type Polyoxometalate-Based Coordination Polymers and Their Application in Horseradish Peroxidase Immobilization. AB - Enzyme immobilization is of increasing importance for biocatalysis, for which good supports are critical. Herein, two new Preyssler-type polyoxometalate (POM) based coordination polymers, namely, {[Cu(H2 biim)2 ][{Cu(H2 biim)2 (MU-H2 O)}2 Cu(H2 biim)(H2 O)2 ]H[({Cu(H2 biim)(H2 O)2 }0.5 )2 ((MU-C3 HN2 Cl2 ){Cu(H2 biim)}2 ){Z(H2 O)P5 W30 O110 }]?x H2 O}n (1: Z=Na, x=9; 2: Z=Ag, x=10; H2 biim=2,2'-biimidazole) were designed and synthesized. Compounds 1 and 2 exhibit the same skeletons, which contain multiple CuII complex fragments and penta supported {ZP5 W30 } (Z=Na, Ag) clusters. They were first employed to immobilize horseradish peroxidase (HRP). Results show that compounds 1 and 2 are good supports for HRP immobilization, and exhibit higher enzyme loading, lower loading times, and excellent reusability. The immobilized HRP (HRP/1 or HRP/2) was further applied to detect H2 O2 , and good sensitivity, wide linear range, low detection limit, and fast response were achieved. This work shows that POM-based hybrid materials are a new kind of promising support for enzyme immobilization. PMID- 28833779 TI - Patient and System Factors Related to Missed Opportunities for Screening in an Electronic Medical Record-driven, Opt-out HIV Screening Program in the Emergency Department. AB - OBJECTIVE: Emergency departments (EDs) have implemented HIV screening using a variety of strategies. This study investigates how specific patient and health system factors in the ED impact who is and is not screened in a combined targeted and nontargeted, electronic medical record (EMR)-driven, opt-out, HIV screening program. METHODS: This was a retrospective, cross-sectional study of ED visits where patients were determined eligible for HIV screening by an EMR algorithm between November 18, 2014, and July 15, 2015. The HIV screening workflow included three sequential events, all of which were required to get screened for HIV at the ED visit. The events were having a blood draw, being informed of the HIV screening policy by an ED nurse at the point of blood draw, and the patient consenting to the HIV test. Each event represented a dichotomous outcome and its association with six patient factors (age, sex, race/ethnicity, marital status, preferred language, and Emergency Severity Index [ESI]) and two health system factors (ED crowding and program phase) was investigated using multivariable modeling. RESULTS: A total of 15,918 ED visits were analyzed. Blood was drawn in 8,388 of 15,918 visits (53%). Of 8,388 visits where blood was drawn, there were 5,947 (71%) visits where ED nurses documented informing patients of the HIV screening policy. Of those visits, patient consent to the HIV test was documented at 3,815 (64%) visits. Patients between 13 and 19 years of age were significantly less likely to have blood drawn, to be informed of the screening policy, and to consent to the HIV test compared to other age groups. Both ED crowding and a patient's ESI were associated with decreased odds of having a blood draw and being informed of HIV screening by an ED nurse, but showed no association with patients consenting to the HIV test. CONCLUSION: Many patients, particularly adolescents and young adults, are missed in ED HIV screening programs that require blood draw and depend on providers to obtain consent for testing. To ensure that these patients are reached, future ED screening programs should strive to develop innovative workflows that allow for blood draws for HIV screening only and streamline the processes of obtaining informed consent and ordering tests for all eligible patients. PMID- 28833780 TI - Stellate ganglion blockade for the treatment of refractory ventricular arrhythmias: A systematic review and meta-analysis. AB - INTRODUCTION: Treatment refractory ventricular arrhythmias (VAs) are often driven and exacerbated by heightened sympathetic tone. We aim to conduct a systematic review and meta-analysis of published studies of a temporary percutaneous stellate ganglion block (SGB) on VA burden and defibrillation episodes in patients with treatment refractory VAs. METHODS: Relevant studies from January 1960 through May 2017 were identified in PubMed and Google Scholar. We performed a patient-level analysis using Student's t-test to compare outcomes before and after SGB. RESULTS: We identified 22 unique case series with a total of 35 patients. Patients were 57 +/- 17 years old and 69% were males with a high burden of VA. A unilateral (left)-sided SGB was used in 85.7% (30 of 35) of cases and the remaining were bilateral SGB. The use of a unilateral or bilateral SGB resulted in a significant reduction of VA episodes (24-hours pre: mean 16.5 [CI 9.7-23.1] events vs. post: mean 1.4 [CI 0.85-2.01] events; P = 0.0002) and need for defibrillation (24-hours pre: mean 14.2 [CI 6.8-21.6] vs. post: mean 0.6 [CI 0.3-0.9]; P = 0.0026). Furthermore, SGB was significantly associated with a reduction of VA burden regardless of etiology of cardiomyopathy, type of ventricular rhythm, and degree of contractile dysfunction. SGB was followed by surgical sympathectomy in 21% of cases. CONCLUSIONS: Early experience suggests that SGB is associated with an acute reduction in the VA burden and offers potential promise for a broader use in high-risk populations. Randomized controlled studies are needed to confirm the safety and efficacy of this therapy. PMID- 28833781 TI - Catalytic Carbon-Carbon Bond-Forming Reactions of Weakly Acidic Carbon Pronucleophiles Using Strong Bronsted Bases as Catalysts. AB - Catalytic carbon-carbon bond-forming reactions of weakly acidic carbon pronucleophiles with N-aryl imines, alpha,beta-unsaturated amides, and others under proton-transfer conditions were developed by designing strongly basic reaction intermediates known as product bases. The reactions proceed smoothly in the presence of a catalytic amount of strong base such as KH or alkaline metal amides. Modification of the metal cations by using chiral macrocyclic crown ethers allowed catalytic asymmetric 1,4-addition reactions to proceed with high enantioselectivities. This concept can be applied to Bronsted-base-catalyzed reactions of a wide range of weakly acidic carbon pronucleophiles. PMID- 28833782 TI - Population transcriptomic characterization of the genetic and expression variation of a candidate progenitor of Miscanthus energy crops. AB - The use of transcriptome data in the study of the population genetics of a species can capture faint signals of both genetic variation and expression variation and can provide a broad picture of a species' genomic response to environmental conditions. In this study, we characterized the genetic and expression diversity of Miscanthus lutarioriparius by comparing more than 16,225 transcripts obtained from 78 individuals, belonging to 10 populations distributed across the species' entire geographic range. We only observed a low level of nucleotide diversity (pi = 0.000434) among the transcriptome data of these populations, which is consistent with highly conserved sequences of functional elements and protein-coding genes captured with this method. Tests of population divergence using the transcriptome data were consistent with previous microsatellite data but proved to be more sensitive, particularly if gene expression variation was considered as well. For example, the analysis of expression data showed that genes involved in photosynthetic processes and responses to temperature or reactive oxygen species stimuli were significantly enriched in certain populations. This differential gene expression was primarily observed among populations and not within populations. Interestingly, nucleotide diversity was significantly negatively correlated with expression diversity within populations, while this correlation was positive among populations. This suggests that genetic and expression variation play separate roles in adaptation and population persistence. Combining analyses of genetic and gene expression variation represents a promising approach for studying the population genetics of wild species and may uncover both adaptive and nonadaptive processes. PMID- 28833783 TI - Intramolecular cyclization of the antimicrobial peptide Polybia-MPI with triazole stapling: influence on stability and bioactivity. AB - Cationic antimicrobial peptides have attracted increasing attention as a novel class of antibiotics to treat infectious diseases caused by pathogenic bacteria. However, susceptibility to protease is a shortcoming in their development. Cyclization is one approach to increase the proteolytic resistance of peptides. Therefore, to improve the proteolytic resistance of Polybia-MPI, we have synthesized the MPI cyclic analogs C-MPI-1 (i-to-i+4) and C-MPI-2 (i-to-i+6) by copper(I)-catalyzed azide-alkyne cycloaddition. Compared with MPI, C-MPI-1 displayed sustained antimicrobial activity and had enhanced anti-trypsin resistance, while C-MPI-2 displayed no antimicrobial activity. The relationship between peptide structure and bioactivity was further investigated by probing the secondary structure of the peptides by circular dichroism. This showed that C-MPI 1 adopted an alpha-helical structure in aqueous solution and, interestingly, had increased alpha-helical conformation in 30 mM sodium dodecyl sulfate and 50% trifluoroethyl alcohol compared with MPI. C-MPI-2 that was not alpha-helical in structure, suggesting that the propensity for alpha-helix conformation may play an important role in cyclic peptide design. In addition, scanning electron microscopy, propidium iodide uptake, and membrane permeabilization assays indicated that MPI and the optimized analog C-MPI-1 had membrane-active action modes, indicating that the peptides would not be susceptible to conventional resistance mechanisms. Our study provides additional insight into the influence of intramolecular cyclization at various positions on peptide structure and biological activity. In conclusion, the design and synthesis of cyclic analogs via click chemistry offer a new strategy for the development of stable antimicrobial agents. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28833784 TI - Menstruation, objectification and health-related quality of life: A questionnaire study. AB - AIMS AND OBJECTIVES: To explore young women's health-related quality of life (HRQOL) and investigate whether menstrual and menarche experiences and objectification predict mental and physical health components of HRQOL. BACKGROUND: Menstruation plays a fundamental role in female biology, in women's relationship to their bodies and consequently in women's health and their HRQOL. DESIGN: Cross-sectional explorative survey design. METHOD: A questionnaire that included the SF-36v2, the Self-objectification Questionnaire (SOQ), the Body Surveillance and Body Shame subscales of the Objectified Body Consciousness Scale, the Belief and Attitudes Towards Menstruation Questionnaire (four subscales), and questions on menarche and menstruation was administered at the end of 2013 to 319 Icelandic women who represented the population by age. The SF 36v2 includes eight dimensions addressing the mental and physical components of HRQOL. Scores are presented as raw data scores and scores based on standardised score of American women and range from 0 to 100 with higher scores indicating better HRQL. A hierarchical multiple linear regression model was employed to calculate significant predictors of mental and physical health components of HRQOL. RESULTS: Mean raw data scores on SF36-v2 dimensions ranged from 54.7 to 91.5. The participants scored below the standardised, mean norm-based score for all dimensions. Secrecy of menstruation, experience of body shame and pain during menstruation predicted worse mental HRQOL. To believe in the proscriptive role and the unpleasantness of menstruation, experience of body shame, medication for menstrual pain and not holding a university education predicted worse physical HRQOL. These two models explained 30% and 22% of the variance of the mental and physical components of SF36-v2, respectively. CONCLUSION: Young women's mental and physical HRQOL is influenced by the specific context of their lives. RELEVANCE TO CLINICAL PRACTICE: Women's health education should take into account the various relationships women may have with their bodies. PMID- 28833785 TI - Benefits of initial CT staging before sentinel lymph node biopsy in patients with head and neck cutaneous melanoma. AB - BACKGROUND: The value of CT at the time of diagnosis for patients with cutaneous head and neck melanoma clinically asymptomatic for metastatic disease is unclear. METHODS: A retrospective medical chart review was performed on 198 consecutive patients identified with primary T1b-T4b head and neck melanoma clinically asymptomatic for metastatic disease referred for sentinel lymph node biopsy procedures between 2004 and 2014. RESULTS: Initial CTs identified clinically occult melanoma metastases in 8.1% and advanced second primary tumors in 3.5% of patients. CT findings were false-negative in 1% and false-positive in 6% of patients. Overall survival (OS) for patients with true-positive CT findings was lower than for the other patients (P < .001). CONCLUSION: CT imaging when staging patients with head and neck melanoma seems to identify more metastases than has been reported for melanoma at other sites. Preoperative CTs decreased the number of sentinel lymph node biopsy (SLNBs), thus avoiding the stress and cost of this surgical procedure in 12% of patients. PMID- 28833786 TI - Widespread gene flow between oceans in a pelagic seabird species complex. AB - Global-scale gene flow is an important concern in conservation biology as it has the potential to either increase or decrease genetic diversity in species and populations. Although many studies focus on the gene flow between different populations of a single species, the potential for gene flow and introgression between species is understudied, particularly in seabirds. The only well-studied example of a mixed-species, hybridizing population of petrels exists on Round Island, in the Indian Ocean. Previous research assumed that Round Island represents a point of secondary contact between Atlantic (Pterodroma arminjoniana) and Pacific species (Pterodroma neglecta and Pterodroma heraldica). This study uses microsatellite genotyping and tracking data to address the possibility of between-species hybridization occurring outside the Indian Ocean. Dispersal and gene flow spanning three oceans were demonstrated between the species in this complex. Analysis of migration rates estimated using bayesass revealed unidirectional movement of petrels from the Atlantic and Pacific into the Indian Ocean. Conversely, structure analysis revealed gene flow between species of the Atlantic and Pacific oceans, with potential three-way hybrids occurring outside the Indian Ocean. Additionally, geolocation tracking of Round Island petrels revealed two individuals travelling to the Atlantic and Pacific. These results suggest that interspecific hybrids in Pterodroma petrels are more common than was previously assumed. This study is the first of its kind to investigate gene flow between populations of closely related Procellariiform species on a global scale, demonstrating the need for consideration of widespread migration and hybridization in the conservation of threatened seabirds. PMID- 28833788 TI - Extraordinary Thermoelectric Performance Realized in n-Type PbTe through Multiphase Nanostructure Engineering. AB - Lead telluride has long been realized as an ideal p-type thermoelectric material at an intermediate temperature range; however, its commercial applications are largely restricted by its n-type counterpart that exhibits relatively inferior thermoelectric performance. This major limitation is largely solved here, where it is reported that a record-high ZT value of ~1.83 can be achieved at 773 K in n type PbTe-4%InSb composites. This significant enhancement in thermoelectric performance is attributed to the incorporation of InSb into the PbTe matrix resulting in multiphase nanostructures that can simultaneously modulate the electrical and thermal transport. On one hand, the multiphase energy barriers between nanophases and matrix can boost the power factor in the entire temperature range via significant enhancement of the Seebeck coefficient and moderately reducing the carrier mobility. On the other hand, the strengthened interface scattering at the intensive phase boundaries yields an extremely low lattice thermal conductivity. This strategy of constructing multiphase nanostructures can also be highly applicable in enhancing the performance of other state-of-the-art thermoelectric systems. PMID- 28833787 TI - Efficacy of a global supportive skin care programme with hydrotherapy after non metastatic breast cancer treatment: A randomised, controlled study. AB - This study investigated the efficacy of post-treatment hydrotherapy as supportive care for management of persistent/long-lasting dermatologic adverse events (dAEs) induced in breast cancer survivors by adjuvant therapy, and its impact on quality of life (QoL). Patients in complete remission after standardised (neo)adjuvant chemotherapy, surgery and radiotherapy combination treatment for infiltrating HR+/HER2-breast carcinoma were enrolled in this randomised, multicentre controlled study 1-5 weeks after completing radiotherapy. The control group (CG, n = 33) received best supportive care and the treatment group (HG, n = 35) received 3-weeks of specific hydrotherapy. The primary criterion was change in QoL (QLQ-BR23) after hydrotherapy. Clinical grading of dAEs, cancer-related QoL (QLQ-C30), dermatologic QoL (DLQI) and general psychological well-being (PGWBI) were assessed. Significant dAEs were found at inclusion in both groups (n = 261). Most items showed significantly greater improvement in the HG versus CG group: QLQ-BR23 (breast [p = .0001] and arm symptoms [p = .0015], systemic therapy side effects [p = .0044], body image [p = .0139]), some dAE grading, DLQI (p = .0002) and PGWBI (p = .0028). Xerosis (88% of patients at inclusion) completely healed in all HG patients. Specific hydrotherapy is an effective supportive care for highly prevalent and long-lasting dAEs occurring after early breast cancer treatment, including chemotherapy, and leads to improved QoL and dermatologic toxicities. PMID- 28833789 TI - Unexpected Rotamerism at the Origin of a Chessboard Supramolecular Assembly of Ruthenium Phthalocyanine. AB - We have investigated the formation and the properties of ultrathin films of ruthenium phthalocyanine (RuPc)2 vacuum deposited on graphite by scanning tunneling microscopy and synchrotron photoemission spectroscopy measurements, interpreted in close conjunction with ab initio simulations. Thanks to its unique dimeric structure connected by a direct Ru-Ru bond, (RuPc)2 can be found in two stable rotameric forms separated by a low-energy barrier. Such isomerism leads to a peculiar organization of the molecules in flat, horizontal layers on the graphite surface, characterized by a chessboard-like alternation of the two rotamers. Moreover, the molecules are vertically connected to form pi-stacked columnar pillars of akin rotamers, compatible with the high conductivity measured in (RuPc)2 powders. Such features yield an unprecedented supramolecular assembly of phthalocyanine films, which could open interesting perspectives toward the realization of new architectures of organic electronic devices. PMID- 28833790 TI - Pycnogenol Cytotoxicity in Pancreatic INS-1E beta cells Induced by Calcium Dysregulation. AB - Natural standardized flavonoid extract from the bark of Pinus pinaster, Pycnogenol (Pyc), was recently found to decrease intensively the activity of sarcoplasmic reticulum Ca2+ -ATPase of rabbit skeletal muscle (SERCA1). On the basis of this inhibitory effect in a cell-free system and similarities of SERCA1 to its other isoforms, proapoptotic properties of Pyc may be expected in cellular systems. Pycnogenol (40-100 MUg/mL) induced a concentration-dependent decrease of the viability of pancreatic INS-1E beta cells associated with induction of apoptosis. In addition, intracellular Ca2+ level increase was found along with reduction of protein expression level of SERCA2b and impairment of insulin secretion by beta cells. These facts indicate that Pyc may induce apoptosis by impairment of calcium homeostasis. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28833792 TI - Obituary: Howard B. Eichenbaum (1947-2017). PMID- 28833791 TI - LytM factors affect the recruitment of autolysins to the cell division site in Caulobacter crescentus. AB - Most bacteria possess a peptidoglycan cell wall that determines their morphology and provides mechanical robustness during osmotic challenges. The biosynthesis of this structure is achieved by a large set of synthetic and lytic enzymes with varying substrate specificities. Although the biochemical functions of these proteins are conserved and well-investigated, the precise roles of individual factors and the regulatory mechanisms coordinating their activities in time and space remain incompletely understood. Here, we comprehensively analyze the autolytic machinery of the alphaproteobacterial model organism Caulobacter crescentus, with a specific focus on LytM-like endopeptidases, soluble lytic transglycosylases and amidases. Our data reveal a high degree of redundancy within each protein family but also specialized functions for individual family members under stress conditions. In addition, we identify two lytic transglycosylases and an amidase as new divisome components that are recruited to midcell at distinct stages of the cell cycle. The midcell localization of these proteins is affected by two LytM factors with degenerate catalytic domains, DipM and LdpF, which may serve as regulatory hubs coordinating the activities of multiple autolytic enzymes during cell constriction and fission respectively. These findings set the stage for in-depth studies of the molecular mechanisms that control peptidoglycan remodeling in C. crescentus. PMID- 28833794 TI - A Phosphanthrene Oxide Host with Close Sphere Packing for Ultralow-Voltage-Driven Efficient Blue Thermally Activated Delayed Fluorescence Diodes. AB - A phosphanthrene oxide host, 5,10-diphenyl-phosphanthrene 5,10-dioxide (DPDPO2 A), with intra- and intermolecular hydrogen bonds achieves spheroidal cis configuration and close sphere packing. DPDPO2 A realizes effective exciton suppression and excellent and balanced carrier transporting ability, both at the same time, demonstrating favorable photoluminescence quantum yield of 84% from its blue thermally activated delayed fluorescence (TADF) dye, namely bis[4-(9,9 dimethyl-9,10-dihydroacridine) phenyl]sulfone, doped films and high electron and hole mobility at the level of 10-4 and 10-5 cm2 V-1 s-1 , respectively. DPDPO2 A endows its blue TADF devices with record-low driving voltages, e.g., turn-on voltage of 2.5 V, and the state-of-the-art efficiencies with maxima of 22.5% for external quantum efficiency and 52.9 lm W-1 for power efficiency, which is the best comprehensive performance to date of ultralow-voltage-driven blue TADF diodes. PMID- 28833793 TI - Impact of simulation-based learning on immediate outcomes of temporary haemodialysis catheter placements by nephrology fellows. AB - AIM: Traditional apprenticeship model (AM) of teaching in invasive procedures such as temporary haemodialysis catheter (THDC) insertion can result in propagation of errors and complications. Simulation-based learning (SBL) offers standardization of skills and allows trainees to repeatedly practice invasive procedures prior to performing them on actual patient. METHODS: Retrospective cohort study of first-, second- and third-year Nephrology Fellows from a tertiary teaching hospital from September 2008 to September 2015. The intervention group (n = 9) received simulation training in ultrasound-guided THDC placement. The historical control group (n = 12) received training through traditional AM. The primary and secondary outcomes were the immediate complications and success rates of THDC insertion. RESULTS: A total of 2481 THDCs were placed in 1787 patients. Success rate of internal jugular THDC placement for AM vs. SBL Fellow was 99.8% versus 100% (P = 0.90), while the success rate for femoral THDC placement was 99.6% versus 99.2% (P = 0.53). SBL Fellows reported fewer overall peri-procedure complications (8.3% vs. 11.2%, P = 0.02) and mechanical complications (1% vs. 2.4%, P = 0.02) compared to AM Fellows. The rate of reported technical difficulty was similar (7.5% vs. 9.2%, P = 0.17). After adjusting for side and site of THDC placement, body mass index and laboratory indices, THDC inserted by AM Fellows were independently associated with increased overall peri-procedure complications (OR = 1.396, 95% CI: 1.052-1.854, P = 0.02) and mechanical complications (OR = 2.481, 95% CI: 1.178-4.810, P = 0.02). CONCLUSIONS: Simulation-based learning was associated with lower procedure related complications and should be an integral component in the teaching of procedural skills in Nephrology. PMID- 28833795 TI - Women's experiences with healthcare professionals after suffering from gender based violence: An interview study. AB - AIMS AND OBJECTIVES: This study sought to describe how women in Mexico who have suffered from gender-based violence experience their encounters with healthcare professionals. BACKGROUND: Gender-based violence is a worldwide problem. Previous studies have described that women feel they are not being cared for appropriately during their encounters with healthcare professionals. This study was conducted in Mexico, which has a high rate of gender inequality. DESIGN: A descriptive, qualitative study was conducted. METHODS: Face-to-face interviews were conducted with seven women. An inductive content analysis was used to analyse the interviews. RESULTS: The analyses resulted in four categories: Feelings of guilt about being abused, Feelings of being unimportant, Feelings of taking time and Feelings of being insecure/secure. The women emphasised the importance of healthcare professionals taking time out of their busy schedules for them. When they treated the women with respect and genuine interest, the women felt secure. When the healthcare professionals did not meet these expectations, feelings of frustration and mistrust were elicited. CONCLUSIONS: Feelings of being listened to and safety were considered important aspects in a positive encounter, whereas feeling a lack of time or interest often led to negative experiences such as frustration with and distrust of the healthcare system. These results imply that healthcare professionals may have deficiencies with regard to how these women are treated because these women do not feel that they receive the proper support. RELEVANCE TO CLINICAL PRACTICE: Education regarding how to approach women who have suffered from gender-based violence is essential for healthcare professionals to establish respectful encounters. The findings of this study stress that relatively simple efforts such as listening to these women's stories and providing them with genuine attention might substantially improve care. PMID- 28833797 TI - Movements of dams milked for fermented horse milk production in Mongolia. AB - Airag, (Fermented horse milk) is a traditional milk product in Mongolia. Herders separate foals from their dams and tie them at a milking site during the daytime to produce airag. To evaluate the effects of horse management on the movement of dams, we tracked three dams in a herd in camp 1 during summer and camp 2 during autumn of 2013 and analyzed their movements during the milking (daytime) and non milking (nighttime) periods in an area famous for its high-quality airag. Dams were gathered every 1.7 +/- 0.0 h between 07.46 and 15.47 hours at the milking sites and milked 4.6 +/- 0.2 times/day during the study period (86 days). Daily cumulative and maximum linear distances from the milking sites were longer (P < 0.01) during the non-milking period than during the milking period. Daily home ranges were 91 and 26 times greater during the non-milking period (P < 0.001) in camps 1 and 2, respectively. The greater range during the non-milking period would reflect the spatial distributions of water, salt and forage. The dams initially used similar areas and gradually shifted their daily home ranges after several days. This shift suggests that the dams grazed farther afield as forage availability declined around the milking site. For better airag production and sustainable pasture use, our results provide insights useful for evaluating the effects of milking management on vegetation and soil in those pastures, for selecting the appropriate milking times and frequency, and for choosing the right timing to shift milking sites. PMID- 28833799 TI - The impact of spousal bereavement on hospitalisations: Evidence from the Scottish Longitudinal Study. AB - This paper estimates the impact of spousal bereavement on hospital inpatient use for the surviving bereaved by following the experience of 94,272 married Scottish individuals from 1991 until 2009 using a difference-in-difference model. We also consider the sample selection issues related to differences in survival between the bereaved and non-bereaved using a simple Cox Proportional-Hazard model. Before conducting these estimations, propensity score approaches are used to re weight the non-bereaved to generate a more random-like comparison sample for the bereaved. We find that those bereaved who survive are both more likely to be admitted and to stay longer in hospital than a comparable non-bereaved cohort. Bereavement is estimated to induce on average an extra 0.24 (95% CI [0.15, 0.33]) hospital inpatient days per year. Similar to previous studies, we estimate the bereaved have a 19.2% (95% CI [12.5%, 26.3%]) higher mortality rate than the comparable non-bereaved cohort. PMID- 28833796 TI - Chromosome arm-specific patterns of polymorphism associated with chromosomal inversions in the major African malaria vector, Anopheles funestus. AB - Chromosomal inversions facilitate local adaptation of beneficial mutations and modulate genetic polymorphism, but the extent of their effects within the genome is still insufficiently understood. The genome of Anopheles funestus, a malaria mosquito endemic to sub-Saharan Africa, contains an impressive number of paracentric polymorphic inversions, which are unevenly distributed among chromosomes and provide an excellent framework for investigating the genomic impacts of chromosomal rearrangements. Here, we present results of a fine-scale analysis of genetic variation within the genome of two weakly differentiated populations of Anopheles funestus inhabiting contrasting moisture conditions in Cameroon. Using population genomic analyses, we found that genetic divergence between the two populations is centred on regions of the genome corresponding to three inversions, which are characterized by high values of FST , absolute sequence divergence and fixed differences. Importantly, in contrast to the 2L chromosome arm, which is collinear, nucleotide diversity is significantly reduced along the entire length of three autosome arms bearing multiple overlapping chromosomal rearrangements. These findings support the idea that interactions between reduced recombination and natural selection within inversions contribute to sculpt nucleotide polymorphism across chromosomes in An. funestus. PMID- 28833798 TI - Expressions of programmed death (PD)-1 and PD-1 ligand (PD-L1) in cervical intraepithelial neoplasia and cervical squamous cell carcinomas are of prognostic value and associated with human papillomavirus status. AB - AIM: The programmed death 1/programmed death 1 ligand (PD-1/PD-L1) pathway can decrease the immune clearance effects of antigen-presenting cells and T lymphocytes to promote immune evasion of cervical cancer cells. However, the effects of this pathway on cervical intraepithelial neoplasia (CIN) progression and squamous cell carcinoma (SCC) metastasis are not clear. We herein investigated whether human papillomavirus infection could affect PD-1 and PD-L1 expression in CIN, and whether their expression is associated with CIN progression and SCC metastasis. METHODS: We collected paraffin-embedded samples from two cohorts of patients: (i) CIN samples from cohort I (40 women who tested positive or negative for high-risk human papillomavirus [HR-HPV] with grades 0, I, and II-III CIN); and (ii) paired primary and metastatic tumor samples from cohort II (20 SCC patients with or without metastasis). Immunohistochemistry was used to detect expressions of PD-L1 in tumor cells and PD-1 in tumor-associated macrophages and tumor-infiltrating lymphocytes. We also measured P16INK4a expression and interferon-gamma levels in the cervical tissues. RESULTS: The most common HPV type seen in both cohorts of patients was HPV16, followed by HPV18. Increase in PD-L1 and PD-1 expression was positively correlated with HPV positivity, increase in CIN grade, and tumor metastasis. Furthermore, upregulation of the PD-1/PD-L1 pathway was associated with decreased expression of the pro-inflammatory cytokine, interferon-gamma and increased expression of P16INK4a . CONCLUSION: Expression of PD-L1 and PD-1 could be used as clinical prognostic biomarkers for evaluating CIN and cervical cancer because of its positive correlation with CIN progression and tumor metastasis. PMID- 28833800 TI - Moral disapproval and perceived addiction to internet pornography: a longitudinal examination. AB - BACKGROUND AND AIMS: Internet pornography use is an increasingly common, yet controversial, behavior. Whereas mental health communities are divided about potentially problematic use patterns, many lay people identify as feeling dysregulated or compulsive in their use. Prior work has labeled this tendency perceived addiction to internet pornography (PA). This study's aims were to (1) assess the association between PA at baseline and other factors, including actual levels of average daily pornography use and personality factors and (2) assess the associations between baseline variables and PA 1 year later. DESIGN: Two large-scale community samples were assessed using online survey methods, with subsets of each sample being recruited for follow-up surveys 1 year later. SETTING: United States. PARTICIPANTS: Participants were adults who had used pornography within the past 6 months recruited in two samples. Sample 1 (n = 1507) involved undergraduate students from three US universities and sample 2 (n = 782) involved web-using adults. Subsets of each sample (sample 1, n = 146; sample 2, n = 211) were surveyed again 1 year later. MEASUREMENTS: At baseline, we assessed average daily pornography use, PA and relevant predictors (e.g. trait neuroticism, trait self-control, trait entitlement, religiousness, moral disapproval of pornography use). One year later, we assessed PA. FINDINGS: Cross sectionally, PA was correlated strongly with moral disapproval of pornography use [sample 1, Pearson's correlation: r = 0.68 (0.65, 0.70); sample 2, r = 0.58 (0.53, 0.63)]. Baseline moral disapproval [sample 1, r = 0.46 (0.33, 0.56); sample 2, r = 0.61 (0.51, 0.69)] and perceived addiction demonstrated relationships with perceived addiction 1 year later. We found inconclusive evidence of a substantial or significant association between pornography use and perceived addiction over time [sample 1, r = 0.13 (-0.02, 0.28); sample 2, r = 0.11 (-0.04, 0.25)]. CONCLUSIONS: Perceived addiction to internet pornography appears to be related strongly to moral scruples around pornography use, both concurrently and over time, rather than with the amount of daily pornography use itself. PMID- 28833801 TI - Hydrogels Based on Ag+ -Modulated Assembly of 5'-Adenosine Monophosphate for Enriching Biomolecules. AB - Supramolecular hydrogels obtained by combining 5'-adenosine monophosphate (AMP) with Ag+ were fabricated in this work. Their gelation capability was enhanced by increasing the concentration of Ag+ or decreasing the pH. The gels are very sensitive to light, which endows them with potential applications as visible light photosensitive materials. Coordination between the nucleobase of AMP and Ag+ , as well as pi-pi stacking of nucleobases, are considered to be the main driving forces for self-assembly. The hydrogels successfully achieved the encapsulation and enrichment of biomolecules. Hydrogen bonding between the amino group of guest molecules and silver nanoparticles along the nanofibers drives the enrichment and is considered to be a crucial interaction. PMID- 28833803 TI - Important statistical considerations in the evaluation of post-market studies to assess whether opioids with abuse-deterrent properties result in reduced abuse in the community. AB - PURPOSE: Abuse, misuse, addiction, overdose, and death associated with non medical use of prescription opioids have become a serious public health concern. Reformulation of these products with abuse-deterrent properties is one approach for addressing this problem. FDA has approved several extended-release opioid analgesics with abuse-deterrent labeling, the bases of which come from pre-market studies. As all opioid analgesics must be capable of delivering the opioid in order to reduce pain, abuse-deterrent properties do not prevent abuse, nor do pre market evaluations ensure that there will be reduced abuse in the community. Utilizing data from various surveillance systems, some recent post-market studies suggest a decline in abuse of extended-release oxycodone after reformulation with abuse-deterrent properties. We discuss challenges stemming from the use of such data. METHODS: We quantify the relationship between the sample, the population, and the underlying sampling mechanism and identify the necessary conditions if valid statements about the population are to be made. The presence of other interventions in the community necessitates the use of comparators. We discuss the principles under which the use of comparators can be meaningful. CONCLUSIONS: Results based on surveillance data need to be interpreted with caution as the underlying sampling mechanisms can bias the results in unpredictable ways. The use of comparators has the potential to disentangle the effect due to the abuse deterrence properties from those due to other interventions. However, identifying a comparator that is meaningful can be very difficult. PMID- 28833802 TI - Analysis of IgG kinetic stability by differential scanning calorimetry, probe fluorescence and light scattering. AB - Monoclonal antibodies of the immunoglobulin G (IgG) type have become mainstream therapeutics for the treatment of many life-threatening diseases. For their successful application in the clinic and a favorable cost-benefit ratio, the design and formulation of these therapeutic molecules must guarantee long-term stability for an extended period of time. Accelerated stability studies, e.g., by employing thermal denaturation, have the great potential for enabling high throughput screening campaigns to find optimal molecular variants and formulations in a short time. Surprisingly, no validated quantitative analysis of these accelerated studies has been performed yet, which clearly limits their application for predicting IgG stability. Therefore, we have established a quantitative approach for the assessment of the kinetic stability over a broad range of temperatures. To this end, differential scanning calorimetry (DSC) experiments were performed with a model IgG, testing chaotropic formulations and an extended temperature range, and they were subsequently analyzed by our recently developed three-step sequential model of IgG denaturation, consisting of one reversible and two irreversible steps. A critical comparison of the predictions from this model with data obtained by an orthogonal fluorescence probe method, based on 8-anilinonaphthalene-1-sulfonate binding to partially unfolded states, resulted in very good agreement. In summary, our study highlights the validity of this easy-to-perform analysis for reliably assessing the kinetic stability of IgGs, which can support accelerated formulation development of monoclonal antibodies by ranking different formulations as well as by improving colloidal stability models. PMID- 28833804 TI - Item response theory analysis applied to the Spanish version of the Personal Outcomes Scale. AB - BACKGROUND: The study of measurements of quality of life (QoL) is one of the great challenges of modern psychology and psychometric approaches. This issue has greater importance when examining QoL in populations that were historically treated on the basis of their deficiency, and recently, the focus has shifted to what each person values and desires in their life, as in cases of people with intellectual disability (ID). Many studies of QoL scales applied in this area have attempted to improve the validity and reliability of their components by incorporating various sources of information to achieve consistency in the data obtained. The adaptation of the Personal Outcomes Scale (POS) in Spanish has shown excellent psychometric attributes, and its administration has three sources of information: self-assessment, practitioner and family. The study of possible congruence or incongruence of observed distributions of each item between sources is therefore essential to ensure a correct interpretation of the measure. The aim of this paper was to analyse the observed distribution of items and dimensions from the three Spanish POS information sources cited earlier, using the item response theory. METHOD: We studied a sample of 529 people with ID and their respective practitioners and family member, and in each case, we analysed items and factors using Samejima's model of polytomic ordinal scales. RESULTS: The results indicated an important number of items with differential effects regarding sources, and in some cases, they indicated significant differences in the distribution of items, factors and sources of information. CONCLUSIONS: As a result of this analysis, we must affirm that the administration of the POS, considering three sources of information, was adequate overall, but a correct interpretation of the results requires that it obtain much more information to consider, as well as some specific items in specific dimensions. The overall ratings, if these comments are considered, could result in bias. PMID- 28833805 TI - Carbon isotope ratios of endogenous steroids in Belgian Blue and Holstein cattle: Method development, reference population studies and application to steroid misuse control. AB - RATIONALE: The misuse of growth promoters in livestock and breeding animals is prohibited according to the laws of the European Union. Among these growth promoters, the detection of endogenous steroids like testosterone, estradiol or progesterone remains especially challenging as concentration-based urinary thresholds may not provide conclusive results due to large inter-individual variations. In addition to the detection of intact steroid esters in blood or hair, carbon isotope ratio (CIR) determination of urinary steroids has commonly been the method of choice. METHODS: A comprehensive sample clean-up procedure was developed and validated, which enables for the first time simultaneous CIR measurements of testosterone metabolites (17alpha-hydroxyandrost-4-en-3-one, 3alpha-hydroxy-5beta-androstan-17-one and 5alpha-androstane-3beta,17alpha-diol), the estradiol metabolite 17alpha-estradiol (ESTR) and the progesterone metabolite 5beta-pregnane-3alpha,20alpha-diol (PD) from a single urine specimen. As endogenous reference compounds 3beta-hydroxyandrost-5-en-17-one and 5-androstene 3beta,17alpha-diol (5EN) were chosen. The method was validated by means of linear mixing models and a reference population encompassing n = 53 Belgian Blue and Holstein cattle was investigated to enable the calculation of population-based Delta13 C thresholds. RESULTS: The combined measurement uncertainty determined for the Delta13 C-values of all steroids under investigation was found to be <0.8 0/00. Within the reference population studies, 5EN was demonstrated to be the most promising endogenous reference compound resulting in comparably low Delta values and accompanying thresholds. For PD, a surprisingly high number of samples (n = 9) yielded significantly 13 C-depleted values and ESTR was only detectable in n = 13 samples. Proof-of-concept was accomplished by investigating two post administration samples. CONCLUSIONS: This first comprehensive investigation on the CIRs of endogenous urinary steroids demonstrated once more the potential of isotope ratios in aiding discrimination between endogenously produced and exogenously administered steroids. By means of the reference population-derived CIRs, it is possible to apply cattle-specific thresholds to differentiate between treated and non-treated animals. PMID- 28833806 TI - Protective and Promotive Effects of Latino Early Adolescents' Cultural Assets Against Multiple Types of Discrimination. AB - Given adversity associated with discrimination, it is important to identify culturally relevant factors that may protect against its harmful effects. Using latent variable interactions, this study examined the moderating effects of cultural assets on the association between multiple types of discrimination and adolescents' adjustment. Participants included 174 seventh- and eighth-grade Latino adolescents (51% girls); majority were of Mexican origin. Peer discrimination was associated with higher internalizing symptoms, whereas cultural assets predicted higher academic motivation above and beyond racial ethnic discrimination, demonstrating a promotive effect. Adolescents' Latino cultural assets also protected against higher levels of externalizing symptoms in the context of high peer discrimination and foreigner objectification. The discussion focuses on the conceptual and applied implications of these findings. PMID- 28833808 TI - Pharmacokinetics, safety and efficacy of a recombinant factor IX product, trenonacog alfa in previously treated haemophilia B patients. AB - INTRODUCTION: Trenonacog alfa (IB1001) is a recombinant factor IX (rFIX) manufactured in Chinese hamster ovary (CHO) cells. IB1001 was evaluated in a multicentre clinical trial with haemophilia B patients. AIM: The aim was to establish IB1001 pharmacokinetic non-inferiority to comparator rFIX, safety and efficacy in previously treated patients (PTPs) with haemophilia B. METHODS: Subjects were severe or moderately severe haemophilia B adult and adolescent PTPs with no history of FIX inhibitors. RESULTS: IB1001 PK non-inferiority to comparator rFIX was demonstrated through ratio of AUC0-infinity in 32 subjects. IB1001 was well tolerated in all 76 treated subjects; the most common adverse drug reaction was headache (2.6% of subjects) and there were no reports of FIX inhibitors. Transient non-inhibitory binding FIX antibodies and anti-CHO cell protein antibodies developed in 21% and 29% of subjects respectively; no safety concerns were associated with development of these antibodies. Prophylaxis (mean duration +/- SD: 17.9 +/- 9.6 months, mean dose: 55.5 +/- 12.9 IU/kg, median 1.0 infusion per week) was effective in preventing bleeds (median annual bleed rate: 1.52, interquartile range: 0.0-3.46). One or two IB1001 infusions resolved 84% of the bleeds, while for 84% of treatments haemostatic efficacy of IB1001 was rated excellent or good. IB1001 haemostatic efficacy for all 19 major surgeries was rated adequate or better than adequate. CONCLUSIONS: IB1001 is safe and efficacious for treatment of bleeds, routine prophylaxis and perioperative management in haemophilia B patients. PMID- 28833809 TI - New ROMP Synthesis of Ferrocenyl Dendronized Polymers. AB - First- and second-generation Percec-type dendronized ferrocenyl norbornene macromonomers containing, respectively, three and nine ferrocenyl termini are synthesized and polymerized by ring-opening metathesis polymerization using Grubbs' third-generation olefin metathesis catalyst with several monomer/catalyst feed ratios between 10 and 50. The rate of polymerization is highly dependent on the generation of the dendronized macromonomers, but all these ring-opening metathesis polymerization reactions are controlled, and near-quantitative monomer conversions are achieved. The numbers of ferrocenyl groups obtained are in agreement with the theoretical ones according to the cyclic voltammetry studies as determined using the Bard-Anson method. PMID- 28833807 TI - The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation. AB - Multipotent mesenchymal stem cells (MSCs) have enormous potential in tissue engineering and regenerative medicine. However, until now, their development for clinical use has been severely limited as they are a mixed population of cells with varying capacities for lineage differentiation and tissue formation. Here, we identify receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a cell surface marker expressed by those MSCs with an enhanced capacity for cartilage formation. We generated clonal human MSC populations with varying capacities for chondrogenesis. ROR2 was identified through screening for upregulated genes in the most chondrogenic clones. When isolated from uncloned populations, ROR2+ve MSCs were significantly more chondrogenic than either ROR2-ve or unfractionated MSCs. In a sheep cartilage-repair model, they produced significantly more defect filling with no loss of cartilage quality compared with controls. ROR2+ve MSCs/perivascular cells were present in developing human cartilage, adult bone marrow, and adipose tissue. Their frequency in bone marrow was significantly lower in patients with osteoarthritis (OA) than in controls. However, after isolation of these cells and their initial expansion in vitro, there was greater ROR2 expression in the population derived from OA patients compared with controls. Furthermore, osteoarthritis-derived MSCs were better able to form cartilage than MSCs from control patients in a tissue engineering assay. We conclude that MSCs expressing high levels of ROR2 provide a defined population capable of predictably enhanced cartilage production. Stem Cells 2017;35:2280 2291. PMID- 28833810 TI - Features of asthma which provide meaningful insights for understanding the disease heterogeneity. AB - BACKGROUND: Data-driven methods such as hierarchical clustering (HC) and principal component analysis (PCA) have been used to identify asthma subtypes, with inconsistent results. OBJECTIVE: To develop a framework for the discovery of stable and clinically meaningful asthma subtypes. METHODS: We performed HC in a rich data set from 613 asthmatic children, using 45 clinical variables (Model 1), and after PCA dimensionality reduction (Model 2). Clinical experts then identified a set of asthma features/domains which informed clusters in the two analyses. In Model 3, we reclustered the data using these features to ascertain whether this improved the discovery process. RESULTS: Cluster stability was poor in Models 1 and 2. Clinical experts highlighted four asthma features/domains which differentiated the clusters in two models: age of onset, allergic sensitization, severity, and recent exacerbations. In Model 3 (HC using these four features), cluster stability improved substantially. The cluster assignment changed, providing more clinically interpretable results. In a 5-cluster model, we labelled the clusters as: "Difficult asthma" (n = 132); "Early-onset mild atopic" (n = 210); "Early-onset mild non-atopic: (n = 153); "Late-onset" (n = 105); and "Exacerbation-prone asthma" (n = 13). Multinomial regression demonstrated that lung function was significantly diminished among children with "Difficult asthma"; blood eosinophilia was a significant feature of "Difficult," "Early-onset mild atopic," and "Late-onset asthma." Children with moderate-to severe asthma were present in each cluster. CONCLUSIONS AND CLINICAL RELEVANCE: An integrative approach of blending the data with clinical expert domain knowledge identified four features, which may be informative for ascertaining asthma endotypes. These findings suggest that variables which are key determinants of asthma presence, severity, or control may not be the most informative for determining asthma subtypes. Our results indicate that exacerbation-prone asthma may be a separate asthma endotype and that severe asthma is not a single entity, but an extreme end of the spectrum of several different asthma endotypes. PMID- 28833811 TI - Sustained participation in annual continuous quality improvement activities improves quality of care for Aboriginal and Torres Strait Islander children. AB - AIM: To determine whether participation in the continuous quality improvement (CQI) Audit and Best Practice for Chronic Disease programme improved care and outcomes for Indigenous children. METHODS: Data were collected from 59 Australian primary health-care centres providing services to Indigenous people and participating in the programme (February 2008 and December 2013). Indigenous children aged less than 2 years and centres that completed three or more consecutive annual audits within the 6-year study period were included. Crude and adjusted logistic generalised estimating equation models were used to examine the effect of year of audit on the delivery of care. Odds ratio (OR) and 95% confidence interval (CI) were calculated. Outcomes were related to age-relevant health issues, including prevention and early intervention. These included administrative, health check, anticipatory guidance and specific health issues. RESULTS: During the audit period, there were 2360 files from 59 centres. Those that had a recall recorded, improved from 84 to 95% (OR 2.44, 95% CI 1.44-4.11). Hearing assessments improved from 52 to 89% (OR 1.37, 95% CI 1.22-1.54). Improvement in anticipatory guidance, treatment and follow-up of medical conditions was almost universal. CONCLUSION: We documented significant improvements in quality of care of Indigenous children. Outcomes and their corresponding treatment and follow-ups improved over time. This appears to be related to services participating in annual CQI activities. However, these services may be more committed to CQI than others and therefore possibly better performing. PMID- 28833812 TI - Multidirectional Wrinkle Patterns Programmed by Sequential Uniaxial Strain with Conformal yet Nontraceable Masks. AB - Surface wrinkling is a promising route to control the mechanical, electrical, and optical properties of materials in a wide range of applications. However, previous artificial wrinkles are restricted to single or random orientation and lacks selectivity. To address this challenge, this study presents multidirectional wrinkle patterns with high selectivity and orientation through sequential uniaxial strain with conformal polymeric shadow masks. The conformal but nontraceable polymeric stencil with microapertures are adhered to a flat substrate prior to oxidation, which forms discrete and parallel wrinkles in confined domains without any contamination. By fully investigating the process, this study displays compound topography of wrinkles consisting of wrinkle islands and surrounding secondary wrinkles on the same surface. With this topography, various diffusion properties are presented: from semi-transparent yet diffusive films to multidirectional diffusive films, which will be available for new types of optical diffuser applications. PMID- 28833813 TI - Development of the Sydney Falls Risk Screening Tool in brain injury rehabilitation: A multisite prospective cohort study. AB - AIMS AND OBJECTIVES: To develop a falls risk screening tool (FRST) sensitive to the traumatic brain injury rehabilitation population. BACKGROUND: Falls are the most frequently recorded patient safety incident within the hospital context. The inpatient traumatic brain injury rehabilitation population is one particular population that has been identified as at high risk of falls. However, no FRST has been developed for this patient population. Consequently in the traumatic brain injury rehabilitation population, there is the real possibility that nurses are using falls risk screening tools that have a poor clinical utility. DESIGN: Multisite prospective cohort study. METHODS: Univariate and multiple logistic regression modelling techniques (backward elimination, elastic net and hierarchical) were used to examine each variable's association with patients who fell. The resulting FRST's clinical validity was examined. RESULTS: Of the 140 patients in the study, 41 (29%) fell. Through multiple logistic regression modelling, 11 variables were identified as predictors for falls. Using hierarchical logistic regression, five of these were identified for inclusion in the resulting falls risk screening tool: prescribed mobility aid (such as, wheelchair or frame), a fall since admission to hospital, impulsive behaviour, impaired orientation and bladder and/or bowel incontinence. The resulting FRST has good clinical validity (sensitivity = 0.9; specificity = 0.62; area under the curve = 0.87; Youden index = 0.54). The tool was significantly more accurate (p = .037 on DeLong test) in discriminating fallers from nonfallers than the Ontario Modified STRATIFY FRST. CONCLUSION: A FRST has been developed using a comprehensive statistical framework, and evidence has been provided of this tool's clinical validity. RELEVANCE TO CLINICAL PRACTICE: The developed tool, the Sydney Falls Risk Screening Tool, should be considered for use in brain injury rehabilitation populations. PMID- 28833814 TI - Climate change and Saharan dust drive recent cladoceran and primary production changes in remote alpine lakes of Sierra Nevada, Spain. AB - Recent anthropogenic climate change and the exponential increase over the past few decades of Saharan dust deposition, containing ecologically important inputs of phosphorus (P) and calcium (Ca), are potentially affecting remote aquatic ecosystems. In this study, we examine changes in cladoceran assemblage composition and chlorophyll-a concentrations over the past ~150 years from high resolution, well-dated sediment cores retrieved from six remote high mountain lakes in the Sierra Nevada Mountains of Southern Spain, a region affected by Saharan dust deposition. In each lake, marked shifts in cladoceran assemblages and chlorophyll-a concentrations in recent decades indicate a regional-scale response to climate and Saharan dust deposition. Chlorophyll-a concentrations have increased since the 1970s, consistent with a response to rising air temperatures and the intensification of atmospheric deposition of Saharan P. Similar shifts in cladoceran taxa across lakes began over a century ago, but have intensified over the past ~50 years, concurrent with trends in regional air temperature, precipitation, and increased Saharan dust deposition. An abrupt increase in the relative abundance of the benthic cladoceran Alona quadrangularis at the expense of Chydorus sphaericus, and a significant increase in Daphnia pulex gr. was a common trend in these softwater lakes. Differences in the magnitude and timing of these changes are likely due to catchment and lake specific differences. In contrast with other alpine lakes that are often affected by acid deposition, atmospheric Ca deposition appears to be a significant explanatory factor, among others, for the changes in the lake biota of Sierra Nevada that has not been previously considered. The effects observed in Sierra Nevada are likely occurring in other Mediterranean lake districts, especially in softwater, oligotrophic lakes. The predicted increases in global temperature and Saharan dust deposition in the future will further impact the ecological condition of these ecosystems. PMID- 28833816 TI - Depletion of HOXA5 inhibits the osteogenic differentiation and proliferation potential of stem cells from the apical papilla. AB - Mesenchymal stem cells (MSCs) are a prospective cell source for tissue regeneration due to their self-renewal abilities and potential to differentiate into different cell lineages, but the molecular mechanisms of the directed differentiation and proliferation are still unknown. Recently, multiple studies have indicated the crucial role of HOX genes in MSC differentiation and proliferation. However, the role of HOXA5 in MSCs remains unknown. Here, we investigated HOXA5 function in stem cells from the apical papilla (SCAPs). After HOXA5 depletion, the results showed a significant decrease in ALP activity and a weakened mineralization ability of SCAPs. The real-time RT-PCR results showed prominently lessened expression of OPN and BSP. The CCK8 and CFSE results displayed inhibited proliferation of SCAPs, and flow cytometry assays revealed arrested cell cycle progression at the S phase. Furthermore, we found that depletion of HOXA5 upregulated p16INK4A and p18INK4C and downregulated the Cyclin A. Our research demonstrated that depletion of HOXA5 inhibited osteogenic differentiation and repressed cell proliferation by arresting cell cycle progression at the S phase via p16INK4A , p18INK4C , and Cyclin A in SCAPs, indicating that HOXA5 has a significant role in maintaining the proliferation and differentiation potential of dental-tissue-derived MSCs. PMID- 28833817 TI - Na/K-ATPase regulates bovine sperm capacitation through raft- and non-raft mediated signaling mechanisms. AB - Highly dynamic lipid microdomains (rafts) in the sperm plasma membrane contain several signaling proteins that regulate sperm capacitation. Na/K-ATPase isoforms (testis-specific isoform ATP1A4 and ubiquitous isoform ATP1A1) are abundant in bovine sperm plasma membrane. We previously reported that incubation of bovine sperm with ouabain, a specific Na/K-ATPase ligand, induced tyrosine phosphorylation of several sperm proteins during capacitation. The objective of this study was to investigate the roles of lipid rafts and non-rafts in Na/K ATPase enzyme activity and signaling during bovine sperm capacitation. Content of ATP1A4 and, to a lesser extent, ATP1A1 was increased in raft and non-raft fractions of capacitated sperm, although non-raft enzyme activities of both isoforms were higher than the corresponding activities in rafts from capacitated sperm. Yet, ATP1A4 was the predominant isoform responsible for total Na/K-ATPase activity in both rafts and non-rafts. A comparative increase in phosphorylation of signaling molecules was observed in both raft (CAV1) and non-raft (EGFR and ERK1/2) membrane fractions during capacitation. Although SRC was phosphorylated in both membrane fractions, the non-raft fraction possessed more of this activated form. We also inferred, by immunoprecipitation, that ATP1A4 interacted with CAV1 and EGFR in the raft fraction, whereas interactions of ATP1A4 with SRC, EGFR, and ERK1/2 occurred in the non-raft fraction of ouabain-capacitated sperm; conversely, ATP1A1 interacted only with CAV1 in both fractions of uncapacitated and capacitated sperm. In conclusion, both raft and non-raft cohorts of Na/K ATPase isoforms contributed to phosphorylation of signaling molecules during bovine sperm capacitation. PMID- 28833818 TI - Considering land-sea interactions and trade-offs for food and biodiversity. AB - With the human population expected to near 10 billion by 2050, and diets shifting towards greater per-capita consumption of animal protein, meeting future food demands will place ever-growing burdens on natural resources and those dependent on them. Solutions proposed to increase the sustainability of agriculture, aquaculture, and capture fisheries have typically approached development from single sector perspectives. Recent work highlights the importance of recognising links among food sectors, and the challenge cross-sector dependencies create for sustainable food production. Yet without understanding the full suite of interactions between food systems on land and sea, development in one sector may result in unanticipated trade-offs in another. We review the interactions between terrestrial and aquatic food systems. We show that most of the studied land-sea interactions fall into at least one of four categories: ecosystem connectivity, feed interdependencies, livelihood interactions, and climate feedback. Critically, these interactions modify nutrient flows, and the partitioning of natural resource use between land and sea, amid a backdrop of climate variability and change that reaches across all sectors. Addressing counter-productive trade offs resulting from land-sea links will require simultaneous improvements in food production and consumption efficiency, while creating more sustainable feed products for fish and livestock. Food security research and policy also needs to better integrate aquatic and terrestrial production to anticipate how cross sector interactions could transmit change across ecosystem and governance boundaries into the future. PMID- 28833819 TI - Intermittent alternance of Brugada ECG patterns: Insights from a unique electrophysiological phenomenon. PMID- 28833820 TI - Identification of complexes involving thallium(I) and thallium(III) with EDTA and DTPA ligands by electrospray ionization mass spectrometry. AB - RATIONALE: Thallium is considered to be an environmental threat; however, its hazardous properties depend on its oxidation state. Tl(III) is approx. 1000-times more toxic compared with Tl(I), therefore identification of each species is essential in order to properly evaluate the associated health hazard. Electrospray ionization mass spectrometry (ESI-MS) allows determination of speciation in solution due to its soft mode of ionization while selective complexation with ligands can distinguish the Tl species. Selective complexation of Tl(I) and Tl(III) ions requires the use of two selective complexing agents and selection of appropriate conditions for this process. METHODS: Tl(I) and Tl(III) ions as well as two ligands (EDTA and DTPA) were used to form binary (single ion + single ligand), ternary (one ion + both ligands) and quaternary systems (both ions and both ligands) under different pH conditions (7 and 8). These mixtures were subjected to the determination of Tl species using ESI-MS operating in positive and negative ion mode. RESULTS: Tl(I) complexes with DTPA were identified at pH 7 and 8, whereas, in the case of EDTA, the complexes were detected only at pH 8. In contrast, Tl(III) formed distinct complexes with EDTA at pH 7 and 8, while with DTPA the complexes were detected only at pH 8. Analysis of the quaternary system (which contained both ions and both ligands) revealed that Tl(I) formed complexes with EDTA, while Tl(III) formed complexes with DTPA at pH 7 and 8. CONCLUSIONS: The obtained results confirmed that the increase in the solution complexity allowed simultaneous identification of different complexes in solutions containing both Tl species. The initial analyses carried out for binary and ternary solutions facilitated the simultaneous determination of specific complexes (Tl(I) with EDTA and Tl(III) with DTPA) in the quaternary system. PMID- 28833821 TI - Investigation of subclinical bacteriuria in cats with dermatological disease receiving long-term glucocorticoids and/or ciclosporin. AB - BACKGROUND: Dogs receiving long-term glucocorticoids or ciclosporin have an increased frequency of bacteriuria. No studies have investigated the frequency of bacteriuria in cats receiving long-term glucocorticoids and/or ciclosporin. HYPOTHESES/OBJECTIVES: To document whether subclinical bacteriuria occurs in cats receiving long-term glucocorticoid and/or ciclosporin for management of chronic disease. ANIMALS: Thirty two cats treated with parenteral glucocorticoids and/or oral glucocorticoids and/or ciclosporin were included. METHODS: Thirty two cats receiving oral glucocorticoids and/or ciclosporin for at least three months or at least two injections of long-acting glucocorticoids within the preceding six months were evaluated. Thirty four healthy cats were used as a control group. Urinalysis and urine culture was performed on urine samples collected by cystocentesis from each cat. RESULTS: In the glucocorticoid/ciclosporin group, none of 32 cats had a positive urine culture. In the control group, one of 34 cats had a positive urine culture. There were no statistically significant differences between the urinalyses from either group. CONCLUSIONS AND CLINICAL IMPORTANCE: There was no evidence to suggest that administration of long-term glucocorticoids and/or ciclosporin is associated with bacteriuria in cats. PMID- 28833822 TI - Maternal voluntary physical activity attenuates delayed neurodevelopment in malnourished rats. AB - NEW FINDINGS: What is the central question of this study? In the present study, a reproducible model of maternal voluntary physical activity was developed to evaluate the adaptive response of physical activity by attenuating the effects of maternal undernutrition on physical features, reflex ontogeny and growth trajectory of offspring during development. What is the main finding and its importance? Maternal physical activity may induce neuronal maturation of sensorimotor connections impacting on the patterns of locomotor activity in malnourished offspring. Thus, physical activity should be considered as a therapeutic means of countering the effects of maternal undernutrition, by providing a useful strategy for enhancing the neuronal activity of children born to mothers who experience a restricted diet during pregnancy. This study evaluated the effects of maternal voluntary physical activity during pregnancy and lactation on somatic growth (SG), reflex ontogeny (RO) and locomotor activity (LA) of rats whose mothers were protein restricted. Virgin female Wistar rats were divided into the following six groups: control, normal protein (C-NP, n = 4); control, low protein (C-LP, n = 4); inactive, normal protein (I-NP, n = 8); inactive, low protein (I-LP, n = 7); very active, normal protein (VA-NP, n = 8); and very active, low protein (VA-LP, n = 6). Voluntary physical activity was recorded daily in dams. The LP groups were fed an 8% casein diet, whereas control groups were fed a 17% casein diet during pregnancy and lactation. Offspring were evaluated in terms of SG (body weight and length, latero-lateral skull axis and anteroposterior head axis) and RO (palmar grasp, righting, free-fall righting, negative geotaxis, cliff avoidance, auditory startle response and vibrissa placing). The LA was evaluated at 23, 45 and 60 days old in the open field. Voluntary physical activity was reduced during pregnancy and lactation independent of the maternal diet. Pups from LP dams showed delayed SG, reflex maturation and patterns of LA when compared with control pups. The C-LP and I-LP pups showed a delayed SG, RO and LA. Pups from VA-LP mothers showed no delay in SG and RO and presented a faster development of patterns of LA. Maternal voluntary physical activity attenuated the effects of LP diet on indicators of neurodevelopment and patterns of LA of offspring. PMID- 28833823 TI - Precise Reproduction of Soft Tissue Structure around the Pontic Area Using Computer-Aided Design and Manufacturing. AB - Reproducing soft tissue contours around a pontic area is important for the fabrication of an esthetic prosthesis, especially in the anterior area. A gingival model that precisely replicates the soft tissue structure around the pontic area can be easily obtained by taking a pick-up impression of an interim fixed dental prosthesis. After a working cast is fabricated using the customary technique, the pick-up model is superimposed onto the working model for the pontic area using computer-aided design and manufacturing (CAD/CAM). A definitive restoration using this technique would be well adapted to the pontic base, which is formed by the interim prosthesis. PMID- 28833824 TI - Effects of latrunculin A on the relocation of sperm IZUMO1 during gamete interaction in mouse. AB - The sperm protein IZUMO1 plays a central role in gamete fusion. In mouse sperm, IZUMO1 is enriched at the acrosomal cap before the acrosome reaction, and at the equatorial segment following this reaction; its relocation is dependent on filamentous actin. How actin polymerization affects IZUMO1 relocation during gamete interaction remains unknown. The present study addressed these processes using latrunculin A (LatA), an inhibitor of actin polymerization. We report that 25 uM LatA blocked actin polymerization in the capacitated sperm head, resulting in a marked decrease in sperm with relocated IZUMO1 during the A23187-induced acrosome reaction and cumulus layer penetration. Treated sperm also exhibited reduced zona pellucida penetration and fertilizing capacity. Interestingly, LatA treated sperm present in the perivitelline space of eggs did not show impaired IZUMO1 relocation. Thus, IZUMO1 relocation represents one method by which eggs may select for or rescue sperm that are competent to undergo gamete adhesion/fusion. These data support the hypothesis that dynamic movement of IZUMO1 is essential for gamete fusion during mouse fertilization. PMID- 28833825 TI - Transcriptomic profiling of adaptive responses to ocean acidification. AB - Some populations of marine organisms appear to have inherent tolerance or the capacity for acclimation to stressful environmental conditions, including those associated with climate change. Sydney rock oysters from the B2 breeding line exhibit resilience to ocean acidification (OA) at the physiological level. To understand the molecular basis of this physiological resilience, we analysed the gill transcriptome of B2 oysters that had been exposed to near-future projected ocean pH over two consecutive generations. Our results suggest that the distinctive performance of B2 oysters in the face of OA is mediated by the selective expression of genes involved in multiple cellular processes. Subsequent high-throughput qPCR revealed that some of these transcriptional changes are exclusive to B2 oysters and so may be associated with their resilience to OA. The intracellular processes mediated by the differentially abundant genes primarily involve control of the cell cycle and maintenance of cellular homeostasis. These changes may enable B2 oysters to prevent apoptosis resulting from oxidative damage or to alleviate the effects of apoptosis through regulation of the cell cycle. Comparative analysis of the OA conditioning effects across sequential generations supported the contention that B2 and wild-type oysters have different trajectories of changing gene expression and responding to OA. Our findings reveal the broad set of molecular processes underlying transgenerational conditioning and potential resilience to OA in a marine calcifier. Identifying the mechanisms of stress resilience can uncover the intracellular basis for these organisms to survive and thrive in a rapidly changing ocean. PMID- 28833826 TI - Ferrocene Derived Bifunctional Phosphine-Catalyzed Asymmetric Oxa-[4+2] Cycloaddition of alpha-Substituted Allenones with Enones. AB - An efficient ferrocene-derived bifunctional phosphine-catalyzed enantioselective oxa-[4+2] cycloaddition of alpha-substituted allenones with a broad range of enones is investigated for the preparation of stereodefined dihydropyrans in good to excellent yields (up to 99 %) and excellent enantioselectivity (up to 99 % ee). Furthermore, a series of valuable chiral polyheterocyclic frameworks can be efficiently achieved in good yields with excellent enantioselectivities. PMID- 28833827 TI - Periostin promotes migration and osteogenic differentiation of human periodontal ligament mesenchymal stem cells via the Jun amino-terminal kinases (JNK) pathway under inflammatory conditions. AB - OBJECTIVES: Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered to be a promising method for periodontitis treatment. The molecular mechanism of functional regulation by MSCs remains unclear, thus limiting their application. Our previous study discovered that Periostin (POSTN) promoted the migration and osteogenic differentiation of periodontal ligament mesenchymal stem cells (PDLSCs), but it is still unclear whether POSTN is able to restore the regenerative potential of PDLSCs under inflammatory conditions. In this study, we investigated the effect of POSTN on PDLSCs under inflammatory conditions and its mechanism. MATERIALS AND METHODS: PDLSCs were isolated from periodontal ligament tissue. TNF-alpha was used at 10 ng/mL to mimic inflammatory conditions. Lentivirus POSTN shRNA was used to knock down POSTN. Recombinant human POSTN (rhPOSTN) was used to stimulate PDLSCs. A scratch assay was used to analyse cell migration. Alkaline phosphatase (ALP) activity, Alizarin Red staining and expression of osteogenesis-related genes were used to investigate the osteogenic differentiation potential. Western blot analysis was used to detect the mitogen activated protein kinases (MAPK) and AKT signalling pathways. RESULTS: After a 10 ng/mL TNF-alpha treatment, knockdown of POSTN impeded scratch closure, inhibited ALP activity and mineralization in vitro, and decreased expression of RUNX2, OSX, OPN and OCN in PDLSCs, while 75 ng/mL rhPOSTN significantly accelerated scratch closure, enhanced ALP activity and mineralization in vitro, and increased expression of RUNX2, OSX, OPN and OCN. In addition, knockdown of POSTN inhibited expression of phosphorylated c-Jun N-terminal kinase (p-JNK), while 75 ng/mL rhPOSTN increased expression of p-JNK in PDLSCs with TNF-alpha treatment. Furthermore, inhibition of JNK by its inhibitor SP600125 dramatically blocked POSTN-enhanced scratch closure, ALP activity and mineralization in PDLSCs. CONCLUSIONS: Our results revealed that POSTN might promote the migration and osteogenic differentiation potential of PDLSCs via the JNK pathway, providing insight into the mechanism underlying MSC biology under inflammatory conditions and identifying a potential target for improving periodontal tissue regeneration. PMID- 28833828 TI - Markers for Guillain-Barre syndrome with poor prognosis: a multi-center study. AB - Guillain-Barre syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (DeltaIgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and DeltaIgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (>=5 points) were associated with an increased risk for mechanical ventilation. Patients with DeltaIgG <1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and DeltaIgG in GBS are clinically relevant in Japan. PMID- 28833829 TI - Long-term outcome of 18 F-fluorodeoxyglucose-positron emission tomography-guided dose painting for head and neck cancer: Matched case-control study. AB - BACKGROUND: The purpose of this study was to report the long-term outcome of 18 F fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET)-guided dose painting for head and neck cancer in comparison to conventional intensity modulated radiotherapy (IMRT) in a matched case-control study. METHODS: Seventy two patients with nonmetastatic head and neck cancer treated with dose painting were compared with 72 control patients matched on tumor site and T classification. Either 18 F-FDG-PET-guided dose painting by contour (DPBC) or voxel intensity-based dose painting by number (DPBN) was performed; control patients underwent standard IMRT. A total median dose to the dose-painted target was 70.2-85.9 Gy/30-32 fractions versus 69.1 Gy/32 fractions with conventional IMRT. In 31 patients, dose painting was adapted to per-treatment changes in the tumor and organs-at-risk (OAR). RESULTS: Median follow-up in living dose-painting and control patients was 87.7 months (range 56.1-119.3) and 64.8 months (range 46.3-83.4), respectively. Five-year local control rates in the dose-painting patients were 82.3% against 73.6% in the control (P = .36); in patients treated to normalized isoeffective doses >91 Gy (NID2Gy) local control reached 85.7% at 5 years against 73.6% in the control group (P =.39). There was no difference in regional (P = .82) and distant control (P = .78). Five-year overall and disease specific survival rates were 36.3% versus 38.1% (P = .50) and 56.5% versus 51.7% (P = .72), respectively. A half of the dose-painting patients developed acute grade >=3 dysphagia (P = .004). Late grade 4 mucosal ulcers at the site of dose escalation in 9 of 72 patients was the most common severe toxicity with dose painting versus 3 of 72 patients with conventional IMRT (P = .11). Patients in the dose-painting group had increased rates of acute and late dysphagia (P = .004 and P = .005). CONCLUSION: Dose-painting strategies can be used to increase dose to specific tumor subvolumes. Five-year local, regional, and distant control rates are comparable with patients treated with conventional IMRT. Volume and intensity of dose escalation should be further tailored, given the possible increase in severe acute and chronic toxicity. Adapting treatment and decreasing dose to the swallowing structures might contribute to lower toxicity rates when applied in smaller tumor volumes. Whether adaptive DPBN can significantly improve outcomes is currently being investigated in a novel clinical trial. PMID- 28833830 TI - Induction of retinal-dependent calcium influx in human melanocytes by UVA or UVB radiation contributes to the stimulation of melanosome transfer. AB - OBJECTIVES: The transfer of melanosomes from melanocytes to neighbouring keratinocytes is critical to protect the skin from the deleterious effects of ultraviolet A (UVA) and ultraviolet B (UVB) irradiation; however, the initial factor(s) that stimulates melanosome transfer remains unclear. In this study, we investigated the induction of retinal-dependent calcium (Ca2+ ) influx in melanocytes (MCs) by UVA or UVB irradiation and the effect of transient receptor potential cation channel subfamily M member 1 (TRPM1) (melastatin1)-related Ca2+ influx on melanosome transfer. MATERIALS AND METHODS: Primary human epidermal MCs were exposed to physiological doses of UVB or UVA light and loaded with a calcium indicator Fluo-4 dye. The change of intracellular calcium of MCs was monitored using a two-photon confocal fluorescence microscopy. MCs were co-cultured with human epidermal keratinocytes (KCs) in the absence or presence of voriconazole (a TRPM1 blocker) or calcium chelators. MCs were also transfected with TRPM1 siRNA for silencing the expression of TRPM1 gene. The melanosome transfer in the co cultured cells was quantitatively analysed using flow cytometry and was further confirmed by immunofluorescent double-staining. The protein levels and distributions of TRPM1, OPN3 and OPN5 in MCs were measured by Western blotting or immunofluorescent staining. RESULTS: The retinal-dependent Ca2+ influx of UVA exposed melanocytes differed greatly from that of UVB-exposed melanocytes in the timing-phase. The protein expression of TRPM1 in mono- and co-cultured MCs was dose-dependently up-regulated by UVA and UVB. TRPM1 siRNA-mediated knockdown and the blockage of TRPM1 channel using a putative antagonist (voriconazole) significantly inhibited melanosome transfer in co-cultures following UVA or UVB exposure. CONCLUSIONS: The distinct time-phases of Ca2+ influx in MCs induced by UVA or UVB contribute to the consecutive stimulation of melanosome transfer, thereby providing a potent photoprotection against harmful UV radiation. PMID- 28833832 TI - Pretreatment ethyl glucuronide levels predict response to a contingency management intervention for alcohol use disorders among adults with serious mental illness. AB - BACKGROUND AND OBJECTIVES: This study investigated if pretreatment ethyl glucuronide (EtG) levels corresponding to light (100 ng/mL), heavy (500 ng/mL), and very heavy (1,000 ng/mL) drinking predicted longest duration of alcohol abstinence (LDA) and proportion of EtG-negative urine tests in outpatients receiving a 12-week EtG-based contingency management (CM) intervention for alcohol dependence. METHODS: Participants were 40 adults diagnosed with alcohol use disorders and serious mental illness who submitted up to 12 urine samples for EtG analysis during a 4-week observation period and were then randomized to 12 weeks of CM for alcohol abstinence and addiction treatment attendance. Alcohol use outcomes during CM as assessed by EtG and self-report were compared across those who did and did not attain a pre-treatment average EtG level of 500 ng/mL-a level that equates to frequent heavy drinking. RESULTS: Only the 500 ng/mL cutoff was associated with significant differences in LDA and proportion of EtG-negative samples during CM. Those with a pre-treatment EtG < 500 ng/mL attained a LDA 2.3 (alcohol) to 2.9 (drugs) weeks longer than pre-treatment heavy drinkers. DISCUSSION AND CONCLUSIONS: The EtG biomarker can be used to determine who will respond to a CM intervention for alcohol use disorders and could inform future trials that are designed to be tailored to individual patients. SCIENTIFIC SIGNIFICANCE: Results suggest pre-treatment EtG cutoffs equivalent to heavy and very heavy drinking predict outcomes in CM. (Am J Addict 2017;26:673-675). PMID- 28833833 TI - Brain activity induced by implicit processing of others' pain and pleasure. AB - Studies indicate that both explicit and implicit processing of affectively charged stimuli may be reflected in specific behavioural markers and physiological signatures. Here, we investigated whether the pleasantness ratings of a neutral target were affected by the subliminal perception of a painful (a slap) or pleasant (a caress) touch delivered to others. In particular, we combined the continuous flash suppression technique with the affective misattribution procedure to explore subliminal processing of observed pain and pleasure in others. Results show that participants rated the neutral target as more or less likeable depending on whether they were subliminally primed with the pleasant or painful facial expression, respectively. The fMRI activity associated with painful and pleasant subliminal priming was mainly present in the anterior prefrontal cortex and the primary sensorimotor cortex, respectively. Thus, our study provides behavioural and neuro-physiological evidence that: (i) emotional reactivity toward positive or negative states of others can occur at an entirely subliminal level; (ii) specific neural substrates underpin reactivity to positive and negative-valence of social emotions. Hum Brain Mapp 38:5562-5576, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28833834 TI - Estimates of effectiveness and reach for 'return on investment' modelling of smoking cessation interventions using data from England. AB - BACKGROUND AND AIMS: Estimating 'return on investment' (ROI) from smoking cessation interventions requires reach and effectiveness parameters for interventions for use in economic models such as the EQUIPT ROI tool (http://roi.equipt.eu). This paper describes the derivation of these parameter estimates for England that can be adapted to create ROI models for use by other countries. METHODS: Estimates were derived for interventions in terms of their reach and effectiveness in: (1) promoting quit attempts and (2) improving the success of quit attempts (abstinence for at least 12 months). The sources were systematic reviews of efficacy supplemented by individual effectiveness evaluations and national surveys. FINDINGS: Quit attempt rates were estimated to be increased by the following percentages (with reach in parentheses): 20% by tax increases raising the cost of smoking 5% above the cost of living index (100%); 10% by enforced comprehensive indoor public smoking bans (100%); 3% by mass media campaigns achieving 400 gross rating points (100%); 40% by brief opportunistic physician advice (21%); and 110% by use of a licensed nicotine product to reduce cigarette consumption (12%). Quit success rates were estimated to be increased by the following ratios: 60% by single-form nicotine replacement therapy (NRT) (5%); 114% by NRT patch plus a faster-acting NRT (2%);124% by prescribed varenicline (5%); 60% by bupropion (1%); 100% by nortriptyline (0%), 10) 298% by cytisine (0%); 40% by individual face-to-face behavioural support (2%); 37% by telephone support (0.5%); 88% by group behavioural support (1%); 63% by text messaging (0.5%); and 19% by printed self-help materials (1%). There was insufficient evidence to obtain reliable, country-specific estimates for interventions such as websites, smartphone applications and e-cigarettes. CONCLUSIONS: Tax increases, indoor smoking bans, brief opportunistic physician advice and use of nicotine replacement therapy (NRT) for smoking reduction can all increase population quit attempt rates. Quit success rates can be increased by provision of NRT, varenicline, bupropion, nortriptyline, cytisine and behavioural support delivered through a variety of modalities. Parameter estimates for the effectiveness and reach of these interventions can contribute to return on investment estimates in support of national or regional policy decisions. PMID- 28833835 TI - Breeding biology and the evolution of dynamic sexual dichromatism in frogs. AB - Dynamic sexual dichromatism is a temporary colour change between the sexes and has evolved independently in a wide range of anurans, many of which are explosive breeders wherein males physically compete for access to females. Behavioural studies in a few species indicate that dynamic dichromatism functions as a visual signal in large breeding aggregations; however, the prevalence of this trait and the social and environmental factors underlying its expression are poorly understood. We compiled a database of 178 anurans with dynamic dichromatism that include representatives from 15 families and subfamilies. Dynamic dichromatism is common in two of the three subfamilies of hylid treefrogs. Phylogenetic comparative analyses of 355 hylid species (of which 95 display dynamic dichromatism) reveal high transition rates between dynamic dichromatism, ontogenetic (permanent) dichromatism and monochromatism reflecting the high evolutionary lability of this trait. Correlated evolution in hylids between dynamic dichromatism and forming large breeding aggregations indicates that the evolution of large breeding aggregations precedes the evolution of dynamic dichromatism. Multivariate phylogenetic logistic regression recovers the interaction between biogeographic distribution and forming breeding aggregations as a significant predictor of dynamic dichromatism in hylids. Accounting for macroecological differences between temperate and tropical regions, such as seasonality and the availability of breeding sites, may improve our understanding of ecological contexts in which dynamic dichromatism is likely to arise in tropical lineages and why it is retained in some temperate species and lost in others. PMID- 28833836 TI - Assessing the infection risk of enteropathogens from consumption of raw vegetables washed with contaminated water in Kathmandu Valley, Nepal. AB - AIMS: To assess diarrhoeal risks from enteropathogenic Escherichia coli, Giardia and Cryptosporidium from consuming raw spinach, cabbage, carrots and tomatoes in Kathmandu Valley, Nepal. METHODS AND RESULTS: The annual infection risk was quantified using the probabilistic Quantitative Microbial Risk Assessment approach, which considered 12 vegetable washing combinations. A new model was used to estimate dose of pathogens per exposure comprising parameters such as pathogen concentration in vegetable wash water before selling and eating, vegetable consumption rate, remaining pathogen ratio after washing, remaining water on vegetables after washing and water treatment removal efficiency. When all washing combinations were considered, high infection risks above the acceptable level of -4 log10 infection per person per year were obtained, whereas the risk was reduced when other sources excluding river water were used. Assuming use of water treated with ceramic filters by all consumers, a 0-2 log10 reduction in the estimated risks was obtained, which was insufficient to achieve the required risk level. CONCLUSION: High risk of diarrhoea prevails among raw vegetable consumers in the valley. SIGNIFICANCE AND IMPACT OF THE STUDY: It is needed to protect vegetable washing water sources and establish advanced water treatment methods to achieve the required level of public health risk. PMID- 28833838 TI - Syndrome specific modules to enhance the Stepping Stones Triple P public health intervention. AB - BACKGROUND: Service responses to behaviour phenotypes include care by expert clinicians, syndrome-specific clinics, disability-specific mental health services and generic mental health services. While these services contribute to care, they are often of limited accessibility. METHODS: We describe a population-wide public health intervention aimed at increasing the accessibility of services to the target population. Stepping Stones Triple P (SSTP) is a public health intervention of known efficacy in reducing behaviour problems when delivered to parents of children aged 0-12 with mixed developmental disabilities. RESULTS: The strategy we discuss involves enhancing SSTP with modules for specific causes of developmental disabilities including Down, Fetal Alcohol, Fragile X, Prader-Willi and Williams syndromes. CONCLUSIONS: We propose that enhancing SSTP with syndrome specific modules will increase the accessibility of support to families who have a child with a specific behaviour phenotype. We suggest that future research should confirm the public health impact of the modified SSTP programme using the RE-AIM framework. PMID- 28833839 TI - 'At the end of the day, it is more important that he stays happy': an interpretative phenomenological analysis of people who have a sibling with 22q11.2 deletion syndrome. AB - BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome. However, there is little research examining the effect of this multisystem disorder on the family, particularly siblings. The current study was a phenomenological exploration of sense-making in siblings of a person with 22q11.2DS. METHOD: Interpretative phenomenological analysis informed a detailed and open examination of being a sibling of a person with 22q11.2DS. Using in depth semistructured interviews, five typically developing siblings (two men, three women) of people with 22q11.2DS were individually interviewed, providing the data set for transcription and thematic analysis. RESULTS: The theme 'They are the priority' overarched two subordinate themes that emerged from participants' descriptions of the struggle with acceptance and finding positive meaning. Participants oscillated between conflicting feelings about their sibling with 22q11.2DS always taking centre stage. For example, they felt anger, guilt and resentment; yet, they also embraced patience, empathy and gratitude. CONCLUSIONS: This phenomenological study provides a foundation for future research relating to 22q11.2DS and fostering family wellbeing, particularly around acceptance and psychological growth. The siblings in this study actively withdrew from their family to allow prioritisation of their affected sibling. However, this does not mean that their needs should be overlooked. There are easily accessible resources to support siblings of individuals with disabilities, and it is important for health professionals and parents to consider these options. PMID- 28833840 TI - Genetic disorders and neurobehavioural phenotypes. PMID- 28833841 TI - Proposed biopsy performance benchmarks for MRI based on an audit of a large academic center. AB - Performance benchmarks exist for mammography (MG); however, performance benchmarks for magnetic resonance imaging (MRI) are not yet fully developed. The purpose of our study was to perform an MRI audit based on established MG and screening MRI benchmarks and to review whether these benchmarks can be applied to an MRI practice. An IRB approved retrospective review of breast MRIs was performed at our center from 1/1/2011 through 12/31/13. For patients with biopsy recommendation, core biopsy and surgical pathology results were reviewed. The data were used to derive mean performance parameter values, including abnormal interpretation rate (AIR), positive predictive value (PPV), cancer detection rate (CDR), percentage of minimal cancers and axillary node negative cancers and compared with MG and screening MRI benchmarks. MRIs were also divided by screening and diagnostic indications to assess for differences in performance benchmarks amongst these two groups. Of the 2455 MRIs performed over 3-years, 1563 were performed for screening indications and 892 for diagnostic indications. With the exception of PPV2 for screening breast MRIs from 2011 to 2013, PPVs were met for our screening and diagnostic populations when compared to the MRI screening benchmarks established by the Breast Imaging Reporting and Data System (BI-RADS) 5 Atlas(r) . AIR and CDR were lower for screening indications as compared to diagnostic indications. New MRI screening benchmarks can be used for screening MRI audits while the American College of Radiology (ACR) desirable goals for diagnostic MG can be used for diagnostic MRI audits. Our study corroborates established findings regarding differences in AIR and CDR amongst screening versus diagnostic indications. PMID- 28833842 TI - Widespread generalist clones are associated with range and niche expansion in allopolyploids of Pacific Northwest Hawthorns (Crataegus L.). AB - Range and niche expansion are commonly associated with transitions to asexuality, polyploidy and hybridity (allopolyploidy) in plants. The ability of asexual polyploids to colonize novel habitats may be due to widespread generalist clones, multiple ecologically specialized clones, or may be a neutral by-product of multiple, independent origins of asexual polyploids throughout the range. We have quantified niche size and divergence for hawthorns of the Pacific Northwest using data from herbarium vouchers with known cytotypes. We find that all polyploid niches diverge from that of the diploid range, and allopolyploids have the broadest niches. Allotetraploids have the largest niche and the widest geographic distribution. We then assessed the genetic mechanism of range expansion by surveying the ecological and geographic distribution of genotypes within each cytotype from sites in which fine-scale habitat assessments were completed. We find no isolation by either geographic or ecological distance in allopolyploids, suggesting high dispersal and colonization ability. In contrast, autotriploids and diploids show patterns of isolation by geographic distance. We also compared the geographic and ecological distributions of clonal genotypes with those of randomly drawn sites of the most widespread cytotype. We found that most clones are geographically widespread and occur in a variety of habitats. We interpret these findings to suggest that patterns of range and niche expansion in Pacific Northwest Hawthorns may stem from these widespread, ecologically generalist clones of hybrid origin. PMID- 28833844 TI - How to design the cost-effectiveness appraisal process of new healthcare technologies to maximise population health: A conceptual framework. AB - This paper presents a conceptual framework to analyse the design of the cost effectiveness appraisal process of new healthcare technologies. The framework characterises the appraisal processes as a diagnostic test aimed at identifying cost-effective (true positive) and non-cost-effective (true negative) technologies. Using the framework, factors that influence the value of operating an appraisal process, in terms of net gain to population health, are identified. The framework is used to gain insight into current policy questions including (a) how rigorous the process should be, (b) who should have the burden of proof, and (c) how optimal design changes when allowing for appeals, price reductions, resubmissions, and re-evaluations. The paper demonstrates that there is no one optimal appraisal process and the process should be adapted over time and to the specific technology under assessment. Optimal design depends on country-specific features of (future) technologies, for example, effect, price, and size of the patient population, which might explain the difference in appraisal processes across countries. It is shown that burden of proof should be placed on the producers and that the impact of price reductions and patient access schemes on the producer's price setting should be considered when designing the appraisal process. PMID- 28833843 TI - A novel model to characterize structure and function of BRCA1. AB - BRCA1 plays a central role in DNA repair. Although N-terminal RING and C-terminal BRCT domains are studied well, the functions of the central region of BRCA1 are poorly characterized. Here, we report a structural and functional analysis of BRCA1 alleles and functional human BRCA1 in chicken B-lymphocyte cell line DT40. The combination of "homologous recombineering" and "RT-cassette" enables modifications of chicken BRCA1 gene in Escherichia coli. Mutant BRCA1 knock-in DT40 cell lines were generated using BRCA1 mutation constructs by homologous recombination with a targeting efficiency of up to 100%. Our study demonstrated that deletion of motifs 2-9 BRCA1Delta/Delta181-1415 (Caenorhabditis elegans BRCA1 mimic) or deletion of motif 1 BRCA1Delta/Delta126-136 decreased cell viability following cisplatin treatment. Furthermore, deletion of motifs 5 and 6 BRCA1Delta/Delta525-881 within DNA-binding region, even the conserved 7-amino acid deletion BRCA1Delta/Delta872-878 within motif 6, caused a decreased cell viability upon cisplatin treatment. Surprisingly, human BRCA1 is functional in DT40 cells as indicated by DNA damage-induced Rad 51 foci formation in human BRCA1 knock-in DT40 cells. These results demonstrate that those conserved motifs within the central region are essential for DNA repair functions of BRCA1. These findings provide a valuable tool for the development of new therapeutic modalities of breast cancer linked to BRCA1. PMID- 28833846 TI - The effectiveness of medical and vocational interventions for reducing sick leave of self-employed workers. AB - We investigate whether interventions by (a) medical doctors and (b) occupational specialists are effective in reducing sick leave durations among self-employed workers. Therefore, we exploit unique administrative data comprising all sick leave claims by self-employed workers insured with a major Dutch private insurer between January 2009 and March 2014. We estimate a multivariate duration model dealing with nonrandom selection into the two intervention types by controlling for observable and unobservable claimant characteristics. We find adverse treatment effects for both interventions, irrespective of whether they are started early or (middle) late in the sickness spell. PMID- 28833845 TI - Detection of Bacillus anthracis spores from environmental water using bioluminescent reporter phage. AB - AIMS: We investigated the ability of a temperate Bacillus anthracis reporter phage (Wbeta::luxAB-2), which transduces bioluminescence to infected cells, to detect viable spores from deliberately contaminated environmental water samples. METHODS AND RESULTS: Environmental water was inoculated with spores and assayed with Wbeta::luxAB-2. Bioluminescent signals directly correlated with input phage and spore concentrations. A limit of detection of 101 and 102 CFU per ml within 8 h was achieved from pond and lake water, respectively. Detection was greatly simplified by minimizing sample processing steps without spore extraction. The complex endogenous microbial flora and salt content of brackish water challenged the assay, extending the detection time to 12 h for a sensitivity of 102 CFU per ml. Phage-mediated bioluminescence was strictly dependent on bacterial physiology, being significantly reduced in mid/late log phase cells. This was shown to be due to an inability of the phage to adsorb. CONCLUSIONS: The reporter phage Wbeta::luxAB-2 displays potential for simplified detection of viable spores from contaminated water samples within 12 h. SIGNIFICANCE AND IMPACT OF THE STUDY: A deliberate aerosol release of spores could lead to widespread contamination, leaving large areas uninhabitable until remediation. An essential requirement of this restoration process is the development of simplified detection assays in different environmental matrices. PMID- 28833847 TI - Simultaneous targeted inhibition of Sox2-Oct4 transcription factors using decoy oligodeoxynucleotides to repress stemness properties in mouse embryonic stem cells. AB - Transcriptional master regulators like Sox2 and Oct4, which are expressed in various human tumors, have been shown to cause tumor growth promotion as well as epithelial dysplasia by means of interfering with progenitor cell differentiation. In order to investigate the potential of Sox2-Oct4 transcription factor decoy (TFD) strategy for differentiation therapy, mouse embryonic stem cells (mESCs) were used in this study as a model of cancer stem cells (CSCs). Sox2-Oct4 complex decoy ODNs (cd-ODNs) were designed according to their elements in the promoter region of Sox2 gene. DNA-protein interactions between decoy ODNs and their corresponding proteins were examined by electrophoretic mobility shift assay (EMSA). Then, decoy and scrambled ODNs were transfected into mESCs with lipofectamine under 2 inhibitors (2i) conditions. Fluorescence and confocal microscopy, cell viability, cell cycle and apoptosis analysis, alkaline phosphatase, embryoid body formation assay, and real-time PCR were used to conduct further investigations. EMSA data showed that Sox2-Oct4 decoy ODNs bound specifically to their recombinant proteins. The results revealed that the synthesized complex decoy can concomitantly target Sox2 and Oct4, which subsequently represses the stemness properties of mESCs compared to controls through decreasing cell viability, arresting cell cycle in G0 /G1 phases, inducing apoptosis, and modulating differentiation in mESCs despite the presence of 2i/LIF in cell culture. While cd-ODN strategy seems to offer great promise for cancer therapy, further studies are still required to put this powerful investigative tool in practice for a wide range of human cancers. PMID- 28833848 TI - An institutional experience with The Paris System: A paradigm shift from ambiguous terminology to more objective criteria for reporting urine cytology. AB - BACKGROUND: Urine cytology is a highly specific modality for diagnosing high grade urothelial carcinoma (HGUC), but plagued by low sensitivity and wide inter observer variability mainly ascribed to the lack of an established template of reporting. The Paris System (TPS) working group proposed such a template at the 2013 International Congress of Cytology, replete with objective criteria for categorising specimens into one of the seven categories: non-diagnostic, negative for HGUC, atypical urothelial cells, suspicious for HGUC, HGUC, low-grade urothelial neoplasm and others (including non-malignant entities). This study was undertaken to determine the impact of TPS criteria in the morphological interpretation of urine samples. METHODS: A total of 255 voided urine specimens from 97 patients who had follow-up biopsies were re-assessed according to TPS criteria and correlated with the final histological diagnosis. RESULTS: Sixty three patients were diagnosed with HGUC, and 34 had low-grade papillary UC on biopsy. Earlier samples from 40 (41.2%) patients were categorised as merely "atypical" wheereas the "positive for malignancy" category was assigned to 33 (34%) patients. After re-evaluation of the same cases using TPS criteria, cytological features in 44 (69.8%) out of 63 HGUC patients were correctly recognised as HGUC and samples from additional seven patients were re-categorised as suspicious for HGUC (total 81%). The sensitivity of the HGUC category in predicting HGUC was 69.8% which rose to 81% when HGUC was grouped with suspicious for HGUC category. CONCLUSION: The criteria outlined by TPS facilitated the standardisation of urine cytology reporting and significantly increased the sensitivity of diagnosing HGUC. PMID- 28833849 TI - Fifty years of child height and weight in Japan and South Korea: Contrasting secular trend patterns analyzed by SITAR. AB - Objectives Japanese and South Koreans have traditionally been shorter than Europeans, but have recently become appreciably taller. The aim was to quantify the secular trend patterns in height and weight growth in the two countries over 50 years using the SITAR growth curve model. Methods Data on mean height and weight by sex in 1-year age groups from 1 to 20 years were obtained by decade in South Korea (1965-2005) and Japan (1950-2010). The data were analyzed using SITAR (SuperImposition by Translation And Rotation), which estimates a mean curve and three adjustments-size, timing and intensity-reflecting how the individual surveys differ from the mean. A sensitivity analysis compared results for the Japanese data based on cohort as well as period. Results Growth patterns in the two countries changed dramatically over the study period, affecting not only height and weight but also developmental age, in that the growth period advanced in timing and shrank in duration. SITAR fitted the data well. The trends were larger in South Korea than Japan, and puberty timing in Japan stabilized by 1970. Most of the height increment seen in adults had already accrued by age 1.5 years, whereas the adult weight increment accrued throughout childhood. Conclusions The secular height trend in these countries represents increased growth in the long bones during infancy, so it can be viewed as the inverse of stunting. There are striking country differences in growth pattern, but they are not easily explained by differences in national income, diet or lifestyle. PMID- 28833850 TI - Influence of breast cancer opportunistic screening on aesthetic surgical outcome: A single-center retrospective study in Switzerland. AB - The aim of this retrospective study is to compare the surgical aesthetic outcome and breast cancer (BC) characteristics in patients with BC detected either by opportunistic screening or clinical diagnosis. 262 women undergoing surgery for BC between 2009 and 2012 were included. The following features were compared in the two groups of patients: (1) age at diagnosis; (2) family history of BC; (3) histology type; (4) tumor diameter; (5) local staging, and (6) type of surgical treatment. In 92/262 (35.1%) cases BC was detected by screening and 170/262 (64.9%) had clinical diagnosis. A positive family history and ductal carcinoma in situ diagnosis were more frequent in patients with clinical diagnosis (P = .001 and P < .0001 respectively). Mean maximum diameter of invasive cancers was significantly greater in symptomatic patients (P < .001). Breast conserving surgery was performed in 76/92 (82.6%) patients with screening and 115/170 (67.6%) with clinical diagnosis. Mastectomy was performed in 16/92 (17.4%) patients with screening and 55/170 (32.3%) with clinical diagnosis. Mastectomy was more frequent in patients with clinical diagnosis of BC (P = .010). No significant group differences were found regarding the other features. This study demonstrated that in opportunistic screening, breast conserving surgery may be applied in a higher number of cases compared to patients presenting with clinical diagnosis, thereby improving life quality of these patients. PMID- 28833851 TI - 2D Sequence-Coded Oligourethane Barcodes for Plastic Materials Labeling. AB - Mixtures of uniform sequence-defined oligourethanes are evaluated as 2D molecular barcodes for labeling three different commodity polymers, namely polystyrene, polyvinylchloride and polyethylene terephthalate. Six different oligourethanes are synthesized by solid-phase iterative synthesis and are coded using a binary monomer alphabet. High-resolution mass spectrometry studies indicate that all oligomers are uniform and sequence-defined. However, instead of using them as individual coded chains, oligomers with different chain-length, mass and sequence are mixed into intentionally polydispersed libraries. In particular, a three component library and a four-component library are created to encode a 2-bytes model binary sequence. These 2D-coded libraries are incorporated in all commodity plastics via a simple solvent casting procedure. Furthermore, in all cases, the oligomer mixtures can be extracted from the host polymer films and deciphered by mass spectrometry, thus opening interesting avenues for anti-counterfeiting and traceability applications. PMID- 28833852 TI - Pharmacist awareness and views towards counterfeit medicine in Lebanon. AB - BACKGROUND: Pharmacists, as healthcare professionals, have patients' well-being and safety as their primary concern. However, the safety and efficacy of treatments may be compromised by the availability of counterfeit medicine (CFM) which could have serious consequences for public health. OBJECTIVES: To assess pharmacist awareness and views towards CFM in Lebanon. METHODS: The study used convenience sampling and selected pharmacists based on their willingness to participate and used a questionnaire as a tool to determine their experiences and views towards CFM. The questionnaires were completed in different regions in Lebanon. KEY FINDINGS: A total of 223 pharmacists participated in the study, and all were able to define CFM, however were inconsistent in their definitions. The majority reported identifying CFM by the medicine's effect (67.7%), followed by cost (66.8%). Almost 43% reported knowing of pharmacists who dispensed CFM. Additionally, participants reported that they believed that pharmacists who dealt with CFM were unprofessional (89.2%) and unethical (86.5%), and that they did it for the 'easy money' (87.9%) and large profit (86.5%). CONCLUSION: The study highlighted the need for additional CFM awareness campaigns with an emphasis on the role that pharmacists have in protecting patients from using CFM. In addition, there is a need for an official CFM definition that distinguishes between the different types of counterfeiting. Furthermore, the Lebanese Ministry of Public Health and regulatory authorities should control and secure the supply chain of medicine in the country and enforce the law. PMID- 28833853 TI - The Pediatric Submersion Score Predicts Children at Low Risk for Injury Following Submersions. AB - OBJECTIVES: Pediatric submersion victims often require admission. We wanted to identify a cohort of children at low risk for submersion-related injury who can be safely discharged from the emergency department (ED) after a period of observation. METHODS: This was a single-center retrospective derivation/validation cross-sectional study of children (0-18 years) who presented postsubmersion to a tertiary care, children's hospital ED from 2008 to 2015. We reviewed demographics, comorbidities, and prehospital and ED course. Primary outcome was safe discharge at 8 hours postsubmersion: normal mentation and vital signs. To identify potential scoring factors, any p-value of <=0.25 was included in binary logistic regression; p-values < 0.05 were included in the final score. In the validation data set, we generated a one-point scoring system for each normal ED item. Receiver operating characteristic curves with area under the curve (AUC) were generated to test sensitivity and specificity. RESULTS: The derivation data set consisted of 356 patients and validation data set of 89 patients. Five factors generated a safe discharge score at 8 hours: normal ED mentation, normal ED respiratory rate, absence of ED dyspnea, absence of need for airway support (bag-valve mask ventilation, intubation, and CPAP), absence of ED systolic hypotension (maximum score = 5; range = 0-5). Only the 80 patients with values for all five factors were included in the sensitivity/specificity analysis. This resulted in an AUC of 0.81 (95% confidence interval [CI] = 0.71 0.91; p < 0.001). Based on the sensitivity/specificity analysis, the discriminative ability peaks at 75% with a score of >=3.5. A score of 4 or higher in the ED would suggest a safe discharge at 8 hours (sensitivity = 88.2% [95% CI = 72.5%-96.7%]; specificity = 62.9% [95% CI = 44.9%-78.5%]; positive predictive value = 69.8% [95% CI = 53.9%-82.8%]; negative predictive value = 84.6% [95% CI = 65.1%-95.6%]). CONCLUSIONS: A risk score can identify children at low risk for submersion-related injury who can be safely discharged from the ED after observation. PMID- 28833854 TI - New methods for modelling EQ-5D-5L value sets: An application to English data. AB - Value sets for the EQ-5D-5L are required to facilitate its use in estimating quality-adjusted life years. An international protocol has been developed to guide the collection of stated preference data for this purpose and has been used to generate EQ-5D-5L valuation data for England. The aim of this paper is report the innovative methods used for modelling those data to obtain a value set. Nine hundred and ninety-six members of the English general public completed time trade off (TTO) and discrete choice experiment (DCE) tasks. We estimate models, with and without interactions, using DCE data only, TTO data only, and TTO/DCE data combined. TTO data are interpreted as both left and right censored. Heteroskedasticity and preference heterogeneity between individuals are accounted for. We use Bayesian methods in the econometric analysis. The final model is chosen based on the deviance information criterion (DIC). Censoring and taking account of heteroskedasticity have important effects on parameter estimation. For DCE data only, TTO data only, and DCE/TTO data combined, models with parameters for all dimensions and levels perform best, as judged by the DIC. Taking account of heterogeneity improves fit, and the multinomial model reports the lowest DIC. This paper presents approaches that suit observed characteristics of EQ-5D-5L valuation data and recognise respondents' preference heterogeneity. The methods described are potentially relevant to other value set studies. PMID- 28833855 TI - Efficacy of vitamin D supplementation in combination with conventional antiviral therapy in patients with chronic hepatitis C infection: a meta-analysis of randomised controlled trials. AB - BACKGROUND: Although a contributory role of vitamin D levels for the development of chronic hepatitis C has been suggested, the efficacy of vitamin D supplementation in combination with conventional antiviral therapy consisting of pegylated interferon-alpha (Peg-IFN-alpha) injection and oral ribavirin (RBV) remains unclear. We investigated its efficacy in the treatment of chronic hepatitis C via a meta-analysis of randomised controlled trials. METHODS: We searched PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov and the bibliographies of relevant articles to locate additional publications in September 2016. Three evaluators independently reviewed and selected eligible studies based on predetermined selection criteria. RESULTS: Of 522 articles meeting our initial criteria, a total of seven open-label, randomised controlled trials involving 548 participants, were included in the final analysis. Vitamin D supplementation in combination with Peg-IFN-alpha injection and oral RBV significantly increased the rate of viral response for hepatitis C at 24 weeks after treatment in a random-effects meta-analysis (relative risk = 1.30; 95% confidence interval = 1.04-1.62; I2 = 75.9%). Also, its significant efficacy was observed in patients with hepatitis C virus genotype 1, which is known to be refractory to antiviral therapy. CONCLUSIONS: In summary, we observed that additional use of vitamin D has a positive effect on sustained viral response rates of patients with chronic hepatitis C infection. However, we cannot establish the efficacy because of substantial heterogeneity, a small sample size and a low methodological quality. PMID- 28833856 TI - Alcohol use and the wage returns to education and work experience. AB - Despite a widely held belief that alcohol use should negatively impact wages, much of the literature on the topic suggests a positive relationship between nonproblematic alcohol use and wages. Studies on the effect of alcohol use on educational attainment have also failed to find a consistent, negative effect of alcohol use on years of education. Thus, the connections between alcohol use, human capital, and wages remain a topic of debate in the literature. In this study, we use the 1997 cohort of the National Longitudinal Survey of Youth to estimate a theoretical model of wage determination that links alcohol use to wages via human capital. We find that nonbinge drinking is associated with lower wage returns to education whereas binge drinking is associated with increased wage returns to both education and work experience. We interpret these counterintuitive results as evidence that alcohol use affects wages through both the allocative and productive efficiency of human capital formation and that these effects operate in offsetting directions. We suggest that alcohol control policies should be more nuanced to target alcohol consumption in the contexts within which it causes harm. PMID- 28833857 TI - Invertebrate population genetics across Earth's largest habitat: The deep-sea floor. AB - Despite the deep sea being the largest habitat on Earth, there are just 77 population genetic studies of invertebrates (115 species) inhabiting non chemosynthetic ecosystems on the deep-sea floor (below 200 m depth). We review and synthesize the results of these papers. Studies reveal levels of genetic diversity comparable to shallow-water species. Generally, populations at similar depths were well connected over 100s-1,000s km, but studies that sampled across depth ranges reveal population structure at much smaller scales (100s-1,000s m) consistent with isolation by adaptation across environmental gradients, or the existence of physical barriers to connectivity with depth. Few studies were ocean wide (under 4%), and 48% were Atlantic-focused. There is strong emphasis on megafauna and commercial species with research into meiofauna, "ecosystem engineers" and other ecologically important species lacking. Only nine papers account for ~50% of the planet's surface (depths below 3,500 m). Just two species were studied below 5,000 m, a quarter of Earth's seafloor. Most studies used single-locus mitochondrial genes revealing a common pattern of non-neutrality, consistent with demographic instability or selective sweeps; similar to deep-sea hydrothermal vent fauna. The absence of a clear difference between vent and non vent could signify that demographic instability is common in the deep sea, or that selective sweeps render single-locus mitochondrial studies demographically uninformative. The number of population genetics studies to date is miniscule in relation to the size of the deep sea. The paucity of studies constrains meta analyses where broad inferences about deep-sea ecology could be made. PMID- 28833858 TI - Lifestyle and Occupational Stress: A Potential Risk Factor for Obstructive Sleep Apnea in Nonobese Male Subjects. AB - PURPOSE: To record the incidence of obstructive sleep apnea (OSA) in nonobese male subjects and investigate the coexistence of lifestyle stress, sleep deprivation, and upper airway inflammation. MATERIALS AND METHODS: 552 patients were assessed during a survey of banks, government and corporate offices, recruitment agencies, and schools between January 2012 and January 2016. After applying the inclusion and exclusion criteria designed for this study, the number of patients tapered down to 120 patients who underwent diagnostic tests, viz. polysomnography, chemiluminiscence immunoassay, nephelometry, and upper airway endoscopy. This revealed the presence of OSA coexistent with elevated serum cortisol, C-reactive protein (CRP), and upper airway inflammation. RESULTS: Polysomnography showed that 57 of 120 patients suffered from OSA. Objective evaluation of these patients exposed an undercurrent of lifestyle stress in 39 patients. CRP and serum cortisol were found to be significantly high (1.60 +/- 0.52 and 7.20 +/- 0.76 MUg/dL, respectively) in 30 patients. Endoscopy revealed 18 patients with moderate, 7 with severe, and 5 with no upper airway inflammation. CONCLUSION: The results of this study demonstrated that OSA was found to be prevalent in the cohort of nonobese male patients studied. Coexistence of lifestyle stress, sleep deprivation, and upper airway inflammation was revealed. PMID- 28833859 TI - Supraventricular tachycardia, pregnancy, and water: A new insight in lifesaving treatment of rhythm disorders. AB - Pregnancy may predispose to paroxysmal supraventricular tachycardia (SVT), in subjects with or without identifiable heart disease. Many physiological conditions such as autonomic nervous system changes, altered systemic hemodynamics, etc. can contribute to the onset of arrhythmias during pregnancy. Some cases reported the occurrence of arrhythmias in relation to systemic fluid variations. We report the case of a pregnant woman who experienced SVT due to fluid depletion, detected by bioimpedance vector analysis (BIVA), which was successfully treated by water repletion under tight BIVA monitoring. Emergency physicians can overcome dangerous drug administration by considering historical examination and using fast and reproducible techniques such as BIVA. PMID- 28833860 TI - Chronic impairment of ERK signaling in glutamatergic neurons of the forebrain does not affect spatial memory retention and LTP in the same manner as acute blockade of the ERK pathway. AB - The ERK/MAPK signaling pathway has been extensively studied in the context of learning and memory. Defects in this pathway underlie genetic diseases associated with intellectual disability, including impaired learning and memory. Numerous studies have investigated the impact of acute ERK/MAPK inhibition on long-term potentiation and spatial memory. However, genetic knockouts of the ERKs have not been utilized to determine whether developmental perturbations of ERK/MAPK signaling affect LTP and memory formation in postnatal life. In this study, two different ERK2 conditional knockout mice were generated that restrict loss of ERK2 to excitatory neurons in the forebrain, but at different time-points (embryonically and post-natally). We found that embryonic loss of ERK2 had minimal effect on spatial memory retention and novel object recognition, while loss of ERK2 post-natally had more pronounced effects in these behaviors. Loss of ERK2 in both models showed intact LTP compared to control animals, while loss of both ERK1 and ERK2 impaired late phase LTP. These findings indicate that ERK2 is not necessary for LTP and spatial memory retention and provide new insights into the functional deficits associated with the chronic impairment of ERK signaling. PMID- 28833861 TI - Cortical inhibition in symptomatic and remitted mania compared to healthy subjects: A cross-sectional study. AB - OBJECTIVES: Transcranial magnetic stimulation (TMS)-derived cortical reactivity studies provide a unique opportunity to non-invasively study gamma amino butyric acid (GABA)-mediated inhibitory neurotransmission in bipolar disorder (BD). Earlier studies were conducted in smaller samples and on patients who were on medications that can potentially confound the results. We aimed to study short interval (SICI) and long-interval intracortical inhibition (LICI) in medication naive/free symptomatic (manic) BD patients (n=39), first episode mania (FEM) patients who had recently (<=6 months) remitted with treatment (remitted FEM; n = 28) and healthy subjects (HSs; n = 45). METHODS: Resting motor threshold (RMT), stimulation intensity to elicit a 1-mV motor evoked potential (MEP) (SI1 mV ), SICI and LICI were measured in three groups using single- and paired-pulse TMS. RESULTS: Motor thresholds were higher in the manic BD and HS groups compared to the remitted FEM group (P < .001). SICI was lower (P = .026) but LICI was higher (P = .044) in the manic BD and remitted FEM groups compared to the HS group. CONCLUSIONS: Lower motor thresholds in remitted FEM perhaps reflect the effect of treatment, and could be studied as potential prognostic neuromarkers. Inverse findings for SICI (reduced) and LICI (increased) in BD indicate a possible differential involvement of the GABAA and GABAB subreceptor systems. These could be trait markers as they are impaired in both mania and euthymia. PMID- 28833862 TI - Thermodynamic Parameters of Temperature-Induced Phase Transition for Brushes onto Nanoparticles: Hydrophilic versus Hydrophobic End-Groups Functionalization. AB - Quantification of the stimuli-responsive phase transition in polymers is topical and important for the understanding and development of novel stimuli-responsive materials. The temperature-induced phase transition of poly(N isopropylacrylamide) (PNIPAm) with one thiol end group depends on the confinement free polymer or polymer brush-on the molecular weight and on the nature of the second end. This paper describes the synthesis of heterotelechelic PNIPAm of different molecular weights with a thiol end group-that specifically binds to gold nanorods and a hydrophilic NIPAm end group by reversible addition fragmentation chain-transfer polymerization. Proton high-resolution magic angle sample spinning NMR spectra are used as an indicator of the polymer chain conformations. The characteristics of phase transition given by the transition temperature, entropy, and width of transition are obtained by a two-state model. The dependence of thermodynamic parameters on molecular weight is compared for hydrophilic and hydrophobic end functional-free polymers and brushes. PMID- 28833863 TI - Are experiences of psychosis associated with unhelpful metacognitive coping strategies? A systematic review of the evidence. AB - This review investigated whether unhelpful metacognitive coping strategies, such as attentional biases, worry, rumination, and thought control, are associated with experiences of psychosis. These processes, known collectively as the Cognitive Attentional Syndrome (CAS), form a central tenet of the Self-Regulatory Executive Function model. Three research questions based on assumptions underlying the CAS were addressed. It was predicted that processes of (a) self focused processing, (b) negative perseverative thinking (worry and rumination), and (c) counterproductive thought control would be associated with experiences of psychosis. A comprehensive search of the literature identified 51 eligible studies: 17 investigated self-focused attention, 25 investigated perseverative processing (worry: n = 18; rumination: n = 10), and 9 investigated thought control strategies. Findings indicated that unhelpful metacognitive coping strategies associated with the CAS are related to experiences of psychosis and appear to share important relationships with distress. Implications for future research and clinical practice are discussed. PMID- 28833864 TI - Integrating anatomy, radiology, pathology, and surgery: An alternative approach in resecting multifocal and multicentric breast carcinoma. AB - The sick lobe hypothesis provides the basis for a lobar approach in radiology, pathology, and surgical treatment of breast cancer. This approach aims to remove the tumor together with the surrounding field of genetic aberrations. Detailed preoperative lobar imaging that properly maps the disease and assesses its extent guides the parenchymal resection. Integration of our knowledge of breast anatomy and pathology with the results of preoperative radiological mapping is critical in assessing the eligibility of patients with multifocal and/or multicentric breast cancer for breast conservation treatment. Through an appropriately selected incision, a multisegment resection of the diseased lobe(s) is performed, which leaves the residual parenchyma in a formation that allows dovetailing of one part into the other, like the way pieces of a jigsaw puzzle fit together. Detailed pathologic analysis of the surgical specimen provides valuable feedback to the radiologist, establishes the completeness of surgical intervention, and generates predictive information for therapeutic decisions. Our approach is a step in continuous search for ideal tailored therapy to avoid under or over treatment of breast cancer patients. PMID- 28833865 TI - Patterns of care for non-small cell lung cancer patients in Belgium: A population based study. AB - Guidelines recommend surgery for Stage I-II, chemoradiation for Stage III and systemic therapy for Stage IV non-small cell lung cancer (NSCLC). However, patient related factors and patient preferences influence treatment decisions. We investigated patterns of care for Belgian NSCLC patients in 2010-2011, based on population-based data from the Belgian Cancer Registry and administrative databases. The relationship between patient characteristics, institutional diagnostic volume, type of treatment and survival was investigated. Overall, 20.8% of patients received no oncological treatment. 59% and 22.1% of Stage I-II patients received primary surgery or (chemo)radiation respectively. 34% of Stage III patients received chemoradiation and 17% of Stage IIIA patients had surgery. 70% of Stage IV patients received chemotherapy or targeted therapy. Moderate variability between centres was observed. For Stage IV, systemic therapy was less frequently used in higher volume centres and 1-year survival was lower in centres that had >= 50 new patients yearly. Although not all NSCLC patients received treatment as ideally recommended by guidelines, these results do not necessarily represent poor quality of care as patient characteristics and preferences need to be taken into account. Treatment options targeted towards patients with co morbidity or unfit patients is warranted to improve outcomes of all NSCLC patients. PMID- 28833867 TI - Development and responses of brain metastases during treatment with trastuzumab emtansine (T-DM1) for HER2 positive advanced breast cancer: A single institution experience. AB - Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that does not cross an intact blood-brain barrier. In the EMILIA trial of T-DM1 vs capecitabine/lapatinib for HER2 positive advanced breast cancer, all patients had baseline brain imaging, and 9/450 (2%) of patients with negative baseline imaging developed new brain disease during T-DM1. We assessed the frequency of brain progression in clinical practice, without routine baseline imaging. We undertook a retrospective study of all patients treated with T-DM1 at the Royal Marsden Hospital from 2011 to 2016. Data collected included baseline characteristics, previous treatment for advanced breast cancer, sites of metastatic disease, duration of T-DM1, sites of progression, and treatment of CNS progression. Fifty five patients were identified who had received a median of two prior lines of treatment (range 0-5). All were HER2 positive; 45 patients had IHC 3+ tumors and 10 were ISH positive. Patients received a median of 12 cycles of T-DM1 (range 1 34), and six remain on treatment at the time of analysis. Before commencing T DM1, 16/55 (29%) had known brain metastases (treated with whole brain [9] stereotactic radiotherapy [6] or both [1]). Brain was the first site of progression in 56% (9/16) patients, with a median time to brain progression of 9.9 months (95% CI 3.9-12.2). In patients without known baseline brain metastases, 17.9% (7/39) developed new symptomatic brain disease during T-DM1, after a median of 7.5 months (95%CI 3.8-9.6). Brain progression was isolated, with control of extra-cranial disease in 4/7 patients. Only one patient was suitable for stereotactic radiotherapy. Median time to extra-cranial progression in all patients was 11.5 months (95% CI 9.1-17.7), and median OS in all patients was 17.8 months (95% CI 14.2-22). In patients not screened for brain metastases at baseline, the brain was the first site of progression in a significant proportion. Baseline brain imaging may have a role in standard practice for patients commencing T-DM1 therapy. PMID- 28833866 TI - Total sleep time and kynurenine metabolism associated with mood symptom severity in bipolar disorder. AB - OBJECTIVE: Chronic, low-level inflammation is associated with symptomatic bipolar disorder (BD) and with chronic insomnia. Disrupted sleep is a feature of episodes of both mania and depression. We examined the effect of neopterin, a marker of cellular immune activation, and kynurenine (KYN), an inflammatory byproduct of the serotonin pathway, on the association between total sleep time and depression severity in BD. METHOD: Twenty-one symptomatic BD participants and 28 healthy controls (HC) were recruited and followed during usual clinical care. At baseline and after symptomatic recovery, total sleep time was objectively measured with actigraphy for 1 week and blood plasma was collected to measure the serotonin precursor tryptophan (TRP), KYN, the KYN/TRP ratio, and neopterin levels. Statistical analyses were conducted using chi-square, independent t tests and hierarchical linear multiple regression models. RESULTS: Total sleep time was correlated positively with depressive severity and negatively with manic severity. TRP was significantly reduced in BD participants compared to HC. KYN, TRP, and the KYN/TRP ratio were associated with depressive severity when total sleep time and body mass index (BMI) were included in the model. The KYN/TRP ratio trended towards a negative association with mania symptoms, controlling for BMI and total sleep time, in acutely symptomatic BD participants. Neopterin was not associated with sleep or mood severity. After usual clinical care, BD participants showed significantly decreased clinical symptoms but no significant differences in sleep phenotype or biomarkers. CONCLUSION: Inflammation, sleep, and mood are closely intertwined. Future research into the effect of inflammation on sleep in BD may lead to clinical markers of outcome. PMID- 28833869 TI - Valuing health-related quality of life: An EQ-5D-5L value set for England. AB - A new version of the EQ-5D, the EQ-5D-5L, is available. The aim of this study is to produce a value set to support use of EQ-5D-5L data in decision-making. The study design followed an international research protocol. Randomly selected members of the English general public completed 10 time trade-off and 7 discrete choice experiment tasks in face-to-face interviews. A 20-parameter hybrid model was used to combine time trade-off and discrete choice experiment data to generate values for the 3,125 EQ-5D-5L health states. Valuation data are available for 996 respondents. Face validity of the data has been demonstrated, with more severe health states generally given lower values. Problems with pain/discomfort and anxiety/depression received the greatest weight. Compared to the existing EQ-5D-3L value set, there are considerably fewer "worse than dead" states (5.1%, compared with over one third), and the minimum value is higher. Values range from -0.285 (extreme problems on all dimensions) to 0.950 (for health states 11211 and 21111). Results have important implications for users of the EQ-5D-5L both in England and internationally. Quality-adjusted life year gains from interventions seeking to improve very poor health may be smaller using this value set and may previously have been overestimated. PMID- 28833870 TI - A critical review of knowledge on nurses with problematic substance use: The need to move from individual blame to awareness of structural factors. AB - Problematic substance use (PSU) among nurses has wide-ranging adverse implications. A critical integrative literature review was conducted with an emphasis on building knowledge regarding the influence of structural factors within nurses' professional environments on nurses with PSU. Five thematic categories emerged: (i) access, (ii) stress, and (iii) attitudes as contributory factors, (iv) treatment policies for nurses with PSU, and (v) the culture of the nursing profession. Conclusions were that an overemphasis on individual culpability and failing predominates in the literature and that crucial knowledge gaps exist regarding the influence of structural factors on driving and shaping nurses' substance use. PMID- 28833871 TI - Electric pulp test threshold responses in healthy incisors, canines, premolars and molars. AB - The purpose of this study was to determine the range of threshold responses of healthy dental pulps and test the reproducibility of the electric pulp test (EPT). Forty-nine dental students participated in the study. Sound teeth in both arches, except third molars, were included. The teeth were isolated using cotton rolls and dried with compressed air, and the threshold responses were recorded. Participants stopped the stimulus increase by pressing the switch at the first sensation of discomfort. The measurements were repeated after 30 days. The obtained data were analysed using SPSS(r) 16.0. The mean thresholds for the maxillary incisors, canines, premolars and molars were 10.77, 21.07, 21.88 and 34.07 MUA, and for mandibular incisors, canines, premolars and molars 9.81, 18.7, 19.24 and 30.1 MUA respectively. The differences between the two measurements were statistically significant for teeth 32, 31, 41 and 42. The EPT was shown to be reproducible for all the teeth tested except mandibular incisors. PMID- 28833868 TI - The Use of Visual Rating Scales to Quantify Brain MRI Lesions in Patients with HIV Infection. AB - BACKGROUND AND PURPOSE: Human immunodeficiency virus (HIV)-infected patients commonly have abnormalities in cerebral white matter that are visible on magnetic resonance imaging (MRI) as hyperintensities (WMHs). Visual rating scales (VRSs) have been used to quantify WMH in other diseases such as cerebral small vessel disease (CSVD), but not in HIV. Such scales are advantageous because they are applicable to routinely acquired MRIs and so are suitable for large-scale studies and clinical care. We sought to establish the utility of three VRSs (the Fazekas, Scheltens, and van Sweiten scales) in HIV. METHODS: The Manhattan HIV Brain Bank (MHBB) is a longitudinal cohort study that performs serial neurologic examinations and neuropsychological testing. All brain MRIs (n = 73) performed for clinical purposes on MHBB participants were scored using the three VRSs. We assessed reliability, validity, and correlation of the VRS with clinical factors relevant to HIV and CSVD. RESULTS: The VRSs all showed acceptable internal consistency and interrater reliability and were highly correlated with one another (r = 0.836-0.916, P < .001). The Fazekas and Scheltens scales demonstrated more WMH in periventricular regions, and the Scheltens scale also suggested a frontal to occipital gradient, with greater WMH frontally. All three VRSs correlated significantly with cognitive impairment (global T score). Age and hepatitis C virus antibody serostatus were the strongest clinical/demographic correlates of WMH, followed by African-American race. CONCLUSIONS: VRSs reliably quantify WMH in HIV-infected individuals and correlate with cognitive impairment. Future studies may find routinely acquired brain MRI quantified by VRS to be an accessible and meaningful neurologic outcome measure in HIV. PMID- 28833872 TI - The chicken or the egg? Adaptation to desiccation and salinity tolerance in a lineage of water beetles. AB - Transitions from fresh to saline habitats are restricted to a handful of insect lineages, as the colonization of saline waters requires specialized mechanisms to deal with osmotic stress. Previous studies have suggested that tolerance to salinity and desiccation could be mechanistically and evolutionarily linked, but the temporal sequence of these adaptations is not well established for individual lineages. We combined molecular, physiological and ecological data to explore the evolution of desiccation resistance, hyporegulation ability (i.e., the ability to osmoregulate in hyperosmotic media) and habitat transitions in the water beetle genus Enochrus subgenus Lumetus (Hydrophilidae). We tested whether enhanced desiccation resistance evolved before increases in hyporegulation ability or vice versa, or whether the two mechanisms evolved in parallel. The most recent ancestor of Lumetus was inferred to have high desiccation resistance and moderate hyporegulation ability. There were repeated shifts between habitats with differing levels of salinity in the radiation of the group, those to the most saline habitats generally occurring more rapidly than those to less saline ones. Significant and accelerated changes in hyporegulation ability evolved in parallel with smaller and more progressive increases in desiccation resistance across the phylogeny, associated with the colonization of meso- and hypersaline waters during global aridification events. All species with high hyporegulation ability were also desiccation-resistant, but not vice versa. Overall, results are consistent with the hypothesis that desiccation resistance mechanisms evolved first and provided the physiological basis for the development of hyporegulation ability, allowing these insects to colonize and diversify across meso- and hypersaline habitats. PMID- 28833873 TI - Early maladaptive schemas associated with dimensional and categorical psychopathology in patients with borderline personality disorder. AB - OBJECTIVE: To ascertain the foundations for a schema-focused therapy model for the treatment of borderline personality disorder. METHODS: The sample consisted of 102 borderline personality disorder outpatients. Dimensional psychopathology was assessed using the Scale for Suicidal Ideation, the Aggression Questionnaire, and the Symptom CheckList Revised. Categorical psychopathology was measured using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I Disorders, Patient Edition. Stepwise linear/logistic multiple regression analyses were used to determine the predictive role of the schema domains tested by the Young Schema Questionnaire on both types of psychopathology. Receiver operating characteristic curves were calculated for those binary outcomes. RESULTS: Regarding dimensional psychopathology, disconnection/rejection predicted greater suicidal ideation (beta = .39, p = .002), physical/overt aggressiveness (beta = .27, p = .05), and psychotic-like symptoms, such as paranoid ideation (beta = .35, p = .003). Other directedness predicted greater anger/inner aggressiveness (beta = .22, p = .05) and internalizing symptoms, such as phobic anxiety (beta = .39, p = .001). Regarding categorical psychopathology, disconnection/rejection significantly predicted the presence of lifetime comorbidities with eating disorders (adjusted odds ratio [AOR] = 1.12, 95% CI = 0.99-1.24) and posttraumatic stress disorder (AOR = 1.2, 95% CI = 1.04-1.3), resulting in a good balance of sensitivity/specificity, respectively (.97/.96 and .88/.89). Other-directedness significantly predicted the absence of lifetime comorbidity with substance-use disorders (AOR = .74, 95% CI = 0.57-0.95). These relationships remained significant after controlling for confounders (e.g., comorbidity with other personality disorders, clinical global severity). CONCLUSIONS: Two schema domains, disconnection/rejection and other-directedness, were directly associated with dimensional and categorical psychopathology among borderline personality disorder patients. These findings provide further information about the foundations and target interventions when implementing schema-focused therapy on this population. PMID- 28833874 TI - Use of granulocyte transfusions among haematology units in England and North Wales. AB - OBJECTIVES: To establish the current use of granulocyte transfusions in haematology patients and explore interest in further research. BACKGROUND: Granulocytes may be used for the treatment of severe infection in neutropenic patients or for primary or secondary prophylaxis. Clinical utility of granulocyte transfusions is unclear, and recent studies have demonstrated equivocal outcomes. Pooled granulocytes are the main granulocyte product used in England and Wales, but there are no data on the patterns of use and little consensus on accepted indications. METHODS: A survey was distributed to UK hospitals delivering intensive chemotherapy. Clinical scenarios were posed, with further questions on clinician experience of using granulocytes, availability of the product, barriers to use and interest in further research. RESULTS: The response rate was 57%; 34.9% of all responses were from allogeneic stem cell transplant centres. Paediatric centres comprised 9.5% respondents, and 19% centres had access to apheresis granulocytes. Of respondents, 58.7% had used granulocytes in the last 3 years, 89.2% of whom used granulocytes to treat refractory infection. There was little consensus on use of granulocytes in the given clinical scenarios even when patients clearly met national guideline criteria. Paediatric centres were overall more likely to recommend granulocyte use. The most frequently identified barrier to use of granulocytes was lack of evidence of effect. Of the respondents, 75% indicated a willingness to participate in further research. CONCLUSION: There remains a lack of consistency about use of granulocytes, which is unsurprising given the lack of clinical data to support their efficacy. We did, however, demonstrate a willingness to participate in further research. PMID- 28833875 TI - Characterization of phenolic compounds in green and red oak-leaf lettuce cultivars by UHPLC-DAD-ESI-QToF/MS using MSE scan mode. AB - Lettuce (Lactuca sativa) is one of the most popular leafy vegetables in the world and constitutes a major dietary source of phenolic compounds with health promoting properties. In particular, the demand for green and red oak-leaf lettuces has considerably increased in the last years but few data on their polyphenol composition are available. Moreover, the usage of analytical edge technology can provide new structural information and allow the identification of unknown polyphenols. In the present study, the phenolic profiles of green and red oak-leaf lettuce cultivars were exhaustively characterized by ultrahigh performance liquid chromatography (UHPLC) coupled online to diode array detection (DAD), electrospray ionization (ESI), and quadrupole time-of-flight mass spectrometry (QToF/MS), using the MSE instrument acquisition mode for recording simultaneously exact masses of precursor and fragment ions. One hundred fifteen phenolic compounds were identified in the acidified hydromethanolic extract of freeze-dried lettuce leaves. Forty-eight of these compounds were tentatively identified for the first time in lettuce, and only 20 of them have been previously reported in oak-leaf lettuce cultivars in literature. Both oak-leaf lettuce cultivars presented similar phenolic composition, except for apigenin glucuronide and dihydroxybenzoic acid, only detected in the green cultivar; and for luteolin-hydroxymalonylhexoside, an apigenin conjugate with molecular formula C40 H54 O19 (monoisotopic MW = 838.3259 u), cyanidin-3-O-glucoside, cyanidin-3-O (3"-O-malonyl)glucoside, cyanidin-3-O-(6"-O-malonyl)glucoside, and cyanidin-3-O (6"-O-acetyl)glucoside, only found in the red cultivar. The UHPLC-DAD-ESI QToF/MSE approach demonstrated to be a useful tool for the characterization of phenolic compounds in complex plant matrices. PMID- 28833876 TI - Females drive asymmetrical introgression from rare to common species in Darwin's tree finches. AB - The consequences of hybridization for biodiversity depend on the specific ecological and evolutionary context in which it occurs. Understanding patterns of gene flow among hybridizing species is crucial for determining the evolutionary trajectories of species assemblages. The recently discovered hybridization between two species of Darwin's tree finches (Camarhynchus parvulus and C. pauper) on Floreana Island, Galapagos, presents an exciting opportunity to investigate the mechanisms causing hybridization and its potential evolutionary consequences under conditions of recent habitat disturbance and the introduction of invasive pathogens. In this study, we combine morphological and genetic analysis with pairing observations to explore the extent, direction and drivers of hybridization and to test whether hybridization patterns are a result of asymmetrical pairing preference driven by females of the rarer species (C. pauper). We found asymmetrical introgression from the critically endangered, larger-bodied C. pauper to the common, smaller-bodied C. parvulus, which was associated with a lack of selection against heterospecific males by C. pauper females. Examination of pairing data showed that C. parvulus females paired assortatively, whereas C. pauper females showed no such pattern. This study shows how sex-specific drivers can determine the direction of gene flow in hybridizing species. Furthermore, our results suggest the existence of a hybrid swarm comprised of C. parvulus and hybrid birds. We discuss the influence of interspecific abundance differences and susceptibility to the invasive parasite Philornis downsi on the observed hybridization and recommend that the conservation of this iconic species group should be managed jointly rather than species-specific. PMID- 28833878 TI - Relatively weak inbreeding depression in selfing but also in outcrossing populations of North American Arabidopsis lyrata. AB - Hermaphroditic plants can potentially self-fertilize, but most possess adaptations that promote outcrossing. However, evolutionary transitions to higher selfing rates are frequent. Selfing comes with a transmission advantage over outcrossing, but self-progeny may suffer from inbreeding depression, which forms the main barrier to the evolution of higher selfing rates. Here, we assessed inbreeding depression in the North American herb Arabidopsis lyrata, which is normally self-incompatible, with a low frequency of self-compatible plants. However, a few populations have become fixed for self-compatibility and have high selfing rates. Under greenhouse conditions, we estimated mean inbreeding depression per seed (based on cumulative vegetative performance calculated as the product of germination, survival and aboveground biomass) to be 0.34 for six outcrossing populations, and 0.26 for five selfing populations. Exposing plants to drought and inducing defences with jasmonic acid did not magnify these estimates. For outcrossing populations, however, inbreeding depression per seed may underestimate true levels of inbreeding depression, because self-incompatible plants showed strong reductions in seed set after (enforced) selfing. Inbreeding depression estimates incorporating seed set averaged 0.63 for outcrossing populations (compared to 0.30 for selfing populations). However, this is likely an overestimate because exposing plants to 5% CO2 to circumvent self incompatibility to produce selfed seed might leave residual effects of self incompatibility that contribute to reduced seed set. Nevertheless, our estimates of inbreeding depression were clearly lower than previous estimates based on the same performance traits in outcrossing European populations of A. lyrata, which may help explain why selfing could evolve in North American A. lyrata. PMID- 28833877 TI - Association between periodontitis and severe asthma in adults: A case-control study. AB - OBJECTIVE: To evaluate the association between periodontitis and severe asthma, with participants in treatment for severe asthma, controlled by therapy. METHODS: A case-control investigation was performed to compare 130 adults with severe asthma with 130 without asthma. Individuals with periodontitis were those with >=4 teeth with >=1 site with probing depth >=4 mm, clinical attachment level >=3 mm, and bleeding upon probing at the same site. Severe asthma diagnosis was based on Global Initiative for Asthma criteria. RESULTS: Association between exposure to periodontitis and severe asthma was found: ORcrude = 2.98 (95% CI: 1.74 5.11). When confounders were considered, the association between exposure to periodontitis and severe asthma was maintained: ORadjusted = 3.01-3.25. Individuals with periodontitis had about a threefold increased risk of severe asthma than those without periodontitis. Frequency of periodontitis in participants with severe asthma was greater than that of those without asthma (46.6% vs 22.3%, p <= .05). CONCLUSIONS: Association between periodontitis and severe asthma was observed. Further investigation is required to determine the direction of this relationship. It may be causal, but it may also be a consequence of the immunopathological process that characterizes asthma, or else, consequence of the medication used for treatment. PMID- 28833879 TI - Into thin air: Predicting PTLD in pediatric lung transplant patients. PMID- 28833881 TI - And the evidence piles on. PMID- 28833884 TI - Disease & fertility: From one generation to the next. PMID- 28833882 TI - Change in Care Transition Practice for Patients With Nonspecific Chest Pain After Emergency Department Evaluation 2006 to 2012. AB - OBJECTIVES: From 2005 to 2010 health care financing shifts in the United States may have affected care transition practices for emergency department (ED) patients with nonspecific chest pain (CP) after ED evaluation. Despite being less acutely ill than those with myocardial infarction, these patients' management can be challenging. The risk of missing acute coronary syndrome is considerable enough to often warrant admission. Diagnostic advances and reimbursement limitations on the use of inpatient admission are encouraging the use of alternative ED care transition practices. In the setting of these health care changes, we hypothesized that there is a decline in inpatient admission rates for patients with nonspecific CP after ED evaluation. METHODS: We retrospectively used the Nationwide ED Sample to quantify total and annual inpatient hospital admission rates from 2006 to 2012 for patients with a final ED diagnosis of nonspecific CP. We assessed the change in admission rates over time and stratified by facility characteristics including safety-net hospital status, U.S. geographic region, urban/teaching status, trauma-level designation, and hospital funding status. RESULTS: The admission rate for all patients with a final ED diagnosis of nonspecific CP declined from 19.2% in 2006 to 11.3% in 2012. Variability across regions was observed, while metropolitan teaching hospitals and trauma centers reflected lower admission rates. CONCLUSION: There was a 41.1% decline in inpatient hospital admission for patients with nonspecific CP after ED evaluation. This reduction is temporally associated with national policy changes affecting reimbursement for inpatient admissions. PMID- 28833883 TI - Molecular Phylogenetic Positions of Two New Marine Gregarines (Apicomplexa) Paralecudina anankea n. sp. and Lecudina caspera n. sp.-from the Intestine of Lumbrineris inflata (Polychaeta) Show Patterns of Co-evolution. AB - Gregarine apicomplexans are unicellular parasites commonly found in the intestines and coeloms of invertebrate hosts. Traits associated with the conspicuous feeding stage of gregarines, known as the trophozoite, have been used in combination with molecular phylogenetic data for species delimitation and the reconstruction of evolutionary history. Trophozoite morphology alone is often inadequate for inferring phylogenetic relationships and delimiting species due to frequent cases of high intraspecific variation combined with relatively low interspecific variation. The current study combined morphological data with small subunit (SSU) rDNA sequences to describe and establish two novel marine gregarine species isolated from the intestine of a polychaete host Lumbrineris inflata collected in British Columbia (Canada): Paralecudina anankea n. sp. and Lecudina caspera n. sp. The sister species to the host is Lumbrineris japonica, which can be found on the opposite side of the Pacific Ocean (Japan) and contains two different species of gregarine parasites: Paralecudina polymorpha and Lecudina longissima. Molecular phylogenetic analyses placed P. anankea n. sp. as the sister species to P. polymorpha and L. caspera n. sp. as the sister species to L. longissima. This phylogenetic pattern demonstrates a co-evolutionary history whereby speciation of the host (Lumbrineris) corresponds with simultaneous speciation of the two different lineages of intestinal gregarines (Paralecudina and Lecudina). PMID- 28833885 TI - Subjective well-being and minimum wages: Evidence from U.S. states. AB - This paper investigates whether increases in minimum wages are associated with higher life satisfaction by using monthly-level state minimum wages and individual-level data from the 2005-2010 Behavioral Risk Factor Surveillance System. The magnitude I find suggests that a 10% increase in the minimum wage is associated with a 0.03-point increase in life satisfaction for workers without a high school diploma, on a 4-point scale. Contrary to popular belief that higher minimum wages hurt business owners, I find little evidence that higher minimum wages lead to the loss of well-being among self-employed people. PMID- 28833886 TI - Lanthanide Fluorobenzoates as Bio-Probes: a Quest for the Optimal Ligand Fluorination Degree. AB - The thorough study of fluorinated benzoates of lanthanides (Eu, Tb, Nd, Er, Yb, Gd, La, Lu) is reported. Their composition in single crystal and powder state revealed two predominant structural motifs. An in-depth luminescence study has been performed on the reported fluorobenzoates, showing, that terbium and europium complexes in solid state possess high luminescence intensity with the quantum yield of up to 69 %. High solubility in most organic solvents, as well as in water, combined with the high luminescence intensity in water solution and non toxicity allowed the testing of europium complexes as bioprobes in cellulo. Among all tested fluorobenzoates, europium 2-fluorobenzoate dihydrate combined the best luminescent properties, thermodynamic stability, aqueous solubility, and non toxicity, and was shown to be a viable bio-marker. PMID- 28833887 TI - Cyclin-Dependent Kinase 4 Regulates Adult Neural Stem Cell Proliferation and Differentiation in Response to Insulin. AB - Insulin is one of the standard components used to culture primary neurospheres. Although it stimulates growth of different types of cells, the effects of insulin on adult neural stem cells (NSCs) have not been well characterized. Here, we reveal that insulin stimulates proliferation, but not survival or self-renewal, of adult NSCs. This effect is mediated by insulin receptor substrate 2 (IRS2) and subsequent activation of the protein kinase B (or Akt), leading to increased activity of the G1-phase cyclin-dependent kinase 4 (Cdk4) and cell cycle progression. Neurospheres isolated from Irs2-deficient mice are reduced in size and fail to expand in culture and this impaired proliferation is rescued by introduction of a constitutively active Cdk4 (Cdk4R24C/R24C ). More interestingly, activation of the IRS2/Akt/Cdk4 signaling pathway by insulin is also necessary for the generation in vitro of neurons and oligodendrocytes from NSCs. Furthermore, the IRS2/Cdk4 pathway is also required for neuritogenesis, an aspect of neuronal maturation that has not been previously linked to regulation of the cell cycle. Differentiation of NSCs usually follows exit from the cell cycle due to increased levels of CDK-inhibitors which prevent activation of CDKs. In contrast, our data indicate that IRS2-mediated Cdk4 activity in response to a mitogen such as insulin promotes terminal differentiation of adult NSCs. Stem Cells 2017;35:2403-2416. PMID- 28833888 TI - Stereospecific Electrophilic Fluorination of Alkylcarbastannatrane Reagents. AB - We report the use of isolable primary and secondary alkylcarbastannatrane nucleophiles in site-specific fluorination reactions. These reactions occur without the need for transition metal catalysis or in situ activation of the nucleophile. In the absence of the carbastannatrane backbone, alkyltin nucleophiles exhibit no activity towards fluorination. When enantioenriched alkylcarbastannatranes are employed, fluorination occurs predominately via a stereoinvertive mechanism to generate highly enantioenriched alkyl fluoride compounds. These conditions can also be extended to stereospecific chlorination, bromination, and iodination reactions. PMID- 28833889 TI - Preoperative breast size affects reconstruction status following mastectomy. AB - Much research has been devoted to why women choose not to be reconstructed following mastectomy. The effect of breast size has not been well explored. The authors aimed to assess the relationship between breast size and reconstructive choices. A single-center retrospective review of women undergoing mastectomy between 2011 and 2014 was performed. Demographics, surgical variables, and reconstruction decisions were analyzed using t tests, Mann-Whitney U tests, and chi-squared tests. Significant (P < .05) variables were included in a multivariable logistic regression model. About 610 patients were analyzed. The median mastectomy specimen weight was 572 g (62-5230 g), which did not correlate with BMI (P = .44). Women who underwent reconstruction had lighter mastectomy specimens, averaging 643 vs 848 g (P < .0001). A regression controlling for ethnicity, insurance status, number of comorbidities, age at mastectomy, cancer stage, BMI, specimen weight, and mastectomy laterality was constructed. Lower specimen weight (P = .005), lower cancer stage (P = .008), bilateral mastectomy (P = .042), and younger age at mastectomy (P < .0001) were significantly associated with reconstruction. Women with larger breasts were less likely to be reconstructed regardless of their BMI and comorbidities. Larger breasted women may be considered worse prosthetic reconstruction candidates due to increased complications and suboptimal aesthetic outcomes but may find the increased invasiveness and recovery of autologous reconstruction an unattractive alternative. Furthermore, it is possible that surgeons may be less supportive of breast reconstruction for larger breasted women if there are concerns about safety or the aesthetic quality of the result. In the future, qualitative research must be done to determine why more larger breasted women choose not to be reconstructed as well as develop better ways to increase their reconstructive options. PMID- 28833890 TI - Fit to predict? Eco-informatics for predicting the catchability of a pelagic fish in near real time. AB - The ocean is a dynamic environment inhabited by a diverse array of highly migratory species, many of which are under direct exploitation in targeted fisheries. The timescales of variability in the marine realm coupled with the extreme mobility of ocean-wandering species such as tuna and billfish complicates fisheries management. Developing eco-informatics solutions that allow for near real-time prediction of the distributions of highly mobile marine species is an important step towards the maturation of dynamic ocean management and ecological forecasting. Using 25 yr (1990-2014) of NOAA fisheries' observer data from the California drift gillnet fishery, we model relative probability of occurrence (presence-absence) and catchability (total catch per gillnet set) of broadbill swordfish Xiphias gladius in the California Current System. Using freely available environmental data sets and open source software, we explore the physical drivers of regional swordfish distribution. Comparing models built upon remotely sensed data sets with those built upon a data-assimilative configuration of the Regional Ocean Modelling System (ROMS), we explore trade-offs in model construction, and address how physical data can affect predictive performance and operational capacity. Swordfish catchability was found to be highest in deeper waters (>1,500 m) with surface temperatures in the 14-20 degrees C range, isothermal layer depth (ILD) of 20-40 m, positive sea surface height (SSH) anomalies, and during the new moon (<20% lunar illumination). We observed a greater influence of mesoscale variability (SSH, wind speed, isothermal layer depth, eddy kinetic energy) in driving swordfish catchability (total catch) than was evident in predicting the relative probability of presence (presence absence), confirming the utility of generating spatiotemporally dynamic predictions. Data-assimilative ROMS circumvent the limitations of satellite remote sensing in providing physical data fields for species distribution models (e.g., cloud cover, variable resolution, subsurface data), and facilitate broad scale prediction of dynamic species distributions in near real time. PMID- 28833891 TI - Relationship between user satisfaction with the levonorgestrel-releasing intrauterine system and bleeding patterns. AB - AIM: Satisfaction with a contraceptive method constitutes an important factor in its acceptance and long-term use. The objective of this study was to assess the relationship between user satisfaction with the 20-MUg/day levonorgestrel releasing intrauterine system (LNG-IUS) and the bleeding patterns reported at two different time-points during follow-up. METHODS: A total of 251 LNG-IUS users aged 18-45 years were invited to answer a questionnaire on their return to the clinic for a routine follow-up visit and again 1 year later. Data were collected face-to-face. RESULTS: Twenty women discontinued prematurely; therefore, the analysis was performed on 231 women. Most users were either highly satisfied (66.6% and 66.2% at the first and second interviews, respectively) or satisfied (26.4% and 26.4% at the first and second interviews, respectively) with the LNG IUS. Satisfaction was related to amenorrhea (P < 0.001) and duration of use (P < 0.001). Prolonged bleeding and spotting were the main causes of dissatisfaction with the device. CONCLUSION: Most LNG-IUS users in this sample were satisfied with the device. The only two factors associated with satisfaction were amenorrhea and duration of use, while prolonged bleeding and spotting were the main causes of dissatisfaction. These findings could be useful for health-care professionals and policy-makers when developing information material for women. The study provides insight into the profile of satisfied LNG-IUS users; however, this information is not suitable for counseling women who are considering using an LNG-IUS. PMID- 28833892 TI - Simulation for Assessment of Milestones in Emergency Medicine Residents. AB - OBJECTIVES: All residency programs in the United States are required to report their residents' progress on the milestones to the Accreditation Council for Graduate Medical Education (ACGME) biannually. Since the development and institution of this competency-based assessment framework, residency programs have been attempting to ascertain the best ways to assess resident performance on these metrics. Simulation was recommended by the ACGME as one method of assessment for many of the milestone subcompetencies. We developed three simulation scenarios with scenario-specific milestone-based assessment tools. We aimed to gather validity evidence for this tool. METHODS: We conducted a prospective observational study to investigate the validity evidence for three mannequin-based simulation scenarios for assessing individual residents on emergency medicine (EM) milestones. The subcompetencies (i.e., patient care [PC]1, PC2, PC3) included were identified via a modified Delphi technique using a group of experienced EM simulationists. The scenario-specific checklist (CL) items were designed based on the individual milestone items within each EM subcompetency chosen for assessment and reviewed by experienced EM simulationists. Two independent live raters who were EM faculty at the respective study sites scored each scenario following brief rater training. The inter-rater reliability (IRR) of the assessment tool was determined by measuring intraclass correlation coefficient (ICC) for the sum of the CL items as well as the global rating scales (GRSs) for each scenario. Comparing GRS and CL scores between various postgraduate year (PGY) levels was performed with analysis of variance. RESULTS: Eight subcompetencies were chosen to assess with three simulation cases, using 118 subjects. Evidence of test content, internal structure, response process, and relations with other variables were found. The ICCs for the sum of the CL items and the GRSs were >0.8 for all cases, with one exception (clinical management GRS = 0.74 in sepsis case). The sum of CL items and GRSs (p < 0.05) discriminated between PGY levels on all cases. However, when the specific CL items were mapped back to milestones in various proficiency levels, the milestones in the higher proficiency levels (level 3 [L3] and 4 [L4]) did not often discriminate between various PGY levels. L3 milestone items discriminated between PGY levels on five of 12 occasions they were assessed, and L4 items discriminated only two of 12 times they were assessed. CONCLUSION: Three simulation cases with scenario-specific assessment tools allowed evaluation of EM residents on proficiency L1 to L4 within eight of the EM milestone subcompetencies. Evidence of test content, internal structure, response process, and relations with other variables were found. Good to excellent IRR and the ability to discriminate between various PGY levels was found for both the sum of CL items and the GRSs. However, there was a lack of a positive relationship between advancing PGY level and the completion of higher-level milestone items (L3 and L4). PMID- 28833894 TI - Reducing the time until psychotherapy initiation reduces sick leave duration in participants diagnosed with anxiety and mood disorders. AB - BACKGROUND: Sick leave in patients with a mental disorder is characterized by having a long duration. Studies suggest that the time until a patient on sick leave for a common mental health disorder initiates evaluation and treatment by a healthcare professional is an important factor in the duration of the sick leave. However, in these studies, the intervention was not performed by a mental health specialist. The aim of this study was to find out whether the length of sick leave was associated with the time before initiating psychotherapy, age, time until returning to work after psychotherapy ends, and duration of psychotherapy. In a further analysis, we examined whether the model composed of age, duration of psychotherapy, and time before initiating psychotherapy predicted the length of sick leave. METHOD: The sample consisted of 2,423 participants, 64.1% (n = 1,554) women and 35.9% (n = 869) men, who were on sick leave for anxiety disorders or depressive disorder. RESULTS: The total duration of the sick leave of participants diagnosed with depression and anxiety was positively associated with the time before beginning psychotherapy. Time before beginning psychotherapy predicted the length of sick leave when the variables age and duration of psychotherapy were controlled. CONCLUSION: It is necessary to reduce the time until beginning psychotherapy in people on sick leave for common mental disorders. PMID- 28833893 TI - Nomenclature of primary amenorrhea: A proposal document of the Japan Society of Obstetrics and Gynecology committee for the redefinition of primary amenorrhea. AB - AIM: The aim of this study was to provide medical terms to describe the condition of a girl who should be evaluated for primary amenorrhea in order to facilitate intervention at an appropriate time. METHODS: We performed a literature and clinical guidelines search for recent practices with regard to menarche and discussed relevant cases that had been experienced by committee members. Additionally, we theoretically reviewed medical terms defined in the Glossary Book of Obstetrics and Gynecology in Japan (Japan Society of Obstetrics and Gynecology, 3rd edition). RESULTS: The committee for the redefinition of primary amenorrhea proposed the introduction of two terms and the deletion of one term that had been defined by the Japan Society of Obstetrics and Gynecology, instead of changing the age definition of primary amenorrhea. 'Delayed menarche' was introduced to describe a condition in which a girl has never experienced cyclic menstruation (menarche) by 15-17 years of age. 'Late menarche' was also introduced to describe a condition in which a girl has experienced menarche at 15 years of age or older. 'Delayed menstruation,' which was defined as a condition in which a girl experiences menarche at 15-18 years of age, was deleted. CONCLUSION: The new terms 'delayed menarche' and 'late menarche' were introduced, and the term 'delayed menstruation' was deleted. The new system might help in the early detection and appropriate treatment of primary amenorrhea. PMID- 28833895 TI - Morphostructural and immunohistochemical study on the role of metallothionein in the detoxification of heavy metals in Apis mellifera L., 1758. AB - Honey is a valuable food produced by bees from sugary substances that they gather in nature. The transformation the nectar into honey, by bees, is long and complex. Except for honey, where heavy metals are absent or are found only in traces, the bees and their products have always been considered excellent biomarkers of such contaminants. We have assumed that the absence of heavy metals in honey is due to the presence of a detoxification system in the digestive system of bees, which involves metallothioneins, proteins that have a role in the homeostatic control of essential and non-essential metals. We have placed the beehives in three different zones: industrial, urban and rural. Investigations were carried out with ICP-MS method for the detection of heavy metals in the guts of honey bees and honey. The metallothioneins have been identified by Immunohistochemical and Western-blotting analisys. The investigations have shown the presence of heavy metals only in bees guts but not in honey, while the presence of metallothionein has been highlighted only in epithelium of the honey sac, demonstrating the existence of an efficient system of detoxification of heavy metals. PMID- 28833896 TI - Prospective Validation of Clinical Score for Males Presenting With an Acute Scrotum. AB - OBJECTIVE: The objective was to validate the Testicular Workup for Ischemia and Suspected Torsion (TWIST) score among pediatric emergency medicine providers for the evaluation of pediatric males presenting with testicular pain and swelling (acute scrotum). METHODS: We conducted a prospective cohort study of males 3 months to 18 years old presenting with an acute scrotum. History and physical examination findings, including components of the TWIST score (hard testicle, absent cremasteric reflex, nausea/vomiting, and high riding testicle) as well as diagnostic results (ultrasound, urine, sexually transmitted infection testing) were recorded. Testicular torsion was confirmed by surgical exploration. Frequencies of patient characteristics, TWIST components, and tests were calculated. We performed the kappa statistic for inter-rater reliability and calculated the test characteristics and receiver operator characteristics curves for the TWIST score (range = 0-7). RESULTS: During the study period 258 males were enrolled in the study; 19 (7.4%) had testicular torsion. The mean (+/-SD) age was 9.8 (+/-0.3) years. The high-risk TWIST score of 7 had 100% specificity (95% confidence interval [CI] = 98%-100%) with 100% positive predictive value (95% CI = 40%-100%) for testicular torsion. The area under the curve was 0.82. The kappa statistic for the overall TWIST score was fair at 0.39. CONCLUSIONS: In this prospective validation of the TWIST score among pediatric emergency providers, the high-risk score demonstrated strong test characteristics for testicular torsion. The TWIST score could be used as part of a standardized approach for evaluation of the pediatric acute scrotum to provide more efficient and effective care. PMID- 28833897 TI - Neodymium Catalyst for the Polymerization of Dienes and Polar Vinyl Monomers. AB - Ziegler-Natta catalysts have played a major role in industry for the polymerization of dienes and vinyl monomers. However, due to the deactivation of the catalyst, this system fails to polymerize polar vinyl monomers such as vinyl acetate, methyl methacrylate, and methyl acrylate. Herein, a catalytic system composed of NdCl3 ?3TEP/TIBA is reported, which promotes a quasi-living polymerization of dienes and is also active for the homopolymerization of polar vinyl monomers. Additionally, this catalytic system generates polymyrcene-b polyisoprene and poly(myrcene)-b-poly(methyl methacrylate) diblock copolymers by sequential monomer addition. To encourage the replacement of petroleum-based polymers by environmentally benign biobased polymers, polymerization of beta myrcene is demonstrated with a catalytic activity of ~106 kg polymer mol Nd-1 h-1 . PMID- 28833898 TI - Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population. AB - Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS-Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA-binding protein of 43 kDa (TDP-43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS-Aging exist. We developed a semi-quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS-Aging, TDP-43, vascular and tau pathology in 672 brains (TDP-43 staining n = 642/672, 96%) donated for the population-based Cambridge City over 75s Cohort and the Cognitive Function and Ageing Study. HS-Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields-of-view (x200 magnification), no vascular damage, no neuron loss in CA2-CA4, but consistent TDP 43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP-43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4-CA2 was not associated with TDP 43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS-Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS-Aging starts from the subicular end of CA1 when it is associated with TDP-43 pathology, and that this neurodegenerative process is likely to be significantly more common than "end-stage" HS-Aging only. PMID- 28833899 TI - Non-invasive assessment of culture media from goat cloned embryos associated with subjective morphology by gas chromatography - mass spectroscopy-based metabolomic analysis. AB - Pre-implantation embryo metabolism demonstrates distinctive characteristics associated with the development potential of embryos. We aim to determine if metabolic differences correlate with embryo morphology. In this study, gas chromatography - mass spectroscopy (GC-MS)-based metabolomics was used to assess the culture media of goat cloned embryos collected from high-quality (HQ) and low quality (LQ) groups based on morphology. Expression levels of amino acid transport genes were further examined by quantitative real-time PCR. Results showed that the HQ group presented higher percentages of blastocysts compared with the LQ counterparts (P < 0.05). Metabolic differences were also present between HQ and LQ groups. The culture media of the HQ group showed lower levels of valin, lysine, glutamine, mannose and acetol, and higher levels of glucose, phytosphingosine and phosphate than those of the LQ group. Additionally, expression levels of amino acid transport genes SLC1A5 and SLC3A2 were significantly lower in the HQ group than the LQ group (P < 0.05, respectively). To our knowledge, this is the first report which uses GC-MS to detect metabolic differences in goat cloned embryo culture media. The biochemical profiles may help to select the most in vitro viable embryos. PMID- 28833900 TI - Treatment of oral lichen planus using 308-nm excimer laser. AB - Oral lichen planus (OLP) is a chronic inflammatory disease, has prolonged courses, repeated attacks and resistance to treatment. The traditional narrow spectrum UVB treatment has an established efficacy on skin lichen planus, and high safety. However, most of ultraviolet phototherapy devices have a huge volume, thereby cannot be used in the treatment of OLP. Lymphocytic infiltration is evident in the lesions of lichen planus, and the direct irradiation of 308-nm excimer laser can induce apoptosis of the T lymphocytes in skin lesions, thereby has a unique therapeutic effect on the diseases involving T lymphocytes. This study aims to investigate the efficacy of 308-nm excimer laser in the treatment of OLP. A total of six OLP patients were enrolled into this study, and further pathological diagnosis was conducted, then 308-nm excimer laser was used in the treatment. The efficacy of 308-nm excimer laser in the treatment of OLP was satisfactory. The clinical symptoms of five patients were significantly improved. In two patients, the erosion surface based on congestion and the surrounding white spots completely disappeared, and clinical recovery was achieved. Three patients achieved partial remission, that is, the erosion surface healed, congestion and white spot area shrunk by more than 1/2 of the primary skin lesions. In the remaining one patient, the erosion surface had not completely healed after treatment, and congestion and white spot area shrunk by less than 1/2 of the primary skin lesions. Only one patients had developed mild pain during the treatment, and this symptom alleviated by itself. The 308-nm excimer laser therapy can serve as a safe and effective treatment for OLP. PMID- 28833902 TI - Multidimensional performance assessment of public sector organisations using dominance criteria. AB - Public sector organisations pursue multiple objectives and serve a number of stakeholders. But stakeholders are rarely explicit about the valuations they attach to different objectives, nor are these valuations likely to be identical. This complicates the assessment of their performance because no single set of weights can be chosen legitimately to aggregate outputs into unidimensional composite scores. We propose the use of dominance criteria in a multidimensional performance assessment framework to identify best practice and poor performance under relatively weak assumptions about stakeholders' preferences. We use as an example providers of hip replacement surgery in the English National Health Service and estimate multivariate multilevel models to study their performance in terms of length of stay, readmission rates, post-operative patient-reported health status and waiting time. We find substantial correlation between objectives and demonstrate that ignoring the correlation can lead to incorrect assessments of performance. PMID- 28833901 TI - Estradiol rapidly increases GluA2-mushroom spines and decreases GluA2-filopodia spines in hippocampus CA1. AB - Hippocampal dendritic spine density rapidly increases following estradiol (E2 ) treatment, but the types of spines and trafficking of synaptic markers have received little investigation. We assessed rapid effects of E2 over time on the density of four spine types (stubby, filopodial, long thin, and mushroom) and trafficking of AMPA receptor subunit GluA2 and PSD95 on tertiary, apical dendrites in CA1. Castrated male rats received 20 MUg kg-1 of E2 or vehicle and were sacrificed 30 or 120 min later. Images of Golgi-Cox impregnated and PSD95/GluA2 stained dendrites were captured under the confocal microscope and quantified with IMARIS-XT. Stubby and filopodial spine densities did not change following treatment. Long-thin spines significantly decreased at 30 min while mushroom spines significantly increased at 120 min. GluA2, PSD95, and GluA2/PSD95 colocalization levels in stubby or long thin spines did not change, but filopodial spines had significantly reduced GluA2 levels at 30 min. Mushroom spines showed significantly increased levels for GluA2, PSD95 and GluA2/PSD95 colocalization at 120 min. Because GluA2 is important for memory consolidation, current results present novel data suggesting that trafficking of GluA2 to mushroom spines provides one mechanism contributing to estradiol's ability to enhance learning and memory by the PI3 signaling pathway. PMID- 28833903 TI - Nonremission and time to remission among remitters in major depressive disorder: Revisiting STAR*D. AB - BACKGROUND: Some individuals with major depressive disorder do not experience a remission even after one or more adequate treatment trials. In some others who experience remission, it happens at variable times. This study sought to estimate the prevalence of nonremission in a large sample of patient participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial and to identify correlates of nonremission and time to remission among remitters. METHODS: Using data from 3,606 participants of STAR*D, the study used cure regression modeling to estimate nonremission and jointly model correlates of nonremission and time to remission among the remitters. RESULTS: Overall, 14.7% of the STAR*D participants were estimated to be nonremitters. Among remitters, the rate of remission declined over time. Greater severity, poorer physical health, and poor adherence with treatments were associated with both nonremission and a longer time to remission among the remitters in multivariable analyses, whereas unemployment, not having higher education, and longer duration of current episode were uniquely associated with nonremission; whereas, treatment in specialty mental health settings, poorer mental health functioning, and greater impairment in role functioning with a longer time to remission among remitters. CONCLUSION: Poor treatment adherence and poor physical health appear to be common risk factors for both nonremission and longer time to remission, highlighting the importance of integrated care models that address both medical and mental healthcare needs and interventions aimed at improving treatment adherence. PMID- 28833905 TI - Titanocene-Catalyzed Radical Opening of N-Acylated Aziridines. AB - Aziridines activated by N-acylation are opened to the higher substituted radical through electron transfer from titanocene(III) complexes in a novel catalytic reaction. This reaction is applicable in conjugate additions, reductions, and cyclizations and suited for the construction of quaternary carbon centers. The concerted mechanism of the ring opening is indicated by DFT calculations. PMID- 28833904 TI - Early childhood trajectories of separation anxiety: Bearing on mental health, academic achievement, and physical health from mid-childhood to preadolescence. AB - BACKGROUND: Separation anxiety disorder is the most prevalent childhood anxiety condition, but no study assessed children for separation anxiety at preschool age and followed them longitudinally and directly until mid-childhood/early adolescence. METHODS: Multi-informant (children, teachers, family), multipoint (at age 8, 10, 12, 13) assessments of 1,290 children of the Quebec Longitudinal Study of Child Development, who had been categorized between age 1.5 and 6 into four specific separation anxiety trajectories (1, low-persistent; 2, low increasing; 3, high-decreasing, and the less common: 4, high-increasing) by growth mixture modeling. Participants in the high-increasing trajectory were compared to participants in the other three trajectories for: (a) child's internalizing and externalizing problem behavior; (b) physical health; (c) academic achievement; (d) maternal anxiety. RESULTS: Multivariate analyses of variance/covariance at separate time points showed the high-increasing trajectory mostly associated with: (a) higher internalizing, but not externalizing, behavior; (b) worse academic achievement (most consistently by comparisons to the normative low-persistent trajectory; (c) higher rates of maternal panic/agoraphobic anxiety; (d) worse physical health (most consistently by comparisons to the low-persistent trajectory). The high-increasing trajectory had twofold to threefold higher incidences of physical illnesses than the normative low-persistent group; this was specific for headaches at age 12 years, chronic asthma at age 10 and 13, and having received asthma-related medication during the past 12 months. CONCLUSIONS: High-increasing separation anxiety in preschool maintains longitudinal relationships to independent health and academic outcomes, at least until preadolescence. This knowledge can inform the deployment of clinical resources at the earlier signs of the more impairing manifestations. PMID- 28833906 TI - Final report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology, on a fact-finding questionnaire on the status of treatment of hereditary breast and ovarian cancer syndrome in Japan. AB - Hereditary breast and ovarian cancer syndrome (HBOC) is a hereditary tumor that can be definitively diagnosed by detection of germline mutation of the BRCA1 or BRCA2 gene. The HBOC Public Awareness and Management Sub-committee of the Tumor Committee, Japan Society of Obstetrics and Gynecology carried out a fact-finding survey on the status of treatment of HBOC in Japan. The directors of medical specialty teaching facilities were notified of the questionnaire by post, with the request for one respondent per facility. The response period was from 8 July 2014 to 31 March 2015. Of the 678 facilities that were asked to compete the questionnaire, 341 (50.3%) responded. The responses are shown in the respective tables. For questions with free responses, similar answers have been grouped together, and the written answers have been freely translated. Based on these results, the Japan Society of Obstetrics and Gynecology considers that the 14 conditions, including consultations by specialist staff, must be met before risk reducing salpingo-oophorectomy is carried out. PMID- 28833907 TI - Toxic toad invasion of Wallacea: A biodiversity hotspot characterized by extraordinary endemism. AB - (a) A map of Wallacea showing islands invaded by Duttaphrynus melanostictus in red, islands inhabited by Varanus komodoensis in blue, and localities of genetic samples in yellow points. (b) A D. melanostictus from Lombok Island. (c) Environmental niche model for the Sunda Islands clade of D. melanostictus projected into Wallacea. Green color indicates very high suitability, yellow color indicates high suitability, and orange color indicates moderate suitability. PMID- 28833908 TI - Regional differences in infant 25-Hydroxyvitamin D: Pilot study of the Japan Environment and Children's Study. AB - BACKGROUND: In recent years, a resurgence in the number of infants with vitamin D deficiency has been noted. In addition to seasonal differences in exposure to ultraviolet (UV) rays, regional differences in dietary habits and lifestyles may affect susceptibility to vitamin D deficiency. No studies have been conducted, however, on infants in multiple regions of Japan to determine the extent of differences in vitamin D status. METHODS: 25-Hydroxyvitamin D (25OHD) was measured on radioimmunoassay in 126 infants aged 2-4 years, who participated in the Pilot Study of the Japan Environment and Children's Study (JECS) by the Ministry of Environment of Japan. A multiple regression model with 25OHD level as the outcome variable, and season and region as explanatory variables, was generated. RESULTS: Both region and season during which infants participated in this study significantly affected 25OHD level (P = 0.0087 and <0.0001, respectively; Wald test). Reflecting decreased exposure to UV rays, infants who were examined in winter had lower 25OHD than those examined in summer. Infants from both Fukuoka Prefecture (33 degrees N) and Kumamoto Prefecture (32 degrees N), however, had lower 25OHD than those from Tochigi Prefecture (36 degrees N), contrary to expectations given the extent of UV exposure. CONCLUSIONS: Regional differences in daily habits and/or environmental factors affect 25OHD level in Japanese infants. The JECS is expected to identify those factors to provide guidance on preventing infantile vitamin D deficiency. PMID- 28833909 TI - Negative emissions from stopping deforestation and forest degradation, globally. AB - Forest growth provides negative emissions of carbon that could help keep the earth's surface temperature from exceeding 2 degrees C, but the global potential is uncertain. Here we use land-use information from the FAO and a bookkeeping model to calculate the potential negative emissions that would result from allowing secondary forests to recover. We find the current gross carbon sink in forests recovering from harvests and abandoned agriculture to be -4.4 PgC/year, globally. The sink represents the potential for negative emissions if positive emissions from deforestation and wood harvest were eliminated. However, the sink is largely offset by emissions from wood products built up over the last century. Accounting for these committed emissions, we estimate that stopping deforestation and allowing secondary forests to grow would yield cumulative negative emissions between 2016 and 2100 of about 120 PgC, globally. Extending the lifetimes of wood products could potentially remove another 10 PgC from the atmosphere, for a total of approximately 130 PgC, or about 13 years of fossil fuel use at today's rate. As an upper limit, the estimate is conservative. It is based largely on past and current practices. But if greater negative emissions are to be realized, they will require an expansion of forest area, greater efficiencies in converting harvested wood to long-lasting products and sources of energy, and novel approaches for sequestering carbon in soils. That is, they will require current management practices to change. PMID- 28833911 TI - Discovery of a Novel Inhibitor of the Hedgehog Signaling Pathway through Cell based Compound Discovery and Target Prediction. AB - Cell-based assays enable monitoring of small-molecule bioactivity in a target agnostic manner and help uncover new biological mechanisms. Subsequent identification and validation of the small-molecule targets, typically employing proteomics techniques, is very challenging and limited, in particular if the targets are membrane proteins. Herein, we demonstrate that the combination of cell-based bioactive-compound discovery with cheminformatic target prediction may provide an efficient approach to accelerate the process and render target identification and validation more efficient. Using a cell-based assay, we identified the pyrazolo-imidazole smoothib as a new inhibitor of hedgehog (Hh) signaling and an antagonist of the protein smoothened (SMO) with a novel chemotype. Smoothib targets the heptahelical bundle of SMO, prevents its ciliary localization, reduces the expression of Hh target genes, and suppresses the growth of Ptch+/- medulloblastoma cells. PMID- 28833910 TI - Tracing biogeochemical subsidies from glacier runoff into Alaska's coastal marine food webs. AB - Nearly half of the freshwater discharge into the Gulf of Alaska originates from landscapes draining glacier runoff, but the influence of the influx of riverine organic matter on the trophodynamics of coastal marine food webs is not well understood. We quantified the ecological impact of riverine organic matter subsidies to glacier-marine habitats by developing a multi-trophic level Bayesian three-isotope mixing model. We utilized large gradients in stable (delta13 C, delta15 N, delta2 H) and radiogenic (Delta14 C) isotopes that trace riverine and marine organic matter sources as they are passed from lower to higher trophic levels in glacial-marine habitats. We also compared isotope ratios between glacial-marine and more oceanic habitats. Based on isotopic measurements of potential baseline sources, ambient water and tissues of marine consumers, estimates of the riverine organic matter source contribution to upper trophic level species including fish and seabirds ranged from 12% to 44%. Variability in resource use among similar taxa corresponded to variation in species distribution and life histories. For example, riverine organic matter assimilation by the glacier-nesting seabirds Kittlitz's murrelet (Brachyramphus brevirostris) was greater than that of the forest-nesting marbled murrelet (B. marmoratus). The particulate and dissolved organic carbon in glacial runoff and near surface coastal waters was aged (12100-1500 years BP 14 C-age) but dissolved inorganic carbon and biota in coastal waters were young (530 years BP 14 C-age to modern). Thus terrestrial-derived subsidies in marine food webs were primarily composed of young organic matter sources released from glacier ecosystems and their surrounding watersheds. Stable isotope compositions also revealed a divergence in food web structure between glacial-marine and oceanic sites. This work demonstrates linkages between terrestrial and marine ecosystems, and facilitates a greater understanding of how climate-driven changes in freshwater runoff have the potential to alter food web dynamics within coastal marine ecosystems in Alaska. PMID- 28833912 TI - Identifying Emergency Department Patients at Low Risk for a Variceal Source of Upper Gastrointestinal Hemorrhage. AB - BACKGROUND: Assessing the likelihood of a variceal versus nonvariceal source of upper gastrointestinal bleeding (UGIB) guides therapy, but can be difficult to determine on clinical grounds. The objective of this study was to determine if there are easily ascertainable clinical and laboratory findings that can identify a patient as low risk for a variceal source of hemorrhage. METHODS: This was a retrospective cohort study of adult ED patients with UGIB between January 2008 and December 2014 who had upper endoscopy performed during hospitalization. Clinical and laboratory data were abstracted from the medical record. The source of the UGIB was defined as variceal or nonvariceal based on endoscopic reports. Binary recursive partitioning was utilized to create a clinical decision rule. The rule was internally validated and test characteristics were calculated with 1,000 bootstrap replications. RESULTS: A total of 719 patients were identified; mean age was 55 years and 61% were male. There were 71 (10%) patients with a variceal UGIB identified on endoscopy. Binary recursive partitioning yielded a two-step decision rule (platelet count > 200 * 109 /L and an international normalized ratio [INR] < 1.3), which identified patients who were low risk for a variceal source of hemorrhage. For the bootstrapped samples, the rule performed with 97% sensitivity (95% confidence interval [CI] = 91%-100%) and 49% specificity (95% CI = 44%-53%). CONCLUSION: Although this derivation study must be externally validated before widespread use, patients presenting to the ED with an acute UGIB with platelet count of >200 * 109 /L and an INR of <1.3 may be at very low risk for a variceal source of their upper gastrointestinal hemorrhage. PMID- 28833913 TI - Urinary beta2-microglobulin and bronchopulmonary dysplasia: Trends in preterm infants. AB - BACKGROUND: The developmental process of bronchopulmonary dysplasia (BPD) is not identical between very preterm infants born small for gestational age (SGA) and those born appropriate for gestational age (AGA). In this study, we compared the pattern of the inflammatory response in infants of each group, by measuring urinary beta2-microglobulin (Ubeta2M) as an alternative, concise, and less invasive biomarker. METHODS: Ubeta2M and clinical details were examined at birth and at 4 weeks of age in 146 very preterm infants. RESULTS: Of the 57 infants diagnosed with BPD, 18 were SGA, and 39 were AGA. Ubeta2M at birth was significantly lower in SGA BPD infants than in AGA BPD infants, but it increased with time. The prevalence of chorioamnionitis (CAM) was significantly lower in SGA BPD infants than in AGA BPD infants, while that of pregnancy-induced hypertension was the opposite. CONCLUSIONS: Exposure to prenatal factors other than CAM may sensitize fetal lungs to become vulnerable to postnatal inflammation in very preterm SGA infants with BPD. PMID- 28833914 TI - Patellofemoral and tibiofemoral alignment in a fully weight-bearing upright MR: Implementation and repeatability. AB - PURPOSE: To develop methods for evaluating 3D patellofemoral and tibiofemoral alignment in vertical open-bore magnetic resonance (MR) scanners, with participants upright and fully weight-bearing; and to evaluate the repeatability of these methods in individuals with patellofemoral osteoarthritis (OA) and in asymptomatic knees. MATERIALS AND METHODS: Our methods extend previously validated, reliable methods for evaluating alignment into an upright MR environment. In 10 participants with early patellofemoral OA and 10 with asymptomatic knees, we acquired sagittal T1 -weighted turbo spin echo images in a 3T scanner to create accurate participant-specific 3D anatomical surface models. In a vertical open-bore 0.5T MR scanner, we obtained lower-resolution sagittal gradient echo images to capture bony position and orientation data. Participants were scanned in a position of squatting with the knees flexed 30 degrees , three separate times to evaluate repeatability. Bone segmentation was performed manually, surface models were registered to data from the 0.5T scanner, and 3D patellofemoral and tibiofemoral alignment was calculated in all six degrees of freedom (three rotations and three translations). RESULTS: Intraclass correlation coefficients (ICCs) were >=0.94, with the exception of patellar spin (0.79). Standard errors of measure (SEM) were <2 degrees rotation and <0.9 mm translation. Repeatability remained adequate when stratified by group, with the exception of patellar spin (ICC 0.57 for asymptomatic knees vs. 0.91 for OA knees). CONCLUSION: We demonstrate methods for evaluating 3D alignment in upright fully weight-bearing participant positions in a vertical open-bore MR scanner. With the exception of patellar spin, repeatability was good to excellent. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:841 847. PMID- 28833915 TI - Simulating plant invasion dynamics in mountain ecosystems under global change scenarios. AB - Across the globe, invasive alien species cause severe environmental changes, altering species composition and ecosystem functions. So far, mountain areas have mostly been spared from large-scale invasions. However, climate change, land-use abandonment, the development of tourism and the increasing ornamental trade will weaken the barriers to invasions in these systems. Understanding how alien species will react and how native communities will influence their success is thus of prime importance in a management perspective. Here, we used a spatially and temporally explicit simulation model to forecast invasion risks in a protected mountain area in the French Alps under future conditions. We combined scenarios of climate change, land-use abandonment and tourism-linked increases in propagule pressure to test if the spread of alien species in the region will increase in the future. We modelled already naturalized alien species and new ornamental plants, accounting for interactions among global change components, and also competition with the native vegetation. Our results show that propagule pressure and climate change will interact to increase overall species richness of both naturalized aliens and new ornamentals, as well as their upper elevational limits and regional range-sizes. Under climate change, woody aliens are predicted to more than double in range-size and herbaceous species to occupy up to 20% of the park area. In contrast, land-use abandonment will open new invasion opportunities for woody aliens, but decrease invasion probability for naturalized and ornamental alien herbs as a consequence of colonization by native trees. This emphasizes the importance of interactions with the native vegetation either for facilitating or potentially for curbing invasions. Overall, our work highlights an additional and previously underestimated threat for the fragile mountain flora of the Alps already facing climate changes, land-use transformations and overexploitation by tourism. PMID- 28833916 TI - Why do oncologists hide the truth? Disclosure of cancer diagnoses to patients in China: A multisource assessment using mixed methods. AB - OBJECTIVE: In the United States and most European countries, cancer diagnoses are disclosed to patients. In China, however, the trend toward full disclosure has progressed slowly. The present study aimed to explore attitudes toward truth telling practice among physicians, patients, patients' family members, and the general population, and reasons for nondisclosure. METHODS: We administered a short survey to 212 physicians, 143 patients with cancer, 413 family members of patients with cancer, and 1415 members of the general population. A MANOVA was performed to examine group differences in attitudes toward cancer disclosure. In addition, we interviewed 20 oncologists. Interview data were analyzed using NVivo10. After the interview, we administered another short survey to 143 patients with cancer. RESULTS: Quantitative data indicated that physicians were the least, and patients the most, in favor of disclosure. Qualitative data among physicians and follow-up surveys among cancer patients revealed 5 reasons for the concealment of cancer diagnoses by physicians, including lack of awareness of patients' right to knowledge, cultural influences, insufficient medical resources and training, families' financial concerns, and the need to protect doctors from violence. CONCLUSION: There is a discrepancy between the needs of patients and those in medical practice. These results deepen our understanding regarding the reasons for oncologists' attitudes toward nondisclosure. PMID- 28833917 TI - Highly Efficient Nondoped OLEDs with Negligible Efficiency Roll-Off Fabricated from Aggregation-Induced Delayed Fluorescence Luminogens. AB - Purely organic emitters that can efficiently utilize triplet excitons are highly desired to cut the cost of organic light-emitting diodes (OLEDs), but most of them require complicated doping techniques for their fabrication and suffer from severe efficiency roll-off. Herein, we developed novel luminogens with weak emission and negligible delayed fluorescence in solution but strong emission with prominent delayed components upon aggregate formation, giving rise to aggregation induced delayed fluorescence (AIDF). The concentration-caused emission quenching and exciton annihilation are well-suppressed, which leads to high emission efficiencies and efficient exciton utilization in neat films. Their nondoped OLEDs provide excellent electroluminescence efficiencies of 59.1 cd A-1 , 65.7 lm W-1 , and 18.4 %, and a negligible current efficiency roll-off of 1.2 % at 1000 cd m-2 . Exploring AIDF luminogens for the construction of nondoped OLEDs could be a promising strategy to advance device efficiency and stability. PMID- 28833918 TI - Attenuation of DNA damage and mRNA gene expression in hypoxic rats using natural antioxidants. AB - This study aimed to explore the efficiency of carnosine (Cs) and/or l-arginine (Agn) in the downregulation of apoptotic and inflammatory molecule expression and DNA damage caused hepatic injury in response to sodium nitrite (Sd)-induced hypoxia in rats. Rats were injected with Sd; Agn or/and Cs were administrated prior to Sd intoxication. Sd significantly decreased hemoglobin concentration and Bcl-2 mRNA expression, while increased expressions of apoptotic markers (Bax and caspase), tumor necrosis factor-alpha, nuclear factor kappa B, and C-reactive protein and the oxidative DNA damage in hepatic tissue. Moreover, administration of Agn or/and Cs exhibited a modulation of the previous parameters. However, concurrent treatment with the forementioned antioxidants modulated these levels. It was concluded that the treatment with the combination of Agn and Cs was the most effective regimen in ameliorating Sd toxicity accompanied by hypoxic stress. PMID- 28833919 TI - Interleukin-10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis. AB - AIM: Recently, the benefit of mesenchymal stem cells (MSCs) as a cell-based therapy for acute liver failure (ALF) has gained much attention, although the mechanism of action of MSCs in the treatment of ALF remains elusive. Pyroptosis is a novel form of programmed cell death with an intense inflammatory response. The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects through inhibiting pyroptosis in ALF. METHODS: Mesenchymal stem cells obtained from C57BL/6 mice were isolated and cultured according to an established protocol. The MSCs were transplanted into mice with D galactosamine (D-Gal)-induced ALF. Liver function, survival rate, histology, and inflammatory factors were determined. Exogenous recombinant rat interleukin (IL) 10, ShIL-RNA, and MCC950 (NLRP3 inhibitor) were given to the mice to explore the therapeutic mechanism of MSCs. Statistical analyses were carried out with spss version 19.0, and all data were analyzed by independent-samples t-test. RESULTS: Injection of IL-10 or MSC transplantation ameliorated D-Gal-induced increase in alanine aminotransferase, aspartate aminotransferase, total bilirubin, NH3, and inflammatory cytokines. Blockage of IL-10 confirmed the therapeutic significance of this cytokine. CONCLUSION: Pyroptosis was inhibited after IL-10 infusion and inhibition of NLRP3 by MCC950 reversed liver dysfunction. PMID- 28833920 TI - Marginal Fit of Lithium Disilicate Crowns Fabricated Using Conventional and Digital Methodology: A Three-Dimensional Analysis. AB - PURPOSE: To compare the marginal fit of lithium disilicate (LD) crowns fabricated with digital impression and manufacturing (DD), digital impression and traditional pressed manufacturing (DP), and traditional impression and manufacturing (TP). MATERIALS AND METHODS: Tooth #15 was prepared for all-ceramic crowns on an ivorine typodont. There were 45 LD crowns fabricated using three techniques: DD, DP, and TP. Microcomputed tomography (micro-CT) was used to assess the 2D and 3D marginal fit of crowns in all three groups. The 2D vertical marginal gap (MG) measurements were done at 20 systematically selected points/crown, while the 3D measurements represented the 3D volume of the gap measured circumferentially at the crown margin. Frequencies of different marginal discrepancies were also recorded, including overextension (OE), underextension (UE), and marginal chipping. Crowns with vertical MG > 120 MUm at more than five points were considered unacceptable and were rejected. The results were analyzed by one-way ANOVA with Scheffe post hoc test (alpha = 0.05). RESULTS: DD crowns demonstrated significantly smaller mean vertical MG (33.3 +/- 19.99 MUm) compared to DP (54.08 +/- 32.34 MUm) and TP (51.88 +/- 35.34 MUm) crowns. Similarly, MG volume was significantly lower in the DD group (3.32 +/- 0.58 mm3 ) compared to TP group (4.16 +/- 0.59 mm3 ). The mean MG volume for the DP group (3.55 +/- 0.78 mm3 ) was not significantly different from the other groups. The occurrence of underextension error was higher in DP (6.25%) and TP (5.4%) than in DD (0.33%) group, while overextension was more frequent in DD (37.67%) than in TP (28.85%) and DP (18.75%) groups. Overall, 4 out of 45 crowns fabricated were deemed unacceptable based on the vertical MG measurements (three in TP group and one in DP group; all crowns in DD group were deemed acceptable). CONCLUSION: The results suggested that digital impression and CAD/CAM technology is a suitable, better alternative to traditional impression and manufacturing. PMID- 28833922 TI - Publication ethics-Where are we today? Part 2: Authorship: What constitutes prior publication? PMID- 28833921 TI - Recovery-related indicators of motor network plasticity according to impairment severity after stroke. AB - BACKGROUND AND PURPOSE: Brain connectivity analysis has been widely used to investigate brain plasticity and recovery-related indicators of patients with stroke. However, results remain controversial because of interindividual variability of initial impairment and subsequent recovery of function. In this study, we aimed to investigate the differences in network plasticity and motor recovery-related indicators according to initial severity. METHODS: We divided participants (16 males and 14 females, aged 54.2 +/- 12.0 years) into groups of different severity by Fugl-Mayer Assessment score, i.e. moderate (50-84), severe (20-49) and extremely severe (<20) impairment groups. Longitudinal resting-state functional magnetic resonance imaging data were acquired at 2 weeks and 3 months after onset. The differences in network plasticity and recovery-related indicators between groups were investigated using network distance and graph measurements. RESULTS: As the level of impairment increased, the network balance was more disrupted. Network balance, interhemispheric connectivity and network efficiency were recovered at 3 months only in the moderate impairment group. However, this was not the case in the extremely severe impairment group. A single connection strength between the ipsilesional primary motor cortex and ventral premotor cortex was implicated in the recovery of motor function for the extremely severe impairment group. The connections of the ipsilesional primary motor cortex-ventral premotor cortex were positively associated with motor recovery as the patients were more severely impaired. CONCLUSIONS: Differences in plasticity and recovery-related indicators of motor networks were noted according to impairment severity. Our results may suggest meaningful implications for recovery prediction and treatment strategies in future stroke research. PMID- 28833923 TI - Surgical upgrade rate of breast atypia to malignancy: An academic center's experience and validation of a predictive model. AB - Atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS) are commonly seen on breast core needle biopsy (CNB). Many institutions recommend excision of these lesions to exclude malignancy. A retrospective chart review was performed on patients who had ADH, ALH, or LCIS on breast CNB from 1/1/08 to 12/31/10 who subsequently had surgical excision of the biopsy site. Study objectives included determining upgrade to malignancy at surgical excision, identification of predictors of upgrade, and validation of a recently published predictive model. Clinical and demographic factors, pathology, characteristics of the biopsy procedure and visible residual lesion were recorded. T test and chi-squared test were used to identify predictors. Classification tree was used to predict upgrade. 151 patients had mean age of 53 years. The mean maximum lesion size on imaging was 11 mm. The primary atypia was ADH in 63.6%, ALH in 27.8%, and LCIS in 8.6%. 16.6% of patients had upgrade to malignancy, with 72% DCIS and 28% invasive carcinoma. Risk factors for upgrade included maximum lesion size (P = .002) and radiographic presence of residual lesion (P = .001). A predictive model based on these factors had sensitivity 78%, specificity 80% and AUC = 0.88. Validating a published nomogram with our data produced accuracy figures (AUC = 0.65) within published CI of 0.63-0.82. In CNB specimens containing ADH, ALH, or LCIS, initial lesion size and presence of residual lesion are predictors of upgrade to malignancy. A validated model may be helpful in developing patient management strategies. PMID- 28833924 TI - Agriculture erases climate-driven beta-diversity in Neotropical bird communities. AB - Earth is experiencing multiple global changes that will, together, determine the fate of many species. Yet, how biological communities respond to concurrent stressors at local-to-regional scales remains largely unknown. In particular, understanding how local habitat conversion interacts with regional climate change to shape patterns in beta-diversity-differences among sites in their species compositions-is critical to forecast communities in the Anthropocene. Here, we study patterns in bird beta-diversity across land-use and precipitation gradients in Costa Rica. We mapped forest cover, modeled regional precipitation, and collected data on bird community composition, vegetation structure, and tree diversity across 120 sites on 20 farms to answer three questions. First, do bird communities respond more strongly to changes in land use or climate in northwest Costa Rica? Second, does habitat conversion eliminate beta-diversity across climate gradients? Third, does regional climate control how communities respond to habitat conversion and, if so, how? After correcting for imperfect detection, we found that local land-use determined community shifts along the climate gradient. In forests, bird communities were distinct between sites that differed in vegetation structure or precipitation. In agriculture, however, vegetation structure was more uniform, contributing to 7%-11% less bird turnover than in forests. In addition, bird responses to agriculture and climate were linked: agricultural communities across the precipitation gradient shared more species with dry than wet forest communities. These findings suggest that habitat conversion and anticipated climate drying will act together to exacerbate biotic homogenization. PMID- 28833925 TI - Efficacy of three-in-one capsule bismuth quadruple therapy for Helicobacter pylori eradication in clinical practice in a multinational patient population. AB - BACKGROUND: Bismuth quadruple therapy (BQT) has been proven superior to standard triple therapy for Helicobacter pylori eradication in randomized clinical trials; however, little is known about the efficacy of BQT in daily routine practice. METHODS: In a single-center cohort study, we analyzed consecutive H. pylori positive patients in whom three-in-one capsule BQT (Pylera(r) + omeprazole) has been prescribed. All patients were instructed in a standardized fashion, and a prospective follow-up was planned. PCR on gastric biospies for clarithromycin and levofloxacin resistance was performed before treatment in a subgroup of patients. Treatment outcome was assessed by 13C urea breath test or by histology not earlier than 4 weeks after end of treatment. RESULTS: Three-in-one capsule BQT has been prescribed in 322 patients. Approximately 70.2% of patients had a migrational background. PCR results were available in 163 patients and identified resistance to clarithromycin and levofloxacin in 29 (17.8%) and 20 (12.3%) of cases, respectively. BQT was prescribed as first-line, second-line, and salvage treatments in 74%, 17%, and 9% of cases, respectively. Five patients discontinued treatment due to side effects (1.8%). By modified intention-to-treat and per protocol analyzes, the overall H. pylori eradication rates were 95.0% (95% CI 94.92%-95.08%) and 96.7% (95% CI 94.6%-98.8%), respectively. The low number of treatment failures (n = 9) did not allow to identify risk factors for failure. CONCLUSION: Three-in-one capsule bismuth quadruple therapy is effective and safe for treatment of H. pylori infection in routine practice, irrespective of the patient's migrational background or the number of previous treatment failures. PMID- 28833926 TI - Effects of remifentanil on esophageal and esophagogastric junction (EGJ) bolus transit in healthy volunteers using novel pressure-flow analysis. AB - BACKGROUND: Remifentanil is associated with subjective dysphagia and an objective increase in aspiration risk. Studies of opioid effects have shown decreased lower esophageal sphincter relaxation. We assessed bolus transit through the esophagus and esophagogastric junction (EGJ) during remifentanil administration using objective pressure-flow analysis. METHODS: Data from 11 healthy young participants (23+/-3 years, 7 M) were assessed for bolus flow through the esophagus and EGJ using high-resolution impedance manometry (ManoscanTM, Sierra Scientific Instruments, Inc., LES Angeles, CA, USA) with 36 pressure and 18 impedance segments. Data were analyzed for esophageal pressure topography and pressure-flow analysis using custom Matlab analyses (Mathworks, Natick, USA). Paired t tests were performed with a P-value of < .05 regarded as significant. KEY RESULTS: Duration of bolus flow through (remifentanil/R 3.0+/-0.3 vs baseline/B 5.0 +/- 0.4 seconds; P < .001) and presence at the EGJ (R 5.1 +/- 0.5 vs B 7.1 +/- 0.5 seconds; P = .001) both decreased during remifentanil administration. Distal latency (R 5.2 +/- 0.4 vs B 7.5 +/- 0.2 seconds; P < .001) and distal esophageal distension-contraction latency (R 3.5 +/- 0.1 vs B 4.7 +/- 0.2 seconds; P < .001) were both reduced. Intrabolus pressures were increased in both the proximal (R 5.3 +/- 0.9 vs B 2.6 +/- 1.3 mm Hg; P = .01) and distal esophagus (R 8.6 +/- 1.7 vs B 3.1 +/- 0.8 mm Hg; P = .001). There was no evidence of increased esophageal bolus residue. CONCLUSIONS AND INFERENCES: Remifentanil induced effects were different for proximal and distal esophagus, with a reduced time for trans-sphincteric bolus flow at the EGJ, suggestive of central and peripheral MU-opioid agonism. There were no functional consequences in healthy subjects. PMID- 28833927 TI - Photocatalytic Synthesis of CdS(core)-CdSe(shell) Quantum Dots with a Heteroepitaxial Junction on TiO2 : Photoelectrochemical Hydrogen Generation from Water. AB - A major challenge in chemistry for the synthesis of hetero-nanostructures is to build up atomically commensurate interfaces for smooth interfacial charge transfer. Photodeposition of CdSe on a CdS-preloaded mesoporous TiO2 nanocrystalline film yields CdS(core)-CdSe(shell) quantum dots (CdS@CdSe/mp-TiO2 ) with a heteroepitaxial nanojunction at 298 K. Two-electrode quantum-dot sensitized photoelectrochemical (QD-SPEC) cells with the structure photoanode |0.25 M Na2 S, 0.35 M Na2 SO3 (solvent=water)| cathode were fabricated. The CdS@CdSe QD-SPEC cell affords a solar-to-current efficiency (STCE) of 0.03 % without external bias under illumination of simulated sunlight (lambda>430 nm, AM 1.5, one sun). By applying 0.1 V between the electrodes, the STCE increases up to 0.048 %, far surpassing the CdS/mp-TiO2 and CdSe/mp-TiO2 photoanode cells. The CdS-CdSe interfacial analysis by high-resolution transmission electron microscopy and the band energy analysis taking the size quantization and the electrolyte effect indicate that the excellent performance of the CdS@CdSe/mp-TiO2 photoanode originates from the effective charge separation due to the cascade-like band edge alignment and the heteroepitaxial junction between CdS and CdSe QDs. In addition, high surface coverage of TiO2 with QDs can contribute to the reduction in the loss of the electron transport from TiO2 to the electron collecting electrode. PMID- 28833928 TI - An exceptional family: Ophiocordyceps-allied fungus dominates the microbiome of soft scale insects (Hemiptera: Sternorrhyncha: Coccidae). AB - Hemipteran insects of the suborder Sternorrhyncha are plant sap feeders, where each family is obligately associated with a specific bacterial endosymbiont that produces essential nutrients lacking in the sap. Coccidae (soft scale insects) is the only major sternorrhynchan family in which obligate symbiont(s) have not been identified. We studied the microbiota in seven species from this family from Israel, Spain and Cyprus, by high-throughput sequencing of ribosomal genes, and found that no specific bacterium was prevalent and abundant in all the tested species. In contrast, an Ophiocordyceps-allied fungus sp.-a lineage widely known as entomopathogenic-was highly prevalent. All individuals of all the tested species carried this fungus. Phylogenetic analyses showed that the Ophiocordyceps allied fungus from the coccids is closely related to fungi described from other hemipterans, and they appear to be monophyletic, although the phylogenies of the Ophiocordyceps-allied fungi and their hosts do not appear to be congruent. Microscopic observations show that the fungal cells are lemon-shaped, are distributed throughout the host's body and are present in the eggs, suggesting vertical transmission. Taken together, the results suggest that the Ophiocordyceps-allied fungus may be a primary symbiont of Coccidae-a major evolutionary shift from bacteria to fungi in the Sternorrhyncha, and an important example of fungal evolutionary lifestyle switch. PMID- 28833929 TI - The Impact of UV Radiation on Paramecium Populations from Alpine Lakes. AB - Paramecium populations from a clear and a glacier-fed turbid alpine lake were exposed to solar simulated ultraviolet (UVR) and photosynthetically active radiation (PAR) at 8 and 15 degrees C. The ciliates were tested for DNA damage (comet assay), behavioral changes, and mortality after UVR + PAR exposure. High DNA damage levels (~58% tail DNA) and abnormal swimming behavior were observed, although no significant changes in cell numbers were found irrespective of the lake origin (clear, turbid), and temperatures. We conclude that environmental stressors such as UVR and their effects may influence the adaptation of ciliates living in alpine lakes. PMID- 28833930 TI - Analyses of Complex Mixtures by F1 Homo-Decoupled Diagonal Suppressed Total Correlation Spectroscopy. AB - A diagonal suppressed F1 decoupled total correlation spectroscopy(TOCSY) experiment is developed for analyses of complex mixtures. In 2D homonuclear correlation, assignment of the cross peaks is crucial for structure elucidation. However, when cross peaks are close to the diagonal peaks in overcrowded spectral regions, their assignment becomes tedious. In complex mixtures, the presence of multiple spectra along with broad and complex proton multiplets owing to homonuclear scalar couplings degrade the resolution to the extent that assignment of various cross peaks becomes tedious or impossible. Herein, a diagonal suppressed total correlation technique with F1 decoupling is presented to improve the resolution of the cross peaks. The resolution of the cross peaks is improved by both diagonal suppression as well as the collapse of the multiplets to singlets. Application of the method to a few mixtures of organic compounds reveals better identification of the cross peaks relative to other TOCSY variants. PMID- 28833931 TI - Rate of Complications Following Spinal Cord Stimulation Paddle Electrode Removal. AB - OBJECTIVE: Spinal cord stimulation (SCS) is a safe, reversible surgical treatment for complex regional pain syndrome and failed back surgery syndrome refractory to conventional medical management. Paddle electrodes are routinely used for the permanent implant because of the reduced risk of migration, lower energy requirements, and expanded coverage options. The risks associated with paddle lead removal are not well defined in the literature. METHODS: We retrospectively reviewed the outcomes of all patients at the Cleveland Clinic who underwent removal of SCS paddle electrodes between 2009 and 2016. RESULTS: We identified 68 patients during this interval who had a paddle electrode removed. The most common reason for removal was loss of coverage or effect (75%), followed by infection (13.24%), and the need for magnetic resonance imaging for diagnostic purposes (8.82%). Postoperative complications occurred in eight patients (11.75%), two of which were classified as major (2.94%). One of these patients developed a postoperative cerebrospinal fluid leak, and another suffered a large suprafascial hematoma. Both patients underwent reoperation. Minor complications were reported in six patients (8.82%) and included wound dehiscence, infection, and prolonged ileus in one case. On average, patients who developed complications lost 20 mL more blood during surgery than those who did not develop complications (p = 0.006). CONCLUSION: One of the benefits of SCS therapy is the reversibility of the procedure. However, removal is not without some risk though the overall risk of minor or major complication is low. Patients who are considering removal should be counseled appropriately. Prophylactic removal is not recommended. However, when removal is needed, surgeons and pain specialists must be familiar with these complications and their management. PMID- 28833932 TI - Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir-containing regimens without sofosbuvir. AB - The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)-containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) +/ ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a-infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV-containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir +/- ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs. PMID- 28833933 TI - NSCs promote hippocampal neurogenesis, metabolic changes and synaptogenesis in APP/PS1 transgenic mice. AB - Adult neurogenesis and synaptic remodeling persist as a unique form of structural and functional plasticity in the hippocampal dentate gyrus (DG) and subventricular zone (SVZ) of the lateral ventricles due to the existence of neural stem cells (NSCs). Transplantation of NSCs may represent a promising approach for the recovery of neural circuits. Here, we aimed to examine effects of highly neuronal differentiation of NSCs transplantation on hippocampal neurogenesis, metabolic changes and synaptic formation in APP/PS1 mice. 12-month old APP/PS1 mice were used for behavioral tests, immunohistochemistry, western blot, transmission electron microscopy and proton magnetic resonance spectroscopy (1H-MRS). The results showed that N-acetylaspartate (NAA) and Glutamate (Glu) levels were increased in the Tg-NSC mice compared with the Tg-PBS and Tg-AD mice 10 weeks after NSCs transplantation. NSC-induced an increase in expression of synaptophysin and postsynaptic protein-95, and the number of neurons with normal synapses was significantly increased in Tg-NSC mice. More doublecortin-, BrdU/NeuN- and Nestin-positive neurons were observed in the hippocampal DG and SVZ of the Tg-NSC mice. This is the first demonstration that engrafted NSCs with a high differentiation rate to neurons can enhance neurogenesis in a mouse model of AD and can be detected by 1H-MRS in vivo. It is suggested that engraft of NSCs can restore memory and promote endogenous neurogenesis and synaptic remodeling, moreover, 1H-MRS can detect metabolite changes in AD mice in vivo. The observed changes in NAA/creatine (Cr) and glutamate (Glu)/Cr may be correlated with newborn neurons and new synapse formation. PMID- 28833934 TI - Characterization of microbiota in Arapaima gigas intestine and isolation of potential probiotic bacteria. AB - AIMS: The aim of this study was to determine the intestinal microbiota of pirarucu (Arapaima gigas) in different growth stages (adult and fingerlings) and to isolate and identify potential probiotic bacteria. METHODS AND RESULTS: High throughput sequencing analysis of the intestinal contents revealed that the majority of sequences belonged to the Proteobacteria, Fusobacteria and Firmicutes phyla. At the genus level, the greatest number of sequences belonged to Bradyrhizobium in adult fish, while Cetobacterium was the most abundant in juvenile fish. Twenty-three lactic-acid bacteria (LABs) were isolated on MRS agar from healthy juvenile fish. The isolates were tested in vitro for probiotic properties. Two isolates (identified as strains of Lactococcus lactis subsp. lactis and Enterococcus faecium) displayed antagonism against all 10 pathogens tested, were nonhaemolytic and maintained good viability for at least 3 weeks when supplemented to fish diets. The presence of a number of antibiotic resistance genes (ARGs), conferring resistance to erythromycin, tetracycline and chloramphenicol, was investigated by PCR. CONCLUSIONS: The absence of ARGs investigated the potential to antagonize pathogens, and favourable growth and survival characteristics indicate that these autochthonous isolates have the potential to be considered probiotics, which will be studied in future in vivo experiments. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has demonstrated, for the first time, the normal microbiota in the A. gigas intestine during different life stages and the presence of LAB strains. It also demonstrated LAB antibiotic resistance and antagonistic behaviour against pathogens isolated from the same fish. PMID- 28833935 TI - Characterization of the triple-component linoleic acid isomerase in Lactobacillus plantarum ZS2058 by genetic manipulation. AB - AIM: To assess the mechanism for conjugated linoleic acid (CLA) production in Lactobacillus plantarum ZS2058. METHODS AND RESULTS: CLA has attracted great interests for decades due to its health-associated benefits including anticancer, anti-atherogenic, anti-obesity and modulation of the immune system. A number of microbial CLA producers were widely reported including lactic acid bacteria. Lactobacillus plantarum ZS2058, an isolate from Chinese traditional fermented food, could convert LA to CLA with various intermediates. To characterize the genetic determinants for generating CLA, a cre-lox-based system was utilized to delete the genes encoding myosin cross-reactive antigen (MCRA), short-chain dehydrogenase/oxidoreductase (DH) and acetoacetate decarboxylase (DC) in Lact. plantarum ZS2058, respectively. Neither intermediate was detected in the corresponding gene deletion mutant. Meanwhile all those mutants could recover the ability to convert linoleic acid to CLA when the corresponding gene was completed. CONCLUSIONS: The results indicated that CLA production was a multiple step reaction catalysed by triple-component linoleate isomerase system encoded by mcra, dh and dc. SIGNIFICANCE AND IMPACT OF THE STUDY: Multicomponent linoleic acid isomerase provided important results for illustration unique mechanism for CLA production in Lact. plantarum ZS2058. Lactobacilli with CLA production ability offer novel opportunities for functional food development. PMID- 28833937 TI - Impact of coculturing Bifidobacterium animalis subsp. lactis HN019 with yeasts on microbial viability and metabolite formation. AB - AIMS: To evaluate the impact of coculturing Bifidobacterium animalis subsp. lactis HN019 with yeasts on microbial viability and metabolite production. METHODS AND RESULTS: Monocultures and bacteria-yeast cocultures of B. lactis HN019 and 10 different yeast strains belonging to different species in skim milk media were fermented at 37 degrees C. The presence of yeasts enhanced the growth rate and metabolic activities of B. lactis HN019, which might be attributed to their antioxidative properties. The viability of yeasts, when cocultured with bifidobacteria, was either unaffected or suppressed, depending on the strain. When the B. lactis HN019 monoculture and cocultures with Saccharomyces cerevisiae EC-1118, Pichia kluyveri FrootZen and Kluyveromyces lactis KL71 were fermented to pH 4.7, there were no significant differences in their organic acid composition. On the other hand, cocultures produced significantly higher quantities of alcohols and/or esters than the monoculture. Coculturing B. lactis HN019 with yeasts did not improve the viability of the probiotic during storage at 10 degrees C for 8 weeks, as the bifidobacteria itself demonstrated satisfactory survival in the fermented SMM. CONCLUSIONS: Coculturing B. lactis HN019 with yeasts accelerated the growth of the bifidobacteria and increased the production aroma-active volatile metabolites. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the potential of utilizing specific yeast species as starter or adjunct cultures to simultaneously improve the growth of fastidious bifidobacteria and modulate the organoleptic properties of fermented food products. PMID- 28833936 TI - Persistent C4d and antibody-mediated rejection in pediatric renal transplant patients. AB - Pediatric renal transplant recipient survival continues to improve, but ABMR remains a significant contributor to graft loss. ABMR prognostic factors to guide treatment are lacking. C4d staining on biopsies, diagnostic of ABMR, is associated with graft failure. Persistent C4d+ on follow-up biopsies has unknown significance, but could be associated with worse outcomes. We evaluated a retrospective cohort of 17 pediatric renal transplant patients diagnosed with ABMR. Primary outcome at 12 months was a composite of >=50% reduction in eGFR, transplant glomerulopathy, or graft failure. Secondary outcome was the UPCR at 12 months. We used logistic and linear regression modeling to determine whether persistent C4d+ on follow-up biopsy was associated with the outcomes. Forty-one percent reached the primary outcome at 12 months. Persistent C4d+ on follow-up biopsy occurred in 41% and was not significantly associated with the primary outcome, but was significantly associated with the secondary outcome (estimate 0.22, 95% CI 0.19-0.25, P < .001), after controlling for confounding factors. Persistent C4d+ on follow-up biopsies was associated with a higher UPCR at 12 months. Patients who remain C4d+ on follow-up biopsy may benefit from more aggressive or prolonged ABMR treatment. PMID- 28833938 TI - Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II-III). AB - The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) +/- ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF +/- RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3-infected patients with cirrhosis for 12 weeks and to genotype 2-infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post-treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF +/- RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8- and 6-week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment-emergent resistance-associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF +/- RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct-acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy. PMID- 28833939 TI - Diradicaloid or Zwitterionic Character: The Non-Tetrahedral Unsaturated Compound [Si4 {N(SiMe3 )Dipp}4 ] with a Butterfly-type Si4 Substructure. AB - The reduction of the tribromoamidosilane {N(SiMe3 )Dipp}SiBr3 (Dipp=2,6-iPr2 C6 H3 ) with potassium graphite or magnesium resulted in the formation of [Si4 {N(SiMe3 )Dipp}4 ] (1), a bicyclo[1.1.0]tetrasilatetraamide. The Si4 motif in 1 does not adopt a tetrahedral substructure and exhibits two three-coordinate and two four-coordinate silicon atoms. The electronic situation on the three coordinate silicon atoms is rationalized with positive and negative polarization based on EPR analysis, magnetization measurements, and DFT calculations as well as 29 Si CP MAS NMR and multinuclear NMR spectroscopy in solution. Reactivity studies with 1 and radical scavengers confirmed the partial charge separation. Compound 1 reacts with sulfur to give a novel type of silicon sulfur cage compound substituted with an amido ligand, [Si4 S3 {N(SiMe3 )Dipp}4 ] (2). PMID- 28833941 TI - Ultrastructure and distribution of antennal sensilla of the chilli thrips Scirtothrips dorsalis hood (Thysanoptera: Thripidae). AB - The chilli thrips, Scirtothrips dorsalis Hood, is a serious pest of numerous important vegetable and ornamental crops. Various signals, especially phytochemical cues, determine the behavior of the phytophagous thrips at host selection. The sensory abilities of S. dorsalis are poorly understood although the antennae of adult are known to possess important sensory structures in orther insects. In this study, the morphology, distribution, and ultrastructure of the antennal sensilla of the S. dorsalis were examined by using scanning and transmission electron microscopy. Microscopy observations revealed that adult male and female S. dorsalis possess filiform antennae. Each antenna comprises a scape, a pedicel, and a flagellum composed of six segments without clear sexual dimorphism in the number and distribution of antennal sensilla. The scape and pedicel exhibit Bohm's bristles, sensilla chaetica, and sensilla campaniform. The external structures of these organs reveal their mechanosensory function. In the flagellum, the most represented sensilla are the multiporous sensilla basiconica, which can be divided into three types of single-walled olfactory sensilla; three types of sensilla chaetica with mechanosensory and gustatory functions; sensilla coeloconica, which possess hollow cuticular spoke channels and represent double walled olfactory sensilla; sensilla capitula and sensilla cavity with thermo hygrosensory functions; and aporous sensilla trichodea with smooth cuticula and mechanosensory function. The putative function of described sensilla is discussed in ralation to host plant selection behavior of S. dorsalis. PMID- 28833940 TI - Taking tests in the magnet: Brain mapping standardized tests. AB - Standardized psychometric tests are sophisticated, well-developed, and consequential instruments; test outcomes are taken as facts about people that impact their lives in important ways. As part of an initial demonstration that human brain mapping techniques can add converging neural-level evidence to understanding standardized tests, our participants completed items from standardized tests during an fMRI scan. We compared tests for diagnosing posttraumatic stress disorder (PTSD) and the correlated measures of Neuroticism, Attachment, and Centrality of Event to a general-knowledge baseline test. Twenty three trauma-exposed participants answered 20 items for each of our five tests in each of the three runs for a total of 60 items per test. The tests engaged different neural processes; which test a participant was taking was accurately predicted from other participants' brain activity. The novelty of the application precluded specific anatomical predictions; however, the interpretation of activated regions using meta-analyses produced encouraging results. For instance, items on the Attachment test engaged regions shown to be more active for tasks involving judgments of others than judgments of the self. The results are an initial demonstration of a theoretically and practically important test-taking neuroimaging paradigm and suggest specific neural processes in answering PTSD related tests. Hum Brain Mapp 38:5706-5725, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28833942 TI - Clinical and histological responses of human dental pulp to MTA and combined MTA/treated dentin matrix in partial pulpotomy. AB - The aim of this study was to compare the responses of mineral trioxide aggregate (MTA) and combined MTA/treated dentin matrix (TDM) as direct pulp capping material. In this clinical trial study, 33 intact third molars in 11 healthy volunteers (three molars in each) were included. Partial pulpotomies were performed in a split mouth manner in two of the third molars in each patient randomly and the third tooth had used as TDM source. The coronal dentin was chopped to dentine chips and transformed to TDM using different concentrations of ethylene diamine tetraacetic acid (EDTA) solution. Pulps were directly capped by MTA alone or using a combination layering of MTA/TDM. Following 6-week clinical and radiological evaluations, each tooth was extracted and prepared for histological evaluation. There were no significant differences in the clinical and radiographic responses or in the quality of dentin bridges (P > 0.05). However, the dentin bridge was significantly thicker in MTA/TDM group than MTA group (P = 0.003). Using the combination of MTA/TDM as a pulp-dressing agent may form a thicker dentin bridge compared to MTA alone. PMID- 28833943 TI - Pediatric Emergency Department Utilization and Reliance by Insurance Coverage in the United States. AB - OBJECTIVES: For many children, the emergency department (ED) serves as the main destination for health care, whether it be for emergent or nonurgent reasons. Through examination of repeat utilization and ED reliance (EDR), in addition to overall ED utilization, we can identify subpopulations dependent on the ED as their primary source of health care. METHODS: Nationally representative data from the 2010 to 2014 Medical Expenditure Panel Survey were used to examine the annual ED utilization of children age 0 to 17 years by insurance coverage. Overall utilization, repeat utilization (two or more ED visits), and EDR (percentage of all health care visits that occur in the ED) were examined using multivariate models, accounting for weighting and the complex survey design. High EDR was defined as having > 33% of outpatient visits in a year being ED visits. RESULTS: A total of 47,926 children were included in the study. Approximately 12% of children visited an ED within a 1-year period. A greater number of children with public insurance (15.2%) visited an ED at least once, compared to privately insured (10.1%) and uninsured (6.4%) children. Controlling for covariates, children with public insurance were more likely to visit the ED (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI] = 1.40-1.73) than children with private insurance, whereas uninsured children were less likely (aOR = 0.64, 95% CI = 0.51-0.81). Children age 3 and under were significantly more likely to visit the ED than children age 15 to 17, whereas female children and Hispanic and non Hispanic other race children were significantly less likely to visit the ED than male children and non-Hispanic white children. Among children with ED visits, 21% had two or more visits to the ED in a 1-year period. Children with public insurance were more likely to have two or more visits to the ED (aOR = 1.53, 95% CI = 1.19-1.98) than children with private insurance whereas there was no significant difference in repeat ED utilization for uninsured children. Publicly insured (aOR = 1.70, 95% CI = 1.47-1.97) and uninsured children (aOR = 1.90, 95% CI = 1.49-2.42) were more likely to be reliant on the ED than children with private insurance. CONCLUSIONS: Health insurance coverage was associated with overall ED utilization, repeat ED utilization, and EDR. Demographic characteristics, including sex, age, income, and race/ethnicity were important predictors of ED utilization and reliance. PMID- 28833944 TI - Genetic variants of microRNA processing genes and risk of non-syndromic orofacial clefts. AB - OBJECTIVE: MicroRNA (miRNA) processing genes play important roles in the craniofacial development. The aim of this study was to explore the associations between single nucleotide polymorphisms (SNPs) of miRNA processing genes with the risk of non-syndromic orofacial clefts (NSOC). METHODS: We genotyped 12 potentially functional SNPs from seven miRNA processing genes (GEMIN3, DROSHA, DGCR8, GEMIN4, PIWIL1, XPO5, and DICER) in a case-control study of 602 NSOC cases and 605 controls. RESULTS: Two SNPs were associated with the susceptibility of CL/P: rs10719 in DROSHA led to an increased risk of cleft lip with or without palate (CL/P) (GA/AA: p = .024, OR = 1.33, 95% CI = [1.04, 1.70]; GG + GA/AA: p = .037, OR = 1.29, 95% CI = [1.02, 1.63]), while rs493760 in DROSHA (CC/TT: p = .049, OR = 0.58, 95% CI = [0.34, 0.99]) could reduce the risk of CL/P. In addition, rs10719 (A)-rs493760 (C) haplotype contributed to a decreased risk of CL/P (OR = 0.77, 95% CI = [0.63, 0.94]), whereas the rs10719 (G)-rs493760 (C) haplotype contributed to the increased risk of cleft palate only (CPO) (OR = 2.70, 95% CI = [1.15, 6.35]). However, there was no difference observed in these SNPs after the Bonferroni correction. CONCLUSION: Taken together, our results provided the potential evidence that rs10719 and rs493760 might contribute to the risk of CL/P and suggested potential genetic basis and mechanisms of CL/P. The lack of association between these SNPs and CPO might be due to the limited sample size of CPO subgroup. PMID- 28833945 TI - Susceptibility of partially desalivated rats to erosive tooth wear by calcium supplemented beverages. AB - OBJECTIVES: To investigate the susceptibility of partially desalivated rats to erosive tooth wear (ETW); the anti-erosive effect of a calcium-supplemented beverage; and the quantification of ETW by microcomputed tomography (micro-CT). METHODS: The study population consisted of thirty-eight rats, divided into partially desalivated (n = 19) and normal salivary flow (n = 19). They were randomly allocated into three subgroups (n = 6-7): A-diet soda, B-diet soda + calcium, C-water (control). Solutions were provided ad libitum for 28 days, and the rats were euthanized afterwards. Each left hemi-mandible was scanned using micro-CT for enamel volume (three molars) calculation. Visual analysis of photographs of the lingual surface of first molars was performed independently by three blinded examiners. Data were statistically analysed (alpha = .05). RESULTS: Micro-CT revealed no significant differences between partially desalivated or normal groups. Rats consuming A had more enamel loss than those consuming B or C, which did not differ from each other. For visual analysis, desalivation did not affect ETW. Rats consuming C showed the lowest ETW, followed by B and then A, for both partially desalivated and normal rats. Spearman correlation between the two ETW quantification methods was -.65. CONCLUSIONS: Partial desalivation did not increase ETW. Ca-containing beverage prevented ETW. Micro-CT quantified ETW, although it was not as sensitive as visual analysis. PMID- 28833946 TI - Photometric Characterization of the Reductive Amination Scope of the Imine Reductases from Streptomyces tsukubaensis and Streptomyces ipomoeae. AB - Imine reductases (IREDs) have emerged as promising enzymes for the asymmetric synthesis of secondary and tertiary amines starting from carbonyl substrates. Screening the substrate specificity of the reductive amination reaction is usually performed by time-consuming GC analytics. We found two highly active IREDs in our enzyme collection, IR-20 from Streptomyces tsukubaensis and IR-Sip from Streptomyces ipomoeae, that allowed a comprehensive substrate screening with a photometric NADPH assay. We screened 39 carbonyl substrates combined with 17 amines as nucleophiles. Activity data from 663 combinations provided a clear picture about substrate specificity and capabilities in the reductive amination of these enzymes. Besides aliphatic aldehydes, the IREDs accepted various cyclic (C4 -C8 ) and acyclic ketones, preferentially with methylamine. IR-Sip also accepted a range of primary and secondary amines as nucleophiles. In biocatalytic reactions, IR-Sip converted (R)-3-methylcyclohexanone with dimethylamine or pyrrolidine with high diastereoselectivity (>94-96 % de). The nucleophile acceptor spectrum depended on the carbonyl substrate employed. The conversion of well-accepted substrates could also be detected if crude lysates were employed as the enzyme source. PMID- 28833947 TI - Establishing the appropriate primary endpoint in haemophilia gene therapy pivotal studies. PMID- 28833948 TI - Charge neutralization in the active site of the catalytic trimer of aspartate transcarbamoylase promotes diverse structural changes. AB - A classical model for allosteric regulation of enzyme activity posits an equilibrium between inactive and active conformations. An alternative view is that allosteric activation is achieved by increasing the potential for conformational changes that are essential for catalysis. In the present study, substitution of a basic residue in the active site of the catalytic (C) trimer of aspartate transcarbamoylase with a non-polar residue results in large interdomain hinge changes in the three chains of the trimer. One conformation is more open than the chains in both the wild-type C trimer and the catalytic chains in the holoenzyme, the second is closed similar to the bisubstrate-analog bound conformation and the third hinge angle is intermediate to the other two. The active-site 240s loop conformation is very different between the most open and closed chains, and is disordered in the third chain, as in the holoenzyme. We hypothesize that binding of anionic substrates may promote similar structural changes. Further, the ability of the three catalytic chains in the trimer to access the open and closed active-site conformations simultaneously suggests a cyclic catalytic mechanism, in which at least one of the chains is in an open conformation suitable for substrate binding whereas another chain is closed for catalytic turnover. Based on the many conformations observed for the chains in the isolated catalytic trimer to date, we propose that allosteric activation of the holoenzyme occurs by release of quaternary constraint into an ensemble of active-site conformations. PMID- 28833949 TI - Argon plasma coagulation treatment of anal high-grade squamous intraepithelial lesions in men who have sex with men living with HIV: results of a 2-year prospective pilot study. AB - OBJECTIVES: Men who have sex with men (MSM) living with HIV are at high risk for anal high-grade squamous intraepithelial lesions (HSILs) and cancer. The best management of anal HSIL remains unclear. Our objective was to assess whether argon plasma coagulation (APC) could be safe, well tolerated and efficient to treat anal HSILs in MSM living with HIV. METHODS: A prospective phase II, open label, pilot study was conducted to evaluate APC to treat anal HSILs in 20 HIV positive MSM. Participants were followed for 2 years after their first treatment. RESULTS: Twenty men with persistent HSILs completed the 2-year study. Their baseline median CD4 count was 490 cells/MUL and 85% had undetectable HIV viral loads. Overall, 65% (13/20) of participants were clear of HSILs at their 24-month visit. The initial response rates after the first, second and third APC treatments were 45%, 44% and 67%, respectively, but recurrences were common. The main side effect was pain during and within 1 week after the treatments. There were no long-term side effects, nor serious adverse events related to the procedure. Cost is a drawback. CONCLUSIONS: APC can be used to treat anal HSILs in HIV-seropositive MSM, and requires repeated treatment because of a high recurrence rate. As successful treatment of human papillomavirus (HPV) infection or eradication of the anal transitional zone remains impossible, HSIL treatment is challenging and requires long-term follow-up. PMID- 28833950 TI - Novel Biodegradable Polymer with Redox-Triggered Backbone Cleavage Through Sequential 1,6-Elimination and 1,5-Cyclization Reactions. AB - In the past decade, the self-immolative biodegradable polymer arose as a novel paradigm for its efficient degradation mechanism and vast potential for advanced biomedical applications. This study reports successful synthesis of a novel biodegradable polymer capable of self-immolative backbone cleavage. The monomer is designed by covalent conjugations of both pendant redox-trigger (p-nitrobenzyl alcohol) and self-immolative linker (p-hydroxybenzyl alcohol) to the cyclization spacer (n-2-(hydroxyethyl)ethylene diamine), which serves as the structural backbone. The polymerization of the monomer with hexamethylene diisocyanate yields a linear redox-sensitive polymer that can systemically degrade via sequential 1,6-elimination and 1,5-cyclization reactions within an effective timeframe. Ultimately, the polymer's potential for biomedical application is simulated through in vitro redox-triggered release of paclitaxel from polymeric nanoparticles. PMID- 28833951 TI - Attitudes toward pessary use among Thai women with pelvic organ prolapse. AB - AIM: This study was conducted to investigate attitudes toward pessary use in Thai women with pelvic organ prolapse (POP). METHODS: Ninety Thai women with symptomatic POP without any history of previous prolapse treatment were recruited. Participants completed a questionnaire about attitudes toward pessary use in Thai language. Patient characteristics and decision-making factors were identified. RESULTS: Forty eight women (53.3%) decided to use a pessary. Most respondents felt that pessary use would improve emotional status (56.2%), pain (52.0%) and quality of life (75%). The opinions of family members and post application bleeding, discharge, irritation and pain were important factors in decision-making. CONCLUSION: Many Thai women with POP prefer a pessary. Their decision is influenced by opinions of family members and complications of pessary use. Counseling about the advantages and uncommon complications of pessary use should be provided to both patients and family members to improve higher pessary acceptance. PMID- 28833953 TI - Mixed state and suicide: Is the effect of mixed state on suicidal behavior more than the sum of its parts? AB - OBJECTIVE: To assess whether suicidal behavior during mixed states exceeds that expected from the manic or depressive components alone. METHODS: This study included 429 participants with bipolar disorder from the National Institute of Mental Health Collaborative Depression Study (CDS). Mood and suicidal behavior were captured using the Longitudinal Interval Follow-up Evaluation and the Schedule of Affective Disorders and Schizophrenia. Suicidal behavior during each mood state, relative to euthymia, was analyzed using Cox regression to allow for repeated events, with a frailty term to account for intra-participant correlation. Mixed states were modeled as a depression-by-mania interaction. RESULTS: Individuals with a history of mixed states were at higher risk of suicidal behavior and spent more time depressed, compared to subjects with no such history. In bipolar I disorder, risk increased during episodes of mania (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.28-2.99, P = .0019) and depression (HR: 5.49, 95% CI: 4.01-7.51, P < .0001) and there was a less than additive effect of mixed states. In bipolar II disorder, risk was increased during episodes of depression (HR: 3.66, 95% CI: 2.51-5.35, P < .0001) and there was no excess risk during mixed states beyond that attributable to the depressed component. Most of the excess risk (71%) among those with a history of mixed states was attributable to a depression predominant course of illness. CONCLUSIONS: Individuals with mixed states are at high risk of suicidal behavior, largely due to more time spent depressed. Clinicians should aggressively treat depression to mitigate suicide risk for patients with or without mixed states. PMID- 28833952 TI - COMT val158met polymorphism links to altered fear conditioning and extinction are modulated by PTSD and childhood trauma. AB - BACKGROUND: Risk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene * environment (G * E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma. METHODS: Male Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points. RESULTS: Before deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals. CONCLUSIONS: These findings support the hypothesis that G * E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies. PMID- 28833961 TI - Clinical relevance of abnormal neuroimaging findings and long-term risk of stroke recurrence. AB - BACKGROUND AND PURPOSE: Previous studies have revealed that the predictors of short- and long-term stroke recurrence are different. We designed a comprehensive stroke recurrence (CSR) model, composed of demographic, clinical and radiological findings, to predict long-term ischaemic stroke recurrences. METHODS: We retrospectively collected the derivation cohort from consecutive patients with first-ever ischaemic stroke within 7 days of symptom onset. Univariate and multivariable Cox regression analysis were used to evaluate the association between 2-year recurrence and demographic, clinical and neuroradiological factors. The CSR score was calculated by adding the integer value of independent predictors that was derived from the beta-coefficient in the multivariable analysis. To qualify the model, we analyzed the receiver operating characteristics curve. We assessed internal validation with bootstrap methods and assessed external validation with another independent cohort. RESULTS: A total of 958 patients were enrolled, and 63 patients had recurrent strokes during the follow-up periods. The rate of stroke recurrence was 7.0% at 2 years. In the multivariable analysis, multiple stage lesions, isolated cortical lesions on diffusion-weighted imaging, severe white matter hyperintensities, multiple lacunar infarctions and relevant arterial stenosis were independently associated with stroke recurrence. The CSR model showed good discrimination [area under the curve (AUC), 0.81 (0.74-0.88)], which was consistent with internal [AUC, 0.75 (0.66-0.85)] and external [AUC, 0.80 (0.69-0.90)] validation. CONCLUSIONS: Abnormal neuroimaging findings, rather than cardiovascular risk factors, are predictive of long-term ischaemic stroke recurrence. Causative mechanism of stroke and underlying hostile brain milieu seem to be associated with long-term stroke recurrence. PMID- 28833962 TI - Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial. AB - OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2*2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials. PMID- 28833964 TI - Stress in caregivers of individuals with intellectual or developmental disabilities: A systematic review of mindfulness-based interventions. AB - BACKGROUND: The efficacy of mindfulness-based interventions (MBIs) for stress and psychological distress in professional caregivers supporting individuals with intellectual or developmental disabilities (IDDs) is reviewed. METHODS: Eight studies met inclusion criteria and were systematically reviewed, including RCTs and single-group designs. RESULTS: As per Reichow, Volkmar, and Cicchetti (Journal of Autism and Developmental Disorders, 38, 2008), three studies were classified as "adequate quality" and five were classified as "weak." There were inconsistent findings in relation to stress, with significant reductions or increases reported by caregivers following MBIs. MBIs consistently improved caregivers' ratings of distress. Process outcomes suggested increased mindful awareness, increased cognitive defusion and reduced thought suppression. Treatment effects were maintained or continued to grow at follow-up. CONCLUSIONS: Caregivers of individuals with IDDs face multiple challenges on a daily basis. This review supports, at least, short-term benefits for MBIs in the management of stress and distress in caregivers of individuals with IDDs. PMID- 28833963 TI - A novel technique for enterotomy closure in stapled laparoscopic intracorporeal anastomosis. AB - AIM: The proximal edge of the enterotomy in a side-to-side anastomosis has been shown to be the site at highest risk of leakage. Several methods have been described to overcome this vulnerability. The technical challenge of intra corporeal anastomosis (ICA) is to re-create angles between tissues and instruments, similar to those in an open anastomosis. The axis between the suture line and the needle driver is paramount and this angle should be < 45 degrees . METHOD: The crotch stitch of the enterotomy is difficult because of the narrow space between the loops and the depth of the anastomosis. The usual technique is suturing right-handed, 'out-in and in-out', colonic edge first to small bowel. The risk of suture misplacement (e.g. 'out-in/out-in' or 'out-out') is similar to open procedures but laparoscopically the second bite is challenging, due to the straight needle-driver. This may lead to asymmetrical closure of the corner resulting in a slightly larger angle on the bowel side and a potential postoperative leak/fistula. Rotating the small bowel loop to counterbalance this issue, risks tearing of the staple line. The rationale is that starting with a back-handed stitch and taking the small bowel edge first would allow the necessary acute angled bite to be achieved. Subsequently, mounting the needle right-handed for taking the colonic edge also allows achievement of an acute angled bite. RESULTS: Our novel technique, named the 'back-handed, left-to-right stitch' technique, is intended to achieve symmetrical approximation of the ileal and colonic edges during laparoscopy, with an optimal closure of the deepest extremity of the enterotomy. Such a stitch, used in a series of 10 patients, may be useful to avoid leaving an opening within this angle and/or to avoid potential technical pitfalls when closing the deepest apex of the enterotomy. CONCLUSION: This 'back-handed, left-to-right' stitch described here allows a properly angled closure of the proximal edge of the enterotomy and a safe approximation of the corner of the enterotomy in a side-to-side ICA. PMID- 28833965 TI - Enzymatic and viability RT-qPCR assays for evaluation of enterovirus, hepatitis A virus and norovirus inactivation: Implications for public health risk assessment. AB - AIM: To assess the potential of a viability dye and an enzymatic reverse transcription quantitative PCR (RT-qPCR) pretreatment to discriminate between infectious and noninfectious enteric viruses. METHODS AND RESULTS: Enterovirus (EntV), norovirus (NoV) GII.4 and hepatitis A virus (HAV) were inactivated at 95 degrees C for 10 min, and four methods were used to compare the efficiency of inactivation: (i) cell culture plaque assay for HAV and EntV, (ii) RT-qPCR alone, (iii) RT-qPCR assay preceded by RNase treatment, and (iv) pretreatment with a viability dye (reagent D (RD)) followed by RT-qPCR. In addition, heat-inactivated NoV was treated with RD coupled with surfactants to increase the efficiency of the viability dye. No treatment was able to completely discriminate infectious from noninfectious viruses. RD-RT-qPCR reduced more efficiently the detection of noninfectious viruses with little to no removal observed with RNase. RD-RT-qPCR method was the closest to cell culture assay. The combination of surfactants and RD did not show relevant improvements on the removal of inactivated viruses signal compared with viability RT-qPCR, with the exception of Triton X-100. CONCLUSION: The use of surfactant/RD-RT-qPCR, although not being able to completely remove the signal from noninfectious viral particles, yielded a better estimation of viral infectivity. SIGNIFICANCE AND IMPACT OF THE STUDY: Surfactant/RD-RT-qPCR may be an advantageous tool for a better detection of infectious viruses with potential significant impact in the risk assessment of the presence of enteric viruses. PMID- 28833966 TI - On the centrality of mixed features in mood disorders: Listening to Kraepelin and Weygandt and moving forward. PMID- 28833967 TI - Qualitative evaluation of a physical activity health promotion programme for people with intellectual disabilities in a group home setting. AB - BACKGROUND: There is a lack of health promotion programming designed to change the physical activity environment of the group home setting. The Menu-Choice programme assists staff in creating physical activity goals alongside residents with intellectual disabilities and provides strategies to incorporate activity into the group home schedule. The purpose of this study was to complete a process evaluation of Menu-Choice utilizing qualitative methods. METHODS: Twelve participants, who completed a 10-week pilot intervention (n = 7 staff, mean age 42; n = 5 residents, mean age 52), participated in face-to-face interviews. Participants represented five group home sites involved in the intervention. RESULTS: Meta-themes included: (i) Programme training, (ii) Programme implementation, (iii) Programme physical activity, (iv) Programme barriers, (v) Programme facilitators and (vi) Programme feedback. CONCLUSIONS: Changes in programme training and simplified programme materials are needed to accommodate identified barriers for implementation. The importance of obtaining increased agency support and policy change is highlighted. PMID- 28833968 TI - Endoscopic characteristics of infection-associated peptic ulcers. AB - BACKGROUND: Aside from Helicobacter pylori, another cause for the development or worsening of gastrointestinal ulcers is scrub typhus, an acute febrile disease caused by Orientia tsutsugamushi. We aimed to compare the endoscopic characteristics of peptic ulcers caused by these infectious agents. METHODS: This retrospective case-control study involved patients who underwent upper gastrointestinal endoscopy at Chosun University Hospital in Korea. We compared endoscopic features and demographic characteristics between patients with H. pylori infection and those with O. tsutsugamushi infection. RESULTS: A total of 141 patients with peptic ulcer were included in the study. Compared to patients with O. tsutsugamushi infection (n = 62; age, 63.8 +/- 12.1 years; male sex, 42%), those with H. pylori infection (n = 79; age, 53.0 +/- 14.8 years; male sex, 81%) were younger and more likely to be male (P < .001 for both). Patients with O. tsutsugamushi infection were more likely to have multiple lesions (40/62, 64.5% vs 37/79, 46.8%; P = .042) and irregular-shaped lesions (27/62, 43.6% vs 20/79, 25.3%; P = .031). Patients with H. pylori infection had higher incidence of hemorrhagic ulcers (26/79, 32.9% vs 8/62, 12.9%; P = .007), and lesions occurred most often in the duodenum (43.0%), followed by the antrum (36.7%), body (34.2%), and angle (12.7%) of the stomach. In patients with O. tsutsugamushi infection, lesions occurred most often in the antrum (70.97%), followed by the duodenum (35.5%), body (22.6%), and angle (14.5%) of the stomach. In both groups, gastric ulcer lesions occurred most often in the antrum, followed by the body and angle of the stomach (36.7% vs 70.97%, 34.2% vs 22.6%, and 12.7% vs 14.5% for gastric ulcers associated with H. pylori and O. tsutsugamushi infection, respectively). Patients with O. tsutsugamushi infection had significantly higher incidence of ulcers on the antrum (70.97% vs 36.7%, P < .001) and the greater curvature (45.2% vs 24.0%, P = .012). Finally, 35.5% of patients with gastric ulcer caused by scrub typhus also had duodenal ulcer. CONCLUSION: This is the first study to compare endoscopic features of peptic ulcers caused by H. pylori and O. tsutsugamushi. Peptic ulcers in patients with H. pylori infection occurred predominantly in the antrum/body/lesser curvature and presented with single, round/oval lesions, while ulcers in patients with scrub typhus occurred predominantly in the antrum/greater curvature and presented with multiple, irregular lesions. Scrub typhus should be considered as a cause of duodenal ulcer in scrub typhus-endemic areas. PMID- 28833969 TI - Enzymatic C-H Oxidation-Amidation Cascade in the Production of Natural and Unnatural Thiotetronate Antibiotics with Potentiated Bioactivity. AB - The selective activation of unreactive hydrocarbons by biosynthetic enzymes has inspired new synthetic methods in C-H bond activation. Herein, we report the unprecedented two-step biosynthetic conversion of thiotetromycin to thiotetroamide C involving the tandem oxidation and amidation of an unreactive ethyl group. We detail the genetic and biochemical basis for the terminal amidation in thiotetroamide C biosynthesis, which involves a uniquely adapted cytochrome P450-amidotransferase enzyme pair and highlights the first oxidation amidation enzymatic cascade reaction leading to the selective formation of a primary amide group from a chemically inert alkyl group. Motivated by the ten fold increase in antibiotic potency of thiotetroamide C ascribed to the acetamide group and the unusual enzymology involved, we enzymatically interrogated diverse thiolactomycin analogues and prepared an unnatural thiotetroamide C analogue with potentiated bioactivity compared to the parent molecule. PMID- 28833970 TI - Single Cell Phenotyping Reveals Heterogeneity Among Hematopoietic Stem Cells Following Infection. AB - The hematopoietic stem cell (HSC) niche provides essential microenvironmental cues for the production and maintenance of HSCs within the bone marrow. During inflammation, hematopoietic dynamics are perturbed, but it is not known whether changes to the HSC-niche interaction occur as a result. We visualize HSCs directly in vivo, enabling detailed analysis of the 3D niche dynamics and migration patterns in murine bone marrow following Trichinella spiralis infection. Spatial statistical analysis of these HSC trajectories reveals two distinct modes of HSC behavior: (a) a pattern of revisiting previously explored space and (b) a pattern of exploring new space. Whereas HSCs from control donors predominantly follow pattern (a), those from infected mice adopt both strategies. Using detailed computational analyses of cell migration tracks and life-history theory, we show that the increased motility of HSCs following infection can, perhaps counterintuitively, enable mice to cope better in deteriorating HSC-niche microenvironments following infection. Stem Cells 2017;35:2292-2304. PMID- 28833971 TI - Umbilical hernia: Influence of adhesive strapping on outcome. AB - BACKGROUND: Adhesive strapping for umbilical hernia has been re-evaluated as a promising treatment. We evaluated the influence of adhesive strapping on the outcome of umbilical hernia. METHODS: We retrospectively evaluated patients with umbilical hernia referred to the present institution from April 2011 to December 2015. Patients who were treated with adhesive strapping were compared with an observation alone group. The adhesive strapping group was also subdivided into two groups: the cure group and the treatment failure group. RESULTS: A total of 212 patients with umbilical hernia were referred to the present institution. Eighty-nine patients were treated with adhesive strapping, while 27 had observation only. The cure rate in the adhesive strapping group was significantly higher than that in the observation group. The duration of treatment of the adhesive strapping group was significantly shorter than that of the observation group. In the adhesive strapping group, the patients in the cure group were treated significantly earlier than those in the treatment failure group (P < 0.001). Furthermore, even in cases of umbilical hernia non-closure, surgical repair was easier after adhesive strapping. CONCLUSION: Adhesive strapping represents a promising treatment for umbilical hernia. To achieve the best results, adhesive strapping should be initiated as early as possible. PMID- 28833972 TI - Range position and climate sensitivity: The structure of among-population demographic responses to climatic variation. AB - Species' distributions will respond to climate change based on the relationship between local demographic processes and climate and how this relationship varies based on range position. A rarely tested demographic prediction is that populations at the extremes of a species' climate envelope (e.g., populations in areas with the highest mean annual temperature) will be most sensitive to local shifts in climate (i.e., warming). We tested this prediction using a dynamic species distribution model linking demographic rates to variation in temperature and precipitation for wood frogs (Lithobates sylvaticus) in North America. Using long-term monitoring data from 746 populations in 27 study areas, we determined how climatic variation affected population growth rates and how these relationships varied with respect to long-term climate. Some models supported the predicted pattern, with negative effects of extreme summer temperatures in hotter areas and positive effects on recruitment for summer water availability in drier areas. We also found evidence of interacting temperature and precipitation influencing population size, such as extreme heat having less of a negative effect in wetter areas. Other results were contrary to predictions, such as positive effects of summer water availability in wetter parts of the range and positive responses to winter warming especially in milder areas. In general, we found wood frogs were more sensitive to changes in temperature or temperature interacting with precipitation than to changes in precipitation alone. Our results suggest that sensitivity to changes in climate cannot be predicted simply by knowing locations within the species' climate envelope. Many climate processes did not affect population growth rates in the predicted direction based on range position. Processes such as species-interactions, local adaptation, and interactions with the physical landscape likely affect the responses we observed. Our work highlights the need to measure demographic responses to changing climate. PMID- 28833973 TI - Successful ustekinumab treatment of noninfectious uveitis and concomitant severe psoriatic arthritis and plaque psoriasis. AB - We report the first successful treatment of noninfectious uveitis with ustekinumab in a patient with severe concomitant psoriasis and psoriatic arthritis who failed to respond to conventional immune suppressants and with contraindications to tumor necrosis factor alpha inhibitors. PMID- 28833974 TI - Jak-inhibitors and UV-B: Potential combined therapy for vitiligo. PMID- 28833975 TI - Genetic testing in intellectual disability psychiatry: Opinions and practices of UK child and intellectual disability psychiatrists. AB - BACKGROUND: An increasing number of genetic causes of intellectual disabilities (ID) are identifiable by clinical genetic testing, offering the prospect of bespoke patient management. However, little is known about the practices of psychiatrists and their views on genetic testing. METHOD: We undertook an online survey of 215 psychiatrists, who were contacted via the Royal College of Psychiatrist's Child and Adolescent and Intellectual Disability Psychiatry mailing lists. RESULTS: In comparison with child and adolescent psychiatrists, intellectual disability psychiatrists ordered more genetic tests, referred more patients to genetic services, and were overall more confident in the genetic testing process. Respondents tended to agree that genetic diagnoses can help patient management; however, management changes were infrequently found in clinical practice. CONCLUSIONS: Differences are apparent in the existing views and practices of child and adolescent and intellectual disability psychiatrists. Developing training and collaboration with colleagues working in genetic services could help to reduce discrepancies and improve clinical practice. PMID- 28833976 TI - What contributes to action plan enactment? Examining characteristics of physical activity plans. AB - OBJECTIVES: Individuals with chronic conditions can benefit from formulating action plans to engage in regular physical activity. However, the content and the successful translation of plans into action, so-called plan enactment, are rarely adequately evaluated. The aim of this study was to describe the content of user specified plans and to examine whether participants were more likely to enact their plans if these plans were highly specific, viable, and instrumental. DESIGN AND METHODS: The study presents secondary analyses from a larger behavioural intervention in cardiac and orthopaedic rehabilitation. The content of 619 action plans from 229 participants was evaluated by two independent raters (i.e., qualitative analyses and ratings of specificity) and by participants themselves (i.e., instrumentality and viability). Plan enactment was also measured via self reports. Multilevel analyses examined the relationship between these plan characteristics and subsequent plan enactment, and between plan enactment and aggregated physical activity. RESULTS: Participants preferred to plan leisure time physical activities anchored around time-based cues. Specificity of occasion cues (i.e., when to act) and highly instrumental plans were positively associated with plan enactment. Interestingly, individuals who planned less specific behavioural responses (i.e., what to do) were more likely to enact their plans. Plan enactment was positively associated with aggregated behaviour. CONCLUSIONS: Interventions should not only emphasize the importance of planning, but also the benefits of formulating specific contextual cues. Planning of the behavioural response seems to require less precision. Allowing for some flexibility in executing the anticipated target behaviour seems to aid successful plan enactment. Statement of Contribution What is already known on this subject? Action planning interventions are efficacious in promoting health behaviour. Characteristics of plan content (i.e., specificity) matter for unconditional behaviour change. Plan enactment (i.e., degree to which plan is followed through) is positively linked to behaviour change. What does this study add? Specificity of occasion cues (i.e., when to act) and highly instrumental plans were positively associated with plan enactment. Individuals who planned less specific behavioural responses (i.e., what to do) were more likely to enact their plans. Planning interventions should focus on specificity of context cues but flexibility of behavioural action. PMID- 28833977 TI - Sound physiological knowledge and principles in modeling shrinking of fishes under climate change. AB - One of the main expected responses of marine fishes to ocean warming is decrease in body size, as supported by evidence from empirical data and theoretical modeling. The theoretical underpinning for fish shrinking is that the oxygen supply to large fish size cannot be met by their gills, whose surface area cannot keep up with the oxygen demand by their three-dimensional bodies. However, Lefevre et al. (Global Change Biology, 2017, 23, 3449-3459) argue against such theory. Here, we re-assert, with the Gill-Oxygen Limitation Theory (GOLT), that gills, which must retain the properties of open surfaces because their growth, even while hyperallometric, cannot keep up with the demand of growing three dimensional bodies. Also, we show that a wide range of biological features of fish and other water-breathing organisms can be understood when gill area limitation is used as an explanation. We also note that an alternative to GOLT, offering a more parsimonious explanation for these features of water-breathers has not been proposed. Available empirical evidence corroborates predictions of decrease in body sizes under ocean warming based on GOLT, with the magnitude of the predicted change increases when using more species-specific parameter values of metabolic scaling. PMID- 28833978 TI - Mammal diversity and metacommunity dynamics in urban green spaces: implications for urban wildlife conservation. AB - As urban growth expands and natural environments fragment, it is essential to understand the ecological roles fulfilled by urban green spaces. To evaluate how urban green spaces function as wildlife habitat, we estimated mammal diversity and metacommunity dynamics in city parks, cemeteries, golf courses, and natural areas throughout the greater Chicago, Illinois, USA region. We found similar alpha-diversity (with the exception of city parks), but remarkably dissimilar communities in different urban green spaces. Additionally, the type of urban green space greatly influenced species colonization and persistence rates. For example, coyotes (Canis latrans) had the highest, but white-tailed deer (Odocoileus virginianus) the lowest probability of persistence in golf courses compared to other green space types. Further, most species had a difficult time colonizing city parks even when sites were seemingly available. Our results indicate that urban green spaces contribute different, but collectively important, habitats for maintaining and conserving biodiversity in cities. PMID- 28833979 TI - Automatic affective responses towards the bed in patients with primary insomnia: evidence for a negativity bias. AB - Ruminating about sleep problems and negatively valenced thinking play a key role in the maintenance of sleep complaints in patients with insomnia. Based on associative learning principles, we hypothesized that repeated co-occurrence of negative thoughts (unconditioned stimulus) and the bedroom environment (conditioned stimulus) results in automatic negative affective responses towards the bed (conditioned response). Twenty-two insomniacs and 22 good sleepers performed a Single-Target Implicit Association Test measuring the strength of automatically triggered affective responses towards the bed. Results revealed a significant group difference, indicating a stronger negative affective response towards the bed in patients with insomnia. No correlations were found between the strength of negative affective responses towards the bed and subjective measures of sleep quality. As it might increase the stress experience further during bedtime, automatic negative responses towards the bed are likely to represent an additional factor accounting for the development and maintenance of sleep disorders and represent a potential target for therapeutic interventions. PMID- 28833980 TI - European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis - endorsed by the European Academy of Neurology. AB - BACKGROUND AND PURPOSE: Current guidelines on cerebral venous thrombosis (CVT) diagnosis and management were issued by the European Federation of Neurological Societies in 2010. We aimed to update the previous European Federation of Neurological Societies guidelines using a clearer and evidence-based methodology. METHOD: We followed the Grading of Recommendations, Assessment, Development and Evaluation system, formulating relevant diagnostic and treatment questions, performing systematic reviews and writing recommendations based on the quality of available scientific evidence. RESULTS: We suggest using magnetic resonance or computed tomographic angiography for confirming the diagnosis of CVT and not routinely screening patients with CVT for thrombophilia or cancer. We recommend parenteral anticoagulation in acute CVT and decompressive surgery to prevent death due to brain herniation. We suggest preferentially using low-molecular weight heparin in the acute phase and not direct oral anticoagulants. We suggest not using steroids and acetazolamide to reduce death or dependency. We suggest using antiepileptics in patients with an early seizure and supratentorial lesions to prevent further early seizures. We could not make recommendations concerning duration of anticoagulation after the acute phase, thrombolysis and/or thrombectomy, therapeutic lumbar puncture, and prevention of remote seizures with antiepileptic drugs. We suggest that, in women who have suffered a previous CVT, contraceptives containing oestrogens should be avoided. We suggest that subsequent pregnancies are safe, but use of prophylactic low-molecular-weight heparin should be considered throughout pregnancy and puerperium. CONCLUSIONS: Multicentre observational and experimental studies are needed to increase the level of evidence supporting recommendations on the diagnosis and management of CVT. PMID- 28833981 TI - Societe Chimique de France Prizes 2017. PMID- 28833982 TI - The N-Terminal Domain of ALS-Linked TDP-43 Assembles without Misfolding. AB - Transactivation response element (TAR) DNA-binding protein 43 (TDP-43) misfolding is implicated in several neurodegenerative diseases characterized by aggregated protein inclusions. Misfolding is believed to be mediated by both the N- and C terminus of TDP-43; however, the mechanistic basis of the contribution of individual domains in the process remained elusive. Here, using single-molecule fluorescence and ensemble biophysical techniques, and a wide range of pH and temperature conditions, we show that TDP-43NTD is thermodynamically stable, well folded and undergoes reversible oligomerization. We propose that, in full-length TDP-43, association between folded N-terminal domains enhances the propensity of the intrinsically unfolded C-terminal domains to drive pathological aggregation. PMID- 28833983 TI - Pregnancy after stillbirth: anxiety and a whole lot more. PMID- 28833984 TI - Psychosis in bipolar disorder: Does it represent a more "severe" illness? AB - OBJECTIVES: Although there is a common clinical assumption that bipolar disorder with psychotic features reflects greater severity than bipolar disorder without psychosis, the existing empirical literature is mixed. This study investigated the phenomenology of psychosis as well as demographic, clinical, functional, and neuropsychological features in a large, cross-sectional sample of participants with bipolar disorder divided by history of psychosis. METHODS: In a large single study, 168 affective-only bipolar disorder (BP-A) participants and 213 bipolar disorder with a history of psychosis (BP-P) participants completed a comprehensive clinical diagnostic interview and neuropsychological testing. t tests, chi-square tests, and Bayes factors were used to investigate group differences or lack thereof. RESULTS: The prevalence of psychosis in this sample (53%) was similar to published reports. Nearly half of BP-P participants experienced grandiose delusions, and relatively few endorsed "first-rank" hallucinations of running commentary or two or more voices conversing. There were no demographic or neuropsychological differences between groups. BP-A participants experienced greater chronicity of affective symptoms and a greater degree of rapid cycling than BP-P participants; there were no other clinical differences between groups. CONCLUSIONS: Overall, these results contradict the conventional notion that bipolar disorder with psychotic features represents a more severe illness than bipolar disorder without a history of psychosis. The presence of psychosis does not appear to be associated with poorer clinical/functional outcome or suggest a greater degree of neuropsychological impairment; conversely, the absence of psychosis was associated with affective chronicity and rapid cycling. Nosological and treatment implications are discussed. PMID- 28833985 TI - Switch to atovaquone and subsequent re-challenge with trimethoprim sulfamethoxazole for Pneumocystis prophylaxis in a kidney transplant population. AB - Kidney transplant recipients who are switched to atovaquone (ATO) from trimethoprim-sulfamethoxazole (TMP/SMX) for Pneumocystis jirovecii pneumonia (PJP) prophylaxis because of adverse events or complications may miss opportunities to be re-challenged with TMP/SMX, the first-line agent. This single site, retrospective study assessed kidney transplant recipients for documented reasons for switching from TMP/SMX to alternate PJP prophylaxis and outcomes of TMP/SMX re-challenge. Out of 166 patients, 155 initially received TMP/SMX; of these, 31 were switched to ATO for various reasons. Fourteen patients receiving ATO were re-challenged with TMP/SMX; all were successfully re-initiated on TMP/SMX therapy. Most patients switched to ATO post kidney transplant secondary to non-hypersensitivity reasons should be re-challenged with TMP/SMX because of the advantages it provides over other agents. PMID- 28833986 TI - Science and the Great Challenges for Society. AB - "... What is the purpose of science? Science is not only a method to solve problems but to identify them, thus regarding it as a servant of our civilization is to only half understand its potential. Science is far more one of the pillars of our civilization as it represents the institutionalization of the willingness to learn ..." Find out more in the Editorial by Jurgen Kaube. PMID- 28833987 TI - Factors influencing behavioral intention to undergo Papanicolaou testing in early adulthood: Comparison of Japanese and Korean women. AB - In this study, we identified the factors influencing behavioral intention to undergo Papanicolaou testing among Japanese and Korean women in early adulthood. Their behavioral intentions were compared in this cross-sectional descriptive study. In total, 887 women (Japanese = 498, Korean = 389) aged 20-39 years participated in this study. Using a self-report questionnaire, knowledge, attitudes, subjective norm, perceived behavioral control, and behavioral intention were surveyed. There were significant differences between Japanese and Korean women's scores on all main variables. For Japanese women, all the variables moderately correlated with behavioral intention. In comparison, for Korean women, all independent variables, except for knowledge, moderately correlated with behavioral intention. Through a multiple regression analysis, age, undergoing Papanicolaou testing, attitudes, subjective norm, and perceived behavioral control were identified as significant predictors of behavioral intention among Japanese women. Among Korean women, job status, undergoing a Papanicolaou test, attitudes, subjective norm, and perceived behavioral control were demonstrated as significant predictors of behavioral intention. Health professionals should consider these factors to encourage Papanicolaou testing in women in early adulthood. PMID- 28833988 TI - Beyond weakness: Characterization of pain, sensory profile and conditioned pain modulation in patients with motor neuron disease: A controlled study. AB - BACKGROUND: Motor neuron diseases (MND) represent a group of disorders that evolve with inexorable muscle weakness and medical management is based on symptom control. However, deeper characterization of non-motor symptoms in these patients have been rarely reported. METHODS: This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on pain and sensory changes. Eighty patients (31 females, 55.7 +/- 12.9 years old) with MND underwent a neurological examination, pain, mood, catastrophizing and psychophysics assessments [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], and were compared to sex- and age matched healthy controls (HC). RESULTS: Chronic pain was present in 46% of patients (VAS =5.18 +/- 2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p < 0.002), and significantly lower CPM scores (4.9 +/- 0.2% vs. 22.1 +/- 0.2%, p = 0.012). QST/CPM results did not differ between MND patients with and without pain. Pain intensity was statistically correlated with anxiety, depression and catastrophism, and spasticity scores were inversely correlated with CPM (rho = -0.30, p = 0.026). CONCLUSIONS: Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate the most appropriate treatment strategies for these patients. SIGNIFICANCE: We report a comprehensive evaluation of pain and sensory abnormalities in motor neuron disease (MND) patients. We assessed the different pain syndromes present in MND with validated tools, and described the QST and conditioned pain modulation profiles in a controlled design. PMID- 28833989 TI - Synergistic immunosuppression and unintended consequences. PMID- 28833990 TI - High-Fidelity Multistate Switching with Anion-Anion and Acid-Anion Dimers of Organophosphates in Cyanostar Complexes. AB - The acid-base switching of complexes formed from anti-electrostatic anion-anion homodimers of organophosphates and cyanostar macrocycles was investigated for the first time. High-fidelity 2:2 complexes were selected by using suitably sized organo substituents. Reversible and direct switching occurs with triflic acid and hydroxide base. An unexpected acid???anion heterodimer was discovered with weaker picric acid, which helped reveal some of the elementary steps. Switching can also proceed in a cooperative (strong anion then weak acid) or stepwise manner (weak acid then strong anion). PMID- 28833991 TI - Investigation of acetylcholinesterase and mammalian DNA topoisomerases, carbonic anhydrase inhibition profiles, and cytotoxic activity of novel bis(alpha aminoalkyl)phosphinic acid derivatives against human breast cancer. AB - The aim of this study was to evaluate biologically active novel molecules having potentials to be drugs by their antitumor properties and by activities of apoptotic caspase and topoisomerase. Following syntheses of novel eight bis(alpha aminoalkyl)phosphinic acid derivatives (4a-h) as a result of array of reactions, compounds were evaluated by cytotoxic effects in vitro on human breast cancer (MCF-7) and normal endothelial (HUVEC) cell lines. All phosphinic acid derivatives were effective for cytotoxicity on both MCF-7 and HUVEC lines, while 4c, 4e, and 4f compounds were found significantly more effective. For the evaluation of antitumor properties of compounds in a highly sensitive method, their effects on inhibiting topoisomerases I and II were investigated. Also, some of the bis(alpha-aminoalkyl)phosphinic acid derivatives (4a, 4e-h) showed nice inhibitory action against acetylcholinesterase and human carbonic anhydrase isoforms I and II. PMID- 28833992 TI - Successful venoarterial extracorporeal membrane oxygenation for prolonged hepatopulmonary syndrome following pediatric liver transplantation: A case report and review of the literature. AB - HPS is a major complicating feature of end-stage liver disease. Diagnosis is clinical, and LT is the only definitive treatment. While the general impression is that HPS improves quickly after transplantation, it may not always be the case. We describe the smallest reported child with HPS prior to LT and requiring prolonged venoarterial extracorporeal membrane oxygenation after LT; especially as it is a rare occurrence, physician managing such cases should be aware of the circumstances under which HPS may require specific treatment. PMID- 28833993 TI - High-fidelity simulation in training dental students for medical life-threatening emergency. AB - INTRODUCTION: Any dental surgeon may be faced with a critical life-threatening emergency situation. In our university, all students in dentistry receive a standard course on emergency first aid. The aim of this prospective, comparative, single-centre study was to determine whether additional training on a high fidelity patient simulator would improve student performance. METHODS: After approval by an Ethical Committee and written informed consent, the students of the Simulation group (n=42) had full-scale high-fidelity training on a patient simulator SimMan 3GTM (3 hours by six students). They participated in pairs in two scenarios (airway obstruction, seizures, allergies, vasovagal syncope, asthma, chest pain). The first scenario was simple, and the second was a progression to cardiac arrest. Three months later, the Simulation group and the Control group (n=42) participated in a test session with two scenarios. The primary end point was the score at the test session (with a standardised scoring grill, direct observation and audio-video recording). Data were median and 25% 75% percentiles. RESULTS: High-fidelity training strongly improved the score on the test obtained by the students of the Simulation group (146 [134-154]) which was much higher (P<.0001) than in the Control group (77 [67-85]). Technical as well as non-technical skills components of the scores were improved. In addition, performances of the Simulation group were increased between the training and the test. Simulation session was very positively assessed by the students. CONCLUSIONS: The results support the systematic introduction of training to critical life-threatening emergency situations on high-fidelity patient simulators the dentistry curriculum. The impact on clinical practice in the dental office remains to be assessed. PMID- 28833994 TI - Cognitive reserve and bipolar disorder. PMID- 28833995 TI - Defining disorders with permeable borders: you say bipolar, I say borderline! PMID- 28833996 TI - The CLOSER trial: a multi-center study on the clinical safety and effectiveness of CloserTM VSS, a novel resorbable transfemoral vascular access sealing system. AB - OBJECTIVES: To evaluate the safety and effectiveness of the Closer Vascular Sealing System (VSS) against prespecified performance goals (PGs) in sealing femoral arterial access following 5-7 Fr procedures. BACKGROUND: Inconsistent safety profiles, costs and learning curves of earlier generation vascular closure devices have limited their widespread use following transfemoral procedures. METHODS: In this prospective single-arm, multi-center trial, we compared the clinical outcomes in patients undergoing 5-7 Fr transfemoral diagnostic or interventional procedures and access sites managed with Closer VSS against pre specified PGs. The primary endpoints were time to hemostasis (TTH) and 30-day access site closure-related major complications; secondary endpoints included time to ambulation (TTA), time to discharge eligibility (TTDE), time to discharge (TTD), 30-day access site minor complications, procedure and device success. RESULTS: A total of 220 subjects (49.5% interventional) were enrolled. The mean TTH was 1.78 +/- 7.81 min in the intention to treat and 0.98 +/- 3.71 min in the per protocol cohort. Median TTH was 0 min with immediate hemostasis achieved in 80.5% of subjects, mean TTA was 2.50 +/- 1.05 hr, and mean TTDE was 2.83 +/- 1.54 hr. Thirty-day follow-up was completed on 219 subjects. There were no access site closure-related major complications, minor complication rate was 0.0% for diagnostic and 2.75% for interventional procedures. CONCLUSIONS: In patients undergoing 5-7 Fr transfemoral diagnostic and interventional procedures, the CLOSER Trial met both its primary effectiveness and safety PGs. Immediate hemostasis was achieved in the majority of patients without major complication. PMID- 28833997 TI - Role of surface electrocardiogram precordial leads in localizing different anatomic sites of ectopic atrial tachycardia arising from lower right atrium in pediatric population. AB - BACKGROUND: The study was designed to examine P wave morphology (PWM) in precordial leads (V1 -V6 ) during ectopic atrial tachycardia (EAT) originating from low right atrium (RA) to identify the anatomic sites of these foci in children. METHODS: Twenty-three consecutive pediatric patients (56% females, mean age 8.5 +/- 2.5) with EAT originating from the low RA underwent detailed atrial endocardial activation mapping and radiofrequency ablation. PWM during EAT was analyzed using standard 12-lead ECG in relation to successful ablation sites in RA. RESULTS: Ectopic atrial tachycardia originated from coronary sinus ostium (CSo) in 12 patients, nonseptal tricuspid annulus (TA) in five, lower crista terminalis (CT) in three and lower free wall in three. In lead V1 , PWM showed a positive pattern during EAT originating from CSo (8/12) [91.7% sensitivity, 100% specificity, 100% positive predictive value (PPV), 100% negative predictive value (NPV)]. A negative pattern was observed in EAT originating from lower free wall (1/3) and nonseptal TA (5/5) [50% sensitivity, 100% specificity, 100% PPV, 75% NPV], while isoelectric pattern was in EAT originating from lower CT (3/3) [100% sensitivity, 100% specificity, 100% PPV, 100% NPV]. In leads V3 -V6 , PWM showed a negative pattern in at least two consecutive leads during EAT from CSo (12/12), nonseptal TA (5/5) and lower free wall (3/3) while it was positive in EAT originating from lower CT (3/3) [100% sensitivity, 95% specificity, 75% PPV and 100% NPV]. CONCLUSIONS: P wave morphology in precordial leads can help differentiate the anatomic sites of EAT from lower RA with high PPVs and NPVs. PMID- 28833998 TI - Association of sickle cell haemoglobinopathies with dental and jaw bone abnormalities. AB - OBJECTIVE: To estimate the association between sickle cell anaemia and trait with dental and jaw bone abnormalities. SUBJECTS AND METHODS: Subjects (n = 369) were allocated to three groups: sickle cell anaemia, trait and control. Dental shape, number, size and position and changes in pulp chamber, root and periapex were analysed by intra-oral periapical radiographs. Integrity of lamina dura, quality of cancellous bone and bone trabeculation were also evaluated. Prevalence ratios (PR) were calculated (alpha = 0.05). RESULTS: Sickle cell anaemia had higher prevalence (PR:8.31) and number of teeth (PR:13.40) with external resorption; higher number of teeth with pulp calcification; partial and total loss of lamina dura; and higher prevalence of changes in trabecular structure of maxilla (PR:6.45) and mandible (PR:5.34). Sickle cell trait showed higher prevalence (PR:1.26) and higher number of teeth (PR:1.98) with partial loss of lamina dura; higher number of teeth with hypercementosis, changes in shape, size, periapex, total loss of lamina dura; and higher prevalence of changes in mandibular trabecular bone (PR:1.43). CONCLUSION: Pulp calcification and external resorption of the root were the most frequent dental alterations in sickle cell anaemia group, while in trait was higher frequency of changes in shape, size, periapex and root. Jaw bone changes were most prevalent in both homozygous and heterozygous subjects. PMID- 28834000 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 36/2017. PMID- 28833999 TI - Corrigendum: Bi(IO3 )F2 : The First Metal Iodate Fluoride with a Very Strong Second Harmonic Generation Effect. PMID- 28834001 TI - Corrigendum: Spectroscopic Capture and Reactivity of a Low-Spin Cobalt(IV)-Oxo Complex Stabilized by Binding Redox-Inactive Metal Ions. PMID- 28834002 TI - Corrigendum: Strategic Utilization of Multifunctional Carbene for Direct Synthesis of Carboxylic-Phosphinic Mixed Anhydride from CO2. PMID- 28834003 TI - Breastfeeding beyond the big smoke: Who provides support for mothers in rural Western Australia? AB - INTRODUCTION: Despite strong and growing evidence for the benefits of exclusive breastfeeding to 6 months of age, few infants in developed countries reach this milestone. Although breastfeeding practice and its determinants are well described for women in metropolitan areas, there is limited evidence for rural and regional areas of Australia. This paper describes the influence of advice and support on breastfeeding duration for women in rural areas of Western Australia in the first 6 months of their infants' lives. METHODS: A cohort of 427 women and their infants were recruited from hospitals in regional Western Australia and followed up for a period of 12 months. Information about feeding methods was gathered in hospital and at a further seven follow-up contacts. RESULTS: Women who had attended antenatal classes were less likely to have ceased exclusively breastfeeding before 6 months than those who had not attended classes (aHR: 0.61, 95% CI: 0.41-0.91). No significant associations were found between provision of information alone and duration of breastfeeding. Breastfeeding advice and support in the first 6 months was most commonly sought from Child Health Nurses, General Practitioners and friends. CONCLUSIONS: Antenatal group education is effective in supporting breastfeeding duration for rural women and should be a key priority for rural health service providers. Health professionals are common sources of breastfeeding support postnatally, however creating and maintaining positive and supportive social networks for mothers might also contribute to increasing the proportion of rural infants who meet the World Health Organization guidelines for exclusive breastfeeding. PMID- 28834004 TI - Elevated serum uric acid level was a notable adverse event during combination therapy with sofosbuvir and ribavirin. AB - AIM: Combination therapy with sofosbuvir and ribavirin (SOF/RBV) has been recently available for chronic hepatitis C patients with genotype 2 (CHG2) in Japan. The domestic phase III clinical trial showed a high antiviral effect with a relatively safe adverse event (AE) profile. Our aim was to report an important AE detected during treatment. METHODS: A prospective multi-institutional study of 12-week combination therapy with SOF/RBV for CHG2 was carried out to evaluate efficacy and safety. RESULTS: The eligible subjects included 142 patients. Out of 50 assessable patients, 16% of the patients were diagnosed with hyperuricemia. The proportions of subjects with grade 1, grade 3, and grade 4 hyperuricemia were 12, 2, and 2%, respectively. Serum uric acid (UA) levels at week 1 of the therapy (W1) were numerically the highest during therapy in patients with hyperuricemia, and the ratio of W1/baseline serum UA levels was significantly higher than that of post-treatment week 4 or 8/baseline serum UA levels in assessable patients. Serum UA levels at W1 were significantly correlated with body mass index. The difference between serum UA levels at W1 and baseline serum UA levels was significantly correlated with the difference between serum creatinine levels at W1 and baseline serum creatinine levels. CONCLUSIONS: Elevated serum UA level was a notable AE associated with SOF/RBV therapy for CHG2. However, because of the small number of subjects, the exact frequency of AEs should be re-evaluated with larger cohorts. We need to remember that elevated serum UA level might develop during the therapy, especially at W1. PMID- 28834005 TI - Between Localization and Delocalization: Ru(cod)2+ Units in the Zintl Clusters [Bi9 {Ru(cod)}2 ]3- and [Tl2 Bi6 {Ru(cod)}]2. AB - Reactions of [K(crypt-222)]2 (TlBi3 )?0.5 en (1 b) with [Ru(cod)(H2 CC(Me)CH2 )2 ] (A) in 1,2-diaminoethane (en) led to the formation of two compounds with new bismuth-rich cluster anions, [K(crypt-222)]3 [Bi9 {Ru(cod)}2 ]?1.5 en (2) and [K(crypt-222)]2 [Tl2 Bi6 {Ru(cod)}]?2 tol (3), alongside the salt of a binary nido cluster, [K(crypt-222)]3 (Tl4 Bi5 )?2 en (4). The anions in 2 and 3 are two further examples of rare heterometallic clusters containing Ru atoms. As one cod ligand is retained on each Ru atom in both clusters, the anions may be viewed as intermediates on the way towards larger, ligand-free intermetalloid clusters. Quantum-chemical studies provided insight into the bonding situation in these clusters. According to these studies, the anion of 2 features both electron precise and electron-deficient parts. Electrospray ionization mass spectrometry analysis indicated that the clusters undergo stepwise fragmentation. PMID- 28834006 TI - Self- and proxy-rated needs in adults with mild to moderate intellectual disabilities: Perspective matters. AB - BACKGROUND: Adults with an intellectual disability should be supported according to their individual needs. The perception of need, however, is influenced by the values and expectations of the judging person. METHOD: Using the Camberwell Assessment of Need for Adults with Developmental and Intellectual Disabilities, self- and proxy-rated needs of n = 193 adults with mild to moderate intellectual disability were compared. RESULTS: Mean total needs and met needs, but not unmet needs, differed significantly between perspectives. As concerns the assessment of specific areas of need, indices revealed a complex and multifaceted pattern of agreement and disagreement. CONCLUSION: Different viewpoints should be considered when assessing needs among adults with intellectual disability. With respect to areas other than basic, everyday areas of need, involvement of the adult with intellectual disability is strongly recommended. The assessment of mental health problems requires the involvement of clinical professionals, assessing problem behavior broad diagnostic measures beyond a standardized instrument. PMID- 28834007 TI - Structures of the N-Terminal Domain of PqsA in Complex with Anthraniloyl- and 6 Fluoroanthraniloyl-AMP: Substrate Activation in Pseudomonas Quinolone Signal (PQS) Biosynthesis. AB - Pseudomonas aeruginosa, a prevalent pathogen in nosocomial infections and a major burden in cystic fibrosis, uses three interconnected quorum-sensing systems to coordinate virulence processes. At variance with other Gram-negative bacteria, one of these systems relies on 2-alkyl-4(1H)-quinolones (Pseudomonas quinolone signal, PQS) and might hence be an attractive target for new anti-infective agents. Here we report crystal structures of the N-terminal domain of anthranilate-CoA ligase PqsA, the first enzyme of PQS biosynthesis, in complex with anthraniloyl-AMP and with 6-fluoroanthraniloyl-AMP (6FABA-AMP) at 1.4 and 1.7 A resolution. We find that PqsA belongs to an unrecognized subfamily of anthranilate-CoA ligases that recognize the amino group of anthranilate through a water-mediated hydrogen bond. The complex with 6FABA-AMP explains why 6FABA, an inhibitor of PQS biosynthesis, is a good substrate of PqsA. Together, our data might pave a way to new pathoblockers in P. aeruginosa infections. PMID- 28834008 TI - Risk of type 2 diabetes in patients with insomnia: A population-based historical cohort study. AB - BACKGROUND: We investigated the risk of type 2 diabetes mellitus (T2DM) in patients with and without insomnia. METHODS: In this historical cohort study, we performed a secondary analysis of data from 2001 to 2010, which was obtained from Taiwan's National Health Insurance Database. We developed a Cox proportional hazard regression model to estimate the effects of insomnia on T2DM risk. Kaplan Meier survival analysis was applied to compare the differences in the cumulative incidence of T2DM between the groups with and without insomnia. RESULTS: During the follow-up period, the T2DM incidence rate of patients with insomnia was significantly higher than that of patients without insomnia (34.7 vs 24.3 per 1000 person-years). Overall, patients with insomnia had a higher risk of T2DM than did patients without insomnia (adjusted hazard ratio, 1.16; 95% confidence interval [CI], 1.10-1.19). Among patients aged younger than 40 years, those with insomnia had a higher risk of T2DM than did the comparison cohort (adjusted hazard ratio, 1.31; 95% CI, 1.14-1.55). Compared with patients without insomnia, the risk tended to increase with the duration of follow-up in patients with insomnia; when the insomnia duration was <4 years, 4 to 8 years, and >8 years, the risk of T2DM increased by 1.14, 1.38, and 1.51 times (95% CI, 1.03-1.17, 1.15 1.49, and 1.20-1.86), respectively. Patients with insomnia had a higher risk of T2DM, and this risk was particularly pronounced among the younger (<=40 years) population. CONCLUSION: Chronic insomnia could be an important risk factor for T2DM. PMID- 28834009 TI - Chemical Synthesis of the Highly Hydrophobic Antiviral Membrane-Associated Protein IFITM3 and Modified Variants. AB - Interferon-induced transmembrane protein 3 (IFITM3) is an antiviral transmembrane protein that is thought to serve as the primary factor for inhibiting the replication of a large number of viruses, including West Nile virus, Dengue virus, Ebola virus, and Zika virus. Production of this 14.5 kDa, 133-residue transmembrane protein, especially with essential posttranslational modifications, by recombinant expression is challenging. In this report, we document the chemical synthesis of IFTIM3 in multi-milligram quantities (>15 mg) and the preparation of phosphorylated and fluorescent variants. The synthesis was accomplished by using KAHA ligations, which operate under acidic aqueous/organic mixtures that excel at solubilizing even the exceptionally hydrophobic C-terminal region of IFITM3. The synthetic material is readily incorporated into model vesicles and forms the basis for using synthetic, homogenous IFITM3 and its derivatives for further studying its structure and biological mode of action. PMID- 28834010 TI - Cryo-EM Structures of Class B GPCR Reveal the Activation Mechanism. AB - Caught in the act: Two-domain G-protein-coupled receptors of the class B family mediate peptide hormone signaling and play a pivotal role in diseases such as diabetes and obesity. Drug discovery for these GPCRs has been difficult, especially when agonists are needed. Now, the first structures of full-length active class B GPCRs have been solved, which illuminates the activation mechanism and could accelerate structure-based drug discovery for class B GPCRs. PMID- 28834011 TI - Protective efficacy of a hydroxy fatty acid against gastric Helicobacter infections. AB - BACKGROUND: We have previously revealed that omega-3 polyunsaturated fatty acids can prevent Helicobacter pylori infection by blocking the futalosine pathway, an alternative route for menaquinone (MK) biosynthesis. MATERIALS AND METHODS: 1, Different H. pylori strains were grown in liquid media supplemented with linoleic acid, an omega-6 fatty acid, or its 10-hydroxy derivative, 10-hydroxy-cis-12 octadecenoic acid (HYA), in the presence or absence of MK. The bacterial numbers in the media were estimated by plating; 2, C57BL/6NCrl mice received drinking water supplemented with different fatty acids starting from 1 week before infection with H. pylori or Helicobacter suis until the end of the experiment. The gastric colonization levels of H. pylori or H. suis were determined 2 weeks after infection by plating or quantitative PCR, respectively; 3, Mice were given HYA, starting 1 week before infection with H. suis and continuing until 6 months after infection, for analysis of the gastric conditions. RESULTS: 1, A low concentration (20 MUmol/L) of HYA in culture broth suppressed the growth of H. pylori, and this inhibition was reduced by MK supplementation; 2, HYA treatment protected mice against H. pylori or H. suis infection; 3, HYA treatment suppressed the formation of lymphoid follicles in the gastric mucus layer after H. suis infection. CONCLUSIONS: HYA prevents gastric Helicobacter infections by blocking their futalosine pathways. Daily HYA supplementation is effective for the prevention of gastric mucosa-associated lymphoid tissue lymphoma induced by persistent infection with H. suis. PMID- 28834012 TI - Synthetic Organic Electrochemistry: Calling All Engineers. AB - Unmet potential: Electrochemistry is the most simple and basic way of altering the redox-states of organic molecules. Despite extensive studies and its demonstrated promise, it has yet to take off in mainstream synthesis. The reason is due to engineering challenges in instrument design. PMID- 28834014 TI - Asymmetries in reciprocal baroreflex mechanisms and chronic pain severity: Focusing on irritable bowel syndrome. AB - BACKGROUND: Objective measures of pain severity remain ill defined, although its accurate measurement is critical. Reciprocal baroreflex mechanisms of blood pressure (BP) control were found to impact differently on pain regulation, and thus their asymmetry was hypothesized to also connect to chronic pain duration and severity. METHODS: Seventy-eight female patients with irritable bowel syndrome (IBS) and 27 healthy women were assessed for IBS severity and chronicity, negative affect, and various measures of resting autonomic function including BP, heart rate and its variability (HRV), baroreceptor-sensitivity to activations and inhibitions, gains of brady- and tachy-cardiac baro-responses, gains of BP falls/rises, and BP start points for these spontaneous baroreflexes. KEY RESULTS: IBS directly and indirectly (through increased negative affect) was associated with asymmetry between baroreceptor activations/inhibitions compared to symmetrical baroreflex reciprocity in the healthy women. In the IBS group, independently of specific IBS symptoms, pain chronicity was associated with (i) decreased BP falls coupled with either (a) decreased tachycardia associated with lower disease severity (earlier "pain resilience" mechanism), or (b) decreased bradycardia associated with higher disease severity (later "pain decompensation" mechanism), or (ii) increased BP start point for baroreceptor activations coupled with either (a) BP increase (delayed "pain adaptation" mechanism) or (b) affect related HRV decrease (delayed "pain aggravation" mechanism). CONCLUSION AND INFERENCES: We anticipate the findings to be a starting point for validating these autonomic metrics of pain suffering and pain coping mechanisms in other chronic pain syndromes to suggest them as biomarkers of its severity and duration for profiling and correct management of chronic pain patients. PMID- 28834013 TI - Management of metastatic prostate cancer in the elderly: identifying fitness for chemotherapy in the post-STAMPEDE world. PMID- 28834015 TI - Healthy lifestyle behaviours for people with intellectual disabilities: An exploration of organizational barriers and enablers. AB - BACKGROUND: The health-related behaviours of people with intellectual disabilities may be determined by organisational influences. This innovative study aimed to explore managers' and staffs' perspectives on organisational influences on the promotion of healthy behaviours for this population. METHOD: A qualitative methodology was employed. Four focus groups with staff and eleven telephone interviews with managers were undertaken across three residential services in one region (Northern Ireland) of the UK. Transcripts were analysed thematically. FINDINGS: The organisations involved in this study did not have the cultural ethos or capacity to sustain consistent support for staff involvement in health promotion. Organisational support and outcome-focused strategies are recommended for encouraging staff involvement in health promotion activities. CONCLUSION: These findings have implications for some organisations that support people with intellectual disabilities in improving the way they facilitate health promotion. They highlight the need for organisational cultures to facilitate knowledge translation and embrace evidence-based health promotion interventions. PMID- 28834016 TI - An Experimental Radical Electrophilicity Index. AB - We present an experimental electrophilicity index (?) for the classification of radicals. The ?-scale is based on the equilibrium constant determined for the reversible addition of a radical R. to an aromatic radicophile (HisNH2 ). This experimental approach is in excellent agreement with the computed global electrophilicity index omega and serves to validate the latter. PMID- 28834017 TI - Covalent Lipid Pocket Ligands Targeting p38alpha MAPK Mutants. AB - A chemical genetic approach is presented to covalently target a unique lipid binding pocket in the protein kinase p38alpha, whose function is not yet known. Based on a series of cocrystal structures, a library of 2-arylquinazolines that were decorated with electrophiles were designed and synthesized to covalently target tailored p38alpha mutants containing artificially introduced cysteine residues. Matching protein-ligand pairs were identified by MS analysis and further validated by MS/MS studies and protein crystallography. The covalent ligands that emerged from this approach showed excellent selectivity towards a single p38alpha mutant and will be applicable as suitable probes in future studies of biological systems to dissect the function of the lipid pocket by means of pharmacological perturbations. PMID- 28834019 TI - Universal Janus Filters for the Rapid Separation of Oil from Emulsions Stabilized by Ionic or Nonionic Surfactants. AB - Existing Janus filters cannot separate oil from emulsions stabilized by nonionic surfactants. Reported herein are universal Janus filters that separate oil from emulsions stabilized by not only ionic but also nonionic surfactants. To prepare such a filter, poly(dimethyl siloxane) (PDMS) is grafted onto one side of a fabric. The other side is then grafted with a copolymer polysoap bearing pendant oligo(ethylene glycol) monolaurate (EL) chains. Upon contact with an emulsion, the grafted polysoap competes with free surfactants, ionic or nonionic, for adsorption onto the emulsified droplets, drawing them to the surfaces of the fabric fibers, and causes them to coalesce locally. The coalesced oil then migrates to the PDMS-coated side of the fabric and selectively permeates it. These novel filters possess enhanced versatility and showcase a new application for polysoaps. PMID- 28834018 TI - GBA mutations in Parkinson disease: earlier death but similar neuropathological features. AB - BACKGROUND AND PURPOSE: Mutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. METHODS: Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared. RESULTS: Twelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81 years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi-quantitative scores for Lewy type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores. CONCLUSIONS: In longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded. PMID- 28834020 TI - Relationships between corpus callosum and language lateralization in patients with schizophrenia and bipolar disorders. AB - OBJECTIVES: The question of whether there is a continuum or a dichotomy among patients with schizophrenia (SZ) and bipolar disorders (BD) has not been clearly resolved and remains a challenge. Thus, the identification of specific biomarkers of these disorders might be helpful. The present study investigated the volume of the corpus callosum (CC) and functional lateralization for language as potential biomarkers and their relationships in SZ and BD. METHODS: The study included 20 patients with SZ, 20 patients with BD and 40 healthy controls (HC). A functional lateralization index (FLI) was computed for each participant within the language comprehension network. For each participant, the volume of the total CC and those of three subregions were extracted. These variables and their anatomo-functional relationships were investigated. RESULTS: In comparison to HC, SZ patients presented a decreased leftward lateralization for language, whereas this was not found in BD patients. However, as compared to SZ patients and HC, BD patients showed a reduction in CC volume associated with a lower leftward lateralization for language. CONCLUSIONS: Our study revealed that SZ patients displayed a reduction of the leftward functional lateralization for language; however, no reduction of CC volume was observed, whereas BD patients presented a decreased volume of the CC associated with a lower leftward asymmetry for language. The results of our study detected distinct anomalies in both SZ and BD that may be considered as specific biomarkers of these disorders related to neurodevelopmental models. PMID- 28834021 TI - Multi-isocentric 4pi volumetric-modulated arc therapy approach for head and neck cancer. AB - OBJECTIVES: To explore the feasibility of multi-isocentric 4pi volumetric modulated arc therapy (MI4pi-VMAT) for the complex targets of head and neck cancers. METHODS: Twenty-five previously treated patients of HNC underwent re planning to improve the dose distributions with either coplanar VMAT technique (CP-VMAT) or noncoplanar MI4pi-VMAT plans. The latter, involving 3-6 noncoplanar arcs and 2-3 isocenters were re-optimized using the same priorities and objectives. Dosimetric comparison on standard metrics from dose-volume histograms was performed to appraise relative merits of the two techniques. Pretreatment quality assurance was performed with IMRT phantoms to assess deliverability and accuracy of the MI4pi-VMAT plans. The gamma agreement index (GAI) analysis with criteria of 3 mm distance to agreement (DTA) and 3% dose difference (DD) was applied. RESULTS: CP-VMAT and MI4pi-VMAT plans achieved the same degree of coverage for all target volumes related to near-to-minimum and near-to-maximum doses. MI4pi-VMUAlphaTau plans resulted in an improved sparing of organs at risk. The average mean dose reduction to the parotids, larynx, oral cavity, and pharyngeal muscles were 3 Gy, 4 Gy, 5 Gy, and 4.3 Gy, respectively. The average maximum dose reduction to the brain stem, spinal cord, and oral cavity was 6.0 Gy, 3.8 Gy, and 2.4 Gy. Pretreatment QA results showed that plans can be reliably delivered with mean gamma agreement index of 97.0 +/- 1.1%. CONCLUSIONS: MI4pi VMAT plans allowed to decrease the dose-volume-metrics for relevant OAR and results are reliable from a dosimetric standpoint. Early clinical experience has begun and future studies will report treatment outcome. PMID- 28834022 TI - Protonation of Ferrocene: A Low-Temperature X-ray Diffraction Study of [Cp2 FeH](PF6 ) Reveals an Iron-Bound Hydrido Ligand. AB - Ferrocene, Cp2 Fe, is quantitatively protonated in a mixture of liquid HF/PF5 to yield [Cp2 FeH](PF6 ), which was characterized by 1 H/13 C NMR and 57 Fe Mossbauer spectroscopy as well as single-crystal X-ray diffraction analysis. X ray diffraction analysis at 100 K revealed a disordered, iron-coordinated hydrido ligand, which was unambiguously located by aspherical atom refinement at 100 K, and by analyzing the non-disordered crystal structure at 30 K, revealing a non agostic structure. PMID- 28834023 TI - Crisaborole: A new and effective nonsteroidal topical drug for atopic dermatitis. PMID- 28834024 TI - Nonmedical versus medical marijuana use among three age groups of adults: Associations with mental and physical health status. AB - BACKGROUND AND OBJECTIVE: Given that 29 U.S. states now have laws allowing medical marijuana use, this study examined mental and physical health correlates of medical versus nonmedical marijuana use among three age groups of adults (18 29, 30-49, and 50+). METHODS: Data came from the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions (N = 36,309 respondents aged 18+). Logistic regression models were used to examine age group differences in associations of substance use and mental disorders and health conditions with medical versus nonmedical marijuana use. RESULTS: Of all respondents, 9.74% (N = 3,784) reported past-year marijuana use. Of all past-year marijuana users, 11.03% (n = 445) reported medical use. Medical marijuana use rates were higher among the 50-64 age group (17.95%) than younger adults, and 32.88% of medical users, compared to 25.25% of nonmedical users, had past-year marijuana use disorder. The odds of medical marijuana use were higher among those with marijuana use disorder (OR = 1.87, 95% CI = 1.40-2.50) and personality disorder (OR = 1.42, 95% CI = 1.03-1.94), with no age group differences. However, older adults with alcohol use disorder and sleep problems and middle-age adults with arthritis had diminished odds of having used medical marijuana relative to young adults. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Given the high rates of marijuana use disorder among medical users, physicians should exercise caution in recommending marijuana for medical purposes, especially for younger adults. More research is needed on medical marijuana's safety and efficacy for patients at risk of marijuana use disorder. (Am J Addict 2017;26:697-706). PMID- 28834026 TI - BACCN clinically commissioned papers. PMID- 28834025 TI - CaO-Based CO2 Sorbents Effectively Stabilized by Metal Oxides. AB - Calcium looping (i.e., CO2 capture by CaO) is a promising second-generation CO2 capture technology. CaO, derived from naturally occurring limestone, offers an inexpensive solution, but due to the harsh operating conditions of the process, limestone-derived sorbents undergo a rapid capacity decay induced by the sintering of CaCO3 . Here, we report a Pechini method to synthesize cyclically stable, CaO-based CO2 sorbents with a high CO2 uptake capacity. The sorbents synthesized feature compositional homogeneity in combination with a nanostructured and highly porous morphology. The presence of a single (Al2 O3 or Y2 O3 ) or bimetal oxide (Al2 O3 -Y2 O3 ) provides cyclic stability, except for MgO which undergoes a significant increase in its particle size with the cycle number. We also demonstrate a direct relationship between the CO2 uptake and the morphology of the synthesized sorbents. After 30 cycles of calcination and carbonation, the best performing sorbent, containing an equimolar mixture of Al2 O3 and Y2 O3 , exhibits a CO2 uptake capacity of 8.7 mmol CO2 g-1 sorbent, which is approximately 360 % higher than that of the reference limestone. PMID- 28834027 TI - Regional news and events. PMID- 28834028 TI - What's in this Issue. PMID- 28834029 TI - 32nd Annual BACCN Conference. PMID- 28834030 TI - The migrant crisis and the importance of developing cultural competence in the intensive care unit. PMID- 28834031 TI - UVA-1 in the treatment of alopecia areata. PMID- 28834032 TI - BK polyomavirus infection after renal transplantation: Surveillance in a resource challenged setting. AB - BACKGROUND: There is a paucity of data available about BK polyomavirus (BKPyV) infection after renal transplantation (RTX) in resource-limited countries with a predominantly living-donor, ABO-compatible RTX program. We aimed to assess BKPyV infection in such patients in a public hospital in India. METHODS: We prospectively evaluated plasma BKPyV replication in 62 patients at 1, 3, 6, 9, and 12 months after RTX. Sustained significant BK viremia (SSBKV) was defined as significant viremia (>=10 000 copies/mL) detected >=2 times, and BKPyV-associated nephropathy (BKVAN) as histologic changes of BKVAN with BK viremia with/without graft dysfunction. RESULTS: All patients underwent RTX without requiring desensitization. Incidence of BK viremia was: 17.7%, 41.9%, 16.1%, 25.8%, and 17.7% at 1, 3, 6, 9, and 12 months, respectively. Of 62 patients, 64.5% had BKPyV viremia during the study, 32.2% had significant viremia, all except one detected in the first 6 months. Nine (14.5%) patients had SSBKV. There was no biopsy proven BKVAN. At the end of 1 year, mean serum creatinine was higher and graft dysfunction was significantly more common in patients with SSBKV compared to those without SSBKV. CONCLUSION: Transient BK viremia is common in low/intermediate immunologic risk RTX recipients in India, with a peak occurring at 3-6 months. Most clear their viremia by 12 months. Graft dysfunction seems to be more frequent in patients with SSBKV, although BKVAN is uncommon on biopsy in these patients. PMID- 28834033 TI - Mechanisms of subzero growth in the cryophile Planococcus halocryophilus determined through proteomic analysis. AB - The eurypsychrophilic bacterium Planococcus halocryophilus is capable of growth down to -15 degrees C, making it ideal for studying adaptations to subzero growth. To increase our understanding of the mechanisms and pathways important for subzero growth, we performed proteomics on P. halocryophilus grown at 23 degrees C, 23 degrees C with 12% w/v NaCl and -10 degrees C with 12% w/v NaCl. Many proteins with increased abundances at -10 degrees C versus 23 degrees C also increased at 23C-salt versus 23 degrees C, indicating a closely tied relationship between salt and cold stress adaptation. Processes which displayed the largest changes in protein abundance were peptidoglycan and fatty acid (FA) synthesis, translation processes, methylglyoxal metabolism, DNA repair and recombination, and protein and nucleotide turnover. We identified intriguing targets for further research at -10 degrees C, including PlsX and KASII (FA metabolism), DD transpeptidase and MurB (peptidoglycan synthesis), glyoxalase family proteins (reactive electrophile response) and ribosome modifying enzymes (translation turnover). PemK/MazF may have a crucial role in translational reprogramming under cold conditions. At -10 degrees C P. halocryophilus induces stress responses, uses resources efficiently, and carefully controls its growth and metabolism to maximize subzero survival. The present study identifies several mechanisms involved in subzero growth and enhances our understanding of cold adaptation. PMID- 28834034 TI - Sensitive Photoacoustic IR Spectroscopy for the Characterization of Amino/Azido Mixed-Linker Metal-Organic Frameworks. AB - Photoacoustic Fourier-transform infrared spectroscopy makes it possible to determine the organic composition of mixed-linker metal-organic frameworks. The sound produced upon IR irradiation enables the discrimination of azido and amino linkers in three different MOF platforms with a sensitivity that is two orders of magnitude higher than that achieved using classic IR analysis. PMID- 28834035 TI - Ethical violations and discriminatory behavior in the MedPhys Match. AB - PURPOSE: The purpose of this survey study is to investigate behaviors in conflict with the ethical standards of the Medical Physics Residency (MedPhys) Match (MPM) process as stated in the MPM rules (a) and with the nondiscrimination regulations of the Equal Employment Opportunity Commission (EEOC) (b), in addition to other behaviors that may in other ways erode the fairness of the system. METHODS: A survey was sent to all applicants and program directors registered for the 2015 and 2016 MPM. Survey questions asked about application, interview, and postinterview experiences, match results, and overall satisfaction with the process. RESULTS: Thirteen percent of 2015 respondents and 20% of 2016 respondents were asked by at least one program how highly they planned to rank them or which program they would rank first. Thirty-seven percent of 2015 and 40% of 2016 program directors indicated that candidates communicated to the program their rank intent, with 22.0% in 2015 and 12.5% in 2016 being told that their program would be ranked first. Twenty-three percent of 2015 respondents indicated being asked by at least one program during the interview about children or plans to have children; including 19% of males and 33% of females. In 2016, these values were 28% overall, 22% male, and 36% female. Fifty-seven percent of 2015 respondents who were asked this question indicated being uncomfortable or very uncomfortable answering, including 27.3% of males and 88.9% of females. In 2016, 42.9% of all respondents indicated being uncomfortable or very uncomfortable answering, including 10.0% of males and 80.0% of females. CONCLUSIONS: In the first two years of the MPM, there were widespread instances of ethical violations and discriminatory questioning during the interview process. Educating both interviewers and candidates on the MPM rules and general EEOC guidelines should decrease these instances and increase the fairness of the residency selection process. PMID- 28834036 TI - Molecular Design of Bisphosphonates To Adjust Their Reactivity toward Metal Sources for the Surfactant-Assisted Synthesis of Mesoporous Films. AB - The precise control of primary reactions in solutions is one of the most significant steps for the nanoscale design of inorganic solids in multidisciplinary fields. However, further growth of the inorganic species to give bulkier species disturbs such designs. The surfactant-assisted synthesis of mesoporous materials is a good strategy for addressing such concerns because pores formed by supramolecularly mediated processes are surrounded by nanometer sized continuous frameworks. Many experiments are generally conducted to optimize the reaction conditions for the synthesis of highly ordered mesostructures. Herein, to minimize such trial-and-error efforts, a new and practical concept is proposed for the precise design of porous materials. By adjusting the reactivity between bisphosphonates and metal sources through molecular design of the starting bisphosphonate compound, it was possible to synthesize mesoporous films with unique compositions by a surfactant-assisted approach. PMID- 28834037 TI - Ligand-Controlled Regiodivergent and Enantioselective Copper-Catalyzed Hydroallylation of Alkynes. AB - A ligand-controlled regiodivergent and enantioselective copper-catalyzed intermolecular hydroallylation of alkynes with allylic phosphates and hydrosilanes has been achieved for the first time. The chiral bidentate sulfonate containing N-heterocyclic carbene ligated CuCl complex leads to enantioenriched SN 2'-type products, whereas the use of the IMesCuCl catalyst affords SN 2-type products. Thus a range of chiral branched and achiral linear 1,4-dienes could be facilely synthesized from readily available alkynes in a regiodivergent manner. PMID- 28834038 TI - Homo- and Heteroleptic Phototoxic Dinuclear Metallo-Intercalators Based on RuII (dppn) Intercalating Moieties: Synthesis, Optical, and Biological Studies. AB - Using a new mononuclear "building block," for the first time, a dinuclear RuII (dppn) complex and a heteroleptic system containing both RuII (dppz) and RuII (dppn) moieties are reported. The complexes, including the mixed dppz/dppn system, are 1 O2 sensitizers. However, unlike the homoleptic dppn systems, the mixed dppz/dppn complex also displays a luminescence "switch on" DNA light-switch effect. In both cisplatin sensitive and resistant human ovarian carcinoma lines the dinuclear complexes show enhanced uptake compared to their mononuclear analogue. Thanks to a favorable combination of singlet oxygen generation and cellular uptake properties all three of the new complexes are phototoxic and display potent activity against chemotherapeutically resistant cells. PMID- 28834039 TI - Molecular Catalysts for N2 Reduction: State of the Art, Mechanism, and Challenges. AB - Fixation of atmospheric nitrogen is central for the production of ammonia, which is the source of nitrogen fertilizers and is also emerging as a promising renewable fuel. While the development of efficient molecular-based artificial nitrogen fixation systems working under mild conditions is probably a Holy Grail, the catalytic reduction of N2 by transition-metal complexes is-above all-the main instrument to progress in the mechanistic understanding of N2 splitting. In this Minireview we first give an overview of molecular-based catalytic systems, including recent breakthroughs, and then we illustrate the alternative pathways for N2 reduction. We mainly focus on multistep hydrogenation of N2 by separated proton and electron sources, with a particular attention for the possibility of proton-coupled electron transfer events. Finally, we try to identify the key factors to achieve catalytic reduction of dinitrogen by metal complexes and to enhance their efficiency. PMID- 28834040 TI - Reliable and simple spectrophotometric determination of sun protection factor: A case study using organic UV filter-based sunscreen products. AB - BACKGROUND: Current in vitro SPF screening method for plant oil body (oleosome) based SPF products possesses significant inconsistency and low reliability in the SPF rating. OBJECTIVES: The primary objective of this study was to evaluate the reliability and reproducibility of spectrophotometrically determined sun protection factor (SPF) from oleosome-based SPF products. The secondary objective was the data comparison of the spectrophotometric measurements against in vivo SPF testing to establish a reliable in vitro test method as a screening assay. METHODS: Octyl methoxycinnamate (UVB filter) and avobenzone (UVA filter) were loaded into safflower oil bodies and formulated into oil-in-water emulsion-based finished products. To evaluate the reliability between in vivo and spectrophotometric test methods, samples were dispatched to a clinical laboratory, and the reported SPF values were compared with spectrophotometric test results. RESULTS: The observed SPF from the in vivo and spectrophotometric test results demonstrated a high correlation for SPF 30 products. Proportional correlation between the two evaluation methods was observed for SPF 15 and 50 products with slightly lesser accuracy with a smaller number of population tested in the clinical studies. CONCLUSIONS: A reliable spectrophotometric screening method for oil body-based SPF formulas has been developed using two broadly used organic UV sunscreen actives as a case study. The results demonstrated a high level of reproducibility and reliability compared to the US FDA-guided in vivo SPF testing method. PMID- 28834041 TI - Formation of Olefins by Eliminative Dimerization and Eliminative Cross-Coupling of Carbenoids: A Stereochemical Exercise. AB - Two carbenoids combine to generate an olefin by a mechanism involving formation of an ate complex, 1,2-metalate rearrangement, and beta-elimination. As each stage of this eliminative coupling is stereospecific, the overall stereochemical outcome can be understood and, in principle fully controlled, providing that the absolute stereochemical configurations of the reacting carbenoid species are defined. In contrast to traditional alkene syntheses, the eliminative cross coupling of carbenoids offers a connective approach to olefins capable of precisely targeting a given isomer regardless of the nature of the features distinguishing the isomers. The formation of olefins by the eliminative dimerization and eliminative cross-coupling of carbenoids is reviewed with a range of illustrative examples, including the reactions of alpha-lithiated haloalkanes, epoxides, and carbamates. An emphasis is placed on stereochemical analysis and methods to generate sp3 -hybridized carbenoids in stereodefined form are surveyed. PMID- 28834042 TI - Changes in serum lipid profiles caused by three regimens of interferon-free direct-acting antivirals for patients infected with hepatitis C virus. AB - AIM: Serum low-density lipoprotein cholesterol (LDL-C) increases during treatment of chronic hepatitis C (CHC) with interferon-free direct-acting antivirals (DAAs). We sought to compare the changes of serum lipid profiles caused by three regimens. METHODS: A total of 216 CHC patients were enrolled. Among 170 patients infected with hepatitis C virus (HCV) genotype 1b, 85 received daclatasvir plus asunaprevir (DCV/ASV) and 85 received sofosbuvir plus ledipasvir (SOF/LDV). Forty six infected with HCV genotype 2 received sofosbuvir plus ribavirin (SOF/RBV). Serum total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol, and triglyceride were measured at baseline and 4, 8, 12 (for all regimens), and 24 weeks (for DCV/ASV) during treatment (4w, 8w, 12w, and 24w, respectively) and 12 and 24 weeks after treatment (p12w and p24w, respectively). RESULTS: In 69 (81.2%) patients who received DCV/ASV and achieved a sustained virologic response at 24 weeks after the end of treatment (SVR24), TC and LDL-C increased significantly from baseline to p24w. In 84 (98.8%) treated with SOF/LDV who achieved SVR24, TC and LDL-C increased significantly from baseline to 8w, and TC decreased significantly from 8w to p12w. The 45 (97.8%) who received SOF/RBV and achieved SVR24 showed no significant changes. At 12w, TC and LDL-C increased to a greater degree in patients receiving SOF/LDV than in those receiving DCV/ASV or SOF/RBV. CONCLUSION: During treatment with DAAs, the serum lipid profile may reflect not only recovery from the disruption of lipid metabolism induced by HCV, but also the pharmacological effects of DAAs. Further investigations are needed to elucidate the effect of DAAs on serum lipid profiles. PMID- 28834044 TI - Urological complications following unstented pediatric renal transplantation. AB - Urological complications which develop post-renal transplantation can be associated with significant morbidity especially in children. We evaluated the occurrence and management of all urological complications in a series of unstented pediatric renal transplants in a tertiary pediatric hospital. We reviewed the medical records of children who underwent unstented renal transplant between January 1996 and December 2014. Postoperative urological complications and the outcomes of their management were analyzed. A total of 160 unstented renal transplants were performed, and 32 urological complications were noted in 29 transplants (18%). There were 20 boys and nine girls with an age range of 2.5 years to 18.4 years. Nine (31%) of these patients had LUTD. The most common complication was VUR occurring in 17 patients (10.6%). Urine leaks occurred in six patients (3.8%) and ureteric obstruction in six patients (3.8%), and three patients (1.9%) had unexplained hydronephrosis. Loss of graft occurred in three patients (1.9%), and one patient died from sepsis post-uretero-ureterostomy. Patients with LUTD had more urological complications (P = .037). Unstenting is feasible in most pediatric renal transplants. LUTD is associated with a higher incidence of urological complications, especially VUR. PMID- 28834045 TI - Does water availability regulate biomass partitioning between trunk and branches? AB - The extent to which a vertical trunk is differentiated from its branches is a key trait for the architecture of trees and may affect interspecific relationships. In this study, we analysed the effect of soil water availability on biomass partitioning for Nothofagus pumilio by means of a nursery experiment. Juvenile trees were subject to three irrigation conditions: no irrigation, intermediate irrigation and high irrigation. Irrigation conditions emulated the mean precipitation of the most representative environments inhabited by N. pumilio. Changes in soil water availability modified the biomass partitioning patterns of trees. In comparison to the other two conditions, high irrigation caused: (i) a higher ratio of biomass partitioning to stems than roots; (ii) more trunk growth in relation to its branches; and (iii) more photosynthetic organs relative to the aboveground biomass. Trunk size relative to that of its most recent branches was not increased by water availability. Water availability may play a significant role in the capacity of N. pumilio for space occupation due to the effects on axis differentiation. PMID- 28834043 TI - Importance of bicarbonate transport in pH control during amelogenesis - need for functional studies. AB - Dental enamel, the hardest mammalian tissue, is produced by ameloblasts. Ameloblasts show many similarities to other transporting epithelia although their secretory product, the enamel matrix, is quite different. Ameloblasts direct the formation of hydroxyapatite crystals, which liberate large quantities of protons that then need to be buffered to allow mineralization to proceed. Buffering requires a tight pH regulation and secretion of bicarbonate by ameloblasts. Many investigations have used immunohistochemical and knockout studies to determine the effects of these genes on enamel formation, but up till recently very little functional data were available for mineral ion transport. To address this, we developed a novel 2D in vitro model using HAT-7 ameloblast cells. HAT-7 cells can be polarized and develop functional tight junctions. Furthermore, they are able to accumulate bicarbonate ions from the basolateral to the apical fluid spaces. We propose that in the future, the HAT-7 2D system along with similar cellular models will be useful to functionally model ion transport processes during amelogenesis. Additionally, we also suggest that similar approaches will allow a better understanding of the regulation of the cycling process in maturation-stage ameloblasts, and the pH sensory mechanisms, which are required to develop sound, healthy enamel. PMID- 28834046 TI - Pollen and stigma size changes during the transition from tristyly to distyly in Oxalis alpina (Oxalidaceae). AB - Pollen and stigma size have the potential to influence male fitness of hermaphroditic plants, particularly in species presenting floral polymorphisms characterised by marked differences in these traits among floral morphs. In this study, we take advantage of the evolutionary transition from tristyly to distyly experienced by Oxalis alpina (Oxalidaceae), and examined whether modifications in the ancillary traits (pollen and stigma size) respond to allometric changes in other floral traits. Also, we tested whether these modifications are in accordance with what would be expected under the hypothesis that novel competitive scenarios (as in distylous-derived reproductive system) exert morph- and whorl-specific selective pressures to match the available stigmas. We measure pollen and stigma size in five populations of O. alpina representing the tristyly distyly transition. A general reduction in pollen and stigma size occurred along the tristyly-distyly transition, and pollen size from the two anther levels within each morph converged to a similar size that was characterised by whorl specific changes (increases or decreases) in pollen size of different anthers in each floral type. Overall, results from this study show that the evolution of distyly in this species is characterised not only by changes in sexual organ position and flower size, but also by morph-specific changes in pollen and stigma size. This evidence supports the importance of selection on pollen and stigma size, which increase fitness of remaining morphs following the evolution of distyly, and raises questions to explore on the functional value of pollen size in heterostylous systems under pollen competition. PMID- 28834047 TI - Interdisciplinary workshop on "mental disorder and self over time". PMID- 28834049 TI - Sono-RAFT Polymerization in Aqueous Medium. AB - The ultrasonic irradiation of aqueous solution is demonstrated to be a suitable source of initiating radicals for a controlled radical polymerization when conducted in the presence of a thiocarbonylthio-containing reversible addition fragmentation chain transfer (RAFT) agent. This allows for a highly "green" method of externally regulated/controlled polymerization with a potentially broad scope for polymerizable monomers and/or polymer structures. PMID- 28834048 TI - Medication contaminants as a potential cause of anaphylaxis to vincristine. AB - Vincristine (VCR) is a vinca alkaloid and common chemotherapeutic that is used to treat multiple pediatric and adult malignancies. Despite its common use, cases of anaphylaxis to VCR are rare and typically isolated to a single individual. We report a series of eight patients with adverse reactions to VCR over the course of 11 months at a single institution, four of which progressed to anaphylaxis and one of which resulted in cardiac arrest. Mass spectrometry analysis of medication lots was performed to test for possible contaminant(s). Our findings highlight the risk of anaphylaxis during therapy with VCR. PMID- 28834050 TI - Intramolecular pi-pi Interactions in Flexibly Linked Partially Fluorinated Bisarenes in the Gas Phase. AB - Three compounds with phenyl and pentafluorophenyl rings bridged by (CH2 )3 and (CH2 )2 SiMe2 units were synthesized by hydrosilylation and C-C coupling reactions. Their solid-state structures are dominated by intermolecular pi stacking interactions, primarily leading to dimeric or chain-type aggregates. Analysis of free molecules in the gas phase by electron diffraction revealed the most abundant conformer to be significantly stabilized by intramolecular pi-pi interactions. For the silicon compounds, structures characterized by sigma-pi interactions between methyl and pentafluorophenyl groups are second lowest in energy and cannot be excluded completely by the gas electron diffraction experiments. C6 H5 (CH2 )3 C6 F5 , in contrast, is present as a single conformer. The gas-phase structures served as a reference for the evaluation of a series of (dispersion-corrected) quantum-chemical calculations. PMID- 28834051 TI - Analytical Description of NMR Relaxation Highlights Correlated Dynamics in Intrinsically Disordered Proteins. AB - The dynamic fluctuations of intrinsically disordered proteins (IDPs) define their function. Although experimental nuclear magnetic resonance (NMR) relaxation reveals the motional complexity of these highly flexible proteins, the absence of physical models describing IDP dynamics hinders their mechanistic interpretation. Combining molecular dynamics simulation and NMR, we introduce a framework in which distinct motions are attributed to local libration, backbone dihedral angle dynamics and longer-range tumbling of one or more peptide planes. This model provides unique insight into segmental organization of dynamics in IDPs and allows us to investigate the presence and extent of the correlated motions that are essential for function. PMID- 28834052 TI - Incidence of Obstructive Sleep Apnea in Elderly Edentulous Patients and the Possible Correlation of Serum Serotonin and Apnea-Hypopnea Index. AB - PURPOSE: To estimate the incidence of obstructive sleep apnea (OSA) in elderly edentulous patients (aged 60-65 years) and investigate a correlation of serum serotonin levels with the apnea-hypopnea index (AHI), respiratory effort-related arousal (RERA), and respiratory disturbance index (RDI). MATERIALS AND METHODS: 381 elderly completely edentulous patients (307 male, 74 female) aged 60 to 65 years with a history of edentulism of 12 to 15 months, seeking oral rehabilitation at the prosthodontic clinic at Saraswati Dental College & Hospital, Lucknow, India, between January 2014 and January 2016 were enrolled for the present study. After application of the inclusion and exclusion criteria of this study, 183 patients (162 male, 21 female) who were found susceptible, were subjected to the BERLIN questionnaire and Epworth Sleepiness Scale (ESS) to assess sleep disordered breathing (SDB) and then put through all-night polysomnography (PSG). On the basis of AHI, RERA, and RDI scores, 156 patients (143 male, 13 female) who tested positive for OSA were classified according to its intensity. All 156 patients underwent body-mass index (BMI) estimation, cephalometry, and intraoral examination for skeletal and soft tissue profile record. Serum serotonin was estimated from whole blood samples for the 156 OSA and the 27 normal patients. The 156 (147 nonobese, 9 obese) OSA-positive patients were provided with complete dentures and were trained to use the same as a modified mandibular advancement device (MAD) during sleep at night. These patients were kept on a quarterly follow-up for 9 months. Data collected was subjected to statistical analysis, and inferences drawn. RESULTS: The incidence of OSA in elderly edentulous subjects was found to be 32.03% in males and 8.91% in females. A mere 9 out of 156 (5.76%) elderly edentulous OSA patients were found to be obese (Class I) on the basis of BMI estimation. Cephalometry of the patients showed that they had a skeletal class I maxillomandibular relationship. AHI scores of nonobese patients revealed that most of the patients had moderate OSA, followed by mild OSA and severe OSA. Serum serotonin levels ranged from 53 to 83 ng/dL. AHI score of the 9 obese patients were in the moderate to severe range, and their serum serotonin levels were 60 to 70 ng/dL. A correlation between severity of OSA and serum serotonin level was validated in this study. CONCLUSION: OSA was found to be prevalent in edentulous subjects due to pharyngeal collapse and decreased neuromuscular control. An inverse relationship of serum serotonin levels and AHI scores was established. PMID- 28834053 TI - Nickel-Catalyzed Reductive Allylation of Tertiary Alkyl Halides with Allylic Carbonates. AB - The construction of all C(sp3 ) quaternary centers has been successfully achieved under Ni-catalyzed cross-electrophile coupling of allylic carbonates with unactivated tertiary alkyl halides. For allylic carbonates bearing C1 or C3 substituents, the reaction affords excellent regioselectivity through the addition of alkyl groups to the unsubstituted allylic carbon terminus. The allylic alkylation method also exhibits excellent functional-group compatibility, and delivers the products with high E selectivity. PMID- 28834054 TI - Herpesviruses excretion in saliva of pediatric transplant recipients. AB - BACKGROUND: Saliva samples could be used for follow-up of herpesviruses infection in pediatric transplant recipients. OBJECTIVE: With the aim of determining the frequency of herpesviral infections in saliva samples after transplantation, and the association with viremia and complications, a pilot longitudinal follow-up of pediatric Cuban transplanted recipients (kidney and liver) was performed. METHODS: Quantitative real-time polymerase chain reaction of cytomegalovirus (CMV), Epstein-Barr virus, herpes simplex virus, human herpesevirus-6 (HHV6), varicella zoster virus, and human herpesvirus-8 were serially assayed in saliva and serum samples from 27 transplanted patients, during 32 weeks after the graft. Samples taken immediately after the graft were used as control samples. RESULTS: Herpesviruses were detected in 88.9% of saliva and in 37.0% of serum samples. HHV6 and CMV were the viruses more frequently detected (70.4%) in saliva and they were significantly more frequent during the follow-up in comparison with control samples (P < .05). Most patients (22/27) had more than one virus shedding concurrently. Patients with CMV in saliva were associated with CMV viremia (P = .009), particularly at the cutoff of 252.5 copies/mL, with a less accurate level of area under the curve. No association between CMV viral load in saliva and viral disease or response to the antiviral treatment was observed. CONCLUSIONS: The association found between CMV shedding in saliva and CMV viremia in this study opens the possibility of future studies of using viral load in saliva as a predictor of viremia. The implementation of herpesviral load in saliva samples for early clinical intervention in pediatric recipients needs a study with a large number of samples for further conclusions. PMID- 28834055 TI - Cost-effectiveness of sacral neuromodulation for chronic refractory constipation in children and adolescents: a Markov model analysis. AB - AIM: This study aimed to assess the cost-effectiveness of sacral neuromodulation (SNM) compared with conservative treatment in children and adolescents with constipation refractory to conservative management. METHOD: A Markov probabilistic model was used, comparing costs and effectiveness of SNM and conservative treatment in children and adolescents aged 10-18 years with constipation refractory to conservative management. Input for the model regarding transition probabilities, utilities and healthcare costs was based on data from a cohort of patients treated in our centre. This cohort consisted of 30 female patients (mean age 16 years) with functional constipation refractory to conservative management. The mean duration of laxative use in this group was 5.9 years. All patients had a test SNM, followed by a permanent SNM in 27/30. Median follow-up was 22.1 months (range 12.2-36.8). The model was run to simulate a follow-up period of 3 years. RESULTS: The mean cumulative costs for the SNM group and the conservative treatment group were ?17 789 (SD ?2492) and ?7574 (SD ?4332) per patient, respectively. The mean quality adjusted life years (QALYs) in the SNM group was 1.74 (SD 0.19), compared with 0.86 (SD 0.14) in the conservatively managed group. The mean incremental cost-effectiveness ratio was ?12 328 per QALY (SD ?4788). Sensitivity analysis showed that the outcomes were robust to a wide range of model assumptions. CONCLUSION: Chronic constipation seriously affects the quality of life of children and adolescents. Preliminary evidence suggests that SNM can improve symptoms and quality of life at a reasonable cost. PMID- 28834056 TI - Consequences of diagnosing a tumor predisposition syndrome in children with cancer: A literature review. AB - Up to 8.5% of children with cancer have a genetic cause for their cancer: a tumor predisposition syndrome (TPS). Diagnosing a TPS is of great importance, as it may have major consequences for clinical care. Patients with TPSs require specific monitoring and management. We present an overview of the cancer-related and noncancer-related consequences for the 36 most common TPSs. PMID- 28834057 TI - Comment on "Cocaine Hydrochloride Structure in Solution Revealed by Three Chiroptical Methods". PMID- 28834058 TI - Electrochemical CO2 Reduction at Glassy Carbon Electrodes Functionalized by MnI and ReI Organometallic Complexes. AB - The catalytic activities towards electrochemical CO2 reduction of two new rhenium and manganese complexes, namely fac-Mn(apbpy)(CO)3 Br (1) and fac-Re(apbpy)(CO)3 Cl (2) (apbpy=4-(4-aminophenyl)-2,2'-bipyridine), in both homogeneous and heterogeneous phases are compared. A glassy carbon electrode (GCE) surface has been functionalized with complexes 1 and 2 by two approaches: a) direct electrochemical oxidation of the amino group with formation of C-N bonds, and b) electrochemical reduction of the corresponding diazonium salts with formation of C-C bonds. The chemically modified GCEs show efficient conversion of CO2 into CO, with turnover numbers (TONs) about 60 times higher than those of the corresponding catalysts in homogeneous solutions, and in a much shorter time. PMID- 28834059 TI - Transanal total mesorectal excision: a method to facilitate dissection when there is only one team available - a video vignette. PMID- 28834061 TI - Vaginal seeding: more questions than answers. PMID- 28834060 TI - Can clinical practice learn about measuring blood pressure from our veterinary colleagues? PMID- 28834062 TI - Generalized pustular drug eruption caused by topical 5-fluorouracil. PMID- 28834063 TI - Aptamer/AuNP Biosensor for Colorimetric Profiling of Exosomal Proteins. AB - Exosomes constitute an emerging biomarker for cancer diagnosis because they carry multiple proteins that reflect the origins of parent cells. Assessing exosome surface proteins provides a powerful means of identifying a combination of biomarkers for cancer diagnosis. We report a sensor platform that profiles exosome surface proteins in minutes by the naked eye. The sensor consists of a gold nanoparticle (AuNP) complexed with a panel of aptamers. The complexation of aptamers with AuNPs protects the nanoparticles from aggregating in a high-salt solution. In the presence of exosomes, the non-specific and weaker binding between aptamers and the AuNP is broken, and the specific and stronger binding between exosome surface protein and the aptamer displaces aptamers from the AuNP surface and results in AuNP aggregation. This aggregation results in a color change and generates patterns for the identification of multiple proteins on the exosome surface. PMID- 28834064 TI - Vitamin D supplementation for vitiligo. PMID- 28834065 TI - Synthesis of [18 F]Fluoroarenes by Nucleophilic Radiofluorination of N Arylsydnones. AB - A practical method for radiofluorination of anilines with [18 F]fluoride via N arylsydnone intermediates is described. These precursors are stable, easy to handle and facilitate direct and regioselective 18 F-labeling to prepare [18 F]fluoroarenes. The value of this methodology is further highlighted by successful application to prepare an 18 F-labeled neuropeptide. PMID- 28834066 TI - Psychophysiological response to acute-high-stress combat situations in professional soldiers. AB - The study of psychophysiological responses of soldiers in combat situations remains a challenge, especially in melee combat-a close proximity unarmed fight defined by high unpredictability. Gaining knowledge about psychophysiological changes in high-stress situations is required to optimise training. This study aimed to analyse modifications in autonomic modulation, cortical arousal, heart rate, muscle strength, blood lactate concentration, and rating of perceived exertion of veteran soldiers in a melee combat simulation. Twenty veteran soldiers were analysed before and after a melee combat simulation in accordance with realistic situations that occur in actual operations areas. The simulation consisted of actions performed by a binomial unit in a security and protection mission in an operations area. The melee combat caused an increase in sympathetic modulation, blood lactate concentration, heart rate, muscle strength, a decreased tendency in cortical arousal, and a lower rating of perceived exertion than the organic response measured. An intense fight-flight response was observed in soldiers by the limbic system activation, causing a misinterpretation of perceived exertion. Finally, implications for the design of simulation environments for tactics training in high-stress professions are discussed. PMID- 28834067 TI - DMSO Chemically Alters Cell Membranes to Slow Exocytosis and Increase the Fraction of Partial Transmitter Released. AB - Dimethyl sulfoxide (DMSO) is frequently used as a solvent in biological studies and as a vehicle for drug therapy; but the side effects of DMSO, especially on the cell environment, are not well understood, and controls with DMSO are not neutral at higher concentrations. Herein, electrochemical measurement techniques are applied to show that DMSO increases exocytotic neurotransmitter release, while leaving vesicular contents unchanged. In addition, the kinetics of release from DMSO-treated cells are faster than that of untreated ones. The results suggest that DMSO has a significant influence on the chemistry of the cell membrane, leading to alteration of exocytosis. A speculative chemical mechanism of the effect on the fusion pore during exocytosis is presented. PMID- 28834068 TI - Reversible Loading of Nanoscale Elements on a Multicomponent Supramolecular Polymer System by Using DNA Strand Displacement. AB - Nucleic acids are excellent building blocks to enable switchable character in supramolecular polymer materials because of their inherent dynamic character and potential for orthogonal self-assembly. Herein, DNA-grafted squaramide bola amphiphiles are used in a multicomponent supramolecular polymer system and it is shown that they can be addressed by DNAlabeled gold nanoparticles (5 and 15 nm) through sequence complementarity. These nanoparticles can be selectively erased or rewritten on-demand by means of DNA-strand displacement. PMID- 28834069 TI - Examination of Organic Vapor Adsorption onto Alkali Metal and Halide Atomic Ions by using Ion Mobility Mass Spectrometry. AB - We utilize ion mobility mass spectrometry with an atmospheric pressure differential mobility analyzer coupled to a time-of-flight mass spectrometer (DMA MS) to examine the formation of ion-vapor molecule complexes with seed ions of K+ , Rb+ , Cs+ , Br- , and I- exposed to n-butanol and n-nonane vapor under subsaturated conditions. Ion-vapor molecule complex formation is indicated by a shift in the apparent mobility of each ion. Measurement results are compared to predicted mobility shifts based upon the Kelvin-Thomson equation, which is commonly used in predicting rates of ion-induced nucleation. We find that n butanol at saturation ratios as low as 0.03 readily binds to all seed ions, leading to mobility shifts in excess of 35 %. Conversely, the binding of n-nonane is not detectable for any ion for saturation ratios in the 0-0.27 range. An inverse correlation between the ionic radius of the initial seed and the extent of n-butanol uptake is observed, such that at elevated n-butanol concentrations, the smallest ion (K+ ) has the smallest apparent mobility and the largest (I- ) has the largest apparent mobility. Though the differences in behavior of the two vapor molecules types examined and the observed effect of ionic seed radius are not accounted for by the Kelvin-Thomson equation, its predictions are in good agreement with measured mobility shifts for Rb+ , Cs+ , and Br- in the presence of n-butanol (typically within 10 % of measurements). PMID- 28834070 TI - Patient Navigation for Patients Frequently Visiting the Emergency Department: A Randomized, Controlled Trial. AB - BACKGROUND: Emergency department (ED) superutilizers (patients with five or more visits/year) comprise only 5% of the patients seen yet comprise 25% of total ED visits. Although the reasons for this are multifactorial, the cost to the patient and the community is exceedingly high. The cost is not just monetary; care of these patients is inappropriately fragmented and their presence in the ED may contribute to overcrowding affecting the community's emergency readiness. Previous studies using staff trained to help patients navigate their care options have had conflicting results. OBJECTIVES: The objective was to determine whether a trained patient navigator (PN) can reduce ED use and costs in superutilizers over a 1-year period. METHODS: Superutilizers were enrolled in a prospective randomized controlled clinical trial. Patients were randomized into the treatment arm and met with a PN who reviewed their diagnosis and associated care plan and identified proper primary care services and community resources for follow-up. The remaining control group was provided standard care. Both groups were given a follow-up call and survey by the PN within 7 days of their visit who assessed primary care follow-up and patient satisfaction using a 4-point Likert scale. After 12 months, the patients' return ED visits and ED costs were compared to the year prior and primary care compliance and satisfaction were measured using Student's t-tests with Bonferroni correction or Mann-Whitney U-tests. RESULTS: A total of 282 patients were enrolled (148 in navigation treatment group, 134 controls). Patients were similarly matched in age, race, sex, insurance, and chief complaints. Overall ED visits decreased during the 12-month study period, compared to the 12 months prior to enrollment (2,249 visits prior to 2,050 visits during study period, -8.8%). There was a greater decrease in ED visits from the preenrollment year to postenrollment year in the treatment group (1,148 visits to 996 visits, -13.2%) compared to the control group (1,101 visits to 1,054 visits, 4.3%; p < 0.05). Overall health care costs (ED and hospital) for all 282 patients decreased in the year after compared to the 12 months prior to enrollment ($3.9M to $3.1M) with a greater decrease in the navigation treatment group (-26.6%) compared to the control group (-17.5%). Patient surveys found no difference in patient satisfaction in the pre- and postenrollment periods but there was an increase in primary care physician (PCP) use over the 12-month follow-up period in the treatment group (6.42 visits/patient) compared to the control group (4.07 visits/patient; p < 0.05). CONCLUSION: Our data showed that the overall number of return ED visits and costs did decrease for both groups, potentially inferring a placebo effect for the use of a PN; however, the decrease in ED visits and costs were greater in the treatment group. One-year follow-up noted an increase in PCP visits in the navigation group. Use of a PN may be cost-effective. PMID- 28834071 TI - Enhanced Photophosphorylation of a Chloroplast-Entrapping Long-Lived Photoacid. AB - Enhancing solar energy conversion efficiency is very important for developing renewable energy, protecting the environment, and producing agricultural products. Efficient enhancement of photophosphorylation is demonstrated by coupling artificial photoacid generators (PAGs) with chloroplasts. The encapsulation of small molecular long-lived PAGs in the thylakoid lumen is improved greatly by ultrasonication. Under visible-light irradiation, a fast intramolecular photoreaction of the PAG occurs and produces many protons, remarkably enhancing the proton gradient in situ. Consequently, compared to pure chloroplasts, the assembled natural-artificial hybrid demonstrates approximately 3.9 times greater adenosine triphosphate (ATP) production. This work will provide new opportunities for constructing enhanced solar energy conversion systems. PMID- 28834072 TI - A severely cholestatic liver graft can be successfully used in deceased donor liver transplantation. AB - The shortage of deceased organs is still a serious issue in Japan. A proactive approach to using liver grafts from extended criteria donors (ECDs) may be one way of expanding the donor pool; however, if it is recklessly attempted, a recipient receiving such a marginal graft can be at risk of mortality due to primary non-function or delayed graft function. We herein report the successful outcome of a recipient receiving a severely cholestatic graft that was considered transplantable because it lacked features characteristic of a long duration of "cholestasis" according to the precise interpretation of a donor biopsy. Plasma exchange was intentionally introduced to prevent toxic insult by hyperbilirubinemia immediately after transplant. Despite transient acute kidney injury immediately after transplant, the patient's renal impairment was well managed with a renal-sparing immunosuppressive regimen consisting of basiliximab and mycophenolate mofetil. Although the use of liver grafts from ECDs still needs to be discussed, especially regarding graft selection and allocation policies, efforts not to discard valuable grafts should be undertaken in our country. PMID- 28834073 TI - Selective Ring-Opening Polymerization of Non-Strained gamma-Butyrolactone Catalyzed by A Cyclic Trimeric Phosphazene Base. AB - A new superbase, the cyclic trimeric phosphazene base (CTPB), was prepared with high yield and purity. In the presence of alcohol, the CTPB serves as a highly efficient organocatalyst for ring-opening polymerization of the "non polymerizable" gamma-butyrolactone to offer well-defined poly(gamma butyrolactone) with high conversions (up to 98 %) at -60 degrees C. The produced polymers have high molecular weights (up to 22.9 kg mol-1 ) and low polydispersity distributions (1.27-1.50). NMR analysis of initiation process and the structural analysis of resulting polymers by MALDI-TOF suggest a mechanism involving an activating initiator which leads only to linear polymers with BnO/H chain ends. PMID- 28834074 TI - Photosalient Phenomena that Mimic Impatiens Are Observed in Hollow Crystals of Diarylethene with a Perfluorocyclohexene Ring. AB - A diarylethene with a perfluorocyclohexene ring formed hollow crystals by sublimation under normal pressure. Upon UV irradiation of the crystals, they showed remarkable photosalient phenomena and scattered into small pieces. The speed of the flying debris released from the crystal by UV irradiation exceeded several meters per second. To clearly show a photosalient effect resembling the scattering behavior of Impatiens on a smaller scale, small fluorescent beads (1 MUm diameter) were inserted into the hollow crystal. Consequently, scattering of the beads was observed as UV irradiation caused deformation and bursting of the hollow structure. This phenomenon is unique to hollow crystals, and the ability to effectively induce remarkable photosalient phenomena is similar to the behavior of hollow-structured Impatiens in nature. PMID- 28834076 TI - The regeneration of macro-porous electrospun poly(E-caprolactone) vascular graft during long-term in situ implantation. AB - Long-term evaluation of vascular grafts is an essential step to facilitate clinical translation. In this study, we investigate the long-term performance of a macro-porous poly(E-caprolactone) (PCL) electrospun vascular graft using the rat abdominal artery replacement model. Long-term patency, endothelialization, and smooth muscle cell regeneration were evaluated, as well as calcification and degradation. The data showed that all the grafts remained open and unobstructed. There was no evidence of aneurysm, stenosis, or calcification one year after implantation. Importantly, neo-vessel was regenerated on the luminal surface of the graft, and was composed of a complete endothelial layer and several layers of smooth muscle cells. The neo-vessel showed vascular physiological function, although not as good as that in native blood vessels, likely due to the remaining scaffold fibers. These data indicated that the PCL macro-porous electrospun vascular graft has potential to be an artery substitute for long-term implantation. Also, this work indicates that continued efforts are needed to develop advanced vascular grafts that exhibit the appropriate balance between the regeneration of the neo-vessel and the complete degradation of the graft materials. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1618-1627, 2018. PMID- 28834077 TI - Synthesis of Phenalenyl-Fused Pyrylium Cations: Divergent C-H Activation/Annulation Reaction Sequence of Naphthalene Aldehydes with Alkynes. AB - Described herein is the synthesis of stable oxonium-doped polycyclic aromatic hydrocarbons (PAHs) by the rhodium-catalyzed C-H activation/annulations of naphthalene-type aldehydes with internal alkynes. This protocol provides four divergent reaction types, including two unexpected annulations with an oxygen transposition process, which lead to diverse types of phenalenyl-fused pyrylium cations comprising a four-, five-, or six-ring-fused pi-conjugated core. The annulations exhibit an exquisite regioselectivity and a high tolerance of sensitive functional groups. These PAHs feature intriguing photophysical properties such as full-color tunable fluorescence emission, high quantum yield, and positively charged core, and can be reduced easily to the phenalenyl radicals. PMID- 28834075 TI - Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: A systematic review. AB - AIMS: Therapeutic inertia, defined as the failure to initiate or intensify therapy in a timely manner according to evidence-based clinical guidelines, is a key reason for uncontrolled hyperglycaemia in patients with type 2 diabetes. The aims of this systematic review were to identify how therapeutic inertia in the management of hyperglycaemia was measured and to assess its extent over the past decade. MATERIALS AND METHODS: Systematic searches for articles published from January 1, 2004 to August 1, 2016 were conducted in MEDLINE and Embase. Two researchers independently screened all of the titles and abstracts, and the full texts of publications deemed relevant. Data were extracted by a single researcher using a standardized data extraction form. RESULTS: The final selection for the review included 53 articles. Measurements used to assess therapeutic inertia varied across studies, making comparisons difficult. Data from low- to middle income countries were scarce. In most studies, the median time to treatment intensification after a glycated haemoglobin (HbA1c) measurement above target was more than 1 year (range 0.3 to >7.2 years). Therapeutic inertia increased as the number of antidiabetic drugs rose and decreased with increasing HbA1c levels. Data were mainly available from Western countries. Diversity of inertia measures precluded meta-analysis. CONCLUSIONS: Therapeutic inertia in the management of hyperglycaemia in patients with type 2 diabetes is a major concern. This is well documented in Western countries, but corresponding data are urgently needed in low- and middle-income countries, in view of their high prevalence of type 2 diabetes. PMID- 28834078 TI - The prevalence and fate of the defunctioning stoma in patients with anal cancer: a regional experience following the ACT II trial. AB - AIM: UK guidance advises the creation of a defunctioning stoma for anal tumours infiltrating the vagina, impending obstruction or significant faecal incontinence. Other patients may be offered a defunctioning stoma at the discretion of the clinician. The purpose of this study was to establish the prevalence and fate of defunctioning stomas in a regional anal cancer service, with reference to the results from the recent ACT II trial. METHOD: Oncological treatment was standardized as described in the ACT II trial. All patients from 2010 to 2013 inclusive were included. Collected data were correlated with both the IMRT guidelines and the outcomes of the ACT II trial. Kaplan-Meier survival analysis was applied to stoma-free survival to the end of the study period. RESULTS: Seventy-six patients were identified during the study period, of whom 51% had a defunctioning stoma. Twenty were performed for anterior tumours without infiltration into the vagina (Group A), whilst 19 had a stoma for indications as set out by the guidelines (Group B). Stoma reversal was performed in 41% of patients, 13/20 in Group A and 3/19 in Group B. The median time to reversal was 11 months. Eleven deaths were recorded and six patients still had their stomas at time of death. Stoma-free survival was 74%. No new ano-vaginal fistulation occurred as a consequence of treatment. CONCLUSION: The tumour features that are indications for defunctioning as advised by the UK IMRT guidelines are associated with a poorer overall outcome, and these stomas are less likely to be reversed. The majority of stomas, however, were formed for anterior tumours without infiltration into the vagina and were more likely to be successfully reversed. PMID- 28834079 TI - Safety and efficacy of MitraClipTM therapy in patients with severely impaired left ventricular ejection fraction: results from the German transcatheter mitral valve interventions (TRAMI) registry. AB - AIMS: The aim of the present study was to assess the safety and efficacy of percutaneous mitral valve repair using the MitraClipTM device in patients with severely reduced systolic left ventricular (LV) function. METHODS AND RESULTS: Among 777 MitraClipTM implantations included in the German mitral valve registry, we identified 256 patients suffering from severely reduced LV function [ejection fraction (EF) <30%] in whom successful percutaneous mitral valve repair was performed. Procedural safety, efficacy, and 1-year outcome was compared with 241 patients with preserved LV function (EF >50%) and 280 patients presenting with an EF 30-50% prior to MitraClipTM therapy. High procedural success rates, low periprocedural complication rates, and low residual mitral regurgitation grades at discharge were achieved throughout all groups. In-hospital mortality was low and comparable in all groups. After 1 year, mortality rates were 24.2% (EF <30%), 17.3% (EF 30-50%), and 18.9% (EF >50%). Major adverse cardiac or cardiovascular event rates were 29.7% (EF <30%), 24.4% (EF 30-50%), and 23.5% (EF >50%). Procedural failure was the main predictor for mortality in EF <30% patients (hazard ratio 10.38; 95% CI 3.71-29.02). Improved clinical symptoms were observed in the majority of patients in all groups. Thus, 69.5% of EF <30% patients improved by one or more New York Heart Association functional class. Compared with patients with preserved LV function, this is a significantly larger proportion (EF >50%: 56.8%; P < 0.05). Moreover, quality of life, being very poor at baseline, improved distinctively in severe heart failure patients. CONCLUSION: In patients with severely reduced systolic LV function undergoing MitraClipTM therapy, procedural safety, efficacy, and clinical improvement after 1 year are comparable to patients with preserved LV function. PMID- 28834080 TI - Longterm outcome of the liver graft: The pathologist's perspective. PMID- 28834081 TI - Molecular Dynamics of Hexamethylbenzene at Low Temperatures: Evidence of Unconventional Magnetism Based on Rotational Motion of Protons. AB - The types of magnetism known to date are all mainly based on contributions from electron motion. We show how rotational motion of protons (H+ ) within the methyl groups in hexamethylbenzene (C6 (CH3 )6 ) also contribute significantly to the magnetic susceptibility. Starting from below 118 K, as the rotational motion of the methyl groups set in, an associated magnetic moment positive in nature due to charge of the protons renders the susceptibility to become anomalously dependent on temperature. Starting from 20 K, the susceptibility diverges with decreasing temperature indicative of spin-spin interactions between methyl groups aligned in a previously unclassified type of anti-ferromagnetic configuration. Complementary dielectric constant measurements also show the existence of magneto-dielectric coupling. Our findings allow for the study of strongly correlated systems that are based on a species that possesses much slower dynamics. PMID- 28834082 TI - Gate-Voltage Control of Borophene Structure Formation. AB - Boron nanostructures are easily charged but how charge carriers affect their structural stability is unknown. We combined cluster expansion methods with first principles calculations to analyze the dependence of the preferred structure of two-dimensional (2D) boron, or "borophene", on charge doping controlled by a gate voltage. At a reasonable doping level of 3.12*1014 cm-2 , the hollow hexagon concentration in the ground state of 2D boron increases to 1/7 from 1/8 in its charge-neutral state. The numerical result for the dependence of hollow hexagon concentration on the doping level is well described by an analytical method based on an electron-counting rule. Aside from in-plane electronic bonding, the hybridization among out-of-plane boron orbitals is crucial for determining the relative stability of different sheets at a given doping level. Our results offer new insight into the stability mechanism of 2D boron and open new ways for the control of the lattice structure during formation. PMID- 28834083 TI - Microstructural white matter tract alteration in Prader-Willi syndrome: A diffusion tensor imaging study. AB - Prader-Willi Syndrome (PWS) is a genetic disorder characterized by infantile hypotonia, hyperphagia, hypogonadism, growth hormone deficiency, intellectual disability, and severe emotional and behavioral problems. The brain mechanisms that underpin these disturbances are unknown. Diffusion tensor imaging (DTI) enables in vivo investigation of the microstructural integrity of white matter pathways. To date, only one study has used DTI to examine white matter alterations in PWS. However, that study used selected regions of interest, rather than a whole brain analysis. In the present study, we used diffusion tensor and magnetic resonance (T 1-weighted) imaging to examine microstructural white matter changes in 15 individuals with PWS (17-30 years) and 15 age-and-gender-matched controls. Whole-brain voxel-wise statistical analysis of FA was carried out using tract-based spatial statistics (TBSS). Significantly decreased fractional anisotropy was found localized to the left hemisphere in individuals with PWS within the splenium of the corpus callosum, the internal capsule including the posterior thalamic radiation and the inferior frontal occipital fasciculus (IFOF). Reduced integrity of these white matter pathways in individuals with PWS may relate to orientating attention, emotion recognition, semantic processing, and sensorimotor dysfunction. PMID- 28834084 TI - Does robot-assisted radical prostatectomy benefit patients with prostate cancer and bone oligometastases? AB - OBJECTIVE: To investigate the peri-operative and oncological outcomes of robot assisted radical prostatectomy (RARP) in patients with oligometastatic prostate cancer (PCa). PATIENTS AND METHODS: We retrospectively reviewed the records of 79 patients with oligometastatic PCa treated with RARP or androgen deprivation therapy (ADT) between 2005 and 2015 at our institution. Of these 79 patients, 38 were treated with RARP and 41 were treated with ADT without local therapy. Oligometastatic disease was defined as the presence of five or fewer hot spots detected by preoperative bone scan. We evaluated peri-operative outcomes, progression-free survival (PFS), and cancer-specific survival (CSS). We analysed data using Kaplan-Meier methods, with log-rank tests and multivariate Cox regression models. RESULTS: Patients treated with RARP experienced similar postoperative complications to those previously reported in RP-treated patients, and fewer urinary complications than ADT-treated patients. PFS and CSS were longer in RARP-treated compared with ADT-treated patients (median PFS: 75 vs 28 months, P = 0.008; median CSS: not reached vs 40 months, P = 0.002). Multivariate analysis further identified RARP as a significant predictor of PFS and CSS (PFS: hazard ratio [HR] 0.388, P = 0.003; CSS: HR 0.264, P = 0.004). CONCLUSIONS: We showed that RARP in the setting of oligometastatic PCa is a safe and feasible procedure which improves oncological outcomes in terms of PFS and CSS. In addition, our data suggest that RARP effectively prevents urinary tract complications from PCa. The study highlights results from expert surgeons and highly selected patients that cannot be extrapolated to all patients with oligometastatic PCa; to confirm our findings, large, prospective, multicentre studies are required. PMID- 28834085 TI - More extended lymph node dissection template at radical prostatectomy detects metastases in the common iliac region and in the fossa of Marcille. AB - OBJECTIVES: To assess the effect of adding lymph nodes (LNs) located along the common iliac vessels and in the fossa of Marcille to the extended pelvic LN dissection (PLND) template at radical prostatectomy (RP). PATIENTS AND METHODS: A total of 485 patients underwent RP and PLND at a referral centre between 2000 and 2008 (historical cohort: classic extended PLND template) and a total of 268 patients between 2010 and 2015 (contemporary cohort: extended PLND template including LNs located along the common iliac vessels and in the fossa of Marcille). Descriptive analyses were used to compare baseline, pathological, complication and functional data between the two cohorts. A logistic regression model was used to assess the template's effect on the probability of detecting LN metastases. RESULTS: Of 80 patients in the historical cohort with pN+ disease, the sole location of metastasis was the external iliac/obturator fossa in 23 (29%), and the internal iliac in 18 (23%), while 39 patients (49%) had metastases in both locations. Of 72 patients in the contemporary cohort with pN+ disease, the sole location of metastasis was the external iliac/obturator fossa in 17 patients (24%), the internal iliac in 24 patients (33%), and the common iliac in one patient (1%), while 30 patients (42%) had metastases in >1 location (including fossa of Marcille in five patients). Among all 46 patients in the contemporary cohort with <=2 metastases, three had one or both metastases in the common iliac region or the fossa of Marcille. The adjusted probability of detecting LN metastases was higher, but not significantly so, in the contemporary cohort. There were no differences between the two cohorts in complication rates and functional outcomes. CONCLUSION: A more extended template detects LN metastases in the common iliac region and the fossa of Marcille and is not associated with a higher risk of complications; however, the overall probability of detecting LN metastases was not significantly higher. PMID- 28834086 TI - Single and combined effects of inflammatory markers on 10 year diabetes incidence: The mediating role of adiposity-Results from the ATTICA cohort study. AB - BACKGROUND: The role of inflammation in diabetes development is not fully elucidated. The aim of this work was to investigate the independent effect of individual inflammatory markers and combinations of them on diabetes incidence and the potential mediating role of obesity. METHODS: In 2001 to 2002, a random sample of 1514 men (18-87 years old) and 1528 women (18-89 years old) was selected to participate in the ATTICA study, where Athens is a major metropolis. Interleukin-6 (IL-6), C-reactive protein (CRP), tumour necrosis factor-alpha, serum amyloid alpha, fibrinogen, and homocysteine were measured. Covariates included various clinical, demographic, and lifestyle characteristics, assessed with standard procedures. In 2012, the 10 year follow-up was performed. Diabetes diagnosis was defined according to American Diabetes Association criteria among n = 1485 participants. RESULTS: One hundred ninety-one incident cases of diabetes were documented, yielding an incidence of 12.9% (13.4% in men and 12.4% in women). After adjustments, only elevated IL-6 increased by 2.2 times the 10 year diabetes risk (third vs first tertile, 95% CI: 1.13, 4.28). After investigating combinations of inflammatory markers, combined elevated levels of CRP and IL-6 or CRP and fibrinogen (both markers >=75th percentile vs <75th percentile) increased the risk by 1.93 times (95% CI: 1.20, 3.08) and 2.37 times (95% CI: 1.37, 4.16), respectively. Body mass index was found to significantly mediate the aggravating effect of inflammation. CONCLUSIONS: The reported results underline the significant role of individual IL-6 or combinations of CRP-IL-6 and CRP fibrinogen in diabetes prediction. Adiposity seems to be primarily responsible for an increase in inflammatory markers, leading through this mechanism to insulin resistance and increasing diabetes risk. PMID- 28834087 TI - Boom-bust dynamics in biological invasions: towards an improved application of the concept. AB - Boom-bust dynamics - the rise of a population to outbreak levels, followed by a dramatic decline - have been associated with biological invasions and offered as a reason not to manage troublesome invaders. However, boom-bust dynamics rarely have been critically defined, analyzed, or interpreted. Here, we define boom-bust dynamics and provide specific suggestions for improving the application of the boom-bust concept. Boom-bust dynamics can arise from many causes, some closely associated with invasions, but others occurring across a wide range of ecological settings, especially when environmental conditions are changing rapidly. As a result, it is difficult to infer cause or predict future trajectories merely by observing the dynamic. We use tests with simulated data to show that a common metric for detecting and describing boom-bust dynamics, decline from an observed peak to a subsequent trough, tends to severely overestimate the frequency and severity of busts, and should be used cautiously if at all. We review and test other metrics that are better suited to describe boom-bust dynamics. Understanding the frequency and importance of boom-bust dynamics requires empirical studies of large, representative, long-term data sets that use clear definitions of boom-bust, appropriate analytical methods, and careful interpretations. PMID- 28834089 TI - Ordered Arrangement and Optical Properties of Silica-Stabilized Gold Nanoparticle PNIPAM Core-Satellite Clusters for Sensitive Raman Detection. AB - Gold-polymer hybrid nanoparticles attract wide interest as building blocks for the engineering of photonic materials and plasmonic (active) metamaterials with unique optical properties. In particular, the coupling of the localized surface plasmon resonances of individual metal nanostructures in the presence of nanometric gaps can generate highly enhanced and confined electromagnetic fields, which are frequently exploited for metal-enhanced light-matter interactions. The optical properties of plasmonic structures can be tuned over a wide range of properties by means of their geometry and the size of the inserted nanoparticles as well as by the degree of order upon assembly into 1D, 2D, or 3D structures. Here, the synthesis of silica-stabilized gold-poly(N-isopropylacrylamide) (SiO2 Au-PNIPAM) core-satellite superclusters with a narrow size distribution and their incorporation into ordered self-organized 3D assemblies are reported. Significant alterations of the plasmon resonance are found for different assembled structures as well as strongly enhanced Raman signatures are observed. In a series of experiments, the origin of the highly enhanced signals can be assigned to the interlock areas of adjacent SiO2 -Au-PNIPAM core-satellite clusters and their application for highly sensitive nanoparticle-enhanced Raman spectroscopy is demonstrated. PMID- 28834088 TI - VEGF synthesis is induced by prostacyclin and TGF-beta in distal lung fibroblasts from COPD patients and control subjects: Implications for pulmonary vascular remodelling. AB - BACKGROUND AND OBJECTIVE: Involvement of pulmonary vascular remodelling is a characteristic sign in COPD. Vascular mediators such as vascular endothelial growth factor (VEGF) and prostacyclin may regulate fibroblast activity. The objective was to study the synthesis of VEGF and interactions with prostacyclin and transforming growth factor (TGF)-beta1 in lung fibroblasts from patients with COPD and healthy control subjects. To further explore the autocrine role of synthesized VEGF on fibroblast activity, studies were performed in human lung fibroblasts (HFL-1). METHODS: Primary distal lung fibroblast cultures were established from healthy individuals and from COPD patients (GOLD stage IV). Lung fibroblasts were stimulated with the prostacyclin analogue iloprost and the profibrotic stimuli TGF-beta1 . VEGF synthesis was measured in the cell culture medium. Changes in proliferation rate, migration and synthesis of the extracellular matrix (ECM) proteins proteoglycans were analysed after stimulations with VEGF-A isoform 165 (VEGF165 ; 1-10 000 pg/mL) in HFL-1. RESULTS: Iloprost and TGF-beta1 significantly increased VEGF synthesis in both fibroblasts from COPD patients and control subjects. TGF-beta1 -induced VEGF synthesis was significantly reduced by the cyclooxygenase inhibitor indomethacin in fibroblasts from COPD patients. VEGF significantly increased proliferation rate and migration capacity in HFL-1. VEGF also significantly increased synthesis of the ECM proteins biglycan and perlecan. The VEGF receptors (VEGFR), VEGFR1, VEGFR2 and VEGFR3, were all expressed in primary lung fibroblasts and HFL-1. CONCLUSION: VEGF is synthesized in high amounts by distal lung fibroblasts and may have a crucial role in ongoing vascular remodelling processes in the distal lung compartments. PMID- 28834090 TI - Identification of Characteristic Components and Foodstuffs in Healthy Japanese Diet and the Health Effects of a Diet with Increased Use Frequency of these Foodstuffs. AB - SCOPE: Our recent study showed that the 1975 Japanese diet exhibited strong health benefits. In the current study, we aimed to develop a diet with even higher health benefits. METHODS: First, to determine the characteristic components in the 1975 diet, we used mass spectrometry for analysis of Japanese diets from several years and performed principal component analysis. Next, a diet with an increased use frequency of foodstuffs contained characteristic components (the modified diet) was prepared and fed to mice. RESULTS: Performed principal component analysis revealed that the 1975 diet contained 14 characteristic components that were found in fish, fruits, vegetables, seaweed, soybean foods, soup stock "dashi", and fermented seasoning. Based on these, the modified diet was prepared and fed to mice. The liver total cholesterol and serum LDL cholesterol decreased significantly in mice fed the modified diet and serum total cholesterol showed a downward trend, compared to mice fed the 1975 diet. There was no difference between the modified diet and the control groups. In addition, serum adiponectin level increased in mice fed the modified diet and serum TBARS and IL-6 levels decreased. CONCLUSION: By modifying the 1975 diet, it was possible to make a diet with more benefit. PMID- 28834091 TI - From Precursor Powders to CsPbX3 Perovskite Nanowires: One-Pot Synthesis, Growth Mechanism, and Oriented Self-Assembly. AB - The colloidal synthesis and assembly of semiconductor nanowires continues to attract a great deal of interest. Herein, we describe the single-step ligand mediated synthesis of single-crystalline CsPbBr3 perovskite nanowires (NWs) directly from the precursor powders. Studies of the reaction process and the morphological evolution revealed that the initially formed CsPbBr3 nanocubes are transformed into NWs through an oriented-attachment mechanism. The optical properties of the NWs can be tuned across the entire visible range by varying the halide (Cl, Br, and I) composition through subsequent halide ion exchange. Single particle studies showed that these NWs exhibit strongly polarized emission with a polarization anisotropy of 0.36. More importantly, the NWs can self-assemble in a quasi-oriented fashion at an air/liquid interface. This process should also be easily applicable to perovskite nanocrystals of different morphologies for their integration into nanoscale optoelectronic devices. PMID- 28834093 TI - Metformin Therapy for the Management of Infertility in Women with Polycystic Ovary Syndrome: Scientific Impact Paper No. 13. PMID- 28834094 TI - Probing Laser-Induced Heterogeneous Microenvironment Changes in Room-Temperature Ionic Liquids. AB - Modulating the heterogeneous microenvironment in room-temperature ionic liquids (RTILs) by external stimuli is an important approach for understanding and designing external field-induced chemical reactions in natural and applied systems. Here, we report for the first time the redistribution of oxygen molecules related to microstructure changes in RTILs induced by an external laser field, which is probed simultaneously by the triplet-state dynamics of porphyrin. A remarkably long-lived triplet state of porphyrin is observed with changes of microstructures after irradiation, suggesting that charge-shifted O2 molecules are induced by the external field and/or rearranged intrinsic ions move from nonpolar domains into the polar domains of RTILs through electrostatic interactions. The results suggest that heterogeneous systems like ionic liquids in the presence of external stimuli can be designed for reaction systems associated with not only O2 but also for CO2 , CS2 , etc. and many other similar solvent molecules for many promising applications. PMID- 28834092 TI - Therapy-Related Explants After Spinal Cord Stimulation: Results of an International Retrospective Chart Review Study. AB - OBJECTIVES: Clinical trials of spinal cord stimulation (SCS) have largely focused on conversion from trial to permanent SCS and the first years after implant. This study evaluates the association of type of SCS and patient characteristics with longer-term therapy-related explants. MATERIALS AND METHODS: Implanting centers in three European countries conducted a retrospective chart review of SCS systems implanted from 2010 to 2013. Ethics approval or waiver was obtained, and informed consent was not required. The chart review recorded implants, follow-up visits, and date and reasons for any explants through mid-2016. Results are presented using Cox regression to determine factors associated with explant for inadequate pain relief. RESULTS: Four implanting centers in three countries evaluated 955 implants, with 8720 visits over 2259 years of follow-up. Median age was 53 years; 558 (58%) were female. Explant rate was 7.9% per year. Over half (94 of 180) of explants were for inadequate pain relief, including 32/462 (6.9%) of implants with conventional nonrechargeable SCS, 37/329 (11.2%) with conventional rechargeable and 22/155 (14.2%) with high-frequency (10 kHz) rechargeable SCS. A higher explant rate was found in univariate regression for conventional rechargeable (HR 1.98, p = 0.005) and high-frequency stimulation (HR 1.79, p = 0.035) than nonrechargeable SCS. After covariate adjustment, the elevated explant rate persisted for conventional rechargeable SCS (HR 1.95, p = 0.011), but was not significant for high-frequency stimulation (HR 1.71, p = 0.069). CONCLUSIONS: This international, real-world study found higher explant rates for conventional rechargeable and high-frequency SCS than nonrechargeable systems. The increased rate for conventional rechargeable stimulation persisted after covariate adjustment. PMID- 28834096 TI - Rapidly evolving vulvar ulcerations in a child. PMID- 28834097 TI - Carboxylation of Aromatic and Aliphatic Bromides and Triflates with CO2 by Dual Visible-Light-Nickel Catalysis. AB - We report the efficient carboxylation of bromides and triflates with K2 CO3 as the source of CO2 in the presence of an organic photocatalyst in combination with a nickel complex under visible light irradiation at room temperature. The reaction is compatible with a variety of functional groups and has been successfully applied to the synthesis and derivatization of biologically active molecules. In particular, the carboxylation of unactivated cyclic alkyl bromides proceeded well with our protocol, thus extending the scope of this transformation. Spectroscopic and spectroelectrochemical investigations indicated the generation of a Ni0 species as a catalytic reactive intermediate. PMID- 28834098 TI - Electrochemically Enabled, Nickel-Catalyzed Amination. AB - Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald-Hartwig-Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar-Cl, Ar-Br, Ar-I, Ar-OTf), amine types (primary and secondary), and even alternative X-H donors (alcohols and amides). PMID- 28834099 TI - Suprapubic single port ileocaecal resection for complicated Crohn's disease - a video vignette. PMID- 28834100 TI - The epidemiology of hepatitis B virus infection in women of reproductive age in highly endemic areas in China. AB - We describe the epidemiology of hepatitis B virus (HBV) infection among women of reproductive age residing in areas of China that are highly endemic for chronic HBV, and provide evidence useful for decision-makers to guide strategies for preventing mother-to-child transmission of HBV, and assess the impact of perinatal transmission PMTCT by projecting HBsAg prevalence trends without interventions. We conducted a cross-sectional HBV serological survey of women, 15 49 years of age, residing in Fujian, Guangdong, Guangxi and Hainan provinces. Demographic and other subject-level data were collected in face-to-face interviews, after which we obtain blood specimens. Specimens were tested for HBV sero-markers by ELISA (Beijing Wantai Biological Pharmacy), and HBV DNA was tested with PCR (Hunan Sansure Biotech). Weighted HBsAg and HBV (either HBsAg+ or anti-HBc+ indicating either present or past infection) prevalences were 11.82% and 57.16%, respectively. Among the HBsAg-positive women, 27% were also HBeAg positive. The proportion of individuals with HBV DNA loads >105 IU/mL declined with increasing age. Among HBsAg-negative women, 0.9% had occult HBV infection. The prevalence of chronic HBV infection among reproductive women in these highly endemic provinces is high, posing a threat to maternal health and risk of mother to-child transmission. Prevention of mother-to-child transmission remains critically important. PMID- 28834101 TI - Reshaping curricula: Culture and mental health in undergraduate health degrees. AB - Australia is a country rich in cultural diversity, with Indigenous Australians having specific cultural values and a variety of spoken languages. In addition, the increasing number of people from migrant and refugee backgrounds requires that health professionals be able to communicate effectively with people from a wide range of cultural backgrounds. This is particularly relevant when undertaking a mental health assessment, because members of diverse communities often face the dual vulnerability of marginalization and stigmatization. This paper reports on the development and evaluation of a virtual teaching and learning resource that prepares health students to be culturally competent in mental health assessment. Four online interprofessional learning journeys were developed. Evaluation of the learning resources was conducted across three participating Australian universities. Quantitative evaluation involved pre- and post-testing using an empathy scale, the Mental Health Nursing Clinical Confidence Scale, and the Cultural Competence Questionnaire informed by the theory of planned behaviour. Qualitative data from focus group interviews explored participants' experiences of using the guided learning journey. Participants reported changes from pretest to post-test in their empathy and attitudes towards culturally and linguistically diverse consumers with significant positive changes in cultural competence, empathy, and attitudes. There was strong satisfaction with the learning materials, indicating that participants valued this 'real world' learning experience. Results require cautious interpretation, given recruitment difficulties in the evaluation phase. However, these learning journeys appear to have potential to be an effective way to challenge attitudes and perceptions, as well as increase cultural competence towards culturally and linguistically diverse consumers. PMID- 28834102 TI - Ventral striatal dopaminergic defect is associated with hallucinations in Parkinson's disease. AB - BACKGROUND AND PURPOSE: Visual hallucinations (VHs) are a common complication of Parkinson's disease (PD). The pathogenesis of VHs in PD is still largely unclear. The aim of this study was to investigate the dopaminergic mechanisms of VHs and specifically whether the degree of striatal dopamine transporter (DAT) function or extrastriatal serotonin transporter (SERT) function can predict the appearance of VHs in patients with PD. METHODS: Twenty-two PD patients scanned with [123 I]FP-CIT single photon emission computed tomography at an early stage of their disease who later developed VHs were identified and compared with 48 non hallucinating PD patients. The groups were matched for age, medication, disease duration and motor symptom severity. Clinical follow-up after the scan was a median (range) of 6.9 (3.8-9.6) years. Imaging analyses were performed with both regions-of-interest-based and voxel-based (Statistical Parametric Mapping) methods for the striatal and extrastriatal regions. RESULTS: The median interval between the scan and the emergence of VHs was 4.8 years. Patients who developed VHs had 18.4% lower DAT binding in the right ventral striatum (P = 0.009), 16.7% lower binding in the left ventral striatum (P = 0.02) and 18.8% lower binding in the right putamen (P = 0.03) compared to patients who did not develop VHs. CONCLUSIONS: Low striatal DAT function may predispose PD patients to VHs, and the regional distribution of the findings suggests a particular role of the ventral striatum. This is in line with non-PD research that has implicated ventral striatal dysfunction in psychosis. PMID- 28834103 TI - Autologous platelet-rich plasma versus conventional therapy for the treatment of chronic venous leg ulcers: A comparative study. AB - BACKGROUND: Chronic venous leg ulcers drastically reduce the quality of life of affected patients. There is heightened interest in autologous platelet-rich plasma (PRP) as one of the promising therapies for leg ulcers. AIM: Our aim was to compare the clinical efficacy of PRP in the management of chronic venous leg ulcers vs conventional treatment. PATIENTS/METHODS: In total, 40 patients with chronic venous leg ulcers were included in the study. Twenty patients were treated with autologous PRP weekly for 6 weeks (Group A), and 20 patients were treated with conventional treatment (compression and dressing) for 6 weeks (Group B). Treatment results were calculated by percentage of improvement in area of the ulcer. RESULTS: Compared to conventional therapy, a highly significant improvement in the ulcer size was observed post-PRP therapy (P-value = .0001). The mean change in the area of the ulcer post-PRP and conventional therapy was 4.92 +/- 11.94 cm and 0.13 +/- 0.27 cm, respectively, while the mean percentage improvement in the area of the ulcer post-PRP and conventional therapy was 67.6% +/- 36.6% and 13.67% +/- 28.06%, respectively. Subjective improvement in pain associated with the ulcer was noted by all patients. CONCLUSIONS: Platelet-rich plasma is a safe nonsurgical procedure for treating chronic venous leg ulcers. Additional studies with larger sample size and longer follow-up periods are required to confirm or refute our findings. PMID- 28834104 TI - Myricetin protects keratinocyte damage induced by UV through IkappaB/NFkappab signaling pathway. AB - OBJECTIVE: The aim of this study was to evaluate the potential molecular mechanism of myricetin that protecting cells from photodamage. METHODS: Myricetin had broadly chemopreventive effects and anti-inflammatory properties. The effect of myricetin was assessed on HaCaT cells. Cell viability assay was carried out. Reactive oxygen species (ROS) level was measured. The expression of pro inflammatory factor COX2 was determined by real-time PCR and Western blot. The protein levels of p-IkappaBa and IkappaBa were determined by Western blot. RESULTS: Myricetin attenuated UV-induced keratinocyte death in a dose-dependent manner as determined by cell viability assay. Pretreatment with myricetin also reduced the UV-induced ROS levels. Myricetin suppresses the upregulation of COX2 induced by UV in keratinocyte as demonstrated by real-time PCR and Western blot. Furthermore, signal transduction studies confirmed that myricetin attenuates the upregulation of COX2 induced by UV via suppression of IkappaB/NFkappaB pathways. CONCLUSION: These results showed that antioxidant property of myricetin can effectively attenuate UV-caused cell damage and suppress the expression of COX2 through the IkappaB/NFkappaB signaling pathways. Myricetin had potential protective effects on UV-induced skin cell damages, which might be used in cosmetic and pharmaceutical industries. PMID- 28834105 TI - Enterolithiasis as a complication of a jejunal diverticulum: an unusual case of small bowel obstruction. PMID- 28834106 TI - alpha-Carbonyl Cations in Sulfoxide-Driven Oxidative Cyclizations. AB - The selective, metal-free generation of alpha-carbonyl cations from simple internal alkynes was accomplished by the addition of a sulfoxide to a densely substituted vinyl cation. The high reactivity of the alpha-carbonyl cations was found to efficiently induce hydrogen and even carbon shift reactions with unusual selecivities. Complex compounds with highly congested tertiary and all-carbon substituted quartenary carbon centers can thus be accessed in a single step from simple precursors. Mechanistic analysis strongly supports the intermediacy of the title compounds and provides a simple predictive scheme for the migratory aptitude of different substituents. PMID- 28834107 TI - Carbon Sources Influence Fumonisin Production in Fusarium proliferatum. AB - Fusarium proliferatum is a worldwide fungal pathogen that produces fumonisins which are harmful to animal and human health. However, environmental factors affecting fumonisin biosynthesis in F. proliferatum are not well understood. Based on our preliminary results, in this study, we investigated the effect of sucrose or mannose as the sole carbon source on fumonisin B (FB) production by F. proliferatum and studied their underlying mechanisms via proteome and gene expression analysis. Our results showed that mannose, used as the sole carbon source, significantly blocked fumonisin B1 and B2 production by F. proliferatum as compared with the use of sucrose. Fifty-seven differentially expressed proteins were successfully identified. The downregulated proteins in the mannose cultured strain were mainly involved in carbon metabolism, response to stress, and methionine metabolism, as compared with the sucrose-cultured strain. Moreover, quantitative real-time PCR analysis indicated that expression of several key genes involved in FB biosynthetic pathway and in transcription regulation were significantly downregulated in the mannose-cultured F. proliferatum, whereas expression of histone deacetylation-related genes were significantly upregulated. These results suggested that the blockage of FB biosynthesis by mannose was associated with the decreases in conversion of acetyl CoA to polyketide, methionine biosynthesis, and NADPH regeneration. More importantly, milder oxidative stress, downregulated expression of genes involved in biosynthetic pathway and transcription regulation, and upregulated expression of genes with histone deacetylation possibly were responsible for the blockage of FB biosynthesis in F. proliferatum. PMID- 28834108 TI - Influence of hang time and location on bacterial contamination of intravenous bags in a veterinary emergency and critical care setting. AB - OBJECTIVE: To assess the rate of bacterial contamination of fluid and ports in intravenous bags in a veterinary emergency room (ER) and intensive care unit (ICU). DESIGN: Experimental model. SETTING: Ninety intravenous fluid bags of lactated balanced-electrolytes solution (1 L) hung in a university hospital. INTERVENTIONS: Bags were hung in 2 different locations in the ER (sink and bins) and one location in the ICU (sink) for 11 days. Bags were punctured 3 times daily with a sterile needle to simulate clinical use. Injection ports were swabbed and 50 mL of fluid were collected in duplicates on days 0, 2, 4, 7, and 10. Aerobic bacterial cultures were performed on the fluid and injection port. Contamination was defined as bacterial growth of a similar phenotype across 2 consecutive times. Increase in the fluid contamination rate from day 0 was tested using an exact binomial test. Port contamination rate between locations was tested using Fisher's exact test. MAIN RESULTS: Combined bacterial growth on injection ports reached a mean (95% confidence interval) of 8.1 (0.005-16.2) cfu/port on day 10. The combined port contamination was 3.3%, 11.1%, 17.8%, and 31.1% on days 0, 2, 4, and 7, respectively. Port contamination was similar between ER and ICU. However, port contamination was higher in the sink versus the bins area (38.3% vs 16.7%, P = 0.032). No fluid bag was contaminated at days 0 and 2. The contamination rate of fluid bag was 1.1% and 4.4% on days 4 and 7, respectively. All bags with contaminated fluid were in the ER (6.7%, 95% exact binomial confidence interval 1.9-16.2%). CONCLUSIONS: Injection port contamination reached 31.1% on day 7. Contamination was more likely when the bags were hung next to a sink. In our model of bag puncture, fluid contamination occurred between days 2 and 4. PMID- 28834109 TI - Implementation of respiratory-gated VMAT on a Versa HD linear accelerator. AB - The accurate delivery of respiratory-gated volumetric modulated arc therapy (VMAT) treatment plans presents a challenge since the gantry rotation and collimator leaves must be repeatedly stopped and set into motion during each breathing cycle. In this study, we present the commissioning process for an Anzai gating system (AZ-733VI) on an Elekta Versa HD linear accelerator and make recommendations for successful clinical implementation. The commissioning tests include central axis dose consistency, profile consistency, gating beam-on/off delay, and comparison of gated versus nongated gamma pass rates for patient specific quality assurance using four clinically commissioned photon energies: 6 MV, 6 FFF, 10 MV, and 10 FFF. The central axis dose constancy between gated and nongated deliveries was within 0.6% for all energies and the analysis of open field profiles for gated and nongated deliveries showed an agreement of 97.8% or greater when evaluated with a percent difference criteria of 1%. The measurement of the beam-on/off delay was done by evaluating images of a moving ball-bearing phantom triggered by the gating system and average beam-on delays of 0.22-0.29 s were observed. No measurable beam-off delay was present. Measurements of gated VMAT dose distributions resulted in decrements as high as 9% in the gamma passing rate as compared to nongated deliveries when evaluated against the planned dose distribution at 3%/3 mm. By decreasing the dose rate, which decreases the gantry speed during gated delivery, the gamma passing rates of gated and nongated treatments can be made equivalent. We present an empirically derived formula to limit the maximum dose rate during VMAT deliveries and show that by implementing a reduced dose rate, a gamma passing rate of greater than 95% (3%/3 mm) was obtained for all plan measurements. PMID- 28834110 TI - A Stereoselective [3+1] Ring Expansion for the Synthesis of Highly Substituted Methylene Azetidines. AB - The reaction of rhodium-bound carbenes with strained bicyclic methylene aziridines results in a formal [3+1] ring expansion to yield highly substituted methylene azetidines with excellent regio- and stereoselectivity. The reaction appears to proceed through an ylide-type mechanism, where the unique strain and structure of the methylene aziridine promotes a ring-opening/ring-closing cascade that efficiently transfers chirality from substrate to product. The resultant products can be elaborated into new azetidine scaffolds containing vicinal tertiary-quaternary and even quaternary-quaternary stereocenters. PMID- 28834111 TI - Parenting stress in caregivers of children with chronic physical condition-A meta analysis. AB - On the basis of the parenting stress model we compared levels of parenting stress in families with and without a child with a chronic physical condition and analysed correlates of parenting stress in families with a child with a chronic condition. A systematic search through electronic databases identified 547 relevant studies that were included in a random-effects meta-analysis. Parents of children with a chronic condition showed small to moderate elevations of general parenting stress and stress related to the parent-child relationship in particular. They showed moderate to large elevations in health-related parenting stress. Parents of children with cancer, cerebral palsy, HIV infection or AIDS, and spina bifida showed the highest levels of parenting stress. Stress levels also varied by illness severity and duration, child age, parental gender and mental health, marital status, marital quality, and levels of perceived support. Behaviour problems of the child and low parental mental health were the strongest correlates of parenting stress. The present results assist with identifying parents at highest needs for interventions aimed at reducing parenting stress. These interventions should address the reduction of child behaviour problems, the promotion of parental mental health, the increase in marital quality and social support in general, and skills for dealing with stressors. PMID- 28834112 TI - The role of CT myelography in sparing the spinal cord during definitive radiotherapy in vertebral hemangioma. AB - INTRODUCTION: The spinal cord is poorly visualized on CT images but is well visualized in MRI images. However, implants used for spinal stabilization can produce artifacts on the MRI images which can interfere with identification of the cord. CT myelography in conjunction with CT simulation helps to clearly delineate the cord. MATERIALS AND METHODS: CT simulation was done in a patient with vertebral hemangioma. Pre- and post myelography images were obtained. Two plans were generated on pre and post myelography CT images using EclipseTM treatment planning system (TPS) version 10.0, Varian Medical Systems, USA. The prescribed total dose to PTV was 40 Gy in 20 fractions. RESULTS: The cord was poorly visualized in the premyelogram CT images. The titanium implants used for spinal cord stabilization produced artifacts in the MRI images. Figure Post myelogram, the contrast lit up the spinal cord. There was an overlap of 0.75 cc volume of the spinal cord with the PTV in the premyelogram images. This volume was reduced to 0 cc in the post myelogram images. There was an overlap of 5.4 cc volume of the PRV of spinal cord with the PTV in the premyelogram images which was reduced to 1 cc in the post myelogram images. The overlap region between the PTV and spinal cord received around 71% of the prescribed dose in premyelogram CT could be reduced to 0% in the post myelogram CT. The mean dose received by the overlap PRV spinal cord and PTV could be increased from 70% in the premyelogram to 92% in the post myelogram plans. CONCLUSION: CT myelogram in conjunction with CT simulation is particularly useful in cases where the tumor margin is very close to the cord and spinal implants are causing distortion of magnetic resonance images. PMID- 28834113 TI - Exercise might prevent cirrhosis in overweight and obese adults. AB - BACKGROUND & AIMS: Exercise in overweight patients with liver disease has improved liver enzymes, insulin levels and quality of life. Scientific evidence is incomplete regarding the role of exercise in the prevention of cirrhosis. We investigated the effect of exercise on the occurrence of cirrhosis in obese and overweight adults. METHODS: Exercise was assessed using the 2012 Adult Preventive Medical Service dataset while cirrhosis was identified using the National Health Insurance Research Database. All participants were aged 40 years and older. Unconditional logistic regression was used to estimate the odds ratios for cirrhosis. RESULTS: Overall, 1586 overweight and 1525 obese adults were identified with cirrhosis. Weekly exercise >150 min was significantly protective for cirrhosis in obese men and women. However, exercise <150 min/wk was significantly protective only in men compared to women. For weekly exercise >150 mins, the odds ratio for cirrhosis in obese men and women was 0.701 (95% CI: 0.584-0.841) and 0.736 (95% CI: 0.562-0.964) respectively. The adjusted odds ratios in overweight men and women were 0.734 (95% CI: 0.622-0.866) and 0.503 (CI: 0.37-0.684). For weekly exercise <150 min/wk, overweight and obese men had odds ratios of 0.879 (CI: 0.0.788-0.98) and 0.874 (CI: 0.782-0.977) compared to 0.918 (95% CI: 0.778-1.083) and 0.916 (95% CI: 0.780-1.075) in overweight and obese women respectively. CONCLUSIONS: Moderate exercise might significantly prevent obese and overweight adults from developing cirrhosis. The benefits appear to be greater for persons who exceed the minimum recommendations of 150 min/wk. PMID- 28834114 TI - Galangin suppresses H2 O2 -induced aging in human dermal fibroblasts. AB - Human skin aging is a progressive process that includes intrinsic aging and extrinsic photodamage, both of which can cause an accumulation of reactive oxygen species (ROS), resulting in dermal fibrosis dysfunction and wrinkle formation. Galangin is a flavonoid that exhibits anti-inflammatory and antioxidative potential. Previous studies have reported that galangin has antioxidative activity against ROS-mediated stress. The aim of the present study is to determine the antiaging effects of galangin on dermal fibroblasts exposed to H2 O2 . In this study, we established a hydrogen peroxide-induced inflammation and aging model using human HS68 dermal fibroblasts. Stimulation of fibroblasts with H2 O2 is associated with skin aging and increased expression of inflammation related proteins, along with downregulation of collagen I/III formation and expression of antioxidative proteins. Galangin effectively reduced NF-kappaB activation, the expression of inflammation-related proteins and cell aging. Galangin also reversed H2 O2 -activated cell senescence in HS68 cells. Our results reveal that galangin protects human dermal fibroblasts by inhibiting NF kappaB activation, decreases the expression of inflammatory factors and upregulates IGF1R/Akt-related proteins, indicating that galangin may be a potential candidate for developing natural antiaging products that protect skin from damage caused by ROS. PMID- 28834115 TI - Transparent and Flexible Supercapacitors with Networked Electrodes. AB - Transparent and flexible energy storage devices have received immense attention due to their suitability for innovative electronics and displays. However, it remains a great challenge to fabricate devices with high storage capacity and high degree of transmittance. This study describes a simple process for fabrication of supercapacitors with ~75% of visible transparency and areal capacitance of ~3 mF cm-2 with high stability tested over 5000 cycles of charging and discharging. The electrodes consist of Au wire networks obtained by a simple crackle template method which are coated with MnO2 nanostructures by electrodeposition process. Importantly, the membrane separator itself is employed as substrate to bring in the desired transparency and light weight while additionally exploiting its porous nature in enhancing the interaction of electrolyte with the active material from both sides of the substrate, thereby enhancing the storage capacity. The method opens up new ways for fabricating transparent devices. PMID- 28834116 TI - Versatile Tri(pyrazolyl)phosphanes as Phosphorus Precursors for the Synthesis of Highly Emitting InP/ZnS Quantum Dots. AB - Tri(pyrazolyl)phosphanes (5R1,R2 ) are utilized as an alternative, cheap and low toxic phosphorus source for the convenient synthesis of InP/ZnS quantum dots (QDs). From these precursors, remarkably long-term stable stock solutions (>6 months) of P(OLA)3 (OLAH=oleylamine) are generated from which the respective pyrazoles are conveniently recovered. P(OLA)3 acts simultaneously as phosphorus source and reducing agent in the synthesis of highly emitting InP/ZnS core/shell QDs. These QDs are characterized by a spectral range between 530-620 nm and photoluminescence quantum yields (PL QYs) between 51-62 %. A proof-of-concept white light-emitting diode (LED) applying the InP/ZnS QDs as a color-conversion layer was built to demonstrate their applicability and processibility. PMID- 28834117 TI - Computational Study of the Molecular Structure and Hydrogen Bonding in the Hamilton Wedge/Cyanuric Acid Binding Motif. AB - Intermolecular binding between a Hamilton wedge and cyanuric acid, a frequently employed binding motif to achieve self-assembly of single-chain polymer nanoparticles, is studied by means of ab initio quantum-chemical and DFT calculations. A conformational analysis of the isolated compounds and the hydrogen-bonded complex reveals several low-energy structures, which are characterized based on their nonplanarity and binding energy. New hypothetical binding motifs are proposed and proven to possess a superior binding energy, upon becoming planar. Comparison to experimentally measured NMR spectroscopy data is made and cases of disagreement are traced back to solvent effects for isolated substituents or to thermally stretched intermolecular bonds for hydrogen-bonded species. Strong linear correlations between NMR chemical shifts and hydrogen-bond lengths are established for all compounds investigated. PMID- 28834118 TI - The transition to adulthood of young adults with IDD: Parents' joint projects. AB - INTRODUCTION: Parents have found the transition to adulthood for their sons or daughters with intellectual and/or developmental disabilities (IDD) particularly challenging. The literature has not examined how parents work together and with others in face of this transition nor has it highlighted parental goals in this process. This study used a perspective based on joint, goal-direct action to describe the projects that Canadian parents engaged in together and with others relative to this transition. METHODS: Using the qualitative action-project method, joint projects between parents and with others were identified from their conversations and followed for 6 months. FINDINGS: Three groups of projects were described: equipping the young adult for adult life, connecting for personal support and managing day-to-day while planning for the future. CONCLUSIONS: Parents act together and with others relative to the transition to adulthood of their young adult children with IDD. These projects are complex and differ in goals, steps, resources and emotional regulation and motivation. PMID- 28834120 TI - The relationship between a blunted morning surge and a reversed nocturnal blood pressure dipping or "riser" pattern. AB - The authors sought to determine the association between the blunted morning blood pressure (BP) surge and nocturnal BP dipping of the "riser" pattern in 501 patients with hypertension enrolled in the ACHIEVE-ONE (Ambulatory Blood Pressure Control and Home Blood Pressure [Morning and Evening] Lowering by the N-Channel Blocker Cilnidipine) trial. The patients' sleep-trough morning BP surge and prewaking surge were calculated and then classified according to their nocturnal systolic BP reduction pattern as extreme dippers, dippers, nondippers, and risers. The prevalence of the riser pattern was significantly higher in both the lowest sleep-trough morning BP surge decile and the prewaking surge decile (blunted surge group) compared with the remaining deciles (56.0% vs 10.4% [P<.0001] and 59.2% vs 10.2% [P<.0001], respectively). The riser pattern was a significant determinant of both blunted sleep-trough morning BP surge (odds ratio, 73.3; P<.0001) and blunted prewaking surge (odds ratio, 14.8; P<.0001). The high prevalence of the riser pattern in patients with blunted morning BP surges may account for the cardiovascular risk previously reported in such patients. PMID- 28834119 TI - Racial differences in nocturnal dipping status in diabetic kidney disease: Results from the STOP-DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) study. AB - While racial variation in ambulatory blood pressure (BP) is known, patterns of diurnal dipping in the context of diabetic kidney disease have not been well defined. The authors sought to determine the association of race with nocturnal dipping status among participants with diabetic kidney disease enrolled in the STOP-DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) trial. The primary outcome was nocturnal dipping percent decrease in average systolic BP from wake to sleep-with categories defined as reverse dippers (decrease <0%), nondippers (0%-<10%), and dippers (>=10%). Twenty-four-hour ambulatory BP monitoring was completed by 108 participants (54% were nondippers, 24% were dippers, and 22% were reverse dippers). In adjusted models, the common odds of reverse dippers vs nondippers/dippers and reverse dippers/nondippers vs dippers was 2.6 (95% confidence interval, 1.2-5.8) times higher in blacks than in whites. Without ambulatory BP monitoring data, interventions that target BP in black patients may be unable to improve outcomes in this high-risk group. PMID- 28834122 TI - Bitter substances from plants used in traditional Chinese medicine exert biased activation of human bitter taste receptors. AB - The number and variety of bitter compounds originating from plants are vast. Whereas some bitter chemicals are toxic and should not be ingested, other compounds exhibit health beneficial effects, which is manifest in the cross cultural believe that the bitterness of medicine is correlated with the desired medicinal activity. The bitter taste receptors in the oral cavity serve as sensors for bitter compounds and, as they are expressed in numerous extraoral tissues throughout the body, may also be responsible for some physiological effects exerted by bitter compounds. Chinese herbal medicine uses bitter herbs since ancient times for the treatment of various diseases; however, the routes by which these herbs modify physiology are frequently not well understood. We therefore screened 26 bitter substances extracted from medical herbs for the activation of the 25 human bitter taste receptors. We identified six receptors activated by in total 17 different bitter compounds. Interestingly, we observed a bias in bitter taste receptor activation with 10 newly identified agonists for the broadly tuned receptor TAS2R46, seven agonists activating the TAS2R14 and two compounds activating narrowly tuned receptors, suggesting that these receptors play dominant roles in the evaluation and perhaps physiological activities of Chinese herbal medicines. PMID- 28834121 TI - You'd better walk alone: Changes in forest composition affect pollination efficiency and pre-dispersal cone damage in Iberian Juniperus thurifera forests. AB - Changes in land-use patterns are a major driver of global environmental change. Cessation of traditional land-use practices has led to forest expansion and shifts in forest composition. Consequently, former monospecific forests maintained by traditional management are progressing towards mixed forests. However, knowledge is scarce on how the presence of other tree species will affect reproduction of formerly dominant species. We explored this question in the wind-pollinated tree Juniperus thurifera. We hypothesised that the presence of heterospecific trees would have a negative effect on cone production and on the proportion of cones attacked by specialised predators. We assessed the relative importance of forest composition on cone production, seed development and pre-dispersal cone damage on nine paired pure and mixed J. thurifera forests in three regions across the Iberian Peninsula. The effects of forest composition on crop size, cone and seed characteristics, as well as damage by pre-dispersal arthropods were tested using mixed models. Cone production was lower and seed abortion higher in mixed forests, suggesting higher pollination failure. In contrast, cone damage by arthropods was higher in pure forests, supporting the hypothesis that presence of non-host plants reduces damage rates. However, the response of each arthropod to forest composition was species-specific and the relative rates of cone damage varied depending on individual tree crops. Larger crop sizes in pure forests compensated for the higher cone damage rates, leading to a higher net production of sound seeds compared to mixed forests. This study indicates that ongoing changes in forest composition after land abandonment may impact tree reproduction. PMID- 28834123 TI - Pregnancy outcomes in women with Budd Chiari Syndrome before onset of symptoms and after treatment. AB - BACKGROUND & AIMS: Pregnancy is known to have poor outcomes in women with Budd Chiari syndrome. There are no data on fertility and pregnancy outcomes prior to onset of symptoms or the effect of therapy on these parameters. We therefore evaluated reproductive profile of women with Budd Chiari Syndrome before the onset of symptoms and after therapy. PATIENTS AND METHODS: Eighty women with Budd Chiari Syndrome (29 years [20-45]) were enrolled over 8 years. Baseline demographic characteristics, disease severity, thrombophilic disorders and treatment were reviewed. Their obstetric history before symptoms and after therapy was noted and compared. RESULTS: Sixty women conceived at least once (150 pregnancies) before symptom onset and 20 had primary infertility. Eighty-one pregnancies resulted in live births and remaining 69 pregnancies had adverse pregnancy outcomes. Post-intervention, 28 women (15 with primary infertility) attempted conception. Thirteen patients conceived 15 times. More women had live births after successful therapy as compared to presymptomatic period (0/28 vs 5/28 P = .000, Odds ratio5.6; 95% CI: 2.16-14.5). In women with primary infertility, conception (0/15 vs 3/15 P = .007, Odds ratio 5, 95% CI: 1.44-17.27) and proportion of live births (0/15 vs 2/15 P = .002, Odds ratio 7.5, 95% CI: 1.71-32.79) was higher as compared to presymptomatic period. CONCLUSION: Primary infertility is common and pregnancy outcomes are poor before the onset of symptoms in women with Budd-Chiari syndrome. Effective therapy of Budd-Chiari syndrome may improve fertility and pregnancy outcomes. PMID- 28834124 TI - Black peel in facial dermatoses. AB - BACKGROUND: Melasma (facial dermatoses) is an acquired chronic disorder of hyperpigmentation over sun exposed parts and continues to be a therapeutic challenge due to the presence of melanin at varying depths in the epidermis and dermis, and many researchers are working hard to find a solution. The main culprit to remain is direct sun exposure, with other factors like drugs, genetic predisposition, thyroid abnormalities, pregnancy, phototoxic and photoallergic cosmetics. Melasma continues to have a remarkable impact on the well-being of affected patients causing deep psychological and social anguish, and with the expansion of cosmetic dermatology globally, treatments that are successful against skin diseases and boost beauty without prolonged recovery periods, or exposing patients to the risks of surgery, are increasingly recognised and acknowledged. Many clinicians have used various peeling in facial acne, scarring, and hyperpigmentations, and there have been no well-controlled studies comparing them with other conventional agents. CASE PRESENTATION: a unique case of facial hyperpigmentation in a black female who presented seeking help which can be attributed to increased aesthetic awareness among people nowadays. A single session of black peel several passes was performed and the lady noted a lightening effect in the following weeks. OBJECTIVE: The aim of this paper is to improve, advance and expand our understanding and the knowledge beyond what is already known to wider colleagues, to impact society at large and to disseminate the findings to wider audiences. Also, the objective of the present paper is to examine the different effect of black peel in the treatment of facial dermatoses, and it gives realistic tips on performing black peeling safely and effectively in ethnic skin groups. This is meant to shed light on some ways for clinical handling and improving our understanding scientifically and educationally. It is the first original case report of interest in the existing literature for the best of my knowledge that had a positive impact for my female patient. METHOD: A single pass of black peel was applied on the lady's face. RESULTS: A pleasing brightening effect was examined and boosted the lady confidence. CONCLUSION: The patient had a positive pleasing experience that she had noticed from a single session application of the black peel. PMID- 28834125 TI - Analysis of survival for patients with chronic kidney disease primarily related to renal cancer surgery. AB - OBJECTIVES: To evaluate predictors of long-term survival for patients with chronic kidney disease primarily due to surgery (CKD-S). Patients with CKD-S have generally good survival that approximates patients who do not have CKD even after renal cancer surgery (RCS), yet there may be heterogeneity within this cohort. PATIENTS AND METHODS: From 1997 to 2008, 4 246 patients underwent RCS at our centre. The median (interquartile range [IQR]) follow-up was 9.4 (7.3-11.0) years. New baseline glomerular filtration rate (GFR) was defined as highest GFR between nadir and 6 weeks after RCS. We retrospectively evaluated three cohorts: no-CKD (new baseline GFR of >=60 mL/min/1.73 m2 ); CKD-S (new baseline GFR of <60 mL/min/1.73 m2 but preoperative GFR of >=60 mL/min/1.73 m2 ); and CKD due to medical aetiologies who then require RCS (CKD-M/S, preoperative and new baseline GFR both <60 mL/min/1.73 m2 ). Analysis focused primarily on non-renal cancer related survival (NRCRS) for the CKD-S cohort. Kaplan-Meier analysis assessed the longitudinal impact of new baseline GFR (45-60 mL/min/1.73 m2 vs <45 mL/min/1.73 m2 ) and Cox regression evaluated relative impact of preoperative GFR, new baseline GFR, and relevant demographics/comorbidities. RESULTS: Of the 4 246 patients who underwent RCS, 931 had CKD-S and 1 113 had CKD-M/S, whilst 2 202 had no-CKD even after RCS. Partial/radical nephrectomy (PN/RN) was performed in 54%/46% of the patients, respectively. For CKD-S, 641 patients had a new baseline GFR of 45-60 mL/min/1.73 m2 and 290 had a new baseline GFR of <45 mL/min/1.73 m2 . Kaplan-Meier analysis showed significantly reduced NRCRS for patients with CKD S with a GFR of <45 mL/min/1.73 m2 compared to those with no-CKD or CKD-S with a GFR of 45-60 mL/min/1.73 m2 (both P <= 0.004), and competing risk analysis confirmed this (P < 0.001). Age, gender, heart disease, and new baseline GFR were all associated independently with NRCRS for patients with CKD-S (all P <= 0.02). CONCLUSION: Our data suggest that CKD-S is heterogeneous, and patients with a reduced new baseline GFR have compromised survival, particularly if <45 mL/min/1.73 m2 . Our findings may have implications regarding choice of PN/RN in patients at risk of developing CKD-S. PMID- 28834126 TI - Introduction to behavioral phenotypes in medical genetics. PMID- 28834127 TI - Successful treatment of metastatic alveolar rhabdomyosarcoma with MGMT gene promoter methylation by temozolomide-based combination chemotherapy. AB - A 3-year-old male presented with a large retroperitoneal mass and multiple metastases. Biopsy results suggested alveolar rhabdomyosarcoma bearing a methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Serum microRNA-206 levels were elevated and remained high after three cycles of vincristine, dactinomycin, and cyclophosphamide (VAC). Replacement of vincristine, irinotecan, and temozolomide (VIT) for VAC induced a marked tumor reduction and normalization of the miR-206 levels. The patient completed 14 cycles of VIT with local radiotherapy and has been in remission for 31 months. Temozolomide could be effective for tumors with a methylated MGMT gene promoter. Individualized therapy is warranted for such patients. PMID- 28834129 TI - Evolution of the Ligand Shell Morphology during Ligand Exchange Reactions on Gold Nanoparticles. AB - Ligand exchange reactions are used to achieve nanoparticles coated with a mixture of ligand molecules. Currently, nothing is known on the evolution of the morphology of the ligand shell during the reaction. Here, we use a recently developed method (based on MALDI-TOF) to follow the evolution of the ligand shell composition and morphology during the reaction. We observe the expected evolution in composition and we find that the ligand shell starts as a random mixture and gradually evolves towards a patchy morphology. When the composition has reached a plateau (i.e. when the reaction is generally assumed to be finished), the ligand shell morphology keeps evolving for days, slowly approaching its equilibrium configuration. PMID- 28834128 TI - Plasma parathyroid hormone and cardiovascular disease in treatment-naive patients with primary hyperparathyroidism: The EPATH trial. AB - Patients with primary hyperparathyroidism are at increased risk for high blood pressure, vascular stiffening, and left ventricular hypertrophy, but previous studies have failed to demonstrate the direct associations with circulating parathyroid hormone (PTH) levels. The authors investigated cross-sectional relationships between PTH and 24-hour pulse wave velocity, nocturnal systolic blood pressure, and left ventricular mass index in patients with primary hyperparathyroidism who were treatment-naive with cinacalcet, renin-angiotensin aldosterone-system inhibitors, and thiazide or loop diuretics. In 76 patients, mean+/-SD of pulse wave velocity, nocturnal systolic blood pressure, and left ventricular mass index values were 9.3+/-1.8 m/s, 116.6+/-17.0 mm Hg, and 92.8+/ 23.0 g/m2. In multivariate linear regression analyses with adjustment for potentially confounding parameters, PTH was independently associated with nocturnal systolic blood pressure (adjusted beta coefficient=.284, P=.040), mean 24-hour pulse wave velocity (beta=.199, P=.001), and left ventricular mass index (beta=.252, P=.025). PTH may promote vascular and cardiac remodeling in primary hyperparathyroidism. Interventional trials are needed to test the antihypertensive and cardioprotective effects of PTH-inhibitory treatment strategies. PMID- 28834130 TI - Lack of mortality in 22 children with sickle cell anemia and severe malarial anemia. AB - Retrospective studies suggest that there is high mortality in children with sickle cell anemia (SCA) and severe malaria. We assessed mortality in Ugandan children with severe malarial anemia (SMA, n = 232) or cerebral malaria (CM, n = 267) by sickle cell hemoglobin genotype. Admission and 2-year follow-up mortality did not differ among children with SMA who had homozygous form of sickle cell hemoglobin (HbSS) versus normal form of adult hemoglobin (admission, 0/22, 0%, vs. 1/208, 0.5%; follow-up, 1/22, 4.5%; 7/207, 3.4%, respectively; all P > 0.6). The single child with CM and HbSS survived. The study findings highlight the need for large prospective studies of malaria-related mortality in children with SCA. PMID- 28834131 TI - Alterations in anterior-posterior patterning and its accompanying changes along the proximal-distal axis during the fin-to-limb transition. AB - The evolution from fins to limbs was one of the most successful innovations for vertebrates, allowing them to vastly expand their behaviors and habitats. Fossil records suggest that morphological changes occurred not only along the proximal distal axis included appearance of the autopod, but also occurred along the anterior-posterior axis included reductions in the size and number of basal bones and digits. This review focuses on recent progress in developmental and genetic studies aimed at elucidating the mechanisms underlying alteration of anterior posterior patterning and its accompanying changes along the proximal-distal axis during the fin-to-limb transition. PMID- 28834132 TI - TiO2 Electron Transport Bilayer for Highly Efficient Planar Perovskite Solar Cell. AB - In planar perovskite solar cells, it is vital to engineer the extraction and recombination of electron-hole pairs at the electron transport layer/perovskite interface for obtaining high performance. This study reports a novel titanium oxide (TiO2 ) bilayer with different Fermi energy levels by combing atomic layer deposition and spin-coating technique. Energy band alignments of TiO2 bilayer can be modulated by controlling the deposition order of layers. The TiO2 bilayer based perovskite solar cells are highly efficient in carrier extraction, recombination suppression, and defect passivation, and thus demonstrate champion efficiencies up to 16.5%, presenting almost 50% enhancement compared to the TiO2 single layer based counterparts. The results suggest that the bilayer with type II band alignment as electron transport layers provides an efficient approach for constructing high-performance planar perovskite solar cells. PMID- 28834133 TI - Electroless Formation of Hybrid Lithium Anodes for Fast Interfacial Ion Transport. AB - Rechargeable batteries based on metallic anodes are of interest for fundamental and application-focused studies of chemical and physical kinetics of liquids at solid interfaces. Approaches that allow facile creation of uniform coatings on these metals to prevent physical contact with liquid electrolytes, while enabling fast ion transport, are essential to address chemical instability of the anodes. Here, we report a simple electroless ion-exchange chemistry for creating coatings of indium on lithium. By means of joint density functional theory and interfacial characterization experiments, we show that In coatings stabilize Li by multiple processes, including exceptionally fast surface diffusion of lithium ions and high chemical resistance to liquid electrolytes. Indium coatings also undergo reversible alloying reactions with lithium ions, facilitating design of high capacity hybrid In-Li anodes that use both alloying and plating approaches for charge storage. By means of direct visualization, we further show that the coatings enable remarkably compact and uniform electrodeposition. The resultant In-Li anodes are shown to exhibit minimal capacity fade in extended galvanostatic cycling when paired with commercial-grade cathodes. PMID- 28834134 TI - Limited fitness costs of herbicide-resistance traits in Amaranthus tuberculatus facilitate resistance evolution. AB - BACKGROUND: The fitness cost of herbicide resistance (HR) in the absence of herbicide selection plays a key role in HR evolution. Quantifying the fitness cost of resistance, however, is challenging, and there exists a knowledge gap in this area. A synthetic (artificially generated) Amaranthus tuberculatus population segregating for five types of HR was subjected to competitive growth conditions in the absence of herbicide selection for six generations. Fitness costs were quantified by using a combination of phenotyping and genotyping to monitor HR frequency changes over generations. RESULTS: In the absence of herbicide selection, a significant fitness cost was observed for resistance to acetolactate synthase-inhibiting herbicides, but not for resistances to atrazine (non-target-site resistance mechanism), protoporphyrinogen oxidase inhibitors, 4 hydroxyphenylpryuvate dioxygenase inhibitors or glyphosate. Glyphosate resistance was conferred by multiple mechanisms in the synthetic population, and further analysis revealed that one mechanism, amplification of the 5 enolypyruvylshikimate-3-phosphate synthase gene, did decrease in frequency. CONCLUSION: Our results indicate that herbicide-resistance mitigation strategies (e.g. herbicide rotation) that rely on the existence of fitness costs in the absence of herbicide selection likely will be largely ineffective in many cases. (c) 2017 Society of Chemical Industry. PMID- 28834135 TI - The Pharmacogenetics of Metformin in Women with Polycystic Ovary Syndrome: A Randomized Trial. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily +/- oral contraceptive pills (150 MUg desogestrel + 30 MUg ethinylestradiol). In the entire study population, treatment was associated with reduced weight (median weight change -2.4 kg, 25th-75th percentile -5.2 to 0.3 kg, p < 0.001) and increased triglycerides (0.2 mmol/L (0.0-0.6 mmol/L), p < 0.01) without significant changes in other lipid parameters or insulin sensitivity (insulinAUC , glucoseAUC during OGTT). None of the evaluated polymorphisms significantly affected any treatment outcome. In conclusion, the genetic variants investigated were not crucial for the clinical response to metformin in PCOS. PMID- 28834137 TI - Evaluation of the expected ventilatory response to metabolic acidosis in chronic hemodialysis patients. AB - INTRODUCTION: Expected pCO2 during metabolic acidosis should be computed to rule out superimposing respiratory acid-base disorders, the latter being featured by too high or too low pCO2 than expected. At least 4 different and inconsistent formulas exist. Based on the common practical rule, the reduction of pCO2 equals 1.2 multiplied by the reduction of serum bicarbonate ([HCO3-]), whereas pCO2 equals to the 2 digit after pH decimal point according to Fulop. Instead, based on Winters' formula, pCO2 equals to 1.5 times [HCO3-] + 8. Finally, a very simple formula has been proposed, it reads pCO2 = [HCO3-] + 15. Beyond the evident simplicity, the latter has been effective in a small hemodialysis cohort but validation in a larger dataset is highly desirable. METHODS: Formulas have been applied to 180 hemodialysis patients' blood samples dataset featured by mild metabolic acidosis (HCO3 >= 14 mEq/L) and root mean square errors (RMSE) associated with each formula were computed. pCO2 reference range was computed as expected pCO2 +/- 2 RMSE. FINDINGS: Fulop's rule and Winters' formula are associated with large prediction errors. Conversely, the common practical rule and the very simple formula are both featured by the same low error (1.7 mmHg). They further show good agreement and pick out the same reference range. DISCUSSION: Superimposing respiratory acid-base disorders can be promptly and effectively ruled out by computing expected pCO2 as [HCO3-] + 15, a very simple formula proved to be interchangeable with the common practical rule that requires computes and assumptions, but leads to same results. PMID- 28834138 TI - EMDR as a treatment for long-term depression: A feasibility study. AB - OBJECTIVE: Current treatments for long-term depression - medication and psychotherapy - are effective for some but not all clients. New approaches need to be developed to complement the ones already available. This study was designed to test the feasibility of using an effective post-traumatic stress disorder treatment for people with long-term depression. DESIGN: A single-case experimental design with replications was undertaken as a feasibility study of eye movement desensitization and reprocessing (EMDR) in treating long-term depression. METHODS: Thirteen people with recurrent and/or long-term depression were recruited from primary care mental health services and given standard protocol EMDR for a maximum of 20 sessions. Levels of depression were measured before and after treatment and at follow-up, clients also rated their mood each day. RESULTS: Eight people engaged with the treatment; seven of these had clinically significant and statistically reliable improvement on the Hamilton Rating Scale for Depression. Daily mood ratings were highly variable both during baseline and intervention. CONCLUSIONS: EMDR is a feasible treatment for recurrent and/or long-term depression. Research on treatment efficacy and effectiveness is now required. PRACTITIONER POINTS: EMDR may be an effective treatment for depression. EMDR could be considered if first-line approaches (CBT and counselling) have been tried and failed. EMDR may be particularly helpful for service users with a history of trauma. PMID- 28834139 TI - Minocycline: A strategy for unresponsive nerve function impairment. PMID- 28834136 TI - No relationship between late HIV diagnosis and social deprivation in newly diagnosed patients in France. AB - OBJECTIVES: The aim of the study was to determine whether there is a relationship between social deprivation and time of HIV diagnosis in France. METHODS: Prospectively collected data from a multicentre database were used in the study. Patients with a first HIV diagnosis between 1 January 2014 and 31 December 2015 were selected from the database. Deprivation was measured using the European Deprivation Index (EDI), which is an ecological index constructed from the address of residence and based on the smallest geographical census unit, in which individuals are classified so as to be comparable with national quintiles. Time of diagnosis was classified as being at an early, intermediate, late, or advanced stage of disease. Age, gender, distance from home to HIV centre, most probable route of infection, and hepatitis B or C coinfection were considered in the analysis. Because of a strong interaction between gender and most probable route of infection, we constructed a 'population' variable: men who have sex with men (MSM), heterosexual men and women. RESULTS: Of 1421 newly diagnosed patients, 44% were diagnosed either late or at an advanced stage of disease, and 46.3% were in the highest deprivation quintile. Using multivariate logistic regression, 'population' [odds ratio (OR) 0.62 (95% confidence interval (CI) 0.48-0.78) for MSM compared with women] and age [OR 1.39 (95% CI 1.07-1.80), 1.72 (1.32-2.23) and 1.86 (1.40-2.47) for the second, third and fourth quartiles, respectively, compared with the first quartile] were found to be related to late diagnosis. EDI level was not related to late HIV diagnosis. CONCLUSIONS: 'Population' seems to be more relevant than EDI to define evidence-based interventions to limit late diagnosis. PMID- 28834140 TI - Advances in normothermic perfusion of the liver. PMID- 28834141 TI - Fatal graft-versus-host disease after living-donor liver transplantation from an HLA-DR-mismatched donor. AB - Acute GVHD is a rare complication after liver transplantation that has a high mortality rate. We experienced an infant case complicated with acute GVHD. An 8 month-old infant with biliary atresia underwent LDLT with a graft obtained from his mother. Their HLAs showed a donor-dominant one-way match, not at HLA-DR but at HLA-A, HLA-B, and HLA-C (recipient; A 31/33, B 51/54, C 1/14, DR 9/11, donor; A 31/-, B 51/-, C 14/-, DR 8/11). The patient exhibited a high fever, skin rash, and diarrhea, and was diagnosed with acute GVHD based on the blood chimerism test. Despite immunosuppression treatment with prednisolone and tacrolimus, plasma exchange, blood transfusion including cord blood transplantation, and antibiotics, the child died on postoperative day 126. Donor-dominant one-way matching at HLA class 1 can be a high-risk factor for acute GVHD despite HLA class 2 mismatching. PMID- 28834142 TI - In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay. AB - The decline of the immune system with age known as immune senescence contributes to inefficient pathogen clearance and is a key risk factor for many aged-related diseases. However, reversing or halting immune aging requires more knowledge about the cell biology of senescence in immune cells. Telomere shortening, low autophagy and mitochondrial dysfunction have been shown to underpin cell senescence. While autophagy has been found to control mitochondrial damage, no link has been made to telomere attrition. In contrast, mitochondrial stress can contribute to telomere attrition and vice versa. Whereas this link has been investigated in fibroblasts or cell lines, it is unclear whether this link exists in primary cells such as human lymphocytes and whether autophagy contributes to it. As traditional methods for measuring telomere length are low throughput or unsuitable for the analysis of cell subtypes within a mixed population of primary cells, we have developed a novel sensitive flow-FISH assay using the imaging flow cytometer. Using this assay, we show a correlation between age and increased mitochondrial reactive oxygen species in CD8+ T-cell subsets, but not with autophagy. Telomere shortening within the CD8+ subset could be prevented in vitro by treatment with a ROS scavenger. Our novel assay is a sensitive assay to measure relative telomere length in primary cells and has revealed ROS as a contributing factor to the decline in telomere length. PMID- 28834143 TI - Effectiveness of instrumental reminiscence intervention on improving coping in healthy older adults. AB - Reminiscence is a psychological intervention that uses the recall of past events, feelings, and thoughts to facilitate pleasure, quality of life, and adjustment to present life. The main goal of this study was to investigate the effect of a reminiscence intervention programme on coping strategies. One hundred fifty healthy older adults attended the reminiscence sessions. In order to evaluate the effects of the programme and find out if its effects lasted over time, we used an experimental design with pretest, posttest, and follow-up assessments, comparing a control group to the intervention group. Repeated-measures analysis of variance showed significant differences in problem-solving coping, positive reappraisal, social support seeking, and avoidance coping with the treatment group obtaining higher scores than the control group in all cases. The effects declined after 3 months, but some differences were found in the treatment group obtaining higher scores in problem-solving coping and positive reappraisal and lower in overt emotional expression. The study suggests that reminiscence therapy contributes to mental health by enhancing coping strategies that can allow the elderly to cope successfully and overcome psychological distress. PMID- 28834144 TI - Differential associations of systolic and diastolic time rate of blood pressure variation with carotid atherosclerosis and plaque echogenicity. AB - In the current study, the authors sought to assess whether the time rate of systolic and diastolic blood pressure variation is associated with advanced subclinical stages of carotid atherosclerosis and plaque echogenicity assessed by gray scale median. The authors recruited 237 consecutive patients with normotension and hypertension who underwent 24-hour ambulatory blood pressure monitoring and carotid artery ultrasonography. There was an independent association between low 24-hour systolic time rate and increased echogenicity of carotid plaques (adjusted odds ratio for highest vs lower tertiles of gray scale median, 0.470; 95% confidence interval, 0.245-0.902 [P = .023]). Moreover, increased nighttime diastolic time rate independently correlated with the presence (adjusted odds ratio, 1.328; P = .015) and number of carotid plaques (adjusted odds ratio, 1.410; P = .003). These results indicate differential associations of the systolic and diastolic components of time rate of blood pressure variation with the presence, extent, and composition of carotid plaques and suggest that when blood pressure variation is assessed, both components should be considered. PMID- 28834145 TI - Imidacloprid-susceptible Nilaparvata lugens individuals exceeded resistant individuals in a mixture population with density pressure. AB - BACKGROUND: Fitness costs associated with insecticide resistance in pest insects have mainly been studied under optimal laboratory conditions. However, resistant insects face more stressors than just insecticides in the field, and how the resistant population reacts to these stressors is of practical importance for the control of pest insects such as the brown planthopper Nilaparvata lugens. The aim of the present study was to explore the impact of population density on the competitiveness of resistant and susceptible individuals. RESULTS: Two isogenic N. lugens populations, a highly imidacloprid-resistant population (HZ-R) with a resistance ratio (RR) of 227.10 and a relatively susceptible population (HZ-S) with an RR of 2.99, were created from a field-resistant population (HZ; RR 62.51). The high resistance levels of HZ-R and HZ were mainly attributable to the overexpression of multiple cytochrome P450 (CYP) genes such as CYP6ER1, CYP6AY1, CYP6CW1 and CYP4CE1 compared with HZ-S, this being supported by piperonyl butoxide synergism. HZ-R was observed to be more resistant to thiacloprid and etofenprox compared with HZ and HZ-S. Most interestingly, in high population density treatments, HZ-S individuals were much more competitive than HZ-R individuals. CONCLUSION: Imidacloprid-resistant individuals of N. lugens are less competitive than their susceptible counterparts under density pressure. (c) 2017 Society of Chemical Industry. PMID- 28834147 TI - Capturing the Unconventional Metallofullerene M@C66 by Trifluoromethylation: A Theoretical Study. AB - The endohedral metallofullerenes M@C66 (M=rare-earth metal) have a unique structure that violates the well-known "isolated pentagon rule" of fullerene science. Although the synthesis of M@C66 has been achieved by using the arc discharge method, the solvent extraction and purification of M@C66 remain challenges because of their radical character and extremely high reactivity. In this paper, the possibility of capturing these missing metallofullerenes by exohedral functionalization of the C66 cage is demonstrated theoretically. Stable trifluoromethylated derivatives of Y@C66 are revealed by density functional theory calculations. Mono- or poly-trifluoromethylation of Y@C66 results in a closed-shell electronic configuration and a large band gap. Thus Y@C66 can be greatly stabilized through trifluoromethylation. The trifluoromethyl group prefers to be attached to the fused pentagon region to relieve local steric strain. The mechanism of isomerization of Y@C66 (CF3 )3 is also investigated and it is found that the attached trifluoromethyl group can migrate from a carbon atom to another via a transition state. PMID- 28834146 TI - Poor adherence to hepatocellular carcinoma surveillance: A systematic review and meta-analysis of a complex issue. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) surveillance is associated with improved outcomes and long-term survival. Our goal is to evaluate adherence rates to HCC surveillance. METHODS: We performed a systematic search of the PubMed and Scopus databases and abstract search of relevant studies from recent major liver meetings. All searches and data extraction were performed independently by two authors. Analysis was via random-effects models and multivariate meta-regression. RESULTS: A total of 22 studies (n = 19 511) met inclusion criteria (original non interventional studies with defined cirrhosis or chronic hepatitis B or chronic hepatitis C with advanced fibrosis populations, and surveillance tests and intervals). Overall adherence rate was 52% (95% CI 38%-66%). Adherence was significantly higher in cirrhotic patients compared to chronic hepatitis B and other high-risk patients, in European compared to North American studies, in less than 12-month compared to yearly surveillance intervals, and in prospective compared to retrospective studies (71%, 95% CI 64%-78% vs 39%, 95% CI 26%-51%, P < .001). The between-study heterogeneity of all above analyses was significant (P < .001). Only the study design (retrospective vs prospective cohort) had statistical significance in a multivariate meta-regression model (P < .05) and could account for some of the differences above. CONCLUSIONS: Overall adherence rate to HCC surveillance was suboptimal at 52% with no significant differences by liver disease aetiology or study location in multivariate meta-regression analysis. Further research and educational efforts are needed to improve the current rate of HCC surveillance. PMID- 28834148 TI - Recurrent malignancy: Are we pushing the envelope? PMID- 28834149 TI - Maternal inheritance of Nanog ortholog in blunt-snout bream. AB - The homeodomain transcription factor Nanog plays an essential role in maintaining pluripotency and self-renewal of embryonic stem cells in mammals. However, the evolutionary conservation of its ortholog in teleosts remains elusive. Here we isolated and characterized a Nanog homolog named as Ma-Nanog in blunt-snout bream (Megalobrama amblycephala). The full-length genomic sequence is 3,326 bp in length and consists of four exons encoding a homeodomain protein of 386 amino acid residues. Comparison of protein sequences revealed that Ma-Nanog is highly homologous to those in other teleosts, particularly in the homeodomain region. During embryogenesis, RNA expression of Nanog was only detected in early developmental embryos, predominantly at the blastula stage, which suggested the transcripts were mainly present in pluripotent stem cells. RNA fluorescence in situ hybridization verified that the signal of the transcripts is present in the germ cells. RNA expression was observed in the oogonia and early stage of oocytes in the ovary, or in the spermatogonia, spermatocytes, and spermatids in the testis. Surprisingly, the transcripts were also detected in adult tissues such as in liver by RT-PCR or qRT-PCR. Subcellular localization of the Nanog protein was also verified in nuclei. Taken together, these results suggested that Ma-Nanog is maternally inherited with conserved features, thus can be potentially used as a marker for stem cells in blunt-snout bream. PMID- 28834150 TI - Atmospheric Pressure Non-Thermal Plasma Activation of CO2 in a Packed-Bed Dielectric Barrier Discharge Reactor. AB - Direct conversion of CO2 into CO and O2 is performed in a packed-bed dielectric barrier discharge (DBD) non-thermal plasma reactor at low temperatures and atmospheric pressure. The maximum CO2 conversion of 22.6 % is achieved when BaTiO3 pellets are fully packed into the discharge gap. The introduction of gamma Al2 O3 or 10 wt % Ni/gamma-Al2 O3 catalyst into the BaTiO3 packed DBD reactor increases both CO2 conversion and energy efficiency of the plasma process. Packing gamma-Al2 O3 or 10 wt % Ni/gamma-Al2 O3 upstream of the BaTiO3 bed shows higher CO2 conversion and energy efficiency compared with that of mid- or downstream packing modes because the reverse reaction of CO2 conversion-the recombination of CO and O to form CO2 -is more likely to occur in mid- and downstream modes. Compared with the gamma-Al2 O3 support, the coupling of the DBD with the Ni catalyst shows a higher CO2 conversion, which can be attributed to the presence of Ni active species on the catalyst surface. The argon plasma treatment of the reacted Ni catalyst provides extra evidence to confirm the role of Ni active species in the conversion of CO2 . PMID- 28834152 TI - Pyogenic variant of primary cutaneous CD30+ anaplastic large-cell lymphoma: Spontaneous remission in a young adult. PMID- 28834151 TI - Performance of non-conventional yeasts in co-culture with brewers' yeast for steering ethanol and aroma production. AB - Increasing interest in new beer types has stimulated the search for approaches to extend the metabolic variation of brewers' yeast. Therefore, we tested two approaches using non-conventional yeast to create a beer with lower ethanol content and a complex aroma bouquet. First, the mono-culture performance was monitored of 49 wild yeast isolates of Saccharomyces cerevisiae (16 strains), Cyberlindnera fabianii (9 strains) and Pichia kudriavzevii (24 strains). Interestingly, both C. fabianii and P. kudriavzevii isolates produced relatively more esters compared with S. cerevisiae isolates, despite their limited fermentation capacity. Next, one representative strain of each species (Sc131, Cf65 and Pk129) was applied as co-culture with brewers' yeast (ratio 1:1). Co cultures with Cf65 and Pk129 resulted in a beer with lower alcohol content (3.5, 3.8 compared with 4.2% v/v) and relatively more esters. At higher inoculum ratios of Cf65 over brewers' yeast, growth inhibition of brewers' yeast was observed, most likely caused by competition for oxygen between brewers' yeast and Cf65 resulting in a reduced level of ethanol and altered aroma profiles. With this study, we demonstrate the feasibility of using non-conventional yeast species in co-cultivation with traditional brewers' yeast to tailor aroma profiles as well as the final ethanol content of beer. PMID- 28834153 TI - Transcript-level expression control of plant NLR genes. AB - Plant NLR genes encode sensitive immune receptors that can mediate the specific recognition of pathogen avirulence effectors and activate a strong defence response, termed effector-triggered immunity. The expression of NLRs requires strict regulation, as their ability to trigger immunity is dependent on their dose, and overexpression of NLRs results in autoimmunity and massive fitness costs. An elaborate interplay of different mechanisms controlling NLR transcript levels allows plants to maximize their defence capacity, whilst limiting negative impact on their fitness. Global suppression of NLR transcripts may be a prerequisite for the fast evolution of new NLR variants and the expansion of this gene family. Here, we summarize recent progress made towards a comprehensive understanding of NLR transcript-level expression control. Multiple mechanistic steps, including transcription as well as co-/post-transcriptional processing and transcript turn-over, contribute to balanced base levels of NLR transcripts and allow for dynamic adjustments to defence situations. PMID- 28834154 TI - Increased myocardial contractility identifies patients with decompensated cirrhosis requiring liver transplantation. AB - Late allocation of organs for transplant impairs post-liver transplantation (LT) survival. Cardiac dysfunction, especially diastolic and autonomic dysfunction, is frequent and plays an important role in the prognosis of patients with cirrhosis. However, the role of myocardial contractility is unexplored, and its prognostic value is controversially discussed. This study analyses the role of myocardial contractility assessed by speckle tracking echocardiography in LT allocation. In total, 168 patients with cirrhosis (training cohort, 111; validation cohort [VC], 57) awaiting LT in 2 centers were included in this retrospective study. Also, 51 patients from the training and all patients from the VC were transplanted, 36 patients of the training and 38 of the VC were alive at the end of follow-up, and 21 nontransplanted patients died. Contractility of the left ventricle (LV) increased with severity of the Child-Pugh score. Interestingly, higher LV contractility in the training cohort patients, especially in those with Child Pugh C, was an independent predictor of reduced transplant-free survival. In male patients, the effects on survival of increased left and right ventricular myocardial contractility were more pronounced. Notably, competing risk analysis demonstrated that increased contractility is associated with earlier LT, which could be confirmed in the VC. Importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post-LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT earlier, but without increased post-LT mortality. Liver Transplantation 24 15-25 2018 AASLD. PMID- 28834155 TI - Pit initiation on nitinol in simulated physiological solutions. AB - Inclusions appear to play a crucial role in the initiation of pitting on nitinol, but the reason remains unclear. Furthermore, it has not been established whether the type of inclusion is a central factor. In this study, potentiodynamic polarization together with scanning electron microscopy and energy dispersive X ray spectroscopy were used to provide more insight into the initiation of pits on electropolished nitinol wire. Corrosion was limited to a single primary pit on each of the few wire samples that exhibited breakdown. The pit contained numerous Ti2 NiOx inclusions, but secondary pits that developed within the primary pit provided evidence that these inclusions were the sites of pit initiation. Although several theories have been proposed to account for pit initiation at inclusions in mechanically polished and electropolished nitinol, titanium depletion in the adjacent alloy matrix appears to provide the most viable explanation. The key factor appears to be the size of the inclusion and therefore the extent of titanium depletion in the alloy matrix. The type of inclusion evidently plays a secondary role at most. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1605-1610, 2018. PMID- 28834156 TI - Super pulse CO2 laser therapy for benign eyelid tumors. AB - BACKGROUND: Benign eyelid tumors occur commonly in daily outpatient services. OBJECTIVES: The aim of this study was to evaluate the treatment of benign eyelid lesions with a super pulse CO2 laser as an alternative to surgical excision. METHODS: This retrospective clinical study included 80 patients with 99 benign eyelid lesions treated with super pulse CO2 laser photocoagulation. The following areas were involved: the upper eyelid in 38 cases, the lower eyelid in 39 cases, and the angulus oculi in seven cases (the eyelid margin was included in 18 cases). The laser spot size ranged from 120 to 200 MUm and the super pulse CO2 laser power density varied between 0.6 and 21.1 W/mm2 . The mean follow-up period was 14.0+/-7.1 months (range five to 30). Histological diagnoses were obtained in 62 of the 80 patients. RESULTS: The cosmetic outcomes of all of the patients were satisfactory after treatment, and the wounds formed dry scabs, with no infections. They were epithelialized within 2-4 weeks with normal-appearing epithelium. Temporarily, the treated area had less hyperpigmentation than the surrounding normal skin, showing no obvious scars or notches. No complications were observed, with no relapses during the follow-up. CONCLUSIONS: The super pulse CO2 laser therapy of the benign eyelid tumors provided satisfactory cosmetic results in this study. It is a convenient, cheap, accessible, and well tolerated alternative to traditional surgery, especially for diffuse tumors, or those positioned close to the lacrimal papillae. PMID- 28834157 TI - Fins into limbs: Recent insights from sarcopterygian fish. AB - Limbs with digits evolved as sarcopterygian fish transitioned to a terrestrial life, giving rise to modern tetrapods. Since the Devonian, most of the sarcopterygian fish diversity became extinct, with the only surviving representatives being two coelacanth and six lungfish species. As the sister group of tetrapods, sarcopterygian fish constitute the ideal models to address questions regarding the transition of vertebrates from water to land. However, distantly related yet experimentally amenable teleost fish species have instead become the organisms of choice for geneticists and developmental biologists. Comparative studies using teleosts, such as zebrafish, have greatly enriched our knowledge on the genetic and regulatory mechanisms underlying fin development. However, their highly derived fin anatomy provides limited insights on the origin of limbs and the teleost-specific whole-genome duplication represents a further complication to comparisons of gene function and regulation. In recent years, refined morphological and behavioral studies and access to lungfish embryos and availability of genetic resources have underscored the value of nontetrapod sarcopterygians as model organisms. Here we review recent studies using lungfishes and coelacanths that shed light on various aspects of the evolution of the tetrapod limb, including the origin of the tetrapod pelvis, limb musculature, digits, locomotion, and regenerative capacity. PMID- 28834158 TI - Clonal characteristics of paired infiltrating and circulating B lymphocyte repertoire in patients with primary biliary cholangitis. AB - BACKGROUND: PBC is a prototypical autoimmune liver disease characterized by portal lymphoplasmacyte infiltration. ALD is a prototypical environment-driven disease, featured by mild lymphocyte infiltration. We hypothesize that B cells are more involved in the pathogenesis of PBC. By analysing the infiltrating B cell repertoire, we aimed to unveil greater oligoclonal expansion and active clonal exchange between liver and periphery in PBC than in ALD patients. METHODS: Using NGS of Ig H chain genes, we analysed the liver-infiltrating and paired peripheral B lymphocyte repertoire from nine PBC and four ALD patients. RESULTS: In the liver of PBC and ALD patients, (i) roughly 10% of the B lymphocytes were clonally related and highly expressed, and there were also lineages that underwent extensive clonal expansion; (ii) there was different use of IGHV/IGHJ segments between PBC and ALD, suggesting distinct Ag exposure backgrounds, but this did not lead to a significant difference in their clonal expansion level. Analysis of data sets from paired samples further revealed, (iii) direct clonal exchange and evolutionally related B cell clones between the infiltrating and peripheral repertoire; (iv) the seeding of the infiltrating clones to periphery, and peripheral ones to the liver, for further extensive evolution. CONCLUSIONS: The oligoclonally expanded nature of the infiltrating B cell repertoire implies B cell immunity is involved in the pathogenesis of both diseases. The observed clonal exchange might provide an approach to identify and monitor the infiltrating B cells through the periphery. PMID- 28834159 TI - A novel protein C-factor VII chimera provides new insights into the structural requirements for cytoprotective protease-activated receptor 1 signaling. AB - : Essentials The basis of cytoprotective protease-activated receptor 1 (PAR1) signaling is not fully understood. Activated protein C chimera (APCFVII-82 ) was used to identify requirements for PAR1 signaling. APCFVII-82 did not initiate PAR1 signaling, but conferred monocyte anti-inflammatory activity. APC-specific light chain residues are required for cytoprotective PAR1 signaling. SUMMARY: Background Activated protein C (APC) cell signaling is largely reliant upon its ability to mediate protease-activated receptor (PAR) 1 proteolysis when bound to the endothelial cell (EC) protein C (PC) receptor (EPCR). Furthermore, EPCR-bound PC modulates PAR1 signaling by thrombin to induce APC-like EC cytoprotection. Objective The molecular determinants of EPCR-dependent cytoprotective PAR1 signaling remain poorly defined. To address this, a PC-factor VII chimera (PCFVII 82 ) possessing FVII N-terminal domains and conserved EPCR binding was characterized. Methods Activated PC-FVII chimera (APCFVII-82 ) anticoagulant activity was measured with calibrated automated thrombography and activated FV degradation assays. APCFVII-82 signaling activity was characterized by the use of reporter assays of PAR1 proteolysis and EC barrier integrity. APCFVII-82 anti inflammatory activity was assessed according to its inhibition of nuclear factor kappaB (NF-kappaB) activation and cytokine secretion from monocytes. Results PCFVII-82 was activated normally by thrombin on ECs, but was unable to inhibit plasma thrombin generation. Surprisingly, APCFVII-82 did not mediate EPCR dependent PAR1 proteolysis, confer PAR1-dependent protection of thrombin-induced EC barrier disruption, or limit PAR1-dependent attenuation of interleukin-6 release from lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, EPCR occupation by active site-blocked APCFVII-82 was, like FVII, unable to mimic EC barrier stabilization induced by PC upon PAR1 proteolysis by thrombin. APCFVII-82 did, however, diminish LPS-induced NF-kappaB activation and tumor necrosis factor alpha release from monocytes in an apolipoprotein E receptor 2-dependent manner, with similar efficacy as wild-type APC. Conclusions These findings identify a novel role for APC light chain amino acid residues outside the EPCR-binding site in enabling cytoprotective PAR1 signaling. PMID- 28834160 TI - A genetic variant in a homocysteine metabolic gene that increases the risk of congenital cardiac septal defects in Han Chinese populations. AB - Elevated homocysteine levels are known to be a risk factor for congenital cardiac septal defects (CCSDs), but the mechanism underlying this effect is unknown. The genetic variants that were significantly associated with circulating homocysteine concentrations have been systematically identified through the genome-wide association studies of one-carbon core metabolites. To examine the role of the genome-wide significant homocysteine related variants in the occurrence of CCSDs, we investigated the association between these variants and CCSDs in Han Chinese populations. Five variants of the genome-wide significant homocysteine-related genes were selected for analysis in two stages of case-controlled studies with a total of 904 CCSD patients and 997 controls. SYT9 expression was detected in human cardiovascular tissue using qRT-PCR. The intronic variant rs11041321 of the SYT9 gene was associated with an increased risk of developing CCSDs in both the separate and combined case-controlled studies. Combined samples from the two stage cohorts had a significant elevation in CCSD risk for the T allele (OR = 1.43, P = 2.6 * 10-6 ), CT genotype and TT genotype (CT: OR = 1.30, TT: OR = 2.21; P = 1 * 10-4 ) compared with the wild-type C allele and CC genotype, respectively. The risky T allele carriers exhibited decreased SYT9 mRNA expression, compared with wild-type C allele carriers. The intronic SYT9 variant rs11041321, which exhibits a significant genome-wide association with circulating homocysteine, was associated with the occurrence of CCSDs. This finding helps to characterize the unexpected role of SYT9 in homocysteine metabolism and the development of CCSDs, which further highlighted the interplay of diet, genetics, and human birth defects. (c) 2017 IUBMB Life, 69(9):700-705, 2017. PMID- 28834161 TI - Temporal and spatial distribution of insecticide-resistance mutations in the green peach aphid Myzus persicae (Hemiptera: Aphididae) on primary and secondary host plants in central Chile. AB - BACKGROUND: The aphid Myzus persicae develops insensitivity to almost all classes of insecticides through target site mutations. The aim of this study was to assess the temporal and spatial distribution of resistant aphids that grow on peach trees and weeds, and establish the role of the secondary hosts as a reservoir of resistant genotypes. RESULTS: The frequency of genotypes (RR, RS, and SS) was affected by the host plant, mainly for knock-down resistance (kdr) and modified acetylcholinesterase (MACE) mutations (P < 0.05). A higher frequency of RS and RR was observed in aphids found on peach trees than on weeds. The frequency of the R allele was significantly higher (P < 0.01) than expected in autumn and on weeds for the kdr and MACE mutations, while the frequency of the S allele was high in all seasons for all insecticide-resistance mutations (P < 0.01). The most abundant multilocus genotype was characterized as being RS for the kdr mutation and SS for both super-kdr and MACE. CONCLUSION: This study provides farm-scale evidence that weeds are not an important reservoir of the R allele, but they are for the S allele. Hence, the presence of heterozygous genotypes on peach trees is most likely attributable to weeds. (c) 2017 Society of Chemical Industry. PMID- 28834162 TI - Whither the genotype-phenotype relationship? An historical and methodological appraisal. AB - More than a century ago, Wilhelm Johannsen proposed the terms "genotype" and "phenotype" to study heredity. Much of what we know about genetics and behavior has evolved since then, especially how causality from genotypes can be inferred from observational studies of phenotypes. Unfortunately, there are genotypes that produce complex clinical-behavioral phenotypes-pleiotropy. In addition, there are often many genotypes that produce the same phenotype, adding a layer of complexity in establishing valid genotype-phenotype relationships. Unlike the relative simplicity of some phenotypes, behavioral phenotypes, especially those characteristics considered aberrant, are multidimensional and often not easily defined operationally. An alternate approach which attempts to identify less evident manifestations below the level of the phenotype but along the pathway to the prospective genotype-endophenotypes-could prove useful in detecting genes that generate these markers. However, operational definitions of intermediate phenotypes vary, less overt neurobiological expressions for some disorders-autism have not been found, and studies of endophenotypes associated with schizophrenia have been not been very successful. Another approach, suggested by Sewall Wright, uses path analysis to identify causal variables that produce phenotypes. Innovative models of causality have been developed recently by genetic epidemiologists that incorporate Mendel's second law, and Mendelian randomization has been successful in identifying genotypes associated with some diseases, for example, diabetes and cancer. Regrettably, shortcomings regarding genetic markers associated with intermediate phenotypes have been found, although there are statistical procedures to remedy matters. As in any science, genetic researchers need to consider carefully the models of causality they choose. PMID- 28834163 TI - Influence of outflow-obstructed liver volume and venous communication development: A three-dimensional volume study in living donors. AB - Living donor liver transplantation using the left liver graft with the middle hepatic vein (MHV) is a well-established procedure. Following such procedures, outflow obstruction occurs in remnant livers. However, the effects of the outflow obstructed liver volume (LVOut-Ob ), with or without venous communication development, remain unclear. The aim of the study is to investigate effects of outflow-obstructed regions by focusing on short-term outcomes and remnant liver hypertrophy in left liver procurement donors. Of 532 donors, we collected data from 119 undergoing left liver procurement with the MHV. Postoperative hepatic parameters, venous communication development, and liver hypertrophy were evaluated in 2 donor groups based on LVOut-Ob . The left liver was procured with the MHV in 119 donors, who formed 2 more groups based on the median LVOut-Ob : large-outflow-obstruction group (n = 60; LVOut-Ob >= 263 mL) and small-outflow obstruction (n = 59; LVOut-Ob < 263 mL) group. Postoperative liver function parameters were significantly impaired in the large-outflow-obstruction group compared with the small-outflow-obstruction group. Postoperative venous communication developed in 52 (66.7%) of 78 donors analyzed. Hypertrophy ratios in remnant right livers and right paramedian sectors were significantly higher in the small-outflow-obstruction group than in the large-outflow-obstruction group (P = 0.01 and P = 0.02, respectively). The liver hypertrophy ratio of outflow obstructed regions was better, especially in small regions developing venous communication (P = 0.001). The postoperative morbidity rate did not differ significantly (P = 0.66). In conclusion, the procurement of the left liver graft with the MHV was safely performed with minimal morbidity by assessing the donor remnant right liver volume with and without outflow obstruction. Attention should be paid that postoperative hepatic parameters and remnant liver hypertrophy were impaired in the remnant livers with large outflow-obstructed regions compared with those with small outflow-obstructed regions. Liver Transplantation 23 1531 1540 2017 AASLD. PMID- 28834164 TI - Children's food and satiety responsiveness in association with post-prandial glucose following a standardized liquid meal. AB - Children's responsiveness to food cues and satiety may put them at greater risk for obesity; however, little is known about the physiological mechanisms underlying children's responsiveness to food and satiety. The objective of this study was to examine the association between children's post-prandial glucose responses and maternal report of their eating behaviours. A secondary data analysis was conducted using partial correlation analyses adjusted for gender in a sample of children aged 5-10 years and their mothers (N = 28 dyads). Standardized liquid meal tests were administered to children and blood samples were obtained over the following 4 h. Mothers completed the Children's Eating Behaviour Questionnaire. An earlier post-prandial peak glucose concentration was associated with greater food responsiveness (r = -0.39, P = 0.04) but not satiety responsiveness. The percent increase in glucose from fasting to peak also tended to be inversely associated with greater food responsiveness (r = -0.38, P = 0.05). Results suggest that earlier and smaller post-prandial glucose excursions may be related to children's response to food cues. Future research should use objective methods to examine whether the association of post-prandial glucose with food responsiveness prospectively contributes to weight gain. PMID- 28834165 TI - A gain-of-function mutation in TNFRSF13B is a candidate for predisposition to familial or sporadic immune thrombocytopenia. AB - : Essentials Positive family histories suggest the existence of hereditary immune thrombocytopenia (ITP). The predisposing gene for familial ITP was screened in two familial ITP patients. The G76S mutation on TNFRSF13B led to immune dysfunction and induced megakaryocyte apoptosis. The G76S mutation on TNFRSF13B is a gain-of-function mutation and a predisposing variant for ITP. SUMMARY: Background Most immune thrombocytopenia (ITP) is sporadic but a positive family history of ITP in some patients suggests that hereditary forms exist. Because of the rarity of familial ITP families available for study and the heterogeneity of sporadic ITP, family linkage analysis or genome-wide association studies are limited. Objectives Based on one ITP pedigree, we try to identify the predisposing gene in familial or sporadic ITP and reveal the way in which it causes thrombocytopenia. Methods Gene expression profiling analysis and whole exome sequencing were performed on samples from family members with ITP, sporadic ITP cases and healthy individuals. We also evaluated the influence of potential pathogenic mutation on immune function and megakaryocyte apoptosis. Results Whole exome sequencing identified a potential pathologic p.G76S heterozygous mutation on the TNFRSF13B gene in familial ITP patients. ITP patients harboring the G76S mutation displayed an upregulated 'cytokine-cytokine receptor interaction' signal, increased serum TNFalpha, IL-17alpha, IFNgamma and BAFF levels, and enhanced binding capacity of APRIL ligand to B cells. Additionally, Epstein-Barr virus (EBV)-transformed B cells with the G76S mutation could induce human megakaryocyte line (Meg-01) apoptosis significantly. Conclusion p.G76S mutation on the TNFRSF13B gene is responsible for ITP, and is a genetic predisposing factor for familial or sporadic ITP. PMID- 28834166 TI - High Figure of Merit (FOM) of Bragg Modes in Au-Coated Nanodisk Arrays for Plasmonic Sensing. AB - Gold-coated nanodisk arrays of nearly micron periodicity are reported that have high figure of merit (FOM) and sensitivity necessary for plasmonic refractometric sensing, with the added benefit of suitability for surface-enhanced Raman scattering (SERS), large-scale microfabrication using standard photolithographic techniques and a simple instrumental setup. Gold nanodisk arrays are covered with a gold layer to excite the Bragg modes (BM), which are the propagative surface plasmons localized by the diffraction from the disk array. This generates surface guided modes, localized as standing waves, leading to highly confined fields confirmed by a mapping of the SERS intensity and numerical simulations with 3D finite element method. The optimal gold-coated nanodisk arrays are applied for refractometric sensing in transmission spectroscopy with better performance than nanohole arrays and they are integrated to a 96-well plate reader for detection of IgY proteins in the nanometer range in PBS. The potential for sensing in biofluids is assessed with IgG detection in 1:1 diluted urine. The structure exhibits a high FOM of up to 46, exceeding the FOM of structures supporting surface plasmon polaritons and comparable to more complex nanostructures, demonstrating that subwavelength features are not necessary for high-performance plasmonic sensing. PMID- 28834167 TI - Feasibility and safety of focal irreversible electroporation as salvage treatment for localized radio-recurrent prostate cancer. AB - OBJECTIVES: To evaluate the feasibility, safety, early quality-of-life (QoL) and oncological outcomes of salvage focal irreversible electroporation (IRE) for radio-recurrent prostate cancer (PCa). PATIENTS AND METHODS: Patients with localized, radio-recurrent PCa without evidence of metastatic or nodal disease were offered focal IRE according to the consensus guidelines. Patients with a minimum follow-up of 6 months were eligible for analysis. Adverse events were monitored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Patient-reported QoL data were collected at baseline, 6 weeks, 3, 6 and 12 months using the Expanded Prostate Cancer Index Composite (EPIC), the American Urological Association (AUA) symptom score and the 12-item short-from health survey (SF-12) physical and mental component summary questionnaires. Oncological control was evaluated according to serial prostate specific antigen (PSA), 6-month multiparametric magnetic resonance imaging (mpMRI) and 12-month prostate biopsy. Wilcoxon's signed rank test was used to assess QoL differences over time in paired continuous variables. RESULTS: A total of 18 patients were included in the analysis. The median follow-up was 21 months. No high-grade adverse events (CTCAE >2) or recto-urethral fistulae occurred. No statistically significant declines were observed in QoL outcomes (n = 11) on the EPIC bowel domain (P = 0.29), AUA symptom score (P = 0.77), or the SF-12 physical (P = 0.17) or SF-12 mental component summary (P = 0.77) questionnaires. At 6 months, patients who had undergone salvage therapy experienced a decline in EPIC sexual domain score (median of 38-24; P = 0.028) and urinary domain (median of 96 92; P = 0.074). Pad-free continence and erections sufficient for intercourse were preserved in 8/11 patients and 2/6 patients at 6 months, respectively. The mpMRI was clear in 11/13 patients, with two single out-field lesions (true-positive and false-positive, respectively). The median (interquartile range) nadir PSA was 0.39 (0.04-0.43) MUg/L. Three and four patients experienced biochemical failure using the Phoenix and Stuttgart definitions of biochemical failure, respectively. Eight out of 10 of the patients were clear of any PCa on follow-up biopsy, whereas two patients had significant PCa on follow-up biopsy (International Society of Urological Pathology grade 5). CONCLUSION: Our short-term safety, QoL and oncological control data show that focal IRE is a feasible salvage option for localized radio-recurrent PCa. A prospective multicentre study (FIRE trial) has been initiated that will provide further insight into the ability of focal IRE to obtain oncological control of radio-recurrent PCa with acceptable patient morbidity. PMID- 28834168 TI - Plasmonic-Based Mechanochromic Microcapsules as Strain Sensors. AB - Efficiently detecting mechanical deformations within materials is critical in a wide range of devices, from micro-electromechanical systems to larger structures in the aerospace industry. This communication reports the fabrication of new mechanochromic micrometer-size capsules enabling the detection of strains. These microcapsules are synthesized using an emulsification approach. They are made of densely packed gold nanoparticles embedded in a spherical silica crust. Billions of these composite spherical microcapsules are fabricated in a single batch. Each microcapsule is an opto-mechanosensor by itself, and can easily be recovered and incorporated into polymer films. When the films are stretched, the microcapsules are deformed into elongated ellipsoidal shapes and the distance between the Au NPs embedded in their shells concomitantly increases. As the extinction of Au NPs depends on the separation between the Au NPs, microcapsules exhibit different colors when they are elongated. These novel sensitive microcapsules can be used to detect and measure strain in polymer films by outputting color information. PMID- 28834169 TI - Transcriptomic profile reveals molecular events associated to focal adhesion and invasion in canine mammary gland tumour cell lines. AB - The prevalence of cancer in animals has increased significantly over the years. Mammary tumours are the most common neoplasia in dogs, in which around 50% are presented in the malignant form. Hence, the development and characterization of in vitro models for the study of canine tumours are important for the improvement of cancer diagnosis and treatment. Thus, the aim of this study was to characterize cell lines derived from canine mammary gland neoplasias which could be further used for basic and applied oncology research. Samples of canine mammary carcinomas were taken for cell culture and 2 cell lines were established and characterized in terms of cell morphology, tumourigenicity and global gene expression. Both cell lines presented spindle-shape morphology and shown common malignant features as in vitro invasion potential and expression of epithelial and mesenchymal proteins. Also, we found gene expression patterns between the 2 cell cultures in comparison to the normal mammary gland tissue. Cells from M25 culture showed a higher invasion and in vivo tumourigenic potential, associated to the overexpression of genes involved in focal adhesion and extracellular matrix communication, such as FN1, ITGA8 and THBS2. The phenotypic characterization of these cells along with their global gene expression profile potentially determine new therapeutic targets for mammary tumours. PMID- 28834170 TI - Response to the letter entitled "Obstructive sleep apnea, excessive daytime sleepiness, and adherence to antihypertensive treatment: Questionnaire survey". PMID- 28834173 TI - Conserved and variable: Understanding mammary stem cells across species. AB - Postnatal mammary gland development requires the presence of mammary stem and progenitor cells (MaSC), which give rise to functional milk-secreting cells and regenerate the mammary epithelium with each cycle of lactation. These long-lived, tissue-resident MaSC are also targets for malignant transformation and may be cancer cells-of-origin. Consequently, MaSC are extensively researched in relation to their role and function in development, tissue regeneration, lactation, and breast cancer. The basic structure and function of the mammary gland are conserved among all mammalian species, from the most primitive to the most evolved. However, species vary greatly in their lactation strategies and mammary cancer incidence, making MaSC an interesting focus for comparative research. MaSC have been characterized in mice, to a lesser degree in humans, and to an even lesser degree in few additional mammals. They remain uncharacterized in most mammalian species, including "ancient" monotremes, marsupials, wild, and rare species, as well as in common and domestic species such as cats. Identification and comparison of MaSC across a large variety of species, particularly those with extreme lactational adaptations or low mammary cancer incidence, is expected to deepen our understanding of development and malignancy in the mammary gland. Here, we review the current status of MaSC characterization across species, and underline species variations in lactation and mammary cancer through which we may learn about the role of MaSC in these processes. (c) 2017 International Society for Advancement of Cytometry. PMID- 28834172 TI - Coherent anti-Stokes Raman scattering (CARS) spectroscopy in Caenorhabditis elegans and Globodera pallida: evidence for an ivermectin-activated decrease in lipid stores. AB - BACKGROUND: Macrocyclic lactones are arguably the most successful chemical class with efficacy against parasitic nematodes. Here we investigated the effect of the macrocyclic lactone ivermectin on lipid homeostasis in the plant parasitic nematode Globodera pallida and provide new insight into its mode of action. RESULTS: A non-invasive, non-destructive, label-free and chemically selective technique called Coherent anti-Stokes Raman scattering (CARS) spectroscopy was used to study lipid stores in G. pallida. We optimised the protocol using the free-living nematode Caenorhabditis elegans and then used CARS to quantify lipid stores in the pre-parasitic, non-feeding J2 stage of G. pallida. This revealed a concentration of lipid stores in the posterior region of J2 s within 24 h of hatching which decreased to undetectable levels over the course of 28 days. We tested the effect of ivermectin on J2 viability and lipid stores. Within 24 h, ivermectin paralysed J2 s. Counterintuitively, over the same time-course ivermectin increased the rate of depletion of J2 lipid, suggesting that in ivermectin-treated J2 s there is a disconnection between the energy requirements for motility and metabolic rate. This decrease in lipid stores would be predicted to negatively impact on J2 infective potential. CONCLUSION: These data suggest that the benefit of macrocyclic lactones as seed treatments may be underpinned by a multilevel effect involving both neuromuscular inhibition and acceleration of lipid metabolism. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28834174 TI - Phenotypes, pleiotropy, and phylogeny. PMID- 28834175 TI - Control-based imputation for sensitivity analyses in informative censoring for recurrent event data. AB - In clinical trials, missing data commonly arise through nonadherence to the randomized treatment or to study procedure. For trials in which recurrent event endpoints are of interests, conventional analyses using the proportional intensity model or the count model assume that the data are missing at random, which cannot be tested using the observed data alone. Thus, sensitivity analyses are recommended. We implement the control-based multiple imputation as sensitivity analyses for the recurrent event data. We model the recurrent event using a piecewise exponential proportional intensity model with frailty and sample the parameters from the posterior distribution. We impute the number of events after dropped out and correct the variance estimation using a bootstrap procedure. We apply the method to an application of sitagliptin study. PMID- 28834176 TI - Climate Change-Related Water Disasters' Impact on Population Health. AB - PURPOSE: Rising global temperatures have resulted in an increased frequency and severity of cyclones, hurricanes, and flooding in many parts of the world. These climate change-related water disasters (CCRWDs) have a devastating impact on communities and the health of residents. Clinicians and policymakers require a substantive body of evidence on which to base planning, prevention, and disaster response to these events. The purpose of this study was to conduct a systematic review of the literature concerning the impact of CCRWDs on public health in order to identify factors in these events that are amenable to preparedness and mitigation. Ultimately, this evidence could be used by nurses to advocate for greater preparedness initiatives and inform national and international disaster policy. DESIGN AND METHODS: A systematic literature review of publications identified through a comprehensive search of five relevant databases (PubMed, Cumulative Index to Nursing and Allied Health Literature [CINAHL], Embase, Scopus, and Web of Science) was conducted using a modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach in January 2017 to describe major themes and associated factors of the impact of CCRWDs on population health. FINDINGS: Three major themes emerged: environmental disruption resulting in exposure to toxins, population susceptibility, and health systems infrastructure (failure to plan-prepare-mitigate, inadequate response, and lack of infrastructure). Direct health impact was characterized by four major categories: weather-related morbidity and mortality, waterborne diseases/water related illness, vector-borne and zoonotic diseases, and psychiatric/mental health effects. Scope and duration of the event are factors that exacerbate the impact of CCRWDs. Discussion of specific factors amenable to mitigation was limited. Flooding as an event was overrepresented in this analysis (60%), and the majority of the research reviewed was conducted in high-income or upper middle /high-income countries (62%), despite the fact that low-income countries bear a disproportionate share of the burden on morbidity and mortality from CCRWDs. CONCLUSIONS: Empirical evidence related to CCRWDs is predominately descriptive in nature, characterizing the cascade of climatic shifts leading to major environmental disruption and exposure to toxins, and their resultant morbidity and mortality. There is inadequate representation of research exploring potentially modifiable factors associated with CCRWDs and their impact on population health. This review lays the foundation for a wide array of further areas of analysis to explore the negative health impacts of CCRWDs and for nurses to take a leadership role in identifying and advocating for evidence-based policies to plan, prevent, or mitigate these effects. CLINICAL RELEVANCE: Nurses comprise the largest global healthcare workforce and are in a position to advocate for disaster preparedness for CCRWDs, develop more robust environmental health policies, and work towards mitigating exposure to environmental toxins that may threaten human health. PMID- 28834177 TI - Opposition to irresponsible global kidney exchange. PMID- 28834178 TI - Randomized controlled trial on mouth rinse and flossing efficacy on interproximal gingivitis and dental plaque. AB - OBJECTIVE: The objective of this study was to compare the efficacy of an essential oils mouth rinse and dental floss on dental plaque accumulation and gingivitis in interproximal areas. METHODS: With informed consent, a parallel randomized controlled clinical trial was developed with 60 third-year dental hygiene students, randomly divided into two non-blind groups of 30 individuals each. For a period of 2 weeks, one group used an essential oils mouth rinse, according to manufacturer's instructions, and the other group flossed twice a day. Both groups received a toothbrush and fluoridated toothpaste for home dental hygiene care. A baseline dental hygiene appointment consisted of tooth scaling, prophylaxis and collection of the study data, using the Lobene modified gingival index; Saxton & Ouderaa gingival bleeding index and the Quigley & Hein modified by Turesky dental plaque index. RESULTS: At baseline, there was no significant difference between the groups for interproximal gingival inflammation (P = .214), gingival bleeding (P = .829) and dental plaque accumulation (P = .860). After 2 weeks of treatment, no significant differences were found between the essential oils mouth rinse and dental flossing for reduction of interproximal gingival inflammation (P = .938) and bleeding (P = .307). Essential oils mouth rinse showed to be significantly better than dental flossing in reducing interproximal dental plaque accumulation (P = .006). CONCLUSION: The use of an essential oils mouth rinse may be advised, as a complement, for patients unable to floss effectively, as it is more effective in reducing interproximal dental plaque accumulation than dental floss. PMID- 28834179 TI - Human pancreatic tumors grown in mice release tissue factor-positive microvesicles that increase venous clot size. AB - : Essentials Tumor-bearing mice have larger venous clots than controls. Human tissue factor is present in clots in tumor-bearing mice. Inhibition of human tissue factor reduces clot size in tumor-bearing mice. This new mouse model may be useful to study mechanisms of cancer-associated thrombosis. SUMMARY: Background Pancreatic cancer patients have a high rate of venous thromboembolism. Human pancreatic tumors and cell lines express high levels of tissue factor (TF), and release TF-positive microvesicles (TF+ MVs). In pancreatic cancer patients, tumor-derived TF+ MVs are present in the blood, and increased levels are associated with venous thromboembolism and decreased survival. Previous studies have shown that mice with orthotopic human or murine pancreatic tumors have circulating tumor-derived TF+ MVs, an activated clotting system, and increased incidence and mean clot weight in an inferior vena cava stenosis model. These results suggest that TF+ MVs contribute to thrombosis. However, the specific role of tumor-derived TF+ MVs in venous thrombosis in mice has not been determined. Objectives To test the hypothesis that tumor-derived TF+ MVs enhance thrombosis in mice. Methods We determined the contribution of TF+ MVs derived from human pancreatic tumors grown orthotopically in nude mice to venous clot formation by using an anti-human TF mAb. We used an inferior vena cava stasis model of venous thrombosis. Results Tumor-bearing mice had significantly larger clots than control mice. Clots from tumor-bearing mice contained human TF, suggesting the incorporation of tumor-derived MVs. Importantly, administration of an anti-human TF mAb reduced clot size in tumor-bearing mice but did not affect clot size in control mice. Conclusions Our results indicate that TF+ MVs released from orthotopic pancreatic tumors increase venous thrombosis in mice. This new model may be useful for evaluating the roles of different factors in cancer-associated thrombosis. PMID- 28834180 TI - Attitudes and barriers to the use of donation after cardiac death livers: Comparison of a United States transplant center survey to the united network for organ sharing data. AB - Transplantation of liver grafts from donation after cardiac death (DCD) is limited. To identify barriers of DCD liver utilization, all active US liver transplant centers (n = 138) were surveyed, and the responses were compared with the United Network for Organ Sharing (UNOS) data. In total, 74 (54%) centers responded, and diversity in attitudes was observed, with many not using organ and/or recipient prognostic variables defined in prior studies and UNOS data analysis. Most centers (74%) believed lack of a system allowing a timely retransplant is a barrier to utilization. UNOS data demonstrated worse 1- and 5 year patient survival (PS) and graft survival (GS) in DCD (PS, 86% and 64%; GS, 82% and 59%, respectively) versus donation after brain death (DBD) recipients (PS, 90% and 71%; GS, 88% and 69%, respectively). Donor alanine aminotransferase (ALT), recipient Model for End-Stage Liver Disease (MELD), and cold ischemia time (CIT) significantly impacted DCD outcomes to a greater extent than DBD outcomes. At 3 years, relisting and retransplant rates were 7.9% and 4.6% higher in DCD recipients. To optimize outcome, our data support the use of DCD liver grafts with CIT <6-8 hours in patients with MELD <= 20. In conclusion, standardization of donor and recipient criteria, defining the impact of ischemic cholangiopathy, addressing donor hospital policies, and developing a strategy for timely retransplant may help to expand the use of these organs. Liver Transplantation 23 1372-1383 2017 AASLD. PMID- 28834182 TI - Joseph Thomas Bagnara (1929-2016), a pioneer of Pigment Cell Biology par excellence. PMID- 28834183 TI - "If you want to go far, go together". PMID- 28834184 TI - Three-Dimensional Architectures Constructed from Transition-Metal Dichalcogenide Nanomaterials for Electrochemical Energy Storage and Conversion. AB - Transition-metal dichalcogenides (TMDs) have attracted considerable attention in recent years because of their unique properties and promising applications in electrochemical energy storage and conversion. However, the limited number of active sites as well as blocked ion and mass transport severely impair their electrochemical performance. The construction of three-dimensional (3D) architectures from TMD nanomaterials has been proven to be an effective strategy to solve the aforementioned problems as a result of their large specific surface areas and short ion and mass transport distances. This Review summarizes the commonly used routes to build 3D TMD architectures and highlights their applications in electrochemical energy storage and conversion, including batteries, supercapacitors, and electrocatalytic hydrogen evolution. The challenges and outlook in this research area are also discussed. PMID- 28834185 TI - Automated analysis of individual sperm cells using stain-free interferometric phase microscopy and machine learning. AB - Currently, the delicate process of selecting sperm cells to be used for in vitro fertilization (IVF) is still based on the subjective, qualitative analysis of experienced clinicians using non-quantitative optical microscopy techniques. In this work, a method was developed for the automated analysis of sperm cells based on the quantitative phase maps acquired through use of interferometric phase microscopy (IPM). Over 1,400 human sperm cells from 8 donors were imaged using IPM, and an algorithm was designed to digitally isolate sperm cell heads from the quantitative phase maps while taking into consideration both the cell 3D morphology and contents, as well as acquire features describing sperm head morphology. A subset of these features was used to train a support vector machine (SVM) classifier to automatically classify sperm of good and bad morphology. The SVM achieves an area under the receiver operating characteristic curve of 88.59% and an area under the precision-recall curve of 88.67%, as well as precisions of 90% or higher. We believe that our automatic analysis can become the basis for objective and automatic sperm cell selection in IVF. (c) 2017 International Society for Advancement of Cytometry. PMID- 28834181 TI - Hospital readmissions following HLA-incompatible live donor kidney transplantation: A multi-center study. AB - Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor-specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22-center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant-matched controls and to waitlist-only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed-effects Poisson regression. In the first month, ILDKTs had a 1.28-fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13-1.46; P < .001). Risk peaked at 6-12 months (relative risk [RR] 1.67, 95% CI 1.49-1.87; P < .001), attenuating by 24-36 months (RR 1.24, 95% CI 1.10-1.40; P < .001). ILDKTs had a 5.86-fold higher readmission risk (95% CI 4.96-6.92; P < .001) in the first month compared to waitlist-only controls. At 12-24 (RR 0.85, 95% CI 0.77-0.95; P = .002) and 24-36 months (RR 0.74, 95% CI 0.66-0.84; P < .001), ILDKTs had a lower risk than waitlist-only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist-only controls should be considered in regulatory/payment schemas and planning clinical care. PMID- 28834186 TI - Preoperative effects of mifepristone for dilation and evacuation after 19 weeks of gestation: a randomised controlled trial. AB - OBJECTIVE: To evaluate mifepristone as an adjunct to, or replacement for, osmotic dilators for cervical preparation in surgical abortion after 19 weeks of gestation. DESIGN: Site-stratified, double-blinded randomised controlled trial. SETTING: Two tertiary care teaching hospitals. POPULATION: Women undergoing dilation and evacuation at 19-236/7 weeks of gestation from November 2013 through November 2015. METHODS: Participants were randomised to receive (1) mifepristone alone (n = 27), (2) osmotic dilators with mifepristone (n = 27) or (3) osmotic dilators with placebo (n = 21) with all receiving pre-procedure misoprostol. MAIN OUTCOME MEASURES: Operative time, preoperative cervical dilation and complications. RESULTS: We enrolled 75 participants; mean gestation 21 weeks. Pre procedure cervical dilation was >=3 cm in 4, 52, and 57% of participants in groups 1, 2, and 3, respectively (P < 0.005). Mifepristone with misoprostol for cervical preparation resulted in longer procedure times compared with osmotic dilators, with median total procedure times of (1) 18.5 (8-52), (2) 12 (7-25), and (3) 13 (6-26) minutes (P <= 0.005). Excluding time required for manual dilation, procedure times were similar: median times from dilation complete to evacuation complete were (1) 10.5 (4-23), (2) 8.5 (5-24), and (3) 10 (4-20) minutes (P = 0.10). Complications occurred in seven cases, six with trainees and one with an attending physician (P = 0.03), with difference by study group not reaching statistical significance (P = 0.12). CONCLUSIONS: Elimination of osmotic dilators has the potential to decrease burden and opportunity cost of cervical preparation. The longer procedure time, related to manual dilation, is offset by decreasing dilator-related preoperative time and discomfort. Provider experience may impact risk when eliminating dilators. TWEETABLE ABSTRACT: Mifepristone and misoprostol for cervical preparation prior to D&E has potential to reduce barriers to care. PMID- 28834188 TI - A Rewritable, Reprogrammable, Dual Light-Responsive Polymer Actuator. AB - We report on the fabrication of a rewritable and reprogrammable dual photoresponsive liquid crystalline-based actuator containing an azomerocyanine dye that can be locally converted into the hydroxyazopyridinium form by acid treatment. Each dye absorbs at a different wavelength giving access to programmable actuators, the folding of which can be controlled by using different colors of light. The acidic patterning is reversible and allows the erasing and rewriting of patterns in the polymer film, giving access to reusable, adjustable soft actuators. PMID- 28834187 TI - Esthetic dermatology and emotional well-being according to gender. AB - INTRODUCTION: There has been an increase in the demand for esthetic dermatology treatments within the general population. The purpose of this study was to analyze, within the scope of general population, the relationship between people's perception of esthetic dermatology treatments and emotional well-being, as well as for differences in gender. METHODS: The Aesthetic Dermatology and Emotional Well-Being (DEBIE) Scale, [Journal of Cosmetic Dermatology vol. 13 (2014) 336-345] was applied to 770 Spanish people over 18 years old. The scale is structured according to six factors and classified into two dimensions: (1) Emotional Well-Being and (2) Perception of Aesthetic Dermatology. Cronbach alpha for the total scale was very high (0.90). Data analysis includes the following: (1) bivariate correlations with Pearson's coefficient; (2) gender differences through Student's t test, and (3) the effect size through R2 and Cohen's d. RESULTS: A statistically significant relationship which is directly proportional has been identified between the degree of emotional well-being of people (self esteem and assertiveness, optimism, and motivation) and the knowledge and attitude toward Aesthetic Dermatology. There are statistically significant differences according to gender: Women have a lower level of emotional well-being than men, as well as greater knowledge and more positive attitude toward Aesthetic Dermatology. CONCLUSIONS: People who are familiar with Aesthetic Dermatology and have a better attitude toward it, are also more self-confident, more optimistic and more motivated; with emotional strength. Regarding gender, it is expected that women may seek more consultation and esthetic dermatology treatments than men do. PMID- 28834189 TI - Evaluation of Post-Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation. AB - The number of epigenetic studies on brain functions and diseases are dramatically increasing, but little is known about the impact of post-mortem intervals and post-sampling effects on DNA modifications such as 5-methylcytosine (5mC) and 5 hydroxymethylcytosine (5hmC). Here, we examined post-mortem-induced changes in global brain 5mC and 5hmC levels at post-mortem intervals up to 540 min., and studied effects of tissue heat stabilization, using LUMA and ELISA. The global 5mC and 5hmC levels were generally higher in the cerebellum of adult rats than neonates. When measured by ELISA, the global 5mC content in adults, but not neonates, decreased with the post-mortem interval reaching a significantly lower level in cerebellum tissue at the post-mortem interval 540 min. (2.9 +/- 0.7%; mean +/- S.E.M.) compared to control (3.7 +/- 0.6%). The global 5hmC levels increased with post-mortem interval reaching a significantly higher level at 540 min. (0.29 +/- 0.06%) compared to control (0.19 +/- 0.03%). This suggests that the post-mortem interval may confound 5mC and 5hmC analysis in human brain tissues as the post-mortem handling could vary substantially. The reactive oxygen species (ROS) level in cerebellum also increased over time, in particular in adults, and may be part of the mechanism that causes the observed post-mortem changes in 5mC and 5hmC. The global 5mC and 5hmC states were unaffected by heat stabilization, allowing analysis of tissues that are stabilized to preserve more labile analytes. Further studies in human samples are needed to confirm post mortem effects on DNA methylation/hydroxymethylation and elucidate details of the underlying mechanisms. PMID- 28834190 TI - Fecal shedding of Campylobacter jejuni and Campylobacter coli among feral pigs in Texas. AB - The population and range of feral pigs in the United States are rapidly expanding, yet key knowledge gaps exist regarding their role in the ecology and transmission of foodborne pathogens. Our objectives were to estimate the prevalence of Campylobacter jejuni and Campylobacter coli shedding among feral pigs throughout Texas and to identify risk factors for positive status. Faecal samples were collected from feral pigs in Texas from February 2014 through May 2015, and target organisms were detected using PCR assays. The prevalence of C. jejuni shedding was 1.6% (6/370), and the prevalence of C. coli shedding was 3.5% (13/370). C. coli shedding was significantly more common (p = .008) among female pigs than among male pigs. Feral pigs may represent a source of human campylobacteriosis. PMID- 28834191 TI - Combined treatment with fractional carbon dioxide laser, autologous platelet-rich plasma, and narrow band ultraviolet B for vitiligo in different body sites: A prospective, randomized comparative trial. AB - BACKGROUND: Multiple treatment options are introduced in treatment of vitiligo but the response is unsatisfactory. OBJECTIVE: In this prospective, randomized, comparative trial, we studied the effect of combined treatment with fractional carbon dioxide (CO2 ) laser, platelet-rich plasma (PRP) injection, and narrowband ultraviolet B (NB-UVB) for stable nonsegmental vitiligo regarding repigmentation grade, patient's satisfaction, and side effects. METHODS: Eighty adult patients with localized nonsegmental vitiligo were enrolled in this study. The patients were randomly categorized to receive 4 lines of treatment; fractional CO2 laser, PRP, combined fractional CO2 laser and PRP, and combined fractional CO2 laser and NB-UVB. The treatment period was 2 months. Patients were clinically evaluated 3 months after the last treatment. Outcome was evaluated by 5-point scale for repigmentation, 10-point visual analog scale for patient's satisfaction, and side effects. RESULTS: Laser and PRP group achieved the best results regarding repigmentation and patient's satisfaction. Sixty percent of the patients developed repigmentation >50% and 40% of patients developed repigmentation >75%. In laser and NB-UVB group, 5% developed repigmentation >75% and 25% developed repigmentation >50%. Only 10% of patients developed repigmentation >75% in laser group and only 20% of patients developed repigmentation >75% in PRP group. CONCLUSIONS: Combination of fractional CO2 laser with PRP injection is a promising treatment for vitiligo, followed by combination of fractional CO2 laser with NB-UVB phototherapy. Both fractional CO2 laser and PRP injection gave poor results if they received alone. PMID- 28834192 TI - Mycosis fungoides with CD30-positive large-cell transformation clinically mimicking scarring alopecia. PMID- 28834193 TI - Visual impairment and blindness in Hungary. AB - AIM: The aim of this study was to estimate the prevalence and causes of blindness, severe visual impairment (SVI), moderate visual impairment (MVI), and early visual impairment (EVI) and its causes in an established market economy of Europe. DESIGN: A cross-sectional population-based survey. METHODS: A sample size of 3675 was calculated using the standard Rapid Assessment of Avoidable Blindness (RAAB) software in Hungary. A total of 105 clusters of 35 people aged 50 years or older were randomly selected with probability proportionate to size by the Hungarian Central Statistical Office. Households within the clusters were selected using compact segment sampling. Visual acuity (VA) was assessed with a Snellen tumbling E-chart with or without a pinhole in the households. RESULTS: The adjusted prevalences of bilateral blindness, SVI, MVI and EVI were 0.9% (95% CI: 0.6-1.2), 0.5% (95% CI: 0.2-0.7), 5.1% (95% CI: 4.3-5.9) and 6.9% (95% CI: 5.9-7.9), respectively. The major causes of blindness in Hungary were age-related macular degeneration (AMD; 27.3%) and other posterior segment diseases (27.3%), cataract (21.2%) and glaucoma (12.1%). Cataract was the main cause of SVI, MVI and EVI. Cataract surgical coverage (CSC) was 90.7%. Of all bilateral blindness in Hungary, 45.5% was considered avoidable. CONCLUSION: This study proved that RAAB methodology can be successfully conducted in industrialized countries, which often lack reliable epidemiologic data. The prevalence of blindness was relatively low, with AMD and other posterior segment diseases being the leading causes, and cataract is still a significant cause of visual impairment. PMID- 28834195 TI - Dominance of Plasmonic Resonant Energy Transfer over Direct Electron Transfer in Substantially Enhanced Water Oxidation Activity of BiVO4 by Shape-Controlled Au Nanoparticles. AB - The performance of plasmonic Au nanostructure/metal oxide heterointerface shows great promise in enhancing photoactivity, due to its ability to confine light to the small volume inside the semiconductor and modify the interfacial electronic band structure. While the shape control of Au nanoparticles (NPs) is crucial for moderate bandgap semiconductors, because plasmonic resonance by interband excitations overlaps above the absorption edge of semiconductors, its critical role in water splitting is still not fully understood. Here, first, the plasmonic effects of shape-controlled Au NPs on bismuth vanadate (BiVO4 ) are studied, and a largely enhanced photoactivity of BiVO4 is reported by introducing the octahedral Au NPs. The octahedral Au NP/BiVO4 achieves 2.4 mA cm-2 at the 1.23 V versus reversible hydrogen electrode, which is the threefold enhancement compared to BiVO4 . It is the highest value among the previously reported plasmonic Au NPs/BiVO4 . Improved photoactivity is attributed to the localized surface plasmon resonance; direct electron transfer (DET), plasmonic resonant energy transfer (PRET). The PRET can be stressed over DET when considering the moderate bandgap semiconductor. Enhanced water oxidation induced by the shape-controlled Au NPs is applicable to moderate semiconductors, and shows a systematic study to explore new efficient plasmonic solar water splitting cells. PMID- 28834194 TI - Pediatric liver transplantation for hepatocellular cancer and rare liver malignancies: US multicenter and single-center experience (1981-2015). AB - A tenth of all pediatric liver transplantations (LTs) are performed for unresectable liver malignancies, especially the more common hepatoblastoma (HBL). Less understood are outcomes after LT for the rare hepatocellular carcinoma, nonhepatoblastoma embryonal tumors (EMBs), and slow growing metastatic neuroendocrine tumors of childhood. Pediatric LT is increasingly performed for rare unresectable liver malignancies other than HBL. We performed a retrospective review of outcomes after LT for malignancy in the multicenter US Scientific Registry of Transplant Recipients (SRTR; n = 677; 1987-2015). We then reviewed the Children's Hospital of Pittsburgh (CHP; n = 74; 1981-2014) experience focusing on LT for unresectable hepatocellular cancer (HCC), EMBs, and metastatic liver tumors (METS). HBL was included to provide reference statistics. In the SRTR database, LT for HCC and HBL increased over time (P < 0.001). Compared with other malignancies, the 149 HCC cases received fewer segmental grafts (P < 0.001) and also experienced 10-year patient survival similar to 15,710 adult HCC LT recipients (51.6% versus 49.6%; P = 0.848, not significant [NS], log-rank test). For 22 of 149 cases with incidental HCC, 10-year patient survival was higher than 127 primary HCC cases (85% [95% confidence interval (CI), 70.6%-100%] versus 48.3% [95% CI, 38%-61%]; P = 0.168, NS) and similar to 3392 biliary atresia cases (89.9%; 95% CI, 88.7%-91%). Actuarial 10-year patient survival for 17 EMBs, 10 METS, and 6 leiomyosarcoma patients exceeded 60%. These survival outcomes were similar to those seen for HBL. At CHP, posttransplant recurrence-free and overall survival among 25 HCC, 17 (68%) of whom had preexisting liver disease, was 16/25 or 64%, and 9/25 or 36%, respectively. All 10 patients with incidental HCC and tumor-node-metastasis stage I and II HCC survived recurrence-free. Only vascular invasion predicted poor survival in multivariate analysis (P < 0.0001). A total of 4 of 5 EMB patients (80%) and all patients with METS (neuroendocrine-2, pseudopapillary pancreatic-1) also survived recurrence-free. Among children, LT can be curative for unresectable HCC confined to the liver and without vascular invasion, incidental HCC, embryonal tumors, and metastatic neuroendocrine tumors. Liver Transplantation 23 1577-1588 2017 AASLD. PMID- 28834197 TI - Clinical flow cytometry: it's not just about reaching a diagnosis. PMID- 28834196 TI - Advanced cell-based modeling of the royal disease: characterization of the mutated F9 mRNA. AB - : Essentials The Royal disease (RD) is a form of hemophilia B predicted to be caused by a splicing mutation. We generated an iPSC-based model of the disease allowing mechanistic studies at the RNA level. F9 mRNA analysis in iPSC-derived hepatocyte-like cells showed the predicted abnormal splicing. Mutated F9 mRNA level was very low but we also found traces of wild type transcripts. SUMMARY: Background The royal disease is a form of hemophilia B (HB) that affected many descendants of Queen Victoria in the 19th and 20th centuries. It was found to be caused by the mutation F9 c.278-3A>G. Objective To generate a physiological cell model of the disease and to study F9 expression at the RNA level. Methods Using fibroblasts from skin biopsies of a previously identified hemophilic patient bearing the F9 c.278-3A>G mutation and his mother, we generated induced pluripotent stem cells (iPSCs). Both the patient's and mother's iPSCs were differentiated into hepatocyte-like cells (HLCs) and their F9 mRNA was analyzed using next-generation sequencing (NGS). Results and Conclusion We demonstrated the previously predicted aberrant splicing of the F9 transcript as a result of an intronic nucleotide substitution leading to a frameshift and the generation of a premature termination codon (PTC). The F9 mRNA level in the patient's HLCs was significantly reduced compared with that of his mother, suggesting that mutated transcripts undergo nonsense-mediated decay (NMD), a cellular mechanism that degrades PTC-containing mRNAs. We also detected small proportions of correctly spliced transcripts in the patient's HLCs, which, combined with genetic variability in splicing and NMD machineries, could partially explain some clinical variability among affected members of the European royal families who had lifespans above the average. This work allowed the demonstration of the pathologic consequences of an intronic mutation in the F9 gene and represents the first bona fide cellular model of HB allowing the study of rare mutations at the RNA level. PMID- 28834199 TI - Porous Hollow-Structured LaNiO3 Stabilized N,S-Codoped Graphene as an Active Electrocatalyst for Oxygen Reduction Reaction. AB - A nanohybrid based on porous and hollow interior structured LaNiO3 stabilized nitrogen and sulfur codoped graphene (LaNiO3 /N,S-Gr) is successfully synthesized for the first time. Such a nanohybrid as an electrocatalyst shows high catalytic activity for oxygen reduction reaction (ORR) in O2 -saturated 0.1 m KOH media. In addition, it demonstrates a comparable catalytic activity, longer working stability, and much better alcohol tolerance compared with commercial Pt/C behavior in same experiment condition. The obtained results are attributed to synergistic effects from the enhanced electrocatalytic active sites on the rich pore channels of porous hollow-structured LaNiO3 spheres and heteroatom doped efficiency on graphene structure. In addition, N,S-Gr can meritoriously stabilize monodispersion of the LaNiO3 spheres, and act as medium bridging for high electrical conductivity, thereby providing large active surface area for O2 adsorption, accelerating reduction reaction, and improving electrochemical stability. Such a hybrid opens an interesting class of highly efficient non-Pt catalysts for ORR in alkaline media. PMID- 28834198 TI - Potent Antimicrobial Activity of Lipidated Short alpha,gamma-Hybrid Peptides. AB - Herein we report the potent antimicrobial activity of alpha,gamma-hybrid lipopeptides composed of 1:1 alternating alpha- and gamma-amino acids. Along with their potent antimicrobial activity against various Gram-positive and Gram negative bacteria, these hybrid lipopeptides were found to be less hemolytic. Studies into the mechanism of action revealed that these short cationic lipopeptides bind and disrupt the bacterial cell membrane. Time-kill kinetics analyses revealed that the potent alpha,gamma-hybrid lipopeptides completely inhibit bacterial growth in less than 20 minutes. Overall, the promising antimicrobial activity along with lower hemolytic activity displayed by these alpha,gamma-hybrid lipopeptides make them well suited for further exploration into the design of potent lipopeptide antibiotics. PMID- 28834200 TI - Relationship of renin-angiotensin system polymorphisms with ambulatory and central blood pressure in patients with hypertension. AB - This study was conducted to explore whether the renin C-5312T, angiotensin II type 1 receptor A1166C, and angiotensin-converting enzyme I/D polymorphisms were associated with ambulatory blood pressure (BP) and central hemodynamics in an untreated hypertensive population. A total of 471 participants with no previous treatment for raised BP were eligible for the study. Ambulatory and central BP were measured. DD carriers had the highest daytime systolic/diastolic BP, nighttime systolic BP, 24-hour systolic BP, and 24-hour diastolic BP values, whereas carriers of DD had higher central systolic BP and augmentation index compared with those with the II genotype. Multivariate regression analysis demonstrated that DD genotype was independently associated with 24-hour systolic BP, 24-hour diastolic BP, central systolic BP, and central augmentation index. There was an independent association of the angiotensin-converting enzyme polymorphism with central and ambulatory BP in Chinese patients with hypertension. PMID- 28834201 TI - Hydrogen Polysulfide Biosignal-Responsive Polymersomes as a Nanoplatform for Distinguishing Intracellular Reactive Sulfur Species (RSS). AB - Reactive sulfur species (RSS) are a family of crucial biosignals for regulating cell processes. Among these, hydrogen polysulfide (H2 Sn , n >= 2) is a hallmark of tumor suppressor activation and regarded as the actual regulator to mediate sulfur-related biology. However, high effective recognition of intracellular H2 Sn is insurmountable due to its extremely low concentration and the disturbance of RSS analogues. Here an H2 Sn -responsive macromolecule that can distinguish H2 Sn from intracellular RSS through polymer degradation in ultrasensitive and highly selective manner is reported. This kind of polymers can further self assemble into vesicular nanostructure. Upon cell uptake, they can be function as "all-in-one" H2 Sn -nanoplatforms, in order to fulfill multiple ambitious tasks including monitoring the H2 Sn biosynthetic pathways, unraveling the puzzles of H2 Sn -mediated cellular events, and conducting H2 Sn pathological milieu specific drug delivery. PMID- 28834202 TI - Hypothesis on a relationship between hyperaldosteronism, inflammation, somatic mutations, and autoimmunity. PMID- 28834203 TI - Traumatic dental injuries in Brazilian children and oral health-related quality of life. AB - BACKGROUND/AIMS: Population-based studies that investigate the impact of TDI on oral health-related quality of life (OHRQoL) among school children and its association with socioeconomic factors are scarce and offer conflicting results. The aim of this study was to evaluate the impact of TDI on OHRQoL among school children and its association with socioeconomic status. MATERIALS AND METHODS: A cross-sectional study was conducted with 588 12-year-old children enrolled in public and private schools in the urban areas in the city of Diamantina (southeastern Brazil). Clinical examinations were performed for the diagnosis of traumatic dental injury based on Andreasen's classification. The Child Perceptions Questionnaire (CPQ11-14 ), which has been validated for the population in Brazil, was employed to evaluate oral health-related quality of life. Socioeconomic status and overjet were also analyzed. Statistical analysis involved the chi-square test and logistic regression. RESULTS: A total of 29.4% of the students exhibited some type of trauma to at least one tooth. A negative impact on oral health-related quality of life was found in 53.1% of the sample. Traumatic dental injury was associated with a high impact on oral health-related quality of life [OR = 1.61 (95% CI: 1.08-2.39)] and overjet >3 mm [OR = 5.42 (95% CI: 3.66-8.02)]. However, no statistically significant associations were found between TDI and socioeconomic status. CONCLUSIONS: Prevalence of traumatic dental injury was high among the children who participated in the study, and it was associated with a high impact on oral health-related quality of life as well as overjet >3 mm. PMID- 28834204 TI - Emergence of Leuconostoc mesenteroides as a causative agent of oozing in carrots stored under non-ventilated conditions. AB - Long-term storage and transport of post-harvest carrots (Daucus carota L.) require a low-temperature, high-relative-humidity environment, usually with low ventilation. Following long-term storage, a slimy exudate (oozing) often appears on the carrots, leading to severe spoilage. We characterized the environmental conditions leading to these symptoms and identified the causative agent. Simulation of non-ventilated storage conditions revealed accumulation of CO2 (to 80%) and ethanol (to 1000 ppm); then, a transparent exudate appeared on the carrot surface which, upon ventilation, developed into tissue browning and soft rot. Peels from oozing carrots contained over 10-fold the total bacterial counts of healthy carrots. The total peel microbiome was determined by 16S rDNA sequencing. During oozing stage, the surface of carrots incubated in a CO2 -rich (98%) environment harboured a bacterial population dominated by Lactobacillales and Enterobacteriales, differing markedly from those incubated in air. Three prevalent bacterial isolates from the oozing carrots were identified as Pantoea agglomerans, Rahnella aquatilis and Leuconostoc mesenteroides. Inoculation of carrot discs with L. mesenteroides, but not the others, induced oozing under high CO2 , suggesting that this bacterium is responsible for oozing of stored carrots. These findings should enable development of approaches to preventing carrot spoilage during long-term storage. PMID- 28834205 TI - Role of ambulatory blood pressure monitoring for the management of hypertension in Asian populations. AB - Out-of-clinic blood pressure (BP) measurement, eg, ambulatory BP monitoring, has a strong association with target organ damage and is a powerful predictor of cardiovascular events compared with clinic BP measurement. Ambulatory BP monitoring can detect masked hypertension or various BP parameters in addition to average 24-hour BP level. Short-term BP variability assessed by standard deviation or average real variability, diminished nocturnal BP fall, nocturnal hypertension, and morning BP surge assessed by ambulatory BP monitoring have all been associated with target organ damage and cardiovascular prognosis. Recently, the authors compared the degree of sleep-trough morning BP surge between a group of Japanese and a group of Western European untreated patients with hypertension and found that sleep-trough morning BP surge in Japanese persons was significantly higher than that in Europeans. Although Asian persons have been known to have a higher incidence of stroke than heart disease, the difference in characteristics of BP indices assessed by ambulatory BP monitoring might be the cause of racial differences in stroke incidence between Asian and Western populations. This review focuses on Asian characteristics for the management of hypertension using ambulatory BP monitoring. PMID- 28834206 TI - GC-MS/MS method for the determination and pharmacokinetic analysis of borneol and muscone in rat after the intravenous administration of Xingnaojing injection. AB - A simple and sensitive gas chromatography with tandem mass spectrometry method was developed and validated for the simultaneous determination of borneol and muscone in rat plasma. The analytes and internal standard, naphthalene, were extracted using a convenient one-step liquid-liquid extraction method with ethyl acetate. The chromatographic separation was realized on a HP-5MS capillary column and detected in multiple reaction monitoring mode. Excellent linearity (R2 >= 0.996) was shown over 10.0-5000 ng/mL for borneol and 2.5-250 ng/mL for muscone. The lower limit of quantitation was 10 and 2.5 ng/mL for borneol and muscone, respectively. The intra- and interday precisions were less than 7.52%, and the accuracy values were between -8.03 and 14.52%. The extraction recovery, matrix effect, and stability were sufficient to meet the Food and Drug Administration criteria. Meanwhile, the assay was successfully applied to the preclinical pharmacokinetic study of borneol and muscone following intravenous administration of Xingnaojing injection, a modern Chinese herbal medicine preparation. PMID- 28834207 TI - Covering traumatic news stories: Factors associated with post-traumatic stress disorder among journalists. AB - The current study examined personal and environmental factors that placed 167 U.S. journalists from diverse media organizations at risk for post-traumatic stress disorder (PTSD) after covering work-related traumatic stories. These factors included exposure to traumatic stressors in their personal lives, work related traumatic stressors, and general organizational stressors. Further, personality attributes and coping styles associated with risk and resiliency were examined. Regression analyses identified avoidant emotional coping, higher levels of perceived organizational stressors, intensity of exposure to work-related traumatic stressors, and personal trauma history as statistically significant risk factors for PTSD. The results provide empirical support for the negative impact of organizational stressors and avoidant emotional coping on journalists covering trauma-related stories. Understanding the organizational climate journalists are working in, as well as the manner in which journalists manage work-related stressors, is important in the development of a more comprehensive model of who may develop work-related PTSD symptoms. Opportunities for news organizations to reduce PTSD risk among journalists are discussed. PMID- 28834209 TI - Impact of Linear Alkyl Length on the Assembly of Twisted Perylene Bisimides: From Molecular Arrangement to Nanostructures. AB - The effect of the length of linear alkyl chains substituted at imine positions on the assembly of tetrachlorinated perylene bisimides (1: PBI with -C6 H13 ; 2: PBI with -C12 H25 ) has been investigated. Solvent-induced assembly was performed in solutions of THF and methanol with varying volume ratios. Morphological (SEM, AFM, and TEM) and spectral (UV/Vis, fluorescence, FTIR, and XRD) methods were used to characterize the assembled nanostructures and the molecular arrangement in the aggregates. It was found that uniform structures could be obtained for both molecules in solutions with a high ratio of methanol. PBI 1 formed rigid nanosheets, whereas 2 assembled into longer nanostripes with a high ratio of length to width. On combining the morphological data with the spectral data, it was suggested that pi-pi stacking predominated in assemblies of 1, and the synergetic effect of van der Waals interactions from the long alkyl chains and pi pi stacking between neighboring building blocks facilitated the growth of the long-range-ordered nanostructures of 2. By changing the linear chain length, the hierarchical assembly of PBIs modified on bay positions could be manipulated effectively. PMID- 28834210 TI - ZnO Film UV Photodetector with Enhanced Performance: Heterojunction with CdMoO4 Microplates and the Hot Electron Injection Effect of Au Nanoparticles. AB - A novel CdMoO4 -ZnO composite film is prepared by spin-coating CdMoO4 microplates on ZnO film and is constructed as a heterojunction photodetector (PD). With an optimized loading amount of CdMoO4 microplates, this composite film PD achieves a ~18-fold higher responsivity than pure ZnO film PD at 5 V bias under 350 nm (0.15 mW cm-2 ) UV light illumination, and its decay time shortens to half of the original value. Furthermore, Au nanoparticles are then deposited to modify the CdMoO4 -ZnO composite film, and the as-constructed photodetector with an optimized deposition time of Au nanoparticles yields an approximately two-fold higher photocurrent under the same condition, and the decay time reduces by half. The introduced CdMoO4 microplates form type-II heterojunctions with ZnO film and improve the photoelectric performance. The hot electrons from Au nanoparticles are injected into the CdMoO4 -ZnO composite film, leading to the increased photocurrent. When the light is off, the Schottky barriers formed between Au nanoparticles and CdMoO4 -ZnO composite film block the carrier transportation and accelerate the decay process of current. The study on Au-nanoparticle-modified CdMoO4 -ZnO composite film provides a facile method to construct ZnO film based PD with novel structure and high photoelectric performance. PMID- 28834208 TI - Heterogeneous stock rats: a model to study the genetics of despair-like behavior in adolescence. AB - Major depressive disorder (MDD) is a complex illness caused by both genetic and environmental factors. Antidepressant resistance also has a genetic component. To date, however, very few genes have been identified for major depression or antidepressant resistance. In this study, we investigated whether outbred heterogeneous stock (HS) rats would be a suitable model to uncover the genetics of depression and its connection to antidepressant resistance. The Wistar Kyoto (WKY) rat, one of the eight founders of the HS, is a recognized animal model of juvenile depression and is resistant to fluoxetine antidepressant treatment. We therefore hypothesized that adolescent HS rats would exhibit variation in both despair-like behavior and response to fluoxetine treatment. We assessed heritability of despair-like behavior and response to sub-acute fluoxetine using a modified forced swim test (FST) in 4-week-old HS rats. We also tested whether blood transcript levels previously identified as depression biomarkers in adolescent human subjects are differentially expressed in HS rats with high vs. low FST immobility. We demonstrate heritability of despair-like behavior in 4 week-old HS rats and show that many HS rats are resistant to fluoxetine treatment. In addition, blood transcript levels of Amfr, Cdr2 and Kiaa1539, genes previously identified in human adolescents with MDD, are differentially expressed between HS rats with high vs. low immobility. These data demonstrate that FST despair-like behavior will be amenable to genetic fine-mapping in adolescent HS rats. The overlap between human and HS blood biomarkers suggest that these studies may translate to depression in humans. PMID- 28834211 TI - Archaeal MutS5 tightly binds to Holliday junction similarly to eukaryotic MutSgamma. AB - Archaeal DNA recombination mechanism and the related proteins are similar to those in eukaryotes. However, no functional homolog of eukaryotic MutSgamma, which recognizes Holliday junction to promote homologous recombination, has been identified in archaea. Hence, the whole molecular mechanism of archaeal homologous recombination has not yet been revealed. In this study, to identify the archaeal functional homolog of MutSgamma, we focused on a functionally uncharacterized MutS homolog, MutS5, from a hyperthermophilic archaeon Pyrococcus horikoshii (phMutS5). Archaeal MutS5 has a Walker ATPase motif-containing amino acid sequence that shows similarity to the ATPase domain of MutSgamma. It is known that the ATPase domain of MutS homologs is also a dimerization domain. Chemical cross-linking revealed that purified phMutS5 has an ability to dimerize in solution. phMutS5 bound to Holliday junction with a higher affinity than to other branched and linear DNAs, which resembles the DNA-binding specificities of MutSgamma and bacterial MutS2, a Holliday junction-resolving MutS homolog. However, phMutS5 has no nuclease activity against branched DNA unlike MutS2. The ATPase activity of phMutS5 was significantly stimulated by the presence of Holliday junction similarly to MutSgamma. Furthermore, site-directed mutagenesis revealed that the ATPase activity is dependent on the Walker ATPase motif of the protein. These results suggest that archaeal MutS5 should stabilize the Holliday junction and play a role in homologous recombination, which is analogous to the function of eukaryotic MutSgamma. PMID- 28834212 TI - Assessment of Appropriateness of an Initial Dosing Regimen of Vancomycin and Development of a New Dosing Nomogram. AB - Vancomycin is a glycopeptide antibiotic used to treat Gram-positive infections including methicillin-resistant Staphylococcus aureus (MRSA). The objectives of this study were to evaluate the appropriateness of the initial dosing regimen of vancomycin, identify factors to be considered in regimen selection and develop a new dosing nomogram. Therapeutic drug monitoring (TDM) data of vancomycin obtained from Seoul National University Hospital from 2011 to 2013 were included in this analysis. The vancomycin trough concentrations at steady-state were estimated using Abbott's PKS software program and then categorized into three levels: subtherapeutic, therapeutic and toxic. The newly developed nomograms were evaluated by analysing the percentage of patients with target vancomycin trough concentration using the data of 2,570 patients of the first TDM cases. Therapeutic level was achieved only in approximately one-fifth of the cases, while 56.0% and 23.8% of the TDMs were considered subtherapeutic and toxic, respectively. As body-weight and creatinine clearance (CrCL) increased, the proportion of patients with a subtherapeutic level increased. Using the newly developed nomogram increased the proportion of patients who achieved therapeutic levels from 23.1% to 45.0% or 13.8% to 36.2% (target, 10-15 and 15-20 mg/L, respectively). These results suggest that the vancomycin concentrations fail to reach the therapeutic level or exceed the safe upper margin of the therapeutic level depending on age, body-weight and CrCL. Considering these factors, the new nomograms provide a strategy to achieve target concentrations of vancomycin more rapidly than existing regimens. PMID- 28834213 TI - Modulating Excitonic Recombination Effects through One-Step Synthesis of Perovskite Nanoparticles for Light-Emitting Diodes. AB - The primary advantages of halide perovskites for light-emitting diodes (LEDs) are solution processability, direct band gap, good charge-carrier diffusion lengths, low trap density, and reasonable carrier mobility. The luminescence in 3 D halide perovskite thin films originates from free electron-hole bimolecular recombination. However, the slow bimolecular recombination rate is a fundamental performance limitation. Perovskite nanoparticles could result in improved performance but processability and cumbersome synthetic procedures remain challenges. Herein, these constraints are overcome by tailoring the 3 D perovskite as a near monodisperse nanoparticle film prepared through a one-step in situ deposition method. Replacing methyl ammonium bromide (CH3 NH3 Br, MABr) partially by octyl ammonium bromide [CH3 (CH2 )7 NH3 Br, OABr] in defined mole ratios in the perovskite precursor proved crucial for the nanoparticle formation. Films consisting of the in situ formed nanoparticles displayed signatures associated with excitonic recombination, rather than that of bimolecular recombination associated with 3 D perovskites. This transition was accompanied by enhanced photoluminescence quantum yield (PLQY~20.5 % vs. 3.40 %). Perovskite LEDs fabricated from the nanoparticle films exhibit a one order of magnitude improvement in current efficiency and doubling in luminance efficiency. The material processing systematics derived from this study provides the means to control perovskite morphologies through the selection and mixing of appropriate additives. PMID- 28834214 TI - Clinical implementation and evaluation of the Acuros dose calculation algorithm. AB - PURPOSE: The main aim of this study is to validate the Acuros XB dose calculation algorithm for a Varian Clinac iX linac in our clinics, and subsequently compare it with the wildely used AAA algorithm. METHODS AND MATERIALS: The source models for both Acuros XB and AAA were configured by importing the same measured beam data into Eclipse treatment planning system. Both algorithms were validated by comparing calculated dose with measured dose on a homogeneous water phantom for field sizes ranging from 6 cm * 6 cm to 40 cm * 40 cm. Central axis and off-axis points with different depths were chosen for the comparison. In addition, the accuracy of Acuros was evaluated for wedge fields with wedge angles from 15 to 60 degrees . Similarly, variable field sizes for an inhomogeneous phantom were chosen to validate the Acuros algorithm. In addition, doses calculated by Acuros and AAA at the center of lung equivalent tissue from three different VMAT plans were compared to the ion chamber measured doses in QUASAR phantom, and the calculated dose distributions by the two algorithms and their differences on patients were compared. Computation time on VMAT plans was also evaluated for Acuros and AAA. Differences between dose-to-water (calculated by AAA and Acuros XB) and dose-to-medium (calculated by Acuros XB) on patient plans were compared and evaluated. RESULTS: For open 6 MV photon beams on the homogeneous water phantom, both Acuros XB and AAA calculations were within 1% of measurements. For 23 MV photon beams, the calculated doses were within 1.5% of measured doses for Acuros XB and 2% for AAA. Testing on the inhomogeneous phantom demonstrated that AAA overestimated doses by up to 8.96% at a point close to lung/solid water interface, while Acuros XB reduced that to 1.64%. The test on QUASAR phantom showed that Acuros achieved better agreement in lung equivalent tissue while AAA underestimated dose for all VMAT plans by up to 2.7%. Acuros XB computation time was about three times faster than AAA for VMAT plans, and computation time for other plans will be discussed at the end. Maximum difference between dose calculated by AAA and dose-to-medium by Acuros XB (Acuros_Dm,m ) was 4.3% on patient plans at the isocenter, and maximum difference between D100 calculated by AAA and by Acuros_Dm,m was 11.3%. When calculating the maximum dose to spinal cord on patient plans, differences between dose calculated by AAA and Acuros_Dm,m were more than 3%. CONCLUSION: Compared with AAA, Acuros XB improves accuracy in the presence of inhomogeneity, and also significantly reduces computation time for VMAT plans. Dose differences between AAA and Acuros_Dw,m were generally less than the dose differences between AAA and Acuros_Dm,m . Clinical practitioners should consider making Acuros XB available in clinics, however, further investigation and clarification is needed about which dose reporting mode (dose to-water or dose-to-medium) should be used in clinics. PMID- 28834215 TI - Intrinsic Ferromagnetism in Mn-Substituted MoS2 Nanosheets Achieved by Supercritical Hydrothermal Reaction. AB - Doping atomically thick nanosheets is a great challenge due to the self purification effect that drives the precipitation of dopants. Here, a breakthrough is made to dope Mn atoms substitutionally into MoS2 nanosheets in a sulfur-rich supercritical hydrothermal reaction environment, where the formation energy of Mn substituting for Mo sites in MoS2 is significantly reduced to overcome the self-purification effect. The substitutional Mn doping is convincingly evidenced by high-angle annular dark-field scanning transmission electron microscopy and X-ray absorption fine spectroscopy characterizations. The Mn-doped MoS2 nanosheets show robust intrinsic ferromagnetic response with a saturation magnetic moment of 0.05 uB Mn-1 at room temperature. The intrinsic ferromagnetism is further confirmed by the reversibility of the magnetic behavior during the cycle of incorporating/removing Li codopants, showing the critical role of Mn 3d electronic states in mediating the magnetic interactions in MoS2 nanosheets. PMID- 28834216 TI - Beyond the M-CSF receptor - novel therapeutic targets in tumor-associated macrophages. AB - Tumor-associated macrophages (TAM) are by now established as important regulators of tumor progression by impacting on tumor immunity, angiogenesis, and metastasis. Hence, a multitude of approaches are currently pursued to intervene with TAM's protumor activities, the most advanced of which being a blockade of macrophage-colony stimulating factor (M-CSF)/M-CSF receptor (M-CSFR) signaling. M CSFR signaling largely impacts on the differentiation of macrophages, including TAM, and hence strongly influences the numbers of these cells in tumors. However, a repolarization of TAM toward a more antitumor phenotype may be more elegant and may yield stronger effects on tumor growth. In this respect, several aspects of TAM behavior could be altered, such as their intratumoral localization, metabolism and regulatory pathways. Intervention strategies could include the use of small molecules but also new generations of biologicals which may complement the current success of immune checkpoint blockers. This review highlights current work on the search for new therapeutic targets in TAM. PMID- 28834217 TI - National surgical mortality audit may be associated with reduced mortality after emergency admission. AB - BACKGROUND: The Western Australian Audit of Surgical Mortality was established in 2002. A 10-year analysis suggested it was the primary driver in the subsequent fall in surgeon-related mortality. Between 2004 and 2010 the Royal Australasian College of Surgeons established mortality audits in other states. The aim of this study was to examine national data from the Australian Institute of Health and Welfare (AIHW) to determine if a similar fall in mortality was observed across Australia. METHOD: The AIHW collects procedure and outcome data for all surgical admissions. AIHW data from 2005/2006 to 2012/2013 was used to assess changes in surgical mortality. RESULTS: Over the 8 years surgical admissions increased by 23%, while mortality fell by 18% and the mortality per admission fell by 33% (P < 0.0001). A similar decrease was seen in all regions. The mortality reduction was overwhelmingly observed in elderly patients admitted as an emergency. CONCLUSION: The commencement of this nation-wide mortality audit was associated with a sharp decline in perioperative mortality. In the absence of any influences from other changes in clinical governance or new quality programmes it is probable it had a causal effect. The reduced mortality was most evident in high-risk patients. This study adds to the evidence that national audits are associated with improved outcomes. PMID- 28834218 TI - Advances in organic-inorganic hybrid sorbents for the extraction of organic and inorganic pollutants in different types of food and environmental samples. AB - The efficiency of the extraction and removal of pollutants from food and the environment has been an important issue in analytical science. By incorporating inorganic species into an organic matrix, a new material known as an organic inorganic hybrid material is formed. As it possesses high selectivity, permeability, and mechanical and chemical stabilities, organic-inorganic hybrid materials constitute an emerging research field and have become popular to serve as sorbents in various separaton science methods. Here, we review recent significant advances in analytical solid-phase extraction employing organic inorganic composite/nanocomposite sorbents for the extraction of organic and inorganic pollutants from various types of food and environmental matrices. The physicochemical characteristics, extraction properties, and analytical performances of sorbents are discussed; including morphology and surface characteristics, types of functional groups, interaction mechanism, selectivity and sensitivity, accuracy, and regeneration abilities. Organic-inorganic hybrid sorbents combined with extraction techniques are highly promising for sample preparation of various food and environmental matrixes with analytes at trace levels. PMID- 28834219 TI - Human leucocyte antigens class II allele and haplotype association with Type 1 Diabetes in Madeira Island (Portugal). AB - This study confirms for Madeira Island (Portugal) population the Type 1 Diabetes (T1D) susceptible and protective Human leucocyte antigens (HLA) markers previously reported in other populations and adds some local specificities. Among the strongest T1D HLA associations, stands out, as susceptible, the alleles DRB1*04:05 (OR = 7.3), DQB1*03:02 (OR = 6.1) and DQA1*03:03 (OR = 4.5), as well as the haplotypes DRB1*04:05-DQA1*03:03-DQB1*03:02 (OR = 100.9) and DRB1*04:04 DQA1*03:01-DQB1*03:02 (OR = 22.1), and DQB1*06:02 (OR = 0.07) and DRB1*15:01 DQA1*01:02-DQB1*06:02 (OR = 0.04) as protective. HLA-DQA1 positive for Arginine at position 52 (Arg52) (OR = 15.2) and HLA-DQB1 negative for Aspartic acid at the position 57 (Asp57) (OR = 9.0) alleles appear to be important genetic markers for T1D susceptibility, with higher odds ratio values than any single allele and than most of the haplotypes. Genotypes generated by the association of markers Arg52 DQA1 positive and Asp57 DQB1 negative increase T1D susceptibility much more than one would expected by a simple additive effect of those markers separately (OR = 26.9). This study also confirms an increased risk for DRB1*04/DRB1*03 heterozygote genotypes (OR = 16.8) and also a DRB1*04-DQA1*03:01-DQB1*03:02 haplotype susceptibility dependent on the DRB1*04 allele (DRB1*04:01, OR = 7.9; DRB1*04:02, OR = 3.2; DRB1*04:04, OR = 22.1). PMID- 28834220 TI - Reconstruction of anomalous portal venous branching in right lobe living donor liver transplantation: Malatya approach. PMID- 28834221 TI - Tolerance after liver transplantation: Where are we? AB - Impeccable management of immunosuppression is required to ensure the best longterm outcomes for liver transplant recipients. This is particularly challenging for children who arguably need 8 decades of graft and patient survival. Too little risks chronic, often subclinical allo-immune injury while too much risks insidious and cumulative toxicities. Historically, immunosuppression minimization or withdrawal has been a strategy to optimize the longevity of liver transplant recipients. The literature is sprinkled with single center reports of operationally tolerant patients - those with apparently normal liver function and liver tests. However, without biopsy evidence of immunological quiescence, confidence in the phenotypic assignment of tolerance is shaky. More recently, multicenter trials of immunosuppression withdrawal for highly selected, stable, longterm adult and pediatric liver recipients have shown tolerance rates, based on both biochemical and histological assessment, of 40% and 60%, respectively. Extended biochemical and histologic follow-up of children over 8 years, equivalent to 7+ years off of drug, suggests that operational tolerance is robust. Therefore, clearly, immunosuppression can be completely and safety withdrawn from highly-selected subsets of adults and children. However, these trials have also confirmed that clinically ideal recipients - those eligible for immunosuppression withdrawal trial - can harbor significant and worrisome inflammation and/or fibrosis. Although the etiology and prognosis of these findings remain unknown, it is reasonable to surmise that they may reflect an anti-donor immune response that is insufficiently controlled. To achieve the outcomes that we are seeking and that our patients are demanding, we desperately need noninvasive but accurate biomarkers that identify whether immunosuppression is neither too much nor too little but "just right." Until these are available, liver histology remains the gold standard to assess allograft health and guide immunosuppression management. Liver Transplantation 23 1601-1614 2017 AASLD. PMID- 28834222 TI - More evidence that salt increases blood pressure and risk of kidney disease from the Science of Salt: A regularly updated systematic review of salt and health outcomes (April-July 2016). AB - The purpose of this review is to identify, summarize, and critically appraise studies on dietary salt and health outcomes that were published from April to July 2016. The search strategy was adapted from a previous systematic review on dietary salt and health. We have revised our criteria for methodological quality and health outcomes, which are applied to select studies for detailed critical appraisals and written commentary. Overall, 28 studies were identified and are summarized in this review. Four of the 28 studies met criteria for methodological quality and health outcomes and five studies underwent detailed critical appraisals and commentary. Three of these studies found adverse effects of salt on health outcomes (chronic kidney disease and blood pressure) and two were neutral (fracture risk/bone mineral density and cognitive impairment). PMID- 28834224 TI - Predicted indirectly recognizable HLA epitopes (PIRCHE): Only the tip of the iceberg? PMID- 28834223 TI - Liver and systemic hemodynamics in children with cirrhosis: Impact on the surgical management in pediatric living donor liver transplantation. AB - Cirrhosis in adults is associated with modifications of systemic and liver hemodynamics, whereas little is known about the pediatric population. The aim of this work was to investigate whether alterations of hepatic and systemic hemodynamics were correlated with cirrhosis severity in children. The impact of hemodynamic findings on surgical management in pediatric living donor liver transplantation (LT) was evaluated. Liver and systemic hemodynamics were studied prospectively in 52 children (median age, 1 year; 33 with biliary atresia [BA]). The hemodynamics of native liver were studied preoperatively by Doppler ultrasound and intraoperatively using invasive flowmetry. Portosystemic gradient was invasively measured. Systemic hemodynamics were studied preoperatively by Doppler transthoracic echocardiography and intraoperatively by using transpulmonary thermodilution. Hemodynamic parameters were correlated with Pediatric End-Stage Liver Disease (PELD) score and the histological degree of fibrosis (collagen proportionate area [CPA]). Cirrhosis was associated with a 60% reduction of pretransplant total liver flow (n = 46; median, 36 mL/minute/100 g of liver) compared with noncirrhotic livers (n = 6; median, 86 mL/minute/100 g; P = 0.002). Total blood flow into the native liver was negatively correlated with PELD (P < 0.001) and liver CPA (P = 0.005). Median portosystemic gradient was 14.5 mm Hg in children with cirrhosis and positively correlated with PELD (P < 0.001). Portal vein (PV) hypoplasia was observed mainly in children with BA (P = 0.02). Systemic hemodynamics were not altered in our children with cirrhosis. Twenty-one children met the intraoperative criteria for PV reconstruction using a portoplasty technique during the LT procedure and had a smaller PV diameter at pretransplant Doppler ultrasound (median = 3.4 mm; P < 0.001). Cirrhosis in children appears also as a hemodynamic disease of the liver, correlated with cirrhosis severity. Surgical technique for PV reconstruction during LT was adapted accordingly. Liver Transplantation 23 1440-1450 2017 AASLD. PMID- 28834225 TI - Controlling Plasmon-Enhanced Fluorescence via Intersystem Crossing in Photoswitchable Molecules. AB - By harnessing photoswitchable intersystem crossing (ISC) in spiropyran (SP) molecules, active control of plasmon-enhanced fluorescence in the hybrid systems of SP molecules and plasmonic nanostructures is achieved. Specifically, SP derived merocyanine (MC) molecules formed by photochemical ring-opening reaction display efficient ISC due to their zwitterionic character. In contrast, ISC in quinoidal MC molecules formed by thermal ring-opening reaction is negligible. The high ISC rate can improve fluorescence quantum yield of the plasmon-modified spontaneous emission, only when the plasmonic electromagnetic field enhancement is sufficiently high. Along this line, extensive photomodulation of fluorescence is demonstrated by switching the ISC in MC molecules at Au nanoparticle aggregates, where strongly enhanced plasmonic hot spots exist. The ISC-mediated plasmon-enhanced fluorescence represents a new approach toward controlling the spontaneous emission of fluorophores near plasmonic nanostructures, which expands the applications of active molecular plasmonics in information processing, biosensing, and bioimaging. PMID- 28834226 TI - Polymeric Redox-Active Electrodes for Sodium-Ion Batteries. AB - Polymer binding agents are critical for the good performance of the electrodes of Na- and Li-ion batteries during cycling as they hold the electroactive material together to form a cohesive assembly because of their mechanical and chemical stability as well as adhesion to the current collector. New redox-active polymer binders that insert Na+ ions and show adhesion properties were synthesized by adding polyether amine blocks (Jeffamine) based on mixed propylene oxide and ethylene oxide blocks to p-phenylenediamine and terephthalaldehyde units to form electroactive Schiff-base groups along the macromolecule. The synthetic parameters and the electrochemical properties of these terpolymers as Na-ion negative electrodes in half cells were studied. Reversible capacities of 300 mAh g-1 (50 wt % conducting carbon) and 200 mAh g-1 (20 wt % conducting carbon) were achieved in powder and Cu-supported electrodes, respectively, for a polySchiff polyether terpolymer synthesized by using a poly(ethylene oxide) block of 600 g mol-1 in place of one third of the aniline units. The new redox-active polymers were also used as a binding agent of another anode material (hard carbon), which led to an increase of the total capacity of the electrode compared to that prepared with other standard fluorinated polymer binders such as poly(vinylidene) fluoride. PMID- 28834227 TI - Hypoxia-induced activin A diminishes endothelial cell vasculogenic activity. AB - Acute ischaemia causes a significant loss of blood vessels leading to deterioration of organ function. Multiple ischaemic conditions are associated with up-regulation of activin A, but its effect on endothelial cells (EC) in the context of hypoxia is understudied. This study evaluated the role of activin A in vasculogenesis in hypoxia. An in vitro vasculogenesis model, in which EC were cocultured with adipose stromal cells (ASC), was used. Incubation of cocultures at 0.5% oxygen led to decrease in EC survival and vessel density. Hypoxia up regulated inhibin BA (monomer of activin A) mRNA by 4.5-fold and activin A accumulation in EC-conditioned media by 10-fold, but down-regulated activin A inhibitor follistatin by twofold. Inhibin BA expression was also increased in human EC injected into ischaemic mouse muscles. Activin A secretion was positively modulated by hypoxia mimetics dimethyloxalylglycine and desferrioxamine. Silencing HIF1alpha or HIF2alpha expression decreased activin A secretion in EC exposed to hypoxia. Introduction of activin A to cocultures decreased EC number and vascular density by 40%; conversely, blockade of activin A expression in EC or its activity improved vasculogenesis in hypoxia. Activin A affected EC survival directly and by modulating ASC paracrine activity leading to diminished ability of the ASC secretome to support EC survival and vasculogenesis. In conclusion, hypoxia up-regulates EC secretion of activin A, which, by affecting both EC and adjacent mesenchymal cells, creates a micro environment unfavourable for vasculogenesis. This finding suggests that blockade of activin A signalling in ischaemic tissue may improve preservation of the affected tissue. PMID- 28834228 TI - Irving Gottesman and the concept of endophenotype. PMID- 28834229 TI - Prophylactic central neck dissection in 68 patients with lateral compartment metastases from well-differentiated thyroid cancer. PMID- 28834230 TI - Renal Impairment Hampers Bisphosphonate Treatment in a Quarter of Lung Cancer Patients with Bone Metastasis. AB - Renal function impairment in lung cancer patients with bone metastases was investigated, as this can limit the application of bisphosphonates representing the gold standard in the management of such cases. Clinicopathological data of 570 lung cancer patients were retrospectively analysed for changes in renal function parameters. Co-morbidities included hypertension (50%), COPD (33%) and diabetes mellitus (15%). Statistical analysis was performed with Fisher's exact tests and a Cox proportional hazards model. In patients suffering from hypertension, both median serum creatinine and blood urea nitrogen (BUN) were higher (81.9 versus 75.8 MUmol/l, p<0.001 and 6.0 versus 5.7 mmol/l, p=0.005, respectively). Such a difference could not be observed in patients with diabetes. In COPD patients, only serum creatinine was higher (81.1 versus 77.3 MUmol/l, p=0.004). In the whole cohort, we found that while at the time of lung cancer diagnosis the ratio of patients in the pathological range (PRR) was 8.67% for serum creatinine (median: 75 MUmol/l) and 14.16% for BUN (median: 5.4 mmol/l), at the time of bone metastasis the PRR for serum creatinine increased to 16.11% (median: 77.0 MUmol/l) and for BUN to 24.07% (median: 6.0 mmol/l), which is a significant increase for both parameters (p<0.001). For the whole cohort, the last laboratory results showed a 26.37% PRR for serum creatinine and 45.66% PRR for BUN (significant increase for both, p<0.001). Multivariate analysis revealed that patients with hypertension had a higher chance for switching to the pathological range sooner (p=0.033, HR: 1.372, CI: 1.025-1.835). Also, the appearance of the bone metastasis correlated with an acceleration of the onset of such a switch (p<0.001, HR: 2.655, CI: 1.581-4.456). Our results suggest that renal function is impaired in a significant proportion of lung cancer patients and highlight the importance of non-nephrotoxic drug in the management of bone metastases. This article is protected by copyright. All rights reserved. PMID- 28834231 TI - Data-Independent Acquisition of HLA Class I Peptidomes on the Q Exactive Mass Spectrometer Platform. AB - The characterization of peptides presented by human leukocyte antigen (HLA) class I molecules is crucial for understanding immune processes, biomarker discovery, and the development of novel immunotherapies or vaccines. Mass spectrometry allows the direct identification of thousands of HLA-bound peptides from cell lines, blood, or tissue. In recent years, data-independent acquisition (DIA) mass spectrometry methods have evolved, promising to increase reproducibility and sensitivity over classical data-dependent acquisition (DDA) workflows. Here, we describe a DIA setup on the Q Exactive mass spectrometer, optimized regarding the unique properties of HLA class I peptides. The methodology enables sensitive and highly reproducible characterization of HLA peptidomes from individual cell lines. From up to 16 DDA analyses of 100 million human cells, more than 10 000 peptides could be confidently identified, serving as basis for the generation of spectral libraries. This knowledge enabled the subsequent interrogation of DIA data, leading to the identification of peptide sets with >90% overlap between replicate samples, a prerequisite for the comparative study of closely related specimens. Furthermore, >3000 peptides could be identified from just one million cells after DIA analysis using a library generated from 300 million cells. The reduction in sample quantity and the high reproducibility of DIA-based HLA peptidome analysis should facilitate personalized medicine applications. PMID- 28834232 TI - Critical assessment of thioguanine treatment for inflammatory bowel diseases: Is it time to rehabilitate this treatment? AB - OBJECTIVE: The potential therapeutic effect of thioguanine in the management of inflammatory bowel disease (IBD) is hindered due to association with vascular hepatotoxicity. The study aimed to assess the evidence for efficacy of thioguanine in IBD management and the association with nodular regenerative hyperplasia (NRH) and other thioguanine-related hepatotoxicities. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for literature search. Due to the lack of randomized controlled trials (RCTs), the search was extended to observational studies. Quality of the included studies were graded A to C based on evaluation tools used to determine efficacy (subjective and objective grading tools) and nodular regenerative hyperplasia safety (liver biopsy and imaging tools). RESULTS: Two hundred and ninety studies were identified, but following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines only 13 studies were evaluated for efficacy and safety of thioguanine. Outcome measures were consistent across the included studies. Thioguanine appeared efficacious and well-tolerated in patients who were intolerant/non-responsive to existing immunomodulators. There was a trend toward a positive association between dose of thioguanine and NRH but not with other adverse events such as liver biochemical abnormalities or with portal hypertension. CONCLUSIONS: The evidence to support thioguanine treatment is limited to observational studies. While encouraging, there is a need for prospective RCTs to determine the role of thioguanine in the management of IBD. PMID- 28834233 TI - A pattern-based risk-stratification scheme for salivary gland cytology: A multi institutional, interobserver variability study to determine applicability. AB - BACKGROUND: Salivary gland aspiration cytology is useful in the preoperative management of patients but remains challenging, because of the extensive morphologic overlap of some tumors limits the ability to always determine the presence of malignancy. In response to this challenge, there has been increasing drive to develop a risk-based categorization scheme for salivary gland aspirates. Herein, the authors examine the interobserver variability of 1 such pattern and risk-based system. METHODS: Select smears and cell-block sections of 50 salivary gland aspirates from 2 large academic centers were digitally imaged. These scanned slides were independently and blindly reviewed by 4 cytopathologists, and each aspirate was assigned to 1 of the proposed pattern-based categories if it was considered neoplastic by the observer. Interobserver agreement was scored and aggregated risks of malignancy were calculated for cases with available surgical follow-up. RESULTS: In total, 42 samples (84%) were considered neoplastic by at least 2 observers and were scored for interobserver agreement: 10 of 42 (23.8%) had uniform agreement, 14 of 42 (33.3%) had majority agreement, and 5 of 42 (11.9%) had divided agreement. Only 9 of 42 samples (21.4%) had minimal agreement, and 4 of 42 (9.5%) had no agreement. Condensation of similar categories was able to improve interobserver agreement and still maintain stratified risk of malignancy. CONCLUSIONS: The proposed pattern-based risk stratification scheme, which could be implemented with the forthcoming Milan System, has good overall interobserver agreement and successfully stratifies the risk of malignancy. Some simplification is possible to make the system easier to use and improve interobserver agreement while maintaining stratification of risk. Cancer Cytopathol 2017;125:776-85. (c) 2017 American Cancer Society. PMID- 28834234 TI - Multicolor flow cytometric analysis of TLR2 and TLR9 expression and function in NK cells from patients with ANCA-associated vasculitis. AB - BACKGROUND: The primary objective of this study was to provide an assessment of NK cells in patients with ANCA-associated vasculitis (AAV). METHODS: Patients were classified based on the presence or absence of ANCAs and compared with healthy controls (HCs). By multiparameter flow cytometry, we evaluated the number and proportion of NK cells (CD3-CD56+) and the CD56dim , CD56bright , CD56dim CD57bright subsets; TLR2 and TLR9 expression; intracellular IFN-gamma production upon stimulation with TLR2 and TLR9 ligands; degranulation activity; serum cytokines; immunohistochemical staining of available biopsies. RESULTS: No differences in the number and proportion of NK cells between patients and HC were observed, except for a lower proportion of CD56dim subset in ANCA-negative patients than in HC (P = 0.02). With respect to HC, TLR2 expression levels were reduced in NK cells from ANCA-negative patients (P = 0.03), in the CD56dim subset of ANCA-positive (P = 0.02) and ANCA-negative patients (P = 0.01), in the CD56bright subset of ANCA-positive patients (P = 0.007), and in the CD56dim CD57bright subset of ANCA-positive (P = 0.04) and ANCA-negative patients (P = 0.03). No differences between patients and HC were found concerning IFN-gamma production and degranulation activity. IL-22 levels were lower in ANCA-positive patients than in HC (P = 0.01). The immunohistochemical analysis showed sporadic CD56+ cells in one renal biopsy, and a diffuse and moderate infiltrate of IL-22+ cells in all renal biopsies and in skin tissue. CONCLUSIONS: Our data suggest a role of infectious stimuli triggering NK cells in AAV pathogenesis. Poor detection of NK cells in affected tissues suggests a marginal involvement in local inflammatory responses. (c) 2017 International Clinical Cytometry Society. PMID- 28834235 TI - Comment on: Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features of dyskeratosis congenita and IMAGe association. PMID- 28834236 TI - When invasive ants meet: effects of outbreeding on queen performance in the tramp ant Cardiocondyla itsukii. AB - Most disturbed habitats in the tropics and subtropics harbor numerous species of invasive ants, and occasionally the same species has been introduced repeatedly from multiple geographical sources. We examined how experimental crossbreeding between sexuals from different populations affects the fitness of queens of the tramp ant Cardiocondyla itsukii, which is widely distributed in Asia and the Pacific Islands. Eggs laid by queens that mated with nestmate males had a higher hatching rate than eggs laid by queens mated to males from neighboring (Hawaii * Kauai) or distant introduced populations (Hawaii/Kauai * Okinawa). Furthermore, inbreeding queens had a longer lifespan and produced a less female-biased offspring sex ratio than queens from allopatric mating. This suggests that the genetic divergence between different source populations may already be so large that in case of multiple invasions eventual crossbreeding might negatively affect the fitness of tramp ants. PMID- 28834237 TI - How to connect classroom and workplace learning. PMID- 28834239 TI - Mesoporous NiS2 Nanospheres Anode with Pseudocapacitance for High-Rate and Long Life Sodium-Ion Battery. AB - It is of great importance to exploit electrode materials for sodium-ion batteries (SIBs) with low cost, long life, and high-rate capability. However, achieving quick charge and high power density is still a major challenge for most SIBs electrodes because of the sluggish sodiation kinetics. Herein, uniform and mesoporous NiS2 nanospheres are synthesized via a facile one-step polyvinylpyrrolidone assisted method. By controlling the voltage window, the mesoporous NiS2 nanospheres present excellent electrochemical performance in SIBs. It delivers a high reversible specific capacity of 692 mA h g-1 . The NiS2 anode also exhibits excellent high-rate capability (253 mA h g-1 at 5 A g-1 ) and long-term cycling performance (319 mA h g-1 capacity remained even after 1000 cycles at 0.5 A g-1 ). A dominant pseudocapacitance contribution is identified and verified by kinetics analysis. In addition, the amorphization and conversion reactions during the electrochemical process of the mesoporous NiS2 nanospheres is also investigated by in situ X-ray diffraction. The impressive electrochemical performance reveals that the NiS2 offers great potential toward the development of next generation large scale energy storage. PMID- 28834238 TI - Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists. AB - : Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients >=65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. SUMMARY: Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged >= 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19 2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence. PMID- 28834240 TI - Microbial biotechnology as a tool to restore degraded drylands. AB - We briefly review how microbial biotechnology can contribute to improve activities aiming to restore degraded drylands and to combat their desertification, which are an integral part of the Sustainable Development Goal 15 of the 2030 Agenda. Microbial biotechnology offers notable promise to improve restoration actions based on the use of biocrust-forming engineered cyanobacteria, which play key roles in maintaining ecosystem structure and functioning in drylands worldwide. Advances in our understanding of microbiome associated to biocrusts and of the signalling involved in the communication among their constituents can also potentially enhance the outcome of restoration activities in drylands. PMID- 28834241 TI - Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN-18. AB - In 2014 and 2015, synthetic cannabinoid receptor agonists NNEI (N-1-naphthalenyl 1-pentyl-1H-indole-3-carboxamide) and MN-18 (N-1-naphthalenyl-1-pentyl-1H indazole-3-carboxamide) were detected in recreationally used and abused products in multiple countries, and were implicated in episodes of poisoning and toxicity. Despite this, the pharmacokinetic profiles of NNEI and MN-18 have not been characterized. In the present study NNEI and MN-18 were incubated in rat and human liver microsomes and hepatocytes, to estimate kinetic parameters and to identify potential metabolic pathways, respectively. These parameters and pathways were then examined in vivo, via analysis of blood and urine samples from catheterized male rats following intraperitoneal (3 mg/kg) administration of NNEI and MN-18. Both NNEI and MN-18 were rapidly cleared by rat and human liver microsomes, and underwent a range of oxidative transformations during incubation with rat and human hepatocytes. Several unique metabolites were identified for the forensic identification of NNEI and MN-18 intake. Interestingly, NNEI underwent a greater number of biotransformations (20 NNEI metabolites versus 10 MN-18 metabolites), yet parent MN-18 was eliminated at a faster rate than NNEI in vivo. Additionally, in vivo elimination was more rapid than in vitro estimates. These data highlight that even closely related synthetic cannabinoids can possess markedly distinct pharmacokinetic profiles, which can vary substantially between in vitro and in vivo models. PMID- 28834242 TI - The XXIV National Meeting in Medicinal Chemistry (NMMC 2016) in Perugia, Italy. AB - A Special Year of Italian Medchem: Guest Editors Violetta Cecchetti and Benedetto Natalini of the University of Perugia look back at the XXIV National Meeting in Medicinal Chemistry (NMMC 2016) held in Perugia, Italy. It was this at special conference where ChemMedChem also held its 10th Anniversary Celebration. In this editorial, they provide highlights of last year's events, including some key presentations now collected in this Special Issue. PMID- 28834243 TI - A Novel and Facile Route to Synthesize Atomic-Layered MoS2 Film for Large-Area Electronics. AB - High-quality and large-area molybdenum disulfide (MoS2 ) thin film is highly desirable for applications in large-area electronics. However, there remains a challenge in attaining MoS2 film of reasonable crystallinity due to the absence of appropriate choice and control of precursors, as well as choice of suitable growth substrates. Herein, a novel and facile route is reported for synthesizing few-layered MoS2 film with new precursors via chemical vapor deposition. Prior to growth, an aqueous solution of sodium molybdate as the molybdenum precursor is spun onto the growth substrate and dimethyl disulfide as the liquid sulfur precursor is supplied with a bubbling system during growth. To supplement the limiting effect of Mo (sodium molybdate), a supplementary Mo is supplied by dissolving molybdenum hexacarbonyl (Mo(CO)6 ) in the liquid sulfur precursor delivered by the bubbler. By precisely controlling the amounts of precursors and hydrogen flow, full coverage of MoS2 film is readily achievable in 20 min. Large area MoS2 field effect transistors (FETs) fabricated with a conventional photolithography have a carrier mobility as high as 18.9 cm2 V-1 s-1 , which is the highest reported for bottom-gated MoS2 -FETs fabricated via photolithography with an on/off ratio of ~105 at room temperature. PMID- 28834244 TI - Striking a new path in reducing cartilage breakdown: combination of antioxidative therapy and chondroanabolic stimulation after blunt cartilage trauma. AB - Cartilage injury can trigger crucial pathomechanisms, including excessive cell death and expression of matrix-destructive enzymes, which contribute to the progression of a post-traumatic osteoarthritis (PTOA). With the intent to create a novel treatment strategy for alleviating trauma-induced cartilage damage, we complemented a promising antioxidative approach based on cell and chondroprotective N-acetyl cysteine (NAC) by chondroanabolic stimulation. Overall, three potential pro-anabolic growth factors - IGF-1, BMP7 and FGF18 - were tested comparatively with and without NAC in an ex vivo human cartilage trauma-model. For that purpose, full-thickness cartilage explants were subjected to a defined impact (0.59 J) and subsequently treated with the substances. Efficacy of the therapeutic approaches was evaluated by cell viability, as well as various catabolic and anabolic biomarkers, representing the present matrix turnover. Although monotherapy with NAC, FGF18 or BMP7 significantly prevented trauma-induced cell dead and breakdown of type II collagen, combination of NAC and one of the growth factors did not yield significant benefit as compared to NAC alone. IGF-1, which possessed only moderate cell protective and no chondroprotective qualities after cartilage trauma, even reduced NAC-mediated cell and chondroprotection. Despite significant promotion of type II collagen expression by IGF-1 and BMP7, addition of NAC completely suppressed this chondroanabolic effect. All in all, NAC and BMP7 emerged as best combination. As our findings indicate limited benefits of the simultaneous multidirectional therapy, a sequential application might circumvent adverse interferences, such as suppression of type II collagen biosynthesis, which was found to be reversed 7 days after NAC withdrawal. PMID- 28834246 TI - Magnetic resonance imaging reveals elevated aortic pulse wave velocity in obese and overweight adolescents. AB - The aortic pulse wave velocity (PWV) measured via cardiac magnetic resonance (CMR) can be used to non-invasively assess changes in arterial stiffness and potential underlying vascular dysfunction. This technique could unmask early arterial dysfunction in overweight and obese youth at risk for cardiovascular disease. We sought to determine the association between vascular stiffness, percentage body fat, body mass index (BMI), and cardiac function in adolescents across the weight spectrum through both CMR and standard applanation tonometry (AT)-based PWV measurements. PWV and left-ventricular cardiac function were assessed using 3.0 T CMR in obese and overweight (OB/OW) participants (n = 12) and controls (n = 7). PWV was also estimated via carotid-femoral AT. OB/OW participants did not differ from healthy-weight controls regarding cardiometabolic risk factors or physical activity levels, but there was a trend towards higher levels of triglycerides in obese/overweight participants (P = 0.07). Mean PWV was higher in obese participants when corrected for age and sex (P = 0.01), and was positively associated with BMI (beta = 0.51, P = 0.02). PWV estimated through AT was not significantly different between groups. Cardiac function measured by left-ventricular ejection fraction z-score was inversely associated with mean PWV (beta = -0.57, P = 0.026). Increasing arterial stiffness and decreasing cardiac function were evident among our overweight and obese cohort. PWV estimated by CMR could detect early increases in arterial stiffness vs. traditional AT measurements of PWV. PMID- 28834245 TI - Pyomelanin from Pseudoalteromonas lipolytica reduces biofouling. AB - Members of the marine bacterial genus Pseudoalteromonas are efficient producers of antifouling agents that exert inhibitory effects on the settlement of invertebrate larvae. The production of pigmented secondary metabolites by Pseudoalteromonas has been suggested to play a role in surface colonization. However, the physiological characteristics of the pigments produced by Pseudoalteromonas remain largely unknown. In this study, we identified and characterized a genetic variant that hyperproduces a dark-brown pigment and was generated during Pseudoalteromonas lipolytica biofilm formation. Through whole genome resequencing combined with targeted gene deletion and complementation, we found that a point mutation within the hmgA gene, which encodes homogentisate 1,2 dioxygenase, is solely responsible for the overproduction of the dark-brown pigment pyomelanin. In P. lipolytica, inactivation of the hmgA gene led to the formation of extracellular pyomelanin and greatly reduced larval settlement and metamorphosis of the mussel Mytilus coruscus. Additionally, the extracted pyomelanin from the hmgA deletion mutant and the in vitro-synthesized pyomelanin also reduced larval settlement and metamorphosis of M. coruscus, suggesting that extracellular pyomelanin released from marine Pseudoalteromonas biofilm can inhibit the settlement of fouling organisms. PMID- 28834247 TI - Regeneration of the cementum and periodontal ligament using local BDNF delivery in class II furcation defects. AB - Periodontal furcation defects are usually addressed by the placement of a physical barrier which may limit the regenerative potential of periodontal wounds. This study morphometrically quantified the regenerative effect of brain derived neurotrophic factor (BDNF) in furcation defects in a non-human primate model. Grade II furcation defects (with and without induced inflammation prior to surgery) were created on the first and second molars of eight non-human primates. Defects were treated with open flap debridement and subsequently filled with either: Group A; BDNF (500 ug mL-1 ) in high-molecular weight-hyaluronic acid (HMW-HA), Group B; BDNF (50 ug mL-1 ) in HMW-HA, Group C; HMW-HA acid only, Group D; unfilled defect, or Group E; BDNF (500 ug mL-1 ) in saline. Periodontal wound healing was observed every 2 weeks by computed-tomography. At 11 weeks all animals were sacrificed and maxillary and mandibular block biopsies were referred for nondecalcified histology. Linear measurements of new cementum (cellular and acellular) and periodontal ligament (PDL) formation were performed. Computerized tomography reconstruction and software quantification demonstrated successful bone fill for all groups. However, histometric assessment demonstrated significantly higher level of total periodontal regeneration for the 500 ug mL-1 BDNF HMW-HA relative to all other groups. No significant differences in cementogenesis were observed among groups. Significantly higher acellular cementum formation was observed for sites where inflammation was not induced prior to surgical procedures. While all groups experienced similar bone fill and cementogenesis, the 500 ug mL-1 BDNF HMW-HA appeared to most effectively repair PDL (minimum increase of ~22% relative to all groups; over 200% relative to unfilled defects). (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1611-1617, 2018. PMID- 28834248 TI - High doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults. AB - AIMS: This study tested the hypothesis that high doses of anti-inflammatory drugs would attenuate the adaptive response to resistance training compared with low doses. METHODS: Healthy men and women (aged 18-35 years) were randomly assigned to daily consumption of ibuprofen (IBU; 1200 mg; n = 15) or acetylsalicylic acid (ASA; 75 mg; n = 16) for 8 weeks. During this period, subjects completed supervised knee-extensor resistance training where one leg was subjected to training with maximal volitional effort in each repetition using a flywheel ergometer (FW), while the other leg performed conventional (work-matched across groups) weight-stack training (WS). Before and after training, muscle volume (MRI) and strength were assessed, and muscle biopsies were analysed for gene and protein expression of muscle growth regulators. RESULTS: The increase in m. quadriceps volume was similar between FW and WS, yet was (averaged across legs) greater in ASA (7.5%) compared with IBU (3.7%, group difference 34 cm3 ; P = 0.029). In the WS leg, muscle strength improved similarly (11-20%) across groups. In the FW leg, increases (10-23%) in muscle strength were evident in both groups yet they were generally greater (interaction effects P < 0.05) for ASA compared with IBU. While our molecular analysis revealed several training effects, the only group interaction (P < 0.0001) arose from a downregulated mRNA expression of IL-6 in IBU. CONCLUSION: Maximal over-the-counter doses of ibuprofen attenuate strength and muscle hypertrophic adaptations to 8 weeks of resistance training in young adults. Thus, young individuals using resistance training to maximize muscle growth or strength should avoid excessive intake of anti-inflammatory drugs. PMID- 28834249 TI - Are educating and promoting interventions effective in oral health?: A systematic review. AB - OBJECTIVE: It is estimated that about 20%-25% of the world's population are suffering from periodontal diseases or severe gum diseases. This requires appropriate interventions. For the development of effective and evidence-based programmes tailored to the target group, the aim of this review was to survey to the effectiveness of oral health education and promotion interventions in the relevant groups of people. METHODS: The electronic databases including PubMed, EMBASE, Web of science and Cochrane Library were searched for English language studies between 2010 and (January-December) 2016. To assess the quality of articles, the checklist was used that includes 19 items. Studies were selected based on PICOs criteria, and finally, 16 studies were entered in our study. RESULTS: A total of 16 articles were selected, classified into two groups (A and B groups), so that group A with short-term effects includes improving knowledge, attitudes, self-efficacy, oral health behaviour (toothbrushing and flossing), theoretical constructs (perceived susceptibility, perceived severity and perceived behavioural control) which consists of 15 articles and group B with long-term effects includes improving decayed teeth, plaque, calculus and bleeding which consists of six articles. CONCLUSION: Approximately, this study supports effectiveness of all oral health education and promotion interventions, especially in short-term outcomes. Regarding the importance of long-term and short-term outcomes for oral health education and promotion programmes, These interventions could be performed in the future with several target groups including family and teachers. PMID- 28834250 TI - Ocular findings in patients with microcephaly can suggest presumed congenital zika virus infection. PMID- 28834251 TI - Microbial biotechnology and circular economy in wastewater treatment. AB - Microbial biotechnology is essential for the development of circular economy in wastewater treatment by integrating energy production and resource recovery into the production of clean water. A comprehensive knowledge about identity, physiology, ecology, and population dynamics of process-critical microorganisms will improve process stability, reduce CO2 footprints, optimize recovery and bioenergy production, and help finding new approaches and solutions. Examples of research needs and perspectives are provided, demonstrating the great importance of microbial biotechnology. PMID- 28834252 TI - Ganglion cell layer measurements correlate with disease severity in patients with Alzheimer's disease. PMID- 28834253 TI - Appetite-Inducing Effects of Homoeriodictyol: Two Randomized, Cross-Over Interventions. AB - SCOPE: Anorexia of aging, characterized by a decrease in appetite and/or food intake, is a major risk factor of under-nutrition and adverse health outcomes in elderly people. Recent in vitro evidence suggests homoeriodictyol (HED), a naturally occurring, bitter-masking flavanone, as a promising agent to increase appetite and food intake. METHODS AND RESULTS: In two cross-over intervention trials, 30 mg NaHED, either solely (n = 10, Study I) or in combination with a 75 g glucose load (n = 17, study II) were administered to healthy adult subjects. Ratings of hunger were assessed at fasting and either 30 min (Study I) or 120 min (Study II) post intervention. Ad libitum energy intake from a standardized breakfast and plasma changes in hunger-/satiety-associated hormones PYY, GLP-1, ghrelin and serotonin were determined after blood drawings. Effects were more pronounced when NaHED was administered in combination with 75 g glucose since ad libitum energy (+ 9.52 +/- 4.60%) and protein (+ 7.08 +/- 7.97%) intake as well as plasma DeltaAUC ghrelin values increased in study II solely, whereas plasma serotonin concentrations decreased after both interventions. CONCLUSIONS: NaHED demonstrated appetizing effects in healthy adults when administered with a glucose load. Long-term intervention studies are warranted to verify these effects in compromised subjects. PMID- 28834254 TI - A cautionary tale for medical managers. PMID- 28834255 TI - Hormones, damned hormones, and statistics. PMID- 28834256 TI - Visceral injury at gynaecological surgery: demonstration of reasonable care affords acceptable defence. PMID- 28834258 TI - Corrigendum. PMID- 28834259 TI - Radiographic Progression in Psoriatic Arthritis Achieving a Good Response to Treatment: Data Using Newer Composite Indices of Disease Activity. AB - OBJECTIVE: To compare radiographic outcomes according to the magnitude of the response utilizing 3 new psoriatic composite disease activity measures (the Psoriatic Arthritis Disease Activity Score [PASDAS], the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis Composite Exercise [GRACE], and the Disease Activity in PsA [DAPSA]). METHODS: The data were taken from the GO REVEAL data set, a large randomized, double-blind study that evaluated the safety and efficacy of 2 doses of the tumor necrosis factor inhibitor golimumab in subjects with active psoriatic arthritis (PsA). Response criteria at 24 weeks were applied across the whole data set, irrespective of treatment group. Radiographic scores at baseline and 24 weeks were assessed using the modified Sharp/van der Heijde method for PsA. RESULTS: Overall, for each measure, radiographic progression was significantly greater in subjects with a moderate or poor outcome, and absent in those with a good outcome. The proportion of subjects without radiographic progression in the good outcome group was 83% using the PASDAS (chi2 = 7.9; P = 0.02), 80% using the GRACE (chi2 = 5.8; P = 0.05), and 76% using the DAPSA (chi2 = 3.4; P = 0.19). CONCLUSION: Response criteria for disease-specific composite measures enable separation between groups in terms of radiographic progression and may therefore be used as suitable targets for interventional studies, as well as in the clinic. PMID- 28834260 TI - RFTS-dependent negative regulation of Dnmt1 by nucleosome structure and histone tails. AB - DNA methylation in promoter regions represses gene expression and is copied over mitotic divisions by Dnmt1. Dnmt1 activity is regulated by its replication foci targeting sequence (RFTS) domain which masks the catalytic pocket. It has been shown that Dnmt1 activity on unmethylated DNA is inhibited in nucleosome cores. In the present study, we aimed to assess the effect of nuclesome formation on maintenance methylation at single CpG resolution. We show that Dnmt1 fully methylates naked linker DNA in dinucleosomes, whereas maintenance methylation was repressed at all CpG sites in nucleosome core particles. Deletion of RFTS partly released obstruction of Dnmt1 activity in core particles. Histone H3 tail peptides inhibited Dnmt1 in an RFTS-dependent manner and repression was modulated by acetylation or methylation. We propose a novel function of RFTS to regulate Dnmt1 activity in nucleosomes. PMID- 28834261 TI - Potential savings in the diagnosis of vestibular schwannoma. AB - INTRODUCTION: Magnetic resonance imaging (MRI) is used to screen patients at risk for vestibular schwannoma (VS). These MRIs are costly and have an extremely low yield; only 3% of patients in the screening population has an actual VS. It might be worthwhile to develop a test to predict VS and refer only a subset of all patients for MRI. OBJECTIVE: To examine the potential savings of such a hypothetical diagnostic test before MRI. DESIGN: We built a decision analytical model of the diagnostic strategy of VS. Input was derived from literature and key opinion leaders. The current strategy was compared to hypothetical new strategies, assigning MRI to the following: (i) all patients with pathology, (ii) all patients with important pathology and (iii) only patients with VS. This resulted in potential cost savings for each strategy. We conducted a budget impact analysis to predict nationwide savings for the Netherlands and the United Kingdom (UK), and a probabilistic sensitivity analysis to address uncertainty. RESULTS: Mean savings ranged from ?256 (95%CI ?250 - ?262) or approximately US$284 (95%CI US$277 - US$291) per patient for strategy 1 to ?293 (95%CI ?290 - ?296) or approximately US$325 (95%CI US$322 - US$328) per patient for strategy 3. Future diagnostic strategies can cost up to these amounts per patient and still be cost saving. Annually, for the Netherlands, ?2.8 to ?3.2 million could be saved and ?10.8 to ?12.3 million for the UK. CONCLUSIONS: The model shows that substantial savings could be generated if it is possible to further optimise the diagnosis of VS. PMID- 28834263 TI - Concise Review: Musculoskeletal Stem Cells to Treat Age-Related Osteoporosis. AB - Age-related (type-II) osteoporosis is a common and debilitating condition driven in part by the loss of bone marrow (BM) mesenchymal stromal cells (MSC) and their osteoblast progeny, leading to reduced bone formation. Current pharmacological regiments targeting age-related osteoporosis do not directly treat the disease by increasing bone formation, but instead use bisphosphonates to reduce bone resorption-a treatment designed for postmenopausal (type-I) osteoporosis. Recently, the bone regenerative capacity of MSCs has been found within a very rare population of skeletal stem cells (SSCs) residing within the larger heterogeneous BM-MSC pool. The osteoregenerative potential of SSCs would be an ideal candidate for cell-based therapies to treat degenerative bone diseases such as osteoporosis. However, to date, clinical and translational studies attempting to improve bone formation through cell transplantation have used the larger, nonspecific, MSC pool. In this review, we will outline the physiological basis of age-related osteoporosis, as well as discuss relevant preclinical studies that use exogenous MSC transplantation with the aim of treating osteoporosis in murine models. We will also discuss results from specific clinical trials aimed at treating other systemic bone diseases, and how the discovery of SSC could help realize the full regenerative potential of MSC therapy to increase bone formation. Finally, we will outline how ancillary clinical trials could be initiated to assess MSC/SSC-mediated bone formation gains in existing and potentially unrelated clinical trials, setting the stage for a dedicated clinical investigation to treat age-related osteoporosis. Stem Cells Translational Medicine 2017;6:1930-1939. PMID- 28834262 TI - Sex differences in lifespan extension with acarbose and 17-alpha estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC2 signaling. AB - Interventions that extend lifespan in mice can show substantial sexual dimorphism. Here, we show that male-specific lifespan extension with two pharmacological treatments, acarbose (ACA) and 17-alpha estradiol (17aE2), is associated, in males only, with increased insulin sensitivity and improved glucose tolerance. Females, which show either smaller (ACA) or no lifespan extension (17aE2), do not derive these metabolic benefits from drug treatment. We find that these male-specific metabolic improvements are associated with enhanced hepatic mTORC2 signaling, increased Akt activity, and phosphorylation of FOXO1a - changes that might promote metabolic health and survival in males. By manipulating sex hormone levels through gonadectomy, we show that sex-specific changes in these metabolic pathways are modulated, in opposite directions, by both male and female gonadal hormones: Castrated males show fewer metabolic responses to drug treatment than intact males, and only those that are also observed in intact females, while ovariectomized females show some responses similar to those seen in intact males. Our results demonstrate that sex-specific metabolic benefits occur concordantly with sexual dimorphism in lifespan extension. These sex-specific effects can be influenced by the presence of both male and female gonadal hormones, suggesting that gonadally derived hormones from both sexes may contribute to sexual dimorphism in responses to interventions that extend mouse lifespan. PMID- 28834264 TI - Wafer-Scale Fabrication of Suspended Single-Walled Carbon Nanotube Arrays by Silver Liquid Dynamics. AB - Suspended single-walled carbon nanotubes (SWNTs) have advantages in mechanical resonators and highly sensitive sensors. Large-scale fabrication of suspended SWNTs array devices and uniformity among SWNTs devices remain a great challenge. This study demonstrates an effective, fast, and wafer-scale technique to fabricate suspended SWNT arrays, which is based on a dynamic motion of silver liquid to suspend and align the SWNTs between the prefabricated palladium electrodes in high temperature annealing treatment. Suspended, strained, and aligned SWNTs are synthesized on a 2 * 2 cm2 substrate with an average density of 10 tubes per micrometer. Under the optimal conditions, almost all SWNTs become suspended. A promising formation model of suspended SWNTs is established. The Kelvin four-terminal resistance measurement shows that these SWNT array devices have extreme low contact resistance. Meanwhile, the suspended SWNT array field effect transistors are fabricated by selective etching of metallic SWNTs using electrical breakdown. This method of large-scale fabrication of suspended architectures pushes the study of nanoscale materials into a new stage related to the electrical physics and industrial applications. PMID- 28834265 TI - Association of Varroa destructor females in multiply infested cells of the honeybee Apis mellifera. AB - The genetic diversity of Varroa destructor (Anderson & Trueman) is limited outside its natural range due to population bottlenecks and its propensity to inbreed. In light of the arms race between V. destructor and its honeybee (Apis mellifera L.) host, any mechanism enhancing population admixture of the mite may be favored. One way that admixture can occur is when two genetically dissimilar mites coinvade a brood cell, with the progeny of the foundresses admixing. We determined the relatedness of 393 pairs of V. destructor foundresses, each pair collected from a single bee brood cell (n = five colonies). We used six microsatellites to identify the genotypes of mites coinvading a cell and calculated the frequency of pairs with different or the same genotypes. We found no deviation from random coinvasion, but the frequency of cells infested by mites with different genotypes was high. This rate of recombination, coupled with a high transmission rate of mites, homogenized the allelic pool of mites within the apiary. PMID- 28834266 TI - Synthesis, enzyme inhibitory kinetics, and computational studies of novel 1-(2-(4 isobutylphenyl) propanoyl)-3-arylthioureas as Jack bean urease inhibitors. AB - In this article, synthesis of a novel 1-(2-(4-isobutylphenyl)propanoyl)-3 arylthioureas (4a-j) as jack bean urease inhibitors has been described. Freshly prepared 2-(4-isobutylphenyl) propanoyl isothiocyanate was treated with substituted aromatic anilines in one pot using anhydrous acetone. The compounds 4e, 4h, and 4j showed IC50 values 0.0086 nm, 0.0081 nm, and 0.0094 nm, respectively. The enzyme inhibitory kinetics results showed that compound 4h inhibit the enzyme competitively while derivatives 4e and 4j are the mixed type inhibitors. The compound 4h reversibly binds the urease enzyme showing Ki value 0.0012 nm. The Ki values for 4e and 4j are 0.0025 nm and 0.003 nm, respectively. The antioxidant activity results reflected that compounds 4b, 4i, and 4j showed excellent radical scavenging activity. Moreover, the cytotoxic activity of the target compounds was evaluated using brine shrimp assay and it was found that all of the synthesized compounds exhibited no cytotoxic effects to brine shrimps. The computational molecular docking and molecular dynamic simulation of title compounds were also performed, and results showed that the wet laboratory findings are in good agreement to the dry laboratory results. Based upon our results, it is proposed that compound 4h may act as a lead candidate to design the clinically useful urease inhibitors. PMID- 28834267 TI - Pet-associated Campylobacteriosis: A persisting public health concern. AB - Campylobacter is regarded as a leading cause of human bacterial gastroenteritis in the United States. We report on a case of laboratory-confirmed Campylobacter jejuni infection in the Commonwealth of Pennsylvania among members of a household living with a laboratory-confirmed but non-speciated Campylobacter-infected puppy. We describe an outbreak of likely dog-associated campylobacteriosis, the risk factors, potential routes of exposure and the clinical features in the exposed family members, which began shortly after exposure to the recently purchased dog. We also provide public health recommendations to prevent Campylobacter infections in veterinary care providers, pet owners and those planning to adopt pets in the future. Finally, this report underscores the importance of the One Health approach when public health responders, human and animal healthcare providers and clinical diagnostic laboratories are tasked with developing effective strategies when investigating, detecting and responding to zoonoses (diseases shared between animals and humans). PMID- 28834268 TI - A Praline-Like Flexible Interlayer with Highly Mounted Polysulfide Anchors for Lithium-Sulfur Batteries. AB - The development of lithium-sulfur (Li-S) batteries is dogged by the rapid capacity decay arising from polysulfide dissolution and diffusion in organic electrolytes. To solve this critical issue, a praline-like flexible interlayer consisting of high-loading titanium oxide (TiO2 ) nanoparticles and relatively long carbon nanofibers is fabricated. TiO2 nanoparticles with a size gradient occupy both the external and internal of carbon fiber and serve as anchors that allow the chemical adsorption of polysulfides through a conductive nanoarchitecture. The porous conductive carbon backbone helps in the physical absorption of polysulfides and provides redox reaction sites to allow the polysulfides to be reused. More importantly, it offers enough mechanical strength to support a high load TiO2 nanoparticle (79 wt%) that maximizes their chemical role, and can accommodate the large volume changes. Significant enhancement in cycle stability and rate capability is achieved for a readily available sulfur/multi-walled carbon nanotube composite cathode simply by incorporating this hierarchically nanostructured interlayer. The design and synthesis of interlayers by in situ integration of metal oxides and carbon fibers via a simple route offers the potential to advance Li-S batteries for practical applications in the future. PMID- 28834269 TI - Prognostic significance of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of stage I lung adenocarcinoma: A retrospective study based on analysis of 110 Chinese patients. AB - BACKGROUND: The aim of this study was to investigate the relationship between predominant subtype, classification, and prognosis in Chinese stage I lung adenocarcinoma patients according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) International Multidisciplinary Lung Adenocarcinoma Classification. METHODS: Between 2000 and 2010, 110 patients with stage I lung adenocarcinoma underwent surgery at Xuanwu Hospital. Two pathologists independently reclassified all resected specimens according to the IASLC/ATS/ERS classification. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. RESULTS: There were no cases of adenocarcinoma in situ, and three cases of minimally invasive adenocarcinoma. There were 107 cases of invasive adenocarcinoma: 12 lepidic, 32 acinar, 30 papillary, 18 micropapillary, and 15 solid predominant subtypes. Patients with micropapillary and solid predominant tumors had significantly poorer disease-free survival compared to those with other subtypes of predominant tumors (P = 0.021). Multivariate analysis revealed that the new classification (P = 0.003) and T stage (P = 0.034) were independent predictors of disease-free and overall survival, respectively. CONCLUSION: The predominant subtype in the primary tumor was associated with prognosis in resected stage I lung adenocarcinoma. PMID- 28834270 TI - Norfloxacin is more effective than Rifaximin in avoiding bacterial translocation in an animal model of cirrhosis. AB - BACKGROUND & AIMS: Norfloxacin administration is useful in preventing bacterial infections in cirrhosis but associated to the generation of resistant species. Rifaximin is known to reach high concentrations in the intestinal lumen without generating relevant resistance in the intestinal flora. Our aim was to compare the effect of Norfloxacin and Rifaximin on intestinal flora composition, bacterial translocation and survival in cirrhotic rats. METHODS: Cirrhosis was induced in rats by oral administration of CCl4 . Animals were divided into three groups: only CCl4 (group I, n = 10); CCl4 + Norfloxacin (group II, n = 17) and CCl4 + Rifaximin (group III, n = 14). Gut bacterial composition, bacterial translocation and cytokine levels were measured. RESULTS: Forty-one rats were finally included. The incidence of viable and non-viable bacterial translocation was significantly reduced in animals receiving Norfloxacin; Rifaximin also decreased the incidence of viable and non-viable bacterial translocation, but did not reach statistical significance. Serum TNF-alpha levels were significantly lower in antibiotic groups. Norfloxacin modified intestinal microbiota, depleting significantly more pathobionts than Rifaximin. CONCLUSION: Norfloxacin is more effective than Rifaximin in preventing bacterial translocation in rats with cirrhosis probably because of its capacity to reduce pathobionts from intestinal microbiota. PMID- 28834271 TI - Target-Selective Fluorescence Imaging and Photocytotoxicity against H2 O2 High Expressing Cancer Cells Using a Photoactivatable Theranostic Agent. AB - A purpose-designed and synthesized H2 O2 -reactive and photoactivatable theranostic agent 1 consisting of 1) an arylboronic acid moiety, 2) pro fluorophore moiety, and 3) photoactivatable moiety (photosensitizer), selectively and effectively reacted with H2 O2 while simultaneously releasing resorufin for fluorescence detection under neutral aqueous conditions. In addition, 1 was cell permeable, and exhibited effective photocytotoxicity against fluorescently visualized cells only upon photoirradiation. The results also showed that 1 produced a selective fluorescence response to H2 O2 , even in living cultured cells. PMID- 28834272 TI - Visual outcomes in patients with neovascular age-related macular degeneration. PMID- 28834273 TI - Hollow ZnO Nanospheres Enhance Anticancer Immunity by Promoting CD4+ and CD8+ T Cell Populations In Vivo. AB - Appropriate adjuvant aiding in generating robust anticancer immunity is crucial for cancer immunotherapy. Herein, hollow ZnO (HZnO) nanospheres are synthesized by a facile method using carbon nanospheres as the template. The HZnO nanospheres significantly promote the cellular uptake of a model antigen, and cytokine secretion by antigen-presenting cells in vitro. HZnO loaded with ovalbumin and polyinosinic-polycytidylic acid (poly(I:C)) inhibits cancer growth and metastasis to inguinal lymph node in a cancer cell challenge model. Moreover, HZnO loaded with autologous cancer antigens inhibits cancer cell growth in a cancer cell re challenge model. HZnO nanospheres significantly improve the CD4+ and/or CD8+ T cell population in splenocytes of mice in both cancer cell challenge model and re challenge model. The HZnO nanospheres can be used for cancer immunotherapy as adjuvant. PMID- 28834274 TI - Improving Protein Detection Confidence Using SWATH-Mass Spectrometry with Large Peptide Reference Libraries. AB - Protein quantification using data-independent acquisition methods such as SWATH MS most commonly relies on spectral matching to a reference MS/MS assay library. To enable deep proteome coverage and efficient use of existing data, in silico approaches have been described to use archived or publicly available large reference spectral libraries for spectral matching. Since implicit in the use of larger libraries is the increasing likelihood of false-discoveries, new workflows are needed to ensure high confidence in protein matching under these conditions. We present a workflow which introduces a range of filters and thresholds aimed at increasing confidence that the resulting proteins are reliably detected and their quantitation is consistent and reproducible. We demonstrated the workflow using extended libraries with SWATH data from human plasma samples and yeast-spiked human K562 cell lysate digest. PMID- 28834275 TI - Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 4-[4 Arylpyridin-1(4H)-yl]benzoic Acid Derivatives as Anti-HIV-1 Agents. AB - The structural similarities between N1 substituted 1,4-dihydropyridines and the known gp41 inhibitors, NB-2 and NB-64, were considered in the current research for the design of some novel anti-HIV-1 agents. A series of novel 4-[4 arylpyridin-1(4H)-yl]benzoic acid derivatives were synthesized and after a comprehensive structural elucidation were screened for in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate to good inhibitory activity against HIV-1 growth and were evaluated for in vitro cytotoxic activity using XTT assay at the concentration of 100 MUm. Among the tested compounds, 1c, 1d and 1e showed potent anti-HIV-1 activity against P24 expression at 100 MUm with inhibition percentage of 84.00%, 76.42% and 80.50%, respectively. All the studied compounds possessed no significant cytotoxicity on MT-2 cell line. The binding modes of these compounds to gp41 binding site were determined through molecular docking study. Docking studies proved 1a as the most potent compound and binding maps exhibited that the activities might be attributed to the electrostatic and hydrophobic interactions and additional H-bonds with the gp41 binding site. The Lipinski's 'rule of five' and drug-likeness criteria were also calculated for the studied compounds. All derivatives obeyed the Lipinski's 'rule of five' and had drug-like features. The findings of this study suggest that novel 4-[4-arylpyridin-1(4H)-yl]benzoic acid might be a promising scaffold for the discovery and development of novel anti-HIV-1 agents. PMID- 28834276 TI - A Facile Route to Ortho-Hydroxyanilnes through an IrIII -Catalyzed Direct C-H Amidation of 2-Phenoxypyridines. AB - A highly efficient and regioselective IrIII -catalyzed C-H amidation of 2 phenoxypyridines has been developed by using sulfonyl azides as an amino source. The amidated products were provided in good-to-excellent yields with broad functional-group tolerance. Furthermore, the 2-pyridyl moiety in the amidated products could be readily removed, thus offering an efficient route to synthetically useful ortho-hydroxyanilnes, which are important building blocks in organic synthesis. PMID- 28834277 TI - Vibrant Soundbridge can improve the most comfortable listening level in sensorineural hearing loss: Our experience with 61 patients. PMID- 28834278 TI - Contribution of mitochondria-derived free radicals to endothelial dysfunction in human skeletal muscle feed arteries: another hazard of the ageing process. PMID- 28834279 TI - The Cytochrome P450 Enzyme Responsible for the Production of (Z)-Norendoxifen in vitro. AB - Norendoxifen, an active metabolite of tamoxifen, is a potent aromatase inhibitor. Little information is available regarding production of norendoxifen in vitro. Here, we conducted a series of kinetic and inhibition studies in human liver microsomes (HLMs) and expressed P450s to study the metabolic disposition of norendoxifen. To validate that norendoxifen was the metabolite of endoxifen, metabolites in HLMs incubates of endoxifen were measured using a HPLC/MS/MS method. To further probe the specific isoforms involved in the metabolic route, endoxifen was incubated with recombinant P450s (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5 and CYP4A11). Formation rates of norendoxifen were evaluated in the absence and presence of P450 isoform specific inhibitors using HLMs. The peak of norendoxifen was found in the incubations consisting of endoxifen, HLMs, and cofactors. The retention times of norendoxifen, endoxifen, and the internal standard (diphenhydramine) were 7.81, 7.97, and 5.86 min, respectively. The Km (app) and Vmax (app) values of norendoxifen formation from endoxifen in HLM was 47.8 MUm and 35.39 pmol min-1 mg-1 . The apparent hepatic intrinsic clearances of norendoxifen formation were 0.74 MUl mg-1 min. CYP3A5 and CYP2D6 were the major enzymes capable of norendoxifen formation from endoxifen with the rates of 0.26 and 0.86 pmol pmol-1 P450 * min. CYP1A2, 3A2, 2C9, and 2C19 also contributed to norendoxifen formation, but the contributions were at least 6-fold lower. One micromolar ketoconazole (CYP3A inhibitor) showed an inhibitory effect on the rates of norendoxifen formation by 45%, but 1 MUm quinidine (CYP2D6 inhibitor) does not show any inhibitory effect. Norendoxifen, metabolism from endoxifen by multiple P450s that including CYP3A5. PMID- 28834280 TI - Metal Phosphides and Phosphates-based Electrodes for Electrochemical Supercapacitors. AB - Phosphorus compounds, such as metal phosphides and phosphates have shown excellent performances and great potential in electrochemical energy storage, which are demonstrated by research works published in recent years. Some of these metal phosphides and phosphates and their hybrids compare favorably with transition metal oxides/hydroxides, which have been studied extensively as a class of electrode materials for supercapacitor applications, where they have limitations in terms of electrical and ion conductivity and device stability. To be specific, metal phosphides have both metalloid characteristics and good electric conductivity. For metal phosphates, the open-framework structures with large channels and cavities endow them with good ion conductivity and charge storage capacity. In this review, we present the recent progress on metal phosphides and phosphates, by focusing on their advantages/disadvantages and potential applications as a new class of electrode materials in supercapacitors. The synthesis methods to prepare these metal phosphides/phosphates are looked into, together with the scientific insights involved, as they strongly affect the electrochemical energy storage performance. Particular attentions are paid to those hybrid-type materials, where strong synergistic effects exist. In the summary, the future perspectives and challenges for the metal phosphides, phosphates and hybrid-types are proposed and discussed. PMID- 28834282 TI - Synthesis of Uniquely Structured Yolk-Shell Metal Oxide Microspheres Filled with Nitrogen-Doped Graphitic Carbon with Excellent Li-Ion Storage Performance. AB - Novel structured composite microspheres of metal oxide and nitrogen-doped graphitic carbon (NGC) have been developed as efficient anode materials for lithium-ion batteries. A new strategy is first applied to a one-pot preparation of composite (FeOx -NGC/Y) microspheres via spray pyrolysis. The FeOx -NGC/Y composite microspheres have a yolk-shell structure based on the iron oxide material. The void space of the yolk-shell microsphere is filled with NGC. Dicyandiamide additive plays a key role in the formation of the FeOx -NGC/Y composite microspheres by inducing Ostwald ripening to form a yolk-shell structure based on the iron oxide material. The FeOx -NGC/Y composite microspheres with the mixed crystal structure of rock salt FeO and spinel Fe3 O4 phases show highly superior lithium-ion storage performances compared to the dense-structured FeOx microspheres with and without carbon material. The discharge capacities of the FeOx -NGC/Y microspheres for the 1st and 1000th cycle at 1 A g-1 are 1423 and 1071 mAh g-1 , respectively. The microspheres have a reversible discharge capacity of 598 mAh g-1 at an extremely high current density of 10 A g-1 . Furthermore, the strategy described in this study is generally applied to multicomponent metal oxide-carbon composite microspheres with yolk shell structures based on metal oxide materials. PMID- 28834281 TI - Cytoreductive nephrectomy for metastatic renal cell carcinoma: inequities in access exist despite improved survival. AB - The use of cytoreductive nephrectomy (CRN) in the targeted therapy era is still debated. We aimed to determine factors associated with reduced use of CRN and determine the effect of CRN on overall survival in patients with metastatic renal cell carcinoma (RCC). All advanced RCC diagnosed between 2001 and 2009 in New South Wales, Australia, were identified from the Central Cancer Registry. Records of treatment and death were electronically linked. Follow-up was to the end of 2011. Multivariable logistic regression analysis was used to determine factors associated with the receipt of CRN. Cox proportional hazards model was used to determine factors associated with survival. A total of 1062 patients were identified with metastatic RCC of whom 289 (27%) received CRN. There was no difference in the use of CRN over the time period of the study. Females (OR 0.68 (95% CI: 0.48-0.96)), unmarried individuals (OR 0.68 (95% CI: 0.48-0.96)), treatment in a nonteaching hospital (OR 0.26 (95% CI: 0.18-0.36)) and individuals without private insurance (OR 0.29 (95% CI: 0.20-0.41)) all had reduced likelihood of receiving CRN. On multivariable analysis, not receiving CRN resulted in a 90% increase in death (HR 1.90 (95% CI: 1.61-2.25)). In addition, increasing age (P < 0.001), increasing Charlson comorbidity status (P = 0.002) and female gender also had a significant independent association with death. Despite a strong association with improved survival, individuals who are elderly, female, have treatment in a nonteaching facility or have no private insurance have a reduced likelihood of receiving CRN. PMID- 28834283 TI - RNAi-mediated ephrin-B2 silencing attenuates astroglial-fibrotic scar formation and improves spinal cord axon growth. AB - AIMS: Astroglial-fibrotic scar formation following central nervous system injury can help repair blood-brain barrier and seal the lesion, whereas it also represents a strong barrier for axonal regeneration. Intensive preclinical efforts have been made to eliminate/reduce the inhibitory part and, in the meantime, preserve the beneficial role of astroglial-fibrotic scar. METHODS: In this study, we established an in vitro system, in which coculture of astrocytes and meningeal fibroblasts was treated with exogenous transforming growth factor beta1 (TGF-beta1) to form astroglial-fibrotic scar-like cell clusters, and thereby evaluated the efficacy of RNAi targeting ephrin-B2 in preventing scar formation from the very beginning. We further tested the effect of RNAi-based mitigation of astroglial-fibrotic scar on spinal axon outgrowth on a custom-made microfluidic platform. RESULTS: We found that siRNA targeting ephrin-B2 significantly reduced both the number and the diameter of cell clusters induced by TGF-beta1 and diminished the expression of aggrecan and versican in the coculture, and allowed for significantly longer extension of outgrowing spinal cord axons into astroglial-fibrotic scar as assessed on the microfluidic platform. CONCLUSIONS: These results suggest that astroglial-fibrotic scar formation and particularly the expression of aggrecan and versican could be mitigated by ephrin-B2 specific siRNA, thus improving the microenvironment for spinal axon regeneration. PMID- 28834284 TI - Cytotechnology education from a Mayo perspective. PMID- 28834286 TI - American Association of Diabetes Educators 2017. AB - Ann M. Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Carracher, Marathe, and Close review the latest developments relevant to researchers and clinicians. PMID- 28834287 TI - Partial nephrectomy margin imaging using structured illumination microscopy. AB - Partial nephrectomy (PN) is the recommended procedure over radical nephrectomy (RN) for patients with renal masses less than 4 cm in diameter (Stage T1a). Patients with less than 4 cm renal masses can also be treated with PN, but have a higher risk for positive surgical margins (PSM). PSM, when present, are indicative of poor clinical outcomes. The current gold-standard histopathology method is not well-suited for the identification of PSM intraoperatively due to processing time and destructive nature. Here, video-rate structured illumination microscopy (VR-SIM) was investigated as a potential tool for PSM detection during PN. A clinical image atlas assembled from ex vivo renal biopsies provided diagnostically useful images of benign and malignant kidney, similar to permanent histopathology. VR-SIM was then used to image entire parenchymal margins of tumor resection covering up to >1800* more margin surface area than standard histology. Aided by the image atlas, the study pathologist correctly classified all parenchymal margins as negative for PSM with VR-SIM, compared to standard postoperative pathology. The ability to evaluate large surgical margins in a short time frame with VR-SIM may allow it to be used intraoperatively as a "safety net" for PSM detection, allowing more patients to undergo PN over RN. PMID- 28834285 TI - miRNA Signatures of Insulin Resistance in Obesity. AB - OBJECTIVE: Extracellular microRNAs (miRNAs) represent functional biomarkers for obesity and related disorders; this study investigated plasma miRNAs in insulin resistance phenotypes in obesity. METHODS: One hundred seventy-five miRNAs were analyzed in females with obesity (insulin sensitivity, n = 11; insulin resistance, n = 19; type 2 diabetes, n = 15) and without obesity (n = 12). Correlations between miRNA level and clinical parameters and levels of 15 miRNAs in a murine obesity model were investigated. RESULTS: One hundred six miRNAs were significantly (adjusted P <= 0.05) different between controls and at least one obesity phenotype, including miRNAs with the following attributes: previously reported roles in obesity and altered circulating levels (e.g., miR-122, miR 192); known roles in obesity but no reported changes in circulating levels (e.g., miR-378a); and no current reported role in, or association with, obesity (e.g., miR-28-5p, miR-374b, miR-32). The miRNAs in the latter group were found to be associated with extracellular vesicles. Forty-eight miRNAs showed significant correlations with clinical parameters; stepwise regression retained let-7b, miR 144-5p, miR-34a, and miR-532-5p in a model predictive of insulin resistance (R2 = 0.57, P = 7.5 * 10-8 ). Both miR-378a and miR-122 were perturbed in metabolically relevant tissues in a murine model of obesity. CONCLUSIONS: This study expands on the role of extracellular miRNAs in insulin-resistant phenotypes of obesity and identifies candidate miRNAs not previously associated with obesity. PMID- 28834288 TI - Greenhouse and field-based studies on the distribution of dimethoate in cotton and its effect on Tetranychus urticae by drip irrigation. AB - BACKGROUND: The two-spotted spider mite, Tetranychus urticae Koch is an important pest of cotton. We investigated the efficacy of dimethoate in controlling T. urticae by drip irrigation. Greenhouse and field experiments were carried out to determine the efficacy of dimethoate to T. urticae and the absorption and distribution of dimethoate in cotton. RESULTS: Greenhouse results showed that cotton leaves received higher amounts of dimethoate compared with cotton roots and stems, with higher amounts in young leaves compared with old leaves and cotyledon having the lowest amounts among leaves. Field results showed the efficacy of dimethoate to T. urticae by drip irrigation varied by volume of dripping water, soil pH and dimethoate dosage. Dimethoate applied at 3.00 kg ha-1 with 200 m3 ha-1 water at weak acidic soil pH (5.70-6.70) through drip irrigation can obtain satisfactory control efficacy (81.49%, 7 days) to T. urticae, without negatively impacting on its natural enemy Neoseiulus cucumeris. The residue of dimethoate in all cotton seed samples were not detectable. CONCLUSIONS: These results demonstrate the effectiveness of applying dimethoate by drip irrigation for control of T. urticae on cotton. This knowledge could aid in the applicability of dimethoate by drip irrigation for field management of T. urticae populations. (c) 2017 Society of Chemical Industry. PMID- 28834290 TI - Erratum: A 10-year united network for organ sharing review of mortality and risk factors in young children awaiting liver transplantation. PMID- 28834289 TI - Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma. AB - Tumor growth and metastasis are determined not by cancer cells alone but also by a variety of stromal cells, various populations of which overexpress platelet derived growth factor receptors (PDGF-Rs). In addition, activation of PI3K-AKT mammalian target of rapamycin (mTOR) signaling is frequently observed in many cancer types as well. mTOR comprises a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In this study, we investigated the impact of molecular-targeting agents including PDGF-R and mTOR inhibitors on the tumor stroma of human kidney cancer and examined the efficacy of combination therapy with these agents against this disease. Treatment with sunitinib did not suppress tumor growth, but significantly decreased stromal reactivity, microvessel density, and pericyte coverage of tumor microvessels in an orthotopic mouse model. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. However, sunitinib and everolimus in combination reduced both the growth rate and stromal reaction. These findings suggest that target molecule-based inhibition of the cancer stromal cell interaction appears promising as an effective antitumor therapy. PMID- 28834291 TI - Lipophilic conformationally constrained spiro carbocyclic 2,6-diketopiperazine-1 acetohydroxamic acid analogues as trypanocidal and leishmanicidal agents: An extended SAR study. AB - We have previously described a number of lipophilic conformationally constrained spiro carbocyclic 2,6-diketopiperazine (2,6-DKP)-1-acetohydroxamic acids as potent antitrypanosomal agents. In this report, we extend the SAR analysis in this class of compounds with respect to in vitro growth inhibition of Trypanosoma and Leishmania parasites. Introduction of bulky hydrophobic substituents at the vicinal position of the basic nitrogen atom in the spiro carbocyclic 2,6-DKP ring system can provide analogues which are potently active against bloodstream form Trypanosoma brucei and exhibit significant activities toward Trypanosoma cruzi epimastogotes and Leishmania infantum promastigotes and intracellular amastigotes. In particular, compounds possessing a benzyl or 4-chlorobenzyl substituent were found to be the most active growth inhibitors, with activities in the low nanomolar and low micromolar ranges for T. brucei and L. infantum, respectively. The benzyl-substituted (S)-enantiomer was the most potent derivative against T. brucei (IC50 = 6.8 nm), T. cruzi (IC50 = 0.21 MUm), and L. infantum promastigotes (IC50 = 2.67 MUm) and intracellular amastigotes (IC50 = 2.60 MUm). Moreover, the (R)-chiral benzyl-substituted derivative and its racemic counterpart displayed significant activities against L. donovani. Importantly, the active compounds show high selectivity in comparison with two mammalian cell lines. PMID- 28834292 TI - Cell Surface Proteomics of N-Linked Glycoproteins for Typing of Human Lymphocytes. AB - Lymphocytes are immune cells that are critical for the maintenance of adaptive immunity. Differentiation of lymphoid progenitors yields B-, T-, and NK-cell subtypes that individually correlate with specific forms of leukemia or lymphoma. Therefore, it is imperative a precise method of cell categorization is utilized to detect differences in distinct disease states present in patients. One viable means of classification involves evaluation of the cell surface proteome of lymphoid malignancies. Specifically, this manuscript details the use of an antibody independent approach known as Cell Surface Capture Technology, to assess the N-glycoproteome of four human lymphocyte cell lines. Altogether, 404 cell surface N-glycoproteins were identified as markers for specific cell types involved in lymphocytic malignancies, including 82 N-glycoproteins that had not been previously been described for B or T cells within the Cell Surface Protein Atlas. Comparative analysis, hierarchical clustering techniques, and label-free quantitation were used to reveal proteins most informative for each cell type. Undoubtedly, the characterization of the cell surface proteome of lymphoid malignancies is a first step toward improving personalized diagnosis and treatment of leukemia and lymphoma. PMID- 28834293 TI - Healing of chronic venous ulcer with topical sevoflurane. AB - The present study assesses the efficacy and safety of topical sevoflurane in chronic venous ulcers and its impact on analgesia and healing. This retrospective study included 30 patients older than 65 years with painful refractory chronic venous ulcers. Patients were treated with topical sevoflurane prior to the usual ulcer cleaning every 2 days for a period of 1 month. Treatment was initiated with a saline solution, followed by direct irrigation of 1 ml of liquid sevoflurane over the wound size, which was measured as cm2 . Sevoflurane had a fast, intense and long-lasting analgesic effect. Latency time ranged from 2 to 7 minutes (3.9 +/- 1.5 minutes), and duration varied from 8 to 18 hours (12 +/- 2.9). The mean ulcer size was 8.4 +/- 9.7 cm2 . There was a progressive decrease in size in all patients, with a mean size of 4.2 +/- 5.4 cm2 at the end of the study. There were no adverse systemic effects. Local adverse effects were mild and transient, including pruritus, erythema and heat. Topical sevoflurane is a new, efficient and safe therapeutic alternative in painful chronic venous ulcers, refractory to usual analgesic treatment. It can improve the ulcer-healing process that shortens the cicatrisation period. PMID- 28834294 TI - Update on Mycoplasma hyopneumoniae infections in pigs: Knowledge gaps for improved disease control. AB - Mycoplasma hyopneumoniae (M. hyopneumoniae) is the primary pathogen of enzootic pneumonia, a chronic respiratory disease in pigs. Infections occur worldwide and cause major economic losses to the pig industry. The present paper reviews the current knowledge on M. hyopneumoniae infections, with emphasis on identification and analysis of knowledge gaps for optimizing control of the disease. Close contact between infected and susceptible pigs is the main route of M. hyopneumoniae transmission. Management and housing conditions predisposing for infection or disease are known, but further research is needed to better understand M. hyopneumoniae transmission patterns in modern pig production systems, and to assess the importance of the breeding population for downstream disease control. The organism is primarily found on the mucosal surface of the trachea, bronchi and bronchioles. Different adhesins and lipoproteins are involved in the adherence process. However, a clear picture of the virulence and pathogenicity of M. hyopneumoniae is still missing. The role of glycerol metabolism, myoinositol metabolism and the Mycoplasma Ig binding protein Mycoplasma Ig protease system should be further investigated for their contribution to virulence. The destruction of the mucociliary apparatus, together with modulating the immune response, enhances the susceptibility of infected pigs to secondary pathogens. Clinical signs and severity of lesions depend on different factors, such as management, environmental conditions and likely also M. hyopneumoniae strain. The potential impact of strain variability on disease severity is not well defined. Diagnostics could be improved by developing tests that may detect virulent strains, by improving sampling in live animals and by designing ELISAs allowing discrimination between infected and vaccinated pigs. The currently available vaccines are often cost-efficient, but the ongoing research on developing new vaccines that confer protective immunity and reduce transmission should be continued, as well as optimization of protocols to eliminate M. hyopneumoniae from pig herds. PMID- 28834296 TI - Is there a real role of postoperative antibiotic administration for mildmoderate acute cholecystitis? A prospective randomized controlled trial. AB - BACKGROUND: In cases of acute cholecystitis (AC), postoperative antibiotic prophylaxis is generally used for the purpose of preventing subsequent infections. However, there is still no standardized guideline regarding antibiotic administration after cholecystectomy. METHODS: A total of 200 patients at five participating hospitals who were admitted for cholecystectomy to treat grade I or II AC were enrolled and randomly allocated to a group given a placebo (group A) or a group given postoperative antibiotics (group B). Surgical outcomes and incidence of postoperative infectious morbidities were reviewed. RESULTS: A total of 188 patients (95 patients in group A and 93 patients in group B) were finally analyzed. The incidence rate of infectious complications (seven cases, 7.4%, in group A and eight cases, 8.6%, in group B, P = 0.794) and overall non infectious complications (seven cases, 7.4%, in group A and six cases, 6.5%, in group B, P = 1.000) showed no significant difference between the two groups. CONCLUSIONS: Absence of postoperative antibiotic administration did not lead to an increase in postoperative infections in cases of mild to moderate AC. Avoidance of unnecessary antibiotic use will reduce the adverse effects of antibiotics and also allow for a tailored treatment strategy according to the severity of cholecystitis. PMID- 28834297 TI - TGF-beta1 targets Smad, p38 MAPK, and PI3K/Akt signaling pathways to induce PFKFB3 gene expression and glycolysis in glioblastoma cells. AB - In human cancers, transforming growth factor-beta1 (TGF-beta1) plays a dual role by acting as both a tumor suppressor and a promoter of tumor metastasis. Although TGF-beta1 contributes to the metabolic reprogramming of cancer cells and tumor associated stromal cells, little is known of the molecular mechanisms connecting this cytokine with enhanced glycolysis. PFKFB3 is a homodymeric bifunctional enzyme, belonging to the family of 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatases, that controls the conversion of fructose-6-phosphate (Fru-6-P) to fructose-2,6-bisphosphate (Fru-2,6-P2 ). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating phosphofructokinase-1, a rate-limiting enzyme in glycolysis. The PFKFB3 gene is involved in cell proliferation via its role in carbohydrate metabolism. Here, we studied the mechanisms connecting TGF-beta1, glucose metabolism, and PFKFB3 in glioblastoma cell lines. We demonstrate that TGF-beta1 upregulates PFKFB3 mRNA and protein expression resulting in an increase in fructose 2,6-bisphosphate concentration, glucose uptake, glycolytic flux and lactate production. Moreover, these increases in PFKFB3 mRNA and protein expression and Fru-2,6-P2 concentration were reduced when the Smad3, p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were inhibited. We demonstrate that inhibition of PFKFB3 activity with 3PO or siRNA mediated knockdown of PFKFB3 significantly eliminated the capacity of the T98G cells to form colonies by TGF-beta1, one of the hallmarks of transformation. Taken together, these results show that TGF-beta1 induces PFKFB3 expression through activation of the p38 MAPK and PI3K/Akt signaling pathways that complement and converge with early activation of Smad signaling. This suggests that PFKFB3 induction by TGF-beta1 can be one of the main mechanisms mediating the reprogramming of glioma cells. PMID- 28834298 TI - The vasorelaxant effect of antidiabetic drug nateglinide via activation of voltage-dependent K+ channels in aortic smooth muscle. AB - AIMS: We investigated the vasorelaxant effect of nateglinide and its related mechanisms using phenylephrine (Phe)-induced precontracted aortic rings. METHODS: Arterial tone measurement was performed in aortic smooth muscle. RESULTS: The application of nateglinide induced vasorelaxation in a concentration-dependent manner. Pretreatment with the large-conductance Ca2+ -activated K+ (BKCa ) channel inhibitor paxilline, the inwardly rectifying K+ (Kir) channel inhibitor Ba2+ , and ATP-sensitive K+ (KATP ) channel inhibitor glibenclamide did not affect the vasorelaxant effect of nateglinide. However, pretreatment with the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine (4-AP) effectively reduced the vasorelaxant effect of nateglinide. Pretreatment with the Ca2+ inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase inhibitor thapsigargin did not change the vasorelaxant effect of nateglinide. Additionally, the vasorelaxant effect of nateglinide was not altered in the presence of an adenylyl cyclase, a protein kinase A, a guanylyl cyclase, or a protein kinase G inhibitor. The vasorelaxant effect of nateglinide was not affected by the elimination of the endothelium. In addition, pretreatment with a nitric oxide synthase inhibitor, L-NAME, and a small-conductance Ca2+ -activated K+ (SKCa ) channel inhibitor, apamin, did not change the vasorelaxant effect of nateglinide. CONCLUSION: Nateglinide induced vasorelaxation via the activation of the Kv channel independent of other K+ channels, Ca2+ channels, intracellular Ca2+ ([Ca2+ ]i ), and the endothelium. PMID- 28834299 TI - Treatment for neovascular age-related macular degeneration in Sweden: outcomes at seven years in the Swedish Macula Register. AB - PURPOSE: To present Swedish Macula Register (SMR) data regarding treatment of neovascular age-related macular degeneration (AMD) in clinical practice since 2008. METHODS: A retrospective register-based study was conducted. Evaluation of baseline demographics, visual outcome and number of injections during this period is presented. RESULTS: Mean age at diagnosis was 79 +/- (SD) 8 years; 65% were female. The proportion of patients with <2 months' duration of symptoms increased from 26% in 2008 to 41% in 2014 (p = 0.001). Mean visual acuity (VA) at baseline increased from 54.3 +/- 15.0 early treatment diabetic retinopathy study (ETDRS) letters in 2008 to 57.8 +/- 15.6 letters in 2014 (CI95 2.6; 4.3; p < 0.001). Mean VA after 1 year of treatment increased from 57.8 +/- 17.7 ETDRS letters for patients who started the treatment in 2008 to 62.8 +/- 16.4 ETDRS letters in patients starting treatment in 2014 (CI95 2.67; 4.64; p < 0.001). During all study years, the proportion of patients with an improvement in VA of between 5 and 15 letters was around 30%, while 14% had VA improvement of more than 15 letters. The mean number of injections during the first treatment year increased from 4.3 +/- 1.9 in 2008 to 5.9 +/- 2.9 in 2014 (CI95 1.40; 1.67; p < 0.001). Seven-year follow-up of 322 eyes showed a mean change of -1 letters from baseline, with a mean of 21 injections for the entire period. CONCLUSION: The duration of symptoms before treatment decreased, while VA at baseline and after 1 year of treatment increased over the years and so did the number of injections. Long-term follow-up demonstrated stable VA. PMID- 28834300 TI - Updating In Vivo and In Vitro Phosphorylation and Methylation Sites of Voltage Gated Kv7.2 Potassium Channels. AB - Voltage-gated Kv7.2 potassium channels regulate neuronal excitability. The gating of these channels is tightly controlled by various mediators and neurotransmitters acting via G protein-coupled receptors; the underlying signaling cascades involve phosphatidylinositol-4,5-bisphosphate (PIP2 ), Ca2+ /calmodulin, and phosphorylation. Recent studies found that the PIP2 sensitivity of Kv7.2 channels is affected by two posttranslational modifications, phosphorylation and methylation, harboured within putative PIP2 -binding domains. In this study, we updated phosphorylation and methylation sites in Kv7.2 either heterologously expressed in mammalian cells or as GST-fusion proteins exposed to recombinant protein kinases by using LC-MS/MS. In vitro kinase assays revealed that CDK5, protein kinase C (PKC) alpha, PKA, p38 MAPK, CamKIIalpha, and GSK3beta could mediate phosphorylation. Taken together, we provided a comprehensive map of phosphorylation and methylation in Kv7.2 within protein-protein and protein-lipid interaction domains. This may help to interpret the functional roles of individual PTM sites in Kv7.2 channels. All MS data are available via ProteomeXchange with the identifier PXD005567. PMID- 28834301 TI - Comparative analysis of diagnostic adequacy rate between aspiration and nonaspiration techniques of fine-needle cytology in patients with thyroid cancer and ultrasonographically suspicious cervical lymph nodes. AB - BACKGROUND: We aimed to compare nonaspiration (NAS) and aspiration (AS) techniques in the evaluation of fine-needle cytology of lymph node (FNC-LN) in terms of diagnostic adequacy of cytologic material. METHODS: One hundred and twenty-three superficial cervical LNs in 75 patients who underwent NAS and AS-FNC LN in the same visit were evaluated. Cytological results were categorized as diagnostic and nondiagnostic. RESULTS: The rates of malignancy were 13.8% in AS versus 16.3% in NAS technique, whereas nondiagnostic cytology was detected in 43.1% and 25.2%, respectively (P = .549 and P < .01). CONCLUSIONS: The diagnostic adequacy rate in NAS-FNC-LN was significantly higher than AS-FNC-LN. However, NAS technique seems to be more simple and comfortable. We suggest both NAS and AS-FNC LN in cytologic evaluation of suspicious cervical LNs until the diagnostic accuracy is determined with prospective studies. PMID- 28834302 TI - Reply. PMID- 28834303 TI - Radioanatomic study of the skull base and septum in Asians: implications for using the nasoseptal flap for anterior skull-base reconstruction. AB - BACKGROUND: The objective of this work was to assess the feasibility of using the nasoseptal flap (NSF) for covering the anterior skull-base defect in Asians, and to compare the results in whites. METHODS: A retrospective radioanatomic analysis was conducted in 100 Korean adult patients. Septal and skull-base dimensions were measured and the feasibility of the NSF in reconstructing a full anterior skull base defect was evaluated. Scans of 49 white patients were analyzed for a comparative study. RESULTS: Among various septal dimensions, the length of the septum was significantly different in Koreans when compared to whites. Skull-base dimensions such as anterior skull-base length and width at the level of the anterior ethmoidal artery were different between the 2 ethnic groups. Individual differences between the anterior width of the hypothetical NSF and the anterior margin of the skull-base defect (2.8 +/- 3.1 vs 6.4 +/- 4.8) and the difference between the hypothetical NSF length and the length of the flap needed for full coverage of the defect were significantly smaller in Korean patients (7.2 +/- 3.8 vs 13.1 +/- 5.6), leading to a statistically higher chance of flap insufficiency. The insufficiency was more often found in female patients. CONCLUSION: The risk of NSF insufficiency for covering the anterior skull-base defect in Koreans is higher relative to whites, and is accentuated in female patients. Efforts to increase the size of the NSF as well as efforts to avoid intraoperative shrinkage of the NSF should be considered to compensate for the relatively small NSF in Asians. PMID- 28834304 TI - Sofosbuvir as treatment against dengue? AB - Dengvaxia(r) (CTD-TDV), the only licensed tetravalent dengue vaccine by Sanofi Pasteur, was made available since 2015. However, administration of CTD-TDV, in general, has not received the prequalification recommendation from the World Health Organization. Having a universal antidengue agent for treatment will therefore beneficial. Accordingly, the development of nucleoside inhibitors specific to dengue viral polymerase that perturb dengue infection has been studied by many. Alternatively, we have used a marketed anti-HCV prodrug sofosbuvir to study its in silico and in vitro effects against dengue. As a result, the active metabolite of sofosbuvir (GS-461203) was predicted to bind to the catalytic motif (Gly-Asp-Asp) of dengue viral polymerase with binding affinity of -6.9 kcal/mol. Furthermore, sofosbuvir demonstrated excellent in vitro viral inhibition with an EC90 of 0.4 MUm. In addition, this study demonstrated the requirement of specific liver enzymes to activate the prodrug into GS-461203 to exert its antidengue potential. All in all, sofosbuvir should be subjected to in-depth studies to provide information of its efficacy toward dengue and its lead potential as DENV polymerase inhibitor in human subjects. In conclusion, we have expended the potential of the clinically available drug sofosbuvir as treatment for dengue. PMID- 28834305 TI - Liver transplant in patients with portal vein thrombosis: Medical and surgical requirements. PMID- 28834306 TI - Arginase - a novel target for cardioprotection by vagal nerve stimulation. PMID- 28834307 TI - The Empowering Role of Profession-Based Student Organizations in Developing Student Leadership Capacity. AB - After recreation and intramural groups, students participate in profession-based organizations more frequently than any other. This chapter explores how these groups can leverage their unique context to accelerate student leadership development and profession-related leadership competencies. PMID- 28834308 TI - Editor's Notes. PMID- 28834309 TI - Building Social Change Oriented Leadership Capacity Among Student Organizations: Developing Students and Campuses Simultaneously. AB - This chapter highlights nontraditional forms of leadership development in student organizations. Using the social change model for leadership as a framework, the authors discuss the ways in which collectivist and activist approaches can result in similar skills obtained through traditional forms of leadership development. PMID- 28834310 TI - The Unique Context of Identity-Based Student Organizations in Developing Leadership. AB - This chapter addresses the important role of identity-based student organizations in developing leadership, particularly for students who may feel marginalized because of their racial/ethnic, religious, or gender identities. Understanding the influence of these groups can help leadership educators develop a more inclusive and diverse perspective on student leadership development. PMID- 28834311 TI - Intentional Design of Student Organizations to Optimize Leadership Development. AB - This chapter addresses how a group's organizational structure can promote or hinder the leadership capacity of its members. The information in this chapter provides insight into structuring student organizations in a way to maximize all members' leadership development. PMID- 28834312 TI - Advancing Student Leader Development Through Student Organization Advising and Institutional Support. AB - This chapter explores the potential and promise of student organization advisors in facilitating student leader development. Through exploration of key aspects of institutional support, the author identifies ways that advisors of all backgrounds contribute to the teaching and learning experiences of students. PMID- 28834313 TI - Student Organizations as Avenues for Leader Learning and Development. AB - This chapter describes theory and research demonstrating that the experiences students have within student organizations, and the people with whom they interact within those organizations, are powerful triggers for leader learning and development. PMID- 28834314 TI - Bridging Secondary and Postsecondary Leadership Experiences: A Toolkit for Leadership Learning Facilitators. AB - This chapter examines the scaffolding of leadership learning and development in student organizations from secondary to postsecondary institutions and explores ways that high school and collegiate advisors can better integrate efforts to help emerging student leaders make the transition from involvement and leadership development from one environment to the other. PMID- 28834315 TI - The Significance of Student Organizations to Leadership Development. AB - Student organizations have existed for almost as long as educational institutions have. This chapter examines the historical role of student organizations in developing leadership capacity in students, as well as their current roles on high school and collegiate campuses in creating transformational environments for student leadership learning and growth. PMID- 28834316 TI - History of parvovirus B19 infection is associated with silent cerebral infarcts. AB - BACKGROUND: The relationship between silent cerebral infarcts (SCIs) and history of parvovirus B19 (B19V) has not been systematically evaluated. As an ancillary study from the Silent Cerebral Infarct Trial (SIT) (NCT00072761), we tested the hypothesis that a history of B19V infection is associated with an increased prevalence of SCIs in children with sickle cell anemia. PROCEDURE: We used a retrospective cross-sectional cohort study design; each participant underwent a brain magnetic resonance imaging (MRI) scan and medical record review for prior B19V infection (n = 958). RESULTS: SCI was present in 30% (287 of 958) of participants and 17% (165 of 958) had a history of B19V infection. Based on prior evidence that low baseline hemoglobin (Hgb) levels are associated with increased odds of SCI, Hgb levels were divided into tertiles (<7.6 g/dl, >=7.6-<=8.5 g/dl, >=8.6 g/dl) and multivariable analysis was used to determine the relationship between the joint effect of prior B19V infection, Hgb levels, and SCI. Prior B19V infection and the lowest Hgb tertile were associated with increased risk of SCI (odds ratio [OR] 2.12; 95% CI, 1.17-3.84; P = 0.013); no prior B19V infection and the highest Hgb tertile were associated with a decreased risk (OR 0.56; 95% CI, 0.38-0.84; P = 0.004). CONCLUSIONS: Efforts to decrease the incidence of B19V infection, such as the development of a B19V vaccine, may decrease SCI prevalence. PMID- 28834317 TI - Thrombin-activatable fibrinolysis inhibitor in human abdominal aortic aneurysm disease. AB - : Essentials Patients with abdominal aortic aneurysms (AAA) develop dense clots that are resistant to lysis. This study explores the role of thrombin-activatable fibrinolysis inhibitor (TAFI) in human AAA. There is evidence of chronically increased TAFI activation in patients with AAA. TAFI may represent a pharmacological target for cardiovascular risk reduction in AAA. SUMMARY: Background Intra-luminal thrombosis is a key factor in growth of abdominal aortic aneurysms (AAAs). Patients with AAA form dense clots that are resistant to fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) has been shown to influence AAA development in murine models. Objective The aim of this study is to characterize the role of TAFI in human AAA. Methods Plasma levels of TAFI, TAFI activation peptide (TAFI-AP), activated/inactivated TAFI (TAFIa/ai) and plasmin-alpha2-antiplasmin complex were measured by ELISAs in patients with AAA (n = 202) and controls (n = 188). Results TAFIa/ai and TAFI-AP levels were higher in patients than controls (median [IQR], 20.3 [14.6-32.8] ng mL-1 vs. 14.2 [11.2 19.3] ng mL-1 and 355.0 [232.4-528.1] ng mL-1 vs. 248.6 [197.1-328.1] ng mL-1 ). TAFIa/ai was positively correlated with TAFI-AP (r = 0.164). Intact TAFI levels were not different between patients and controls (13.4 [11.2-16.1] MUg mL-1 vs. 12.8 [10.6-15.4] MUg mL-1 ). Plasmin-alpha2-antiplasmin was higher in AAA patients than controls (690.0 [489.1-924.3] ng mL-1 vs. 480.7 [392.6-555.3] ng mL 1 ). Conclusions The increase in TAFIa/ai and TAFI-AP suggests an increased TAFI activation in patients with AAA. Prospective studies are required to further elucidate the role of TAFI and fibrinolysis in AAA pathogenesis. PMID- 28834318 TI - Nanoparticles Embedded in Amphiphilic Membranes for Carbon Dioxide Separation and Dehumidification. AB - Polymers containing ethylene oxide (EO) groups have gained significant interest as the EO groups have favorable interactions with polar molecules such as H2 O, quadrupolar molecules such as CO2 , and metal ions. However, the main challenges of poly(ethylene oxide) (PEO) membranes are their weak mechanical properties and high crystallinity nature. The amphiphilic copolymer made from PEO terephthalate and poly(butylene terephthalate) (PEOT/PBT) comprises both hydrophilic and hydrophobic segments. The hydrophilic PEOT segment is thermosensitive, which facilities gas transports whereas the hydrophobic PBT segment is rigid, which provides mechanical robustness. This work demonstrates a new strategy to design amphiphilic mixed matrix membranes (MMMs) by incorporating zeolitic imidazolate framework, ZIF-71, into the PEOT/PBT copolymer. The resultant membrane shows an enhanced CO2 permeability with an ideal CO2 /N2 selectivity surpassing the original PEOT/PBT and Robeson's Upper bound line. The nanoparticles-embedded amphiphilic membranes exhibit characteristics of high transparency and mechanical robustness. Mechanically strong composite hollow fiber membranes consisting of PEOT/PBT/ZIF-71 as the selective layer were also prepared. The resultant hollow fibers possess an excellent CO2 permeance of 131 GPU (gas permeation units), CO2 /N2 selectivity of 52.6, H2 O permeance of 9300 GPU and H2 O/N2 selectivity of 3700, showing great potential for industrial CO2 capture and dehumidification. PMID- 28834319 TI - Esophageal squamous papilloma: A case series and literature review. PMID- 28834320 TI - Different Steric-Twist-Induced Ternary Memory Characteristics in Nonconjugated Copolymers with Pendant Naphthalene and 1,8-Naphthalimide Moieties. AB - Herein, novel random copolymers PMNN and PMNB were designed and synthesized, and the memory devices Al/PMNN and PMNB/ITO both exhibited ternary memory performance. The switching voltages of the OFF-ON1 and ON1-ON2 transitions for both memory devices are around -2.0 and -3.5 V, respectively, and the ON1/OFF, ON2/ON1 current ratios are both up to 103 . The observed tristable electrical conductivity switching could be attributed to field-induced conformational ordering of the naphthalene rings in the side chains, and subsequent charge trapping by 1,8-naphthalimide moieties. More interestingly, by adjusting the connection sites of 1,8-naphthalimide moieties to tune the steric-twist effect, different memory properties were achieved (PMNN showed nonvolatile write once, read many (WORM) memory behavior, whereas PMNB showed volatile static RAM (SRAM) memory behavior). This result will offer a guideline for the design of different high-performance multilevel memory devices by tuning the steric effects of the chemical moieties. PMID- 28834321 TI - Fabrication of Mesoporous Cu Films on Cu Foils and Their Applications to Dopamine Sensing. AB - We previously succeeded to prepare stable mesoporous Cu films on Au-coated conductive working electrodes by using polystyrene-b-poly(oxyethylene) (PS63 000 b-PEO26 000 ) micelles as template and sulfuric acid to increase ionic conductivity. In the present study, we report the preparation of mesoporous Cu films on Cu foil. By changing the Cu salts and electrodeposition potentials, we discuss how these parameters influence the final product. Without having to filtrate interefering species, such as uric acid, ascorbic acid and glucose, the dopamine concentration can be precisely determined by applying a suitable potential. Therefore, non-invasive electrochemical sensing based on mesoporous films will be useful for daily diagnosis of mental disorder. PMID- 28834322 TI - Lipid Metabolism, Abdominal Adiposity, and Cerebral Health in the Amish. AB - OBJECTIVE: To assess the association between peripheral lipid/fat profiles and cerebral gray matter (GM) and white matter (WM) in healthy Old Order Amish (OOA). METHODS: Blood lipids, abdominal adiposity, liver lipid contents, and cerebral microstructure were assessed in OOA (N = 64, 31 males/33 females, ages 18-77). Orthogonal factors were extracted from lipid and imaging adiposity measures. GM assessment used the Human Connectome Project protocol to measure whole-brain average cortical thickness. Diffusion-weighted imaging was used to derive WM fractional anisotropy and kurtosis anisotropy measurements. RESULTS: Lipid/fat measures were captured by three orthogonal factors explaining 80% of the variance. Factor one loaded on cholesterol and/or low-density lipoprotein cholesterol measurements; factor two loaded on triglyceride/liver measurements; and factor three loaded on abdominal fat measurements. A two-stage regression including age/sex (first stage) and the three factors (second stage) examined the peripheral lipid/fat effects. Factors two and three significantly contributed to WM measures after Bonferroni corrections (P < 0.007). No factor significantly contributed to GM. Blood pressure (BP) inclusion did not meaningfully alter the lipid/fat-WM relationship. CONCLUSIONS: Peripheral lipid/fat indicators were significantly and negatively associated with cerebral WM rather than with GM, independent of age and BP level. Dissecting the fat/lipid components contributing to different brain imaging parameters may open a new understanding of the body brain connection through lipid metabolism. PMID- 28834323 TI - The first description of the complete natural history of uveal melanoma by two Scottish surgeons, Allan Burns and James Wardrop. AB - James Wardrop (1782-1869), a young Scottish surgeon and an early ophthalmologist in Edinburgh, is credited for describing in 1809 retinoblastoma as an entity in his treatise 'Observations on Fungus Haematodes or Soft Cancer'. His treatise also reveals that Allan Burns (1781-1813), another young Scottish surgeon and anatomist, had invited Wardrop to assist in enucleating an eye from a 41-year-old Glasgow woman who, in retrospect, had a uveal melanoma. Her eye had become blind 4 months after symptoms of exudative retinal detachment had appeared, and it had become painful after a further 2-4 months. The tumour eventually perforated the sclera, and she died within a year thereafter of hepatic metastases. Burns and Wardrop went on to publish detailed parallel accounts of the symptoms, signs, ophthalmic pathology and post-mortem findings regarding the primary, recurrent and metastatic tumour. Burns may have performed the post-mortem after exhuming the body, a common occurrence in early 19th Century Scotland, a thriving hub for teaching morbid anatomy to young surgeons at the time. PMID- 28834324 TI - Use of spiritual coping strategies by gender, race/ethnicity, and religion at 1 and 3 months after infant's/child's intensive care unit death. AB - BACKGROUND AND PURPOSE: In the United States, 57,000 children (newborn to 18 years) die annually. Bereaved parents may rely on religious or spiritual beliefs in their grief. The study's purpose was to examine differences in parents' use of spiritual and religious coping practices by gender, race/ethnicity, and religion at 1 and 3 months after infant/ICU death. METHODS: The sample consisted of 165 bereaved parents, 78% minority. The Spiritual Coping Strategies Scale was used to measure religious and spiritual coping practices, separately. One-way ANOVAs indicated that Black non-Hispanic mothers used significantly more religious coping practices at 3 months than White non-Hispanic mothers. Protestant and Catholic parents used more religious coping practices than the "no" and "other" religion groups at 1 and 3 months. Within the 30 mother-father dyads (paired t tests), mothers reported significantly greater use of religious coping practices at 1 and 3 months and spiritual coping practices at 3 months than fathers. CONCLUSION: Religious coping practices were most commonly used by Black mothers and Protestant and Catholic parents. Within dyads, mothers used more spiritual and religious coping practices than fathers. IMPLICATIONS FOR PRACTICE: These findings are beneficial for healthcare personnel in providing support to bereaved parents of diverse races/ethnicities and religions. PMID- 28834325 TI - Digital PCR analysis of circulating tumor DNA: a biomarker for chondrosarcoma diagnosis, prognostication, and residual disease detection. AB - Conventional chondrosarcoma is the most common primary bone tumor in adults. Prognosis corresponds with tumor grade but remains variable, especially for individuals with grade (G) II disease. There are currently no biomarkers available for monitoring or prognostication of chondrosarcoma. Circulating tumor DNA (ctDNA) has recently emerged as a promising biomarker for a broad range of tumor types. To date, little has been done to study the presence of ctDNA and its potential utility in the management of sarcomas, including chondrosarcoma. In this study, we have assessed ctDNA levels in a cohort of 71 patients, 32 with sarcoma, including 29 individuals with central chondrosarcoma (CS) and 39 with locally aggressive and benign bone and soft tissue tumors, using digital PCR. In patients with CS, ctDNA was detected in pretreatment samples in 14/29 patients, which showed clear correlation with tumor grade as demonstrated by the detection of ctDNA in all patients with GIII and dedifferentiated disease (n = 6) and in 8/17 patients with GII disease, but never associated with GI CS. Notably detection of ctDNA preoperatively in GII disease was associated with a poor outcome. A total of 14 patients with CS had ctDNA levels assessed at multiple time points and in most patients there was a clear reduction following surgical removal. This research lays the foundation for larger studies to assess the utility of ctDNA for chondrosarcoma diagnosis, prognostication, early detection of residual disease and monitoring disease progression. PMID- 28834326 TI - Proposal for a gold standard for cosmetic evaluation after breast conserving therapy: Results from the St George and Wollongong Breast Boost trial. AB - INTRODUCTION: Breast cosmesis is an important endpoint of breast conserving therapy (BCT), but a gold standard method of its evaluation is not yet established. The St. George and Wollongong Randomised Breast Boost trial used five different methods of cosmetic assessment, including both subjective and objective, to comprehensively evaluate the cosmetic outcome of the trial patients. This current study analyses the level of concordance between these methods in an attempt to determine a possible standard in the evaluation of breast cosmesis. METHODS: Patients attending follow-up clinic reviews at 5 years post breast radiotherapy were evaluated. Patients completed a cosmesis and functional assessment questionnaire, assessing clinicians completed an EORTC (European Organization for Research and Treatment of Cancer) cosmetic rating questionnaire and photographs were obtained. The photographs were later assessed by a panel of five experts, as well as analysed using the objective pBRA (relative Breast Retraction Assessment) and the BCCT.core (Breast Cancer Conservative Treatment.cosmetic results) computer software. Scores were dichotomised to excellent/good and fair/poor. Pairwise comparisons between all methods, except pBRA, were carried out using overall agreement calculations and kappa scores. pBRA scores were compared on a continuous scale with each of the other dichotomised scores obtained by the other four methods. RESULTS: Of 513 St George patients alive at 5 years, 385 (75%) attended St George for follow-up and consented to photography. Results showed that assessment by physicians in clinic and patient self-assessment were more favourable regarding overall cosmetic outcome than evaluation of photographs by the panel or the BCCT.core software. Excellent/good scores by clinician-live and patient self-assessments were 93% and 94% respectively (agreement 89%), as compared to 75% and 74% only by BCCT.core and panel assessments respectively (agreement 83%, kappa 0.57). For the pBRA measurements, there was a statistically significant difference (P <0.001) between scores for excellent/good versus fair/poor cosmesis by all four methods. The range of median pBRA measurements for fair/poor scores was 13.4-14.8 and for excellent/good scores was 8.0-9.4. CONCLUSION: Incorporating both BCCT.core assessment and patient self-assessment could potentially provide the basis of a gold standard method of breast cosmetic evaluation. BCCT.core represents an easy, time efficient, reproducible, cost effective and reliable method, however, it lacks the functional and psychosocial elements of cosmesis that only patient self reported outcomes can provide. PMID- 28834328 TI - OMIP-040: Optimized gating of human prostate cellular subpopulations. PMID- 28834327 TI - Reading comprehension of ambiguous sentences by school-age children with autism spectrum disorder. AB - : Weak central coherence (processing details over gist), poor oral language abilities, poor suppression, semantic interference, and poor comprehension monitoring have all been implicated to affect reading comprehension in individuals with autism spectrum disorder (ASD). This study viewed the contributions of different supporting skills as a collective set of skills necessary for context integration-a multi-component view-to examine individual differences in reading comprehension in school-age children (8-14 years) with ASD (n = 23) and typically developing control peers (n = 23). Participants completed a written ambiguous sentence comprehension task in which participants had to integrate context to determine the correct homonym meaning via picture selection. Both comprehension products (i.e., offline representations after reading) and processes (i.e., online processing during reading) were evaluated. Results indicated that children with ASD, similar to their TD peers, integrated the context to access the correct homonym meanings while reading. However, after reading the sentences, when participants were asked to select the meanings, both groups experienced semantic interference between the two meanings. This semantic interference hindered the children with ASD's sentence representation to a greater degree than their peers. Individual differences in age/development, word recognition, vocabulary breadth (i.e., number of words in the lexicon), and vocabulary depth (i.e., knowledge of the homonym meanings) contributed to sentence comprehension in both children with ASD and their peers. Together, this evidence supports a multi-component view, and that helping children with ASD develop vocabulary depth may have cascading effects on their reading comprehension. Autism Res 2017, 10: 2002-2022. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Like their peers, children with ASD were able to integrate context, or link words while reading sentences with ambiguous words (words with two meanings). After reading the sentences, both groups found it hard to pick the correct meaning of the ambiguous sentence and this decision was more difficult for the participants with ASD. Older children, children with better word reading abilities, and children with higher vocabularies were better at understanding ambiguous sentences. Helping children with ASD to develop richer vocabularies could be important for improving their reading comprehension. PMID- 28834329 TI - Strain Breeding Enhanced Heterologous Cellobiohydrolase Secretion by Saccharomyces cerevisiae in a Protein Specific Manner. AB - The yeast Saccharomyces cerevisiae has a long association with alcoholic fermentation industries and has received renewed interest as a biocatalyst for second-generation bioethanol production. Rational engineering strategies are used to create yeast strains for consolidated bioprocessing of lignocellulosic biomass. Although significant progress is made in this regard with the expression of different cellulolytic activities in yeast, cellobiohydrolase (CBH) titers remain well below ideal levels. Through classical breeding, S. cerevisiae strains with up to twofold increased CBH secretion titers is obtained in strains expressing a single gene copy. An increase of up to 3.5-fold in secreted cellobiohydrolase activity is subsequently shown for strains expressing the heterologous gene on a high copy episomal vector. To our knowledge, this is the first report of classical breeding being used to enhance heterologous protein secretion and also the most significant enhancement of CBH secretion in yeast yet reported. This enhanced secretion phenotype is specific for cellobiohydrolase I secretion, indicating that reporter protein properties might be a major determining factor for efficient protein secretion in yeast. By exploring the latent potential of different S. cerevisiae strains, the authors show that the allele pool of various strains is a valuable engineering resource to enhance secretion in yeast. PMID- 28834330 TI - Effect of Listening to Music on Patient Anxiety and Pain Perception during Urodynamic Study: Randomized Controlled Trial. AB - OBJECTIVE: Urodynamic studies (UDS) include assessments of the physics and physiology of the lower urinary tract (LUT). It is an invasive test and patients can feel fear and anxiety, especially at the beginning of the test. The aim of this study was to determine whether listening to music during urodynamic study decreases patient anxiety and pain. METHODS: Sixty-two patients who underwent urodynamic study were randomized into the following groups: no music (group 1, n = 30) or classical music (group 2, n = 32) during the procedure. Patient anxiety levels were quantified using the State-Trait Anxiety Inventory (STAI) and Beck's Anxiety Inventory (BAI). A visual analog scale (VAS) was used for self-assessment of discomfort and willingness among patients to have a repeat urodynamic study. RESULTS: Demographic characteristics, mean age, duration of procedure, systolic and diastolic blood pressure (SBP and DBP) and heart rate before procedure were statistically significantly similar between the two groups. Statistically significant differences were detected between the two groups in the mean pain score on VAS (4.1 +/- 1.4 vs 2.6 +/- 1.8), mean post-procedural STAI score (46 +/ 5.8 vs 37.3 +/- 5) and mean BAI score (14.2 +/- 1.7 vs 3.5 +/- 0.7). SBP and DBP and heart rate were similar between the groups. CONCLUSION: Music is a cheap, safe and effective intervention that has gained increasing recognition as an effective tool to reduce pain and anxiety. Listening to music during urodynamic study reduced patient pain and anxiety. PMID- 28834332 TI - Virtual reality-based proficiency test in direct ophthalmoscopy. PMID- 28834331 TI - Core fecal microbiota of domesticated herbivorous ruminant, hindgut fermenters, and monogastric animals. AB - In this pilot study, we determined the core fecal microbiota composition and overall microbiota diversity of domesticated herbivorous animals of three digestion types: hindgut fermenters, ruminants, and monogastrics. The 42 animals representing 10 animal species were housed on a single farm in Ireland and all the large herbivores consumed similar feed, harmonizing two of the environmental factors that influence the microbiota. Similar to other mammals, the fecal microbiota of all these animals was dominated by the Firmicutes and Bacteroidetes phyla. The fecal microbiota spanning all digestion types comprised 42% of the genera identified. Host phylogeny and, to a lesser extent, digestion type determined the microbiota diversity in these domesticated herbivores. This pilot study forms a platform for future studies into the microbiota of nonbovine and nonequine domesticated herbivorous animals. PMID- 28834333 TI - Effect of large instrument use on shaping ability and debris extrusion of rotary and reciprocating systems. AB - AIM: The aim of the present study was to evaluate the effect of large instrument use on the shaping ability and apical debris extrusion of rotary and reciprocating systems in oval-shaped root canals. METHODS: Forty-five mandibular premolars, with an 18-mm long, oval-shaped single canal, and apical diameter ranging from 300 to 350 MUm, were separated into three groups (n=15), according to the system used: ProTaper Universal group, F5 (0.50/0.05); ProTaper Next (PTN group), X5 (0.50/0.06); and Reciproc (RC group), R50 (0.50/0.05). Cone-beam computed tomography was performed before and after preparation to analyze apical transportation (AT), centering ability (CA), and change in root canal diameter (CRCD). For evaluating apical debris extrusion, the roots were coupled to pre weighed glass receptacles to collect the extruded debris during preparation. RESULTS: All systems promoted AT and apical debris extrusion; the latter was higher for the PTN group (P<.05). No system presented perfect CA. The RC group demonstrated the largest CRCD (P<.05). CONCLUSIONS: As consequences of their use, the large instruments promoted undesirable AT and debris extrusion, irrespective of the system used to perform root canal preparation. Moreover, no system was able to remain perfectly centralized within the root canal. PMID- 28834334 TI - Enhanced Hepatic Functions of Genetically Modified Mouse Hepatoma Cells by Spheroid Culture for Drug Toxicity Screening. AB - While hepatic cell lines are mainly used for in vitro drug induced toxicity studies, they exhibit limited functionalities. To overcome this, the authors have employed genetically engineered mouse hepatoma cells, Hepa/8F5, wherein expression of liver enriched transcription factors is induced by doxycycline leading to increased functionality. Further enhancement in functionality is achieved by spheroid culture in a previously developed 3D cell culture platform. Cells are seeded in presence of temperature-responsive poly(N isopropylacrylamide) on poly(N-isopropylacrylamide--co-gelatin) cryogel scaffold based high throughput platform. Cells seeded in presence of poly(N isopropylacrylamide) and induced with doxycycline exhibited highest functionalities. There is an increase of ~26, 36, and 39% in albumin secretion, ammonia removal, and CYP3A4 activity, respectively. Morphological analysis showed arrest in cell proliferation and enlarged nucleus in presence of doxycyline and spheroid formation in presence of poly(N-isopropylacrylamide). Drug induced liver toxicity studies revealed that cells induced with doxycycline are resistive to tamoxifen but sensitive to acetaminophen whereas, cultures initiated in presence of poly(N-isopropylacrylamide) are resistive to both the drugs which is indicative of diffusional barrier of the spheroids. The authors conclude that Hepa/8F5 cells show enhanced functionality in cryogel based spheroid culture platform which can be successfully used for high throughput screening of hepatic toxicity in vitro. PMID- 28834335 TI - Hierarchical ZnIn2 S4 /MoSe2 Nanoarchitectures for Efficient Noble-Metal-Free Photocatalytic Hydrogen Evolution under Visible Light. AB - A highly efficient visible-light-driven photocatalyst is urgently necessary for photocatalytic hydrogen generation through water splitting. Herein, ZnIn2 S4 hierarchical architectures assembled as ultrathin nanosheets were synthesized by a facile one-pot polyol approach. Subsequently, the two-dimensional-network-like MoSe2 was successfully hybridized with ZnIn2 S4 by taking advantage of their analogous intrinsic layered morphologies. The noble-metal-free ZnIn2 S4 /MoSe2 heterostructures show enhanced photocatalytic H2 evolution compared to pure ZnIn2 S4 . It is noteworthy that the optimum nanocomposite of ZnIn2 S4 /2 % MoSe2 photocatalyst displays a high H2 generation rate of 2228 MUmol g-1 h-1 and an apparent quantum yield (AQY) of 21.39 % at 420 nm. This study presents an unprecedented ZnIn2 S4 /MoSe2 metal-sulfide-metal-selenide hybrid system for H2 evolution. Importantly, the present efficient hybridization strategy reveals the potential of hierarchical nanoarchitectures for a multitude of energy storage and solar energy conversion applications. PMID- 28834337 TI - Recent buzz in malaria research. AB - In this Commentary, we highlight the latest findings in three active areas of malaria research: Plasmodium biology; host response; and malaria control, prevention and treatment. PMID- 28834336 TI - Electric-Field-Tunable Conductivity in Graphene/Water and Graphene/Ice Systems. AB - This study demonstrates that the application of an external electrical potential to a phenyl-sulfonic functionalized graphene (SG)/water suspension distinctly enhances its electrical conductivity via the structural transition from isolated clusters to a 3D SG network. Microstructural and alternating current impedance spectroscopy studies indicate that the surface charge plays an important role in the state of dispersion and connectivity of the SG in the suspension due to the potential-dependent interactions with functional groups on the SG surface in the presence of an external electrical potential. In addition, the conductive SG/ice can be produced via liquid-solid phase transition of the SG/water suspension in the presence of an external electrical potential, which shows a one-order magnitude improvement in electrical conductivity compared with pure ice. The electric-field-tunable property advances the understanding of nanofluid systems and has many potential applications. PMID- 28834339 TI - Introduction to the Special Issue on Malaria. AB - This minireview series highlights recent developments in malaria research. The reviews cover diverse topics, from conventional antimalarial therapies and the strategies used to circumvent the emergence of drug resistance, to the latest approaches for the discovery and validation of new druggable targets and for the development of effective antimalarial vaccines. PMID- 28834340 TI - Malaria, metabolism and mathematical models. AB - Understanding the dynamic behaviour of the Plasmodium falciparum metabolism during infection can help identify targets for drug development. In this Commentary, we highlight recently published studies in The FEBS Journal that cover mathematical modelling of glycolysis in P. falciparum and the identification and in vivo validation of metabolic drug targets. PMID- 28834341 TI - Corrigendum. PMID- 28834343 TI - Corrigendum. PMID- 28834344 TI - Unusual presentation of poorly differentiated primary pulmonary synovial sarcoma (PD-PPSS) diagnosed by EBUS-TBNA with cytogenetic confirmation-A diagnostic challenge. AB - Poorly differentiated primary pulmonary synovial sarcoma (PD-PPSS) is a rare, aggressive neoplasm, which occurs in 0.5% cases of all lung malignancies. The diagnosis of PD-PPSS can be very challenging on cytology samples. We present here an unusual case of PD-PPSS diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), in the setting of known history of diffuse large B-cell lymphoma. Diff-Quik and Papanicolaou stains showed cellular specimen with clusters of highly atypical small round blue cells admixed with lymphoid elements; and some with denuded cytoplasm. Cell block further showed molding, crush artifact and atypical mitotic figures. A differential diagnosis based on extended immunohistochemical work-up was Ewing?s sarcoma/PNET versus poorly differentiated synovial sarcoma. Fluorescent in-situ hybridization (FISH) showed SYT gene rearrangement at 18q11.2. In this report, we describe the cytomorphological features, diagnostic pitfalls, challenges, potential mimics, and importance of acquisition of adequate material for the ancillary work-up on the cell block. PMID- 28834345 TI - Novel Magnetic-Luminescent Janus Nanoparticles for Cell Labeling and Tumor Photothermal Therapy. AB - Magnetic-luminescent nanocomposites have multiple uses including multimodal imaging, magnetic targeted drug delivery, and cancer imaging-guided therapies. In this work, dumbbell-like MnFe2 O4 -NaYF4 Janus nanoparticles are synthesized via a two-step thermolysis approach. These synthesized nanoparticles exhibit stability in aqueous solutions and very low cytotoxicity after poly(acryl amide) modification. High cellular uptake efficiency is observed for the folic acid conjugated MnFe2 O4 -NaYF4 in human esophagus carcinoma cells (Eca-109) due to the upconversion luminescence properties as well as the folate targeting potential. The MnFe2 O4 -NaYF4 also strongly absorbs light in the near-infrared range and rapidly converts to heat energy. It is demonstrated that Eca-109 cells incubated with MnFe2 O4 -NaYF4 are killed with high efficiency after 808 nm laser irradiation. Furthermore, the growth of tumors in mice (grown from Eca-109 cells) is highly inhibited by the photothermal effects of MnFe2 O4 -NaYF4 efficiently. Histological analysis reveals no pathological change and inflammatory response in heart, liver, spleen, lung, or kidney. The low toxicity, excellent luminescence, and highly efficient photothermal therapy properties of MnFe2 O4 -NaYF4 Janus nanoparticles illustrated in this work support their vast potential for nanomedicine and cancer therapy. PMID- 28834346 TI - Cofactor Engineering for Enhanced Production of Diols by Klebsiella pneumoniae From Co-Substrate. AB - Diols, such as 1,3-propanediol (1,3-PDO) and 2,3-butanediol (2,3-BDO), have several promising properties for many synthetic reactions. Here, the cofactor engineering strategy, including the construction of Entner-Doudoroff pathway and transhydrogenase-based NADH regeneration system, was applied in producing diols from mixtures of glucose and glycerol. Entner-Doudoroff pathway had a high regeneration rate of NAD(P)H. This work described a strategy to administrate intracellular NADH/NAD+ ratio and improved the concentration of diols. The improvement of NADH/NAD+ ratio also effected gene transcription level of the central carbon pathway and cell growth. Finally, the intracellular NADH/NAD+ ratio in KP-APZDUT was increased by 92.8% compared to the KP-T and the concentration, yield and productivity of diols were increased to 110.8 g L-1 , 0.78 mol mol-1 , and 3.46 g Lh-1 , respectively. The strategy described here provides an approach to achieve a recombinant strain which is capable of producing diols with high yield and productivity. To the best of our knowledge, the Entner-Doudoroff pathway has not yet been used to produce 1,3-PDO or 2,3-BDO in Klebsiella pneumoniae. PMID- 28834347 TI - A Multiple Structure-Design Strategy towards Ultrathin Niobate Perovskite Nanosheets with Thickness-Dependent Photocatalytic Hydrogen-Evolution Performance. AB - Hydrogen production by catalytic water splitting using sunlight holds great promise for clean and sustainable energy source. Despite the efforts made in the past decades, challenges still exist in pursuing solid catalysts with light harvesting capacity, large surface areas and efficient utilities of the photogenerated carrier, at the same time. Here, a multiple structure design strategy leading to highly enhanced photocatalytic performance on hydrogen production from water splitting in Dion-Jacobson perovskites KCa2 Nan-3 Nbn O3n+1 is described. Specifically, chemical doping (N/Nb4+ ) of the parent oxides via ammoniation improved the ability of sunlight harvesting efficiently; subsequent liquid exfoliation of the doped perovskites yielded ultrathin [Ca2 Nan-3 Nbn O3n+1 ]- nanosheets with greatly increased surface areas. Significantly, the maximum hydrogen evolution appears in the n=4 nanosheets, which suggests the most favorable thickness for charge separation in such perovskite-type catalysts. The optimized black N/Nb4+ -[Ca2 NaNb4 O13 ]- nanosheets show greatly enhanced photocatalytic performance, as high as 973 MUmol h-1 with Pt loading, on hydrogen evolution from water splitting. As a proof-of-concept, this work highlights the feasibility of combining various chemical strategies towards better catalysts and precise thickness control of two-dimensional materials. PMID- 28834348 TI - Relapsing Polychondritis Diagnosed by Fusion Images of Gallium-67 Uptake on Computed Tomography and Single-Photon-Emission Computed Tomography. PMID- 28834349 TI - Extramedullary plasmacytoma in the airway of an HIV-positive child. AB - We describe a case of an extramedullary plasmacytoma (EMP) in an HIV-positive child. An 11- year-old, HIV-infected female patient, on antiretroviral therapy since 2010, was referred with difficult to control asthma and bronchiectasis. The lesion was identified on CT chest following persisting reduced air entry and unilateral wheezing on the right. Rigid bronchoscopy identified a large pedunculated fleshy mass in the right main bronchus. Biopsy revealed it to be a plasmacytoma. Right main bronchus sleeve resection was done with complete removal of the tumor. Histology confirmed it to be a solitary plasmacytoma localized to the right main bronchus. PMID- 28834350 TI - Processing of co-reference in autism spectrum disorder. AB - : Accuracy for reading comprehension and inferencing tasks has previously been reported as reduced for individuals with autism spectrum disorder (ASD), relative to typically developing (TD) controls. In this study, we used an eye movements and reading paradigm to examine whether this difference in performance accuracy is underpinned by differences in the inferential work required to compute a co referential link. Participants read two sentences that contained a category noun (e.g., bird) that was preceded by and co-referred to an exemplar that was either typical (e.g., pigeon) or atypical (e.g., penguin). Both TD and ASD participants showed an effect of typicality for gaze durations upon the category noun, with longer times being observed when the exemplar was atypical, in comparison to typical. No group differences or interactions were detected for target processing, and verbal language proficiency was found to predict general reading and inferential skill. The only difference between groups was that individuals with ASD engaged in more re-reading than TD participants. These data suggest that readers with ASD do not differ in the efficiency with which they compute anaphoric links on-line during reading. Autism Res 2017, 10: 1968-1980. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) have previously been reported to have difficulties with reading comprehension. This study examined whether a difference in the speed with which individuals with ASD form connections between words (co-reference processing) may contribute to comprehension difficulties. No evidence was found to suggest that ASD readers differ to typically developing readers in the speed of co-reference processing. Therefore, this data would suggest that differences in co-reference processing are unlikely to account for reading comprehension difficulties in ASD. PMID- 28834351 TI - Preliminary insights into the occurrence of similar clones of extended-spectrum beta-lactamase-producing bacteria in humans, animals and the environment in Tanzania: A systematic review and meta-analysis between 2005 and 2016. AB - The emergence and spread of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-PE) are complex and of the public health concern across the globe. This review aimed at assessing the ESBL-PE clones circulating in humans, animals and the environment to provide evidence-based insights for combating ESBL-PE using One Health approach. Systematic search from Medline/PubMed, Google Scholar and African Journals Online was carried out and retrieved nine eligible articles (of 131) based on phenotypic and genotypic detection of ESBL-PE between 2005 and 2016 in Tanzania. Analysis was performed using STATA 11.0 software to delineate the prevalence of ESBL-PE, phenotypic resistance profiles and clones circulating in the three interfaces. The overall prevalence of ESBL-PE in the three interfaces was 22.6% (95% CI: 21.1-24.2) with the predominance of Escherichia coli (E. coli) strains (51.6%). The majority of ESBL-PE were resistant to the commonly used antimicrobials such as trimethoprim sulfamethoxazole and tetracycline/doxycycline, 38%-55% were resistant to ciprofloxacin and all were sensitive to meropenem/imipenem. ESBL-PE infections were more associated with deaths compared to non-ESBL-PE infections. Strikingly, E. coli ST38, ST131 and ST2852 were found to intersect variably across the three interfaces. The predominant allele, blaCTX-M-15, was found mostly in the conjugative IncF plasmids connoting transmission potential. The high prevalence of ESBL-PE and shared clones across the three interfaces, including the global E. coli ST131 clone, indicates wide and inter-compartmental spread that calls for One Health genomic-driven studies to track the resistome flow. PMID- 28834353 TI - A New Energy-Saving Catalytic System: Carbon Dioxide Activation by a Metal/Carbon Catalyst. AB - The conversion of CO2 into useful chemicals is an attractive method to reduce greenhouse gas emissions and to produce sustainable chemicals. However, the thermodynamic stability of CO2 means that a lot of energy is required for its conversion into chemicals. Here, we suggest a new catalytic system with an alternative heating system that allows minimal energy consumption during CO2 conversion. In this system, electrical energy is transferred as heat energy to the carbon-supported metal catalyst. Fast ramping rates allow high operating temperatures (Tapp =250 degrees C) to be reached within 5 min, which leads to an 80-fold decrease of energy consumption in methane reforming using CO2 (DRM). In addition, the consumed energy normalized by time during the DRM reaction in this current-assisted catalysis is sixfold lower (11.0 kJ min-1 ) than that in conventional heating systems (68.4 kJ min-1 ). PMID- 28834352 TI - Global profiling of alternative splicing landscape responsive to drought, heat and their combination in wheat (Triticum aestivum L.). AB - Plant can acquire tolerance to environmental stresses via transcriptome reprogramming at transcriptional and alternative splicing (AS) levels. However, how AS coordinates with transcriptional regulation to contribute to abiotic stresses responses is still ambiguous. In this study, we performed genome-wide analyses of AS responses to drought stress (DS), heat stress (HS) and their combination (HD) in wheat seedlings, and further compared them with transcriptional responses. In total, we found 200, 3576 and 4056 genes exhibiting significant AS pattern changes in response to DS, HS and HD, respectively, and combined drought and heat stress can induce specific AS compared with individual one. In addition, wheat homeologous genes exhibited differential AS responses under stress conditions that more AS events occurred on B subgenome than on A and D genomes. Comparison of genes regulated at AS and transcriptional levels showed that only 12% of DS-induced AS genes were subjected to transcriptional regulation, whereas the proportion increased to ~40% under HS and HD. Functional enrichment analysis revealed that abiotic stress-responsive pathways tended to be highly overrepresented among these overlapped genes under HS and HD. Thus, we proposed that transcriptional regulation may play a major role in response to DS, which coordinates with AS regulation to contribute to HS and HD tolerance in wheat. PMID- 28834354 TI - TRPM5 in the battle against diabetes and obesity. AB - TRPM5 is a non-selective monovalent cation channel activated by increases in intracellular Ca2+ . It has a distinct expression pattern: expression is detected in chemosensitive tissues from solitary chemosensory cells to the taste receptor cells and in pancreatic beta-cells. The role of TRPM5 has been investigated with the use of knockout mouse models. Trpm5-/- mice have a lack of type II taste perception and show reduced glucose-induced insulin secretion. Expression levels of TRPM5 are reduced in obese, leptin-signalling-deficient mice, and mutations in TRPM5 have been associated with type II diabetes and metabolic syndrome. In this review, we aim to give an overview of the activation, selectivity, modulation and physiological roles of TRPM5. PMID- 28834355 TI - Mesenchymal Stem Cells Relevance in Multicellular Bioengineered 3D In Vitro Tumor Models. AB - In vitro 3D tumor microenvironment mimicking models are gathering momentum as alternatives to traditional 2D flat monolayer cultures due to their potential for recapitulating major cancer hallmarks. To fulfill such potential, it is crucial that 3D tumor testing platforms completely emulate in vitro the complex in vivo tumor niche and its cellular constituents. Mesenchymal stem cells (MSCs) are recognized to play a pivotal multi-modulatory role in cancer, generating interest as biological targets and as key tumor suppressing, or tumor promoting effectors. This review discusses the biological influence of different types of MSCs in the tumor microenvironment and showcases recent studies that engineer 3D MSCs-cancer cells co-cultures as advanced in vitro therapy testing platforms. A special focus is given to MSCs-cancer 3D co-culture set-up parameters, challenges, and future opportunities. Understanding cancer-MSCs crosstalk and their underlying effects is envisioned to support the development of advanced 3D in vitro disease models for discovery of forefront cancer treatments. PMID- 28834356 TI - Reply. PMID- 28834357 TI - Fitness consequences of a clock pollinator filter in Nicotiana attenuata flowers in nature. AB - Nicotiana attenuata flowers, diurnally open, emit scents and move vertically to interact with nocturnal hawkmoth and day-active hummingbird pollinators. To examine the fitness consequences of these floral rhythms, we conducted pollination trials in the plant's native habitat with phase-shifted flowers of plants silenced in circadian clock genes. The results revealed that some pollination benefits observed under glasshouse conditions were not reproduced under natural field conditions. Floral arrhythmicity increased pollination success by hummingbirds, while reducing those by hawkmoths in the field. Thus, floral circadian rhythms may influence a plant's fitness by filtering pollinators leading to altered seed set from outcrossed pollen. PMID- 28834360 TI - RAS Inhibitor Is Not Associated With Cardiovascular Benefits in Patients Undergoing Hemodialysis in Japan. AB - Definitive evidence of whether renin angiotensin system (RAS) inhibition is beneficial on cardiovascular events (CVE) among patients undergoing hemodialysis (HD) is lacking. The objective of this study was to investigate the association of RAS inhibitor usage with CVEs in patients enrolled in the Dialysis Outcomes Practice Pattern Study in Japan (J-DOPPS). Association of RAS inhibitor prescription with outcomes including all-cause death, death caused by CVE, and hospitalization due to cardiac failure was investigated by using a multivariable Cox proportional hazards model. Of the 3848 patients enrolled, 1784 (45%) patients were treated by RAS inhibitors. After adjusting for potential cofounders by Cox proportional hazards models, we found a statistically insignificant but positive association of RAS inhibitor usage with death caused by CVE (HR: 1.46, 95%CI: 0.96-2.23, P = 0.08). Similar results were observed in the association of RAS inhibitor with all-cause death, hospitalization due to cardiac failure, and hospitalization due to CV disease (HR for all-cause death: 1.24, 95%CI: 0.84 1.48, P = 0.28, HR for hospitalization due to cardiac failure: 1.24, 95%CI: 0.84 1.81, P = 0.28, and HR for hospitalization due to CV disease: 1.20, 95%CI: 0.95 1.51, P = 0.13). Sensitivity analyses using propensity scores gave similar results. RAS inhibition did not show favorable association with CVEs suggesting that RAS inhibition alone was insufficient to reduce the risk of CV complications in patients undergoing HD. Some strategies in addition to RAS inhibition may be needed to protect against CVEs in this population. PMID- 28834358 TI - Intrinsic and adaptive myelination-A sequential mechanism for smart wiring in the brain. AB - The concept of adaptive myelination-myelin plasticity regulated by activity-is an important advance for the field. What signals set up the adaptable pattern in the first place? Here we review work that demonstrates an intrinsic pathway within oligodendrocytes requiring only an axon-shaped substrate to generate multilayered and compacted myelin sheaths of a physiological length. Based on this, we discuss a model we proposed in 2015 which argues that myelination has two phases intrinsic and then adaptive-which together generate "smart wiring," in which active axons become more myelinated. This model explains why prior studies have failed to identify a signal necessary for central nervous system myelination and argues that myelination, like synapses, might contribute to learning by the activity-dependent modification of an initially hard-wired pattern. (c) 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 68-79, 2018. PMID- 28834362 TI - Is High-Volume Online Hemodiafiltration Associated With Malnutrition? AB - Chronic malnutrition is a common problem in patients with end-stage renal disease on hemodialysis. Some studies have reported albumin loss into dialysis fluid during postdilution online hemodiafiltration (OL-HDF). The aim of the study was to assess the nutritional status of patients on high-volume OL-HDF and to demonstrate that higher convective clearances are not associated with malnutrition due to possible loss of nutrients with ultrafiltration. Demographic and clinical data, corporal composition with bioimpedance spectroscopy, dialysis features, albumin loss into dialysis fluid and laboratory parameters were collected in twenty-eight patients with ESRD undergoing postdilution OL-HDF with stable convective volumes over 28 L/session. Convective volume (CV) in the last six months was 32.51 +/- 3.52 L per session. Cross-sectional analysis of dialysis features showed 32.7 +/- 3.34 L of CV and high reduction rates of beta-2 microglobulin (84.2 +/- 3.8%) and cystatin-C (81.6 +/- 3.47%). Beta-2 microglobulin reduction showed a positive correlation with prealbumin levels (P = 0.048). CV was only correlated with cystatin-C reduction (P = 0.025). Estimated albumin loss into dialysis fluid (1.82 +/- 1.05 g/session) was not related to laboratory or bioimpedance nutritional parameters, or to CV. Among patients with higher CV, serum albumin levels maintained more stability during the observational period. High volume OL-HDF results in better convective clearances and is not associated with malnutrition. Albumin and nutrients loss into dialysis fluid should not be a limiting factor of the substitution volume. PMID- 28834364 TI - Simple and sensitive determination of malondialdehyde in human urine and saliva using UHPLC-MS/MS after derivatization with 3,4-diaminobenzophenone. AB - Malondialdehyde has been used as a biomarker for lipid peroxidation in biological samples. An ultra-high performance liquid chromatography with tandem mass spectrometry method was developed to determine the levels of malondialdehyde in human urine and saliva samples. To select the optimum derivatization reagent from four diamino compounds, the reactivity and sensitivity of their derivatives were compared, and 3,4-diaminobenzophenone was selected. The optimum reaction conditions for malondialdehyde with 3,4-diaminobenzophenone were as follows: a reagent dosage of 50 mg/L, pH of 4, and reaction for 30 min at 50 degrees C. The formed derivative product was analyzed using ultra-high performance liquid chromatography with tandem mass spectrometry without additional extraction or concentration steps. In the optimal conditions, the method was used to determine malondialdehyde concentration in human urine and saliva samples. The limits of quantification for malondialdehyde in biological samples were over a concentration range of 0.1-0.3 MUg/L. Additionally, the calibration curve showed a linearity greater than r2 = 0.997. The method was used to analyze 14 human urine and saliva samples from healthy volunteers. Malondialdehyde was detected in the concentration range of 1.7-33.6 MUg/g creatinine in all human urine samples and 0.1-1.3 MUg/L in all human saliva samples. PMID- 28834363 TI - Decreased Expression of Thrombomodulin in Endothelial Cells by Fibroblast Growth Factor-23/alpha-Klotho. AB - Chronic kidney disease (CKD) has been known to be a state of excessive fibroblast growth factor-23 (FGF23) and alpha-Klotho deficiency. Patients undergoing hemodialysis have an increased mortality risk associated with cardiovascular disease and endothelial dysfunction. The mechanism responsible for the relationship of FGF23 to endothelial damage in these patients has been unclear. On the other hands, increasing evidences have demonstrated that thrombomodulin (TM) plays an important role in the endothelial barrier. Here, we report the suppression of membrane TM, in a dose-dependent manner, in human umbilical vein endothelial cells after FGF23 and FGF23/alpha-Klotho stimulation. In addition, the levels of soluble TM, which reflect endothelial cell injury, were much higher in cell supernatants after FGF23 and FGF23/alpha-Klotho stimulation than in the control supernatant. This study indicates a possible mechanism by which excessive levels of FGF23 are involved in endothelial TM disruption, which has been implicated as a potential cardiovascular risk factor in patients with CKD, especially in HD patients. PMID- 28834365 TI - Spontaneous testicular atrophy occurs despite normal spermatogonial proliferation in a Tp53 knockout rat. AB - The tumor suppressor protein p53 (TP53) has many functions in cell cycle regulation, apoptosis, and DNA damage repair and is also involved in spermatogenesis in the mouse. To evaluate the role of p53 in spermatogenesis in the rat, we characterized testis biology in adult males of a novel p53 knockout rat (SD-Tp53tm1sage ). p53 knockout rats exhibited variable levels of testicular atrophy, including significantly decreased testis weights, atrophic seminiferous tubules, decreased seminiferous tubule diameter, and elevated spermatocyte TUNEL labeling rates, indicating a dysfunction in spermatogenesis. Phosphorylated histone H2AX protein levels and distribution were similar in the non-atrophic seminiferous tubules of both genotypes, showing evidence of pre-synaptic DNA double-strand breaks in leptotene and zygotene spermatocytes, preceding cell death in p53 knockout rat testes. Quantification of the spermatogonial stem cell (SSC) proliferation rate with bromodeoxyuridine (BrdU) labeling, in addition to staining with the undifferentiated type A spermatogonial marker GDNF family receptor alpha-1 (GFRA1), indicated that the undifferentiated spermatogonial population was normal in p53 knockout rats. Following exposure to 0.5 or 5 Gy X ray, p53 knockout rats exhibited no germ cell apoptotic response beyond their unirradiated phenotype, while germ cell death in wild-type rat testes was elevated to a level similar to the unexposed p53 knockout rats. This study indicates that seminiferous tubule atrophy occurs following spontaneous, elevated levels of spermatocyte death in the p53 knockout rat. This phenomenon is variable across individual rats. These results indicate a critical role for p53 in rat germ cell survival and spermatogenesis. PMID- 28834367 TI - The value of nature: Economic, intrinsic, or both? PMID- 28834366 TI - Electrolyte Engineering: Optimizing High-Rate Double-Layer Capacitances of Micropore- and Mesopore-Rich Activated Carbon. AB - Various types of electrolyte cations as well as binary cations are used to optimize the capacitive performance of activated carbon (AC) with different pore structures. The high-rate capability of micropore-rich AC, governed by the mobility of desolvated cations, can outperform that of mesopore-rich AC, which essentially depends on the electrolyte conductivity. PMID- 28834368 TI - Paleolimnology can provide the missing long-term perspective in ecotoxicology research. PMID- 28834369 TI - Reducing repetition of regulatory vertebrate ecotoxicology studies. PMID- 28834371 TI - Learned Discourse: Timely Scientific Opinions. PMID- 28834370 TI - Do ecosystems have ethical rights? PMID- 28834372 TI - Shifting politics and environmental assessment of large infrastructure projects. PMID- 28834373 TI - ADHD Medication, Dietary Patterns, Physical Activity, and BMI in Children: A Longitudinal Analysis of the ECLS-K Study. AB - OBJECTIVE: This study examined relationships between attention deficit/hyperactivity disorder (ADHD), stimulant use, and BMI change in a nationally representative cohort of children as well as differences in diet and physical activity that may mediate associations between stimulant use and BMI change. METHODS: By using the Early Childhood Longitudinal Study-Kindergarten Cohort 1998-1999 (N = 8,250), we modeled BMI and z score change by ADHD and stimulant start time, examined the odds of unhealthy diet and physical activity predicted by ADHD and stimulant use, and performed mediation analysis assessing indirect effects of health behaviors. RESULTS: Early stimulant use predicted short-term BMI reductions, but any stimulant use predicted increased BMI growth between fifth grade (mean age = 11.2 years) and eighth grade (mean age = 14.3 years). Children with ADHD had higher odds of poor diet regardless of medication. Health behaviors were not associated with BMI change after controlling for medication use. CONCLUSIONS: Stimulant use predicted higher BMI trajectory between fifth and eighth grade but did not affect dietary or physical activity patterns. Future research should explore potential mechanisms by which early and long-term stimulant use may affect metabolism, while clinicians should initiate nutrition counseling with families of children with ADHD, regardless of medication prescription, at or shortly after diagnosis. PMID- 28834375 TI - Prominent regression of corneal deposits in Fabry disease 16 years after initiation of enzyme replacement therapy. PMID- 28834374 TI - Differential Distribution of Renal Nerves in the Sympathetic Ganglia of the Rat. AB - The renal nerve plexus comprises efferent and afferent fibers. It controls urine production and bodily fluid homeostasis. Efferent fibers to the kidney include sympathetic nerve fibers from their main ganglia, the prevertebral suprarenal ganglia (SrG), and the paravertebral sympathetic chain ganglia (ChG). In the present study, we examined topological innervation from these ganglia to the renal parenchymal segments of the left kidney of the rat. Fluoro-Gold was injected into the rostral or caudal poles of the left kidney. Approximately 50% of the cells in the SrG of rats injected in the rostral pole were labeled, while 60% of the cells in the ChG T13 of rats injected in the caudal pole were labeled. In addition, we performed dual-probe retrograde tracing of the nerves using two kinds of fluorescent-conjugated cholera toxins (f-CTbs) injected into the rostral and caudal poles of the left kidney. The cells labeled with each f-CTb were distributed differently in the left SrG and the lower ChGs; no dual-labeled cells were found in these ganglia. Anterograde tracing with pCAGGS-tdTomato vector transfected into the left SrG showed that tdTomato-labeled nerve varicosities extended to the cortical arterioles and urinary tubules. Immunohistochemistry revealed that they were positive to tyrosine hydroxylase and synaptophysin, suggesting that they possessed sympathetic nerve endings. Our results show that renal efferent nerves in the SrG may control the rostral part of the kidney and innervate the multiple effectors in the cortex. Anat Rec, 300:2263-2272, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28834376 TI - Nephropathies. PMID- 28834377 TI - Wacker Oxidation of Terminal Alkenes Over ZrO2 -Supported Pd Nanoparticles Under Acid- and Cocatalyst-Free Conditions. AB - Highly efficient Wacker oxidation of aromatic or aliphatic terminal alkenes into methyl ketones and benzofurans is developed by using reusable Pd0 nanoparticles (NPs) supported on ZrO2 under acid- and cocatalyst-free conditions. Molecular oxygen or air can be utilized as the terminal oxidant, which results in the formation of H2 O as the only theoretical byproduct. The activation of the Pd NPs by O2 plays an important role in promoting this reaction. Interestingly, PdO supported on ZrO2 showed no activity. Additionally, the Pd particle size significantly affects the catalytic activity, with an apparent optimal diameter of 4-12 nm. In addition to the heterogeneous catalyst forms, the Pd NPs can be generated from a Pd0 complex during the reaction, and these particles are even recyclable. PMID- 28834378 TI - Autophagic dysfunction and autophagosome escape in the mdx mus musculus model of Duchenne muscular dystrophy. AB - AIM: Duchenne muscular dystrophy is caused by the absence of functional dystrophin protein and results in a host of secondary effects. Emerging evidence suggests that dystrophic pathology includes decreased pro-autophagic signalling and suppressed autophagic flux in skeletal muscle, but the relationship between autophagy and disease progression is unknown. The purpose of this investigation was to determine the extent to which basal autophagy changes with disease progression. We hypothesized that autophagy impairment would increase with advanced disease. METHODS: To test this hypothesis, 7-week-old and 17-month-old dystrophic diaphragms were compared to each other and age-matched controls. RESULTS: Changes in protein markers of autophagy indicate impaired autophagic stimulation through AMPK, however, robust pathway activation in dystrophic muscle, independent of disease severity. Relative protein abundance of p62, an inverse correlate of autophagic degradation, was dramatically elevated with disease regardless of age. Likewise, relative protein abundance of Lamp2, a lysosome marker, was decreased twofold at 17 months of age in dystrophic muscle and was confirmed, along with mislocalization, in histological samples, implicating lysosomal dysregulation in this process. In dystrophic muscle, autophagosome-sized p62-positive foci were observed in the extracellular space. Moreover, we found that autophagosomes were released from both healthy and dystrophic diaphragms into the extracellular environment, and the occurrence of autophagosome escape was more frequent in dystrophic muscle. CONCLUSION: These findings suggest autophagic dysfunction proceeds independent of disease progression and blunted degradation of autophagosomes is due in part to decreased lysosome abundance, and contributes to autophagosomal escape to the extracellular space. PMID- 28834379 TI - Medical students' views of clinical environments. AB - BACKGROUND: Monitoring the quality of clinical learning environments (CLEs) is immensely important in medical education. Objective indicators of the quality of the CLE can be used to measure learner perceptions and to inform educational improvements; however, many established tools were not designed for use in clinical settings and are not theoretically grounded. Our aim was to apply a new tool to the new context of a UK setting to explore the perceptions of senior medical students in a number of different CLEs. Monitoring the quality of clinical learning environments is immensely important in medical education METHODS: The four-factor Undergraduate Clinical Education Environment Measure (UCEEM) was translated into English, and used to gather final-year medical students' perceptions of four different specialties they had rotated through: Emergency Medicine (EM), General Surgery (GS), Medicine for the Elderly (ME), and Obstetrics and Gynaecology (O&G). The UCEEM was distributed in paper form. Students were asked to complete it in relation to two of the four specialties. RESULTS/FINDINGS: Year-5 medical students (n = 132) returned a completed UCEEM. For opportunities to learn in and through work experience EM was reported the most positively. ME was perceived to be the most prepared for student entry. Students reported being well received by staff and made to feel part of the team within GS, EM and ME, but less so in O&G. DISCUSSION: UCEEM appears to be a useful tool for evaluating medical student perceptions of CLEs. Theoretically robust, UCEEM is straightforward to administer and to score. It has the potential to be used by time-pressured educators to collect baseline and comparative data for evaluation and improvement purposes. PMID- 28834380 TI - Soil and brownfield bioremediation. AB - Soil contamination with petroleum hydrocarbons, persistent organic pollutants, halogenated organic chemicals and toxic metal(loid)s is a serious global problem affecting the human and ecological health. Over the past half-century, the technological and industrial advancements have led to the creation of a large number of brownfields, most of these located in the centre of dense cities all over the world. Restoring these sites and regeneration of urban areas in a sustainable way for beneficial uses is a key priority for all industrialized nations. Bioremediation is considered a safe economical, efficient and sustainable technology for restoring the contaminated sites. This brief review presents an overview of bioremediation technologies in the context of sustainability, their applications and limitations in the reclamation of contaminated sites with an emphasis on brownfields. Also, the use of integrated approaches using the combination of chemical oxidation and bioremediation for persistent organic pollutants is discussed. PMID- 28834381 TI - Small airway oscillometry indices: Repeatability and bronchodilator responsiveness in young children. AB - INTRODUCTION: The impulse oscillometry (IOS) indices absolute and relative difference between respiratory resistance at 5 and 20 Hz (R5-20 and R5-20%, respectively) and the area under the reactance curve (AX) are postulated to reflect small airway function. Data on their cutoff values to evaluate bronchodilator responsiveness (BDR) or between-visit changes after interventions are limited in young children. METHODS: We evaluated the BDR of 103 healthy children aged 2-7 years, who received either salbutamol (n = 84) or placebo (n = 19) in order to determine cutoff values for BDR of R5-20, R5-20%, and AX. We then determined the repeatability within and between two IOS measurements 7-14 days apart in young children aged 4-8 years with asthmatic symptoms (n = 43), including cutoff values for significant between-visit changes. RESULTS: The investigated IOS parameters showed marked BDR (fifth percentile cutoff of 75-110% of the baseline value) in healthy children, whereas no significant changes were seen after inhalation of placebo. The agreement within the triplicate IOS measurement was excellent (ICC > 0.80), and the agreement of results between visits was good (ICC > 0.60). A change in R5-20, R5-20%, and AX of 0.65, 1.08, and 0.84 z-scores, respectively, would exceed 95% confidence intervals for between-visit variability. CONCLUSION: We introduce cutoff values for BDR of R5 20, R5-20%, and AX, and their repeatability indices and cutoff limits for significant between-visit changes. These IOS parameters may show greater variability than the conventional IOS indices during follow-up, but the between visit agreement remains good, providing potentially useful endpoints for monitoring lung function in young children. PMID- 28834382 TI - Application of a screening method for fentanyl and its analogues using UHPLC-QTOF MS with data-independent acquisition (DIA) in MSE mode and retrospective analysis of authentic forensic blood samples. AB - The steady appearance of new fentanyl analogues and the associated overdose deaths require the development of sensitive screening approaches to detect these compounds in biological samples and seizures. We developed a targeted screening method to detect 50 4-anilidopiperidine-related fentanyl analogues in whole blood using ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry in data-independent acquisition mode. Sample preparation was performed using protein precipitation on a fully automated robotic setup. Thirteen analogues were selected to validate the method. A small matrix ion enhancement effect (110-123%) was observed for all of the compounds; the recovery ranged from 67% to 81% and the process efficiency from 81% to 98%. Limit of detection was within 0.0005-0.001 mg/kg and limit of identification ranged from 0.001 to 0.005 mg/kg. In the retrospective analysis of 2339 forensic blood samples, the major finding was fentanyl (n = 56), followed by alfentanil (n = 5) and remifentanil (n = 1). Identification of 34 fentanyl analogues was based on the predicted product ions resulting from common fentanyl-specific collision induced cleavages, particularly on the product ion result of the fragmentation on the C-N bond between the phenylamide moiety and the piperidine ring. The proposed hypothesis was supported by the targeted analysis of 16 fentanyl analogues using this method and available published mass spectral data sources for fentanyl analogues. A targeted screening method for 50 fentanyl analogues was successfully validated and implemented to analyse authentic blood samples, where identifying targeted fentanyl analogues was tentatively achieved without using reference standards. PMID- 28834383 TI - Visual motion and rapid auditory processing are solid endophenotypes of developmental dyslexia. AB - Although a genetic component is known to have an important role in the etiology of developmental dyslexia (DD), we are far from understanding the molecular etiopathogenetic pathways. Reduced measures of neurobiological functioning related to reading (dis)ability, i.e. endophenotypes (EPs), are promising targets for gene finding and the elucidation of the underlying mechanisms. In a sample of 100 nuclear families with DD (229 offspring) and 83 unrelated typical readers, we tested whether a set of well-established, cognitive phenotypes related to DD [i.e. rapid auditory processing (RAP), rapid automatized naming (RAN), multisensory nonspatial attention and visual motion processing] fulfilled the criteria of the EP construct. Visual motion and RAP satisfied all testable criteria (i.e. they are heritable, associate with the disorder, co-segregate with the disorder within a family and represent reproducible measures) and are therefore solid EPs of DD. Multisensory nonspatial attention satisfied three of four criteria (i.e. it associates with the disorder, co-segregates with the disorder within a family and represents a reproducible measure) and is therefore a potential EP for DD. Rapid automatized naming is heritable but does not meet other criteria of the EP construct. We provide the first evidence of a methodologically and statistically sound approach for identifying EPs for DD to be exploited as a solid alternative basis to clinical phenotypes in neuroscience. PMID- 28834384 TI - Association of S100 calcium-binding protein A12, receptor for advanced glycation endproducts, and nuclear factor-kappaB expression with inflammation in pulp tissues from tooth caries. AB - AIM: S100 calcium-binding protein A1 (S100A12) is a pro-inflammatory molecule which is secreted during inflammation and induces chemotaxis and the production of pro-inflammatory cytokines via interaction with receptor for advanced glycation endproducts (RAGE) and subsequent, activation of nuclear factor-kappaB (NF-kappaB). The present study was designed to determine the expression levels of S100A12, RAGE, and NF-kappaB in the inflamed pulp of carried teeth. METHODS: In the present study, mRNA from 50 inflamed pulp and 50 healthy pulp were used for expression studies using real-time polymerase chain reaction. The expression levels of S100A12, RAGE, and NF-kappaB were compared between inflamed and healthy tissues. RESULTS: The results revealed that the expression of S100A12, but not of RAGE or NF-kappaB, was significantly decreased in inflamed pulp when compared to healthy pulp. mRNA levels of RAGE were also increased in the inflamed pulp taken from men when compared with women. CONCLUSION: The results suggest that S100A12 does not participate in the induction of inflammation in dental pulp. However, RAGE can participate in the inflammation in the pulp of males. PMID- 28834385 TI - Long-term results of deep sclerectomy in normal-tension glaucoma. AB - PURPOSE: To study the long-term outcome of deep sclerectomy with and without mitomycin-C (MMC) in patients with normal-tension glaucoma (NTG). METHODS: We prospectively analysed consecutive patients randomized to surgery performed either with (MMC group) or without (non-MMC) MMC. Surgery was considered totally successful if, after surgery, the preoperative intra-ocular pressure (IOP) level was reduced by 25% without medication, and a qualified success if medication was required to achieve the same limits. RESULTS: A total of 37 patients were enrolled, 15 in the MMC and 22 in the non-MMC group. The median (range) follow-up was 7.9 (1.0-9.0) years, with a drop-out of three (8%) patients. The preoperative IOP was 15 (11-21) mmHg in the MMC and 15 (10-19) mmHg in the non-MMC group. At the last 6- to 9-year follow-up, IOP was significantly reduced to 9 (2-13) mmHg (p = 0.002) and 10 (5-13) mmHg (p < 0.001). The overall (groups combined) complete and qualified success rates were 50% and 71%, with no significant difference between groups (p = 0.48 and p = 0.25). Goniopuncture was performed in 87% and 100% of eyes in the MMC and non-MMC groups (p = 0.14). Needling with MMC injection was performed 0 (0-1) times in the MMC group and 0.5 (0-4) times in the non-MMC group (p = 0.056). We encountered no cases of hyphema, shallow anterior chamber, hypotony maculopathy, choroidal effusion, late bleb leakage, blebitis, endophthalmitis or malignant glaucoma. CONCLUSION: In NTG, long-term significant IOP reduction can be achieved with deep sclerectomy with a low incidence of sight threatening complications. PMID- 28834386 TI - Metallic bionanocatalysts: potential applications as green catalysts and energy materials. AB - Microbially generated or supported nanocatalysts have potential applications in green chemistry and environmental application. However, precious (and base) metals biorefined from wastes may be useful for making cheap, low-grade catalysts for clean energy production. The concept of bionanomaterials for energy applications is reviewed with respect to potential fuel cell applications, bio catalytic upgrading of oils and manufacturing 'drop-in fuel' precursors. Cheap, effective biomaterials would facilitate progress towards dual development goals of sustainable consumption and production patterns and help to ensure access to affordable, reliable, sustainable and modern energy. PMID- 28834387 TI - Evaluation of a platelet lysate bilayered system for periodontal regeneration in a rat intrabony three-wall periodontal defect. AB - With currently available therapies, full regeneration of lost periodontal tissues after periodontitis cannot be achieved. In this study, a combined compartmentalized system was tested, composed of (a) a platelet lysate (PL)-based construct, which was placed along the root aiming to regenerate the root cementum and periodontal ligament, and (b) a calcium phosphate cement composite incorporated with hyaluronic acid microspheres loaded with PL, aiming to promote the regeneration of alveolar bone. This bilayered system was assessed in a 3-wall periodontal defect in Wistar rats. The periodontal healing and the inflammatory response of the materials were scored for a period up to 6 weeks after implantation. Furthermore, histomorphometrical measurements were performed to assess the epithelial downgrowth, the formation of alveolar bone, and the formation of new connective tissue attachment. Our data showed that the stabilization of platelet-origin proteins on the root surface increased the overall periodontal healing score and restricted the formation of long epithelial junctions. Nevertheless, the faster degradation of the cement component with incorporated hyaluronic acid microspheres compromised the stability of the system, which hampered the periodontal regeneration. Overall, in this work, we proved the positive therapeutic effect of the immobilization of a PL-based construct over the root surface in a combined compartmentalized system to assist predictable healing of functional periodontium. Therefore, after optimization of the hard tissue analogue, the system should be further elaborated in (pre)clinical validation studies. PMID- 28834388 TI - Dry eye disease and oxidative stress. AB - Dry eye, an age-related condition, is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability. Environmental factors are also often implicated in dry eye including exposure to pollutants, ultraviolet (UV) radiation and ozone as well as the chronic use of preserved eyedrops such as in the treatment of glaucoma. These factors increase oxidative stress and ocular surface inflammation. Here, we reviewed the cellular, animal and clinical studies that point to the role of oxidative stress in dry eye disease. The biomarkers used to indicate oxidative damage in ocular surface tissues include 8-hydroxy-2 deoxyguanosine (8-OHdG), 4 hydroxynonenal (HNE) and malondialdehyde (MDD). Antioxidative defences in the ocular surface occur in the form of tear proteins such as lactoferrin and S100A proteins, and enzymes such as superoxide dismutase (SOD), peroxidase, catalase and mitochondrial oxidative enzymes. An imbalance between the level of reactive oxygen species (ROS) and the action of protective enzymes will lead to oxidative damage, and possibly inflammation. A small number of interventional studies suggest that oxidative stress may be directly targeted in topical therapy of dry eye treatment. For example, in vitro studies suggest that L-carnitine and pterostilbene, a blueberry component may reduce oxidative stress, and in animal studies, alpha-lipoic acid (ALP) and selenoprotein P may be helpful. Examples of treatments used in clinical trials include vitamin B12 eyedrops and iodide iontophoresis. With recent emphasis on ageing medicine and preventive holistic health, as well as the role of environmental science, research on oxidative stress in the ocular surface is likely to have increasing impact in the coming years. PMID- 28834389 TI - Indications and techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018. AB - The Tokyo Guidelines 2013 (TG13) include new topics in the biliary drainage section. From these topics, we describe the indications and new techniques of biliary drainage for acute cholangitis with videos. Recently, many novel studies and case series have been published across the world, thus TG13 need to be updated regarding the indications and selection of biliary drainage based on published data. Herein, we describe the latest updated TG13 on biliary drainage in acute cholangitis with meta-analysis. The present study showed that endoscopic transpapillary biliary drainage regardless of the use of nasobiliary drainage or biliary stenting, should be selected as the first-line therapy for acute cholangitis. In acute cholangitis, endoscopic sphincterotomy (EST) is not routinely required for biliary drainage alone because of the concern of post-EST bleeding. In case of concomitant bile duct stones, stone removal following EST at a single session may be considered in patients with mild or moderate acute cholangitis except in patients under anticoagulant therapy or with coagulopathy. We recommend the removal of difficult stones at two sessions after drainage in patients with a large stone or multiple stones. In patients with potential coagulopathy, endoscopic papillary dilation can be a better technique than EST for stone removal. Presently, balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) is used as the first-line therapy for biliary drainage in patients with surgically altered anatomy where BE-ERCP expertise is present. However, the technical success rate is not always high. Thus, several studies have revealed that endoscopic ultrasonography-guided biliary drainage (EUS-BD) can be one of the second-line therapies in failed BE-ERCP as an alternative to percutaneous transhepatic biliary drainage where EUS-BD expertise is present. PMID- 28834390 TI - Implementation of Treat-to-Target for Rheumatoid Arthritis in the US: Analysis of Baseline Data From a Randomized Controlled Trial. AB - OBJECTIVE: A treat-to-target (TTT) strategy is recommended in rheumatoid arthritis (RA). However, health care providers' adherence to TTT in clinical practice remains unclear. We examined adherence to TTT in RA at US rheumatology sites. METHODS: We used baseline information from the randomized controlled Treat to-Target in RA: Collaboration to Improve Adoption and Adherence trial, which recruited 641 patients from 46 providers practicing at 11 US sites. We obtained data on the implementation of TTT, patient covariates, provider characteristics, and site variables. We examined the implementation of TTT using 4 cardinal features: recording a disease target, recording a disease activity measure, engaging in shared decision-making, and changing treatment if not at disease target. These features were assessed across sites and providers. We calculated a TTT implementation score as the percentage of features noted. We examined the association between patient, provider, and site covariates and TTT implementation score using proportional odds models. RESULTS: The implementation of TTT at baseline was suboptimal: 64.3% of visits had none of the TTT components present, 33.1% had 1 component, 2.3% had 2 components, and 0.3% had all components. The implementation of TTT was significantly different across providers and sites (P < 0.0001 for all). In the multivariable model, we observed that more experience as a rheumatologist was associated with a higher implementation score (P = 0.01 for trend). Compared with fellows, providers with >20 years of experience in practice were more likely to have more TTT components recorded (odds ratio 7.68 [95% confidence interval 1.46-40.52]). CONCLUSION: We found that adherence to a TTT strategy in RA was suboptimal, and it differed across providers and sites. PMID- 28834392 TI - Will the real author please stand up? PMID- 28834391 TI - Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cells: Preclinical Efficacy and Safety in Cervical Spinal Cord Injury. AB - Cervical spinal cord injury (SCI) remains an important research focus for regenerative medicine given the potential for severe functional deficits and the current lack of treatment options to augment neurological recovery. We recently reported the preclinical safety data of a human embryonic cell-derived oligodendrocyte progenitor cell (OPC) therapy that supported initiation of a phase I clinical trial for patients with sensorimotor complete thoracic SCI. To support the clinical use of this OPC therapy for cervical injuries, we conducted preclinical efficacy and safety testing of the OPCs in a nude rat model of cervical SCI. Using the automated TreadScan system to track motor behavioral recovery, we found that OPCs significantly improved locomotor performance when administered directly into the cervical spinal cord 1 week after injury, and that this functional improvement was associated with reduced parenchymal cavitation and increased sparing of myelinated axons within the injury site. Based on large scale biodistribution and toxicology studies, we show that OPC migration is limited to the spinal cord and brainstem and did not cause any adverse clinical observations, toxicities, allodynia, or tumors. In combination with previously published efficacy and safety data, the results presented here supported initiation of a phase I/IIa clinical trial in the U.S. for patients with sensorimotor complete cervical SCI. Stem Cells Translational Medicine 2017;6:1917 1929. PMID- 28834393 TI - Brief Report: Drug-Free Long-Term Remission in Severe Behcet's Disease Following Withdrawal of Successful Anti-Tumor Necrosis Factor Treatment. AB - OBJECTIVE: To test the hypothesis that remission of Behcet's disease (BD) in patients with severe vital organ involvement is maintained after withdrawal of successful anti-tumor necrosis factor (anti-TNF) treatment. METHODS: This single center, retrospective, longitudinal outcomes study focused on consecutive patients with disease refractory to treatment with conventional immunosuppressant agents who responded to add-on long-term anti-TNF treatment that was subsequently discontinued. The end point was the proportion of patients remaining in complete remission for at least 3 years after withdrawal of anti-TNF treatment. RESULTS: In our BD cohort comprising 87 patients, 29 were eligible for analysis. All of these patients had disease that was refractory to conventional immunosuppressive therapy and had received successful anti-TNF treatment for a median of 2 years (interquartile range [IQR] 1.1-2.0) before treatment discontinuation. Of these patients, 12 (41%) achieved the study end point. The remaining 17 patients experienced a relapse within 1 year (IQR 0.6-1.5) after discontinuation. Re treatment with anti-TNF was safe and effective in 14 (82%) of 17 patients; so far, 4 of these patients also achieved the study end point. Overall, 16 patients have remained in complete remission (median 6.5 years [IQR 5.5-8]). Ten of these patients are in drug-free remission (treated with anti-TNF agents, mainly for sight-threatening disease), and 6 are in azathioprine-maintained remission (treated with anti-TNF agents for ocular, intestinal, or central nervous system involvement). Notably, patients in drug-free remission were significantly younger and had a significantly shorter duration of BD when anti-TNF treatment was initiated compared to patients receiving azathioprine maintenance treatment. CONCLUSION: Drug-free, long-term remission after withdrawal of successful anti TNF treatment is feasible in patients with severe BD. Because an anti-TNF agent induced "cure" cannot be differentiated from spontaneous remission by natural history, prospective studies should examine whether anti-TNF agents should be used as first-line treatment for the induction of remission in every patient with vital organ involvement. PMID- 28834394 TI - 3D Printing Hierarchical Silver Nanowire Aerogel with Highly Compressive Resilience and Tensile Elongation through Tunable Poisson's Ratio. AB - Metallic aerogels have attracted intense attention due to their superior properties, such as high electrical conductivity, ultralow densities, and large specific surface area. The preparation of metal aerogels with high efficiency and controllability remains challenge. A 3D freeze assembling printing technique integrated with drop-on-demand inkjet printing and freeze casting are proposed for metallic aerogels preparation. This technique enables tailoring both the macrostructure and microstructure of silver nanowire aerogels (SNWAs) by integrating programmable 3D printing and freeze casting, respectively. The density of the printed SNWAs is controllable, which can be down to 1.3 mg cm-3 . The ultralight SNWAs reach high electrical conductivity of 1.3 S cm-1 and exhibit excellent compressive resilience under 50% compressive strain. Remarkably, the printing methodology also enables tuning aerogel architectures with designed Poisson's ratio (from negative to positive). Moreover, these aerogel architechtures with tunable Poisson's ratio present highly electromechanical stability under high compressive and tensile strain (both strain up to 20% with fully recovery). PMID- 28834396 TI - Rehospitalization after intermittent levosimendan treatment in advanced heart failure patients: a meta-analysis of randomized trials. AB - AIMS: Intermittent levosimendan administration has been suggested to improve survival in patients with advanced heart failure (AdHF). Quality of life is a key issue for AdHF patients and is negatively affected by frequent hospitalizations. METHODS AND RESULTS: CENTRAL, Google Scholar, MEDLINE/PubMed, Scopus, and the Cochrane Central Register of clinical trials (updated 15/1/2017) were searched for randomized controlled trials investigating the effect of intermittent levosimendan administration in patients with AdHF. The primary outcome was the number of patients requiring rehospitalization 3 months after the end of treatment. A total of 319 patients from six trials were included. Overall pooled analysis showed that the use of levosimendan was associated with a significant reduction in the number of rehospitalizations at 3 months: 33/207 (16%) vs. 39/113 (35%), risk ratio 0.40, 95% confidence interval 0.27-0.59, P < 0.001, I2 = 0%. This result was confirmed by sensitivity analyses. CONCLUSIONS: Within the limitations of this meta-analysis including also studies in which endpoints were not independently adjudicated and not clearly specified, repetitive or intermittent administration of levosimendan for patients with AdHF was associated with a reduction in the rehospitalization rate at 3 months. Large, high-quality randomized controlled trials are needed to confirm this finding. PMID- 28834397 TI - Angelica Lactones: From Biomass-Derived Platform Chemicals to Value-Added Products. AB - The upgrading of biomass-derived compounds has arisen in recent years as a very promising research field in both academia and industry. In this sense, a lot of new processes and products have been developed, often involving levulinic acid as a starting material or intermediate. In the last few years, though, other scaffolds have been receiving growing attention, especially, angelica lactones. Considering these facts and the emergent applications of said molecules, in this review we will discuss their preparation and applications; the use of these frameworks as starting materials in organic synthesis to produce potential bioactive compounds will be covered, as will their use as a foundation to highly regarded compounds such as liquid alkanes with prospective use as fuels and polymers. PMID- 28834395 TI - Charting the genotype-phenotype map: lessons from the Drosophila melanogaster Genetic Reference Panel. AB - Understanding the genetic architecture (causal molecular variants, their effects, and frequencies) of quantitative traits is important for precision agriculture and medicine and predicting adaptive evolution, but is challenging in most species. The Drosophila melanogaster Genetic Reference Panel (DGRP) is a collection of 205 inbred strains with whole genome sequences derived from a single wild population in Raleigh, NC, USA. The large amount of quantitative genetic variation, lack of population structure, and rapid local decay of linkage disequilibrium in the DGRP and outbred populations derived from DGRP lines present a favorable scenario for performing genome-wide association (GWA) mapping analyses to identify candidate causal genes, polymorphisms, and pathways affecting quantitative traits. The many GWA studies utilizing the DGRP have revealed substantial natural genetic variation for all reported traits, little evidence for variants with large effects but enrichment for variants with low P values, and a tendency for lower frequency variants to have larger effects than more common variants. The variants detected in the GWA analyses rarely overlap those discovered using mutagenesis, and often are the first functional annotations of computationally predicted genes. Variants implicated in GWA analyses typically have sex-specific and genetic background-specific (epistatic) effects, as well as pleiotropic effects on other quantitative traits. Studies in the DGRP reveal substantial genetic control of environmental variation. Taking account of genetic architecture can greatly improve genomic prediction in the DGRP. These features of the genetic architecture of quantitative traits are likely to apply to other species, including humans. WIREs Dev Biol 2018, 7:e289. doi: 10.1002/wdev.289 This article is categorized under: Invertebrate Organogenesis > Flies. PMID- 28834398 TI - ER/Golgi trafficking is facilitated by unbranched actin filaments containing Tpm4.2. AB - We have identified novel actin filaments defined by tropomyosin Tpm4.2 at the ER. EM analysis of mouse embryo fibroblasts (MEFs) isolated from mice expressing a mutant Tpm4.2 (Tpm4Plt53/Plt53 ), incapable of incorporating into actin filaments, revealed swollen ER structures compared with wild-type (WT) MEFs (Tpm4+/+ ). ER-to-Golgi, but not Golgi-to-ER trafficking was altered in the Tpm4Plt53/Plt53 MEFs following the transfection of the temperature sensitive ER associated ts045-VSVg construct. Exogenous Tpm4.2 was able to rescue the ER-to Golgi trafficking defect in the Tpm4Plt53/Plt53 cells. The treatment of WT MEFs with the myosin II inhibitor, blebbistatin, blocked the Tpm4.2-dependent ER-to Golgi trafficking. The lack of an effect on ER-to-Golgi trafficking following treatment of MEFs with CK666 indicates that branched Arp2/3-containing actin filaments are not involved in anterograde vesicle trafficking. We propose that unbranched, Tpm4.2-containing filaments have an important role in maintaining ER/Golgi structure and that these structures, in conjunction with myosin II motors, mediate ER-to-Golgi trafficking. PMID- 28834400 TI - Cryopreservation of canine cardiosphere-derived cells: Implications for clinical application. AB - The clinical application of cardiosphere-derived cells (CDCs) to treat cardiac disease has gained increasing interest over the past decade. Recent clinical trials confirm their regenerative capabilities, although much remains to be elucidated about their basic biology. To develop this new treatment modality, in a cost effective and standardized workflow, necessitates the creation of cryopreserved cell lines to facilitate access for cardiac patients requiring urgent therapy. Cryopreservation may however lead to alterations in cell behavior and potency. The aim of this study was to investigate the effect of cryopreservation on canine CDCs. CDCs and mesenchymal stem cells (MSCs) isolated from five dogs were characterized. CDCs demonstrated a population doubling time that was unchanged by cryopreservation (fresh vs. cryopreserved; 57.13 +/- 5.27 h vs. 48.94 +/- 9.55 h, P = 0.71). This was slower than for MSCs (30.46 h, P < 0.05). The ability to form clones, self-renew, and commit to multiple lineages was unaffected by cryopreservation. Cryopreserved CDCs formed larger cardiospheres compared to fresh cells (P < 0.0001). Fresh CDCs showed a high proportion of CD105+ (89.0% +/- 4.98) and CD44+ (99.68% +/- 0.13) cells with varying proportions of CD90+ (23.36% +/- 9.78), CD34+ (7.18% +/- 4.03) and c-Kit+ (13.17% +/- 8.67) cells. CD45+ (0.015% +/- 0.005) and CD29+ (2.92% +/- 2.46) populations were negligible. Increasing passage number of fresh CDCs correlated with an increase in the proportion of CD34+ and a decrease in CD90+ cells (P = 0.003 and 0.03, respectively). Cryopreserved CDCs displayed increased CD34+ (P < 0.001) and decreased CD90+ cells (P = 0.042) when compared to fresh cells. Overall, our study shows that cryopreservation of canine CDCs is feasible without altering their stem characteristics, thereby facilitating their utilization for clinical trials. (c) 2017 International Society for Advancement of Cytometry. PMID- 28834399 TI - Opioid Tripeptides Hybridized with trans-1-Cinnamylpiperazine as Proliferation Inhibitors of Pancreatic Cancer Cells in Two- and Three-Dimensional in vitro Models. AB - According to the World Health Organization, the mortality rate among patients with pancreatic cancer will increase in the upcoming years. Gemcitabine is the first choice for treatment of pancreatic malignancy, but increasing resistance to this drug is decreasing its overall efficacy. Studies on new therapies that target metabolic pathways, growth factor inhibitors, and tumor stroma or tumor stem cells are currently underway in many research groups. Herein we report the bioactive properties (cytotoxicity and hemolytic activity) of synthetic peptidomimetics containing an opioid tripeptide fragment (Tyr-R1 -R2 -; where R1 is d-Ala or d-Thr, and R2 is Phe or Trp) hybridized with trans-1 cinnamylpiperazine. These compounds are stable in plasma up to 96 h and exhibit low hemotoxicity and good inhibitory effects on cancer cell growth in two- and three-dimensional in vitro models of pancreatic cancer. PMID- 28834401 TI - Neutrophils, G-CSF and their contribution to breast cancer metastasis. AB - Evidence is mounting for a role for neutrophils in breast cancer progression to metastasis. However, the role of G-CSF in neutrophil biology in a cancer setting remains to be defined. Herein we discuss the most recent clinical and experimental evidence for neutrophils and G-CSF in the promotion of metastasis, demonstrating a potential mechanistic link between them. Understanding this link is imperative both for the development of diagnostic tests and for therapies targeting neutrophils to improve the treatment of breast cancer patients with or at risk of developing metastatic disease. As a high neutrophil-to-lymphocyte ratio in patients predicts poor outcome, while mild neutropenia predicts an improved outcome, we urge caution in the use of G-CSF in neutrophil recovery following chemotherapy as there is increasing evidence in preclinical models that G-CSF can promote metastasis. PMID- 28834402 TI - Concise Review: Fetal Membranes in Regenerative Medicine: New Tricks from an Old Dog? AB - The clinical application of the fetal membranes dates back to nearly a century. Their use has ranged from superficial skin dressings to surgical wound closure. The applications of the fetal membranes are constantly evolving, and key to this is the uncovering of multiple populations of stem and stem-like cells, each with unique properties that can be exploited for regenerative medicine. In addition to pro-angiogenic and immunomodulatory properties of the stem and stem-like cells arising from the fetal membranes, the dehydrated and/or decellularized forms of the fetal membranes have been used to support the growth and function of other cells and tissues, including adipose-derived mesenchymal stem cells. This concise review explores the biological origin of the fetal membranes, a history of their use in medicine, and recent developments in the use of fetal membranes and their derived stem and stem-like cells in regenerative medicine. Stem Cells Translational Medicine 2017;6:1767-1776. PMID- 28834403 TI - Dry Reforming of Methane in a Gliding Arc Plasmatron: Towards a Better Understanding of the Plasma Chemistry. AB - Dry reforming of methane (DRM) in a gliding arc plasmatron is studied for different CH4 fractions in the mixture. The CO2 and CH4 conversions reach their highest values of approximately 18 and 10 %, respectively, at 25 % CH4 in the gas mixture, corresponding to an overall energy cost of 10 kJ L-1 (or 2.5 eV per molecule) and an energy efficiency of 66 %. CO and H2 are the major products, with the formation of smaller fractions of C2 Hx (x=2, 4, or 6) compounds and H2 O. A chemical kinetics model is used to investigate the underlying chemical processes. The calculated CO2 and CH4 conversion and the energy efficiency are in good agreement with the experimental data. The model calculations reveal that the reaction of CO2 (mainly at vibrationally excited levels) with H radicals is mainly responsible for the CO2 conversion, especially at higher CH4 fractions in the mixture, which explains why the CO2 conversion increases with increasing CH4 fraction. The main process responsible for CH4 conversion is the reaction with OH radicals. The excellent energy efficiency can be explained by the non-equilibrium character of the plasma, in which the electrons mainly activate the gas molecules, and by the important role of the vibrational kinetics of CO2 . The results demonstrate that a gliding arc plasmatron is very promising for DRM. PMID- 28834404 TI - Synthesis of Renewable Lubricant Alkanes from Biomass-Derived Platform Chemicals. AB - The catalytic synthesis of liquid alkanes from renewable biomass has received tremendous attention in recent years. However, bio-based platform chemicals have not to date been exploited for the synthesis of highly branched lubricant alkanes, which are currently produced by hydrocracking and hydroisomerization of long-chain n-paraffins. A selective catalytic synthetic route has been developed for the production of highly branched C23 alkanes as lubricant base oil components from biomass-derived furfural and acetone through a sequential four step process, including aldol condensation of furfural with acetone to produce a C13 double adduct, selective hydrogenation of the adduct to a C13 ketone, followed by a second condensation of the C13 ketone with furfural to generate a C23 aldol adduct, and finally hydrodeoxygenation to give highly branched C23 alkanes in 50.6 % overall yield from furfural. This work opens a general strategy for the synthesis of high-quality lubricant alkanes from renewable biomass. PMID- 28834406 TI - Morphology of the Toe Flexor Muscles in Older Adults With Toe Deformities. AB - OBJECTIVE: It has been suggested that atrophied or weak toe flexor muscles are associated with the formation of toe deformities, but there is little evidence to support this theory. This study aimed to determine whether the size of the toe flexor muscles differed in older adults with and without toe deformities. METHODS: Forty-four older adults (>60 years) were recruited for the study. Each participant had their feet assessed for the presence of hallux valgus or lesser toe deformities. Intrinsic and extrinsic toe flexor muscles were imaged with an ultrasound system using a standardized protocol. Assessor-blinded measurements of muscle thickness and cross-sectional area were taken using Image J software. RESULTS: Participants with lesser toe deformities (n = 20) were found to have significantly smaller quadratus plantae (P = 0.003), flexor digitorum brevis (P = 0.013), abductor hallucis (P = 0.004), and flexor hallucis brevis (P = 0.005) muscles than the participants without any toe deformities (n = 19). Female participants with hallux valgus (n = 10) were found to have significantly smaller abductor hallucis (P = 0.048) and flexor hallucis brevis (P = 0.013) muscles than the female participants without any toe deformities (n = 10; P < 0.05). CONCLUSION: This is the first study to use ultrasound to investigate the size of the toe flexor muscles in older adults with hallux valgus and lesser toe deformities compared to otherwise healthy older adults. The sizes of the abductor hallucis and flexor hallucis brevis muscles were decreased in participants with hallux valgus, whereas the quadratus plantae, flexor digitorum brevis, abductor hallucis, and flexor hallucis brevis muscles were smaller in the participants with lesser toe deformities. PMID- 28834405 TI - Otomycosis in immunocompetent patients: Clinical and mycological features. Our experience with 40 cases. PMID- 28834407 TI - Psychometric Testing of INTEGRARE, an Instrument for the Assesment of Pressure Ulcer Risk in Inpatients. AB - PURPOSE: The aim of this study is to evaluate the psychometric properties of INTEGRARE, an instrument based on Nursing Outcome Classification. METHOD: A multicenter, cross-sectional, methodological design was used. FINDINGS: The study included 3,835 patients. Internal consistency alpha = 0.86. Confirmatory factor analysis demonstrated the unidimensionality of the scale, indicating a good model fit (CMIN/DF = 4; GFI, CFI, NFI, IFI = 0.999; RMSEA = 0.028). CONCLUSIONS: INTEGRARE is a valid and reliable instrument with high sensitivity, specificity, and diagnostic accuracy in measuring pressure ulcer (PU) risk in inpatients. IMPLICATIONS FOR NURSING PRACTICE: This instrument allows us to know the effectiveness of nursing interventions, providing evidence for the validation of the diagnosis Risk for pressure ulcer (00249) as well as on health outcomes, due to the fact that PUs are nursing-sensitive outcomes. OBJETIVO: Evaluar las propiedades psicometricas de INTEGRARE, un instrumento basado en la Clasificacion de Resultados de Enfermeria. METODO: Se opto por un diseno transversal multicentrico. RESULTADOS: El estudio incluyo a 3,835 pacientes. Consistencia interna alpha = 0.86. El analisis factorial confirmatorio demostro la unidimensionalidad de la escala, indicando un buen ajuste del modelo (CMIN/DF = 4; GFI, CFI, NFI, IFI = 0.999; RMSEA = 0.028). CONCLUSIONES: INTEGRARE es un instrumento valido y fiable con alta sensibilidad, especificidad y precision diagnostica en la medicion de riesgo de ulcera por presion (UPP) en pacientes hospitalizados. IMPLICACIONES PARA LA PRACTICA ENFERMERA: Este instrumento nos permite conocer la efectividad de las intervenciones enfermeras, aportando evidencia para la validacion del diagnostico Riesgo de ulcera por presion (00249), asi como sobre los resultados de salud, debido a que las UPP son resultados sensibles a la practica enfermera. PMID- 28834408 TI - Performance of ovarian cyst fluid fine-needle aspiration cytology. AB - BACKGROUND: Although ovarian fine-needle aspiration (FNA) cytology is not commonly used as a primary modality of diagnosis for patients with ovarian lesions, many ovarian cysts are aspirated intraoperatively and occasionally for diagnostic purposes. Therefore, the ability to interpret these specimens remains critical. Previous studies have suggested a high specificity but low sensitivity as a limitation. The objective of the current study was to further explore the use and performance of ovarian cyst FNA for diagnosing malignancy at the study institution. METHODS: The electronic database was searched from 1998 through 2016 for ovarian cyst fluid cytology specimens; any concurrent or follow-up surgical pathology; and clinical information including patient age, radiology findings, and procedure type. Test performance was calculated using the surgical pathology diagnosis as the gold standard. RESULTS: A total of 459 ovarian cyst FNA specimens had the following diagnoses: 416 (90.6%) were diagnosed as benign, 32 (7.0%) as atypical, 4 (0.9%) as suspicious, and 7 (1.5%) as malignant. Overall, 300 specimens (65.4%) had a corresponding surgical pathology specimen. On follow up, the rate of malignancy (including borderline neoplasms) for benign FNA was 10 of 264 specimens (3.8%), that for atypical FNA was 0 of 24 specimens (0%), that for suspicious FNA was 5 of 5 specimens (100%), and that for malignant FNA was 7 of 7 specimens (100%). Test sensitivity was 54.0% and test specificity was 100%. The positive predictive value was 1.00 and the negative predictive value was 0.97, with a disease (malignancy) prevalence of 7.33%. CONCLUSIONS: Ovarian cyst fluid cytology is highly specific and moderately sensitive for the detection of ovarian malignancies. A negative FNA is reassuring for patients with a low pretest probability of malignancy. Cancer Cytopathol 2018;126:112-21. (c) 2017 American Cancer Society. PMID- 28834409 TI - Identification of distinct cytomorphologic features in the diagnosis of NIFTP at the time of preoperative FNA: Implications for patient management. AB - BACKGROUND: A major reclassification occurred with the redesignation of noninvasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its indolent nature. The aim of this study was to determine whether distinct cytomorphologic features could be identified on preoperative fine-needle aspiration (FNA) when NIFTP cases were compared with invasive follicular variant of papillary thyroid carcinoma (FVPTC) subtypes. METHODS: Thyroid resection cases with the diagnosis of FVPTC from 2012 to 2016 were reclassified as NIFTP, invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC), and invasive FVPTC subtypes. Corresponding FNA specimens were retrieved and retrospectively reviewed. A univariate analysis using Fisher's exact test was performed to determine any differences in the frequencies of various cytomorphologic features among NIFTP, IEFVPTC, and FVPTC cases. A multivariate analysis was performed to identify any independent salient features that would be helpful in differentiating NIFTP from its invasive counterparts. RESULTS: The study population consisted of 93 cases, including 51 cases of NIFTP, 21 cases of IEFVPTC, and 21 cases of infiltrative FVPTC. Demographics such as age, sex, and tumor size were comparable across the 3 groups. A predominantly microfollicular pattern, an absence of nuclear pseudo inclusions, and less frequent nuclear elongations and grooves were significantly more likely to be associated with NIFTP versus its invasive counterparts. The absence of nuclear pseudo-inclusions and the presence of a microfollicular pattern were the only independent predictors of a NIFTP diagnosis. CONCLUSIONS: This study demonstrates that NIFTP cases have distinguishing cytomorphologic characteristics in comparison with invasive FVPTC cases. Therefore, a preoperative cytologic evaluation provides clues that can aid in the distinction between NIFTP and its invasive counterparts. Cancer Cytopathol 2017;125:865-75. (c) 2017 American Cancer Society. PMID- 28834411 TI - Dyslipidemia, Alcohol Consumption, and Obesity as Main Factors Associated With Poor Control of Urate Levels in Patients Receiving Urate-Lowering Therapy. AB - OBJECTIVE: In real life, in a substantial proportion of gouty patients receiving urate-lowering therapy (ULT), urate levels are not maintained below the target of 6.0 mg/dl. We aimed to search for factors associated with poor control of serum uric acid (UA) levels in a large population of patients with gout receiving ULT. METHODS: This cross-sectional study involved adults with gout in primary care who were receiving ULT. Demographics, gout history, comorbidities, lifestyle, clinical factors, concomitant treatments, and laboratory data were compared in well-controlled gout (serum UA <=6.0 mg/dl) versus poorly controlled gout (serum UA >6.0 mg/dl) on univariate and multivariate analyses. RESULTS: Among the 1,995 patients receiving ULT, only 445 (22.3%) had reached the target of 6.0 mg/dl serum UA. Such patients had a lower rate of gout flares within the previous year than patients without the target (mean +/- SD 1.7 +/- 1.4 versus 2.1 +/- 1.4; P < 0.0001). The main factors associated with poor serum UA level control in multivariate analysis were low high-density lipoprotein cholesterol level (adjusted odds ratio [OR] 0.5 [95% confidence interval (95% CI) 0.26-0.96]; P = 0.04), high total cholesterol level (OR 1.83 [95% CI 1.29-2.60]; P = 0.0007), increased waist circumference (OR 1.55 [95% CI 1.11-2.13]; P = 0.008), and alcohol consumption (OR 1.52 [95% CI 1.15-2.00]; P = 0.003). CONCLUSION: Dyslipidemia, abdominal obesity, and alcohol consumption are the main factors associated with a poor response to ULT. Knowledge of these factors might help physicians identify cases of gout that may be less likely to achieve target urate level. PMID- 28834410 TI - Prognostic role of stereotactic body radiation therapy for elderly patients with advanced and medically inoperable pancreatic cancer. AB - The role of stereotactic body radiation therapy for the elderly with advanced or medically inoperable pancreatic cancer was still debated. Therefore, we evaluated the value of stereotactic body radiation therapy and its association with survival of those patients. A total of 417 elderly patients were retrospectively reviewed from 2012 to 2015. Overall survival (OS), progression-free survival (PFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and toxicities were analyzed. Prescription doses ranged from 30-46.8 Gy in 5-8 fractions. Median age was 73 years old. Median OS, PFS, LRFS, and DMFS were 10, 8, 10, and 9.5 months, respectively. One-year OS, PFS, LRFS, and DMFS rate were 35.5%, 18.2%, 26.6%, and 27.1%, respectively. Tumor stage and tumor response at 6 months and CA19-9 levels normalization at 3 months after treatment were independent predictors of OS, PFS, LRFS, and DMFS. Patients with early-stage cancer, better tumor response, and normalization of CA19-9 levels had significantly longer OS, PFS, LRFS, and DMFS. Patients with the prodrug of 5-FU and radiotherapy had longer survival than those with gemcitabine-based chemotherapy and radiotherapy. Patients who received BED10 >= 60 Gy achieved better tumor response compared with those who received BED10 < 60 Gy. Two patients had grade 4 intestinal strictures. No grade 3 or higher hematologic toxicities occurred. Stereotactic body radiation therapy is safe and effective for elderly patients with advanced or medically inoperable pancreatic cancer. Early efficacy could be predictive of prognosis. Higher doses may be associated with efficacy but need further investigation. PMID- 28834412 TI - Risk of Hepatitis B Virus Reactivation in Patients With Inflammatory Arthritis Receiving Disease-Modifying Antirheumatic Drugs: A Systematic Review and Meta Analysis. AB - OBJECTIVE: To assess hepatitis B virus (HBV) reactivation rates in patients with resolved or chronic HBV infection, receiving disease-modifying antirheumatic drugs (DMARDs) and with or without antiviral prophylaxis. METHODS: We conducted a systematic review and meta-analysis. Electronic searches were conducted in PubMed, Medline, and Embase using Ovid through December 31, 2015. A search strategy was developed for each database using the following inclusion criteria: for participants, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and resolved or chronic HBV infection; for intervention, tumor necrosis factor (TNF) inhibitors or non-TNF biologic or nonbiologic DMARDs; and for outcome, HBV reactivation. Four reviewers independently extracted study data and assessed study quality using the Newcastle-Ottawa Scale. To determine the pooled HBV reactivation rate, the variances of the raw proportions were stabilized using a Freeman-Tukey-type arcsine square root transformation, using a random-effects model. RESULTS: Twenty-five studies met the inclusion criteria. The overall pooled rate of HBV reactivation was 1.6% (95% confidence interval [95% CI] 0.8-2.6) in patients with resolved HBV. Similar rates were observed in resolved patients taking TNF inhibitors (1.4% [95% CI 0.5-2.6]), non-TNF biologics (6.1% [95% CI 0.0-16.6]), and nonbiologic DMARDs (1.7% [95% CI 0.2 4.2]). We also found that the reactivation rate was lower in patients with chronic HBV infection who received antiviral prophylaxis (9.0% [95% CI 4.1-15.5]) than in those who did not (14.6% [95% CI 4.3-29.0]). CONCLUSION: We found that the HBV reactivation rate in inflammatory arthritis patients receiving DMARDs was low in resolved patients and moderate in patients with chronic HBV infection. Further, lower rates were observed in patients with chronic HBV infection who were using antiviral prophylaxis. PMID- 28834413 TI - Accessory-lobed accessory cardiac bronchus: Presentation and treatment in a pediatric patient. AB - Accessory cardiac bronchus (ACB) is a supernumerary bronchus usually arising from right main or intermediate bronchus. We report the case of a 9-year-old male who presented a 6-month history characterized by two right pneumonia episodes followed by persistent productive cough, recurrent bloody sputum, and chest x-ray persistence of a segmental thickening of right inferior lobe. Bronchoscopy revealed no abnormalities. Computed tomography documented an accessory-lobed ACB originating from right lower brochus. Surgical removal of ACB and related parenchyma was approached thoracoscopically and converted to thoracotomy for evidence of a bronchial injury. Two-year follow-up showed no recurrent infections or respiratory symptoms. PMID- 28834414 TI - Mind-body problem and hippocampus. AB - Commentary on Faw's comprehensive response to a previous commentary ('Hippocampus as a wormhole' by Ralf-Peter Behrendt, doi: 10.1002/wcs.1446) on Faw and Faw's paper (doi: 10.1002/wcs.1412). WIREs Cogn Sci 2017, e1447. doi: 10.1002/wcs.1447. PMID- 28834415 TI - Response to 'Hippocampus as a wormhole: gateway to consciousness'. AB - Reply to: Behrendt R-P. Hippocampus as a wormhole: gateway to consciousness. WIREs Cogn Sci 2017, e1446. doi: 10.1002/wcs.1446. PMID- 28834416 TI - Hippocampus as a wormhole: gateway to consciousness. AB - Commentary on: Faw M, Faw B. Neurotypical subjective experience is caused by a hippocampal simulation. WIREs Cogn Sci 2017, e1412. doi: 10.1002/wcs.1412. PMID- 28834417 TI - Special Section on Continuous Bioprocessing and Welcome Professor Liu to the Editorial Board. PMID- 28834418 TI - Quasi-experimental study on the effectiveness of a flipped classroom for teaching adult health nursing. AB - AIM: The effectiveness of flipped learning as one of the teaching methods of active learning has been left unexamined in nursing majors, compared to the frequent attempts to uncover the effectiveness of it in other disciplines. The purpose of this study was to reveal the effectiveness of flipped learning pedagogy in an adult health nursing course, controlling for other variables. METHODS: The study applied a quasi-experimental approach, comparing pre- and post test results in learning outcomes. Included in this analysis were the records of 81 junior nursing major students. The convenience sampling method was used to select the participants. Those in the experimental group were exposed to a flipped classroom experience that was given after the completion of their traditional class. The students' learning outcomes and the level of critical thinking skills were evaluated before and after the intervention of the flipped classroom. RESULTS: After the flipped classroom experience, the scores of the students' achievement in subject topics and critical thinking skills, specifically intellectual integrity and creativity, showed a greater level of increase than those of their controlled counterparts. This remained true even after controlling for previous academic performance and the level of creativity. CONCLUSION: This study confirmed the effectiveness of the flipped classroom as a measure of active learning by applying a quantitative approach. But, regarding the significance of the initial contribution of flipped learning in the discipline of nursing science, carrying out a more authentic experimental study could justify the impact of flipped learning pedagogy. PMID- 28834419 TI - Organozinc-Mediated Direct C-C Bond Formation via C-N Bond Cleavage of Ammonium Salts. AB - We report a direct cross-coupling reaction between diarylzinc (Ar2 Zn) and aryltrimethylammonium salts (ArNMe3+ ?- OTf) in the presence of LiCl, via C-N bond cleavage. The reaction takes place smoothly upon heating in THF without any external catalyst, enabling an efficient and chemoselective formation of biaryl products. Mechanistic studies indicate that the reaction proceeds through a single electron transfer route. PMID- 28834421 TI - Association Between Peripheral Adipokines and Inflammation Markers: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Obesity-induced inflammation potentially promotes a variety of chronic conditions. This study aimed to summarize cross-sectional associations between adipose tissue-derived hormones (leptin and adiponectin) and inflammatory biomarkers (C-reactive protein [CRP], interleukin [IL]-6, and tumor necrosis factor [TNF]-alpha) by means of meta-analysis. METHODS: A systematic search of the databases EMBASE and MEDLINE (PubMed) up to January 2017 was conducted. Data were independently extracted and evaluated by two reviewers. Pooled effect sizes and 95% confidence intervals were calculated using random-effects models. RESULTS: After the initial search, 5,907 publications were retrieved; of these, an overall 60 studies with 45,210 participants were deemed eligible for inclusion in the meta-analysis. Positive correlations with inflammatory biomarkers were observed for leptin (pooled Rho = 0.35, 0.20, and 0.20 for CRP, IL-6, and TNF alpha, respectively), whereas the respective correlations with adiponectin were negative (pooled Rho = -0.18, -0.14, and -0.12 for CRP, IL-6, and TNF-alpha, respectively). Stratification by age showed that the observed correlations tended to be weaker with the increasing age of participants. No apparent differences were observed by sex and adiposity status. CONCLUSIONS: This is the first quantitative synthesis of human studies on the association between circulating adipokines and inflammation biomarkers. Potential influence of age on these associations requires further evaluation. PMID- 28834420 TI - Advances and bottlenecks in microbial hydrogen production. AB - Biological production of hydrogen is poised to become a significant player in the future energy mix. This review highlights recent advances and bottlenecks in various approaches to biohydrogen processes, often in concert with management of organic wastes or waste CO2 . Some key bottlenecks are highlighted in terms of the overall energy balance of the process and highlighting the need for economic and environmental life cycle analyses with regard also to socio-economic and geographical issues. PMID- 28834422 TI - Adapting realist synthesis methodology: The case of workplace harassment interventions. AB - Realist synthesis techniques can be used to assess complex interventions by extracting and synthesizing configurations of contexts, mechanisms, and outcomes found in the literature. Our novel and multi-pronged approach to the realist synthesis of workplace harassment interventions describes our pursuit of theory to link macro and program level theories. After discovering the limitations of a dogmatic approach to realist synthesis, we adapted our search strategy and focused our analysis on a subset of data. We tailored our realist synthesis to understand how, why, and under what circumstances workplace harassment interventions are effective. The result was a conceptual framework to test our theory-based interventions and provide the basis for subsequent realist evaluation. Our experience documented in this article contributes to an understanding of how, under what circumstances, and with what consequences realist synthesis principles can be customized. PMID- 28834424 TI - Corrigendum: Towards an Understanding of Li2 O2 Evolution in Li-O2 Batteries: An In Operando Synchrotron X-ray Diffraction Study. PMID- 28834423 TI - Khat (Catha edulis) and its oral health effects: An updated review. AB - Khat or qat (Catha edulis) is a plant that grows in East Africa and southern Arabia. The leaves and twigs of this small tree are chewed by several millions of people worldwide for their stimulating amphetamine-like effects. The reported prevalence of khat chewing in Europe and the USA is on the rise, especially with global migration. Long-term khat chewing has several detrimental general and oral health effects. The aim of the present study was to review the current literature regarding khat use and its association with oral and dental diseases, with particular emphasis on its link with oral keratotic white lesions and oral cancer. We searched the literature to identify all relevant articles. Studies showed that khat is associated with several oral and dental conditions, including keratotic white lesions, mucosal pigmentation, periodontal disease, tooth loss, plasma cell stomatitis, and xerostomia. There are limited data on the incidence of dental caries among khat chewers. The evidence that khat chewing is a risk factor for oral cancer is still weak, and is mainly based on anecdotal case reports and uncontrolled studies. PMID- 28834426 TI - Detection of respiratory syncytial virus (RSV) at birth in a newborn with respiratory distress. AB - Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children. From the nasopharyngeal or conjunctival mucosa of infected individuals, RSV spreads to the lower respiratory tract causing acute bronchiolitis and pneumonia after an incubation period of 4-6 days. In addition to its well-documented tropism for the airway epithelium, it has been shown previously that RSV can also spread hematogenously and efficiently infect extrapulmonary tissues of human hosts. Furthermore, it has been shown in animal models that RSV can spread transplacentally from the respiratory tract of a pregnant mother to the lungs of the fetus. This report describes a documented case of neonatal RSV infection strongly suggestive of prenatal transmission of this infection in humans from an infected mother to her offspring. PMID- 28834427 TI - The Formation of Silicate-Stabilized Passivating Layers on Pyrite for Reduced Acid Rock Drainage. AB - Acid and metalliferous release occurring when sulfide (principally pyrite) containing rock from mining activities and from natural environments is exposed to the elements is acknowledged as a major environmental problem. Acid rock drainage (ARD) management is both challenging and costly for operating and legacy mine sites. Current technological solutions are expensive and focused on treating ARD on release rather than preventing it at source. We describe here a viable, practical mechanism for reduced ARD through the formation of silicate-stabilized iron oxyhydroxide surface layers. Without silicate, oxidized pyrite particles form an overlayer of crystalline goethite or lepidocrocite with porous structure. With silicate addition, a smooth, continuous, coherent and apparently amorphous iron oxyhydroxide surface layer is observed, with consequent pyrite dissolution rates reduced by more than 90% at neutral pH. Silicate is structurally incorporated within this layer and inhibits the phase transformation from amorphous iron (oxy)hydroxide to goethite, resulting in pyrite surface passivation. This is confirmed by computational simulation, suggesting that silicate-doping of a pseudoamorphous iron oxyhydroxide (ferrihydrite structure) is thermodynamically more stable than the equivalent undoped structure. This mechanism and its controlling factors are described. As a consequence of the greatly reduced acid generation rate, neutralization from on-site available reactive silicate minerals may be used to maintain neutral pH, after initial limestone addition to achieve neutral pH, thus maintaining the integrity of these layers for effective ARD management. PMID- 28834425 TI - Promotion of cell proliferation by the proto-oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization. AB - Oral squamous cell carcinoma (OSCC) develops through a multistep carcinogenic process involving field cancerization. The DEK gene is a proto-oncogene with functions in genetic and epigenetic modifications, and has oncogenic functions, including cellular proliferation, differentiation, and senescence. DEK overexpression is associated with malignancies; however, the functional roles of DEK overexpression are unclear. We demonstrated that DEK-expressing cells were significantly increased in human dysplasia/carcinoma in situ and OSCC. Furthermore, we generated ubiquitous and squamous cell-specific doxycycline (DOX) inducible Dek mice (iDek and iDek-e mice respectively). Both DOX+ iDek and iDek-e mice did not show differences in the oral mucosa compared with DOX- mice. In the environment exposed to carcinogen, DOX-treated (DOX+) iDek mice showed field cancerization and OSCC development. Microarray analysis revealed that DEK overexpression was mediated by the upregulation of DNA replication- and cell cycle-related genes, particularly those related to the G1 /S transition. Tongue tumors overexpressing DEK showed increased proliferating cell nuclear antigen and elongator complex protein 3 expression. Our data suggest that DEK overexpression enhanced carcinogenesis, including field cancerization, in OSCC by stimulating the G1 /S phase transition and promoting DNA replication, providing important insights into the potential applications of DEK as a target in the treatment and prevention of OSCC. PMID- 28834428 TI - Highly Efficient and Scalable Compound Decomposition of Two-Electron Integral Tensor and Its Application in Coupled Cluster Calculations. AB - The representation and storage of two-electron integral tensors are vital in large-scale applications of accurate electronic structure methods. Low-rank representation and efficient storage strategy of integral tensors can significantly reduce the numerical overhead and consequently time-to-solution of these methods. In this work, by combining pivoted incomplete Cholesky decomposition (CD) with a follow-up truncated singular vector decomposition (SVD), we develop a decomposition strategy to approximately represent the two electron integral tensor in terms of low-rank vectors. A systematic benchmark test on a series of 1-D, 2-D, and 3-D carbon-hydrogen systems demonstrates high efficiency and scalability of the compound two-step decomposition of the two electron integral tensor in our implementation. For the size of the atomic basis set, Nb, ranging from ~100 up to ~2,000, the observed numerical scaling of our implementation shows [Formula: see text] versus [Formula: see text] cost of performing single CD on the two-electron integral tensor in most of the other implementations. More importantly, this decomposition strategy can significantly reduce the storage requirement of the atomic orbital (AO) two-electron integral tensor from [Formula: see text] to [Formula: see text] with moderate decomposition thresholds. The accuracy tests have been performed using ground- and excited-state formulations of coupled cluster formalism employing single and double excitations (CCSD) on several benchmark systems including the C60 molecule described by nearly 1,400 basis functions. The results show that the decomposition thresholds can be generally set to 10-4 to 10-3 to give acceptable compromise between efficiency and accuracy. PMID- 28834429 TI - Novel Low-Temperature Process for Perovskite Solar Cells with a Mesoporous TiO2 Scaffold. AB - The most efficient organic-inorganic perovskite solar cells (PSCs) contain the conventional n-i-p mesoscopic device architecture using a semiconducting TiO2 scaffold combined with a compact TiO2 blocking layer for selective electron transport. These devices achieve high power conversion efficiencies (15-22%) but mainly require high-temperature sintering (>450 degrees C), which is not possible for temperature-sensitive substrates. Thus far, comparably little effort has been spent on alternative low-temperature (<150 degrees C) routes to realize high-efficiency TiO2-based PSCs; instead, other device architectures have been promoted for low-temperature processing. In this paper the compatibility of the conventional mesoscopic TiO2 device architecture with low-temperature processing is presented for the first time with the combination of electron beam evaporation for the compact TiO2 and UV treatment for the mesoporous TiO2 layer. Vacuum evaporation is introduced as an excellent deposition technique of uniform compact TiO2 layers, adapting smoothly to the rough fluorine-doped tin oxide substrate surface. Effective removal of organic binders by UV light is shown for the mesoporous scaffold. Entirely low-temperature-processed PSCs with TiO2 scaffold reach encouraging stabilized efficiencies of up to 18.2%. This process fulfills all requirements for monolithic tandem devices with high-efficiency silicon heterojunction solar cells as the bottom cell. PMID- 28834430 TI - Quantitative Analysis of the Molecular Dynamics of P3HT:PCBM Bulk Heterojunction. AB - The optoelectronic properties of blends of conjugated polymers and small molecules are likely to be affected by the molecular dynamics of the active layer components. We study the dynamics of regioregular poly(3-hexylthiophene) (P3HT):phenyl-C61-butyric acid methyl ester (PCBM) blends using molecular dynamics (MD) simulation on time scales up to 50 ns and in a temperature range of 250-360 K. First, we compare the MD results with quasi-elastic neutron-scattering (QENS) measurements. Experiment and simulation give evidence of the vitrification of P3HT upon blending and the plasticization of PCBM by P3HT. Second, we reconstruct the QENS signal based on the independent simulations of the three phases constituting the complex microstructure of such blends. Finally, we found that P3HT chains tend to wrap around PCBM molecules in the amorphous mixture of P3HT and PCBM; this molecular interaction between P3HT and PCBM is likely to be responsible for the observed frustration of P3HT, the plasticization of PCBM, and the partial miscibility of P3HT and PCBM. PMID- 28834431 TI - Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38alpha MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine. AB - We recently reported 1a (skepinone-L) as a type I p38alpha MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives. PMID- 28834432 TI - Formation of Highly Pure and Patterned Carbon Nanotube Films on a Variety of Substrates by a Wet Process Based on Light-Induced Dispersibility Switching. AB - A simple fabrication method for patterned carbon nanotube (CNT) films is presented, using the concept of light-induced dispersibility switching with a photoresponsive dispersant. A comparison with other dispersants highlights the important role played by an azobenzene-derived cationic molecule as a photoisomerizable dispersant in the successful manufacture of patterned CNT films. Upon UV irradiation for a short time (~0.5 min), a dispersion composed of CNTs and photoresponsive dispersant exhibited a dispersibility change due to the photoisomerization of the photoresponsive dispersant, and then the dispersant detached-CNT deposited onto the substrate. Our method enables patterned CNT films to be obtained directly from CNT dispersions onto various substrates such as glass, polyethylene terephthalate, and silicone rubber, expanding the possible applications of CNT films. Furthermore, the process minimizes the amount of the residual dispersant in the fabricated CNT film, reducing the amount of impurities, and improving the quality of the patterned CNT film. PMID- 28834433 TI - Meroterpenoids with Protein Tyrosine Phosphatase 1B Inhibitory Activity from a Hyrtios sp. Marine Sponge. AB - Three new meroterpenoids, hyrtiolacton A (1), nakijinol F (2), and nakijinol G (3), along with three known ones, nakijinol B (4), nakijinol E (5), and dactyloquinone A (6), were isolated and characterized from a Hyrtios sp. marine sponge collected from the South China Sea. The new structures were determined based on extensive analysis of HRESIMS and NMR data, and their absolute configurations were assigned by a combination of single-crystal X-ray diffraction and electronic circular dichroism analyses. Hyrtiolacton A (1) represents an unprecedented meroterpenoid featuring an unusual 2-pyrone attached to the sesquiterpene core, which is the first example of a pyrone-containing 4,9 friedodrimane-type sesquiterpene. These compounds were evaluated for their protein tyrosine phosphatase (PTP1B) inhibitory and cytotoxic activities. Nakijinol G (3) showed PTP1B inhibitory activity with an IC50 value of 4.8 MUM but no cytotoxicity against four human cancer cell lines. PMID- 28834434 TI - Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria. AB - In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo /achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria. PMID- 28834435 TI - Thermometry of Plasmonic Heating by Inelastic Electron Tunneling Spectroscopy (IETS). AB - The electronic and lattice heating accompanying plasmonic structures under illumination is suggested to be utilized in a broad range of thermoplasmonic applications. Specifically, in molecular electronics precise determination of the temperature of illuminated junctions is crucial, because the temperature dependent energy distribution of charge carriers in the leads affects the possibility to steer various light-controlled conductance processes. Existing optical methods to characterize the local temperature in all these applications lack the spatial resolution to probe the few nanometers in size hot spots and therefore typically report average values over a diffraction limited length scale. Here we demonstrate that inelastic electron tunneling spectroscopy of molecular junctions based on thiol-alkyl chains can be used to precisely measure the temperature of metal nanoscale gaps under illumination. The nature of this measurement guarantees that the reported temperature indeed characterizes the confined volume in which heat is produced by the relaxation of hot carriers. Using a simple model, we suggest that the accuracy of the method enables also one to semiquantify the energy distribution of the hot carriers. PMID- 28834436 TI - Landscape Scale Study of the Net Effect of Proximity to a Neonicotinoid-Treated Crop on Bee Colony Health. AB - Since 2013, the European Commission has restricted the use of three neonicotinoid insecticides as seed dressings on bee-attractive crops. Such crops represent an important source of forage for bees, which is often scarce in agro-ecosystems. However, this benefit has often been overlooked in the design of previous field studies, leaving the net impact of neonicotinoid treated crops on bees relatively unknown. Here, we determine the combined benefit (forage) and cost (insecticide) of oilseed rape grown from thiamethoxam-treated seeds on Bombus terrestris and Apis mellifera colonies. In April 2014, 36 colonies per species were located adjacent to three large oilseed rape fields (12 colonies per field). Another 36 were in three nearby locations in the same agro-ecosystem, but several kilometers distant from any oilseed rape fields. We found that Bombus colony growth and reproduction were unaffected by location (distant versus adjacent) following the two month flowering period. Apis colony and queen survival were unaffected. However, there was a small, but significant, negative relationship between honey and pollen neonicotinoid contamination and Apis colony weight gain. We hypothesize that any sublethal effects of neonicotinoid seed dressings on Bombus colonies are potentially offset by the additional foraging resources provided. A better understanding of the ecological and agronomic factors underlying neonicotinoid residues is needed to inform evidence-based policy. PMID- 28834437 TI - Challenge For Cancer Survivorship: Improving Care Through Categorization by Risk. PMID- 28834438 TI - Germline Testing for Individuals With Pancreatic Cancer: The Benefits and Challenges to Casting a Wider Net. PMID- 28834439 TI - Reply to P. Tralongo et al. PMID- 28834440 TI - Maintenance Lenalidomide After Transplantation in Multiple Myeloma Prolongs Survival-In Most. PMID- 28834441 TI - Pathologic Outcomes of Architectural Distortion on Digital 2D Versus Tomosynthesis Mammography. AB - OBJECTIVE: The purpose of this study is to compare the risk of malignancy associated with architectural distortion detected on 2D digital mammography (DM) versus digital breast tomosynthesis (DBT). MATERIALS AND METHODS: We performed a retrospective review of architectural distortion cases recommended for biopsy from September 2007 to February 2011, the period before DBT integration (hereafter known as the DM group), and from January 2013 to June 2016, the period after DBT integration (hereafter known as the DBT group). Medical records were reviewed for imaging findings and pathology results. RESULTS: Architectural distortion was more commonly detected in the DBT group than the DM group (0.14% [274/202,438 examinations] vs 0.07% [121/166,661 examinations]; p < 0.001). The positive predictive value of architectural distortion for malignancy was significantly lower in the DBT group than the DM group (50.7% [139/274 cases] vs 73.6% [89/121 cases]; p < 0.001). Radial scar was the most common nonmalignant finding in both groups, but it was more common in the DBT group (33.2% [91/274] vs 11.6% [14/121]; p < 0.001). In the DBT group, architectural distortion without correlative findings on ultrasound was less likely to represent malignancy than was architectural distortion with correlative findings on ultrasound (29.2% [31/106] vs 66.5% [105/158]; p < 0.001). CONCLUSION: Architectural distortion is more commonly detected on DBT than DM and is less likely to represent malignancy on DBT. Architectural distortion on DBT is less likely to represent malignancy if there is no sonographic correlate; however, biopsy is warranted even in the absence of a sonographic correlate, given the nearly 30% risk of malignancy in this setting. PMID- 28834442 TI - MRI of Native Knee Cartilage Delamination Injuries. AB - OBJECTIVE: The purpose of this article is to describe the normal imaging appearance of cartilage and the pathophysiologic findings, imaging appearance, and surgical management of cartilage delamination. CONCLUSION: Delamination injuries of knee cartilage signify surgical lesions that can lead to significant morbidity without treatment. These injuries may present with clinical symptoms identical to those associated with meniscal injury, and arthroscopic identification can be difficult, thereby creating a role for imaging diagnosis. A low sensitivity of imaging identification of delamination injury of the knee is reported in the available literature, although vast improvements in MRI of cartilage have since been introduced. PMID- 28834443 TI - Diffusion Kurtosis Imaging Helps to Predict Upgrading in Biopsy-Proven Prostate Cancer With a Gleason Score of 6. AB - OBJECTIVE: The purpose of this study was to investigate whether diffusion kurtosis imaging (DKI) is useful for predicting upgrades in Gleason score (GS) in biopsy-proven prostate cancer with a GS of 6. MATERIALS AND METHODS: A total of 46 patients with biopsy-proven GS 6 prostate cancer, 3-T DWI results, and surgical pathologic results were retrospectively included in the study. DWI data were postprocessed with monoexponential and DK models to quantify the apparent diffusion coefficient (ADC), apparent diffusion for gaussian distribution (Dapp), and apparent kurtosis coefficient (Kapp). The volume of the lesions, prostate specific antigen (PSA) level, and diffusion variables (ADCmin, Dappmin, Kappmax, ADCmean, Dappmean, and Kappmean) were evaluated. PSA and DKI were combined as a parameter in a logistic regression model. The utility of these parameters in predicting an upgrade in GS was analyzed with ROC regression. RESULTS: The rate of GS upgrade was 50.0% (23/46). The GS upgrade group had significantly lower ADCmin (p = 0.007), ADC mean (p = 0.003), D appmin (p < 0.001), and Dappmean (p = 0.001) values and significantly higher Kappmax (p = 0.003), Kappmean (p = 0.005), and PSA (p = 0.004) values than the group that did not have an upgrade. Among single parameters, Kappmax had the highest ROC AUC value (0.819, p < 0.05), and among all the parameters and models, PSA-Kappmax had the highest AUC (0.868, p < 0.05) and Youden index (0.6522). CONCLUSION: The results showed that DKI may help in prediction of GS upgrade in biopsy-proven GS 6 prostate cancer. The comprehensive consideration of DKI and PSA may be a promising approach to predicting GS upgrade. PMID- 28834444 TI - Diagnostic Performance of CT for Diagnosis of Fat-Poor Angiomyolipoma in Patients With Renal Masses: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The purpose of this article is to systematically review and perform a meta-analysis of the diagnostic performance of CT for diagnosis of fat-poor angiomyolipoma (AML) in patients with renal masses. MATERIALS AND METHODS: MEDLINE and EMBASE were systematically searched up to February 2, 2017. We included diagnostic accuracy studies that used CT for diagnosis of fat-poor AML in patients with renal masses, using pathologic examination as the reference standard. Two independent reviewers assessed the methodologic quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Sensitivity and specificity of included studies were calculated and were pooled and plotted in a hierarchic summary ROC plot. Sensitivity analyses using several clinically relevant covariates were performed to explore heterogeneity. RESULTS: Fifteen studies (2258 patients) were included. Pooled sensitivity and specificity were 0.67 (95% CI, 0.48-0.81) and 0.97 (95% CI, 0.89-0.99), respectively. Substantial and considerable heterogeneity was present with regard to sensitivity and specificity (I2 = 91.21% and 78.53%, respectively). At sensitivity analyses, the specificity estimates were comparable and consistently high across all subgroups (0.93-1.00), but sensitivity estimates showed significant variation (0.14-0.82). Studies using pixel distribution analysis (n = 3) showed substantially lower sensitivity estimates (0.14; 95% CI, 0.04-0.40) compared with the remaining 12 studies (0.81; 95% CI, 0.76-0.85). CONCLUSION: CT shows moderate sensitivity and excellent specificity for diagnosis of fat-poor AML in patients with renal masses. When methods other than pixel distribution analysis are used, better sensitivity can be achieved. PMID- 28834445 TI - Biologic Profiles of Invasive Breast Cancers Detected Only With Digital Breast Tomosynthesis. AB - OBJECTIVE: The purpose of this study was to analyze the clinicopathologic and immunohistochemical features of invasive breast cancers detected only with digital breast tomosynthesis (DBT), compared with those of cancers detected with both DBT and full-field digital mammography (FFDM). MATERIALS AND METHODS: The medical records of 261 women (108 without and 153 with symptoms) with invasive breast cancers who underwent FFDM and DBT between April 2015 and June 2016 were retrospectively reviewed. To assess detectability, all DBT and FFDM images were reviewed independently by three radiologists blinded to clinicopathologic information. The reference standard was established by an unblinded consensus review of all images. Clinicopathologic and immunohistochemical features were analyzed according to the detectability status. RESULTS: Of the 261 cancers, 223 (85.4%) were detected with both DBT and FFDM (both-detected group). Twenty-four cancers (9.2%) not detected with FFDM (DBT-only group) were classified by DBT as a mass (58.3%), architectural distortion (33.3%), or asymmetry (8.3%). The remaining 14 cancers (5.4%) were not detected with either DBT or FFDM (both occult group). On multivariate analysis, a dense breast parenchyma (p = 0.007), small tumor size (<= 2 cm; p = 0.027), and luminal A-like subtype (estrogen receptor positive or progesterone receptor positive or both, human epidermal growth factor receptor 2 negative, and Ki-67 expression < 14%; p = 0.008) were significantly associated with the DBT-only group. For 108 screening-detected cancers, a dense breast parenchyma (p = 0.007) and luminal A-like subtype (p = 0.008) also maintained significance. CONCLUSION: The addition of DBT to FFDM in screening would aid in the detection of less-aggressive subtypes of invasive breast cancers in women with dense breasts. PMID- 28834446 TI - "Scout No Scan" Technique Reduces Patient Radiation Exposure During CT-Guided Spine Biopsy. AB - OBJECTIVE: The objective of this article is to report our experience with a technique for CT-guided spine biopsies that we refer to as the "scout no scan" technique. CONCLUSION: The scout no scan technique can significantly lower radiation exposure while maintaining high diagnostic yields for CT-guided spinal biopsies. PMID- 28834447 TI - Revisiting Nonmass Enhancement in Breast MRI: Analysis of Outcomes and Follow-Up Using the Updated BI-RADS Atlas. AB - OBJECTIVE: The purpose of this study is to assess the frequency of reclassification of nonmass enhancement (NME) as background parenchymal enhancement (BPE) and to determine positive predictive values (PPVs) of NME descriptors using the revised BI-RADS atlas. MATERIALS AND METHODS: A retrospective review of our institution's MRI database from January 1, 2009, through March 30, 2012, identified 6220 contrast-enhanced breast MRI examinations. All findings prospectively assessed as NME and rated as BI-RADS categories 3, 4, and 5 (n = 386) were rereviewed in consensus by two radiologists who were blinded to pathologic findings with the fifth edition of the BI-RADS lexicon. Findings considered as postsurgical, associated with known cancers, NME given a BI-RADS category 3 assessment before 2009, previously biopsied, and those reclassified as BPE, focus, or mass were excluded (n = 181). Medical records were reviewed for demographics and outcomes. RESULTS: Two hundred five women were included (mean age, 48.8 years; range, 21-84 years). Seventy-seven of 386 findings (20.0%) were reclassified as BPE, and patients with BPE were younger than those with NME (mean age, 43.9 years; range, 31-62 years) (p = 0.003). Pathology results for 144 of 205 (70.2%) patients included 52 malignant, 11 high risk, and 81 benign lesions. The highest PPVs for distribution patterns were 34.5% (10/29) for segmental and 100.0% (3/3) for diffuse distribution. The highest PPVs for internal enhancement patterns were 36.7% (11/30) for clustered ring enhancement and 27.5% (11/40) for clumped enhancement. No difference for NME malignancy rate was noted according to BPE (10/52 [19.2%] marked or moderate; 42/153 [27.5%] mild or minimal, p = 0.24). Thirty-two percent (17/52) of malignant NMEs had high T2 signal. CONCLUSION: Careful assessment of findings as BPE versus NME can improve PPVs, particularly in younger women. Although clustered ring enhancement had one of the study's highest PPVs, this number falls below previously published rates. Reliance on T2 signal as a benign feature may be misleading, because one-third of malignancies had T2 signal. PMID- 28834448 TI - Discrimination Between Calcium Hydroxyapatite and Calcium Oxalate Using Multienergy Spectral Photon-Counting CT. AB - OBJECTIVE: We aimed to determine whether multienergy spectral photon-counting CT could distinguish between clinically relevant calcium crystals at clinical x-ray energy ranges. Energy thresholds of 15, 22, 29, and 36 keV and tube voltages of 50, 80, and 110 kVp were selected. Images were analyzed to assess differences in linear attenuation coefficients between various concentrations of calcium hydroxyapatite (54.3, 211.7, 808.5, and 1169.3 mg/cm3) and calcium oxalate (2000 mg/cm3). CONCLUSION: The two lower concentrations of hydroxyapatite were distinguishable from oxalate at all energy thresholds and tube voltages, whereas discrimination at higher concentrations depended primarily on the energy thresholds used. Multienergy spectral photon-counting CT shows promise for distinguishing these calcium crystals. PMID- 28834449 TI - Hook of the Hamate: The Spectrum of Often Missed Pathologic Findings. AB - OBJECTIVE: The purposes of this article are to review hook of the hamate anatomy, describe the imaging features of the spectrum of pathologic conditions, and discuss the pearls and pitfalls of imaging for clinical decision making for pathologic entities affecting the hook of the hamate. CONCLUSION: Knowledge of the anatomy, imaging appearance, and clinical management of hook of the hamate abnormalities is important for radiologists in guiding the care of patients with ulnar-sided wrist symptoms. PMID- 28834450 TI - Frequency of Angiomyolipomas Among Echogenic Nonshadowing Renal Masses (> 4 mm) Found at Ultrasound and the Utility of MRI for Diagnosis. AB - OBJECTIVE: The purpose of this study is to evaluate what percentage of echogenic nonshadowing renal lesions larger than 4 mm found at ultrasound are angiomyolipomas (AMLs) and to review how to diagnose AMLs, with particular emphasis on the increasing role played by MRI. MATERIALS AND METHODS: The study data were obtained at a single institution over a period of 45 months. Although some patients were being reviewed for specific symptoms, such as hematuria, pain, or recurrent urinary tract infections, most of the findings were incidental. Follow-up data on 158 lesions in 132 patients were available. Confirmation of diagnosis was made with follow-up imaging or with histopathologic examination. RESULTS: Ninety-eight (62.0%) of the lesions were AMLs, eight (5.1%) were renal cell carcinomas, three (1.9%) were oncocytomas, 17 (10.8%) were artifacts, seven (4.4%) were fat, five (3.2%) were calculi, another eight (5.1%) were scars, and 12 (7.6%) were complicated cysts. The mean age of patients with AML was significantly lower than that of patients without AML (61.71 [SD, 13.25] years vs 68.80 [SD, 17.85] years; p = 0.005). There was a female association with AMLs (p < 0.001). CONCLUSION: Echogenic nonshadowing renal lesions larger than 4 mm seen at ultrasound should not be assumed to represent an AML without follow-up because a percentage of renal cell carcinomas will be missed. Although certain ultrasound features can be useful in differentiating an AML from a renal cell carcinoma and CT is frequently diagnostic, an understanding of MRI is important because it can potentially detect lipid-poor AMLs. PMID- 28834451 TI - CT Findings of Traumatic Bucket-Handle Mesenteric Injuries. AB - OBJECTIVE: The purpose of this study is to describe a specific type of blunt traumatic mesenteric injury called a bucket-handle tear, review its varied CT appearances, and discuss the role of CT in its detection. CONCLUSION: A bucket handle mesenteric injury is a rare but life-threatening blunt traumatic injury that can be difficult to detect prospectively on CT and for which delays in diagnosis and definitive surgical management can result in poor outcomes. PMID- 28834452 TI - Reminiscing on Remnants: Imaging of Meckel Diverticulum and Its Complications in Adults. AB - OBJECTIVE: Meckel diverticulum may become symptomatic if it is complicated by hemorrhage, intestinal obstruction, diverticulitis, or tumor. Although classically described in children, it is often missed in adults because of lack of suspicion and difficulty in detection. The purpose of this article is to review the imaging findings and management of Meckel diverticulum and its complications. CONCLUSION: Although it is infrequently encountered incidentally, Meckel diverticulum should be considered especially when interpreting examinations for abdominal pain, small-bowel obstruction, and gastrointestinal bleeding. PMID- 28834454 TI - Differences in Body Fatness, Fat Patterning and Cardio-Respiratory Fitness Between Groups of Australian Children Formed on the Basis of Physical Activity and Television Viewing Guidelines. AB - BACKGROUND: Evidence suggests that a substantial proportion of children meet guidelines for sufficient physical activity, but also exceed TV guidelines. Health-related consequences of this combination are unknown. METHODS: 843 children, (age 10-11 y), were surveyed for health-related fitness [endurance performance (20 m MST), skinfolds, waist girth], daily TV and moderate-to vigorous physical activity (MVPA). Children were grouped using daily TV (<= 120 min) and MVPA (>= 60 min) guidelines: hiTV-hiMVPA/"technoactives"'; hiTV loMVPA/"screenies"; and loTV-hiMVPA/"sporties." Groups were compared on health related fitness measures. RESULTS: There was a trend (P = 0.07) towards higher girls' skinfolds among "screenies" than "sporties." Boys' waist girths were higher among "technoactives" than "sporties" (P = 0.008). Male "technoactives" outperformed "screenies" on the 20 m MST (P = 0.03). Female "sporties" (P = 0.004) and "technoactives" (P = 0.0002) outperformed "screenies" on the 20 m MST. CONCLUSIONS: "Technoactives" were no different than "sporties" on endurance fitness but exhibited less favorable fat distribution among boys. Overall, "screenies" exhibited the least favorable health profiles. PMID- 28834455 TI - Socio-Demographic Variations in Walking for Transport and for Recreation or Exercise Among Adult Australians. AB - BACKGROUND: Walking is integral to strategies to promote physical activity. We identified socio-demographic variations in walking for transport, and for recreation or exercise. METHODS: Representative population data (n = 3392) from Australia were collected using computer assisted telephone interviewing, to examine adults' participation in moderate- or brisk-paced walking for transport and walking for recreation or exercise; walking "sufficient" to meet the current public health guideline (>= 150 min/wk); and, the contributions of total walking to meeting the guideline for total physical activity. RESULTS: Rates of sufficient walking for transport (10% for men, 9% for women) were lower than those for walking for recreation or exercise (14% for both genders). Few socio demographic differences emerged. Men over age 60 y were significantly less likely (OR = 0.40) to walk for transport; men age 45 to 59 y were more likely (OR = 1.56) to walk for recreation or exercise. Walking contributed more toward meeting the current public health guideline among women (15% to 21%) than among men (6% to 8%). CONCLUSIONS: There is potential for socially equitable increases in participation, through a focus on both walking for transport and on walking for recreation or exercise; attention to gender differences would be helpful. PMID- 28834456 TI - Relationships Between GIS Environmental Features and Adolescent Male Physical Activity: GIS Coding Differences. AB - BACKGROUND: It is not clear if relationships between GIS obtained environmental features and physical activity differ according to the method used to code GIS data. METHODS: Physical activity levels of 210 Boy Scouts were measured by accelerometer. Numbers of parks, trails, gymnasia, bus stops, grocery stores, and restaurants within the commonly used 400 m and 1-mile (1609.3 m) buffers of subject residences and distance to the nearest feature were calculated. Residential density, connectivity, and crime rate were calculated. Regression models with minutes of sedentary, light, or moderate-to-vigorous activity as dependent variables and environmental and demographics as independent variables were run with backward deletion of environmental variables. RESULTS: Park, crime, and gym variables were associated with physical activity, but relationships varied according to whether a 400 m, 1 mile, or nearest criteria was used. CONCLUSION: Environmental variables were associated with the physical activity of adolescent males, but the association was method dependent. PMID- 28834457 TI - Measuring Children's Activity Levels: The Association Between Step-Counts and Activity Time. AB - BACKGROUND: The primary purpose of this study was to describe the association between activity time and step counts in children. METHODS: Subjects were 590 students (334 girls, 256 boys) with each gender having a mean age of 9.2 +/- 1.8 y. All subjects wore the Walk4Life 2505 pedometer for four consecutive weekdays. This pedometer simultaneously measures both step counts and activity time. RESULTS: Boys accumulated significantly more minutes of activity time/day (140.9 +/- 39.6 vs. 126.3 +/- 38.1), steps/day (13,348 +/- 4131 vs. 11,702 +/- 3923), and steps per min (93.99 +/- 5.8 vs. 91.85 +/- 5.8) than girls (P < 0.001) Steps/day was a significant predictor of activity time/day (P < 0.0001). CONCLUSIONS: Boys accumulate more steps per day and more activity time per day than girls. There is a strong association between steps per day and activity time in children. Daily steps per minute as a measure of free living physical activity in children is explored. PMID- 28834458 TI - Perceptions of Neighborhood Sidewalks on Walking and Physical Activity Patterns in a Southeastern Community in the US. AB - BACKGROUND: The purpose of this study was to examine the relationships between perceptions of neighborhood sidewalks and race, and walking and physical activity (PA) patterns in a southeastern US community. METHODS: A telephone survey was administered to a stratified sample of adults (N = 1148). Physical activity was categorized according to the CDC/ACSM recommendations. Respondents were also asked if they walked for at least 10 min at a time for recreation, exercise, transportation, or while at work. RESULTS: A greater proportion (44%) of respondents who reported having neighborhood sidewalks were irregular walkers (OR = 1.88; 95% CI = 1.13, 3.11). For whites, (but not for non-whites) the perceived presence of sidewalks increased the odds for meeting recommended PA levels (P < 0.05; OR = 3.59, 95% CI = 1.05, 12.24). CONCLUSIONS: Presence of neighborhood sidewalks was related to irregular walking levels of respondents. Sidewalk presence was related to PA in whites, but was not related to activity patterns of non-whites. PMID- 28834453 TI - Intravesical rAd-IFNalpha/Syn3 for Patients With High-Grade, Bacillus Calmette Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. AB - Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNalpha/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd IFNalpha/Syn3 (randomly assigned 1:1 to 1 * 1011 viral particles (vp)/mL or 3 * 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNalpha/Syn3 (1 * 1011 vp/mL, n = 21; 3 * 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNalpha/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNalpha/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy. PMID- 28834459 TI - An Exploratory Analysis of Adherence Patterns and Program Completion of a Pedometer-Based Physical Activity Intervention. AB - BACKGROUND: We examined participant characteristics related to pedometer program adherence and completion. METHODS: Participants (n = 177, age = 43 +/- 9 y, BMI = 29.5 +/- 6.2 kg/m2) were from sedentary workplaces. Baseline steps/day for women (n = 153) was 7230 +/- 3447 versus men (n = 24) 8265 +/- 2849 (P < 0.05). Records included pedometer use, days/week goals were achieved, and steps/day. Program completers (n = 104) fulfilled pre- and post-program assessments and at least 8 wk of recording. Non-completers (n = 53) met neither requirement, but pre-program data were available. RESULTS: There were no significant differences in sex, age, education, or time at work between completion strata. The only significant baseline difference was an initial "worry about completing the program" (completer < non-completer; P < 0.05). The pedometer-based program was most successful in increasing physical activity in overweight or class I obese individuals. Participants with lower baseline steps/day were also more likely to complete the program. CONCLUSION: The study findings have potential to inform effective health promotion planning. PMID- 28834461 TI - Sports and Character Development. PMID- 28834460 TI - Physical Activity, Media Time, and Body Composition in Young Children. AB - BACKGROUND: It is uncertain as to whether physical activity (PA) may influence the body composition of young children. PURPOSE: To determine the association between PA, media time, and body composition in children age 4 to 7 y. METHODS: 100 children (52 girls, 48 boys) were assessed for body-mass index (BMI), body fat, fat mass (FM), and fat-free mass using dual energy x-ray absorbtiometryptiometry (DXA). PA was monitored using accelerometers and media time was reported by parental proxy. RESULTS: In general, correlations were low to moderate at best (r < 0.51), but in the expected direction. Total media time and TV were significantly associated with BMI (r = 0.51, P < 0.05) and FM (r = 0.29 to 0.30, P < 0.05) in girls. In boys, computer usage was significantly associated with FM in boys (r = 0.31, P < 0.05). CONCLUSION: The relatively low correlations suggest that other factors may influence the complex, multi factorial body composition phenotype of young children. PMID- 28834462 TI - Neighborhood and Individual Socio-Economic Variations in the Contribution of Occupational Physical Activity to Total Physical Activity. AB - BACKGROUND: There is an inverse relationship between individual socio-economic status (SES) and amount of occupational physical activity. The role of the socio economic environment is, however, less clear. This study examined the independent influences of neighborhood and individual SES on absolute and relative amount of occupational physical activity. It also examined the moderating effects of neighborhood SES on the relationship between individual SES and occupational physical activity. METHODS: Employees (n = 1236) resident in high or low SES neighborhoods were assessed on socio-demographic factors, including educational attainment and household income, and physical activity. RESULTS: Neighborhood SES and individual SES were independently inversely related to absolute and relative amount of occupational physical activity. Significant interactions between neighborhood SES and level of educational attainment in the contribution of total and vigorous occupational physical activity to total physical activity were found. CONCLUSIONS: Neighborhood SES can function as a moderator in the relationship between individual SES and occupational physical activity. PMID- 28834463 TI - Erratum. AB - In the article "The Effectiveness of Urban Design and Land Use and Transport Policies and Practices to Increase Physical Activity: A Systematic Review" which appeared in Vol. 3, Supplement 1, of the Journal, Figure 4 was omitted from page S63. PMID- 28834464 TI - The Economic Cost of Physical Inactivity and Excess Weight in American Adults. AB - BACKGROUND: Physical inactivity and excess weight in American adults have reached epidemic levels. This article describes how cost data from previously conducted analyses in several states were used to quantify the costs of physical inactivity and excess weight among American adults. METHODS: Medical and workers' compensation cost data on selected medical conditions were obtained from various health plans and state agencies in seven states. Productivity loss norms were obtained from published studies. RESULTS: The estimated financial burden which includes direct medical care, workers' compensation, and productivity loss costs among the seven states is $93.32 billion for physical inactivity and $94.33 billion for excess weight. The estimated nationwide cost of these risk factors is approximately $507 billion with projected costs exceeding $708 billion in 2008. Projected cost-savings of $31 billion per year could be realized with a 5% drop in these risk factors. CONCLUSION: The cost of physical inactivity and excess weight among American adults is significant. More research on best-of-class interventions to curtail the high prevalence of these risk factors is needed. PMID- 28834465 TI - Relationships Between Engaging in Recommended Levels of Physical Activity and Health-Related Quality of Life Among Hypertensive Adults. AB - BACKGROUND: Hypertension (HTN), which affects more than 65 million Americans, is associated with poor health-related quality of life (HRQOL). Regular physical activity (PA) has been shown to reduce blood pressure and is associated with higher levels of HRQOL. METHODS: Using self-reports from 60,321 hypertensive adults age 18 y or older who participated in the 2003 Behavioral Risk Factor Surveillance Survey, we examined the independent relationship between engaging in recommended levels of moderate or vigorous PA and four measures of HRQOL developed by the Centers for Disease Control and Prevention. RESULTS: For all age and racial/ethnic groups and both sexes, the proportion of hypertensive adults with 14 or more unhealthy days (physical or mental) in the past month was significantly lower among those who attained recommended levels of PA than among physically inactive adults. CONCLUSIONS: Participation in regular PA is one of several lifestyle strategies available to control and prevent HTN. These results suggest that PA is associated with higher levels of HRQOL among adults with HTN and highlight the importance of health programs that promote participation in regular PA. PMID- 28834466 TI - [What Are the Individual, Family, and Social Characteristics Differentiating Prepubertal from Pubertal Anorexia Nervosa?] PMID- 28834467 TI - Use of Liver Imaging and Biopsy in Clinical Practice. PMID- 28834468 TI - Rheumatic Heart Disease - An Iceberg in Tropical Waters. PMID- 28834470 TI - Man versus Nature - Also Sprach Zarathustra and an End-of-Life House Call. PMID- 28834469 TI - Cost-Effectiveness of Intensive versus Standard Blood-Pressure Control. AB - BACKGROUND: In the Systolic Blood Pressure Intervention Trial (SPRINT), adults at high risk for cardiovascular disease who received intensive systolic blood pressure control (target, <120 mm Hg) had significantly lower rates of death and cardiovascular disease events than did those who received standard control (target, <140 mm Hg). On the basis of these data, we wanted to determine the lifetime health benefits and health care costs associated with intensive control versus standard control. METHODS: We used a microsimulation model to apply SPRINT treatment effects and health care costs from national sources to a hypothetical cohort of SPRINT-eligible adults. The model projected lifetime costs of treatment and monitoring in patients with hypertension, cardiovascular disease events and subsequent treatment costs, treatment-related risks of serious adverse events and subsequent costs, and quality-adjusted life-years (QALYs) for intensive control versus standard control of systolic blood pressure. RESULTS: We determined that the mean number of QALYs would be 0.27 higher among patients who received intensive control than among those who received standard control and would cost approximately $47,000 more per QALY gained if there were a reduction in adherence and treatment effects after 5 years; the cost would be approximately $28,000 more per QALY gained if the treatment effects persisted for the remaining lifetime of the patient. Most simulation results indicated that intensive treatment would be cost-effective (51 to 79% below the willingness-to-pay threshold of $50,000 per QALY and 76 to 93% below the threshold of $100,000 per QALY), regardless of whether treatment effects were reduced after 5 years or persisted for the remaining lifetime. CONCLUSIONS: In this simulation study, intensive systolic blood-pressure control prevented cardiovascular disease events and prolonged life and did so at levels below common willingness-to-pay thresholds per QALY, regardless of whether benefits were reduced after 5 years or persisted for the patient's remaining lifetime. (Funded by the National Heart, Lung, and Blood Institute and others; SPRINT ClinicalTrials.gov number, NCT01206062 .). PMID- 28834471 TI - Evolocumab in Patients with Cardiovascular Disease. PMID- 28834472 TI - Evolocumab in Patients with Cardiovascular Disease. PMID- 28834473 TI - Evolocumab in Patients with Cardiovascular Disease. PMID- 28834474 TI - Adjuvant Capecitabine for Breast Cancer. PMID- 28834475 TI - Adjuvant Capecitabine for Breast Cancer. PMID- 28834476 TI - Trial of Minocycline in Clinically Isolated Syndrome of Multiple Sclerosis. PMID- 28834477 TI - Trial of Minocycline in Clinically Isolated Syndrome of Multiple Sclerosis. PMID- 28834478 TI - Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. PMID- 28834479 TI - Stretching the Scope - Becoming Frontline Addiction-Medicine Providers. PMID- 28834480 TI - Case 26-2017. PMID- 28834481 TI - Sweet's Syndrome in a Patient with Rheumatoid Arthritis. PMID- 28834482 TI - Adalimumab for Uveitis in Juvenile Idiopathic Arthritis. PMID- 28834484 TI - More on Co-Occurrence of COMT and BRCA1/2 Variants in a Population. PMID- 28834485 TI - More on Co-Occurrence of COMT and BRCA1/2 Variants in a Population. PMID- 28834486 TI - Anti-CD19 CAR T Cells in CNS Diffuse Large-B-Cell Lymphoma. PMID- 28834489 TI - Venous Congestion in Ischemic Bowel. PMID- 28834490 TI - Physical Activity and Public Health: The Emergence of a Subdiscipline-Report from the International Congress on Physical Activity and Public Health April 17-21, 2006, Atlanta, Georgia, USA. PMID- 28834488 TI - Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015. AB - BACKGROUND: Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low-income and middle-income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study. METHODS: We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod-MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty. RESULTS: We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age-standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age-standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub-Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability-adjusted life-years due to rheumatic heart disease globally. CONCLUSIONS: We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25-year period. The health related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.). PMID- 28834492 TI - JPAH at Three Years. PMID- 28834491 TI - Reliability of the 7-Day Physical Activity Recall in a Biracial Group of Inactive and Active Adults. AB - BACKGROUND: Physical activity recall (PAR) reliability was estimated in a three site sample of African American and white adults. The sample was sedentary at baseline and more varied in physical activity 24 months later. Intraclass correlation coefficients (ICCs) were used to estimate the number of PAR assessments necessary to obtain a reliability of 0.70 at both timepoints. METHODS: The PAR was administered <= 30 d apart at baseline (n = 547) and 24 months (n = 648). Energy expenditure ICC was calculated by race, gender, and age. RESULTS: Baseline reliability was low for all groups with 4-16 PARs estimated to attain reliable data. ICCs at 24 months were similar (ICC = 0.54-0.55) for race and age group, with 2-3 PARs estimated to reach acceptable reliability. At 24 months, women were more reliable reporters than men. CONCLUSION: Low sample variability in activity reduced reliability, highlighting the importance of evaluating diverse groups. Despite evaluating a sample with greater physical activity variability, an estimated 2-3 PARs were necessary to obtain acceptable reliability. PMID- 28834493 TI - Prevalence of Physical Activity and Sedentary Behaviors in US High School Students by Metropolitan Status and Geographic Region. AB - BACKGROUND: Geographic differences in the prevalence of physical activity (PA) have been found among adults in the US; similar studies have not been conducted among adolescents. METHODS: Using nationally representative cross-sectional data from the CDC's 2003 Youth Risk Behavior Survey, we estimated the prevalence of PA and sedentary behaviors by metropolitan status and geographic region. RESULTS: The prevalence of PA was lowest and prevalence of sedentary behavior highest for urban students. Students from the South reported the lowest prevalence of PA and the highest prevalence of TV watching, while students from the West generally reported the highest PA prevalence and lowest sedentary behavior prevalence. Prevalence differences ranged from < 1.0% to > 15%, with most differences falling between 5% and 10%. CONCLUSIONS: Findings mirror regional variations previously observed in adult PA. We need to understand factors that contribute to lower PA in youth living in the South and in urban settings. PMID- 28834494 TI - Physical Inactivity and Life Expectancy in Canada. AB - BACKGROUND: Although the prevalence of physical inactivity is high in Canada, few studies have assessed its public health impact. METHODS: A cause-deleted methodology was employed to estimate the effects of physical inactivity on life expectancy. Life expectancy in 2002 was estimated from an abridged life table analysis, which was repeated after removing deaths from physical inactivity. Deaths from physical inactivity were estimated from published population attributable fractions for coronary artery disease, stroke, hypertension, colon cancer, breast cancer, and type 2 diabetes. RESULTS: Life expectancy was 79.7 y in the total population, 77.2 y in males, and 82.1 y in females. Compared to overall life expectancy, physical inactivity cause-deleted values were 0.86 y lower in the total population, 0.65 y lower in males, and 1.0 y lower in females. CONCLUSIONS: Life expectancy could be increased by over 10 months if Canadians could be encouraged to be physically active. PMID- 28834496 TI - Small Business Policies Toward Employee and Community Promotion of Physical Activity. AB - BACKGROUND: Basic information is needed to develop strategies for promoting physical activity (PA) in small business. This preliminary study described small business policies encouraging PA. METHODS: Interviews were completed at 98 small businesses (5-100 employees) in 2003. Business policies encouraging PA participation by employees and the public were assessed. Stage of Change was used to describe intentions to develop such policies. RESULTS: A total of 53 PA policies (12 employee; 41 public) existed. The most common employee policy was incentives for gym memberships (41.7%). The most popular public policy was sport team sponsorships (60.1%). Most businesses (60.2%) were not thinking about creating a policy for PA while 33.7% had a policy in place (20.4% > 6 months). CONCLUSION: Small businesses have few PA policies and most are not thinking about such policies. Research should determine why this is the case and what approaches could stimulate the development of PA policies. PMID- 28834495 TI - Reliability and Validity of a Brief Tool to Measure Children's Physical Activity. AB - BACKGROUND: We assessed the validity and reliability of a modified Godin-Leisure Time Exercise Questionnaire in youth in grades 6 through 8. METHODS: The questionnaire was completed by 250 children twice at a 1 wk interval to assess reliability. After the second questionnaire administration the children wore an accelerometer for 7 d (criterion measure). RESULTS: Pearson correlations between the first and second reports of frequency of participation in strenuous and moderate physical activity were 0.68 and 0.51, respectively. Self-reported participation in strenuous activity was weakly correlated with strenuous activity as measured by accelerometer (r = 0.23, P = 0.01). A weak non-significant correlation was found between reported versus measured engagement in moderate activity (r = 0.13, P = 0.07). CONCLUSION: Findings suggest the questionnaire evaluated in this study may be of very limited use for assessing children's physical activity. PMID- 28834497 TI - Cross-Sectional Relationship Between Physical Activity and Falls in Older Adults, United States 2003. AB - BACKGROUND: Falls are a major health problem for older adults. The purpose of this study is to examine the cross-sectional association between non-occupational physical activity and falls and fall-related injuries in US adults age 65 y or older. METHODS: Respondents age 65 y or older were selected from the 2003 Behavioral Risk Factor Surveillance System (n = 47,619). RESULTS: The age adjusted incidence of falls was significantly higher among inactive respondents (16.3%, 95% CI: 15.2-17.6) than insufficiently active (12.3%, 95% CI: 11.4-13.2) or active (12.6%, 95% CI: 11.6-13.7) respondents. After controlling for sex, age, education, and body-mass index, active and insufficiently active respondents were significantly less likely to have fallen and were significantly less likely to have had a fall-related injury than their inactive peers. CONCLUSION: These results show that active and insufficiently active older adults experience a lower incidence of falls than their inactive peers. PMID- 28834498 TI - The Role of Schools in Preventing Childhood Obesity. PMID- 28834500 TI - Erratum. AB - In the article "An Exploratory Analysis of Adherence Patterns and Program Completion of a Pedometer-Based Physical Activity Intervention" which appeared in Vol. 3, No. 2 of the Journal, Figure 4 on page 217 was printed with an incorrect caption; Figure 4 with the correct caption appears below. PMID- 28834499 TI - Physical Activity, Overweight, and Perceptions of Neighborhood Environments Among Portuguese Girls. AB - BACKGROUND: The purpose of this study was 1) to compare physical activity levels according to body-mass index; 2) to determine which, if any, neighborhood perceived attributes were related to overweight. METHODS: The sample comprised 610 girls age 14.7 +/- 1.6 y. Girls were grouped into normal weight and overweight. Environmental variables and physical activity were assessed by questionnaire. RESULTS: No significant differences were found in physical activity levels between normal weight and overweight girls. Logistic regression analysis revealed that girls who agreed that "there is so much traffic on the streets that it makes it unpleasant to walk in the neighborhood" were more likely to be overweight (OR = 1.78; 95% CI 1.10 to 2.89). CONCLUSION: The study found no relationship between perceptions of the environment and overweight among Portuguese girls, except for perceptions of security for walking in the neighborhood. PMID- 28834501 TI - The Effect of Season on Physical Activity Among Older Adults in King County, Washington. AB - BACKGROUND: Effective promotion of physical activity among older adults, and the evaluation of those efforts, requires a better understanding of the impact of seasonal patterns on physical activity. METHODS: This article used data from the Behavioral Risk Factor Surveillance Survey, a population-based telephone survey, to examine the association between levels of physical activity among older adults and season of the year, temperature, and rainfall. RESULTS: A statistically significant seasonal pattern was identified for general physical activity; for example, recommended physical activity was 62% higher in relative terms in June than in December (63% active versus 39%). However, no significant association was found between season and walking, and rainfall and temperature did not appear to influence the level of activity over and above the effect of season. CONCLUSIONS: Evaluations of walking programs for seniors may not need to make adjustments for seasonality when measuring impact using pre/post surveys. PMID- 28834502 TI - Feasibility of a Campus-Based "Buddy System" to Promote Physical Activity: Canadian Students' Perspectives. AB - OBJECTIVE: To explore the characteristics of a university-wide buddy system that students would be receptive to using. METHODS: This study targeted a heterogeneous sample of undergraduate university students age 18 to 25 y. An experienced moderator, using a semi-structured interview guide, conducted 13 focus groups (n = 65). Focus group discussions were audio recorded and transcribed verbatim. Inductive content analysis was conducted independently by two researchers. Measures were incorporated throughout to ensure data trustworthiness. RESULTS: The value of this campus-based physical activity intervention was emphasized by the vast majority of participants. Five main themes exemplified students' preferences: sign-up methods; matching criteria; social components; policies and procedures; and contact methods. CONCLUSION: Students confirmed that a campus-based program tailored to their needs and preferences will be more effective than those to which they currently have access. Given the small number of physically active Canadian university students, a campus-based program that is appealing is important for the health of this population. PMID- 28834504 TI - Are People Physically Inactive Because of Their Genes? PMID- 28834503 TI - But What About Swimming and Cycling? How to "Count" Non-Ambulatory Activity When Using Pedometers to Assess Physical Activity. AB - BACKGROUND: The aims of this study were to describe the amount of non-ambulatory physical activity (PA) undertaken by a sample of Australian workers, and to evaluate different methods of accounting for non-ambulatory activities when using pedometers to measure physical activity. METHODS: Adults age 18 to 64 y (N = 204) wore a pedometer and recorded steps and non-step activity in a logbook for 7 d. Non-ambulatory activity was recorded by 28% of the participants (N = 52) with cycling and swimming the most frequently reported. RESULTS: The mean time reported for non-ambulatory activities was 82.8 (standard deviation 80.0) min/wk. On average, participants recorded 8873 (standard deviation 2757) steps/d. Time in non-ambulatory activities was converted to steps equivalents using three different conversion methods. Use of the three methods added 333 to 721 steps/d in the whole sample, but 1153 to 2566 steps/d for those who reported non ambulatory activity. CONCLUSIONS: Suggestions are provided for accounting for non ambulatory activities in interventions which rely on step count measures. PMID- 28834505 TI - Reliability and Accuracy of the AMP 331 for Activity Monitoring and Energy Expenditure Prediction in Young Adults. AB - BACKGROUND: A new triaxial accelerometer (AMP 331) provides a novel approach to understanding free-living activity through its ability to measure real time speed, cadence, and step length. This study examined the reliability and accuracy of the AMP 331, along with construction of prediction equations for oxygen consumption and energy cost. METHODS: Young adult volunteers (n = 41) wearing two AMP units walked and ran on a treadmill with energy cost data simultaneously collected through indirect calorimetry. RESULTS: Statistically significant differences exist in inter-AMP unit reliability for speed and step length and in accuracy between the AMP units and criterion measures for speed, oxygen consumption, and energy cost. However, the differences in accuracy for speed were very small during walking (<= 0.16 km/h) and not clinically relevant. Prediction equations constructed for walking oxygen uptake and energy expenditure demonstrated R2 between 0.76 to 0.90 and between subject deviations were 1.53 mL O2 . kg-1 . min-1 and 0.43 kcal/min. CONCLUSIONS: In young adults, the AMP 331 is acceptable for monitoring walking speeds and the output can be used in predicting energy cost during walking but not running. PMID- 28834506 TI - Correlates of Pedometer-Assessed Physical Activity in Cypriot Elementary School Children. AB - BACKGROUND: The purpose of this study was to examine the association between pedometer-assessed physical activity and a number of individual, social, and environmental correlates among Cypriot elementary school children. METHODS: School children in grades 5 and 6 (N = 104) and their parents (N = 70) wore pedometers for five consecutive weekdays and completed questionnaires assessing potential correlates of steps/d. RESULTS: A hierarchical regression analysis indicated that gender, weekly frequency of sports club attendance, and hours playing outside accounted for 32% of the variance in steps/d. In addition, children with a body-mass index (BMI) above the 85th percentile (based on age and gender) scored significantly lower steps/d than children with a BMI below the 85th percentile. CONCLUSIONS: This study suggested that correlates of steps/d in children are similar to the findings of other studies using different measures of physical activity behavior. PMID- 28834507 TI - Muscle Strength and Postural Stability in Healthy, Older Women: Implications for Fall Prevention. AB - BACKGROUND: Effect of muscle strength and balance on falls has not been well researched in healthy older women. The purpose of this study was to compare lower extremity strength and balance in older healthy women during each decade of life and to investigate which factors are different in women with a history of falling. METHODS: We retrospectively studied 240 women age 50-89 y. Measures of muscle strength, postural stability, and incidence of falls over the past year were obtained from client charts at Texas Woman's University's Health Promotion & Research Center from 1996 to 2002. RESULTS: Strength declined significantly with age in all muscle groups except knee extensors. Age, hip flexor and abductor strength, and postural stability were significantly different in women who had fallen. CONCLUSIONS: Strength decline was not consistent across muscle groups. Women who were older, had less hip flexor or abductor strength, or less balance were more likely to have fallen. PMID- 28834508 TI - System for Observing Play and Recreation in Communities (SOPARC): Reliability and Feasibility Measures. AB - BACKGROUND: New tools are needed to examine physical activity and the contexts in which it occurs. Community parks contribute to physical activity, but measuring activity and associated variables in them is challenging because area contexts change and the numbers and characteristics of users are highly variable. METHODS: We developed SOPARC (System for Observing Play and Recreation in Communities) and tested its use by observing 16,244 individuals in 165 park areas. Reliabilities included 472 simultaneous measures by independent observers. RESULTS: Correlations between observers on number of area participants was 0.99 for female and male park users. Reliabilities (i.e., percent agreement) for age (89%, females; 85%, males), race/ethnic (80%, females; 82%, males), and activity level (80%, females; 88%, males) groupings met acceptable criteria. Reliabilities for area contexts (i.e., usable, accessible, supervised, organized, equipped) exceeded 94%. CONCLUSIONS: SOPARC is a reliable and feasible instrument for assessing physical activity and associated contextual data in community settings. PMID- 28834509 TI - Proximity to School and Physical Activity Among Middle School Girls: The Trial of Activity for Adolescent Girls Study. AB - BACKGROUND: Proximity to routine destinations is an important correlate of physical activity. We examined the association between distance from school and physical activity in adolescent girls. METHODS: We mapped the addresses of 1554 sixth-grade girls who participated in the Trial of Activity for Adolescent Girls (TAAG) Study and calculated the shortest distance from home to school along the street network. Using a hierarchical design we examined the association between MET-weighted moderate to vigorous physical activity (MW- MVPA) and distance to school, while controlling for potential confounders. RESULTS: Distance to school was inversely associated with weekday MW- MVPA for middle school girls. For every mile the girls lived from their schools, they engaged in an average of 13 fewer MET-weighted minutes per week. CONCLUSIONS: Distance to school is inversely associated with MW-MVPA. The most adversely affected girls lived more than 5 miles from school. Time spent commuting could explain reduced time for physical activity. PMID- 28834510 TI - Community Design and Access to Recreational Facilities as Correlates of Adolescent Physical Activity and Body-Mass Index. AB - BACKGROUND: Neighborhood-level environmental features have been associated with adult physical activity and weight status, but this link has not been established for adolescents. METHODS: Community design and access to recreational facilities variables were derived using geographic information systems (GIS) for 799 adolescents (age 11 to 15 y, mean = 12.8 y, 53% girls, 43% ethnic minority). Environment variables were calculated for a 1-mile buffer around each participant's residence. Accelerometers measured min/d of physical activity. RESULTS: Number of nearby recreation facilities and number of nearby parks correlated positively with girls' physical activity, and intersection density inversely related to girls' physical activity. Retail floor area ratio correlated positively with boys' physical activity. No community design or access to recreation variables were related to BMI-percentile. CONCLUSIONS: There was limited evidence that both community design and access to recreation facilities variables were associated with adolescent physical activity, but additional built environment variables need to be studied that have particular relevance for youth. PMID- 28834511 TI - A Framework for Physical Activity Policy Research. AB - BACKGROUND: Although policy approaches are traditionally an important element of public health efforts to address major health problems, public health policy around physical activity remains poorly defined and developed. METHODS: After extensive literature searches and reviews of policy frameworks developed for other public health issues such as tobacco control and injury prevention, the Centers for Disease Control and Prevention hosted a series of workshops and discussions on physical activity policy. RESULTS: A simple model describing relationships among policy, the environment, behavior, and health was developed, a framework for organizing and conceptualizing policy interventions was described, and priorities for public health efforts to promote physical activity were proposed. CONCLUSIONS: An expanded focus on physical activity policy interventions is warranted, and such efforts can complement physical activity promotion efforts at other levels. The addition of researchers with expertise in the policy sciences will enhance the work of existing multidisciplinary teams. PMID- 28834512 TI - Environmental Justice: Obesity, Physical Activity, and Healthy Eating. AB - BACKGROUND: The term "environmental justice" refers to efforts to address the disproportionate exposure to and burden of harmful environmental conditions experienced by low-income and racial/ethnic minority populations. METHODS: Based on computer and manual searches, this paper presents a review of articles in the published literature that discuss disparities in physical activity, dietary habits, and obesity among different populations. RESULTS: This paper provides evidence that economically disadvantaged and racial/ethnic minority populations have substantial environmental challenges to overcome to become physically active, to acquire healthy dietary habits, and to maintain a healthy weight. For example, residents living in poorer areas have more environmental barriers to overcome to be physically active. CONCLUSIONS: We propose a research agenda to specifically address environmental justice with regard to improving physical activity, dietary habits, and weight patterns. PMID- 28834483 TI - Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes. AB - BACKGROUND: The previously published results of the Systolic Blood Pressure Intervention Trial showed that among participants with hypertension and an increased cardiovascular risk, but without diabetes, the rates of cardiovascular events were lower among those who were assigned to a target systolic blood pressure of less than 120 mm Hg (intensive treatment) than among those who were assigned to a target of less than 140 mm Hg (standard treatment). Whether such intensive treatment affected patient-reported outcomes was uncertain; those results from the trial are reported here. METHODS: We randomly assigned 9361 participants with hypertension to a systolic blood-pressure target of less than 120 mm Hg or a target of less than 140 mm Hg. Patient-reported outcome measures included the scores on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Veterans RAND 12-Item Health Survey, the Patient Health Questionnaire 9-item depression scale (PHQ-9), patient-reported satisfaction with their blood-pressure care and blood-pressure medications, and adherence to blood pressure medications. We compared the scores in the intensive-treatment group with those in the standard-treatment group among all participants and among participants stratified according to physical and cognitive function. RESULTS: Participants who received intensive treatment received an average of one additional antihypertensive medication, and the systolic blood pressure was 14.8 mm Hg (95% confidence interval, 14.3 to 15.4) lower in the group that received intensive treatment than in the group that received standard treatment. Mean PCS, MCS, and PHQ-9 scores were relatively stable over a median of 3 years of follow up, with no significant differences between the two treatment groups. No significant differences between the treatment groups were noted when participants were stratified according to baseline measures of physical or cognitive function. Satisfaction with blood-pressure care was high in both treatment groups, and we found no significant difference in adherence to blood-pressure medications. CONCLUSIONS: Patient-reported outcomes among participants who received intensive treatment, which targeted a systolic blood pressure of less than 120 mm Hg, were similar to those among participants who received standard treatment, including among participants with decreased physical or cognitive function. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062 .). PMID- 28834513 TI - Making Physical Activity Research Relevant to Policy Makers. PMID- 28834514 TI - Identifying and Measuring Urban Design Qualities Related to Walkability. AB - BACKGROUND: In active living research, measures used to characterize the built environment have been mostly gross qualities such as neighborhood density and park access. This project has developed operational definitions and measurement protocols for subtler urban design qualities believed to be related to walkability. METHODS: Methods included: 1) recruiting an expert panel; 2) shooting video clips of streetscapes; 3) rating urban design qualities of streetscapes by the expert panel; 4) measuring physical features of streetscapes from the video clips; 5) testing inter-rater reliability of physical measurements and urban design quality ratings; 6) statistically analyzing relationships between physical features and urban design quality ratings, 7) selecting of qualities for operationalization, and 8) developing of operational definitions and measurement protocols for urban design qualities based on statistical relationships. RESULTS: Operational definitions and measurement protocols were developed for five of nine urban design qualities: imageability, visual enclosure, human scale, transparency, and complexity. CONCLUSIONS: A field survey instrument has been developed, tested in the field, and further refined for use in active living research. PMID- 28834515 TI - Development of a Direct Observation Instrument to Measure Environmental Characteristics of Parks for Physical Activity. AB - BACKGROUND: The study's purpose is to describe the development and evaluate the reliability (inter-observer agreement) and validity (rater agreement with a gold standard) of a direct observation instrument to assess park characteristics that may be related to physical activity. METHODS: A direct observation instrument of 181 items was developed based on a conceptual model consisting of the following domains: features, condition, access, esthetics, and safety. Fifteen pairs of observers were trained and sent to two parks simultaneously to assess two Target Areas each. RESULTS: Overall domain reliability was 86.9%, and overall geographic area reliability was 87.5%. Overall domain validity was 78.7% and overall geographic area validity was 81.5%. CONCLUSIONS: Inter-rater reliability and validity were generally good, although validity was slightly lower than reliability. Objective items showed the highest reliability and validity. Items that are time-sensitive may need to be measured on multiple occasions, while items asking for subjective responses may require more supervised practice. PMID- 28834517 TI - Active Living Research in Light of the TRB/IOM Report. PMID- 28834516 TI - Neighborhood Correlates of Urban Trail Use. AB - PURPOSE: To model urban trail traffic as a function of neighborhood characteristics and other factors including weather and day of week. METHODS: We used infrared monitors to measure traffic at 30 locations on five trails for periods ranging from 12 months to more than 4 y. We measured neighborhood characteristics using geographic information systems, satellite imagery, and US Census and other secondary data. We used multiple regression techniques to model daily traffic. RESULTS: The statistical model explains approximately 80% of the variation in trail traffic. Trail traffic correlates positively and significantly with income, neighborhood population density, education, percent of neighborhood in commercial use, vegetative health, area of land in parking, and mean length of street segments in access networks. Trail traffic correlates negatively and significantly with the percentage of neighborhood residents in age groups greater than 64 and less than 5. CONCLUSIONS: Trail traffic is significantly correlated with neighborhood characteristics. Health officials can use these findings to influence the design and location of trails and to maximize opportunities for increases in physical activity. PMID- 28834518 TI - Development and Reliability and Validity Testing of an Audit Tool for Trail/Path Characteristics: The Path Environment Audit Tool (PEAT). AB - BACKGROUND: To determine how trail characteristics may influence use, reliable and valid audit tools are needed. METHODS: The Path Environment Audit Tool (PEAT) was developed with design, amenity, and aesthetics/maintenance items. Two observers independently audited 185 trail segments at 6 Massachusetts facilities. GPS-derived items were used as a "gold standard." Kappa (k) statistics, observed agreement and intraclass correlation coefficients (ICCs) were calculated to assess inter-observer reliability and validity. RESULTS: Fifteen of 16 primary amenity items had k-values >= 0.49 ("moderate") and all had observed agreement >= 81%. Seven binary design items had k-values ranging from 0.19 to 0.71 and three of 5 ordinal items had ICCs >= 0.52. Only two aesthetics/maintenance items (n = 7) had moderate ICCs. Observed agreement between PEAT and GPS items was >= 0.77; k-values were >= 0.57 for 7 out of 10 comparisons. CONCLUSIONS: PEAT has acceptable reliability for most of its primary items and appears ready for use by researchers and practitioners. PMID- 28834519 TI - Physical Activity and Changes in Health Care Costs in Late Middle Age. AB - BACKGROUND: Physical activity has clear health benefits but there remains uncertainty about how it affects health care costs. OBJECTIVE: To examine how physical activity is associated with changes in health expenditure for a national sample age 54 to 69 y, and estimate how this association varies across people with different chronic diseases and health behaviors. METHODS: Data were from the Health and Retirement Study, a national longitudinal survey of late middle age Americans. RESULTS: Correcting for baseline differences in active and inactive groups, physical activity was associated with reduced health care costs of about 7% over 2 y (or $483 annually). CONCLUSIONS: Regular physical activity in late middle age may lower health expenditure over time, and the effect is likely to be more pronounced for the obese, smokers, and individuals with some baseline health problems. While substantially large for the health care system, our estimates are much smaller than health-unadjusted comparisons or cross-sectional effects. PMID- 28834520 TI - Measuring Physical Environments of Parks and Playgrounds: EAPRS Instrument Development and Inter-Rater Reliability. AB - BACKGROUND: Reliable and comprehensive measurement of physical activity settings is needed to examine environment-behavior relations. METHODS: Surveyed park professionals (n = 34) and users (n = 29) identified park and playground elements (e.g., trail) and qualities (e.g., condition). Responses guided observational instrument development for environmental assessment of public recreation spaces (EAPRS). Item inter-rater reliability was evaluated following observations in 92 parks and playgrounds. Instrument revision and further reliability testing were conducted with observations in 21 parks and 20 playgrounds. RESULTS: EAPRS evaluates trail/path, specific use (e.g., picnic), water-related, amenity (e.g., benches), and play elements, and their qualities. Most EAPRS items had good excellent reliability, particularly presence/number items. Reliability improved from the original (n = 1088 items) to revised (n = 646 items) instrument for condition, coverage/shade, and openness/visibility items. Reliability was especially good for play features, but cleanliness items were generally unreliable. CONCLUSIONS: The EAPRS instrument provides comprehensive assessment of parks' and playgrounds' physical environment, with generally high reliability. PMID- 28834521 TI - Standards for Environmental Measurement Using GIS: Toward a Protocol for Protocols. AB - BACKGROUND: Interdisciplinary research regarding how the built environment influences physical activity has recently increased. Many research projects conducted jointly by public health and environmental design professionals are using geographic information systems (GIS) to objectively measure the built environment. Numerous methodological issues remain, however, and environmental measurements have not been well documented with accepted, common definitions of valid, reliable variables. METHODS: This paper proposes how to create and document standardized definitions for measures of environmental variables using GIS with the ultimate goal of developing reliable, valid measures. Inherent problems with software and data that hamper environmental measurement can be offset by protocols combining clear conceptual bases with detailed measurement instructions. RESULTS: Examples demonstrate how protocols can more clearly translate concepts into specific measurement. CONCLUSIONS: This paper provides a model for developing protocols to allow high quality comparative research on relationships between the environment and physical activity and other outcomes of public health interest. PMID- 28834522 TI - The Second Active Living Research Conference: Signs of Maturity. PMID- 28834523 TI - Operational Definitions of Walkable Neighborhood: Theoretical and Empirical Insights. AB - BACKGROUND: The concept of walkable neighborhoods is increasingly important in physical activity research and intervention. However, limited theoretical understanding and measurable definitions remain a challenge. METHODS: This paper reviews theories defining neighborhoods and offers an empirical approach to identify measurable attributes and thresholds of walkable neighborhoods. Bivariate and multivariate analyses are used for self-reported socio-demographic background, neighborhood walking behavior and perception, and objective measures of environments. RESULTS: Environmental attributes positively associated with walking sufficiently to meet health recommendations included higher residential density and smaller street-blocks around home, and shorter distances to food and daily retail facilities from home. Threshold distances for eating/drinking establishments and grocery stores were 860 and 1445 feet. CONCLUSIONS: Results questioned theoretical constructs of neighborhoods centered on recreation and educational uses. They pointed to finer mixes of uses than those characterizing suburban neighborhoods, and small spatial units of analysis and intervention to capture and promote neighborhood walkability. PMID- 28834524 TI - Correlates of Walking for Transportation or Recreation Purposes. AB - BACKGROUND: Walking is a popular recreational activity and a feasible travel mode. Associations exist between walking and the built environment, but knowledge is lacking about specific environmental conditions associated with different purposes of walking. METHODS: This cross-sectional study used a survey of 438 adults and objective environmental measures. Multinomial logit models estimated the odds of walking for recreation or transportation purposes. RESULTS: Utilitarian destinations were positively associated with transportation walking, but recreational destinations were not associated with any walking. Residential density was correlated with both purposes of walking, and sidewalks with recreation walking only. Hills were positively associated with recreation walking and negatively with transportation walking. CONCLUSIONS: Physical environment contributed significantly to explain the probability of walking. However, different attributes of environment were related to transportation versus recreation walking, suggesting the need for multiple and targeted interventions to effectively support walking. PMID- 28834525 TI - The Effectiveness of Urban Design and Land Use and Transport Policies and Practices to Increase Physical Activity: A Systematic Review. AB - BACKGROUND: Although a number of environmental and policy interventions to promote physical activity are being widely used, there is sparse systematic information on the most effective approaches to guide population-wide interventions. METHODS: We reviewed studies that addressed the following environmental and policy strategies to promote physical activity: community-scale urban design and land use policies and practices to increase physical activity; street-scale urban design and land use policies to increase physical activity; and transportation and travel policies and practices. These systematic reviews were based on the methods of the independent Task Force on Community Preventive Services. Exposure variables were classified according to the types of infrastructures/policies present in each study. Measures of physical activity behavior were used to assess effectiveness. RESULTS: Two interventions were effective in promoting physical activity (community-scale and street-scale urban design and land use policies and practices). Additional information about applicability, other effects, and barriers to implementation are provided for these interventions. Evidence is insufficient to assess transportation policy and practices to promote physical activity. CONCLUSIONS: Because community- and street-scale urban design and land-use policies and practices met the Community Guide criteria for being effective physical activity interventions, implementing these policies and practices at the community-level should be a priority of public health practitioners and community decision makers. PMID- 28834526 TI - Psychiatric genetics - Does diagnosis matter? PMID- 28834529 TI - SSCF/CCNP 2017 graduate studentship for biomedical research in schizophrenia and psychosis. PMID- 28834527 TI - The neurobiology of transition to psychosis: clearing the cache. AB - The prepsychotic phase of schizophrenia is not only important for indicated prevention strategies, but also crucial for developing mechanistic models of the emergence of frank psychosis (transition). This commentary highlights the work of Dukart and colleagues, published in this issue of the Journal of Psychiatry and Neurosicence, who sought to identify MRI-based anatomic endophenotypes of psychosis in a well-characterized sample of patients with at-risk mental state (ARMS) and first-episode psychosis (FEP). Conceptual and translational challenges in clarifying the neurobiology of transitional prepsychotic states are discussed. A role of intracortical myelin in the neurobiology of transition is proposed. Transition may not be an outcome of "progressive structural deficits"; it may occur due to inadequate compensatory responses in the predisposed. The need to revise our current "deficit-oriented" models of neurobiology of psychosis in the wake of burgeoning evidence indicating a dynamic process of cortical reorganization is emphasized. PMID- 28834528 TI - Advances in understanding and treating mental illness: proceedings of the 40th Canadian College of Neuropsychopharmacology Annual Meeting Symposia. PMID- 28834530 TI - Treating delayed sleep-wake phase disorder in young adults. PMID- 28834532 TI - Clinical Evidence of OsseoSpeed EV Implants: A Retrospective Study and Characterization of the Newly Introduced System. AB - This retrospective study sought to compare a new implant (Astra Tech OsseoSpeed EV) with its predecessor (Astra Tech OsseoSpeed TX) by scanning electron microscopy and interferometry. Radiographic data from 19 patients who underwent implant restoration with EV (n = 49) with a median follow-up of 16 months were evaluated for mean bone level (MBL) changes from delivery of the definitive prosthesis. EV and TX did not differ in surface roughness, and both systems had a tight seal at the implant-abutment interface. The median MBL change of the EV was -0.02 mm mesiodistally after a median follow-up period of 16 months. Greater maintenance of MBL was found in the screw-retained restorations (n = 17) compared to cemented (0.35 +/- 0.33 mm and -0.38 +/- 0.76 mm, respectively; P = .03). The data suggest that EV shows minimal levels of bone loss and high implant survival. PMID- 28834531 TI - Maxillary Sinus Elevation Surgery with ChronOS and Autogenous Bone Graft: Immunohistochemical Assessment of RUNX2, VEGF, TRAP, and Osteocalcin. AB - The purpose of this study was to evaluate a composite graft of ChronOS, a beta tricalcium phosphate (beta-TCP), mixed 1:1 with an autogenous bone graft in human maxillary sinus augmentation. A total of 12 maxillary sinuses were grafted with an autogenous bone graft (control group), and 9 maxillary sinuses were grafted with ChronOS mixed 1:1 with an autogenous bone graft (test group). After 6 months, biopsy samples were obtained concurrent to the placement of dental implants and were subjected to histomorphometric and immunohistochemical analyses for Runt-related transcription factor 2 (RUNX2), vascular endothelial growth factor (VEGF), tartrate-resistant acid phosphatase, and osteocalcin. Histologic analysis of samples obtained from the test group revealed the presence of immature bone, while samples from the control group indicated lamellar bone formation. However, both types of bone grafts were well vascularized. The new bone formation averaged 25.4% +/- 6.4% in the test group and 38.6% +/- 10.5% in the control group (P = .001). Immunostaining of samples in the test group showed high cellular turnover. The outcomes of this study demonstrate a delay in bone formation but intense cellular differentiation after 6 months of bone graft healing in the test group. The amount of immature bone and the immunostaining for RUNX2 and VEGF provide evidence of an osteogenic pathway that can improve the bone formation rate. PMID- 28834533 TI - Detecting and Learning New Words: The Impact of Advancing Age and Hearing Loss. AB - Purpose: Lexical acquisition was examined in children and adults to determine if the skills needed to detect and learn new words are retained in the adult years. In addition to advancing age, the effects of hearing loss were also examined. Method: Measures of word recognition, detection of nonsense words within sentences, and novel word learning were obtained in quiet for 20 children with normal hearing and 21 with hearing loss (8-12 years) as well as for 15 adults with normal hearing and 17 with hearing loss (58-79 years). Listeners with hearing loss were tested with and without high-frequency acoustic energy to identify the type of amplification (narrowband, wideband, or frequency lowering) that yielded optimal performance. Results: No differences were observed between the adults and children with normal hearing except for the adults' better nonsense word detection. The poorest performance was observed for the listeners with hearing loss in the unaided condition. Performance improved significantly with amplification to levels at or near that of their counterparts with normal hearing. With amplification, the adults performed as well as the children on all tasks except for word recognition. Conclusions: Adults retain the skills necessary for lexical acquisition regardless of hearing status. However, uncorrected hearing loss nearly eliminates these skills. PMID- 28834534 TI - Efficacy of Electropalatography for Treating Misarticulation of /r/. AB - Purpose: The purpose of the present study was to document the efficacy of electropalatography (EPG) for the treatment of rhotic errors in school-age children. Despite a growing body of literature using EPG for the treatment of speech sound errors, there is little systematic evidence about the relative efficacy of EPG for rhotic errors. Method: Participants were 5 English-speaking children aged 6;10 to 9;10, who produced /r/ at the word level with < 30% accuracy but otherwise showed typical speech, language, and hearing abilities. Therapy was delivered in twice-weekly 30-min sessions for 8 weeks. Results: Four out of 5 participants were successful in achieving perceptually and acoustically accurate /r/ productions during within-treatment trials. Two participants demonstrated generalization of /r/ productions to nontreated targets, per blinded listener ratings. Conclusions: The present findings support the hypothesis that EPG can improve production accuracy in some children with rhotic errors. However, the utility of EPG is likely to remain variable across individuals. For rhotics, EPG training emphasizes one possible tongue configuration consistent with accurate rhotic production (lateral tongue contact). Although some speakers respond well to this cue, the narrow focus may limit lingual exploration of other acceptable tongue shapes known to facilitate rhotic productions. PMID- 28834535 TI - Esrrb, an estrogen-related receptor involved in early development, pluripotency, and reprogramming. AB - Estrogen-related receptor b (Esrrb) is part of a family of three orphan nuclear receptors with broad expression profiles and a generic function in regulating energy metabolism in mammals. However, Esrrb performs specific functions during early mouse development, in pluripotent and multipotent populations of the embryo as well as in primordial germ cells. Moreover, Esrrb also impinges upon the control of self-renewal in embryo-derived stem cells and enhances reprogramming. Here, we review the function of Esrrb with special emphasis on its role in pluripotency. Esrrb activity at crucial regulatory elements of the pluripotency network, coupled with its role as a mitotic bookmarking factor and the ability to reset cellular metabolism, might explain its potent functions in ensuring the stability of pluripotency and driving the late stages of reprogramming. Hence, we argue that Esrrb represents a key addition to the pantheon of transcription factors sustaining pluripotent stem cell identity in mice. Understanding the mechanisms governing the interplay between different estrogen-related receptors (ERRs) and their specificity of action may clarify the role these factors play during preimplantation development and in pluripotent cells in both mouse and humans. PMID- 28834536 TI - Spatial capture-mark-resight estimation of animal population density. AB - Sightings of previously marked animals can extend a capture-recapture dataset without the added cost of capturing new animals for marking. Combined marking and resighting methods are therefore an attractive option in animal population studies, and there exist various likelihood-based non-spatial models, and some spatial versions fitted by Markov chain Monte Carlo sampling. As implemented to date, the focus has been on modeling sightings only, which requires that the spatial distribution of pre-marked animals is known. We develop a suite of likelihood-based spatial mark-resight models that either include the marking phase ("capture-mark-resight" models) or require a known distribution of marked animals (narrow-sense "mark-resight"). The new models sacrifice some information in the covariance structure of the counts of unmarked animals; estimation is by maximizing a pseudolikelihood with a simulation-based adjustment for overdispersion in the sightings of unmarked animals. Simulations suggest that the resulting estimates of population density have low bias and adequate confidence interval coverage under typical sampling conditions. Further work is needed to specify the conditions under which ignoring covariance results in unacceptable loss of precision, or to modify the pseudolikelihood to include that information. The methods are applied to a study of ship rats Rattus rattus using live traps and video cameras in a New Zealand forest, and to previously published data. PMID- 28834538 TI - Claudin7b is required for the formation and function of inner ear in zebrafish. AB - Zebrafish has become an excellent model for studying the development and function of inner ear. We report here a zebrafish line in which claudin 7b (cldn7b) locus is interrupted by a Tol2 transposon at its first intron. The homozygous mutants have enlarged otocysts, smaller or no otoliths, slowly formed semicircular canals, and insensitiveness to sound stimulation. These abnormal phenotypes and hearing loss of inner ear could be mostly rescued by injection of cldn7b-mRNA into one-cell stage homozygous mutant embryos. Mechanistically, cldn7b-deficiency interrupted the formation of apical junction complexes (AJCs) in otic epithelial cells of inner ear and the ion-homeostasis of endolymph, which then led to the loss of proper contact between otoliths and normally developed hair cells in utricle and saccule or aberrant mechanosensory transduction. Thus, Cldn7b is essential for the formation and proper function of inner ear through its unique role in keeping an initial integrity of otic epithelia during zebrafish embryogenesis. PMID- 28834537 TI - An assessment of hair cortisol among postpartum Brazilian mothers and infants from a high-risk community in Sao Paulo: Intra-individual stability and association in mother-infant dyads. AB - This study examined maternal-infant synchrony of hair cortisol at 12 months after birth and the intra-individual stability of maternal hair cortisol in the postpartum period. Participants were selected from an ongoing Sao Paulo birth cohort project, where families are considered to be "high-risk" due to their chronic stress experiences, with the majority living in slums (favelas). Cortisol was collected through 3-cm segments of hair samples, with values representing approximate levels of cortisol from 9 to 12 months for mothers and children and 6 to 12 months for mothers. Maternal and infant cortisol values reflecting chronic stress 9-12 months after birth were highly correlated (r = .61, p < .001); earlier maternal cortisol levels (6-9 months) and child cortisol levels at 9-12 months (r = .51, p < .001) were also correlated. Maternal cortisol values showed stability over time (r = .79, p < .001). These maternal-infant correlations are high compared to the existing literature on hair cortisol in other mother-child dyads, suggesting stronger synchrony under high-risk contexts where families are faced with challenging circumstances. PMID- 28834539 TI - Butyrate stimulates the growth of human intestinal smooth muscle cells by activation of yes-associated protein. AB - Intestinal smooth muscle cells play a critical role in the remodeling of intestinal structure and functional adaptation after bowel resection. Recent studies have shown that supplementation of butyrate (Bu) contributes to the compensatory expansion of a muscular layer of the residual intestine in a rodent model of short-bowel syndrome (SBS). However, the underlying mechanism remains elusive. In this study, we found that the growth of human intestinal smooth muscle cells (HISMCs) was significantly stimulated by Bu via activation of Yes Associated Protein (YAP). Incubation with 0.5 mM Bu induced a distinct proliferative effect on HISMCs, as indicated by the promotion of cell cycle progression and increased DNA replication. Notably, YAP silencing by RNA interference or its specific inhibitor significantly abolished the proliferative effect of Bu on HISMCs. Furthermore, Bu induced YAP expression and enhanced the translocation of YAP from the cytoplasm to the nucleus, which led to changes in the expression of mitogenesis genes, including TEAD1, TEAD4, CTGF, and Cyr61. These results provide evidence that Bu stimulates the growth of human intestinal muscle cells by activation of YAP, which may be a potential treatment for improving intestinal adaptation. PMID- 28834540 TI - CCL18-dependent translocation of AMAP1 is critical for epithelial to mesenchymal transition in breast cancer. AB - AMAP1 was a GTPase-activating protein that regulates cytoskeletal structures in focal adhesions, circular dorsal ruffles, and promote cell differentiation in tumor cells. But the activation and function of AMAP1 in breast cancer remain largely unexplored. Here we show that AMAP1 was phosphorylated and translocated to plasma membrane and formed a stable complex with Pyk2 in response to CCL18. Moreover, CCL18-dependent AMAP1 translocation interfered the AMAP1-IKK-beta interaction, resulting in nuclear factor-kappaB (NF-kappaB) activation. Depletion of AMAP1 expression by RNAi efficiently reversed the CCL18-induced epithelial to mesenchymal transition (EMT) of breast cancer cells and as well as CCL18-induced adhesion, migration and invasion. Strikingly, AMAP1 overexpression was found in breast cancers that had undergone metastasis and was strongly predictive of poor prognosis in breast cancers. Given that AMAP1 mediated CCL18-induce activation of NF-kappaB and promoted breast cancer metastasis, AMAP1 may represent a therapeutic target for the eradication of breast cancer metastasis. PMID- 28834541 TI - Sudden Unexpected Deaths Due to Intracranial Meningioma: Presentation of Six Fatal Cases, Review of the Literature, and A Discussion of the Mechanisms of Death. AB - Deaths due to meningiomas are routinely diagnosed in clinical practice because this neoplasm tends to present with the typical progression of neurological deficits. On the other hand, sudden unexpected deaths due to meningiomas are rarely described in the literature. The study presents six fatal cases of previously undiagnosed intracranial meningiomas from the Cook County Medical Examiner's Office from 1998 to 2014. The most common explanation of the mechanism of sudden death due to intracranial neoplasms is a rapid increase in intracranial pressure produced by the mass effect of the neoplasm. Other mechanisms of death include acute intracranial and intratumoral hemorrhage, and benign neoplasms that grow in the vicinity of vital centers altering neural discharge in autonomic pathways leading to cardiac suppression or lethal arrhythmia. Forensic pathologists must keep in mind that sudden unexpected death caused by intracranial meningiomas, although extremely rare, may be encountered in the forensic setting. PMID- 28834542 TI - The Accuracy and Applicability of 3D Modeling and Printing Blunt Force Cranial Injuries. AB - The purpose of this study was to determine the factors affecting the accuracy of 3D models and 3D prints of cranial blunt force trauma, to evaluate the applicability and limitations of modeling such injuries. Three types of cranial blunt force lesions were documented (hinge, depressed, and comminuted) using three forms of surface scanning (laser, structured light scanner, and photogrammetry) at two different quality settings (standard and high). 3D printed models of the lesions were produced using two different materials (a gypsum-like composite powder called VisiJet(r) PXL and an acrylic engineered composite plastic called VisiJet(r) M3 in crystal colour). The results of these analyzes indicate the prints in this study exhibit some statistically significant differences from the actual bone lesions, but details of the lesions can be reproduced to within 2 mm accuracy. PMID- 28834543 TI - Adipokines are dysregulated in patients with hidradenitis suppurativa. PMID- 28834544 TI - Causal Learning Across Culture and Socioeconomic Status. AB - Extensive research has explored the ability of young children to learn about the causal structure of the world from patterns of evidence. These studies, however, have been conducted with middle-class samples from North America and Europe. In the present study, low-income Peruvian 4- and 5-year-olds and adults, low-income U.S. 4- and 5-year-olds in Head Start programs, and middle-class children from the United States participated in a causal learning task (N = 435). Consistent with previous studies, children learned both specific causal relations and more abstract causal principles across culture and socioeconomic status (SES). The Peruvian children and adults generally performed like middle-class U.S. children and adults, but the low-SES U.S. children showed some differences. PMID- 28834545 TI - Sex Estimation from Human Cranium: Forensic and Anthropological Interest of Maxillary Sinus Volumes. AB - Sex estimation is a key objective of forensic science. We aimed to establish whether maxillary sinus volumes (MSV) could assist in estimating an individual's sex. One hundred and three CT scans were included. MSV were determined using three-dimensional reconstructions. Two observers performed three-dimensional MSV reconstructions using the same methods. Intra- and interobserver reproducibility were statistically compared using the intraclass correlation coefficient (ICC) (alpha = 5%). Both intra- and interobserver reproducibility were perfect regarding MSV; both ICCs were 100%. There were no significant differences between right and left MSV (p = 0.083). No correlation was found between age and MSV (p > 0.05). We demonstrated the existence of sexual dimorphism in MSV (p < 0.001) and showed that MSV measurements gave a 68% rate of correct allocations to sex group. MSV measurements could be useful to support sex estimation in forensic medicine. PMID- 28834546 TI - Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment. AB - Mirogabalin (DS-5565) is a novel preferentially selective alpha2 delta-1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open-label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]) were enrolled and completed the study. The AUClast increased with severity of renal impairment; the geometric least-squares mean ratios of AUClast compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUClast increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment-related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD. PMID- 28834547 TI - High-Resolution Melting (HRM) of Hypervariable Mitochondrial DNA Regions for Forensic Science. AB - Forensic strategies commonly are proceeding by analysis of short tandem repeats (STRs); however, new additional strategies have been proposed for forensic science. Thus, this article standardized the high-resolution melting (HRM) of DNA for forensic analyzes. For HRM, mitochondrial DNA (mtDNA) from eight individuals were extracted from mucosa swabs by DNAzol reagent, samples were amplified by PCR and submitted to HRM analysis to identify differences in hypervariable (HV) regions I and II. To confirm HRM, all PCR products were DNA sequencing. The data suggest that is possible discriminate DNA from different samples by HRM curves. Also, uncommon dual-dissociation was identified in a single PCR product, increasing HRM analyzes by evaluation of melting peaks. Thus, HRM is accurate and useful to screening small differences in HVI and HVII regions from mtDNA and increase the efficiency of laboratory routines based on forensic genetics. PMID- 28834548 TI - A comparison of food crispness based on the cloud model. AB - : The cloud model is a typical model which transforms the qualitative concept into the quantitative description. The cloud model has been used less extensively in texture studies before. The purpose of this study was to apply the cloud model in food crispness comparison. The acoustic signals of carrots, white radishes, potatoes, Fuji apples, and crystal pears were recorded during compression. And three time-domain signal characteristics were extracted, including sound intensity, maximum short-time frame energy, and waveform index. The three signal characteristics and the cloud model were used to compare the crispness of the samples mentioned above. The crispness based on the Ex value of the cloud model, in a descending order, was carrot > potato > white radish > Fuji apple > crystal pear. To verify the results of the acoustic signals, mechanical measurement and sensory evaluation were conducted. The results of the two verification experiments confirmed the feasibility of the cloud model. The microstructures of the five samples were also analyzed. The microstructure parameters were negatively related with crispness (p < .01). PRACTICAL APPLICATIONS: The cloud model method can be used for crispness comparison of different kinds of foods. The method is more accurate than the traditional methods such as mechanical measurement and sensory evaluation. The cloud model method can also be applied to other texture studies extensively. PMID- 28834549 TI - Climate signals in tree-ring delta18 O and delta13 C from southeastern Tibet: insights from observations and forward modelling of intra- to interdecadal variability. AB - Stable isotopes in tree rings are increasingly used as proxies for climatic and ecophysiological changes. However, uncertainties remain about the strength and consistency of their response to environmental variation at different temporal (i.e. seasonal to inter-decadal) scales. We developed 5 yr of intra-seasonal and 62 yr of early- and late-wood delta13 C and delta18 O series of Smith fir (Abies georgei var. smithii) on the southeastern Tibetan Plateau, and used a process based forward model to examine the relative importance of environmental and physiological controls on the isotopic data. In this temperate high-altitude region, the response, both delta18 O and delta13 C, is primarily to variations in relative humidity, but by different processes. In delta18 O, the response is via source water delta18 O but also arises from leaf water 18 O enrichment. In delta13 C, the response is via changes in stomatal conductance but is modified by carry-over effects from prior periods. We conclude that tree-ring delta18 O may be a more robust climate proxy than delta13 C, and delta13 C may be more suited to studies of site-related physiological responses to the local environment. PMID- 28834550 TI - Osteocalcin-dependent regulation of glucose metabolism and fertility: Skeletal implications for the development of insulin resistance. AB - The skeleton has recently emerged as a critical insulin target tissue that regulates whole body glucose metabolism and male reproductive function. While our understanding of these new regulatory axes remains in its infancy, the bone specific protein, osteocalcin, has been shown to be centrally involved. Undercarboxylated osteocalcin acts as a secretagogue in a feed-forward loop to stimulate pancreatic beta-cell proliferation and insulin secretion, improve insulin sensitivity, and promote testosterone production. Importantly, dysregulation of insulin signaling in bone causes a reduction in serum osteocalcin levels that is associated with elevated blood glucose and reduced serum insulin levels, suggesting that the skeleton may play a significant role in the development of diet-induced insulin resistance. Insulin signaling is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) which becomes hyper-activated in response to nutrient overload. Loss- and gain-of function models suggest that mTORC1 function in bone is essential for normal skeletal development; however, the role of this complex in the regulation of glucose metabolism remains to be determined. This review highlights our current understanding of the role played by osteocalcin in the skeletal regulation of glucose metabolism and fertility. In particular, it examines data emerging from transgenic mouse models which have revealed a pancreas-bone-testis regulatory axis and discusses recent human studies which seek to corroborate findings from mouse models with clinical observations. Moreover, we review recent studies which suggest dysregulation of insulin signaling in bone leads to the development of insulin resistance and discuss the potential role of mTORC1 signaling in this process. PMID- 28834551 TI - Risk assessment of a new acceptance testing procedure for conventional linear accelerators. AB - PURPOSE: New techniques and materials have recently been developed to expedite the conventional linac acceptance testing procedure (Med Phys. 2017;22), which use the electronic portal imaging device (EPID) for data collection. This new procedure is designed to be more efficient and robust than the conventional approach. The purpose of this work was to perform a comparative risk assessment of the two acceptance testing procedures (ATPs). MATERIALS AND METHODS: Failure Modes and Effects Analysis was used to assess risks for both ATP approaches. Five domain experts (Medical Physicists) comprised the analysis team. The risk assessment method and ranking scales were adopted from the AAPM TG-100. The number of failure pathways and associated risk priority numbers (RPNs) for the two ATP approaches were compared. RPNs > 100 were considered high-priority failure modes. RESULTS: Fewer failure pathways were determined for the new ATP (ATPEPID ) compared to the conventional ATP (ATPconv ) resulting in a 44% difference (n = 233 vs. n = 534, respectively). There were also 35% fewer RPNs > 100 for the ATPEPID (n = 40) compared to the ATPconv (n = 114). Failure pathways and RPNs > 100 for individual ATP tests were 2.0 and 3.5 times higher, on average, for the ATPconv compared to the ATPEPID , respectively. The EPID pixel sensitivity map was identified as a high risk failure for the ATPEPID . CONCLUSIONS: Potential errors due to human factors were decreased for the ATPEPID compared to ATPconv so it is possible that a largely automated linac ATP can mitigate many error occurrences. Manufacturers should be careful when designing an EPID-based ATP to address errors in the EPID pixel sensitivity map which can potentially lead to a significant impact on patients' treatment. PMID- 28834552 TI - Magnetic resonance imaging versus computed tomography to plan hemilaminectomies in chondrodystrophic dogs with intervertebral disc extrusion. AB - OBJECTIVE: To determine the influence of preoperative computed tomography (CT) versus magnetic resonance (MR) on hemilaminectomies planned to treat thoracolumbar (TL) intervertebral disc (IVD) extrusions in chondrodystrophic dogs. STUDY DESIGN: Prospective clinical study. SAMPLE POPULATION: Forty chondrodystrophic dogs with TL IVD extrusion and preoperative CT and MR studies. METHODS: MR and CT images were randomized and reviewed by 4 observers masked to the dog's identity and corresponding imaging studies. Observers planned the location along the spine, side, and extent (number of articular facets to be removed) based on individual reviews of CT and MR studies. Intra-observer agreement was determined between overall surgical plan, location, side, and size of the hemilaminectomy planned on CT versus MR of the same dog. RESULTS: Similar surgical plans were developed based on MR versus CT in 43.5%-66.6% of dogs, depending on the observer. Intra-observer agreement in location, side, and size of the planned hemilaminectomy based on CT versus MR ranged between 48.7%-66.6%, 87%-92%, and 51.2%-71.7% of dogs, respectively. Observers tended to plan larger laminectomy defects based on MR versus CT of the same dog. CONCLUSION: Findings from this study indicated considerable differences in hemilaminectomies planned on preoperative MR versus CT imaging. Surgical location and size varied the most; the side of planned hemilaminectomies was most consistent between imaging modalities. PMID- 28834553 TI - Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome. AB - CONTEXT: Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment. OBJECTIVE: To evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS. DESIGN: This is a 24-week open-label prospective, randomized, clinical study. PATIENTS AND MEASUREMENTS: This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 MUg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks. RESULTS: After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 +/- 1.29 kg vs 2.28 +/- 0.55 kg, P < .001) and total fat% (4.67 +/- 0.09% vs 1.11 +/- 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 +/- 0.58 vs 0.59 +/- 0.12, P < .001) and increased the menstrual frequency ratio (0.62 +/- 0.12 vs 0.37 +/- 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE-treated patients was significantly higher than MET-treated patients (43.60% vs 18.70%, P < .05). CONCLUSIONS: Short-term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS. PMID- 28834554 TI - Naringenin inhibits osteoclastogenesis through modulation of helper T cells secreted IL-4. AB - Naringenin (NAR) is a natural predominant flavanone and has a wide range of pharmacological activities. The aim of this study was to investigate the protective mechanisms of NAR on RANKL-induced osteoclastogenesis and osteoclast bone resorption. T cells were divided into four groups under different concentrations of NAR (0, 25, 50, 100 uM). CD4+ T cell subsets in different groups were evaluated by flow cytometry. TRAP staining, pit formation assays and F-actin ring immunofluorescent staining were performed. In addition, gene expression of osteoclast-specific markers was analyzed by qPCR and Western blot. Our results showed that compared with the control group, there were relatively fewer Th1 and Th17 cells and more Th2 cells and Treg cells in the NAR groups. Besides, the number of TRAP-positive multinucleated osteoclasts, the areas of bone resorption pits and the size and number of F-actin rings were notably decreased in the bone marrow macrophages (BMMs) treated with T-cell supernatant containing NAR. Moreover, NAR treatment dramatically reduced the expressions of cathepsin K, c-Fos, DC-STAMP, NFATc1, TRAP, and V-ATPase d2 at mRNA and protein levels. However, these effects were abolished by adding a neutralizing antibody against IL-4. In conclusion, NAR suppressed RANKL-induced osteoclastogenesis and osteoclast bone resorption by promoting the release of IL-4 from T cells. PMID- 28834555 TI - A method to detect landmark pairs accurately between intra-patient volumetric medical images. AB - PURPOSES: An image processing procedure was developed in this study to detect large quantity of landmark pairs accurately in pairs of volumetric medical images. The detected landmark pairs can be used to evaluate of deformable image registration (DIR) methods quantitatively. METHODS: Landmark detection and pair matching were implemented in a Gaussian pyramid multi-resolution scheme. A 3D scale-invariant feature transform (SIFT) feature detection method and a 3D Harris Laplacian corner detection method were employed to detect feature points, i.e., landmarks. A novel feature matching algorithm, Multi-Resolution Inverse Consistent Guided Matching or MRICGM, was developed to allow accurate feature pairs matching. MRICGM performs feature matching using guidance by the feature pairs detected at the lower resolution stage and the higher confidence feature pairs already detected at the same resolution stage, while enforces inverse consistency. RESULTS: The proposed feature detection and feature pair matching algorithms were optimized to process 3D CT and MRI images. They were successfully applied between the inter-phase abdomen 4DCT images of three patients, between the original and the re-scanned radiation therapy simulation CT images of two head-neck patients, and between inter-fractional treatment MRIs of two patients. The proposed procedure was able to successfully detect and match over 6300 feature pairs on average. The automatically detected landmark pairs were manually verified and the mismatched pairs were rejected. The automatic feature matching accuracy before manual error rejection was 99.4%. Performance of MRICGM was also evaluated using seven digital phantom datasets with known ground truth of tissue deformation. On average, 11855 feature pairs were detected per digital phantom dataset with TRE = 0.77 +/- 0.72 mm. CONCLUSION: A procedure was developed in this study to detect large number of landmark pairs accurately between two volumetric medical images. It allows a semi-automatic way to generate the ground truth landmark datasets that allow quantitatively evaluation of DIR algorithms for radiation therapy applications. PMID- 28834556 TI - Deterministic direct aperture optimization using multiphase piecewise constant segmentation. AB - PURPOSE: Direct aperture optimization (DAO) attempts to incorporate machine constraints in the inverse optimization to eliminate the post-processing steps in fluence map optimization (FMO) that degrade plan quality. Current commercial DAO methods utilize a stochastic or greedy approach to search a small aperture solution space. In this study, we propose a novel deterministic direct aperture optimization that integrates the segmentation of fluence map in the optimization problem using the multiphase piecewise constant Mumford-Shah formulation. METHODS: The Mumford-Shah based direct aperture optimization problem was formulated to include an L2-norm dose fidelity term to penalize differences between the projected dose and the prescribed dose, an anisotropic total variation term to promote piecewise continuity in the fluence maps, and the multiphase piecewise constant Mumford-Shah function to partition the fluence into pairwise discrete segments. A proximal-class, first-order primal-dual solver was implemented to solve the large scale optimization problem, and an alternating module strategy was implemented to update fluence and delivery segments. Three patients of varying complexity-one glioblastoma multiforme (GBM) patient, one lung (LNG) patient, and one bilateral head and neck (H&N) patient with 3 PTVs were selected to test the new DAO method. For each patient, 20 non-coplanar beams were first selected using column generation, followed by the Mumford-Shah based DAO (DAOMS ). For comparison, a popular and successful approach to DAO known as simulated annealing-a stochastic approach-was replicated. The simulated annealing DAO (DAOSA ) plans were then created using the same beam angles and maximum number of segments per beam. PTV coverage, PTV homogeneity D95D5, and OAR sparing were assessed for each plan. In addition, high dose spillage, defined as the 50% isodose volume divided by the tumor volume, as well as conformity, defined as the van't Riet conformation number, were evaluated. RESULTS: DAOMS achieved essentially the same OAR doses compared with the DAOSA plans for the GBM case. The average difference of OAR Dmax and Dmean between the two plans were within 0.05% of the plan prescription dose. The lung case showed slightly improved critical structure sparing using the DAOMS approach, where the average OAR Dmax and Dmean were reduced by 3.67% and 1.08%, respectively, of the prescription dose. The DAOMS plan substantially improved OAR dose sparing for the H&N patient, where the average OAR Dmax and Dmean were reduced by over 10% of the prescription dose. The DAOMS and DAOSA plans were comparable for the GBM and LNG PTV coverage, while the DAOMS plan substantially improved the H&N PTV coverage, increasing D99 by 6.98% of the prescription dose. For the GBM and LNG patients, the DAOMS and DAOSA plans had comparable high dose spillage but slightly worse conformity with the DAOMS approach. For the H&N plan, DAOMS was considerably superior in high dose spillage and conformity to the DAOSA . The deterministic approach is able to solve the DAO problem substantially faster than the simulated annealing approach, with a 9.5- to 40-fold decrease in total solve time, depending on the patient case. CONCLUSIONS: A novel deterministic direct aperture optimization formulation was developed and evaluated. It combines fluence map optimization and the multiphase piecewise constant Mumford-Shah segmentation into a unified framework, and the resulting optimization problem can be solved efficiently. Compared to the widely and commercially used simulated annealing DAO approach, it showed comparable dosimetry behavior for simple plans, and substantially improved OAR sparing, PTV coverage, PTV homogeneity, high dose spillage, and conformity for the more complex head and neck plan. PMID- 28834557 TI - Association of CYP2R1 rs10766197 with MS risk and disease progression. AB - BACKGROUND: MS is a neurodegenerative autoimmune disease resulting from a complex interaction of genetic and environmental factors. Among these, vitamin D and genetic variants associated with vitamin D-metabolism gain great attention. The aim of our study was to assess five SNPs in NADSYN1 and CYP2R1 genes in relation to serum 25-OH-vitamin D3 levels in MS patients and controls. METHODS: 25-OH vitamin D3 levels and genotyping of CYP2R1- and NADSYN1-SNPs were investigated both in MS patients and in healthy controls. RESULTS: The analysis revealed lower 25-OH-vitamin D3 concentrations in MS patients than in controls and an association of rs10766197 CYP2R1 SNP with MS risk. After stratifying MS patients according to gender, we found that the minor allele A of rs10766197 had a higher frequency in men in comparison to women affected by MS. Additionally, the presence of allele A in men was associated with disease progression, assessed by EDSS and MSSS scores. CONCLUSION: The findings of our study open new perspectives for a role of CYP2R1 in both risk and progression of MS, with sex-related differences. PMID- 28834559 TI - Improving the prehospital safety of steroid-dependent patients in northern England: A hospital-initiated ambulance service registration pathway. PMID- 28834560 TI - Immobilized enzyme reactors based on monoliths: Effect of pore size and enzyme loading on biocatalytic process. AB - Macroporous monolithic columns with different mean pore size (from 360 to 2020 nm) and appropriate flow-through properties were synthesized using free radical in situ copolymerization of glycidyl methacrylate, 2-hydroxyethyl methacrylate and ethylene dimethacrylate. In order to predict the composition of porogen mixture to generate the pores in the interested size interval, the Hildebrand theory was used. Ribonuclease A and its specific low- and macromolecular substrates cytidine-2',3'-cyclic monophosphate sodium salt and RNA were applied as model system. The effect of mean pore size of macroporous monoliths used for enzyme immobilization on molecular recognition and biocatalytic characteristics was examined. The monitoring of RNA degradation was performed using anion exchange HPLC on monolithic CIM DEAE analytical column. The high efficiency of heterogeneous biocatalysts obtained comparatively to the catalytic reaction of RNA degradation in solution was demonstrated. Additionally, the series of six monolithic immobilized enzyme reactors with different amount of biocatalyst was prepared and studied regarding to the biocatalytic properties at recirculation mode at two experimental variants, e.g. (i) fixed range of concentrations of circulated substrate solutions, and (ii) fixed range of substrate/enzyme molar ratios. PMID- 28834562 TI - Potential Drug-Drug Interactions Among Critically Ill Pediatric Patients in a Tertiary Pulmonary Center. AB - Patients in the pediatric intensive care unit (PICU) are at increased risk of potential drug-drug interactions (pDDIs) because of the complexity of pharmacotherapy. The current study aimed to assess the rate, pattern, risk factors, and management of pDDIs in the PICU of an academic pulmonary hospital. A prospective observational study was conducted for 6 months. Pharmacotherapy data of PICU-admitted patients were evaluated by a clinical pharmacologist. Interacting drugs, reliability, mechanism, potential outcome, and clinical management of pDDIs were identified using the Lexi-Interact database. Logistic regression was applied to analyze the risk factors that could be associated with the interactions. One hundred and twenty-three medication profiles were evaluated during the study period. Diseases of the respiratory system were the main diagnoses among intensive care unit (ICU)-admitted patients (56.1%). A total of 38.6% of the patients exposed to at least 1 major and/or contraindicated interaction during ICU admission. Most pDDIs occurred through metabolic (35.4%) and additive (34.8%) mechanisms. The existence of pDDIs was significantly associated with the number of prescribed medications. Exposure to pDDIs is frequent in critically ill pediatric patients and related to the number of medications. Daily and close cooperation between clinicians and clinical pharmacologists is recommended to prevent harmful outcomes of DDIs. PMID- 28834561 TI - Life-cycle studies with 2 marine species and bisphenol A: The mysid shrimp (Americamysis bahia) and sheepshead minnow (Cyprinodon variegatus). AB - Bisphenol A (BPA) is a high production volume compound primarily used to produce epoxy resins and polycarbonate plastic. Exposure to low concentrations of BPA occurs in freshwater and marine systems, primarily from wastewater treatment plant discharges. The dataset for chronic toxicity of BPA to freshwater organisms includes studies on fish, amphibians, invertebrates, algae, and aquatic plants. To broaden the dataset, a 1.5-generation test with sheepshead minnow (Cyprinodon variegatus) and a full life-cycle test with mysid shrimp (Americamysis bahia) were conducted. Testing focused on apical endpoints of survival, growth and development, and reproduction. The respective no-observed-effect concentration (NOEC) and lowest-observed-effect concentration (LOEC) values of 170 and 370 ug/L for mysid and 66 and 130 MUg/L for sheepshead were based on reduced fecundity. The hazardous concentrations for 5% of the species (HC5) values of 18 MUg/L were calculated from species sensitivity distributions (SSDs) with freshwater-only data and combined freshwater and marine data. Inclusion of marine data resulted in no apparent difference in SSD shape, R2 values for the distributions, or HC5 values. Upper-bound 95th percentile concentrations of BPA measured in marine waters of North America and Europe (0.024 and 0.15 MUg/L, respectively) are below the HC5 value of 18 MUg/L. These results suggest that marine and freshwater species are of generally similar sensitivity and that chronic studies using a diverse set of species can be combined to assess the aquatic toxicity of BPA. Environ Toxicol Chem 2018;37:398-410. (c) 2017 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28834563 TI - Determination of electroosmotic and electrophoretic mobility of DNA and dyes in low ionic strength solutions. AB - Nanocoding, a genome analysis platform, relies on very low ionic strength conditions to elongate DNA molecules up to 1.06 (fully stretched DNA = 1). Understanding how electroosmotic and electrophoretic forces vary, as ionic strength decreases, will enable better Nanocoding devices, or other genome analysis platforms, to be developed. Using gel electrophoresis to determine overall mobility (includes contributions from electrophoretic and electroosmotic forces) in different ionic strength conditions, linear DNA molecules (pUC19 (2.7 kb), pBR322 (4.4 kb), PhiX174 (5.4 kb), and PSNAPf-H2B (6.2 kb)) were analyzed in varying gel concentrations (1.50, 1.25, 1.00, 0.75, and 0.50%). Additionally, buffer concentration (Tris-EDTA, TE) was varied to determine free solution mobility at different ionic strength solutions. As ionic strength decreased from 13.8 to 7.3 mM, overall mobility increased. As TE buffer decreased (< 7.3 mM), overall mobility drastically decreased as ionic strength decreased. Rhodamine B dye was utilized to determine the electroosmotic mobility. As the ionic strength decreased, electroosmotic mobility increased. The experimental electrophoretic mobility was compared to theoretical considerations for electrophoretic mobility (Pitts and Debye-Huckel-Onsager). Electroosmotic forces decreased the overall mobility of DNA molecules and bromophenol blue migration in a gel matrix as ionic strength decreased. PMID- 28834564 TI - The predictive value of demonstrable stress incontinence during basic office evaluation and urodynamics in women without symptomatic urinary incontinence undergoing vaginal prolapse surgery. AB - AIMS: Women with pelvic organ prolapse without symptoms of urinary incontinence (UI) might demonstrate stress urinary incontinence (SUI) with or without prolapse reduction. We aimed to determine the value of demonstrable SUI during basic office evaluation or urodynamics in predicting SUI after vaginal prolapse repair in these women. METHODS: Women included in the CUPIDO trials without bothersome UI or UI more than once a week were eligible if they had undergone prolapse repair without incontinence surgery. The diagnostic and predictive value of demonstrable SUI was studied for postoperative SUI (POSUI). POSUI was defined as bothersome SUI at 1-year follow-up or treatment for SUI in the first postoperative year. RESULTS: In 45% (77/173) of the included women urodynamics was performed. In 19% (32/172) SUI was demonstrated with basic office evaluation, against 29% (22/77) with urodynamics. Nine percent (16/172) developed POSUI, six women underwent surgery for de novo SUI. Women with demonstrable SUI were more at risk to face POSUI: twenty-eight percent versus five percent (Diagnostic Odds Ratio: 7; 95%CI 3-22). Urodynamics predicted one more woman having POSUI, but all women who underwent treatment for de novo SUI showed SUI during basic office evaluation. Test performance did not improved with the adding of urodynamics. CONCLUSIONS: The predictive value of demonstrable SUI in symptomatically continent women undergoing vaginal prolapse repair is limited. Urodynamics added no value. The twenty-eight percent POSUI risk must be balanced against the increased complication risk if a prophylactic midurethral sling is considered. PMID- 28834565 TI - Utility of magnetic resonance elastography for predicting ascites in patients with chronic liver disease. AB - OBJECTIVE: This study aimed to evaluate the utility of magnetic resonance elastography (MRE) as a non-invasive method for predicting ascites in patients with chronic liver disease (CLD). METHODS: A total of 208 CLD patients underwent MRE to measure liver stiffness (LS) at our institution from March 2013 to June 2015. We evaluated the diagnostic performance of MRE for predicting the presence of ascites using receiver-operating characteristic (ROC) curve analysis and compared the performance with that of serum fibrosis markers. Multivariate logistic regression analysis was performed to identify factors associated with the presence of ascites. The cumulative incidence of ascites was examined in patients without ascites at baseline. The pathological stage of liver fibrosis was evaluated in 81 CLD patients using histopathologic diagnosis. RESULTS: Of the 208 patients, 41 had ascites. The optimal cut-off LS value for the presence of ascites was 6.0 kPa (area under the ROC curve = 0.87). The area under the ROC curve for the presence of ascites was significantly higher for MRE than that for fibrosis markers. Multivariate analysis revealed that LS >6.0 kPa is an independent risk factor for the presence of ascites. The cumulative incidence of ascites was significantly higher among those with LS values >6.0 kPa. There was significantly greater diagnostic accuracy for liver fibrosis stage >=4 with MRE than that with fibrosis markers. CONCLUSIONS: Compared with serum fibrosis markers, MRE has higher diagnostic performance in predicting the presence of ascites. MRE-based LS has the potential to predict the presence of ascites in CLD patients. PMID- 28834566 TI - Selective F or Br Functionalization of Dibenzofuran for Application as Host Materials of Phosphorescent Organic Light-Emitting Diodes. AB - Four dibenzofuran-type host materials substituted with a carbazolylcarbazole moiety were synthesized to investigate the effect of substitution position on the material parameters and device performances of host materials. The carbazolylcarbazole moiety was substituted at the 1-, 2-, 3-, and 4-positions of dibenzofuran by F or Br for a comprehensive study of the positional effect of dibenzofuran-derived host materials. Systematic synthesis and comparison of the four host materials revealed that 1-, 2-, and 4-position modification was better than 3-position modification for high triplet energy and high external quantum efficiency. PMID- 28834567 TI - Ethnic Differences in Peripheral Skeletal Development Among Urban South African Adolescents: A Ten-Year Longitudinal pQCT Study. AB - There are no longitudinal pQCT data of bone growth and development from sub Saharan Africa, where rapid environmental, societal, and economic transitions are occurring, and where fracture rates are predicted to rise. The aim of this study was to compare skeletal development in black and white South African adolescents using longitudinal data from the Birth to Twenty study. The Birth to Twenty Bone Health subcohort consisted of 543 adolescents (261 [178 black] girls, 282 [201 black] boys). Annual pQCT measurements of the radial and tibial metaphysis and diaphysis were obtained between ages 12 and 22 years (distal metaphysis: cross sectional area [CSA] and trabecular bone mineral density [BMD]; diaphysis: total and cortical CSA, cortical BMD, and polar stress-strain index [SSIp]). Age at peak height velocity (APHV) was calculated to account for differences in maturational timing between ethnic groups and sexes. Mixed-effects models were used to describe trajectories for each pQCT outcome. Likelihood-ratio tests were used to summarize the overall difference in trajectories between black and white participants within each sex. APHV (mean +/- SD years) was similar in black (11.8 +/- 0.8) and white (12.2 +/- 1.0) girls, but delayed in black (14.2 +/- 1.0) relative to white boys (13.3 +/- 0.8). By 4 years post-APHV, white adolescents had significantly greater cortical CSA and SSIp than black adolescents at the radius. There were no significant differences at the radial metaphysis but there was some divergence, such that black adolescents had greater radial trabecular BMD by the end of follow-up. At the tibia, white adolescents had lower diaphyseal CSA and SSIp, and greater metaphyseal CSA. There was no ethnic difference in tibial trabecular BMD. There are ethnic differences in bone growth and development, independent of maturation, in South African adolescents. This work gives new insights into the possible etiology of childhood fractures, which occur most commonly as peripheral sites. (c) 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. PMID- 28834568 TI - Methylated polycyclic aromatic hydrocarbons and/or their metabolites are important contributors to the overall estrogenic activity of polycyclic aromatic hydrocarbon-contaminated soils. AB - In the present study 42 polycyclic aromatic compounds (PACs) were investigated for their estrogenic potential using the VM7Luc4E2 transactivation assay. Relative potencies were determined for mass-balance analysis. In addition, compounds were tested in combination with the estrogen receptor (ER) antagonist ICI182,780 (ICI) and the aryl hydrocarbon receptor antagonist/CYP1A1 inhibitor alpha-naphthoflavone. Luciferase induction and CYP1A1-dependent ethoxyresorufin-O deethylase (EROD) activity were measured to assess whether the estrogenic activity was elicited by the compound itself and/or by its metabolites. Relative potencies ranged between 10-7 and 10-4 . The ability of ICI to decrease luciferase activity stimulated by all compounds indicated that the induction responses were ER-dependent. The aryl hydrocarbon receptor antagonist/CYP1A1 inhibitor alpha-naphthoflavone decreased luciferase induction and EROD activity by several compounds, including the methylated chrysenes, suggesting that metabolites of these chemicals contributed to ER activation. Several PACs, such as acridine and its derivatives, appear to directly activate the ER. Furthermore, extracts of soils from industrial areas were examined using this bioassay, and estrogenic activity was detected in all soil samples. Mass-balance analysis using a combination of relative potencies and chemical analysis of the samples suggested that polycyclic aromatic hydrocarbons (PAHs) and alkylated PAHs, such as 1- and 3-methylchrysene, are important contributors to the overall estrogenic activity. However, these results revealed that a considerable proportion of the estrogenic activity in the soil remained unexplained, indicating the presence of other significant estrogenic compounds. Environ Toxicol Chem 2018;37:385-397. (c) 2017 SETAC. PMID- 28834569 TI - Adverse Childhood Experiences and Criminal Extremity: New Evidence for Sexual Homicide. AB - Adverse childhood experiences are associated with a wide range of behavioral, health, and psychiatric deficits and have recently been used to study the development of serious offending careers. Unfortunately, this research paradigm has largely ignored forensic populations. This study utilized the adverse childhood experiences framework to examine the associations between exposure to violence, victimization, and total adverse childhood experiences on sexual homicide using a sample of 616 incarcerated adult male sexual offenders from Canada 85 of whom committed sexual homicide. Epidemiological tables of odds revealed that a gradient of adverse childhood experiences was associated with sexual homicide, but that the most significant risks were for offenders who had the most extensive abuse histories. In adjusted models, exposure to violence, victimization, and total adverse childhood experiences increased the odds of sexual homicide by 334%, 249%, and 546%, respectively. These effects intensified in models adjusted for childhood enuresis, cruelty to animals, parental abandonment, deviant sexual behaviors, poor self-image, and sexual problems to 559%, 326%, and 849%, respectively. The adverse childhood experiences framework is a systematic way to organize the criminogenic developmental sequela in sexual homicide. PMID- 28834570 TI - Differential response patterns of kisspeptin and RFamide-related peptide to photoperiod and sex steroid feedback in the Djungarian hamster (Phodopus sungorus). AB - Many animals synchronise their reproductive activity with the seasons to optimise the survival of their offspring. This synchronisation involves switching on and off their gonadotrophic axis. Ever since their discovery as key regulators of gonadotrophin-releasing hormone (GnRH) neurones, the hypothalamic RF-amide peptides kisspeptin and RFamide-related peptide (RFRP) have been a major focus of research on the seasonal regulation of the gonadotrophic axis. In the present study, we investigated the regulation of both neuropeptides in the Djungarian hamster, a major animal model for the study of seasonal reproduction. During the long-day breeding period, kisspeptin neurones in the anteroventral periventricular area are solely controlled by a positive sex steroid feedback and, in the arcuate nucleus, they are subject to a very strong negative sex steroid feedback associated with a minor photoperiodic effect. During short-day sexual quiescence, the disappearance of this hormonal feedback leads to high levels of kisspeptin in arcuate neurones. Notably, chronic central administration of kisspeptin is able to over-ride the photoperiodic inhibition of the gonadotrophic axis and reactivate the reproductive function. Therefore, our data suggest that kisspeptin secretion by arcuate neurones during sexual quiescence is inhibited by mechanisms upstream of kisspeptin neurones. RFRP expression is solely controlled by photoperiod, being strongly reduced in short days independently of the sex steroid feedback. Thus, kisspeptin and RFRP display contrasting patterns of expression and regulation. Upstream mechanisms controlling these neurones should be the focus of further studies on the roles of these RFamide neuropeptides in the seasonal control of reproduction. PMID- 28834571 TI - The impact of ageing, fasting and high-fat diet on central and peripheral glucose tolerance and glucose-sensing neural networks in the arcuate nucleus. AB - Obesity and ageing are risk factors for diabetes. In the present study, we investigated the effects of ageing, obesity and fasting on central and peripheral glucose tolerance and on glucose-sensing neuronal function in the arcuate nucleus of rats, with a view to providing insight into the central mechanisms regulating glucose homeostasis and how they change or are subject to dysfunction with ageing and obesity. We show that, following a glucose load, central glucose tolerance at the level of the cerebrospinal fluid (CSF) and plasma is significantly reduced in rats maintained on a high-fat diet (HFD). With ageing, up to 2 years, central glucose tolerance was impaired in an age-dependent manner, whereas peripheral glucose tolerance remained unaffected. Ageing-induced peripheral glucose intolerance was improved by a 24-hour fast, whereas central glucose tolerance was not corrected. Pre-wean, immature animals have elevated basal plasma glucose levels and a delayed increase in central glucose levels following peripheral glucose injection compared to mature animals. Electrophysiological recording techniques revealed an energy-status-dependent role for glucose-excited, inhibited and adapting neurones, along with glucose-induced changes in synaptic transmission. We conclude that ageing affects central glucose tolerance, whereas HFD profoundly affects central and peripheral glucose tolerance and, in addition, glucose-sensing neurones adapt function in an energy-status-dependent manner. PMID- 28834572 TI - Multiple genetic variants associated with posttransplantation diabetes mellitus in Chinese Han populations. AB - OBJECTIVES: Posttransplantation diabetes mellitus (PTDM) is a major complication after solid organ transplantation. This study is to investigate the association of nine genetic variant factors and PTDM in Chinese Han patients. METHODS: HLA-DP (rs3077, rs9277535), HLA-DQ (rs7453920), signal transducer and activator of transcription 4 (STAT4) (rs7574865), IL-28B (rs12979860, rs8099917, and rs12980275), and IL-18 (rs1946518 and rs187238) were investigated in 260 liver transplant recipients (PTDM vs non-PTDM) by high-resolution melting curve analysis. Serum interleukin (IL)-1beta, IL-6, IL-8, IL-17, interferon-gamma, inducible protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b were analyzed by a Bio-Plex suspension array system (Bio Plex Multiplex Immunoassays, Bio-Rad, Hercules, CA, USA). RESULTS: Signal transducer and activator of transcription 4 (rs7574865) T allele and IL-18 (rs1946518) A allele increase the risk for insulin resistance and PTDM. CONCLUSIONS: Recipients with STAT4 (rs7574865) T allele are associated with an increased concentration of IL-1beta, interferon-gamma, monocyte chemoattractant protein, and macrophage inflammatory protein-1b. The genetic variants of STAT4 (rs7574865) and IL-18 (rs1946518) may be new important markers for PTDM. PMID- 28834573 TI - Sexual dimorphism in epicuticular compounds despite similar sexual selection in sex role-reversed seed beetles. AB - Sexual selection imposed by mating preferences is often implicated in the evolution of both sexual dimorphism and divergence between species in signalling traits. Epicuticular compounds (ECs) are important signalling traits in insects and show extensive variability among and within taxa. Here, we investigate whether variation in the multivariate EC profiles of two sex role-reversed beetle species, Megabruchidius dorsalis and Megabruchidius tonkineus, predicts mate attractiveness and mating success in males and females. The two species had highly distinct EC profiles and both showed significant sexual dimorphism in ECs. Age and mating status in both species were also distinguishable by EC profile. Males and females of both species showed significant association between their EC profile and attractiveness, measured both as latency to mating and as success in mate-choice trials. Remarkably, the major multivariate vector describing attractiveness was correlated in both species, both sexes, and in both choice and no-choice experiments such that increased attractiveness was in all cases associated with a similar multivariate modification of EC composition. Furthermore, in both sexes this vector of attractiveness was associated with more male-like EC profiles, as well as those characterizing younger and nonvirgin individuals, which might reflect a general preference for individuals of high condition in both sexes. Despite significant sexual selection on EC composition, however, we found no support for the proposition that sexual selection is responsible for divergence in ECs between these species. PMID- 28834574 TI - B cell activating factor (BAFF) and BAFF receptors: fakes and facts. AB - Analysis of B cell activating factor (BAFF) receptors before and after B cell depletion therapy (BCDT) might offer a clue to the understanding of whether some B cell subsets may represent useful biomarkers of biological and clinical responses. Among the BAFF receptors in a cohort of rheumatoid arthritis (RA) patients, the AA have shown, by fluorescence activated cell sorter (FACS) analysis of median fluorescence intensity (MFI), that transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) do not change, whereas the most important, BAFF receptor 3 (BR3), appears to be decreased before as well as after BCDT in all B cell subsets but not in plasmablasts, the most important subset, depleted by BCDT. PMID- 28834575 TI - Unexpected stasis in a changing world: Lake nutrient and chlorophyll trends since 1990. AB - The United States (U.S.) has faced major environmental changes in recent decades, including agricultural intensification and urban expansion, as well as changes in atmospheric deposition and climate-all of which may influence eutrophication of freshwaters. However, it is unclear whether or how water quality in lakes across diverse ecological settings has responded to environmental change. We quantified water quality trends in 2913 lakes using nutrient and chlorophyll (Chl) observations from the Lake Multi-Scaled Geospatial and Temporal Database of the Northeast U.S. (LAGOS-NE), a collection of preexisting lake data mostly from state agencies. LAGOS-NE was used to quantify whether lake water quality has changed from 1990 to 2013, and whether lake-specific or regional geophysical factors were related to the observed changes. We modeled change through time using hierarchical linear models for total nitrogen (TN), total phosphorus (TP), stoichiometry (TN:TP), and Chl. Both the slopes (percent change per year) and intercepts (value in 1990) were allowed to vary by lake and region. Across all lakes, TN declined at a rate of 1.1% year-1 , while TP, TN:TP, and Chl did not change. A minority (7%-16%) of individual lakes had changing nutrients, stoichiometry, or Chl. Of those lakes that changed, we found differences in the geospatial variables that were most related to the observed change in the response variables. For example, TN and TN:TP trends were related to region-level drivers associated with atmospheric deposition of N; TP trends were related to both lake and region-level drivers associated with climate and land use; and Chl trends were found in regions with high air temperature at the beginning of the study period. We conclude that despite large environmental change and management efforts over recent decades, water quality of lakes in the Midwest and Northeast U.S. has not overwhelmingly degraded or improved. PMID- 28834576 TI - Mammalian target of rapamycin as a therapeutic target in osteoporosis. AB - The mechanistic target of rapamycin (mTOR) plays a key role in sensing and integrating large amounts of environmental cues to regulate organismal growth, homeostasis, and many major cellular processes. Recently, mounting evidences highlight its roles in regulating bone homeostasis, which sheds light on the pathogenesis of osteoporosis. The activation/inhibition of mTOR signaling is reported to positively/negatively regulate bone marrow mesenchymal stem cells (BMSCs)/osteoblasts-mediated bone formation, adipogenic differentiation, osteocytes homeostasis, and osteoclasts-mediated bone resorption, which result in the changes of bone homeostasis, thereby resulting in or protect against osteoporosis. Given the likely importance of mTOR signaling in the pathogenesis of osteoporosis, here we discuss the detailed mechanisms in mTOR machinery and its association with osteoporosis therapy. PMID- 28834579 TI - Topical flurbiprofen toxicosis in a cat. AB - OBJECTIVE: To describe the clinical presentation and treatment of a cat with flurbiprofen toxicosis due to topical cream exposure. CASE SUMMARY: A 3-year-old castrated male domestic shorthair cat presented to an emergency and referral center for acute lethargy, hematemesis, and anemia. Severe azotemia was observed on serum biochemistry panel. The patient's anemia was treated with packed RBC transfusion, and treatment with crystalloid fluids, famotidine, pantoprazole, ampicillin, and sucralfate were begun on presentation. Anemia became intractable and the patient received multiple packed RBC and whole blood transfusions. Severe gastric ulcerations and duodenal perforation were confirmed via gastroduodenoscopy, and the patient was treated with surgical excision and repair of duodenal perforation. Azotemia resolved with IV fluid therapy, and anemia resolved following surgery. The patient recovered and was discharged after 9 days of hospitalization. The patient had likely been exposed to the owner's compounded pain relief cream containing 10% flurbiprofen. There was confirmation of flurbiprofen exposure via acid extraction urine analysis at a university toxicology laboratory. NEW OR UNIQUE INFORMATION PROVIDED: This is the first described case of flurbiprofen toxicosis due to topical cream exposure in a cat. PMID- 28834577 TI - From phenologs to silent suppressors: Identifying potential therapeutic targets for human disease. AB - Orthologous phenotypes, or phenologs, are seemingly unrelated phenotypes generated by mutations in a conserved set of genes. Phenologs have been widely observed and accepted by those who study model organisms, and allow one to study a set of genes in a model organism to learn more about the function of those genes in other organisms, including humans. At the cellular and molecular level, these conserved genes likely function in a very similar mode, but are doing so in different tissues or cell types and can result in different phenotypic effects. For example, the RAS-RAF-MEK-MAPK pathway in animals is a highly conserved signaling pathway that animals adopted for numerous biological processes, such as vulval induction in Caenorhabditis elegans and cell proliferation in mammalian cells; but this same gene set has been co-opted to function in a variety of cellular contexts. In this review, I give a few examples of how suppressor screens in model organisms (with a emphasis on C. elegans) can identify new genes that function in a conserved pathway in many other organisms. I also demonstrate how the identification of such genes can lead to important insights into mammalian biology. From such screens, an occasional silent suppressor that does not cause a phenotype on its own is found; such suppressors thus make for good candidates as therapeutic targets. PMID- 28834578 TI - Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain. AB - Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal-regulated kinase (ERK), and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown. Phosphorylation of ERK1/2 in lingual nerve crush (LNC) rats was observed in SGCs. To evaluate the role of neuron-SGC interactions under neuropathic pain, calcitonin gene-related peptide (CGRP)-immunoreactive (IR), phosphorylated ERK1/2 (pERK1/2)-IR and glial fibrillary acidic protein (GFAP)-IR cells in the TG were studied in LNC rats. The number of CGRP-IR neurons and neurons encircled with pERK1/2-IR SGCs was significantly larger in LNC rats compared with sham rats. The percentage of large sized CGRP-IR neurons was significantly higher in LNC rats. The number of CGRP-IR neurons, neurons encircled with pERK1/2-IR SGCs, and neurons encircled with GFAP IR SGCs was decreased following CGRP receptor blocker CGRP8-37 or mitogen activated protein kinase/ERK kinase 1 inhibitor PD98059 administration into the TG after LNC. Reduced thresholds to mechanical and heat stimulation to the tongue in LNC rats were also significantly recovered following CGRP8-37 or PD98059 administration. The present findings suggest that CGRP released from TG neurons activates SGCs through ERK1/2 phosphorylation and TG neuronal activity is enhanced, resulting in the tongue hypersensitivity associated with lingual nerve injury. The phenotypic switching of large myelinated TG neurons expressing CGRP may account for the pathogenesis of tongue neuropathic pain. PMID- 28834580 TI - The Physical Effects of Contact and Close-Distance Gunfire on Sweatshirt Fleece. AB - Powder stippling caused by the impact of propellant particles during close distance gunfire has been previously described on skin and solid objects only. Additionally, radial tearing has been described as clear evidence of a contact distance shot, requiring no further testing. Patterns of discrete perforating holes (referred to here as "stippling perforations") and other physical damage on sweatshirt fleece fabrics were prepared. Using the firearm and ammunition in this study, stippling perforations were observed to a maximum muzzle-to-target distance of 35 cm (10 inches). In addition, radial tearing and disintegration were present (and often more extensive) at greater than contact distance. The presence of stippling perforations could augment muzzle-to-target distance estimates generated using the Griess test, or allow distance estimates when the Griess test is not feasible. Unlike what has been previously reported, testing on the original evidence (or similar substitute) is warranted when physical damage is used to estimate shooting distance. PMID- 28834582 TI - Controlled crosslinking of trimethylolpropane trimethacrylate for preparation of organic monolithic columns for capillary liquid chromatography. AB - Organic monolithic columns based on single crosslinking of trimethylolpropane trimethacrylate (TRIM) monomer were prepared in a single step by living/controlled free-radical polymerization. Full optimization of the preparation, such as using different percentages of TRIM and different amounts of radical promoter as well as various porogen solvents were explored. The resulting monolithic columns were characterized by scanning electronic microscopy and nitrogen sorption for structure morphology studies and surface area measurements, respectively. Using capillary liquid chromatography, 150 MUm i.d. columns were applied to separate a mixture of small hydrophobic molecules. The results indicated that column performance is highly sensitive to the type and the amount of porogen solvents used in the polymerization mixture composition. Good resolution factors and methylene selectivity were obtained, indicating the promising potential of this material for capillary liquid chromatography separations. PMID- 28834583 TI - Role of the Adsorbed Oxygen Species in the Selective Electrochemical Reduction of CO2 to Alcohols and Carbonyls on Copper Electrodes. AB - The electrochemical reduction of CO2 into fuels has gained significant attention recently as source of renewable carbon-based fuels. The unique high selectivity of copper in the electrochemical reduction of CO2 to hydrocarbons has called much interest in discovering its mechanism. In order to provide significant information about the role of oxygen in the electrochemical reduction of CO2 on Cu electrodes, the conditions of the surface structure and the composition of the Cu single crystal electrodes were controlled over time. This was achieved using pulsed voltammetry, since the pulse sequence can be programmed to guarantee reproducible initial conditions for the reaction at every fraction of time and at a given frequency. In contrast to the selectivity of CO2 reduction using cyclic voltammetry and chronoamperometric methods, a large selection of oxygenated hydrocarbons was found under alternating voltage conditions. Product selectivity towards the formation of oxygenated hydrocarbon was associated to the coverage of oxygen species, which is surface-structure- and potential-dependent. PMID- 28834584 TI - A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder. AB - Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A. PMID- 28834581 TI - Pyrrolo[2,3-d]pyrimidine (7-deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides. AB - 7-Deazapurine (pyrrolo[2,3-d]pyrimidine) nucleosides are important analogues of biogenic purine nucleosides with diverse biological activities. Replacement of the N7 atom with a carbon atom makes the five-membered ring more electron rich and brings a possibility of attaching additional substituents at the C7 position. This often leads to derivatives with increased base-pairing in DNA or RNA or better binding to enzymes. Several types of 7-deazapurine nucleosides with potent cytostatic or cytotoxic effects have been identified. The most promising are 7 hetaryl-7-deazaadenosines, which are activated in cancer cells by phosphorylation and get incorporated both to RNA (causing inhibition of proteosynthesis) and to DNA (causing DNA damage). Mechanism of action of other types of cytostatic nucleosides, 6-hetaryl-7-deazapurine and thieno-fused deazapurine ribonucleosides, is not yet known. Many 7-deazaadenosine derivatives are potent inhibitors of adenosine kinases. Many types of sugar-modified derivatives of 7 deazapurine nucleosides are also strong antivirals. Most important are 2'-C methylribo- or 2'-C-methyl-2'-fluororibonucleosides with anti-HCV activities (several compounds underwent clinical trials). Some underexplored areas of potential interest are also outlined. PMID- 28834585 TI - A combined learning algorithm for prostate segmentation on 3D CT images. AB - PURPOSE: Segmentation of the prostate on CT images has many applications in the diagnosis and treatment of prostate cancer. Because of the low soft-tissue contrast on CT images, prostate segmentation is a challenging task. A learning based segmentation method is proposed for the prostate on three-dimensional (3D) CT images. METHODS: We combine population-based and patient-based learning methods for segmenting the prostate on CT images. Population data can provide useful information to guide the segmentation processing. Because of inter-patient variations, patient-specific information is particularly useful to improve the segmentation accuracy for an individual patient. In this study, we combine a population learning method and a patient-specific learning method to improve the robustness of prostate segmentation on CT images. We train a population model based on the data from a group of prostate patients. We also train a patient specific model based on the data of the individual patient and incorporate the information as marked by the user interaction into the segmentation processing. We calculate the similarity between the two models to obtain applicable population and patient-specific knowledge to compute the likelihood of a pixel belonging to the prostate tissue. A new adaptive threshold method is developed to convert the likelihood image into a binary image of the prostate, and thus complete the segmentation of the gland on CT images. RESULTS: The proposed learning-based segmentation algorithm was validated using 3D CT volumes of 92 patients. All of the CT image volumes were manually segmented independently three times by two, clinically experienced radiologists and the manual segmentation results served as the gold standard for evaluation. The experimental results show that the segmentation method achieved a Dice similarity coefficient of 87.18 +/- 2.99%, compared to the manual segmentation. CONCLUSIONS: By combining the population learning and patient-specific learning methods, the proposed method is effective for segmenting the prostate on 3D CT images. The prostate CT segmentation method can be used in various applications including volume measurement and treatment planning of the prostate. PMID- 28834586 TI - Efficacy and residues of permethrin-incorporated nets used to protect maize grains post-harvest. AB - BACKGROUND: Pest control in post-harvest food storage represents a great challenge in the sustainable prevention of food losses, and insecticide-treated netting may represent a valid alternative to traditional practices such as the direct application of insecticides. In our work, the efficacy of a permethrin incorporated net, in combination with polypropylene or jute sacking, was tested for the control of Sitophilus oryzae. Contamination of maize grain by permethrin from the treated netting was also evaluated. RESULTS: A 98% control of S. oryzae was achieved using permethrin-treated netting. Both jute and polypropylene acted as additional barriers, increasing efficacy to 100%. The results also showed the contamination of maize kernel by permethrin released from the treated netting. The concentration of residues in maize kernels increased with increasing temperature; however, use of jute or polypropylene significantly reduced (by 87% to 97%) the concentration of residues transferred to maize kernels. CONCLUSIONS: Permethrin-treated netting provided a high level of efficacy in the post-harvest protection of maize. Several factors influenced permethrin residue concentrations in grains when treated nets are used. Therefore, solutions should be found to prevent contamination of food stored in the bags that are treated with insecticides. (c) 2017 Society of Chemical Industry. PMID- 28834587 TI - Understanding the Photovoltaic Performance of Perovskite-Spirobifluorene Solar Cells. AB - Lead halide perovskite solar cells with remarkable power conversion efficiency have attracted much attention in recent years. However, there still exist many problems with their use that are not completely understood, and further studies are needed. Herein, the hole-transport layer dependence of the photovoltaic performance of perovskite solar cells is investigated in detail. It is found that devices freshly prepared using pristine 2,2',7,7'-tetrakis-(N,N-di-p methoxyphenylamine)-9,9'-spirobifluorene (spiro-OMeTAD) and Li-doped spiro-OMeTAD as hole-transport layers exhibit S-shaped current density-voltage curves with poor fill factors. The devices show progressively improved fill factors and efficiencies upon exposure to air, which is attributed to air-induced conductivity improvement in the spiro-OMeTAD layer. After introducing a cobalt salt dopant (FK209) into the spiro-OMeTAD layer, the corresponding devices show remarkable performance without the need of air exposure. These results confirm that the dopant not only increases the conductivity of spiro-OMeTAD layer, but also tunes the surface potential, which helps to improve charge transport and reduce the recombination loss. PMID- 28834588 TI - Fluorescence Electrochemical Microscopy: Capping Agent Effects with Ethidium Bromide/DNA Capped Silver Nanoparticles. AB - Fluorescence microscopy and electrochemistry were employed to examine capping agent dynamics in silver nanoparticles capped with DNA intercalated with ethidium bromide, a fluorescent molecule. The capped NPs were studied first electrochemically, demonstrating that the intercalation of the capping agent promotes oxidation of the silver core, occurring at 0.50 V (vs. Ag, compared with 1.15 V for Ag NPs capped in DNA alone). Second, fluorescence electrochemical microscopy revealed that the electron transfer from the nanoparticles is gated by the capping agent, allowing dynamic insights unobservable using electrochemistry alone. PMID- 28834589 TI - Trichalcogenasumanene ortho-Quinones: Synthesis, Properties, and Transformation into Various Heteropolycycles. AB - The regioselective transformation of heterobuckybowl trichalcogenasumanenes 1 a,b at peripheral butoxy groups afforded trichalcogenasumanene ortho-quinones 2 a,b. Compounds 2 a,b are distinct from 1 a,b in terms of their molecular geometry and electronic state; that is, they have a shallower bowl depth and show absorbance in the NIR region. The reaction of 2 a,b with diamines resulted in a variety of heteropolycycles, including molecular spoon 3 a-6 a, planar pi-systems 3 b-6 b, and highly twisted [7-6-6]-fused systems 7 a,b. These new heteropolycycles had different optical/electrical properties: 4 a,b showed hole mobility of approximately 0.002 cm2 V-1 s-1 , 6 a displayed red emission in both solution and the solid state, and 7 a,b formed tight stacks of the curved pi-surface. PMID- 28834591 TI - Estimating Travel Time in Bank Filtration Systems from a Numerical Model Based on DTS Measurements. AB - An approach is presented to determine the seasonal variations in travel time in a bank filtration system using a passive heat tracer test. The temperature in the aquifer varies seasonally because of temperature variations of the infiltrating surface water and at the soil surface. Temperature was measured with distributed temperature sensing along fiber optic cables that were inserted vertically into the aquifer with direct push equipment. The approach was applied to a bank filtration system consisting of a sequence of alternating, elongated recharge basins and rows of recovery wells. A SEAWAT model was developed to simulate coupled flow and heat transport. The model of a two-dimensional vertical cross section is able to simulate the temperature of the water at the well and the measured vertical temperature profiles reasonably well. MODPATH was used to compute flowpaths and the travel time distribution. At the study site, temporal variation of the pumping discharge was the dominant factor influencing the travel time distribution. For an equivalent system with a constant pumping rate, variations in the travel time distribution are caused by variations in the temperature-dependent viscosity. As a result, travel times increase in the winter, when a larger fraction of the water travels through the warmer, lower part of the aquifer, and decrease in the summer, when the upper part of the aquifer is warmer. PMID- 28834592 TI - Mukaiyama Award: F. Glorius and Y. Nakao Wissenschaftspreis der Stadt Ulm: C. Streb BioTrans Senior Award: M. T. Reetz BioTrans Junior Award: F. Hollmann. PMID- 28834593 TI - Characterization of purine-rich element binding protein B as a novel biomarker in acute myelogenous leukemia prognostication. AB - Acute myelogenous leukemia (AML) is an aggressive hematologic cancer characterized by infiltration of proliferative, clonal, abnormally differentiated cells of myeloid lineage in the bone marrow and blood. Malignant cells in AML often exhibit chromosomal and other genetic or epigenetic abnormalities that are useful in prognostic risk assessment. In this study, the relative expression and novel single-stranded DNA (ssDNA) binding function of purine-rich element binding proteins A and B (Puralpha and Purbeta) were systematically evaluated in established leukemia cell lines and in lineage committed myeloid cells isolated from patients diagnosed with a hematologic malignancy. Western blotting revealed that Puralpha and Purbeta are markedly elevated in CD33+ /CD66b+ cells from AML patients compared to healthy subjects and to patients with other types of myeloid cell disorders. Results of in silico database analysis of PURA and PURB mRNA expression during hematopoiesis in conjunction with the quantitative immunoassay of the ssDNA-binding activities of Puralpha and Purbeta in transformed leukocyte cell lines pointed to Purbeta as the more distinguishing biomarker of myeloid cell differentiation status. Purbeta ssDNA-binding activity was significantly increased in myeloid cells from AML patients but not from individuals with other myeloid-related diseases. The highest levels of Purbeta activity were detected in myeloid cells from primary AML patients and from AML patients displaying other risk factors forecasting a poor prognosis. Collectively, these findings suggest that the enhanced ssDNA-binding activity of Purbeta in transformed myeloid cells may serve as a unique and measurable phenotypic trait for improving prognostic risk stratification in AML. PMID- 28834594 TI - Specific Detection of Extended-Spectrum beta-Lactamase Activities with a Ratiometric Fluorescent Probe. AB - The dissemination of antimicrobial resistance around the world is one of the biggest threats to global public health. The acquisition and expression of extended-spectrum beta-lactamases (ESBLs) in pathogenic bacterial are mainly responsible for bacterial resistance to third-generation cephalosporins. Reported herein is a ratiometric fluorescent probe for the detection of the activity of ESBLs. This imaging reagent adopts the core structure of cefotaxime as an enzymatic recognition moiety, and exhibits excellent selectivity to ESBLs over other beta-lactamases. The specific activation of this sensor by ESBLs can lead to over 2500-fold changes in the fluorescent ratio, which is independent of the concentration of the probe and environmental conditions. Further experiments have demonstrated that this ratiometric fluorescent probe can distinguish bacteria with extended-spectrum antibiotic resistance from a group of clinically important pathogens within a short period of time. PMID- 28834595 TI - Fraxitoxin, a New Isochromanone Isolated from Diplodia fraxini. AB - A new isochromanone, named fraxitoxin, was isolated together with (-)-mellein and tyrosol from liquid cultures of Diplodia fraxini, a pathogen involved in the etiology of canker and dieback disease of Fraxinus spp. in Europe. It was characterized as 5-methoxy-3-methylisochroman-1-one using spectroscopic methods (essentially NMR and HR-EI-MS). Its absolute configuration (R) at C(3) was assigned by electronic circular dichroism (ECD) measurements and calculations. Phytotoxic activity of the compound was evaluated on ash, cork and holm oak leaves at concentration of 1 mg/ml by the leaf-puncture assay. Interestingly, fraxitoxin caused necrotic lesions only on ash leaves. PMID- 28834596 TI - Evaluation of biological fluid analysis using the sysmex XN automatic hematology analyzer. AB - BACKGROUND: Hematological cytometers with a biological fluid module could potentially correct the limitations of the manual chamber method. This study evaluates the agreement between the manual technique and the Sysmex XN-1000 analyzer for white blood cell (WBC) and red blood cell (RBC) counts, as well as for leukocyte differentiation in different types of fluids. This study also evaluates the advantages of incorporating the technique in routine laboratory work. METHODS: One hundred and three fluid samples examined were 45 ascite (AF), 21 synovial (SF), 33 pleural (PF), and 31 cerebrospinal (CSF) fluid samples. All cell counting was performed with a Sysmex XN-1000 and a Fuchs-Rosenthal counting chamber. May Grundwald-Giemsa stain was used for manual WBC differentiation. The manual analysis data were obtained in duplicate by the same two observers. Passing-Bablok regression and the Kappa index were used to evaluate the interchangeability and concordance. RESULTS: Good agreement was observed for WBC differentiation in all fluids and for WBC counts in SF and PF. An optimal Kappa index was obtained, which indicated agreement and clinical significance for WBC and RBC counts in CSF and for RBC counts in PF. There was disagreement for WBC and RBC analysis in AF, with significantly higher results from the Sysmex XN-1000 than from the manual method. A reduction in laboratory response time was observed when using the automatic method. CONCLUSIONS: Except for AF, the Sysmex XN-1000 results agree with those of the manual method, although to different degrees depending on the fluid type. (c) 2017 International Clinical Cytometry Society. PMID- 28834597 TI - Engaging hepatitis C infected patients in cost-effectiveness analyses: A literature review. AB - : Cost-effectiveness analyses (CEAs) of hepatitis C virus (HCV) treatment strategies have become common, but few appear to include patient engagement or the patient perspective. The objectives of the current study were to (1) identify published HCV CEA studies that include patient input and (2) derive insights on patient-informed variable and outcome selection to build a framework for future economic analyses of HCV. A literature search was conducted using SCOPUS, EMBASE, and PubMed from January 1, 2012 to May 28, 2017. Terms sought included a combination of "incremental cost-effectiveness ratio" OR "economic evaluation" OR "cost effectiveness analysis" OR "cost utility analysis" OR "budget impact analysis" OR "cost benefit analysis" AND "hepatitis C". A total of 1,040 articles were identified in the search and seven articles were selected for further evaluation after abstracts and the full text of eligible articles were screened. One economic evaluation used direct patient engagement to account for patient preferences in the final model. The study endpoints identified included a variety of clinical, social, psychological, and economic outcomes. Costs primarily focused on productivity loss, missed work, out-of-pocket treatment costs, and indirect costs to family or friends supporting the patient. CONCLUSION: To date, the inclusion of the patient voice through patient engagement as part of methods in cost-effectiveness research in existing published studies has been limited. Future CEA studies should consider how patient engagement may impact economic models and their implementation into practice. (Hepatology 2017). PMID- 28834598 TI - Comparison of noninvasive and invasive point-of-care testing methods with reference method for hemoglobin measurement. AB - BACKGROUND: Rapid and practical point-of-care testing (POCT) devices become more popular, especially in blood donation centers for determining predonation hemoglobin (Hb) concentrations. The purpose of this study was to evaluate accordance between the POCT methods and the venous method as the reference to Hb screening. METHODS: A total of 353 subjects with no known significant health problems were included in the study. Hb screening was performed by two different POCT methods, a noninvasive method (Haemospect, MBR, Germany) and an invasive method (HemoControl, EKF Diagnostic, Germany), and a venous method as the reference (Sysmex XE-2100, Sysmex Europe, Germany). The obtained results were compared. RESULTS: The sensitivity and the specificity values of the invasive POCT method (83.3%, 87.9%) were higher than the noninvasive POCT method (66.7%, 77.1%). The Bland-Altman analysis was evaluated for both sexes and the bias of the noninvasive POCT method of the males (-0.97 g/dL) was higher than the bias of the invasive POCT method of the males (-0.07 g/dL). We found a better correlation between the invasive POCT method (r = .908) compared with the venous method than the noninvasive POCT method (r = .634). CONCLUSION: Predonation Hb measurements must be performed with accurate, precise, and practical methods. Although the noninvasive POCT method was practical and painless, it had lower levels of specificity and sensitivity, and more false deferral and pass rates than the invasive POCT method. The POCT methods agreeable to the venous method as the reference might be suitable for Hb screening especially for centers of excessive numbers of blood donation. PMID- 28834599 TI - The value of macrophage inhibitory cytokine-1 level in differentiating benign from malignant solitary pulmonary nodules. AB - INTRODUCTION: Macrophage inhibitory cytokine-1 (MIC-1), a transforming growth factor-beta superfamily cytokine, is involved in tumor pathogenesis, and its measurement can be used as a clinical tool for the diagnosis of a wide range of cancers. OBJECTIVES: The aim of this study was to explore the diagnostic value of serum MIC-1 in patients with solitary pulmonary nodules (SPNs). METHODS: Serum specimens from 158 malignant SPN patients, 110 benign SPN patients, along with 120 healthy volunteers. The levels of serum MIC-1 were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Serum levels of MIC-1 in malignant SPN patients were significantly higher than those in benign SPN patients (P < .01), or those in healthy volunteers (P < .01). With a cutoff of 685.8 pg/ml, the sensitivity and specificity of MIC-1 in differentiating between malignant SPN patients and benign SPN patients, and between malignant SPN patients and healthy volunteers was, 56.3% and 92.7%, and 65.8% and 96.7%, respectively. An area under the curve (AUC) for malignant SPN resulting from MIC-1, which was significantly better than any other tumor markers tested including carbohydrate antigens 12-5 (CA125), and carcinoembryonic antigen (CEA). CONCLUSIONS: In conclusion, measurement of serum MIC-1 levels could be considered as a diagnostic biomarker for malignant SPN patients. PMID- 28834601 TI - Cytological markers for predicting ALK-positive pulmonary adenocarcinoma. AB - BACKGROUND: ALK gene rearrangement is an important class of gene mutations in pulmonary adenocarcinoma. ALK-positive pulmonary adenocarcinoma exhibits characteristic histological features, such as signet ring cell carcinoma (SRCC) and a mucinous cribriform structure. However, when insufficient histological specimens are obtained, ALK-positivity must be predicted based on cytological features. The purpose of this study was to clarify the cytological characteristics of ALK-positive pulmonary adenocarcinoma. METHODS: We compared the cytological findings of 16 ALK-positive cases with 40 ALK-negative cases. We examined various cytoplasmic features of SRCC, including the presence of pink, yellow, or orange mucin; green, vacuolar, or vesicular cytoplasm; and green globular cytoplasmic secretions. We also examined whether the SRCC cells exhibited a pattern of individually scattered cells, the formation of cell clusters, and formation of a mucinous cribriform pattern. RESULTS: A univariate analysis showed that significantly frequent cytological findings included pink mucin, green cytoplasm, vacuolar cytoplasm, vesicular cytoplasm, green globular cytoplasmic secretions, an individually scattered pattern, cluster formation, and a mucinous cribriform structure (all, P < .05). A stepwise multivariate logistic regression analysis identified three significant contributing factors: pink mucin (P = .03), vesicular cytoplasm (P = .06), and an individually scattered pattern (P = .01) of SRCC. If the specimens showed two or three of these features, the sensitivity and specificity were both 88% for the prediction of ALK-positive cancers. CONCLUSION: Three cytological features of SRCC (pink mucin, vesicular cytoplasm, and an individually scattered pattern) could be useful cytological markers for the prediction of ALK-positive pulmonary adenocarcinoma. PMID- 28834602 TI - DOES TRAINING IN THE CIRCLE OF SECURITY FRAMEWORK INCREASE RELATIONAL UNDERSTANDING IN INFANT/CHILD AND FAMILY WORKERS? AB - This article evaluated whether attendance at Circle of Security training workshops resulted in attendees showing greater empathy and attachment-related knowledge and understanding, and fewer judgmental responses to viewing a stressful parent-child interaction. Participants were 202 practitioners who attended and completed a 2-day (n = 70), 4-day (n = 105), or 10-day (n = 27) COS training workshop in Australia or New Zealand in 2015. In a pre/post design, participant reactions to a video clip of a challenging parent-child interaction were coded for empathic, judgmental, or attachment-focused language. Attachment understanding was coded in response to questions about the greatest challenge that the dyad faced. In all training conditions, participants provided significantly more attachment-focused descriptors and showed significantly greater attachment understanding after training, but significantly fewer empathic descriptors. While participants at the longer workshops provided significantly fewer judgmental/critical descriptors, there was no change for those attending the 2-day workshop. Irrespective of workshop duration or professional background, participants took a more relational perspective on the vignette after the training workshops. More detailed research is required to establish the extent to which this increased knowledge and understanding is retained and integrated into infant mental health practice with parents and young children. PMID- 28834600 TI - Dendritic Fibrous Nanosilica for Catalysis, Energy Harvesting, Carbon Dioxide Mitigation, Drug Delivery, and Sensing. AB - Morphology-controlled nanomaterials such as silica play a crucial role in the development of technologies for addressing challenges in the fields of energy, environment, and health. After the discovery of Stober silica, followed by that of mesoporous silica materials, such as MCM-41 and SBA-15, a significant surge in the design and synthesis of nanosilica with various sizes, shapes, morphologies, and textural properties has been observed in recent years. One notable invention is dendritic fibrous nanosilica, also known as KCC-1. This material possesses a unique fibrous morphology, unlike the tubular porous structure of various conventional silica materials. It has a high surface area with improved accessibility to the internal surface, tunable pore size and pore volume, controllable particle size, and, importantly, improved stability. Since its discovery, a large number of studies have been reported concerning its use in applications such as catalysis, solar-energy harvesting, energy storage, self cleaning antireflective coatings, surface plasmon resonance-based ultrasensitive sensors, CO2 capture, and biomedical applications. These reports indicate that dendritic fibrous nanosilica has excellent potential as an alternative to popular silica materials such as MCM-41, SBA-15, Stober silica, and mesoporous silica nanoparticles. This Review provides a critical survey of the dendritic fibrous nanosilica family of materials, and the discussion includes the synthesis and formation mechanism, applications in catalysis and photocatalysis, applications in energy harvesting and storage, applications in magnetic and composite materials, applications in CO2 mitigation, biomedical applications, and analytical applications. PMID- 28834603 TI - Lifetime cost for type 2 diabetes mellitus in Singapore. AB - BACKGROUND: The mean annual direct medical cost of type 2 diabetes mellitus (T2DM) in Singapore has been found to be SGD 2034 using the prevalence-based approach, but the lifetime direct medical cost of T2DM in Singapore remains largely unknown. The aim of the present study was to determine the lifetime direct medical cost attributable to T2DM and provide estimates of potential savings if T2DM can be prevented or delayed. METHODS: The incidence-based approach was used for the cost-of-illness analysis. Yearly medical expenses were obtained from a regional health system database in Singapore to estimate the lifetime medical cost of T2DM patients. Then, the lifetime medical cost of non T2DM subjects was predicted using a regression model. From the database, gender- and age-specific annual survival rates of T2DM and non-T2DM subjects were obtained and survival-adjusted yearly expenses over the estimated remaining life span were added to obtain lifetime medical costs. The difference between T2DM and non-T2DM subjects was attributed to excess direct medical costs of T2DM. RESULTS: The excess lifetime medical expenses for T2DM patients were SGD 132 506, 108 589, 83 326 and 70 110 when the age of T2DM diagnosis was 40, 50, 60, and 65 years, respectively. CONCLUSIONS: Even though T2DM patients have a lower life expectancy, T2DM is associated with substantially higher lifetime medical costs. Delaying the onset of T2DM, especially in the young, may lead to lower lifetime medical expenses. If prevention costs can be kept sufficiently low, effective T2DM prevention efforts would likely lead to a reduction in long-term medical costs. PMID- 28834605 TI - Electrocatalytic Conversion of Carbon Dioxide and Nitrate Ions to Urea by a Titania-Nafion Composite Electrode. AB - CO2 and nitrate ions were successfully converted to urea by a TiO2 -Nafion nanocomposite electrode under ambient conditions. The composite electrode was constructed by dropcasting the mixture of P25 titania and Nafion solution on an indium-doped tin oxide (ITO) electrode. When the electrode was electrolyzed in CO2 -saturated 0.1 m KNO3 (pH 4.5) solution at -0.98 V versus Ag/AgCl, urea was formed with a Faradaic efficiency of 40 %. The other reduced products obtained were NH3 , CO, and H2 . PMID- 28834604 TI - Deficiency of aminopeptidase P1 causes behavioral hyperactivity, cognitive deficits, and hippocampal neurodegeneration. AB - Metabolic diseases affect various organs including the brain. Accumulation or depletion of substrates frequently leads to brain injury and dysfunction. Deficiency of aminopeptidase P1, a cytosolic proline-specific peptidase encoded by the Xpnpep1 gene, causes an inborn error of metabolism (IEM) characterized by peptiduria in humans. We previously reported that knockout of aminopeptidase P1 in mice causes neurodevelopmental disorders and peptiduria. However, little is known about the pathophysiological role of aminopeptidase P1 in the brain. Here, we show that loss of aminopeptidase P1 causes behavioral and neurological deficits in mice. Mice deficient in aminopeptidase P1 (Xpnpep1-/- ) display abnormally enhanced locomotor activities in both the home cage and open-field box. The aminopeptidase P1 deficiency in mice also resulted in severe impairments in novel-object recognition, the Morris water maze task, and contextual, but not cued, fear memory. These behavioral dysfunctions were accompanied by epileptiform electroencephalogram activity and neurodegeneration in the hippocampus. However, mice with a heterozygous mutation for aminopeptidase P1 (Xpnpep1+/- ) exhibited normal behaviors and brain structure. These results suggest that loss of aminopeptidase P1 leads to behavioral, cognitive and neurological deficits. This study may provide insight into new pathogenic mechanisms for brain dysfunction related to IEMs. PMID- 28834606 TI - Secreted frizzled-related protein 5 protects against oxidative stress-induced apoptosis in human aortic endothelial cells via downregulation of Bax. AB - This study was undertaken to determine the role of secreted frizzled-related protein 5 (SFRP5) in endothelial oxidative injury. Human aortic endothelial cells (HAECs) were exposed to different oxidative stimuli and examined for SFRP5 expression. The effects of SFRP5 overexpression and knockdown on cell viability, apoptosis, and reactive oxygen species production were measured. HAECs treated with angiotensin (Ang) II (1 MUM) or oxidized low-density lipoprotein (oxLDL) (150 MUg/mL) showed a significant increase in SFRP5 expression. Overexpression of SFRP5 significantly attenuated the viability suppression and apoptosis induction by Ang II and oxLDL, whereas the knockdown of SFRP5 exerted opposite effects. Overexpression of SFRP5 prevented ROS formation and beta-catenin activation and reduced Bax expression. Co-expression of Bax significantly reversed the anti apoptotic effect of SFRP5 overexpression, whereas knockdown of Bax restrained Ang II- and oxLDL-induced apoptosis in HAECs. Taken together, SFRP5 confers protection against oxidative stress-induced apoptosis through inhibition of beta catenin activation and downregulation of Bax. PMID- 28834607 TI - Association of baseline vitamin D level with genetic determinants and virologic response in patients with chronic hepatitis B. AB - AIM: The role of vitamin D in individuals with chronic hepatitis B (CHB) is unclear. We aimed to explore the association of baseline vitamin D level with genetic determinants and week-104 treatment outcome in CHB patients. METHODS: Baseline serum 25-hydroxycholecalciferol (25(OH)D) levels and genetic polymorphism within GC, DHCR7, and CYP2R1 were determined in stored serum of 560 patients who were enrolled into a multicenter, randomized, controlled study and completed 104 weeks of telbivudine monotherapy or telbivudine-based optimized therapy. Virologic response was defined as hepatitis B virus DNA <300 copies/mL (52 IU/mL) at week 104. RESULTS: The mean 25(OH)D value was 29.64 ng/mL. The percentage of patients with vitamin D insufficiency (<30 ng/mL) and vitamin D deficiency (<20 ng/mL) were 55.0% and 20.9%, respectively. Gender, season, latitude, and GC rs2282679 polymorphism were independent factors of vitamin D status. Patients with sufficient vitamin D (>=30 ng/mL) achieved a higher virologic response rate than those with vitamin D insufficiency (81.7% vs. 67.2%, P < 0.001). The area under the curve of 25(OH)D to predict virologic response was 0.65 (P < 0.001; 95% confidence interval, 0.62-0.67). On multivariate analysis, 25(OH)D level was an independent predictor of virologic response, but not associated with hepatitis B envelope antigen (HBeAg) seroconversion or alanine aminotransferase (ALT) normalization. CONCLUSIONS: Vitamin D insufficiency was highly prevalent in treatment-naive CHB patients in mainland China. Latitude and genetic determinants affect vitamin D status. Baseline vitamin D level can predict week-104 virologic response, but not HBeAg seroconversion or ALT normalization. PMID- 28834609 TI - Application of 3D Laser Scanner to Forensic Engineering. AB - In the case of building collapses and overturned structures, a three-dimensional (3D) collapse or overturn model is required to reconstruct the accident. As construction sites become increasingly complex and large, 3D laser scanning is sometimes the best tool to accurately document and store the site conditions. This case report presents one case of a structure collapse and one case of an overturned crane reconstructed by a 3D laser scanner. In the case of structural collapse of a prefabricated shoring system, a 3D model reconstructed all the members successfully, a task that is nearly impossible using a scale such as a tape measure. The reconstructed prefabricated shoring system was verified through a structural analysis through comparison with the construction drawings to investigate faults in construction. In the case of the overturned crane, the jib angle and other major dimensions were successfully acquired through 3D laser scanning and used to estimate the working radius. As a result, the propriety of the working radius with the given lifting load was successfully determined. PMID- 28834608 TI - Accuracy of self-reported smoking abstinence in clinical trials of hospital initiated smoking interventions. AB - AIMS: To estimate the prevalence and predictors of failed biochemical verification of self-reported abstinence among participants enrolled in trials of hospital-initiated smoking cessation interventions. DESIGN: Comparison of characteristics between participants who verified and those who failed to verify self-reported abstinence. SETTINGS: Multi-site randomized clinical trials conducted between 2010 and 2014 in hospitals throughout the United States. PARTICIPANTS: Recently hospitalized smokers who reported tobacco abstinence 6 months post-randomization and provided a saliva sample for verification purposes (n = 822). MEASUREMENTS: Outcomes were salivary cotinine-verified smoking abstinence at 10 and 15 ng/ml cut-points. Predictors and correlates included participant demographics and tobacco use; hospital diagnoses and treatment; and study characteristics collected via surveys and electronic medical records. FINDINGS: Usable samples were returned by 69.8% of the 1178 eligible trial participants who reported 7-day point prevalence abstinence. The proportion of participants verified as quit was 57.8% [95% confidence interval (CI) = 54.4, 61.2; 10 ng/ml cut-off] or 60.6% (95% CI = 57.2, 63.9; 15 ng/ml). Factors associated independently with verification at 10 ng/ml were education beyond high school education [odds ratio (OR) = 1.51; 95% CI = 1.07, 2.11], continuous abstinence since hospitalization (OR = 2.82; 95% CI = 2.02, 3.94), mailed versus in-person sample (OR = 3.20; 95% CI = 1.96, 5.21) and race. African American participants were less likely to verify abstinence than white participants (OR = 0.64; 95% CI = 0.44, 0.93). Findings were similar for verification at 15 ng/ml. Verification rates did not differ by treatment group. CONCLUSIONS: In the United States, high rates (40%) of recently hospitalized smokers enrolled in smoking cessation trials fail biochemical verification of their self-reported abstinence. PMID- 28834610 TI - Nestin expression is dynamically regulated in cardiomyocytes during embryogenesis. AB - The transcriptional factors implicated in the expression of the intermediate filament protein nestin in cardiomyocytes during embryogenesis remain undefined. In the heart of 9,5-10,5 day embryonic mice, nestin staining was detected in atrial and ventricular cardiomyocytes and a subpopulation co-expressed Tbx5. At later stages of development, nestin immunoreactivity in cardiomyocytes gradually diminished and was absent in the heart of 17,5 day embryonic mice. In the heart of wild type 11,5 day embryonic mice, 54 +/- 7% of the trabeculae expressed nestin and the percentage was significantly increased in the hearts of Tbx5+/- and Gata4+/- embryos. The cell cycle protein Ki67 and transcriptional coactivator Yap-1 were still prevalent in the nucleus of nestin(+) -cardiomyocytes identified in the heart of Tbx5+/- and Gata4+/- embryonic mice. Phorbol 12,13-dibutyrate treatment of neonatal rat ventricular cardiomyocytes increased Yap-1 phosphorylation and co-administration of the p38 MAPK inhibitor SB203580 led to significant dephosphorylation. Antagonism of dephosphorylated Yap-1 signalling with verteporfin inhibited phorbol 12,13-dibutyrate/SB203580-mediated nestin expression and BrdU incorporation of neonatal cardiomyocytes. Nestin depletion with an AAV9 containing a shRNA directed against the intermediate filament protein significantly reduced the number of neonatal cardiomyocytes that re entered the cell cycle. These findings demonstrate that Tbx5- and Gata4-dependent events negatively regulate nestin expression in cardiomyocytes during embryogenesis. By contrast, dephosphorylated Yap-1 acting via upregulation of the intermediate filament protein nestin plays a seminal role in the cell cycle re entry of cardiomyocytes. Based on these data, an analogous role of Yap-1 may be prevalent in the heart of Tbx5+/- and Gata4+/- mice. PMID- 28834611 TI - A Molecular Method to Detect Wound Cells in Bloodstains Resultant of Sharp Force Injuries for Crime Scene Reconstruction. AB - Previous research by the authors on an animal model showed that bloodstains can contain additional information about their somatic origin in the form of wound cells. Bloodstains produced by a gunshot wound to the head were distinguished from bloodstains produced by a gunshot wound to the chest by testing the stains for a brain microRNA marker. In this study, the effectiveness of the technique was examined on blood drops shed externally from a stab wound to the liver of rat carcasses. Specifically, investigations were conducted on the liver microRNA marker, rno-mir-122-3p, with the QIAGEN miScript System, and PCR analysis. Between the two stabbing methods used, 67% of the scalpel blades and 57% of the blood drops tested positive for rno-mir-122-3p; however, other samples tested negative giving inconclusive results as to the wound-of-origin. The amount of the liver cells in the bloodstains appeared to be related to the extent of trauma. PMID- 28834612 TI - Reply to Comments by Pescitelli and Bruhn on "Cocaine Hydrochloride Structure in Solution Revealed by Three Chiroptical Methods". PMID- 28834613 TI - An aptamer-based paper microfluidic device for the colorimetric determination of cocaine. AB - A method utilizing paper microfluidics coupled with gold nanoparticles and two anticocaine aptamers has been developed to detect seized cocaine samples. The ready-to-use format involves the use of a paper strip that produces a color change resulting from the salt-induced aggregation of gold nanoparticles producing a visible color change indicating the presence of the drug. This format is specific for the detection of cocaine. The visual LOD for the method was 2.5 MUg and the camera based LOD was 2.36 MUg. The operation of the device is easy and rapid, and does not require extensive training or instrumentation. All of the materials utilized in the device are safe and environmental friendly. This device should prove a useful tool for the screening of forensic samples. PMID- 28834614 TI - Molecular Engineering of Tetracyclic 2,3-Dihydro-1H-benzo[2,3]-benzofuro[4,5 e][1,3]oxazine Derivatives: Evaluation for Potential Anticancer Agents. AB - Water-mediated one-pot Mannich type condensation of dibenzo[b,d]furan-2-ol with different amines resulted in a large library of novel 2,3-dihydro-1H benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives in moderate to excellent yields. The ortho-aminomethylation of the dibenzofuranols proceeded smoothly in the presence of various aromatic/aliphatic amines and paraformaldehyde, followed by cyclization. All the newly synthesized tetracyclic 2,3-dihydro-1H benzo[2,3]benzofuro[4,5-e][1,3]oxazine derivatives were chemically characterized and screened for their cytotoxicity activity by cell viability assay (MTT test) against three human cancer cell lines and antibacterial activity by determining the minimum inhibitory concentration (MIC) against four bacterial strains. Among all the derivatives, MCV-24 showed promising anticancer activity by inhibiting the cell proliferation of an ovarian cancer cell line (SKOV3) with an IC50 value at 7.5 uM, whereas MCV-24 to MCV-30 derivatives showed moderate activity against a lung cancer cell line (A549) with an IC50 value ranging from 11 to 15.9 uM. Besides MCV-29, -30, and -31 also exhibited broad-spectrum antibacterial activity. Among all new compounds, MCV-24-30 showed promising anticancer and MCV 29-31 antibacterial activity. PMID- 28834615 TI - Self-assembled liver organoids recapitulate hepatobiliary organogenesis in vitro. AB - : Several three-dimensional cell culture systems are currently available to create liver organoids. In gneral, these systems display better physiologic and metabolic aspects of intact liver tissue compared with two-dimensional culture systems. However, none reliably mimic human liver development, including parallel formation of hepatocyte and cholangiocyte anatomical structures. Here, we show that human fetal liver progenitor cells self-assembled inside acellular liver extracellular matrix scaffolds to form three-dimensional liver organoids that recapitulated several aspects of hepatobiliary organogenesis and resulted in concomitant formation of progressively more differentiated hepatocytes and bile duct structures. The duct morphogenesis process was interrupted by inhibiting Notch signaling, in an attempt to create a liver developmental disease model with a similar phenotype to Alagille syndrome. CONCLUSION: In the current study, we created an in vitro model of human liver development and disease, physiology, and metabolism, supported by liver extracellular matrix substrata; we envision that it will be used in the future to study mechanisms of hepatic and biliary development and for disease modeling and drug screening. (Hepatology 2017; 00:000 000). PMID- 28834616 TI - Call to Action: The Case for Advancing Disaster Nursing Education in the United States. AB - PURPOSE: Climate change, human conflict, and emerging infectious diseases are inexorable actors in our rapidly evolving healthcare landscape that are triggering an ever-increasing number of disaster events. A global nursing workforce is needed that possesses the knowledge, skills, and abilities to respond to any disaster or large-scale public health emergency in a timely and appropriate manner. The purpose of this article is to articulate a compelling mandate for the advancement of disaster nursing education within the United States with clear action steps in order to contribute to the achievement of this vision. DESIGN AND METHODS: A national panel of invited disaster nursing experts was convened through a series of monthly semistructured conference calls to work collectively towards the achievement of a national agenda for the future of disaster nursing education. FINDINGS: National nursing education experts have developed consensus recommendations for the advancement of disaster nursing education in the United States. This article proposes next steps and action items to achieve the desired vision of national nurse readiness. CONCLUSIONS: Novel action steps for expanding disaster educational opportunities across the continuum of nursing are proposed in response to the current compelling need to prepare for, respond to, and mitigate the impact of disasters on human health. U.S. educational institutions and health and human service organizations that employ nurses must commit to increasing access to a variety of quality disaster related educational programs for nurses and nurse leaders. CLINICAL RELEVANCE: Opportunities exist to strengthen disaster readiness and enhance national health security by expanding educational programming and training for nurses. PMID- 28834617 TI - Mid wall fibrosis on CMR with late gadolinium enhancement may predict prognosis for LVAD and transplantation risk in patients with newly diagnosed dilated cardiomyopathy-preliminary observations from a high-volume transplant centre. AB - BACKGROUND: Patients with newly diagnosed dilated cardiomyopathy (DCM) and advanced heart failure have a very high morbidity and mortality with an unpredictable clinical course. We investigated the role of cardiovascular magnetic resonance (CMR) imaging using late gadolinium enhancement (LGE) in this cohort of high-risk patients. We hypothesized that LGE has high prognostic value in primary DCM patients referred for possible transplantation/left ventricular assist device (LVAD) consideration. METHODS: Over 49 consecutive months, 61 consecutives DCM patients were referred for standard CMR(1.5T, GE) to interrogate the LV pattern, distribution, and extent of LGE (MultiHance, Princeton, NJ). Inclusion criteria for a primary non-ischaemic DCM and EF <45% were met in 31 patients. DCM patients were categorized into: (i) presence of midwall LV stripe (+Stripe) and (ii) absence of midwall stripe (-Stripe) groups. Primary outcome was defined by the composite of death, need for LV assist device (LVAD), and urgent orthotopic cardiac transplantation (Tx) during a 12-month follow-up period. Kaplan-Meier survival analysis was conducted grouping patients by +Stripe and -Stripe. RESULTS: There were no differences between groups for demographics, blood pressure, labs, baseline LVEF, NYHA class, or invasive haemodynamics. There were 18 patients (58%) with +Stripe. Nine events occurred: seven patients required urgent Tx and/or LVAD implantation and two patients died. The +Stripe categorization strongly predicted the need for LVAD, urgent Tx surgery, and death (log-rank = 9, P = 0.002). All the events occurred in the +Stripe patients with no MACE experienced in the -Stripe group. The -Stripe group experienced marked signs of improvement in LVEF (P = 0.01) at follow-up. LVEDD was predictive of need for LVAD/Tx and death by univariate analysis. Otherwise, no common clinical metric such as LVEF, LVEDV, RVEF, RVEDV, or any invasive haemodynamic parameter predicted MACE. CONCLUSIONS: The presence of +Stripe on CMR is strongly predictive of LVAD, transplant need, and death during a 12-month follow-up period in DCM patients in this proof of concept study. All -Stripe patients survived without experiencing any events. Incorporating CMR imaging into routine clinical practice may have prognostic value in DCM patients; indicating conservative management in low-risk patients while expectantly managing high-risk patients. PMID- 28834618 TI - Clinical significance of bilateral leg edema and added value of monitoring weight gain during follow-up of patients with established heart failure. AB - PURPOSE: This study evaluated the clinical characteristics of bilateral leg edema during follow-up of heart failure (HF) patients and determined the added value of monitoring fluid weight gain for deciding whether this non-specific sign is a more clinically relevant sign. METHODS: Retrospective analysis was performed on 1826 visits from 83 ambulatory patients with established mild-to-moderate HF. Evaluated HF-related signs included leg edema, pulmonary crackles, S3, weight gain, and ultrasound pleural effusion. RESULTS: During follow-up, 75 patients with 161 visits had at least one of the following HF-related events: weight gain (n = 107), leg edema (n = 90), ultrasound pleural effusion (n = 85), pulmonary crackles (n = 29), and S3 (n = 16). Compared with the events of sole leg edema (n = 23), leg edema events with additional HF-related sign(s) (n = 67) accompanied more symptomatic worsening (7% vs. 55%, P < 0.0001), and a higher incidence (61% vs. 96%, P = 0.0002) and magnitude of increased serum B-type natriuretic peptide. Sole leg edema events rarely progressed to worsening HF before the next regular clinic visit. Patients with the event of both leg edema and weight gain more often experienced worsening HF requiring extra clinic visits and/or hospitalization. Amongst a total of 67 leg edema events with additional HF related signs, 56 (84%) coexisted with weight gain. Therefore, additional monitoring of weight gain efficiently distinguished the clinically significant leg edema events from insignificant sole leg edema events. CONCLUSIONS: During follow-up of mild-to-moderate HF patients, sole leg edema appeared around 30% of the leg edema events, which is considered clinically insignificant. Additional checking for weight gain could be useful for determining whether this sign is a clinically relevant HF-related sign. The appearance of these both signs during follow-up of established HF patients should be intentionally watched or treated by extra diuretics and/or drug adjustment to prevent worsening of HF. PMID- 28834620 TI - Hyaluronic Acid Graft Copolymers with Cleavable Arms as Potential Intravitreal Drug Delivery Vehicles. AB - Treatment of retinal diseases currently demands frequent intravitreal injections due to rapid clearance of the therapeutics. The use of high molecular weight polymers can extend the residence time in the vitreous and prolong the injection intervals. This study reports a water soluble graft copolymer as a potential vehicle for sustained intravitreal drug delivery. The copolymer features a high molecular weight hyaluronic acid (HA) backbone and poly(glyceryl glycerol) (PGG) side chains attached via hydrolysable ester linkers. PGG, a polyether with 1,2 diol groups in every repeating unit available for conjugation, serves as a detachable carrier. The influence of synthesis conditions and incubation in physiological media on the molecular weight of HA is studied. The cleavage of the PGG grafts from the HA backbone is quantified and polymer-from-polymer release kinetics are determined. The biocompatibility of the materials is tested in different cell cultures. PMID- 28834619 TI - Efficacy and safety of supramaximal titrated inhibition of renin-angiotensin aldosterone system in idiopathic dilated cardiomyopathy. AB - AIMS: The optimal dosing strategies for blocking the renin-angiotensin aldosterone system in idiopathic dilated cardiomyopathy (IDCM) are poorly known. We sought to determine the long-term efficacy and safety of supramaximal titration of benazepril and valsartan in patients with IDCM. METHODS AND RESULTS: 480 patients with IDCM in New York Heart Association functional class II-IV and with left ventricular ejection fraction <=35% were randomly assigned to extended release metoprolol (mean 152 mg/day, range 23.75-190), low-dose benazepril (20 mg/day), low-dose valsartan (160 mg/day), high-dose benazepril (mean 69 mg/day, range 40-80), and high-dose valsartan (mean 526 mg/day, range 320-640). After a median follow-up of 4.2 years, high-dose benazepril and valsartan, compared with their respective low dosages, resulted in 41% and 52% risk reduction in the primary endpoint of all-cause death or admission for heart failure (P = 0.042 and 0.002), promoted functional improvement, and reversed remodelling as assessed by New York Heart Association classes, quality-of-life scores, and echocardiographic recording of left ventricular ejection fraction, left ventricular end-diastolic volume, mitral regurgitation, and wall motion score index. Compared with metoprolol, high-dose valsartan reduced risk for the primary endpoint by 46% (P = 0.006), whereas high-dose benazepril and both low-dose groups showed no significant difference. Major adverse events involved hypotension and renal impairment but were largely tolerated. CONCLUSIONS: Supramaximal doses of benazepril and valsartan were well tolerated and produced extra benefit than their low dosages in clinical outcome and cardiac reverse remodelling in patients with IDCM and modest-severe heart failure. ClinicalTrials.gov identifier: NCT01917149. PMID- 28834621 TI - Isolation of a phytotoxic isocoumarin from Diaporthe eres-infected Hedera helix (English ivy) and synthesis of its phytotoxic analogs. AB - BACKGROUND: The fungus Diaporthe eres was isolated from a fungal pathogen infected leaf of Hedera helix (English ivy) exhibiting necrosis. It is hypothesized that the causative fungus produces phytotoxins as evidenced by necrotic lesions on the leaves. RESULTS: The fungus was isolated and grown in Czapek Dox broth culture medium and potato dextrose broth culture medium and identified as Diaporthe eres. The ethyl acetate extracts of the culture broths were phytotoxic to lettuce (Lactuca sativa) and bentgrass (Agrostis stolonifera). 3,4-Dihydro-8-hydroxy-3,5-dimethylisocoumarin (1) and tyrosol (2) were isolated and identified as the phytotoxic constituents. Six analogs of 3,4-dihydro isocoumarin were synthesized and shown to be phytotoxic. The synthesized 3,4 dihydro-8-hydroxy-3,7-dimethylisocoumarin and 3,4-dihydro-8-hydroxy-3,3,7 trimethylisocoumarin were two- to three-fold more phytotoxic than the naturally occurring 1 in a Lemna paucicostata growth bioassay. CONCLUSION: Synthesis and herbicidal activities of the several new analogs of 1 are reported for the first time. These promising molecules should be used as templates for synthesis and testing of more analogs. (c) 2017 Society of Chemical Industry. PMID- 28834622 TI - Development of the Endoscopic Endonasal Sinus and Skull Base Surgery Questionnaire. AB - BACKGROUND: The patients' perspective of health outcomes has become important input for assessing treatment effects. However, existing endoscopic endonasal surgery (EES) instruments are not fully aligned with the concept of health related quality of life (HRQoL). A prospective cohort study was therefore conducted to develop a suitable quality-of-life tool to assess nasal morbidity after EES: the Endoscopic Endonasal Sinus and Skull Base Surgery Questionnaire (EES-Q). METHODS: The study included 300 patients: 207 with sinus pathology and 93 with anterior skull base pathology. The EES-Q was administered prior to surgery and postoperatively (2 weeks, 3 months, and 1 year). Psychometric instrument properties were tested and relevant health domains were formulated. Seventy-two items were generated by the conventional psychometric approach. An exploratory factor analysis was used to test construct validity. The optimal number of factors to retain was determined by using the eigenvalues-greater-than 1 rule and scree plot. Orthogonal varimax rotation was used to enhance interpretability. Internal consistency was assessed using the Cronbach alpha. RESULTS: The factor analysis yielded a 3-factor solution, representing physical, psychological, and social functioning. The final version of the instrument consisted of 30 items with a high internal consistency (>0.80) for all 3 HRQoL domains. CONCLUSIONS: The EES-Q is a comprehensive, multidimensional, disease specific instrument. A distinguishing characteristic is that, apart from the physical and psychological domains, the EES-Q also encompasses a social domain. Understanding different HRQoL aspects in patients undergoing EES may help caregivers restore, improve, or preserve the patient's health through individualized care, which depends on identifying their specific needs. PMID- 28834623 TI - Hepatitis B Virus-Hepatitis D Virus mother-to-child co-transmission: A retrospective study in a developed country. AB - BACKGROUND & AIMS: Hepatitis B Virus (HBV) DNA during chronic infection can reach levels at which mother-to-child (MTC) transmission frequently occurs despite passive-active immunization of newborns. Hepatitis D Virus (HDV) RNA can reach high levels, we assessed HBV/HDV MTC co-transmission. METHODS: Monocentric retrospective study (registered in ClinicalTrials.gov (NCT02044055)), after informed consent in HBV/HDV co-infected women pregnant between 01/01/2004 and 01/01/2015 in Paris, France. The children were tested when 24 months of age or older. RESULTS: Twenty-two (3%) of 742 HBV infected women, HDV co-infected, gave birth to 54 children during the study period. HBV DNA was above 5 Log10 I.U/mL in 10 pregnancies previous any treatment, with HDV RNA of less than 2.3 Log10 I.U/mL. HDV RNA was above 5 Log10 I.U/mL in eight pregnancies previous any treatment, with HBV DNA of less than 1.5 Log10 I.U/mL. Inverse patterns of HBV DNA and HDV RNA were observed in 17 of 35 (49%) pregnancies: 13 (76%) received no HBV treatment; four (24%) were treated. HBV DNA was under 5 Log10 I.U/mL in 46 of the 50 assessed women (92%) at birth. Of the 36 assessed children, given passive active immunization, 24 (66%) were protected, 10 (28%) were neither infected nor protected, one was chronically HBV infected, and one had a past HBV infection. HDV Ab was negative in the 36 children. CONCLUSIONS: These results suggest that HBV/HDV MTC co-transmission is exceptional. Studies are needed, mainly in developing countries. PMID- 28834624 TI - Capturing "Extraordinary" Soft-Assembled Charge-Like Polypeptides as a Strategy for Nanocarrier Design. AB - The rational design of nanomedicines is a challenging task given the complex architectures required for the construction of nanosized carriers with embedded therapeutic properties and the complex interface of these materials with the biological environment. Herein, an unexpected charge-like attraction mechanism of self-assembly for star-shaped polyglutamates in nonsalty aqueous solutions is identified, which matches the ubiquitous "ordinary-extraordinary" phenomenon previously described by physicists. For the first time, a bottom-up methodology for the stabilization of these nanosized soft-assembled star-shaped polyglutamates is also described, enabling the translation of theoretical research into nanomaterials with applicability within the drug-delivery field. Covalent capture of these labile assemblies provides access to unprecedented architectures to be used as nanocarriers. The enhanced in vitro and in vivo properties of these novel nanoconstructs as drug-delivery systems highlight the potential of this approach for tumor-localized as well as lymphotropic delivery. PMID- 28834626 TI - Steps forward in regulatory pathways for acute and chronic heart failure. AB - A workshop was organized by the Agenzia Italiana del Farmaco (AIFA) to discuss unmet needs and ways forward in the development of medicines in heart failure, their rationale, and cost-effective use. An integrated, multidisciplinary approach, including patients' needs and perspectives, was advocated by all the participants as the way to the most effective treatment regimens. More work is needed for reaching consensus on clinical and functional endpoints, for validating patient reported outcomes and measurements of well-being. Similarly, the integration into the clinical programmes of the health technology assessment/payers perspective, in particular, the evaluation of 'real-life' treatment effectiveness and of health as a value, would help in shifting the development and authorization of medicines from the molecule paradigm to their evaluation in the context of the whole health care regimen. Through this kind of workshop, AIFA is trying to build a template for meetings devoted to debate unmet needs with all stakeholders towards tentative road maps for the future. PMID- 28834625 TI - Rational Optimization of Supramolecular Catalysts for the Rhodium-Catalyzed Asymmetric Hydrogenation Reaction. AB - Rational design of catalysts for asymmetric transformations is a longstanding challenge in the field of catalysis. In the current contribution we report a catalyst in which a hydrogen bond between the substrate and the catalyst plays a crucial role in determining the selectivity and the rate of the catalytic hydrogenation reaction, as is evident from a combination of experiments and DFT calculations. Detailed insight allowed in silico mutation of the catalyst such that only this hydrogen bond interaction is stronger, predicting that the new catalyst is faster. Indeed, we experimentally confirmed that optimization of the catalyst can be realized by increasing the hydrogen bond strength of this interaction by going from a urea to phosphine oxide H-bond acceptor on the ligand. PMID- 28834627 TI - Predictive power of late gadolinium enhancement for myocardial recovery in chronic ischaemic heart failure: a HEART sub-study. AB - BACKGROUND: The amount of myocardial scar measured by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging predicts regional recovery in wall motion following revascularization. Previous studies have been conducted in patients with a relatively recent myocardial insult and relatively preserved left ventricular (LV) function. In this sub-study of a clinical trial, the predictive value of LGE, and other CMR-derived data, for myocardial recovery in patients with chronic severe ischaemic cardiomyopathy was assessed. METHODS: Twenty-two patients with severe LV impairment of ischaemic origin were enrolled as a sub-study of a trial that randomly assigned patients to revascularization or not in addition to guideline-indicated pharmacological therapy. Patients underwent a CMR study at baseline and 6 months. Scans were qualitatively and quantitatively assessed for wall motion, rest/stress myocardial perfusion, and LGE. RESULTS: The median duration of heart failure was 13 (inter-quartile range 5 21) months. Patients had severe LV dilatation [end-diastolic volume (EDV) 280 +/- 77 mL] and reduction in LV ejection fraction (LVEF) (29 +/- 10%). The percentage scar burden by LGE was 17 +/- 9%. Patient characteristics of those undergoing revascularization (n = 7) or not (n = 14) were similar. Myocardial perfusion reserve index (MPRI) improved following revascularization (MPRI 1.17 vs. 1.57, P < 0.0001) but not following medical therapy (1.39 vs. 1.32, P = 0.54). However, LVEF improved in patients whether or not they had revascularization. In the revascularization group, 14% of dysfunctional segments with LGE <25% and 22% of dysfunctional segments with LGE <50% had improved contractile function. However, the transmural extent of LGE did not predict contractile recovery following revascularization or pharmacological therapy (P = 0.19, P = 0.42). LVEDV improved overall (280 +/- 77 to 269 +/- 83 mL, P = 0.05); improvement was associated with heart failure duration (P = 0.04). CONCLUSIONS: In patients with chronic severe LV impairment of ischaemic origin, duration of heart failure is a better predictor of recovery than transmural extent of LGE, following medical therapy or successful revascularization. This suggests that the extent of myocardial remodelling is more important for LV recovery than the presence and extent of prior infarction alone and that LGE should not be the sole determinant of treatment method in severe LV systolic dysfunction of ischaemic origin. PMID- 28834628 TI - Improving care for patients with acute heart failure: before, during and after hospitalization. AB - Acute heart failure (AHF) is a common and serious condition that contributes to about 5% of all emergency hospital admissions in Europe and the USA. Here, we present the recommendations from structured discussions among an author group of AHF experts in 2013. The epidemiology of AHF and current practices in diagnosis, treatment, and long-term care for patients with AHF in Europe and the USA are examined. Available evidence indicates variation in the quality of care across hospitals and regions. Challenges include the need for rapid diagnosis and treatment, the heterogeneity of precipitating factors, and the typical repeated episodes of decompensation requiring admission to hospital for stabilization. In hospital, care should involve input from an expert in AHF and auditing to ensure that guidelines and protocols for treatment are implemented for all patients. A smooth transition to follow-up care is vital. Patient education programmes could have a dramatic effect on improving outcomes. Information technology should allow, where appropriate, patient telemonitoring and sharing of medical records. Where needed, access to end-of-life care and support for all patients, families, and caregivers should form part of a high-quality service. Eight evidence-based consensus policy recommendations are identified by the author group: optimize patient care transitions, improve patient education and support, provide equity of care for all patients, appoint experts to lead AHF care across disciplines, stimulate research into new therapies, develop and implement better measures of care quality, improve end-of-life care, and promote heart failure prevention. PMID- 28834629 TI - Sexual function in patients supported with left ventricular assist device and with heart transplant. AB - AIMS: Sexual dysfunction is common among patients with heart failure (HF) and considered an important hamper to quality of life. While implantation of left ventricular assist device (LVAD) may prolong and improve life in advanced HF, limited data are available on its impact on sexual function. The aim of this study is to evaluate sexual function in LVAD patients and compare this with patients after heart transplantation (HTx). METHODS AND RESULTS: Sexual activity and satisfaction of stable patients with durable LVAD or after HTx were evaluated using a validated questionnaire and visual analogue scale from 0 to 10. Data were collected from 31 patients (mean age 59 +/- 12 years, 87% male), 17 after HTx and 14 with LVAD. Pleasure or satisfaction with sex was significantly higher in HTx patients (P = 0.0005). In total, 29% LVAD patients and 71% HTx patients reported content with sexual activity. Recalled satisfaction with sex life pre-operation was comparable between the groups. During support, satisfaction with sex life using visual analogue scale was 7.6 +/- 3.1 for HTx versus 3.9 +/- 4.0 for LVAD patients (P = 0.017). In total, 11 LVAD patients (79%) reported specific problems in sexual function including erectile dysfunction or vaginal dryness (8, 57%); problems with the LVAD, cable, or batteries (5, 36%); problems with orgasm (4,29%); and other problems such as fear of injury, feeling depressed, partner issues, self-image, and pain (1, 7% each). CONCLUSION: Sexual dysfunction occurs in patients with LVAD support and may be more prominent than after HTx. Problems limiting sexual function related to physiological, psychological, and equipment merit consideration during follow-up. PMID- 28834630 TI - Summary of basic science activities at the European Society of Cardiology Congress in Barcelona 2014. AB - With >35 000 participants, the European Society of Cardiology (ESC) congress was one of the biggest ESC events ever and basic science activities were well implemented. I here summarize the basic science activities during the congress. This includes a section 'Basic science activities in a nutshell' summarizing the most important sessions as well as 'Emerging science activities in the ESC' section with special focus on novel research fields such as the characterization of long non-coding RNAs in cardiovascular research. PMID- 28834631 TI - Altered myocardial force generation in end-stage human heart failure. AB - AIMS: This study aimed to elucidate the molecular background of increased Ca2+ sensitivity of force production in cardiomyocytes of end-stage human heart failure. METHODS AND RESULTS: Ca2+ -activated isometric force and the cross bridge specific rate of force redevelopment (ktr ) were determined in Triton skinned myocytes from end-stage failing and non-failing donor hearts. Measurements (control: pH 7.2, 0 mM inorganic phosphate (Pi )) were performed under test conditions that probed either the Ca2+ -regulatory function of the thin filaments (pH 6.5), the kinetics of the actin-myosin cross-bridge cycle (10 mM Pi ), or both (pH 6.5, 10 mM Pi ). The control maximal Ca2+ -activated force (Fo ) and ktrmax did not differ between failing and non-failing myocytes. At submaximal [Ca2+ ], however, both force and ktr were higher in failing than in donor myocytes. The difference in the Ca2+ sensitivities of force production was preserved when the thin filament regulatory function was perturbed by acidosis (pH 6.5) but was abolished by cross-bridge modulation (i.e. by Pi ) both at pH 7.2 and at pH 6.5. Pi induced a larger reduction in force but a smaller increase in ktr in the failing myocytes than in the non-failing myocytes at submaximal [Ca2+ ]. CONCLUSION: The enhanced Pi sensitivity of the actin-myosin interaction suggests that the Pi release step of the actin-myosin cross-bridge cycle is modified during end-stage human heart failure. This might be of functional importance when Pi accumulates (e.g. during cardiac ischaemia). Moreover, this alteration can influence cardiac energetics and the clinical efficacy of sarcomere targeted agents in human heart failure. PMID- 28834632 TI - Heart rate reduction with ivabradine improves left ventricular function and reverses multiple pathological maladaptations in dogs with chronic heart failure. AB - PURPOSE: We tested the hypothesis that heart rate (HR) reduction with ivabradine (IVA) leads to reversal of structural, biochemical, and molecular maladaptations characteristic of the heart failure (HF) state. HR reduction with IVA has been shown to improve left ventricular (LV) systolic function and clinical outcome in patients with HF. METHODS: Studies were performed in 16 HF dogs produced by intracoronary microembolizations [LV ejection fraction (EF) ~35%]. Dogs were randomized to 3-month oral therapy with IVA (30 mg Bid, n = 8) or to no therapy (Control, n = 8). LV tissue was obtained from all dogs at the end of therapy and used for molecular, biochemical, and histological studies. RESULTS: Average 24-h ambulatory Holter monitoring showed a significant decrease of HR in IVA-treated dogs compared with controls. Compared with pre-therapy, LV EF decreased at 3 months in controls (36 +/- 1 vs. 32 +/- 2%, P < 0.05) but increased significantly with IVA (40 +/- 3 vs. 35 +/- 3%, P < 0.05). Treatment with IVA was associated with (i) improved LV diastolic function; (ii) increased sarcoplasmic reticulum Ca2+ uptake and ATPase activity; (iii) decreased plasma levels of vasoactive neurohormones, natriuretic peptides, and pro-inflammatory cytokines; (iv) normalization of messenger RNA gene expression of multiple signalling pathways; and (v) reduced cardiomyocyte apoptosis and hypertrophy. CONCLUSION: In dogs with HF, HR reduction with IVA reversed many of the structural, biochemical, and molecular maladaptations characteristic of HF. The findings support the concept that HR reduction in HF can elicit benefits, albeit indirect, on a host of maladaptations implicated in the progressive worsening of the HF state. PMID- 28834633 TI - Clinical trials update from the European Society of Cardiology meeting 2014: PARADIGM-HF, CONFIRM-HF, SIGNIFY, atrial fibrillation, beta-blockers and heart failure, and vagal stimulation in heart failure. AB - This article provides an overview of trials relevant to the pathophysiology, prevention, and treatment of heart failure, presented at the European Society of Cardiology meeting held in Barcelona in autumn 2014. Trials reported here include PARADIGM-HF (LCZ696 versus enalapril in heart failure), CONFIRM-HF (treatment of iron deficiency in heart failure), and SIGNIFY (ivabradine in patients with stable coronary artery disease). In addition, we discuss recent developments in the treatment of atrial fibrillation and the lack of benefit with the use of beta blockers in these patients. Finally, the article describes recent advances in the use of vagal stimulation in patients with heart failure. (c) 2014 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. PMID- 28834634 TI - When to increase or reduce sodium loading in the management of fluid volume status during acute decompensated heart failure. AB - Sodium restriction has been believed to be indispensible to manage fluid overload during acute decompensated heart failure (ADHF). However, recently, it was reported that a change in aggression of sodium and water restriction did not affect the outcome of ADHF. In contrast, current data suggest that small amount of hypertonic saline solution with high-dose furosemide produces an improvement in haemodynamic and clinical parameters without any severe adverse effects. In this perspective, first, we are going to describe the effects of sodium loading on neurohormonal activation, body's sodium balance, and renal function in chronic heart failure and the efficacy of loop diuretics in ADHF. Then, we are going to explain the possible mechanisms by which sodium loading enhances the efficacy of loop diuretics and about the clinical conditions during which sodium loading should be avoided. PMID- 28834635 TI - Effects of the Formulations of Silicon-Based Composite Anodes on their Mechanical, Storage, and Electrochemical Properties. AB - In this work, the effects of the formulation of silicon-based composite anodes on their mechanical, storage, and electrochemical properties were investigated. The electrode formulation was changed through the use of hydrogenated or modified (through the covalent attachment of a binding additive such as polyacrylic acid) silicon and acetylene black or graphene sheets as conducting additives. A composite anode with a covalently grafted binder had the highest elongation without breakages and strong adhesion to the current collector. These mechanical properties depend significantly on the conductive carbon additive used and the use of graphene sheets instead of acetylene black can improve elongation and adhesion significantly. After 180 days of storage under ambient conditions, the electronic conductivity and discharge capacity of the modified silicon electrode showed much smaller decreases in these properties than those of the hydrogenated silicon composite electrode, indicating that the modification can result in passivation and a constant composition of the active material. Moreover, the composite Si anode has a high packing density. Consequently, thin-film electrodes with very high material loadings can be prepared without decreased electrochemical performance. PMID- 28834636 TI - Intraosseous Rosai-Dorfman disease diagnosed by touch imprint cytology evaluation: A case series. AB - Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD) is a rare benign disorder that primarily affects the lymph nodes. Localized lymphadenopathy is the most common clinical manifestation of this disorder. However, RDD has been described in several extra-nodal sites including the head and neck region, soft tissue, skin, upper respiratory tract, gastro intestinal tract and central nervous system (CNS). Involvement of the bone is considered very rare, occurring in less than 10% patients. RDD is one of the histiocytoses and the differential diagnosis includes entities such as Langerhans cell histiocytosis and Erdheim-Chester disease. In the rare intraosseous variant, the clinical and radiologic differential diagnosis is broader and includes neoplasms such as osteosarcoma and Ewing sarcoma. In this report, we describe three cases of extra-nodal, intraosseous RDD where touch imprint cytology played a crucial role in diagnosis. Two of the cases initially presented with involvement of the head and neck region and later developed intraosseous disease; while the third patient presented with primary bone involvement. The diagnosis was established by core biopsy with touch imprints of the bone lesions. The cytologic samples showed numerous histiocytes, often with neutrophils within their cytoplasm (emperipolesis) in addition to lymphocytes and plasma cells. The diagnosis of RDD was confirmed with appropriate immunohistochemical stains. Our account of these three cases of intraosseous Rosai-Dorfman disease highlights the role of cytology in the diagnosis of this rare entity. PMID- 28834637 TI - Permanent catheter drainage system for palliation of diuretic-resistant cardiac ascites. AB - We report the case of a 69-year-old man with dilated cardiomyopathy treated with a permanent catheter drainage system for diuretic resistant cardiac ascites. At 1 year follow-up, the patient had no heart failure related hospitalisations, displayed improved quality of life measures and had incurred no complications related to the catheter. Permanent tunnelled catheters are widely used to treat malignant ascites but may also be considered for palliation of cardiac ascites. PMID- 28834638 TI - Circulating biomarker responses to medical management vs. mechanical circulatory support in severe inotrope-dependent acute heart failure. AB - BACKGROUND: Severe inotrope-dependent acute heart failure (AHF) is associated with poor clinical outcomes. There are currently no well-defined blood biomarkers of response to treatment that can guide management or identify recovery in this patient population. In the present study, we characterized the levels of novel and emerging circulating biomarkers of heart failure in patients with AHF over the first 30 days of medical management or mechanical circulatory support (MCS). We hypothesized a shared a plasma proteomic treatment response would be identifiable in both patient groups, representing reversal of the AHF phenotype. METHODS AND RESULTS: Time course plasma samples of the first 30 days of therapy, obtained from patients managed medically (n = 8) or with implantable MCS (n = 5), underwent semi-targeted and candidate biomarker analyses, using multiple reaction monitoring (MRM) mass spectrometry, antibody arrays, and enzyme-linked immunosorbent assays. Differentially expressed proteins were identified using robust limma for MRM and antibody array data. Patients managed medically or with implantable MCS had a shared proteomic signature of six plasma proteins: circulating cardiotrophin 1, cardiac troponin T, clusterin, and dickopff 1 increased, while levels of C-reactive protein and growth differentiation factor 15 decreased in both groups over the 30 day time course. CONCLUSIONS: We have characterized the temporal proteomic signature of clinical recovery in AHF patients managed medically or with MCS, over the first 30 days of treatment. Changes in biomarker expression over the time course of treatment may provide a basis for understanding the biological basis of AHF, potentially identifying novel markers and pathophysiologic mechanisms of recovery. PMID- 28834639 TI - Rationale and design of a pilot randomized controlled trial to assess the role of intravenous ferric carboxymaltose in Asian patients with heart failure (PRACTICE ASIA-HF). AB - AIMS: Iron deficiency (ID) is highly prevalent in patients with heart failure (HF) worldwide regardless of haemoglobin levels. Results from therapeutic trials of intermittently dosed intravenous (i.v.) iron are promising in the ambulatory Caucasian population with HF with reduced left ventricular ejection fraction, although evidence is scarce in Asia. The Pilot Randomized Controlled Trial to Assess the Role of Intravenous Ferric Carboxymaltose in Asian Patients with Heart Failure aims to assess the effect of single-dose i.v. ferric carboxymaltose (FCM) in a multi-ethnic Asian population with HF and ID. METHODS AND RESULTS: This is an open-label, randomized, placebo-controlled trial recruiting stabilized inpatients with decompensated HF (regardless of left ventricular ejection fraction), ID [defined as serum ferritin <300 ng/mL if transferrin saturation <20%] and haemoglobin <=14 g/dL. Patients from two tertiary institutions were randomized in a 1:1 ratio to receive a single dose of either i.v. FCM (Ferinject(r)) 1000 mg or i.v. normal saline. The primary endpoint is the change in 6-min walk distance at Weeks 4 and 12, and secondary endpoints are changes at Weeks 4 and 12 in (i) quality of life as measured by the Kansas City Cardiomyopathy Questionnaire and Visual Analogue Scale scores and (ii) New York Heart Association functional class. CONCLUSIONS: Preliminary efficacy data on i.v. FCM therapy in Asian HF are expected from this pilot study to support larger scale multicentre therapeutic i.v. FCM trials within Asia. PMID- 28834640 TI - A Self-Assembled Oligopeptide as a Versatile NMR Alignment Medium for the Measurement of Residual Dipolar Couplings in Methanol. AB - Residual dipolar coupling (RDC) is a powerful structural parameter for the determination of the constitution, conformation, and configuration of organic molecules. Herein, we report the first liquid crystal-based orienting medium that is compatible with MeOH, thus enabling RDC acquisitions of a wide range of intermediate to polar organic molecules. The liquid crystals were produced from self-assembled oligopeptide nanotubes (AAKLVFF), which are stable at very low concentrations. The presented alignment medium is highly homogeneous, and the size of RDCs can be scaled with the concentration of the peptide. To assess the accuracy of the RDC measurement by employing this new medium, seven bioactive natural products from different classes were chosen and analyzed. The straightforward preparation of the anisotropic alignment sample will offer a versatile and robust protocol for the routine RDC measurement of natural products. PMID- 28834641 TI - Effects of triiodothyronine replacement therapy in patients with chronic stable heart failure and low-triiodothyronine syndrome: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVES: The present study assessed the changes in functional, biochemical, and echocardiographic measures following long-term liothyronine therapy in heart failure (HF) patients with low-triiodothyronine (T3) syndrome (LT3S). METHODS: In the present placebo-controlled, double-blind study, adult patients with clinically stable New York Heart Association functional class I-III systolic HF and LT3S receiving standard HF therapy were randomly assigned 1:1 to receive oral liothyronine or placebo for 6 weeks. Low-T3 syndrome was defined as a serum free T3 of less than the lower limit of normal (<2.4 pg/mL) with normal thyroid stimulating hormone (thyrotropin) and free thyroxin values. RESULTS: Fifty patients, including 39 (78%) men with a mean +/- standard deviation age of 60 +/- 15 years were included. The 6-min walk distance increased in the liothyronine group by 93 +/- 16 m and in the placebo group by 67 +/- 28 m, resulting in a treatment effect of 26 m (P = 0.003). A higher decrease of high-sensitivity C reactive protein level was seen in the liothyronine group than in the placebo group (P = 0.009). Liothyronine markedly decreased serum N-terminal pro-brain natriuretic peptide level compared with the placebo (P = 0.01). A significant increase was also seen in the left ventricular ejection fraction by liothyronine as compared with the placebo (<0.001). CONCLUSION: Triiodothyronine replacement by chronic liothyronine therapy seems to safely benefit stable HF patients with LT3S receiving optimal HF medications. PMID- 28834642 TI - Falsely high B-type natriuretic peptide concentration in patients without heart failure attributed to AxSYM assay: case series of eight subjects. AB - We report a case series of eight subjects complaining of non-specific chest pain without heart failure, but with apparent high concentrations of plasma B-type natriuretic peptide (BNP). No positive clinical characteristics were identified in physical examinations, cardiac imaging, laboratory findings, or pulmonary function tests. However, we observed unusually high BNP values when analysing blood samples of the patients using the AxSYM assay, and this was not supported by readings from Triage(r) or ADVIA Centaur(r) assays on the same samples, which showed BNP within the normal range. We believe that the possibility for false readings for high BNP levels in healthy individuals measured by AxSYM assay should be taken into account by physicians in clinical practice to avoid medical errors. PMID- 28834643 TI - Hypercapnia in patients with acute heart failure. AB - AIMS: Non-invasive positive pressure ventilation rapidly improves the symptoms of acute heart failure (AHF). A portion of patients, however, are forced to be intubated even though intubation is associated with serious complications, and hypercapnia is often observed in AHF requiring intubation. The purpose of this study is to examine the clinical profile and management of hypercapnia in AHF patients. METHODS AND RESULTS: We examined the arterial blood gas analysis in 193 consecutive AHF patients (73 +/- 12 years, 61% men) at admission. Many patients (n = 129, 66.8%) had already been treated with oxygen by the ambulance staff. Hypercapnia (PaCO2 at admission >45 mmHg) and hypocapnia (PaCO2 < 35 mmHg) were observed in 33.7% and 32.6%, respectively. Whereas 16 (24.6%) hypercapnic patients were intubated, there were only one (1.5%) normocapnic and no hypocapnic patients intubated. Patients with hypercapnia are more likely to be in the New York Heart Association Class IV (96.9% vs. 78.9%, P < 0.001), to have acute onset within 6 h (50.8% vs. 25.0%, P < 0.001), and to have radiographic pulmonary oedema (84.6% vs. 57.8%, P < 0.001) than those with hypo-normocapnia. Hypercapnia was more frequent in patients with acute cardiogenic pulmonary oedema than in those with acute decompensated heart failure (51.9% vs. 23.6%, P < 0.001). At discharge, hypercapnia was observed in 17.8% of patients who were hypercapnic at admission. CONCLUSION: Hypercapnia emerged in AHF acutely and transiently, was associated with immediate airway intervention, and was possibly involved in the pathophysiology of acute pulmonary oedema. Patients with acute onset dyspnoea should have their respiratory status carefully managed. These pathophysiological findings are expected to be utilized in treating or preventing AHF. PMID- 28834644 TI - Palliative care needs in patients hospitalized with heart failure (PCHF) study: rationale and design. AB - AIMS: The primary aim of this study is to provide data to inform the design of a randomized controlled clinical trial (RCT) of a palliative care (PC) intervention in heart failure (HF). We will identify an appropriate study population with a high prevalence of PC needs defined using quantifiable measures. We will also identify which components a specific and targeted PC intervention in HF should include and attempt to define the most relevant trial outcomes. METHODS: An unselected, prospective, near-consecutive, cohort of patients admitted to hospital with acute decompensated HF will be enrolled over a 2-year period. All potential participants will be screened using B-type natriuretic peptide and echocardiography, and all those enrolled will be extensively characterized in terms of their HF status, comorbidity, and PC needs. Quantitative assessment of PC needs will include evaluation of general and disease-specific quality of life, mood, symptom burden, caregiver burden, and end of life care. Inpatient assessments will be performed and after discharge outpatient assessments will be carried out every 4 months for up to 2.5 years. Participants will be followed up for a minimum of 1 year for hospital admissions, and place and cause of death. Methods for identifying patients with HF with PC needs will be evaluated, and estimates of healthcare utilisation performed. CONCLUSION: By assessing the prevalence of these needs, describing how these needs change over time, and evaluating how best PC needs can be identified, we will provide the foundation for designing an RCT of a PC intervention in HF. PMID- 28834645 TI - Ischemic stroke and heart failure: facts and numbers. AB - Heart failure (HF) is pandemic in the modern society. Comorbidities of HF come increasingly to the fore in today's patient presentation and demand multidisciplinary treatment concepts. Ischemic stroke is a major comorbidity in HF patients and frequently contributes to the adverse outcome and functional dependency. Patients with HF are two-fold to three-fold more likely to suffer an ischemic stroke, have more than two times higher mortality and show worse functional outcome after stroke compared with non-HF subjects. The risk of recurrent stroke is about two-fold elevated in patients with HF. The risk of stroke increased with time duration of HF from 18 per 100 cases in the first year of HF to 47 per 1000 patients within the next 4-5 years. Moreover, so called 'silent' strokes (clinically asymptomatic brain lesions) are two to four times more likely in HF patients. In turn, 10-24% of stroke patients have HF. Specific characteristics of the interaction between ischemic stroke and HF have been uncovered in recent years. However, gaps in present knowledge need to be addressed in future studies. What are the detailed pathophysiologic links beyond atrial fibrillation, stroke patterns, and time courses in the interaction? What implication has HF with preserved versus reduced ejection fraction? Does treatment of HF prevents ischemic stroke or reduces stroke-related sequelae? This editorial provides a condensed overview on current insights and presents facts and numbers on the interaction between heart failure and ischemic stroke. PMID- 28834646 TI - Phospholipases AtPLDzeta1 and AtPLDzeta2 function differently in hypoxia. AB - Besides hydrolyzing different membrane phospholipids, plant phospholipases D and molecular species of their byproducts phosphatidic acids (PLDs/PAs) are involved in diverse cellular events such as membrane-cytoskeleton dynamics, hormone regulation and biotic and/or abiotic stress responses at cellular or subcellular levels. Among the 12 Arabidopsis PLD genes, PLDzeta1 and PLDzeta2 uniquely possess Ca2+ -independent phox (PX) and pleckstrin (PH) homology domains. Here, we report that mutants deficient in these PLDs, pldzeta1 and pldzeta2, show differential sensitivities to hypoxia stimulus. In the present study, we used protoplasts of wild type and mutants and compared the hypoxia-induced changes in the levels of three major signaling mediators such as cytoplasmic free calcium [Ca2+cyt. ], hydrogen peroxide (H2 O2 ) and PA. The concentrations of cytosolic Ca2+ and H2 O2 were determined by fluorescence microscopy and the fluorescent dyes Fura 2-AM and CM-H2 DCFDA, specific for calcium and H2 O2 , respectively, while PA production was analyzed by an enzymatic method. The study reveals that AtPLDzeta1 is involved in reactive oxygen species (ROS) signaling, whereas AtPLDzeta2 is involved in cytosolic Ca2+ signaling pathways during hypoxic stress. Hypoxia induces an elevation of PA level both in Wt and pldzeta1, while the PA level is unchanged in pldzeta2. Thus, it is likely that AtPLDzeta2 is involved in PA production by a calcium signaling pathway, while AtPLDzeta1 is more important in ROS signaling. PMID- 28834647 TI - Clinical and pathological features of anti-neutrophil cytoplasmic antibody associated vasculitis in patients with minor urinary abnormalities. AB - AIM: Kidney biopsy is the gold standard for diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but it is unknown whether vasculitis can be detected from AAV patients with minor urinary abnormalities. METHODS: Ninety ANCA-positive patients undergoing kidney biopsy were evaluated retrospectively after being divided into two groups, which were group A (minor urinary abnormalities with both proteinuria <0.5 g/day and red blood cells <=5/high power field) and group B (major urinary abnormalities except group A). RESULTS: Thirteen patients were included in group A and 77 patients were in group B. Crescentic glomeruli were detected less frequently in group A than in group B (61.5% vs. 92.2%, P < 0.01). The percentage of crescentic glomeruli relative to total glomeruli was significantly lower in group A than in group B (median [interquartile range]; 2.7% [0-5.2%] vs. 27.3% [8.1-56.1%], P < 0.01). Vasculitis of the small renal arteries was detected more frequently in group A than in group B without significant difference (30.8% vs. 19.5%, P = 0.46). Overall renal vasculitis (crescentic glomeruli and/or small renal artery vasculitis) was detected less frequently in group A than in group B (69.2% vs. 92.2%, P = 0.03). CONCLUSIONS: These findings indicate that renal biopsy can be a useful tool for histological diagnosis of ANCA-associated vasculitis in ANCA positive patients with minor urinary abnormalities, even though the rate of renal vasculitis to the total number of glomeruli sampled is lower in patients with minor urinary abnormalities than patients with major abnormalities. PMID- 28834648 TI - Long non-coding RNA CRALA is associated with poor response to chemotherapy in primary breast cancer. AB - BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women, and has become the second leading cause of cancer death among women worldwide. Chemoresistance has become an important problem in breast cancer clinics. The identification of new mechanisms affecting chemosensitivity is of great clinical value for the treatment of breast cancer. METHODS: The expression levels of chemoresistance-associated long non-coding RNA (CRALA), a newly discovered long non-coding RNA, were measured by quantitative real time-PCR in 79 pre-treatment biopsied primary breast cancer samples. Small interfering RNAs were used to knockdown CRALA expression. The effect of CRALA on chemosensitivity was evaluated using cell growth assay. RESULTS: Non-responding tumors (poor response to chemotherapy, 32 samples) had fourfold higher CRALA expression than responding tumors (good response to chemotherapy, 47 samples). CRALA is upregulated in chemoresistant breast cancer cell lines compared to their parental lines. Silencing of CRALA in chemoresistant breast cancer cells resensitizes the cells to chemotherapy in vitro. Furthermore, univariate and multivariate analysis showed that higher CRALA expression was significantly associated with poor prognosis in 144 breast cancer patients. CONCLUSION: The study findings indicate that CRALA expression may be an important biomarker for predicting the clinical response to chemotherapy and prognosis in breast cancer patients. It is possible to target CRALA to reverse chemoresistance in breast cancer patients. PMID- 28834649 TI - Hepatitis E virus as a cause of acute hepatitis acquired in Switzerland. AB - BACKGROUND: Autochthonous hepatitis E is increasingly recognized as zoonotic infection in western countries. Serological assays have varying sensitivity and specificity. METHODS: We implemented molecular testing to identify and characterize acute hepatitis E acquired in Switzerland. RESULTS: Ninety-three cases of mostly symptomatic acute hepatitis E acquired in Switzerland were documented by PCR between November 2011 and December 2016. Median HEV RNA was 7.5 x 104 IU/mL (range, 5.3 to 4.7 x 107 IU/mL). HEV genotyping was successful in 78 patients, revealing genotype 3 in 75 and genotype 4 in three patients. Phylogenetic analyses revealed a few limited geographical and temporal clusters. Of the 91 patients with available anti-HEV IgM serology, four were negative; three of these were also IgG-negative, likely as a result of immunosuppression, and one was IgG-positive, a constellation compatible with HEV reinfection. Median age of the patients was 58 years (range, 20-80 years); 71 (76.3%) were men and 49 of these (69.0%) were >= 50 years old. The clinical course was particularly severe in patients with underlying chronic liver disease, with fatal outcome in two patients. Six patients (6.5%) presented with neuralgic amyotrophy. CONCLUSIONS: Nucleic acid-based diagnosis reveals HEV as a relevant cause of acute hepatitis in Switzerland. Middle-aged and elderly men constitute the majority of symptomatic patients. Testing for HEV should be included early in the diagnostic workup of acute hepatitis and of neuralgic amyotrophy, a typical extrahepatic manifestation of HEV genotype 3 infection. PMID- 28834650 TI - Interfacial Water Drives Improved Proton Transport in Siliceous Nanocomposite Nafion Thin Films. AB - Nafion proton exchange membranes dehydrate when they are used in the gas phase and in high-temperature applications, such as fuel cells and (photo)electrolysis. Retaining a high level of membrane hydration under such conditions can be achieved by using inorganic fillers, but has never been demonstrated for thin films. Herein, several types of siliceous nanoparticles were incorporated for the first time into Nafion thin films. For composite Nafion materials, increased water uptake does not always induce increased proton conductivity. Here, increased water uptake did result in higher proton conductivity due to a synergistic effect within the composite film. The nanocomposites displayed a higher water uptake than could be expected based on the water uptake of the individual materials. Excess water present at the Nafion-filler interface was found to cause the proton conductivity of nanocomposite Nafion/Ludox AS-40 thin films to double compared with pristine Nafion at low relative humidity (from 2 to 4 mS cm-2 ). Knowledge about the properties of such interfaces will allow for the better design of self-humidifying nanocomposite Nafion membranes, films, and catalyst layers. PMID- 28834651 TI - Gene flow from single and stacked herbicide-resistant rice (Oryza sativa): modeling occurrence of multiple herbicide-resistant weedy rice. AB - BACKGROUND: ProvisiaTM rice (PV), a non-genetically engineered (GE) quizalofop resistant rice, will provide growers with an additional option for weed management to use in conjunction with Clearfield(r) rice (CL) production. Modeling compared the impact of stacking resistance traits versus single traits in rice on introgression of the resistance trait to weedy rice (also called red rice). Common weed management practices were applied to 2-, 3- and 4-year crop rotations, and resistant and multiple-resistant weedy rice seeds, seedlings and mature plants were tracked for 15 years. RESULTS: Two-year crop rotations resulted in resistant weedy rice after 2 years with abundant populations (exceeding 0.4 weedy rice plants m-2 ) occurring after 7 years. When stacked trait rice was rotated with soybeans in a 3-year rotation and with soybeans and CL in a 4-year rotation, multiple-resistance occurred after 2-5 years with abundant populations present in 4-9 years. When CL rice, PV rice, and soybeans were used in 3- and 4-year rotations, the median time of first appearance of multiple-resistance was 7-11 years and reached abundant levels in 10-15 years. CONCLUSION: Maintaining separate CL and PV rice systems, in rotation with other crops and herbicides, minimized the evolution of multiple herbicide-resistant weedy rice through gene flow compared to stacking herbicide resistance traits. (c) 2017 Society of Chemical Industry. PMID- 28834652 TI - Solid Phase Stepwise Synthesis of Polyethylene Glycols. AB - Polyethylene glycol (PEG) and derivatives with eight and twelve ethylene glycol units were synthesized by stepwise addition of tetraethylene glycol monomers on a polystyrene solid support. The monomer contains a tosyl group at one end and a dimethoxytrityl group at the other. The Wang resin, which contains the 4 benzyloxy benzyl alcohol function, was used as the support. The synthetic cycle consists of deprotonation, Williamson ether formation (coupling), and detritylation. Cleavage of PEGs from solid support was achieved with trifluoroacetic acid. The synthesis including monomer synthesis was entirely chromatography-free. PEG products including those with different functionalities at the two termini were obtained in high yields. The products were analyzed with ESI and MALDI-TOF MS and were found close to monodispersity. PMID- 28834653 TI - Muscle wasting in ageing and chronic illness. AB - PURPOSE: As life expectancy increases, muscle wasting is becoming a more and more important public health problem. This review summarizes the current knowledge of pathophysiological mechanisms underlying muscle loss in ageing and chronic diseases such as heart failure and discusses evolving interventional strategies. RECENT FINDINGS: Loss of skeletal muscle mass and strength is a common phenomenon in a wide variety of disorders associated with ageing and morbidity-associated catabolic conditions such as chronic heart failure. Muscle wasting in ageing but otherwise healthy human beings is referred to as sarcopenia. Unlike cachexia in advanced stages of chronic heart failure, muscle wasting per se is not necessarily associated with weight loss. In this review, we discuss pathophysiological mechanisms underlying muscle loss in sarcopenia and cachexia, highlight similarities and differences of both conditions, and discuss therapeutic targets and possible treatments, such as exercise training, nutritional support, and drugs. Candidate drugs to treat muscle wasting disease include myostatin antagonists, ghrelin agonists, selective androgen receptor molecules, megestrol acetate, activin receptor antagonists, espindolol, and fast skeletal muscle troponin inhibitors. SUMMARY: Present approaches to muscle wasting disease include exercise training, nutritional support, and drugs, although particularly the latter remain currently restricted to clinical studies. Optimizing skeletal muscle mass and function in ageing and chronic illness including heart failure is one of the chapters that are far from finished and gains future potential for new therapeutic interventions to come. PMID- 28834654 TI - The EJHF last Editor's legacy: how can a high impact factor be built? AB - The European Journal of Heart Failure (EJHF) has reached a high impact factor making it one of the most important cardiology journals. I discuss herein what could be the main causes of such high ranking. Publication of the European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure has had the most important role with a number of citations, which has been approximately 10 times that of the other most cited articles of the same year. Other position statements, reviews, design papers, and research articles about landmark topics have given major contributions. With respect to the different clinical presentations, articles about heart failure with preserved ejection fraction and about advanced heart failure have gained many citations. Epidemiology, biomarkers, medical treatment, and devices have attracted most of the interest. In conclusion, being able to look ahead and to publish what is going to become important remains a major challenge. That of EJHF has been a success story, to date, and learning from the past may help to build upon this achievement. PMID- 28834655 TI - Heart failure in Southeast Asia: facts and numbers. AB - Southeast Asia is home to a growing population of >600 million people, the majority younger than 65 years, but among whom, rapid epidemiological transition has led to high rates of premature death from non-communicable diseases (chiefly cardiovascular disease) (up to 28% in the Philippines vs. 12% in UK). There is a strikingly high prevalence of stage A heart failure (HF) risk factors in Southeast Asia, particularly hypertension (>24% in Cambodia and Laos vs. 13-15% in UK and USA), tobacco smoking (>36% in Indonesia), physical inactivity (>50% in Malaysia) and raised blood glucose (10-11% in Brunei, Malaysia, Singapore and Thailand) in spite of a low prevalence of overweight/obesity (21-26% in Southeast Asia vs. 67-70% in UK and USA). Accordingly, the prevalence of symptomatic HF appears to be higher in Southeast Asian countries compared with the rest of the world. Epidemiologic trends in Singapore showed a sharp 38% increase in age adjusted HF hospitalizations (from 85.4 per 10 000 in 1991 to 110.3 per 10 000 in 1998) with notable ethnic differences (hospitalization rates ~35% higher in Malays and Indians vs. Chinese; mortality 3.5 times higher in Malays vs. Indians and Chinese). Furthermore, Southeast Asian patients present with acute HF at a younger age (54 years) compared with USA patients (75 years) but have more severe clinical features, higher rates of mechanical ventilation, longer lengths of stay (6 vs. 4.2 days) and higher in-hospital mortality (4.8 vs. 3.0%). Finally, there is under-usage of guideline-recommended HF medical therapies (prescribed in 31 63% of patients upon discharge) and device therapies in Southeast Asia. Large gaps in knowledge that need to be addressed in Southeast Asia include the prevalence of HF with preserved ejection fraction, clinical outcomes, barriers to recommended therapies and their cost-effectiveness, as well as possible ethnicity specific pathophysiologic mechanisms. PMID- 28834656 TI - Pharmacological inhibition of the triggering receptor expressed on myeloid cells 1 limits reperfusion injury in a porcine model of myocardial infarction. AB - AIMS: Limitation of ischemia/reperfusion injury is a major therapeutic target after acute myocardial infarction (AMI). Toll-like receptors are implicated in the inflammatory response that occurs during reperfusion. The triggering receptor expressed on myeloid cells (TREM)-1 acts as an amplifier of the immune response triggered by toll-like receptor engagement. We hypothesized that administration of a TREM-1 inhibitory peptide (LR12) could limit reperfusion injury in a porcine model of AMI. METHODS AND RESULTS: AMI was induced in 15 adult minipigs by a closed-chest coronary artery occlusion-reperfusion technique. Animals were randomized to receive LR12 or vehicle before reperfusion (LR12 n = 7, vehicle n = 8), and were monitored during 18 h. AMI altered hemodynamics and cardiac function, as illustrated by a drop of mean arterial pressure, cardiac index, cardiac power index, ejection fraction, and real-time pressure-volume loop derived parameters. TREM-1 inhibition by LR12 significantly improved these dysfunctions (P < 0.03) and limited infarct size, as assessed by lower creatine phosphokinase and troponin I concentrations (P < 0.005). Pulmonary, renal, and hepatic impairments occurred after AMI and were attenuated by LR12 administration as assessed by a better PaO2 to FiO2 ratio, a less positive fluid balance, and lower liver enzymes levels (P < 0.05). CONCLUSION: Inhibition of the TREM-1 pathway by a synthetic peptide limited myocardial reperfusion injury in a clinically relevant porcine model of AMI. PMID- 28834657 TI - Plasma amino-terminal pro B-type natriuretic peptide as a predictor of late cardiovascular mortality in patients with acute lung disorders: a prospective, observational cohort study. AB - AIMS: Pneumonia and acute exacerbations of obstructive lung diseases (AEOLD) are associated with a significant long-term mortality. Elevated level of amino terminal pro B-type natriuretic peptide (NT-proBNP) is a predictor of late all cause mortality in these disorders but the pathophysiological basis for this is unknown. The present study was conducted to define the predictive role of NT proBNP on late cardiovascular mortality among patients with acute lung disorders. METHODS AND RESULTS: This prospective, observational cohort study included 269 hospitalized patients with pneumonia or AEOLD. Plasma level of NT-proBNP, age, sex, body mass index, arterial blood oxygen saturation, C-reactive protein, and urea were recorded. The survival and causes of death were recorded after a median of six years. NT-proBNP > 666 ng/mL was related to cardiovascular mortality with an adjusted hazard ratio of 2.93 (1.19-7.18). This risk was of similar magnitude to that associated with diabetes and greater than that associated with arterial hypertension, hypercholesterolemia, and smoking. NT-proBNP was also related to all-cause mortality with adjusted hazard ratio of 2.39 (1.49-3.85) per 10 times increase in NT-proBNP concentration. However, the association between NT-proBNP and non-cardiovascular mortality did not reach statistical significance [adjusted hazard ratio 1.89 (0.93-3.85)]. CONCLUSION: NT-proBNP concentration during pneumonia or AEOLD was strongly associated with late cardiovascular mortality but not with non-cardiovascular mortality. The results suggest that the increase in NT-proBNP during acute lung disorders may reveal occult cardiac diseases arousing a question whether patients with acute pulmonary disorders with elevated NT proBNP levels should be subjected to further diagnostic or therapeutic cardiovascular interventions. PMID- 28834658 TI - Skeletal muscle weakness is related to insulin resistance in patients with chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) is associated with insulin resistance, indicating impairment in the control of energy metabolism. Insulin resistance in CHF relates to symptomatic status and independently predicts poor prognosis. We sought to determine whether insulin sensitivity is related to skeletal muscle strength in patients with CHF, taking into account muscle size and perfusion. METHODS: Quadriceps muscle size (square centimetre cross-sectional area at mid femur level, computed tomography), isometric quadriceps muscle strength [absolute (in N) and strength per unit muscle area (N/cm2 )], resting-leg blood flow (plethysmography) and maximal oxygen consumption (treadmill exercise test) were measured in 33 patients with CHF (left ventricular ejection fraction 28 +/- 3.2%, mean +/- Standard Error of the mean (SEM)) and 20 healthy controls. Insulin sensitivity was assessed by intravenous glucose tolerance tests and minimal modelling analysis. RESULTS: Right quadriceps strength (-27.0%, P < 0.0001), strength per muscle area (-18.0%, P < 0.003) and insulin sensitivity (-64.2%, P < 0.001) were lower in patients with CHF. The correlation between insulin sensitivity and absolute muscle strength was significant in the CHF group (r = 0.54, P = 0.001) and borderline in controls (r = 0.47, P = 0.06). This association remained significant between insulin sensitivity and strength per muscle area (CHF: r = 0.52, P < 0.01; controls: r = 0.62, P < 0.05). In stepwise regression analyses in CHF, only insulin sensitivity emerged as a predictor of strength per unit area of muscle [standardized coefficient (SC) = 0.45, P = 0.006; diuretic dose, SC = -0.31, P = 0.051; R2 = 0.37, P = 0.001], while age, left ventricular ejection fraction, maximal oxygen consumption, fasting glucose and insulin and blood flow were excluded. In controls, only insulin sensitivity remained in the final regression model (SC = 0.62, P = 0.004; R2 = 0.39, P = 0.004). CONCLUSIONS: The myofibril contractile function of the quadriceps, i.e. functional quality of skeletal muscle, is strongly related to insulin sensitivity in patients with CHF and in healthy controls, independently of muscle size. Therapies aimed at improving insulin sensitivity in patients with CHF may clarify whether this relationship is causal. PMID- 28834659 TI - Determinants of submaximal exercise capacity in patients at risk for heart failure with preserved ejection fraction-results from the DIAST-CHF study. AB - OBJECTIVES AND BACKGROUND: The aim of this study was to identify determinants of submaximal exercise capacity as measured by 6 min walking distance in patients at risk for heart failure with preserved ejection fraction (HFpEF). METHODS: A cross sectional analysis from the prospective cohort programme Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that included a total of 1937 patients (age, 50-85 years) with >1 risk factor (hypertension, atherosclerotic disease, diabetes mellitus, and obstructive sleep apnoea) was carried out. Besides comprehensive clinical phenotyping, standardized 6 min walk test and state-of-the-art echocardiography were performed, and blood samples for biomarker assessment were obtained. Patients with an ejection fraction <50% or without evaluable exercise test were excluded from this analysis. RESULTS: One thousand three hundred eighty-seven patients fulfilled all criteria for this analysis. In the univariate analysis, 6 min walk distance was inversely related to E/e' values (P < 0.001). In the multivariate analysis, 6 min walk distance decreased significantly with age, female sex, increasing body mass index, diabetes, chronic obstructive lung disease, and peripheral artery disease. However, the association of 6 min walk distance with resting parameters of diastolic function was significantly attenuated with multivariate regression. In contrast, mid-regional pro-adrenomedullin, mid-regional pro-atrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide were independently associated with submaximal exercise capacity when added to the base model (all P < 0.001). CONCLUSIONS: Classical risk factors for heart failure and neuroendocrine activation are independently associated with sub-maximal exercise capacity, while diastolic function parameters obtained at rest were not. This observation substantiates the role of co-morbidities as relevant contributors to the clinical picture of HFpEF and the limitation of resting indices of diastolic function for diagnosing HFpEF. PMID- 28834660 TI - The CHA2 DS2 -VASc score as a predictor of high mortality in hospitalized heart failure patients. AB - AIMS: Atrial fibrillation (AF) is common in patients with heart failure (HF). CHA2 DS2 -VASc score was originally employed as a risk assessment tool for stroke in patients with AF; however, it has recently been used to predict not only stroke but also various cardiovascular diseases beyond the original AF field. We aimed to verify the CHA2 DS2 -VASc score as a risk assessment tool to predict mortality in patients with HF. METHODS AND RESULTS: Consecutive 1011 patients admitted for treatment of HF were divided into three groups based on their CHA2 DS2 -VASc scores: score 1-3 group (n = 317), score 4-6 group (n = 549) and score 7-9 group (n = 145). Of the 1011 HF patients, 387 (38.3%) had AF. We compared patient characteristics among the three groups and prospectively followed for all cause mortality. Although left ventricular ejection fraction was similar among all three groups, all-cause mortality was higher in the score 4-6 group and score 7-9 group than in the score 1-3 group (37.9 and 29.3% vs. 15.1%, log-rank P < 0.001). In the multivariable Cox proportional hazard analysis, the CHA2 DS2 -VASc score 7-9 was an independent predictor of all-cause mortality (all HF patients: hazard ratio (HR) 1.822, P = 0.011; HF patients with AF: HR 1.951, P = 0.031; HF patients without AF: HR 2.215, P = 0.033). CONCLUSIONS: The CHA2 DS2 -VASc score was an independent predictor of all-cause mortality in HF patients with or without AF. This comprehensive risk assessment score may help identify HF patients who are at high risk for mortality in HF patient. PMID- 28834661 TI - Intraoperative crush smear cytology of vertebral chondroblastoma: A diagnostic challenge. AB - Chondroblastoma is a rare, cartilage producing primary neoplasm of the bone. Although generally benign, chondroblastoma is placed in the "intermediate, rarely metastasizing" category in the 2013 World Health Organization classification of bone tumors. It typically involves the epiphysis of long tubular bones and is exceptionally located in the vertebral column. To the best of our knowledge, less than 35 cases of vertebral chondroblastoma have been reported in the literature. We report a case of chondroblastoma involving D6 -D7 vertebrae in a 17-year-old male patient, diagnosed on intraoperative crush cytology and later confirmed on histopathology. Intraoperative crush cytology is rarely been used for the diagnosis of bone lesions. Till date, this is the third case of vertebral chondroblastoma being diagnosed on cytology and first case being diagnosed on intraoperative crush smear cytology. Previous two cases were diagnosed on fine needle aspiration cytology. Chondroblastoma possesses distinct and diagnostic cytological features, which allows correct diagnosis even in the rarer locations like vertebral column. Crush cytology can be helpful in the rapid intraoperative diagnosis of vertebral chondroblastoma leading to early proper management of the patient. PMID- 28834662 TI - Human immunodeficiency virus-associated heart failure in sub-Saharan Africa: evolution in the epidemiology, pathophysiology, and clinical manifestations in the antiretroviral era. AB - The survival of patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) who have access to highly active antiretroviral therapy (ART) has dramatically increased in recent times. This review focuses on HIV-associated heart failure in sub-Saharan Africa (SSA). In HIV infected persons, heart failure may be related to pathology of the pericardium, the myocardium, the valves, the conduction system, or the coronary and pulmonary vasculature. HIV-associated heart failure can be because of direct consequences of HIV infection, autoimmune reactions, pro-inflammatory cytokines, opportunistic infections (OIs) or neoplasms, use of ART or therapy for OIs and presence of traditional cardiovascular risk factors. Myocardial involvement includes diastolic dysfunction, asymptomatic left ventricular dysfunction, cardiomyopathy, myocarditis, fibrosis, and steatosis. Pericardial diseases include pericarditis, pericardial effusions (rarely causing tamponade), pericardial constriction, and effusive-constrictive syndromes. Coronary artery disease is commonly reported in industrial nations, although its prevalence is thought to be low in HIV-infected persons from SSA. PMID- 28834664 TI - Plasma calcidiol, calcitriol, and parathyroid hormone and risk of new onset heart failure in a population-based cohort study. AB - BACKGROUND: Heart failure (HF) is a major problem in the Western world, with increasing prevalence and incidence. Because HF cannot be cured, prevention of HF is of utter importance. Calcidiol, calcitriol, and parathyroid hormone (PTH) have been identified as risk factors for cardiovascular disease. However, their association with new onset HF remains to be established. We investigated whether calcidiol, calcitriol, and PTH could be used to identify those subjects at risk for new onset HF, and if they had additive predictive value over established risk predictors like N-terminal-pro Brain-type natriuretic peptide and highly sensitive Troponin-T. METHODS AND RESULTS: We examined 7470 HF-free participants in Prevention of Renal and Vascular End-stage Disease, a community-based cohort study in Groningen, the Netherlands (latitude 53 degrees N, mean age: 49 years, 48% male). During follow-up time of 12.6 years (interquartile range: 12.3-12.9), 281 participants (4%) developed HF: 181 (66%) HF with reduced and 94 (34%) HF with preserved ejection fraction (HFrEF [left ventricular ejection fraction <= 40%], and HFpEF [left ventricular ejection fraction >= 50%], respectively). Mean (+/-SD) of calcidiol was 58 (+/-24) nmol/L, mean calcitriol 145 (+/-48) pmol/L, and median (interquartile range) PTH was 3.7 (3.0-4.6) pmol/L. Calcidiol levels were univariately associated with new onset HF [hazard ratio (HR) 0.82 (95% CI 0.69-0.96)], but calcitriol levels were not [HR 0.85 (95% CI 0.71-1.03)]. PTH levels kept their predictive value after adjustment for age, sex, and day of blood withdrawal (HR 1.26 [95% CI 1.04-1.53]). However, in our full model this association was lost [HR 1.10 (95% CI 0.92-1.32)]. Calcidiol, calcitriol, and PTH could not differentiate between new onset HFrEF or HFpEF. CONCLUSIONS: After adjustment for confounding factors, a single measurement of plasma calcidiol, calcitriol, or PTH was not associated with risk of developing HF. Screening for these markers to identify subjects at risk for new onset HF cannot be advocated. PMID- 28834663 TI - Development and validation of a novel non-contact monitor of nocturnal respiration for identifying sleep-disordered breathing in patients with heart failure. AB - AIMS: At least 50% of patients with heart failure (HF) may have sleep-disordered breathing (SDB). Overnight in-hospital polysomnography (PSG) is considered the gold standard for diagnosis, but a lack of access to such testing contributes to under-diagnosis of SDB. Therefore, there is a need for simple and reliable validated methods to aid diagnosis in patients with HF. The aim of this study was to investigate the accuracy of a non-contact type IV screening device, SleepMinderTM (SM), compared with in-hospital PSG for detecting SDB in patients with HF. METHODS AND RESULTS: The study included 75 adult patients with systolic HF and suspected SDB who underwent simultaneous PSG and SM recordings. An algorithm was developed from the SM signals, using digital signal processing and pattern recognition techniques to calculate the SM apnoea-hypopnoea index (AHI). This was then compared with expert-scored PSGAHI . The SM algorithm had 70% sensitivity and 89% specificity for identifying patients with clinically significant SDB (AHI >= 15/h). At this threshold, it had a positive likelihood ratio of 6.3 and a negative likelihood ratio of 0.16. The overall accuracy of the SMAHI algorithm was 85.8% as shown by the area under a receiver operator characteristic curve. The mean AHI with SM was 3.8/h (95% confidence interval 0.5 7.1) lower than that with PSG. CONCLUSIONS: The accuracy of the non-contact type IV screening device SM is good for clinically significant SDB in patients with systolic HF and could be considered as a simple first step in the diagnostic pathway. PMID- 28834665 TI - The late sodium current in heart failure: pathophysiology and clinical relevance. AB - Large and growing body of data suggest that an increased late sodium current (INa,late ) can have a significant pathophysiological role in heart failure and other heart diseases. The first goal of this article is to describe how INa,late functions under physiological circumstances. The second goal is to show the wide range of cellular mechanisms that can increase INa,late in cardiac disease, and also to describe how the up-regulated INa,late contributes to the pathophysiology of heart failure. The final section of the article discusses the possible use of INa,late -modifying drugs in heart failure, on the basis of experimental and preclinical data. PMID- 28834666 TI - Effects of long-term endurance and resistance training on diastolic function, exercise capacity, and quality of life in asymptomatic diastolic dysfunction vs. heart failure with preserved ejection fraction. AB - BACKGROUND: The long-term effects of exercise training (ET) in diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF) are unknown. The present study compared the long-term effects of ET on exercise capacity, diastolic function, and quality of life (QoL) in patients with DD vs. HFpEF. METHODS: A total of n = 43 patients with asymptomatic DD (n = 19) or HFpEF [DD and New York Heart Association (NYHA) >=II, n = 24] and left ventricular ejection fraction >=50% performed a combined endurance/resistance training over 6 months (2-3/week) on top of usual care. Cardiopulmonary exercise testing, echocardiography, and QoL were obtained at baseline and follow-up. RESULTS: Patients were 62 +/- 8 years old (37% female). In the HFpEF group, 67% of patients were in NYHA class II (33% in NYHA III). Exercise capacity (peak oxygen consumption, peak VO2 ) differed at baseline (DD 29.2 +/- 8.7 mL/min/kg vs. HFpEF 17.8 +/- 4.6 mL/min/kg; P = 0.004). After 6 months, peak VO2 increased significantly (P < 0.044) to 19.7 +/- 5.8 mL/min/kg in the HFpEF group and also in the DD group (to 32.8 +/- 8.5 mL/min/kg; P < 0.002) with no overall difference between the groups (P = 0.217). E/e' ratio (left ventricular filling index) decreased from 12.2 +/- 3.5 to 10.1 +/- 3.0 (P < 0.002) in patients with HFpEF and also in patients with DD (10.7 +/- 3.1 vs. 9.5 +/- 2.3; P = 0.03; difference between groups P = 0.210). In contrast, left atrial volume index decreased in the HFpEF group (P < 0.001) but remained stable within the DD group (difference between groups P = 0.015). After 6 months, physical QoL (Minnesota living with heart failure Questionnaire, 36-item short form health survey), general health perception, and 9-item patient health questionnaire score only improved in HFpEF (P < 0.05). In contrast, vitality improved in both groups (difference between groups P = 0.708). CONCLUSION: A structured 6 months ET programme effectively improves exercise capacity and diastolic function in patients with DD and overt HFpEF. Therefore, controlled lifestyle modification with physical activity is effective both in DD and HFpEF. PMID- 28834667 TI - Late-onset hypogonadism in men with systolic heart failure: prevalence, clinical associates, and impact on long-term survival. AB - BACKGROUND: Male ageing is characterized by diminished circulating androgens with several adverse psychosomatic consequences and can be aggravated by concomitant chronic diseases. According to the European Male Aging Study (EMAS) Group, late onset hypogonadism (LOH) refers to testosterone deficiency accompanied by sexual complaints. AIM: We investigated the prevalence of LOH in men with systolic heart failure (HF), and its clinical determinants and prognostic consequences. METHODS: Among 201 men with systolic HF (age: 60 +/- 11 years), serum total testosterone (TT) was assessed using an immunoassay, and estimated free testosterone (eFT) was calculated using Vermeulen's formula. LOH was diagnosed when TT < 3.2 ng/mL and eFT < 64 pg/mL were accompanied by three sexual symptoms (decrease in the number of morning erections, reduced potency, and low libido) of at least moderate severity assessed using the Aging Males' Symptoms Scale. RESULTS: Decreased frequency of morning erections, reduced potency, and low libido were experienced by 56%, 62%, and 55% of men with HF, respectively; whereas 67%, 61%, and 44% of subjects complained of at least one, two, and three symptoms, respectively. Hypogonadal TT and eFT were observed in 34% and 47% of patients, respectively; and in 33% subjects, both TT and eFT were reduced. Finally, 30 men with HF (15%) were diagnosed with LOH as compared with 2% in a European male population (EMAS). In a multivariable model, older age and higher serum uric acid were independently associated with greater LOH prevalence (both P < 0.05). Among men aged <=60 years (but not in those aged >60 years), LOH increased 5-year all-cause mortality in the univariable model; however, when adjusted for HF severity, the association lost its statistical significance. CONCLUSIONS: Men with systolic HF commonly report sexual complaints. LOH-the combination of sexual dysfunction and testosterone deficiency-occurs more frequently than in a general male population. LOH does not affect long-term mortality, when adjusted for HF severity. PMID- 28834668 TI - Rationale and design of the CONFIRM-HF study: a double-blind, randomized, placebo controlled study to assess the effects of intravenous ferric carboxymaltose on functional capacity in patients with chronic heart failure and iron deficiency. AB - BACKGROUND: Iron deficiency (ID) is a common co-morbidity associated with chronic heart failure (CHF), which has unfavourable clinical and prognostic consequences. In Ferinject Assessment in Patients with IRon Deficiency and Chronic Heart Failure (FAIR-HF), the treatment with i.v. ferric carboxymaltose (FCM) improved symptoms and quality of life over a 24 week period. Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (CONFIRM-HF) was designed to test a simplifieddosage scheme of FCM during a longer follow-up period. METHODS: CONFIRM-HF, a double-blind, multi-centre, prospective, randomized, two-arm study, enrolled ambulatory patients with symptomatic CHF [New York Heart Association (NYHA) class II/III] with left ventricular ejection fraction <=45%, BNP >100 pg/mL, or NT-proBNP >400 pg/mL, presence of ID [defined as ferritin <100 ng/mL, or ferritin 100-300 ng/mL if transferrin saturation (TSAT) <20%], and haemoglobin (Hb) <15 g/dL. Patients were randomized 1:1 to treatment with FCM or placebo for 52 weeks. Primary endpoint is change in 6-minute walk test (6MWT) distance from baseline to Week 24. Secondary endpoints are: change in 6MWT from baseline to Weeks 6, 12, 36, and 52; Patient Global Assessment score at Weeks 6, 12, 24, 36, and 52; and change from baseline to Weeks 6, 12, 24, 36, and 52 in NYHA class, fatigue score, and quality of life. Safety endpoints include overall safety over the treatment period of 52 weeks. Study medication was administered in single doses as undiluted bolus injection of up to 1000 mg of iron or normal saline at Day 0 and Week 6 up to iron repletion. Further doses of study medication could be administered at Weeks 12, 24, and 36 if a patient still had ID. RESULTS: Overall, 304 patients were recruited in 41 centres in nine countries. CONCLUSION: This study will provide further information on the efficacy and safety of iron therapy with i.v. FCM in CHF patients with ID over a 1 year period using a simplified dosing scheme. PMID- 28834670 TI - Research in acute and chronic heart failure is busier then ever worldwide and demands more publishing space: introducing ESC Heart Failure, the sister journal of the European Journal of Heart Failure. PMID- 28834669 TI - Heart failure: preventing disease and death worldwide. AB - : Heart failure is a life-threatening disease and addressing it should be considered a global health priority. At present, approximately 26 million people worldwide are living with heart failure. The outlook for such patients is poor, with survival rates worse than those for bowel, breast or prostate cancer. Furthermore, heart failure places great stresses on patients, caregivers and healthcare systems. Demands on healthcare services, in particular, are predicted to increase dramatically over the next decade as patient numbers rise owing to ageing populations, detrimental lifestyle changes and improved survival of those who go on to develop heart failure as the final stage of another disease. It is time to ease the strain on healthcare systems through clear policy initiatives that prioritize heart failure prevention and champion equity of care for all. Despite the burdens that heart failure imposes on society, awareness of the disease is poor. As a result, many premature deaths occur. This is in spite of the fact that most types of heart failure are preventable and that a healthy lifestyle can reduce risk. Even after heart failure has developed, premature deaths could be prevented if people were taught to recognize the symptoms and seek immediate medical attention. Public awareness campaigns focusing on these messages have great potential to improve outcomes for patients with heart failure and ultimately to save lives. Compliance with clinical practice guidelines is also associated with improved outcomes for patients with heart failure. However, in many countries, there is considerable variation in how closely physicians follow guideline recommendations. To promote equity of care, improvements should be encouraged through the use of hospital performance measures and incentives appropriate to the locality. To this end, policies should promote the research required to establish an evidence base for performance measures that reflect improved outcomes for patients. Continuing research is essential if we are to address unmet needs in caring for patients with heart failure. New therapies are required for patients with types of heart failure for which current treatments relieve symptoms but do not address the disease. More affordable therapies are desperately needed in the economically developing world. International collaborative research focusing on the causes and treatment of heart failure worldwide has the potential to benefit tens of millions of people. Change at the policy level has the power to drive improvements in prevention and care that will save lives. It is time to make a difference across the globe by confronting the problem of heart failure. A CALL TO ACTION: POLICY RECOMMENDATIONS: We urge policymakers at local, national and international levels to collaborate and act on the following recommendations. PROMOTE HEART FAILURE PREVENTION: Support the development and implementation of public awareness programmes about heart failure. These should define heart failure in simple and accessible language, explain how to recognize the symptoms and emphasize that most types of heart failure are preventable.Highlight the need for healthcare professionals across all clinical disciplines to identify patients with illnesses that increase the risk of heart failure and to prescribe preventive medications.Prioritize the elimination of infectious diseases in parts of the world where they still cause heart failure. IMPROVE HEART FAILURE AWARENESS AMONGST HEALTHCARE PROFESSIONALS: Encourage the development and use of heart failure education programmes for all appropriate healthcare professionals. These should aim to improve the prevention, diagnosis, treatment and long-term management of heart failure and raise awareness of clinical practice guidelines. ENSURE EQUITY OF CARE FOR ALL PATIENTS WITH HEART FAILURE: Provide a healthcare system that delivers timely access to diagnostic services and treatment of heart failure, as well as a seamless transition to long-term management.Ensure that the best available and most appropriate care is consistently provided to all patients with heart failure through efficient use of resources. SUPPORT AND EMPOWER PATIENTS AND THEIR CAREGIVERS: Provide resources for the education and practical support of patients with heart failure and their families or other caregivers, empowering them to engage proactively in long-term care. PROMOTE HEART FAILURE RESEARCH: Fund and encourage international collaborative research to improve understanding of the patterns, causes and effects of modern day heart failure and how the disease can be prevented across the globe.Fund and encourage research into new and more affordable therapies and medical devices for all types of heart failure.Fund and encourage research into evidence-based healthcare performance measures that reflect improved clinical outcomes for patients with heart failure. PMID- 28834671 TI - Frailty may be a risk marker for adverse outcome in patients with congestive heart failure. AB - AIMS: To examine the availability of frailty concept with objective criteria for risk stratification in patients with congestive heart failure (CHF). METHODS AND RESULTS: Study design was secondary analysis of our CHF cohort. We selected 181 patients who completed clinical assessments and were successfully followed 2-year post discharge. To set frailty criteria, grip strength <26 kg in men and <17 kg in women (weakness) and performance measure for activities of daily living-8 ?21 points (exhaustion) were defined for predicting 6 min walking distance <300 m (slowness) by the receiver-operating characteristics. During 2 years of follow up, subjects who met all the criteria had a 4 times greater risk of cardiac event compared with those with no frailty criteria. CONCLUSION: The findings of present study suggest that frailty criteria may serve as a new clinical marker for management of patients with CHF. PMID- 28834672 TI - The economic impact of patients with heart failure on the Lebanese healthcare system. AB - AIMS: This paper aimed to calculate the annual cost for heart failure (HF) patients in Lebanon. METHODS AND RESULTS: Heart failure care can reach up to $31 billion annually in the USA. Data in Lebanon are lacking. Estimating it based on USA data is biased; hence, collecting data from all healthcare providers will reflect the actual cost in Lebanon. Data were collected from all healthcare providers on HF hospitalization during the year 2012. In addition, data from 600 outpatient visits were collected by medical students to estimate the cost for outpatient care. The total cost was calculated by adding up all hospitalization cost-plus outpatient-estimated cost. There were 72 000 individuals suffering from HF. The hospitalization care in Lebanon is largely delivered by the public sector (91% public vs 9% private). However, the outpatient care is largely paid cash by patients. The direct cost for HF hospitalizations paid by the public and the private sector was $38 081 535. The average cost for each HF hospitalization was $3769. The direct cost for outpatients care was estimated at $65 592 000. The average cost for outpatient care was $911 per patient per year. The annual total direct cost was calculated at $103 673 535. The true cost was almost one third the extrapolated cost based on US statistics ($103 673 535 vs 268 370 607, respectively). CONCLUSIONS: The annual total direct cost for HF patients in Lebanon in 2012 was $103 673 535, which is much less than the extrapolated cost based on US statistics. PMID- 28834673 TI - Non-thrombotic fatal pulmonary embolism with a 'rule-out' CT scan. AB - We report on a 36-year-old woman suffering from metastasized breast cancer and severe dyspnoea owing to right heart failure. Symptoms and findings were highly suggestive of pulmonary embolism. In rare cases, pulmonary embolism is caused not by migration of venous thrombi but by emboli of other origin. Patients with cancer can suffer from non-thrombotic pulmonary embolism, either by (macroscopic) embolization of tumour mass or by microembolism also known as microscopic tumour microangiopathy. In patients with cancer with clinical presentation highly suggestive of pulmonary embolism, with echocardiographic findings confirming right ventricular dysfunction, and with negative CT angiography, pulmonary tumour microembolism should be considered as possible diagnosis. PMID- 28834674 TI - Night-time electromechanical activation time, pulsatile hemodynamics, and discharge outcomes in patients with acute heart failure. AB - AIMS: Both electromechanical activation time (EMAT) and pulsatile hemodynamics measured during the hospitalization course are useful in the prediction of cardiovascular outcomes in patients with acute heart failure syndrome (AHFS). We investigated whether night-time monitoring of EMAT with the ambulatory acoustic cardiography is superior to the measures of pulsatile hemodynamics for prediction of AHFS post-discharge outcomes. METHODS AND RESULTS: A total of 97 patients (71.1 +/- 15.4 years old, 81% male, and 73.8% systolic heart failure) hospitalized for AHFS were included. Before discharge, 24 h ambulatory acoustic cardiography and a comprehensive echocardiographic and pulsatile hemodynamic study were performed to assess the mean 24 h, daytime, and night-time EMAT, carotid systolic blood pressure (SBP) and pulse pressure (PP), amplitude of the reflected pressure wave from a decomposed carotid pressure wave (Pb), and carotid femoral pulse wave velocity (cfPWV), in addition to measurement of N-terminal pro brain natriuretic peptide (NT-proBNP) levels. During a mean follow-up of 389 +/- 281 days, 49 patients (50.5%) experienced events including re-hospitalization for heart failure, myocardial infarction, stroke, or death. Pulsatile hemodynamics, including carotid SBP and PP and Pb, but not cfPWV, and night-time EMAT, but not daytime EMAT, significantly predicted post-discharge events when age and NT proBNP were accounted for (all P < 0.05). In a final model with adjustment for age and NT-proBNP, night-time EMAT, but not Pb, significantly predicted post discharge events [hazard ratio per 1 SD and 95% confidence intervals: 1.33 (1.05 1.69), P < 0.05]. CONCLUSION: Pre-discharge night-time EMAT may be a better predictor for post-discharge adverse events than the measures of the pulsatile hemodynamics in patients with AHFS. PMID- 28834675 TI - The impact of cisplatinum-based chemotherapy on ventricular function and cardiovascular risk factors in female survivors after malignant germ cell cancer. AB - AIMS: Among male cancer survivors, cisplatinum-based chemotherapy (CBCT) is associated with impaired left ventricle (LV) diastolic function, increased risk of metabolic syndrome, and increased cardiovascular morbidity and mortality. Comparable data in females are limited. The long-term effects of cisplatin on right ventricle (RV) function are unknown in both genders. We aimed to investigate the impact of CBCT on cardiovascular risk factors and cardiac function in female survivors after malignant ovarian germ cell tumour (MOGCT). METHODS AND RESULTS: This national cross-sectional follow-up study recruited MOGCT survivors, diagnosed from 1980-09 (n = 153). Seventy-four (48%) participated in out-patient visit, of whom 41 had received CBCT (62% of all CBCT): median age, 35 years (range, 18-64 years); median time since CBCT, 14 years (range, 5-31 years). Participants were categorized into high-CBCT (n = 19) and low-CBCT (n = 22) groups and compared with age-matched healthy females. All participants underwent laboratory tests and echocardiography to determine cardiac function. Compared with low-CBCT participants, the high-CBCT group showed significantly impaired RV function, as evaluated by tricuspid annular plane systolic excursion (22.6 +/- 2.4 mm vs. 26.3 +/- 3.6 mm; P < 0.001); RV S' (10.7 +/- 1.9 cm/s vs. 12.4 +/- 2.3 cm/s; P = 0.01); RV global longitudinal strain ( 23.4 +/- 2.4% vs. -25.7 +/- 3.7%; P = 0.02), and tricuspid annular displacement (21 +/- 2 mm vs. 24 +/- 3 mm; P = 0.001). LV diastolic function was impaired in the high-CBCT group compared with controls. Patients and controls exhibited similar metabolic syndrome prevalences. CONCLUSIONS: Among long-term survivors of MOGCT, CBCT was associated with impaired RV function and LV diastolic function. Unlike men, women do not appear to have an elevated risk of metabolic syndrome after CBCT. PMID- 28834676 TI - Prospective study on changes in blood variables in pregnant women at higher risk of peripartum cardiomyopathy. AB - AIMS: Echocardiography is necessary for the diagnosis of peripartum cardiomyopathy (PPCM). Multifetal pregnancies (MFP) and hypertensive disorders (HD) are prominent risk factors for PPCM. To determine which blood variables exhibit greater change in a late stage of pregnancy in women with MFP and/or HD compared with women with normotensive singleton pregnancies. METHODS AND RESULTS: Serum levels of six variables-high-sensitive troponin I (hs-TnI), N-terminal fragment of precursor protein brain-type natriuretic peptide (NT-proBNP), myoglobin, creatine kinase-myocardial band, ferritin, and prolactin-were compared between 29 women with MFP (n = 13) and/or HD (n = 18) and 100 women with normotensive singleton pregnancies (control group). None of 129 women developed PPCM. All variables increased significantly peripartum in both groups. In 29 women with MFP and/or HD, the elevated hs-TnI and NT-proBNP levels (median) were significantly higher compared with the control group (5.4 vs. 3.7 pg/mL for hs TnI with P = 0.002, 185 vs. 68 pg/mL for NT-proBNP with P = 0.007), and the prevalence rate of more than 90th percentile value specific for the 129 women was significantly more frequent for hs-TnI (>12.2 pg/mL; 31% [9/29] vs. 4.0% [4/100], P < 0.001) and tended to be more frequent for NT-proBNP (>342 pg/mL; 21% [6/29] vs. 7.0%, P = 0.072). CONCLUSIONS: Both hs-TnI and NT-proBNP were likely to increase markedly in women with MFP and/or HD. The combination of hs-TnI and NT proBNP may contribute to better selection of candidates for echocardiography. PMID- 28834677 TI - Efficacy of mineralocorticoid receptor antagonism in the acute myocardial infarction phase: eplerenone versus spironolactone. AB - AIMS: The selective mineralocorticoid receptor (MR) antagonist eplerenone given early in patients with acute myocardial infarction (MI) improves clinical outcome, whereas little is known about the effectiveness of early spironolactone therapy. We aimed to compare the ability of eplerenone and spironolactone to promote cardiac repair after experimental MI. METHODS AND RESULTS: Starting immediately after coronary artery ligation, C57BL/6J mice were treated with placebo, eplerenone, or spironolactone. At 7 days, treatment with eplerenone or spironolactone reduced thinning and expansion of healing infarct and improved early left ventricular chamber enlargement. Remarkably, eplerenone therapy resulted in significantly greater improvement than spironolactone of left ventricular contractile function and relaxation, associated with a more considerable leftward and downward shift of the pressure volume curve. Seven-day survival rate was significantly increased only in eplerenone treated mice. Moreover, eplerenone was superior to spironolactone in ameliorating neovessel formation in the injured myocardium. Optimized flow cytometry analysis of the monocyte differentiation marker Ly6C revealed predominant accumulation of Ly6Chigh monocytes/macrophages at the site of ischemic injury during the early inflammatory phase in placebo-treated mice. In contrast, MR antagonism, especially by eplerenone, led to a skewing of the monocyte/macrophage population toward a higher frequency of healing promoting Ly6Clow cells. CONCLUSION: The MR antagonist eplerenone versus spironolactone showed superior efficacy during the acute MI phase with more beneficial effects on survival, early cardiac dilation, and functional decline. Modulation of monocyte maturation and enhanced infarct neovessel formation appears to play a pivotal role. PMID- 28834678 TI - Clinical characteristics and management of hospitalized and ambulatory patients with heart failure-results from ESC heart failure long-term registry-Egyptian cohort. AB - AIMS: Our aim is to describe the clinical characteristics and management of patients hospitalized with acute heart failure (HHF) and ambulatory patients with chronic heart failure (CHF) in Egypt and compare them with heart failure (HF) patients from other countries in the European Society of Cardiology-Heart Failure (ESC-HF) registry. METHODS AND RESULTS: The ESC-HF Long-term Registry is a prospective, multi-centre, observational study of patients presenting to cardiology centres in member countries of the ESC. From April 2011 to February 2014, a total of 2145 patients with HF were recruited from 20 centres all over Egypt. Of these patients, 1475 (68.8%) were hospitalized with HHF, while 670 (31.2%) had CHF. Less than one-third (32.1%) of all patients were females. HHF patients {median age of 61 years [interquartile range (IQR), 53-69]} were older than CHF patients [median age of 57 years (IQR,46-64)]; P < 0.0001. They had more diabetes mellitus (45.4% vs. 31.8%; P < 0.0001). Left ventricular ejection fraction > 45% was present in 22% of HHF vs. 25.6% of CHF (P = 0.17). Atrial fibrillation existed in about a quarter of all patients (24.5%). Ischaemic heart disease was the main cause of HF in Egyptian patients. All-cause in-hospital mortality was 5%. Egyptian patients presented at a much earlier age than in other regions in the registry. They had more diabetes mellitus. Atrial fibrillation prevalence was remarkably lower. Other co-morbidities (renal dysfunction, stroke, and peripheral arterial disease) occurred less frequently. CONCLUSION: Patients in the Egyptian cohort exhibited distinct features from HF patients in other countries in the ESC-HF Long-term Registry. PMID- 28834679 TI - In vivo and ex vivo functional characterization of left ventricular remodelling after myocardial infarction in mice. AB - AIMS: The interest in cardiac remodelling (REM) has steadily increased during recent years. The aim of this study was to functionally characterize REM following myocardial infarction (MI) in mice using high-end in vivo and ex vivo methods. METHODS AND RESULTS: Myocardial infarction or sham operation was induced in A/J mice. Six weeks later, mice underwent cardiac magnetic resonance imaging and were subsequently sacrificed for ex vivo measurements on the isolated heart. Thereafter, hearts were trichrome stained for infarction size calculation. Magnetic resonance imaging showed significantly reduced ejection fraction (P < 0.01) as well as increased end-systolic and end-diastolic volumes (P < 0.01) after MI. The mean infarct size was 48.8 +/- 6.9% of left ventricle. In the isolated working heart coronary flow (time point 20': 6.6 +/- 0.9 vs. 13.9 +/- 1.6 mL/min, P < 0.01), cardiac output (time point 20': 17.5 +/- 2.6 vs. 36.1 +/- 4.3 mL/min, P < 0.01) and pump function (80 mmHg: 2.15 +/- 0.88 vs. 4.83 +/- 0.76, P < 0.05) were significantly attenuated in MI hearts during all measurements. Systolic and diastolic wall stress were significantly elevated in MI animals. CONCLUSION: This two-step approach is reasonable, since data quality increases while animals are not exposed to major additional interventions. Both the working heart and magnetic resonance imaging offer a reliable characterization of the functional changes that go along with the development of post-MI REM. By combining these two techniques, additional information such as wall stress can be evaluated. PMID- 28834680 TI - The Role of Cathodic Current in Plasma Electrolytic Oxidation of Aluminum: Phenomenological Concepts of the "Soft Sparking" Mode. AB - A comprehensive analysis of experimental data relating to so-called "soft sparking" mode of plasma electrolytic oxidation (PEO) has been undertaken. The transition to the soft sparking mode is accompanied by a number of characteristic effects, such as a decrease in anodic voltage, acoustic and light emission, increase in hysteresis in transient current-voltage curves, improved uniformity of the discharge distribution on the surface, disappearance of atomic lines, and development of continuous radiation in the optical emission spectra. An explanation of the main features of PEO process operated under soft sparking conditions is proposed assuming the existence of a specific narrow region in the coating thickness, where the main anodic voltage drops. Because of high electric field in this "active zone", both anodic oxidation of the metal substrate and high-energy processes may take place. According to this assertion, the soft sparking mode of PEO is caused by cathodic polarization (a) eliminating the potential barrier at the oxide-electrolyte interface due to local acidification and (b) increasing electric field at the metal-oxide interface during subsequent anodic half-cycle due to narrowing of low-conductive part within the active zone. Based on this consideration, it is possible to account for the main characteristic phenomena accompanying the PEO process on aluminum under alternating polarization. PMID- 28834681 TI - Heterologous Expression of Pteris vittata Arsenite Antiporter PvACR3;1 Reduces Arsenic Accumulation in Plant Shoots. AB - Arsenic (As) is a toxic carcinogen so it is crucial to decrease As accumulation in crops to reduce its risk to human health. Arsenite (AsIII) antiporter ACR3 protein is critical for As metabolism in organisms, but it is lost in flowering plants. Here, a novel ACR3 gene from As-hyperaccumulator Pteris vittata, PvACR3;1, was cloned and expressed in Saccharomyces cerevisiae (yeast), Arabidopsis thaliana (model plant), and Nicotiana tabacum (tobacco). Yeast experiments showed that PvACR3;1 functioned as an AsIII-antiporter to mediate AsIII efflux to an external medium. At 5 MUM AsIII, PvACR3;1 transgenic Arabidopsis accumulated 14-29% higher As in the roots and 55-61% lower As in the shoots compared to WT control, showing lower As translocation. Besides, transgenic tobacco under 5 MUM AsIII or AsV also showed similar results, indicating that expressing PvACR3;1 gene increased As retention in plant roots. Moreover, observation of PvACR3;1-green fluorescent protein fusions in transgenic Arabidopsis showed that PvACR3;1 protein localized to the vacuolar membrane, indicating that PvACR3;1 mediated AsIII sequestration into vacuoles, consistent with increased root As. In addition, soil experiments showed ~22% lower As in the shoots of transgenic tobacco than control. Thus, our study provides a potential strategy to limit As accumulation in plant shoots, representing the first report to decrease As translocation by sequestrating AsIII into vacuoles, shedding light on engineering low-As crops to improve food safety. PMID- 28834682 TI - Conceptual Problem with Calculating Electron Densities in Finite Basis Density Functional Theory. AB - It is discussed that finite basis Density Functional Theory (DFT) calculations using a single Kohn-Sham determinant cannot reproduce, in a strict mathematical sense, the exact electron density corresponding to the same finite basis. This is because the DFT density derives from an idempotent first order density matrix, while the exact (full CI) density can only be obtained from a nonidempotent one. The problem is absent for the original Kohn-Sham integro-differential equations or if a strictly complete basis set is assumed. PMID- 28834683 TI - Global prevalence of alcohol use and binge drinking during pregnancy, and fetal alcohol spectrum disorder. AB - Alcohol use during pregnancy is an established cause of fetal alcohol spectrum disorder (FASD), with heavy drinking during pregnancy being explicitly linked to fetal alcohol syndrome (FAS). This paper presents recent estimates of the prevalence of: (i) any amount of alcohol use during pregnancy; (ii) one or more binge drinking episode(s) (4 or more standard drinks on a single occasion) during pregnancy; (iii) FAS; and (iv) FASD among the general population globally and by World Health Organization region. It is apparent, based on the presented estimates, that alcohol use and binge drinking occur frequently among pregnant women in many countries and as a result, FASD is a prevalent alcohol-related developmental disability. Urgent action is required around the globe to eliminate prenatal alcohol exposure and prevent future children, adolescents, and adults from having FASD. PMID- 28834686 TI - Thanks to Professor Bradbury, and looking forward to the coming years for Avian Pathology. PMID- 28834684 TI - Discussing Health Care Expenses in the Oncology Clinic: Analysis of Cost Conversations in Outpatient Encounters. AB - PURPOSE: ASCO identified oncologist-patient conversations about cancer costs as an important component of high-quality care. However, limited data exist characterizing the content of these conversations. We sought to provide novel insight into oncologist-patient cost conversations by determining the content of cost conversations in breast cancer clinic visits. METHODS: We performed content analysis of transcribed dialogue from 677 outpatient appointments for breast cancer management. Encounters featured 677 patients with breast cancer visiting 56 oncologists nationwide from 2010 to 2013. RESULTS: Cost conversations were identified in 22% of visits (95% CI, 19 to 25) and had a median duration of 33 seconds (interquartile range, 19 to 62). Fifty-nine percent of cost conversations were initiated by oncologists (95% CI, 51 to 67), who most commonly brought up costs for antineoplastic agents. By contrast, patients most frequently brought up costs for diagnostic tests. Thirty-eight percent of cost conversations mentioned cost-reducing strategies (95% CI, 30 to 46), which most commonly sought to lower patient costs for endocrine therapies and symptom-alleviating treatments. The three most commonly discussed cost-reducing strategies were: switching to a lower cost therapy/diagnostic, changing logistics of the intervention, and facilitating copay assistance. CONCLUSION: We identified cost conversations in approximately one in five breast cancer visits. Cost conversations were mostly oncologist initiated, lasted < 1 minute, and dealt with a wide range of health care expenses. Cost-reducing strategies were mentioned in more than one third of cost conversations and often involved switching antineoplastic agents for lower-cost alternatives or altering logistics of diagnostic tests. PMID- 28834687 TI - Weight loss enhances hepatic antioxidant status in a NAFLD model induced by high fat diet. AB - Nonalcoholic fatty liver disease (NAFLD) is a benign condition that can progress to more severe liver damage in a process mediated, in part, by disturbances in redox balance. Additionally, some argue that it is set to become the main cause of end-stage liver disease in the near future. Here, we investigated whether diet induced weight loss is able to reverse hepatic lipid accumulation and reduce oxidative stress in liver from C57BL/6 mice fed a high-fat (HF) diet. Male C57BL/6 mice were divided into 4 groups: standard chow (SC; 10% energy from fat, 16 weeks); HF (50% energy from fat, 16 weeks); SC-HF (SC for 8 weeks followed by HF for 8 weeks); and HF-SC (HF for 8 weeks followed by SC for 8 weeks). The HF diet during 8 (SC-HF) and 16 weeks (HF) downregulated messenger RNA levels and protein expression of Nrf2 and endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) in the liver; caused liver steatosis; affected liver function markers; increased intra abdominal and subcutaneous adipose tissue; and induced glucose intolerance and hypercholesterolemia compared with controls (SC). Diet-induced weight loss significantly reduced the intrahepatic lipid accumulation, improved glucose tolerance, and restored both gene and protein expression of the antioxidant enzymes. Our findings suggest that a dietary intervention aimed to induce weight loss may exert protective effects in NAFLD as it can reduce hepatic oxidative stress and intrahepatic lipid accumulation, which can hinder the progression of this condition to more severe states. PMID- 28834688 TI - Innate immune genes in persistent mating-induced endometritis in horses. AB - Persistent mating-induced endometritis (PMIE) severely decreases fertility in horses. The aim of the present study was to evaluate differences between horses susceptible to PMIE and a control group in terms of the expression of selected immune response and effector genes, and the effects of oestrous cycle stage on this expression. Endometrial biopsies from 18 uterine samples of mares in the control group (eight in dioestrus, 10 in oestrus) and 16 PMIE-susceptible mares (four in dioestrus, 12 in oestrus) were analysed by quantitative real-time reverse transcription-polymerase chain reaction. Genes for pathogen recognition receptors Toll-like receptor 2 (TLR2) and NLR family CARD domain containing 5 (NLRC5), as well as tissue-specific inhibitor of metalloproteinase 1 (TIMP1), C-X C motif chemokine ligand (CXCL) 9, CXCL10 and CXCL11 and uteroferrin were expressed at similar levels in the control group and in susceptible mares. Genes for C-C motif chemokine ligand 2 (CCL2) and the antimicrobial peptides secreted phospholipase A2 (sPLA2), lipocalin 2 and lactoferrin were all expressed at higher levels in susceptible compared with control mares. The expression of genes for the antimicrobial peptides equine beta-defensin 1 (EBD1), lysozyme (LYZ) and secretory leukoprotease inhibitor (SLPI) was also higher in susceptible than control mares. The diagnostic sensitivity of assays for EBD1, LYZ and SLP1 gene expression to detect susceptibility to PMIE was estimated to be 100%, 94% and 100% respectively, with specificities of 83%, 78% and 78% respectively. When all three tests were positive, the specificity increased to 94%, with an overall sensitivity of 94%. The present study has yielded insights into pathophysiological changes in mares susceptible to PMIE and identified robust diagnostic markers (EBD1, LYZ and SLPI) for susceptibility to this disease. PMID- 28834689 TI - Association of physicians perceived barriers with human papillomavirus vaccination initiation. AB - Physician recommendation is a strong predictor of vaccine uptake, however their perceived barriers may prevent vaccination. Therefore, we determined the association between physicians' perceived barriers to HPV vaccination and vaccination initiation. We surveyed pediatricians in a large network of clinics in Houston, Texas to assess their perceived barriers to vaccinating adolescents. We combined survey data with electronic medical records to determine HPV vaccination initiation over a 12-month study period (July 2014-June 2015). Patients were 11-18year olds who had not begun the vaccination series, had a physician visit during the study period, and whose physician completed the survey. We conducted a multilevel model clustered by physician controlling for patient and physician demographics to calculate the association between physician reported barriers and HPV vaccination initiation. Among 36,827 patients seen by 134 pediatricians, 18.6% initiated HPV vaccination. The relative risk of initiating HPV vaccination were lower for patients whose physician reported concerns about HPV vaccine safety (RR: 0.75, 95% CI: 0.58-0.97), efficacy (RR: 0.73, 95% CI: 0.54-0.99), and the financial burden of the vaccine on patients (RR: 0.72, 95% CI: 0.58-0.88). After controlling for patient and physician characteristics, physician concern about the financial burden on patients was significantly associated with lower relative risk of initiating HPV vaccination (RR: 0.76, 95% CI: 0.64-0.90). In this large study we observed that physician reported barriers are associated with HPV vaccination initiation. Interventions should be implemented to educate physicians on vaccine safety, efficacy, and that there is no patient cost for CDC-recommended vaccines. PMID- 28834690 TI - Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma. AB - The long noncoding RNA Malat1 has been reported to be an oncogene that promotes tumor progress and correlates with prognosis in glioma. Growing evidence shows that autophagy plays a very important role in tumorigenesis and tumor cell survival, but whether Malat1 regulates autophagy in glioma is still unclear. In this study, we found that Malat1 expression and autophagy activity were significantly increased in glioma tissues compared with adjacent normal tissues. Additionally, Malat1 level was positively correlated with the expression of LC3 II (autophagy marker) mRNA in vivo. In vitro assays revealed that Malat1 significantly promoted autophagy activation and cell proliferation in glioma cells. More importantly, inhibition of autophagy by 3-MA relieved Malat1-induced cell proliferation. These data demonstrated that Malat1 activates autophagy and increases cell proliferation in glioma. We further investigated the molecular mechanisms whereby Malat1 functioned on glioma cell autophagy and proliferation. We found that Malat1 served as an endogenous sponge to reduce miR-101 expression by directly binding to miR-101. Moreover, Malat1 abolished the suppression effects of miR-101 on glioma cell autophagy and proliferation, which involved in upregulating the expression of miR-101 targets STMN1, RAB5A and ATG4D. Overall, our study elucidated a novel Malat1-miR-101-STMN1/RAB5A/ATG4D regulatory network that Malat1 activates autophagy and promotes cell proliferation by sponging miR 101 and upregulating STMN1, RAB5A and ATG4D expression in glioma cells. PMID- 28834691 TI - Quenching activity of carnosine derivatives towards reactive carbonyl species: Focus on alpha-(methylglyoxal) and beta-(malondialdehyde) dicarbonyls. AB - The study combines HPLC-based with MS-based competitive analyses to evaluate the quenching activity of a set of carnosine derivatives towards methylglyoxal (MGO) and malondialdehyde (MDA) chosen as representative of alpha- and beta dicarbonyls, respectively. The obtained results underline that these derivatives are moderately reactive towards MDA with which they form the corresponding N propenal adduct via Michael addition. In contrast they proved a rather poor quenching activity towards MGO with which they can condense to give MOLD-like adducts through a concerted mechanism involving more quenchers molecules. Even though both quenching mechanisms involve the amino group in its neutral form, in silico studies revealed that the reported reactivity values depend on different stereo-electronic parameters which are reflected in the different observed quenching mechanism. Finally, the MGO quenching reactivity and the unselective (and unwanted) pyridoxal quenching are found to be influenced by the same parameters thus rationalizing the known difficulty in the design of potent and selective quenchers towards beta-dicarbonyls. PMID- 28834692 TI - Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor-Receptor Interactions. AB - Dysregulation of tumor necrosis factor (TNF) receptor signaling is a key feature of various inflammatory disorders. Current treatments for TNF-related diseases function either by sequestering ligand or blocking ligand-receptor interactions, which can cause dangerous side effects by inhibiting the receptors that are not involved in the disease condition. Thus, alternate strategies that target receptor-receptor interactions are needed. We hypothesized that the soluble extracellular domain (ECD) of long isoform of death receptor 5 (DR5) could block endogenous receptor assembly, mimicking the biological effect of decoy receptors that lack the death domain to trigger apoptosis. Using live-cell fluorescence resonance energy transfer studies, we demonstrated that soluble ECD disrupts endogenous DR5-DR5 interactions. Cell viability assays were used to demonstrate the complete inhibition of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the ECD, although TRAIL is still able to bind to the receptor. Importantly, we used mutagenesis to prove that the inhibition of TRAIL-induced apoptosis by the ECD predominantly comes from the disruption of DR5 oligomerization and not ligand sequestration. Inhibition of death receptor activation should have important therapeutic applications in diseases such as nonalcoholic fatty liver disease. More generally, this approach should be generalized to enable the inhibition of other TNF receptor signaling mechanisms that are associated in a wide range of clinical conditions. PMID- 28834693 TI - A novel stereotaxic system for implanting a curved lead to two intracranial targets with high accuracy. AB - BACKGROUND: The multi-target deep brain stimulation (DBS) aimed at improving symptoms related to different nuclei is a promising research direction. However, to implant a single lead into multiple targets simultaneously is difficult with the current lead implantation method. NEW METHOD: We proposed a novel stereotaxic system used for implanting a curved lead to any two targets of the brain, and used the theoretical "curved lead method". First, a customized novel stereotaxic system was fabricated, and a solid cranial model with six fixed internal targets was made; second, CT scan was performed to locate the fixed internal targets; third, five curved leads were implanted to five selected pairs of targets, each following the calculated parameters of "curved lead pathway" with the novel stereotaxic system, respectively. Finally, CT scans were performed again to determine the exact locations of the curved leads. RESULTS: The five curved leads accurately passed through the five pairs of combined targets, respectively, and the average vector error of curved lead implantation was 0.70+/-0.24mm. COMPARISON WITH EXISTING METHOD(S): In most situations, performing a multiple target DBS procedure with the current stereotaxic systems means increased number of implanted leads, increased incidence of operative complications, and increased medical costs. However, the novel stereotaxic system could guide a single lead to reach two selected targets of the brain with high accuracy. CONCLUSIONS: The novel stereotaxic system enables curved lead implantation with high accuracy, and can be considered as a useful complement to the current stereotaxic system. PMID- 28834694 TI - Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: First case report. AB - Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder resulting in hyper-activation of inflammatory cytokines. If left untreated, the uncontrolled inflammatory response can lead to significant tissue injury and potentially life-threatening multi-organ dysfunction. Conventional immunosuppressive agents are available for the management of HLH, including dexamethasone, cyclosporine, and etoposide; however, patients may not respond to these therapies. Clinicians may turn toward alternative pharmacologic agents that likely have less clinical evidence. We describe a case of secondary HLH that did not respond favorably to conventional treatments. Serum inflammatory markers continued to rise significantly with clinical deterioration and worsening pancytopenia. The severe thrombocytopenia and neutropenia were deemed to have contributed to a spontaneous subdural hematoma and candidemia, respectively. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, was then utilized as a novel salvage therapy based on available in vivo murine data at the time. Following initiation, there was improvement seen in several disease markers, including serum ferritin, lactate dehydrogenase, fibrinogen, and liver function tests. However, the pancytopenia did not show signs of recovery. The patient ultimately expired after 7days of ruxolitinib treatment. It is unclear if the improvement in disease markers was attributed to JAK inhibition alone. However, this experience combined with the positive in vivo murine data suggests that ruxolitinib may serve as a potential treatment option for HLH, pending the release of more robust data. To our knowledge, this is the first human case report describing the use of ruxolitinib for HLH. Future studies are warranted to determine the role of ruxolitinib in this setting. PMID- 28834695 TI - Multimodality therapy improves survival in intramedullary spinal cord metastasis of lung primary. AB - BACKGROUND: Most metastatic spinal cord lesions are located either in the intradural, extramedullary, or in the epidural compartments. Intramedullary spinal cord metastasis (ISCM) is a rare central nervous system spread of cancer. The aim of this report was to evaluate ISCM in the published literature. METHODS: A literature review of PubMed from 1960 to 2016 was undertaken for the publications having demographic, clinical, histological, and outcome data. RESULTS: A total of 59 relevant papers were identified, showing 128 cases of intramedullary metastasis from lung cancer. The incidence of lung cancer as the primary malignancy with intramedullary metastasis was 56%. The median time from diagnosis of primary to intramedullary metastasis was 6months. Survival improved with multimodality therapy compared to monotherapy (4monthsvs. 6.3months) (hazard ratio=0.501; 95% confidence interval, 0.293-0.857). CONCLUSION: Lung cancer is the predominant cause of intramedullary involvement of the spinal cord. Overall prognosis is poor, although a multimodality approach was associated with improved survival. PMID- 28834696 TI - Semicarbazide disturbs the reproductive system of male zebrafish (Danio rerio) through the GABAergic system. AB - Semicarbazide (SMC), an emerging water contaminant, exerts anti-estrogenic effects in female zebrafish. However, the exact influence of SMC on male reproduction remains unclear. In this study, adult male zebrafish were exposed to 1-1000MUg/L SMC in a semi-static system for 28 d prior to examining the testicular somatic index (TSI), testis histology, plasma sex hormone levels, and the transcription of genes involved in reproduction. The results showed that testicular morphology was altered and TSI was down-regulated by high concentrations of SMC (>=100MUg/L and 1000MUg/L, respectively). Plasma testosterone and 17beta-estradiol concentrations were significantly decreased by all of the SMC treatments, along with down-regulation of the corresponding steroidogenic gene transcripts. These changes were associated with the inhibition of gamma-aminobutyric acid synthesis and function, in addition to the decreased expression of reproductive regulators. Our results contribute to elucidating the mechanisms underlying the adverse reproductive effects of SMC in male zebrafish. PMID- 28834697 TI - Recommended standards for conducting and reporting ethnopharmacological field studies. AB - ETHNOPHARMACOLOGICAL RELEVANCE: What are the minimum methodological and conceptual requirements for an ethnopharmacological field study? How can the results of ethnopharmacological field studies be reported so that researchers with different backgrounds can draw on the results and develop new research questions and projects? And how should these field data be presented to get accepted in a scientific journal such as the Journal of Ethnopharmacology? The objective of this commentary is to create a reference that covers the basic standards necessary during planning, conducting and reporting of field research. MATERIALS AND METHODS: We focus on conducting and reporting ethnopharmacological field studies on medicinal plants or materia medica and associated knowledge of a specific people or region. The article highlights the most frequent problems and pitfalls, and draws on published literature, fieldwork experience, and extensive insights from peer-review of field studies. RESULTS: Research needs to be ethical and legal, and follow local and national regulations. Primary ethnopharmacological field data need to be collected and presented in a transparent and comprehensible way. In short this includes: 1) Relevant and concise research questions, 2) Thorough literature study encompassing all available information on the study site from different disciplines, 3) Appropriate methods to answer the research questions, 4) Proper plant use documentation, unambiguously linked to voucher specimens, and 5) Qualitative and quantitative analyses of the collected data, the latter relying on use-reports as basic units. CONCLUSION: Although not exhaustive, we provide an overview of the necessary main issues to consider for field research and data reporting including a list of minimal standards and recommendations for best practices. For methodological details and how to correctly apply specific methods, we refer to further reading of suggested textbooks and methods manuals. PMID- 28834698 TI - EMT: Mechanisms and therapeutic implications. AB - Metastasis, the dissemination of cancer cells from primary tumors, represents a major hurdle in the treatment of cancer. The epithelial-mesenchymal transition (EMT) has been studied in normal mammalian development for decades, and it has been proposed as a critical mechanism during cancer progression and metastasis. EMT is tightly regulated by several internal and external cues that orchestrate the shifting from an epithelial-like phenotype into a mesenchymal phenotype, relying on a delicate balance between these two stages to promote metastatic development. EMT is thought to be induced in a subset of metastatic cancer stem cells (MCSCs), bestowing this population with the ability to spread throughout the body and contributing to therapy resistance. The EMT pathway is of increasing interest as a novel therapeutic avenue in the treatment of cancer, and could be targeted to prevent tumor cell dissemination in early stage patients or to eradicate existing metastatic cells in advanced stages. In this review, we describe the sequence of events and defining mechanisms that take place during EMT, and how these interactions drive cancer cell progression into metastasis. We summarize clinical interventions focused on targeting various aspects of EMT and their contribution to preventing cancer dissemination. PMID- 28834700 TI - The systematics and biogeography of African tailorbirds (Cisticolidae: Artisornis) with comment on the choice of Bayesian branch-length prior when analyzing heterogeneous data. AB - The Long-billed Tailorbird (Artisornis moreaui), one of Africa's rarest birds, has a strikingly disjunct distribution, the origin of which has long puzzled biogeographers. One small population (subspecies moreaui) occurs in sub-montane forest in the East Usambara Mountains, a sky island near the coast of northern Tanzania, and another (subspecies sousae) on Serra Jeci in northwestern Mozambique, 950km away. The African Tailorbird, the putative sister-species of Long-billed Tailorbird, also occurs in the East Usambara Mountains and on Serra Jeci, but in addition occupies all the Eastern Arc Mountain forests between these disjunct sites. Stuart (1981) hypothesized that the two tailorbird distributions could be explained by strong ecological competition, with African Tailorbird populations having eliminated Long-billed Tailorbird populations via competitive exclusion in montane forests between the East Usambara and Serra Jeci. If such competitive exclusion explains these geographic distributions, the co-occurrence of the two species in the East Usambara and at Serra Jeci may be ephemeral, with the status of Long-billed Tailorbird especially in doubt. We sought to (1) determine whether the two species of African tailorbirds are indeed sister species, and (2) test predictions from Stuart's (1981) competitive exclusion hypothesis using genetic data. Phylogenetic analyses of our seven gene dataset (3 mtDNA, 4 introns; 4784bp) indeed place these two species together in the genus Artisornis. Instead of finding shallow divergence among African Tailorbird populations and deep divergence between Long-billed Tailorbird populations as expected from Stuart's hypothesis, we recover deep genetic divergence and geographic structure among populations of both tailorbird species. This result is consistent with long-term co-existence of the two species at East Usambara and Serra Jeci. Observational data from both the East Usambara and Serra Jeci suggest that the two species have diverged in use of forest canopy strata. From a conservation standpoint, our results suggest that extinction of the Long-billed Tailorbird as a function of competition with African Tailorbird is highly unlikely, and should not be viewed as imminent. Threats to its survival are instead anthropogenic, and conservation measures should take this into account. Finally, our empirical results suggest that mis-specification of the branch length prior in Bayesian analyses of mitochondrial DNA data can have a profound effect on the overall tree-length (sum of branch-lengths), whereas the topology and support values tend to remain more stable. In contrast, mis-specification of the branch-length prior had a lesser impact on all aspects of the nuclear-only DNA analyses. This problem may be exacerbated when mitochondrial and nuclear DNA analyses are combined in a total evidence approach. PMID- 28834701 TI - Bilirubin concentration is positively associated with haemoglobin concentration and inversely associated with albumin to creatinine ratio among Indigenous Australians: eGFR Study. AB - : Low serum bilirubin concentrations are reported to be strongly associated with cardio-metabolic disease, but this relationship has not been reported among Indigenous Australian people who are known to be at high risk for diabetes and chronic kidney disease (CKD). HYPOTHESIS: serum bilirubin will be negatively associated with markers of chronic disease, including CKD and anaemia among Indigenous Australians. METHOD: A cross-sectional analysis of 594 adult Aboriginal and Torres Strait Islander (TSI) people in good health or with diabetes and markers of CKD. Measures included urine albumin: creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), haemoglobin (Hb) and glycated haemoglobin (HbA1c). Diabetes was defined by medical history, medications or HbA1c>=6.5% or >=48mmol/mol. Anaemia was defined as Hb<130g/L or <120g/L in males and females respectively. A multivariate regression analysis examining factors independently associated with log-bilirubin was performed. RESULTS: Participants mean (SD) age was 45.1 (14.5) years, and included 62.5% females, 71.7% Aboriginal, 41.1% with diabetes, 16.7% with anaemia, 41% with ACR>3mg/mmol and 18.2% with eGFR<60mL/min/1.73m2. Median bilirubin concentration was lower in females than males (6 v 8MUmol/L, p<0.001) and in Aboriginal than TSI participants (6 v 9.5MUmol/L, p<0.001). Six factors explained 35% of the variance of log-bilirubin; Hb and cholesterol (both positively related) and ACR, triglycerides, Aboriginal ethnicity and female gender (all inversely related). CONCLUSION: Serum bilirubin concentrations were positively associated with Hb and total cholesterol, and inversely associated with ACR. Further research to determine reasons explaining lower bilirubin concentrations among Aboriginal compared with TSI participants are needed. PMID- 28834702 TI - Aqueous acetone fractionation of kraft, organosolv and soda lignins. AB - Technical lignins are structurally heterogeneous and polydisperse. This work describes the use of a simple and green method for lignin fractionation, using different proportions of acetone (40 and 60%) in water. Lignins from three different sources (wheat straw organosolv lignin, wheat straw soda lignin and softwood kraft lignin) were used in this fractionation protocol. The obtained fractions showed different molar mass and functional groups. The lower molar mass fractions showed more phenolic hydroxyl groups and carboxylic acid moieties than higher molar mass fractions, which also possessed much higher amounts of carbohydrates. The chemical characterization of these fractionated lignins showed that the PREC fraction was exceptionally pure and homogeneous lignin. Its total lignin content was >96% for all three lignins and it was practically free from carbohydrates and inorganics (ash). Furthermore, PREC fraction possessed the highest carbon content for the three lignin samples (63.05-69.26%). These results illustrate that the proposed aqueous acetone fractionation protocol could indeed produce pure and uniform lignin fraction and it was applicable for lignins from different sources. PMID- 28834699 TI - T cell engaging bispecific antibody (T-BsAb): From technology to therapeutics. AB - Harnessing the power of the human immune system to treat cancer is the essence of immunotherapy. Monoclonal antibodies engage the innate immune system to destroy targeted cells. For the last 30years, antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity have been the main mechanisms of anti-tumor action of unconjugated antibody drugs. Efforts to exploit the potentials of other immune cells, in particular T cells, culminated in the recent approval of two T cell engaging bispecific antibody (T-BsAb) drugs, thereby stimulating new efforts to accelerate similar platforms through preclinical and clinical trials. In this review, we have compiled the worldwide effort in exploring T cell engaging bispecific antibodies. Our special emphasis is on the lessons learned, with the hope to derive insights in this fast evolving field with tremendous clinical potential. PMID- 28834703 TI - Magnetic chitosan-based adsorbent prepared via Pickering high internal phase emulsion for high-efficient removal of antibiotics. AB - A novel magnetic chitosan-g-poly(2-acrylamide-2-methylpropanesulfonic acid) (CTS g-AMPS) porous adsorbent was prepared by grafting the AMPS onto the CTS in the Fe3O4 stabilized Pickering high internal phase emulsions (Pickering-HIPEs) and used for the adsorptive removal of the antibiotics tetracycline (TC) and chlorotetracycline (CTC). The results of the structure characterization showed that porous structure of the adsorbent can be tuned easily by altering amount of Fe3O4-MNPs-M and the electrostatic attraction of between SO3- and CTC, TC was the main adsorption driving force. The adsorption capacities of the adsorbent for TC and CTC can be reached to 806.60 and 876.60mg/g in a wide pH ranged from 3.0 to 11.0, respectively. And the adsorption equilibrium can be reached within 90min for TC and 50min for CTC. The magnetic porous adsorbent had good reusability, which can still attain a high adsorption capacity of 759.82 and 842.99mg/g for TC and CTC after five consecutive adsorption cycles, respectively. Therefore, the as prepared CTS-g-AMPS magnetic adsorbent is potential to be used for adsorption removal of antibiotics from water. PMID- 28834704 TI - Preparation of CMC-g-P(SPMA) super adsorbent hydrogels: Exploring their capacity for MB removal from waste water. AB - A novel superadsorbent anionic hydrogel was synthesized by grafting of poly (3 sulfopropyl methacrylate), P(SPMA), onto carboxymethyl cellulose (CMC). CMC-g P(SPMA) superadsorbent hydrogel was applied as an efficient and sustainable adsorbent to remove methylene blue (MB) from waste water. Batch adsorption experiments showed that the solution pH had an obvious effect on the adsorption capacity with an optimal sorption pH at 6. The CMC-g-P(SPMA) hydrogel had rapid adsorption kinetics for MB and the adsorption equilibrium reached within 40min. The adsorption kinetics were more accurately described by pseudo second-order model and the Langmuir-fitted adsorption isotherms revealed a maximum capacity of 1675mg/g. The current anionic hydrogel is reusable as the adsorption capacity remained at 89% level after five adsorption-desorption cycles. CMC-g-P(SPMA) hydrogel was presented as a sustainable promising adsorbent with high adsorption capacity and good regenerability for effective cationic dyes removal. PMID- 28834705 TI - Adsorptive removal of cationic methylene blue dye using carboxymethyl cellulose/k carrageenan/activated montmorillonite composite beads: Isotherm and kinetic studies. AB - In the present study, new composite beads based on carboxymethyl cellulose (CMC)/k-carrageenan (kC)/activated montmorillonite (AMMT) were prepared for adsorptive removal of cationic methylene blue (MB) as a dye model. The structure and morphology of the composite beads were investigated by FT-IR and SEM, while the thermal properties were tested using TGA. Factors affecting the removal percent of MB such as CMC/kC/AMMT ratios, initial MB concentration, pH medium, adsorbent dosage, solution temperature, and agitation speed were also explored. Results demonstrated that MB removal (%) exceeded 92% after 120 min using CMC/kC/AMMT (1:1:0.4 ratio) compared to 69% in case of free AMMT beads. Moreover, data obtained from isotherm studies were fitted well to Langmuir model (R2=0.999), and the kinetics of adsorption followed pseudo-second order model. Finally, the composite beads showed good reusability for MB dye removal with high efficiency. Results obtained from this study suggest that the prepared composite beads could be applied effectively for removing cationic dyes from aqueous solutions. PMID- 28834706 TI - Flavonoids-induced redox cycling of copper ions leads to generation of reactive oxygen species: A potential role in cancer chemoprevention. AB - Flavonoids, a class of polyphenols are known to be effective inducers of apoptosis and cytotoxicity in cancer cells. It is believed that antioxidant activity of polyphenols cannot fully account for induction of apoptosis and chemotherapeutic prevention in various cancers. In this article, by employing single cell alkaline gel electrophoresis (comet assay), we established that antioxidants, flavonoids such as (myricetin=MN, fisetin=FN, quercetin=QN, kaempferol=KL and galangin=GN) can cause cellular DNA breakage, also act as pro oxidant in presence of transition metal ion such as copper. It was observed that the extent of cellular DNA breakage was found significantly higher in presence of copper. Hydroxyl radicals are generated as a sign of flavonoids' pro-oxidant nature through redox recycling of copper ions. Further, a dose-dependent inhibition of proliferation of breast cancer cells MDA-MB-231 by MN was found leading to pro-oxidant cell death, as assessed by MTT assay. Since levels of copper are considerably elevated in tissue, cell and serum during various malignancies, suggesting that cancer cells would be more subject to copper induced oxidative DNA breakage. Such a copper dependent pro-oxidant cytotoxic mechanism better explains the anticancer activity and preferential cytotoxicity of dietary phytochemicals against cancer cells. PMID- 28834707 TI - Efficacy of carboxymethyl chitosan against Candida tropicalis and Staphylococcus epidermidis monomicrobial and polymicrobial biofilms. AB - Polymicrobial biofilms with fungi and bacteria are the leading cause for the failure of medical devices and related infections. In this study, antibiofilm activities of carboxymethyl chitosan (CM-chitosan) on monomicrobial and polymicrobial biofilms of Staphylococcus epidermidis and Candida tropicalis in vitro were evaluated. CM-chitosan was effective as a sole agent, inhibiting both monomicrobial and polymicrobial biofilms in microplates and also on the silicone surface in short- and long-term periods. Biofilm architecture was investigated by scanning electron microscopy and confocal laser scanning microscopy was used to examine living/dead organisms within biofilm. CM-chitosan inhibited planktonic growth as well as adhesion. Further biofilm formation was inhibited by CM chitosan added at 90min or 12h after biofilm initiation. CM-chitosan may serve as a possible antibiofilm agent to limit monomicrobial and polymicrobial biofilm. PMID- 28834708 TI - Parvalbumin, but not calretinin, neurons express high levels of alpha1-containing GABAA receptors, alpha7-containing nicotinic acetylcholine receptors and D2 dopamine receptors in the basolateral amygdala of the rat. AB - The generation of emotional responses by the basolateral amygdala is largely determined by the balance of excitatory and inhibitory inputs to its principal neurons - the pyramidal cells. The activity of these neurons is tightly controlled by g-aminobutyric acid (GABA)ergic interneurons, especially by those expressing parvalbumin (PV) and calretinin (CR). Although it is known that GABAergic, cholinergic and dopaminergic fibres make synapses on PV and CR cells, knowledge of the various receptors which are used by these cells is still incomplete. Thus, the present study investigates whether neurons expressing PV or CR co-express specific GABA, acetylcholine and/or dopamine receptors in the basolateral amygdala of the rat. The results show that almost two-thirds of PV neurons co-express high concentrations of alpha1 subunit of GABAA receptor, and more than half of them co-express high levels of alpha7 subunit of nicotinic acetylcholine receptor and/or D2-subtype of dopamine receptor. In contrast, a smaller percentage of CR neurons had detectable amounts of these receptors and at lower levels of abundance in most cases. In conclusion, the present results indicate that not only principal neurons but also GABAergic interneurons have specific receptors, which allow these cells to respond to the GABAergic, cholinergic and dopaminergic inputs coming to the basolateral amygdala of the rat. Since these cells receive intrinsic GABAergic inputs, they are strongly interconnected. Since they also receive extrinsic cholinergic and dopaminergic inputs, such stimulation may result in stimulus-driven feed-forward control of the principal neurons. The effects of such control may be either feed-forward inhibition of the principal neurons via alpha7 nicotinic acetylcholine receptors or disinhibition of these cells via D2-dopamine receptors. PMID- 28834709 TI - Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients. AB - OBJECTIVE: To identify possible correlations between skin blood perfusion (BP) and dermal thickness (DT) in different skin areas of systemic sclerosis (SSc) patients. METHODS: Sixty-two SSc patients, according to 2013 EULAR/ACR criteria, and 62 healthy subjects (CNT) were enrolled. Skin BP was analysed by laser speckle contrast analysis (LASCA) at the level of dorsum of the middle phalanx of the third fingers, dorsal aspect of the hands and zygoma. DT was assessed by both skin high frequency ultrasound (US) and modified Rodnan skin score (mRSS) in the same above reported areas. All patients were studied also by nailfold videocapillaroscopy (NVC) to assess the proper pattern of microvascular damage ("Early", "Active", or "Late"). RESULTS: At the level of finger dorsum a statistically significant negative correlation was observed in SSc patients between skin BP and both ultrasound-DT (p=0.0005 r=0.43) and mRSS (p=0.0007 r=0.42), but not at the level of hand dorsum and zygoma. No statistically significant correlation was present between skin BP and ultrasound-DT at any level in CNT. In detail, SSc patients, compared to CNT, showed a statistically significant lower BP only at level of fingers (median PU 72.6 vs 136.1 respectively, p<0.0001) and a statistically significant higher ultrasound-DT at the level of dorsum of 3th finger bilaterally (median mm 0.9 vs 0.7, p<0.0001), dorsum of hands (median mm 0.9 vs 0.7, p<0.0001) and zygoma (median mm 0.8 vs 0.7, p<0.0001). A significant positive correlation between ultrasound-DT and mRSS was observed in SSc patients at level of the three areas (dorsum of fingers p<0.0001 r=0.51; dorsum of hands p=0.03 r=0.27; zygoma p=0.0001 r=0.45). A progressive decrease of skin BP and increase of ultrasound-DT was found correlated with the progression of the severity of NVC patterns. CONCLUSIONS: This study demonstrates for the first time in SSc patients a significant inverse relationship between skin BP, measured by LASCA, and DT, evaluated by both US and mRSS, at the level of dorsum of the middle phalanx of the third fingers. PMID- 28834710 TI - Novel NMR Techniques to Study Structural and Dynamical Properties of DNA Quadruplexes. PMID- 28834711 TI - And Yet It Moves. PMID- 28834712 TI - A Third Look at the Structure of Leiomodin Bound to Actin. PMID- 28834713 TI - ParamAP: Standardized Parameterization of Sinoatrial Node Myocyte Action Potentials. AB - Sinoatrial node myocytes act as cardiac pacemaker cells by generating spontaneous action potentials (APs). Much information is encoded in sinoatrial AP waveforms, but both the analysis and the comparison of AP parameters between studies is hindered by the lack of standardized parameter definitions and the absence of automated analysis tools. Here we introduce ParamAP, a standalone cross-platform computational tool that uses a template-free detection algorithm to automatically identify and parameterize APs from text input files. ParamAP employs a graphic user interface with automatic and user-customizable input modes, and it outputs data files in text and PDF formats. ParamAP returns a total of 16 AP waveform parameters including time intervals such as the AP duration, membrane potentials such as the maximum diastolic potential, and rates of change of the membrane potential such as the diastolic depolarization rate. ParamAP provides a robust AP detection algorithm in combination with a standardized AP parameter analysis over a wide range of AP waveforms and firing rates, owing in part to the use of an iterative algorithm for the determination of the threshold potential and the diastolic depolarization rate that is independent of the maximum upstroke velocity, a parameter that can vary significantly among sinoatrial APs. Because ParamAP is implemented in Python 3, it is also highly customizable and extensible. In conclusion, ParamAP is a powerful computational tool that facilitates quantitative analysis and enables comparison of sinoatrial APs by standardizing parameter definitions and providing an automated work flow. PMID- 28834714 TI - Rotation of Guanine Amino Groups in G-Quadruplexes: A Probe for Local Structure and Ligand Binding. AB - Nucleic acids are dynamic molecules whose functions may depend on their conformational fluctuations and local motions. In particular, amino groups are dynamic components of nucleic acids that participate in the formation of various secondary structures such as G-quadruplexes. Here, we present a cost-efficient NMR method to quantify the rotational dynamics of guanine amino groups in G quadruplex nucleic acids. An isolated spectrum of amino protons from a specific tetrad-bound guanine can be extracted from the nuclear Overhauser effect spectroscopy spectrum based on the close proximity between the intra-residue imino and amino protons. We apply the method in different structural contexts of G-quadruplexes and their complexes. Our results highlight the role of stacking and hydrogen-bond interactions in restraining amino-group rotation. The measurement of the rotation rate of individual amino groups could give insight into the dynamic processes occurring at specific locations within G-quadruplex nucleic acids, providing valuable probes for local structure, dynamics, and ligand binding. PMID- 28834715 TI - Bridging Microscopic and Macroscopic Mechanisms of p53-MDM2 Binding with Kinetic Network Models. AB - Under normal cellular conditions, the tumor suppressor protein p53 is kept at low levels in part due to ubiquitination by MDM2, a process initiated by binding of MDM2 to the intrinsically disordered transactivation domain (TAD) of p53. Many experimental and simulation studies suggest that disordered domains such as p53 TAD bind their targets nonspecifically before folding to a tightly associated conformation, but the microscopic details are unclear. Toward a detailed prediction of binding mechanisms, pathways, and rates, we have performed large scale unbiased all-atom simulations of p53-MDM2 binding. Markov state models (MSMs) constructed from the trajectory data predict p53 TAD binding pathways and on-rates in good agreement with experiment. The MSM reveals that two key bound intermediates, each with a nonnative arrangement of hydrophobic residues in the MDM2 binding cleft, control the overall on-rate. Using microscopic rate information from the MSM, we parameterize a simple four-state kinetic model to 1) determine that induced-fit pathways dominate the binding flux over a large range of concentrations, and 2) predict how modulation of residual p53 helicity affects binding, in good agreement with experiment. These results suggest new ways in which microscopic models of peptide binding, coupled with simple few-state binding flux models, can be used to understand biological function in physiological contexts. PMID- 28834716 TI - Electrostatic Interactions at the Dimer Interface Stabilize the E. coli beta Sliding Clamp. AB - Sliding clamps are ring-shaped oligomeric proteins that encircle DNA and associate with DNA polymerases for processive DNA replication. The dimeric Escherichia coli beta-clamp is closed in solution but must adopt an open conformation to be assembled onto DNA by a clamp loader. To determine what factors contribute to the stability of the dimer interfaces in the closed conformation and how clamp dynamics contribute to formation of the open conformation, we identified conditions that destabilized the dimer and measured the effects of these conditions on clamp dynamics. We characterized the role of electrostatic interactions in stabilizing the beta-clamp interface. Increasing salt concentration results in decreased dimer stability and faster subunit dissociation kinetics. The equilibrium dissociation constant of the dimeric clamp varies with salt concentration as predicted by simple charge-screening models, indicating that charged amino acids contribute to the remarkable stability of the interface at physiological salt concentrations. Mutation of a charged residue at the interface (Arg-103) weakens the interface significantly, whereas effects are negligible when a hydrophilic (Ser-109) or a hydrophobic (Ile-305) amino acid is mutated instead. It has been suggested that clamp opening by the clamp loader takes advantage of spontaneous opening-closing fluctuations at the clamp's interface, but our time-resolved fluorescence and fluorescence correlation experiments rule out conformational fluctuations that lead to a significant fraction of open states. PMID- 28834717 TI - Major Reaction Coordinates Linking Transient Amyloid-beta Oligomers to Fibrils Measured at Atomic Level. AB - The structural underpinnings for the higher toxicity of the oligomeric intermediates of amyloidogenic peptides, compared to the mature fibrils, remain unknown at present. The transient nature and heterogeneity of the oligomers make it difficult to follow their structure. Here, using vibrational and solid-state nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, we show that freely aggregating Abeta40 oligomers in physiological solutions have an intramolecular antiparallel configuration that is distinct from the intermolecular parallel beta-sheet structure observed in mature fibrils. The intramolecular hydrogen-bonding network flips nearly 90 degrees , and the two beta-strands of each monomeric unit move apart, to give rise to the well-known intermolecular in-register parallel beta-sheet structure in the mature fibrils. Solid-state nuclear magnetic resonance distance measurements capture the interstrand separation within monomer units during the transition from the oligomer to the fibril form. We further find that the D23-K28 salt-bridge, a major feature of the Abeta40 fibrils and a focal point of mutations linked to early onset Alzheimer's disease, is not detectable in the small oligomers. Molecular dynamics simulations capture the correlation between changes in the D23 K28 distance and the flipping of the monomer secondary structure between antiparallel and parallel beta-sheet architectures. Overall, we propose interstrand separation and salt-bridge formation as key reaction coordinates describing the structural transition of the small Abeta40 oligomers to fibrils. PMID- 28834718 TI - Protonation-State-Dependent Communication in Cytochrome c Oxidase. AB - Proton transfer in cytochrome c oxidase from the cellular inside to the binuclear redox center (BNC) can occur through two distinct pathways, the D- and K channels. For the protein to function as both a redox enzyme and a proton pump, proton transfer into the protein toward the BNC or toward a proton loading site (and ultimately through the membrane) must be highly regulated. The PR -> F transition is the first step in a catalytic cycle that requires proton transfer from the bulk at the N-side to the BNC. Molecular dynamics simulations of the PR > F intermediate of this transition, with 16 different combinations of protonation states of key residues in the D- and K-channel, show the impact of the K-channel on the D-channel to be protonation-state dependent. Strength as well as means of communication, correlations in positions, or communication along the hydrogen-bonded network depends on the protonation state of the K-channel residue K362. The conformational and hydrogen-bond dynamics of the D-channel residue N139 is regulated by an interplay of protonation in the D-channel and K362. N139 thus assumes a gating function by which proton passage through the D channel toward E286 is likely facilitated for states with protonated K362 and unprotonated E286. In contrast, proton passage through the D-channel is hindered by N139's preference for a closed conformation in situations with protonated E286. PMID- 28834719 TI - Conversion of OprO into an OprP-like Channel by Exchanging Key Residues in the Channel Constriction. AB - Under phosphate-limiting conditions, the channels OprP and OprO are induced and expressed in the outer membrane of Pseudomonas aeruginosa. Despite their large homology, the phosphate-specific OprP and the diphosphate-specific OprO pores show structural differences in their binding sites situated in the constriction region. Previously, it was shown that the mutation of amino acids in OprP (Y62F and Y114D) led to an exchange in substrate specificity similar to OprO. To support the role of these key amino acids in the substrate sorting of these specific channels, the reverse mutants for OprO (F62Y, D114Y, and F62Y/D114Y) were created in this study. The phosphate and diphosphate binding of the generated channels was studied in planar lipid bilayers. Our results show that mutations of key residues indeed reverse the substrate specificity of OprO to OprP and support the view that just a few strategically positioned amino acids are mainly responsible for its substrate specificity. PMID- 28834720 TI - Spontaneous Membrane Translocating Peptides: The Role of Leucine-Arginine Consensus Motifs. AB - We previously used an orthogonal high-throughput screen to select peptides that spontaneously cross synthetic lipid bilayers without bilayer disruption. Many of the 12-residue spontaneous membrane translocating peptides (SMTPs) selected from the library contained a 5-residue consensus motif, LRLLR in positions 5-9. We hypothesized that the conserved motif could be a necessary and sufficient minimal motif for translocation. To test this and to explore the mechanism of spontaneous membrane translocation, we synthesized seven arginine placement variants of LRLLRWC and compared their membrane partitioning, translocation, and perturbation to one of the parent SMTPs, called "TP2". Several motif variant peptides translocate into synthetic vesicles with rates that are similar to TP2. However, the peptide containing the selected motif, LRLLRWC, was not the fastest; sequence context is also important for translocation efficiency. Although none of these peptides permeabilize bilayers, the motif peptides translocate faster at higher peptide to lipid ratios, suggesting that bilayer perturbation and/or cooperative interactions are important for their translocation. On the other hand, TP2 translocates slower as its concentration is increased, suggesting that TP2 translocates as a monomer and is inhibited by lateral interactions in the membrane. TP2 and the LRLLR motif peptide induce lipid translocation, suggesting that lipids chaperone them across the bilayer. The other motif peptides do not induce lipid flip-flop, suggesting an alternate mechanism. Concatenated motifs translocate slower than the motifs alone. Variants of TP2 with shorter and longer arginine side-chain analogs translocate slower than TP2. In summary, these results suggest that multiple patterns of leucine and arginine can support spontaneous membrane translocation, and that sequence context is important for the contribution of the motifs. Because motifs do not make simple, additive contributions to spontaneous translocation, rational engineering of novel SMTPs will remain difficult, providing even more reason to pursue SMTP discovery with synthetic molecular evolution. PMID- 28834721 TI - Divide & Conquer: Surfactant Protein SP-C and Cholesterol Modulate Phase Segregation in Lung Surfactant. AB - Lung surfactant (LS) is an essential system supporting the respiratory function. Cholesterol can be deleterious for LS function, a condition that is reversed by the presence of the lipopeptide SP-C. In this work, the structure of LS-mimicking membranes has been analyzed under the combined effect of SP-C and cholesterol by deuterium NMR and phosphorus NMR and by electron spin resonance. Our results show that SP-C induces phase segregation at 37 degrees C, resulting in an ordered phase with spectral features resembling an interdigitated state enriched in dipalmitoylphosphatidylcholine, a liquid-crystalline bilayer phase, and an extremely mobile phase consistent with small vesicles or micelles. In the presence of cholesterol, POPC and POPG motion seem to be more hindered by SP-C than dipalmitoylphosphatidylcholine. The use of deuterated cholesterol did not show signs of specific interactions that could be attributed to SP-C or to the other hydrophobic surfactant protein SP-B. Palmitoylation of SP-C had an indirect effect on the extent of protein-lipid perturbations by stabilizing SP-C structure, and seemed to be important to maximize differences among the lipids participating in each phase. These results shed some light on how SP-C-induced lipid perturbations can alter membrane structure to sustain LS functionality at the air-liquid interface. PMID- 28834722 TI - Does Ceramide Form Channels? The Ceramide-Induced Membrane Permeabilization Mechanism. AB - Ceramide is a sphingolipid involved in several cellular processes, including apoptosis. It has been proposed that ceramide forms large and stable channels in the mitochondrial outer membrane that induce cell death through direct release of cytochrome c. However, this mechanism is still debated because the membrane permeabilizing activity of ceramide remains poorly understood. To determine whether the mechanism of ceramide-induced membrane leakage is consistent with the hypothesis of an apoptotic ceramide channel, we have used here assays of calcein release from liposomes. When assaying liposomes containing sphingomyelin and cholesterol, we observed an overall gradual phenomenon of contents release, together with some all-or-none leakage (at low ceramide concentrations or short times). The presence of channels in the bilayer should cause only an all-or-none leakage. When liposomes poor in sphingomyelin/cholesterol or mimicking the lipid composition of the mitochondrial outer membrane were tested, we did not detect any leakage. In consequence, the hypothesis of formation of large ceramide channels in the membrane is not consistent with our results. Instead we propose that the presence of ceramide in one of the membrane monolayers causes a surface area mismatch between both monolayers, which leads to vesicle collapse. The gradual phenomenon of calcein release would be due to a competition between two ceramide effects; namely, lateral segregation that facilitates permeabilization, and at longer times, trans-bilayer flip-flop that opposes asymmetric lateral segregation and causes a mismatch. PMID- 28834723 TI - Determination of the Membrane Translocation pK of the pH-Low Insertion Peptide. AB - The pH-low insertion peptide (pHLIP) is a leading peptide technology to target the extracellular acidosis that characterizes solid tumors. The pHLIP binds to lipid membranes, and responds to acidification by undergoing a coupled folding/membrane insertion process. In the final transmembrane state, the C terminus of pHLIP gets exposed to the cytoplasm of the target cell, providing a means to translocate membrane-impermeable drug cargoes across the plasma membrane of cancer cells. There exists a need to develop improved pHLIP variants to target tumors with greater efficiency. Characterization of such variants typically relies on determining the pK parameter, the pH midpoint of peptide insertion into the lipid bilayer. Here we report that the value of the pK can be strongly dependent on the method used for its determination. Membrane insertion of pHLIP involves at least four intermediate states, which are believed to be linked to the staggered titration of key acidic residues. We propose that some spectroscopic methods are influenced more heavily by specific membrane folding intermediates, and as a result yield different pK values. To address this potential problem, we have devised an assay to independently monitor the environment of the two termini of pHLIP. This approach provides insights into the conformation pHLIP adopts immediately before the establishment of the transmembrane configuration. Additionally, our data indicate that the membrane translocation of the C terminus of pHLIP, the folding step more directly relevant to drug delivery, occurs at more acidic pH values than previously considered. Consequently, such a pK difference could have substantial ramifications for assessing the translocation of drug cargoes conjugated to pHLIP. PMID- 28834724 TI - Omecamtiv Mecarbil Abolishes Length-Mediated Increase in Guinea Pig Cardiac Myofiber Ca2+ Sensitivity. AB - Omecamtiv mecarbil (OM) is a pharmacological agent that augments cardiac contractile function by enhancing myofilament Ca2+ sensitivity. Given that interventions that increase myofilament Ca2+ sensitivity have the potential to alter length-dependent activation (LDA) of cardiac myofilaments, we tested the influence of OM on this fundamental property of the heart. This is significant not only because LDA is prominent in cardiac muscle but also because it contributes to the Frank-Starling law, a mechanism by which the heart increases stroke volume in response to an increase in venous return. We measured steady state and dynamic contractile indices in detergent-skinned guinea pig (Cavia porcellus) cardiac muscle fibers in the absence and presence of 0.3 and 3.0 MUM OM at two different sarcomere lengths (SLs), short SL (1.9 MUm) and long SL (2.3 MUm). Myofilament Ca2+ sensitivity, as measured by pCa50 (-log of [Ca2+]free concentration required for half-maximal activation), increased significantly at both short and long SLs in OM-treated fibers when compared to untreated fibers; however, the magnitude of increase in pCa50 was twofold greater at short SL than at long SL. A consequence of this greater increase in pCa50 at short SL was that pCa50 did not increase any further at long SL, suggesting that OM abolished the SL dependency of pCa50. Furthermore, the SL dependency of rate constants of cross bridge distortion dynamics (c) and force redevelopment (ktr) was abolished in 0.3 MUM-OM-treated fibers. The negative impact of OM on the SL dependency of pCa50, c, and ktr was also observed in 3.0-MUM-OM-treated fibers, indicating that cooperative mechanisms linked to LDA were altered by the OM-mediated effects on cardiac myofilaments. PMID- 28834725 TI - Crystal Structure of Leiomodin 2 in Complex with Actin: A Structural and Functional Reexamination. AB - Leiomodins (Lmods) are a family of actin filament nucleators related to tropomodulins (Tmods), which are pointed end-capping proteins. Whereas Tmods have alternating tropomyosin- and actin-binding sites (TMBS1, ABS1, TMBS2, ABS2), Lmods lack TMBS2 and half of ABS1, and present a C-terminal extension containing a proline-rich domain and an actin-binding Wiskott-Aldrich syndrome protein homology 2 (WH2) domain that is absent in Tmods. Most of the nucleation activity of Lmods resides within a fragment encompassing ABS2 and the C-terminal extension. This fragment recruits actin monomers into a polymerization nucleus. Here, we revise a recently reported structure of this region of Lmod2 in complex with actin and provide biochemical validation for the newly revised structure. We find that instead of two actin subunits connected by a single Lmod2 polypeptide, as reported in the original structure, the P1 unit cell contains two nearly identical copies of actin monomers, each bound to Lmod2's ABS2 and WH2 domain, with no electron density connecting these two domains. Moreover, we show that the two actin molecules in the unit cell are related to each other by a local twofold noncrystallographic symmetry axis, a conformation clearly distinct from that of actin subunits in the helical filament. We further find that a proposed actin binding site within the missing connecting region of Lmod2, termed helix h1, does not bind actin in vitro and that the electron density assigned to it in the original structure corresponds instead to a WH2 domain with opposite backbone directionality. Polymerization assays using Lmod2 mutants of helix h1 and the WH2 domain support this conclusion. Finally, we find that deleting the C-terminal extension of Lmod1 and Lmod2 results in an approximately threefold decrease in the nucleation activity, which is only partially accounted for by the lack of the WH2 domain. PMID- 28834726 TI - Prospects for Human Erythrocyte Skeleton-Bilayer Dissociation during Splenic Flow. AB - Prospects of vesiculation occurring during splenic flow of erythrocytes are addressed via model simulations of RBC flow through the venous slits of the human spleen. Our model is multiscale and contains a thermally activated rate-dependent description of the entropic elasticity of the RBC spectrin cytoskeleton, including domain unfolding/refolding. Our model also includes detail of the skeleton attachment to the fluidlike lipid bilayer membrane, including a specific accounting for the expansion/contraction of the skeleton that may occur via anchor protein diffusive motion, that is, band 3 and glycophorin, through the membrane. This ability allows us to follow the change in anchor density and thereby the strength of the skeleton/membrane attachment. We define a negative pressure between the skeleton/membrane connection that promotes separation; critical levels for this are estimated using published data on the work of adhesion of this connection. By following the maximum range of negative pressure, along with the observed slight decrease in skeletal density, we conclude that there must be biochemical influences that probably include binding of degraded hemoglobin, among other things, that significantly reduce effective attachment density. These findings are consistent with reported trends in vesiculation that are believed to occur in cases of various hereditary anemias and during blood storage. Our findings also suggest pathways for further study of erythrocyte vesiculation that point to the criticality of understanding the biochemical phenomena involved with cytoskeleton/membrane attachment. PMID- 28834727 TI - Mechanics of Fluid-Filled Interstitial Gaps. I. Modeling Gaps in a Compact Tissue. AB - Fluid-filled interstitial gaps are a common feature of compact tissues held together by cell-cell adhesion. Although such gaps can in principle be the result of weak, incomplete cell attachment, adhesion is usually too strong for this to occur. Using a mechanical model of tissue cohesion, we show that, instead, a combination of local prevention of cell adhesion at three-cell junctions by fluidlike extracellular material and a reduction of cortical tension at the gap surface are sufficient to generate stable gaps. The size and shape of these interstitial gaps depends on the mechanical tensions between cells and at gap surfaces, and on the difference between intracellular and interstitial pressures that is related to the volume of the interstitial fluid. As a consequence of the dependence on tension/tension ratios, the presence of gaps does not depend on the absolute strength of cell adhesion, and similar gaps are predicted to occur in tissues of widely differing cohesion. Tissue mechanical parameters can also vary within and between cells of a given tissue, generating asymmetrical gaps. Within limits, these can be approximated by symmetrical gaps. PMID- 28834728 TI - Mechanics of Fluid-Filled Interstitial Gaps. II. Gap Characteristics in Xenopus Embryonic Ectoderm. AB - The ectoderm of the Xenopus embryo is permeated by a network of channels that appear in histological sections as interstitial gaps. We characterized this interstitial space by measuring gap sizes, angles formed between adjacent cells, and curvatures of cell surfaces at gaps. From these parameters, and from surface tension values measured previously, we estimated the values of critical mechanical variables that determine gap sizes and shapes in the ectoderm, using a general model of interstitial gap mechanics. We concluded that gaps of 1-4 MUm side length can be formed by the insertion of extracellular matrix fluid at three cell junctions such that cell adhesion is locally disrupted and a tension difference between cell-cell contacts and the free cell surface at gaps of 0.003 mJ/m2 is generated. Furthermore, a cell hydrostatic pressure of 16.8 +/- 1.7 Pa and an interstitial pressure of 3.9 +/- 3.6 Pa, relative to the central blastocoel cavity of the embryo, was found to be consistent with the observed gap size and shape distribution. Reduction of cell adhesion by the knockdown of C cadherin increased gap volume while leaving intracellular and interstitial pressures essentially unchanged. In both normal and adhesion-reduced ectoderm, cortical tension of the free cell surfaces at gaps does not return to the high values characteristic of the free surface of the whole tissue. PMID- 28834729 TI - Myosin Clusters of Finite Size Develop Contractile Stress in 1D Random Actin Arrays. AB - Myosin-powered force generation and contraction in nonmuscle cells underlies many cell biological processes and is based on contractility of random actin arrays. This contractility must rely on a microscopic asymmetry, the precise mechanism of which is not completely clear. A number of models of mechanical and structural asymmetries in actomyosin contraction have been posited. Here, we examine a contraction mechanism based on a finite size of myosin clusters and anisotropy of force generation by myosin heads at the ends of the myosin clusters. We use agent based numerical simulations to demonstrate that if average lengths of actin filaments and myosin clusters are similar, then the proposed microscopic asymmetry leads to effective contraction of random 1D actomyosin arrays. We discuss the model's implication for mechanics of contractile rings and stress fibers. PMID- 28834730 TI - alpha-Actinin Induces a Kink in the Transmembrane Domain of beta3-Integrin and Impairs Activation via Talin. AB - Integrin-mediated signaling is crucial for cell-substrate adhesion and can be triggered from both intra- and extracellular interactions. Although talin binding is sufficient for inside-out activation of integrin, other cytoplasmic proteins such as alpha-actinin and filamin can directly interfere with talin-mediated integrin activation. Specifically, alpha-actinin plays distinct roles in regulating alphaIIbbeta3 versus alpha5beta1 integrin. It has been shown that alpha-actinin competes with talin for binding to the cytoplasmic tail of beta3 integrin, whereas it cooperates with talin for activating integrin alpha5beta1. In this study, molecular dynamics simulations were employed to compare and contrast molecular mechanisms of alphaIIbbeta3 and alpha5beta1 activation in the presence and absence of alpha-actinin. Our results suggest that alpha-actinin impairs integrin signaling by both undermining talin binding to the beta3 integrin cytoplasmic tail and inducing a kink in the transmembrane domain of beta3-integrin. Furthermore, we showed that alpha-actinin promote talin association with beta1-integrin by restricting the motion of the cytoplasmic tail and reducing the entropic barrier for talin binding. Taken together, our results showed that the interplay between talin and alpha-actinin regulates signal transmission via controlling the conformation of the transmembrane domain and altering natural response modes of integrins in a type-specific manner. PMID- 28834731 TI - Passive and Active Microrheology of the Intestinal Fluid of the Larval Zebrafish. AB - The fluids of the intestine serve as a physical barrier to pathogens, a medium for the diffusion of nutrients and metabolites, and an environment for commensal microbes. The rheological properties of intestinal mucus have therefore been the subject of many investigations, thus far limited to in vitro studies due to the difficulty of measurement in the natural context of the gut. This limitation especially hinders our understanding of how the gut microbiota interact with the intestinal space, since examination of this calls not only for in vivo measurement techniques, but for techniques that can be applied to model organisms in which the microbial state of the gut can be controlled. We have addressed this challenge with two complementary approaches. We performed passive microrheological measurements using thermally driven nanoparticles and active microrheology using micron-scale ellipsoidal magnetic microparticles, in both cases using light-sheet fluorescence microscopy to optically access the intestinal bulb of the larval zebrafish, a model vertebrate. We present viscosity measurements in germ-free animals (devoid of gut microbes), animals colonized by a single bacterial species, and conventionally reared animals, and find that in all cases, the mucin-rich intestinal liquid is well described as a Newtonian fluid. Surprisingly, despite known differences in the number of secretory cells in germ-free zebrafish and their conventional counterparts, the fluid viscosity for these two groups is very similar, as measured with either technique. Our study provides, to our knowledge, the first in vivo microrheological measurements of the intestinal space in living animals, and we comment on its implications for timescales of host-microbe interactions in the gut. PMID- 28834732 TI - Location of the TEMPO Moiety of TEMPO-PC in Lipid Bilayers. PMID- 28834733 TI - Development of a phosphorylated Momordica charantia protein system for inhibiting susceptible dose-dependent C. albicans to available antimycotics: An allosteric regulation of protein. AB - A regulatory Momordica charantia protein system was constructed allosterically by in vitro protein phosphorylation, in an attempt to evaluate antimycological pluripotency against dose-dependent susceptibilities in C. albicans. Fungal strain lineages susceptible to ketoconazole, econazole, miconazole, 5 flucytosine, nystatin and amphotericin B were prepared in laboratory, followed by identification via antifungal susceptibility testing. Protein phosphorylation was carried out in reactions with 5'-adenylic, guanidylic, cytidylic and uridylic acids and cyclic adenosine triphosphate, through catalysis of cyclin-dependent kinase 1, protein kinase A and protein kinase C respectively. Biochemical analysis of enzymatic reactions indicated the apparent Michaelis-Menten constants and maximal velocity values of 16.57-91.97mM and 55.56-208.33MUM.min-1, together with an approximate 1:1 reactant stoichiometric ratio. Three major protein phosphorylation sites were theoretically predicted at Thr255, Thr102 and Thr24 by a KinasePhos tool. Additionally, circular dichroism spectroscopy demonstrated that upon phosphorylation, protein folding structures were decreased in random coil, beta6-sheet and alpha1-helix partial regions. McFarland equivalence standard testing yielded the concentration-dependent inhibition patterns, while fungus was grown in Sabouraud's dextrose agar. The minimal inhibitory concentrations of 0.16-0.51MUM (at 50% response) were obtained for free protein and phosphorylated counterparts. With respect to the 3-cycling susceptibility testing regimen, individuals of total protein forms were administrated in-turn at 0.14MUM/cycle. Relative inhibition ratios were retained to 66.13-81.04% of initial ones regarding the ketoconazole-susceptible C. albicans growth. An inhibitory protein system, with an advantage of decreasing antifungal susceptibilities to diverse antimycotics, was proposed because of regulatory pluripotency whereas little contribution to susceptibility in itself. PMID- 28834734 TI - ONTD induces growth arrest and apoptosis of human hepatoma Bel-7402 cells though a peroxisome proliferator-activated receptor gamma-dependent pathway. AB - ONTD (3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile) is a novel synthetic derivative of glycyrrhetinic acid (GA), which has been reported to exhibit anti-inflammatory and anti-tumor activities through its mechanisms are not fully understood. Previously, we demonstrated that ONTD induces apoptosis of human hepatoma cells via a MAPK-dependent mitochondrial pathway. Recently, ONTD was found to increase sub-G1 accumulation and Annexin-V positive staining, indicating apoptotic induction effect. It was also be found that ONTD increase the PPAR-gamma activity, reduce the phosphorylation of Akt and increase phosphatase and tensin homologue (PTEN) protein expression in hepatocellular carcinoma (HCC) Bel-7402 cells, and these were associated with the inhibition of cells proliferation. More importantly, these effects could be diminished by GW9662, a specific PPAR-gamma antagonist, suggesting that ONTD can act as a ligand of PPAR-gamma. Taken together, our novel observations suggested that ONTD may have potential implication in HCC prevention and treatment, and showed for the first time that the anti-tumor effect of ONTD may also be mediated through modulation of the PPAR-gamma activation and mediated by the PTEN/Akt signaling pathway. The present study also supports ONTD as a potential drug candidate for chemoprevention or chemotherapy of HCC. PMID- 28834735 TI - A photochemical kinetic model for solid dosage forms. AB - Photochemical kinetic models to describe the solution phase degradation of pharmaceutical compounds have been extensively reported, but formalisms applicable to the solid phase under polychromatic light have not received as much attention. The objective of this study was to develop a mathematical model to describe the solid state photodegradation of pharmaceutical powder materials under different area/volumetric scales and light exposure conditions. The model considered the previous formalism presented for photodegradation kinetics in solution phase with important elements applied to static powder material being irradiated with a polychromatic light source. The model also included the influence of optical phenomena (i.e. reflectance, scattering factors, etc.) by applying Beer-Lambert law to light attenuation, including effects of powder density. Drug substance and drug product intermediates (blends and tablet cores) were exposed to different light sources and intensities. The model reasonably predicted the photodegradation levels of powder beds of drug substance and drug product intermediates under white and yellow lights with intensities around 5 11kLux. Importantly, the model estimates demonstrated that the reciprocity law for photoreactions was held. Further model evaluation showed that, due to light attenuation, the powder bed is in virtual darkness at cake depths greater than 500MUm. At 100MUm, the photodegradation of the investigated compound is expected to be close to 100% in 10days under white fluorescent halophosphate light at 9.5kLux. For tablets, defining the volume over exposed surface area ratio is more challenging. Nevertheless, the model can consider a bracket between worst and best cases to provide a reasonable photodegradation estimate. This tool can be significantly leveraged to simulate different light exposure scenarios while assessing photostability risk in order to define appropriate control strategy in manufacturing. PMID- 28834736 TI - Establishing a safe, rapid, convenient and low-cost antiviral assay of interferon bioactivity based on recombinant VSV expressing GFP. AB - The methods of the quantitative assay of the antiviral activity of interferons (IFNs) (type I, II or III) are very important during carrying out of the research of them, since they were found. Here a recombinant vesicular stomatitis virus expressing green fluorescent protein (GFP) (VSV/GFP) and MDBK cells were used to develop an antiviral assay (AVA) for IFNs. This method was carried out on a 96 well cell culture plate, and the half reduction of virus replication was quantified by assaying GFP. To quantify GFP, cell lysis buffer was directly added to the wells infected with VSV/GFP to lyse cells, the VSV/GFP was then inactivated, and relative fluorescence unit (RFU) of GFP was measured and used to calculate the antiviral activity. This method needed only one step instead of three steps in the staining method with naphthol blue black, medium with phenol red can be used, and it had good reproducibility. The GFP-containing samples could be stored at 4 degrees C in a wet box for at least 1 week without affecting the assay results. In addition, the results obtained with this method were similar to those obtained with the staining method. In conclusion, a safe, rapid, convenient and low-cost AVA of IFN based on recombinant VSV/GFP was established. PMID- 28834737 TI - Immunocapture loop-mediated isothermal amplification assays for the detection of canine parvovirus. AB - A loop-mediated isothermal amplification (LAMP) assay was used for rapid canine parvovirus (CPV) diagnosis. To reduce the time required and increase the sensitivity of the assay, an immunocapture (IC) technique was developed in this study to exclude the DNA extraction step in molecular diagnostic procedures for CPV. A polyclonal rabbit anti-CPV serum was produced against VP2-EpC that was cloned via DNA recombination. The polyclonal anti-VP2-EpC serum was used for virus capture to prepare microtubes. IC-LAMP was performed to amplify a specific CPV target gene sequence from the CPV viral particles that were captured on the microtubes, and the amplicons were analyzed using agarose electrophoresis or enzyme-linked immunosorbent assay (IC-LAMP-ELISA) and lateral-flow dipstick (IC LAMP-LFD). The detection sensitivities of IC-LAMP, IC-LAMP-ELISA, and IC-LAMP-LFD were 10-1, 10-1, and 10-1 TCID50/mL, respectively. Using the IC-LAMP-ELISA and IC LAMP-LFD assays, the complete CPV diagnostic process can be achieved within 1.5h. Both of the developed IC-LAMP-based assays are simple, direct visual and efficient techniques that are applicable to the detection of CPV. PMID- 28834738 TI - Structural hemispheric asymmetries underlie verbal Stroop performance. AB - Performance on tasks involving cognitive control such as the Stroop task is often associated with left lateralized brain activations. Based on this neuro functional evidence, we tested whether leftward structural grey matter asymmetries would also predict inter-individual differences in combatting Stroop interference. To check for the specificity of the results, both a verbal Stroop task and a spatial one were administered to a total of 111 healthy young individuals, for whom T1-weighted magnetic resonance imaging (MRI) images were also acquired. Surface thickness and area estimations were calculated using FreeSurfer. Participants' hemispheres were registered to a symmetric template and Laterality Indices (LI) for the surface thickness and for the area at each vertex in each participant were computed. The correlation of these surface LI measures with the verbal and spatial Stroop effects (incongruent-congruent difference in trial performance) was assessed at each vertex by means of general linear models at the whole-brain level. We found a significant correlation between performance and surface area LI in an inferior posterior temporal cluster (overlapping with the so-called visual word form area, VWFA), with a more left-lateralized area in this region associated with a smaller Stroop effect only in the verbal task. These results point to an involvement of the VWFA for higher-level processes based on word reading, including the suppression of this process when required by the task, and could be interpreted in the context of cross-hemispheric rivalry. PMID- 28834739 TI - Coronary Artery Formation Is Driven by Localized Expression of R-spondin3. AB - Coronary arteries are essential to support the heart with oxygen, and coronary heart disease is one of the leading causes of death worldwide. The coronary arteries form at highly stereotyped locations and are derived from the primitive vascular plexus of the heart. How coronary arteries are remodeled and the signaling molecules that govern this process are poorly understood. Here, we have identified the Wnt-signaling modulator Rspo3 as a crucial regulator of coronary artery formation in the developing heart. Rspo3 is specifically expressed around the coronary stems at critical time points in their development. Temporal ablation of Rspo3 at E11.5 leads to decreased beta-catenin signaling and a reduction in arterial-specific proliferation. As a result, the coronary stems are defective and the arterial tree does not form properly. These results identify a mechanism through which localized expression of RSPO3 induces proliferation of the coronary arteries at their stems and permits their formation. PMID- 28834740 TI - Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination. AB - The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfbret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration. PMID- 28834741 TI - Dopamine Encodes Retrospective Temporal Information in a Context-Independent Manner. AB - The dopamine system responds to reward-predictive cues to reflect a prospective estimation of reward value, although its role in encoding retrospective reward related information is unclear. We report that cue-evoked dopamine release in the nucleus accumbens core encodes the time elapsed since the previous reward or rather the wait time. Specifically, a cue that always follows the preceding reward with a short wait time elicits a greater dopamine response relative to a distinct cue that always follows the preceding reward with a long wait time. Differences in the dopamine response between short wait and long wait cues were evident even when these cues were never experienced together within the same context. Conditioned responding updated accordingly with a change in cue-evoked dopamine release but was unrelated to a difference in the dopamine response between cues. Collectively, these findings illustrate that the cue-evoked dopamine response conveys a subjective estimation of the relative reward rate. PMID- 28834743 TI - Constitutive Immune Activity Promotes Tumorigenesis in Drosophila Intestinal Progenitor Cells. AB - Gut innate immune defenses control bacterial populations and protect the host interior from invasion. Although excess intestinal immune activity frequently promotes inflammatory illnesses, we know little about the consequences of chronic innate immune activity exclusively in endodermal gut cells of an otherwise normal animal. To address this question, we examined the consequences of persistent inflammatory signals in adult fly intestinal progenitor cells. We found that constitutive immune activity disrupts expression of homeostatic regulators such as Notch pathway components and induces hyperplasia throughout the gut. Consistent with these observations, we found that persistent immune signals interfere with progenitor cell differentiation and exacerbate the formation of Notch-dependent intestinal tumors. These findings uncover a link between constitutive immune activity and tumorigenesis in intestinal stem cells. PMID- 28834742 TI - The Proprioceptive System Regulates Morphologic Restoration of Fractured Bones. AB - Successful fracture repair requires restoration of bone morphology and mechanical integrity. Recent evidence shows that fractured bones of neonatal mice undergo spontaneous realignment, dubbed "natural reduction." Here, we show that natural reduction is regulated by the proprioceptive system and improves with age. Comparison among mice of different ages revealed, surprisingly, that 3-month-old mice exhibited more rapid and effective natural reduction than newborns. Fractured bones of null mutants for transcription factor Runx3, lacking functional proprioceptors, failed to realign properly. Blocking Runx3 expression in the peripheral nervous system, but not in limb mesenchyme, recapitulated the null phenotype, as did inactivation of muscles flanking the fracture site. Egr3 knockout mice, which lack muscle spindles but not Golgi tendon organs, displayed a less severe phenotype, suggesting that both receptor types, as well as muscle contraction, are required for this regulatory mechanism. These findings uncover a physiological role for proprioception in non-autonomous regulation of skeletal integrity. PMID- 28834744 TI - Mediator MED23 Links Pigmentation and DNA Repair through the Transcription Factor MITF. AB - DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf, by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases. PMID- 28834745 TI - Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization. AB - The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs). PMID- 28834746 TI - PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity. AB - PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity. PMID- 28834747 TI - Triggering of NOD2 Receptor Converts Inflammatory Ly6Chigh into Ly6Clow Monocytes with Patrolling Properties. AB - The signals that regulate the fate of circulating monocytes remain unknown. In the present study, we demonstrate that triggering of the NOD2 receptor by muramyl dipeptide (MDP) converts inflammatory Ly6Chigh monocytes into patrolling Ly6Clow monocytes. Administration of MDP to Nr4a1-/- mice, which lack Ly6Clow monocytes, or to Ly6Clow-depleted mice led to the emergence of blood-patrolling monocytes with a profile similar to that of Ly6Clow monocytes, including high expression of CX3CR1 and LFA1. Using intravital microscopy in animal models of inflammatory diseases, we also found that converted Ly6Chigh monocytes patrol the endothelium of blood vessels and that their presence contributes to a reduction in the inflammatory response following MDP injection. Our results demonstrate that NOD2 contributes to the regulation of blood monocytes and suggest that it could be therapeutically targeted to treat inflammatory diseases. PMID- 28834748 TI - Serotonergic Modulation of Sensory Representation in a Central Multisensory Circuit Is Pathway Specific. AB - Many studies have explored how neuromodulators affect synaptic function, yet little is known about how they modify computations at the microcircuit level. In the dorsal cochlear nucleus (DCN), a region that integrates auditory and multisensory inputs from two distinct pathways, serotonin (5-HT) enhances excitability of principal cells, predicting a generalized reduction in sensory thresholds. Surprisingly, we found that when looked at from the circuit level, 5 HT enhances signaling only from the multisensory input, while decreasing input from auditory fibers. This effect is only partially explained by an action on auditory nerve terminals. Rather, 5-HT biases processing for one input pathway by simultaneously enhancing excitability in the principal cell and in a pathway specific feed-forward inhibitory interneuron. Thus, by acting on multiple targets, 5-HT orchestrates a fundamental shift in representation of convergent auditory and multisensory pathways, enhancing the potency of non-auditory signals in a classical auditory pathway. PMID- 28834749 TI - Composition and Control of a Deg/ENaC Channel during Presynaptic Homeostatic Plasticity. AB - The homeostatic control of presynaptic neurotransmitter release stabilizes information transfer at synaptic connections in the nervous system of organisms ranging from insect to human. Presynaptic homeostatic signaling centers upon the regulated membrane insertion of an amiloride-sensitive degenerin/epithelial sodium (Deg/ENaC) channel. Elucidating the subunit composition of this channel is an essential step toward defining the underlying mechanisms of presynaptic homeostatic plasticity (PHP). Here, we demonstrate that the ppk1 gene encodes an essential subunit of this Deg/ENaC channel, functioning in motoneurons for the rapid induction and maintenance of PHP. We provide genetic and biochemical evidence that PPK1 functions together with PPK11 and PPK16 as a presynaptic, hetero-trimeric Deg/ENaC channel. Finally, we highlight tight control of Deg/ENaC channel expression and activity, showing increased PPK1 protein expression during PHP and evidence for signaling mechanisms that fine tune the level of Deg/ENaC activity during PHP. PMID- 28834750 TI - Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior. AB - The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)->mPFC circuit that controls depression-like behavior. PMID- 28834751 TI - Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance. AB - Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that affect energy balance. Identification of which VTA DA neurons mediate behaviors that limit weight gain has been hindered, however, by the lack of molecular markers to distinguish VTA DA populations. Here, we identified a specific subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) and preferentially comprise mesolimbic, but not mesocortical, DA neurons. Genetically targeted ablation of VTA NtsR1 neurons uncouples motivated feeding and physical activity, biasing behavior toward energy expenditure and protecting mice from age-related and diet induced weight gain. VTA NtsR1 neurons thus represent a molecularly defined subset of DA neurons that are essential for the coordination of energy balance. Modulation of VTA NtsR1 neurons may therefore be useful to promote behaviors that prevent the development of obesity. PMID- 28834752 TI - Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion. AB - Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor. PMID- 28834753 TI - Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Missegregation in Cancer. AB - Chromosomal instability is a hallmark of cancer and correlates with the presence of extra centrosomes, which originate from centriole overduplication. Overduplicated centrioles lead to the formation of centriole rosettes, which mature into supernumerary centrosomes in the subsequent cell cycle. While extra centrosomes promote chromosome missegregation by clustering into pseudo-bipolar spindles, the contribution of centriole rosettes to chromosome missegregation is unknown. We used multi-modal imaging of cells with conditional centriole overduplication to show that mitotic rosettes in bipolar spindles frequently harbor unequal centriole numbers, leading to biased chromosome capture that favors binding to the prominent pole. This results in chromosome missegregation and aneuploidy. Rosette mitoses lead to viable offspring and significantly contribute to progeny production. We further show that centrosome abnormalities in primary human malignancies frequently consist of centriole rosettes. As asymmetric centriole rosettes generate mitotic errors that can be propagated, rosette mitoses are sufficient to cause chromosome missegregation in cancer. PMID- 28834755 TI - Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells. AB - Proper telomere length is essential for embryonic stem cell (ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotent state similar to that of two-cell (2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomere extension in these cells. However, the mechanism by which Zscan4 extends telomeres remains elusive. Here, we show that Zscan4 facilitates telomere elongation by inducing global DNA demethylation through downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1 and promotes their degradation, which depends on the E3 ubiquitin ligase activity of Uhrf1. Blocking DNA demethylation prevents telomere elongation associated with Zscan4 expression, suggesting that DNA demethylation mediates the effect of Zscan4. Our results define a molecular pathway that contributes to the maintenance of telomere length homeostasis in mESCs. PMID- 28834754 TI - SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination. AB - DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutieres syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity. PMID- 28834756 TI - Regulation of Peripheral Myelination through Transcriptional Buffering of Egr2 by an Antisense Long Non-coding RNA. AB - Precise regulation of Egr2 transcription is fundamentally important to the control of peripheral myelination. Here, we describe a long non-coding RNA antisense to the promoter of Egr2 (Egr2-AS-RNA). During peripheral nerve injury, the expression of Egr2-AS-RNA is increased and correlates with decreased Egr2 transcript and protein levels. Ectopic expression of Egr2-AS-RNA in dorsal root ganglion (DRG) cultures inhibits the expression of Egr2 mRNA and induces demyelination. In vivo inhibition of Egr2-AS-RNA using oligonucleotide GapMers released from a biodegradable hydrogel following sciatic nerve injury reverts the EGR2-mediated gene expression profile and significantly delays demyelination. Egr2-AS-RNA gradually recruits H3K27ME3, AGO1, AGO2, and EZH2 on the Egr2 promoter following sciatic nerve injury. Furthermore, expression of Egr2-AS-RNA is regulated through ERK1/2 signaling to YY1, while loss of Ser184 of YY1 regulates binding to Egr2-AS-RNA. In conclusion, we describe functional exploration of an antisense long non-coding RNA in peripheral nervous system (PNS) biology. PMID- 28834757 TI - Peptide-Based Scaffolds Support Human Cortical Progenitor Graft Integration to Reduce Atrophy and Promote Functional Repair in a Model of Stroke. AB - Stem cell transplants offer significant hope for brain repair following ischemic damage. Pre-clinical work suggests that therapeutic mechanisms may be multi faceted, incorporating bone-fide circuit reconstruction by transplanted neurons, but also protection/regeneration of host circuitry. Here, we engineered hydrogel scaffolds to form "bio-bridges" within the necrotic lesion cavity, providing physical and trophic support to transplanted human embryonic stem cell-derived cortical progenitors, as well as residual host neurons. Scaffolds were fabricated by the self-assembly of peptides for a laminin-derived epitope (IKVAV), thereby mimicking the brain's major extracellular protein. Following focal ischemia in rats, scaffold-supported cell transplants induced progressive motor improvements over 9 months, compared to cell- or scaffold-only implants. These grafts were larger, exhibited greater neuronal differentiation, and showed enhanced electrophysiological properties reflective of mature, integrated neurons. Varying graft timing post-injury enabled us to attribute repair to both neuroprotection and circuit replacement. These findings highlight strategies to improve the efficiency of stem cell grafts for brain repair. PMID- 28834759 TI - Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus. PMID- 28834758 TI - Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics. AB - There is growing interest in using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an "allogenized" mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts. PMID- 28834760 TI - Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. PMID- 28834761 TI - Novel pan PI3K inhibitor-induced apoptosis in APL cells correlates with suppression of telomerase: An emerging mechanism of action of BKM120. AB - The intertwining between cancer pathogenesis and perturbation of multitude signaling pathways ushered the cancer therapeutic approaches into an unbounded route of targeted therapies. For the nonce and among the plethora of promising inhibitors, intense interest has focused on small molecules targeting different component of PI3K axis. Intrigued by the constant activation of PI3K in leukemia, this study aimed to investigate the effects of BKM120, as the excelled member of pan PI3K inhibitors, in a panel of hematologic malignant cell lines. The resulting data showed that BKM120 exerted a concentration-dependent growth suppressive effect; however, IC50 values varied among the tested cells. Our results outlined that the blockage of PI3K in NB4, as the most sensitive cell line, resulted in a caspase-3-dependent apoptosis probably through NFkappaB mediated suppression of c-Myc and hTERT. As far we are aware, to date, there have been no reports of BKM120 effect on enzymatic repression of telomerase, and this study represents for the first time that the anti-proliferative effect of the inhibitor on NB4 is mediated by down-regulation of telomerase; shedding new light on the novel mechanism of action of BKM120. PMID- 28834762 TI - Charting the protomap of the human telencephalon. AB - The cerebral cortex is divided stereotypically into a number of functionally distinct areas. According to the protomap hypothesis formulated by Rakic neural progenitors in the ventricular zone form a mosaic of proliferative units that provide a primordial species-specific cortical map. Positional information of newborn neurons is maintained during their migration to the overlying cortical plate. Much evidence has been found to support this hypothesis from studies of primary cortical areas in mouse models in particular. Differential expansion of cortical areas and the introduction of new functional modules during evolution might be the result of changes in the progenitor cells. The human cerebral cortex shows a wide divergence from the mouse containing a much higher proportion of association cortex and a more complicated regionalised repertoire of neuron sub types. To what extent does the protomap hypothesis hold true for the primate brain? This review summarises a growing number of studies exploring arealised gene expression in the early developing human telencephalon. The evidence so far is that the human and mouse brain do share fundamental mechanisms of areal specification, however there are subtle differences which could lead us to a better understanding of cortical evolution and the origins of neurodevelopmental diseases. PMID- 28834763 TI - Overcoming resistance to cisplatin by inhibition of glutathione S-transferases (GSTs) with ethacraplatin micelles in vitro and in vivo. AB - Platinum-based DNA-adducting agents are used extensively in the clinic for cancer chemotherapy. However, the anti-tumor efficacy of these drugs is severely limited by cisplatin resistance, and this can lead to the failure of chemotherapy. One of cisplatin resistance mechanisms is associated with overexpression of glutathione S-transferases (GSTs), which would accelerate the deactivation of cisplatin and decrease its antitumor efficiency. Nanoscale micelles encapsulating ethacraplatin, a conjugate of cisplatin and ethacrynic acid (an effective GSTs inhibitor), can enhance the accumulation of active cisplatin in cancer cells by inhibiting the activity of GSTs and circumventing deactivation of cisplatin. In vitro and in vivo results provide strong evidence that GSTs inhibitor-modified cisplatin prodrug combined with nanoparticle encapsulation favor high effective platinum accumulation, significantly enhanced antitumor efficacy against cisplatin-resistant cancer and decreased system toxicity. It is believed that these ethacraplatin-loaded micelles have the ability of overcoming resistance of cancers toward cisplatin and will improve the prospects for chemotherapy of cisplatin-resistant cancers in the near future. PMID- 28834764 TI - Metal-carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA. AB - The development of effective therapies to control methicillin-resistant Staphylococcus aureus (MRSA) infections is challenging because antibiotics can be degraded by the production of certain enzymes, for example, beta-lactamases. Additionally, the antibiotics themselves fail to penetrate the full depth of biofilms formed from extracellular polymers. Nanoparticle-based carriers can deliver antibiotics with better biofilm penetration, thus combating bacterial resistance. In this study, we describe a general approach for the construction of beta-lactam antibiotics and beta-lactamase inhibitors co-delivery of nanoantibiotics based on metal-carbenicillin framework-coated mesoporous silica nanoparticles (MSN) to overcome MRSA. Carbenicillin, a beta-lactam antibiotic, was used as an organic ligand that coordinates with Fe3+ to form a metal carbenicillin framework to block the pores of the MSN. Furthermore, these beta lactamase inhibitor-loaded nanoantibiotics were stable under physiological conditions and could synchronously release antibiotic molecules and inhibitors at the bacterial infection site to achieve a better elimination of antibiotic resistant bacterial strains and biofilms. We confirmed that these beta-lactamase inhibitor-loaded nanoantibiotics had better penetration depth into biofilms and an obvious effect on the inhibition of MRSA both in vitro and in vivo. PMID- 28834765 TI - RGD peptide-modified fluorescent gold nanoclusters as highly efficient tumor targeted radiotherapy sensitizers. AB - Radiotherapy is a leading treatment approach of cancer therapy. While it is effective in killing tumor cells, it can also cause serious damage to surrounding normal tissue. Targeted radiotherapy with gold nanoparticle-based radiosensitizers is actively being investigated, and considered as a promising means to enhance the efficacy of radiotherapy against tumors under a relatively low and safe radiation dose. In this work, we report a green and one-step strategy to synthesize fluorescent gold nanoclusters by using a commercialized cyclic arginine-glycine-aspartic acid (c(RGDyC)) peptide as the template. The nanoclusters inherit special properties of both the Au core (red/NIR fluorescence emission and strong radiosensitizing effect) and c(RGDyC) shell (active cancer cell-targeting ability and good biocompatibility), and can be applied as fluorescent probes to stain alphavbeta3 integrin-positive cancer cells, as well as radiosensitizing agents to boost the killing efficacy of radiotherapy. Our data suggest that the as-designed gold nanoclusters have excellent biocompatibility, bright red/NIR fluorescence, active tumor targeting property, and strong radiosensitizing effect, making them highly promising towards potential clinical translation. PMID- 28834766 TI - CO2 saturated water as two-phase flow for fouling control in reverse electrodialysis. AB - When natural feed waters are used in the operation of a reverse electrodialysis (RED) stack, severe fouling on the ion exchange membranes and spacers occurs. Fouling of the RED stack has a strong influence on the gross power density output; which can decrease up to 50%. Moreover, an increase in the pressure loss occurs between the feed water inlet and outlet, increasing the pumping energy and thus decreasing the net power density that can be obtained. In this work, we extensively investigated the use of CO2 saturated water as two-phase flow cleaning for fouling mitigation in RED using natural feed waters. Experiments were performed in the REDstack research facility located at the Afsluitdijk (the Netherlands) using natural feed waters for a period of 60 days. Two different gas combinations were experimentally investigated, water/air sparging and water/CO2 (saturated) injection. Air is an inert gas mixture and induces air sparging in the stack. In the case of CO2, nucleation, i.e. the spontaneous formation of bubbles, occurs at the spacer filaments due to depressurization of CO2 saturated water, inducing cleaning. Results showed that stacks equipped with CO2 saturated water can produce an average net power density of 0.18 W/m2 under real fouling conditions with minimal pre-treatment and at a low outside temperature of only 8 degrees C, whereas the stacks equipped with air sparging could only produce an average net power density of 0.04 W/m2. Electrochemical impedance spectroscopy measurements showed that the stacks equipped with air sparging increased in stack resistance due to the presence of stagnant bubbles remaining in the stack after every air injection. Furthermore, the introduction of CO2 gas in the feed water introduces a pH decrease in the system (carbonated solution) adding an additional cleaning effect in the system, thus avoiding the use of environmentally unwanted cleaning chemicals. PMID- 28834767 TI - Reducing ultrafiltration membrane fouling during potable water reuse using pre ozonation. AB - Wastewater reclamation has increasingly become popular to secure potable water supply. Low-pressure membrane processes such as microfiltration (MF) and ultrafiltration (UF) play imperative roles as a barrier of macromolecules for such purpose, but are often limited by membrane fouling. Effluent organic matter (EfOM), including biopolymers and particulates, in secondary wastewater effluents have been known to be major foulants in low-pressure membrane processes. Hence, the primary aim of this study was to investigate the effects of pre-ozonation as a pre-treatment for UF on the membrane fouling caused by EfOM in secondary wastewater effluents for hydrophilic regenerated cellulose (RC) and hydrophobic polyethersulfone (PES) UF membranes. It was found that greater fouling reduction was achieved by pre-ozonation for the hydrophilic RC membrane than the hydrophobic PES membrane at increasing ozone doses. In addition, the physicochemical property changes of EfOM, including biopolymer fractions, by pre ozonation were systemically investigated. The classical pore blocking model and the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theories were employed to scrutinize the fouling alleviation mechanism by pre-ozonation. As a result, the overarching mechanisms of fouling reduction were attributed to the following key reasons: (1) Ozone degraded macromolecules such as biopolymers like proteins and polysaccharides into smaller fractions, thereby increasing free energy of cohesion of EfOM and rendering them more hydrophilic and stable; (2) pre ozonation augmented the interfacial free energy of adhesion between foulants and the RC/PES membranes, leading to the increase of repulsions and/or the decrease of attractions; and (3) pre-ozonation prolonged the transition from pore blocking to cake filtration that was a dominant fouling mechanism, thereby reducing fouling. PMID- 28834768 TI - Microcystis aeruginosa-laden water treatment using enhanced coagulation by persulfate/Fe(II), ozone and permanganate: Comparison of the simultaneous and successive oxidant dosing strategy. AB - In this study, the application of enhanced coagulation with persulfate/Fe(II), permanganate and ozone for Microcystis-laden water treatment was investigated. Two oxidant dosage strategies were compared in terms of the organic removal performance: a simultaneous dosing strategy (SiDS) and a successive dosing strategy (SuDS). To optimize the oxidant species, oxidant doses and oxidant dosage strategy, the zeta potential, floc size and dimension fraction, potassium release and organic removal efficiency during the coagulation of algae-laden water were systematically investigated and comprehensively discussed. Ozonation causes most severe cell lysis and reduces organic removal efficiency because it releases intracellular organics. Moreover, ozonation can cause the release of odor compounds such as 2-methylisoborneol (2-MIB) and geosmin (GSM). With increasing doses, the performance of pollutant removal by coagulation enhanced by persulfate/Fe(II) or permanganate did not noticeably improve, which suggests that a low dosage of persulfate/Fe(II) and permanganate is the optimal strategy to enhance coagulation of Microcystis-laden water. The SiDS performs better than the SuDS because more Microcystis cell lysis occurs and less DOC is removed when oxidants are added before the coagulants. PMID- 28834769 TI - Sodium-copper hexacyanoferrate-functionalized magnetic nanoclusters for the highly efficient magnetic removal of radioactive caesium from seawater. AB - Sodium-copper hexacyanoferrate (NaCuHCF)-functionalized magnetic nanoadsorbents were fabricated for the highly efficient magnetic removal of radioactive caesium from seawater. The magnetic nanoclusters (MNCs), composed of many individual Fe3O4 nanoparticles, were covalently coated with polyethyleneimine (PEI) to functionalize the MNC surfaces with NaCuHCF. After simple immobilization of Cu and Na ferrocyanide on the NC surface, the resulting NaCuHCF-functionalized MNCs showed good magnetic properties and a significant adsorption capacity for Cs+ with a high content of NaCuHCF (36.04%). The adsorption kinetics and isotherms were well fit to a pseudo-second-order model and Langmuir isotherm, respectively. The sorption of 97.35% Cs by the NaCuHCF-PEI-MNCs completed in less than 5 min, and the maximum adsorption capacity of the adsorbent was 166.67 mg/g. The NaCuHCF PEI-MNCs selectively adsorbed Cs even in the presence of various competing ions, such as Na, K, Mg, and Ca, and the Cs removal mechanism was revealed as ion exchange between Cs in solution and Na in the NaCuHCF-PEI-MNCs. In radioactive tests, our adsorbent displayed excellent removal performance in real seawater with a high removal efficiency exceeding 99.73%, a decontamination factor exceeding 372, and a high stability in water over a wide pH range from 4 to 10 with negligible leaching of Fe. PMID- 28834770 TI - Effect of zinc-lysine on growth, yield and cadmium uptake in wheat (Triticum aestivum L.) and health risk assessment. AB - Cadmium (Cd) is among the most widespread toxic trace elements found in agricultural soils due to various anthropogenic activities. The role of micronutrient-amino chelates on reducing Cd toxicity in crop plants is recently introduced. The current study was conducted to highlight the role of foliar application of zinc-lysine (Zn-lys) complex on biochemical and growth parameters and Cd uptake in wheat (Triticum aestivum) grown in aged Cd-contaminated soil. Foliar concentration of Zn-lys (0, 10, 20, and 30 mg L-1) was applied at different time intervals (2nd, 3rd, 5th and 7th week of sowing) and plants were harvested at maturity. Folliar application of Zinc-lys significantly increased the photosynthesis, grain yield, enzyme activities and Zn contents in different plant tissues. Zinc-lys reduced Cd contents in grains, shoot and root as well as reduced the oxidative stress in wheat linearly in a dose-additive manner. Taken together, Zn-lys chelate efficiently improved wheat growth and fortified Zn contents while reduced Cd concentration in plant in a Zn-deficient Cd contaminated soil. Although, health risk index (HRI) from the soil sampling area seems to be lower than <1 for Cd but may exceed due to long-term consumption of grains produced from such contaminated soil. Foliar applied Zn-lys reduced HRI which may help to reduce health risks associated with Cd. PMID- 28834771 TI - Fe(II)/Cu(II) interaction on goethite stimulated by an iron-reducing bacteria Aeromonas Hydrophila HS01 under anaerobic conditions. AB - Copper is a trace element essential for living creatures, but copper content in soil should be controlled, as it is toxic. The physical-chemical-biological features of Cu in soil have a significant correlation with the Fe(II)/Cu(II) interaction in soil. Of significant interest to the current study is the effect of Fe(II)/Cu(II) interaction conducted on goethite under anaerobic conditions stimulated by HS01 (a dissimilatory iron reduction (DIR) microbial). The following four treatments were designed: HS01 with alpha-FeOOH and Cu(II) (T1), HS01 with alpha-FeOOH (T2), HS01 with Cu(II) (T3), and alpha-FeOOH with Cu(II) (T4). HS01 presents a negligible impact on copper species transformation (T3), whereas the presence of alpha-FeOOH significantly enhanced copper aging contributing to the DIR effect (T1). Moreover, the violent reaction between adsorbed Fe(II) and Cu(II) leads to the decreased concentration of the active Fe(II) species (T1), further inhibiting reactions between Fe(II) and iron (hydr)oxides and decelerating the phase transformation of iron (hydr)oxides (T1). From this study, the effects of the Fe(II)/Cu(II) interaction on goethite under anaerobic conditions by HS01 are presented in three aspects: (1) the accelerating effect of copper aging, (2) the reductive transformation of copper, and (3) the inhibition effect of the phase transformation of iron (hydr)oxides. PMID- 28834772 TI - Primary analysis of the Mandarin-speaking sub-study within the Sydney diabetes prevention program. AB - AIM: There is strong and consistent evidence from large scale randomised controlled trials that type 2 diabetes can be prevented or delayed through lifestyle modification which improves diet quality, increases physical activity and achieves weight loss in people at risk. Worldwide, the prevalence of type 2 diabetes is increasing in individuals of Chinese descent. Culturally tailored programs are required to address the risk in the Chinese population. This paper analyses effectiveness of a culturally tailored community-based lifestyle modification program (Sydney Diabetes Prevention Program (SDPP)) targeting Mandarin speakers. The SDPP was a 12 month translational study aiming to promote increased physical activity and dietary changes. Effectiveness was assessed through the improvement of anthropometric, metabolic, physical activity and dietary outcomes and number of goals met. METHODS: Seventy-eight Mandarin speaking participants at a high risk (Australian Diabetes Risk, AUSDRISK>=15) of developing diabetes were recruited for this study. RESULTS: In this cohort, waist circumference, total cholesterol and fat intake significantly improved at the 12 month review. In comparison to the English-speaking stream, the Mandarin-speaking stream achieved fewer improvements in outcomes and goals. CONCLUSION: The SDPP was not effective in reducing the risk factors associated with developing type 2 diabetes in this cohort of high risk Mandarin-speaking individuals living in Sydney. PMID- 28834773 TI - Genome-wide DNA methylation variation in maternal and cord blood of gestational diabetes population. AB - AIMS: Gestational diabetes mellitus (GDM) has always been a concerning issue for pregnant women. In recent studies, GDM was found to be related to epigenetic modifications, which would alter gene expressions, thus affecting the patients' and their offspring's health, leading to a higher probability of developing metabolic syndromes and diabetes later in life. METHODS: In this study, we collected both maternal and cord blood samples from 16 pregnant women and their newborns, including eight exposed to GDM. GDM was diagnosed via a 75g oral glucose tolerance test (OGTT) at 24-28weeks of pregnancy. DNA methylation was measured at 841,573 CpG sites via the Infinium HumanMethylationEPIC BeadChip. An Ingenuity Pathway Analysis was conducted afterwards to identify genes and pathways epigenetically affected by GDM. RESULTS: We identified the top 200 loci and their corresponding genes in the maternal blood group (n=151) and cord blood group (n=167), both of which were methylated differently in the GDM and unexposed group. Metabolic disease-related pathways and molecules, such as interleukin-6 and interleukin-10 were identified in both groups. These results suggested that GDM has epigenetic effects on both mother and their offspring, which might result in future metabolic syndromes or diabetes. CONCLUSIONS: The high-throughput platform enabled us to analyze methylation sites throughout the genome and identify the most promising genes and pathways associated with GDM. PMID- 28834774 TI - In-depth insight into facet-dependent charge movement behaviors and photo-redox catalysis: A case of {001} and {010} facets BiOCl. AB - A central issue in understanding photo-redox catalysis is the facet-dependent charge movement behaviors that include bulk charge separation, surface charge transfer and interfacial charge migration. To get in-depth insight into these complicated processes steered by different exposing facets, herein BiOCl with exposed (001) and (010) facets engaged as the model are investigated. The BiOCl (010) and BiOCl-(001) single-crystalline sheets are separately synthesized via hydrothermal and hydrolysis routes. In contrast to BiOCl-(010), BiOCl-(001) demonstrates highly promoted photo-redox performance for H2 generation and degradation of pollutants. The facet-dependent charge movement behaviors were surveyed by surface photovoltage spectroscopy (SPV), transient photocurrent, linear sweep voltammetry, continuous wavelength photocurrent, and electrochemical impedance spectrum (EIS). All the photoelectrochemical and photoelectric measurement results reflect that BiOCl-(001) exhibits superior charge separation and migration efficiencies in the whole charge movement process than the BiOCl (010). Besides, a higher charge carrier density (3.1-fold enhancement) was also observed for BiOCl-(001) compared to BiOCl-(010). Our current work is expected to further our understanding on facet-dependent charge movement behaviors and offer new insight into design of high-performance photocatalytic/photoelectrochemical materials. PMID- 28834775 TI - Furosemide removal in constructed wetlands: Comparative efficiency of LECA and Cork granulates as support matrix. AB - The removal efficiency of LECA and cork granulates as support matrix for pharmaceuticals active compounds in a constructed wetland system was investigated using the diuretic drug Furosemide. Kinetics studies were performed testing three different concentrations of Furosemide in an ultrapure water matrix, along seven days. LECA achieved higher removal values compared to cork granulates. However, cork granulates presented a higher removal in the first 24 h of contact time compared to the other adsorbent. The kinetic studies showed that LECA and cork granulates have different adsorption behaviours for Furosemide which is controlled by different adsorption mechanisms. Both materials showed good removal efficiencies and a combination of the two should be further explored in order to applied both materials as support matrix to cope with different furosemide concentrations. PMID- 28834776 TI - Regional analysis of groundwater phosphate concentrations under acidic sandy soils: Edaphic factors and water table strongly mediate the soil P-groundwater P relation. AB - Historic long-term P application to sandy soils in NW-Europe has resulted in abundant sorption, saturation and eventually leaching of P from soil to the groundwater. Although many studies recognize the control of site-specific factors like soil texture and phosphate saturation degree (PSD), the regional-scaled relevance of effects exerted by single factors controlling P leaching is unclear. Very large observational datasets of soil and groundwater P content are furthermore required to reveal indirect controls of soil traits through mediating soil variables. We explored co-variation of phreatic groundwater orthophosphate (o-P) concentration and soil factors in sandy soils in Flanders, Belgium. Correlation analyses were complemented with an exploratory model derived using 'path analysis'. Data of oxalate-extractable Al, Fe, P and pHKCl, phosphate sorption capacity (PSC) and PSD in three depth layers (0-30, 30-60, 60-90 cm), topsoil SOC, % clay and groundwater depth (fluctuation) were interpolated to predict soil properties on exact locations of a very extensive net of groundwater monitoring wells. The mean PSD was only poorly correlated to groundwater o-P concentration, indicating the overriding control of other factors in the transport of P to the groundwater. A significant (P < 0.01) positive non-linear relationship was found between groundwater o-P concentrations and pHKCl for all depth layers. Likewise, lower SOC% (P < 0.01) and shallower groundwater level (MHL or MLL) corresponded (P < 0.01) with higher o-P concentrations. Groundwater o-P unexpectedly correlated positively to clay% and path analysis indicated this to be an indirect effect of the groundwater level. Path analysis furthermore indicated an important indirect control of pH on groundwater o-P concentrations and a considerable direct effect of Pox, 0-90, Alox, 0-90 and MHL. The fact that groundwater o-P concentration was stronger controlled by soil pH and groundwater table depth than by PSD indicates the likely oversimplification of the latter index to measure the long-term potential risk of P leaching. Accounting for controls on leaching not included in PSD via an alternative index, however, seems problematic as in Flanders for example groundwater o-P turned out to be higher in finer textured soils or soils with higher pedogenic Fe content, probably because of their lower pedogenic Al content and higher soil pH. Path analysis of extensive soil and groundwater datasets seems a viable way to identify prime local determinants of soil P leaching and could be further on used for 'ground truthing' more complex P-migration simulation models. PMID- 28834777 TI - Improved sensitivity for W-band Gd(III)-Gd(III) and nitroxide-nitroxide DEER measurements with shaped pulses. AB - Chirp and shaped pulses have been recently shown to be highly advantageous for improving sensitivity in DEER (double electron-electron resonance, also called PELDOR) measurements due to their large excitation bandwidth. The implementation of such pulses for pulse EPR has become feasible due to the availability of arbitrary waveform generators (AWG) with high sampling rates to support pulse shaping for pulses with tens of nanoseconds duration. Here we present a setup for obtaining chirp pulses on our home-built W-band (95GHz) spectrometer and demonstrate its performance on Gd(III)-Gd(III) and nitroxide-nitroxide DEER measurements. We carried out an extensive optimization procedure on two model systems, Gd(III)-PyMTA-spacer-Gd(III)-PyMTA (Gd-PyMTA ruler; zero-field splitting parameter (ZFS) D~1150MHz) as well as nitroxide-spacer-nitroxide (nitroxide ruler) to evaluate the applicability of shaped pulses to Gd(III) complexes and nitroxides, which are two important classes of spin labels used in modern DEER/EPR experiments. We applied our findings to ubiquitin, doubly labeled with Gd-DOTA-monoamide (D~550MHz) asa model for a system with a small ZFS. Our experiments were focused on the questions (i) what are the best conditions for positioning of the detection frequency, (ii) which pump pulse parameters (bandwidth, positioning in the spectrum, length) yield the best signal-to-noise ratio (SNR) improvements when compared to classical DEER, and (iii) how do the sample's spectral parameters influence the experiment. For the nitroxide ruler, we report an improvement of up to 1.9 in total SNR, while for the Gd-PyMTA ruler the improvement was 3.1-3.4 and for Gd-DOTA-monoamide labeled ubiquitin it was a factor of 1.8. Whereas for the Gd-PyMTA ruler the two setups pump on maximum and observe on maximum gave about the same improvement, for Gd-DOTA-monoamide a significant difference was found. In general the choice of the best set of parameters depends on the D parameter of the Gd(III) complex. PMID- 28834778 TI - Outcomes of radioembolization for unresectable hepatocellular carcinoma in patients with marginal functional hepatic reserve. AB - PURPOSE: To evaluate the outcomes of radioembolization (RE) as a therapy for unresectable hepatocellular carcinoma (HCC) in patients with marginal functional hepatic reserve. METHODS: A retrospective review of 471 patients (1/2010-7/2015) treated with RE (Therasphere, BTG, UK) was performed. A total of 36 patients (mean age: 66.1+/-9.3, male: 86.1%) underwent therapy for HCC with a MELD>=15 (median: 16, range: 15-22). Baseline demographics of the study cohort were as follows: etiology (HCV: 26, 72.2%), cirrhosis (n=32, 88.9%), ECOG 0 (n=16, 44.4%), Child-Pugh class (A=15, B=19, C=2), unilobar distribution (n=27, 75%), AFP>200 (n=11, 30.6%), portal vein thrombosis (PVT, n=7, 19.4%), metastasis (n=3, 8.3%). Outcomes analyzed included CTCAEv4.03 laboratory toxicities (120-day), imaging response (mRECIST), progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 42 treatments were performed with mean dose of 2.02+/ 1.23GBq. The cumulative grade 3/4 toxicity was 28% overall and 21% for bilirubin at 120-days. The objective response and disease control rates were 48.3% (14/29) and 69% (20/29) respectively. The median (95% CI) PFS was 5.9 (4.4-7.7) months. Ten (27.8%) patients received additional locoregional therapy at a median (IQR) of 138 (102-243) days post RE. The mean (95% CI) OS was 21.9 (14.8-29.0) months. The absence of PVT was associated with improved OS (p=0.005) Disease control at 90-days was also associated with an OS benefit (p=0.037). CONCLUSIONS: Patients with unresectable HCC and marginal functional hepatic reserve treated with RE had favorable objective response and disease control rates, both predictive of overall survival. PMID- 28834779 TI - Revisiting the prognostic value of monocyte chemotactic protein 1 and interleukin 6 in the sepsis-3 era. AB - BACKGROUND: Monocyte Chemotactic Protein 1 (MCP1) and latest sepsis-3 criteria are poorly represented within studies evaluating biomarkers in sepsis. Therefore, this study evaluates the prognostic value of MCP-1 compared to interleukin-6 (IL 6) in patients with sepsis and septic shock according to sepsis-3 criteria. METHODS: 136 patients with sepsis or septic shock were included within 24h of intensive care unit (ICU) admission. MCP-1, IL-6, procalcitonin (PCT), C-reactive protein (CRP) and white blood cells (WBC) were measured on days 1, 3 and 8. All cause mortality was followed up at 30days and 6months. RESULTS: Both MCP-1 and IL 6 levels revealed valuable prognostic discrimination of 30-day and 6-months all cause mortality on day 1 and 3 (MCP-1: range of AUCs 0.62-0.65, p<0.039; IL-6: range of AUCs 0.65-0.70, p<0.021) compared to PCT, CRP, SOFA and APACHE II score. MCP-1 levels within the 4th quartile revealed the highest mortality at 30days and 6months compared to patients with lower levels (range of hazard ratio (HR)=2.1 3.3, p<0.041). The prognostic value of MCP-1 sustained in multivariate regression models and was comparable to that of IL-6. CONCLUSION: Both MCP-1 and IL-6 revealed prognostic value for short- and mid-term all-cause mortality in patients with sepsis and septic shock according to latest sepsis-3 definitions. PMID- 28834780 TI - Predictors of mortality in adults with sickle cell patients admitted to intensive care unit in SMC: Methodological issues. PMID- 28834781 TI - Clinical management of elderly patients with epilepsy; the use of lacosamide in a single center setting. AB - INTRODUCTION: Lacosamide (LCM) is a third-generation antiepileptic drug (AED) for which there is limited experience in the treatment of elderly patients with epilepsy. This study was performed to evaluate the use of LCM in this particular patient group, focusing on its tolerability and effectiveness. This is a retrospective, single-center study, in patients over 60years old treated with LCM between 1/2010 and 5/2015. Altogether, 233 elderly patients receiving LCM were identified; of these, 67 fulfilled the inclusion criteria, i.e., LCM administered for at least 2weeks. RESULTS: Lacosamide was initiated for acute seizure disorders (prolonged complex partial seizures, recurrent seizures, or status epilepticus) in 54 patients (81%) and for chronic epilepsy in 13 patients in an outpatient setting. The mean follow-up period for LCM treatment was 14months. The mean daily dose of LCM at the end of follow-up was 368mg (range: 100-600) for those 57 patients that continued treatment. Ten patients (15%) stopped LCM treatment but none because of lack of efficacy and only three patients (4%) because of side effects. The most frequent side effects were dizziness, fatigue, and tremor. CONCLUSIONS: Lacosamide was well tolerated even at relatively high doses and in combination therapy. PMID- 28834782 TI - Improved strategies for DNP-enhanced 2D 1H-X heteronuclear correlation spectroscopy of surfaces. AB - We demonstrate that dynamic nuclear polarization (DNP)-enhanced 1H-X heteronuclear correlation (HETCOR) measurements of hydrogen-rich surface species are better accomplished by using proton-free solvents. This approach notably prevents HETCOR spectra from being obfuscated by the solvent-derived signals otherwise present in DNP measurements. Additionally, in the hydrogen-rich materials studied here, which included functionalized mesoporous silica nanoparticles and metal organic frameworks, the use of proton-free solvents afforded higher sensitivity gains than the commonly used solvents containing protons. We also explored the possibility of using a solvent-free sample formulation and the feasibility of indirect detection in DNP-enhanced HETCOR experiments. PMID- 28834783 TI - Addition of acetate improves stability of power generation using microbial fuel cells treating domestic wastewater. AB - Power generation using microbial fuel cells (MFCs) must provide stable, continuous conversion of organic matter in wastewaters into electricity. However, when relatively small diameter (0.8cm) graphite fiber brush anodes were placed close to the cathodes in MFCs, power generation was unstable during treatment of low strength domestic wastewater. One reactor produced 149mW/m2 before power generation failed, while the other reactor produced 257mW/m2, with both reactors exhibiting severe power overshoot in polarization tests. Using separators or activated carbon cathodes did not result in stable operation as the reactors continued to exhibit power overshoot based on polarization tests. However, adding acetate (1g/L) to the wastewater produced stable performance during fed batch and continuous flow operation, and there was no power overshoot in polarization tests. These results highlight the importance of wastewater strength and brush anode size for producing stable and continuous power in compact MFCs. PMID- 28834784 TI - Determination of fat content in chicken hamburgers using NIR spectroscopy and the Successive Projections Algorithm for interval selection in PLS regression (iSPA PLS). AB - Determining fat content in hamburgers is very important to minimize or control the negative effects of fat on human health, effects such as cardiovascular diseases and obesity, which are caused by the high consumption of saturated fatty acids and cholesterol. This study proposed an alternative analytical method based on Near Infrared Spectroscopy (NIR) and Successive Projections Algorithm for interval selection in Partial Least Squares regression (iSPA-PLS) for fat content determination in commercial chicken hamburgers. For this, 70 hamburger samples with a fat content ranging from 14.27 to 32.12mgkg-1 were prepared based on the upper limit recommended by the Argentinean Food Codex, which is 20% (ww-1). NIR spectra were then recorded and then preprocessed by applying different approaches: base line correction, SNV, MSC, and Savitzky-Golay smoothing. For comparison, full-spectrum PLS and the Interval PLS are also used. The best performance for the prediction set was obtained for the first derivative Savitzky Golay smoothing with a second-order polynomial and window size of 19 points, achieving a coefficient of correlation of 0.94, RMSEP of 1.59mgkg-1, REP of 7.69% and RPD of 3.02. The proposed methodology represents an excellent alternative to the conventional Soxhlet extraction method, since waste generation is avoided, yet without the use of either chemical reagents or solvents, which follows the primary principles of Green Chemistry. The new method was successfully applied to chicken hamburger analysis, and the results agreed with those with reference values at a 95% confidence level, making it very attractive for routine analysis. PMID- 28834785 TI - What is the optimal treatment for symptomatic patients with isolated coronary myocardial bridge? A systematic review and pooled analysis. AB - BACKGROUND: Myocardial bridging is a common coronary anomaly, with few severe adverse events but a relevant symptom burden. Myocardial bridging treatment, however, remains uncertain because of the lack of randomized trials. MATERIAL: MEDLINE/PubMed was systematically screened for studies reporting on isolated myocardial bridging diagnosed at coronary angiography or with coronary computed tomography in patients admitted for suspected angina or with an acute coronary syndrome. Baseline, treatment and outcome data were appraised and pooled according to treatment (medical therapy, bypass surgery/myotomy or stenting). RESULTS: A total of 899 patients in 18 studies were included with a low prevalence of traditional risk factors, especially diabetes (15.6%, interquartile range 2.5-21.5). After a median of 31.0 months (interquartile range 12.4-37.1), major cardiovascular events (composite of death, myocardial infarction or target vessel revascularization) occurred in only 3.4% of the study patients and 78.7% [70.5-86.9; 95% confidence intervals (CI)] were managed conservatively and free of symptoms. When an invasive strategy was planned, freedom from angina was higher in patients treated with surgery [84.5% (78.4-90.7; 95% CI)] than in those treated with stenting [54.7% (38.9-70.6; 95% CI)]. Patients in the stenting group experienced a high incidence of major cardiovascular events related to target vessel revascularization [40.07% (19.83-60.32; 95% CI)]. Meta-regression showed that patients treated with beta-blockers or with a history of hypertension were more likely to remain free from angina (B -0.6, P = 0.013; B -0.66, P = 0.006). CONCLUSION: Patients with symptomatic isolated myocardial bridging generally have a good long-term prognosis. Pharmacological treatment alone, especially with beta blockers, is able to improve angina in most cases. Surgical treatment appears to be more effective than stenting in nonresponders. PMID- 28834786 TI - Intravascular imaging of coronary artery disease: recent progress and future directions. AB - : Although coronary angiography represents a well established diagnostic modality for percutaneous coronary intervention guidance, recent intravascular imaging techniques, such as intravascular ultrasound, optical coherence tomography (OCT) and near-infrared spectroscopy offer advantages on top of angiography, enhancing the efficacy of lesion evaluation and potentially optimizing the acute and long term percutaneous coronary intervention outcomes.In addition, recently new generation imaging options have emerged, such as high-definition intravascular ultrasound, polarization-sensitive OCT, intravascular photoacoustic imaging and ultrafast heartbeat OCT. In this review, the current data on the available intravascular imaging techniques, their clinical utility as well as recent technical progresses will be summarized. PMID- 28834787 TI - Transition of care to an adult provider. AB - PURPOSE OF REVIEW: The transition from adolescence to young adulthood can be a difficult and overwhelming time. Many adult care providers are unaware of the issues facing adolescents and young adults. Often the focus is on older patients and their problems. Internists, family practitioners and obstetricians and Gynecologists (OBGYNs) typically care for these patients. Often, young adults view their obstetrician and gynecologist as their primary care physician, so reviewing the issues facing this age group is important. RECENT FINDINGS: Lifestyle habits begun in childhood frequently continue throughout life. Adolescence and young adulthood are times when change in these habits may be easier to enforce. Reviewing nutrition, exercise, risky behaviors, preventive health objectives, sexuality and mental health are of utmost importance in the transition of care from a pediatric to an adult provider. SUMMARY: The transition from adolescence to young adulthood can be difficult for patients. Knowledge of these issues is crucial to the adult provider caring for these patients. Although visits frequently are short in duration, using screening tools and checklists filled out by the patient prior to the visit may be beneficial. PMID- 28834788 TI - Associations Between Family Member BMI and Obesity Status of Children with Autism Spectrum Disorder. AB - OBJECTIVE: To determine whether there is an association between parent and sibling obesity status and obesity status in children with autism spectrum disorder (ASD). METHODS: We examined predictors of obesity in children with ASD with body mass index data for the proband, 1 sibling, and 2 parents using data from the multisite Simons Simplex Collection. RESULTS: In a stepwise logistic regression model, proband obesity status was associated with obesity status of the sibling (odds ratio [OR] 2.66; 95% confidence interval [CI], 1.92-3.70), mother (OR 2.10; 95% CI, 1.59-2.77), and father (OR 1.51; 95% CI, 1.15-1.98). Proband obesity was also related to somatic complaints (OR 1.60; 95% CI, 1.006 2.53), mood stabilizers (OR 1.80; 95% CI, 1.19-2.72), internalizing problems (OR 1.60; 95% CI, 1.14-2.30), age (OR 1.01; 95% CI, 1.00-1.01), and some adaptive functioning domains (OR 0.987; 95% CI, 0.977-0.997). Race, ethnicity, income, sex, and maternal education were not significant predictors. CONCLUSION: Familial factors were generally the strongest predictors of obesity rather than medication use, demographics, or psychological characteristics. Results support a family centered approach to treatment of obesity in children with ASD. PMID- 28834789 TI - Sexual functioning in patients with chronic hepatitis C: a systematic review. AB - Chronic hepatitis C virus (HCV) infection is a systematic disease that affects several aspects of patients' well-being, including physical, mental, social, and sexual quality of life. In recent years, there has been a growing body of literature focusing on HCV patients' sexual health, providing evidence of clinically significant and enduring disturbances that disrupt everyday living, but commonly evade clinicians' attention. Relevant studies are characterized by considerable methodological heterogeneity and their findings should be interpreted using a systematic and integrative approach. In this context, we performed a systematic literature review on the topic of HCV patients' sexual functioning aiming at identifying high-quality investigations reporting scientifically sound and clinically useful data. We performed a thorough search of PudMed, ScienceDirect, and GoogleScholar according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. Twenty-five articles were included to the review, reporting data from over 5300 chronic HCV patients. Sexual dysfunction, predominantly in the domains of sexual desire, drive, and satisfaction, is commonly reported by HCV patients at rates ranging between 19 and 88%. The current review yielded three distinct patterns of sexual impairment, namely, precirrhotic sexual impairment, cirrhosis induced sexual decline, and interferon-associated sexual difficulties. Our search yielded significant findings on the prevalence, the characteristics, and the determinants of HCV-associated sexual dysfunction. In addition, we detected several areas of scientific controversy and inadequate information, thus highlighting novel directions for future research. PMID- 28834790 TI - Comparison of treatment efficacy 1 and 2 years after thyroid remnant ablation with 1110 versus 5550 MBq of iodine-131 in patients with intermediate-risk differentiated thyroid cancer. AB - BACKGROUND: Radioiodine ablation may be associated with improved survival in patients with intermediate-risk follicular cell differentiated thyroid cancer (FCDTC). The aim of this study was to compare ablation efficacy of 1110 versus 5500 MBq of iodine-131 (I) in FCDTC patients with intermediate risk. METHODS: Thirty-nine patients with intermediate-risk FCDTC (T3N0, T1-2N1b and T1-3N1a) were treated with 1110 MBq of I and compared with 43 age-matched and sex-matched patients who received 5550 MBq of I. Patients with invasive histology, extensive lymph node involvement, and preablation thyroglobulin (Tg) of more than 100 ng/ml were excluded from the study. All patients underwent total or near total thyroidectomy with or without lymph node dissection. Response to treatment was evaluated 1 and 2 years after I treatment. RESULTS: We studied four male and 78 female patients, age range 21-69 years. Preablation Tg level was 12.7+/-17.8 and 15.8+/-22.6 ng/ml in patients in the low-dose and high-dose groups, respectively (P=0.48). Anti-Tg antibody level as well as T and N staging were not significantly different in the two groups (P>0.2). One and 2 years after treatment, an excellent response was noted in 19 and 22 patients in the low-dose group and in 16 and 23 patients in the high-dose group, respectively (P>0.3). Using logistic regression analysis, preablation Tg was the only significant factor in the prediction of an incomplete response 2 years after therapy. CONCLUSION: 1110 MBq of I was as effective as 5550 MBq of I in the treatment of FCDTC patients with intermediate risk 1 and 2 years after therapy. PMID- 28834793 TI - Surgical ventricular remodeling: should we STICH or not? AB - PURPOSE OF REVIEW: The surgical management of patients with ischemic cardiomyopathy, especially those with left ventricular ejection fractions less than 20% has historically been controversial. The original trials of surgical revascularization versus medical therapy intentionally excluded those patients with an ejection fraction less than 35%. The significant advances in medical therapy for heart failure over the past 30 years (beta-blockade, angiotensin converting enzyme inhibitors, internal cardiac defibrillator and so on) also mandated a reevaluation of the potential benefits of surgical revascularization in this high-risk subset. The purpose of this review is to examine the data from the Surgical Treatment for Ischemic Heart Failure (STICH) trial, initially reported in 2009 and 2011. RECENT FINDINGS: Recent reports published in 2016 have now clearly defined the role of surgery over medical therapy for these patients. Furthermore, although the benefits of surgical ventricular reconstruction were once questioned by the results of STICH, further analyses identify that an appropriately selected patient who undergoes a technically adequate operation will derive benefit from surgical ventricular reconstruction. SUMMARY: The conclusions from the various substudies examining STICH trial data now indicate that in surgical candidates with graftable coronary artery disease, surgical revascularization provides a reduction in overall mortality, cardiovascular deaths and hospitalizations, independent of symptoms, baseline left ventricular size or function and surprisingly, regardless of any viability or evidence of inducible ischemia. PMID- 28834792 TI - Antiplatelet treatment in diabetic patients with acute coronary syndrome undergoing percutaneous coronary intervention: a GReek AntiPlatElet registry substudy. AB - BACKGROUND AND AIMS: We compared the clinical outcome of diabetic versus nondiabetic patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in the GReek AntiPlatElet (GRAPE) registry. PATIENTS AND METHODS: GRAPE is a prospective observational study, focusing on contemporary antiplatelet use in moderate-risk to high-risk ACS patients receiving PCI. Major adverse cardiovascular events (MACE), (composite of death, nonfatal myocardial infarction, urgent revascularization, and stroke) and bleeding events (Bleeding Academic Research Consortium definition) at 1 year of follow-up were analyzed using propensity score adjustment. A subanalysis according to diabetes mellitus (DM) status was performed. RESULTS: Out of 2047 registered patients, 469 (22.9%) were diabetic. Complete 1-year follow-up was available in 95.1% of patients. MACE occurred in 12.2 and 7.2% of those patients with and without DM, respectively [adjusted hazard ratio (HR), 95% confidence interval (CI)=1.27 (0.89-1.79), P=0.2]. Observed BARC type >=3 bleeding risk was not higher in diabetic patients: adjusted HR (95% CI)=1.20 (0.79-1.84). In the subgroup of clopidogrel-treated patients (N=238), MACE rate was significantly higher in diabetic compared with nondiabetic cohort [13.4 vs. 9%, adjusted HR (95% CI)=1.68 (1.07-2.64), P=0.03]. In the subgroup of ticagrelor-treated or prasugrel-treated patients (N=228), MACE rate did not differ significantly between diabetic and nondiabetic patients: 9.6 versus 5%, adjusted HR (95% CI)=1.35 (0.77-2.37), P=0.38. CONCLUSION: In 'real life' ACS undergoing PCI, diabetic patients have higher - although not significantly - MACE rate and no difference in bleeding events. This difference in MACE was significant among clopidogrel-treated patients, whereas when newer antiplatelet agents were used the negative impact of DM on ischemic events was eliminated. PMID- 28834791 TI - Multifractality, Interactivity, and the Adaptive Capacity of the Human Movement System: A Perspective for Advancing the Conceptual Basis of Neurologic Physical Therapy. AB - BACKGROUND AND PURPOSE: Physical therapists seek to optimize movement as a means of reducing disability and improving health. The short-term effects of interventions designed to optimize movement ultimately are intended to be adapted for use across various future patterns of behavior, in potentially unpredictable ways, with varying frequency, and in the context of multiple tasks and environmental conditions. In this perspective article, we review and discuss the implications of recent evidence that optimal movement variability, which previously had been associated with adaptable motor behavior, contains a specific complex nonlinear feature known as "multifractality." SUMMARY OF KEY POINTS: Multifractal movement fluctuation patterns reflect robust physiologic interactivity occurring within the movement system across multiple time scales. Such patterns provide conceptual support for the idea that patterns of motor behavior occurring in the moment are inextricably linked in complex, physiologic ways to patterns of motor behavior occurring over much longer periods. The human movement system appears to be particularly tuned to multifractal fluctuation patterns and exhibits the ability to reorganize its output in response to external stimulation embedded with multifractal features. RECOMMENDATIONS FOR CLINICAL PRACTICE: As a fundamental feature of human movement, multifractality opens new avenues for conceptualizing the link between physiologic interactivity and adaptive capacity. Preliminary evidence supporting the positive influence of multifractal rhythmic auditory stimulation on the gait patterns of individuals with Parkinson disease is used to illustrate how physical therapy interventions might be devised to specifically target the adaptive capacity of the human movement system.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A183). PMID- 28834794 TI - Quality of life after coronary artery bypass graft surgery versus percutaneous coronary intervention: what do the trials tell us? AB - PURPOSE OF REVIEW: With an ever-aging population, the treatment of multi-vessel coronary artery disease (CAD) has increasingly become focused not only on mortality, but on symptom relief and improving quality of life (QOL). The purpose of this review is to present a summary on the subject of QOL after percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG), highlighting the latest comparative trials in the field. RECENT FINDINGS: About 1 month after revascularization, patients recovering from either PCI or CABG report improvements in angina frequency. However, at 6 months and in the years that follow, angina relief is significantly better after CABG compared with PCI. Correspondingly, the use of antiangina medication is significantly higher following PCI, even in recent years with the use of drug-eluting stents. Regarding general health status, at the 1-month time point, PCI patients have recovered faster than those who have had surgery, reporting fewer physical limitations, less bodily pain, and greater QOL and treatment satisfaction. Nevertheless, these differences disappear by 6 months, and in the years thereafter, CABG patients report fewer physical limitations compared with those who have undergone PCI. About 5 years after revascularization, significant benefits remain favoring CABG in term of physical, emotional, and mental health. SUMMARY: Patients with multivessel coronary artery disease attain important QOL benefits following revascularization with either PCI or CABG. Percutaneous treatments lead to a more rapid recovery and improved short-term health status compared with CABG at 1 month. However, surgery results in greater angina relief and improved QOL compared with PCI 6 months after revascularization and beyond. PMID- 28834795 TI - Microvascular reactivity monitored with near-infrared spectroscopy is impaired after induction of anaesthesia in cardiac surgery patients: An observational study. AB - BACKGROUND: Induction of anaesthesia causes significant macrohaemodynamic changes, but little is known about its effects on the microcirculation. However, alterations in microvascular perfusion are known to be associated with impaired tissue oxygenation and organ dysfunction. Microvascular reactivity can be assessed with vascular occlusion testing, which evaluates the response of tissue oxygen saturation to transient ischaemia and reperfusion. OBJECTIVE: The aim of the current study was to evaluate the effects of an opioid-based anaesthesia induction on microvascular reactivity. We hypothesised that despite minimal blood pressure changes, microvascular function would be impaired. DESIGN: Prospective, observational study. SETTING: Single-centre, tertiary university teaching hospital, Belgium. PATIENTS: Thirty-five adult patients scheduled for elective coronary artery bypass grafting surgery. INTERVENTION: Microvascular reactivity was assessed before and 30 min after anaesthesia induction by means of vascular occlusion testing and near-infrared spectroscopy. MAIN OUTCOME MEASURES: Tissue oxygen saturations, desaturation rate, recovery time (time from release of cuff to the maximum value) and rate of recovery were determined. RESULTS: Data are expressed as median (minimum to maximum). Tissue oxygen saturation was higher after induction of anaesthesia [70 (54 to 78) vs. 73 (55 to 94)%, P = 0.015]. Oxygen consumption decreased after induction, appreciable by the higher minimum tissue oxygen saturation [45 (29 to 69) vs. 53 (28 to 81)%, P < 0.001] and the slower desaturation rate [11 (4 to 18) vs. 9 (5 to 16)% min, P < 0.001]. After induction of anaesthesia, recovery times were longer [40 (20 to 120) vs. 48 (24 to 356) s, P = 0.004] and the rate of recovery was lower [114 (12 to 497) vs. 80 (3 to 271)% min, P < 0.001]. CONCLUSION: After induction of anaesthesia, oxygen consumption was decreased. The longer recovery times and slower rates of recovery indicate impaired microvascular reactivity after induction of anaesthesia. TRIAL REGISTRATION: The research project was registered at ClinicalTrials.gov (NCT02034682). PMID- 28834796 TI - Does a one year age gap modify the influence of age, maturation and anthropometric parameters as determinants of performance among youth elite soccer players? AB - Since age-groups in soccer often comprise children born within a two-year timeframe, characteristics that define the profile of a successful player may not be appropriate for the oldest or youngest players of the same age group. Therefore, this study aimed to determine to what extent performance was influenced by age, maturation and body size in elite soccer players with barely one year age gap. Anthropometry, 15-m sprint test, modified Barrow's agility test, Yo-Yo intermittent recovery test level 1, countermovement jump, and handgrip test were conducted in players aged twelve and under (n=82, 11.1 +/- 0.6 years; Mean +/- SD) and between twelve and thirteen (n=79, 12.8 +/- 0.6 years; Mean +/- SD). A total score of performance, chronological age and age at peak height velocity were calculated. Descriptive statistics, Student's t-tests, and multiple linear regressions were performed. The explained variance in composite score was greater in the older (54%) than in the younger (30%) players. Sum of skinfolds was the primary predictor of 15-m sprint and countermovement jump in the younger group whereas in the older group chronological age and body size appeared as predictors of performance (41%). Body size explained the variance in most tests in older players. In the younger group biological maturity status explained the variance in endurance (35%) and handgrip (59%) tests. In summary, chronological age and sum of skinfolds influenced most tests; however, predictors differed between age groups. These findings highlight the importance of assessing individual differences in young male soccer players regardless of their similarity in age. PMID- 28834797 TI - Strength and Hypertrophy Adaptations Between Low- vs. High-Load Resistance Training: A Systematic Review and Meta-analysis. AB - Schoenfeld, BJ, Grgic, J, Ogborn, D, and Krieger, JW. Strength and hypertrophy adaptations between low- vs. high-load resistance training: a systematic review and meta-analysis. J Strength Cond Res 31(12): 3508-3523, 2017-The purpose of this article was to conduct a systematic review of the current body of literature and a meta-analysis to compare changes in strength and hypertrophy between low- vs. high-load resistance training protocols. Searches of PubMed/MEDLINE, Cochrane Library, and Scopus were conducted for studies that met the following criteria: (a) an experimental trial involving both low-load training [<=60% 1 repetition maximum (1RM)] and high-load training (>60% 1RM); (b) with all sets in the training protocols being performed to momentary muscular failure; (c) at least one method of estimating changes in muscle mass or dynamic, isometric, or isokinetic strength was used; (d) the training protocol lasted for a minimum of 6 weeks; (e) the study involved participants with no known medical conditions or injuries impairing training capacity. A total of 21 studies were ultimately included for analysis. Gains in 1RM strength were significantly greater in favor of high- vs. low-load training, whereas no significant differences were found for isometric strength between conditions. Changes in measures of muscle hypertrophy were similar between conditions. The findings indicate that maximal strength benefits are obtained from the use of heavy loads while muscle hypertrophy can be equally achieved across a spectrum of loading ranges. PMID- 28834798 TI - Estimated Coverage to Address Financial Barriers to HIV Preexposure Prophylaxis Among Persons With Indications for Its Use, United States, 2015. AB - BACKGROUND: An estimated 1.2 million American adults engage in sexual and drug use behaviors that place them at significant risk of acquiring HIV infection. Engagement in health care for the provision of daily oral antiretroviral medication as preexposure prophylaxis (PrEP), when clinically indicated, could substantially reduce the number of new HIV infections in these persons. However, resources to cover the financial cost of PrEP care are anticipated barriers for many of the populations with high numbers of new HIV infections. METHODS: Using nationally representative data, we estimated the current national met and unmet need for financial assistance with covering the cost of PrEP medication, clinical visits, and laboratory tests among adults with indications for its use, overall and by transmission risk population. RESULTS: This study found that of the 1.2 million adults estimated to have indications for PrEP use, <1% (~7300) are in need of financial assistance for both PrEP medication and clinical care, at an estimated annual cost of $89 million. An additional 7% (~86,300) are in need of financial assistance only for PrEP clinical care at an estimated annual cost of $119 million. CONCLUSIONS: This information on PrEP care costs, insurance coverage, and unmet financial need among persons in key HIV transmission risk subpopulations can inform policy makers at all levels as they consider how to address remaining financial barriers to the use of PrEP and accommodate any changes in eligibility for various insurance and financial assistance programs that may occur in coming years. PMID- 28834800 TI - Developing a Mobile App for Neuroscience Nurses. AB - In this month's Magnet(r) Perspectives column, the recipient of the 2016 Magnet Nurse of the Year(r) Award for New Knowledge, Innovations, and Improvements shares her journey to develop and disseminate a mobile application for nurses who care for neurological patients. "Neuroscience nurse" puts the latest, evidence based information at the fingertips of nurses at the bedside in an effort to increase confidence when caring for patients with stroke, traumatic brain injury, and other neurological impairments.Nurse practitioner Christi DeLemos explains where she got the idea and how she went about implementing it. She also discusses the ways in which the Magnet(r) environment at University of California (UC) Davis Medical Center encouraged and supported her. Since neurological nurse was released in 2015, more than 3000 users in 19 countries have downloaded it. The app's success led to the production of a teaching video to help nurses perform a neurological examination. In addition to her role at UC Davis Medical Center, DeLemos is president of the World Federation of Neuroscience Nurses. PMID- 28834799 TI - Brief Report: Stigma and HIV Care Continuum Outcomes Among Ethiopian Adults Initiating ART. AB - BACKGROUND: Stigma harms the mental health of HIV-positive individuals and reduces adherence to antiretroviral therapy (ART), but less is known about stigma and other outcomes across the HIV care continuum. METHODS: Among 1180 Ethiopian adults initiating ART at 6 urban HIV clinics, we examined the relationship of internalized, anticipated, and enacted stigma to HIV care-related outcomes ascertained by interview (repeat HIV-positive testing, provider vs. self-referred testing, missed clinic visit before ART initiation, eagerness to begin ART), and by abstraction of routinely collected clinical data (late ART initiation, 3-month gap in care following ART initiation). Logistic regression was used to assess the association of each type of stigma with each outcome, adjusting for potential confounders. RESULTS: Scoring higher on each stigma domain was associated with 50%-90% higher odds of repeat HIV-positive testing. High internalized stigma was associated with higher odds of provider vs. self-referred test [adjusted odds ratio (aOR)high vs. low: 1.7; 95% confidence interval (CI): 1.3 to 2.2]. Higher anticipated stigma was associated with lower eagerness to begin ART (aORhigh vs. low: 0.55; 0.35-0.87; aORmedium vs. low: 0.45; 95% CI: 0.30 to 0.69). Any enacted stigma was associated with higher odds of a missed visit (aORany vs. none 1.8; 1.2-2.8). Stigma was not associated with late ART-initiation or with a subsequent gap in care. DISCUSSION AND CONCLUSIONS: These findings provide further evidence of the importance of measuring and addressing stigma across the entire care continuum. Future work should test hypotheses about specific stigma domains and outcomes in prospective intervention or observational studies. PMID- 28834801 TI - The DAISY Award: A Patient-Family Perspective of Compassionate and Extraordinary Care. AB - What does it mean to patients and families to recognize the extraordinary and compassionate care provided by amazing nurses? The triple aim framework of the Institute for Healthcare Improvement includes the patient/family experience as 1 of the 3 targets contributing to better healthcare outcomes. In this column, the perspective of recognizing "their" nurse with The DAISY Award will be shared by a patient's family. PMID- 28834802 TI - Guiding Principles for Creating Value and Meaning for the Next Generation of Nurse Leaders. AB - The wave of retirements is beginning to hit nursing, taking a toll on our cadre of nursing leaders. Ongoing healthcare reform is adding to the stress burden and exerting an effect on nurse leader turnover. The next generation of leaders will likely come from our millennial nurses, who have different attitudes toward work than previous generations. The AONE assembled a panel of experts to create guidelines to assist nurse executives in recruiting the next generation of talent into formal leadership roles. PMID- 28834803 TI - Embedding a Professional Practice Model Across a System. AB - Professional practice models (PPMs) are an integral part of any organization on the Magnet(r) journey, whether initial designation or redesignation. Through the journey, the PPM should become embedded within the nursing culture. Leadership at multiple levels is crucial to ensure successful adoption and implementation. PMID- 28834804 TI - Stages of Adoption Concern and Technology Acceptance in a Critical Care Nursing Unit. AB - OBJECTIVE: The aim of this study is to examine the stages of concern (self, task, and impact) and usability (trust, perceived usefulness, and ease of use) shifts experienced by nurses adopting new technology. BACKGROUND: Patient care processes in critical care units can be disrupted with the incorporation of information technology. New users of technology typically transition through stages of concern and experience shifts in acceptance during assimilation. METHODS: Critical care nurses (N = 41) were surveyed twice: (1) pre, immediately after training, and (2) post, 3 months after implementation of technology. RESULTS: From presurvey to postsurvey, self-concerns decreased 14%, whereas impact concerns increased 22%. Furthermore, there was a 30% increase in trust and a 17% increase in perceived usefulness, even with a 27% decrease in ease of use. CONCLUSION: Adoption of new technology requires critical care nurses to adapt current practices, which may improve trust and perceived usefulness yet decrease perceptions of ease of use. PMID- 28834805 TI - Using Gamification to Improve Productivity and Increase Knowledge Retention During Orientation. AB - BACKGROUND: Nursing administrators must provide cost-effective and efficient ways of orientation training. Traditional methods including classroom lecture can be costly with low retention of the information. Gamification engages the user, provides a level of enjoyment, and uses critical thinking skills. PURPOSE: The aim of this study is to explore the effectiveness, during orientation, of 3 different teaching methods: didactic, online modules, and gamification. Specifically, is there a difference in nurses' clinical knowledge postorientation using these learning approaches? METHODS: A quasi-experimental study design with a 115-person convenience sample split nurses into 3 groups for evaluation of clinical knowledge before and after orientation. RESULTS: The gamification orientation group had the highest mean scores postorientation compared with the didactic and online module groups. CONCLUSIONS: Findings demonstrate gamification as an effective way to teach when compared with more traditional methods. Staff enjoy this type of learning and retained more knowledge when using gaming elements. PMID- 28834806 TI - Building a Culture of Authentic Partnership: One Academic Health Center Model for Nursing Leadership. AB - Senior nursing leaders from the University of Kentucky (UK) College of Nursing and UK HealthCare have explored the meaning of an authentic partnership. This article quantifies the tangible benefits and outcomes from this maturing academic nursing and clinical practice partnership. Benefits include inaugural academic nursing participation in health system governance, expanded integration of nursing research programs both in the college and in the health science center, and the development of collaborative strategies to address nursing workforce needs. PMID- 28834807 TI - Scope of Practice Barriers for Advanced Practice Registered Nurses: A State Task Force to Minimize Barriers. AB - Collegial relationships, administrative champions, and persistence are key components to breaking down barriers to advanced practice RN (APRN) practice. This article addresses how Iowa APRNs in a state-sanctioned task force identified barriers for practicing at the top of their licensure in a full practice authority state including defending the right to control the scope of nursing practice in court. PMID- 28834808 TI - Histologic Grade 1 Is Associated With Increased Nonrelapsed Mortality in Lower Gastrointestinal Graft Versus Host Disease. AB - Histologic confirmation is considered a standard practice to diagnose gastrointestinal graft versus host disease (GI GVHD) and is often used in making treatment decisions. A histologic grade is often determined in cases that are diagnosed with GI GVHD. Although extensive crypt loss (histologic grade 4) is associated with high nonrelapse mortality (NRM), the prognostic value for the more common grade 1 is poorly understood. As clinical decisions are made on the degree of histologic evidence, it is important to establish its prognostic significance. Therefore, we evaluated 309 patients who underwent endoscopic biopsy for suspected GI GVHD within 6 months posttransplant between 2009 and 2012. The presence of histologic grade 1 was associated with increased NRM (hazard ratio=2.7, P=0.02) when compared with one of negative biopsy in patients with lower but not isolated upper GI GVHD. Multivariate competing-risk regression analysis confirmed the independent impact of histologic grade 1 in patients with early clinical stages of lower GI GVHD (stage 0 to 2) (hazard ratio=2.7, P=0.044). When compared with advanced histologic grades, histologic grade 1 did not lessen the adverse outcome for patients with advanced lower GI GVHD (stage 3 to 4) (cumulative incidence NRM of 84%). In conclusion, the presence of histologic grade 1 is associated with increased NRM in patients presenting with lower GI GVHD (stages 0 to 2) and is sufficient evidence for decision to initiate therapy. At the same time, histologic grade 1 does not lessen the markedly adverse impact of advanced lower GI GVHD (stage 3 to 4) and is not synonymous with "mild" GVHD. PMID- 28834809 TI - High-grade Mullerian Adenosarcoma: Genomic and Clinicopathologic Characterization of a Distinct Neoplasm With Prevalent TP53 Pathway Alterations and Aggressive Behavior. AB - Mullerian adenosarcoma harbors low malignant potential, except in cases with myometrial invasion or sarcomatous overgrowth. The presence of a high-grade stromal component has been proposed as an important pathologic predictor of outcome. We hypothesized that high-grade adenosarcoma has distinct clinical and molecular features, distinct from low-grade adenosarcoma. We analyzed the clinicopathologic features and follow-up of 9 high-grade adenosarcomas and a control group of 9 low-grade adenosarcomas. Comprehensive genomic analysis of the high-grade group was performed targeting exons of 409 oncogenes and tumor suppressor genes. In 1 case, the high-grade and low-grade components were separately sequenced. High-grade and low-grade adenosarcomas were comparable in patient age, myometrial invasion, and stage at presentation. Sarcomatous overgrowth was observed in 2/9 (22%) low-grade and 8/9 (89%) high-grade adenosarcomas. Six of 9 (67%) patients with high-grade adenosarcoma developed rapid recurrence; 1 died of her disease. Conversely, no low-grade tumors recurred or metastasized. Sequencing of high-grade adenosarcomas revealed frequent TP53 pathway alterations, identified in 7/9 (78%) cases. p53 expression by immunohistochemistry highly correlated with mutation status. Copy number variations occurred at a mean of 28.8 per tumor; most frequently involved genes included CDK4, MDM2, GNAS, SGK1, and DICER1. High-grade adenosarcoma is an aggressive neoplasm with propensity for short-interval recurrence and metastasis. The proportion of copy number alterations is similar to that reported for adenosarcoma with sarcomatous overgrowth. However, the high frequency of TP53 abnormalities is a novel finding, indicating that high-grade adenosarcoma is a distinct subset with driver TP53 pathway alterations. p53 immunohistochemistry can be used to confirm the presence of a high-grade component. Given its aggressive potential, the presence of any high-grade component in an adenosarcoma should be reported, even in the absence of sarcomatous overgrowth. PMID- 28834810 TI - BRAF V600E Mutations Occur in a Subset of Glomus Tumors, and Are Associated With Malignant Histologic Characteristics. AB - Glomus tumors are rare mesenchymal neoplasms with a phenotype akin to the modified smooth muscle cells of the glomus body. Most are benign, but rare examples show malignant histologic characteristics and aggressive behavior. We recently encountered a malignant glomus tumor with BRAF V600E mutation. We sought to study a large cohort for this mutation, with particular attention to associated malignant histologic characteristics. Tumors were classified based on WHO criteria as benign, uncertain malignant potential (glomus tumors of uncertain malignant potential-GT-UMP), or malignant. Tumors were screened for BRAF V600E by immunohistochemistry, and positive staining was evaluated further by Sanger sequencing. A total of 102 glomus tumors were included and classified as benign (57, 56%), GT-UMP (15, 15%) and malignant (30, 29%). Tumors occurred in patients aged 8 to 89.9 years (median: 50.2), without sex predilection (55% men). Most occurred in the superficial soft tissue (84%) and upper extremities (55%). Six of 95 tested cases had BRAF V600E mutation (6%), including 0 of 57 benign tumors, 3 of 14 GT-UMP (21%), and 3 of 24 malignant tumors (12%). Follow-up was obtained for 59 cases (median: 75.7 mo, range: 7.8 to 268.5). Three of 11 malignant tumors (27%) had progressive disease: 1 with metastasis to brain and heart, 1 with enlarging residual disease, and 1 with recurrence. Two of 4 GT-UMP (50%) had progressive disease: 1 with metastasis to lung, and 1 with local recurrence (50%). Three of 44 benign tumors (7%) had local recurrence. Two of 5 patients with BRAF V600E had progression, including 1 GT-UMP with local recurrence and 1 malignant tumor with enlarging residual disease. In summary, BRAF V600E mutation was detected in 6% of glomus tumors, all of which were malignant or GT-UMP. This mutation may be associated with a malignant phenotype, although study of additional cases is needed. In patients with progressive disease, BRAF could be a promising therapeutic target. PMID- 28834811 TI - Development of Cell Analysis Software for Cultivated Corneal Endothelial Cells. AB - PURPOSE: To develop analysis software for cultured human corneal endothelial cells (HCECs). METHODS: Software was designed to recognize cell borders and to provide parameters such as cell density, coefficient of variation, and polygonality of cultured HCECs based on phase contrast images. Cultured HCECs with high or low cell density were incubated with Ca-free and Mg-free phosphate buffered saline for 10 minutes to reveal the cell borders and were then analyzed with software (n = 50). RESULTS: Phase contrast images showed that cell borders were not distinctly outlined, but these borders became more distinctly outlined after phosphate-buffered saline treatment and were recognized by cell analysis software. The cell density value provided by software was similar to that obtained using manual cell counting by an experienced researcher. Morphometric parameters, such as the coefficient of variation and polygonality, were also produced by software, and these values were significantly correlated with cell density (Pearson correlation coefficients -0.62 and 0.63, respectively). CONCLUSIONS: The software described here provides morphometric information from phase contrast images, and it enables subjective and noninvasive quality assessment for tissue engineering therapy of the corneal endothelium. PMID- 28834812 TI - Long-Term Follow-up of Intrastromal Corneal Ring Segments (210-Degree Arc Length) in Central Keratoconus With High Corneal Asphericity. AB - PURPOSE: To assess the long-term outcomes of implanting intrastromal corneal ring segments (ICRSs) to correct central keratoconus with a high corneal asphericity value. METHODS: Forty-three eyes with central keratoconus with a corneal asphericity value >=-1.00 were evaluated before and after implanting an inferior 210-degree arc-length Ferrara-type AFR5 ICRS (AJL Ophthalmic, Spain). Logarithm of the minimum angle of resolution uncorrected (UDVA) and best-corrected (CDVA) distance visual acuity, corneal asphericity, root mean square for coma-like aberrations [computed for the Zernike terms Z (3, 1) and Z (3, -1)], and residual refractive errors analyzed using vector analysis were recorded before and at all follow-up visits. The postoperative follow-up duration was 3 years in all cases. RESULTS: Mean UDVA (logarithm of the minimum angle of resolution scale) rose from 1.18 +/- 0.59 to a postoperative 0.53 +/- 0.39 after ICRS implantation (P < 0.0001). Mean CDVA varied in turn from 0.36 +/- 0.18 to 0.17 +/- 0.10 (P < 0.0001). CDVA remained unchanged or improved in all eyes after surgery. Both UDVA and CDVA were stable over the postoperative period (P > 0.05). The spherical equivalent declined steeply after ICRS implantation (P < 0.0001). Both spherical equivalent and refractive cylinder were stable over the postoperative period. The corneal asphericity and root mean square values for coma-like aberrations exhibited statistically significant decreases 6 months after ICRS implantation (P < 0.0001) and were also stable over postoperative follow-up (P > 0.05). CONCLUSIONS: These results suggest that implanting a single, inferior, 210-degree arc-length Ferrara-type ICRS is a safe, effective, and stable procedure for treating patients with central hyperprolate keratoconus. PMID- 28834813 TI - Recovery From Amiodarone-Induced Cornea Verticillata by Application of Topical Heparin. AB - PURPOSE: To report a case of amiodarone-induced vortex keratopathy-associated anatomical findings and subjective visual perception before and after treatment with topical heparin eye drops. METHODS: Case report. RESULTS: A 76-year-old man complained of halos in his vision in both his eyes due to prominent bilateral cornea verticillata. For treatment of cornea verticillata, we prescribed unpreserved eye drops of a sterile, phosphate-free solution of 0.1% sodium hyaluronate with 1300 IU/mL heparin sodium 3 times daily to the left eye, whereas the other side served as the control. The area of corneal deposits was measured by 2 examiners before and at the 1- and 3-month examination. At last follow-up, cornea verticillata had been reduced from 6 to 2 mm in area by approximately 66% from grade-III to grade-II amiodarone keratopathy. CONCLUSIONS: In patients using amiodarone, clearing of cornea verticillata may be achieved by topical use of unpreserved eye drops of a sterile, phosphate-free solution of 0.1% sodium hyaluronate with 1300 IU/mL heparin sodium. PMID- 28834814 TI - Systematic Review and Meta-Analysis of Clinical Outcomes of Descemet Membrane Endothelial Keratoplasty Versus Descemet Stripping Endothelial Keratoplasty/Descemet Stripping Automated Endothelial Keratoplasty. AB - PURPOSE: To review and compare the published reports of Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping endothelial keratoplasty/Descemet stripping automated endothelial keratoplasty (DSEK/DSAEK) procedures with regard to endothelial cell density/loss, best spectacle-corrected visual acuity, central corneal thickness, subjective outcomes (patient's reported satisfaction/preference), and postoperative complications. METHODS: A thorough search was conducted in the databases including AMED, EMBASE, Cochrane Database of Systematic Reviews, and MEDLINE without date restrictions. Systematic reviews, meta-analysis, randomized controlled trials, case series, and audits comparing DMEK and DSAEK were included. RESULTS: DMEK is superior to DSAEK for the following outcomes: visual acuity, central corneal thickness, and patient satisfaction. There was a statistically significant difference in the mean spectacle-corrected visual acuity at 6 months for DMEK (mean = 0.161, SD = 0.129) and DSAEK eye (mean = 0.293, SD = 0.153) conditions; t (297) = 8.042, P < 0.0001. The pooled mean difference was -0.13 (95% confidence interval, -0.16 to -0.09) and I = 44%, indicating better visual acuity for DMEK. Mean postoperative endothelial cell density showed statistically no significant difference in the mean values for DMEK (mean = 1855, SD = 442) and DSAEK eye (mean = 1872, SD = 429) conditions; t (336) = 0.375, P = 0.708. A higher proportion of patients prefer DMEK to DSAEK. However, DSAEK is superior to DMEK with respect to the need for rebubbling as the rebubbling rate was higher in the DMEK group. CONCLUSIONS: Although DMEK is associated with a higher rate of rebubbling, better visual outcomes were seen in DMEK. PMID- 28834815 TI - Effect of Multipurpose Solution Combined With Autophagy Inhibitors on Adhesion of Acanthamoeba trophozoites to Silicone Hydrogel Contact Lenses. AB - PURPOSE: The aim of the study was to evaluate the effect of multipurpose contact lens (CL) solution (MPS) combined with autophagy inhibitors on the adhesion properties of Acanthamoeba castellanii (AC) trophozoites to silicone hydrogel CLs. METHODS: AC trophozoites were inoculated onto discs trimmed from a silicone hydrogel CL with plasma surface treatment. After 18 hours, the number of adherent AC trophozoites on the CL treated with MPS was counted under phase-contrast microscopy. We analyzed the efficacy of MPS combined with autophagy inhibitors, 3 methyladenine (0.1, 1, and 5 mM) and chloroquine (10, 100 MUM, and 1 mM), on Acanthamoeba adhesion by electron microscopy. RESULTS: Adhesion of AC trophozoites to the CL treated with MPS (average number of trophozoites adhered to the CL: 61.2 +/- 8.1) was significantly lower compared with that of the CL treated without MPS (83.8 +/- 10.2) (P = 0.027). In MPS application, the number of adhered AC trophozoites treated with 3-methyladenine [8.2 +/- 2.5 for 5 mM (P = 0.008)] or chloroquine [19.4 +/- 7.6 for 100 MUM (P = 0.038) and 5.3 +/- 1.9 for 1 mM (P = 0.001)] was significantly reduced compared with the sample without autophagy inhibitors. However, the number of adherent AC trophozoites was not significantly reduced in less than 5 mM in 3-methyladenine [50.4 +/- 5.1 for 0.1 mM (P = 0.084) and 43.1 +/- 5.0 for 1 mM (P = 0.079)] and 100 MUM in chloroquine [40.6 +/- 13.5 for 10 MUM (P = 0.075)]. 3-methyladenine induced blebby structures or disrupted the membranes of AC trophozoites. AC trophozoites treated with chloroquine showed undigested organelles in the cytoplasm of Acanthamoeba cells. CONCLUSIONS: MPS combined with 3-methyladenine or chloroquine reduced the adhesion rate of AC trophozoites rather than MPS containing only polyhexamethylene biguanide. Appropriate concentrations of autophagy inhibitors, 3-methyladenine and chloroquine, added to commercial MPS should be considered to decrease the clinical rate of Acanthamoeba keratitis. PMID- 28834816 TI - Donor-Derived Conjunctival-Limbal Melanoma After a Keratolimbal Allograft. AB - PURPOSE: To report a single case of donor-derived conjunctival-limbal melanoma that occurred after a keratolimbal allograft (KLAL). METHODS: Case report and literature review. RESULTS: A 56-year-old white woman with a history of bilateral limbal stem cell deficiency developed a donor-related melanoma after a KLAL. Three months after undergoing an uncomplicated KLAL, the patient presented with hemorrhagic nodules within her conjunctiva and transplanted tissue. Excisional biopsy was performed, and the pathology results revealed melanoma cells. Although the donor of the KLAL had a history of metastatic melanoma, the ocular tissue was in compliance with all eye bank requirements for donation. After discovery of the tumor, the patient's systemic immunosuppression was stopped. Within 1 week, the patient demonstrated a dramatic improvement in the size of the lesion. One month after the initial biopsy, the KLAL tissue was excised, and a pathology report revealed that there were no viable tumor cells on the ocular surface. As the limbal stem cell deficiency recurred, the eye underwent placement of a Boston type 1 keratoprosthesis. CONCLUSIONS: We present a case of conjunctival-limbal melanoma after a KLAL from a donor who had a history of metastatic melanoma. In response to this case, the US eye banking guidelines were amended to include stricter parameters for vascularized ocular tissue transplantation. PMID- 28834817 TI - Promotion of Corneal Epithelial Wound Healing in Diabetic Rats by the Fibronectin Derived Peptide PHSRN. AB - PURPOSE: Topical application of the fibronectin-derived peptide PHSRN facilitates corneal epithelial wound healing in healthy animals and in patients with nonhealing epithelial defects. We have now examined the effect of PHSRN eye drops on the healing of corneal epithelial wounds in diabetic rats. METHODS: Wistar rats were injected intraperitoneally with streptozotocin to induce diabetes or with a vehicle as a control. Four weeks after confirmation of the corresponding presence or absence of glycosuria, a 3-mm-diameter portion of the corneal epithelium of the right eye was excised and eye drops containing PHSRN (200 MUM) or phosphate-buffered saline (PBS) vehicle were administered to the injured eye every 6 hours. RESULTS: The area of the epithelial defect did not differ significantly among the 4 experimental groups (diabetic or nondiabetic rats treated with PHSRN or vehicle) at 12 hours after wounding. At 18 hours, however, the area of the defect in diabetic rats treated with PHSRN (0.50 +/- 0.34 mm) was significantly (P < 0.05) smaller than that in diabetic rats treated with PBS (1.06 +/- 0.42 mm) and was similar to that in nondiabetic rats treated with PBS (0.60 +/- 0.23 mm). The decrease in the size of the epithelial defect in diabetic rats treated with PHSRN was also found to be dependent on the dose of the peptide. CONCLUSIONS: Administration of PHSRN significantly facilitated healing of corneal epithelial wounds in diabetic rats, which suggests that PHSRN eye drops warrant further investigation as a treatment option for patients with diabetic keratopathy. PMID- 28834818 TI - Agreement of Corneal Diameter Measurements Obtained by a Swept-source Biometer and a Scheimpflug-based Topographer. AB - PURPOSE: To assess the agreement between a swept-source optical biometry device (IOLMaster 700) and a Scheimpflug-based topography device (Pentacam HR) in measuring the corneal diameter. METHODS: A total of 100 eyes from 100 cataract surgery candidates were enrolled. The white-to-white (WTW) distance measurements provided by both devices were recorded and analyzed. A paired t test was performed to compare the mean values of the WTW distance between the IOLMaster 700 and Pentacam HR. The Bland-Altman analysis was used to evaluate the agreement between the measurements of both devices. RESULTS: Mean age (+/-SD) of the participants was 65.9 +/- 3.3 years, and 58 (58%) were men. The mean WTW distances measured by the IOLMaster 700 and Pentacam HR were 11.72 +/- 0.45 mm and 11.41 +/- 0.42 mm, respectively (P < 0.001). The overall 95% limits of agreement were -0.17 and 0.78 mm. The 95% limits of agreement between the measurements of the 2 devices were -0.30 and 0.84 versus -0.07 and 0.72 for eyes with WTW distances of <=11.50 mm versus >11.50 mm, respectively. CONCLUSIONS: According to the results of this study, the IOLMaster 700 may overestimate the WTW distance measurements by up to 0.78 mm compared with the Pentacam HR, so these 2 devices should not be used interchangeably for this purpose. The agreement is somehow weaker for eyes with WTW distances of 11.50 mm or less than those with WTW distances greater than 11.50 mm. PMID- 28834819 TI - Self-Retained Amniotic Membrane Combined With Antiviral Therapy for Herpetic Epithelial Keratitis. AB - PURPOSE: To evaluate the therapeutic benefit of self-retained cryopreserved amniotic membrane in conjunction with oral antiviral therapy in herpetic epithelial keratitis. METHODS: Retrospective review of 4 patients with primary (1 eye) and recurrent (3 eyes) unilateral herpetic epithelial keratitis treated with cryopreserved amniotic membrane through the placement of the PROKERA Slim (PKS) (Bio-Tissue, Inc) in conjunction with oral acyclovir. Their symptoms, conjunctival inflammation, corneal staining, and visual acuity were compared before and after treatment. RESULTS: Herpetic epithelial keratitis presented as dendritic (3 eyes) and geographic (1 eye) epithelial lesions. After epithelial debridement and placement of the PKS for 5 +/- 3.7 days, all patients reported significant relief of symptoms, rapid corneal epithelialization, and reduction of ocular surface inflammation. The visual acuity was also improved in all eyes from 0.7 +/- 0.7 to 0.4 +/- 0.7 logarithm of the minimum angle of resolution (P = 0.2). They remained symptom-free during a follow-up period of 2.7 to 50.8 (20.3 +/- 21.7) months. CONCLUSIONS: The PKS in conjunction with oral acyclovir facilitates the ease of early intervention to accelerate restoration of a normal corneal epithelium in herpetic epithelial keratitis. PMID- 28834820 TI - Comparison of the Center and Flex-Center Methods of Corneal Endothelial Cell Analysis in the Presence of Guttae. AB - PURPOSE: To compare endothelial cell analysis by the center and flex-center methods in corneas with guttae of differing severity and to determine the minimum countable cell number for using only the flex-center method. METHODS: Forty-seven eyes with corneal guttae and 50 age-matched normal controls were enrolled in the study. Three images were captured in each central cornea with the noncontact specular microscope. Endothelial cell density (ECD), coefficient of variation (CV), and percentage of hexagonal cells (HEX) were analyzed by trained graders, using both center and flex-center methods. RESULTS: Consistent ECD and HEX values were obtained in normal eyes by both methods (P > 0.05). In corneas with guttae, ECD values obtained by the center method were 2.4% higher than those obtained with the flex-center method (P < 0.001). ECD values derived by both methods disagreed only when <30 cells were identified or <20 cells were analyzed. CV values obtained by the center method were 17.1% (P < 0.001) lower than those obtained by the flex-center method. HEX values obtained with both methods (P > 0.05) agreed. Regardless of guttae density, the ECD, CV, and HEX values of 3 images of each eye were in agreement (P > 0.05). CONCLUSIONS: In corneas with guttae, both center and flex-center methods can reliably determine ECD. Although current practice recommends the center method when at least 100 cells can be counted, our study suggests that the center method can provide a reliable ECD value when there are >=30 contiguous countable cells in a central cornea endothelial image. The flex-center method is recommended when <30 contiguous cells are identified. PMID- 28834821 TI - Therapeutic Femtosecond Laser-Assisted Lamellar Keratectomy for Multidrug Resistant Nocardia Keratitis. AB - PURPOSE: To describe the novel use of femtosecond laser technology for therapeutic resection of infectious foci in a case of multidrug-resistant Nocardia asteroides keratitis. METHODS: A 30-year-old man presented with a corneal infiltrate. Cultures were taken, and fortified vancomycin and tobramycin were initiated. After 3 negative cultures and minimal improvement on various broad-spectrum antibiotics, all topical medications were stopped and a final fourth corneal culture grew N. asteroides. Treatment with topical amikacin was initiated, but the infection continued to worsen. With drug sensitivities still pending, the patient's clinical status continued to deteriorate rapidly, despite treatment with amikacin, gatifloxacin, and polymyxin B/trimethoprim. The femtosecond laser was then used to perform targeted lamellar keratectomy. RESULTS: Femtosecond laser-assisted lamellar keratectomy successfully removed the infected tissue and allowed for increased penetration of topical antibiotics. Drug sensitivities finally returned, revealing multidrug resistance and sensitivity only to trimethoprim/sulfamethoxazole and tobramycin, some of which the patient had previously tried and failed. The infection fully resolved after readministering polymyxin B/trimethoprim and tobramycin, leaving minimal residual scarring. CONCLUSIONS: Multidrug-resistant N. asteroides keratitis can be difficult to manage even with appropriate antibiotic therapy based on drug sensitivity testing. Femtosecond laser-assisted resections may facilitate treatment in these cases by safely and precisely debulking infected tissue and enhancing penetration of topical medications. PMID- 28834822 TI - A Prospective Randomized Study on Operative Treatment for Simple Distal Tibial Fractures-Minimally Invasive Plate Osteosynthesis Versus Minimal Open Reduction and Internal Fixation. AB - OBJECTIVES: To compare the radiologic and clinical results of minimally invasive plate osteosynthesis (MIPO) and minimal open reduction and internal fixation (ORIF) for simple distal tibial fractures. DESIGN: Randomized prospective study. SETTING: Three level 1 trauma centers. PATIENTS: Fifty-eight patients with simple and distal tibial fractures were randomized into a MIPO group (treatment with MIPO; n = 29) or a minimal group (treatment with minimal ORIF; n = 29). These numbers were designed to define the rate of soft tissue complication; therefore, validation of superiority in union time or determination of differences in rates of delayed union was limited in this study. INTERVENTION: Simple distal tibial fractures treated with MIPO or minimal ORIF. MAIN OUTCOME MEASUREMENTS: The clinical outcome measurements included operative time, radiation exposure time, and soft tissue complications. To evaluate a patient's function, the American Orthopedic Foot and Ankle Society ankle score (AOFAS) was used. Radiologic measurements included fracture alignment, delayed union, and union time. RESULTS: All patients acquired bone union without any secondary intervention. The mean union time was 17.4 weeks and 16.3 weeks in the MIPO and minimal groups, respectively. There was 1 case of delayed union and 1 case of superficial infection in each group. The radiation exposure time was shorter in the minimal group than in the MIPO group. Coronal angulation showed a difference between both groups. The American Orthopedic Foot and Ankle Society ankle scores were 86.0 and 86.7 in the MIPO and minimal groups, respectively. Minimal ORIF resulted in similar outcomes, with no increased rate of soft tissue problems compared to MIPO. CONCLUSIONS: Both MIPO and minimal ORIF have high union rates and good functional outcomes for simple distal tibial fractures. Minimal ORIF did not result in increased rates of infection and wound dehiscence. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28834823 TI - Biomechanical Analysis of the Proximal Femoral Locking Compression Plate: Do Quality of Reduction and Screw Orientation Influence Construct Stability? AB - OBJECTIVES: To investigate biomechanically in a human cadaveric model the failure modes of the proximal femoral locking compression plate and explore the underlying mechanism. METHODS: Twenty-four fresh-frozen paired human cadaveric femora with simulated unstable intertrochanteric fractures (AO/OTA 31-A3.3) were assigned to 4 groups with 6 specimens each for plating with proximal femoral locking compression plate. The groups differed in the quality of fracture reduction and plating fashion of the first and second proximal screws as follows: (1) anatomic reduction with on-axis screw placement; (2) anatomic reduction with off-axis screw placement; (3) malreduction with on-axis screw placement; (4) malreduction with off-axis screw placement. The specimens were tested until failure using a protocol with combined axial and torsional loading. Mechanical failure was defined as abrupt change in machine load-displacement data. Clinical failure was defined as 5 degrees varus tilting of the femoral head as captured with optical motion tracking. RESULTS: Initial axial stiffness (in N/mm) in groups 1 to 4 was 213.6 +/- 65.0, 209.5 +/- 134.0, 128.3 +/- 16.6, and 106.3 +/- 47.4, respectively. Numbers of cycles to clinical and mechanical failure were 16,642 +/- 10,468 and 8695 +/- 1462 in group 1, 14,076 +/- 3032 and 7449 +/- 5663 in group 2, 8800 +/- 8584 and 4497 +/- 2336 in group 3, and 9709 +/- 3894 and 5279 +/- 4119 in group 4. Significantly higher stiffness and numbers of cycles to both clinical and mechanical failure were detected in group 1 in comparison with group 3, P <= 0.044. CONCLUSIONS: Generally, malreduction led to significantly earlier construct failure. The observed failures were cut-out of the proximal screws in the femoral head, followed by either screw bending, screw loosening, or screw fracture. Proper placement of the proximal screws in anatomically reduced fractures led to significantly higher construct stability. Our data also indicate that once the screws are placed off-axis (>5 degrees), the benefit of an anatomic reduction is lost. PMID- 28834824 TI - Comparison of Central Corneal Thickness Measurements Using Ultrasonic Pachymetry, Anterior Segment OCT and Noncontact Specular Microscopy. AB - PURPOSE: To evaluate and compare central corneal thickness (CCT) values measured with anterior segment optical coherence tomography (AS-OCT), noncontact specular microscopy (NCSM), and ultrasound pachymetry (USP). MATERIALS AND METHODS: CCT was measured in 182 healthy eyes without ocular abnormalities other than refractive errors. Three consecutive measurements of CCT by the same examiner were obtained during the same session. The testing sequence of AS-OCT and NCSM was randomly selected. The USP always was performed after the noncontact examinations. RESULTS: The average CCT measured by AS-OCT, NCSM, and USP were 535.8+/-35.5, 547.7+/-38.2, and 537.4+/-37.5 MUm, respectively. The mean differences between modalities were 11.8+/-14.7 MUm (P<0.01) between NCSM and AS OCT, 10.3+/-17.7 MUm (P<0.01) between NCSM and USP and 1.6+/-8.6 MUm (P=0.02) between USP and AS-OCT. CONCLUSIONS: AS-OCT, NCSM, and USP showed an overall strong agreement in measuring CCT. However, CCT measurements with AS-OCT showed a good correlation to those obtained by USP, NCSM tended to give statistically significant higher CCT readings than either alternative and showed the worse repeatability indices. On the basis of our results, CCT measurement obtained with different instruments cannot be considered directly interchangeable. PMID- 28834829 TI - Line Laser as an Assistance for Facial and Dental Midlines Evaluation in Single Splint Orthognathic Surgery. AB - Coincidence of facial and dental midlines is one of the important goals in orthognathic-orthodontic treatment to achieve optimum facial aesthetics and good occlusal functions. Tools assisting diagnosis of facial midline are usually ruler or dental floss. These tools are usually hand held and hinder the global sight required in facial evaluation. Line laser device projects a steady narrow laser line and is commonly used in construction and carpentry to replace traditional chalk line tool. The authors take the advantages of line laser and incorporate it into facial evaluation in the authors' practice of single-splint orthognathic surgery.During June 2013 to May 2015, the authors used line laser device to evaluate facial and dental midlines in 28 patients of facial asymmetry requiring orthognathic surgery during consultation in office and intraoperative evaluation. The details of integrating this device to practice are described. All the patients showed improved facial symmetry and coincidence of facial and dental midlines after operation. Postoperative orthodontics were finished smoothly.Line laser is available from general utility stores and is safe to use according to laser safety regulation. From the authors' experiences, it is burden free to apply in facial and dental midlines evaluation and improves the practice. PMID- 28834828 TI - Intraocular Pressure Responses to Maximal Cycling Sprints Against Different Resistances: The Influence of Fitness Level. AB - PURPOSE: This study investigated the acute effect of maximal cycling sprint against difference resistances on intraocular pressure (IOP) depending on participants' fitness level. METHODS: In total, 26 physically active collegiate men performed 5 maximal cycling sprints against different resistances in a randomized order, and IOP was measured immediately before and after each sprint. Participants were divided in 2 subgroups (low fit and high fit) according to their maximum power output relative to body weight to assess the influence of fitness level. Two identical testing sessions were performed to assess the repeatability of IOP values. RESULTS: We found that IOP decreases with the lightest resistance (P<0.01), whereas IOP increases with heavier resistances (P<0.01), and it showed a positive linear tendency (r=0.99). Our results suggest that participants' fitness level seems to influence IOP responses, with a more stable response in the high-fit group. A strong intersession repeatability of IOP values was observed (intraclass correlation coefficient range, 0.82 to 0.98; coefficients of variations range, 1.76% to 6.23%). CONCLUSIONS: We conclude that (1) IOP is sensitive to cycling resistance in all-out sprints, with a lowering effect on the lightest resistance and an increasing effect with medium and heavy resistances, (2) high fitness level is beneficial to avoid IOP fluctuations during sprints, and (3) these changes are comparable when measured on 2 different days under the same experimental conditions. A progressive involvement in physical activity may be desirable to avoid IOP peaks during highly demanding physical effort. Future studies are needed to clarify the consequences of exercise in glaucoma patients. PMID- 28834825 TI - Intraocular Pressure Fluctuations and 24-Hour Continuous Monitoring for Glaucoma Risk in Wind Instrument Players. AB - PURPOSE: The purpose of this study is to investigate the influence of playing a wind instrument on intraocular pressure (IOP) and to monitor 24-hour (IOP) fluctuations in wind musicians of symphony and wind orchestras to compare IOP levels during normal daily activities with IOP levels during playing. METHODS: Professional and amateur musicians of symphony and wind orchestras were invited to participate. A total of 42 participants, 9 with glaucoma, underwent a routine ophthalmologic examination. IOP measurements were taken before and immediately after 20 minutes of playing wind instruments. In addition, 6 participants underwent 24-hour IOP monitoring with the Triggerfish (Sensimed AG, Switzerland) sensing contact lens, during which they kept an activity logbook. RESULTS: Eleven professionals and 31 amateur musicians participated in the study. A total of 7 eyes of 6 patients underwent additional 24-hour IOP monitoring. Mean IOP before playing was 13.6+/-2.6 mm Hg, IOP change after playing was +1.5+/-2.2 mm Hg with a significant difference between professionals (2.5+/-1.5 mm Hg) and amateurs (1.1+/-2.3 mm Hg). There were no significant differences in IOP change between subjects with or without glaucoma. During 24-hour IOP monitoring there were slight increases in IOP while playing an instrument, but also during other activities and overnight. These latter IOP levels were similar or even higher than the IOP rise caused by playing a wind instrument. CONCLUSIONS: IOP often rises after playing wind instruments, but similar or even higher IOP levels seem to occur during common other daily activities or at night. These peaks may be relevant for glaucomatous field progression and treatment of glaucoma patients. PMID- 28834826 TI - Valsalva Maneuver-induced Changes in Anterior Lamina Cribrosa Surface DEPTH: A Comparison Between Normal and Glaucomatous Eyes. AB - PURPOSE: The purpose of this study is to investigate the influence of the Valsalva maneuver (VM) on anterior lamina cribrosa surface depth (ALCSD), and to compare normal with treated glaucomatous eyes in terms of this effect. METHODS: Thirty-two patients (32 eyes) with early-to-moderate glaucoma under treatment and 30 normal healthy participants (30 eyes) were prospectively enrolled. Study subjects performed the VM by blowing through a mouthpiece attached to a handheld manometer; expiratory pressure during the maneuver ranged from 35 to 40 mm Hg. Swept-source optical coherence tomography B-scans were performed during phase 2 of the VM (from 10 to 15 s). RESULTS: The ALCSD was significantly different in the normal eyes only, decreasing by 31.90+/-14.81 MUm (-8.79%; 394.85+/-53.63 MUm at baseline vs. 362.95+/-44.23 MUm during the VM; P<0.001). In the glaucomatous eyes, the ALCSD decreased by only 3.57+/-4.91 MUm (-0.75%; 473.85+/-64.35 MUm at baseline vs. 470.28+/-68.18 MUm during the VM; P=0.092). In multivariate regression analysis, the mean ALCSD change was greater when the central corneal thickness was thinner in glaucomatous eyes (standardized beta value=0.21; P=0.02), whereas that was greater in normal eye when baseline IOP was lower (standardized beta value=0.37; P<0.001). CONCLUSIONS: During the VM, the ALCSD was decreased in normal eyes, but was not significantly changed in eyes with treated glaucoma. These results suggest that the physiology of LC displacement in response to IOP and cerebrospinal fluid pressure dynamics might differ between normal and glaucomatous eyes. PMID- 28834827 TI - Change in Visual Field Progression Following Treatment Escalation in Primary Open angle Glaucoma. AB - PURPOSE: To evaluate the effect of treatment escalation on the rate of visual field progression in patients with primary open-angle glaucoma (POAG). PATIENTS AND METHODS: Multicenter database study. We reviewed the electronic records of 171 patients with POAG under medical hypotensive treatment who underwent 5 consecutive visits 6 months apart before and after medical treatment escalation or additive laser trabeculoplasty. We calculated the rate of visual field progression (mean deviation change per year) before and after treatment escalation. RESULTS: The mean duration of follow-up was 5.1+/-0.5 years and the mean number of visual field examinations was 10.2+/-0.2. In 139 eyes with medical treatment escalation, the rate of progression was significantly reduced [from 0.57 to -0.29 dB/y; P=0.022; intraocular pressure (IOP) reduction 11.1%]. In detail, the rate of progression was significantly reduced after escalation from mono to dual therapy, dual to triple therapy, and from mono to triple therapy ( 0.35 to -0.24 dB/y, P=0.018; -1.01 to -0.48 dB/y, P=0.038; -1.04 to -0.35 dB/y, P=0.020, respectively). In 32 eyes with additive laser trabeculoplasty, the rate of progression was significantly reduced (-0.60 to -0.24 dB/y; P=0.014; IOP reduction 9.4%). CONCLUSIONS: Medical treatment escalation or additive laser trabeculoplasty significantly reduced the rate of visual field progression in POAG. Larger IOP reduction has a greater probability of reducing glaucoma progression. PMID- 28834830 TI - Analysis of Orbital Volume Measurements Following Reduction and Internal Fixation Using Absorbable Mesh Plates and Screws for Patients With Orbital Floor Blowout Fractures. AB - INTRODUCTION: Hinge-shaped fractures are common type of orbital floor blowout fractures, for which reduction and internal fixation is ideal. Nonetheless, orbital floor reconstruction using alloplastic materials without reducing the number of bone fragments is the most frequently used procedure. Therefore, this study analyzed and compared the outcomes between open reduction and internal fixation using absorbable mesh plates and screws, and orbital floor reconstruction, by measuring the orbital volume before and after surgery. METHOD: Among patients with orbital floor blowout fractures, this study was conducted on 28 patients who underwent open reduction and internal fixation, and 27 patients who underwent orbital floor reconstruction from December 2008 to September 2015. The mechanism of injury, ophthalmic symptoms before and after surgery, and the degree of enophthalmos were examined; subsequently, the volumes of the affected and unaffected sides were measured before and after surgery based on computed tomography images. This study compared the degree of recovery in the correction rate of the orbital volume, ophthalmic symptoms, and enophthalmos between the 2 groups. RESULT: The patients who underwent open reduction and internal fixation, and the patients who underwent orbital floor reconstruction showed average correction rates of 100.36% and 105.24%, respectively. Open reduction and internal fixation showed statistically, significantly superior treatment outcomes compared with orbital floor reconstruction. The ophthalmic symptoms and incidence of enophthalmos completely resolved in both groups. CONCLUSION: For orbital floor blowout fractures, open reduction and internal fixation using absorbable mesh plates and screws was a feasible alternative to orbital floor reconstruction. PMID- 28834831 TI - The New Anatomical Classification System for Orbital Exenteration Defect. AB - BACKGROUND: The unique anatomy of the orbita and the different behavior of each malignant tumor cause us to perform the various types of orbital exenteration that yields to varying defect each of which has own specific demands in terms of the reconstruction. Current classification of orbital exenteration defects seems not to be adequate to provide detailed description. This study reviews 50 exenteration defects to offer a more effective anatomical classification system. METHODS: Over a 15 years period, 50 orbital exenteration defects in 47 patients were reconstructed. Defects were categorized according to the resected orbital wall, dura, and ethmoid resection. If the maxillectomy was performed, A or B was added to define the type of maxillectomy as partial (intact palate) or total maxillectomy, respectively. According to these criteria, 4 types of defect patterns were determined including Type 0 (n = 5) with intact orbital wall, Type I (n = 9) with sino-orbital fistula, Type II (n = 4) with crania-orbital fistula with intact dura, Type III (n = 6) with crania-orbital fistula associated with dura defect, and Type IV (n = 8) with cranio-nasal-orbital fistula. There were 12 partial (A) and 6 total maxillectomy (B) defects along with the orbital exenteration. RESULTS: There was no major complication except one. The minor wound-healing problems occurred in 7 patients. Nine patients (19%) used prosthesis. Twenty-two (46.8%) patients chose a patch to cover the area. The remaining 16 patients were not able to use any type of prosthesis because of the reconstruction methods. CONCLUSION: The authors believe that the authors' anatomical classification system provides more precise description of the defect which eventually enhances the success rate of both reconstruction and resection. PMID- 28834832 TI - An Epithelioid Hemangioendothelioma of the Head and Neck. AB - An epithelioid hemangioendothelioma (EHE) is a rare vascular tumor of the head and neck region, which carries a risk of recurrence and metastasis. Its etiology is still unclear. It frequently involves the lungs, liver, and bones. Rarely, it may manifest in other parts of the body. Pathologic immunohistochemical investigations are essential to make the definite diagnosis. As it is uncommon, there is no standardized protocol for the treatment of EHE. Herein, the authors report a rare patient with of an EHE localized in the head and neck region. PMID- 28834833 TI - Differential Diagnosis Between Nasal Septal Schwannoma and Nasal Septal Neurofibroma. AB - Recently, as the authors experienced nasal septal schwannoma and nasal septal neurofibroma with similar clinical symptoms but different endoscopic findings, the authors tried to review all the literatures previously reported on the "Nasal septal schwannoma and Nasal septal neurofibroma." The aim of this study is to thoroughly review previously reported patients with nasal septal schwannomas and neurofibromas and to describe similar and different features focusing on the differential diagnosis between the 2 entities. On the basis of our review, the authors made some important conclusions. First, benign peripheral nerve tumors originating from the nasal septum are uncommon. Especially, nasal septal neurofibroma is extremely rare that only 5 patients were reported. So, more clinical reports of benign peripheral nerve tumors are necessary to elucidate the differences between nasal septal schwannoma and nasal septal neurofibroma. Second, there are some similar features between nasal septal schwannoma and nasal septal neurofibroma such as clinical symptoms, endoscopic findings, and treatment strategy. However, since there seem to be some differences in nasal endoscopic findings, they may be helpful for the provisional diagnosis, and so more patients should be reported to verify that point. Third, image study, especially magnetic resonance imaging (MRI), is considered to be a useful tool for differential diagnosis of benign peripheral nerve tumors originating from the nasal septum. So, more clinical reports reporting MRI findings are needed to verify the differences. Last, because of distinctive histologic appearances of benign peripheral nerve tumors, it is usually not difficult to make the distinction between nasal septal schwannoma and nasal septal neurofibroma. However, immunohistochemical stains including S-100 protein, calretinin, CD 34, factor XIIIa, and CD56 are necessary when it is difficult to differentiate between 2 disease entities. PMID- 28834834 TI - Three-Dimensional Analysis of Midfacial Soft Tissue Changes After Maxillary Posterior Impaction and Intraoral Vertical Ramus Osteotomy for Mandibular Setback in Class III Patients. AB - This study investigated the correlation between the 3-dimensional changes in midfacial soft tissues, including the parasagittal area and maxilla-mandible complex, after Le Fort I maxillary posterior impaction and bilateral intraoral vertical ramus osteotomy (B-IVRO), using cone-beam computed tomography (CBCT). This retrospective study included 22 skeletal Class III patients (6 men and 16 women; mean age 21.6 years) who underwent orthognathic surgery. Three-dimensional CBCT images taken before and 1 year after surgery were superimposed based on the cranial base. Midfacial soft tissues, including those in the parasagittal area (paranasal area, anterior cheek area, lateral cheek area) and midsagittal areas of the face, were evaluated using reconstructed CBCT images. Correlations and the ratios between soft tissue and hard tissue movement were calculated. After surgery, both paranasal areas showed significant forward movement (about 2.0 mm) and the largest upward movement (about 0.15 mm) among the 3 areas. The paranasal areas moved forward with a ratio of 0.5, according to vertical movement of B. Orthognathic surgery using Le Fort I maxillary posterior impaction with B-IVRO mandibular setback results in forward movement of midfacial soft tissues, even though sagittal movement of the maxilla is limited because facial muscles and retaining ligaments pull the redundant soft tissues, which are caused by vertical movement of the maxilla-mandible. This midfacial soft tissue change with maxillary posterior impaction could be advantageous to patients who have paranasal depression and protrusion of the upper lip owing to proclined upper incisors, which are prevalent among Asian Class III patients. PMID- 28834835 TI - Esophageal Stricture in a Child With Habit of Acidic Drinks. AB - A 12-year-old boy with Down syndrome referred to the authors' department with dysphagia and growth retardation. Dysphagia was especially with solid foods and had a 12-month history. When he was 7, he had started to drink Coke and from that time he had a Coke drinking habit. Every day he was drinking more than 2 L Coke and was eating meals in small amounts. Investigations of the patient revealed esophageal stricture related to acidic drink habit and gastro-oesephageal reflux. The patient was treated with recurrent bouginage, antireflux medication, and nutrional support. The patient became symptom free from 13 months and gained weight. The clinicians should take the nutrition habits into consideration when evaluating the esophageal stricture patients. PMID- 28834836 TI - Prediction of Late Enophthalmos Using Preoperative Orbital Volume and Fracture Area Measurements in Blowout Fracture. AB - Enophthalmos caused by orbital volume expansion is the traditional indication for blowout fracture operation, but it may not appear immediately after orbital trauma due to periorbital swelling. The purpose of this study was to investigate the correlations of the orbital volume ratio (OVR) and, orbital fracture area (OFA) with the late enophthalmos measurement in unilateral pure blowout fracture. Seventy-two patients who had experienced a blowout fracture were divided into 2 groups, the conservative treatment group (n = 40) and the operative treatment group (n = 32). The authors measured the preoperative OVR and OFA using three dimensional facial bone computed tomography and investigated their relationship with late enophthalmos that obtained 6 months after orbital trauma. In both conservative and operative groups, there were significant positive correlations between the OVR and OFA (P < 0.05). In the conservative group, both the OVR and OFA showed significant positive correlations with late enophthalmos, but the OVR (r = 0.777) was more closely correlated with enophthalmos than the OFA (r = 0.739). Quantitative measurements of OVR and OFA are useful parameters that can predict the extent of late enophthalmos and are useful in planning the treatment of blowout fracture. PMID- 28834837 TI - Open Versus Closed Reduction of Maxillary Fractures: Complications and Resource Utilization. AB - INTRODUCTION: Maxillary fractures are frequently managed depending on the surgeon's preferences, nature of the injury, presence of associated injuries, and comorbidities. Current literature advocates open reduction with plating versus closed techniques. However, data defining associated costs and complications comparing the 2 approaches remains lacking. METHODS: National Inpatient Sample (2006-2011) was examined for patients undergoing closed or open (76.73-76.74) reduction of maxillary fractures. Treatment-related complications were regarded as re-exploration of surgical site, hemorrhage, hematoma, seroma, wound infection, and dehiscence. RESULTS: Overall, 22,157 patients were identified. There were 18,874 closed and 3283 open procedures. Median age was 35 (interquartile range 27). Median length of stay (LOS) was 4 days. Median total charges were reported as 51486.80 USD. Males comprised 77% of the cohort. 68% of patients were Caucasian. Private payer/HMO accounted for the largest source of health care coverage (43.5%). On risk-adjusted multivariate analysis, there was no difference in surgical approach regarding incidence of postoperative complications. Males (2.73), nonprivate insurer payer (P = 0.002), South region (2.49), and transferred patients (2.55) had higher incidence of complications. Presence of chronic pulmonary disease (2.87) and coagulopathy (6.62) also increased risk of complications. Length of stay was shorter for open reduction (0.68) versus closed. Total charges were also less for open approach (0.37). CONCLUSION: While surgical approach did not affect complications, open approach favorably affected LOS and total charges. Future studies should focus on comorbidities, demographics, and associated injuries in relation to resource utilization for maxillary fractures. In current economic environment, such information might further dictate management options. PMID- 28834838 TI - Anatomical Relationship of the Inferior Bundle of the Incisivus Labii Inferioris With the Depressor Labii Inferioris and the Platysma. AB - The current study examined the inferior bundle of the incisivus labii inferioris muscle (ILI) and its morphologic and spatial relationships with regard to the depressor labii inferioris muscle (DLI) and the platysma. Incisivus labii inferioris muscles and their inferior bundles were investigated in 50 specimens from embalmed Korean adult cadavers. The inferior bundle of the ILI was divided from the originating fibers of the ILI, and it was present in all specimens (100%). The inferior bundle of the ILI could be distinguished into the transverse and inferolateral slips according to their courses and locations. The inferior bundle of the ILI was classified into 3 types according to the presence of the transverse and inferolateral slips. In Type I (44%), the inferior bundle of the ILI had both the transverse and inferolateral slips. In Type II (48%), the inferior bundle of the ILI had only the transverse slip. In Type III (8%), the inferior bundle of the ILI had only the inferolateral slip. The transverse and inferolateral slips were usually attached to the deep fibers of both the platysma lateral to the DLI and the lateral portion of the DLI via aponeurosis, just below the ILI and above the inferior margin of the mandible, respectively. The new anatomical findings of the present study might contribute to the understanding of the detailed movements required to raise the lower lip. This knowledge will be useful for botulinum toxin type A therapies, various facial surgeries, orthodontic treatment, and electromyographic analyses in this area. PMID- 28834839 TI - Use of Acellular Allogenic Dermal Matrix (MegaDerm) in Orbital Wall Reconstruction: A Comparison With Absorbable Mesh Plate and Porous Polyethylene. AB - The selection of materials for orbital wall reconstruction has been a matter of debate. This study aimed to evaluate the effectiveness of an acellular allogenic dermal matrix (ADM) as an orbital wall reconstruction material and to compare the results of orbital wall reconstruction with the ADM to those of reconstruction with the more widely used absorbable mesh plate and porous polyethylene. We retrospectively reviewed the clinical charts and computed tomography images of 73 patients who underwent orbital reconstruction at 1 institution between March 2013 and February 2014. In the ADM group, the mean defect size of 29 patients was 2.89 cm. After orbital wall reconstruction with ADM, patients with preoperative enophthalmos (7 patients), limited range of eyeball movement (6 patients), and diplopia (12 patients) showed improvements. In the comparative study, the 3 groups showed no significant differences with respect to age distribution (P = 0.522), defect size (P = 0.455), and preoperative findings such as enophthalmos (P = 0.811), diplopia (P = 0.357), and limited range of eyeball movement (P = 0.795). All the preoperative symptoms improved in every group, and in the ADM group, no complication was observed during the postoperative follow-up. ADM is a biocompatible material that combines the flexibility and rigidity required to support the orbital soft tissue. Therefore, it could be an excellent alternative material for orbital wall reconstruction. PMID- 28834840 TI - Osseous Flap of Galea and Periosteum Filled With Mesenchymal Stem Cells, Platelet Rich Plasma, Bone Dust, and Hyaluronic Acid. AB - Reconstructive surgery to craniofacial deformities caused by tumor ressections, traumas or congenital malformation are frequent in medicine practice. It aims to provide the patients with better quality of life and functional improvement of speech, breathing, chewing, and swallowing. Many are the techniques described in the literature to recover bone defects. This study evaluated a vascularized galeal and periosteum flap in rabbits, which could possibly substitute the bone graft in reconstructive surgery, especially for facial defects. It involved rabbits, divided into 12 groups, submitted to a surgical procedure to construct the galea and periosteum cranial flap filled with fragments of cranial bone, platelet-rich plasma, mesenchimal stem cells, and hyaluronic acid. The evaluation methods included image examinations and histological analysis.The results demonstrated bone formation with the use of platelet-rich plasma, mesenchimal stem cells, and bone fragments. The use of several enrichment materials of osseous cellular stimulation improved the quality and bone tissue organization. The more enrichment factor used, the better the tissue quality result was.Much research should be done to improve the methods and to analyze if results in human have the same bone formation as it happened in rabbits. PMID- 28834841 TI - Lymphatic Malformation Architecture: Implications for Treatment With OK-432. AB - PURPOSE: Herein, the authors aim to describe their findings of novel architectural types of lymphatic malformations (LM) and explain the relationship between these architectures and OK-432 treatment outcomes. METHODS: A retrospective review was conducted of all patients diagnosed with a LM treated with OK-432 at the Vascular Anomalies Clinic at BC Children's Hospital from December 2002 to January 2012. RESULTS: Twenty-seven patients were included in the study. Sixty percent of lesions were present by 2 years of age with the majority located in the head and neck (59%). The average number of sclerotherapy procedures was 1.4 per patient. Treatment under fluoroscopic guidance revealed 3 new LM architectures: open-cell microcystic, closed-cell microcystic, and lymphatic channel. Response to treatment was complete or good for 14/19 macrocystic and for 1/2 mixed lesions. Open-cell microcystic LMs gave a complete or good response for 3/3, which was attributed to OK-432 freely communicating between cysts. Closed-cell microcystic LM had localized cysts that did not allow OK-432 to freely communicate and were associated with partial responses, 2/2. The lymphatic channel had a partial response. There were 2 minor complications and 1 instance of recurrence. CONCLUSIONS: The identification of 3 new LM architectures expands the current accepted classification to include: open-cell microcystic, closed-cell microcystic, and lymphatic channels. The majority of complete responses to OK-432 were found with macrocystic lesions. Open-cell microcystic lesions respond better to OK-432 than closed-cell microcystic lesions, and lymphatic channels may respond to OK-432. These key architecture-response relationships have direct clinical implications for treatment with OK-432 sclerotherapy. PMID- 28834842 TI - The Decanal Divide: Women in Decanal Roles at U.S. Medical Schools. AB - PURPOSE: To test the hypotheses that women in medical school dean-level (decanal) positions occupy lower-rank and more image- and education-focused positions than men, and that state and woman-led schools have more women in decanal positions. METHOD: Data were collected on September 10-18, 2016, from Web sites of 136 allopathic, U.S. medical schools accredited by the Liaison Committee on Medical Education and represented on the roster of accredited MD programs in the United States with full accreditation as of June 22, 2016. Statistical significance of differences between comparison groups was assessed using Student t test with P < .05 indicating significance. Correlation between parameters was determined by Spearman rank correlation test with P < .05 indicating significant correlation. RESULTS: Findings demonstrate that only 15% (22/149) of deans and interim deans are women, and the prevalence of women in decanal positions decreases with ascending professional rank (R = 0.93; P < .05). Women are most prevalent in decanal positions focusing on education and mentoring or institutional public image and least prevalent in those focusing on corporate strategy and policy, finance, or government relations. Schools with a woman as dean or interim dean have a higher percentage of decanal positions occupied by women than those with a man as dean or interim dean (P < .05). State and private medical schools do not differ from one another in this regard. CONCLUSIONS: Gender stereotypes and models appear to continue to drive the number and roles of women in decanal positions. PMID- 28834843 TI - Step Up-Not On-The Step 2 Clinical Skills Exam: Directors of Clinical Skills Courses (DOCS) Oppose Ending Step 2 CS. AB - Recently, a student-initiated movement to end the United States Medical Licensing Examination Step 2 Clinical Skills and the Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation has gained momentum. These are the only national licensing examinations designed to assess clinical skills competence in the stepwise process through which physicians gain licensure and certification. Therefore, the movement to end these examinations and the ensuing debate merit careful consideration. The authors, elected representatives of the Directors of Clinical Skills Courses, an organization comprising clinical skills educators in the United States and beyond, believe abolishing the national clinical skills examinations would have a major negative impact on the clinical skills training of medical students, and that forfeiting a national clinical skills competency standard has the potential to diminish the quality of care provided to patients. In this Perspective, the authors offer important additional background information, outline key concerns regarding the consequences of ending these national clinical skills examinations, and provide recommendations for moving forward: reducing the costs for students, exploring alternatives, increasing the value and transparency of the current examinations, recognizing and enhancing the strengths of the current examinations, and engaging in a national dialogue about the issue. PMID- 28834844 TI - Barriers to Career Flexibility in Academic Medicine: A Qualitative Analysis of Reasons for the Underutilization of Family-Friendly Policies, and Implications for Institutional Change and Department Chair Leadership. AB - PURPOSE: Academic medical and biomedical professionals need workplace flexibility to manage the demands of work and family roles and meet their commitments to both, but often fail to use the very programs and benefits that provide flexibility. This study investigated the reasons for faculty underutilization of work-life programs. METHOD: As part of a National Institutes of Health-funded study, in 2010 the authors investigated attitudes of clinical and/or research biomedical faculty at the University of California, Davis, toward work-life policies, and the rationale behind their individual decisions regarding use of flexibility policies. The analysis used verbatim responses from 213 of 472 faculty (448 unstructured comments) to a series of open-ended survey questions. Questions elicited faculty members' self-reports of policy use, attitudes, and evaluations of the policies, and their perceptions of barriers that limited full benefit utilization. Data were coded and analyzed using a grounded theory approach. RESULTS: Faculty described how their utilization of workplace flexibility benefits was inhibited by organizational influences: the absence of reliable information about program eligibility and benefits, workplace norms and cultures that stigmatized program participation, influence of uninformed/unsupportive department heads, and concerns about how participation might burden coworkers, damage collegial relationships, or adversely affect workflow and grant funding. CONCLUSIONS: Understanding underuse of work-life programs is essential to maximize employee productivity and satisfaction, minimize turnover, and provide equal opportunities for career advancement to all faculty. The findings are discussed in relation to specific policy recommendations, implications for institutional change, and department chair leadership. PMID- 28834845 TI - Primary Care Residents in Teaching Health Centers: Their Intentions to Practice in Underserved Settings After Residency Training. AB - PURPOSE: To describe the residents who chose to train in teaching health centers (THCs), which are community-based ambulatory patient care sites that sponsor primary care residencies, and their intentions to practice in underserved settings. METHOD: The authors surveyed all THC residents training in academic years 2013-2014, 2014-2015, and 2015-2016, comparing their demographic characteristics with data for residents nationally, and examined THC residents' intentions to practice in underserved settings using logistic regression analysis. RESULTS: The overall survey response rate was 89% (1,031/1,153). THC resident respondents were similar to residents nationally in family medicine, geriatrics, internal medicine, obstetrics-gynecology, pediatrics, and psychiatry in terms of gender, age, race, and ethnicity. Twenty-nine percent (283) of respondents came from a rural background, and 46% (454) had an educationally and/or economically disadvantaged background. More than half (524; 55%) intended to practice in an underserved setting on completion of their training. Respondents were more likely to intend to practice in an underserved area if they came from a rural background (odds ratio 1.58; 95% confidence interval 1.08, 2.32) or disadvantaged background (odds ratio 2.81; 95% confidence interval 1.91, 4.13). CONCLUSIONS: THCs attract residents from rural and/or disadvantaged backgrounds who seem to be more inclined to practice in underserved areas than those from urban and economically advantaged roots. THC residents' intentions to practice in underserved areas indicate that primary care training programs sponsored by community-based ambulatory patient care sites represent a promising strategy to improve the U.S. health care workforce distribution. PMID- 28834846 TI - Can We Increase the Value and Decrease the Cost of Clinical Skills Assessment? AB - Although the authors do not agree with medical students' bid to end the United States Medical Licensing Examination Step 2 Clinical Skills or Comprehensive Osteopathic Medical Licensing Examination Level 2-Performance Evaluation tests, they concur with Ecker and colleagues that conducting further research to support the validity argument, providing greater feedback on performance, and exploring options to reduce costs are important for addressing students' concerns. Evidence to support the validity of clinical skills exam scores and associated inferences already exists. What is lacking, and would help further justify the use of these examinations, is more evidence to support the "extrapolation" argument-that is, is performance on these examinations related to actual patient care? Enhanced feedback on exam performance should also be considered. While performance data from licensing examinations should be used judiciously given the primary purpose of these tests, additional data would be helpful to learners and their institutions. Centralized testing remains the least costly design, but efficiencies of standardized patient training, case development, and scoring can be reviewed. Scoring modifications made in the past several years at substantial cost should be evaluated to determine whether they have achieved desired goals. Testing organizations can and should embrace these essential elements of transparency and accountability to address concerns about the value of clinical skills examinations. PMID- 28834847 TI - New Onset of Diabetes and Pancreatic Exocrine Insufficiency After Pancreaticoduodenectomy for Benign and Malignant Tumors: A Systematic Review and Meta-analysis of Long-term Results. AB - OBJECTIVE: The aim of this study was to assess the frequency and severity of new onset of diabetes mellitus (NODM) and pancreatic exocrine insufficiency (PEI) after pancreaticoduodenectomy (PD) for benign and malignant tumors. SUMMARY BACKGROUND DATA: When PD is performed on patients for benign tumors, the question of long-term metabolic dysfunctions becomes of importance. METHODS: Medline/PubMed, Embase, and Cochrane Library were searched for articles reporting results of measuring endocrine and exocrine pancreatic functions after PD. The methodological quality of 19 studies was assessed by means of the Newcastle Ottawa scale and Moga-Score. The mean weighted overall percentages of NODM and PEI after PD were calculated with a 95% confidence interval (CI). RESULTS: Of 1295 patients, data valid-for-efficacy-analysis are based on 845 patients measuring pancreatic endocrine and on 964 patients determining exocrine functions after PD. The cumulative incidence of NODM was 40 of 275 patients (14.5%; 95% CI: 10.3-18.7) in the benign tumor group, 25 of 161 (15.5%; 95% CI: 9.9-21.2) in the malignant tumor group, and 91 of 409 patients (22.2%; 95% CI: 18.2-26.3) in the benign and malignant tumor group. Comparing the frequency of NODM after PD revealed significant differences between the groups (benign vs benign and malignant P < 0.0121; malignant vs benign and malignant P < 0.0017). Exocrine pancreatic insufficiency was found in the benign tumor group in 76 of 301 patients (25.2%; 95% CI: 20.3-30.7) and in the malignant tumor group in 80 of 163 patients (49.1%, 95% CI: 41.4-56.8) (P < 0.0001). CONCLUSION: The results of a significant increase of NODM after PD for benign and malignant tumors and a significant decrease of exocrine functions contribute to a rational weighting of metabolic long-term risks following PD. PMID- 28834848 TI - UK Policy on Doctor Remediation: Trajectories and Challenges. AB - Around the world, policy-makers, academics, and health service professionals have become increasingly aware of the importance of remediation, the process by which poor performance is "remedied," as part of the changing landscape of medical regulation. It is, therefore, an opportune time to critique the UK experience with remediation policy. This article frames, for the first time, the UK remediation policy as developing from a central policy aim that was articulated in the 1990s: to accelerate the identification of underperformance and, subsequently, remedy any problems identified as soon as possible. In pursuit of this aim, three policy trajectories have emerged: professionalizing and standardizing remediation provision; linking remediation with other forms of regulation, namely relicensure (known in the UK as medical revalidation); and fostering obligations for doctors to report themselves and others for remediation needs. The operationalization of policy along these trajectories, and the challenges that have arisen, has relevance for anyone seeking to understand or indeed improve remediation practices within any health care system. It is argued here that the UK serves as an example of the more general challenges posed by seeking to integrate remediation policy within broader frameworks of medical governance, in particular systems of relicensure, and the need to develop a solid evidence base for remediation practices. PMID- 28834849 TI - A Review of Digital, Social, and Mobile Technologies in Health Professional Education. AB - INTRODUCTION: Digital, social, and mobile technologies (DSMTs) can support a wide range of self-directed learning activities, providing learners with diverse resources, information, and ways to network that support their learning needs. DSMTs are increasingly used to facilitate learning across the continuum of health professional education (HPE). Given the diverse characteristics of DSMTs and the formal, informal, and nonformal nature of health professional learning, a review of the literature on DSMTs and HPE could inform more effective adoption and usage by regulatory organizations, educators, and learners. METHODS: A scoping review of the literature was performed to explore the effectiveness and implications of adopting and using DSMTs across the educational continuum in HPE. A data extraction tool was used to review and analyze 125 peer-reviewed articles. Common themes were identified by thematic analysis. RESULTS: Most articles (56.0%) related to undergraduate education; 31.2% to continuing professional development, and 52.8% to graduate/postgraduate education. The main DSMTs described include mobile phones, apps, tablets, Facebook, Twitter, and YouTube. Approximately half of the articles (49.6%) reported evaluative outcomes at a satisfaction/reaction level; 45.6% were commentaries, reporting no evaluative outcomes. Most studies reporting evaluative outcomes suggest that learners across all levels are typically satisfied with the use of DSMTs in their learning. Thematic analysis revealed three main themes: use of DSMTs across the HPE continuum; key benefits and barriers; and best practices. DISCUSSION: Despite the positive commentary on the potential benefits and opportunities for enhancing teaching and learning in HPE with DSMTs, there is limited evidence at this time that demonstrates effectiveness of DSMTs at higher evaluative outcome levels. Further exploration of the learning benefits and effectiveness of DSMTs for teaching and learning in HPE is warranted. PMID- 28834850 TI - Initial Cast Correction as a Predictor of Treatment Outcome Success for Infantile Idiopathic Scoliosis. AB - BACKGROUND: Cast treatment for infantile idiopathic scoliosis patients ultimately corrects deformity in varying amounts. As the reasons for these differential outcomes are not fully elucidated, the aim of this study was to identify clinical and radiographic variables correlated with better cast correction. METHODS: Patients in the Children's Spine Study Group and Growing Spine Study Group registries who underwent cast treatment for idiopathic scoliosis between 2005 and 2013 with 1-year minimum follow-up were included. Data including major curve and rib-vertebra angle difference before cast, initial in-cast application, after cast treatment, and at most recent follow-up were collected. Univariable and multivariable regression analyses were used to identify factors associated with lower major curves at most recent follow-up. RESULTS: A total of 68 patients were identified and followed for a mean of 2.5 (range, 1.1 to 5.4) years after cast treatment. Cast treatment lasted an average of 16.7 months, with a median of 6 cast applications (range, 2 to 19). Twenty-five subjects (37%) had a most recent major curve <15 degrees (success), whereas 43 had a curve that was >15 degrees (unresolved). Multivariable linear regression determined that younger age (P=0.02), smaller precast major curve (P<0.001), and greater percent major curve correction in initial cast (P=0.006) were associated with smaller major curve at most recent follow-up. Multivariable logistic regression determined that success patients were younger than unresolved patients (average age, 1.4 vs. 2.1 y; P=0.003), and had smaller in-cast major curves after initial cast application (average, 18 vs. 27 degrees; P=0.002). CONCLUSIONS: Infantile idiopathic scoliosis patients casted at an earlier age, with smaller major curves, and greater percent major curve correction in initial cast have the best prognosis. Patients' percent major curve correction, which may represent curve flexibility and/or cast quality, is a predictor of treatment success when age and precast major curve are also taken into account. LEVEL OF EVIDENCE: Level III retrospective study. PMID- 28834851 TI - Incidence and Fusion of Os Trigonum in a Healthy Pediatric Population. AB - BACKGROUND: Accessory ossicles off the talus (os trigonum) are a common radiographic finding seen within the foot with variable symptomatology in adult and pediatric patients. Although most studies have examined the incidence of these anatomic variants in a retrospective manner, few have longitudinally followed the behavior of os trigonum over time. The aim of this study was to investigate the incidence, mean age of appearance and fusion, and fusion rate of os trigonum in a large cohort of asymptomatic pediatric patients. METHODS: A total of 2620 serial digitized unilateral foot and ankle radiographs from 261 healthy white children (age range, 0.25 to 7 y at enrollment) were retrospectively reviewed. Radiographs were examined to determine the incidence of os trigonum, noting age of appearance and if present, the age of fusion. Skeletal maturity was graded based on ossification pattern of the calcaneal apophysis. RESULTS: Radiographic evidence of os trigonum was present in 18% of patients (n=16 females, n=15 males) with radiographs extending 1 SD beyond the average age of os trigonum appearance. There was no difference in incidence between females and males (P=0.27), and os trigonum was found to appear at a significantly younger age in females (9.1+/-1.8 y) than males (10.4+/-2.0 y, P=0.04). Overall, 70% (n=26) of subjects with os trigonum achieved fusion by age 17 (mean, 9.5+/ 1.6 y in females, 11.2+/-1.6 in males) with no significant difference between sexes (P=0.61). Grading of skeletal maturity at the time of fusion showed that both male and female subjects underwent fusion on average between calcaneal stages 2 and 3 (P=0.5). CONCLUSIONS: This study confirms a relatively large prevalence of os trigonum in a random pediatric population, and clarifies both the average age of onset and high rate of fusion at a relatively narrow range of skeletal maturity. LEVEL OF EVIDENCE: Prognostic level II-retrospective study. PMID- 28834852 TI - Quengel Casting for the Management of Pediatric Knee Flexion Contractures: A 26 Year Single Institution Experience. AB - BACKGROUND: Quengel casting was introduced in 1922 for nonsurgical treatment of knee flexion contractures (KFC) associated with hemophilic arthropathy. It consists of an extension-desubluxation hinge fixed to a cast allowing for gradual correction of a flexion deformity while preventing posterior tibial subluxation. The purpose of this study is to report 1 center's experience with this technique for the treatment of pediatric KFC. METHODS: A retrospective review was conducted over a 26-year period. All patients with KFC treated with Quengel casting were included. Demographic data, associated medical conditions, adjunctive soft tissue releases, complications, and the need for late surgical intervention were recorded. Tibiofemoral angle measurements in maximal extension were recorded at initiation and termination of casting, 1-year follow-up, and final follow-up. Success was defined as no symptomatic recurrence of KFC or need for subsequent surgery. RESULTS: Eighteen patients (26 knees) were treated for KFC with Quengel casting. Average age at initiation of casting was 8.1 years with average follow up of 59.9 months. Fifteen knees (58%) underwent soft tissue releases before casting. An average of 1.5 casts per knee were applied over an average of 23.9 days. Average KFC before casting was 50.6 degrees (range, 15 to 100 degrees) which improved to 5.96 degrees (0 to 40 degrees) at cast removal (P<0.00001). Sixteen patients (22 knees) had 1-year follow-up or failed casting before 1 year. Of these, 11 knees (50%) had a successful outcome. Residual KFC of those treated successfully was 6.8 degrees (range, 0 to 30 degrees) at 1 year and 8.2 degrees (range, 0 to 30 degrees) at final follow-up, averaging 71.4 months (P=0.81). Of the 11 knees deemed failures, all had recurrence of deformity within an average of 1 year from cast removal. Surgical release before Quengel casting did not improve the chances for success (P=0.09). CONCLUSIONS: Quengel casting can improve pediatric KFC an average of 44.2 degrees with minimal complications. Although 50% of treated patients will demonstrate significant recurrence or need later surgery, the majority of those treated successfully have durable results at intermediate term follow-up. LEVEL OF EVIDENCE: Level IV-therapeutic study. PMID- 28834853 TI - Motion Necessary to Achieve Mallet Internal Rotation Positions in Children With Brachial Plexus Birth Palsy. AB - BACKGROUND: Upper extremity function in children with brachial plexus birth palsy (BPBP) is assessed with clinical tests such as the Mallet classification, which uses a hand to spine position to assess shoulder internal rotation, or the modified Mallet classification, which adds an additional internal rotation task (hand to belly). Children with BPBP frequently have difficulty performing the hand to spine task. This study compared scapulothoracic and glenohumeral (GH) parameters associated with successful completion of the hand to spine and hand to belly modified Mallet positions. METHODS: Motion capture measurement of 32 children with BPBP was performed in hand on spine, internal rotation (hand to belly), hand to mouth, and maximal humerothoracic extension positions. Modified Mallet scores were determined by a hand surgeon. RESULTS: Children with better hand to spine performance demonstrated significantly greater GH extension and a nonsignificant trend toward increased GH internal rotation compared with children with scores <3. Children with better internal rotation position performance demonstrated significantly greater GH internal rotation and no significant difference in GH extension. Hand on spine and internal rotation Mallet scores moderately correlated (Pearson r=0.469); however, 54% of children who could place their palms flat on their bellies could not reach behind their backs. CONCLUSIONS: Successfully reaching behind one's back requires both internal rotation and extension, representing a multiplanar motion. The hand to belly performance is less affected by extension and should be considered for internal rotation assessment, particularly for children undergoing surgical intervention that may affect internal rotation. LEVEL OF EVIDENCE: Level II. PMID- 28834854 TI - Foreword. PMID- 28834855 TI - Choice of Fluids for Resuscitation of the Critically Ill: What Nurses Need to Know. AB - Fluid administration is one of the most universal interventions in the intensive care unit; however, there remains a lack of optimal fluid choice in clinical practice. With increasing evidence suggesting that the choice and dose of fluid may influence patient outcomes, it is important to have an understanding of the differences between the various fluid products and these potential effects in order for nurses to navigate the critically ill patient. This article reviews properties, adverse effects, and monitoring of commonly used colloid and crystalloid fluids, providing information that may aid in fluid selection in the intensive care unit. PMID- 28834856 TI - Review of Continuous Infusion Neuromuscular Blocking Agents in the Adult Intensive Care Unit. AB - The use of continuous infusion neuromuscular blocking agents remains controversial. The clinical benefit of these medications may be overshadowed by concerns of propagating intensive care unit-acquired weakness, which may prolong mechanical ventilation and impair the inability to assess neurologic function or pain. Despite these risks, the use of neuromuscular blocking agents in the intensive care unit is indicated in numerous clinical situations. Understanding pharmacologic nuances and clinical roles of these agents will aid in facilitating safe use in a variety of acute disease processes. This article provides clinicians with information regarding pharmacologic differences, indication for use, adverse effects, recommended doses, ancillary care, and monitoring among agents used for continuous neuromuscular blockade. PMID- 28834857 TI - Oral Agents for the Management of Agitation and Agitated Delirium in Critically Ill Patients. AB - Agitation is one of the most common issues that critically ill patients experience. Medications used to manage agitation are often administered intravenously or intramuscularly in the acutely agitated, critically ill patient. However, a multimodal approach that utilizes multiple routes of administration may be appropriate. This review summarizes the available literature on oral antipsychotics, clonidine, and valproic acid to manage agitation in critically ill patients while also focusing on their pharmacology and appropriate monitoring. Despite inconclusive findings from different studies, antipsychotics, clonidine, and valproic acid may provide benefit for specific patient populations. As more evidence emerges, these agents may start playing a greater role in the management of agitation, which is not amenable to first-line agents. As health care professionals, it is prudent to be familiar with their dosing regimens, common adverse effects, and the monitoring required to maximize patient benefits and minimize harms. PMID- 28834858 TI - Diuretic Resistance in Acute Decompensated Heart Failure: A Challenging Clinical Conundrum. AB - Most patients with acute decompensated heart failure (ADHF) present with signs and symptoms of volume overload, and those with a significant history of diuretic exposure may demonstrate varying degrees of diuretic resistance. Although this phenomenon is commonly reported, no consensus definition exists and recommendations regarding an optimal therapeutic approach remain limited. Optimizing the use of intravenous (IV) loop diuretic therapy is the most common initial approach, and therapy may be augmented by the addition of a thiazide-type diuretic or an IV vasodilator. Patients whose resistance to diuretic therapy is due to low cardiac output may require inotropic therapy, and other options (eg, ultrafiltration and vasopressin antagonists) may be considered in select populations. The purpose of this review is to describe diuretic resistance and its underlying mechanisms in ADHF, as well as the most commonly employed strategies for overcoming it. A stepwise approach to managing volume overload in patients with ADHF and diuretic resistance is also provided. PMID- 28834859 TI - Novel Psychoactive Substances and Trends of Abuse. AB - The purpose of this paper is to review the most common and quickest growing classes of novel, or new, psychoactive substances. Abuse of novel psychoactive substances continues to increase, resulting in subsequent increases in hospitalizations. Furthermore, the chemical structures are ever-changing and substances are increasing in potency. Reviewing the chemistry behind these agents will facilitate a better understanding of the toxicity associated with them and allow for successful identification of and management in the critical care unit. Being familiar with the most common psychoactive substances and trends of abuse, as well as the challenges health care providers face when managing intoxication, is essential to the overall understanding and care of these critically ill patients. PMID- 28834860 TI - Review of Infectious Disease Prophylaxis in Solid Organ Transplantation. AB - As immunosuppressive therapy has evolved over the years, rejection rates in solid organ transplant have declined, but infections remain a significant cause of morbidity and mortality in this population. Prophylaxis against bacterial, viral, and fungal infections is often used to prevent infection from common pathogens during high-risk periods. As an integral part of the multidisciplinary medical team, it is important that nurses caring for transplant recipients be familiar with methods to detect and prevent infectious diseases in this population. This article presents a review of risk factors for and prevalence of common infectious pathogens, as well as important considerations regarding prophylactic medications in solid organ transplant recipients. PMID- 28834861 TI - Opportunistic Pulmonary Infections in the Solid Organ Transplant Recipient: A Focus on Drug Therapy. AB - Immunosuppression required to prevent allograft rejection in the solid organ transplant recipient increases vulnerability to infections. Given continuous environmental exposure, the lungs are increasingly susceptible to bacterial, viral, and fungal opportunistic infections. Drug therapy options for the treatment of opportunistic pulmonary infections are used infrequently. These medications are often classified as high risk with specific administration instructions, as well as a multitude of toxicities. Therefore, in this article, we will discuss select pulmonary opportunistic infections and their associated drug therapies. PMID- 28834862 TI - Pharmaceutical Cost Savings in the Intensive Care Unit. AB - Health care costs are rising in the United States with a significant amount of this spend attributed to pharmaceutical costs. The reasons for rising pharmaceutical costs are multifactorial and may include the increase in single source manufacturers of generic medications, drug shortages, the Food and Drug Administration's unapproved drug approval initiative, and generic rebranding. Many of these factors impact the intensive care unit directly creating the need to implement cost-savings strategies to ensure the financial health of an organization and reduce the financial burden for patients. To mitigate rising costs, we have outlined a number of both operational and clinical cost-savings measures derived from the literature and from institutional experience. Engaging the multidisciplinary team in the development and implementation of these initiatives will ensure their success and will maximize their impact. PMID- 28834863 TI - Liver Transplantation for the Treatment of Complicated Iatrogenic Biliary Injuries: A National Review from the UNOS Data Set. AB - BACKGROUND: Liver transplantation (LT) is rarely indicated in the management of iatrogenic bile duct injuries (IBDI), but occasionally, it becomes the only remaining therapy. The purpose of this study is to evaluate potential complications of IBDI and their impact on perioperative mortality, graft, and patient survival after LT. METHODS: The United Network for Organ Sharing database was queried for all LT performed in the United States between 1994 and 2014. Of the 101 238 liver transplants performed, 61 were related to IBDI. We performed a case matched analysis in a 5:1 ratio. RESULTS: The median age for patients with IBDI was 50.16 +/- 11.7 years with a mean Model End-Stage Liver Disease score of 22.6 +/- 9.8. Patients receiving LT for IBDI were more likely women (54.1%, P = 0.001), had lower incidence of hepatitis C virus infection (4.9%, P = 0.001) and longer cold ischemic time (P = 0.001). The mean body mass index was 25.5 +/- 5.2 in patients transplanted for IBDI. IBDI was recognized as the strongest independent predictor associated with eightfold increased risk of early graft loss (P = 0.001; odds ratio, 8.4) and a 2.9-fold increased risk of 30-day mortality after LT in a case matched analysis (P = 0.03). CONCLUSIONS: IBDI is an uncommon but challenging indication for LT. These patients have significantly increased rates of early graft loss. IBDI is an independent factor related to increased risk of perioperative death after LT. Further studies are needed to determine the causes of perioperative complications and identify potential modifiable factors to improve outcomes in patients undergoing transplantation for IBDI. PMID- 28834864 TI - Effects of tamoxifen on urinary incontinence: Case report and review of literature. AB - RATIONALE: Tamoxifen has been used in women with hormone receptor-positive breast cancer and has been shown to successfully reduce both recurrence and mortality. On the contrary, long-term use of tamoxifen has hormone-related urogenital side effects which decrease the quality of life of the patients. PATIENT CONCERNS: In this case report, we present a breast cancer patient receiving tamoxifen who developed urinary incontinence; we discuss the effects of tamoxifen on urinary incontinence, which decreases quality of life of the patients who were evaluated in our clinic. DIAGNOSES: Breast cancer, urinary incontinence. INTERVENTIONS: Temporarily discontinuing tamoxifen. OUTCOMES: Urinary incontinence resolved. LESSONS: Based on the case we reported and literature, estrogen can cause a dose dependent increase in incontinence, but more preclinical and clinical studies of both estrogen and SERMs are needed to support this notion; given the fact that some small-scale clinical studies have not proven a direct relationship between tamoxifen and urinary incontinence. We suggest that clinicians faced with the issue should temporarily stop usage of the drug once the complaint of urinary incontinence arises. PMID- 28834865 TI - Gender differences in the relationship between socioeconomic status and height loss among the elderly in South Korea: Korean National Health and Nutrition Examination Survey 2008-2010. AB - This study aimed to examine average height loss and the relationship between height loss and socioeconomic status (SES) among the elderly in South Korea.Data were obtained from the Korean National Health and Nutrition Examination Survey 2008-2010. A total of 5265 subjects (2818 men and 2447 women) were included. Height loss was calculated as the difference between the subject's self-reported maximum adult height and their measured current height. The height loss values were divided into quartiles (Q1-Q4) for men and women. SES was determined using a self-reported questionnaire for education level, family income, and occupation.Height loss was associated with SES in all age groups, and mean height loss increased with age. In the relationship between education level and maximum height loss (Q4), men with <=6, 7-9, or 10-12 years of education had higher odds ratios for the prevalence of height loss (Q4) than men with the highest education level (>=13 years). With regard to the relationship between the income level and height loss (Q4), the subjects with the lowest income had an increased prevalence of maximum height loss (Q4) than the subjects with the highest income (odds ratios = 2.03 in men and 1.94 in women). Maximum height loss (Q4) was more prevalent in men and women with a low SES and less prevalent in men with a high SES than in men with a middle SES.Height loss (Q4) was associated with education level in men and with income level (especially low income) in men and women. Height loss was also associated with a low SES in men and women. PMID- 28834866 TI - Liver cirrhosis caused by chronic Budd-Chiari syndrome. AB - Chronic Budd-Chiari syndrome (BCS) is a rare cause of liver cirrhosis (LC) and tends to be misdiagnosed in clinical practice. In order to characterize LC caused by chronic BCS, we conducted this retrospective observational study. Medical records of all patients who were initially diagnosed as chronic BCS with LC when discharged from our department from January, 2011 to October, 2016 were reviewed. Cirrhotic patients with known causes and cases lacked key data were excluded. Data of remaining patients was collected and analyzed. A total of 15 cases were included in this study. Patients with LC caused by chronic BCS were characterized by preserved liver function and prominent portal hypertension (PH). Abdominal distention and edema of lower extremities were most common initial manifestations. Intra- or extrahepatic collaterals on imaging studies were of great importance for differential diagnosis. Most of these patients received interventional angioplasty followed by anticoagulation with warfarin and survived without obvious complications of PH. Chronic BCS was a rare but important cause of LC and should always be considered in patients with chronic liver disease and so-called cryptogenic LC. Early diagnosis and timely treatment may improve outcome. Correct interpretation of imaging examinations was fundamental to avoiding misdiagnosis. PMID- 28834867 TI - Cortical blindness and not optic neuritis as a cause of vision loss in a Sjogren's syndrome (SS) patient with the neuromyelitis optica spectrum disorder (NMOSD): Challenges of ascribing demyelinating syndromes to SS: a case report. AB - RATIONALE: The conception that multiple sclerosis may be challenging to distinguish from demyelinating manifestations of Sjogren's syndrome (SS) was introduced more than 30 years ago. However, it is now recognized that the neuromyelitis optica spectrum disorder (NMOSD) may occur more frequently in SS as opposed to multiple sclerosis. Characteristic NMOSD features can include severe attacks of optic neuritis, myelitis which is frequently longitudinally-extensive (spanning at least three vertebral segments on magnetic resonance imaging [MRI]), and an association with anti-aquaporin-4 antibodies. In addition, whereas NMOSD was initially thought to spare the brain, it is now recognized that brain lesions occur in a majority of NMOSD patients. Therefore, it is important for the multi disciplinary team of physicians who care for SS patients to understand this widening spectrum of NMOSD as encompassing brain lesions. In this case-report we describe clinical features, radiographic findings, and treatment of a SS NMOSD patient presenting with severely decreased visual acuity, visual hallucinations, and encephalopathy. PATIENT CONCERNS: The SS NMOSD patient presented with rapid, bilateral onset of severely decreased visual acuity and was therefore suspected as having bilateral optic neuritis. DIAGNOSIS: However, the patient lacked stigmata of optic neuritis, instead had visual hallucinations and encephalopathy suggestive of cortical blindness, and was noted to have occipital lobe lesions on brain MRI. Other radiographic findings included simultaneous enhancement of brainstem and periventricular lesions. INTERVENTIONS: The patient was initially treated with methylprednisolone with no change in her neurological deficits. She was then treated with plasma exchange therapy. OUTCOMES: The patient had resolution of decreased visual acuity, visual hallucinations, encephalopathy, and contrast-enhancing brain lesions in response to plasma exchange therapy. LESSON: We provide the first example of severely decreased visual acuity in a NMOSD patient due to cortical blindness and not bilateral optic neuritis. This finding expands the spectrum of central nervous system syndromes and brain lesions which may occur in NMOSD. The synchronous enhancement of a brainstem lesion (known to occur in NMOSD) with occipital lobe lesions also suggests that our patient's occipital lobe findings were due to NMOSD. All of our patient's findings had an excellent clinical and radiographic response to plasma exchange therapy. PMID- 28834868 TI - Outcomes of intrathecal baclofen therapy in patients with cerebral palsy and acquired brain injury. AB - Intrathecal baclofen (ITB) has been known to reduce spasticity which did not respond to oral medications and botulinum toxin treatment. However, few results have been reported comparing the effects of ITB therapy in patients with cerebral palsy (CP) and acquired brain injury. This study aimed to investigate beneficial and adverse effects of ITB bolus injection and pump therapy in patients with CP and to compare outcomes to patients with acquired brain injury such as traumatic brain injury and hypoxic brain injury. ITB test trials were performed in 37 patients (19 CP and 18 acquired brain injury). Based on ambulatory function, CP patients were divided into 2 groups: 11 patients with nonambulatory CP and 8 patients with ambulatory CP. Change of spasticity was evaluated using the Modified Ashworth Scale. Additional positive or negative effects were also evaluated after ITB bolus injection. In patients who received ITB pump implantation, outcomes of spasticity, subjective satisfaction and adverse events were evaluated until 12 months post-treatment. After ITB bolus injection, 32 patients (86.5%) (CP 84.2% versus acquired brain injury 88.9%) showed a positive response of reducing spasticity. However, 8 patients with CP had negative adverse effects. Particularly, 3 ambulatory CP patients showed standing impairment and 1 ambulatory CP patient showed impaired gait pattern such as foot drop because of excessive reduction of lower extremity muscle tone. Ambulatory CP patients received ITB pump implantation less than patients with acquired brain injury after ITB test trials (P = .003 by a chi-squared test). After the pump implantation, spasticity was significantly reduced within 1 month and the effect maintained for 12 months. Seventeen patients or their caregivers (73.9%) were very satisfied, whereas 5 patients (21.7%) suffered from adverse events showed no subjective satisfaction. In conclusion, ITB therapy was effective in reducing spasticity in patients with CP and acquired brain injury. Before ITB pump implantation, it seems necessary to perform the ITB bolus injection to verify beneficial effects and adverse effects especially in ambulatory CP. PMID- 28834869 TI - Acute myopathy following intra-muscular injection of compound betamethasone: A case report. AB - RATIONALE: We report a case of acute steroid myopathy in a patient with eczema receiving one dose of intra-muscular injection of Compound betamethasone. PATIENT CONCERNS: Acute steroid myopathy (ASM) is usually caused by exogenous corticosteroids, and typically, occurs with therapy using intravenous corticosteroids at high doses. DIAGNOSES: The patient was considered as a diagnosis of acute steroid myopathy. INTERVENTIONS: The patient was treated with non-steroid anti-inflammatory drug and other symptomatic therapy. OUTCOMES: ASM was gradually improved after 2 weeks symptomatic treatment and completely recovered after one-month treatment. LESSONS: The diagnosis of steroid myopathy is a clinical diagnosis based on characteristic symptoms. Higher dose of steroids, especially fluorinated steroids, for longer periods of time increases the risk of steroid-induced myopathy. PMID- 28834870 TI - Diagnostic value of brain natriuretic peptide and beta-endorphin plasma concentration changes in patients with acute left heart failure and atrial fibrillation. AB - RATIONALE: This study aims to evaluate the diagnostic value of beta-endorphin (beta-EP) and brain natriuretic peptid (BNP) plasma concentrations for the early diagnosis of acute left heart failure and atrial fibrillation. PATIENT CONCERNS: A total of 45 patients were included. These patients comprised 23 male and 22 female patients,and 20 healthy subjects who underwent physical examinations in the Outpatient Department during the same periodwere included and assigned to the control group. DIAGNOSES: The diagnos stand was that of the Chinese guidelines for the diagnosis and treatment of heart failure. INTERVENTIONS: Enzyme-linked immunosorbent assay was performed to detect the plasma concentration of beta-EP and BNP in the treatment and control groups, and electrocardiogram targeting was performed to determine the left ventricular ejection fraction (LVEF). OUTCOMES: BNP, beta-EP, and LVEF levels were higher in the treatment group (688.01 +/- 305.78 ng/L, 394.06 +/- 180.97 ng/L, and 70.48 +/- 16.62%) compared with the control group (33.90 +/- 8.50 ng/L, 76.87 +/- 57.21 ng/L, and 32.11 +/- 5.25%). The P-values were .015, .019, and .026, respectively, which were <.05. The difference was statistically significant. The BNP and beta-EP's 4 correlations (r = 0.895, P <.001), BNP, beta-EP, and the combination of BNP and beta-EP for acute left heart failure diagnosis in maximizing Youden index sensitivity, specific degree, area under the ROC curve (AUC), and 95% confidence interval (CI) were respectively 93.5%, 81.3%, 0.921, 0.841, 0.921; 80.5%, 78.6%, 0.697, 0.505, 0.697; 94.1%, 83.5%, 0.604 to 0.979, and 0.604. Acute left heart failure in patients with LVEF acuity plasma BNP and beta-EP 50% group was obviously lower than that in the LVEF <50% group (P <.01). BNP, beta-EP, and LVEF were negatively correlated (r = -0.741, -0.635, P = .013, .018). LESSONS: beta-EP and BNP have high specificity and sensitivity for detecting early acute left heart failure and atrial fibrillation in patients, which is convenient, easy to perform, and suitable for clinical applications. PMID- 28834871 TI - Bioinformatics analysis of gene expression profiling for identification of potential key genes among ischemic stroke. AB - This study aimed to identify the key differentially expressed genes (DEGs) following ischemic stroke (IS).The GSE22255 microarray dataset, which contains samples from peripheral blood mononuclear cells of 20 IS patients and 20 sex- and age-matched controls, was downloaded from the Gene Expression Omnibus. After data pre-processing, DEGs were identified using the Linear Models for Microarray Data package in R. The Search Tool for the Retrieval of Interacting Genes database was used to predict the interactions among the products of DEGs, and then Cytoscape software was used to visualize the protein-protein interaction (PPI) network. DEGs in the PPI network were then analyzed using the Database for Annotation, Visualization, and Integrated Discovery online software to predict their underlying functions through functional and pathway enrichment analyses.A total of 144 DEGs were identified in IS samples compared with control samples, including 75 upregulated and 69 downregulated genes. Genes with higher degrees in the PPI network included FOS (degree = 26), TP53 (degree = 22), JUN (degree = 20), EGR1 (degree = 18), JUNB (degree = 16), and ATF3 (degree = 15), and these genes may function in IS by interacting with each other (e.g., EGR1-JUN, EGR1 TP53, ATF3-FOS, and JUNB-FOS). Functional enrichment analysis indicated that the downregulated TP53 gene was enriched in immune response and protein targeting categories.ATF3 and EGR1 may have an important protective effect on IS, whereas FOS, JUN, and JUNB may be associated with the development of IS. In addition, TP53 may function as an indicator of poor prognosis for IS through its association with the immune response and protein targeting. PMID- 28834872 TI - Twenty-four-hour ambulatory blood pressure monitoring in very elderly patients: Comparison of in-hospital versus home follow-up results. AB - Elevated blood pressure (BP) is frequently diagnosed in very elderly hospitalized patients. Accurate diagnosis of hypertension is challenging in the hospital environment, due to the "white coat effect," and both overtreatment and undertreatment can adversely affect clinical outcome. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) has the potential to avoid the "white coat effect" and accurately guide the management of hypertension. However, effects of the hospital environment on ABPM are unknown in the very elderly. We set out to enroll 45 patients, age >=70 years, with elevated conventional BP during hospitalization in this observational study. It was prespecified by protocol to assess initially the difference between 24-hour BP during hospital-admission and home follow-up. Subsequent analysis should investigate the change in anxiety (Hospital Anxiety and Depression Scale-A [HADS-A]) after discharge, the correlation with change in 24-hour BP after discharge, and the prevalence of orthostatic hypertension. Thirty-one patients were included in the final analysis (age 83.5 +/- 4.4 years; 71% female). Twenty-four-hour BP decreased significantly after hospital discharge (systolic from 133.5 +/- 15.6 to 126.2 +/- 14.4 mm Hg [millimeter of mercury], P = .008; diastolic from 71.0 +/- 9.0 to 68.3 +/- 8.6 mm Hg, P = .046). Anxiety level (HADS-A) decreased significantly after discharge, from 7.5 (interquartile range [IQR]: 4.0-13.8) to 5.0 (IQR: 4.0-8.0, P = .012). The change in anxiety was a predictor of change in systolic BP after discharge (F[1,20] = 5.9, P = .025). Sixty-one percent of the patients had significant orthostatic hypotension during hospital stay. In conclusion, 24-hour BP in very elderly patients is lower in the home environment than during hospitalization. This phenomenon seems to be directly linked to a lower anxiety-level at home. Reassessing hypertension at home may decrease the need for (intensified) antihypertensive medical therapy in a substantial number of patients. This is particularly important in the very elderly, who have a high prevalence of symptomatic and asymptomatic orthostatic hypotension, making them prone to hazardous effects of antihypertensive therapy. PMID- 28834873 TI - A Bayesian network meta-analysis of whole brain radiotherapy and stereotactic radiotherapy for brain metastasis. AB - This study was conducted to compare the effects of whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRS) in treatment of brain metastasis.A systematical retrieval in PubMed and Embase databases was performed for relative literatures on the effects of WBRT and SRS in treatment of brain metastasis. A Bayesian network meta-analysis was performed by using the ADDIS software. The effect sizes included odds ratio (OR) and 95% confidence interval (CI). A random effects model was used for the pooled analysis for all the outcome measures, including 1-year distant control rate, 1-year local control rate, 1-year survival rate, and complication. The consistency was tested by using node-splitting analysis and inconsistency standard deviation. The convergence was estimated according to the Brooks-Gelman-Rubin method.A total of 12 literatures were included in this meta-analysis. WBRT + SRS showed higher 1-year distant control rate than SRS. WBRT + SRS was better for the 1-year local control rate than WBRT. SRS and WBRT + SRS had higher 1-year survival rate than the WBRT. In addition, there was no difference in complication among the three therapies.Comprehensively, WBRT + SRS might be the choice of treatment for brain metastasis. PMID- 28834874 TI - Common bile duct stones associated with pancreatobiliary reflux and disproportionate bile duct dilatation. AB - Occult pancreatobiliary reflux (PBR) in patients with a normal pancreatobiliary junction has been studied by various methods, but the exact etiology, mechanisms, and implications of this reflux have not yet been clarified. The aim of this study was to investigate the degree of PBR and patterns of biliary ductal dilatation in patients with acute calculous cholangitis by endoscopic retrograde cholangiopancreatography (ERCP).We retrospectively evaluated the degree of PBR and pattern of bile duct dilatation in patients with acute calculous cholangitis due to distal CBD (common bile duct) stones (Group A) as compared with patients with malignant CBD obstruction due to distal CBD cancer (Group B). All related data were prospectively collected. Bile juice was aspirated at the proximal CBD for measurement of biliary amylase and lipase before the injection of contrast dye. The diameters of the CBD and the peripheral intrahepatic duct (IHD) were calculated after contrast dye injection. Patients with pancreatobiliary maljunction and/or gallstone pancreatitis were excluded from the study.ERCP was performed on 33 patients with calculous cholangitis (Group A) and 12 patients with malignant CBD obstruction (Group B). Mean levels of bile amylase and lipase were significantly higher (P < .05) in group A (1387 and 6737 U/l, respectively) versus those in group B (32 and 138 U/l, respectively). Thirty patients in group A (90.9%) showed disproportionate dilatation (i.e., CBD was and IHD was not dilated), whereas only 4 patients in group B (33%) showed disproportionate dilatation.The results of this study suggest that patients with calculous cholangitis exhibit PBR that is associated with disproportionate bile duct dilatation. PMID- 28834875 TI - Histological improvement of liver fibrosis in well-treated patients with autoimmune hepatitis: A cohort study. AB - Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease that if left untreated may lead to the development of cirrhosis. Previous studies on AIH patients have suggested that fibrosis and even cirrhosis can be reversed by medical treatment. The aim of this study was to evaluate the efficacy of medical treatment for protection of developing fibrosis and cirrhosis.A total of 258 liver biopsies from 101 patients (72 women, 29 men) were analyzed by a single pathologist and classified according to the Ishak grading (inflammation) and staging (fibrosis) system. Liver histology was stratified according to the temporal changes of fibrosis stage (increased, decreased, or stable), and groups were compared.Complete or partial response to medical treatment was 94.9%. Reduction of fibrosis stage from the first to the last biopsy was seen in 63 patients (62.4%). We found an association between a reduction in the fibrosis stage and continuous glucocorticoid medication, as well as lowered scores of inflammation at last biopsy. Twenty-one patients had cirrhosis (Ishak stage 6) at least in one of the previous biopsies, but only 5 patients at the last biopsy.Histological improvement is common in AIH patients that respond to medical treatment, and a reduction or stabilization of fibrosis stage occurs in about 2/3 of such patients. PMID- 28834876 TI - Associations between body mass index and the risk of mortality from lung cancer: A dose-response PRISMA-compliant meta-analysis of prospective cohort studies. AB - BACKGROUND: Whether body mass index (BMI) is associated with the risk of mortality from lung cancer (LC) is controversial, and the shape of dose-response relationship on this topic is not well-established. Thus, a dose-response meta analysis was performed to clarify this association. METHODS: A search of PubMed and EMBASE was conducted, and 2-stage random-effect dose-response model was used to yield summary relative risks and its shape. RESULTS: Fifteen prospective cohort studies were eligible for inclusion criteria. The combined relative risks per 5 kg/m in BMI for risk of LC mortality is 0.94 (95% confidence interval] 0.92 0.96), and nonlinear association was found (Pnonlinearity < .0001), which indicated that compared with higher BMI, lower BMI showed higher LC mortality risk. Subgroup analyses revealed that this obesity paradox remained regardless of number of cases, follow-up duration, and study location, but this relationship was not observed among nonsmokers. CONCLUSION: A nonlinear association between BMI and the risk of LC mortality was found, and higher BMI participants have a lower risk of LC death than slim people. PMID- 28834877 TI - First venous thromboembolism and hormonal contraceptives in young French women. AB - Information on the clinical and biological characteristics of combined hormonal contraceptives (CHC) users experiencing a venous thromboembolism (VTE) event is scarce. Better knowledge of factors determining the VTE risk in CHC users could help identify women at high risk.Data were obtained from a large cohort of consecutive women with the first documented VTE event. Cross-sectional analysis of clinical and biological characteristics of the women was performed.Of the 3009 women with the first VTE included, 31% were nonusers and 69% CHC users at time of VTE. CHC users were significantly younger (29.0 +/- 7.2) than nonusers (31.6 +/- 7.1) (P < .001). No difference in VTE familial history was observed between the 2 groups. Compared with nonusers, the CHC users experienced more frequently pulmonary embolism: odds ratio (OR) = 1.28 (1.06-1.55; 95% confidence interval [CI]), factor V Leiden mutations were more frequent in this group (OR = 1.41 [1.11-1.80; 95% CI]). Venous sclerotherapy and travel were associated with VTE in CHC users, whereas surgery and bed rest were significantly associated with VTE in nonusers. Finally, 2/3 of CHC users with VTE had additional VTE risk factors.CHC users experiencing the first VTE differ from nonusers with respect to clinical and genetic background. Better understanding of the characteristics of VTE and associated risk factors could allow more appropriate management of these women and contribute to more accurate benefit-risk assessment before prescribing a CHC. PMID- 28834878 TI - Unburied versus buried wires for fixation of pediatric lateral condyle distal humeral fractures: A meta-analysis. AB - Open reduction and internal fixation with Kirschner (K) wires has been reported as an efficient and convenient technique for pediatric lateral condyle distal humeral fractures. However, no single study has been large enough to definitively determine whether the K-wires should be buried or unburied. Therefore, we performed a meta-analysis pooling the results from several clinical trials to compare the outcome of using buried versus unburied K-wires. Potential academic articles were identified from the Cochrane Library, Medline (1966-2017.3), PubMed (1966-2017.3), Embase (1980-2017.3), ScienceDirect (1985-2017.3), and other databases. Gray studies were identified from the references of included literature reports. RevMan 5.1 was used to analyze the pooling of data. Nonrandomized controlled trials were included in this meta-analysis. There was a significant difference in the duration of wires in situ (MD = -13.28, 95% confidence interval: -16.42 to -10.14, P < .00001). No significant differences were found regarding infection, superficial infection, total complications, delayed union, or reoperation. Unburied K-wire fixation for treatment of lateral condyle distal humeral fractures in children does not increase the total infection rate, superficial infection, reoperation rate, or complications. However, unburied K-wire fixation is of benefit for early extraction and impartial cost savings. PMID- 28834879 TI - Effect of acid-base balance on postoperative course in children with hypoplastic left heart syndrome after the modified Norwood procedure. AB - Hypoplastic left heart syndrome (HLHS) is a congenital heart defect that requires 3-stage cardiac surgical treatment and multidirectional specialist care. The condition of newborns in the first postoperative days following the modified Norwood procedure is characterized by considerable hemodynamic instability that may result in a sudden cardiac arrest. It is believed that the most important cause of hemodynamic instability is the fluctuations in redistribution between pulmonary and systemic blood flow.The paper analyzes the postoperative course in 40 neonates with HLHS following the modified Norwood procedure performed under deep hypothermic cardiopulmonary bypass hospitalized in Cardiac Surgical Intensive Care Unit (CSICU) in the years 2014-2015. For all hospitalized children, the arterial blood acid-base balance (ABB) parameters (pH, pO2, pCO2, HCO3, base excess (BE), and lactic acid) were measured 2 times a day during the first 5 postoperative days. The main goal of the studies is to analysis of ABB parameters and their influence on the clinical state of newborns with HLHS. Several descriptors were concerned to describe the neonates clinical state: the date of the surgery (the day of life when the child was operated on), the duration (number of days) of mechanical ventilation employment, the time of hospitalization in intensive care unit, and the total duration of treatment in CSICU.The statistical analysis of the particular ABB parameters revealed a significant dependence (P < .001) between the values of pH, pO2, pCO2, HCO3, BE, lactic acid, and all concerned descriptors of the newborn clinical state.The article shows that monitoring the ABB parameters, proper interpretation of the results, and appropriate modification of pharmacotherapy and respiratory treatment are crucial for therapeutic results and survival rates in neonates with HLHS after the modified Norwood procedure. PMID- 28834880 TI - Metastatic spread of solid subtype lung adenocarcinoma to the small intestine with anemia and melena: A case report. AB - RATIONALE: Metastasis to the small intestine from a primary lung cancer is rare, and is associated with a poor prognosis. Early diagnosis of small intestine metastasis is difficult because of the low incidence of clinically apparent symptoms. PATIENT CONCERNS: Clinical data and treatment of a 59-year-old man with small intestine metastasis from primary solid subtype lung adenocarcinoma are summarized. DIAGNOSES: A man who was previously diagnosed with stage IIIA (T3N2M0) lung adenocarcinoma (solid subtype) came to our hospital for postoperative radiotherapy. Laboratory tests indicated anemia and melena. The patient was initially believed to have digestive ulcer and was treated with omeprazole, which proved to be ineffective. We conducted an abdominal computed tomography (CT) contrast scan and discovered a mass in the small intestine mass. Further positron emission tomography-computed tomography (PET-CT) imaging indicated the small intestine mass with fluorodeoxyglucose uptake. INTERVENTIONS: The patient underwent an enterectomy and anastomosis. Pathological analysis confirmed the diagnosis of small intestinal metastasis from lung cancer with concomitant mesenteric lymph node metastasis. OUTCOMES: One month after the operation, hemoglobin levels became normal, and the patient had good quality of life. However, 3 months after the operation, the patient suffered from anemia again. An abdominal CT scan indicated a new small intestine mass. Progression continued rapidly, and the patient died of hemorrhagic shock 5.5 months after the resection of the small intestine mass. LESSONS: Although uncommon, if lung cancer patients present with anemia and melena, enteric metastasis should be part of the differential diagnosis. Abdominal CT scans and PET-CT are effective for early diagnosis. The prognosis of metastatic spread of solid subtype lung adenocarcinoma to the small intestine with mesenteric lymph node metastasis is poor. Subgroups of patients benefitting from metastasectomy and more effective systemic therapy need to be further investigated. PMID- 28834881 TI - Does pyogenic liver abscess increase the risk of delayed-onset primary liver cancer?: Evidence from a nationwide cohort study. AB - Delayed-onset primary liver cancer (PLC) including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in patients with pyogenic liver abscess (PLA) is not common. The relationship between PLA and delayed-onset PLC is unclear. We investigated the association in a nationwide cohort study.From Taiwan National Health Insurance claims data, a cohort of 17,531 patients with PLA was generated after excluding patients with a history of cancer (n = 2034) and those diagnosed with PLC (n = 572) and other cancers (n = 627) within 1 year of a diagnosis of PLA. An age-, sex-, index year-, and diabetes mellitus (DM)-matched control cohort of 70,124 persons without PLA was selected from the same dataset. Both cohorts were followed up until the end of 2011. The risk of PLC was estimated for both cohorts.The incidence of PLC was nearly 2-fold greater in the PLA group than in the control cohort (29.3 per 10,000 person-years vs. 16.2 per 10,000 person-years). The incidences of HCC and ICC were 1.5- (22.1 per 10,000 person-years vs. 15.0 per 10,000 person-years) and 11-fold greater (6.73 per 10,000 person-years vs. 0.62 per 10,000 person-years), respectively, in the PLA group than in the control cohort. The PLA cohort also had high risks of PLC (adjusted hazard ratio [aHR] = 1.56; 95% confidence interval [CI] = 1.35-1.81), HCC (aHR = 1.34; 95% CI = 1.15-1.57), and ICC (aHR = 6.94; 95% CI = 4.23 11.57).In conclusion, in this nationwide cohort study, PLA increased the risk of delayed-onset PLC. PMID- 28834882 TI - Retrospective observational study about reducing the false negative rate of the sentinel lymph node biopsy: Never underestimate the effect of subjective factors. AB - Reducing the false negative rate of sentinel lymph node biopsy (SLNB) for breast cancer patients has always been a focus of clinical research. We aimed to map the sentinel lymph nodes (SLNs) in detail, and analyze the factors related to SLNs located at locations that are often ignored by surgeons, to reduce the rate of false negatives from SLNB. A retrospective analysis involving 545 breast cancer patients who underwent SLNB in west China hospital between August 2010 and February 2016 was performed. Blue dye, radioisotope, or combined methods were used for tracing SLNs. Using blue dye, radioisotope, and a combination of blue dye and radioisotope successfully traced SLNs in 479, 507, and 525 patients, the detection rate was 88.2%, 93.9%, and 97.4%, respectively. Among the 1559 detected SLNs, 139 (9.6%) were located at the latissimus dorsi lateral margin, and 108 (6.9%) were located at level 2. Subcutaneous injection of radioisotope (P = .004) and intradermal injection of blue dye (P = .002) were independent factors associated with SLNs distributed at level 2 and the latissimus dorsi lateral margin, respectively. It was noteworthy that 2 of 7 patients had skipping metastasis in level 2, so subcutaneous injection of the isotope is strongly recommended for tracing SLNs distributed in level 2 because of the possibility of skipping metastasis. Though intradermal injection of blue dye was superior methods for tracing SLNs located at the latissimus dorsi lateral margin, we surprisingly found those patients with metastasis to the latissimus dorsi lateral margin nodes also could have metastasis to level 1 (expect for the latissimus dorsi lateral margin) nodes, it seemed that maybe there is no need to excise SLNs at the latissimus dorsi lateral margin in SLNB, whether such nodes should be regarded as useful for SLNB still needs to be determined by further large, multicenter clinical studies. PMID- 28834883 TI - Effect of charted mental illness on reperfusion therapy in hospitalized patients with an acute myocardial infarction in Florida. AB - Patients with mental illness carry risk factors that predispose them to excess cardiovascular mortality from an acute myocardial infarction (AMI) compared to the general population. The aim of this study was to determine if patients with AMI and charted mental illness (CMI) received less reperfusion therapy following an AMI, compared to AMI patients without CMI in a recent sample population from Florida.A secondary analysis of data was conducted using the Florida Agency for Health Care Administration (FL-AHCA) hospital discharge registry. Adults hospitalized with an AMI from 01/01/2010 to 12/31/2015 were included for the analysis. The dependent variable was administration of reperfusion therapy (thrombolytic, percutaneous coronary intervention [PCI], and coronary artery bypass graft [CABG]), and the independent variable was the presence of CMI (depression, schizophrenia, and bipolar disorder). Multivariate logistic regression models were used to test the association controlling for age, gender, ethnicity, race, health insurance, and comorbidities.The database included 61,614 adults (31.3% women) hospitalized with AMI in Florida. The CMI population comprised of 1036 patients (1.7%) who were on average 5 years younger than non CMI (60.2 +/-12.8 versus 65.2 +/-14.1; P < .001). Compared with patients without CMI, patients with CMI had higher proportions of women, governmental health insurance holders, and those with more comorbidities. The adjusted odds ratio indicated that patients with CMI were 30% less likely to receive reperfusion therapy compared with those without CMI (OR = 0.7; 95% CI = 0.6-0.8). Within the AMI population including those with and without CMI, women were 23% less likely to receive therapy than men; blacks were 26% less likely to receive reperfusion therapy than whites; and those holding government health insurances were between 20% and 40% less likely to receive reperfusion therapy than those with private health insurance.Patients with AMI and CMI were statistically significantly less likely to receive reperfusion therapy compared with patients without CMI. These findings highlight the need to implement AMI management care aimed to reduce disparities among medically vulnerable patients (those with CMI, women, blacks, and those with governmental health insurance). PMID- 28834884 TI - Impact of personality and social support on posttraumatic stress disorder after traffic accidents. AB - This study aims to investigate the relationships of personality and social support with posttraumatic stress disorder (PTSD) after traffic accidents.The 90 Symptom Checklist (SCL-90) and Eysenck Personality Questionnaire (EPQ) were completed 1 week after trauma. The Checklist-Civilian Version (PCL-C) was surveyed 3 months after discharge.PCL-C score of 38 was used as cutoff point. The older age and lower education significantly increased the PTSD incidence. SCL-90 score was positively correlated with PTSD symptom score. The psychoticism (P) (0.230) and neuroticism (N) (0.302) was positively correlated with PTSD symptom score in a linear relationship. Objective support, subjective support, exploitation degree, and social support were negatively associated with PTSD scores. Force symptoms, psychoticism, subjective support, introversion, and extroversion could explain 65.0% of degree of variation for PTSD with the estimated standard error of 4.758.PTSD associated social factors include force symptoms, psychoticism, subjective support, introversion, and extroversion. PMID- 28834885 TI - Morphological analysis of interbody fusion following posterior lumbar interbody fusion with cages using computed tomography. AB - Posterior lumbar interbody fusion (PLIF) using cages in conjunction with pedicle screw fixation is considered the gold standard for surgical treatment of degenerative lumbar spine disorders due to its biomechanical stability and high fusion rate. However, research regarding patterns of fusion in the interbody space during the early postoperative period is lacking.Sixty consecutive patients were recruited from May 2013 to June 2015. All patients underwent PLIF using 2 titanium cages filled with local bone chips from decompressed lamina and facet bone in conjunction with pedicle screw fixation. Computed tomography scans were obtained 3 to 6 months following surgery in order to evaluate the partial fusion state. Computed tomography (CT) classification of fusion morphology was divided into 8 groups and then into compartments according to fusion space, and the rate of fusion for each was calculated. Further follow-up was conducted to confirm fusion state and assess outcomes.The most frequent pattern of interbody fusion was bilateral intra-cage fusion with unilateral lateral bridging of extra-cage areas (N = 36, 43.4%); the least frequent was interspace bridging of the 2 cages alone (N = 0, 0%). The fusion rate for the intra-cage area (Compartment 1) reached 100%. However, the fusion in the lateral space outside of cages (Compartment 2) was not satisfactory, though reasonable (72.3%). All patients were confirmed as achieving adequate fusion at the final follow-up, with improved clinical outcomes.Widening of the contact area between the vertebral body and cages is recommended to promote increased interbody fusion during the early postoperative period. PMID- 28834886 TI - Therapeutic efficacy and safety of laparoscopic surgery versus microsurgery for varicocele of adult males: A meta-analysis. AB - OBJECTIVES: This study aimed to systemically evaluate the efficacy and safety of laparoscopy versus microsurgery in the surgical therapy of varicocele in male adults. METHODS: Relevant literature, published between January 1995 and October 2012, were searched in Pubmed/Medline database, OVID, EMBASE, Chinese Biology Medicine disc (CBMdisc), CNKI, CEBM?CCD, and Cochrane database. The newly published papers were also manually searched. Randomized controlled trials (RCT) related to the surgical interventions of varicocele were included, and full texts were obtained. Each study was evaluated with the Cochrane Risk of Bias tool. Two investigators collected data independently to produce the meta-analysis. RESULTS: Five RCTs met the inclusion criteria and included 554 patients. Data were merged by the RevMan5.1 software. The sperm concentration increased significantly after surgery (WMD = 4.28; 95% CI = 4.16, 6.99; P < .00001, Z = 7.72). There was no significant difference in the postoperative hospital stay between laparoscopy and microsurgery (WMD = 0.24, 95% CI = 0.44, 0.93; P = .49, Z = 0.69). The operation time of laparoscopy was significantly shorter than that of microsurgery (WMD = 40.31, 95% CI = 37.77, 42.86; P < .00001, Z = 31.03). The incidence of hydrocele reduced significantly after microsurgery as compared to laparoscopy (WMD = 0.05, 95% CI = 0.01, 0.27; P = .0005, Z = 3.49). The postoperative recurrence rate after microsurgery was significantly lower than that after laparoscopy (WMD = 0.10, 95% CI = 0.04, 0.25; P < .00001, Z = 5.01). CONCLUSION: No significant differences were found between microsurgery and laparoscopy for the increase of sperm concentration and operation time. Compared to the laparoscopy group, the microsurgery group had lower postoperative incidence of hydrocele and recurrence rate, but longer in the operation time. PMID- 28834887 TI - C-reactive protein and risk of ovarian cancer: A systematic review and meta analysis. AB - BACKGROUND: Although several studies have suggested an association between elevated C-reactive protein (CRP) and ovarian cancer risk, others have yielded contradictory results. To address this issue, we conducted a meta-analysis. METHODS: Studies were identified by searching PubMed and EMBASE up to July 2017 without language restrictions. Six case-control studies and 1 cohort study were included, including 1898 ovarian cancer cases. Pooled risk estimates were generated by using the fixed-effect model or the random-effect model based on the heterogeneity between studies. RESULTS: As our data shown, the combined ORs were 1.04 (95%CI: 0.90-1.21) and 1.34 (95% CI: 1.06-1.70) for the risk in the second and third tertiles of CRP with those in the bottom tertile, respectively. Subgroup analysis showed that with respect to the top tertile of CRP level, the association was significant for studies obtaining CRP from serum (OR=1.99; 95% CI: 1.30-3.07), conducted in the USA (OR = 1.41; 95% CI: 1.15-1.72), using high sensitivity immunotubidimetric assay (OR = 1.37; 95% CI: 1.14-1.64), using Hs-CRP (OR = 1.46; 95% CI: 1.21-1.75) and with follow-up period longer than 10 years (OR = 1.41; 95% CI: 1.18-1.70). CONCLUSION: Collectively, our findings propose that serum CRP levels may serve as an indicator of ovarian cancer risk. Further studies are needed to definitively identify the role of CRP in the etiology of ovarian cancer. PMID- 28834888 TI - Trend analysis of end-of-life care between hospice and nonhospice groups of cancer patients in Taiwan for 2002-11. AB - The aim of the study is to examine the effect of hospice care on quality of end of-life (EOL) care for patients with advanced cancer in Taiwan between 2002 and 2011.It is a population-based longitudinal study following National Health Insurance medical care claims of hospice and nonhospice patients with advanced cancer in their last month of life.Utilization of hospice service doubled from 10.5% to 21.5% over the study period. Of 12,682 patients identified as having advanced cancer, 7975 (62.88%) were found to have 1 or more quality indicators (QIs) of poor EOL cancer care. After adjustments, those receiving hospice cares had a significant reduction in incidence of chemotherapy in the last 14 days of life as well as intensive care unit (ICU) admission and cardiopulmonary resuscitation (CPR) in the last month of life. The hospice care group also had significant increases in having more than 1 hospitalization and dying under hospital care, but no change in having more than 1 emergency room (ER) visit. The hospice group curve of estimated incidence rates of each QI was consistently below that of the nonhospice group in chemotherapy-with the difference between the 2 curves increasing over time-ICU admission, and CPR, and above that of the nonhospice group for dying in a hospital and having more than 1 hospitalization over the study period. The 2 groups overlapped on ER visits. Overall, hospice care was associated with less chance to have 1 or more QIs of EOL care for advanced cancer patients (RR = 0.56, 95% CI: 0.52-0.60, P < .001).The utilization of hospice services doubled over the 10-year study period. Hospice care was associated with better EOL care in patients with advanced cancer. PMID- 28834889 TI - The association between peptic ulcer diseases and mental health problems: A population-based study: a STROBE compliant article. AB - This study aimed to investigate the association between the prevalence of peptic ulcer disease (PUD) and mental health problems, such as severe stress, depressive mood, and suicidal ideation.The population-based cross-sectional study was comprised of 14,266 subjects participating in the fourth annual Korea National Health and Nutrition Examination survey from 2007 to 2009. The participants were divided into 2 groups according to the self-reported questionnaires: the PUD group and the non-PUD group. The association between PUD and mental health problems, such as severe stress, depressed mood, suicidal ideation, and psychological counseling history, were evaluated by using multivariate analysis and logistic regression.Among the 14,266 participants over 19-years old, 813 participants (5.6%) had PUD. Compared to the non-PUD group (n = 13,453), the PUD group had a significantly higher percentage of males, current smokers, and heavy drinkers, lower education status, lower income, and greater presence of diabetes mellitus, hypertension, metabolic syndrome and mental health problems, including severe stress, depressed mood, suicidal ideation, and psychological counseling history. After adjustment for lifestyle and medical and environmental factors, mental health problems were found to be associated with a significantly higher risk for PUD.Psychological problems, such as severe stress, depressed mood, suicidal ideation, and psychological counseling, were associated with PUD prevalence. PMID- 28834890 TI - Therapeutic effect of enterprise stent-assisted embolization for very small ruptured intracranial aneurysms. AB - Enterprise stent has been widespread used in wide-necked intracranial aneurysms and good efficacy has been achieved, but there are few reports on its applications in very small ruptured intracranial aneurysms in literatures. This study aimed to evaluate the safety and efficacy of Enterprise stent-assisted coiling embolization of very small ruptured intracranial aneurysms.We retrospectively reviewed the clinical and imaging data from 37 patients with very small ruptured intracranial aneurysms who had SAC using Enterprise stents performed from February 2012 to July 2016 in our department. Data collected and analyzed included patient demographics, morphologic features of the aneurysm, treatment results, and follow-up results. Clinical outcomes were evaluated by the Glasgow Outcome Scale (GOS).Enterprise stents were successfully implanted in all 37 patients with very small ruptured intracranial aneurysms. Of the 37 individuals, 28 patients exhibited complete occlusion at Raymond grade I, 5 patients exhibited occlusion at Raymond grade II, and 4 patients at Raymond grade III. Procedure-related complications occurred in 3 of 37 patients (8.1%), including 1 case of intraprocedure aneurysm rupture who died from cerebral herniation caused by severe postoperative cerebral ischemia during the hospital stay, and the other 2 complications were acute in-stent thrombosis, and occlusion of parent artery caused by falling-off internal carotid artery plaque, respectively. A total of 36 patients underwent postoperative clinical follow-up visits for 6 to 24 months of which 31 patients recovered (GOS >= 4). One patient had hemiplegic paralysis, and no rehemorrhage was found. A total of 25 patients underwent follow-up digital subtraction angiography (DSA) at 3-21 months postintervention, in whom there were 22 cases with complete occlusion, 2 cases with recurrence of aneurysm neck, and 1 case with in-stent restenosis, but there was no patient with neurologic deficits.The Enterprise stent-assisted coiling embolization can be a safe and effective technique for treatment of very small ruptured intracranial aneurysms. PMID- 28834891 TI - Interdisciplinary rehabilitation for a patient with incomplete cervical spinal cord injury and multimorbidity: A case report. AB - RATIONALE: This report describes interdisciplinary rehabilitation for a 51-year old male recovering from incomplete cervical spinal cord injury (SCI) and multiple comorbidities following an automobile accident. PATIENT CONCERNS: The patient was admitted to a rehabilitation specialty hospital approximately 2 months post SCI and 2 separate surgical fusion procedures (C3-C6). DIAGNOSES: Clinical presentation at the rehabilitation hospital included moderate to severe motor strength loss in both upper and lower extremities, a percutaneous endoscopic gastronomy tube (PEG), dysphagia, bowel/bladder incontinence, dependence on a mechanical lift and tilting wheelchair due to severe orthostatic hypotension, and pre-existing shoulder pain from bilateral joint degeneration. INTERVENTIONS: The interdisciplinary team formally coordinated rehabilitative care from multiple disciplines. Internal medicine managed medications, determined PEG removal, monitored co-morbid conditions, and overall progress. Chiropractic care focused on alleviating shoulder and thoracic pain and improving spinal and extremity mobility. Physical therapy addressed upright tolerance, transfer, gait, and strength training. Occupational therapy focused on hand coordination and feeding/dressing activities. Psychology assisted with coping strategies. Nursing ensured medication adherence, nutrient intake, wound prevention, and incontinence management, whereas physiatry addressed abnormal muscle tone. OUTCOMES: Eleven months post-admission the patient's progress allowed discharge to a long-term care facility. At this time he was without dysphagia or need for a PEG. Orthostatic hypotension and bilateral shoulder pain symptoms were also resolved while bowel/bladder incontinence and upper and lower extremity motor strength loss remained. He was largely independent in transferring from bed to wheelchair and in upper body dressing. Lower body dressing/bathing required maximal assistance. Gait with a 2-wheeled walker was possible up to 150 feet with verbal cues and occasional stabilizing assistance. LESSONS: Several specialties functioning within an interdisciplinary team fulfilled complementary roles to support rehabilitation for a patient with SCI. PMID- 28834892 TI - The association between Staphylococcus aureus nasal colonization and symptomatic infection in children in Korea where ST72 is the major genotype: A prospective observational study. AB - This study was performed to investigate the concordance in terms of molecular characteristics and antimicrobial susceptibility between colonizing and clinical Staphylococcus aureus isolates obtained from children in Korea, where ST72 is the major genotype.This was a prospective observational descriptive study of culture confirmed S aureus infections obtained from children <=18 years old admitted to Asan Medical Center Children's Hospital in Seoul, Korea, from March 2014 to April 2015. Molecular studies including multilocus sequence typing (MLST), SCCmec typing, polymerase chain reaction amplification of the Panton-Valentine leukocidin (PVL) genes, and antibiotic susceptibility tests were performed on S aureus isolates obtained from nares and clinical specimens.During the study period, 126 clinically significant S aureus infections were identified. Nasal swab cultures were made from 113 of the 126 children, and 46.0% (52/113) showed S aureus colonization. The overall concordance between colonizing and clinical isolates by methicillin susceptibility was 94.2% (49/52); all 3 discordant cases were HA-MSSA cases with nasal MRSA. Among the 37 pairs of colonizing and clinical S aureus isolates included in the genotyping analysis, ST72-SCCmec type IV was the most prevalent clone and the PVL genes were positive in 2 patients. Among the 31 pairs of healthcare-associated cases, concordance rates by methicillin susceptibility and sequence type (ST) were 90.3% (28/31) and 84% (26/31), respectively. For the 6 pairs of community-associated (CA) S aureus including 3 CA-MRSA cases, 100% concordance was observed by methicillin susceptibility and ST.The concordance between isolates obtained from children who required medical services was relatively high in Korean children where ST72-SCCmec type IV is the predominant clone as the colonizer and the pathogen. It is suggested that decolonization and continuous care to prevent transmission could be effective in managing and preventing both HA- and CA-SA infections in our setting. PMID- 28834893 TI - Does the choice of tariff matter?: A comparison of EQ-5D-5L utility scores using Chinese, UK, and Japanese tariffs on patients with psoriasis vulgaris in Central South China. AB - There is an increasing trend globally to develop country-specific tariffs that can theoretically better reflect population's preferences on health states for preference-based health-related quality-of-life instruments, also known as multiattribute utility instruments. This study focused on the most recently developed 5-level version of EuroQol-5 Dimension (EQ-5D) questionnaire, 1 of the world's most well-known multiattribute utility instruments, and aimed to empirically explore the agreements and known-group validities of applying the country-specific tariff versus tariffs developed from other countries using a sample of psoriasis vulgaris patients in Mainland China.A convenience sampling framework was adopted to recruit patients diagnosed with psoriasis vulgaris from Xiangya Hospital, Central South University, China, between May 2014 and February 2015. The 5-level EuroQol-5 dimensions (EQ-5D-5L) utilities were scored by using the Chinese, Japanese, and UK tariffs. Health state utilities were compared using a range of nonparametric test. The intraclass correlation coefficients and Bland Altman plots were used to examine the agreements among the 3 EQ-5D-5L scores. Health state utility decrements between known groups were investigated using both effect size and a regression analysis.In all, 350 patients (aged 16 years or older) were recruited. There were significant differences among the 3 national tariff sets. Overall, 3 tariffs showed excellent agreements (intraclass correlation coefficient >0.90); however, the wide limits of agreement from the Bland-Altman plots suggest that these tariffs cannot be used interchangeably. The EQ-5D-5L scores using the Chinese-specific tariff showed the best known-group validity than the other 2 tariffs in this Chinese patient sample. The evidence from this study supports the choice of the country-specific tariff to be used in Mainland China. PMID- 28834894 TI - Value of radial probe endobronchial ultrasound-guided transbronchial biopsy and computer tomography-guided transthoracic needle aspiration in the diagnosis of peripheral pulmonary lesions. AB - Computer tomography-guided transthoracic needle aspiration (CT-TTNA) is a minimally invasive technique for sampling peripheral lung lesions. Radial endobronchial ultrasound-guided transbronchial biopsy (rEBUS-TBB) is an alternative. The present study analyzed and compared rEBUS-TBB and CT-TTNA in the diagnosis of peripheral pulmonary lesions (PPL).Clinical data of 513 patients with PPL who underwent an rEBUS-TBB or CT-TTNA examination were analyzed retrospectively. The positive diagnostic rate, complication rate, and influencing factors of the 2 methods were compared.The positive diagnostic rate and complication rate were significantly higher in CT-TTNA than rEBUS-TBB (P = .001; P < .001, respectively). The rEBUS-TBB group showed a higher positive diagnostic rate in larger lesions (>2 cm) than in smaller (<=2 cm) (P = .012), and was lower in the lesions proximal to the chest wall than those distally located (P = .046); no significant difference was observed in the different pulmonary segments (P = .109). In the CT-TTNA group, the positive diagnostic rate in larger lesions did not differ significantly than the smaller lesions (P = .05); it differed significantly in different segments (P = .044). The incidence of pneumothorax was lower in lesions proximal to the chest wall than those located distally (P = .037). In the rEBUS-TBB group, the success rate of the exploration and biopsy of the lesions was 87.4%; the rate of exploration of larger lesions and with bronchial sign was higher than smaller lesions and without bronchial sign (P < .001; P < .001, respectively) while that of lesions close to the chest wall was lower than those distally located (P = .006).rEBUS-TBB and CT-TTNA are effective and safe in the diagnosis of PPL. The positive diagnostic rate of CT-TTNA is higher than rEBUS-TBB. The incidence of pneumothorax in CT-TTNA is higher than rEBUS-TBB. CT-TTNA is selected for smaller lesions close to the chest wall; rEBUS TBB is used for lesions larger, distal from the chest wall or with a bronchial sign. PMID- 28834895 TI - Pseudo-spontaneous nystagmus in horizontal semicircular canal canalolithiasis. AB - Benign paroxysmal positional vertigo (BPPV) involving horizontal semicircular canal (HSCC) is characterized by direction-changing positional nystagmus (DCPN) in a supine roll test, and the occurrence of spontaneous nystagmus in HSCC BPPV has been reported recently. The aim of this study is to investigate the characteristics of pseudo-spontaneous nystagmus (PSN) in patients with HSCC canalolithiasis, and evaluate the effect of the presence of PSN on treatment outcome.Between April 2014 and January 2016, 75 and 59 patients with HSCC canalolithiasis and cupulolithiasis, respectively, were enrolled. Spontaneous and positional nystagmus were examined.PSN was observed in 31 of 75 patients (41%) with HSCC canalolithiasis, and 55 of 59 patients (93%) with HSCC cupulolithiasis. PSN persisted during the period of observation, which was at least 1 minute in all patients with PSN. In HSCC canalolithiasis, direction-reversing nystagmus was observed in 58 patients (25 bilateral and 33 unilateral). Nine of 25 patients with bilateral direction-reversing nystagmus, and 22 of 33 patients with unilateral direction-reversing nystagmus showed PSN. None of 17 patients without direction-reversing nystagmus showed PSN. The direction of PSN corresponded to that of direction-reversing nystagmus in all 22 patients with unilateral direction-reversing nystagmus. The proportion of patients who recovered after 1 session of repositioning maneuver was not significantly different between patients with and without PSN (P = .867).PSN was observed more commonly in HSCC cupulolithiasis than canalolithiasis. The pathophysiologic mechanism underlying PSN can be explained by natural inclination of HSCC and medial to lateral orientation of the HSCC cupular axis in cupulolithiasis, and by spontaneous reversal of initial positional nystagmus (direction-reversing nystagmus) generated by short-term adaptation of vestibulo-ocular reflex in canalolithiasis. The presence of PSN in HSCC canalolithiasis may not affect the treatment outcome. PMID- 28834897 TI - Protection of xenon against postoperative oxygen impairment in adults undergoing Stanford Type-A acute aortic dissection surgery: Study protocol for a prospective, randomized controlled clinical trial. AB - OBJECTIVES: The available evidence shows that hypoxemia after Stanford Type-A acute aortic dissection (AAD) surgery is a frequent cause of several adverse consequences. The pathogenesis of postoperative hypoxemia after AAD surgery is complex, and ischemia/reperfusion and inflammation are likely to be underlying risk factors. Xenon, recognized as an ideal anesthetic and anti-inflammatory treatment, might be a possible treatment for these adverse effects. METHODS/DESIGN: The trial is a prospective, double-blind, 4-group, parallel, randomized controlled, a signal-center clinical trial. We will recruit 160 adult patients undergoing Stanford type-A AAD surgery. Patients will be allocated a study number and will be randomized on a 1:1:1:1 basis to receive 1 of the 3 treatment options (pulmonary inflated with 50% xenon, 75% xenon, or 100% xenon) or no treatment (control group, pulmonary inflated with 50% nitrogen). The aims of this study are to clarify the lung protection capability of xenon and its possible mechanisms in patients undergoing the Stanford type-A AAD surgery. DISCUSSION: This trial uses an innovative design to account for the xenon effects of postoperative oxygen impairment, and it also delineates the mechanism for any benefit from xenon. The investigational xenon group is considered a treatment intervention, as it includes 3 groups of pulmonary static inflation with 50%, 75%, and 100% xenon. It is suggested that future trials might define an appropriate concentration of xenon for the best practice intervention. PMID- 28834896 TI - Vasectomy and cardiovascular disease risk: A systematic review and meta-analysis. AB - BACKGROUND: Even though several studies comparing vasectomy and cardiovascular disease (CVD) risk have been reported, most are small series with conflicting results. However, the extent of the risk is still uncertain. We therefore explored whether an association exists between vasectomy and CVD incidence and mortality. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library databases for relevant studies published before January 2017. Multivariate adjusted odds ratio (OR) and associated 95% confidence intervals (CIs) and those by subgroups were extracted and pooled using random-effects models. RESULTS: Overall, 12 observational studies (2 cross-sectional studies, 4 case-control studies, and 6 retrospective cohort studies) comprising 299,436 participants were identified. There was no statistically significant relationship between vasectomy and CVD risk (OR: 0.90, 95% CI: 0.81-1.00). Moreover, vasectomy was not associated with CVD mortality (OR: 0.90, 95% CI: 0.81-1.00), coronary heart disease (CHD) incidence (OR: 0.94, 95% CI: 0.88-1.01), stroke incidence (OR: 0.90, 95% CI: 0.72-1.13), and myocardial infarction (MI) incidence (OR: 0.95, 95% CI: 0.88-1.02), with no significant publication bias. In subgroup analyses, the findings on the association between vasectomy and CVD risk were consistent. CONCLUSION: Our findings suggest that vasectomy is not associated with the excess risk of CVD incidence and mortality. Nevertheless, large-volume, well-designed observational studies, with different ethnic populations, low risk of bias, and adjusted confounding factors, are awaited to confirm and update the findings of this analysis. PMID- 28834898 TI - Long-term follow-up of secondary amyloidosis patients treated with tumor necrosis factor inhibitor therapy: A STROBE-compliant observational study. AB - There are no treatment modalities, which were proven to prevent the deposition of amyloid, proteinuria, and loss of renal function due to amyloidosis. Anti-tumor necrosis factor agents (anti-TNFs) were shown to decrease the production of serum amyloid A protein.We aimed to evaluate the long-term efficacy and safety of anti TNFs in secondary (AA) amyloidosis patients treated in a single center.Thirty seven patients with AA amyloidosis were started an anti-TNF for AA amyloidosis between March 2001 and June 2008 and followed until May 2016 unless deceased. They were surveyed for the endpoints of death, development of end-stage renal disease (ESRD), switch to another agent due to worsening of amyloidosis and adverse events.Among the 37 patients, 12 (32%) had died, 9 (24%) had ESRD, and 8 (22%) had started another group of biologic due to worsening of amyloidosis indicated by an increase in proteinuria, 5 (14%) patients are still doing well with anti-TNFs, and 3 (8%) are off treatment at the end of a median follow-up of 10 (interquartile range [IQR]: 5.5-10.5) years since the start of anti-TNFs and 10 (IQR: 8-13) years since the diagnosis of AA amyloidosis. Most common serious adverse events were sepsis and thrombotic events observed in 8 and 4 patients, respectively.Treatment with anti-TNFs may be associated with a higher survival rate compared with historic cohorts of AA amyloidosis, especially when started early with a lower serum creatinine level at baseline. Caution is needed regarding serious adverse events, especially infections. PMID- 28834899 TI - Predicting the risk of postoperative liver failure and overall survival using liver and spleen stiffness measurements in patients with hepatocellular carcinoma. AB - Postoperative liver failure (PLF) is the primary cause of morbidity and mortality after hepatic resection for hepatocellular carcinoma (HCC). In this study, we evaluated the efficacy of liver stiffness (LS) and spleen stiffness (SS), as measured by transient elastography (TE), for predicting the risk of PLF and overall survival (OS) in these patients.This prospective cohort study included 54 patients diagnosed with HCC who underwent hepatic resection between March 2013 and March 2014. Preoperative measurement of LS and SS using TE was performed on all patients underwent. The predictivity of LS and SS for PLF was assessed by receiver operating characteristic curve analysis. OS according to LS and SS was analyzed using the Kaplan-Meier method and compared using the log-rank test.PLF developed in seven (12.96%) patients. LS was significantly higher in patients with than in those without PLF (P = .03). The area under the curve of LS for predicting PLF was 0.76 (95% confidence interval, 0.62-0.86; P = .02). However, there was no significant difference in SS between patients with and without PLF (P = .36). Moreover, patients with an LS <16.2 kPa had significantly better OS than those with an LS >=16.2 kPa (P = .028). No significant difference in OS was observed between patients with an SS of <22.3 and >=22.3 kPa (P = .378).LS measured by TE can be used to predict the risk of PLF as well as OS in patients with HCC who have undergone hepatic resection. However, SS obtained using TE was not found to be a significant predictor for PLF and OS in our patients. PMID- 28834900 TI - Composite hepatocellular carcinoma and small cell carcinoma with early nodal metastasis: A case report. AB - RATIONALE: Hepatocellular carcinoma (HCC) is known to grow in a mosaic pattern, and it can sometimes be combined with non-hepatocellular cells. Despites the variety of combination, HCC with a significant neuroendocrine carcinoma (NEC) component remains very rare. Most of the reported cases were treated as conventional HCC with a relatively poor prognosis. Early diagnosis may lead to a better treatment modality. Here, we report a case of composite HCC and small cell carcinoma (SCC) with nodal metastasis of the SCC component alone. PATIENT CONCERNS: A 65-year-old man with chronic viral hepatitis C presented with abdominal discomfort for 2 months. Computed tomography and angiography of the liver showed a 4.3 cm hypervascular tumor in segment 4 and enlargement of the perihilar and paracaval lymph nodes. INTERVENTIONS: Extended left lobectomy and regional lymph node dissection were performed. DIAGNOSIS: The hepatic tumor was heterogeneous with two distinct gross components. The green part showed a grade III hepatocellular carcinoma with an immunoreaction to Hep Par 1, glypican 3 and alpha-fetoprotein, whereas the white part exhibited a small cell carcinoma, as evidenced by expressions of chromogranin A and synaptophysin. The lymph node was metastasized by the SCC component. The SCC part was also positive for vimentin with perivascular accentuation. beta-catenin immunostain showed reduced membranous expression in the SCC component, as compared to HCC. OUTCOMES: The patient expired 39 days after the surgical intervention. LESSONS: Clinicians should be highly alert to a composite hepatic tumor, especially in dealing with a small heterogeneous tumor (< 5 cm) with early lymph node metastasis. PMID- 28834901 TI - Outcomes of 23-gauge pars plana vitrectomy combined with phacoemulsification and capsulotomy without intraocular lens implantation in rhegmatogenous retinal detachment associated with choroidal detachment. AB - Rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) is a special type of complex retinal detachment, and usually has a poor prognosis. This study aimed to assess the anatomical outcomes of 23-gauge pars plana vitrectomy (23G PPV) combined with phacoemulsification (phaco) and capsulotomy without intraocular lens (IOL) implantation in patients with RRDCD.Seventy-six consecutive patients with RRDCD, who underwent retinal repair surgery from January 2010 to December 2014, were retrospectively analyzed. Forty patients underwent 23G PPV + phaco + IOL implantation, and 36 underwent 23G PPV + phaco + capsulotomy without IOL implantation (i.e., aphakia). All cases were filled with silicone oil. The follow-up time was 6 months after silicone oil was removed. Multivariate logistic regression analysis was the statistical method used.The overall retinal anatomical reattachment rate was 58% (44/76): 40% (16/40) of patients receiving 23G PPV + phaco + IOL implantation; and 78% (28/36) of patients receiving 23G PPV + phaco + capsulotomy + aphakia (P = .007).Surgical repair using 23G PPV + phaco + capsulotomy without IOL implantation can improve anatomical reattachment rates in patients with RRDCD. PMID- 28834902 TI - Cushing's syndrome secondary to typical pulmonary carcinoid with mutation in BCOR gene: A case report. AB - RATIONALE: Typical pulmonary carcinoid is a kind of low-grade malignancy neuroendocrine tumor. Cushing's syndrome is a very rare clinical feature of typical pulmonary carcinoid caused by hypercorticism. Complete tumor resection is the standard curative treatment for primary typical pulmonary carcinoid. However, our knowledge on the gene level of typical pulmonary carcinoid is limited. PATIENT CONCERNS: A 42-year-old man was admitted to our hospital for progressive weight gain within one year. No other obvious symptoms were obsessed in this patient. He was clinical diagnosed with ectopic adrenocorticotropic hormone syndrome through hormonal tests and imaging exams. Positron emission tomography computed tomography detected a pulmonary nodule localized in the middle lobe of the lung and it is thought to be the ectopic source. INTERVENTION: This patient received a pulmonary wedge resection. After the surgery, a genetic sequencing was performed and it reported a mutation (S1240Cfs*21) in the BCOR gene. DIAGNOSIS: Postoperative pathology confirmed the diagnosis of ACTH-producing typical pulmonary carcinoid. OUTCOMES: The patient had a smooth postoperative course and no recurrence of the tumor was found for 3 years. LESSONS: Mutation in BCOR gene is quite common in pulmonary neuroendocrine tumor and it has been proven to play a role in the development of some tumor. We herein first report BCOR gene mutation in Cushing's syndrome secondary to TPC and it may become a promising therapeutic target in the future. PMID- 28834903 TI - The cost-saving effect and prevention of medication errors by clinical pharmacist intervention in a nephrology unit. AB - Medication errors may lead to adverse drug events (ADEs), which endangers patient safety and increases healthcare-related costs. The on-ward deployment of clinical pharmacists has been shown to reduce preventable ADEs, and save costs. The purpose of this study was to evaluate the ADEs prevention and cost-saving effects by clinical pharmacist deployment in a nephrology ward.This was a retrospective study, which compared the number of pharmacist interventions 1 year before and after a clinical pharmacist was deployed in a nephrology ward. The clinical pharmacist attended ward rounds, reviewed and revised all medication orders, and gave active recommendations of medication use. For intervention analysis, the numbers and types of the pharmacist's interventions in medication orders and the active recommendations were compared. For cost analysis, both estimated cost saving and avoidance were calculated and compared.The total numbers of pharmacist interventions in medication orders were 824 in 2012 (preintervention), and 1977 in 2013 (postintervention). The numbers of active recommendation were 40 in 2012, and 253 in 2013. The estimated cost savings in 2012 and 2013 were NT$52,072 and NT$144,138, respectively. The estimated cost avoidances of preventable ADEs in 2012 and 2013 were NT$3,383,700 and NT$7,342,200, respectively. The benefit/cost ratio increased from 4.29 to 9.36, and average admission days decreased by 2 days after the on-ward deployment of a clinical pharmacist.The number of pharmacist's interventions increased dramatically after her on-ward deployment. This service could reduce medication errors, preventable ADEs, and costs of both medications and potential ADEs. PMID- 28834904 TI - Current treatment status and barriers for patients with chronic HCV infection in mainland China: A national multicenter cross-sectional survey in 56 hospitals. AB - Chronic hepatitis C virus (HCV) infection is a serious public health problem worldwide. China, as the country with the largest number of HCV infections in the world, plays a significant role in eliminating hepatitis C. Due to different financial situations and education background, hepatitis C patients take different actions for their disease treatment and management. Therefore, antiviral treatment status should be attached great importance to learn the medical demand of patients. A nationwide, multicenter survey was conducted from July 2015 to June 2016. Of 1798 inpatients and outpatients with chronic HCV from 56 hospitals participated in the survey. Each patient completed the questionnaire with questions about his/her antiviral therapy status, perception of treatment barriers, and expectations for future treatment. In total 1622 patients, including 1241 with chronic hepatitis C, 344 with cirrhosis, and 37 patients with hepatocellular carcinoma, fulfilled data collection requirements and finally were included in analysis. Overall, up to 30.7% of the patients had not or currently does not intend to receive antiviral therapy. The main reason was expecting more potent and well-tolerance medication (31.5%), followed by the fear of interferon related side effects (27.5%). Multiple regression analysis showed that the patient's annual income, the severity of HCV, and comorbidity were independent predictors of not receiving antiviral therapy. The whole patients were expecting more potent and well tolerance medication available soon. In summary, Peg-IFN/RBV treatment regimen cannot meet the need of patients well, and safe and efficient direct-acting antivirals are urgently needed in mainland China. PMID- 28834905 TI - Modified staging classification for intrahepatic cholangiocarcinoma based on the sixth and seventh editions of the AJCC/UICC TNM staging systems. AB - Intrahepatic cholangiocarcinoma (ICC) was differentiated from hepatocellular carcinoma, as defined in the American Joint Committee on Cancer (AJCC) 6th edition staging manual, using the revised staging system described in the AJCC 7th edition staging manual. This study was conducted to analyze the application of the AJCC 6th and 7th edition staging classifications and to evaluate a modified staging classification to potentially reduce the limitations associated with the different AJCC staging systems.We compared the prognostic value of cancer staging using data from the Surveillance, Epidemiology, and End Results database (N = 2124). The Kaplan-Meier method and Cox regression models were used to analyze survival. The Harrell concordance index (C-index) was used to analyze the discriminative abilities of cancer staging.Patients with stages I and II disease were found to have similar prognoses according to the 6th edition staging system. Using the 7th edition staging system, a low proportion of patients had stage III disease (5.0%), and the hazard ratio (HR) for stage III disease was comparable to that of stage IV disease (stage III and IV, 2.653 and 2.694). We modified the AJCC staging classification by adopting the 7th edition T, N, and M definitions and the 6th edition staging definitions. Consequently, the proportion of patients with stage III disease increased (22.8%). The HR for stage IV disease was higher than that for stage III disease (stage III and IV, 2.425 and 2.956). Meanwhile, the C-index of the modified AJCC staging system was 0.721 (95% CI: 0.696-0.745), which was significantly higher than the AJCC 7th edition staging system (0.694, P < .001), and the AJCC 6th edition staging system (0.712, P = .033). Moreover, in the stratified data, the differences between the stages identified using the modified AJCC staging classification were significant, especially among patients over 60 years in age, white patients and patients who underwent surgery.These findings suggest that the modified AJCC staging classification may be applicable to the staging of ICC and can be adopted in clinical practice. PMID- 28834906 TI - Comparing the efficacy of short-segment pedicle screw instrumentation with and without intermediate screws for treating unstable thoracolumbar fractures. AB - It is generally acknowledged that short-segment pedicle screw instrumentation is the preferred surgical method for thoracolumbar fractures. However, the use of short-segment instrumentation with or without intermediate screws at the fracture level remains controversial.We retrospectively evaluated 44 patients (28 men, 16 women) with unstable thoracolumbar fractures. The patients were divided into 2 groups according to the surgical method used. In group 1, 24 patients underwent surgery with a posterior approach via short-segment pedicle screw instrumentation (1 level above and 1 level below the fractured level). In group 2, 20 patients received an additional 2 screws at the fractured vertebrae. Clinical and radiologic parameters were evaluated before surgery and at 1 week, 6 months, and 1 year after surgery.We found no significant difference in the demographic characteristics between the 2 groups. No significant difference was observed in the operative time and intraoperative blood loss between the 2 groups. Clinical outcomes also showed no significant differences between the groups preoperatively or at all follow-up periods. The correction of the Cobb angle (CA) 1 week after surgery was better in group 2, whereas the anterior vertebral body height of the fractured level (AVHF) and compression ratio of the AVHF (AVHFCR) were not significantly different between the 2 groups 1 week after surgery. Moreover, group 2 had better maintenance of restored CA, AVHF, and AVHFCR at the fractured level than did group 1 at 6 months and 1 year postoperatively. In addition, the reduction of mid-sagittal diameter (MSD) of spinal canal 1 week and 1 year after surgery was better in group 2. Besides, bone fragments in the spinal canal have a tendency to be less in group 2 1 week and 1 year after surgery.Reinforcement with intermediate screws for a single thoracolumbar fracture not only enhanced the stability of the internal fixation system, but it was also conducive to the correction of kyphosis and the maintenance of the reduction effects. Furthermore, this method is helpful to restore the spinal canal and reduce the bone fragments in the spinal canal. However, more long-term follow-up studies are needed. PMID- 28834907 TI - Prevalence of type 2 diabetes and impaired fasting glucose in patients affected by rheumatoid arthritis: Results from a cross-sectional study. AB - Although the better management of rheumatoid arthritis (RA) has significantly improved the long-term outcome of affected patients, a significant proportion of these may develop associated comorbidities including cardiometabolic complications. However, it must be pointed out that a comprehensive cardiometabolic evaluation is still poorly integrated into the management of RA patients, due to a limited awareness of the problem, a lack of appropriate clinical studies, and optimal strategies for cardiovascular (CV) risk reduction in RA. In addition, although several studies investigated the possible association between traditional CV risk factors and RA, conflicting results are still available.On this basis, we planned this cross-sectional study, aimed at investigating the prevalence of type 2 diabetes (T2D) and impaired fasting glucose (IFG) in RA patients compared with age- and gender- matched control individuals. Furthermore, we analyzed the role of both traditional and RA-related CV risk factors in predicting T2D and IFG.We observed an increased prevalence of T2D in RA patients when compared with age- and gender-matched controls. Regression analyses demonstrated that the presence of high blood pressure (HBP), a longer disease duration, and exposure to corticosteroids (CCS) were significantly associated with an increased likelihood of being classified as T2D. In addition, we observed an increased prevalence of IFG in RA patients when compared with age- and gender-matched controls. Regression analyses demonstrated that a higher body mass index (BMI), the presence of metabolic syndrome (MetS), higher levels of total cholesterol, the presence of radiographic damage, and higher serum levels of C-reactive protein (CRP) were significantly associated with an increased likelihood of presenting IFG.In this cross-sectional study, we observed an increased prevalence of T2D and IFG in an Italian cohort of RA patients when compared with age- and gender-matched control individuals. Interestingly, both RA-specific features, such as disease duration, CCS exposure, and radiographic damage, and traditional CV risk factors, such as HBP and MetS, were significantly associated with glucose metabolism abnormalities. PMID- 28834908 TI - Association of lymphocyte-to-monocyte ratio with in-hospital and long-term major adverse cardiac and cerebrovascular events in patients with ST-elevated myocardial infarction. AB - In recent years, lymphocyte-to-monocyte ratio (LMR) has become a novel indirect marker of inflammation, which has been demonstrated to be associated with poor prognosis of oncology and cardiovascular disease. The aim of the study was to assess the relationship between LMR on admission and in-hospital and long-term major adverse cardiac and cerebrovascular events (MACCE) in patients with ST elevated myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI).A total of 306 STEMI patients were enrolled and grouped according to tertiles of LMR from the blood samples obtained in the emergency room on admission. Total white blood cell count, differential count of neutrophil, lymphocyte, monocyte, and other factors were evaluated.The median follow-up period was 21 months (1-36 months). As the LMR decreased, in-hospital nonfatal myocardial infarction and cardiovascular mortality increased (P = .002, P = .009, respectively). And long-term stroke/TIA, TVR, nonfatal myocardial infarction, and cardiovascular mortality also increased with decreasing LMR (P = .012, P = .001, P = .003, P = .002, respectively). The receiver operating characteristic (ROC) curve of LMR for predicting MACCE showed the sensitivity of 76% and specificity of 78% and the optimal cut-off value was determined as 2.62. In multivariate analysis, after adjusting for confounders, LMR was an independent predictor of in-hospital and long-term MACCE (odds ratio [OR] 1.192 [1.069-1.315] P < .001, OR 1.239 [1.125-1.347] P < .001, respectively).The LMR is an independent predictor of in-hospital and long-term MACCE in patients with STEMI after primary PCI. Our results suggest that this simple, inexpensive, relatively available inflammatory marker may have significant effects on the treatment and prognosis in patients with STEMI. PMID- 28834909 TI - Kidney stones may increase the risk of coronary heart disease and stroke: A PRISMA-Compliant meta-analysis. AB - BACKGROUND: We aimed to quantitatively assess the potential relationship between kidney stones and coronary heart disease or stroke. METHODS: A meta-analysis was conducted on eligibly studies published before 31 May 2016 in PubMed or Embase. The data were pooled, and the relationship was assessed by the random-effect model with inverse variance-weighted procedure. The results were expressed as relative risk (RR) with 95% confidence intervals (95%CI). RESULTS: Eight studies of 11 cohorts (n = 11) were included in our analysis with 3,658,360 participants and 157,037 cases. We found that a history of kidney stones was associated with increased risk of coronary heart disease (CHD) (RR = 1.24; 95%CI: 1.14-1.36; I = 79.0%, n = 11); similar effect on myocardial infarction, a serious condition of CHD, was observed (RR = 1.24; 95%CI: 1.10-1.40; I = 80.4%, n = 8). We also found that a history of kidney stones may increase the risk of stroke (RR = 1.21, 95%CI: 1.06-1.38; I = 54.7%, n = 4). In subgroup analysis, the risk of coronary heart disease was higher in men (RR = 1.23, 95%CI: 1.02-1.49) while the risk for stroke was higher in women (RR = 1.12; 95%CI: 1.03-1.21). No obvious publications bias was detected (Egger test: P = .47). CONCLUSION: Kidney stones are associated with increased risk of coronary heart disease and stroke, and the effect may differ by sex. PMID- 28834910 TI - Application of different ventilator modes in patients with amyotrophic lateral sclerosis according to certain clinical situations: A Case Report. AB - RATIONALE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that involves limb, axial, bulbar, and respiratory muscles. Fatigue and weakness of the respiratory muscles eventually induce respiratory insufficiency, which is one of the main causes of death in patients with ALS. In ALS patients with respiratory insufficiency, application of a ventilator is indispensable. Although there are various modes of ventilation, these modes are classified roughly into volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV). There have been several reports that VCV is preferable to PCV in neuromuscular disorder patients, such as ALS patients, but there is still debate on which ventilator mode is better. PATIENT CONCERNS: Respiratory difficulty despite ventilator application. DIAGNOSIS: Three ALS patients with respiratory difficulty. INTERVENTION: Changing ventilator mode to improve symptoms of respiratory difficulty. OUTCOMES: Considering case 1 shows that the VCV mode may have an advantage in managing respiratory insufficiency of patients in situations where the inner diameter of the airway decreases because of increased sputum. In contrast, cases 2 and 3, it is shown that changing to the PCV mode may be one of the treatment options if not enough tidal volume can be supplied to resolve respiratory insufficiency because of an increase in leakage volume. LESSONS: Therefore, in this study, through considering several cases of ALS patients whose clinical symptoms were improved by changing ventilation mode, we tried to investigate the adequacy of each ventilation mode under certain clinical situations. PMID- 28834911 TI - The clinical utility of splenic fluorodeoxyglucose uptake for diagnosis and prognosis in patients with macrophage activation syndrome. AB - The aim of the study was to evaluate splenic glucose metabolism in macrophage activation syndrome (MAS), characterized by overwhelming systemic inflammation. Splenic F-fluorodeoxyglucose (FDG) uptake was compared in patients with MAS and sepsis using positron emission tomography/computed tomography (PET/CT).Clinical and FDG-PET/CT findings from patients with MAS and those with culture-proven sepsis were evaluated. The standardized uptake value (SUV) for the spleen and liver were measured. The maximum of the spleen to liver SUV ratio (SLRmax) was calculated as spleen SUVmax/liver SUVmean. The radiological splenic volume was also measured, and splenic metabolic volume (MV) was defined as the total splenic volume with an SLRmean > 1.14. The association between clinical features, laboratory variables, and SLRmax was analyzed.The median SLRmax and splenic MV were significantly higher in patients with MAS (n = 38) than they were in those with sepsis (n = 15) (SLRmax: 1.51 vs 1.09, P = .001; MV: 346.0 vs 154.0, P = .015). Multivariate analyses revealed that SLRmax > 1.31 was useful for discriminating between MAS and sepsis. SLRmax positively correlated with ferritin and lactate dehydrogenase level in MAS. Furthermore, MAS patients with high splenic FDG uptake (SLRmax > 1.72) had higher in-hospital mortality compared to those with moderate to low splenic FDG uptake (P = .013).This study was the first to demonstrate that splenic FDG uptake is significantly elevated in patients with MAS compared to those with sepsis. This may be useful to differentiate between MAS and sepsis, and to predict poor prognosis in patients with MAS. PMID- 28834912 TI - Frontal intradiploic meningioma with progressive intracranial invasion: A rare case report. AB - RATIONALE: Intradiploic meningiomas are a subset of extradural meningiomas that arise in the skull. They are mostly localized in the frontoparietal and orbital regions, and they are often mistaken for primary bone tumors. PATIENT CONCERNS: The patient was a 48-year-old man with headache and a 12-year history of frontal cranium occupation, which was first discovered in 2005 and enlarged in 2009. The patient had a history of fracture in his frontal cranium 12 years ago. The computed tomography and magnetic resonance imaging revealed an occupation and intracranial invasion in frontal cranium. And the angiography showed an occlusion at the anterior part of sagittal sinus. INTERVENTIONS: Bilateral frontal craniotomy, intracranial tumor resection, and cranioplasty were performed. DIAGNOSIS: Histologic examination confirmed an intradiploic ectopic meningioma (World Health Organization Grade I). OUTCOMES: He was discharged with no neurological deficits 3 days after surgery. At the 6-month clinical follow-up, there was no tumor recurrence or other complaints. LESSONS: In this study, we present the case of a frontal intradiploic meningioma with progressive intracranial invasion and review the radiographic and clinical findings of patients with primary intraosseous meningioma. PMID- 28834913 TI - Abdominal girth and vertebral column length aid in predicting intrathecal hyperbaric bupivacaine dose for elective cesarean section. AB - Currently, there is no consensus on how to determine the optimal dose of intrathecal bupivacaine for an individual undergoing an elective cesarean section. In this study, we developed a regression equation between intrathecal 0.5% hyperbaric bupivacaine volume and abdominal girth and vertebral column length, to determine a suitable block level (T5) for elective cesarean section patients.In phase I, we analyzed 374 parturients undergoing an elective cesarean section that received a suitable dose of intrathecal 0.5% hyperbaric bupivacaine after a combined spinal-epidural (CSE) was performed at the L3/4 interspace. Parturients with T5 blockade to pinprick were selected for establishing the regression equation between 0.5% hyperbaric bupivacaine volume and vertebral column length and abdominal girth. Six parturient and neonatal variables, intrathecal 0.5% hyperbaric bupivacaine volume, and spinal anesthesia spread were recorded. Bivariate line correlation analyses, multiple line regression analyses, and 2-tailed t tests or chi-square test were performed, as appropriate. In phase II, another 200 parturients with CSE for elective cesarean section were enrolled to verify the accuracy of the regression equation.In phase I, a total of 143 parturients were selected to establish the following regression equation: YT5 = 0.074X1 - 0.022X2 - 0.017 (YT5 = 0.5% hyperbaric bupivacaine volume for T5 block level; X1 = vertebral column length; and X2 = abdominal girth). In phase II, a total of 189 participants were enrolled in the study to verify the accuracy of the regression equation, and 155 parturients with T5 blockade were deemed eligible, which accounted for 82.01% of all participants.This study evaluated parturients with T5 blockade to pinprick after a CSE for elective cesarean section to establish a regression equation between parturient vertebral column length and abdominal girth and 0.5% hyperbaric intrathecal bupivacaine volume. This equation can accurately predict the suitable intrathecal hyperbaric bupivacaine dose for elective cesarean section. PMID- 28834914 TI - Pure laparoscopic right hepatectomy in a patient with situs inversus totalis: A case report. AB - RATIONALE: Hepatectomy in a patient with situs inversus totalis (SIT) is technically challenging, and pure laparoscopic major hepatectomy has not been previously described. PATIENT CONCERNS: A 70-year-old male with SIT was referred to our hospital for investigation and treatment of a liver mass in segment 5/6. DIAGNOSIS: Computed tomography (CT) and magnetic resonance imaging (MRI) showed features of chronic liver disease and a 5-cm sized mass with a bulging contour at segment 5/6. INTERVENTIONS: Pure laparoscopic right hepatectomy was performed. OUTCOMES: There was no intraoperative complication and the procedure was completed without a transfusion. The patient recovered well and was discharged on postoperative day 8. LESSONS: Considering the position of the port sites and the assistant, and the operator's hand for the working port, a pure laparoscopic right hepatectomy can be a feasible procedure, even in a patient with SIT. PMID- 28834915 TI - Ki67 is a biological marker of malignant risk of gastrointestinal stromal tumors: A systematic review and meta-analysis. AB - BACKGROUND: Ki67 is a good marker of cell proliferation in a variety of tumors. High ki67 levels are usually associated with poor prognosis. However, the relationship between Ki67 expression and the risk of malignancy of gastrointestinal stromal tumors (GISTs) is still poorly defined. The current meta analysis was initiated to address this issue. METHODS: Studies reporting Ki67 expression and the risk of malignancy in GIST were found by searching Cochrane Library, PubMed, Medline, and Embase until October 31, 2016. A total of 9 studies involving 982 patients were included. Pooled odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated using a fixed-effect model. RESULTS: Meta-analysis showed no significant difference in the incidence of Ki67 overexpression between the very low NIH group and the low NIH group (OR: 0.66, 95% CI: 0.25-1.76; P = .41, Pheterogeneity = .25). However, the incidence of Ki67 overexpression gradually increased from the low NIH group to the high NIH group (OR: 0.46, 95% CI: 0.27-0.80; P = .005, Pheterogeneity = .13) and (OR: 0.22, 95% CI: 0.15-0.34; P < .00001, Pheterogeneity = .33). CONCLUSIONS: There were more GIST patients with Ki67 overexpression in the intermediate and high NIH groups than in the low NIH group. Ki67 overexpression may be a useful marker of the risk of malignant GIST transformation. PMID- 28834916 TI - Factors predicting dysphagia after anterior cervical surgery: A multicenter retrospective study for 2 years of follow-up. AB - A multicenter retrospective study.The purpose of this study was to explore risk factors of dysphagia after anterior cervical surgery and factors affecting rehabilitation of dysphagia 2 years after surgery.Patients who underwent anterior cervical surgery at 3 centers from January 2010 to January 2013 were included. The possible factors included 3 aspects: demographic variables-age, sex, body mass index (BMI): hypertension, diabetes, heart disease, smoking, alcohol use, diagnose (cervical spondylotic myelopathy or ossification of posterior longitudinal ligament), preoperative visual analogue scale (VAS), Oswestry Disability Index (ODI), Japanese Orthopaedic Association (JOA), surgical-related variables-surgical option (ACDF, ACCF, ACCDF, or Zero profile), operation time, blood loss, operative level, superior fusion segment, incision length, angle of C2 to C7, height of C2 to C7, cervical circumference, cervical circumference/height of C2 to C7.The results of our study indicated that the rate of dysphagia at 0, 3, 6, 12, and 24 months after surgery was 20%, 5.4%, 2.4%, 1.1%, and 0.4%, respectively. Our results showed that age (58.8 years old), BMI (27.3 kg/m), course of disease (11.6 months), operation time (103.2 min), blood loss (151.6 mL), incision length (9.1 cm), cervical circumference (46.8 cm), angle of C2 to C7 (15.3 degrees ), cervical circumference/height of C2 to C7 (4.8), preoperative VAS (7.5), and ODI (0.6) in dysphagia group were significantly higher than those (52.0, 24.6, 8.6, 88.2, 121.6, 8.6, 42.3, 12.6, 3.7, 5.6, and 0.4, respectively) in nondysphagia group; however, height of C2 to C7 (9.9 vs 11.7 cm) and preoperative JOA (8.3 vs 10.7) had opposite trend between 2 groups. We could also infer that female, smoking, diabetes, ossification of posterior longitudinal ligament, ACCDF, multilevel surgery, and superior fusion segment including C2 to C3 or C6 to C7 were the risk factors for dysphagia after surgery immediately. However, till 2 years after surgery, only 2 risk factors, smoking and diabetes, could slow rehabilitation of dysphagia.Many factors could significantly increase rate of dysphagia after anterior cervical surgery. Operation time as a vital factor markedly increases immediate postoperative dysphagia and smoking, as the most important factor, lower recovery of dysphagia. Further study is needed to prove if these factors could influence dysphagia. PMID- 28834918 TI - Endobronchial melanoma metastasis 40 years after the excision of the primary cutaneous tumor: A case report. AB - RATIONALE: Endobronchial melanoma metastases are rare, comprising 4.5% of all endobronchial metastases. They are diagnosed at a median time of 48 months from primary tumor presentation, and survival of these patients is poorer when accompanied by other metastatic sites or malignant pleural effusion. We present a case of endobronchial melanoma metastasis happening 40 years after the initial diagnosis. The need of adjuvant techniques in the diagnosis of this tumor is highlighted and a short review on this rare phenomenon is provided. PATIENTS CONCERNS: An 83-year old nonsmoking woman, presented with dyspnea. DIAGNOSES: Left lung atelectasis was found. INTERVENTIONS: Endobronchial resection of a tumor of the left main stem bronchus was achieved by rigid bronchoscopy under general anesthesia with complete reventilation of the left lung. OUTCOMES: Histopathological, immunohistochemical and molecular diagnostics of the resected tumor led to a diagnosis of an endobronchial melanoma metastasis. LESSONS: Melanoma is a type of tumor that cannot be regarded as cured even after long disease-free periods, and thus, any new symptomatology in these patients warrants stringent work up. PMID- 28834917 TI - MicroRNA expression profiling and bioinformatics analysis of dysregulated microRNAs in obstructive sleep apnea patients. AB - Obstructive sleep apnea (OSA) is a common chronic obstructive sleep disease in clinic. The purpose of our study was to use bioinformatics analysis to identify microRNAs (miRNAs) that are differentially expressed between OSA patients and healthy controls.Serum samples were collected from OSA patients and healthy controls. To better reveal the sample specificity of differentially expressed microRNAs, supervised hierarchical clustering was conducted. We used the microT CDS and TargetScan databases to predict target genes of the differentially expressed microRNAs and selected the common genes. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to evaluate many coexpression relationships. Moreover, we used these potential microRNA-target pairs and coexpression relationships to construct a regulatory coexpression network using Cytoscape software. Functional analysis of microRNA target genes was conducted with FunRich.A total of 104 microRNAs that were differentially expressed between OSA patients and healthy controls were identified. Supervised hierarchical clustering was conducted based on the expression of the 104 microRNAs in the OSA patients and healthy controls. Overall, 6621 potential target genes were predicted, and 119 target genes were screened based on coexpression coefficients in the STRING database. A regulatory coexpression network was constructed that included 23 differentially expressed microRNAs and 18 of the most related potential target genes. Metabolic signaling pathways were the most highly enriched category. Differentially expressed microRNAs, such as hsa-miR-485-5p, hsa-miR-107, hsa-miR-574-5p, and hsa-miR-199-3p, might participate in OSA. The target gene CAD might also be closely related to OSA.Our results may provide a basis for the pathogenesis of OSA and the study of disease diagnosis, prevention, and treatment. However, more experiments are needed to verify these predictions. PMID- 28834919 TI - A CASE OF NEUROFIBROMATOSIS TYPE 2 WITH UNUSUAL CLINICAL FEATURES. AB - PURPOSE: To report a case of a neurofibromatosis Type 2 with unusual clinical features. METHODS: Observational clinical case report. RESULTS: A 22-year-old woman was referred with bilateral blurred vision and macular "scars." Ocular examination revealed bilateral posterior subcapsular and cortical cataract, optic disk swelling, hyperpigmented macular lesions, epiretinal membrane, and macular temporal dragging. Spectral-domain optical coherence tomographic imaging showed bilateral epiretinal membranes, peripapillary nerve fiber layer thickening, and vitreoretinal tractional bands. In the right eye, focal choroidal excavation was noted at the site of the macular lesion. In fluorescein angiography, mild vascular leakage, capillary nonperfusion, and ground glass hyperfluorescence was seen in temporal periphery of the right eye. Brain imaging showed intracranial calcification and vestibular schwannoma, which was removed by a neurosurgeon. A clinical diagnosis of neurofibromatosis Type 2 was made. CONCLUSION: A case of neurofibromatosis Type 2 with some possibly novel or rare findings, namely, focal choroidal excavation, ash leaf spots, and intracranial calcifications was presented. PMID- 28834920 TI - CASE REPORT OF SEVERE PROLIFERATIVE RETINOPATHY IN A PATIENT WITH CONGENITAL LIPODYSTROPHY. AB - PURPOSE: A case report of a patient with severe proliferative retinopathy due to congenital lipodystrophy. METHODS: We reviewed the medical history, imaging, and surgical procedures of a 25-year-old woman with a history of congenital lipodystrophy, presenting with bilateral combined tractional and exudative retinal detachment, poorly controlled diabetes mellitus, and extreme dislipidemia. RESULTS: The patient underwent retinal detachment repair surgery both eyes. On the last follow-up, both retinae were flat, and visual acuity had improved in the right eye to J3 for near and finger counting 3 m for distance. CONCLUSION: Surgery combining pars plana vitrectomy and scleral bucking successfully flattened both retinae and significantly improved visual acuity in one eye in this case of bilateral retinal detachment with combined tractional and exudative components in a patient with congenital lipodystrophy. Surgical control of retinal complications is thus possible, provided there is adequate control of the underlying risk factors. PMID- 28834921 TI - MULTIPLE SEROUS PIGMENT EPITHELIAL DETACHMENTS IN ASSOCIATION WITH MAJOR WEIGHT LOSS: CASE REPORT AND REVIEW OF THE LITERATURE. AB - PURPOSE: To report about two cases with bilateral multiple serous pigment epithelial detachments (sPED) following major acute weight loss. METHODS: Retrospective chart review of patients who presented with bilateral multiple sPED following acute major weight loss. The files were reviewed for their general and ophthalmic history, medication, ophthalmic status, optical coherence tomography (OCT) and enhanced depth imaging, fluorescein and indocyanine green angiography, arterial pressure, and laboratory workup. RESULTS: Two patients, both women, aged 45 and 50 years were identified. The sPED counted 50 and 5, respectively. They were located in the mid-periphery and the macula. Multimodal imaging including optical coherence tomography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography did not reveal an underlying ocular pathology. However, both patients had a thick choroid (455 MUm and 542 MUm). They both had gone through intentional major weight loss induced by protein-rich Dukan's diet ( 20 kg in 3 months) and gastric bypass with protein-enriched diet (-35 kg in less than 1 year), respectively. They were substituted with vitamins (vitamin B, C, D). CONCLUSION: Bilateral multiple serous PEDs may occur in the context of acute major weight loss and protein-rich diet. The precise pathogenesis remains to be elucidated. However, potential candidates include the protein-, mineral- and/or vitamin-related metabolism disturbing the pigment epithelium function. A predisposition for a central serous chorioretinopathy like response might have contributed. PMID- 28834922 TI - Relationship Between the CYP2C19 Phenotype Using the Voriconazole-to-Voriconazole N-Oxide Plasma Concentration Ratio and Demographic and Clinical Characteristics of Japanese Patients With Different CYP2C19 Genotypes. AB - BACKGROUND: Although voriconazole (VRCZ) is metabolized to VRCZ N-oxide principally by CYP2C19, VRCZ clearance is affected by multiple factors. In this study, we investigated the relationship between the CYP2C19 phenotype using the VRCZ-to-VRCZ N-oxide plasma concentration ratio (VRCZ/N-oxide) and demographic and clinical characteristics of Japanese patients taking VRCZ. METHODS: A total of 65 Japanese patients taking VRCZ for prophylaxis or treatment of fungal infection were enrolled in this study. Stepwise selection multiple linear regression analysis was performed to investigate the effect of factors on the VRCZ/N-oxide ratio. RESULTS: In patients not undergoing concurrent treatment with a drug influencing CYP2C19 activity (n = 54), the VRCZ/N-oxide ratio with definite thresholds for CYP2C19 genotypes, CYP2C19*1/*1, *1/*2 + *1/*3 + *2/*17, and *2/*2 + *2/*3, was specifically identified in patients taking VRCZ (<0.48, >=0.48 < and <0.82 and >=0.82). However, the VRCZ/N-oxide ratio could not be predicted based solely on the CYP2C19 genotype (R = 0.053). The route of VRCZ administration, C-reactive protein concentration determined on the same day as VRCZ plasma concentration measurement, CYP2C19 extensive metabolizer, and patient age were independent factors influencing the VRCZ/N-oxide ratio (R = 0.489, standardized regression coefficient = 0.385, 0.380, -0.231, and 0.231; P = 0.001, 0.001, 0.032, and 0.036, respectively). CONCLUSIONS: It is possible to comprehensively evaluate CYP2C19 activity using the actual measured value of the VRCZ/N-oxide ratio in patients taking VRCZ. The predictive performance of the VRCZ/N-oxide ratio was improved by including the route of administration, C reactive protein level, and patient age in addition to the CYP2C19 genotype as predictive factors. PMID- 28834924 TI - Letters. PMID- 28834927 TI - The role of the nurse coordinator in the enhanced recovery after surgery program. PMID- 28834930 TI - Recognizing normal pressure hydrocephalus in older adults. PMID- 28834931 TI - Evidence-based approaches to breaking down language barriers. PMID- 28834928 TI - Cultural competence: A nurse educator's guide. PMID- 28834932 TI - Easing the final journey. PMID- 28834933 TI - Disparity in RN disciplinary actions by gender. PMID- 28834934 TI - Understanding the role of convex skin barriers in ostomy care. PMID- 28834935 TI - Professional development: Branching out beyond the bedside. PMID- 28834936 TI - Ending the stigma. PMID- 28834923 TI - Stress and Addiction: When a Robust Stress Response Indicates Resiliency. AB - OBJECTIVE: Stress reactivity research has traditionally focused on the idea that exaggerated responses to stress may have adverse effects on health. Accumulating evidence suggests that attenuated responses to stress and delayed recovery may also be problematic. METHODS: This review focuses on the role of the stress response of the hypothalamic-pituitary-adrenocortical axis, the endogenous opioid system, and the cardiovascular system in hypertension, pain perception, and addictive behaviors. Results from multiple methods of assessment and stress paradigms conducted in our laboratory over the past two decades are integrated with research from other investigators and with existing theories. RESULTS: Research indicates that exaggerated biological and physiological responses to stress and attenuated pain perception are associated with hypertension and risk for cardiovascular diseases. This research complements work linking reduced stress responses with enhanced pain sensitivity and discomfort. Multiple studies have also demonstrated that an attenuated stress response is linked to exacerbation of withdrawal symptoms and relapse in nicotine addiction. Evidence indicates important moderators (i.e., sex, personality traits, and early life adversity) and hypothalamic-pituitary-adrenocortical- and endogenous opioid system-related mechanisms in the altered response to stress. I integrate these findings in a conceptual model emphasizing that robust stress responses in the context of addiction and relapse should be considered as a marker of resiliency. CONCLUSIONS: A blunted stress response may indicate long-term physiological dysregulation that could usher harmful consequences for cardiovascular disease, pain perception, and addictive disorders. The impact of dysregulation is influenced by multiple individual and situational factors that should be considered in evaluating the clinical significance of stress response dysregulation. PMID- 28834937 TI - Falls simulation room: Do you see what your patient sees? PMID- 28834938 TI - Yellow fever. PMID- 28834940 TI - International public health emergencies: Lessons learned in West Africa. PMID- 28834941 TI - Selective Stimulation of Facial Muscles Following Chronic Intraneural Electrode Array Implantation and Facial Nerve Injury in the Feline Model. AB - BACKGROUND: Our group has previously shown that activation of specific facial nerve (FN) fiber populations and selective activation of facial musculature can be achieved through acute intraneural multichannel microelectrode array (MEA) implantation in the feline model. HYPOTHESIS: Selective stimulation of facial muscles will be maintained in the setting of 1) chronic and 2) acute MEA implantation after FN injury and subsequent recovery. METHODS: This study included seven cats. In three cats with normal facial function, 4-channel penetrating MEAs were implanted chronically in the FN and tested biweekly for 6 months. Electrical current pulses were delivered to each channel individually, and elicited electromyographic (EMG) voltage outputs were recorded for each of several facial muscles. For FN injury experiments, two cats received a standardized hemostat-crush injury, and two cats received a transection reapproximation injury to the FN main trunk. These four underwent acute implantation of MEA and EMG recording in terminal experiments 4 months postinjury. RESULTS: Stimulation through individual channels selectively activated restricted nerve populations, resulting in activation of individual muscles in cats with chronic MEA implantation and after nerve injury. Increasing stimulation current levels resulted in increasing EMG voltage responses in all patients. Nerve histology showed only minor neural tissue reaction to the implant. CONCLUSION: We have established in the animal model the ability of a chronically implanted MEA to selectively stimulate restricted FN fiber populations and elicit activations in specific facial muscles. Likewise, after FN injury, selective stimulation of restricted FN fiber populations and subsequent activation of discrete facial muscles can be achieved after acute MEA implantation. PMID- 28834942 TI - Using Electrically-evoked Compound Action Potentials to Estimate Perceptive Levels in Experienced Adult Cochlear Implant Users. AB - HYPOTHESIS: The cochlear implant (CI) fitting level prediction accuracy of electrically-evoked compound action potential (ECAP) should be enhanced by the addition of demographic data in models. INTRODUCTION: No accurate automated fitting of CI based on ECAP has yet been proposed. METHODS: We recorded ECAP in 45 adults who had been using MED-EL CIs for more than 11 months and collected the most comfortable loudness level (MCL) used for CI fitting (prog-MCL), perception thresholds (meas-THR), and MCL (meas-MCL) measured with the stimulation used for ECAP recording. Linear mixed models taking into account cochlear site factors were computed to explain prog-MCL, meas-MCL, and meas-THR. RESULTS: Cochlear region and ECAP threshold were predictors of the three levels. In addition, significant predictors were the ECAP amplitude for the prog-MCL and the duration of deafness for the prog-MCL and the meas-THR. Estimations were more accurate for the meas-THR, then the meas-MCL, and finally the prog-MCL. CONCLUSION: These results show that 1) ECAP thresholds are more closely related to perception threshold than to comfort level, 2) predictions are more accurate when the inter subject and cochlear regions variations are considered, and 3) differences between the stimulations used for ECAP recording and for CI fitting make it difficult to accurately predict the prog-MCL from the ECAP recording. Predicted prog-MCL could be used as bases for fitting but should be used with care to avoid any uncomfortable or painful stimulation. PMID- 28834943 TI - Clinical Characteristics of Benign Recurrent Vestibulopathy: Clearly Distinctive From Vestibular Migraine and Meniere's Disease? AB - OBJECTIVE: We aimed to systematically investigate the clinical characteristics of benign recurrent vestibulopathy (BRV), vestibular migraine (VM), and Meniere's disease (MD) and to assess whether clinical symptoms exist that are unique to BRV. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. METHODS: Between January 2015 and November 2016, patients were prospectively recruited at a specialized dizziness clinic. Patients were included if they met the diagnostic criteria for BRV, VM, or MD which was evaluated by simultaneous consultation of an otorhinolaryngologist and neurologist. All patients received a comprehensive clinical examination that included vestibular tests and pure-tone audiometry. A questionnaire was designed to systematically document symptoms of the three vestibular disorders. RESULTS: A total of 122 patients were included in our study, 65 (53%) were females in whom 29 (24%) were postmenopausal. The mean age was 55.5 +/- 13.7 years and the mean age of onset of vertigo attacks was 49.2 +/- 14.8 years (n = 119). Forty-five (37%) patients had a clinical diagnosis of BRV, 34 (28%) of VM, and 43 (35%) of MD. No symptom could be identified which was specifically linked to BRV. In patients with BRV, similar to those with VM, we found a female preponderance (p = 0.05 in BRV, p = 0.001 in VM). Patients with VM reported significantly more often a positive history of motion sickness (p = 0.01). In addition, canal paresis was most profound in patients with MD (p = 0.001). CONCLUSION: We found no clinical characteristics that were distinctive for BRV. However, we did find several distinctive clinical features for VM and MD which may assist the physician in their history taking. PMID- 28834944 TI - HIGH-RISK INTRAOCULAR RETINOBLASTOMA: Comparison Between Asian Indians and Americans From Two Major Referral Centers. AB - PURPOSE: To identify the differences in the clinical and histopathologic features in eyes with advanced intraocular retinoblastoma in a developing country (India) versus a developed country (USA). METHODS: Retrospective study. RESULTS: Of 524 patients with retinoblastoma who underwent primary enucleation, 331 were from India, and 193 were from the USA. Asian Indians were older at presentation (35 months vs. 29 months; P = 0.02), had thicker tumors (13.8 mm vs. 12.4 mm; P = 0.0001) compared with Americans. High-risk intraocular retinoblastoma was more common in Asian Indians with a 2-fold greater risk compared with Americans (35% vs. 23%; odds ratio = 1.83; P = 0.003). Statistically significant differences in the histopathologic features (Asian Indians vs. Americans) included massive (>=3 mm) choroidal infiltration (17% vs. 6%; P = 0.0003) and optic nerve infiltration (48% vs. 15%; P = 0.0001). Asian Indians had a 5-fold greater risk of having optic nerve invasion (odds ratio = 5.45; P < 0.0001) and 3-fold greater risk of massive choroidal invasion (odds ratio = 2.80; P < 0.0001) compared with Americans. With appropriate use of adjuvant systemic chemotherapy, the difference in the rates of systemic metastasis (5% vs. 2%, P = 0.67) and related death in both countries (5% vs. 0%, P = 0.14) were not statistically significant. CONCLUSION: High-risk intraocular retinoblastoma is more common in Asian Indians compared with Americans. PMID- 28834945 TI - Diagnostic and Therapeutic Challenges. PMID- 28834946 TI - IDENTIFYING FEATURES OF EARLY AND LATE AGE-RELATED MACULAR DEGENERATION: A Comparison of Multicolor Versus Traditional Color Fundus Photography. AB - PURPOSE: To compare multicolor (MC) and traditional color fundus photography (CFP) in their ability to detect features of early and late age-related macular degeneration (AMD). METHODS: Study design: Observational case series. PARTICIPANTS: fundus images captured using standard CFP and MC imaging from 33 patients attending hospital clinics and 26 participants from the pilot phase of the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA). Systematic grading of early and late AMD features; (hard drusen, soft drusen, reticular pseudodrusen, pigment clumping, non-geographic atrophy hypopigmentation, atrophy, hemorrhage, and fibrosis) on CFP and MC. RESULTS: There were 105 eyes with gradable images for comparison. Using CFP as the gold standard, sensitivity values for MC ranged from 100% for atrophy, non-geographic atrophy hypopigmentation, and fibrosis to 69.7% for pigment clumping. Specificity values were high: >80% for all features. On using MC as the comparator, CFP had lower sensitivity for the detection of early AMD features (27.8% for reticular drusen to 77.8% for non-geographic atrophy hypopigmention). Analysis of OCT in discrepant cases showed better agreement with MC for all AMD lesions, except hemorrhage and non-geographic atrophy hypopigmentation. For pigment clumping, CFP and MC were in equal agreement with OCT. CONCLUSION: Multicolor retinal imaging allowed for improved detection and definition of AMD features. PMID- 28834947 TI - CLASSIFICATION AND QUANTITATIVE ANALYSIS OF GEOGRAPHIC ATROPHY JUNCTIONAL ZONE USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: The junctional zone at the border of areas of geographic atrophy (GA) in eyes with nonneovascular age-related macular degeneration is an important target region for future therapeutic strategies. The goal of this study was to perform a detailed classification and quantitative characterization of the junctional zone using spectral domain optical coherence tomography. METHODS: Spectral domain optical coherence tomography volume cube scans (Spectralis OCT, 1024 * 37, Automatic Real Time > 9) were obtained from 15 eyes of 11 patients with GA because of nonneovascular age-related macular degeneration. Volume optical coherence tomography data were imported into previously described validated grading software (3D-OCTOR), and manual segmentation of the retinal pigment epithelium (RPE) and photoreceptor layers was performed on all B-scans (total of 555). Retinal pigment epithelium and photoreceptor defect maps were produced for each case. The borders of the photoreceptor defect area and RPE defect area were delineated individually on separate annotation layers. The two outlines were then superimposed to compare the areas of overlap and nonoverlap. The perimeter of the RPE defect area was calculated by the software in pixels. The superimposed outline of the photoreceptor defect area and the RPE defect area was scrutinized to classify the overlap configuration of the junctional zone into one of three categories: Type 0, exact correspondence between the edge of the RPE defect and photoreceptor defect; Type 1, loss of photoreceptors outside and beyond the edge of the RPE defect; Type 2, preservation of photoreceptors beyond the edge of the RPE defect. The relative proportion of the various border configurations was expressed as a percentage of the perimeter of the RPE defect. Each configuration was then classified into four subgroups according to irregularity of the RPE band and the presence of debris. RESULTS: Fifteen eyes of 11 patients (mean age: 79.3 +/- 4.3 years; range: 79-94 years) were included in this study. Seventeen GA lesions were analyzed. Two hundred and thirty-two B-scans were found to pass through the GA lesions, yielding 612 individual GA borders which were separately analyzed and classified. The mean area of the RPE defect was 4.0 +/- 4.4 mm, which was significantly smaller than that of the photoreceptor defect which measured 4.4 +/- 4.1 mm (paired t test, P = 0.037). On average, 18.0 +/- 9.6% (range, 2.3-36.6%) of the junctional zone was of the Type 0 configuration, 57.3 +/- 19.0% (range, 21.3-96.8%) was Type 1, and 24.7 +/- 18.0% (range, 0.9-64.4%) was Type 2. Type 1 was more prevalent than Type 0 and 2 (analysis of variance, P = 0.000). Debris was present at the margin of the defect in 24.3% (149 of 612) of all assessed junctional zones; 20.0% (14 of 70) of Type 0 junctions, 28.7% (120 of 418) of Type 1, and 12.1% (15 of 124) of Type 2. Debris was more common in Type 1 than Type 2 junctions (P < 0.001). Retinal pigment epithelial irregularity was present at the margin of the defect in 34.8% (213 of 612) of all assessed junctional zones; 52.9% (37 of 70) of Type 0 junctions, 38.0% (159 of 418) of Type 1, and 13.7% (17 of 124) of Type 2. Retinal pigment epithelial irregularity was present more often at Type 0 and Type 1 than at Type 2 junctions (P < 0.001 for both). CONCLUSION: The size of the optical coherence tomography-visible RPE and photoreceptor defect in GA lesions differ significantly. There were significant areas where the photoreceptor outer segments were preserved despite the absence of visible RPE cells, and also areas of photoreceptor outer segment loss despite apparent RPE preservation. These findings have implications for development of therapeutic strategies, particularly cell-replacement approaches. PMID- 28834948 TI - Diagnostic and Therapeutic Challenges. PMID- 28834949 TI - BENEFIT OF INTRAOPERATIVE OPTICAL COHERENCE TOMOGRAPHY FOR VITREOMACULAR SURGERY IN HIGHLY MYOPIC EYES. AB - PURPOSE: To report the feasibility and information provided by intraoperative optical coherence tomography (iOCT) during vitreomacular surgery in highly myopic eyes. METHODS: Retrospective observational case series on consecutive highly myopic eyes that underwent vitreomacular surgery with iOCT for epiretinal membrane (ERM), macular hole, and myopic foveoschisis. The main outcome was the qualitative and quantitative assessment of retinal changes: detection of persistent epiretinal structures, new openings, central macular thickness, and macular hole diameters after each step of the surgical procedure. Quantitative measurements (in pixels) were manually obtained on iOCT video screen captures. RESULTS: Twenty-two eyes were included: six ERMs, 10 macular holes, and 6 with myopic foveoschisis. An unsuspected postpeeling macular opening was detected by iOCT in 2/22 eyes. Intraoperative optical coherence tomography also allowed for detecting the presence of residual fragments of the vitreous cortex in 6/12 eyes after surgically induced posterior vitreous detachment. Intraoperative optical coherence tomography detected residual fragments of the internal limiting membrane in 5/21 eyes after internal limiting membrane peeling, and residual fragments of ERM in 3/15 eyes with ERM. Quantitative analysis did not find any significant change in central macular thickness and macular hole diameters before and after ERM and internal limiting membrane peeling. CONCLUSION: In highly myopic eyes, iOCT could help assess undetected macular openings and otherwise posterior vitreous status and epiretinal structure peeling. PMID- 28834950 TI - DISEASE ACTIVITY AFTER DEVELOPMENT OF LARGE SUBRETINAL HEMORRHAGE IN POLYPOIDAL CHOROIDAL VASCULOPATHY. AB - PURPOSE: To investigate changes in disease activity after a large subretinal hemorrhage in polypoidal choroidal vasculopathy. METHODS: Fifty-two polypoidal choroidal vasculopathy eyes with large subretinal hemorrhage (at initial presentation [n = 33, Group 1] or developed during follow-up [n = 19, Group 2]) were enrolled. Thirty polypoidal choroidal vasculopathy eyes without subretinal hemorrhage were enrolled as controls. All subretinal hemorrhages were treated with pneumatic displacement. Other active lesions were treated with intravitreal ranibizumab on an as-needed basis. Injection-free period, 1-year injection numbers, and polyp presence on indocyanine green angiography were analyzed. RESULTS: The injection frequency significantly diminished after hemorrhage (1.2 +/- 1.8 in Group 1 and 1.1 +/- 2.1 in Group 2) compared with control eyes (3.9 +/ 3.0) in both groups (both P < 0.001) and the prehemorrhage period (4.7 +/- 1.4) in Group 2 (P < 0.001). The median injection-free period after hemorrhage was 12.0 months in both groups. At least one polypoidal lesion disappeared after hemorrhage in 7 of 10 eyes (70%) with comparable indocyanine green angiography. CONCLUSION: The activity of a polypoidal choroidal vasculopathy lesion diminished after a large subretinal hemorrhage, which was associated with rupture of major polyps. PMID- 28834951 TI - ACUTE PSEUDOPHAKIC CYSTOID MACULAR EDEMA IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To study macular capillary changes and vessel density in acute pseudophakic cystoid macular edema (PCME) before and after treatment using optical coherence tomography angiography. METHODS: Retrospective observational case-control study of seven consecutive patients (eight eyes) with PCME and eight age-matched control eyes imaged with optical coherence tomography angiography (RTVue XR Avanti; Optovue, Inc, Fremont, CA) using Projection Removal Artifacts software. Vessel density was calculated. RESULTS: The mean time to diagnosis of PCME was 2.3 +/- 0.9 months after surgery. At initial examination, the superficial capillary plexus pattern was near-normal in all PCME eyes, although it was attenuated in the deep capillary plexus. The mean vessel density of the superficial capillary plexus in PCME eyes was slightly but significantly lower than in control eyes (47.8 +/- 3.8% vs. 52.9 +/- 4.0%, P = 0.01), the difference being greater in the deep capillary plexus (44.1 +/- 7.4% vs. 54.2 +/- 3.2%, P = 0.007). After resolution of the edema, the deep capillary plexus completely recovered its normal pattern and the vessel density in both plexuses was no longer different from that observed in control eyes. CONCLUSION: Macular vessel density after resolution of an acute PCME did not differ from that of normal control eyes in both the superficial capillary plexus and deep capillary plexus, unlike macular edema in retinal vaso-occlusive diseases. PMID- 28834952 TI - MACULAR TELANGIECTASIA TYPE 2: Quantitative Analysis of a Novel Phenotype and Implications for the Pathobiology of the Disease. AB - PURPOSE: To investigate retinal microcystoid spaces in macular telangiectasia type 2 with spectral domain optical coherence tomography. METHODS: Retrospective review of 135 patients enrolled in the MacTel Natural History Observation and Registry Study at Moorfields Eye Hospital, United Kingdom. One hundred seventy two eyes from 86 patients who had a comparable scan protocol of at least 30 MUm interval were included for analysis. Retinal microcystoid spaces were identified and segmented and metrics analyzed. RESULTS: From 172 eyes of 86 patients, microcystoid spaces were found in 11 eyes (6.4%) from 8 patients (9.3%). The mean number of microcystoid spaces per eye was 12.9 +/- 18.2. Most were located in the inner nuclear layer. The inferonasal quadrant of the macula was the least commonly affected region. Microcystoid spaces were distributed entirely within the assumed macular telangiectasia area on blue light reflectance in all but 2 eyes (4 of 142 microcysts). The median diameter of the microcystoid spaces was 31 MUm (range 15 MUm-80 MUm). CONCLUSION: Microcystoid spaces as a phenotype of macular telangiectasia should be considered in the differentials for microcystic edema. Understanding the pathogenesis of these lesions may provide further insight into the role of Muller cell dysfunction in this disorder. PMID- 28834953 TI - SQUEEZER-A NEW DEVICE FOR VITREORETINAL SURGERY. PMID- 28834954 TI - Low Varicella Zoster Virus Seroprevalence Among Young Children in the Democratic Republic of the Congo. AB - BACKGROUND: Varicella zoster virus (VZV) causes both varicella (chickenpox) and herpes zoster (shingles) and is associated with significant global morbidity. Most epidemiological data on VZV come from high-income countries, and to date there are limited data on the burden of VZV in Africa. METHODS: We assessed the seroprevalence of VZV antibodies among children in the Democratic Republic of Congo in collaboration with the 2013-2014 Demographic and Health Survey. Dried blood spot samples collected from children 6-59 months of age were run on DynexTM Technologies Multiplier FLEX(r) chemiluminescent immunoassay platform to assess serologic response. Multivariate logistic regression was then used to determine risk factors for VZV seropositivity. RESULTS: Serologic and survey data were matched for 7,195 children 6-59 months of age, among whom 8% were positive and 2% indeterminate for VZV antibodies in weighted analyses. In multivariate analyses, the odds of seropositivity increased with increasing age, increasing socioeconomic status, mother's education level, rural residence, and province (South Kivu, North Kivu, Bandundu, Bas Congo had the highest odds of a positive test result compared with Kinshasa). CONCLUSION: Our data suggest that VZV is circulating in DRC, and seropositivity is low among children 6-59 months. Seropositivity increased with age and varied by other sociodemographic factors, such as geographic location. This study provides the first nationally representative estimates of VZV infection among children in the DRC. PMID- 28834956 TI - Enterovirus Infection and Subsequent Risk of Kawasaki Disease: A Population-based Cohort Study. AB - BACKGROUND: The relationship of enterovirus (EV) infection and Kawasaki disease (KD) is still unclear. The purpose of this study was to conduct a population based cohort study to determine the relationship between KD and EV infection in Taiwan. METHODS: A population-based cohort study was conducted to analyze the children file (age < 18 years) of the Taiwan National Health Insurance program between 2000 and 2008. In total, 285,636 children with EV infection and 285,636 children without EV infection were included and followed up. The subsequent KD was the major outcome event. RESULTS: The cumulative incidence of KD was significantly higher in the EV-infected cohort than in the non-EV-infected cohort (log-rank test, P < 0.001). The overall incidence of KD was 56% higher in the EV infected cohort than in the non-EV-infected cohort, with an adjusted hazard ratio of 1.56 (95% confidence interval: 1.44-1.69). Stratified analysis showed higher KD risk associated with previous EV infection in children 3-5 years old, in girls, in children living in less urbanization levels, in children with parental low-income occupation, and in children with allergic diseases. CONCLUSIONS: There is a higher association between KD and previous EV infection in Taiwanese children, especially in those 3-5 years old, with female sex, with less urbanization level, with low-income parental occupation, and with allergy. PMID- 28834955 TI - Higher Transplacental Pathogen-Specific Antibody Transfer Among Pregnant Women Randomized to Triple Antiretroviral Treatment Versus Short Course Zidovudine. AB - BACKGROUND: HIV-1 infection may impair transplacental antibody transfer to infants. The impact of highly active antiretroviral treatment (ART) given during pregnancy on transplacental antibody transport is unknown. METHODS: HIV-1 infected pregnant women with CD4 counts between 200 - 500 were randomized to short-course zidovudine (ZDV) or triple ART at 32 weeks gestation for prevention of mother-to-child HIV-1 transmission. Levels of maternal antibody against measles, pneumococcus and rotavirus at delivery, and antibody transfer to the baby through cord blood, were compared between trial arms. RESULTS: Overall, 141 and 148 women were randomized to triple ART and ZDV, respectively; cord blood was available for a subset (n = 20 in triple ART and n = 22 in ZDV). Maternal antibody levels to all pathogens during pregnancy and at delivery were not significantly different between arms. Within each arm, antibody levels at delivery were lower than at enrolment. For all antibodies, a woman's levels before delivery were an important predictor of amount transferred to her infant. Women on triple ART transferred higher levels of pathogen-specific antibodies when compared with women on short course ZDV. CONCLUSIONS: Women on triple ART transferred higher levels of pathogen-specific antibodies compared with women on ZDV alone. PMID- 28834958 TI - Standards for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiac Care (ECC). PMID- 28834957 TI - Adverse Events Following Vaccination With Bivalent rLP2086 (Trumenba(r)): An Observational, Longitudinal Study During a College Outbreak and a Systematic Review. AB - BACKGROUND: In February 2015, two unlinked culture-confirmed cases of Neisseria meningitidis serogroup B (MenB) disease occurred at a local college in Rhode Island ("college X") within 3 days. This represented a 489-fold increase in the incidence of MenB disease, and an outbreak was declared. For the first time, bivalent rLP2086 (Trumenba) was selected as a mandatory intervention response. A mass vaccination clinic was coordinated, which provided a unique opportunity to collect safety data in a real-world population of college-age participants. Though the Advisory Committee on Immunization Practices recommends MenB vaccination for college-age individuals (16-23 year olds), there is limited quantifiable safety data available for this population. METHODS: The Dillman total design survey method was used. Adverse events of bivalent rLP2086 were solicited and quantified retrospectively 2-4 months following each dose of vaccine. Safety data from six clinical trials were used as comparison tools. RESULTS: The most commonly reported adverse event following vaccination was injection site pain. Reported rates of injection site pain, fatigue, myalgia, fever, and chills were similar than those reported in clinical trials. Reported rates of headache were lower than in clinical trials. CONCLUSIONS: This study is the first to examine adverse events of bivalent rLP2086 in a real-world setting where more than 90% of a college-age population was vaccinated. PMID- 28834959 TI - ? PMID- 28834960 TI - ? PMID- 28834961 TI - [Selected Quality Characteristics Of Out-Patient Psychosocial Cancer Counseling Centers In Germany: A Nationwide Analysis]. AB - Objectives Quality assurance has become increasingly relevant in the field of outpatient psychosocial cancer counseling. At the same time, no studies are currently available that analyze outpatient psychosocial cancer counseling centers in Germany with respect to standards of service quality. Therefore, this study aimed to determine whether these centers meet selected quality criteria of outpatient psychosocial cancer counseling. Methods Based on quality standards of outpatient psychosocial cancer counseling previously developed by us in a Delphi study, we surveyed 106 out of 151 German psychosocial outpatient cancer counseling centers registered in a publicly accessible data base of Germany's cancer information service in Heidelberg with respect to the selected quality characteristics. Data analysis used descriptive statistical techniques. Results The centers of the sample differ in how many of them fulfill the quality standards selected for analysis here. More than 90% provide the services described by the standards as required. In contrast, in the personnel domain, there appears to be room for improvement with respect to the amount of service hours available for psychologists and the number of counselors with advanced training in psycho-oncology. Also, external supervision and case conferences turn out to be quality characteristics with room for improvement in the domain of quality assurance as do distress screening in the domain of diagnostics and using systematic documentation. Conclusion Referring to recent standards of quality of outpatient psychosocial cancer counseling allowed us to delineate strength and weaknesses that may serve as starting points for quality improvement in the centers providing psychosocial cancer counseling. However, further research is necessary to arrive at a more comprehensive picture of the degree to which outpatient psychosocial cancer counseling centers in Germany comply with current standards of service quality. PMID- 28834962 TI - Artificial Syndrome of Inappropriate Antidiuresis Model as Potential Use for Diagnostic and Therapeutic Strategies. AB - Hyponatremia is the most frequent electrolyte disorder with the syndrome of inappropriate antidiuresis (SIADH) being its predominant cause. Physiological studies in patients with SIADH are difficult to interpret due to usually several comorbidities and polymedication. Therefore, a SIADH model in healthy volunteers would be very helpful to allow insight in this complex disease and to test new therapeutic approaches. The aim of the study was to create a SIADH model with evaluation of subsequent physiological changes.The prospective interventional study on 14 healthy volunteers was carried out at the University Hospital Basel. The intervention was done by induction of hypotonic hyponatremia through hydration and administration of desmopressin. Clinical and laboratory parameters in a SIADH model were the main outcome of the measure.14 participants (64% males), BMI 23.1 kg/m2 (+/-2.4), aged 28.6 years (+/-9), completed the study. Through the intervention, serum sodium level decreased from 140 mmol/l (+/-1.3) to 132 mmol/l (+/-2.0) and serum osmolality from 286 mmol/kg (+/-4.7) to 267 mmol/kg (+/-3.5). Simultaneously urine osmolality increased to 879 mmol/kg (+/ 97.7) and urine sodium to 213 mmol/l (+/-51.5) verifying the artificial SIADH model. A significant decrease of copeptin (5 pmol/l (+/-1.9) to 2.6 pmol/l (+/ 0.5), p 0.002), aldosterone (314.7 pmol/l (+/-154.1) to 86.7 pmol/l (+/-23.6), p 0.019), and renin (21.2 ng/l (+/-26.7) to 3.6 ng/l (3.2), p 0.035) were noted, while NT-proBNP and MR-proANP significantly increased (31.7 ng/l (+/-18.6) to 50.5 ng/l (+/-33.0), p 0.001; 48.4 pmol/l (+/-16.8) to 56.8 pmol/l (+/-9.0), p 0.003).In conclusion, we were able to induce an artificial SIADH in healthy volunteers and study the changes of various hormonal biomarkers involved. This SIADH model could be helpful in evaluating diagnostic and therapeutic approaches. PMID- 28834963 TI - Lipofuscin Accumulation in Cortisol-Producing Adenomas With and Without PRKACA Mutations. AB - The adrenal cortex accumulates lipofuscin granules with age. Lipofuscin accumulation is also seen in adrenocortical tumors associated with Cushing syndrome (CS), particularly those with PRKAR1A mutations, such as in primary pigmented nodular adrenocortical disease (PPNAD). We investigated the presence of lipofuscin in cortisol-producing adenomas (CPAs) responsible for CS with and without the PRKACA (pLeu206Arg) somatic mutation. Ten paraffin-embedded sections of CPAs from cases with overt CS with (n=4) and without (n=6) a PRKACA mutation were microscopically examined through three detection methods, the hematoxylin Eosin (H & E) staining, the Fontana Masson (FM) staining using light microscopy, and lipofuscin autofluorescence, using confocal laser scanning microscopy (CLSM). Sections were examined quantitatively according to the intensity of the pigmentation, as well as qualitatively based on the total number of granular pigments at all visual fields per tissue slide. Tissues from CPAs were compared to peritumoral adjacent tissues (n=5), to Conn adenomas (n=4), and PPNAD (n=3). CPAs had significantly higher number of lipofuscin-pigment granules compared to peritumoral adrenal tissue and Conn adenomas (46.9+/-9.5 vs. 3.8+/-4.8, p=0.0001). The presence of the PRKACA mutation did not increase the chances of pigmentation in the form of lipofuscin granules within CPAs associated with CS. Thus, all CPAs leading to CS accumulate lipofuscin, which presents like pigmentation sometimes seen macroscopically but always detected microscopically. PPNAD caused by PRKAR1A mutations is the best known adrenal lesion leading to CS associated with intense lipofuscin pigmentation and this was confirmed here; CPAs harboring PRKACA mutations did not have statistically significantly more pigmentation than CPAs without mutation, but a larger study might have shown a difference. PMID- 28834964 TI - ? AB - Increased plasma aldosterone concentration is significantly associated with dementia, which is accentuated by diabetes mellitus (DM). Angiotensin II (AngII) deteriorates cognitive function through neuronal degradation. Lipoproteins, a major source of cholesterol for aldosterone biosynthesis, undergo glycoxidative modifications in the presence of hyperglycemia. We hypothesize that there would be a pathophysiological link between diabetically-modified lipoproteins, angiotensin II, and increased plasma aldosterone concentration for induction of cognitive impairment. Glycoxidized lipoproteins produce significantly more aldosterone from AngII-sensitized adrenocortical cells compared to their native counterparts. The elucidation of signaling mechanisms revealed that modified lipoproteins follow the similar signaling mechanism like AngII for adrenocortical aldosterone release via ERK1/2 and Janus kinase-2 (Jak-2)-mediated pathways. The enhanced aldosterone release from AngII-sensitized adrenocortical cells induced by glycoxidatively modified lipoproteins may play a crucial role in cognitive dysfunction in diabetic individuals along with AngII via a prevailing mode of signaling cascade involving ERK1/2- and Jak-2-dependent pathways. PMID- 28834965 TI - Response Evaluation of Malignant Liver Lesions After TACE/SIRT: Comparison of Manual and Semi-Automatic Measurement of Different Response Criteria in Multislice CT. AB - Purpose To compare measurement precision and interobserver variability in the evaluation of hepatocellular carcinoma (HCC) and liver metastases in MSCT before and after transarterial local ablative therapies. Materials and Methods Retrospective study of 72 patients with malignant liver lesions (42 metastases; 30 HCCs) before and after therapy (43 SIRT procedures; 29 TACE procedures). Established (LAD; SAD; WHO) and vitality-based parameters (mRECIST; mLAD; mSAD; EASL) were assessed manually and semi-automatically by two readers. The relative interobserver difference (RID) and intraclass correlation coefficient (ICC) were calculated. Results The median RID for vitality-based parameters was lower from semi-automatic than from manual measurement of mLAD (manual 12.5 %; semi automatic 3.4 %), mSAD (manual 12.7 %; semi-automatic 5.7 %) and EASL (manual 10.4 %; semi-automatic 1.8 %). The difference in established parameters was not statistically noticeable (p > 0.05). The ICCs of LAD (manual 0.984; semi automatic 0.982), SAD (manual 0.975; semi-automatic 0.958) and WHO (manual 0.984; semi-automatic 0.978) are high, both in manual and semi-automatic measurements. The ICCs of manual measurements of mLAD (0.897), mSAD (0.844) and EASL (0.875) are lower. This decrease cannot be found in semi-automatic measurements of mLAD (0.997), mSAD (0.992) and EASL (0.998). Conclusion Vitality-based tumor measurements of HCC and metastases after transarterial local therapies should be performed semi-automatically due to greater measurement precision, thus increasing the reproducibility and in turn the reliability of therapeutic decisions. Key points . Liver lesion measurements according to EASL and mRECIST are more precise when performed semi-automatically.. . The higher reproducibility may facilitate a more reliable classification of therapy response.. . Measurements according to RECIST and WHO offer equivalent precision semi automatically and manually.. Citation Format . Hoink AJ, Schulke C, Koch R et al. Response Evaluation of Malignant Liver Lesions After TACE/SIRT: Comparison of Manual and Semi-Automatic Measurement of Different Response Criteria in Multislice CT. Fortschr Rontgenstr 2017; 189: 1067 - 1075. PMID- 28834966 TI - Checklist and Scoring System for the Assessment of Soft Tissue Preservation in CT Examinations of Human Mummies: Application to the Tyrolean Iceman. AB - Purpose Soft tissues make a skeleton into a mummy and they allow for a diagnosis beyond osteology. Following the approach of structured reporting in clinical radiology, a recently developed checklist was used to evaluate the soft tissue preservation status of the Tyrolean Iceman using computed tomography (CT). The purpose of this study was to apply the "Checklist and Scoring System for the Assessment of Soft Tissue Preservation in CT Examinations of Human Mummies" to the Tyrolean Iceman, and to compare the Iceman's soft tissue preservation score to the scores calculated for other mummies. Materials and Methods A whole-body (CT) (SOMATOM Definition Flash, Siemens, Forchheim, Germany) consisting of five scans, performed in January 2013 in the Department of Radiodiagnostics, Central Hospital, Bolzano, was used (slice thickness 0.6 mm; kilovolt ranging from 80 to 140). For standardized evaluation the "CT Checklist and Scoring System for the Assessment of Soft Tissue Preservation in Human Mummies" was used. Results All checkpoints under category "A. Soft Tissues of Head and Musculoskeletal System" and more than half in category "B. Organs and Organ Systems" were observed. The scoring system accounted for a total score of 153 (out of 200). The comparison of the scores between the Iceman and three mummy collections from Vilnius, Lithuania, and Palermo, Sicily, as well as one Egyptian mummy resulted in overall higher soft tissue preservation scores for the Iceman. Conclusion Application of the checklist allowed for standardized assessment and documentation of the Iceman's soft tissue preservation status. The scoring system allowed for a quantitative comparison between the Iceman and other mummies. The Iceman showed remarkable soft tissue preservation. Key Points . The approach of structured reporting can be transferred to paleoradiology.. . The checklist allowed for standardized soft tissue assessment and documentation.. . The scoring system facilitated a quantitative comparison among mummies.. . Based on CT, the Tyrolean Iceman demonstrated remarkable soft tissue preservation.. Citation Format . Panzer S, Pernter P, Piombino-Mascali D et al. Checklist and Scoring System for the Assessment of Soft Tissue Preservation in CT Examinations of Human Mummies: Application to the Tyrolean Iceman. Fortschr Rontgenstr 2017; 189: 1152 - 1160. PMID- 28834967 TI - Strategies in Interventional Radiology: Formation of an Interdisciplinary Center of Vascular Anomalies - Chances and Challenges for Effective and Efficient Patient Management. AB - Background Radiology is an interdisciplinary field dedicated to the diagnosis and treatment of numerous diseases and is involved in the development of multimodal treatment concepts. Method Interdisciplinary case management, a broad spectrum of diagnostic imaging facilities and dedicated endovascular radiological treatment options are valuable tools that allow radiology to set up an interdisciplinary center for vascular anomalies. Results Image-based diagnosis combined with endovascular treatment options is an essential tool for the treatment of patients with highly complex vascular diseases. These vascular anomalies can affect numerous parts of the body so that a multidisciplinary treatment approach is required for optimal patient care. Conclusion This paper discusses the possibilities and challenges regarding effective and efficient patient management in connection with the formation of an interdisciplinary center for vascular anomalies with strengthening of the clinical role of radiologists. Key points . Vascular anomalies, which include vascular tumors and malformations, are complex to diagnose and treat.. . There are far more patients with vascular anomalies requiring therapy than interdisciplinary centers for vascular anomalies - there is currently a shortage of dedicated interdisciplinary centers for vascular anomalies in Germany that can provide dedicated care for affected patients.. . Radiology includes a broad spectrum of diagnostic and minimally invasive therapeutic tools which allow the formation of an interdisciplinary center for vascular anomalies for effective, efficient and comprehensive patient management.. Citation Format . Sadick M, Dally FJ, Schonberg SO et al. Strategies in Interventional Radiology: Formation of an Interdisciplinary Center of Vascular Anomalies - Chances and Challenges for Effective and Efficient Patient Management. Fortschr Rontgenstr 2017; 189: 957 - 966. PMID- 28834968 TI - Microwave Ablation (MWA): Basics, Technique and Results in Primary and Metastatic Liver Neoplasms - Review Article. AB - Purpose The locoregional interventional oncological treatment approach is an accepted modality for liver neoplasms, especially for hepatocellular carcinoma (HCC) and oligonodular liver metastases. Materials and Methods The main aim of ablation therapies like microwave ablation (MWA) is to eradicate all malignant cells in a minimally invasive technique under imaging guidance while preserving the healthy tissue with a sufficient safety margin (at least 5 mm) surrounding the ablated lesion. Results Ablation therapy can be performed via a percutaneous, laparoscopic or intraoperative approach under ultrasound, MRI or CT guidance for adequate localization and monitoring of the ablation process. Conclusion Ablation is the method of choice for oligonodular HCCs <= 3 cm. The technical success rate varies from 88 % to 98 % and progression-free survival (PFS) at 3 years from 27 % to 91.7 %. The same criteria apply to the therapy of liver metastases. Key Points . Careful selection of patients proves to be essential for optimum results of MWA. . Interventionists should be familiar with all aspects of complication and rapid assessment of imaging methods in order to evaluate induced damage by thermal ablation. . MWA seems to have some advantages over radiofrequency ablation, like shorter ablation time, less pain, less heat sink effect; however, scientific proof is needed. Citation Format . Vogl TJ, Nour-Eldin A, Hammerstingl RM et al. Microwave Ablation (MWA): Basics, Technique and Results in Primary and Metastatic Liver Neoplasms - Review Article. Fortschr Rontgenstr 2017; 189: 1055 1066. PMID- 28834969 TI - ? PMID- 28834970 TI - ? PMID- 28834971 TI - ? PMID- 28834972 TI - [Healthcare Research into Anti-VEGF Therapy: Selection and Methodological Precautions]. AB - Health care research has emerged as an approach to assess and improve quality of care and patient outcomes in the real world. It also has the potential to reduce healthcare costs by providing evidence to guide healthcare decisions.Randomised controlled trials (RCTs) theoretically offer the ideal study design to support treatment decisions. In RCTs, randomisation (formal chance) determines treatment allocation, which prevents selection bias from distorting the parameters of anti VEGF treatment effects. Despite this advantage, only a minority of patients qualify for inclusion in neovascular age-related macular degeneration or diabetic macular oedema trials, which limits the validity of the results to the whole patient population seen in clinical practice. The evidence base for anti-VEGF is deficient in terms of matching the characteristics of patients encountered in clinical practice, and a more representative sample of older people and those with significant disability must be included in future trials. RCTs often do not address other knowledge gaps, including treatment delay, comparisons for less frequent types of CNV, monitoring of rare or late toxicity events or systemic safety.Observational studies, or studies in which treatment allocation occurs independently of investigators' choice or randomisation, can complement RCTs by providing data that is more relevant to the circumstances under which intravitreal therapy is routinely practiced. However, it is important to be aware of the strengths and limitations of such observational study designs, in order to optimise the design as well as the analytic techniques. Selection bias and loss to-follow-up cause make comprehensive interpretation and careful analysis necessary. Future reports should focus on time-to-event analysis, as this is much less prone to loss-to-follow-up and improves adherence of (functionally) one-eyed or good responders. Observational studies and pragmatic trials can test new hypotheses and possible license extensions. The bearing of RCT findings on day-to day practice can then be assessed. The data can be interpreted in a more meaningful manner by practicing clinicians if evidence is integrated from a variety of different study designs and methodologies. PMID- 28834973 TI - Simple Rules, Not So Simple: The Use of International Ovarian Tumor Analysis (IOTA) Terminology and Simple Rules in Inexperienced Hands in a Prospective Multicenter Cohort Study. AB - OBJECTIVES: To analyze how well untrained examiners - without experience in the use of International Ovarian Tumor Analysis (IOTA) terminology or simple ultrasound-based rules (simple rules) - are able to apply IOTA terminology and simple rules and to assess the level of agreement between non-experts and an expert. METHODS: This prospective multicenter cohort study enrolled women with ovarian masses. Ultrasound was performed by non-expert examiners and an expert. Ultrasound features were recorded using IOTA nomenclature, and used for classifying the mass by simple rules. Interobserver agreement was evaluated with Fleiss' kappa and percentage agreement between observers. RESULTS: 50 consecutive women were included. We observed 46 discrepancies in the description of ovarian masses when non-experts utilized IOTA terminology. Tumor type was misclassified often (n = 22), resulting in poor interobserver agreement between the non-experts and the expert (kappa = 0.39, 95 %-CI 0.244 - 0.529, percentage of agreement = 52.0 %). Misinterpretation of simple rules by non-experts was observed 57 times, resulting in an erroneous diagnosis in 15 patients (30 %). The agreement for classifying the mass as benign, malignant or inconclusive by simple rules was only moderate between the non-experts and the expert (kappa = 0.50, 95 %-CI 0.300 - 0.704, percentage of agreement = 70.0 %). The level of agreement for all 10 simple rules features varied greatly (kappa index range: -0.08 - 0.74, percentage of agreement 66 - 94 %). CONCLUSION: Although simple rules are useful to distinguish benign from malignant adnexal masses, they are not that simple for untrained examiners. Training with both IOTA terminology and simple rules is necessary before simple rules can be introduced into guidelines and daily clinical practice. PMID- 28834974 TI - [A painful nodule of the pinna]. PMID- 28834975 TI - [Suspicious tumor of the oropharynx in a child]. PMID- 28834976 TI - [Fibrinous lesions of the larynx in a 34-year old patient]. PMID- 28834977 TI - [Hearing test results of 18- to 20-year old men preceding military conscription from 2008-2010]. AB - OBJECTIVE: High-frequency hearing loss is known to increase with age, whereas the amount and rate of increase of hearing loss in younger people is still unclear. A large proportion of young age groups is expected to preserve normal hearing. Therefore, the requirements for screening methods are particularly high and the motivation to participate is low. The obligatory examinations preceding military conscription include a pure-tone audiogram and thus allow the analysis of the hearing status of young male adults. MATERIAL AND METHODS: The prevalence of hearing impairment was determined using air-conduction thresholds of 18- to 20 year old men, from 54 German registration offices (KWEA), measured in 2008 to 2010. The criterion was based on candidates exceeding a threshold of 20 dB HL for one of the frequencies 3, 4, or 6 kHz in at least one ear. This very strict criterion was compared to other definitions of hearing impairment. RESULTS: The prevalence of hearing impairment was, on average, 15.3 % and thus in the same range as in other studies. However, the results of single KWEA differed by up to a factor of 10. CONCLUSIONS: Due to high fluctuations in measurement quality in the KWEA, regional differences in hearing thresholds of young men are not resolvable and it remains unclear whether the hearing loss has increased in comparison to earlier studies. The high variability of measurements near thresholds requires permanent quality inspections. However, hearing thresholds derived from screening cannot be evaluated applying the same criteria as for hearing tests in audiological centers or studies. PMID- 28834978 TI - [Examination of Bell's palsy in consideration of the Austrian private accident insurance]. AB - In western Europe peripheral facial palsy is the most common cranial nerve disorder. The constitutional palsy may be ideopathic or combined with other disorders, above all Lyme's disease and otogenic zoster. The traumatic palsy is nearly always combined with other severe injuries and above all caused by accidents.Constitutional palsies have a less degree of partial recovery compared to the traumatic forms. The expert has to evaluate the actual status of palsy at the time of examination and also to consider prognostic outcome. The Austrian private accident insurance covers the risk of injuries caused by an accident. Accident according to the meaning of the insurance is a term of wide comprehension including facial palsy due to tick bite. First of all accidental dysfunctions are covered by the insurance. However, the insurance also offers restricted coverage concerning aesthetic consequences as a result of dysfunction. PMID- 28834979 TI - ? PMID- 28834980 TI - [Diagnosis of Internal Hernia After Roux-en-Y gastric bypass in Bariatric Patients by CT Imaging]. PMID- 28834982 TI - Clinical Value of Contrast Enema Prior to Ileostomy Closure. AB - Purpose To determine the value of routine contrast enema of loop ileostomy before elective ileostomy closure regarding the influence on the clinical decision making. Materials and Methods Retrospective analysis of contrast enemas at a tertiary care center between 2005 und 2011. Patients were divided into two groups: Group I with ileostomy reversal, group II without ileostomy closure. Patient-related parameters (underlying disease, operation method) and parameters based on the findings (stenosis, leakage of anastomosis, incontinence) were evaluated. Results Analyzing a total of 252 patients in 89 % (group I, n = 225) ileostomy closure was performed. In 15 % the radiologic report was the only diagnostic modality needed for therapy decision; in 36 % the contrast enema and one or more other diagnostic methods were decisive. In 36 % the radiological report of the contrast imaging was not relevant for decision at all. In 11 % (group II, n = 27) no ileostomy closure was performed. In this group in 11 % the radiological report of the contrast enema was the only decision factor for not performing the ileostomy reversal. In 26 % one or more examination was necessary. In 26 % the result of the contrast examination was not relevant. Conclusion The radiologic contrast imaging of loop ileostomy solely plays a minor role in complex surgical decision-making before planned reversal, but is important as first imaging method in detecting complications and often leads to additional examinations. Key points . Contrast enema of loop ileostomy before planned ileostomy closure is a frequently performed examination.. . There exist no general guidelines that give further recommendations on decision-making planning ileostomy closure.. . The radiologic contrast imaging of loop ileostomy solely plays a minor role in decision-making before planned reversal, but is important as first imaging method.. Citation Format . Goetz A, da Silva NP, Moser C et al. Clinical Value of Contrast Enema Prior to Ileostomy Closure. Fortschr Rontgenstr 2017; 189: 855 - 863. PMID- 28834984 TI - ? PMID- 28834983 TI - ? PMID- 28834985 TI - ? PMID- 28834986 TI - ? PMID- 28834988 TI - ? PMID- 28834987 TI - ? PMID- 28834989 TI - ? PMID- 28834990 TI - ? PMID- 28834991 TI - ? PMID- 28834992 TI - ? PMID- 28834993 TI - ? PMID- 28834994 TI - ? PMID- 28834995 TI - ? PMID- 28834996 TI - Uterine Extramedullary Plasmacytoma as a Primary Manifestation of Multiple Myeloma. AB - The association between plasmacytomas and multiple myeloma (MM) is well described, and in about one third of the cases of plasmacytoma the additional study will lead to the diagnosis of MM. The finding of plasmacytomas in the genital tract is extremely rare, with sparse cases described in the literature, and these cases pose a challenge regarding the optimal guidance and treatment. This paper describes a case of uterine extramedullary plasmacytoma in a 79-year old woman with complaints of postmenopausal abnormal uterine bleeding. The complementary study led to the diagnosis of uterine plasmacytoma and, subsequently, of MM. Despite the unfavorable outcome of this case, we consider pertinent to report it because it constitutes a differential diagnosis to be taken into account in the approach of pelvic masses. PMID- 28834997 TI - Prevalence of Maternal Morbidity and Its Association with Socioeconomic Factors: A Population-based Survey of a City in Northeastern Brazil. AB - Purpose To identify the prevalence of maternal morbidity and its socioeconomic, demographic and health care associated factors in a city in Northeastern Brazil. Methods A cross-sectional and population-based study was conducted, with a design based on multi-stage complex sampling. A validated questionnaire was applied to 848 women aged between 15 and 49 years identified in 8,227 households from 60 census tracts of Natal, the capital of the state of Rio Grande do Norte (RN), Brazil. The main outcome measure was maternal morbidity. The Poisson regression analysis, with 5% significance, was used for the analysis of the associated factors. Results The prevalence of maternal morbidity was of 21.2%. A bivariate analysis showed the following variables associated with an increased number of obstetric complications: non-white race (prevalence ratio [PR] =1.23; 95% confidence interval [95%CI]: 1.04-1.46); lower socioeconomic status (PR = 1.33; 95%CI: 1.12-1.58); prenatal care performed in public services (PR = 1.42; 95%CI: 1.16-1.72): women that were not advised during prenatal care about where they should deliver (PR = 1.24; 95%CI: 1.05-1.46); delivery in public services (PR = 1.63; 95%CI: 1.30-2.03); need to search for more than one hospital for delivery (PR = 1.22; 95%CI: 1.03-1.45); and no companion at all times of delivery care (PR = 1.25, 95%CI: 1.05-1.48). The place where the delivery occurred (public or private) and the socioeconomic status remained significant in the final model. Conclusion Women in a worse socioeconomic situation and whose delivery was performed in public services had a higher prevalence of maternal morbidity. Such an association reinforces the need to strengthen public policies to tackle health inequalities through actions focusing on these determinants. PMID- 28834998 TI - Knowledge and Compliance in Practices in Diagnosis and Treatment of Syphilis in Maternity Hospitals in Teresina - PI, Brazil. AB - Objective To assess the knowledge and compliance of health professionals regarding the diagnostic and treatment practices for syphilis in patients admitted for childbirth in public maternity hospitals in the city of Teresina, in the state of Piaui, Northeastern Brazil. Methods A cross-sectional study was performed in 2015 with obstetricians and nurses working in the public maternity hospitals in Teresina (n = 159) using a self-administered questionnaire, with 5% of losses and 10% of refusals. The study used 21 evaluation criteria: 13 of them were related to knowledge (5 on serological tests and 8 on treatment adequacy); 8 were related to practices (3 on diagnosis, 4 on treatment, and 1 on post-test counseling). The knowledge of and compliance to the practices was estimated as the proportion of health professionals' answers that were in agreement with Brazilian Ministry of Health protocols. Results The obstetricians were in agreement with two criteria concerning the knowledge of serological tests, one for diagnostic practices, and one for treatment practice. Among nurses, no single match between actual procedures and guidelines was observed. Conclusions Low compliance with the protocols results in missed opportunities for the diagnosis and treatment of pregnant and postpartum women and their partners. Strategies for training and integrating the various professional groups, improved data recording on prenatal cards, and greater accountability of the hospital team in managing the women's partners are needed to overcome the barriers identified in the study and to interrupt the syphilis transmission chain. PMID- 28834999 TI - [Impact of Case Numbers on the 5-Year Survival Rate of Unicondylar Knee Replacements in Germany]. AB - BACKGROUND: Reported survival rates of unicondylar knee arthroplasty (UKA) vary considerably. The influences of patient characteristics and the type of implant have already been examined. This analysis investigated the influence of hospital volume on 5-year-survival rate, using administrative claims data of Germany's largest health insurance provider. METHODS: We analysed administrative claims data for 20,946 UKAs covered by the German local healthcare funds (Allgemeine Ortskrankenkasse, AOK) between 2006 and 2012. Survival rates were estimated using Kaplan-Meier analysis. The influence of hospital case numbers on 5-year survival was analysed by means of multivariable Cox regression adjusted for patient characteristics. We estimated hazard ratios (HR) with 95% confidence intervals for five hospital volume categories: < 12 cases, 13 - 24 cases, 25 - 52 cases, 53 - 104 cases, > 104 cases (per hospital and year). RESULTS: The overall 5-year Kaplan-Meier survival rate was 87.8% (95%-CI: 87.3 - 88.3%). This increased with hospital volume (< 12 cases: 84.1% vs. > 104 cases: 93.2%). The analysis identified low hospital volume as an independent risk factor for surgical revision (< 12 cases: HR = 2.13 [95%-CI 1.83 - 2.48]; 13 - 24 cases: HR = 1.94 [95%-CI: 1.67 - 2.25]; 25 - 52 cases: HR = 1.66 [95%-CI: 1.41 - 1.96]; 53 - 104 cases: HR = 1.51 [95%-CI: 1.28 - 1.77]; > 104 cases: reference category). DISCUSSION: Our analysis revealed a significant relationship between hospital case numbers and 5-year survival rate, which increases with hospital volume. The risk of surgical revision within 5 years in hospitals with fewer than 25 UKAs per year is approximately twice as high as in hospitals with more than 104 cases. PMID- 28835000 TI - [Therapy of Periprosthetic Shoulder Infection]. AB - There are several therapeutic options for the treatment of periprosthetic joint infections of shoulder arthroplasties. In acute infections, the implant can remain in place with open debridement, septic lavage with antibacterial solutions such as octinedine or polyhexanide solution and exchange of all mobile components. In late infections, the therapeutic options after removal of the infected implant are: permanent spacer, resection arthroplasty, one stage revision and two stage revision with or without a temporary spacer. The functional results are best for one stage revisions, with similar prosthetic survival to two stage revisions. For one stage revisions, the microorganism has to be identified prior to revision surgery, in order to use targeted antibiotics locally in the cement, and systemically. PMID- 28835001 TI - Maternal Age and Trajectories of Risky Alcohol Use: A Prospective Study. AB - BACKGROUND: No prospective study of maternal alcohol use has focused on age at transition to motherhood as a predictor of trajectories of risky drinking. The goal of this study was to examine the impact of maternal age at first birth on trajectories of alcohol use beyond recommended levels over a 17-year span. METHODS: Pregnant women (N = 456) were recruited at an urban prenatal clinic. The women (13 to 42 years old; 64% African American, 36% White) were interviewed about alcohol use during pregnancy and at 6, 10, 14, and 16 years postpartum. Growth mixture modeling (GMM) was used to identify trajectories of risky drinking. Maternal age at first birth was then regressed onto trajectory class membership. RESULTS: The GMM on maternal alcohol use identified 3 groups of mothers as a function of alcohol use before, during, and after the pregnancy. The majority of mothers (66%) were identified as having low-risk trajectories of alcohol use over the 17-year span. However, 2 groups were in the higher-risk categories, with 23% identified as being in a long-term high-risk trajectory, and 11% in a short-term high-risk trajectory group. Maternal age at first birth predicted membership in a high-risk group: Younger mothers were more likely to be classified into a long-term high-risk alcohol use group. CONCLUSIONS: Younger mothers were more likely to engage in risky drinking early in pregnancy, continuing 6 to 14 years postpartum. These results can help physicians target mothers who are likely to exceed current NIAAA guidelines of abstinence during pregnancy, and no more than 7 drinks per week in the postpartum. PMID- 28835002 TI - Cripto Enhances Proliferation and Survival of Mesenchymal Stem Cells by Up Regulating JAK2/STAT3 Pathway in a GRP78-Dependent Manner. AB - Cripto is a small glycosylphosphatidylinositol-anchored signaling protein that can detach from the anchored membrane and stimulate proliferation, migration, differentiation, vascularization, and angiogenesis. In the present study, we demonstrated that Cripto positively affected proliferation and survival of mesenchymal stem cells (MSCs) without affecting multipotency. Cripto also increased expression of phosphorylated janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), 78 kDa glucose regulated protein (GRP78), c-Myc, and cyclin D1. Notably, treatment with an anti GRP78 antibody blocked these effects. In addition, pretreatment with STAT3 short interfering RNA (siRNA) inhibited the increase in p-JAK2, c-Myc, cyclin D1, and BCL3 levels caused by Cripto and attenuated the pro-survival action of Cripto on MSCs. We also found that incubation with Cripto protected MSCs from apoptosis caused by hypoxia or H2O2 exposure, and the level of caspase-3 decreased by the Cripto-induced expression of B-cell lymphoma 3-encoded protein (BCL3). These effects were sensitive to down-regulation of BCL3 expression by BCL3 siRNA. Finally, we showed that Cripto enhanced expression levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). In summary, our results demonstrated that Cripto activated a novel biochemical cascade that potentiated MSC proliferation and survival. This cascade relied on phosphorylation of JAK2 and STAT3 and was regulated by GRP78. Our findings may facilitate clinical applications of MSCs, as these cells may benefit from positive effects of Cripto on their survival and biological properties. PMID- 28835003 TI - Regulation of Pharmacogene Expression by microRNA in The Cancer Genome Atlas (TCGA) Research Network. AB - Individual differences in drug responses are associated with genetic and epigenetic variability of pharmacogene expression. We aimed to identify the relevant miRNAs which regulate pharmacogenes associated with drug responses. The miRNA and mRNA expression profiles derived from data for normal and solid tumor tissues in The Cancer Genome Atlas (TCGA) Research Network. Predicted miRNAs targeted to pharmacogenes were identified using publicly available databases. A total of 95 pharmacogenes were selected from cholangiocarcinoma and colon adenocarcinoma, as well as kidney renal clear cell, liver hepatocellular, and lung squamous cell carcinomas. Through the integration analyses of miRNA and mRNA, 35 miRNAs were found to negatively correlate with mRNA expression levels of 16 pharmacogenes in normal bile duct, liver, colon, and lung tissues (p<0.05). Additionally, 36 miRNAs were related to differential expression of 32 pharmacogene mRNAs in those normal and tumorigenic tissues (p<0.05). These results indicate that changes in expression levels of miRNAs targeted to pharmacogenes in normal and tumor tissues may play a role in determining individual variations in drug response. PMID- 28835004 TI - Analysis of Kudoa septempunctata as a cause of foodborne illness and its associated differential diagnosis. PMID- 28835005 TI - Novel energy crops for Mediterranean contaminated lands: Valorization of Dittrichia viscosa and Silybum marianum biomass by pyrolysis. AB - Establishing energy crops could be a cost-efficient alternative towards the valorization of the plant biomass produced in contaminated lands, where they would not compete with food production for land use. Dittrichia viscosa and Silybum marianum are two native Mediterranean species recently identified as potential energy crops for degraded lands. Here, we present the first characterization of the decomposition of the biomass of these species during thermo-chemical conversion (pyrolysis). Using a greenhouse study we evaluated whether the quality of D. viscosa and S. marianum biomass for energy production through pyrolysis could be substantially influenced by the presence of high concentrations of soluble trace element concentrations in the growing substrate. For each species, biomass produced in two different soil types (with contrasted trace element concentrations and pH) had similar elemental composition. Behavior during thermal decomposition, activation energies and concentrations of pyrolysis gases were also similar between both types of soils. Average activation energy values were 295 and 300 kJ mol-1 (for a conversion value of alpha = 0.5) for S. marianum and D. viscosa, respectively. Results suggest that there were no major effects of soil growing conditions on the properties of the biomass as raw material for pyrolysis, and confirm the interest of these species as energy crops for Mediterranean contaminated lands. PMID- 28835006 TI - Growth of Chlorella vulgaris and nutrient removal in the wastewater in response to intermittent carbon dioxide. AB - In this study, Chlorella vulgaris (C. vulgaris) were cultured in cell culture flask supplied with intermittent CO2 enriched gas. The impact of CO2 concentration (from 1% to 20% v/v) on the growth of C. vulgaris cultured in domestic wastewater was exploited in various perspectives which include biomass, specific growth rate, culture pH, carbon consumption, and the removal of nitrogen and phosphorus compounds. The results showed that the maximum microalgal biomass concentration, 1.12 g L-1, was achieved with 10% CO2 as a feed gas. At 20% CO2 the growth of C. vulgaris suffered from inhibition during initial 1.5 d, but acclimated to low pH (6.3 in average) with relatively higher specific growth rate (0.3-0.5 d-1) during subsequent culture period. After the rapid consumption of ammonium in the wastewater, an obvious decline in the nitrate concentration was observed, indicating that C. vulgaris prefer ammonium as a primary nitrogen source. The total nitrogen and phosphorus decreased from 44.0 mg L-1 to 2.1-5.4 mg L-1 and from 5.2 mg L-1 to 0-0.6 mg L-1 within 6.5 d under the aeration of 1 20% CO2, respectively, but no significant difference in consumed nitrogen versus phosphorus ratio was observed among different CO2 concentration. The kinetics of nutrients removal were also determined through the application of pseudo first order kinetic model. 5-10% CO2 aeration was optimal for the growth of C. vulgaris in the domestic wastewater, based on the coupling of carbon consumption, microalgal biomass, the nutrients removal and kinetics constants. PMID- 28835007 TI - Impacts of biochar addition on soil dissolved organic matter characteristics in a wheat-maize rotation system in Loess Plateau of China. AB - Biochar amendment in soil has the potential to sequester carbon, improve soil quality and mitigate greenhouse gas (GHG) emission in agriculture, but the impact of biochar amendments on dissolved organic matter (DOM) properties of soils in the fertilized agro-ecosystem has received little research attention. This study performed a long-term field experiment to assess the influence of biochar amendments (different addition rate: 4 t ha-1 and 8 t ha-1) on DOM characteristics in soils in wheat-maize rotation system in Loess Plateau of China by exploiting fluorescence excitation-emission spectrophotometry and parallel factor analysis (EEM-PARAFAC). Our results showed that the content of soil DOM was significantly influenced by the addition of biochar, and the higher biochar addition markedly increased the mean concentration of dissolved organic carbon (DOC) (from 83.99 mg kg-1 to 144.27 mg kg-1) in soils under the same fertilizer application. Three identified fluorescent components (fulvic acid-like, humic acid-like and tryptophan-like) were found, and fluorescence intensity of those components (especially humic-like material) was enhanced with the increasing DOC in the biochar treatments but the composition of DOM was not changed. These findings would be beneficial to understand the biochar's effects and processes in decreasing GHG emissions from soils. PMID- 28835008 TI - Thiamethoxam and picoxystrobin reduce the survival and overload the hepato nephrocitic system of the Africanized honeybee. AB - Apis mellifera perform important pollination roles in agroecosystems. However, there is often intensive use of systemic pesticides in crops, which can be carried to the colony by forage bees through the collection of contaminated pollen and nectar. Inside the colony, pollen loads are stored by bees that add honey and several enzymes to this pollen. Nevertheless, intra-colonial chronic exposure could induce sublethal effects in young bees exposed to a wide range of pesticides present in these pollen loads. This study was aimed to both determine the survival rate and evaluate the sublethal effects on the hepato-nephrocitic system in response to continuous oral exposure to lower concentrations of neonicotinoid thiamethoxam (TXT) and picoxystrobin fungicide (PXT). Exposure to a single chemical and co-exposure to both pesticides were performed in newly emerged honeybee workers. A significant decrease in the bee survival rates was observed following exposure to TXT (0.001 ng a.i./MUL) and PXT (0.018 ng a.i./MUL), as well as following co-exposure to TXT+PXT/2. After five days of continuous exposure, TXT induced sub-lethal effects in the organs involved in the detoxification of xenobiotics, such as the fat body and pericardial cells, and it also induced a significant increase in the hemocyte number. Thus, the hepato nephrocitic system (HNS) reached the greatest level of activity of pericardial cells as an attempt to eliminate this toxic compound from hemolymph. The HNS was activated at low levels by PXT without an increase in the hemocyte number; however, the mobilization of neutral glycoconjugates from the trophocytes of the fat body was prominent only in this group. TXT and PXT co-exposure induced intermediary morphological effects in trophocytes and pericardial cells, but oenocytes from the fat body presented with atypical cytoplasm granulation only in this group. These data showed that the realistic concentrations of these pesticides are harmful to newly emerged Africanized honeybees, indicating that intra-colonial chronic exposure drastically reduces the longevity of bees exposed to neonicotinoid insecticide (TXT) and the fungicide strobilurin (PXT) as in single and co-exposure. Additionally, the sublethal effects observed in the organs constituting the HNS suggest that the activation of this system, even during exposure to low concentrations of theses pesticides, is an attempt to maintain homeostasis of the bees. These data together are alarming because these pesticides can affect the performance of the entire colony. PMID- 28835009 TI - Corrigendum to "Attention-deficit hyperactivity disorder, its treatment with medication and the probability of developing a depressive disorder: A nationwide population-based study in Taiwan" [J. Affect. Disord. 189 (2016) 110-117]. PMID- 28835010 TI - Corrigendum to: Bereavement-related depression: Did the changes induced by DSM-V make a difference? Results from a large population-based survey of French residents [Clesse et al., J. Affect. Disord. 182 (2015) 82-90]. PMID- 28835011 TI - Corrigendum to "Omega-6 fatty acids and greater likelihood of suicide risk and major depression in early pregnancy" [J. Affect. Disord. 152-154 (2014) 76-82]. PMID- 28835012 TI - Corrigendum to "Effects of comorbidity and early age of onset in young people with Bipolar Disorder on self harming behaviour and suicide attempts". PMID- 28835013 TI - Corrigendum to: Antidepressants worsen rapid-cycling course in bipolar disorder: A STEP-BD randomized clinical trial. J. Affect. Disord. (Jun. 10, 2015); http://dx.doi.org/10.1016/j.jad.2015.04.054. PMID- 28835014 TI - Positive imagery cognitive bias modification (CBM) and internet-based cognitive behavioural therapy (iCBT): A randomized controlled trial. PMID- 28835015 TI - Smart device-based testing for medical students in Korea: satisfaction, convenience, and advantages. AB - The aim of this study was to investigate respondents' satisfaction with smart device-based testing (SBT), as well as its convenience and advantages, in order to improve its implementation. The survey was conducted among 108 junior medical students at Kyungpook National University School of Medicine, Korea, who took a practice licensing examination using SBT in September 2015. The survey contained 28 items scored using a 5-point Likert scale. The items were divided into the following three categories: satisfaction with SBT administration, convenience of SBT features, and advantages of SBT compared to paper-and-pencil testing or computer-based testing. The reliability of the survey was 0.95. Of the three categories, the convenience of the SBT features received the highest mean (M) score (M= 3.75, standard deviation [SD]= 0.69), while the category of satisfaction with SBT received the lowest (M= 3.13, SD= 1.07). No statistically significant differences across these categories with respect to sex, age, or experience were observed. These results indicate that SBT was practical and effective to take and to administer. PMID- 28835016 TI - Palestinian pharmacists' knowledge of issues related to using psychotropic medications in older people: a cross-sectional study. AB - PURPOSE: The purpose of this study was to assess the knowledge of pharmacists practicing in Palestine of issues related to using psychotropic medications in older people. METHODS: The study was conducted with a cross-sectional observational design using a questionnaire. A total of 400 pharmacists responded to a 19-statement knowledge test related to the use of psychotropic medications in older people. The study was conducted from July 2016 to February 2017. The reliability and internal consistency of the study tool was assessed using the test-retest method and the Cronbach alpha. Categorical groups were compared using the chi-square test and the Spearman rank correlation. RESULTS: On the 19 statement knowledge test, the median score was 55.3% with an interquartile range of 21.9%. In a comparison of the demographic and practice-related variables of the pharmacists who scored >= 50% on the 19-statement knowledge test with those who scored < 50%, age, gender, and having taken a course on psychotropic medications were found to be significantly associated with performance, as shown by the chi-square test and Spearman correlation. CONCLUSION: Pharmacists practicing in Palestine possess less than optimal knowledge of issues related to the use of psychotropic medications in older people. Continuing educational interventions and/or training might be helpful in improving pharmacists' knowledge of issues related to using psychotropic medications in older people. PMID- 28835018 TI - Effect of FGF-2, TGF-beta-1, and BMPs on Teno/Ligamentogenesis and Osteo/Cementogenesis of Human Periodontal Ligament Stem Cells. AB - The periodontal ligament (PDL) is the connective tissue between tooth root and alveolar bone containing mesenchymal stem cells (MSC). It has been suggested that human periodontal ligament stem cells (hPDLSCs) differentiate into osteo/cementoblast and ligament progenitor cells. The periodontitis is a representative oral disease where the PDL tissue is collapsed, and regeneration of this tissue is important in periodontitis therapy. Fibroblast growth factor-2 (FGF-2) stimulates proliferation and differentiation of fibroblastic MSCs into various cell lineages. We evaluated the dose efficacy of FGF-2 for cytodifferentiation of hPDLSCs into ligament progenitor. The fibrous morphology was highly stimulated even at low FGF-2 concentrations, and the expression of teno/ligamentogenic markers, scleraxis and tenomodulin in hPDLSCs increased in a dose dependent manner of FGF-2. In contrast, expression of the osteo/cementogenic markers decreased, suggesting that FGF-2 might induce and maintain the ligamentogenic potential of hPDLSCs. Although the stimulation of tenocytic maturation by TGF-beta1 was diminished by FGF-2, the inhibition of the expression of early ligamentogenic marker by TGF-beta1 was redeemed by FGF-2 treatment. The stimulating effect of BMPs on osteo/cementogenesis was apparently suppressed by FGF-2. These results indicate that FGF-2 predominantly differentiates the hPDLSCs into teno/ligamentogenesis, and has an antagonistic effect on the hard tissue differentiation induced by BMP-2 and BMP-4. PMID- 28835017 TI - Cariporide Enhances the DNA Damage and Apoptosis in Acid-tolerable Malignant Mesothelioma H-2452 Cells. AB - The Na+/H+ exchanger is responsible for maintaining the acidic tumor microenvironment through its promotion of the reabsorption of extracellular Na+ and the extrusion of intracellular H+. The resultant increase in the extracellular acidity contributes to the chemoresistance of malignant tumors. In this study, the chemosensitizing effects of cariporide, a potent Na+/H+-exchange inhibitor, were evaluated in human malignant mesothelioma H-2452 cells preadapted with lactic acid. A higher basal level of phosphorylated (p)-AKT protein was found in the acid-tolerable H-2452AcT cells compared with their parental acid sensitive H-2452 cells. When introduced in H-2452AcT cells with a concentration that shows only a slight toxicity in H-2452 cells, cariporide exhibited growth suppressive and apoptosis-promoting activities, as demonstrated by an increase in the cells with pyknotic and fragmented nuclei, annexin V-PE(+) staining, a sub G0/G1 peak, and a G2/M phase-transition delay in the cell cycle. Preceding these changes, a cariporide-induced p-AKT down-regulation, a p53 up-regulation, an ROS accumulation, and the depolarization of the mitochondrial-membrane potential were observed. A pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 markedly augmented the DNA damage caused by the cariporide, as indicated by a much greater extent of comet tails and a tail moment with increased levels of the p-histone H2A.X, p-ATMSer1981, p-ATRSer428, p-CHK1Ser345, and p-CHK2Thr68, as well as a series of pro-apoptotic events. The data suggest that an inhibition of the PI3K/AKT signaling is necessary to enhance the cytotoxicity toward the acid-tolerable H-2452AcT cells, and it underlines the significance of proton-pump targeting as a potential therapeutic strategy to overcome the acidic microenvironment-associated chemotherapeutic resistance. PMID- 28835019 TI - Small RNA Transcriptome of Hibiscus Syriacus Provides Insights into the Potential Influence of microRNAs in Flower Development and Terpene Synthesis. AB - MicroRNAs (miRNAs) are essential small RNA molecules that regulate the expression of target mRNAs in plants and animals. Here, we aimed to identify miRNAs and their putative targets in Hibiscus syriacus, the national flower of South Korea. We employed high-throughput sequencing of small RNAs obtained from four different tissues (i.e., leaf, root, flower, and ovary) and identified 33 conserved and 30 novel miRNA families, many of which showed differential tissue-specific expressions. In addition, we computationally predicted novel targets of miRNAs and validated some of them using 5' rapid amplification of cDNA ends analysis. One of the validated novel targets of miR477 was a terpene synthase, the primary gene involved in the formation of disease-resistant terpene metabolites such as sterols and phytoalexins. In addition, a predicted target of conserved miRNAs, miR396, is SHORT VEGETATIVE PHASE, which is involved in flower initiation and is duplicated in H. syriacus. Collectively, this study provides the first reliable draft of the H. syriacus miRNA transcriptome that should constitute a basis for understanding the biological roles of miRNAs in H. syriacus. PMID- 28835020 TI - Effects of Adenoviral Gene Transduction on the Stemness of Human Bone Marrow Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (MSCs) are currently being evaluated as a cell-based therapy for tissue injury and degenerative diseases. Recently, several methods have been suggested to further enhance the therapeutic functions of MSCs, including genetic modifications with tissue- and/or disease-specific genes. The objective of this study was to examine the efficiency and stability of transduction using an adenoviral vector in human MSCs. Additionally, we aimed to assess the effects of transduction on the proliferation and multipotency of MSCs. The results indicate that MSCs can be transduced by adenoviruses in vitro, but high viral titers are necessary to achieve high efficiency. In addition, transduction at a higher multiplicity of infection (MOI) was associated with attenuated proliferation and senescence-like morphology. Furthermore, transduced MSCs showed a diminished capacity for adipogenic differentiation while retaining their potential to differentiate into osteocytes and chondrocytes. This work could contribute significantly to clinical trials of MSCs modified with therapeutic genes. PMID- 28835023 TI - [Application of holistic integrative medicine in stomatology]. PMID- 28835021 TI - Engineering and Application of Zinc Finger Proteins and TALEs for Biomedical Research. AB - Engineered DNA-binding domains provide a powerful technology for numerous biomedical studies due to their ability to recognize specific DNA sequences. Zinc fingers (ZF) are one of the most common DNA-binding domains and have been extensively studied for a variety of applications, such as gene regulation, genome engineering and diagnostics. Another novel DNA-binding domain known as a transcriptional activator-like effector (TALE) has been more recently discovered, which has a previously undescribed DNA-binding mode. Due to their modular architecture and flexibility, TALEs have been rapidly developed into artificial gene targeting reagents. Here, we describe the methods used to design these DNA binding proteins and their key applications in biomedical research. PMID- 28835024 TI - [Occlusion: current situation and prospect in view of holistic integrative medicine]. AB - The rise of holistic integrative medicine (HIM) is an inevitable consequence of modern medical development which emphasizes the change from specialization to integration of the most advanced medical knowledge. It does not mean a simple collection of the medical theories, but means the digestion of those theories for the clinical practical application. Because occlusal therapy is characterized as not only a high level of individualization, but also a relation to many stomatology and other disciplines, such as plastic surgery, orthopedics, neurosciences and psychology. It needs the HIM to guide the clinical practice. With undertaking occlusal therapy, to avoid the limitation due to the excessive specialized disciplines, and to provide effective treatment plans for abnormal occlusion induced diseases, it is necessary to develop the discipline of the holistic integrative stomatology. PMID- 28835022 TI - Application of Functional Near-Infrared Spectroscopy to the Study of Brain Function in Humans and Animal Models. AB - Functional near-infrared spectroscopy (fNIRS) is a noninvasive optical imaging technique that indirectly assesses neuronal activity by measuring changes in oxygenated and deoxygenated hemoglobin in tissues using near-infrared light. fNIRS has been used not only to investigate cortical activity in healthy human subjects and animals but also to reveal abnormalities in brain function in patients suffering from neurological and psychiatric disorders and in animals that exhibit disease conditions. Because of its safety, quietness, resistance to motion artifacts, and portability, fNIRS has become a tool to complement conventional imaging techniques in measuring hemodynamic responses while a subject performs diverse cognitive and behavioral tasks in test settings that are more ecologically relevant and involve social interaction. In this review, we introduce the basic principles of fNIRS and discuss the application of this technique in human and animal studies. PMID- 28835025 TI - [Oral maxillofacial-head and neck tumor and holistic integrative medicine]. AB - The advance of clinical diagnosis and treatment in oral and maxillofacial-head and neck tumors has been through the process of specialization and multidisciplinary cooperation. In most cases, a single discipline cannot meet the requirements of diagnosis and treatment, which needs the cooperation of oral and maxillofacial surgery, otolaryngology and oncology approach and therapeutic method such as surgery, radiotherapy and chemotherapy. Holistic integrative medicine aims at integrating the most effective clinical practice experience and patients' individual situation and prognosis, establishing new medical mode conforming to the modern concept and fulfilling the medical system adapting to the specific characteristics of the diseases. PMID- 28835026 TI - [Application of holistic integrative medicine in orthodontics]. AB - Holistic integrative medicine (HIM) is a new medical knowledge system, which is formed based on the theory of HIM. HIM treats people as a whole by combining the results of basic medical research, clinical practice and clinical research during the treatment process. The concept of HIM runs through the education and treatment of orthodontics. HIM is the trending norm of both modern medicine and orthodontics. This review is about the concept of HIM and the advantages and disadvantages of specialization. Moreover, this review also discusses the vital role of HIM in orthodontic treatment and development. PMID- 28835027 TI - [Periodontology from the perspective of holistic integrative medicine]. AB - Medical diciplines have been gradually differentiated and specialized during its developement, and problems due to deep specialization have been increasingly apparent. Its performance is as follows: dental specialists tends to focus on a certain narrow area and ignore neither the patients as a whole existence nor the role of the environmental factors. In this article, the author tries to show the holistic integrative medicine (HIM) from the point of view of periodontal specialty. In fact, the pathogenesis, the differential diagnosis and the treatment of periodontal diseases along with the role of preventive dentistry and basic medicine for periodontology must be considered as a whole using the philosophy of HIM. The future development of periodontal specialty should absorb the achievements of other medical and dental diciplines. Periodontist should pay more attention to HIM. The author also gives some thoughts and suggestions on how to practice HIM in the field of periodontics. PMID- 28835028 TI - [Holistic integrative medicine: application in prevention and treatment of oral mucosal diseases]. AB - Holistic integrative medicine (HIM), as one of the important ideas in the field of medicine, arouses great concern recently. HIM regards the human body as a whole, turns data and evidence in medical research back to facts, integrates technologies and experience developed in clinical research into medical skills. The repeated practices at the levels of fact, experience, and medical skills will generate true knowledge to solve the wide spread problems brought by linearized thinking and fragmented knowledge. With the development of highly divided medical disciplines, how to utilize and practice HIM has become a common concern of the medical community. Specialization of stomatology, which is a first level discipline like medicine, has also become a trend for years. However, holistic concept cannot be overlooked, especially in the development of oral medicine. This article aims at the communication and exchange of knowledge about HIM among dental professionals. In order to serve the patients better, the authors look forward to practicing the HIM concept in the field of oral medicine through the efforts of us all. PMID- 28835029 TI - [Efficacy of subgingival glycine air polishing on patients with early peri implant diseases]. AB - Objective: To compare the clinical efficacies of subgingival glycine air polishing and ultrasonic scaling combined with 0.12% chlorhexidine rinsing on patients with early peri-implant diseases (peri-implant mucositis and early peri implantitis). Methods: Twenty-two systemically healthy patients with totally 42 implants and early peri-implant diseases, were recruited in this study. The patients were randomly divided into the test group and the control group. Patients in the test group were treated with subgingival glycine air polishing and patients in the control group were treated with ultrasonic scalers combined with 0.12% chlorhexidine rinsing. Periodontal parameters such as probing depth, bleeding index, plaque index and clinical attachment loss, at baseline and 2 months after treatment, respectively, were collected and compared between the test and control groups. Results: For the natural teeth, the parameters of probing depth, bleeding index, plaque index and attachment loss in the two groups were significantly improved after treatments (medians were 0.48 mm vs 0.22 mm, 1.00 vs-0.13, 0.38 vs 0.50, 0.48 mm vs 0.22 mm, respectively for test and control group). There was no statistical difference of median between the two groups after treatment except for that of the attachment loss (medians, 0.48 mm vs 0.22 mm, P=0.034). For the implants, differences of parameters in the two groups at baseline were insignificant. After treatments, the probing depths significantly decreased by 0.67 mm and 0.33 mm in the test group and the control group, respectively. The inter-group differences, however, were insignificant. Significant difference of the bleeding index after treatment was found in the test group (P=0.019), but not in the control group. No adverse reactions were found on patients in the two groups after treatments. Conclusions: Efficacy of subgingival glycine air polishing and ultrasonic scaling combined with 0.12% chlorhexidine rinsing is competitive on patients with early peri-implant diseases. However, the former treatment may be more effective oncontrolling the early peri-implant inflammation. PMID- 28835030 TI - [Effect of dentin proteoglycans on the stability of resin-dentin bonds against artificial saliva storage]. AB - Objective: To investigate the potential effect of proteoglycans (PG) and glycosaminoglycans (GAG) on the stability of resin-dentin bonds against artificial saliva storage. Methods: Seventy-two extracted molars were used to obtain standard dentin bonding surface, and the specimens were etched for 15 s with 37% phosphoric acid and divided into three groups using a table of random number. Then the three groups undergone different incubating procedures as follow: specimens in chondroitinase ABC (C-ABC) group were incubated with C-ABC, specimens in trypsin (TRY) group were incubated with trypsin, and specimens in the control group were incubated with deionized water. All specimens were incubated at 37 C for 48 h in the oscillators. Then specimens in each group were randomly assigned into three subgroups (n=8) as follows: immediate control subgroup, aging subgroups with artificial saliva storage for 6 months and 12 months. Microtensile bond strength (MUTBS), fracture mode, bonding interface morphology and nanoleakage were evaluated. Results: Immediately and with artificial saliva storage for 6 months and 12 mouths, the MUTBS of TRY group ([49.04+/-3.57], [37.01+/-3.21] and [35.27+/-3.56] MPa) were significantly higher than those in the control group ([40.71+/-3.32], [28.87+/-2.34] and [24.20+/ 2.07] MPa) (P<0.05). The immediate MUTBS of C-ABC group ([32.94+/-2.45] MPa) was significantly lower than that of the control group (P<0.05). While with artificial saliva storage for 6 months and 12 mouths, the MUTBS of C-ABC group ([26.46+/-2.45] and [22.50+/-2.58] MPa) were no differences with those of the control group (P>0.05). The ratio of cohesive fracture increased with the extension of aging time. Some narrow gaps were found in hybrid layer of the control group with artificial saliva storage for 6 months and 12 mouths. Conclusions: Removal of PG increased the MUTBS and durable bonds to dentin, while removal of GAG decreased the MUTBS, however, it can be of help to create more durable bonds to dentin. PMID- 28835031 TI - [Effect of polydimethylsiloxane matrix elasticity on osteogenic differentiation of rat marrow stromal cells]. AB - Objective: To investigate the effect of polydimethylsiloxane (PDMS) matrix elasticity on osteogenic differentiation of rat marrow stromal cells (rBMSC). Methods: A series of PDMS composite substrates with different elastic modulus were constructed by adjusting the relative concentrations of cross-linking agent. The Young's modulus was used to describe the elasticity of PDMS after measurement by atomic force microscope (AFM). After surface modification, rBMSC was seeded on PDMS matrix, and 7 days after rBMSC was cultured on the five different Young's moduli matrix, the differences of osteogenic differentiation of rBMSC were observed by the method of real-time PCR, Western blotting, and alkaline phosphatase assay. Results: The PDMS was suitable for cell culture after surface modification, and by altering the concentration of cross-linking agent, PDMS could mimic the majority of the tissues' elasticity in vivo. The related osteogenic differentiation markers expression showed significant difference between the five matrixes (P<0.05), including type I collagen (Col-I), osteocalcin (OCN), osteopontin (OPN) and bone morphogenetic protein 2 (BMP2). The expression of osteogenic markers was up-regulated in the group that the Young's modulus was (354.1+/-40.9) kPa (P<0.05). Conclusions: PDMS is a tunable elasticity matrix which could be used in the investigation of inducing rBMSCs into osteoblastic lineages. PDMS substrate stiffness has an obvious influence on rBMSC osteogenic differentiation. PMID- 28835032 TI - [Effects of Porphyromonas endodontalis lipopolysaccharides on the expression of matrix metalloproteinase-9 in mouse osteoblasts]. AB - Objective: To evaluate the effects of lipopolysaccharides (LPS) extracted from Porphyromonas endodontalis (Pe) on the expression of matrix metalloproteinase-9 (MMP-9) mRNA and protein as well as enzyme activity in MC3T3-E1 cells and the role of nuclear factor-kappaB (NF-kappaB) in the process, so as to investigate the expression of MMP-9 dependent signaling pathways in mouse osteoblasts induced by Pe LPS. Methods: The experiment was conducted in 3 sessions: MC3T3-E1 cells were treated with various concentrations of Pe LPS (0-20 mg/L) and 10 mg/L Pe LPS for different time intervals (0-48 h). The expression of MMP-9 mRNA and protein were detected by real-time reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), while the enzyme activity was detected by gelatin zymography method. The expression of MMP-9 mRNA was also detected in 10 mg/L Pe LPS treated MC3T3-El cells after pretreated with specific NF-kappaB inhibitor BAY 11-7082 for l h. Statistical analysis was performed using one-way ANOVA and Dunnett t test with SPSS 13.0 software package. Results: The levels of MMP-9 mRNA and protein increased significantly after the treatment with various concentrations of Pe LPS (0-20 mg/L), which indicated that Pe LPS induced osteoblasts to express MMP-9 in dose dependent manners. The expression of MMP-9 protein increased from (5 395+/-362) ng/L (blank control group) to (12 684+/-375) ng/L (20 mg/L group). Maximal induction of MMP-9 mRNA expression was found in the MC3T3-E1 cells treated with 10 mg/L Pe LPS for 24 h. The expression of MMP-9 mRNA in the 20 mg/L group was about 7 times than that in the blank control group. After 24 h, the expression of MMP-9 mRNA decreased. Maximal expression of MMP-9 protein was found in the MC3T3-E1 cells treated with 10 mg/L Pe LPS for 48 h ([35 055+/-2 346] ng/L) showing the highest enzyme activity. The mRNA of MMP-9 decreased significantly after pretreatment with 10 umol/L BAY 11-7082 for 1 h. Conclusions: Pe LPS might induce the expression of MMP-9 in MC3T3-E1 cells through the signaling of NF-kappaB. PMID- 28835033 TI - [An interpretation of the TNM classification for lip and oral cavity tumor in the cancer staging manual of American Joint Committee on Cancer (8th edition)]. PMID- 28835035 TI - [Intrusion of multiple supraerupted molars using interim restoration: a case report]. PMID- 28835034 TI - [Analysis and discussion of risk factors related to dental implant failure]. AB - The implant prosthesis has been extensively used in clinic recently, and implant failure is appearing. Many factors may cause the failure, and they work together generally. This paper summarizes and analyzes the failure cases related to implant treatment and relevant risk factors of oral implants in Department of Implantation, School of Stomatology, The Fourth Military Medical University during the past six years, in order to improve the success rate of implant prosthesis and provide guidance for clinical application. PMID- 28835036 TI - [A case of hemophagocytic syndrome secondary to extranodal nasal type NK/T cell lymphoma IIB]. PMID- 28835038 TI - [Current situation and future of tumor ablation in China]. PMID- 28835037 TI - [Impact of anchorage implant design factors on its primary stability]. AB - During the past decade, the anchorage implants have been widely used in the orthodontic treatment. Many scholars have studied the influence of different factors on anchorage implant's primary stability, including anchorage implant's material properties, structural design, surgical procedure, bone condition, loading force's magnitude and direction. This article is to review the influence of anchorage implant's shape, dimension, neck design and thread design on its primary stability. PMID- 28835039 TI - [National restricted medical technology--Expert interpretation: Standardized management and clinical application's quality control index of tumor ablation technology]. PMID- 28835040 TI - [The standard application of ablation technique in surgical treatment of hepatic tumor]. PMID- 28835041 TI - [The interpretation on ESWT indications and contraindications of international society for medical shockwave treatment]. PMID- 28835042 TI - [Analysis of early response to the antipsychotic treatment and related factors in acute schizophrenia patients]. AB - Objective: The objective was to assess the relationship between early response and later response to antipsychotics, and the relationship between antipsychotics and early response. Methods: Data were retrospectively analyzed from patients with schizophrenia and they were hospitalized in the Second Affiliated Hospital of Xinxiang Medical College from May, 2013 to September, 2015.The patients were divided into theearly response group (PANSS total score improvement >=20% at week 2) and early nonresponse group.General information, the use of drug and the Positive and Negative Syndrome Scale (PANSS) on before and 2, 4, 6 weeks after treatment were compared between the two groups.The relation between early response and late response and the effect of drug selection on early response were analyzed by correlation analysis and regression analysis. Results: Relative to early nonresponders, early responders were significantly more likely to have lower PANSS scores (total scores on 2, 4, 6 weeks after treatment 66.2+/-11.8 vs 84.5+/-10.9, 55.9+/-13.2 vs 70.9+/-13.7, 48.9+/-13.1 vs 60.6+/-14.9, all P<0.05) and higher PANSS scores improvement at 2, 4, 6 weeks after treatment (total scores improvement on 2, 4, 6 weeks after treatment (37+/-14)% vs (9+/-7)%, (56+/ 19)% vs (32+/-18)%, (68+/-20)% vs (49+/-21)%, all P<0.05). The correlation coefficient between PANSS total score improvement at week 2 and at week 4, 6 were 0.730 and 0.541, respectively (all P<0.05). Olanzapine had more PANSS total score improvement than aripiprazole, quetiapine and ziprasidone (2 weeks after treatment (29+/-19)% vs (19+/-16)%, (18+/-15)%, (17+/-15)%, 4 weeks after treatment (51+/-21)% vs (37+/-25)%, (39+/-18)%, (37+/-22)%, all P<0.05). The protective factor for early response was olanzapine (P<0.05). Conclusions: Early responders are associated with faster and greater improvement in symptoms, the type of antipsychotic has impacts on early response, early non-responders can benefit from adjustment of treatment. PMID- 28835043 TI - [Application of magnetic resonance imaging to predict the type and severity of placenta accreta]. AB - Objective: To investigate the value of magnetic resonance imaging (MRI) in predicting the type and severity of placenta accreta (PA). Methods: The clinical data of 67 PA cases in Peking University Third Hospital from January, 2015 to November, 2016 were analyzed retrospectively.Cases were classified according to the direct and indirect MRI signs.Chi-square test was applied to disclose the difference between different PA types and MRI signs.MRI signs with statistical significance were further calculated by the area under ROC curve (AUC) value analysis to reveal the correlation between specific signs and the type/severity of PA. Results: Among the 67 cases, 24 cases were of mild PA and 43 cases were of severe PA.Statistical difference was found between the two PA groups in some signs such as placenta tissues invading the uterus myometrium, placenta tissues extending beyond the uterus outline, the uniformity of placental signal, abnormal vessel imaging in the placenta basilar part, Bladder Tent Sign and the discontinuity of low signal zone in the gap between bladder and placenta.AUC analysis showed that the above MRI signs had the stronger correlations between the type/severity of PA, compared with other signs. Conclusion: Not only can MRI be used to predict the type of PA, but also it can be used to predict the location and severity of PA, which has an important reference value for clinical works. PMID- 28835044 TI - [Clinical efficacy of acute intraoperative encephalocele prevention strategy for severe traumatic brain injury]. AB - Objective: To explore the clinical efficacy of prevention strategy for acute intraoperative encephalocele of patients with severe traumatic brain injury (sTBI). Methods: A total of 173 patients with sTBI, who treated in Emergency Neurosurgery Department of Shandong University Qilu Hospital from January, 2011 to September, 2015 were collected and divided into research group and control group, according to their therapeutic strategy.The clinical data during hospitalization and prognosis 1 year after injury was analyzed retrospectively to clarify the effect of acute encephalocele prevention strategy. Results: There were no statistically significant differences in sex, age, preoperative Glasgow coma scale score and imaging type of lesion between patients from the two groups.The highest intraoperative intracranial pressure in the research group and control group were (35.71+/-4.13) mmHg and(34.85+/-3.81) mmHg, respectively.The acute encephalocele incidence of the research group (7 cases, 6.5%) was significantly lower than that of the control group (13 cases, 19.7%) (P<0.01). Subgroup analysis showed that the incidence of acute encephalocele in patients with only unilateral lesions was low (1.3%), while higher (19.4%) in patients with both unilateral lesions and other secondary lesions or diffuse brain swelling.The prognosis of the patients was evaluated by Glasgow Outcome Scale according to the follow-up 1 year after injury, and it was suggested that the percentage of patients with good outcome in the research group (62 cases, 57.9%) was remarkably higher than that in the control group (26 cases, 39.4%) (P=0.018). Conclusions: For sTBI patients with high risk of acute encephalocele, prevention strategy was found to be able to retard the progression of delayed hematoma and diffuse brain swelling, prevent the acute encephalocele during operation, and then significantly improve the prognosis. PMID- 28835045 TI - [Analysis of gene mutation and clinical characteristics in patients with idiopathic epilepsy]. AB - Objective: To explore the association between gene mutations and clinical characteristics in Chinese patients with epilepsy. Methods: A total of twenty three patients with idiopathic epilepsy admitted to the Xuanwu Hospital of Capital Medical University from January 2014 to July 2016 were included.The age at onset of epilepsy ranged from 8 months to 31 years.All patients were screened for mutations by next-generation of sequencing (NGS), using a targeted capture panel of epilepsy and related seizures to screen forgene causative for or related to epilepsy.Some mutations were verified for inheritance by Sanger sequencing of two generations in the family.The differences in clinical characteristics among different mutation carriers were compared. Results: A total of 38 mutations were identified in 23 patients.Most of the patients presented with tonic-clonic seizures, and most were not accompanied by mental retardation.Causative genes were dominated by those encoding ion channel, enzyme and proteins with special functions.Although mutation carriers for genes encoding ion channel proteins and those with special functions were not significantly different in age at onset, types of seizure, family history or complications(P>0.05), patients presenting with tonic-clonic seizures had higher frequency of mutations in genes encoding ion channel (15/15)than those encoding proteins with special function(16/20)(P=0.066). Conclusions: NGS is a useful technology in detecting mutations in patients with various types of epilepsy and aiding in etiological diagnosis of the disease.Tonic-clonic seizures may correlate with mutations in genes encoding ion channel. PMID- 28835046 TI - [Evaluation of the proximal femur geometry in patients with elderly osteoporotic hip fractures]. AB - Objective: To investigate the relationship between the proximal femur geometry and elderly osteoporotic hip fractures. Methods: From May 2015 to December 2015, 137 patients with elderly osteoporotic hip fractures were involved.69 cases were in the fracture group and 68 cases were in the control group.CT scan were performed on all patients and the proximal femur geometry parameters were measured, including the neck width (NW), neck length (NL), neck shaft angle (NSA), femur head diameter (FHD), head height (HH) and Offset.Statistical analysis was performed between two groups. Results: The results of single factor analysis showed that age, sex, NL, FHD, NSA and Offset had significantly differences between two groups (P<0.05). The multiple Logistic regression analysis showed that age, sex, NL and NSA were independent risk factor for the hip fractures.The ROC curve analysis showed that area under curve (AUC) were 0.818, 0.818 and 0.725, respectively. Conclusions: The patients with older age, longer NL and larger NSA might be prone to hip fracture and it was an effective and feasible method to reconstruct and measure the CT data of the proximal femur with Mimics software. PMID- 28835047 TI - [Foundation of preoperative prognosis estimation model for glioblastoma multiforme]. AB - Objective: This study explored the preoperative prognostic factors of patients with glioblastoma multiforme (GBM) in order to propose a preoperative prognosis estimation model. Methods: The clinical data of 416 patients diagnosed with GBM in Beijing Tiantan Hospital affiliated to Capital Medical University from 2008 to 2015 were retrospectively reviewed.A total of nine factors: gender, age, duration of symptoms, preoperative epilepsy, preoperative muscle weakness, preoperative headache, preoperative KPS score, tumor location and tumor diameter were enrolled in the survival analysis.The significant factors identified by Kaplan-Meier plot were further collected in the multivariate Cox regression analysis.On the basis of multivariate analysis results, a preoperative prognosis estimation model was founded. Results: Univariate analysis showed that Age >=50 years, without preoperative epilepsy, tumor located in non-frontotemporal lobe, tumor diameter >=6 cm and preoperative KPS score <70 were prognostic risk factors (P<0.05). Multivariate analysis revealed that Age >=50 years, without preoperative epilepsy, tumor located in non-frontotemporal lobe were independent risk factors (P<0.05). The prognostic estimation model based on the independent risk factors divided the whole cohort into three subgroups with different survival (P<0.001). Conclusions: The more risk factors, the higher score but poorer prognosis. Patients in the high-risk group had lower gross total resection degree but higher rate of postoperative complications, which suggested that aggressive resection was not suitable for high-risk patients. PMID- 28835048 TI - [The study of hearing loss after microvascular decompression for hemifacial spasm]. AB - Objective: To compare the difference of hearing loss after microvascular decompression for hemifacial spasm between control and experimental groups, and to explore the possible causes. Methods: A retrospective analysis including 443 patients was performed, including 203 cases of group A (before the operation was improved) and 240 cases of group B (after the operation was improved). Chi-square test was used to compare the rate of hearing loss. Results: There were 18(8.9%) cases with postoperative hearing loss in group A, including 9 cases of conductive hearing loss and 9 cases of sensorineural hearing loss.While 2 cases of conductive hearing loss and 3 cases of sensorineural hearing loss occurred in group B. Conductive hearing loss and sensorineural hearing loss of two groups had the significant deference (P=0.015 and P=0.04). Conclusion: The type of hearing loss after microvascular decompression for hemifacial spasm included conductive and sensorineural hearing loss.It could be reduced by early closing of the mastoid air chamber, avoiding continuous traction of the cerebellum, avoiding excessive irrigation and exhaust, and intraoperative auditory brainstem evoked potential monitoring. PMID- 28835049 TI - [Preliminary clinical efficacy of percutaneous transcystic papilla balloon dilation for removing common bile duct stones]. AB - Objective: To evaluate the feasibility, safety, and preliminary efficacy of percutaneous transcystic papilla balloon dilation for the common bile duct stones. Methods: A total of 11 patients with the common bile duct stones without dilatation of the intrahepatic bile ducts treated with percutaneous transcystic papilla balloon dilation in multiple center from April 2013 to May 2015 were analyzed retrospectively.In these 11 patients, there were 3 males and 8 females.And the average age was 68(52-91) years old.All patients had no obviously dilated intrahepatic bile duct, 6 patients were not suitable for endoscopic treatment or surgery, 4 patients refused endoscopic or surgical treatment and 1 patient had a history of failed endoscopic treatment.The white blood cell count, CA19-9, total bilirubin, direct bilirubin, AST, ALT and serum amylase level were recorded before the procedure, 1 week, and 1 month later.Early complications, such as cholangitis, pancreatitis, hemorrhage, and perforation were evaluated. Results: Technical success was achieved in all the 11 cases.The level of CA19-9, total bilirubin and direct bilirubin decreased significantly 1 week and 1 month after the procedure.One patient suffered from biliary tract infection.No severe complications, such as perforation of biliary or gastrointestinal tract, occurred during the follow up.Common bile duct stone recurred in 1 patient 2 years after the procedure. Conclusions: For cases who are not suitable for endoscopic treatment, surgery, or percutaneous transhepatic approach to treat the common bile duct stones, percutaneous transcystic papilla dilation is technically feasible and safe, and seems to be an appropriate alternative strategy. PMID- 28835050 TI - [Implantation of the irradiation stent system intoportal vein: studies on normal beagles]. AB - Objective: To assess the feasibility and safety of the irradiation stent system in portal vein on normal beagles. Methods: A portal vein irradiation stent system was composed of an Iodine-125 seeds-carrier and a conventional stent.Twenty beagle dogs were randomly assigned to receive treatment with a conventional stent (5 beagle dogs) or an irradiation stent system (15 beagle dogs in three groups received 11.1, 22.2, 33.3 MBq radioactivity, n=5 in each dose group). Follow-up methods included blood biochemical test, color Doppler sonographyand CT scan at 0, 15, 30, 60, and 120 days after implantation of irradiation stent system.Pathological tissues were obtained from sacrificed beagle dogs on the 120th day. Results: The portal vein irradiation stent systems and the conventional stents were successfully deployed into the targeted portal vein segment in all beagles, none was dislodged during the deployment or the follow-up period.Differences of blood biochemical indexes and portal vein flow volume measured by color Doppler sonography were not significant (P>0.05). Stent systems were morphologically intact and patent.None of the peripheral organs had hemorrhage, necrosis or perforation.Pathological tissues revealed that the systems were surrounded by fibrous tissues and a few inflammatory cells, but with no significant differences in all groups. Conclusion: It indicates that portal veinirradiation stent system is safe in all dose groups, and it is feasible to design a special irradiation stent system for each patient according to the size of the portal vein tumor thrombus. PMID- 28835051 TI - [RNA interference targeting DNA-PKcs inhibits glioma cells malignancies and enhances temozolomide sensitivity]. AB - Objective: To investigate the effect of DNA dependent protein kinase catalytic subunit (DNA-PKcs) on glioma proliferation, invasion and temozolomide sensitivity, and also to explore the potential mechanisms. Methods: Human glioma cell lines H4 and U87 were chosen to carry out RNA interference transfection, and then divided into negative control group (blank group) and siRNA group (test group). The knockdown efficacy of DNA-PKcs siRNA was tested by quantitative PCR and Western blot. The MTS assay and Transwell assay were used to investigate the effect of DNA-PKcs knockdown on glioma cell growth and invasion, respectively. We also used MTS assay to investigate the IC(50) value of temozolomide in negative control group and siRNA groups. Result: Compared with blank group, DNA-PKcs specific siRNA significantly downregulated both mRNA and protein level of DNA PKcs. MTS assay results demonstrated that 72-hours proliferation of test group were only 52.48%, 54.70% (H4) and 52.98%, 50.45% (U87) of the blank group's counterpart. Transwell assay results showed that the invasiveness abilities of blank and test groups were 1.00+/-0.03, 0.41+/-0.05, 0.39+/-0.04 (H4) and 1.00+/ 0.02, 0.28+/-0.04, 0.27+/-0.04 (U87). Moreover, knockdown of DNA-PKcs significantly decreased the temozolomide IC(50) value (H4: 249+/-27, 97+/-39, 88+/-35; U87: 485+/-41, 86+/-49, 73+/-38). Further we applied the Western blot to reveal the mechanism of inhibitory effect of DNA-PKcs knockdown on glioma malignancies and temozolomide sensitivity. We found that downregulation of DNA PKcs reduced the activity of AKT signal and the expression of its downstream effectors, such as c-Myc, MMP9, and Survivin. Conclusion: RNA interference targeting DNA-PKcs could inhibit glioma malignancies and enhance temozolomide sensitivity. The inhibitory effect of DNA-PKcs knockdown on those biological activities were mainly through inhibition of AKT signal and its downstream effectors. PMID- 28835052 TI - [Enhanced recovery after surgery in bariatric and metabolic procedure]. PMID- 28835053 TI - [Analysis of survival and treatment outcome of young patients with high-risk diffuse large B cell lymphoma]. AB - Objective: To analyze clinical feature and treatment outcome of young patients with high-risk diffuse large B cell lymphoma. Methods: A total of 122 young patients with high-risk diffuse large B cell lymphoma who were treated in Third Hospital of Peking University during the period from January 2000 to April 2015 were retrospectively analyzed, and the clinical features, laboratory data were included in Kaplan-Meier and prognostic analysis. Results: In our center, the incidence of young high-risk DLBCL was 27.1% in all DLBCL patients, median age was 44.0 years, 99.2% patients belong to III and IVstage, 50% patients had more than two extranodal organs involvement, and the higher proliferation index(Ki 67>=80%) was present in 63.1% of patients, Immunohistochemistry showed that 36.7% patients in 30 cases were double-expressed DLBCL. The overall response rate(ORR) for the whole group was 79.4%, the complete response rate was 39.7% , the 3, 5 year progression free survival rate was 59.8% and 57.0%, the 3, 5-year overall survival rate was 63.5% and 57.8%, respectively. 44.3% patients were refractory relapsed DLBCL. Rituximab can improve the survival of patients and 3-year overall survival rate was 75.2% vs 46.1%(P=0.001). High-dose chemotherapy was superior to CHOP regimen which 3-year overall survival rate was 84.6% vs 54.1%(P=0.006). Compared with chemotherapy group , auto-hematopoietic stem cell transplantation can improve prognosis of patients and 3-year overall survival rate was 93.4% vs 48.3%(P<0.001). The level of Ki-67, B symptom, ECOG score, the level of LDH, WBC and albumin, ESR level, anemia, rituximab therapy, initial regimens, ASCT, initial treatment outcome and refractory-relapsed were predictive of overall survival. Multivariate analysis indicated that albumin level(RR=5.462, P=0.019), initial treatment outcome(RR=34.863, P<0.001) and refractory-relapsed (RR=24.374, P<0.001)were independent prognostic risk factors. Conclusions: Young patients with high-risk DLBCL were highly aggressive in clinical and pathological features . Rituximab and high-dose regimens can improve the survival of patients. PMID- 28835054 TI - [Clinical and pathological differences between papillary thyroid carcinoma with Graves' disease and papillary thyroid carcinoma with Hashimoto's thyroiditis]. AB - Objective: To explore the clinical and pathological differences between papillary thyroid carcinoma (PTC) with Graves' disease (GD) and PTC with Hashimoto's thyroiditis (HT). Methods: A total of 33 PTC patients with GD and 132 PTC patients with HT in the First Affiliated Hospital of China Medical University from January 2009 to December 2015 were enrolled. The clinical and histopathological data were analyzed. Results: The average serum concentration of thyroid stimulating hormone (TSH) of PTCs with GD was significantly lower than PTCs with HT [0.01 (0, 0.10) mU/L vs 2.28(1.51, 3.14) mU/L, P<0.001]. However, there was no significant difference between the two groups in nodule diameter [(15.7+/-7.0) mm vs (13.5+/-7.8)mm, P=0.14], percentage of lymph node metastasis (LNM) [33.3%(11/33) vs 39.4%(52/132), P=0.52], TNM stage III-IV disease [12.1%(4/33) vs 11.4% (15/132), P=1.00], papillary thyroid micro-carcinoma (PTMC) [60.6% (20/33) vs 60.6%(80/132), P=1.00]and classic PTC in all its variant patterns [81.8%(27/33) vs 75.0%(99/132), P=0.36]. The age (P<0.01, OR=0.95, 95%CI: 0.92-0.98) and PTMC (P<0.01, OR=0.30, 95%CI: 0.13-0.67), rather than TSH (P=0.08) were independently correlated with LNM. Recurrence rate of PTC with GD was significantly lower than PTC with HT (log-rank test, P=0.03). In Cox proportional hazards regression model, variant pattern of PTC was independently correlated with recurrence rate (P<0.05). Conclusions: GD with PTC wasn't different from HT concomitant with PTC, except for thyroid function test. In addition, recurrence rate of PTC with GD was lower than that of PTC with HT after controlling TSH in the same level. PMID- 28835055 TI - [Patients of Escherichia coli bloodstream infection: analysis of antibiotic resistance and predictors of mortality]. AB - Objective: To analyze the drug resistance of Escherichia coli (E.coli) from bloodstream infection (BSI) and the predictors of mortality in E. coli bloodstream infection (BSI). Methods: The clinical data of 139 E. coli BSI cases diagnosed from January 2012 to December 2015 in The Second Affiliated Hospital of Zhejiang University School of Medicine, Lanxi Branch (Lanxi People's Hospital), Zhejiang Province, were retrospectively analyzed. The antimicrobial susceptibility testing was performed using Vitek 2 system. Extended-spectrum beta lactamases (ESBLs) were detected by disk diffusion confirmatory testing. The factors associated with ESBLs-producing strains were identified by univariate analysis. Multivariate analysis was used to identify independent predictors of infection mortality by applying Logistic regression. Results: 42.4% of E. coli isolates were ESBLs-producing. The resistant rate of imipenem was 0.7%. The percent of ESBLs in hospital-acquired infection was higher than that in community acquired infection but without statistical significance (48.7% versus 40.0%, P=0.350). Univariate analysis suggested that the percent of ESBLs-producing strains in BSI happened on >=15 d after admission and in BSI of biliary tract infection source was 76.9% and 68.0%, which were much higher than those in BSI happened on <15 d after admission and in BSI of non-biliary tract infection source (34.6% and 36.8%, P=0.013 and 0.004). The overall mortality of E. coli BSI was 13.7%. Multivariate Logistic regression analysis indicated that Sequential Organ Failure Assessment (SOFA ) score (OR=1.393, P<0.001), ceftazidime non susceptibility (OR=4.444, P=0.018) and liver cirrhosis (OR=13.513, P=0.001) were independent risk factors of mortality. Conclusions: The frequency of ESBLs producing E. coli was high in primary hospital of Zhejiang Province. SOFA score, ceftazidime non-susceptibility and cirrhosis were predictors of poor outcome in E. coli BSI. PMID- 28835056 TI - [Application of optical coherence tomography angiography in evaluation of retinal microvascular changes in patients with obstructive sleep apnea syndrome]. AB - Objective: To assess the changes of retinal microvasculature in patients with obstructive sleep apnea syndrome (OSAS) evaluated by optical coherence tomography (OCTA). Methods: Adult OSAS patients who visited Beijing Tongren Hospital from Jan 2016 to Apr 2016 and complained of snoring were included in this study. The patients' general information, results of polysomnography, and OCTA parameters were collected. Patients were divided into three groups according to their apnea hypopnea index (AHI) results: Mild-moderate group, AHI<=30/h; Severe group, 30/h60/h, and clinical characteristics, polysomnography and OCTA parameters among the three groups were compared. Results: A total of 27 patients were included in this study with 21 males (77.8%) and 6 females (22.2%). Mean age was (41.7+/-10.0) years, and the mean body mass index was (27.9+/-4.5) kg/m(2;) Neck circumference was 31-48 cm, mean (39.8+/ 4.3) cm; 8 patients (29.6%) suffered from hypertension that could be controlled; Epworth sleepiness scale scored 1-18 points and mean (8.5+/-4.4) scores; AHI ranged between 5.5 and 92.1/h with a mean of (46.4+/-28.6)/h. There were 9 (33.3%), 7 (25.9%), and 11 (40.7%) patients in mild-moderate group, severe group, and extremely severe group, respectively. Compared with severe group, the optic nerve head and radial peripapillary capillaries (RPC) peripapillary vascular density in extremely severe group were significantly decreased (62.4%+/-1.9% vs 60.3%+/-1.9%, P=0.041; 64.7%+/-1.7% vs 62.2%+/-2.3%, P=0.036). Conclusions: OCTA has rapid, safe, and objective characteristics in assessing the retinal microvascular changes in OSAS patients. Retinal microvascular damage in patients with OSAS is associated with the disease severity. Reduction of retinal microvascular density in patients with OSAS may be associated with intermittent hypoxia. PMID- 28835057 TI - [Comparative analysis of open surgical repair and endovascular aortic repair in the treatment of abdominal aortic aneurysm implicated visceral arteries]. AB - Objective: To evaluate the value of open surgery repair and endovascular aortic repair in the treatment of abdominal aortic aneurysm which implicate visceral arteries. Methods: From January 2012 to October 2016, 26 patients were reviewed. According to the treatment, they were divided into open surgery group (n=7) and endovascular repair group(n=19). Then, the characteristics and relative data of follow-up of the two groups were analysis. Results: In open surgery group, there were 7 patients. All of them were men, median age 58(41-62) years and 1 patient were older than 75 years. And in endovascular repair group, there were 19 patients(14 men) of median age 72(66-76) years, 8 patients were older than 75 years. Patients in endovascular repair group were significantly older than who were in open surgery group (Z=-13.06, P<0.05). Complications of open surgery group and endovascular repair group were 57.14% and 15.79% respectively. There was no statistically significant difference (chi(2)=3.13, P>0.05). During follow up, the diameters of aneurysm which planted stents were smaller than before. Conclusions: In the treatment of abdominal aortic aneurysm implicated visceral arteries, open surgery is mainly suitable for the patients with low-risk. But the rate of complications was high. By contrast, endovascular aortic repair with small trauma and high safety, has becoming the first choice. PMID- 28835058 TI - [Effection of combining dexmedetomidine with lidocaine cream on response to tracheal extubation in pediatric tonsillectomy]. AB - Objective: To evaluate the effects of combining dexmedetomidine with lidocaine cream on extubation reaction in pediatric tonsillectomy. Methods: Eighty children scheduled for tonsillectomy from January to June 2016 in the Lanzhou University Second Hospital, were randomly divided into group C (controll group), group D (dexmedetomidine group), group L (lidocaine cream group)and group R (combing dexmedetomidine with lidocaine group) by digital random table method (n=20). In group D and R, dexmedetomidine 1 MUg/kg was injected intravenously after general anesthesia induction, and the same volume of normal saline was given in group L and C. Meanwhile, the children in group L and R were intubated with endotracheal tube coated with compound lidocaine cream at first third, while the children were intubated with endotracheal tube coated with liquid paraffin in group D and C. Heart rate(HR), systolic blood pressure(SBP), diastolic blood pressure(DBP) and saturation of pulse oximetry(SPO(2)) were recorded at the time of baseline(T0), before(T1) and immediately (T2) extubation, 1(T3), 5(T4), 10(T5)minutes after extubation. The time of spontaneous breathing recovery and extubation were recorded. Cough score, agitation score and adverse reactions were evaluated during the peri-extubation period. Results: During extubation, HR were (86.70+/ 6.53), (89.30+/-4.93), (86.00+/-4.05) beats per minute at T1, T2, T3 respectively in group D, and they were (90.35+/-6.60), (91.20+/-6.44), (90.20+/-5.43) beats per minute in group L and were (85.70+/-8.67), (88.10+/-8.75), (86.95+/-7.73) beats per minute in group R. HR were (96.15+/-10.16), (97.75+/-10.93), (94.35+/ 7.26) beats per minute at T1, T2, T3 respectively in group C. HR were significantly lower in group D, R and L than that in group C at T1, T2, T3(F=6.754, 5.655, 7.191, all P<0.05). Cough score were (1.80+/-0.70), (1.55+/ 0.69), (1.25+/-0.44) in group D, L and R respectively. All of them were significantly lower than that in group C(2.45+/-1.05) (F=0.614, P<0.05). Cough score were significantly lower in group R than that in group D(P<0.05). Agitation score were (1.95+/-0.83), (1.75+/-0.72) in group D and R respectively, and they were significantly lower than that in group C(2.90+/-1.21)(F=9.245, P<0.05). Agitation incidence were 20%, 15% respectively in group D and R, and they were significantly lower than that in group C(60%) (chi(2)=21.554, P<0.05). Conclusion: Combining dexmedetomidine with lidocaine cream can effectively alleviate stress and cough reaction during extubation in pediatric tonsillectomy. PMID- 28835059 TI - [Efficacy of patient-controlled intravenous analgesia with hydromorphone hydrochloride plus flurbiprofen axetil after endoscopic sinus surgery]. AB - Objective: To evaluate the efficacy of patient-controlled intravenous analgesia (PCIA)with hydromorphone hydrochloride plusflurbiprofen axetil after endoscopic sinus surgery(ESS). Methods: One hundred patients of American Society of Anesthesiologists physical status I or II, scheduled for ESS under total intraveous anesthesia with postoperative PCIA in Beijing Tongren Hospital from October 2015 to April 2016 were randomly divided into 3 groups according to the different formula of PCIA pumpin each group: Group A (hydromorphone hydrochloride 1 MUg.kg(-1).h(-1)+ flurbiprofen axetil 200 mg), Group B(hydromorphone hydrochloride 2 MUg.kg(-1).h(-1)), Group C( hydromorphone hydrochloride 1 MUg.kg( 1).h(-1)). The dosage of PCIA in each group was calculated for 50 h, and was diluted in 100 ml normal saline. All the pump was set up background infusion at a rate of 2 ml/h with a 2 ml bolus dose and a 15 min lock-time.Visual analogue scale (VAS) and Ramsay sedation scores at time points of postoperative 1, 4, 8, 12, 24, 48 h, the number of attempts to press bolus and rate of adverse effects within 48 h were recorded. The differences were compared among the groups. Results: VAS at postoperative 1, 4, 8, 12 h in Group A was (1.9+/-0.6), (1.8+/ 0.6), (1.6+/-0.6), and (1.2+/-0.4) respectively, in Group B was (1.8+/-0.4), (1.7+/-0.7), (1.6+/-0.6), and (1.3+/-0.5) respectively, in Group C was (2.5+/ 0.9), (1.7+/-0.7), (1.6+/-0.6), and (1.3+/-0.5) respectively. The difference among each group were statistically significant (F=8.661, 3.105, 4.903, 13.846, P<0.05). VAS in Group A was similar to that in Group B(P>0.05), but was lower than that in Group C(P<0.05). The number of attempts to press bolus within 48 h in group A was 1.4+/-1.0, which was less than in Group C(2.2+/-1.8 , P<0.05). Ramsay sedation score at postoperative 1, 4, 8 h in Group A was (2.4+/-0.6), (2.2+/-0.6), and (2.2+/-0.4) respectively, in Group B was (2.8+/-0.7), (2.6+/ 0.7), and (2.4+/-0.6) respectively, in Group C was (2.3+/-0.6), (2.1+/-0.4), and (2.1+/-0.2) respectively. The difference among each group were statistically significant (F=5.660, 6.782, 7.141, P<0.05). Ramsay sedation score in group A was similar to that in Group C(P>0.05), but was lower than that in Group B(P<0.05). The total rate of adverse effects in Group A was 8.8%, which was similar to that in Group C (9.1%, chi(2)=0.001, P>0.05), but was significantly lower than that in Group B (42.5%, chi(2)=9.99, P<0.05). Conclusion: 1 MUg.kg(-1).h(-1) hydromorphone hydrochloride plus 200 mg flurbiprofen axetil is effective on PCIA for patients after ESS and can reduce the dosage of hydromorphone hydrochloride and the rate of adverse effects as well. PMID- 28835061 TI - [Outcome of negative pressure wound therapy on diabetic foot ulcers: an observational study]. AB - Objective: To compare the treatment effects between negative pressure wound therapy (NPWT) and traditional therapy in diabetic patients with foot ulcers. Methods: Diabetic patients with foot ulcers were selected from Endocrinology Ward between January 2015 and December 2016. All the patients were consecutively selected to receive NPWT in addition to the traditional therapy. Each patient receiving NPWT was individually matched with a patient receiving only traditional therapy and selected as the control group. Patients were controlled in both groups for age, sex and history of diabetes, hemoglobin A1c (HbA1c) level, and severity of the ulcer. Each patient received therapy for 3 months and was evaluated at the end of treatment. Treatment efficacy was evaluated by examining the lesion area before and after the therapy. Outcomes were compared between the two groups using the Chi square test. Results: A total of 62 patients were included in the study, with 31 cases in each group.Three months later, in the NPWT group, 26 patients had good therapeutic effects, 5 patients had poor efficacy, and 4 patients underwent the surgical treatment. While in the control group, only 18 patients had good therapeutic effects, 13 patients had poor efficacy, and 6 patients underwent surgical treatment. The effective percentage was significantly higher in NPWT group than that of the control group(P<0.05). Conclusion: NPWT can effectively improve the healing process of patients with diabetic foot ulcers in 3 months. PMID- 28835060 TI - [Significance of monitoring the gradients between transcutaneous PCO(2) and end tidal PCO(2) in patients with septic shock]. AB - Objective: To investigate the significance of monitoring the gradients between transcutaneous PCO(2) and end-tidal PCO(2) [P(c-et)CO(2)] in patients with septic shock. Method: Thirty-five mechanically ventilated patients with early septic shock were enrolled as the study group and 18 non-septic shock patients with stable hemodynamics as the control group between May 2014 and October 2016. The patients with septic shock were treated by early goal-directed therapy (EGDT) within 6 hours since hospitalization. The differences of baseline level of P(c et)CO(2) and arterial lactate concentration (LAC) between the two groups and the variations of these indexes after EGDT in the study group were compared respectively. Results: The baseline levels of P(c-et)CO(2) and LAC in patients with septic shock were significantly higher than those of the control group [(26.0+/-16.2) mmHg vs (11.0+/-5.6) mmHg (1 mmHg=0.133 kPa) and (4.0+/-1.7) mmol/L vs (1.6+/-0.6)mmol/L, all P=0.000]. The area under receiver operator characteristic (ROC) curve (AUC) for baseline P(c-et)CO(2) and LAC was 0.924 (95%CI: 0.851-0.996) and 0.931 (95%CI: 0.872-1.000), respectively. P(c-et)CO(2) >12.6 mmHg and LAC >2.5 mmol/L could discriminate septic shock patients from those without shock with the same sensibility of 97% and the specificity of 83% and 78% respectively. With regard to the prognosis (Day 28) of the patients with septic shock, AUC for baseline P(c-et)CO(2) and LAC was 0.709 (95%CI: 0.533 0.886) and 0.714 (95%CI: 0.545-0.883), respectively. P(c-et)CO(2) >20.0 mmHg and LAC>3.6 mmol/L could discriminate survivors from non-survivors with the same sensibility of 92% and the same specificity of 76%. All the patients in the study group completed EGDT within 6 hours after admission, 20 (57.1%) passed EGDT and 17 (85.0%) survived, 15 (42.9%) failed EGDT and 4 (26.7%) survived, and the survival rates were significantly different (F=9.844, P=0.001). After EGDT, P(c et)CO(2) (21.0+/-9.5 mmHg) and LAC(3.3+/-2.5 mmol/L)reduced significantly compared with the baselines (P=0.008 and P=0.046), and the associated AUC was 0.905(95%CI: 0.792-1.000) and 0.747 (95%CI: 0.576-0.917)respectively. P(c et)CO(2) > 16.5 mmHg and LAC > 3.1 mmol/L could discriminate survivors from non survivors with the sensibility of 97% and 91%, and the specificity of 78% and 69%, respectively. Conclusions: P(c-et)CO(2) >12.6 mmHg could play the same role as LAC in recognizing early septic shock. EGDT was an effective therapy for the septic shock and P(c-et)CO(2) reflected efficacy. P(c-et)CO(2)>20 mmHg before EGDT and >16.5 mmHg after EGDT both could predict the 28 d prognosis of patients with septic shock, and the effect of the former was equal to that of LAC, but the latter was better than LAC. PMID- 28835063 TI - [Process of the degradation in vivo and biosafety of biodegradable magnesium alloy stent]. AB - Objective: To observe the degradation process of biodegradable magnesium alloy stent (BMAS) in vivo in order to evaluate its degradation time and biological safety. Methods: Twenty-four male New Zealand white rabbits were divided into two groups: group A (n=12) and group B (n=12). The BMAS (a total of 12) was implanted in the infrarenal aorta of each rabbit in group A, while group B was the control group, without treatment. Color Doppler ultrasound was used at the 1, 2, 3, 4 months postoperatively to observe the degradation process of stents in group A. The arterial blood samples and main organs of two groups were also collected for biochemical examination and biosafety. Degradation assessment included transmission X-ray tomography (XRT), scanning electron microscope (SEM) and energy dispersion spectrum (EDS). Results: The XRT showed that the morphology of the stent was basically intact at 1 month after implantation, then scaffold composites were gradually degraded and absorbed. Degradation was basically completed at 4 months after operation. The early degradation products were Mg(2+) , then gradually replaced by Ca(2+) , P and other inorganic composition. There was no obvious adverse reactions in group A during the 4 months follow-up period. There was no statistical difference between the two groups in blood biochemical and pathological results (all P>0.05). Conclusion: BMAS can be degraded within 4 months in the abdominal aorta of rabbit, and the main degradation products are Ca(2+) and P, with good biosafety. PMID- 28835062 TI - [Effects of chronic intermittent hypoxia on left ventricular myocardial contractibility in a rabbit model of obstructive sleep apnea]. AB - Objective: To explore the effects of chronic intermittent hypoxia (CIH) on left ventricular myocardial contractibility in a rabbit model of obstructive sleep apnea (OSA). Methods: Based on random number table, twenty-four rabbits were randomly divided into three groups: operation, sham, and control groups, each with 8 rabbits. The rabbit model for OSA in operation group was established by repeatedly closing the airway and then reopening it. Upper airway obstructions were conducted on rabbits every day, which were alternately closed for 15 s and then reopened for 75 s in a 90 s-long cycle, for 8 h each day over 3 months. The sham rabbits were subjected to the same surgical procedure but no airway obstructions were applied. The control animals were subjected to no intervention. The blood pressure, left ventricular function parameters were assessed before and after the experiment. And the relative expressions of myosin heavy chain alpha/beta (alpha-MHC and beta-MHC) mRNAs in myocardium were observed for all rabbits by real time fluorescent quantitative polymerase chain reaction 3 months later. Results: After 3 months, all rabbits in the operation group manifested sleepiness and the blood pressure rose gradually [(114.25+/-4.20) vs (93.88+/ 2.10) mmHg, P<0.01]. Compared with the sham operation and the control groups, the left ventricular end-systolic volume [(6.05+/-1.62) vs (2.83+/-0.49) and (2.74+/ 0.32) ml, P<0.001] and the left ventricular end-diastolic volume [(1.61+/-0.78) vs (0.83+/-0.13) and (0.82+/-0.10) ml] in operation group were obviously higher, the left ventricular ejection fraction [(63.9+/-4.2) % vs (74.3+/-2.5) % and (75.8+/-3.8) %], left ventricular fractional shortening [(32.2+/-2.1) % vs (41.8+/-1.8) % and (42.1+/-1.8) %] and stroke volume [(1.46+/-0.13) vs (1.93+/ 0.21) and (1.98+/-0.24) ml/s] were decreased (all P<0.001). Besides, the maximal rate of the increase of left ventricular pressure [(4 154+/-360) vs (6 802+/-492) and (6 759+/-206) mmHg/s], the maximal rate of the decrease of left ventricular pressure [(4 994+/-621) vs (6 330+/-314) and (6 591+/-225) mmHg/s] in the operation group decreased markedly, left ventricular end diastolic pressure (LVEDP) increased [(6.5+/-1.6) vs (3.3+/-0.8) and (3.2+/-0.9) mmHg] (all P<0.001). The relative expression of alpha-MHC mRNA in left ventricular myocardial tissue was lower and the relative expression of beta-MHC mRNA was higher in operation group than those in the sham operation and the control groups (P<0.05). There were no significant difference in the relevant indicators of cardiac function, and in the relative expressions of alpha-MHC mRNA and the beta MHC mRNA between the control group and the sham operation group (P>0.05). Conclusions: Repeated intermittent hypoxia can induce hypertension and myocardial contractibility damage in OSA model rabbit simulating upper airway obstruction. PMID- 28835064 TI - [Spinal analgesic mechanism of minocycline in formalin-induced inflammatory pain]. AB - Objective: To investigate the spinal analgesic mechanism of minocycline in formalin-induced inflammatory pain. Methods: Behavioral test: Male Sprague-Dawley rats(3-5-week old) were randomly assigned into four groups: control, model, vehicle-controlled and minocycline group. Ten percent neutral formalin was injected subcutaneously into the right hind paw dorsum of the rats in model, vehicle-controlled and minocycline group. Normal saline was injected subcutaneously into the right hind paw dorsum of the rats in control group. Before 1 h of formalin injection, the rats in vehicle-controlled and minocycline group received intraperitoneal injection of saline and minocycline, respectively. Licking and lifting time was observed as the behavior results of inflammatory pain. Electrophysiologic experiment: In vitro spinal cord parasagittal slices were prepared from the same rats as above. The effect of minocycline on spontaneous inhibitory postsynaptic currents(sIPSCs) of substantia gelatinosa(SG) neurons was observed using whole-cell patch-clamp technique. Results: Compared with the control group, the licking and lifting time in the model group was significantly increased. Compared with the vehicle-controlled group, the licking and lifting time in the minocycline group was significantly decreased. Minocycline significantly increased the frequency(t=9.32, P<0.05)but not the amplitude(t=1.54, P>0.05) of sIPSCs of SG neurons, the frequency of sIPSCs of control and minocycline group were (2.5+/-0.3)Hz and (5.2+/-0.6)Hz, respectively. When calcium was removed from the extracellular solution, the frequency before and after minocycline perfusion were (0.9+/-0.1)Hz and (0.9+/-0.1)Hz, respectively, the amplitude before and after minocycline perfusion were (18.2+/ 0.7)pA and (18.5+/- 0.6)pA, respectively, the difference of frequency or amplitude was not statistically significant(t=0.32, 0.82, all P>0.05). However, minocycline still increased the frequency of sIPSCs when glutamate receptor antagonists 6-Cyano-7-nitroquinoxaline-2, 3-dione(CNQX) and D-(-)-2-Amino-5 phosphonopentanoic acid(APV) were included in extracellular solution(t=13.51, P<0.05), the frequency of sIPSCs were (2.0+/-0.1)Hz and (4.3+/-0.4)Hz, respectively. Minocycline still increased the frequency of IPSCs when voltage gated sodium channel blocker tetrodotoxin(TTX) were included in extracellular solution(t=8.67, P<0.05), the frequency of IPSCs were (2.2+/-0.2)Hz and (5.2+/ 0.5)Hz. Conclusion: Minocycline can attenuate formalin-induced inflammatory pain which may be associated with its increase in the inhibitory synaptic transmission of SG neurons. PMID- 28835065 TI - [Review of the major work and challenge of emergency medical rescue from gas explosion accident in Hangzhou]. AB - In order to ameliorate the prognosis of patients in burn disaster, national emergency medical rescue expert teams are usually dispatched to incident areas. This article discusses the major work and challenges of the medical rescue expert teams using example of rescuing gas explosion accident in Hangzhou in last few days and author's personal experience of previous mission. The foremost mission of medical rescue expert teams is to provide feasible strategic advice for burn disaster rescue and pivotal critical care support. The medical rescue expert teams always begin their work in hospitals lack of experience in disaster rescue. According to the characteristics of"7.21"Hangzhou gas explosion accident, the medical rescue expert teams focus on reassessment of the severity and hidden injuries of all patients, referral of patients according to the homeostasis status in patients with different severity, developing medical safety strategies, medical-related public safety strategies, and nosocomial infection control measure for rescue work. Furthermore, the medical rescue expert teams join the treatment for some critically ill patients and sudden emergency cases. The main challenges of medical rescue experts faced are accumulation and improvement of personal medical skill and powerful psychological endurance. Psychological counseling can play beneficial role in rescue group. In addition, establishing coordinated relationship among national emergency medical rescue expert teams, local administration, and local medical group shall be beneficial to disaster rescue. PMID- 28835066 TI - [Attaching importance to molecular imaging techniques and promoting precision diagnosis in burns]. AB - The explosive growth and advancement of computer science in recent decades have prompted the rapid development and wide applications of imaging techniques in life science, which have brought about revolutionary changes in modern medicine. Nowadays, it is possible to visualize multiple physiological and disease processes, precisely and non-invasively, in a living human body. Modern medicine has even started"reading the mind", to diagnose psychology, behavior and degenerative disorders of human brain. The border between the organic and inorganic diseases in old dogma is disappearing because imaging techniques have"visualized"the neurological and tissue changes of inorganic disorders. Severe burn injury is associated with very complicated pathological processes, which are always at the borderline between life and death. Complete recovery of patients with severe burn injury, if possible, may take years of time. Hence, a real-time monitoring of the disease process is of pivotal importance in early recognition and prevention of life-threatening complications and in assessing the therapeutic efficacy for a less-eventful recovery. Here we review and introduce some potential applications of modern imaging techniques in burn care and research, which may benefit burn patients. Some techniques are still in their early or pre-clinical stage and some are mature techniques in other fields of medicine, which are potentially applicable in burn diagnosis and treatment through our research. We intend to bring your interest to this field which may eventually lead to new revenues improving our clinical work on burn victims. PMID- 28835067 TI - [Brief disserting on the balance of internal environment in burn disease]. AB - The essential internal environment in human being involves water, electrolyte, and acid-base balance, which is the basis of balance and stability of internal environment in other systems. For burn patients, the balance of internal environment, referring to metabolism, nutrition, inflammatory response, and immunoreaction, is one of the most important aspects in burn disease. This paper aims to briefly elaborate the balance of internal environment after burn, with the purpose to promote the basic and clinical research in this field. PMID- 28835068 TI - [Effects of omega-3 polyunsaturated fatty acids on damage of intestinal mucosa of rats with severe burn in early stage and the mechanism]. AB - Objective: To observe the effects of omega-3 polyunsaturated fatty acids (PUFA) on damage of intestinal mucosa of rats with severe burn in early stage and to explore the mechanism. Methods: One hundred and twenty SD rats were divided into sham injury group, pure burn group, and omega-3 PUFA group according to the random number table, with 40 rats in each group. Rats in sham injury group were sham injured, while rats in pure burn group and omega-3 PUFA group were inflicted with 30% total body surface area full-thickness scald (hereinafter referred to as burn) on the back. Rats in sham injury group and pure burn group were injected with normal saline solution (1 mL/kg) by tail vein, while rats in omega-3 PUFA group were injected with omega-3 PUFA solution (1 mL/kg) by the same way at 5 minutes post injury. At post injury hour (PIH) 3, 6, 12, 24, and 48, abdominal aorta blood and intestinal mucosa were collected from 8 rats in each group, respectively. Serum content of diamine oxidase (DAO) was detected by spectrophotography. Serum content of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) was determined by enzyme-linked immunosorbent assay. Protein expression of NF-kappaB-p65 in intestinal mucosa was determined by Western blotting. Data were processed with analysis of variance of factorial design, one way analysis of variance, chi-square test, LSD test, and Bonferroni correction. Results: (1) At all time points post injury, serum content of DAO of rats in pure burn group and omega-3 PUFA group was significantly higher than that in sham injury group (with P values below 0.01), and serum content of DAO of rats in omega-3 PUFA group was significantly lower than that in pure burn group (with P values below 0.01). (2) At all time points post injury, serum content of TNF alpha and IL-6 of rats in pure burn group and omega-3 PUFA group was significantly higher than that in sham injury group (with P values below 0.01), and serum content of TNF-alpha and IL-6 of rats in omega-3 PUFA group was obviously lower than that in pure burn group (with P values below 0.01). (3) At all time points post injury, protein expressions of NF-kappaB-p65 in intestinal mucosa of rats in pure burn group and omega-3 PUFA group were significantly higher than those in sham injury group (with P values below 0.01). At PIH 3, 6, 12, 24, and 48, protein expressions of NF-kappaB-p65 in intestinal mucosa of rats in omega-3 PUFA group were 1.398+/-0.016, 1.999+/-0.948, 2.803+/-0.065, 1.739+/ 0.602, and 1.484+/-0.645, obviously lower than 2.096+/-0.113, 3.402+/-0.189, 4.183+/-0.558, 3.618+/-0.408, and 2.614+/-0.775 in pure burn group (with P values below 0.01). Conclusions: The omega-3 PUFA may alleviate intestinal mucosa injury of rats with severe burn in early stage through reducing protein expression of NF kappaB-p65 of intestinal mucosa, serum content of DAO, TNF-alpha, and IL-6, and inhibiting inflammatory response. PMID- 28835069 TI - [Changes of content and mRNA expression of gelsolin and proliferation activity of T-lymphocyte in spleen of mice with severe burn injury]. AB - Objective: To investigate the changes of content and mRNA expression of gelsolin and proliferation activity of T-lymphocyte in spleen of mice with severe burn injury, so as to determine the optimum intervention time of gelsolin. Methods: Eighty male BALB/c mice were divided into sham injury group and burn group according to the random number table, with 40 mice in each group. Mice in burn group were inflicted with 15% total body surface area full-thickness scald (hereinafter referred to as burn) on the back. Immediately after injury, mice in burn group were hypodermic injected with 1 mL normal saline, with iodophor smeared on back once a day to prevent infection. Mice in sham injury group were sham injured without fluid infusion and smearing iodophor. At post injury hour (PIH) 0 (immediately), 8, 24, 48, and 72, spleen of 8 mice of each group were harvested aseptically, respectively. Proliferation activity of T-lymphocyte was determined with methyl-thiazolyl-tetrazolium colorimetry method; gelsolin content of spleen was determined with enzyme-linked immunosorbent assay; mRNA expression of gelsolin of spleen was determined with real-time fluorescent quantitative reverse transcription polymerase chain reaction. Data were processed with analysis of variance of factorial design, one-way analysis of variance, LSD test and Bonferroni correction. Results: (1) There was no significant difference in proliferation activity of T-lymphocyte in spleen of mice in two groups at PIH 0 (P>0.05). Proliferation activity of T-lymphocyte in spleen of mice in sham injury group was significantly higher than that in burn group at PIH 8, 24, 48, and 72 (with P values below 0.05). There was no significant difference in proliferation activity of T-lymphocyte in spleen of mice in sham injury group at each time point post injury (F=0.756, P>0.05). Proliferation activity of T-lymphocyte in spleen of mice in burn group at PIH 8 was 0.12+/-0.04, significantly lower than that at PIH 0, 24, 48, and 72 in the same group (0.73+/-0.07, 0.56+/-0.07, 0.51+/ 0.09, and 0.59+/-0.07, respectively, with P values below 0.05). (2) There was no significant difference in gelsolin content of spleen of mice in two groups at PIH 0 (P>0.05). Gelsolin content of spleen of mice in sham injury group was significantly higher than that in burn group at PIH 8, 24, 48, and 72 (with P values below 0.05). There was no significant difference in gelsolin content of spleen of mice in sham injury group at each time point post injury (F=1.083, P>0.05). Gelsolin content of spleen of mice in burn group at PIH 8 was (11.9+/ 2.6) pg/mg, significantly lower than that at PIH 0, 24, 48, and 72 in the same group [(37.7+/-2.9), (19.9+/-4.0), (24.1+/-4.1), and (24.6+/-4.0) pg/mg, respectively, with P values below 0.05]. (3) There was no significant difference in mRNA expression of gelsolin of spleen of mice in two groups at PIH 0 (P>0.05). The mRNA expressions of gelsolin of spleen of mice in sham injury group were significantly higher than those in burn group at PIH 8, 24, 48, and 72 (with P values below 0.05). There was no significant difference in mRNA expression of gelsolin of spleen of mice in sham injury group at each time point post injury (F=0.413, P>0.05). The mRNA expression of gelsolin of spleen of mice in burn group at PIH 8 was 0.307+/-0.064, significantly lower than that at PIH 0, 24, 48, and 72 in the same group (0.944+/-0.023, 0.625+/-0.091, 0.744+/-0.104, and 0.821+/-0.072, respectively, with P values below 0.05). Conclusions: Severe burn injury could induce decrease of proliferation activity of T-lymphocyte and content and mRNA expressions of gelsolin in spleen of mice, and all of them decreased into the lowest at PIH 8. Optimum intervention time of gelsolin for severe burn would be before PIH 8. PMID- 28835070 TI - [Analysis on the risk factors of diabetic foot ulcer in diabetic patients of Uyghur nationality and Han nationality in the Xinjiang Uygur Autonomous Region]. AB - Objective: To explore the risk factors of diabetic foot ulcer (DFU) in diabetic patients of Uyghur nationality and Han nationality in the Xinjiang Uygur Autonomous Region. Methods: Clinical data of 640 diabetic patients admitted to our ward from January 2015 to November 2016, conforming to the study criteria, were retrospectively analyzed. Patients were divided into DFU group (n=403) and non-DFU group (n=237) according to whether DFU occurred or not. The data of gender, age, nationality, body mass index (BMI), smoking, drinking, binge eating, triglyceride (TG), total cholesterol (TC), and high-density lipoprotein (HDL) of patients between two groups were compared with chi-square test and t test. Indexes with statistically significant differences between two groups were selected, and they were processed with non-conditional multivariate logistic regression analysis to screen the independent risk factors of DFU. The possible risk factors of DFU of patients of Uyghur nationality and Han nationality were further processed with non-conditional multivariate logistic regression analysis respectively to screen the independent risk factors of DFU of patients of Uyghur nationality and Han nationality. Results: (1) There were no statistically significant differences in gender, age, TC, and HDL of patients between two groups (with chi(2)=0.149, t values respectively 1.163, 1.033, and 1.026, P values above 0.05). There were statistically significant differences in nationality, BMI, smoking, drinking, binge eating, and TG of patients between two groups (with chi(2) values from 4.778 to 13.694, t values respectively 4.703 and 4.237, P<0.05 or P<0.01). (2) Nationality, BMI, smoking, drinking, binge eating, and TG were the independent risk factors of DFU(with odds ratios respectively 1.488, 1.527, 1.736, 1.738, 1.382, and 1.648, 95% confidence intervals respectively 1.315-3.175, 1.488-4.393, 1.834-4.675, 1.474-2.695, 1.342-4.678, and 1.105-6.747, P values below 0.05). (3) Smoking, drinking, binge eating, and TG were the independent risk factors of DFU in diabetic patients of Uyghur nationality (with odds ratios respectively 1.673, 1.387, 1.328, and 1.486, 95% confidence intervals respectively 1.384-1.765, 1.414-1.659, 1.423-1.687, and 1.150-1.670, P values below 0.05). BMI, smoking, and drinking were the independent risk factors of DFU in diabetic patients of Han nationality (with odds ratios respectively 2.442, 1.604, and 1.251, 95% confidence intervals respectively 2.223-2.699, 1.268-2.028, and 1.164-1.344, P<0.05 or P<0.01). Conclusions: Smoking, drinking, binge eating, and TG were the independent risk factors of DFU in diabetic patients of Uyghur nationality. BMI, smoking, and drinking were the independent risk factors of DFU in diabetic patients of Han nationality. PMID- 28835071 TI - [Effects of axial vascular network flap of scalp or anterolateral thigh perforator flap with fascia lata on repairing defects after radical resection of scalp carcinoma in patients]. AB - Objective: To observe the effects of axial vascular network flap of scalp or anterolateral thigh perforator flap with fascia lata on repairing defects after radical resection of scalp carcinoma in patients. Methods: From February 2006 to December 2015, twenty-one patients with scalp carcinoma were admitted to our hospital, and the carcinoma invaded external lamina or full-thickness of skull and dura mater. After perfect preoperative examination, carcinoma and scalp tissue in 3 to 5 cm from the edge of carcinoma, external lamina or full-thickness of skull and invaded dura mater were resected and sentinel lymph nodes around carcinoma were cleaned in 3 to 4 days after admission. The postoperative defects with size reached from 11 cm*8 cm to 22 cm*18 cm. The flap transplantation was performed at the same time when quick frozen pathological examination results of resected scalp carcinoma margin tissue, skull, dura mater margin and basal tissue, and sentinel lymph nodes showed completely negative. Defects in 3 elderly patients were repaired by single or multiple axial scalp vascular network flaps, with the resected flaps size ranged from 12 cm*7 cm to 19 cm*14 cm. Defects in the other 18 patients were repaired by anterolateral thigh perforator flaps with fascia lata, with the resected flaps size ranged from 13 cm*10 cm to 23 cm*19 cm and the resected fascia lata size ranged from 8 cm*7 cm to 10 cm*10 cm. The head donor site of flap was repaired by medium thickness skin of head and back; the thigh donor site of flap was repaired by medium thickness skin of thigh on the same side. All patients gave up postoperative radiotherapy, chemotherapy, and other follow-up treatments. Results: After operation, the flap and skin in all patients survived completely, with no vascular crisis or other condition. During the follow-up for 6 months to 9 years, all patients showed good appearance except for baldness in operation area of head, with no obvious malformation in head donor site of flap and skin, no swollen external hernia in the brain tissue, and no local recurrence or distant metastasis of carcinoma. The appearance of thigh donor site of flap and skin was good, with normal muscle strength and movement of lower limbs. Conclusions: Patients with scalp carcinoma were performed with radical resection of carcinoma, and axial vascular network flap of scalp or anterolateral thigh perforator flap with fascia lata were applied to repair the postoperative defects, with good appearance of head operation area and no local recurrence or distant metastasis of carcinoma. PMID- 28835072 TI - [Advances in preparation and clinical application of amniotic membrane graft]. AB - Amniotic membrane has been used as wound dressing for more than 100 years. With the development of the preservation and preparation techniques, amniotic membrane is widely used in ophthalmology, burns, plastic surgery, dentistry, and neurosurgery. In recent years, as more and more amniotic membrane is used in chronic wounds, it will be a new treatment method for wounds. This paper is a brief review about advances in preparation and clinical application of amniotic membrane graft. PMID- 28835073 TI - [Advances in the research of effects of heat-shock factor 1 and heat-shock proteins on wound healing and the mechanism]. AB - Heat-shock proteins (HSPs) are the protective proteins expressed by cells under stress. Heat-shock factors (HSFs) are the key factors to regulate HSPs. Researches about the effects of HSF1 and HSPs in cells after stress and the mechanism have become the important entry point to explore the cell response in wound healing after trauma. This article reviews the effects of HSPs and HSF1 which regulate the proteins on wound healing and the mechanism, so as to deliver message for studying effects of intervening HSF1 on expression of HSPs and wound healing and the mechanism. PMID- 28835074 TI - [Advances in the research of effects of circulating fibroblasts on wound repair]. AB - Wound repair is a complex process involving multiple disciplines, cell factors, cell types, and signaling pathways. In recent years, many researches showed that circulating fibroblasts (cFbs) deriving from bone marrow and residing in peripheral blood, played a role in wound repair by migrating to wound sites, differentiating into fibroblasts and myofibroblasts, and secreting cytokines, extracellular matrix, chemokines, growth factors, and antigen-presenting molecules, etc. cFbs also involve in three phases of inflammation, proliferation, and remodeling in wound repair of diabetes, ulcers, burns and other wounds, which indicate that they could be a potential treatment for wound repair. This article aims to review the latest development in circulating fibroblasts and wound repair. PMID- 28835075 TI - [Advances in the research of negative-pressure wound therapy inducing the vascularization of dermal substitute]. AB - In clinical practice, skin defects resulted from various acute and chronic diseases occur frequently. Dermal substitute (DS), known as dermal regenerative template, is used more and more widely, but the slow process of vascularization limits its clinical application. At present, there are many strategies developed to enhance the process of vascularization, such as modifying the structure of dermal scaffolds, prevascularization by seeding stem cells and/or endothelial cells. Recently, negative-pressure wound therapy (NPWT) emerged and rapidly became popular in promoting wound healing due to its intrinsic advantages. Furthermore, some researchers introduced this technique to accelerate the vascularization process of DS. This paper represents a comprehensive overview on the efficiency of NPWT in different combination models, and the related mechanism. PMID- 28835076 TI - [Current treatment in advanced hepatocellular carcinoma and prospects for immuno oncology therapy]. AB - Treatment of patients with advanced hepatocellular carcinoma (HCC) remains a huge challenge since a widely accepted therapeutic strategy has not been identified. There are some special features in patients with HCC in China, such as are mainly related to hepatitis B virus infection, often diagnosed as advanced or end-stage disease, and usually have a poorer prognosis compared with patients in western countries. Hence, appropriate treatments are urgently needed for these patients. Notably, immune-oncology therapy has been received increased attention in recent years. Based on promising results observed in clinical trials, immune-oncology therapy has been approved for treatment of various malignant diseases and brings a new hope to the treatment of advanced HCC. The review summarizes the current situation of advanced HCC treatment in China and discusses the prospects of immuno-oncology therapy. PMID- 28835077 TI - [Effect of mesenchymal stem cells on the apoptosis of breast cancer cells induced by cisplatin]. AB - Objective: To investigate the effect of mesenchymal stem cells (MSCs) on apoptosis of breast cancer cell line MCF-7 induced by cisplatin (DDP), MSCs derived from breast cancer (BC-MSCs) or adjacent non-cancerous tissues (BN-MSCs) were isolated, cultured and identified. Methods: BC-MSCs and BN-MSCs were isolated and cultured by tissue adherent method. The differentiation potential of BC-MSCs was detected by osteogenic and adipogenic induction, and cell surface markers of BC-MSCs and BN-MSCs were evaluated by flow cytometry. MCF-7 cells were co-treated with DDP and conditioned medium (CM) collected from BC-MSCs and BN MSCs after being cultured for 48 hours, respectively. Inhibition rate of cell proliferation was evaluated by MTT. Cell apoptosis and viability were detected by MUSE cell analyzer. Cytokines in MSC-CM were detected by Luminex liquid chip. Interleukin 6 (IL-6) mRNA expressions in MCF-7 cells with different treatment were detected by RT-PCR. Results: The morphology of BC-MSCs and BN-MSCs successfully isolated and cultured was uniform fibroblast-like clusters under the microscope. These cells expressed high levels of CD29 and CD44, but neither CD14 nor CD34 were detected. MSCs could also differentiate into osteoblasts and adipocytes after specific induction. After treatment with 2.5, 5, 10, 20, 40 and 80 MUmol/L DDP, the inhibitory rates of proliferation of MCF-7 cells in DDP group were (17.33+/-2.00)%, (22.37+/-0.73)%, (30.77+/-1.23)%, (44.93+/-1.27)%, (62.03 +/-1.97)% and (73.93+/-1.10)%, respectively. While the inhibitory rates of DDP+ BC-MSCs group were (8.27+/-0.63)%, (11.50+/-1.30)%, (20.57+/-0.93)%, (32.60 +/ 1.90)%, (52.27+/-0.73)% and (62.13+/-2.17)%, respectively. The inhibitory rates of DDP+ BN-MSCs group were (12.90+/-1.60)%, (16.53+/-2.87)%, (25.90+/-1.50)%, (39.40+/-2.40)%, (57.40+/-0.70)% and (69.03+/-1.07)%, respectively. The inhibitory rates of DDP+ BC-MSCs group were significantly lower than those of DDP group (P<0.05). The apoptotic rates of MCF-7 cells in DDP group, DDP+ BC-MSCs group and DDP+ BN-MSCs group were (47.77+/-1.98)%, (29.20+/-2.12)% and (37.92+/ 2.21)%, respectively. The apoptotic rates of DDP group was significantly higher than that of DDP+ BC-MSCs group (P<0.05). The cell viabilities of MCF-7 in DDP group, DDP+ BC-MSCs group and DDP+ BN-MSCs group were 0.52+/-0.02, 0.72+/-0.02 and 0.64+/-0.02, respectively. The cell viability of DDP group was significantly lower than that of DDP+ BC-MSCs group (P<0.05). The result of Luminex liquid chip analysis showed that, the level of IL-6 in BC-MSCs group increased 2.50+/-0.68 fold when compared with BN-MSCs group (P<0.05). The relative expressions of IL-6 mRNA in DDP group and DDP+ BC-MSCs group were 1.02+/-0.10 and 7.58+/-0.55, respectively, with a statistically significant difference (P<0.01). The apoptotic rates of MCF-7 cells in DDP+ BC-MSCs group with or without IL-6 neutralizing antibody were (27.41+/-1.95)% and (42.45+/-2.87)%, respectively, with a statistically significant difference (P<0.05). The cell viabilities of MCF-7 cells in DDP+ BC-MSCs group with or without IL-6 neutralizing antibody were (72.40+/-2.60)% and (59.76+/-3.89)%, respectively, with a statistically significant difference (P<0.05). Conclusions: BC-MSCs and BN-MSCs have been isolated and cultured successfully. Compared with BN-MSCs, BC-MSCs could attenuate the effect of DDP on MCF-7 cells, evidently decrease the apoptosis and increase the proliferation and vitality in an IL-6 dependent manner. PMID- 28835078 TI - [Killing effect of icotinib combined with CIK on human lung adenocarcinoma cells in vitro]. AB - Objective: To explore the inhibitory effect of icotinib combined with cytokine induced killer (CIK) on various human lung adenocarcinoma cell lines in vitro. Methods: The inhibitory effect of icotinib alone or icotinib combined with CIK on HCC827 and A549 cells was detected by cell counting kit-8(CCK-8). The apoptosis was detected by flow cytometry via Annexin V/PI staining. The effect of icotinib on CIK phenotype was detected by flow cytometry. Results: The inhibitory rates of HCC827 cells treated with 1.5, 3, 6, 12 MUmol/L icotinib were (5.64+/-0.05)%, (8.62+/-0.45)%, (14.57+/-0.65)% and (18.52+/-0.91)%, respectively. The inhibitory rates of A549 cells were (1.64+/-0.48)%, (2.09+/-0.28)%, (3.69+/-0.45)%, (4.41+/ 0.58)%, respectively. At the same concentration, the inhibitory rate of HCC827 cells with icotinib treatment was significantly higher than that of A549 cells (P<0.05). When the effector/target ratio was 10?1, 20?1 or 40?1, the inhibitory rates of HCC827 cells co-cultured with CIK were (15.17+/-2.33)%, (42.59+/-7.18)%, (62.59+/-8.95)%, respectively, and the inhibitory rates of A549 were(16.99+/ 2.81)%, (46.31+/-1.89)%, (58.24+/-4.23)%, respectively. The inhibitory rate of HCC827 cells co-cultured with CIK was not significantly different from that of A549 cells at the same effector/target ratio (P(10?1)=0.299, P(20?1)=0.318, P(40?1)=0.366). When the effector/target ratio of CIK combined with 6 MUmol/L icotinib was 10?1, 20?1 or 40?1, the inhibitory rates of HCC827 cells were (37.07+/-3.50)%, (76.03+/-6.55)%, (80.34+/-10.69)%, respectively, and the inhibitory rates of A549 cells were(25.72+/-1.41)%, (52.76+/-3.82)%, (62.26+/ 1.94)%, respectively. The inhibitory rates of 6 MUmol/L icotinib combined with CIK were significantly higher than those of icotinib group and CIK group alone at the same effector/target ratio (P<0.05), except for the effector/target ratio at 40?1 on A549 cells (P=0.089). Moreover, all of the combination index (CI) of combined group were <1 (P<0.05). The apoptotic rates of HCC827 and A549 cells induced by icotinib combined with CIK were significantly higher than those of icotinib group and blank control group (P<0.05), especially the proportion of late apoptotic or necrotic cells.Increasing effector/target ratio of CIK contributed to stronger inhibition(P<0.05). The expressional rate of CIK phenotype with or without icotinib treatment was not significantly different from each other(P>0.05). Conclusions: EGFR mutant lung adenocarcinoma cells are more sensitive to icotinib, while the EGFR mutation status has no effect on the killing effect of CIK cells. icotinib combined with CIK has a synergistic effect on the inhibition of tumor growth, and icotinib has no any impact on the phenotype of CIK cells. PMID- 28835079 TI - [Effect of concurrent chemoradiotherapy and radiotherapy alone on peripheral myeloid-derived suppressor and T regulatory cells in patients with nasopharyngeal cancer]. AB - Objective: To investigate the percentage of myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) in peripheral blood of nasopharyngeal cancer (NPC) patients undergoing concurrent chemoradiotherapy or radiotherapy alone. Methods: Sixty NPC patients who received radiotherapy or concurrent chemoradiotherapy from September 2012 to November 2015 and 20 healthy individuals were included in this study. For the patients, the blood samples were collected at four time points: pre-radiation (Pre-RT), reaching a dose of 40 Gy (RT-40 Gy), finishing radiation (RT-finish) and three months after finishing radiation (3m post-RT). Flow cytometry was used to evaluate the percentage of Treg (CD4(+) CD25(+) CD127(low/-)) and MDSC (HLA-DR(-)CD11b(+) CD33(+) ) cells in peripheral blood. Results: Treg and MDSC cells were present in peripheral blood lymphocytes of healthy individuals as a percentage of (7.50+/-1.62)% and (1.08+/-0.48)%, respectively. The proportions of peripheral Treg cells in patients at Pre-RT, RT 40 Gy, RT-finish and 3m-post-RT time points were (8.42+/- 1.52)%, (9.10+/-1.57)%, (8.87+/-1.56)% and (7.31+/-1.43)%, respectively, showing a statistically significant difference between Pre-RT and the other groups (P<0.05). At Pre-RT point, the percentage of Treg cells in Stage III-IV patients [(8.63+/-1.39)%] was higher than that in Stage I-II [(7.65+/-1.94)%, P=0.042]. Moreover, the proportions of peripheral MDSC cells in patients at Pre-RT, RT-40 Gy, RT-finish and 3m-post-RT time points were (2.14+/-1.21)%, (4.08+/-1.90)%, (3.76+/-1.31)% and (1.52+/-0.88)%, respectively. The percentages of MDSC cells at RT-40 Gy and RT-finish points were significantly higher than those at Pre-RT, while the percentage of MDSC cells at 3m-post-RT was significantly lower than those at Pre RT (P<0.05). At Pre-RT point, the percentage of MDSC cells in Stage III-IV patients [(2.25+/-1.26)%] was higher than that in Stage I-II [(1.35+/-0.66)%, P=0.007]. At RT-finish point, the proportions of MDSC and Treg cells in patients with III-IV grade of radiation induced oral mucositis [(4.41+/-1.27)% and (9.91+/ 1.23)%] were significantly higher than those in I-II grade patients [(3.15+/ 1.04)% and (8.41+/-1.52)%, both of P<0.05]. Conclusions: The proportions of MDSC and Treg cells in initial treated NPC patients are higher than healthy individuals, and they are also associated with the tumor stages. During the concurrent chemoradiotherapy and radiation, the percentage of MDSC and Treg cells is elevated, suggesting a decreased immune activity. The increase of MDSC and Treg cells is related to radiation induced oral mucositis. PMID- 28835080 TI - [High throughput-targeted sequencing panel for exploring radiosensitivity associated genes in esophageal squamous cell carcinoma]. AB - Objective: To explore radiosensitivity-associated genes in esophageal squamous cell carcinoma by targeted sequencing panel. Methods: The peripheral blood from 22 esophageal squamous cell carcinoma (ESCC) patients received radiotherapy alone were collected, respectively. The genomic DNA (gDNA) of peripheral blood was extracted and used to create a library of gDNA restriction fragments. The gDNA restriction fragments were hybridized to the HaloPlex probe capture library, which comprises 356 cancer genes selected from the Catalogue of Somatic Mutations in Cancer (Cosmic) database of 2011 updated edition. The sequencing data were aligned by the Genome Analysis Toolkit GATK (version 3.0) and Picar. The single nucleotide polymorphism and inserted-deletion (SNP/InDel) variations were annotated by online database. The pathway enrichment was analyzed by Ingenuity Pathway analysis (IPA). Moreover, according to the short-period curative effect, 22 patients were divided into two groups: the radiation- sensitivity group (CR+ PR) and the radiation-resistant group (PD+ SD). The nonsynonymous mutation sites were statistically analyzed and the genes associated with radiosensitivity of ESCC were screened. Results: More than 97% sequencing reads were aligned to human genome reference sequence and more than 90% sequencing reads were the target sequences. SNP/InDel database annotation results showed that the mutations of 22 cases mainly distributed in exons, and the mutant types were mainly missense and synonymous single nucleotide variant (SNV). There were 23 genes of high-frequency mutation associated with esophageal cancer. Pathway enrichment by IPA showed that 3 pathways were associated with the development of esophageal cancer, which were roles of BRCA1 in DNA damage response pathway, DNA double-strand break repair by non-homologous end joining pathway and ATM signaling pathway. According to the curative effect, five genes including mismatch repair system component (PMS1), fibronectin 1(FN1), mutL homolog 1 (MLH1), B-Raf proto-oncogene, serine/threonine kinase (BRAF), patched 1 (PTCH1) and cytochrome P450 family 2 subfamily C member 19 (CYP2C19) were associated with radiosensitivity of ESCC patients.Moreover, the PTCH1 was mutated in all of 22 ESCC patients, while the variations of rs199476092 and rs202111971 sites of PTCH1 were only identified in the radiation-resistant group. Conclusions: We find that the variations of rs199476092 and rs202111971 in the encoding region of PTCH1 gene are significantly associated with radiosensitivity of ESCC patients. PMID- 28835081 TI - [The clinicopathological features and risk factors of recurrence in patients with mucinous borderline ovarian tumors]. AB - Objective: To investigate the clinicopathological features and risk factors in patients with mucinous borderline ovarian tumors (MBOT). Methods: From 1999 to 2006, 66 MBOT patients in our hospital with more than ten-year follow-up were enrolled retrospectively. They were re-classified according to the literature. The clinicopathological features of different subgroups, including age, preoperative serum tumor markers, surgical methods, pathological features, surgical pathology staging, as well as the risk factors of recurrence and survival were analyzed. Results: Median age was 39 years in 66 patients. Before the surgery, 33.3% (20/60) patients had elevated CA125 and 51.7% (30/58) had elevated CA199. The accurate rate for fast frozen pathology of resected specimen was 73.4%. 21 patients underwent conservative surgery and 45 patients underwent extensive surgery. 57 patients underwent comprehensive operation and 43 cases (75.4%) resulted in stage I. 48 of the 66 patients (72.7%) had intestinal-type tumors (IMBT) and 18 patients (27.3%) had endocervical-like tumors (EMBT). The median follow-up was 150 months. Eight recurrences (12.1%) were identified. The mean time between surgery to the initial recurrence was 26.4 months (13 to 50 months). Recurrence rate of IMBT was higher than that of EMBT (14.6% versus 5.6%) with no significance (P>0.05). All patients with pseudomyxoma had disease recurrence. Recurrence rate of stage III patients was significantly higher than that of stage I patients (33.3% versus 9.3%, P<0.05). During the follow-up period, tumor-related death occurred in 2 cases with a 10-year survival rate of 95.4%. Kaplan-Meier method and Log Rank analysis showed that clinical staging and peritonealmyxoma were adverse prognostic factors (P<0.05). Although the recurrence rate of patients undergoing conservative surgery was higher than that of patients with extensive surgery (23.8% versus 6.7%, P=0.047), the overall survival was almost the same between these two groups (P>0.05). Conclusions: MBOT patients have relatively good prognosis. IMBT are more common than EMBT subtypes, but recurrence rate and patient survival were almost the same between these two groups. Patients with pseudomyxoma was more likely to have disease recurrence. Patients who underwent conservative surgery resulted in higher recurrence rate but did not affect the overall survival of patient. Pseudomyxoma and clinical staging were adverse prognostic factors in MBOT patients. PMID- 28835082 TI - [Fluorescence in situ hybridization combined with cytomorphology for the detection of lung cancer in bronchial brushing specimens]. AB - Objective: To evaluate the diagnostic value of fluorescence in situ hybridization (FISH) combined with bronchial brushing cytology for detecting lung cancer. Methods: Centromeric enumeration probes (CEPs) for chromosomes 7, 8 and 17 were used in FISH assay. The combination of FISH and cytology was analyzed in 69 bronchial brushing specimens. Results: The positive rates of CEP7, CEP8 and CEP17 in malignant cases diagnosed by cytology were 50.0%, 80.8% and 65.4%, respectively. CEP8 probe showed significantly higher positive rate than CEP7 (P=0.015). In the samples of suspicious of malignancy, the positive rates of CEP7, CEP8 and CEP17 were 46.6%, 66.7% and 58.8%, respectively. While in atypical cases, the positive rates of these three probes were 20.0%, 33.3% and 25.0%, respectively. There was no statistical difference between suspicious of malignancy and atypical cases (P>0.05) as well as between malignant and suspicious of malignancy (P>0.05). No chromosome aberrations were found in normal cases diagnosed by cytology. The positive rates of these three probes in adenocarcinoma (ADC) were slightly higher than those in squamous cell carcinoma and small cell lung cancer. However, only CEP8 probe showed statistically difference between ADC and small cell lung cancer (P=0.044). The combination of cytology and FISH using any one of the three-probe set (CEP7, CEP8 and CEP17) showed the sensitivity and specificity of 80.3% and 100.0%, while those of cytology were 54.1% and 100.0%, respectively. Conclusions: FISH combined with cytomorphology assisted the cytology diagnosis of suspicious of malignancy and atypical cases. Therefore, it significantly improved the diagnostic sensitivity for lung cancer without sacrificing specificity. PMID- 28835083 TI - [CT and MRI findings of primary hepatic neuroendocrine neoplasm]. AB - Objective: To study imaging features of primary hepatic neuroendocrine neoplasm (PHNEN) with CT and MRI. Methods: CT/MRI findings of ten patients with pathologically confirmed PHNEN were retrospectively analyzed. The result was compared with pathologic features classified by the 2010 WHO classification of gastro-entero-pancreatic neuroendocrine tumor which was also compared with the conventional method. Results: Six cases of neuroendocrine tumor (NET), all of which were classified as grade 2 (G2), consisted of 5 cases of carcinoid and 1 case of atypical carcinoid. Four cases of neuroendocrine carcinoma (NEC) classified as grade 3 (G3) were composed of 1 case of atypical carcinoid and 3 cases of small cell carcinoma. On the basis of conventional classification method, CT/MRI features were as follows: (1) Carcinoid: For 5 carcinoid cases, two with solitary mass, two with dominant masses and satellite nodules, and one with diffused nodules. Four cases were cystic-solid and one was solid. Four showed low density on plain CT and moderate to obvious enhancement in arterial phase. Three showed consistent enhancement in portal and delayed phase while one showed rapid washout in portal phase. Four showed low density in delayed phase. One case with cystic degeneration showed hypo-intensity on T1W, hyper-intensity on T2W and halo like hyper-intensity on DWI. In dynamic MRI, the solid part of tumor showed obvious enhancement in arterial phase, consistent enhancement in portal phase with slight washout and homogeneous or slight hypo-geneous signal density in delayed phase. (2) Atypical carcinoid: Two cases presented with cystic solid mass. They were all dominant masses with satellite nodules. They showed low density on plain CT and mild to moderate enhancement in arterial phase. One case showed rapid washout in portal and delayed phase with embolus in portal vein. The other case showed consistent enhancement in portal phase and hypo-density in delayed phase without enhancement of satellite nodules. (3) Small cell neuroendocrine carcinoma: Three cases of small cell carcinoma were composed of one cystic-solid tumor, one solid tumor and one dominant mass with satellite nodules. Two cases showed low density in CT plain scan while one with cystic degeneration presented hypo-intensity on T1W, hype-rintensity on T2W and halo like hyper-intensity on DWI. Dynamic CT and MRI showed mild to moderate enhancement in arterial phase, consistent enhancement in portal phase and low density or hypo-intensity in delayed phase. Conclusion: PHNEN has specific features on CT and MRI which are valuable in diagnosis and differential diagnosis. PMID- 28835084 TI - [A multicenter clinical study for the comparison of S-1 versus capecitabine in the treatment of advanced breast cancer]. AB - Objective: To investigate the safety, efficacy and prognostic factors of S-1 versus capecitabine in patients with advanced breast cancer (ABC). Methods: From January 1, 2012 to December 31, 2014, 154 ABC patients with pathological diagnosis were separated into two groups: S-1 with or without the 3rd generation chemotherapy drug (group S-1) and capecitabine with or without the 3rd generation chemotherapy drug (Group capecitabine). The efficacy, side effects and prognostic factors were compared between the two groups. Results: There were 70 patients in group S-1 and 84 patients in group capecitabine. The objective response rates (ORR) were 31.4% (22/70) in group S-1 and 28.6% (24/84) in group capecitabine. The disease control rates (DCR) were 74.3% (52/70) and 83.3% (70/84), respectively. There were no significant differences in DCR and ORR between two groups (P>0.05). The DCR of patients treated with capecitabine monotherapy was significantly higher than that of S-1 monotherapy [94.4%(17/18) and 64.0%(16/25), P=0.028]. The median PFS was 7.5 and 8.9 months for the patients in the group S-1 and group capecitabine, with no statistically significant difference (P=0.423). The 1-year survival rates of group S-1 and group capecitabine were 81.4% and 66.7%, respectively, with no significant differences(P=0.020). Univariate analysis showed that ER and/or PR status (P=0.004), T stage (P=0.041), and molecular typing (P=0.046) were associated with PFS. Multivariate analysis showed ER and/or PR status (P=0.034) was an independent prognostic factor related with PFS. The incidence of hemoglobin reduction was 14.3% (10/70) and 36.9% (31/84) in the group S-1 and group capecitabine, and the differences were statistically significant (P=0.002). There was no significant difference in the incidence of leukopenia, neutropenia, thrombocytopenia and hand-foot syndrome between the two groups(P>0.05). Conclusions: S-1 and capecitabine are both effective for advanced breast cancer. Neither ORR nor DCR were significantly different between these two groups. The incidence of gastrointestinal reactions and thrombocytopenia of S-1 was slightly lower than that of capecitabine. PMID- 28835085 TI - [Management of T3 supraglottic carcinoma: a retrospective study]. AB - Objective: To discuss the strategy of therapeutic management of T3 supraglottic carcinoma. Methods: A retrospective analysis of 459 patients with T3 supraglottic carcinoma treated in our hospital was performed. We evaluated the results of different managements, including surgery alone, preoperative radiotherapy, postoperative radiotherapy and radiotherapy alone. The extent of the lesion was also put into analysis. Statistical analysis of the overall survival (OS), cause specific survival (CSS), local control (LC), regional control(RC), function conservation (FC) were performed with the statistical package from SPSS. Results: In all patients, the rates of 5-year OS, CSS, LC, RC and FC were 64.2%, 71.2%, 87.8%, 78.8% and 64.5% respectively. The OS, LC and FC of the patients treated by surgery alone, preoperative radiotherapy and postoperative radiotherapy had no significant difference, and were remarkably better than that of patients treated by radiotherapy alone (P<0.001). In 412 patients treated by surgery, 300 patients received function-conservation laryngectomy. 209 patients (50.7%, 209/412) survived and maintained well-function of larynx for 5 years, which was significantly better than those in the radiotherapy alone group (27.7%, 13/47). The patients with the lesion invading the pre-epiglottic space but limited in supraglottic area had better OS (70.2%), LC (93.5%) and FC (85.1%). The rate of 5 year neck lymphatic metastasis was 56.2%(258/459), and the 5-year OS of patients with N0, N1, N2 and N3 stage were 76.0%, 66.2%, 50.5% and 13.0% respectively. Conclusions: Surgical treatment was the best therapeutic approach for T3 supraglottic laryngeal carcinoma. Most patients with T3 lesions are suitable for function-conservation laryngectomy. Surgical procedure was determined by tumor invaded location and extension. The combined therapy of surgery and radiotherapy had no significant advantage. PMID- 28835086 TI - [Value of modified TI-RADS in the diagnosis of medullary thyroid carcinoma]. AB - Objective: To investigate the value of modified thyroid imaging reporting and data system (TI-RADS) in the sonographic diagnosis of medullary thyroid carcinoma (MTC), and to evaluate the sonographic differences among MTC, papillary thyroid carcinoma (PTC) and benign nodules in order to improve the ultrasound diagnostic accuracy of MTC. Methods: 646 cases of thyroid lesions confirmed by pathology in our hospital were divided into the MTC group (64 cases), PTC group (414 cases) and benign group (168 cases). The ultrasonographic characteristics of these groups were retrospectively analyzed. All of the 646 cases were classified by modified TI-RADS grading criteria. The diagnostic accuracy of MTC and ultrasonic manifestations of MTC, PTC and benign nodular were assessed. Results: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of modified TI-RADS for MTC were 87.5%, 89.9%, 72.6%, 88.8%, and 67.2%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of modified TI-RADS for PTC were 96.1%, 59.5%, 85.4%, 86.2% and 85.6%. The intraclass correlation coefficient (ICC) of three different physicians for thyroid nodules was 0.983 by the modified TI-RADS. MTC were mostly located in middle and upper parts of the thyroid (85.9%, 55/64), hypoechoic or extremely hypoechoic (89.1%, 57/64), with relatively smooth margin (35.9%, 23/64), aspect ratio<1 (53.1%, 34/64), abundant blood flow (31.2%, 20/64), and high lymph node metastasis rate (51.6%, 33/64). These differences were statistically significant when compared to PTC (P<0.05). Conclusions: Repeatability of modified TI-RADS for MTC was high, and is slightly lower than that for PTC. MTC had specific features: mostly located in middle and upper parts of the thyroid, hypoechoic or extremely hypoechoic, relatively smooth margin, aspect ratio<1, abundant blood flow and high lymph node metastasis rate. PMID- 28835087 TI - [Clinical analysis of secondary cervical lymph node dissection in papillary thyroid carcinoma]. AB - Objective: To investigate the value of secondary cervical lymph node dissection in papillary thyroid carcinoma (PTC). Methods: PTC patients with recurrence re operated in a previously dissected area at our hospital during 2000-2016 were included in this analysis. Patients were divided according to the operative interval of 6 months. The level and number of lymph node metastasis and the number of lymph node dissection were analyzed to calculate the ratio of lymph node metastasis. Results: A total of 336 PTC patients received 360 side lateral cervical lymph nodes dissection. The ratio of recurrence in unilateral lateral neck is 92.9%(312/336). The ratio of recurrence in multiple levels (more than two regions) were 47.5% (171/360). The recurrence ratio of level II, III, IV and V were 55.6%(200/360), 44.2%(159/360), 59.7%(215/360) and 10.3%(37/360), respectively. Lymph node metastases were inclined to level II (33.6%) and IV (35.8%). The mean number of lymph node dissection and metastasis in the group of operative interval <= 6 months was 26.56 per case and 4.37 per case, respectively. The mean number of lymph node dissection and metastasis in the group of operative interval >6 months was 16.80 per case and 3.20 per case, respectively. The number of lymph node dissection and metastasis between these two groups were significantly different (P=0.001, P<0.001). Conclusions: Lymph node metastasis of PTC patients with secondary cervical lymph node dissection are inclined to level II and level IV. Moreover, multi-level metastasis is not rare. Level II and level IV require more attention in the first operation. Most of the patients undergo reoperation because of residual lymph nodes from the previous treatment. Normalization and completeness of the initial dissection are particularly important to PTC patients. PMID- 28835088 TI - [Survival and the value of adjuvant chemotherapy in esophageal squamous cell carcinoma patients with lymphatic metastasis]. AB - Objective: To investigate the prognosis and the value of adjuvant chemotherapy in esophageal squamous cell carcinoma (ESCC) patients with lymphatic metastasis. Methods: From Jan, 2008 to Dec, 2011, 329 patients with ESCC who underwent two field radical resection(R0), had lymphatic metastasis and survived over three months were enrolled in this study. There were 246 males and 83 females. The median age was 61 years-old. Site of lesion was located at upper- in 23, middle- in 226 and lower-thoracic segment in 80 patients. There were 114 patients treated with surgery alone and 215 patients with adjuvant chemotherapy. Prognostic factors including adjuvant chemotherapy were assessed in ESCC patients with lymphatic metastasis. Results: In 329 ESCC patients with lymphatic metastasis, the 1-, 3-, 5-years overall survival (OS) rate and progress-free survival (PFS) rate were 74.5%, 31.7%, 24.5%, and 55.1%, 27.8%, 24.2%, respectively. Median OS and PFS were 22 and 15 months, respectively. Multivariate analysis showed that, site of lesion and disease stage were independent factors for OS and PFS (P<0.05). Adjuvant chemotherapy was also an independent prognostic factor for OS (P<0.05). Subgroup analysis showed that adjuvant chemotherapy could improve OS mainly in patients of males, ages<=60, tumor length <6 cm, well- or mediated differentiated squamous cell carcinoma, stage pT3, pN2 and IIIB (P<0.05). Conclusions: ESCC patients with lymphatic metastasis had poor prognosis. Site of lesion and disease stage were important prognositic factors for survival. Adjuvant chemotherapy could improve survival in specific patients. PMID- 28835089 TI - [A case of everolimus maintenance therapy of primary platinum-resistant ovarian clear cell carcinoma]. PMID- 28835090 TI - [Clinical value of p16/Ki-67 immunocytochemical dual staining in cervical cancer screening]. AB - Objective: to investigate the clinical value of p16/Ki-67 immunocytochemical dual staining (abbreviated as p16/Ki-67 dual staining) in cervical intraepithelial neoplasia (CIN) and cervical cancer screening. Methods: From July to November 2015, a total of 980 women attending cervical cancer screening and receiving high risk human papillomavirus (HR-HPV) test and thinprep cytologic test (TCT) were included in the study. p16/Ki-67 immunocytochemical dual staining was performed on residual cytologic specimens and compared with histopathology results. Results: The expression risks of p16/Ki-67 in HPV16/18 group and another HR-HPV group were higher than HPV negative group, with an odds ratio of 10.64 (95%CI: 5.66~20.02) and 5.40 (95%CI: 3.62~8.04), respectively. The positive rate of p16/Ki-67 increased with the grade of TCT and histologic diagnosis, and was higher in both CIN2 and CIN3 groups than normal group (P<0.05). The sensitivity of p16/Ki-67 to detect CIN2+ and CIN3+ lesions was 89.3% and 94.1%, respectively, and the specificity was 69.3% and 66.8%, respectively. The sensitivity of TCT to detect CIN2+ and CIN3+ lesions was 60.7% and 64.7%, respectively, and the specificity was 49.3% and 49.1%, respectively. Conclusions: Compared with TCT, p16/Ki-67 dual staining has higher sensitivity and specificity. It can identify high-grade cervical lesions and guide the classification of CIN. p16/Ki-67 dual staining in conjunction with HPV test may be considered as an efficient method for cervical cancer screening. PMID- 28835091 TI - Gastric Adenocarcinoma with Systemic Metastasis Involving the Intraocular Choroid and Duodenum. AB - Gastric cancer with double metastasis to the orbit and duodenum is extremely rare. We report the case of a patient with gastric adenocarcinoma who presented with synchronous orbital and duodenal metastases at the time of initial diagnosis. A 60-year-old man presented with a 1-month history of visual disorder and pain in his right eye. He underwent ophthalmological examinations. The biopsy results suggested intraocular metastatic carcinoma. We conducted a systemic evaluation to identify primary malignancy. Finally, a diagnosis of advanced gastric adenocarcinoma with multi-organ metastasis was made. He planned to be treated with systemic chemotherapy. PMID- 28835092 TI - Management of Percutaneous Endoscopic Gastrostomy Site Gastric Ulcer in a Patient with an Esophageal Stricture and Hiatus Hernia. AB - Percutaneous endoscopic gastrostomy (PEG) is commonly performed for feeding difficulties, in patients suffering from complications of nasopharyngeal carcinoma and its treatment, namely radiotherapy and surgery. This case report describes the challenges in hemostasis and subsequent re-establishment of enteral access for feeding, in an elderly patient with a history of NPC, treated surgically, followed by radiotherapy, who presented with massive hematemesis following reinsertion of her PEG shortly after an accidental dislodgement. Her previous nasopharyngectomy, wide field radiation therapy, and radical neck dissection precluded nasogastric tube feeding, and the presence of a large hiatus hernia made reinsertion of a new PEG technically challenging. This case highlights the methods used to overcome the above challenges. PMID- 28835094 TI - Ischemic Necrosis of the Gastric Remnant without Splenic Infarction Following Subtotal Gastrectomy. AB - Gastric remnant necrosis after a subtotal gastrectomy is an extremely uncommon complication due to the rich vascular supply of the stomach. Despite its rareness, it must be carefully addressed considering the significant mortality rate associated with this condition. Patients vulnerable to ischemic vascular disease in particular need closer attention and should be treated more cautiously. When gastric remnant necrosis is suspected, an urgent endoscopic examination must be performed. We report a case of gastric remnant necrosis following a subtotal gastrectomy and discuss possible risk factors associated with this complication. PMID- 28835093 TI - Voriconazole-refractory invasive aspergillosis. AB - Invasive aspergillosis (IA) is one of the most common life-threatening complications in immunocompromised patients. Voriconazole is currently the drug of choice for IA treatment. However, some patients with IA suffer clinical deterioration despite voriconazole therapy. Management of voriconazole-refractory IA remains challenging; no useful recommendations have yet been made. Voriconazole-refractory IA can be further categorized as disease attributable to misdiagnosis or co-infection with another mold; inadequate blood voriconazole blood; inadequate tissue drug concentrations attributable to angioinvasion; immune reconstitution inflammatory syndrome; or infection with voriconazole resistant Aspergillus. Hence, when encountering a case of voriconazole-refractory IA, it is necessary to schedule sequential tests to decide whether medical treatment or surgical intervention is appropriate; to adjust the voriconazole dose via drug monitoring; to seek CYP2C19 polymorphisms; to monitor serum galactomannan levels; and to examine the drug susceptibility of the causative Aspergillus species. PMID- 28835095 TI - Revealing the Cytotoxicity of Residues of Phosphazene Catalysts Used for the Synthesis of Poly(ethylene oxide). AB - We herein report a case study on the toxicity of residual catalyst in metal-free polymer. Eight-arm star-like poly(ethylene oxide)s were successfully synthesized via phosphazene-catalyzed ring-opening polymerization of ethylene oxide using sucrose as an octahydroxy initiator. The products were subjected to MTT assay using human cancer cell lines (MDA-MB-231 and A2780). Comparison between the crude and purified products clearly revealed that the residual phosphazenium salts were considerably cytotoxic, regardless of the anionic species, and that the cytotoxicity of more bulky t-BuP4 salt was higher than that of t-BuP2 salt. Such results have therefore put forward the necessity for removal of the catalyst residues from PEO-based polymers synthesized through phosphazene catalysis for biorelated applications and for the development of less or nontoxic organocatalysts for such polymers. PMID- 28835097 TI - Tautomerization of Thymine Using Ultraviolet Light. AB - Ultraviolet-light-induced changes to the nucleobase thymine deposited onto a MoS2 surface were studied using photoelectron spectroscopy and first-principles calculations. These measurements suggest changes in the molecular structure indicated by changes in core electron binding energies. The experimental work has been interpreted by means of ab initio calculations using coupled cluster singles and doubles (CCSD) linear response theory. Contrary to the expected behavior, i.e., the dimerization of two thymine molecules into a pyrimidine dimer, a shift between two tautomeric forms was observed upon UV-exposure. Exposure to ionizing radiation is known to induce damage in many biological molecules, and the present work gives additional insight into its effects on thymine, the interactions of the molecules, and finally how certain UV photoproducts may be avoided. PMID- 28835096 TI - Reversibility of Covalent, Broad-Spectrum Serine beta-Lactamase Inhibition by the Diazabicyclooctenone ETX2514. AB - ETX2514 is a non-beta-lactam serine beta-lactamase inhibitor in clinical development that has greater potency and broader spectrum of beta-lactamase inhibition than the related diazabicyclooctanone avibactam. Despite opening of its cyclic urea ring upon acylation, avibactam can recyclize and dissociate intact from certain beta-lactamases. We investigated reversibility of ETX2514 acylation of 10 serine beta-lactamases representing Ambler classes A, C, and D. Dissociation rate constants varied widely between enzymes and were lowest for class D. For most enzymes, the covalent adduct mass was that of ETX2514 (277 Da). OXA-10 was acylated with 277 and 197 Da adducts, consistent with loss of the sulfate moiety. KPC-2 showed only the 197 Da adduct. ETX2514 recyclized and dissociated intact from AmpC, CTX-M-15, P99, SHV-5 and TEM-1 but not from KPC-2, OXA-10, OXA-23, OXA-24, or OXA-48. Inactivation partition ratios were 1 for all enzymes except KPC-2, for which it increased to 3.0 after 2 h. This result and mass spectrometry showed that KPC-2 very slowly degraded ETX2514. Nevertheless, ETX2514 restored beta-lactam activity to equal potency against isogenic Pseudomonas aeruginosa strains each overexpressing one of the 10 beta-lactamases. PMID- 28835098 TI - Air Emissions Damages from Municipal Drinking Water Treatment Under Current and Proposed Regulatory Standards. AB - Water treatment processes present intersectoral and cross-media risk trade-offs that are not presently considered in Safe Drinking Water Act regulatory analyses. This paper develops a method for assessing the air emission implications of common municipal water treatment processes used to comply with recently promulgated and proposed regulatory standards, including concentration limits for, lead and copper, disinfection byproducts, chromium(VI), strontium, and PFOA/PFOS. Life-cycle models of electricity and chemical consumption for individual drinking water unit processes are used to estimate embedded NOx, SO2, PM2.5, and CO2 emissions on a cubic meter basis. We estimate air emission damages from currently installed treatment processes at U.S. drinking water facilities to be on the order of $500 million USD annually. Fully complying with six promulgated and proposed rules would increase baseline air emission damages by approximately 50%, with three-quarters of these damages originating from chemical manufacturing. Despite the magnitude of these air emission damages, the net benefit of currently implemented rules remains positive. For some proposed rules, however, the promise of net benefits remains contingent on technology choice. PMID- 28835099 TI - Glutathione-Sensitive Hyaluronic Acid-Mercaptopurine Prodrug Linked via Carbonyl Vinyl Sulfide: A Robust and CD44-Targeted Nanomedicine for Leukemia. AB - 6-Mercaptopurine (6-MP) is an essential medicine used for treating leukemia in the clinics. 6-MP suffers, however, from poor water solubility, low bioavailability, and significant side effects. Here, we designed CD44-targeted glutathione-sensitive hyaluronic acid-mercaptopurine prodrug (HA-GS-MP) linked via carbonyl vinyl sulfide for safer and enhanced treatment of acute myeloid leukemia (AML). HA-GS-MP obtained with 50 kDa HA and 6-MP conjugation content of 6.9 wt % showed excellent water solubility with a hydrodynamic size of ca. 15 nm. Intriguingly, HA-GS-MP was extremely stable, without any drug leakage, under physiological environment while rapidly releasing 6-MP in response to 10 mM glutathione. HA-GS-MP exhibited obvious targetability and markedly enhanced antitumor effect to OCI/AML-2 human AML cells (IC50 = 16.9 MUg 6-MP equiv./mL). The pharmacokinetic studies displayed that Cy5-labeled HA-GS-MP had a long circulation time in mice (elimination half-life = 4.37 h). The in vivo fluorescence images demonstrated strong and persistent accumulation of Cy5 labeled HA-GS-MP from 4 to 48 h post injection in the subcutaneous OCI/AML-2 tumor in nude mice. Notably, HA-GS-MP while causing little side effects induced significantly enhanced growth inhibition of OCI/AML-2 tumor and better survival rate of OCI/AML-2 tumor-bearing mice as compared to free 6-MP. Carbonyl vinyl sulfide-linked hyaluronic acid-mercaptopurine prodrug has appeared to be a simple and smart nanomedicine for targeted treatment of AML. PMID- 28835100 TI - o-(p-Methoxyphenylethynyl)phenyl Glycosides: Versatile New Glycosylation Donors for the Highly Efficient Construction of Glycosidic Linkages. AB - A novel alkyne-activation-based glycosylation protocol using o-(p methoxyphenylethynyl)phenyl (MPEP) glycoside was established. The glycosyl MPEP donors were shelf-stable and could be prepared efficiently via Sonogashira reaction from the corresponding o-iodophenyl (IP) glycosides. The outstanding stability of IP glycosides as well as their efficient transformations to MPEP glycosides dramatically facilitates the syntheses of MPEP glycosyl donors and IP glycosyl acceptors. Furthermore, they make the MPEP glycosylation protocol applicable to the latent-active oligosaccharide and glycoconjugate synthetic strategy, with IP glycosides as the latent form and MPEP glycosides as the active form, as illustrated by the highly efficient fabrication of Streptococcus pneumoniae type 3 trisaccharide. The phenolic glycoside nature of MPEP glycosides bestows on the new glycosyl donors enhanced stability compared to their thioglycoside counterparts toward activation conditions applied for glycosyl trichloroacetimidate (TCAI) and o-alkynylbenzoate (ABz) donor. Thus, MPEPs can also be utilized in the selective one-pot glycosylation strategy, as exemplified by the syntheses of oligosaccharides via successive glycosylations with glycosyl TCAI, ABz, and EPMP as donors. Despite sharing identical promotion conditions with thioglycoside donors, the odor-free starting material (IP), the stable departure structure of the leaving group (3-iodobenzofuran), and the decreased nucleophilicity of the o-MPEP glycoside help to eliminate the three major shortcomings of the thioglycoside donors (unpleasant odor of starting material, detrimental interference of the cleaved leaving group, and aglycon intra- or intermolecular migration) while maintaining the prominent features of the thioglycoside methodology, including the broad substrate scopes, the mild promotion conditions, the stability of glycosyl donors, and the versatile applications in existing glycoside synthesis strategies. Based on the experimental results, a mechanism for MPEP activation was proposed, which was supported by systematic mechanistic investigations, including trapping of active intermediates, design of a vital disarmed rhamnosyl donor, and isolation and characterization of the departure species of the leaving group. PMID- 28835101 TI - Competition between HO2 and H2O2 Reactions with CH2OO/anti-CH3CHOO in the Oligomer Formation: A Theoretical Perspective. AB - Understanding Criegee chemistry has become one of the central topics in atmospheric studies recently. Ozonolysis of unsaturated hydrocarbons is believed to be an important pathway of secondary organic aerosol (SOA). However, the SOA formation mechanisms via Criegee chemistry are still poorly understood. Here, we systematically study the competition between HO2 and H2O2 reactions with CH2OO/anti-CH3CHOO in the oligomer formations. The calculated results show that oligomers having Criegee intermediates as the chain units are produced by the sequential addition of Criegee intermediates (CIs) to HO2 and H2O2 molecules. The addition reactions are predicted to be strongly exothermic, and the apparent activation barriers are estimated to be negative, suggesting that these reactions are feasible both thermochemically and dynamically. Compared to the barriers of 4CH2OO + HO2 and 4CH2OO + H2O2 reactions, it can be found that the first two CH2OO addition reactions in the former case are favored, while the last two CH2OO addition reactions in the latter case are preferable. A similar conclusion is also obtained from those of the 4anti-CH3CHOO + HO2/H2O2 systems. The mechanistic insights can motivate future experimental studies of the effect of longer-chain CIs on the formation of SOA, which plays an important role on air quality and climate change. PMID- 28835102 TI - Mechanism of the Nitric Oxide Dioxygenase Reaction of Mycobacterium tuberculosis Hemoglobin N. AB - Many globins convert *NO to innocuous NO3- through their nitric oxide dioxygenase (NOD) activity. Mycobacterium tuberculosis fights the oxidative and nitrosative stress imposed by its host (the toxic effects of O2*- and *NO species and their OONO- and *NO2 derivatives) through the action of truncated hemoglobin N (trHbN), which catalyzes the NOD reaction with one of the highest rates among globins. The general NOD mechanism comprises the following steps: binding of O2 to the heme, diffusion of *NO into the heme pocket and formation of peroxynitrite (OONO-), isomerization of OONO-, and release of NO3-. Using quantum mechanics/molecular mechanics free-energy calculations, we show that the NOD reaction in trHbN follows a mechanism in which heme-bound OONO- undergoes homolytic cleavage to give FeIV?O2- and the *NO2 radical but that these potentially harmful intermediates are short-lived and caged by the heme pocket residues. In particular, the simulations show that Tyr33(B10) side chain is shielded from FeIV?O2- and *NO2 (and protected from irreversible oxidation and nitration) by forming stable hydrogen bonds with Gln58(E11) side chain and Leu54(E7) backbone. Aromatic residues Phe46(CD1), Phe32(B9), and Tyr33(B10) promote NO3- dissociation via C-H...O bonding and provide stabilizing interactions for the anion along its egress route. PMID- 28835104 TI - New Physical Insights: Magnetic Resonance Methods and Applications. PMID- 28835103 TI - Nanofertilizer for Precision and Sustainable Agriculture: Current State and Future Perspectives. AB - The increasing food demand as a result of the rising global population has prompted the large-scale use of fertilizers. As a result of resource constraints and low use efficiency of fertilizers, the cost to the farmer is increasing dramatically. Nanotechnology offers great potential to tailor fertilizer production with the desired chemical composition, improve the nutrient use efficiency that may reduce environmental impact, and boost the plant productivity. Furthermore, controlled release and targeted delivery of nanoscale active ingredients can realize the potential of sustainable and precision agriculture. A review of nanotechnology-based smart and precision agriculture is discussed in this paper. Scientific gaps to be overcome and fundamental questions to be answered for safe and effective development and deployment of nanotechnology are addressed. PMID- 28835105 TI - New Physical Insights: Magnetic Resonance Methods and Applications. PMID- 28835106 TI - Adaptation of the global frameworks for community based rehabilitation in southern Africa: a proof of concept. AB - INTRODUCTION: Community based rehabilitation (CBR) has evolved over the last 30 years and now focuses on empowering persons with disabilities to access and benefit from a wide range of services. The essence and ethos of CBR is captured in several global frameworks, such as the UN Convention on the Rights of People with Disabilities (2006) and the CBR guidelines (2010). The latter contains the CBR matrix. All 15 countries in southern Africa are implementing CBR mostly in rural areas, but the policy framework to guide CBR in the region is unknown. The purpose of the study was to determine to what extent countries in southern Africa have adapted the global frameworks available for CBR. METHODS: A CBR policy analysis using proof-of-concept methodology was undertaken. Policy documents on CBR were sought from relevant government departments or agencies. Multiple methods and media, including web searches, searches for grey literature, social media and contact through an elaborate network of colleagues working in the region, were employed to execute the search strategy. Data were organized using NVivo software, and three independent raters coded the emergent themes using the CBR matrix. RESULTS: Only Namibia, South Africa, Tanzania and Zimbabwe have specific policy content for CBR. These, however, lacked structure; the content was predominantly aligned to health. Inclusion of key international concepts such as mainstreaming and empowerment were superfluous when present. CONCLUSIONS: The CBR policy environment in southern Africa appears inadequate. Contingent factors that preclude adaptation of the global frameworks available for CBR appear to be at play. These warrant further investigation. PMID- 28835107 TI - Why has increased provision of psychiatric treatment not reduced the prevalence of mental disorder? PMID- 28835108 TI - ICD-11 and DSM-5 personality trait domains capture categorical personality disorders: Finding a common ground. AB - OBJECTIVE: The five personality disorder trait domains in the proposed International Classification of Diseases, 11th edition and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition are comparable in terms of Negative Affectivity, Detachment, Antagonism/Dissociality and Disinhibition. However, the International Classification of Diseases, 11th edition model includes a separate domain of Anankastia, whereas the Diagnostic and Statistical Manual of Mental Disorders, 5th edition model includes an additional domain of Psychoticism. This study examined associations of International Classification of Diseases, 11th edition and Diagnostic and Statistical Manual of Mental Disorders, 5th edition trait domains, simultaneously, with categorical personality disorders. METHOD: Psychiatric outpatients ( N = 226) were administered the Structured Clinical Interview for DSM-IV Axis II Personality Disorders Interview and the Personality Inventory for DSM-5. International Classification of Diseases, 11th edition and Diagnostic and Statistical Manual of Mental Disorders, 5th edition trait domain scores were obtained using pertinent scoring algorithms for the Personality Inventory for DSM-5. Associations between categorical personality disorders and trait domains were examined using correlation and multiple regression analyses. RESULTS: Both the International Classification of Diseases, 11th edition and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition domain models showed relevant continuity with categorical personality disorders and captured a substantial amount of their information. As expected, the International Classification of Diseases, 11th edition model was superior in capturing obsessive-compulsive personality disorder, whereas the Diagnostic and Statistical Manual of Mental Disorders, 5th edition model was superior in capturing schizotypal personality disorder. CONCLUSION: These preliminary findings suggest that little information is 'lost' in a transition to trait domain models and potentially adds to narrowing the gap between Diagnostic and Statistical Manual of Mental Disorders, 5th edition and the proposed International Classification of Diseases, 11th edition model. Accordingly, the International Classification of Diseases, 11th edition and Diagnostic and Statistical Manual of Mental Disorders, 5th edition domain models may be used to delineate one another as well as features of familiar categorical personality disorder types. A preliminary category-to-domain 'cross walk' is provided in the article. PMID- 28835109 TI - County level incidence rates of chronic lymphocytic leukemia are associated with residential radon levels. AB - AIM: We previously reported that incidence rates for chronic lymphocytic leukemia (CLL) among US states are significantly correlated with levels of residential radon (RR). Because these correlations could be influenced by confounding and/or misclassification among large geographic units, we reinvestigated them using smaller geographic units that better reflect exposure and disease at the individual level. METHODS: We examined the relationships between CLL and RR per county in 478 counties with publicly-available data. RESULTS: After adjustment for ultraviolet radiation, a possible risk factor for CLL, county rates for CLL and RR were significantly correlated among males and females both together and separately (p < 0.0001). CONCLUSION: CLL is significantly associated with RR at the county level. PMID- 28835110 TI - Priorities in the assessment and management of perinatal mood disorders. PMID- 28835111 TI - Diagnostic value of apparent diffusion coefficient in differentiating between high-grade gliomas and brain metastases. AB - Background High-grade gliomas (HGGs) and brain metastases (BMs) can display similar imaging characteristics on conventional MRI. In HGGs, the peritumoral edema may be infiltrated by the malignant cells, which was not observed in BMs. Purpose To determine whether the apparent diffusion coefficient values could differentiate HGGs from BMs. Material and Methods Fifty-seven patients underwent conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) before treatment. The minimum and mean ADC in the enhancing tumor (ADCmin, ADCmean) and the minimum ADC in the peritumoral region (ADCedema) were measured from ADC maps. To determine whether there was a statistical difference between groups, ADC values were compared. A receiver operating characteristic (ROC) curve analysis was used to determine the cutoff ADC value for distinguishing between HGGs and BMs. Results The mean ADCmin values in the intratumoral regions of HGGs were significantly higher than those in BMs. No differences were observed between groups regarding ADCmean values. The mean ADCmin values in the peritumoral edema of HGGs were significantly lower than those in BMs. According to ROC curve analysis, a cutoff value of 1.332 * 10-3 mm2/s for the ADCedema generated the best combination of sensitivity (95%) and specificity (84%) for distinguishing between HGGs and BMs. The same value showed a sensitivity of 95.6% and a specificity of 100% for distinguishing between GBMs and BMs. Conclusion ADC values from DWI were found to distinguish between HGGs and solitary BMs. The peritumoral ADC values are better than the intratumoral ADC values in predicting the tumor type. PMID- 28835112 TI - A framework to create more mentally healthy workplaces: A viewpoint. AB - Mental illness is now the leading cause of long-term sickness absence among Australian workers, with significant costs to the individual, their employers and society more broadly. However, to date, there has been little evidence-informed guidance as to what workplaces should be doing to enhance their employees' mental health and wellbeing. In this article, we present a framework outlining the key strategies employers can implement to create more mentally healthy workplaces. The five key strategies outlined are as follows: (1) designing work to minimise harm, (2) building organisational resilience through good management, (3) enhancing personal resilience, (4) promoting early help-seeking and (5) supporting recovery and return to work. A narrative review is utilised to outline the theoretical evidence for this framework and to describe the available research evidence for a number of key example interventions for each of the five strategies. While each workplace needs to develop tailored solutions, the five strategy framework proposed in this review will hopefully provide a simple framework for employers and those advising them to use when judging the adequacy of existing services and considering opportunities for further enhancements. PMID- 28835113 TI - Endothelial Cell Inflammation and Antioxidant Capacity are Associated With 6 Minute Walk Performance in Patients With Symptomatic Peripheral Artery Disease. AB - We determined whether 6-minute walk total distance and pain-free distance were associated with circulating biomarkers of antioxidant capacity and inflammation and with cultured endothelial cell inflammation, oxidative stress, and apoptosis in 251 patients with symptomatic peripheral artery disease (PAD). In multivariate analyses, pain-free distance during the 6-minute walk test was negatively associated with dyslipidemia ( P < .001), chronic kidney disease ( P = .004), and transient transfection, nuclear factor kappa-Light-Chain-Enhancer of activated B (NF-kappaB) cultured endothelial cells ( P = .007) and was positively associated with height ( P = .008). Furthermore, total distance walked during the 6-minute walk test was negatively associated with cultured endothelial cell NF-kappaB ( P < .001), coronary artery disease ( P = .009), and body mass index ( P = .022) and was positively associated with ankle-brachial index ( P < .001), male sex ( P < .001), and hydroxyl radical antioxidant capacity ( P < .001). The 6-minute walk performance in symptomatic patients with PAD was associated with vascular biomarkers, as walking distances were negatively associated with cultured endothelial cell inflammation and positively associated with circulating antioxidant capacity. The clinical implication is that behavioral interventions designed to alleviate endothelial cell inflammation and increase circulating antioxidant capacity, such as exercise and antioxidant intake, may improve ambulation of patients with PAD during submaximal exercise that is typically performed during daily activities. PMID- 28835114 TI - Challenges faced when identifying patients for combination immunotherapy. AB - In 1996, Jim Allison demonstrated that blocking the immune regulatory molecule CTLA-4 with anit-CTLA4 antibody led to enhance tumor responses in mice. It would take an additional 15 years for human studies to confirm the potency and clinical efficacy of anti-CTLA4, ultimately leading to US FDA approval of the first checkpoint inhibitor, ipilimumab. Now with a plethora of immune-modulating agents demonstrating single agent safety and benefit across many tumor types, investigation on the optimal combination of immune-based therapies has begun in earnest. While there are many challenges, a central one is how to select which combination for which patient is the best. Here we review the current approaches that a practitioner can use to achieve this therapeutic goal. PMID- 28835116 TI - Estimation of the Percentage of Newly Diagnosed HIV-Positive Persons Linked to HIV Medical Care in CDC-Funded HIV Testing Programs. AB - Missing data create challenges for determining progress made in linking HIV positive persons to HIV medical care. Statistical methods are not used to address missing program data on linkage. In 2014, 61 health department jurisdictions were funded by Centers for Disease Control and Prevention (CDC) and submitted data on HIV testing, newly diagnosed HIV-positive persons, and linkage to HIV medical care. Missing or unusable data existed in our data set. A new approach using multiple imputation to address missing linkage data was proposed, and results were compared to the current approach that uses data with complete information. There were 12,472 newly diagnosed HIV-positive persons from CDC-funded HIV testing events in 2014. Using multiple imputation, 94.1% (95% confidence interval (CI): [93.7%, 94.6%]) of newly diagnosed persons were referred to HIV medical care, 88.6% (95% CI: [88.0%, 89.1%]) were linked to care within any time frame, and 83.6% (95% CI: [83.0%, 84.3%]) were linked to care within 90 days. Multiple imputation is recommended for addressing missing linkage data in future analyses when the missing percentage is high. The use of multiple imputation for missing values can result in a better understanding of how programs are performing on key HIV testing and HIV service delivery indicators. PMID- 28835117 TI - Measuring Opportunities for Engaging in Meaningful Home-Based Activities in Housing Services for People With Psychiatric Disabilities: Development of the Perceived Meaning of Activity in Housing (PMA-H). AB - There is a scarcity of instruments for assessing opportunities for residents with psychiatric disabilities to engage in meaningful home-based activities. We thus developed the Perceived Meaning of Activity in Housing (PMA-H), containing four subscales (activity opportunities, social interaction, developing as a person, and organization and planning). The aim of the study was to investigate the content validity, utility, internal consistency and concurrent and criterion validity of the PMA-H, as well as possible floor and ceiling effects. One hundred and fifty-five residents in supported housing (SH) and 111 in ordinary housing with support (OHS) completed the PMA-H. The SH group also competed the Community Oriented Programs Environment Scale (COPES). A majority of the participants found the content of the PMA-H relevant, easy to complete, and the time for completion as reasonable. Internal consistency varied between 0.85 and 0.92 for the subscales. Logical associations with COPES indicated construct validity. The subscales social interaction and developing as a person could discriminate between the SH and OHS groups, whereas activity opportunities could not. No floor or ceiling effects were found. This study indicated adequate initial psychometric properties of the PMA-H. It can thus be used in housing settings to assess the residents' perceived opportunities for meaningful activity in the housing context. PMID- 28835118 TI - Effectiveness of group reminiscence therapy for people living with dementia in a day care centers in Taiwan. AB - Objective To explore as a pilot study the effects of group reminiscence therapy upon depression of people living with dementia within dementia-specific day care centers. Method A unique pre-test-post-test, quasi-experimental design counterbalanced with a qualitative grounded theory video analysis of facial expression and behavior was used to measure the effects of group reminiscence therapy. The study recruited 21 participants in total from two dementia-specific day care centers. Results The findings highlighted improvements in depression, communication, and positive mood after group reminiscence intervention. The results also showed that participants scored higher on average during the Chinese New Year and marriage reminiscence activities compared to the other activities, revealing the subject matters extraordinarily significance. Conclusion This study provides evidence supporting the proposition that undertaking a cultural focus reminiscence therapy may produce significant psychosocial improvements for a person with dementia. PMID- 28835119 TI - Exposure to nature gardens has time-dependent associations with mood improvements for people with mid- and late-stage dementia: Innovative practice. AB - Exposure to green space and nature has a potential role to play in the care of people with dementia, with possible benefits including improved mood and slower disease progression. In this observational study at a dementia care facility in the UK, we used carer-assessed measures to evaluate change in mood of residents with mid- to late-stage dementia following exposure to a nature garden. We found that exposure to nature was associated with a beneficial change in patient mood. There was a non-linear relationship between time spent outdoors and mood outcome. Improvements in patient mood were associated with relatively short duration exposures to nature, and no additional measureable increases in mood were found with exposures beyond 80-90 minutes duration. Whilst further investigation is required before causality can be determined, these results raise important questions for policy about the integration of outdoor space into the design of dementia care facilities and programmes. PMID- 28835115 TI - "Only a Life Lived for Others Is Worth Living": Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions. AB - SIGNIFICANCE: Oxygenated polyunsaturated lipids are known to play multi functional roles as essential signals coordinating metabolism and physiology. Among them are well-studied eicosanoids and docosanoids that are generated via phospholipase A2 hydrolysis of membrane phospholipids and subsequent oxygenation of free polyunsaturated fatty acids (PUFA) by cyclooxygenases and lipoxygenases. Recent Advances: There is an emerging understanding that oxygenated PUFA phospholipids also represent a rich signaling language with yet-to-be-deciphered details of the execution machinery-oxygenating enzymes, regulators, and receptors. Both free and esterified oxygenated PUFA signals are generated in cells, and their cross-talk and inter-conversion through the de-acylation/re acylation reactions is not sufficiently explored. CRITICAL ISSUES: Here, we review recent data related to oxygenated phospholipids as important damage signals that trigger programmed cell death pathways to eliminate irreparably injured cells and preserve the health of multicellular environments. We discuss the mechanisms underlying the trans-membrane redistribution and generation of oxygenated cardiolipins in mitochondria by cytochrome c as pro-apoptotic signals. We also consider the role of oxygenated phosphatidylethanolamines as proximate pro-ferroptotic signals. FUTURE DIRECTIONS: We highlight the importance of sequential processes of phospholipid oxygenation and signaling in disease contexts as opportunities to use their regulatory mechanisms for the identification of new therapeutic targets. PMID- 28835120 TI - The "Body Mass Index" of Flexible Ureteroscopes. AB - OBJECTIVE: To assess the "body mass index" (BMI) (weight and length) of 12 flexible ureteroscopes (digital and fiber optic) along with the light cables and camera heads, to make the best use of our instruments. MATERIALS AND METHODS: Twelve different brand-new flexible ureteroscopes from four different manufacturers, along with eight camera heads and three light cables were evaluated. Each ureteroscope, camera head, and light cable was weighted; the total length of each ureteroscope, shaft, handle, flexible end-tip, and cable were all measured. RESULTS: According to our measurements (in grams [g]), the lightest ureteroscope was the LithoVue (277.5 g), while the heaviest was the URF V2 (942.5 g). The lightest fiber optic endoscope was the Viper (309 g), while the heaviest was the Cobra (351.5 g). Taking into account the entirety of the endoscopes, the lightest ureteroscope was the Lithovue and the heaviest was the Wolf Cobra with the Wolf camera "3 CHIP HD KAMERA KOPF ENDOCAM LOGIC HD" (1474 g). The longest ureteroscope was the URF-P6 (101.6 cm) and the shortest was the LithoVue (95.5 cm); whereas the Viper and Cobra had the longest shaft (69 cm) and URF-V had the shortest shaft (67.2 cm). The URF-V2 had the longest flexible end tip (7.6 cm), while the LithoVue had the shortest end-tip (5.7 cm) in both directions (up/down), while the URF-V had the shortest upward deflection (3.7 cm). CONCLUSIONS: Newer more versatile digital endoscopes were lighter than their traditional fiber optic counterparts in their entirety, with disposable endoscope having a clear advantage over other reusable ureteroscopes. Knowing the "BMI" of our flexible ureteroscopes is an important information that every endourologist should always take into consideration. PMID- 28835121 TI - Comparative analysis of thermal-assisted high pressure and thermally processed mango pulp: Influence of processing, packaging, and storage. AB - Storage stability and shelf-life of mango pulp packed in three different packaging films and processed using an optimized thermal-assisted high pressure processing treatment 'HPP' (600 MPa/52 C/10 min) was analyzed during refrigerated (5 C) and accelerated (37 C) storage and compared with the conventional thermal treatment 'TT' (0.1 MPa/95 C/15 min). After processing, HPP resulted in relatively lower total color difference (3.5), retained higher ascorbic acid (95%), total phenolics (106%), total flavonoids content (118%) in mango pulp compared to TT, with values of 5.0, 62, 83, 73%, respectively. However, HPP led to ~50% enzymes inactivation (pectin methylesterase, polyphenol oxidase, peroxidase) in comparison to >90% obtained during TT. Both HPP and TT resulted in > 5 log10 units reduction of the studied microorganisms to give a safe product. In contrast to the refrigerated storage, quality changes under accelerated conditions were found to be considerably rapid and dependent on packaging material irrespective of the method of processing. Shelf-life under refrigeration was limited by microbial growth and sensory quality; whereas, browning restricted the shelf-life during accelerated storage. HPP in aluminum-based retort pouch was adjudged superior processing -packaging combination for maximizing the shelf-life of mango pulp to 120 and 58 days during refrigerated and accelerated storage, respectively. In comparison, TT led to higher quality changes upon processing than HPP and resulted in shelf-life of 110 and 58 days under the same packaging and storage conditions, respectively. PMID- 28835122 TI - Biological and environmental determinants of 12-minute run performance in youth. AB - BACKGROUND: The 12-minute run is a commonly used indicator of cardiorespiratory fitness in youth. Variation in growth and maturity status as potential correlates of test performance has not been systematically addressed. AIM: To evaluate biological and environmental determinants of 12-minute run performance in Portuguese youth aged 7-17 years. SUBJECTS AND METHODS: Mixed-longitudinal samples of 187 boys and 142 girls were surveyed in 1996, 1997 and 1998. The 12 minute run was the indicator of cardiorespiratory fitness. Height, body mass and five skinfolds were measured and skeletal maturity was assessed. Physical activity, socioeconomic status and area of residence were obtained with a questionnaire. Multi-level modelling was used for the analysis. RESULTS: Chronological age and sum of five skinfolds were significant predictors of 12 minute run performance. Older boys and girls ran longer distances than younger peers, while high levels of subcutaneous fat were associated with shorter running distances. Rural boys were more proficient in the 12-minute run than urban peers. Skeletal maturity, height, body mass index, physical activity and socioeconomic status were not significant predictors of 12-minute run performances. CONCLUSIONS: Age and sum of skinfolds in both sexes and rural residence in boys are significant predictors of 12-minute run performance in Portuguese youth. PMID- 28835123 TI - Advances in Gene Therapy for Hemophilia. AB - Gene therapy provides hope for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene copy to replace the hemophilic patient's own defective gene. Hemophilia may be considered a "low-hanging fruit" for gene therapy because a small increment in blood factor levels (>=2% of normal) significantly improves the bleeding tendency from severe to moderate, eliminating most spontaneous bleeds. After decades of research, the first trial to provide clear evidence of efficiency after gene transfer in patients with hemophilia B using adeno-associated virus vectors was reported by the authors' group in 2011. This has been followed by unprecedented activity in this area, with the commencement of seven new early-phase trials involving >55 patients with hemophilia A or hemophilia B. These studies have, in large part, generated promising clinical data that lay a strong foundation for gene therapy to move forward rapidly to market authorization. This review discusses the data from the authors' studies and emerging results from other gene therapy trials in both hemophilia A and B. PMID- 28835124 TI - In vitro and in vivo characteristics of biogenic high surface silica nanoparticles in A549 lung cancer cell lines and Danio rerio model systems for inorganic biomaterials development. AB - Silica based organic-inorganic hybrids are turned over the most necessitate biomaterial due to their exotic biomedical properties. Colloidal silica nanoparticles (SNPs) of high surface area are synthesized from the bamboo wastes (leave biomass) as a viable and promising alternative to synthetic silica sol through alkaline extraction process. Physico-chemical properties of the prepared silica powders are examined employing extensive characterization tools. The characteristic results of the silica sol demonstrate amorphous particles (average size: 25 nm) with relatively high surface area (428 m2 g-1) and spherical morphology. The teratogenicity of the surface and size dependant SNPs is evaluated using an alternative animal model, zebrafish (Danio rerio) in comparison with micron sized particles. LDH based cytotoxicity assay reveals non significant cell damage in all the tested silica particles. Less mortality, uptake and dysfunctionalities of the organs during the developmental stages of zebrafish treated with bulk and nanoparticles confirm their biocompatibility. The least DNA strand breakage during genotoxic assay and teratogenic parameters are found to exhibit desirable bioactivity of SNPs for clinical applications even at higher concentrations. For the first time, bamboo derived silica sol induced genotoxicity is assessed at molecular level to understand the interaction mechanism with the fish genome. PMID- 28835125 TI - Small But Increasingly Mighty: Latest Advances in AAV Vector Research, Design, and Evolution. AB - Recombinant gene delivery vectors derived from naturally occurring or genetically engineered adeno-associated viruses (AAV) have taken center stage in human gene therapy, fueled by rapidly accumulating and highly encouraging clinical data. Nonetheless, it has also become evident that the current generation of AAV vectors will require improvements in transduction potency, antibody evasion, and cell specificity in order to realize their full potential and to widen applicability in larger patient cohorts. Fortunately, in the recent past, the field has seen a flurry of exciting new developments that enhance our understanding of AAV vector biology, including virus-host interactions, and/or that expand our arsenal of technologies for AAV capsid design and evolution. This review highlights a collection of latest advances in these areas, which, in the authors' opinion, hold particular promise to propel the AAV vector field forward in the near future, especially when applied in combination. These include fundamental novel insights into the AAV life cycle, from an unexpected role of autophagy and interactions with other viruses to the (re-)discovery of a universal AAV receptor and the function of AAV-AAP for capsid assembly. Concurrently, recent successes in the rational design of next-generation synthetic AAV capsids are pointed out, exemplified by the structure-guided derivation of AAV mutants displaying robust in vivo immune evasion. Finally, a variety of new and innovative strategies for high-throughput generation and screening of AAV capsid libraries are briefly reviewed, including Cre recombinase based selection, ancestral AAV capsid reconstruction, and DNA barcoding of AAV genomes. All of these examples showcase the present momentum in the AAV field and, together with work by many other academic or industrial entities, raise substantial optimism that the remaining hurdles for human gene therapy with AAV vectors will (soon) be overcome. PMID- 28835126 TI - Ventriculoperitoneal shunts in neonates: a retrospective study of outcomes with antibiotic-impregnated catheters and a modified peri-operative antibiotic protocol. AB - BACKGROUND: CSF infection is a significant complication of ventriculoperitoneal (VP) shunts and results in prolonged hospital stay, developmental delay and decreased quality of life. To decrease the high rates of neonatal VP shunt infections, an updated clinical guideline that included the use of antibiotic impregnated shunts and a revised peri-operative antibiotic protocol was introduced in our neonatal unit. In this study, we evaluated the efficacy of these new guidelines in reducing the CSF shunt infection rates. METHODS: A retrospective cohort study of neonates (<=28 days) who had VP shunt insertions in our unit. RESULTS: 24 neonates in the first epoch received plain silastic shunt catheters (Feb 2002-April 2007), and 23 in the second epoch (August 2007-July 2015) received AIS catheters and a revised perioperative antibiotic protocol. Patient demographics were similar between both cohorts. Shunt related CSF infections were reduced in epoch 2 (2/23, 8.7%) compared to epoch 1 (5/24, 20.8%), but the results were not statistically significant (OR 0.36 (0.063 2.090); p = 0.256). Amongst neonates that needed VP shunt revision due to any cause, the median time interval between insertion to revision was significantly later in epoch 2 (epoch 1, 48 days (3-99); epoch 2, 148 days (20-396); p = 0.013). CONCLUSIONS: AIS catheters and a 48-hour perioperative antibiotic regimen may be beneficial in neonatal hydrocephalus. Adequately powered RCTs in the neonatal population are needed to confirm these findings. PMID- 28835127 TI - Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial. AB - Over the past decade, vectors derived from adeno-associated virus (AAV) have established themselves as a powerful tool for in vivo gene transfer, allowing long-lasting and safe transgene expression in a variety of human tissues. Nevertheless, clinical trials demonstrated how B and T cell immune responses directed against the AAV capsid, likely arising after natural infection with wild type AAV, might potentially impact gene transfer safety and efficacy in patients. Seroprevalence studies have evidenced that most individuals carry anti-AAV neutralizing antibodies that can inhibit recombinant AAV transduction of target cells following in vivo administration of vector particles. Likewise, liver- and muscle-directed clinical trials have shown that capsid-reactive memory CD8+ T cells could be reactivated and expanded upon presentation of capsid-derived antigens on transduced cells, potentially leading to loss of transgene expression and immune-mediated toxicities. In celebration of the 25th anniversary of the European Society of Gene and Cell Therapy, this review article summarizes progress made during the past decade in understanding and modulating AAV vector immunogenicity. While the knowledge generated has contributed to yield impressive clinical results, several important questions remain unanswered, making the study of immune responses to AAV a priority for the field of in vivo transfer. PMID- 28835128 TI - Formulation for a novel inhaled peptide therapeutic for idiopathic pulmonary fibrosis. AB - A caveolin-1 scaffolding domain, CSP7, is a newly developed peptide for the treatment of idiopathic pulmonary fibrosis. To develop a CSP7 formulation for further use we have obtained, characterized and compared a number of lyophilized formulations of CSP7 trifluoroacetate with DPBS and in combination with excipients (mannitol and lactose at molar ratios 1:5, 70 and 140). CSP7 trifluoroacetate was stable (>95%) in solution at 5 and 25 degrees C for up to 48 h and tolerated at least 5 freeze/thaw cycles. Lyophilized cakes of CSP7 trifluoroacetate with excipients were stable (>96%) for up to 4 weeks at room temperature (RT), and retained more than 98% of the CSP7 trifluoroacetate in the solution at 8 h after reconstitution at RT. The lyophilized CSP7 formulations were stable for up to 10 months at 5 degrees C protected from moisture. Exposure of the lyophilized cakes of CSP7 to 75% relative humidity (RH) resulted in an increase in the absorbed moisture, promoted crystallization of the excipients and induced reversible formation of CSP7 aggregates. Increased molar ratio of mannitol slightly affected formation of the aggregates. In contrast, lactose significantly decreased (up to 20 times) aggregate formation with apparent saturation at the molar ratio of 1:70. The possible mechanisms of stabilization of CSP7 trifluoroacetate in solid state by lactose include physical state of the bulking agent and the interactions between lactose and CSP7 trifluoroacetate (e.g. formation of a Schiff base with the N-terminal amino group of CSP7). Finally, CSP7 trifluoroacetate exhibited excellent stability during nebulization of formulations containing mannitol or lactose. PMID- 28835130 TI - Adaptation to a changed body. Experiences of living with long-term pelvic girdle pain after childbirth. AB - PURPOSE: To explore how women experience living with long-term pregnancy-related pelvic girdle pain. MATERIALS AND METHODS: Nine women with persistent pregnancy related pelvic girdle pain of 2-13 years were recruited by means of purposive sampling from long-term follow-up studies. The women were 28-42 years of age and had given birth to 2-3 children. Audio-taped in-depth interview with open-ended questions were used with the guiding question 'How do you experience living with pregnancy-related pelvic girdle pain?'. The Empirical Phenomenological Psychological method was chosen for analysis. RESULTS: The pregnancy-related pelvic girdle pain syndrome has a profound impact on everyday life for many years after pregnancy. Three constituents were identified as central to the experience of living with pregnancy-related pelvic girdle pain: (1) the importance of the body for identity, (2) the understanding of pain, and (3) stages of change. The manner in which the women experienced their pain was interpreted in terms of two typologies: the ongoing struggle against the pain, and adaptation and acceptance. CONCLUSION: The participants' narratives highlighted that the pain led to severe functional limitations that threatened their capability to perform meaningful daily activities, and interfered with their sense of identity. It appears essential to meet with each patient individually and to manage long-term pregnancy-related pelvic girdle pain as a pain syndrome. IMPLICATIONS FOR REHABILITATION Chronic pregnancy-related pelvic girdle pain * Pregnancy-related pelvic girdle pain impairs women's capacity to perform meaningful activities of daily life for many years after pregnancy. * The participants' narratives highlighted that the pain interfered with their sense of identity. * It appears essential to meet with each patient individually and to manage long-term pregnancy-related pelvic girdle pain as a pain syndrome. PMID- 28835129 TI - Preclinical renal chemo-protective potential of Prunus amygdalus Batsch seed coat via alteration of multiple molecular pathways. AB - Prunus amygdalus Batsch (almond) is a classical nutritive traditional Indian medicine. Along with nutritive with anti-oxidant properties, it is, clinically, used in the treatment of various diseases with underlying anti-oxidant mechanism. This study is an effort to scrutinise the renal protective effect of P. amygdalus Batsch or green almond (GA) seed coat extract and its underlying mechanism in animal model of Ferric nitrilotriacetate (Fe-NTA) induced renal cell carcinoma (RCC). RCC was induced in Swiss Albino Wistar rats by intraperitoneal injection of Fe-NTA. The rats were then treated with ethanolic extract of GA (25, 50 and 100 mg/kg per oral) for 22 weeks. Efficacy of GA administration was evaluated by change in biochemical, renal, macroscopical and histopathological parameters and alterations. Additionally, interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and inflammatory mediator including prostaglandin E2 (PGE2), nuclear factor-kappa B (NF-kappaB) were also observed to explore the possible mechanisms. The oral administration of GA significantly (p < .001) altered the Fe-NTA induced RCC in rats by inhibition of renal nodules, decolourisation of tissues, tumour promoter marker including thymidine 3[H] incorporation, ornithine decarboxylase, renal parameters and anti-oxidant parameters in serum. Additionally, GA treatment significantly (p < .001) down regulated the IL-6, IL-1beta, TNF-alpha, inflammatory mediators PGE2 and NF kappaB in a dose-dependent manner. Histopathology observation supported the renal protective effect of GA by alteration in necrosis, size of Bowman capsules and inflammatory cells. Hence, it can be concluded that GA possesses observable chemo protective action and effect on Fe-NTA induced RCC via dual inhibition mechanism one by inhibiting free radical generation and second by inhibiting inflammation. PMID- 28835131 TI - IL-1beta and TNFalpha inhibit GPR120 (FFAR4) and stimulate GPR84 (EX33) and GPR41 (FFAR3) fatty acid receptor expression in human adipocytes: implications for the anti-inflammatory action of n-3 fatty acids. AB - Regulation of the expression of GPCR fatty acid receptor genes has been examined in human adipocytes differentiated in culture. TNFalpha and IL-1beta induced a marked reduction in GPR120 expression, mRNA level falling 17-fold at 24 h in adipocytes incubated with TNFalpha. In contrast, GPR84 mRNA was dramatically increased by these cytokines (>500-fold for IL-1beta at 4 h); GPR41 expression was also stimulated. Rosiglitazone did not affect GPR84 expression, but GPR120 and GPR41 expression increased. Dexamethasone, insulin, linoleic and docosahexaenoic acids (DHA), and TUG891 (GPR120 agonist) had little effect on GPR120 and GPR84 expression. TUG891 did not attenuate the pro-inflammatory actions of TNFalpha and IL-1beta. DHA slightly countered the actions of IL-1beta on CCL2, IL6 and ADIPOQ expression, though not on secretion of these adipokines. GPR120 and GP84 gene expression in human adipocytes is highly sensitive to pro inflammatory mediators; the inflammation-induced inhibition of GPR120 expression may compromise the anti-inflammatory action of GPR120 agonists. PMID- 28835132 TI - Two-year experience of multi-disciplinary team (MDT) outcomes for brain metastases in a tertiary neuro-oncology centre. AB - Brain metastases (BMs) are the most common intracranial tumour in adults and form a significant proportion of the neuro-oncology workload. Their management has progressed significantly in the last few decades but a gold-standard evidence based management strategy has not been defined to date and several guidelines based on available evidence exist to support clinical decision-making. This paper evaluates the decision-making process of the neuro-oncology multi-disciplinary team (MDT) in a tertiary neuro-oncology centre over a two-year period. A retrospective review of all patients with BM discussed in the MDT was conducted. Data on patient demographics, tumour characteristics and MDT decision were collected from the MDT database, clinical notes and imaging studies. Patients were stratified into the three recursive partitioning analysis (RPA) classes and according to the graded prognostic assessment (GPA) score. MDT decisions were analysed by RPA class and for GPA score as well as single versus multiple BM. There were 362 patients with BM, representing 22% of the total cases discussed at the MDT. Decision-making was largely consistent with available guidelines. A concrete treatment decision was reached in 77.5% of patients and 32.2% of these received neurosurgical input. More patients with solitary BM underwent surgery compared to multiple BM (p = 0.001), and more patients in RPA classes I and II had surgical resection compared to class III (p = 0.005 and 0.001, respectively). Surgical patients also had higher GPA scores compared to palliative patients (p = 0.005). A greater absolute number and proportion of patients in RPA class II vs. class I underwent neurosurgical intervention. These patients were stratified into class II because of their age but would otherwise have been placed into class I. Survival data were available for 195 patients (53.8%) at 1 year post MDT discussion. A pattern of declining survival was observed along RPA classes which was statistically significant (p = 0.0025). Median survival was 4.7 (0-41), 3.7 (0-23), and 2.5 (range 0-24) months for RPA class I, II and III respectively. A similar pattern that did not reach statistical significance was found between GPA scores (p = 0.101). Median survival was 3 (0-13), 4.6 (range 0-41), and 4.6 (0 35) months for GPA scores 0-1.0, 1.5-2.5 and 3-4.0, respectively. Patient selection was generally in accordance to RPA class and GPA scoring, with the exception of surgery offered to elderly patients: this can be explained by the increasing number of otherwise fit patients as population ages. PMID- 28835133 TI - An improved surface for enhanced stem cell proliferation and osteogenic differentiation using electrospun composite PLLA/P123 scaffold. AB - Poly-L-lactic acid (PLLA) nano fibrous scaffolds prepared by electrospinning technology have been used widely in tissue engineering applications. However, PLLA scaffolds are hydrophobic in nature, moreover the fibrous porous structure produced by electrospinning makes the scaffolds even more hydrophobic which generally limits cell attachment and proliferation. Polymer blending is one of the several efforts used so far to enhance hydrophilicity and recognized as an easy cost-effective approach for the manipulation physiochemical properties of polymeric biomaterials. Pluronic block copolymers containing hydrophilic poly(ethylene oxide) (PEO) blocks and hydrophobic poly(propylene oxide) (PPO) blocks are arranged in triblock structure: PEO-PPO-PEO. It is commonly used recently to blend hydrophobic polymers to enhance hydrophilicity for pharmaceutical and tissue engineering applications. In this study, novel pluronic P123 blend PLLA electrospun nanofibre scaffolds with improved hydrophilicity and biological properties were fabricated. The surface morphology and surface chemistry of the nanofibre scaffolds were characterized by scanning electron microscope (SEM) and FTIR analyses. Surface hydrophilicity and change in mechanical properties were studied. The ability of the scaffolds to support the attachment, and proliferation and differentiation of human adipose tissue derived MSCs, were evaluated generally. The fabricated scaffolds have completely improved, hydrophilicity, similar osteogenic differentiation potential with plasma-treated PLLA nanofibre scaffold, and hence P123 blend PLLA electrospun nanofibre scaffolds are a very good and cost effective choice as a scaffold for bone tissue engineering application. PMID- 28835134 TI - Bleeding during pregnancy is associated with familial preterm birth. AB - PURPOSE: the purpose of this study is to identify risk factors for familial, likely genetically-determined, preterm birth. MATERIALS AND METHODS: We performed a case-control study, enrolling 211 patients (103 cases and 108 controls). Cases delivered between 20 and 35 weeks gestation, with a prior preterm birth or first degree relative born prematurely. Controls delivered between 37-42 weeks. Groups were compared using a comprehensive questionnaire validated by medical record. Multivariate logistic regression assessed risk factor associations. RESULTS: Of cases, 30% reported bleeding during pregnancy compared with 5% of controls, adjusted odds ratio (adjOR) 9.0, 95%CI 3.31-24.47. Of cases that delivered at 20 28 weeks, 44.8% reported bleeding during pregnancy compared with 24.6% at 29-35 weeks, p = .04. Other associations were prior first-trimester miscarriage adjOR 2.55 (CI 1.21-5.35) or second-trimester miscarriage, adjOR 6.3 (CI 1.76-22.56). CONCLUSIONS: Bleeding during pregnancy and prior miscarriage were significantly associated with familial preterm birth. The magnitude of effect for bleeding in pregnancy was higher with earlier preterm births. These associations warrant further investigation. PMID- 28835135 TI - A prognostic 4-lncRNA expression signature for lung squamous cell carcinoma. AB - The outcomes of Lung squamous cell carcinoma (LUSC) is still challenging to evaluate or predict. We aimed to screen prognostic lncRNAs and to mine their roles in LUSC. RNA-Seq data of primary lung cancer were extracted from the Cancer Genome Atlas. Generally, changed lncRNAs in cancer samples were screened and analyzed in univariate survival analysis for identification of prognostic lncRNAs. Robust likelihood-based survival model was generated and random sampling iterations were performed 1000 times to calculate the frequency of feature key lncRNAs. Clustering and multivariate survival analysis of these lncRNAs was used to evaluate their functions and impacts on prognosis. Finally, the stability and validity of the optimal clustering model were verified. In total, we obtained 5664 generally changed lncRNAs among primary lung cancer samples, including 289 identified relating to prognosis in univariate survival analysis. Robust likelihood-based survival modelling for 1000 iterations generated 11 feature lncRNAs with frequency larger than 300. Their interacting proteins were found participating in DNA repairing and cell proliferation. Among stable assembly of 11 lncRNAs, a 4-lncRNA model was selected finally with high stability and feasibility. The ideal 4-lncRNA model can cluster patient samples with significant difference, providing new avenues for the prognostic predication of LUSC. PMID- 28835136 TI - Cytocompatible chitosan-graft-mPEG-based 5-fluorouracil-loaded polymeric nanoparticles for tumor-targeted drug delivery. AB - Biodegradable materials like chitosan (CH) and methoxy polyethylene glycol (mPEG) are widely being used as drug delivery carriers for various therapeutic applications. In this study, copolymer (CH-g-mPEG) of CH and carboxylic acid terminated mPEG was synthesized by carbodiimide-mediated acid amine reaction. The resultant hydrophilic copolymer was characterized by Fourier transform infrared spectroscopy and 1H NMR studies, revealing its relevant functional bands and proton peaks, respectively. Blank polymeric nanoparticles (B-PNPs) and 5 fluorouracil loaded polymeric nanoparticles (5-FU-PNPs) were formulated by ionic gelation method. Furthermore, folic acid functionalized FA-PNPs and FA-5-FU-PNPs were prepared for folate receptor-targeted drug delivery. FA-5-FU-PNPs were characterized by particle size, zeta potential, and in vitro drug release studies, resulting in 197.7 nm, +29.9 mv, and sustained drug release of 88% in 24 h, respectively. Cytotoxicity studies were performed for FA-PNPs and FA-5-FU-PNPs in MCF-7 cell line, which exhibited a cell viability of 80 and 41%, respectively. In vitro internalization studies were carried out for 5-FU-PNPs and FA-5-FU-PNPs which demonstrated increased cellular uptake of FA-5-FU-PNPs by receptor-mediated transport. Significant (p < .01) reduction (1.5-fold) of reactive oxygen species (ROS) accumulation was observed in lipopolysaccharides-stimulated RAW264.7 macrophages, revealing its potent antioxidant property. From the obtained results, it is concluded that folic acid functionalization of 5-FU-PNPs is an ideal approach for sustained and targeted drug delivery, thereby influencing better therapeutic effect. PMID- 28835137 TI - Redox-responsive PEGylated self-assembled prodrug-nanoparticles formed by single disulfide bond bridge periplocymarin-vitamin E conjugate for liver cancer chemotherapy. AB - Periplocymarin (PPM), a cardiac glycoside, has a narrow therapeutic index, poor tumor selectivity and severe cardiovascular toxicity which hinder its wide clinical applications in cancer treatment. Herein, we report novel redox responsive prodrug-nanoparticles (MPSSV-NPs) self-assembled by co nanoprecipitation of PPM-vitamin E conjugate and a PEG derivative of linoleate (mPEG2000-LA) in water. It was found that the characteristics of PPM-vitamin E nanoparticles (PSSV-NPs) were improved through co-nanoprecipitation with increased percentages of mPEG2000-LA. Moreover, the MPSSV-NPs were optimized according to the in vitro release and cytotoxicity study. Furthermore, the optimized MPSSV-NPs dramatically enhanced the circulation time and tumor distribution of PSSV-NPs after single intravenous injection. The in vivo studies in malignant H22-bearing mice revealed that MPSSV-NPs could effectively suppress tumor growth without causing obvious systemic toxicity. Altogether, these results suggested that MPSSV-NPs could offer a safe, multifunctional and viable nanoplatform for cardiac glycosides in cancer treatment. PMID- 28835138 TI - A comparison of the different features of quadripolar left ventricular pacing leads to deliver cardiac resynchronization therapy. AB - INTRODUCTION: Cardiac Resynchronization therapy (CRT) improves the quality of life and reduces morbidity and mortality of certain patients with heart failure. However, not all patients respond positively after CRT and about one third of cases do not experience benefit. Suboptimal biventricular pacing may account for this and quadripolar left ventricular (LV) leads have emerged in the last years to address issues relating to inadequate delivery of CRT. AREAS COVERED: This review article concisely summarizes the main technical characteristics of the quadripolar LV leads either currently available in the market today or under final stages of development. Focus is given in recent advancements in the area and challenging aspects and controversies, future implications as well as opportunities for further development. EXPERT COMMENTARY: Quadripolar LV pacing leads have now become the standard of care in CRT. Currently a multitude of lead options is available to the clinician. The selection process of the most appropriate lead is far from the 'one size fits all' concept. Further development of quadripolar LV leads is currently ongoing and it is anticipated to contribute towards the release of more technologically advantageous leads which will enable the delivery of optimal CRT therapy with the lowest rate of complications. PMID- 28835139 TI - Generation of Induced Pluripotent Stem Cells from Amniotic Fluid Cells of a Fetus with Hb Bart's Disease. AB - Induced pluripotent stem cells (iPSCs) derived from diseased patients behave as a powerful tool for biomedical research and may provide a source for replacement therapies. In this study, we generated iPSCs from amniotic fluid cells of a fetus with Hb Bart's (gamma4) disease (- -/- -). The established iPSCs showed pluripotency similar to that of human embryonic stem cells. They were able to differentiate into various somatic cell types and maintained normal karyotypes after long periods of culture in vitro. The patient-specific iPSCs offer a valuable model for advancing alpha-thalassemia (alpha-thal) research and early treatment of the affected fetuses. PMID- 28835140 TI - Normative data for diagnosing auditory processing disorder in Norwegian children aged 7-12 years. AB - OBJECTIVE: The main purpose of this research was to obtain normative data for auditory processing tests for Norwegian speaking children. DESIGN: Participants were administered routine audiological tests and an auditory processing test battery consisting of Filtered Words, Competing Words, Dichotic Digits, Gaps In Noise, Duration- and Frequency Pattern, Binaural Masking Level Difference and HIST Speech in Noise test. A group of 10-year-old children were retested after two weeks. The effects ear, age and gender and the test-retest reliability were investigated. STUDY SAMPLE: There were 268 normal hearing children aged 7-12 years who participated in the study. RESULTS: Results revealed no differences between genders. The children showed improving performance by age on all tests, except from the Gaps In Noise and Binaural Masking Level Difference. As expected, the children showed a right ear advantage on dichotic speech tests that decreased with age. The test-retest reliability for the tests was good, with a small learning effect on the Filtered Words test. CONCLUSION: Normative data were established and the preferred tests for diagnosing Auditory Processing Disorder were suggested for Norwegian children aged 7-12 years. PMID- 28835141 TI - Transplantation of stromal-derived factor 1alpha and basic fibroblast growth factor primed insulin-producing cells reverses hyperglycaemia in diabetic rats. AB - The defective insulin production is associated with severely reduced islet cell mass leading to diabetes. Growth factors preconditioned stem cells have arisen as an effective therapy to treat many diseases including diabetes. The current study was designed to assess the effect of pretreatment of ASCs derived IPCs with combination of stromal cell derived factor 1 alpha (SDF1alpha) and basic fibroblast growth factor (bFGF) in improving glucose tolerance in streptozotocin induced diabetic rats. The results showed maximally significant reduction in hyperglycaemia and fibrosis, while up-regulation of survival and pancreas specific genes, insulin levels and homing of transplanted cells in SDF-1alpha + bFGF IPCs transplanted rats as compared with other groups. Moreover, increased expression of insulin, glucagon and Glut-2 in pancreas of the SDF-1alpha + bFGF IPCs transplanted group indicated more regeneration of pancreas. Hence, the use of IPCs preconditioned with SDF-1alpha + bFGF would be more effective for treating diabetes. PMID- 28835142 TI - A retrospective study comparing outcomes in a midwestern US population after introduction of IADPSG guidelines for gestational diabetes. AB - OBJECTIVE: More evidence is required to endorse the 1-step approach for gestational diabetes mellitus (GDM) for clinical practice. Since 2010, our department has pragmatically allowed faculty to self-select the guidelines they use to screen and diagnose GDM. We sought to compare the maternal and neonatal outcomes from these two simultaneous cohorts. STUDY DESIGN: We performed a retrospective cohort study of all singleton pregnancies delivered between October 2011 and -November 2013 at our hospital. Patients were excluded if they had preexisting diabetes, were not screened or screened inappropriately, or their fetus had congenital anomalies. Patients were grouped by their screening strategy, and maternal and neonatal outcomes were analyzed. RESULTS: The 1-step group had a higher incidence of GDM (21.6% versus 5.0%). Initial results suggested higher rates of neonatal hypoglycemia, phototherapy for hyperbilirubinemia, and a lower rate of gestational HTN. After adjustment, these differences disappeared, but a lower rate of large for gestational age (LGA) infants was discovered (adjusted odds ratios (aOR) 0.78). CONCLUSION: The picture remains unclear as to whether the 1-step approach is associated with significantly improved outcomes compared with the 2-step approach. We did find a lower risk for a LGA infant in our 1-step cohort, but it is unlikely that the 1 step approach would be cost-effective due to the absence of other improved outcomes. PMID- 28835143 TI - Neonatal cerebral lesions predict 2-year neurodevelopmental impairment in children treated with laser surgery for twin-twin transfusion syndrome. AB - OBJECTIVE: The objective of this study is to assess whether postnatally detected cerebral abnormalities are predictive of neurodevelopmental impairment (NDI) in survivors of twin-twin transfusion syndrome (TTTS) that underwent laser surgery. MATERIALS AND METHODS: Ninety-nine children treated for TTTS had neurodevelopmental assessment at age 2-years (+/-6 weeks). 'High-risk survivors' had cerebral imaging in the neonatal period. 'High-risk survivors' were defined as (1) delivered at <32 weeks; or (2) cerebral imaging clinically indicated. NDI was a composite outcome of: Battelle Developmental Inventory 2nd edition (BDI-2) score <70, cerebral palsy, blindness, and/or deafness. Multilevel logistic regression with robust standard errors was used to evaluate associations between cerebral lesions and NDI. RESULTS: Fifty-six children were 'high-risk survivors' and had neonatal cerebral imaging. Ten twins (18%) had at least one cerebral lesion, including grade 1-2 intraventricular hemorrhage (8), cystic periventricular leukomalacia (2), ventriculomegaly (1), and bilateral subependymal cyst (1). The risk of NDI in the 'high-risk survivors' was 7% (4/56) compared with 0% (0/43) in the remaining group. Among 'high-risk survivors', cerebral lesions were a significant risk factor for NDI (OR = 19.28, p < .001). CONCLUSIONS: Among 'high-risk survivors' of TTTS treated with laser surgery, cerebral lesions identified on neonatal imaging were associated with NDI at 2 years. PMID- 28835144 TI - External iliac artery Doppler assessment in the prediction of adverse pregnancy outcomes. AB - PURPOSE: The purpose of this study is to investigate the potential role of the mean external iliac artery pulsatility index (EIA-PI) as a predictor of adverse obstetric outcomes such as preeclampsia, gestational hypertension and small for gestational age (SGA). METHODS: In women attending for first trimester screening at 11 + 0-13 + 6 weeks of gestation, we recorded maternal characteristics and measured EIA mean PI and uterine artery mean PI. We compared EIA mean PI in those that developed preeclampsia (n = 84), gestational hypertension (n = 50) or small for gestational age (n = 444) with those unaffected (n = 3736). Regression analysis was used to first determine which of the factors among the maternal variables were significant predictors of EIA mean PI in the unaffected group and, second, to predict adverse pregnancy outcomes. RESULTS: In the unaffected group, EIA mean PI increased with maternal age and decreased with mean blood pressure. Additionally, EIA mean PI was lower in cigarette smokers. Compared with the unaffected group, EIA mean PI was significantly lower in women who develop gestational hypertension or SGA below third centile. CONCLUSION: EIA mean PI in the first trimester is decreased in women who develop gestational hypertension and in those complicated by SGA below third centile. More studies are needed to confirm these findings. PMID- 28835145 TI - Knitters in a Day Center: The Significance of Social Participation for People With Mild to Moderate Dementia. AB - This article explores how people with dementia interact and solve problems while participating in social activities. The present article highlights social participation and interaction among elderly women with mild dementia who engaged in knitting as their main activity. The data were collected through participant observation at a day center in a Norwegian city, and the analysis revealed that the social activity of knitting facilitated conversations about different topics, required various forms of memory and problem solving, and involved different participant statuses. Being part of the knitting group appeared to help the participants maintain their skills and facilitated sociability. PMID- 28835146 TI - Relational quality, illness interference, and partner support in Meniere's disease. AB - OBJECTIVE: The current study aimed to better understand how patients and their significant others (SOs) cope with Meniere's disease (MD). DESIGN: The study used a cross-sectional design and the data were collected using questionnaires. STUDY SAMPLE: Seventy-five dyads in which one person had MD. RESULTS: SOs of patients with MD not only experienced activity and participation restrictions but also had positive experiences. In relational quality, the SOs reported uncertainty of their future, limited visits in noisy places, limited activities as walking, watching TV, and participating in social life. The illness interference correlated with the patients' complaints, and most significant was the problem of imbalance. The quality of life was significantly reduced in patients with MD, and the illness interference in terms of quality of life was correlated with the SOs in items related to mood and anxiety. The stress related conditions of the SOs were correlated with two positive items (e.g. alleviating the stress factor). The SOs could also identify one positive item (i.e., improved relationship). CONCLUSIONS: Perceptions of MD as interfering in couples' lives influence dyadic coping in unique ways. The current study identified that dyadic coping has both positive aspects and limitations as a consequence of their partner's MD. PMID- 28835148 TI - Effects of glucose control on arterial stiffness in patients with type 2 diabetes mellitus and hypertension: An observational study. AB - Objective We evaluated the association of glucose control with changes in arterial stiffness, inflammatory markers, and oxidative stress markers. Methods Sixty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA1c] >= 9%) and hypertension were enrolled in this study. The patients were divided into two groups based on their post-treatment HbA1c level: HbA1c <= 7% (well-controlled group, n = 28) and HbA1c > 7% (uncontrolled group, n = 36). The pulse wave velocity, augmentation index, and markers of inflammation and oxidative stress were measured and analyzed. Results The patients' mean baseline HbA1c level was 11.7%. There were no differences in any baseline parameters between the two groups except the duration of diabetes. The mean HbA1c level was significantly lower at 12 weeks in the well-controlled than uncontrolled group (6.1% vs. 9.0%, respectively), but there were no significant differences in the pulse wave velocity (0.33 +/- 0.95 vs. 0.36 +/- 1.44 m/s), aortic augmentation index (5.1 +/- 8.3 vs. 0.7 +/- 11.6), or markers of inflammation and oxidative stress. Conclusions Short-term glycemic control did not influence the arterial stiffness in patients with type 2 diabetes mellitus and hypertension. PMID- 28835147 TI - Characteristics of resveratrol and serotonin on antioxidant capacity and susceptibility to oxidation of red blood cells in stored human blood in a time dependent manner. AB - Objective In stored red blood cells (RBCs), which are used in diseases (e.g., acute blood loss and leukaemia), storage lesions arise by oxidative stress and other factors over time. This study investigated the protective effects of resveratrol and serotonin on stored RBCs. Methods Blood from each donor (n = 10) was placed in different bags containing 70 mL of citrate phosphate dextrose (total volume: 500 mL) and divided into three groups (n = 30): control, 60 ug/mL resveratrol, and 60 ug/mL serotonin. Malondialdehyde (MDA) and glutathione (GSH) levels, activity of glutathione peroxidase (GSH-Px), catalase, and carbonic anhydrase (CA), and susceptibility to oxidation in RBCs, and pH in whole blood were measured at baseline and on days 7, 14, 21, and 28. Results MDA levels and susceptibility to oxidation were increased in all three groups time-dependently, but this increase was greater in the serotonin group than in the other groups. Activity of GSH-Px, CAT, and CA, as well as GSH levels, were decreased in the control and serotonin groups time-dependently, but were significantly preserved in the resveratrol group. The pH was decreased in all groups time-dependently. Conclusion Our study shows that resveratrol attenuates susceptibility to oxidation of RBCs and protects their antioxidant capacity, and partially preserves CA activity time-dependently. PMID- 28835150 TI - Aggressive development of an aneurysmal bone cyst of the proximal femur in a paediatric patient: a case report. AB - We report development of an aneurysmal bone cyst (ABC) that was located in the proximal region of the femur in an 11-year-old girl. Over a period of 30 weeks, the ABC showed fulminant local progression, with destruction of the bone, which led to an abrupt loss of function of the left hip. The standard tumour treatment protocol was followed. We performed embolisation of the tumour followed by a biopsy, which confirmed the diagnosis of ABC. The outcome was negative with total destruction of the proximal third of the femur, despite repeating the embolisation. Because of the unfavourable local progression, a second biopsy was performed and we reconfirmed the initial diagnosis. The final decision regarding the therapeutic approach was total hip arthroplasty with femoral reconstruction with a prosthesis. Following this treatment, the patient's outcome was favourable, with complete recovery of function and no local relapse. PMID- 28835152 TI - Corrigendum. PMID- 28835151 TI - Range in systolic blood pressure and care-needs certification in long-term care insurance in community-dwelling older patients with chronic kidney disease. AB - Objective Low systolic blood pressure (SBP) is associated with an increased risk for cardiovascular morbidity/mortality in older patients with chronic kidney disease (CKD). The present study evaluated the association between range in blood pressure and first care-needs certification in the Long-term Care Insurance (LTCI) system or death in community-dwelling older subjects with or without CKD. Methods CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2 or dipstick proteinuria of + or greater. Our study was conducted in 1078 older subjects aged 65-94 years. Associations were estimated using the Cox proportional hazards model. Results During 5 years of follow-up, 135 first certifications and 53 deaths occurred. Among patients with CKD, moderate SBP (130 159 mmHg) was associated with a significantly lower adjusted risk of subsequent total certification (hazard ratio [HR] = 0.44) and subsequent certification owing to dementia (HR = 0.17) compared with SBP < 130 mmHg. These relationships were not observed in non-CKD subjects. Conclusion Lower SBP of <130 mmHg may predict a higher risk for subsequent first care-needs certification in LTCI, especially for dementia, in community-dwelling patients with CKD. PMID- 28835154 TI - Pectus excavatum and adjuvant radiotherapy for early stage breast cancer: balancing dose to target versus heart. PMID- 28835153 TI - Efficacy of Pentax airway scope versus Macintosh laryngoscope when used by novice personnel: A prospective randomized controlled study. AB - Objective To determine whether intubation education using the Pentax Airway Scope (AWS) in normal airways is more useful than direct laryngoscopy (Macintosh laryngoscope) in novice personnel. Methods Eleven intern doctors without intubation experience performed 60 sequential intubations with each device on a manikin and 10 sequential intubations in adult patients. The time required for successful intubation, percentage of glottic opening (POGO) score, number of intubation attempts, and number of dental injuries were analyzed for each intubation technique. Results The mean (standard deviation) time required for successful intubation decreased as the number of intubations increased and was significantly shorter with the Pentax AWS than direct laryngoscope [22.6 (7.3) vs. 29.6 (10.0) and 33.0 (8.0) vs. 44.7 (5.6) s, respectively] in both the manikin and clinical studies. The Pentax AWS was also associated with higher POGO scores than the direct laryngoscope [81.7 (8.9) vs. 55.1 (13.2) and 80.9 (9.7) vs. 49.6 (16.5), respectively] and fewer intubation attempts. Fewer dental injuries occurred with the Pentax AWS in the manikin study. Conclusions Novices performed intubation more rapidly and easily with an improved laryngeal view using the Pentax AWS. We suggest that intubation education with video laryngoscopy should be mandatory along with direct laryngoscope training. PMID- 28835156 TI - Patient's dignity in intensive care unit: A critical ethnography. AB - BACKGROUND: Maintaining patient's dignity in intensive care units is difficult because of the unique conditions of both critically-ill patients and intensive care units. OBJECTIVES: The aim of this study was to uncover the cultural factors that impeded maintaining patients' dignity in the cardiac surgery intensive care unit. RESEARCH DESIGN: The study was conducted using a critical ethnographic method proposed by Carspecken. Participants and research context: Participants included all physicians, nurses and staffs working in the study setting (two cardiac surgery intensive care units). Data collection methods included participant observations, formal and informal interviews, and documents assessment. In total, 200 hours of observation and 30 interviews were performed. Data were analyzed to uncover tacit cultural knowledge and to help healthcare providers to reconstruct the culture of their workplace. Ethical Consideration: Ethical approval for the study from Ethics committee of Isfahan University of Medical Sciences was obtained. FINDINGS: The findings of the study fell into the following main themes: "Presence: the guarantee for giving enough attention to patients' self-esteem", "Instrumental and objectified attitudes", "Adherence to the human equality principle: value-action gap", "Paternalistic conduct", "Improper language", and "Non-interactive communication". The final assertion was "Reductionism as a major barrier to the maintaining of patient's dignity". DISCUSSION: The prevailing atmosphere in subculture of the CSICU was reductionism and paternalism. This key finding is part of the biomedical discourse. As a matter of fact, it is in contrast with dignified care because the latter necessitate holistic attitudes and approaches. CONCLUSION: Changing an ICU culture is not easy; but through increasing awareness and critical self reflections, the nurses, physicians and other healthcare providers, may be able to reaffirm dignified care and cure in their therapeutic relationships. PMID- 28835155 TI - Cervical screening in Denmark - a success followed by stagnation. AB - INTRODUCTION: Despite an intensive screening activity, the incidence of cervical cancer in Denmark has remained stable for the last 15 years, while regional differences have increased. To search for explanations, we investigated possible weaknesses in the screening program. MATERIAL AND METHODS: Data on the screen targeted women were retrieved from Statistics Denmark. Data on screening activity were retrieved from the annual reports from 2009 to 2015 on quality of cervical screening. Coverage was calculated as proportion of screen-targeted women with at least one cytology sample within recommended time intervals. Insufficient follow up was calculated as proportion of abnormal and unsatisfactory samples not followed up within recommended time intervals. Diagnostic distribution was calculated for samples with a satisfactory cytology diagnosis. RESULTS: Coverage remained stable at 75%-76% during the study period. Annually, approximately 100,000 women are screened before they are eligible for invitation, and 600,000 invitations and reminders are issued resulting in screening of 200,000 women. In 2009, 21% of abnormal and unsatisfactory samples were not followed up within the recommended time interval; a proportion that had decreased to 15% in 2015. Overall, 11% of satisfactory samples with a cytology diagnosis were abnormal, but with surprising variation from 6% to 15% across regions. DISCUSSION: The success of a screening program depends first of all on coverage and timely follow-up of abnormal findings. Our analysis indicated that the currently high incidence of cervical cancer in Denmark may partly be due to low screening coverage. Also worrisome is a high proportion of non-timely follow-up of abnormal findings. Innovative ways to improve coverage and follow-up are urgently needed. PMID- 28835157 TI - Breaking Magic: Foreign Language Suppresses Superstition. AB - In three studies we found that reading information in a foreign language can suppress common superstitious beliefs. Participants read scenarios either in their native or a foreign language. In each scenario, participants were asked to imagine performing an action (e.g., submitting a job application) under a superstitious circumstance (e.g., broken mirror; four-leaf clover) and to rate how they would feel. Overall, foreign language prompted less negative feelings towards bad-luck scenarios, less positive feelings towards good-luck scenarios, while it exerted no influence on non-superstitious, control scenarios. We attribute these findings to language-dependent memory. Superstitious beliefs are typically acquired and used in contexts involving the native language. As a result, the native language evokes them more forcefully than a foreign language. PMID- 28835158 TI - Situational judgment tests: Who knows the right answers? PMID- 28835159 TI - Increased DNA methylation in the parvalbumin gene promoter is associated with methamphetamine dependence. AB - AIM: The parvalbumin (PV)-containing subgroup of GABAergic neurons is particularly affected in schizophrenia and animal models of psychosis, including after methamphetamine (METH) administration. We investigated whether METH dependence and METH-induced psychosis may involve an effect on DNA methylation of the PVALB promoter. MATERIALS & METHODS: The methylation of a PVALB promoter sequence was determined in 100 METH-dependent and 102 control subjects using pyrosequencing. RESULTS: A significant increase in PVALB methylation was observed in METH dependence and METH-induced psychosis. No significant effect on long interspersed nucleotide element-1 methylation, a measure of global DNA methylation, was observed. CONCLUSION: These results demonstrate a specific association between elevated PVALB methylation and METH-induced psychosis. This finding may contribute to the GABAergic deficits associated with METH dependence. PMID- 28835160 TI - Adaptive radiotherapy for locally advanced non-small cell lung cancer: dosimetric gain and treatment outcome prediction. PMID- 28835162 TI - The Experience of Trauma Resulting From the Loss of a Child and Posttraumatic Growth-The Mediating Role of Coping Strategies (Loss of a Child, PTG, and Coping). AB - The aim of the study was to determine the mediating role of coping strategies in the relationship between intensity of trauma resulting from the loss of a child and posttraumatic growth (PTG). The study included a group of 76 persons who regarded the loss of a child as a traumatic event. The majority (55.3%) of respondents were women. The age of the participants ranged from 18 to 62 years ( M = 35.88; SD = 9.52). A visual scale to measure intensity of trauma was used, and the Polish versions of the Posttraumatic Growth Inventory and Coping Inventory (Brief-Cope). The subjects revealed PTG, primarily in terms of appreciating of life and relating to others. Seeking social support, both emotional and instrumental, plays a mediating role between the intensity of trauma and PTG. Encouraging people who have experienced trauma to seek social support may not only enable adaptation to the situation but also contribute to the occurrence of PTG. PMID- 28835164 TI - Living With Prophylactic ICD Therapy and the Risk of Sudden Cardiac Death: How Patients Negotiate Solutions and Problems. AB - Prophylactic implantable cardioverter defibrillator (ICD) therapy treats potentially lethal cardiac arrhythmias in patients who have not previously experienced such but are at considerable risk due to underlying heart disease. Most patients are unaware of their risk of sudden cardiac death (SCD) until the ICD is introduced to them. Thus, the problem of risk of death and the solution of ICD therapy are presented simultaneously. Based on ethnographic fieldwork in Danish hospitals, this article illustrates how clinicians narrate prophylactic ICD therapy as a benign therapy preventing risk of death and providing the good life. However, risk of SCD is not the most pressing problem for the patients. The article argues that the solution of ICD therapy ignores patients' experience of living with severe heart disease and introduces the risk of shock therapy. For patients, a good life does not equal absence of risk of death but a life without heart disease. PMID- 28835165 TI - An Efficient Method for Generation of Knockout Human Embryonic Stem Cells Using CRISPR/Cas9 System. AB - Human embryonic stem cells (hESCs) represent a promising tool to study functions of genes during development, to model diseases, and to even develop therapies when combined with gene editing techniques such as CRISPR/CRISPR-associated protein-9 nuclease (Cas9) system. However, the process of disruption of gene expression by generation of null alleles is often inefficient and tedious. To circumvent these limitations, we developed a simple and efficient protocol to permanently downregulate expression of a gene of interest in hESCs using CRISPR/Cas9. We selected p53 for our proof of concept experiments. The methodology is based on series of hESC transfection, which leads to efficient downregulation of p53 expression even in polyclonal population (p53 Low cells), here proven by a loss of regulation of the expression of p53 target gene, microRNA miR-34a. We demonstrate that our approach achieves over 80% efficiency in generating hESC clonal sublines that do not express p53 protein. Importantly, we document by a set of functional experiments that such genetically modified hESCs do retain typical stem cells characteristics. In summary, we provide a simple and robust protocol to efficiently target expression of gene of interest in hESCs that can be useful for laboratories aiming to employ gene editing in their hESC applications/protocols. PMID- 28835166 TI - I don't know where to look: the impact of intolerance of uncertainty on saccades towards non-predictive emotional face distractors. AB - Attentional bias to uncertain threat is associated with anxiety disorders. Here we examine the extent to which emotional face distractors (happy, angry and neutral) and individual differences in intolerance of uncertainty (IU), impact saccades in two versions of the "follow a cross" task. In both versions of the follow the cross task, the probability of receiving an emotional face distractor was 66.7%. To increase perceived uncertainty regarding the location of the face distractors, in one of the tasks additional non-predictive cues were presented before the onset of the face distractors and target. We did not find IU to impact saccades towards non-cued face distractors. However, we found IU, over Trait Anxiety, to impact saccades towards non-predictive cueing of face distractors. Under these conditions, IU individuals' eyes were pulled towards angry face distractors and away from happy face distractors overall, and the speed of this deviation of the eyes was determined by the combination of the cue and emotion of the face. Overall, these results suggest a specific role of IU on attentional bias to threat during uncertainty. These findings highlight the potential of intolerance of uncertainty-based mechanisms to help understand anxiety disorder pathology and inform potential treatment targets. PMID- 28835163 TI - An epigenome-wide association study of inflammatory response to fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network. AB - AIM: Fenofibrate, a PPAR-alpha inhibitor used for treating dyslipidemia, has well documented anti-inflammatory effects that vary between individuals. While DNA sequence variation explains some of the observed variability in response, epigenetic patterns present another promising avenue of inquiry due to the biological links between the PPAR-alpha pathway, homocysteine and S adenosylmethionine - a source of methyl groups for the DNA methylation reaction. HYPOTHESIS: DNA methylation variation at baseline is associated with the inflammatory response to a short-term fenofibrate treatment. METHODS: We have conducted the first epigenome-wide study of inflammatory response to daily treatment with 160 mg of micronized fenofibrate over a 3-week period in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 750). Epigenome wide DNA methylation was quantified on CD4+ T cells using the Illumina Infinium HumanMethylation450 array. RESULTS: We identified multiple CpG sites significantly associated with the changes in plasma concentrations of inflammatory cytokines such as high sensitivity CRP (hsCRP, 7 CpG sites), IL-2 soluble receptor (IL-2sR, one CpG site), and IL-6 (4 CpG sites). Top CpG sites mapped to KIAA1324L (p = 2.63E-10), SMPD3 (p = 2.14E-08), SYNPO2 (p = 5.00E-08), ILF3 (p = 1.04E-07), PRR3, GNL1 (p = 6.80E-09), FAM50B (p = 3.19E-08), RPTOR (p = 9.79e-07) and several intergenic regions (p < 1.03E-07). We also derived two inflammatory patterns using principal component analysis and uncovered additional epigenetic hits for each pattern before and after fenofibrate treatment. CONCLUSION: Our study provides preliminary evidence of a relationship between DNA methylation and inflammatory response to fenofibrate treatment. PMID- 28835167 TI - Searching for prohibited items in mental-health hospitals: A randomised controlled trial of two metal-detecting technologies. AB - Weapons and other items with potential to cause harm are usually prohibited in mental-health hospitals and other psychiatric facilities. Detecting such prohibited items (PIs) can be problematic, particularly if concealed, and metal detectors are commonly used to search for such items. Our study compared two types of metal detection: continuous wave detection (CWD) by hand-held metal detector (HHMD) and magnetic anomaly detection (MAD) by a static pole device. In the study, real and dummy PIs were hidden on test subjects and in a simulated body cavity. The results showed MAD to be significantly superior to CWD in detecting small concealed PIs containing ferrous metal. The MAD pole found 100% of the real PIs on the test subjects and in the simulated body cavity. The CWD HHMD found only 5.2% of the real PIs, and these were limited to those on the test subjects, as it detected none in the simulated body cavity. In addition, the time taken to search by MAD pole was shorter than time taken to search by CWD HHMD. PMID- 28835168 TI - Structure-activity relationship analysis of carbobicyclo and oxabicyclo succinimide analogs as potential androgen receptor antagonists. AB - Prostate cancer (PCa) is a frequently diagnosed male cancer and the second leading cause of cancer-related death in many countries. Due to various amino acid mutations that occurred in the ligand binding domain of androgen receptor (AR), the patients were observed insensitive, even resistant to the marketed antiandrogens such as bicalutamide and enzalutamide, which emphasizes the urgent need for novel antiandrogens to solve drug resistance problem. Recently a series of carbobicyclo and oxabicyclo succinimide analogs were reported to effectively antagonize AR. In this study, to explore the structural requirements for these AR antagonists, we performed quantitative structure-activity relationship analysis on carbobicyclo and oxabicyclo succinimide analogs by using two-dimensional multiple linear regressions (MLR) method and three-dimension comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. The obtained models show satisfactory results with proper reliabilities and powerful external predictability. Moreover, the CoMFA and CoMSIA contour maps can intuitively represent key features associated with bioactivities. These models may offer guidance for the rational design and modification of new lead compounds for antiandrogens. PMID- 28835169 TI - Computational design of Phe-Tyr dipeptide and preparation, characterization, cytotoxicity studies of Phe-Tyr dipeptide loaded PLGA nanoparticles for the treatment of hypertension. AB - Phe-Tyr dipeptide which was investigated in Wakame food with greatest ACE inhibitory activity is used as a pharmaceutical drug for the treatment of hypertension, cardiovascular diseases, and diabetic nephropathy. To improve the bioavailability of Phe-Tyr, a delivery system based on poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with Phe-Tyr (Phe-Tyr-PLGA NPs) for treating hypertension and cardiovascular diseases was prepared in this study. In the experiments, poly(lactic-co-glycolic acid) (PLGA) and Phe-Tyr dipeptide-loaded PLGA nanoparticles were prepared using the double emulsion (w/o/w) method. The characterizations of the nanoparticles were performed with a UV-vis spectrometer, the Zeta-sizer system, and FTIR spectrometer. The optimum size of the Phe-Tyr dipeptide-loaded PLGA nanoparticle was obtained with a 213.8 nm average particle size, and a 0.061 polydispersity index, -19.5 mV zeta potential, 34% of loaded and 90.09% of encapsulation efficiency. From TEM analysis, it was clearly seen that the dipeptide loaded nanoparticles had the spherical and non-aggregated morphology and Phe-Tyr dipeptide loaded-PLGA nanoparticles were obtained successfully. Cell toxicity of nanoparticles at different concentrations was assayed with XTT methods on L929 fibroblast cells. This study determined that the nanoparticles have low toxicity at lower concentration and toxicity augmented with increasing concentration of dipeptide. To analyze the effect of solvents on structure of Phe-Tyr, Molecular dynamics simulation was performed with GROMACS program and molecular orbital calculations were carried out to obtain structural and electronic properties of dipeptide. Moreover, molecular docking calculations were also employed to model and predict protein-drug interactions. PMID- 28835170 TI - Survival forests for data with dependent censoring. AB - Tree-based methods are very powerful and popular tools for analysing survival data with right-censoring. The existing methods assume that the true time-to event and the censoring times are independent given the covariates. We propose different ways to build survival forests when dependent censoring is suspected, by using an appropriate estimator of the survival function when aggregating the individual trees and/or by modifying the splitting rule. The appropriate estimator used in this paper is the copula-graphic estimator. We also propose a new method for building survival forests, called p-forest, that may be used not only when dependent censoring is suspected, but also as a new survival forest method in general. The results from a simulation study indicate that these modifications improve greatly the estimation of the survival function in situations of dependent censoring. A real data example illustrates how the proposed methods can be used to perform a sensitivity analysis. PMID- 28835171 TI - Factors Related to Injury Prevention Programming by Missouri School Nurses. AB - Schools often offer injury prevention (IP) programs, but little is known about the types of programs provided or how school nurses decide which to choose. Nurses in the Missouri School Health Services Staffing Survey Database were sent a survey in spring, 2011, to describe school-based IP efforts being offered. A multivariate linear regression was conducted to delineate factors associated with offering IP programs. In total, 522 school nurses participated (33% response rate). The highest priority for selecting an IP program was perceived program effectiveness (92.3% agreement, n = 482). Determinants of offering IP programs included being asked to identify a speaker, being a high school, receiving funding in the last year, prioritizing evidence-based programs, perceiving that administrators support professional development, and knowing how to address patterns of injuries. School nurses should be competent in planning, implementing, and evaluating IP programs, and additional training may be required to accomplish this. PMID- 28835172 TI - Preventing recurrence from distal deep vein thrombosis: Still searching for answers. PMID- 28835173 TI - Taking Account of Gender Differences When Designing Interventions in Occupational Health? Lessons from a Study of the "Healthy Enterprise" Standard in Quebec: Les differences de genre sont-elles prises en compte lors de la conception des interventions de prevention en sante au travail? Resultats d une etude sur la norme "Entreprises en Sante" dans les entreprises au Quebec. AB - The literature shows substantial differences in occupational exposures between men and women, both between and within occupations, but remains very sparse on whether interventions are tailored to gender differences in the workplace. Our objective was to determine whether gender differences are taken into account when designing prevention interventions. This study is part of a project on the evaluation of interventions implemented in the framework of the "Healthy Enterprise" standard in Quebec organizations. Three sets of quantitative and qualitative data were collected in seven organizations and triangulated. Our results show that in the process of elaborating and implementing activities, the main objectives were to reach a maximum number of workers and meet the needs identified in a health and risk diagnosis. Activities were not tailored to the needs of specific subgroups of employees, such as gender or age. Not distinguishing men's and women's situations in this diagnosis may play a role in intervention design. Resume La litterature montre des differences d'exposition au travail importantes entre les hommes et les femmes, y compris a categories d'emploi identiques. Les etudes sur l'adaptation des interventions de prevention aux differences de genre dans les milieux de travail sont quasiment inexistantes dans la litterature. Notre objectif etait de determiner dans quelle mesure les differences de genre sont prises en compte lors de la conception des interventions de prevention. Cette etude fait partie d'un projet d'evaluation des interventions mises en ?uvre dans le cadre de la norme "Entreprises en santee au Quebec. Trois series de donnees quantitatives et qualitatives ont ete collectees aupres de sept organisations et analysees par triangulation. Nos resultats montrent que lors du processus d'elaboration des activites, les principaux objectifs etaient d'atteindre un nombre maximal de travailleurs et de remplir les besoins identifies dans le diagnostic des risques et de la sante des travailleurs. Le fait que la situation des hommes et des femmes n'ait pas ete analysee separement dans le diagnostic peut avoir joue un rale dans ce resultat. Les activites de prevention n'ont pas ete concues en tenant compte de sous groupes de travailleurs en fonction du genre ou de l'age. PMID- 28835174 TI - Personal identity narratives of therapeutic songwriting participants following Spinal Cord Injury: A case series analysis. AB - CONTEXT/OBJECTIVE: Spinal Cord Injury (SCI) patients face unique identity challenges associated with physical limitations, higher comorbid depression, increased suicidality and reduced subjective well-being. Post-injury identity is often unaddressed in subacute rehabilitation environments where critical physical and functional rehabilitation goals are prioritized. Therapeutic songwriting has demonstrated prior efficacy in promoting healthy adjustment and as a means of expression for post-injury narratives. The current study sought to examine the identity narratives of therapeutic songwriting participants. DESIGN: Case-series analysis of the individual identity trajectories of eight individuals. SETTING: Subacute rehabilitation facility, Victoria, Australia. PARTICIPANTS: Eight individuals with an SCI; 7 males and 1 female. INTERVENTION: Six-week therapeutic songwriting intervention facilitated by a music therapist to promote identity rehabilitation. OUTCOME MEASURES: Identity, subjective well-being and distress, emotional state. RESULTS: Three participants demonstrated positive trajectories and a further three showed negative trajectories; remaining participants were ambiguous in their response. Injury severity differentiated those with positive trajectories from those with negative trajectories, with greater injury severity apparent for those showing negative trends. Self-concept also improved more in those with positive trajectories. Core demographic variables did not however meaningfully predict the direction of change in core identity or wellbeing indices. CONCLUSION: Identity-focused songwriting holds promise as a means of promoting healthy identity reintegration. Further research on benefits for those with less severe spinal injuries is warranted. PMID- 28835175 TI - Beneficial effect of statins on total mortality in abdominal aortic aneurysm (AAA) repair. AB - In this single center, retrospective cohort study we wished to compare early and total mortality for all patients treated for abdominal aortic aneurysms (AAA) with open surgery who were taking statins compared to those who were not. A cohort of 640 patients with AAA was treated with open surgery between 1999 and 2012. Patients were consecutively recruited from a source population of 390,000; 21.3% were female, and the median age was 73 years. The median follow-up was 3.93 years, with an interquartile range of 1.79-6.58 years. The total follow-up was 2855 patient-years. An explanatory strategy was used. The propensity score (PS) was implemented to control for selection bias and confounders. The crude effect of statin use showed a 78% reduction of the 30-day mortality. A stratified analysis using the Mantel-Haenszel method on quintiles of the PS gave an adjusted effect of the odds ratio equal to 0.43 (95% CI: 0.18-0.96), indicating a 57% reduction of the 30-day mortality for statin users. The adjusted rate ratio was 0.62 (95% CI: 0.45-0.83), indicating a reduction of long-term mortality of 38% for statin users compared to non-users for a median follow-up of 3.93 years. This retrospective cohort study showed a significant beneficial effect of statin use on early and long-term survival for patients treated with open surgery. To be conclusive, our results need to be replicated by a randomized clinical trial. PMID- 28835176 TI - Locked-in syndrome post snake bite: a rare presentation. PMID- 28835177 TI - Organic loading rate effect on the acidogenesis of cheese whey: a comparison between UASB and SBR reactors. AB - Volatile fatty acids (VFA) production and degree of acidification (DA) were investigated in the anaerobic treatment of cheese whey by comparison of two processes: a continuous process using a laboratory upflow anaerobic sludge blanket (UASB) reactor and a discontinuous process using a sequencing batch reactor (SBR). The main purpose of this work was to study the organic loading rate (OLR) effect on the yield of VFA in two kinds of reactors. The predominant products in the acidogenic process in both reactors were: acetate, propionate, butyrate and valerate. The maximum DA obtained was 98% in an SBR at OLR of 2.7 g COD L-1 d-1, and 97% in the UASB at OLR at 15.1 g COD L-1 d-1. The results revealed that the UASB reactor was more efficient at a medium OLR with a higher VFA yield, while with the SBR reactor, the maximum acidification was obtained at a lower OLR with changes in the VFA profile at different OLRs applied. PMID- 28835179 TI - Journal of Health Psychology policy on data sharing. PMID- 28835178 TI - Raising a beautiful swan: a phenomenological-hermeneutic interpretation of health professionals' experiences of participating in a mealtime intervention inspired by Protected Mealtimes. AB - The British concept named Protected Mealtimes is known for stopping all non-acute activities and giving health professionals an opportunity to focus on providing patients their meals without being interrupted or disturbed. PM involves a cultural and behavioural change in the clinical setting, since health professionals are asked to adjust their daily routines. This study investigate how health professionals experience participating in a mealtime intervention inspired by the concept of Protected Mealtimes and intend to change mealtime practices. Three focus group interviews was conducted and included a total of 15 interdisciplinary staff members. After transcribing the interviews, the text material was analysed and interpreted in a three-methodological-step process inspired by the French philosopher Paul Ricoeur. In the analysis and interpretation three themes was identified. The themes were: (1) a chance towards a new and better scene; (2) a step towards a more neurologically friendly environment; and (3) a renewed view of the neurological patients. This study concludes that to the health professionals, the intervention was meaningful in several ways because it created structure during mealtimes and emphasized the importance of creating a calm environment for both patients and health professionals. The intervention was described as an eye-opening and well-regarded event in the field of neurological care that facilitated community, and reflections on nursing care and professional identity were expressed. PMID- 28835180 TI - Clinical relevance of the modified physical performance test versus the short physical performance battery for detecting mobility impairments in older men with peripheral arterial disease. AB - PURPOSE: The study is to compare the Modified Physical Performance Test (MPPT) and Short Physical Performance Battery (SPPB) as metrics of mobility and function in older men with peripheral arterial disease (PAD). MATERIALS AND METHODS: A total of 51 men (55-87 years) with PAD underwent functional testing including the SPPB, MPPT, Walking Impairment Questionnaire (WIQ), stair ascent, and 6-min walk distance. Individuals were grouped according to SPPB and MPPT scores as not limited on either, limited only on the MPPT, or limited on both. RESULTS: The MPPT identified a higher proportion of patients as being functionally limited than the SPPB (p < 0.001). Men identified as limited only by the MPPT, and not the SPPB, were subsequently confirmed to have lower function on all measures compared to those not identified as limited by either the SPPB or the MPPT (p < 0.02). CONCLUSIONS: These findings suggest the MPPT is an appropriate measure to identify early declines in men with PAD and may identify global disability better than SPPB. Implications for rehabilitation Individuals with peripheral arterial disease have low activity levels and are at risk for a loss of independence and global disability. Early detection of decline in mobility and global function would allow for interventions before large changes in ambulatory ability or a loss of functional independence occur. This study shows the Modified Physical Performance Test may be an appropriate test to identify early decline in function in men with peripheral arterial disease. PMID- 28835181 TI - Determinants of participating in life after spinal cord injury - advice for health professionals arising from an examination of shared narratives. AB - PURPOSE: To explore the perceived determinants of participation in life after spinal cord injury and incorporate these into a framework for the promotion of participation suitable for use by rehabilitation professionals. METHOD: Four people with spinal cord injury and one health service researcher engaged in a process of sharing narratives of life after spinal cord injury over a period of one year. The narratives were distilled using thematic analysis. RESULTS: The relevant subset of data from the narratives categorized as This is what we think determines our participation in life was analyzed in depth to reveal nine themes (1) The world can be my friend or foe; (2) I am who I am; (3) It is a personal journey; (4) Some like to talk, others like to do; (5) We have the technology; (6) A support network is vital and it can be built; (7) Life involves tradeoffs; (8) Push; and (9) Be flexible. These themes were combined into a framework for the promotion of participation to be used by rehabilitation professionals. The collaboratively developed framework has three aspects - Help me, Encourage me and Accept. CONCLUSION: The proposed participation promotion framework is grounded in the narratives of the research group but needs to be tested before it can be endorsed for practice. Implications for Rehabilitation In order to promote participation in life after spinal cord injury rehabilitation professionals can help people with spinal cord injury to negotiate the world, build and maintain a support crew and access equipment and technology. Spinal cord injury rehabilitation professionals can encourage people with spinal cord injury to push themselves, be assertive and be flexible, as these attributes can assist participation in life after spinal cord injury. In the pursuit of participation goals, rehabilitation professionals must accept the individuality of each person with spinal cord injury, respect that they may or may not be willing to make tradeoffs to achieve participation goals and that they are on an ever changing life journey. PMID- 28835182 TI - Proton radiography for inline treatment planning and positioning verification of small animals. AB - INTRODUCTION: As proton therapy becomes increasingly well established, there is a need for high-quality clinically relevant in vivo data to gain better insight into the radiobiological effects of proton irradiation on both healthy and tumor tissue. This requires the development of easily applicable setups that allow for efficient, fractionated, image-guided proton irradiation of small animals, the most widely used pre-clinical model. MATERIAL AND METHODS: Here, a method is proposed to perform dual-energy proton radiography for inline positioning verification and treatment planning. Dual-energy proton radiography exploits the differential enhancement of object features in two successively measured two dimensional (2D) dose distributions at two different proton energies. The two raw images show structures that are dominated by energy absorption (absorption mode) or scattering (scattering mode) of protons in the object, respectively. Data post processing allowed for the separation of both signal contributions in the respective images. The images were evaluated regarding recognizable object details and feasibility of rigid registration to acquired planar X-ray scans. RESULTS: Robust, automated rigid registration of proton radiography and planar X ray images in scattering mode could be reliably achieved with the animal bedding unit used as registration landmark. Distinguishable external and internal features of the imaged mouse included the outer body contour, the skull with substructures, the lung, abdominal structures and the hind legs. Image analysis based on the combined information of both imaging modes allowed image enhancement and calculation of 2D water-equivalent path length (WEPL) maps of the object along the beam direction. DISCUSSION: Fractionated irradiation of exposed target volumes (e.g., subcutaneous tumor model or brain) can be realized with the suggested method being used for daily positioning and range determination. Robust registration of X-ray and proton radiography images allows for the irradiation of tumor entities that require conventional computed tomography (CT)-based planning, such as orthotopic lung or brain tumors, similar to conventional patient treatment. PMID- 28835183 TI - Evidence of a Task-Independent Neural Signature in the Spectral Shape of the Electroencephalogram. AB - Genetic and neurophysiological studies of electroencephalogram (EEG) have shown that an individual's brain activity during a given cognitive task is, to some extent, determined by their genes. In fact, the field of biometrics has successfully used this property to build systems capable of identifying users from their neural activity. These studies have always been carried out in isolated conditions, such as relaxing with eyes closed, identifying visual targets or solving mathematical operations. Here we show for the first time that the neural signature extracted from the spectral shape of the EEG is to a large extent independent of the recorded cognitive task and experimental condition. In addition, we propose to use this task-independent neural signature for more precise biometric identity verification. We present two systems: one based on real cepstrums and one based on linear predictive coefficients. We obtained verification accuracies above 89% on 4 of the 6 databases used. We anticipate this finding will create a new set of experimental possibilities within many brain research fields, such as the study of neuroplasticity, neurodegenerative diseases and brain machine interfaces, as well as the mentioned genetic, neurophysiological and biometric studies. Furthermore, the proposed biometric approach represents an important advance towards real world deployments of this new technology. PMID- 28835185 TI - Primary pulmonary arterial hypertension with preserved right ventricular function leads to lower extremity venous insufficiency. AB - Objectives Pulmonary hypertension with heart failure is related to venous insufficiency. However, there is no clear data whether pulmonary arterial hypertension with preserved right ventricular function cause venous insufficiency. In this study, we aim to investigate the relation between pulmonary arterial pressure with venous insufficiency in pulmonary arterial hypertension patients with preserved right ventricular function. Methods Between January 2012 and October 2014, 38 patients with a diagnosis of pulmonary arterial hypertension and 47 control group patients were included. Venous disability score and venous segmental disease score of both groups were calculated in order to measure venous insufficiency. The relationship between venous disability score and venous segmental disease scores and mean pulmonary arterial pressure and World Heart Organization functional capacity was examined. Results Total venous segmental disease score (5 +/- 3.9 vs. 2 +/- 1.8 p < 0.001), right venous segmental disease score (2.6 +/- 2.2 vs. 1 +/- 0.9 p < 0.001), left venous segmental disease score (2.4 +/- 2.2 vs. 1 +/- 0.9 p < 0.001), and venous disability scores (2.2 +/-1 vs. 1.6 +/- 0.7 p < 0.001) of patients with pulmonary arterial hypertension were higher than the control group. While the total venous segmental disease score was highly related to mean pulmonary arterial pressure (r = 0.829, p < 0.001), the venous disability score was only weakly related (r = 0.343, p = 0.037). Total venous segmental disease score (r = 0.606, p < 0.001) and venous disability scores (r = 0.601, p < 0.001) were moderately related with World Health Organization functional capacity intensity. Conclusions The degree of venous insufficiency increase in accordance with the mean pulmonary arterial pressure even in patients with preserved right ventricular function. PMID- 28835184 TI - Physician failure to stratify patients hospitalized with acute pulmonary embolism. AB - OBJECTIVES: In 2011, the AHA recommended risk stratification of patients with acute pulmonary embolism (PE). Failure to risk stratify may cause under recognition of intermediate-risk PE and its attendant short- and long-term consequences. We sought to determine if patients hospitalized with acute PE were appropriately risk stratified according to the 2011 AHA Scientific Statement within our hospital system and whether differences exist in adherence to risk stratification by hospital or treating hospital service. We also wished to know the frequency of in-hospital consultations for acute PE which might assist in the risk stratification process. METHODS: This is a retrospective chart audit of all patients hospitalized with a diagnosis of acute PE between January 2011 and December 2013 at our 937-bed metropolitan, three hospital system comprised of academic University, neuroscience Specialty, and teaching Community hospitals. We evaluated the presence of imaging, laboratory tests, and specialty consultation within 72 h of PE diagnosis by hospital. RESULTS: 701 patients with acute PE were admitted to our hospital system during the study period. 308 patients (43.9%) met criteria for intermediate-risk PE. 347 patients (49.5%) were considered 'Low-Risk - At Risk', patients defined in a low-risk category not having undergone all recommended risk stratification testing and so truly may have been in a higher risk category. No specialty consultations were utilized for 265 patients (37.8%). CONCLUSIONS: Our large metropolitan hospital system inadequately risk stratifies hospitalized patients with acute PE. Because nearly one-half of patients with acute PE did not have all recommended testing, clinicians may be under recognizing patients with intermediate-risk PE and their risk for long-term morbidity. Specialty consultations were underutilized and may help guide medical decision-making. PMID- 28835186 TI - Comparison of propaten heparin-bonded vascular graft with distal anastomotic patch versus autogenous saphenous vein graft in tibial artery bypass. AB - Introduction Heparin-bonded expanded polytetrafluoroethylene grafts (Propaten, WL Gore, Flagstaff, AZ, USA) have been shown to have superior patency compared to standard prosthetic grafts in leg bypass. This study analyzed the outcomes of Propaten grafts with distal anastomotic patch versus autogenous saphenous vein grafts in tibial artery bypass. Methods A retrospective analysis of prospective collected data was performed during a recent 15-year period. Sixty-two Propaten bypass grafts with distal anastomotic patch (Propaten group) were compared with 46 saphenous vein graft (vein group). Pertinent clinical variables including graft patency and limb salvage were analyzed. Results Both groups had similar clinical risk factors, bypass indications, and target vessel for tibial artery anastomoses. Decreased trends of operative time (196 +/- 34 min vs. 287 +/- 65 min, p = 0.07) and length of hospital stay (5.2 +/- 2.3 days vs. 7.5 +/- 3.6, p = 0.08) were noted in the Propaten group compared to the vein group. Similar primary patency rates were noted at four years between the Propaten and vein groups (85%, 71%, 64%, and 57%, vs. 87%, 78%, 67%, and 61% respectively; p = 0.97). Both groups had comparable secondary patency rates yearly in four years (the Propaten group: 84%, 76%, 74%, and 67%, respectively; the vein group: 88%, 79%, 76%, and 72%, respectively; p = 0.94). The limb salvage rates were equivalent between the Propaten and vein group at four years (84% vs. 92%, p = 0.89). Multivariate analysis showed active tobacco usage and poor run-off score as predictors for graft occlusion. Conclusions Propaten grafts with distal anastomotic patch have similar clinical outcomes compared to the saphenous vein graft in tibial artery bypass. Our data support the use of Propaten graft with distal anastomotic patch as a viable conduit of choice in patients undergoing tibial artery bypass. PMID- 28835187 TI - Evaluation of the renal function using serum Cystatin C following open and endovascular aortic aneurysm repair. AB - Objectives Controversies regarding renal function impairment after open and endovascular aortic aneurysm repair still exist. The purpose of this study was to evaluate the renal function following open repair and endovascular aneurysm repair using Cystatin C. Methods This prospective, observational case-control study was conducted in tertiary referral centre over 3 years, starting from 2012. In total, 60 patients operated due to infrarenal AAA either by means of open repair (30 patients) or endovascular aneurysm repair (30 patients) were included in the study. Biochemical markers of renal function (sCr, urea, potassium) were recorded pre-operatively and at these specific time points, immediately after the operation and at discharge, home (third postoperative day, endovascular aneurysm repair group) or from intensive care unit (third postoperative day, open repair group). Multivariate and propensity score adjustments were used to control for the baseline differences between the groups. Results Creatinine levels in serum remained unchanged during the hospital stay in both groups without significant differences at any time point. Cystatin C levels in endovascular aneurysm repair patients significantly increased postoperatively and restored to values comparable to baseline at the discharge (0.865 +/- 0.319 vs. *0.962 +/- 0.353 vs. 0.921 +/- 0.322, * p < 0.001). Cystatin C levels in patients treated with the open surgery was decreasing over time but not statistically significant comparing to Cystatin C values at the admission. However, decrease in Cystatin C serum levels in patients treated with conventional surgery resulted in statistically significant lower values compared to endovascular aneurysm repair patients both postoperatively and at the time of discharge (0.760 +/- 0.225 vs. 0.962 +/- 0.353, p < 0.05; 0.750 vs. 0.156, p < 0.05). Both multivariate linear regression models and propensity score adjustment confirm that, even after correction for previously observed intergroup differences, type of surgery, i.e. endovascular aneurysm repair is independently associated with the higher levels of Cystatin C both postoperatively and at the discharge. Conclusions Dynamics of Cystatin C levels have been proven as a more vulnerable marker of renal dysfunction. Endovascular aneurysm repair is associated with higher levels of kidney injury markers. PMID- 28835188 TI - Neutrophils, a candidate biomarker and target for radiation therapy? AB - BACKGROUND: Neutrophils are the most abundant blood-circulating white blood cells, continuously generated in the bone marrow. Growing evidence suggests they regulate the innate and adaptive immune system during tumor evolution. This review will first summarize the recent findings on neutrophils as a key player in cancer evolution, then as a potential biomarker, and finally as therapeutic targets, with respective focuses on the interplay with radiation therapy. A complex interplay: Neutrophils have been associated with tumor progression through multiple pathways. Ionizing radiation has cytotoxic effects on cancer cells, but the sensitivity to radiation therapy in vivo differ from isolated cancer cells in vitro, partially due to the tumor microenvironment. Different microenvironmental states, whether baseline or induced, can modulate or even attenuate the effects of radiation, with consequences for therapeutic efficacy. Inflammatory biomarkers: Inflammation-based scores have been widely studied as prognostic biomarkers in cancer patients. We have performed a large retrospective cohort of patients undergoing radiation therapy (1233 patients), with robust relationship between baseline blood neutrophil count and 3-year's patient's overall survival in patients with different cancer histologies. (Pearson's correlation test: p = .001, r = -.93). Therapeutic approaches: Neutrophil targeting agents are being developed for the treatment of inflammatory and autoimmune diseases. Neutrophils either can exert antitumoral (N1 phenotype) or protumoral (N2 phenotype) activity, depending on the Tumor Micro Environment. Tumor associated N2 neutrophils are characterized by high expression of CXCR4, VEGF, and gelatinase B/MMP9. TGF-beta within the tumor microenvironment induces a population of TAN with a protumor N2 phenotype. TGF-beta blockade slows tumor growth through activation of CD8 + T cells, macrophages, and tumor associated neutrophils with an antitumor N1 phenotype. CONCLUSIONS: This supports the need for prospective neutrophils evaluation in clinical trials, making neutrophils a predictive biomarker with potential specific therapies. PMID- 28835189 TI - Understanding Nursing Handoffs: Safety Scholarship in Nursing. PMID- 28835190 TI - Corrigendum. PMID- 28835191 TI - T cell optimization for the treatment of pancreatic cancer. AB - INTRODUCTION: Pancreatic cancer remains a deadly disease despite advances in surgery, chemotherapy, and radiation therapy. Treatment failure is likely due to intense chemoresistance and immunosuppression. Therefore, new treatment paradigms are urgently needed. Immunotherapy, particularly adoptive T cell transfer, is a highly-personalized therapy that involves the isolation and ex vivo expansion of tumor-specific T cells before administration to cancer-bearing hosts. Areas covered: This review summarizes different strategies of adoptive T cell therapy and their application in pancreatic cancer treatment. It also highlights recent advances and gives discussion on the future directions in T cell-based immunotherapy for pancreatic cancer. Expert opinion: Pancreatic ductal adenocarcinoma is extremely challenging to treat, in part, due to intense desmoplastic reaction and immunosuppression. The recent progress in cancer immunotherapy triggers a hope to use immunotherapeutic modality to treat pancreatic cancer. Immunotherapy is generally well tolerated, and has the potential to function as a monotherapy or in synergistic combination with conventional chemotherapy. We must make efforts to optimize the immunotherapeutic regimen and to select patients to treat based on their biological profile. To accomplish this goal, an intense collaboration is needed to bridge between bench and bedside. PMID- 28835192 TI - The effect of adding active flexion to modified Kleinert regime on outcomes for zone 1 to 3 flexor tendon repairs. A prospective randomized trial. AB - : In a prospective randomized study, we studied whether adding active flexion to a modified Kleinert regime changed outcomes of flexor tendon repairs in zone 1, 2 and 3 in 73 fingers (53 patients). Evaluation included active range of finger motion, grip and pinch strengths. Twelve months after surgery, the increase in range of active finger motion after adding active flexion was insignificant compared with that with the modified Kleinert regime. According to the Strickland criteria, 20 out of 29 fingers had excellent or good recovery after adding active flexion, as did 28 out of 34 fingers with the modified Kleinert regime; we could not detect significant improvement of the good and excellent rate. At 6 months, the pinch strength was significantly higher with the addition of active flexion. We failed to find that adding active finger flexion to the modified Kleinert regime improves the overall long-term results of repairs in zone 1 to 3, though recovery appeared faster, and the good and excellent recovery of zone 2 repairs was 17% greater with the active flexion protocol. LEVEL OF EVIDENCE: I. PMID- 28835193 TI - Adjustment for time-dependent unmeasured confounders in marginal structural Cox models using validation sample data. AB - Large databases used in observational studies of drug safety often lack information on important confounders. The resulting unmeasured confounding bias may be avoided by using additional confounder information, frequently available in smaller clinical "validation samples". Yet, no existing method that uses such validation samples is able to deal with unmeasured time-varying variables acting as both confounders and possible mediators of the treatment effect. We propose and compare alternative methods which control for confounders measured only in a validation sample within marginal structural Cox models. Each method corrects the time-varying inverse probability of treatment weights for all subject-by-time observations using either regression calibration of the propensity score, or multiple imputation of unmeasured confounders. Two proposed methods rely on martingale residuals from a Cox model that includes only confounders fully measured in the large database, to correct inverse probability of treatment weight for imputed values of unmeasured confounders. Simulation demonstrates that martingale residual-based methods systematically reduce confounding bias over naive methods, with multiple imputation including the martingale residual yielding, on average, the best overall accuracy. We apply martingale residual based imputation to re-assess the potential risk of drug-induced hypoglycemia in diabetic patients, where an important laboratory test is repeatedly measured only in a small sub-cohort. PMID- 28835194 TI - Inequities in access to inpatient rehabilitation after stroke: an international scoping review. AB - Background Inequities in accessing inpatient rehabilitation after stroke have been reported in many countries and impact on patient outcomes. Objective To explore variation in international recommendations regarding which patients should receive inpatient rehabilitation after stroke and to describe reported access to rehabilitation. Methods A scoping review was conducted to identify clinical guidelines with recommendations regarding which patients should access inpatient rehabilitation after stroke, and data regarding the proportion of patients accessing stroke rehabilitation. Four bibliographic databases and grey literature were searched. Results Twenty-eight documents were included. Selection criteria for post-acute inpatient rehabilitation were identified for 14 countries or regions and summary data on the proportion of patients receiving inpatient rehabilitation were identified for 14 countries. In Australia, New Zealand, and the United Kingdom, it is recommended that all patients with stroke symptoms should access rehabilitation, whereas guidelines from the United States, Canada, and Europe did not consistently recommend rehabilitation for people with severe stroke. Access to inpatient rehabilitation ranged from 13% in Sweden to 57% in Israel. Differences in availability of early supported discharge/home rehabilitation programs and variations in reporting methods may influence the ability to reliably compare access to rehabilitation between regions. Conclusion Recommendations regarding which patients with moderate and severe strokes should access ongoing rehabilitation are inconsistent. Clinical practice guidelines from different countries regarding post-stroke rehabilitation do not always reflect the evidence regarding the likely benefits to people with stroke. Inequity in access to rehabilitation after stroke is an international issue. PMID- 28835195 TI - Molecular microdeletion analysis of infertile men with karyotypic Y chromosome abnormalities. AB - Objectives To investigate azoospermic factor (AZF) microdeletions in infertile men from northeastern China with karyotypic Y chromosome abnormalities. Methods G banding of metaphase chromosomes and karyotype analysis were performed in all infertile male patients. Genomic DNA was isolated and used to analyze classical AZF microdeletions by PCR. The regions and sequence-tagged sites of AZFa (SY86, SY84), AZFb (SY127, SY134, SY143), and AZFc (SY152, SY254, SY255, SY157) were sequenced by multiplex PCR. Results A total of 190 Y chromosome abnormality carriers were found, of whom 35 had AZF microdeletions. These were most common in 46,X,Yqh- patients, followed by 45,X/46,XY patients. Most microdeletions were detected in the AZFb + c region, including 48.57% of all AZF microdeletion cases. AZF partial deletions were also seen in these patients. Overall, AZF microdeletions were detected in 38.5% Y chromosome abnormality carriers, and most were observed in 46,X,Yqh- individuals. Loss of SY152 was seen in all 35 patients, with SY254/SY255 detected in 34 of 35 patients. Conclusions AZF microdeletions were detected in 38.5% of Y chromosome abnormality carriers. This indicates that AZF microdeletion screening is advisable for individuals with karyotypic Y chromosome abnormalities. PMID- 28835196 TI - Prevalence of recreational drug use reported by men who have sex with men attending sexual health clinics in Manchester, UK. AB - Recreational drug use (RDU) has been reported to be disproportionately higher in men who have sex with men (MSM) when compared to their heterosexual counterparts. To identify RDU, links to risky sexual practices and infections for MSM attending three sexual health clinics across Manchester, United Kingdom, a retrospective case note review was conducted using a random powered sample of service users attending three sites during 2014. Three hundred and fifty-seven case notes were reviewed across three sites. Eighteen per cent of service users reported any type of RDU. Use of at least one of the three drugs associated with chemsex (crystal methamphetamine, mephedrone, gamma hydroxybutyrate/gamma butyrolactone) was reported by 3.6%. A statistically significant difference was identified between non-drug users and any-drug users reporting: group sex (odds ratio [OR] 5.88, p = 0.013), condomless receptive anal intercourse (CRAI) (OR 2.77, p = 0.003) and condomless oral intercourse (OR 2.52, p = 0.016). A statistically significant difference was identified between chemsex-related drug user and non-drug user groups reporting: group sex (OR 13.05, p = 0.023), CRAI (OR 3.69, p = 0.029) and condomless insertive anal intercourse (OR 1.27, p = 0.039). There was also a statistically higher incidence of gonorrhoea infection in chemsex-related drug use compared with those not using drugs (p = 0.002, OR 6.88). This study identifies that substance use is common in MSM attending sexual health clinics in Manchester. High-risk sexual practices and certain sexually transmitted infections are more common in MSM reporting RDU. PMID- 28835197 TI - Saliva use in sex: Associations with use of smartphone dating applications in men who have sex with men. AB - Smartphone dating applications have become a primary source for men who have sex with men (MSM) to meet sexual partners. It has been found that MSM who used smartphone dating applications are at higher risk of gonorrhoea, but the reasons remain unknown. This study aimed to investigate whether MSM who met their partners via smartphone dating applications are more likely to engage in sexual practices such as rimming (oro-anal sex), and use of partner's saliva as a lubricant, that are associated with the risk of gonorrhoea. A cross-sectional study was conducted among 1672 MSM attending the Melbourne Sexual Health Centre, Australia, between 31 July 2014 and 30 June 2015. Multivariate logistic regression was conducted to examine the associations between sources of meeting partners and the two aforementioned sexual practices. MSM who used smartphone dating applications were 1.78 (95% CI: 1.38-2.28) times more likely to get rimmed, and 1.63 (95% CI: 1.27-2.09) times more likely to use partner's saliva as a lubricant during anal sex, compared to other sources, after adjusting for age and other sources for meeting partners. These practices are highly associated with gonorrhoea. PMID- 28835198 TI - Intervention to improve management of acute hepatitis C infection in a UK sexual health clinic. AB - A case note review was conducted for all newly-diagnosed acute hepatitis C virus (HCV)-infected patients attending our sexual health clinic pre- and post implementation of an HCV clinic proforma between January 2010 and September 2016. In total, 87 patient notes were included (40 pre-intervention, 47 post intervention) of whom 81 were HIV-positive. Data were collected regarding documentation of the following: baseline investigations, four-weekly HCV viral load monitoring, risk assessment, partner notification, advice given and Public Health England (PHE) notification. Appropriate baseline investigations, four weekly monitoring of HCV viral loads, risk assessment and advice documentation all improved in the post-intervention group when compared to pre-intervention. PHE notification and partner notification remained below the national standard post-intervention, with educational measures among relevant staff implemented accordingly. This audit demonstrates improvement across several key areas post clinic proforma implementation. PMID- 28835199 TI - Long-Term Results of Ulnar-Basilic Fistula Versus Radiocephalic Fistula for Maintenance Hemodialysis Access. AB - OBJECTIVE: The aim of this study is to compare the rate of primary patency and secondary patency achieved by ulnar-basilic arteriovenous fistula (UBAVF) and radiocephalic arteriovenous fistula (RCAVF) in the maintenance of hemodialysis access. METHODS: This retrospective analysis consists of 365 patients who had a forearm UBAVF or RCAVF between January 2012 and December 2015. Of these patients, 44 patients were treated with UBAVF, while 321 patients were treated with RCAVF. Demographics, primary patency, and secondary patency were documented and compared. RESULTS: Primary patency rates at 1 and 2 years were 77.2% and 63.9% in group UBAVF and 88.1% and 71.3% in group RCAVF, respectively. Secondary patency rates at 1 and 2 years were 93.0% and 78.8% in group UBAVF and 98.7% and 80.9% in group RCAVF, respectively. The Kaplan-Meier analysis showed that the primary and secondary patency rates were all without statistical difference between the 2 groups. CONCLUSION: Given the similar patency rate between UBAVF and RCAVF, the UBAVF could be considered as a reliable alternative when an RCAVF is not possible. PMID- 28835200 TI - Research productivity of doctor of physical therapy faculty promoted in the southeastern United States. AB - BACKGROUND: Little information exists on the research productivity of successfully promoted tenure-track Doctor of Physical Therapy (DPT) faculty. OBJECTIVE: To determine the research productivity that typically results in successful promotion. DESIGN: We collected publicly available curriculum vitae (CVs) from faculty currently in accredited DPT programs and who had been successfully promoted from an institution in the southeastern USA from 2000 through 2016. Total publication count, journal impact factor, funding, citations, and other metrics were analysed from 45 subjects of 22 of the 64 CAPTE-accredited DPT programs in the southeast. RESULTS: None of the studied metrics were normally distributed with time to promotion as determined by a Shapiro-Wilk test. These faculty exhibited a median publication count of 4, range 0 to 43; median of average citation count of 12.4, range 0 to 87.25; median of average journal impact factor of 2.866, range 0 to 6.280; median external funding received of $9910, range $0.00 to $19 543 198; and median author h-index of 3, range 0 to 17. The median number of years before promotion was 6, ranging from 3 to 13 years. Linear regression analysis indicates a poor fit with no significant correlation between years before promotion and any of the studied metrics. No correlation between journal impact factor and number of citations was observed (m = -0.22, p = 0.728, R2 = 0.0003). Prior to promotion 31% (14 of 45) did not receive external funding and 24% (11 of 45) had a 0 h-index. The Carnegie Classification of the institution did not significantly correlate with research productivity metrics in this dataset (p = 0.213). CONCLUSION: While faculty unsuccessful in promotion were not identifiable using this method, this research can be used by faculty and committees to evaluate research productivity against regional data and promote competitive standards with peer institutions. ABBREVIATIONS: CAPTE: Commission on Accreditation in Physical Therapist Education; DPT: Doctor of Physical Therapy. PMID- 28835201 TI - IRAK-M alters the polarity of macrophages to facilitate the survival of Mycobacterium tuberculosis. AB - BACKGROUND: Intracellular bacterium, Mycobacterium tuberculosis (M. tb), infects specifically macrophages as host cells. IRAK-M, a member of IRAK family, is a negative regulator in TLR signaling and specifically expresses in monocytes and macrophages. The role of IRAK-M in intracellular growth of M. tb and macrophage polarization was explored, for deeply understanding the pathogenesis of M. tb, the significance of IRAK-M to innate immunity and pathogen-host interaction. METHODS: IRAK-M expression was detected in M. tb infected macrophages and in human lung tissue of pulmonary tuberculosis with immunofluorescence staining, Western blot and immunohistochemistry. IRAK-M knock-down and over-expressing cell strains were constructed and intracellular survival of M. tb was investigated by acid-fast staining and colony forming units. Molecular markers of M1-type (pSTAT1 and iNOS) and M2-type (pSTAT6 and Arg-1) macrophages were detected using Western blot in IRAK-M knockdown U937 cells infected with M. tb H37Rv. U937 cells were stimulated with immunostimulant CpG7909 into M1 status and then infected with M. tb H37Rv. Expression of IRAK-M, IRAK-4 and iNOS was detected with immunofluorescence staining and Western blot, to evaluate the effect of IRAK-M to CpG directed M1-type polarization of macrophages during M. tb infection. Molecules related with macrophage's bactericidal ability such as Hif-1 and phosphorylated ERK1/2 were detected with immunohistochemistry and Western blot. RESULTS: IRAK-M increased in M. tb infected macrophage cells and also in human lung tissue of pulmonary tuberculosis. IRAK-M over-expression resulted in higher bacterial load, while IRAK-M interference resulted in lower bacterial load in M. tb infected cells. During M. tb infection, IRAK-M knockdown induced M1-type, while inhibited M2-type polarization of macrophage. M1-type polarization of U937 cells induced by CpG7909 was inhibited by M. tb infection, which was reversed by IRAK-M knockdown in U937 cells. IRAK-M affected Hif-1 and MAPK signaling cascade during M. tb infection. CONCLUSIONS: Conclusively, IRAK-M might alter the polarity of macrophages, to facilitate intracellular survival of M. tb and affect Th1-type immunity of the host, which is helpful to understanding the pathogenesis of M. tb. PMID- 28835202 TI - Upper and lower respiratory tract microbiota in horses: bacterial communities associated with health and mild asthma (inflammatory airway disease) and effects of dexamethasone. AB - BACKGROUND: The microbial composition of the equine respiratory tract, and differences due to mild equine asthma (also called Inflammatory Airway Disease (IAD)) have not been reported. The primary treatment for control of IAD in horses are corticosteroids. The objectives were to characterize the upper and lower respiratory tract microbiota associated with respiratory health and IAD, and to investigate the effects of dexamethasone on these bacterial communities using high throughput sequencing. RESULTS: The respiratory microbiota of horses was dominated by four major phyla, Proteobacteria (43.85%), Actinobacteria (21.63%), Firmicutes (16.82%), and Bacteroidetes (13.24%). Fifty genera had a relative abundance > 0.1%, with Sphingomonas and Pantoea being the most abundant. The upper and lower respiratory tract microbiota differed in healthy horses, with a decrease in richness in the lower airways, and 2 OTUs that differed in abundance. There was a separation between bacterial communities in the lower respiratory tract of healthy and IAD horses; 6 OTUs in the tracheal community had different abundance with disease status, with Streptococcus being increased in IAD horses. Treatment with dexamethasone had an effect on the lower respiratory tract microbiota of both heathy and IAD horses, with 8 OTUs increasing in abundance (including Streptococcus) and 1 OTU decreasing. CONCLUSIONS: The lower respiratory tract microbiota differed between healthy and IAD horses. Further research on the role of Streptococcus in IAD is warranted. Dexamethasone treatment affected the lower respiratory tract microbiota, which suggests that control of bacterial overgrowth in IAD horses treated with dexamethasone could be part of the treatment strategy. PMID- 28835204 TI - Erratum to: The photosensor protein Ppr of Rhodocista centenaria is linked to the chemotaxis signalling pathway. PMID- 28835203 TI - Epigenetic variation between urban and rural populations of Darwin's finches. AB - BACKGROUND: The molecular basis of evolutionary change is assumed to be genetic variation. However, growing evidence suggests that epigenetic mechanisms, such as DNA methylation, may also be involved in rapid adaptation to new environments. An important first step in evaluating this hypothesis is to test for the presence of epigenetic variation between natural populations living under different environmental conditions. RESULTS: In the current study we explored variation between populations of Darwin's finches, which comprise one of the best-studied examples of adaptive radiation. We tested for morphological, genetic, and epigenetic differences between adjacent "urban" and "rural" populations of each of two species of ground finches, Geospiza fortis and G. fuliginosa, on Santa Cruz Island in the Galapagos. Using data collected from more than 1000 birds, we found significant morphological differences between populations of G. fortis, but not G. fuliginosa. We did not find large size copy number variation (CNV) genetic differences between populations of either species. However, other genetic variants were not investigated. In contrast, we did find dramatic epigenetic differences between the urban and rural populations of both species, based on DNA methylation analysis. We explored genomic features and gene associations of the differentially DNA methylated regions (DMR), as well as their possible functional significance. CONCLUSIONS: In summary, our study documents local population epigenetic variation within each of two species of Darwin's finches. PMID- 28835205 TI - Prehypertension and psychosocial risk factors among university students in ASEAN countries. AB - BACKGROUND: Existing evidence suggests that the cardiovascular morbidities are increasing among pre-hypertensive individuals compared to normal. The aim of this study was to evaluate the prevalence of prehypertension, hypertension and to identify psychosocial risk factors for prehypertension among university students in Association of South East Asian Nation (ASEAN) countries. METHODS: Based on a cross-sectional survey, the total sample included 4649 undergraduate university students (females = 65.3%; mean age 20.5, SD = 2.9, age range of 18-30 years) from 7 ASEAN countries (Indonesia, Laos, Malaysia, Myanmar, Philippines, Thailand and Vietnam). Blood pressure, anthropometric, health behaviour and psychosocial variables were measured. RESULTS: Overall, 19.0% of the undergraduate university students across ASEAN countries had prehypertension, 6.7% hypertension and 74.2% were normotensives. There was country variation in prehypertension prevalence, ranging from 11.3% in Indonesia and 11.5% in Malaysia to above 18% in Laos, Myanmar and Thailand. In multivariate analysis, sociodemographic variables (male gender, living in an upper middle income country, and living on campus or off campus on their own), nutrition and weight variables (not being underweight and obese, having once or more times soft drinks in a day and never or rarely having chocolate or candy), heavy drinking and having depressive symptoms were associated with prehypertension. CONCLUSION: The study found a high prevalence of prehypertension in ASEAN university students. Several psychosocial risk factors including male gender, obesity, soft drinks consumption, heavy drinking and depression symptoms have been identified which can help in intervention programmes. PMID- 28835206 TI - An optimised protocol for isolation of RNA from small sections of laser-capture microdissected FFPE tissue amenable for next-generation sequencing. AB - BACKGROUND: Formalin-fixed paraffin embedded (FFPE) tissue constitutes a vast treasury of samples for biomedical research. Thus far however, extraction of RNA from FFPE tissue has proved challenging due to chemical RNA-protein crosslinking and RNA fragmentation, both of which heavily impact on RNA quantity and quality for downstream analysis. With very small sample sizes, e.g. when performing Laser capture microdissection (LCM) to isolate specific subpopulations of cells, recovery of sufficient RNA for analysis with reverse-transcription quantitative PCR (RT-qPCR) or next-generation sequencing (NGS) becomes very cumbersome and difficult. METHODS: We excised matched cancer-associated stroma (CAS) and normal stroma from clinical specimen of FFPE canine mammary tumours using LCM, and compared the commonly used protease-based RNA isolation procedure with an adapted novel technique that additionally incorporates a focused ultrasonication step. RESULTS: We successfully adapted a protocol that uses focused ultrasonication to isolate RNA from small amounts of deparaffinised, stained, clinical LCM samples. Using this approach, we found that total RNA yields could be increased by 8- to 12-fold compared to a commonly used protease-based extraction technique. Surprisingly, RNA extracted using this new approach was qualitatively at least equal if not superior compared to the old approach, as Cq values in RT-qPCR were on average 2.3-fold lower using the new method. Finally, we demonstrate that RNA extracted using the new method performs comparably in NGS as well. CONCLUSIONS: We present a successful isolation protocol for extraction of RNA from difficult and limiting FFPE tissue samples that enables successful analysis of small sections of clinically relevant specimen. The possibility to study gene expression signatures in specific small sections of archival FFPE tissue, which often entail large amounts of highly relevant clinical follow-up data, unlocks a new dimension of hitherto difficult-to-analyse samples which now become amenable for investigation. PMID- 28835207 TI - Adverse events following immunization with pentavalent vaccine: experiences of newly introduced vaccine in Iran. AB - BACKGROUND: The most important factors that affect the incidence of vaccine related complications are the constituent biological components of the vaccine, injection site reactions, age and sex. The aim of this study is to determine the incidence rate of adverse events following immunization with pentavalent vaccine (DTPw-Hep B-Hib (PRP-T) vaccine (pentavac) (adsorbed) is manufactured by Serum Institute of India ltd), which was introduced in Iran in November 2014. It is important to monitor vaccine-related adverse events because of the role of vaccine safety in immunization program success. METHODS: This study was a mixed cohort study that included 1119 children less than 1 year of age. In 2015, the children were referred to Hamadan health centers to receive pentavalent vaccine at 2, 4 and 6 months of age. The data were collected from the parents of the children using a questionnaire that was administered either face-to-face or by telephone. The cumulative incidence of side effects and risk ratio was reported with 95% confidence intervals (CI). Chi-squared tests and logistic regressions were used to investigate the association between the variables. RESULTS: The cumulative incidence rate of pentavalent-related adverse events during 48 h following immunization was estimated to be 15.8% for swelling, 10.9% for redness, 44.2% for pain, 12.6% for mild fever, 0.1% for high fever, 20.0% for drowsiness, 15.0% for loss of appetite, 32.9% for irritability, 4.6% for vomiting and 5.5% for persistent crying. There is no evidence for the occurrence of convulsion and encephalopathy among children who receive pentavalent vaccines. CONCLUSION: Further large studies with long time follow up are required to address rare events include convulsions, encephalopathy or persistent crying. However, Findings urge immunization programs to use pentavalent vaccinations and to continue implementing the current immunization program in children under 1 year of age. PMID- 28835208 TI - Whole genome sequencing and comparative transcriptome analysis of a novel seawater adapted, salt-resistant rice cultivar - sea rice 86. AB - BACKGROUND: Rice (Oryza sativa) is critical for human nutrition worldwide. Due to a growing population, cultivars that produce high yields in high salinity soil are of major importance. Here we describe the discovery and molecular characterization of a novel sea water adapted rice strain, Sea Rice 86 (SR86). RESULTS: SR86 can produce nutritious grains when grown in high salinity soil. Compared to a salt resistant rice cultivar, Yanfen 47 (YF47), SR86 grows in environments with up to 3X the salt content, and produces grains with significantly higher nutrient content in 12 measured components, including 2.9X calcium and 20X dietary fiber. Whole genome sequencing demonstrated that SR86 is a relatively ancient indica subspecies, phylogenetically close to the divergence point of the major rice varietals. SR86 has 12 chromosomes with a total genome size of 373,130,791 bps, slightly smaller than other sequenced rice genomes. Via comparison with 3000 rice genomes, we identified 42,359 putative unique, high impact variants in SR86. Transcriptome analysis of SR86 grown under normal and high saline conditions identified a large number of differentially expressed and salt-induced genes. Many of those genes fall into several gene families that have established or suggested roles in salt tolerance, while others represent potentially novel mediators of salt adaptation. CONCLUSIONS: Whole genome sequencing and transcriptome analysis of SR86 has laid a foundation for further molecular characterization of several desirable traits in this novel rice cultivar. A number of candidate genes related to salt adaptation identified in this study will be valuable for further functional investigation. PMID- 28835209 TI - Altered sensitivity to social gaze in the FMR1 premutation and pragmatic language competence. AB - BACKGROUND: The FMR1 premutation affects 1:291 women and is associated with a range of cognitive, affective, and physical health complications, including deficits in pragmatic language (i.e., social language). This study investigated attention to eye gaze as a fundamental social-cognitive skill that may be impaired in the FMR1 premutation and could underlie pragmatic deficits. Given the high prevalence of the FMR1 premutation, efforts to define its phenotype and mechanistic underpinnings have significant public health implications. METHODS: Thirty-five women with the FMR1 premutation and 20 control women completed an eye tracking paradigm that recorded time spent dwelling within the eye region in response to a face displaying either direct or averted gaze. Pragmatic language ability was coded from a conversational sample using the Pragmatic Rating Scale. RESULTS: Women with the FMR1 premutation failed to show attentional preference to direct gaze and spent more time dwelling on the averted eyes relative to controls. While dwelling on the eyes was associated with better pragmatic language performance in controls, these variables were unrelated in the women with the FMR1 premutation. CONCLUSIONS: Altered sensitivity to social gaze, characterized by increased salience of averted gaze, was observed among women with the FMR1 premutation. Furthermore, women with the FMR1 premutation were unable to capitalize on information conveyed through the eyes to enhance social communicative engagement, which differed from patterns seen in controls. These findings contribute to the growing characterization of social and communication phenotypes associated with the FMR1 premutation. PMID- 28835210 TI - High-density 80 K SNP array is a powerful tool for genotyping G. hirsutum accessions and genome analysis. AB - BACKGROUND: High-throughput genotyping platforms play important roles in plant genomic studies. Cotton (Gossypium spp.) is the world's important natural textile fiber and oil crop. Upland cotton accounts for more than 90% of the world's cotton production, however, modern upland cotton cultivars have narrow genetic diversity. The amounts of genomic sequencing and re-sequencing data released make it possible to develop a high-quality single nucleotide polymorphism (SNP) array for intraspecific genotyping detection in cotton. RESULTS: Here we report a high throughput CottonSNP80K array and its utilization in genotyping detection in different cotton accessions. 82,259 SNP markers were selected from the re sequencing data of 100 cotton cultivars and used to produce the array on the Illumina Infinium platform. 77,774 SNP loci (94.55%) were successfully synthesized on the array. Of them, 77,252 (99.33%) had call rates of >95% in 352 cotton accessions and 59,502 (76.51%) were polymorphic loci. Application tests using 22 cotton accessions with parent/F1 combinations or with similar genetic backgrounds showed that CottonSNP80K array had high genotyping accuracy, good repeatability, and wide applicability. Phylogenetic analysis of 312 cotton cultivars and landraces with wide geographical distribution showed that they could be classified into ten groups, irrelevant of their origins. We found that the different landraces were clustered in different subgroups, indicating that these landraces were major contributors to the development of different breeding populations of modern G. hirsutum cultivars in China. We integrated a total of 54,588 SNPs (MAFs >0.05) associated with 10 salt stress traits into 288 G. hirsutum accessions for genome-wide association studies (GWAS), and eight significant SNPs associated with three salt stress traits were detected. CONCLUSIONS: We developed CottonSNP80K array with high polymorphism to distinguish upland cotton accessions. Diverse application tests indicated that the CottonSNP80K play important roles in germplasm genotyping, variety verification, functional genomics studies, and molecular breeding in cotton. PMID- 28835211 TI - Handgrip strength values of Portuguese older adults: a population based study. AB - BACKGROUND: Handgrip strength is used to identify sarcopenia and frailty phenotypes, being a potential predictor of mortality in older adults. However, uniformity is lacking in the reference values. This study aimed to describe handgrip strength values of older population aged >=65 years in Portugal, considering the possible influence of anthropometric parameters. METHODS: A cross sectional study was conducted in Portugal, among 1500 older adults aged >=65 years old, according to "The Nutrition UP 65 Study Protocol". Demographic data were collected and cognitive performance, subjective general health, physical activity, anthropometric parameters and nutritional status were assessed and analysed. Handgrip strength data was obtained with a Jamar dynamometer. A Pubmed/Medline search was carried out to compare handgrip strength data between Portuguese older adults and other older populations. RESULTS: Handgrip strength was higher among men than among women (30.3 +/- 9.2 Kgf vs 18 +/- 5.4 Kgf, p < 0.001, respectively). In general, handgrip strength values of Portuguese older adults were lower than other older populations. In our sample, age, cognitive and nutritional status, self-reported sitting time and practice of physical activity were significantly correlated with handgrip strength in both sexes. Concerning anthropometric parameters, height was the most significantly correlated with handgrip strength (r = 0.34, p < 0.001, in women and r = 0.40, p < 0.001, in men). CONCLUSION: This study described, for the first time, handgrip strength values of Portuguese population aged >=65 years, according to age and to sex specific tertiles of height. The definition of handgrip strength reference values in this age group merits further reflection. PMID- 28835212 TI - Spondylodiscitis due to Parvimonas micra diagnosed by the melting temperature mapping method: a case report. AB - BACKGROUND: It has been suggested that more than 100 bacterial species can be identified using only seven universal bacterial primer sets in the melting temperature (Tm) mapping method and that these findings can be obtained within 3 h of sterile site collection. CASE PRESENTATION: A 67-year-old Japanese man with type 2 diabetes visited our hospital complaining of progressive lower back pain for 2 months. The patient was suspected to have spondylodiscitis on magnetic resonance imaging of the spine. Blood culture and transcutaneous vertebral biopsy were subsequently performed. Using the Tm mapping method, Parvimonas micra was detected from a transcutaneous vertebral biopsy specimen in 3 h. Gram-positive cocci were also detected by Gram staining and P. micra was identified directly from the anaerobic blood culture by matrix-assisted laser desorption ionization time of flight mass spectrometry. Four days after admission, the biopsy specimen culture isolate was identified as P. micra. CONCLUSIONS: The Tm mapping method may be useful for the diagnosis of bacterial infections where diagnosis is challenging because of the difficulty of culturing. PMID- 28835213 TI - Evaluation of the mobile nurse training (MNT) intervention - a step towards improvement in intrapartum practices in Bihar, India. AB - BACKGROUND: Evidence shows that improving the quality of intrapartum care is critical for maternal survival. However, a significant rise in the proportion of facility-based births over the last decade in India - attributable to a cash transfer program - has not resulted in a corresponding reduction in maternal mortality, thanks, in part, to low-skilled care at facilities. The current study evaluated a mobile knowledge-based intervention aimed at improving quality of care by mentoring in-service staff nurses at public obstetric facilities. METHODS: An independent evaluation team conducted baseline and post-intervention assessments at every facility using a mix of methods that included training assessments and Direct Observation of Deliveries. The assessment involved passive observation of pregnant women from the time of their admission at the facility and recording the obstetric events and delivery-related practices on a pre formatted checklist-based tool. Maternal practices were classified into positive and negative ones and scored. Linear regression analysis was used to evaluate the association of MNT intervention with summary scores for positive, negative and overall practice scores. We evaluated retention of intervention effect by comparing the summary scores at baseline, immediately following intervention and 1 year after intervention. RESULTS: In both unadjusted and adjusted analyses, the intervention was found to be significantly associated with improvement in positive practice score (Unadjusted: parameter estimate (beta) = 16.90; 95% confidence interval (CI) = 15.20, 18.60. Adjusted: beta = 13.14; 95% CI = 10.97, 15.32). The intervention was also significantly associated with changes in negative practice score, which was reverse coded to represent positive change (Unadjusted: beta = 11.66; 95% CI = 10.06, 13.27. Adjusted: beta = 2.99; 95% CI = 1.35, 4.63), and overall practice score (Unadjusted: beta = 15.74; 95% CI = 14.39, 17.08; Adjusted: beta = 10.89; 95% CI = 9.18, 12.60). One year after the intervention, negative practices continued to improve, albeit at a slower rate; positive labor practices and overall labor practice remained higher than the baseline but with some decline over time. CONCLUSIONS: Findings suggest that in low resource settings, interventions to strengthen quality of human resources and care through mentoring works to improve intrapartum maternal care. PMID- 28835214 TI - Ageing, exposure to pollution, and interactions between climate change and local seasons as oxidant conditions predicting incident hematologic malignancy at KINSHASA University clinics, Democratic Republic of CONGO (DRC). AB - BACKGROUND: The global burden of hematologic malignancy (HM) is rapidly rising with aging, exposure to polluted environments, and global and local climate variability all being well-established conditions of oxidative stress. However, there is currently no information on the extent and predictors of HM at Kinshasa University Clinics (KUC), DR Congo (DRC). This study evaluated the impact of bio clinical factors, exposure to polluted environments, and interactions between global climate changes (EL Nino and La Nina) and local climate (dry and rainy seasons) on the incidence of HM. METHODS: This hospital-based prospective cohort study was conducted at Kinshasa University Clinics in DR Congo. A total of 105 black African adult patients with anaemia between 2009 and 2016 were included. HM was confirmed by morphological typing according to the French-American-British (FAB) Classification System. Gender, age, exposure to traffic pollution and garages/stations, global climate variability (El Nino and La Nina), and local climate (dry and rainy seasons) were potential independent variables to predict incident HM using Cox regression analysis and Kaplan Meier curves. RESULTS: Out of the total 105 patients, 63 experienced incident HM, with an incidence rate of 60%. After adjusting for gender, HIV/AIDS, and other bio-clinical factors, the most significant independent predictors of HM were age >= 55 years (HR = 2.4; 95% CI 1.4-4.3; P = 0.003), exposure to pollution and garages or stations (HR = 4.9; 95% CI 2-12.1; P < 0.001), combined local dry season + La Nina (HR = 4.6; 95%CI 1.8-11.8; P < 0.001), and combined local dry season + El Nino (HR = 4; 95% CI 1.6 9.7; P = 0.004). HM types included acute myeloid leukaemia (28.6% n = 18), multiple myeloma (22.2% n = 14), myelodysplastic syndromes (15.9% n = 10), chronic myeloid leukaemia (15.9% n = 10), chronic lymphoid leukaemia (9.5% n = 6), and acute lymphoid leukaemia (7.9% n = 5). After adjusting for confounders using Cox regression analysis, age >= 55 years, exposure to pollution, combined local dry season + La Nina and combined local dry season + El Nino were the most significant predictors of incident hematologic malignancy. CONCLUSION: These findings highlight the importance of aging, pollution, the dry season, El Nino and La Nina as related to global warming as determinants of hematologic malignancies among African patients from Kinshasa, DR Congo. Cancer registries in DRC and other African countries will provide more robust database for future researches on haematological malignancies in the region. PMID- 28835216 TI - Landscape genomics reveal that ecological character determines adaptation: a case study in smoke tree (Cotinus coggygria Scop.). AB - BACKGROUND: The adaptive evolution of species response to environment are the key issues in molecular ecology and evolutionary biology. The direction of adaptive differentiation of species in regions lacking strong selection pressure is usually diverse. However, the driving mechanism of the diverse adaptive differentiation for regional species is still undetermined to date. In this study, we used landscape genomics modelling to infer the adaptive evolution of Cotinus coggygria in China's warm-temperate zone. RESULTS: Using fifteen natural populations and nine start codon targeted (SCoT) markers, a total of 1131 unambiguous loci were yielded. Our results showed two genetic groups existed in the fifteen natural populations of C. coggygria, which is due to the divergent selection driven by six environmental factors. Environmental association analyses revealed the environmental variables related to precipitation were associated with high numbers of environment-associated loci. CONCLUSIONS: Our results indicated that the ecological characters of C. coggygria, i.e. avoiding wetness and tolerating drought, determine its adaptive evolution. This study provides a reference that ecological character determines the adaptive evolution of species in regions lacking strong selection pressure. PMID- 28835215 TI - Plasmodium falciparum malaria parasite var gene expression is modified by host antibodies: longitudinal evidence from controlled infections of Kenyan adults with varying natural exposure. AB - BACKGROUND: The PfEMP1 family of Plasmodium falciparum antigens play a key role in pathogenesis of severe malaria through their insertion into the surface of parasite infected erythrocytes, and adhesion to host cells. Previous studies have suggested that parasites expressing PfEMP1 subclasses group A and DC8, associated with severe malaria, may have a growth advantage in immunologically naive individuals. However, this idea has not been tested in longitudinal studies. METHODS: Here we assessed expression of the var genes encoding PfEMP1, in parasites sampled from volunteers with varying prior exposure to malaria, following experimental infection by sporozoites (PfSPZ). Using qPCR, we tested for associations between the expression of various var subgroups in surviving parasite populations from each volunteer and 1) the levels of participants' antibodies to infected erythrocytes before challenge infection and 2) the apparent in vivo parasite multiplication rate. RESULTS: We show that 1) expression of var genes encoding for group A and DC8-like PfEMP1 were associated with low levels of antibodies to infected erythrocytes (alphaIE) before challenge, and 2) expression of a DC8-like CIDRalpha1.1 domain was associated with higher apparent parasite multiplication rate in a manner that was independent of levels of prior antibodies to infected erythrocytes. CONCLUSIONS: This study provides insight into the role of antibodies to infected erythrocytes surface antigens in the development of naturally acquired immunity and may help explain why specific PfEMP1 variants may be associated with severe malaria. TRIAL REGISTRATION: Pan African Clinical Trial Registry: PACTR201211000433272 . Date of registration: 10th October 2012. PMID- 28835217 TI - Ketamine attenuates the glutamatergic neurotransmission in the ventral posteromedial nucleus slices of rats. AB - BACKGROUND: Ketamine is a frequently used intravenous anesthetic, which can reversibly induce loss of consciousness (LOC). Previous studies have demonstrated that thalamocortical system is critical for information transmission and integration in the brain. The ventral posteromedial nucleus (VPM) is a critical component of thalamocortical system. Glutamate is an important excitatory neurotransmitter in the brain and may be involved in ketamine-induced LOC. METHODS: The study used whole-cell patch-clamp to observe the effect of ketamine (30 MUM-1000 MUM) on glutamatergic neurotransmission in VPM slices. RESULTS: Ketamine significantly decreased the amplitude of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs), but only higher concentration of ketamine (300 MUM and 1000 MUM) suppressed the frequency of sEPSCs. Ketamine (100 MUM-1000 MUM) also decreased the amplitude of glutamatergic miniature excitatory postsynaptic currents (mEPSCs), without altering the frequency. CONCLUSIONS: In VPM neurons, ketamine attenuates the glutamatergic neurotransmission mainly through postsynaptic mechanism and action potential may be involved in the process. PMID- 28835218 TI - A parallel-group randomized clinical trial of individually tailored, multidisciplinary, palliative rehabilitation for patients with newly diagnosed advanced cancer: the Pal-Rehab study protocol. AB - BACKGROUND: The effect of early palliative care and rehabilitation on the quality of life of patients with advanced cancer has been only sparsely described and needs further investigation. In the present trial we combine elements of early, specialized palliative care with cancer rehabilitation in a 12-week individually tailored, palliative rehabilitation program initiated shortly after a diagnosis of advanced cancer. METHODS: This single center, randomized, controlled trial will include 300 patients with newly diagnosed advanced cancer recruited from the Department of Oncology, Vejle Hospital. The patients are randomized to a specialized palliative rehabilitation intervention integrated in standard oncology care or to standard oncology care alone. The intervention consists of a multidisciplinary group program, individual consultations, or a combination of both. At baseline and after six and 12 weeks the patients will be asked to fill out questionnaires on symptoms, quality of life, and symptoms of depression and anxiety. Among the symptoms and problems assessed, patients are asked to indicate the problem they need help with to the largest extent. The effect of the intervention on this problem is the primary outcome measure of the study. Secondary outcome measures include survival and economic consequences. DISCUSSION: To our knowledge the Pal-Rehab study is the first randomized, controlled, phase III trial to evaluate individually tailored, palliative rehabilitation in standard oncology care initiated shortly after an advanced cancer diagnosis. The study will contribute with evidence on the effectiveness of implementing early palliative care in standard oncology treatment and hopefully offer new knowledge and future directions as to the content of palliative rehabilitation programs. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02332317 , registered retrospectively on December 30, 2014. One study participant had been enrolled at the time. PMID- 28835219 TI - Clinical decision-making and health-related quality of life during first-line and maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC): findings from a real-world setting. AB - BACKGROUND: Maintenance therapy (MT) with pemetrexed has been shown to improve overall and progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC), without impairing patients' health-related quality of life (HRQOL) substantially. Comprehensive data on HRQOL under real-life conditions are necessary to enable informed decision-making. This study aims to (1) assess HRQOL during first-line chemotherapy and subsequent MT and (2) record patients' and physicians' reasons leading to clinical decisions on MT. METHODS: Patients treated for NSCLC at three Austrian medical centres were included. HRQOL was assessed at every chemotherapy cycle using the EORTC QLQ-C30/+LC13 questionnaire. Semi-structured interviews were conducted before MT initiation and at the time of discontinuation to evaluate patients' and physicians' reasons for treatment decisions. Longitudinal QOL analysis was based on linear mixed models. RESULTS: Sixty-one (73%) out of 84 patients were considered for MT. Thirty-six patients (43%) received MT and 29 (35%) discontinued therapy. Decisions on MT initiation (in 20 cases by the physician vs 4 by the patient) and discontinuation (19 vs 10) were mainly voiced by the physician. Treatment toxicity of first-line chemotherapy was the main reason for rejection of MT in patients with stable disease and was more often indicated by patients than clinicians. HRQOL data were collected from 83 patients at 422 assessment time points and indicated significantly lower symptom severity during MT compared with first-line therapy for nausea and vomiting (p = 0.006), sleep disturbances (p < 0.001), appetite loss (p = 0.043), constipation (p = 0.017) and chest pain (p = 0.022), and a deterioration in emotional functioning (p = 0.023) and cognitive functioning (p = 0.044) during MT. CONCLUSIONS: Our results indicate that HRQOL and symptom burden improve between first-line treatment to MT in some respects, although some late toxicity persists. Discrepancies between patients' and physicians' perception of reasons for rejecting MT were evident. Thus, the integration of patient-reported outcomes, such as HRQOL, is required to enable shared decision-making and personalised healthcare based on mutual understanding of treatment objectives. PMID- 28835220 TI - Cardiovascular magnetic resonance feature tracking in small animals - a preliminary study on reproducibility and sample size calculation. AB - BACKGROUND: Cardiovascular magnetic resonance feature tracking (CMR-FT) is a novel tissue tracking technique developed for noninvasive assessment of myocardial motion and deformation. This preliminary study aimed to evaluate the observer's reproducibility of CMR-FT in a small animal (mouse) model and define sample size calculation for future trials. METHODS: Six C57BL/6 J mice were selected from the ongoing experimental mouse model onsite and underwent CMR with a 3 Tesla small animal MRI scanner. Myocardial deformation was analyzed using dedicated software (TomTec, Germany) by two observers. Left ventricular (LV) longitudinal, circumferential and radial strain (EllLAX, EccSAX and ErrSAX) were calculated. To assess intra-observer agreement data analysis was repeated after 4 weeks. The sample size required to detect a relative change in strain was calculated. RESULTS: In general, EccSAX and EllLAX demonstrated highest inter observer reproducibility (ICC 0.79 (0.46-0.91) and 0.73 (0.56-0.83) EccSAX and EllLAX respectively). In contrast, at the intra-observer level EllLAX was more reproducible than EccSAX (ICC 0.83 (0.73-0.90) and 0.74 (0.49-0.87) EllLAX and EccSAX respectively). The reproducibility of ErrSAX was weak at both observer levels. Preliminary sample size calculation showed that a small study sample (e.g. ten animals to detect a relative 10% change in EccSAX) could be sufficient to detect changes if parameter variability is low. CONCLUSIONS: This pilot study demonstrates good to excellent inter- and intra-observer reproducibility of CMR FT technique in small animal model. The most reproducible measures are global circumferential and global longitudinal strain, whereas reproducibility of radial strain is weak. Furthermore, sample size calculation demonstrates that a small number of animals could be sufficient for future trials. PMID- 28835221 TI - Quality of life and trust among young people with narcolepsy and their families, after the Pandemrix(r) vaccination: protocol for a case-control study. AB - BACKGROUND: The extensive vaccination programme against swine flu resulted in an increased incidence of narcolepsy among children and adolescents. There is a need to explore if these young persons' experiences have affected their trust in healthcare, their willingness to participate in future prevention programmes, and their contacts with the healthcare system. The overall aim is to identify factors important for the life-situation of children and adolescents with narcolepsy and their families, and factors that correlate with trust in healthcare. METHODS/DESIGN: Data will be collected via questionnaires from all available children with narcolepsy following the vaccination and their families, as well as a control group of children with diabetes and their families. Longitudinal descriptive interviews will also be conducted with a selection of 20-25 children and their families. Techniques from media research will be used for Internet based data collection and analysis of information relating to narcolepsy from social media. DISCUSSION: This project will use the situation of young persons with narcolepsy after the swine flu vaccination as a case to build a model that can be used in situations where trust in healthcare is essential. This model will be based on findings from the included studies on how trust is influenced by support, quality of life, burden of disease, impact on family, and use of social media. The model developed in this project will be beneficial in future situations where trust in healthcare is essential, such as new pandemic outbreaks but also for "everyday" adherence to health advice. PMID- 28835222 TI - Genome-wide association and targeted analysis of copy number variants with psoriatic arthritis in German patients. AB - BACKGROUND: Psoriatic Arthritis (PsA) is a chronic inflammatory disease of the joints. PsA is etiologically complex, and 11 susceptibility loci have been identified so far. Most of these overlap with loci associated with psoriasis vulgaris (PsV), the most common psoriatic skin manifestation which is also frequently seen in PsA patients. In addition, two copy number variants (CNVs) are associated with PsV, one of which, located within the LCE3 gene cluster, is also associated with PsA. Finally, an intergenic deletion has been reported as a PsA specific CNV. METHODS: We performed a genome-wide association study (GWAS) of CNVs in PsA and assessed the contribution to disease risk by CNVs at known psoriasis susceptibility loci. RESULTS: After stringent quality assessment and validation of CNVs of the GWAS with an alternative quantitative method, two significantly associated CNVs remained, one near UXS1, the other one at the TRB locus. However, MLPA analysis did not confirm the CN state in ~1/3 of individuals, and an analysis of an independent case-control-study failed to confirm the initial associations. Furthermore, detailed PCR-based analysis of the sequence at TRB revealed the existence of a more complex genomic sequence most accurately represented by freeze hg18 which accordingly failed to confirm the hg19 sequence. Only rare CNVs were detected at psoriasis susceptibility loci. At three of 12 susceptibility loci with CNVs (CSMD1, IL12B, RYR2), CN variability was confirmed independently by MLPA. Overall, the rate of CNV confirmation by MLPA was strongly dependent upon CNV type, CNV size and the number of array markers involved in a CNV. CONCLUSION: Although we identified PsA associations at several loci and confirmed that the common CNVs at these sites were real, ~1/3 of the common CNV states could not be reproduced. Furthermore, replication analysis failed to confirm the original association. Furthermore, SNP array-based analyses of CNVs were found to be more reliable for deletions than duplications, independent of the respective CNV allele frequency. CNVs are thus good candidate disease variants, while the methods to detect them should be applied cautiously and reproduced by an independent method. PMID- 28835223 TI - Development of nomograms to predict axillary lymph node status in breast cancer patients. AB - BACKGROUND: Prediction of axillary lymph node (ALN) status preoperatively is critical in the management of breast cancer patients. This study aims to develop a new set of nomograms to accurately predict ALN status. METHODS: We searched the National Cancer Database to identify eligible female breast cancer patients with profiles containing critical information. Patients diagnosed in 2010-2011 and 2012-2013 were designated the training (n = 99,618) and validation (n = 101,834) cohorts, respectively. We used binary logistic regression to investigate risk factors for ALN status and to develop a new set of nomograms to determine the probability of having any positive ALNs and N2-3 disease. We used ROC analysis and calibration plots to assess the discriminative ability and accuracy of the nomograms, respectively. RESULTS: In the training cohort, we identified age, quadrant of the tumor, tumor size, histology, ER, PR, HER2, tumor grade and lymphovascular invasion as significant predictors of ALNs status. Nomogram-A was developed to predict the probability of having any positive ALNs (P_any) in the full population with a C-index of 0.788 and 0.786 in the training and validation cohorts, respectively. In patients with positive ALNs, Nomogram-B was developed to predict the conditional probability of having N2-3 disease (P_con) with a C index of 0.680 and 0.677 in the training and validation cohorts, respectively. The absolute probability of having N2-3 disease can be estimated by P_any*P_con. Both of the nomograms were well-calibrated. CONCLUSIONS: We developed a set of nomograms to predict the ALN status in breast cancer patients. PMID- 28835224 TI - Are heart toxicities in breast cancer patients important for radiation oncologists? A practice pattern survey in German speaking countries. AB - BACKGROUND: To assess the personal beliefs of radiation oncologists regarding heart sparing techniques in breast cancer patients. METHODS: Between August 2015 and September 2015, a survey was sent to radiation oncology departments in Germany, Austria and Switzerland. 82 radiation oncology departments answered the questionnaire: 16 university clinics and 66 other departments. Most (87.2%) of the participants had >10 years of radiation oncology experience. RESULTS: 89.2% of the participants felt that there is enough evidence to support heart sparing for breast cancer patients. The most important dose parameter was considered the mean heart dose (69.1%). The personal "safe" dose to the heart was considered to be 5 Gy (range: 0-40 Gy). The main impediment in offering all breast cancer patients heart-sparing techniques seems to be the fact that these techniques are time/ resource consuming (46.5% of the participants). CONCLUSIONS: Most radiation oncologists believe that there is enough evidence to support heart sparing for breast cancer patients. But translating this belief into a wide practice will need better dosimetric and clinical data on what patients are expected to profit most, specific guidelines for which patients' heart sparing techniques should be performed, as well as recognition of the time/resource consumption of these techniques. PMID- 28835225 TI - Specificity versus redundancy in the RAP2.4 transcription factor family of Arabidopsis thaliana: transcriptional regulation of genes for chloroplast peroxidases. AB - BACKGROUND: The Arabidopsis ERFIb / RAP2.4 transcription factor family consists of eight members with highly conserved DNA binding domains. Selected members have been characterized individually, but a systematic comparison is pending. The redox-sensitive transcription factor RAP2.4a mediates chloroplast-to-nucleus redox signaling and controls induction of the three most prominent chloroplast peroxidases, namely 2-Cys peroxiredoxin A (2CPA) and thylakoid- and stromal ascorbate peroxidase (tAPx and sAPx). To test the specificity and redundancy of RAP2.4 transcription factors in the regulation of genes for chloroplast peroxidases, we compared the DNA-binding sites of the transcription factors in tertiary structure models, analyzed transcription factor and target gene regulation by qRT-PCR in RAP2.4, 2-Cys peroxiredoxin and ascorbate peroxidase T DNA insertion lines and RAP2.4 overexpressing lines of Arabidopsis thaliana and performed promoter binding studies. RESULTS: All RAP2.4 proteins bound the tAPx promoter, but only the four RAP2.4 proteins with identical DNA contact sites, namely RAP2.4a, RAP2.4b, RAP2.4d and RAP2.4h, interacted stably with the redox sensitive part of the 2CPA promoter. Gene expression analysis in RAP2.4 knockout lines revealed that RAP2.4a is the only one supporting 2CPA and chloroplast APx expression. Rap2.4h binds to the same promoter region as Rap2.4a and antagonizes 2CPA expression. Like the other six RAP2.4 proteins, Rap2.4 h promotes APx mRNA accumulation. Chloroplast ROS signals induced RAP2.4b and RAP2.4d expression, but these two transcription factor genes are (in contrast to RAP2.4a) insensitive to low 2CP availability, and their expression decreased in APx knockout lines. RAP2.4e and RAP2.4f gradually responded to chloroplast APx availability and activated specifically APx expression. These transcription factors bound, like RAP2.4c and RAP2.4g, the tAPx promoter, but hardly the 2CPA promoter. CONCLUSIONS: The RAP2.4 transcription factors form an environmentally and developmentally regulated transcription factor network, in which the various members affect the expression intensity of the others. Within the transcription factor family, RAP2.4a has a unique function as a general transcriptional activator of chloroplast peroxidase activity. The other RAP2.4 proteins mediate the fine-control and adjust the relative availability of 2CPA, sAPx and tAPx. PMID- 28835226 TI - Intraocular lens power calculation using standard formulas and ray tracing after DMEK in patients with Fuchs endothelial dystrophy. AB - BACKGROUND: The study presented here aims to optimize the accuracy of intraocular lens (IOL) power calculations in patients after DMEK by evaluation of the impact of the altered anterior/posterior corneal curvature relationship. METHODS: Scheimpflug-based Oculus Pentacam imaging was performed after DMEK surgery for Fuchs endothelial dystrophy. The IOL power was calculated for all patients by ray tracing, aiming for postoperative emmetropia. We also performed the IOL calculation using four third-generation formulas (SRK-T, Hoffer-Q, Holladay-1 and Haigis). The residual refractions for the individual target IOL were compared and analyzed. RESULTS: This retrospective study included 42 eyes of 33 patients (age 68.73 +/- 10.11 years) after DMEK surgery. The differences between the expected residual refraction based on ray tracing and that predicted with the third generation formulas were statistically significant (all formulas p < 0.001). The highest mean difference in the residual refraction between the target IOL measured by ray tracing and that calculated with third-generation formulas was found for the Haigis formula (0.90 +/- 0.40 D), and the lowest mean difference for the SRK/T formula (0.73 +/- 0.49 D). CONCLUSIONS: DMEK surgery induced a relevant change in the anterior to posterior corneal curvature relationship; this needs to be taken into account in the IOL power calculation to avoid hyperopic refractive surprises. PMID- 28835227 TI - Better Indigenous Risk stratification for Cardiac Health study (BIRCH) protocol: rationale and design of a cross-sectional and prospective cohort study to identify novel cardiovascular risk indicators in Aboriginal Australian and Torres Strait Islander adults. AB - BACKGROUND: Of the estimated 10-11 year life expectancy gap between Indigenous (Aboriginal and Torres Strait Islander people) and non-Indigenous Australians, approximately one quarter is attributable to cardiovascular disease (CVD). Risk prediction of CVD is imperfect, but particularly limited for Indigenous Australians. The BIRCH (Better Indigenous Risk stratification for Cardiac Health) project aims to identify and assess existing and novel markers of early disease and risk in Indigenous Australians to optimise health outcomes in this disadvantaged population. It further aims to determine whether these markers are relevant in non-Indigenous Australians. METHODS/DESIGN: BIRCH is a cross sectional and prospective cohort study of Indigenous and non-Indigenous Australian adults (>= 18 years) living in remote, regional and urban locations. Participants will be assessed for CVD risk factors, left ventricular mass and strain via echocardiography, sleep disordered breathing and quality via home based polysomnography or actigraphy respectively, and plasma lipidomic profiles via mass spectrometry. Outcome data will comprise CVD events and death over a period of five years. DISCUSSION: Results of BIRCH may increase understanding regarding the factors underlying the increased burden of CVD in Indigenous Australians in this setting. Further, it may identify novel markers of early disease and risk to inform the development of more accurate prediction equations. Better identification of at-risk individuals will promote more effective primary and secondary preventive initiatives to reduce Indigenous Australian health disadvantage. PMID- 28835228 TI - Vitamin D supplementation in cutaneous malignant melanoma outcome (ViDMe): a randomized controlled trial. AB - BACKGROUND: Previous studies have investigated the protective effect of vitamin D serum levels, at diagnosis and during the follow-up period after treatment, on melanoma outcome. In the present study we assess whether vitamin D supplementation, in the follow-up period after diagnosis and surgical resection of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and Vitamin D Receptor immunoreactivity in the primary tumor. METHODS/DESIGN: This study is a multicenter randomized double blind placebo- controlled phase III trial. Patients between the age of 18 and 80 years diagnosed and treated surgically for a melanoma stage IB-III are eligible for randomization in a 1:1 ratio to active treatment or placebo. The study drug is taken each month and consists of either 100,000 International Unit cholecalciferol or arachidis oleum raffinatum used as a placebo. The primary endpoint is relapse free survival. The secondary endpoints are 25 hydroxyvitamin D3 serum levels at diagnosis and at 6 month intervals, melanoma subtype, melanoma site and stage of melanoma at diagnosis according to the 2009 American Joint Committee on Cancer melanoma staging and classification. At randomization a bloodsample is taken for DNA analysis. The study is approved by the local Ethics Committees. DISCUSSION: If we can confirm our hypothesis that vitamin D supplementation after removal of the tumor has a protective effect on relapse of cutaneous malignant melanoma we may reduce the burden of CMM at several levels. Patients, diagnosed with melanoma may have a better clinical outcome and improved quality of life. There will be a decrease in health care costs related to treatment of metastatic disease and there will be a decrease in loss of professional years, which will markedly reduce the economic burden of the disease. TRIAL REGISTRATION: Clinical Trial.gov, NCT01748448 , 05/12/2012. PMID- 28835229 TI - Does dapagliflozin regress left ventricular hypertrophy in patients with type 2 diabetes? A prospective, double-blind, randomised, placebo-controlled study. AB - BACKGROUND: Patients with diabetes have a two to fourfold increased risk for development of and death from cardiovascular disease [CVD]. The current oral hypoglycaemic agents result in limited reduction in this cardiovascular risk. Sodium glucose linked co-transporter type 2 [SGLT2] inhibitors are a relatively new class of antidiabetic agent that have been shown to have potential cardiovascular benefits. In support of this, the EMPA-REG trial showed a striking 38% and 35% reduction in cardiovascular mortality and heart failure [HF] hospitalisation respectively. The exact mechanism (s) responsible for these effects remain (s) unclear. One potential mechanism is regression of Left ventricular hypertrophy (LVH). METHODS: The DAPA-LVH trial is a prospective, double-blind, randomised, placebo-controlled 'proof of concept' single-centre study that has been ongoing since January 2017. It is designed specifically to assess whether the SGLT2 inhibitor dapagliflozin regresses left ventricular [LV] mass in patients with diabetes and left ventricular hypertrophy [LVH]. We are utilising cardiac and abdominal magnetic resonance imaging [MRI] and ambulatory blood pressure monitoring to quantify the cardiovascular and systemic effects of dapagliflozin 10 mg once daily against standard care over a 1 year observation period. The primary endpoint is to detect the changes in LV mass. The secondary outcomes are to assess the changes in, LV volumes, blood pressure, weight, visceral and subcutaneous fat. DISCUSSION: This trial will be able to determine if SGLT2 inhibitor therapy reduces LV mass in patient with diabetes and LVH thereby strengthening their position as oral hypoglycaemic agents with cardioprotective benefits. TRIAL REGISTRATION: Clinical Trials.gov: NCT02956811 . Registered November 2016. PMID- 28835230 TI - The association between socioeconomic status and visual impairments among primary glaucoma: the results from Nationwide Korean National Health Insurance Cohort from 2004 to 2013. AB - BACKGROUND: Glaucoma is one of the most leading causes of permanent visual impairments in Korea, and social expenses spent for the glaucoma are increasing. This study is to identify association between socioeconomic status and the visual impairments caused by primary glaucoma in Korea. METHODS: This study is based on a cohort study using stratified representative samples in the National Health Insurance claim data from 2002 to 2013 with 1,025,340 representative subjects. Target subjects were patients who are newly diagnosed with primary glaucoma from 2004 to 2013. We conducted a multiple logistic regression analysis depending on the occurrence of visual impairment and its temporal order compared to the glaucoma diagnosis. RESULTS: Among 1728 patients with primary glaucoma, those with low and middle income shows higher odds ratio (OR) of the visual impairments than those with high income group (low income; OR = 3.42, 95% Confidential Interval (CI):2.06-5.66, middle income; OR = 2.13, 95% CI: 1.28-3.55), in case of the occurrence of the visual impairments preceded the diagnosis of glaucoma. CONCLUSIONS: Glaucoma patients without pre-existing glaucoma history before visual impairment have higher association between socioeconomic status and the occurrence of visual impairments by primary glaucoma. Since glaucoma had not been diagnosed and recognized yet, the differences may have been derived from the disparities of the awareness of the glaucoma. These findings call attention to the correlation between socioeconomic factors and the visual impairments by glaucoma, and raise public health needs over the importance of glaucoma awareness and eye screening for glaucoma, especially for low socioeconomic status. PMID- 28835231 TI - Trends in the number and the quality of trial protocols involving children submitted to a French Institutional Review Board. AB - BACKGROUND: There is a great need for high quality clinical research for children. The European Pediatric Regulation aimed to improve the quality of clinical trials in order to increase the availability of treatments for children. The main purpose of this study was to assess the evolution of both the number and the quality of pediatric trial protocols that were submitted to a French Institutional Review Board (IRB00009118) before and after the initiation of the EU Pediatric Regulation. METHODS: All protocols submitted to the IRB00009118 between 2003 and 2014 and conducting research on subjects under eighteen years of age were eligible. The quality of randomized clinical trials was assessed according to the guidelines developed by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network and ranked using the Jadad score. RESULTS: Out of 622 protocols submitted to the Institutional Review Board (IRB), 21% (133/622) included children. Among these 133 pediatric protocols, the number of submitted pediatric protocols doubled between the two studied periods. From 2003 to 2008, 47 protocols including 21 institutionally sponsored were submitted to the IRB and from 2009 until 2014, 86 protocols including 48 institutionally sponsored were submitted. No significant trend was observed on the quality of RCTs. The overall median score of RCTs on the Jadad scale was high (3.5), 70.0% of protocols had a Jadad score >= 3, and 30.0% had a score < 3. CONCLUSION: Following the EU Pediatric Regulation, the number of pediatric protocols submitted to the IRB00009118 tends to increase, but no change was noticed regarding their quality. PMID- 28835232 TI - Full fusion of proximal thoracic curve helps to prevent postoperative cervical tilt in Lenke type 2 adolescent idiopathic scoliosis patients with right-elevated shoulder. AB - BACKGROUND: To date, no study had reported the phenomenon of deteriorated postoperative cervical tilt in Lenke type 2 adolescent idiopathic scoliosis patients. The purpose of this study is to evaluate the cervical tilt in Lenke type 2 adolescent idiopathic scoliosis patients with right-elevated shoulder treated by either full fusion or partial/non fusion of the proximal thoracic curve. METHODS: A total of 30 Lenke type 2 AIS patients with preoperative right elevated shoulder underwent posterior spinal instrumentation from 2009 to 2011 were included in this study. All the subjects were divided into 2 groups according to the selection of upper instrumented vertebra. There were 14 cases proximally fused to T1 or T2 (Group A) and 16 cases proximally fused to T3 or below (Group B). Both standing anteroposterior and sagittal X-ray films of the spine obtained preoperatively, one week after the operation, and at a minimum of two-year follow-up were analyzed with respect to the following parameters: cervical tilt, T1 tilt, proximal thoracic Cobb angle, main thoracic Cobb angle, apical vertebral translation of proximal thoracic curve, apical vertebral translation of main thoracic curve, radiographic shoulder height, cervical lordosis, proximal thoracic kyphosis and main thoracic kyphosis. RESULTS: Most (83.3%) of the patients in these two groups gained satisfactory shoulder balance after surgery. However, the cervical tilt significantly improved in group A (p < 0.001) but deteriorated in group B (p < 0.001). In group A, the decrease of cervical tilt significantly positively correlated with that of T1 tilt (p < 0.001). In group B, the increase of cervical tilt significantly positively correlated with both the increase of T1 tilt (p < 0.001) and the increase of apical vertebral translation of proximal thoracic curve (p < 0.05). CONCLUSIONS: Lenke type 2 AIS patients with right-elevated shoulder gain improved shoulder but deteriorated cervical tilt after partial/non fusion of proximal thoracic curve. Full fusion of proximal thoracic curve helps to prevent the residual cervical tilt in these patients. PMID- 28835233 TI - Responsiveness of the PROMIS(r) measures to changes in disease status among pediatric nephrotic syndrome patients: a Midwest pediatric nephrology consortium study. AB - BACKGROUND: Nephrotic syndrome represents a condition in pediatric nephrology typified by a relapsing and remitting course, proteinuria and the presence of edema. The PROMIS measures have previously been studied and validated in cross sectional studies of children with nephrotic syndrome. This study was designed to longitudinally validate the PROMIS measures in pediatric nephrotic syndrome. METHODS: One hundred twenty seven children with nephrotic syndrome between the ages of 8 and 17 years participated in this prospective cohort study. Patients completed a baseline assessment while their nephrotic syndrome was active, a follow-up assessment at the time of their first complete proteinuria remission or study month 3 if no remission occurred, and a final assessment at study month 12. Participants completed six PROMIS measures (Mobility, Fatigue, Pain Interference, Depressive Symptoms, Anxiety, and Peer Relationships), the PedsQL version 4.0, and two global assessment of change items. RESULTS: Disease status was classified at each assessment: nephrotic syndrome active in 100% at baseline, 33% at month 3, and 46% at month 12. The PROMIS domains of Mobility, Fatigue, Pain Interference, Depressive Symptoms, and Anxiety each showed a significant overall improvement over time (p < 0.001). When the PROMIS measures were compared to the patients' global assessment of change, the domains of Mobility, Fatigue, Pain Interference, and Anxiety consistently changed in an expected fashion. With the exception of Pain Interference, change in PROMIS domain scores did not correlate with changes in disease activity. PROMIS domain scores were moderately correlated with analogous PedsQL domain scores. CONCLUSION: This study demonstrates that the PROMIS Mobility, Fatigue, Pain Interference, and Anxiety domains are sensitive to self-reported changes in disease and overall health status over time in children with nephrotic syndrome. The lack of significant anchoring to clinically defined nephrotic syndrome disease active and remission status may highlight an opportunity to improve the measurement of HRQOL in children with nephrotic syndrome through the development of a nephrotic syndrome disease-specific HRQOL measure. PMID- 28835234 TI - Altitude and COPD prevalence: analysis of the PREPOCOL-PLATINO-BOLD-EPI-SCAN study. AB - BACKGROUND: COPD prevalence is highly variable and geographical altitude has been linked to it, yet with conflicting results. We aimed to investigate this association, considering well known risk factors. METHODS: A pooled analysis of individual data from the PREPOCOL-PLATINO-BOLD-EPI-SCAN studies was used to disentangle the population effect of geographical altitude on COPD prevalence. Post-bronchodilator FEV1/FVC below the lower limit of normal defined airflow limitation consistent with COPD. High altitude was defined as >1500 m above sea level. Undiagnosed COPD was considered when participants had airflow limitation but did not report a prior diagnosis of COPD. RESULTS: Among 30,874 participants aged 56.1 +/- 11.3 years from 44 sites worldwide, 55.8% were women, 49.6% never smokers, and 12.9% (3978 subjects) were residing above 1500 m. COPD prevalence was significantly lower in participants living at high altitude with a prevalence of 8.5% compared to 9.9%, respectively (p < 0.005). However, known risk factors were significantly less frequent at high altitude. Hence, in the adjusted multivariate analysis, altitude itself had no significant influence on COPD prevalence. Living at high altitude, however, was associated with a significantly increased risk of undiagnosed COPD. Furthermore, subjects with airflow limitation living at high altitude reported significantly less respiratory symptoms compared to subjects residing at lower altitude. CONCLUSION: Living at high altitude is not associated with a difference in COPD prevalence after accounting for individual risk factors. However, high altitude itself was associated with an increased risk of undiagnosed COPD. PMID- 28835235 TI - Development of diabetes-specific quality of life module to be in conjunction with the World Health Organization quality of life scale brief version (WHOQOL-BREF). AB - BACKGROUND: Although numerous health-related quality of life (HRQoL) instruments are available for patients with diabetes, the length of these measures may limit their feasibility to routine practice. Also, these measures do not distinguish items for generic and diabetes-specific HRQoL. This study was aimed to develop a diabetes-specific quality of life questionnaire module (DMQoL) to be in conjunction with the World Health Organization Quality of Life scale brief version (WHOQOL-BREF). METHODS: One hundred seventeen patients with diabetes were enrolled from a medical center in Taiwan. The item content of DMQoL was constructed based on an extensive review of existing HRQoL instruments for diabetes, expert discussions and patient interviews. A series of psychometric tests were conducted to ensure the reliability and validity of DMQoL. The WHOQOL BREF served as an existing HRQoL measure for construct validity testing. The response scale of DMQoL was adopted from the 5-point Likert scale of WHOQOL-BREF. RESULTS: A total of 10 items without ceiling or floor effects were selected from 20 items. Exploratory factor analysis (EFA) with parallel analysis and Rasch analysis concluded that the 10 items were embedded in the same underlying concept. The corrected item-total correlations and factor loadings from EFA were all above 0.4. The internal consistency of the 10 items was satisfactory (Cronbach's alpha = 0.84). The DMQoL total score was moderately correlated with that of WHOQOL-BREF (r = 0.48, p < 0.001). The known-group validity showed that patients with HbA1c <= 7% had significantly higher mean scores of DMQoL than did those with HbA1c > 8% (3.66 +/- 0.47 vs. 3.41 +/- 0.53; p = 0.037). CONCLUSIONS: The DMQoL with only 10 items is developed and it is sensitive to the change of diabetes progression in early phases (e.g., glycemic changes). The combination of WHOQOL-BREF and DMQoL provides a comprehensive picture of overall HRQoL in patients with diabetes and enhance the instrument's ability to detect clinically meaningful changes in diabetes. PMID- 28835236 TI - Impact of copper oxide nanomaterials on differentiated and undifferentiated Caco 2 intestinal epithelial cells; assessment of cytotoxicity, barrier integrity, cytokine production and nanomaterial penetration. AB - BACKGROUND: Copper oxide nanomaterials (CuO NMs) are exploited in a diverse array of products including antimicrobials, inks, cosmetics, textiles and food contact materials. There is therefore a need to assess the toxicity of CuO NMs to the gastrointestinal (GI) tract since exposure could occur via direct oral ingestion, mucocillary clearance (following inhalation) or hand to mouth contact. METHODS: Undifferentiated Caco-2 intestinal cells were exposed to CuO NMs (10 nm) at concentrations ranging from 0.37 to 78.13 MUg/cm2 Cu (equivalent to 1.95 to 250 MUg/ml) and cell viability assessed 24 h post exposure using the alamar blue assay. The benchmark dose (BMD 20), determined using PROAST software, was identified as 4.44 MUg/cm2 for CuO NMs, and 4.25 MUg/cm2 for copper sulphate (CuSO4), which informed the selection of concentrations for further studies. The differentiation status of cells and the impact of CuO NMs and CuSO4 on the integrity of the differentiated Caco-2 cell monolayer were assessed by measurement of trans-epithelial electrical resistance (TEER), staining for Zonula occludens-1 (ZO-1) and imaging of cell morphology using scanning electron microscopy (SEM). The impact of CuO NMs and CuSO4 on the viability of differentiated cells was performed via assessment of cell number (DAPI staining), and visualisation of cell morphology (light microscopy). Interleukin-8 (IL-8) production by undifferentiated and differentiated Caco-2 cells following exposure to CuO NMs and CuSO4 was determined using an ELISA. The copper concentration in the cell lysate, apical and basolateral compartments were measured with Inductive Coupled Plasma Optical Emission Spectrometry (ICP-OES) and used to calculate the apparent permeability coefficient (Papp); a measure of barrier permeability to CuO NMs. For all experiments, CuSO4 was used as an ionic control. RESULTS: CuO NMs and CuSO4 caused a concentration dependent decrease in cell viability in undifferentiated cells. CuO NMs and CuSO4 translocated across the differentiated Caco-2 cell monolayer. CuO NM mediated IL-8 production was over 2-fold higher in undifferentiated cells. A reduction in cell viability in differentiated cells was not responsible for the lower level of cytokine production observed. Both CuO NMs and CuSO4 decreased TEER values to a similar extent, and caused tight junction dysfunction (ZO-1 staining), suggesting that barrier integrity was disrupted. CONCLUSIONS: CuO NMs and CuSO4 stimulated IL-8 production by Caco-2 cells, decreased barrier integrity and thereby increased the Papp and translocation of Cu. There was no significant enhancement in potency of the CuO NMs compared to CuSO4. Differentiated Caco-2 cells were identified as a powerful model to assess the impacts of ingested NMs on the GI tract. PMID- 28835237 TI - Gestational age at birth and behavioral problems from four to 11 years of age: birth cohort study. AB - BACKGROUND: Studies conducted mainly in high-income countries have shown that preterm births are associated with increased risk of behavioral problems and psychiatric disorders. The aim of this study was to assess the prevalence of behavioral problems from middle-childhood to early-adolescence according to gestational age at birth in a middle-income setting. METHODS: A population-based birth cohort (n = 4231) in Pelotas, Brazil, was followed-up in several occasions from birth to 11 years. Estimated GA was based on last menstrual period or, when unknown or inconsistent, on the Dubowitz method. Behavioral problems were assessed at 4 (Child Behavior Checklist - CBCL), and at 6 and 11 years (Development and Well-Being Assessment - DAWBA) tool. Maternal socio-economic characteristics and depression at 2, 4 and 6 years post-partum, child perinatal characteristics and breastfeeding duration were used as confounders. Analyses were run by linear and logistic regression. RESULTS: Three thousand two hundred four children had full information on gestational age, CBCL and DAWBA. At 4 years, mean total (42.9 +/- 24.0) and mean externalizing (18.8 +/- 9.1) CBCL scores were higher among preterm girls born at <34 weeks than among full term girls (33.2 +/- 15.1 and 15.0 +/- 6.6, respectively). After controlling for confounders the association was no longer significant. At the age of 6 years there was no association between gestational age and behavior, neither in crude nor in adjusted analyses. Odds ratio for any psychiatric disorders at 11 years was 60% (1.6; 1.1-2.1) higher among those born at 34-36 weeks than in full-term children, but the association disappeared in adjusted analyses. CONCLUSION: At this large cohort, behavioral problems from middle-childhood to early-adolescence are more related to family socio-economic characteristics and to other child perinatal conditions than to gestational age at birth. PMID- 28835238 TI - Predictive ability of the start back tool: an ancillary analysis of a low back pain trial from Danish general practice. AB - BACKGROUND: Low back pain (LBP) is a common cause of contact with the primary healthcare sector. In some patients, symptoms quickly resolve, but others develop long-lasting pain and disability. To improve the care pathway for patients with LBP, the STarT Back Tool (STarT) questionnaire has been developed. It helps initial decision-making by subgrouping patients on the basis of their prognosis and helps to target treatment according to prognosis. An assumption behind the use of STarT is the ability to predict functional improvement. This assumption has never been tested in a population that consists exclusively of patients enrolled when consulting a Danish general practitioner for LBP. The aim of this study was to investigate STarT's ability to predict a 30% improvement in the Roland Morris Disability Questionnaire (RMDQ) score. METHODS: This was an ancillary analysis using data from a Danish guideline implementation study (registered at ClinicalTrials.gov NCT01699256). An inclusion criterion was age 18 to 65 years of age. Exclusion criteria were pregnancy, fractures, and signs of underlying pathology. Patient-reported STarT score and the Roland Morris Disability Questionnaire were administered at baseline and again after 4, 8, and 52 weeks. RESULTS: Between January 2013 and July 2014, 475 patients from the original trial participated with questionnaires. From this subpopulation, 441 (92.8%) patients provided information regarding STarT. Baseline and eight-week RMDQ data were available for 304 (64.0%) patients. After 8 weeks, 61 (65.6%) in the low-risk group, 67 (54.9%) in the medium-risk group, and 33 (37.1%) in the high-risk group had achieved a 30% improvement in the RMDQ score. After 8 weeks, high-risk patients were at 61% (95% CI: 20-125%, P < 0.001) higher risk of not achieving a 30% improvement in the RMDQ score compared with patients in either the low-risk group or the medium-risk group. CONCLUSION: STarT was predictive for functional improvement in patients from general practice with LBP. TRIAL REGISTRATION: ClinicalTrials.gov NCT01699256 , Nov 29, 2016 (registered retrospectively). PMID- 28835239 TI - Prospective comparison of the anterior and lateral approach in hemiarthroplasty for hip fractures: a study protocol. AB - BACKGROUND: The Direct Anterior Approach (DAA) is an alternative approach to the currently most used Lateral Approach (LA) for hip replacement in femoral neck fracture patients. Compared to the LA, the DAA minimizes soft tissue damage. Sparing muscle tissue may facilitate early and improved postoperative mobility. It may also be associated with fewer complications, increased quality of life and lower 1-year mortality. The aim of this study is to compare postoperative complications, hip function and patient mobility after hemiarthroplasty via the anterior or lateral approach following a displaced femoral neck fracture. METHODS: 138 elderly patients with displaced femoral neck fractures will be operated using either the direct anterior approach or the lateral approach for a hemiarthroplasty in a single centre, prospective, comparative cohort study. The choice of surgical approach will depend on the expertise of the trauma surgeon on call. The primary outcome of this study will be the functionality of the hip after surgery measured using the Harris Hip Score during routine outpatient check ups. Secondary outcomes include surgical and non-surgical complication rates, admission time, postoperative pain, rehabilitation time, performance in activities of daily living, health-related quality of life measured, cognitive function and balance. DISCUSSION: Many approaches are known for hip replacement arthroplasty in trauma patients with little consensus on the preferred method. Identifying the best approach facilitating an adequate and fast recovery could optimize patient independence and quality of life and minimize rehabilitation costs, morbidity and mortality rates. The study design will reflect daily clinical practice and aims to present an accurate depiction of clinical outcomes. TRIAL REGISTRATION: This trial entered the Dutch Trial Registry with registration number (NTR)6238 on the 24th of April 2017. http://www.trialregister.nl/trialreg/index.asp . Protocol version 2.0 16-03-2017. PMID- 28835240 TI - Sharing Histories-a transformative learning/teaching method to empower community health workers to support health behavior change of mothers. AB - BACKGROUND: One of the keys to improving health globally is promoting mothers' adoption of healthy home practices for improved nutrition and illness prevention in the first 1000 days of life from conception. Customarily, mothers are taught health messages which, even if simplified, are hard to remember. The challenge is how to promote learning and behavior change of mothers more effectively in low resource settings where access to health information is poor, educational levels are low, and traditional beliefs are strong. METHODS: In addressing that challenge, a new learning/teaching method called "Sharing Histories" is in development to improve the performance of female community health workers (CHWs) in promoting mothers' behaviors for maternal, neonatal and child health (MNCH). RESULTS: This method builds self-confidence and empowerment of CHWs in learning sessions that are built on guided sharing of their own memories of childbearing and child care. CHWs can later share histories with the mother, building her trust and empowerment to change. For professional primary health care staff who are not educators, Sharing Histories is simple to learn and use so that the method can be easily incorporated into government health systems and ongoing CHW programs. CONCLUSIONS: I present here the Sharing Histories method, describe how it differs from other social and behavior change methods, and discuss selected literature from psychology, communications, and neuroscience that helps to explain how and why this method works as a transformative tool to engage, teach, transform, and empower CHWs to be more effective change agents with other mothers in their communities, thereby contributing to the attainment of the Sustainable Development Goals. PMID- 28835241 TI - Rectal carcinoma and multiple gastrointestinal stromal tumors (GIST) of the small intestine in a patient with neurofibromatosis type 1: a case report. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomally dominant inherited disorder characterized by multiple pigmented skin spots (cafe-au-lait spots) and neurofibroma. NF1 is associated with a wide variety of benign or malignant tumors. We report a NF1 patient who received surgical treatment for rectal carcinoma and multifocal small intestinal gastrointestinal stromal tumors (GISTs). CASE PRESENTATION: A 70-year-old female patient with NF1 was referred to our hospital after a positive fecal occult blood test. Locally advanced rectal carcinoma was detected in the upper rectum using colonoscopy. A submucosal tumor 20 mm in diameter was detected in the duodenal bulb during the upper gastrointestinal endoscopy. The biopsy specimen from the duodenum was GIST with positive immunostaining of KIT and CD34 microscopically. Laparoscopic low anterior resection for rectal carcinoma and local excision of the duodenal GIST were performed successfully. During the operation, five white small nodules were found on the serosa of the jejunum. One nodule was excised for histological examination. The resected rectal tumor was a well-differentiated adenocarcinoma with multiple lymph nodes metastases according to the histology. The duodenal tumor was found to be low-risk GIST. Moreover, the nodule from the jejunum was very low risk GIST. An excised skin wart was neurofibroma according to the histology. CONCLUSIONS: GIST or carcinomas have been reported to occasionally occur in the digestive tract of the patients with NF1. We present a rare case of a NF1 patient with GISTs and colorectal carcinoma. PMID- 28835243 TI - Symptom clusters and related factors in bladder cancer patients three months after radical cystectomy. AB - BACKGROUND: To identify symptom distress and clusters in patients 3 months after radical cystectomy and to explore their potential predictors. METHODS: A cross sectional design was used to investigate 99 bladder cancer patients 3 months after radical cystectomy. Data were collected by demographic and disease characteristic questionnaires, the symptom experience scale of the M.D. Anderson symptom inventory, two additional symptoms specific to radical cystectomy, and the functional assessment of cancer therapy questionnaire. A factor analysis, stepwise regression, and correlation analysis were applied. RESULTS: Three symptom clusters were identified: fatigue-malaise, gastrointestinal, and psycho urinary. Age, complication severity, albumin post-surgery (negative), orthotropic neobladder reconstruction, adjuvant chemotherapy and American Society of Anesthesiologists (ASA) scores were significant predictors of fatigue-malaise. Adjuvant chemotherapy, orthotropic neobladder reconstruction, female gender, ASA scores and albumin (negative) were significant predictors of gastrointestinal symptoms. Being unmarried, having a higher educational level and complication severity were significant predictors of psycho-urinary symptoms. The correlations between clusters and for each cluster with quality of life were significant, with the highest correlation observed between the psycho-urinary cluster and quality of life. CONCLUSIONS: Bladder cancer patients experience concurrent symptoms that appear to cluster and are significantly correlated with quality of life. Moreover, symptom clusters may be predicted by certain demographic and clinical characteristics. PMID- 28835244 TI - Improving preconception health and care: a situation analysis. AB - BACKGROUND: The purpose of this situation analysis was to explore the views of health and non-health professionals working with women of childbearing age on current and future delivery of preconception care in one National Health Service (NHS) Board area in Scotland. METHODS: The situation analysis was undertaken using a mixed methods approach. Six focus groups were conducted organised by profession - general practitioners (GPs), practice nurses, health visitors, family nurses, guidance teachers and youth workers. Existing evidence of effective preconception care interventions informed focus group guides. A survey was undertaken with community pharmacists which provided qualitative data for analysis. Focus group transcripts were analysed by two researchers using a thematic analysis approach. RESULTS: There was lack of awareness of preconception health and its importance amongst the target group. Levels of unplanned pregnancy hampered efforts to deliver interventions. Professional knowledge, capacity and consistency of practice were viewed as challenges, as was individual compliance with preconception care advice. Improvement requires multifaceted action, including ensuring the school curriculum adequately prepares adolescents for future parenthood, increasing awareness through communication and marketing, supporting professional knowledge and practice and capitalising on existing opportunities for preconception care, and ensuring services are equitable and targeted to need. CONCLUSIONS: Delivery of preconception care needs to be improved both before and between pregnancies to improve outcomes for women and infants. Action is required at individual, organisational and community levels to ensure this important issue is at the forefront of preventative care and preventative spending. PMID- 28835242 TI - Granulocytic myeloid-derived suppressor cells suppress virus-specific CD8+ T cell responses during acute Friend retrovirus infection. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) can suppress T cell responses in several different diseases. Previously these suppressive cells were observed to expand in HIV patients and in a mouse retrovirus model, yet their suppressive effect on virus-specific CD8+ T cells in vitro and in vivo has not been characterized thus far. RESULTS: We used the Friend retrovirus (FV) model to demonstrate that MDSCs expand and become activated during the late phase of acute FV infection. Only the subpopulation of granulocytic MDSCs (gMDSCs) but not monocytic MDSC suppressed virus-specific CD8+ T cell proliferation and function in vitro. gMDSCs expressed arginase 1, high levels of the inhibitory ligand PD-L1 and the ATP dephosphorylating enzyme CD39 on the cell surface upon infection. All three molecules were involved in the suppressive effect of the gMDSCs in vitro. MDSC depletion experiments in FV-infected mice revealed that they restrict virus specific CD8+ T cell responses and thus affect the immune control of chronic retroviruses in vivo. CONCLUSIONS: Our study demonstrates that MDSCs become activated and expand during the acute phase of retrovirus infection. Their suppressive activity on virus-specific CD8+ T cells may contribute to T cell dysfunction and the development of chronic infection. PMID- 28835245 TI - Prevalence of dyslipidaemia and risk factors in Chinese coal miners: a cross sectional survey study. AB - BACKGROUND: Although coal miners are susceptible to dyslipidaemia owing to their highly risky and stressful working environment as well as unhealthy lifestyle, very few studies have focused on this issue thus far. Therefore, this study investigated the current epidemiological characteristics of dyslipidaemia among Chinese coal miners. METHODS: Demographic, anthropometric, and biochemical data were gathered from 4341 coal miners in China. Dyslipidaemia was diagnosed based on the serum lipid levels. Univariate and multivariate logistic regression analyses were used to assess the related risk factors for dyslipidaemia. RESULTS: The average concentrations of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were 5.01 +/- 0.93 mmol/L, 1.90 +/- 1.72 mmol/L, 1.21 +/- 0.35 mmol/L, and 3.15 +/- 0.80 mmol/L, respectively. Additionally, 38.08% of participants had a high TC level, 25.84% had a low HDL-C level, 35.08% had a high LDL-C level, and 40.46% had a high TG level. The overall prevalence of dyslipidaemia was 68.28% (95% CI: 66.90-69.66%). Factors associated with dyslipidaemia were age, sex, marital status, monthly family income, type of work, length of service, smoking status, smoking index, drinking status, alcohol consumption per day, elevated fasting glucose, hypertension, obesity and abdominal obesity. CONCLUSIONS: Our study's results indicated a very high prevalence of dyslipidaemia among Chinese coal miners and identified various risk factors for dyslipidaemia. PMID- 28835246 TI - The contribution of risk factors to socioeconomic inequalities in multimorbidity across the lifecourse: a longitudinal analysis of the Twenty-07 cohort. AB - BACKGROUND: Multimorbidity is a major challenge to health systems globally and disproportionately affects socioeconomically disadvantaged populations. We examined socioeconomic inequalities in developing multimorbidity across the lifecourse and investigated the contribution of five behaviour-related risk factors. METHODS: The Twenty-07 study recruited participants aged approximately 15, 35, and 55 years in 1987 and followed them up over 20 years. The primary outcome was development of multimorbidity (2+ health conditions). The relationship between five different risk factors (smoking, alcohol consumption, diet, body mass index (BMI), physical activity) and the development of multimorbidity was assessed. Social patterning in the development of multimorbidity based on two measures of socioeconomic status (area-based deprivation and household income) was then determined, followed by investigation of potential mediation by the five risk factors. Multilevel logistic regression models and predictive margins were used for statistical analyses. Socioeconomic inequalities in multimorbidity were quantified using relative indices of inequality and attenuation assessed through addition of risk factors. RESULTS: Multimorbidity prevalence increased markedly in all cohorts over the 20 years. Socioeconomic disadvantage was associated with increased risk of developing multimorbidity (most vs least deprived areas: odds ratio (OR) 1.46, 95% confidence interval (CI) 1.26-1.68), and the risk was at least as great when assessed by income (OR 1.53, 95% CI 1.25-1.87) or when defining multimorbidity as 3+ conditions. Smoking (current vs never OR 1.56, 1.36-1.78), diet (no fruit/vegetable consumption in previous week vs consumption every day OR 1.57, 95% CI 1.33-1.84), and BMI (morbidly obese vs healthy weight OR 1.88, 95% CI 1.42 2.49) were strong independent predictors of developing multimorbidity. A dose response relationship was observed with number of risk factors and subsequent multimorbidity (3+ risk factors vs none OR 1.91, 95% CI 1.57-2.33). However, the five risk factors combined explained only 40.8% of socioeconomic inequalities in multimorbidity development. CONCLUSIONS: Preventive measures addressing known risk factors, particularly obesity and smoking, could reduce the future multimorbidity burden. However, major socioeconomic inequalities in the development of multimorbidity exist even after taking account of known risk factors. Tackling social determinants of health, including holistic health and social care, is necessary if the rising burden of multimorbidity in disadvantaged populations is to be redressed. PMID- 28835247 TI - The modified south African triage scale system for mortality prediction in resource-constrained emergency surgical centers: a retrospective cohort study. AB - BACKGROUND: The South African Triage Scale (SATS) was developed to facilitate patient triage in emergency departments (EDs) and is used by Medecins Sans Frontieres (MSF) in low-resource environments. The aim was to determine if SATS data, reason for admission, and patient age can be used to develop and validate a model predicting the in-hospital risk of death in emergency surgical centers and to compare the model's discriminative power with that of the four SATS categories alone. METHODS: We used data from a cohort hospitalized at the Nap Kenbe Surgical Hospital in Haiti from January 2013 to June 2015. We based our analysis on a multivariate logistic regression of the probability of death. Age cutoff, reason for admission categorized into nine groups according to MSF classifications, and SATS triage category (red, orange, yellow, and green) were used as candidate parameters for the analysis of factors associated with mortality. Stepwise backward elimination was performed for the selection of risk factors with retention of predictors with P < 0.05, and bootstrapping was used for internal validation. The likelihood ratio test was used to compare the combined and restricted models. These models were also applied to data from a cohort of patients from the Kunduz Trauma Center, Afghanistan, to validate mortality prediction in an external trauma patients population. RESULTS: A total of 7618 consecutive hospitalized patients from the Nap Kenbe Hospital were analyzed. Variables independently associated with in-hospital mortality were age > 45 and < = 65 years (odds ratio, 2.04), age > 65 years (odds ratio, 5.15) and the red (odds ratio, 65.08), orange (odds ratio, 3.5), and non-trauma (odds ratio, 3.15) categories. The combined model had an area under the receiver operating characteristic curve (AUROC) of 0.8723 and an AUROC corrected for optimism of 0.8601. The AUROC of the model run on the external data-set was 0.8340. The likelihood ratio test was highly significant in favor of the combined model for both the original and external data-sets. CONCLUSIONS: SATS category, patient age, and reason for admission can be used to predict in-hospital mortality. This predictive model had good discriminative ability to identify ED patients at a high risk of death and performed better than the SATS alone. PMID- 28835248 TI - Long-term survival following hepatectomy, radiation, and chemotherapy for recurrent pancreatic carcinoma: a case report. AB - BACKGROUND: Recurrent pancreatic carcinoma (PC) is generally well known to have a poor prognosis. Cases in which multidisciplinary treatments have been remarkably effective are rare. CASE PRESENTATION: Herein, we reported a case of long-term survival following a combination of hepatectomy for a liver metastasis and radiation and chemotherapy for abdominal lymph node metastases after a curative pancreaticoduodenectomy for PC. A 51-year-old Japanese man underwent a pancreaticoduodenectomy following a PC diagnosis in December 2011. After the surgery, the patient received 16 cycles of gemcitabine (GEM) adjuvant chemotherapy. Abdominal computed tomography (CT) after therapy with GEM (17 months after surgery) revealed a 1-cm nodule in the liver, for which the patient underwent partial hepatectomy in May 2013. Approximately 1 month after the hepatectomy, the patient underwent adjuvant chemotherapy using tegafur/gimeracil/oteracil (S-1) for 12 months. Approximately 1 year after the second surgery, an abdominal CT scan detected the abdominal lymph node metastases, for which the patient underwent radiation therapy. After the radiation therapy, combination therapy with 5-fluorouracil(5-FU)/leucovorin plus oxaliplatin or irinotecan was started in September 2014; 59 cycles of this chemotherapy have been administered up to the time of this report. At 67 months after the pancreaticoduodenectomy and 50 months after the hepatectomy, the patient has remained healthy with no relapse or recurrent lesions. CONCLUSION: We have managed a long-term survivor who underwent hepatectomy for liver metastasis and radiation therapy and chemotherapy for abdominal lymph node metastases after curative pancreaticoduodenectomy for PC. PMID- 28835249 TI - Effects of exercise training on patients with lung cancer who underwent lung resection: a meta-analysis. AB - BACKGROUND: The efficacy of exercise training in patients with lung cancer after lung resection has not been well established yet. Therefore, we performed a meta analysis to investigate the efficiency of exercise training in patients with lung cancer after lung resection. METHODS: Several databases were searched for eligible randomised controlled trials (RCTs). The primary outcome was quality of life, and the secondary outcomes included 6-min walk distance (6MWD), forced expiratory volume in 1 s (FEV1) and postoperative complications (POCs). Weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs) were calculated by random-effects model. RESULTS: Six RCTs involving 438 patients were enrolled in this meta-analysis. The pooled WMDs of the scores were 2.41 (95% CI = -5.20 to 10.02; P = 0.54) and -0.46 (95% CI = -20.52 to 19.61; P = 0.96) for the physical and mental components of the 36-item short-form scale, respectively. The pooled WMDs were 23.50 m (95% CI = -22.04 to 69.03; P = 0.31) for 6MWD and 0.03 L (95% CI = -0.19 to 0.26; P = 0.76) for FEV1. Finally, the pooled RRs were 0.79 (95% CI = 0.41 to 1.53; P = 0.49) for POCs. CONCLUSIONS: Insufficient evidence is available to support the efficacy of exercise training in patients with lung cancer after lung resection. Further studies must confirm our findings and investigate the long-term effects of exercise training on patients with lung cancer following lung resection. PMID- 28835250 TI - Dark-blood late gadolinium enhancement without additional magnetization preparation. AB - BACKGROUND: This study evaluates a novel dark-blood late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) method, without using additional magnetization preparation, and compares it to conventional bright blood LGE, for the detection of ischaemic myocardial scar. LGE is able to clearly depict myocardial infarction and macroscopic scarring from viable myocardium. However, due to the bright signal of adjacent left ventricular blood, the apparent volume of scar tissue can be significantly reduced, or even completely obscured. In addition, blood pool signal can mimic scar tissue and lead to false positive observations. Simply nulling the blood magnetization by choosing shorter inversion times, leads to a negative viable myocardium signal that appears equally as bright as scar due to the magnitude image reconstruction. However, by combining blood magnetization nulling with the extended grayscale range of phase sensitive inversion-recovery (PSIR), a darker blood signal can be achieved whilst a dark myocardium and bright scar signal is preserved. METHODS: LGE was performed in nine male patients (63 +/- 11y) using a PSIR pulse sequence, with both conventional viable myocardium nulling and left ventricular blood nulling, in a randomized order. Regions of interest were drawn in the left ventricular blood, viable myocardium, and scar tissue, to assess contrast-to-noise ratios. Maximum scar transmurality, scar size, circumferential scar angle, and a confidence score for scar detection and maximum transmurality were also assessed. Bloch simulations were performed to simulate the magnetization levels of the left ventricular blood, viable myocardium, and scar tissue. RESULTS: Average scar-to blood contrast was significantly (p < 0.001) increased by 99% when nulling left ventricular blood instead of viable myocardium, while scar-to-myocardium contrast was maintained. Nulling left ventricular blood also led to significantly (p = 0.038) higher expert confidence in scar detection and maximum transmurality. No significant changes were found in scar transmurality (p = 0.317), normalized scar size (p = 0.054), and circumferential scar angle (p = 0.117). CONCLUSIONS: Nulling left ventricular blood magnetization for PSIR LGE leads to improved scar to-blood contrast and increased expert confidence in scar detection and scar transmurality. As no additional magnetization preparation is used, clinical application on current MR systems is readily available without the need for extensive optimizations, software modifications, and/or additional training. PMID- 28835251 TI - Noise-assisted multivariate empirical mode decomposition for multichannel EMG signals. AB - BACKGROUND: Ensemble Empirical Mode Decomposition (EEMD) has been popularised for single-channel Electromyography (EMG) signal processing as it can effectively extract the temporal information of the EMG time series. However, few papers examine the temporal and spatial characteristics across multiple muscle groups in relation to multichannel EMG signals. EXPERIMENT: The experimental data was obtained from the Center for Machine Learning and Intelligent Systems, University of California Irvine (UCI). The data was donated by the Nueva Granada Military University and the Technopark node Manizales in Colombia. The databases of 11 male subjects from the healthy group were taken into the study. The subjects undergo three exercise programs, leg extension from a sitting position (sitting), flexion of the leg up (standing), and gait (walking), while four electrodes were placed on biceps femoris (BF), vastus medialis (VM), rectus femoris (RF), and semitendinosus (ST). METHODS: Based on the experimental data, a comparative study is provided by assessing the Empirical Mode Decomposition (EMD)-based approaches, EEMD, Multivariate EMD (MEMD), and Noise-Assisted MEMD (NA-MEMD). The outcomes from these approaches are then quantitatively estimated on the basis of three criterions, the number of Intrinsic Mode Functions (IMFs), mode-alignment and mode-mixing. RESULTS: Both MEMD and NA-MEMD methods (except EEMD) can guarantee equal numbers of IMFs. For mode-alignment and mode-mixing, NA-MEMD is optimal compared with MEMD and EEMD, and MEMD is merely better than EEMD. CONCLUSIONS: This study proposes the NA-MEMD approach for multichannel EMG signal processing. This finding implies that NA-MEMD is effective for simultaneously analysing IMFs based frequency bands. It has a vital clinical implication in exploring the neuromuscular patterns that enable the multiple muscle groups to coordinate while performing the functional activities of daily living. PMID- 28835252 TI - Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats. AB - BACKGROUND: Neuroinflammation plays hypertensive roles in the uninjured autonomic nuclei of the central nervous system, while its mechanisms remain unclear. The present study is to investigate the effect of neuroinflammation on autophagy in the neurons of the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside. METHODS: Stress induced hypertension (SIH) was induced by electric foot-shock stressors with noise interventions in rats. Systolic blood pressure (SBP) and the power density of the low frequency (LF) component of the SAP spectrum were measured to reflect sympathetic vasomotor activity. Microglia activation and pro-inflammatory cytokines (PICs (IL-1beta, TNF-alpha)) expression in the RVLM were measured by immunoblotting and immunostaining. Autophagy and autophagic vacuoles (AVs) were examined by autophagic marker (LC3 and p62) expression and transmission electron microscopy (TEM) image, respectively. Autophagy flux was evaluated by RFP-GFP tandem fluorescent LC3 (tf-LC3) vectors transfected into the RVLM. Tissue levels of glutamate, gamma aminobutyric acid (GABA), and plasma levels of norepinephrine (NE) were measured by using high-performance liquid chromatography (HPLC) with electrochemical detection. The effects of the cisterna magna infused minocycline, a microglia activation inhibitor, on the abovementioned parameters were analyzed. RESULTS: SIH rats showed increased SBP, plasma NE accompanied by an increase in LF component of the SBP spectrum. Microglia activation and PICs expression was increased in SIH rats. TEM demonstrated that stress led to the accumulation of AVs in the RVLM of SIH rats. In addition to the Tf-LC3 assay, the concurrent increased level of LC3-II and p62 suggested the impairment of autophagic flux in SIH rats. To the contrary, minocycline facilitated autophagic flux and induced a hypotensive effect with attenuated microglia activation and decreased PICs in the RVLM of SIH rats. Furthermore, SIH rats showed higher levels of glutamate and lower level of GABA in the RVLM, while minocycline attenuated the decrease in GABA and the increase in glutamate of SIH rats. CONCLUSIONS: Collectively, we concluded that the neuroinflammation might impair autophagic flux and induced neural excitotoxicity in the RVLM neurons following SIH, which is involved in the development of SIH. PMID- 28835253 TI - Plasmodium falciparum HRP2 ELISA for analysis of dried blood spot samples in rural Zambia. AB - BACKGROUND: Dried blood spots are commonly used for sample collection in clinical and non-clinical settings. This method is simple, and biomolecules in the samples remain stable for months at room temperature. In the field, blood samples for the study and diagnosis of malaria are often collected on dried blood spot cards, so development of a biomarker extraction and analysis method is needed. METHODS: A simple extraction procedure for the malarial biomarker Plasmodium falciparum histidine-rich protein 2 (HRP2) from dried blood spots was optimized to achieve maximum extraction efficiency. This method was used to assess the stability of HRP2 in dried blood spots. Furthermore, 328 patient samples made available from rural Zambia were analysed for HRP2 using the developed method. These samples were collected at the initial administration of artemisinin-based combination therapy and at several points following treatment. RESULTS: An average extraction efficiency of 70% HRP2 with a low picomolar detection limit was achieved. In specific storage conditions HRP2 was found to be stable in dried blood spots for at least 6 months. Analysis of patient samples showed the method to have a sensitivity of 94% and a specificity of 89% when compared with microscopy, and trends in HRP2 clearance after treatment were observed. CONCLUSIONS: The dried blood spot ELISA for HRP2 was found to be sensitive, specific and accurate. The method was effectively used to assess biomarker clearance characteristics in patient samples, which prove it to be ideal for gaining further insight into the disease and epidemiological applications. PMID- 28835254 TI - Using routinely recorded data in the UK to assess outcomes in a randomised controlled trial: The Trials of Access. AB - BACKGROUND: In the UK, routinely recorded data may benefit prospective studies including randomised controlled trials (RCTs). In an on-going study, we aim to assess the feasibility of access and agreement of routinely recorded clinical and non-clinical data compared to data collected during a RCT using standard prospective methods. This paper will summarise available UK routinely recorded data sources and discuss our experience with the feasibility of accessing routinely recorded data for participants of a RCT before finally proposing recommendations for improving the access and implementation of routinely recorded data in RCTs. METHODS: Setting: the case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK, multicentre, phase IV RCT assessing the clinical and cost-effectiveness of antiepileptic drug treatments for newly diagnosed epilepsy. PARTICIPANTS: 98 participants have provided written consent to permit the request of routinely recorded data. Study procedures: routinely recorded clinical and non-clinical data were identified and data requested through formal applications from available data holders for the duration that participants have been recruited into SANAD II. The feasibility of accessing routinely recorded data during a RCT is assessed and recommendations for improving access proposed. RESULTS: Secondary-care clinical and socioeconomic data is recorded on a national basis and can be accessed, although there are limitations in the application process. Primary-care data are recorded by a number of organisations on a de-identified basis but access for specific individuals has not been feasible. Access to data recorded by non-clinical sources, including The Department for Work and Pensions and The Driving and Vehicle Licensing Agency, was not successful. CONCLUSIONS: Recommendations discussed include further research to assess the attributes of routinely recorded data, an assessment of public perceptions and the development of strategies to collaboratively improve access to routinely recorded data for research. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN30294119 . Registered on 3 July 2012. EudraCT No: 2012-001884-64. Registered on 9 May 2012. PMID- 28835255 TI - Association of experienced and evaluative well-being with health in nine countries with different income levels: a cross-sectional study. AB - BACKGROUND: It is important to know whether the relationships between experienced and evaluative well-being and health are consistent across countries with different income levels. This would allow to confirm whether the evidence found in high income countries is the same as in low- and middle-income countries and to suggest policy recommendations that are generalisable across countries. We assessed the association of well-being with health status; analysed the differential relationship that positive affect, negative affect, and evaluative well-being have with health status; and examined whether these relationships are similar across countries. METHODS: In this cross-sectional study, interviews were conducted amongst 53,269 adults from nine countries in Africa, Asia, Europe, and Latin America. Evaluative well-being was measured with a short version of the World Health Organization (WHO) Quality of Life instrument, and experienced well being was measured with the Day Reconstruction Method. Decrements in health were assessed with the 12-item version of WHO Disability Assessment Schedule 2.0. Block-wise linear regression and structural equation models were employed. RESULTS: Considering the overall sample, evaluative well-being was more strongly associated with health (beta = -0.35) than experienced well-being (beta = -0.14), and negative affect was more strongly associated with health (beta = 0.10) than positive affect (beta = -0.02). The relationship between health and well-being was similar across countries. Lower scores in evaluative well-being and a higher age were the factors more strongly related with a worse health. CONCLUSIONS: The different patterns observed across countries may be related to differences in the countries' gross domestic product, social protection system, economic situation, health care provision, lifestyle behaviours, or living conditions. The fact that evaluative well-being is more predictive of health than experienced well-being suggests that our level of satisfaction with our lives might be more important for our health than the actual emotions than we experience in our day-to-day lives and points out the need of interventions that improve the way people evaluate their lives. PMID- 28835256 TI - Preoperative radiotherapy improves survival in rectal signet-ring cell carcinoma a population-based study. AB - BACKGROUND: To investigate the clinical value of preoperative and postoperative radiotherapy (RT) in patients with rectal signet-ring cell carcinoma (SRCC). METHODS: Using the Surveillance, Epidemiology, and End Results program patients with stage II-III rectal SRCC were retrospectively included between 1988 and 2012. Univariate and multivariate Cox regression analyses were performed to analyze the effect of preoperative and postoperative RT on cause-specific survival (CSS). RESULTS: A total of 292 patients were included: 138 patients received preoperative RT, 101 patients received postoperative RT, and 53 patients underwent surgery alone. Overall, 5- and 10-year CSS was 43.8 and 37.6%, respectively. Preliminary survival analysis demonstrated that preoperative RT improved CSS versus surgery alone, especially in patients with stage III disease. Multivariate analysis demonstrated that preoperative RT was independent predictors for CSS in stage III rectal SRCC. CSS in preoperative and postoperative RT groups was comparable. CONCLUSIONS: Preoperative RT significantly improved survival outcomes in patients with stage III rectal SRCC. PMID- 28835258 TI - Acute hypopituitarism associated with periorbital swelling and cardiac dysfunction in a patient with pituitary tumor apoplexy: a case report. AB - BACKGROUND: Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. CASE PRESENTATION: An 83-year old Japanese man developed acute anterior hypopituitarism; he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. CONCLUSIONS: Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy. PMID- 28835257 TI - Long noncoding RNAs coordinate functions between mitochondria and the nucleus. AB - In animal cells, mitochondria are the primary powerhouses and metabolic factories. They also contain genomes and can produce mitochondrial-specific nucleic acids and proteins. To maintain homeostasis of the entire cell, an intense cross-talk between mitochondria and the nucleus, mediated by encoded noncoding RNAs (ncRNAs), as well as proteins, is required. Long ncRNAs (lncRNAs) contain characteristic structures, and they are involved in the regulation of almost every stage of gene expression, as well as being implicated in a variety of disease states, such as cancer. In the coordinated signaling system, several lncRNAs, transcribed in the nucleus but residing in mitochondria, play a key role in regulating mitochondrial functions or dynamics. For example, RMRP, a component of the mitochondrial RNase MRP, is important for mitochondrial DNA replication and RNA processing, and the steroid receptor RNA activator, SRA, is a key modulator of hormone signaling and is present in both the nucleus and mitochondria. Some RNA-binding proteins maybe play a role in the lncRNAs transport system, such as HuR, GRSF1, SHARP, SLIRP, PPR, and PNPASE. Furthermore, a series of nuclear DNA-encoded lncRNAs were implicated in mitochondria-mediated apoptosis, mitochondrial bioenergetics and biosynthesis, and glutamine metabolism. The mitochondrial genome can also encode a set of lncRNAs, and they are divided into three categories: (1) lncND5, lncND6, and lncCyt b RNA; (2) chimeric mitochondrial DNA-encoded lncRNAs; and (3) putative mitochondrial DNA encoded lncRNAs. It has been reported that the mitochondrial DNA-encoded lncRNAs appear to operate in the nucleus. The molecular mechanisms underlying trafficking of the mitochondrial DNA-encoded lncRNAs to the nucleus in mammals are only now beginning to emerge. In conclusion, both nuclear- and mitochondrial DNA-encoded lncRNAs mediate an intense intercompartmental cross-talk, which opens a rich field for investigation of the mechanism underlying the intercompartmental coordination and the maintenance of whole cell homeostasis. PMID- 28835259 TI - The therapeutic use of the dog in Spain: a review from a historical and cross cultural perspective of a change in the human-dog relationship. AB - In Spain, studies about traditional knowledge related to biodiversity have focused on vascular plants. For this reason, our review concentrates on the identification and inventory of zootherapeutic resources, particularly those involving the dog (Canis lupus familiaris Linnaeus, 1758) throughout the twentieth century to the present. A qualitative systematic review in the fields of ethnomedicine, ethnozoology and folklore was made. Automated searches in the most important databases and digital libraries were performed. All related works were examined thoroughly and information was obtained from 55 documentary sources. We have listed a total of 63 remedies to treat and/or prevent 49 human illnesses and conditions. In 20 of the documented reports the whole animal was used and the use of pups was recommended in 12 cases. Saliva was the healing element in 10 remedies, and faeces were the therapeutic basis for nine, while bitch's milk was for seven of them. Skin, fur and meat were next in significance. Currently, healing remedies based on the use of the dog are not part of Spanish ethnomedicine and considering them so would be ahistorical. Indeed, the custom of allowing a dog to lick one's wounds to assist in their healing and cicatrisation has survived in only a few groups of people. However, we can state that the ethnomedical use of the dog exists and has been transferred to "animal-assisted therapy". PMID- 28835260 TI - Genomic insights into potential interdependencies in microbial hydrocarbon and nutrient cycling in hydrothermal sediments. AB - BACKGROUND: Deep-sea hydrothermal vents are hotspots for productivity and biodiversity. Thermal pyrolysis and circulation produce fluids rich in hydrocarbons and reduced compounds that stimulate microbial activity in surrounding sediments. Several studies have characterized the diversity of Guaymas Basin (Gulf of California) sediment-inhabiting microorganisms; however, many of the identified taxa lack cultures or genomic representations. Here, we resolved the metabolic potential and community-level interactions of these diverse communities by reconstructing and analyzing microbial genomes from metagenomic sequencing data. RESULTS: We reconstructed 115 microbial metagenome assembled genomes comprising 27 distinct archaeal and bacterial phyla. The archaea included members of the DPANN and TACK superphyla, Bathyarchaeota, novel Methanosarcinales (GoM-Arc1), and anaerobic methane-oxidizing lineages (ANME-1). Among the bacterial phyla, members of the Bacteroidetes, Chloroflexi, and Deltaproteobacteria were metabolically versatile and harbored potential pathways for hydrocarbon and lipid degradation and a variety of respiratory processes. Genes encoding enzymes that activate anaerobic hydrocarbons for degradation were detected in Bacteroidetes, Chloroflexi, Latescibacteria, and KSB1 phyla, while the reconstructed genomes for most candidate bacteria phyla (Aminicenantes, Atribacteria, Omnitrophica, and Stahlbacteria) indicated a fermentative metabolism. Newly obtained GoM-Arc1 archaeal genomes encoded novel pathways for short-chain hydrocarbon oxidation by alkyl-coenzyme M formation. We propose metabolic linkages among different functional groups, such as fermentative community members sharing substrate-level interdependencies with sulfur- and nitrogen-cycling microbes. CONCLUSIONS: Overall, inferring the physiologies of archaea and bacteria from metagenome-assembled genomes in hydrothermal deep-sea sediments has revealed potential mechanisms of carbon cycling in deep-sea sediments. Our results further suggest a network of biogeochemical interdependencies in organic matter utilization, hydrocarbon degradation, and respiratory sulfur cycling among deep-sea-inhabiting microbial communities. PMID- 28835261 TI - Core Outcome Domains for early phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus. AB - BACKGROUND: The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is, therefore to, develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. METHODS: The 'Core Outcome Measures in Tinnitus: International Delphi' (COMIT'ID) study will use a mixed-methods approach that incorporates input from health care users at the pre-Delphi stage, a modified three-round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following Core Outcome Set publication. DISCUSSION: The COMIT'ID study aims to develop a Core Outcome Domain Set that is agreed as critically important for deciding whether a treatment for subjective tinnitus is effective. Such a recommendation would help to standardise future clinical trials worldwide and so we will determine if participation increases use of the Core Outcome Set in the long term. TRIAL REGISTRATION: This project has been registered (November 2014) in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative. PMID- 28835262 TI - Natural antibody responses to Plasmodium falciparum MSP3 and GLURP(R0) antigens are associated with low parasite densities in malaria patients living in the Central Region of Ghana. AB - BACKGROUND: Plasmodium falciparum genetic diversity and multiplicity of infection (MOI) are parasite features that have been suggested to influence the acquisition of protective immunity against malaria. This study sought to assess the relationship between MOI and parasite density (PD) in malaria patients living in the Central Region of Ghana and to determine whether naturally occurring antibody levels against P. falciparum GLURP (PF3D7_1035300) and MSP3 (PF3D7_1035400) antigens are associated with decreased parasite load. METHODS: Dried filter paper blood blots were obtained from children and adults diagnosed with uncomplicated P. falciparum malaria. Microscopy was used to estimate P. falciparum parasite density and polymerase chain reaction (PCR) amplification of the polymorphic regions of msp1 (PF3D7_0930300) and msp2 (PF3D7_0206800) was used for parasite genotyping and MOI determination. ELISA was used to measure the serum IgG concentration of R0 fragment of GLURP (GLURP(R0)) and MSP3 antibodies. RESULTS: All 115 samples were positive for P. falciparum by PCR using either the msp1 or msp2 genotyping primer sets. The most prevalent msp1 and msp2 alleles were KI and 3D7, respectively. The geometric mean (GM) for MOI determined by both msp1 and msp2 genotyping was 1.3 for the entire population and was generally higher in children than in adults. Seropositivity was estimated at 67 and 63% for GLURP(R0) and MSP3 antibodies, respectively, and antibody titers were negatively correlated with parasite density. CONCLUSIONS: The negative correlation between naturally occurring GLURP(R0) and MSP3 antibody levels and parasite density observed in this study suggest that augmenting the antibody response with the GMZ2 vaccine could enhance protection in the Central Region of Ghana. PMID- 28835263 TI - Revisiting the in vivo GlnR-binding sites at the genome scale in Bacillus subtilis. AB - BACKGROUND: In Bacillus subtilis, two major transcriptional factors, GlnR and TnrA, are involved in a sophisticated network of adaptive responses to nitrogen availability. GlnR was reported to repress the transcription of the glnRA, tnrA and ureABC operons under conditions of excess nitrogen. As GlnR and TnrA regulators share the same DNA binding motifs, a genome-wide mapping of in vivo GlnR-binding sites was still needed to clearly define the set of GlnR/TnrA motifs directly bound by GlnR. METHODS: We used chromatin immunoprecipitation coupled with hybridization to DNA tiling arrays (ChIP-on-chip) to identify the GlnR DNA binding sites, in vivo, at the genome scale. RESULTS: We provide evidence that GlnR binds reproducibly to 61 regions on the chromosome. Among those, 20 regions overlap the previously defined in vivo TnrA-binding sites. In combination with real-time in vivo transcriptional profiling using firefly luciferase, we identified the alsT gene as a new member of the GlnR regulon. Additionally, we characterized the GlnR secondary regulon, which is composed of promoter regions harboring a GlnR/TnrA box and bound by GlnR in vivo. However, the growth conditions revealing a GlnR-dependent regulation for this second category of genes are still unknown. CONCLUSIONS: Our findings show an extended overlap between the GlnR and TnrA in vivo binding sites. This could allow efficient and fine tuning of gene expression in response to nitrogen availability. GlnR appears to be part of complex transcriptional regulatory networks, which involves interactions between different regulatory proteins. PMID- 28835264 TI - Extensive intramuscular manifestation of sarcoidosis with initially missed diagnosis and delayed therapy: a case report. AB - BACKGROUND: Sarcoidosis is a multisystemic granulomatous disorder, which in nearly all cases involves the lungs and other organs. Isolated forms of sarcoidosis within the muscles, but without lung involvement, are extremely rare and can lead to delayed or even false diagnosis. CASE PRESENTATION: A 52-year-old white, Swiss man presented with painful arm cramps and a history of symptoms over the previous 3 years. In the initial clinical investigation, our patient also showed edema in both legs without any other complaints. After performing an magnetic resonance imaging scan of his extremities and a positron emission tomography/computed tomography scan, diffuse myositis was described. The subsequent muscle biopsy provided the surprising diagnosis of muscle sarcoidosis, without involvement of the lungs or any other organ. After starting therapy with glucocorticoids, his symptoms improved immediately. CONCLUSIONS: Sarcoidosis is a common disorder, which in most cases affects the lungs. In this case report an isolated sarcoidosis is described without lung involvement, but with involvement of the muscles of the extremities and the trunk. Reported cases of sarcoidosis only involving skeletal muscle and without lung involvement are extremely rare. Radiologists should consider this presentation of sarcoidosis to avoid delayed diagnosis and therapy. PMID- 28835266 TI - Medicinal and commercial uses of ostrich products in Tanzania. AB - BACKGROUND: Traditional communities have been utilizing animal products for numerous purposes and have for a long time contributed to the accumulation of world knowledge. Local people in Tanzania and elsewhere in Africa, have been using birds including ostriches as pets or their products such as meat, eggs as food; their body parts such as feathers, bones and hide for ornaments but more importantly have used such products in traditional medicine and rituals. Nevertheless, there is a general lack of information about the differences that exist between local people with different cultures, and the best use of such products to improve their livelihoods. This study aimed to determine the use of ostrich products among people residing around Serengeti National Park and explore the potential of improving livelihoods through game ranching. METHODS: Use of the products was compared between that of agriculturalists with long hunting traditions in the Serengeti District to the west of Serengeti National Park (SNP) and the largely pastoral community in the Ngorongoro District to the east by using semistructured questionnaires in June 2006. RESULTS: A total of 115 respondents were interviewed, and the majority (74.5%) in the Serengeti district admitted that ostriches were mainly hunted for their products by snares, while in the Ngorongoro district, 98.2% of the respondents said that villagers only gathered products such as feathers and eggs. Ostriches were hunted for food, ornamentation, medical and economic purposes, and eggs and oil, which are believed to have medicinal properties, were used for the treatment of various ailments, including asthma. This indigenous knowledge of the medicinal value of ostrich products must be integrated with scientific knowledge to prove the supposed medical efficacy of the products. Ostrich products also had market value and were thus sold to the villagers. CONCLUSION: Since it has been found that ostrich products are commercially used, legal establishment of markets through game ranching, might improve local livelihood while simultaneously promoting the conservation of ostriches, whose populations are declining, by reducing hunting pressure. Ostrich farming and conservation education programs are recommended. PMID- 28835265 TI - Conservation and divergence of small RNA pathways and microRNAs in land plants. AB - BACKGROUND: As key regulators of gene expression in eukaryotes, small RNAs have been characterized in many seed plants, and pathways for their biogenesis, degradation, and action have been defined in model angiosperms. However, both small RNAs themselves and small RNA pathways are not well characterized in other land plants such as lycophytes and ferns, preventing a comprehensive evolutionary perspective on small RNAs in land plants. RESULTS: Using 25 representatives from major lineages of lycophytes and ferns, most of which lack sequenced genomes, we characterized small RNAs and small RNA pathways in these plants. We identified homologs of DICER-LIKE (DCL), ARGONAUTE (AGO), and other genes involved in small RNA pathways, predicted over 2600 conserved microRNA (miRNA) candidates, and performed phylogenetic analyses on small RNA pathways as well as miRNAs. Pathways underlying miRNA biogenesis, degradation, and activity were established in the common ancestor of land plants, but the 24-nucleotide siRNA pathway that guides DNA methylation is incomplete in sister species of seed plants, especially lycophytes. We show that the functional diversification of key gene families such as DCL and AGO as observed in angiosperms occurred early in land plants followed by parallel expansion of the AGO family in ferns and angiosperms. We uncovered a conserved AGO subfamily absent in angiosperms. CONCLUSIONS: Our phylogenetic analyses of miRNAs in bryophytes, lycophytes, ferns, and angiosperms refine the time-of-origin for conserved miRNA families as well as small RNA machinery in land plants. PMID- 28835267 TI - Workplace violence in a tertiary care Israeli hospital - a systematic analysis of the types of violence, the perpetrators and hospital departments. AB - BACKGROUND: Worldwide, there is a widespread and disturbing pattern of violence towards healthcare workers. However, violent occurrences in Israeli hospitals have often been unrecognized and underreported. Moreover, most studies have not sufficiently differentiated among the different types of violence. To examine the different types of violence experienced by nurses and physicians, the types of perpetrators and the specialty fields involved. METHODS: A quantitative questionnaire was used to assess the incidence of a "basket" of violent behaviors, divided into eight types of violent manifestations. The study population consisted of 729 physicians and nurses in a variety of hospital divisions and departments (surgery, oncology, intensive care, ambulatory services including day care, and emergency room) in a large general hospital. Six hundred seventy-eight of them responded to the survey for a response rate of 93%; about two thirds of respondents (446) were nurses and about one third (232) were physicians. The questionnaires were completed during staff meetings and through subsequent follow-up efforts. RESULTS: In the 6 months preceding the survey, the respondents experienced about 700 incidents of passive aggressive behavior, 680 of verbal violence and 81 of sexual harassment. Types of violence differed between patients and companions; for example, the latter exhibited more verbal, threatening and passive aggressive behaviors. Violence was reported in all departments (ranging from 52-96%), with the departments most exposed to violence being the emergency room and outpatient clinics. Nurses in the emergency room were 5.5 times at a higher risk of being exposed to violence than nurses in the internal medicine department. Nurses were exposed to violence almost twice as much as physicians. There was a positive association between the physician's rank and his/her exposure to violence. A multiple regression model found that being older reduced the risk of being exposed to violence, for both physicians and nurses. CONCLUSIONS: These findings suggest that uniform definitions of a range of different violent behaviors and assessments of their prevalence are important to creating an improved discourse about hospital violence in both research and operational settings. The study findings could assist policy makers in the Israeli healthcare system in implementing interventions on a national level and can promote leaders' commitment to violence prevention and management. This is an important contribution, as executive commitment is necessary and critical for the necessary organizational changes to occur. PMID- 28835268 TI - Perioperative antibiotic prophylaxis in the treatment of acute cholecystitis (PEANUTS II trial): study protocol for a randomized controlled trial. AB - BACKGROUND: The additional value of perioperative antibiotic prophylaxis in preventing infectious complications after emergency cholecystectomy for acute cholecystitis is a much-debated subject in the surgical community. Evidence-based guidelines are lacking, and consequently the use of antibiotic prophylaxis varies greatly among surgeons and hospitals. Recently, high-level evidence became available demonstrating that postoperative antibiotic prophylaxis in patients with acute cholecystitis does not reduce the risk of infectious complications. Preoperative antibiotic prophylaxis in relation to the risk of infectious complications, however, has never been studied. METHODS: The PEANUTS II trial is a randomized, controlled, multicenter, open-label noninferiority trial whose aim is to determine the utility of preoperative antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. Patients with mild or moderate acute cholecystitis, as defined according the Tokyo Guidelines, will be randomly assigned to a single preoperative dose of antibiotic prophylaxis (2000 mg of first-generation cephalosporin delivered intravenously) or no antibiotic prophylaxis before emergency cholecystectomy. The primary endpoint is a composite endpoint consisting of all postoperative infectious complications occurring during the first 30 days after surgery. Secondary endpoints include all the individual components of the primary endpoint, all other complications, duration of hospital stay, and total costs. The hypothesis is that the absence of antibiotic prophylaxis is noninferior to the presence of antibiotic prophylaxis. A noninferiority margin of 10% is assumed. With a 1-sided risk of 2.5% and a power of 80%, a total of 454 subjects will have to be included. Analysis will be performed according to the intention-to-treat principle. DISCUSSION: The PEANUTS II trial will provide evidence-based advice concerning the utility of antibiotic prophylaxis in patients undergoing emergency cholecystectomy for acute calculous cholecystitis. TRIAL REGISTRATION: Netherlands Trial Register, NTR5802 . Registered on 4 June 2016. PMID- 28835269 TI - Insecticide resistance status of three malaria vectors, Anopheles gambiae (s.l.), An. funestus and An. mascarensis, from the south, central and east coasts of Madagascar. AB - BACKGROUND: Insecticide-based vector control, which comprises use of insecticide treated bed nets (ITNs) and indoor residual spraying (IRS), is the key method to malaria control in Madagascar. However, its effectiveness is threatened as vectors become resistant to insecticides. This study investigated the resistance status of malaria vectors in Madagascar to various insecticides recommended for use in ITNs and/or IRS. METHODS: WHO tube and CDC bottle bioassays were performed on populations of Anopheles gambiae (s.l.), An. funestus and An. mascarensis. Adult female An. gambiae (s.l.) mosquitoes reared from field-collected larvae and pupae were tested for their resistance to DDT, permethrin, deltamethrin, alpha cypermethrin, lambda-cyhalothrin, bendiocarb and pirimiphos-methyl. Resting An. funestus and An. mascarensis female mosquitoes collected from unsprayed surfaces were tested against permethrin, deltamethrin and pirimiphos-methyl. The effect on insecticide resistance of pre-exposure to the synergists piperonyl-butoxide (PBO) and S,S,S-tributyl phosphorotrithioate (DEF) also was assessed. Molecular analyses were done to identify species and determine the presence of knock-down resistance (kdr) and acetylcholinesterase resistance (ace-1 R ) gene mutations. RESULTS: Anopheles funestus and An. mascarensis were fully susceptible to permethrin, deltamethrin and pirimiphos-methyl. Anopheles gambiae (s.l.) was fully susceptible to bendiocarb and pirimiphos-methyl. Among the 17 An. gambiae (s.l.) populations tested for deltamethrin, no confirmed resistance was recorded, but suspected resistance was observed in two sites. Anopheles gambiae (s.l.) was resistant to permethrin in four out of 18 sites (mortality 68-89%) and to alpha cypermethrin (89% mortality) and lambda-cyhalothrin (80% and 85%) in one of 17 sites, using one or both assay methods. Pre-exposure to PBO restored full susceptibility to all pyrethroids tested except in one site where only partial restoration to permethrin was observed. DEF fully suppressed resistance to deltamethrin and alpha-cypermethrin, while it partially restored susceptibility to permethrin in two of the three sites. Molecular analysis data suggest absence of kdr and ace-1 R gene mutations. CONCLUSION: This study suggests involvement of detoxifying enzymes in the phenotypic resistance of An. gambiae (s.l.) to pyrethroids. The absence of resistance in An. funestus and An. mascarensis to pirimiphos-methyl and pyrethroids and in An. gambiae (s.l.) to carbamates and organophosphates presents greater opportunity for managing resistance in Madagascar. PMID- 28835270 TI - Coming back from the edge: a qualitative study of a professional support unit for junior doctors. AB - BACKGROUND: It is known that many trainee doctors around the world experience work satisfaction but also considerable work stress in the training period. Such stress seems to be linked to multiple factors including workload, level of support and growing cultural inculcation into unwillingness to show any personal or professional weakness. In the United Kingdom, junior doctors are qualified medical practitioners who have gained a degree in Medicine and are now working while training to become a specialist (consultant) or a general practitioner. The period of medical training can be particularly stressful for some UK junior doctors, in common with their counterparts in other countries. UK Postgraduate Medical Deaneries provide support for those who need it via Professional Support Units (PSUs); however little is known about the perceptions and experiences of the doctors who access and utilise this support. This study aimed to generate qualitative insight into how the (PSU) provided by one UK Deanery is experienced by the trainees who accessed it. We aimed to investigate whether such experience intersects with the progressive socialisation of trainee doctors into the notion that doctors do not get ill. METHODS: Through in-depth telephone interviews with eight female junior doctors, we explored the benefits and problems associated with using a PSU with reference to the formation of trainee doctors' professional identities, and conducted a thematic analysis. RESULTS: Themes identified illustrate the process of accepting, accessing and benefiting from PSU support. These are: Medical identity intact (it will never happen to me); Denial of disrupted medical identity; Being on the edge: accepting help; Role of PSU in 'recovery' process; Repaired identity / coming back from the edge; Different ways to be a doctor. The gendered sample occurred simply as it was females who responded to study invitations. Whilst we present some related aspects (such as "manning up" as part of keeping going), analyses of this small sample showed that medical identity as a doctor in training was more salient than a gendered experience of help seeking in this study. CONCLUSIONS: This study highlights the initial reluctance of female junior doctors to seek help from the PSU, as acknowledging their own difficulties spoiled their identity as a competent doctor. However, once engaged with the PSU, the findings exemplify its role in repairing medical identity, by offering different and acceptable ways to be a doctor. We interpret these findings within Goffman's theoretical framework of stigma conferring a spoiled identity on recipients, and how this may then be repaired. Reducing the stigma attached to initial help-seeking among junior doctors is crucial to increase ease of access to the PSU and to improve the experiences of doctors who encounter challenges during their training. PMID- 28835271 TI - Randomized supplementation of 4000 IU vitamin D3 daily vs placebo on the prevalence of anemia in advanced heart failure: the EVITA trial. AB - BACKGROUND: Low 25-hydroxyvitamin D (25OHD) levels (< 75 nmol/l) are inversely associated with anemia prevalence. Since anemia and low 25OHD levels are common in patients with heart failure (HF), we aimed to investigate whether vitamin D supplementation can reduce anemia prevalence in advanced HF. METHODS: EVITA (Effect of Vitamin D on Mortality in Heart Failure) is a randomized, placebo controlled clinical trial in patients with initial 25OHD levels < 75 nmol/l. Participants received either 4000 IU vitamin D3 daily or a matching placebo for 36 months. A total of 172 patients (vitamin D group: n = 85; placebo group: n = 87) were investigated in this pre-specified secondary data analysis. Hemoglobin (Hb) and other hematological parameters were measured at baseline and study termination. Assessment of between-group differences in anemia prevalence and Hb concentrations was performed at study termination, while adjusting for baseline differences. RESULTS: In the vitamin D and placebo group, baseline proportions of patients with anemia (Hb < 12.0 g/dL in females and < 13.0 g/dL in males) were 17.2% and 10.6%, respectively (P = 0.19). At study termination, the proportion of patients with anemia in the vitamin D and placebo groups was 32.2% and 31.8%, respectively (P > 0.99). There was no between-group difference in change in the Hb concentrations (- 0.04 g/dL [95%CI:-0.53 to 0.45 g/dL]; P = 0.87). Results regarding anemia risk and Hb concentrations were similar in the subgroup of patients with chronic kidney disease (vitamin D group: n = 26; placebo group: n = 23). Moreover, results did not differ substantially when data analysis was restricted to patients with deficient baseline 25OHD levels. CONCLUSIONS: A daily vitamin D supplement of 4000 IU did not reduce anemia prevalence in patients with advanced HF. Data challenge the clinical relevance of vitamin D supplementation to increase Hb levels. TRIAL REGISTRATION: The study was registered at EudraCT (No. 2010-020793-42) and clinicaltrials.gov ( NCT01326650 ). PMID- 28835272 TI - Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. AB - BACKGROUND: Neuroinflammation is an important secondary injury mechanism that has dual beneficial and detrimental roles in the pathophysiology of traumatic brain injury (TBI). Compelling data indicate that statins, a group of lipid-lowering drugs, also have extensive immunomodulatory and anti-inflammatory properties. Among statins, atorvastatin has been demonstrated as a neuroprotective agent in experimental TBI; however, there is a lack of evidence regarding its effects on neuroinflammation during the acute phase of TBI. The current study aimed to evaluate the effects of atorvastatin therapy on modulating the immune reaction, and to explore the possible involvement of peripheral leukocyte invasion and microglia/macrophage polarization in the acute period post-TBI. METHODS: C57BL/6 mice were subjected to TBI using a controlled cortical impact (CCI) device. Either atorvastatin or vehicle saline was administered orally starting 1 h post TBI for three consecutive days. Short-term neurological deficits were evaluated using the modified neurological severity score (mNSS) and Rota-rod. Brain invading leukocyte subpopulations were analyzed by flow cytometry and immunohistochemistry. Pro- and anti-inflammatory cytokines and chemokines were examined using enzyme-linked immunosorbent assay (ELISA). Markers of classically activated (M1) and alternatively activated (M2) microglia/macrophages were then determined by quantitative real-time PCR (qRT-PCR) and flow cytometry. Neuronal apoptosis was identified by double staining of terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) staining and immunofluorescence labeling for neuronal nuclei (NeuN). RESULTS: Acute treatment with atorvastatin at doses of 1 mg/kg/day significantly reduced neuronal apoptosis and improved behavioral deficits. Invasions of T cells, neutrophils and natural killer (NK) cells were attenuated profoundly after atorvastatin therapy, as was the production of pro-inflammatory cytokines (IFN-gamma and IL-6) and chemokines (RANTES and IP-10). Notably, atorvastatin treatment significantly increased the proportion of regulatory T cells (Tregs) in both the peripheral spleen and brain, and at the same time, increased their main effector cytokines IL-10 and TGF beta1. We also found that atorvastatin significantly attenuated total microglia/macrophage activation but augmented the M2/M1 ratio by both inhibiting M1 polarization and enhancing M2 polarization. CONCLUSIONS: Our data demonstrated that acute atorvastatin administration could modulate post-TBI neuroinflammation effectively, via a mechanism that involves altering peripheral leukocyte invasion and the alternative polarization of microglia/macrophages. PMID- 28835273 TI - Meausures of organizational characteristics associated with adoption and/or implementation of innovations: A systematic review. AB - BACKGROUND: This paper identifies and describes measures of constructs relevant to the adoption or implementation of innovations (i.e., new policies, programs or practices) at the organizational-level. This work is intended to advance the field of dissemination and implementation research by aiding scientists in the identification of existing measures and highlighting methodological issues that require additional attention. METHODS: We searched for published studies (1973 2013) in 11 bibliographic databases for quantitative, empirical studies that presented outcome data related to adoption and/or implementation of an innovation. Included studies had to assess latent constructs related to the "inner setting" of the organization, as defined by the Consolidated Framework for Implementation Research. RESULTS: Of the 76 studies included, most (86%) were cross sectional and nearly half (49%) were conducted in health care settings. Nearly half (46%) involved implementation of evidence-based or "best practice" strategies; roughly a quarter (26%) examined use of new technologies. Primary outcomes most often assessed were innovation implementation (57%) and adoption (34%); while 4% of included studies assessed both outcomes. There was wide variability in conceptual and operational definitions of organizational constructs. The two most frequently assessed constructs included "organizational climate" and "readiness for implementation." More than half (55%) of the studies did not articulate an organizational theory or conceptual framework guiding the inquiry; about a third (34%) referenced Diffusion of Innovations theory. Overall, only 46% of articles reported psychometric properties of measures assessing latent organizational characteristics. Of these, 94% (33/35) described reliability and 71% (25/35) reported on validity. CONCLUSIONS: The lack of clarity associated with construct definitions, inconsistent use of theory, absence of standardized reporting criteria for implementation research, and the fact that few measures have demonstrated reliability or validity were among the limitations highlighted in our review. Given these findings, we recommend that increased attention be devoted toward the development or refinement of measures using common psychometric standards. In addition, there is a need for measure development and testing across diverse settings, among diverse population samples, and for a variety of types of innovations. PMID- 28835274 TI - Primary care in an unstable security, humanitarian, economic and political context: the Kurdistan Region of Iraq. AB - BACKGROUND: This study presents a descriptive synthesis of Kurdistan Region of Iraq's (KRI) primary care system, which is undergoing comprehensive primary care reforms within the context of a cross-cutting structural economic adjustment program and protracted security, humanitarian, economic and political crises. METHODS: The descriptive analysis used a framework operationalizing Starfield's classic primary care model for health services research. A scoping review was performed using relevant sources, and expert consultations were conducted for completing and validating data. RESULTS: The descriptive analysis presents a complex narrative of a primary care system undergoing classical developmental processes of transitioning middle-income countries. The system is simultaneously under tremendous pressure to adapt to the continuously changing, complex and resource-intensive needs of sub-populations exhibiting varying morbidity patterns, within the context of protracted security, humanitarian, economic, and political crises. Despite exhibiting significant resilience in the face of the ongoing crises, the continued influx of IDPs and Syrian refugees, coupled with extremely limited resources and weak governance at policy, organizational and clinical levels threaten the sustainability of KRI's public primary care system. Diverse trajectories to the strengthening and development of primary care are underway by local and international actors, notably the World Bank, RAND Corporation, UN organizations and USAID, focusing on varying imperatives related to the protracted humanitarian and economic crises. CONCLUSIONS: The convergence, interaction and outcomes of the diverse initiatives and policy approaches in relation to the development of KRI's primary care system are complex and highly uncertain. A common vision of primary care is required to align resources, initiatives and policies, and to enable synergy between all local and international actors involved in the developmental and humanitarian response. Further research that integrates the knowledge synthesized in this article, and enables actors in KRI to learn from their own experiences and efforts, along with those of other jurisdictions, would be invaluable towards the ongoing development of primary care. PMID- 28835275 TI - New trend in colorectal cancer in Germany: are young patients at increased risk for advanced colorectal cancer? AB - BACKGROUND: The role of colonoscopy in the screening of colorectal cancer (CRC) has been unequivocally established. In Germany, screening colonoscopy with full insurance reimbursement is available for individuals aged 55 and above, and/or for persons with well-known risk factors for CRC. However, advanced CRC is not uncommon in individuals below 55 years. This study was designed to investigate the incidence of advanced CRC in patients < 55 years. METHODS: A retrospective analysis of data from a prospectively maintained CRC database of a university hospital in Germany was performed. Using the recommended age for screening colonoscopy as cutoff, the study population was divided into two groups: < 55 years (study group) and >= 55 years (control group). Both groups were compared with regard to the extent of CRC using the UICC stages. Only surgically managed patients were included for analysis. Advanced CRC was defined as UICC stage III or IV. RESULTS: Complete follow-up data was available for 609 patients treated between 2009 and 2013. The study group included 83 patients, 42 females and 41 males with a median age of 48.0 +/- 10 years, while the control group was made up of 526 patients, 230 females and 296 males with a median age of 75.5 +/- 8.3 years. Both groups were comparable with regard to gender distribution, p = 0.24. Significantly more patients from the study group were diagnosed with advanced CRC in comparison to the control group, 56.6 vs. 43.9%, p = 0.03. There was no statistically significant difference amongst both groups with respect to cancer related mortality, 10.8 vs. 12.5%, p = 0.66. CONCLUSION: Patients below the recommended age for screening colonoscopy might be at increased risk for advanced CRC. There is need to decrease the recommended age for screening colonoscopy to prevent CRC or enable an early diagnosis in patients below 55 years. PMID- 28835276 TI - Role enactment of facilitation in primary care - a qualitative study. AB - BACKGROUND: Facilitation is a widely used implementation method in quality improvement. Reviews reveal a variety of understandings of facilitation and facilitator roles. Research suggests that facilitation interventions should be flexible and tailored to the needs and circumstances of the receiving organisations. The complexity of the facilitation field and diversity of potential facilitator roles fosters a need to investigate in detail how facilitation is enacted. Hence, the purpose of this study was to explore the enactment of external peer facilitation in general practice in order to create a stronger basis for discussing and refining facilitation as an implementation method. METHODS: The facilitation intervention under study was conducted in general practice in the Capital Region of Denmark in order to support an overall strategy for implementing chronic disease management programmes. We observed 30 facilitation visits in 13 practice settings and had interviews and focus groups with facilitators. We applied an explorative approach in data collection and analysis, and conducted an inductive thematic analysis. RESULTS: The facilitators mainly enacted four facilitator roles: teacher, super user, peer and process manager. Thus, apart from trying to keep the process structured and focused the facilitators were engaged in didactic presentations and hands-on learning as they tried to pass on factual information and experienced based knowledge as well as their own enthusiasm towards implementing practice changes. While occasional challenges were observed with enacting these roles, more importantly we found that a coaching based role which was also envisioned in the intervention design was only sparsely enacted meaning that the facilitators did not enable substantial internal group discussions during their facilitation visits. CONCLUSION: Facilitation is a complex phenomenon both conceptually and in practice. This study complements existing research by showing how facilitation can be enacted in various ways and by suggesting that some facilitator roles are more likely to be enacted than others, depending on the context and intervention design and the professional background of the facilitators. This complexity requires caution when comparing and evaluating facilitation studies and highlights a need for precision and clarity about goals, roles, and competences when designing, conducting, and reporting facilitation interventions. PMID- 28835277 TI - Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice. AB - BACKGROUND: A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA. METHODS: MIA (0.3 mg/10 MUl) was injected into the right knee joint of male C57BL/6 mice (20-34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.) and serpinA1 (10 MUg i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 MUg i.p. days 0 to 1) and PAR2 knockout animals. RESULTS: MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control). CONCLUSIONS: Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets. PMID- 28835278 TI - Alpha1A-adrenoceptor antagonist improves underactive bladder associated with diabetic cystopathy via bladder blood flow in rats. AB - BACKGROUND: Patients with diabetes experience lower urinary tract symptoms. Cystopathy may evolve into underactive bladder (UAB), depending on the degree and duration of the symptoms. In the present study, we aimed to investigate the effects of silodosin, an alpha1A-adrenoceptor (AR) antagonist, on UAB in a rat model of diabetes mellitus (DM). METHODS: Female Sprague-Dawley rats (6 weeks old) were administered streptozotocin (STZ) (50 mg/kg, i.v.) to establish a DM model. One week after STZ administration, vehicle or silodosin (0.3 or 1 mg/kg/day) was delivered subcutaneously through an osmotic pump. Nine weeks after STZ administration (8 weeks after drug treatment), a catheter was implanted into the bladder under urethane anesthesia. After the measurement of emptied bladder blood flow (BBF), saline was continuously infused into the bladder and intravesical pressure and micturition volume were measured. In another experiment, the bladder was isolated and nerve markers were quantified. RESULTS: A cystometrogram showed that bladder capacity (BC), residual volume (RV), and bladder extension (BC/bladder weight) increased by 7.43, 10.47, and 3.59 times, respectively, in vehicle rats in comparison with normal rats. These findings suggested the occurrence of UAB-like symptoms in this model. Silodosin (1 mg/kg/day) inhibited the increase in BC and RV by 49.0% and 46.8%, respectively, and caused a decrease in BBF of approximately 25.5% (when the difference between normal and vehicle was set as 100%) in STZ rats. The nerve marker expression levels tended to be decreased in the bladders of STZ rats and these effects were ameliorated by silodosin. CONCLUSIONS: The STZ rats showed increased bladder extension and RV, symptoms that were suggestive of UAB, and these symptoms were ameliorated by silodosin. These results suggested that the alpha1A-AR antagonist would be useful for the prevention or treatment of UAB. PMID- 28835279 TI - Abeta accumulation causes MVB enlargement and is modelled by dominant negative VPS4A. AB - BACKGROUND: Alzheimer's disease (AD)-linked beta-amyloid (Abeta) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Abeta accumulation and tau pathology are incompletely understood. METHODS: MVB size and Abeta fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy. MVB-dysfunction, modelled by expression of dominant negative VPS4A (dnVPS4A), was analysed by biochemical methods and exosome isolation. RESULTS: Here we show that AD transgenic neurons have enlarged MVBs compared to wild type neurons. Uptake of exogenous Abeta also leads to enlarged MVBs in wild type neurons and generates fibril-like structures in endocytic vesicles. With time fibrillar oligomers/fibrils can extend out of the endocytic vesicles and are eventually detectable extracellularly. Further, endosomal sorting complexes required for transport (ESCRT) components were found associated with amyloid plaques in AD transgenic mice. The phenotypes previously reported in AD transgenic neurons, with net increased intracellular levels and reduced secretion of Abeta, were mimicked by blocking recycling of ESCRT-III by dnVPS4A. DnVPS4A further resembled AD pathology by increasing tau phosphorylation at serine 396 and increasing markers of autophagy. CONCLUSIONS: We demonstrate that Abeta leads to MVB enlargement and that amyloid fibres can form within the endocytic pathway of neurons. These results are consistent with the scenario of the endosome-lysosome system representing the site of initiation of Abeta aggregation. In turn, a dominant negative form of the CHMP2B-interacting protein VPS4A, which alters MVBs, leads to accumulation and aggregation of Abeta as well as tau phosphorylation, mimicking the cellular changes in AD. PMID- 28835280 TI - Epidemiological study of suicide by physical methods between 1993 and 2013 in Ilam province, Iran. AB - BACKGROUND: Suicide by aggressive physical methods such as firearms, hanging, and jumping is well known; however, different factors may influence a person while selecting a particular method. The aim of this study was to investigate the epidemiological factors involved in the selection and use of different physical methods for suicide over a long-term period in Ilam province, Iran. METHODS: The present study was conducted retrospectively between 1993 and 2013 using recorded data from a comprehensive system for registration of suicide attempts in Ilam University of Medical Sciences. The epidemiological characteristics included person, time and place variables, and the outcomes of the suicide attempts. The chi square, univariate and multivariate logistic regression models were used for data analysis. RESULTS: Totally, 1516 suicide attempts were evaluated (the annual incidence rate: 19/100,000 individuals). The most commonly used suicide method in females (88.4%) and males (38.9%) was self-immolation. Furthermore, the annual incidence rate among males and females was within the age group of 15-24 years (24.6 and 47.8/100,000 individuals). The risk of death by suicide in the age group of 55-64 years was 2.93 compared with the age group of 10-14 years (OR = 2.93; 95% CI = 0.64-13.54, P = 0.168). CONCLUSION: This study revealed that self immolation was the most selected physical method of suicide and had the highest incidence rate, and inflicted the survivors with severe physical and mental complications. In order to reduce the use of physical methods, especially self immolation, life skills training becomes more important than ever. PMID- 28835281 TI - Lysosomal processing of progranulin. AB - BACKGROUND: Mutations resulting in progranulin (PGRN) haploinsufficiency cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. PGRN is localized to the lysosome and important for proper lysosome function. However, the metabolism of PGRN in the lysosome is still unclear. RESULTS: Here, we report that PGRN is processed into ~10 kDa peptides intracellularly in multiple cell types and tissues and this processing is dependent on lysosomal activities. PGRN endocytosed from the extracellular space is also processed in a similar manner. We further demonstrated that multiple cathepsins are involved in PGRN processing and cathepsin L cleaves PGRN in vitro. CONCLUSIONS: Our data support that PGRN is processed in the lysosome through the actions of cathepsins. PMID- 28835282 TI - Low plasma vitamin A concentration is associated with tuberculosis in Moroccan population: a preliminary case control study. AB - BACKGROUND: Vitamin A plays numerous roles in immune system. Its deficiency alters both the innate and adaptive immunity. Previous results reported that the micronutrients deficiency, particularly vitamin A, is observed in patients with tuberculosis. Thus, we aimed in this study to assess vitamin A concentrations in Moroccan patients with tuberculosis to set up a large efficacy study of vitamin A supplementation for TB infected patients. Plasma retinol concentration was measured by HPLC in 44 recently diagnosed TB patients and 40 healthy controls. RESULTS: We showed that plasma vitamin A is significantly lower in tuberculosis patients as compared to healthy controls (p < 0.0001). Moreover, no significant association was found between vitamin A deficiency and, TB severity and patients' ages. CONCLUSION: Our study confirms the association between low vitamin A levels and tuberculosis disease. PMID- 28835283 TI - Identifying pre-hospital factors associated with outcome for major trauma patients in a regional trauma network: an exploratory study. AB - BACKGROUND: Major trauma is often life threatening and the leading cause of death in the United Kingdom (UK) for adults aged less than 45 years old. This study aimed to identify pre-hospital factors associated with patient outcomes for major trauma within one Regional Trauma Network. METHOD: Secondary analysis of pre hospital audit data and patient outcome data from the Trauma Audit Research Network (TARN) was undertaken. The primary outcome used in analysis was 'Status at Discharge' (alive/deceased). Independent variables considered included 'Casualty Characteristics' such as mechanism of injury (MOI), age, and physiological measurements, as well as 'Response Characteristics' such as response timings and skill mix. Binary Logistic Regression analysis using the 'forward stepwise' method was undertaken for physiological measures taken at the scene. RESULTS: The study analysed 1033 major trauma records (mean age of 38.5 years, SD 21.5, 95% CI 37-40). Adults comprised 82.6% of the sample (n = 853), whilst 12.9% of the sample were children (n = 133). Men comprised 68.5% of the sample (n = 708) in comparison to 28.8% women (n = 298). Glasgow Coma Score (GCS) (p < 0.000), Respiration Rate (p < 0.001) and Age (p < 0.000), were all significant when associated with the outcome 'Status at Discharge' (alive/deceased). Isolated bivariate associations provided tentative support for response characteristics such as existing dispatching practices and the value of rapid crew arrival. However, these measurements appear to be of limited utility in predictive modelling of outcomes. DISCUSSION: The complexity of physiological indices potentially complicate their predictive utility e.g. whilst a Systolic Blood Pressure (SBP) of < 90 mmHg serves as a trigger for bypass to a Major Trauma Centre, the utility of this observation is nullified in cases of Traumatic Brain Injury. Analysis suggested that as people age, outcomes from major trauma significantly worsened. This finding is consistent with existing research highlighting the relationship between trauma in elderly patients and poorer outcomes. CONCLUSION: Findings lend further validity to GCS, Respiration Rate and Age as predictive triggers for transport to a Major Trauma Centre. Analysis of interactions between response times, skill mix and triage demand further exploration but tentatively support the 'Golden Hour' concept and suggest a potential 'load and go and play on the way' approach. PMID- 28835284 TI - Maintaining immobilisation devices on trauma patients during CT: a feasibility study. AB - BACKGROUND: To reduce the possibility of secondary deterioration of spinal injuries, it is desirable to maintain the spinal immobilisation that is applied in the prehospital setting throughout computed tomography (CT) scanning. A previous study found that metallic components within the inflation valve of the vacuum mattresses caused CT artefacts. The aim of our study was to investigate the effect of vacuum mattresses with plastic valves on CT artefacts, the radiation dose, and noise compared to a trauma transfer board and the spine boards currently used in our trauma system. METHODS: We scanned an anthropomorphic whole body phantom with different immobilisation devices on a 128 slice CT scanner using the standard polytrauma CT-protocol at our institution. The phantom was scanned without any immobilisation device and with three different vacuum mattresses, two spine boards, and one trauma transfer board. Two radiologists independently assessed the artefacts. Agreement between the two radiologists was measured using the kappa coefficient. The radiation dose and noise were assessed. RESULTS: One spine board produced major artefacts due to its metal components. One of the vacuum mattresses resulted in artefacts that impaired clinical judgement. Otherwise, the artefacts predominantly did not impede clinical judgement and were mainly subtle. One of the vacuum mattresses resulted in no artefacts that affected clinical judgement. The overall inter rater agreement was substantial (0.86, kappa 0.77). We did not observe any artefacts due to plastic valves. The mean CT radiation dose was slightly higher for two of the devices in the head series than that for the trauma transfer board, used as the standard in our system. Only marginal differences were noted for the other devices and series. Small differences in image noise were found between the devices. CONCLUSIONS: Our results indicate that it is feasible to maintain some vacuum mattresses with plastic valves on trauma patients during CT scanning. The tested mattresses did not result in a considerably increased radiation dose or artefacts that hampered clinical judgement. One of the tested vacuum mattresses produced no artefacts that hampered clinical judgement whatsoever. PMID- 28835285 TI - Points to consider: efficacy and safety evaluations in the clinical development of ultra-orphan drugs. AB - BACKGROUND: The unmet medical needs of individuals with very rare diseases are high. The clinical trial designs and evaluation methods used for 'regular' drugs are not applicable in the clinical development of ultra-orphan drugs (<1000 patients) in many cases. In order to improve the clinical development of ultra orphan drugs, we examined several points regarding the efficient evaluations of drug efficacy and safety that could be conducted even with very small sample sizes, based on the review reports of orphan drugs approved in Japan. RESULTS: The clinical data packages of 43 ultra-orphan drugs approved in Japan from January 2001 to December 2014 were investigated. Japanese clinical trial data were not included in the clinical data package for eight ultra-orphan drugs, and non-Japanese clinical trial data were included for six of these eight drug. Japanese supportive data that included retrospective studies, published literature, clinical research and Japanese survey results were clinical data package attachments in 22 of the 43 ultra-orphan drugs. Multinational trials were conducted for three ultra-orphan drugs. More than two randomized controlled trials (RCTs) were conducted for only 11 of the 43 ultra-orphan drugs. The smaller the number of patients, the greater the proportion of forced titration and optional titration trials were conducted. Extension trials were carried out for enzyme preparations and monoclonal antibodies with high ratio. Post-marketing surveillance of all patients was required in 36 of the 43 ultra-orphan drugs. For ultra-orphan drugs, clinical endpoints were used as the primary efficacy endpoint of the pivotal trial only for two drugs. The control groups in RCTs were classified as follows: placebo groups different dosage groups, and active controls groups. Sample sizes have been determined on the basis of feasibility for some ultra-orphan drugs. We provide "Draft Guidance on the Clinical Development of Ultra-Orphan Drugs" based on this research. CONCLUSIONS: The development of ultra-orphan drugs requires various arrangements regarding evidence collection, data sources and the clinical trial design. We expect that this draft guidance is useful for ultra-orphan drugs developments in future. PMID- 28835286 TI - Habits and customs of crab catchers in southern Bahia, Brazil. AB - BACKGROUND: Brazilian mangrove forests are widely distributed along the coast and exploited by groups of people with customs and habits as diverse as the biology of the mangrove ecosystems. This study identifies different methods of extracting crabs that inhabit the mangrove belts; some of these activities, such as catching individual crabs by hand, are aimed at maintaining natural stocks of this species in Mucuri (south Bahia), Brazil. METHODS: In the studied community, illegal hunting activities that violate Brazilian legislation limiting the use of tangle netting in mangrove ecosystem were observed. RESULTS: According to our observations, fishermen, to catch individual crabs, use the tangle-netting technique seeking to increase income and are from families that have no tradition of extraction. CONCLUSIONS: This analysis leads us to conclude that catchers from economically marginalised social groups enter mangroves for purposes of survival rather than for purposes of subsistence, because the catching by tangle-netting is a predatory technique. Tangle-netting technique increase caught but also increases their mortality rate. We emphasise that traditional catching methods are unique to Brazil and that manual capturing of crab should be preserved through public policies aimed at maintaining the crab population. PMID- 28835288 TI - The Relationship Between Infection Prevention Staffing Levels, Certification, and Publicly Reported Hospital-Acquired Condition Scores. PMID- 28835287 TI - Development of a loop-mediated isothermal amplification technique and comparison with quantitative real-time PCR for the rapid visual detection of canine neosporosis. AB - BACKGROUND: Dogs are the definitive hosts of Neospora caninum and play an important role in the transmission of the parasite. Despite the high sensitivity of existing molecular tools such as quantitative real-time PCR (qPCR), these techniques are not suitable for use in many countries because of equipment costs and difficulties in implementing them for field diagnostics. Therefore, we developed a simplified technique, loop-mediated isothermal amplification (LAMP), for the rapid visual detection of N. caninum. METHODS: LAMP specificity was evaluated using a panel containing DNA from a range of different organisms. Sensitivity was evaluated by preparing 10-fold serial dilutions of N. caninum tachyzoites and comparing the results with those obtained using qPCR. Assessment of the LAMP results was determined by recognition of a colour change after amplification. The usefulness of the LAMP assay in the field was tested on 396 blood and 115 faecal samples from dogs, and one placenta from a heifer collected in Lopburi, Nakhon Pathom, Sa Kaeo, and Ratchaburi provinces, Thailand. RESULTS: Specificity of the LAMP technique was shown by its inability to amplify DNA from non-target pathogens or healthy dogs. The detection limit was the equivalent of one genome for both LAMP and qPCR. LAMP and qPCR detected positive N. caninum infection in 15 of 396 (3.8%) blood samples; LAMP detected 9/115 (7.8%) positive faecal samples, while qPCR detected 5/115 (4.3%) positive faecal samples. The placental tissue was shown to be positive by both techniques. Agreement between LAMP and qPCR was perfect in blood samples (kappa value, 1.00) and substantial in faecal samples (kappa value, 0.697). CONCLUSIONS: This is the first known LAMP assay developed for the amplification of N. caninum. The technique effectively and rapidly detected the parasite with high sensitivity and specificity and was cost-effective. This assay could be used in the field to confirm the diagnosis of canine or bovine neosporosis. PMID- 28835289 TI - Prediction of Recurrent Clostridium Difficile Infection Using Comprehensive Electronic Medical Records in an Integrated Healthcare Delivery System. AB - : BACKGROUND Predicting recurrent Clostridium difficile infection (rCDI) remains difficult. METHODS: We employed a retrospective cohort design. Granular electronic medical record (EMR) data had been collected from patients hospitalized at 21 Kaiser Permanente Northern California hospitals. The derivation dataset (2007-2013) included data from 9,386 patients who experienced incident CDI (iCDI) and 1,311 who experienced their first CDI recurrences (rCDI). The validation dataset (2014) included data from 1,865 patients who experienced incident CDI and 144 who experienced rCDI. Using multiple techniques, including machine learning, we evaluated more than 150 potential predictors. Our final analyses evaluated 3 models with varying degrees of complexity and 1 previously published model. RESULTS Despite having a large multicenter cohort and access to granular EMR data (eg, vital signs, and laboratory test results), none of the models discriminated well (c statistics, 0.591-0.605), had good calibration, or had good explanatory power. CONCLUSIONS Our ability to predict rCDI remains limited. Given currently available EMR technology, improvements in prediction will require incorporating new variables because currently available data elements lack adequate explanatory power. Infect Control Hosp Epidemiol 2017;38:1196-1203. PMID- 28835291 TI - Occurrence and diversity of arthropod-transmitted pathogens in red foxes (Vulpes vulpes) in western Austria, and possible vertical (transplacental) transmission of Hepatozoon canis. AB - Red fox (Vulpes vulpes) is the most abundant wild canid species in Austria, and it is a well-known carrier of many pathogens of medical and veterinary concern. The main aim of the present study was to investigate the occurrence and diversity of protozoan, bacterial and filarial parasites transmitted by blood-feeding arthropods in a red fox population in western Austria. Blood (n = 351) and spleen (n = 506) samples from foxes were examined by PCR and sequencing and the following pathogens were identified: Babesia canis, Babesia cf. microti (syn. Theileria annae), Hepatozoon canis, Anaplasma phagocytophilum, Candidatus Neoehrlichia sp. and Bartonella rochalimae. Blood was shown to be more suitable for detection of Babesia cf. microti, whilst the spleen tissue was better for detection of H. canis than blood. Moreover, extremely low genetic variability of H. canis and its relatively low prevalence rate observed in this study may suggest that the parasite has only recently been introduced in the sampled area. Furthermore, the data presented here demonstrates, for the first time, the possible vertical transmission of H. canis from an infected vixen to the offspring, and this could explain the very high prevalence in areas considered free of its main tick vector(s). PMID- 28835290 TI - Temperature-dependent development of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) and its larval parasitoid, Habrobracon hebetor (Say) (Hymenoptera: Braconidae): implications for species interactions. AB - Habrobracon hebetor (Say) is a parasitoid of various Lepidoptera including Helicoverpa armigera (Hubner), a key pest of different crops and vegetables. The development of both H. armigera and H. hebetor were simultaneously evaluated against a wide range of constant temperatures (10, 15, 17.5, 20, 25, 27.5, 30, 35, 37.5 and 40 degrees C). Helicoverpa armigera completed its development from egg to adult within a temperature range of 17.5-37.5 degrees C and H. hebetor completed its life cycle from egg to adult within a temperature range of 15-40 degrees C. Based on the Ikemoto and Takai model the developmental threshold (To) and thermal constant (K) to complete the immature stages, of H. armigera were calculated as 11.6 degrees C and 513.6 DD, respectively, and 13 degrees C and 148 DD, respectively, for H. hebetor. Analytis/Briere-2 and Analytis/Briere-1 were adjudged the best non-linear models for prediction of phenology of H. armigera and H. hebetor, respectively and enabled estimation of the optimum (Topt) and maximum temperature (Tmax) for development with values of 34.8, 38.7, 36.3, and 43 degrees C for host and the parasitoid, respectively. Parasitisation by H. hebetor was maximal at 25 degrees C but occurred even at 40 degrees C. This study suggests although high temperature is limiting to insects, our estimates of the upper thermal limits for both species are higher than previously estimated. Some biological control of H. armigera by H. hebetor may persist in tropical areas, even with increasing temperatures due to climate change. PMID- 28835292 TI - Reproduction biotechnologies in germplasm banking of livestock species: a review. AB - Many biotechnologies are currently used in livestock breeding with the aim of improving reproductive efficiency and increasing the rate of genetic progress in production animals. Semen cryopreservation is the most widely used cryobiotechnology, although vitrification techniques now allow embryos and oocytes to be banked in ever-increasing numbers. Cryopreservation of other types of germplasm (reproductive tissue in general) is also possible, although the techniques are still in the early stages of development for use in livestock species. Although still in their infancy, these techniques are increasingly being used in aquaculture. Germplasm conservation enables reproductive tissues from both animals and fish to be preserved to generate offspring in the future without having to maintain large numbers of living populations of these species. However, such measures need careful planning and coordination. This review explains why the preservation of genetic diversity is needed for livestock and fish, and describes some of the issues involved in germplasm banking. Furthermore, some recent developments in semen handling leading to improved semen cryopreservation and biosecurity measures are also discussed. PMID- 28835293 TI - Effect of a photoperiodic green light programme during incubation on embryo development and hatch process. AB - This study was conducted to evaluate the effect of a 12-h light, 12-h dark (12L : 12D) photoperiod of green light during day 1 to day 18 of incubation time, on embryo growth, hormone concentration and the hatch process. In the test group, monochromatic light was provided by a total of 204 green light-emitting diodes (522 nm) mounted in a frame which was placed above the top tray of eggs to give even spread of illumination. No light-dark cycle was used in the control group. Four batches of eggs (n=300/group per batch) from fertile Ross 308 broiler breeders were used in this experiment. The beak length and crown-rump length of embryos incubated under green light were significantly longer than that of control embryos at day 10 and day 12, respectively (P<0.01). Furthermore, green light-exposed embryos had a longer third toe length compared with control embryos at day 10, day 14 and day 17 (P=0.02). At group level (n=4 batches), light stimulation had no effect on chick weight and quality at take-off, the initiation of hatch and hatch window. However, the individual hatching time of the light exposure focal chicks (n=33) was 3.4 h earlier (P=0.49) than the control focal chicks (n=36) probably due to the change in melatonin rhythm of the light group. The results of this study indicate that green light accelerates embryo development and alters hatch-related hormones (thyroid and corticosterone), which may result in earlier hatching. PMID- 28835294 TI - Factors affecting storage of Slovak native rabbit semen in the gene bank. AB - In this study, fresh and frozen-thawed semen of Nitra and Zobor rabbit breeds were evaluated for potential inter-breed or inter-male differences in sperm quality traits. Individual male semen from four rabbits of each breed were diluted (v:v; 1:1) in a freezing medium composed of a commercial diluent, 16% of dimethyl sulphoxide (DMSO), 4% of Ficoll 70 and 2% of sucrose and frozen in liquid nitrogen vapours before being plunged into liquid nitrogen. Different motility traits, viability and plasma membrane integrity of fresh and frozen thawed semen were evaluated in vitro using computer-assisted sperm analysis and flow cytometry. To evaluate the sperm fertilization ability, artificial insemination of fresh and frozen-thawed sperm was performed. Our results showed the effect of breed (P <= 0.05) on frozen-thawed sperm viability and plasma membrane integrity. Moreover, individual variability in semen quality among the rabbits was revealed (0.31 to 0.71 among quality traits). Our results thereby confirmed that the cryopreservation procedure could not ensure comparable sperm post-thaw survival for different breeds or males. Nevertheless, correlations between numbers of fresh total motile and progressively moving sperm and several quality parameters measured post thawing were revealed. Therefore, we suggest that the objective assessment of fresh rabbit sperm motility may be an effective indicator of frozen-thawed semen quality. Consequently, regular semen assessment is required in order to preserve good-quality insemination doses from native breeds. PMID- 28835295 TI - Confirmatory factor analysis of the Beck Depression Inventory-II in patients with advanced cancer: A theory-driven approach. AB - OBJECTIVE: The diagnosis and treatment of depression are complicated by the presence of a serious medical illness, such as cancer. The role of inflammation in the pathophysiology of depression remains unknown; however, the symptom cluster of sickness behavior is more clearly related to inflammation. Symptom clusters may provide the specificity needed to improve treatment outcomes. The purpose of this study is to use confirmatory factor analysis to examine the construct of sickness behavior in patients with advanced cancer using the Beck Depression Inventory-II (BDI-II). METHOD: Patients (N = 167) were recruited from chemotherapy clinics and the Department of Psychiatry at Memorial Sloan Kettering Cancer Center. Symptoms were a priori delineated using the factor labels sickness behavior and negative affectivity (two-factor model), and affective, cognitive, and sickness behavior (three-factor model). These data were also fit for a more traditional model using affective, cognitive, and somatic factors. RESULTS: The mean total BDI-II score was 14.74 (SD = 8.52; range = 1-46). Fit statistics for all models were good, but the novel three-factor model with sickness behavior provided the best fit: chi2(186) = 273.624; p < 0.001; root-mean-square error of approximation = 0.053; comparative fit index = 0.949. SIGNIFICANCE OF RESULTS: Both the two- and three-factor models provide support for the unique construct of sickness behavior in patients with advanced cancer. High factor correlations with the BDI-II and other measures of distress were observed, which raises questions about theoretically distinct, but related, constructs. PMID- 28835296 TI - Characterizing environmental risk factors for West Nile virus in Quebec, Canada, using clinical data in humans and serology in pet dogs. AB - The identification of specific environments sustaining emerging arbovirus amplification and transmission to humans is a key component of public health intervention planning. This study aimed at identifying environmental factors associated with West Nile virus (WNV) infections in southern Quebec, Canada, by modelling and jointly interpreting aggregated clinical data in humans and serological data in pet dogs. Environmental risk factors were estimated in humans by negative binomial regression based on a dataset of 191 human WNV clinical cases reported in the study area between 2011 and 2014. Risk factors for infection in dogs were evaluated by logistic and negative binomial models based on a dataset including WNV serological results from 1442 dogs sampled from the same geographical area in 2013. Forested lands were identified as low-risk environments in humans. Agricultural lands represented higher risk environments for dogs. Environments identified as impacting risk in the current study were somewhat different from those identified in other studies conducted in north eastern USA, which reported higher risk in suburban environments. In the context of the current study, combining human and animal data allowed a more comprehensive and possibly a more accurate view of environmental WNV risk factors to be obtained than by studying aggregated human data alone. PMID- 28835297 TI - Structural and Chemical Analysis of Hydroxyapatite (HA)-Boron Nitride (BN) Nanocomposites Sintered Under Different Atmospheric Conditions. AB - Calcium phosphate derivatives have been widely employed in medical and dental applications for hard tissue repair, as they are the main inorganic constitution of hard tissue; such as bones and teeth. Owing to their excellent osteoconductive and bioactive properties, hydroxyapatite- (HA) based ceramics are the best candidates of this group for medical, bioscience, and dental applications. However, when replacing a bone or tooth, HA is not able to sustain similar mechanical properties. In this study, to improve the mechanical properties, nanoscale hexagonal boron nitride with different compositional percentages was added to the nano HA to form composites. The effect of compositional changes and sintering parameters on microstructural and morphological properties of the ceramic composites was comparatively investigated. Detailed chemical characterization of the composite materials was carried out using X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and energy-dispersive X-ray spectroscopy, whereas scanning electron microscopy and atomic force microscopy investigations were employed to monitor morphological and surface features. Additional transmission electron microscopy investigations were carried out to reveal the nanostructure and crystal structure of the composites. PMID- 28835298 TI - High-Resolution Field Emission Scanning Electron Microscopy (FESEM) Imaging of Cellulose Microfibril Organization in Plant Primary Cell Walls. AB - We have used field emission scanning electron microscopy (FESEM) to study the high-resolution organization of cellulose microfibrils in onion epidermal cell walls. We frequently found that conventional "rule of thumb" conditions for imaging of biological samples did not yield high-resolution images of cellulose organization and often resulted in artifacts or distortions of cell wall structure. Here we detail our method of one-step fixation and dehydration with 100% ethanol, followed by critical point drying, ultrathin iridium (Ir) sputter coating (3 s), and FESEM imaging at a moderate accelerating voltage (10 kV) with an In-lens detector. We compare results obtained with our improved protocol with images obtained with samples processed by conventional aldehyde fixation, graded dehydration, sputter coating with Au, Au/Pd, or carbon, and low-voltage FESEM imaging. The results demonstrated that our protocol is simpler, causes little artifact, and is more suitable for high-resolution imaging of cell wall cellulose microfibrils whereas such imaging is very challenging by conventional methods. PMID- 28835299 TI - Paid employment and common mental disorders in 50-64-year olds: analysis of three cross-sectional nationally representative survey samples in 1993, 2000 and 2007. AB - AIMS: Associations between employment status and mental health are well recognised, but evidence is sparse on the relationship between paid employment and mental health in the years running up to statutory retirement ages using robust mental health measures. In addition, there has been no investigation into the stability over time in this relationship: an important consideration if survey findings are used to inform future policy. The aim of this study is to investigate the association between employment status and common mental disorder (CMD) in 50-64-year old residents in England and its stability over time, taking advantage of three national mental health surveys carried out over a 14-year period. METHODS: Data were analysed from the British National Surveys of Psychiatric Morbidity of 1993, 2000 and 2007. Paid employment status was the primary exposure of interest and CMD the primary outcome - both ascertained identically in all three surveys (CMD from the revised Clinical Interview Schedule). Multivariable logistic regression models were used. RESULTS: The prevalence of CMD was higher in people not in paid employment across all survey years; however, this association was only present for non-employment related to poor health as an outcome and was not apparent in those citing other reasons for non-employment. Odds ratios for the association between non-employment due to ill health and CMD were 3.05 in 1993, 3.56 in 2000, and 2.80 in 2007, after adjustment for age, gender, marital status, education, social class, housing tenure, financial difficulties, smoking status, recent physical health consultation and activities of daily living impairment. CONCLUSIONS: The prevalence of CMD was higher in people not in paid employment for health reasons, but was not associated with non-employment for other reasons. Associations had been relatively stable in strength from 1993 to 2007 in those three cross sectional nationally representative samples. PMID- 28835300 TI - SGEM Hot Off the Press: Delayed complications of sternal fractures. PMID- 28835301 TI - Feeding dried distillers grains with solubles to lactating beef cows: impact of excess protein and fat on post-weaning progeny growth, glucose tolerance and carcass traits. AB - Feeding dried distillers grains with solubles (DDGS), a feed high in fat and protein, to lactating beef cows can alter milk production and composition, resulting in improved pre-weaning growth of progeny. This alteration in milk profile may consequently alter the growth and carcass composition of the offspring after weaning. Therefore, Angus*Simmental steers (n=48) whose dams were fed one of two diets supplemented with either DDGS or soybean meal (CON) from calving to mid-lactation were placed in a feedlot to determine the effects of maternal nutrition during lactation on progeny development and carcass composition. Cow-calf pairs were allotted to two treatments at birth based on cow and calf BW, breed and age. Maternal diets were isocaloric (3.97 MJ/kg NEg) and consisted of rye hay supplemented with DDGS at 1% of BW (19.4% CP; 8.76% fat) or rye hay and corn silage supplemented with CON (11.7% CP; 2.06% fat). After conclusion of the treatments at 129 days postpartum, cow-calf pairs were comingled and managed as one group until weaning at 219 days postpartum. Steers were then transitioned to a common diet composed of 60% DDGS, 34% corn silage and 6% vitamin/mineral supplement and were placed indoors in individual pens with slatted floors. An intravenous glucose tolerance test (IVGTT) was performed 134 days after feedlot entry on 16 steers (CON, n=7; DDGS, n=9) to determine the effect of maternal diet on glucose and insulin sensitivity. Steers were slaughtered at a target BW of 645 kg. Categorical and continuous data were analyzed using the GLIMMIX and MIXED procedures of SAS, respectively. Steers from DDGS dams tended to be heavier on day 85 of feedlot finishing (P=0.09) compared with steers from CON dams. However, there were no differences in final weight, average daily gain, dry matter intake or efficiency (gain:feed, P?0.18). Maternal treatments did not affect progeny days on feed (P=0.15), despite a mean difference of 9 days in favor of DDGS. Glucose and insulin concentrations and area under the curve of progeny as measured by IVGTT were not affected by maternal diet (P?0.16). Maternal DDGS supplementation decreased marbling score (P=0.04), but did not influence carcass grading percentage or any other carcass characteristic (P?0.17). PMID- 28835302 TI - Successful vitrification of whole juvenile testis in the critically endangered cyprinid honmoroko (Gnathopogon caerulescens). AB - Sperm cryopreservation is a valuable conservation method for endangered fish species. Here we report an easy and efficient cryopreservation method for juvenile whole testis by vitrification and successful sperm production from the vitrified whole testis via in vitro spermatogenesis in the critically endangered cyprinid honmoroko (Gnathopogon caerulescens). Juvenile testis (approximately 10 mm in length and 1 mm in width), consisting predominantly of spermatogonia, were aseptically dissected out and adherent fatty and non-testicular tissues were subsequently removed. Then, the testes were rapidly cooled on a nylon mesh by direct immersion in liquid nitrogen after serial exposures to pretreatment solution (PS), containing 2 M ethylene glycol (EG) and 1 M dimethyl sulfoxide (DMSO), for 20 or 30 min and vitrification solution (VS), containing 3 M EG, 2 M DMSO, and 0.5 M sucrose, for 5, 10, or 20 min. The highest survival rate of testicular cells (84.0%) was obtained from testes vitrified by immersion in PS for 20 min and in VS for 10 min. Spermatogonia were recovered from the vitrified testis by dissociation and cell culture produced many haploid sperm. Fertility and developmental competence were confirmed by in vitro fertilization assays. These results indicate that the vitrification of juvenile whole testis provides a new strategy to preserve the genetic resources of endangered fishes without affecting their reproductive population. PMID- 28835303 TI - Mitotic index and morphological characteristics of ovarian small follicles from goats submitted to nutritionally unbalanced regimens. AB - The objective of this study was to assess the influence of nutritional regimens such as adequate feeding, restricted feeding, and underfeeding-refeeding on the follicle growth and development from caprine ovaries. Goats were divided into three different groups (n = 5 per group). For 24 weeks, goats received elephant grass plus concentrate to provide 1.5 (n = 5) and 0.72 (n = 10) times the energy requirements for maintenance of live weight. Underfed goats were subsequently refed for 6 weeks with the diet of the nourished group (1.5 times the energetic requirements of maintenance). Follicular morphology and morphometry, as well as granulosa cells mitotic index were assessed. Ovarian follicles were classified as small or large preantral follicles, or as small or large antral follicles. Ovarian volume was smaller in animals from both underfed and refed groups than in those animals from fed group. Although no difference in the total number of normal follicles was observed among the nutritional groups, underfed animals presented higher percentages of atretic preantral and small antral follicles when compared with fed animals. Large antral follicles from underfed and refed goats presented a lower mitotic index when compared with fed ones. In conclusion, ovaries from goats challenged with prolonged undernutrition will be functionally compromised, which is characterized by atresia of preantral and small antral follicles and decreased mitotic index of large antral follicles. Refeeding those animals will not recover ovarian function to a same level experienced by goats fed a diet with adequate energy requirements. PMID- 28835304 TI - Active immunization against GnRH in pre-pubertal domestic mammals: testicular morphometry, histopathology and endocrine responses in rabbits, guinea pigs and ram lambs. AB - Effective tools for male contraception are important in the control of reproduction in animal populations. The aim of the present study was to evaluate the effects of active immunization against gonadotropin-releasing hormone (GnRH) on male reproductive function assessing testicular morphological changes and serum-gonadotropin levels in pre-pubertal rabbits, guinea pigs and ram lambs. An anti-GnRH vaccine was developed by linking a GnRH-homologous molecule to a tetanus clostridial toxoid (Al(OH)3 coadjuvant). After vaccination protocols testicular morphometry, histopathological alterations and endocrine responses (FSH, LH, testosterone and cortisol serum levels) were evaluated. Testicular volume was significantly reduced in vaccinated animals with respect to the control group in rabbits, guinea pigs and ram lambs (P<0.05 to P<0.001). The anti GnRH vaccine generated a reduction in testicular volume of 15-, 27- and 11-fold, respectively. Tubule diameters decreased in the vaccinated group with respect to the control ~2.0-, 1.2- and 3.5-fold, respectively (P<0.001). Tubule, intertubular and lumen volumes significantly decreased in vaccinated rabbits (P<0.05), guinea pigs and ram lambs (P<0.01). Vaccinated animals of the three species showed significant reductions in spermatogonial numbers (10- to 40-fold; P<0.01). Sperm was absent in all seminiferous tubules of all rabbits, and most individuals of guinea pigs (80%) and ram lambs (60%). No significant differences were observed between vaccinated and control groups regarding FSH and LH during the experiments in the three experimental species/models used. Testosterone, however, was only significantly lower (~22-fold, P<0.01) in vaccinated rabbits. In conclusion, the present study demonstrated that pre-pubertal active immunization against GnRH leads to endocrine disruption and marked differences on testicular morphometry, development and activity among lagomorphs, hystricomorphs and ovine species with species-specific sensitivity regarding the anti-GnRH immune response. PMID- 28835305 TI - Cannabinoid hyperemesis syndrome presentation to the emergency department: A two year multicentre retrospective chart review in a major urban area. AB - OBJECTIVE: Cannabinoid hyperemesis syndrome (CHS) is a paradoxical side effect of cannabis use. Patients with CHS often present multiple times to the emergency department (ED) with cyclical nausea, vomiting, and abdominal pain, and are discharged with various misdiagnoses. CHS studies to date are limited to case series. The objective was to examine the epidemiology of CHS cases presenting to two major urban tertiary care centre EDs and one urgent care centre over a 2-year period. METHODS: Using explicit variables, trained abstractors, and standardized abstraction forms, we abstracted data for all adults (ages 18 to 55 years) with a presenting complaint of vomiting and/or a discharge diagnosis of vomiting and/or cyclical vomiting, during a 2-year period. The inter-rater agreement was measured using a kappa statistic. RESULTS: We identified 494 cases: mean age 31 (+/-11) years; 36% male; and 19.4% of charts specifically reported cannabis use. Among the regular cannabis users (>three times per week), 43% had repeat ED visits for similar complaints. Moreover, of these patients, 92% had bloodwork done in the ED, 92% received intravenous fluids, 89% received antiemetics, 27% received opiates, 19% underwent imaging, 8% were admitted to hospital, and 8% were referred to the gastroenterology service. The inter-rater reliability for data abstraction was kappa=1. CONCLUSIONS: This study suggests that CHS may be an overlooked diagnosis for nausea and vomiting, a factor that can possibly contribute to unnecessary investigations and treatment in the ED. Additionally, this indicates a lack of screening for CHS on ED history, especially in quantifying cannabis use and eliciting associated symptoms of CHS. PMID- 28835306 TI - Plane of nutrition during the rearing phase for replacement ewes of four genotypes: II - effects on performance during first pregnancy and to weaning, and of their progeny. AB - Plane of nutrition (PN) offered to ewe replacements during the rearing phase (8 to 17 months) and first pregnancy may affect reproductive and progeny performance when replacements are joined at ~19 months. The effects of PN offered to spring born ewe replacements during their first winter (winter_1), second summer (summer_2) and subsequent winter (mid and late pregnancy; winter_2) were evaluated, over 3 consecutive years, using 287 ewe lambs of four genotypes: Charmoise*Scottish Blackface (C*SBF), Belclare*SBF (Bel*SBF), Belclare (Bel) and Belclare*SBF (heterozygous for a gene, either FecGH or FecXG mutations, that increases ovulation rate: BelMG*SBF). Ewe lambs were offered, daily, a deferred grazed herbage allowance (HA) of either 0.75 or 1.75 kg dry matter during winter_1. During summer_2 the replacements were set-stocked to maintain sward heights of 4 or 6 cm. Ewes were housed during mid and late pregnancy (winter_2) and offered either medium or high-feed-value grass silage, thus yielding a 2*2*2 factorial design. Increasing HA during winter_1 and residual sward height during summer_2 increased ewe BW post joining (P0.05) on number of lambs reared. Increasing HA during winter_1 increased lamb BW at birth (P<0.05) and reduced carcass fat score (P<0.05). There was a significant interaction between PN offered during winter_1 and summer_2 for average daily gain (ADG) from birth to 5 weeks (P<0.01) and from 5 to 10 weeks (P<0.05): progeny of replacements that experienced either a high or low PN throughout the rearing phase had lower ADG than lambs born to the replacements that experienced a low PN only during winter_1 or summer_2. Increasing PN during winter_2 increased ewe BW (P<0.001), lamb BW at birth (P<0.001) and weaning (P<0.05) and reduced the proportion of ewes that failed to lamb (P<0.01). Ewe genotype had a significant (P<0.001) effect on litter size (1.48 to 2.45), number of lambs reared, lamb BW at birth and weaning, lamb ADG and age at slaughter. It is concluded that, among the nutrition treatments examined, increasing PN during mid and late pregnancy had the greatest effect on ewe and progeny performance. Although increasing PN offered during winter_1 increased lamb birth BW, PN offered during summer_2 had no effect on lamb performance. There were no significant interactions between PN and ewe genotype. PMID- 28835307 TI - QTL mapping of a natural genetic polymorphism for long-term parasite persistence in Daphnia populations. AB - Knowing the determinants of the geographic ranges of parasites is important for understanding their evolutionary ecology, epidemiology and their potential to expand their range. Here we explore the determinants of geographic range in the peculiar case of a parasite species - the microsporidian Hamiltosporidium tvaerminnensis - that has a limited geographic distribution in a wide-spread host - Daphnia magna. We conducted a quantitative trait loci (QTLs) analysis with monoclonal F2 D. magna populations originating from a cross between a susceptible northern European genotype and a resistant central European genotype. Contrary to our expectations, long-term persistence turned out to be a quantitative trait across the F2 offspring. Evidence for two QTLs, one epistatic interaction and for further minor QTL was found. This finding contrasts markedly with the previously described bimodal pattern for long-term parasite persistence in natural host genotypes across Europe and leaves open the question of how a quantitative genetic trait could determine the disjunct geographic distribution of the parasite across Europe. PMID- 28835308 TI - Research Letter: Auto-activation deficit in schizophrenia: a case report. PMID- 28835310 TI - Chylothorax following paediatric cardiac surgery: a case-control study. AB - OBJECTIVES: The aims of this study were to investigate risk factors for the development of postoperative chylothorax following paediatric congenital heart surgery and to investigate the impact of a management guideline on management strategies and patient outcome. METHODS: All patients with chylothorax following cardiac surgery at the Royal Children's Hospital, Melbourne, over a 48-month period beginning in January 2008 were identified. A control group, matched for age, date of surgery, and sex, was identified. To investigate potential risk factors, univariable and multivariable logistic regression models were constructed with paired analysis. To examine the effect of a standardised management protocol, data before and after the implementation of the guideline were compared. RESULTS: In total, 121 cases of chylothorax were identified, with 121 controls, matched for age at surgery, date of surgery, and sex. The incidence of chylothorax was 5.23%. Increasing surgical complexity (univariable OR 0.17 for the least complex versus the most complex group, p=0.02), closed-heart surgeries (OR 0.07 for open versus closed, p<0.001), and redo chest incisions (OR 10.0 for redo versus virgin, p<0.001) were significantly associated with chylothorax. The standardised management protocol had no significant impact on either drainage duration or management strategy. CONCLUSIONS: We have replicated the previously reported association between surgical complexity and chylothorax risk, and have shown, for the first time, that redo chest openings are also associated with a significantly increased risk. The implementation of a standardised management protocol in our institution did not result in a significant change in either chylothorax drainage duration or management strategy. PMID- 28835309 TI - Impaired cerebral autoregulation and elevation in plasma glial fibrillary acidic protein level during cardiopulmonary bypass surgery for CHD. AB - BACKGROUND: Cerebrovascular reactivity monitoring has been used to identify the lower limit of pressure autoregulation in adult patients with brain injury. We hypothesise that impaired cerebrovascular reactivity and time spent below the lower limit of autoregulation during cardiopulmonary bypass will result in hypoperfusion injuries to the brain detectable by elevation in serum glial fibrillary acidic protein level. METHODS: We designed a multicentre observational pilot study combining concurrent cerebrovascular reactivity and biomarker monitoring during cardiopulmonary bypass. All children undergoing bypass for CHD were eligible. Autoregulation was monitored with the haemoglobin volume index, a moving correlation coefficient between the mean arterial blood pressure and the near-infrared spectroscopy-based trend of cerebral blood volume. Both haemoglobin volume index and glial fibrillary acidic protein data were analysed by phases of bypass. Each patient's autoregulation curve was analysed to identify the lower limit of autoregulation and optimal arterial blood pressure. RESULTS: A total of 57 children had autoregulation and biomarker data for all phases of bypass. The mean baseline haemoglobin volume index was 0.084. Haemoglobin volume index increased with lowering of pressure with 82% demonstrating a lower limit of autoregulation (41+/-9 mmHg), whereas 100% demonstrated optimal blood pressure (48+/-11 mmHg). There was a significant association between an individual's peak autoregulation and biomarker values (p=0.01). CONCLUSIONS: Individual, dynamic non-invasive cerebrovascular reactivity monitoring demonstrated transient periods of impairment related to possible silent brain injury. The association between an impaired autoregulation burden and elevation in the serum brain biomarker may identify brain perfusion risk that could result in injury. PMID- 28835311 TI - Systematic Review of Published Primary Studies of Neuropsychology and Neuroimaging in Trichotillomania. AB - OBJECTIVES: Existing models of trichotillomania (TTM; hair pulling disorder) rely heavily on a biological predisposition or biological pathogenesis of the disorder, but fail to capture the specific neuropsychological mechanisms involved. The present systematic review aims to scope existing neuropsychological studies of TTM to explore gaps in current models. METHODS: A systematic literature search was conducted to detect all published primary studies using neuropsychological and neuroimaging measures in a cohort of individuals experiencing TTM. Studies addressing neuropsychological function were divided into domains. Findings from imaging studies were considered within brain regions and across methodology. RESULTS: Thirty studies with a combined 591 participants with TTM, 372 healthy controls and 225 participants in other types of control group were included. Sixteen studies investigated neuropsychological parameters, and 14 studies pursued neuroimaging technologies. Available studies that used neuropsychological assessments and reported a statistically significant difference between those with TTM and controls ranged in effect size from 0.25 to 1.58. All domains except verbal ability and visual ability reported a deficit. In neuroimaging studies, several structural and functional brain changes were reported that might be of significance to TTM. Only tentative conclusions can be made due to the use of multiple methodologies across studies, a major limitation to meaningful interpretations. CONCLUSIONS: Positive neuropsychological and neuroimaging results require replication, preferably with multi-site studies using standardized methodology. Increased standardized testing and analyses across the literature, as a whole, would improve the utility and interpretability of knowledge in this field. (JINS, 2018, 24, 188-205). PMID- 28835312 TI - Geospatial Distribution of Local Health Department Tweets and Online Searches About Ebola During the 2014 Ebola Outbreak. AB - OBJECTIVE: This study compared the geospatial distribution of Ebola tweets from local health departments (LHDs) to online searches about Ebola across the United States during the 2014 Ebola outbreak. METHODS: Between September and November 2014, we collected all tweets sent by 287 LHDs known to be using Twitter. Coordinates for each Ebola tweet were imported into ArcGIS 10.2.2 to display the distribution of tweets. Online searches with the search term "Ebola" were obtained from Google Trends. A Pearson's correlation test was performed to assess the relationship between online search activity and per capita number of LHD Ebola tweets by state. RESULTS: Ebola tweets from LHDs were concentrated in cities across the northeast states, including Philadelphia and New York City. In contrast, states with the highest online search queries for Ebola were primarily in the south, particularly Oklahoma and Texas. A weak, negative, non-significant correlation (r=-0.03, P=0.83, 95% CI: -0.30, 0.25) was observed between online search activity and per capita number of LHD Ebola tweets by state. CONCLUSIONS: We recommend that LHDs consider using social media to communicate possible disease outbreaks in a timely manner, and that they consider using online search data to tailor their messages to align with the public health interests of their constituents. (Disaster Med Public Health Preparedness. 2018; 12: 287-290). PMID- 28835313 TI - "Giant within a giant": a case of typical Kawasaki disease with a giant coronary aneurysm and a large coronary thrombus - a rare case report. AB - Kawasaki disease is a febrile vasculitis affecting young children, which may lead to coronary aneurysms. Echocardiography, although sensitive in detecting coronary aneurysms, has a limited role in diagnosing coronary thrombus. Here we report the case of a 10-year-old boy who presented with typical features of Kawasaki disease with giant coronary aneurysms. His follow-up echocardiogram revealed coronary arterial thrombus. PMID- 28835314 TI - Evaluation of Skin Damage from Accidental Removal of a Hemostatic Wound Clamp (The iTClamp). AB - BACKGROUND: Controlling bleeding early in the prehospital and military setting is an extremely important and life-saving skill. Wound clamping is a newly introduced technique that may augment both the effectiveness and logistics of wound packing with any gauze product. As these devices may be inadvertently removed, the potential consequences of such were examined in a simulated, extreme, inadvertent disengagement. METHODS: The wound clamp used was an iTClamp (Innovative Trauma Care; Edmonton, Alberta, Canada) that was applied and forcefully removed (skin-pull) from the skin of both a human cadaver and swine. Sixty skin-pull tests were sequentially performed to measure the pull weight required to remove the device, any potential skin and device damage, how the device failed, and if the device could be re-applied. RESULTS: Observations of the skin revealed that other than the expected eight small needle holes from device application, no other damage to the skin was sustained in 98.3% of cases. Conversely, of the 60 devices pulled, 93.3% of the devices sustained no damage and all could be re-applied. Four (6.7%) of the devices remained in place despite a maximum pull weight >22lb F (pound-force). The mean pull weights for pin bar pull were (lb F ): vertical 9.2 (SD=5.0); perpendicular 2.5 (SD=1.7); and parallel 5.3 (SD=3.1). For the encompassed pull position group, mean pull weights were (lb F ): vertical 5.7 (SD=2.3); perpendicular 3.0 (SD=2.5); and parallel 14.5 (SD=3.5). The overall mean for all groups was 6.7 (SD=5.2). The two main reasons that the iTClamp was pulled off were because the friction lock let go or the needles slipped out of one side of the skin due to the angle of the pull. CONCLUSION: Inadvertent, forcible removal of the iTClamp created essentially no skin damage seen when the wound clamp was forcibly removed from either cadaver or swine models in a variety of positions and directions. Thus, the risks of deployment in operational environments do not seem to be increased. Mckee JL , Lakshminarasimhan P , Atkinson I , LaPorta AJ , Kirkpatrick AW . Evaluation of skin damage from accidental removal of a hemostatic wound clamp (the iTClamp). Prehosp Disaster Med. 2017;32(6):651-656. PMID- 28835315 TI - Understanding adolescent personality pathology from growth trajectories of childhood oddity-CORRIGENDUM. PMID- 28835316 TI - Plane of nutrition during the rearing phase for replacement ewes of four genotypes: I - effects on growth and development, and on ovulation rate at first joining. AB - Plane of nutrition (PN) offered to ewe replacements during the rearing phase (8 to 17 months) affects BW at joining and may affect reproductive performance when joined at ~19 months. The effects of PN offered to ewe replacements during their first winter (winter_1) and second summer (summer_2) were evaluated over 3 consecutive years, using 287 spring-born ewe lambs, representing four genotypes (Belclare (Bel), Charmoise*Scottish Blackface (C*SBF), Bel*SBF (Bel*SBF), Bel*SBF that were heterozygous either FecGH or FecXG mutations that increase ovulation rate (OR) (BelMG*SBF)). During extended (deferred) grazing in winter_1 (November to March) the lambs were offered herbage DM allowances (HA) of 0.75 (L) or 1.75 (H) kg/day. During summer_2 (March to August) the replacements were set stocked to maintain sward heights of 4 (L) or 6 (H) cm, thus yielding a 2*2 factorial design for the nutrition treatments (71 to 73 animals/treatment). Increasing HA during winter_1, and residual sward height during summer_2, increased (P0.05) on OR. Mean BW at joining was 53.3, 56.8, 56.6 and 61.7 (SEM 0.74) kg for ewes offered the LL, LH, HL and HH treatments, respectively. Mean OR of C*SBF and BelMG*SBF differed (P<0.001) from that of Bel*SBF by -0.58 and +0.47, respectively. Correlations between linear measurements (LMs) of body size and BW at 7, 12 and 17 months were all positive and significant (P<0.001). The precision of the set of LMs as a predictor of BW at joining improved with age (R 2 0.46, 0.54 and 0.74 at 7, 12 and 17 months) but BW at a given age was a better predictor at all age time points. Chest girth was the best predictor, among the LMs, of BW at joining and its explanatory power increased with age. Equations developed using LMs at 7, 12 or 17 months, to predict BW at joining exhibited biases of -2.1, -1.5 and +0.9 kg, respectively. It is concluded that whilst altering PN during the rearing phase changed BW by 16% it had no effect on OR. There was no interaction (P>0.05) between the PN offered during winter_1 and summer_2, or PN and ewe genotype for BW at joining or OR. LMs, either at 7, 12 or 17 months of age, are useful predictors of BW at joining. PMID- 28835318 TI - Overexpression of LACTB, a Mitochondrial Protein, that Inhibits Proliferation and Invasion in Glioma Cells. AB - LACTB, a mitochondrial protein, was ubiquitously expressed in different mammalian tissues, such as liver, heart and skeletal muscle. It has been showed that LACTB is down-expressed in breast cancers, suppresses the proliferation and promotes the apoptosis of breast cancers. However, its role in progression and prognosis of glioma remains unknown. In this study, we analyzed the clinicopathological features and outcomes of LACTB expression in 98 glioma patients and investigated the effects of LACTB over-expressing on the proliferation, invasion and angiogenesis of glioma cells in vitro. We observed a significant decrease of LACTB expression in glioma and down-expression of LACTB is correlated with a poor prognosis of glioma patients. Moreover, Cox regression analysis reveals that the LACTB is an independent prognostic indicator for glioma patients. Over-expression of LACTB could suppress the proliferation, invasion and angiogenesis of glioma cells. In addition, over-expression of LACTB could inhibit the expression of PCNA, MMP2, MMP9 and VEGF. Taken together, these data indicate that LACTB may serve as a promising therapeutic target for gliomas. PMID- 28835317 TI - miR-216a-3p Inhibits the Proliferation, Migration, and Invasion of Human Gastric Cancer Cells via Targeting RUNX1 and Activating the NF-kappaB Signaling Pathway. AB - This work aims to elucidate the effects and the potential underlying mechanisms of microRNA-216a-3p (miR-216a-3p) on the proliferation, migration, and invasion of gastric cancer (GC) cells. In this study, we revealed that the expression of miR-216a-3p was significantly elevated in GC tissues and cell lines. The different expression level of miR-216a-3p was firmly correlated with clinicopathological characteristics of GC patients. We next demonstrated that upregulation of miR-216a-3p could dramatically promote the ability of proliferation, migration, and invasion of GC cells using a series of experiments, whereas downregulation essentially inhibited these properties. Additionally, through bioinformatics analysis and biological approaches, we confirmed that runt related transcription factor 1 (RUNX1) was a direct target of miR-216a-3p, and overexpression of RUNX1 could reverse the potential effect of miR-216a-3p on GC cells. Furthermore, mechanistic investigation using Western blot analysis showed that downregulation of RUNX1 by miR-216a-3p could stimulate the activation of NF kappaB signaling pathway. In summary, this work proved that miR-216a-3p can promote GC cell proliferation, migration, and invasion via targeting RUNX1 and activating the NF-kappaB signaling pathway. Therefore, miR-216a-3p/RUNX1 could be a possible molecular target for innovative therapeutic agents against GC. PMID- 28835319 TI - Long Noncoding RNA PlncRNA-1 Promotes Colorectal Cancer Cell Progression by Regulating the PI3K/Akt Signaling Pathway. AB - Accumulating evidence has indicated that long noncoding RNA (lncRNA) PlncRNA-1 plays an important regulatory role in cancers. However, the expression and biological functions of PlncRNA-1 in colorectal cancer (CRC) are still unclear. In the present study, we determined the expression of PlncRNA-1 in CRC and explored the function of PlncRNA-1 on CRC cell progression. The results showed that PlncRNA-1 was significantly increased in CRC tissues and cell lines; high PlncRNA-1 expression was associated with depth of invasion, lymph node metastasis, and TNM stage of CRC patients. Kaplan-Meier curve analysis showed that patients with high PlncRNA-1 expression had a poor overall survival. PlncRNA 1 knockdown remarkably reduced cell proliferation, migration, and invasion and promoted cell apoptosis in vitro. In vivo xenograft experiments showed that PlncRNA-1 inhibition significantly suppressed tumor growth. Finally, we used an agonist (740Y-P) of the PI3K/Akt signaling pathway; function assays showed that PlncRNA-1 exerted its effects by targeting the PI3K/Akt signaling pathway in CRC. Taken together, our data suggested that PlncRNA-1 might act as an oncogene in CRC progression and serve as a potential biomarker and therapeutic target for the treatment of CRC. PMID- 28835320 TI - Baicalein Inhibits the Proliferation of Cervical Cancer Cells Through the GSK3beta-Dependent Pathway. AB - Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, has been reported to possess multiple pharmacological activities, such as anticancer and anti-inflammatory properties. This study investigated the effect of baicalein in cervical cancer cells. Cell growth curve and MTT assay were performed and revealed that baicalein inhibited the proliferation of SiHa and HeLa cells in a dose-dependent manner. We further found that baicalein arrested the cell cycle of SiHa and HeLa cells at the G0/G1 phase by suppressing the expression of cyclin D1 through the downregulation of phosphorylated protein kinase B (p-AKT) and phosphorylated glycogen synthase kinase 3beta (p-GSK3beta) according to FACS assays and Western blotting. Moreover, when CHIR-99021, a GSK3beta inhibitor, was added to baicalein-treated SiHa cells, the expression of cyclin D1 was recovered, and cell proliferation was promoted. In conclusion, these data indicated that baicalein suspended the cell cycle at the G0/G1 phase via the downregulation of cyclin D1 through the AKT-GSK3beta signaling pathway and further inhibited the proliferation of SiHa and HeLa cervical cancer cells. PMID- 28835321 TI - Managing chronic conditions care across primary care and hospital systems: lessons from an Australian Hospital Avoidance Risk Program using the Flinders Chronic Condition Management Program. AB - Objective The study aimed to determine the impact of the Flinders Chronic Condition Management Program for chronic condition self-management care planning and how to improve its use with Bendigo Health's Hospital Admission Risk Program (HARP).Methods A retrospective analysis of hospital admission data collected by Bendigo Health from July 2012 to September 2013 was undertaken. Length of stay during admission and total contacts post-discharge by hospital staff for 253 patients with 644 admissions were considered as outcome variables. For statistical modelling we used the generalised linear model.Results The combination of the HARP and Flinders Program was able to achieve significant reductions in hospital admissions and non-significant reduction in emergency department presentations and length of stay. The generalised linear model predicted that vulnerable patient groups such as those with heart disease (P=0.037) and complex needs (P<0.001) received more post-discharge contacts by HARP staff than those suffering from diabetes, renal conditions and psychosocial needs when they lived alone. Similarly, respiratory (P<0.001), heart disease (P=0.015) and complex needs (P=0.050) patients had more contacts, with an increased number of episodes than those suffering from diabetes, renal conditions and psychosocial needs.Conclusion The Flinders Program appeared to have significant positive impacts on HARP patients that could be more effective if high-risk groups, such as respiratory patients with no carers and respiratory and heart disease patients aged 0-65, had received more targeted care.What is known about the topic? Chronic conditions are common causes of premature death and disability in Australia. Besides mental and physical impacts at the individual level, chronic conditions are strongly linked to high costs and health service utilisation. Hospital avoidance programs such as HARP can better manage chronic conditions through a greater focus on coordination and integration of care across primary care and hospital systems. In support of HARP, self-management interventions such as the Flinders Program aim to help individuals better manage their medical treatment and cope with the impact of the condition on their physical and mental wellbeing and thus reduce health services utilisation.What does this paper add? This paper sheds light on which patients might be more or less likely to benefit from the combination of the HARP and Flinders Program, with regard to their impact on reductions in hospital admissions, emergency department presentations and length of stay. This study also sheds light on how the Flinders Program could be better targeted towards and implemented among high need and high-cost patients to lessen chronic disease burden on Australia's health system.What are the implications for practitioners? Programs targeting vulnerable populations and applying evidence-based chronic condition management and self-management support achieve significant reductions in potentially avoidable hospitalisation and emergency department presentation rates, though sex, type of chronic condition and living situation appear to matter. Benefits might also accrue from the combination of contextual factors (such as the Flinders Program, supportive service management, clinical champions in the team) that work synergistically. PMID- 28835322 TI - The Gender Feeling Amplitude: an instrument to assist clinicians with the assessment of gender diverse adolescents. AB - : Background The Gender Feeling Amplitude (GFA) is a 68-item list of words and phrases with which to identify the feelings and severity of a young person's distress regarding their gender identity and gender diversity, and takes ~1min to administer. METHOD: For this pilot study, 67 adolescents and youth who sought support, confirmation or intervention (either via themselves or their parents) regarding gender diversity or gender transition were given the GFA in a face-to face meeting before the beginning of an assessment procedure for gender diversity. Forty-three assigned females and 24 assigned males aged between 10 and 20 years were analysed by frequency of item, age and assigned gender. RESULTS: Of the 68 items, those circled by close to 50% or more of the participants were 'self-conscious', 'awkward' and 'don't fit in'. One-third or more circled the words 'shy', 'supported', 'hopeful', 'discomfort', 'as if I'm not being seen properly', 'forced to be something I'm not', 'depressed' and 'stressed'. CONCLUSION: Comparisons showed some variations in responses by both assigned gender and age, and the discussion includes ways the GFA may be able to assist a health practitioner with explorations of gender diversity and interventions for counselling. PMID- 28835323 TI - Developing the evidence base for gender- and age-relevant school sex education: questionnaire findings from an adolescent sample using an augmented theory of planned behaviour. AB - BACKGROUND: Positive adolescent sexual health is supported by effective school based sex education. Methods to promote positive sexual health need to reflect determinants of contraception intention, which must include understanding gender and age (year group) differences. To date, there has been limited theory-based exploration of these determinants in school age participants, placing limitations on sexual health educators to tailor learning most effectively. METHODS: Cross sectional survey data were collected from UK school pupils (n=1378) aged 12-16 years. Measures included theory of planned behaviour, prototype willingness, anticipated regret and knowledge items. Linear regression determined significant predictors of intention to use condoms, the oral contraceptive pill and emergency contraception (EC). The significance of differences by gender and school year was evaluated using t-tests and analysis of variance (ANOVA). RESULTS: Three distinct predictive models emerged for condom, pill and EC use, predicting 36%, 18% and 23% of variance respectively. Attitude, gender and anticipated regret for unprotected sex significantly predicted intention for all types of contraception (P<0.001). The effects of other explanatory variables differed by contraceptive. Girls scored higher on all variables except condom intention, and intention scores peaked in Year 10. CONCLUSION: Intention to use condoms, the pill and EC have different predictive profiles, with girls more strongly motivated and Year 10 a crucial stage for intention. Social comparisons and control beliefs exert different effects across contraceptive types, whereas attitudes and anticipated regret are consistently strong influences. The findings suggest clear scope for supporting sexual health and well being through modified school sex education. PMID- 28835325 TI - Gall Bladder Gone Astray. PMID- 28835324 TI - Resection or Transplant in Early Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) has an incidence of 5-10 per 100 000 persons per year in the Western world. In 20% of cases, surgical liver resection (LR) or liver transplantation (LT) can be performed. LT results in longer survival, as it involves resection not only of the tumor, but of pre - cancerous tissue as well. The optimal allocation of donor organs depends on the identification of patients for whom LR is adequate treatment. In this meta analysis, we compare LT and LR for patients with early HCC and wellcompensated cirrhosis. METHODS: A systematic review of the pertinent literature was followed by a subgroup analysis of the studies in which patients with early HCC and wellcompensated cirrhosis were followed up after either LR or LT. Overall survival at 1, 3, and 5 years, as well as morbidity and mortality, were compared in a random effects meta-analysis. RESULTS: 54 studies with a total of 13 794 patients were included. Among patients with early HCC, the overall survival after LT became higher than the overall survival after LR 5 years after surgery (66.67% versus 60.35%, odds ratio 0.60 [0.45; 0.78], p <0.001); there was no significant difference 1 year or 3 years after surgery. Nor was there any significant difference in morbidity or mortality between the two types of treatment in this subgroup. These findings contrast with the results obtained in all of the studies, which documented significantly better survival 3 years after LT. CONCLUSION: Three years after surgery, the survival rates and complication rates of patients with early HCC treated with either LR or LT are comparable. Resection should therefore be the preferred form of treatment if the prerequisites for it are met. In case of recurrent tumor, these patients can still be evaluated for liver transplantation. This strategy could improve the allocation of donor organs. PMID- 28835327 TI - Tension Pneumocephalus Due to an Osteoma of the Frontal Sinus. PMID- 28835326 TI - Juvenile Stroke. AB - BACKGROUND: So-called juvenile stroke, i.e., stroke in a person aged 18 to 55, affects approximately 30 000 persons per year in Germany and is thus an important cause of mortality and permanent morbidity. The spectrum of causes of stroke is broader in this age group than in older patients and is also differently distributed. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed and on current guideline recommendations. RESULTS: Juvenile strokes are often caused by cardiogenic emboli (ca. 25%) and by vascular dissection (ca. 20%). Approximately 10% are due to rare causes such as vasculitis or thrombophilia, 25-50% remain cryptogenic, and 20-30% meet the criteria for an embolic stroke of undetermined source (ESUS). A rational diagnostic algorithm should be applied that is based on the relative frequencies of the potential causes. The acute treatment of ischemic stroke is the same for patients of all ages: the patient must be transferred as soon as possible to a hospital where a vascular recanalization procedure can be performed. From age 40 onward, there is a steep rise in vascular risk factors and therefore also in the resulting macro- and microangiopathy, which lead, in turn, to stroke. Only 40% of patients with juvenile stroke are ever able to return to their original occupation, and approximately one-third remain permanently unable to work. CONCLUSION: The high rates of cryptogenic stroke and ESUS among patients with juvenile stroke indicate that uncertainties remain in the diagnosis and treatment of this entity. The identification of rare causes of juvenile stroke requires a major diagnostic effort. Which diagnostic tests are useful or necessary in which patients is a matter that is currently decided on an individual basis. This is true, above all, of the indication for long-term cardiac monitoring. PMID- 28835328 TI - Positional Skull Deformities. AB - BACKGROUND: Especially in the first 6 months of life, skull deformities manifesting as a uni- or bilateral flattening of the occiput often give rise to questions of differential diagnosis and potential treatment. In this review, the authors summarize the current understanding of risk factors for this condition, and the current state of the relevant diagnostic assessment and options for treatment. METHODS: The recommendations given in this selective review of the literature are based on current studies and on existing guidelines on the prevention of sudden infant death, the recommendations of the German Society for Pediatric Neurology (Deutsche Gesellschaft fur Neuropadiatrie), and the American guidelines on the treatment of positional plagiocephaly in infancy. RESULTS: Pre , peri-, and postnatal risk factors can contribute to the development of positional skull deformities. These deformities can be diagnosed and classified on the basis of their clinical features, supplemented in unclear cases by ultrasonography of the cranial sutures. The putative relationship between positional skull deformities and developmental delay is currently debated. The main preventive and therapeutic measure is parent education to foster correct positioning habits (turning of the infant to the less favored side; prone positioning on occasion when awake) and beneficial stimulation of the infant (to promote lying on the less favored side). If the range of motion of the head is limited, physiotherapy is an effective additional measure. In severe or refractory cases, a skull orthosis (splint) may be useful. CONCLUSION: The parents of children with positional skull deformities should be comprehensively informed about the necessary preventive and therapeutic measures. Treatment should be initiated early and provided in graded fashion, according to the degree of severity of the problem. Parental concern about the deformity should not be allowed to lead to a rejection of the reasonable recommendation for a supine sleeping position. PMID- 28835329 TI - Imitation is the Sincerest Form of Flattery. PMID- 28835331 TI - A 76-Year-Old Woman With Chest Pain and Tarry Stool. PMID- 28835330 TI - In Reply. PMID- 28835332 TI - Prospective observational study to assess the need for postoperative antibiotics following surgical incision and drainage of skin and soft tissue abscess in pediatric patients. AB - BACKGROUND: Post-operative antibiotics are often utilized for skin and soft tissue infection (SSTI) requiring surgical incision and drainage (I&D). We propose that antibiotics are unnecessary following I&D. METHODS: Patients aged 3months to 6years with SSTI of the buttocks, groin, thigh, and/or labia requiring I&D were prospectively enrolled. The primary outcome was the proportion of patients requiring re-drainage and/or antibiotics for SSTI recurrence, within 30days. Follow-up consisted of a 30-day phone call, with optional 2-week office visit, combined with chart review for patients lost to follow-up. A one-sample binomial proportion with 95% confidence interval (CI) was used to examine non inferiority for rate of treatment success, using previously published success rates for patients receiving antibiotics post-operatively (95.9%, with a 7% margin of equivalence). RESULTS: A total of 92 patients were enrolled. All patients received pre-operative antibiotics. There was one treatment failure (success rate 0.989, CI 0.941-0.999). The recurrence rate was noninferior to previously-published data for patients receiving postoperative antibiotics (p<0.001). Subgroup analysis of patients who completed 30-day follow-up yielded a success rate of 0.973, CI 0.858-0.999 and evidence of non-inferiority (p=0.04). CONCLUSIONS: Post-operative management excluding antibiotics should be considered for patients who undergo I&D for SSTI. LEVEL OF EVIDENCE: Level II (prospective cohort study with <80% follow-up). PMID- 28835333 TI - Corrigendum to "Mind-body interactions in the regulation of airway inflammation in asthma: A PET study of acute and chronic stress" [Brain Behav. Immun. 58 (2016) 18-30]. PMID- 28835334 TI - Risk Stratification in Multinodular Goiter: A Retrospective Review of Sonographic Features, Histopathological Results, and Cancer Risk. AB - PURPOSE: In the management of thyroid nodules, although the potential for malignancy exists, there is also the potential for overtreatment of subclinical disease. Although the TI-RADS (Thyroid Imaging-Reporting and Data System) system outlines a risk stratification score based on suspicious ultrasound findings, it has not been universally accepted. Many TI-RADS 2 or 3 patients proceed to fine needle aspiration biopsy (FNAB), potentially unnecessarily. The aim of the study was to identify whether lesions within a multinodular goiter (MNG) without suspicious features can be followed with ultrasound rather than biopsied as is recommended for single nodules. METHODS: Pathology records were retrospectively analysed for proven MNGs over a 5-year period. A total of 293 cases were identified. FNAB, prebiopsy ultrasound images, and reports were identified for each case. Images were reviewed and assessed for sonographically suspicious criteria guided by TI-RADS. Logistic regression was applied to determine if any sonographic features were associated with neoplasia. Odds ratios with 95% confidence intervals were calculated. RESULTS: Of 293 samples, 14 (4.7%) were neoplastic. Having no suspicious features conferred an average risk of 0.0339 (95% confidence interval: 0.02831-0.04087) of neoplasia. Risk of neoplasm significantly increased by having 1 and >1 suspicious feature (P < .001). Regarding cytological results, of 237 patients with Thy-2 cytology, 159 were followed up and 8 had a neoplasm. CONCLUSION: Ultrasound can be used to estimate risk of neoplasia in MNG. In the absence of suspicious radiological findings, follow-up with ultrasound rather than FNAB may be appropriate in patients who have a low clinical suspicion for neoplasia. PMID- 28835335 TI - The Positive Outcome of MRI-Guided Vacuum Assisted Core Needle Breast Biopsies Is Not Influenced by a Prior Negative Targeted Second-Look Ultrasound. AB - PURPOSE: The study sought to investigate the outcome of breast magnetic resonance guided biopsies as a function of the indication for magnetic resonance imaging (MRI), the MRI features of the lesions, and the performance or not of a targeted second-look ultrasound (SLUS) prior breast MRI-guided biopsy. METHODS: We identified 158 women with MRI-detected breast lesions scheduled for MRI-guided biopsy (2007-2013). Patient demographics, performance of targeted SLUS, imaging characteristics, and subsequent pathology results were reviewed. RESULTS: Three biopsies were deferred, and 155 lesions were biopsied under MRI guidance (155 women; median age 55.14 years; range 27-80 years). Ninety-eight women underwent a SLUS prior to the MRI-guided biopsy (63%). Of the 155 biopsied lesions, 23 (15%) were malignant, 106 (68%) were benign, and 26 (17%) were high risk. Four of 15 surgically excised high-risk lesions were upgraded to malignancy (27%). Most of the biopsied lesions corresponded to non-mass-like enhancement (81%, 126 of 155) and most of the biopsies (52%, 81 of 155) were performed in a screening context. No demographic or MRI features were associated with malignancy. No differences were noted between the 2 subgroups (prior SLUS vs no prior SLUS) except for the presence of a synchronous carcinoma associated with a likelihood of targeted SLUS before MRI-guided biopsy (P = .001). CONCLUSION: A negative SLUS does not influence the pathology outcome of a suspicious lesion biopsied under MR guidance. PMID- 28835337 TI - The assassination of a hypothesis by non-critical interpretation of molecular data: A comment on. AB - In a recent paper, Sharma et al. (2017) tested the hypothesis that eggs attached to males' legs in podoctid harvestmen are laid by conspecifics. Using molecular methods, they falsify the "paternal care hypothesis" and suggest that the eggs belong to spiders. Here we raise several criticisms to the authenticity of this finding and present arguments supporting the hypothesis that eggs belong to harvestmen and are not accidentally attached to the males. We argue that the falsification of the paternal care hypothesis in podoctids is premature and based on non-critical interpretation of molecular data. PMID- 28835338 TI - Perceived neighborhood quality, family processes, and trajectories of child and adolescent externalizing behaviors in the United States. AB - RATIONALE: Externalizing behavior problems are common among children and adolescents, and have considerable negative impacts on their long-term health and wellbeing. Substantial evidence supports a link between neighborhood conditions and externalizing behaviors. However, the timing of neighborhood effects on the developmental course of externalizing behaviors and the role of family and peer processes in shaping neighborhood effects remains unclear. OBJECTIVE: The current study aims to examine the relationship between perceived neighborhood quality and trajectories of child externalizing behaviors in a U.S. nationally representative cohort, focusing on the timing of neighborhood effects and the role of family and peer processes in mediating these effects. METHODS: The study included 3563 children who participated in three consecutive waves of Child Development Supplement of the Panel Study of Income Dynamics in 1997, 2002 and 2007. In a latent growth curve model (LGCM), we estimated trajectories of externalizing behaviors and the effects of perceived neighborhood quality on the trajectories, using parental, family and peer processes as potential mediators. RESULTS: At baseline, better neighborhood quality was moderately associated with fewer externalizing behaviors among seven-to twelve-year-olds, but was not associated with externalizing behaviors among children six years and younger. During follow up, better neighborhood quality was associated with small decreases in externalizing behaviors, primarily mediated by lower levels of parental distress and family conflict. CONCLUSIONS: This study suggests that better perceived neighborhood quality contributes to fewer externalizing behaviors throughout childhood and adolescence, and that parental distress and family conflict are the main mediators of these effects. Given the pervasiveness of exposure to adverse neighborhood conditions, efforts to reduce concentrated poverty and improve neighborhood environments may improve children and adolescents' mental health at the population level. PMID- 28835336 TI - Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease. AB - BACKGROUND: Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion. METHODOLOGY: PWCF homozygous for the DeltaF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and MU-calpain assays. FINDINGS: Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating MU-calpain. In vivo and in vitro, increased MU-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion. INTERPRETATION: Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion. PMID- 28835339 TI - Blood-tumor barrier opening changes in brain metastases from pre to one-month post radiation therapy. AB - PURPOSE: Blood-tumor barrier is a limiting factor for effectiveness of systemic therapy to brain metastases. This study aimed to assess the extent and time course of BTB opening in BM following whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) to determine optimal timing for systemic therapy. MATERIALS AND METHOD: 30 patients received WBRT or SRS and a total of 64 metastatic lesions were analyzed. Dynamic contrast-enhanced MRI were acquired, to quantify a transfer constant (Ktrans), pre-RT, 1-2weeks after starting RT (Wk1 2), and 1-month post-RT (1M post-RT). Lesions were categorized as either low or high permeability based upon the pre-RT percentage volume of a lesion with Ktrans>0.005min-1 (%Vall) less or greater than 50%. Time-course changes of %Vall after RT were analyzed. RESULTS: Fifty-seven lesions had high-permeability and seven had low-permeability at baseline. Intra-patient and inter-lesion heterogeneity was observed in six patients who had both low- (n=7) and high permeability lesions (n=10). Also, lesion permeability showed a significant size effect at baseline. For high-permeability lesions, either received WBRT (n=43) or SRS (n=14), %Vall decreased non-significantly following RT (from 85.4% pre-RT to 76.9% 1M post-RT). For low-permeability lesions (n=7, all received WBRT), %Vall increased from 5.6% pre-RT to 30.2% at Wk1-2 and to 52.6% 1M-post (p=0.01). CONCLUSION: Our preliminary results suggest that 2-4weeks after RT, when BTB opening is high for both low- and high-permeability brain metastatic lesions, could be optimal time to start systemic therapy. PMID- 28835341 TI - Nodal cilia-driven flow: Development of a computational model of the nodal cilia axoneme. AB - Cilia-driven nodal flow is important in the determination of left-right asymmetry in the body. Several theoretical and computational models have been proposed to explain the mechanics of ciliary motion, although the full mechanism remains unknown. Here, we developed a three-dimensional nodal cilia axoneme model using a finite element-boundary element coupling method, and investigated the mechanics of nodal ciliary motion. We found that the rotational orbit was strongly dependent on the dynein activation frequency. We also investigated flow field generated by the ciliary rotation, and the flow strength decayed as r-3 at the far field from the cilium. Our numerical results also suggest that experimentally observed tilt angle theta=2pi/9 is sufficiently large to make a leftward flow. These findings are helpful in better understanding ciliary motion and nodal flow. PMID- 28835340 TI - Quantification of bladder wall biomechanics during urodynamics: A methodologic investigation using ultrasound. AB - Overactive bladder is often characterized by biomechanical changes in the bladder wall, but there is no established method to measure these changes in vivo. The goal of this study was to develop a novel method to determine detrusor wall biomechanical parameters during urodynamics through the incorporation of transabdominal ultrasound imaging. Individuals with overactive bladder (OAB) underwent ultrasound imaging during filling. The fill rate was 10% of the cystometric capacity per minute as determined by an initial fill. Transabdominal ultrasound images were captured in the midsagittal and transverse planes at 1min intervals. Using image data and Pves, detrusor wall tension, stress, and compliance were calculated. From each cross-sectional image, luminal and wall areas along with inner perimeters were measured. In the sagittal and transverse planes, wall tension was calculated as Pves*luminal area, wall stress as tension/wall area, and strain as the change in perimeter normalized to the perimeter at 10% capacity. Elastic modulus was calculated as stress/strain in the medial-lateral and cranial-caudal directions. Patient-reported fullness sensation was continuously recorded. Data from five individuals with OAB showed that detrusor wall tension, volume, and strain had the highest correlations to continuous bladder sensation of all quantities measured. This study demonstrates how detrusor wall tension, stress, strain, and elastic modulus can be quantified by adding ultrasound imaging to standard urodynamics. This technique may be useful in diagnosing and better understanding the biomechanics involved in OAB and other bladder disorders. PMID- 28835342 TI - Loss of ACL function leads to alterations in tibial plateau common dynamic contact stress profiles. AB - It has been suggested that the repetitive nature of altered joint tissue loading which occurs after anterior cruciate ligament (ACL) rupture can contribute to the development of osteoarthritis (OA). However, changes in dynamic knee joint contact stresses after ACL rupture have not been quantified for activities of daily living. Our objective was to characterize changes in dynamic contact stress profiles that occur across the tibial plateau immediately after ACL transection. By subjecting sensor-augmented cadaveric knees to simulated gait, and analyzing the resulting contact stress profiles using a normalized cross-correlation algorithm, we tested the hypothesis that common changes in dynamic contact stress profiles exist after ACL injury. Three common profiles were identified in intact knees, occurring on the: (I) posterior lateral plateau, (II) posterior medial plateau, and (III) central region of the medial plateau. In ACL-transected knees, the magnitude and shape of the common dynamic stress profiles did not change, but their locations on the tibial plateau and the number of knees identified for each profile changed. Furthermore, in the ACL transected knees, a unique common contact stress profile was identified in the posterior region of the lateral plateau near the tibial spine. This framework can be used to understand the regional and temporal changes in joint mechanics after injury. PMID- 28835343 TI - Hemodynamic characteristics of flow around a deformable stenosis. AB - Clinical studies reported that some vulnerable stenoses deformed their shape in a blood vessel based on flow condition. However, the effects of shape variation on flow characteristics remain unclear. The flow characteristics are known to affect vulnerable stenosis rupture and fractional flow reserve (FFR) value which has been widely used as a diagnostic tool for stenosis. Vulnerable stenosis rupture occurs when the structural stress exerted on a fibrous cap exceeds its tolerable threshold. The stress magnitude is determined from the spatial distribution of static pressure around the stenosis. In the present study, the static pressure distribution and the FFR value in deformable stenosis were investigated with related other flow characteristics. Two phantom models were fabricated to mimic deformable and nondeformable stenoses using polydimethylsiloxane. The flow characteristics were observed under a steady-flow condition at three Reynolds numbers (Re=500, 1000, 1500) using a particle image velocimetry. The pressure drop across the stenosis models were measured using a pressure sensor to determine effects of shape deformation on FFR value. Shape variations and jet deflections were clearly observed in the deformable stenosis model, and the effective severity of the stenosis increased up to 17.2%. The shape variations of deformable stenosis model increased the static pressure difference at the upstream and downstream sides of the stenosis. The pressure drop across the deformable stenosis model was significantly higher than that of the nondeformable stenosis model. The present results substantiate that stenosis deformability should be carefully considered to diagnose the rupture of vulnerable stenosis. PMID- 28835344 TI - Identification of preliminary core outcome domains for communication about childhood vaccination: An online Delphi survey. AB - BACKGROUND: Communication interventions for childhood vaccination are promising strategies to address vaccine hesitancy, but current research is limited by the outcomes measured. Most studies measure only vaccination-related outcomes, with minimal consideration of vaccine hesitancy-relevant intermediate outcomes. This impedes understanding of which interventions or elements are effective. It is also unknown which outcomes are important to the range of stakeholders affected by vaccine hesitancy. Outcome selection shapes the evidence base, informing future interventions and trials, and should reflect stakeholder priorities. Therefore, our aim was to identify which outcome domains (i.e. broad outcome categories) are most important to different stakeholders, identifying preliminary core outcome domains to inform evaluation of three common vaccination communication types: (i) communication to inform or educate, (ii) remind or recall, and (iii) enhance community ownership. METHODS: We conducted a two-stage online Delphi survey, involving four stakeholder groups: parents or community members, healthcare providers, researchers, and government or non-governmental organisation representatives. Participants rated the importance of eight outcome domains for each of the three communication types. They also rated specific outcomes within one domain ("attitudes or beliefs") and provided feedback about the survey. RESULTS: Collectively, stakeholder groups prioritised outcome domains differently when considering the effects of different communication types. For communication that aims to (i) inform or educate, the most important outcome domain is "knowledge or understanding"; for (ii) reminder communication, "vaccination status and behaviours"; and for (iii) community engagement communication, "community participation". All stakeholder groups rated most outcome domains as very important or critical. The highest rated specific outcome within the "attitudes or beliefs" domain was "trust". CONCLUSION: This Delphi survey expands the field of core outcomes research and identifies preliminary core outcome domains for measuring the effects of communication about childhood vaccination. The findings support the argument that vaccination communication is not a single homogenous intervention - it has a range of purposes, and vaccination communication evaluators should select outcomes accordingly. PMID- 28835345 TI - Dual use issues in research - A subject of increasing concern? AB - Dual use is defined as the application of materials, knowledge or technologies for military or terrorist purposes, as well as for good. In biological science, it is considered to be a growing threat as the genetics of pathogenicity traits and toxins are becoming on one hand elucidated in a detail that was not anticipated 20years ago and on the other hand technological advances in genetic engineering and synthetic biology are continually enabling easier access to these technologies. On a theoretical and policy level, much has happened over the past decade, but translating these policies and concepts to operational level awareness and robust processes requires more attention. Where the research is conducted, scientists have to make ethical judgements and account for their data sharing and publication policies. How can we ensure the requirement for dual use review is taken on board, but is not skewing research detrimentally and imposing a disproportionate burden? PMID- 28835346 TI - The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-alpha chloro-2'-beta-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors. AB - Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-alpha-chloro-2'-beta-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection. PMID- 28835347 TI - Cytotoxic effect of sanguiin H-6 on MCF-7 and MDA-MB-231 human breast carcinoma cells. AB - Sanguiin H-6 is a dimer of casuarictin linked by a bond between the gallic acid residue and one of the hexahydroxydiphenic acid units. It is an effective compound extracted from Rubus coreanus. It has an anticancer effect against several human cancer cells; however, its effect on breast cancer cells has not been clearly demonstrated. Thus, we aimed to investigate the anticancer effect and mechanism of action of sanguiin H-6 against two human breast carcinoma cell lines (MCF-7 and MDA-MB-231). We found that sanguiin H-6 significantly reduced cell viability in a concentration-dependent manner. It also increased the rates at which MCF-7 and MDA-MB-231 cells underwent apoptosis. Furthermore, sanguiin H 6 induced the cleavage of caspase-8, caspase-3, and poly(ADP-ribose) polymerase, which resulted in apoptosis. However, cleavage of caspase-9 was only detectable in MCF-7 cells. In addition, sanguiin H-6 increased the ratio of Bax to Bcl-2 in both MCF-7 and MDA-MB-231 cells. These findings suggest that sanguiin H-6 is a potent therapeutic agent against breast cancer cells. In addition, it exerts its anticancer effect in an estrogen-receptor-independent manner. PMID- 28835348 TI - Synthesis, antimicrobial activity, structure-activity relationship and cytotoxic studies of a new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene) 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones. AB - A new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro 2H-benzo[b][1,4]oxazin-2-ones 23-26, incorporating pharmaceutically privileged substructures such as cyclopropyl, naphthyl, biphenyl and cyclohexylphenyl were synthesized in excellent yields. All the synthesized compounds were screened for their in vitro antibacterial activity against gram-(+)ve and gram-(-)ve bacterial species i.e. S. griseus, S. aureus, B. subtillis and E. coli as well as in vitro antifungal activity against fungal species i.e. F. oxysporium, A. niger, P. funiculosum and T. reesei, respectively. In this study, compounds containing cyclopropyl and cyclohexylphenyl substructures were identified as promising antimicrobial agents than standard drugs, ampicillin and chloramphenicol as well as ketoconazole. SAR study illustrates that electron-withdrawing groups increases the antibacterial as well as antifungal activity of 2-oxo-benzo[1,4]oxazines and vice versa. Compounds 23e and 26e, the most active compounds of the series, displayed promising antibacterial activity than Ampicillin and Chloramphenicol. Moreover, compound 26d showed promising antifungal potency as compared to Ketoconazole. Cytotoxic studies of the active compounds i.e. 23c-e, 24e, 25d and 26d-e found to be non-toxic in nature in 3T3 fibroblast cell lines using MTT assay. PMID- 28835349 TI - Nrf2 activators from Glycyrrhiza inflata and their hepatoprotective activities against CCl4-induced liver injury in mice. AB - Glycyrrhiza inflata (licorice) has been used to treat liver diseases for a long history. However, the bioactive compounds are still not clear. In this work, 77 compounds, including 9 new ones, were isolated from the EtOAc extract of the roots and rhizomes of G. inflata. The Nrf2 activation activities of all compounds were screened using ARE-luciferase reporter assay on HepG2C8 cells. The results indicated a number of chalcones were potent Nrf2 activators, including 11 (licochalcone A, 4.07-fold), 12 (licochalcone B, 5.17-fold), and 19 (echinatin, 4.09-fold). Further studies indicated that 11, 12 and 19 remarkably attenuated CCl4-induced acute liver injury in mice (10 or 50mg/kg, 7days, ig.). These compounds could be promising hepatoprotective natural agents. PMID- 28835350 TI - Development of water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents. AB - In this work, four series of tertiary amine-containing derivatives of 3,5 dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against Mycobacterium tuberculosis CNCTC My 331/88 (H37Rv), comparable to those of the first-line drugs isoniazid and rifampicin. The presence of two tertiary amines in these N-benzylpiperazine derivatives enabled us to prepare water-soluble dihydrochloride salts, overcoming the serious drawback of previously described 3,5-dinitrophenyl tetrazole and oxadiazole lead compounds. The water-soluble 3,5 dinitrophenyl tetrazole and oxadiazole antitubercular agents described in this work are good candidates for further in vitro and in vivo pharmacokinetic and pharmacodynamic studies. PMID- 28835351 TI - Emerging therapeutic modalities for acute myeloid leukemia (AML) in older adults. AB - Treatment for the older adult with acute myeloid leukemia (AML) is challenging, due to both more aggressive disease biology as well as patient-related risk factors that limit tolerance of intensive chemotherapy. The use of prognostic models and comprehensive geriatric assessments can help hematologists evaluate the suitability of intensive chemotherapy for individual patients. For older patients considered fit for intensive chemotherapy, standard induction therapy should be given, followed by consideration of reduced intensity allogeneic stem cell transplantation. Patients considered unfit for intensive therapy are standardly treated with hypomethylating agents. Several new therapeutic agents have shown promising results either by improving intensive chemotherapy (CPX 351), by improving upon lower intensity therapy (venetoclax, antibody drug conjugates), or by targeting somatic mutations (FLT3 inhibitors and others). PMID- 28835352 TI - Dendrites fragmentation induced by oscillating cavitation bubbles in ultrasound field. AB - The fragmentation of the dendrites of succinonitrile (SCN)-2-wt.% acetone organic transparent alloy caused by ultrasound-induced cavitation bubbles was studied by using ultra-high-speed digital camera with a rate of 40,000fps. Real-time imaging reveals that the vibrating cavitation bubbles can fragment not only secondary arms but also the primary ones under high ultrasound power. The secondary arms always broke at their roots as a result of stress concentration induced by oscillated cavitation bubble and then ripped off from their primary arms. Generally the fragment process takes tens of milliseconds from bending to breaking, while the break always occurs immediately in less than 25MUs. PMID- 28835353 TI - A Web-Based and Print-Based Computer-Tailored Physical Activity Intervention for Prostate and Colorectal Cancer Survivors: A Comparison of User Characteristics and Intervention Use. AB - BACKGROUND: Physical activity (PA) is beneficial in improving negative physical and psychological effects of cancer. The rapidly increasing number of cancer survivors, resulting from aging and improved cancer care, emphasizes the importance to develop and provide low cost, easy accessible PA programs. Such programs could be provided through the Internet, but that could result in the exclusion of cancer survivors not familiar with the Internet. Therefore, we developed a computer-tailored PA intervention for prostate and colorectal cancer survivors in which both Web-based and print materials are provided, and participants can choose their own preferred delivery mode. OBJECTIVE: The aim of this study was to assess participants' characteristics related to delivery mode and use of intervention materials. METHODS: We studied characteristics of participants using Web-based and printed intervention materials in a randomized controlled trial (RCT). Prostate and colorectal cancer survivors recruited from hospitals were randomized to OncoActive (computer-tailored PA intervention) or a usual-care control group. OncoActive participants received both Web-based and printed materials. Participants were classified into initial print- or Web-based participants based on their preferred mode of completion of the first questionnaire, which was needed for the computer-tailored PA advice. Intervention material use during the remainder of the intervention was compared for initial print- or Web-based participants. Additionally, participants were classified into those using only print materials and those using Web-based materials. Differences in participant characteristics and intervention material use were studied through analysis of variance (ANOVAs), chi-square tests, and logistic regressions. RESULTS: The majority of the participants in the intervention group were classified as initial Web-based participants (170/249, 68.3%), and 84.9% (191/249) used Web-based intervention materials. Dropout was low (15/249, 6.0%) and differed between initial Web-based (4/170, 2.4%) and print-based (11/79, 14%) participants. Participants were less likely to start Web-based with higher age (odds ratio [OR]=0.93), longer time since last treatment (OR=0.87), and higher fatigue (OR=0.96), and more likely with higher education (OR=4.08) and having completed treatments (OR=5.58). Those who were older (OR=0.93) and post treatment for a longer time (OR=0.86) were less likely to use Web-based intervention materials. Initial print-based participants predominantly used print-based materials, whereas initial Web-based participants used both print- and Web-based materials. CONCLUSIONS: To our knowledge, this is one of the first studies that assessed participant characteristics related to delivery mode in an intervention in which participants had a free choice of delivery modes. Use of print-based materials among the initial Web-based participants was substantial, indicating the importance of print-based materials. According to our findings, it may be important to offer Web- and print-based materials alongside each other. Providing Web-based materials only may exclude older, less educated, more fatigued, or currently treated participants; these groups are especially more vulnerable and could benefit most from PA interventions. PMID- 28835355 TI - Efficacy of Lactobacillus Reuteri DSM 17938 for the Treatment of Acute Gastroenteritis in Children: Protocol of a Randomized Controlled Trial. AB - BACKGROUND: Acute gastroenteritis (AGE) is one of the most common diseases among children. Oral rehydration therapy is the key treatment. However, despite proven efficacy, it remains underused. This is because oral rehydration solution neither reduces the frequency of bowel movements and fluid loss nor shortens the duration of illness. Hence, there is interest in adjunctive treatments. According to the 2014 guidelines developed by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, the use of the following probiotics may be considered in the management of children with AGE in addition to rehydration therapy: Lactobacillus rhamnosus GG (low quality of evidence; strong recommendation) and Saccharomyces boulardii (low quality of evidence; strong recommendation). Less compelling evidence is available for Lactobacillus reuteri DSM 17938 (very low quality of evidence; weak recommendation). OBJECTIVE: Considering that evidence on L reuteri remains limited, the goal of the study is to assess the effectiveness of L reuteri DSM 17938 in the treatment of AGE in children. Children vaccinated and not vaccinated against rotavirus will be evaluated separately. METHODS: This will be a double-blind, placebo-controlled, randomized trial. Children between 1 and 60 months of age with AGE, defined as a change in stool consistency to loose or liquid form (according to the Bristol Stool Form scale or Amsterdam Stool Form scale) and/or an increase in the frequency of evacuations (typically >=3 in 24 h) lasting for no longer than 5 days, will be recruited. A total of 72 children will receive either L reuteri DSM 17938 at a dose of 2*108colony-forming units twice daily or matching placebo for 5 consecutive days. A similar sample size for rotavirus vaccinated and nonvaccinated children is planned. The primary outcome measure is the duration of diarrhea. Two separate studies and reports for rotavirus vaccinated and nonvaccinated children are planned. RESULTS: The recruitment started in January 2017 and is planned to be finalized in June 2018 for rotavirus nonvaccinated children. The recruitment of rotavirus-vaccinated children may be slower due to a relatively low coverage rate in Poland. Data analysis and submission to a peer reviewed journal is expected within 3 months after completion of the study. CONCLUSION: This study will add to current knowledge on the efficacy of L reuteri DSM 17938 for the management of AGE. TRIAL REGISTRATION: ClinicalTrials.gov NCT02989350; https://clinicaltrials.gov/ct2/show/NCT02989350 (Archived by WebCite at http://www.webcitation.org/6slOFkyTH). PMID- 28835354 TI - Comparing Inpatient Satisfaction Collected via a Web-Based Questionnaire Self Completion and Through a Telephone Interview: An Ancillary Study of the SENTIPAT Randomized Controlled Trial. AB - BACKGROUND: Assessing the satisfaction of patients about the health care they have received is relatively common nowadays. In France, the satisfaction questionnaire, I-Satis, is deployed in each institution admitting inpatients. Internet self-completion and telephone interview are the two modes of administration for collecting inpatient satisfaction that have never been compared in a multicenter randomized experiment involving a substantial number of patients. OBJECTIVE: The objective of this study was to compare two modes of survey administration for collecting inpatient satisfaction: Internet self completion and telephone interview. METHODS: In the multicenter SENTIPAT (acronym for the concept of sentinel patients, ie, patients who would voluntarily report their health evolution on a dedicated website) randomized controlled trial, patients who were discharged from the hospital to home and had an Internet connection at home were enrolled between February 2013 and September 2014. They were randomized to either self-complete a set of questionnaires using a dedicated website or to provide answers to the same questionnaires administered during a telephone interview. As recommended by French authorities, the analysis of I Satis satisfaction questionnaire involved all inpatients with a length of stay (LOS), including at least two nights. Participation rates, questionnaire consistency (measured using Cronbach alpha coefficient), and satisfaction scores were compared in the two groups. RESULTS: A total of 1680 eligible patients were randomized to the Internet group (n=840) or the telephone group (n=840). The analysis of I-Satis concerned 392 and 389 patients fulfilling the minimum LOS required in the Internet and telephone group, respectively. There were 39.3% (154/392) and 88.4% (344/389) responders in the Internet and telephone group, respectively (P<.001), with similar baseline variables. Internal consistency of the global satisfaction score was higher (P=.03) in the Internet group (Cronbach alpha estimate=.89; 95% CI 0.86-0.91) than in the telephone group (Cronbach alpha estimate=.84; 95% CI 0.79-0.87). The mean global satisfaction score was lower (P=.03) in the Internet group (68.9; 95% CI 66.4-71.4) than in the telephone group (72.1; 95% CI 70.4-74.6), with a corresponding effect size of the difference at -0.253. CONCLUSIONS: The lower response rate issued from Internet administration should be balanced with a likely improved quality in satisfaction estimates, when compared with telephone administration, for which an interviewer effect cannot be excluded. TRIAL REGISTRATION: Clinicaltrials.gov NCT01769261 ; http://clinicaltrials.gov/ct2/show/NCT01769261 (Archived by WebCite at http://www.webcitation.org/6ZDF5lA41). PMID- 28835356 TI - A Brain Phenotype for Stressor-Evoked Blood Pressure Reactivity. AB - BACKGROUND: Individuals who exhibit large-magnitude blood pressure (BP) reactions to acute psychological stressors are at risk for hypertension and premature death by cardiovascular disease. This study tested whether a multivariate pattern of stressor-evoked brain activity could reliably predict individual differences in BP reactivity, providing novel evidence for a candidate neurophysiological source of stress-related cardiovascular risk. METHODS AND RESULTS: Community-dwelling adults (N=310; 30-51 years; 153 women) underwent functional magnetic resonance imaging with concurrent BP monitoring while completing a standardized battery of stressor tasks. Across individuals, the battery evoked an increase systolic and diastolic BP relative to a nonstressor baseline period (M ?systolic BP/?diastolic BP=4.3/1.9 mm Hg [95% confidence interval=3.7-5.0/1.4-2.3 mm Hg]). Using cross validation and machine learning approaches, including dimensionality reduction and linear shrinkage models, a multivariate pattern of stressor-evoked functional magnetic resonance imaging activity was identified in a training subsample (N=206). This multivariate pattern reliably predicted both systolic BP (r=0.32; P<0.005) and diastolic BP (r=0.25; P<0.01) reactivity in an independent subsample used for testing and replication (N=104). Brain areas encompassed by the pattern that were strongly predictive included those implicated in psychological stressor processing and cardiovascular responding through autonomic pathways, including the medial prefrontal cortex, anterior cingulate cortex, and insula. CONCLUSIONS: A novel multivariate pattern of stressor-evoked brain activity may comprise a phenotype that partly accounts for individual differences in BP reactivity, a stress-related cardiovascular risk factor. PMID- 28835357 TI - Activation of gamma2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury. AB - RATIONALE: AMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear. OBJECTIVE: We sought to determine the role of gamma2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the gamma-subunit in the heart. METHODS AND RESULTS: We found that gamma2 but not gamma1 or gamma3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing gamma2 subunit phosphorylated and inactivated RNA Pol I (polymerase I)-associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent downregulation of pre-rRNA level led to attenuated endoplasmic reticulum (ER) stress and cell death. Deleting gamma2-AMPK led to increases in pre-rRNA level, ER stress markers, and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of gamma2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of gamma2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of gamma1-AMPK, the lack of gamma2-AMPK sensitizes the heart to myocardial ischemia/reperfusion injury. The cKO failed to suppress pre rRNA level during ischemia/reperfusion and showed a greater infarct size. Conversely, cardiac-specific overexpression of gamma2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced. CONCLUSIONS: The gamma2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased gamma2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform specific function of gamma2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection. PMID- 28835358 TI - Combined Action of Human Commensal Bacteria and Amorphous Silica Nanoparticles on the Viability and Immune Responses of Dendritic Cells. AB - Dendritic cells (DCs) regulate the host-microbe balance in the gut and skin, tissues likely exposed to nanoparticles (NPs) present in drugs, food, and cosmetics. We analyzed the viability and the activation of DCs incubated with extracellular media (EMs) obtained from cultures of commensal bacteria (Escherichia coli, Staphylococcus epidermidis) or pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus) in the presence of amorphous silica nanoparticles (SiO2 NPs). EMs and NPs synergistically increased the levels of cytotoxicity and cytokine production, with different nanoparticle dose response characteristics being found, depending on the bacterial species. E. coli and S. epidermidis EMs plus NPs at nontoxic doses stimulated the secretion of interleukin-1beta (IL-1beta), IL-12, IL-10, and IL-6, while E. coli and S. epidermidis EMs plus NPs at toxic doses stimulated the secretion of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), IL-4, and IL-5. On the contrary, S. aureus and P. aeruginosa EMs induced cytokines only when they were combined with NPs at toxic concentrations. The induction of maturation markers (CD86, CD80, CD83, intercellular adhesion molecule 1, and major histocompatibility complex class II) by commensal bacteria but not by pathogenic ones was improved in the presence of noncytotoxic SiO2 NP doses. DCs consistently supported the proliferation and differentiation of CD4+ and CD8+ T cells secreting IFN-gamma and IL-17A. The synergistic induction of CD86 was due to nonprotein molecules present in the EMs from all bacteria tested. At variance with this finding, the synergistic induction of IL-1beta was prevalently mediated by proteins in the case of E. coli EMs and by nonproteins in the case of S. epidermidis EMs. A bacterial costimulus did not act on DCs after adsorption on SiO2 NPs but rather acted as an independent agonist. The inflammatory and immune actions of DCs stimulated by commensal bacterial agonists might be altered by the simultaneous exposure to engineered or environmental NPs. PMID- 28835359 TI - Mother-Newborn Pairs in Malawi Have Similar Antibody Repertoires to Diverse Malaria Antigens. AB - Maternal antibodies may play a role in protecting newborns against malaria disease. Plasmodium falciparum parasite surface antigens are diverse, and protection from infection requires allele-specific immunity. Although malaria specific antibodies have been shown to cross the placenta, the extent to which antibodies that respond to the full repertoire of diverse antigens are transferred from the mother to the infant has not been explored. Understanding the breadth of maternal antibody responses and to what extent these antibodies are transferred to the child can inform vaccine design and evaluation. We probed plasma from cord blood and serum from mothers at delivery using a customized protein microarray that included variants of malaria vaccine target antigens to assess the intensity and breadth of seroreactivity to three malaria vaccine candidate antigens in mother-newborn pairs in Malawi. Among the 33 paired specimens that were assessed, mothers and newborns had similar intensity and repertoire of seroreactivity. Maternal antibody levels against vaccine candidate antigens were the strongest predictors of infant antibody levels. Placental malaria did not significantly impair transplacental antibody transfer. However, mothers with placental malaria had significantly higher antibody levels against these blood-stage antigens than mothers without placental malaria. The repertoire and levels of infant antibodies against a wide range of malaria vaccine candidate antigen variants closely mirror maternal levels in breadth and magnitude regardless of evidence of placental malaria. Vaccinating mothers with an effective malaria vaccine during pregnancy may induce high and potentially protective antibody repertoires in newborns. PMID- 28835361 TI - Blinding indices and blinding scenarios of practitioners and patients with acupuncture needles for double blinding. PMID- 28835360 TI - Chlamydia trachomatis: the Persistent Pathogen. AB - Chlamydia trachomatis is an obligate intracellular bacterium whose only natural host is humans. Although presenting as asymptomatic in most women, genital tract chlamydial infections are a leading cause of pelvic inflammatory disease, tubal factor infertility, and ectopic pregnancy. C. trachomatis has evolved successful mechanisms to avoid destruction by autophagy and the host immune system and persist within host epithelial cells. The intracellular form of this organism, the reticulate body, can enter into a persistent nonreplicative but viable state under unfavorable conditions. The infectious form of the organism, the elementary body, is again generated when the immune attack subsides. In its persistent form, C. trachomatis ceases to produce its major structural and membrane components, but synthesis of its 60-kDa heat shock protein (hsp60) is greatly upregulated and released from the cell. The immune response to hsp60, perhaps exacerbated by repeated cycles of productive infection and persistence, may promote damage to fallopian tube epithelial cells, scar formation, and tubal occlusion. The chlamydial and human hsp60 proteins are very similar, and hsp60 is one of the first proteins produced by newly formed embryos. Thus, the development of immunity to epitopes in the chlamydial hsp60 that are also present in the corresponding human hsp60 may increase susceptibility to pregnancy failure in infected women. Delineation of host factors that increase the likelihood that C. trachomatis will avoid immune destruction and survive within host epithelial cells and utilization of this knowledge to design individualized preventative and treatment protocols are needed to more effectively combat infections by this persistent pathogen. PMID- 28835362 TI - Association Between Acidosis Soon After Reperfusion and Contrast-Induced Nephropathy in Patients With a First-Time ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is associated with poor outcomes in patients with acute myocardial infarction. However, the predictors of CIN have yet to be fully elucidated. METHODS AND RESULTS: The study included 273 consecutive patients with a first-time ST-segment elevation myocardial infarction who underwent reperfusion within 12 hours of symptom onset. The exclusion criteria were hemodialysis, mechanical ventilation, or previous coronary artery bypass grafting. All patients underwent arterial blood gas analysis soon after reperfusion. CIN was defined as an increase of 0.5 mg/dL in serum creatinine or a 25% increase from baseline between 48 and 72 hours after contrast medium exposure. Acidosis was defined as an arterial blood pH <7.35. CIN was observed in 35 patients (12.8%). Multivariable logistic regression analysis with forward stepwise algorithm revealed a significant association between CIN and the following: reperfusion time, the prevalence of hypertension, peak creatine kinase MB, high-sensitivity C-reactive protein on admission, and the incidence of acidosis (P<0.05). Multivariable logistic regression analysis revealed that the incidence of acidosis was associated with CIN when adjusted for age, male sex, body mass index, amount of contrast medium used, estimated glomerular filtration rate on admission, glucose level on admission, high-sensitivity C-reactive protein on admission, and left ventricular ejection fraction (P<0.05). Moreover, the incidence of acidosis was associated with CIN when adjusted for the Mehran CIN risk score (odds ratio: 2.229, P=0.049). CONCLUSIONS: The incidence of acidosis soon after reperfusion was associated with CIN in patients with a first time ST-segment elevation myocardial infarction. PMID- 28835363 TI - The Metabolic Syndrome and Risk of Sudden Cardiac Death: The Atherosclerosis Risk in Communities Study. AB - BACKGROUND: Prior studies have demonstrated a link between the metabolic syndrome and increased risk of cardiovascular mortality. Whether the metabolic syndrome is associated with sudden cardiac death is uncertain. METHODS AND RESULTS: We characterized the relationship between sudden cardiac death and metabolic syndrome status among participants of the ARIC (Atherosclerosis Risk in Communities) Study (1987-2012) free of prevalent coronary heart disease or heart failure. Among 13 168 participants, 357 (2.7%) sudden cardiac deaths occurred during a median follow-up of 23.6 years. Participants with the metabolic syndrome (n=4444) had a higher cumulative incidence of sudden cardiac death than those without it (n=8724) (4.1% versus 2.3%, P<0.001). After adjustment for participant demographics and clinical factors other than components of the metabolic syndrome, the metabolic syndrome was independently associated with sudden cardiac death (hazard ratio, 1.70, 95% confidence interval, 1.37-2.12, P<0.001). This relationship was not modified by sex (interaction P=0.10) or race (interaction P=0.62) and was mediated by the metabolic syndrome criteria components. The risk of sudden cardiac death varied according to the number of metabolic syndrome components (hazard ratio 1.31 per additional component of the metabolic syndrome, 95% confidence interval, 1.19-1.44, P<0.001). Of the 5 components, elevated blood pressure, impaired fasting glucose, and low high-density lipoprotein were independently associated with sudden cardiac death. CONCLUSIONS: We observed that the metabolic syndrome was associated with a significantly increased risk of sudden cardiac death irrespective of sex or race. The risk of sudden cardiac death was proportional to the number of metabolic syndrome components. PMID- 28835364 TI - Home- and community-based growth monitoring to reduce early life growth faltering: an open-label, cluster-randomized controlled trial. AB - Background: Despite the continued high prevalence of faltering growth, height monitoring remains limited in many low- and middle-income countries.Objective: The objective of this study was to test whether providing parents with information on their child's height can improve children's height and developmental outcomes.Design: Villages in Chipata District, Zambia (n = 127), were randomly assigned with equal probability to 1 of 3 groups: home-based growth monitoring (HBGM), community-based growth monitoring including nutritional supplementation for children with stunted growth (CBGM+NS), and control. Primary study outcomes were individual height-for-age z score (HAZ) and overall child development assessed with the International Fetal and Newborn Growth Consortium for the 21st Century Neurodevelopment Assessment tool. Secondary outcomes were weight-for-age z score (WAZ), protein consumption, breastfeeding, and general dietary diversity.Results: We enrolled a total of 547 children with a median age of 13 mo at baseline. Estimated mean difference (beta) in HAZ was 0.127 (95% CI: 0.107, 0.361) for HBGM and -0.152 (95% CI: -0.341, 0.036) for CBGM+NS. HBGM had no impact on child development [beta: -0.017 (95% CI: -0.133, 0.098)]; CBGM+NS reduced overall child development scores by -0.118 SD (95% CI: -0.230, -0.006 SD). Both interventions had larger positive effects among children with stunted growth at baseline, with estimated interaction effects of 0.503 (95% CI: 0.160, 0.846) and 0.582 (95% CI: 0.134, 1.030) for CBGM+NS and HBGM, respectively. HBGM increased mean WAZ [beta = 0.183 (95% CI: 0.037, 0.328)]. Both interventions improved parental reports of children's protein intake.Conclusions: The results from this trial suggest that growth monitoring has a limited effect on children's height and development, despite improvements in self-reported feeding practices. HBGM had modest positive effects on children with stunted growth. Given its relatively low cost, this intervention may be a cost-effective tool for increasing parental efforts toward reducing children's physical growth deficits. This trial was registered at clinicaltrials.gov as NCT02242539. PMID- 28835365 TI - Coffee consumption after myocardial infarction and risk of cardiovascular mortality: a prospective analysis in the Alpha Omega Cohort. AB - Background: Consumption of coffee, one of the most popular beverages around the world, has been associated with a lower risk of cardiovascular and all-cause mortality in population-based studies. However, little is known about these associations in patient populations.Objective: This prospective study aimed to examine the consumption of caffeinated and decaffeinated coffee in relation to cardiovascular disease (CVD) mortality, ischemic heart disease (IHD) mortality, and all-cause mortality in patients with a prior myocardial infarction (MI).Design: We included 4365 Dutch patients from the Alpha Omega Cohort who were aged 60-80 y (21% female) and had experienced an MI <10 y before study enrollment. At baseline (2002-2006), dietary data including coffee consumption over the past month was collected with a 203-item validated food-frequency questionnaire. Causes of death were monitored until 1 January 2013. HRs for mortality in categories of coffee consumption were obtained from multivariable Cox proportional hazard models, adjusting for lifestyle and dietary factors.Results: Most patients (96%) drank coffee, and the median total coffee intake was 375 mL/d (~3 cups/d). During a median follow-up of 7.1 y, a total of 945 deaths occurred, including 396 CVD-related and 266 IHD-related deaths. Coffee consumption was inversely associated with CVD mortality, with HRs of 0.69 (95% CI: 0.54, 0.89) for >2-4 cups/d and 0.72 (0.55, 0.95) for >4 cups/d, compared with 0-2 cups/d. Corresponding HRs were 0.77 (95% CI: 0.57, 1.05) and 0.68 (95% CI: 0.48, 0.95) for IHD mortality and 0.84 (95% CI: 0.71, 1.00) and 0.82 (95% CI: 0.68, 0.98) for all-cause mortality, respectively. Similar associations were found for decaffeinated coffee and for coffee with additives.Conclusion: Drinking coffee, either caffeinated or decaffeinated, may lower the risk of CVD and IHD mortality in patients with a prior MI. This study was registered at clinicaltrials.gov as NCT03192410. PMID- 28835366 TI - Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y. AB - Background: Vitamin D deficiency is implicated in a range of common complex diseases that may be prevented by gestational vitamin D repletion. Understanding the metabolic mechanisms related to in utero vitamin D exposure may therefore shed light on complex disease susceptibility.Objective: The goal was to analyze the programming role of in utero vitamin D exposure on children's metabolomics profiles.Design: First, unsupervised clustering was done with plasma metabolomics profiles from a case-control subset of 245 children aged 3 y with and without asthma from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), in which pregnant women were randomly assigned to vitamin D supplementation or placebo. Thereafter, we analyzed the influence of maternal pre- and postsupplement vitamin D concentrations on cluster membership. Finally, we used the metabolites driving the clustering of children to identify the dominant metabolic pathways that were influential in each cluster.Results: We identified 3 clusters of children characterized by 1) high concentrations of fatty acids and amines and low maternal postsupplement vitamin D (mean +/- SD; 27.5 +/- 11.0 ng/mL), 2) high concentrations of amines, moderate concentrations of fatty acids, and normal maternal postsupplement vitamin D (34.0 +/- 14.1 ng/mL), and 3) low concentrations of fatty acids, amines, and normal maternal postsupplement vitamin D (35.2 +/- 15.9 ng/mL). Adjusting for sample storage time, maternal age and education, and both child asthma and vitamin D concentration at age 3 y did not modify the association between maternal postsupplement vitamin D and cluster membership (P = 0.0014). Maternal presupplement vitamin D did not influence cluster membership, whereas the combination of pre- and postsupplement concentrations did (P = 0.03).Conclusions: Young children can be clustered into distinct biologically meaningful groups by their metabolomics profiles. The clusters differed in concentrations of inflammatory mediators, and cluster membership was influenced by in utero vitamin D exposure, suggesting a prenatal programming role of vitamin D on the child's metabolome. This trial was registered at clinicaltrials.gov as NCT00920621. PMID- 28835367 TI - FGFR2 amplification in colorectal adenocarcinoma. AB - FGFR2 is recurrently amplified in 5% of gastric cancers and 1%-4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations. PMID- 28835368 TI - Prolonged, Uninterrupted Sedentary Behavior and Glycemic Biomarkers Among US Hispanic/Latino Adults: The HCHS/SOL (Hispanic Community Health Study/Study of Latinos). AB - BACKGROUND: Excessive sedentary time is ubiquitous in developed nations and is associated with deleterious health outcomes. Few studies have examined whether the manner in which sedentary time is accrued (in short or long bouts) carries any clinical relevance. The purpose of this study was to examine the association of prolonged, uninterrupted sedentary behavior with glycemic biomarkers in a cohort of US Hispanic/Latino adults. METHODS: We studied 12 083 participants from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), a population based study of Hispanic/Latino adults 18 to 74 years of age. Homeostatic model assessment of insulin resistance and glycosylated hemoglobin were measured from a fasting blood sample, and 2-hour glucose was measured after an oral glucose tolerance test. Sedentary time was objectively measured with a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. RESULTS: After adjustment for potential confounders and moderate to vigorous physical activity, longer sedentary bout duration was dose dependently associated with increased homeostatic model assessment of insulin resistance (P for trend<0.001) and 2-hour glucose levels (P for trend=0.015). These associations were not independent of total sedentary time; however, a significant interaction between sedentary bout duration and total sedentary time was observed. Evaluation of the joint association of total sedentary time and sedentary bout duration showed that participants in the upper quartile for both sedentary characteristics (ie, high total sedentary time and high sedentary bout duration) had the highest levels of homeostatic model assessment of insulin resistance (P<0.001 versus low group for both sedentary characteristics) and 2 hour glucose (P=0.002 versus low group for both sedentary characteristics). High total sedentary time or high sedentary bout duration alone were not associated with differences in any glycemic biomarkers. CONCLUSIONS: Accruing sedentary time in prolonged, uninterrupted bouts may be deleteriously associated with biomarkers of glucose regulation. PMID- 28835369 TI - Racial Differences in Home Dialysis Utilization and Outcomes in Canada. AB - BACKGROUND AND OBJECTIVES: Data on racial disparities in home dialysis utilization and outcomes are lacking in Canada, where health care is universally available. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied patients starting maintenance dialysis between 1996 and 2012 in the Canadian Organ Replacement Register, stratified by race: white, Asian, black, Aboriginal, Indian subcontinent, and other. The association between race and treatment with home dialysis was examined using generalized linear models. Secondary outcomes assessed racial differences in all-cause mortality and technique failure using a Fine and Gray competing risk model. RESULTS: 66,600 patients initiated chronic dialysis between 1996 and 2012. Compared with whites (n=46,092), treatment with home dialysis was lower among Aboriginals (n=3866; adjusted relative risk, RR, 0.71; 95% confidence interval, CI, 0.66 to 0.76) and higher in Asians (n=4157; adjusted RR, 1.28; 95% CI, 1.22 to 1.35) and others (n=2170; adjusted RR, 1.12; 95% CI, 1.04 to 1.20) but similar in blacks (n=2143) and subcontinent Indians (n=2809). Black (adjusted hazard ratio, HR, 1.31; 95% CI, 1.16 to 1.48) and Aboriginal (adjusted HR, 1.19; 95% CI, 1.06 to 1.33) patients treated with peritoneal dialysis had a significantly higher adjusted risk of technique failure compared with whites, whereas Asians had a lower risk (adjusted HR, 0.89; 95% CI, 0.82 to 0.99). In patients on peritoneal dialysis, the risk of death was significantly lower in Asians (adjusted HR, 0.83; 95% CI, 0.75 to 0.92), blacks (adjusted HR, 0.71; 95% CI, 0.59 to 0.85), and others (adjusted HR, 0.79; 95% CI, 0.68 to 0.92) but higher in Aboriginals (adjusted HR, 1.16; 95% CI, 1.02 to 1.32) compared with whites. Among patients on home hemodialysis, no significant racial differences in patient and technique survival were observed, which may be limited by the low number of events among each subgroups. CONCLUSIONS: With the exception of Aboriginals, all racial minority groups in Canada were as likely to be treated with home dialysis compared with whites. However, significant racial differences exist in outcomes. PMID- 28835370 TI - Screening for atrial fibrillation in Canadian pharmacies: an economic evaluation. AB - BACKGROUND: Screening for undiagnosed atrial fibrillation may lead to treatment with oral anticoagulation therapy, which can decrease the risk of ischemic stroke. The objective of this study was to conduct an economic evaluation of the Program for the Identification of 'Actionable' Atrial Fibrillation in the Pharmacy Setting (PIAAF-Pharmacy), which screened 1145 participants aged 65 years or more at 30 community pharmacies in Ontario and Alberta between October 2014 and April 2015. METHODS: We used a 2-part decision model to evaluate the short- and long-term costs and quality-adjusted life-years (QALYs) of a pharmacy screening program for atrial fibrillation compared to no screening. Data from the PIAAF-Pharmacy study were used for the short-term model, and the relevant literature was used to extrapolate the benefits of the PIAAF-Pharmacy study in the long-term model. Costs and QALYs were calculated from a payer perspective over a lifetime horizon and were discounted at 1.5%/year. RESULTS: Screening for atrial fibrillation in pharmacies was associated with higher costs ($26) and more QALYs (0.0035) compared to no screening, yielding an incremental cost per QALY gained of $7480. Univariate and probabilistic sensitivity analyses confirmed that screening for atrial fibrillation in a pharmacy setting was a cost-effective strategy. INTERPRETATION: Our results support screening for atrial fibrillation in Canadian pharmacies. Given this finding, efforts should be made by provincial governments and pharmacies to implement such programs in Canada. The addition of atrial fibrillation screening alongside screening and management of other cardiovascular conditions may help to reduce the burden of stroke. PMID- 28835371 TI - B-cell Receptor Signaling Regulates Metabolism in Chronic Lymphocytic Leukemia. AB - Peripheral blood chronic lymphocytic leukemia (CLL) cells are quiescent but have active transcription and translation processes, suggesting that these lymphocytes are metabolically active. Based on this premise, the metabolic phenotype of CLL lymphocytes was investigated by evaluating the two intracellular ATP-generating pathways. Metabolic flux was assessed by measuring glycolysis as extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation as oxygen consumption rate (OCR) and then correlated with prognostic factors. Further, the impact of B-cell receptor signaling (BCR) on metabolism was determined by genetic ablation and pharmacological inhibitors. Compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in CLL cells. ECAR was consistently low, but OCR varied considerably in human patient samples (n = 45). Higher OCR was associated with poor prognostic factors such as ZAP 70 positivity, unmutated IGHV, high beta2M levels, and higher Rai stage. Consistent with the association of ZAP 70 and IGHV unmutated status with active BCR signaling, genetic ablation of BCR mitigated OCR in malignant B cells. Similarly, knocking out PI3Kdelta, a critical component of the BCR pathway, decreased OCR and ECAR. In concert, PI3K pathway inhibitors dramatically reduced OCR and ECAR. In harmony with a decline in metabolic activity, the ribonucleotide pools in CLL cells were reduced with duvelisib treatment. Collectively, these data demonstrate that CLL metabolism, especially OCR, is linked to prognostic factors and is curbed by BCR and PI3K pathway inhibition.Implications: This study identifies a relationship between oxidative phosphorylation in CLL and prognostic factors providing a rationale to therapeutically target these processes. Mol Cancer Res; 15(12); 1692 703. (c)2017 AACR. PMID- 28835372 TI - Pervasive coexpression of spatially proximal genes is buffered at the protein level. AB - Genes are not randomly distributed in the genome. In humans, 10% of protein coding genes are transcribed from bidirectional promoters and many more are organised in larger clusters. Intriguingly, neighbouring genes are frequently coexpressed but rarely functionally related. Here we show that coexpression of bidirectional gene pairs, and closeby genes in general, is buffered at the protein level. Taking into account the 3D architecture of the genome, we find that co-regulation of spatially close, functionally unrelated genes is pervasive at the transcriptome level, but does not extend to the proteome. We present evidence that non-functional mRNA coexpression in human cells arises from stochastic chromatin fluctuations and direct regulatory interference between spatially close genes. Protein-level buffering likely reflects a lack of coordination of post-transcriptional regulation of functionally unrelated genes. Grouping human genes together along the genome sequence, or through long-range chromosome folding, is associated with reduced expression noise. Our results support the hypothesis that the selection for noise reduction is a major driver of the evolution of genome organisation. PMID- 28835373 TI - Condensin II plays an essential role in reversible assembly of mitotic chromosomes in situ. AB - Condensins I and II are multisubunit complexes that play a central role in mitotic chromosome assembly. Although both complexes become concentrated along the axial region of each chromatid by metaphase, it remains unclear exactly how such axes might assemble and contribute to chromosome shaping. To address these questions from a physico-chemical point of view, we have established a set of two step protocols for inducing reversible assembly of chromosome structure in situ, namely within a whole cell. In this assay, mitotic chromosomes are first expanded in a hypotonic buffer containing a Mg2+-chelating agent and then converted into different shapes in a NaCl concentration-dependent manner. Both chromatin and condensin-positive chromosome axes are converted into near-original shapes at 100 mM NaCl. This assay combined with small interfering RNA depletion demonstrates that the recovery of chromatin shapes and the reorganization of axes are highly sensitive to depletion of condensin II but less sensitive to depletion of condensin I or topoisomerase IIalpha. Furthermore, quantitative morphological analyses using the machine-learning algorithm wndchrm support the notion that chromosome shaping is tightly coupled to the reorganization of condensin II-based axes. We propose that condensin II makes a primary contribution to mitotic chromosome architecture and maintenance in human cells. PMID- 28835375 TI - Direct fluorescent-dye labeling of alpha-tubulin in mammalian cells for live cell and superresolution imaging. AB - Genetic code expansion and bioorthogonal labeling provide for the first time a way for direct, site-specific labeling of proteins with fluorescent-dyes in live cells. Although the small size and superb photophysical parameters of fluorescent dyes offer unique advantages for high-resolution microscopy, this approach has yet to be embraced as a tool in live cell imaging. Here we evaluated the feasibility of this approach by applying it for alpha-tubulin labeling. After a series of calibrations, we site-specifically labeled alpha-tubulin with silicon rhodamine (SiR) in live mammalian cells in an efficient and robust manner. SiR labeled tubulin successfully incorporated into endogenous microtubules at high density, enabling video recording of microtubule dynamics in interphase and mitotic cells. Applying this labeling approach to structured illumination microscopy resulted in an increase in resolution, highlighting the advantages in using a smaller, brighter tag. Therefore, using our optimized assay, genetic code expansion provides an attractive tool for labeling proteins with a minimal, bright tag in quantitative high-resolution imaging. PMID- 28835374 TI - Low-affinity binding in cis to P2Y2R mediates force-dependent integrin activation during hantavirus infection. AB - Pathogenic hantaviruses bind to the plexin-semaphorin-integrin (PSI) domain of inactive, beta3 integrins. Previous studies have implicated a cognate cis interaction between the bent conformation beta5/beta3 integrins and an arginine glycine-aspartic acid (RGD) sequence in the first extracellular loop of P2Y2R. With single-molecule atomic force microscopy, we show a specific interaction between an atomic force microscopy tip decorated with recombinant alphaIIbbeta3 integrins and (RGD)P2Y2R expressed on cell membranes. Mutation of the RGD sequence to RGE in the P2Y2R removes this interaction. Binding of inactivated and fluorescently labeled Sin Nombre virus (SNV) to the integrin PSI domain stimulates higher affinity for (RGD)P2Y2R on cells, as measured by an increase in the unbinding force. In CHO cells, stably expressing alphaIIbbeta3 integrins, virus engagement at the integrin PSI domain, recapitulates physiologic activation of the integrin as indicated by staining with the activation-specific mAB PAC1. The data also show that blocking of the Galpha13 protein from binding to the cytoplasmic domain of the beta3 integrin prevents outside-in signaling and infection. We propose that the cis interaction with P2Y2R provides allosteric resistance to the membrane-normal motion associated with the switchblade model of integrin activation, where the development of tensile force yields physiological integrin activation. PMID- 28835376 TI - Cysteine residues in the cytoplasmic carboxy terminus of connexins dictate gap junction plaque stability. AB - Gap junctions are cellular contact sites composed of clustered connexin transmembrane proteins that act in dual capacities as channels for direct intercellular exchange of small molecules and as structural adhesion complexes known as gap junction nexuses. Depending on the connexin isoform, the cluster of channels (the gap junction plaque) can be stably or fluidly arranged. Here we used confocal microscopy and mutational analysis to identify the residues within the connexin proteins that determine gap junction plaque stability. We found that stability is altered by changing redox balance using a reducing agent-indicating gap junction nexus stability is modifiable. Stability of the arrangement of connexins is thought to regulate intercellular communication by establishing an ordered supramolecular platform. By identifying the residues that establish plaque stability, these studies lay the groundwork for exploration of mechanisms by which gap junction nexus stability modulates intercellular communication. PMID- 28835377 TI - Distinct effects of tubulin isotype mutations on neurite growth in Caenorhabditis elegans. AB - Tubulins, the building block of microtubules (MTs), play a critical role in both supporting and regulating neurite growth. Eukaryotic genomes contain multiple tubulin isotypes, and their missense mutations cause a range of neurodevelopmental defects. Using the Caenorhabditis elegans touch receptor neurons, we analyzed the effects of 67 tubulin missense mutations on neurite growth. Three types of mutations emerged: 1) loss-of-function mutations, which cause mild defects in neurite growth; 2) antimorphic mutations, which map to the GTP binding site and intradimer and interdimer interfaces, significantly reduce MT stability, and cause severe neurite growth defects; and 3) neomorphic mutations, which map to the exterior surface, increase MT stability, and cause ectopic neurite growth. Structure-function analysis reveals a causal relationship between tubulin structure and MT stability. This stability affects neuronal morphogenesis. As part of this analysis, we engineered several disease-associated human tubulin mutations into C. elegans genes and examined their impact on neuronal development at the cellular level. We also discovered an alpha-tubulin (TBA-7) that appears to destabilize MTs. Loss of TBA-7 led to the formation of hyperstable MTs and the generation of ectopic neurites; the lack of potential sites for polyamination and polyglutamination on TBA-7 may be responsible for this destabilization. PMID- 28835379 TI - Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research. AB - Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti-PD-1 (programmed death-1), and anti-PD-L1 (PD-ligand 1) drugs by the FDA for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single-agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single-agent anti-PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this article, we describe a novel use of sequential, multiple assignment, randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within an individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity. Clin Cancer Res; 24(4); 730-6. (c)2017 AACR. PMID- 28835378 TI - Density imaging of heterochromatin in live cells using orientation-independent DIC microscopy. AB - In eukaryotic cells, highly condensed inactive/silenced chromatin has long been called "heterochromatin." However, recent research suggests that such regions are in fact not fully transcriptionally silent and that there exists only a moderate access barrier to heterochromatin. To further investigate this issue, it is critical to elucidate the physical properties of heterochromatin such as its total density in live cells. Here, using orientation-independent differential interference contrast (OI-DIC) microscopy, which is capable of mapping optical path differences, we investigated the density of the total materials in pericentric foci, a representative heterochromatin model, in live mouse NIH3T3 cells. We demonstrated that the total density of heterochromatin (208 mg/ml) was only 1.53-fold higher than that of the surrounding euchromatic regions (136 mg/ml) while the DNA density of heterochromatin was 5.5- to 7.5-fold higher. We observed similar minor differences in density in typical facultative heterochromatin, the inactive human X chromosomes. This surprisingly small difference may be due to that nonnucleosomal materials (proteins/RNAs) (~120 mg/ml) are dominant in both chromatin regions. Monte Carlo simulation suggested that nonnucleosomal materials contribute to creating a moderate access barrier to heterochromatin, allowing minimal protein access to functional regions. Our OI DIC imaging offers new insight into the live cellular environments. PMID- 28835380 TI - Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers. AB - Purpose: The potential of the high-affinity CXCR4 antagonist BL-8040 as a monotherapy-mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019).Experimental Design: The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open-label phase, in which 8 subjects received a single injection of BL-8040 (1 mg/kg) and approximately 4 hours later underwent a standard leukapheresis procedure. The engraftment potential of the purified mobilized CD34+ cells was further evaluated by transplanting the cells into NSG immunodeficient mice.Results: BL-8040 was found safe and well tolerated at all doses tested (0.5-1 mg/kg). The main treatment-related adverse events were mild to moderate. Transient injection site and systemic reactions were mitigated by methylprednisolone, paracetamol, and promethazine pretreatment. In the first part of the study, BL-8040 triggered rapid and substantial mobilization of WBCs and CD34+ cells in all tested doses. Four hours postdose, the count rose to a mean of 8, 37, 31, and 35 cells/MUL (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis revealed substantial mobilization of immature dendritic, T, B, and NK cells. In the second part, the mean CD34+ cells/kg collected were 11.6 * 106 cells/kg. The graft composition was rich in immune cells.Conclusions: The current data demonstrate that BL-8040 is a safe and effective monotherapy strategy for the collection of large amounts of CD34+ cells and immune cells in a one-day procedure for allogeneic HSPC transplantation. Clin Cancer Res; 23(22); 6790-801. (c)2017 AACR. PMID- 28835381 TI - Reliability of Examination Findings in Suspected Community-Acquired Pneumonia. AB - BACKGROUND: The authors of national guidelines emphasize the use of history and examination findings to diagnose community-acquired pneumonia (CAP) in outpatient children. Little is known about the interrater reliability of the physical examination in children with suspected CAP. METHODS: This was a prospective cohort study of children with suspected CAP presenting to a pediatric emergency department from July 2013 to May 2016. Children aged 3 months to 18 years with lower respiratory signs or symptoms who received a chest radiograph were included. We excluded children hospitalized <=14 days before the study visit and those with a chronic medical condition or aspiration. Two clinicians performed independent examinations and completed identical forms reporting examination findings. Interrater reliability for each finding was reported by using Fleiss' kappa (kappa) for categorical variables and intraclass correlation coefficient (ICC) for continuous variables. RESULTS: No examination finding had substantial agreement (kappa/ICC > 0.8). Two findings (retractions, wheezing) had moderate to substantial agreement (kappa/ICC = 0.6-0.8). Nine findings (abdominal pain, pleuritic pain, nasal flaring, skin color, overall impression, cool extremities, tachypnea, respiratory rate, and crackles/rales) had fair to moderate agreement (kappa/ICC = 0.4-0.6). Eight findings (capillary refill time, cough, rhonchi, head bobbing, behavior, grunting, general appearance, and decreased breath sounds) had poor to fair reliability (kappa/ICC = 0-0.4). Only 3 examination findings had acceptable agreement, with the lower 95% confidence limit >0.4: wheezing, retractions, and respiratory rate. CONCLUSIONS: In this study, we found fair to moderate reliability of many findings used to diagnose CAP. Only 3 findings had acceptable levels of reliability. These findings must be considered in the clinical management and research of pediatric CAP. PMID- 28835382 TI - Utility of Blood Culture Among Children Hospitalized With Community-Acquired Pneumonia. AB - BACKGROUND AND OBJECTIVES: National guidelines recommend blood cultures for children hospitalized with presumed bacterial community-acquired pneumonia (CAP) that is moderate or severe. We sought to determine the prevalence of bacteremia and characterize the microbiology and penicillin-susceptibility patterns of positive blood culture results among children hospitalized with CAP. METHODS: We conducted a cross-sectional study of children hospitalized with CAP in 6 children's hospitals from 2007 to 2011. We included children 3 months to 18 years of age with discharge diagnosis codes for CAP using a previously validated algorithm. We excluded children with complex chronic conditions. We reviewed microbiologic data and classified positive blood culture detections as pathogens or contaminants. Antibiotic-susceptibility patterns were assessed for all pathogens. RESULTS: A total of 7509 children hospitalized with CAP were included over the 5-year study period. Overall, 34% of the children hospitalized with CAP had a blood culture performed; 65 (2.5% of patients with blood cultures; 95% confidence interval [CI]: 2.0%-3.2%) grew a pathogen. Streptococcus pneumoniae accounted for 78% of all detected pathogens. Among detected pathogens, 50 (82%) were susceptible to penicillin. Eleven children demonstrated growth of an organism nonsusceptible to penicillin, representing 0.43% (95% CI: 0.23%-0.77%) of children with blood cultures obtained and 0.15% (95% CI: 0.08%-0.26%) of all children hospitalized with CAP. CONCLUSIONS: Among children without comorbidities hospitalized with CAP in a non-ICU setting, the rate of bacteremia was low, and isolated pathogens were usually susceptible to penicillin. Blood cultures may not be needed for most children hospitalized with CAP. PMID- 28835383 TI - Estrogen Receptor beta Is a Novel Target in Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome and suboptimal chemotherapeutics. Here, a high-throughput screen identified diosmetin, a citrus flavonoid, with anti-AML activity. Diosmetin imparted selective toxicity against leukemia and leukemia stem cells in vitro and in vivo with no effect on normal hematopoietic stem cells. Mechanistically, we demonstrated that diosmetin targets estrogen receptor (ER) beta. ERbeta expression conferred cell sensitivity, as patient-derived AML cells with high levels of ERbeta were sensitive, whereas cells with low ERbeta were insensitive to diosmetin. Knockdown of ERbeta confirmed resistance, whereas overexpression enhanced sensitivity to diosmetin, which was demonstrated to be mediated by reactive oxygen species signaling. In summary, these studies highlight targeting of ERbeta with diosmetin as a potential novel therapeutic strategy for the treatment of AML. Mol Cancer Ther; 16(11); 2618-26. (c)2017 AACR. PMID- 28835384 TI - EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL. AB - The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2 Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased B-cell maturation and a greater dependence on B-cell activation signaling. Mol Cancer Ther; 16(11); 2586 97. (c)2017 AACR. PMID- 28835385 TI - Targeting Phosphatidylinositol 3-Kinase Signaling Pathway for Therapeutic Enhancement of Vascular-Targeted Photodynamic Therapy. AB - Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT. Here, three clinically relevant small-molecule inhibitors (BYL719, BKM120, and BEZ235) of the PI3K pathway were evaluated in combination with verteporfin-PDT. Although all three inhibitors were able to synergistically enhance PDT response in endothelial cells, PDT combined with dual PI3K/mTOR inhibitor BEZ235 exhibited the strongest synergism, followed in order by combinations with pan-PI3K inhibitor BKM120 and p110alpha isoform-selective inhibitor BYL719. Combination treatments of PDT and BEZ235 exhibited a cooperative inhibition of antiapoptotic Bcl-2 family protein Mcl-1 and induced more cell apoptosis than each treatment alone. In addition to increasing treatment lethality, BEZ235 combined with PDT effectively inhibited PI3K pathway activation and consequent endothelial cell proliferation after PDT alone, leading to a sustained growth inhibition. In the PC-3 prostate tumor model, combination treatments improved treatment outcomes by turning a temporary tumor regrowth delay induced by PDT alone to a more long-lasting treatment response. Our study strongly supports the combination of vascular-targeted PDT and PI3K pathway inhibitors, particularly mTOR inhibitors, for therapeutic enhancement. Mol Cancer Ther; 16(11); 2422-31. (c)2017 AACR. PMID- 28835388 TI - College-Aged Males Experience Attenuated Sweet and Salty Taste with Modest Weight Gain. AB - Background: Human and animal studies report a blunted sense of taste in people who are overweight or obese, with heightened sensitivity also reported after weight loss. However, it is unknown if taste changes concurrently with weight gain.Objective: This study investigated the association of weight gain with changes in suprathreshold taste intensity perception in a free-living population of young adults.Methods: Taste response, anthropometric measures, and diet changes were assessed with a longitudinal study design in first-year college students 3 times throughout the academic year. At baseline, 93 participants (30 males, 63 females) were an average of 18 y old, with a body mass index (in kg/m2) of 21.9. Sweet, umami, salty, sour, and bitter taste intensities were evaluated at 3 concentrations by using the general Labeled Magnitude Scale. Ordinary least squares regression models assessed the association of weight gain and within person taste change, adjusting for sex, race, and diet changes.Results: Participants gained an average of 3.9% in weight, ranging from -5.7% to +13.8%. With each 1% increase in body weight, males perceived sweet and salty as less intense, with taste responses decreasing by 11.0% (95% CI: -18.9%, -2.3%; P = 0.015) and 7.5% (95% CI: -13.1%, -1.5%; P = 0.015) from baseline, respectively. Meanwhile, females did not experience this decrement, and even perceived a 6.5% increase (95% CI: 2.6%, 10.5%; P = 0.007) in sour taste with similar amounts of weight gain. Changes in the consumption of meat and other umami-rich foods also negatively correlated with umami taste response (-39.1%; 95% CI: -56.3%, -15.0%; P = 0.004).Conclusions: A modest weight gain is associated with concurrent taste changes in the first year of college, especially in males who experience a decrement in sweet and salty taste. This suggests that young-adult males may be susceptible to taste loss when gaining weight. PMID- 28835386 TI - Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. AB - Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (>=20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P <= 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598-608. (c)2017 AACR. PMID- 28835387 TI - Supplementing Breakfast with a Vitamin D and Leucine-Enriched Whey Protein Medical Nutrition Drink Enhances Postprandial Muscle Protein Synthesis and Muscle Mass in Healthy Older Men. AB - Background: A promising strategy to help older adults preserve or build muscle mass is to optimize muscle anabolism through providing an adequate amount of high quality protein at each meal.Objective: This "proof of principle" study investigated the acute effect of supplementing breakfast with a vitamin D and leucine-enriched whey protein medical nutrition drink on postprandial muscle protein synthesis and longer-term effect on muscle mass in healthy older adults.Methods: A randomized, placebo-controlled, double-blind study was conducted in 24 healthy older men [mean +/- SD: age 71 +/- 4 y; body mass index (in kg/m2) 24.7 +/- 2.8] between September 2012 and October 2013 at the Unit of Human Nutrition, University of Auvergne, Clermont-Ferrand, France. Participants received a medical nutrition drink [test group; 21 g leucine-enriched whey protein, 9 g carbohydrates, 3 g fat, 800 IU cholecalciferol (vitamin D3), and 628 kJ] or a noncaloric placebo (control group) before breakfast for 6 wk. Mixed muscle protein fractional synthesis rate (FSR) was measured at week 0 in the basal and postprandial state, after study product intake with a standardized breakfast with the use of l-[2H5]-phenylalanine tracer methodology. The longer term effect of the medical nutrition drink was evaluated by measurement of appendicular lean mass, representing skeletal muscle mass at weeks 0 and 6, by dual-energy X-ray absorptiometry.Results: Postprandial FSR (0-240 min) was higher in the test group than in the control group [estimate of difference (ED): 0.022%/h; 95% CI: 0.010%/h, 0.035%/h; ANCOVA, P = 0.001]. The test group gained more appendicular lean mass than the control group after 6 wk (ED: 0.37 kg; 95% CI: 0.03, 0.72 kg; ANCOVA, P = 0.035), predominantly as leg lean mass (ED: 0.30 kg; 95% CI: 0.03, 0.57 kg; ANCOVA, P = 0.034).Conclusions: Supplementing breakfast with a vitamin D and leucine-enriched whey protein medical nutrition drink stimulated postprandial muscle protein synthesis and increased muscle mass after 6 wk of intervention in healthy older adults and may therefore be a way to support muscle preservation in older people. This trial was registered at www.trialregister.nl as NTR3471. PMID- 28835389 TI - Dietary Methionine Restriction Alleviates Hyperglycemia in Pigs with Intrauterine Growth Restriction by Enhancing Hepatic Protein Kinase B Signaling and Glycogen Synthesis. AB - Background: Individuals with intrauterine growth restriction (IUGR) are prone to developing type 2 diabetes mellitus (T2DM). Dietary methionine restriction (MR) improves insulin sensitivity and glucose homeostasis in individuals with normal birth weight (NBW).Objective: This study investigated the effects of MR on plasma glucose concentration and hepatic and muscle glucose metabolism in pigs with IUGR.Methods: Thirty female NBW and 60 same-sex spontaneous IUGR piglets (Landrace * Yorkshire) were selected. After weaning (day 21), the piglets were fed diets with adequate methionine (NBW-CON and IUGR-CON) or 30% less methionine (IUGR-MR) (n = 6). At day 180, 1 pig with a body weight near the mean of each replication was selected for biochemical analysis.Results: The IUGR-CON group showed 41.6%, 68.6%, and 67.1% higher plasma glucose concentration, hepatic phosphoenolpyruvate carboxykinase activity, and glucose-6-phosphatase activity, respectively, than the NBW-CON group (P < 0.05). Muscle glycogen content and glycogen synthase activity were 36.9% and 38.8% lower, respectively, in the IUGR CON than the NBW-CON group (P < 0.05), respectively, and there was decreased hepatic and muscle protein kinase B phosphorylation in the IUGR-CON group (P < 0.05). Compared with the IUGR-CON pigs, the IUGR-MR pigs had 28.7% lower plasma glucose concentrations (P < 0.05), which were similar to those of the NBW-CON pigs (P >= 0.05). The hepatic glycogen content and glycogen synthase activity of the IUGR-MR pigs were 62.9% and 50.8% higher than those of the IUGR-CON pigs (P < 0.05) and 53.5% and 84.3% higher than the NBW-CON pigs (P < 0.05), respectively. The IUGR-MR pigs' hepatic and muscle protein kinase B phosphorylation was higher than that of the IUGR-CON pigs (P < 0.05) and similar to that of the NBW-CON pigs (P >= 0.05).Conclusion: MR attenuates hyperglycemia in IUGR pigs by enhancing hepatic protein kinase B signaling and glycogen synthesis, implying a potential nutritional strategy to prevent type 2 diabetes mellitus in IUGR offspring. PMID- 28835390 TI - Excessive Vitamin E Intake Does Not Cause Bone Loss in Male or Ovariectomized Female Mice Fed Normal or High-Fat Diets. AB - Background: Animal studies on the effects of vitamin E on bone health have yielded conflicting and inconclusive results, and to our knowledge, no studies have addressed the effect of vitamin E on bone in animals consuming a high-fat diet (HFD).Objective: This study aimed to evaluate the effect of excessive vitamin E on bone metabolism in normal male mice and ovariectomized female mice fed a normal diet (ND) or HFD.Methods: In the first 2 experiments, 7-wk-old male mice were fed an ND (16% energy from fat) containing 75 (control), 0 (vitamin E free), or 1000 (high vitamin E) mg vitamin E/kg (experiment 1) or an HFD (46% energy from fat) containing 0, 200, 500, or 1000 mg vitamin E/kg (experiment 2) for 18 wk. In the third experiment, 7-wk-old sham-operated or ovariectomized female mice were fed the ND (75 mg vitamin E/kg) or HFD containing 0 or 1000 mg vitamin E/kg for 8 wk. At the end of the feeding period, blood and femurs were collected to measure bone turnover markers and analyze histology and microcomputed tomography.Results: In experiments 1 and 2, vitamin E intake had no effect on plasma alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) activity, or bone formation, resorption, or volume in femurs in mice fed the ND or HFDs. In experiment 3, bone volume was significantly reduced (85%) in ovariectomized mice compared with that in sham-operated mice (P < 0.05), but it did not differ among mice fed the 3 diets. Plasma ALP and TRAP activities and bone formation and resorption in femur were similar among ovariectomized mice fed the HFD containing 0 or 1000 mg vitamin E/kg.Conclusions: The results suggest that excess vitamin E intake does not cause bone loss in normal male mice or in ovariectomized or sham-operated female mice, regardless of dietary fat content. PMID- 28835391 TI - Fructo-oligosaccharide-Induced Transient Increases in Cecal Immunoglobulin A Concentrations in Rats Are Associated with Mucosal Inflammation in Response to Increased Gut Permeability. AB - Background: The mechanism underlying transient increases in immunoglobulin (Ig) A concentrations in the cecal contents of rats fed fructo-oligosaccharide (FOS) is unclear.Objective: This study was designed to test whether increased IgA concentrations represent one aspect of the inflammatory response to increased permeability induced by FOS in the cecum.Methods: Seven-week-old male Wistar rats were fed a fiber-free semipurified diet (FFP) with or without supplemental FOS (60 g/kg diet) for 9 or 58 d [experiment (expt.) 1], 7 d (expt. 2), or 7 or 56 d (expt. 3). In addition to measuring IgA concentrations in cecal content, we assessed gut permeability, inflammatory responses (expt. 1), the number of IgA plasma cells in the cecal lamina propria, polymeric Ig receptor (pIgR) expression in the cecal mucosa (expt. 2), and the condition of the cecal mucus layer (expt. 3).Results: The cecal IgA concentration in the FOS-fed rats was 15-fold higher than that of the rats fed FFP for 9 d (P < 0.05). Gut permeability estimated by urinary chromium-EDTA excretion, bacterial translocation to mesenteric lymph nodes, myeloperoxidase activity, and expression of inflammatory cytokine genes in the cecal mucosa was greater in the FOS-fed rats than in the rats fed FFP for 9 d. These effects were not observed in the rats fed FOS for 58 d (expt. 1). Accompanying the higher cecal IgA concentration, pIgR protein and the number of IgA plasma cells in the cecal mucosa were higher in the FOS-fed rats than in the rats fed FFP for 7 d (expt. 2). Destruction of the mucus layer on the epithelial surface, as evidenced by Alcian blue staining in the cecal sections, was evident in the rats fed FOS for 7 d, but the mucus layer appeared normal in the rats fed FOS for 56 d (expt. 3).Conclusions: These findings suggest that transient increases in cecal IgA concentrations induced by FOS in rats are associated with mucosal inflammation in response to increased gut permeability; these are presumably evoked by disruption of the cecal mucus barrier. The observed responses could contribute to the maturation of the gut immune system. PMID- 28835393 TI - High exposure to endotoxin in farming is associated with less new-onset pollen sensitisation. AB - OBJECTIVES: Little is known about risk factors for new onset and loss of atopic sensitisation in adulthood. The aim is to examine the longitudinal effect of quantitatively assessed endotoxin exposures on changes in specific allergen sensitisation in young adults. METHODS: The cohort consisted of 1113 young Danish farmers and rural controls, with a mean age of 19 years at baseline. Sensitisation to birch pollen, grass pollen, cat dander and house dust mite was measured by specific IgE levels in serum samples from baseline and at 15 years' follow-up. Changes in sensitisation were analysed in relation to cumulative endotoxin exposure during follow-up, considering early life farm exposure. RESULTS: Endotoxin exposure during follow-up was significantly associated with less new onset of specifically grass and birch pollen sensitisation. For the highest versus lowest quartile of cumulative endotoxin exposure, the OR for new onset IgE sensitisation was 0.35 (0.13-0.91) for birch and 0.14 (0.05-0.50) for grass. On the other hand, loss of pollen sensitisation showed a positive, although mostly non-significant, association with increased levels of endotoxin exposure. Endotoxin exposure was not associated with significant changes in cat dander and house dust mite sensitisation. CONCLUSIONS: High exposure to endotoxin during young adulthood appears to protect against new onset of pollen sensitisation, independent of childhood farm exposure. PMID- 28835394 TI - Sleep duration as a mediator between an alternating day and night shift work schedule and metabolic syndrome among female hospital employees. AB - OBJECTIVES: The main objective was to determine whether sleep duration on work shifts mediates the relationship between a current alternating day and night shift work schedule and metabolic syndrome among female hospital employees. The secondary objective was to assess whether cumulative lifetime shift work exposure was associated with metabolic syndrome. METHODS: In this cross-sectional study of 294 female hospital employees, sleep duration was measured with the ActiGraph GT3X+. Shift work status was determined through self-report. Investigation of the total, direct and indirect effects between shift work, sleep duration on work shifts and metabolic syndrome was conducted using regression path analysis. Logistic regression was used to determine the association between cumulative shift work exposure and metabolic syndrome. RESULTS: Shift work is strongly associated with metabolic syndrome (ORTotal=2.72, 95% CI 1.38 to 5.36), and the relationship is attenuated when work shift sleep duration is added to the model (ORDirect=1.18, 95% CI 0.49 to 2.89). Sleep duration is an important intermediate between shift work and metabolic syndrome (ORIndirect=2.25, 95% CI 1.27 to 4.26). Cumulative shift work exposure is not associated with metabolic syndrome in this population. CONCLUSIONS: Sleep duration mediates the association between a current alternating day-night shift work pattern and metabolic syndrome. PMID- 28835392 TI - Epigallocatechin Gallate Has a Neurorescue Effect in a Mouse Model of Parkinson Disease. AB - Background: Parkinson disease (PD) is a neurodegenerative disorder that has been associated with many factors, including oxidative stress, inflammation, and iron accumulation. The antioxidant, anti-inflammatory, and iron-chelating properties of epigallocatechin gallate (EGCG), a major polyphenol in green tea, may offer protection against PD.Objective: We sought to determine the neurorescue effects of EGCG and the role of iron in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD.Methods: We evaluated the neurorescue effect of EGCG (25 mg/kg, 7 d, oral administration) against MPTP-induced (20 mg/kg, 3 d, intraperitoneal injection) neurodegeneration in C57 male black mice. Thirty mice weighing ~25 g were divided into 3 groups: control, MPTP, and MPTP + EGCG. The neurorescue effect of EGCG was assessed with the use of motor behavior tests, neurotransmitter analysis, oxidative stress indicators, and iron-related protein expression.Results: Compared with the control group, MPTP treatment shortened the mice's latency to fall from the rotarod by 16% (P < 0.05), decreased the striatal dopamine concentration by 58% (P < 0.001) and dihydroxyphenylacetic acid by 35% (P < 0.05), and increased serum protein carbonyls by 71% (P = 0.07). However, EGCG rescued MPTP-induced neurotoxicity by increasing the rotational latency by 17% (P < 0.05) to a value similar to the control group. Striatal dopamine concentrations were 40% higher in the MPTP + EGCG group than in the MPTP group (P < 0.05), but the values were significantly lower than in the control group. Compared with the MPTP and control groups, mice in the MPTP + EGCG group had higher substantia nigra ferroportin expression (44% and 35%, respectively) (P < 0.05) but not hepcidin and divalent metal transporter 1 expression.Conclusion: Overall, our study demonstrated that EGCG regulated the iron-export protein ferroportin in substantia nigra, reduced oxidative stress, and exerted a neurorescue effect against MPTP-induced functional and neurochemical deficits in mice. PMID- 28835395 TI - Long-term prognosis for neck-shoulder pain and disorders: a 14-year follow-up study. AB - OBJECTIVES: The long-term prognosis for neck-shoulder pain and disorders and the impact of shoulder exposure among former sewing machine operators were investigated in a 14-year follow-up study. METHODS: Information on neck-shoulder pain and disorders was collected by questionnaire and clinical examination at baseline in 243 female sewing machine operators and by questionnaire 14 years later. During follow-up, information on comorbidity and job exposures was obtained from registers and by linking register-based D-ISCO 88 codes with a job exposure matrix. Logistic regression analyses were performed to examine associations between neck-shoulder pain and disorders at baseline and neck shoulder pain and physical functioning at follow-up. RESULTS: We found an association between neck-shoulder disorders at baseline and neck-shoulder pain at follow-up (OR 5.9;95% CI 1.9 to 17.7), and between neck-shoulder pain at baseline and neck-shoulder pain at follow-up (OR 8.2;95% CI 3.5 to 19.2). Associations between neck-shoulder disorders and pain at baseline and limited physical functioning at follow-up had ORs of 5.0 (95% CI 1.5 to 16.1) and 2.2 (95% CI 1.1 to 4.6), respectively. In women still working in 2008, the association between neck-shoulder pain in 1994 and in 2008 seemed to be stronger for those in jobs with high job shoulder exposure. CONCLUSIONS: The results suggest a long-term adverse prognosis for neck-shoulder pain. High job shoulder exposure can worsen this prognosis for those who continue working. This knowledge could influence the counselling given to similar workers and emphasises the need to prevent neck shoulder pain. PMID- 28835396 TI - Human dorsal root ganglion in vivo morphometry and perfusion in Fabry painful neuropathy. AB - OBJECTIVE: To evaluate functional and morphometric magnetic resonance neurography of the dorsal root ganglion and peripheral nerve segments in patients with Fabry painful neuropathy. METHODS: In this prospective study, the lumbosacral dorsal root ganglia and proximal peripheral nerve segments of the lower extremity were examined in 11 male patients with Fabry disease by a standardized 3T magnetic resonance neurography protocol. Volumes of L3 to S2 dorsal root ganglia, perfusion parameters of L5-S1 dorsal root ganglia and the spinal nerve L5, and the cross-sectional area of the proximal sciatic nerve were compared to healthy controls. RESULTS: Dorsal root ganglia of patients with Fabry disease were symmetrically enlarged by 78% (L3), 94% (L4), 122% (L5), 115% (S1), and 119% (S2) (p < 0.001). In addition, permeability of the blood-tissue interface was decreased by 53% (p < 0.001). This finding was most pronounced in the peripheral zone of the dorsal root ganglion containing the cell bodies of the primary sensory neurons (p < 0.001). Spinal nerve permeability showed no difference between patients with Fabry disease and controls (p = 0.7). The sciatic nerve of patients with Fabry disease at the thigh level showed an increase in cross sectional area by 48% (p < 0.001). CONCLUSIONS: Patients with Fabry disease have severely enlarged dorsal root ganglia with dysfunctional perfusion. This may be due to glycolipid accumulation in the dorsal root ganglia mediating direct neurotoxic effects and decreased neuronal blood supply. These alterations were less pronounced in peripheral nerve segments. Thus, the dorsal root ganglion might play a key pathophysiologic role in the development of neuropathy and pain in Fabry disease. PMID- 28835398 TI - Vertebral artery stenosis: The hurdles of stenting are too high. PMID- 28835397 TI - Utilization of rehabilitation therapy services in Parkinson disease in the United States. AB - OBJECTIVE: To examine rehabilitation therapy utilization for Parkinson disease (PD). METHODS: We identified 174,643 Medicare beneficiaries with a diagnosis of PD in 2007 and followed them through 2009. The main outcome measures were annual receipt of physical therapy (PT), occupational therapy (OT), or speech therapy (ST). RESULTS: Outpatient rehabilitation fee-for-service use was low. In 2007, only 14.2% of individuals with PD had claims for PT or OT, and 14.6% for ST. Asian Americans were the highest users of PT/OT (18.4%) and ST (18.4%), followed by Caucasians (PT/OT 14.4%, ST 14.8%). African Americans had the lowest utilization (PT/OT 7.8%, ST 8.2%). Using logistic regression models that accounted for repeated measures, we found that African American patients (adjusted odds ratio [AOR] 0.63 for PT/OT, AOR 0.63 for ST) and Hispanic patients (AOR 0.97 for PT/OT, AOR 0.91 for ST) were less likely to have received therapies compared to Caucasian patients. Patients with PD with at least one neurologist visit per year were 43% more likely to have a claim for PT evaluation as compared to patients without neurologist care (AOR 1.43, 1.30-1.48), and this relationship was similar for OT evaluation, PT/OT treatment, and ST. Geographically, Western states had the greatest use of rehabilitation therapies, but provider supply did not correlate with utilization. CONCLUSIONS: This claims-based analysis suggests that rehabilitation therapy utilization among older patients with PD in the United States is lower than reported for countries with comparable health care infrastructure. Neurologist care is associated with rehabilitation therapy use; provider supply is not. PMID- 28835399 TI - A case-control study of hormonal exposures as etiologic factors for ALS in women: Euro-MOTOR. AB - OBJECTIVE: To investigate the role of hormonal risk factors for amyotrophic lateral sclerosis (ALS) among women from 3 European countries. METHODS: ALS cases and matched controls were recruited over 4 years in Ireland, Italy, and the Netherlands. Hormonal exposures, including reproductive history, breastfeeding, contraceptive use, hormonal replacement therapy, and gynecologic surgical history, were recorded with a validated questionnaire. Logistic regression models adjusted for age, education, study site, smoking, alcohol, and physical activity were used to determine the association between female hormones and ALS risk. RESULTS: We included 653 patients and 1,217 controls. Oral contraceptive use was higher among controls (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51 0.84), and a dose-response effect was apparent. Hormone replacement therapy (HRT) was associated with a reduced risk of ALS only in the Netherlands (OR = 0.57, 95% CI 0.37-0.85). These findings were robust to sensitivity analysis, but there was some heterogeneity across study sites. CONCLUSIONS: This large case-control study across 3 different countries has demonstrated an association between exogenous estrogens and progestogens and reduced odds of ALS in women. These results are at variance with previous findings, which may be partly explained by differential regulatory, social, and cultural attitudes toward pregnancy, birth control, and HRT across the countries included. Our results indicate that hormonal factors may be important etiologic factors in ALS; however, a full understanding requires further investigation. PMID- 28835400 TI - Stenting for symptomatic vertebral artery stenosis: The Vertebral Artery Ischaemia Stenting Trial. AB - OBJECTIVE: To compare in the Vertebral Artery Ischaemia Stenting Trial (VIST) the risks and benefits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for symptomatic vertebral artery stenosis. METHODS: VIST was a prospective, randomized, open-blinded endpoint clinical trial performed in 14 hospitals in the United Kingdom. Participants with symptomatic vertebral stenosis >=50% were randomly assigned (1:1) to vertebral angioplasty/stenting plus BMT or to BMT alone with randomization stratified by site of stenosis (extracranial vs intracranial). Because of slow recruitment and cessation of funding, recruitment was stopped after 182 participants. Follow-up was a minimum of >=1 year for each participant. RESULTS: Three patients did not contribute any follow-up data and were excluded, leaving 91 patients in the stent group and 88 in the medical group. Mean follow-up was 3.5 (interquartile range 2.1-4.7) years. Of 61 patients who were stented, stenosis was extracranial in 48 (78.7%) and intracranial in 13 (21.3%). No periprocedural complications occurred with extracranial stenting; 2 strokes occurred during intracranial stenting. The primary endpoint of fatal or nonfatal stroke occurred in 5 patients in the stent group vs 12 in the medical group (hazard ratio 0.40, 95% confidence interval 0.14 1.13, p = 0.08), with an absolute risk reduction of 25 strokes per 1,000 person years. The hazard ratio for stroke or TIA was 0.50 (p = 0.05). CONCLUSIONS: Stenting in extracranial stenosis appears safe with low complication rates. Large phase 3 trials are required to determine whether stenting reduces stroke risk. ISRCTNCOM IDENTIFIER: ISRCTN95212240. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with symptomatic vertebral stenosis, angioplasty with stenting does not reduce the risk of stroke. However, the study lacked the precision to exclude a benefit from stenting. PMID- 28835402 TI - Quality improvement in neurology: Essential Tremor Quality Measurement Set. PMID- 28835401 TI - Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy. AB - OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in treatment naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348). METHODS: Alemtuzumab-treated patients received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; >=1-point Expanded Disability Status Scale [EDSS] score increase [>=1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; >=1 point EDSS decrease [baseline score >=2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs). RESULTS: Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0-5, 79.7% were free of 6 month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2-4, remaining low in year 5 (years 1-5: -0.59%, -0.25%, -0.19%, -0.15%, and -0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined. CONCLUSIONS: Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses. CLINICALTRIALSGOV IDENTIFIER: NCT00530348; NCT00930553. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS. PMID- 28835404 TI - Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open label study. AB - OBJECTIVE: To assess long-term safety and efficacy of anti-calcitonin gene related peptide receptor erenumab in patients with episodic migraine (EM). METHODS: Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial (NCT01952574) who continued in an open-label extension (OLE) study will receive erenumab 70 mg every 4 weeks for up to 5 years. This preplanned interim analysis, conducted after all participants had completed the 1-year open label follow-up, evaluated changes in monthly migraine days (MMD), achievement of >=50%, >=75%, and 100% reductions, Headache Impact Test (HIT-6) score, Migraine Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety. Data reported as observed without imputation for missing data. RESULTS: Of 472 patients enrolled in the parent study, 383 continued in the OLE with a median exposure to erenumab of 575 days (range 28-822 days). Mean (SD) MMD were 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days). At week 64, 65%, 42%, and 26% achieved >=50%, >=75%, and 100% reduction in MMD, respectively. Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64. MSQ and MIDAS improvements from baseline were maintained through week 64. Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo. CONCLUSIONS: One-year efficacy, supported by functional improvements and favorable safety and tolerability profiles, supports further investigation of erenumab as a preventive treatment in patients with EM. CLINICALTRIALSGOV IDENTIFIER: NCT01952574. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with episodic migraine, erenumab reduces long-term MMD and improves headache-related disability and migraine-specific quality of life. PMID- 28835403 TI - Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings. AB - OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy. METHODS: In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; >=1-point Expanded Disability Status Scale [EDSS] score increase [>=1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; >=1 point EDSS decrease [baseline score >=2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed. RESULTS: Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3-5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1-5: -0.48%, -0.22%, -0.10%, -0.19%, 0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter. CONCLUSIONS: Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years. PMID- 28835405 TI - Incidence and management of seizures after ischemic stroke: Systematic review and meta-analysis. AB - OBJECTIVE: We conducted a meta-analysis of the incidence of early and late seizures following ischemic stroke as well as a systematic review of their pharmacologic treatment. METHODS: Observational studies that reported incidence of seizures following ischemic stroke and those that reported treatment response to any particular antiepileptic drugs (AEDs) were included. Risk of bias was assessed by predefined study characteristics. Random effects meta-analysis was conducted for all studies where data were available for the incidence of early and late stroke-related seizures. Heterogeneity was measured with I2 statistic and sensitivity analyses were performed using prespecified variables. A qualitative synthesis of studies reporting use of AEDs for stroke-related seizures was performed. RESULTS: Forty-one studies from 10,554 articles were identified; 35 studies reported incidence of stroke-related seizures and 6 studies reported effects of specific AEDs. Most studies were of low to moderate quality. Rate of early seizures was 3.3% (95% confidence interval 2.8%-3.9%, I2 = 92.8%), while the incidence of late seizures or epilepsy was 18 per 1,000 person years (95% confidence interval 1.5-2.2, I2 = 94.1%). The high degree of heterogeneity could not be explained from the sensitivity analyses. For management of stroke-related seizures, no single AED was found to be more effective over others, though newer AEDs were associated with fewer side effects. CONCLUSIONS: The burden of stroke-related seizures and epilepsy due to ischemic stroke is substantial. Further studies are required to determine risk factors for epilepsy following ischemic stroke and optimal secondary prevention. PMID- 28835406 TI - Can immune reprogramming with alemtuzumab induce permanent remission in multiple sclerosis? PMID- 28835408 TI - Sugar addiction: is it real? A narrative review. AB - In animal studies, sugar has been found to produce more symptoms than is required to be considered an addictive substance. Animal data has shown significant overlap between the consumption of added sugars and drug-like effects, including bingeing, craving, tolerance, withdrawal, cross-sensitisation, cross-tolerance, cross-dependence, reward and opioid effects. Sugar addiction seems to be dependence to the natural endogenous opioids that get released upon sugar intake. In both animals and humans, the evidence in the literature shows substantial parallels and overlap between drugs of abuse and sugar, from the standpoint of brain neurochemistry as well as behaviour. PMID- 28835407 TI - Sleep architecture and the risk of incident dementia in the community. AB - OBJECTIVE: Sleep disturbance is common in dementia, although it is unclear whether differences in sleep architecture precede dementia onset. We examined the associations between sleep architecture and the prospective risk of incident dementia in the community-based Framingham Heart Study (FHS). METHODS: Our sample comprised a subset of 321 FHS Offspring participants who participated in the Sleep Heart Health Study between 1995 and 1998 and who were aged over 60 years at the time of sleep assessment (mean age 67 +/- 5 years, 50% male). Stages of sleep were quantified using home-based polysomnography. Participants were followed for a maximum of 19 years for incident dementia (mean follow-up 12 +/- 5 years). RESULTS: We observed 32 cases of incident dementia; 24 were consistent with Alzheimer disease dementia. After adjustments for age and sex, lower REM sleep percentage and longer REM sleep latency were both associated with a higher risk of incident dementia. Each percentage reduction in REM sleep was associated with approximately a 9% increase in the risk of incident dementia (hazard ratio 0.91; 95% confidence interval 0.86, 0.97). The magnitude of association between REM sleep percentage and dementia was similar following adjustments for multiple covariates including vascular risk factors, depressive symptoms, and medication use, following exclusions for persons with mild cognitive impairment at baseline and following exclusions for early converters to dementia. Stages of non-REM sleep were not associated with dementia risk. CONCLUSIONS: Despite contemporary interest in slow-wave sleep and dementia pathology, our findings implicate REM sleep mechanisms as predictors of clinical dementia. PMID- 28835409 TI - Towards a three-dimensional framework of centrally regulated and goal-directed exercise behaviour: a narrative review. AB - The Central Governor Model (CGM) ignited a paradigm shift from concepts of catastrophic failure towards central regulation of exercise performance. However, the CGM has focused on the central integration of afferent feedback in homeostatic control. Accordingly, it neglected the important role of volitional self-regulatory control and the integration of affective components inherently attached to all physiological cues. Another limitation is the large reliance on the Gestalt phenomenon of perceived exertion. Thus, progress towards a comprehensive multidimensional model of perceived fatigability and exercise regulation is needed. Drawing on Gate Control Theory of pain, we propose a three dimensional framework of centrally regulated and goal-directed exercise behaviour, which differentiates between sensory, affective and cognitive processes shaping the perceptual milieu during exercise. We propose that: (A) perceived mental strain and perceived physical strain are primary determinants of pacing behaviour reflecting sensory-discriminatory processes necessary to align planned behaviour with current physiological state, (B) core affect plays a primary and mediatory role in exercise and performance regulation, and its underlying two dimensions hedonicity and arousal reflect affective-motivational processes triggering approach and avoidance behaviour, and (C) the mindset-shift associated with an action crisis plays a primary role in volitional self regulatory control reflecting cognitive-evaluative processes between further goal pursuit and goal-disengagement. The proposed framework has the potential to enrich theory development in centrally regulated and goal-directed exercise behaviour by emphasising the multidimensional dynamic processes underpinning perceived fatigability and provides a practical outline for investigating the complex interplay between the psychophysiological determinants of pacing and performance during prolonged endurance exercise. PMID- 28835411 TI - Gender dysphoria: referral for ear, nose, and throat or facial surgeries. PMID- 28835410 TI - Injury profile suffered by targets of antipersonnel improvised explosive devices: prospective cohort study. AB - OBJECTIVE: To describe pattern 1 injuries caused by the antipersonnel improvised explosive device (AP-IED) in comparison to those previously described for antipersonnel mines (APM). DESIGN: Prospective cohort study of 100 consecutive pedestrian victims of an AP-IED, with traumatic amputation without regard for gender, nationality or military status. SETTING: Multinational Medical Unit at Kandahar Air Field, Afghanistan. PARTICIPANTS: One hundred consecutive patients, all male, 6-44 years old. MAIN OUTCOME MEASURES: The details of injuries were recorded to describe the pattern and characterise the injuries suffered by the target of AP-IEDs. The level of amputation, the level of soft tissue injury, the fracture pattern (including pelvic fractures) as well as perineal, gluteal, genital and other injuries were recorded. RESULTS: Victims of AP-IED were more likely, compared with APM victims, to have multiple amputations (70.0% vs 10.4%; p<0.001) or genital injury (26% vs 13%; p=0.007). Multiple amputations occurred in 70 patients: 5 quadruple amputations, 27 triple amputations and 38 double amputations. Pelvic fracture occurred in 21 victims, all but one of whom had multiple amputations. Severe perineal, gluteal or genital injuries were present in 46 patients. Severe soft tissue injury was universal, with injection of contaminated soil along tissue planes well above entry sites. There were 13 facial injuries, 9 skull fractures and 3 traumatic brain injuries. Eleven eye injuries were seen; none of the victims with eye injuries were wearing eye protection. The casualty fatality rate was at least 19%. The presence of more than one amputation was associated with a higher rate of pelvic fracture (28.6% vs 3.3%; p=0.005) and perineal-gluteal injury (32.6% vs 11.1%; p=0.009). CONCLUSION: The injury pattern suffered by the target of the AP-IED is markedly worse than that of conventional APM. Pelvic binders and tourniquets should be applied at the point of injury to patients with multiple amputations or perineal injuries. PMID- 28835412 TI - Chronic vertigo: treat with exercise, not drugs. PMID- 28835413 TI - Salmonella Thompson splenic abscess in a healthy female. AB - A 26-year-old woman presented with a 5-day history of fever and 3-day history of left upper quadrant abdominal pain and cough associated with left shoulder tip pain. Initial blood cultures did not display growth. On CT imaging, there was a cyst measuring 7.2*8 cm originally interpreted to be haemorrhagic in nature. Repeat cultures during admission revealed Salmonella Thompson. Percutaneous drainage and antibiotic treatment, rather than splenectomy, was successfully pursued with the patient afebrile and in no pain at 6 weeks follow-up. PMID- 28835414 TI - Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials. PMID- 28835416 TI - Suspected sepsis: summary of NICE guidance. PMID- 28835418 TI - Stem cell-derived exosomes: a novel vector for tissue repair and diabetic therapy. AB - Exosomes are extracellular vesicles (EVs) secreted from a majority of cell types. Exosomes play a role in healthy and pathogenic intercellular interactions via the transfer of proteins, lipids and RNA. The contents and effects of exosomes vary depending on the properties of the originating cell. Exosomes secreted from some cell types, including stem cells, carry biological factors implicated in the protection, regeneration and angiogenesis of damaged tissues. Due to these properties, exosomes have attracted attention as a novel vector for regenerative therapies. Exosomes as a therapeutic tool could have applications for the treatment of many disorders characterized by chronic tissue damage. Exosomes derived from stem cells could be applied to repair or prevent damage from the complications of diabetes mellitus. The immunomodulatory and reparative properties of stem cell-derived exosomes could protect or even restore an early stage type 1 diabetic patient's original islets from autoimmune destruction. Exosomes could also possibly suppress graft rejection of pancreatic islet transplants. Therefore, it is our recommendation that the treatment of diabetes mellitus using exosome-based therapies be further explored. Development of novel therapies using exosomes is slowed by a limited understanding of their mechanisms. This hurdle must be overcome to pave the way for clinical trials and ultimately the adaptation of exosomes as a therapeutic vector. PMID- 28835417 TI - Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity. AB - For thymic selection and responses to pathogens, T cells interact through their alphabeta T cell receptor (TCR) with peptide-major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR-MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V-J gene combination can be selected by a single MHC II. PMID- 28835419 TI - Glomerular mesangial cell recruitment and function require the co-receptor neuropilin-1. AB - Proteinuria has been reported in cancer patients receiving agents that target the transmembrane receptor neuropilin-1 (Nrp1) suggesting potential adverse effects on glomerular function. Here we show that Nrp1 is highly expressed by mesangial cells and that genetic deletion of the Nrp1 gene from PDGF receptor-beta+ mesangial cells results in proteinuric disease and glomerulosclerosis, leading to renal failure and death within 6 wk of age in mice. The major defect is a failure of mesangial cell migration that is required to establish the mature glomerular tuft. In vitro data show that the potent chemotactic effect of PDGFB is lost in Nrp1-deficient mesangial cells. Biochemical analyses reveal that Nrp1 is required for PDGFB-dependent phosphorylation of p130 Crk-associated substrate (p130Cas), a large-scaffold molecule that is involved in motility of other cell types. In stark contrast, matrix adhesion and activation of ERK and Akt, which mediate proliferation of mesangial cells in response to PDGFB, are unaffected by the absence of Nrp1. Taken together, these results identify a critical cell autonomous role for Nrp1 in the migratory behavior of mesangial cells and may help explain the renal effects that occur in patients receiving Nrp1-inhibitory drugs. PMID- 28835420 TI - Evaluating the voiding spot assay in mice: a simple method with complex environmental interactions. AB - The voiding spot assay (VSA) on filter paper is an increasingly popular method for studying lower urinary tract physiology in mice. However, the ways VSAs are performed differ significantly between laboratories, and many variables are introduced compared with the mouse's normal housing situation. Rodents are intelligent social animals, and it is increasingly understood that social and environmental stresses have significant effects on their physiology. Surprisingly, little is known about whether change of environment during VSA affects mouse voiding and what the best methodologies are for retaining "natural" micturition patterns. It is well known that stress-related neuropeptide corticotropin-releasing factor is significantly elevated and induces dramatic voiding changes when rodents encounter stresses. Therefore we hypothesized that changes in the environmental situation could potentially alter voiding during VSA. We have examined multiple factors to test whether they affect female mouse voiding patterns during VSA, including cage type, cage floor, water availability, water bottle location, single or group housing, and different handlers. Our results indicate that mice are surprisingly sensitive to changes in cage type and floor surface, water bottle location, and single/group housing, each of which induces significant changes in voiding patterns, indicative of a stress response. In contrast, neither changing handler nor 4 h of water deprivation affected voiding patterns. Our data indicate that VSA should be performed under conditions as close as possible to the mouse's normal housing. Optimizing VSA methodology will be useful in uncovering voiding alterations in both genetic and disease models of lower urinary dysfunctions. PMID- 28835422 TI - Tumor-Associated Macrophages Promote Epigenetic Silencing of Gelsolin through DNA Methyltransferase 1 in Gastric Cancer Cells. AB - Epigenetic repression of the tumor suppressor gelsolin (GSN) is frequently observed in cancers. Chronic inflammation can promote tumor progression via aberrant DNA methylation. In this study, we investigated the role of tumor associated macrophages (TAMs) in DNA methylation of the GSN gene during gastric cancer progression. Immunofluorescence staining of 121 gastric cancer tissues showed aberrant localization of GSN and DNA methyltransferase 1 (DNMT1) and juxtaposition of DNMT1 and M2 TAMs. Decreased GSN protein and mRNA expression and increased DNA methylation in the GSN promoter were observed in gastric cancer cell lines and clinical specimens. To examine the effect of TAMs on DNA methylation in gastric cancer cells, we performed in vitro coculture assays and found increased DNMT1 expression but decreased GSN expression in gastric cancer cells after coculture with U937 cells. Knockdown of DNMT1 expression in gastric cancer cells could abort U937 coculture-mediated GSN downregulation. Meanwhile, CCL5 was the main chemokine upregulated in coculture medium. Treatment with CCL5 could induce DNMT1 expression in gastric cancer cells via STAT3 signaling. Inhibiting DNMT1 activity with procainamide, inhibiting DNA methylation with 5 AZA, or inhibiting CCL5/CCR5 signaling with maraviroc reduced tumor growth in vivo In conclusion, upregulation of DNMT1 by CCL5/CCR5/STAT3 signaling is critical for TAM-mediated GSN silencing in gastric cancer. This study identified potential targets for gastric cancer therapy. Cancer Immunol Res; 5(10); 885-97. (c)2017 AACR. PMID- 28835421 TI - Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF). AB - Afferent arteriole (Af-Art) resistance is modulated by two intrinsic nephron feedbacks: 1) the vasoconstrictor tubuloglomerular feedback (TGF) mediated by Na+ K+-2Cl- cotransporters (NKCC2) in the macula densa and blocked by furosemide and 2) the vasodilator connecting tubule glomerular feedback (CTGF), mediated by epithelial Na+ channels (ENaC) in the connecting tubule and blocked by benzamil. High salt intake reduces Af-Art vasoconstrictor ability in Dahl salt-sensitive rats (Dahl SS). Previously, we measured CTGF indirectly, by differences between TGF responses with and without CTGF inhibition. We recently developed a new method to measure CTGF more directly by simultaneously inhibiting NKCC2 and the Na+/H+ exchanger (NHE). We hypothesize that in vivo during simultaneous inhibition of NKCC2 and NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (PSF) in Dahl SS and that is enhanced with a high salt intake. In the presence of furosemide alone, increasing nephron perfusion did not change the PSF in either Dahl salt-resistant rats (Dahl SR) or Dahl SS. When furosemide and an NHE inhibitor, dimethylamiloride, were perfused simultaneously, an increase in tubular flow caused Af-Art dilatation that was demonstrated by an increase in PSF. This increase was greater in Dahl SS [4.5 +/- 0.4 (SE) mmHg] than in Dahl SR (2.5 +/- 0.3 mmHg; P < 0.01). We confirmed that CTGF causes this vasodilation, since benzamil completely blocked this effect. However, a high salt intake did not augment the Af-Art dilatation. We conclude that during simultaneous inhibition of NKCC2 and NHE in the nephron, CTGF induces Af-Art dilatation and a high salt intake failed to enhance this effect. PMID- 28835423 TI - Cost-effectiveness of age-related macular degeneration study supplements in the UK: combined trial and real-world outcomes data. AB - AIMS: To evaluate the cost-effectiveness of Age-Related Eye Disease Study (AREDS) 1 & 2 supplements in patients with either bilateral intermediate age-related macular degeneration, AREDS category 3, or unilateral neovascular age-related macular degeneration AMD (nAMD), AREDS category 4. METHODS: A patient-level health state transition model based on levels of visual acuity in the better seeing eye was constructed to simulate the costs and consequences of patients taking AREDS vitamin supplements. SETTING: UK National Health Service (NHS). The model was populated with data from AREDS and real-world outcomes and resource use from a prospective multicentre national nAMD database study containing 92 976 ranibizumab treatment episodes. INTERVENTIONS: Two treatment approaches were compared: immediate intervention with AREDS supplements or no supplements. MAIN OUTCOME MEASURES: quality-adjusted life years (QALYs) and healthcare costs were accrued for each strategy, and incremental costs and QALYs were calculated for the lifetime of the patient. One-way and probabilistic sensitivity analyses were employed to test the uncertainty of the model. RESULTS: For AREDS category 3, the incremental cost-effectiveness ratio was L30 197. For AREDS category 4 compared with no intervention, AREDS supplements are more effective (10.59 vs 10.43 QALYs) and less costly (L52 074 vs 54 900) over the lifetime of the patient. CONCLUSIONS: The recommendation to publicly fund AREDS supplements to category 3 patients would depend on the healthcare system willingness to pay. In contrast, initiating AREDS supplements in AREDS category 4 patients is both cost saving and more effective than no supplement use and should therefore be considered in public health policy. PMID- 28835424 TI - Compressed 3D and 2D digital images versus standard 3D slide film for the evaluation of glaucomatous optic nerve features. AB - SYNOPSIS: Clinicians can feel confident compressed three-dimensional digital (3DD) and two-dimensional digital (2DD) imaging evaluating important features of glaucomatous disc damage is comparable to the previous gold standard of stereoscopic slide film photography, supporting the use of digital imaging for teleglaucoma applications. BACKGROUND/AIMS: To compare the sensitivity and specificity of 3DD and 2DD photography with stereo slide film in detecting glaucomatous optic nerve head features. METHODS: This prospective, multireader validation study imaged and compressed glaucomatous, suspicious or normal optic nerves using a ratio of 16:1 into 3DD and 2DD (1024*1280 pixels) and compared both to stereo slide film. The primary outcome was vertical cup-to-disc ratio (VCDR) and secondary outcomes, including disc haemorrhage and notching, were also evaluated. Each format was graded randomly by four glaucoma specialists. A protocol was implemented for harmonising data including consensus-based interpretation as needed. RESULTS: There were 192 eyes imaged with each format. The mean VCDR for slide, 3DD and 2DD was 0.59+/-0.20, 0.60+/-0.18 and 0.62+/ 0.17, respectively. The agreement of VCDR for 3DD versus film was kappa=0.781 and for 2DD versus film was kappa=0.69. Sensitivity (95.2%), specificity (95.2%) and area under the curve (AUC; 0.953) of 3DD imaging to detect notching were better (p=0.03) than for 2DD (90.5%; 88.6%; AUC=0.895). Similarly, sensitivity (77.8%), specificity (98.9%) and AUC (0.883) of 3DD to detect disc haemorrhage were better (p=0.049) than for 2DD (44.4%; 99.5%; AUC=0.72). There was no difference between 3DD and 2DD imaging in detecting disc tilt (p=0.7), peripapillary atrophy (p=0.16), grey crescent (p=0.1) or pallor (p=0.43), although 3D detected sloping better (p=0.013). CONCLUSIONS: Both 3DD and 2DD imaging demonstrates excellent reproducibility in comparison to stereo slide film with experts evaluating VCDR, notching and disc haemorrhage. 3DD in this study was slightly more accurate than 2DD for evaluating disc haemorrhage, notching and sloping. PMID- 28835425 TI - Polycystic ovary syndrome with asynchronous bilateral adnexal torsion in a natural cycle. AB - Cases involving polycystic ovaries (PCOs) with adnexal torsion in a natural cycle without ovulation induction are rare, and no reports of such cases have described asynchronous bilateral adnexal torsion. Here, we report a case of PCO syndrome (PCOS) with asynchronous bilateral adnexal torsion in a natural cycle. The patient was a 37-year-old woman with a history of 2 gravidas 1 para. Her primary complaint was left lower abdominal pain. Ultrasonography and MRI identified multiple uterine myomas occupying the pelvis and the left ovary, with oedematous swelling that had moved ventrally to the uterus. She was diagnosed with adnexal torsion and underwent emergency laparoscopic adnexectomy. Nine months after surgery, she experienced right lower abdominal pain. Ultrasonography revealed suspected right adnexal torsion and she underwent emergency surgery. The right ovary was twisted 540 degrees counterclockwise and swollen to 7 cm in size, with partial polycystic changes. She was histopathologically diagnosed with a PCO, and the final diagnosis, which also considered the endocrine test results, was PCOS. In PCOS, adnexal torsion may occur if the swollen ovary moves because of a hysteromyoma or other cause. Accordingly, torsion should be considered during the follow-up of patients with PCOS. PMID- 28835426 TI - Suspected case of lipoedema in Japanese woman with a characteristic histology in skin biopsy. PMID- 28835427 TI - Large pectoral haematoma post-transradial catheterisation: an unusual but avoidable complication. AB - Large pectoral haematoma is an extremely rare complication of transradial catheterisation. Branch or main vessel injury due to luminal passage of guidewires and catheters may lead to bleeding and haematoma formation at adjacent sites along the vessel track. We present a 53-year-old post-transradial catheterisation patient, who complained of chest pain due to right axillary artery branch perforation causing haematoma, which was emergently managed by embolisation with autologous coagulated blood. PMID- 28835428 TI - Oral mucosal grafting combined with tenonplasty for ocular surface and lid margin reconstruction in an atypical sectorial chemical burn. AB - A 46-year-old woman presented with chemical injury in both eyes after the instillation of undefined eye-drops prescribed by quack. She had an atypical presentation in the form of bilateral severe necrosis of both lids and whole palpebral conjunctiva. Extensive debridement with conjunctival epitheliectomy, tenonplasty and amniotic membrane transplantation (AMT) was performed. Characteristic differences from typical chemical injuries were a sectorial involvement of ocular surface and keratinisation over distorted lid margins. Lid margin needed replacement by labial mucous membrane for the restoration of ocular surface. Ocular surface reconstruction with AMT in acute phase and mucous membrane grafting for involved lid margins in late phase achieves vision salvage and avoids late complications in drug-induced chemical injury. PMID- 28835429 TI - A rare case of pulmonary toxoplasmosis in a patient with undifferentiated inflammatory arthritis on chronic methotrexate and corticosteroid therapy. AB - Pulmonary toxoplasmosis is a serious pulmonary condition caused by the protozoan Toxoplasma gondii It typically affects immunocompromised patients presenting acutely with cough, fever, myalgias, arthralgias and lymphadenopathy, and chronically with persistent cough and dyspnoea. Because of its protean features, it can mimic many more common lung conditions in the immunocompromised patient, including atypical pneumonia, Pneumocystis pneumonia and interstitial lung disease. In this article, we present the case of a 55-year-old woman who presented to our hospital with persistent dyspnoea and cough, initially suspected to have an arthritis-related interstitial lung disease. She received a final diagnosis of pulmonary toxoplasmosis after lung biopsy demonstrated Toxoplasma cysts, later confirmed by serology. Treatment with trimethoprim-sulfamethoxazole resulted in significant improvement of her respiratory symptoms after 3 months. PMID- 28835430 TI - Filarial breast lump. AB - Lymphatic filariasis is one of the most debilitating and disfiguring scourges among all diseases. This report presents a case of a woman with recurrent breast nodularity after being previously operated for a suspected breast neoplasm. We would like to highlight the issue of similar clinical presentation of a filarial breast lump and other breast lesions leading to inappropriate therapy. PMID- 28835431 TI - Cheyne-Stokes respiration: poor prognostic sign in a patient with heart failure. PMID- 28835432 TI - The role of Ca2+-activated Cl- current in tone generation in the rabbit corpus cavernosum. AB - Rabbit corpus cavernosum smooth muscle (RCCSM) cells express ion channels that produce Ca2+-activated Cl- (IClCa) current, but low sensitivity to conventional antagonists has made its role in tone generation difficult to evaluate. We have reexamined this question using two new generation IClCa blockers, T16Ainh-A01 and CaCCinh-A01. Isolated RCCSM cells were studied using the perforated patch method. Current-voltage protocols revealed that both L-type Ca2+ current and IClCa T16Ainh-A01 and CaCCinh-A01 (10 MUM) reduced IClCa by ~85%, while 30 MUM abolished it. L-type Ca2+ current was unaffected by 10 MUM CaCCinh-A01 but was reduced by 50% at 30 MUM CaCCinh-A01, 46% at 10 MUM T16Ainh-A01, and 78% at 30 MUM T16Ainh-A01. Both drugs reduced spontaneous isometric tension in RCCSM strips, by 60-70% at 10 MUM and >90% at 30 MUM. Phenylephrine (PE)-enhanced tension was also reduced (ED50 = 3 MUM, CaCCinh-A01; 14 MUM, T16Ainh-A01). CaCCinh-A01 at 10 MUM had little effect on 60 mM KCl contractures, though they were reduced by 30 MUM CaCCinh-A01 and T16Ainh-A01 (10 MUM and 30 MUM) consistent with their effects on L-type Ca2+ current. Both drugs also reversed the stimulatory effect of PE on intracellular Ca2+ waves, studied with laser scanning confocal microscopy in isolated RCCSM cells. In conclusion, although both drugs were effective blockers of IClCa, the effect of T16Ainh-A01 on L-type Ca2+ current precludes its use for evaluating the role of IClCa in tone generation. However, 10 MUM CaCCinh-A01 selectively blocked IClCa versus L-type Ca2+ current and reduced spontaneous and PE-induced tone, suggesting that IClCa is important in maintaining penile detumescence. PMID- 28835433 TI - Integration of TRPC6 and NADPH oxidase activation in lysophosphatidylcholine induced TRPC5 externalization. AB - Lipid oxidation products, including lysophosphatidylcholine (lysoPC), activate canonical transient receptor potential 6 (TRPC6) channels, and the subsequent increase in intracellular Ca2+ leads to TRPC5 activation. The goal of this study is to elucidate the steps in the pathway between TRPC6 activation and TRPC5 externalization. Following TRPC6 activation by lysoPC, extracellular regulated kinase (ERK) is phosphorylated. This leads to phosphorylation of p47phox and subsequent NADPH oxidase activation with increased production of reactive oxygen species. ERK activation requires TRPC6 opening and influx of Ca2+ as evidenced by the failure of lysoPC to induce ERK phosphorylation in TRPC6-/- endothelial cells. ERK siRNA blocks the lysoPC-induced activation of NADPH oxidase, demonstrating that ERK activation is upstream of NADPH oxidase. The reactive oxygen species produced by NADPH oxidase promote myosin light chain kinase (MLCK) activation with phosphorylation of MLC and TRPC5 externalization. Downregulation of ERK, NADPH oxidase, or MLCK with the relevant siRNA prevents TRPC5 externalization. Blocking MLCK activation prevents the prolonged rise in intracellular calcium levels and preserves endothelial migration in the presence of lysoPC. PMID- 28835434 TI - Stretch activation properties of Drosophila and Lethocerus indirect flight muscle suggest similar calcium-dependent mechanisms. AB - Muscle stretch activation (SA) is critical for optimal cardiac and insect indirect flight muscle (IFM) power generation. The SA mechanism has been investigated for decades with many theories proposed, but none proven. One reason for the slow progress could be that multiple SA mechanisms may have evolved in multiple species or muscle types. Laboratories studying IFM SA in the same or different species have reported differing SA functional properties which would, if true, suggest divergent mechanisms. However, these conflicting results might be due to different experimental methodologies. Thus, we directly compared SA characteristics of IFMs from two SA model systems, Drosophila and Lethocerus, using two different fiber bathing solutions. Compared with Drosophila IFM, Lethocerus IFM isometric tension is 10- or 17-fold higher and SA tension was 5- or 10-fold higher, depending on the bathing solution. However, the rate of SA tension generation was 9-fold faster for Drosophila IFM. The inverse differences between rate and tension in the two species causes maximum power output to be similar, where Drosophila power is optimized in the bathing solution that favors faster muscle kinetics and Lethocerus in the solution that favors greater tension generation. We found that isometric tension and SA tension increased with calcium concentration for both species in both solutions, reaching a maximum plateau around pCa 5.0. Our results favor a similar mechanism for both species, perhaps involving a troponin complex that does not fully calcium activate the thin filament thus leaving room for further tension generation by SA. PMID- 28835435 TI - miR-15b negatively correlates with lipid metabolism in mammary epithelial cells. AB - Mammary epithelial cells are regulated by steroid hormones, growth factors, and even microRNAs. miR-15b has been found to regulate lipid metabolism in adipocytes; however, its effects on lipid metabolism in mammary epithelial cells, the cells of lipid synthesis and secretion, are as yet unknown. The main purpose of this investigation was to explore the effect of miR-15b on lipid metabolism in mammary epithelial cells, along with the underlying mechanisms. miR-15b was overexpressed or inhibited by miRNA mimics or inhibitors; subsequently, lipid formation in mammary epithelial cells, and proteins related to lipid metabolism, were investigated. Through overexpression or inhibition of miR-15b expression, the current investigation found that miR-15b downregulates lipid metabolism in mammary epithelial cells and is expressed differentially at various stages of mouse and goat mammary gland development. Inhibition of miR-15b expression increased lipid content in mammary epithelial cells through elevation of the lipid synthesis enzyme fatty acid synthetase (FASN), and overexpression of miR 15b reduced lipid content in mammary epithelial cells with decreasing levels of FASN. Moreover, the steroid hormones estradiol and progesterone decreased miR-15b expression with a subsequent increase in lipid formation in mammary epithelial cells. The expression of miR-15b was lower during lactation and negatively correlated with lipid synthesis proteins, which suggests that it may be involved in lipid synthesis and milk production. miR-15b might be a useful target for altering lipid production and milk yield. PMID- 28835436 TI - In vitro contraction protects against palmitate-induced insulin resistance in C2C12 myotubes. AB - We are interested in understanding mechanisms that govern the protective role of exercise against lipid-induced insulin resistance, a key driver of type 2 diabetes. In this context, cell culture models provide a level of abstraction that aid in our understanding of cellular physiology. Here we describe the development of an in vitro myotube contraction system that provides this protective effect, and which we have harnessed to investigate lipid-induced insulin resistance. C2C12 myocytes were differentiated into contractile myotubes. A custom manufactured platinum electrode system and pulse stimulator, with polarity switching, provided an electrical pulse stimulus (EPS) (1 Hz, 6-ms pulse width, 1.5 V/mm, 16 h). Contractility was assessed by optical flow flied spot noise mapping and inhibited by application of ammonium acetate. Following EPS, myotubes were challenged with 0.5 mM palmitate for 4 h. Cells were then treated with or without insulin for glucose uptake (30 min), secondary insulin signaling activation (10 min), and phosphoinositide 3-kinase-alpha (PI3Kalpha) activity (5 min). Prolonged EPS increased non-insulin-stimulated glucose uptake (83%, P = 0.002), Akt (Thr308) phosphorylation (P = 0.005), and insulin receptor substrate 1 (IRS-1)-associated PI3Kalpha activity (P = 0.048). Palmitate reduced insulin specific action on glucose uptake (-49%, P < 0.001) and inhibited insulin stimulated Akt phosphorylation (P = 0.049) and whole cell PI3Kalpha activity (P = 0.009). The inhibitory effects of palmitate were completely absent with EPS pretreatment at the levels of glucose uptake, insulin responsiveness, Akt phosphorylation, and whole cell PI3Kalpha activity. This model suggests that muscle contraction alone is a sufficient stimulus to protect against lipid induced insulin resistance as evidenced by changes in the proximal canonical insulin-signaling pathway. PMID- 28835437 TI - CLEC-2 contributes to hemostasis independently of classical hemITAM signaling in mice. AB - C-type lectin-like receptor 2 (CLEC-2) is a platelet receptor that is critical during development in blood-lymph separation and implicated in thrombus stability in thrombosis and hemostasis. It is the only known platelet activatory receptor that participates in both of these aspects of platelet function, and it is the only one to signal through a hemi-immunoreceptor tyrosine-based activation motif (hemITAM). Current investigations into the function of CLEC-2 in vivo have focused on knockout (KO) studies in which both the receptor and its signaling are deleted, making it impossible to explore the possible signaling-independent functions of the receptor, which are indicated by its only known physiological ligand, podoplanin, being an integral membrane protein. In this report, we present a novel knockin mouse model that maintains the expression of a CLEC-2 receptor that cannot signal through its hemITAM (Y7A KI). Remarkably, this mouse phenocopies the blood-lymphatic mixing and lethality of CLEC-2 KO models, but not their hemostatic/thrombotic defect. However, treatment of Y7A KI mice with Fab' fragments of the function-blocking anti-CLEC-2 antibody, INU1, resulted in a thrombus formation defect in vivo and ex vivo, revealing a hemITAM signaling independent role for CLEC-2 in hemostasis and thrombosis. PMID- 28835438 TI - Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1 mutant acute myeloid leukemia. AB - NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound Npm1cA/+;NrasG12D/+ or Npm1cA;Flt3ITD share a number of features: Hox gene overexpression, enhanced self renewal, expansion of hematopoietic progenitors, and myeloid differentiation bias. However, Npm1cA;Flt3ITD mutants displayed significantly higher peripheral leukocyte counts, early depletion of common lymphoid progenitors, and a monocytic bias in comparison with the granulocytic bias in Npm1cA/+;NrasG12D/+ mutants. Underlying this was a striking molecular synergy manifested as a dramatically altered gene expression profile in Npm1cA;Flt3ITD , but not Npm1cA/+;NrasG12D/+ , progenitors compared with wild-type. Both double-mutant models developed high penetrance AML, although latency was significantly longer with Npm1cA/+;NrasG12D/+ During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1cA/+;NrasG12D/+ mice showed acquisition of other human AML mutations, including IDH1 R132Q. We also find, using primary Cas9-expressing AMLs, that Hoxa genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with NPM1c/FLT3-ITD vs NPM1/NRAS G12D-mutant AML and functionally confirm the role of HOXA genes in NPM1c-driven AML. PMID- 28835439 TI - Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. AB - There is uncertainty regarding the effectiveness and occurrence of thromboembolic events in patients treated with prothrombin complex concentrates (PCCs) for the management of major bleeding events (MBEs) on rivaroxaban or apixaban. We investigated the effectiveness of PCCs given for the management of MBEs in patients on rivaroxaban or apixaban. Between 1 January 2014 and 1 October 2016, we prospectively included patients on rivaroxaban or apixaban treated with PCCs for the management of MBEs. The effectiveness of PCCs was assessed by using the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria for the assessment of the effectiveness of major bleeding management. The safety outcomes were thromboembolic events and all-cause mortality within 30 days after treatment with PCCs. A total of 84 patients received PCCs for the reversal of rivaroxaban or apixaban due to a MBE. PCCs were given at a median (interquartile range) dose of 2000 IU (1500-2000 IU). Intracranial hemorrhage (ICH) was the most common site of bleeding requiring reversal (n = 59; 70.2%), followed by gastrointestinal bleeding in 13 (15.5%) patients. Management with PCCs was assessed as effective in 58 (69.1%) patients and ineffective in 26 (30.9%) patients. Most patients with ineffective hemostasis with PCCs had ICH (n = 16; 61.5%). Two patients developed an ischemic stroke, occurring 5 and 10 days after treatment with PCC. Twenty-seven (32%) patients died within 30 days after a MBE. The administration of PCCs for the management of MBEs associated with rivaroxaban or apixaban is effective in most cases and is associated with a low risk of thromboembolism. Our findings are limited by the absence of a control group in the study. PMID- 28835440 TI - Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment. AB - Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10%); the most common were -Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those in which -Y was the only clonal abnormality, and all others. We found that patients with non -Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52% vs 70%, P = .02), EFS (68% vs 86%, P = .02), TFS (76% vs 94%, P < .01), and OS (79% vs 94%, P = .03). In a multivariate analysis, non -Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95% confidence interval, 1.15-6.89; P = .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL <10% at 3 months was included in the analysis. In conclusion, non -Y CCA/Ph- are associated with decreased survival when emerging in patients with chronic-phase CML across various TKIs. This trial was registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, and #NCT00050531 (imatinib); #NCT00254423 (dasatinib); #NCT00129740 (nilotinib); and NCT01570868 (ponatinib). PMID- 28835442 TI - CYP-Mediated Sulfoximine Deimination of AZD6738. AB - In hepatic S9 and human liver microsomes (HLMs) the sulfoximine moiety of the ATR inhibitor AZD6738 is metabolized to its corresponding sulfoxide (AZ8982) and sulfone (AZ0002). The initial deimination to AZ8982 is nominally a reductive reaction, but in HLMs it required both NADPH and oxygen and also was inhibited by 1-aminobenzotriazole at a concentration of 1 mM. Studies conducted in a panel of 11 members of the cytochrome P450 (P450) family (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 CYP2J2, CYP3A4, and CYP3A5) confirmed that deimination was an oxidative process that was mediated largely by CYP2C8 with some CYP2J2 involvement, whereas the subsequent oxidation to sulfone was carried out largely by CYP2J2, CYP3A4, and CYP3A5. There was no measureable metabolism in flavin-containing monooxygenase (FMO) enzymes FMO3, FMO5 or NADPH cytochrome C reductase. Studies using Silensomes, a commercially available HLM in which specific members of the P450 family have been inhibited by selective mechanism based inhibitors, showed that when CYP2C8 was inhibited, the rate of deimination was reduced by 95%, suggesting that CYP2J2 is only playing a minor role in HLMs. When CYP3A4 was inhibited, the rate increased by 58% due to the inhibition of the subsequent sulfone formation. Correlation studies conducted in HLM samples from different individuals confirmed the role of CYP2C8 in the deimination over CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Hence, although nominally a reduction, the deimination of AZD6738 to its sulfoxide metabolite AZ8982 is an oxidation mediated by CYP2C8, and this metabolite is subsequently oxidized to the sulfone (AZ0002) largely by CYP3A. PMID- 28835441 TI - Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. AB - Relapse has emerged as the most important cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT). To test the hypothesis that natural killer (NK) cells can decrease the risk of leukemia relapse, we initiated a phase 1 dose-escalation study of membrane-bound interleukin 21 (mbIL21) expanded donor NK cells infused before and after haploidentical HSCT for high-risk myeloid malignancies. The goals were to determine the safety, feasibility, and maximum tolerated dose. Patients received a melphalan-based reduced-intensity conditioning regimen and posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. NK cells were infused on days -2, +7, and +28 posttransplant. All NK expansions achieved the required cell number, and 11 of 13 patients enrolled received all 3 planned NK-cell doses (1 * 105/kg to 1 * 108/kg per dose). No infusional reactions or dose-limiting toxicities occurred. All patients engrafted with donor cells. Seven patients (54%) developed grade 1-2 acute GVHD (aGVHD), none developed grade 3-4 aGVHD or chronic GVHD, and a low incidence of viral complications was observed. One patient died of nonrelapse mortality; 1 patient relapsed. All others were alive and in remission at last follow-up (median, 14.7 months). NK-cell reconstitution was quantitatively, phenotypically, and functionally superior compared with a similar group of patients not receiving NK cells. In conclusion, this trial demonstrated production feasibility and safety of infusing high doses of ex vivo-expanded NK cells after haploidentical HSCT without adverse effects, increased GVHD, or higher mortality, and was associated with significantly improved NK-cell number and function, lower viral infections, and low relapse rate posttransplant. PMID- 28835443 TI - A statewide evaluation of seven strategies to reduce opioid overdose in North Carolina. AB - BACKGROUND: In response to increasing opioid overdoses, US prevention efforts have focused on prescriber education and supply, demand and harm reduction strategies. Limited evidence informs which interventions are effective. We evaluated Project Lazarus, a centralised statewide intervention designed to prevent opioid overdose. METHODS: Observational intervention study of seven strategies. 74 of 100 North Carolina counties implemented the intervention. Dichotomous variables were constructed for each strategy by county-month. Exposure data were: process logs, surveys, addiction treatment interviews, prescription drug monitoring data. Outcomes were: unintentional and undetermined opioid overdose deaths, overdose-related emergency department (ED) visits. Interrupted time-series Poisson regression was used to estimate rates during preintervention (2009-2012) and intervention periods (2013-2014). Adjusted IRR controlled for prescriptions, county health status and time trends. Time-lagged regression models considered delayed impact (0-6 months). RESULTS: In adjusted immediate-impact models, provider education was associated with lower overdose mortality (IRR 0.91; 95% CI 0.81 to 1.02) but little change in overdose-related ED visits. Policies to limit ED opioid dispensing were associated with lower mortality (IRR 0.97; 95% CI 0.87 to 1.07), but higher ED visits (IRR 1.06; 95% CI 1.01 to 1.12). Expansions of medication-assisted treatment (MAT) were associated with increased mortality (IRR 1.22; 95% CI 1.08 to 1.37) but lower ED visits in time-lagged models. CONCLUSIONS: Provider education related to pain management and addiction treatment, and ED policies limiting opioid dispensing showed modest immediate reductions in mortality. MAT expansions showed beneficial effects in reducing ED-related overdose visits in time-lagged models, despite an unexpected adverse association with mortality. PMID- 28835444 TI - Injuries and alcohol management plans in remote Indigenous communities: a two community comparison. AB - To curb high rates of alcohol-related violence and injury in Indigenous communities, alcohol management plans (AMPs) were implemented in 2002-2003 and tightened in 2008. This project compares injury presentations and alcohol involvement from two Indigenous Cape York communities, one that entered full prohibition and one that did not. Aclinical file audit was performed for the period 2006-2011, capturing changes in alcohol availability. Medical files were searched for injury presentation documenting type of injury, cause of injury (including alcohol), date of injury and outcomes of all presenting injuries for the time period 1 January 2006 to 31 December 2011, capturing the major changes of the 2008 AMP restrictions. Findings indicated injury presentation rates were higher in both communities before prohibition than afterwards andreduction was more pronounced in community 2 (prohibition). Ongoing research is imperative, as this area is characterised by a near-absence of evidence. PMID- 28835445 TI - Angiogenic conditioning of peripheral blood mononuclear cells promotes fracture healing. AB - OBJECTIVES: The objective of this study was to investigate the therapeutic effect of peripheral blood mononuclear cells (PBMNCs) treated with quality and quantity control culture (QQ-culture) to expand and fortify angiogenic cells on the acceleration of fracture healing. METHODS: Human PBMNCs were cultured for seven days with the QQ-culture method using a serum-free medium containing five specific cytokines and growth factors. The QQ-cultured PBMNCs (QQMNCs) obtained were counted and characterised by flow cytometry and real-time polymerase chain reaction (RT-PCR). Angiogenic and osteo-inductive potentials were evaluated using tube formation assays and co-culture with mesenchymal stem cells with osteo inductive medium in vitro. In order to evaluate the therapeutic potential of QQMNCs, cells were transplanted into an immunodeficient rat femur nonunion model. The rats were randomised into three groups: control; PBMNCs; and QQMNCs. The fracture healing was evaluated radiographically and histologically. RESULTS: The total number of PBMNCs was decreased after QQ-culture, however, the number of CD34+ and CD206+ cells were found to have increased as assessed by flow cytometry analysis. In addition, gene expression of angiogenic factors was upregulated in QQMNCs. In the animal model, the rate of bone union was higher in the QQMNC group than in the other groups. Radiographic scores and bone volume were significantly associated with the enhancement of angiogenesis in the QQMNC group. CONCLUSION: We have demonstrated that QQMNCs have superior potential to accelerate fracture healing compared with PBMNCs. The QQMNCs could be a promising option for fracture nonunion.Cite this article: K. Mifuji, M. Ishikawa, N. Kamei, R. Tanaka, K. Arita, H. Mizuno, T. Asahara, N. Adachi, M. Ochi. Angiogenic conditioning of peripheral blood mononuclear cells promotes fracture healing. Bone Joint Res 2017;6: 489-498. DOI: 10.1302/2046-3758.68.BJR-2016-0338.R1. PMID- 28835446 TI - White-nose syndrome increases torpid metabolic rate and evaporative water loss in hibernating bats. AB - Fungal diseases of wildlife typically manifest as superficial skin infections but can have devastating consequences for host physiology and survival. White-nose syndrome (WNS) is a fungal skin disease that has killed millions of hibernating bats in North America since 2007. Infection with the fungus Pseudogymnoascus destructans causes bats to rewarm too often during hibernation, but the cause of increased arousal rates remains unknown. On the basis of data from studies of captive and free-living bats, two mechanistic models have been proposed to explain disease processes in WNS. Key predictions of both models are that WNS affected bats will show 1) higher metabolic rates during torpor (TMR) and 2) higher rates of evaporative water loss (EWL). We collected bats from a WNS negative hibernaculum, inoculated one group with P. destructans, and sham inoculated a second group as controls. After 4 mo of hibernation, TMR and EWL were measured using respirometry. Both predictions were supported, and our data suggest that infected bats were more affected by variation in ambient humidity than controls. Furthermore, disease severity, as indicated by the area of the wing with UV fluorescence, was positively correlated with EWL, but not TMR. Our results provide the first direct evidence that heightened energy expenditure during torpor and higher EWL independently contribute to WNS pathophysiology, with implications for the design of potential treatments for the disease. PMID- 28835448 TI - Cyclical blood flow restriction resistance exercise: a potential parallel to remote ischemic preconditioning? AB - Remote ischemic preconditioning (RIPC) is characterized by the cyclical application of limb blood flow restriction and reperfusion and has been shown to protect vital organs during a subsequent ischemic insult. Blood flow restriction exercise (BFRE) similarly combines bouts of blood flow restriction with low intensity exercise and thus could potentially emulate the protection demonstrated by RIPC. One concern with BFRE, however, is the potential for an augmented rise in sympathetic outflow due to greater activation of the exercise pressor reflex. Because of the use of lower workloads, however, we hypothesized that BFRE would elicit an attenuated increase in sympathetic outflow [assessed via plasma norepinephrine (NE) and mean arterial pressure (MAP)] and middle cerebral artery velocity (MCAv) when compared with conventional exercise (CE). Fifteen subjects underwent two leg press exercise interventions: 1) BFRE-220 mmHg bilateral thigh occlusion at 20% 1 rep-max (1RM), and 2) CE-65% 1RM without occlusion. Each condition consisted of 4 * 5-min cycles of exercise, with 3 * 10-reps in each cycle. Five minutes of rest and reperfusion (for BFRE) followed each cycle. MAP increased with exercise (P < 0.001) and was 4-5 mmHg higher with CE versus BFRE (P <= 0.09). Mean MCAv also increased with exercise (P < 0.001) and was higher with CE compared with BFRE during the first bout of exercise only (P = 0.07). Plasma NE concentration increased with CE only (P < 0.001) and was higher than BFRE throughout exercise (P <= 0.02). The attenuated sympathetic response, combined with similar cerebrovascular responses, suggest that cyclical BFRE could be explored as an alternative to CE in the clinical setting. PMID- 28835447 TI - Combining remote ischemic preconditioning and aerobic exercise: a novel adaptation of blood flow restriction exercise. AB - Remote ischemic preconditioning (RIPC) can attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) restricts blood flow to exercising muscles. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction-reperfusion, reflecting the RIPC model. A concern about BFRE, however, is potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit greater increases in sympathetic outflow and arterial pressure than conventional exercise (CE) when performed at the same relative intensity. We also assessed the cerebrovascular responses due to potential implementation of BFRE in stroke rehabilitation. Fourteen subjects performed treadmill exercise at 65-70% maximal heart rate with and without intermittent BFR (4 * 5-min intervals of bilateral thigh-cuff pressure followed by 5-min reperfusion periods). Mean arterial pressure (MAP), plasma norepinephrine (NE), and middle and posterior cerebral artery velocities (MCAv and PCAv) were compared between trials. As expected, BFRE elicited higher concentration NE compared with CE (1249 +/- 170 vs. 962 +/- 114 pg/ml; P = 0.06). Unexpectedly, however, there were no differences in MAP between conditions (overall P = 0.33), and MAP was 4-5 mmHg lower with BFRE versus CE during the reperfusion periods (P <= 0.05 for reperfusion periods 3 and 4). There were no differences in MCAv or PCAv between trials (P >= 0.22), suggesting equivalent cerebrometabolic demand. The exaggerated sympathoexcitatory response with BFRE was not accompanied by higher MAP, likely because of the cyclical reperfusions. This cyclical BFRE paradigm could be adapted to cardiac or stroke rehabilitation, where exercising patients could benefit from the cardio and cerebro protection associated with RIPC. PMID- 28835449 TI - Fluorescence quenching by metal centered porphyrins and poryphyrin enzymes. AB - Fluorescence spectroscopy and microscopy have been used extensively to monitor biomolecules, especially reactive oxygen species (ROS) and, more recently, reactive sulfide (RSS) species. Nearly all fluorophores are either excited by or emit light between 450 and 550 nm, which is similar to the absorbance of heme proteins and metal-centered porphyrins. Here we examined the effects of catalase (Cat), reduced and oxidized hemoglobin (Hb and metHb), albumin (alb), manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), iron protoporphyrin IX (hemin), and copper protoporphyrin IX (CuPPIX) on the fluorescence properties of fluorescein. We also examined the effects of catalase and MnTBAP on fluorophores for ROS (dichlorofluorescein, DCF), polysulfides (3',6'-di(O thiosalicyl)fluorescein, SSP4), and H2S (7-azido-4-methylcoumarin, AzMC) previously activated by H2O2, a mixed polysulfide (H2Sn, n = 1-7) and H2S, respectively. All except albumin concentration dependently inhibited fluorophore fluorescence and absorbed light between 450 and 550 nm, suggesting that the inhibitory effect was physical not catalytic. Catalase inhibition of fluorescein fluorescence was unaffected by sodium azide, dithiothreitol, diamide, tris(2 carboxyethyl)phosphine (TCEP), or iodoacetate, supporting a physical inhibitory mechanism. Catalase and TBAP augmented, then inhibited DCF fluorescence, but only inhibited SSP4 and AzMC fluorescence indicative of a substrate-specific catalytic oxidation of DCF and nonspecific fluorescence inhibition of all three fluorophores. These results suggest caution must be exercised when using any fluorescent tracers in the vicinity of metal-centered porphyrins. PMID- 28835450 TI - The differential role of reactive oxygen species in early and late stages of cancer. AB - The large doses of vitamins C and E and beta-carotene used to reduce reactive oxygen species (ROS) production and oxidative damages in cancerous tissue have produced disappointing and contradictory results. This therapeutic conundrum was attributed to the double-faced role of ROS, notably, their ability to induce either proliferation or apoptosis of cancer cells. However, for a ROS-inhibitory approach to be effective, it must target ROS when they induce proliferation rather than apoptosis. On the basis of recent advances in redox biology, this review underlined a differential regulation of prooxidant and antioxidant system, respective to the stage of cancer. At early precancerous and neoplastic stages, antioxidant activity decreases and ROS appear to promote cancer initiation via inducing oxidative damage and base pair substitution mutations in prooncogenes and tumor suppressor genes, such as RAS and TP53, respectively. Whereas in late stages of cancer progression, tumor cells escape apoptosis by producing high levels of intracellular antioxidants, like NADPH and GSH, via the pentose phosphate pathway to buffer the excessive production of ROS and related intratumor oxidative injuries. Therefore, antioxidants should be prohibited in patients with advanced stages of cancer and/or undergoing anticancer therapies. Interestingly, the biochemical and biophysical properties of some polyphenols allow them to selectively recognize tumor cells. This characteristic was exploited to design and deliver nanoparticles coated with low doses of polyphenols and containing chemotherapeutic drugs into tumor-bearing animals. First results are encouraging, which may revolutionize the conventional use of antioxidants in cancer. PMID- 28835452 TI - MHRA alert about Nexplanon migration. PMID- 28835451 TI - Obesity-induced vascular inflammation involves elevated arginase activity. AB - Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (ECs) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC-A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high-fat/high sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular ECs and increased expression of tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), interleukin 10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and ECs. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltration by inflammatory macrophages, while reducing reparative macrophages. Additionally, adipocyte size and fibrosis increased and capillary density decreased in VAT. These effects of HFHS, except for weight gain and hyperglycemia, were prevented or reduced in mice lacking EC-A1 or treated with the arginase inhibitor 2-(S) amino-6-boronohexanoic acid (ABH). In mouse aortic ECs, exposure to high glucose (25 mM) and Na palmitate (200 MUM) reduced nitric oxide production and increased A1, TNF-alpha, VCAM-1, ICAM-1, and MCP-1 mRNA, and monocyte adhesion. Knockout of EC-A1 or ABH prevented these effects. HFHS diet-induced VAT inflammation is mediated by EC-A1 expression/activity. Limiting arginase activity is a possible therapeutic means of controlling obesity-induced vascular and VAT inflammation. PMID- 28835453 TI - AIP and the somatostatin system in pituitary tumours. AB - Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response. PMID- 28835454 TI - Developing design principles for a Virtual Hospice: improving access to care. AB - OBJECTIVES: Providing access to hospice services will become increasingly difficult due to the pressures of an ageing population and limited resources. To help address this challenge, a small number of services called Virtual Hospice have been established. This paper presents early-stage design work on a Virtual Hospice to improve access to services provided by a hospice (Highland Hospice) serving a largely remote and rural population in Scotland, UK. METHODS: The study was structured as a series of Experience Labs with Highland Hospice staff, healthcare professionals and patients. Experience Labs employ a participatory design approach where participants are placed at the centre of the design process, helping to ensure that the resultant service meets their needs. Data from the Experience Labs were analysed using qualitative thematic analysis and design analysis. RESULTS: A number of themes and barriers to accessing Highland Hospice services were identified. In response, an initial set of seven design principles was developed. Design principles are high-level guidelines that are used to improve prioritisation and decision making during the design process by ensuring alignment with research insights. The design principles were piloted with a group of stakeholders and gained positive feedback. CONCLUSIONS: The design principles are intended to guide the ongoing development of the Highland Hospice Virtual Hospice. However, the challenges faced by Highland Hospice in delivering services in a largely remote and rural setting are not unique. The design principles, encompassing digital and non-digital guidelines, or the design approach could be applied by other hospices in the UK or overseas. PMID- 28835455 TI - Observational study of sleep disturbances in advanced cancer. AB - OBJECTIVES: To determine the prevalence of nightmares, sleep terrors and vivid dreams in patients with advanced cancer (and the factors associated with them in this group of patients). METHODS: The study was a multicentre, prospective observational study. Participants were patients with locally advanced/metastatic cancer, who were under the care of a specialist palliative care team. Data were collected on demographics, cancer diagnosis, cancer treatment, current medication, performance status, sleep quality (Pittsburgh Sleep Quality Index), dreams and nightmares, and physical and psychological symptoms (Memorial Symptom Assessment Scale-Short Form). RESULTS: 174 patients completed the study. Sleep quality was poor in 70.5% participants and was worse in younger patients and in inpatients (hospital, hospice). 18% of patients reported nightmares, 8% sleep terrors and 34% vivid dreams. Nightmares were associated with poor sleep quality and greater sleep disturbance; nightmares were also associated with greater physical and psychological burden. Nightmares (and vivid dreams) were not associated with the use of opioid analgesics. CONCLUSIONS: Nightmares do not seem to be especially common in patients with advanced cancer, and when they do occur, there is often an association with sleep disturbance, and/or physical and psychological burden. PMID- 28835456 TI - Systematic review of pharmacological therapies for the management of ischaemic pain in patients with non-reconstructable critical limb ischaemia. AB - BACKGROUND: Critical limb ischaemia (CLI) is a severe manifestation of peripheral arterial disease, characterised by chronic ischaemic rest pain, ulcers or gangrene. Management of ischaemic pain is challenging in patients with no options for revascularisation and optimal pharmacological therapies have not been established. OBJECTIVES: To identify and evaluate the effectiveness of pharmacological therapies to treat ischaemic pain secondary to non reconstructable CLI. METHODS: This systematic review was reported in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline. Comprehensive searches of three electronic databases, a PubMed-related articles link search, grey literature search and hand-searches of the bibliographies of relevant papers and textbooks were performed. Studies recruiting adult patients with CLI of any aetiology were eligible for inclusion. Surgical and revascularisation procedures, and all invasive interventions were excluded. RESULTS: Of 792 studies, six met full inclusion criteria. These studies researched the use of intravenous lidocaine, intravenous ketamine, oral gabapentin and the combination of transdermal buprenorphine and epidural morphine/ropivacaine infusion. All studies showed an improvement in severity of ischaemic pain in CLI but with varying side effect profiles and quality. The extracted studies showed substantial heterogeneity and therefore a meta-analysis was not performed. CONCLUSION: The pharmacological management of pain secondary to non-reconstructable CLI is a challenging review topic. No recommendations of pharmacological agents can be made following this review but a number of novel approaches to manage pain in this cohort have shown positive results and require further investigation. PMID- 28835457 TI - Neuroendocrine Modulation of IL-27 in Macrophages. AB - Heterodimeric IL-27 (p28/EBV-induced gene 3) is an important member of the IL 6/IL-12 cytokine family. IL-27 is predominantly synthesized by mononuclear phagocytes and exerts immunoregulatory functional activities on lymphocytic and nonlymphocytic cells during infection, autoimmunity or neoplasms. There is a great body of evidence on the bidirectional interplay between the autonomic nervous system and immune responses during inflammatory disorders, but so far IL 27 has not been defined as a part of these multifaceted neuroendocrine networks. In this study, we describe the role of catecholamines (as mediators of the sympathetic nervous system) related to IL-27 production in primary mouse macrophages. Noradrenaline and adrenaline dose-dependently suppressed the release of IL-27p28 in LPS/TLR4-activated macrophages, which was independent of alpha1 adrenoceptors. Instead, beta2 adrenoceptor activation was responsible for mediating gene silencing of IL-27p28 and EBV-induced gene 3. The beta2 adrenoceptor agonists formoterol and salbutamol mediated suppression of IL-27p28 production, when triggered by zymosan/TLR2, LPS/TLR4, or R848/TLR7/8 activation, but selectively spared the polyinosinic-polycytidylic acid/TLR3 pathway. Mechanistically, beta2 adrenergic signaling reinforced an autocrine feedback loop of macrophage-derived IL-10 and this synergized with inhibition of the JNK pathway for limiting IL-27p28. The JNK inhibitors SP600125 and AEG3482 strongly decreased intracellular IL-27p28 in F4/80+CD11b+ macrophages. In endotoxic shock of C57BL/6J mice, pharmacologic activation of beta2 adrenoceptors improved the severity of shock, including hypothermia and decreased circulating IL-27p28. Conversely, IL-27p28 was 2.7-fold increased by removal of the catecholamine producing adrenal glands prior to endotoxic shock. These data suggest a novel role of the sympathetic neuroendocrine system for the modulation of IL-27 dependent acute inflammation. PMID- 28835458 TI - IL-2 Shapes the Survival and Plasticity of IL-17-Producing gammadelta T Cells. AB - IL-17-producing gammadelta T (gammadeltaT-17) cells have proved to be an important early source of IL-17 in many inflammatory settings and are emerging as an important participant in protumor immune responses. Considering that their peripheral activation depends largely on innate signals rather than TCR ligation, it is important to understand what mechanisms exist to curb unwanted activation. Expression of the high-affinity IL-2R on gammadeltaT-17 cells prompted us to investigate a role for this cytokine. We found gammadeltaT-17 cells to be enriched, not depleted, in IL-2-deficient mice. The absence of IL-2 also resulted in higher IL-17 production and the emergence of IL-17+IFN-gamma+ double producers. Furthermore, the addition of IL-2 to in vitro cultures of sorted gammadeltaT-17 cells was able to moderate IL-17 and affect differentiation into polyfunctional cytokine-producing cells. Interestingly, the Vgamma6+ subset was more susceptible to the effects of IL-2 than Vgamma4+ gammadeltaT-17 cells. We also found that unlike other gammadelta T cells, gammadeltaT-17 cells do not produce IL-2, but express Blimp-1, a known transcriptional repressor of IL-2. Although IL-2 was able to induce robust proliferation of gammadeltaT-17 cells, it did not sustain viability, negatively impacting their survival via downregulation of the IL-7R. Taken together, these data indicate that IL-2 can augment the gammadeltaT-17 response in favor of short-lived effectors with limited plasticity, particularly in the presence of IL-1beta and IL-23. In this way, IL-2 may act to curtail the innate-like response of gammadeltaT-17 cells upon arrival of IL-2-producing adaptive immune cells at the site of inflammation. PMID- 28835459 TI - Termination of the Activating NK Cell Immunological Synapse Is an Active and Regulated Process. AB - Cellular cytotoxicity is essential for the elimination of virus-infected and cancerous cells by NK cells. It requires a direct cellular contact through the establishment of an immunological synapse (IS) between the NK cell and the target cell. In this article, we show that not only the establishment of the IS, but also its maintenance is a highly regulated process. Ongoing receptor-proximal signaling events from activating NK cell receptors and actin dynamics were necessary to maintain a stable contact in an energy-dependent fashion, even after the IS was formed successfully. More importantly, the initiation of a contact to a new susceptible target cell resulted in accelerated detachment from an old target cell. We propose that the maintenance of an existing IS is a dynamic and regulated process to allow for effective serial killing of NK cells. PMID- 28835460 TI - Lack of Trex1 Causes Systemic Autoimmunity despite the Presence of Antiretroviral Drugs. AB - Biallelic mutations of three prime repair exonuclease 1 (TREX1) cause the lupus like disease Aicardi-Goutieres syndrome in which accumulation of a yet unknown endogenous DNA substrate of TREX1 triggers a cyclic GMP-AMP synthase-dependent type I IFN response and systemic autoimmunity. Products of reverse transcription originating from endogenous retroelements have been suggested to be a major substrate for TREX1, and reverse transcriptase inhibitors (RTIs) were proposed as a therapeutic option in autoimmunity ensuing from defects of TREX1. In this study, we treated Trex1-/- mice with RTIs. The serum RTI levels reached were sufficient to block retrotransposition of endogenous retroelements. However, the treatment did not reduce the spontaneous type I IFN response and did not ameliorate lethal inflammation. Furthermore, long interspersed nuclear elements 1 retrotransposition was not enhanced in the absence of Trex1. Our data do not support the concept of retroelement-derived cDNA as key triggers of systemic autoimmunity in Trex1-deficient humans and mice and motivate the continuing search for the pathogenic IFN-inducing Trex1 substrate. PMID- 28835461 TI - Ectopic Expression of Self-Antigen Drives Regulatory T Cell Development and Not Deletion of Autoimmune T Cells. AB - Type 1 diabetes is a T cell-mediated autoimmune disease that is characterized by Ag-specific targeting and destruction of insulin-producing beta cells. Although multiple studies have characterized the pathogenic potential of beta cell specific T cells, we have limited mechanistic insight into self-reactive autoimmune T cell development and their escape from negative selection in the thymus. In this study, we demonstrate that ectopic expression of insulin epitope B:9-23 (InsB9-23) by thymic APCs is insufficient to induce deletion of high- or low-affinity InsB9-23-reactive CD4+ T cells; however, we observe an increase in the proportion and number of thymic and peripheral Foxp3+ regulatory T cells. In contrast, the MHC stable insulin mimetope (InsB9-23 R22E) efficiently deletes insulin-specific T cells and prevents escape of high-affinity thymocytes. Collectively, these results suggest that Ag dose and peptide-MHC complex stability can lead to multiple fates of insulin-reactive CD4+ T cell development and autoimmune disease outcome. PMID- 28835462 TI - A novel Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever. AB - OBJECTIVE: Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) is a recently described monogenic autoinflammatory disease. The causal p.S242R MEFV mutation disrupts a binding motif of the regulatory 14-3-3 proteins within pyrin. Here, we investigate a family with clinical features consistent with PAAND in whom the novel p.E244K MEFV mutation, located in the +2 site of the 14-3-3 binding motif in pyrin, has been found. METHODS: Multiplex cytokine analyses were performed on p.E244K patient and control serum. Peripheral blood mononuclear cells were stimulated ex vivo with lipopolysaccharide (LPS). In vitro, inflammasome complex formation was evaluated by flow cytometry of Apoptosis associated Speck-like protein containing a Caspase recruitment domain (ASC) specks. Interleukin-1beta (IL-1beta) and IL-18 production was quantified by ELISA. The ability of the p.E244K pyrin mutation to interact with 14-3-3 was assessed by immunoprecipitation. RESULTS: PAAND p.E244K patient serum displayed a different cytokine profile compared with patients with Familial Mediterranean Fever (FMF). In overexpression models, p.E244K pyrin was associated with decreased 14-3-3 binding and increased ASC speck formation. THP-1 monocytes expressing PAAND pyrin mutations demonstrated spontaneous caspase-1-dependent IL 1beta and IL-18 secretion, as well as cell death, which were significantly greater than those of wild-type and the FMF-associated mutation p.M694V. CONCLUSION: In PAAND, disruption of the +2 position of a 14-3-3 binding motif in pyrin results in its constitutive activation, with spontaneous production of IL 1beta and IL-18, associated with inflammatory cell death. The altered serum cytokine profile may explain the different clinical features exhibited by PAAND patients compared with those with FMF. PMID- 28835463 TI - B-cell receptor sequencing of anti-citrullinated protein antibody (ACPA) IgG expressing B cells indicates a selective advantage for the introduction of N glycosylation sites during somatic hypermutation. PMID- 28835465 TI - The effects of structural damage on functional disability in psoriatic arthritis. AB - BACKGROUND: Functional outcomes are central in patients with chronic inflammatory musculoskeletal diseases. In a secondary data analysis of the GO-REVEAL trial (NCT00265096), we investigated wether structural damage is linked to functional impairment in patients with psoriatic arthritis (PsA), a link that is still elusive in this disease. METHODS: We analysed 363 patients enrolled in the GO REVEAL study and obtained modified Sharp/van der Heijde Scores (mSvdHS) from X rays performed at baseline, after 24, 52 and 104 weeks. Using longitudinal analyses, we assessed the effect of total mSvdHS (and its subscores, joint space narrowing (JSN) and erosions (ERO)) on functional status (measured by the Health Assessment Questionnaire) in all patients and in those attaining remission (n=117). Furthermore, we analysed wether structural damage reduces the responsiveness of functional limitations to treatment in a subgroup of responders who had functional impairment at baseline (n=67). Additionally, internal and external validation analyses were performed. RESULTS: The effect of damage on function was seen in the disease activity-adjusted models using total mSvdHS (p=0.005), JSN (p=0.019) and ERO (p=0.001) as well as in the remission analyses for mSvdHS (p=0.029) and JSN (p=0.010), respectively. Functional responsiveness was limited by increasing total mSvdHS (p=0.010), JSN (p=0.002) and ERO (p=0.040). The results were validated using other functional outcomes and in an independent clinical cohort. CONCLUSIONS: In PsA, structural damage, particularly JSN, has implications for physical function. Functional outcomes have an irreversible component that is strongly related to the extent of joint destruction. This needs to be considered when targeting functional outcomes in clinical practice. PMID- 28835464 TI - Mapping and predicting mortality from systemic sclerosis. AB - OBJECTIVES: To determine the causes of death and risk factors in systemic sclerosis (SSc). METHODS: Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. RESULTS: We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. CONCLUSION: Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival. PMID- 28835466 TI - Mitochondria-driven assembly of a cortical anchor for mitochondria and dynein. AB - Interorganelle contacts facilitate communication between organelles and impact fundamental cellular functions. In this study, we examine the assembly of the MECA (mitochondria-endoplasmic reticulum [ER]-cortex anchor), which tethers mitochondria to the ER and plasma membrane. We find that the assembly of Num1, the core component of MECA, requires mitochondria. Once assembled, Num1 clusters persistently anchor mitochondria to the cell cortex. Num1 clusters also function to anchor dynein to the plasma membrane, where dynein captures and walks along astral microtubules to help orient the mitotic spindle. We find that dynein is anchored by Num1 clusters that have been assembled by mitochondria. When mitochondrial inheritance is inhibited, Num1 clusters are not assembled in the bud, and defects in dynein-mediated spindle positioning are observed. The mitochondria-dependent assembly of a dual-function cortical anchor provides a mechanism to integrate the positioning and inheritance of the two essential organelles and expands the function of organelle contact sites. PMID- 28835468 TI - Can we save the NHS by reducing unwarranted variation? PMID- 28835469 TI - Sea-ice induced growth decline in Arctic shrubs. AB - Measures of increased tundra plant productivity have been associated with the accelerating retreat of the Arctic sea-ice. Emerging studies document opposite effects, advocating for a more complex relationship between the shrinking sea-ice and terrestrial plant productivity. I introduce an autoregressive plant growth model integrating effects of biological and climatic conditions for analysing individual ring-width growth time series. Using 128 specimens of Salix arctica, S. glauca and Betula nana sampled across Greenland to Svalbard, an overall negative effect of the retreating June sea-ice extent was found on the annual growth. The negative effect of the retreating June sea-ice was observed for younger individuals with large annual growth allocations and with little or no trade-off between previous and current year's growth. PMID- 28835467 TI - DNA repair factor RAD18 and DNA polymerase Polkappa confer tolerance of oncogenic DNA replication stress. AB - The mechanisms by which neoplastic cells tolerate oncogene-induced DNA replication stress are poorly understood. Cyclin-dependent kinase 2 (CDK2) is a major mediator of oncogenic DNA replication stress. In this study, we show that CDK2-inducing stimuli (including Cyclin E overexpression, oncogenic RAS, and WEE1 inhibition) activate the DNA repair protein RAD18. CDK2-induced RAD18 activation required initiation of DNA synthesis and was repressed by p53. RAD18 and its effector, DNA polymerase kappa (Polkappa), sustained ongoing DNA synthesis in cells harboring elevated CDK2 activity. RAD18-deficient cells aberrantly accumulated single-stranded DNA (ssDNA) after CDK2 activation. In RAD18-depleted cells, the G2/M checkpoint was necessary to prevent mitotic entry with persistent ssDNA. Rad18-/- and Polkappa-/- cells were highly sensitive to the WEE1 inhibitor MK-1775 (which simultaneously activates CDK2 and abrogates the G2/M checkpoint). Collectively, our results show that the RAD18-Polkappa signaling axis allows tolerance of CDK2-mediated oncogenic stress and may allow neoplastic cells to breach tumorigenic barriers. PMID- 28835470 TI - Ospreys do not teach offspring how to kill prey at the nest. AB - There is strong evidence for teaching in only a handful of species, most of which are cooperative breeders, leading some researchers to suggest that teaching may be more likely to evolve in such species. Alternatively, this initial distribution could be an artefact of the popularity and tractability of cooperative breeders as behavioural study systems. Therefore, establishing or refuting this potential evolutionary link requires researchers to assess potential cases of teaching in more non-cooperatively breeding species. We tested for teaching in the osprey (Pandion haliaetus), a non-cooperatively-breeding bird anecdotally reported to teach hunting skills to their offspring. We tested whether parents brought back more live prey to the nest as their offspring got older, allowing the latter to practice killing prey in a manner analogous to the progressive teaching seen in meerkats. We found the opposite trend to that predicted by the teaching hypothesis, indicating that ospreys do not teach their young at the nest. PMID- 28835471 TI - Genetic Screen for Postembryonic Development in the Zebrafish (Danio rerio): Dominant Mutations Affecting Adult Form. AB - Large-scale forward genetic screens have been instrumental for identifying genes that regulate development, homeostasis, and regeneration, as well as the mechanisms of disease. The zebrafish, Danio rerio, is an established genetic and developmental model used in genetic screens to uncover genes necessary for early development. However, the regulation of postembryonic development has received less attention as these screens are more labor intensive and require extensive resources. The lack of systematic interrogation of late development leaves large aspects of the genetic regulation of adult form and physiology unresolved. To understand the genetic control of postembryonic development, we performed a dominant screen for phenotypes affecting the adult zebrafish. In our screen, we identified 72 adult viable mutants showing changes in the shape of the skeleton as well as defects in pigmentation. For efficient mapping of these mutants and mutation identification, we devised a new mapping strategy based on identification of mutant-specific haplotypes. Using this method in combination with a candidate gene approach, we were able to identify linked mutations for 22 out of 25 mutants analyzed. Broadly, our mutational analysis suggests that there are key genes and pathways associated with late development. Many of these pathways are shared with humans and are affected in various disease conditions, suggesting constraint in the genetic pathways that can lead to change in adult form. Taken together, these results show that dominant screens are a feasible and productive means to identify mutations that can further our understanding of gene function during postembryonic development and in disease. PMID- 28835472 TI - Dissecting Causal Pathways Using Mendelian Randomization with Summarized Genetic Data: Application to Age at Menarche and Risk of Breast Cancer. AB - Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor, keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI), and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly available data to better understand causal mechanisms. PMID- 28835473 TI - Fatty Acid Metabolic Remodeling During Type 2 Diabetes Remission After Bariatric Surgery. AB - Hypertrophic remodeling of white adipose tissues is associated with overexposure of lean organs to circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs), ultimately leading to insulin resistance. Bariatric surgery promotes type 2 diabetes (T2D) remission through a succession of weight loss-dependent and -independent mechanisms. However, the longitudinal contribution of adipocyte size reduction and fatty acid metabolic handling remain unknown. Here we show that severely obese participants with T2D display hypertriglyceridemia and excessive systemic lipolysis during intravenous lipid overload. Three days after biliopancreatic diversion with duodenal switch (DS), whole-body glycerol turnover was normalized and associated with lower HOMA-insulin resistance index. A mean excess weight loss of 84% was achieved 12 months after DS. The smaller subcutaneous adipocyte size predicted better glycemic control in T2D. TG disposal and acylcarnitine production during lipid overload, along with muscle insulin sensitivity, improved with weight loss. Nevertheless, systemic NEFA fluxes and NEFA spillover remained similar, suggesting that increased NEFA storage capacity per volume of adipose tissue exactly compensated for the decrease in fat mass during weight loss. In conclusion, T2D remission after DS is mainly associated with greater circulating TG disposal, lower systemic lipolysis, and better fatty acid handling by lean tissues. PMID- 28835474 TI - Multi-scale quantification of tissue behavior during amniote embryo axis elongation. AB - Embryonic axis elongation is a complex multi-tissue morphogenetic process responsible for the formation of the posterior part of the amniote body. How movements and growth are coordinated between the different posterior tissues (e.g. neural tube, axial and paraxial mesoderm, lateral plate, ectoderm, endoderm) to drive axis morphogenesis remain largely unknown. Here, we use quail embryos to quantify cell behavior and tissue movements during elongation. We quantify the tissue-specific contribution to axis elongation using 3D volumetric techniques, then quantify tissue-specific parameters such as cell density and proliferation. To study cell behavior at a multi-tissue scale, we used high resolution 4D imaging of transgenic quail embryos expressing fluorescent proteins. We developed specific tracking and image analysis techniques to analyze cell motion and compute tissue deformations in 4D. This analysis reveals extensive sliding between tissues during axis extension. Further quantification of tissue tectonics showed patterns of rotations, contractions and expansions, which are consistent with the multi-tissue behavior observed previously. Our approach defines a quantitative and multi-scale method to analyze the coordination between tissue behaviors during early vertebrate embryo morphogenetic events. PMID- 28835475 TI - Stroke and methamphetamine use in young adults: a review. AB - BACKGROUND: Methamphetamine use and stroke are significant public health problems. Strokes among people aged below 45 years are much less common than in older age groups but have significant mortality and morbidity. Methamphetamine is a putative cause of strokes among younger people. METHODS: A review of methamphetamine-related strokes was conducted. Bibliographic databases were searched until February 2017 for articles related to methamphetamine and stroke. Both haemorrhagic and ischaemic strokes were considered. RESULTS: Of 370 articles screened, 77 were selected for inclusion. There were 81 haemorrhagic and 17 ischaemic strokes reported in case reports and series. Both types were approximately twice as common in males. Route of administration associated with haemorrhagic stroke was typically oral or injecting, but for ischaemic stroke inhalation was most common. Haemorrhagic stroke was associated with vascular abnormalities in a third of cases. One quarter of individuals completely recovered, and a third died following haemorrhagic stroke. One-fifth completely recovered, and one-fifth died following ischaemic stroke. CONCLUSIONS: There is a preponderance of haemorrhagic strokes associated with methamphetamine use in young people, and methamphetamine-related stroke is associated with poor clinical outcomes. Mechanisms of methamphetamine-associated stroke include hypertension, vasculitis, direct vascular toxicity and vasospasm. In a period of rising worldwide methamphetamine use, the incidence of methamphetamine-related stroke will increase, with a consequent increase in the burden of disease contributed by such events. PMID- 28835476 TI - Assessing Clinical Microbiology Practice Guidelines: American Society for Microbiology Ad Hoc Committee on Evidence-Based Laboratory Medicine Practice Guidelines Assessment. AB - As part of the American Society for Microbiology (ASM) Evidence-Based Laboratory Medicine Practice Guidelines Committee of the Professional Practice Committee, an ad hoc committee was formed in 2014 to assess guidelines published by the committee using an assessment tool, Appraisal of Guidelines for Research Evaluation II (AGREE II). The AGREE II assessment helps reviewers determine whether published guidelines are robust, transparent, and clear in presenting practice recommendations in a standardized manner. Identifying strengths and weaknesses of practice guidelines by ad hoc assessments helps with improving future guidelines through the participation of key stakeholders. This minireview describes the development of the ad hoc committee and results from their review of several ASM best practices guidelines and a non-ASM practice guideline from the Emergency Nurses Association. PMID- 28835477 TI - Is Staphylococcus lugdunensis Significant in Clinical Samples? AB - The implication of coagulase-negative staphylococci in human diseases is a major issue, particularly in hospital settings wherein these species often act as opportunistic pathogens. In addition, some coagulase-negative staphylococci such as S. lugdunensis have emerged as pathogenic bacteria, implicated in severe infections, particularly, osteoarticular infections, foreign-body-associated infections, bacteremia, and endocarditis. In vitro studies have shown the presence of several putative virulence factors such as adhesion factors, biofilm production, and proteolytic factors that might explain clinical manifestations. Taken together, the clinical and microbiological data might change the way clinicians and microbiologists look at S. lugdunensis in clinical samples. PMID- 28835478 TI - Towards a Universal Molecular Microbiological Test. AB - The standard paradigm for microbiological testing is dependent on the presentation of a patient to a clinician. Tests are then requested based on differential diagnoses using the patient's symptoms as a guide. The era of high throughput genomic methods has the potential to replace this model for the first time with what could be referred to as "hypothesis-free testing." This approach utilizes one of a variety of methodologies to obtain a sequence from potentially any nucleic acid in a clinical sample, without prior knowledge of its content. We discuss the advantages of such an approach and the challenges in making this a reality. PMID- 28835479 TI - Variable Sensitivity in Molecular Detection of Zika Virus in European Expert Laboratories: External Quality Assessment, November 2016. AB - Zika virus (ZIKV) infections are a significant public health concern. A strong capability for ZIKV detection is an absolute requirement for adequate preparedness and response strategies and individual patient care. The objective of this study was to assess and improve the capability of European expert laboratories for molecular testing for ZIKV through an external quality assessment (EQA) scheme. Laboratories were provided a panel of 12 samples which included negative samples, samples containing African- or Asian-lineage ZIKV at various concentrations (103 to 109 copies/ml), and samples containing dengue virus, yellow fever virus, or chikungunya virus. The results were analyzed on the basis of the outcomes of testing for the samples and the extraction and detection method used. Samples with a ZIKV RNA status scored correctly by >50% of the laboratories were designated the core sample. A total of 85 panel outcomes were submitted by 50 laboratories in 31 countries. The results designated all samples as core samples. Thirty-three percent (28/85) of the panel outcomes identified all samples. Analysis at the laboratory level showed that only 40% of the laboratories (20/50), representing 45% of the countries, scored sufficiently; i.e., they had at least one test operational that scored all core samples correctly. There is a need for improvement of the molecular detection of ZIKV in 60% of the participating laboratories. While the specificity of the tests was more robust, the results of the EQA showed large variation in test sensitivity. Improvements should focus on both nucleic acid extraction and ZIKV detection methods. PMID- 28835481 TI - Incremental cost-effectiveness of algorithm-driven genetic testing versus no testing for Maturity Onset Diabetes of the Young (MODY) in Singapore. AB - BACKGROUND: Offering genetic testing for Maturity Onset Diabetes of the Young (MODY) to all young patients with type 2 diabetes has been shown to be not cost effective. This study tests whether a novel algorithm-driven genetic testing strategy for MODY is incrementally cost-effective relative to the setting of no testing. METHODS: A decision tree was constructed to estimate the costs and effectiveness of the algorithm-driven MODY testing strategy and a strategy of no genetic testing over a 30-year time horizon from a payer's perspective. The algorithm uses glutamic acid decarboxylase (GAD) antibody testing (negative antibodies), age of onset of diabetes (<45 years) and body mass index (<25 kg/m2 if diagnosed >30 years) to stratify the population of patients with diabetes into three subgroups, and testing for MODY only among the subgroup most likely to have the mutation. Singapore-specific costs and prevalence of MODY obtained from local studies and utility values sourced from the literature are used to populate the model. RESULTS: The algorithm-driven MODY testing strategy has an incremental cost-effectiveness ratio of US$93 663 per quality-adjusted life year relative to the no testing strategy. If the price of genetic testing falls from US$1050 to US$530 (a 50% decrease), it will become cost-effective. CONCLUSION: Our proposed algorithm-driven testing strategy for MODY is not yet cost-effective based on established benchmarks. However, as genetic testing prices continue to fall, this strategy is likely to become cost-effective in the near future. PMID- 28835480 TI - Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy. AB - BACKGROUND: Fabry disease is characterised by the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in vascular endothelial cells. Enzyme replacement therapy (ERT) clears this accumulation. We analysed plasma proteome profiles before and after ERT to characterise its molecular pathology. METHODS: Two-dimensional electrophoresis and matrix-assisted laser desorption/ionisation-time of flight tandem mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) were done using plasma samples before and after ERT in eight patients with classical Fabry disease RESULTS: After short term ERT (4-12 months), the levels of 15 plasma proteins involved in inflammation, oxidative and ischaemic injury, or complement activation were reduced significantly. Among them, beta-actin (ACTB), inactivated complement C3b (iC3b), and C4B were elevated significantly in pre-ERT Fabry disease plasma compared with control plasma. After longer-term ERT (46-96 months), iC3b levels gradually decreased, whereas the levels of other proteins varied. The gradual reduction of iC3b was comparable to that of Gb3 levels. In addition, iC3b increased significantly in pre-ERT Fabry disease mouse plasma, and C3 deposits were notable in renal tissues of pre-enzyme replacement therapy patients. CONCLUSION: These results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation. PMID- 28835483 TI - Targeting von Willebrand Factor-Mediated Inflammation. PMID- 28835482 TI - APOL1 and Cardiovascular Disease: A Story in Evolution. PMID- 28835484 TI - Fueling Platelets: Where Does the Glucose Come From? PMID- 28835485 TI - When Flow Goes Slow, von Willebrand Factor Can Bind Red Blood Cells. PMID- 28835486 TI - Procoagulant Platelets: Further Details but Many More Questions. PMID- 28835487 TI - Endothelial Functions. AB - The endothelium plays important roles in modulating vascular tone by synthesizing and releasing a variety of endothelium-derived relaxing factors, including vasodilator prostaglandins, NO, and endothelium-dependent hyperpolarization factors, as well as endothelium-derived contracting factors. Endothelial dysfunction is mainly caused by reduced production or action of these relaxing mediators. Accumulating evidence has demonstrated that endothelial functions are essential to ensure proper maintenance of vascular homeostasis and that endothelial dysfunction is the hallmark of a wide range of cardiovascular diseases associated with pathological conditions toward vasoconstriction, thrombosis, and inflammatory state. In the clinical settings, evaluation of endothelial functions has gained increasing attention in view of its emerging relevance for cardiovascular disease. Recent experimental and clinical studies in the vascular biology field have demonstrated a close relationship between endothelial functions and cardiovascular disease and the highlighted emerging modulators of endothelial functions, new insight into cardiovascular disease associated with endothelial dysfunction, and potential therapeutic and diagnostic targets with major clinical implications. We herein will summarize the current knowledge on endothelial functions from bench to bedside with particular focus on recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology. PMID- 28835488 TI - Insight Into the Editor: Christian Weber, MD. PMID- 28835489 TI - Epstein-Barr Virus LMP1-Mediated Oncogenicity. AB - Epstein-Barr virus latent membrane protein 1 (LMP1) is expressed in multiple human malignancies, including nasopharyngeal carcinoma and Hodgkin and immunosuppression-associated lymphomas. LMP1 mimics CD40 signaling to activate multiple growth and survival pathways, in particular, NF-kappaB. LMP1 has critical roles in Epstein-Barr virus (EBV)-driven B-cell transformation, and its expression causes fatal lymphoproliferative disease in immunosuppressed mice. Here, we review recent developments in studies of LMP1 signaling, LMP1-induced host dependency factors, mouse models of LMP1 lymphomagenesis, and anti-LMP1 immunotherapy approaches. PMID- 28835490 TI - Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases. AB - Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8+ T cells plus a milder expansion of CD56dim NKG2A+ KIR- natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8+ T cells, but overall CD8+ T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control.IMPORTANCE Epstein-Barr virus (EBV) is transmitted orally, replicates in the throat, and then invades the B lymphocyte pool through a growth-transforming latent infection. While primary infection in childhood is usually asymptomatic, delayed infection is associated with infectious mononucleosis (IM), a febrile illness in which patients have high circulating viral loads and an exaggerated virus-induced immune response involving both CD8+ T cells and natural killer (NK) cells. Here we show that in five cases of asymptomatic infection, viral loads in the blood were as high as those in patients during the acute phase of IM, whereas the cell-mediated responses, even when they resembled those in patients during the acute phase of IM in timing and quality, were never as exaggerated. We infer that IM symptoms arise as a consequence not of the virus infection per se but of the hyperactivated immune response. Interestingly, there were idiosyncratic differences among asymptomatic cases in the relationship between the viral load and the response kinetics, emphasizing how much there is still to learn about primary EBV infection. PMID- 28835491 TI - HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates. AB - Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation.IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within a subset of individuals. To achieve this goal, an improved understanding of vaccine-elicited responses, including at the monoclonal Ab level, is essential. Here, we isolated and characterized a panel of vaccine-elicited cross-reactive neutralizing MAbs targeting the Env V3 loop that moderately neutralized several primary viruses and recapitulated the serum neutralizing antibody response. Striking similarities between the cross-reactive V3 NAbs elicited by vaccination in macaques and natural infections in humans illustrate commonalities between the vaccine- and infection-induced responses to V3 and support the feasibility of exploring the V3 epitope as a HIV-1 vaccine target in nonhuman primates. PMID- 28835492 TI - HIV-1 Resistance to Dolutegravir Is Affected by Cellular Histone Acetyltransferase Activity. AB - Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretrovirals to be approved for the treatment of HIV infection. Canonical resistance to these competitive inhibitors develops through substitutions in the integrase active site that disrupt drug-protein interactions. However, resistance against the newest integrase inhibitor, dolutegravir (DTG), is associated with an R263K substitution at the C terminus of integrase that causes resistance through an unknown mechanism. The integrase C-terminal domain is involved in many processes over the course of infection and is posttranslationally modified via acetylation of three lysine residues that are important for enzyme activity, integrase multimerization, and protein-protein interactions. Here we report that regulation of the acetylation of integrase is integral to the replication of HIV in the presence of DTG and that the R263K mutation specifically disrupts this regulation, likely due to enhancement of interactions with the histone deacetylase I complex, as suggested by coimmunoprecipitation assays. Although no detectable differences in the levels of cell-free acetylation of the wild-type (WT) and mutated R263K enzymes were observed, the inhibition of cellular histone acetyltransferase enzymes sensitized the NL4.3WT virus to DTG, while NL4.3R263K was almost completely unaffected. When levels of endogenous acetylation were manipulated in virus-producing cells, inhibitors of acetylation enhanced the replication of NL4.3R263K, whereas inhibition of deacetylation greatly diminished the replication of NL4.3WT Taken together, these results point to a pivotal role of acetylation in the resistance mechanism of HIV to some second-generation integrase strand transfer inhibitors, such as DTG.IMPORTANCE This is, to our knowledge, the first report of the influence of posttranslational modifications on HIV drug resistance. Both viral replication and resistance to second generation integrase strand transfer inhibitors of both WT and INSTI-resistant HIV strains were differentially affected by acetylation, likely as a result of altered interactions between integrase and the cellular deacetylation machinery. Many "shock and kill" strategies to eradicate HIV manipulate endogenous levels of acetylation in order to reactivate latent HIV. However, our results suggest that some drug-resistant viruses may differentially respond to such stimulation, which may complicate the attainment of this goal. Our future work will further illuminate the mechanisms involved. PMID- 28835493 TI - PrP P102L and Nearby Lysine Mutations Promote Spontaneous In Vitro Formation of Transmissible Prions. AB - Accumulation of fibrillar protein aggregates is a hallmark of many diseases. While numerous proteins form fibrils by prion-like seeded polymerization in vitro, only some are transmissible and pathogenic in vivo To probe the structural features that confer transmissibility to prion protein (PrP) fibrils, we have analyzed synthetic PrP amyloids with or without the human prion disease associated P102L mutation. The formation of infectious prions from PrP molecules in vitro has required cofactors and/or unphysiological denaturing conditions. Here, we demonstrate that, under physiologically compatible conditions without cofactors, the P102L mutation in recombinant hamster PrP promoted prion formation when seeded by minute amounts of scrapie prions in vitro Surprisingly, combination of the P102L mutation with charge-neutralizing substitutions of four nearby lysines promoted spontaneous prion formation. When inoculated into hamsters, both of these types of synthetic prions initiated substantial accumulation of prion seeding activity and protease-resistant PrP without transmissible spongiform encephalopathy (TSE) clinical signs or notable glial activation. Our evidence suggests that PrP's centrally located proline and lysine residues act as conformational switches in the in vitro formation of transmissible PrP amyloids.IMPORTANCE Many diseases involve the damaging accumulation of specific misfolded proteins in thread-like aggregates. These threads (fibrils) are capable of growing on the ends by seeding the refolding and incorporation of the normal form of the given protein. In many cases such aggregates can be infectious and propagate like prions when transmitted from one individual host to another. Some transmitted aggregates can cause fatal disease, as with human iatrogenic prion diseases, while other aggregates appear to be relatively innocuous. The factors that distinguish infectious and pathogenic protein aggregates from more innocuous ones are poorly understood. Here we have compared the combined effects of prion seeding and mutations of prion protein (PrP) on the structure and transmission properties of synthetic PrP aggregates. Our results highlight the influence of specific sequence features in the normally unstructured region of PrP that influence the infectious and neuropathogenic properties of PrP-derived aggregates. PMID- 28835494 TI - ZIC2 is Essential for Maintenance of Latency and is a Target of an Immediate Early Protein during KSHV Lytic Reactivation. AB - Bivalent histone modifications are defined as repressive and activating epigenetic marks that simultaneously decorate the same genomic region. The H3K27me3 mark silences gene expression while H3K4me3 mark prevents the region from becoming permanently silenced and prepares the domain for activation when needed. Specific regions of Kaposi's sarcoma-associated herpesvirus (KSHV) latent episomes are "poised" to be activated by the KSHV replication and transcription activator (K-Rta). How KSHV episomes are prepared such that they maintain latent infection and switch to lytic replication by K-Rta remains unclear. K-Rta transactivation activity requires a protein degradation function, thus we hypothesized that identification of cellular substrates of K-Rta may provide insight into the maintenance of KSHV latent infection and the switch to lytic replication.Here we show that a zinc finger protein, ZIC2, a key regulator for central nervous system development, is a substrate of K-Rta, and is responsible for maintaining latency. K-Rta directly interacted with ZIC2 and functioned as an E3 ligase to ubiquitinate ZIC2. ZIC2 localized at immediate-early and early gene cluster regions of the KSHV genome, contributed to tethering Polycomb Repressive Complex 2 though physical interaction thus maintaining H3K27me3 marks at the K Rta promoter. Accordingly, depletion of ZIC2 shifted balance of bivalent histone modifications towards more active forms and induced KSHV reactivation in naturally infected cells. We suggest that ZIC2 turnover by K-Rta is a strategy employed by KSHV to favor the transition from latency to lytic replication.IMPORTANCE Post-translational histone modifications regulate the accessibility of transcriptional factors to DNA; thus, they have profound effects on gene expression (e.g., viral reactivation). KSHV episomes are known to possess bivalent chromatin domains. How such KSHV chromatin domains are maintained to be reactivatable by K-Rta remains unclear. We found that ZIC2, an essential transcriptional factor for stem cell pluripotency, plays a role in maintaining KSHV latent infection in naturally infected cells. We found that ZIC2 degradation by K-Rta shifts bivalent histone marks to a more active configuration, leading to KSHV reactivation. ZIC2 interacts and maintains Polycomb Repressor Complex 2 at the K-Rta promoter. Our findings uncover (i) a mechanism utilized by KSHV to maintain latent infection, (ii) a latency-lytic cycle switch operated by K-Rta, and (iii) a molecular mechanism of ZIC2 mediated local histone modification. PMID- 28835495 TI - Uncoupling of Protease trans-Cleavage and Helicase Activities in Pestivirus NS3. AB - The nonstructural protein NS3 from the Flaviviridae family is a multifunctional protein that contains an N-terminal protease and a C-terminal helicase, playing essential roles in viral polyprotein processing and genome replication. Here we report a full-length crystal structure of the classical swine fever virus (CSFV) NS3 in complex with its NS4A protease cofactor segment (PCS) at a 2.35-A resolution. The structure reveals a previously unidentified ~2,200-A2 intramolecular protease-helicase interface comprising three clusters of interactions, representing a "closed" global conformation related to the NS3-NS4A cis-cleavage event. Although this conformation is incompatible with protease trans-cleavage, it appears to be functionally important and beneficial to the helicase activity, as the mutations designed to perturb this conformation impaired both the helicase activities in vitro and virus production in vivo Our work reveals important features of protease-helicase coordination in pestivirus NS3 and provides a key basis for how different conformational states may explicitly contribute to certain functions of this natural protease-helicase fusion protein.IMPORTANCE Many RNA viruses encode helicases to aid their RNA genome replication and transcription by unwinding structured RNA. Being naturally fused to a protease participating in viral polyprotein processing, the NS3 helicases encoded by the Flaviviridae family viruses are unique. Therefore, how these two enzyme modules coordinate in a single polypeptide is of particular interest. Here we report a previously unidentified conformation of pestivirus NS3 in complex with its NS4A protease cofactor segment (PCS). This conformational state is related to the protease cis-cleavage event and is optimal for the function of helicase. This work provides an important basis to understand how different enzymatic activities of NS3 may be achieved by the coordination between the protease and helicase through different conformational states. PMID- 28835496 TI - Expression and Subcellular Localization of the Kaposi's Sarcoma-Associated Herpesvirus K15P Protein during Latency and Lytic Reactivation in Primary Effusion Lymphoma Cells. AB - The K15P membrane protein of Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with multiple cellular signaling pathways and is thought to play key roles in KSHV-associated endothelial cell angiogenesis, regulation of B-cell receptor (BCR) signaling, and the survival, activation, and proliferation of BCR negative primary effusion lymphoma (PEL) cells. Although full-length K15P is ~45 kDa, numerous lower-molecular-weight forms of the protein exist as a result of differential splicing and poorly characterized posttranslational processing. K15P has been reported to localize to numerous subcellular organelles in heterologous expression studies, but there are limited data concerning the sorting of K15P in KSHV-infected cells. The relationships between the various molecular weight forms of K15P, their subcellular distribution, and how these may differ in latent and lytic KSHV infections are poorly understood. Here we report that a cDNA encoding a full-length, ~45-kDa K15P reporter protein is expressed as an ~23- to 24-kDa species that colocalizes with the trans-Golgi network (TGN) marker TGN46 in KSHV infected PEL cells. Following lytic reactivation by sodium butyrate, the levels of the ~23- to 24-kDa protein diminish, and the full-length, ~45-kDa K15P protein accumulates. This is accompanied by apparent fragmentation of the TGN and redistribution of K15P to a dispersed peripheral location. Similar results were seen when lytic reactivation was stimulated by the KSHV protein replication and transcription activator (RTA) and during spontaneous reactivation. We speculate that expression of different molecular weight forms of K15P in distinct cellular locations reflects the alternative demands placed upon the protein in the latent and lytic phases.IMPORTANCE The K15P protein of Kaposi's sarcoma-associated herpesvirus (KSHV) is thought to play key roles in disease, including KSHV associated angiogenesis and the survival and growth of primary effusion lymphoma (PEL) cells. The protein exists in multiple molecular weight forms, and its intracellular trafficking is poorly understood. Here we demonstrate that the molecular weight form of a reporter K15P molecule and its intracellular distribution change when KSHV switches from its latent (quiescent) phase to the lytic, infectious state. We speculate that expression of different molecular weight forms of K15P in distinct cellular locations reflects the alternative demands placed upon the protein in the viral latent and lytic stages. PMID- 28835497 TI - Cysteines and N-Glycosylation Sites Conserved among All Alphaherpesviruses Regulate Membrane Fusion in Herpes Simplex Virus 1 Infection. AB - Neurotropism is a defining characteristic of alphaherpesvirus pathogenicity. Glycoprotein K (gK) is a conserved virion glycoprotein of all alphaherpesviruses that is not found in other herpesvirus subfamilies. The extracellular amino terminus of gK has been shown to be important to the ability of the prototypic alphaherpesvirus herpes simplex virus 1 (HSV-1) to enter neurons via axonal termini. Here, we determined the role of the two conserved N-linked glycosylation (N48 and N58) sites of gK in virus-induced cell fusion and replication. We found that N-linked glycosylation is important to the regulation of HSV-1-induced membrane fusion since mutating N58 to alanine (N58A) caused extensive virus induced cell fusion. Due to the known contributions of N-linked glycosylation to protein processing and correct disulfide bond formation, we investigated whether the conserved extracellular cysteine residues within the amino terminus of gK contributed to the regulation of HSV-1-induced membrane fusion. We found that mutation of C37 and C114 residues led to a gK-null phenotype characterized by very small plaque formation and drastic reduction in infectious virus production, while mutation of C82 and C243 caused extensive virus-induced cell fusion. Comparison of N-linked glycosylation and cysteine mutant replication kinetics identified disparate effects on infectious virion egress from infected cells. Specifically, cysteine mutations caused defects in the accumulation of infectious virus in both the cellular and supernatant fractions, while glycosylation site mutants did not adversely affect virion egress from infected cells. These results demonstrate a critical role for the N glycosylation sites and cysteines for the structure and function of the amino terminus of gK.IMPORTANCE We have previously identified important entry and neurotropic determinants in the amino terminus of HSV-1 glycoprotein K (gK). Alphaherpesvirus-mediated membrane fusion is a complex and highly regulated process that is not clearly understood. gK and UL20, which are highly conserved across all alphaherpesviruses, play important roles in the regulation of HSV-1 fusion in the context of infection. A greater understanding of mechanisms governing alphaherpesvirus membrane fusion is expected to inform the rational design of therapeutic and prevention strategies to combat herpesviral infection and pathogenesis. This work adds to the growing reports regarding the importance of gK to alphaherpesvirus pathogenesis and details important structural features of gK that are involved in gK-mediated regulation of virus-induced membrane fusion. PMID- 28835498 TI - Structural Transitions of the Conserved and Metastable Hantaviral Glycoprotein Envelope. AB - Hantaviruses are zoonotic pathogens that cause severe hemorrhagic fever and pulmonary syndrome. The outer membrane of the hantavirus envelope displays a lattice of two glycoproteins, Gn and Gc, which orchestrate host cell recognition and entry. Here, we describe the crystal structure of the Gn glycoprotein ectodomain from the Asiatic Hantaan virus (HTNV), the most prevalent pathogenic hantavirus. Structural overlay analysis reveals that the HTNV Gn fold is highly similar to the Gn of Puumala virus (PUUV), a genetically and geographically distinct and less pathogenic hantavirus found predominantly in northeastern Europe, confirming that the hantaviral Gn fold is architecturally conserved across hantavirus clades. Interestingly, HTNV Gn crystallized at acidic pH, in a compact tetrameric configuration distinct from the organization at neutral pH. Analysis of the Gn, both in solution and in the context of the virion, confirms the pH-sensitive oligomeric nature of the glycoprotein, indicating that the hantaviral Gn undergoes structural transitions during host cell entry. These data allow us to present a structural model for how acidification during endocytic uptake of the virus triggers the dissociation of the metastable Gn-Gc lattice to enable insertion of the Gc-resident hydrophobic fusion loops into the host cell membrane. Together, these data reveal the dynamic plasticity of the structurally conserved hantaviral surface.IMPORTANCE Although outbreaks of Korean hemorrhagic fever were first recognized during the Korean War (1950 to 1953), it was not until 1978 that they were found to be caused by Hantaan virus (HTNV), the most prevalent pathogenic hantavirus. Here, we describe the crystal structure of HTNV envelope glycoprotein Gn, an integral component of the Gn-Gc glycoprotein spike complex responsible for host cell entry. HTNV Gn is structurally conserved with the Gn of a genetically and geographically distal hantavirus, Puumala virus, indicating that the observed alpha/beta fold is well preserved across the Hantaviridae family. The combination of our crystal structure with solution state analysis of recombinant protein and electron cryo-microscopy of acidified hantavirus allows us to propose a model for endosome-induced reorganization of the hantaviral glycoprotein lattice. This provides a molecular-level rationale for the exposure of the hydrophobic fusion loops on the Gc, a process required for fusion of viral and cellular membranes. PMID- 28835499 TI - Nipah and Hendra Virus Nucleoproteins Inhibit Nuclear Accumulation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT2 by Interfering with Their Complex Formation. AB - Henipaviruses, such as Nipah (NiV) and Hendra (HeV) viruses, are highly pathogenic zoonotic agents within the Paramyxoviridae family. The phosphoprotein (P) gene products of the paramyxoviruses have been well characterized for their interferon (IFN) antagonist activity and their contribution to viral pathogenicity. In this study, we demonstrated that the nucleoprotein (N) of henipaviruses also prevents the host IFN signaling response. Reporter assays demonstrated that the NiV and HeV N proteins (NiV-N and HeV-N, respectively) dose dependently suppressed both type I and type II IFN responses and that the inhibitory effect was mediated by their core domains. Additionally, NiV-N prevented the nuclear transport of signal transducer and activator of transcription 1 (STAT1) and STAT2. However, NiV-N did not associate with Impalpha5, Impbeta1, or Ran, which are members of the nuclear transport system for STATs. Although P protein is known as a binding partner of N protein and actively retains N protein in the cytoplasm, the IFN antagonist activity of N protein was not abolished by the coexpression of P protein. This suggests that the IFN inhibition by N protein occurs in the cytoplasm. Furthermore, we demonstrated that the complex formation of STATs was hampered in the N protein expressing cells. As a result, STAT nuclear accumulation was reduced, causing a subsequent downregulation of interferon-stimulated genes (ISGs) due to low promoter occupancy by STAT complexes. This novel route for preventing host IFN responses by henipavirus N proteins provides new insight into the pathogenesis of these viruses.IMPORTANCE Paramyxoviruses are well known for suppressing interferon (IFN)-mediated innate immunity with their phosphoprotein (P) gene products, and the henipaviruses also possess P, V, W, and C proteins for evading host antiviral responses. There are numerous studies providing evidence for the relationship between viral pathogenicity and antagonistic activities against IFN responses by P gene products. Meanwhile, little attention has been paid to the influence of nucleoprotein (N) on host innate immune responses. In this study, we demonstrated that both the NiV and HeV N proteins have antagonistic activity against the JAK/STAT signaling pathway by preventing the nucleocytoplasmic trafficking of STAT1 and STAT2. This inhibitory effect is due to an impairment of the ability of STATs to form complexes. These results provide new insight into the involvement of N protein in viral pathogenicity via its IFN antagonism. PMID- 28835500 TI - Human Papillomavirus 16 (HPV-16), HPV-18, and HPV-31 E6 Override the Normal Phosphoregulation of E6AP Enzymatic Activity. AB - The human papillomavirus (HPV) E6 oncoproteins recruit the cellular ubiquitin ligase E6AP/UBE3A to target cellular substrates for proteasome-mediated degradation, and one consequence of this activity is the E6 stimulation of E6AP autoubiquitination and degradation. Recent studies identified an autism-linked mutation within E6AP at T485, which was identified as a protein kinase A phosphoacceptor site and which could directly regulate E6AP ubiquitin ligase activity. In this study, we have analyzed how T485-mediated regulation of E6AP might affect E6 targeting of some of its known substrates. We show that modulation of T485 has no effect on the ability of E6 to direct either p53 or Dlg for degradation. Furthermore, T485 regulation has no effect on HPV-16 or HPV-31 E6-induced autodegradation of E6AP but does affect HPV-18 E6-induced autodegradation of E6AP. In cells derived from cervical cancers, we find low levels of both phosphorylated and nonphosphorylated E6AP in the nucleus. However, ablation of E6 results in a dramatic accumulation of phospho-E6AP in the cytoplasm, whereas nonphosphorylated E6AP accumulates primarily in the nucleus. Interestingly, E6AP phosphorylation at T485 confers association with 14-3-3 proteins, and this interaction seems to be important, in part, for the ability of E6 to recruit phospho-E6AP into the nucleus. These results demonstrate that HPV E6 overrides the normal phosphoregulation of E6AP, both in terms of its enzymatic activity and its subcellular distribution.IMPORTANCE Recent reports demonstrate the importance of phosphoregulation of E6AP for its normal enzymatic activity. Here, we show that HPV E6 is capable of overriding this regulation and can promote degradation of p53 and Dlg regardless of the phosphorylation status of E6AP. Furthermore, E6 interaction with E6AP also significantly alters how E6AP is subject to autodegradation and suggests that this is not a simple stimulation of an already-existing activity but rather a redirection of E6AP activity toward itself. Furthermore, E6-mediated regulation of the subcellular distribution of phospho-E6AP appears to be dependent, in part, upon the 14-3-3 family of proteins. PMID- 28835501 TI - Inherited Chromosomally Integrated Human Herpesvirus 6 Genomes Are Ancient, Intact, and Potentially Able To Reactivate from Telomeres. AB - The genomes of human herpesvirus 6A (HHV-6A) and HHV-6B have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere, and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern nonintegrated HHV-6 strains for which complete sequences are currently available. In addition, ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 +/- 10,600 years ago. Despite the antiquity of some, and possibly most, germ line HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation.IMPORTANCE Inheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date, but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here, we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes, and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immunocompromised patients, in particular in organ transplantation and in stem cell therapy. PMID- 28835503 TI - Murine Olfactory Bulb Interneurons Survive Infection with a Neurotropic Coronavirus. AB - Viral infection of the central nervous system is complicated by the mostly irreplaceable nature of neurons, as the loss of neurons has the potential to result in permanent damage to brain function. However, whether neurons or other cells in the CNS sometimes survive infection and the effects of infection on neuronal function are largely unknown. To address this question, we used the rJHM strain (rJ) of mouse hepatitis virus, (MHV), a neurotropic coronavirus, which causes acute encephalitis in susceptible strains of mice. To determine whether neurons or other CNS cells survive acute infection with this virulent virus, we developed a recombinant JHMV that expresses Cre recombinase (rJ-Cre) and infected mice that universally expressed a silent (floxed) version of tdTomato. Infection of these mice with rJ-Cre resulted in expression of tdTomato in host cells. The results showed that some cells were able to survive the infection, as demonstrated by continued tdTomato expression after virus antigen could no longer be detected. Most notably, interneurons in the olfactory bulb, which are known to be inhibitory, represented a large fraction of the surviving cells. In conclusion, our results indicated that some neurons are resistant to virus mediated cell death and provide a framework for studying the effects of prior coronavirus infection on neuron function.Importance. We developed a novel recombinant virus that allows for the study of cells that survive an infection by a central nervous system-specific strain of murine coronavirus. Using this virus, we identified neurons and to a lesser extent, non-neuronal cells in the brain that were infected during the acute phase of the infection and survived for approximately two weeks until the mice succumbed to the infection. We focused on neurons and glial cells within the olfactory bulb because the virus enters the brain at this site. Our results show that interneurons of the olfactory bulb were the primary cell type able to survive infection. Further, these results indicate that this system will be useful for functional and gene expression studies of cells in the brain that survive acute infection. PMID- 28835502 TI - CD8+ T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection. AB - Zika virus (ZIKV) infection causees neurologic complications, including Guillain Barre syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8+ T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8+ T cell response was elicited, major histocompatibility complex class I-restricted CD8+ T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8+ T cells was developed, and virus-specific memory CD8+ T cells were generated in these mice. The CD8+ T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8+ T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection.IMPORTANCE ZIKV infection has severe clinical consequences, including Guillain-Barre syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8+ T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKV-specific CD8+ T cells in vivo, which simplified the detection and evaluation of ZIKV-specific immune responses. In addition, the finding that tetramer positive memory CD8+ T cell responses were generated and that CD8+ T cells can traffic to a ZIKV-infected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design. PMID- 28835504 TI - Attenuated Human Parainfluenza Virus Type 1 Expressing the Respiratory Syncytial Virus (RSV) Fusion (F) Glycoprotein from an Added Gene: Effects of Prefusion Stabilization and Packaging of RSV F. AB - Human respiratory syncytial virus (RSV) is the most prevalent worldwide cause of severe respiratory tract infection in infants and young children. Human parainfluenza virus type 1 (HPIV1) also causes severe pediatric respiratory illness, especially croup. Both viruses lack vaccines. Here, we describe the preclinical development of a bivalent RSV/HPIV1 vaccine based on a recombinant HPIV1 vector, attenuated by a stabilized mutation, that expresses RSV F protein modified for increased stability in the prefusion (pre-F) conformation by previously described disulfide bond (DS) and hydrophobic cavity-filling (Cav1) mutations. RSV F was expressed from the first or second gene position as the full length protein or as a chimeric protein with its transmembrane and cytoplasmic tail (TMCT) domains substituted with those of HPIV1 F in an effort to direct packaging in the vector particles. All constructs were recovered by reverse genetics. The TMCT versions of RSV F were packaged in the rHPIV1 particles much more efficiently than their full-length counterparts. In hamsters, the presence of the RSV F gene, and in particular the TMCT versions, was attenuating and resulted in reduced immunogenicity. However, the vector expressing full-length RSV F from the pre-N position was immunogenic for RSV and HPIV1. It conferred complement-independent high-quality RSV-neutralizing antibodies at titers similar to those of wild-type RSV and provided protection against RSV challenge. The vectors exhibited stable RSV F expression in vitro and in vivo In conclusion, an attenuated rHPIV1 vector expressing a pre-F-stabilized form of RSV F demonstrated promising immunogenicity and should be further developed as an intranasal pediatric vaccine.IMPORTANCE RSV and HPIV1 are major viral causes of acute pediatric respiratory illness for which no vaccines or suitable antiviral drugs are available. The RSV F glycoprotein is the major RSV neutralization antigen. We used a rHPIV1 vector, bearing a stabilized attenuating mutation, to express the RSV F glycoprotein bearing amino acid substitutions that increase its stability in the pre-F form, the most immunogenic form that elicits highly functional virus neutralizing antibodies. RSV F was expressed from the pre-N or N-P gene position of the rHPIV1 vector as a full-length protein or as a chimeric form with its TMCT domain derived from HPIV1 F. TMCT modification greatly increased packaging of RSV F into the vector particles but also increased vector attenuation in vivo, resulting in reduced immunogenicity. In contrast, full-length RSV F expressed from the pre-N position was immunogenic, eliciting complement-independent RSV neutralizing antibodies and providing protection against RSV challenge. PMID- 28835505 TI - Interferon regulatory factor-1 (IRF-1) protects against chikungunya virus induced immunopathology by restricting infection in muscle cells. AB - The innate immune system protects cells against viral pathogens in part through the autocrine and paracrine actions of interferons (IFN)-alpha/beta (type I), gamma (type II), and -lambda (type III). The transcription factor interferon regulatory factor (IRF)-1 has a demonstrated role in shaping innate and adaptive antiviral immunity by inducing the expression of IFN stimulated genes (ISGs) and mediating signals downstream of IFN-gamma. Although ectopic expression experiments have suggested an inhibitory function of IRF-1 against infection of alphaviruses in cell culture, its role in vivo remains unknown. Here, we infected Irf1-/- mice with two distantly related arthritogenic alphaviruses, chikungunya (CHIKV) and Ross River (RRV), and assessed the early antiviral functions of IRF-1 prior to induction of adaptive B and T cell responses. IRF-1 expression limited CHIKV-induced foot swelling in joint-associated tissues and prevented dissemination of CHIKV and RRV at early time points. Virological and histological analysis revealed greater infection of muscle tissues in Irf1-/- compared to wild type mice. The antiviral actions of IRF-1 appeared independent of the induction of type I IFN or effects of type II and III IFNs but were associated with altered local pro-inflammatory cytokine and chemokine responses and differential infiltration of myeloid cell subsets. Collectively, our in vivo experiments suggest that IRF-1 restricts CHIKV and RRV infection in stromal cells, especially muscle cells, and this controls local inflammation and joint-associated swelling.IMPORTANCE Interferon regulatory factor (IRF)-1 is a transcription factor that regulates the expression of a broad range of antiviral host defense genes. In this study, using Irf1-/- mice, we investigated the role of IRF-1 in modulating pathogenesis of two related arthritogenic alphaviruses, chikungunya and Ross River viruses. Our studies show that IRF-1 controlled alphavirus replication and swelling in joint-associated tissues within days of infection. Detailed histopathological and virological analyses revealed that IRF-1 preferentially restricted CHIKV infection in cells of non-hematopoietic lineage, including muscle cells. The antiviral actions of IRF-1 resulted in decreased local inflammatory responses in joint associated tissues, which prevented immunopathology. PMID- 28835506 TI - The K186E Amino Acid Substitution in the Canine Influenza Virus H3N8 NS1 Protein Restores Its Ability To Inhibit Host Gene Expression. AB - Canine influenza viruses (CIVs) are the causative agents of canine influenza, a contagious respiratory disease in dogs, and include the equine-origin H3N8 and the avian-origin H3N2 viruses. Influenza A virus (IAV) nonstructural protein 1 (NS1) is a virulence factor essential for counteracting the innate immune response. Here, we evaluated the ability of H3N8 CIV NS1 to inhibit host innate immune responses. We found that H3N8 CIV NS1 was able to efficiently counteract interferon (IFN) responses but was unable to block general gene expression in human or canine cells. Such ability was restored by a single amino acid substitution in position 186 (K186E) that resulted in NS1 binding to the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a cellular protein involved in pre-mRNA processing. We also examined the frequency distribution of K186 and E186 among H3N8 CIVs and equine influenza viruses (EIVs), the ancestors of H3N8 CIV, and experimentally determined the impact of amino acid 186 in the ability of different CIV and EIV NS1s to inhibit general gene expression. In all cases, the presence of E186 was responsible for the control of host gene expression. In contrast, the NS1 protein of H3N2 CIV harbors E186 and blocks general gene expression in canine cells. Altogether, our results confirm previous studies on the strain-dependent ability of NS1 to block general gene expression. Moreover, the observed polymorphism on amino acid 186 between H3N8 and H3N2 CIVs might be the result of adaptive changes acquired during long term circulation of avian-origin IAVs in mammals.IMPORTANCE Canine influenza is a respiratory disease of dogs caused by two CIV subtypes, the H3N8 and H3N2 viruses, of equine and avian origins, respectively. Influenza NS1 is the main viral factor responsible for the control of host innate immune responses, and changes in NS1 can play an important role in host adaptation. Here we assessed the ability of H3N8 CIV NS1 to inhibit host innate immune responses and gene expression. The H3N8 CIV NS1 did not block host gene expression, but this activity was restored by a single amino acid substitution (K186E), which was responsible for NS1 binding to the host factor CPSF30. In contrast, the H3N2 CIV NS1, which contains E186, blocks general gene expression. Our results suggest that the ability to block host gene expression is not required for influenza virus replication in mammals but might be important in the long-term adaptation of avian-origin influenza viruses to mammals. PMID- 28835508 TI - Thwarting endogenous stress: BRCA protects against aldehyde toxicity. PMID- 28835507 TI - Genome editing for scalable production of alloantigen-free lentiviral vectors for in vivo gene therapy. AB - Lentiviral vectors (LV) are powerful and versatile vehicles for gene therapy. However, their complex biological composition challenges large-scale manufacturing and raises concerns for in vivo applications, because particle components and contaminants may trigger immune responses. Here, we show that producer cell-derived polymorphic class-I major histocompatibility complexes (MHC I) are incorporated into the LV surface and trigger allogeneic T-cell responses. By disrupting the beta-2 microglobulin gene in producer cells, we obtained MHC free LV with substantially reduced immunogenicity. We introduce this targeted editing into a novel stable LV packaging cell line, carrying single-copy inducible vector components, which can be reproducibly converted into high-yield LV producers upon site-specific integration of the LV genome of interest. These LV efficiently transfer genes into relevant targets and are more resistant to complement-mediated inactivation, because of reduced content of the vesicular stomatitis virus envelope glycoprotein G compared to vectors produced by transient transfection. Altogether, these advances support scalable manufacturing of alloantigen-free LV with higher purity and increased complement resistance that are better suited for in vivo gene therapy. PMID- 28835509 TI - Quantal Fluctuations in Central Mammalian Synapses: Functional Role of Vesicular Docking Sites. AB - Quantal fluctuations are an integral part of synaptic signaling. At the frog neuromuscular junction, Bernard Katz proposed that quantal fluctuations originate at "reactive sites" where specific structures of the presynaptic membrane interact with synaptic vesicles. However, the physical nature of reactive sites has remained unclear, both at the frog neuromuscular junction and at central synapses. Many central synapses, called simple synapses, are small structures containing a single presynaptic active zone and a single postsynaptic density of receptors. Several lines of evidence indicate that simple synapses may release several synaptic vesicles in response to a single action potential. However, in some synapses at least, each release event activates a significant fraction of the postsynaptic receptors, giving rise to a sublinear relation between vesicular release and postsynaptic current. Partial receptor saturation as well as synaptic jitter gives to simple synapse signaling the appearance of a binary process. Recent investigations of simple synapses indicate that the number of released vesicles follows binomial statistics, with a maximum reflecting the number of docking sites present in the active zone. These results suggest that at central synapses, vesicular docking sites represent the reactive sites proposed by Katz. The macromolecular architecture and molecular composition of docking sites are presently investigated with novel combinations of techniques. It is proposed that variations in docking site numbers are central in defining intersynaptic variability and that docking site occupancy is a key parameter regulating short term synaptic plasticity. PMID- 28835510 TI - A systematic review of performance-enhancing pharmacologicals and biotechnologies in the Army. AB - INTRODUCTION: In 2015, the Australian Army commissioned a systematic review to assess the evidence on effectiveness and safety of pharmacological and biotechnological products for cognitive enhancement specifically in Army personnel. METHODS: Searches for studies examining biotechnological and pharmacological products in Army populations were conducted in December 2015. Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO were searched without date or language restrictions. WHO's International Clinical Trials Registry Platform and ClinicalTrials.gov were searched to identify ongoing trials. Studies meeting inclusion criteria were evaluated for risk of bias using Cochrane's Risk of Bias tool. Due to heterogeneity of findings, meta-analysis could not be conducted. Findings were synthesised narratively and by vote-counting method. RESULTS: Sixteen pharmacological enhancement products were evaluated in 22 randomised controlled trials (RCTs), involving 1284 personnel. Only three of the studies were published since 2010. The interventions evaluated were varied, including supplements (eg, carbohydrate), stimulants (eg, caffeine) and hormones (eg, melatonin). Generally, caffeine provided an improvement in performance compared with placebo on 5/7 reported cognitive outcomes, followed by levothyroxine (four cognitive outcomes) and prazosin (three cognitive outcomes). Performance results were mixed (finding an improvement and no effect in comparison to placebo) for caffeine and melatonin on two outcomes. No evidence was found pertaining to biotechnological products. Studies rarely reported safety outcomes (eg, adverse events and addiction). CONCLUSION: Findings from this review need to be interpreted with considerable caution. Future studies should include outcomes such as acute and long-term adverse events, and should evaluate cognitive performance using cognitive tests that are specific to the Army population. PMID- 28835511 TI - Retrospective analysis of four-year injury data from the Infantry Training Centre, Catterick. AB - INTRODUCTION: Musculoskeletal injury (MSKI) represents a considerable threat to the effectiveness and productivity of military organisations globally. The impact on the medical chain, occupational disposal with associated loss of working days and associated financial burden have far-reaching consequence. The moral and legal responsibility to reduce avoidable injuries through risk assessment and prevention strategies is fundamental to governance and a key component of best practice. METHODS: A retrospective observational analysis was performed of 4101 MSKIs presenting from a total inflow of 10 498 British Army Infantry recruits recorded over four consecutive training years between 2012 and 2016. Injury incidence, site, type and week of training were recorded and analysed. RESULTS: The total incidence of all MSKI was observed as 39.1%. Overuse injuries were the most common subclassification of injury type (24.5%), followed by trauma (8.8%) and then stress fractures (5.7%). Causes of medical discharge over a four-year cumulative incidence were from overuse injuries (59.3%), stress fractures (21.5%) and trauma (19.2%). 45.5% of all MSKIs presented within the first eight weeks of training. CONCLUSIONS: MSKI data highlighted the requirement for a comprehensive service evaluation of the Combat Infantryman's Course and subsequent justification for the introduction of an injury prevention intervention - Project OMEGA. PMID- 28835512 TI - Non-battle injury among repatriated UK armed forces since cessation of combat operations: a prospective observational study. AB - AIM: To describe the mechanisms, burden of injury, inpatient management and rehabilitation requirements of wounded military personnel at the UK Role 4 (R4) facility within the first 12 months following cessation of combat operations in Afghanistan. METHODS: All aeromedical evacuations were recorded prospectively between October 2014 and October 2015. Demographic, logistical and clinical data were derived manually from referring medical unit and patient movement requests in addition to host nation and R4 medical records. RESULTS: Ninety-five patients were repatriated to R4 following traumatic injury: 98.9% (n=94) were male, and median age was 27 years (IQR 25-36 years). The most common mechanisms of injury (MOIs) were sports 26.3% (n=25), falls <2 m 11.6% (n=11) and road traffic collisions 9.8% (n=9). The most common anatomical regions of injury were isolated lower limb 24.1% (n=22), isolated hand 20.0% (n=19) and polytrauma 14.7% (n=14). Median Injury Severity Score was 4 (IQR 4-9), mean 8 (range 1-41). Eleven patients (11.6%) were discharged to rehabilitation units, of whom 7 (63.6%) required neurorehabilitation. CONCLUSION: Although service personnel sustain civilian-type injuries, the specific rehabilitation goals and shift in the acute rehabilitation requirements for military personnel must be considered in the absence of enduring combat operations. It is notable that permanent medical downgrading secondary to trauma still occurs outside of warfare. The colocation of civilian major trauma services and R4 has ensured a mutually beneficial partnership that contributes to institutional memory and improves the coordination of patient pathways. The importance of relevant resource allocation, training, support and logistical considerations remain, even during the current scale of military activity overseas. PMID- 28835513 TI - FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. AB - : On October 24, 2016, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck & Co., Inc., https://www.merck.com) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test, as follows: (a) first-line treatment of patients with mNSCLC whose tumors have high PD-L1 expression (tumor proportion score [TPS] >=50%), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and (b) treatment of patients with mNSCLC whose tumors express PD-L1 (TPS >=1%), with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.Approval was based on two randomized, open-label, active controlled trials demonstrating statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy. In KEYNOTE-024, patients with previously untreated mNSCLC who received pembrolizumab (200 mg intravenously [IV] every 3 weeks) had a statistically significant improvement in OS (hazard ratio [HR] 0.60; 95% confidence interval [CI]: 0.41-0.89; p = .005), and significant improvement in PFS (HR 0.50; 95% CI: 0.37-0.68; p < .001). In KEYNOTE-010, patients with disease progression on or after platinum-containing chemotherapy received pembrolizumab IV 2 mg/kg, 10 mg/kg, or docetaxel 75 mg/m2 every 3 weeks. The HR and p value for OS was 0.71 (95% CI: 0.58-0.88), p < .001 comparing pembrolizumab 2 mg/kg with chemotherapy and the HR and p value for OS was 0.61 (95% CI: 0.49-0.75), p < .001 comparing pembrolizumab 10 mg/kg with chemotherapy. IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval expands the pembrolizumab indication in second-line treatment of lung cancer to include all patients with programmed death-ligand 1-expressing non small cell lung cancer. PMID- 28835514 TI - Salvage Therapy in Advanced Adult Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis of Randomized Trials. AB - BACKGROUND: Prognosis for patients with metastatic soft tissue sarcomas (STS) is dismal, with median overall survival (OS) of 8-12 months. The role of second-line therapy has been inconsistently investigated over the last 20 years. This systematic review and meta-analysis was performed to assess the efficacy of salvage treatment in pretreated adult type STS, gastrointestinal stromal tumor (GIST) excluded. MATERIAL AND METHODS: PubMed, Web of Science, SCOPUS, EMBASE, CINAHL, and The Cochrane Library were searched for randomized phase II/phase III trials exploring second- or beyond therapy lines in pretreated metastatic STS. Two independent investigators extracted data; the quality of eligible studies was resolved by consensus. Hazard ratio (HR) of death and progression (OS and progression-free survival [PFS]) and odds ratio (OR) for response rate (RR) were pooled in a fixed- or random-effects model according to heterogeneity. Study quality was assessed with the Cochrane's risk of bias tool, and publication bias with funnel plots. RESULTS: Overall, 10 randomized trials were selected. The pooled HR for death was 0.81 (95% confidence interval [CI] 0.73-0.9). Second-line therapy reduced the risk of progression by 49% (HR = 0.51, 95% CI 0.34-0.76). This translated into an absolute benefit in OS and PFS by 3.3 and 1.6 months, respectively. Finally, RR with new agents or chemotherapy doublets translated from 4.3% to 7.6% (OR = 1.78, 95% CI 1.22-2.50). CONCLUSION: Better survival is achieved in patients treated with salvage therapies (chemotherapy, as single or multiple agents or targeted biological agents). A 3-months gain in OS and an almost double RR is observed. Second lines also attained a reduction by 50% the risk of progression. IMPLICATIONS FOR PRACTICE: There is some evidence that salvage therapies after first-line failure are able to improve outcome in metastatic soft tissue sarcoma (STS). Trabectedin, gemcitabine-based therapy, and pazopanib are currently approved drugs used after conventional upfront treatment. This meta-analysis reviews the benefit of new agents used in randomized trials in comparison with no active treatments or older agents for recurrent/progressed STS. The results show that modern drugs confer a statistically significant 3 month benefit in terms of overall survival, and an increase in response rate. Despite a limited improvement in outcome, currently approved second-line therapy should be offered to patients with good performance status. PMID- 28835515 TI - A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus. AB - Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na+- and K+-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP 1R agonist drugs may be a useful therapeutic strategy for treating raised ICP. PMID- 28835516 TI - An RNA interference screen identifies druggable regulators of MeCP2 stability. AB - Alterations in gene dosage due to copy number variation are associated with autism spectrum disorder, intellectual disability (ID), and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG binding protein 2 (MeCP2) that even a twofold change in MeCP2 protein-either increased or decreased-results in distinct disorders with overlapping features including ID, autistic behavior, and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2, whereas duplications spanning the MECP2 locus result in MECP2 duplication syndrome (MDS), which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MeCP2 can reverse the course of disease, there are currently no U.S. Food and Drug Administration approved therapies available to clinically modulate MeCP2 abundance. We used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MeCP2 stability. Two putative modulators of MeCP2, HIPK2 (homeodomain-interacting protein kinase 2) and PP2A (protein phosphatase 2A), were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 in the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of altered MECP2 dosage. PMID- 28835517 TI - Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma. AB - Oncolytic virotherapy is rapidly progressing through clinical evaluation. However, the therapeutic efficacy of oncolytic viruses in humans has been less than expected from preclinical studies. We describe an anticancer drug screen for compounds that enhance M1 oncolytic virus activity in hepatocellular carcinoma (HCC). An inhibitor of the valosin-containing protein (VCP) was identified as the top sensitizer, selectively increasing potency of the oncolytic virus up to 3600 fold. Further investigation revealed that VCP inhibitors cooperated with M1 virus suppressed inositol-requiring enzyme 1alpha (IRE1alpha)-X-box binding protein 1 (XBP1) pathway and triggered irresolvable endoplasmic reticulum (ER) stress, subsequently promoting robust apoptosis in HCC. We show that VCP inhibitor improved the oncolytic efficacy of M1 virus in several mouse models of HCC and primary HCC tissues. Finally, this combinatorial therapeutic strategy was well tolerated in nonhuman primates. Our study identifies combined VCP inhibition and oncolytic virus as a potential treatment for HCC and demonstrates promising therapeutic potential. PMID- 28835518 TI - A lower-extremity exoskeleton improves knee extension in children with crouch gait from cerebral palsy. AB - The ability to walk contributes considerably to physical health and overall well being, particularly in children with motor disability, and is therefore prioritized as a rehabilitation goal. However, half of ambulatory children with cerebral palsy (CP), the most prevalent childhood movement disorder, cease to walk in adulthood. Robotic gait trainers have shown positive outcomes in initial studies, but these clinic-based systems are limited to short-term programs of insufficient length to maintain improved function in a lifelong disability such as CP. Sophisticated wearable exoskeletons are now available, but their utility in treating childhood movement disorders remains unknown. We evaluated an exoskeleton for the treatment of crouch (or flexed-knee) gait, one of the most debilitating pathologies in CP. We show that the exoskeleton reduced crouch in a cohort of ambulatory children with CP during overground walking. The exoskeleton was safe and well tolerated, and all children were able to walk independently with the device. Rather than guiding the lower limbs, the exoskeleton dynamically changed the posture by introducing bursts of knee extension assistance during discrete portions of the walking cycle, a perturbation that resulted in maintained or increased knee extensor muscle activity during exoskeleton use. Six of seven participants exhibited postural improvements equivalent to outcomes reported from invasive orthopedic surgery. We also demonstrate that improvements in crouch increased over the course of our multiweek exploratory trial. Together, these results provide evidence supporting the use of wearable exoskeletons as a treatment strategy to improve walking in children with CP. PMID- 28835519 TI - Impact of prior errors on visuomotor adaptation and savings: experimental considerations and clinical implications. AB - The motor system retains learning from visuomotor adaptation tasks in the form of "savings" to enable faster readaptation to similar perturbations in the future. Leow et al. (J Neurophysiol 116: 1603-1614, 2016) suggest that the experience of prior errors during relearning is necessary for savings while repetition of prior actions may not be sufficient. These findings provide novel insight into factors that contribute to visuomotor adaptation and can be applied to future experimental and clinical research. PMID- 28835520 TI - Microglia-mediated synaptic elimination in neuronal development and disease. AB - It has recently become clear that microglia, the immune cells of the central nervous system, are far more active in the healthy brain than previously thought. Microglia facilitate many stages of brain development by shaping neuronal connectivity via synaptic elimination. Dysfunction of these same processes likely underlies a wide range of neurological and neurodevelopmental disorders. PMID- 28835521 TI - Intrinsic frequency biases and profiles across human cortex. AB - Recent findings in monkeys suggest that intrinsic periodic spiking activity in selective cortical areas occurs at timescales that follow a sensory or lower order-to-higher order processing hierarchy (Murray JD, Bernacchia A, Freedman DJ, Romo R, Wallis JD, Cai X, Padoa-Schioppa C, Pasternak T, Seo H, Lee D, Wang XJ. Nat Neurosci 17: 1661-1663, 2014). It has not yet been fully explored if a similar timescale hierarchy is present in humans. Additionally, these measures in the monkey studies have not addressed findings that rhythmic activity within a brain area can occur at multiple frequencies. In this study we investigate in humans if regions may be biased toward particular frequencies of intrinsic activity and if a full cortical mapping still reveals an organization that follows this hierarchy. We examined the spectral power in multiple frequency bands (0.5-150 Hz) from task-independent data using magnetoencephalography (MEG). We compared standardized power across bands to find regional frequency biases. Our results demonstrate a mix of lower and higher frequency biases across sensory and higher order regions. Thus they suggest a more complex cortical organization that does not simply follow this hierarchy. Additionally, some regions do not display a bias for a single band, and a data-driven clustering analysis reveals a regional organization with high standardized power in multiple bands. Specifically, theta and beta are both high in dorsal frontal cortex, whereas delta and gamma are high in ventral frontal cortex and temporal cortex. Occipital and parietal regions are biased more narrowly toward alpha power, and ventral temporal lobe displays specific biases toward gamma. Thus intrinsic rhythmic neural activity displays a regional organization but one that is not necessarily hierarchical.NEW & NOTEWORTHY The organization of rhythmic neural activity is not well understood. Whereas it has been postulated that rhythms are organized in a hierarchical manner across brain regions, our novel analysis allows comparison of full cortical maps across different frequency bands, which demonstrate that the rhythmic organization is more complex. Additionally, data-driven methods show that rhythms of multiple frequencies or timescales occur within a particular region and that this nonhierarchical organization is widespread. PMID- 28835522 TI - Functional and molecular plasticity of gamma and alpha1 GABAA receptor subunits in the dorsal motor nucleus of the vagus after experimentally induced diabetes. AB - Chronic experimentally induced hyperglycemia augments subunit-specific gamma aminobutyric acid A (GABAA) receptor-mediated inhibition of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). However, the contribution of alpha1 or gamma GABAA receptor subunits, which are ubiquitously expressed on central nervous system neurons, to this elevation in inhibitory tone have not been determined. This study investigated the effect of chronic hyperglycemia/hypoinsulinemia on alpha1- and gamma-subunit-specific GABAA receptor-mediated inhibition using electrophysiological recordings in vitro and quantitative RT-PCR. DMV neurons from streptozotocin-treated mice demonstrated enhancement of both phasic and tonic inhibitory currents in response to application of the alpha1-subunit-selective GABAA receptor-positive allosteric modulator zolpidem. Responses to low concentrations of the GABAA receptor antagonist gabazine suggested an additional increased contribution of gamma subunit-containing receptors to tonic currents in DMV neurons. Consistent with the functional elevation in alpha1- and gamma-subunit-dependent activity, transcription of both the alpha1- and gamma2-subunits was increased in the dorsal vagal complex of streptozotocin-treated mice. Overall, these findings suggest an increased sensitivity to both zolpidem and gabazine after several days of hyperglycemia/hypoinsulinemia, which could contribute to altered parasympathetic output from DMV neurons in diabetes.NEW & NOTEWORTHY Glutamate and GABA signaling in the dorsal vagal complex is elevated after several days of chronic hyperglycemia in a mouse model of type 1 diabetes. We report persistently enhanced GABAA receptor-mediated responses to the somnolescent zolpidem in preganglionic vagal motor neurons. These results imply a broader impact of chronic hyperglycemia on central vagal function than previously appreciated and reinforce the hypothesis that diabetes effects in the brain can impact regulation of metabolic homeostasis. PMID- 28835523 TI - Role of digit placement control in sensorimotor transformations for dexterous manipulation. AB - Dexterous manipulation relies on the ability to modulate grasp forces to variable digit position. However, the sensorimotor mechanisms underlying such critical ability are not well understood. The present study addressed whether digit force to-position modulation relies entirely on feedback of digit placement and force, or on the integration of such feedback with motor commands responsible for digit positioning. In two experiments, we asked 25 subjects to estimate the index fingertip position relative to the thumb (perception test) or to grasp and lift an object with an asymmetrical mass distribution while preventing object roll (action test). Both tests were performed after subjects' digits were placed actively or passively at different distances (active and passive condition, respectively) and without visual feedback. Because motor commands for digit positioning would be integrated with position and force feedback in the active condition, we hypothesized this condition to be characterized by greater accuracy of digit position estimation and digit force-to-position modulation. Surprisingly, discrimination of digit position and force-to-position modulation was statistically indistinguishable in the active and passive conditions. We conclude that voluntary commands for digit positioning are not essential for accurate estimation of finger position or modulation of digit forces to variable digit position. Thus digit force-to-position modulation can be implemented by integrating sensory feedback of digit position and voluntary commands of digit force production following contact.NEW & NOTEWORTHY This study was designed to understand the sensorimotor mechanisms underlying digit force-to-position modulation required for manipulation. Surprisingly, estimation of relative digit position and force-to-position modulation was accurate regardless of whether the digits were passively or actively positioned. Therefore, accurate estimation of digit position does not require an efference copy of active digit positioning, and the hypothesized advantage of active over passive movement on estimation of end-point position appears to be task and effector dependent. PMID- 28835524 TI - Distinct coordinate systems for adaptations of movement direction and extent. AB - Learned compensations for perturbed visual feedback of movement extent and direction generalize differently to unpracticed movement directions, which suggests different underlying neural mechanisms. Here we investigated whether gain and rotation adaptations are consistent with representation in different coordinate systems. Subjects performed a force-aiming task with the wrist and learned different gains or rotations for different force directions. Generalization was tested without visual feedback for the same extrinsic directions but with the forearm in a different pronation-supination orientation. When the change in forearm orientation caused the adapted visuomotor map to conflict in extrinsic and joint-based coordinates, rotation generalization occurred in extrinsic coordinates but with reduced magnitude. In contrast, gain generalization appeared reduced and phase shifted. When the forearm was rotated further, such that all imposed perturbations aligned in both joint-based and extrinsic coordinates in both postures, rotation generalization was further reduced, whereas there was neither reduction nor phase shift in the pattern of extent generalization. These results show that rotation generalization was expressed in extrinsic coordinates, and that generalization magnitude was modulated by posture. In contrast, gain generalization appeared to depend on target direction defined by an integrated combination of extrinsic and joint based coordinates and was not reduced substantially by posture changes alone. Although the quality of the model fit underlying our interpretation prevents us from making strong conclusions, the data suggest that adaptations of movement direction and extent are represented according to distinct coordinate systems.NEW & NOTEWORTHY Visuomotor gain and rotation adaptations generalize differently to novel movement directions, which suggests different neural mechanisms. When extrinsic and joint-based coordinates are effectively dissociated in an isometric aiming task, we find that they also generalize in different coordinate systems. Specifically, rotation generalized in extrinsic coordinates and decayed as posture departed from that adopted during adaptation. In contrast, gain generalization was expressed according to mixed extrinsic/joint-based coordinates and was not substantially reduced by postural changes. PMID- 28835525 TI - Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress. AB - This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (age 33 +/- 12 yr), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during 1) functional residual capacity apnea (FRCApnea) and 2) continued RBR. Data from RBR were analyzed at matched (i.e., to FRCApnea) hemoglobin saturation (HbSat) levels (RBRMatched) or more severe levels (RBREnd). A third protocol compared alternating periods (30 s) of FRC and RBR (FRC-RBRALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71 +/- 6%; P = NS), RBRMatched was associated with reduced AP frequency and APs per burst compared with FRCApnea (both P < 0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRCApnea (+10 +/- 2; P < 0.001) but not during RBRMatched (+1 +/- 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (HbSat: 56 +/- 13 vs. 71 +/- 6%; P < 0.001), RBREnd was associated with a restrained increase in the APs per burst (FRCApnea: +18 +/- 7; RBREnd: +11 +/- 5) and total AP clusters (FRCApnea: +10 +/- 2; RBREnd: +6 +/- 4) (both P < 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P < 0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P = NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even extreme, chemoreflex stress.NEW & NOTEWORTHY The current study demonstrates that the sympathetic neural recruitment patterns observed during chemoreflex activation induced by rebreathing or apnea are restrained and/or inhibited by the act of ventilation per se, despite similar, or even greater, levels of severe chemoreflex stress. Therefore, ventilation modulates not only the timing of sympathetic bursts but also the within-burst axonal recruitment normally observed during progressive chemoreflex stress. PMID- 28835526 TI - Parkinsonism and vigilance: alteration in neural oscillatory activity and phase amplitude coupling in the basal ganglia and motor cortex. AB - Oscillatory neural activity in different frequency bands and phase-amplitude coupling (PAC) are hypothesized to be biomarkers of Parkinson's disease (PD) that could explain dysfunction in the motor circuit and be used for closed-loop deep brain stimulation (DBS). How these putative biomarkers change from the normal to the parkinsonian state across nodes in the motor circuit and within the same subject, however, remains unknown. In this study, we characterized how parkinsonism and vigilance altered oscillatory activity and PAC within the primary motor cortex (M1), subthalamic nucleus (STN), and globus pallidus (GP) in two nonhuman primates. Static and dynamic analyses of local field potential (LFP) recordings indicate that 1) after induction of parkinsonism using the neurotoxin MPTP, low-frequency power (8-30 Hz) increased in the STN and GP in both subjects, but increased in M1 in only one subject; 2) high-frequency power (~330 Hz) was present in the STN in both normal subjects but absent in the parkinsonian condition; 3) elevated PAC measurements emerged in the parkinsonian condition in both animals, but in different sites in each animal (M1 in one subject and GPe in the other); and 4) the state of vigilance significantly impacted how oscillatory activity and PAC were expressed in the motor circuit. These results support the hypothesis that changes in low- and high-frequency oscillatory activity and PAC are features of parkinsonian pathophysiology and provide evidence that closed loop DBS systems based on these biomarkers may require subject-specific configurations as well as adaptation to changes in vigilance.NEW & NOTEWORTHY Chronically implanted electrodes were used to record neural activity across multiple nodes in the basal ganglia-thalamocortical circuit simultaneously in a nonhuman primate model of Parkinson's disease, enabling within-subject comparisons of electrophysiological biomarkers between normal and parkinsonian conditions and different vigilance states. This study improves our understanding of the role of oscillatory activity and phase-amplitude coupling in the pathophysiology of Parkinson's disease and supports the development of more effective DBS therapies based on pathophysiological biomarkers. PMID- 28835527 TI - Anatomy and physiology of phrenic afferent neurons. AB - Large-diameter myelinated phrenic afferents discharge in phase with diaphragm contraction, and smaller diameter fibers discharge across the respiratory cycle. In this article, we review the phrenic afferent literature and highlight areas in need of further study. We conclude that 1) activation of both myelinated and nonmyelinated phrenic sensory afferents can influence respiratory motor output on a breath-by-breath basis; 2) the relative impact of phrenic afferents substantially increases with diaphragm work and fatigue; 3) activation of phrenic afferents has a powerful impact on sympathetic motor outflow, and 4) phrenic afferents contribute to diaphragm somatosensation and the conscious perception of breathing. Much remains to be learned regarding the spinal and supraspinal distribution and synaptic contacts of myelinated and nonmyelinated phrenic afferents. Similarly, very little is known regarding the potential role of phrenic afferent neurons in triggering or modulating expression of respiratory neuroplasticity. PMID- 28835528 TI - A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl- from acidic organelles in amacrine cells. AB - gamma-Amino butyric acid (GABA) and glycine typically mediate synaptic inhibition because their ligand-gated ion channels support the influx of Cl- However, the electrochemical gradient for Cl- across the postsynaptic plasma membrane determines the voltage response of the postsynaptic cell. Typically, low cytosolic Cl- levels support inhibition, whereas higher levels of cytosolic Cl- can suppress inhibition or promote depolarization. We previously reported that nitric oxide (NO) releases Cl- from acidic organelles and transiently elevates cytosolic Cl-, making the response to GABA and glycine excitatory. In this study, we test the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the NO-dependent efflux of organellar Cl- We first establish the mRNA and protein expression of CFTR in our model system, cultured chick retinal amacrine cells. Using whole cell voltage-clamp recordings of currents through GABA-gated Cl- channels, we examine the effects of pharmacological inhibition of CFTR on the NO-dependent release of internal Cl- To interfere with the expression of CFTR, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing. We find that both pharmacological inhibition and CRISPR/Cas9-mediated knockdown of CFTR block the ability of NO to release Cl- from internal stores. These results demonstrate that CFTR is required for the NO-dependent efflux of Cl- from acidic organelles.NEW & NOTEWORTHY Although CFTR function has been studied extensively in the context of epithelia, relatively little is known about its function in neurons. We show that CFTR is involved in an NO-dependent release of Cl- from acidic organelles. This internal function of CFTR is particularly relevant to neuronal physiology because postsynaptic cytosolic Cl- levels determine the outcome of GABA- and glycinergic synaptic signaling. Thus the CFTR may play a role in regulating synaptic transmission. PMID- 28835529 TI - Vowel generalization and its relation to adaptation during perturbations of auditory feedback. AB - Repeated perturbations of auditory feedback during vowel production elicit changes not only in the production of the perturbed vowel (adaptation) but also in the production of nearby vowels that were not perturbed (generalization). The finding that adaptation generalizes to other, nonperturbed vowels suggests that sensorimotor representations for vowels are not independent; instead, the goals for producing any one vowel may depend in part on the goals for other vowels. The present study investigated the dependence or independence of vowel representations by evaluating adaptation and generalization in two groups of speakers exposed to auditory perturbations of their first formant (F1) during different vowels. The speakers in both groups who adapted to the perturbation exhibited generalization in two nonperturbed vowels that were produced under masking noise. Correlation testing was performed to evaluate the relations between adaptation and generalization as well as between the generalization in the two nonperturbed vowels. These tests identified significant coupling between the F1 changes of adjacent vowels but not nonadjacent vowels. The pattern of correlation findings indicates that generalization was due in part to feedforward representations that are partly shared across adjacent vowels, possibly to maintain their acoustic contrast.NEW & NOTEWORTHY Speech adaptations to alterations, or perturbations, of auditory feedback have provided important insights into sensorimotor representations underlying speech. One finding from these studies that is yet to be accounted for is vowel generalization, which describes the effects of repeated perturbations to one vowel on the production of other vowels that were not perturbed. The present study used correlation testing to quantify the effects of changes in a perturbed vowel on neighboring (i.e., similar) nonperturbed vowels. The results identified significant correlations between the changes of adjacent, but not nonadjacent, vowel pairs. This finding suggests that generalization is partly a response to adaptation and not solely due to the auditory perturbation. PMID- 28835530 TI - Rapid visuomotor feedback gains are tuned to the task dynamics. AB - Adaptation to novel dynamics requires learning a motor memory, or a new pattern of predictive feedforward motor commands. Recently, we demonstrated the upregulation of rapid visuomotor feedback gains early in curl force field learning, which decrease once a predictive motor memory is learned. However, even after learning is complete, these feedback gains are higher than those observed in the null field trials. Interestingly, these upregulated feedback gains in the curl field were not observed in a constant force field. Therefore, we suggest that adaptation also involves selectively tuning the feedback sensitivity of the sensorimotor control system to the environment. Here, we test this hypothesis by measuring the rapid visuomotor feedback gains after subjects adapt to a variety of novel dynamics generated by a robotic manipulandum in three experiments. To probe the feedback gains, we measured the magnitude of the motor response to rapid shifts in the visual location of the hand during reaching. While the feedback gain magnitude remained similar over a larger than a fourfold increase in constant background load, the feedback gains scaled with increasing lateral resistance and increasing instability. The third experiment demonstrated that the feedback gains could also be independently tuned to perturbations to the left and right, depending on the lateral resistance, demonstrating the fractionation of feedback gains to environmental dynamics. Our results show that the sensorimotor control system regulates the gain of the feedback system as part of the adaptation process to novel dynamics, appropriately tuning them to the environment.NEW & NOTEWORTHY Here, we test whether rapid visuomotor feedback responses are selectively tuned to the task dynamics. The responses do not exhibit gain scaling, but they do vary with the level and stability of task dynamics. Moreover, these feedback gains are independently tuned to perturbations to the left and right, depending on these dynamics. Our results demonstrate that the sensorimotor control system regulates the feedback gain as part of the adaptation process, tuning them appropriately to the environment. PMID- 28835532 TI - Sensitivity of the STAT-VIEW rapid self-test and implications for use during acute HIV infection. AB - OBJECTIVES: HIV testing is an important step towards diminishing incident infections. Rapid self-tests whose use is becoming more common in France could help increase access to testing, yet could fail to diagnose HIV during acute HIV infection (AHI). The aim of the present study was to evaluate HIV-detection sensitivity of a commonly used rapid self-test (STAT-VIEW HIV1/2), compared with another point-of-care rapid test (INSTI), among patients presenting with AHI. METHODS: Individuals tested at Saint-Antoine Hospital (Paris, France) with negative or indeterminate western blot (WB) results and detectable HIV-RNA were included. Rapid tests were performed retrospectively on stored serum. Patients with and without reactive rapid tests were compared, while probability of having a reactive test was modelled across infection duration using logistic regression. RESULTS: Of the 40 patients with AHI, 23 (57.5%) had a reactive STAT-VIEW rapid test. Patients with non-reactive versus reactive tests had a significantly shorter median time since infection (p=0.01), time since onset of symptoms (p=0.009), higher proportion with Fiebig stage III versus IV (p=0.003), negative WB results (p=0.007), higher HIV-RNA levels (p=0.001) and lower CD4+ and CD8+ cell count (p=0.03, p<0.001, respectively). When examining sensitivity over the course of AHI duration, the probability of HIV detection was 75.5% at 5 weeks from HIV transmission. The INSTI provided similar results with respect to proportion of reactive tests (62.5%), determinants for non-reactive test and probability of HIV detection at 5 weeks of infection (85.0%). CONCLUSIONS: Over half of AHI patients had reactive serology using the STAT-VIEW rapid self-test when performed on serum samples. Considering that detection sensitivity increased substantially over infection time, individuals should not rely on a negative result to accurately exclude HIV infection within at least 5 weeks of potential HIV exposure. Notwithstanding strong recommendations against rapid test use during AHI, some utility in detecting HIV is observed 5-12 weeks after transmission. PMID- 28835533 TI - A phase II clinical study to assess the feasibility of self and partner anal examinations to detect anal canal abnormalities including anal cancer. AB - OBJECTIVE: Anal cancer is a common cancer among men who have sex with men (MSM); however, there is no standard screening protocol for anal cancer. We conducted a phase II clinical trial to assess the feasibility of teaching MSM to recognise palpable masses in the anal canal which is a common sign of anal cancer in men. METHODS: A clinician skilled in performing digital anorectal examinations (DARE) used a pelvic manikin to train 200 MSM, aged 27-78 years, how to do a self-anal examination (SAE) for singles or a partner anal examination (PAE) for couples. The clinician then performed a DARE without immediately disclosing results, after which the man or couple performed an SAE or PAE, respectively. Percentage agreement with the clinician DARE in addition to sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the SAE, PAE and overall. RESULTS: Men had a median age of 52 years, 42.5% were African American and 60.5% were HIV positive. DARE detected abnormalities in 12 men while the men's SAE/PAEs detected 9 of these. A total of 93.0% of men classified the health of their anal canal correctly (95% CI 89.5 to 96.5). Overall percentage agreement, sensitivity and specificity were 93.0%, 75.0% and 94.2%, respectively, while PPV and NPV were 45.0% and 98.3%, respectively. The six men who detected the abnormality had nodules/masses >=3 mm in size. More than half of men (60.5%) reported never checking their anus for an abnormality; however, after performing an SAE/PAE, 93.0% said they would repeat it in the future. CONCLUSION: These results suggest that tumours of >=3 mm may be detectable by self or partner palpation among MSM and encourage further investigation given literature suggesting a high cure rate for anal cancer tumours <=10 mm. PMID- 28835534 TI - Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G. AB - Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected. PMID- 28835531 TI - The divisive normalization model of V1 neurons: a comprehensive comparison of physiological data and model predictions. AB - The physiological responses of simple and complex cells in the primary visual cortex (V1) have been studied extensively and modeled at different levels. At the functional level, the divisive normalization model (DNM; Heeger DJ. Vis Neurosci 9: 181-197, 1992) has accounted for a wide range of single-cell recordings in terms of a combination of linear filtering, nonlinear rectification, and divisive normalization. We propose standardizing the formulation of the DNM and implementing it in software that takes static grayscale images as inputs and produces firing rate responses as outputs. We also review a comprehensive suite of 30 empirical phenomena and report a series of simulation experiments that qualitatively replicate dozens of key experiments with a standard parameter set consistent with physiological measurements. This systematic approach identifies novel falsifiable predictions of the DNM. We show how the model simultaneously satisfies the conflicting desiderata of flexibility and falsifiability. Our key idea is that, while adjustable parameters are needed to accommodate the diversity across neurons, they must be fixed for a given individual neuron. This requirement introduces falsifiable constraints when this single neuron is probed with multiple stimuli. We also present mathematical analyses and simulation experiments that explicate some of these constraints. PMID- 28835535 TI - Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8+ T cells. AB - Effective T cell responses against invading pathogens require the concerted production of three key cytokines: TNF-alpha, IFN-gamma, and IL-2. The cytokines functionally synergize, but their production kinetics widely differ. How the differential timing of expression is regulated remains, however, poorly understood. We compared the relative contribution of transcription, mRNA stability, and translation efficiency on cytokine production in murine effector and memory CD8+ T cells. We show that the immediate and ample production of TNF alpha is primarily mediated by translation of preformed mRNA through protein kinase C (PKC)-induced recruitment of mRNA to polyribosomes. Also, the initial production of IFN-gamma uses translation of preformed mRNA. However, the magnitude and subsequent expression of IFN-gamma, and of IL-2, depends on calcium induced de novo transcription and PKC-dependent mRNA stabilization. In conclusion, PKC signaling modulates translation efficiency and mRNA stability in a transcript-specific manner. These cytokine-specific regulatory mechanisms guarantee that T cells produce ample amounts of cytokines shortly upon activation and for a limited time. PMID- 28835536 TI - Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts. AB - Cancer is as unique as the person fighting it. With the exception of a few biomarker-driven therapies, patients go through rounds of trial-and-error approaches to find the best treatment. Using patient-derived cell lines, we show that zebrafish larvae xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intratumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, and angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI [5 fluorouracil(FU)+irinotecan+folinic acid] than to FOLFOX (5 FU+oxaliplatin+folinic acid), not only between isogenic tumors but also within the same tumor. We directly compared zebrafish xenografts with mouse xenografts and show that relative sensitivities obtained in zebrafish are maintained in the rodent model. Our data also illustrate how KRAS mutations can provide proliferation advantages in relation to KRASWT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish patient-derived xenografts (zPDX) and provide proof-of-concept experiments that compare response to chemotherapy and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting. PMID- 28835537 TI - XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction. AB - The M2 proton channel of influenza A is a drug target that is essential for the reproduction of the flu virus. It is also a model system for the study of selective, unidirectional proton transport across a membrane. Ordered water molecules arranged in "wires" inside the channel pore have been proposed to play a role in both the conduction of protons to the four gating His37 residues and the stabilization of multiple positive charges within the channel. To visualize the solvent in the pore of the channel at room temperature while minimizing the effects of radiation damage, data were collected to a resolution of 1.4 A using an X-ray free-electron laser (XFEL) at three different pH conditions: pH 5.5, pH 6.5, and pH 8.0. Data were collected on the Inwardopen state, which is an intermediate that accumulates at high protonation of the His37 tetrad. At pH 5.5, a continuous hydrogen-bonded network of water molecules spans the vertical length of the channel, consistent with a Grotthuss mechanism model for proton transport to the His37 tetrad. This ordered solvent at pH 5.5 could act to stabilize the positive charges that build up on the gating His37 tetrad during the proton conduction cycle. The number of ordered pore waters decreases at pH 6.5 and 8.0, where the Inwardopen state is less stable. These studies provide a graphical view of the response of water to a change in charge within a restricted channel environment. PMID- 28835538 TI - Genomic diversification of giant enteric symbionts reflects host dietary lifestyles. AB - Herbivorous surgeonfishes are an ecologically successful group of reef fish that rely on marine algae as their principal food source. Here, we elucidated the significance of giant enteric symbionts colonizing these fishes regarding their roles in the digestive processes of hosts feeding predominantly on polysiphonous red algae and brown Turbinaria algae, which contain different polysaccharide constituents. Using metagenomics, single-cell genomics, and metatranscriptomic analyses, we provide evidence of metabolic diversification of enteric microbiota involved in the degradation of algal biomass in these fishes. The enteric microbiota is also phylogenetically and functionally simple relative to the complex lignocellulose-degrading microbiota of terrestrial herbivores. Over 90% of the enzymes for deconstructing algal polysaccharides emanate from members of a single bacterial lineage, "Candidatus Epulopiscium" and related giant bacteria. These symbionts lack cellulases but encode a distinctive and lineage-specific array of mostly intracellular carbohydrases concurrent with the unique and tractable dietary resources of their hosts. Importantly, enzymes initiating the breakdown of the abundant and complex algal polysaccharides also originate from these symbionts. These are also highly transcribed and peak according to the diel lifestyle of their host, further supporting their importance and host-symbiont cospeciation. Because of their distinctive genomic blueprint, we propose the classification of these giant bacteria into three candidate genera. Collectively, our findings show that the acquisition of metabolically distinct "Epulopiscium" symbionts in hosts feeding on compositionally varied algal diets is a key niche partitioning driver in the nutritional ecology of herbivorous surgeonfishes. PMID- 28835539 TI - Motile cilia create fluid-mechanical microhabitats for the active recruitment of the host microbiome. AB - We show that mucociliary membranes of animal epithelia can create fluid mechanical microenvironments for the active recruitment of the specific microbiome of the host. In terrestrial vertebrates, these tissues are typically colonized by complex consortia and are inaccessible to observation. Such tissues can be directly examined in aquatic animals, providing valuable opportunities for the analysis of mucociliary activity in relation to bacteria recruitment. Using the squid-vibrio model system, we provide a characterization of the initial engagement of microbial symbionts along ciliated tissues. Specifically, we developed an empirical and theoretical framework to conduct a census of ciliated cell types, create structural maps, and resolve the spatiotemporal flow dynamics. Our multiscale analyses revealed two distinct, highly organized populations of cilia on the host tissues. An array of long cilia ([Formula: see text]25 [Formula: see text]m) with metachronal beat creates a flow that focuses bacteria sized particles, at the exclusion of larger particles, into sheltered zones; there, a field of randomly beating short cilia ([Formula: see text]10 [Formula: see text]m) mixes the local fluid environment, which contains host biochemical signals known to prime symbionts for colonization. This cilia-mediated process represents a previously unrecognized mechanism for symbiont recruitment. Each mucociliary surface that recruits a microbiome such as the case described here is likely to have system-specific features. However, all mucociliary surfaces are subject to the same physical and biological constraints that are imposed by the fluid environment and the evolutionary conserved structure of cilia. As such, our study promises to provide insight into universal mechanisms that drive the recruitment of symbiotic partners. PMID- 28835540 TI - Size and dielectric properties of skeletal stem cells change critically after enrichment and expansion from human bone marrow: consequences for microfluidic cell sorting. AB - The capacity of bone and cartilage to regenerate can be attributed to skeletal stem cells (SSCs) that reside within the bone marrow (BM). Given SSCs are rare and lack specific surface markers, antibody-based sorting has failed to deliver the cell purity required for clinical translation. Microfluidics offers new methods of isolating cells based on biophysical features including, but not limited to, size, electrical properties and stiffness. Here we report the characterization of the dielectric properties of unexpanded SSCs using single cell microfluidic impedance cytometry (MIC). Unexpanded SSCs had a mean size of 9.0 um; larger than the majority of BM cells. During expansion, often used to purify and increase the number of SSCs, cell size and membrane capacitance increased significantly, highlighting the importance of characterizing unaltered SSCs. In addition, MIC was used to track the osteogenic differentiation of SSCs and showed an increased membrane capacitance with differentiation. The electrical properties of primary SSCs were indistinct from other BM cells precluding its use as an isolation method. However, the current studies indicate that cell size in combination with another biophysical parameter, such as stiffness, could be used to design label-free devices for sorting SSCs with significant clinical impact. PMID- 28835541 TI - Modelling variability in cardiac electrophysiology: a moment-matching approach. AB - The variability observed in action potential (AP) cardiomyocyte measurements is the consequence of many different sources of randomness. Often ignored, this variability may be studied to gain insight into the cell ionic properties. In this paper, we focus on the study of ionic channel conductances and describe a methodology to estimate their probability density function (PDF) from AP recordings. The method relies on the matching of observable statistical moments and on the maximum entropy principle. We present four case studies using synthetic and sets of experimental AP measurements from human and canine cardiomyocytes. In each case, the proposed methodology is applied to infer the PDF of key conductances from the exhibited variability. The estimated PDFs are discussed and, when possible, compared to the true distributions. We conclude that it is possible to extract relevant information from the variability in AP measurements and discuss the limitations and possible implications of the proposed approach. PMID- 28835542 TI - Host population structure and treatment frequency maintain balancing selection on drug resistance. AB - It is a truism that antimicrobial drugs select for resistance, but explaining pathogen- and population-specific variation in patterns of resistance remains an open problem. Like other common commensals, Streptococcus pneumoniae has demonstrated persistent coexistence of drug-sensitive and drug-resistant strains. Theoretically, this outcome is unlikely. We modelled the dynamics of competing strains of S. pneumoniae to investigate the impact of transmission dynamics and treatment-induced selective pressures on the probability of stable coexistence. We find that the outcome of competition is extremely sensitive to structure in the host population, although coexistence can arise from age-assortative transmission models with age-varying rates of antibiotic use. Moreover, we find that the selective pressure from antibiotics arises not so much from the rate of antibiotic use per se but from the frequency of treatment: frequent antibiotic therapy disproportionately impacts the fitness of sensitive strains. This same phenomenon explains why serotypes with longer durations of carriage tend to be more resistant. These dynamics may apply to other potentially pathogenic, microbial commensals and highlight how population structure, which is often omitted from models, can have a large impact. PMID- 28835543 TI - Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake. AB - Intrinsic of non-alcoholic fatty liver diseases is an aberrant accumulation of triglycerides (steatosis), which occurs inhomogeneously within lobules. To improve our understanding of the mechanisms involved in this zonation patterning, we developed a mathematical multicompartment model of hepatic fatty acid metabolism accompanied by blood flow simulations. A model analysis determines the influence of the uptake process of fatty acids, the porto-central gradient of plasma fatty acid concentration, and the oxygen supply via blood on the zonation of triglyceride accumulation. From this theoretical perspective, the plasma oxygen gradient, but not the fatty acid gradient, leads the way to a zonated triglyceride accumulation by its decisive role in oxidative processes. In addition, the uptake mechanism of fatty acids seems to be fundamental for a pericentral dominance of steatosis. However, the mechanism of cellular fatty acid uptake from the blood is still under debate. Our theoretical approach supports the transporter-mediated uptake mechanism and reveals that the maximal velocity of fatty acid uptake affects the switching between a periportal and a pericentral triglyceride accumulation. Further research on hepatic fatty acid uptake is needed to push forward our understanding of aberrant triglyceride accumulation in diet-induced steatosis. PMID- 28835544 TI - Optimization of fermentation conditions for the production of curcumin by engineered Escherichia coli. AB - Curcumin is a plant secondary metabolite with outstanding therapeutic effects. Therefore, there is a great interest in developing new strategies to produce this high-value compound in a cheaper and environmentally friendly way. Curcumin heterologous production in Escherichia coli using artificial biosynthetic pathways was previously demonstrated using synthetic biology approaches. However, the culturing conditions to produce this compound were not optimized and so far only a two-step fermentation process involving the exchange of culture medium allowed high concentrations of curcumin to be obtained, which limits its production at an industrial scale. In this study, the culturing conditions to produce curcumin were evaluated and optimized. In addition, it was concluded that E. coli BL21 allows higher concentrations of curcumin to be produced than E. coli K-12 strains. Different isopropyl beta-d-thiogalactopyranoside concentrations, time of protein expression induction and substrate type and concentration were also evaluated. The highest curcumin production obtained was 959.3 uM (95.93% of per cent yield), which was 3.1-fold higher than the highest concentration previously reported. This concentration was obtained using a two-stage fermentation with lysogeny broth (LB) and M9. Moreover, terrific broth was also demonstrated to be a very interesting alternative medium to produce curcumin because it also led to high concentrations (817.7 uM). The use of this single fermentation medium represents an advantage at industrial scale and, although the final production is lower than that obtained with the LB-M9 combination, it leads to a significantly higher production of curcumin in the first 24 h of fermentation. This study allowed obtaining the highest concentrations of curcumin reported so far in a heterologous organism and is of interest for all of those working with the heterologous production of curcuminoids, other complex polyphenolic compounds or plant secondary metabolites. PMID- 28835545 TI - Rab7b modulates autophagic flux by interacting with Atg4B. AB - Autophagy (macroautophagy) is a highly conserved eukaryotic degradation pathway in which cytosolic components and organelles are sequestered by specialized autophagic membranes and degraded through the lysosomal system. The autophagic pathway maintains basal cellular homeostasis and helps cells adapt during stress; thus, defects in autophagy can cause detrimental effects. It is therefore crucial that autophagy is properly regulated. In this study, we show that the cysteine protease Atg4B, a key enzyme in autophagy that cleaves LC3, is an interactor of the small GTPase Rab7b. Indeed, Atg4B interacts and co-localizes with Rab7b on vesicles. Depletion of Rab7b increases autophagic flux as indicated by the increased size of autophagic structures as well as the magnitude of macroautophagic sequestration and degradation. Importantly, we demonstrate that Rab7b regulates LC3 processing by modulating Atg4B activity. Taken together, our findings reveal Rab7b as a novel negative regulator of autophagy through its interaction with Atg4B. PMID- 28835546 TI - ER remodeling by the large GTPase atlastin promotes vacuolar growth of Legionella pneumophila. AB - The pathogenic bacterium Legionella pneumophila replicates in host cells within a distinct ER-associated compartment termed the Legionella-containing vacuole (LCV). How the dynamic ER network contributes to pathogen proliferation within the nascent LCV remains elusive. A proteomic analysis of purified LCVs identified the ER tubule-resident large GTPase atlastin3 (Atl3, yeast Sey1p) and the reticulon protein Rtn4 as conserved LCV host components. Here, we report that Sey1/Atl3 and Rtn4 localize to early LCVs and are critical for pathogen vacuole formation. Sey1 overproduction promotes intracellular growth of L. pneumophila, whereas a catalytically inactive, dominant-negative GTPase mutant protein, or Atl3 depletion, restricts pathogen replication and impairs LCV maturation. Sey1 is not required for initial recruitment of ER to PtdIns(4)P-positive LCVs but for subsequent pathogen vacuole expansion. GTP (but not GDP) catalyzes the Sey1 dependent aggregation of purified, ER-positive LCVs in vitro Thus, Sey1/Atl3 dependent ER remodeling contributes to LCV maturation and intracellular replication of L. pneumophila. PMID- 28835548 TI - Chromatin remodeling: a complex affair. PMID- 28835549 TI - A toothless dwarf dolphin (Odontoceti: Xenorophidae) points to explosive feeding diversification of modern whales (Neoceti). AB - Toothed whales (Odontoceti) are adapted for catching prey underwater and possess some of the most derived feeding specializations of all mammals, including the loss of milk teeth (monophyodonty), high tooth count (polydonty), and the loss of discrete tooth classes (homodonty). Many extant odontocetes possess some combination of short, broad rostra, reduced tooth counts, fleshy lips, and enlarged hyoid bones-all adaptations for suction feeding upon fishes and squid. We report a new fossil odontocete from the Oligocene (approx. 30 Ma) of South Carolina (Inermorostrum xenops, gen. et sp. nov.) that possesses adaptations for suction feeding: toothlessness and a shortened rostrum (brevirostry). Enlarged foramina on the rostrum suggest the presence of enlarged lips or perhaps vibrissae. Phylogenetic analysis firmly places Inermorostrum within the Xenorophidae, an early diverging odontocete clade typified by long-snouted, heterodont dolphins. Inermorostrum is the earliest obligate suction feeder within the Odontoceti, a feeding mode that independently evolved several times within the clade. Analysis of macroevolutionary trends in rostral shape indicate stabilizing selection around an optimum rostral shape over the course of odontocete evolution, and a post-Eocene explosion in feeding morphology, heralding the diversity of feeding behaviour among modern Odontoceti. PMID- 28835550 TI - Perception of the average size of multiple objects in chimpanzees (Pan troglodytes). AB - Humans can extract statistical information, such as the average size of a group of objects or the general emotion of faces in a crowd without paying attention to any individual object or face. To determine whether summary perception is unique to humans, we investigated the evolutional origins of this ability by assessing whether chimpanzees, which are closely related to humans, can also determine the average size of multiple visual objects. Five chimpanzees and 18 humans were able to choose the array in which the average size was larger, when presented with a pair of arrays, each containing 12 circles of different or the same sizes. Furthermore, both species were more accurate in judging the average size of arrays consisting of 12 circles of different or the same sizes than they were in judging the average size of arrays consisting of a single circle. Our findings could not be explained by the use of a strategy in which the chimpanzee detected the largest or smallest circle among those in the array. Our study provides the first evidence that chimpanzees can perceive the average size of multiple visual objects. This indicates that the ability to compute the statistical properties of a complex visual scene is not unique to humans, but is shared between both species. PMID- 28835547 TI - IFITM3 requires an amphipathic helix for antiviral activity. AB - Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that blocks virus fusion with cell membranes. IFITM3 has been suggested to alter membrane curvature and fluidity, though its exact mechanism of action is unclear. Using a bioinformatic approach, we predict IFITM3 secondary structures and identify a highly conserved, short amphipathic helix within a hydrophobic region of IFITM3 previously thought to be a transmembrane domain. Consistent with the known ability of amphipathic helices to alter membrane properties, we show that this helix and its amphipathicity are required for the IFITM3-dependent inhibition of influenza virus, Zika virus, vesicular stomatitis virus, Ebola virus, and human immunodeficiency virus infections. The homologous amphipathic helix within IFITM1 is also required for the inhibition of infection, indicating that IFITM proteins possess a conserved mechanism of antiviral action. We further demonstrate that the amphipathic helix of IFITM3 is required to block influenza virus hemagglutinin-mediated membrane fusion. Overall, our results provide evidence that IFITM proteins utilize an amphipathic helix for inhibiting virus fusion. PMID- 28835551 TI - Land cover and forest connectivity alter the interactions among host, pathogen and skin microbiome. AB - Deforestation has detrimental consequences on biodiversity, affecting species interactions at multiple scales. The associations among vertebrates, pathogens and their commensal/symbiotic microbial communities (i.e. microbiomes) have important downstream effects for biodiversity conservation, yet we know little about how deforestation contributes to changes in host microbial diversity and pathogen abundance. Here, we tested the effects of landcover, forest connectivity and infection by the chytrid fungus Batrachochytrium dendrobatidis (Bd) on amphibian skin bacterial diversity along deforestation gradients in Brazilian landscapes. If disturbance to natural habitat alters skin microbiomes as it does in vertebrate host communities, then we would expect higher host bacterial diversity in natural forest habitats. Bd infection loads are also often higher in these closed-canopy forests, which may in turn impact skin-associated bacterial communities. We found that forest corridors shaped composition of host skin microbiomes; high forest connectivity predicted greater similarity of skin bacterial communities among host populations. In addition, we found that host skin bacterial diversity and Bd loads increased towards natural vegetation. Because symbiotic bacteria can potentially buffer hosts from Bd infection, we also evaluated the bi-directional microbiome-Bd link but failed to find a significant effect of skin bacterial diversity reducing Bd infections. Although weak, we found support for Bd increasing bacterial diversity and/or for core bacteria dominance reducing Bd loads. Our research incorporates a critical element in the study of host microbiomes by linking environmental heterogeneity of landscapes to the host-pathogen-microbiome triangle. PMID- 28835552 TI - Patterns of predator neophobia: a meta-analytic review. AB - Neophobia, the fear of novel stimuli, plays a major role in animal ecology. Here, we review studies on predator neophobia and explore its underlying patterns within an ecological framework. Predator neophobia is typically assessed by observing behaviours in novel areas that bring potential risk from unknown predators, or by observing behaviours towards certain kinds of objects and odours that are novel. We conducted a literature review across taxa, surveying research on baseline and induced neophobia versus controls. We calculated effect sizes for the intensity of neophobic responses, and categorized data according to six factors (taxa, age class, background type, trophic position, test cue type and experimental treatment type). While accounting for each of the other factors, we found that baseline neophobia was stronger among birds and mammals, and towards novel areas, relative to other taxa and cue types. Baseline neophobia was lower for wild-caught animals and for those that were higher in trophic position, compared with those reared in captivity and from lower trophic levels. By contrast, induced neophobia was similar in intensity across taxa, background types and testing cue types, while again being lower among upper trophic-level members and among juvenile animals. Although induced neophobia occurred across all treatment types, brain lesions induced stronger neophobia than predation risk or social isolation. We discuss potential mechanisms underlying these results and highlight gaps in the literature. PMID- 28835553 TI - Genetic and linguistic histories in Central Asia inferred using approximate Bayesian computations. AB - Linguistic and genetic data have been widely compared, but the histories underlying these descriptions are rarely jointly inferred. We developed a unique methodological framework for analysing jointly language diversity and genetic polymorphism data, to infer the past history of separation, exchange and admixture events among human populations. This method relies on approximate Bayesian computations that enable the identification of the most probable historical scenario underlying each type of data, and to infer the parameters of these scenarios. For this purpose, we developed a new computer program PopLingSim that simulates the evolution of linguistic diversity, which we coupled with an existing coalescent-based genetic simulation program, to simulate both linguistic and genetic data within a set of populations. Applying this new program to a wide linguistic and genetic dataset of Central Asia, we found several differences between linguistic and genetic histories. In particular, we showed how genetic and linguistic exchanges differed in the past in this area: some cultural exchanges were maintained without genetic exchanges. The methodological framework and the linguistic simulation tool developed here can be used in future work for disentangling complex linguistic and genetic evolutions underlying human biological and cultural histories. PMID- 28835554 TI - Evolution of a predator-induced, nonlinear reaction norm. AB - Inducible, anti-predator traits are a classic example of phenotypic plasticity. Their evolutionary dynamics depend on their genetic basis, the historical pattern of predation risk that populations have experienced and current selection gradients. When populations experience predators with contrasting hunting strategies and size preferences, theory suggests contrasting micro-evolutionary responses to selection. Daphnia pulex is an ideal species to explore the micro evolutionary response of anti-predator traits because they face heterogeneous predation regimes, sometimes experiencing only invertebrate midge predators and other times experiencing vertebrate fish and invertebrate midge predators. We explored plausible patterns of adaptive evolution of a predator-induced morphological reaction norm. We combined estimates of selection gradients that characterize the various habitats that D. pulex experiences with detail on the quantitative genetic architecture of inducible morphological defences. Our data reveal a fine scale description of daphnid defensive reaction norms, and a strong covariance between the sensitivity to cues and the maximum response to cues. By analysing the response of the reaction norm to plausible, predator-specific selection gradients, we show how in the context of this covariance, micro evolution may be more uniform than predicted from size-selective predation theory. Our results show how covariance between the sensitivity to cues and the maximum response to cues for morphological defence can shape the evolutionary trajectory of predator-induced defences in D. pulex. PMID- 28835555 TI - Local and regional controls of phylogenetic structure at the high-latitude range limits of corals. AB - Understanding how range-edge populations will respond to climate change is an urgent research priority. Here, we used a phylogenetic community ecology approach to examine how ecological and evolutionary processes shape biodiversity patterns of scleractinian corals at their high-latitude range limits in eastern Australia. We estimated phylogenetic signal in seven ecologically important functional traits and conducted tests of phylogenetic structure at local and regional scales using the net relatedness (NRI) and nearest taxon indices (NTI) for the presence/absence and abundance data. Regional tests showed light phylogenetic clustering, indicating that coral species found in this subtropical-to-temperate transition zone are more closely related to each other than are species on the nearby, more northerly Great Barrier Reef. Local tests revealed variable patterns of phylogenetic clustering and overdispersion and higher than expected phylogenetic turnover among sites. In combination, these results are broadly consistent with the hierarchical filtering model, whereby species pass through a regional climatic filter based on their tolerances for marginal conditions and subsequently segregate into local assemblages according to the relative strength of habitat filtering and species interactions. Conservatism of tested traits suggests that corals will likely track their niches with climate change. Nevertheless, high turnover of lineages among sites indicates that range shifts will probably vary among species and highlights the vulnerability and conservation significance of high-latitude reefs. PMID- 28835556 TI - Stabilizing selection on individual pattern elements of aposematic signals. AB - Warning signal variation is ubiquitous but paradoxical: low variability should aid recognition and learning by predators. However, spatial variability in the direction and strength of selection for individual elements of the warning signal may allow phenotypic variation for some components, but not others. Variation in selection may occur if predators only learn particular colour pattern components rather than the entire signal. Here, we used a nudibranch mollusc, Goniobranchus splendidus, which exhibits a conspicuous red spot/white body/yellow rim colour pattern, to test this hypothesis. We first demonstrated that secondary metabolites stored within the nudibranch were unpalatable to a marine organism. Using pattern analysis, we demonstrated that the yellow rim remained invariable within and between populations; however, red spots varied significantly in both colour and pattern. In behavioural experiments, a potential fish predator, Rhinecanthus aculeatus, used the presence of the yellow rims to recognize and avoid warning signals. Yellow rims remained stable in the presence of high genetic divergence among populations. We therefore suggest that how predators learn warning signals may cause stabilizing selection on individual colour pattern elements, and will thus have important implications on the evolution of warning signals. PMID- 28835558 TI - Nest prospecting brown-headed cowbirds 'parasitize' social information when the value of personal information is lacking. AB - Brood parasites face considerable cognitive challenges in locating and selecting host nests for their young. Here, we test whether female brown-headed cowbirds, Molothrus ater, could use information acquired from observing the nest prospecting patterns of conspecifics to influence their own patterns of nest selection. In laboratory-based experiments, we created a disparity in the amount of personal information females had about the quality of nests. Females with less personal information about the quality of two nests spent more time investigating the nest that more knowledgeable females investigated. Furthermore, there was a strong negative relationship between individual's ability to track nest quality using personal information and their tendency to copy others. These two contrasting strategies for selecting nests are equally effective, but lead to different patterns of parasitism. PMID- 28835557 TI - A hypothesis on a role of oxytocin in the social mechanisms of speech and vocal learning. AB - Language acquisition in humans and song learning in songbirds naturally happen as a social learning experience, providing an excellent opportunity to reveal social motivation and reward mechanisms that boost sensorimotor learning. Our knowledge about the molecules and circuits that control these social mechanisms for vocal learning and language is limited. Here we propose a hypothesis of a role for oxytocin (OT) in the social motivation and evolution of vocal learning and language. Building upon existing evidence, we suggest specific neural pathways and mechanisms through which OT might modulate vocal learning circuits in specific developmental stages. PMID- 28835559 TI - Mechanics of evolutionary digit reduction in fossil horses (Equidae). AB - Digit reduction is a major trend that characterizes horse evolution, but its causes and consequences have rarely been quantitatively tested. Using beam analysis on fossilized centre metapodials, we tested how locomotor bone stresses changed with digit reduction and increasing body size across the horse lineage. Internal bone geometry was captured from 13 fossil horse genera that covered the breadth of the equid phylogeny and the spectrum of digit reduction and body sizes, from Hyracotherium to Equus To account for the load-bearing role of side digits, a novel, continuous measure of digit reduction was also established-toe reduction index (TRI). Our results show that without accounting for side digits, three-toed horses as late as Parahippus would have experienced physiologically untenable bone stresses. Conversely, when side digits are modelled as load bearing, species at the base of the horse radiation through Equus probably maintained a similar safety factor to fracture stress. We conclude that the centre metapodial compensated for evolutionary digit reduction and body mass increases by becoming more resistant to bending through substantial positive allometry in internal geometry. These results lend support to two historical hypotheses: that increasing body mass selected for a single, robust metapodial rather than several smaller ones; and that, as horse limbs became elongated, the cost of inertia from the side toes outweighed their utility for stabilization or load-bearing. PMID- 28835560 TI - The processing of images of biological threats in visual short-term memory. AB - The idea that there is enhanced memory for negatively, emotionally charged pictures was examined. Performance was measured under rapid, serial visual presentation (RSVP) conditions in which, on every trial, a sequence of six photo images was presented. Briefly after the offset of the sequence, two alternative images (a target and a foil) were presented and participants attempted to choose which image had occurred in the sequence. Images were of threatening and non threatening cats and dogs. The target depicted either an animal expressing an emotion distinct from the other images, or the sequences contained only images depicting the same emotional valence. Enhanced memory was found for targets that differed in emotional valence from the other sequence images, compared to targets that expressed the same emotional valence. Further controls in stimulus selection were then introduced and the same emotional distinctiveness effect obtained. In ruling out possible visual and attentional accounts of the data, an informal dual route topic model is discussed. This places emphasis on how visual short-term memory reveals a sensitivity to the emotional content of the input as it unfolds over time. Items that present with a distinctive emotional content stand out in memory. PMID- 28835563 TI - Photo Quiz: A 55-Year-Old Male with Hoarseness of Voice and Laryngeal Mass. PMID- 28835562 TI - Social disappointment explains chimpanzees' behaviour in the inequity aversion task. AB - Chimpanzees' refusal of less-preferred food when an experimenter has previously provided preferred food to a conspecific has been taken as evidence for a sense of fairness. Here, we present a novel hypothesis-the social disappointment hypothesis-according to which food refusals express chimpanzees' disappointment in the human experimenter for not rewarding them as well as they could have. We tested this hypothesis using a two-by-two design in which food was either distributed by an experimenter or a machine and with a partner present or absent. We found that chimpanzees were more likely to reject food when it was distributed by an experimenter rather than by a machine and that they were not more likely to do so when a partner was present. These results suggest that chimpanzees' refusal of less-preferred food stems from social disappointment in the experimenter and not from a sense of fairness. PMID- 28835564 TI - Prevalence and Predictive Values: a Micro-Comic Strip. PMID- 28835561 TI - Rapid functional and evolutionary changes follow gene duplication in yeast. AB - Duplication of genes or genomes provides the raw material for evolutionary innovation. After duplication a gene may be lost, recombine with another gene, have its function modified or be retained in an unaltered state. The fate of duplication is usually studied by comparing extant genomes and reconstructing the most likely ancestral states. Valuable as this approach is, it may miss the most rapid evolutionary events. Here, we engineered strains of Saccharomyces cerevisiae carrying tandem and non-tandem duplications of the singleton gene IFA38 to monitor (i) the fate of the duplicates in different conditions, including time scale and asymmetry of gene loss, and (ii) the changes in fitness and transcriptome of the strains immediately after duplication and after experimental evolution. We found that the duplication brings widespread transcriptional changes, but a fitness advantage is only present in fermentable media. In respiratory conditions, the yeast strains consistently lose the non tandem IFA38 gene copy in a surprisingly short time, within only a few generations. This gene loss appears to be asymmetric and dependent on genome location, since the original IFA38 copy and the tandem duplicate are retained. Overall, this work shows for the first time that gene loss can be extremely rapid and context dependent. PMID- 28835565 TI - The Brief Case: Scopulariopsis Endocarditis-a Case of Mistaken Takayasu's Arteritis. PMID- 28835566 TI - Correction for Eck et al., "Robust Microbiota-Based Diagnostics for Inflammatory Bowel Disease". PMID- 28835567 TI - Closing the Brief Case: Scopulariopsis Endocarditis-a Case of Mistaken Takayasu's Arteritis. PMID- 28835568 TI - Answer to September 2017 Photo Quiz. PMID- 28835569 TI - Zebrafish nephrosin helps host defence against Escherichia coli infection. AB - Neutrophils play important roles in innate immunity and are mainly dependent on various enzyme-containing granules to kill engulfed microorganisms. Zebrafish nephrosin (npsn) is specifically expressed in neutrophils; however, its function is largely unknown. Here, we generated an npsn mutant (npsnsmu5 ) via CRISPR/Cas9 to investigate the in vivo function of Npsn. The overall development and number of neutrophils remained unchanged in npsn-deficient mutants, whereas neutrophil antibacterial function was defective. Upon infection with Escherichia coli, the npsnsmu5 mutants exhibited a lower survival rate and more severe bacterial burden, as well as augmented inflammatory response to challenge with infection when compared with wild-type embryos, whereas npsn-overexpressing zebrafish exhibited enhanced host defence against E. coli infection. These findings demonstrated that zebrafish Npsn promotes host defence against bacterial infection. Furthermore, our findings suggested that npsn-deficient and overexpressing zebrafish might serve as effective models of in vivo innate immunity. PMID- 28835572 TI - Time-spatial Labeling Inversion Pulse (Time-SLIP) with Pencil Beam Pulse: A Selective Labeling Technique for Observing Cerebrospinal Fluid Flow Dynamics. AB - We assessed labeling region selectivity on time-spatial labeling inversion pulse (Time-SLIP) with pencil beam pulse (PB Time-SLIP) for the use of visualizing cerebrospinal fluid (CSF) flow dynamics. We compared the selectivity of labeling to the third and fourth ventricles between PB Time-SLIP and conventional Time SLIP (cTime-SLIP) in eight volunteers and one patient using a 1.5T MRI. PB Time SLIP provided more selective labeling in CSF than cTime-SLIP, particularly in complex anatomical regions. PMID- 28835571 TI - An ancient FMRFamide-related peptide-receptor pair induces defence behaviour in a brachiopod larva. AB - Animal behaviour often comprises spatially separated sub-reactions and even ciliated larvae are able to coordinate sub-reactions of complex behaviours (metamorphosis, feeding). How these sub-reactions are coordinated is currently not well understood. Neuropeptides are potential candidates for triggering larval behaviour. However, although their immunoreactivity has been widely analysed, their function in trochozoan larvae has only been studied for a few cases. Here, we investigate the role of neuropeptides in the defence behaviour of brachiopod larvae. When mechanically disturbed, the planktonic larvae of Terebratalia transversa protrude their stiff chaetae and sink down slowly. We identified endogenous FLRFamide-type neuropeptides (AFLRFamide and DFLRFamide) in T. transversa larvae and show that the protrusion of the chaetae as well as the sinking reaction can both be induced by each of these peptides. This also correlates with the presence of FLRFamidergic neurons in the apical lobe and adjacent to the trunk musculature. We deorphanized the AFLRFamide/DFLRFamide receptor and detected its expression in the same tissues. Furthermore, the ability of native and modified FLRFamide-type peptides to activate this receptor was found to correspond with their ability to trigger behavioural responses. Our results show how FLRFamide-type neuropeptides can induce two coherent sub reactions in a larva with a simple nervous system. PMID- 28835570 TI - AMP-activated protein kinase: a therapeutic target in intestinal diseases. AB - Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a highly conserved energy sensor, has a crucial role in cardiovascular, neurodegenerative and inflammatory diseases, as well as in cancer and metabolic disorders. Accumulating studies have demonstrated that AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine, indicating an essential role of AMPK in intestinal health. AMPK inactivation is an aetiological factor in intestinal dysfunctions. This review summarizes the favourable outcomes of AMPK activation on intestinal health, and discusses AMPK as a potential therapeutic target for intestinal diseases. PMID- 28835573 TI - Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer. AB - Thymidylate synthase (TS) is essential in thymidylate biosynthesis and DNA replication. Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in pyrimidine catabolism and is important in catabolism of 5-fluorouracil (5-FU). The significance of TS and DPD expressed in lung cancer remains controversial. Here we analyzed the relationship between TS and DPD expression and clinicopathological features of lung cancer. Enzyme-linked immunosorbent assays (ELISAs) were used to measure TS and DPD levels in paired tumor and non-tumor lung tissues obtained from 168 patients (107 adenocarcinomas, 39 squamous cell carcinomas, and 22 others), who had operations at the Shinshu University Hospital from 2004 to 2007 and were followed up for a median of 57.0 months. TS and DPD expression levels were higher in tumor tissues, and TS expression levels were significantly lower in adenocarcinomas than those in other subtypes. In addition, patients with low TS levels survived longer compared with patents with high TS levels. By contrast, DPD expression levels were not correlated with overall patient survival. Importantly, patients with low TS and DPD levels exhibited significantly prolonged survival than those with high TS and DPD. Among the 168 patients, 59 patients were treated with tegafur-uracil (UFT), a DPD-inhibitory fluoropyrimidine, and the UFT-treated patients with high TS and high DPD levels showed worst prognosis. Our study demonstrates a significant correlation between low TS expression levels and long-term prognosis of patients with lung cancer. Thus, ELISA is a clinically useful method to measure TS and DPD expression in lung cancer tissues. PMID- 28835574 TI - Validating the short measure of the Effort-Reward Imbalance Questionnaire in older workers in the context of New Zealand. AB - OBJECTIVES: The objective of this study was to validate a short version of the Effort-Reward-Imbalance (ERI) questionnaire in the context of New Zealand among older full-time and part-time employees. METHODS: Data were collected from 1694 adults aged 48-83 years (mean 60 years, 53% female) who reported being in full- or part-time paid employment in the 2010 wave of the New Zealand Health, Work and Retirement study. Scale reliability was evaluated by item-total correlations and Cronbach's alpha. Factorial validity was assessed using multi-group confirmatory factor analyses assessing nested models of configural, metric, scalar and strict invariance across full- and part-time employment groups. Logistic regressions estimated associations of effort-reward ratio and over-commitment with poor physical/mental health, and depressive symptoms. RESULTS: Internal consistency of ERI scales was high across employment groups: effort 0.78-0.76; reward 0.81-0.77, and over-commitment 0.83-0.80. The three-factor model displayed acceptable fit in the overall sample (X2/df = 10.31; CFI = 0.95; TLI = 0.94; RMSEA = 0.075), and decrements in model fit indices provided evidence for strict invariance of the three-factor ERI model across full-time and part-time employment groups. High effort-reward ratio scores were consistently associated with poor mental health and depressive symptoms for both employment groups. High over-commitment was associated with poor mental health and depressive symptoms in both groups and also with poor physical health in the full-time employment group. CONCLUSIONS: The short ERI questionnaire appears to be a valid instrument to assess adverse psychosocial work characteristics in old full-time and part-time employees in New Zealand. PMID- 28835575 TI - Reliability of smartphone-based gait measurements for quantification of physical activity/inactivity levels. AB - OBJECTIVES: Objective measurements using built-in smartphone sensors that can measure physical activity/inactivity in daily working life have the potential to provide a new approach to assessing workers' health effects. The aim of this study was to elucidate the characteristics and reliability of built-in step counting sensors on smartphones for development of an easy-to-use objective measurement tool that can be applied in ergonomics or epidemiological research. METHODS: To evaluate the reliability of step counting sensors embedded in seven major smartphone models, the 6-minute walk test was conducted and the following analyses of sensor precision and accuracy were performed: 1) relationship between actual step count and step count detected by sensors, 2) reliability between smartphones of the same model, and 3) false detection rates when sitting during office work, while riding the subway, and driving. RESULTS: On five of the seven models, the inter-class correlations coefficient (ICC (3,1)) showed high reliability with a range of 0.956-0.993. The other two models, however, had ranges of 0.443-0.504 and the relative error ratios of the sensor-detected step count to the actual step count were +/-48.7%-49.4%. The level of agreement between the same models was ICC (3,1): 0.992-0.998. The false detection rates differed between the sitting conditions. CONCLUSIONS: These results suggest the need for appropriate regulation of step counts measured by sensors, through means such as correction or calibration with a predictive model formula, in order to obtain the highly reliable measurement results that are sought in scientific investigation. PMID- 28835576 TI - Serial Arterial Spin Labeling May Be Useful in Assessing the Therapeutic Course of Cerebral Venous Thrombosis: Case Reports. AB - We report two cases of cerebral venous thrombosis (CVT) which serial arterial spin labeling (ASL) was useful in evaluating the clinical course of the disease. A 48-year-old female presented with acute seizure, and was diagnosed as transverse-sigmoid sinus thrombosis. ASL imaging revealed low signal intensity in the right temporal lobe, suggesting the decreased perfusion by elevated venous pressure. Soon after the treatment, while the development of venous collateral has not fully observed by magnetic resonance (MR) angiography, low ASL signal within the right temporal lobe have shown remarkable improvement. A 65-year-old female presented with vomiting and subsequent seizure was diagnosed as superior sagittal sinus thrombosis. The low ASL signal within the right frontal lobe seen in the acute stage improved to the normal level by the course of time, before the good collateral can be seen by MR angiography. This is the first report to assess the sequential change of the cerebral perfusion of CVT by ASL, and ASL may provide additional useful information in combination with conventional modalities. PMID- 28835577 TI - Prevalence of lung function impairment among Greek cement production workers: a cross-sectional study. AB - Greece is a significant cement producing country. The aim of this study was to investigate the prevalence and risk factors of lung function impairment among Greek cement workers. One hundred thirty- seven cement production workers participated in this study. In addition, 110 employees not exposed to cement dust comprised the control group. The concentration of cement total dust at workplace varied from 1.1 to 11.6 mg/m3. In only one of the measurements, the Threshold Limit Level of 10 mg/m3 has been exceeded. Cement production workers presented a higher prevalence of FEV1<80% in comparison to controls (13.9% vs. 2.7%; Chi Square Test; p=0.002). Multivariate analysis has shown that cement production workers have recorded an almost 5 fold risk of low lung function, as expressed by FEV1<80%, in comparison to the reference population OR=4.92; 95% C.I.=1.22 12.62). Current smoking was associated with an almost 4- fold increased risk of FEV1<80% (OR=3.91;95% C.I.=1.32-11.56). In conclusion, we found a high prevalence of impaired lung function among Greek cement production workers, despite the fact that total and inhalable dust levels were below the occupational exposure limits. PMID- 28835578 TI - Altered immune responses in broiler chicken husbandry workers and their association with endotoxin exposure. AB - Exposure to bioaerosols in indoor animal farms associates with respiratory illnesses, but little is known about the immune modulation to chicken farmers. This study aimed to compare the general immunity of chicken farmers with those of control subjects with non-agricultural jobs. Blood taken from the farmers and controls was subjected to plasma IgE and IgG subclass measurements. Isolated peripheral blood mononuclear cells (PBMC) were stimulated and cytokine production was measured. Indoor total and respirable dust levels and their endotoxin (LPS) and aflatoxin (AF) levels in the farms were measured. In total, 29 chicken farmers on 19 farms and 14 age- and sex-matched office workers participated. Hematological differences were not observed. The farmers tended to have higher serum IgE and IgG subclass levels with significance for IgG1. The cytokines released by PBMC from farmers indicated skewing toward Type-2 helper T-cell responses: interferon (IFN)-gamma:interleukin (IL)-4 and IFNgamma:IL-13 ratios were significantly lower than for control PBMC. The farms had 707.1 EU/m3 LPS in total dust, and 15.8 EU/m3 LPS in respirable dust. Farmers exhibited immune skewing towards allergic immune responses that correlated with the LPS levels on their farms. Chicken farmers may be at risk of respiratory allergies due to occupational endotoxin exposure. PMID- 28835579 TI - Additional Value of Brachial-Ankle Pulse Wave Velocity to Single-Photon Emission Computed Tomography in the Diagnosis of Coronary Artery Disease. AB - AIM: The aim of this study was to investigate whether information on arterial stiffness can improve the value of single-photon emission computed tomography (SPECT) in the detection of obstructive coronary artery disease (CAD). METHODS: A total of 233 patients (age: 62.2+/-10.8 years, 60.3% males) with detected ischemia on SPECT undergoing invasive coronary angiography (ICA) and brachial ankle pulse wave velocity (baPWV) measurement within a month was retrospectively reviewed. RESULTS: Of the 233 patients, 190 (81.5%) had obstructive CAD (>=50% luminal stenosis). The difference in baPWV according to the presence of obstructive CAD was significant in patients in the mild ischemia group [summed stress score (SSS): 4-8] (1,770+/-364 cm versus 1,490+/-328 cm, p<0.001) but not in the moderate (SSS: 9-13) or severe (SSS: >=14) ischemia groups (p>0.05 for each). Receiver operating characteristic curve analyses showed that the diagnostic value of baPWV for obstructive CAD was significant only in patients in the mild ischemia group (area under curve: 0.714; p=0.001) but not in the moderate or severe ischemia groups (p>0.05 for each). Adding information on baPWV to SPECT results and clinical parameters significantly increased diagnostic accuracy in the detection of obstructive CAD in patients with mild ischemia (integrated discrimination improvement p=0.006) but not in those with moderate or severe ischemia on SPECT (p>0.05 for each). CONCLUSIONS: The results of this study suggest that baPWV may have additional value to SPECT for the detection of obstructive CAD, especially in patients with mild ischemia on SPECT. PMID- 28835580 TI - Epoxyeicosatrienoic Acids are Mediated by EPHX2 Variants and may be a Predictor of Early Neurological Deterioration in Acute Minor Ischemic Stroke. AB - AIM: To investigatethe association of plasma epoxyeicosatrienoic acids (EETs) with early neurologic deterioration (END), and whether EETs are mediated by EPHX2 variants in patients with minor ischemic stroke (MIS). METHOD: This was a prospective, multi-center observational study in patients with acute MIS in the Chinese population.Plasma EETs levels were measured on admission. Single nucleotide polymorphisms (SNPs) of EPHX2 rs751141 were genotyped using mass spectrometry. The primary outcome was END within 10 days after admission. END was defined as an increase in NIHSS of 2 or more points. The degree of disability was assessed using the modified Rankin Scale (mRS) at 3 months after admission. RESULTS: A total of 322 patients were enrolled, of which 85 patients (26.4%) experienced END. The mean EETs level was 64.1+/-7.5 nmol/L. EETs levels were significantly lower in patients with END compared to patients without END. Frequency of EPHX2 rs751141 GG was higher in patients with END than in patients without END, and EPHX2 rs751141 GG genotype was associated with lower EETs levels. Low level (<64.4 nmol/L) of EETs was an independent predictor of END (first and second quartiles) in multivariate analyses. END was associated with a higher risk of poor outcome (mRS scores 3-6) at 3 months. CONCLUSION: END is fairly common and associated with poor outcomes in acute MIS. EPHX2 variants may mediate EETs levels, and low levels of EETs may be a predictor for END in acute MIS. PMID- 28835581 TI - Carotid Artery Parameters After Combined Exercise Training in Women with Sarcopenic Obesity. PMID- 28835583 TI - Aneurysmal Subarachnoid Hemorrhage in the Elderly over Age 75: A Systematic Review. AB - The number of elderly patients with an aneurysmal subarachnoid hemorrhage (aSAH) has been increasing in aging- or aged societies in many countries. A treatment strategy for the elderly with aSAH has not been established, although many studies have been published emphasizing poor outcome for aSAH. The aim of this study was to analyze the factors and treatments affecting outcome in aSAH in the elderly in a systematic review of the literature by investigating patients over age 75. A literature search was done for "elderly aSAH" in PubMed and Embase. Literature with a clear description of treatment measures for aneurysmal occlusion and outcome was selected. Twelve studies, consisted of 816 cases, met the eligibility criteria. Patient characteristics included 83.2% female, 33.8% poor clinical grade on admission, 57.1% Fischer group 3, and 41% internal carotid artery aneurysm. As complications, symptomatic vasospasm was seen in 25.5% of patients, hydrocephalus in 31.1%, and medical complication in 38.4%. Favorable outcome was 35.0% in total, 45.3% for clipping, 36.3% for coiling, and 9.0% for conservative treatment. Several studies by multivariate analysis indicated that poor clinical grade on admission could be a risk factor for neurological outcome and mortality. Advanced age and selection of conservative treatment without aneurysmal occlusion could be a risk factor for mortality. Patients under age 85 with good clinical grade on admission can be candidates for treatment of aneurysm repair. However, treatment for patients over age 85 or with poor clinical grade should be carefully determined. PMID- 28835582 TI - n-3 Polyunsaturated Fatty Acids: Promising Nutrients for Preventing Cardiovascular Disease. AB - The adoption of the Western-style diet, with decreased fish intake and lack of exercise, has increased the prevalence of cardiovascular disease (CVD) in Japan. Statin treatment has been established to reduce the risk of cardiovascular events; however, 60%-70% of these events occur despite its use. Thus, the residual risk for CVD should be identified and resolved to reduce further cardiovascular events. The serum levels of n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid and docosahexaenoic acid, are reportedly associated with an increased incidence of cardiovascular events and mortality, whereas the addition of n-3 PUFA treatment to the statin treatment decreases cardiovascular events. Similar to statins, n-3 PUFAs have pleiotropic effects in addition to lipid-modifying effects. Pre-clinical and clinical studies have shown that n-3 PUFAs prevent cardiovascular events by ameliorating endothelial function and attenuating lipid accumulation, vascular inflammation, and macrophage recruitment, thereby causing coronary plaque development and rupture. Taken together, n-3 PUFAs are comprehensively able to attenuate the atherogenic response. Therefore, n-3 PUFA intake is recommended to prevent cardiovascular events, particularly in patients with multiple cardiovascular risk factors. PMID- 28835584 TI - Role of Glyceraldehyde-Derived AGEs and Mitochondria in Superoxide Production in Femoral Artery of OLETF Rat and Effects of Pravastatin. AB - A complication of diabetes mellitus is the over-production of vascular superoxides, which contribute to the development of arteriosclerosis and peripheral arterial disease (PAD). Hyperglycemia induces the formation and accumulation of advanced glycation end-products (AGEs), which in turn stimulate vascular superoxide production. The mechanism underlying AGE-mediated vascular superoxide production remains to be clarified in lower limb complications associated with diabetes. In the present study, we investigated the role of AGEs and the mitochondrial respiratory complex in superoxide production in femoral arteries using the type 2 diabetes model Otsuka Long-Evans Tokushima Fatty (OLETF) rats [vs. non-diabetic Long-Evans Tokushima Otsuka (LETO) rats]. The effects of in vivo administration of pravastatin on superoxide production in femoral arteries were also examined. Using chemiluminescent assays, luminescence microscopy, and competitive enzyme-linked immunosorbent assay (ELISA), we determined that vascular superoxide production and serum glyceraldehyde-derived AGEs (Glycer-AGEs) increased in OLETF rats. Pravastatin inhibited these responses without changing serum total cholesterol concentrations. The mitochondrial complex II inhibitor thenoyltrifluoroacetone (TTFA) also inhibited vascular superoxide production. Application of Glycer-AGEs in situ increased superoxide production in the vascular wall of femoral arteries from pravastatin-treated OLETF rats, which was then inhibited by TTFA. These results suggest that hyperglycemia increases serum Glycer-AGEs, which subsequently induce superoxide production in the femoral artery of OLETF rats in a mitochondrial complex II dependent manner. Collectively, our results have partially elucidated the pathological mechanisms leading to diabetes-related PAD, and indicate dual beneficial actions of pravastatin for the prevention of oxidative damage to the vascular wall. PMID- 28835585 TI - The History and Future of Unlinked Total Elbow Arthroplasty. AB - Unlinked total elbow arthroplasty (TEA), which has no mechanical connection between the humeral and ulnar components, has theoretical advantages based on its near-normal elbow kinematics and the preservation of bone stock. Unlinked TEA is appropriate only for patients who have limited bone loss or limited deformity and good ligamentous function. This is because postoperative instability has been a major complication of unlinked prostheses. The concept and goal of unlinked TEA is to share the loading stress on the bone implant interface with the surrounding tissues. Although the loosening rate of unlinked prostheses theoretically should be lower than that of linked prostheses (which have a mechanical connection between the humeral and ulnar components), there is no clear evidence that unlinked TEAs are superior to linked TEAs in this respect. However, we believe that primary TEA should be performed using an unlinked TEA, especially for younger patients, because revision surgery for unlinked TEA results in longer prosthesis survival than revision surgery for linked TEA. Improvement of the design of unlinked prostheses and the introduction of less invasive surgical techniques are required to reduce postoperative instability. PMID- 28835586 TI - Effects of Additive Tolvaptan vs. Increased Furosemide on Heart Failure With Diuretic Resistance and Renal Impairment - Results From the K-STAR Study. AB - BACKGROUND: Although diuretic resistance leading to residual congestion is a known predictor of a poorer heart failure (HF) prognosis, better therapeutic strategies for effective and safe decongestion have not been established.Methods and Results:In this study, 81 HF patients with fluid retention (despite taking >=40 mg/day furosemide (FUR)), with an estimated glomerular filtration rate <45 mL/min/1.73 m2, were randomized into 2 groups and administered either <=15 mg/day additive tolvaptan (TLV) or <=40 mg/day increased FUR for 7 days. Changes in urine volume between baseline and mean urine volume during treatment were significantly higher in the TLV than FUR group (P=0.0003). Although there was no significant decrease in body weight or improved signs and symptoms of congestion between the 2 groups, the increase in serum creatinine on Day 7 from baseline was significantly smaller in the TLV than FUR group (P=0.038). Multiple logistic regression analysis revealed that additive TLV (odds ratio 0.157, 95% confidence interval 0.043-0.605, P=0.001) was an independent clinical factor for improved renal function during treatment compared with increased FUR. CONCLUSIONS: In HF patients with residual congestion and renal dysfunction refractory to standard therapy, additive TLV increased urine volume without further renal impairment compared with patients who received an increased dose of FUR. PMID- 28835587 TI - 18F-Fluorodeoxyglucose Positron Emission Tomography 10 Days Before Onset of Aortic Dissection. PMID- 28835588 TI - Trend in the Prevalence of Atrial Fibrillation During the Past 15 Years in Iwate (Northeastern Area of Japan). AB - BACKGROUND: The trend in age-specific prevalence of atrial fibrillation (AF) in Japan has not been reported.Methods and Results:Age-specific prevalence (40-49, 50-59, 60-69, 70-79 and 80-89 years old) of AF in Iwate Prefecture was determined in 1997, 2002, 2007 and 2012 (n=818,577). A positive linear trend in the prevalence of AF across calender years was observed only in males in their 60 s and 70 s. The direct age-standardized rate in males increased from 1.55% to 1.85%, while the rate in females remained around 0.5%. CONCLUSIONS: The age specific prevalence of AF has increased only in elderly males. PMID- 28835590 TI - Association Between Preoperative Frailty and Mortality in Patients With Critical Limb Ischemia Following Infrainguinal Bypass Surgery - Usefulness of the Barthel Index. AB - BACKGROUND: Most patients with critical limb ischemia (CLI) exhibit severe comorbidities accompanied by frailty. This study assessed and risk-stratified mortality after infrainguinal bypass (IB) in CLI and investigated the effects of frailty.Methods and Results:The study retrospectively reviewed 107 consecutive CLI patients who had undergone de novo IB due to atherosclerotic disease. Data regarding patient age, comorbidities, laboratory data, and functional status were collected; functional status was evaluated using the Barthel index (BI) and nutritional status was evaluated using albumin concentrations and body mass index (BMI). Mean (+/-SD) BI and BMI were 75+/-16 and 22+/-4 kg/m2, respectively. BI (hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.94-0.99, P=0.004), BMI (HR 0.85; 95% CI 0.75-0.95, P=0.003), atrial fibrillation (AF; HR 5.31; 95% CI 2.12-13.30, P<0.001), and ejection fraction (EF; HR 0.94; 95% CI 0.91-0.98, P=0.003) were independent predictors of mortality. Patients were divided into 2 groups based on BI (BI >75, n=71; and BI <70, n=36). Survival after IB was significantly lower for the lower BI group (P<0.001, log-rank test). After propensity score matching, post-IB survival remained significantly lower in the lower BI group (P=0.02). CONCLUSIONS: BI, BMI, AF, and EF were independently associated with all-cause mortality after IB for CLI. BI and BMI may be useful in identifying and optimizing treatment for high-risk frail patients. PMID- 28835589 TI - Proposed Cutoff Value of Brachial-Ankle Pulse Wave Velocity for the Management of Hypertension. AB - BACKGROUND: The optimal cutoff values of the brachial-ankle pulse wave velocity (baPWV) for predicting cardiovascular disease (CVD) were examined in patients with hypertension.Methods and Results:A total of 7,656 participants were followed prospectively. The hazard ratio for the development of CVD increased significantly as the baPWV increased, independent of conventional risk factors. The receiver-operating characteristic curve analysis showed that the optimal cutoff values for predicting CVD was 18.3 m/s. This cutoff value significantly predicted THE incidence of CVD. CONCLUSIONS: The present analysis suggests that the optimal cutoff value for CVD in patients with hypertension is 18.3 m/s. PMID- 28835591 TI - Rasd1 is an estrogen-responsive immediate early gene and modulates expression of late genes in rat anterior pituitary cells. AB - Dexamethasone-induced Ras-related protein 1 (Rasd1) is a member of the Ras superfamily of monomeric G proteins that have a regulatory function in signal transduction. Here we investigated the role of Rasd1 in regulating estrogen induced gene expression in primary cultures of rat anterior pituitary cells. Rasd1 mRNA expression in anterior pituitary cells decreased after treatment with forskolin or serum and increased after treatment with 17beta-estradiol (E2). Increases in Rasd1 mRNA expression occurred as early as 0.5 h after E2 treatment, peaked at 1 h and were sustained for as long as 96 h. This rapid and profound increase in Rasd1 mRNA expression induced by E2 was also seen in GH4C1 cells, an estrogen receptor-positive somatolactotroph cell line. Among pituitary estrogen responsive late genes studied, basal mRNA expression of Pim3 and Igf1 genes was decreased by RNA interference-mediated knockdown of Rasd1 expression, whereas basal expression of the Giot1 gene was increased. Moreover, Rasd1 knockdown enhanced stimulation of Pim3 mRNA expression and attenuated inhibition of Fosl1 mRNA expression 24 h after E2 treatment. These changes in mRNA expression were accompanied by enhanced activity of promoters containing CRE, AP-1 and SRE binding sequences. These results suggest that Rasd1 is an estrogen-responsive immediate early gene and modulates E2 induction of at least several late genes in anterior pituitary cells. PMID- 28835592 TI - Importin alpha-importin beta complex mediated nuclear translocation of insulin like growth factor binding protein-5. AB - Insulin-like growth factor-binding protein (IGFBP)-5 is a secreted protein that binds to IGFs and modulates IGF actions, as well as regulates cell proliferation, migration, and apoptosis independent of IGF. Proper cellular localization is critical for the effective function of most signaling molecules. In previous studies, we have shown that the nuclear IGFBP-5 comes from ER-cytosol retro translocation. In this study, we further investigated the pathway mediating IGFBP 5 nuclear import after it retro-translocation. Importin-alpha5 was identified as an IGFBP-5-interacting protein with a yeast two-hybrid system, and its interaction with IGFBP-5 was further confirmed by GST pull down and co immunoprecipitation. Binding affinity of IGFBP-5 and importins were determined by surface plasmon resonance (IGFBP-5/importin-beta: KD=2.44e-7, IGFBP-5/importin alpha5: KD=3.4e-7). Blocking the importin-alpha5/importin-beta nuclear import pathway using SiRNA or dominant negative impotin-beta dramatically inhibited IGFBP-5-EGFP nuclear import, though importin-alpha5 overexpress does not affect IGFBP-5 nuclear import. Furthermore, nuclear IGFBP-5 was quantified using luciferase report assay. When deleted the IGFBP-5 nuclear localization sequence (NLS), IGFBP-5DeltaNLS loss the ability to translocate into the nucleus and accumulation of IGFBP-5DeltaNLS was visualized in the cytosol. Altogether, our findings provide a substantially evidence showed that the IGFBP-5 nuclear import is mediated by importin-alpha/importin-beta complex, and NLS is critical domain in IGFBP-5 nuclear translocation. PMID- 28835593 TI - Pitfalls in early biochemical evaluation after transsphenoidal surgery in patients with acromegaly. AB - Although the current remission criteria for acromegaly are clear and concise, some pitfalls have been reported in early endocrinological evaluation after surgery. To evaluate the long-term (>4 year) outcome and to detect the pitfalls in early evaluation, we retrospectively reviewed 128 patients with acromegaly who underwent primary transsphenoidal surgery during 2011 and 2012. These included 66 men and 62 women, aged from 7 to 76 (mean 46) years old. 49 patients (38.3%) were preoperatively treated with somatostatin analog (SSA). Follow-up period ranged from 52 to 75 (63) months. Long-term remission using the current consensus criteria was achieved in 107 patients (83.6%), 105 of which patient had achieved remission in early evaluation. In 5 patients with preoperative SSA treatment, IGF 1 levels re-elevated more than one year after surgery. Five female patients without pretreatment with SSA showed delayed normalization of IGF-1 between 13 to 27 months postoperatively, two of which patients satisfied the remission criteria. In conclusion, the long-term results can be reliably predicted by the remission criteria early after surgery in most patients with acromegaly. For the accurate evaluation within a year after surgery, however, influence of preoperative treatment with SSA, delayed normalization of IGF-1, and poor GH suppression due to low insulin resistance must be considered, particularly in women. PMID- 28835594 TI - Expression and biochemical characterization of a multifunctional glycosidase from the thermophilic Bacillus licheniformis SR01. AB - A gene (gkdA) (741 bp) encoding a putative protein of 247 amino acids was cloned from the Bacillus licheniformis SR01. The protein was expressed in Escherichia coli BL21 with a molecular mass estimated by SDS-PAGE of approximately 28.03 kDa and showed a calculating isoelectric point (pI) of 6.42. Structure analysis and function identification showed that the enzyme was a multifunctional glycosidase. Its specific activity was 0.013 U/MUg. The recombinant glycosidase showed a maximum activity at 50 degrees C and pH 7.0. It was very stable below 90 degrees C and may have heat activation at higher temperatures. The relative residual activity was still more than 80% after 120 min at pH 5.0-10.0. The enzyme activity was inhibited by Cu2+, Fe2+, Ca2+, Mg2+, Co2+, Li+, SDS and EDTA, activated by Ca2+, and not affected by Mn2+ and K+. Under simulated stomach, and in vitro intestine, conditions, the enzyme retained 80%, and more than 100%, activity, respectively, after incubation for 90 min. The excellent properties of this enzyme, specifically its thermal stability and multifunctional abilities, give it potential application in the field of feed processing and other high temperature processing industries. PMID- 28835595 TI - Identification and characterization of a cell wall porin from Gordonia jacobaea. AB - Gordonia jacobaea is a bacterium belonging to the mycolata group characterized by its ability to produce carotenoids. Mycolic acids in the cell wall contribute to reducing the permeability of their envelopes requiring the presence of channel forming proteins to allow the exchange of hydrophilic molecules with the surrounding medium. Identification and purification of the channel-forming proteins was accomplished by SDS-PAGE, Mass spectrometry and Mass peptide fingerprinting and the channel-forming activity was studied by reconstitution in lipid bilayers. Here, we describe for the first time the presence of a cell-wall protein from G. jacobaea with channel-forming activity. Our results suggest that this protein bears a low similarity to other hypothetical proteins from the genus Gordonia of uncharacterized functions. The channel has an average single-channel conductance of 800 pS in 1 M KCl, is moderately anion-selective, and does not show any voltage dependence for voltages between +100 and -100 mV. The channel characteristics suggest that this protein could be of relevance in the import and export of negatively charged molecules across the cell wall. This could contribute to design treatments for mycobacterial infections, as well as being of interest in biotechnology applications. PMID- 28835596 TI - Laser-prepared and bonding-filled fissure sealing: SEM and OCT analysis of marginal and internal adaptation. AB - This study assessed the effect of bur or Er:YAG laser preparation on marginal and internal adaptation of conventional and extended fissure sealing (FS) with a 3 component etch-and-rinse (Optibond FL; OFL) and a 1-component self-etch (Scotchbond Universal; SB) adhesive system. Scanning electron microscope analysis was performed before and after thermocycling/occlusal load and additional optical coherence tomography evaluation was carried out for internal marginal assessment. Significant differences were observed between the groups (ANOVA, p<0.05). Laser prepared and non-etched FS suffered from marginal degradation after fatigue. When enamel was etched with H3PO4 and independently of the adhesive system, laser technique was equally effective to bur-preparation with percentages of continuous margins ranging from 96 to 99%, being laser less invasive than bur preparation. This is clinically relevant in paediatric dentistry as minimally invasive FS can be performed with laser and adhesive systems used as fissure sealants. Nevertheless, enamel etch with phosphoric acid is still necessary. PMID- 28835597 TI - Treatment of post-orthodontic white spot lesions with CPP-ACP paste: A three year follow up study. AB - To determine the efficacy of topical applications of 10% casein phosphopeptide amorphous calcium phosphate (CPP-ACP) paste in reverting white spot lesions (WSLs) after fixed orthodontic treatment. Forty one participants were randomly assigned to either the test group (CPP-ACP) or the control group (only fluoride toothpaste). All patients used regular fluoride-containing toothpaste. CPPACP paste or fluoridated toothpaste was applied on to tooth surfaces with WSLs twice a day during 36-month after de-bonding. The labial/buccal surfaces of teeth were assessed by use of DIAGNOdent pen (DD), Gorelick Index and ICDAS II criteria at baseline (T1) and 36-month (T2) follow-up visits. The total counts of Streptococcus mutans and Lactobacillus were obtained at T1 and T2. DMFT, DMFS, stimulated flow rate and buffer capacity were calculated in two appointments. Daily usage of CPP-ACP paste was not better than normal care for improving the appearance of WSLs after 36 months. PMID- 28835598 TI - Influence of material thickness on fractural strength of CAD/CAM fabricated ceramic crowns. AB - The fracture behavior of CAD/CAM fabricated crowns was investigated as a function of material thickness for six silicate ceramic materials: Mark II, e.max CAD, Celtra Duo milled, Celtra Duo fired, Suprinity, Enamic. Crowns with thicknesses 0.5/1.0/1.5 mm were fabricated with CEREC and adhesively seated to dies fabricated with stereolithography technology (n=144). Thermomechanical loading and fractural loading was performed. Statistical analysis was done with one-way ANOVA and post-hoc Scheffe test. For 1.5 mm, all crowns survived fatigue testing, for 1.0 mm, survival was 100% only for materials e.max CAD and Suprinity. For 0.5 mm, best survival rate was 37.5% for Suprinity. Maximum fractural loading significantly varied among the groups. For 0.5 mm, highest value was found for Suprinity (660.1 N). Mark II showed lowest values for 1.0 mm (482.0 N), and 1.5 mm groups (634.8 N). e.max CAD showed highest values for 1.0 mm (774.2 N), and 1.5 mm groups (1,240.8 N). PMID- 28835599 TI - Effect of a calcium phosphate and fluoride paste on prevention of enamel demineralization. AB - This study aimed to examine the anti-demineralization capacities of (a) tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous (DCPA) and 950 ppm fluoride paste, (b) casein phosphopeptide amorphous calcium phosphate paste and (c) 950 ppm fluoride solution using optical coherence tomography (OCT). Enamel blocks were cut from the bovine incisors and treated using one of the above-mentioned three materials or deionized water as control (n=10). All samples were subjected to a demineralization gel for 1 h followed by a remineralization solution for 23 h. This experimental cycle was repeated for 28 days. The specimens were imaged using OCT at baseline and at four stages and measured lesion depth using image analysis software (ImageJ). Repeated measures ANOVA revealed that demineralization time, material and their interaction significantly affected the optical lesion depth (p<0.001). TTCP and DCPA and 950 ppm fluoride paste and 950 ppm fluoride solution showed significantly lower lesion progress compare to other groups (p<0.05). PMID- 28835600 TI - Titanium removable denture based on a one-metal rehabilitation concept. AB - The use of a single metal for all restorations would be necessary because it protects against metal corrosion caused by the contact of different metals. For this "one-metal rehabilitation" concept, non-alloyed commercially pure (CP) titanium should be used for all restorations. Titanium frameworks have been cast and used for the long term without catastrophic failure, whereas they have been fabricated recently using computer-aided design/computer-aided manufacturing (CAD/CAM). However, the milling process for the frameworks of removable partial dentures (RPDs) is not easy because they have very complicated shapes and consist of many components. Currently, the fabrication of RPD frameworks has been challenged by one-process molding using repeated laser sintering and high-speed milling. Laser welding has also been used typically for repairing and rebuilding titanium frameworks. Although laboratory and clinical problems still remain, the one-metal rehabilitation concept using CP titanium as a bioinert metal can be recommended for all restorations. PMID- 28835601 TI - Surface treatment and modification of metals to add biofunction. AB - To add biocompatibility or biofunction to metal surface, an intelligent interface between metals and tissues must be acquired. Tremendous surface modification techniques are currently studied to create the intelligent interface. In particular, bone formation or bone bonding is major purpose of the surface modifications. Time transient of surface modification techniques are summarized and the importance of roughened or porous surface to combine materials with bone tissue is demonstrated. As an example of surface modification, electrodeposition of poly(ethylene glycol) to inhibit biofilm formation is introduced. A dual functional surface is formed on titanium by micro arc oxidation. In addition, the effect of topography on the elongation and differentiation of human mesenchymal stem cells was confirmed on the hybrid micrometer-level and nanometer-level grooves of titanium surface. Metal surface is possibly biofunctionalized by various surface modification techniques. PMID- 28835602 TI - Non-biodegradable polymer particles for drug delivery: A new technology for "bio active" restorative materials. AB - To develop dental restorative materials with "bio-active" functions, addition of the capability to release active agents is an effective approach. However, such functionality needs to be attained without compromising the basic properties of the restorative materials. We have developed novel non-biodegradable polymer particles for drug delivery, aimed for application in dental resins. The particles are made using 2-hydroxyethyl methacrylate (HEMA) and a cross-linking monomer trimethylolpropane trimethacrylate (TMPT), with a hydrophilic nature to adsorb proteins or water-soluble antimicrobials. The polyHEMA/TMPT particles work as a reservoir to release fibroblast growth factor-2 (FGF-2) or cetylpyridinium chloride (CPC) in an effective manner. Application of the polyHEMA/TMPT particles loaded with FGF-2 to adhesives, or those loaded with CPC to resin-based endodontic sealers or denture bases/crowns is a promising approach to increase the success of the treatments by conferring "bio-active" properties to these materials to induce tissue regeneration or to inhibit bacterial infection. PMID- 28835603 TI - Clinical Characteristics and Prognostic Factors in Bone Metastases from Lung Cancer. AB - BACKGROUND This study investigated the prognostic factors of bone metastases from lung cancer. MATERIAL AND METHODS From March 2014 to March 2015, 168 patients with bone metastases from lung cancer treated at our hospital were included and the clinical data were reviewed. The Kaplan-Meier survival curves were calculated and analyzed using the log-rank univariate test. Multivariate regression analysis was conducted using Cox's regression model. RESULTS The overall median survival of the 168 patients was 13 months. The 1-year survival was 54.3% and the 2-year survival was 12.9%. Univariate regression analysis indicated that the pathologic types, number of bone metastases, clinical stage, ECOG scores, and serum ALP levels were significantly correlated with survival (P<0.05). Multivariate regression analysis indicated that the number of bone metastases, clinical stage, and serum ALP levels were significantly correlated with prognosis (P<0.05). The risk associated with multiple bone metastases was 1.72 times of that of single bone metastasis (P=0.029); the risk associated with advanced clinical stage was 1.49 times of that of early clinical stage (P=0.001); and the risk associated with a high serum ALP level was 1.75 times of that of the low serum ALP level (P=0.006). CONCLUSIONS Pathologic types, number of bone metastases, clinical stage, ECOG scores, and serum ALP levels were the prognostic factors for bone metastases from lung cancer. PMID- 28835604 TI - Spontaneously Ruptured Paraovarian Tumor of Borderline Malignancy with Extremely Elevated Serum Carbohydrate Antigen 125 (CA125) Levels: A Comparison of the Imaging and Pathological Features. AB - BACKGROUND Paraovarian cysts are common and are generally benign; however, they are frequently misdiagnosed as being of ovarian origin. Conversely, paraovarian tumors of borderline malignancy are extremely rare. Especially, no cases of spontaneous rupture have been reported, and all previous reports had normal serum carbohydrate antigen (CA) 125 level. As for imaging findings, the presence of papillary projections in the lumen of paraovarian tumors does not always indicate malignancy or benignancy, which makes the preoperative distinction difficult. CASE REPORT We report a case involving a 22-year-old Asian woman with a spontaneously ruptured paraovarian tumor of borderline malignancy. The serum CA125 concentration was extremely elevated, at 28,831 U/mL. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a collapsed unilocular cystic lesion with multiple papillary projections. On MRI, the papillary projections showed two different patterns, which corresponded to the pathological findings. CONCLUSIONS Ruptured paraovarian tumors of borderline malignancy may show extremely high serum CA125 values. Furthermore, specific MRI findings may be useful in evaluating the malignancy of paraovarian tumors. PMID- 28835605 TI - Duality and quantum state engineering in cavity arrays. AB - A system of two coupled cavities with N - 1 photons is shown to be dynamically equivalent to an array of N coupled cavities containing one photon. Every transition in the two cavity system has a dual phenomenon in terms of photon transport in the cavity array. This duality is employed to arrive at the required coupling strengths and nonlinearities in the cavity array so that controlled photon transfer is possible between any two cavities. This transfer of photons between two of the cavities in the array is effected without populating the other cavities. The condition for perfect transport enables perfect state transfer between any two cavities in the array. Further, possibility of high fidelity generation of generalized NOON states in two coupled cavities, which are dual to the Bell states of the photon in the cavity array, is established. PMID- 28835606 TI - Diffusive and arrested transport of atoms under tailored disorder. AB - Ultracold atoms in optical lattices offer a unique platform for investigating disorder-driven phenomena. While static disordered site potentials have been explored in a number of experiments, a more general, dynamical control over site energy and off-diagonal tunnelling disorder has been lacking. The use of atomic quantum states as synthetic dimensions has introduced the spectroscopic, site resolved control necessary to engineer more tailored realisations of disorder. Here, we present explorations of dynamical and tunneling disorder in an atomic system by controlling laser-driven dynamics of atomic population in a momentum space lattice. By applying static tunnelling phase disorder to a one-dimensional lattice, we observe ballistic quantum spreading. When the applied disorder fluctuates on time scales comparable to intersite tunnelling, we instead observe diffusive atomic transport, signalling a crossover from quantum to classical expansion dynamics. We compare these observations to the case of static site energy disorder, where we directly observe quantum localisation.Cold atom quantum simulation has had challenges in realising the tailored, dynamic types of disorder relevant to real materials. Here, the authors use synthetic momentum space lattices to engineer spatially and dynamically controlled disorder to observe ballistic, diffusive, and arrested atomic transport. PMID- 28835607 TI - Clinical evaluation of whole blood prothrombin time (PT) and international normalized ratio (INR) using a Laser Speckle Rheology sensor. AB - Prothrombin time (PT) and the associated international normalized ratio (INR) are routinely tested to assess the risk of bleeding or thrombosis and to monitor response to anticoagulant therapy in patients. To measure PT/INR, conventional coagulation testing (CCT) is performed, which is time-consuming and requires the separation of cellular components from whole blood. Here, we report on a portable and battery-operated optical sensor that can rapidly quantify PT/INR within seconds by measuring alterations in the viscoelastic properties of a drop of whole blood following activation of coagulation with thromboplastin. In this study, PT/INR values were measured in 60 patients using the optical sensor and compared with the corresponding CCT values. Our results report a close correlation and high concordance between PT/INR measured using the two approaches. These findings confirm the accuracy of our optical sensing approach for rapid PT/INR testing in whole blood and highlight the potential for use at the point-of-care or for patient self-testing. PMID- 28835608 TI - A multidimensional phasor approach reveals LAURDAN photophysics in NIH-3T3 cell membranes. AB - Mammalian cell membranes have different phospholipid composition and cholesterol content, displaying a profile of fluidity that depends on their intracellular location. Among the dyes used in membrane studies, LAURDAN has the advantage to be sensitive to the lipid composition as well as to membrane fluidity. The LAURDAN spectrum is sensitive to the lipid composition and dipolar relaxation arising from water penetration, but disentangling lipid composition from membrane fluidity can be obtained if time resolved spectra could be measured at each cell location. Here we describe a method in which spectral and lifetime information obtained in different measurements at the same plane in a cell are used in the phasor plot providing a solution to analyze multiple lifetime or spectral data through a common visualization approach. We exploit a property of phasor plots based on the reciprocal role of the phasor plot and the image. In the phasor analysis each pixel of the image is associated with a phasor and each phasor maps to pixels and features in the image. In this paper the lifetime and spectral fluorescence data are used simultaneously to determine the contribution of polarity and dipolar relaxations of LAURDAN in each pixel of an image. PMID- 28835609 TI - Myosin efflux promotes cell elongation to coordinate chromosome segregation with cell cleavage. AB - Chromatid segregation must be coordinated with cytokinesis to preserve genomic stability. Here we report that cells clear trailing chromatids from the cleavage site by undergoing two phases of cell elongation. The first phase relies on the assembly of a wide contractile ring. The second phase requires the activity of a pool of myosin that flows from the ring and enriches the nascent daughter cell cortices. This myosin efflux is a novel feature of cytokinesis and its duration is coupled to nuclear envelope reassembly and the nuclear sequestration of the Rho-GEF Pebble. Trailing chromatids induce a delay in nuclear envelope reassembly concomitant with prolonged cortical myosin activity, thus providing forces for the second elongation. We propose that the modulation of cortical myosin dynamics is part of the cellular response triggered by a "chromatid separation checkpoint" that delays nuclear envelope reassembly and, consequently, Pebble nuclear sequestration when trailing chromatids are present at the midzone.Chromatid segregation must be coordinated with cytokinesis to preserve genomic stability. Here the authors show that cells clear trailing chromatids from the cleavage site in a two-step cell elongation and demonstrate the role of myosin efflux in the second phase. PMID- 28835611 TI - Ranking of Nodal Infection Probability in Susceptible-Infected-Susceptible Epidemic. AB - The prevalence, which is the average fraction of infected nodes, has been studied to evaluate the robustness of a network subject to the spread of epidemics. We explore the vulnerability (infection probability) of each node in the metastable state with a given effective infection rate tau. Specifically, we investigate the ranking of the nodal vulnerability subject to a susceptible-infected-susceptible epidemic, motivated by the fact that the ranking can be crucial for a network operator to assess which nodes are more vulnerable. Via both theoretical and numerical approaches, we unveil that the ranking of nodal vulnerability tends to change more significantly as tau varies when tau is smaller or in Barabasi-Albert than Erdos-Renyi random graphs. PMID- 28835610 TI - Glutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation. AB - Activation of autophagy and elevation of glutamine synthesis represent key adaptations to maintain amino acid balance during starvation. In this study, we investigate the role of autophagy and glutamine on the regulation of mTORC1, a critical kinase that regulates cell growth and proliferation. We report that supplementation of glutamine alone is sufficient to restore mTORC1 activity during prolonged amino acid starvation. Inhibition of autophagy abolishes the restorative effect of glutamine, suggesting that reactivation of mTORC1 is autophagy-dependent. Inhibition of glutaminolysis or transamination impairs glutamine-mediated mTORC1 reactivation, suggesting glutamine reactivates mTORC1 specifically through its conversion to glutamate and restoration of non-essential amino acid pool. Despite a persistent drop in essential amino acid pool during amino acid starvation, crosstalk between glutamine and autophagy is sufficient to restore insulin sensitivity of mTORC1. Thus, glutamine metabolism and autophagy constitute a specific metabolic program which restores mTORC1 activity during amino acid starvation.mTORC1 is a critical kinase that regulates cell growth and proliferation. Here the authors show that glutamine metabolism is sufficient to restore mTORC1 activity during prolonged amino acid starvation in an autophagy dependent manner. PMID- 28835612 TI - Reorganization of mammalian body wall patterning with cloacal septation. AB - Septation of the cloaca is a unique mammalian adaptation that required a novel reorganization of the perineum-the caudal portion of the trunk body wall not associated with the hindlimb. Fish, the basal vertebrates, separate ventrolateral body wall musculature of the trunk into two discrete layers, while most tetrapods expand this pattern in the thorax and abdomen into four. Mammals, the only vertebrate group to divide the cloaca into urogenital and anorectal portions, exhibit complex muscle morphology in the perineum. Here we describe how perineal morphology in a broad sample of mammals fits into patterning of trunk musculature as an extension of the four-layer ventrolateral muscular patterning of the thorax and abdomen. We show that each perineal muscle layer has a specific function related to structures formed by cloacal septation. From superficial to deep, there is the subcutaneous layer, which regulates orifice closure, the external layer, which supplements both erectile and micturition function, the internal layer, which provides primary micturition and defecation regulation, and the transversus layer, which provides structural support for pelvic organs. We elucidate how the four-layer body wall pattern, restricted to the non-mammal tetrapod thorax and abdomen, is observed in the mammalian perineum to regulate function of unique perineal structures derived from cloacal septation. PMID- 28835613 TI - Residual Risk Factors to Predict Major Adverse Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients with and without Diabetes Mellitus. AB - A prospective observational study was conducted to investigate the residual risk factors to predict recurrence of major adverse cardiovascular events (MACE) in atherosclerotic cardiovascular disease (ASCVD) patients with a high prevalence under lipid-lowering therapy, particularly in the subpopulations of diabetic and nondiabetic individuals. A total of 5,483 adults (with a mean age of 66.4 and 73.3% male) with established coronary heart disease, cerebrovascular disease, or peripheral artery disease were identified from the T-SPARCLE multi-center registry. Of them, 38.6% had diabetes. The residual risk factors for MACE are divergent in these atherosclerotic patients with and without diabetes. In diabetic subpopulation, the risk of MACE was significantly increased with heart failure (HF), chronic kidney disease (CKD) stage 4-5 (vs. stage 1-2), without beta blocker use, and higher non-HDL-C, after controlling for covariates including statin use and the intensity of therapy. Increased LDL-C and TG levels were also associated with increased risk, but to a much less extent. Among nondiabetic individuals, HF, CKD stage 4-5, and history of myocardial infarction were the significant independent predictors of MACE. It is suggested that ASCVD patients with concomitant diabetes need stricter control of lipid, particularly non-HDL-C levels, to reduce cardiovascular risk when on statin therapy. PMID- 28835614 TI - Light-Triggered Soft Artificial Muscles: Molecular-Level Amplification of Actuation Control Signals. AB - The principle of control signal amplification is found in all actuation systems, from engineered devices through to the operation of biological muscles. However, current engineering approaches require the use of hard and bulky external switches or valves, incompatible with both the properties of emerging soft artificial muscle technology and those of the bioinspired robotic systems they enable. To address this deficiency a biomimetic molecular-level approach is developed that employs light, with its excellent spatial and temporal control properties, to actuate soft, pH-responsive hydrogel artificial muscles. Although this actuation is triggered by light, it is largely powered by the resulting excitation and runaway chemical reaction of a light-sensitive acid autocatalytic solution in which the actuator is immersed. This process produces actuation strains of up to 45% and a three-fold chemical amplification of the controlling light-trigger, realising a new strategy for the creation of highly functional soft actuating systems. PMID- 28835615 TI - Logic programming reveals alteration of key transcription factors in multiple myeloma. AB - Innovative approaches combining regulatory networks (RN) and genomic data are needed to extract biological information for a better understanding of diseases, such as cancer, by improving the identification of entities and thereby leading to potential new therapeutic avenues. In this study, we confronted an automatically generated RN with gene expression profiles (GEP) from a cohort of multiple myeloma (MM) patients and normal individuals using global reasoning on the RN causality to identify key-nodes. We modeled each patient by his or her GEP, the RN and the possible automatically detected repairs needed to establish a coherent flow of the information that explains the logic of the GEP. These repairs could represent cancer mutations leading to GEP variability. With this reasoning, unmeasured protein states can be inferred, and we can simulate the impact of a protein perturbation on the RN behavior to identify therapeutic targets. We showed that JUN/FOS and FOXM1 activities are altered in almost all MM patients and identified two survival markers for MM patients. Our results suggest that JUN/FOS-activation has a strong impact on the RN in view of the whole GEP, whereas FOXM1-activation could be an interesting way to perturb an MM subgroup identified by our method. PMID- 28835616 TI - Leukocytic Toll-Like Receptor 2 Deficiency Preserves Cardiac Function And Reduces Fibrosis In Sustained Pressure Overload. AB - An involement of Toll-like receptor 2 (TLR2) has been established in cardiac dysfunction after acute myocardial infarction; however, its role in chronic pressure overload is unclear. We sought to evaluate the role of TLR2 in cardiac hypertrophy, fibrosis and dysfunction in sustained pressure overload. We induced pressure overload via transverse aortic constriction (TAC) in TLR2-/- and wild type (WT) mice, and followed temporal changes over 8 weeks. Despite similar increases in heart weight, left ventricular (LV) ejection fraction (EF) and diastolic function (mitral E/A ratio) were preserved in TLR2-/- mice but impaired in WT mice following TAC. TAC produced less LV fibrosis in TLR2-/- mice associated with lower mRNA levels of collagen genes (Col1a1 and Col3a1) and lower protein level of TGFbeta1, compared to WT mice. Following TAC, the influx of macrophages and CD3 T cells into LV was similar between TLR2-/- and WT mice, whereas levels of cyto/chemokines were lower in the heart and plasma in TLR2-/- mice. TLR2-/- bone marrow-derived cells protected against LVEF decline and fibrosis following TAC. Our findings show that leukocytic TLR2 deficiency protects against LV dysfunction and fibrosis probably via a reduction in inflammatory signaling in sustained pressure overload. PMID- 28835617 TI - The homology and function of the lung plates in extant and fossil coelacanths. AB - The presence of a pulmonary organ that is entirely covered by true bone tissue and fills most of the abdominal cavity is hitherto unique to fossil actinistians. Although small hard plates have been recently reported in the lung of the extant coelacanth Latimeria chalumnae, the homology between these hard structures in fossil and extant forms remained to be demonstrated. Here, we resolve this question by reporting the presence of a similar histological pattern-true cellular bone with star-shaped osteocytes, and a globular mineralisation with radiating arrangement-in the lung plates of two fossil coelacanths (Swenzia latimerae and Axelrodichthys araripensis) and the plates that surround the lung of the most extensively studied extant coelacanth species, L. chalumnae. The point-for-point structural similarity of the plates in extant and fossil coelacanths supports their probable homology and, consequently, that of the organ they surround. Thus, this evidence questions the previous interpretations of the fatty organ as a component of the pulmonary complex of Latimeria. PMID- 28835619 TI - The zero effect: voxel-based lesion symptom mapping of number transcoding errors following stroke. AB - Zero represents a special case in our numerical system because it is not represented on a semantic level. Former research has shown that this can lead to specific impairments when transcoding numerals from dictation to written digits. Even though, number processing is considered to be dominated by the left hemisphere, studies have indicated that both left as well as right hemispheric stroke patients commit errors when transcoding numerals including zeros. Here, for the first time, a large sample of subacute stroke patients (N = 667) was assessed without being preselected based on the location of their lesion, or a specific impairment in transcoding zero. The results show that specific errors in transcoding zeros were common (prevalence = 14.2%) and a voxel-based lesion symptom mapping analysis (n = 153) revealed these to be related to lesions in and around the right putamen. In line with former research, the present study argues that the widespread brain network for number processing also includes subcortical regions, like the putamen with connections to the insular cortex. These play a crucial role in auditory perception as well as attention. If these areas are lesioned, number processing tasks with higher attentional and working memory loads, like transcoding zeros, can be impaired. PMID- 28835618 TI - Identification of an insect-produced olfactory cue that primes plant defenses. AB - It is increasingly clear that plants perceive and respond to olfactory cues. Yet, knowledge about the specificity and sensitivity of such perception remains limited. We previously documented priming of anti-herbivore defenses in tall goldenrod plants (Solidago altissima) by volatile emissions from a specialist herbivore, the goldenrod gall fly (Eurosta solidaginis). Here, we explore the specific chemical cues mediating this interaction. We report that E,S conophthorin, the most abundant component of the emission of male flies, elicits a priming response equivalent to that observed for the overall blend. Furthermore, while the strength of priming is dose dependent, plants respond even to very low concentrations of E,S-conophthorin relative to typical fly emissions. Evaluation of other blend components yields results consistent with the hypothesis that priming in this interaction is mediated by a single compound. These findings provide insights into the perceptual capabilities underlying plant defense priming in response to olfactory cues.Plants are able to prime anti herbivore defenses in response to olfactory cues of insect pests. Here, Helms et al. identify the insect pheromone E,S-conophthorin produced by the goldenrod gall fly as the specific chemical component that elicits this priming response in goldenrod plants. PMID- 28835620 TI - Short and Long-Term Outcomes After Surgical Procedures Lasting for More Than Six Hours. AB - Long-term all-cause mortality and dependency after complex surgical procedures have not been assessed in the framework of value-based medicine. The aim of this study was to investigate the postoperative and long-term outcomes after surgical procedures lasting for more than six hours. Retrospective cohort study of patients undergoing a first elective complex surgical procedure between 2004 and 2013. Heart and transplant surgery was excluded. Mortality and dependency from the healthcare system were selected as outcome variables. Gender, age, ASA, creatinine, albumin kinetics, complications, benign vs malignant underlying condition, number of drugs at discharge, and admission and length of stay in the ICU were recorded as predictive variables. Some 620 adult patients were included in the study. Postoperative, <1year and <5years cumulative mortality was 6.8%, 17.6% and 45%, respectively. Of patients discharged from hospital after surgery, 76% remained dependent on the healthcare system. In multivariate analysis for postoperative, <1year and <5years mortality, postoperative albumin concentration, ASA score and an ICU stay >7days, were the most significant independent predictive variables. Prolonged surgery carries a significant short and long-term mortality and disability. These data may contribute to more informed decisions taken concerning major surgery in the framework of value-based medicine. PMID- 28835621 TI - Genetic basis of mycotoxin susceptibility differences between budding yeast isolates. AB - Micophenolic acid (MPA) is an immunosuppressant mycotoxin which impairs yeast cell growth to variable degrees depending on the genetic background. Such variation could have emerged from several phenomena, including MPA gene resistance mutations and variations in copy number and localisation of resistance genes. To test this, we evaluated MPA susceptibility in four S. cerevisiae isolates and genetically dissected variation through the identification of Quantitative Trait Loci. Via linkage analysis we identified six QTLs, majority of which were located within subtelomeres and co-localised with IMD2, an inosine monophosphate dehydrogenase previously identified underlying MPA drug resistance in yeast cells. From chromosome end disruption and bioinformatics analysis, it was found that the subtelomere localisation of IMD2 within chromosome ends is variable depending on the strain, demonstrating the influence of IMD2 on the natural variation in yeast MPA susceptibility. Furthermore, GxE gene expression analysis of strains exhibiting opposite phenotypes indicated that ribosome biogenesis, RNA transport, and purine biosynthesis were impaired in strains most susceptible to MPA toxicity. Our results demonstrate that natural variation can be exploited to better understand the molecular mechanisms underlying mycotoxin susceptibility in eukaryote cells and demonstrate the role of subtelomeric regions in mediating interactions with the environment. PMID- 28835623 TI - Mapping of electromagnetic waves generated by free-running self-oscillating devices. AB - Near-field mapping has proven to be a powerful technique for characterizing and diagnosing antennas in the microwave frequency range. However, conventional measurement methods based on a network analyzer cannot be applied to on-chip antenna devices extensively studied for future wireless communication in the millimeter wave (mm-wave) (30-300 GHz) and terahertz (THz) wave (0.1-10 THz) frequency regions. Here, we present a new asynchronous mapping technique to investigate the spatial distribution of not only the amplitude but also the phase of the electric field generated by free-running, self-oscillating generators including CMOS oscillators, Gunn oscillators, resonant tunneling diodes, and quantum cascaded lasers. Using a photonic-electronic hybrid measurement system, a wide frequency coverage, minimal invasiveness of the field to be measured, and phase distribution measurements with a theoretically-limited sensitivity are simultaneously achieved. As a proof-of-concept experiment, we demonstrate the mapping of a mm-wave (77 GHz) generated by a free-running Gunn oscillator and antenna characterization based on near-to-far field transformation. PMID- 28835622 TI - Nanodiamond arrays on glass for quantification and fluorescence characterisation. AB - Quantifying the variation in emission properties of fluorescent nanodiamonds is important for developing their wide-ranging applicability. Directed self-assembly techniques show promise for positioning nanodiamonds precisely enabling such quantification. Here we show an approach for depositing nanodiamonds in pre determined arrays which are used to gather statistical information about fluorescent lifetimes. The arrays were created via a layer of photoresist patterned with grids of apertures using electron beam lithography and then drop cast with nanodiamonds. Electron microscopy revealed a 90% average deposition yield across 3,376 populated array sites, with an average of 20 nanodiamonds per site. Confocal microscopy, optimised for nitrogen vacancy fluorescence collection, revealed a broad distribution of fluorescent lifetimes in agreement with literature. This method for statistically quantifying fluorescent nanoparticles provides a step towards fabrication of hybrid photonic devices for applications from quantum cryptography to sensing. PMID- 28835624 TI - Unraveling the correlation between microbiota succession and metabolite changes in traditional Shanxi aged vinegar. AB - Shanxi aged vinegar (SAV) is a well-known vinegar produced by traditional solid state fermentation and has been used in China for thousands of years. However, how microorganisms and their metabolites change along with fermentation is unclear. Here, 454 high-throughput sequencing and denaturing gradient gel electrophoresis were used to investigate the composition of microbial community. Metabolites were further analyzed by gas chromatography-mass spectrometry and high-performance liquid chromatography. Results showed that the composition of bacterial community changed dramatically at different stages of fermentation. The bacterial genera (relative abundance > 0.1%) decreased from 17 in daqu (starter used in starch saccharification) to 2 at the 12th day of alcohol fernemtation (AF). 15 bacterial genera at the 1st day of acetic acid fermentation (AAF) decreased to 4 genera, involving Acetobacter (50.9%), Lactobacillus (47.9%), Komagataeibacter (formerly Gluconacetobacter, 0.7%) and Propionibacterium (0.1%) at the 7th day of AAF. The structure of fungal community was more homogeneous. Saccharomyces and Saccharomycopsis were predominant in AF and AAF. A total of 87 kinds of nonvolatile metabolites were detected. Canonical correspondence analysis showed a significant correlation between the microbiota succession and the formation of metabolites during the fermentation of SAV. This study provides detailed information for the fermentation mechanism of traditional SAV. PMID- 28835625 TI - Nanoscale spectrum analyzer based on spin-wave interference. AB - We present the design of a spin-wave-based microwave signal processing device. The microwave signal is first converted into spin-wave excitations, which propagate in a patterned magnetic thin-film. An interference pattern is formed in the film and its intensity distribution at appropriate read-out locations gives the spectral decomposition of the signal. We use analytic calculations and micromagnetic simulations to verify and to analyze the operation of the device. The results suggest that all performance figures of this magnetoelectric device at room temperature (speed, area, power consumption) may be significantly better than what is achievable in a purely electrical system. We envision that a new class of low-power, high-speed, special-purpose signal processors can be realized by spin-waves. PMID- 28835626 TI - Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/beta-catenin signaling. AB - The Wnt/beta-catenin pathway has been involved in regulating inflammation in various infectious and inflammatory diseases. Sepsis is a life-threatening condition caused by dysregulated inflammatory response to infection with no effective therapy available. Recently elevated Wnt/beta-catenin signaling has been detected in sepsis. However, its contribution to sepsis-associated inflammatory response remains to be explored. In this study, we show that inhibition of Wnt/beta-catenin signaling reduces inflammation and mitigates sepsis-induced organ injury. Using in vitro LPS-stimulated RAW264.7 macrophages, we demonstrate that a small-molecule inhibitor of beta-catenin responsive transcription, iCRT3, significantly reduces the LPS-induced Wnt/beta-catenin activity and also inhibits TNF-alpha production and IkappaB degradation in a dose dependent manner. Intraperitoneal administration of iCRT3 to C57BL/6 mice, subjected to cecal ligation and puncture-induced sepsis, decreases the plasma levels of proinflammatory cytokines and organ injury markers in a dose-dependent manner. The histological integrity of the lungs is improved with iCRT3 treatment, along with reduced lung collagen deposition and apoptosis. In addition, iCRT3 treatment also decreases the expression of the cytokines, neutrophil chemoattractants, as well as the MPO activity in the lungs of septic mice. Based on these findings we conclude that targeting the Wnt/beta-Catenin pathway may provide a potential therapeutic approach for treatment of sepsis. PMID- 28835627 TI - Evolutionary pathway analysis and unified classification of East Asian lineage of Mycobacterium tuberculosis. AB - Due to its rapid spread and association with the numerous outbreaks, the global spread of East Asian lineage of Mycobacterium tuberculosis strains presents a global concern. Although there were many attempts to describe its population structure, no consensus has been reached yet. To define unbiased classification that will facilitate future studies of this lineage, we analyzed the performance and congruence of eight different genotyping schemes based on phylogenetic analysis of 1,398 strains from 32 countries using whole-genome sequencing (WGS) data. We confirm that East Asian lineage comprises two major clades, designated proto-Beijing, which harbors unusual 43-signal spoligoprofile, and Beijing, with well-known spoligoprofile (deleted signals from 1 to 34). We show that different genotyping methods give high consistency results in description of ancient Beijing strains while the classification of modern Beijing strains is significantly divergent due to star-shaped phylogeny. Using WGS data we intersect different studies and for the first time provide balanced classification with well-defined major groups and their genetic markers. Our reconstructed phylogenetic tree can also be used for further analysis of epidemiologically important clusters and their ancestors as well as white spots of unclassified strains, which are prospective areas of research. PMID- 28835629 TI - Metabolic activity of mature biofilms of Mycobacterium tuberculosis and other non tuberculous mycobacteria. AB - Mycobacteria are classified into two groups, fast- and slow-growing. Often, fast growing mycobacteria are assumed to have a higher metabolic activity than their slower counterparts, but in mature biofilms this assumption might not be correct. Indeed, when measuring the metabolic activity of mycobacterial biofilms with two independent non-invasive techniques (isothermal microcalorimetry and tunable diode laser absorption spectrometry), mature biofilms of slow- and fast-growing species appeared more alike than expected. Metabolic heat production rate was 2298 +/- 181 uW for M. smegmatis and 792 +/- 81 uW for M. phlei, while M. tuberculosis and M. bovis metabolic heat production rates were between these values. These small differences were further confirmed by similar oxygen consumption rates (3.3 +/- 0.2 nMole/s and 1.7 +/- 0.3 nMole/s for M. smegmatis and M. tuberculosis, respectively). These data suggest that the metabolic potential of slow-growing mycobacterial biofilms has been underestimated, particularly for pathogenic species. PMID- 28835630 TI - Crab Spider Lures Prey In Flowerless Neighborhoods. AB - One fundamental question in prey luring systems is to understand how visual signals are interpreted by the receiver. Predators lure prey by falsely imitating the signal of a model, or may exploit sensory preferences of the receivers, which search for rewarding signals. Crab spiders reflect ultraviolet (UV) light, ambush pollinators on flowers, and manipulate flower UV signals altering the behavior and response of prey. Whereas crab spiders typically depend on flowers to forage, adult Epicadus heterogaster departs from this standard behavior by preying on pollinators upon green leaves, even in the absence of flowers nearby. This species has a conspicuous abdomen resembling the shape of a flower, which may reflect UV signals similar to that of flowers, and thus attract pollinators. Nevertheless, no empirical evidence is available that E. heterogaster foraging on leaves mimics flowers, nor how this crab spider interacts with its prey. Field and laboratory experiments demonstrated that UV reflection of adult E. heterogaster is the main signal responsible for the attraction of pollinators. This is the first study to demonstrate that a crab spider attracts pollinators regardless of flower UV signal, which may represent an evolutionary pathway beyond the dependence of flowers. PMID- 28835628 TI - The receptor genes PfBMPR1B and PfBAMBI are involved in regulating shell biomineralization in the pearl oyster Pinctada fucata. AB - Mounting evidence suggests that TGFbeta/BMP signaling pathway is most likely involved in shell biomineralization in molluscs, but the function of pathway receptors is poorly studied. Here, we cloned and identified two homologous BMP receptor genes, PfBMPR1B and PfBAMBI, from the pearl oyster Pinctada fucata. Real time quantitative PCR and in situ hybridization revealed that these genes were expressed in mantle edge and pallial, specifically located at the outer epithelia. Knockdown of PfBMPR1B by RNA interference (RNAi) significantly decreased the expression levels of matrix protein (MP) genes and induced the abnormal ultrastructure of prismatic and nacreous layers. Conversely, knockdown of PfBAMBI significantly increased the expression levels of a portion of MP genes and induced the overgrowth of nacreous layer crystals. In the RNAi and shell notching experiments, MP gene expressions were competitively regulated by PfBMPR1B and PfBAMBI. In addition, the receptor inhibitor LDN193189 reduced the expression levels of MP genes in mantle primary cells and larvae, and induced abnormal D-shaped shell formation during larval development. Collectively, these results clearly show that PfBMPR1B and PfBAMBI are involved in regulating shell biomineralization in P. fucata. Our study therefore provides the direct evidence that BMP receptors participate in mollusc biomineralization. PMID- 28835631 TI - Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis. AB - The mechanism by which dominantly inherited mutations in the housekeeping gene GARS, which encodes glycyl-tRNA synthetase (GlyRS), mediate selective peripheral nerve toxicity resulting in Charcot-Marie-Tooth disease type 2D (CMT2D) is still largely unresolved. The transmembrane receptor protein neuropilin 1 (Nrp1) was recently identified as an aberrant extracellular binding partner of mutant GlyRS. Formation of the Nrp1/mutant GlyRS complex antagonises Nrp1 interaction with one of its main natural ligands, vascular endothelial growth factor-A (VEGF-A), contributing to neurodegeneration. However, reduced extracellular binding of VEGF A to Nrp1 is known to disrupt post-natal blood vessel development and growth. We therefore analysed the vascular system at early and late symptomatic time points in CMT2D mouse muscles, retina, and sciatic nerve, as well as in embryonic hindbrain. Mutant tissues show no difference in blood vessel diameter, density/growth, and branching from embryonic development to three months, spanning the duration over which numerous sensory and neuromuscular phenotypes manifest. Our findings indicate that mutant GlyRS-mediated disruption of Nrp1/VEGF-A signalling is permissive to maturation and maintenance of the vasculature in CMT2D mice. PMID- 28835632 TI - A Genome-Wide Identification of the WRKY Family Genes and a Survey of Potential WRKY Target Genes in Dendrobium officinale. AB - The WRKY family, one of the largest families of transcription factors, plays important roles in the regulation of various biological processes, including growth, development and stress responses in plants. In the present study, 63 DoWRKY genes were identified from the Dendrobium officinale genome. These were classified into groups I, II, III and a non-group, each with 14, 28, 10 and 11 members, respectively. ABA-responsive, sulfur-responsive and low temperature responsive elements were identified in the 1-k upstream regulatory region of DoWRKY genes. Subsequently, the expression of the 63 DoWRKY genes under cold stress was assessed, and the expression profiles of a large number of these genes were regulated by low temperature in roots and stems. To further understand the regulatory mechanism of DoWRKY genes in biological processes, potential WRKY target genes were investigated. Among them, most stress-related genes contained multiple W-box elements in their promoters. In addition, the genes involved in polysaccharide synthesis and hydrolysis contained W-box elements in their 1-k upstream regulatory regions, suggesting that DoWRKY genes may play a role in polysaccharide metabolism. These results provide a basis for investigating the function of WRKY genes and help to understand the downstream regulation network in plants within the Orchidaceae. PMID- 28835633 TI - The changing epidemiological characteristics of severe fever with thrombocytopenia syndrome in China, 2011-2016. AB - Severe fever with thrombocytopenia syndrome (SFTS) is emerging and the number of SFTS cases increased year by year in China. In order to explore the epidemiology trend, we analyzed the changing epidemiological characteristics of SFTS cases in different years and compare characteristics in different provinces. From 2011 to 2016, a total of 5360 laboratory-confirmed SFTS cases were reported and annual case numbers increased year by year. Most SFTS cases occurred in individuals aged between 40 years and 80 years (91.57%), but age distributions of SFTS cases in different years were significantly different and the median ages increased slightly year by year. The numbers of affected counties from 2011 to 2016 increased sharply from 98 to 167. Of note, the seasonal distributions of SFTS cases in different provinces were significantly different (Fisher = 712.157, P = 0.000) and provinces in south regions showed earlier epidemic peak and longer epidemics durations. The median time from illness onset to confirmation of different years was significantly different (chi2 = 896.088, P = 0.000) and it peaked in 2014. Furthermore, case fatality rate was associated with province, year, and age of SFTS cases. These results may be helpful for authorities to better preventive strategy and improve interventions against SFTS. PMID- 28835634 TI - Altitude control in honeybees: joint vision-based learning and guidance. AB - Studies on insects' visual guidance systems have shed little light on how learning contributes to insects' altitude control system. In this study, honeybees were trained to fly along a double-roofed tunnel after entering it near either the ceiling or the floor of the tunnel. The honeybees trained to hug the ceiling therefore encountered a sudden change in the tunnel configuration midways: i.e. a "dorsal ditch". Thus, the trained honeybees met a sudden increase in the distance to the ceiling, corresponding to a sudden strong change in the visual cues available in their dorsal field of view. Honeybees reacted by rising quickly and hugging the new, higher ceiling, keeping a similar forward speed, distance to the ceiling and dorsal optic flow to those observed during the training step; whereas bees trained to follow the floor kept on following the floor regardless of the change in the ceiling height. When trained honeybees entered the tunnel via the other entry (the lower or upper entry) to that used during the training step, they quickly changed their altitude and hugged the surface they had previously learned to follow. These findings clearly show that trained honeybees control their altitude based on visual cues memorized during training. The memorized visual cues generated by the surfaces followed form a complex optic flow pattern: trained honeybees may attempt to match the visual cues they perceive with this memorized optic flow pattern by controlling their altitude. PMID- 28835635 TI - Topological superconductors from one-dimensional periodically modulated Majorana chains. AB - By analogy to the topological models of fermions in one-dimensional periodically modulated lattices, we provide a systematic method to construct topological superconductors in BDI class. We then create superlattices of Majorana fermions to interpolate several Majorana chains, and realize topological superconductors with arbitrary winding numbers. Two kinds of chiral symmetries are identified in the systems with multiple chains. Of the two winding numbers associated to the chiral symmetries, one counts the number of zero-energy modes, while the other counts the difference of the numbers of alpha- and beta-type Majorana zero states. We also show that one alpha- and one beta-type Majorana zero modes collapse into fractional charged zero states when they are spatially intertwined. In the systems with odd number of chains, it induces topological superconductors with coexistence of fractional charged zero states and Majorana zero states. Finally by introducing symmetry breaking term, we present an intuitive explanation of the Z2 nature of the topological invariant in the D class. PMID- 28835636 TI - Potential inhibitors designed against NDM-1 type metallo-beta-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria. AB - NDM-1 and its variants are the most prevalent types of metallo-beta-lactamases, hydrolyze almost all antibiotics of beta-lactam group leading to multiple-drug resistance in bacteria. No inhibitor has yet been obtained for NDM-1 or other class of metallo-beta-lactamases. Therefore, strategies to identify novel anti beta-lactamase agents with specific mechanisms of action are the need of an hour. In this study, we have reported the discovery of novel non-beta-lactam inhibitors against NDM-1 by multi-step virtual screening approach. The potential for virtually screened drugs was estimated through in vitro cell assays. Five chemical compounds were finally purchased and evaluated experimentally for their efficacies to inhibit NDM-1 producing bacterial cells, in vitro. The dissociation constants (Kd), association constant (Ka), stoichiometry (n) and binding energies (DeltaG) of compounds with the respective targets were determined using isothermal titration calorimetry (ITC). Molecular dynamic simulation carried out for 25 ns revealed that these complexes were stable throughout the simulation with relative RMSD in acceptable range. Moreover, Microbiological and kinetic studies further confirmed high efficacies of these inhibitors by reducing the minimum inhibitory concentration (MIC) and catalysis of antibiotics by beta lactamases in the presence of inhibitors. Therefore, we conclude that these potential inhibitors may be used as lead molecules for future drug candidates. PMID- 28835637 TI - Cutaneous pigmentation modulates skin sensitivity via tyrosinase-dependent dopaminergic signalling. AB - We propose a new mechanism of sensory modulation through cutaneous dopaminergic signalling. We hypothesize that dopaminergic signalling contributes to differential cutaneous sensitivity in darker versus lighter pigmented humans and mouse strains. We show that thermal and mechanical cutaneous sensitivity is pigmentation dependent. Meta-analyses in humans and mice, along with our own mouse behavioural studies, reveal higher thermal sensitivity in pigmented skin relative to less-pigmented or albino skin. We show that dopamine from melanocytes activates the D1-like dopamine receptor on primary sensory neurons. Dopaminergic activation increases expression of the heat-sensitive TRPV1 ion channel and reduces expression of the mechanically-sensitive Piezo2 channel; thermal threshold is lower and mechanical threshold is higher in pigmented skin. PMID- 28835638 TI - Shared genetic variants for polypoidal choroidal vasculopathy and typical neovascular age-related macular degeneration in East Asians. AB - Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neovascular AMD (tAMD). We aim to examine the extent to which common genetic variants are shared between these two subtypes. We performed the meta-analysis of association in a total of 1062 PCV patients, 1157 tAMD patients and 5275 controls of East Asian descent from the Genetics of AMD in Asians Consortium at the 34 known AMD loci. A total of eight loci were significantly associated with PCV, including age-related maculopathy susceptibility 2 (ARMS2)-HtrA serine peptidase 1 (HTRA1), complement factor H (CFH), C2-CFB-SKIV2L, CETP, VEGFA, ADAMTS9-AS2 and TGFBR1 (P<5 * 10-4) from the single-nucleotide polymorphism-based test and COL4A3 from the gene-based tests (Pgene=2.02 * 10-4). PCV and tAMD are genetically highly correlated (rg=0.69, P=4.68 * 10-3), with AMD known loci accounting for up to 36% variation. Weaker association for PCV was observed at ARMS2-HTRA1 (Pdif=4.39 * 10-4) and KMT2E SRPK2(Pdif=4.43 * 10-3), compared with tAMD. Variants at CFH, CETP and VEGFA exhibited different association signals in East Asians, in contrast to those in European individuals. Our data suggest a substantially shared genetic susceptibility for PCV and tAMD, while also highlight the unique associations for PCV, which is useful in understanding the pathogenesis of PCV. PMID- 28835639 TI - Dietary Fat Intake Modulates Effects of a Frequent ACE Gene Variant on Glucose Tolerance with association to Type 2 Diabetes. AB - The frequent ACE insertion/deletion polymorphism (I/D) is, albeit inconsistently, associated with impaired glucose tolerance and insulin resistance. We recently observed an enhanced upregulation of ACE by elevated fat intake in GG-carriers of the I/D-surrogate rs4343 variant and therefore investigated its potential nutrigenetic role in glucose metabolism. In this nutritional intervention study 46 healthy and non-obese twin pairs consumed recommended low fat diets for 6 weeks before they received a 6-week high fat (HF) diet under isocaloric conditions. Intravenous glucose tolerance tests were performed before and after 1 and 6 weeks of HF diet. While glucose tolerance did not differ between genotypes at baseline it significantly declined in GG-carriers after 6 weeks HF diet (p = 0.001) with higher 2 h glucose and insulin concentrations compared to AA/AG carriers (p = 0.003 and p = 0.042). Furthermore, the gene-diet interaction was confirmed in the cross-sectional Metabolic Syndrome Berlin Potsdam study (p = 0.012), with the GG-genotypes being significantly associated with prevalent type 2 diabetes for participants with high dietary fat intake >=37% (GG vs. AA/AG, OR 2.36 [1.02-5.49], p = 0.045). In conclusion, the association between the rs4343 variant and glucose tolerance is modulated by dietary fat intake. The ACE rs4343 variant is a novel nutrient-sensitive type 2 diabetes risk marker potentially applicable for nutrigenetic dietary counseling. PMID- 28835640 TI - Pregnancy reduces the perception of anxiety. AB - In humans, stress can be contagiously transmitted via chemosignals on a subconscious level. This study investigates how pregnancy affects neural responses to anxiety chemosignals. Using cotton pads, 28 men donated axillary sweat immediately before an academic examination (anxiety sweat) and during ergometer training (control). Via a constant-flow olfactometer, samples were presented (oddball paradigm) to 12 non-pregnant (NP) women, 14 women in their first (T1), and 18 in their third (T3) trimester of pregnancy. Chemosensory event related potentials and current source densities (CSD) were analysed (60 electrode setup). Compared to NP-women, pregnant women display diminished evaluative processing of the sweat samples (targets; P3-1/ P3-2 amplitudes) and delayed evaluative processing of the anxiety sweat (targets; P3-2 latency). T3-women show attenuated early processing (targets; N1 amplitude) compared to NP-women, and reduced evaluative processing compared to T1-women (standards; P3-2 amplitude). CSDs (P3-1/ P3-2 latency ranges) reveal that T1- and T3-women show an atypical activation distribution to anxiety sweat. Most participants were unable to detect the sweat samples (anxiety sweat: 79.5%, sport sweat 88.6%). The results demonstrate that the processing of anxiety chemosignals progressively vanishes during pregnancy. This effect is likely to occur without any cognitive control. PMID- 28835642 TI - Maximum entropy models capture melodic styles. AB - We introduce a Maximum Entropy model able to capture the statistics of melodies in music. The model can be used to generate new melodies that emulate the style of a given musical corpus. Instead of using the n-body interactions of (n-1) order Markov models, traditionally used in automatic music generation, we use a k nearest neighbour model with pairwise interactions only. In that way, we keep the number of parameters low and avoid over-fitting problems typical of Markov models. We show that long-range musical phrases don't need to be explicitly enforced using high-order Markov interactions, but can instead emerge from multiple, competing, pairwise interactions. We validate our Maximum Entropy model by contrasting how much the generated sequences capture the style of the original corpus without plagiarizing it. To this end we use a data-compression approach to discriminate the levels of borrowing and innovation featured by the artificial sequences. Our modelling scheme outperforms both fixed-order and variable-order Markov models. This shows that, despite being based only on pairwise interactions, our scheme opens the possibility to generate musically sensible alterations of the original phrases, providing a way to generate innovation. PMID- 28835643 TI - Evolution of regular geometrical shapes in fiber lumens. AB - The geometry of polymeric hollow fibers for hemodialysis or desalination is a key factor determining their performance. Deformations are frequently observed, but they are rather random. Here we were able to exactly control the shape evolution of the internal channels or lumens of polymeric hollow fibers, leading to polygonal geometries with increasing number of sides. The elasticity of the incipient channel skin and instabilities during fiber formation are affected by the internal coagulant fluid composition and flow rate; and highly influence the polygonal shape. We propose a holistic explanation by analyzing the thermodynamic, kinetic and rheological aspects involved in the skin formation and their synergy. PMID- 28835641 TI - RNA-aptamers-in-droplets (RAPID) high-throughput screening for secretory phenotypes. AB - Synthetic biology and metabolic engineering seek to re-engineer microbes into "living foundries" for the production of high value chemicals. Through a "design build-test" cycle paradigm, massive libraries of genetically engineered microbes can be constructed and tested for metabolite overproduction and secretion. However, library generation capacity outpaces the rate of high-throughput testing and screening. Well plate assays are flexible but with limited throughput, whereas droplet microfluidic techniques are ultrahigh-throughput but require a custom assay for each target. Here we present RNA-aptamers-in-droplets (RAPID), a method that greatly expands the generality of ultrahigh-throughput microfluidic screening. Using aptamers, we transduce extracellular product titer into fluorescence, allowing ultrahigh-throughput screening of millions of variants. We demonstrate the RAPID approach by enhancing production of tyrosine and secretion of a recombinant protein in Saccharomyces cerevisiae by up to 28- and 3-fold, respectively. Aptamers-in-droplets affords a general approach for evolving microbes to synthesize and secrete value-added chemicals.Screening libraries of genetically engineered microbes for secreted products is limited by the available assay throughput. Here the authors combine aptamer-based fluorescent detection with droplet microfluidics to achieve high throughput screening of yeast strains engineered for enhanced tyrosine or streptavidin production. PMID- 28835644 TI - CO2 and temperature decoupling at the million-year scale during the Cretaceous Greenhouse. AB - CO2 is considered the main greenhouse gas involved in the current global warming and the primary driver of temperature throughout Earth's history. However, the soundness of this relationship across time scales and during different climate states of the Earth remains uncertain. Here we explore how CO2 and temperature are related in the framework of a Greenhouse climate state of the Earth. We reconstruct the long-term evolution of atmospheric CO2 concentration (pCO2) throughout the Cretaceous from the carbon isotope compositions of the fossil conifer Frenelopsis. We show that pCO2 was in the range of ca. 150-650 ppm during the Barremian-Santonian interval, far less than what is usually considered for the mid Cretaceous. Comparison with available temperature records suggest that although CO2 may have been a main driver of temperature and primary production at kyr or smaller scales, it was a long-term consequence of the climate-biological system, being decoupled or even showing inverse trends with temperature, at Myr scales. Our analysis indicates that the relationship between CO2 and temperature is time scale-dependent at least during Greenhouse climate states of the Earth and that primary productivity is a key factor to consider in both past and future analyses of the climate system. PMID- 28835645 TI - The evolution of animal Argonautes: evidence for the absence of antiviral AGO Argonautes in vertebrates. AB - In addition to mediating regulation of endogenous gene expression, RNA interference (RNAi) in plants and invertebrates plays a crucial role in defense against viruses via virus-specific siRNAs. Different studies have demonstrated that the functional diversity of RNAi in animals is linked to the diversification of the Argonaute superfamily, central components of RISCs (RNA induced silencing complexes). The animal Argonaute superfamily is traditionally grouped into AGO and PIWI Argonautes. Yet, by performing phylogenetic analyses and determining the selective evolutionary pressure in the metazoan Argonaute superfamily, we provide evidence for the existence of three conserved Argonaute lineages between basal metazoans and protostomes, namely siRNA-class AGO, miRNA-class AGO and PIWI Argonautes. In addition, it shown that the siRNA-class AGO lineage is characterized by high rates of molecular evolution, suggesting a role in the arms race with viruses, while the miRNA-class AGOs display strong sequence conservation. Interestingly, we also demonstrate that vertebrates lack siRNA class AGO proteins and that vertebrate AGOs display low rates of molecular evolution. In this way, we provide supportive evidence for the loss of the antiviral siRNA-class AGO group in vertebrates and discuss the consequence hereof on antiviral immunity and the use of RNAi as a loss of function tool in these animals. PMID- 28835646 TI - Elucidation of the molecular responses to waterlogging in Sesbania cannabina roots by transcriptome profiling. AB - Sesbania cannabina, a multipurpose leguminous crop, is highly resistant to waterlogging stress. However, the scant genomic resources in the genus Sesbania have greatly hindered further exploration of the mechanisms underlying its waterlogging tolerance. Here, the genetic basis of flooding tolerance in S. cannabina was examined by transcriptome-wide gene expression changes using RNA Seq in seedlings exposed to short-term (3 h) and long-term (27 h) waterlogging. After de- novo assembly, 213990 unigenes were identified, of which 145162 (79.6%) were annotated. Gene Ontology and pathway enrichment analyses revealed that the glycolysis and fermentation pathways were stimulated to produce ATP under hypoxic stress conditions. Energy-consuming biosynthetic processes were dramatically repressed by short and long term waterlogging, while amino acid metabolism was greatly induced to maintain ATP levels. The expression pattern of 10 unigenes involved in phenylpropanoid biosynthesis, glycolysis, and amino acid metabolism revealed by qRT-PCR confirmed the RNA-Seq data. The present study is a large scale assessment of genomic resources of Sesbania and provides guidelines for probing the molecular mechanisms underlying S. cannabina waterlogging tolerance. PMID- 28835647 TI - Comparative transcriptomic analysis reveals the roles of ROS scavenging genes in response to cadmium in two pak choi cultivars. AB - To identify key regulatory genes involved in ROS scavenging in response to cadmium (Cd) exposure in pak choi, eight cDNA libraries from Cd-treated and Cd free roots of two cultivars, Baiyewuyueman (high Cd accumulator) and Kuishan'aijiaoheiye (low Cd accumulator), were firstly performed by RNA sequencing. Totally 0.443 billion clean reads and 244,190 unigenes were obtained from eight transcriptome. About 797 and 1167 unigenes encoding ROS related proteins and transcription factors were identified. Of them, 11 and 16 ROS scavenging system related DEGs, and 29 and 15 transcription factors related DEGs were found in Baiyewuyueman and Kuishan'aijiaoheiye, respectively. Ten ROS scavenging genes (Cu/Zn-SOD, GST1, PODs, TrxR2, PrxR, FER3 and NDPK) showed higher expression levels in Cd-exposed seedings of Baiyewuyueman than those of Kuishan'aijiaoheiye. Four genes (GPX, APX, GRX and GST3) specifically expressed in Cd-free roots of Kuishan'aijiaoheiye. For transcription factors, ERF12/13/22 and WRKY31 was up-regulated by Cd in Baiyewuyueman, while in Kuishan'aijiaoheiye, Cd induced down-regulations of bZIP, NAC and ZFP families. The results indicate that the two cultivars differed in the mechanism of ROS scavenging in response to Cd stress. Fe SOD1, POD A2/44/54/62 and GST1 may be responsible for the difference of Cd tolerance between Baiyewuyueman and Kuishan'aijiaoheiye. PMID- 28835648 TI - BioFlow: a non-invasive, image-based method to measure speed, pressure and forces inside living cells. AB - Cell motility is governed by a complex molecular machinery that converts physico chemical cues into whole-cell movement. Understanding the underlying biophysical mechanisms requires the ability to measure physical quantities inside the cell in a simple, reproducible and preferably non-invasive manner. To this end, we developed BioFlow, a computational mechano-imaging method and associated software able to extract intracellular measurements including pressure, forces and velocity everywhere inside freely moving cells in two and three dimensions with high spatial resolution in a non-invasive manner. This is achieved by extracting the motion of intracellular material observed using fluorescence microscopy, while simultaneously inferring the parameters of a given theoretical model of the cell interior. We illustrate the power of BioFlow in the context of amoeboid cell migration, by modelling the intracellular actin bulk flow of the parasite Entamoeba histolytica using fluid dynamics, and report unique experimental measures that complement and extend both theoretical estimations and invasive experimental measures. Thanks to its flexibility, BioFlow is easily adaptable to other theoretical models of the cell, and alleviates the need for complex or invasive experimental conditions, thus constituting a powerful tool-kit for mechano-biology studies. BioFlow is open-source and freely available via the Icy software. PMID- 28835649 TI - Extracellular-matrix-mediated osmotic pressure drives Vibrio cholerae biofilm expansion and cheater exclusion. AB - Biofilms, surface-attached communities of bacteria encased in an extracellular matrix, are a major mode of bacterial life. How the material properties of the matrix contribute to biofilm growth and robustness is largely unexplored, in particular in response to environmental perturbations such as changes in osmotic pressure. Here, using Vibrio cholerae as our model organism, we show that during active cell growth, matrix production enables biofilm-dwelling bacterial cells to establish an osmotic pressure difference between the biofilm and the external environment. This pressure difference promotes biofilm expansion on nutritious surfaces by physically swelling the colony, which enhances nutrient uptake, and enables matrix-producing cells to outcompete non-matrix-producing cheaters via physical exclusion. Osmotic pressure together with crosslinking of the matrix also controls the growth of submerged biofilms and their susceptibility to invasion by planktonic cells. As the basic physicochemical principles of matrix crosslinking and osmotic swelling are universal, our findings may have implications for other biofilm-forming bacterial species.Most bacteria live in biofilms, surface-attached communities encased in an extracellular matrix. Here, Yan et al. show that matrix production in Vibrio cholerae increases the osmotic pressure within the biofilm, promoting biofilm expansion and physical exclusion of non-matrix producing cheaters. PMID- 28835650 TI - Disparate subcellular location of putative sortase substrates in Clostridium difficile. AB - Clostridium difficile is a gastrointestinal pathogen but how the bacterium colonises this niche is still little understood. Sortase enzymes covalently attach specific bacterial proteins to the peptidoglycan cell wall and are often involved in colonisation by pathogens. Here we show C. difficile proteins CD2537 and CD3392 are functional substrates of sortase SrtB. Through manipulation of the C-terminal regions of these proteins we show the SPKTG motif is essential for covalent attachment to the cell wall. Two additional putative substrates, CD0183 which contains an SPSTG motif, and CD2768 which contains an SPQTG motif, are not cleaved or anchored to the cell wall by sortase. Finally, using an in vivo asymmetric cleavage assay, we show that despite containing a conserved SPKTG motif, in the absence of SrtB these proteins are localised to disparate cellular compartments. PMID- 28835652 TI - Litter chemistry explains contrasting feeding preferences of bacteria, fungi, and higher plants. AB - Litter decomposition provides a continuous flow of organic carbon and nutrients that affects plant development and the structure of decomposer communities. Aim of this study was to distinguish the feeding preferences of microbes and plants in relation to litter chemistry. We characterized 36 litter types by 13C-CPMAS NMR spectroscopy and tested these materials on 6 bacteria, 6 fungi, and 14 target plants. Undecomposed litter acted as a carbon source for most of the saprophytic microbes, although with a large variability across litter types, severely inhibiting root growth. An opposite response was found for aged litter that largely inhibited microbial growth, but had neutral or stimulatory effects on root proliferation. 13C-CPMAS NMR revealed that restricted resonance intervals within the alkyl C, methoxyl C, O-alkyl C and di-O-alkyl C spectral regions are crucial for understanding litter effects. Root growth, in contrast to microbes, was negatively affected by labile C sources but positively associated with signals related to plant tissue lignification. Our study showed that plant litter has specific and contrasting effects on bacteria, fungi and higher plants, highlighting that, in order to understand the effects of plant detritus on ecosystem structure and functionality, different microbial food web components should be simultaneously investigated. PMID- 28835651 TI - Brain plasticity following MI-BCI training combined with tDCS in a randomized trial in chronic subcortical stroke subjects: a preliminary study. AB - Brain-computer interface-assisted motor imagery (MI-BCI) or transcranial direct current stimulation (tDCS) has been used in stroke rehabilitation, though their combinatory effect is unknown. We investigated brain plasticity following a combined MI-BCI and tDCS intervention in chronic subcortical stroke patients with unilateral upper limb disability. Nineteen patients were randomized into tDCS and sham-tDCS groups. Diffusion and perfusion MRI, and transcranial magnetic stimulation were used to study structural connectivity, cerebral blood flow (CBF), and corticospinal excitability, respectively, before and 4 weeks after the 2-week intervention. After quality control, thirteen subjects were included in the CBF analysis. Eleven healthy controls underwent 2 sessions of MRI for reproducibility study. Whereas motor performance showed comparable improvement, long-lasting neuroplasticity can only be detected in the tDCS group, where white matter integrity in the ipsilesional corticospinal tract and bilateral corpus callosum was increased but sensorimotor CBF was decreased, particularly in the ipsilesional side. CBF change in the bilateral parietal cortices also correlated with motor function improvement, consistent with the increased white matter integrity in the corpus callosum connecting these regions, suggesting an involvement of interhemispheric interaction. The preliminary results indicate that tDCS may facilitate neuroplasticity and suggest the potential for refining rehabilitation strategies for stroke patients. PMID- 28835653 TI - Rapid Prototyping of Polymeric Nanopillars by 3D Direct Laser Writing for Controlling Cell Behavior. AB - Mammalian cells have been widely shown to respond to nano- and microtopography that mimics the extracellular matrix. Synthetic nano- and micron-sized structures are therefore of great interest in the field of tissue engineering, where polymers are particularly attractive due to excellent biocompatibility and versatile fabrication methods. Ordered arrays of polymeric pillars provide a controlled topographical environment to study and manipulate cells, but processing methods are typically either optimized for the nano- or microscale. Here, we demonstrate polymeric nanopillar (NP) fabrication using 3D direct laser writing (3D DLW), which offers a rapid prototyping across both size regimes. The NPs are interfaced with NIH3T3 cells and the effect of tuning geometrical parameters of the NP array is investigated. Cells are found to adhere on a wide range of geometries, but the interface depends on NP density and length. The Cell Interface with Nanostructure Arrays (CINA) model is successfully extended to predict the type of interface formed on different NP geometries, which is found to correlate with the efficiency of cell alignment along the NPs. The combination of the CINA model with the highly versatile 3D DLW fabrication thus holds the promise of improved design of polymeric NP arrays for controlling cell growth. PMID- 28835654 TI - A method to generate small-scale, high-resolution sedimentary bedform architecture models representing realistic geologic facies. AB - Small-scale (mm to m) sedimentary structures (e.g. ripple lamination, cross bedding) have received a great deal of attention in sedimentary geology. The influence of depositional heterogeneity on subsurface fluid flow is now widely recognized, but incorporating these features in physically-rational bedform models at various scales remains problematic. The current investigation expands the capability of an existing set of open-source codes, allowing generation of high-resolution 3D bedform architecture models. The implemented modifications enable the generation of 3D digital models consisting of laminae and matrix (binary field) with characteristic depositional architecture. The binary model is then populated with petrophysical properties using a textural approach for additional analysis such as statistical characterization, property upscaling, and single and multiphase fluid flow simulation. One example binary model with corresponding threshold capillary pressure field and the scripts used to generate them are provided, but the approach can be used to generate dozens of previously documented common facies models and a variety of property assignments. An application using the example model is presented simulating buoyant fluid (CO2) migration and resulting saturation distribution. PMID- 28835655 TI - Involvement of oxidative modification of proteins related to ATP synthesis in the left ventricles of hamsters with cardiomyopathy. AB - Inflammation enhanced by accumulation of reactive oxygen species plays an essential role in the progression of cardiovascular diseases. Using the 2D oxyblot analysis and 2D-difference image gel electrophoresis (2D-DIGE), we compared the levels of ROS-induced carbonyl modification of myocardial proteins in the whole left ventricles between 6-week-old hamsters with dilated (TO-2) and hypertrophic cardiomyopathy (Bio14.6) and control hamsters (F1B). Then, 2D electrophoresis combined with MALDI-TOF/TOF tandem mass spectrometry detected 18 proteins with increased carbonyl level in cardiomyopathy hamsters compared with control hamster. Carbonyl modification of proteins related to ATP synthesis, including citric acid cycle and electron transport system, was observed in the hearts of hamsters with both types of cardiomyopathy. Further analysis indicated that left ventricular carbonyl production correlated negatively with succinyl CoA:3-ketoacid-coenzyme A transferase 1 activity (r 2 = 0.60, P = 0.0007) and ATP concentration (r 2 = 0.29, P = 0.037), suggesting that protein carbonylation has negative effects on the levels of these biomolecules. Furthermore, carbonyl production significantly correlated with plasma Troponin T level (r 2 = 0.33, P = 0.026). Reduction of energy metabolism by oxidative damage may contribute to the development of left ventricular impairment in cardiomyopathy. PMID- 28835656 TI - The role of transparency cues in afterimage color perception. AB - : Recent evidence has shown that afterimage perception and completion are amenable to contextual information. It has previously been shown that placing an outline around part of the afterimage can induce colors in areas that were uncolored. A thorough explanation of this effect is lacking, although this color completion was thought to be due to a diffusion-like filling-in of the uncolored patch with colors of the surrounding areas. Here, we show that an important step in visual completion is the decomposition of the visual scene into different depth layers, i.e. scission, which, we show, is guided by transparency cues in the van Lier et al. STUDY: In three experiments, we show that when decomposition is prevented, color completion does not occur. We also show that this decomposition can induce color completion in real images. These results demonstrate that transparency information plays an important role in determining visual color completion processes. PMID- 28835657 TI - Multimodal magnetic resonance imaging in relation to cognitive impairment in neuromyelitis optica spectrum disorder. AB - Cognitive impairment (CI) is reported in 29-57% of patients with neuromyelitis optica spectrum disorder (NMOSD). However, the pathophysiology underlying CI in NMOSD is poorly understood. The present study aims to investigate the predictive values of various conventional and quantitative MRI parameters for cognitive performance in patients with NMOSD. Neurological assessment and conventional, diffusion tensor, and volumetric MRI sequences were collected form 73 patients with NMOSD and 44 healthy controls (HCs). Patients with >=3 failed tests were considered to have CI. Brain lesion load, gray matter (GM) and white matter (WM) atrophy, deep GM (DGM) atrophy, cortical thickness, and diffuse microstructural WM damage were assessed. Twenty-three (32%) patients with NMOSD had CI. Compared to cognitively preserved (CP) individuals, patients with CI had atrophy in the WM, thalamus, and caudate, decreased fractional anisotropy (FA) and increased mean diffusivity in their WM. A multivariate model indicated that mean FA values in the WM and volume in the nucleus accumbens (NAc) were associated with overall cognition (p = 0.002 and p = 0.008, respectively). Diffuse microstructural damage in the WM and DGM atrophy in the NAc are the strongest predictors of cognitive impairment in patients with NMOSD. PMID- 28835658 TI - Preprocessing of emotional visual information in the human piriform cortex. AB - This study examines the processing of visual information by the olfactory system in humans. Recent data point to the processing of visual stimuli by the piriform cortex, a region mainly known as part of the primary olfactory cortex. Moreover, the piriform cortex generates predictive templates of olfactory stimuli to facilitate olfactory processing. This study fills the gap relating to the question whether this region is also capable of preprocessing emotional visual information. To gain insight into the preprocessing and transfer of emotional visual information into olfactory processing, we recorded hemodynamic responses during affective priming using functional magnetic resonance imaging (fMRI). Odors of different valence (pleasant, neutral and unpleasant) were primed by images of emotional facial expressions (happy, neutral and disgust). Our findings are the first to demonstrate that the piriform cortex preprocesses emotional visual information prior to any olfactory stimulation and that the emotional connotation of this preprocessing is subsequently transferred and integrated into an extended olfactory network for olfactory processing. PMID- 28835659 TI - Changes in the intestinal microbiota following the administration of azithromycin in a randomised placebo-controlled trial among infants in south India. AB - Macrolides are among the most widely prescribed antibiotics worldwide. However, their impact on the gut's bacterial microbiota remains uncertain. We characterised the intestinal microbiota in 6-11 month-old infants in India who received a 3-day course of azithromycin or placebo during a randomised trial of oral poliovirus vaccine immunogenicity (CTRI/2014/05/004588). In 60 infants per study arm, we sequenced the V4 region of the bacterial 16S rRNA gene in stool samples collected before and 12 days after finishing treatment. We also tested for the presence of common bacterial, viral, and eukaryotic enteropathogens in the same samples using real-time PCR in a Taqman array card (TAC) format. Azithromycin induced a modest decline in microbiota richness and a shift in taxonomic composition driven by a reduction in the relative abundance of Proteobacteria and Verrucomicrobia (specifically Akkermansia muciniphila). The former phylum includes pathogenic strains of Escherichia coli and Campylobacter spp. that declined in prevalence based on the TAC assay. These findings differ from previous observations among older children and adults in Europe and North America, suggesting that the effects of azithromycin on the bacterial microbiota may be specific to the age and geographic setting of its recipients. PMID- 28835660 TI - The efficacy of biliary and serum macrophage inhibitory cytokine-1 for diagnosing biliary tract cancer. AB - The serum macrophage inhibitory cytokine-1 (MIC-1) levels are elevated in some inflammatory conditions and cancers. We thus compared the levels of biliary and serum MIC-1 and conventional tumour markers between 23 biliary tract cancer (BTC) patients (malignant group) and 29 benign biliary disease patients (benign group) and found that all markers were significantly elevated in the malignant group. The levels of two markers were higher in early BTC (Stage I/II, n = 15) than in the benign group: biliary MIC-1 [12 (0-2153) vs. 678 (0-4429) pg/ml, P < 0.01] and serum CA19-9 [13 (2-15,682) vs. 45.1 (2-10,478) U/ml, P = 0.02]. A receiver operating characteristic curve analysis revealed that the area under the curve for biliary MIC-1 was greater than that for serum CA19-9 (0.77 vs. 0.73). The cut off value for biliary MIC-1 in diagnosing early BTC was 581.6 pg/ml, and this value yielded a sensitivity, specificity and accuracy of 71.4%, 82.8%, and 79.1%, respectively. The sensitivity of biliary MIC-1 for diagnosing early BTC was superior to that of biliary cytology (71.4% vs. 8.33%, P < 0.01), and the combination of serum MIC-1 with CA19-9 (cut-off value = 4021.2 pg/ml, 42.4 U/ml) was useful for screening BTC (sensitivity = 82.6%, specificity = 72.4%). In conclusion, biliary MIC-1 can effectively diagnose early BTC. PMID- 28835661 TI - Association between Serum Folate and Insulin Resistance among U.S. Nondiabetic Adults. AB - Recent studies have suggested that epigenetic alterations, particularly DNA methylation, play a crucial role in the pathogenesis of insulin resistance. Folate is a key source of the one-carbon group for DNA methylation, whereas the association and mechanistic linkage between folate status and insulin resistance remains unclear with very limited experimental support. We performed a cross sectional study of 1530 nondiabetic adults in the 2011-2012 National Health and Nutrition Examination Survey (NHANES). We examined associations between serum folate and insulin resistance using multiple linear regression models adjusted for potential confounders. We detected a significant inverse relationship for serum folate, where a 25% increase in serum folate was associated with a 3.06% (95% CI, -4.72, -1.37) and 2.77% (95% CI, -4.36, -1.77) decline in HOMA-IR and insulin respectively, and a 2.55% (95% CI, 0.93, 4.21) increase in G/I ratio. Our findings demonstrate that serum folate was inversely associated with insulin resistance in U.S. nondiabetic adults. PMID- 28835663 TI - Choroid Plexitis and Ependymitis by Magnetic Resonance Imaging are Biomarkers of Neuronal Damage and Inflammation in HIV-negative Cryptococcal Meningoencephalitis. AB - CNS cryptococcal meningoencephalitis in both HIV positive (HIV+) and HIV negative (HIV-) subjects is associated with high morbidity and mortality despite optimal antifungal therapy. We thus conducted a detailed analysis of the MR imaging findings in 45 HIV- and 11 HIV+ patients to identify imaging findings associated with refractory disease. Ventricular abnormalities, namely ependymitis and choroid plexitis were seen in HIV- but not in HIV+ subjects. We then correlated the imaging findings in a subset of HIV- subjects (n = 17) to CSF levels of neurofilament light chain (NFL), reflective of axonal damage and sCD27, known to best predict the presence of intrathecal T-cell mediated inflammation. We found that ependymitis on brain MRI was the best predictor of higher log(sCD27) levels and choroid plexitis was the best predictor of higher log(NFL) levels. The availability of predictive imaging biomarkers of inflammation and neurological damage in HIV- subjects with CNS cryptococcosis may help gauge disease severity and guide the therapeutic approach in those patients. PMID- 28835662 TI - Pancreatic islet macroencapsulation using microwell porous membranes. AB - Allogeneic islet transplantation into the liver in combination with immune suppressive drug therapy is widely regarded as a potential cure for type 1 diabetes. However, the intrahepatic system is suboptimal as the concentration of drugs and nutrients there is higher compared to pancreas, which negatively affects islet function. Islet encapsulation within semipermeable membranes is a promising strategy that allows for the islet transplantation outside the suboptimal liver portal system and provides environment, where islets can perform their endocrine function. In this study, we develop a macroencapsulation device based on thin microwell membranes. The islets are seeded in separate microwells to avoid aggregation, whereas the membrane porosity is tailored to achieve sufficient transport of nutrients, glucose and insulin. The non-degradable, microwell membranes are composed of poly (ether sulfone)/polyvinylpyrrolidone and manufactured via phase separation micro molding. Our results show that the device prevents aggregation and preserves the islet's native morphology. Moreover, the encapsulated islets maintain their glucose responsiveness and function after 7 days of culture (stimulation index above 2 for high glucose stimulation), demonstrating the potential of this novel device for islet transplantation. PMID- 28835664 TI - The activation of PPARgamma by 2,4,6-Octatrienoic acid protects human keratinocytes from UVR-induced damages. AB - Increasing attention is addressed to identify products able to enhance skin photoprotection and to prevent skin carcinogenesis. Several studies have demonstrated that the alpha-melanocyte stimulating hormone (alphaMSH), acting on a functional MC1R, provides a photoprotective effect by inducing pigmentation, antioxidants and DNA repair. We discovered a link between alphaMSH and the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPARgamma), suggesting that some of the alphaMSH protective effects may be dependent on PPARgamma transcriptional activity. Moreover, we demonstrated that the activation of PPARgamma by the parrodiene 2,4,6-octatrienoic acid (Octa) induces melanogenesis and antioxidant defence in human melanocytes and counteracts senescence-like phenotype in human fibroblasts. In this study, we demonstrate that the activation of PPARgamma by Octa exerts a protective effect against UVA- and UVB-induced damage on normal human keratinocytes (NHKs), the major target cells of UV radiation. Octa promotes the antioxidant defence, augments DNA repair and reduces the induction of proteins involved in UV-induced DNA damage response. Our results contribute to deepen the analysis of the alphaMSH/PPARgamma connection and suggest perspectives for the development of new molecules and formulations able to prevent cutaneous UV damage by acting on the different skin cell populations through PPARgamma activation. PMID- 28835665 TI - Optical Control of Tumor Induction in the Zebrafish. AB - The zebrafish has become an increasingly popular and valuable cancer model over the past few decades. While most zebrafish cancer models are generated by expressing mammalian oncogenes under tissue-specific promoters, here we describe a method that allows for the precise optical control of oncogene expression in live zebrafish. We utilize this technique to transiently or constitutively activate a typical human oncogene, kRASG12V, in zebrafish embryos and investigate the developmental and tumorigenic phenotypes. We demonstrate the spatiotemporal control of oncogene expression in live zebrafish, and characterize the different tumorigenic probabilities when kRASG12V is expressed transiently or constitutively at different developmental stages. Moreover, we show that light can be used to activate oncogene expression in selected tissues and single cells without tissue-specific promoters. Our work presents a novel approach to initiate and study cancer in zebrafish, and the high spatiotemporal resolution of this method makes it a valuable tool for studying cancer initiation from single cells. PMID- 28835666 TI - Thoracic radiotherapy (TRT) improved survival in both oligo- and polymetastatic extensive stage small cell lung cancer. AB - There has been no previous study on the efficacy of the thoracic radiotherapy (TRT) in oligometastatic or polymetastatic extensive stage small-cell lung cancer (ES-SCLC) to the overall survival (OS). In a group of 270 ES-SCLC cases retrospective study, 78 patients (28.9%) had oligometastases and 192 (71.1%) had polymetastases, among which 51 oligometastatic patients (65.4%) and 93 polymetastatic patients (51.6%) received TRT. Propensity score matching (PSM) was utilized. The 2-year OS, progression free survival (PFS) and local control (LC) in oligometastatic and polymetastatic patients were 22.8% and 4.5% (p < 0.001), 12.0% and 3.8% (p < 0.001), and 36.7% and 6.1% (p < 0.001), respectively. The 2 year OS in oligometastatic patients with the chemotherapy + radiotherapy and chemotherapy alone were 25.2% and 12.7% (p = 0.002), in contrast to 10.0% and 6.8% (p = 0.030) in polymetastatic patients. The estimated hazard ratios for survival were 2.9 and 1.7 for both oligometastatic and polymetastatic patients with radiotherapy. The polymetastatic group has a lower LC (6.1% v.s. 36.7%, (p < 0.001)), due to polymetastases patients receiving involved-sites radiotherapy with low dose schemas. TRT improved OS of patients with oligometastases and polymetastases. Our study demonstrated that aggressive TRT might be a suitable addition of chemotherapy when treating ES-SCLC patients with oligometastases and polymetastases. PMID- 28835667 TI - Dynamic reverse phase transformation induced high-strain-rate superplasticity in low carbon low alloy steels with commercial potential. AB - Superplastic materials are capable of exhibiting large tensile elongation at elevated temperature, which is of great industrial significance because it forms the basis of a fabrication method to produce complex shapes. Superplasticity with elongation larger than 500% has been widely realized in many metals and alloys, but seldomly been succeeded in low carbon low alloy steel, even though it is commercially applied in the largest quantity. Here we report ultrahigh superplastic elongation of 900-1200% in the FeMnAl low carbon steels at high strain rate of 10-2-10-3 s-1. Such high-strain-rate superplasticity was attributed to dynamic austenite reverse phase transformation from a heavily cold rolled ferrite to fine-grained ferrite/austenite duplex microstructure and subsequent limited dynamic grain coarsening, under which a large fraction of high angle boundaries can be resulted for superplastic deformation. It is believed that this finding of the low carbon low alloy steel with ultrahigh superplasticity and relative low cost would remarkably promote the application of superplastic forming technique in automobile, aeronautical, astronautical and other fields. PMID- 28835668 TI - Simulation of Subject-Specific Progression of Knee Osteoarthritis and Comparison to Experimental Follow-up Data: Data from the Osteoarthritis Initiative. AB - Economic costs of osteoarthritis (OA) are considerable. However, there are no clinical tools to predict the progression of OA or guide patients to a correct treatment for preventing OA. We tested the ability of our cartilage degeneration algorithm to predict the subject-specific development of OA and separate groups with different OA levels. The algorithm was able to predict OA progression similarly with the experimental follow-up data and separate subjects with radiographical OA (Kellgren-Lawrence (KL) grade 2 and 3) from healthy subjects (KL0). Maximum degeneration and degenerated volumes within cartilage were significantly higher (p < 0.05) in OA compared to healthy subjects, KL3 group showing the highest degeneration values. Presented algorithm shows a great potential to predict subject-specific progression of knee OA and has a clinical potential by simulating the effect of interventions on the progression of OA, thus helping decision making in an attempt to delay or prevent further OA symptoms. PMID- 28835669 TI - Nevirapine induced mitochondrial dysfunction in HepG2 cells. AB - Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor frequently used in combination with other antiretroviral agents for highly active antiretroviral therapy (HAART) of patients infected with the human immunodeficiency virus type 1 (HIV-1). However NVP can cause serious, life threatening complications. Hepatotoxicity is one of the most severe adverse effects, particularly in HIV patients with chronic hepatitis C virus co-infection as these patients can develop liver toxicity after a relatively short course of treatment. However, the mechanism of NVP-associated hepatotoxicity remains unclear. This study sought to investigate the effect of NVP on protein expression in liver cells using a proteomic approach. HepG2 cells were treated or not treated with NVP and proteins were subsequently resolved by two-dimensional gel electrophoresis. A total of 33 differentially regulated proteins were identified, of which nearly 40% (13/33) were mitochondrial proteins. While no obvious differences were observed between NVP treated and untreated cells after staining mitochondria with mitotracker, RT-PCR expression analysis of three mitochondrially encoded genes showed all were significantly up-regulated in NVP treated cells. Mitochondrial dysfunction was observed in response to treatment even with slightly sub-optimal therapeutic treatment concentrations of NVP. This study shows that NVP induces mitochondrial dysregulation in HepG2 cells. PMID- 28835670 TI - The Arabidopsis defensin gene, AtPDF1.1, mediates defence against Pectobacterium carotovorum subsp. carotovorum via an iron-withholding defence system. AB - Plant defensins (PDFs) are cysteine-rich peptides that have a range of biological functions, including defence against fungal pathogens. However, little is known about their role in defence against bacteria. In this study, we showed that the protein encoded by ARABIDOPSIS THALIANA PLANT DEFENSIN TYPE 1.1 (AtPDF1.1) is a secreted protein that can chelate apoplastic iron. Transcripts of AtPDF1.1 were induced in both systemic non-infected leaves of Arabidopsis thaliana plants and those infected with the necrotrophic bacterium Pectobacterium carotovorum subsp. carotovorum (Pcc). The expression levels of AtPDF1.1 with correct subcellular localization in transgenic A. thaliana plants were positively correlated with tolerance to Pcc, suggesting its involvement in the defence against this bacterium. Expression analysis of genes associated with iron homeostasis/deficiency and hormone signalling indicated that the increased sequestration of iron by apoplastic AtPDF1.1 overexpression perturbs iron homeostasis in leaves and consequently activates an iron-deficiency-mediated response in roots via the ethylene signalling pathway. This in turn triggers ethylene-mediated signalling in systemic leaves, which is involved in suppressing the infection of necrotrophic pathogens. These findings provide new insight into the key functions of plant defensins in limiting the infection by the necrotrophic bacterium Pcc via an iron-deficiency-mediated defence response. PMID- 28835671 TI - A Chinese herbal formula, Jian-Pi-Yi-Shen decoction, improves muscle atrophy via regulating mitochondrial quality control process in 5/6 nephrectomised rats. AB - Muscle atrophy is one of the serious complications of chronic kidney disease (CKD). Dysregulation of mitochondrial quality control (MQC) process, including decrease mitochondrial biogenesis, impair mitochondrial dynamics and induce activation of mitophagy, play an important role in mediating muscle wasting. This study aimed to observe effects of Jian-Pi-Yi-Shen (JPYS) decoction on muscle atrophy in CKD rats and explore its possible mechanism on regulation of MQC processes. The 5/6 nephrectomised rats were randomly allocated into 2 groups: CKD group and JPYS group. Besides, a sham-operated rats as sham group. All rats were treated for 6 weeks. Results showed that administration of JPYS decoction prevented body weight loss, muscle loss, muscle fiber size decrease, muscle protein degradation, and increased muscle protein systhesis. In addition, JPYS decoction increased the mitochondrial content and biogenesis proteins, and down regulated the autophagy and mitophagy proteins. Furthermore, JPYS decoction increased mitochondrial fusion proteins, while decreased mitochondrial fission proteins. In conclusion, JPYS decoction increased mitochondrial content and biogenesis, restore the balance between fission and fusion, and inhibited autophagy-lysosome pathway (mitophagy). Collectively, our data showed that JPYS decoction to be beneficial to muscle atrophy in CKD, which might be associated with the modulation of MQC process. PMID- 28835672 TI - Osteoporosis: Discontinuing denosumab discouraged. PMID- 28835673 TI - The case for periodontitis in the pathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA), an autoimmune disease that affects ~1% of the human population, is driven by autoantibodies that target modified self-epitopes, whereas ~11% of the global adult population are affected by severe chronic periodontitis, a disease in which the commensal microflora on the tooth surface is replaced by a dysbiotic consortium of bacteria that promote the chronic inflammatory destruction of periodontal tissue. Despite differences in aetiology, RA and periodontitis are similar in terms of pathogenesis; both diseases involve chronic inflammation fuelled by pro-inflammatory cytokines, connective tissue breakdown and bone erosion. The two diseases also share risk factors such as smoking and ageing, and have strong epidemiological, serological and clinical associations. In light of the ground-breaking discovery that Porphyromonas gingivalis, a pivotal periodontal pathogen, is the only human pathogen known to express peptidylarginine deiminase, an enzyme that generates citrullinated epitopes that are recognized by anti-citrullinated protein antibodies, a new paradigm is emerging. In this Review, the clinical and experimental evidence supporting this paradigm is discussed and the potential mechanisms involved in linking periodontitis to RA are presented. PMID- 28835675 TI - Biodegradable elastic nanofibrous platforms with integrated flexible heaters for on-demand drug delivery. AB - Delivery of drugs with controlled temporal profiles is essential for wound treatment and regenerative medicine applications. For example, bacterial infection is a key challenge in the treatment of chronic and deep wounds. Current treatment strategies are based on systemic administration of high doses of antibiotics, which result in side effects and drug resistance. On-demand delivery of drugs with controlled temporal profile is highly desirable. Here, we have developed thermally controllable, antibiotic-releasing nanofibrous sheets. Poly(glycerol sebacate)- poly(caprolactone) (PGS-PCL) blends were electrospun to form elastic polymeric sheets with fiber diameters ranging from 350 to 1100 nm and substrates with a tensile modulus of approximately 4-8 MPa. A bioresorbable metallic heater was patterned directly on the nanofibrous substrate for applying thermal stimulation to release antibiotics on-demand. In vitro studies confirmed the platform's biocompatibility and biodegradability. The released antibiotics were potent against tested bacterial strains. These results may pave the path toward developing electronically controllable wound dressings that can deliver drugs with desired temporal patterns. PMID- 28835674 TI - Soy Improves Cardiometabolic Health and Cecal Microbiota in Female Low-Fit Rats. AB - Phytoestrogen-rich soy is known to ameliorate menopause-associated obesity and metabolic dysfunction for reasons that are unclear. The gut microbiota have been linked with the development of obesity and metabolic dysfunction. We aimed to determine the impact of soy on cardiometabolic health, adipose tissue inflammation, and the cecal microbiota in ovariectomized (OVX) rats bred for low running capacity (LCR), a model that has been previously shown to mimic human menopause compared to sham-operated (SHM) intact control LCR rats. In this study, soy consumption, without affecting energy intake or physical activity, significantly improved insulin sensitivity and body composition of OVX rats bred for low-running capacity. Furthermore, soy significantly improved blood lipid profile, adipose tissue inflammation, and aortic stiffness of LCR rats. Compared to a soy-free control diet, soy significantly shifted the cecal microbial community of LCR rats, resulting in a lower Firmicutes:Bacteroidetes ratio. Correlations among metabolic parameters and cecal bacterial taxa identified in this study suggest that taxa Prevotella, Dorea, and Phascolarctobacterium may be taxa of interest. Our results suggest that dietary soy ameliorates adiposity, insulin sensitivity, adipose tissue inflammation, and arterial stiffness and exerts a beneficial shift in gut microbial communities in a rat model that mimics human menopause. PMID- 28835676 TI - Homozygous p.Ser267Phe in SLC10A1 is associated with a new type of hypercholanemia and implications for personalized medicine. AB - SLC10A1 codes for the sodium-taurocholate cotransporting polypeptide (NTCP), which is a hepatocellular transporter for bile acids (BAs) and the receptor for hepatitis B and D viruses. NTCP is also a target of multiple drugs. We aimed to evaluate the medical consequences of the loss of function mutation p.Ser267Phe in SLC10A1. We identified eight individuals with homozygous p.Ser267Phe mutation in SLC10A1 and followed up for 8-90 months. We compared their total serum BAs and 6 species of BAs with 170 wild-type and 107 heterozygous healthy individuals. We performed in-depth medical examinations and exome sequencing in the homozygous individuals. All homozygous individuals had persistent hypercholanemia (P = 5.8 * 10-29). Exome sequencing excluded the involvement of other BA metabolism associated genes in the hypercholanemia. Although asymptomatic, all individuals had low vitamin D levels. Of six adults that were subjected to bone mineral density analysis, three presented with osteoporosis/osteopenia. Sex hormones and blood lipids were deviated in all subjects. Homozygosity of p.Ser267Phe in SLC10A1 is associated with asymptomatic hypercholanemia. Individuals with homozygous p.Ser267Phe in SLC10A1 are prone to vitamin D deficiency, deviated sex hormones and blood lipids. Surveillance of these parameters may also be needed in patients treated with drugs targeting NTCP. PMID- 28835677 TI - RIPK1 protects hepatocytes from death in Fas-induced hepatitis. AB - Hepatocyte death is a central event during liver disease progression, in which immune cells play key roles by activating members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF), including TNFR1 (TNFRSF1A), Fas (TNFRSF6) and TRAIL-R2 (TNFRSF10B). Receptor Interacting Protein Kinase 1 (RIPK1) emerged as a signaling node downstream of these receptors. In the case of TNFR1, RIPK1 has been demonstrated to paradoxically serve as a scaffold to promote the survival of hepatocytes and as a kinase to kill them. To evaluate whether RIPK1 also protects hepatocytes from death in response to FasL or TRAIL, we took advantage of liver parenchymal cell-specific Ripk1 knockout mice (Ripk1 LPC-KO). We found that Ripk1 LPC-KO mice, as well as primary hepatocytes derived from them, were more susceptible to Fas-mediated apoptosis than their respective WT counterparts. Fas induced hepatocyte death was independent of TNF-alpha signaling. Interestingly, while TRAIL administration did not induce hepatitis in Ripk1 LPC-KO mice or in their WT counterparts, its combination with IFN-gamma only induced TNF-alpha dependent apoptosis in the Ripk1 LPC-KO mice. Together, our data demonstrate the protective role of RIPK1 downstream of Fas and highlight the general protective function of RIPK1 in hepatocytes exposed to inflammatory conditions, where TNF alpha, FasL and/or TRAIL are present. PMID- 28835678 TI - Altered cortical brain activity in end stage liver disease assessed by multi channel near-infrared spectroscopy: Associations with delirium. AB - Delirium is a common and serious psychiatric syndrome caused by an underlying medical condition. It is associated with significant mortality and increased healthcare resource utilization. There are few biological markers of delirium, perhaps related to the etiologic heterogeneity of the syndrome. Functional near infrared spectroscopy (fNIRS) is an optical topography system to measure changes in the concentration of oxygenated hemoglobin ([oxy-Hb]) in the cerebral cortex. We examined whether altered cortical brain activity in delirious patients with end stage liver disease (ESLD) is detected by fNIRS. We found that the [oxy-Hb] change during the verbal fluency task (VFT) was reduced in patients with ESLD compared with healthy controls (HC) in the prefrontal and bi-temporal regions. The [oxy-Hb] change during the sustained attention task (SAT) was elevated in patients with ESLD compared to HC in the prefrontal and left temporal regions. Notably, [oxy-Hb] change in the left dorsolateral prefrontal cortex during SAT showed a positive correlation with the severity of delirium. Our results suggest that [oxy-Hb] change in the prefrontal cortex during the sustained attention task measured with fNIRS might serve as a biological marker associated with delirium in ESLD patients. PMID- 28835679 TI - Amoeboid-mesenchymal migration plasticity promotes invasion only in complex heterogeneous microenvironments. AB - During tissue invasion individual tumor cells exhibit two interconvertible migration modes, namely mesenchymal and amoeboid migration. The cellular microenvironment triggers the switch between both modes, thereby allowing adaptation to dynamic conditions. It is, however, unclear if this amoeboid mesenchymal migration plasticity contributes to a more effective tumor invasion. We address this question with a mathematical model, where the amoeboid mesenchymal migration plasticity is regulated in response to local extracellular matrix resistance. Our numerical analysis reveals that extracellular matrix structure and presence of a chemotactic gradient are key determinants of the model behavior. Only in complex microenvironments, if the extracellular matrix is highly heterogeneous and a chemotactic gradient directs migration, the amoeboid mesenchymal migration plasticity allows a more widespread invasion compared to the non-switching amoeboid and mesenchymal modes. Importantly, these specific conditions are characteristic for in vivo tumor invasion. Thus, our study suggests that in vitro systems aiming at unraveling the underlying molecular mechanisms of tumor invasion should take into account the complexity of the microenvironment by considering the combined effects of structural heterogeneities and chemical gradients on cell migration. PMID- 28835680 TI - Transcriptome analysis of ankylosing spondylitis patients before and after TNF alpha inhibitor therapy reveals the pathways affected. AB - Tumor necrosis factor-alpha (TNF-alpha) inhibitors are highly effective in suppressing inflammation in ankylosing spondylitis (AS) patients, and operate by suppression of TFN-alpha and downstream immunological pathways. To determine the mechanisms of action of TNF-alpha inhibitors in AS patients, we used transcriptomic and bioinformatic approaches on peripheral blood mononuclear cells from AS patients pre and post treatment. We found 656 differentially expressed genes, including the genome-wide significant AS-associated genes, IL6R, NOTCH1, IL10, CXCR2 and TNFRSF1A. A distinctive gene expression profile was found between male and female patients, mainly because of sex chromosome-linked genes and interleukin 17 receptor C, potentially accounting for the differences in clinical manifestation and treatment response between the genders. In addition to immune and inflammation regulatory pathways, like intestinal immune network for IgA production, cytokine-cytokine receptor interaction, Ras signaling pathway, allograft rejection and hematopoietic cell lineage, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses revealed that infection-associated pathways (influenza A and toxoplasmosis) and metabolism-associated pathways were involved in response to TNF-alpha inhibitor treatment, providing insight into the mechanism of TNF-alpha inhibitors. PMID- 28835681 TI - Fast kinetics of magnesium monochloride cations in interlayer-expanded titanium disulfide for magnesium rechargeable batteries. AB - Magnesium rechargeable batteries potentially offer high-energy density, safety, and low cost due to the ability to employ divalent, dendrite-free, and earth abundant magnesium metal anode. Despite recent progress, further development remains stagnated mainly due to the sluggish scission of magnesium-chloride bond and slow diffusion of divalent magnesium cations in cathodes. Here we report a battery chemistry that utilizes magnesium monochloride cations in expanded titanium disulfide. Combined theoretical modeling, spectroscopic analysis, and electrochemical study reveal fast diffusion kinetics of magnesium monochloride cations without scission of magnesium-chloride bond. The battery demonstrates the reversible intercalation of 1 and 1.7 magnesium monochloride cations per titanium at 25 and 60 degrees C, respectively, corresponding to up to 400 mAh g-1 capacity based on the mass of titanium disulfide. The large capacity accompanies with excellent rate and cycling performances even at room temperature, opening up possibilities for a variety of effective intercalation hosts for multivalent-ion batteries.Magnesium rechargeable batteries potentially offer high-energy density, safety, and low cost. Here the authors show a battery that reversibly intercalates magnesium monochloride cations with excellent rate and cycle performances in addition to the large capacity. PMID- 28835682 TI - Outcome switching in randomized controlled oncology trials reporting on surrogate endpoints: a cross-sectional analysis. AB - Inconsistent reporting of clinical trials is well-known in the literature. Despite this, factors associated with poor practice such as outcome switching in clinical trials are poorly understood. We performed a cross-sectional analysis to evaluate the prevalence of, and the factors associated with outcome switching. PubMed and Embase were searched for pharmaceutical randomized controlled trials (RCTs) in oncology reporting on a surrogate primary outcome published in 2015. Outcome switching was present in 18% (39/216). First-author male sex was significantly more likely associated with outcome switching compared to female sex with an OR of 3.05 (95% CI 1.07-8.64, p = 0.04) after multivariable adjustment. For-profit funded RCTs were less likely associated with outcome switching compared to non-profit funded research with an OR of 0.22 (95% CI 0.07 0.74, p = 0.01). First author male sex was more likely associated with outcome switching compared to female sex in drug oncology RCTs reporting on a primary surrogate endpoint. For-profit funded research was less likely associated with outcome switching compared to research funded by non-profit organizations. Furthermore, 18 percent of drug oncology trials reporting on a surrogate endpoint could have a higher risk of false positive results due to primary outcome switching. PMID- 28835683 TI - The relative contribution of target-site mutations in complex acaricide resistant phenotypes as assessed by marker assisted backcrossing in Tetranychus urticae. AB - The mechanisms underlying insecticide and acaricide resistance in insects and mites are often complex, including additive effects of target-site insensitivity, increased metabolism and transport. The extent to which target-site resistance mutations contribute to the resistance phenotype is, however, not well studied. Here, we used marker-assisted backcrossing to create 30 congenic lines carrying nine mutations (alone, or in combination in a few cases) associated with resistance to avermectins, pyrethroids, mite growth inhibitors and mitochondrial complex III inhibitors (QoI) in a polyphagous arthropod pest, the spider mite Tetranychus urticae. Toxicity tests revealed that mutations in the voltage-gated sodium channel, chitin synthase 1 and cytochrome b confer high levels of resistance and, when fixed in a population, these mutations alone can result in field failure of acaricide treatment. In contrast, although we confirmed the implication of mutations in glutamate-gated chloride channels in abamectin and milbemectin insensitivity, these mutations do not lead to the high resistance levels that are often reported in abamectin resistant strains of T. urticae. Overall, this study functionally validates reported target-site resistance mutations in T. urticae, by uncoupling them from additional mechanisms, allowing to finally investigate the strength of the conferred phenotype in vivo. PMID- 28835684 TI - Modulation of SOX2 expression delineates an end-point for paclitaxel effectiveness in breast cancer stem cells. AB - Tumor relapse in triple negative breast cancer patients has been implicated to chemoresistant cancer stem cells (CSCs), which under favorable conditions culminate in tumor re-formation and metastasis. Hence, eradication of CSCs during systemic chemotherapy is imperative. CSCs were sorted using immuno-phenotyping and aldefluor assay. Gene expression profiling of normal breast stem cells and breast CSCs from chemo-treated patients were carried out. Silencing SOX2 was achieved by siRNA method. Mammosphere culture and wound healing assays were carried out to assess efficacy of CSCs. Microarray analysis revealed elevated expression of SOX2, ABCG2 and TWIST1, unraveling an intertwined pluripotency chemoresistance-EMT axis. Although paclitaxel treatment led to temporary arrest of cell migration, invasiveness resumed after drug removal. The 'twist in the tale' was a consistently elevated expression of TWIST1, substantiating that TWIST1 can also promote stemness and chemoresistance in tumors; hence, its eradication was imperative. Silencing SOX2 increased chemo-sensitivity and diminished sphere formation, and led to TWIST1 down regulation. This study eventually established that SOX2 silencing of CSCs along with paclitaxel treatment reduced SOX2-ABCG2-TWIST1 expression, disrupted sphere forming capacity and also reduced invasiveness by retaining epithelial-like properties of the cells, thereby suggesting a more comprehensive therapy for TNBC patients in future. PMID- 28835686 TI - Genome-wide comparative analyses of correlated and uncorrelated phenotypes identify major pleiotropic variants in dairy cattle. AB - While single nucleotide polymorphisms (SNPs) associated with multiple phenotype have been reported, the knowledge of pleiotropy of uncorrelated phenotype is minimal. Principal components (PCs) and uncorrelated Cholesky transformed traits (CT) were constructed using 25 raw traits (RTs) of 2841 dairy bulls. Multi-trait meta-analyses of single-trait genome-wide association studies for RT, PC and CT in bulls were validated in 6821 cows. Most PCs and CTs had substantial estimates of heritability, suggesting that genes affect phenotype via diverse pathways. Phenotypic orthogonalizations did not eliminate pleiotropy: the meta-analysis achieved an agreement of significant pleiotropic SNPs (p < 1 * 10-5, n = 368) between RTs (416), PCs (466) and CTs (425). From this overlap we identified 21 lead SNPs with 100% validation rate containing two clusters: one consisted of DGAT1 (chr14:1.8 M+), MGST1 (chr5:93 M+), PAEP (chr11:103 M+) and GPAT4 (chr27:36 M+) affecting protein, milk and fat yield and the other included CSN2 (chr6:87 M+), MUC1 (chr3:15.6 M), GHR (chr20:31.2 M+) and SDC2 (chr14:70 M+) affecting protein and milk yield. Combining beef cattle data identified correlated SNPs representing CAPN1 (chr29:44 M+) and CAST (chr 7:96 M+) loci affecting beef tenderness, showing pleiotropic effects in dairy cattle. Our findings show that SNPs with a large effect on one trait are likely to have small effects on other uncorrelated traits. PMID- 28835685 TI - A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration. AB - We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naive AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 * 10-6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment. PMID- 28835687 TI - Development of a novel immunoassay to detect interactions with the transactivation domain of p53: application to screening of new drugs. AB - Tumor protein p53 acts as a trans-activator that negatively regulates cell division by controlling a set of genes required for cell cycle regulation, making it a tumor suppressor in different types of tumors. Because the transcriptional activity of p53 plays an important role in the occurrence and development of tumors, reactivation of p53 transcriptional activity has been sought as a novel cancer therapeutic strategy. There is great interest in developing high throughput assays to identify inhibitors of molecules that bind the transcription activation domain of p53, especially for wt p53-containing tumors. In the present study, taking MDM2 as an example, a novel amplified luminescent proximity homogeneous assay (AlphaLISA) was modified from a binding competition assay to detect the interactions between the transcription-activation domain of p53 and its ligands. This assay can be adapted as a high-throughput assay for screening new inhibitors. A panel of well-known p53-MDM2 binding inhibitors was used to validate this method, and demonstrated its utility, sensitivity and robustness. In summary, we have developed a novel protein-protein interaction detection immunoassay that can be used in a high-throughput format to screen new drug candidates for reactivation of p53. This assay has been successfully validated through a series of p53-MDM2 binding inhibitors. PMID- 28835688 TI - The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts. AB - Levels of active Rac1 at epithelial junctions are partially modulated via interaction with Ajuba, an actin binding and scaffolding protein. Here we demonstrate that Ajuba interacts with the Cdc42 GTPase activating protein CdGAP, a GAP for Rac1 and Cdc42, at cell-cell contacts. CdGAP recruitment to junctions does not require Ajuba; rather Ajuba seems to control CdGAP residence at sites of cell-cell adhesion. CdGAP expression potently perturbs junctions and Ajuba binding inhibits CdGAP activity. Ajuba interacts with Rac1 and CdGAP via distinct domains and can potentially bring them in close proximity at junctions to facilitate activity regulation. Functionally, CdGAP-Ajuba interaction maintains junctional integrity in homeostasis and diseases: (i) gain-of-function CdGAP mutants found in Adams-Oliver Syndrome patients strongly destabilize cell-cell contacts and (ii) CdGAP mRNA levels are inversely correlated with E-cadherin protein expression in different cancers. We present conceptual insights on how Ajuba can integrate CdGAP binding and inactivation with the spatio-temporal regulation of Rac1 activity at junctions. Ajuba provides a novel mechanism due to its ability to bind to CdGAP and Rac1 via distinct domains and influence the activation status of both proteins. This functional interplay may contribute towards conserving the epithelial tissue architecture at steady-state and in different pathologies. PMID- 28835689 TI - The small GTPase, nucleolar GTP-binding protein 1 (NOG1), has a novel role in plant innate immunity. AB - Plant defense responses at stomata and apoplast are the most important early events during plant-bacteria interactions. The key components for the signaling of stomatal defense and nonhost resistance have not been fully characterized. Here we report the newly identified small GTPase, Nucleolar GTP-binding protein 1 (NOG1), functions for plant immunity against bacterial pathogens. Virus-induced gene silencing of NOG1 compromised nonhost resistance in N. benthamiana and tomato. Comparative genomic analysis showed that two NOG1 copies are present in all known plant species: NOG1-1 and NOG1-2. Gene downregulation and overexpression studies of NOG1-1 and NOG1-2 in Arabidopsis revealed the novel function of these genes in nonhost resistance and stomatal defense against bacterial pathogens, respectively. Specially, NOG1-2 regulates guard cell signaling in response to biotic and abiotic stimuli through jasmonic acid (JA)- and abscisic acid (ABA)-mediated pathways. The results here provide valuable information on the new functional role of small GTPase, NOG1, in guard cell signaling and early plant defense in response to bacterial pathogens. PMID- 28835690 TI - Neuroprotective effects of a Coeloglossum viride var. Bracteatum extract in vitro and in vivo. AB - The excessive release and accumulation of glutamate in the brain is known to be associated with excitotoxicity. CE, an extract derived from the plant Coeloglossum viride var. Bracteatum, exerted neuroprotective effects against amyloid toxicity and oxidative stress in cortical neurons. The aims of this study are to examine whether CE also attenuates glutamate neurotoxicity in rat primary cultured cortical neurons and to determine the effect of CE in vivo. According to the results of MTT, LDH release, and TUNEL assays, the CE treatment significantly reduced glutamate-induced neurotoxicity in a dose-dependent manner. Moreover, the protective effects of CE were blocked by an Akt inhibitor, LY294002, suggesting that the PI3K/Akt signalling pathway is involved in the neuroprotective effects of CE. In addition, CE might regulate the PKC-GluA2 axis to prevent neuronal apoptosis. CE also protected against dopaminergic neuronal loss in a mouse model of MPTP-induced PD. Based on our results, CE exerted neuroprotective effects both in vitro and in vivo, thus providing a potential therapeutic target for the treatment or prevention of neurodegeneration. PMID- 28835691 TI - Proteomic analysis of phytase transgenic and non-transgenic maize seeds. AB - Proteomics has become a powerful technique for investigating unintended effects in genetically modified crops. In this study, we performed a comparative proteomics of the seeds of phytase-transgenic (PT) and non-transgenic (NT) maize using 2-DE and iTRAQ techniques. A total of 148 differentially expressed proteins (DEPs), including 106 down-regulated and 42 up-regulated proteins in PT, were identified. Of these proteins, 32 were identified through 2-DE and 116 were generated by iTRAQ. It is noteworthy that only three proteins could be detected via both iTRAQ and 2-DE, and most of the identified DEPs were not newly produced proteins but proteins with altered abundance. These results indicated that many DEPs could be detected in the proteome of PT maize seeds and the corresponding wild type after overexpression of the target gene, but the changes in these proteins were not substantial. Functional classification revealed many DEPs involved in posttranscriptional modifications and some ribosomal proteins and heat-shock proteins that may generate adaptive effects in response to the insertion of exogenous genes. Protein-protein interaction analysis demonstrated that the detected interacting proteins were mainly ribosomal proteins and heat shock proteins. Our data provided new information on such unintended effects through a proteomic analysis of maize seeds. PMID- 28835692 TI - The vaginal microbiome of pregnant women is less rich and diverse, with lower prevalence of Mollicutes, compared to non-pregnant women. AB - The vaginal microbiome plays an important role in maternal and neonatal health. Imbalances in this microbiota (dysbiosis) during pregnancy are associated with negative reproductive outcomes, such as pregnancy loss and preterm birth, but the underlying mechanisms remain poorly understood. Consequently a comprehensive understanding of the baseline microbiome in healthy pregnancy is needed. We characterized the vaginal microbiomes of healthy pregnant women at 11-16 weeks of gestational age (n = 182) and compared them to those of non-pregnant women (n = 310). Profiles were created by pyrosequencing of the cpn60 universal target region. Microbiome profiles of pregnant women clustered into six Community State Types: I, II, III, IVC, IVD and V. Overall microbiome profiles could not be distinguished based on pregnancy status. However, the vaginal microbiomes of women with healthy ongoing pregnancies had lower richness and diversity, lower prevalence of Mycoplasma and Ureaplasma and higher bacterial load when compared to non-pregnant women. Lactobacillus abundance was also greater in the microbiomes of pregnant women with Lactobacillus-dominated CSTs in comparison with non-pregnant women. This study provides further information regarding characteristics of the vaginal microbiome of low-risk pregnant women, providing a baseline for forthcoming studies investigating the diagnostic potential of the microbiome for prediction of adverse pregnancy outcomes. PMID- 28835693 TI - MicroRNA profile for health risk assessment: Environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery. AB - Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker based environmental health risk assessment. PMID- 28835694 TI - Coherent Raman Imaging of Live Muscle Sarcomeres Assisted by SFG Microscopy. AB - In this study, we used spectrally focused coherent anti-Stokes Raman scattering (spCARS) microscopy assisted by sum-frequency generation (SFG) to monitor the variations in the structural morphology and molecular vibrations of a live muscle of Caenorhabditis elegans. The subunits of the muscle sarcomeres, such as the M line, myosin, dense body, and alpha-actinin, were alternatively observed using spCARS microscopy for different sample orientations, with the guidance of a myosin positional marker captured by SFG microscopy. Interestingly enough, the beam polarization dependence of the spCARS contrasts for two parallel subunits (dense body and myosin) showed a ~90 degrees phase difference. The chemically sensitive spCARS spectra induced by the time-varying overlap of two pulses allowed (after a robust subtraction of the non-resonant background using a modified Kramers-Kronig transformation method) high-fidelity detection of various genetically modified muscle sarcomeres tuned to the C-H vibration (2800-3100 cm 1). Conversely, SFG image mapping assisted by phase-retrieved spCARS spectra also facilitated label-free monitoring of the changes in the muscle content of C. elegans that are associated with aging, based on the hypothesis that the C-H vibrational modes could serve as qualitative chemical markers sensitive to the amount and/or structural modulation of the muscle. PMID- 28835695 TI - Hypoxia imaging in cells and tumor tissues using a highly selective fluorescent nitroreductase probe. AB - Hypoxia is a characteristic of locally advanced solid tumors, resulting from an imbalance between oxygen consumption and supply. In hypoxic solid tumors, an increased expression of nitroreductase (NTR) is detected, therefore, the development of NTR-targeted fluorescent probes to selectively and efficiently detect hypoxia in vivo is of utmost importance. In this study, a probe (1) has been designed and tested for effective optical detection of NTR in vitro and in vivo. The reduction of probe (1), catalyzed by NTR, resulted in changes of the electron-withdrawn nitrogen group into an electron-donation amino group. In addition, breakage of the O-C bond ensured selective fluorescence enhancement. The in vitro response towards exogenous NTR, from rat liver microsomes, resulted in the optical enhancement during the detection process. In vivo imaging of caerorhabditis elegans (C.elegan) further confirmed the detection of NTR by probe (1). Moreover, probe (1) was successfully used for the detection of hypoxia in both HI5 cells, and a murine tumor model, which demonstrates the potential of probe (1) for application in fluorescence bioimaging studies, and tumor hypoxia diagnosis. PMID- 28835696 TI - Simulative Global Warming Negatively Affects Cotton Fiber Length through Shortening Fiber Rapid Elongation Duration. AB - Global warming could possibly increase the air temperature by 1.8-4.0 degrees C in the coming decade. Cotton fiber is an essential raw material for the textile industry. Fiber length, which was found negatively related to the excessively high temperature, determines yarn quality to a great extent. To investigate the effects of global warming on cotton fiber length and its mechaism, cottons grown in artificially elevated temperature (34.6/30.5 degrees C, Tday/Tnight) and ambient temperature (31.6/27.3 degrees C) regions have been investigated. Becaused of the high sensitivities of enzymes V-ATPase, PEPC, and genes GhXTH1 and GhXTH2 during fiber elongation when responding to high temperature stress, the fiber rapid elongation duration (FRED) has been shortened, which led to a significant suppression on final fiber length. Through comprehensive analysis, Tnight had a great influence on fiber elongation, which means Tn could be deemed as an ideal index for forecasting the degree of high temperature stress would happen to cotton fiber property in future. Therefore, we speculate the global warming would bring unfavorable effects on cotton fiber length, which needs to take actions in advance for minimizing the loss in cotton production. PMID- 28835697 TI - Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture. AB - The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2 mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-alpha based antiviral normalized the ER stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation. PMID- 28835698 TI - In vivo photothermal optical coherence tomography of endogenous and exogenous contrast agents in the eye. AB - Optical coherence tomography (OCT) has become a standard-of-care in retinal imaging. OCT allows non-invasive imaging of the tissue structure but lacks specificity to contrast agents that could be used for in vivo molecular imaging. Photothermal OCT (PT-OCT) is a functional OCT-based technique that has been developed to detect absorbers in a sample. We demonstrate in vivo PT-OCT in the eye for the first time on both endogenous (melanin) and exogenous (gold nanorods) absorbers. Pigmented mice and albino mice (n = 6 eyes) were used to isolate the photothermal signal from the melanin in the retina. Pigmented mice with laser induced choroidal neovascularization lesions (n = 7 eyes) were also imaged after a systemic injection of gold nanorods to observe their passive accumulation in the retina. This experiment demonstrates the feasibility of PT-OCT to image the distribution of both endogenous and exogenous absorbers in the mouse retina. PMID- 28835700 TI - Effect of Crystal Orientation on Femtosecond Laser-Induced Thermomechanical Responses and Spallation Behaviors of Copper Films. AB - Ultrafast thermomechanical responses and spallation behaviours of monocrystal copper films irradiated by femtosecond laser pulse are investigated using molecular dynamics simulation (MDS). Films with <100>, <110> and <111> crystal orientations along the thickness direction were studied. The results show that the crystal orientation has a significant effect on femtosecond laser-induced thermomechanical responses and spallation behaviors of monocrystal copper films. The discrepancy between normal stresses in copper films with different crystal orientation leads to distinct differences in lattice temperature. Moreover, the copper films with different crystal orientations present distinct spallation behaviors, including structural melting (atomic splashing) and fracture. The melting depth of <100> copper film is lower than that of <110> and <111> copper films for the same laser intensity. The dislocations and slip bands are formed and propagate from the solid-liquid interface of <110> and <111> copper films, while these phenomena do not appear in <100> copper film. Additionally, numerous slip bands are generated in the non-irradiated surface region of copper films due to reflection of mechanical stress. These slip bands can finally evolve into cracks (nanovoids) with time, which further result in the fracture of the entire films. PMID- 28835699 TI - Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL. AB - Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase and a molecule of adaptor that we have shown is important for non-small-cell lung cancer (NSCLC). We investigated if MET is a target of CBL and if enhanced in CBL-altered NSCLC. We showed that CBL wildtype cells have lower MET expression than CBL mutant cells. Ubiquitination of MET was also decreased in CBL mutant cells compared to wildtype cells. Mutant cells were also more sensitive to MET inhibitor SU11274 than wild-type cells. sh-RNA-mediated knockdown of CBL enhanced cell motility and colony formation in NSCLC cells, and these activities were inhibited by SU11274. Assessment of the phospho-kinome showed decreased phosphorylation of pathways involving MET, paxillin, EPHA2, and VEGFR. When CBL was knocked down in the mutant cell line H1975 (erlotinib-resistant), it became sensitive to MET inhibition. Our findings suggest that CBL status is a potential positive indicator for MET-targeted therapeutics in NSCLC. PMID- 28835701 TI - Deep-ultraviolet second-harmonic generation by combined degenerate four-wave mixing and surface nonlinearity polarization in photonic crystal fiber. AB - Deep-ultraviolet (UV) second-harmonics (SHs) have important applications in basic physics and applied sciences. However, it still remains challenging to generate deep-UV SHs especially in optical fibers. Here, for the first time, we experimentally demonstrate the deep-UV SH generations (SHGs) by combined degenerate four-wave mixing (FWM) and surface nonlinearity polarization in an in house designed and fabricated air-silica photonic crystal fiber (PCF). When femtosecond pump pulses with average input power P av of 650 mW and center wavelength lambda p of 810, 820, 830, and 840 nm are coupled into the normal dispersion region close to the zero-dispersion wavelength of the fundamental mode of the PCF, the anti-Stokes waves induced by degenerate FWM process are tunable from 669 to 612 nm. Then, they serve as the secondary pump, and deep-UV SHs are generated within the wavelength range of 334.5 to 306 nm as a result of surface nonlinearity polarization at the core-cladding interface of the PCF. The physical mechanism of the SHGs is confirmed by studying the dependences of the output power P SH of the SHs on the PCF length and time. Finally, we also establish a theoretical model to analyze the SHGs. PMID- 28835702 TI - Comparison of patterns and prognosis among distant metastatic breast cancer patients by age groups: a SEER population-based analysis. AB - To investigate the effects of age at diagnosis on metastatic breast cancer and patients' prognosis, we collected patient data from the Surveillance, Epidemiology, and End Results (SEER) database. We finally identified 4932 eligible metastatic breast cancer patients diagnosed between 2010-2013, including 850 younger patients (<50 years), 2,540 middle-aged patients (50-69 years) and 1,542 elder patients (>69 years). The results revealed that in stage IV patients, elder patients were more likely to have lung metastasis (P < 0.001) and less likely to have only distant lymphatic spread (P = 0.004). Higher proportion of younger (34.9%) and middle-aged (36.2%) patients had multiple metastatic sites than elder patients (28.3%) (P < 0.001). In survival analysis, younger patients presented the best prognosis, while elder patients had the worst both in overall survival (chi2 = 121.9, P < 0.001) and breast cancer-specific survival (chi2 = 69.8, P < 0.001). Age at diagnosis was an independent prognostic factor for metastatic breast cancer patients. Moreover, patients with bone metastasis only had superior survival compared to other metastatic patients (P < 0.001). Brain metastasis only group and multiple sites metastasis group had the poorest prognosis (P < 0.05). We hope the results will provide insights into a better understanding of distant metastatic breast cancer. PMID- 28835703 TI - Neuroprotective Effects of CGP3466B on Apoptosis Are Modulated by Protein-L isoaspartate (D-aspartate) O-methyltransferase/Mst1 Pathways after Traumatic Brain Injury in Rats. AB - Neuronal apoptosis chiefly contributes to the cell loss following traumatic brain injury (TBI). CGP3466B is a compound related to the anti-Parkinsonism drug R-(-) deprenyl. Previous studies have illuminated anti-apoptosis effects of CGP3466B in different cell lines, but the underlying mechanisms have not been fully elucidated. Mammalian sterile 20 (STE20)-like kinase1 (Mst1) is a core component of the Hippo signaling pathway. Protein-L-isoaspartate (D-aspartate) O methyltransferase (PCMT1) is an enzyme that repairs damaged L-isoaspartyl residues in proteins. The present study was performed to investigate the neuroprotective effects of CGP3466B and to determine a potential PCMT1/Mst1 neuronal anti-apoptotic pathway after TBI. Double immunofluorescence staining demonstrated that PCMT1 and Mst1 are co-located in neurons. Administration of CGP3466B improved neurological function, downregulated the ROS level and alleviated brain edema at 24 h after TBI. CGP3466B alleviates neuronal apoptosis by increasing PCMT1 expression and subsequently inhibiting MST1 activation, resulting in changing the expression levels of Bax, Bcl-2 and active-caspase3. The TUNEL staining results also support the anti-apoptosis effects of CGP3466B. The anti-apoptotic effects of CGP3466B were abolished by chelerythrine, an Mst1 activator, without changing PCMT1 levels. In conclusion, our findings suggest CGP3466B may have a promising therapeutic potential by modulating PCMT1/Mst1 signaling pathway after TBI injury. PMID- 28835704 TI - Interfacial charge distributions in carbon-supported palladium catalysts. AB - Controlling the charge transfer between a semiconducting catalyst carrier and the supported transition metal active phase represents an elite strategy for fine turning the electronic structure of the catalytic centers, hence their activity and selectivity. These phenomena have been theoretically and experimentally elucidated for oxide supports but remain poorly understood for carbons due to their complex nanoscale structure. Here, we combine advanced spectroscopy and microscopy on model Pd/C samples to decouple the electronic and surface chemistry effects on catalytic performance. Our investigations reveal trends between the charge distribution at the palladium-carbon interface and the metal's selectivity for hydrogenation of multifunctional chemicals. These electronic effects are strong enough to affect the performance of large (~5 nm) Pd particles. Our results also demonstrate how simple thermal treatments can be used to tune the interfacial charge distribution, hereby providing a strategy to rationally design carbon-supported catalysts.Control over charge transfer in carbon-supported metal nanoparticles is essential for designing new catalysts. Here, the authors show that thermal treatments effectively tune the interfacial charge distribution in carbon-supported palladium catalysts with consequential changes in hydrogenation performance. PMID- 28835705 TI - Discovery and characterization of the feline miRNAome. AB - The domestic cat is an important human companion animal that can also serve as a relevant model for ~250 genetic diseases, many metabolic and degenerative conditions, and forms of cancer that are analogous to human disorders. MicroRNAs (miRNAs) play a crucial role in many biological processes and their dysregulation has a significant impact on important cellular pathways and is linked to a variety of diseases. While many species already have a well-defined and characterized miRNAome, miRNAs have not been carefully studied in cats. As a result, there are no feline miRNAs present in the reference miRNA databases, diminishing the usefulness of medical research on spontaneous disease in cats for applicability to both feline and human disease. This study was undertaken to define and characterize the cat miRNAome in normal feline tissues. High throughput sequencing was performed on 12 different normal cat tissues. 271 candidate feline miRNA precursors, encoding a total of 475 mature sequences, were identified, including several novel cat-specific miRNAs. Several analyses were performed to characterize the discovered miRNAs, including tissue distribution of the precursors and mature sequences, genomic distribution of miRNA genes and identification of clusters, and isomiR characterization. Many of the miRNAs were regulated in a tissue/organ-specific manner. PMID- 28835706 TI - iNOS promotes hypothalamic insulin resistance associated with deregulation of energy balance and obesity in rodents. AB - Inducible nitric oxide (iNOS)-mediated S-nitrosation of the metabolic signaling pathway has emerged as a post-translational modification that triggers insulin resistance in obesity and aging. However, the effects of S-nitrosation in controlling energy homeostasis are unknown. Thus, in the present study we aimed to evaluate the effects of S-nitrosation in insulin signaling pathway in the hypothalamus of rodents. Herein, we demonstrated that the intracerebroventricular infusion of the nitric oxide (NO) donor S-nitrosoglutathione (GSNO) promoted hypothalamic insulin signaling resistance and replicated the food intake pattern of obese individuals. Indeed, obesity induced S-nitrosation of hypothalamic IR and Akt, whereas inhibition of iNOS or S-nitrosation of insulin signaling pathway protected against hypothalamic insulin resistance and normalized energy homeostasis. Overall, these findings indicated that S-nitrosation of insulin signaling pathway is required to sustain hypothalamic insulin resistance in obesity. PMID- 28835708 TI - Exploring dengue genome to construct a multi-epitope based subunit vaccine by utilizing immunoinformatics approach to battle against dengue infection. AB - Dengue is considered as a major health issue which causes a number of deaths worldwide each year; tropical countries are majorly affected by dengue outbreaks. It is considered as life threatening issue because, since many decades not a single effective approach for treatment and prevention of dengue has been developed. Therefore, to find new preventive measure, we used immunoinformatics approaches to develop a multi-epitope based subunit vaccine for dengue which can generate various immune responses inside the host. Different B-cell, TC cell, and TH cell binding epitopes were predicted for structural and non-structural proteins of dengue virus. Final vaccine constructs consisting of TC and TH cell epitopes and an adjuvant (beta-defensin) at N-terminal of the construct. Presence of B-cell and IFN-gamma inducing epitopes confirms the humoral and cell mediated immune response developed by designed vaccine. Designed vaccine was not found allergic and was potentially antigenic in nature. Modeling of tertiary structure and the refined model was used for molecular docking with TLR-3 (immune receptor). Molecular docking and dynamics simulation confirms the microscopic interactions between ligand and receptor. In silico cloning approach was used to ensure the expression and translation efficiency of vaccine within an expression vector. PMID- 28835707 TI - Fusion or Fission: The Destiny of Mitochondria In Traumatic Brain Injury of Different Severities. AB - Mitochondrial dynamics are regulated by a complex system of proteins representing the mitochondrial quality control (MQC). MQC balances antagonistic forces of fusion and fission determining mitochondrial and cell fates. In several neurological disorders, dysfunctional mitochondria show significant changes in gene and protein expression of the MQC and contribute to the pathophysiological mechanisms of cell damage. In this study, we evaluated the main gene and protein expression involved in the MQC in rats receiving traumatic brain injury (TBI) of different severities. At 6, 24, 48 and 120 hours after mild TBI (mTBI) or severe TBI (sTBI), gene and protein expressions of fusion and fission were measured in brain tissue homogenates. Compared to intact brain controls, results showed that genes and proteins inducing fusion or fission were upregulated and downregulated, respectively, in mTBI, but downregulated and upregulated, respectively, in sTBI. In particular, OPA1, regulating inner membrane dynamics, cristae remodelling, oxidative phosphorylation, was post-translationally cleaved generating differential amounts of long and short OPA1 in mTBI and sTBI. Corroborated by data referring to citrate synthase, these results confirm the transitory (mTBI) or permanent (sTBI) mitochondrial dysfunction, enhancing MQC importance to maintain cell functions and indicating in OPA1 an attractive potential therapeutic target for TBI. PMID- 28835709 TI - Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors. AB - PDX1+/NKX6-1+ pancreatic progenitors (PPs) give rise to endocrine cells both in vitro and in vivo. This cell population can be successfully differentiated from human pluripotent stem cells (hPSCs) and hold the potential to generate an unlimited supply of beta cells for diabetes treatment. However, the efficiency of PP generation in vitro is highly variable, negatively impacting reproducibility and validation of in vitro and in vivo studies, and consequently, translation to the clinic. Here, we report the use of a proteomics approach to phenotypically characterize hPSC-derived PPs and distinguish these cells from non-PP populations during differentiation. Our analysis identifies the pancreatic secretory granule membrane major glycoprotein 2 (GP2) as a PP-specific cell surface marker. Remarkably, GP2 is co-expressed with NKX6-1 and PTF1A in human developing pancreata, indicating that it marks the multipotent pancreatic progenitors in vivo. Finally, we show that isolated hPSC-derived GP2+ cells generate beta-like cells (C-PEPTIDE+/NKX6-1+) more efficiently compared to GP2- and unsorted populations, underlining the potential therapeutic applications of GP2.Pancreatic progenitors (PPs) can be derived from human pluripotent stem cells in vitro but efficiency of differentiation varies, making it hard to sort for insulin producing cells. Here, the authors use a proteomic approach to identify the secretory granule membrane glycoprotein 2 as a marker for PDX1+/NKX6-1+ PPs. PMID- 28835710 TI - Aspirin metabolite sodium salicylate selectively inhibits transcriptional activity of ATF6alpha and downstream target genes. AB - In response to ER stress, activating transcription factor 6 (ATF6) traffics from ER to Golgi apparatus where it is activated by cleavage before being translocated as transcription factor to the cell nucleus. In this work we describe ATF6alpha as a newly target of the aspirin metabolite sodium salicylate (NaSal). NaSal treatment of cells induces increases in ATF6alpha mRNA and protein levels, but these events are not accompanied by ATF6 activation. Conversely, NaSal inhibited ATF6 transactivating activity elicited by various ER stress-inducing stimuli in different cell types. This resulted in reduced expression of a subset of ATF6alpha target genes. Mechanistically, exposure of cells to NaSal results in ATF6alpha trapping at the Golgi apparatus, thus preventing nuclear translocation. This study provides evidence that NaSal compound restrains the activity of ATF6alpha, thereby preventing activation of a specific subset of ER-stress responsive genes implicated in different cellular responses. PMID- 28835711 TI - Development of a versatile and conventional technique for gene disruption in filamentous fungi based on CRISPR-Cas9 technology. AB - Filamentous fungi represent an invaluable source of pharmaceutically active compounds. The development of versatile methods to genetically manipulate filamentous fungi is of great value for improving the low yields of bioactive metabolites and expanding chemical diversity. The CRISPR-Cas9-based system has become a common platform for genome editing in a variety of organisms. However, recent application of this technology in filamentous fungi is limited to model strains, a versatile method for efficient gene disruption in different fungi is lacking. Here, we investigated the utility of the CRISPR-Cas9 system in a less studied fungus Nodulisporium sp. (No. 65-12-7-1), and we have developed an efficient CRISPR-Cas9-based gene disruption strategy by simultaneous transformation of in vitro transcriptional gRNA and the linear maker gene cassette into the Cas9-expressing fungi. We found that the linear marker gene cassette could not only allow for selection of transformants, but also significantly enhance the gene disruption efficiency by inserting itself into the Cas9 cut site. Moreover, the above approach also demonstrated its efficiency in two other phylogenetically distinct strains Aspergillus oryzae NSAR1 and Sporormiella minima (No. 40-1-4-1) from two different classes of Ascomycota. These results suggested that a versatile CRISPR-Cas9-based gene disruption method in filamentous fungi was established. PMID- 28835712 TI - Association between taste receptor (TAS) genes and the perception of wine characteristics. AB - Several studies have suggested a possible relationship between polymorphic variants of the taste receptors genes and the acceptance, liking and intake of food and beverages. In the last decade investigators have attempted to link the individual ability to taste 6-n-propylthiouracil (PROP) and the sensations, such as astringency and bitterness, elicited by wine or its components, but with contradictory results. We have used the genotype instead of the phenotype (responsiveness to PROP or other tastants), to test the possible relation between genetic variability and the perception of wine characteristic in 528 subjects from Italy and the Czech Republic. We observed several interesting associations, among which the association between several TAS2R38 gene single nucleotide polymorphisms (P = 0.002) and the TAS2R16-rs6466849 polymorphism with wine sourness P = 0.0003). These associations were consistent in both populations, even though the country of origin was an important factor in the two models, thus indicating therefore that genetics alongside cultural factors also play a significant role in the individual liking of wine. PMID- 28835713 TI - A novel prognostic index-neutrophil times gamma-glutamyl transpeptidase to lymphocyte ratio (NgammaLR) predicts outcome for patients with hepatocellular carcinoma. AB - Clinical outcomes of patients with hepatocellular carcinoma (HCC) are highly variable. This study aims to identify and validate a simple, readily available, and objective prognostic index for the management of HCC. Data from 724 HCC patients undergoing curative resection were evaluated and randomly divided into two cohorts for building and validating the prognostic index. A best model, NgammaLR = (neutrophil count [109/L] * gamma-glutamyl transpeptidase [U/L]) /(lymphocyte count [109/L] * U/L), was selected. An optimal cut-off value of 103.6 for NgammaLR stratified patients into high NgammaLR (>103.6) and low NgammaLR (<=103.6) groups. NgammaLR > 103.6 was closely associated with HCC malignant characteristics. Elevated NgammaLR predicted a worse overall survival (OS) and progression-free survival (PFS) for HCC patients and remained an independent predictor for both types of survival. Moreover, early recurrence rates in patients with NgammaLR > 103.6 were higher than that in patients with NgammaLR <= 103.6 (P < 0.0001). NgammaLR was an important independent predictor of survival for HCC patients and might be a new promising method to identify patients at different risks of early recurrence and survival after curative resection. PMID- 28835714 TI - Surgical outcomes from limiting the use of nonabsorbable suture in tunica albuginea plication for Peyronie's disease. AB - Tunica albuginea plication (TAP) surgery for Peyronie's disease (PD) is classically described using nonabsorbable suture. Many patients are aware of nodularity at the suture sites (50-88%), and some find them painful (10-33%). We explore whether limiting permanent sutures provides a durable correction of curve and report the incidence of bothersome nodules. Beginning in 2007, we modified our TAP procedure to limit the use of permanent sutures. We reviewed all patients who underwent TAP procedures from 2007 to 2014 at our institution. Patients were contacted to complete a previously published survey regarding postoperative satisfaction. In total, 142 PD patients underwent the TAP procedure and 81/142 (57%) completed the postoperative survey. Mean office follow-up and survey follow up were 17.3 and 56.3 months, respectively. Of the surveyed patients, 6.2% complained of a bothersome residual curve, 19.8% experienced nodularity and 4.9% reported bothersome nodules. Men with dorsal curves experienced less painful nodularity than those with ventral (P=0.047) or lateral curves (P=0.017). In total, 4/142 (2.8%) of men underwent repeat intervention. At long-term follow-up, limiting permanent sutures during TAP procedures for PD is durable with respect to curvature correction and has encouragingly low levels of nodularity and bother at suture sites. PMID- 28835715 TI - Shade Inhibits Leaf Size by Controlling Cell Proliferation and Enlargement in Soybean. AB - To gain more insight into the physiological function of shade and how shade affects leaf size, we investigated the growth, leaf anatomical structure, hormones and genes expressions in soybean. Soybean seeds were sown in plastic pots and were allowed to germinate and grow for 30 days under shade or full sunlight conditions. Shade treated plants showed significantly increase on stem length and petiole length, and decrease on stem diameters, shoot biomass and its partition to leaf also were significantly lower than that in full sunlight. Smaller and thinner on shade treated leaves than corresponding leaves on full sunlight plants. The decreased leaf size caused by shade was largely attributable to cell proliferation in young leaves and both cell proliferation and enlargement in old leaves. Shade induced the expression of a set of genes related to cell proliferation and/or enlargement, but depended on the developmental stage of leaf. Shade significantly increased the auxin and gibberellin content, and significantly decreased the cytokinin content in young, middle and old leaves. Taken together, these results indicated that shade inhibited leaf size by controlling cell proliferation and enlargement, auxin, gibberellin and cytokinin may play important roles in this process. PMID- 28835716 TI - The ERK-1 function is required for HSV-1-mediated G1/S progression in HEP-2 cells and contributes to virus growth. AB - The herpes simplex virus 1 is able to readdress different cellular pathways including cell cycle to facilitate its replication and spread. During infection, the progression of the cell cycle from G1 to S phase makes the cellular replication machinery accessible to viral DNA replication. In this work we established that HSV-1, in asynchronized HEp-2 cells, strictly controls cell cycle progression increasing S-phase population from 9 hours post infection until the end of HSV-1 replication. The G1/S phases progression depends on two important proteins, cyclin E and CDK2. We demonstrate that their phosphorylated status and then their activity during the infection is strongly correlated to viral replication events. In addition, HSV-1 is able to recruit and distribute ERK1/2 proteins in a spatio-temporal fashion, highlighting its downstream regulatory effects on cellular processes. According with this data, using chemical inhibitor U0126 and ERK dominant negative cells we found that the lack of ERK1 activity affects cyclin E protein accumulation, viral gene transcription and percentage of the cells in S phase, during the viral replication. These data suggested a complex interaction between ERK, cell cycle progression and HSV-1 replication. PMID- 28835718 TI - Metastasis: Throwing oil into the flames. PMID- 28835717 TI - Establishment and genomic characterization of the new chordoma cell line Chor-IN 1. AB - Chordomas are rare, slowly growing tumors with high medical need, arising in the axial skeleton from notochord remnants. The transcription factor "brachyury" represents a distinctive molecular marker and a key oncogenic driver of chordomas. Tyrosine kinase receptors are also expressed, but so far kinase inhibitors have not shown clear clinical efficacy in chordoma patients. The need for effective therapies is extremely high, but the paucity of established chordoma cell lines has limited preclinical research. Here we describe the isolation of the new Chor-IN-1 cell line from a recurrent sacral chordoma and its characterization as compared to other chordoma cell lines. Chor-IN-1 displays genomic identity to the tumor of origin and has morphological features, growth characteristics and chromosomal abnormalities typical of chordoma, with expression of brachyury and other relevant biomarkers. Chor-IN-1 gene variants, copy number alterations and kinome gene expression were analyzed in comparison to other four chordoma cell lines, generating large scale DNA and mRNA genomic data that can be exploited for the identification of novel pharmacological targets and candidate predictive biomarkers of drug sensitivity in chordoma. The establishment of this new, well characterized chordoma cell line provides a useful tool for the identification of drugs active in chordoma. PMID- 28835721 TI - Immunotherapy: Searching in the immune checkpoint black box. PMID- 28835719 TI - Unravelling biology and shifting paradigms in cancer with single-cell sequencing. AB - The fundamental operative unit of a cancer is the genetically and epigenetically innovative single cell. Whether proliferating or quiescent, in the primary tumour mass or disseminated elsewhere, single cells govern the parameters that dictate all facets of the biology of cancer. Thus, single-cell analyses provide the ultimate level of resolution in our quest for a fundamental understanding of this disease. Historically, this quest has been hampered by technological shortcomings. In this Opinion article, we argue that the rapidly evolving field of single-cell sequencing has unshackled the cancer research community of these shortcomings. From furthering an elemental understanding of intra-tumoural genetic heterogeneity and cancer genome evolution to illuminating the governing principles of disease relapse and metastasis, we posit that single-cell sequencing promises to unravel the biology of all facets of this disease. PMID- 28835723 TI - Targeting neoantigens to augment antitumour immunity. PMID- 28835720 TI - Therapy-related myeloid neoplasms: when genetics and environment collide. AB - Therapy-related myeloid neoplasms (t-MN) arise as a late effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this Review, we discuss recent developments that reframe our understanding of the genetic and environmental aetiology of t-MN. Emerging data are illuminating who is at highest risk of developing t-MN, why t-MN are chemoresistant and how we may use this information to treat and ultimately prevent this lethal disease. PMID- 28835724 TI - Identification of PAH Isomeric Structure in Cosmic Dust Analogues: the AROMA setup. AB - We developed a new analytical experimental setup called AROMA (Astrochemistry Research of Organics with Molecular Analyzer) that combines laser desorption/ionization techniques with ion trap mass spectrometry. We report here on the ability of the apparatus to detect aromatic species in complex materials of astrophysical interests and characterize their structures. A limit of detection of 100 femto-grams has been achieved using pure polycyclic aromatic hydrocarbon (PAH) samples, which corresponds to 2x108 molecules in the case of coronene (C24H12). We detected the PAH distribution in the Murchison meteorite, which is made of a complex mixture of extraterrestrial organic compounds. In addition, collision induced dissociation experiments were performed on selected species detected in Murchison, which led to the first firm identification of pyrene and its methylated derivatives in this sample. PMID- 28835725 TI - Cost of Aging. PMID- 28835722 TI - Evolutionary biology of high-risk multiple myeloma. AB - The outcomes for the majority of patients with myeloma have improved over recent decades, driven by treatment advances. However, there is a subset of patients considered to have high-risk disease who have not benefited. Understanding how high-risk disease evolves from more therapeutically tractable stages is crucial if we are to improve outcomes. This can be accomplished by identifying the genetic mechanisms and mutations driving the transition of a normal plasma cell to one with the features of the following disease stages: monoclonal gammopathy of undetermined significance, smouldering myeloma, myeloma and plasma cell leukaemia. Although myeloma initiating events are clonal, subsequent driver lesions often occur in a subclone of cells, facilitating progression by Darwinian selection processes. Understanding the co-evolution of the clones within their microenvironment will be crucial for therapeutically manipulating the process. The end stage of progression is the generation of a state associated with treatment resistance, increased proliferation, evasion of apoptosis and an ability to grow independently of the bone marrow microenvironment. In this Review, we discuss these end-stage high-risk disease states and how new information is improving our understanding of their evolutionary trajectories, how they may be diagnosed and the biological behaviour that must be addressed if they are to be treated effectively. PMID- 28835726 TI - Asymptotics of empirical eigenstructure for high dimensional spiked covariance. AB - We derive the asymptotic distributions of the spiked eigenvalues and eigenvectors under a generalized and unified asymptotic regime, which takes into account the magnitude of spiked eigenvalues, sample size, and dimensionality. This regime allows high dimensionality and diverging eigenvalues and provides new insights into the roles that the leading eigenvalues, sample size, and dimensionality play in principal component analysis. Our results are a natural extension of those in Paul (2007) to a more general setting and solve the rates of convergence problems in Shen et al. (2013). They also reveal the biases of estimating leading eigenvalues and eigenvectors by using principal component analysis, and lead to a new covariance estimator for the approximate factor model, called shrinkage principal orthogonal complement thresholding (S-POET), that corrects the biases. Our results are successfully applied to outstanding problems in estimation of risks of large portfolios and false discovery proportions for dependent test statistics and are illustrated by simulation studies. PMID- 28835727 TI - Fat tissue is not a reservoir for radiocesium in wild boars. AB - Meat of wild boars is not only known for high 137Cs activity concentrations but also for the remarkable constancy of these levels. Even decades after the Chernobyl accident, the 137Cs levels in wild boar meat in Central Europe have not declined but even partly increased. In the present study, we investigated an unusual hypothesis for this very unusual phenomenon: may the boars' fat tissue act as a reservoir for radiocesium? We investigated fat and muscle tissues of four wild boars in Western Germany and found that the 137Cs concentrations in fat were in the range of 10-30% of the respective activities in muscle tissue. Hence, the hypothesis was refuted. PMID- 28835728 TI - Phase contrast imaging X-ray computed tomography: Quantitative characterization of human patellar cartilage matrix with topological and geometrical features. AB - Current assessment of cartilage is primarily based on identification of indirect markers such as joint space narrowing and increased subchondral bone density on x ray images. In this context, phase contrast CT imaging (PCI-CT) has recently emerged as a novel imaging technique that allows a direct examination of chondrocyte patterns and their correlation to osteoarthritis through visualization of cartilage soft tissue. This study investigates the use of topological and geometrical approaches for characterizing chondrocyte patterns in the radial zone of the knee cartilage matrix in the presence and absence of osteoarthritic damage. For this purpose, topological features derived from Minkowski Functionals and geometric features derived from the Scaling Index Method (SIM) were extracted from 842 regions of interest (ROI) annotated on PCI CT images of healthy and osteoarthritic specimens of human patellar cartilage. The extracted features were then used in a machine learning task involving support vector regression to classify ROIs as healthy or osteoarthritic. Classification performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). The best classification performance was observed with high-dimensional geometrical feature vectors derived from SIM (0.95 +/- 0.06) which outperformed all Minkowski Functionals (p < 0.001). These results suggest that such quantitative analysis of chondrocyte patterns in human patellar cartilage matrix involving SIM-derived geometrical features can distinguish between healthy and osteoarthritic tissue with high accuracy. PMID- 28835729 TI - Volumetric Characterization of Human Patellar Cartilage Matrix on Phase Contrast X-Ray Computed Tomography. AB - Phase contrast X-ray computed tomography (PCI-CT) has recently emerged as a novel imaging technique that allows visualization of cartilage soft tissue, subsequent examination of chondrocyte patterns, and their correlation to osteoarthritis. Previous studies have shown that 2D texture features are effective at distinguishing between healthy and osteoarthritic regions of interest annotated in the radial zone of cartilage matrix on PCI-CT images. In this study, we further extend the texture analysis to 3D and investigate the ability of volumetric texture features at characterizing chondrocyte patterns in the cartilage matrix for purposes of classification. Here, we extracted volumetric texture features derived from Minkowski Functionals and gray-level co-occurrence matrices (GLCM) from 496 volumes of interest (VOI) annotated on PCI-CT images of human patellar cartilage specimens. The extracted features were then used in a machine-learning task involving support vector regression to classify ROIs as healthy or osteoarthritic. Classification performance was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). The best classification performance was observed with GLCM features correlation (AUC = 0.83 +/- 0.06) and homogeneity (AUC = 0.82 +/- 0.07), which significantly outperformed all Minkowski Functionals (p < 0.05). These results suggest that such quantitative analysis of chondrocyte patterns in human patellar cartilage matrix involving GLCM-derived statistical features can distinguish between healthy and osteoarthritic tissue with high accuracy. PMID- 28835730 TI - Design and characterization of a low profile NaI(Tl) gamma camera for dedicated molecular breast tomosynthesis. AB - A new low profile gamma camera is being developed for use in a dual modality (x ray transmission and gamma-ray emission) tomosynthesis system. Compared to the system's current gamma camera, the new camera has a larger field of view (~20*25 cm) to better match the system's x-ray detector (~23*29 cm), and is thinner (7.3 cm instead of 10.3 cm) permitting easier camera positioning near the top surface of the breast. It contains a pixelated NaI(Tl) array with a crystal pitch of 2.2 mm, which is optically coupled to a 4*5 array of Hamamatsu H8500C position sensitive photomultiplier tubes (PSPMTs). The manufacturer-provided connector board of each PSPMT was replaced with a custom designed board that a) reduces the 64 channel readout of the 8*8 electrode anode of the H8500C to 16 channels (8X and 8Y), b) performs gain non-uniformity correction, and c) reduces the height of the PSPMT-base assembly, 37.7 mm to 27.87 mm. The X and Y outputs of each module are connected in a lattice framework, and at two edges of this lattice, the X and Y outputs (32Y by 40X) are coupled to an amplifier/output board whose signals are fed via shielded ribbon cables to external ADCs. The camera uses parallel hole collimation. We describe the measured camera imaging performance, including intrinsic and extrinsic spatial resolution, detection sensitivity, uniformity of response, energy resolution for 140 keV gamma rays, and geometric linearity. PMID- 28835731 TI - Youth Participatory Action Research (YPAR) 2.0: how technological innovation and digital organizing sparked a food revolution in East Oakland. AB - This article argues that technological innovation is transforming the flow of information, the fluidity of social action, and is giving birth to new forms of bottom up innovation that are capable of expanding and exploding old theories of reproduction and resistance because 'smart mobs', 'street knowledge', and 'social movements' cannot be neutralized by powerful structural forces in the same old ways. The purpose of this article is to develop the concept of YPAR 2.0 in which new technologies enable young people to visualize, validate, and transform social inequalities by using local knowledge in innovative ways that deepen civic engagement, democratize data, expand educational opportunity, inform policy, and mobilize community assets. Specifically this article documents how digital technology (including a mobile, mapping and SMS platform called Streetwyze and paper-mapping tool Local Ground) - coupled with 'ground-truthing' - an approach in which community members work with researchers to collect and verify 'public' data - sparked a food revolution in East Oakland that led to an increase in young people's self-esteem, environmental stewardship, academic engagement, and positioned urban youth to become community leaders and community builders who are connected and committed to health and well-being of their neighborhoods. This article provides an overview of how the YPAR 2.0 Model was developed along with recommendations and implications for future research and collaborations between youth, teachers, neighborhood leaders, and youth serving organizations. PMID- 28835732 TI - Complete convergence of randomly weighted END sequences and its application. AB - We investigate the complete convergence of partial sums of randomly weighted extended negatively dependent (END) random variables. Some results of complete moment convergence, complete convergence and the strong law of large numbers for this dependent structure are obtained. As an application, we study the convergence of the state observers of linear-time-invariant systems. Our results extend the corresponding earlier ones. PMID- 28835734 TI - Embedded-Based Graphics Processing Unit Cluster Platform for Multiple Sequence Alignments. AB - High-end graphics processing units (GPUs), such as NVIDIA Tesla/Fermi/Kepler series cards with thousands of cores per chip, are widely applied to high performance computing fields in a decade. These desktop GPU cards should be installed in personal computers/servers with desktop CPUs, and the cost and power consumption of constructing a GPU cluster platform are very high. In recent years, NVIDIA releases an embedded board, called Jetson Tegra K1 (TK1), which contains 4 ARM Cortex-A15 CPUs and 192 Compute Unified Device Architecture cores (belong to Kepler GPUs). Jetson Tegra K1 has several advantages, such as the low cost, low power consumption, and high applicability, and it has been applied into several specific applications. In our previous work, a bioinformatics platform with a single TK1 (STK platform) was constructed, and this previous work is also used to prove that the Web and mobile services can be implemented in the STK platform with a good cost-performance ratio by comparing a STK platform with the desktop CPU and GPU. In this work, an embedded-based GPU cluster platform will be constructed with multiple TK1s (MTK platform). Complex system installation and setup are necessary procedures at first. Then, 2 job assignment modes are designed for the MTK platform to provide services for users. Finally, ClustalW v2.0.11 and ClustalWtk will be ported to the MTK platform. The experimental results showed that the speedup ratios achieved 5.5 and 4.8 times for ClustalW v2.0.11 and ClustalWtk, respectively, by comparing 6 TK1s with a single TK1. The MTK platform is proven to be useful for multiple sequence alignments. PMID- 28835733 TI - In Vivo Assessment of Elasticity of Child Rib Cortical Bone Using Quantitative Computed Tomography. AB - Elasticity of the child rib cortical bone is poorly known due to the difficulties in obtaining specimens to perform conventional tests. It was shown on the femoral cortical bone that elasticity is strongly correlated with density for both children and adults through a unique relationship. Thus, it is assumed that the relationships between the elasticity and density of adult rib cortical bones could be expanded to include that of children. This study estimated in vivo the elasticity of the child rib cortical bone using quantitative computed tomography (QCT). Twenty-eight children (from 1 to 18 y.o.) were considered. Calibrated QCT images were prescribed for various thoracic pathologies. The Hounsfield units were converted to bone mineral density (BMD). A relationship between the BMD and the elasticity of the rib cortical bone was applied to estimate the elasticity of children's ribs in vivo. The estimated elasticity increases with growth (7.1 +/- 2.5 GPa at 1 y.o. up to 11.6 +/- 1.9 GPa at 18 y.o.). This data is in agreement with the few previous values obtained using direct measurements. This methodology paves the way for in vivo assessment of the elasticity of the child cortical bone based on calibrated QCT images. PMID- 28835735 TI - Adaptive Multiview Nonnegative Matrix Factorization Algorithm for Integration of Multimodal Biomedical Data. AB - The amounts and types of available multimodal tumor data are rapidly increasing, and their integration is critical for fully understanding the underlying cancer biology and personalizing treatment. However, the development of methods for effectively integrating multimodal data in a principled manner is lagging behind our ability to generate the data. In this article, we introduce an extension to a multiview nonnegative matrix factorization algorithm (NNMF) for dimensionality reduction and integration of heterogeneous data types and compare the predictive modeling performance of the method on unimodal and multimodal data. We also present a comparative evaluation of our novel multiview approach and current data integration methods. Our work provides an efficient method to extend an existing dimensionality reduction method. We report rigorous evaluation of the method on large-scale quantitative protein and phosphoprotein tumor data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) acquired using state-of-the-art liquid chromatography mass spectrometry. Exome sequencing and RNA-Seq data were also available from The Cancer Genome Atlas for the same tumors. For unimodal data, in case of breast cancer, transcript levels were most predictive of estrogen and progesterone receptor status and copy number variation of human epidermal growth factor receptor 2 status. For ovarian and colon cancers, phosphoprotein and protein levels were most predictive of tumor grade and stage and residual tumor, respectively. When multiview NNMF was applied to multimodal data to predict outcomes, the improvement in performance is not overall statistically significant beyond unimodal data, suggesting that proteomics data may contain more predictive information regarding tumor phenotypes than transcript levels, probably due to the fact that proteins are the functional gene products and therefore a more direct measurement of the functional state of the tumor. Here, we have applied our proposed approach to multimodal molecular data for tumors, but it is generally applicable to dimensionality reduction and joint analysis of any type of multimodal data. PMID- 28835736 TI - Health care Professionals' Experiences and Needs When Delivering End-of-Life Care to Children: A Qualitative Study. AB - Pediatric end-of-life care (EOL care) entails challenging tasks for health care professionals (HCPs). Little is known about HCPs' experiences and needs when providing pediatric EOL care in Switzerland. This study aimed to describe the experiences and needs of HCPs in pediatric EOL care in Switzerland and to develop recommendations for the health ministry. The key aspect in EOL care provision was identified as the capacity to establish a relationship with the dying child and the family. Barriers to this interaction were ethical dilemmas, problems in collaboration with the interprofessional team, and structural problems on the level of organizations. A major need was the expansion of vocational training and support by specialized palliative care teams. We recommend the development of a national concept for the provision of EOL care in children, accompanied by training programs and supported by specialized pediatric palliative care teams located in tertiary children's hospitals. PMID- 28835737 TI - Higher Ant Diversity in Native Vegetation Than in Stands of the Invasive Arundo, Arundo donax L., Along the Rio Grande Basin in Texas, USA. AB - Our hypothesis was that there will be greater ant biodiversity in heterogeneous native vegetation compared with Arundo stands. Changes in ant biodiversity due to Arundo invasion may be one of the ecological changes in the landscape that facilitates the invasion of cattle fever ticks from Mexico where they are endemic. Ants collected in pitfall traps were identified and compared between native vegetation and stands of Arundo, Arundo donax L., monthly for a year at 10 locations. A total of 82 752 ants representing 28 genera and 76 species were collected. More ants were collected in the native vegetation which also had greater species richness and biological diversity than ants collected from Arundo stands. It is suggested that the greater heterogeneous nature of native vegetation provided greater and more predictable nourishment in the form of nectars and more abundant arthropod prey when compared with Arundo stands. PMID- 28835738 TI - Is Outpatient Thyroid Surgery for Everyone? AB - Thyroidectomy is a common surgical procedure. Traditionally, surgeons have performed thyroidectomy on an inpatient basis. However, consistent with current trends in surgery, some practices are transitioning thyroidectomy to an outpatient setting. Although concerns for hypocalcemia and postoperative bleeding exist regardless of surgeon experience, multiple studies demonstrate that outpatient thyroidectomy is safe in the hands of high-volume surgeons. Indeed, experienced thyroid surgeons who perform thyroidectomy in an outpatient setting experience excellent patient outcomes and reduced costs. However, outpatient thyroidectomy may not be suitable for all surgeons, hospitals, or patients. When evaluating whether to implement an outpatient thyroid program, a practice should consider a number of important factors including the team performing the procedure, the hospital, and the patient. With the appropriate staff education and experience, hospital setting, and patient selection, practices in a multitude of settings can successfully develop a safe, cost-effective outpatient thyroid program. PMID- 28835739 TI - Effects of Ligand Halogenation on the Electron Localization, Geometry and Spin State of Low-Coordinate (beta-Diketiminato)iron Complexes. AB - This contribution explores the influences of incorporating electron-withdrawing CF3 and halide groups into beta-diketiminate iron complexes of tetrazene and isocyanide. The synthesis of a new halogenated beta-diketimine (LCF3,ClH) was accomplished via two different methods, including a novel microwave-assisted synthesis that improves the yield of the difficult condensation. Treatment of an iron(II) complex of this ligand with reductant and azide gives two diiron complexes with novel tetrazenes as bridging ligands. Structural and Mossbauer data show that the bridging tetrazene is a radical anion. The halogenation of the supporting ligand also influences iron(I) complexes of the type LFe(CNtBu)2, which are low-spin and square-planar with alkyl substituents but high-spin and pseudotetrahedral with halogen substituents. DFT calculations suggest that the changes from halogenation come from a combination of steric and electronic effects, and that the electronic influence of ligand halogenation is minor. PMID- 28835740 TI - Women's and Men's Differing Experiences of Health, Lifestyle, and Aging with Multiple Sclerosis. AB - BACKGROUND: The growing population of older people with multiple sclerosis (MS) has led to more interest in understanding factors associated with healthy aging. We aimed to determine whether older women and men with MS have different health and lifestyle behaviors and whether there are sex differences in contributors to perceived health. METHODS: Data were obtained from a postal survey involving 743 Canadians older than 55 years with MS for at least 20 years. Sex differences in health, lifestyle, mood, and socioeconomics were examined using analysis of variance. Multiple regression was used to build explanatory models of health perception. RESULTS: Despite no differences in age, years with MS, disability, fatigue, or social support, older men (n = 166) experienced lower perceived health and lower resilience and participated less in life roles than older women (n = 577). Men experienced more depressive symptoms, and women reported more anxiety. Depression was the strongest predictor of health perception in both women and men (beta = -2.40 and -5.19, respectively, for each 3-point increase in depressive symptoms). Other contributors included household participation, fatigue, resilience, and disability in women and physical activity, financial flexibility, and alcohol use in men. CONCLUSIONS: Older men exhibit poorer adaptation to aging with MS than older women. PMID- 28835741 TI - Preferences for Multiple Sclerosis Treatments: Using a Discrete-Choice Experiment to Examine Differences Across Subgroups of US Patients. AB - BACKGROUND: The growing number of treatments for relapsing multiple sclerosis (MS) provides opportunities to consider patient preferences in treatment decisions. METHODS: We designed a Web-based, discrete-choice experiment survey to analyze treatment preferences in patients with relapsing-remitting MS (RRMS). The survey presented hypothetical MS treatments defined by six attributes: risk of MS progression, time between relapses, risk of serious infection, treatment-related flu-like symptoms and gastrointestinal symptoms, and route and frequency of administration. Preference weights estimated with random-parameters logit were used to calculate importance scores and preference shares among three pairs of subsamples. RESULTS: Patients with a self-reported physician diagnosis of RRMS (N = 301) completed the survey: 56% rated their disability level as normal or mild; 43% currently used a self-injectable treatment. Respondents with normal or mild disability levels placed greater weight on avoiding injections with flu-like symptoms and risk of progression, whereas patients with worse disability placed greater weight on reducing risk of progression and risk of serious infection. Patients taking injectables placed the most weight on risk of progression and risk of serious infection, whereas respondents not taking injectables placed the most weight on route and frequency of administration. Differences in preferences between subgroups were significant (P < .05). The presence of common adverse events associated with daily pills and injectables altered predicted preferences for route of administration. CONCLUSIONS: Preferences of patients with RRMS varied depending on current treatment and disability level, especially regarding mode of administration. Considering patient preferences for treatment features may lead to higher treatment satisfaction and adherence. PMID- 28835742 TI - Associations Between Bladder Dysfunction and Falls in People with Relapsing Remitting Multiple Sclerosis. AB - BACKGROUND: Bladder dysfunction and falls are common in people with multiple sclerosis (MS), but associations between these problems are unclear. We sought to clarify the association between specific types of bladder dysfunction and prospectively recorded falls in people with MS. METHODS: Fifty-one people aged 18 to 50 years with relapsing-remitting MS and mild-to-moderate disability (Expanded Disability Status Scale score <=6.0) completed a self-report questionnaire regarding urinary incontinence, urgency, and frequency at baseline and then prospectively recorded their falls daily for 3 months using fall calendars. Participants were classified as recurrent fallers (two or more falls) or nonrecurrent fallers (fewer than 2 falls) for one regression model and then as fallers (one or more falls) or nonfallers (no falls) for another regression model. Associations between baseline bladder dysfunction and faller status were assessed using logistic regression adjusted for the potential confounders of age, sex, and disability. RESULTS: Fifteen participants were recurrent fallers, 36 were nonrecurrent fallers, 32 were fallers, and 19 were nonfallers. After adjusting for age, sex, and disability, there was a significant association between urinary urgency with incontinence and recurrent falls in the 3 months after baseline (odds ratio, 57.57; 95% CI, 3.43-966.05; P = .005). CONCLUSIONS: Urinary urgency with incontinence is associated with recurrent falls in people with relapsing-remitting MS with mild-to-moderate disability. Further research is needed to better understand the mechanisms underlying this association and to evaluate the effect of bladder management programs on falls. PMID- 28835743 TI - How Beliefs About Bladder Dysfunction Among Health-Care Professionals Influence Clinical Practice Development: Perspectives of Allied Health Professionals, Nurses, and Managers. AB - BACKGROUND: Bladder dysfunction can affect up to 75% of people with multiple sclerosis (MS) on several important life domains. It is a multifaceted problem that remains underdiagnosed by health-care professionals. The aims of this study were to understand the perceptions of Irish health-care professionals regarding bladder dysfunction and to explore current service provision for people with MS. METHODS: Two focus groups, three dyadic interviews, and one semistructured interview with 14 health-care professionals lasting up to 90 minutes were audio recorded. Participants included eight physiotherapists, two occupational therapists, three nurses, and one clinical case manager from acute and community settings. RESULTS: Thematic analysis of transcripts yielded two key themes. The first theme involves the underlying beliefs of health-care professionals, their clinical practice, and experiential knowledge in the model of clinical practice development in relation to bladder management. The second theme addresses the pivotal points in this model where change can be implemented to optimize bladder management. The first element of change encompasses the interaction between clinical practice and experiential knowledge of health-care professionals. The second element of change incorporates how acknowledgment of individual beliefs of health-care professionals can further inform clinical practice and experiential knowledge. CONCLUSIONS: These findings suggest that health-care professionals need to be aware of their beliefs in relation to bladder dysfunction. Examining these beliefs may influence how people with MS access health service provision for this disabling symptom. This type of reflexive practice may facilitate changes to existing perceptions and reduce the reluctance to discuss bladder symptoms. PMID- 28835744 TI - Depression and Age at First Neurology Appointment Associated with Receipt of Behavioral Medicine Services Within 1 Year in a Multiple Sclerosis Population. AB - BACKGROUND: Patients with multiple sclerosis (MS) newly seen by a neurologist may benefit from early psychological intervention owing to the reciprocal relationship between stress and disease progression. However, it is uncertain what factors contribute to patients' receiving these services. METHODS: Logistic regression analysis of prospectively gathered data evaluated how demographic and disease characteristics and emotional/physical health factors contributed to referral to receive behavioral medicine (BM) services within 1 year of their first neurology appointment at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. Survival analyses then evaluated whether this resulted in earlier receipt of services. RESULTS: Although many factors were associated with receiving BM services during univariate analyses (age, race, marital status, years since MS onset, depression, stress, and quality of life), when considering multivariable interactions, only two variables remained significant: age (odds ratio [OR] = 0.86, 95% confidence interval [CI], 0.80-0.92) and depression (OR = 1.56, 95% CI, 1.39-1.75). Survival analyses did not show differences in time to BM services for stratifications of age or depression scores. CONCLUSIONS: Younger patients and patients with more severe depression were more likely to receive BM services within 1 year of their first neurology appointment. Future research will focus on evaluating whether these are also the patients in greatest need of services or whether they are simply more open to receiving them. PMID- 28835745 TI - Cultural Adaptation, Validity, and Factor Structure of the Jalowiec Coping Scale in Iranian Women with Multiple Sclerosis: Which Coping Strategies Are Most Common and Effective? AB - BACKGROUND: The aims of this study were to evaluate the Jalowiec Coping Scale (JCS) psychometrically in Iranian women with multiple sclerosis (MS) and to identify the most frequent and efficacious coping strategies. METHODS: A total of 306 women with MS participated in a cross-sectional study. A demographics questionnaire, the JCS, and the Perceived Stress Scale were administered. Forward backward translation was used to achieve a Persian version of the scale. Cronbach alpha and test-retest were assessed for reliability. Convergent and discriminant validity were tested using an item-scaling procedure. The association of the JCS with perceived stress was examined using multiple regression. The factor structure was also explored using rotated exploratory factor analysis. RESULTS: Participants had a mean (SD) age of 32.0 (6.6) years, and nearly half reported visual impairment as the first symptom of disease. Cronbach alpha for the scale was 0.898 and for the subscales ranged from 0.254 to 0.778. Relatively good convergent and discriminant validity were achieved (success rate >=69%). Subscales assessing optimistic, fatalistic, and emotive coping predicted stress levels. A four-factor solution explained 30% of the total variance. Optimistic and supportive coping styles were the most common and effective styles, respectively, reported. CONCLUSIONS: The JCS may be useful in assessing coping strategies in Iranian women with MS. Further studies are needed to better understand how coping styles used in practice are similar to their theoretical constructs. PMID- 28835746 TI - Effect of Cognitive Demand on Functional Mobility in Ambulatory Individuals with Multiple Sclerosis. AB - BACKGROUND: As disease progresses, cognitive demands may affect functional mobility in individuals with multiple sclerosis (MS). The Timed Up and Go (TUG) test assesses functional mobilityin populationssuch as MS. A cognitive-demanding task can be added to the TUG test to assess its effect on functional mobility. METHODS: People with MS (n = 52) and controls (n = 57) performed three versions of the TUG test: TUG alone (TUG-alone), TUG plus reciting the alphabet (TUG alpha), and TUG plus subtracting numbers by 3s (TUG-3s). Times to complete the TUG tests were compared among controls and three groups of participants with MS created using Expanded Disability Status Scale (EDSS) scores 0 to 3.5, 4.0 to 5.5, and 6. Differences among groups were analyzed using split-plot analysis of variance. RESULTS: Group and TUG type were significant (P < .001 for both), with no interaction effect of group * TUG type (P = .21). Mean times were 8.7, 9.4, and 11.1 seconds to perform the TUG-alone, TUG-alpha, and TUG-3s, respectively. Mean times for groups were 8.0, 8.2, 11.1, and 11.6 seconds for controls and individuals with MS and EDSS 0 to 3.5, 4.0 to 5.5, and 6, respectively. CONCLUSIONS: People with MS with an EDSS score greater than 3.5 had a statistically significant reduction in performance of the TUG test even with the addition of a simple cognitive task, which might have implications for a person's more complex everyday activities. PMID- 28835747 TI - Editorial. PMID- 28835748 TI - Four Transgenerational Demographic Performance of Moina macrocopa Exposed to Chronic Levels of Cadmium. AB - In this study, we quantified intergenerational, demographic variability of Moina macrocopa subjected to cadmium stress. Exposure of M macrocopa to cadmium (0.2, 0.3, and 0.4 mg/L as CdCl2) through 4 consecutive generations revealed changes in demographic responses not only in survivorship variables but also in reproductive parameters. Long-term demographic responses varied differently, depending on the demographic trait and the concentration of heavy metal in the medium. With the exception of generation time, all life history traits were significantly and adversely influenced due to increase in Cd concentrations. The average life span of M macrocopa varied up to 40% depending on Cd level and the generation of exposure. The highest gross reproductive rates were recorded in controls, while the lowest (~30% less) were recorded at the highest Cd level. Survival-weighted net reproductive rates were reduced by nearly 50% due to Cd toxicity. The rate of population increase per day of M macrocopa was also significantly affected (~25%) by Cd as compared to controls. This cladoceran showed a dose-response to Cd toxicity with a significance in both magnitude and frequency of offspring production. PMID- 28835749 TI - Corrigendum: Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation. AB - [This corrects the article on p. 138 in vol. 4, PMID: 24106489.]. PMID- 28835750 TI - Adjuvant Second-Dose Chemotherapy before Surgery for Patients with Locally Advanced Rectal Malignancy Is Not Beneficial: A Systematic Review and Meta Analysis. AB - BACKGROUND: Preoperative chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer, although tumor responses vary widely; some patients may achieve a pathologic complete response rate (pCR) after chemoradiotherapy. Controversy exists with regard to the efficacy of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy, compared with chemoradiotherapy alone. METHODS: PubMed, the Cochrane Library, and Embase databases were searched for comparative studies of patients with locally advanced rectal cancer that were published between January 1991 and January 2016. Efficacies of different preoperative combination chemotherapy regimens and neoadjuvant chemoradiotherapy (group A) were compared with chemoradiotherapy alone (group B) in a meta-analysis using Review Manager v5.2. RESULTS: Three prospective randomized controlled trials and two prospective nonrandomized controlled trials comprising 444 cases were eligible for analysis. No significant difference was detected in the rate of pCR (50/223, 22.4% versus 35/223, 15.7%; relative risk, RR: 1.42 [95% confidence interval, CI: 0.97-2.09], p = 0.07) between the two groups. The rate of tumor regression was similar for both groups (122/203, 60.1% versus 111/203, 54.7%; RR: 1.11 [95% CI: 0.94-1.29], p = 0.22). CONCLUSIONS: Adjuvant chemotherapy with preoperative chemoradiotherapy did not significantly improve the rate of pCR nor the rate of T and N downstaging. PMID- 28835751 TI - Radiofrequency Ablation for Treatment of Refractory Gastric Antral Vascular Ectasia: A Systematic Review of the Literature. AB - BACKGROUND AND STUDY AIMS: GAVE is an uncommon cause of upper nonvariceal bleeding and often manifests itself as occult bleeding with chronic anemia. To date, the standard of care for GAVE is endoscopic treatment with thermoablative techniques. Despite good technical results, approximately two thirds of patients remain dependent on transfusions after the therapy. One of the emerging and more promising endoscopic treatments for GAVE is radiofrequency ablation (RFA). The aim of this study is to perform a systematic review of literature in order to assess current evidence supporting the effectiveness of this technique for treatment of refractory GAVE. MATERIALS AND METHODS: Through electronic search, we identified 14 records, and after removal of duplicates and irrelevant studies, we selected 10 studies on radiofrequency ablation of GAVE: 4 prospective open label single-center studies, 1 retrospective multicentric study, and 5 case reports. RESULTS: Among all 72 treated patients reported in literature, 74.3% achieved a clinical response, while nonfatal AEs have been reported in 4.2% of cases. CONCLUSIONS: Despite some qualitative limitations, all literature data support effectiveness of RFA for treatment of refractory GAVE. In the future, large prospective controlled trials with adequate follow-up are needed to better assess the effectiveness and safety of this procedure. PMID- 28835752 TI - The Ball Welding Bar: A New Solution for the Immediate Loading of Screw-Retained, Mandibular Fixed Full Arch Prostheses. AB - PURPOSE: To present a new intraoral welding technique, which can be used to manufacture screw-retained, mandibular fixed full-arch prostheses. METHODS: Over a 4-year period, all patients with complete mandibular edentulism or irreparably compromised mandibular dentition, who will restore the masticatory function with a fixed mandibular prosthesis, were considered for inclusion in this study. The "Ball Welding Bar" (BWB) technique is characterised by smooth prosthetic cylinders, interconnected by means of titanium bars which are adjustable in terms of distance from ball terminals and are inserted in the rotating rings of the cylinders. All the components are welded and self-posing. RESULTS: Forty-two patients (18 males; 24 females; mean age 64.2 +/- 6.7 years) were enrolled and 210 fixtures were inserted to support 42 mandibular screw-retained, fixed full arch prostheses. After two years of loading, 2 fixtures were lost, for an implant survival rate of 97.7%. Five implants suffered from peri-implant mucositis and 3 implants for peri-implantitis. Three of the prostheses (3/42) required repair for fracture (7.1%): the prosthetic success was 92.9%. CONCLUSIONS: The BWB technique seems to represent a reliable technique for the fabrication of screw-retained mandibular fixed full-arch prostheses. This study was registered in the ISRCTN register with number ISRCTN71229338. PMID- 28835753 TI - Phenolics in Primula veris L. and P. elatior (L.) Hill Raw Materials. AB - Primula veris L. and Primula elatior (L.) Hill represent medicinal plants used for the production of herbal teas and preparations with antioxidant and expectorant activity. Flowers and roots of both species possess the same biological activity. In the presented study, raw materials of wild growing P. veris and P. elatior were compared in terms of the content and composition of phenolic compounds using a fast and simple HPLC-DAD method. The study showed that flowers of both species were rich in flavonoids. However, P. veris flowers were characterized with a distinctly higher content of isorhamnetin-3-O-glucoside, astragalin, and (+)-catechin, whereas P. elatior occurred to be a richer source of rutoside and isorhamnetin-3-O-rutinoside. Hyperoside was found exclusively in P. elatior flowers. Phenolic glycosides (primverin and primulaverin) were identified only in the roots. Their content was about ten times higher in P. veris in comparison with P. elatior underground organs. The obtained results clearly show that both Primula species differ distinctly in terms of the content and composition of phenolic compounds. The compounds differentiating both species to the highest degree (hyperoside, in flowers, as well as primverin and primulaverin, in the roots) may be useful chemical markers in the identification and evaluation of both species. PMID- 28835754 TI - Transit-Amplifying Cells in the Fast Lane from Stem Cells towards Differentiation. AB - Stem cells have a high potential to impact regenerative medicine. However, stem cells in adult tissues often proliferate at very slow rates. During development, stem cells may change first to a pluripotent and highly proliferative state, known as transit-amplifying cells. Recent advances in the identification and isolation of these undifferentiated and fast-dividing cells could bring new alternatives for cell-based transplants. The skin epidermis has been the target of necessary research about transit-amplifying cells; this work has mainly been performed in mammalian cells, but further work is being pursued in other vertebrate models, such as zebrafish. In this review, we present some insights about the molecular repertoire regulating the transition from stem cells to transit-amplifying cells or playing a role in the transitioning to fully differentiated cells, including gene expression profiles, cell cycle regulation, and cellular asymmetrical events. We also discuss the potential use of this knowledge in effective progenitor cell-based transplants in the treatment of skin injuries and chronic disease. PMID- 28835755 TI - Intestinal Stem Cell Niche: The Extracellular Matrix and Cellular Components. AB - The intestinal epithelium comprises a monolayer of polarised columnar cells organised along the crypt-villus axis. Intestinal stem cells reside at the base of crypts and are constantly nourished by their surrounding niche for maintenance, self-renewal, and differentiation. The cellular microenvironment including the adjacent Paneth cells, stromal cells, smooth muscle cells, and neural cells as well as the extracellular matrix together constitute the intestinal stem cell niche. A dynamic regulatory network exists among the epithelium, stromal cells, and the matrix via complex signal transduction to maintain tissue homeostasis. Dysregulation of these biological or mechanical signals could potentially lead to intestinal injury and disease. In this review, we discuss the role of different intestinal stem cell niche components and dissect the interaction between dynamic matrix factors and regulatory signalling during intestinal stem cell homeostasis. PMID- 28835757 TI - Avoiding Misdiagnosis Due to Antibody Interference with Serum Free Thyroxin. AB - INTRODUCTION: Interfering antibodies are capable of causing potentially misleading results in automated thyroid hormone immunoassays. CASE PRESENTATION: We report the case of a 46- year-old female patient with autoimmune hypothyroidism in chronic replacement treatment with levothyroxine who was presented 8 years after diagnosis with a thyroid function test showing an increased level of TSH and a very high level of FT4. Interference in the laboratory serum free thyroxin (FT4) test was suspected, due to the lack of symptoms of hyperthyroidism and a different immunoassay platform confirmed a low FT4 result. The discrepancy between the two results was explained by the presence of antiT4-autoantibodies. CONCLUSIONS: Antibody interference with serum free thyroxine must be considered when clinical findings and laboratory results show discrepancies. PMID- 28835756 TI - Quality Evaluation of Human Bone Marrow Mesenchymal Stem Cells for Cartilage Repair. AB - Quality evaluation of mesenchymal stem cells (MSCs) based on efficacy would be helpful for their clinical application. In this study, we aimed to find the factors of human bone marrow MSCs relating to cartilage repair. The expression profiles of humoral factors, messenger RNAs (mRNAs), and microRNAs (miRNAs) were analyzed in human bone marrow MSCs from five different donors. We investigated the correlations of these expression profiles with the capacity of the MSCs for proliferation, chondrogenic differentiation, and cartilage repair in vivo. The mRNA expression of MYBL1 was positively correlated with proliferation and cartilage differentiation. By contrast, the mRNA expression of RCAN2 and the protein expression of TIMP-1 and VEGF were negatively correlated with proliferation and cartilage differentiation. However, MSCs from all five donors had the capacity to promote cartilage repair in vivo regardless of their capacity for proliferation and cartilage differentiation. The mRNA expression of HLA-DRB1 was positively correlated with cartilage repair in vivo. Meanwhile, the mRNA expression of TMEM155 and expression of miR-486-3p, miR-148b, miR-93, and miR 320B were negatively correlated with cartilage repair. The expression analysis of these factors might help to predict the ability of bone marrow MSCs to promote cartilage repair. PMID- 28835758 TI - Association of Insulinoma and Type 2 Diabetes Mellitus. AB - The association of diabetes mellitus and insulinoma is unusual. We are reporting the case of a 58 years old patient having diabetes mellitus type 2 for several years. This patient was well balanced with oral anti-diabetic treatment. However, the diagnosis of insulinoma was discussed due to recent episodes of hypoglycemia that persisted even after stopping the treatment. Abdominal CT allowed the topographic diagnosis. The patient underwent a caudal pancreatectomy. Furthermore, the postoperative period shows that the diabetes mellitus requires the oral anti-diabetic treatment and basal insulin have to be stable. Then, the occurrence of hypoglycemia in the diabetic mellitus type 2 and, especially the persistence after discontinuation of therapy, suggest the unusual diagnosis of insulinoma as illustrated in our observation. PMID- 28835759 TI - Associated Factors of Bone Mineral Density and Osteoporosis in Elderly Males. AB - BACKGROUND: Low bone mineral density and osteoporosis is prevalent in elderly subjects. This study aimed to determine the associated factors of bone mineral density and osteoporosis in elderly males. METHODS: All participants of the Amirkola health and ageing project cohort aged 60 years and older entered the study. Bone mineral density at femoral neck and lumbar spine was assessed by the dual energy X-ray absorptiometry (DXA) method. Osteoporosis was diagnosed by the international society for clinical densitometry criteria and the association of bone mineral density and osteoporosis with several clinical, demographic and biochemical parameters. Multiple logistic regression analysis was used to determine independent associations. RESULTS: A total of 553 patients were studied and 90 patients (16.2%) had osteoporosis at either femoral neck or lumbar spine. Diabetes, obesity, metabolic syndrome, overweight, and quadriceps muscle strength > 30 kg, metabolic syndrome, abdominal obesity and education level were associated with higher bone mineral density and lower prevalence of osteoporosis, whereas age, anemia, inhaled corticosteroids and fracture history were associated with lower bone mineral density and higher prevalence of osteoporosis (P = 0.001). After adjustment for all covariates, osteoporosis was negatively associated only with diabetes, obesity, overweight, and QMS > 30 kg and positively associated with anemia and fracture history. The association of osteoporosis with other parameters did not reach a statistical level. CONCLUSIONS: The findings of the study indicate that in elderly males, diabetes, obesity and higher muscle strength was associated with lower prevalence of osteoporosis and anemia, and prior fracture with higher risk of osteoporosis. This issue needs further longitudinal studies. PMID- 28835760 TI - Testicular Adrenal Rests Tumors and Testicular Microlithiasis in a Brazilian Case Series with Classic Congenital Adrenal Hyperplasia. AB - BACKGROUND: Testicular adrenal rest tumors are a benign condition characterized by the presence of remnants of adrenal tissue within the testes that can lead to infertility. Testicular microlithiasis are calculus deposits within the seminiferous tubules. Both are described in congenital adrenal hyperplasia. OBJECTIVES: Describe the frequency of testicular adrenal rest tumors and testicular microlithiasis in a Brazilian case series of patients with classic congenital adrenal hyperplasia and to also relate these changes to disease control and hypothalamic-pituitary-gonadal axis disorders. METHODS: Case series study. An ultrasound examination of the scrotum was performed on 12 patients between the ages of 5.33 to 22 (14.72 +/- 5.26) years. Testicular adrenal rest tumors were classified according to the degree of testicular infiltration in stages by adapting the Grinten's classification, ranging from the absence of testicular adrenal rests visible by ultrasound (stage <= 1) to chronic obstruction of the testicular parenchyma with irreversible damage of the testicle (stage 5). RESULTS: Six patients (5 salt wasting and 1 simple virilizing) with an average age of 17.27 +/- 3.09 years and have gone through puberty showed testicular adrenal rest tumors (Grinten stage >= 3). In 2 of the patients there was a coincidence with testicular microlithiasis. The frequency of testicular adrenal rest tumors did not relate with the levels of serum 17 hydroxyprogesterone and androstenedione. In 3 patients with testicular adrenal rest tumors, gonadotropin levels were suggestive of hypergonadotropic hypogonadism and one of hypogonadotropic hypogonadism. CONCLUSIONS: Testicular adrenal rest tumors were found in greater frequency during puberty and was not related to hormonal control in this group. Some of them happened with testicular microlithiasis. PMID- 28835761 TI - The Effect of n-3 Polyunsaturated Fatty Acids Supplementation on Serum Irisin in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Diabetes refers to a group of metabolic diseases with blood glucose of higher than normal ranges. Furthermore, n-3 polyunsaturated fatty acids are necessary for the regulation of the activity of human function. The effect of n-3 PUFA on diabetes has been investigated in animal studies, yet, the exact amount has not been set, to date. Irisin, as a new myokine, is released from skeletal muscle and Irisin levels decrease as a result of physical inactivity, overweightness, and obesity. Also, the reduction of serum irisin level is associated with development of insulin resistance and type 2 diabetes. This study was performed to assess the effects of n-3 PUFA supplementation on serum irisin level in patients with diabetes. METHODS: This randomized clinical trial included 43 patients with type 2 diabetes (21 patients in the placebo group and 22 patients in the n-3 PUFA supplement group). They were randomized to groups, one receiving 10 weeks of either n-3 PUFA supplement and the other the placebo (1250 mg capsule, three times per day). Samples were also matched by age, gender, and body mass index (BMI) in the 2 groups. Anthropometric measurements, demographic information and dietary intakes were obtained both before and after the intervention. Serum irisin levels were measured before and after the intervention using human irisin enzyme linked immunosorbent assay (ELISA) kit. Independent t test was used to compare the mean outcomes between groups. RESULTS: At baseline, irisin serum levels were not significantly different between the placebo and n-3 PUFA supplementation groups (P > 0.05). However, a significant change was observed between the groups after intervention (P = 0.04). Also there was a significant difference in mean change (after versus before the intervention) (P = 0.05). Compared to the placebo, n-3 PUFA supplementation decreased serum FBS and HbA1C (P = 0.036 and 0.001; respectively). Also, there were significant differences between changes of diastolic blood pressure and HOMA-IR after the intervention between the groups. The duration of illness was not considered as a confounding factor because there was no significant association between irisin level (after versus before the intervention) and the illness duration. CONCLUSIONS: The current study indicated that n-3 PUFA supplementation with a dosage of 1250 mg three times per day, resulted in increased serum irisin level of diabetic patients. PMID- 28835762 TI - Graves' Thyrotoxicosis Presenting as Schizophreniform Psychosis: A Case Report and Literature Review. AB - Psychosis, as the first presentation of thyrotoxicosis, is extremely rare. Consequently, it is often misdiagnosed as a primary psychiatric disorder, especially in developing countries with poor healthcare facilities. Owing to the high level of illiteracy and lack of knowledge, it is fairly common to ascribe many illnesses to spiritual attacks in Nigeria and other African countries, especially when the disease is rarely seen or is associated with psychiatric manifestations. Herein, we present the case of a teenage female Nigerian and review the literature on this subject. PMID- 28835763 TI - The Effects of Testosterone Deficiency and Its Replacement on Inflammatory Markers in Rats: A Pilot Study. AB - BACKGROUND: Testosterone deficiency is linked to low-grade inflammation in humans, but this condition is not replicated in an animal study. The current study aims at determining the effects of testosterone deficiency and its replacement on the circulating inflammatory cytokine level in orchidectomized male rats. METHODS: Three-month-old Sprague-Dawley male rats (n = 18) were randomized equally into 3 groups. Bilateral orchidectomy was performed on 2 groups. The sham group was subjected to similar surgical stress, but their testes were retained. One of the orchidectomized groups received intramuscular injection of 7 mg/kg testosterone enanthate suspended in peanut oil weekly and the other 2 groups received equivolume of peanut oil injection. After 8 weeks, the rats were sacrificed and their blood was collected for the analysis of the levels of inflammatory cytokines and testosterone. RESULTS: Testosterone level was significantly lower in the untreated orchidectomized group compared to the sham group. Testosterone replacement significantly increased the level of testosterone in the orchidectomized rats compared to the sham and untreated orchidectomized rats. Interleukin-1 alpha (IL-1alpha), interleukin-1 beta (IL-1beta), and tumor necrosis factor alpha (TNFalpha) showed an increasing trend in orchidectomized rats, albeit not statistically significant. Interleukin-6 (IL-6) level increased significantly in the orchidectomized group compared to the sham group. Testosterone replacement at the supraphysiological dose did not alter the level of inflammatory cytokines significantly in orchidectomized rats. CONCLUSIONS: Testosterone deficiency can elicit a state of low-grade inflammation, shown by an increase in interleukin-6 level, but exogenous supraphysiological testosterone replacement does not suppress the inflammation. PMID- 28835764 TI - Evidence-Based and Patient-Oriented Inositol Treatment in Polycystic Ovary Syndrome: Changing the Perspective of the Disease. PMID- 28835765 TI - Chylothorax Associated with Substernal Goiter in Graves' Disease Treated with Radioactive Iodine. AB - INTRODUCTION: We present a rare case of chylothorax associated with an intrathoracic goiter in Graves' disease that was treated with radioactive iodine. CASE REPORT: A 23-year-old woman with Graves' disease was referred to our clinic with a pleural effusion, dyspnea, characteristic bilateral proptosis, and a diffuse goiter. The pleural fluid biochemistry was consistent with chylothorax. However, the chylothorax did not decrease with conservative therapy. Therefore, RAI was administered. Subsequently, the chylothorax and goiter improved more quickly than expected. CONCLUSIONS: This case illustrates that chylothorax associated with a substernal goiter in Graves' disease can be treated successfully with radioactive iodine instead of surgery. PMID- 28835766 TI - Effects of the Hydroalcoholic Extract of Zingiber officinale on Arginase I Activity and Expression in the Retina of Streptozotocin-Induced Diabetic Rats. AB - BACKGROUND: Emerging evidence suggests that an increased arginase activity is involved in vascular dysfunction in experimental animals. Zingiber officinale Roscoe, commonly known as ginger, has been widely used in the traditional medicine for treatment of diabetes. OBJECTIVES: This study aimed at investigating the effects of the hydroalcoholic extract of Z. officinale on arginase I activity and expression in the retina of streptozotocin (STZ)-induced diabetic rats. METHODS: In this experimental study, 16 male Wistar rats weighing 200 - 250 g were assessed. Diabetes was induced via a single intraperitoneal injection of STZ (60 mg/kg body weight). The rats were randomly allocated into four experimental groups. Untreated healthy and diabetic controls received 1.5 mL/kg distilled water. Treated diabetic rats received 200, and 400 mg/kg of the Z. officinale extract dissolved in distilled water (1.5 mL/kg). Body weight, blood glucose and insulin concentration were measured by standard methods. The arginase I activity and expression were determined by spectrophotometric and western blot analysis, respectively. RESULTS: Our results showed that blood glucose concentration was significantly decreased in diabetic rats treated with the extract compared to untreated diabetic controls (P < 0.01). Treatment with 400 mg/kg of the extract reduced arginase I activity and expression (P < 0.05). A significant elevation in body weight was observed in diabetic rats treated with the extract. Serum insulin was significantly increased in diabetic rats treated with 400 mg/kg of the extract compared to diabetic controls (P < 0.05). CONCLUSIONS: Our results suggest that the Z. officinale hydroalcoholic extract may potentially be a promising therapeutic option for treating diabetes-induced vascular disorders, possibly through reducing arginase I activity and expression in the retina. PMID- 28835767 TI - Passiflora cincinnata Extract Delays the Development of Motor Signs and Prevents Dopaminergic Loss in a Mice Model of Parkinson's Disease. AB - Passiflora cincinnata Masters is a Brazilian native species of passionflower. This genus is known in the American continent folk medicine for its diuretic and analgesic properties. Nevertheless, few studies investigated possible biological effects of P. cincinnata extracts. Further, evidence of antioxidant actions encourages the investigation of possible neuroprotective effects in animal models of neurodegenerative diseases. This study investigates the effect of the P. cincinnata ethanolic extract (PAS) on mice submitted to a progressive model of Parkinson's disease (PD) induced by reserpine. Male (6-month-old) mice received reserpine (0.1 mg/kg, s.c.), every other day, for 40 days, with or without a concomitant treatment with daily injections of PAS (25 mg/kg, i.p.). Catalepsy, open field, oral movements, and plus-maze discriminative avoidance evaluations were performed across treatment, and immunohistochemistry for tyrosine hydroxylase was conducted at the end. The results showed that PAS treatment delayed the onset of motor impairments and prevented the occurrence of increased catalepsy behavior in the premotor phase. However, PAS administration did not modify reserpine-induced cognitive impairments. Moreover, PAS prevented the decrease in tyrosine hydroxylase immunostaining in the substantia nigra pars compacta (SNpc) induced by reserpine. Taken together, our results suggested that PAS exerted a neuroprotective effect in a progressive model of PD. PMID- 28835768 TI - Several Indicators of Critical Transitions for Complex Diseases Based on Stochastic Analysis. AB - Many complex diseases (chronic disease onset, development and differentiation, self-assembly, etc.) are reminiscent of phase transitions in a dynamical system: quantitative changes accumulate largely unnoticed until a critical threshold is reached, which causes abrupt qualitative changes of the system. Understanding such nonlinear behaviors is critical to dissect the multiple genetic/environmental factors that together shape the genetic and physiological landscape underlying basic biological functions and to identify the key driving molecules. Based on stochastic differential equation (SDE) model, we theoretically derive three statistical indicators, that is, coefficient of variation (CV), transformed Pearson's correlation coefficient (TPC), and transformed probability distribution (TPD), to identify critical transitions and detect the early-warning signals of the phase transition in complex diseases. To verify the effectiveness of these early-warning indexes, we use high-throughput data for three complex diseases, including influenza caused by either H3N2 or H1N1 and acute lung injury, to extract the dynamical network biomarkers (DNBs) responsible for catastrophic transition into the disease state from predisease state. The numerical results indicate that the derived indicators provide a data based quantitative analysis for early-warning signals for critical transitions in complex diseases or other dynamical systems. PMID- 28835769 TI - A Multicriteria Approach to Find Predictive and Sparse Models with Stable Feature Selection for High-Dimensional Data. AB - Finding a good predictive model for a high-dimensional data set can be challenging. For genetic data, it is not only important to find a model with high predictive accuracy, but it is also important that this model uses only few features and that the selection of these features is stable. This is because, in bioinformatics, the models are used not only for prediction but also for drawing biological conclusions which makes the interpretability and reliability of the model crucial. We suggest using three target criteria when fitting a predictive model to a high-dimensional data set: the classification accuracy, the stability of the feature selection, and the number of chosen features. As it is unclear which measure is best for evaluating the stability, we first compare a variety of stability measures. We conclude that the Pearson correlation has the best theoretical and empirical properties. Also, we find that for the stability assessment behaviour it is most important that a measure contains a correction for chance or large numbers of chosen features. Then, we analyse Pareto fronts and conclude that it is possible to find models with a stable selection of few features without losing much predictive accuracy. PMID- 28835770 TI - A network pharmacology-based strategy deciphers the underlying molecular mechanisms of Qixuehe Capsule in the treatment of menstrual disorders. AB - BACKGROUND: QiXueHe Capsule (QXHC) is a Chinese patent drug that is extensively used for the treatment of menstrual disorders. However, its underlying pharmacological mechanisms have not been fully elucidated. METHODS: A list of QXHC putative targets were predicted using MetaDrug. An interaction network using links between QXHC putative targets and the known therapeutic targets of menstrual disorders was constructed. QXHC candidate targets were also identified via calculating the topological feature values of nodes in the network. Additionally, molecular docking simulation was performed to determine the binding efficiency of QXHC compound-putative target pairs. RESULTS: A total of 1022 putative targets were predicted for 311 chemical components containing in QXHC. Following the calculation of topological features of QXHC putative target-known therapeutic target of menstrual disorder network, 66 QXHC candidate targets for the treatment of menstrual disorders were identified. Functionally, QXHC candidate targets were significantly associated with several biological pathways, such as VEGF and Chemokine signaling pathways, Alanine/aspartate/glutamate metabolism, Long-term depression and T/B cell receptor signaling pathway. Moreover, molecular docking simulation demonstrated that there were 20 pairs of QXHC chemical component-candidate target had the strong binding free energy. CONCLUSIONS: This novel and scientific network pharmacology-based study holistically deciphers that the pharmacological mechanisms of QXHC in the treatment of menstrual disorders may be associated with its involvement into hemopoiesis, analgesia, nutrients absorption and metabolism, mood regulation, as well as immune modulation. PMID- 28835771 TI - Nucleotides upstream of the Kozak sequence strongly influence gene expression in the yeast S. cerevisiae. AB - BACKGROUND: In the yeast Saccharomyces cerevisiae, as in every eukaryotic organism, the mRNA 5'-untranslated region (UTR) is important for translation initiation. However, the patterns and mechanisms that determine the efficiency with which ribozomes bind mRNA, the elongation of ribosomes through the 5'-UTR, and the formation of a stable translation initiation complex are not clear. Genes that are highly expressed in S. cerevisiae seem to prefer a 5'-UTR rich in adenine and poor in guanine, particularly in the Kozak sequence, which occupies roughly the first six nucleotides upstream of the START codon. RESULTS: We measured the fluorescence produced by 58 synthetic versions of the S. cerevisiae minimal CYC1 promoter (pCYC1min), each containing a different 5'-UTR. First, we replaced with adenine the last 15 nucleotides of the original pCYC1min 5'-UTR-a theoretically optimal configuration for high gene expression. Next, we carried out single and multiple point mutations on it. Protein synthesis was highly affected by both single and multiple point mutations upstream of the Kozak sequence. RNAfold simulations revealed that significant changes in the mRNA secondary structures occur by mutating more than three adenines into guanines between positions -15 and -9. Furthermore, the effect of point mutations turned out to be strongly context-dependent, indicating that adenines placed just upstream of the START codon do not per se guarantee an increase in gene expression, as previously suggested. CONCLUSIONS: New synthetic eukaryotic promoters, which differ for their translation initiation rate, can be built by acting on the nucleotides upstream of the Kozak sequence. Translation efficiency could, potentially, be influenced by another portion of the 5'-UTR further upstream of the START codon. A deeper understanding of the role of the 5'-UTR in gene expression would improve criteria for choosing and using promoters inside yeast synthetic gene circuits. PMID- 28835772 TI - Faecal biomarkers for screening small bowel inflammation in patients with Crohn's disease: a prospective study. AB - BACKGROUND: The value of faecal biomarkers for screening small bowel inflammation in patients with Crohn's disease (CD) remains to be elucidated. This prospective study was to evaluate the utility of faecal biomarkers for detecting small intestinal inflammation. METHODS: A total of 122 consecutive patients with a diagnosis of CD in the small intestine were screened for eligibility. Computed tomography enterography (CTE) was undertaken to evaluate small bowel inflammation followed by colonoscopy to confirm no large bowel involvement. Seventy eligible patients with inflammation confined to the small intestine were included. Faecal samples were collected for assaying calprotectin, lactoferrin and haemoglobin. For assessing the degree of small bowel inflammation, a semi-quantitative scoring system (CTE0, normal; CTE1, mild; CTE2, moderate; CTE3, severe) was applied. RESULTS: The median calprotectin, lactoferrin and haemoglobin levels were significantly higher in patients with small bowel inflammation, CTE scores 1-3 (n = 42) versus 0 (n = 28): calprotectin, 330 versus 40 ng/ml, p < 0.0001; lactoferrin, 14 versus 3 ng/ml, p < 0.0001; haemoglobin, 29.5 versus 6.5 ng/ml, p = 0.005. There was a strong positive relationship between the faecal biomarkers and CTE score: calprotectin, p < 0.0001; lactoferrin, p < 0.0001; haemoglobin, p = 0.0004. A cutoff value of 140 ng/ml for calprotectin had a sensitivity of 69% and a specificity of 82% with an area under the receiver operating characteristic curve (AUC) of 0.82 to detect small bowel inflammation (CTE scores 1-3), while lactoferrin 6 ng/ml had a sensitivity of 69% and a specificity of 79% with an AUC of 0.83, and haemoglobin 9 ng/ml showed a sensitivity of 71% and a specificity of 39% with an AUC of 0.70. CONCLUSIONS: Faecal calprotectin, lactoferrin, and to a lesser degree haemoglobin are relevant biomarkers for screening small bowel inflammation in CD patients without large bowel involvement. Further well designed large-scale studies in this clinical setting should strengthen our findings. PMID- 28835773 TI - Clinical factors related to false-positive rates of patency capsule examination. AB - BACKGROUND: Retention is the most common complication of capsule endoscopy (CE), and is reported to occur in 0-13% of cases. To avoid retention, a PillCam patency capsule (PC) is used in patients with suspected intestinal stenosis. However, a relatively low positive predictive value of the PC examination has been reported previously. The aims of this study were to clarify the accuracy of PC examination and to evaluate clinical factors related to cases of false-positive detection. METHODS: We performed a retrospective single-center study of 282 consecutive patients referred for PC examination. Patients in which the PC could not pass through the small bowel within 33 h were classified into the 'no patency' group. The 'no patency' group was investigated for evidence of significant stenosis upon further examinations, including CE, double-balloon endoscopy, and small bowel follow-through after PC examination. Clinical factors related to small bowel patency and false-positive cases were evaluated. RESULTS: We included 161 male (57.1%) and 121 female (42.9%) patients with a mean age of 47.5 +/- 17.7 years. Of the 282 patients enrolled, 27 patients exhibited 'no patency' upon PC examination. Multivariate analysis showed that clinical factors related to 'no patency' included Crohn's disease, abdominal symptoms, stenosis upon imaging, and previous abdominal surgery. Upon further examination, nine cases in the 'no patency' group had significant stenosis. Sensitivity, specificity, and negative and positive predictive values of PC examination for detecting small bowel stenosis were 93.8%, 96.6%, 99.6%, and 62.5%, respectively, and the only clinical factor related to false-positive cases was constipation (p < 0.05). CONCLUSION: We found a relatively low positive predictive value of PC examination and that constipation was related to false-positive results. To extend the implications of CE indications, clinical study focusing on these results is expected. PMID- 28835774 TI - Endoscopic management of complications of self-expandable metal stents for treatment of malignant esophageal stenosis and tracheoesophageal fistulas. AB - BACKGROUND: Self-expandable metal stent (SEMS) implantation may rapidly improve the symptoms of malignant esophageal stenosis and tracheoesophageal fistulas (TEF). However, dysphagia often returns subsequently and repeated endoscopic intervention may be necessary. The aims of the study were to identify the risk factors of complications, and the frequency and efficacy of repeated endoscopic interventions; and to provide technical recommendations on appropriate stent selection. METHODS: We analyzed retrospectively the clinical data of 212 patients with locally advanced esophageal cancer who underwent SEMS implantation. RESULTS: A total of 238 SEMS implantations were performed with 99.06% technical success and 1.26% procedure-related deaths in the enrolled 212 cases. Complications occurred in 84 patients (39.62%) and in 55 cases (25.94%) repeated endoscopic procedures were required. Early reintervention 24-48 h after the stent implantations was necessary due to stent migration (12 cases), arrhythmia (2 cases), intolerable retrosternal pain (1 case) and dyspnea (1 case). An average of 1.98 repeated gastroscopies (range 1-6; median 2), 13.58 weeks (range 1.5-48; median 11) after the stent implantation were performed during the follow-up period: 37 stent repositions, 23 restent implantations, 15 endoscopic esophageal dilations and 7 stent removals. In 48 cases (87.3%) oral feeding of patients was made possible by endoscopic interventions. CONCLUSIONS: In a quarter of SEMS implantations, complications occur that can be successfully managed by endoscopic interventions. Our experiences have shown that individualized stent choice may substantially reduce the complications rate and make repeated endoscopic interventions easier. PMID- 28835775 TI - Commutability and concordance of four hepatitis B virus DNA assays in an international multicenter study. AB - BACKGROUND: HBV DNA is the most important molecular marker in hepatitis B, used to determine treatment indication and monitoring. Most patients require lifelong hepatitis B virus (HBV) management, thus viral load (VL) monitoring may be performed at different laboratories, with different HBV assays, which may result in different VL results. This multicenter study compares the commutability and concordance of results from four different HBV DNA assays: CAP/CTM HBVv2, HPS/CTM HBVv2 and the new cobas 6800/8800 HBV and cobas 4800 HBV assays. METHODS: Across all four assays, HBV limit of detection (LoD) and linearity at lower concentrations were assessed using panels traceable to the World Health Organization international standard, and concordance was investigated at the important medical decision cutoffs 2000 and 20,000 IU/ml, using specimens from HBV-positive patients. RESULTS: The calculated LoD via a probit curve was 2.7 IU/ml for cobas 6800/8800 HBV, 2.8 IU/ml for cobas 4800 HBV, 9.6 IU/ml for CAP/CTM HBVv2, and 6.2 IU/ml for HPS/CTM HBVv2. The average accuracy was comparable between cobas 6800/8800 HBV, cobas 4800 HBV and CAP/CTM HBVv2 (0.04 0.05 log10 IU/ml), while a slightly lower accuracy was documented for HPS/CTM HBVv2 (-0.16 log10 IU/ml). A total of 211-245 clinical samples were used for a pairwise comparison. Mean paired log differences ranged from -0.17 log10 IU/ml to -0.01 log10 IU/ml. Coefficient of determination was over 98% for all pairs with high overall percent agreement at the 2000 and 20,000 IU/ml cutoffs (from 91.7% to 96.3%). In a subset of samples with VL+/-0.5 log10 to the 2000 and 20,000 IU/ml thresholds, concordance was still 72% and 82%, respectively. CONCLUSIONS: The new cobas 6800/8800 HBV and 4800 HBV assays show high accuracy in samples with low-level viremia and a high concordance with the established HBV tests, CAP/CTM HBVv2 and HPS/CTM HBVv2, at 2000 and 20,000 IU/ml. Thus, all four HBV assays have high commutability and may be used interchangeably in routine clinical practice. PMID- 28835776 TI - Rapid liver and spleen stiffness improvement in compensated advanced chronic liver disease patients treated with oral antivirals. AB - BACKGROUND: We aimed to investigate the early changes in liver and spleen stiffness measurement (LSM, SSM) in hepatitis C virus (HCV) patients with compensated advanced chronic liver disease (cACLD) treated with new antivirals (DAA) to elucidate factors determining the initial change in stiffness and its implications for the long-term follow up of HCV-cured patients. METHODS: A total of 41 patients with cACLD who started DAA therapy underwent LSM and SSM at baseline, week 4, end of treatment (EOT), 24 and 48 weeks of follow up using transient elastography. RESULTS: LSM improved rapidly during the first 4 weeks of treatment (baseline: 20.8kPa; week 4: 17.5kPa, p = 0.002), with no significant changes between week 4 and EOT (18.3kPa, p = 0.444) and between EOT and 48-week follow up (14.3kPa, p = 0.148). Likewise, SSM improved rapidly (baseline: 45.7kPa; week 4: 33.8kPa, p = 0.047), with no significant changes between week 4 and EOT (30.8kPa, p = 0.153) and between EOT and 48-week follow up (31.2kPa, p = 0.317). A higher decrease in LSM was observed in patients with baseline ALT ? twofold upper limit normal (2 * ULN) than in those with ALT < 2 * ULN (-5.7kPa versus -1.6kPa). Patients who presented a decrease in LSM ? 10% during treatment compared with those with LSM < 10% decrease, showed lower SSM values, higher platelet counts and lower bilirubin levels at 24-week follow up. Those with decrease in SSM ? 10%, presented a higher increase in platelets than those with SSM < 10% change (p = 0.015). CONCLUSIONS: LSM and SSM decrease very rapidly during DAA treatment in cACLD patients suggesting that it most probably reflects a reduction in inflammation rather than in fibrosis. cACLD patients should be maintained under surveillance independently of stiffness changes, because advanced fibrosis can still be present. PMID- 28835777 TI - Current status on the place of FOLFIRINOX in metastatic pancreatic cancer and future directions. AB - Pancreatic cancer (PC) incidence rates are rapidly increasing in developed countries, with half the patients being metastatic at diagnosis. For decades, fluorouracil, then gemcitabine regimens were the preferred palliative first-line options for fit patients with metastatic PC. FOLFIRINOX (a combination of bolus and infusional fluorouracil, leucovorin, irinotecan and oxaliplatin) was introduced to clinical practice in 2010 due to the results of the phase II/III trial (PRODIGE 4/ACCORD 11) comparing FOLFIRINOX with single-agent gemcitabine as first-line treatment for patients with MPC. Median overall survival, progression free survival, and objective response rate were superior with FOLFIRINOX over gemcitabine and there was prolonged time to definitive deterioration in quality of life. Although FOLFIRINOX was also associated with increased toxicity, mainly febrile neutropenia and diarrhea, there has been rapid uptake of this regimen. This review closely examines optimal management and prevention of toxicities, international recommendations for first-line treatment, and use of modified FOLFIRINOX protocols. In this review, we also look at the potential benefit of FOLFIRINOX in selected groups of patients: second-line therapy, adjuvant chemotherapy, induction therapy in patients with borderline resectable and locally advanced PC. Robust validation of the FOLFIRINOX regimen in these settings requires confirmation in further randomized trials. PMID- 28835778 TI - Effectiveness of intra-articular therapies in osteoarthritis: a literature review. AB - Osteoarthritis is a painful, chronic disease with widespread burden on patients, communities, health and social care systems. Conservative therapies, such as nonpharmacological interventions, systemic drug treatment and intra-articular therapies are used before resorting to surgery; nonetheless, disease control often remains inadequate. Recent advances in osteoarthritis management have aimed to provide greater variety of treatment options. Here, we summarize a targeted literature review evaluating efficacy and safety of intra-articular therapies for osteoarthritis. Injections of intra-articular therapies directly into the joint avoid conventional barriers to joint entry, increase bioavailability and lower systemic toxicity. Intra-articular corticosteroids and hyaluronic acid are established United States Food and Drug Administration (US FDA)/European Medicines Agency (EMA)-approved treatments; however, concerns exist regarding effect duration, safety, effectiveness across populations and heterogeneity. Newer therapies, such as autologous blood products and mesenchymal stem cells, are in development. Benefits of autologous blood products (e.g. platelet-rich plasma, autologous conditioned serum) include an expected improved safety profile and direct targeting of osteoarthritis-related pathophysiology. Autologous conditioned serum is cell-free and manufactured by a standardized process, whereas platelet-rich plasma composition and characteristics can vary. Currently, only limited efficacy comparisons between these biological treatments can be drawn; long-term clinical and safety studies are needed to increase the efficacy evidence base and earn consideration in treatment frameworks. PMID- 28835780 TI - Complementary and Alternative Medicine and Osteoarthritis. AB - Patients with osteoarthritis experience high levels of pain, psychological distress and have limited therapeutic options. Emerging evidence from clinical trials suggests that both acupuncture and Tai Chi mind-body therapies are safe and effective treatments for osteoarthritis. Acupuncture has effects over and above those of 'sham acupuncture' and the most robust evidence to date demonstrates that acupuncture does have short-term benefits and is a reasonable referral option for patients with symptomatic osteoarthritis. Tai Chi is a mind body exercise that enhances cardiovascular fitness, muscular strength, balance, and physical function. It also appears to be associated with reduced stress and anxiety and depression, as well as improved quality of life. Thus, Tai Chi may be safely recommended to patients with osteoarthritis as a complementary and alternative medical approach to affect patient well-being. Integrative approaches combine the best of conventional medicine and complementary and alternative medicine to ultimately improve patient care. These modalities may lead to the development of better disease modifying strategies that could improve symptoms and decrease the progression of osteoarthritis. This overview synthesizes the current body of knowledge about Chinese mind-body medicine to better inform clinical decision-making for our rheumatic patients. PMID- 28835779 TI - Tumor necrosis factor-alpha (TNFalpha) inhibitors in the treatment of nonradiographic axial spondyloarthritis: current evidence and place in therapy. AB - Nonradiographic axial spondyloarthritis (SpA) and radiographic SpA (also known as ankylosing spondylitis) are currently considered as two stages or forms of one disease (axial SpA). The treatment with tumor necrosis factor-alpha (TNFalpha) inhibitors has been authorized for years for ankylosing spondylitis. In recent years, most of the anti-TNFalpha agents have also been approved for the treatment of nonradiographic axial SpA by the European Medicines Agency (EMA) and similar authorities in many countries around the world (but not in the US), increasing the number of possible therapies for this indication. Data from several clinical trials have demonstrated the good efficacy and safety profiles from those anti TNFalpha agents. Presently, a large number of patients achieve a satisfactory clinical control with the current therapies, however, there remains a percentage refractory to nonsteroidal anti-inflammatory drugs (NSAIDs) and TNFalpha inhibitors; therefore, several new drugs are currently under investigation. In 2015, the first representative of a new class of biologics [an interleukin (IL) 17 inhibitor] secukinumab, was approved for the treatment of ankylosing spondylitis; a clinical trial in nonradiographic axial SpA is currently underway. In this review, we discuss the recent data on efficacy and safety of TNFalpha inhibitors focusing on the treatment of nonradiographic axial SpA. PMID- 28835781 TI - IPUMS International: A review and future prospects of a unique global statistical cooperation programme. AB - At the invitation of the University of Minnesota Population Center (MPC) the author carried out an assessment of the IPUMS International integrated census microdata programme during January - March 2016. The terms of reference included the assessment of the measures taken by the MPC to safe guard the security of the microdata, the quality and adequacy of services provided, characteristics of users and satisfaction with IPUMS, use of available microdata, support to participating developing country National Statistical Offices (NSOs) and adequacy of a proposed Remote Data Center (RDC). The conclusions of the review are that IPUMS International is a unique, flexible, successful and secure programme for managing access to anonymized, harmonised and integrated microdata to academic users and policy makers. While currently the user base is predominantly in developed countries, steps are being taken to expand usage by researchers world wide. The physical, methodological and technical arrangements for safeguarding the security and confidentiality of the data files are excellent; the possibilities of breaches are minimal. Data users have very positive opinions of the quality of the data, scope of services and expertise of staff but desire more detailed, up-to-date microdata. NSOs rate IPUMS International and its services positively but request advanced methodological training for staff and regular information on the use of their country's data. IPUMS International planned activities are presented and their contributions to census methodology are highlighted. PMID- 28835783 TI - Plasma Kallikrein Inhibitors for the Treatment of Retinal Vascular Permeability Associated with Diabetic Retinopathy and Diabetic Macular Edema. PMID- 28835782 TI - Genetic Transformation and Hairy Root Induction Enhance the Antioxidant Potential of Lactuca serriola L. AB - Lactuca serriola L. is a herbaceous species, used for human nutrition and medicinal purposes. The high antioxidant capacity of L. serriola indicates the possibility of enhancing its edible and health potential by increasing the flavonoid and phenolic contents. The present study aimed at enhancing the production of phenolics and flavonoids by hairy root cultures in Lactuca serriola transformed with Agrobacterium rhizogenes strain AR15834 harbouring the rolB gene. The genetic transformation of rolB in transformed roots was validated, and rolB expression level was evaluated using real-time qPCR analysis. Expression levels of flavonoid biosynthesis genes (CHI, PAL, FLS, and CHS) were assessed in the hairy and nontransformed roots. Results showed higher expression levels in the transgenic roots than in the nontransformed ones (p < 0.01). Transgenic hairy roots exhibited a 54.8-96.7% increase in the total phenolic content, 38.1-76.2% increase in the total flavonoid content, and 56.7-96.7% increase in the total reducing power when compared with the nontransgenic roots (p < 0.01). DPPH results also revealed that the transgenic hairy roots exhibited a 31.6-50% increase in antioxidant potential, when compared to normal roots. This study addressed the enhancement of secondary metabolite biosynthesis by hairy root induction in L. serriola. PMID- 28835784 TI - Potential of PI3Kbeta Inhibitors in the Treatment of Cancer and Other Diseases. PMID- 28835785 TI - Inhibitors of CD73 May Provide a Treatment for Cancer and Autoimmune Diseases. PMID- 28835786 TI - Homobispiperidinyl Derivatives as Liver X Receptor Beta Agonists, Compositions, and Their Use. PMID- 28835787 TI - C5-C6 Carbocyclic-Fused Iminothiadiazine Dioxides as BACE Inhibitors, Their Compositions, and Their Use. PMID- 28835788 TI - Pyrazine Analogs for the Treatment of Protozoal Infections. PMID- 28835789 TI - Dihydrothieno-pyridin-one and Tetrahydrothieno-azepinone Inhibitors of Enhancer of Zeste Homologue 2. PMID- 28835790 TI - N-Acylbenzenesulfonamide Dihydro-1,3,4-oxadiazole Hybrids: Seeking Selectivity toward Carbonic Anhydrase Isoforms. AB - A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racemic mixture led to the isolation of the levorotatory eutomer exhibiting an increase of hCA XII inhibition potency and selectivity with respect to hCA II. Computational studies corroborated these data. Overall our data indicate that both substitution pattern and stereochemistry of dihydro-1,3,4-oxadiazole could be considered as key factors to determine activity and selectivity toward hCA isozymes. These results can provide further indication for the design and optimization of selective hCA inhibitors. PMID- 28835791 TI - Synthesis and Activity of a New Series of Antileishmanial Agents. AB - We have determined that tetrahydroindazoles such as 1 show potent activity against Leishmania donovani, the causative agent of leishmaniasis. While the Hsp90 activity and anticancer properties of 1 have previously been explored, we present here our efforts to optimize their activity against L. donovani via the synthesis of novel analogues designed to probe the hydrophobic pocket of the protozoan Hsp90 orthologue, specifically through the auspices of functionalization of an amine embedded into the scaffold. PMID- 28835792 TI - Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries. AB - From a screening campaign that included mixture-based libraries containing more than 6 million compounds, a lead series of bis-cyclic guanidines was identified as the most promising. Lead optimization resulted in the identification of potent (IC50 < 500 nM) and selective compounds within this series as well as potent and selective monoguanidines. PMID- 28835793 TI - Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168). AB - The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kalpha, PI3Kbeta, PI3Kdelta, and PI3Kgamma isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition. PMID- 28835794 TI - Conjugation of Paclitaxel to Hybrid Peptide Carrier and Biological Evaluation in Jurkat and A549 Cancer Cell Lines. AB - Paclitaxel (PTX) is one of the most potent cancer drugs; however, its low solubility and strong systemic side effects limit its clinical applications. To overcome these issues, new drug formulations and chemical modifications have been proposed. In this study, we present conjugation of PTX to hybrid collagen-cell penetrating peptide (COL-CPP) carriers. The peptide carrier is highly soluble and utilizes a unique stabilization strategy: folding into a triple helix. Here, we report the formation of PTX-COL-CPP prodrug that has similar drug potency as free PTX when tested in Jurkat (human T lymphocyte of acute T cell leukemia) cells but not in A549 (human epithelial of lung carcinoma) cells. Confocal images and flow cytometry show that this behavior originates from lower cellular uptake of COL CPP and endosomal entrapment of the prodrug in A549, but not in Jurkat cells. PMID- 28835795 TI - Branched Peptides: Acridine and Boronic Acid Derivatives as Antimicrobial Agents. AB - The emergence of microbial resistance presents a challenge in the development of next generation therapeutics. Herein, we report the discovery of branched peptides decorated with acridine and boronic acid moieties with potent antimicrobial activity. The results revealed minimal inhibitory concentrations (MICs) as low as 1 MUg/mL against Staphylococcus aureus, Candida albicans, and Escherichia coli. These peptides were nonhemolytic, and significantly inhibited growth of C. albicans in suspension and biofilm formation. Structure-activity relationship studies suggest the acridine functional group as a driving force for the potent inhibition observed against bacteria. PMID- 28835796 TI - Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors. AB - Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 MUM. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH SY5Y cells as both did not increase the acetylation of histone H3 and alpha tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications. PMID- 28835797 TI - Design, Synthesis, and Biological Evaluation of the First c-Met/HDAC Inhibitors Based on Pyridazinone Derivatives. AB - Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, 2m, inhibited c-Met kinase and HDAC1, with IC50 values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound 2m inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule. PMID- 28835798 TI - Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson's Disease and Depression. AB - Adenosine A2A receptor (A2AAdoR) antagonism is a nondopaminergic approach to Parkinson's disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1 f]purin-2-one derivatives that displays functional antagonism of the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson's disease (haloperidol induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models). PMID- 28835799 TI - Discovery of Potent EV71 Capsid Inhibitors for Treatment of HFMD. AB - Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD), which can spread its infections to the central nervous and other systems with severe consequences. The viral caspid protein VP1 is a well-known target for antiviral efficacy because its occupancy by suitable compounds could stabilize the virus capsid, thus preventing uncoating of virus for RNA release. In this Letter, design, synthesis, and biological evaluation of novel anti-EV71 agents (aminopyridyl 1,2,5-thiadiazolidine 1,1-dioxides) are described. One of the most promising compounds (14) showed excellent antiviral activity against EV71 (EC50 = 4 nM) and exhibited excellent in vivo efficacy in the EV71 infected mouse model. PMID- 28835800 TI - Design and Optimization of Benzopiperazines as Potent Inhibitors of BET Bromodomains. AB - A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound FT001, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11). PMID- 28835801 TI - Synthetic Antibacterial Peptide Exhibits Synergy with Oxacillin against MRSA. AB - One proposed solution to the crisis of antimicrobial resistant (AMR) infections is the development of molecules that potentiate the activity of antibiotics for AMR bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Rather than develop broad spectrum compounds, we developed a peptide that could potentiate the activity of a narrow spectrum antibiotic, oxacillin. In this way, the combination treatment could narrowly target the resistant pathogen and limit impact on host flora. We developed a peptide, ASU014, composed of a S. aureus binding peptide and a S. aureus inhibitory peptide conjugated to a branched peptide scaffold, which has modest activity against S. aureus but exhibits synergy with oxacillin for MRSA both in vitro and in a MRSA skin infection model. The low concentration of ASU014 and sub-MIC concentration of oxacillin necessary for activity suggest that this molecule is a candidate for future medicinal chemistry optimization. PMID- 28835802 TI - Cyclic Biphalin Analogues Incorporating a Xylene Bridge: Synthesis, Characterization, and Biological Profile. AB - In this work we enhanced the ring lipophilicity of biphalin introducing a xylene moiety, thus obtaining three cyclic regioisomers. Novel compounds have similar in vitro activity as the parent compound, but one of these (6a) shows a remarkable increase of in vivo antinociceptive effect. Nociception tests have disclosed its significant high potency and the more prolonged effect in eliciting analgesia, higher than that of biphalin and of the disulfide-bridge-containing analogue (7). PMID- 28835803 TI - Evaluation of Oxetan-3-ol, Thietan-3-ol, and Derivatives Thereof as Bioisosteres of the Carboxylic Acid Functional Group. AB - The oxetane ring serves as an isostere of the carbonyl moiety, suggesting that oxetan-3-ol may be considered as a potential surrogate of the carboxylic acid functional group. To investigate this structural unit, as well as thietan-3-ol and the corresponding sulfoxide and sulfone derivatives, as potential carboxylic acid bioisosteres, a set of model compounds has been designed, synthesized, and evaluated for physicochemical properties. Similar derivatives of the cyclooxygenase inhibitor, ibuprofen, were also synthesized and evaluated for inhibition of eicosanoid biosynthesis in vitro. Collectively, the data suggest that oxetan-3-ol, thietan-3-ol, and related structures hold promise as isosteric replacements of the carboxylic acid moiety. PMID- 28835804 TI - Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models. AB - Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models. PMID- 28835805 TI - Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity. AB - The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells. PMID- 28835806 TI - Design, Synthesis, and Antibacterial Activity of a Multivalent Polycationic Calix[4]arene-NO Photodonor Conjugate. AB - The role of nitric oxide (NO) as an antimicrobial and anticancer agent continues to stimulate the search of compounds generating NO in a controlled fashion. Photochemical generators of NO are particularly appealing due to the accurate spatiotemporal control that light-triggering offers. This contribution reports a novel molecular construct in which multiple units of 3-(trifluoromethyl)-4 nitrobenzenamine NO photodonor are clustered and spatially organized by covalent linkage to a calix[4]arene scaffold bearing two quaternary ammonium groups at the lower rim. This multivalent calix[4]arene-NO donor conjugate is soluble in hydro alcoholic solvent where it forms nanoaggregates able to release NO under the exclusive control of visible light inputs. The light-stimulated antibacterial activity of the nanoconstruct is demonstrated by the effective bacterial load reduction of Gram-positive Staphylococcus aureus ATCC 6538 and Gram-negative Escherichia coli ATCC 10536. PMID- 28835807 TI - 1-Benzyl-3-aryl-2-thiohydantoin Derivatives as New Anti-Trypanosoma brucei Agents: SAR and in Vivo Efficacy. AB - A high throughput screening and subsequent hit validation identified compound 1 as an inhibitor of Trypanosoma brucei parasite growth. Extensive structure activity relationship optimization based on antiparasitic activity led to the highly potent compounds, 1-(4-fluorobenzyl)-3-(4-dimethylamino-3-chlorophenyl)-2 thiohydantoin (68) and 1-(2-chloro-4-fluorobenzyl)-3-(4-dimethylamino-3 methoxyphenyl)-2-thiohydantoin (76), with a T. brucei EC50 of 3 and 2 nM, respectively. This represents >100-fold improvement in potency compared to compound 1. In vivo efficacy experiments of 68 and 76 in an acute mouse model of Human African Trypanosomiasis showed a 100% cure rate after 4 days of oral treatment at 50 mg/kg twice per day. PMID- 28835808 TI - Build Your Own Equiluminance Helmet. AB - A wearable 'helmet' version of the S cone isolating technique was constructed to explore vision at equiluminance. For my high school summer science project, I visited parks and streets while wearing the helmet and report that the helmet appears to have captured the main properties described for the large-scale, more cumbersome stage version. PMID- 28835809 TI - Effects of Lip Color on Perceived Lightness of Human Facial Skin. AB - Whereas geometric illusions in human faces have been reported by several studies, illusions of color or lightness in faces have seldom been explored. Here, we psychophysically investigated whether lip color influences facial skin's perceived lightness. Results of Experiment 1 demonstrated that redder lips lightened and darker lips darkened the perceived complexion. These lightness or darkness inducing effects differ from the classical illusion of lightness contrast in nonface objects for two reasons. First, illusory effects are more assimilative than contrastive. Second, the inducing area (i.e., lips) is much smaller than the influenced area (facial skin). Experiment 2 showed that the assimilative lightness induction was caused by holistic processing of faces. This is the first study to scientifically substantiate the claim of cosmetics manufacturers and makeup artists that lip colors can alter perceived facial skin color. Implications for face perception, lightness illusion, and perceptual effects of cosmetics are discussed. PMID- 28835810 TI - The Eye Pupil's Response to Static and Dynamic Illusions of Luminosity and Darkness. AB - Pupil diameters were recorded with an eye-tracker while participants observed cruciform patterns of gray-scale gradients that evoked illusions of enhanced brightness (glare) or of enhanced darkness. The illusions were either presented as static images or as dynamic animations which initially appeared as a pattern of filled squares that-in a few seconds-gradually changed into gradients until the patterns were identical to the static ones. Gradients could either converge toward the center, resulting in a central region of enhanced, illusory, brightness or darkness, or oriented toward each side of the screen, resulting in the perception of a peripheral ring of illusory brightness or darkness. It was found that pupil responses to these illusions matched both the direction and intensity of perceived changes in light: Glare stimuli resulted in pupil constrictions, and darkness stimuli evoked dilations of the pupils. A second experiment found that gradients of brightness were most effective in constricting the pupils than isoluminant step-luminance, local, variations in luminance. This set of findings suggest that the eye strategically adjusts to reflect in a predictive manner, given that these brightness illusions only suggest a change in luminance when none has occurred, the content within brightness maps of the visual scene. PMID- 28835811 TI - Novice Readers: The Role of Focused, Selective, Distributed and Alternating Attention at the First Year of the Academic Curriculum. AB - The ability to read depends on different cognitive skills. This study investigated the role of the main components of attention (selective attention, focused attention, distributed attention, and alternating attention) on the different dimensions of reading skills in novice readers. Participants were 288 Italian children, who attended the first year of primary school. Attention and reading skills (reading "comprehension," "accuracy," and "speed") were measured. Different components of attention influence each dimension of reading. Moreover, both the correctness and rapidity at which attention operates play a pivotal role in learning to read. Interestingly, selective attention is involved in all dimensions of reading. These findings may have educational and practical relevance. The early assessment of attention might favor the development of new strategies of intervention in dyslexic children and in children at risk of developing learning difficulties. PMID- 28835812 TI - Effect of Viewing Angle on Volume Perceptions for Paired Tumblers. AB - This study examined how tumbler characteristics influenced the perception of volume at different viewing angles. Three tumbler characteristics were individually examined, namely, shape, size, and elongation. At four viewing angles (0 degrees , 30 degrees , 60 degrees , and 90 degrees ), 50 participants poured a certain amount of liquid (150 or 200 mL) into a designated tumbler according to their perception. Results showed that tumbler size and elongation influenced volume perception. At viewing angles of 0 degrees and 30 degrees , the participants poured more liquid into short-wide tumblers than into tall slender tumblers. At viewing angles of 60 degrees and 90 degrees , the results were opposite. The reason may be that the change of viewing angle made the participant's sight cues from the container diameter more visible than those from the container height. Similar results were obtained for the pair of small and large tumblers. However, no effect of viewing angle on tumblers with different geometric shapes was observed. The contradictory results in comparison with those of previous studies may be related to viewing angle; in addition, the effect of viewing angle was also influenced by the characteristics of tumblers. PMID- 28835813 TI - Voluntary and Involuntary Movements Widen the Window of Subjective Simultaneity. AB - Forming a coherent percept of an event requires different sensory inputs originating from the event to be bound. Perceiving synchrony aids in binding of these inputs. In two experiments, we investigated how voluntary movements influence the perception of simultaneity, by measuring simultaneity judgments (SJs) for an audiovisual (AV) stimulus pair triggered by a voluntary button press. In Experiment 1, we manipulated contiguity between the action and its consequences by introducing delays between the button press and the AV stimulus pair. We found a widened window of subjective simultaneity (WSS) when the action feedback relationship was time contiguous. Introducing a delay narrowed the WSS, suggesting that the wider WSS around the time of an action might facilitate perception of simultaneity. In Experiment 2, we introduced an involuntary condition using an externally controlled button to assess the influence of action related predictive processes on SJs. We found a widened WSS around the action time, regardless of movement type, supporting the influence of causal relations in the perception of synchrony. Interestingly, the slopes of the psychometric functions in the voluntary condition were significantly steeper than the slopes in the involuntary condition, suggesting a role of action-related predictive mechanisms in making SJs more precise. PMID- 28835814 TI - The Impact of Face Inversion on Animacy Categorization. AB - Face animacy perception is categorical: Gradual changes in the real/artificial appearance of a face lead to nonlinear behavioral responses. Neural markers of face processing are also sensitive to face animacy, further suggesting that these are meaningful perceptual categories. Artificial faces also appear to be an "out group" relative to real faces such that behavioral markers of expert-level processing are less evident with artificial faces than real ones. In the current study, we examined how categorical processing of real versus doll faces was impacted by the face inversion effect, which is one of the most robust markers of expert face processing. We examined how explicit categorization of faces drawn from a real/doll morph continuum was affected by face inversion (Experiment 1) and also how the response properties of the N170 were impacted by face animacy and inversion. We found that inversion does not change the position or steepness of the category boundary measured behaviorally. Further, neural markers of face processing are equally impacted by inversion regardless of whether they are elicited by real faces or doll faces. On balance, our results indicate that inversion has a limited impact on the categorical perception of face animacy. PMID- 28835815 TI - Correction to Figures: A Reply to Hwang and Peli (2014). AB - In Hwang and Peli (2014), few errors occurred in computing the angular disparities. The direction of peripheral depth distortion (the angular disparity differences between what it is in real-world 3D viewing and S3D viewing) is reversed when the computational errors were corrected, making the perception of the peripheral depth to be expanded, not compressed. This reply points to the error and provides the corrected figures. Correcting these errors does not affect the general conclusion that S3D viewed on single screen display induces peripheral depth distortion which may be a cause of visually induced motion sickness. PMID- 28835816 TI - A quantitative, multi-national and multi-stakeholder assessment of barriers to the adoption of cell therapies. AB - Cellular therapies, such as stem cell-based treatments, have been widely researched and numerous products and treatments have been developed. Despite this, there has been relatively limited use of these technologies in the healthcare sector. This study sought to investigate the perceived barriers to this more widespread adoption. An anonymous online questionnaire was developed, based on the findings of a pilot study. This was distributed to an audience of clinicians, researchers and commercial experts in 13 countries. The results were analysed for all respondents, and also sub-grouped by geographical region, and by profession of respondents. The results of the study showed that the most significant barrier was manufacturing, with other factors such as efficacy, regulation and cost-effectiveness being identified by the different groups. This study further demonstrates the need for these important issues to be addressed during the development of cellular therapies to enable more widespread adoption of these treatments. PMID- 28835817 TI - Do we really need more evidence to use hepatitis C positive donor kidney more liberally? AB - The number of patients listed active for kidney transplantation has continued to rise over the last 10 years, leading to significantly increased wait-list time for patients awaiting kidney transplantation in the USA. This increased demand has led to a supply-demand mismatch and should prompt clinicians to seek timely solutions to improve access to available organs. Hepatitis C virus positive [HCV(+)] kidneys continue to be discarded without clear evidence that they lead to poor outcomes in the current era of highly efficacious HCV treatment with direct-acting antiviral agents (DAAs). Increased utilization of HCV(+) donor kidneys will decrease wait-list time and improve availability of donor organs. Emerging data suggests that HCV can be successfully treated with DAAs after kidney transplantation with 100% sustained virologic response rates and no significant changes from baseline kidney function. Utilization of HCV(+) donor kidneys should be considered more liberally in the era of highly effective HCV treatment. Further studies are warranted to assess the long-term effect of HCV(+) donor kidneys in transplant recipients in the new era of DAAs. PMID- 28835818 TI - The prevalence of tuberculosis among prisoners in Ethiopia: a systematic review and meta-analysis of published studies. AB - BACKGROUND: Except individual studies with varying prevalence rates, there are no national prevalence studies conducted in prison settings in Ethiopia. Appropriate estimates of the disease is essential to formulate health service plans most fitted for prisoners. Therefore, this systematic review and meta-analysis was designed to pool the results of individual studies and estimate the prevalence of tuberculosis among prisoners in Ethiopia. METHODS: MEDLINE/PubMed, Cochran library, and Google scholar databases were searched for potential studies on the prevalence of tuberculosis among prisoners in Ethiopia. A total of 177 titles were identified and 10 studies met the inclusion criteria. Descriptive and quantitative data of the included studies were presented in tables and forest plots. Potential sources of heterogeneity across studies were assessed using the Cochrane's Q and I2 tests. The MetaXL (version 5.3) was employed to compute the pooled prevalence of TB using the random effect model and 95% confidence interval. RESULT: Based on the ten studies included in the meta-analysis, about 4086 prisoners were infected with tuberculosis (TB). The pooled prevalence of TB among prisoners was therefore 8.33% (95% CI; 6.28%-10.63%) and the pooled point prevalence was estimated at 888 per 100,000 prison population (95% CI; 531-1333). The prevalence of TB using microscopy alone was 6.59% (95% CI: 3.96-9.50%) whereas the prevalence of TB when microscopy is combined with either culture or molecular tests was 8.57% (95% CI: 4.94-12.6%). CONCLUSION: The pooled prevalence of tuberculosis among prisoners in Ethiopia is expectedly high. This high prevalence could explain the spread of TB within prisons and between prisoners and varies communities. Thus; attention should be given to prison settings to prevent the transmission and emergence of drug resistance TB both in inmates and general population. Further studies covering large scale prison population are needed to design effective diagnostic, treatment and preventive methods. PMID- 28835819 TI - Could Eosinophilia predict clinical severity in nasal polyps? AB - BACKGROUND: Although nasal polyps are one of the most frequent diseases, their etiopathogenesis remains unclear.Since eosinophils are the main inflammatory cells in the substantial proportion of nasal polyp tissues, they are considered potentially responsible for the etiopathogenesis and prognosis of the disease. Aim of this study was to investigate the relation between mucosal and peripheral eosinophilia and their relation with disease severity in nasal polyps. METHODS: The study included 53 patients with nasal polyps who underwent endoscopic sinus surgery. Preoperative Lund-MacKay computed tomography (CT) scores and the Lund Kennedy endoscopic scores of the patients were recorded. Nasal polyp tissues were stained with hematoxylin and eosin, eosinophil counts were performed using high power field (HPF, 400*) under the light microscope, and the patients were grouped as those with high mucosal eosinophil count and those with low mucosal eosinophil count. RESULTS: The mean Lund-MacKay CT score and the mean Lund-Kennedy endoscopic score were higher in the patients with high mucosal eosinophil count than in those with low mucosal eosinophil count. Likewise, the mean Lund-MacKay CT score and the mean Lund-Kennedy endoscopic scores were significantly higher in the patients with high peripheral eosinophil count than in those with low peripheral eosinophil count (p < 0.05 for both). Moreover, the mean peripheral eosinophil count was significantly higher in the patients with high mucosal eosinophil count than in those with low mucosal eosinophil count (p < 0.05). CONCLUSION: Mucosal and peripheral eosinophilia can be used as a marker to predict disease severity in nasal polyps. PMID- 28835821 TI - Slow ventricular tachycardia presenting with acute liver failure. AB - OBJECTIVES: Cardiac hepatopathy is an important differential diagnosis of acute liver failure. Slow ventricular tachycardia (slow VT) is a ventricular tachycardia (VT), in which heart rate is below the typical frequency of VT. We here report a case of acute liver failure in a patient with slow VT. METHODS: The 64-year old male patient with history of cardiac pacemaker implantation for complete atrioventricular block was referred to our intensive care unit because of acute liver failure. RESULTS: Workup identified cardiac failure as cause of hepatopathy; however, reason for cardiac failure remained unknown even after left heart catheterization with coronary angiography. Finally, the analysis of cardiac pacemaker recordings led to the diagnosis of slow VT. This could not be terminated with either electric cardioversion or pharmacological treatment, and the patient died of cardiac failure. CONCLUSION: Diagnosis of VT can be challenging if occurring at unexpected slow heart rates. Analysis of pacemaker recordings could help to make the diagnosis of slow VT. PMID- 28835820 TI - The coexistence of psychiatric and gastrointestinal problems in children with restrictive eating in a nationwide Swedish twin study. AB - BACKGROUND: Restrictive eating problems are rare in children but overrepresented in those with neurodevelopmental problems. Comorbidities decrease wellbeing in affected individuals but research in the area is relatively scarce. This study describes phenotypes, regarding psychiatric and gastrointestinal comorbidities, in children with restrictive eating problems. METHODS: A parental telephone interview was conducted in 9- or 12-year old twins (n = 19,130) in the Child and Adolescent Twin Study in Sweden. Cases of restrictive eating problems and comorbid problems were established using the Autism, Tics-AD/HD and other Comorbidities inventory, parental reports of comorbidity as well as data from a national patient register. In restrictive eating problem cases, presence of psychiatric and gastrointestinal comorbidity was mapped individually in probands and their co-twin. Two-tailed Mann-Whitney U tests were used to test differences in the mean number of coexisting disorders between boys and girls. Odds ratios were used to compare prevalence figures between individuals with or without restrictive eating problems, and Fisher exact test was used to establish significance. RESULTS: Prevalence of restrictive eating problems was 0.6% (concordant in 15% monozygotic and 3% of dizygotic twins). The presence of restrictive eating problems drastically increased odds of all psychiatric problems, especially autism spectrum disorder in both sexes (odds ratio = 11.9 in boys, odds ratio = 10.1 in girls), obsessive-compulsive disorder in boys (odds ratio = 11.6) and oppositional defiant disorder in girls (odds ratio = 9.22). Comorbid gastrointestinal problems, such as lactose intolerance (odds ratio = 4.43) and constipation (odds ratio = 2.91), were the most frequent in girls. Boy co-twins to a proband with restrictive eating problems generally had more psychiatric problems than girl co-twins and more girl co-twins had neither somatic nor any psychiatric problems at all. CONCLUSIONS: In children with restrictive eating problems odds of all coexisting psychiatric problems and gastrointestinal problems are significantly increased. The study shows the importance of considering comorbidities in clinical assessment of children with restrictive eating problems. PMID- 28835823 TI - Cerebral venous sinus thrombosis in homocystinuria: Dietary intervention in conjunction with anticoagulation. AB - The presentation of cerebral venous sinus thrombosis may be acute or chronic with a progressive clinical course. The diagnosis can be challenging, and there are several clinical syndromes associated with the disease. It is also an uncommon but recognised complication of homocystinuria. We describe a case where early anticoagulation, together with dietary intervention, was associated with a favourable clinical outcome. PMID- 28835822 TI - A case report: Glycopyrrolate for treatment of exercise-induced hyperhidrosis. AB - OBJECTIVE: Hyperhidrosis can cause dehydration and exercise intolerance. There are several case reports of extremely high sweat rates in athletes. We present as case report of a 17-year-old male with the highest sweat rate recorded in the literature (5.8 L/h). Our goal was to determine if glycopyrrolate, an anticholinergic medication with primarily anti-muscarinic effects that is known to decrease sweat production, would reduce the sweat rate of our subject in a controlled exercise setting. METHODS: Our patient and a control subject were subjected to an exercise protocol consisting of running on a treadmill (5.4-6.7 mile/h at 1 degrees of incline) in a warm climate-controlled chamber after receiving 0, 2, or 4 mg of glycopyrrolate. Core temperature, heart rate, rater of perceived exertion, and sweat rate were monitored in both subjects. RESULTS: Glycopyrrolate dose was not significantly correlated with decreased sweat rate and maximal core temperature. However, the clinical effect of reducing the sweat rate was very strong. The improvement of the subject's sweat rate allowed him to successfully return to sport. CONCLUSION: Our findings suggest that low-dose glycopyrrolate may be a safe and effective method of controlling exertional hyperhidrosis. PMID- 28835824 TI - Acute recurrent lymphocytic meningitis in an immunocompetent HIV-positive African woman: Is it a Mollaret's meningitis or not? AB - We report a case of acute recurrent meningitis in an HIV-positive immunocompetent woman. In this case, a 34-year-old African woman with a known HIV infection presented with symptoms of acute meningitis. She was on combination antiretroviral therapy with abacavir, lamivudine, and nevirapine. Her HIV RNA level was <70 IU/mL, and CD4 counts were 640 cells/mm3. This indicates that she was not immunocompromised. She was febrile on examination, with marked neck stiffness. Her cerebrospinal fluid revealed raised white cell counts with 100% lymphocytes and mildly raised protein. Polymerase chain reaction confirmed herpes simplex type 2 meningitis. She recovered fully with aciclovir 800 mg three times a day. However, she was readmitted with a similar presentation 5 months after the initial admission. Her cerebrospinal fluid confirmed recurrent herpes simplex type 2 meningitis. This case alerts the profession to the possibility of non opportunistic infections in an immunocompetent HIV-positive patient and of herpes simplex virus type 2 causing recurrent lymphocytic meningitis. PMID- 28835825 TI - Lemierre's syndrome, necrotizing pneumonia and staphylococcal septic shock treated with extracorporeal life support. AB - OBJECTIVES: Lemierre's syndrome cause by methicillin-sensitive Staphylococcus aureus is rare, but can lead to necrotizing pneumonia and septicaemia. When treating such patient with extracorporeal life support source control can be both challenging and controversial. METHODS: In this report we present a 12 year old male who presented with Lemierre's syndrome from which he developed septic shock and severe necrotizing pneumonia. He also showed multiple pulmonary embolisms from the internal jugular vein thrombi, resulting in acute respiratory distress syndrome. RESULTS: The patient was treated with extracorporeal life support. Subsequent computed tomography revealed multiple abscesses throughout his lungs and around vertebral bodies C1 and C2, for which source control with drainage of the cervical abscesses was achieved while on extracorporeal life support. The necrotizing pneumonia gradually improved, and partial pneumectomy was avoided. He was successfully separated from extracorporeal life support and respiratory support and recovered from his illness. Follow-up imaging showed almost complete resolution of the pulmonary abscesses. Osteomyelitis of C1/C2 and severe muscle wasting required a prolonged hospital stay. CONCLUSION: This case highlights the challenges of supporting patients suffering from disseminated staphylococcal sepsis with extracorporeal life support and the key role of source control and demonstrates the value of using extracorporeal life support in necrotizing pneumonia. PMID- 28835826 TI - An atypical case of trigeminal trophic syndrome: A legal medicine perspective in medical responsibility. AB - BACKGROUND: Trigeminal trophic syndrome is a rare complication of peripheral or central damage to the trigeminal nerve characterized by anesthesia, paresthesia and a secondary persistent facial ulceration. METHODS: We describe the case of a 40-year-old woman with previous history of Le Fort I osteotomy for a class III malocclusion who developed trigeminal trophic syndrome. Atypically, the cutaneous symptoms appeared bilaterally and 8 years after surgery. RESULTS: Differential diagnosis was based on clinical history, tissue biopsy and serologic evaluation. Atypical findings could be linked to the surgical burdens of Le Fort I osteotomy, a procedure characterized by a bilateral incision on the maxillofacial bones with a reasonable probability of causing a bilateral injury of the peripheral branches of the trigeminal nerve. CONCLUSION: Although the long delay between trigeminal trophic syndrome onset and surgery and the absence of adequate medical evidence cannot confirm a link with previous surgery in this case, the increasing number of maxillofacial surgery cases suggests that this complication may be more frequent in the next decades, and thus, involved specialists should be aware of this condition as a possible complication of maxillofacial surgery procedures. PMID- 28835827 TI - Epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome in a European child with KCNJ10 mutations: A case report. AB - BACKGROUND: Epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome is a multi-organ disorder that links to autosomal recessive mutations in the KCNJ10 gene, which encodes for the Kir4.1 potassium channel. It is mostly described in consanguineous, non-European families. CASE REPORT: A European male of non consanguineous birth, with early-onset, static ataxic motor disorder, intellectual disability and epilepsy, imitating cerebral palsy, presented with additional findings of renal tubulopathy, sensorineural deafness and normal neuroimaging leading to the diagnosis of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome. The patient was heterozygous for two KCNJ10 mutations: a missense mutation (p.R65C) that is already published and a not yet published duplication (p.F119GfsX25) that creates a premature truncation of the protein. Both mutations are likely damaging. Parental testing has not been performed, and therefore, we do not know for certain whether the mutations are on different alleles. This young man presents some clinical and laboratory features that differ from previously reported patients with epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome. CONCLUSION: The necessity of accurate diagnosis through genetic testing in patients with static motor disorders resembling cerebral palsy phenotypes, atypical clinical features and noncontributory neuroimaging is emphasized. PMID- 28835828 TI - A case with a large intracoronary mobile mass diagnosed with a calcified thrombus using optical frequency domain imaging and intravascular ultrasound. AB - OBJECTIVES: A calcified thrombus is rare, but needs to be recognized and to be differentiated from calcified nodule. METHODS: We report a case of acute coronary syndrome and a large intracoronary mobile mass, which was identified as a calcified thrombus by optical frequency domain imaging and intravascular ultrasound. RESULTS: Successful direct stenting indicated that mobile mass was a calcified thrombus, not a calcified nodule. CONCLUSIONS: Cardiologists should be aware that an intracoronary mobile mass could be a calcified thrombus. This diagnosis can be confirmed through the combined use of optical frequency domain imaging and intravascular ultrasound. PMID- 28835829 TI - Conjunctival leiomyosarcoma: A fairly common tumour in an uncommon site. AB - BACKGROUND: Leiomyosarcomas of soft tissue are malignant tumours that are not infrequently encountered in clinical medicine and histopathology. Such sarcomas of the eye are, however, a rare occurrence. PURPOSE: Herein, the histopathological features of a case of conjunctival leiomyosarcoma are described. A 38-year-old HIV-positive male, who was otherwise fit and healthy, presented with redness of his right eye and a mass of the conjunctiva. Clinically, he did not have any soft-tissue masses elsewhere in the body. METHOD: He underwent monoblock excision of the conjunctival mass which was confirmed histologically to be a leiomyosarcoma. Unfortunately, the patient had not returned for follow-up examination. CONCLUSION: The differential diagnosis of a conjunctival spindle cell neoplasm is broad. While a spindle cell carcinoma is the most likely tumour, other tumours must be borne in mind so as not to misdiagnose primary sarcomas in this unusual location. PMID- 28835830 TI - Extra-articular chondromatosis of flexor and extensor compartments of the hand: Case report and review of literature. AB - OBJECTIVES: Tenosynovial chondromatosis is an uncommon type of chondro-dysplasia of synovial and connective tissue. We report a case of a patient with a primary right wrist extra-articular chondromatosis extending to the flexor and the extensor compartments. METHODS: Until now, there has been no study describing double surgical access for such a case. RESULTS: Due to the extension, two surgical accesses are required to completely remove the neoformation. CONCLUSIONS: At 2 years of follow-up, the good functional-clinical results and absence of recurrence confirm the validity of our surgical strategy. PMID- 28835832 TI - Suprapubic varicose vein formation during pregnancy following pre-pregnancy pelvic vein embolisation with coils, without any residual pelvic venous reflux or obstruction. AB - Suprapubic varicose veins are usually indicative of unilateral iliac vein occlusion and venous collateralisation. We report two cases of suprapubic varicose veins following pelvic vein embolisation and subsequent pregnancy; both presented without residual pelvic venous reflux or pelvic venous obstruction. In both cases, there was no significant flow in the suprapubic veins indicating that they were not acting as a collateral post-pregnancy. One patient had this venous abnormality treated successfully with TRansluminal Occlusion of Perforators, followed by foam sclerotherapy to the main part of the suprapubic vein. This patient has since completed the reminder of her lower limb varicose vein treatment. We suggest that pregnancy may have caused prolonged intermittent compression of the left common iliac vein, and that this, together with the physiological impact of previous embolisation procedures, obstructed venous drainage from the left leg resulting in collateral vein formation within the 9 month gestation period. PMID- 28835831 TI - Three-dimensional optical frequency domain imaging of a true bifurcation lesion after stent implantation using the jailed semi-inflated balloon technique. AB - OBJECTIVE: Percutaneous coronary intervention for coronary bifurcation lesion is very challenging, especially for true bifurcation lesions. Although the jailed semi-inflated balloon technique is one of the established methods for treatment of coronary bifurcation lesions, little is known regarding the configuration of the side branch orifice after stent implantation using this technique. METHODS: We report a 73-year-old male patient with angina pectoris who was successfully treated with percutaneous coronary stent implantation for a true bifurcation lesion of the right coronary artery with an obtuse angle using the jailed semi inflated balloon technique. RESULTS: Three-dimensional optical frequency domain imaging clearly showed that there were no signs of plaque or carina shift into the side branch after stent implantation using this technique. CONCLUSIONS: This case report highlights that the jailed semi-inflated balloon technique is a safe and useful treatment for coronary true bifurcation lesions with an obtuse angle. PMID- 28835833 TI - Clinical Electrophysiology: A Glimpse Into The Future. PMID- 28835835 TI - Practical Implementation of Anticoagulation Strategy for Patients Undergoing Cardioversion of Atrial Fibrillation. AB - Anticoagulation is routinely prescribed to patients with persistent AF before cardioversion to reduce the risk of thromboembolic events. As direct oral anticoagulants (DOACs) have a rapid onset of action, a consistent anticoagulant effect, if taken correctly, and do not need monitoring or dose adjustments, there is considerable interest in their use for patients with AF undergoing cardioversion. Post-hoc analyses show that DOACs are safe to use prior to and following cardioversion. In addition, two randomised controlled trials, X-VeRT and ENSURE-AF, have demonstrated the efficacy and safety of the DOACs rivaroxaban and edoxaban, respectively, in this setting. The use of DOACs allows cardioversions to be performed promptly and reduces the number of cancelled procedures compared with the use of warfarin. PMID- 28835834 TI - Supraventricular Arrhythmias in Patients with Adult Congenital Heart Disease. AB - An increasing number of patients with congenital heart disease survive to adulthood; such prolonged survival is related to a rapid evolution of successful surgical repairs and modern diagnostic techniques. Despite these improvements, corrective atrial incisions performed at surgery still lead to subsequent myocardial scarring harbouring a potential substrate for macro-reentrant atrial tachycardia. Macroreentrant atrial tachycardias are the most common (75 %) type of supraventricular tachycardia (SVT) in patients with adult congenital heart disease (ACHD). Patients with ACHD, atrial tachycardias and impaired ventricular function - important risk factors for sudden cardiac death (SCD) - have a 2-9 % SCD risk per decade. Moreover, ACHD imposes certain considerations when choosing antiarrhythmic drugs from a safety aspect and also when considering catheter ablation procedures related to the inherent cardiac anatomical barriers and required expertise. Expert recommendations for physicians managing these patients are therefore mandatory. This review summarises current evidence-based developments in the field, focusing on advances in and general recommendations for the management of ACHD, including the recently published recommendations on management of SVT by the European Heart Rhythm Association. PMID- 28835836 TI - Atrial Flutter, Typical and Atypical: A Review. AB - Clinical electrophysiology has made the traditional classification of rapid atrial rhythms into flutter and tachycardia of little clinical use. Electrophysiological studies have defined multiple mechanisms of tachycardia, both re-entrant and focal, with varying ECG morphologies and rates, authenticated by the results of catheter ablation of the focal triggers or critical isthmuses of re-entry circuits. In patients without a history of heart disease, cardiac surgery or catheter ablation, typical flutter ECG remains predictive of a right atrial re-entry circuit dependent on the inferior vena cava-tricuspid isthmus that can be very effectively treated by ablation, although late incidence of atrial fibrillation remains a problem. Secondary prevention, based on the treatment of associated atrial fibrillation risk factors, is emerging as a therapeutic option. In patients subjected to cardiac surgery or catheter ablation for the treatment of atrial fibrillation or showing atypical ECG patterns, macro re-entrant and focal tachycardia mechanisms can be very complex and electrophysiological studies are necessary to guide ablation treatment in poorly tolerated cases. PMID- 28835838 TI - Evolution of Force Sensing Technologies. AB - In order to Improve the procedural success and long-term outcomes of catheter ablation techniques for atrial fibrillation (AF), an Important unfulfilled requirement is to create durable electrophysiologically complete lesions. Measurement of contact force (CF) between the catheter tip and the target tissue can guide physicians to optimise both mapping and ablation procedures. Contact force can affect lesion size and clinical outcomes following catheter ablation of AF. Force sensing technologies have matured since their advent several years ago, and now allow the direct measurement of CF between the catheter tip and the target myocardium in real time. In order to obtain complete durable lesions, catheter tip spatial stability and stable contact force are important. Suboptimal energy delivery, lesion density/contiguity and/or excessive wall thickness of the pulmonary vein-left atrial (PV-LA) junction may result in conduction recovery at these sites. Lesion assessment tools may help predict and localise electrical weak points resulting in conduction recovery during and after ablation. There is increasing clinical evidence to show that optimal use of CF sensing during ablation can reduce acute PV re-conduction, although prospective randomised studies are desirable to confirm long-term favourable clinical outcomes. In combination with optimised lesion assessment tools, contact force sensing technology has the potential to become the standard of care for all patients undergoing AF catheter ablation. PMID- 28835837 TI - Atrial Fibrillation and Anticoagulation in Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) represents a common inherited cardiac disorder with well-known complications Including stroke and sudden cardiac death. There is a recognised association between HCM and the development of AF. This review describes the epidemiology of AF within the HCM population and analyses the risk factors for the development of AF. It further discusses the outcomes associated with AF in this population, including the evidence in support of higher stroke risk in patients with HCM with AF compared with the general AF population. Finally, the evidence and recommendations for anticoagulation in this patient group are addressed. PMID- 28835839 TI - Percutaneous Catheter Ablation of Epicardial Accessory Pathways. AB - Radiofrequency (RF) catheter ablation is the treatment of choice in patients with accessory pathways (APs) and Wolff-Parkinson-White syndrome. Endocardial catheter ablation has limitations, including the inability to map and ablate intramural or subepicardial APs. Some of these difficulties can be overcome using an epicardial approach performed through the epicardial venous system or by percutaneous catheterisation of the pericardial space. When a suspected left inferior or infero-paraseptal AP is refractory to ablation or no early activation is found at the endocardium, a transvenous approach via the coronary sinus is warranted because such epicardial pathways can be in close proximity to the coronary venous system. Associated congenital abnormalities, such as right atrial appendage, right ventricle diverticulum, coronary sinus diverticulum and absence of coronary sinus ostium, may also hamper a successful outcome. Percutaneous epicardial subxiphoid approach should be considered when endocardial or transvenous mapping and ablation fails. Epicardial mapping may be successful. It can guide and enhance the effectiveness of endocardial ablation. The finding of no epicardial early activation leads to a more persistent new endocardial attempt. When both endocardial and epicardial ablation are unsuccessful, open-chest surgery is the only option to eliminate the AP. PMID- 28835840 TI - Coupling gene-based and classic veterinary diagnostics improves interpretation of health and immune function in the Agassiz's desert tortoise (Gopherus agassizii). AB - The analysis of blood constituents is a widely used tool to aid in monitoring of animal health and disease. However, classic blood diagnostics (i.e. hematologic and plasma biochemical values) often do not provide sufficient information to determine the state of an animal's health. Field studies on wild tortoises and other reptiles have had limited success in drawing significant inferences between blood diagnostics and physiological and immunological condition. However, recent research using gene transcription profiling in the threatened Mojave desert tortoise (Gopherus agassizii) has proved useful in identifying immune or physiologic responses and overall health. To improve our understanding of health and immune function in tortoises, we evaluated both standard blood diagnostic (body condition, hematologic, plasma biochemistry values, trace elements, plasma proteins, vitamin A levels) and gene transcription profiles in 21 adult tortoises (11 clinically abnormal; 10 clinically normal) from Clark County, NV, USA. Necropsy and histology evaluations from clinically abnormal tortoises revealed multiple physiological complications, with moderate to severe rhinitis or pneumonia being the primary cause of morbidity in all but one of the examined animals. Clinically abnormal tortoises had increased transcription for four genes (SOD, MyD88, CL and Lep), increased lymphocyte production, biochemical enzymes and organics, trace elements of copper, and decreased numbers of leukocytes. We found significant positive correlations between increased transcription for SOD and increased trace elements for copper, as well as genes MyD88 and Lep with increased inflammation and microbial insults. Improved methods for health assessments are an important element of monitoring tortoise population recovery and can support the development of more robust diagnostic measures for ill animals, or individuals directly impacted by disturbance. PMID- 28835841 TI - Swimming performance in juvenile shortnose sturgeon (Acipenser brevirostrum): the influence of time interval and velocity increments on critical swimming tests. AB - The most utilized method to measure swimming performance of fishes has been the critical swimming speed (UCrit) test. In this test, the fish is forced to swim against an incrementally increasing flow of water until fatigue. Before the water velocity is increased, the fish swims at the water velocity for a specific, pre arranged time interval. The magnitude of the velocity increments and the time interval for each swimming period can vary across studies making the comparison between and within species difficult. This issue has been acknowledged in the literature, however, little empirical evidence exists that tests the importance of velocity and time increments on swimming performance in fish. A practical application for fish performance is through the design of fishways that enable fish to bypass anthropogenic structures (e.g. dams) that block migration routes, which is one of the causes of world-wide decline in sturgeon populations. While fishways will improve sturgeon conservation, they need to be specifically designed to accommodate the swimming capabilities specific for sturgeons, and it is possible that current swimming methodologies have under-estimated the swimming performance of sturgeons. The present study assessed the UCrit of shortnose sturgeon using modified UCrit to determine the importance of velocity increment (5 and 10 cm s-1) and time (5, 15 and 30 min) intervals on swimming performance. UCrit was found to be influenced by both time interval and water velocity. UCrit was generally lower in sturgeon when they were swum using 5cm s-1 compared with 10 cm s-1 increments. Velocity increment influences the UCrit more than time interval. Overall, researchers must consider the impacts of using particular swimming criteria when designing their experiments. PMID- 28835843 TI - Foraging for fast food: the changing diets of wildlife. PMID- 28835842 TI - How experimental biology and ecology can support evidence-based decision-making in conservation: avoiding pitfalls and enabling application. AB - Policy development and management decisions should be based upon the best available evidence. In recent years, approaches to evidence synthesis, originating in the medical realm (such as systematic reviews), have been applied to conservation to promote evidence-based conservation and environmental management. Systematic reviews involve a critical appraisal of evidence, but studies that lack the necessary rigour (e.g. experimental, technical and analytical aspects) to justify their conclusions are typically excluded from systematic reviews or down-weighted in terms of their influence. One of the strengths of conservation physiology is the reliance on experimental approaches that help to more clearly establish cause-and-effect relationships. Indeed, experimental biology and ecology have much to offer in terms of building the evidence base that is needed to inform policy and management options related to pressing issues such as enacting endangered species recovery plans or evaluating the effectiveness of conservation interventions. Here, we identify a number of pitfalls that can prevent experimental findings from being relevant to conservation or would lead to their exclusion or down-weighting during critical appraisal in a systematic review. We conclude that conservation physiology is well positioned to support evidence-based conservation, provided that experimental designs are robust and that conservation physiologists understand the nuances associated with informing decision-making processes so that they can be more relevant. PMID- 28835844 TI - Polar bears experience skeletal muscle atrophy in response to food deprivation and reduced activity in winter and summer. AB - When reducing activity and using stored energy during seasonal food shortages, animals risk degradation of skeletal muscles, although some species avoid or minimize the resulting atrophy while experiencing these conditions during hibernation. Polar bears may be food deprived and relatively inactive during winter (when pregnant females hibernate and hunting success declines for other demographic groups) as well as summer (when sea ice retreats from key foraging habitats). We investigated muscle atrophy in samples of biceps femoris collected from free-ranging polar bears in the Southern Beaufort Sea (SBS) throughout their annual cycle. Atrophy was most pronounced in April-May as a result of food deprivation during the previous winter, with muscles exhibiting reduced protein concentration, increased water content, and lower creatine kinase mRNA. These animals increased feeding and activity in spring (when seal prey becomes more available), initiating a period of muscle recovery. During the following ice melt of late summer, ~30% of SBS bears abandon retreating sea ice for land; in August, these 'shore' bears exhibited no muscle atrophy, indicating that they had fully recovered from winter food deprivation. These individuals subsequently scavenged whale carcasses deposited by humans and by October, had retained good muscle condition. In contrast, ~70% of SBS bears follow the ice north in late summer, into deep water with less prey. These 'ice' bears fast; by October, they exhibited muscle protein loss and rapid changes in myosin heavy-chain isoforms in response to reduced activity. These findings indicate that, unlike other bears during winter hibernation, polar bears without food in summer cannot mitigate atrophy. Consequently, prolonged summer fasting resulting from climate change induced ice loss creates a risk of greater muscle atrophy and reduced abilities to travel and hunt. PMID- 28835845 TI - Sleep disturbances and semen quality in an Italian cross sectional study. AB - INTRODUCTION: In order to obtain information about the relationship between sleep disturbances and sperm parameters, we analyzed data from a study conducted in a Italian Fertility Clinic, in men of couples seeking help for infertility. PATIENTS AND METHODS: Male partners with or without a medical history of reproductive organ diseases (cryptorchidism, varicocele, orchitis, testicular torsion) were eligible for the study. There were 382 men evaluated from May 2014 to November 2016, all of whom completed a self-administered questionnaire on general lifestyle habits. Then all men underwent semen analysis. A total of 382 men aged 26 to 67 years (median age 39 year interquartile range 37-42) were recruited. MAIN RESULTS: A total of 46.3% reported having sleep disturbances. In multivariate analysis, in absence of reproductive organ diseases, semen volume was lower in patients with difficulty in initiating sleep (2.0 ml, IQR 1.5-3.0 vs 3.0 ml, IQR 2.0-3.3, p = .01), whereas in presence of reproductive organ diseases motility A was lower in patients with early morning awakening (25.0%, IQR 15.0 35.0 vs. 40.0%, IQR 30.0-50.0, p = .001). In overweight men, semen volume was lower in patients with difficulty in initiating sleep (2.0 ml, IQR 1.5-3.0 vs 3.0 ml, IQR 2.0-3.0, p = .03). Moreover, among current smokers, patients with difficulty in initiating sleep had semen volume lower (1.5 ml, IQR 1.5-2.5 vs 3.0 ml, IQR 2.0-3.5, p = .0003) and sperm concentration higher (40 millions/ml, IQR 15-60 vs 10 millions/ml, IQR 5-50 p = .03) but total sperm count was not significant different. CONCLUSION: Further studies are necessary to elucidate the relationship between sleep quality and semen parameters, which may have important public health implication. PMID- 28835846 TI - Association between shift work and microalbuminuria: data from KNHANES(2012 2014). AB - BACKGROUND: Shift work disturbs workers' biological clocks and this condition can cause various health problems including cardiovascular disease. The elevated albuminuria level has been significantly associated with the risk of the cardiovascular disease even within a normal reference range. Therefore, this study aimed to investigate the association between shift work and microalbuminuria. METHODS: Workers aged over 20 years from the fifth and sixth Korea National Health and Nutrition Examination Survey(KNHANES 2012-2014; n = 3000) were included in this analysis. The multiple logistic regression analysis was performed to determine the association between shift work and microalbuminuria stratified by gender. RESULTS: The prevalence of microalbuminuria in male subjects was higher among day workers, but the difference was not significant. However, the prevalence of microalbuminuria among females was higher in shift workers with statistical significance. For female, the Odds ratio of microalbuminuria in shift workers was significantly higher with 1.86 (95% CI 1.02-3.39) compared with day workers. After dividing into 5 subgroups of the shift work pattern, the odds ratio of microalbuminuria for fixed night shift was significantly higher at 4.68 (95% CI 1.29-17.00) compared with day workers. CONCLUSIONS: This study showed that shift work was associated with microalbuminuria in female workers. Especially we found out the association between fixed night shift and microalbuminuria in female workers. PMID- 28835847 TI - Patient perspectives of an individualized diabetes care management plan. AB - PURPOSE: This cross sectional study examines patients' knowledge, attitudes and beliefs about a diabetic care management plan (DCMP) that was developed to provide patient education on diabetes guidelines and display individual diabetic core measures. Secondary objectives included a comparison of diabetic core measures [hemoglobin A1C (HbA1C), systolic and diastolic blood pressure (SBP, DBP), low-density lipoprotein (LDL) and urine microalbumin (Um)] before and after DCMP implementation. We hypothesize this tool will contribute to patients' awareness of current disease status, diabetes knowledge and diabetic core value improvement over time. METHODS: A consecutive sample of 102 adult patients with diabetes mellitus type 2 in a primary care setting participated. Patients' perspectives on the care plan and knowledge about diabetes was collected via survey after care plan implementation. A comparison of selected diabetic core measures was conducted at baseline and post-DCMP. Descriptive statistics summarized survey response and diabetic core measures. A repeated measures ANOVA was used to assess change in diabetic core measures over time. RESULTS: Participants understood the DCMP (96%), found it important because it explained their laboratory results and medications (89%) and believed it would help them to have better diabetic control (99%). There was a significant interaction between time and being at goal pre-DCMP for HbA1c, SBP and LDL. Patients not at goal pre DCMP for the above measures decreased significantly over time (P = <0.01 for HbA1c, SBP and LDL). Participants at goal for all diabetic core measures increased pre- to post-DCMP from 13% to 20% (P = 0.28). CONCLUSION: Patients perceived the diabetic care management plan favorably and their diabetic core measurements improved over time. This simple and reproducible self-management intervention can enhance self-management in a patient population with diabetes mellitus type 2. PMID- 28835849 TI - The Impact on Central Blood Pressure and Arterial Stiffness Post Renal Denervation in Patients With Stage 3 and 4 Chronic Kidney Disease: The Prairie Renal Denervation Study. AB - BACKGROUND: Central aortic blood pressures and arterial stiffness are better indicators of cardiovascular outcomes than brachial blood pressures. However, their response to renal denervation (RDN) in patients with stage 3 and stage 4 chronic kidney disease (CKD) has not yet been examined. OBJECTIVE: To evaluate the impact of RDN on central blood pressures, brachial (office and ambulatory) blood pressures, arterial stiffness, glomerular filtration rate (GFR), 24-hour urine protein, and selective cardiac parameters observed on echocardiograms. DESIGN: Single-center, single-arm with pre-RDN/post-RDN follow-up. SETTING: Patients are being recruited from the multidisciplinary CKD clinic. PATIENTS: Fifty consecutive patients with stage 3 or stage 4 CKD and resistant hypertension, with no radiological or laboratory evidence of secondary causes of hypertension. MEASUREMENTS: The key measurements are central blood pressures, pulse wave velocity, ambulatory 24-hour blood pressure, office blood pressures on BP Tru, GFR, 24-hour urine protein and sodium, blood pressure medication, and doses. METHODS: For our primary outcome, we will compare changes in central blood pressures from baseline to 6 months post RDN using a paired t test or Mann Whitney U test. Secondary outcomes will examine changes in central blood pressures from baseline to 3, 12, 18, and 24 months post RDN as well as changes in office pressures, GFR, 24-hour urine protein and sodium, and medications at all time points using mixed-model analyses of variance or Friedman test. Multiple regression may be used to control for potential covariates. LIMITATIONS: Single center study, with no sham arm. CONCLUSIONS: Aortic blood pressure, rather than brachial blood pressure, optimally reflects the load placed on the left ventricle. Aortic blood pressure is also better associated with cardiovascular outcomes. If our study shows a preferential decrease in central blood pressures and improvements in cardiac parameters on echocardiograms post RDN, this may influence the way in which blood pressures are managed in clinics and offices. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01832233). PMID- 28835848 TI - A Description of Advanced Chronic Kidney Disease Patients in a Major Urban Center Receiving Conservative Care. AB - BACKGROUND: Conservative/palliative (nondialysis) management is an option for some individuals for treatment of stage 5 chronic kidney disease (CKD). Little is known about these individuals treated with conservative care in the Canadian setting. OBJECTIVE: To describe the characteristics of patients treated with conservative care for category G5 non-dialysis CKD in a Canadian context. DESIGN: Retrospective chart review. SETTING: Urban nephrology center. PATIENTS: Patients with G5 non-dialysis CKD (estimated glomerular filtration rate <15 mL/min/1.73 m2). MEASUREMENTS: Baseline patient demographic and clinical characteristics of conservative care follow-up, advanced care planning, and death. METHODS: We undertook a descriptive analysis of individuals enrolled in a conservative care program between January 1, 2009, and June 30, 2015. RESULTS: One hundred fifty four patients were enrolled in the conservative care program. The mean age and standard deviation was 81.4 +/- 9.0 years. The mean modified Charlson Comorbidity Index score was 3.4 +/- 2.8. The median duration of conservative care participation was 11.5 months (interquartile range: 4-25). Six (3.9%) patients changed their modality to dialysis. One hundred three (66.9%) patients died during the study period. Within the deceased cohort, most (88.2%) patients completed at least some advanced care planning before death, and most (81.7%) of them died at their preferred place. Twenty-seven (26.7%) individuals died in hospital. LIMITATIONS: Single-center study with biases inherent to a retrospective study. Generalizability to non-Canadian settings may be limited. CONCLUSIONS: We found that individuals who chose conservative care were very old and did not have high levels of comorbidity. Few individuals who chose conservative care changed modality and accepted dialysis. The proportions of engagement in advanced care planning and of death in place of choice were high in this population. Death in hospital was uncommon in this population. PMID- 28835850 TI - Risk-Based Triage for Nephrology Referrals Using the Kidney Failure Risk Equation. AB - BACKGROUND: In some jurisdictions, routine reporting of the estimated glomerular filtration rate (eGFR) has led to an increase in nephrology referrals and wait times. OBJECTIVE: We describe the use of the Kidney Failure Risk Equation (KFRE) as part of a triage process for new nephrology referrals for patients with chronic kidney disease stages 3 to 5 in a Canadian province. DESIGN: A quasi experimental study design was used. SETTING: This study took place in Manitoba, Canada. MEASUREMENTS: Demographics, laboratory values, referral numbers, and wait times were compared between periods. METHODS: In 2012, we adopted a risk-based cutoff of 3% over 5 years using the KFRE as a threshold for triage of new referrals. Referrals who did not meet other prespecified criteria (such as pregnancy, suspected glomerulonephritis, etc) and had a kidney failure risk of <3% over 5 years were returned to primary care with recommendations based on diabetes and hypertension guidelines. The average wait time and number of consults seen between the pretriage (January 1, 2011, to December 31, 2011) and posttriage period (January 1, 2013, to December 31, 2013) were compared using a general linear model. RESULTS: In the pretriage period, the median number of referrals was 68/month (range: 44-76); this increased to 94/month (range: 61-147) in the posttriage period. In the posttriage period, 35% of referrals were booked as urgent, 31% as nonurgent, and 34% of referrals were not booked. The median wait times improved from 230 days (range: 126-355) in the pretriage period to 58 days (range: 48-69) in the posttriage period. LIMITATIONS: We do not have long term follow-up on patients triaged as low risk. Our study may not be applicable to nephrology teams operating under capacity without wait lists. We did not collect detailed information on all referrals in the pretriage period, so any differences in our pretriage and posttriage patient groups may be unaccounted for. CONCLUSIONS: Our risk-based triage scheme is an effective health policy tool that led to improved wait times and access to care for patients at highest risk of progression to kidney failure. PMID- 28835851 TI - A Survey of Canadian Nephrologists Assessing Prognostication in End-Stage Renal Disease. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) frequently have a relatively poor prognosis with complex care needs that depend on prognosis. While many means of assessing prognosis are available, little is known about how Canadian nephrologists predict prognosis, whether they routinely share prognostic information with their patients, and how this information guides management. OBJECTIVE: To guide improvements in the management of patients with ESRD, we aimed to better understand how Canadian nephrologists consider prognosis during routine care. DESIGN AND METHODS: A web-based multiple choice survey was designed, and administered to adult nephrologists in Canada through the e-mail list of the Canadian Society of Nephrology. The survey asked the respondents about their routine practice of estimating survival and the perceived importance of prognostic practices and tools in patients with ESRD. Descriptive statistics were used in analyzing the responses. RESULTS: Less than half of the respondents indicated they always or often make an explicit attempt to estimate and/or discuss survival with ESRD patients not on dialysis, and 25% reported they do so always or often with patients on dialysis. Survival estimation is most frequently based on clinical gestalt. Respondents endorse a wide range of issues that may be influenced by prognosis, including advance care planning, transplant referral, choice of dialysis access, medication management, and consideration of conservative care. LIMITATIONS: This is a Canadian sample of self-reported behavior, which was not validated, and may be less generalizable to non-Canadian health care jurisdictions. CONCLUSIONS: In conclusion, prognostication of patients with ESRD is an important issue for nephrologists and impacts management in fairly sophisticated ways. Information sharing on prognosis may be suboptimal. PMID- 28835852 TI - Degummed crude canola oil, sire breed and gender effects on intramuscular long chain omega-3 fatty acid properties of raw and cooked lamb meat. AB - BACKGROUND: Omega-3 long-chain (>=C20) polyunsaturated fatty acids (omega3 LC PUFA) confer important attributes to health-conscious meat consumers due to the significant role they play in brain development, prevention of coronary heart disease, obesity and hypertension. In this study, the omega3 LC-PUFA content of raw and cooked Longissimus thoracis et lumborum (LTL) muscle from genetically divergent Australian prime lambs supplemented with dietary degummed crude canola oil (DCCO) was evaluated. METHODS: Samples of LTL muscle were sourced from 24 first cross ewe and wether lambs sired by Dorset, White Suffolk and Merino rams joined to Merino dams that were assigned to supplemental regimes of degummed crude canola oil (DCCO): a control diet at 0 mL/kg DM of DCCO (DCCOC); 25 mL/kg DM of DCCO (DCCOM) and 50 mL/kg DCCO (DCCOH). Lambs were individually housed and offered 1 kg/day/head for 42 days before being slaughtered. Samples for cooked analysis were prepared to a core temperature of 70 degrees C using conductive dry-heat. RESULTS: Within raw meats: DCCOH supplemented lambs had significantly (P < 0.05) higher concentrations of eicosapentaenoic (EPA, 20:5omega3) and EPA + docosahexaenoic (DHA, 22:6omega3) acids than those supplemented with DCCOM or DCCOC; Dorset sired lambs contained significantly (P < 0.05) more EPA and EPA + DHA than other sire breeds; diet and sire breed interactions were significant (P < 0.05) in affecting EPA and EPA + DHA concentrations. In cooked meat, omega3 LC PUFA concentrations in DCCOM (32 mg/100 g), DCCOH (38 mg/100 g), Dorset (36 mg/100 g), White Suffolk (32 mg/100 g), ewes (32 mg/100 g) and wethers (33 mg/100 g), all exceeded the minimum content of 30 mg/100 g of edible cooked portion of EPA + DHA for Australian defined 'source' level omega3 LC-PUFA classification. CONCLUSION: These results present that combinations of dietary degummed crude canola oil, sheep genetics and culinary preparation method can be used as effective management tools to deliver nutritionally improved omega3 LC-PUFA lamb to meat consumers. PMID- 28835853 TI - Obesity prevalence and related risk of comorbidities among HIV+ patients attending a New England ambulatory centre. AB - BACKGROUND: Human immunodeficiency virus infection and obesity are pro inflammatory conditions that, when occurring together, may pose a synergistic risk for diabetes and cardiovascular disease. PURPOSE: The aim of the current study was (i) to document the prevalence of obesity in HIV+ patients treated at the Miriam Hospital Immunology Center (Providence, RI) and (ii) to investigate the relationship between obesity and comorbidities. METHODS: The study population consisted of 1,489 HIV+ adults (70% men; average age 48 +/- 11 years) treated between 01/01/2012 and 06/30/2014. Separate logistic regressions tested the associations between overweight and obesity and comorbid diagnoses (diabetes, hypertension and cardiovascular disease), as compared with normal weight. Covariates included age, gender and smoking status. RESULTS: Approximately 37% of patients were overweight (body mass index 25.0-29.9), and an additional 28% were obese (body mass index >=30.0). Obesity was associated with higher odds of comorbid diabetes (OR = 3.26, CI = 1.98-5.39) and hypertension (OR = 2.11, CI = 1.49-2.98). There was no significant association between obesity and the presence of cardiovascular disease (OR = 1.12, CI = 0.66-1.90). Overweight was associated only with higher odds of comorbid diabetes (OR = 1.72; CI = 1.02-2.88). CONCLUSION: Our findings demonstrate a heightened risk of comorbidities in overweight and obese HIV + patients. Future studies should investigate whether weight loss interventions for this population can reduce cardiovascular and metabolic risk factors as they do in other populations. PMID- 28835856 TI - Bacteria as Potential Indicators of Heavy Metal Contamination in a Tropical Mangrove and the Implications on Environmental and Human Health. AB - Heavy metal (HM) exposure has been associated with human health diseases like cancer, kidney and liver damage, neurological disorders, motor skills, low bone density and learning problems. With the beginning of the industrialization, the heavy metals in high concentration contribute to putting on the risk the humans in the vicinity. Our study site is located in Catano, Puerto Rico. This is a highly industrialized area. It is surrounded by a recreational park, a rum distillery, two thermoelectric factories, and was impacted by CAPECO (oil refinery) explosion in 2009. Las Cucharillas marsh is part of The San Juan Bay Estuary System, considered as a critical wildlife area. The mangrove marsh has three of the four mangrove species found in PR Laguncularia racemosa, Avicennia germinans and Rhizophora mangle. This study was aimed at seven different heavy metals: Arsenic (As), Cadmium (Cd), Chromium (Cr), Lead (Pb), Zinc (Zn), Mercury (Hg) and Copper (Cu). These metals at high concentrations are of human health concern due to their toxicity, persistence, bioaccumulative and bio magnification potentials. Contamination of surface sediments with HM affects the food chain, starting with marine organisms up to humans. The people who live near the contaminated area and the local fishermen are at high risk of exposure. Studies reveal that certain microorganisms can resist the toxicity of heavy metals even at high concentrations. Our study pretends to exploit the sensitive nature of some bacteria to HM and use them as bioindicators. The objective of this research is to assess the bacterial community on the mangrove marsh, identify these bacteria and correlate bacterial species with the type and concentration of the metals found on the site. Our preliminary results with the BIOLOG(r) identification were five bacteria that are: Carnobacterium inhibens, Cupriavidus gilardii, Enterococcus maloduratus, Microbacterium flavescens and Ralstonia pickettii. This study will continue with an assessment of the exposure of different concentrations of heavy metals to our identified bacteria and underlying the mechanisms of degradation, magnification and or bioconcentration of these heavy metals. PMID- 28835855 TI - Chemotherapeutic xCT inhibitors sorafenib and erastin unraveled with the synaptic optogenetic function analysis tool. AB - In the search for new potential chemotherapeutics, the compounds' toxicity to healthy cells is an important factor. The brain with its functional units, the neurons, is especially endangered during the radio- and chemotherapeutic treatment of brain tumors. The effect of the potential compounds not only on neuronal survival but also neuronal function needs to be taken into account. Therefore, in this study we aimed to comprehend the biological effects of chemotherapeutic xCT inhibition on healthy neuronal cells with our synaptic optogenetic function analysis tool (SOFA). We combined common approaches, such as investigation of morphological markers, neuronal function and cell metabolism. The glutamate-cystine exchanger xCT (SLC7A11, system Xc-) is the main glutamate exporter in malignant brain tumors and as such a relevant drug target for treating deadly glioblastomas (WHO grades III and IV). Recently, two small molecules termed sorafenib (Nexavar) and erastin have been found to efficiently block xCT function. We investigated neuronal morphology, metabolic secretome profiles, synaptic function and cell metabolism of primary hippocampal cultures (containing neurons and glial cells) treated with sorafenib and erastin in clinically relevant concentrations. We found that sorafenib severely damaged neurons already after 24 h of treatment. Noteworthy, also at a lower concentration, where no morphological damage or metabolic disturbance was monitored, sorafenib still interfered with synaptic and metabolic homeostasis. In contrast, erastin-treated neurons displayed mostly inconspicuous morphology and metabolic rates. Key parameters of proper neuronal function, such as synaptic vesicle pool sizes, were however disrupted following erastin application. In conclusion, our data revealed that while sorafenib and erastin effectively inhibited xCT function they also interfered with essential neuronal (synaptic) function. These findings highlight the particular importance of investigating the effects of potential neurooncological and general cancer chemotherapeutics also on healthy neuronal cells and their function as revealed by the SOFA tool. PMID- 28835854 TI - Retinal and choroidal angiogenesis: a review of new targets. AB - Retinal and choroidal neovascularization are a major cause of significant visual impairment, worldwide. Understanding the various factors involved in the accompanying physiopathology is vital for development of novel treatments, and most important, for preserving patient vision. The intraocular use of anti vascular endothelial growth factor therapeutics has improved management of the retinal and choroidal neovascularization but some patients do not respond, suggesting other vascular mediators may also contribute to ocular angiogenesis. Several recent studies examined possible new targets for future anti-angiogenic therapies. Potential targets of retinal and choroidal neovascularization therapy include members of the platelet-derived growth factor family, vascular endothelial growth factor sub-family, epidermal growth factor family, fibroblast growth factor family, transforming growth factor-beta superfamily (TGF-beta1, activins, follistatin and bone morphogenetic proteins), angiopoietin-like family, galectins family, integrin superfamily, as well as pigment epithelium derived factor, hepatocyte growth factor, angiopoietins, endothelins, hypoxia-inducible factors, insulin-like growth factors, cytokines, matrix metalloproteinases and their inhibitors and glycosylation proteins. This review highlights current antiangiogenic therapies under development, and discusses future retinal and choroidal pro- and anti-angiogenic targets as wells as the importance of developing of new drugs. PMID- 28835857 TI - Maintenance of the Results of Stage II Lower Limb Lymphedema Treatment after Normalization of Leg Size. AB - OBJECTIVE: The aim of this study was to identify strategies to transfer responsibility of the maintenance of the results of lymphedema treatment to the patient. METHODS: Maintenance of the reduction of edema was evaluated in a prospective clinical trial in patients with Stage II leg lymphedema. Twenty-one lymphedematous lower limbs were evaluated in Clinica Godoy in 2014 and 2016. The evaluation was done by volumetry at baseline and weekly thereafter for volume control. Patients wore Venosan(r) cotton 20/30 and 30/40 mmHg elastic compression stockings followed by a custom-made inelastic stocking made of grosgrain fabric. The Friedman test for multiple comparisons and Conover post hoc test were used for statistical analysis with an alpha error of 5%. RESULTS: On comparing leg volume changes using the different types of stockings, the 20/30 mmHg elastic compression stockings failed in the first week to maintain the volume reductions but the 30/40 mmHg compression stockings did not allow significant increases in volume (p value > 0.05). During one week, the grosgrain stocking reduced leg volumes to baseline values (p value = 0.24). CONCLUSION: Higher compression of elastic stockings is better than lower compression but the inelastic grosgrain stocking is even better than both to maintain the results. PMID- 28835858 TI - Case Report of First Angiography-Based On-Line FFR Assessment during Coronary Catheterization. AB - Fractional flow reserve (FFR), an index of the hemodynamic severity of coronary stenoses, is derived from hyperemic pressure measurements and requires a pressure monitoring guide wire and hyperemic stimulus. Although it has become the standard of reference for decision-making regarding coronary revascularization, the procedure remains underutilized due to its invasive nature. FFRangio is a novel technology that uses the patient's hemodynamic data and routine angiograms to generate a complete three-dimensional coronary tree, with color-coded display of the FFR values at each point along the vessels. After being proven to be as accurate as invasive FFR measurements in an off-line study, this case report presents the first on-line application of the system in the catheterization lab. Here too, a high concordance between FFRangio and invasive FFR was observed. In light of the demonstrated capabilities of the FFRangio system, it should emerge as an important tool for clinical decision-making regarding revascularization in patients with coronary artery disease. PMID- 28835859 TI - Bone Marrow-Liver-Spleen Type of Large B-Cell Lymphoma Associated with Hemophagocytic Syndrome: A Rare Aggressive Extranodal Lymphoma. AB - Recently, an unusual subtype of large B-cell lymphoma (LBCL) with distinctive clinicopathologic features has been recognized; it is characterized by involvement of bone marrow with or without liver and/or spleen, but no lymph node or other extranodal sites, usually associated with fever, anemia, and hemophagocytic lymphohistiocytosis (HLH). Because of this distinctive clinical presentation, it has been designated "bone marrow-liver-spleen" (BLS) type of LBCL. To date there is only one series of 11 cases of BLS type of LBCL with detailed clinical, pathologic, and cytogenetic data. Herein, we describe a case of BLS type LBCL presenting with associated HLH in a 73-year-old female. The bone marrow core biopsy showed cytologically atypical large lymphoma cells present in a scattered interstitial distribution and hemophagocytosis and infrequent large lymphoma cells were seen in the bone marrow aspirate smears. Circulating lymphoma cells were not seen in the peripheral blood smears. The patient underwent treatment with chemotherapy (R-CHOP) but unfortunately passed away 2 months after initial presentation. BLS type of LBCL is a very rare and clinically aggressive lymphoma whose identification may be delayed by clinicians and hematopathologists due to its unusual clinical presentation and pathologic features. PMID- 28835860 TI - Herpes Simplex Virus Hepatitis: A Presentation of Multi-Institutional Cases to Promote Early Diagnosis and Management of the Disease. AB - OBJECTIVE: To compare three cases of Herpes simplex virus (HSV) hepatitis to increase early diagnosis of the disease. Case 1. A 23-year-old man with Crohn's disease and oral HSV. HSV hepatitis was diagnosed clinically and he improved with acyclovir. Case 2. An 18-year-old G1P0 woman with transaminitis. Despite early empiric acyclovir therapy, she died due to fulminant liver failure. Case 3. A 65 year-old woman who developed transaminitis after liver transplant. Diagnosis was confirmed by biopsy and she had resolution of acute liver failure with acyclovir. CONCLUSION: It is imperative that clinicians be aware of patients at high risk for developing HSV hepatitis to increase timely diagnosis and prevent morbidity and fatality. PMID- 28835861 TI - Vertebral Artery Caught in the Fracture Gap after Traumatic C2/3 Spondylolisthesis. AB - BACKGROUND CONTEXT: Patient with a C2 fracture and entrapment of the right vertebral artery in the fracture gap. PURPOSE: Presentation of a case with follow up until end of treatment. STUDY DESIGN: Case report. METHODS: A 25-year-old woman was brought into our emergency room after falling while riding a horse. She complained of pain in the cervical spine. Clinical examinations showed local tenderness at the upper cervical spine and painful impairment of the mobility of the neck, with no signs of neurological impairment. Radiological diagnostics revealed a traumatic C2/3 spondylolisthesis. A computer tomography (CT) angiographic scan showed a dislocation of the right vertebral artery into the fracture gap without injury to the artery. Open reduction and osteosynthesis were considered of too high risk. Therefore, we conducted fracture treatment with closed reduction and halo fixation. After removal of the halo fixator, the patient was given a soft cervical collar and was advised to rest for additional 6 weeks before beginning gradual activity. RESULTS: Conventional follow-up revealed osseous consolidation and a CT angiographic scan showed consistent blood flow to the artery. CONCLUSION: Halo fixation was a safe and effective therapy strategy in the case of vertebral artery entrapment after traumatic C2 spondylolisthesis. PMID- 28835862 TI - Late Onset Cobalamin Disorder and Hemolytic Uremic Syndrome: A Rare Cause of Nephrotic Syndrome. AB - Hemolytic uremic syndrome (HUS) is an unrare and severe thrombotic microangiopathy (TMA) caused by several pathogenetic mechanisms among which Shiga toxin-producing Escherichia coli infections and complement dysregulation are the most common. However, very rarely and particularly in neonates and infants, disorders of cobalamin metabolism (CblC) can present with or be complicated by TMA. Herein we describe a case of atypical HUS (aHUS) related to CblC disease which first presented in a previously healthy boy at age of 13.6 years. The clinical picture was initially dominated by nephrotic range proteinuria and severe hypertension followed by renal failure. The specific treatment with high dose of hydroxycobalamin rapidly obtained the remission of TMA and the complete recovery of renal function. We conclude that plasma homocysteine and methionine determinations together with urine organic acid analysis should be included in the diagnostic work-up of any patient with TMA and/or nephrotic syndrome regardless of age. PMID- 28835863 TI - Clozapine-Induced Microseizures, Orofacial Dyskinesia, and Speech Dysfluency in an Adolescent with Treatment Resistant Early Onset Schizophrenia on Concurrent Lithium Therapy. AB - Clozapine is an atypical antipsychotic used in the treatment of refractory schizophrenia. It has a well-known side effect profile, including agranulocytosis, decreased seizure threshold, and tardive dyskinesia. In addition, numerous case reports have described clozapine-induced stuttering in adults. However, there has been only one previous case report describing it in the adolescent population. In addition, concurrent lithium therapy has been shown to enhance the neurotoxic effects of antipsychotics and lower the seizure threshold. Here, we report on the development of clozapine-induced microseizures, orofacial dyskinesia, and stuttering in a 17-year-old adolescent male with treatment of refractory early onset schizophrenia on clozapine and concurrent lithium therapy. The patient's symptoms of schizophrenia responded well to the clozapine regimen. However, with the escalating dose of clozapine, the patient developed speech dysfluency in the form of stuttering and perioral twitching. An electroencephalogram confirmed seizure activity. Due to similarities with tardive dyskinesia, symptoms of microseizures induced by atypical antipsychotics may not be accurately diagnosed. A multidisciplinary treatment of speech dysfluency is of particular importance in the adolescent schizophrenic patients, who are expected to have longer duration of lifetime exposure to antipsychotics and in whom peer group interaction is crucial for normal personal and social development. PMID- 28835864 TI - Hypokalemic Paralysis due to Primary Sjogren Syndrome: Case Report and Review of the Literature. AB - Tubulointerstitial nephritis (TIN) is the main renal involvement associated with primary Sjogren syndrome (pSS). TIN can manifest as distal renal tubular acidosis (RTA), nephrogenic diabetes insipidus, proximal tubular dysfunction, and others. We present a 31-year-old female with hypokalemic paralysis due to distal RTA (dRTA). She received symptomatic treatment and hydroxychloroquine with a good response. There is insufficient information on whether to perform a kidney biopsy in these patients or not. The evidence suggests that there is an inflammatory background and therefore a potential serious affection to these patients, such as hypokalemic paralysis. We found 52 cases of hypokalemic paralysis due to dRTA in pSS patients. The majority of those patients were treated only with symptomatic medication. Patients who received corticosteroids had stable evolution even though they did not have another symptomatology. With such heterogeneous information, prospective studies are needed to assess the value of adding corticosteroids as a standardized treatment of this manifestation. PMID- 28835865 TI - Primitive Neuroectodermal Tumor and Wegener's Granulomatosis of the Kidney: A Curious Combination of Two Rare Entities. AB - Wegener's granulomatosis (WG) is characterized by necrotizing polyangiitis involving the respiratory tract and kidneys. It causes segmental necrotizing glomerulonephritis in the kidneys. In rare cases, a renal pseudotumor may be seen because of the granulomatous process. Association of WG with renal malignancy, however, is very uncommon. We report a case of a patient who presented several years after being treated for WG with malignant hypertension and an infiltrating mass in the right kidney. The histopathology of radical nephrectomy specimen showed presence of primitive neuroectodermal tumor (PNET). Association of renal cell carcinoma (RCC) with WG has been documented in a few cases, but PNET in such circumstances has not been reported. Long-term immunosuppressive treatment is a known risk factor in the development of malignancies, so it is proposed that the occurrence of RCC in WG may have been a side effect of cyclophosphamide treatment. It is not clear whether the same mechanism for PNET holds true in the present case. It is important to make a differential diagnosis between true malignancy and pseudotumors in WG as these entities cannot be distinguished based solely on imaging. We suggest a need to routinely screen the WG patients for increased risk of urologic malignancies. PMID- 28835866 TI - An Attempt to Establish a Common Animal Model for Hepatorenal Fibrosis in Rats. AB - It is already a proven fact that there exists a relationship between CLD (chronic liver disease) and kidney disease but still there is no available combined animal model of liver and kidney fibrosis on the same animal. An animal model is one of the important research tools in the field of medical science because it is important to build a model that can simulate the disease condition so that the particular disease can be studied. Therefore, the aim of this study is to build a less expensive, less time consuming, and reproducible model of hepatorenal fibrosis on rats. We administered combined intraperitoneal injection of CCl4 (Carbon Tetrachloride) and BSA (Bovine Serum Albumin) on a female Wistar rats. At the end, the liver and kidney tissues were examined under microscope to see whether we were successful in establishing the model or not. The results show that liver fibrosis was marked but the changes on the kidneys were mild. In this study, we were able to induce significant fibrosis in the liver and early stages of fibrosis in the kidneys. The result also demonstrated that the addition of BSA conferred a liver protective effect against CCl4 induced hepatotoxicity, whereas combination of CCl4 and BSA proved to be detrimental for kidneys. PMID- 28835867 TI - Total Blood Loss After Transfemoral Amputations Is Twice the Intraoperative Loss: An Observational Cohort Study of 81 Nontraumatic Amputations. AB - INTRODUCTION: Underestimation of the actual blood loss in patients undergoing nontraumatic transfemoral amputation (TFA) can impact negatively on outcome in these often frail patients, with very limited physiological reserves. The primary aim of this study is to estimate the total blood loss (TBL) after TFA, and second, to evaluate the impact of blood loss on 30-day mortality and medical complications. METHODS: A single-center retrospective cohort study conducted from 2013 to 2015. The TBL was calculated on the fourth postoperative day. It was based on the hemoglobin levels, transfusions, and the estimated blood volume. RESULTS: Eighty-one patients undergoing TFA were included for final analysis. The median TBL was 964 mL (interquartile range [IQR]: 443-1558). The intraoperative blood loss (OBL) was 400 mL (IQR: 200-500). The median difference between TBL and OBL was 688 mL (IQR: 124-1075). The patient received red blood cell (RBC) transfusion of a median amount of 2 units. Higher number of transfusions (>2) did not impact the outcome. From multivariable analysis, it was evident that the TBL increased significantly in patients with renal disease prior to surgery, (P = .034). The TBL itself was not independently associated with increased 30-day mortality or medical complications. CONCLUSION: The TBL after TFAs is significantly greater than the volume estimated intraoperatively and increases significantly in the presence of renal disease prior to surgery. An increased TBL and requirement for RBC transfusion is not directly associated with 30-day mortality or medical complications. A high vigilance for anemia seems advisable when planning for TFA surgery. Research on optimum blood conservation and transfusion strategies during TFA is warranted. PMID- 28835868 TI - Anterior Cervical Discectomy With Fusion Using a Local Source for Cancellous Autograft: A Biomechanical Analysis of Vertebral Body Stability in an Osteopenic Bone Model. AB - BACKGROUND: Anterior cervical discectomy with fusion is an effective treatment for patients having cervical radiculopathy and myelopathy. To reduce morbidity associated with autograft taken from the iliac crest without sacrificing high fusion rates, a novel technique that harvests bone from the vertebral body adjacent to the operative disc space has been proposed. The effects of square and round bone graft harvest techniques on the mechanical stability of the osteopenic donor vertebrae are unknown. We analyzed the biomechanical implications of the technique by subjecting osteopenic models to uniaxial compression to compare yield strengths of surgically altered and unaltered specimens. METHODS: Biomechanical grade polyurethane foam was cut into 60 different 12 mm * 17 mm * 20 mm blocks. The foam had a density of 10 pounds per cubic foot, simulating osteoporotic bone. Rectangular prism (4 mm * 4 mm * 6 mm) and cylindrical cores (r = 2 mm, h = 8 mm) were removed from 20 blocks per group. Twenty samples were left intact as a control group. Anterior plate screws were applied to the models and a Polyether ether ketone (PEEK) interbody spacer was placed on top. Samples underwent uniaxial compression at 0.1 mm/s until mechanical failure. Points of structural failure were determined using a 0.1% offset on a force-displacement curve and compared to determine the reductions in compressive strength. RESULTS: The mean force eliciting structural failure for intact samples was 450.6 N. Average failure forces for rectangular prisms and cylindrical cores removed were 383.2 and 395.4 N, respectively. Removal of a rectangular prismatic core of the necessary volume resulted in a 15.0% reduction in compressive strength, while removal of a cylindrical core of comparable volume facilitated a reduction of 12.2%. CONCLUSION: Local autograft harvested from adjacent vertebrae reduces morbidity associated with a second surgical site while minimally reducing the compressive strength of the donor vertebra in an osteopenic model, lending credence to the efficacy of this technique in elderly patient populations. PMID- 28835869 TI - Comminuted Patella Fracture in Elderly Patients: A Systematic Review and Case Report. AB - OBJECTIVES: To review comminuted patella fracture in the elderly patients and examine the surgical options to avoid complications such as fixation failure and poor functional outcome. To provide an example of mesh augmentation in comminuted patella fracture in the elderly patients. DATA SOURCES: A literature review was conducted by the authors independently using Ovid, Medline, Cochrane, PubMed, and Clinical Key in English. We aimed to review data on patients older than 65 with comminuted patella fracture. Search conducted between July and December 2015. STUDY SELECTION: Search terms included patella fracture, elderly, and fixation failure. Abstracts were included if they were a case report, cohort series, or randomized control trial. Further inclusion criteria were that they were available in full text and included patient age(s), operative details, follow-up, and outcome discussion. DATA EXTRACTION: Each study was assessed according to its level of evidence, number of patients, age of patients, fracture patterns described, complications of treatment, and results summarized. DATA SYNTHESIS: Paucity of data and heterogeneity of studies limited statistical analysis. Data are presented as a review table with the key points summarized. CONCLUSION: In patella fracture, age >65 years and comminuted fracture pattern are predictors of increased fixation failure and postoperative stiffness, warranting special consideration. There is a trend toward improved functional outcomes when augmented fixation using mesh or plates is used in this group. Further level 1 studies are required to compare and validate new treatment options and compared them to standard surgical technique of tension band wire construct. PMID- 28835870 TI - Preoperative Factors Influencing Decision Between Hemiarthroplasty and Total Hip Arthroplasty in Femoral Neck Fractures in Indian Patients-Retrospective Single Center Study. AB - INTRODUCTION: The percentage of elderly population is increasing worldwide, with increasing incidence of femoral neck fractures. An increasing trend of arthroplasty for femoral neck fracture is observed. We aim to retrospectively analyze the preoperative factors that seem to influence the decision between hemiarthroplasty and total hip arthroplasty for managment of the same. MATERIALS AND METHODS: Patients admitted with femoral neck fracture during January 2010 to March 2015 in our institute were included in the study. The preinjury independency status was assessed using Katz index scoring system. Based on the data obtained from case sheets, the patients were segregated into hemiarthroplasty group and total hip arthroplasty group. Variables that preferentially appeared in the individual group were identified. RESULTS: A total of 206 hips of 199 patients were included in the study. The factors that seem to influence the decision between hemiarthroplasty and total hip arthroplasty with a statistical significance were age, Katz index score, and American Society of Anesthesiologists (ASA) grade. Higher ASA grades caused delay in surgery, increasing the length of hospital stay, and these patients more commonly underwent hemiarthroplasty. DISCUSSION: Patients' preinjury functional status influenced the decision between hemiarthroplasty and total hip arthroplasty, especially in the age between 65 and 80 years. Preoperative comorbidities did not prevent the patient from undergoing total hip replacement due to early optimization for surgery with the help of the dedicated orthogeriatric team. CONCLUSION: We conclude that preinjury functional independency of a patient is an important decisive factor in the choice between hemiarthroplasty and total hip arthroplasty. In addition to other factors including age and comorbidity pattern, scoring methods for preinjury functional status of patient could aid in decision making. Early optimization, early surgery, and faster rehabilitation help the patients to achieve their preinjury functional status. PMID- 28835871 TI - Multimodal Pain Management in Older Elective Arthroplasty Patients. AB - BACKGROUND: Pain management after elective arthroplasty in older adults is complicated due to the risk of undertreatment of postoperative pain and potential adverse effects from analgesics, notably opioids. Using combinations of analgesics has been proposed as potentially beneficial to achieve pain control with lower opioid doses. OBJECTIVE: We compared a multimodal pain protocol with a traditional one, in older elective arthroplasty patients, measuring self-rated pain, incidence of postoperative delirium, quantity and cost of opioid analgesics consumed. METHODS: One hundred fifty-eight patients, 70 years and older, admitted to tertiary care for elective arthroplasty were prospectively assessed postoperative days 1-3. Patients received either traditional postoperative analgesia (acetaminophen plus opioids) or a multimodal pain protocol (acetaminophen, opioids, gabapentin, celecoxib), depending on surgeon preference. Self-rated pain, postoperative delirium, and time to achieve standby-assist ambulation were compared, as were total opioid doses and analgesic costs. RESULTS: Despite receiving significantly more opioid analgesics (traditional: 166.4 mg morphine-equivalents; multimodal: 442 mg morphine equivalents; t = 10.64, P < .0001), there was no difference in self-rated pain, delirium, or mobility on postoperative days 1-3. Costs were significantly higher in the multimodal group (t = 9.15, P < .0001). Knee arthroplasty was associated with higher pain scores than hip arthroplasty, with no significant difference in opioid usage. CONCLUSION: A multimodal approach to pain control demonstrated no benefit over traditional postoperative analgesia in elective arthroplasty patients, but with significantly higher amounts of opioid consumed. This poses a potential risk regarding tolerability in frail older adults and results in increased drug costs. PMID- 28835872 TI - Disparities in Total Hip Arthroplasty Versus Hemiarthroplasty in the Management of Geriatric Femoral Neck Fractures. AB - INTRODUCTION: Recent clinical evidence suggests that total hip arthroplasty (THA) provides improved clinical outcomes as compared to hemiarthroplasty (HA) for displaced femoral neck fractures in elderly individuals. However, THA is still utilized relatively infrequently. Few studies have evaluated the factors affecting utilization and the role socioeconomics plays in THA versus HA. METHODS: In the United States, the National Inpatient Sample (NIS) database was used to identify patients treated surgically for femoral neck fracture, between 2009 and 2010. Patients were identified using International Classification of Diseases, Ninth Revision, codes for closed, transcervical femoral neck fractures and closed fractures at unspecified parts of the femoral neck. All candidate predictors of THA versus HA were entered into a multilevel mixed-effect regression model. RESULTS: Older patient age, being Asian or Pacific Islander, and having Medicaid payer status were all associated with lower odds of receiving THA. Patients with private insurance including Health Maintenance organization (HMO) had higher odds of THA as did patients with other insurance. Odds of THA were significantly lower among patients in teaching hospitals and higher at hospitals with greater THA volume. DISCUSSION: Ethnicity, payer status, hospital size, and institutional THA volume were all associated with the utilization of THA versus HA in the treatment of geriatric femoral neck fractures. LEVEL OF EVIDENCE: Level III Retrospective Cohort study. PMID- 28835873 TI - Hip Fractures in Centenarians: Has Care Improved in the National Hip Fracture Database Era? AB - INTRODUCTION: The number of centenarians in the United Kingdom is increasing. An associated increase in the incidence of hip fractures in the extreme elderly population is expected. The National Hip Fracture Database (NHFD) initiative was introduced in 2007 aiming to improve hip fracture care. There is a paucity of literature on the outcomes of centenarians with hip fractures since its introduction. The aim of this study is to report our experience of hip fractures in centenarians in the era since the introduction of the NHFD to assess outcomes in terms of mortality, time to surgery, length of stay, and complications. METHODS: A retrospective case note study of all centenarians managed for a hip fracture over a 7-year period at a London district general hospital. RESULTS: We report on 22 centenarians sustaining 23 hip fractures between 2008 and 2015. Twenty-one fractures were managed operatively. For patients managed operatively, in-hospital, 30-day, 3-month, 6-month, 1-year, 2-year, 3-year, and 5-year cumulative mortalities were 30%, 30%, 39%, 50%, 77%, 86%, 95%, and 100%, respectively. In-hospital mortality was 100% for those managed nonoperatively. Mean time to surgery was 1.6 days (range: 0.7-6.3 days). Mean length of stay on the acute orthopedic ward was 23 days (range: 2-51 days). Seventy-one percent had a postoperative complication most commonly a hospital-acquired pneumonia or urinary tract infection. CONCLUSION: Compared to a series of centenarians with hip fractures prior to the introduction of the NHFD, we report a reduced time to surgery. Mortality and hospital length of stay were similar. PMID- 28835874 TI - Testing the Hip Abductor Muscle Strength of Older Persons Using a Handheld Dynamometer. AB - OBJECTIVE: To investigate the reliability of a clinically applicable method of dynamometry to assess and monitor hip abductor muscle strength in older persons. DESIGN: Bilateral isometric hip abductor muscle strength measured with a handheld dynamometer, patients supine with the contralateral hip positioned directly against a wall for stabilization. Reliability determined by comparing intra assessor and inter-assessor results and comparison to a criterion standard (stabilized dynamometer with patients in the standing position). SETTING: UniSA Nutritional Physiology Research Centre. PARTICIPANTS: Twenty-one patients older than 65 years were recruited from the Royal Adelaide Hospital. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICCs), bias, and limits of agreement calculated to determine reliability. RESULTS: Intra-assessor and inter assessor ICCs were high (0.94 and 0.92-0.94, respectively). There was no intra assessor bias and narrow limits of agreement (+/-2.4%). There was a small inter assessor bias but narrow limits of agreement (0.6%-0.9% and +/- 2.3%, respectively). There was a wide variation comparing results to the criterion standard (+/-5.0%-5.2% limits of agreement), highlighting problems attributed to difficulties that the test population had with the standing position used in the criterion standard test. CONCLUSIONS: Testing older persons' hip abductor muscle strength while in the supine position with optimal pelvic stabilization using a handheld dynamometer is highly reliable. While further studies must be done to assess patients with specific pathologies, this test has potential application to monitor and evaluate the effects of surgical interventions and/or rehabilitation protocols for a variety of conditions affecting hip abductor function such as hip fractures and arthritis. PMID- 28835875 TI - Hip Fractures in Elderly People: Surgery or No Surgery? A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Increasing numbers of patients with hip fractures also have advanced comorbidities. A majority are treated surgically. However, a significantly increasing percentage of medically unfit patients with unacceptably high risk of perioperative death are treated nonoperatively. Important questions about patients' prefracture quality of life (QOL) and future perspectives should be asked before considering different treatment options to assess what kind of treatment is advisable in frail elderly high-risk patients with a hip fracture. OBJECTIVE: The aim of this review was to provide an overview of differences in mortality, health-related QOL [(HR)QOL], functional outcome, and costs between nonoperative management (NOM) and operative management (OM) of hip fractures in patients above 65 years. METHODS: A systematic literature search was performed in EMBASE, OvidSP, PubMed, Cochrane Central, and Web of Science for observational studies and trials. Observational studies and randomized controlled trials comparing NOM with OM in hip fracture patients were selected. The methodological quality of the selected studies was assessed according to the Methodological Index for Nonrandomized Studies (MINORS) or Furlan checklist. RESULTS: Seven observational studies were included with a total of 1189 patients, of whom 242 (20.3%) were treated conservatively. The methodological quality of the studies was moderate (mean: 14.7, standard deviation [SD]: 1.5). The 30-day and 1-year mortalities were higher in the nonoperative group (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 1.43-10.96; OR: 3.84, 95% CI: 1.57-9.41). None of the included studies compared QOL, functional outcome, or health-care costs between the 2 groups. CONCLUSION: This systematic review and meta-analysis demonstrated that only a few studies with small number of patients comparing NOM with OM were published. A significantly higher 30-day and 1-year mortality was revealed in nonoperatively treated hip fracture patients. No data were found examining (HR)QOL and costs. Further work is needed to enable shared decision-making and to initiate NOM in frail elderly patients with advanced comorbidity and limited life expectancy. PMID- 28835876 TI - Impacts of Robotic Compliance and Bone Bending on Simulated in vivo Knee Kinematics. AB - Robotic testing offers researchers the opportunity to quantify native tissue loads for the structures of the knee joint during activities of daily living. These loads may then be translated into design requirements for future treatments and procedures to combat the early onset of knee degeneration following an injury. However, high knee loads during testing have the potential to deflect a robotic end effector and cause inaccuracies in the applied kinematics. Furthermore, bone bending could also induce kinematic change. This study aimed to quantify the effects of robotic compliance and bone bending on the accuracy of simulated in vivo kinematics in a KUKA KRC210 serial robotic system. Six (6) human cadaver knees were subjected to cyclic human gait motion while 6 DOF forces and torques were recorded at the joint. A Vicon T-Series camera system was used to independently record the applied kinematics. Periods of highest kinematic deviation occurred during instances of low joint loading, suggesting negligible levels of forced deflection for simulations of moderate levels of activity while results of this small study indicate that high physiologic loading poses low risk of deviation from target kinematics, further testing is necessary to confirm. PMID- 28835877 TI - Colloidal quantum dot based solar cells: from materials to devices. AB - Colloidal quantum dots (CQDs) have attracted attention as a next-generation of photovoltaics (PVs) capable of a tunable band gap and low-cost solution process. Understanding and controlling the surface of CQDs lead to the significant development in the performance of CQD PVs. Here we review recent progress in the realization of low-cost, efficient lead chalcogenide CQD PVs based on the surface investigation of CQDs. We focus on improving the electrical properties and air stability of the CQD achieved by material approaches and growing the power conversion efficiency (PCE) of the CQD PV obtained by structural approaches. Finally, we summarize the manners to improve the PCE of CQD PVs through optical design. The various issues mentioned in this review may provide insight into the commercialization of CQD PVs in the near future. PMID- 28835878 TI - Managing crime through migration law in Australia and the United States: a comparative analysis. AB - This article examines the intertwining of migration law and criminal law - termed 'crimmigration' by scholars - in Australia and the United States of America, and its implications for non-citizens who engage in criminal conduct. Our comparison of the two systems demonstrates that the laws and policies in both jurisdictions are similar to a significant degree. Both have strong exclusionary policies characterised by sweeping visa cancellation/removal powers, a heavy focus on enforcement, and limited review rights. In Australia, legislative amendments in 2014 have given the executive greater powers to cancel visas and remove non citizens on character grounds as a means of ensuring national security and public safety. This has coincided with a new law enforcement body created within the Australian Department of Immigration. These changes reflect a repurposing of migration law as a tool for managing criminal threats based on the concept of 'risk management'. Drawing on the experience of the United States - where such a 'risk management' approach is entrenched - we query the utility of this shift and highlight the potential pitfalls of pursuing such a policy for Australia. PMID- 28835879 TI - 'Speaking Truth' Protects Underrepresented Minorities' Intellectual Performance and Safety in STEM. AB - We offer and test a brief psychosocial intervention, Speaking Truth to EmPower (STEP), designed to protect underrepresented minorities' (URMs) intellectual performance and safety in science, technology, engineering, and math (STEM). STEP takes a 'knowledge as power' approach by: (a) providing a tutorial on stereotype threat (i.e., a social contextual phenomenon, implicated in underperformance and early exit) and (b) encouraging URMs to use lived experiences for generating be prepared coping strategies. Participants were 670 STEM undergraduates [URMs (Black/African American and Latina/o) and non-URMs (White/European American and Asian/Asian American)]. STEP protected URMs' abstract reasoning and class grades (adjusted for grade point average [GPA]) as well as decreased URMs' worries about confirming ethnic/racial stereotypes. STEP's two-pronged approach-explicating the effects of structural 'isms' while harnessing URMs' existing assets-shows promise in increasing diversification and equity in STEM. PMID- 28835880 TI - Frequency of consumption of specific food items and symptoms of preeclampsia and eclampsia in Indian women. AB - BACKGROUND: Preeclampsia/eclampsia is responsible for upwards of 20% of maternal morbidity and mortality in developing countries. OBJECTIVE: We examined the relationship between frequency of food intake and symptoms of preeclampsia eclampsia and eclampsia among Indian women aged 15-49 (n = 39,657) for the most recent live birth in the 5 years preceding the National Family Health Survey-3 (2005-2006). Multiple logistic regression analysis was used to estimate the association between frequency of intake of specific food items, and self-reported symptoms of preeclampsia eclampsia and eclampsia, adjusting for maternal age, and other potential socio-demographic confounders. RESULTS: Daily consumption of milk or curd (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.81-0.96), green leafy vegetables, chicken/meat and weekly pulses/beans consumption are associated with substantially lower risk of preeclampsia eclampsia. Eclampsia risk is higher among those who consumed fruits (ORs ranges from 1.18 to 1.44) and chicken/meat occasionally (OR: 1.28; 95% CI: 1.11-1.48), and lower among those consuming vegetables daily. CONCLUSION: Frequency of consumption of specific food items is associated with occurrence of preeclampsia eclampsia and eclampsia symptoms in Indian women. PMID- 28835881 TI - Reasons for operation cancellations at a teaching hospital: prioritizing areas of improvement. AB - PURPOSE: To report rates of and reasons for operation cancellation, and to prioritize areas of improvement. METHODS: Retrospective data were extracted from the monthly reports of cancelled listed operations. Data on 14 theatres were collected by the office of quality assurance at Jordan University Hospital from August 2012 to April 2016. Rates and reasons for operation cancellation were investigated. A Pareto chart was constructed to identify the reasons of highest priority. RESULTS: During the period of study, 6,431 cases (9.31%) were cancelled out of 69,066 listed cases. Patient no-shows accounted for 62.52% of cancellations. A Pareto analysis showed that around 80% of the known reasons for cancellation after admission were due to a lack of surgical theatre time (30%), incomplete preoperative assessment (21%), upper respiratory tract infection (19%), and high blood pressure (13%). CONCLUSION: This study identified the most common reasons for operation cancellation at a teaching hospital. Potential avoidable root causes and recommended interventions were suggested accordingly. Future research, available resources, hospital policies, and strategic measures directed to tackle these reasons should take priority. PMID- 28835882 TI - Transoral endoscopic thyroidectomy for papillary thyroid microcarcinoma: initial experience of a single surgeon. AB - PURPOSE: Recently, transoral endoscopic thyroidectomy (TOET) is receiving attention because it is regarded as a true minimally invasive surgery in that it does not leave scars on any part of the body and the area of flap dissection is similar to that of open surgery. In this study, we present the surgical procedures and initial outcomes of TOET in the treatment of papillary thyroid microcarcinoma (PTMC) patients. METHODS: The medical records of patients who underwent TOET for PTMC between July 2016 and February 2017 were retrospectively reviewed. Indication of TOET was PTMC without capsular invasion or lymph node metastasis on preoperative imaging studies. RESULTS: Ten female patients were enrolled. Seven patients underwent thyroid lobectomy and three patients underwent isthmusectomy. The mean age and tumor size was 43.3 +/- 11.5 years and 0.6 +/- 0.2 cm, respectively. Operation time for lobectomy and isthmusectomy was 121.1 +/ 30.7 (range, 65-148) and 90.0 +/- 9.2 minutes (range, 82-100 minutes), respectively. The mean number of retrieved lymph nodes was 2.7 +/- 1.7. Two patients had transient vocal cord palsy, which recovered in three months. There was no case with subcutaneous emphysema, surgical site infection, postoperative bleeding, or mental nerve injury. CONCLUSION: TOET was feasible and could be performed safely for PTMC. TOET might become a new treatment option for the patients who do not want to leave visible scars on the body. PMID- 28835883 TI - Are prophylactic antibiotics necessary in elective laparoscopic cholecystectomy, regardless of patient risk? AB - PURPOSE: The average rate of surgical site infections (SSIs) for laparoscopic cholecystectomy (LC) has been reported in the literature to be between 0.4% and 6.3%. Also, these recent reviews have concluded that a prophylactic antibiotics for elective LCs in low-risk patients is not useful, but there were no results in high-risk patients. METHODS: The aim of this study was to investigate the role of a single dose of first-generation cephalosporin as a prophylactic antibiotic for patients undergoing elective LC, regardless of patient risk. This randomized clinical trial was conducted from October 2013 to December 2014 by single surgeon at our hospital. Patients were randomized into two groups by following method. Odd-numbered patients (group A) received 1-g cefazolin intravenously within 30 minutes before incision, whereas even-numbered patients (group B) received normal saline intravenously instead of prophylactic antibiotics, with the aim of including 100 patients in each group. SSIs were recorded and compared between the groups. RESULTS: There were no differences in preoperative demographics and postoperative findings between the groups. There were no superficial and deep SSIs in either group, 9 cases of superficial seromas developed (4.5%) in the cohort: 4 in group A (4%) and 5 in group B (5%). There were no significant associations between SSIs and the use of prophylactic antibiotics in either group. Additionally, the high-risk group did not show a significantly increased rate of SSIs. CONCLUSION: Based on our study, prophylactic antibiotics are not necessary in elective LC, regardless of patient risk. PMID- 28835884 TI - Comparative analysis of the same technique-the same surgeon approach in the surgical treatment of pilonidal sinus disease: a retrospective cohort study. AB - PURPOSE: Although there are several surgical methods for treatment of sacrococcygeal pilonidal sinus, there is no widespread consensus. In this study, we aimed to compare primary closure, Limberg, and modified Limberg flap techniques, with each performed by each of 3 surgeons. METHODS: A total of 802 patients who were operated on for pilonidal sinus disease were included in this retrospective cohort study. Patients were evaluated in 3 groups: group 1 (limited excision + primary closure), group 2 (large excision + Limberg flap technique), and group 3 (large excision + modified Limberg technique). Development of early or late period complications was accepted as primary outcome. RESULTS: Mean patient age was 28.1 +/- 6.7 years. Operation time in group 1 was 44.0 +/- 14.5 minutes, and was shorter in comparison to other 2 groups (P < 0.001). One or more complications developed in 171 patients (21.3%) within study group. Highest complication rate was in group 1, with a rate of 30.7% (P < 0.001). Rate of wound dehiscence and recurrence in group 1 were differed significantly from other groups (P < 0.001 and P = 0.001, respectively). CONCLUSION: Based on the same technique-the same surgeon approach, comparison of surgical methods for treatment of pilonidal sinus showed that modified Limberg and Limberg techniques are superior to primary closure technique in terms of general complication, wound dehiscence, and recurrence rates. PMID- 28835885 TI - Meaningful standard of reference for appendiceal perforation: pathology, surgery, or both? AB - PURPOSE: This retrospective study was aimed to determine if appendiceal perforation identified pathologically but not surgically is clinically meaningful. METHODS: The study consists of 2 parts. First, we reviewed 74 studies addressing appendiceal perforation published in 2012 and 2013. Second, in a cross sectional study, we classified 1,438 adolescents and adults (mean age, 29.3 +/- 8.4 years; 785 men) with confirmed appendicitis as "nonperforation" (n = 1,083, group 1), "pathologically-identified perforation" (n = 55, group 2), "surgically identified perforation" (n = 202, group 3), or "pathologically- and surgically identified perforation" (n = 98, group 4). The 4 groups were compared for the frequency of laparoscopic appendectomy and the length of hospital stay using multivariable logistic regression analyses. RESULTS: The reference standard for appendiceal perforation was frequently missing or inconsistent in the previous studies. Laparoscopic appendectomies were less frequent in groups 3 (52.5%, P = 0.001) and 4 (65%, P = 0.040) than in group 1 (70.7%), while group 2 (73%, P = 0.125) did not significantly differ from group 1. Median hospital stays were 2.9, 3.0, 5.1, and 6.0 days for groups 1-4, respectively. Prolonged hospital stay (>=3.7 days) was more frequent in groups 3 (77.7%, P < 0.001) and 4 (89%, P < 0.001) than in group 1 (23.4%), while group 2 (35%, P = 0.070) did not significantly differ from group 1. CONCLUSION: We recommend using surgical rather than pathologic findings as the reference standard for the presence of appendiceal perforation in future investigations. PMID- 28835886 TI - Early experience of transilluminated cryosurgery for varicose vein with saphenofemoral reflux: review of 84 patients (131 limbs). AB - PURPOSE: Varicose veins with great saphenous vein (GSV) insufficiency is prevalent. Among various surgical treatments for varicose veins, cryosurgery of GSV is an alternative minimally invasive technique that could leave fewer scars and replace conventional stripping with ambulatory phlebectomy. This study sought to assess outcomes including efficacy and safety of cryosurgery for varicose veins. METHODS: One hundred thirty-one limbs in 84 patients (37 male, 47 female; mean age, 53.3 years) with varicose veins were treated with cryosurgery over a 2 year period. The patients were followed for postoperative complication with surveillance of recurrence. The analyzed variables included age, sex, symptom, operative time (from skin incision to the application of elastic bandages on the legs for compression purposes), and postoperative complications including bruising, hematoma, superficial thrombophlebitis, cellulitis, seroma, cutaneous nerve damage, and wound complication. RESULTS: The mean operative time was 64.7 minutes for both limbs and 44 minutes for single limbs. The median number of incisions was 2. For stripping of GSV, one incision at the groin was necessary. Postoperative complications included an episode of hematoma in 3 limbs (2.3%), cutaneous nerve damage in 3 limbs (2.3%), cellulitis in 2 patients (1.5%), and seroma in 1 limb (0.8%). No wound infection, thrombophlebitis or deep venous thrombosis was observed. During follow-up (mean follow-up period, 13.5 months; range, 3-28 months), there was no recurrence. CONCLUSION: Cryosurgery to treat varicose veins is an effective and safe treatment modality in terms of postoperative complication, cosmetic result, and recurrence. PMID- 28835887 TI - Validation of the Korean version of the walking impairment questionnaire in patients with peripheral arterial disease. AB - PURPOSE: Intermittent claudication is the most common early symptom of peripheral arterial occlusive disease. Walking impairment questionnaire (WIQ) is a short, inexpensive, easy-to-complete questionnaire to assess intermittent claudication and can provide data of usual walking. The purpose of this study is to validate the new Korean version of WIQ. METHODS: Total 51 patients with claudication were enrolled. While 4 patients were dropped out, 47 patients with claudication into were divided groups based on the treatment received: surgery (n = 33) and medication (n = 14). The surgery group was subdivided into the bypass (n = 13) and intervention (n = 20) groups. WIQ score, ankle-brachial index (ABI), and treadmill test scores were assessed initially and after 12 weeks. RESULTS: The WIQ scores were significantly correlated with ABI and pain-free walking distance (PFWD) and maximum walking distance (MWD) in all groups (except for MWD in the intervention group). Speed and stair-climb scores (2 WIQ domains) were well correlated with ABI, PFWD, and MWD. Distance scores were mostly correlated with ABI, PFWD, and MWD in all groups except ABI in the bypass and intervention groups and MWD in the bypass group. Reproducibility was observed in all groups (intraclass correlation coefficient > 0.8). CONCLUSION: The Korean version of the WIQ is valid and reproducible, and can be effectively used to assess Korean patients with intermittent claudication. PMID- 28835888 TI - Primary hepatic peripheral T-cell lymphoma mimicking hepatocellular carcinoma: a case report. AB - Peripheral T-cell lymphomas (PTCLs) are aggressive neoplasms which may involve the liver. The imaging manifestations of hepatic lymphoma are highly variable and show overlapping appearances of numerous other hepatic diseases. As the management and prognosis of lymphoma differ markedly from those of other malignant diseases, prompt diagnosis and early effective treatment are very important. Here, we report an atypical case of primary PTCL not otherwise specified involving the liver that exhibited a solitary hepatic mass mimicking hepatocellular carcinoma (HCC) on CT. Liver biopsy is not commonly recommended in highly suspicious cases of HCC. However, in a patient without risk factors for HCC, consideration of other diagnostic possibilities is required and needle biopsy may be a more rational choice. An imaging approach, based on a careful review of clinical and laboratory findings is essential to prevent false-positive diagnosis of HCC and subsequent invasive treatment. PMID- 28835889 TI - Grey Turner's and Cullen's signs induced by spontaneous hemorrhage of the abdominal wall after coughing. AB - Grey Turner's and Cullen's signs are rare clinical signs, which most appear in patients with severe acute pancreatitis. The present patient complained of abdominal pain after coughing. However, contrast-enhanced CT revealed a hemorrhage of the abdominal wall. Therefore, spontaneous hemorrhage of the abdominal wall was diagnosed. The patient recovered through immobilization and hemostasis therapy. This case report and literature review aims to remind clinicians of manifestations and treatment of spontaneous hemorrhage. PMID- 28835890 TI - ERRATUM: Correction of funding statement in ACKNOWLEDGEMENTS section. Effectiveness of thymoquinone, zeolite, and platelet-rich plasma in model of corrosive oesophagitis induced in rats. AB - [This corrects the article on p. 396 in vol. 92, PMID: 28580343.]. PMID- 28835891 TI - Patient experience of lung volume reduction procedures for emphysema: a qualitative service improvement project. AB - The aim of this service improvement project was to gain understanding of the patient experience of lung volume reduction surgery (LVRS) and endobronchial valve (EBV) placement, from referral through to post-discharge care. Focus group interviews were carried out in two tertiary centres in London and Leicester, UK. Sixteen patients who had undergone lung volume reduction surgery (LVRS), endobronchial valve (EBV) placement, or both, were recruited. Prior to participation in each focus group, participants completed a questionnaire to guide and focus discussion. Thematic analysis identified common themes to the participant experience of receiving lung volume reduction interventions. Themes included patient focus on declining health and the need to "fight" for a referral; consequences of having procedures and potential unexpected complications; and vulnerability post discharge and limited continuity of care. Participants were clear that the benefits of having had either LVRS or EBV procedures outweighed any difficulties experienced. Participants were keen to have further similar interventions if appropriate. These data confirm the need to develop more systematic lung volume reduction pathways, provide appropriate information, and ensure that post-discharge care is optimal. PMID- 28835892 TI - Adipose Extracellular Matrix/Stromal Vascular Fraction Gel Secretes Angiogenic Factors and Enhances Skin Wound Healing in a Murine Model. AB - Mesenchymal stem cells are an attractive cell type for cytotherapy in wound healing. The authors recently developed a novel, adipose-tissue-derived, injectable extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel) for stem cell therapy. This study was designed to assess the therapeutic effects of ECM/SVF-gel on wound healing and potential mechanisms. ECM/SVF-gel was prepared for use in nude mouse excisional wound healing model. An SVF cell suspension and phosphate-buffered saline injection served as the control. The expression levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and monocyte chemotactic protein-1 (MCP-1) in ECM/SVF-gel were analyzed at different time points. Angiogenesis (tube formation) assays of ECM/SVF-gel extracts were evaluated, and vessels density in skin was determined. The ECM/SVF gel extract promoted tube formation in vitro and increased the expression of the angiogenic factors VEGF and bFGF compared with those in the control. The expression of the inflammatory chemoattractant MCP-1 was high in ECM/SVF-gel at the early stage and decreased sharply during the late stage of wound healing. The potent angiogenic effects exerted by ECM/SVF-gel may contribute to the improvement of wound healing, and these effects could be related to the enhanced inflammatory response in ECM/SVF-gel during the early stage of wound healing. PMID- 28835893 TI - Male Partners of Infertile Couples with Seminal Infections of Human Papillomavirus Have Impaired Fertility Parameters. AB - Several studies have addressed the impact of viral infections on male infertility. However, it is still unknown whether human papillomavirus (HPV) can alter seminal parameters. The aim of this study was to determine the prevalence of HPV in the semen of male partners of couples seeking fertility evaluation. Additionally, we assessed the possibility that HPV infections affect seminal parameters. A total of 229 semen samples were collected from men in the Sperm Analysis Section of Sao Camilo Laboratory of Maringa, Brazil, between October 2015 and March 2016. Basic seminal parameters were analyzed, and HPV was detected and genotyped by polymerase chain reaction. HPV DNA was detected in 16.6% of samples. Of these, 10.5% had single type HPV infections, 6.1% had multiple HPV infections, 5.7% had exclusively high-risk HPV, and 6.1% had exclusively low-risk HPV. Samples positive for single and multiple types of HPV were associated with abnormal viscosity, and samples positive for multiple HPV types were also associated with hypospermia, higher pH, and increased leukocyte numbers. These findings suggest that the male partners of infertile couples with seminal HPV infections may have prostate disturbances indicative of glandular dysfunction, which may influence fertility. PMID- 28835894 TI - Prognostic Assessment and Management of Liver Cirrhosis. PMID- 28835896 TI - Long Noncoding RNAs Act as Novel Biomarkers for Hepatocellular Carcinoma: Progress and Prospects. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and confers a poor prognosis. Novel diagnostic or prognostic biomarkers and effective therapeutic targets for HCCs are urgently needed. Currently, dozens of long noncoding RNAs (lncRNAs) have been identified as playing critical roles in cancer development and progression. Advanced studies have shown that several well-known lncRNAs are dysregulated in HCC tissue as compared to adjacent noncancerous tissue. Furthermore, highly stable cell-free circulating nucleic acids (cfCNAs), including lncRNAs, aberrantly expressed in the plasma of HCC patients, have been detected. In this review, we focus on the most extensively investigated lncRNAs in HCC and discuss the potential of HCC-related lncRNAs as novel biomarkers for early diagnosis and prognosis. PMID- 28835895 TI - Antiangiogenic Therapy for Diabetic Nephropathy. AB - Angiogenesis has been shown to be a potential therapeutic target for early stages of diabetic nephropathy in a number of animal experiments. Vascular endothelial growth factor (VEGF) is the main mediator for abnormal angiogenesis in diabetic glomeruli. Although beneficial effects of anti-VEGF antibodies have previously been demonstrated in diabetic animal experiments, recent basic and clinical evidence has revealed that the blockade of VEGF signaling resulted in proteinuria and renal thrombotic microangiopathy, suggesting the importance of maintaining normal levels of VEGF in the kidneys. Therefore, antiangiogenic therapy for diabetic nephropathy should eliminate excessive glomerular angiogenic response without accelerating endothelial injury. Some endogenous antiangiogenic factors such as endostatin and tumstatin inhibit overactivation of endothelial cells but do not specifically block VEGF signaling. In addition, the novel endothelium derived antiangiogenic factor vasohibin-1 enhances stress tolerance and survival of the endothelial cells, while inhibiting excess angiogenesis. These factors have been demonstrated to suppress albuminuria and glomerular alterations in a diabetic mouse model. Thus, antiangiogenic therapy with promising candidates will possibly improve renal prognosis in patients with early stages of diabetic nephropathy. PMID- 28835897 TI - Clinical and Pathological Variation of Charcot-Marie-Tooth 1A in a Large Chinese Cohort. AB - Charcot-Marie-Tooth 1A (CMT1A) caused by peripheral myelin protein 22 (PMP22) gene duplication is the most common form of hereditary polyneuropathy. Twenty four genetically confirmed CMT1A patients with sural nerve biopsies were enrolled in this study. The clinical picture included a great variability of phenotype with mean onset age of 22.2 +/- 14.5 years (1-55 years). Pathologically, we observed a severe reduction in myelinated fiber density showing three types of changes: pure onion bulb formation in 3 cases (12.5%), onion bulb formation with axonal sprouts in 10 cases (41.7%), and focally thickened myelin with onion bulb formation or/and axonal sprouts in 11 cases (45.8%). We observed no significant correlation between nerve fiber density and disease duration. There was no significant difference between the 3 pathological types in terms of clinical manifestations, nerve fiber density, and g-ratio. Our study indicates that there is marked variability in the age of onset of CMT1A, as well as significant pathological changes without deterioration with the development of the disease. Focally thickened myelin is another common morphological feature of demyelination. PMID- 28835898 TI - Chronic Effects of Resistance Training in Breast Cancer Survivors. AB - Objective. To analyse effects of resistance training (RT) in breast cancer survivors (BCS) and how protocols and acute variables were manipulated. Methods. Search was made at PubMed, Science Direct, and LILACS. All articles published between 2000 and 2016 were considered. Studies that met the following criteria were included: written in English, Spanish, or Portuguese; BCS who have undergone surgery, chemotherapy, and/or radiotherapy; additional RT only; analysis of muscle performance, body mass composition (BMC), psychosocial parameters, or blood biomarkers. Results. Ten studies were included. PEDro score ranged from 5 to 9. Rest interval and cadence were not reported. Two studies reported continuous training supervision. All reported improvements in muscle strength, most with low or moderate effect size (ES), but studies performed with high loads presented large ES. Five described no increased risk or exacerbation of lymphedema. Most studies that analysed BMC showed no relevant changes. Conclusions. RT has been shown to be safe for BCS, with no increased risk of lymphedema. The findings indicated that RT is efficient in increasing muscle strength; however, only one study observed significant changes in BMC. An exercise program should therefore consider the manipulation of acute and chronic variables of RT to obtain optimal results. PMID- 28835900 TI - Dietary Genistein Influences Number of Acetylcholine Receptors in Female Diabetic Jejunum. AB - BACKGROUND: Intestinal dysfunction in the ob/ob mouse model of diabetes mimics that seen clinically. METHODS: We determined the effects of a 4-week genistein diet (600 mg genistein/kg food) on intestinal function (contractility, morphology, AChR, and motility) in female ob/ob and lean mice. RESULTS: Contractility of the jejunum in response to incrementally increasing concentrations of KCl was comparable in ob/ob females and lean controls regardless of a genistein-diet. There were no changes in the wall thickness measured. We assessed the number of clusters of AChR in the jejunum wall; AChR were decreased by 48% in ob/ob mice versus leans, and the genistein diet reversed this. In utilizing a video-imaging system to evaluate gastrointestinal motility, we determined that the distance between consecutive contractile events was significantly increased by 1.87-fold in ob/ob mice versus leans, and the genistein diet was without effect. CONCLUSIONS: These data suggest that slowed intestinal transit in the diabetic ob/ob mouse may be due in part to decreased AChR and decreased contraction events occurring per unit time. A genistein diet rescues the number of AChR to levels of leans yet did not change the number of contractile events. Feeding ob/ob mice a genistein-rich diet has potential therapeutic benefits towards improving the debilitating diabetes-related gastrointestinal dysfunction. PMID- 28835899 TI - Acute Elevated Glucose Promotes Abnormal Action Potential-Induced Ca2+ Transients in Cultured Skeletal Muscle Fibers. AB - A common comorbidity of diabetes is skeletal muscle dysfunction, which leads to compromised physical function. Previous studies of diabetes in skeletal muscle have shown alterations in excitation-contraction coupling (ECC)-the sequential link between action potentials (AP), intracellular Ca2+ release, and the contractile machinery. Yet, little is known about the impact of acute elevated glucose on the temporal properties of AP-induced Ca2+ transients and ionic underlying mechanisms that lead to muscle dysfunction. Here, we used high-speed confocal Ca2+ imaging to investigate the temporal properties of AP-induced Ca2+ transients, an intermediate step of ECC, using an acute in cellulo model of uncontrolled hyperglycemia (25 mM, 48 h.). Control and elevated glucose-exposed muscle fibers cultured for five days displayed four distinct patterns of AP induced Ca2+ transients (phasic, biphasic, phasic-delayed, and phasic-slow decay); most control muscle fibers show phasic AP-induced Ca2+ transients, while most fibers exposed to elevated D-glucose displayed biphasic Ca2+ transients upon single field stimulation. We hypothesize that these changes in the temporal profile of the AP-induced Ca2+ transients are due to changes in the intrinsic excitable properties of the muscle fibers. We propose that these changes accompany early stages of diabetic myopathy. PMID- 28835901 TI - Beneficial Effects of Prebiotic Saccharomyces cerevisiae Mannan on Allergic Asthma Mouse Models. AB - One of the unmet needs for asthma management is a new therapeutic agent with both anti-inflammatory and anti-smooth muscle (ASM) remodeling effects. The mannose receptor (MR) family plays an important role in allergen uptake and processing of major allergens Der p 1 and Fel d 1. We have previously reported that ASM cells express a mannose receptor (ASM-MR) and that mannan derived from Saccharomyces cerevisiae (SC-MN) inhibits mannosyl-rich lysosomal hydrolase-induced bovine ASM cell proliferation. Using a humanized transgenic mouse strain (huASM-MRC2) expressing the human MRC2 receptor in a SM tissue-specific manner, we have demonstrated that ASM hyperplasia/hypertrophy can occur as early as 15 days after allergen challenge in this mouse model and this phenomenon is preventable with SC MN treatment. This proof-of-concept study would facilitate future development of a potential asthma therapeutic agent with dual function of anti-inflammatory and anti-smooth muscle remodeling effects. PMID- 28835902 TI - The Microbiome in Connective Tissue Diseases and Vasculitides: An Updated Narrative Review. AB - OBJECTIVE: To provide a narrative review of the most recent data concerning the involvement of the microbiome in the pathogenesis of connective tissue diseases (CTDs) and vasculitides. METHODS: The PubMed database was searched for articles using combinations of words or terms that included systemic lupus erythematosus, systemic sclerosis, autoimmune myositis, Sjogren's syndrome, undifferentiated and mixed CTD, vasculitis, microbiota, microbiome, and dysbiosis. Papers from the reference lists of the articles and book chapters were reviewed, and relevant publications were identified. Abstracts and articles written in languages other than English were excluded. RESULTS: We found some evidence that dysbiosis participates in the pathogenesis of systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, and Behcet's disease, but there are still few data concerning the role of dysbiosis in other CTDs or vasculitides. CONCLUSIONS: Numerous studies suggest that alterations in human microbiota may be involved in the pathogenesis of inflammatory arthritides as a result of the aberrant activation of the innate and adaptive immune responses. Only a few studies have explored the involvement of dysbiosis in other CTDs or vasculitides, and further research is needed. PMID- 28835903 TI - Flow Cytometric Analysis of Drug-induced HIV-1 Transcriptional Activity in A2 and A72 J-Lat Cell Lines. AB - The main obstacle to eradicating HIV-1 from patients is post-integration latency (Finzi et al., 1999). Antiretroviral treatments target only actively replicating virus, while latent infections that have low or no transcriptional activity remain untreated (Sedaghat et al., 2007). A combination of antiretroviral treatments with latency-purging strategies may accelerate the depletion of latent reservoirs and lead to a cure (Geeraert et al., 2008). Current strategies to reactivate HIV-1 from latency include use of prostratin, a non-tumor-promoting phorbol ester (Williams et al., 2004), BET inhibitors (Filippakopoulos et al., 2010; Delmore et al., 2011), and histone deacetylase (HDAC) inhibitors, such as suberoylanilidehydroxamic acid (i.e., SAHA or Vorinostat) (Kelly et al., 2003; Archin et al., 2009; Contreras et al., 2009; Edelstein et al., 2009). As the mechanisms of HIV-1 latency are diverse, effective reactivation may require combinatorial strategies (Quivy et al., 2002). The following protocol describes a flow cytometry-based method to quantify transcriptional activation of the HIV-1 long terminal repeat (LTR) upon drug treatment. This protocol is optimized for studying latently HIV-1-infected Jurkat (J-Lat) cell lines that contain a GFP cassette. J-Lats that contain a different reporter, for example Luciferase, can be treated with drugs as described but have to be analyzed differently. PMID- 28835904 TI - Expression and Purification of the Cas10-Csm Complex from Staphylococci. AB - CRISPR-Cas (Clustered regularly interspaced short palindromic repeats-CRISPR associated proteins) is a class of prokaryotic immune systems that degrade foreign nucleic acids in a sequence-specific manner. These systems rely upon ribonucleoprotein complexes composed of Cas nucleases and small CRISPR RNAs (crRNAs). Staphylococcus epidermidis and Staphylococcus aureus are bacterial residents on human skin that are also leading causes of antibiotic resistant infections (Lowy, 1998; National Nosocomial Infections Surveillance, 2004; Otto, 2009). Many staphylococci possess Type III-A CRISPR-Cas systems (Marraffini and Sontheimer, 2008; Cao et al., 2016), which have been shown to prevent plasmid transfer and protect against viral predators (Goldberg et al., 2014; Hatoum-Aslan et al., 2014; Samai et al., 2015) in these organisms. Thus, gaining a mechanistic understanding of these systems in the native staphylococcal background can lead to important insights into the factors that impact the evolution and survival of these pathogens. Type III-A CRISPR-Cas systems encode a five-subunit effector complex called Cas10-Csm (Hatoum-Aslan et al., 2013). Here, we describe a protocol for the expression and purification of Cas10-Csm from its native S. epidermidis background or a heterologous S. aureus background. The method consists of a two-step purification protocol involving Ni2+-affinity chromatography and a DNA affinity biotin pull-down, which together yield a pure preparation of the Cas10-Csm complex. This approach has been used previously to analyze the effects of mutations on Cas10-Csm complex integrity (Hatoum-Aslan et al., 2014), crRNA formation (Hatoum-Aslan et al., 2013), and to detect binding partners that directly interact with the core Cas10-Csm complex (Walker et al., 2016). Importantly, this approach can be easily adapted for use in other Staphylococcus species to probe and understand their native Type III-A CRISPR-Cas systems. PMID- 28835905 TI - In vitro Assay to Measure DNA Polymerase beta Nucleotide Insertion Coupled with the DNA Ligation Reaction during Base Excision Repair. AB - We previously reported that oxidized nucleotide insertion by DNA polymerase beta (pol beta) can confound the DNA ligation step during base excision repair (BER) (Caglayan et al., 2017). Here, we describe a method to investigate pol beta nucleotide insertion coupled with DNA ligation, in the same reaction mixture including dGTP or 8-oxo-dGTP, pol beta and DNA ligase l. This in vitro assay enables us to measure the products for correct vs. oxidized nucleotide insertion, DNA ligation, and ligation failure, i.e., abortive ligation products, as a function of reaction time. This protocol complements our previous publication and describes an efficient way to analyze activities of BER enzymes and the functional interaction between pol beta and DNA ligase I in vitro. PMID- 28835906 TI - Dense sgRNA Library Construction Using a Molecular Chipper Approach. AB - Genetic screens using single-guide-RNA (sgRNA) libraries and CRISPR technology have been powerful to identify genetic regulators for both coding and noncoding regions of the genome. Interrogating functional elements in noncoding regions requires sgRNA libraries that are densely covering, and ideally inexpensive, easy to implement and flexible for customization. We present a Molecular Chipper protocol for generating dense sgRNA libraries from genomic regions of interest. This approach utilizes a combination of random fragmentation and a Type III restriction enzyme to derive a dense coverage of sgRNA library from input DNA. PMID- 28835907 TI - Behavioral and Functional Assays for Investigating Mechanisms of Noxious Cold Detection and Multimodal Sensory Processing in Drosophila Larvae. AB - To investigate cellular, molecular and behavioral mechanisms of noxious cold detection, we developed cold plate behavioral assays and quantitative means for evaluating the predominant noxious cold-evoked contraction behavior. To characterize neural activity in response to noxious cold, we implemented a GCaMP6 based calcium imaging assay enabling in vivo studies of intracellular calcium dynamics in intact Drosophila larvae. We identified Drosophila class III multidendritic (md) sensory neurons as multimodal sensors of innocuous mechanical and noxious cold stimuli and to dissect the mechanistic bases of multimodal sensory processing we developed two independent functional assays. First, we developed an optogenetic dose response assay to assess whether levels of neural activation contributes to the multimodal aspects of cold sensitive sensory neurons. Second, we utilized CaMPARI, a photo-switchable calcium integrator that stably converts fluorescence from green to red in presence of high intracellular calcium and photo-converting light, to assess in vivo functional differences in neural activation levels between innocuous mechanical and noxious cold stimuli. These novel assays enable investigations of behavioral and functional roles of peripheral sensory neurons and multimodal sensory processing in Drosophila larvae. PMID- 28835908 TI - Photothrombotic Induction of Capillary Ischemia in the Mouse Cortex during in vivo Two-photon Imaging. AB - Photothrombosis of blood vessels refers to the activation of a circulating photosensitive dye with a green light to induce clotting in vivo (Watson et al., 1985). Previous studies have described how a focused green laser could be used to noninvasively occlude pial arterioles and venules at the brain surface (Schaffer et al., 2006; Nishimura et al., 2007; Shih et al., 2013). Here we show that small regions of the capillary bed can similarly be occluded to study the ischemic response within the capillary system of the mouse cerebral cortex. The advantage of this approach is that the ischemic zone is restricted to a diameter of approximately 150-250 MUm. This permits higher quality two-photon imaging of degenerative processes that would be otherwise difficult to visualize with models of large-scale stroke, due to excessive photon scattering. A consequence of capillary occlusion is leakage of the blood-brain barrier (BBB). Here, through the use of two-photon imaging data sets, we show how to quantify capillary leakage by determining the spatial extent and localization of intravenous dye extravasation. PMID- 28835909 TI - Assay to Measure Interactions between Purified Drp1 and Synthetic Liposomes. AB - A mitochondrion is a dynamic intracellular organelle that actively divides and fuses to control its size, number and shape in cells. A regulated balance between mitochondrial division and fusion is fundamental to the function, distribution and turnover of mitochondria (Roy et al., 2015). Mitochondrial division is mediated by dynamin-related protein 1 (Drp1), a mechano-chemical GTPase that constricts mitochondrial membranes (Tamura et al., 2011). Mitochondrial membrane lipids such as phosphatidic acid and cardiolipin bind Drp1, and Drp1-phospholipid interactions provide key regulatory mechanisms for mitochondrial division (Montessuit et al., 2010; Bustillo-Zabalbeitia et al., 2014; Macdonald et al., 2014; Stepanyants et al., 2015; Adachi et al., 2016). Here, we describe biochemical experiments that quantitatively measure interactions of Drp1 with lipids using purified recombinant Drp1 and synthetic liposomes with a defined set of phospholipids. This assay makes it possible to define the specificity of protein-lipid interaction and the role of the head group and acyl chains. PMID- 28835910 TI - Reintegration of Women Post Obstetric Fistula Repair: Experience of Family Caregivers. AB - In northern Ghana, families traditionally function as the main provider of care. The role of family, however, is becoming increasingly challenged with the social shifts in Ghanaian culture moving from extended kinship to nuclear households. This has implications for the care of women post obstetric fistula (OF) repair and their family members who assist them to integrate back into their lives prior to developing the condition. This research is part of a larger critical ethnographic study which explores a culture of reintegration. For this article, we draw attention to the findings related to the experience of family caregivers who care for women post OF repair in northern Ghana. It is suggested that although family caregivers are pleased to have their family member return home, there are many unanticipated physical, emotional, and economic challenges. Findings lead to recommendations for enhancing the reintegration process and the need for adequate caregiving support. PMID- 28835912 TI - Use of the Bayley Scales of Infant and Toddler Development, Third Edition, to Assess Developmental Outcome in Infants and Young Children in an Urban Setting in South Africa. AB - BACKGROUND: The Bayley Scales of Infant and Toddler Development (III) is a tool developed in a Western setting. AIM: To evaluate the development of a group of inner city children in South Africa with no neonatal risk factors using the Bayley Scales of Infant and Toddler Development (III), to determine an appropriate cut-off to define developmental delay, and to establish variation in scores done in the same children before and after one year of age. METHODS: Cohort follow-up study. RESULTS: 74 children had at least one Bayley III assessment at a mean age of 19.4 months (95% CI 18.4 to 20.4). The mean composite cognitive score was 92.2 (95% CI 89.4 to 95.0), the mean composite language score was 94.8 (95% CI 92.5 to 97.1), and mean composite motor score was 98.8 (95% CI 96.8 to 101.0). No child had developmental delay using a cut-off score of 70. In paired assessments above and below one year of age, the cognitive score remained unchanged, the language score decreased significantly (p = 0.001), and motor score increased significantly (p = 0.004) between the two ages. CONCLUSION: The Bayley Scales of Infant and Toddler Development (III) is a suitable tool for assessing development in urban children in southern Africa. PMID- 28835911 TI - Perceptions of Adolescent Pregnancy Among Teenage Girls in Rakai, Uganda. AB - The leading causes of death and disability among Ugandan female adolescents aged 15 to 19 years are pregnancy complications, unsafe abortions, and childbirth. Despite these statistics, our understanding of how girls perceive adolescent pregnancy is limited. This qualitative study explored the social and contextual factors shaping the perceptions of adolescent pregnancy and childbirth among a sample of 12 currently pregnant and 14 never pregnant girls living in the rural Rakai District of Uganda. Interviews were conducted to elicit perceived risk factors for pregnancy, associated community attitudes, and personal opinions on adolescent pregnancy. Findings indicate that notions of adolescent pregnancy are primarily influenced by perceptions of control over getting pregnant and readiness for childbearing. Premarital pregnancy was perceived as negative whereas postmarital pregnancy was regarded as positive. Greater understanding of the individual and contextual factors influencing perceptions can aid in development of salient, culturally appropriate policies and programs to mitigate unintended adolescent pregnancies. PMID- 28835913 TI - Modeling the Impact of Bed-Net Use and Treatment on Malaria Transmission Dynamics. AB - We modeled the impact of bed-net use and insecticide treated nets (ITNs), temperature, and treatment on malaria transmission dynamics using ordinary differential equations. To achieve this we formulated a simple model of mosquito biting rate that depends on temperature and usage of insecticides treated bed nets. We conducted global uncertainty and sensitivity analysis using Latin Hypercube Sampling (LHC) and Partial Rank Correlation Coefficient (PRCC) in order to find the most effective parameters that affect malaria transmission dynamics. We established the existence of the region where the model is epidemiologically feasible. We conducted the stability analysis of the disease-free equilibrium by the threshold parameter. We found the condition for the existence of the endemic equilibrium and provided necessary condition for its stability. Our results show that the peak of mosquitoes biting rate occurs at a range of temperature values not on a single value as previously reported in literature. The results also show that the combination of treatment and ITNs usage is the most effective intervention strategy towards control and eradication of malaria transmissions. Sensitivity analysis results indicate that the biting rate and the mosquitoes death rates are the most important parameters in the dynamics of malaria transmission. PMID- 28835914 TI - The role of floridoside in osmoadaptation of coral-associated algal endosymbionts to high-salinity conditions. AB - The endosymbiosis between Symbiodinium dinoflagellates and stony corals provides the foundation of coral reef ecosystems. The survival of these ecosystems is under threat at a global scale, and better knowledge is needed to conceive strategies for mitigating future reef loss. Environmental disturbance imposing temperature, salinity, and nutrient stress can lead to the loss of the Symbiodinium partner, causing so-called coral bleaching. Some of the most thermotolerant coral-Symbiodinium associations occur in the Persian/Arabian Gulf and the Red Sea, which also represent the most saline coral habitats. We studied whether Symbiodinium alter their metabolite content in response to high-salinity environments. We found that Symbiodinium cells exposed to high salinity produced high levels of the osmolyte 2-O-glycerol-alpha-d-galactopyranoside (floridoside), both in vitro and in their coral host animals, thereby increasing their capacity and, putatively, the capacity of the holobiont to cope with the effects of osmotic stress in extreme environments. Given that floridoside has been previously shown to also act as an antioxidant, this osmolyte may serve a dual function: first, to serve as a compatible organic osmolyte accumulated by Symbiodinium in response to elevated salinities and, second, to counter reactive oxygen species produced as a consequence of potential salinity and heat stress. PMID- 28835915 TI - Seismic evidence for complex sedimentary control of Greenland Ice Sheet flow. AB - The land-terminating margin of the Greenland Ice Sheet has slowed down in recent decades, although the causes and implications for future ice flow are unclear. Explained originally by a self-regulating mechanism where basal slip reduces as drainage evolves from low to high efficiency, recent numerical modeling invokes a sedimentary control of ice sheet flow as an alternative hypothesis. Although both hypotheses can explain the recent slowdown, their respective forecasts of a long term deceleration versus an acceleration of ice flow are contradictory. We present amplitude-versus-angle seismic data as the first observational test of the alternative hypothesis. We document transient modifications of basal sediment strengths by rapid subglacial drainages of supraglacial lakes, the primary current control on summer ice sheet flow according to our numerical model. Our observations agree with simulations of initial postdrainage sediment weakening and ice flow accelerations, and subsequent sediment restrengthening and ice flow decelerations, and thus confirm the alternative hypothesis. Although simulated melt season acceleration of ice flow due to weakening of subglacial sediments does not currently outweigh winter slowdown forced by self-regulation, they could dominate over the longer term. Subglacial sediments beneath the Greenland Ice Sheet must therefore be mapped and characterized, and a sedimentary control of ice flow must be evaluated against competing self-regulation mechanisms. PMID- 28835916 TI - The evolutionary basis of premature migration in Pacific salmon highlights the utility of genomics for informing conservation. AB - The delineation of conservation units (CUs) is a challenging issue that has profound implications for minimizing the loss of biodiversity and ecosystem services. CU delineation typically seeks to prioritize evolutionary significance, and genetic methods play a pivotal role in the delineation process by quantifying overall differentiation between populations. Although CUs that primarily reflect overall genetic differentiation do protect adaptive differences between distant populations, they do not necessarily protect adaptive variation within highly connected populations. Advances in genomic methodology facilitate the characterization of adaptive genetic variation, but the potential utility of this information for CU delineation is unclear. We use genomic methods to investigate the evolutionary basis of premature migration in Pacific salmon, a complex behavioral and physiological phenotype that exists within highly connected populations and has experienced severe declines. Strikingly, we find that premature migration is associated with the same single locus across multiple populations in each of two different species. Patterns of variation at this locus suggest that the premature migration alleles arose from a single evolutionary event within each species and were subsequently spread to distant populations through straying and positive selection. Our results reveal that complex adaptive variation can depend on rare mutational events at a single locus, demonstrate that CUs reflecting overall genetic differentiation can fail to protect evolutionarily significant variation that has substantial ecological and societal benefits, and suggest that a supplemental framework for protecting specific adaptive variation will sometimes be necessary to prevent the loss of significant biodiversity and ecosystem services. PMID- 28835917 TI - Multiple-wavelength neutron holography with pulsed neutrons. AB - Local structures around impurities in solids provide important information for understanding the mechanisms of material functions, because most of them are controlled by dopants. For this purpose, the x-ray absorption fine structure method, which provides radial distribution functions around specific elements, is most widely used. However, a similar method using neutron techniques has not yet been developed. If one can establish a method of local structural analysis with neutrons, then a new frontier of materials science can be explored owing to the specific nature of neutron scattering-that is, its high sensitivity to light elements and magnetic moments. Multiple-wavelength neutron holography using the time-of-flight technique with pulsed neutrons has great potential to realize this. We demonstrated multiple-wavelength neutron holography using a Eu-doped CaF2 single crystal and obtained a clear three-dimensional atomic image around trivalent Eu substituted for divalent Ca, revealing an interesting feature of the local structure that allows it to maintain charge neutrality. The new holography technique is expected to provide new information on local structures using the neutron technique. PMID- 28835918 TI - Identifying time scales for violation/preservation of Stokes-Einstein relation in supercooled water. AB - The violation of the Stokes-Einstein (SE) relation D ~ (eta/T)-1 between the shear viscosity eta and the translational diffusion constant D at temperature T is of great importance for characterizing anomalous dynamics of supercooled water. Determining which time scales play key roles in the SE violation remains elusive without the measurement of eta. We provide comprehensive simulation results of the dynamic properties involving eta and D in the TIP4P/2005 supercooled water. This enabled the thorough identification of the appropriate time scales for the SE relation Deta/T. In particular, it is demonstrated that the temperature dependence of various time scales associated with structural relaxation, hydrogen bond breakage, stress relaxation, and dynamic heterogeneities can be definitely classified into only two classes. That is, we propose the generalized SE relations that exhibit "violation" or "preservation." The classification depends on the examined time scales that are coupled or decoupled with the diffusion. On the basis of the classification, we explain the physical origins of the violation in terms of the increase in the plateau modulus and the nonexponentiality of stress relaxation. This implies that the mechanism of SE violation is attributed to the attained solidity upon supercooling, which is in accord with the growth of non-Gaussianity and spatially heterogeneous dynamics. PMID- 28835920 TI - Mach-Zehnder interferometry using spin- and valley-polarized quantum Hall edge states in graphene. AB - Confined to a two-dimensional plane, electrons in a strong magnetic field travel along the edge in one-dimensional quantum Hall channels that are protected against backscattering. These channels can be used as solid-state analogs of monochromatic beams of light, providing a unique platform for studying electron interference. Electron interferometry is regarded as one of the most promising routes for studying fractional and non-Abelian statistics and quantum entanglement via two-particle interference. However, creating an edge-channel interferometer in which electron-electron interactions play an important role requires a clean system and long phase coherence lengths. We realize electronic Mach-Zehnder interferometers with record visibilities of up to 98% using spin- and valley-polarized edge channels that copropagate along a pn junction in graphene. We find that interchannel scattering between same-spin edge channels along the physical graphene edge can be used to form beamsplitters, whereas the absence of interchannel scattering along gate-defined interfaces can be used to form isolated interferometer arms. Surprisingly, our interferometer is robust to dephasing effects at energies an order of magnitude larger than those observed in pioneering experiments on GaAs/AlGaAs quantum wells. Our results shed light on the nature of edge-channel equilibration and open up new possibilities for studying exotic electron statistics and quantum phenomena. PMID- 28835919 TI - Carryover effects of larval exposure to different environmental bacteria drive adult trait variation in a mosquito vector. AB - Conditions experienced during larval development of holometabolous insects can affect adult traits, but whether differences in the bacterial communities of larval development sites contribute to variation in the ability of insect vectors to transmit human pathogens is unknown. We addressed this question in the mosquito Aedes aegypti, a major arbovirus vector breeding in both sylvatic and domestic habitats in Sub-Saharan Africa. Targeted metagenomics revealed differing bacterial communities in the water of natural breeding sites in Gabon. Experimental exposure to different native bacterial isolates during larval development resulted in significant differences in pupation rate and adult body size but not life span. Larval exposure to an Enterobacteriaceae isolate resulted in decreased antibacterial activity in adult hemolymph and reduced dengue virus dissemination titer. Together, these data provide the proof of concept that larval exposure to different bacteria can drive variation in adult traits underlying vectorial capacity. Our study establishes a functional link between larval ecology, environmental microbes, and adult phenotypic variation in a holometabolous insect vector. PMID- 28835922 TI - From the surface to the seafloor: How giant larvaceans transport microplastics into the deep sea. AB - Plastic waste is a pervasive feature of marine environments, yet little is empirically known about the biological and physical processes that transport plastics through marine ecosystems. To address this need, we conducted in situ feeding studies of microplastic particles (10 to 600 MUm in diameter) with the giant larvacean Bathochordaeus stygius. Larvaceans are abundant components of global zooplankton assemblages, regularly build mucus "houses" to filter particulate matter from the surrounding water, and later abandon these structures when clogged. By conducting in situ feeding experiments with remotely operated vehicles, we show that giant larvaceans are able to filter a range of microplastic particles from the water column, ingest, and then package microplastics into their fecal pellets. Microplastics also readily affix to their houses, which have been shown to sink quickly to the seafloor and deliver pulses of carbon to benthic ecosystems. Thus, giant larvaceans can contribute to the vertical flux of microplastics through the rapid sinking of fecal pellets and discarded houses. Larvaceans, and potentially other abundant pelagic filter feeders, may thus comprise a novel biological transport mechanism delivering microplastics from surface waters, through the water column, and to the seafloor. Our findings necessitate the development of tools and sampling methodologies to quantify concentrations and identify environmental microplastics throughout the water column. PMID- 28835921 TI - Adult-onset obesity is triggered by impaired mitochondrial gene expression. AB - Mitochondrial gene expression is essential for energy production; however, an understanding of how it can influence physiology and metabolism is lacking. Several proteins from the pentatricopeptide repeat (PPR) family are essential for the regulation of mitochondrial gene expression, but the functions of the remaining members of this family are poorly understood. We created knockout mice to investigate the role of the PPR domain 1 (PTCD1) protein and show that loss of PTCD1 is embryonic lethal, whereas haploinsufficient, heterozygous mice develop age-induced obesity. The molecular defects and metabolic consequences of mitochondrial protein haploinsufficiency in vivo have not been investigated previously. We show that PTCD1 haploinsufficiency results in increased RNA metabolism, in response to decreased protein synthesis and impaired RNA processing that affect the biogenesis of the respiratory chain, causing mild uncoupling and changes in mitochondrial morphology. We demonstrate that with age, these effects lead to adult-onset obesity that results in liver steatosis and cardiac hypertrophy in response to tissue-specific differential regulation of the mammalian target of rapamycin pathways. Our findings indicate that changes in mitochondrial gene expression have long-term consequences on energy metabolism, providing evidence that haploinsufficiency of PTCD1 can be a major predisposing factor for the development of metabolic syndrome. PMID- 28835923 TI - Correlation-induced superconductivity dynamically stabilized and enhanced by laser irradiation. AB - Studies on out-of-equilibrium dynamics have paved a way to realize a new state of matter. Superconductor-like properties above room temperatures recently suggested to be in copper oxides achieved by selectively exciting vibrational phonon modes by laser have inspired studies on an alternative and general strategy to be pursued for high-temperature superconductivity. We show that the superconductivity can be enhanced by irradiating laser to correlated electron systems owing to two mechanisms: First, the effective attractive interaction of carriers is enhanced by the dynamical localization mechanism, which drives the system into strong coupling regions. Second, the irradiation allows reaching uniform and enhanced superconductivity dynamically stabilized without deteriorating into equilibrium inhomogeneities that suppress superconductivity. The dynamical superconductivity is subject to the Higgs oscillations during and after the irradiation. Our finding sheds light on a way to enhance superconductivity that is inaccessible in equilibrium in strongly correlated electron systems. PMID- 28835924 TI - Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5. AB - Vomocytosis, or nonlytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date, the host signaling events that underpin expulsion remain entirely unknown. We use a targeted inhibitor screen to identify the MAP kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages, whereas stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host signaling regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies. PMID- 28835926 TI - Crystallization-induced emission enhancement: A novel fluorescent Au-Ag bimetallic nanocluster with precise atomic structure. AB - We report the first noble metal nanocluster with a formula of Au4Ag13(DPPM)3(SR)9 exhibiting crystallization-induced emission enhancement (CIEE), where DPPM denotes bis(diphenylphosphino)methane and HSR denotes 2,5-dimethylbenzenethiol. The precise atomic structure is determined by x-ray crystallography. The crystalline state of Au4Ag13 shows strong luminescence at 695 nm, in striking contrast to the weak emission of the amorphous state and hardly any emission in solution phase. The structural analysis and the density functional theory calculations imply that the compact C-H?pi interactions significantly restrict the intramolecular rotations and vibrations and thus considerably enhance the radiative transitions in the crystalline state. Because the noncovalent interactions can be easily modulated via varying the chemical environments, the CIEE phenomenon might represent a general strategy to amplify the fluorescence from weakly (or even non-) emissive nanoclusters. PMID- 28835925 TI - High-density array of ferroelectric nanodots with robust and reversibly switchable topological domain states. AB - The exotic topological domains in ferroelectrics and multiferroics have attracted extensive interest in recent years due to their novel functionalities and potential applications in nanoelectronic devices. One of the key challenges for these applications is a realization of robust yet reversibly switchable nanoscale topological domain states with high density, wherein spontaneous topological structures can be individually addressed and controlled. This has been accomplished in our work using high-density arrays of epitaxial BiFeO3 (BFO) ferroelectric nanodots with a lateral size as small as ~60 nm. We demonstrate various types of spontaneous topological domain structures, including center convergent domains, center-divergent domains, and double-center domains, which are stable over sufficiently long time but can be manipulated and reversibly switched by electric field. The formation mechanisms of these topological domain states, assisted by the accumulation of compensating charges on the surface, have also been revealed. These results demonstrated that these reversibly switchable topological domain arrays are promising for applications in high-density nanoferroelectric devices such as nonvolatile memories. PMID- 28835927 TI - Liquid crystalline cellulose-based nematogels. AB - Physical properties of composite materials can be pre-engineered by controlling their structure and composition at the mesoscale. However, approaches to achieving this are limited and rarely scalable. We introduce a new breed of self assembled nematogels formed by an orientationally ordered network of thin cellulose nanofibers infiltrated with a thermotropic nematic fluid. The interplay between orientational ordering within the nematic network and that of the small molecule liquid crystal around it yields a composite with highly tunable optical properties. By means of combining experimental characterization and modeling, we demonstrate submillisecond electric switching of transparency and facile responses of the composite to temperature changes. Finally, we discuss a host of potential technological uses of these self-assembled nematogel composites, ranging from smart and privacy windows to novel flexible displays. PMID- 28835928 TI - Impaired DNA replication derepresses chromatin and generates a transgenerationally inherited epigenetic memory. AB - Impaired DNA replication is a hallmark of cancer and a cause of genomic instability. We report that, in addition to causing genetic change, impaired DNA replication during embryonic development can have major epigenetic consequences for a genome. In a genome-wide screen, we identified impaired DNA replication as a cause of increased expression from a repressed transgene in Caenorhabditis elegans. The acquired expression state behaved as an "epiallele," being inherited for multiple generations before fully resetting. Derepression was not restricted to the transgene but was caused by a global reduction in heterochromatin associated histone modifications due to the impaired retention of modified histones on DNA during replication in the early embryo. Impaired DNA replication during development can therefore globally derepress chromatin, creating new intergenerationally inherited epigenetic expression states. PMID- 28835930 TI - Probing topology by "heating": Quantized circular dichroism in ultracold atoms. AB - We reveal an intriguing manifestation of topology, which appears in the depletion rate of topological states of matter in response to an external drive. This phenomenon is presented by analyzing the response of a generic two-dimensional (2D) Chern insulator subjected to a circular time-periodic perturbation. Because of the system's chiral nature, the depletion rate is shown to depend on the orientation of the circular shake; taking the difference between the rates obtained from two opposite orientations of the drive, and integrating over a proper drive-frequency range, provides a direct measure of the topological Chern number (nu) of the populated band: This "differential integrated rate" is directly related to the strength of the driving field through the quantized coefficient eta0 = nu/h2, where h = 2pi h is Planck's constant. Contrary to the integer quantum Hall effect, this quantized response is found to be nonlinear with respect to the strength of the driving field, and it explicitly involves interband transitions. We investigate the possibility of probing this phenomenon in ultracold gases and highlight the crucial role played by edge states in this effect. We extend our results to 3D lattices, establishing a link between depletion rates and the nonlinear photogalvanic effect predicted for Weyl semimetals. The quantized circular dichroism revealed in this work designates depletion rate measurements as a universal probe for topological order in quantum matter. PMID- 28835929 TI - Tunable chiral metal organic frameworks toward visible light-driven asymmetric catalysis. AB - A simple and effective strategy is developed to realize visible light-driven heterogeneous asymmetric catalysis. A chiral organic molecule, which only has very weak catalytic activity in asymmetric alpha-alkylation of aldehydes under visible light, is utilized as the ligand to coordinate with different types of metal ions, including Zn2+, Zr4+, and Ti4+, for construction of crystalline metal organic frameworks (MOFs). Impressively, when used as heterogeneous catalysts, all of the synthesized MOFs exhibit markedly enhanced activity. Furthermore, the asymmetric catalytic performance of these MOFs could be easily altered by selecting different metal ions, owing to the tunable electron transfer property between metal ions and chiral ligands. This work will provide a new approach for fabrication of heterogeneous catalysts and trigger more enthusiasm to conduct the asymmetric catalysis driven by visible light. PMID- 28835933 TI - flusight: interactive visualizations for infectious disease forecasts. PMID- 28835931 TI - T-cell Responses in Individuals Infected with Zika Virus and in Those Vaccinated Against Dengue Virus. AB - BACKGROUND: The outbreak of Zika virus (ZIKV) infection in Brazil has raised concerns that infection during pregnancy could cause microcephaly and other severe neurodevelopmental malformations in the fetus. The mechanisms by which ZIKV causes fetal abnormalities are largely unknown. The importance of pre infection with dengue virus (DENV), or other flaviviruses endemic to Brazil, remains to be investigated. It has been reported that antibodies directed against DENV can increase ZIKV infectivity by antibody dependent enhancement (ADE), suggesting that a history of prior DENV infection might worsen the outcome of ZIKV infection. METHODS: We used bioinformatics tools to design 18 peptides from the ZIKV envelope containing predicted HLA-I T-cell epitopes and investigated T cell cross-reactivity between ZIKV-infected individuals and DENV-vaccinated subjects by IFNgamma ELISPOT. RESULTS: Three peptides induced IFNgamma production in both ZIKV-infected subjects and in DENV-vaccinated individuals. Flow cytometry indicated that 1 ZIKV peptide induced a CD4+ T-cell response in DENV-vaccinated subjects. CONCLUSIONS: We demonstrated that vaccination against DENV induced a T cell response against ZIKV and identified one such CD4+ T-cell epitope. The ZIKV reactive CD4+ T cells induced by DENV vaccination and identified in this study could contribute to the appearance of cross-reactive antibodies mediating ADE. PMID- 28835934 TI - Causes of infertility in view of Iranian traditional medicine: A review. AB - Infertility is one of the most important reproductive health concerns in the conventional medicine. Iranian traditional medicine presents different viewpoints in this regard which they could be of benefit and a good guide for the society of medicine. This study sought to provide the comprehensive investigation on the causes of infertility according to Iranian traditional medicine for understanding of old sages' ideas and categorizing of the causes of infertility. In this narrative review, we searched causes of infertility in traditional medicine books and available articles in this field. Iranian traditional physicians have investigated the causes of infertility in couples and attributed them to male and female causes. They have divided the main causes of infertility in both sexes into structural and functional abnormalities, that both traditional medicine and conventional medicine have a lot of participations, but the traditional medicine believes holistic approach in the treatment of diseases and the involvement of all parts of the body particularly specialty board members (heart, liver, brain, ovary, and testicles) in the proper conduct activities in different parts of the body such as reproduction system. There is also special attention to temperament Mizaj disorders. Given the numerous commonalities existing between traditional and conventional medicine in categorizing the causes of infertility, Iranian traditional medicine methods can be applied as a complementary solution in infertility. It could be also subject to further research and investigation due to its opposition to modern medicine in some regards. PMID- 28835932 TI - Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression. AB - Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Using western blot analyses and quantitative real-time PCR (qPCR) we assessed the effects of five-weeks of chronic unpredictable stress (CUS) exposure on the expression of GABA synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin (CB), parvalbumin (PV) and calretinin (CR)), and neuropeptides co-expressed in GABAergic neurons (somatostatin (SST), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and cholecystokinin (CCK)) in the prefrontal cortex (PFC) and hippocampus (HPC) of rats. We also investigated the effects of corticosterone (CORT) and dexamethasone (DEX) exposure on these markers in vitro in primary cortical and hippocampal cultures. We found that CUS induced significant reductions of GAD67 protein levels in both the PFC and HPC of CUS exposed rats, but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely SST and NPY, in the PFC, suggesting these cell types may be selectively vulnerable to chronic stress. Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder. PMID- 28835935 TI - Protective effect of hydroalcoholic extract of Teucrium polium on diabetes induced testicular damage and serum testosterone concentration. AB - BACKGROUND: Diabetes has an adverse effect on spermatogenesis by rising oxidative stress. OBJECTIVE: The aim of this study was to investigate the effect of Teucrium Polium extract administration on spermatogenesis and testicular structure in diabetic rats induced with Streptozotocin. MATERIALS AND METHODS: 32 male Wistar rats were randomly divided into four groups (n=8/each): control group, diabetic group received distilled water, and two experimental groups included diabetic rats treated with 50 and 100 mg/body weigh of Teucrium Polium extract for 6 six weeks. After six weeks, the left testis had been removed and the morphometrical study was performed. Blood samples were collected from the ophthalmic veins of the rats and plasma levels of glucose and testosterone hormone were measured afterward. RESULTS: The reduction in diameters of the seminiferous tubules and thickening of the wall of the seminiferous tubules (p=0.05) were seen in diabetic rats. Also, the degenerative changes in cells arrangement have been observed. Statistical analysis showed the use of Teucrium Polium significantly improved the above disorders in treatment group (100 mg/BW) in contrast to the non treated diabetic group (p=0.05), but no significant difference was seen between the experimental group treated with 50 mg/BW of Teucrium polium and diabetic group (p=0.08). These data also revealed that treatment of diabetic rats with 100 mg/BW of Teucrium Polium extract significantly improves the change in serum glucose (p=0.001) and testosterone (p=0.03). CONCLUSION: The results of the present study indicate that diabetes produces degenerative changes in the testis of rats and administration of Teucrium polium reduces complications resulted from diabetes. PMID- 28835936 TI - N-acetyl cysteine in ovulation induction of PCOS women underwent intrauterine insemination: An RCT. AB - BACKGROUND: N-acetyl cysteine (NAC) was proposed as an adjuvant to clomiphene citrate for ovulation induction in patients with polycystic ovary syndrome (PCOS) without clomiphene citrate resistance. OBJECTIVE: To evaluate the effect of NAC on pregnancy rate in PCOS patients who were candidates for intrauterine insemination. MATERIALS AND METHODS: In this randomized clinical trial, 97 PCOS women aged 18-38 years were enrolled in two groups, randomly. For the case group (n=49), NAC (1.2 gr)+ clomiphene citrate (100 mg) + letrozole (5mg) were prescribed daily from the third day of menstruation cycle for five days. The control group (n=48) had the same drug regimen without NAC. In order to follicular development, recombinant human follicle stimulating hormone (r-hFSH; Gonal-F(r)) was injected on days of 7-11 menstrual cycles in all participants. When the follicle size was 18mm or more, 10000 IU human chorionic gonadotropin was injected intramuscular and the intrauterine insemination was performed after 34-36 hr. RESULTS: There were not significant differences between study groups regarding mean endometrial thickness (p=0.14), the mean number of mature follicles (p=0.20), and the pregnancy rate (p=0.09). CONCLUSION: NAC is ineffective in inducing or augmenting ovulation in PCOS patients who were candidates for intrauterine insemination and cannot be recommended as an adjuvant to CC in such patients. PMID- 28835937 TI - Leukemia inhibitory factor increases the proliferation of human endometrial stromal cells and expression of genes related to pluripotency. AB - BACKGROUND: Concerning the low population of human endometrial mesenchymal cells within the tissue and their potential application in the clinic and tissue engineering, some researches have been focused on their in vitro expansion. OBJECTIVE: The aim of this study was to evaluate the effect of leukemia inhibitory factor (LIF) as a proliferative factor on the expansion and proliferation of human endometrial stromal cells. MATERIALS AND METHODS: In this experimental study, the isolated and cultured human endometrial stromal cells from women at ovulatory phase aged 20-35 years, after fourth passage were divided into control and LIF-treated groups. In the experimental group, the endometrial cells were treated by 10 ng/ml LIF in culture media and the cultured cells without adding LIF considered as control group. Both groups were evaluated and compared for proliferation rate using MTT assay, for CD90 marker by flow cytometric analysis and for the expression of Oct4, Nanog, PCNA and LIFr genes using real-time RT-PCR. RESULTS: The proliferation rate of control and LIF treated groups were 1.17+/-0.17 and 1.61+/-0.06 respectively and there was a significant increase in endometrial stromal cell proliferation following in vitro treatment by LIF compared to control group (p=0.049). The rate of CD90 positive cells was significantly increased in LIF-treated group (98.96+/-0.37%) compared to control group (94.26+/-0.08%) (p=0.0498). Also, the expression ratio of all studied genes was significantly increased in the LIF-treated group compared to control group (p=0.0479). CONCLUSION: The present study showed that LIF has a great impact on proliferation, survival, and maintenance of pluripotency of human endometrial stromal cells and it could be applicable in cell therapies. PMID- 28835938 TI - Valproic acid induces histologic changes and decreases androgen receptor levels of testis and epididymis in rats. AB - BACKGROUND: Valproic acid (VPA), an anti-epileptic drug, can cause male subfertility. However, the degree to which testicular and epididymal histopathologies and androgen receptor (AR) expression are changed under VPA treatment has never been reported. OBJECTIVE: To investigate the histopathological changes and AR protein levels of testis and epididymis in VPA treated rats for every single day. MATERIALS AND METHODS: Sixty-four adult male Wistar rats were divided into control and VPA-treated groups (n=8/ each). Treated rats were injected with 500 mg/ kgBW, intraperitoneally, VPA for 10 consecutive days. At the end of every experimental day, all reproductive parameters including histology by hematoxylin and eosin staining and protein expression of AR by Immuno-Western blot in testis and epididymis were examined. RESULTS: VPA-treated rats showed dramatically changes in testicular and epididymal histopathologies compared to control group. The multinucleated giant cells and sloughing of germ cells were observed on day 6. The germ cell disintegration and increased intercellular spaces of seminiferous tubular epithelium appeared in days 7-10 of VPA treatment. Additionally, extensive multinucleated giant cells and complete exfoliation were clearly found from days 8-10. Such exfoliated germ cells were clearly seen in its epididymal lumen at day 10. The increasing rate of sperm concentration was approximately 32.31% of that in control group at day 10 (p=0.03). Moreover, the protein expressions of testicular and epididymal AR (% intensity/ 80 ug protein lysate) was decreased in VPA-treated rats compared with control. CONCLUSION: VPA treatment induces histologic changes of germ cell epithelium in seminiferous tubules and decreases the expression of testicular and epididymal androgen receptors. PMID- 28835939 TI - Accuracy of color Doppler ultrasonography and magnetic resonance imaging in diagnosis of placenta accreta: A survey of 82 cases. AB - BACKGROUND: Placenta adhesive disorder (PAD) is one of the most common causes of postpartum hemorrhage and peripartum hysterectomy. The main risk factors are placenta previa and prior uterine surgery such as cesarean section. Diagnosis of placenta adhesive disorders can lead to a decrease of maternal mortality and morbidities. OBJECTIVE: The purpose of this study was to compare the accuracy of color Doppler ultrasonography and magnetic resonance imaging (MRI) in the diagnosis of PADs. MATERIALS AND METHODS: In this is cross-sectional study, Eighty-two pregnant women who were high risk for PAD underwent color Doppler ultrasound and MRI after 18 weeks of gestation. The sonographic and MRI findings were compared with the final pathologic or clinical findings. P<0.05 was considered statistically significant. RESULTS: Mean maternal age was 31.42+/-4.2 years. The average gravidity was third pregnancy. 46% of patients had placenta previa. The history of the previous cesarean section was seen in 79 cases (96%). The diagnosis of placenta adhesive disorder was found in 17 cases (21%). Doppler sonography sensitivity was 87% and MRI sensitivity was 76% (p=0.37). Doppler sonography specificity was 63% and MRI specificity was 83% (p=0.01). CONCLUSION: Women with high-risk factors for PAD should undergo Doppler ultrasonography at first. When results on Doppler sonography are equivocal for PAD, MRI can be performed due to its high specificity. PMID- 28835940 TI - Pregnancy outcome of "delayed start" GnRH antagonist protocol versus GnRH antagonist protocol in poor responders: A clinical trial study. AB - BACKGROUND: Management of poor-responding patients is still major challenge in assisted reproductive techniques (ART). Delayed-start GnRH antagonist protocol is recommended to these patients, but little is known in this regards. OBJECTIVE: The goal of this study was assessment of delayed-start GnRH antagonist protocol in poor responders, and in vitro fertilization (IVF) outcomes. MATERIALS AND METHODS: This randomized clinical trial included sixty infertile women with Bologna criteria for ovarian poor responders who were candidate for IVF. In case group (n=30), delayed-start GnRH antagonist protocol administered estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin. Control group (n=30) treated with estrogen priming antagonist protocol. Finally, endometrial thickness, the rates of oocytes maturation, , embryo formation, and pregnancy were compared between two groups. RESULTS: Rates of implantation, chemical, clinical, and ongoing pregnancy in delayed-start cycles were higher although was not statistically significant. Endometrial thickness was significantly higher in case group. There were no statistically significant differences in the rates of oocyte maturation, embryo formation, and IVF outcomes between two groups. CONCLUSION: There is no significant difference between delayed-start GnRH antagonist protocol versus GnRH antagonist protocol. PMID- 28835941 TI - Gaining comprehensive data about sexual knowledge through surveys. AB - BACKGROUND: Delivery of sexual health services rely on rigorous facts extracted from surveys, but often those facts cannot be available due to the lack of culturally-sensitive questionnaires. OBJECTIVE: our aim was to show the validity and reliability of the Persian version of the Acquisition of Sexual Information Test (ASIT), a measure selected due to its assemblages with Iranian culture. MATERIALS AND METHODS: Forward-backward procedure was applied to translate the questionnaire. Cross-sectional study was carried out and psychometric properties of the Iranian version were tested in a thirty sample of reproductive-age women. Face validity was assessed by qualitative and quantitative methods. Content validity was also assessed by calculating two quantitative indicators as content validity index (CVI) and content validity ratio (CVR). Reliability was assessed by test-retest analyses. RESULTS: Impact score was 1.5, the majority of participants (83.3%) stated that the overall level of questionnaire was high but some of the questions were irrelevant to sexual knowledge. Many questions (90%) gained a CVR less than 0.56, and all of them gained CVIs lower than 0.7. Correlation in test-retest reliability was 0.85. CONCLUSION: sexual knowledge questionnaire seems to be culturally inappropriate for Iranian women. Although, we need survey data for assessing the evidence-based needs for sexual health and best practice, but the questions addressing various dimensions of sexuality must be culturally sensitive, comprehensive and appropriate. Our findings suggest that ASIT as a well-known measure should be used in Iranian population with caution. PMID- 28835942 TI - The Impact of Reduced Injected Radioactivity on Image Quality of Molecular Breast Imaging Tomosynthesis. AB - This study's objective is to compare image quality in 3-D molecular breast imaging tomosynthesis (MBIT) with that in planar molecular breast imaging (MBI) over a range of breast radioactivity concentrations. Using gelatin and point source phantoms lesion contrast, lesion signal-to-noise ratio (SNR) and spatial resolution were compared for a range of lesion sizes and depths. For both MBI and MBIT, lesion contrast is essentially constant with changing activity while SNR decreases by a factor of 1.5 - 2 between 100% and 25% activity levels. For nearly all lesion sizes and locations contrast and SNR are significantly higher for MBIT than MBI, potentially permitting greater reductions in injected dose. Spatial resolution in MBI is dependent on lesion depth but independent of lesion location with MBIT. Reconstructed MBIT spatial resolution is substantially better than that in the projection images, suggesting future use of higher sensitivity collimators for even further reductions in injected activity. PMID- 28835943 TI - DNA tetrahedron nanostructures for biological applications: biosensors and drug delivery. AB - With the rapid development of DNA nanotechnology, various DNA nanostructures with different shapes and sizes have been self-assembled using "bottom-up" fabrication strategies and applied to a wide range of fields such as biosensors, drug delivery and tools for molecular biology. As a classical and simple polyhedron, DNA tetrahedron can be easily synthesised by a one-step assembly. Due to the excellent biocompatibility and cellular permeability, it provides a universal and promising platform to construct a series of biosensors and drug delivery systems for living cells studies. Moreover, the high programmability of DNA tetrahedron determines its capability to perform artful design and combine with other materials. Herein, we review and summarise the development and applications of DNA tetrahedron in living cell studies. We mainly focus on two parts, cellular biosensors for the detection of nucleic acids, proteins, small molecules and cancer cells and drug delivery systems for chemotherapy, immunotherapy, photodynamic therapy and gene silencing. With the rapid progress in DNA tetrahedron as well as DNA nanotechnology, new avenues and opportunities have opened up in analytical chemistry, molecular biology and medicine. PMID- 28835944 TI - Strategic design of a ruthenium catalyst for both CO2 reduction and H2O oxidation: the electronic influence of the co-ligands. AB - A new ruthenium(ii) complex capable of catalysing both CO2 reduction and water oxidation was designed and synthesised. The electro-catalytic efficiency and robustness of the complex together with the electronic effect of its co-ligands were investigated to develop next generation dual activity electrocatalysts. PMID- 28835947 TI - Effect of incarcerated HF on the exohedral chemical reactivity of HF@C60. AB - The first chemical modification on the brand new endohedral HF@C60 is reported. In particular, the isomerization from optically pure (2S,5S)-cis pyrrolidino[3,4:1,2][60]fullerene 2b to (2S,5R)-trans pyrrolidino[3,4:1,2][60]fullerene 2b has been studied and compared with empty C60 (2a) and endohedral H2O@C60 (3). The comparative study shows a kinetic order for the isomerization process of H2O@C60 > HF@C60 > C60, thus confirming the effect of the incarcerated species on the zwitterionic intermediate stability. PMID- 28835949 TI - Understanding the responses of Saccharomyces cerevisiae yeast strain during dehydration processes using synchrotron infrared spectroscopy. AB - For the first time, synchrotron infrared spectroscopy was performed on yeast during dehydration processes in real time with simultaneously controlled relative humidity and temperature. This led us to investigate the biochemical modification in relation to the dehydration of Saccharomyces cerevisiae. The correlation between the hydration level and yeast survival was observed. Following the test conditions, the modification of the protein structure was observed. However, no evident modification of the lipid composition resulting from dehydration was observed. Furthermore, the results showed that the medium rich in nutrients and glutathione precursors can improve yeast survival during dehydration at 45 degrees C. This could be related to the high relative amounts of CH3 groups in the lipid composition assigned to the low lipid oxidation level in this case. Our work demonstrated the feasibility of using S-FTIR for investigating yeast responses to dehydration processes in real time. This method can be used for understanding the effect of dehydration/rehydration on the biochemical modification of yeast. PMID- 28835950 TI - Deformation mechanisms of sub-micrometer thermoplastic vulcanizates obtained by reaction-induced phase separation of miscible poly(epsilon caprolactone)/dimethacrylate systems. AB - The micromechanical deformation mechanisms of sub-MUm thermoplastic vulcanizates (TPVs) based on poly(epsilon-caprolactone) (PCL) and cross-linked methacrylate rubbers were studied by time-resolved small-angle X-ray scattering (SAXS) and wide-angle X-ray diffraction (WAXD) measurements in order to better understand the underlying deformation mechanisms responsible for the high elongation at break and good elastic recovery of sub-MUm TPVs. It is demonstrated that, in contrast to neat PCL, the interlamellar void formation in the PCL matrix and subsequent coalescence of voids is suppressed by the presence of the rubber (nano)particles in these TPVs. The deformation of the TPVs under tensile conditions is dominated by yielding of the PCL matrix, which is initially localized at the equatorial regions of the rubber particles and progresses towards the polar regions at higher strains. Re-ordering of the crystal structures is both time and stress dependent, and stress relaxation of the TPV under tension is primarily governed by the break-up of the crystal lamellae at the equatorial regions of the rubber particles. This study demonstrates that the rubber particle size as well as chemical grafting of thermoplastic polymer chains onto the surface of cross-linked rubber particles are important parameters to control the mechanical deformation behavior of TPVs. PMID- 28835951 TI - Profiling and quantifying endogenous molecules in single cells using nano-DESI MS. AB - Molecular profiling of single cells has the potential to significantly advance our understanding of cell function and cellular processes of importance to health and disease. In particular, small molecules with rapid turn-over rates can reveal activated metabolic pathways resulting from an altered chemical environment or cellular events such as differentiation. Consequently, techniques for quantitative metabolite detection acquired in a higher throughput manner are needed to characterize the biological variability between seemingly homogenous cells. Here, we show that nanospray desorption electrospray ionization (nano DESI) mass spectrometry (MS) enables sensitive molecular profiling and quantification of endogenous species in single cells in a higher throughput manner. Specifically, we show a large number of detected amino acids and phospholipids, including plasmalogens, readily detected from single cheek cells. Further, by incorporating a phosphatidylcholine (PC) internal standard into the nano-DESI solvent, we determined the total amount of PC in one cell to be 1.2 pmoles. Finally, we describe a higher throughput approach where molecules in single cells are automatically profiled. These developments in single cell analysis provide a basis for future studies to understand cellular processes related to drug effects, cell differentiation and altered chemical microenvironments. PMID- 28835952 TI - Challenges in bimetallic multilayer structure formation: Pt growth on Cu monolayers on Ru(0001). AB - In a joint experimental and theoretical study, we investigated the formation and morphology of PtCu/Ru(0001) bimetallic surfaces grown at room and higher temperatures under UHV conditions. We obtained the PtCu/Ru(0001) surfaces by deposition of Pt atoms on a previously created Cu/Ru(0001) structure which includes only one Cu monolayer. Bimetallic surfaces prepared at different Pt coverages are investigated using STM imaging, revealing the existence of reconstruction lines and Cu islands. Although primarily created Cu islands continue growing in size by increasing Pt coverage, a continuous formation of new Cu islands is observed. This leads to an atypical exponential increase of the island density as well as to an atypical behavior of the average number of atoms per island for low Pt coverages. Although coalescence of the islands is observed for high Pt coverages, the island density remains almost constant in that regime. In order to understand the trends observed in the experiments, we study the stability of these surfaces, atom adsorption, and adatom diffusion using periodic density functional theory calculations. On the basis of the experimental observations and the first-principles calculations, we suggest a model that includes exchange of Pt adatoms with Cu surface atoms, Pt and Cu adatom diffusion, and attractive (repulsive) interactions between Cu (Pt) adatoms with substitutional Pt surface atoms, which explains the main trends in island formation and growth observed in the experiment. PMID- 28835953 TI - Simultaneous label-free screening of G-quadruplex active ligands from natural medicine via a microfluidic chip electrophoresis-based energy transfer multi biosensor strategy. AB - Rapid screening of active compounds plays a crucial role in the research and application of complex natural medicines. Herein, a new method of simultaneous label-free multi-drug screening based on a selective aptamer carboxyfluorescein/graphene oxide energy transfer optical sensor combined with microfluidic chip electrophoretic separation is reported. In this study, seven traditional Chinese medicinal monomers were chosen as targets for the screening of G-quadruplex ligands. The screening results of the G-quadruplex active ligands, including daidzein, berberine hydrochloride, jatrorrhizine hydrochloride, and fangchinoline, and non-active ligands, including geniposide and oxymatrine, were consistent with those reported in literature. Moreover, one new potential G4DNA active drug, jujuboside A, was identified. Molecular simulation of the interaction between G4DNA and drugs was also carried out using HyperChem and AutoDock to verify the results of the experimental screening. It further demonstrated the reliability of our strategy. This novel separation and concentration based multi-sensing strategy provides a simple, rapid, and sensitive tool for simultaneous multi-drug screening, which is very meaningful for drug screening and bio-interaction analysis. PMID- 28835954 TI - A highly efficient 2D exfoliated metal dichalcogenide for the on-farm rapid monitoring of non-esterified fatty acids. AB - Herein, we report on the development of an electrochemically active liquid exfoliated 2D MoS2 nanosheet based biointerface for the on-farm monitoring of non esterified fatty acid (NEFA) biomarkers. PMID- 28835955 TI - Engineering defects and photocatalytic activity of TiO2 nanoparticles by thermal treatments in NH3 and subsequent surface chemical etchings. AB - TiO2 nanoparticles with N dopants were prepared by thermal treatments in NH3 and their surface defects were controlled by post chemical etching in HF to find out the influence of the N dopants on photoactivity. The effect of N-doping is found to enhance the photoactivity of TiO2, but is strongly dependent on the degree of N-doping and the detailed distribution of nitrogen species within the TiO2 nanoparticles. In particular, the N-rich layers formed near the surface are found to contribute to the enhanced photoactivity due to the reduced band gap. But, the increase in the N concentration may induce defects that act as recombination centers and reduce the photoactivity. Subsequent chemical etching in HF confirms the existence of the substitutional N species near the surface from the observation of paramagnetic N species. But, prolonged HF treatments are found to decrease the photoactivity primarily due to the removal of the N-rich surface layers that are responsible for the enhanced photoactivity. Our results show that the photoactivity of N-doped TiO2 is strongly influenced by the type and the density of the N dopants induced by the N doping. PMID- 28835956 TI - Defluorination and covalent grafting of fluorinated graphene with TEMPO in a radical mechanism. AB - Fluorinated graphene (FG) can be regarded as the representative two-dimensional (2D) material to study the characteristics of "2D chemistry", whereas its derivative reaction mechanism is still required to be revealed for the destination of deciduous fluorine atoms after defluorination of FG. Herein, we proposed a particular derivative reaction of FG by employing 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO) as the attacking reagent, and the products were characterized via Electron Paramagnetic Resonance Spectroscopy (EPR), Mass Spectrometry (MS) and X-ray photoelectron spectroscopy (XPS). It was demonstrated that the defluorination caused by TEMPO occurred in a radical mechanism, thus leading to formations of new spin centers on graphene nanosheets as well as C[double bond, length as m-dash]C bonds. More importantly, the deciduous fluorine atoms after defluorination, which existed in TEMPO fluoride molecules, have been detected for the first time. Meanwhile, some TEMPO molecules were covalently grafted on the nanosheet, which resulted from the coupled reaction between TEMPO radical and the spin center on the FG nanosheet. These findings deepen the research of derivative reactions of FG, meanwhile providing a particular view to investigate the chemistry characteristics of 2D materials from a radical mechanism. PMID- 28835957 TI - Rotaxane synthesis exploiting the M(i)/M(iii) redox couple. AB - In the context of advancing the use of metal-based building blocks for the construction of mechanically interlocked molecules, we herein describe the preparation of late transition metal containing [2]rotaxanes (1). Capture and subsequent retention of the interlocked assemblies are achieved by the formation of robust and bulky complexes of rhodium(iii) and iridium(iii) through hydrogenation of readily accessible rhodium(i) and iridium(i) complexes [M(COD)(PPh3)2][BArF4] (M = Rh, 2a; Ir, 2b) and reaction with a bipyridyl terminated [2]pseudorotaxane (3.db24c8). This work was underpinned by detailed mechanistic studies examining the hydrogenation of 1 : 1 mixtures of 2 and bipy in CH2Cl2, which proceeds with disparate rates to afford [M(bipy)H2(PPh3)2][BArF4] (M = Rh, 4a[BArF4], t = 18 h @ 50 degrees C; Ir, 4b[BArF4], t < 5 min @ RT) in CH2Cl2 (1 atm H2). These rates are reconciled by (a) the inherently slower reaction of 2a with H2 compared to that of the third row congener 2b, and (b) the competing and irreversible reaction of 2a with bipy, leading to a very slow hydrogenation pathway, involving rate-limiting substitution of COD by PPh3. On the basis of this information, operationally convenient and mild conditions (CH2Cl2, RT, 1 atm H2, t <= 2 h) were developed for the preparation of 1, involving in the case of rhodium-based 1a pre hydrogenation of 2a to form [Rh(PPh3)2]2[BArF4]2 (8) before reaction with 3.db24c8. In addition to comprehensive spectroscopic characterisation of 1, the structure of iridium-based 1b was elucidated in the solid-state using X-ray diffraction. PMID- 28835958 TI - Low-lying, Rydberg states of polycyclic aromatic hydrocarbons (PAHs) and cyclic alkanes. AB - TD-DFT calculations of low-lying, Rydberg states of a series of polycyclic hydrocarbons and cyclic alkanes are presented. Systematic variations in binding energies and photoelectron angular distributions for the first members of the s, p and d Rydberg series are predicted for increasing molecular complexity. Calculated binding energies are found to be in very good agreement with literature values where they exist for comparison. Experimental angle-resolved photoelectron spectroscopy results are presented for coronene, again showing very good agreement with theoretical predictions of binding energies and also for photoelectron angular distributions. The Dyson orbitals for the small "hollow" carbon structures, cubane, adamantane and dodecahedrane, are shown to have close similarities to atomic s, p and d orbitals, similar to the superatom molecular orbitals (SAMOs) reported for fullerenes, indicating that these low-lying, diffuse states are not restricted to pi-conjugated molecules. PMID- 28835959 TI - [AlCl3(BnMe2-tacn)] - a new metal chelate scaffold for radiofluorination by Cl/F exchange. AB - Radiofluorination of a 2.63 MUM solution (pH 4, NaOAc buffer) of [AlCl3(BnMe2 tacn)] via treatment with 2.99 mol. equiv. of [19F]KF doped with cyclotron produced [18F]F- target water, with heating to 80-100 degrees C for 1 h, gives up to 24% 18F incorporation. SPE purification of the [Al19F218F(BnMe2-tacn)] radio-product gives >99% RCP, with excellent stability (>99% RCP after 3 h). PMID- 28835960 TI - Trapping and sensing of hazardous insecticides by chemically modified single walled carbon nanotubes. AB - The use of insecticides in agriculture is a common practice all over the world, but they are often known to be harmful towards the human body. This requires attention by experimentalists and theorists alike. In this work, using Born Oppenheimer molecular dynamics (BOMD) and density functional theory (DFT) calculations, we have demonstrated the efficient trapping of several hazardous insecticide molecules on a carbon nanotube (CNT) surface. Our BOMD simulations suggest that under ambient conditions, though pristine CNTs are quite inefficient, transition metal atom (TM) incorporated nitrogen doped CNTs can trap the hazardous molecules at room temperature efficiently. Thorough investigations exhibit the presence of strong eta6 bonding between the aromatic group of the pesticide and the TM adatom of the defective CNT, leading to the trapping of the molecules on the CNT surface. These CNTs are efficient trapping agents even in the presence of water and quite robust for any pesticides with aromatic group(s) in them. Furthermore, interestingly, the charge transfer interactions between the molecules and the defective CNTs lead to molecule specific optical absorption spectra of the composites, effectively developing defective CNTs as a detective optical sensor for pesticide molecules. PMID- 28835961 TI - Change in the structure and function of lectin by photodissociation of NO. AB - We have shown here that the structure and sugar-binding activity of lectin can be changed by the photodissociation of NO. Intramolecular S-S bonds are photogenerated from SNO in the protein, which can be used to photo-control the structure and function of proteins. PMID- 28835962 TI - Palladium-catalysed alkene chain-running isomerization. AB - We report a method for palladium-catalysed chain-running isomerization of terminal and internal alkenes. Using an air-stable 2,9-dimethylphenanthroline palladium catalyst in combination with NaBAr4 promoter, olefins are converted to the most stable double bond isomer at -30 to 20 degrees C. Silyl enol ethers are readily formed from silylated allylic alcohols. Fluorinated substituents are compatible with the reaction conditions, allowing the synthesis of fluoroenolates. Catalyst loading as low as 0.05% can be employed on a gram scale. PMID- 28835964 TI - A high-resolution natural abundance 33S MAS NMR study of the cementitious mineral ettringite. AB - Despite the widespread occurrence of sulfur in both natural and man-made materials, the 33S nucleus has only rarely been utilised in solid-state NMR spectroscopy on account of its very low natural abundance (0.76%), low NMR frequency (nu0 = 30.7 MHz at B0 = 9.4 T), and significant nuclear quadrupole moment (spin I = 3/2, Q = -69.4 mb). Satellite-transition magic angle spinning (STMAS) is an NMR method for obtaining high-resolution spectra of half-integer quadrupolar nuclei (spin I > 1/2) in solids and is notable for its intrinsic sensitivity advantage over the similar multiple-quantum (MQMAS) method, especially for nuclei with low NMR frequencies. In this work we demonstrate the feasibility of natural abundance 33S STMAS NMR experiments at B0 = 9.4 T and 20.0 T using a model sulfate sample (Na2SO4 + K2SO4 in a 1 : 1 molar ratio). Furthermore, we undertake a natural abundance 33S STMAS NMR study of the cement forming mineral ettringite (Ca6Al2(SO4)3(OH)12.26H2O) at B0 = 9.4 T and 20.0 T, resolving a discrepancy in the literature between two previous conventional 33S MAS NMR studies and obtaining an alternative set of 33S NMR parameters that is simultaneously consistent with the MAS and STMAS data at both field strengths. PMID- 28835966 TI - Understanding CO2 capture mechanisms in aqueous hydrazine via combined NMR and first-principles studies. AB - Aqueous amines are currently the most promising solution for large-scale CO2 capture from industrial sources. However, molecular design and optimization of amine-based solvents have proceeded slowly due to a lack of understanding of the underlying reaction mechanisms. Unique and unexpected reaction mechanisms involved in CO2 absorption into aqueous hydrazine are identified using 1H, 13C, and 15N NMR spectroscopy combined with first-principles quantum-mechanical simulations. We find production of both hydrazine mono-carbamate (NH2-NH-COO-) and hydrazine di-carbamate (-OOC-NH-NH-COO-), with the latter becoming more populated with increasing CO2 loading. Exchange NMR spectroscopy also demonstrates that the reaction products are in dynamic equilibrium under ambient conditions due to CO2 exchange between mono-carbamate and di-carbamate as well as fast proton transfer between un-protonated free hydrazine and mono-carbamate. The exchange rate rises steeply at high CO2 loadings, enhancing CO2 release, which appears to be a unique property of hydrazine in aqueous solution. The underlying mechanisms of these processes are further evaluated using quantum mechanical calculations. We also analyze and discuss reversible precipitation of carbamate and conversion of bicarbonate to carbamates. The comprehensive mechanistic study provides useful guidance for optimal design of amine-based solvents and processes to reduce the cost of carbon capture. Moreover, this work demonstrates the value of a combined experimental and computational approach for exploring the complex reaction dynamics of CO2 in aqueous amines. PMID- 28835965 TI - Concentrations of estrogen and progesterone in breast milk and their relationship with the mother's diet. AB - The aim of the present study was to determine the concentrations of estradiol (E2), estriol (E3) and progesterone in breast milk over different lactation periods, and to assess their relationship with the mother's diet. Ninety-six breast milk samples as well as 24-hour dietary records from 32 lactating mothers were collected on day 1 (colostrum), day 14 (transitional milk) and day 42 (mature milk) after delivery in Hangzhou, China. The concentrations of E2, E3 and progesterone differed significantly through different periods of lactation (p < 0.001). The content of E2 in colostrum, transitional milk and mature milk was 1.60 +/- 0.96 MUg L-1, 0.83 +/- 0.36 MUg L-1 and 1.26 +/- 0.48 MUg L-1, respectively. The concentrations of E3 were 2.09 +/- 1.66 MUg L-1, 2.23 +/- 1.74 MUg L-1 and 4.64 +/- 2.15 MUg L-1, respectively. The concentrations of progesterone were 6.10 +/- 8.30 MUg L-1, 4.25 +/- 4.76 MUg L-1 and 1.70 +/- 2.42 MUg L-1, respectively. The concentration of progesterone in breast milk was significantly negatively correlated with the intake of protein (p = 0.015), fat (p = 0.008), vegetables (p = 0.012), and meat and eggs (p = 0.036), while the concentration of E3 was significantly positively correlated with the intake of soy products (p = 0.025). This information indicates that the concentrations of E2, E3 and progesterone in breast milk varied over the lactating period. Dietary intake will to some extent affect the contents of E3 and progesterone in breast milk. PMID- 28835967 TI - ? PMID- 28835971 TI - [The eye and rheumatic diseases]. PMID- 28835968 TI - PON1 L55M and Q192R gene polymorphisms and CAD risks in patients with hyperlipidemia : Clinical study of possible associations. AB - OBJECTIVE: A decreased plasma high density lipoprotein (HDL) cholesterol level is a strong risk factor for coronary artery disease (CAD). Antioxidant activity of HDL mainly lies in the activity of paraoxonase (PON). This study aimed to investigate the relationships between PON1 L55M and Q192R polymorphisms, and the risks of CAD in patients with hyperlipidemia. METHODS: From January 2014 to January 2016, 244 patients were divided into hyperlipidemia, hyperlipidemia + CAD, and control groups. The hyperlipidemia and hyperlipidemia + CAD groups were designated as the case group. Serum PON1 concentrations were measured using the enzyme-linked immunosorbent assay. After isolating genomic DNA, the PON1 L55M and Q192R genes were amplified by polymerase chain reaction and sequenced. RESULTS: In the case group, the genotypes LM and LL were detected significantly more often than in the control group, as were the alleles R (33.33%, 42.12%) and L (22.78%, 29.11%). The frequency of QR and RR genotypes was significantly higher in the hyperlipidemia + CAD group than in the hyperlipidemia group; the allele R in the hyperlipidemia + CAD group (42.77%) was more frequent than in the hyperlipidemia group (23.78%). The Q192R polymorphism was associated with low serum PON1 concentrations, and the lowest concentration was observed in the 192QR + 192RR genotype (P = 0.03). Logistic regression analysis showed a significant correlation between the 192R allele and smoking (P = 0.03), body mass index (P = 0.02), systolic blood pressure (P = 0.004), total cholesterol (P = 0.03), triglycerides (P = 0.01), HDL (P = 0.004), and low density lipoprotein (P = 0.02). CONCLUSION: The PON1 alleles 192R and 55L are associated with CAD, and the Q192R polymorphism may be a risk factor for CAD. PMID- 28835974 TI - [Hypercalcemic crisis and hypocalcemic tetany]. AB - A serum calcium level >3.5 mmol/l together with clinical symptoms such as muscle weakness, fatigue, nausea, vomiting, pancreatitis or even coma are characteristic for a hypercalcemic crisis (HC). Primary hyperparathyroidism (1HPT) and malignancy-associated hypercalcemia are the most frequent causal diseases for a HC. The analysis of serum levels for calcium, phosphorous, intact parathyroid hormone, electrophoresis and renal function parameters indicate which further radiological, scintigraphic or serum diagnostic steps are adequate to identify the cause of the patient's acute situation (i. e. most frequently 1HPT or malignant disease with bone involvement, e. g. myeloma) and thus to initiate the required surgical or oncological intervention. However, the primary goals in the treatment of HC include correcting dehydration and improving kidney function, lowering calcium levels and decreasing osteoclastic bone resorption. The goals are accomplished by volume repletion, forced diuresis, antiresorptive agents and hemodialysis on an intensive care unit. Hypocalcemic tetany (HT) is the consequence of severely lowered calcium levels (<2.0 mmol/l), usually in patients with chronic hypocalcemia. The causal disease for hypocalcemic tetany is frequently a lack of parathyroid hormone (PTH), (e. g. as a complication of thyroid surgery) or, rarely, resistance to PTH. HT due to severe and painful clinical symptoms requires rapid i. v. calcium replacement by central venous catheter on an intensive care unit. For the treatment of chronic hypocalcemia oral calcium and 25OH-vitamin D or even 1,25(OH)2-vitamin D3 and magnesium supplements may be necessary to achieve the desired low normal calcium levels. Thiazides are useful to reduce renal calcium loss and to stabilize the calcium levels. Some patients continue to exhibit clinical symptoms despite adequate calcium levels; in these cases s. c. parathyroid hormone 1-84 should be considered to stabilize calcium levels and to lower the dosage of calcium and vitamin D supplements. PMID- 28835975 TI - [Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. AB - Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients. PMID- 28835978 TI - Erratum to: Abstracts of the 53rd Annual Meeting of the EASD, Lisbon 2017. Abstract 788: 'Pharmacokinetics and tolerability of oral semaglutide in subjects with renal impairment'. PMID- 28835976 TI - [Medicinal treatment of tricuspid valve regurgitation]. AB - The vast majority of tricuspid valve regurgitations are of low degree without prognostic relevance in healthy individuals; however, morbidity and mortality increase with the degree of regurgitation, which can be secondary to either primary (structural) or secondary (functional) alterations of the valve. Due to the frequent lack of symptoms, echocardiographic examinations should be annually performed in patients with higher degree (at least moderate) tricuspid valve regurgitation, in particular in the presence of risk factors. Individual therapeutic management strategies should consider the etiology of the tricuspid valve regurgitation, the degree of regurgitation, the valve pathology and the risk-to-benefit ratio of the envisaged therapeutic procedure. Medicinal treatment options for tricuspid valve regurgitation are limited and generalized recommendations cannot be provided due to the lack of conclusive clinical trials. Symptomatic therapeutic measures encompass especially (loop) diuretics for the reduction of preload and afterload of the right ventricle. Pharmaceutical reduction of the heart rate should be avoided in patients with right heart insufficiency. While symptomatic therapeutic measures are often associated with only moderate effects, the most effective therapy of tricuspid valve regurgitation consists in the treatment of underlying illnesses, in most cases pulmonary hypertension due to pulmonary arterial hypertension (PAH), left heart disease or acute pulmonary embolism. Based on a number of published clinical studies and licensing of new drugs, treatment options for patients with PAH and heart failure with reduced ejection fraction (HFrEF) have substantially improved during the past years allowing for a differentiated, individualized management. PMID- 28835980 TI - Can routine data from prisoners' files be used to estimate prevalence rates of illicit drug use among prisoners? AB - OBJECTIVES: The paper examines whether routine data from prisoners' files is a useful basis to estimate prevalence rates of illicit drug use among prisoners. METHODS: Medico-legal files of 190 younger (20-49 years) and 190 older (50-75 years) male prisoners from 13 prisons in Switzerland were analysed. Indications of illicit drug use were extracted based on recorded legal measures, notes from health care professionals, diagnoses related to the use of illicit substances, prescribed medications, other treatment indicators, and results from mandatory drug tests in prison. RESULTS: Estimated lifetime prevalence of illicit drug use based on those indicators is 50.0% for younger and 24.2% for older prisoners. Current cannabis use is an estimated 10.0% and current cocaine, opioids, or other drug use 4.7% for younger prisoners. Among older prisoners, prevalence of current cannabis use is an estimated 3.2% and of other drug use 0.5%. CONCLUSIONS: The paper concludes that analysing routine data is a reasonable alternative to surveys if prisoners' files are kept more complete and concise and if data is collected for no other purpose than to benefit prisoners' health. PMID- 28835979 TI - [Instantaneous wave-free ratio (iFR(r)) in patients with coronary artery disease]. AB - Coronary angiography is considered as the gold standard in the morphological representation of coronary artery stenosis. Coronary angiography is often performed without preprocedural non-invasive proof of ischemia and the assessment of the severity of a coronary lesion by morphology is very subjective. Thus, invasive fractional flow reserve (FFR) measurement represents the current standard for estimation of the hemodynamic relevance of coronary artery stenosis and facilitates decision making for percutaneous coronary intervention (PCI) and stenting. The FFR-guided revascularization strategy has been classified as a class IA recommendation in the 2014 ESC/EACTS guidelines on myocardial revascularization. Both the DEFER and the FAME studies showed no treatment advantage of hemodynamically irrelevant stenosis. By use of FFR (and targeted interventions), clinical results could be improved as well as the procedure costs were reduced; however, the use in clinical practice is still limited due to the need of adenosine administration and a significant prolongation of the procedure. Instantaneous wave-free ratio (iFR(r)) is a new innovative approach for the determination of the hemodynamic relevance of coronary stenosis which can be obtained at rest without the use of vasodilators. Regarding periprocedural complications as well as prognosis, iFR(r) showed non-inferiority compared to FFR in the SWEDEHEART and DEFINE-FLAIR trials. PMID- 28835981 TI - A perforation procedure for pulmonary atresia with intact ventricular septum : Egyptian experience and adaptations. AB - BACKGROUND: Pulmonary atresia with intact ventricular septum (PA-IVS) is an uncommon disorder with significant morphological heterogeneity. The use of percutaneous radiofrequency (RF)-assisted perforation of the atretic valve and subsequent balloon dilation provides a relatively easy but expensive procedure that is expected to establish ante-grade flow through the pulmonary valve in most patients. OBJECTIVES: The aim of the study was to attempt a cost reduction by using catheters and wires readily available in our catheter laboratory. METHODS: A total of 50 patients presenting with PA-IVS to Cairo University Children's Hospital (CUCH) were taken to the catheterization laboratory for radiofrequency perforation using the Baylis RFP-100 generator (Baylis Medical, Montreal, Canada) or the stiff end of a coronary wire. A hybrid approach was used in selected cases. RESULTS: The overall success rate for valve perforation was 92% (46 cases), 80% of which had successful primary perforation (40 cases). Success correlated with both tricuspid valve (TV) annulus and pulmonary valve (PV) annulus Z-scores, with P values of 0.2 and 0.5, respectively. CONCLUSION: The management of PA-IVS is complex. This is a disease that necessitates a dedicated team and working collaboration between the cardiologists and cardiac surgeons. Cost limitation is essential in developing countries and innovative ideas to reduce costs are essential, especially if comparable success can be expected. PMID- 28835982 TI - Effects of paricalcitol on cardiovascular outcomes and renal function in patients with chronic kidney disease : A meta-analysis. AB - BACKGROUND: Paricalcitol, a selective activator of the vitamin D receptor (VDR), influences calcium and phosphorus homeostasis and bone metabolism. Whether paricalcitol reduces cardiovascular risk and protects renal function remains unclear. To systematically evaluate this in patients with chronic kidney disease (CKD), we conducted a meta-analysis of published randomized controlled trials (RCTs). METHODS: We searched MEDLINE, Embase, the Cochrane Library, and reference lists for RCTs comparing paricalcitol with placebo in stage 2-5 CKD (including pre-dialysis and renal replacement patients). The Cochrane quality assessment method was used to evaluate study quality. Results were summarized as risk ratios (RRs) for dichotomous outcomes or mean differences (MD) for continuous outcomes. RESULTS: We included 21 studies comprising 1894 patients. Compared to placebo, paricalcitol reduced the risk of cardiovascular events (RR 0.55; 95% CI 0.35 0.87; p = 0.01), but the RR of hypercalcemia associated with paricalcitol was 6.50 (95% CI 3.21-13.15; p < 0.00001). Paricalcitol cannot significantly change systolic blood pressure and cardiac structure. Although proteinuria reduction was achieved more frequently with paricalcitol (RR 1.51; 95% CI 1.25-1.82; p < 0.0001), it did not significantly reduce proteinuria level compared to placebo. Paricalcitol could not protect renal function to delay CKD progression, since it reduced the glomerular filtration rate (MD -3.15; 95% CI -4.35--1.96; p < 0.0001) and elevated serum creatinine (MD 0.93; 95% CI 0.10-0.68; p = 0.008). CONCLUSION: Paricalcitol reduces the risk of cardiovascular events in CKD patients but increases the risk of hypercalcemia and cannot improve cardiac structure. Meanwhile, it cannot significantly reduce proteinuria level or protect renal function. PMID- 28835983 TI - The contribution of alcohol consumption and smoking to educational inequalities in life expectancy among Swedish men and women during 1991-2008. AB - OBJECTIVES: To assess the level and changes in contribution of smoking and alcohol-related mortality to educational differences in life expectancy in Sweden. METHODS: We used register data on the Swedish population at ages 30-74 during 1991-2008. Cause of death was used to identify alcohol-related deaths, while smoking-related mortality was estimated using lung cancer mortality to indirectly assess the impact of smoking on all-cause mortality. RESULTS: Alcohol consumption and smoking contributed to educational differences in life expectancy. Alcohol-related mortality was higher among men and contributed substantially to inequalities among men and made a small (but increasing) contribution to inequalities among women. Smoking-related mortality decreased among men but increased among women, primarily among the low educated. At the end of the follow-up, smoking-related mortality were at similar levels among men and women. The widening gap in life expectancy among women could largely be attributed to smoking. CONCLUSIONS: Smoking and alcohol consumption contribute to educational differences in life expectancy among men and women. The majority of the widening in the educational gap in mortality among women can be attributed to alcohol and smoking-related mortality. PMID- 28835984 TI - Relapsing/remitting type 1 diabetes. AB - AIMS/HYPOTHESIS: Type 1 diabetes is believed to be an autoimmune disease associated with irreversible loss of insulin secretory function that follows a chronic progressive course. However, it has been speculated that relapsing/remitting disease progression may occur in type 1 diabetes. METHODS: We report the case of an 18-year-old girl with Graves' disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple islet autoantibodies, presenting with relapsing/remitting hyperglycaemia. Peripheral blood mononuclear cells were analysed for islet autoimmunity. RESULTS: There were two instances of hyperglycaemia relapse during CIDP flare-ups that required insulin therapy and remitted after i.v. immunoglobulin (IVIG) therapy improving neurological symptoms. A diagnosis of type 1 diabetes was assigned on the basis of insulin need, HbA1c and islet autoantibodies. Insulin requirements disappeared following IVIG treatment and peaked during CIDP flare-ups. Pro- and anti-inflammatory cytokine responses were noted against islet autoantigens. CONCLUSIONS/INTERPRETATION: We provide clinical evidence of relapsing/remitting type 1 diabetes associated with IVIG treatment and the regulation of islet autoimmunity. Despite sufficient residual beta cell mass, individuals can experience episodes of impaired glycaemia control. This disconnect between beta cell mass and function highlighted by our case may have implications for the use of beta cell function as the primary endpoint for immune intervention trials aiming to protect beta cell mass rather than function. Immune modulation may restore beta cell function and glycaemic control. PMID- 28835985 TI - [Echocardiographic imaging of the tricuspid valve]. AB - Pathologies of the right heart and the tricuspid valve were not recognized to be of prognostic relevance for many years. Available evidence showing the progressive nature of right heart diseases with direct impact on patient survival have changed current understanding of its clinical importance. Visualization and a profound understanding of the right heart anatomy are prerequisites for the development of modern and still experimental treatment strategies. Transthoracic and transesophageal echocardiography enable a standardized and clear visualization and assessment of the right heart anatomy and its pathological changes. PMID- 28835986 TI - [Complex vulvar reconstruction following female genital mutilation/cutting]. AB - BACKGROUND: Female genital mutilation/cutting (FGM/C) is a worldwide problem affecting millions of women and is especially common in Africa and Arabia. Women suffer from serious physical and psychological problems. Anatomic reconstruction, therefore, is an important and life-changing option for many affected women. OBJECTIVES: This work gives a short overview of specialized techniques invented by the author for functional and aesthetic vulvar reconstruction following FGM/C. This work does not intend to provide anatomic or surgical details. MATERIALS AND METHODS: The anterior obturator artery perforator flap (aOAP flap), the omega domed flap (OD flap), and a microsurgical procedure called neurotizing and molding of the clitoral stump (NMCS procedure) are described. RESULTS: The aOAP flap for vulvar reconstruction, the OD-flap for clitoral prepuce reconstruction, and the NMCS-procedure for reconstruction of the clitoral tip provided natural, reliable, and long-lasting results, all of which normalize the anatomy of the mutilated outer female genitalia. CONCLUSIONS: The reconstructive options presented contribute to re-establish normal anatomy and, thus, support women's health and relieve the burden forced upon them by FGM/C. PMID- 28835987 TI - Lateral parapatellar and subvastus approaches are superior to the medial parapatellar approach in terms of soft tissue perfusion. AB - PURPOSE: The arthrotomy techniques of knee surgery may cause varying degrees of disruption to the tissue blood supply. The aim of this study was to investigate the effects of the medial parapatellar (MPPa), midvastus (MVa), subvastus (SVa) and lateral parapatellar (LPPa) approaches on regional tissue perfusion of the knee. METHODS: In this experimental study, a total of 28 female rabbits were applied with four different arthrotomy techniques as Group MPPa, Group MVa, Group SVa and Group LPPa. The blood supply of the tissue around the knee was examined by scintigraphic imaging including the perfusion reserve and T max, and biochemical alteration of the oxidative stress parameters including malondialdehyde (MDA), fluorescent oxidation products (FlOPs), and histopathological findings were evaluated on tissue samples after 3 weeks. RESULTS: The perfusion reserve was increased in all four groups compared to the healthy, contralateral knees. In the Group LPPa, the vascularity was significantly increased compared to the Group MPPa (p = 0.006). In the examination of biochemical parameters, the increase in MDA levels was statistically significant in the Group MPPa compared with the Group LPPa (p = 0.004), and in the Group MVa compared with the Group LPPa (p = 0.006). The increase in the value of MDA levels was striking in the Group MPPa and Group MVa compared with the control group (p = 0.004, p = 0.004, respectively). The increase in another oxidative stress parameter, the tissue FlOPs levels, was statistically significant in the Group MPPa compared with the control group (p = 0.035). CONCLUSION: The LPPa and SVa caused less oxidative stress and less disruption of the muscle blood supply, in biochemical and scintigraphic parameters, compared to the MPPa and MVa. Therefore, in clinical practice, the SVa is preferable to the MPPa and MVa in total knee arthroplasty and the LPPa should be preferred more frequently in selected cases with critical soft tissue viability. PMID- 28835988 TI - VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells. AB - AIM/HYPOTHESIS: Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle. METHODS: Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII. RESULTS: C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator activated receptor gamma co-activator 1alpha (PGC-1alpha) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and inflammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1alpha levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor. CONCLUSIONS/INTERPRETATION: These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2. PMID- 28835989 TI - IDXL: Species Tree Inference Using Internode Distance and Excess Gene Leaf Count. AB - We propose an extension of the distance matrix methods NJst and ASTRID to infer species trees from incongruent gene trees having Incomplete Lineage Sorting. Both approaches consider the average internode distance (ID) between individual taxa pairs as the distance measure. The measure ID does not use the root of a tree, and thus may not always infer the relative position of a taxon with respect to the root. We define a novel distance measure excess gene leaf count (XL) between individual couplets. The XL measure is computed using the root of a tree. It is proved to be additive, and is shown to infer the relative order of divergence among individual couplets better. We propose a novel method IDXL which uses both the XL and ID measures for species tree construction. IDXL is shown to perform better than NJst and other distance matrix approaches for most of the biological and simulated datasets. Having the same computational complexity as NJst, IDXL can be applied for species tree inference on large-scale biological datasets. PMID- 28835990 TI - Cerebellar compartments for the processing of kinematic and kinetic information related to hindlimb stepping. AB - We previously showed that proprioceptive sensory input from the hindlimbs to the anterior cerebellar cortex of the cat may not be simply organized with respect to a body map, but it may also be distributed to multiple discrete functional areas extending beyond classical body map boundaries. With passive hindlimb stepping movements, cerebellar activity was shown to relate to whole limb kinematics as does the activity of dorsal spinocerebellar tract (DSCT) neurons. For DSCT activity, whole limb kinematics provides a solid functional framework within which information about limb forces, such as those generated during active stepping, may also be embedded. In this study, we investigated this idea for the spinocerebellar cortex activity by examining the activity of cerebellar cortical neurons during both passive bipedal hindlimb stepping and active stepping on a treadmill. Our results showed a functional compartmentalization of cerebellar responses to hindlimb stepping movements depending on the two types of stepping and strong relationships between neural activities and limb axis kinematics during both. In fact, responses to passive and active stepping were generally different, but in both cases their waveforms were related strongly to the limb axis kinematics. That is, the different stepping conditions modified the kinematics representation without producing different components in the response waveforms. In sum, cerebellar activity was consistent with a global kinematics framework serving as a basis upon which detailed information about limb mechanics and/or about individual limb segments might be imposed. PMID- 28835991 TI - Characterizing Coastal Ecosystem Service Trade-offs with Future Urban Development in a Tropical City. AB - With rapid urbanization in the coastal zone and increasing habitat losses, it is imperative to understand how urban development affects coastal biodiversity and ecosystem service provision. Furthermore, it is important to understand how habitat fragments can best be incorporated into broader land use planning and coastal management, in order to maximize the environmental benefits they provide. In this study, we characterized the trade-offs between (a) urban development and individual mangrove environmental indicators (habitat quality and ecosystem services), and (b) between different environmental indicators in the tropical nation of Singapore. A range of biological, biophysical, and cultural indicators, including carbon, charcoal production, support for offshore fisheries, recreation, and habitat quality for a threatened species were quantified using field-based, remote sensing, and expert survey methods. The shape of the trade off Pareto frontiers was analyzed to assess the sensitivity of environmental indicators for development. When traded off individually with urban development, four out of five environmental indicators were insensitive to development, meaning that relatively minor degradation of the indicator occurred while development was below a certain threshold, although indicator loss accelerated once this threshold was reached. Most of the pairwise relationships between the five environmental indicators were synergistic; only carbon storage and charcoal production, and charcoal production and recreational accessibility showed trade offs. Trade-off analysis and land use optimization using Pareto frontiers could be a useful decision-support tool for understanding how changes in land use and coastal management will impact the ability of ecosystems to provide environmental benefits. PMID- 28835992 TI - Controversies on lung cancers manifesting as part-solid nodules. AB - PURPOSE: Summarise survival of patients with resected lung cancers manifesting as part-solid nodules (PSNs). METHODS: PubMed/MEDLINE and EMBASE databases were searched for all studies/clinical trials on CT-detected lung cancer in English before 21 December 2015 to identify surgically resected lung cancers manifesting as PSNs. Outcome measures were lung cancer-specific survival (LCS), overall survival (OS), or disease-free survival (DFS). All PSNs were classified by the percentage of solid component to the entire nodule diameter into category PSNs <80% or category PSNs >=80%. RESULTS: Twenty studies reported on PSNs <80%: 7 reported DFS and 2 OS of 100%, 6 DFS 96.3-98.7%, and 11 OS 94.7-98.9% (median DFS 100% and OS 97.5%). Twenty-seven studies reported on PSNs >=80%: 1 DFS and 2 OS of 100%, 19 DFS 48.0%-98.0% (median 82.6%), and 16 reported OS 43.0%-98.0% (median DFS 82.6%, OS 85.5%). Both DFS and OS were always higher for PSNs <80%. CONCLUSION: A clear definition of the upper limit of solid component of a PSN is needed to avoid misclassification because cell-types and outcomes are different for PSN and solid nodules. The workup should be based on the size of the solid component. KEY POINTS: * Lung cancers manifesting as PSNs are slow growing with high cure rates. * Upper limits of the solid component are important for correct interpretation. * Consensus definition is important for the management of PSNs. * Median disease-free-survival (DFS) increased with decreasing size of the nodule. PMID- 28835993 TI - Metastatic and non-metastatic lymph nodes: quantification and different distribution of iodine uptake assessed by dual-energy CT. AB - OBJECTIVES: To evaluate quantification of iodine uptake in metastatic and non metastatic lymph nodes (LNs) by dual-energy CT (DECT) and to assess if the distribution of iodine within LNs at DECT correlates with the pathological structure. METHODS: Ninety LNs from 37 patients (23 with lung and 14 with gynaecological malignancies) were retrospectively selected. Information of LNs sent for statistical analysis included Hounsfield units (HU) at different energy levels; decomposition material densities fat-iodine, iodine-fat, iodine-water, water-iodine. Statistical analysis included evaluation of interobserver variability, material decomposition densities and spatial HU distribution within LNs. RESULTS: Interobserver agreement was excellent. There was a significant difference in iodine-fat and iodine-water decompositions comparing metastatic and non-metastatic LNs (p < 0.001); fat-iodine and water-iodine did not show significant differences. HU distribution showed a significant gradient from centre to periphery within non-metastatic LNs that was significant up to 20-30% from the centre, whereas metastatic LNs showed a more homogeneous distribution of HU, with no significant gradient. CONCLUSIONS: DECT demonstrated a lower iodine uptake in metastatic compared to non-metastatic LNs. Moreover, the internal iodine distribution showed an evident gradient of iodine distribution from centre to periphery in non-metastatic LNs, and a more homogeneous distribution within metastatic LNs, which corresponded to the pathological structure. KEY POINTS: * This study demonstrated a lower iodine uptake in metastatic than non-metastatic LNs. * Internal distribution of HU was different between metastatic and non metastatic lymph nodes. * The intranodal iodine distribution disclosed a remarkable correlation with the histological LN structure. PMID- 28835994 TI - A new twist in the coil: functions of the coiled-coil domain of structural maintenance of chromosome (SMC) proteins. AB - The higher-order organization of chromosomes ensures their stability and functionality. However, the molecular mechanism by which higher order structure is established is poorly understood. Dissecting the activity of the relevant proteins provides information essential for achieving a comprehensive understanding of chromosome structure. Proteins of the structural maintenance of chromosome (SMC) family of ATPases are the core of evolutionary conserved complexes. SMC complexes are involved in regulating genome dynamics and in maintaining genome stability. The structure of all SMC proteins resembles an elongated rod that contains a central coiled-coil domain, a common protein structural motif in which two alpha-helices twist together. In recent years, the imperative role of the coiled-coil domain to SMC protein activity and regulation has become evident. Here, we discuss recent advances in the function of the SMC coiled coils. We describe the structure of the coiled-coil domain of SMC proteins, modifications and interactions that are mediated by it. Furthermore, we assess the role of the coiled-coil domain in conformational switches of SMC proteins, and in determining the architecture of the SMC dimer. Finally, we review the interplay between mutations in the coiled-coil domain and human disorders. We suggest that distinctive properties of coiled coils of different SMC proteins contribute to their distinct functions. The discussion clarifies the mechanisms underlying the activity of SMC proteins, and advocates future studies to elucidate the function of the SMC coiled coil domain. PMID- 28835995 TI - Spirosoma gilvum sp. nov., Isolated from Beach Soil. AB - A Gram-reaction-negative, nonmotile, rod-shaped, aerobic bacterial strain, designated 15J10-9T5T, was isolated from beach soil on Jeju Island, South Korea, and was characterized taxonomically using a polyphasic approach. Comparative 16S rRNA gene sequence analysis showed that the isolate belonged to the family Cytophagaceae in the phylum Bacteroidetes, and was most closely related to Spirosoma aerolatum PR1012kT (96.1%) and Spirosoma panaciterrae DSM 21099T (95.7%). The detection of menaquinone MK-7 as the predominant respiratory quinone, a fatty acid profile with summed feature 3 (C16:1 omega7c/C16:1 omega6c), C16:1 omega5c, and iso-C15:0 as the major components, and a polar lipid profile with phosphatidylethanolamine as the major component also supported the affiliation of strain 15J10-9T5T in the genus Spirosoma. The G+C content of the genomic DNA was 47.7 mol %. The isolate could be clearly differentiated from its closest neighbors based on its phenotypic, phylogenetic, chemotaxonomic, and genotypic features. Therefore, strain 15J10-9T5T represents a novel species of the genus Spirosoma, for which the name Spirosoma gilvum sp. nov. is proposed. The type strain is 15J10-9T5T (=KCTC 52033T = JCM 31997T). PMID- 28835996 TI - [Work and training conditions of residents in urology in Germany : Results of a 2015 nationwide survey by the German Society of Residents in Urology]. AB - BACKGROUND: High-quality urologic residency training programs are crucial to secure both the future of our specialty and patient care. However, little is known about the current training and working conditions among German urology residents. OBJECTIVES: To comprehensively assess the training- and working conditions among urologic residents in Germany. MATERIALS AND METHODS: The GeSRU invited all German urologic residents to complete an online survey on training- and work conditions. Furthermore, the model of effort-reward imbalance (ERI) was applied to measure psychosocial strain at work. RESULTS: A total of 476 urologic residents participated in the survey. Workdays are characterized by high pace and workload and economic considerations. This comes at the cost of professional training, research and family time. Due to these circumstances, a relevant part of residents draws or at least considers consequences. Psychosocial strain among participants is high and conveys a risk for physicians' health and patients' quality of care. CONCLUSION: Our findings call for an adjustment of urologic working and training conditions to preserve high-quality medical treatment and to ensure an attractive working environment. PMID- 28835997 TI - Chromosomes 1BS and 1RS for control of male fertility in wheats and triticales with cytoplasms of Aegilops kotschyi, Ae. mutica and Ae. uniaristata. AB - KEY MESSAGE: Engineered chromosomes 1BS and 1RS offer a new alternative in the development of hybrid systems in bread wheat and triticale. In the cytoplasmic male sterility system for hybrid wheat based on the cytoplasm of Triticum timopheevi fertility restoration is difficult, with few good restorer genes available. In the system based on the cytoplasms of Aegilops kotschyi, Ae. uniaristata and Ae. mutica, essentially all chromosomes 1B carry locus Rf multi that restores male fertility; male sterility manifests itself in wheats with the 1RS.1BL translocation where 1BS chromosome arm is missing. To generate male sterile wheats without the 1RS.1BL translocation, the 1BS arm was cytogenetically engineered to replace the segment with Rf multi with two short inserts of rye chromatin. Conversely, to enhance fertility restoration by doubling the number of restorers present for eventual use in wheat and triticale, a region of 1BS with Rf multi was inserted into 1RS. Alloplasmic wheats with Rf multi removed were completely male sterile; alloplasmic wheats with engineered 1RS carrying Rf multi and without normal 1B were male fertile. An exception to the ubiquitous presence of Rf multi is T. spelta var. duhamelianum; four accessions tested in this study gave inconsistent results but some did not restore male fertility. Engineered chromosomes 1BS and 1RS and chromosomes 1B of T. spelta offer a new alternative for practical application of a cytoplasmic male sterility system in the development of hybrid wheat and hexaploid triticale. PMID- 28835998 TI - The paradox of proteasome granules. AB - Profound knowledge is available for the structure, function and regulation of proteasomes, the key proteases for ubiquitin-dependent protein degradation in dividing cells. Far less understood are proteasome structure and function in quiescence, the resting phase of our body's cells, as in yeast cells grown to stationary phase. In quiescent yeast proteasomes exit the nucleus and accumulate in cytoplasmic protein droplets, called proteasome storage granules (PSG). PSG like structures also exist in non-dividing mammalian cells suggesting that the mechanism underlying PSG organization is conserved from yeast to human. The PSG has physiological significance as it protects yeast cells against stress and confers fitness during aging. The molecular architecture of PSG remains an enigma, since PSG freely move as spherical units without being surrounded by membranes through the cytoplasm. They rapidly resolve with the resumption of cell proliferation and proteasomes reenter the nucleus. Our systems biology and biochemical data revealed that PSG are mainly composed of proteasomes and free ubiquitin. Often intrinsically disordered proteins undergo liquid phase separations, allowing soluble proteins to condense into protein droplets in an aqueous solution. The question is which proteins and factors nucleate PSG formation, since proteasomes composed of folded subunits are able to degrade intrinsically disordered proteins. PMID- 28835999 TI - Glucocerebrosidase expression patterns in the non-human primate brain. AB - Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene. Mutations in GBA1 gene lead to Gaucher's disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alpha-synuclein, a common neuropathological finding underlying Parkinson's disease (PD) and dementia with Lewy bodies. However, it is also worth noting that a direct link between GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date. Bearing in mind that a number of strategies increasing GCase expression for the treatment of PD are currently under development, here we sought to analyze the baseline expression of GCase in the brain of Macaca fascicularis, which has often been considered as the gold-standard animal model of PD. Although as with other lysosomal enzymes, GCase is expected to be ubiquitously expressed, here a number of regional variations have been consistently found, together with several specific neurochemical phenotypes expressing very high levels of GCase. In this regard, the most enriched expression of GCase was constantly found in cholinergic neurons from the nucleus basalis of Meynert, dopaminergic cells in the substantia nigra pars compacta, serotoninergic neurons from the raphe nuclei, as well as in noradrenergic neurons located in the locus ceruleus. Moreover, it is also worth noting that moderate levels of expression were also found in a number of areas within the paleocortex and archicortex, such as the entorhinal cortex and the hippocampal formation, respectively. PMID- 28836000 TI - AntCaller: an accurate variant caller incorporating ancient DNA damage. AB - Ancient DNA obtained from ancient samples, such as sediments, bones, and teeth, is an important genetic resource that can be used to reconstruct an evolutional history of humans, animals, and plants. The application of high-throughput sequencing enables the research of ancient DNA to be conducted in a whole genome scale. However, post-mortem DNA damage mainly caused by deamination of cytosine to uracil (or methylated cytosine to thymine) may confound the variant calling and downstream analysis. In this article, we develop a Python program to implement a new variant caller, "AntCaller", which extracts the information on nucleotide substitutions from sequencing data and calculates the probability of each genotype based on a Bayesian rule. Through both simulation studies and real data analyses, it was shown that our method reduced the false discovery rate caused by nucleotide misincorporations and outperformed two mainstream variant callers (i.e., GATK and SAMtools) in terms of calling accuracy. In a real application with serious DNA damage, AntCaller still outperformed GATK and SAMtools combined with quality score recalling. PMID- 28836003 TI - [Method for the quality assessment of data collection processes in epidemiological studies]. AB - CONTEXT: For a quantitative evaluation of primary data collection processes in epidemiological surveys based on accompaniments and observations (in the field), there is no description of test criteria and methodologies in relevant literature and thus no known application in practice. Therefore, methods need to be developed and existing procedures adapted. OBJECTIVE: The aim was to identify quality-relevant developments within quality dimensions by means of inspection points (quality indicators) during the process of data collection. As a result we seek to implement and establish a methodology for the assessment of overall survey quality supplementary to standardized data analyses. METHOD/CONCEPT: Monitors detect deviations from standard primary data collection during site visits by applying standardized checklists. Quantitative results - overall and for each dimension - are obtained by numerical calculation of quality indicators. Score results are categorized and color coded. This visual prioritization indicates necessity for intervention. RESULT: The results obtained give clues regarding the current quality of data collection. This allows for the identification of such sections where interventions for quality improvement are needed. In addition, process quality development can be shown over time on an intercomparable basis. DISCUSSION: This methodology for the evaluation of data collection quality can identify deviations from norms, focalize quality analyses and help trace causes for significant deviations. PMID- 28836001 TI - The reduced myofilament responsiveness to calcium contributes to the negative force-frequency relationship in rat cardiomyocytes: role of reactive oxygen species and p-38 map kinase. AB - The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility. However, a decrease (negative FFR) or no effect (flat FFR) on contractile force in response to an elevation of heart rate is present in the normal rat or in human heart failure. Reactive oxygen species (ROS) can act as intracellular signaling molecules activating diverse kinases as calcium-calmodulin-dependent protein kinase II (CaMKII) and p-38 MAP kinase (p 38K). Our aim was to elucidate the intracellular molecules implicated in the FFR of isolated rat ventricular myocytes. The myocytes were field-stimulated via two platinum electrodes. Sarcomere length was recorded with a video camera. Ca2+ transients and intracellular pHi were recorded by epifluorescence. Increasing frequency from 0.5 to 3 Hz decreased cell shortening without changes in pHi. This negative FFR was changed to positive FFR when the myocytes were pre-incubated with the ROS scavenger MPG, the NADPH oxidase blocker apocynin, or by inhibiting mitochondrial ROS production with 5-HD. Similar results were obtained when the cells were pre-incubated with the CaMKII blocker, KN-93, or the p-38K inhibitor, SB-202190. Consistently, the levels of phosphorylation of p-38K and the oxidation of CaMKII were significantly higher at 2 Hz than at 0.5 Hz. Despite the presence of positive inotropic effect during stimulation frequency enhancement, Ca2+ transient amplitudes were reduced in MPG- and SB-202190-treated myocytes. In conclusion, our results indicate that the activation of the intracellular pathway involving ROS-CaMKII-p-38K contributes to the negative FFR of rat cardiomyocytes, likely by desensitizing the response of contractile myofilaments to Ca2+. PMID- 28836004 TI - Scale-up cultivation enhanced arachidonic acid accumulation by red microalgae Porphyridium purpureum. AB - The present study attempts to cultivate Porphyridium purpureum under different scale-up conditions for further development and commercialization of microalgae derived PUFAs such as ARA and EPA. Different temperatures (25, 30, and 35 degrees C) and light intensities (70, 165, and 280 MUmol/m2s) were applied to the 50 L pilot-scale cultivation of P. purpureum in ASW. The cultivation under the light intensity of 280 MUmol/m2s at 35 degrees C obtained biomass concentration up to 9.52 g/L, total fatty acid content to 56.82 mg/g, and ARA content to 22.29 mg/g. While the maximum EPA content of 7.00 mg/g was achieved under the light intensity of 280 MUmol/m2s at 25 degrees C and the highest ratio of UFAs to TFAs of 74.66% was also obtained in this trial. Both biomass concentration and TFAs content were improved by increasing light intensity and temperature. Moreover, the ratio of ARA to EPA was enhanced by increasing cultivation temperature under the light intensity of 280 MUmol/m2s. In contrast with flask culture, the conversion of linoleic acid (C18:2) to ARA was enhanced in scale-up culture, leading to more ARA content. Phosphate limitation enhanced the synthesis of lipid and LPUFAs. Moreover, the biomass concentration and biosynthesis of palmitic acid were preferred by sufficient C (NaHCO3). PMID- 28836002 TI - Severe refractory CIDP: a case series of 10 patients treated with bortezomib. AB - Treatment options for patients with aggressive chronic inflammatory demyelinating neuropathy are limited and include the anti-CD20 antibody rituximab and the immunosuppressive regime cyclophosphamide. We aimed to investigate retrospectively the efficacy of bortezomib, a proteasome inhibitor tackling highly metabolically active cell types such as plasma cells, in a case series of 10 treatment refractory CIDP patients. All patients reported showed a deterioration of the clinical CIDP scores under first-line treatment or escalating treatment with cyclophosphamide or rituximab. One or two cycles of bortezomib treatment (each cycle with 1.3 mg/m2 administered s.c. on days 1, 4, 8, and 11) stabilized the majority of the patients (n = 6) during treatment and even improved clinical and electrophysiological parameters of four patients up to 1 year later. No relevant side-effects were reported. Two patients received autologous peripheral blood stem cell transplantation after bortezomib, which led to fatal infections. We conclude that bortezomib could be an attractive escalating treatment option with a good side-effect profile for patients with treatment refractory CIDP. PMID- 28836005 TI - Grading Dysphagia as a Toxicity of Head and Neck Cancer: Differences in Severity Classification Based on MBS DIGEST and Clinical CTCAE Grades. AB - Clinician-reported toxicity grading through common terminology criteria for adverse events (CTCAE) stages dysphagia based on symptoms, diet, and tube dependence. The new dynamic imaging grade of swallowing toxicity (DIGEST) tool offers a similarly scaled five-point ordinal summary grade of pharyngeal swallowing as determined through results of a modified barium swallow (MBS) study. This study aims to inform clinicians on the similarities and differences between dysphagia severity according to clinical CTCAE and MBS-derived DIGEST grading. A cross-sectional sample of 95 MBS studies was randomly selected from a prospectively-acquired MBS database among patients treated with organ preservation strategies for head and neck cancer. MBS DIGEST and clinical CTCAE dysphagia grades were compared. DIGEST and CTCAE dysphagia grades had "fair" agreement per weighted kappa of 0.358 (95% CI .231-.485). Using a threshold of DIGEST >= 3 as reference, CTCAE had an overall sensitivity of 0.50, specificity of 0.84, and area under the curve (AUC) of 0.67 to identify severe MBS-detected dysphagia. At less than 6 months, sensitivity was 0.72, specificity was 0.76, and AUC was 0.75 while at greater than 6 months, sensitivity was 0.22, specificity was 0.90, and AUC was 0.56 for CTCAE to detect dysphagia as determined by DIGEST. Classification of pharyngeal dysphagia on MBS using DIGEST augments our understanding of dysphagia severity according to the clinically-derived CTCAE while maintaining the simplicity of an ordinal scale. DIGEST likely complements CTCAE toxicity grading through improved specificity for physiologic dysphagia in the acute phase and improved sensitivity for dysphagia in the late-phase. PMID- 28836007 TI - [Immunometabolism and inflammation : "The cell is what it eats"]. PMID- 28836006 TI - Management of superior vena cava syndrome in critically ill cancer patients. AB - PURPOSE: The purpose of this study is to describe the management and outcome of critically ill cancer patients with Superior Vena Cava Syndrome (SVCS). METHODS: All cancer patients admitted to the medical intensive care unit (ICU) of the Saint-Louis University Hospital for a SVCS between January 2004 and December 2016 were included. RESULTS: Of the 50 patients included in the study, obstruction of the superior vena cava was partial in two-thirds of the cases and complete in one third. Pleural effusion was reported in two-thirds of the patients, pulmonary atelectasis in 16 (32%), and pulmonary embolism in five (10%). Computed tomography of the chest showed upper airway compression in 18 (36%) cases, while echocardiography revealed 22 (44%) pericardial effusions. The causes of SVCS were diagnosed one (0-3) day after ICU admission, using interventional radiology procedures in 70% of the cases. Thirty (60%) patients had hematological malignancies, and 20 (40%) had solid tumors. Fifteen (30%) patients required invasive mechanical ventilation, seven (14%) received vasopressors, and renal replacement therapy was implemented in three (6%). ICU, in-hospital, and 6-month mortality rates were 20, 26, and 48%, respectively. The cause of SVCS was the only factor independently associated with day 180 mortality by multivariate analysis. Patients with hematological malignancies had a lower mortality than those with solid tumors (27 versus 80%) (odds ratio 0.12, 95% confidence interval (0.02-0.60), p < 0.01). CONCLUSION: Airway obstruction and pleural and pericardial effusions contributed to the unstable condition of cancer patients with SVCS. The vital prognosis of SVCS was mainly related to the underlying diagnosis. PMID- 28836008 TI - Alpha2-adrenoceptors in adrenomedullary chromaffin cells: functional role and pathophysiological implications. AB - Chromaffin cells from the adrenal medulla participate in stress responses by releasing catecholamines into the bloodstream. Main control of adrenal catecholamine secretion is exerted both neurally (by the splanchnic nerve fibers) and humorally (by corticosteroids, circulating noradrenaline, etc.). It should be noted, however, that secretory products themselves (catecholamines, ATP, opioids, ascorbic acid, chromogranins) could also influence the secretory response in an autocrine/paracrine manner. This form of control is activity-dependent and can be either inhibitory or excitatory. Among the inhibitory influences, it stands out the one mediated by alpha2-adrenergic autoreceptors activated by released catecholamines. alpha2-adrenoceptors are G protein-coupled receptors capable to inhibit exocytotic secretion through a direct interaction of Gbetagamma subunits with voltage-gated Ca2+ channels. Interestingly, upon intense and/or prolonged stimulation, alpha2-adrenergic receptors become desensitized by the intervention of G protein-coupled receptor kinase 2 (GRK2). In several experimental models of heart failure, there has been reported the up-regulation of GRK2 and the loss of functioning of inhibitory alpha2-adrenoceptors resulting in enhanced release of adrenomedullary catecholamines. Given the importance of circulating catecholamines in the pathophysiology of heart failure, the recovery of alpha2 adrenergic modulation of the secretory response from chromaffin cells appears as a novel strategy for a better control of the patients with this cardiac disease. PMID- 28836009 TI - Contralateral cerebral hemoglobin oxygen saturation changes in patients undergoing thoracotomy with general anesthesia with or without paravertebral block: a randomized controlled trial. AB - PURPOSE: Perioperative analgesia during thoracotomy is often achieved by combining paravertebral block (PVB) with general anesthesia (GA). Functional near infrared spectroscopy (NIRS) can detect changes in cerebral oxygenation resulting from nociceptive stimuli in the awake state or under sedation. We used NIRS to measure changes in cerebral blood flow provoked by thoracotomy incision made under GA and determine how these changes were influenced by supplementation of GA with PVB. METHODS: Thirty-four patients undergoing elective thoracotomy were enrolled. Patients were randomly assigned to a group receiving only GA, or GA combined with PVB (GA + PVB). Changes in cerebral oxygenated hemoglobin (DeltaO2Hb), deoxygenated-Hb (DeltaHHb), and total-Hb (DeltatotalHb) were evaluated by NIRS as surgery began. RESULTS: In the GA group, DeltaO2Hb was significantly higher in the hemisphere contralateral to the side of surgery when the incision was made and 2 min after incision compared with the ipsilateral side (start of surgery, P < 0.01; 2 min, P < 0.05). In contrast, there were no significant changes in the DeltaO2Hb at any of the time points in the GA + PVB group. Comparable with DeltaO2Hb, the concentration of DeltatotalHb was significantly higher in the contralateral hemisphere in the GA group at the start of surgery (P < 0.05). CONCLUSIONS: Changes in the cerebral O2Hb concentration were detected by NIRS immediately after surgical incision under GA, but not in the presence of a PNB. NIRS could be used to monitor surgical pain. PVB inhibited changes in oxygenation induced by incision-provoked pain. PMID- 28836010 TI - The potential for intercellular mechanical interaction: simulations of single chondrocyte versus anatomically based distribution. AB - Computational studies of chondrocyte mechanics, and cell mechanics in general, have typically been performed using single cell models embedded in an extracellular matrix construct. The assumption of a single cell microstructural model may not capture intercellular interactions or accurately reflect the macroscale mechanics of cartilage when higher cell concentrations are considered, as may be the case in many instances. Hence, the goal of this study was to compare cell-level response of single and eleven cell biphasic finite element models, where the latter provided an anatomically based cellular distribution representative of the actual number of cells for a commonly used [Formula: see text] edge cubic representative volume in the middle zone of cartilage. Single cell representations incorporated a centered single cell model and eleven location-corrected single cell models, the latter to delineate the role of cell placement in the representative volume element. A stress relaxation test at 10% compressive strain was adopted for all simulations. During transient response, volume- averaged chondrocyte mechanics demonstrated marked differences (up to 60% and typically greater than 10%) for the centered single versus the eleven cell models, yet steady-state loading was similar. Cell location played a marked role, due to inhomogeneity of the displacement and fluid pressure fields at the macroscopic scale. When the single cell representation was corrected for cell location, the transient response was consistent, while steady-state differences on the order of 1-4% were realized, which may be attributed to intercellular mechanical interactions. Anatomical representations of the superficial and deep zones, where cells reside in close proximity, may exhibit greater intercellular interactions, but these have yet to be explored. PMID- 28836011 TI - Retinal sensitivity after displacement of submacular hemorrhage due to polypoidal choroidal vasculopathy: effectiveness and safety of subretinal tissue plasminogen activator. AB - PURPOSE: To investigate the effectiveness of displacement of submacular hemorrhage (SMH) caused by polypoidal choroidal vasculopathy (PCV) by assessing retinal sensitivity using microperimetry. METHODS: We retrospectively reviewed the medical records of 11 consecutive PCV patients with SMH. All patients underwent vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-air exchange, followed by antivascular endothelial growth factor therapy using a pro re nata regimen. The retinal sensitivity was measured by use of microperimetry before and after surgery. RESULTS: The mean (SD) age of the patients was 74.1 +/- 9.4 years. The mean SMH diameter was 6.8 +/- 5.2 disc diameters. The best-corrected visual acuity (BCVA), mean retinal sensitivity, and mean number of measure points with a sensitivity >=10 dB before the surgery were 0.94 +/- 0.49, 4.2 +/- 4.5 dB, and 15.6 +/- 15.1 points, respectively. These had significantly improved 6 months after surgery (0.39 +/- 0.37, 15.6 +/- 7.3 dB, and 50.9 +/- 22.2 points, respectively; P < 0.05 for all outcome measures). The mean number of measure points with an absolute scotoma before surgery had decreased significantly 6 months after surgery (from 40.5 +/- 15.0 to 9.4 +/- 16.0 points; P < 0.001). CONCLUSIONS: Displacement of SMH effectively improves retinal sensitivity as well as BCVA. PMID- 28836013 TI - Enhanced survival of ischemic skin flap by combined treatment with bone marrow derived stem cells and low-level light irradiation. AB - The aim of this study is to examine the enhanced survival effect of ischemic skin flap by combined treatment with bone marrow-derived stem cells (BMSCs) and low level light irradiation (LLLI). The neovasculogenic effect of BMSCs induced by LLLI was detected using a wound healing and tube formation assay. ICR mice were divided into four groups: control group, LLLI group, BMSCs group, and combine treated group. The percentage of skin flap necrosis area was calculated on the seventh post-operative day. Specimens were harvested for histologic analyses. LLLI promoted BMSC migration and tube formation. The flap survival rate of combined treated group was significantly higher than that of the control group. Histologic results demonstrated a significant increase in neovascularization in the combined treatment group. This study demonstrates that combination treatment of BMSCs and LLLI could enhance the survival of ischemic skin flap in a mouse model. PMID- 28836012 TI - A cost-effectiveness comparisons of adult spinal deformity surgery in the United States and Japan. AB - PURPOSE: Information about the cost-effectiveness of surgical procedures for adult spinal deformity (ASD) is critical for providing appropriate treatments for these patients. The purposes of this study were to compare the direct cost and cost-effectiveness of surgery for ASD in the United States (US) and Japan (JP). METHODS: Retrospective analysis of 76 US and 76 JP patients receiving surgery for ASD with >=2-year follow-up was identified. Data analysis included preoperative and postoperative demographic, radiographic, health-related quality of life (HRQOL), and direct cost for surgery. An incremental cost-effectiveness ratio (ICER) was determined using cost/quality-adjusted life years (QALY). The cost/QALY was calculated from the 2-year cost and HRQOL data. RESULTS: JP exhibited worse baseline spinopelvic alignment than the US (pelvic incidence and lumbar lordosis: 35.4 degrees vs 22.7 degrees , p < 0.01). The US had more three column osteotomies (50 vs 16%), and shorter hospital stay (7.9 vs 22.7 days) (p < 0.05). The US demonstrated worse postoperative ODI (41.3 vs. 33.9%) and greater revision surgery rate (40 vs 10%) (p < 0.05). Due to the high initial cost and revision frequency, the US had greater total cost ($92,133 vs. $49,647) and cost/QALY ($511,840 vs. $225,668) at 2-year follow-up (p < 0.05). CONCLUSION: Retrospective analysis comparing the direct costs and cost-effectiveness of ASD surgery in the US vs JP demonstrated that the total direct costs and cost/QALY were substantially higher in the US than JP. Variations in patient cohort, healthcare costs, revision frequencies, and HRQOL improvement influenced the cost/QALY differential between these countries. PMID- 28836014 TI - KLF10 transcription factor regulates hepatic glucose metabolism in mice. AB - AIM/HYPOTHESIS: Abnormal activation of hepatic gluconeogenesis leads to hyperglycaemia. However, the molecular mechanisms underlying dysregulated hepatic gluconeogenesis remain to be fully defined. Here, we explored the physiological role of Kruppel-like factor 10 (KLF10) in regulating hepatic glucose metabolism in mice. METHODS: Hepatic KLF10 expression in wild-type C57BL/6J mice, the db/db mouse model of diabetes, the ob/ob mouse model of obesity and high-fat-diet induced obese (DIO) mice was measured. Adenoviruses expressing Klf10 or Klf10 specific short-hairpin RNA were injected into wild-type C57BL/6J mice, db/db or DIO mice. Expression of gluconeogenic genes in the liver and blood glucose levels were measured. GTTs and pyruvate tolerance tests were performed. The molecular mechanism by which KLF10 regulates hepatic glucose metabolism was explored. RESULTS: Hepatic KLF10 expression was regulated by nutritional status in wild type mice and upregulated in diabetic, obese and DIO mice. Overexpression of KLF10 in primary hepatocytes increased the expression of gluconeogenic genes and cellular glucose output. C57BL/6J mice with KLF10 overexpression in the liver displayed increased blood glucose levels and impaired glucose tolerance. Conversely, hepatic KLF10 knockdown in db/db and DIO mice decreased blood glucose levels and improved glucose tolerance. Furthermore, luciferase reporter gene assay and chromatin immunoprecipitation analysis indicated that KLF10 activates Pgc-1alpha (also known as Ppargc1a) gene transcription via directly binding to its promoter region. CONCLUSIONS/INTERPRETATION: KLF10 is an important regulator of hepatic glucose metabolism and modulation of KLF10 expression in the liver may be an attractive approach for the treatment of type 2 diabetes. PMID- 28836015 TI - Role of protein-glutathione contacts in defining glutaredoxin-3 [2Fe-2S] cluster chirality, ligand exchange and transfer chemistry. AB - Monothiol glutaredoxins (Grx) serve as intermediate cluster carriers in iron sulfur cluster trafficking. The [2Fe-2S]-bound holo forms of Grx proteins display cysteinyl coordination from exogenous glutathione (GSH), in addition to contact from protein-derived Cys. Herein, we report mechanistic studies that investigate the role of exogenous glutathione in defining cluster chirality, ligand exchange, and the cluster transfer chemistry of Saccharomyces cerevisiae Grx3. Systematic perturbations were introduced to the glutathione-binding site by substitution of conserved charged amino acids that form crucial electrostatic contacts with the glutathione molecule. Native Grx3 could also be reconstituted in the absence of glutathione, with either DTT, BME or free L-cysteine as the source of the exogenous Fe-S ligand contact, while retaining full functional reactivity. The delivery of the [2Fe-2S] cluster to Grx3 from cluster donor proteins such as Isa, Nfu, and a [2Fe-2S](GS)4 complex, revealed that electrostatic contacts are of key importance for positioning the exogenous glutathione that in turn influences the chiral environment of the cluster. All Grx3 derivatives were reconstituted by standard chemical reconstitution protocols and found to transfer cluster to apo ferredoxin 1 (Fdx1) at rates comparable to native protein, even when using DTT, BME or free L-cysteine as a thiol source in place of GSH during reconstitution. Kinetic analysis of cluster transfer from holo derivatives to apo Fdx1 has led to a mechanistic model for cluster transfer chemistry of native holo Grx3, and identification of the likely rate-limiting step for the reaction. PMID- 28836016 TI - Impact of age on short- and long-term mortality of patients with ST-elevation myocardial infarction in the VIENNA STEMI network. AB - BACKGROUND AND AIM: Our senescent society includes a growing number of elderly people suffering from ST-elevation myocardial infarction (STEMI); however, exactly this population is often underrepresented in randomized trials. Hence, our aim was to investigate the influence of age on patient characteristics, as well as short- and long-term outcome in the Vienna STEMI registry. METHODS: We included all patients of the Vienna STEMI registry (2003-2009). Patients were stratified into age cohorts (<=45, 46-59, 60-79 and >=80 years, respectively). Differences between cohorts were investigated by descriptive statistics and regression models. Crude and adjusted mortality rates were investigated using log rank test and Cox regression models, respectively. The influence of treatment on mortality was further investigated using propensity score matching. RESULTS: A total of 4579 patients fulfilled the criteria for further investigation. With rising age of cohorts, the number of females, diabetes mellitus (DM), hypertension (HTN), previous myocardial infarction (MI), shock, no reperfusion therapy and anterior wall infarction significantly increased. In contrast, the number of patients with a positive family history, smoking and hyperlipidemia (HLP) significantly declined. Log rank analysis showed significant differences between age cohorts for short- and long-term mortality. Cox regression analysis for short-term mortality revealed an independent association for age at the event, HTN and shock, while age, smoking, DM, HTN, HLP, previous MI and shock independently influenced long-term mortality after correction for confounders. Also, we found a significant association of age and total ischemic time (TIT), which however had no influence on long-term mortality (interaction term p = 0.236). Propensity score matching revealed reduced mortality rates for patients who received reperfusion therapy compared to conservative management, irrespective of age. CONCLUSIONS: Increasing age independently influenced short- and long-term mortality in patients with STEMI in the Vienna STEMI network. The TIT significantly increased with baseline age, but had no impact on mortality. Furthermore, reperfusion therapy exerted beneficial effects irrespective of the patients' age. PMID- 28836017 TI - Improving the catalytic characteristics of lipase-displaying yeast cells by hydrophobic modification. AB - Lipase-displaying yeast cells are a promising alternative to the conventional immobilised lipases for organic bioconversions. However, the hydrophilic characteristics of the yeast cell surface may impede efficient immobilisation. Herein, we tested three methods to enhance the hydrophobicity of the surface of Candida antarctica lipase B-displaying Pichia pastoris cells, co-displaying a fungal hydrophobin, coating with ionic liquids, and adding decane as a hydrophobic carbon source during fermentation. Modified cells showed higher surface hydrophobicity and superior esterification of C6-C18 saturated fatty acids in hydrophobic solvents. When used for biodiesel synthesis, modified cells exhibited an improved initial reaction rate and equilibrium fatty acid methyl ester yield. We systematically discuss the influence of cell surface hydrophobicity on the catalytic properties, and the results provide guidance for improving the catalytic efficiency and operational characteristics of lipase displaying yeast cells for organic bioconversions. PMID- 28836018 TI - Chronic stress, energy transduction, and free-radical production in a reptile. AB - Stress hormones, such as corticosterone, play a crucial role in orchestrating physiological reaction patterns shaping adapted responses to stressful environments. Concepts aiming at predicting individual and population responses to environmental stress typically consider that stress hormones and their effects on metabolic rate provide appropriate proxies for the energy budget. However, uncoupling between the biochemical processes of respiration, ATP production, and free-radical production in mitochondria may play a fundamental role in the stress response and associated life histories. In this study, we aim at dissecting sub cellular mechanisms that link these three processes by investigating both whole organism metabolism, liver mitochondrial oxidative phosphorylation processes (O2 consumption and ATP production) and ROS emission in Zootoca vivipara individuals exposed 21 days to corticosterone relative to a placebo. Corticosterone enhancement had no effect on mitochondrial activity and efficiency. In parallel, the corticosterone treatment increased liver mass and mitochondrial protein content suggesting a higher liver ATP production. We also found a negative correlation between mitochondrial ROS emission and plasma corticosterone level. These results provide a proximal explanation for enhanced survival after chronic exposure to corticosterone in this species. Importantly, none of these modifications affected resting whole-body metabolic rate. Oxygen consumption, ATP, and ROS emission were thus independently affected in responses to corticosterone increase suggesting that concepts and models aiming at linking environmental stress and individual responses may misestimate energy allocation possibilities. PMID- 28836020 TI - Change of the N-terminal codon bias combined with tRNA supplementation outperforms the selected fusion tags for production of human D-amino acid oxidase as active inclusion bodies. AB - OBJECTIVES: To optimize the production of active inclusion bodies (IBs) containing human D-amino acid oxidase (hDAAO) in Escherichia coli. RESULTS: The optimized initial codon region combined with the coexpressed rare tRNAs, fusion of each of the N-terminal partners including cellulose-binding module, thioredoxin, glutathione S-transferase and expressivity tag, deletion of the incorporated linker, and improvement of tRNA abundance affected the production and activity for oxidizing D-alanine of the hDAAO in IBs. Compared with the optimized fusion constructs and expression host, IBs yields and activity were increased to 2.6- and 2.8-fold respectively by changing the N-terminal codon bias of the hDAAO. The insoluble hDAAO codon variant displayed the same substrate specificity as the soluble one for oxidizing D-alanine, D-serine and D-aspartic acid. The freshly prepared hDAAO codon variant was used for analyzing the L serine racemization activity of the bacterially expressed maize serine racemase. CONCLUSIONS: Optimization of the N-terminal codon bias combined with the coexpression of rare tRNAs is a novel and efficient approach to produce active IBs of the hDAAO. PMID- 28836019 TI - A new classification system for degenerative spondylolisthesis of the lumbar spine. AB - PURPOSE: There is no consensus for a comprehensive analysis of degenerative spondylolisthesis of the lumbar spine (DSLS). A new classification system for DSLS based on sagittal alignment was proposed. Its clinical relevance was explored. METHODS: Health-related quality-of-life scales (HRQOLs) and clinical parameters were collected: SF-12, ODI, and low back and leg pain visual analog scales (BP-VAS, LP-VAS). Radiographic analysis included Meyerding grading and sagittal parameters: segmental lordosis (SL), L1-S1 lumbar lordosis (LL), T1-T12 thoracic kyphosis (TK), pelvic incidence (PI), pelvic tilt (PT), and sagittal vertical axis (SVA). Patients were classified according to three main types-1A: preserved LL and SL; 1B: preserved LL and reduced SL (<=5 degrees ); 2A: PI-LL >=10 degrees without pelvic compensation (PT < 25 degrees ); 2B: PI-LL >=10 degrees with pelvic compensation (PT >= 25 degrees ); type 3: global sagittal malalignment (SVA >=40 mm). RESULTS: 166 patients (119 F: 47 M) suffering from DSLS were included. Mean age was 67.1 +/- 11 years. DSLS demographics were, respectively: type 1A: 73 patients, type 1B: 3, type 2A: 8, type 2B: 22, and type 3: 60. Meyerding grading was: grade 1 (n = 124); grade 2 (n = 24). Affected levels were: L4-L5 (n = 121), L3-L4 (n = 34), L2-L3 (n = 6), and L5-S1 (n = 5). Mean sagittal parameter values were: PI: 59.3 degrees +/- 11.9 degrees ; PT: 24.3 degrees +/- 7.6 degrees ; SVA: 29.1 +/- 42.2 mm; SL: 18.2 degrees +/- 8.1 degrees . DSLS types were correlated with age, ODI and SF-12 PCS (rho = 0.34, p < 0.05; rho = 0.33, p < 0.05; rho = -0.20, and p = 0.01, respectively). CONCLUSION: This classification was consistent with age and HRQOLs and could be a preoperative assessment tool. Its therapeutic impact has yet to be validated. LEVEL OF EVIDENCE: 4. PMID- 28836021 TI - Hip abductor tendinitis after ACL reconstruction with patellar tendon graft in soccer players. A new clinical complication. AB - Although ACL reconstruction remains a complex procedure with possible complications, affecting mainly the knee function, but no complications affecting the hip function have been already mentioned in the literature. Here in, we discuss the demographics, clinical course and outcomes of a rare complication such as hip abductors tendinitis, developed in soccer amateur athletes after ACL reconstruction with patellar tendon graft. PMID- 28836022 TI - Covalent-display of an active chimeric-recombinant tissue plasminogen activator on polyhydroxybutyrate granules surface. AB - OBJECTIVE: To develop a deliberately engineered expression and purification system for an active chimeric-recombinant tissue plasminogen activator (crtPA) using co-expression with polyhydroxybutyrate (PHB) operon genes. RESULTS: Fusion of crtPA with PhaC-synthase simplified the purification steps through crtPA sedimentation with PHB particles. Moreover, the covalently immobilized crtPA was biologically active as shown in a chromogenic assay. Upon WELQut-protease activity, the released single-chain crtPA converted to the two-chain form which produced a pattern of bands with approx. MW of 32 and 11 kDa in addition to the full length crtPA. CONCLUSION: Fusion of crtPA with PhaC-synthase not only simplifies purification from the bacterial host lysate, but also co-expression of PHB operon genes creates an oxidative environment, thereby reducing the inclusion body formation possibility. The isolated crtPA-PHB granules exhibited crtPA serine protease activity. Thus, fusion with the PhaC protein could be used as a scaffold for covalent displaying of functional disulfide-rich proteins. PMID- 28836023 TI - Studies on reaction of glutathionylcobalamin with hypochlorite. Evidence of protective action of glutathionyl-ligand against corrin modification by hypochlorite. AB - Glutathionylcobalamin (GSCbl), a tight complex of glutathione (GSH) with cobalamin(III), is readily oxidized to aquacobalamin by hypochlorite. Corrin macrocycle remains unmodified in the presence of threefold excess of hypochlorite, whereas aqua- and cyanocobalamins are partially transformed to chlorinated species under the same conditions. The suggested mechanism of reaction between GSCbl and hypochlorite involves subsequent oxidation of thiol and amino groups and dissociation of oxidized glutathione from Co(III)-ion. PMID- 28836024 TI - Prognostic factors for disease-free and overall survival of patients with uterine carcinosarcoma. AB - BACKGROUND: Uterine carcinosarcoma (UCS) is a relatively rare and very aggressive tumor. The predictors of survival for patients with UCS have not been determined clearly yet. The aim of the present study was to investigate the possible predictors of disease-free survival (DFS) and overall survival (OS) for patients with UCS. METHODS AND MATERIALS: All patients with UCS who were treated surgically at a university-based Gynecology Oncology Clinic between January 2008 and December 2014 were recruited into this retrospective cohort study. Data regarding clinical, pathologic and treatment information were obtained retrospectively from hospital records. The Kaplan-Meier method was used to calculate DFS and OS, and Cox regression analysis was performed to define the effects of risk factors on survival. RESULTS: A total of 88 UCS patients with a median age of 64.5 years were included in the study. Forty-seven (53.4%) patients were diagnosed with stage III disease and seven (7.9%) with stage IV disease. The median follow-up time was 16 months. Among all patients, 60 (68.1%) underwent lymphadenectomy. Optimal cytoreductive surgery was achieved in 67 (76.1%) patients. Stepwise variable selection Cox regression analysis showed that lymph node metastasis was associated with poor DFS (hazard ratio 6.524; 95% CI 2.625 16.211; P < 0.001) and OS (hazard ratio 6.993; 95% CI 2.631-18.587; P < 0.001). Subgroup analysis in both early and advanced-stage diseases revealed no significant impact of risk factors on survival. CONCLUSIONS: Lymph node metastasis is the most significant prognostic factor associated with poor DFS and OS in UCS patients. PMID- 28836025 TI - Anatomical topography of the inferior lumbar triangle for transversus abdominis block. AB - BACKGROUND: Rapid development of anesthetic techniques of thoracic paravertebral block required to redefine anatomical landmarks of the inferior lumbar (Petit) triangle (ILT). Anesthesiologists are mainly interested in the ILT to perform the transversus abdominis plane (TAP) block. The aim of this study was to provide comprehensive information of the ILT to improve the success of TAP block. METHODS: Descriptional anatomy of ILTs such as dimensions, space, area, and types was analyzed in 25 preserved adult male cadavers. RESULTS: The ILT was identified in 100% out of all explored cadavers' lumbar regions. The predominant triangle was the acute-angled shaped (46%). The ILT in terms of the surface area was classified into four distinct types: Type I with a surface area <8 cm2 was identified in 50%. Type II or intermediate triangles with a surface area of 8-12 cm2 were detected in 36%. Type III or large triangles with a surface area >12 cm2 were found in 14%. Type 0 or no triangle did not exhibit a triangle. For the orientation zone over the posterior lumbar region, it was measured with the distances from the posterior median line (M) to the apex (A), medial point (B), and lateral point (C) of the triangle. MA; as M1A transverse line: 103.3 +/- 21.3 mm (left) and 106.4 +/- 18.4 mm (right), MB; as M2B transverse line; 102.4 +/- 21.8 mm (left) and 105 +/- 17.9 mm (right), MC; as M3C transverse line; 119 +/- 20.5 mm (left) and 120 +/- 19.2 mm (right) were measured. In addition, the measurements of the vertical lines were measured. M1A-M2B and M1A-M3C vertical lines were 20.1-22.8 mm (left-right) and 30-29 mm (left-right), respectively. CONCLUSIONS: The shape, the size, useful points, geometry, and topography of the ILT are important to determine the orientation points during block procedures. It is possible to visualize the needle pathway in different shape of ILT to ultrasound-guided TAP block. Anesthetic intervention needs to be individualized, depending upon the size of the triangle. The findings may be useful in establishing the area with the highest probability of localization of the ILT which can improve both the safety and efficiency of TAP block. PMID- 28836027 TI - Temporary Anorgasmia Following Uterine Artery Embolization for Symptomatic Uterine Fibroids. AB - We report a rare case of temporary anorgasmia following uterine artery embolization (UAE) performed for symptomatic uterine fibroids. To our knowledge, this is only the second time that this complication has been reported in the literature. We briefly explore the possible pathophysiologic explanations for this complication and review the effects of UAE compared to hysterectomy on sexual functioning in women. PMID- 28836026 TI - Individual radiation exposure from computed tomography: a survey of paediatric practice in French university hospitals, 2010-2013. AB - OBJECTIVES: To describe computed tomography (CT) scanning parameters, volume CT dose index (CTDIvol) and dose-length product (DLP) in paediatric practice and compare them to current diagnostic reference levels (DRLs). METHODS: The survey was conducted in radiology departments of six major university hospitals in France in 2010-2013. Data collection was automatised to extract and standardise information on scanning parameters from DICOM-header files. CTDIvol and DLP were estimated based on Monte Carlo transport simulation and computational reference phantoms. RESULTS: CTDIvol and DLP were derived for 4,300 studies, four age groups and 18 protocols. CTDIvol was lower in younger patients for non-head scans, but did not vary with age for routine head scans. Ratios of 95th to 5th percentile CTDIvol values were 2-4 for most body parts, but 5-7 for abdominal examinations and 4-14 for mediastinum CT with contrast, depending on age. The 75th percentile CTDIvol values were below the national DRLs for chest (all ages) and head and abdominal scans (>=10 years). CONCLUSION: The results suggest the need for a better optimisation of scanning parameters for routine head scans and infrequent protocols with patient age, enhanced standardisation of practices across departments and revision of current DRLs for children. KEY POINTS: * CTDIvol varied little with age for routine head scans. * CTDIvol was lowest in youngest children for chest or abdominal scans. * Individual and inter department variability warrant enhanced standardisation of practices. * Recent surveys support the need for revised diagnostic reference levels. * More attention should be given to specific protocols (sinuses, neck, spine, mediastinum). PMID- 28836028 TI - Prevalence and clinical outcomes of hip fractures and subchondral insufficiency fractures of the femoral head in patients with tumour-induced osteomalacia. AB - PURPOSE: Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by phosphaturic mesenchymal tumours, leading to great distress due to bone pain and affecting quality of life (QoL). This study aimed to investigate the prevalence and clinical outcomes of hip fractures and subchondral insufficiency fractures (SIF) of the femoral head. METHODS: Twelve TIO patients were treated between January 2000 and December 2016 at our hospital. All underwent surgery for the tumour causing TIO, and complete removal of the tumour was accomplished in nine of 12 cases. Plain radiographs of the hip were obtained in all cases, and magnetic resonance imaging (MRI) was obtained from 15 hips representing eight patients before tumour removal. We evaluated the prevalence of hip fractures or SIF and their clinical outcomes. RESULTS: Hip fractures were observed in six of 12 cases, and the total number of fractures was nine, of which five were femoral neck, two were intertrochanteric and two were subtrochanteric fractures. Conservative treatment, regardless of complete remission of TIO, was successful except in one case with impending subtrochanteric fracture. SIFs were observed in 11 of 24 hips. Seven of 11 hips with SIF showed progression after surgery for tumour resection. CONCLUSIONS: Hip fractures and SIF are highly prevalent in TIO patients. Surgical and medical treatment for TIO is sufficient for treating hip fractures conservatively. However, SIF tends to show progression of femoral head collapse, serving as the main cause of pain after successful TIO treatment. PMID- 28836029 TI - Increased risk of arterial thromboembolism in older men with breast cancer. AB - PURPOSE: Male breast cancer is a rare and understudied disease predominantly affecting men over age 60. Risk of arterial thromboembolic events (ATE) in men increases with age. We examined ATE risk following primary breast cancer diagnosis in elderly men. METHODS: Men with primary breast cancer diagnoses from 2002 to 2011 were identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Cases were individually matched by age, sex, race, registry, and comorbidities with controls without cancer using SEER Medicare's 5% noncancer sample. Medicare claims were used to identify ATE, defined as myocardial infarction or ischemic stroke. Cumulative incidence of ATE was calculated using competing risk methodology, with death considered a competing event. Cox proportional hazards analysis was used to compare rates of ATE among cases and controls. RESULTS: Three months following primary breast cancer diagnosis, ATE risk in the cohort of 881 men was 80% higher than matched controls (hazard ratio 1.8; 95% confidence interval 1.0-3.2). Six months post cancer diagnosis, 5.7% of cases had experienced ATE, whereas only 3.5% of controls had (HR 1.6; 95% CI 1.0-2.6). ATE risk remained elevated 12 months post cancer diagnosis. Among cases, risk of death was threefold higher in men who developed ATE. CONCLUSIONS: We provide population-based evidence that male breast cancer patients have a substantially elevated risk of ATE in the first year following a cancer diagnosis compared with matched controls. Care providers should consider this heightened risk when evaluating cardiovascular health in men with a recent breast cancer diagnosis. PMID- 28836030 TI - Bilateral chylothorax following anterior cervical spine surgery. AB - Bilateral chylothorax following anterior cervical spine surgery is very rare. This report documents the first case of chylothorax after anterior cervical spine surgery through a right-side surgical approach. Unidentified chyle leakage can easily remain unrecognized and, thus, is difficult to treat. For early diagnosis and treatment, it is very important to consider the possibility of chylothorax following anterior cervical spine surgery, even when using a right-side surgical approach. PMID- 28836031 TI - A field screening test for the assessment of concentrations and mobility of potentially toxic elements in soils: a case study on urban soils from Rome and Novi Sad. AB - The increasing demand for environmental pollution control results in the development and use of new procedures for the determination of dangerous chemicals. Simple screening methods, which can be used directly in the field for a preliminary assessment of soil contamination, seem to be extremely advantageous. In our laboratory, we developed and optimized a rapid test for a preliminary evaluation of both the concentration and the mobility of some potentially toxic metals in soils. This screening test consists of a single extraction of the soil sample with a buffer solution, followed by the titration of the extracted solution with dithizone to determine the contents of bi-valent heavy metals (such as Pb, Cu, Zn, and Cd). This screening method was then directly applied in the field during the sampling campaign in the framework of an Italian-Serbian collaborative project, finalized in the study of metal availability in soils. The results obtained in the field with the rapid test were compared with those obtained in the laboratory following the conventional procedure commonly used to evaluate metal bioavailability (diethylenetriaminepentaacetic extraction). Moreover, selected samples were analyzed sequentially in the laboratory using the standardized BCR three-step sequential extraction procedure. The screening test gave results conceptually in good agreement with those obtained via the BCR procedure. These preliminary data show that the proposed screening test is a reliable method for the preliminary rapid evaluation of metal total concentrations and of potential metal mobility in soils, supporting sampling activities directly in the field. PMID- 28836032 TI - Enhanced dimethyl phthalate biodegradation by accelerating phthalic acid di oxygenation. AB - The aerobic biodegradation of dimethyl phthalate (DMP) is initiated with two hydrolysis reactions that generate an intermediate, phthalic acid (PA), that is further biodegraded through a two-step di-oxygenation reaction. DMP biodegradation is inhibited when PA accumulates, but DMP's biodegradation can be enhanced by adding an exogenous electron donor. We evaluated the effect of adding succinate, acetate, or formate as an exogenous electron donor. PA removal rates were increased by 15 and 30% for initial PA concentrations of 0.3 and 0.6 mM when 0.15 and 0.30 mM succinate, respectively, were added as exogenous electron donor. The same electron-equivalent additions of acetate and formate had the same acceleration impacts on PA removal. Consequently, the DMP-removal rate, even PA coexisting with DMP simultaneously, was accelerated by 37% by simultaneous addition of 0.3 mM succinate. Thus, lowering the accumulation of PA by addition of an electron increased the rate of DMP biodegradation. PMID- 28836033 TI - Predictability and inconsistencies in the cognitive outcome of early treated PKU patients. AB - Long-term cognitive outcome and treatment of adult early treated (ET)PKU patients is a main issue in PKU research. We questioned whether the intellectual development of ETPKU patients is stable and to what extent its variation may be predicted by the quality of metabolic control. The aims of the present longitudinal retrospective study were to assess in young adult ETPKU patients: i) the relationship between IQ and metabolic control during the first two decades of life; and ii) the intra- and interindividual variability in the developmental trajectory which cannot be predicted by the disease's biomarkers. We collected biochemical data from 65 ETPKU patients (diagnostic blood Phe > 360 MUmol/l) who were assessed twice for IQ (Wechsler Intelligence Scale) during their lifetime (mean age: 10.2 and 19.6 years, respectively). Results show that in ETPKU patients IQ over the second decade of life remained stable in about half of the patients (51%); while the rest experienced a gain (7 to 15 points) or loss (7 to 28 points) in IQ scores (23 and 26% respectively) whatever the quality of metabolic control was. The main factor affecting the second IQ was the value of the first IQ (p < 0.000) whose effect overruled that of the markers of metabolic control. Looking at the developmental trajectory of our ETPKU patients, the present study disclosed a remarkable interindividual variability in their cognitive outcome and also an inconsistent linkage between cognitive performances and biochemical control, thus supporting the hypothesis of an individual resilience or vulnerability to Phe in young adult ETPKU. PMID- 28836034 TI - Spatio-temporal study of environmental nontuberculous mycobacteria isolated from Wardha district in Central India. AB - During the last two decades, nontuberculous mycobacteria (NTM) have gained in importance but there is still a paucity of data, particularly for environmental isolates. We studied, over a period of two years, the spatio-temporal features of NTM isolates obtained from different environmental sources in Wardha district, India. A total of 1398 samples (699 each of soil and water) were tested and 170 (12.2%) yielded NTM isolates, including 123 from soil and 47 from water samples. Out of 170 NTM isolates, 107 (63%) belonged to potentially pathogenic mycobacteria (PPM) and 63 (37%) to the less pathogenic mycobacterial (LPM) group. Overall, maximum isolation was obtained in rainy season (20.3%) followed by winter (13.5%), post rainy (8.7%) and summer seasons (5.8%). Mycobacterium fortuitum, Mycobacterium gordonae and Mycobacterium avium complex (MAC) were common isolates followed by Mycobacterium flavescens, Mycobacterium scrofulaceum, Mycobacterium simiae and Mycobacterium marinum. From soil, isolation of NTM was highest from grounds used for community gatherings (42.8%) followed by soil from residential premises (27.7%) and near the wells (26.0%). From drinking water sources, highest NTM isolation was obtained from wells (15.4%) followed by treated water tanks (6.9%), household receptacles (6.3%), hand pumps (5.6%) and tap water supply (3.5%). Isolation from natural canal water was 6.6%, while from drainage and waste water ponds isolation was 8.3%. The results of the study revealed that in Wardha district, NTM are present both in the soil and drinking water. As NTM can be pathogenic, particularly in immune-compromised individuals, these can be of potential risk to the human population. PMID- 28836035 TI - Familial associations of male breast cancer with other cancers. AB - PURPOSE: Male breast cancer is associated with female breast cancer in families but whether male breast cancer clusters with other discordant cancers has not been studied. As concordant male breast cancers are utterly rare, discordant associations of male breast cancer with other cancers may reveal genetic and possible environmental risk factors contributing to male breast cancer susceptibility. METHODS: We calculated relative risks (RRs) for male breast cancer in families with discordant cancers, and conversely, for discordant cancers in families of male breast cancer patients, based on 15.7 million individuals in the Swedish Family-Cancer Database. RESULTS: Among 1428 male breast cancer patients, 16.2% had a female relative diagnosed with breast cancer. Ovarian and female anal cancers showed the strongest associations with male breast cancer (p value < 0.0005). The other significant associations included colorectal, small intestinal, and thyroid cancers, cancer of unknown primary and non-Hodgkin lymphoma but these were each based on a single positive association with male breast cancer. The RRs for male breast cancer were increased in families in which multiple patients were diagnosed with diverse cancers, reaching an RR of 2.58 when three or more family members were affected. CONCLUSIONS: The results suggest that male breast cancer shares susceptibility with a number of other cancers but confirmation is needed in other datasets. PMID- 28836037 TI - Intramedullary placement of ventricular shunts: a review of using bone as a distal cerebrospinal absorption site in treating hydrocephalus. AB - PURPOSE: Intraosseous (IO) vascular access has been used since the Second World War and is warranted when there is an emergency and/or urgent need to replenish the vascular pool. Despite long-term and satisfactory results from delivering large quantities of intravenous fluid via the medullary space of bone, use of this space for a distant receptacle for cerebrospinal fluid (CSF) diversion has seldom been considered. METHODS: The current paper reviews the literature regarding the bony medullary space as a receptacle for intravenous fluid and CSF. RESULTS: Previous authors have demonstrated the potential of the diploic space of the calvaria for CSF shunting. Pugh and colleagues tested the ability of the cranium to receive and absorb a small amount of tracer fluid. CONCLUSION: The literature suggests that intraosseous placement of ventricular diversionary shunts is an alternative to more traditional sites such as the pleural cavity and peritoneum. When these latter locations are not available or are contraindicated, placement in the medullary space of bone is another option available to the surgeon. PMID- 28836036 TI - Modulation of adenylate cyclase signaling in association with MKK3/6 stabilization under combination of SAC and berberine to reduce HepG2 cell survivability. AB - Cancer cells often have faulty apoptotic pathways resulting in sustenance of survivability, tumour metastasis and resistance to anticancer drugs. Alternate strategies are sought to improve therapeutic efficacy and therefore HepG2 cells were treated with S-allyl-cysteine (SAC) and berberine (BER) to analyze their mechanistic impact upon necroptosis along with its interacting relationship to apoptosis. In the present study we observed that SAC and BER exposure reduced NFkappabeta nuclear translocation through adenylate cyclase-cAMP-protein kinaseA axis and eventually evaded c-FLIP inhibition. Effective RIP1 k63 polyubiquitination and persistent MKK3/MKK6 expression during drug treatment potentiated caspase8 activity via p53-DISC conformation. Resultant tBid associated lysosomal protease mediated AIF truncation induced DNA fragmentation and persuaded effector caspase mediated scramblase activation resulting induction of necroptosis in parallel to apoptotic events. SAC+BER effectively reduced Rb phosphorylation resulting insignificant nuclear E2F presence led to ending of cell proliferation. Therefore necroptosis augmented the drug response and may be targeted alongside cell proliferation inhibition in formation of efficient therapeutics against liver cancer. PMID- 28836038 TI - The effects of stimulus parameters on auditory evoked potentials of Carassius auratus. AB - Whole-brain responses to sound are easily measured through auditory evoked potentials (AEP), but it is unclear how differences in experimental parameters affect these responses. The effect of varying parameters is especially unclear in fish studies, the majority of which use simple sound types and then extrapolate to natural conditions. The current study investigated AEPs in goldfish (Carassius auratus) using sounds of different durations (5, 10, and 20 ms) and frequencies (200, 500, 600 and 700 Hz) to test stimulus effects on latency and thresholds. We quantified differences in latency and threshold in comparison to a 10-ms test tone, a duration often used in AEP fish studies. Both response latency and threshold were significantly affected by stimulus duration, with latency patterning suggesting that AEP fires coincident with a decrease in stimulus strength. Response latency was also significantly affected by presentation frequency. These results show that stimulus type has important effects on AEP measures of hearing and call for clearer standards across different measures of AEP. Duration effects also suggest that AEP measures represent summed responses of duration-detecting neural circuit, but more effort is needed to understand the neural drivers of this commonly used technique. PMID- 28836039 TI - Fully-automated left ventricular mass and volume MRI analysis in the UK Biobank population cohort: evaluation of initial results. AB - UK Biobank, a large cohort study, plans to acquire 100,000 cardiac MRI studies by 2020. Although fully-automated left ventricular (LV) analysis was performed in the original acquisition, this was not designed for unsupervised incorporation into epidemiological studies. We sought to evaluate automated LV mass and volume (Siemens syngo InlineVF versions D13A and E11C), against manual analysis in a substantial sub-cohort of UK Biobank participants. Eight readers from two centers, trained to give consistent results, manually analyzed 4874 UK Biobank cases for LV end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF) and LV mass (LVM). Agreement between manual and InlineVF automated analyses were evaluated using Bland-Altman analysis and the intra-class correlation coefficient (ICC). Tenfold cross-validation was used to establish a linear regression calibration between manual and InlineVF results. InlineVF D13A returned results in 4423 cases, whereas InlineVF E11C returned results in 4775 cases and also reported LVM. Rapid visual assessment of the E11C results found 178 cases (3.7%) with grossly misplaced contours or landmarks. In the remaining 4597 cases, LV function showed good agreement: ESV -6.4 +/- 9.0 ml, 0.853 (mean +/- SD of the differences, ICC) EDV -3.0 +/- 11.6 ml, 0.937; SV 3.4 +/- 9.8 ml, 0.855; and EF 3.5 +/- 5.1%, 0.586. Although LV mass was consistently overestimated (29.9 +/- 17.0 g, 0.534) due to larger epicardial contours on all slices, linear regression could be used to correct the bias and improve accuracy. Automated InlineVF results can be used for case-control studies in UK Biobank, provided visual quality control and linear bias correction are performed. Improvements between InlineVF D13A and InlineVF E11C show the field is rapidly advancing, with further improvements expected in the near future. PMID- 28836040 TI - Two Gut-Associated Yeasts in a Tephritid Fruit Fly have Contrasting Effects on Adult Attraction and Larval Survival. AB - Yeast-insect interactions have been well characterized in drosophilid flies, but not in tephritid fruit flies, which include many highly polyphagous pest species that attack ripening fruits. Using the Queensland fruit fly (Bactrocera tryoni) as our model tephritid species, we identified yeast species present in the gut of wild-collected larvae and found two genera, Hanseniaspora and Pichia, were the dominant isolates. In behavioural trials using adult female B. tryoni, a fruit agar substrate inoculated with Pichia kluyveri resulted in odour emissions that increased the attraction of flies, whereas inoculation with Hanseniaspora uvarum, produced odours that strongly deterred flies, and both yeasts led to decreased oviposition. Larval development trials showed that the fruit-agar substrate inoculated with the 'deterrent odour' yeast species, H. uvarum, resulted in significantly faster larval development and a greater number of adult flies, compared to a substrate inoculated with the 'attractive odour' yeast species, P. kluyveri, and a yeast free control substrate. GC-MS analysis of volatiles emitted by H. uvarum and P. kluyveri inoculated substrates revealed significant quantitative differences in ethyl-, isoamyl-, isobutyl-, and phenethyl- acetates, which may be responsible for the yeast-specific olfactory responses of adult flies. We discuss how our seemingly counterintuitive finding that female B. tryoni flies avoid a beneficial yeast fits well with our understanding of female choice of oviposition sites, and how the contrasting behavioural effects of H. uvarum and P. kluyveri raises interesting questions regarding the role of yeast specific volatiles as cues to insect vectors. A better understanding of yeast tephritid interactions could assist in the future management of tephritid fruit fly pests through the formulation of new "attract and kill" lures, and the development of probiotics for mass rearing of insects in sterile insect control programs. PMID- 28836041 TI - A glimpse at short-term controls of evapotranspiration along the southern slopes of Kilimanjaro. AB - Future climate characteristics of the southern Kilimanjaro region, Tanzania, are mainly determined by local land-use and global climate change. Reinforcing increasing dryness throughout the twentieth century, ongoing land transformation processes emphasize the need for a proper understanding of the regional-scale water budget and possible implications on related ecosystem functioning and services. Here, we present an analysis of scintillometer-based evapotranspiration (ET) covering seven distinct habitat types across a massive climate gradient from the colline savanna woodlands to the upper-mountain Helichrysum zone (940 to 3960 m.a.s.l.). Random forest-based mean variable importance indicates an outstanding significance of net radiation (R net) on the observed ET across all elevation levels. Accordingly, topography and frequent cloud/fog events have a dampening effect at high elevations, whereas no such constraints affect the energy and moisture-rich submontane coffee/grassland level. By contrast, long-term moisture availability is likely to impose restrictions upon evapotranspirative net water loss in savanna, which particularly applies to the pronounced dry season. At plot scale, ET can thereby be approximated reasonably using R net, soil heat flux, and to a lesser degree, vapor pressure deficit and rainfall as predictor variables (R 2 0.59 to 1.00). While multivariate regression based on pooled meteorological data from all plots proves itself useful for predicting hourly ET rates across a broader range of ecosystems (R 2 = 0.71), additional gains in explained variance can be achieved when vegetation characteristics as seen from the NDVI are considered (R 2 = 0.87). To sum up, our results indicate that valuable insights into land cover-specific ET dynamics, including underlying drivers, may be derived even from explicitly short-term measurements in an ecologically highly diverse landscape. PMID- 28836042 TI - Coumarin-Rhodamine Hybrids-Novel Probes for the Optical Measurement of Viscosity and Polarity. AB - A comprehensive systematic study of absorption and fluorescence properties in solvents of varying viscosity and polarity of three novel and red-emitting coumarin-rhodamine hybrid derivatives with differences in the rigidity of their substituents is presented. This includes ethanol-polyethylene glycol, toluene polyethylene glycol, and toluene-paraffin mixtures. Moreover, protonation-induced effects on the spectroscopic properties are studied. A viscosity-induced emission enhancement was observed for all coumarin-rhodamine hybrid derivatives. MCR2 bearing a julolidine donor showed the expected low sensitivity to viscosity whereas MCR3 with its freely rotatable diphenylamino substituent revealed a particularly pronounced sensitivity to this parameter. Moreover, MCR2 shows an enhancement in emission in the open, i.e., protonated form in conjunction with a largely Stokes shift fluorescence in the deep red spectral region. This enables the application of these dyes as viscosity sensors and as far red emitting pH sensitive probes. PMID- 28836044 TI - Dentate granule progenitor cell properties are rapidly altered soon after birth. AB - Neurogenesis occurs during the embryonic period and ceases soon after birth in the neocortex, but continues to occur in the hippocampus even in the adult. The embryonic neocortex has radial glia or progenitor cells expressing brain lipid binding protein (BLBP), whereas the adult hippocampus has radial granule progenitor cells expressing BLBP and glial fibrillary acidic protein (GFAP) in the subgranular zone. We previously found that embryonic hippocampal granule progenitor cells express GFAP, but not BLBP, indicating that these cells are different from both embryonic neocortical and adult granule progenitor cells. In the present study, as the first step towards understanding the mechanism of persistent hippocampal neurogenesis, we aimed to determine the stage at which embryonic-type granule progenitors become adult-type progenitors using mouse Gfap GFP transgenic mice. During the embryonic stages, Gfap-GFP-positive (Gfap-GFP+) cells were distributed in the entire developing dentate gyrus (DG), whereas BLBP positive (BLBP+) cells were mainly present in the fimbria and subpial region, and to some extent in the DG. Up to postnatal day 0 (P0), double-positive cells were scarcely detected. However, at P1, one-third of the Gfap-GFP+ cells in the DG suddenly began to weakly express BLBP. Thereafter, Gfap-GFP+/BLBP+ cells rapidly increased in number, and extended their radial processes in the inner granular cell layer. At P14 and in the adult, two-thirds of the Gfap-GFP+ cells in the subgranular zone showed BLBP immunoreactivity. These results suggest that the properties of hippocampal granule progenitor cells are rapidly altered from an embryonic to adult type soon after birth. PMID- 28836043 TI - Expression of neurotensin receptor 1 in endometrial adenocarcinoma is correlated with histological grade and clinical outcome. AB - The promalignant effects of neurotensin (NTS) are sustained in many solid tumors, including hormone-dependent cancers. As the endometrium is also subjected to hormonal regulation, we evaluated the contribution of NTS to endometrial carcinogenesis. Neurotensin receptor 1 (NTSR1) expression and NTSR1 promoter methylation (HM450) were analyzed in 385 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Additionally, from a series of 100 endometrial carcinomas, and 66 benign endometrium samples, NTS and NTSR1 labeling was evaluated by immunohistochemistry. Using TCGA series, NTSR1 messenger RNA (mRNA) level was negatively correlated with overall survival (OS) and progression-free survival (PFS) (p = 0.0012 and p = 0.0116, respectively), and positively correlated with the grade (p = 0.0008). When including only endometrioid carcinomas, NTSR1 mRNA level continued to be negatively correlated with OS (log rank: p < 0.0001) and PFS (log-rank: p = 0.002). A higher NTSR1 mRNA level was significantly associated with a loss of NTSR1 promoter methylation. Immunohistochemical expression of NTS and NTSR1 was significantly increased in adenocarcinoma (n = 100), as compared to benign endometrium (p < 0.001). NTSR1 expression was positively correlated with grade (p = 0.004). High immunohistochemical expression of cytoplasmic NTSR1 was significantly correlated with a shorter OS and PFS (p < 0.001 and p = 0.001, respectively). This correlation remained significant when excluding non-endometrioid subtypes (p = 0.04 and p = 0.02, respectively). In multivariate analysis, the expression of NTSR1 was an independent prognostic factor (p = 0.004). NTSR1 overexpression is a poor prognostic factor in endometrial cancer, highlighting the contribution of NTS in endometrial cancer progression and its uses as a prognostic marker, and as a potential therapeutic target. PMID- 28836045 TI - Extreme Learning Machine Framework for Risk Stratification of Fatty Liver Disease Using Ultrasound Tissue Characterization. AB - Fatty Liver Disease (FLD) is caused by the deposition of fat in liver cells and leads to deadly diseases such as liver cancer. Several FLD detection and characterization systems using machine learning (ML) based on Support Vector Machines (SVM) have been applied. These ML systems utilize large number of ultrasonic grayscale features, pooling strategy for selecting the best features and several combinations of training/testing. As result, they are computationally intensive, slow and do not guarantee high performance due to mismatch between grayscale features and classifier type. This study proposes a reliable and fast Extreme Learning Machine (ELM)-based tissue characterization system (a class of Symtosis) for risk stratification of ultrasound liver images. ELM is used to train single layer feed forward neural network (SLFFNN). The input-to-hidden layer weights are randomly generated reducing computational cost. The only weights to be trained are hidden-to-output layer which is done in a single pass (without any iteration) making ELM faster than conventional ML methods. Adapting four types of K-fold cross-validation (K = 2, 3, 5 and 10) protocols on three kinds of data sizes: S0-original, S4-four splits, S8-sixty four splits (a total of 12 cases) and 46 types of grayscale features, we stratify the FLD US images using ELM and benchmark against SVM. Using the US liver database of 63 patients (27 normal/36 abnormal), our results demonstrate superior performance of ELM compared to SVM, for all cross-validation protocols (K2, K3, K5 and K10) and all types of US data sets (S0, S4, and S8) in terms of sensitivity, specificity, accuracy and area under the curve (AUC). Using the K10 cross-validation protocol on S8 data set, ELM showed an accuracy of 96.75% compared to 89.01% for SVM, and correspondingly, the AUC: 0.97 and 0.91, respectively. Further experiments also showed the mean reliability of 99% for ELM classifier, along with the mean speed improvement of 40% using ELM against SVM. We validated the symtosis system using two class biometric facial public data demonstrating an accuracy of 100%. PMID- 28836046 TI - Gastrointestinal Manifestations of Hereditary Hemorrhagic Telangiectasia (HHT): A Systematic Review of the Literature. AB - Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis. PMID- 28836047 TI - Adaptive regulation of riboflavin transport in heart: effect of dietary riboflavin deficiency in cardiovascular pathogenesis. AB - Deficiency or defective transport of riboflavin (RF) is known to cause neurological disorders, cataract, cardiovascular anomalies, and various cancers by altering the biochemical pathways. Mechanisms and regulation of RF uptake process is well characterized in the cells of intestine, liver, kidney, and brain origin, while very little is known in the heart. Hence, we aimed to understand the expression and regulation of RF transporters (rRFVT-1 and rRFVT-2) in cardiomyocytes during RF deficiency and also investigated the role of RF in ischemic cardiomyopathy and mitochondrial dysfunction in vivo. Riboflavin uptake assay revealed that RF transport in H9C2 is (1) significantly higher at pH 7.5, (2) independent of Na+ and (3) saturable with a Km of 3.746 uM. For in vivo studies, male Wistar rats (110-130 g) were provided riboflavin deficient food containing 0.3 +/- 0.05 mg/kg riboflavin for 7 weeks, which resulted in over expression of both RFVTs in mRNA and protein level. RF deprivation resulted in the accumulation of cardiac biomarkers, histopathological abnormalities, and reduced mitochondrial membrane potential which evidenced the key role of RF in the development of cardiovascular pathogenesis. Besides, adaptive regulation of RF transporters upon RF deficiency signifies that RFVTs can be considered as an effective delivery system for drugs against cardiac diseases. PMID- 28836048 TI - Male antenna morphology and its effect on scramble competition in false garden mantids. AB - Well-developed antennae are crucial for many insects, but especially for scramble competitors, who race to find their mates using female sex cues. In these systems, the ability of males to locate females quickly is thought to be under strong selection. A rarely tested assumption is that males with more sensory structures are able to locate females faster. In the present study, we used the false garden mantid Pseudomantis albofimbriata to investigate male antennal morphology and its effect on male efficiency in finding a mate. We used scanning electron microscopy to describe the major sensilla types and their arrangement along the length of male antennae. We also conducted field enclosure trials relating male antennal morphology to scramble competition in this system. We identified six different types of antennal sensilla (cheatic, trichoid, basiconic, grooved peg, ceolocapitular and campaniform) on male P. albofimbriata antennae. As expected, males who had more trichoid sensilla located females quicker than did males with fewer sensilla. Results of the current study suggest that antenna morphology plays a significant role in mate location and hence scramble competition in the P. albofimbriata mating system. PMID- 28836049 TI - Endoscopic electrocauterization of pyriform sinus fistula. AB - To determine the efficacy of endoscopic electrocauterization for pyriform sinus fistula (PSF) using a flexible Bugbee cautery electrode. From 2009 to 2016, a total of eight patients with acute suppurative thyroiditis or cervical abscess secondary to PSF were retrospectively registered in our study (three males, five females; median age 6.5 years). All patients underwent endoscopic electrocauterization as treatment for PSF. Six of eight patients had no recurrence after the initial endoscopic electrocauterization of PSF. One patient with recurrence developed symptoms 9 days after cauterization and another experienced recurrence after 2 years. Mean follow-up for the eight patients was 50 months (range 5-96 months). No post-operative complication was reported. Endoscopic electrocauterization appears to be a less-invasive, safe, and effective method for the treatment of PSF. PMID- 28836051 TI - A Systematic Review of the Role of Gender in Securing and Maintaining Employment Among Youth and Young Adults with Disabilities. AB - Purpose There is a critical need for gender-specific vocational supports for young adults with disabilities as they transition to employment. We conducted a systematic review to explore the role of gender in securing and maintaining employment. Methods Systematic searches of seven databases identified 48 studies meeting our inclusion criteria. Using a narrative synthesis approach, these studies were analyzed in terms of the characteristics of the participants, methodology, results, and quality of the evidence. Results Among the 48 studies, 112,473 participants (56% male), mean age (of the total sample) was 21, represented across ten countries. Twenty-one studies reported that young men with disabilities had better employment outcomes than women with disabilities. Eight studies showed that females with disabilities had better employment outcomes than males. Five studies reported that there were no gender differences in employment outcomes for youth with various disabilities. With regards to maintaining employment, men with disabilities often work more hours and have better wages compared to women with disabilities. There are several gender-related barriers and facilitators to maintaining employment including social supports and gender role expectations. Conclusions Our findings highlight that there is a critical need for gender-specific vocational supports for young adults with disabilities. PMID- 28836050 TI - Dansyl Based "Turn-On" Fluorescent Sensor for Cu2+ Ion Detection and the Application to Living Cell Imaging. AB - A new "turn-on" fluorescent chemosensor based on dansyl derivative was prepared for Cu2+ ion sensing. Hydroxyl, imine and azomethine groups in Schiff base derived compound 1 were deliberately introduced for facilitating the binding of Cu2+ ion. Of screen metal ions, compound 1 showed a high degree of selectivity toward Cu2+ ion. Other interfering metal ions did not affect the fluorescence intensity of compound 1, except Hg2+ and Fe3+ ions exhibited a significant degree of fluorescence quenching. Upon binding of Cu2+ ion, compound 1 displayed a chelation enhanced fluorescence (CHEF) resulting in increasing of the fluorescence intensity. The molecular optimized geometry indicated the binding ratio between compound 1 and Cu2+ ion at 1:1 with the binding constant of 1.68 * 10- 7 M- 1. The optimized condition for sensing ability of compound 1 with a detection limit of 5 * 10- 7 M was found at the physiological pH 7.2 with the excitation wavelength of 366 nm. Due to no cytotoxicity and good photophysical properties, compound 1 was extended its application for the detection of Cu2+ ion in Vero cells. Compound 1 could be potentially used as an intracellular fluorescent chemosensor for tracking Cu2+ ion. Graphical Abstract. PMID- 28836053 TI - New classification for the thoracic paraaortic lymph nodes of patients with esophageal squamous cell carcinoma. AB - PURPOSE: To create a new classification for the thoracic paraaortic lymph nodes (No. 112ao) of patients with esophageal squamous cell carcinoma (ESCC). Classification of these nodes in ESCC patients has been the focus of very few reports. METHODS: The subjects of this study were 27 patients with positive No. 112ao nodes on computed tomography (CT) images before treatment. We divided the No. 112ao nodes into No. 112aoA, located on the esophageal side as anterior No. 112ao nodes, and No. 112aoP, located on the opposite side of the esophagus as posterior No. 112ao nodes. We examined the association between No. 112aoA and No. 112aoP and clinicopathological factors. Recurrence-free survival (RFS) was compared between the No. 112aoA- and No. 112aoP-positive groups. RESULTS: There were 12 patients in the No. 112aoA-positive group and 15 patients in the No. 112aoP-positive group. The No. 112aoP-positive group had significantly worse RFS than the No. 112aoA-positive group (p = 0.004). Cox multivariate analysis of RFS revealed that No. 112aoP positivity was an independent prognostic factor (p = 0.043). CONCLUSIONS: Our new classification of No. 112ao nodes into No. 112aoA and No. 112aoP is useful clinically. No. 112aoP could correspond to the clinical N4 category of patients with ESCC. PMID- 28836052 TI - Coronary CT angiography characteristics of OCT-defined thin-cap fibroatheroma: a section-to-section comparison study. AB - OBJECTIVES: To evaluate whether plaque characteristics as assessed by coronary computed tomography angiography (CCTA) were associated with the presence of a thin-cap fibroatheroma (TCFA)-a precursor of plaque rupture-defined by optical coherence tomography (OCT) in a section-to-section-level comparison. METHODS: From 28 symptomatic patients, 31 coronary lesions were evaluated on 727 cross sections co-registered by both CCTA and OCT. CCTA plaque characteristics included low attenuation plaque (LAP, <30 HU), napkin ring sign (NRS), positive remodelling (PR, remodelling index >=1.10), and spotty calcification and plaque area and plaque burden. By OCT, presence of TCFA, lumen area and arc of lipid were determined. RESULTS: OCT revealed a TCFA in 69 (9.4%) sections from 19 (61.2 %) lesions. In per-section analysis, OCT-TCFA showed higher frequency of CCTA detected LAP (58.0% vs. 18.5%), NRS (31.9% vs. 8.8%) and PR (68.1% vs. 48.0%) and greater plaque burden (70.6% vs. 61.9%) as compared to sections without OCT-TCFA (all p < 0.05). In multivariable analysis, LAP (odds ratio [OR] 4.05, p < 0.001) and NRS (OR 2.47, p = 0.005) were associated with OCT-TCFA. CCTA-measured lumen area correlated well with OCT-measured lumen area (R = 0.859, limits of agreement -0.5 +/- 3.7 mm2). CONCLUSIONS: LAP and NRS in CCTA were associated with the presence of OCT-defined TCFA in a section-to-section comparison. KEY POINTS: * CT defined LAP and NRS were associated with OCT-defined TCFA * OCT-TCFA showed higher frequency of LAP, NRS, PR and greater plaque burden * Non-calcified plaque area was correlated with OCT-measured lipid arc. PMID- 28836054 TI - Molecular study of ABCB1 gene and its correlation with imatinib response in chronic myeloid leukemia. AB - PURPOSE: The introduction and success of imatinib mesylate have become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, despite its high efficiency, resistance to imatinib has emerged as a significant problem, which may in part be caused by pharmacogenetic variability. Three single-nucleotide polymorphisms (C1236T, G2677T/A, C3435T) and/or mRNA expression changes of ABCB1 gene were demonstrated to be associated with inter-individual variability of imatinib response in CML patients. In this study, we aimed to examine whether genetic variations and/or altered expression of ABCB1 gene may influence response to imatinib. METHODS: Sixty nine CML Tunisian patients, undergoing imatinib therapy, were enrolled in this study. These were divided into two groups: responders and non-responders to imatinib. The relative transcript expression levels of ABCB1 gene and the distribution of allele and genotype frequency of ABCB1 SNPs were compared between these two categories of patients. Linkage disequilibrium tests and haplotypes analysis were also studied. RESULTS: Our results showed that the mRNA expression level of ABCB1 gene did not differ significantly between the two categories of patients. In addition, results obtained from ABCB1 polymorphisms study and their correlation with imatinib response showed that the optimal response rate to imatinib did not differ significantly between C1236T, G2677T/A or C3435T genotypes. However, haplotype analysis showed that the 1236C-2677A-3435C haplotype was observed only in imatinib non-responders' patients suggesting that CAC haplotype was linked to higher risk of imatinib resistance. CONCLUSION: Furthermore, analyses of ABCB1 haplotypes should be taken into account to study the relationship between ABCB1 genotypes and imatinib efficacy. PMID- 28836055 TI - Operating Room Efficiency before and after Entrance in a Benchmarking Program for Surgical Process Data. AB - Operating room (OR) efficiency continues to be a high priority for hospitals. In this context the concept of benchmarking has gained increasing importance as a means to improve OR performance. The aim of this study was to investigate whether and how participation in a benchmarking and reporting program for surgical process data was associated with a change in OR efficiency, measured through raw utilization, turnover times, and first-case tardiness. The main analysis is based on panel data from 202 surgical departments in German hospitals, which were derived from the largest database for surgical process data in Germany. Panel regression modelling was applied. Results revealed no clear and univocal trend of participation in a benchmarking and reporting program for surgical process data. The largest trend was observed for first-case tardiness. In contrast to expectations, turnover times showed a generally increasing trend during participation. For raw utilization no clear and statistically significant trend could be evidenced. Subgroup analyses revealed differences in effects across different hospital types and department specialties. Participation in a benchmarking and reporting program and thus the availability of reliable, timely and detailed analysis tools to support the OR management seemed to be correlated especially with an increase in the timeliness of staff members regarding first case starts. The increasing trend in turnover time revealed the absence of effective strategies to improve this aspect of OR efficiency in German hospitals and could have meaningful consequences for the medium- and long-run capacity planning in the OR. PMID- 28836057 TI - Personhood, pregnancy, and gender: a reply to Hershenov and Hershenov. PMID- 28836056 TI - The prognostic significance of inflammation-based markers in patients with recurrent gastric cancer. AB - PURPOSE: The aim of this study was to evaluate the prognostic impact of inflammation-based markers, including the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI), in patients with recurrent gastric cancer (RGC). METHODS: This study reviewed 167 patients with RGC. A receiver operating characteristics (ROC) curve analysis was performed to determine the NLR and PNI cutoff values. The prognostic significance of the NLR and PNI was evaluated by a multivariate analysis. RESULTS: The optimal NLR and PNI cutoff values for predicting the 1-year survival after recurrence were 2.2 and 47, respectively. A univariate analysis revealed that the NLR (p < 0.001) and PNI (p < 0.001) were significantly associated with the survival time after recurrence, along with the histology, peritoneal recurrence, carbohydrate antigen 19-9, and chemotherapy for recurrence. In the multivariate analysis, a higher NLR (p < 0.001) and a lower PNI (p = 0.002) were independent predictors of a shorter survival time. Among the patients who underwent chemotherapy, the NLR and PNI were also independent prognostic factors. CONCLUSIONS: Inflammation-based markers, including the NLR and PNI, are simple and useful clinical biomarkers that can be used to predict the survival time of patients with RGC. PMID- 28836058 TI - Long-term effects of etelcalcetide as intravenous calcimimetic therapy in hemodialysis patients with secondary hyperparathyroidism. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT) is a serious major complication in hemodialysis patients with chronic kidney disease. Long-term maintenance of serum phosphate, calcium, and parathyroid hormone (PTH) levels in appropriate ranges in these patients is a major challenge. We investigated the efficacy and safety of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis. METHODS: This study was a multicenter open-label study. A total of 191 hemodialysis patients with serum intact PTH (iPTH) > 240 pg/mL were enrolled. Etelcalcetide was administered thrice weekly for 52 weeks, with an initial dose of 5 mg and flexibility to adjust the dose between 2.5 and 15 mg and to adjust the dosing of concomitant medications for SHPT. The efficacy endpoint was the proportion of patients with serum iPTH decreased to the target range (60-240 pg/mL). RESULTS: Serum iPTH levels decreased immediately after etelcalcetide was started. At the end of the study, 87.5% (95% confidence interval 81.4-92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels. Adverse events, mostly mild to moderate, were reported by 96.8% of patients and led to study discontinuation in 7.4% of patients. Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1%, with 0.5, 1.1, and 1.1% considered treatment-related. CONCLUSIONS: Etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52 weeks in Japanese hemodialysis patients, and was safe and well tolerated. REGISTRATION NUMBER: JapicCTI-142665. PMID- 28836059 TI - Posterior reversible encephalopathy syndrome in children with kidney disease. AB - Posterior reversible encephalopathy syndrome (PRES) has been described as a neurological condition observed in a variety of clinical settings and is characterized by focal neurological deficits, seizures, headaches, altered mental status, and visual impairment, associated with transient typical lesions on neuroimaging, predominantly in the posterior part of the brain. The most common risk factors for PRES are hypertension, renal diseases, and the use of calcineurin inhibitors. The incidence of PRES in children with renal disorders varies between 4 and 9%, according to different reports. Vasogenic cerebral edema is considered the major pathophysiological mechanism of PRES. There are two main theories regarding the genesis of this edema: (1) hyperperfusion, due to autoregulatory failure of the cerebral vasculature, and (2) hypoperfusion, due to vasoconstriction of the cerebral arteries. In addition, PRES might also be the result of a systemic inflammatory state causing endothelial dysfunction. The management of PRES includes BP control, treatment of seizures, and removal of or reduction in calcineurin inhibitors. Intravenous administration of antihypertensive therapy is preferred, and various drugs have been used in this regard, including nicardipine, labetalol, sodium nitroprusside, and hydralazine. The prognosis of PRES is usually benign, except for rare cases with intracranial hemorrhage. PMID- 28836060 TI - Delays contributing to the development and repair of obstetric fistula in northern Tanzania. AB - INTRODUCTION AND HYPOTHESIS: Delays in receiving obstetric care during labor contribute to high rates of maternal morbidity in sub-Saharan Africa. This exploratory study was conducted to identify important delays experienced during the development and subsequent repair of obstetric fistula in northern Tanzania. METHODS: Sixty women presenting to a tertiary hospital with obstetric fistula completed structured surveys about the birth experience that led to fistula development and their experiences seeking surgical repair. A subset of 30 provided qualitative accounts. Clinical data were collected postsurgery. Data were analyzed according to a four-delay model, with iterative analysis allowing for triangulation of all sources. RESULTS: During the index pregnancy, women labored for a median of 48 h. Most women (53/60; 88.3%) delivered in a facility but labored for a median of 12.4 h before deciding to seek care (Delay 1). Women spent a median of 1.25 h traveling to a facility (Delay 2). After presenting to care, 15/51 (29.4%) waited at least an hour to see a medical provider, and 35/53 (66.0%) required transfer to another facility (Delay 3). Women lived with fistula for a median of 10 years (Delay 4). Qualitative data provided context and a deeper understanding of the factors contributing to each delay. CONCLUSIONS: Critical delays exist both outside and within the healthcare system that contribute to the development and timely repair of obstetric fistula. Healthcare system strengthening, particularly with regard to emergency obstetric care, is critical to reduce the burden of obstetric fistula in women in Tanzania. PMID- 28836061 TI - A Re-examination of the Effect of Masker Phase Curvature on Non-simultaneous Masking. AB - Forward masking of a sinusoidal signal is determined not only by the masker's power spectrum but also by its phase spectrum. Specifically, when the phase spectrum is such that the output of an auditory filter centred on the signal has a highly modulated ("peaked") envelope, there is less masking than when that envelope is flat. This finding has been attributed to non-linearities, such as compression, reducing the average neural response to maskers that produce more peaked auditory filter outputs (Carlyon and Datta, J Acoust Soc Am 101:3636-3647, 1997). Here we evaluate an alternative explanation proposed by Wotcjzak and Oxenham (Wojtczak and Oxenham, J Assoc Res Otolaryngol 10:595-607, 2009). They reported a masker phase effect for 6-kHz signals when the masker components were at least an octave below the signal frequency. Wotcjzak and Oxenham argued that this effect was inconsistent with cochlear compression, and, because it did not occur at lower signal frequencies, was also inconsistent with more central compression. It was instead attributed to activation of the efferent system reducing the response to the subsequent probe. Here, experiment 1 replicated their main findings. Experiment 2 showed that the phase effect on off-frequency forward masking is similar at signal frequencies of 2 and 6 kHz, provided that one equates the number of components likely to interact within an auditory filter centred on the signal, thereby roughly equating the effect of masker phase on the peakiness of that filter output. Experiment 3 showed that for some subjects, masker phase also had a strong influence on off-frequency backward masking of the signal, and that the size of this effect correlated across subjects with that observed in forward masking. We conclude that the masker phase effect is mediated mainly by cochlear non-linearities, with a possible additional effect of more central compression. The data are not consistent with a role for the efferent system. PMID- 28836062 TI - Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating beta/gamma-Secretases. AB - Chronic cerebral hypoperfusion (CCH) contributes to the Alzheimer's-like pathogenesis, but the relationship between CCH and the occurrence of Alzheimer's disease (AD) remains obscure. The aim is to elucidate the potential pathophysiological mechanism in the field of amyloid-beta (Abeta) pathology induced by CCH. A rat model of CCH has been developed with permanent bilateral occlusion of common carotid arteries (BCCAO). The cognitive function of rats was tested by the Morris water maze. The levels of Abeta (Abeta40 and Abeta42) and soluble amyloid precursor protein (sAPP: sAPPalpha and sAPPbeta) were determined by enzyme linked immunosorbent assay. The expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), presenilin1 (PS1), nicastrin (NCT), anterior pharynx-defective 1alpha (Aph-1alpha) and presenilin enhancer 2 (Pen-2), sAPPalpha and sAPPbeta were detected by Western blotting. Morris water maze test showed that CCH induced decline in learning and memory related to Abeta levels in the hippocampus. The levels of sAPPalpha, ADAM10 and ADAM17 in the hippocampus of CCH rats were higher than the control ones (P < 0.05); the levels of sAPPbeta, BACE and BACE1 increased more than the control ones (P < 0.05). CCH intervention (1-week or 4-week) markedly increased the expression of PS1, Aph-1alpha and Pen-2 in the hippocampus of rats, but had no effect on NCT. CCH contributed to cognitive impairment and altered the amyloidogenic and non-amyloidogenic pathway of APP processing by boosting the activity of beta-secretase/gamma-secretase and alpha-secretase respectively. The non-amyloidogenic pathway can't overcome the damage role of the amyloidogenic pathway in the process of chronic cerebral hypoperfusion which promotes amyloid-beta pathogenesis. PMID- 28836063 TI - Prognostic significance of Fuhrman grade and age for cancer-specific and overall survival in patients with papillary renal cell carcinoma: results of an international multi-institutional study on 2189 patients. AB - PURPOSE: Because the prognostic impact of the clinical and pathological features on cancer-specific survival (CSS) and overall survival (OS) in patients with papillary renal cell carcinoma (papRCC) is still controversial, we want to assess the impact of clinicopathological features, including Fuhrman grade and age, on survival in surgically treated papRCC patients in a large multi-institutional series. METHODS: We established a comprehensive multi-institutional database of surgically treated papRCC patients. Histopathological data collected from 2189 patients with papRCC after radical nephrectomy or nephron-sparing surgery were pooled from 18 centres in Europe and North America. OS and CSS probabilities were estimated using the Kaplan-Meier method. Multivariable competing risks analyses were used to assess the impact of Fuhrman grade (FG1-FG4) and age groups (<50 years, 50-75 years, >75 years) on cancer-specific mortality (CSM). RESULTS: CSS and OS rates for patients were 89 and 81% at 3 years, 86 and 75% at 5 years and 78 and 41% at 10 years after surgery, respectively. CSM differed significantly between FG 3 (hazard ratio [HR] 4.22, 95% confidence interval [CI] 2.17-8.22; p < 0.001) and FG 4 (HR 8.93, 95% CI 4.25-18.79; p < 0.001) in comparison to FG 1. CSM was significantly worse in patients aged >75 (HR 2.85, 95% CI 2.06-3.95; p < 0.001) compared to <50 years. CONCLUSIONS: FG is a strong prognostic factor for CSS in papRCC patients. In addition, patients older than 75 have worse CSM than patients younger than 50 years. These findings should be considered for clinical decision making. PMID- 28836064 TI - Treatment of severe psoriasis in children: recommendations of an Italian expert group. AB - : This article provides comprehensive recommendations for the systemic treatment of severe pediatric psoriasis based on evidence obtained from a systematic review of the literature and the consensus opinion of expert dermatologists and pediatricians. For each systemic treatment, the grade of recommendation (A, B, C) based on the treatment's approval by the European Medicines Agency for childhood psoriasis and the experts' opinions is discussed. The grade of recommendation for narrow-band-ultraviolet B phototherapy, cyclosporine, and retinoids is C, while that for methotrexate is C/B. The use of adalimumab, etanercept, and ustekinumab has a grade A recommendation. No conventional systemic treatments are approved for pediatric psoriasis. Adalimumab is approved by the European Medicines Agency as a first-line treatment for severe chronic plaque psoriasis in children (>= 4 years old) and adolescents. Etanercept and ustekinumab are approved as second line therapy in children >= 6 and >= 12 years, respectively. CONCLUSION: A treatment algorithm as well as practical tools (i.e., tabular summaries of differential diagnoses, treatment mechanism of actions, dosing regimens, control parameters) are provided to assist in therapeutic reasoning and decision-making for individual patients. These treatment recommendations are endorsed by major Italian Pediatric and Dermatology Societies. What is Known: * Guidelines for the treatment of severe pediatric psoriasis are lacking and most traditional systemic treatments are not approved for use in young patients. Although there has been decades of experience with some of the traditional agents such as phototherapy, acitretin, and cyclosporine in children, there are no RCTs on their pediatric use while RCTs investigating new biologic agents have been performed. What is New: * In this manuscript, an Italian multidisciplinary team of experts focused on treatment recommendations for severe forms of psoriasis in children based on an up-to-date review of the literature and experts' opinions. PMID- 28836066 TI - The Future Vocation of Neural Stem Cells: Lineage Commitment in Brain Development and Evolution. AB - Understanding the fate commitment of neural stem cells is critical to identify the regulatory mechanisms in developing brains. Genetic lineage-tracing has provided a powerful strategy to unveil the heterogeneous nature of stem cells and their descendants. However, recent studies have reported controversial data regarding the heterogeneity of neural stem cells in the developing mouse neocortex, which prevents a decisive conclusion on this issue. Here, we review the progress that has been made using lineage-tracing analyses of the developing neocortex and discuss stem cell heterogeneity from the viewpoint of comparative and evolutionary biology. PMID- 28836067 TI - Is nigrostriatal dopaminergic deficit necessary for Holmes tremor to develop? The DaTSCAN and IBZM SPECT study. AB - Holmes's tremor (HT) is assumed to be the result of coexistence of nigrostriatal dopaminergic system impairment and the lesion of cerebello-thalamic pathways. It was suggested that dopaminergic deficiency is responsible for rest tremor, and lack of compensatory cerebellar function leads to spill of tremor into voluntary movements. Cases of HT with and without abnormalities of the presynaptic part of dopaminergic nigrostriatal were published and these findings raised the question of possibility of the postsynaptic lesion. Three patients with HT diagnosed according to criteria of Consensus Statement on Tremor were studied. In all of them SPECT imaging with ligands of presynaptic (I 123-FP CIT-DaTSCAN) and postsynaptic (I 123-iodobenzamide-IBZM) nigrostriatal dopaminergic neurons was performed. Indices of uptake in caudate and putamen normalized to nonspecific uptake in occipital cortex and indices of asymmetry for each whole striatum as well as for putamen and caudate separately were calculated. SPECT studies did not reveal asymmetry of DaTSCAN and IBZM binding in striatum in all studied subjects. The current clinical diagnostic criteria of HT are presumably insufficiently specific and when using them we identify patients both with and without the involvement of dopaminergic system. These two groups may represent tremor disorders of similar phenomenology but of different pathomechanism. PMID- 28836068 TI - Rates and Predictors of Vaccinations Among Inflammatory Bowel Disease Patients Receiving Anti-Tumor Necrosis Factor Agents. AB - BACKGROUND: As an important quality measure, the rates of recommended immunizations among immunocompromised inflammatory bowel disease (IBD) patients in community practice have not been well studied. AIMS: This study sought to investigate the rates and predictors of recommended immunizations and screening tests among IBD patients receiving anti-tumor necrosis factor (TNF) therapy in a large integrated healthcare organization. METHODS: We conducted a retrospective cohort study of 1401 IBD patients on anti-TNF therapy between 2010 and 2013 within the Kaiser Permanente Northern California healthcare system. The rates of vaccinations and screening tests were quantified, and the associated predictors were investigated. RESULTS: Vaccination rates for influenza and pneumococcus were 43.5 and 24.1%, respectively. The majority of patients (73.7%) received hepatitis B screening and/or vaccine. Patients receiving infliximab had higher rates of pneumococcal vaccine (P = 0.002), hepatitis B screening (P < 0.001), and tuberculin skin test (P < 0.001) compared with patients receiving adalimumab. Older patient age (>=50 years) was associated with higher likelihood of having HBsAg test (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0, P = 0.002), influenza vaccine (OR 2.6 [2.1-3.4], P < 0.001), and pneumococcal vaccine (OR 4.0 [3.0-5.3], P < 0.001). In contrast, older providers (>=50 years) were associated with significantly lower likelihood of their patients' having hepatitis A and B screening tests, and pneumococcal vaccination. CONCLUSIONS: The rates of immunizations for IBD patients receiving anti-TNF treatment were lower than recommended. Structured reminders for vaccinations and education for both patients and providers (older physicians in particular) may prove beneficial in improving immunization rates among immunocompromised IBD patients. PMID- 28836070 TI - Shining a White Light on Barrett's Esophagus: What Does the BING Classification Bring? PMID- 28836069 TI - Enhanced expression of Pafah1b1 causes over-migration of cerebral cortical neurons into the marginal zone. AB - Mutations of PAFAH1B1 cause classical lissencephaly in humans. In addition, duplications and triplications of PAFAH1B1 are found in individuals with intellectual disability and other neurological disorders suggesting that proper brain development is highly sensitive to the PAFAH1B1 dosage. To examine the effect of PAFAH1B1 over-dosage in neural development, especially in migration of neurons and layer formation during cerebral cortical development, we overexpressed Pafah1b1 in migrating neurons in the mouse embryonic cortex using in utero electroporation. Enhanced expression of Pafah1b1 in radially-migrating neurons resulted in their over-migration into the marginal zone. Neurons that invaded the marginal zone were oriented abnormally. Layer distribution of Pafaha1b1-overexpressing neurons shifted more superficially than control neurons. Some of the Pafaha1b1-overexpressing future layer 4 neurons changed their positions to layers 2/3. Furthermore, they also changed their layer marker expression from layer 4 to layers 2/3. These results suggest that overexpression of Pafah1b1 affects the migration of neurons and disrupts layer formation in the developing cerebral cortex, and further support the idea that appropriate dosage of Pafah1b1 is crucial for the proper development of the brain. PMID- 28836065 TI - A multi-stage genome-wide association study of uterine fibroids in African Americans. AB - Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women's Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16-1.30), p value = 7.82 * 10-9). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 * 10 8). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids. PMID- 28836072 TI - Postmortem studies of deep brain stimulation for Parkinson's disease: a systematic review of the literature. AB - Deep brain stimulation (DBS), arguably the greatest therapeutic advancement in the treatment of Parkinson's disease since dopamine replacement therapy, is now routinely used. While the exact mechanisms by which DBS works still remain unknown, over the past three decades since it was first described, we have gained significant insight into several of the processes involved. Though often overlooked in this regard, increasing numbers of postmortem and autopsy studies are contributing significantly to our understanding. In this manuscript, we review the literature involving the pathological findings from autopsies in patients who have undergone deep brain stimulation surgeries for Parkinson's disease. The major results show that multiple stereotactic targeting methods can be accurate at placing leads in the desired nuclei that help with clinically effective results, that perioperative complications and inaccurate diagnosis as determined by autopsy can lead to suboptimal stimulation effect and that the normal long-term effects of chronic stimulation include fibrosis around the electrodes and a mild immune response. In addition, recent results suggest mechanisms by which DBS might be effective in Parkinson's disease i.e., through rescuing pathological changes in microvasculature and by promoting the proliferation of neural progenitor cells. PMID- 28836071 TI - A dedicated lumbar puncture clinic: performance and short-term patient outcomes. AB - The purpose of the study was to evaluate patient outcomes, including success rates, factors associated with unsuccessful procedures and frequency of post lumbar puncture headaches (PLPH), at a dedicated academic outpatient lumbar puncture (LP) clinic. All patients referred to our LP clinic between June 1, 2014 and May 31, 2015 were included in this consecutive observational series. We collected information about patient characteristics, operational parameters of the procedure, and complications. We also recorded rates of participation in biomedical research involving use of cerebrospinal fluid. Univariate analysis used Student's t test and Fisher's exact test. Logistic regression was used to determine independent risk factors associated with unsuccessful LP and PLPH. The mean age of patients referred to our LP clinic was 46 +/- 17 years. Of the 307 referrals, 281 patients (92%) started the procedure, with successful acquisition of CSF in 267 (95%). Factors contributing to unsuccessful procedures included higher body mass index [odds ratio (OR) 1.8], older age (OR 1.9), and female sex (OR 10.3). The rate of PLPH was 5.7%. Younger age (OR 0.5), female sex (OR 6.9), high mean arterial pressure (OR 2.2), and a traumatic LP (OR 10.0) were identified as risk factors for PLPH. Notably, 202 patients (72%) consented to biomedical research. A standardized approach to outpatient LP demonstrates high procedural success rate, low PLPH rate, and high participation in biomedical research. Awareness of a group of patients at higher risk for complications including procedure failure or PLPH provides guidance for decision-making regarding referral to the outpatient LP clinic. PMID- 28836073 TI - A ten years (2007-2016) retrospective serological survey for Seneca Valley virus infection in major pig producing states of Brazil. AB - Seneca Valley virus (SVV) is the etiological agent of vesicular disease in pigs, clinically indistinguishable of classical viral vesicular infections, including foot-and-mouth disease. The first outbreaks of SVV infection in Brazil were reported in 2014. However, it was not known whether the virus was circulating in Brazilian pig herds before this year. This study is a retrospective serological investigation of porcine health status to SVV in Brazil. Serum samples (n = 594) were grouped in before (2007-2013, n = 347) and after (2014-2016, n = 247) SVV outbreaks in Brazil. Twenty-three pig herds were analyzed, of which 19 and 4 were sampled before and after the beginning of SVV outbreaks, respectively. Two herds sampled after 2014 presented animals with SVV-associated clinical manifestations, while the other two housed asymptomatic pigs. Anti-SVV antibodies were evaluated by virus neutralization test. The results demonstrated that pig herds of different Brazilian geographical regions and distinct pig categories were negative to anti-SVV antibodies in sera obtained before 2014. Antibodies to SVV were detected only in serum samples obtained after 2014, particularly in herds with the presence of pigs with SVV-clinical signs. These results present robust serological evidence that the SVV was not present in the major Brazilian pig producing regions prior to 2014. PMID- 28836074 TI - Crowding-out effect of coal industry investment in coal mining area: taking Shanxi province in China as a case. AB - The rapid development of coal industry in Shanxi province in China has important effects on its economic development. A large amount of money has been invested into the coal industry and other related industries during the recent years. However, research on the investment effect of Shanxi's coal industry was rare. In order to analyze the investment effect of coal industry, based on the crowding out effect model, cointegration test, and the data available in Shanxi Statistical Yearbooks, this paper calculates the effect between coal industry investment and other 17 industry investment. The results show that the investment of coal industry produces crowding-out effect on food industry, building materials industry, and machinery industry. Increasing 1% of the coal industry investment can reduce 0.25% of the food industry investment, or 0.6% of building materials industry investment, or 0.52% of the machinery industry investment, which implies that Shanxi province should adjust coal industrial structure, promote the balance development of coal industry and other industries, so as to promote its economic growth. PMID- 28836075 TI - Antitumor evaluation and 3D-QSAR studies of a new series of the spiropyrroloquinoline isoindolinone/aza-isoindolinone derivatives by comparative molecular field analysis (CoMFA). AB - In current study, antitumor activity of two series of the newly synthesized spiropyrroloquinoline isoindolinone and spiropyrroloquinoline aza-isoindolinone scaffolds was evaluated against three human breast normal and cancer cell lines (MCF-10A, MCF-7 and SK-BR-3) and compared with cytotoxicity values of doxorubicin and colchicine as the standard drugs. It was found that several compounds were endowed with cytotoxicity in the low micromolar range. Among these two series, compounds 6i, 6j, 6k and 7l, 7m, 7n, 7o containing 3-ethyl-1H-indole moiety were found to be highly effective against both cancer cell lines ranging from [Formula: see text] to [Formula: see text] in comparison with the corresponding analogs. Compared with human cancer cells, the most potent compounds did not show high cytotoxicity against human breast normal MCF-10A cells. Generally, most of the evaluated compounds 6a-l and 7a-o series showed more antitumor activity against SK-BR-3 than MCF-7 cells. Moreover, comparative molecular field analysis (CoMFA) as a popular tools of three-dimensional quantitative structure-activity relationship (3D-QSAR) studies was carried out on 27 spiropyrroloquinolineisoindolinone and spiropyrroloquinolineaza-isoindolinone derivatives with antitumor activity against on SK-BR-3 cells. The obtained CoMFA models showed statistically excellent performance, which also possessed good predictive ability for an external test set. The results confirm the important effect of molecular steric and electrostatic interactions of these compounds on in vitro cytotoxicity against SK-BR-3. PMID- 28836076 TI - A cross docking pipeline for improving pose prediction and virtual screening performance. AB - Pose prediction and virtual screening performance of a molecular docking method depend on the choice of protein structures used for docking. Multiple structures for a target protein are often used to take into account the receptor flexibility and problems associated with a single receptor structure. However, the use of multiple receptor structures is computationally expensive when docking a large library of small molecules. Here, we propose a new cross-docking pipeline suitable to dock a large library of molecules while taking advantage of multiple target protein structures. Our method involves the selection of a suitable receptor for each ligand in a screening library utilizing ligand 3D shape similarity with crystallographic ligands. We have prospectively evaluated our method in D3R Grand Challenge 2 and demonstrated that our cross-docking pipeline can achieve similar or better performance than using either single or multiple receptor structures. Moreover, our method displayed not only decent pose prediction performance but also better virtual screening performance over several other methods. PMID- 28836077 TI - Circulating IL-8 levels are increased in patients with type 2 diabetes and associated with worse inflammatory and cardiometabolic profile. AB - AIMS: Interleukin-8 (IL-8) is a chemokine involved in systemic immunity, macrophages infiltration and activation in adipose tissue and may play a significant role in the pathogenesis of type 2 diabetes (T2D) and atherosclerosis. Aims of this study were to evaluate circulating IL-8 levels in adult patients with T2D in comparison with non-diabetic subjects and to describe clinical and biochemical correlates of IL-8 concentration. METHODS: For this cross-sectional study, we enrolled 79 consecutive T2D individuals referring to our diabetes outpatient clinics at Sapienza University of Rome, and 37 sex, age and BMI comparable non-diabetic subjects as a control group. Clinical parameters and medical history were recorded; fasting blood sampling was performed for biochemistry and for measuring serum IL-8, IL-6, TNF-alpha, CRP, adiponectin and 25(OH)vitamin D [25(OH)D] levels. RESULTS: Patients with T2D exhibited significantly higher serum IL-8 levels than non-diabetic subjects (69.27 +/- 112.83 vs. 16.03 +/- 24.27 pg/mL, p < 0.001). In diabetic patients, increased IL 8 concentration correlated with higher IL-6 (p < 0.001), TNF-alpha (p = 0.02), FBG (p = 0.035), HbA1c (p = 0.04) and LDL-C (p = 0.04) and with lower adiponectin (p = 0.02) and 25(OH)D (p = 0.003) concentrations. CONCLUSIONS: Patients with T2D display a marked elevation of circulating IL-8 levels which identify subjects with worse inflammatory, glycometabolic and lipid profile and lower vitamin D levels. Further studies are warranted for evaluating a possible role of IL-8 as a novel marker for risk stratification in T2D patients. PMID- 28836078 TI - Stress enhanced calcium kinetics in a neuron. AB - Accurate modeling of the mechanobiological response of a Traumatic Brain Injury is beneficial toward its effective clinical examination, treatment and prevention. Here, we present a stress history-dependent non-spatial kinetic model to predict the microscale phenomena of secondary insults due to accumulation of excess calcium ions (Ca[Formula: see text]) induced by the macroscale primary injuries. The model is able to capture the experimentally observed increase and subsequent partial recovery of intracellular Ca[Formula: see text] concentration in response to various types of mechanical impulses. We further establish the accuracy of the model by comparing our predictions with key experimental observations. PMID- 28836079 TI - Changes in wind erosion over a 25-year restoration chronosequence on the south edge of the Tengger Desert, China: implications for preventing desertification. AB - Wind erosion is a primary cause of desertification as well as being a serious ecological problem in arid and semi-arid areas across the world. To determine mechanisms for restoring desertified lands, an unrestored shifting sand dune and three formerly shifting sand dunes (desertified lands) that had been enclosed and afforested for 5, 15, and 25 years were selected for evaluation on the south edge of the Tengger Desert, China. Based on sampling heights between 0.2 and 3 m, the critical threshold average wind speed was 6.5 m s-1 at 2 m where the sand transport rate was reduced from 285.9 kg m-2 h-1 on the unrestored dunes to 9.1 and 1.8 kg m-2 h-1 on the sites afforested and enclosed for 5 and 15 years, respectively. The percentage of wind eroded area was reduced from 99.9% on the unrestored dune to 94.5, 9.0, and 0.5% on the sites afforested and enclosed for 5, 15, and 25 years, respectively. Wind erosion was effectively reduced after 15 years. Although there were different driving factors for wind erosion mitigation on the different restoration stages, an increase in the vegetation cover, surface roughness, soil shear strength, soil clay content, organic matter, and reduction in the near-surface wind speed were the primary variables associated with the restoration chronosequence. We conclude that reducing the wind speed and developing a biological crust through vegetation restoration were the critical components for restoration of desertified land. PMID- 28836080 TI - The Willingness of Non-Industrial Private Forest Owners to Enter California's Carbon Offset Market. AB - While non-industrial private forest landowners have a significant amount of forest landholdings in the US, they are underrepresented in the California cap and-trade market forest offset program. Additional participation could benefit both the market and non-industrial private forest landowners. We developed a mail questionnaire which served as both a survey instrument and outreach tool about the market. Questions covered forest ownership objectives, landowners' future plans for forests, views of climate change, and attitudes and intentions regarding forest carbon offset project development. We sampled from five Northern California counties for a total of 143 usable surveys. Three different groups of landowners were identified based on their management objectives: amenity (including protecting nature and recreation); legacy (passing land to children and/or maintaining a farm or ranch); and income. Landowner objective groups differed on several key variables, particularly related to potential motivations for joining the market, while all landowners expressed concerns about protocol requirements. Regardless of ownership objectives, over half expressed that receiving revenue from their forests would be an important motivator to join, though most were unwilling to satisfy protocol requirements, even after learning of the potential benefits of program participation. Thus, participation appears to be limited by the costly and complex project development process, as well as a lack of landowner awareness. Extending these lessons, we assert that different landowners may approach payment for ecosystem services programs with different needs, awareness, and motivations, which provide important lessons for those who conduct landowner outreach and for PES program designers. PMID- 28836081 TI - Emission analysis on the effect of nanoparticles on neat biodiesel in unmodified diesel engine. AB - Biodiesels derived from the mahua seeds are established as a promising alternative for the diesel fuel owing to its non-edible nature and improved properties. TiO2 nanoparticle in powder form is added to neat mahua oil biodiesel (BD100) to examine its effect on emission characteristics. TiO2 nanoparticle is chosen as an additive owing to its catalytic effect, higher surface energy, and larger surface to volume ratio. TiO2 nanoparticle with an average size of 60 nm was synthesized by sol-gel route. TiO2 nanoparticles are added with mahua biodiesel (BD100) at 100 and 200 ppm. Mahua oil biodiesel doped with 100 and 200 ppm of TiO2 nanoparticles are referred as BD100T100 and BD100T200. A constant speed diesel engine is employed for the experimental trail. Engine is fueled with diesel, BD100, BD100T100, and BD100T200, respectively. Experimental result confirmed that the modified fuels (BD100T200 and BD100T100) showed a significant reduction in all the emissions. Further, the addition of TiO2 nanoparticle (200 ppm) to mahua biodiesel gave respective reduction of 9.3, 5.8, 6.6, and 2.7% in carbon monoxide, hydrocarbon, nitrogen oxide, and smoke emissions when compared to neat mahua biodiesel. PMID- 28836082 TI - Gender Norm Salience Across Middle Schools: Contextual Variations in Associations Between Gender Typicality and Socioemotional Distress. AB - Youth who feel they do not fit with gender norms frequently experience peer victimization and socioemotional distress. To gauge differences between schools, the current study examined the longitudinal effects of school-level gender norm salience-a within-school association between gender typicality and peer victimization-on socioemotional distress across 26 ethnically diverse middle schools (n boys = 2607; n girls = 2805). Boys (but not girls) reporting lower gender typicality experienced more loneliness and social anxiety in schools with more salient gender norms, even when accounting for both individual and school level victimization. Greater gender norm salience also predicted increased depressed mood among boys regardless of gender typicality. These findings suggest particular sensitivity among boys to environments in which low gender typicality is sanctioned. PMID- 28836083 TI - Microwave breast cancer detection using time-frequency representations. AB - Microwave-based breast cancer detection has been proposed as a complementary approach to compensate for some drawbacks of existing breast cancer detection techniques. Among the existing microwave breast cancer detection methods, machine learning-type algorithms have recently become more popular. These focus on detecting the existence of breast tumours rather than performing imaging to identify the exact tumour position. A key component of the machine learning approaches is feature extraction. One of the most widely used feature extraction method is principle component analysis (PCA). However, it can be sensitive to signal misalignment. This paper proposes feature extraction methods based on time frequency representations of microwave data, including the wavelet transform and the empirical mode decomposition. Time-invariant statistics can be generated to provide features more robust to data misalignment. We validate results using clinical data sets combined with numerically simulated tumour responses. Experimental results show that features extracted from decomposition results of the wavelet transform and EMD improve the detection performance when combined with an ensemble selection-based classifier. PMID- 28836084 TI - Effect of ultrasonic irradiation on bacterial biofilms. AB - PURPOSE: The purpose of this study was to clarify the effect of ultrasonic irradiation on biofilm produced by Staphylococcus epidermidis (S. epidermidis), which causes central venous catheter-related infections. MATERIALS AND METHODS: Staphylococcus epidermidis (S. epidermidis, ATCC 35984 RP 62A) was used in this study. First, biofilm was prepared from S. epidermidis on the bottom of the upper left well of a 6-well plate. Next, the biofilm was irradiated for 24 h with 1-MHz ultrasound (US) in the continuous wave mode to serve as the US irradiation group. The acoustic power irradiated below the bottom of the well was 3.8 mW. As a control (non-US irradiation group), non-irradiated biofilm on the bottom of a 6 well plate was incubated at 37 degrees C in an atmosphere of 5.0% CO2. After US irradiation, the bottoms of the wells were stained with 0.1% crystal violet for 60 s. To extract the crystal violet, 99.5% ethanol was added to the wells, and the extracted solutions were measured at an absorbance of 595 nm. RESULT: The absorbance of the US irradiation group was significantly less than that of the non-US irradiation group (p < 0.01). CONCLUSION: US irradiation can decrease the amount of S. epidermidis biofilm when the duration of US irradiation is sufficiently long even if the acoustic intensity is low. PMID- 28836085 TI - Real-world vehicle emissions as measured by in situ analysis of exhaust plumes. AB - We conducted a 60-day roadside measurement campaign on a busy street in Munster, Germany, during summer 2016. We used gas and particle concentration measurements with high temporal resolution (10 Hz) to quantify both the emission ratios of nitrogen oxides per carbon dioxide (NO x /CO2) for over 70,000 individual exhaust plumes as well as the emission ratios for size-resolved particle numbers per carbon dioxide (d(PN CO2-1)/dlogD) for about 10,000 plumes. The real-world fleet passing by the measurement station consisted of passenger cars (85%), buses (5.9%), light duty commercial vehicles (5.7%), trucks (1.7%), and motorcycles (1.6%). The median measured NO x /CO2 ratio was 3.33 g kg-1. The median measured PN/CO2 emission ratio for particles with diameters between 0.03 and 10 MUm was 5.6 * 1014 kg-1. We compared our results with the Handbook Emission Factors for Road Transport (HBEFA) and the Euro 5 and Euro 6 emission standards by employing traffic counts, assuming the diesel-to-gasoline ratios of vehicles according to registration statistics, and estimating that stop-and-go traffic occurred 65% of the time. Using a conservative estimate, our median ratios exceeded the HBEFA data by more than 65% for NO x /CO and by a factor of about 100 for PN/CO2. Furthermore, our median NO x emission per kilometer travelled (NO x km-1) exceeded the Euro 5 emission limit for diesel cars by a factor of 3 and exceeded the Euro 6 limit by almost a factor of 7. Additionally, our median particle number emission (PN km-1) exceeded the Euro 5 and Euro 6 limits of diesel cars by a factor of almost 150. These results confirm the presumption that the emissions of a real-world traffic fleet comprehensively exceed the legal limits. Very likely, the widespread presence of defeat devices in vehicle emission control systems plays a major role in this discrepancy. This has a strong impact on the apparent inability of authorities to comply with the legal limits of the NO2 concentrations in urban air. PMID- 28836086 TI - Spiritual Health and Physical Activity Among Iranian Pregnant Women. AB - This study was aimed to investigate the relationship between spiritual health and physical activity among Iranian pregnant women during 2015. A cross-sectional descriptive-analytic design was adopted. A total number of 411 participants were selected by convenience sampling from Iranian women who regularly attended health centers for prenatal care. Data were collected using demographic questionnaire and Health-Promoting Lifestyle Profile questionnaire, 2nd edition. (Spiritual health and physical activity are two components of health-promoting lifestyle.) The data were analyzed, using descriptive statistics, t test, one-way ANOVA, Pearson's correlation coefficient, and regression. p values <0.05 were considered significant. The mean age of pregnant women was 27.90 +/- 6.03 years. Spiritual health had the highest score (25.86 +/- 4.7) and physical activity had the lowest score (11.31 +/- 3.27), among six Health-Promoting Lifestyle Profile subscales. In fact, there was a statistically significant correlation between spiritual health and physical activity (p = 0.000). According to results, pregnant women have higher spiritual health and lower physical activity scores. There was a statistically significant correlation between spiritual health and physical activity. The findings of this study can be used in prenatal care, midwifery education, and maternal health policies. PMID- 28836087 TI - Early Colorectal Cancer Detected by Machine Learning Model Using Gender, Age, and Complete Blood Count Data. AB - BACKGROUND: Machine learning tools identify patients with blood counts indicating greater likelihood of colorectal cancer and warranting colonoscopy referral. AIMS: To validate a machine learning colorectal cancer detection model on a US community-based insured adult population. METHODS: Eligible colorectal cancer cases (439 females, 461 males) with complete blood counts before diagnosis were identified from Kaiser Permanente Northwest Region's Tumor Registry. Control patients (n = 9108) were randomly selected from KPNW's population who had no cancers, received at >=1 blood count, had continuous enrollment from 180 days prior to the blood count through 24 months after the count, and were aged 40-89. For each control, one blood count was randomly selected as the pseudo-colorectal cancer diagnosis date for matching to cases, and assigned a "calendar year" based on the count date. For each calendar year, 18 controls were randomly selected to match the general enrollment's 10-year age groups and lengths of continuous enrollment. Prediction performance was evaluated by area under the curve, specificity, and odds ratios. RESULTS: Area under the receiver operating characteristics curve for detecting colorectal cancer was 0.80 +/- 0.01. At 99% specificity, the odds ratio for association of a high-risk detection score with colorectal cancer was 34.7 (95% CI 28.9-40.4). The detection model had the highest accuracy in identifying right-sided colorectal cancers. CONCLUSIONS: ColonFlag(r) identifies individuals with tenfold higher risk of undiagnosed colorectal cancer at curable stages (0/I/II), flags colorectal tumors 180-360 days prior to usual clinical diagnosis, and is more accurate at identifying right sided (compared to left-sided) colorectal cancers. PMID- 28836088 TI - Feasibility assessment for successfully visualizing the fetal heart utilizing spatiotemporal image correlation. AB - PURPOSE: Spatiotemporal image correlation (STIC) is an excellent imaging modality for observing the fetal heart. High-quality STIC volume data are needed for an antenatal anatomic survey to diagnose congenital heart disease. We aimed to clarify the causes of unsuccessful STIC volume data acquisition and describe a more accurate, efficient STIC examination. METHODS: This cross-sectional study of 1124 women with fetuses assessed risk factors for unsuccessful acquisition of STIC volume data. Logistic regression analysis quantified the relation between unsuccessful acquisition and clinical variables, including maternal body mass index (BMI), shadowing artifacts due to unexpected fetal limb movement (SAU), estimated fetal weight (EFW), gestational age (GA), use of volume rendering images in four-dimensional ultrasonography (4D-US), fetal heart rate (FHR), maternal age, anterior placenta, and prior lower abdominal surgery. RESULTS: STIC volume data acquisition was unsuccessful in 210 of 1124 (18.6%) cases. SAU, BMI >= 28 kg/m2, not using volume rendering images in 4D-US, EFW >= 1300 g, and anterior placenta were independent risk factors for unsuccessful STIC data acquisition. CONCLUSIONS: Avoiding SAU was the most important factor for accurate, efficient STIC evaluations for diagnosing congenital heart disease antenatally. The risk was not explained by lack of sonographer proficiency. Volume rendering images in 4D-US is a promising approach to successful acquisition of STIC volume data. PMID- 28836090 TI - The use of latent variable mixture models to identify invariant items in test construction. AB - PURPOSE: Patient-reported outcome measures (PROMs) are frequently used in heterogeneous patient populations. PROM scores may lead to biased inferences when sources of heterogeneity (e.g., gender, ethnicity, and social factors) are ignored. Latent variable mixture models (LVMMs) can be used to examine measurement invariance (MI) when sources of heterogeneity in the population are not known a priori. The goal of this article is to discuss the use of LVMMs to identify invariant items within the context of test construction. METHODS: The Draper-Lindely-de Finetti (DLD) framework for the measurement of latent variables provides a theoretical context for the use of LVMMs to identify the most invariant items in test construction. In an expository analysis using 39 items measuring daily activities, LVMMs were conducted to compare 1- and 2-class item response theory models (IRT). If the 2-class model had better fit, item-level logistic regression differential item functioning (DIF) analyses were conducted to identify items that were not invariant. These items were removed and LVMMs and DIF testing repeated until all remaining items showed MI. RESULTS: The 39 items had an essentially unidimensional measurement structure. However, a 1-class IRT model resulted in many statistically significant bivariate residuals, indicating suboptimal fit due to remaining local dependence. A 2-class LVMM had better fit. Through subsequent rounds of LVMMs and DIF testing, nine items were identified as being most invariant. CONCLUSIONS: The DLD framework and the use of LVMMs have significant potential for advancing theoretical developments and research on item selection and the development of PROMs for heterogeneous populations. PMID- 28836089 TI - Risk factors for sodium valproate-induced renal tubular dysfunction. AB - OBJECTIVE: To explore the risk factors for the development of sodium valproate (VPA)-induced renal tubular dysfunction for early diagnosis and treatment. STUDY DESIGN: The subjects were selected from patients who were diagnosed with epilepsy and administered VPA. Blood and spot urine samples were collected and measured the concentration of VPA, the level of serum phosphorus, serum uric acid, serum free carnitine, serum cystatin-c, and urine beta2-microglobulin (BMG). Patients with urine BMG/creatinine levels above 219.2 were treated as renal proximal tubular dysfunction (RTD), with all others treated as non-RTD. RESULTS: Eighty seven patients, 4-48 years, 53 men and 34 women, were studied. RTD group is 17 patients and non-RTD group is 70 patients. Univariate analyses revealed that the RTD patients were more likely to be bedridden, receiving enteral tube feeding, taking more anticonvulsants, and demonstrating significantly lower serum levels of free carnitine, uric acid, and phosphorus. Among them, bedridden, free serum carnitine, and phosphorus levels were associated with the development of RTD by multivariate analysis. CONCLUSIONS: Bedridden patients receiving VPA are susceptible to hypocarnitinemia, which can cause RTD and may lead to FS. Therefore, urinary BMG should be measured regularly in all patients receiving VPA to assess renal tubular function. An additional measurement of serum free carnitine level should be considered in patients who developed RTD. Supplementation of carnitine for those patients to prevent such complication deserves for further study. PMID- 28836091 TI - Small drinking water systems under spatiotemporal water quality variability: a risk-based performance benchmarking framework. AB - Traditional approaches for benchmarking drinking water systems are binary, based solely on the compliance and/or non-compliance of one or more water quality performance indicators against defined regulatory guidelines/standards. The consequence of water quality failure is dependent on location within a water supply system as well as time of the year (i.e., season) with varying levels of water consumption. Conventional approaches used for water quality comparison purposes fail to incorporate spatiotemporal variability and degrees of compliance and/or non-compliance. This can lead to misleading or inaccurate performance assessment data used in the performance benchmarking process. In this research, a hierarchical risk-based water quality performance benchmarking framework is proposed to evaluate small drinking water systems (SDWSs) through cross comparison amongst similar systems. The proposed framework (R WQI framework) is designed to quantify consequence associated with seasonal and location-specific water quality issues in a given drinking water supply system to facilitate more efficient decision-making for SDWSs striving for continuous performance improvement. Fuzzy rule-based modelling is used to address imprecision associated with measuring performance based on singular water quality guidelines/standards and the uncertainties present in SDWS operations and monitoring. This proposed R WQI framework has been demonstrated using data collected from 16 SDWSs in Newfoundland and Labrador and Quebec, Canada, and compared to the Canadian Council of Ministers of the Environment WQI, a traditional, guidelines/standard based approach. The study found that the R WQI framework provides an in-depth state of water quality and benchmarks SDWSs more rationally based on the frequency of occurrence and consequence of failure events. PMID- 28836092 TI - Four symptoms define the piriformis syndrome: an updated systematic review of its clinical features. AB - PURPOSE: To update the evidence on the clinical features of the piriformis syndrome since the first systematic review published in 2010. METHOD: A systematic review of all case, cross-sectional and prevalence studies. RESULTS: The commonest features reported were: buttock pain, pain aggravated on sitting, external tenderness near the greater sciatic notch and pain on any maneuver that increases piriformis muscle tension, and limitation of straight leg raising. The quality of case reports since the previous review has not improved with considerable under-reporting of presumed negative tests. Three recent cross sectional and prevalence studies have been reported, but the two larger studies are at high risk of bias. CONCLUSIONS: Piriformis syndrome can be defined by a quartet of symptoms and signs. Many physical tests have been described, but the accuracy of these tests and the symptoms cannot be concluded from studies to date. Straight leg raising does not rule out the diagnosis. Piriformis syndrome is at a stage previously encountered with herniated intervertebral disc: that piriformis muscle pathology can cause sciatica has been demonstrated, but its prevalence among low back pain and sciatica sufferers and the diagnostic accuracy of clinical features requires cross-sectional studies free of incorporation and verification biases. One small cross-sectional study provides an encouraging example of how such studies could be conducted but would need replication in a broader population and better reporting. PMID- 28836093 TI - On the Relation Between General Intelligence and Psychopathic Traits: An Examination of Inpatient Adolescents. AB - A substantial literature has investigated relations between intelligence and psychopathic traits. At the construct level, findings have been mixed, with a small negative relation found. At the facet level however, a positive relation between verbal intelligence and the interpersonal facet of psychopathy, and a negative relation between verbal intelligence and the lifestyle factor of psychopathy emerge. To date, this research has largely neglected adolescents and prior research has focused on clinical and incarcerated populations, while failing to control for psychopathology. The current study sought to address these limitations by examining the relation between intelligence and psychopathy at the construct, facet, and trait level in a sample of inpatient adolescents. At the bivariate level, verbal intelligence was related to dishonest charm, unemotionality, impulsiveness, and manipulation. In regression analyses, however, verbal intelligence lost significance as a predictor of all but impulsiveness. Gender and severity of psychopathology accounted for most significant relations. PMID- 28836094 TI - One stone two birds: novel carbon nanotube/Bi4VO8Cl photocatalyst for simultaneous organic pollutants degradation and Cr(VI) reduction. AB - In this work, visible light-responsive carbon nanotubes (CNTs)/Bi4VO8Cl composite photocatalysts have been prepared by a facile in situ hydrothermal method and characterized by various techniques. The photocatalytic properties of the photocatalysts are evaluated by the degradation of refractory azo-dye methyl orange (MO), hexavalent chromium Cr(VI), and bisphenol A (BPA) in water under visible light irradiation. It is found that the as-prepared composite with 4 wt% CNTs shows an optimal photocatalytic performance, and its photocatalytic activity is 30% higher than that of pure Bi4VO8Cl. The enhanced photocatalytic activity is ascribed to the synergetic effects induced by increased light absorption, increased adsorption efficiency for pollutant, and suppressed recombination rate of photogenerated charge carriers. Furthermore, efficient removals of Cr(VI), bisphenol A (BPA), and combined contamination of Cr(VI) and BPA over CNTs/Bi4VO8Cl composite further confirm that the degradation of organic pollutants is a photocatalytic mechanism rather than photosensitization of dye. Of particular importance is that removal efficiency of single pollutant can be promoted by the coexistence of the Cr(VI) and organics. The mechanism of synergetic promotion is discussed and attributed to the accelerated separation of charge carriers resulted from their simultaneously being captured by pollutants. Moreover, the CNTs/Bi4VO8Cl composite exhibits good stability and recycling performance in the photocatalytic degradation process. Therefore, the composite photocatalysts developed in the present work are expected to have the potential in purification of complex wastewater. Graphical abstract The separation of photogenerated charge carriers and adsorbing capacity as well as visible light absorption ability of Bi4VO8Cl are significantly promoted by coupling with carbon nanotubes. Simultaneous removal of Cr(VI) and organic pollutants can be achieved by CNTs/Bi4VO8Cl composite photocatalysts under visible light irradiation. PMID- 28836095 TI - Selenoprotein N Was Required for the Regulation of Selenium on the Uterine Smooth Muscle Contraction in Mice. AB - Selenium (Se) is an essential micronutrient affecting various aspects of health. The balance of the Se concentration has an important protective and promoter effect on physiological function in inducing muscular disorders in smooth muscle. Selenoprotein N (SelN) is closely related to Ca2+ release. The present study aimed to determine the effects and mechanism of action of dietary Se on uterine smooth muscle contraction via SelN using a mouse model. Quantitative polymerase chain reaction (qPCR) analysis was performed to detect mRNA levels. Western blotting was performed to detect protein levels. The results of the immunohistochemical analysis showed that Se had an effect on the uterine smooth muscle. The Se-supplement increased the release of Ca2+, Ca2+-calmodulin (CaM) expression, myosin light chain kinase (MLCK) expression, and myosin light chain (MLC) phosphorylation but did not affect ROCK and RhoA in uterine smooth muscle. Furthermore, the lack of Se showed an opposite impact. The effects of Se regulation were closely related to SelN. The interference of mouse SelN was performed on the uterine smooth muscle cell. Additionally, the results displayed the regulation of Se on the release of Ca2+, CaM expression, MLCK expression, and MLC phosphorylation were significant inhibited, and there was no effect on ROCK and RhoA. In conclusion, Se played an important role in regulating the process of contraction in uterine smooth muscle with SelN. PMID- 28836096 TI - DNA helix: the importance of being AT-rich. AB - The AT-rich DNA is mostly associated with condensed chromatin, whereas the GC rich sequence is preferably located in the dispersed chromatin. The AT-rich genes are prone to be tissue-specific (silenced in most tissues), while the GC-rich genes tend to be housekeeping (expressed in many tissues). This paper reports another important property of DNA base composition, which can affect repertoire of genes with high AT content. The GC-rich sequence is more liable to mutation. We found that Spearman correlation between human gene GC content and mutation probability is above 0.9. The change of base composition even in synonymous sites affects mutation probability of nonsynonymous sites and thus of encoded proteins. There is a unique type of housekeeping genes, which are especially unsafe when prone to mutation. Natural selection which usually removes deleterious mutations, in the case of these genes only increases the hazard because it can descend to suborganismal (cellular) level. These are cell cycle-related genes. In accordance with the proposed concept, they have low GC content of synonymous sites (despite them being housekeeping). The gene-centred protein interaction enrichment analysis (PIEA) showed the core clusters of genes whose interactants are modularly enriched in genes with AT-rich synonymous codons. This interconnected network is involved in double-strand break repair, DNA integrity checkpoints and chromosome pairing at mitosis. The damage of these genes results in genome and chromosome instability leading to cancer and other 'error catastrophes'. Reducing the nonsynonymous mutations, the usage of AT-rich synonymous codons can decrease probability of cancer by above 20-fold. PMID- 28836098 TI - PROMIS Pain Interference and Physical Function Scores Correlate With the Foot and Ankle Ability Measure (FAAM) in Patients With Hallux Valgus. AB - BACKGROUND: Traditional patient-reported outcome instruments like the Foot and Ankle Ability Measure (FAAM) quantify patient disability but often are limited by responder burden and incomplete questionnaires. The Patient-Reported Outcome Measurement Information System (PROMIS) overcomes such obstacles through computer adaptive technology and can capture outcome data from various domains including physical and psychosocial function. Prior work has compared the FAAM with PROMIS physical function; however, there is little evidence comparing the association between foot and ankle-specific tools like the FAAM with more general outcomes measures of PROMIS pain interference and depression in foot and ankle conditions. QUESTIONS/PURPOSES: (1) We asked whether there was a relationship between FAAM Activities of Daily Living (ADL) scores with PROMIS physical function, pain interference, and depression in patients with hallux valgus. (2) Additionally, we asked if we could identify specific factors that are associated with variance in FAAM and PROMIS physical function scores in patients with hallux valgus. METHODS: Eighty-five new patients with either a primary or secondary diagnosis of hallux valgus based on clinic billing codes from July 2015 to February 2016 were retrospectively identified. Patients completed FAAM ADL paper-based surveys and electronic PROMIS questionnaires for physical function, pain interference, and depression from new patient visits at a single time. Spearman rho correlations were performed between FAAM ADL and PROMIS scores. Analyses then were used to identify differences in FAAM ADL and PROMIS physical function measures based on demographic variables. Stepwise linear regressions then determined which demographic and/or outcome variable(s) accounted for the variance in FAAM ADL and PROMIS physical function scores. RESULTS: FAAM scores correlated strongly with PROMIS physical function (r = 0.70, p < 0.001), moderately with PROMIS pain interference (r = -0.65, p < 0.001), and weakly with PROMIS depression (r = 0.35, p < 0.001) scores. Regression analyses showed that PROMIS pain interference scores alone were associated with sizeable portions of the variance in FAAM ADL (R2 = 0.44, p < 0.001) and PROMIS physical function (R2 = 0.57, p < 0.001) measures. CONCLUSIONS: PROMIS function and pain measures correlated with FAAM ADL scores, highlighting the interrelationship of pain and function when assessing outcomes in patients with hallux valgus. PROMIS tools allow for more-efficient data collection across multiple domains and, moving forward, may be better poised to monitor changes in pain and function with time compared with traditional outcome measures like the FAAM. CLINICAL RELEVANCE: The relationships shown here between PROMIS and FAAM scores further support the use of PROMIS tools in outcomes-based research. In patients with hallux valgus, pain-related disability appears to be a central feature of the patient-experience. Future studies should assess the association of various outcome domains on other common foot and ankle diagnoses. PMID- 28836100 TI - Iron: a Strong Element in the Pathogenesis of Chronic Hyperglycaemia After Acute Pancreatitis. AB - Evidence shows an association between markers of iron metabolism and glucose metabolism in type 2 diabetes mellitus. Acute pancreatitis is the largest contributor to diabetes of the exocrine pancreas. However, the pathogenesis of new-onset pre-diabetes or diabetes after pancreatitis remains unclear. This study aimed to investigate associations between markers of iron metabolism and glucose metabolism following acute pancreatitis. Fasting blood samples were collected to analyse markers of glucose metabolism (haemoglobin A1c) and iron metabolism (hepcidin, ferritin, and soluble transferrin receptor). Participants were categorised into two groups: normoglycaemia after acute pancreatitis and chronic hyperglycaemia after acute pancreatitis. Binary logistic and linear regression analyses were conducted, and potential confounders were adjusted for in multivariable analyses. A total of 83 individuals following an episode of acute pancreatitis were included, of whom 19 developed chronic hyperglycaemia. Hepcidin was significantly increased in individuals with chronic hyperglycaemia after acute pancreatitis in two adjusted models (p = 0.045 and p = 0.048). Ferritin was significantly decreased in individuals with chronic hyperglycaemia after acute pancreatitis in three adjusted models (p = 0.016, p = 0.009, and p = 0.011). Soluble transferrin receptor was not significantly associated with chronic hyperglycaemia after acute pancreatitis. These findings suggest that iron metabolism is significantly altered in individuals with chronic hyperglycaemia after acute pancreatitis and may provide better insights into the pathogenesis of new-onset diabetes after pancreatitis. PMID- 28836097 TI - Animal Models of Diabetic Retinopathy. AB - PURPOSE OF REVIEW: Diabetic retinopathy (DR) is one of the most common complications associated with chronic hyperglycemia seen in patients with diabetes mellitus. While many facets of DR are still not fully understood, animal studies have contributed significantly to understanding the etiology and progression of human DR. This review provides a comprehensive discussion of the induced and genetic DR models in different species and the advantages and disadvantages of each model. RECENT FINDINGS: Rodents are the most commonly used models, though dogs develop the most similar morphological retinal lesions as those seen in humans, and pigs and zebrafish have similar vasculature and retinal structures to humans. Nonhuman primates can also develop diabetes mellitus spontaneously or have focal lesions induced to simulate retinal neovascular disease observed in individuals with DR. DR results in vascular changes and dysfunction of the neural, glial, and pancreatic beta cells. Currently, no model completely recapitulates the full pathophysiology of neuronal and vascular changes that occur at each stage of diabetic retinopathy; however, each model recapitulates many of the disease phenotypes. PMID- 28836099 TI - Cutaneous Manifestations of Small-Vessel Leukocytoclastic Vasculitides in Childhood. AB - In childhood, cutaneous small-vessel vasculitides include Henoch-Schonlein syndrome, a systemic vasculitis, and Finkelstein-Seidlmayer syndrome, a skin limited vasculitis. Both Henoch-Schonlein and Finkelstein-Seidlmayer syndromes are seen more frequently in white or Asian compared with black children and occur especially in winter and spring with a male-to-female ratio of approximately 2:1. In everyday clinical practice, both conditions are diagnosed on clinical grounds without histological confirmation. The characteristic cutaneous hallmarks of Henoch-Schonlein syndrome include a purpuric rash in all and a subcutaneous edema in approximately every second case, which are often preceded by non-specific red or pink macular elements that mimic a non-itching urticarial rash. Recent data point out that Henoch-Schonlein children often present further cutaneous findings such as Kobnerization, Rumpel-Leede capillary fragility phenomenon, and blistering eruptions. Children with Finkelstein-Seidlmayer syndrome are usually <=24 months of age and not ill-appearing. They present with (a) large, round, red to purpuric plaques (often with a targetoid appearance) predominantly over the cheeks, ears, and extremities and (b) often tender non-pitting edema of the distal extremities, ears, and face (without pruritus). Both in Henoch-Schonlein syndrome and Finkelstein-Seidlmayer syndrome, there is often scrotal involvement. The cutaneous findings remit without sequelae within 2 months in Henoch-Schonlein and 3 weeks in Finkelstein-Seidlmayer syndrome. PMID- 28836101 TI - Bilateral macular infarction after gemcitabine and carboplatin chemotherapy. AB - PURPOSE: To report a case of macular infarction after doublet chemotherapy with gemcitabine and carboplatin. METHODS: A middle-aged lady presenting with bilateral macular infarction post-chemotherapy for metastatic cervical malignancy was investigated for thromboembolic risks and treated. RESULTS: The macular perfusion and edema improved with control of hypertension and treatment with pentoxifylline. Visual improvement was satisfactory, and the possible associated risk such as hypertension was noted. CONCLUSION: This case underscores the need for active screening of patients on chemotherapy with gemcitabine and carboplatin for retinal vascular occlusive changes when hypertension is associated. PMID- 28836103 TI - Melancholy, Acculturation, and Relief: A Brief Essay on the Religion of Ordinarity. AB - Han is not an idiosyncratic, psychological experience that is peculiar to Koreans, but a multifaceted mode of melancholy experienced by many and various people. What makes this psychological experience particularly familiar to Koreans, however, is that this phenomenon is colored by various, macroscopic factors common in the Korean context, such as sociocultural rigidness, historical instability, political feudality, and economic vulnerability. In this sense, han is an acculturated, multifaceted melancholy. Not only that, it has developed its own religiousness, the goal of which is the restoration of ordinarity, because the state of han premises extraordinary, abnormal, or tension-provoking situations. The explicit and implicit religious idioms developing in the religion of han, such as tongsung-kido and wishing-for-blessing, evolve around this religious telos, helping individuals in Korea restore and live ordinarity. PMID- 28836102 TI - Sensory Neuronopathies. AB - PURPOSE OF REVIEW: The sensory neuronopathies are sensory-predominant polyneuropathies that result from damage to the dorsal root and trigeminal sensory ganglia. This review explores the various causes of acquired sensory neuronopathies, the approach to diagnosis, and treatment. RECENT FINDINGS: Diagnostic criteria have recently been published and validated to allow differentiation of sensory neuronopathies from other polyneuropathies. On the basis of serial electrodiagnostic studies, the treatment window for the acquired sensory neuronopathies has been identified as approximately 8 months. If treatment is initiated within 2 months of symptom onset, there is a better opportunity for improvement of the patient's condition. Even though sensory neuronopathies are rare, significant progress has been made regarding characterization of their clinical, electrophysiologic, and imaging features. This does not hold true, however, for treatment. There have been no randomized controlled clinical trials to guide management of these diseases, and a standard treatment approach remains undetermined. PMID- 28836104 TI - Involvement of aberrantly expressed microRNAs in the pathogenesis of head and neck squamous cell carcinoma. AB - MicroRNAs (miRNAs) are small noncoding RNAs that act as fine-tuners of the post transcriptional control of protein-coding or noncoding RNAs by repressing translation or cleaving RNA transcripts in a sequence-dependent manner in cells. Accumulating evidence have been indicated that aberrantly expressed miRNAs are deeply involved in human pathogenesis, including cancers. Surprisingly, these small, single-stranded RNAs (18-23 nucleotides) have been shown to function as antitumor or oncogenic RNAs in several types of cancer cells. A single miRNA has regulating hundreds or thousands of different mRNAs, and individual mRNA has been regulated by multiple different miRNAs in normal cells. Therefore, tightly controlled RNA networks can be disrupted by dysregulated of miRNAs in cancer cells. Investigation of novel miRNA-mediated RNA networks in cancer cells could provide new insights in the field of cancer research. In this review, we focus on head and neck squamous cell carcinoma (HNSCC) and discuss current findings of the involvement of aberrantly expressed miRNAs in the pathogenesis of HNSCC. PMID- 28836105 TI - Surgical and pathological outcomes of robotic-assisted radical cystectomy for bladder cancer in the community setting. AB - Robotic-assisted radical cystectomy (RARC) with urinary diversion is commonly performed in community hospitals. While little data exist on RARC outcomes in this setting, community hospitals may improve access to care for bladder cancer patients. We conducted a retrospective review of 76 patients who underwent RARC between 2006 and 2016 by two robotic-trained surgeons in two local community hospitals. A total of 76 patients (60 males and 16 females; ages 46-89) underwent RARC with extended pelvic lymphadenectomy and urinary diversion (69 ileal conduits, 7 neobladders) for muscle-invasive bladder carcinoma (79%), recurrent high-grade carcinoma (17%), unresectable tumor (2%), or refractory gross hematuria from chemotherapy (2%). Median-estimated surgical blood loss (EBL) was 400 mL, and median operating time was 386 min. Transfusion rate was 22% and median length of hospital stay was 6 days. Our 90-day complication rate was 47%, with no mortalities in the 90-day post-operative period. The majority of complications (58%) were Clavien grade 1-2. We observed a significant difference in incidence of complications among patients receiving neobladder vs. ileal conduit (p = 0.002). On pathology, zero patients had positive bladder specimen margins. Among 28 patients with at least 3-year follow-up, overall survival was 85.7%, and among 9 patients with at least 5-year follow-up, overall survival was 100%. Contrary to some studies, our findings suggest similar short-term surgical and pathologic outcomes for RARC performed in the community hospital setting compared to high volume centers. We defined several criteria for low volume centers to effectively and safely perform RARC. PMID- 28836106 TI - The impact of adjuvant therapy for patients with high-risk diffuse WHO grade II glioma. AB - Despite recent randomized, prospective evidence supporting use of RT and chemotherapy (CRT) for high-risk low-grade gliomas (LGG), many patients have historically received RT alone, chemotherapy alone or observation postoperatively. The purpose of this study is to evaluate outcomes for historical treatments in comparison to CRT for high-risk diffuse WHO grade II glioma patients. Records from 309 adults with WHO grade II glioma (1997-2008) eligible for RTOG 9802 (incomplete resection/biopsy or age >=40 years) were retrospectively reviewed. Kaplan-Meier estimates were used for progression-free survival (PFS) and overall survival (OS). The Cox proportional hazards model was used for estimates of risk ratios for univariate and multivariate analyses. Median follow-up was 10.6 years. Adjuvant treatments included radiotherapy (RT) alone (45%), observation (31%), CRT (21%) and chemotherapy alone (3%). Non astrocytic histology, TERT promoter mutation, 1p/19q codeletion and extensive resections were associated with improved PFS and OS on univariate analysis (all p < 0.05). IDH mutations and adjuvant CRT was associated with improved PFS (all p < 0.05). On multivariate analysis, histology, molecular grouping and extent of resection were significantly associated with PFS and OS. In addition, multivariate analysis revealed that CRT was associated with improved PFS and OS compared with RT alone, and improved PFS compared with observation. This study confirms the benefit of adding chemotherapy to RT compared with RT alone or observation. These findings emphasize the need for aggressive treatment in patients with high-risk LGG. PMID- 28836107 TI - Neural Network Classifier for Automatic Detection of Invasive Versus Noninvasive Airway Management Technique Based on Respiratory Monitoring Parameters in a Pediatric Anesthesia. AB - Children undergoing general anesthesia require airway monitoring by an anesthesia provider. The airway may be supported with noninvasive devices such as face mask or invasive devices such as a laryngeal mask airway or an endotracheal tube. The physiologic data stored provides an opportunity to apply machine learning algorithms distinguish between these modes based on pattern recognition. We retrieved three data sets from patients receiving general anesthesia in 2015 with either mask, laryngeal mask airway or endotracheal tube. Patients underwent myringotomy, tonsillectomy, adenoidectomy or inguinal hernia repair procedures. We retrieved measurements for end-tidal carbon dioxide, tidal volume, and peak inspiratory pressure and calculated statistical features for each data element per patient. We applied machine learning algorithms (decision tree, support vector machine, and neural network) to classify patients into noninvasive or invasive airway device support. We identified 300 patients per group (mask, laryngeal mask airway, and endotracheal tube) for a total of 900 patients. The neural network classifier performed better than the boosted trees and support vector machine classifiers based on the test data sets. The sensitivity, specificity, and accuracy for neural network classification are 97.5%, 96.3%, and 95.8%. In contrast, the sensitivity, specificity, and accuracy of support vector machine are 89.1%, 92.3%, and 88.3% and with the boosted tree classifier they are 93.8%, 92.1%, and 91.4%. We describe a method to automatically distinguish between noninvasive and invasive airway device support in a pediatric surgical setting based on respiratory monitoring parameters. The results show that the neural network classifier algorithm can accurately classify noninvasive and invasive airway device support. PMID- 28836108 TI - Hyperglycemia induces attention and gait deficits in diabetic mellitus patients. AB - AIMS: Patients with diabetes mellitus experience a large number of falls and bone fractures that are not related solely to complications of the disease. The purpose of our study was to determine whether transient hyperglycemia affects attentional functions and gait. METHODS: This was a case-control study. We asked 17 patients with type 1 or type 2 diabetes mellitus to perform three visual tests and one visual and auditory attention test (Phasic Alert A1-4 and A2-3, Go/No Go, Intermodal Comparison). Mean response time (ms) and total number of errors were assessed. Ten of the patients also performed a tandem gait test consisting of three steps. The total distance travelled (TDT, in mm) by the center of pressure was measured with a pressure-sensitive calibrated platform. Transient hyperglycemia was defined as blood glucose level greater than 13, 8 mmol/L at the time of the test. These same patients were retested 1-3 days later at a blood glucose level at least 5, 5 mmol/L lower than the initial values (T24-72h). Nineteen patients with diabetes mellitus were matched with the original participants and performed the same test under normoglycemic conditions. RESULTS: During transient hyperglycemia, the mean response time (ms) and the TDT were significantly longer. The mean response time for the four tests increased by 53, 5 ms (P < 0.001). There was no increase in the number of errors. The TDT of the center of pressure increased significantly by 102 mm (P < 0.001). CONCLUSIONS: Transient hyperglycemia alters attention and gait in patients with diabetes mellitus. PMID- 28836109 TI - IRMPD Action Spectroscopy, ER-CID Experiments, and Theoretical Studies of Sodium Cationized Thymidine and 5-Methyluridine: Kinetic Trapping During the ESI Desolvation Process Preserves the Solution Structure of [Thd+Na]. AB - Thymidine (dThd) is a fundamental building block of DNA nucleic acids, whereas 5 methyluridine (Thd) is a common modified nucleoside found in tRNA. In order to determine the conformations of the sodium cationized thymine nucleosides [dThd+Na]+ and [Thd+Na]+ produced by electrospray ionization, their infrared multiple photon dissociation (IRMPD) action spectra are measured. Complementary electronic structure calculations are performed to determine the stable low energy conformations of these complexes. Geometry optimizations and frequency analyses are performed at the B3LYP/6-311+G(d,p) level of theory, whereas energies are calculated at the B3LYP/6-311+G(2d,2p) level of theory. As protonation preferentially stabilizes minor tautomers of dThd and Thd, tautomerization facilitated by Na+ binding is also considered. Comparisons of the measured IRMPD and computed IR spectra find that [dThd+Na]+ prefers tridentate (O2,O4',O5') coordination to the canonical 2,4-diketo form of dThd with thymine in a syn orientation. In contrast, [Thd+Na]+ prefers bidentate (O2,O2') coordination to the canonical 2,4-diketo tautomer of Thd with thymine in an anti orientation. Although 2,4-dihydroxy tautomers and O2 protonated thymine nucleosides coexist in the gas phase, no evidence for minor tautomers is observed for the sodium cationized species. Consistent with experimental observations, the computational results confirm that the sodium cationized thymine nucleosides exhibit a strong preference for the canonical form of the thymine nucleobase. Survival yield analyses based on energy-resolved collision-induced dissociation (ER-CID) experiments suggest that the relative stabilities of protonated and sodium cationized dThd and Thd follow the order [dThd+H]+ < [Thd+H]+ < [dThd+Na]+ < [Thd+Na]+. Graphical Abstract ?. PMID- 28836110 TI - Effects of Photodynamic Therapy on the Growth and Antifungal Susceptibility of Scedosporium and Lomentospora spp. AB - Scedosporium and Lomentospora species are the second most frequent colonizing, allergenic, or invasive fungal pathogens in patients with cystic fibrosis, and are responsible for infections varying from cutaneous and subcutaneous tissue infections caused by traumatic inoculation to severe systemic diseases in immunocompromised patients. The clinical relevance of fungal airway colonization for individual patients harboring Scedosporium and Lomentospora species is still an underestimated issue. The high resistance of Scedosporium and Lomentospora species to antifungal drugs has highlighted the need for alternative treatment modalities, and antimicrobial photodynamic therapy may be one such alternative. In this study, methylene blue was applied as a photosensitizing agent to 6 type strains of Scedosporium and Lomentospora species, and we irradiated the strains using a light-emitting diode (635 +/- 10 nm, 12 J/cm2). We evaluated the effects of photodynamic therapy on strain growth and on the in vitro susceptibility of the strains to itraconazole, voriconazole, posaconazole, and amphotericin B. A colony-forming unit reduction of up to 5.2 log10 was achieved. Minimal inhibitory concentration ranges also decreased significantly with photoinactivation. Photodynamic therapy improved both the inactivation rates and the antifungal susceptibility profile of all fungal isolates tested. PMID- 28836111 TI - Excretory-secretory product of third-stage Gnathostoma spinigerum larvae induces apoptosis in human peripheral blood mononuclear cells. AB - Human gnathostomiasis caused by third-stage Gnathostoma spinigerum larvae (G. spinigerum L3) is an important zoonotic disease in tropical areas of the world. The excretory-secretory products (ES) that are excreted by infective larva play a significant role in host immune evasion and tissue destruction. To investigate the poorly understood mechanisms of G. spinigerum L3 pathogenesis, we focused on the potential effect of ES on inducing apoptosis in human immune cells by using human peripheral blood mononuclear cells (PBMCs) as a model. Early and late apoptosis of PBMCs were assessed following the exposure of these cells to G. spinigerum L3 ES (0.1, 0.5, and 1.0 MUg/ml) for 6-48 h. The apoptotic cells were identified by flow cytometric staining of PBMC with FITC-annexin V and propidium iodide. The expression of regulatory genes related to apoptosis mechanisms in ES treated PBMCs was investigated using a Human Apoptosis RT2 ProfilerTM PCR Array. The results showed significant levels of early phase apoptosis at 18 h and of late phase apoptosis at 24 h. We speculate that this apoptosis in PBMCs occurs via the extrinsic pathway. Apoptosis in the ES-induced PBMCs was observed as quickly as 90 min after exposure, and the highest effect was observed at 18-24 h. Furthermore, ES can trigger apoptosis lasting for 48 h. Our findings expand the understanding of one of the mechanisms involved, immune-evasive strategy mechanism used by G. spinigerum larvae during human gnathostomiasis. PMID- 28836112 TI - Structural insights on biologically relevant cationic membranes by ESR spectroscopy. AB - Cationic bilayers have been used as models to study membrane fusion, templates for polymerization and deposition of materials, carriers of nucleic acids and hydrophobic drugs, microbicidal agents and vaccine adjuvants. The versatility of these membranes depends on their structure. Electron spin resonance (ESR) spectroscopy is a powerful technique that employs hydrophobic spin labels to probe membrane structure and packing. The focus of this review is the extensive structural characterization of cationic membranes prepared with dioctadecyldimethylammonium bromide or diC14-amidine to illustrate how ESR spectroscopy can provide important structural information on bilayer thermotropic behavior, gel and fluid phases, phase coexistence, presence of bilayer interdigitation, membrane fusion and interactions with other biologically relevant molecules. PMID- 28836113 TI - Association of obesity and diabetes with thyroid nodules. AB - AIM: There are conflicting data concerning the possibility that obesity and diabetes raise the risk of thyroid nodules. The incidence of thyroid nodules is increasing, as is that of obesity and diabetes; therefore, understanding whether these metabolic and nutritional disorders influence nodular thyroid disease is important for organizing prevention strategies. This study investigated the association between thyroid nodules, obesity, diabetes, and dietary habits. MATERIALS AND METHODS: A cohort of randomly selected adults (455 males, 746 females; age: 18-90 years) living in Palermo (Italy), a mild iodine deficiency area, was cross-sectionally investigated. Participants underwent high-resolution ultrasonographic evaluation of the thyroid, and answered a food frequency questionnaire. Laboratory blood measurements were obtained in 587 participants. RESULTS AND DISCUSSION: Thyroid nodules were detected in 475 (39.5%) participants. The number of thyroid nodules was correlated with age (r = 0.19; P < 0.001), gender (r = 0.08; P = 0.005), and body mass index (r = 0.07; P = 0.02). No significant correlation was observed between the number of nodules and glycated hemoglobin, serum insulin concentrations, and homeostasis model assessment of insulin resistance. Age-adjusted and gender-adjusted prevalence of both overweight/obesity and type 2 diabetes of each group of participants divided according to the number of nodules significantly increased with the number of nodules (P < 0.05 in both cases). The group of participants with nodules exhibited a significantly lower age-adjusted and gender-adjusted habitual intake of milk (P = 0.02). Multivariate regression analysis showed that age, gender, body mass index, diabetes, and habitual consumption of milk were independently correlated with presence of thyroid nodules. CONCLUSION: This study seems to indicate that an association exists between obesity, diabetes, and thyroid nodules. PMID- 28836114 TI - Investigating successive Australian barley breeding populations for stable resistance to leaf rust. AB - KEY MESSAGE: Genome-wide association studies of barley breeding populations identified candidate minor genes for pairing with the adult plant resistance gene Rph20 to provide stable leaf rust resistance across environments. Stable resistance to barley leaf rust (BLR, caused by Puccinia hordei) was evaluated across environments in barley breeding populations (BPs). To identify genomic regions that can be combined with Rph20 to improve adult plant resistance (APR), two BPs genotyped with the Diversity Arrays Technology genotyping-by-sequencing platform (DArT-seq) were examined for reaction to BLR at both seedling and adult growth stages in Australian environments. An integrated consensus map comprising both first- and second-generation DArT platforms was used to integrate QTL information across two additional BPs, providing a total of four interrelated BPs and 15 phenotypic data sets. This enabled identification of key loci underpinning BLR resistance. The APR gene Rph20 was the only active resistance region consistently detected across BPs. Of the QTL identified, RphQ27 on chromosome 6HL was considered the best candidate for pairing with Rph20. RphQ27 did not align or share proximity with known genes and was detected in three of the four BPs. The combination of RphQ27 and Rph20 was of low frequency in the breeding material; however, strong resistance responses were observed for the lines carrying this pairing. This suggests that the candidate minor gene RphQ27 can interact additively with Rph20 to provide stable resistance to BLR across diverse environments. PMID- 28836115 TI - Management of ascites and hepatorenal syndrome. AB - Ascites represents the most common decompensating event in patients with liver cirrhosis. The appearance of ascites is strongly related to portal hypertension, which leads to splanchnic arterial vasodilation, reduction of the effective circulating volume, activation of endogenous vasoconstrictor systems, and avid sodium and water retention in the kidneys. Bacterial translocation further worsens hemodynamic alterations of patients with cirrhosis and ascites. The first line treatment of uncomplicated ascites is a moderate sodium-restricted diet combined with diuretic treatment. In patients who develop refractory ascites, paracentesis plus albumin represents the most feasible option. Transjugular intrahepatic portosystemic shunt placement is a good alternative for selected patients. Other treatments such as vasoconstrictors and automated low-flow pumps are two potential options still under investigations. Ascites is associated with a high risk of developing further complications of cirrhosis such as dilutional hyponatremia, spontaneous bacterial peritonitis and/or other bacterial infections and acute kidney injury (AKI). Hepatorenal syndrome (HRS) is the most life threatening type of AKI in patients with cirrhosis. The most appropriate medical treatment in patients with AKI-HRS is the administration of vasoconstrictors plus albumin. Finally, ascites impairs both the quality of life and survival in patients with cirrhosis. Thus, all patients with ascites should be evaluated for the eligibility for liver transplantation. The aim of this article is to review the management of patients with cirrhosis, ascites and HRS. PMID- 28836117 TI - Using Goat's Milk, Barley Flour, Honey, and Probiotic to Manufacture of Functional Dairy Product. AB - Stirred yogurt manufactured using probiotic culture which usually called Rayeb milk in the Middle East region is one of the most important functional fermented milk products. To increase the health and functionality properties to this product, some ingredients like fruits, cereal, and whey protein are used in production. This study was carried out to prepare functional Rayeb milk from goat's milk, barley flour (15%) and honey (4%) mixtures using ABT culture. Also, vanilla and cocoa powder were used as flavorings. Adding barley flour and honey to goat's milk increased curd tension and water-holding capacity and decreased coagulation time and susceptibility to syneresis. The values of carbohydrate, total solids, dietary fiber, ash, total protein, water soluble nitrogen, total volatile fatty acids, unsaturated fatty acids, oleic, linoleic, alpha-linolenic acids, and antioxidant activity were higher in Rayeb milk supplemented with barley flour and honey than control. The viabilities of Lactobacillus acidophilus and Bifidobacterium lactis Bb12 (Chr. Hansen's Lab A/S) increased in fortified Rayeb milk. The recommended level of 107 cfu g-1 of bifidobacteria as a probiotic was exceeded for these samples. Addition of vanilla (0.1%) or cocoa powder (0.5%) improved the sensory properties of fortified Rayeb milk. PMID- 28836118 TI - Racial Differences in Neighborhood Attainment: The Contributions of Interneighborhood Migration and In Situ Change. AB - Recent research shows that as they age, blacks experience less improvement than whites in the socioeconomic status of their residential neighborhoods. Using data from the Panel Study of Income Dynamics and U.S. decennial censuses, we assess the relative contribution of residential mobility and in situ neighborhood change (i.e., change surrounding nonmobile neighborhood residents) to the black-white difference in changes in neighborhood socioeconomic status and racial composition. Results from decomposition analyses show that the racial difference in in situ neighborhood change explains virtually all the black-white difference in neighborhood socioeconomic status change. In contrast, racial differences in residential mobility explain the bulk of the black-white difference in neighborhood racial compositional change. Among blacks and whites initially residing in low-income and predominantly minority neighborhoods, whites experience a much greater increase than blacks in the socioeconomic status of their neighborhoods and the percentage of their neighbors who are non-Hispanic white. These differences are driven primarily by racial differences in the economic and racial composition of local (intracounty) movers' destination neighborhoods and secondarily by black-white differences in the likelihood of moving long distances. PMID- 28836116 TI - Mechanisms and Effects Posed by Neurotoxic Products of Cyanobacteria/Microbial Eukaryotes/Dinoflagellates in Algae Blooms: a Review. AB - Environmental toxins produced by cyanobacteria and dinoflagellates have increasingly become a public health concern due to their ability to damage several tissues in humans. In particular, emerging evidence has called attention to the neurodegenerative effects of the cyanobacterial toxin beta-N-methylamino-L alanine (BMAA). Furthermore, other toxins such as anatoxin, saxitoxin, microcystin, nodularin and ciguatoxin also have a different range of effects on human tissues, including hepatotoxicity, neurotoxicity and gastrointestinal irritation. However, the vast majority of known environmental toxins have not yet been examined in the context of neurodegenerative disease. This review aims to investigate whether neurotoxic mechanisms can be demonstrated in all aforementioned toxins, and whether there exists a link to neurodegeneration. Management of toxin exposure and potential neuroprotective compounds is also discussed. Collectively, all aforementioned microbial toxins are likely to exert some form of neuronal damage, with many of their modes of action consistent with neurodegeneration. This is important in advancing our current understanding of the cytotoxic potential of environmental toxins upon human brain function, particularly in the context of age-related neurodegenerative disease. PMID- 28836119 TI - Cross-Cultural Study of Information Processing Biases in Chronic Fatigue Syndrome: Comparison of Dutch and UK Chronic Fatigue Patients. AB - PURPOSE: This study aims to replicate a UK study, with a Dutch sample to explore whether attention and interpretation biases and general attentional control deficits in chronic fatigue syndrome (CFS) are similar across populations and cultures. METHOD: Thirty eight Dutch CFS participants were compared to 52 CFS and 51 healthy participants recruited from the UK. Participants completed self-report measures of symptoms, functioning, and mood, as well as three experimental tasks (i) visual-probe task measuring attentional bias to illness (somatic symptoms and disability) versus neutral words, (ii) interpretive bias task measuring positive versus somatic interpretations of ambiguous information, and (iii) the Attention Network Test measuring general attentional control. RESULTS: Compared to controls, Dutch and UK participants with CFS showed a significant attentional bias for illness-related words and were significantly more likely to interpret ambiguous information in a somatic way. These effects were not moderated by attentional control. There were no significant differences between the Dutch and UK CFS groups on attentional bias, interpretation bias, or attentional control scores. CONCLUSION: This study replicated the main findings of the UK study, with a Dutch CFS population, indicating that across these two cultures, people with CFS demonstrate biases in how somatic information is attended to and interpreted. These illness-specific biases appear to be unrelated to general attentional control deficits. PMID- 28836120 TI - Return to Work in Employees on Sick Leave due to Neck or Shoulder Pain: A Randomized Clinical Trial Comparing Multidisciplinary and Brief Intervention with One-Year Register-Based Follow-Up. AB - Purpose The aim of this study was to evaluate the effect of a multidisciplinary intervention (MDI) compared to a brief intervention (BI) with respect to return to work (RTW), pain and disability in workers on sick leave because of neck or shoulder pain. Methods 168 study participants with sickness absence for 4-16 weeks due to neck or shoulder pain were enrolled in a hospital-based clinical study and randomized to either MDI or BI. The primary outcome was RTW obtained by a national registry on public transfer payments. Secondary outcomes were self reported pain and disability levels. One-year follow-up RTW rates were estimated by Cox proportional hazard regression adjusted for gender, age, sick leave prior to inclusion, part-time sick leave and clinical diagnosis. Secondary outcomes were analysed using logistic and linear regression analysis for pain and disability, respectively. Results In the MDI group, 50 participants (59%) experienced four or more continuous weeks of RTW while 48 (58%) returned to work in the BI group during the 1 year of follow-up. Results showed a statistically non significant tendency towards a lower rate of RTW in the MDI group than in the BI group (adjusted HR = 0.84, 95% CI 0.54, 1.31). There were no statistically significant differences in secondary outcomes between the MDI and BI groups. Conclusion The brief and the multidisciplinary interventions performed equally with respect to both primary and secondary outcomes. The added focus on RTW in the multidisciplinary group did not improve RTW rates in this group. PMID- 28836121 TI - Nerve Decompression Improves Spinal Synaptic Plasticity of Opioid Receptors for Pain Relief. AB - Nerve decompression is an essential therapeutic strategy for pain relief clinically; however, its potential mechanism remains poorly understood. Opioid analgesics acting on opioid receptors (OR) within the various regions of the nervous system have been used widely for pain management. We therefore hypothesized that nerve decompression in a neuropathic pain model of chronic constriction injury (CCI) improves the synaptic OR plasticity in the dorsal horn, which is in response to alleviate pain hypersensitivity. After CCI, the Sprague Dawley rats were assigned into Decompression group, in which the ligatures around the sciatic nerve were removed at post-operative week 4 (POW 4), and a CCI group, in which the ligatures remained. Pain hypersensitivity, including thermal hyperalgesia and mechanical allodynia, was entirely normalized in Decompression group within the following 4 weeks. Substantial reversal of mu- and delta-OR immunoreactive (IR) expressions in Decompression group was detected in primary afferent terminals in the dorsal horn. In Decompression group, mu-OR antagonist (CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 [Disulfide Bridge: 2-7]) and delta OR antagonist (NTI, 17-(cyclopropylmethyl)-6,7-dehydro-4,5alpha-epoxy-3,14 dihydroxy-6,7-2',3'-indolomorphinan hydrochloride) re-induced pain hypersensitivity by intrathecal administration in a dose-responsive manner. Additionally, mu-OR agonist (DAMGO, [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin) and delta-OR agonist (SNC80, ((+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1 piperazinyl)-3-methoxybenzyl]-N,N-diethyl-benzamide) were administrated intrathecally to attenuating CCI-induced chronic and acute pain hypersensitivity dose-dependently. Our current results strongly suggested that nerve decompression provides the opportunity for improving the synaptic OR plasticity in the dorsal horn and pharmacological blockade presents a novel insight into the therapeutic strategy for pain hypersensitivity. PMID- 28836122 TI - Improved Miniaturized Linear Ion Trap Mass Spectrometer Using Lithographically Patterned Plates and Tapered Ejection Slit. AB - We present a new two-plate linear ion trap mass spectrometer that overcomes both performance-based and miniaturization-related issues with prior designs. Borosilicate glass substrates are patterned with aluminum electrodes on one side and wire-bonded to printed circuit boards. Ions are trapped in the space between two such plates. Tapered ejection slits in each glass plate eliminate issues with charge build-up within the ejection slit and with blocking of ions that are ejected at off-nominal angles. The tapered slit allows miniaturization of the trap features (electrode size, slit width) needed for further reduction of trap size while allowing the use of substrates that are still thick enough to provide ruggedness during handling, assembly, and in-field applications. Plate spacing was optimized during operation using a motorized translation stage. A scan rate of 2300 Th/s with a sample mixture of toluene and deuterated toluene (D8) and xylenes (a mixture of o-, m-, p-) showed narrowest peak widths of 0.33 Th (FWHM). Graphical Abstract ?. PMID- 28836123 TI - Polyesters from Macrolactones Using Commercial Lipase NS 88011 and Novozym 435 as Biocatalysts. AB - The demand for environmentally friendly products allied with the depletion of natural resources has increased the search for sustainable materials in chemical and pharmaceutical industries. Polyesters are among the most widely used biodegradable polymers in biomedical applications. In this work, aliphatic polyesters (from globalide and omega-pentadecalactone) were synthesized using a new commercial biocatalyst, the low-cost immobilized NS 88011 lipase (lipase B from Candida antarctica immobilized on a hydrophobic support). Results were compared with those obtained under the same conditions using a traditional, but more expensive, commercial biocatalyst, Novozym 435 (lipase B from C. antarctica immobilized on Lewatit VP OC). When NS 88011 was used in the polymerization of globalide, longer reaction times (240 min)-when compared to Novozym 435-were required to obtain high yields (80-90 wt%). However, higher molecular weights were achieved. When poly(omega-pentadecalactone) was synthesized, high yields and molecular weights (130,000 g mol-1) were obtained and the enzyme concentration showed strong influence on the polyester properties. This is the first report describing NS 88011 in polymer synthesis. The use of this cheaper enzymatic preparation can provide an alternative for polyester synthesis via enzymatic ring opening polymerization. PMID- 28836124 TI - Checkpoint immunotherapy in head and neck cancers. AB - Checkpoint inhibitors have recently gained FDA approval for the treatment of cisplatin-resistant recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) by outperforming standard of care chemotherapy and inducing durable responses in a subset of patients. These monoclonal antibodies unleash the patient's own immune system to target cancer cells. HNSCC is a good target for these agents as there is ample evidence of active immunosurveillance in the head and neck and a number of immune evasion mechanisms by which HNSCCs form progressive disease including via the PD-1/PD-L1 axis. As HNSCCs typically possess a moderately high mutation burden, they should express numerous mutation derived antigen targets for immune detection. However, with response rates less than 20% in clinical trials, there is a need for biomarkers to screen patients as well as clinical trials evaluating novel combinations to improve outcomes. The aim of this review is to provide historical and mechanistic context for the use of checkpoint inhibitors in head and neck cancer and provide a perspective on the role of novel checkpoints, biomarkers, and combination therapies that are evolving in the near term for patients with HNSCC. PMID- 28836125 TI - Automatic optic disk detection in retinal images using hybrid vessel phase portrait analysis. AB - We propose vessel vector-based phase portrait analysis (VVPPA) and a hybrid between VVPPA and a clustering method proposed earlier for automatic optic disk (OD) detection called the vessel transform (VT). The algorithms are based primarily on the location and direction of retinal blood vessels and work equally well on fine and poor quality images. To localize the OD, the direction vectors derived from the vessel network are constructed, and points of convergence of the resulting vector field are examined by phase portrait analysis. The hybrid method (HM) uses a set of rules acquired from the decision model to alternate the use of VVPPA and VT. To identify the OD contour, the scale space (SS) approach is integrated with VVPPA, HM, and the circular approximation (SSVVPPAC and SSHMC). We test the proposed combination against state-of-the-art OD detection methods. The results show that the proposed algorithms outperform the benchmark methods, especially on poor quality images. Specifically, the HM gets the highest accuracy of 98% for localization of the OD regardless of the image quality. Testing the segmentation routines SSVVPPAC and SSHMC against the conventional methods shows that SSHMC performs better than the existing methods, achieving the highest PPV of 71.81% and the highest sensitivity of 70.67% for poor quality images. Furthermore, the HM can supplement practically any segmentation model as long as it offers multiple OD candidates. In order to prove this claim, we test the efficiency of the HM in detecting retinal abnormalities in a real clinical setting. The images have been obtained by portable lens connected to a smart phone. In detecting the abnormalities related to diabetic retinopathy (DR), the algorithm provided 94.67 and 98.13% for true negatives and true positives, respectively. PMID- 28836126 TI - Effects of Micro-environmental pH of Liposome on Chemical Stability of Loaded Drug. AB - Liposome is a promising carrier system for delivering bioactive molecules. However, the successful delivery of pH-sensitive molecules is still limited by the intrinsic instability of payloads in physiological environment. Herein, we developed a special liposome system that possesses an acidic micro-environment in the internal aqueous chamber to improve the chemical stability of pH-sensitive payloads. Curcumin-loaded liposomes (Cur-LPs) with varied internal pH values (pH 2.5, 5.0, or 7.4) were prepared. These Cur-LPs have similar particle size of 300 nm, comparable physical stabilities and analogous in vitro release profiles. Interestingly, the chemical stability of liposomal curcumin in 50% fetal bovine serum and its anticancer efficacy in vitro are both micro-environmental pH dependent (Cur-LP-2.5 > Cur-LP-5.0 > Cur-LP-7.4). This serum stability still has space to be further enhanced to improve the applicability of Cur-LP. In conclusion, creating an acidic micro-environment in the internal chamber of liposome is feasible and efficient to improve the chemical stability of pH sensitive payloads. PMID- 28836127 TI - Relaxed chromatin induced by histone deacetylase inhibitors improves the oligonucleotide-directed gene editing in plant cells. AB - Improving efficiency of oligonucleotide-directed mutagenesis (ODM) is a prerequisite for wide application of this gene-editing approach in plant science and breeding. Here we have tested histone deacetylase inhibitor treatments for induction of relaxed chromatin and for increasing the efficiency of ODM in cultured maize cells. For phenotypic assay we produced transgenic maize cell lines expressing the non-functional Green Fluorescent Protein (mGFP) gene carrying a TAG stop codon. These transgenic cells were bombarded with corrective oligonucleotide as editing reagent to recover GFP expression. Repair of green fluorescent protein function was monitored by confocal fluorescence microscopy and flow cytometry was used for quantification of correction events. Sequencing PCR fragments of the GFP gene from corrected cells indicated a nucleotide exchange in the stop codon (TAG) from T to G nucleotide that resulted in the restoration of GFP function. We show that pretreatment of maize cells with sodium butyrate (5-10 mM) and nicotinamide (1-5 mM) as known inhibitors of histone deacetylases can cause elevated chromatin sensitivity to DNase I that was visualized in agarose gels and confirmed by the reduced presence of intact PCR template for the inserted exogenous mGFP gene. Maize cells with more relaxed chromatin could serve as an improved recipient for targeted nucleotide exchange as indicated by an average of 2.67- to 3.62-fold increase in GFP-positive cells. Our results stimulate further studies on the role of the condition of the recipient cells in ODM and testing the application of chromatin modifying agents in other, programmable nuclease-based genome-editing techniques in higher plants. PMID- 28836129 TI - Enlighting the Shadow for Advanced Hepatocellular Carcinoma: Immunotherapy with Immune Checkpoint Inhibitors. AB - Hepatocellular carcinoma has still been one of the cancer with increasing incidence and highest mortality rate in the world. Although many new promising developments have been defined in hepatocarcinogenesis, with a short survival the treatment of patients with advanced hepatocellular carcinoma is an emerging issue. On the recent decade, only one anti-angiogenic agent sorafenib improved overall survival with costing a hardly manageable toxicity. Novel immunotherapeutic agents, especially immune checkpoint inhibitors are on the edge of more effective but less toxic treatments for these patients. In this article the activity of immune checkpoint inhibitors, anti-CTLA-4 and anti-PD1 antibodies for the treatment of patients with advanced hepatocellular cancer will be reviewed. PMID- 28836128 TI - Purinergic Antagonism Prevents Mitochondrial Dysfunction and Behavioral Deficits Associated with Dopaminergic Toxicity Induced by 6-OHDA in Rats. AB - Purinoceptors are present in neurons, microglia and oligodendrocytes and regulate dopamine (DA) release, striatal-related function and striatal neuronal and DA cells damage. Therefore, purinoceptors may be involved in the pathology of Parkinson's disease (PD) and purinergic antagonism may show neuroprotective effect. The study investigated the role of the non-selective purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2', 4'-disulfonic acid (PPADS) and a selective purinergic receptor P2X7 receptor antagonist Brilliant Blue G (BBG) against 6-OHDA induced dopaminergic neurotoxicity in rats; while adenosine triphosphate (ATP) was used as a P2X receptor agonist. Behavioral parameters like spontaneous motor activity, narrow beam walk, footprint, bar catalepsy, grip strength and rotarod tests were performed to evaluate motor deficits in PD. Striatal DA contents were estimated as neurochemical measures of PD. Mitochondrial studies and oxidative status were assessed to investigate the mechanism of purinergic system antagonists. Involvement of purinergic receptors in apoptosis was assessed by expressing cytochrome-C, caspase-9 and caspase-3. Both the antagonists not only attenuated 6-OHDA induced motor deficits but also protected against 6-OHDA induced DA depletion in the striatum. Oxidative stress, mitochondrial integrity and dysfunction were attenuated by purinergic antagonists. Further, they attenuated mitochondrial-linked apoptosis as observed by a decrease in expression of cytochrome-C, caspase-9 and caspase-3. Therefore, purinoceptor antagonism shows neuroprotective effect in 6-OHDA induced dopamine toxicity through preservation of mitochondrial bioenergetics and anti-apoptotic activities. PMID- 28836130 TI - The Role of Brachial Pulse Pressure as an Indicator of Intracranial Atherosclerosis: The Atahualpa Project. AB - INTRODUCTION: Carotid siphon calcifications (CSC) are an important imaging marker of systemic atherosclerosis. Routine assessment of asymptomatic CSC may allow the implementation of intervention strategies before catastrophic cerebrovascular events occur. AIM: To assess whether brachial PP determinations might independently predicts the presence and severity of CSC in community-dwelling adults. METHODS: All Atahualpa residents aged >=40 years were invited for the practice of a non-enhanced CT scan of the head, and those who signed the informed consent and had no contraindications for this exam were enrolled. The brachial PP was calculated by subtracting the mean diastolic pressure from the mean systolic pressure obtained from three different readings with individuals in the sitting position. RESULTS: Of 830 eligible candidates, 663 (80%) were included. The mean brachial PP was 56.4 +/- 19.9 mmHg; 182 persons (27.4%) had PP levels >65 mmHg. CT revealed Grade 1 CSC in 356 (54%), Grade 2 in 141 (21%), Grade 3 in 128 (19%), and Grade 4 in 38 (6%) subjects. Predictive margins of PP (delta method) were significantly lower in individuals with Grade 1 CSC than in the other groups. In the best adjusted linear model, PP levels increased up to 11.7 mmHg as the severity of CSC increased (beta 11.71; 95% C.I. 5.36-18.08: p < 0.001). CONCLUSION: This study provides evidence on the relationship between brachial PP levels and intracranial atherosclerosis. Calculation of the PP may be used for detecting candidates for CT screening, reducing costs during population-based surveys, particularly in remote areas. PMID- 28836131 TI - Redefining the pharmacology and pharmacy subject category in the journal citation reports using medical subject headings (MeSH). AB - Background The Journal Citation Reports (JCR) Pharmacology and Pharmacy subject category is heterogeneous. The inclusion of journals with basic and clinical scopes, which have different citation patterns, compromises comparability of impact factors among journals within the category. Objective To subdivide the Pharmacology and Pharmacy category into basic pharmacology, clinical pharmacology, and pharmacy based on the analyses of Medical Subject Headings (MeSH) as a proxy of journals' scopes. Setting JCR. Method All articles, and respective MeSH, published in 2013, 2014, and 2015 in all journals included in the 2014 JCR Pharmacology and Pharmacy category were retrieved from PubMed. Several models using a combination of the 14 MeSH categories and specific MeSH tree branches were tested using hierarchical cluster analysis. Main outcome measure Distribution of journals across the subcategories of the JCR Pharmacology and Pharmacy subject category. Results A total of 107,847 articles from 214 journals were included. Nine different models combining the MeSH categories M (Persons) and N (Health Care) with specific MeSH tree branches (selected ad-hoc) and Pharmacy-specific MeSH (identified in previous research) consistently grouped 142 journals (66.4%) in homogeneous groups reflecting their basic and clinical pharmacology, and pharmacy scopes. Ultimately, journals were clustered into: 150 in basic pharmacology, 43 in clinical pharmacology, 16 in basic pharmacology and clinical pharmacology, and 5 in pharmacy. Conclusion The reformulation of the Pharmacology and Pharmacy category into three categories was demonstrated by the consistent results obtained from testing nine different clustering models using the MeSH terms assigned to their articles. PMID- 28836132 TI - Lactate Levels with Chronic Metformin Use: A Narrative Review. AB - Metformin has been associated with lactic acidosis. Lactate levels are not commonly tested in clinical practice, and it is unclear to what extent metformin would typically increase lactate levels with chronic use. The aim of this review was to determine whether regular monitoring of the plasma lactate level would be beneficial in avoiding lactate accumulation and, ultimately, minimising the incidence of lactic acidosis in metformin-treated patients.A comprehensive search of PubMed, Embase, Web of Science, Cochrane and International Pharmaceutical Abstracts databases covering the period up to 30 May 2017 was performed. Search terms included combinations of terms and keywords, including "metformin", "lactate", "lactic acid" and "lactic acidosis". Cases series of lactic acidosis or metformin-associated lactic acidosis were excluded.Of 1539 potentially relevant articles, a total of 52 reported lactate levels from routine/regular pathological tests in metformin users. The studies were subdivided into four themes, regarding metformin usage and the reported lactate levels in patients who: (1) did not have contraindications to the use of metformin; (2) had contraindications, or renal impairment but without other contraindications; (3) exercised; or (4) also received any nucleoside reverse transcriptase inhibitor. Studies have reported that metformin treatment could increase lactate level of users. However, most results showed that the lactate level remained in the normal range.No definitive conclusions on the benefits of regular lactate monitoring in patients taking metformin can be made. Future research on larger populations focusing on the measurement of lactate levels with continuous metformin use is warranted. PMID- 28836133 TI - The UMP Exact Test and the Confidence Interval for Person Parameters in IRT Models. AB - In educational and psychological measurement when short test forms are used, the asymptotic normality of the maximum likelihood estimator of the person parameter of item response models does not hold. As a result, hypothesis tests or confidence intervals of the person parameter based on the normal distribution are likely to be problematic. Inferences based on the exact distribution, on the other hand, do not suffer from this limitation. However, the computation involved for the exact distribution approach is often prohibitively expensive. In this paper, we propose a general framework for constructing hypothesis tests and confidence intervals for IRT models within the exponential family based on exact distribution. In addition, an efficient branch and bound algorithm for calculating the exact p value is introduced. The type-I error rate and statistical power of the proposed exact test as well as the coverage rate and the lengths of the associated confidence interval are examined through a simulation. We also demonstrate its practical use by analyzing three real data sets. PMID- 28836135 TI - Mandatory Risk Assessment Reduces Venous Thromboembolism in Bariatric Surgery Patients. AB - INTRODUCTION: Bariatric surgery patients are at high risk for venous thromboembolism (VTE), and chemoprophylaxis is recommended. METHODS: Sheikh Khalifa Medical City (SKMC) is an American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) member since 2009. We report the rates of VTE in bariatric surgery patients from 2010 to 2016 compared to ACS NSQIP bariatric surgery programs before and after switching from heparin to low molecular weight heparin (LMWH), initiating mandatory risk assessment using Caprini scoring for VTE and adopting an aggressive strategy for high-risk patients regarding dosage of LMWH and chemoprophylaxis after discharge. RESULTS: During the study period, there were 1152 cases (laparoscopic Roux-en-Y gastric bypass (LRYGB) 625 and laparoscopic sleeve gastrectomy (LSG) 527) at Bariatric & Metabolic Institute (BMI) Abu Dhabi compared to 65,693 cases (LRYGB 32,130 and LSG 33,563) at ACS NSQIP bariatric surgery programs. VTE rates remained stable at ACS NSQIP bariatric surgery programs from 2010 to 2016 (0.45, 0.45, 0.45, 0.25, 0.35, 0.3, and 0.3%). In contrast, VTE rates at BMI Abu Dhabi decreased from 2.2% in 2011 to 0.35% after we adopted an aggressive strategy to VTE without an increase in bleeding complications. LRYGB patients with VTE had higher OR time, leak, collection, and mortality at ACS NSQIP hospitals compared to those at BMI Abu Dhabi. In contrast, rates were similar in LSG patients with VTE. CONCLUSION: Changing our approach to VTE management led our VTE rates to decrease and become like those of ACS NSQIP bariatric surgery patients in LSG and LRYGB. PMID- 28836136 TI - Highly Conductive PEDOT:PSS Transparent Hole Transporting Layer with Solvent Treatment for High Performance Silicon/Organic Hybrid Solar Cells. AB - Efficient Si/organic hybrid solar cells were fabricated with dimethyl sulfoxide (DMSO) and surfactant-doped poly(3,4-ethylenedioxythiophene): polystyrene (PEDOT:PSS). A post-treatment on PEDOT:PSS films with polar solvent was performed to increase the device performance. We found that the performance of hybrid solar cells increase with the polarity of solvent. A high conductivity of 1105 S cm- 1 of PEDOT:PSS was achieved by adopting methanol treatment, and the best efficiency of corresponding hybrid solar cells reaches 12.22%. X-ray photoelectron spectroscopy (XPS) and RAMAN spectroscopy were utilized to conform to component changes of PEDOT:PSS films after solvent treatment. It was found that the removal of the insulator PSS from the film and the conformational changes are the determinants for the device performance enhancement. Electrochemical impedance spectroscopy (EIS) was used to investigate the recombination resistance and capacitance of methanol-treated and untreated hybrid solar cells, indicating that methanol-treated devices had a larger recombination resistance and capacitance. Our findings bring a simple and efficient way for improving the performance of hybrid solar cell. PMID- 28836134 TI - Brain explorer for connectomic analysis. AB - Visualization plays a vital role in the analysis of multimodal neuroimaging data. A major challenge in neuroimaging visualization is how to integrate structural, functional, and connectivity data to form a comprehensive visual context for data exploration, quality control, and hypothesis discovery. We develop a new integrated visualization solution for brain imaging data by combining scientific and information visualization techniques within the context of the same anatomical structure. In this paper, new surface texture techniques are developed to map non-spatial attributes onto both 3D brain surfaces and a planar volume map which is generated by the proposed volume rendering technique, spherical volume rendering. Two types of non-spatial information are represented: (1) time series data from resting-state functional MRI measuring brain activation; (2) network properties derived from structural connectivity data for different groups of subjects, which may help guide the detection of differentiation features. Through visual exploration, this integrated solution can help identify brain regions with highly correlated functional activations as well as their activation patterns. Visual detection of differentiation features can also potentially discover image based phenotypic biomarkers for brain diseases. PMID- 28836137 TI - Reducing measurement errors during functional capacity tests in elders. AB - BACKGROUND: Accuracy is essential to the validity of functional capacity measurements. AIM: To evaluate the error of measurement of functional capacity tests for elders and suggest the use of the technical error of measurement and credibility coefficient. METHODS: Twenty elders (65.8 +/- 4.5 years) completed six functional capacity tests that were simultaneously filmed and timed by four evaluators by means of a chronometer. A fifth evaluator timed the tests by analyzing the videos (reference data). RESULTS: The means of most evaluators for most tests were different from the reference (p < 0.05), except for two evaluators for two different tests. There were different technical error of measurement between tests and evaluators. The Bland-Altman test showed difference in the concordance of the results between methods. Short duration tests showed higher technical error of measurement than longer tests. In summary, tests timed by a chronometer underestimate the real results of the functional capacity. DISCUSSION: Difference between evaluators' reaction time and perception to determine the start and the end of the tests would justify the errors of measurement. CONCLUSION: Calculation of the technical error of measurement or the use of the camera can increase data validity. PMID- 28836138 TI - The Effect of Contact Non-equilibrium Plasma on Structural and Magnetic Properties of Mn X Fe3 - X O4 Spinels. AB - Nano-sized manganese ferrites Mn x Fe3 - x O4 (x = 0-1.3) were prepared using contact non-equilibrium plasma (CNP) in two different pH (11.5 and 12.5). The influence of synthesis conditions (e.g., cation ratio and initial pH) on phase composition, crystallite size, and magnetic properties were investigated employing X-ray diffraction (XRD), differential thermal analysis (DTA), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and magnetic measurement techniques. The formation of monodispersed faceted ferrite particles at x = 0-0.8 was shown. The FTIR spectra revealed reflection in region 1200-1700 cm-1 caused by the presence of water adsorbed on the surface of Fe3 - x Mn x O4 micro-granules or embedded into their crystal lattice. The most sensitivity of reflection spectra to the composition changes takes place within a 400-1200 cm-1 range, typical to the stretching vibrations of Fe(Mn)-O (up to 700 cm-1 ), Fe(Mn)-OH, and Fe(Mn)-OH2 bonds (over 700 cm-1). The XRD results showed that the nanocrystalline Mn x Fe3 - x O4 (0 < x < 1.0) had cubic spinel crystal structure with average crystallite size 48-49 A. The decrease of crystalline size with the x increase was also observed. PMID- 28836139 TI - Post-mortem CT imaging of the lungs: pathological versus non-pathological findings. AB - Nowadays, the modern computed tomography techniques are more and more applied in forensic investigations. The detection of abnormalities in post-mortem computed tomography (PMCT) imaging of the lungs is very common. As in clinical imaging, also in post-mortem imaging the right interpretation of alterations has an extreme importance for the assessment of correct conclusions. This is even crucial when the radiologist who approaches the PMCT images is not routinely involved in forensic cases. The aim of this article is to provide radiologists who approach PMCT imaging cases with some indications for a proper and correct interpretation of pulmonary findings, to avoid misleading forensic conclusions. Particularly, the following issues will be addressed: PMCT imaging of post-mortem changes of the lungs; PMCT imaging of pathological lungs [(a) in thoracic trauma cases, (b) in cases without thoracic trauma]. Finally, the possible pitfalls in interpretation of PMCT imaging of the lungs will be also discussed. PMID- 28836140 TI - Association between hospital volume and receipt of treatment and survival in patients with glioblastoma. AB - The relation between hospital volume and outcomes for patients with glioblastoma is unknown. We undertook this study to determine the effect of hospital volume on treatment received and its effect on survival in patients with glioblastoma. We included patients from the National Cancer Database diagnosed with a glioblastoma from 2006 to 2013. Hospital volume was calculated by examining the treating facilities average number of cases per year and grouping them into tertiles: (low < 9.25, medium 9.26-23.88, and high >= 23.39). Treatment was defined as receiving any type of therapeutic surgery, radiation or chemotherapy. Using regression models we examined the relation between hospital volume to treatment received and survival with adjustment for clinical, socioeconomic and institutional factors. The study included 68,726 patients of which 91.8% received treatment. Among patients diagnosed at low volume facilities, 90.1% received treatment versus 94.2% in high volume facilities (p < 0.0001). Compared to low volume centers, the odds ratio of receiving any treatment was 1.01 (CI 95% CI: 0.95-1.09) and 1.43 (95% CI: 1.31-1.55) for medium volume and high volume facilities, respectively. On multivariate analysis for survival among those who received treatment, the hazard of mortality was decreased at high volume (HR 0.92, 95% CI 0.89-0.94) facilities compared to low volume facilities. Patients diagnosed with glioblastoma at a high volume facility (>=23.39 cases per year) have an increased likelihood of receiving treatment. Furthermore, glioblastoma patients may significantly improve their survival by choosing to receive care at a high-volume hospital. PMID- 28836141 TI - Exposure of children aged 0-7 years to perfluorinated compounds in Foshan, China. AB - To evaluate the exposure of children to 14 perfluorinated compounds (PFCs) in a typical and representative industrial city, plasma samples from 476 children aged 0-7 years in Foshan, China, were analysed. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in 100% of the samples, accounting for 82.27 and 11.46% of the total PFC concentrations, respectively, while PFOS peaked at age 0-1 years, for which the mean and median concentrations were 113.71 and 83.65 ng/mL, respectively, while PFOA peaked at age 3-4 years, for which the mean and median concentrations were 10.68 and 6.58 ng/mL, respectively. The concentrations of PFOS, perfluorohexane sulfonate and perfluorohexanoic acid decreased with age among children aged 0-7 years, and no gender-related differences were found in the concentrations of PFCs. A high correlation was found among all PFCs, especially between PFCs of similar carbon chains (r = 0.161 0.695, p < 0.05). In addition, the concentrations of PFOS and PFOA in children's plasma in Foshan were up to 40-fold higher than those reported in China and other countries. In conclusion, children in Foshan have extensive exposure to PFCs, especially in infancy. Further studies are needed to explore the impact of PFCs on children who live in a typical and representative industrial city in China. Graphical abstract ?. PMID- 28836143 TI - Lateral lymph node metastasis in a patient with T1 upper rectal cancer treated by lateral lymph node dissection: a case report and brief literature review. AB - BACKGROUND: Lateral lymph node (LLN) metastasis may occur in patients with advanced rectal cancers of which the lower margins are located at or below the peritoneal reflection. However, LLN metastasis from a T1 rectal cancer is rare. Here, we report a case of LLN metastasis from a T1 upper rectal cancer that was successfully treated by sequential LLN dissection. CASE PRESENTATION: A 56-year old man was referred to our hospital for the treatment of a T1 upper rectal cancer. We performed a laparoscopic low anterior resection. Histological examination showed a moderately differentiated adenocarcinoma with submucosal layer invasion; the invasion depth was classified as head invasion, without vessel or lymph duct invasion. Tumor budding was classified as grade 1. A total of six lymph nodes were harvested, and no lymph node metastases were detected. The postoperative course was uneventful. At 6 months after surgery, however, the serum carcinoembryonic antigen levels were elevated, and abdominal computed tomography (CT) revealed swollen lymph nodes in the right internal and common iliac artery area. Positron emission tomography with CT revealed hot spots in the same lesions. A retrospective re-evaluation of the preoperative CT images revealed no apparent swollen lymph nodes; however, an unusual soft tissue area was detected around the right internal iliac artery. A right LLN dissection was performed. Fifteen lymph nodes were resected, and histologically, metastases of adenocarcinoma were identified in 3 nodes. The postoperative course was again uneventful. The patient was given 12 cycles of adjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin). The patient remains healthy and with no signs of recurrence at 30 months after the second surgery. CONCLUSIONS: LLN metastasis occurs very rarely in patients with T1 upper rectal cancer and no risk factors for lymph node metastasis; however, a careful perioperative examination of the LLN should be performed. In cases involving LLN metastasis, a LLN dissection may be a therapeutic option if performed with curative intent. PMID- 28836142 TI - Cystic lesions of the parotid gland: radiologic-pathologic correlation according to the latest World Health Organization 2017 Classification of Head and Neck Tumours. AB - The latest World Health Organization 2017 Classification of Head and Neck Tumours includes a new chapter on tumors and tumor-like lesions of the neck and lymph nodes. Tumor-like lesions include a variety of cystic lesions of the parotid gland. Cystic lesions of the parotid gland can be divided into three groups: non neoplastic cysts, benign tumors with macrocystic change, and malignant tumors with macrocystic change. It is important to distinguish these lesions from one another because treatment and patient management differ among the three groups. The purpose of this review is to describe the magnetic resonance imaging and scintigraphy findings and the histopathologic characteristics of each parotid gland lesion based on the latest World Health Organization 2017 Classification of Head and Neck Tumours and to summarize the key points of differential diagnosis for cystic lesions of the parotid gland. PMID- 28836144 TI - Laying the Foundations of Lifelong Health at the Beginning of Life: Islamic Perspective. AB - In this systematic literature review, all the Shiite-Islamic documents (Quran and Hadith) without any time limitation were surveyed, analyzed and synthesized for the purpose of determining the foundations of lifelong health. The data were analyzed and combined using inductive qualitative content analysis method. Two main categories were emerged from the analysis: "prevention of health problems" and "health maintenance and promotion." In conclusion based on Islamic perspective, the foundations of comprehensive health of a person, i.e., health in all physical, mental, social, and spiritual dimensions, are begun to form at four stages: the time of marriage of his parents, the moment of their conception, when he is unborn in his mother womb, and during infancy period. Observing religion instructions in this regard is not the sufficient condition for being completely healthy; however, such instructions can provide a base for being a healthy person. PMID- 28836145 TI - Interactions between visual working memory representations. AB - We investigated whether the representations of different objects are maintained independently in working memory or interact with each other. Observers were shown two sequentially presented orientations and required to reproduce each orientation after a delay. The sequential presentation minimized perceptual interactions so that we could isolate interactions between memory representations per se. We found that similar orientations were repelled from each other whereas dissimilar orientations were attracted to each other. In addition, when one of the items was given greater attentional priority by means of a cue, the representation of the high-priority item was not influenced very much by the orientation of the low-priority item, but the representation of the low-priority item was strongly influenced by the orientation of the high-priority item. This indicates that attention modulates the interactions between working memory representations. In addition, errors in the reported orientations of the two objects were positively correlated under some conditions, suggesting that representations of distinct objects may become grouped together in memory. Together, these results demonstrate that working-memory representations are not independent but instead interact with each other in a manner that depends on attentional priority. PMID- 28836147 TI - Reduced emotional empathy in adults with subclinical ADHD: evidence from the empathy and systemizing quotient. AB - Studies in children with ADHD suggest impairments in social cognitive functions, whereas studies in adults with ADHD are scarce and inconclusive. The aim of this study was to investigate the relationship between ADHD traits and self-reported social cognitive style in a sample of adults from the general population. For this purpose, a community sample of 685 adults filled out online self-report questionnaires about ADHD symptoms (ADHD Rating Scale, ARS), social cognitive functioning and friendships. The Empathy Quotient (EQ) with the subscales Cognitive Empathy (CE), Emotional Empathy (EE) and Social Skills (SS), and the Systemizing Quotient (SQ) were included for measuring social cognitive style and the Friendship Questionnaire (FQ) for the quality of friendships. Participants who met the DSM-5 criteria on the ARS ('subclinical ADHD'; n = 56) were compared regarding their social cognitive functioning scores with a control group (n = 56) that was matched for age, sex and student status. With small effect sizes, the subclinical ADHD group showed reduced EE scores on the EQ and a more male social cognitive profile. This result was not influenced by sex or ADHD subtype. This study points to a relationship between traits of ADHD and the emotional aspect of empathy, whereas more complex aspects of empathy were unrelated. These findings should be corroborated in clinical patients with ADHD, employing neuropsychological tests rather than self-report questionnaires. PMID- 28836148 TI - Anti-diabetic actions of esculentin-2CHa(1-30) and its stable analogues in a diet induced model of obesity-diabetes. AB - Actions of esculentin-2CHa(1-30) (GFSSIFRGVAKFASKGLGKDLAKLGVDLVA) and its analogues, ([D-Arg7, D-Lys15, D-Lys23]-esculentin-2CHa(1-30) and [Lys15 octanoate]-esculentin-2CHa(1-30), were evaluated in high-fat fed NIH Swiss mice with impaired glucose tolerance and insulin resistance. Twice-daily i.p. administration of the esculentin-2CHa(1-30) peptides (75 nmol/kg body weight) or exendin-4 (25 nmol/kg) for 28 days reduced body weight, without altering cumulative energy intake. All peptides reduced blood glucose levels by 6-12 mmol/l concomitant with lower plasma insulin levels, with significance evident from day 6. All peptides improved glucose tolerance, insulin sensitivity, blood glucose profile over 24 h and decreased HbA1c to a similar extent as exendin-4. The peptides also reduced high fat diet-induced increases in plasma GLP-1 and glucagon. None of the peptides altered bone mineral density/content or lean mass but decreased fat mass. Islets isolated from peptide-treated mice exhibited improved glucose-, alanine- and GLP-1-stimulated insulin secretion. Islet morphometric analyses revealed that exendin-4 and the esculentin-2CHa(1-30) peptides significantly reduced islet, beta and alpha cell areas compared to high fat controls. Esculentin-2CHa(1-30) peptides markedly reduced high fat diet induced increase in beta cell proliferation and apoptosis. Peptide treatments had beneficial effects on expression of islet genes (Ins1, Slc2a2, Pdx1) and skeletal muscle genes involved in insulin action (Slc2a4, Pdk1, Irs1, Akt1). High-fat diet significantly increased LDL cholesterol which was reduced by the acylated esculentin-2CHa(1-30) analogue. Peptide treatments did not alter circulating concentrations of amylase and marker enzymes of liver function, indicating a lack of toxicity. These data indicate that esculentin-2CHa(1-30) and its analogues may be useful for improvement of blood glucose control and weight loss in type 2 diabetes. PMID- 28836149 TI - Nutrient Restriction Increases Circulating and Hepatic Ceramide in Dairy Cows Displaying Impaired Insulin Tolerance. AB - The progression of insulin resistance in dairy cows represents a maternal adaptation to support milk production during heightened energy demand; however, excessive adipose tissue lipolysis can develop. In diabetic non-ruminants, the mechanisms that mediate insulin resistance involve the sphingolipid ceramide. We tested the hypothesis that ceramide accumulates in dairy cows experiencing lipolysis and insulin resistance. Nine dairy cows were utilized in a replicated 3 * 3 Latin square design. Cows were ad libitum fed, nutrient-restricted (NR), or NR with nicotinic acid (NA; 5 mg of NA/h per kg BW; delivered i.v.) for 34 h. When provided access, cows were ad libitum fed a mixed ration of grass hay and ground corn to meet requirements. Intake for NR cows was limited to vitamins and minerals. Nicotinic acid was administered to suppress lipolysis. Saline was infused in cows not provided NA. At 32 and 33 h of treatment, a liver biopsy and insulin tolerance test were performed, respectively. Samples were analyzed using colorimetry, immunoassay, and mass spectrometry. Nutrient restriction increased serum fatty acids and ceramide levels, and impaired insulin sensitivity; however, NA infusion was unable to prevent these responses. We also show that NR increases hepatic ceramide accumulation, a response that was positively associated with serum ceramide supply. Our data demonstrate that circulating and hepatic 24:0-Cer are inversely associated with systemic insulin tolerance, an effect not observed for the 16:0 moiety. In conclusion, our results suggest that ceramide accrual represents a metabolic adaptation to nutrient restriction and impaired insulin action in dairy cows. PMID- 28836150 TI - Anticoagulation for the treatment of venous thromboembolism in patients with brain metastases: a meta-analysis and systematic review. AB - The risk benefit decision in providing anticoagulation for patients with brain metastases is amongst the most difficult decisions faced by clinicians. The purpose of our study was to evaluate both the risk of intracerebral hemorrhage (ICH) associated with anticoagulation therapy and the effect of anticoagulation on survival in patients with brain metastases and venous thromboembolism (VTE). A systematic review of the literature was performed via the PubMed, EMBASE, and the Cochrane databases. Our initial search resulted in 1304 unique citations, and 5 studies satisfied all eligibility criteria and were included for analysis. The odds ratio for development of ICH in the setting of anticoagulation was 1.37 (CI 0.86-2.17, p = 0.18). The hazard ratio for survival was 0.96 (CI 0.51-1.81, p = 0.90). While limited, the best available evidence suggests that there is no increased risk of ICH and no survival benefit associated with providing anticoagulation to patients with brain metastases who develop VTE. These patients merit individualized discussion of the risk and benefit of anticoagulation therapy. Current guidelines should be updated to include more recent studies and highlight the uncertainty of the net clinical benefit associated with anticoagulation. PMID- 28836151 TI - It's Time to Start Changing the Game: A 12-Week Workplace Team Sport Intervention Study. AB - BACKGROUND: A 12-week multi-team sport programme was provided to employees of a large services organisation and conducted in workplaces. This programme was used to investigate the short-term effect of regular sports team participation on individual employee and organisational health. METHODS: A large services organisation participated in this study. Two regional worksites of office workers were assigned as the team sport (intervention) (n = 28 participants) or control (n = 20 participants) groups. The team sport sessions were underpinned by psychological behaviour change theory and consisted of weekly 1-h team sport sessions for 12 weeks. Measures of aerobic fitness, physical activity behaviour, group cohesion, interaction and communication, psychological wellbeing, health, anthropometrics and workplace experiences were recorded pre- and post intervention. Data were analysed using a series of mixed ANOVAs. RESULTS: After 12 weeks significant improvements were observed in VO2 max (+ 4.5 +/- 5.8 ml/min kg, P < .002, eta 2p = .182), interpersonal communication within teams (+ 3%, P < .042, eta 2p = .087) and mean weekly physical activity duration (+ 154.74', P < .002, eta 2p = .071) in the intervention group. A significant (P < .012, eta 2p = .130) effect on body composition was observed in the intervention group. CONCLUSIONS: Participation in team sport may be an effective method to improve the aerobic fitness and physical activity behaviour of employees, and promote interpersonal communication between colleagues. Individual health outcomes and social interactions have the capacity to influence the health of the organisation. The extent of which these findings are replicable across a scope of organisations should be examined objectively over the long term. PMID- 28836152 TI - Effect of Dietary Supplementation of Novel Probiotic Bacteria Bacillus vireti 01 on Antioxidant Defence System of Freshwater Prawn Challenged with Pseudomonas aeruginosa. AB - The aim of the present work was to isolate probiotic bacteria from the intestinal tract of healthy freshwater prawn Macrobrachium rosenbergii and to examine the effect of the isolated probiotic Bacillus vireti 01 in controlling Pseudomonas aeruginosa infection. This is probably the first report on the isolation of probiotic B. vireti 01 from the intestine of M. rosenbergii. The compounds present in B. vireti 01 were identified using GC-MS analysis. The effect of B. vireti 01-incorporated diet on survival and antioxidant enzymes was studied in M. rosenbergii for 2 weeks. Decreased mortality was observed in M. rosenbergii which were administered with the probiotic diet compared to control diet. The antioxidant defence enzymes activities such as SOD, catalase and GSH were analysed in various organs of M. rosenbergii probiotic-treated and control groups. Antioxidant enzyme activities were considerably lowered (p < 0.01) in the muscles, hepatopancreas and gills of prawns infected by P. aeruginosa when compared to that of prawns fed with the probiotic-supplemented diet. The histopathological results suggest that the hepatopancreas, gills and muscles infected with P. aeruginosa were altered structurally. The result of the present work demonstrates that the probiotic B. vireti 01 could be used as a substitute to antibiotics for treating P. aeruginosa infection in prawns. PMID- 28836153 TI - Agreement between venous and arterial blood gas analysis of acid-base status in critical care and ward patients: a retrospective cohort study. AB - PURPOSE: To determine whether the use of venous blood gases can be a suitable alternative to arterial sampling to evaluate acid-base status. METHODS: The database of the clinical laboratory in a large academic hospital was searched for records of venous blood gas analysis and an arterial sample taken within ten minutes from the same patient. Bland-Altman analyses of pH, pCO2, and lactate were performed for samples obtained from patients separately from within and outside the intensive care unit (ICU). RESULTS: In 2,296 paired arterial-venous samples from 351 ICU patients, the bias was 0.044, -6.2 mmHg, and -0.07 mEq.L-1 for pH, pCO2, and lactate, respectively. The range of agreement centred on this bias (upper minus lower level of agreement) was 0.134, 16.7 mmHg, and 1.35 mEq.L 1 for pH, pCO2, and lactate, respectively. Intraclass correlation coefficients (ICCs) were 0.79, 0.76, and 0.99 for pH, pCO2, and lactate, respectively, indicating excellent agreement. Multiple samples obtained from the same patient had a median standard deviation of 0.02, 2.77 mmHg, and 0.18 mEq.L-1 for pH, pCO2, and lactate, respectively. Similar agreement was observed in samples from patients outside the ICU, although the ICC was only 0.53 for pCO2. CONCLUSIONS: Venous gases are suitable for initial evaluation of acid-base status in critically ill patients. Based on clinical evaluation, an arterial sample may then be considered for confirmation, and thereafter, venous blood gases could be sufficient for monitoring response to treatment. PMID- 28836154 TI - Randomized controlled trial of moderate hypothermia versus deep hypothermia anesthesia on brain injury during Stanford A aortic dissection surgery. AB - This study aimed to compare the effects of moderate versus deep hypothermia anesthesia for Stanford A aortic dissection surgery on brain injury. A total of 82 patients who would undergo Stanford A aortic dissection surgery were randomized into two groups: moderate hypothermia group (MH, n = 40, nasopharyngeal temperature 25 degrees C, and rectal temperature 28 degrees C) and deep hypothermia group (DH, n = 42, nasopharyngeal temperature 20 degrees C, and rectal temperature 25 degrees C). Different vascular replacement techniques including aortic root replacement, Bentall, and Wheat were used. The intraoperative and postoperative indicators of these patients were recorded. There were no differences in intraoperative and postoperative measures between MH and DH groups. The concentrations of neuron-specific enolase and S-100beta increased with operation time, and were significantly lower in MH group than those in the DH group (P < 0.05). The occurrence rates of complications including chenosis, postoperative agitation, and neurological complications in MH group were significantly lower than in DH group. The recovery time, postoperative tube, and ICU intubation stay were significantly shorter in MH group than those in DH group (P < 0.05). There were no significant differences revealed in hospital stay and death rate. MH exhibited better cerebral protective effects, less complications, and shorter tube time than DH in surgery for Stanford A aortic dissection. PMID- 28836155 TI - Statistical Evaluation of Trace Metals, TSH and T4 in Blood Serum of Thyroid Disease Patients in Comparison with Controls. AB - The present study is based on the measurement of concentrations of selected trace metals (Fe, Zn, Cu, Co, Mn, Ni, Cr, Cd and Pb) and thyroid hormones (TSH and T4) in blood serum of hypothyroid and hyperthyroid patients in comparison with healthy donors/controls in order to establish the imbalances of the trace metals in diseased subjects. The serum samples were digested in HNO3-HClO4 mixture and quantification of the metals was performed by flame atomic absorption spectrometry. Average levels of Fe, Ni, Cu, Cr, Pb and TSH were found to be significantly higher (p < 0.05) in the serum of hypothyroid patients compared with other donor categories, while mean concentrations of Mn, Cd and T4 were significantly elevated in the serum of hyperthyroid patients compared with other donor groups (p < 0.05). The correlation pattern of trace metals in the serum of patient groups revealed significantly different mutual associations compared with the controls. PCA and CA pointed out the interferences of the toxic metals with essential metals in the serum of both patient groups compared with the controls. Most of the metals exhibited noticeable disparities in their concentrations based on gender, food habits and tobacco use for all donor groups. Thus, the pathogenesis of thyroid diseases is significantly affecting the essential trace and toxic metals balance in both patients groups. PMID- 28836156 TI - Guidelines in review: ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease. PMID- 28836157 TI - Relevance of Haemodynamics in Treating Pre-eclampsia. AB - Blood pressure is a way of describing the end result of changes in cardiac output, intravascular volume and peripheral resistance. It has certain advantages in that it is a reproducible and easily measured parameter, but in itself, it offers only a limited understanding of the underlying haemodynamics. In pregnancy, profound haemodynamic changes occur and in hypertensive diseases of pregnancy defining a condition by blood pressure alone risks missing the underlying cause. Partly, this has been a problem of ascribing the cause of hypertensive syndromes to the placenta which has inhibited rigorous research into other possible causes of haemodynamic dysfunction. It is becoming increasingly evident that hypertension in pregnancy may be associated with primarily high cardiac output or high peripheral resistance. A knowledge of the underlying type of hypertension may allow more rational treatment of these conditions in pregnancy rather than therapeutic attempts at controlling blood pressure by any means possible as an end in itself. PMID- 28836158 TI - Associations of Proton-Pump Inhibitors and H2 Receptor Antagonists with Chronic Kidney Disease: A Meta-Analysis. AB - BACKGROUND/AIMS: The aim of this meta-analysis was to assess the risks of chronic kidney disease (CKD) and/or end-stage kidney disease (ESRD) in patients who are taking proton-pump inhibitors (PPIs) and/or H2 receptor antagonists (H2RAs). METHODS: Comprehensive literature review was conducted utilizing MEDLINE and EMBASE databases through April 2017 to identify all studies that investigated the risks of CKD or ESRD in patients taking PPIs/H2RAs versus those without PPIs/H2RAs. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. The protocol for this study is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017067252). RESULTS: Five studies with 536,902 participants were patients were identified and included in the data analysis. When compared with non-PPIs users, the pooled risk ratio (RR) of CKD or ESRD in patients with PPI use was 1.33 (95% CI 1.18-1.51). Pre specified subgroup analysis (stratified by CKD or ESRD status) demonstrated pooled RRs of 1.22 (95% CI 1.14-1.30) for association between PPI use and CKD and 1.88 (95% CI 1.71-2.06) for association between PPI use and ESRD, respectively. However, there was no association between the use of H2RAs and CKD with a pooled RR of 1.02 (95% CI 0.83-1.25). When compared with the use of H2RAs, the pooled RR of CKD in patients with PPI use was 1.29 (95% CI 1.22-1.36). CONCLUSIONS: Our study demonstrates statistically significant 1.3-fold increased risks of CKD and ESRD in patients using PPIs, but not in patients using H2RAs. PMID- 28836159 TI - Motivating Older Adults with Cancer to Keep Moving: the Implications of Lifestyle Interventions on Physical Activity. AB - PURPOSE OF REVIEW: The purposes of this review are to describe the unique needs and preferences of older adults with cancer regarding physical activity and to outline the essential characteristics associated with increased physical activity resulting from lifestyle interventions in older adults. RECENT FINDINGS: Functional decline is accelerated in inactive and sedentary older adults. Even a modest increase in physical activity can improve physical function for older cancer survivors. Participation in physical activity is influenced by diverse individual-level factors, behavioral characteristics and skills and social and environmental factors. Thus, programs that are tailored to older adults' preferences provide social support and remove obstacles to participation may be more effective, particularly for older adults with low physical activity and sedentary lifestyle. PMID- 28836160 TI - Perioperative Medication Management in the Rheumatic Diseases. PMID- 28836162 TI - Prevalence of morphometric vertebral fractures in "difficult" patients with acromegaly with different biochemical outcomes after multimodal treatment. AB - INTRODUCTION: Skeletal fragility with high risk of vertebral fractures is an emerging complication of acromegaly in close relationship with duration of active disease. The aim of this cross-sectional study was to evaluate the prevalence and determinants of vertebral fractures in males and females with a history of long standing active acromegaly undergoing treatment with Pegvisomant. SUBJECTS AND METHODS: Thirty-eight patients (25 females, 13 males) with acromegaly under Pegvisomant therapy were evaluated for vertebral fractures and bone mineral density at lumbar spine and femoral neck. Gonadal status, serum IGF1 levels and growth hormone receptor genotype were also assessed. RESULTS: Vertebral fractures were detected in 12 patients (31.6%). Fractured patients had longer duration of active disease (p = 0.01) with higher frequency of active acromegaly (p = 0.04), received higher dose of Pegvisomant (p = 0.008), and were more frequently hypogonadic (p = 0.02) as compared to patients who did not fracture. Stratifying the patients for gender, vertebral fractures were significantly associated with Pegvisomant dose (p = 0.02) and untreated hypogonadism (p = 0.02) in males and with activity of disease (p = 0.03), serum insulin-like growth factor-I values (p = 0.01) and d3GHR polymorphism (p = 0.005) in females. No significant association was found between vertebral fractures and bone mineral density at either skeletal site. CONCLUSION: Vertebral fractures are a frequent complication of long standing active acromegaly. When patients are treated with Pegvisomant, vertebral fractures may occur in close relationship with active acromegaly and coexistent untreated hypogonadism. PMID- 28836161 TI - Control of neuronal excitability by Group I metabotropic glutamate receptors. AB - Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu1 and mGlu5. Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein dependent pathway involves mainly Galphaq, which can activate PLCbeta, leading initially to the formation of IP3 and diacylglycerol. IP3 can release Ca2+ from cellular stores resulting in activation of Ca2+-dependent ion channels. Intracellular Ca2+, together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors. PMID- 28836163 TI - Blood Glutamate Reducing Effect of Hemofiltration in Critically Ill Patients. AB - Glutamate toxicity plays a well-established role in secondary brain damage following acute and chronic brain insults. Previous studies have demonstrated the efficacy of hemodialysis and peritoneal dialysis in reducing blood glutamate levels. However, these methods are not viable options for hemodynamically unstable patients. Given more favorable hemodynamics, longer treatment, and less needed anticoagulation, we investigated whether hemofiltration could be effective in lowering blood glutamate levels. Blood samples were taken from 10 critically ill patients immediately before initiation of hemofiltration and after 1, 2, 4, 6, and 12 h, for a total of 6 blood samples. Samples were sent for determination of glutamate, glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), hemoglobin, hematocrit, urea, creatinine, glucose, sodium, potassium, platelet, and white blood cell (WBC) levels. There was a statistically significant reduction in blood glutamate levels at all time points compared to baseline levels. There was no difference in levels of GOT or GPT. Hemofiltration can be a promising method of reducing blood glutamate levels, especially in critically ill patients where hemodialysis and peritoneal dialysis may be contraindicated. PMID- 28836164 TI - Interpretation of thyroid scintigraphy is inconsistent among endocrinologists. PMID- 28836165 TI - Influenza vaccination rates before and after admission to nursing homes in Germany. AB - BACKGROUND: Influenza vaccination is highly recommended for nursing home residents. However, it is known that vaccination coverage is low in the general population. AIMS: We aim to find out whether influenza vaccination coverage differs for nursing home residents between the year before and after admission and factors determining the chance to receive vaccination. METHODS: Claims data of the health insurance fund DAK of at least 65-year-olds were used. The proportion of residents with influenza vaccination were compared in the year before and after the admission stratified by several covariates. A multivariate logistic regression analysis was conducted to obtain predictors for influenza vaccination after admission. RESULTS: Vaccination coverage was overall higher in the year after admission (53.0%) than before (38.3%). Differences in vaccination coverage between most covariates evened out after admission. Differences remained for region of residence and number of comorbidities. The strongest predictor for receiving a vaccination after admission was the vaccination status before admission (OR 3.5; 95% CI 3.3-3.6) followed by region and number of comorbidities. DISCUSSION: Overall, vaccination coverage of nursing home residents remains lower than recommended. Doctor-patient contacts whether due to care for comorbidities or as a continuation of the relation over the time of admission to the nursing home seem to assure vaccination for residents. CONCLUSION: Clear and unambiguous evidence of vaccine safety and efficacy for different subgroups within the same age group as well as organizational efforts to increase vaccination within nursing homes would be recommended. PMID- 28836168 TI - The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury. AB - Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity. Far from this being a disadvantage, the ATP-impoverished slice can serve as a useful and experimentally-tractable surrogate for the injured brain, which experiences similar depletion of cellular ATP. We have shown that the restoration of cellular ATP in brain slices to in vivo values is possible with a simple combination of D ribose and adenine (RibAde), two substrates for ATP synthesis. Restoration of ATP in slices to physiological levels has implications for synaptic transmission and plasticity, whilst in the injured brain in vivo RibAde shows encouraging positive results. Given that ribose, adenine, and a third compound, allopurinol, are all separately in use in man, their combined application after acute brain injury, in accelerating ATP synthesis and increasing the reservoir of the neuroprotective metabolite, adenosine, may help reduce the morbidity associated with stroke and traumatic brain injury. PMID- 28836167 TI - Attenuation of ductus arteriosus intimal thickening in preterm sheep twins compared with singletons. AB - Preterm twins have a higher morbidity rate of patent ductus arteriosus (PDA) than do singletons. However, the effect of multiple births on maturation of the ductus arteriosus (DA) has not been reported. Because intimal thickening (IT) is required for DA anatomical closure, we examined IT development in the DA of preterm twins and singletons. Sheep DA tissues obtained from preterm fetuses were subjected to elastica van Gieson staining to evaluate IT. The total IT score in each DA was the sum of the IT scores obtained from six evenly divided parts of the DA, which was positively correlated with gestational ages in singletons. Total IT scores were smaller in preterm twins than in singletons, although no difference in gestational age, birth weight, or gender ratio was observed. These data suggest that IT development of the DA is attenuated in sheep preterm twins, which may affect the higher morbidity of PDA. PMID- 28836166 TI - Laparoscopic complete mesocolic excision via mesofascial separation for left sided colon cancer. AB - PURPOSE: To evaluate the safety and feasibility of laparoscopic complete mesocolic excision (CME) via mesofascial separation for left-sided colon cancer. METHODS: We evaluated prospectively collected data on 65 consecutive patients with stage I-III left-sided colon cancer, who underwent laparoscopic CME between October 2011 and September 2016. After the exclusion of 5 patients who had T4b or other active tumors, 60 patients were the subjects of this analysis. The completeness of CME, preservation of the hypogastric nerve, operative data, pathological findings, complications, and length of hospital stay were assessed. RESULTS: CME completeness was graded as the mesocolic and intramesocolic plane in 54 and 6 patients, respectively. The hypogastric nerve was preserved in all patients. A total of 17, 12, 28, and 3 patients had T1, T2, T3, and T4a tumors, respectively. The mean number of lymph nodes retrieved was 16.2, and lymph node metastasis was identified in 22 patients. The mean operative time and intraoperative blood loss were 283 min and 38 ml, respectively. One patient had an intraoperative complication and six patients had postoperative complications. The hospital stay was 12 days. CONCLUSION: Laparoscopic CME via mesofascial separation is a safe and feasible procedure for left-sided colon cancer. PMID- 28836170 TI - Purification, Characterization of Amylase from Indigenously Isolated Aureobasidium pullulans Cau 19 and Its Bioconjugates with Gold Nanoparticles. AB - The amylase from Aureobasidium pullulans Cau 19 was purified by ammonium sulfate precipitation and Sephadex G-100 chromatography with a 9.25-fold increase in specific activity as compared to crude enzyme. Km and turn over values of the enzyme were 6.25 mg/mL and 5.0 * 102/min, respectively. Effect of different metal ions on the purified enzyme was investigated; 1 mM calcium (Ca) and cobalt (Co) enhanced enzyme activity by twofold; copper (Cu) had no effect on the activity of the enzyme. Mercury (Hg) 1 mM caused 90% inactivation whereas iron (Fe) and manganese (Mn) caused 10 to 16% inhibition. Amylase from A. pullulans Cau 19 was bioconjugated to gold nanoparticles synthesized using the biomass of A. pullulans Cau 19. Fourier transform infrared spectroscopy confirmed the conjugation of the enzyme to the gold nanoparticles. Though, only 20% of the added enzyme was adsorbed/conjugated on gold nanoparticles, 80% of the adsorbed activity could be estimated in the assay. The conjugated enzyme exhibited better tolerance to a broad pH range of 3.0-9.0 and higher temperatures compared with native enzyme. PMID- 28836171 TI - In Vitro Characterization of Lactobacillus Strains Isolated from Fruit Processing By-Products as Potential Probiotics. AB - Nine wild Lactobacillus strains, namely Lactobacillus plantarum 53, Lactobacillus fermentum 56, L. fermentum 60, Lactobacillus paracasei 106, L. fermentum 250, L. fermentum 263, L. fermentum 139, L. fermentum 141, and L. fermentum 296, isolated from fruit processing by-products were evaluated in vitro for a series of safety, physiological functionality, and technological properties that could enable their use as probiotics. Considering the safety aspects, the resistance to antibiotics varied among the examined strains, and none of the strains presented hemolytic and mucinolytic activity. Regarding the physiological functionality properties, none of the strains were able to deconjugate bile salts; all of them presented low to moderate cell hydrophobicity and were able to autoaggregate, coaggregate with Listeria monocytogenes and Escherichia coli, and antagonize pathogenic bacteria. Exposure to pH 2 sharply decreased the survival of the examined strains after 1- or 2-h exposure; variable decreases were noted after 3-h exposure to pH 3. Overall, exposure to pH 5 and to bile salts (0.15, 0.3, and 1%) did not decrease the strains' survival. Examined strains presented better ability to survive from the exposure to simulated gastrointestinal conditions in laboratorial media and milk than in grape juice. Considering the technological properties, all the strains were positive for proteolytic activity and EPS and diacetyl production, and most of them had good tolerance to 1-4% NaCl. These results indicate that wild Lactobacillus strains isolated from fruit processing by-products could present performance compatible with probiotic properties and technological features that enable the development of probiotic foods with distinct characteristics. PMID- 28836169 TI - The Simultaneous Effects of Socioeconomic Disadvantage and Child Health on Children's Cognitive Development. AB - Family socioeconomic status (SES) and child health are so strongly related that scholars have speculated child health to be an important pathway through which a cycle of poverty is reproduced across generations. Despite increasing recognition that SES and health work reciprocally and dynamically over the life course to produce inequality, research has yet to address how these two pathways simultaneously shape children's development. Using longitudinal data from the Fragile Families and Child Wellbeing Study and marginal structural models, we ask three questions: (1) how does the reciprocal relationship between socioeconomic disadvantage and child health affect estimates of each circumstance on children's cognitive development?; (2) how do their respective effects vary with age?; and (3) do family SES and child health have differential effects on cognitive development across population subgroups? The results show that the negative effects of socioeconomic disadvantage and poor health are insensitive to their reciprocal relationships over time. We find divergent effects of socioeconomic disadvantage and poor health on children's cognitive trajectories, with a widening pattern for family SES effects and a leveling-off pattern for child health effects. Finally, the effects of socioeconomic disadvantage are similar across all racial/ethnic groups, while the effects of child health are largely driven by white children. We discuss theoretical and policy implications of these findings for future research. PMID- 28836172 TI - Organic Gallium Treatment Improves Osteoporotic Fracture Healing Through Affecting the OPG/RANKL Ratio and Expression of Serum Inflammatory Cytokines in Ovariectomized Rats. AB - This study aimed to investigate the impact of organic gallium (OG) on osteoporotic fracture healing in ovariectomized female Sprague-Dawley rats, as well as study the mechanisms of OG on osteoporotic fracture healing. Forty-five female Sprague-Dawley rats were divided into three groups: sham operation group (Sxas control group), ovariectomized group (Ovx), and Ovx treated with OG group (Ovx + OG). Rat femoral fractures were studied using a standardized fracture healing model utilizing bone fixation with an intramedullary pin. Six weeks later, analyses of micro-CT, histomorphometric, RNA extraction, RT-qPCR, and serum were performed following sacrifice of all mice. In comparison with Ovx group, OG can significantly increase bone volume (BV), tissue volume (TV), BV/TV radio, bone strength, callus bony area, and as similar to BMP-2 expression. OG treatment elevated OPG messenger RNA (mRNA) and inhibited RANKL mRNA, and showed an effect on OPG/RANKL ratio. OG treatment can inhibit the expression of TNF alpha and IL-6. In conclusion, current study results indicate that organic OG can positively affect the OPG/RANKL ratio and inhibit the expression of serum inflammatory cytokines; thus, it can improve osteoporotic fracture healing. PMID- 28836173 TI - HPV-47-Induced and Tattoo-associated Verrucae Planae: Report of a Case and Review of the Literature. AB - The human papillomavirus (HPV), of which more than 200 different types have so far been identified, is an infectious disease impacting skin and mucous membranes. Several genera exist with distinct clinical impact. However, with ornamental tattoos increasing in popularity, a number of mostly cutaneous side effects have also been reported, such as infections, allergic reactions, or even a rise of malignant tumours within the tattoo. We report the first case of a beta1-HPV-type infection in cutaneous lesions in terms of verrucae vulgares near a tattoo in an immunocompetent adult without pre-existing conditions, and discuss possible relationships and etiologic concerns of this association. PMID- 28836174 TI - Higher Frequency of Nocturnal Blood Pressure Dipping but Not Heart Rate Dipping in Inflammatory Bowel Disease. AB - BACKGROUND: Masked hypertension (MHTN) and lack of nocturnal dipping in blood pressure (BP) have been linked to the state of inflammation. AIMS: We aimed to assess the frequency of nocturnal patterns of BP and heart rate (HR) in patients with IBD. METHODS: Sixty-three normotensive patients with confirmed IBD during remission and 63 healthy subjects were enrolled in a case-control study. All subjects were monitored for BP and HR over a period of 24 h under ambulatory setting. Means for BP and HR were calculated for nighttime and daytime periods. Daytime BP >= 135/85 mmHg, nighttime BP >= 120/70 mmHg, and 24-h average BP >= 130/80 mmHg were defined as MHTN. The main end points of this study were lack of >10% nocturnal decrease in the systolic BP (NDP-BP) and in HR (NDP-HR). RESULTS: After exclusion of 8 patients with IBD from analysis, 55 patients and 63 control subjects (49% men) with a mean age of 37.5 +/- 11.0 years were enrolled. NDP-BP was more common in the IBD group compared to controls (55 vs. 33%; P = 0.026). MHTN was detected in 24% of IBD patients compared to 8% among controls (P = 0.017). Meanwhile, NDP-HR was observed in 22% of the IBD patients and 30% of the control group (P = 0.402). IBD remained a significant predictor of NDP-BP (odds ratio 2.60, 95% confidence interval 1.19-5.51) following an adjustment for age and gender. CONCLUSIONS: IBD is associated with higher frequency of NDP-BP and MHTN; however, nocturnal changes in HR were similar in both groups. PMID- 28836177 TI - Erratum to: Practical Approach to Initiating SGLT2 Inhibitors in Type 2 Diabetes. PMID- 28836176 TI - Elevated hardness of peripheral gland on real-time elastography is an independent marker for high-risk prostate cancers. AB - OBJECTIVES: To examine the role of quantitative real-time elastography (RTE) features on differentiation between high-risk prostate cancer (PCA) and non-high risk prostatic diseases in the initial transperineal biopsy setting. METHODS: We retrospectively included 103 patients with suspicious PCA who underwent both RTE and initial transperineal prostate biopsy. Patients were grouped into high-risk and non-high-risk categories according to the D'Amico's risk stratification. With computer assistance based on MATLAB programming, three features were extracted from RTE, i.e., the median hardness within peripheral gland (PG) (H med), the ratio of the median hardness within PG to that outside PG (H ratio), and the ratio of the hard area within PG to the total PG area (H ar). A multiple regression model incorporating an RTE feature, age, transrectal ultrasound finding, and prostate volume was used to identify markers for high-risk PCA. RESULTS: Forty-seven patients (45.6%) were diagnosed with PCA and 34 (33.0%) were diagnosed with high-risk PCA. Three RTE features were all statistically higher in high-risk PCA than in non-high-risk diseases (p < 0.001), indicating that the PGs in high-risk PCA patients were harder than those in non-high-risk patients. A high H ratio, high age, and low prostate volume were found to be independent markers for PCAs (p < 0.05), among which the high H ratio was the only independent marker for high-risk PCAs (p = 0.012). When predicting high-risk PCAs, the multiple regression achieved an area under receiver operating characteristic curve of 0.755, sensitivity of 73.5%, and specificity of 71.0%. CONCLUSIONS: The elevated hardness of PG identified high-risk PCA and served as an independent marker of high-risk PCA. As a non-invasive imaging modality, the RTE could be potentially used in routine clinical practice for the detection of high-risk PCA to decrease unnecessary biopsies and reduce overtreatment. PMID- 28836175 TI - Canagliflozin: A Review in Type 2 Diabetes. AB - Canagliflozin (Invokana(r)) is a sodium-glucose co-transporter-2 (SGLT2) inhibitor indicated in various countries worldwide for the once-daily oral treatment of type 2 diabetes (T2D). Canagliflozin lowers blood glucose levels independently of insulin, with the inhibition of SGLT2 reducing renal reabsorption of glucose and increasing excretion of glucose in the urine. In well designed clinical trials, canagliflozin (as first-line monotherapy or add-on therapy to other antihyperglycaemic agents) improved glycaemic control in adults with T2D, including those of older age and/or at high cardiovascular (CV) risk, and also had beneficial effects on their bodyweight and blood pressure (BP). CV risk reduction, as well as possible renal benefits, were also seen with canagliflozin in T2D patients at high CV risk in the CANVAS Program, an integrated analysis of two large CV outcomes studies. Canagliflozin was generally well tolerated, had a low risk of hypoglycaemia and was most commonly associated with adverse events such as genital and urinary tract infections and increased urination, consistent with its mechanism of action. Although the amputation and fracture risk observed among recipients of the drug require further investigation, canagliflozin is an important option for T2D management in adults. PMID- 28836179 TI - Facile Synthesis of Colored and Conducting CuSCN Composite Coated with CuS Nanoparticles. AB - Conductivity-tunable, different colored CuS nanoparticle-coated CuSCN composites were synthesized in a single pot using a mixture of copper sulfate and sodium thiosulfate in the presence of triethyl amine hydrothiocyanate (THT) at the ambient condition. When these reagents are mixed in 1:1:1 molar ratio, white-gray colored CuSCN was produced. In the absence of THT, microsized dark blue-colored CuS particles were produced. However, when THT is present in the solution mixture by different amounts, colored conducting CuS nanoparticle-coated CuSCN composite was produced. CuS nanoparticles are not deposited on CuSCN soon after mixing these regents, but it takes nearly overnight to see the color change (CuS production) in the white CuSCN dispersed mixture. TEM analysis shows that composite consists of hexagonal CuS nanoparticles in the range of ~ 3-10 nm in size. It is interesting to note that CuS-coated CuSCN possesses higher conductivity than neat CuS or CuSCN. Moreover, strong IR absorption was observed for CuS-coated CuSCN composite compared to neat CuS (absence of THT) or CuSCN. Lowest resistivity of 0.05 Omega cm was observed for annealed (250 degrees C) CuS-coated CuSCN particles (adding 10 ml of THT) under nitrogen atmosphere. Also, this simple method could be extended to be used in the synthesis of CuS-coated composites on the other nanomaterials such as metal oxides, polymers, and metal nanoparticles. PMID- 28836178 TI - Contributions to lateral balance control in ambulatory older adults. AB - BACKGROUND: In older adults, impaired control of standing balance in the lateral direction is associated with the increased risk of falling. Assessing the factors that contribute to impaired standing balance control may identify areas to address to reduce falls risk. AIM: To investigate the contributions of physiological factors to standing lateral balance control. METHODS: Two hundred twenty-two participants from the Pittsburgh site of the Health, Aging and Body Composition Study had lateral balance control assessed using a clinical sensory integration balance test (standing on level and foam surface with eyes open and closed) and a lateral center of pressure tracking test using visual feedback. The center of pressure was recorded from a force platform. Multiple linear regression models examined contributors of lateral control of balance performance, including concurrently measured tests of lower extremity sensation, knee extensor strength, executive function, and clinical balance tests. Models were adjusted for age, body mass index, and sex. RESULTS: Larger lateral sway during the sensory integration test performed on foam was associated with longer repeated chair stands time. During the lateral center of pressure tracking task, the error in tracking increased at higher frequencies; greater error was associated with worse executive function. The relationship between sway performance and physical and cognitive function differed between women and men. DISCUSSION: Contributors to control of lateral balance were task-dependent. Lateral standing performance on an unstable surface may be more dependent upon general lower extremity strength, whereas visual tracking performance may be more dependent upon cognitive factors. CONCLUSIONS: Lateral balance control in ambulatory older adults is associated with deficits in strength and executive function. PMID- 28836180 TI - Effect of Liraglutide on Type B Insulin Resistance Syndrome and Insulin Allergy in Type 2 Diabetes: A Case Report. AB - INTRODUCTION: The appearance of anti-insulin antibodies or an allergy to insulin occasionally causes clinical problems with glycemic control in insulin users. METHODS: In the present report, we describe a therapeutic approach that was employed for a man with type 2 diabetes who had insulin allergy, anti-insulin antibodies, and anti-insulin receptor antibodies that developed during his insulin treatment. RESULTS: We started the patient on liraglutide, a glucagon like peptide-1 receptor agonist, and attained glycemic control without incurring any side effects. Two years after liraglutide induction, his blood glucose was being maintained at a healthy level by liraglutide monotherapy. CONCLUSION: Liraglutide may be a therapeutic option for patients with insulin allergy, anti insulin antibodies, and type B insulin resistance syndrome, as it represents an alternative strategy to insulin. PMID- 28836181 TI - A Simulation Exercise to Raise Learners' Awareness of the Physical and Cognitive Changes in Older Adults. AB - OBJECTIVE: The growing number of older adults with cognitive impairment is increasing the need for healthcare services. However, there is a great shortage of geriatric trained primary care providers and psychiatrists. A positive attitude towards people with cognitive impairment is associated with better quality of life among residents of long-term care settings. This led us to develop a simulation exercise to raise learners' awareness of, and attentiveness to, physical and cognitive changes experienced by the aging population. METHODS: Fifty-one learners rotating through Psychiatry at the Michael E. DeBakey VA Medical Center received the 10-min training over 1 year. The Approaches to Dementia Questionnaire was used to measure attitudes towards older persons with cognitive impairment. Pre- and postsimulation data subscores for the Hope, Person centered, and total score were calculated, and a paired sample t test was conducted. RESULTS: Results of the questionnaire showed statistically significant improvement in the Approaches to Dementia Questionnaire scores among participants after they completed the simulation exercise, indicating an increase in positive attitudes. The mean difference in the total score of the Approaches to Dementia Questionnaire was 3.22, with a 95% CI of 1.67 to 4.74, t = 4.20, df (47), p < .000, r = .64, and a medium effect size of d = .61. CONCLUSIONS: On the basis of these findings, the simulation exercise can be used for improving learners' attitudes towards those with cognitive impairment. PMID- 28836182 TI - NAD+-dependent HDAC inhibitor stimulates Monascus pigment production but inhibit citrinin. AB - Monascus species are edible fungi due to the production of food colorant and other beneficial compounds. Hence, it has been an attractive thesis to improve their productivities. Increasing numbers of investigations revealed that regulating the activities of histone deacetylases can significantly perturb secondary metabolites (SM) production at a global level. In this study, dihydrocoumarin (DHC, an inhibitor of the Sirtuin family of NAD+-dependent deacetylases) was used to treat Monascus ruber for evaluating its effects on organism growth and SM production. The results revealed that the variation trends of colonial sizes, biomass and mycotoxin were in a dose-dependent manner. Generally, they decreased with the increased DHC concentrations in the designed range. But the variation trend of pigment was different. Comparison of SM profile, three new peaks occurred to the mycelia extractions from DHC-treated strain corresponding to molecular weights 402, 416 and 444, respectively. These three compounds were identified as Monasfluol B, Monascus azaphilone C and acetyl monasfluol B (a new Monascus chemical pigment structure). In short, DHC can stimulate M. ruber strain to produce more pigment-like polyketides but inhibition of mycotoxin (citrinin). PMID- 28836183 TI - Conservative heavy metal total discharge schemes. AB - Currently, according to Taiwan's Water Pollution Control Act, the environmental control of waterbodies and water quality depends on the effluent standards and the standard of water quality in the rivers. The Act demands that each stationary pollution source comply with the effluent standard before being discharged into the rivers, and that the overall water quality in the river shall not exceed the declared standard of water quality. To improve the condition of the waterbodies and water quality of the rivers, the Environmental Protection Administration (EPA) in Taiwan has made stricter regulations concerning the discharge standard. Such regulations will help to reduce the weight of individual pollutants discharged; the discharged wastewater, however, will still gradually worsen the water quality of the rivers even after complying with the effluent standard since some of the pollutant dischargers may decrease the concentration of pollutants by diluting the water before discharging; thus, the total weight of metals discharged in the rivers will not be reduced, and the water quality in the areas where the pollutant sources are concentrated will not thereby be significantly improved. To protect the irrigation water and farmlands from being polluted by discharged heavy metals in industrial wastewater, the EPA started controlling the sources in accordance with the total quantity control (TQC) as defined in the Water Pollution Control Act, in the hope of perfecting the environmental protection of waterbodies and water quality, as well as ensuring clean water sources without any pollution for the rivers, land, and people. PMID- 28836184 TI - Grand Theft Auto is a "Sandbox" Game, but There are Weapons, Criminals, and Prostitutes in the Sandbox: Response to Ferguson and Donnellan (2017). AB - In this issue, (Ferguson, C. J., & Donnellan, B. D., Journal of Youth and and Adolescence, published online 21 June 2017) criticize one of our studies (Gabbiadini, A., Riva, P., Andrighetto, L., Volpato, C., & Bushman, B. J., PLoS ONE, 11: 1-14, 2016) that found violent sexist video games can reduce empathy for female violence victims in male players who identify with violent male game characters, and do so by increasing masculine beliefs. Their main criticism is a "straw person" argument built on a claim that we never made (i.e., a direct effect of sexist-violent video games on empathy). They also made several other criticisms of our article. We appreciate the opportunity to respond to their criticisms in this article. We also point out some flaws in their reanalysis. Despite their criticisms, the core contributions of our original article remain intact. PMID- 28836185 TI - High-Throughput Screen Fails to Identify Compounds That Enhance Residual Enzyme Activity of Mutant N-Acetyl-alpha-Glucosaminidase in Mucopolysaccharidosis Type IIIB. AB - BACKGROUND: In the severe neurodegenerative disorder mucopolysaccharidosis type IIIB (MPSIIIB or Sanfilippo disease type B), deficiency of the lysosomal enzyme N acetyl-alpha-glucosaminidase (NAGLU) results in accumulation of heparan sulfate. Patients present with a severe, rapidly progressing phenotype (RP) or a more attenuated, slowly progressing phenotype (SP). In a previous study, residual NAGLU activity in fibroblasts of SP patients could be increased by culturing at 30 degrees C, probably as a result of improved protein folding and lysosomal targeting under these conditions. Chaperones are molecules which influence protein folding and could therefore have therapeutic potential in SP MPSIIIB patients. Here we studied the effects of 1,302 different compounds on residual NAGLU activity in SP MPSIIIB patient fibroblasts including 1,280 approved compounds from the Prestwick Chemical Library. METHODS: Skin fibroblasts of healthy controls, an SP MPSIIIB patient (homozygous for the temperature sensitive mutation p.S612G) and an RP MPSIIIB patient (homozygous for the p.R297* mutation and non-temperature sensitive), were used. A high-throughput assay for measurement of NAGLU activity was developed and validated, after which 1,302 different molecules were tested for their potential to increase NAGLU activity. RESULTS: None of the compounds tested were able to enhance NAGLU activity. CONCLUSIONS: This high-throughput screen failed to identify compounds that could enhance residual activity of mutant NAGLU in fibroblasts of SP MPSIIIB patients with temperature sensitive mutations. To therapeutically simulate the positive effect of lower temperatures on residual NAGLU activity, first more insight is needed into the mechanisms underlying this temperature dependent increase. PMID- 28836186 TI - Effect of In Situ Annealing Treatment on the Mobility and Morphology of TIPS Pentacene-Based Organic Field-Effect Transistors. AB - In this work, organic field-effect transistors (OFETs) with a bottom gate top contact structure were fabricated by using a spray-coating method, and the influence of in situ annealing treatment on the OFET performance was investigated. Compared to the conventional post-annealing method, the field effect mobility of OFET with 60 degrees C in situ annealing treatment was enhanced nearly four times from 0.056 to 0.191 cm2/Vs. The surface morphologies and the crystallization of TIPS-pentacene films were characterized by optical microscope, atomic force microscope, and X-ray diffraction. We found that the increased mobility was mainly attributed to the improved crystallization and highly ordered TIPS-pentacene molecules. PMID- 28836187 TI - Erratum to: Hydrolysis and Dissolution of Amyloids by Catabodies. PMID- 28836188 TI - Heme Oxygenase-1-Inducing Activity of 4-Methoxydalbergione and 4'-Hydroxy-4 methoxydalbergione from Dalbergia odorifera and Their Anti-inflammatory and Cytoprotective Effects in Murine Hippocampal and BV2 Microglial Cell Line and Primary Rat Microglial Cells. AB - Dalbergia odorifera T. Chen (Leguminosae) grows in Central and South America, Africa, Madagascar, and Southern Asia. D. odorifera possesses many useful pharmacological properties, such as antioxidative and anti-inflammatory activities in various cell types. 4-Methoxydalbergione (MTD) and 4'-hydroxy-4 methoxydalbergione (HMTD) were isolated from the EtOH extract of D. odorifera by several chromatography methods. The chemical structures were elucidated by nuclear magnetic resonance (NMR) and mass spectrum (MS). Anti-inflammatory and cytoprotective effects were examined using BV2 microglial cells and murine hippocampus. MTD and HMTD were demonstrated to induce heme oxygenase (HO)-1 protein levels through the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in BV2 microglial cells, while only MTD upregulated HO-1 in HT22 cells. MTD and HMTD induced HO-1 expression through JNK MAPK pathway in BV2 cells, whereas only MTD activated the ERK and p38 pathways in HT22 cells. MTD was also shown to activated MTD and HMTD suppressed lipopolysaccharide-stimulated nitric oxide (NO) and prostaglandin E2 production by inhibiting inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in a dose-dependent manner. Furthermore, MTD and HMTD attenuated pro-inflammatory cytokine productions. These anti-inflammatory effects were found to be mediated through the nuclear factor-kappa B (NF-kappaB) pathway. MTD exhibited neuroprotective effects on glutamate-induced neurotoxicity by promoting HO-1 in HT22 cells. The anti-inflammatory and cytoprotective effects of MTD and HMTD were partially reversed by an HO inhibitor tin protoporphyrin IX. In addition, MTD and HMTD inhibited pro-inflammatory cytokines and NF-kappaB pathway in primary rat microglia. These findings suggest that MTD and HMTD have therapeutic potential against neurodegenerative diseases accompanied by microglial activation and/or oxidative cellular injury. PMID- 28836189 TI - Evaluation and Management of Erectile Dysfunction in the Hypertensive Patient. AB - PURPOSE OF REVIEW: The prevalence of hypertension and erectile dysfunction has steadily increased, and greater than 40% of men with erectile dysfunction concurrently share a diagnosis of hypertension. The treatment of the patient with both diseases poses a clinical challenge as both are closely correlated and share multiple overlapping risk factors.To address the recognized knowledge gap among clinicians who care for these patients, we will review the current literature on the diagnosis and treatment of erectile dysfunction in the hypertensive patient and will provide recommendations for the management of this challenging patient population. RECENT FINDINGS: The pharmacological treatment of hypertension may adversely affect sexual function, and certain treatments for erectile dysfunction are contraindicated or cautioned against with certain antihypertensive agents. In review of the literature, we find that the clinician should opt to use an angiotensin-receptor blocker followed by an angiotensin-converting enzyme inhibitor or calcium channel blocker for the treatment of hypertension in patients with erectile dysfunction. Other agents require careful consideration for adverse effects on sexual function. Men with erectile dysfunction should be assessed for cardiovascular fitness for sexual activity, and PDE-5 inhibitors remain the first-line treatment for erectile dysfunction. PMID- 28836191 TI - Human Fibrotic Diseases: Current Challenges in Fibrosis Research. AB - Human fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals, the incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents. The fibrotic disorders encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse and in several instances have remained elusive, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrotic tissue in affected organs causing their dysfunction and ultimate failure. Despite the remarkable heterogeneity in the etiologic mechanisms responsible for the development of fibrotic diseases and in their clinical manifestations, numerous studies have identified activated myofibroblasts as the common cellular element ultimately responsible for the replacement of normal tissues with nonfunctional fibrotic tissue. Critical signaling cascades, initiated primarily by transforming growth factor-beta (TGF beta), but also involving numerous cytokines and signaling molecules which stimulate profibrotic reactions in myofibroblasts, offer potential therapeutic targets. Here, we briefly review the current knowledge of the molecular mechanisms involved in the development of tissue fibrosis and point out some of the most important challenges to research in the fibrotic diseases and to the development of effective therapeutic approaches for this often fatal group of disorders. Efforts to further clarify the complex pathogenetic mechanisms of the fibrotic process should be encouraged to attain the elusive goal of developing effective therapies for these serious, untreatable, and often fatal disorders. PMID- 28836192 TI - The Bleomycin Model of Pulmonary Fibrosis. AB - Interstitial lung disease (ILD) comprises a large number of chronic lung disease characterized by varying degrees of inflammation and fibrosis. Mostly they are idiopathic including idiopathic pulmonary fibrosis (IPF), which is a specific disorder characterized by progressive fibrosis leading commonly to end-stage lung disease, respiratory failure, and fatal outcome. IPF and many of these fibrotic ILDs lack effective therapy despite recent approval of two drugs to slow progression in certain IPF patients. Because there are no natural models for IPF, the use of animal models that reproduce key known features of the disease is warranted. Thus, different animal models have been developed to investigate key mechanisms underlying pathogenesis of pulmonary fibrosis and identify potential therapeutic targets for IPF. While no animal model can recapitulate all features of human disease, several are available to address select features of IPF and other fibrotic ILDs. Historically, among the first to be developed and used widely is the bleomycin model, which is the best-characterized and currently most extensively used animal model due to its ability to reproduce many aspects of IPF and other fibrotic ILDs, good reproducibility, and ease of induction. Studies using the bleomycin model have identified many of the cellular and molecular mechanisms now recognized as being important in pathogenesis of IPF and other fibrotic ILDs, as well as novel therapies for these diseases, including two recent drugs approved for treatment of IPF. This chapter will describe commonly used techniques for induction of the model by endotracheal administration of bleomycin through surgical and nonsurgical (transoral instillation). PMID- 28836190 TI - Lead poisoning: acute exposure of the heart to lead ions promotes changes in cardiac function and Cav1.2 ion channels. AB - Lead ions (Pb2+) possess characteristics similar to Ca2+. Because of this and its redox capabilities, lead causes different toxic effects. The neurotoxic effects have been well documented; however, the toxic effects on cardiac tissues remain allusive. We utilized isolated guinea pig hearts and measured the effects of Pb2+ on their contractility and excitability. Acute exposure to extracellular Pb2+ had a negative inotropic effect and increased diastolic tension. The speed of contraction and relaxation were affected, though the effects were more dramatic on the speed of contraction. Excitability was also altered. Heart beat frequency increased and later diminished after lead ion exposure. Pro-arrhytmic events, such as early after-depolarization and a reduction of the action potential plateau, were also observed. In isolated cardiomyocytes and tsA 201 cells, extracellular lead blocked currents through Cav1.2 channels, diminished their activation, and enhanced their fast inactivation, negatively affecting their gating currents. Thus, Pb2+ was cardiotoxic and reduced cardiac contractility, making the heart prone to arrhythmias. This was due, in part, to Pb2+ effects on the Cav1.2 channels; however, other channels, transporters or pathways may also be involved. Acute cardiotoxic effects were observed at Pb2+ concentrations achievable during acute lead poisoning. The results suggest how Cav1.2 gating can be affected by divalent cations, such as Pb2, and also suggest a more thorough evaluation of heart function in individuals affected by lead poisoning. PMID- 28836193 TI - Intradermal Injections of Bleomycin to Model Skin Fibrosis. AB - Systemic sclerosis (scleroderma) is a fibrotic condition characterized by immunologic abnormalities, vascular injury, and increased accumulation of extracellular matrix proteins in the affected organs. Although the etiology of scleroderma has not yet been fully elucidated, a growing body of evidence suggests that extracellular matrix overproduction by activated fibroblasts results from a complex interaction among endothelial cells, immunocytes, and fibroblasts, involving a number of mediators such as cytokines, chemokines, growth factors, and their receptors. For a better understanding of the pathophysiology of scleroderma, animal models are important tools. They reproduce several histological as well as biochemical aspects resembling human scleroderma, and we can learn lots of new findings through animal studies. On the other hand, it must be emphasized that there are no animal models so far exhibiting all the aspects of human scleroderma, and studying animal models cannot answer all the problems of human scleroderma. This paper introduces current concepts of various animal models for scleroderma and discusses their advantages/disadvantages, contribution to our understanding of the pathogenesis, and therapeutic approach for human scleroderma. PMID- 28836194 TI - Assessing the Effects of Fibrosis on Lung Function by Light Microscopy-Coupled Stereology. AB - Pulmonary diseases such as fibrosis are characterized by structural abnormalities that lead to impairment of proper lung function. Stereological analysis of serial tissue sections allows detection and quantitation of subtle changes in lung architecture. Here, we describe a stereology-based method of assessing pathology induced changes in lung structure. PMID- 28836195 TI - Transplanting Human Skin Grafts onto Nude Mice to Model Skin Scars. AB - Hypertrophic scar (HTS) is a common outcome of deep dermal wound healing mainly followed mechanical, chemical, and thermal injuries in the skin. Because of the lack of the most effective prevention and treatment, it is particularly important to establish an ideal dermal animal model for improving the understanding of the pathogenesis and exploring therapeutic approaches of HTS. Compared to other dermal fibrotic animal models in rabbits, red Duroc pigs, guinea pigs, rats, and mice, the approach that uses normal human split-thickness skin grafted onto nude or other immunodeficient mice which develop scars that resemble human HTS offers the advantages of lower cost, easier manipulation, and shorter research period. In this chapter, we will introduce the detailed procedures to create the ideal dermal fibrotic mouse model. PMID- 28836196 TI - Hypertrophic Scarring in the Rabbit Ear: A Practical Model for Studying Dermal Fibrosis. AB - Excessive fibrous tissue deposition after injury in the form of hypertrophic scar remains a major clinical challenge. The development of an animal model for such scarring has been extremely difficult because of a major difference between the healing process in laboratory animals and humans. Here, we describe the rabbit ear model for excessive dermal scarring which has some clinical and histological resemblance to human hypertrophic scar. Since its development, this model has been widely used to study the cellular and molecular biology of hypertrophic scarring and evaluate the efficacy of new therapeutic agents. PMID- 28836197 TI - Mouse and Rat Models of Induction of Hepatic Fibrosis and Assessment of Portal Hypertension. AB - Portal hypertension either develops due to progressive liver fibrosis or is the consequence of vascular liver diseases such as portal vein thrombosis or non cirrhotic portal hypertension. This chapter focuses on different rodent models of liver fibrosis with portal hypertension and also in few non-cirrhotic portal hypertension models. Importantly, after the development of portal hypertension, the proper assessment of drug effects in the portal and systemic circulation should be discussed. The last part of the chapter is dedicated in these techniques to assess the in vivo hemodynamics and the ex vivo techniques of the isolated liver perfusion and vascular contractility. PMID- 28836198 TI - Mouse Models of Corneal Scarring. AB - Corneal scarring is an obligatory consequence of stroma corneal injury and is a major cause of decreased visual quality and vision loss worldwide. There are currently no satisfactory intervention therapies for corneal fibrosis. In this chapter, we describe well-established in vivo corneal wound models to allow researchers to investigate epithelial and stromal responses to corneal injury. PMID- 28836199 TI - Modeling Cardiac Fibrosis in Mice: (Myo)Fibroblast Phenotype After Ischemia. AB - Cardiac (myo)fibroblasts play a key role in the regulation of wound healing and pathogenic remodeling after myocardial infarction. Impaired scar formation and alterations of the extracellular matrix network precipitate cardiac dysfunction leading to increased morbidity and mortality. Therapeutic approaches addressing (myo)fibroblast phenotype appear to be useful in preventing progressive structural, electrical, and functional impairment and heart failure.Permanent ligation of the left anterior descending coronary artery has proven to be a valuable experimental model to investigate the arrays of pathways/mechanisms involved in cardiac repair and extracellular matrix remodeling in ischemic heart failure. Here we describe the surgical procedure to occlude the left coronary artery in mice. Moreover, we present an accurate method to isolate (myo)fibroblasts from ischemic myocardium, with maintenance of the functional phenotype, using the specific marker for mouse cardiac fibroblasts mEF-SK4. The protocol can be completed within a few hours, and the isolated fibroblasts/myofibroblasts are suitable for downstream molecular biology applications, like gene expression profiling and cell culture. PMID- 28836200 TI - Characterization of Mesenchymal-Fibroblast Cells Using the Col1a2 Promoter/Enhancer. AB - Excessive deposition of extracellular matrix (ECM) is a common hallmark of fibrotic diseases in various organs. Chiefly among this ECM are collagen types I and III, secreted by local fibroblasts, and other mesenchymal cells recruited for repair purposes. In the last two decades, the search for a fibroblast-specific promoter/enhancer has intensified in order to control the regulation of ECM in these cells and limit the scarring of the fibrotic process. In our previous work, we characterized an enhancer region 17 kb upstream of the Col1a2 gene transcription start site. This enhancer in transgenic mice is expressed mainly in mesenchymal cells during development and in adults upon injury. When driving transgenes such as beta-galactosidase or luciferase, this construct acts as an informative reporter of collagen transcription and is predictive of collagen type I deposition. In this chapter, we provide detailed protocols for identifying similar enhancers and using the sequence to generate a construct for transfection and producing transgenic animals. We also provided information on the use of luminescence in transgenic mice, tissue processing, as well as using cre/lox system to obtain conditional gain and loss of function in mice. PMID- 28836201 TI - Isolation and Culture of Primary Murine Hepatic Stellate Cells. AB - Hepatic stellate cells (HSCs) are found in the perisinusoidal space of the liver (i.e., the space of Disse). They represent 5-8% of the total number of liver cells. In normal liver, these cells have a quiescent phenotype and are characterized by numerous fat vacuoles that store vitamin A in a form of retinyl ester. In injured liver, these cells transdifferentiate into a myofibroblast phenotype, become highly proliferative and are responsible for excess collagen synthesis and deposition during fibrosis. Due to their exceptional pathophysiological relevance, several isolation and purification protocols of primary HSCs have been established that provide the basis for studying HSC biology in vitro. We here describe a method for high-purity isolation of HSCs from mice. This protocol includes the enzymatic digestion of the liver tissue by pronase and collagenase, cellular enrichment by centrifugation of the crude cell suspension through a Nycodenz density gradient, and a final (optional) flow cytometric enrichment that allows generating ultrapure HSC fractions. PMID- 28836202 TI - Isolation and Culture of Adipose-Derived Stromal Cells from Subcutaneous Fat. AB - Cells with mesenchymal stem cell characteristics can be isolated from human adipose tissue stroma. Relative ease of isolation in large numbers and their ability for expansion and differentiation means that they are becoming a preferred cell type for mesenchymal regenerative medicine applications. In addition to expansion and differentiation capacity, they also express valuable paracrine activities which promote tissue formation and wound healing, including pro- and anti-fibrotic mediators. Here we describe a method for routine isolation of adipose stromal cells, culture expansion, and characterization by differentiation and then production of conditioned media. PMID- 28836203 TI - Isolation of Live Fibroblasts by Fluorescence-Activated Cell Sorting. AB - Flow cytometry is a powerful tool in cell biology in that it allows real-time characterization of cellular phenotypes. Additionally, through the process of fluorescence-activated cell sorting (FACS), living cells can be isolated for future in vitro experiments, including single cell analysis. Here we describe the isolation of live fibroblasts from the dermis of the skin in mice using FACS. This method circumvents the need for ex vivo expansion in cell culture, which can alter phenotypic and functional characteristics of cells. PMID- 28836204 TI - Detection of Infiltrating Mast Cells Using a Modified Toluidine Blue Staining. AB - Mast cells are part of the immune system and characteristically contain histamine and heparin-rich basophilic granules. While these cells are usually associated with allergy and anaphylaxis, they also promote wound healing and angiogenesis and confer protection against pathogens. The presence of these cells is sometimes indicative of a poor prognosis, especially in skin cancer, pancreatic cancer, and lymphoma. Toluidine blue staining of acid-fast granules is an established method for the identification and quantification of mast cells. Generating detailed information on the location of mast cells within tissues is problematic using this technique and often requires serial sections from adjacent tissue to be separately stained with hematoxylin and eosin (H&E). Staining serial sections is not always possible, particularly if the sample is very small or rare. In such cases, a method of simultaneously identifying and localizing mast cells in a tissue would be advantageous. Toluidine blue and H&E are not commonly combined because H&E includes repetitive washes in water, which may affect the efficacy of the aqueous-soluble toluidine blue. We have developed and tested a novel staining technique that integrates toluidine blue between hematoxylin and eosin in one simple procedure. This protocol works on both frozen and formalin-fixed, paraffin embedded tissue and readily allows for the identification of purple-stained mast cells against a clean H&E background. This facilitates a more accurate localization and proper counting of mast cells in normal and affected tissue. PMID- 28836205 TI - Cell-Populated Collagen Lattice Models. AB - Investigation of cell function is often hampered by the complexity of the tissue context. This problem is circumvented by isolating cells from tissues and analyzing their behavior in culture. Most cell types are cultured as monolayers on planar, rigid Petri dishes, an environment that does not reflect the spatial, three-dimensional cellular environment in vivo. Culture in three-dimensional collagen lattices has been devised to optimize in vitro culture conditions and to provide a more physiologic "in vivo-like" environment. Collagen lattices can easily be manipulated to suit diverse cell types and to provide variable mechanical forces. Cells can be imaged in such surroundings, and gene expression as well as protein production and activity can be monitored. PMID- 28836206 TI - Traction Force Measurement Using Deformable Microposts. AB - Recent findings suggest that mechanical forces strongly influence wound repair and fibrosis across multiple organ systems. Traction force is vital to the characterization of cellular responses to mechanical stimuli. Using hydrogel based traction force microscopy, a FRET-based tension sensor, or microengineered cantilevers, the magnitude of traction forces can be measured. Here, we describe a traction force measurement methodology using a dense array of elastomeric microposts. This platform can be used to measure the traction force of a single cell or a colony of cells with or without geometric confinement. PMID- 28836207 TI - Mechanical Deformation of Cultured Cells with Hydrogels. AB - Polyacrylamide hydrogels can be used to culture cells in a range of stiffness that can closer mimic physiological environments. Changes in environmental stiffness have been documented in conditions such as fibrosis, cancer, and aging. In this chapter, we describe a method in which we pour gels directly into multiwell plates using a plastic support that covalently binds to the polymerizing hydrogel. The hydrogel is then crosslinked to calfskin collagen using a crosslinker. The result is a thick hydrogel, scalable to any size plate, which covers the entire surface of the well with no edge effects. The gels can be routinely assembled and are easily reproducible. These scaffolds are used as in vitro models to study fibroblast reaction to variation in environmental stiffness. PMID- 28836208 TI - Preparation of Decellularized Lung Matrices for Cell Culture and Protein Analysis. AB - The limited available treatment options for patients with chronic lung diseases, such as fibrosis, lead to poor prognosis after diagnosis and short survival rates. An exciting new bioengineering approach utilizes de- and recellularization of lung tissue to potentially overcome donor organ shortage and immune reactions toward the received transplant. The goal of decellularization is to create a scaffold which contains the necessary framework for stability and functionality for regenerating lung tissue while removing immunomodulatory factors by removal of cells. After decellularization, the scaffold could be re-functionalized by repopulation with the patient's own stem/progenitor cells to create a fully functional organ or can be used as ex vivo models of disease. In this chapter the decellularization of lung tissue from multiple species (i.e., rodents, pigs, and humans) as well as disease states such as fibrosis is described. We discuss and describe the various quality control measures which should be used to characterize decellularized scaffolds, methods for protein analysis of the remaining scaffold, and methods for recellularization of scaffolds. PMID- 28836209 TI - Type I Collagen Purification from Rat Tail Tendons. AB - Type I collagen, or collagen I, is the most abundant protein in the human body and provides strength and resiliency to tissues such as bone, tendons, ligaments, and skin. Collagen I forms macromolecular networks in which resident mesenchymal cells are embedded. Cell-extracellular matrix interactions are critical not only for maintenance of tissue properties but also for guiding and orienting the phenotype of resident cells. Cues from the extracellular matrix have been shown to be critical in pathophysiologies such as fibrosis, aging, and cancer. Hence, the details of these interactions are being scrutinized to better understand the mechanisms of such diseases and conditions. Many in vitro assays, such as cell embedded collagen lattices, preparation of hydrogels, adhesion assays, etc., have been developed to study various aspects of cell-extracellular matrix interactions. All these in vitro models rely on utilizing high-quality purified collagen I. Here, we provide state-of-the-art collagen I extraction protocol and useful tips to produce high-quality purified collagen I solutions. We also provide a detailed protocol for pepsin digestion of collagen I, for a highly reliable collagen concentration assay, and guidelines for conducting quality controls to validate purified collagen solutions. Collagen I prepared with these procedures is highly suitable for many in vitro applications. PMID- 28836210 TI - Purification of Human Plasma/Cellular Fibronectin and Fibronectin Fragments. AB - A method is described for the purification of plasma fibronectins based on a combination of gelatin- and arginine-Sepharose chromatography steps. Cellular fibronectin can be purified from an osteosarcoma fibroblast cell line by affinity chromatography using a monoclonal antibody anti-fibronectin as ligand. Furthermore, we also provide a protocol for the purification of fibronectin domains obtained by fractionation of thermolysin-digested plasma fibronectin on ion-exchange/gel filtration chromatography columns. Assessment of the fibronectin purity is performed by SDS-PAGE, while the ligand binding activities of specific fibronectin domains are determined by ELISA. PMID- 28836211 TI - Laser Capture Microdissection of Tissue Sections for High-Throughput RNA Analysis. AB - The heterogeneous nature of most human organs and tissues represents a common challenge when analyzing specific structures or cells. Laser capture microdissection (LCM) enables isolation of pure cells from a mixed population of cells or tissue samples via usage of laser energy. Combined with high-throughput gene or protein techniques, compartment specific analysis elucidating the role of specialized cell types in physiological or pathophysiological activity can be performed. This chapter describes the crucial steps that have to be taken into consideration when designing and conducting a LCM project. Detailed protocols describing the workflow from project planning to high-throughput analysis of LCM material used in our laboratory are provided. Routinely occurring challenges and appropriate solutions, e.g., when working with fibrotic tissue are described. PMID- 28836212 TI - Collagen Quantification in Tissue Specimens. AB - Collagen is the major extracellular protein in mammals. Accurate quantification of collagen is essential in the biomaterials (e.g., reproducible collagen scaffold fabrication), drug discovery (e.g., assessment of collagen in pathophysiologies, such as fibrosis), and tissue engineering (e.g., quantification of cell-synthesized collagen) fields. Although measuring hydroxyproline content is the most widely used method to quantify collagen in biological specimens, the process is very laborious. To this end, the SircolTM Collagen Assay is widely used due to its inherent simplicity and convenience. However, this method leads to overestimation of collagen content due to the interaction of Sirius red with basic amino acids of non-collagenous proteins. Herein, we describe the addition of an ultrafiltration purification step in the process to accurately determine collagen content in tissues. PMID- 28836213 TI - Methods for the Assessment of Active Transforming Growth Factor-beta in Cells and Tissues. AB - The potent and pluripotent cytokine TGFbeta has important roles in normal homeostasis and disease pathogenesis. Once released from cells, TGFbeta exists in both latent and functionally active forms. Large amounts of latent TGFbeta are secreted from cells and sequestered in extracellular matrix, only a small proportion of which is activated at any given time. Accurate assessment of TGFbeta activity levels is an important measurement in biological research and requires methods distinct from measuring total levels of TGFbeta expression as small changes in TGFbeta activity levels could be masked by the large amounts of latent TGFbeta available to be measured. In this chapter, we describe detailed experimental methods for assessing levels of active TGFbeta in cells and tissues. This chapter includes methods for the assessment of TGFbeta activity in cells in vitro, in ex vivo precision cut tissue, and in vivo. PMID- 28836214 TI - Visualizing In Vitro Type I Collagen Fibrillogenesis by Transmission Electron Microscopy. AB - Techniques and protocols for the in vitro formation of collagen type I fibrils and the extensive biochemical variation of the fibrillogenesis conditions are presented. In all cases, the incubation and fibrillogenesis product can be readily monitored by transmission electron microscopic study of negatively stained specimens. Representative TEM data is presented and discussed within the context of the products of the fibrillogenesis protocols, from which the extensive biochemical and structural possibilities of this integrated approach can be appreciated. PMID- 28836215 TI - Histological and Electron Microscope Staining for the Identification of Elastic Fiber Networks. AB - Elastic fibers are a major component of the extracellular matrix and are present in many tissues. Routine histology and standard electron microscopy procedures often do not allow for clear identification of elastic fibers making their organization and ultrastructure difficult to study. In this paper, we describe staining methods and procedures to enhance the contrast of elastin at both the light and electron microscope levels. PMID- 28836216 TI - Method for Picrosirius Red-Polarization Detection of Collagen Fibers in Tissue Sections. AB - The extracellular matrix is critical in guiding cell behavior in normal and pathologic tissues, particularly in cancers and fibrosis. Highlighting the organization (or disorganization) of a collagen-containing matrix can be very useful for understanding or grading pathophysiological conditions. The picrosirius red stain (also called "Sirius red" stain) is one of the best understood histochemical techniques able to selectively highlight collagen networks. Relatively inexpensive, the technique relies on the birefringent properties of collagen molecules. While the picrosirius red stain alone does not selectively bind collagen network, it becomes more specific than the other common collagen stains when combined with polarized light detection. This is why the selective histochemical procedure for collagen detection should be called the picrosirius-polarization method. In this chapter, we will provide essential explanation and detailed protocols and tips to allow collagen researchers not only to better understand how this staining technique works but also to easily apply this technique to their collagen-related research. PMID- 28836217 TI - Probing Collagen Organization: Practical Guide for Second-Harmonic Generation (SHG) Imaging. AB - Second-harmonic generation (SHG) microscopy is a powerful microscopy technique for imaging collagen and other biological molecules using a label-free approach. SHG microscopy offers the advantages of a nonlinear imaging modality together with those ones of a coherent technique. These features make SHG microscopy the ideal tool for imaging collagen at high resolution and for characterizing its organization at various hierarchical levels. Considering that collagen organization plays a crucial role in fibrosis and in its development, it would be beneficial for the researcher working in the field of fibrosis to have a manual listing crucial points to be considered when imaging collagen using SHG microscopy. This chapter provides an answer to this demand with state-of-the-art protocols, methods, and laboratory tips related to SHG microscopy. We also discuss advantages and limitations of the use of SHG for studying fibrosis. PMID- 28836218 TI - Methods for Quantifying Fibrillar Collagen Alignment. AB - Recent evidence has implicated collagen, particularly fibrillar collagen, in a number of diseases ranging from osteogenesis imperfecta and asthma to breast and ovarian cancer. A key property of collagen that has been correlated with disease has been the alignment of collagen fibers. Collagen can be visualized using a variety of imaging techniques including second-harmonic generation (SHG) microscopy, polarized light microscopy, and staining with dyes or antibodies. However, there exists a great need to easily and robustly quantify images from these modalities for individual fibers in specified regions of interest and with respect to relevant boundaries. Most currently available computational tools rely on calculation of pixel-wise orientation or global window-wise orientation that do not directly calculate or give visible fiber-wise information and do not provide relative orientation against boundaries. We describe and detail how to use a freely available, open-source MATLAB software framework that includes two separate but linked packages "CurveAlign" and "CT-FIRE" that can address this need by either directly extracting individual fibers using an improved fiber tracking algorithm or directly finding optimal representation of fiber edges using the curvelet transform. This curvelet-based framework allows the user to measure fiber alignment on a global, region of interest, and fiber basis. Additionally, users can measure fiber angle relative to manually or automatically segmented boundaries. This tool does not require prior experience of programming or image processing and can handle multiple files, enabling efficient quantification of collagen organization from biological datasets. PMID- 28836219 TI - Exploring the Nano-Surface of Collagenous and Other Fibrotic Tissues with AFM. AB - Atomic force microscope (AFM) is a powerful and invaluable tool for imaging and probing the mechanical properties of biological samples at the nanometric scale. The importance of nano-scale characterization and nanomechanics of soft biological tissues is becoming widely appreciated, and AFM offers unique advantages in this direction. In this chapter, we describe the procedure to collect data sets (imaging and mechanical properties measurement) of collagen gels and tumor tissues. We provide step-by-step instructions throughout the procedure, from sample preparation to cantilever calibration, data acquisition, analysis, and visualization, using two commercial AFM systems (PicoPlus and Cypher ES) and software that accompanied the AFM systems and/or are freeware available (WSxM, AtomicJ). Our protocols are written specifically for these two systems and the mentioned software; however, most of the general concepts can be readily translated to other AFM systems and software. PMID- 28836220 TI - Spectral Unmixing Methods and Tools for the Detection and Quantitation of Collagen and Other Macromolecules in Tissue Specimens. AB - Collagen and other components in the extracellular matrix are proving of increasing importance for the understanding of complex cell and tissue interactions in a variety of settings. Detection and quantitation of these components can still prove challenging, and a number of techniques have been developed. We focus here on methods in fluorescence-based assessments, including multiplexed immunodetection and the use of simpler histochemical stains, both complemented by linear unmixing techniques. Typically, differentiating these components requires the use of a set of optical filters to isolate each fluorescent compound from each other and from often bright background autofluorescence signals. However, standard fluorescent microscopes are usually only able to separate a limited number of components. If the emission spectra of the fluorophores are spectrally distinct, but overlapping, sophisticated spectral imaging or computational methods can be used to optimize separation and quantitation. This chapter describes spectral unmixing methodology and associated open-source software tools available to analyze multispectral as well as simple color (RGB) images. PMID- 28836221 TI - Simple Analysis of Deposited Gene Expression Datasets for the Non Bioinformatician: How to Use GEO for Fibrosis Research. AB - In the past decade, high-throughput techniques have facilitated the "-omics" research. Transcriptomic study, for instance, has advanced our understanding on the expression landscape of different human diseases and cellular mechanisms. The National Center for Biotechnology Center (NCBI) initialized Genetic Expression Omnibus (GEO) to promote the sharing of transcriptomic data to facilitate biomedical research. In this chapter, we will illustrate how to use GEO to search and analyze the public available transcriptomic data, and we will provide easy to follow protocol for researchers to data mine the powerful resources in GEO to retrieve relevant information that can be valuable for fibrosis research. PMID- 28836222 TI - The Implementation of Managed Entry Agreements in Central and Eastern Europe: Findings and Implications. AB - BACKGROUND: Managed entry agreements (MEAs) are a set of instruments to facilitate access to new medicines. This study surveyed the implementation of MEAs in Central and Eastern Europe (CEE) where limited comparative information is currently available. METHOD: We conducted a survey on the implementation of MEAs in CEE between January and March 2017. RESULTS: Sixteen countries participated in this study. Across five countries with available data on the number of different MEA instruments implemented, the most common MEAs implemented were confidential discounts (n = 495, 73%), followed by paybacks (n = 92, 14%), price-volume agreements (n = 37, 5%), free doses (n = 25, 4%), bundle and other agreements (n = 19, 3%), and payment by result (n = 10, >1%). Across seven countries with data on MEAs by therapeutic group, the highest number of brand names associated with one or more MEA instruments belonged to the Anatomical Therapeutic Chemical (ATC) L group, antineoplastic and immunomodulating agents (n = 201, 31%). The second most frequent therapeutic group for MEA implementation was ATC-A, alimentary tract and metabolism (n = 87, 13%), followed by medicines for neurological conditions (n = 83, 13%). CONCLUSIONS: Experience in implementing MEAs varied substantially across the region and there is considerable scope for greater transparency, sharing experiences and mutual learning. European citizens, authorities and industry should ask themselves whether, within publicly funded health systems, confidential discounts can still be tolerated, particularly when it is not clear which country and party they are really benefiting. Furthermore, if MEAs are to improve access, countries should establish clear objectives for their implementation and a monitoring framework to measure their performance, as well as the burden of implementation. PMID- 28836223 TI - Outcomes of Two-Step Revisional Bariatric Surgery: Reasons for the Gastric Banding Explantation Matter. AB - PURPOSE: The purpose of this study is to determine whether the reason for gastric band explantation would influence percentage excess weight loss (%EWL) following revisional Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). MATERIALS & METHODS: This is a retrospective cohort study, whose data are maintained in a prospective surgical database. The study period was from January 2012 to March 2017. Revisional surgeries were performed in a two-step manner, namely, first surgery LAGB explantation and second surgery (RYGB or SG). Two-way between-groups analysis of variance was used to examine effects of reason for band explantation (failed versus complication) and type of revisional surgery (RYGB versus SG) on %EWL at 10 months, 1 and 2 years. RESULTS: Cohort included 171 patients-146 women (85.4%) and 25 men, median age 51 years (range 22-76). Band-related complications accounted for 55% of explantations. Overall, 95 patients (56%) underwent a revisional RYGB, and 76 patients underwent a revisional SG. There was no difference in age or gender in terms of reason for band explantation or choice of revisional surgery. There was no difference in morbidity between the two groups (SG 2.6% versus RYGB 4.2%; p = .464). Patients undergoing revisional RYGB for failed weight loss had a significantly lower %EWL at 2 years compared to patients undergoing an SG for failed weight loss (p = .014) or an RYGB for band-related complications (p = .021). CONCLUSION: Patients undergoing revisional RYGB following band explantation for failed weight loss have a significantly lower %EWL at 2 years compared to patients undergoing an SG for failed weight loss or an RYGB for band-related complications. PMID- 28836224 TI - Frozen Section Evaluation of Margin Status in Primary Squamous Cell Carcinomas of the Head and Neck: A Correlation Study of Frozen Section and Final Diagnoses. AB - Frozen section is routinely used for intraoperative margin evaluation in carcinomas of the head and neck. We studied a series of frozen sections performed for margin status of head and neck tumors to determine diagnostic accuracy. All frozen sections for margin control of squamous carcinomas of the head and neck were studied from a 66 month period. Frozen and permanent section diagnoses were classified as negative or malignant. Correlation of diagnoses was performed to determine accuracy. One thousand seven hundred and ninety-six pairs of frozen section and corresponding permanent section diagnoses were obtained. Discordances were found in 55 (3.1%) pairs. In 35 pairs (1.9%), frozen section was reported as benign, but permanent sections disclosed carcinoma. In 21 cases, the discrepancy was due to sampling and in the remaining cases it was an interpretive error. In 20 cases (1.1%), frozen section was malignant, but the permanent section was interpreted as negative. Frozen section is an accurate method for evaluation of operative margins for head and neck carcinomas with concordance between frozen and permanent results of 97%. Most errors are false negative results with the majority of these being due to sampling issues. PMID- 28836225 TI - PET should not replace routine SPECT MPS for the assessment of patients with known or suspected CAD. PMID- 28836229 TI - How the mind shapes action: Offline contexts modulate involuntary episodic retrieval. AB - Involuntary retrieval of previous stimulus-response episodes is a centerpiece of many theories of priming, episodic binding, and action control. Typically it is assumed that by repeating a stimulus from trial n-1 to trial n, involuntary retrieval is triggered in a nearly automatic fashion, facilitating (or interfering with) the to-be-executed action. Here we argue that changes in the offline context weaken the involuntary retrieval of previous episodes (the offline context is defined to be the information presented before or after the focal stimulus). In four conditions differing in cue modality and target modality, retrieval was diminished if participants changed the target selection criterion (as indicated by a cue presented before the selection took place) while they still performed the same task. Thus, solely through changes in the offline context (cue or selection criterion), involuntary retrieval can be weakened in an effective way. PMID- 28836226 TI - The Ketone Body beta-Hydroxybutyrate Does Not Inhibit Synuclein Mediated Inflammasome Activation in Microglia. AB - Parkinson's disease (PD) is recognized as the most common neurodegenerative movement disorder and results in debilitating motor deficits. The accumulation and spread of neurotoxic synuclein aggregates in the form of Lewy bodies is a key pathological feature of PD. Chronic activation of the NLRP3 inflammasome by protein aggregates is emerging as a major pathogenic mechanism in progressive neurodegenerative disorders and is considered an important therapeutic target. Recently the ketone body, beta-hydroxy butyrate (BHB), was shown to efficiently inhibit the NLRP3 inflammasome in macrophages, and in vivo models of inflammatory disease. Furthermore, BHB can readily cross the blood brain barrier suggesting that it could have therapeutic benefits for the management of PD. In this study, we evaluated if BHB could inhibit chronic microglial inflammasome activation induced by pathological fibrillar synuclein aggregates. Interestingly, we found that BHB treatment almost completely blocked all aspects of inflammasome activation and pyroptosis induced by ATP and monosodium urate (MSU) crystals, consistent with previously published reports in macrophages. Surprisingly however, BHB did not inhibit inflammasome activation and release of IL-1beta or caspase-1 induced by synuclein fibrils. Our results demonstrate that BHB does not block the upstream pathways regulating inflammasome activation by synuclein fibrils and suggest that synuclein mediated inflammasome activation proceeds via distinct mechanisms compared to traditional NLRP3 activators such as ATP and MSU. PMID- 28836230 TI - Bounds for phylogenetic network space metrics. AB - Phylogenetic networks are a generalization of phylogenetic trees that allow for representation of reticulate evolution. Recently, a space of unrooted phylogenetic networks was introduced, where such a network is a connected graph in which every vertex has degree 1 or 3 and whose leaf-set is a fixed set X of taxa. This space, denoted [Formula: see text], is defined in terms of two operations on networks-the nearest neighbor interchange and triangle operations which can be used to transform any network with leaf set X into any other network with that leaf set. In particular, it gives rise to a metric d on [Formula: see text] which is given by the smallest number of operations required to transform one network in [Formula: see text] into another in [Formula: see text]. The metric generalizes the well-known NNI-metric on phylogenetic trees which has been intensively studied in the literature. In this paper, we derive a bound for the metric d as well as a related metric [Formula: see text] which arises when restricting d to the subset of [Formula: see text] consisting of all networks with [Formula: see text] vertices, [Formula: see text]. We also introduce two new metrics on networks-the SPR and TBR metrics-which generalize the metrics on phylogenetic trees with the same name and give bounds for these new metrics. We expect our results to eventually have applications to the development and understanding of network search algorithms. PMID- 28836231 TI - Reduction of foveal bulges and other anatomical changes in fellow eyes of patients with unilateral idiopathic macular hole without vitreomacular pathologic changes. AB - PURPOSE: To compare the foveal characteristics in fellow eyes (FE) of patients with unilateral idiopathic macular hole without vitreomacular pathologic changes with eyes of healthy controls. METHODS: Forty-seven FE and 52 eyes of 52 age- and sex-matched healthy controls were studied. Quantitative assessment of the dome shaped appearance of the hyperreflective lines that represent external limiting membrane (ELM_bulge) and inner outer segment junctions (IS/OS_bulge) were made by optical coherence tomography (OCT) images. Inner retinal complex thickness (IRCT) was quantitatively assessed at 1000 and 2000 MUm of the foveal center in nasal and temporal quadrants. Presence of alterations in the inner retinal outer layers and central foveal thickness (CFT) were also analyzed. RESULTS: Significantly lower ELM_bulge (p < 0.0001; Mann-Whitney test) and IS/OS_bulge (p < 0.001; student t test) and higher cases with COST alterations, expressed as a diffuse line (p < 0.006; Chi2 test) were found in FE than control eyes. IRCT were significantly reduced in FE at all the studied locations when comparing to control eyes (p < 0.05; student t test), maintaining anatomical proportionality among locations. CONCLUSION: FE without pathologic vitreomacular interactions seems to present some central cone alterations that may be related to other causes than vitreomacular traction. PMID- 28836232 TI - Diencephalic pediatric low-grade glioma harboring the BRAF V600E mutation presenting with various morphologies in sequential biopsy specimens. AB - A 5-year-old boy underwent biopsy of an intra-axial calcified tumor in the hypothalamus, which was incidentally found. Based on the presence of ganglion like cells combined with glial cell element, the pathological diagnosis was ganglioglioma. Because the tumor grew gradually in size over the next 2 years, he underwent chemotherapy with temozolomide. However, at 8 years of age, the boy developed hydrocephalus and the cystic lesion had re-grown. Endoscopic cyst fenestration and tumor biopsy was performed, and pathological diagnosis was tentatively oligodendroglioma based on the presence of tumor cells with a perinuclear halo. At 10 years of age, hydrocephalus recurred and the cystic lesion had re-grown. A second round of endoscopic cyst fenestration and tumor biopsy led to a pathological diagnosis of pilocytic astrocytoma due to a biphasic appearance with areas of dense tumor cells and microcystic areas, tumor cells with eosinophilic processes, and the presence of an eosinophilic granular body. Genetic analysis of the first biopsy successfully identified the BRAF V600E mutation. Because pathological diagnosis of diencephalic low-grade glioma harboring BRAF V600E would be sometimes difficult due to pathological variations, pathological diagnosis should be performed under the consideration of molecular diagnosis of BRAF V600E for optimal diagnosis and treatment. PMID- 28836233 TI - Regulatory effects on particulate pollution in the early hours of Chinese New Year, 2015. AB - Human activities are a key driver of air pollution, so it is hardly surprising that celebrations affect air quality. The use of fireworks contributes to high particulate concentrations in many parts of the world, with the Chinese Lunar New Year (spring festival) particularly noticeable, as firecrackers are traditionally used to drive off evil spirits. Fireworks lead to short-term peaks in the concentration of PM10, PM2.5 and SO2. Regulatory actions that restrict the use of fireworks have been evident in China since the 1990s. This paper investigates the particulate concentrations in nine Chinese cities (Beijing, Chengdu, Chongqing, Tianjin, Xi'an, Nanjing, Shanghai, Guangzhou and Shenzhen, along with Hong Kong (a Special Administrative Region) and Taipei and Kaohsiung (Taiwan) with a particular focus on the celebrations of 2015. Extremely high concentrations of particulate matter were observed, with some sites revealing peak PM10 concentrations in excess of 1000 MUg m-3 in the early hours of the New Year. In Beijing, Tianjin and Chongqing, the activities caused high particulate matter concentrations at most sites throughout the city. These peaks in particulate load in the early hours of Chinese New Year do not appear to be closely related to meteorological parameters. However, in cities where fireworks appear to be better regulated, there are fewer sharp pollution peaks just after midnight, although lowered air quality can still be found in the outer parts of some cities, remote from regulatory pressures. A few cities seem to have been effective at reducing the impact of the celebrations on air quality, with Nanjing a recent example. An increasing focus on light displays and electric lanterns also seems to offer a sense of celebration with much reduced impacts on air quality. PMID- 28836236 TI - Urinary incontinence in home care: a representative multicenter study on prevalence, severity, impact on quality of life, and risk factors. AB - OBJECTIVES: The objective of the study was to determine the prevalence and severity of urinary incontinence and associated factors in patients receiving home care nursing service. METHODS: From June to September 2015, a multicenter cross-sectional study was conducted in 923 patients from 102 home care services throughout Germany. The ICIQ-SF was used to determine the characteristics of UI and its impact on QoL. To determine the risks for UI, demographic and social risks, the Barthel Index and medical diagnoses were determined in descriptive and logistic regression analysis. RESULTS: The prevalence of UI was 62.5% (95% CI 59.3-65.6). The most common reasons for UI were before getting to the toilet 27.6% and when coughing or sneezing 27.3%. If the amount of leakage was medium (high), the mean of the impact on QoL was 4.9, SD 2.7 (5.0, SD 3.6). If the frequency of UI was higher than once a day (permanent), the mean of the impact on QoL was 4.2, SD 2.7 (4.8, SD 3.2). The results of the logistic regression analysis show the highest odds ratios for mobility-inability to walk (4.49), presence of dementia (2.59), and female sex (1.81). The metric variables age (1.02), Barthel Index (0.93), and BMI (1.05) were also statistically significant. CONCLUSIONS: The prevalence of UI in home care in Germany is high. Since UI is strongest associated with (im-) mobility, preserving or regaining patients' mobility should play a central role in providing care to avoid/minimize UI. PMID- 28836234 TI - Weight Management in Patients with Type 1 Diabetes and Obesity. AB - PURPOSE OF REVIEW: Patients with type 1 diabetes (T1D) are typically viewed as lean individuals. However, recent reports showed that their obesity rate surpassed that of the general population. Patients with T1D who show clinical signs of type 2 diabetes such as obesity and insulin resistance are considered to have "double diabetes." This review explains the mechanisms of weight gain in patients with T1D and how to manage it. RECENT FINDINGS: Weight management in T1D can be successfully achieved in real-world clinical practice. Nutrition therapy includes reducing energy intake and providing a structured nutrition plan that is lower in carbohydrates and glycemic index and higher in fiber and lean protein. The exercise plan should include combination stretching as well as aerobic and resistance exercises to maintain muscle mass. Dynamic adjustment of insulin doses is necessary during weight management. Addition of anti-obesity medications may be considered. If medical weight reduction is not achieved, bariatric surgery may also be considered. PMID- 28836235 TI - Biophysical approaches in the study of biomembrane solubilization: quantitative assessment and the role of lateral inhomogeneity. AB - Detergents are amphiphilic molecules widely used to solubilize biological membranes and/or extract their components. Nevertheless, because of the complex composition of biomembranes, their solubilization by detergents has not been systematically studied. In this review, we address the solubilization of erythrocytes, which provide a relatively simple, robust and easy to handle biomembrane, and of biomimetic models, to stress the role of the lipid composition on the solubilization process. First, results of a systematic study on the solubilization of human erythrocyte membranes by different series of non ionic (Triton, CxEy, Brij, Renex, Tween), anionic (bile salts) and zwitterionic (ASB, CHAPS) detergents are shown. Such quantitative approach allowed us to propose Resat-the effective detergent/lipid molar ratio in the membrane for the onset of hemolysis as a new parameter to classify the solubilization efficiency of detergents. Second, detergent-resistant membranes (DRMs) obtained as a result of the partial solubilization of erythrocytes by TX-100, C12E8 and Brij detergents are examined. DRMs were characterized by their cholesterol, sphingolipid and specific proteins content, as well as lipid packing. Finally, lipid bilayers of tuned lipid composition forming liposomes were used to investigate the solubilization process of membranes of different compositions/phases induced by Triton X-100. Optical microscopy of giant unilamellar vesicles revealed that pure phospholipid membranes are fully solubilized, whereas the presence of cholesterol renders the mixture partially or even fully insoluble, depending on the composition. Additionally, Triton X-100 induced phase separation in raft-like mixtures, and selective solubilization of the fluid phase only. PMID- 28836237 TI - Synthesis of Geraniol Esters in a Continuous-Flow Packed-Bed Reactor of Immobilized Lipase: Optimization of Process Parameters and Kinetic Modeling. AB - With increasing demand for perfumes, flavors, beverages, and pharmaceuticals, the various associated industries are resorting to different approaches to enhance yields of desired compounds. The use of fixed-bed biocatalytic reactors in some of the processes for making fine chemicals will be of great value because the reaction times could be reduced substantially as well as high conversion and yields obtained. In the current study, a continuous-flow packed-bed reactor of immobilized Candida antarctica lipase B (Novozym 435) was employed for synthesis of various geraniol esters. Optimization of process parameters such as biocatalyst screening, effect of solvent, mole ratio, temperature and acyl donors was studied in a continuous-flow packed-bed reactor. Maximum conversion of ~ 87% of geranyl propionate was achieved in 15 min residence time at 70 degrees C using geraniol and propionic acid with a 1:1 mol ratio. Novozym 435 was found to be the most active and stable biocatalyst among all tested. Ternary complex mechanism with propionic acid inhibition was found to fit the data. PMID- 28836239 TI - [Reconsideration of hot topics on laparoscopic radical gastrectomy]. AB - Laparoscopic radical gastrectomy(LRG) has been popularized with the development of laparoscopic surgical techniques. As a result of the requirement of surgical skill of LRG, the evidence is always highly demanded. The surgical safety and radical resection of tumor is one of the most important principles. Based on published studies and authors' own experience, this article discusses the following topics on laparoscopic gastrectomy: (1)Indications of surgery: Laparoscopic gastrectomy for early gastric cancer is accepted all over the world. For locally advanced gastric cancer, laparoscopic gastrectomy with D2 dissection is considered to be safe and feasible based on domestic studies, especially the CLASS research. (2)Positions and approaches: Classic approaches of laparoscopic gastrectomy include left-side approach, right-side approach, anterior approach and posterior approach. Left-side position is the first choice in China, which is suitable for most laparoscopic gastrectomy. Meanwhile, right-side position is most recommended in Japan and Korea. The selection of approach could be varied by the feature of the tumor, the anatomy of the tumor and the habit of surgeons. (3) Lymphadenectomy of the superior area of pancreas: Based on Japanese Classification of Gastric Carcinoma (14th edition), Chinese Expert Consensus on Quality Control of Laparoscopic Radical Gastrectomy for Gastric Cancer (2017 edition) and authors' own experience, we define the lymph node dissection margin of the superior area of pancreas in laparoscopic distal gastrectomy with D2 dissection as follows: right side is the left wall of portal vein; left side is the posterior gastric artery; upper side is the commissure of diaphragmatic crura; lower side is the anterosuperior side of common hepatic artery and splenic artery; posterior side (on the right side of coeliac trunk) is the plane composed of portal vein, common hepatic artery and the root of coeliac trunk; posterior side (on the left side of coeliac trunk) is the Gerota's fascia. (4) Bursectomy or not: Bursectomy is not recommended as standard procedure in cT3 or cT4a gastric cancer based on the results of JCOG1001. However, to achieve a better surgical plane, dissection of anterior lobe of transverse mesocolon and pancreatic capsule in some area is accepted. (5) Totally laparoscopic reconstruction of digestive tract: along with the development of equipment and modification of anastomosis, the totally laparoscopic reconstruction of digestive tract becomes more and more welcome in laparoscopic gastrectomy as it provides a better and larger surgical scene compared to small incision assisted surgery. The whole procedure of anastomosis is overlooked by laparoscopy, without any over traction of tissue. PMID- 28836240 TI - [Recognition of specialization of minimally invasive treatment for gastric cancer in the era of precision medicine]. AB - With the introduction and promotion of "precision medicine" conception, the history of disease occurrence, progression and prognosis has been deeply investigated with more accuracy, and the surgical treatment concept has become more precise and minimally invasive. With the rapid development of minimally invasive technique, laparoscopic gastrectomy has become an important part for treatment of gastric cancer. A number of randomized controlled clinical trials, such as KLASS-01 and CLASS-01, have demonstrated that laparoscopic gastrectomy is safe and feasible for treatment of early and locally advanced gastric cancer, respectively. Endoscopic treatment would also be considered with strict indications. The surgical safety is identical between standard laparoscopy surgery and open surgery for local advanced gastric cancer. Radical cure, organ function preservation and reduced surgical trauma are the basic rules for minimally invasive treatment for gastric cancer. Specialized treatment mode, which consists of precise evaluation of tumor location, gastrectomy and lymph node resection, reduced surgical trauma and control of postsurgical complications, is the premise for implementation of minimally invasive surgery. Accurate preoperative staging, strict indication of operation, accurate quality control and postoperative management are important warrants for the effect of minimally invasive treatment in patients with gastric cancer. With standard diagnosis and treatment procedures, the specialized treatment mode for gastric cancer combined with standard surgical resection is an important force to promote the development of minimally invasive surgery. And what should we do to train and promote gastric cancer treatment in primary medical care centers is an urgent problem. With the development of equipment, minimally invasive treatment will be more professional, more precise, safer and less invasive. In the era of precision medicine, with deeper exploring the pathogenesis of gastric cancer, promoting the development of specialized treatment mode and strengthened surgical team training could meet the demand for minimally invasive treatment of gastric cancer. Therefore, specialized minimally invasive treatment is the trend of minimally invasive treatment for gastric cancer in the new era. PMID- 28836238 TI - Protective Effects of Autologous Bone Marrow Mononuclear Cells After Administering t-PA in an Embolic Stroke Model. AB - Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke but poses risk for hemorrhagic transformation (HT). Cell therapy has been investigated as a potential therapy to improve recovery after stroke by the modulation of inflammatory responses and the improvement of blood-brain barrier (BBB) integrity, both of which are associated with HT after t-PA. In our present study, we studied the effect of autologous bone marrow mononuclear cells (MNCs) in an embolic stroke model. We administered MNCs in a rat embolic stroke 2 h after administering t-PA. We observed that even though autologous MNCs did not alter the incidence of HT, they decreased the severity of HT and reduced BBB permeability. One possible mechanism could be through the inhibition of MMP3 released by astrocytes via JAK/STAT pathway as shown by our in vitro cell interaction studies. PMID- 28836241 TI - [Standardized development of transanal endoscopic microsurgery]. AB - Transanal endoscopic microsurgery (TEM) is currently the only one-port system in endoscopic surgery, which a direct endoluminal approach can lead to the target organ through a natural opening of human body. TEM has been applied in colorectal surgery for over 3 decades. Compared with radical surgery, TEM has the advantages, such as quicker recovery, shorter hospital stay and fewer complications. One perfect TEM surgical system, which mainly consists of three parts, namely peculiar rectoscope for surgery, special surgical instruments and imaging system, is the foundation of standardized development of TEM. Accurate preoperative evaluation and staging is the key for good outcomes in TEM technology. In addition to digital examination of rectum, rigid sigmoidoscopy(or rectoscopy) should be routinely performed to confirm the location of the lesion and record it in a "time-in-clock" form. For lesions with undetermined nature, biopsy should be performed. For patients with rectal tumor, pelvic MRI examination can be used on the basis of routine endorectal ultrasonography (ERUS). Endoluminal suture is the challenge for standardized development of TEM, especially for those with large intestinal wall defects. Professional training is required to master suture technique. In 2016, the consensus of experts on TEM technology was formulated by TEM Study Group of Colorectal Cancer Specialty Committee of Chinese Anticancer Association. The recommended surgical indications for TEM include (1)rectal adenoma; (2)early rectal cancer with good histopathological features; (3)extended resection of locally malignant polyps by colonoscopy; (4)other rectal tumors suitable for local resection; (5)benign stricture or anastomotic stricture of the rectum; (6)repair of anastomotic leakage after low anterior resection of rectum; (7)diagnosis of rectal hemorrhage; (8)biopsy of rectum and surrounding lesions; (9)repair of rectovaginal fistula or mucosal flap transposition of the internal mouth of anal fistula; (10)treatment of rectal foreign body. With the maturity of TEM technology, the indication of TEM continues to expand. Nowadays, TEM is applicable to rectal neuroendocrine tumor or gastrointestinal stromal tumor resection, as well as rectovaginal fistula repair. It can even serve as a "bottom up" operation platform for transanal total mesorectal excision (taTME). This article introduces the standardization of TEM, its current indications, novel implications, and future perspectives, expecting that TEM will be further popularized and healthily developed in China. PMID- 28836242 TI - [Discussion on standardized implementation of laparoscopic radical lymphadenectomy for distal gastric cancer]. AB - Laparoscopic radical gastrectomy for gastric cancer has been widely applied in clinical practice, and its indications have been extended from early gastric cancer to advanced gastric cancer. It is acknowledged that laparoscopic radical gastrectomy is technically challenging because of the complexity of anatomy, rich blood supply, and extensive lymph node dissection. This paper primarily intends to share the experience of laparoscopic radical D2 gastrectomy for distal gastric cancer with details of choosing the location of Trocar, surgical approaches and the sequence of lymph node dissection. All the surgeries were performed at Department of General Surgery and Gastrointestinal Surgery, Guangdong General Hospital. The finding suggests that a correct laparoscopic Trocar placement is the foundation of adequate surgical field visualization. Under most circumstances, the observation hole should be around 2 cm below the umbilicus and the operating hole should be close to the bilateral clavicle midline. Furthermore, proper surgical approach and sequence of lymph node dissection are the prerequisites for successful laparoscopic radical D2 gastrectomy, as well as the reassurance of dissecting lymph node safely and comprehensively. The position of surgical team adopted in our center is that the surgeon stands to the left of the patient, with laparoscope operator stands in between patient's legs while the first assistant positions himself opposite the surgeon on the right side of the patient. This position correlates to the rules of sequential lymph node dissection, which is "from left to right", "from proximal to distal" and "from inferior to superior". Therefore, it is conductive to inferior and superior pylorus region dissection and it can effectively prevent subsidiary-injury. In our center, the procedure of lymph node dissection has been standardized: the initial step is to undergo station 4sb dissection and greater gastric curvature clearance; then change the patient's position to clean the sub-pyloric lymph node region and cut off the duodenum by linear stapler; followed by the clearance of inferior region of the pylorus and the upper margin of the pancreas; in the final step, the first and the third groups of lymph node dissection is performed. Although varied surgical approaches and sequences of lymph node dissection are applied in different hospitals, the techniques required for laparoscopic D2 radical gastrectomy for gastric cancer are sophisticated and advanced in general. Radical lymph node dissection is complicated, urging surgeons to familiarize themselves with the anatomy of gastric peripheral vascular system and characteristics of lymph node drainage. By designing and implementing effective strategies, such as formulating a regular team, positioning surgical team reasonably, changing a patient's posture during operation, choosing an appropriate surgical approach and following a logically sequence of lymph node dissection, surgeons can standardize the complete surgical procedure, which ultimately reduces bleeding during surgery and shortens the operative time. PMID- 28836243 TI - [How to standardize transanal total mesorectum excision]. AB - Transanal total mesorectum excision (taTME) is a novel approach to treat rectal cancer by colorectal surgeons. How to standardize taTME is important for colorectal surgeons, especially at their initial attempt. They can start this approach cautiously only after they master skilled laparoscopic technique and pelvic anatomy, get the knowledge of taTME clearly, and are approved by healthcare department. The female patients with age <70 years old, distance of 5 to 7 cm from tumor inferior margin to anal verge, tumor size <3 cm, cTNM stage 2 cm; (2) macroscopically intramucosal differentiated carcinomas (pT1a) with ulcer and with diameter <=2 cm; (3) macroscopically intramucosal undifferentiated carcinomas (pT1a) without ulcer and with diameter <=2 cm. Methods of preoperative evaluation include endoscopy, CT, and endoscopic ultrasonography (EUS). For tumor size greater than 3 cm and undifferentiated lesions, evaluation should be carried out carefully in order to avoid the underestimation of T staging. During endoscopic surgery, the extent, nature, and depth of the lesion should be clearly defined again, if necessary, assisted by staining endoscopy. In order to avoid complications such as bleeding and perforation, stanch bleeding and aspiration of gas should be performed promptly during the operation. After endoscopic resection, when pathology reveals positive margin of resected specimen, lesions invading deep submucosa, vascular involvement or peri-gastric lymph node metastasis, additional surgery should be recommended. Even if the patients have been evaluated as radical treatment, close follow-up is still necessary. Only when surgeons strictly obey the indications of endoscopic treatment, make the accurate evaluations for the patients before operation, undergo endoscopic operation carefully, and perform the follow up closely, the patients can be benefit from endoscopic therapy really. PMID- 28836245 TI - [Use of gastric tube in construction technique thoracoscopic and laparoscopic Ivor-Lewis esophagectomy]. AB - OBJECTIVE: To discuss the safety and feasibility of gastric tube in construction technique in total thoracoscopic and laparoscopic Ivor-Lewis esophagectomy. METHODS: Clinical data of 358 patients with esophageal cancer who underwent the Ivor-Lewis procedure by the same surgical team in our department from June 2015 to June 2016 were retrospectively analyzed. Patients were divided into two groups: group MI (mini-incision): 92 patients undergoing extracorporeally gastric tube through a 4-cm abdominal mini-incision after gastric mobilization; group TL (total laparoscopy): 266 patients undergoing gastric tube made by total laparoscopy and jejunostomy. Intra-operative and postoperative data were compared between two groups. RESULTS: Of 358 patients, 290 were male and 68 were female. The average age was (62.3+/-15.6) years. The tumor location ratio of group TL and group MI was 27.1%(72/266) and 25.0%(23/92) in middle thoracic esophageal cancer, 35.3%(94/266) and 34.8%(32/92) in mid-lower thoracic esophageal cancer, and 37.6%(100/266) and 40.2%(37/92) in lower thoracic esophageal cancer, respectively. In group TL and group MI, 42.1% (112/266) and 46.7%(43/92) patients were stage I( to II(a; 57.9%(154/266) and 53.3%(49/92) patients were stage II(b to III(a, respectively. All the patients from two groups received successful Ivor Lewis esophagectomy. There were no significant differences between group TL and MI in operative time [abdominal operative time: (65.6+/-25.8) min vs. (62.3+/ 25.6) min; thoracic operative time: (180.3+/-37.4) min vs. (178.1+/-39.2) min; time of making gastric tube:(16.1+/-3.2) min vs.(15.7+/-3.5) min], blood loss [abdominal: (60.5+/-19.8) ml vs. (62.3+/-20.9) ml; thoracic: (228.7+/-47.3) ml vs. (231.6+/-46.8) ml], and the number of lymph nodes dissection (abdominal: 8.9+/-1.8 vs. 8.7+/-1.6; mediastinal: 21.2+/-3.6 vs. 20.8+/-3.8)(all P>0.05). And there were no significant differences in occurrence of postoperative anastomotic leakage [4.5%(12/266) vs. 4.3%(4/92), chi2=0.845, P=0.948], postoperative hospital stay [(12.2+/-4.8) d vs. (13.1+/-5.1) d, t=1.525, P=0.128] and average hospitalization cost(5.5+/-2.1 vs. 5.3+/-1.2, t=0.865, P=0.172) (ten thousand yuan, RMB) between group TL and MI. CONCLUSION: During minimally invasive Ivor Lewis esophagectomy, gastric tube by total laparoscopy is safe and reliable. PMID- 28836246 TI - [Clinical experience of combined laparoscopic-endoscopic Heller myotomy and modified Dor fundoplication for cardiochalasia]. AB - OBJECTIVE: To investigate the efficacy of combined laparoscopic-endoscopic lower esophageal sphincterotomy and modified Dor fundoplication for cardiochalasia patients. METHODS: Clinical data of 11 cardiochalasia patients who underwent combined laparoscopic-endoscopic lower esophageal sphincterotomy and modified Dor fundoplication by the same medical team from January 2015 to December 2016 at The Second Hospital of Jilin University were retrospectively analyzed. The procedure was as follows: an incision was made in the anterior wall of esophagus and dissection of esophageal muscular layer was performed, then the bulged esophageal mucosa was covered by the fundus after 180 degrees fold to the right (fundoplication), finally the gastric fundus was joined to the right diaphragmatic foot by 3 to 5 knotted suture. The efficacy was judged by the Eckardt scoring standard: the postoperative Eckardt score <=3 points indicated effectiveness, otherwise the treatment was invalid. RESULTS: Combined laparoscopic-endoscopic lower esophageal sphincterotomy and modified Dor fundoplication was completed successfully in all the 11 patients without any subsequent laparotomy and death. The mean operative time was 85 (78 to 137) min, blood loss was 15 (5 to 35) ml, and no upper digestive tract perforation occurred. The mean postoperative hospital stay was 7.0(6 to 9) d. After the operation, the pressure of lower esophageal sphincter decreased significantly compared to that before operation [(5.31+/-6.23) mmHg vs. (35.72+/-17.13) mmHg, P<0.05], and the Eckardt score decreased significantly as well (0.53+/-0.56 vs. 6.17+/-1.17, P<0.05). During the follow-up of 2 to 23 months, there was no postoperative mortality. One case experienced mild gastroesophageal reflux 6 months after operation, and another patient had recurrent dysphagia 17 months after operation, who both were improved after receiving proton pump inhibitors or gastric dynamic drugs, and balloon dilation. CONCLUSION: Combined laparoscopic endoscopic lower esophageal sphincterotomy and modified Dor fundoplication is an effective and safe surgical procedure for cardiochalasia with minimal invasion and fast recovery. PMID- 28836247 TI - [Application and effect evaluation of an self-made device to fix liver in laparoscopic radical gastrectomy]. AB - OBJECTIVE: To introduce the application and clinical effect of self-made liver fixing device in laparoscopic radical gastrectomy. METHODS: Clinical data of 469 patients underwent laparoscopic radical gastrectomy in Nanfang Hospital, Southern Medical University from March 2014 to January 2017 were analyzed retrospectively. In laparoscopic radical gastrectomy, self-made liver fixing device was used to expose surgical field covered by hepatic lobe in gastric lesser curvature and hepatic flexure of colon. Manufacture of the self-made liver fixing device: appropriate length of the catheter was cut according to the size of liver; the lotus suture needle with a thread was put through two catheters to connect them. Then the prepared liver fixing device was sent into abdominal cavity through a 12 mm Trocar hole with needle holder and was fixed on the free hepatic lateral hepatogastric ligament with hemo-lock. Finally the application effect of the liver fixing device was evaluated by reviewing the surgical videos. RESULTS: A mean time of 40.3 seconds was required to complete liver fixing by using the self made liver fixing device in laparoscopic radical gastrectomy and liver did not slip down in all the cases. Liver secondary manual fixing by assistants was 2 times averagely. Three cases had mild liver injury. CONCLUSION: The self-made liver fixing device in laparoscopic radical gastrectomy is easy to operate and can effectively expose sufficient surgical field, with high security and convenient materials. PMID- 28836248 TI - [Criminal fold priority separating reduces splenic injury in laparoscopic radical gastrectomy]. AB - OBJECTIVE: To explore the value of criminal fold priority separating (CFPS) in reduction of iatrogenic splenic injury in laparoscopic radical gastrectomy. METHODS: Complete videos of 270 patients undergoing laparoscopic radical gastrectomy in Guangdong Provincial Hospital of Chinese Medicine were reviewed. Anatomic features of criminal fold (CF) were summarized. The relationship between CFPS and iatrogenic splenic injury was examined. CF was defined as the ligament between omentum and spleen. CFPS was defined as that CF was separated before the left half gastrocolic omentum was dissected. Splenic injury was further compared between CFPS group and non-CFPS group. RESULTS: CF occurred in 81.5% cases (220/270), presenting one bunch or multiple bunches. CF appeared most commonly in the lower pole of spleen (76.7%, 207/270), then in middle spleen (14.1%, 38/270) and upper pole (9.6%, 26/270). CFPS was performed in 20% cases (54/270) and 80% cases (216/270) were non-CFPS. The incidence of iatrogenic splenic injury was 11.1% (30/270), and this incidence of CFPS group was lower as compared to non CFPS group (3.7%, 2/54 vs. 13.0%, 28/216), but the difference was not significant (P=0.07). Of 30 patients with splenic injury, 24(80%) were due to traction of CF and all were in non-CFPS group. Instrument injury occurred in 20% cases(6/30) and 2 were in CFPS group and 4 were in non-CFPS group. Most iatrogenic splenic injuries were successfully handled with electrocoagulation, adhesive and compression, except 2 patients underwent open splenectomy for serious splenic injury in non-CFPS group. CONCLUSION: In laparoscopic surgery for gastric cancer, iatrogenic splenic injury mostly results from improper traction of CF and CFPS can reduce the incidence of iatrogenic splenic injury. PMID- 28836249 TI - [Comparison of intra-abdominal infection between intracorporeal anastomosis and extracorporeal anastomosis in patients undergoing laparoscopic right hemicolectomy]. AB - OBJECTIVE: To compare the difference of intra-abdominal infection between intracorporeal anastomosis (IA) and extracorporeal anastomosis (EA) in patients undergoing laparoscopic right hemicolectomy within postoperative 30 days. METHODS: Clinical date of right colon cancer patients undergoing laparoscopic right hemicolectomy at the Department of Colorectal Surgery, PUMCH from January 1st, 2013 to October 31st, 2016 were retrospectively analyzed. Patients with stage IV cancers which could not be radically resected, emergency operation and conversion to open surgery were excluded. The intracorporeal anastomosis and extracorporeal anastomosis were compared in the items of operation time, postoperative infection and postoperative hospital stay. RESULTS: A total of 194 patients were enrolled in the study, including 73 patients with IA and 121 patients with EA. No significant differences were found in gender, age, previous operation history, tumor site and T stage of the tumor between two groups (all P>0.05). There were also no significant differences in mean operative time (162.4 minutes vs. 167.7 minutes, P=0.257), time to first flatus (3.3 days vs. 3.4 days, P=0.744), number of harvested lymph nodes (30.3 nodes vs. 33.8 nodes, P=0.071) and postoperative hospital stay (7 days vs. 7 days, P=0.067) between two groups. The incidence of intra-abdominal infection in patients with IA was significantly higher than that in those with EA [13.7%(10/73) vs. 1.7%(2/121), P=0.001], while the differences of the incidence of wound infection [1.4%(1/73) vs. 3.3%(4/121), P=0.652], respiratory infection [1.4%(1/73) vs. 3.3%(4/121), P=0.652] and urinary tract infection [2.7%(2/73) vs. 0.8%(1/121), P=0.558] were not significant. CONCLUSION: Compared with EA, IA may increase the risk of intra-abdominal infection in patients undergoing laparoscopic right hemicolectomy. PMID- 28836250 TI - [Clinical efficacy of superior mesenteric artery-oriented laparoscopic complete mesocolic excision in the treatment of right colonic cancer]. AB - OBJECTIVE: To investigate the clinical efficacy of superior mesenteric artery (SMA)-oriented laparoscopic complete mesocolic excision (CME) with a medial-to lateral approach in the treatment of right colonic cancer. METHODS: A total of 166 patients with right colonic cancer who were admitted to The First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2016 underwent SMA-oriented laparoscopic CME by the same surgical team. Clinical data of these patients were retrospectively analyzed. RESULTS: All the 166 cases were enrolled in this study, including 96 male and 70 female patients. Right colon adenocarcinoma was diagnosed by preoperative colonoscopy, enhanced computerized tomography(CT) and pathological examination, and the tumor was resectable. There were no emergency surgery patients for bowel obstruction or perforation, no patients with multiple primary cancers, and no stage IIII( patients with liver or lung metastasis. All the patients underwent SMA-oriented laparoscopic CME successfully, without conversion to laparotomy. No ureteral injury, duodenal injury, and superior mesenteric vein injury occurred during the operation. R0 resections were performed in all the cases. The average operation time was (102.4+/-28.3) min, blood loss was (67.2+/-26.3) ml, number of lymph nodes retrieved was 20.5+/-7.6, postoperative anal exhaust time was (2.1+/-1.1) d, postoperative hospital stay was (7.9+/-1.4) d. There was no perioperative death or anastomotic leakage. Two patients with small bowel obstruction were readmitted within 30 days after operation. The postoperative complications occurred in 15.1%(25/166) of the patients, including wound infection (2 cases), chylous fistula (20 cases), anastomotic bleeding (1 case), small bowel obstruction (2 cases). A total of 161 patients (97.0%) were followed up for 1 to 24 months, and 10 patients had distant metastasis during the follow-up period. The 2-year overall survival (OS) rate was 96.4%. CONCLUSION: Superior mesenteric artery oriented laparoscopic complete mesocolic excision with a medial-to-lateral approach for right colonic cancer has good short-term efficacy. PMID- 28836251 TI - [Robotic-assisted transanal total mesorectal excision for lower rectal cancer]. AB - OBJECTIVE: To explore the availability of Da Vinci robotic-assisted transanal total mesorectal excision(taTME) for lower rectal cancer, which have been regarded as challenging situations in rectal cancer surgery. METHODS: The medical records of a patient who underwent robotic-assisted transanal total mesorectal excision, coloanal anastomosis and ileostomy for lower rectal cancer on May 31st 2017 were reported. RESULTS: The case was a sixty-three year-old male patient with a body mass index of 19.1 kg/m2. Preoperative examinations showed the tumor size was 4 cm*4 cm*3 cm. With a distance from the anal verge of 4 cm.The tumor was moderately differentiated and staged as cT3N2M0.taTME was performed successfully and the patient recovered quickly without any complications. The histological report showed a complete mesorectal excision with freee distal and circumferential margins. CONCLUSION: Robotic-assisted taTME is available. Robotics may help to overcome technical difficulties. PMID- 28836252 TI - [Comparison of oncology outcomes and anal function among laparoscopic partial, subtotal and total intersphincteric resection for low rectal cancers]. AB - OBJECTIVE: To compare the oncology outcomes and anal function among laparoscopic partial, subtotal and total intersphincteric resection(ISR) for low rectal cancers. METHODS: From June 2011 to February 2016, a total of 79 consecutive patients with low rectal cancers underwent laparoscopic ISR with hand-sewn coloanal anastomosis at our department. According to the distal tumor margin, partial ISR (internal sphincter resection at the dentate line) was used to treat tumors with distance <1 cm from the anal sphincter (n=28), subtotal ISR was adopted for the tumors locating between the dentate line and intersphincteric groove (n=34), and total ISR (resection at the dentate line) was applied in the treatment of intra-anal tumors (n=17). Anal function was evaluated by a standardized gastrointestinal questionnaire, Wexner incontinence score and Kirwan's classification. Metaphase oncological results and postoperative anal function were compared among three groups, and. RESULTS: Other than the distance of tumor low margin to dentate line (P=0.000) and serum CEA level (P=0.040), no significant differences were noted in baseline data among 3 groups (all P>0.05). The median follow up was 21(8-61) months. The 3-year disease-free survival rates in laparoscopic partial, subtotal and total ISR groups were 91.1%, 88.9%, 88.2% (P=0.901) and the 3-year local relapse-free survival rates were 91.1%, 72.9%, 80.2%(P=0.658), whose all differences were not significant. Thirty-eight patients who did not receive neoadjuvant chemoradiotherapy and underwent ileostomy closure for at least 24 months completed the evaluation of anal function, including 14 cases in partial group, 15 cases in subtotal group and 9 cases in total group. Of 38 patients, 73.7%(28/38) was classified as good function (Wexner incontinence score <=10) and no patient adopted a colostomy because of severe fecal incontinence(Kirwan classification=grade 5). Furthermore, there were no significant differences in Wexner incontinence score and Kirwan classification among 3 groups (all P>0.05). However, patients with chronic anastomotic stoma stenosis showed worse anal function than those without stenosis [Wexner incontinence score: 18(9-20) vs 6(0-18), P=0.000; Kirwan grading: 3(2-4) vs. 2(1 4), P=0.002]. CONCLUSIONS: As the ultimate sphincter-saving technique, laparoscopic ISR can result in better oncologic outcomes and better anal function for patients with low rectal cancers. The different procedures of ISR may not affect the efficacy, but chronic anastomotic stoma stenosis deteriorates incontinence status. PMID- 28836253 TI - [Effect of nano carbon tattooing on the lesion localization in the early colon cancer for additional surgical procedure after endoscopic resection]. AB - OBJECTIVE: To explore the effect of nano carbon tattooing on the lesion localization in the early colon cancer for additional surgical procedure after endoscopic resection. METHODS: Thirty-five patients with early colon cancer accepted additional surgical procedures after endoscopic resection in Fuzhou General Hospital of PLA from May 2014 to November 2016. All the patients underwent nano carbon tattooing before the end of endoscopic resection: 0.1 ml carbon nanoparticles suspension was respectively injected into the normal intestinal submucosa from 1 cm outside the 4 sites (upper, lower, left and right) of the lesion border by colonoscopy, marking the original lesion location and guiding the subsequent additional surgery. Data of these 35 cases were summarized. RESULTS: All the 35 cases, including 22 males and 13 females, with a mean age of 46.5 years(range 35-70), completed the endoscopic disposable carbon nano marking, and the mean operative time was 7.5 minutes(range 5-10). No bleeding, no perforation and no adverse reaction occurred. Four to 21(10+/-3.5) days after endoscopic resection, the patients received the additional surgery as a result of pathological specimens of endoscopic resection in 10 cases of vascular invasion, 7 cases of severe submucosal infiltration, 7 cases of more than grade G2 in tumor budding, 6 cases of poorly differentiated adenocarcinoma and undifferentiated carcinoma, and 5 cases of positive margin. All the patients underwent laparoscopic surgery. The mean time of intraoperative detection and lesion location was 3.0 minutes(range 1-5). All tattooings were clearly visible under the naked eye. The colon wedge resection were performed in 5 cases, colon segment resection in 14 cases, and radical resection of colon cancer in 16 cases. The operative time was 45 to 180(120+/-30) min, and the blood loss was 50 ~ 200(50+/-15) ml. There was no intraoperative complications. The first gas passage time was 12 to 48(24+/-8) h. The postoperative hospital stay was 10 to 3(6.5+/ 2.5) d. There was no postoperative complication and no perioperative mortality. CONCLUSION: Nano carbon tattooing is helpful for the accurate location of primary lesions in the additional surgical operation after endoscopic resection of early colon cancer, and it can improve the safety and precision of surgical procedures, especially for laparoscopic surgery. PMID- 28836254 TI - [Usefulness of self-made gasbag double-cannula stool drainage device for prevention of anastomotic leakage following anterior resection]. AB - OBJECTIVE: To evaluate the efficacy of self-made gasbag double-cannula stool drainage device for prevention of anastomotic leakage following anterior resection. METHODS: Clinical data of 169 rectal cancer patients in the 8th Affiliated Hospital of Sun Yat-sen University between October 2010 and October 2016 were retrospectively analyzed. Among them, a self-made gasbag double-cannula stool drainage device was placed in 71 patients(stool drainage group), and the remaining 98 patients were taken as control. After an anastomosis, the drainage device was transanally placed by the assistant and the distal tube of drainage device was stretched more than 15 cm from anastomosis. The gasbag was inflated to fully expand the intestine. The main tube was fixed on perianal skin with 7-0 suture, kept more than 3-5 cm outside the anus, and connected to the drainage bag. The incidence of anastomotic leakage was compared between the two groups. RESULTS: The baseline data were similar between the two groups (all P>0.05). The differences in operative time, intraoperative blood loss, and time to bowel function recovery were not statistically significant (all P>0.05), however, time to oral intake and postoperative stay were shorter in stool drainage group as compared to the control group (both P<0.05). There was no perioperative death in both groups. In stool drainage group, there were 6 cases whose drainage device was pulled out within 48 hours due to intolerance. The ruptured gasbag was replaced 5 times and the tube was clogged by fecal material 21 times. After flushing, the tube did not recanalized and was pulled out in 3 cases. The incidence of anastomotic leakage in stool drainage group was significantly lower than that in the control group (2.8% vs. 11.2%, P=0.043). As for the low anastomosis (the distance to anal verge less than 5 cm), the incidence of anastomotic leakage in stool drainage group was also significantly lower than that in the control group (2.3% vs. 15.4%, P=0.028), while as for the high anastomosis, the difference was not statistically significant (3.6% vs. 3.0%, P=0.906). Logistic regression analysis revealed that the presence of a stool drainage device was an independent protective factor for anastomotic leakage (OR=0.316, 95%CI:0.114 ~ 0.769, P=0.003). CONCLUSIONS: The self-made gasbag double-cannula stool drainage device effectively prevents anastomotic leakage after anterior resection of rectal cancer. However it is not suitable for those patients with high anastomosis. PMID- 28836255 TI - [Application research of presacral space drainage tube combined with subcutaneous vacuum pressure suction in the laparoscopic-assisted abdominoperineal resection]. AB - OBJECTIVE: To study the management for the perineal incision after laparoscopic assisted abdominoperineal resection for rectal cancer. METHODS: Clinical data of 87 patients undergoing laparoscopic Miles operation for lower rectal cancer from June 2009 to February 2014 were collected and studied. Presacral space drainage group: presacral space drainage tube was applied in 42 patients. Combined drainage group: presacral space drainage tube combined with subcutaneous vacuum pressure suction was applied in 45 cases. In combined drainage group, except the presacral drainage tube, another drainage tube was placed subcutaneously and connected to a negative pressure ball, which was fixed on the lateral anterior of perineal wound by the further incision and drainage. After subcutaneous tube was placed for 2 weeks, as drainage fluid was limpid and <15 ml/d for 3 days, meanwhile no obvious pelvic fluid was detected by ultrasound, and the wound healed quite well without redness and edema, then the subcutaneous tube with the negative pressure ball could be removed. RESULTS: There were 51 males and 36 females with the mean age of 26-78(56.9+/-10.8) years old. The laparoscopic Miles operation was successfully completed in all the cases without death and complications. The drainage tube was placed for 4-13(8.0+/-2.5) days in presacral space drainage group, and for 4-14(6.7+/-2.4) days in combined drainage group. The subcutaneous tube was placed for 14-24(15.8+/-3.0) days. The primary healing rate of perineal wound in presacral space drainage group and combined drainage group was 66.7%(28/42) and 91.1%(41/45) respectively, while the perineal wound infection rate was 21.4%(9/42) and 4.4%(2/45) respectively, whose differences between two groups were both significant (chi2=7.911, P=0.005 and chi2=5.674, P=0.017). CONCLUSION: Presacral space drainage tube combined with subcutaneous vacuum pressure suction in laparoscopic-assisted abdominoperineal resection for rectal cancer has better efficacy and lower infection rate for perineal incision, which is worth wide application. PMID- 28836256 TI - [Risk factors analysis of the early colorectal carcinoma after endoscopic non curative resection: A retrospective clinical study of 56 cases]. AB - OBJECTIVE: To explore the risk factors contributing to the progression-free survival rate of patients undergoing endoscopic non-curative resection. METHODS: Clinicopathological data of patients with early colorectal carcinoma and intraepithelial neoplasia undergoing endoscopic resection in our department from January 2009 to January 2015 were collected. Associated factors affecting the progression-free survival rate of the early colorectal carcinoma after endoscopic non-curative resection were analyzed. Any of the following conditions was defined as endoscopic non-curative resection: (1) positive lateral or vertical cutting margin; (2) submucosa invasion depth >=1 000 MUm; (3) vascular or lymphatic invasion; (4) low differentiation, including signet ring cell carcinoma or mucinous adenocarcinoma; (5) high grade tumor budding. RESULTS: Clinicopathological data of 840 cases were collected. According to China's Endoscopic Screening, Diagnosis and Treatment Guidelines for Early Colorectal Cancer, 56(56/840, 6.7%) cases were defined as the non-curative resection, the metastasis or recurrence rate was 14.3%(8/56), 3-year progression-free survival rate was 85.7%(48/56), and 3-year overall survival rate was 94.6%(53/56). Univariate prognostic analysis showed that 3-year progression-free survival rate in low and moderate-high differentiation adenocarcinoma was 25.0% and 90.4%(chi2=6.711, P=0.010), in patients with submucosa invasion depth >=2 000 MUm and <2 000 MUm was 75.0% and 93.8%(chi2=6.745, P=0.009), and in patients with and without vascular or lymphatic invasion was 60.0% and 88.2%(chi2=7.708, P=0.005), whose differences were all significant. Multivariate Cox regression analysis revealed that low differentiation adencarcinoma (P=0.015, HR=8.021, 95%CI: 1.499 42.921), invasion depth >=2 000 MUm (HR=6.823, 95%CI: 1.299-35.848) and vascular or lymphatic invasion (HR=18.143, 95%CI: 2.079-158.358) were independent risk factors for the progression-free survival rate of the early colorectal carcinoma after endoscopic non-curative resection. CONCLUSION: Pathology after endoscopic non-curative resection for early colorectal carcinoma indicates that low differentiation adenocarcinoma, submucosa invasion depth >=2 000 MUm and vascular or lymphatic invasion are independent risk factors of poor prognosis. PMID- 28836257 TI - [Efficacy comparison of the laparoscopic total extraperitoneal prosthetic and the Lichtenstein herniorrhaphy for inguinal hernia]. AB - OBJECTIVE: To compare the efficacy and safety between laparoscopic total extraperitoneal prosthetic (TEP) and Lichtenstein herniorrhaphy in the treatment of inguinal hernia (IH). METHODS: Clinical data of 158 IH patients at our hospital from October 2015 to October 2016 were retrospectively analyzed. Among 158 patients, 85 patients underwent TEP (TEP group), and 73 underwent Lichtenstein herniorrhaphy(Lichtenstein group). Patients of TEP group received general anesthesia. The space between suprapubic space and iliac fossa was separated with attention to protect the spermatic cord during the operation so as to avoid excessive separation. When the patch was placed, the internal margin exceeded the contralateral pubic tubercle, the lateral margin reached the anterior superior iliac spine, there was at least 2 cm overlap between the superior margin and the joint tendon, the lower margin was inserted into the suprapubic bladder space(Retzius space), and the lateral lower margin was at least 6 cm to internal ring. Lichtenstein group received local anesthesia or continuous epidural anesthesia and all underwent routine Lichtenstein herniorrhaphy. Operative time, postoperative conditions and recurrence were compared between two groups. RESULTS: Among these 158 patients, 129 were male and 29 were female, with an age ranging from 26 to 75 years (median 42 years). Baseline data were not significantly different between two groups(all P>0.05). There was no perioperative death and serious complications in two groups. The difference was not statistically significant in operative time[(47.6+/-5.4) minutes vs. (48.9+/-6.3) minutes, t=0.238, P=1.024]. But TEP group was better than Lichtenstein group in terms of intraoperative blood loss [(7.53+/-2.31) ml vs. (11.41+/-4.49) ml, t=5.783, P=0.032], postoperative bedtime [(1.25+/-0.32) days vs. (2.83+/-0.52) days, t=5.294, P=0.041], postoperative hospital stay [(2.38+/-1.14) days vs. (3.46+/-1.81) days, t=5.482, P=0.037], and postoperative pain score (1.27+/-0.47 vs. 3.42+/-1.93, t=5.639, P=0.034). Follow-up was 12-16 months (median 10 months). In TEP and Lichtenstein group after operation, incision infection occurred in both 1 case, edema of the scrotum or labia minora developed in 2 patients and 3 cases respectively, chronic pain was found in one and 2 cases respectively. The patients were followed up for 5 to 16 months(median 10 months), and recurrences was observed in 1 case both in TEP group and Lichtenstein group respectively. CONCLUSION: Laparoscopic total extraperitoneal prosthetic is safe and effective in the treatment of inguinal hernia, which is better than Lichtenstein herniorrhaphy in fast recovery, less trauma and more comfort, and worthy of clinical promotion. PMID- 28836258 TI - [Application of transanal total mesorectal excision in radical surgery for rectal cancer]. AB - Transanal total mesorectal excision (taTME) is a novel operative approach of the radical surgery for rectal cancer, and has been a hot topic in colorectal surgery for years. TaTME aims to solve some problems from previous TME, such as exposure of peripheral mid-lower rectal space, judge of distal cutting margin, and to carry out completely minimal invasive operation. According to the degree of completion of different surgical approach, taTME can be divided into laparoscopic assisted taTME (hybrid taTME) and fully through the anal approach to complete the taTME (pure taTME). At present, the anal operation equipment suitable for taTME is divided into two types: transnasal endoscopic microsurgical platform (TEM-TME) and transnasal minimally invasive surgical platform (TAMIS-TME). Until now, there is no consensus on the indications of taTME. For the treatment of some special circumstances resulting in surgical difficulties, such as low rectal cancer, male, obesity, patients with narrow pelvis, tumor depth of invasion to the surrounding tissue, tumor diameter >4 cm, tissue distortions by neoadjuvant therapy and refractory benign disease, taTME has potential advantages. As for contraindications, obstructive rectal cancer, emergency surgery and advanced tumors should currently be regarded as contraindications of taTME. It was reported that taTME was safe and feasible, and had a satisfactory short-term outcomes in several centers in China. The operation is characterized by good TME quality, distal margin and circumferential margins, especially in overweight patients with narrow pelvis. The surgical principle is the eternal cornerstone to ensure the radical tumor resection and the safety of patients. The laparoscopic technique is widely used in China and surgeons are going to be skilled with laparoscopic surgeries for low rectal cancers. This situation postpones the development of taTME. It is challenging and disputing to advocate taTME to replace transabdominal laparoscopic surgery for low rectal cancer at recent times. If we have suitable instrument to dissect the root nodes and have the evidence from several ongoing clinical trials, we hope taTME could become a pure transanal approach because of its unique cosmetic superiority, without any abdominal invasive incisions. PMID- 28836259 TI - Cartilage matrix remodelling differs by disease state and joint type. AB - Dramatic alterations in mechanical properties have been documented for osteoarthritic (OA) cartilage. However, the matrix composition underlying these changes has not been mapped and their aetiology is not entirely understood. We hypothesised that an understanding of the cartilage matrix heterogeneity could provide insights into the origin of these OA-related alterations. We generated serial transverse cryo sections for 7 different cartilage conditions: 2 joint sites (knee and hip), 2 disease states (healthy and OA) and 3 tissue depths (superficial, middle and deep). By laser capture microscopy, we acquired ~200 cartilage matrix specimens from territorial (T) and interterritorial (IT) regions for all 7 conditions. A standardised matrix area was collected for each condition for a total of 0.02 +/- 0.001 mm3 (corresponding to 20 ug of tissue) from a total of 4800 specimens. Extracted proteins were analysed for abundance by targeted proteomics. For most proteins, a lower IT/T ratio was observed for the OA disease state and knee joint type. A major cause of the altered IT/T ratios was the decreased protein abundance in IT regions. The collagenase-derived type III collagen neo-epitope, indicative of collagen proteolysis, was significantly more abundant in OA cartilage. In addition, it was enriched on average of 1.45-fold in IT relative to T matrix. These results were consistent with an elevated proteolysis in IT regions of OA cartilage, due to degenerative influences originating from synovial tissue and/or produced locally by chondrocytes. In addition, they offered direct evidence for dynamic remodelling of cartilage and provided a cogent biochemical template for understanding the alterations of matrix mechanical properties. PMID- 28836261 TI - Reduction of nitric oxide level results in maturation promoting factor destabilization during spontaneous meiotic exit from diplotene arrest in rat cumulus oocytes complexes cultured in vitro. AB - Nitric oxides (NO) act as one of the major signal molecules and modulate various cell functions including oocyte meiosis in mammals. The present study was designed to investigate the mechanism of NO action during spontaneous meiotic exit from diplotene arrest (EDA) in rat cumulus oocytes complexes (COCs) cultured in vitro. Diplotene-arrested COCs collected from ovary of immature female rats after 20 IU pregnant mare's serum gonadotropins (PMSG) for 48 h were exposed to various concentrations of NO donor, S-nitroso-N-acetyl penicillamine (SNAP) and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AG) for 3 h in vitro and downstream factors were analyzed. Our results suggest that SNAP inhibited, while AG induced EDA in a concentration-dependent manner. The iNOS mediated total NO, cyclic nucleotides and cell division cycle 25B (Cdc25B) levels were reduced significantly. The decreased Cdc25B was associated with the increased Thr14/Tyr15 phosphorylated cyclin-dependent kinase 1 (Cdk1) level and decreased Thr161 phosphorylated Cdk1 as well as cyclin B1 levels leading to maturation promoting factor (MPF) destabilization. The destabilized MPF finally induced spontaneous EDA. Taken together, these results suggest that reduction of iNOS-mediated NO level destabilizes MPF during spontaneous EDA in rat COCs cultured in vitro. PMID- 28836260 TI - Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. AB - : Homocysteine is a sulphur-containing non-proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy-induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up-regulates pathogenic genes and down-regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy-induced vascular injury leads to neuronal damage and disease. Also, an HHcy activated sympathetic system and HHcy-injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy induced vascular injury, which are further considered as potential therapeutic targets in this condition. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. PMID- 28836262 TI - Immune status of patients with haemophilia A before exposure to factor VIII: first results from the HEMFIL study. AB - Previous cross-sectional studies showed that some patients with haemophilia A (HA) without inhibitor presented a pro-inflammatory profile during factor VIII (FVIII) replacement therapy. Furthermore, an anti-inflammatory/regulatory state was described in HA patients after inhibitor development. However, no study investigated the levels of these biomarkers before exposure to exogenous FVIII. This study investigated the immunological profile of previously untreated patients (PUPs) with HA in comparison with non-haemophiliac boys. A panel of chemokines and cytokines was evaluated in the plasma of 40 PUPs with HA and 47 healthy controls. The presence of microparticles was assessed in the plasma of 32 PUPs with HA and 47 healthy controls. PUPs with HA presented higher levels of CXCL8 (IL8), IL6, IL4, IL10, IL2, IL17A (IL17), and lower levels of CXCL10 (IP 10) and CCL2 (MCP-1) than the age-matched healthy controls (P < 0.05). We also observed higher levels of microparticles derived from endothelium, erythrocytes, platelets, leucocytes, neutrophils, and T lymphocytes in patients in comparison with controls (P < 0.05). Compared with controls, PUPs with HA presented a distinct immunological profile, characterized by a prominent pro-inflammatory status that appears to be regulated by IL4 and IL10. PMID- 28836263 TI - B cells require Type 1 interferon to produce alloantibodies to transfused KEL expressing red blood cells in mice. AB - BACKGROUND: Alloantibodies to red blood cell (RBC) antigens can cause significant hemolytic events. Prior studies have demonstrated that inflammatory stimuli in animal models and inflammatory states in humans, including autoimmunity and viremia, promote alloimmunization. However, molecular mechanisms underlying these findings are poorly understood. Given that Type 1 interferons (IFN-alpha/beta) regulate antiviral immunity and autoimmune pathology, the hypothesis that IFN alpha/beta regulates RBC alloimmunization was tested in a murine model. STUDY DESIGN AND METHODS: Leukoreduced murine RBCs expressing the human KEL glycoprotein were transfused into control mice (WT), mice lacking the unique IFN alpha/beta receptor (IFNAR1-/- ), or bone marrow chimeric mice lacking IFNAR1 on specific cell populations. Anti-KEL IgG production, expressed as mean fluorescence intensity (MFI), and B-cell differentiation were examined. RESULTS: Transfused WT mice produced anti-KEL IgG alloantibodies (peak response MFI, 50.4). However, the alloimmune response of IFNAR1-/- mice was almost completely abrogated (MFI, 4.2; p < 0.05). The response of bone marrow chimeric mice lacking IFNAR1 expression in all hematopoietic cells or specifically in B cells was also diminished (MFI, 3.8 and 5.4, respectively, compared to control chimeras, MFI, 65.6; p < 0.01). Accordingly, transfusion-induced differentiation of IFNAR1-/- B cells into germinal center B cells and plasma cells was significantly reduced, compared to WT B cells. CONCLUSIONS: This study demonstrates that B cells require signaling from IFN-alpha/beta to produce alloantibodies to the human KEL glycoprotein in mice. These findings provide a potential mechanistic basis for inflammation-induced alloimmunization. If these findings extend to human studies, patients with IFN-alpha/beta-associated conditions may have an elevated risk of alloimmunization and benefit from personalized transfusion protocols. PMID- 28836264 TI - Development of Molecularly Targeted Therapies to Treat Pediatric Malignancies. AB - Drugs and biologics developed to treat children with cancer have been historically developed in adults for adult indications. Although leading to many useful drugs and biologics to treat pediatric cancer, future development of molecularly targeted therapies (MTTs) should be directed toward pediatric tumors more specifically to maximize antitumor efficacy while minimizing acute morbidity and long-term disability. This will put pediatric clinicians closer to the goal of cure for all children diagnosed with cancer. PMID- 28836265 TI - Effect of atopic dermatitis on quality of life and its psychosocial impact in Asian adolescents. AB - BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) is a common condition affecting up to 20% of the paediatric population in Singapore. It is often associated with significant psychosocial morbidity and can affect patients' quality of life (QOL) tremendously. This study investigated the varying lifestyle impacts, and psychosocial domains most affected by AD in adolescent children in Singapore. METHODS: A prospective study evaluating the impact of AD on the QOL of adolescents was conducted over a 6-month period from July to December 2014. Adolescents aged 11-16 years with varying eczema severity were recruited. Eczema severity was determined by using the eczema area and severity index (EASI) scores. Lifestyle impact of AD was evaluated using patient-reported children's dermatology life quality index (CDLQI) scores. Statistical analysis was performed using an analysis of one-way variance and Student's t-test. RESULTS: A total of 50 patients were enrolled and divided into three groups: mild (<10.3), moderate (10.3-20.9) and severe (>20.9) eczema based on EASI scores. Patients with mild and moderate eczema had lower CDLQI scores. Adolescents were most affected by the disruption that their symptoms had on their leisure and physical activities and sleep as a result of itch and scratching, respectively. CONCLUSION: Chronic sufferers of severe eczema experience poorer QOL than those with mild or moderate eczema. They also experience significant psychosocial impact as a consequence of their condition. PMID- 28836266 TI - Late (>= 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation might be an effective and safe alternative. OBJECTIVES: To determine if administration of inhalation corticosteroids after the first week of life until 36 weeks PMA to preterm infants at high risk of developing BPD is effective and safe in reducing the incidence of death and BPD as separate or combined outcomes. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 4), MEDLINE via PubMed (1966 to 19 May 2017), Embase (1980 to 19 May 2017), and CINAHL (1982 to 19 May 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included randomised controlled trials comparing inhalation corticosteroids, started >= 7 days postnatal age (PNA) but before 36 weeks PMA, to placebo in ventilated and non-ventilated infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhalation corticosteroids. DATA COLLECTION AND ANALYSIS: We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcome was death or BPD at 36 weeks PMA. Secondary outcomes were the combined outcome death or BPD at 28 days PNA, the seperate outcomes of death and BPD at both 28 days PNA, and at 36 weeks PMA, and short-term respiratory outcomes, such as failure to extubate; total days of mechanical ventilation and oxygen use; and the need for systemic corticosteroids. We contacted the original trialists to verify the validity of extracted data and to provide missing data. We analysed all data using Review Manager 5. When possible, we performed meta-analysis using typical risk ratio (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes along with their 95% confidence intervals (CI). We analysed ventilated and non-ventilated participants separately.We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We included eight trials randomising 232 preterm infants in this review. Inhalation corticosteroids did not reduce the separate or combined outcomes of death or BPD. The meta-analyses of the studies showed a reduced risk in favor of inhalation steroids regarding failure to extubate at seven days (typical RR (TRR) 0.80, 95% CI 0.66 to 0.98; 5 studies, 79 infants) and at the latest reported time point after treatment onset (TRR 0.60, 95% CI 0.45 to 0.80; 6 studies, 90 infants). However, both analyses showed increased statistical heterogeneity (I2 statistic 73% and 86%, respectively). Furthermore, inhalation steroids did not impact total duration of mechanical ventilation or oxygen dependency. There was a trend toward a reduction in the use of systemic corticosteroids in infants receiving inhalation corticosteroids (TRR 0.51, 95% CI 0.26 to 1.00; 4 studies, 74 infants; very low quality evidence). There was a paucity of data on short- and long-term adverse effects. Our results should be interpreted with caution because the total number of randomised participants is relatively small, and most trials differed considerably in participant characteristics, inhalation therapy, and outcome definitions. AUTHORS' CONCLUSIONS: Based on the results of the currently available evidence, inhalation corticosteroids initiated at >= 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo-controlled trials are needed to establish the efficacy and safety of inhalation corticosteroids. PMID- 28836267 TI - When and How Can Real World Data Analyses Substitute for Randomized Controlled Trials? AB - Regulators consider randomized controlled trials (RCTs) as the gold standard for evaluating the safety and effectiveness of medications, but their costs, duration, and limited generalizability have caused some to look for alternatives. Real world evidence based on data collected outside of RCTs, such as registries and longitudinal healthcare databases, can sometimes substitute for RCTs, but concerns about validity have limited their impact. Greater reliance on such real world data (RWD) in regulatory decision making requires understanding why some studies fail while others succeed in producing results similar to RCTs. Key questions when considering whether RWD analyses can substitute for RCTs for regulatory decision making are WHEN one can study drug effects without randomization and HOW to implement a valid RWD analysis if one has decided to pursue that option. The WHEN is primarily driven by externalities not controlled by investigators, whereas the HOW is focused on avoiding known mistakes in RWD analyses. PMID- 28836268 TI - Sacral anatomy of the phytosaur Smilosuchus adamanensis, with implications for pelvic girdle evolution among Archosauriformes. AB - The sacrum - consisting of those vertebrae that articulate with the ilia - is the exclusive skeletal connection between the hindlimbs and axial skeleton in tetrapods. Therefore, the morphology of this portion of the vertebral column plays a major role in the evolution of terrestrial locomotion. Whereas most extant reptiles only possess the two plesiomorphic sacral vertebrae, additional vertebrae have been incorporated into the sacrum multiple times independently among early-diverging archosaurian (crocodylians + birds) clades. Phytosauria was a diverse, abundant, and cosmopolitan clade of archosauriforms throughout the Late Triassic, but postcrania of this clade are rarely described and few species level taxonomic placements of phytosaurian postcranial material are available, potentially hampering knowledge of morphological disparity in the postcranial skeleton among phytosaurs. Here, we describe the sacrum of Smilosuchus adamanensis, a phytosaur recovered from the Upper Triassic Chinle Formation of Arizona. This sacrum consists of the two primordial sacral vertebrae, but has a vertebra incorporated from the trunk into the sacrum (= a dorsosacral) and is therefore the first Late Triassic phytosaur and one of the first non-archosaurian archosauromorphs to be described with more than two sacral vertebrae. Our interpretation of this element as a dorsosacral is justified by the lateral extent of the dorsosacral ribs, clear surfaces of articulation between the distal ends of the dorsosacral ribs and the first primordial sacral ribs, and the scar on the medial surface of each ilium for articulation with each dorsosacral rib. Additionally, we provide the first detailed description of the vertebral junction formed by two anteriorly projecting flanges on the first primordial sacral ribs and their corresponding facets on the centrum of the dorsosacral. Computed tomographic (CT) imaging reveals that the two primordial sacrals are not co ossified and that the dorsosacral morphology of this specimen is not the result of obvious pathology. We place this incorporation of a trunk vertebra into the phytosaurian sacrum in a broader evolutionary context, with this shift in vertebral identity occurring at least seven times independently among Triassic archosauriforms, including at least three times in early crocodylian-line archosaurs and at least four times among bird-line archosaurs. Additionally, anteriorly projecting flanges of sacral ribs which articulate with the anterior adjacent centrum have evolved several times in archosauriforms, and we interpret 'shared' sacral ribs (= a sacral rib that articulates with two adjacent sacral centra more or less equally) present in some archosaurian clades as a more extreme example of this morphology. In extant taxa the highly conserved Hox gene family plays a central role in the patterning of the axial skeleton, especially vertebral identity; therefore, the independent incorporation of a trunk vertebra into the sacrum across multiple archosauriform lineages may suggest a homologous underlying developmental mechanism for this evolutionary trend. PMID- 28836269 TI - Association Between Spousal Caregiver Well-Being and Care Recipient Healthcare Expenditures. AB - OBJECTIVES: To measure the association between spousal depression, general health, fatigue and sleep, and future care recipient healthcare expenditures and emergency department (ED) use. DESIGN: Prospective cohort study. SETTING: Health and Retirement Study. PARTICIPANTS: Home-dwelling spousal dyads in which one individual (care recipient) was aged 65 and older and had one or more activity of daily living or instrumental activity of daily living disabilities and was enrolled in Medicare Part B (N = 3,101). EXPOSURE: Caregiver sleep (Jenkins Sleep Scale), depressive symptoms (Center for Epidemiologic Studies Depression-8 Scale), and self-reported general health measures. MEASUREMENTS: Primary outcome was care recipient Medicare expenditures. Secondary outcome was care recipient ED use. Follow-up was 6 months. RESULTS: Caregiver depressive symptoms score and six of 17 caregiver well-being measures were prospectively associated with higher care recipient expenditures after minimal adjustment (P < .05). Higher care recipient expenditures remained significantly associated with caregiver fatigue (cost increase, $1,937, 95% confidence interval (CI) = $770-3,105) and caregiver sadness (cost increase, $1,323, 95% CI = $228-2,419) after full adjustment. Four of 17 caregiver well-being measures, including severe fatigue, were significantly associated with care recipient ED use after minimal adjustment (P < .05). Greater odds of care recipient ED use remained significantly associated with caregiver fatigue (odds ratio (OR) = 1.24, 95% CI = 1.01-1.52) and caregiver fair to poor health (OR = 1.23, 95% CI = 1.04-1.45) after full adjustment. Caregiver total sleep score was not associated with care recipient outcomes. CONCLUSION: Poor caregiver well-being, particularly severe fatigue, is independently and prospectively associated with higher care recipient Medicare expenditures and ED use. PMID- 28836270 TI - Macroevolutionary constraints to tolerance: trade-offs with drought tolerance and phenology, but not resistance. AB - Plant tolerance of herbivory, i.e., the ability to recover after damage, is an important component of how plants cope with herbivores. Tolerance has long been hypothesized to be constrained evolutionarily by plant resistance to herbivores, traits that allow plants to cope with stressful growing conditions, and traits that influence the timing of damage in relation to reproduction. Variation in tolerance and resistance can be caused by differences in the identity of the plant (e.g., genotype, species, clade) and by the context of the herbivore threat (e.g., identity of the herbivore, type of damage it causes, abiotic conditions in which the plant is growing). To date, the vast majority of studies have explored trade-offs with tolerance within species. Here, we test hypotheses of constraints on tolerance using comparative approaches in a clade of mustards, emphasizing the variety of contexts in which damage is realistically tolerated. We estimated tolerance to leaf damage, tolerance to apical clipping at the bolting stage - simulating browsing -, and resistance to a specialist and generalist lepidopteran herbivore for a group of native mustards, grown in field soils unique to each population and in a common potting soil. Resistance to herbivores was soil dependent, while surprisingly, tolerance was not. Phylogenetic signal in resistance to specialist and generalist lepidopteran herbivores was present, but only when plants were grown in field soils. Tolerance had low phylogenetic signal. Tolerance to leaf damage was unrelated to tolerance to simulated browse. We found no evidence for a resistance-tolerance trade-off, and some evidence for a soil-dependent positive correlation between tolerance and resistance to both herbivores. Drought-tolerant species had poorer ability to tolerate browse damage, and earlier flowering species tended to be less tolerant to leaf damage. Our results suggest that tolerance trades off with traits that allow mostly annual, monocarpic Streptanthus (s.l.) to persist in drought-prone conditions but is largely unrelated to resistance to herbivores. Our study highlights a need for a new framework for tolerance to herbivory that explicitly acknowledges that the relationship among tolerance, resistance, and traits that ameliorate abiotic stress. PMID- 28836272 TI - Psychedelic Drugs as Therapeutics: No Illusions About the Challenges. AB - Interest in the potential therapeutic benefits of psychedelic agents has recently increased. In addition to psilocybin, a wide variety of agents with psychedelic properties have been proposed and partially tested. However, the challenges of obtaining approval to market a restricted psychotomimetic agent are formidable. PMID- 28836271 TI - Roadmap for investigating epigenome deregulation and environmental origins of cancer. AB - The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene-environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor-specific ("fingerprints") that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed and advances in epigenomics that may help in understanding the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed and how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment. PMID- 28836273 TI - Clotrimazole microemulsion and microemulsion-based gel: evaluation of buccal drug delivery and irritancy using chick chorioallantoic membrane as the model. AB - OBJECTIVES: To investigate the efficacy of clotrimazole microemulsion (CTZ-ME) and its gel form, clotrimazole microemulsion-based gel (CTZ-MBG), for the treatment of oral candidiasis. METHODS: CTZ-ME and CTZ-MBG were characterized for droplet size and texture, respectively. The ex-vivo permeation study and irritancy assessment of CTZ-ME and CTZ-MBG were performed using chick chorioallantoic membrane (CAM) as the model. Antifungal activity against Candida albicans ATCC 10 231 of CTZ-ME and CTZ-MBG was determined by agar diffusion method compared to the blank counterparts. KEY FINDINGS: CTZ-ME contained nano sized droplets and CTZ-MBG had acceptable firmness and spreadability. CTZ-ME exhibited faster CAM permeation of the drug and larger inhibition zone than CTZ MBG as the increased viscosity of CTZ-MBG resulted in more retardation and higher fluctuations in drug diffusion. As there were no detectable visual changes in CAM blood vessels after applying CTZ-ME or CTZ-MBG, both formulations were non irritants. CONCLUSIONS: CTZ-ME and CTZ-MBG could deliver the drug through CAM, the model for buccal delivery. Additionally, they did not cause irritancy and had effective antifungal activity against C. albicans. The results indicated that CTZ ME and CTZ-MBG were potential effective antifungal formulations to treat oral candidiasis. PMID- 28836274 TI - Interconception care for women with a history of gestational diabetes for improving maternal and infant outcomes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse health outcomes for mothers and their infants both perinatally and long term. Women with a history of GDM are at risk of recurrence in subsequent pregnancies and may benefit from intervention in the interconception period to improve maternal and infant health outcomes. OBJECTIVES: To assess the effects of interconception care for women with a history of GDM on maternal and infant health outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (7 April 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials, including quasi-randomised controlled trials and cluster randomised trials evaluating any protocol of interconception care with standard care or other forms of interconception care for women with a history of GDM on maternal and infant health outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility. In future updates of this review, at least two review authors will extract data and assess the risk of bias of included studies; the quality of the evidence will be assessed using the GRADE approach. MAIN RESULTS: No eligible published trials were identified. We identified a completed randomised controlled trial that was designed to evaluate the effects of a diet and exercise intervention compared with standard care in women with a history of GDM, however to date, it has only published results on women who were pregnant at randomisation (and not women in the interconception period). We also identified an ongoing trial, in obese women with a history of GDM planning a subsequent pregnancy, which is assessing the effects of an intensive lifestyle intervention, supported with liraglutide treatment, compared with usual care. We also identified a trial that was designed to evaluate the effects of a weight loss and exercise intervention compared with lifestyle education also in obese women with a history of GDM planning a subsequent pregnancy, however it has not yet been published. These trials will be re considered for inclusion in the next review update. AUTHORS' CONCLUSIONS: The role of interconception care for women with a history of GDM remains unclear. Randomised controlled trials are required evaluating different forms and protocols of interconception care for these women on perinatal and long-term maternal and infant health outcomes, acceptability of such interventions and cost effectiveness. PMID- 28836275 TI - Impact of treatment and outcomes for patients with posttransplant drug-associated thrombotic microangiopathy. AB - BACKGROUND: Drug-induced transplant-associated thrombotic microangiopathy (DTA TMA) is a rare but serious complication that can occur after hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) without guidelines for optimal management of this condition. STUDY DESIGN AND METHODS: Given the ambiguity surrounding the treatment for DTA-TMA, we conducted a retrospective review to evaluate the impact of different treatment strategies in DTA-TMA patients. Our primary endpoint was to determine the overall response rate (ORR) for DTA-TMA based on the type of treatment modality chosen while secondary endpoints included the time to response, relapse rates, and overall survival for DTA-TMA cases. RESULTS: There were a total of 14 DTA-TMA patients of whom nine were post-HCT and five were post-SOT. Most of the DTA-TMA cases were due to tacrolimus (n = 11) with a minority related to sirolimus (n = 3). A total of nine of 14 patients demonstrated response and five had no response to therapy. The ORR among the DTA-TMA patients after HCT and SOT who received plasma exchange (PLEX) were 25 and 100%, respectively. The ORRs among the patients (includes HCT and SOT) who received rituximab (n = 3) and eculizumab (n = 5) were 67 and 60%, respectively. There were two relapses noted in our study and both were in the HCT group. CONCLUSION: While discontinuation of the offending agent may be sufficient for treatment of DTA-TMA after HCT, PLEX may be a reasonable option for DTA-TMA after SOT. Although the results are encouraging with rituximab and eculizumab in the treatment of DTA-TMA, larger prospective studies are needed to validate our findings. PMID- 28836276 TI - The expression, localization and function of alpha7 nicotinic acetylcholine receptor in rat corpus cavernosum. AB - OBJECTIVES: Alpha7 nicotinic acetylcholine receptor (alpha7-nAChR), an emerging pharmacological target for a variety of medical conditions, is expressed in the most mammalian tissues with different effects. So, this study was designed to investigate the expression, localization and effect of alpha7-nAChR in rat corpus cavernosum (CC). METHODS & KEY FINDINGS: Reverse transcription polymerase chain reaction (RT-PCR) revealed that alpha7-nAChR was expressed in rat CC and double immunofluorescence studies demonstrated the presence of alpha7-nAChR in corporal neurons. The rat CC segments were mounted in organ bath chambers and contracted with phenylephrine (0.1 MUm -300 MUm) to investigate the relaxation effect of electrical field stimulation (EFS,10 Hz) assessed in the presence of guanethidine (adrenergic blocker, 5 MUm) and atropine (muscarinic cholinergic blocker, 1 MUm) to obtain non-adrenergic non-cholinergic (NANC) response. Cumulative administration of nicotine significantly potentiated the EFS-induced NANC relaxation (-log EC50 = 7.5 +/- 0.057). Whereas, the potentiated NANC relaxation of nicotine was significantly inhibited with different concentrations of methyllycaconitine citrate (alpha7-nAChR antagonist, P < 0.05) in preincubated strips. L-NAME (non-specific nitric oxide synthase inhibitor, 1 MUm) completely blocked the neurogenic relaxation induced by EFS plus nicotine. CONCLUSION: To conclude alpha7-nAChR is expressed in rat CC and modulates the neurogenic relaxation response to nicotine. PMID- 28836278 TI - Systematic review: cost-effectiveness of direct-acting antivirals for treatment of hepatitis C genotypes 2-6. AB - BACKGROUND: The availability of direct-acting antivirals (DAAs) has dramatically changed the landscape of hepatitis C virus (HCV) therapy; however, the cost and budget requirements for DAA treatment have been widely debated. AIMS: To systematically review published studies evaluating the cost-effectiveness of DAAs for HCV genotype 2-6 infections, and synthesise and re-evaluate results with updated drug prices. METHODS: We conducted a systematic search of various electronic databases, including Medline, EMBASE, Cochrane library and EconLit for cost-effectiveness studies published from 2011 to 2016. Studies evaluating DAAs for genotypes 2-6 were included. Reported costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were abstracted. We re estimated ICERs by varying the price of DAAs from $20 000 to $100 000, and estimated the threshold price at which DAA regimens would be deemed cost effective (ICER<=$100 000/QALY). RESULTS: A total of 92 ICERs for 7 different DAA regimens from 10 published articles were included. Among the abstracted 92 ICERs, 20 were for genotype 2, 40 for genotype 3, 30 for genotype 4, 2 for genotype 5 and none for genotype 6; therefore, only genotypes 2-5 were analysed. At the discounted price of $40 000, 87.0% analyses found DAA regiments to be cost effective, and 7.6% found to be cost-saving. The median threshold price below which DAAs would be deemed cost-effective was between $144 400 and $225 000, and cost-saving between $17 300 and $25 400. CONCLUSIONS: HCV treatment with DAAs is highly cost-effective in patients with HCV genotypes 2-5 at a $100 000/QALY threshold. Timely HCV treatment would be an optimal strategy from both a public health and economic perspective. PMID- 28836277 TI - The risk of preterm birth and growth restriction in pregnancy after cancer. AB - It is unclear whether cancer and its treatments increase the risk of adverse pregnancy outcomes. Our aim was to examine whether cancer survivors have higher risks of poor outcomes in pregnancies conceived after diagnosis than women without cancer, and whether these risks differ by cancer type and race. Diagnoses from cancer registries were linked to pregnancy outcomes from birth certificates in three U.S. states. Analyses were limited to the first, live singleton birth conceived after diagnosis. Births to women without a previous cancer diagnosis in the registry were matched to cancer survivors on age at delivery, parity, race/ethnicity and education. Log-binomial regression was used to estimate risk ratios. Cervical cancer survivors had higher risks of preterm birth (Risk ratio = 2.8, 95% Confidence interval: 2.1, 3.7), as did survivors of invasive breast cancer (RR = 1.3, 95% CI: 1.1, 1.7) and leukemia (RR = 2.1, 95% CI: 1.3, 3.5). We observed a higher risk of small for gestational age (SGA) infants (<10% of weight for age based on a national distribution) in survivors of brain cancer (RR = 1.7, 95% CI: 1.1, 2.8) and extranodal non-Hodgkin lymphoma (RR = 2.3, 95% CI: 1.5, 3.6). We did not see an increased risk of infants born preterm, low birth weight, or SGA in pregnancies conceived after ductal carcinoma in situ, thyroid cancer, melanoma, or Hodgkin lymphoma. While our results are reassuring for survivors of many cancers, some will need closer monitoring during pregnancy. PMID- 28836279 TI - Open flap debridement of peri-implantitis with or without adjunctive systemic antibiotics: A randomized clinical trial. AB - AIMS: To investigate clinical, radiographic and microbiological outcome over 12 months following open flap debridement of peri-implantitis with or without antibiotics. MATERIALS AND METHODS: Peri-implantitis was surgically treated with or without Zithromax(r) in 19 control and 20 test individuals. Probing pocket depth (PPD), gingival inflammation (BOP), intra-oral radiographs and microbial samples were studied. Per protocol and intent-to-treat analyses were performed. RESULTS: The mean difference (reduction) in PPD values between baseline and month 12 in the test and control groups was 1.7 mm (SD +/- 1.1, 95% CI: 1.1, 2.3, p < .001) and 1.6 mm (SD +/- 1.5, 95% CI: 0.8, 2,4, p < .001), respectively. Data analysis failed to show study group differences for BOP, PPD, radiographic bone level and microbial load. Successful treatment (per protocol: PPD <= 5 mm, no BOP, no suppuration and no bone loss >=0.5 mm) at 12 months in test and control groups was 7/15 (46.7%) and 4/16 (25.0%). Bacterial load reduction was similar in study groups with a temporary reduction following treatment. CONCLUSIONS: Surgical treatment of peri-implantitis with adjunctive systemic azithromycin did not provide 1-year clinical benefits in comparison with those only receiving open flap debridement. PMID- 28836280 TI - Molecular characterisation of a case of dicentric Y presented as nonobstructive azoospermia with testicular early maturation arrest. AB - The dicentric Y chromosome is the most common cytogenetically visible structural abnormality of Y chromosome. The sites of break and fusion of dicentric Y are variable, but break and fusion at Yq12 (proximal to the pseudoautosomal region 2/PAR 2) is very rare. Dicentric Y chromosome is unstable during cell division and likely to generate chromosomal mosaicism. Here, we report a case of infertile male with nonmosaic 46,XY where chromosome Y was dicentric with break and fusion at Yq12 (proximal to PAR 2). Clinical presentation of the case was nonobstructive azoospermia due to early maturation arrest at the primary spermatocyte stage. Various molecular techniques such as FISH, STS-PCR and DNA microarray were carried out to characterise genetic defect leading to testicular maturation arrest in the patient. The break and fusion was found at Yq12 (proximal to PAR 2) and resulted in near total duplication of Y chromosome (excluding PAR 2). The reason for maturation arrest seems due to CNVs of PARs (gain in PAR 1 and loss of PAR 2) and azoospermia factors (gain). PMID- 28836281 TI - Periodontal manifestations of Ehlers-Danlos syndromes: A systematic review. AB - AIM: Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders, characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Periodontal EDS (pEDS) is a specific EDS subtype caused by heterozygous mutations in complement 1 subunit genes C1R and C1S, with early severe periodontitis as predominant clinical feature. We aimed to systematically assess the spectrum of periodontal abnormalities in all EDS subtypes. MATERIALS AND METHODS: An electronic and manual search was conducted in three databases (Medline, LIVIVO, CENTRAL). Publications of all study designs written in English/German without date restriction evaluating periodontal features in EDS were included. RESULTS: Thirty articles on pEDS and thirteen articles on other EDS subtypes were analysed. In pEDS, early severe periodontitis (98.4%) and gingival recession (87.1%) are the predominant features. Reports on periodontal manifestations in other EDS subtypes are rare. Described were severe gingival enlargement in dermatosparaxis EDS, and localized periodontal breakdown related to teeth with shortened roots in classical EDS (n = 3, respectively). CONCLUSION: Early severe periodontitis is the hallmark of pEDS; there is no evidence that it is part of the clinical phenotype of other EDS subtypes. Stringent analyses of periodontal manifestations in most EDS subtypes are missing. Prospero registration number CRD42017056889. PMID- 28836282 TI - White matter fiber integrity of the saccadic eye movement network differs between schizophrenia and healthy groups. AB - Recent diffusion tensor imaging (DTI) studies suggest that altered white matter fiber integrity is a pathophysiological feature of schizophrenia. Lower white matter integrity is associated with poor cognitive control, a characteristic of schizophrenia that can be measured using antisaccade tasks. Although the functional neural correlates of poor antisaccade performance have been well documented, fewer studies have investigated the extent to which white matter fibers connecting the functional nodes of this network contribute to antisaccade performance. The aim of the present study was to assess the white matter structural integrity of fibers connecting two functional nodes (putamen and medial frontal eye fields) of the saccadic eye movement network implicated in poor antisaccade performance in schizophrenia. To evaluate white matter integrity, DTI was acquired on subjects with schizophrenia and two comparison groups: (a) behaviorally matched healthy comparison subjects with low levels of cognitive control (LCC group), and (b) healthy subjects with high levels of cognitive control (HCC group). White matter fibers were tracked between functional regions of interest generated from antisaccade fMRI activation maps, and measures of diffusivity were quantified. The results demonstrated lower white matter integrity in the schizophrenia group than in the HCC group, but not the LCC group who showed similarly poor cognitive control performance. Overall, the results suggest that these alterations are not specific to the disease process of schizophrenia, but may rather be a function of uncontrolled cognitive factors that are concomitant with the disease but also observed in some healthy people. PMID- 28836283 TI - Two novel ABCG2 alleles resulting in a Jr(a-) phenotype. PMID- 28836284 TI - Imatinib-induced psoriasiform eruption in a patient with chronic myeloid leukemia. PMID- 28836285 TI - Periodontal treatment modulates gene expression of endothelial progenitor cells in diabetic patients. AB - BACKGROUND: Periodontitis is closely linked with type 2 diabetes mellitus (T2DM) and endothelial dysfunction. This study investigated the effects of periodontal treatment on immuno-inflammatory gene expression of endothelial progenitor cells (EPCs) in diabetic patients. METHODS: Eighteen T2DM patients with moderate to severe chronic periodontitis were randomly assigned to the Treatment group with oral hygiene instruction (OHI), scaling and root debridement (n = 11), and Control group (n = 7) with OHI alone. Peripheral blood samples were taken for biochemical analysis and culture of EPCs at baseline and 6 months after the treatment. PCR array-based profiling of 84 Toll-like receptor signalling-related genes in EPCs was firstly assessed for four randomly selected patients from the Treatment group. The differentially expressed genes were then further validated by qPCR in both groups. RESULTS: All subjects in the Treatment group significantly improved their periodontal conditions. Among the 84 genes tested, IL-6 and IL-8 transcripts were significantly downregulated with over twofold change after the treatment, and this observation was further validated by qPCR in all subjects from both groups (p < .05). CONCLUSION: This preliminary study suggests that periodontal treatment may contribute to a notable reduction in immuno-inflammatory gene expression measured by IL-6 and IL-8 transcripts in EPCs. PMID- 28836287 TI - Precision Pharmacotherapy Enables Precision Medicine. PMID- 28836286 TI - Metabolic tracing analysis reveals substrate-specific metabolic deficits in platelet storage lesion. AB - BACKGROUND: Storage of platelets (PLTs) results in a progressive defect termed PLT storage lesion (PSL). The PSL is characterized by poor PLT quality on a variety of assays. Metabolic defects are thought to underlie the PSL; thus this study was designed to quantitatively probe specific metabolic pathways over PLT storage. STUDY DESIGN AND METHODS: Relative incorporation of stable isotope labeled substrates was quantified by isotopologue analysis of key acyl-coenzyme A (CoA) thioester products for fresh, viable (after collection, Days 2-5), and expired PLTs (after Day 5). We examined the incorporation of acetate, glucose, and palmitate into acetyl- and succinyl-CoA via liquid chromatography-tandem mass spectrometry. RESULTS: Storage-related defects in the incorporation of acetyl-CoA derived from acetate and palmitate were observed. Carbon derived from palmitate and acetate in succinyl-CoA was reduced over storage time. Glucose incorporation into succinyl-CoA increased in viable PLTs and then decreased in expired PLTs. Carbon derived from octanoate and pyruvate remained partially able to incorporate into acetyl- and succinyl-CoA in expired PLTs, with high variability in pyruvate incorporation. CONCLUSION: Isotopologue analysis is useful in probing substrate specific defects in the PSL. PMID- 28836288 TI - Mineral trioxide aggregate and other bioactive endodontic cements: an updated overview - part I: vital pulp therapy. AB - Mineral trioxide aggregate (MTA) is a bioactive endodontic cement (BEC) mainly comprised of calcium and silicate elements. The cement was introduced by Torabinejad in the 1990s and has been approved by the Food and Drug Administration to be used in the United States in 1997. A number of new BECs have also been introduced to the market, including BioAggregate, Biodentine, BioRoot RCS, calcium-enriched mixture cement, Endo-CPM, Endocem, EndoSequence, EndoBinder, EndoSeal MTA, iRoot, MicroMega MTA, MTA Bio, MTA Fillapex, MTA Plus, NeoMTA Plus, OrthoMTA, Quick-Set, RetroMTA, Tech Biosealer and TheraCal LC. It has been claimed that these materials have properties similar to those of MTA without its drawbacks. In this article, the chemical composition and the application of MTA and other BECs for vital pulp therapy (VPT), including indirect pulp cap, direct pulp cap, partial pulpotomy, pulpotomy and partial pulpectomy, have been reviewed and compared. Based on selected keywords, all papers regarding chemical composition and VPT applications of BECs had been reviewed. Most of the materials had calcium and silicate in their composition. Instead of referring to the cements based on their chemical compositions, we suggest the term 'bioactive endodontic cements (BECs)', which seems more appropriate for these materials because, in spite of differences in their chemical compositions, bioactivity is a common property for all of them. Numerous articles were found regarding use of BECs as VPT agents for indirect and direct pulp capping, partial pulpotomy and cervical pulpotomy. Most of these investigations used MTA for VPT. In most studies, newly introduced materials have been compared to MTA. Some of the BECs have shown promising results; however, the number of their studies compared to investigations on MTA is limited. Most studies had several methodological shortcomings. Future investigations with rigorous methods and materials are needed. PMID- 28836289 TI - Illuminating seizures: optogenetic approaches to studying networks in epilepsy. PMID- 28836290 TI - Association between dental visits for periodontal treatment and type 2 diabetes mellitus in an elderly Japanese cohort. AB - AIM: There is an association between type 2 diabetes mellitus (T2DM) and periodontitis. We examined the association between the dental visit status and diabetes status in the Japanese elderly population. MATERIALS AND METHODS: In total, 14,551 participants, aged 75 or 80 years, who underwent systemic health examinations were analysed. Three independent variables of dental visit status were investigated according to dental claims data, including whether dental treatment was received, type of dental treatment (no visit, periodontal treatment, or other dental treatment), and number of days of periodontal treatment (0, 1-4, or >=5 days). We performed multivariate logistic and linear regression analyses to examine the relationship between dental visit status and diabetes status. RESULTS: The multivariate odds ratio (OR) for T2DM was significantly lower (0.74, 95% confidence interval: 0.66-0.82) for subjects who received periodontal treatment compared with those who did not receive dental treatment. Subjects who received periodontal treatment had a significantly lower OR for T2DM, regardless of the number of days of treatment. In the multivariate linear regression model, receiving periodontal treatment was significantly associated with decrease in A1c (p < .05). CONCLUSION: Dental visits to receive periodontal treatment were associated with a better diabetes status in the Japanese elderly population. PMID- 28836291 TI - Introducing the concept of "CSF-shift edema" in traumatic brain injury. AB - Brain edema after severe traumatic brain injury (TBI) plays an important role in the outcome and survival of injured patients. It is also one of the main targets in the therapeutic approach in the current clinical practice. To date, the pathophysiology of traumatic brain swelling is complex and, being that it is thought to be mainly cytotoxic and vasogenic in origin, not yet entirely understood. However, based on new understandings of the hydrodynamic aspects of cerebrospinal fluid (CSF), an additional mechanism of brain swelling can be considered. An increase in pressure into the subarachnoid space, secondary to traumatic subarachnoid hemorrhage, would result in a rapid shift of CSF from the cisterns, through the paravascular spaces, into the brain, resulting in an increase of brain water content. This mechanism of brain swelling would be termed as "CSF-shift edema." This "CSF-shift," promoted by a pressure gradient, leads to increased pressure inside the paravascular spaces and the interstitium of the brain, disturbing the functions of the paravascular system, with implications of secondary brain injury. Cisternostomy, an emerging surgical treatment, would reverse the direction of the CSF-shift, allowing for a decrease in brain swelling. In addition, this technique would reduce the pressure in the paravascular spaces and interstitium, leading to a recovery of the functionality of the paravascular system. PMID- 28836292 TI - Non-invasive diagnosis and treatment strategies for traumatic brain injury: an update. AB - PURPOSE OF REVIEW: Traumatic Brain Injury (TBI) remains the leading cause of morbidity and mortality in U.S. Since the last decade, there have been several advances in the understanding and management of TBI that have shown the potential to improve outcomes. The aim of this review is to provide a useful overview of these potential diagnostic and treatment strategies that have yet to be proven, along with an assessment of their impact on outcomes after a TBI. RECENT FINDINGS: Recent technical advances in the management of a TBI are grounded in a better understanding of the pathophysiology of primary and secondary insult to the brain after a TBI. Hence, clinical trials on humans should proceed in order to evaluate their efficacy and safety. SUMMARY: Mortality associated with TBI remains high. Nonetheless, new diagnostic and therapeutic techniques have the potential to enhance early detection and prevention of secondary brain insult. PMID- 28836294 TI - How fast monoamine oxidases decompose adrenaline? Kinetics of isoenzymes A and B evaluated by empirical valence bond simulation. AB - This work scrutinizes kinetics of decomposition of adrenaline catalyzed by monoamine oxidase (MAO) A and B enzymes, a process controlling the levels of adrenaline in the central nervous system and other tissues. Experimental kinetic data for MAO A and B catalyzed decomposition of adrenaline are reported only in the form of the maximum reaction rate. Therefore, we estimated the experimental free energy barriers form the kinetic data of closely related systems using regression method, as was done in our previous study. By using multiscale simulation on the Empirical Valence Bond (EVB) level, we studied the chemical reactivity of the MAO A catalyzed decomposition of adrenaline and we obtained a value of activation free energy of 17.3 +/- 0.4 kcal/mol. The corresponding value for MAO B is 15.7 +/- 0.7 kcal/mol. Both values are in good agreement with the estimated experimental barriers of 16.6 and 16.0 kcal/mol for MAO A and MAO B, respectively. The fact that we reproduced the kinetic data and preferential catalytic effect of MAO B over MAO A gives additional support to the validity of the proposed hydride transfer mechanism. Furthermore, we demonstrate that adrenaline is preferably involved in the reaction in a neutral rather than in a protonated form due to considerably higher barriers computed for the protonated adrenaline substrate. The results are discussed in the context of chemical mechanism of MAO enzymes and possible applications of multiscale simulation to rationalize the effects of MAO activity on adrenaline level. PMID- 28836293 TI - Genetic driver mutations define the expression signature and microenvironmental composition of high-grade gliomas. AB - High-grade gliomas (HGG), including glioblastomas, are characterized by invasive growth, resistance to therapy, and high inter- and intra-tumoral heterogeneity. The key histological hallmarks of glioblastoma are pseudopalisading necrosis and microvascular proliferation, which allow pathologists to distinguish glioblastoma from lower-grade gliomas. In addition to being genetically and molecularly heterogeneous, HGG are also heterogeneous with respect to the composition of their microenvironment. The question of whether this microenvironmental heterogeneity is driven by the molecular identity of the tumor remains controversial. However, this question is of utmost importance since microenvironmental, non-neoplastic cells are key components of the most radiotherapy- and chemotherapy-resistant niches of the tumor. Our work demonstrates a versatile, reliable, and reproducible adult HGG mouse model with NF1-silencing as a driver mutation. This model shows significant differences in tumor microenvironment, expression of subtype-specific markers, and response to standard therapy when compared to our established PDGFB-overexpressing HGG mouse model. PDGFB-overexpressing and NF1-silenced murine tumors closely cluster with human proneural and mesenchymal subtypes, as well as PDGFRA-amplified and NF1 deleted/mutant human tumors, respectively, at both the RNA and protein expression levels. These models can be generated in fully immunocompetent mixed or C57BL/6 genetic background mice, and therefore can easily be incorporated into preclinical studies for cancer cell-specific or immune cell-targeting drug discovery studies. PMID- 28836295 TI - Microglia may compensate for dopaminergic neuron loss in experimental Parkinsonism through selective elimination of glutamatergic synapses from the subthalamic nucleus. AB - Parkinson's disease (PD) symptoms do not become apparent until most dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate, suggesting that compensatory mechanisms play a role. Here, we investigated the compensatory involvement of activated microglia in the SN pars reticulata (SNr) and the globus pallidus (GP) in a 6-hydroxydopamine-induced rat hemiparkinsonism model. Activated microglia accumulated more markedly in the SNr than in the SNc in the model. The cells had enlarged somata and expressed phagocytic markers CD68 and NG2 proteoglycan in a limited region of the SNr, where synapsin I- and postsynaptic density 95-immunoreactivities were reduced. The activated microglia engulfed pre- and post-synaptic elements, including NMDA receptors into their phagosomes. Cells in the SNr and GP engulfed red fluorescent DiI that was injected into the subthalamic nucleus (STN) as an anterograde tracer. Rat primary microglia increased their phagocytic activities in response to glutamate, with increased expression of mRNA encoding phagocytosis-related factors. The synthetic glucocorticoid dexamethasone overcame the stimulating effect of glutamate. Subcutaneous single administration of dexamethasone to the PD model rats suppressed microglial activation in the SNr, resulting in aggravated motor dysfunctions, while expression of mRNA encoding glutamatergic, but not GABAergic, synaptic elements increased. These findings suggest that microglia in the SNr and GP become activated and selectively eliminate glutamatergic synapses from the STN in response to increased glutamatergic activity. Thus, microglia may be involved in a negative feedback loop in the indirect pathway of the basal ganglia to compensate for the loss of dopaminergic neurons in PD brains. PMID- 28836296 TI - Enzyme-Assisted Metal-Organic Framework Sensing System for Diethylstilbestrol Detection. AB - As novel fluorescent-sensing materials, metal-organic frameworks (MOFs) have shown great potential in environmental monitoring. However, most of the researches are limited to traditional pollutants, whereas the application of MOFs to the detection of the pollutants with more complicated structures, such as endocrine disrupting chemicals (EDCs), has rarely been explored. The difficulties faced in the sensing of EDCs include their electronic stability and the structural similarity among homologues, which could be overcome by the incorporation of enzymatic reaction. In this work, the first example of enzyme assisted MOF-fluorescent-sensing was developed for the analysis of diethylstilbestrol (DES, a synthetic estrogen). In this system, DES is first oxidized by HRP/H2 O2 quantitatively to its quinone form, and then the quinone product is selectively captured by a stilbene based luminescent MOF to induce fluorescence response. By the tandem sensitization and filtration of enzymatic reaction and MOF adsorption, this method shows high sensitivity (DL=89 nm) and can distinguish DES from other similar-structured EDCs. PMID- 28836297 TI - High risk of stent thrombosis in the first 6 months after coronary stenting: Do not discontinue clopidogrel early after ACS. AB - OBJECTIVES: To estimate the incidence of stent thrombosis (ST) after early discontinuation of clopidogrel. BACKGROUND: Premature discontinuation of clopidogrel is the strongest risk factor for ST. In contrast, recent studies suggest that shorter dual antiplatelet therapy (DAPT) can be discontinued as soon as 3 months after stenting. However, these studies included very few ACS patients and were not powered for ST. Hence, little is known about the occurrence of ST in high-risk populations when DAPT is discontinued early. METHODS: This is a subanalysis of The Dutch ST Registry 437 ST cases (mainly first-generation DES and BMS). Acute coronary syndrome was the indication for index-PCI in 74% of the patients. Clopidogrel discontinuation rates in ST patients and matched controls were used to calculate the absolute incidence of ST after early clopidogrel discontinuation. RESULTS: The overall rate of ST after cessation of clopidogrel was 4.6% (95%CI: 3.9-5.4%), as compared to 1.7% (95%CI: 1.5-1.9%) in patients who did not discontinue clopidogrel. The incidence of ST was 35.4% when clopidogrel was discontinued in the first 30 days after index-PCI declining to 11.7% when clopidogrel was discontinued in the first 180 days. CONCLUSIONS: This dedicated ST registry shows that ST rates were very high when clopidogrel was discontinued before 6 months after index-PCI and therefore suggests that clopidogrel discontinuation in the first 6 months after ACS should be avoided. PMID- 28836298 TI - A qualitative examination of patients experiences of dietitians ' consultation engagement styles within nephrology. AB - BACKGROUND: Dietitians provide individuals with tailored, practical nutritional advice. For this reason, skills in effective interpersonal communication are essential. In the case of chronic kidney disease, the specifics of dietary advice may change according to renal function. The conveyance of accurate dietary advice and compliance is critical and requires full engagement with the service. The effect of communication styles on patients ' engagement experiences with renal dietetics is unknown. Accordingly, the present study aimed to explore patients ' engagement experiences with renal dietitians. METHODS: A qualitative phenomenology study using semi-structured in-depth interviews was undertaken with 20 adult renal service users who had engaged with renal dietitians to receive dietary advice. Interpretive phenomenological analysis was used to analyse data. RESULTS: Two main themes emerged from consultation experiences: helpful and unhelpful engagement styles. Individuals reporting helpful engagement styles experienced dietitians ' communication as empathetic, demonstrating positive regard for their lifestyles. However, individuals who reported experiences of unhelpful engagement styles found dietetic care indifferent and communication styles paternalistic. These individuals continued to engage reluctantly despite unhelpful engagement experiences, but felt disempowered. These diverse experiences of engagement can be interpreted by means of 'ego states' within the theoretical model of transactional analysis (TA). Adult ego states may underpin a helpful engagement style whilst a dietitians ' parental ego state was more likely to precipitate an unhelpful engagement style. CONCLUSIONS: Ego states, in the context of TA theory, can help to explain the way in which patients engage with renal dietitians. Attention should be given to the employment of a humanistic approach within dietetic consultations. Dietitans need to ensure that they can demonstrate expertise and confidence in the specific communication skills required for patient-centred care. PMID- 28836299 TI - Rapid ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry and selected reaction monitoring strategy for the identification and quantification of minor spinacetin derivatives in spinach. AB - RATIONALE: Spinach is green leafy vegetable which is a rich source of flavonoids, phenolic acids, carotenoids, and vitamins A, C and E. It contains unique flavonoids which have significant anticarcinogenic, antiinflammatory and free radical scavenging activities. The present study reports the systematic identification and quantification of novel flavonoids by ultra-high-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (UHPLC/HR-QTOFMS). METHODS: An ultrasonication technique was used for the extraction of flavonoids from spinach. A rapid and reliable analytical method was established for the identification of flavonoids from methanolic extract. Flavonoids were characterized by their ultraviolet (UV) spectra, high-resolution accurate masses and MS/MS fragmentation pathways obtained using electrospray ionization (ESI). Furthermore, precursor ions from the intact molecule, and the resulting product ions, were monitored by selected reaction monitoring (SRM) with different collision energies in positive and negative ion mode. RESULTS: For the first time, five minor spinacetin derivatives were identified under optimized SRM and broadband collision-induced dissociation (+bbCID) conditions. Fragmentation pathways were proposed for spectra obtained in ESI positive ion mode. The use of HR-QTOFMS and SRM allowed us to differentiate between molecules with the same nominal mass. The identified spinacetin derivatives were found to be acylated with ferulic and coumaric acids. CONCLUSIONS: UHPLC interfaced with HR-QTOFMS in combination with SRM provides a rapid, reliable and highly sensitive method for the identification of flavonoids, and potentially other bioactive compounds, in a complex matrix. PMID- 28836300 TI - Cerebral amyloid angiopathy initially occurs in the meningeal vessels. AB - To clarify the frequency of CAA in the brain parenchyma and subarachnoid space (SAS), we counted sections of blood vessels showing positive staining for Abeta in the SAS, cerebral cortex (CC) and cerebral white matter (WM) using paraffin embedded sections of the frontal, temporal and occipital lobes. The specimens had been taken for routine neuropathological examination from the brains of 105 Japanese patients (aged 40-95 years) selected from among 200 consecutive patients autopsied between 1989 and 2015 at our hospital. We examined the anatomical ratios of blood-vessel sections in the SAS relative to the CC in three selected CAA cases, and those of Abeta-positive blood-vessel sections in CAA cases. CAA was found in 53 of the 105 cases (50.5%), and the youngest patient affected was a 51-year-old man. The incidence of CAA increased with age. The anatomical ratio of blood vessel sections in the SAS relative to the CC was 1/3.70-1/4.37 (mean: 1/3.94). The ordinary CAA group, in which CAA was seen in both the SAS and CC, included 41 cases (77.4%). In 37 of these cases, the SAS/CC ratio of Abeta positive blood vessels was 1/0.05-1/0.66 (mean: 1/0.26), and in the other four cases the ratio was 1/1-1/1.5. In the ordinary CAA group, the SAS/CC ratio of Abeta-positive blood vessels was smaller than the anatomical ratio. The meningeal CAA group, in which CAA was found only in the SAS, included 12 cases (22.6%). These patients ranged in age from their fifties to their nineties. There was no case in which CAA was limited only to the CC. We concluded that CAA initially develops in the meningeal blood vessels, and not in the cortical blood vessels. CAA in the WM was seen in 10 cases, not only in nine cases that were severe, but also in a mild case. PMID- 28836301 TI - A pilot study on the feasibility of training nurses to formulate multicomponent oral health interventions in a residential aged care facility. AB - OBJECTIVES: This 10 weeks feasibility study investigated whether residential care nurses with 12 hours advanced oral health training in assessments and saliva testing could formulate, implement and monitor individualised oral care plans of early dementia residents. METHOD: Four trained lead advocate nurses using SXI-D, OHIP14, oral health assessment tool (OHAT) assessments and a modified saliva test formulated nurse scheduled comprehensive oral care plans (NSCOCPs) by selecting and scheduling preventive products and procedures multiple times throughout the day to alkalise the mouth of 8 residents as an adjunct to assisted brushing and high-fluoride toothpaste. RESULTS: Nurse assessments, saliva tests and care plans were validated against oral health therapist (OHT) findings. Care plan agreement between Nurse and OHT intervention selection and scheduling was high (75%-88%). Untrained nurse compliance was very high, 86%-99% for the 4930 scheduled interventions. Untrained nurses delivered multiple scheduled interventions by following NSCOCPs despite initially not understanding the reason for each of 9 interventions categories. NSCOCPs could track and monitor whether a recommended intervention had been completed by general nursing staff over 3 nursing shifts. CONCLUSION: The role of nurses may have to be expanded beyond traditional roles to meet the growth and changes in oral health needs in residential facilities. Intensive training of a few lead advocate nurses to assess risk and formulate individualised NSCOCPs provides a method to transfer knowledge to untrained staff and deliver multicomponent preventive interventions soon after entry into residential care where timely visits by dental professionals to examine residents and prescribe preventive interventions are infrequent or unlikely. PMID- 28836303 TI - Stability-indicating assay method for acotiamide: Separation, identification and characterization of its hydroxylated and hydrolytic degradation products along with a process-related impurity by ultra-high-performance liquid chromatography/electrospray ionization quadrupole time-of-flight tandem mass spectrometry. AB - RATIONALE: The presence of impurities and degradation products will affect the pharmacokinetic, pharmacodynamic properties and alter the safety of a drug. Hence, the development of a stability-indicating assay method is an integral part of quality product development and is crucial for the regulatory approval of drug products. METHODS: Acotiamide was subjected to stress degradation under hydrolytic, oxidative, photo and thermal stress conditions. The resulted degradation products (DPs), as well as a process-related impurity (IMP), were selectively separated from the drug on a Waters Acquity HSS cyano column (100 * 2.1 mm, 1.8 MUm) with a mobile phase containing a gradient mixture of 0.1% formic acid and acetonitrile (ACN) at a flow rate of 0.25 mL min-1 . RESULTS: The drug was found to degrade under hydrolytic (acidic and basic), oxidative and photolytic stress while it remained stable under neutral hydrolytic and thermal stress conditions. The seven degradation products (DPs) and one process-related impurity (IMP) were observed. All the DPs and process-related IMP were well separated by the developed ultra-high-performance liquid chromatography (UHPLC) method and subsequently characterized by UHPLC/electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS). The proposed UHPLC method was validated with respect to specificity, linearity, accuracy, precision and robustness as per ICH guideline, Q2 (R1). CONCLUSIONS: All the observed DPs were new and formed by hydrolysis of an amide bond, phenyl ring hydroxylation and hydrolysis of the methoxy group of the phenyl ring. The despropyl process-related impurity was observed and well separated from the drug. The proposed UHPLC mass spectrometric method has greater utility in the identification of DPs in much less time with excellent selectivity. PMID- 28836302 TI - Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression. AB - Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently described a model combining noninflammatory cytodegeneration (via cuprizone) with the classic active experimental autoimmune encephalomyelitis (Cup/EAE model), which exhibits inflammatory forebrain lesions. Here, we describe the histopathological characteristics and progression of these Cup/EAE lesions. We show that inflammatory lesions develop at various topographical sites in the forebrain, including white matter tracts and cortical and subcortical grey matter areas. The lesions are characterized by focal demyelination, discontinuation of the perivascular glia limitans, focal axonal damage, and neutrophil granulocyte extravasation. Transgenic mice with enhanced green fluorescent protein-expressing microglia and red fluorescent protein-expressing monocytes reveal that both myeloid cell populations contribute to forebrain inflammatory infiltrates. EAE triggered inflammatory cerebellar lesions were augmented in mice pre-intoxicated with cuprizone. Gene expression studies suggest roles of the chemokines Cxcl10, Ccl2, and Ccl3 in inflammatory lesion formation. Finally, follow-up experiments in Cup/EAE mice with chronic disease revealed that forebrain, but not spinal cord, lesions undergo spontaneous reorganization and repair. This study underpins the significance of brain-intrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation. PMID- 28836304 TI - Impaired microglia process dynamics post-stroke are specific to sites of secondary neurodegeneration. AB - Stroke induces tissue death both at the site of infarction and at secondary sites connected to the primary infarction. This latter process has been referred to as secondary neurodegeneration (SND). Using predominantly fixed tissue analyses, microglia have been implicated in regulating the initial response at both damage sites post-stroke. In this study, we used acute slice based multiphoton imaging, to investigate microglia dynamic process movement in mice 14 days after a photothrombotic stroke. We evaluated the baseline motility and process responses to locally induced laser damage in both the peri-infarct (PI) territory and the ipsilateral thalamus, a major site of post-stroke SND. Our findings show that microglia process extension toward laser damage within the thalamus is lost, yet remains robustly intact within the PI territory. However, microglia at both sites displayed an activated morphology and elevated levels of commonly used activation markers (CD68, CD11b), indicating that the standardly used fixed tissue metrics of microglial "activity" are not necessarily predictive of microglia function. Analysis of the purinergic P2 Y12 receptor, a key regulator of microglia process extension, revealed an increased somal localization on nonresponsive microglia in the thalamus. To our knowledge, this is the first study to identify a non responsive microglia phenotype specific to areas of SND post-stroke, which cannot be identified by the classical assessment of microglia activation but rather the localization of P2 Y12 to the soma. PMID- 28836305 TI - Highly Microporous Nitrogen-doped Carbon Synthesized from Azine-linked Covalent Organic Framework and its Supercapacitor Function. AB - Porous carbons with nitrogen-doped (N-doped) structures are promising materials for advanced energy conversion and storage applications, including supercapacitors and fuel cell catalysts. In this study, microporous N-doped carbon was successfully fabricated through carbonization of covalent organic frameworks (COFs) with an azine-linked two-dimensional molecular network (ACOF1). In the carbonized ACOF1, micropores with diameters smaller than 1 nm are selectively formed, and a high specific surface area (1596 cm2 g-1 ) is achieved. In addition, the highly porous structure with N-doped sites results in enhancement of the electrochemical capacitance. Detailed investigation for the micropore-forming process reveals that the formation of nitrogen gas during the thermal degradation of the azine bond contributes to the microporous structure formation. Therefore, the present direct carbonization approach using COFs allows the fabrication of microporous heteroatom-doped carbons, based on molecularly designed COFs, toward future electrochemical and energy applications. PMID- 28836306 TI - Can grip strength and/or walking speed be simple indicators of the deterioration in tongue pressure and jaw opening force in older individuals? AB - OBJECTIVES: Swallowing-related muscle strength decreases due to sarcopenia, and older people are at risk for sarcopenia and the resultant dysphagia. However, no studies have assessed the direct relationships between whole-body strength and swallowing-related muscles. Therefore, this study investigates the relationships between decreased whole-body strength, which is easily evaluated, and swallowing related muscle strength. MATERIALS AND METHODS: A total of 197 elderly individuals (97 men aged 78.5 +/- 6.6 years and 100 women aged 77.8 +/- 6.2 years) were enrolled. Grip strength, walking speed, tongue pressure and jaw opening force were measured, and the effects of age and the relationships between whole-body strength and swallowing-related muscle strength were investigated. RESULTS: With respect to age-related changes, tongue pressure, jaw opening force, grip strength and walking speed decreased with age in men and women. The relationships between whole-body strength and swallowing-related muscle strength were analysed, with age used as the control variable. Among men, tongue pressure was correlated with grip strength and walking speed, whereas jaw opening force was correlated with grip strength. Among women, neither tongue pressure nor jaw opening force was correlated with grip strength or walking speed. CONCLUSIONS: There was a sex-based difference in the correlations between whole-body strength and swallowing-related muscle strength. Among men, swallowing-related muscle strength was correlated with whole-body strength, and grip strength could thus serve as a simple indicator for swallowing-related muscle strength. CLINICAL RELEVANCE: Decreased swallowing-related muscle strength can be inferred in cases involving male patients for whom decreased grip strength is measured during physical examination or is otherwise suggested (eg, by an inability to open plastic bottles). PMID- 28836307 TI - Genetic dissection of oligodendroglial and neuronal Plp1 function in a novel mouse model of spastic paraplegia type 2. AB - Proteolipid protein (PLP) is the most abundant integral membrane protein in compact central nervous system myelin, and null mutations of the PLP1 gene cause spastic paraplegia type 2 (SPG2). SPG2 patients and PLP-deficient mice exhibit only moderate abnormalities of myelin but progressive degeneration of long axons. Since Plp1 gene products are detected in a subset of neurons it has been suggested that the loss of neuronal Plp1 expression could be the cause of the axonal pathology. To test this hypothesis, we created mice with a floxed Plp1 allele for selective Cre-mediated recombination in neurons. We find that recombination of Plp1 in excitatory projection neurons does not cause neuropathology, whereas oligodendroglial targeting of Plp1 is sufficient to cause the entire neurodegenerative spectrum of SPG2 including axonopathy and secondary neuroinflammation. We conclude that PLP-dependent loss of oligodendroglial support is the primary cause of axonal degeneration in SPG2. PMID- 28836308 TI - Siglec-H is a microglia-specific marker that discriminates microglia from CNS associated macrophages and CNS-infiltrating monocytes. AB - Several types of myeloid cell are resident in the CNS. In the steady state, microglia are present in the CNS parenchyma, whereas macrophages reside in boundary regions of the CNS, such as perivascular spaces, the meninges and choroid plexus. In addition, monocytes infiltrate into the CNS parenchyma from circulation upon blood-brain barrier breakdown after CNS injury and inflammation. Although several markers, such as CD11b and ionized calcium-binding adapter molecule 1 (Iba1), are frequently used as microglial markers, they are also expressed by other types of myeloid cell and microglia-specific markers were not defined until recently. Previous transcriptome analyses of isolated microglia identified a transmembrane lectin, sialic acid-binding immunoglobulin-like lectin H (Siglec-H), as a molecular signature for microglia; however, this was not confirmed by histological studies in the nervous system and the reliability of Siglec-H as a microglial marker remained unclear. Here, we demonstrate that Siglec-H is an authentic marker for microglia in mice by immunohistochemistry using a Siglec-H-specific antibody. Siglec-H was expressed by parenchymal microglia from developmental stages to adulthood, and the expression was maintained in activated microglia under injury or inflammatory condition. However, Siglec-H expression was absent from CNS-associated macrophages and CNS infiltrating monocytes, except for a minor subset of cells. We also show that the Siglech gene locus is a feasible site for specific targeting of microglia in the nervous system. In conclusion, Siglec-H is a reliable marker for microglia that will allow histological identification of microglia and microglia-specific gene manipulation in the nervous system. PMID- 28836310 TI - Deep neural network-based computer-assisted detection of cerebral aneurysms in MR angiography. AB - BACKGROUND: The usefulness of computer-assisted detection (CAD) for detecting cerebral aneurysms has been reported; therefore, the improved performance of CAD will help to detect cerebral aneurysms. PURPOSE: To develop a CAD system for intracranial aneurysms on unenhanced magnetic resonance angiography (MRA) images based on a deep convolutional neural network (CNN) and a maximum intensity projection (MIP) algorithm, and to demonstrate the usefulness of the system by training and evaluating it using a large dataset. STUDY TYPE: Retrospective study. SUBJECTS: There were 450 cases with intracranial aneurysms. The diagnoses of brain aneurysms were made on the basis of MRA, which was performed as part of a brain screening program. FIELD STRENGTH/SEQUENCE: Noncontrast-enhanced 3D time of-flight (TOF) MRA on 3T MR scanners. ASSESSMENT: In our CAD, we used a CNN classifier that predicts whether each voxel is inside or outside aneurysms by inputting MIP images generated from a volume of interest (VOI) around the voxel. The CNN was trained in advance using manually inputted labels. We evaluated our method using 450 cases with intracranial aneurysms, 300 of which were used for training, 50 for parameter tuning, and 100 for the final evaluation. STATISTICAL TESTS: Free-response receiver operating characteristic (FROC) analysis. RESULTS: Our CAD system detected 94.2% (98/104) of aneurysms with 2.9 false positives per case (FPs/case). At a sensitivity of 70%, the number of FPs/case was 0.26. DATA CONCLUSION: We showed that the combination of a CNN and an MIP algorithm is useful for the detection of intracranial aneurysms. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:948-953. PMID- 28836311 TI - Suspension rates of students with autism or intellectual disabilities in Maryland from 2004 to 2015. AB - BACKGROUND: Little research exists on suspension of students with autism or intellectual disabilities. We examined suspension rates of students with autism or intellectual disability in Maryland from 2004 to 2015 to understand whether race and disability status predicted the odds of being suspended. METHOD: We used school enrollment data and school suspension data in Maryland for analysis. Descriptive statistics by race and disability category were calculated. Logistic regression was used to examine differences in odds of suspension by race and by disability (ID and autism) each year. RESULTS: Suspension rates in Maryland decreased overall from 2004 to 2015, but African American students with intellectual disability or no disability were significantly more likely to be suspended. White students with autism and White students with intellectual disability had significantly higher odds of suspension than White students without a disability. CONCLUSIONS: Overall risk for suspension in Maryland decreased over time. African American students with autism or intellectual disability, as well as white students with autism or intellectual disability, experienced significantly higher odds of suspension when compared to their White students without a disability. This relatively unexplored issue commands attention from researchers and policymakers alike. PMID- 28836309 TI - Epidemiology and prognosis of candidaemia in elderly patients. AB - The aim of the study was to analyse the epidemiology and prognosis of candidaemia in elderly patients. We performed a comparison of clinical presentation of candidaemia according to age and a study of hazard factors within a prospective programme performed in 29 hospitals. One hundred and seventy-six episodes occurred in elderly patients (>75 years), 227 episodes in middle-aged patients (61-75 years) and 232 episodes in younger patients (16-60 years). Central venous catheter, parenteral nutrition, neutropenia, immunosuppressive therapy and candidaemia caused by Candida parapsilosis were less frequent in elderly patients. These patients received inadequate antifungal therapy (57.3%) more frequently than middle-aged and younger patients (40.5% P < .001). Mortality during the first week (20%) and 30 days (42%) was higher in elderly patients. The variables independently associated with mortality in elderly patients during the first 7 days were acute renal failure (OR: 2.64), Pitt score (OR: 1.57) and appropriate antifungal therapy (OR: 0.132). Primary candidaemia (OR: 2.93), acute renal failure (OR: 3.68), Pitt score (OR: 1.38), appropriate antifungal therapy (OR: 0.3) and early removal of the central catheter (OR: 0.47) were independently associated with 30-day mortality.In conclussion, inadequate antifungal treatment is frequently prescribed to elderly patients with candidaemia and is related with early and late mortality. PMID- 28836312 TI - Premature ventricular contraction-induced concealed retrograde penetration: Electrocardiographic manifestations on anterograde ventricular preexcitation. AB - In patients with manifest anterograde ventricular preexcitation, the electrocardiographic manifestation of the anomalous conduction through the simultaneous conduction over the atrioventricular (AV) node and the accessory pathway ("delta wave"); depends on several factors, the most representative being the conduction velocity over one or another connection. Occasionally, ventricular ectopic beats may present with retrograde penetration over one or both conduction pathways (AV node and/or accessory pathway), impacting on the morphology of the next immediate anterogradely conducted QRS. We present a case of a young patient with WPW syndrome and ectopic ventricular beats with different manifestations on the postectopic QRS due to concealed penetration of different conduction pathways. PMID- 28836313 TI - Gene therapy for heart failure: time to go back to the drawing board. PMID- 28836314 TI - The trajectories of cannabis and tobacco policies in the United States, Uruguay, Canada and Portugal: is more cross-substance learning possible outside the United States? PMID- 28836315 TI - Inotropic myocardial reserve deficiency is the predominant feature of exercise haemodynamics in cardiac amyloidosis. AB - AIMS: This study aimed to characterize invasive haemodynamics during exercise in subjects with cardiac amyloidosis (CA). METHODS AND RESULTS: The study population numbered 44 subjects. Group A (CA-positive, n = 24) comprised wild-type transthyretin patients (n = 10), familial transthyretin amyloidosis mutation carriers (ATTRm) with cardiac involvement (n = 5), and light-chain amyloidosis patients with cardiac involvement (n = 9). Group B (CA-negative, n = 20) comprised four healthy ATTRm subjects without cardiac involvement documented by 11 C-PIB positron emission tomography and 16 healthy controls. All subjects underwent a symptom-limited, semi-supine exercise test with expired gas analysis and simultaneous right heart catheterization. CA patients had lower peak oxygen consumption [15 +/- 6 mL/min/kg bodyweight (bwt) vs. 33 +/- 7 mL/min/kg bwt; P < 0.0001] than controls. Myocardial reserve during exercise was significantly reduced in CA patients as reflected in a small increase in stroke volume index (SVI) and cardiac index (CI) compared with controls [DeltaSVI: 4 mL/m2 (range: -1 to 8) vs. 14 mL/m2 (range: 5-25); P < 0.0001; DeltaCI: 2 +/- 2 L/min vs. 7 +/- 2 L/min; P < 0.0001]. During exercise, CA patients had significantly higher left and right ventricular filling pressures than controls. Furthermore, CA patients had severely impaired pulmonary arterial compliance (PAC) compared with controls [2.9 mL/mmHg (range: 2.1-4.5) vs. 7.5 mL/mmHg (range: 5.7-10.4); P < 0.0001]. CONCLUSIONS: Cardiac amyloid deposits are associated with severely reduced inotropic myocardial reserve and increased left and right ventricular filling pressures during exercise. Furthermore, CA subjects have severely reduced PAC, which may contribute to right heart failure and reduced exercise capacity. PMID- 28836316 TI - Maximum permissible load for Kiso horses trotting over a short, straight course. AB - This study aimed to determine the load-bearing capacity of trotting Kiso horses using gait analysis. Ten Kiso horses with a height at withers of 128 cm were included. Their riders were fitted with a marker (70 mm in diameter placed on their chest) recorded by two digital DVD cameras while trotting along a short, straight course. In total, eight tests were performed for each horse: the first with a 70 kg load; six with randomly loaded weights ranging 80-130 kg; and then a final test again with a 70 kg load. Three-dimensional movement of the marker was analyzed using a motion capture system. The time series of vertical displacement of the marker underwent spectrum analysis by the maximum entropy method, and the autocorrelation coefficient was calculated. The first two peaks of the autocorrelation were defined as symmetry and regularity, and their sum was defined as stability. Regularity in the 120 kg test (0.54) was lower than that in the first 70 kg test (0.61), and stability in the 120 kg test (1.31) was lower than that in the first 70 kg test (1.42). We concluded that the maximum permissible load for a trotting Kiso horse is < 120 kg, which represents 31% of its bodyweight. PMID- 28836317 TI - CCBuilder 2.0: Powerful and accessible coiled-coil modeling. AB - : The increased availability of user-friendly and accessible computational tools for biomolecular modeling would expand the reach and application of biomolecular engineering and design. For protein modeling, one key challenge is to reduce the complexities of 3D protein folds to sets of parametric equations that nonetheless capture the salient features of these structures accurately. At present, this is possible for a subset of proteins, namely, repeat proteins. The alpha-helical coiled coil provides one such example, which represents ~ 3-5% of all known protein-encoding regions of DNA. Coiled coils are bundles of alpha helices that can be described by a small set of structural parameters. Here we describe how this parametric description can be implemented in an easy-to-use web application, called CCBuilder 2.0, for modeling and optimizing both alpha-helical coiled coils and polyproline-based collagen triple helices. This has many applications from providing models to aid molecular replacement for X-ray crystallography, in silico model building and engineering of natural and designed protein assemblies, and through to the creation of completely de novo "dark matter" protein structures. CCBuilder 2.0 is available as a web-based application, the code for which is open-source and can be downloaded freely. http://coiledcoils.chm.bris.ac.uk/ccbuilder2. LAY SUMMARY: We have created CCBuilder 2.0, an easy to use web-based application that can model structures for a whole class of proteins, the alpha-helical coiled coil, which is estimated to account for 3-5% of all proteins in nature. CCBuilder 2.0 will be of use to a large number of protein scientists engaged in fundamental studies, such as protein structure determination, through to more-applied research including designing and engineering novel proteins that have potential applications in biotechnology. PMID- 28836318 TI - Social cognition and metacognition in social anxiety: A systematic review. AB - Cognitive-behavioural and metacognitive approaches to emotional disorder implicate beliefs in social anxiety, but the types of beliefs differ across these perspectives. Cognitive models suggest that social beliefs about the self (i.e., high standards and conditional and unconditional beliefs) are central. In contrast, the metacognitive model gives centre stage to metacognitive beliefs (i.e., positive and negative beliefs about thinking) as main contributors to the maintenance of the disorder. Despite an expanding research interest in this area, the evidence for such contributions has not yet been reviewed. This study set out to systematically review relevant cross-sectional, longitudinal, and experimental investigations of the direct and indirect (through cognitive processes, such as anticipatory processing, self-focused attention, the post-mortem, and avoidance) relationships of social and metacognitive beliefs with social anxiety. Clinical and nonclinical samples were included, and correlation and regression coefficients as well as results from group comparisons (e.g., t tests and analyses of variance) were extracted. Overall, 23 papers were located, through PsycINFO, PubMed, and Web of Science, and reviewed using narrative synthesis. The results showed a robust positive relationship between social beliefs and social anxiety that appeared to be mediated by cognitive processes. Specific metacognitive beliefs were found to positively contribute to social anxiety both directly and indirectly, through cognitive processes. The study's findings are limited to 2 models of social anxiety and other minor limitations (e.g., grey literature was excluded). With these accounted for, the results are discussed in terms of the conceptualization and treatment of social anxiety and suggestions for future research are made. PMID- 28836319 TI - Paediatric palliative care and intellectual disability-A unique context. AB - BACKGROUND: Paediatric palliative care is a nuanced area of practice with additional complexities in the context of intellectual disability. There is currently minimal research to guide clinicians working in this challenging area of care. METHOD: This study describes the complex care of children with life limiting conditions and intellectual disability by means of a literature synthesis and commentary with "best-practice" guide. RESULTS: As few articles concerning children with intellectual disability and palliative care needs were identified by formal systematic review, our expert consensus group has drawn from the paediatric palliative, oncology and adult intellectual disability literature to highlight common clinical challenges encountered in the day-to-day care of children with intellectual disability and life-limiting conditions. CONCLUSION: A longitudinal child- and family-centred approach is key to ensuring best-practice care for families of children with life-limiting conditions and intellectual disability. As highlighted by the great absence of literature addressing this important patient population, further research in this area is urgently required. PMID- 28836320 TI - The Perth Emergency Laparotomy Audit. AB - BACKGROUND: Emergency laparotomies (ELs) are associated with high mortality and substantial outcome variation. There is no prospective Australian data on ELs. The aim of this study was to audit outcome after ELs in Western Australia. METHODS: A 12-week prospective audit was completed in 10 hospitals. Data collected included patient demographics, the clinical pathway, preoperative risk assessment and outcomes including 30-day mortality and length of stay. RESULTS: Data were recorded for 198 (76.2%) of 260 patients. The 30-day mortality was 6.5% (17/260) in participating hospitals, and 5.4% (19 of 354) across Western Australia. There was minimal variation between the three tertiary hospitals undertaking 220 of 354 (62.1%) ELs. The median and mean post-operative lengths of stay, excluding patients who died, were 8 and 10 days, respectively. In the 48 patients with a prospectively documented risk of >=10%, both a consultant surgeon and anaesthetist were present for 68.8%, 62.8% were admitted to critical care and 45.8% commenced surgery within 2 h. The mortality in those retrospectively (62; 31%) and prospectively risk-assessed was 9.5% and 5.2%, respectively. CONCLUSION: This prospective EL audit demonstrated low 30-day mortality with little inter hospital variation. Individual hospitals have scope to improve their standards of care. The importance of prospective risk assessment is clear. PMID- 28836321 TI - Association between left atrial enlargement and obstructive sleep apnea in a general population of 71-year-old men. AB - Left atrial enlargement has been shown to be associated with obstructive sleep apnea in patients with coronary artery disease and in sleep clinic cohorts. However, data from the general population are limited. The aim of this study was to investigate whether there is an association between obstructive sleep apnea and left atrial enlargement in a random sample from a general population of 71 year-old men. As part of the longitudinal population study The Study of Men Born in 1943, we analysed cross-sectional data for 411 men, all 71 years old, who had participated in an overnight home sleep study and a standardized echocardiographic examination. Of the 411 men, 29.4% had moderate to severe obstructive sleep apnea [apnea-hypopnea index score of >=15 (n = 121)]. These participants showed a significantly higher frequency of systolic heart failure, hypertension, overweight, had greater waist circumference as well as higher left atrial areas compared with men with no or mild obstructive sleep apnea (23.7 +/- 5.5 cm2 versus 21.6 +/- 4.5 cm2 , P < 0.001). In a linear regression analysis, obstructive sleep apnea was significantly associated with left atrial enlargement after adjusting for overweight, atrial fibrillation, heart failure with reduced ejection fraction, hypertension and mitral regurgitation. Compared with individuals without obstructive sleep apnea, the mean left atrial area was 1.7 +/ 1.5 cm2 larger in men with severe obstructive sleep apnea (P < 0.05) and 1.3 +/- 1.1 cm2 larger among men with moderate obstructive sleep apnea (P < 0.05). In this cross-sectional study of 71-year-old men from the general population, left atrial area was independently associated with prevalence and severity of obstructive sleep apnea. PMID- 28836322 TI - Clonal integration facilitates spread of Paspalum paspaloides from terrestrial to cadmium-contaminated aquatic habitats. AB - Cadmium (Cd) is a hazardous environmental pollutant with high toxicity to plants, which has been detected in many wetlands. Clonal integration (resource translocation) between connected ramets of clonal plants can increase their tolerance to stress. We hypothesised that clonal integration facilitates spread of amphibious clonal plants from terrestrial to Cd-contaminated aquatic habitats. The spread of an amphibious grass Paspalum paspaloides was simulated by growing basal older ramets in uncontaminated soil connected (allowing integration) or not connected (preventing integration) to apical younger ramets of the same fragments in Cd-contaminated water. Cd contamination of apical ramets of P. paspaloides markedly decreased growth and photosynthetic capacity of the apical ramets without connection to the basal ramets, but did not decrease these properties with connection. Cd contamination did not affect growth of the basal ramets without connection to the apical ramets, but Cd contamination of 4 and 12 mg.l-1 significantly increased growth with connection. Consequently, clonal integration increased growth of the apical ramets, basal ramets and whole clones when the apical ramets were grown in Cd-contaminated water of 4 and 12 mg.l-1 . Cd was detected in the basal ramets with connection to the apical ramets, suggesting Cd could be translocated due to clonal integration. Clonal integration, most likely through translocation of photosynthates, can support P. paspaloides to spread from terrestrial to Cd-contaminated aquatic habitats. Amphibious clonal plants with a high ability for clonal integration are particularly useful for re vegetation of degraded aquatic habitats caused by Cd contamination. PMID- 28836323 TI - Impact of gastric reflux on asthma in clinical practice. PMID- 28836324 TI - Hematopoietic stem cell transplantation in children with Griscelli syndrome: A single-center experience. AB - GS2 is a rare autosomal recessive disease characterized by hypopigmentation, variable immunodeficiency with HLH. HSCT is the only curative treatment for GS2. We analyzed the outcome of 10 children with GS2 who underwent HSCT at our center between October 1997 and September 2013. The median age of the patients at transplant was 13.5 months (range, 6-58 months). All of the patients developed HLH before HSCT and received HLH 94 or HLH 2004 protocols. Donors were HLA identical relatives in 8 patients, HLA-mismatched relatives in 2 patients. Engraftment was achieved in all except one patient. None of the patients developed acute GVHD. Chronic GVHD occurred in one and veno-occlusive disease occurred in four patients. Eight of the patients are under remission without any neurologic sequelae-median time of disease-free survival is 92.4 months. The present study shows successful transplant outcome without long-term neurologic sequelae in patients with GS2 who underwent HSCT from HLA-related donors. PMID- 28836325 TI - Total Synthesis of Actinophyllic Acid. AB - Herein we report a total synthesis of the indolohydroazocine natural product actinophyllic acid. The target molecule was retrosynthetically deconvoluted to render a greatly simplified and symmetrical [4.4.1] bicyclic trienone, the desymmetrization of which was carefully examined under a variety of conditions, including oxidative, reductive, and transition-metal-catalyzed transformations. Ultimately, the successful synthetic strategy featured chemoselective catalytic dihydroxylation, desymmetrizing nitrile oxide dipolar cycloaddition, and palladium-catalyzed aminoarylation to sequentially modify the three olefins within the trienone, followed by a late-stage reductive cascade indolization and alkylation to complete the target molecule. PMID- 28836326 TI - Overexpression of AtPAD4 in transgenic Brachypodium distachyon enhances resistance to Puccinia brachypodii. AB - Brachypodium distachyon (L.) has recently emerged as a model for temperate grasses for investigating the molecular basis of plant-pathogen interactions. Phytoalexin deficient 4 (PAD4) plays a regulatory role in mediating expression of genes involved in plant defence. In this research, we generated transgenic B. distachyon plants constitutively overexpressing AtPAD4. Two transgenic B. distachyon lines were verified using PCR and GUS phenotype. Constitutive expression of AtPAD4 in B. distachyon enhanced resistance to Puccinia brachypodii. P. brachypodii generated less urediniospores on transgenic than on wild-type plants. AtPAD4 overexpression enhanced salicylic acid (SA) levels in B. distachyon-infected tissues. qRT-PCR showed that expression of pathogenesis related 1 (PR1) and other defence-related genes were up-regulated in transformed B. distachyon following infection with P. brachypodii. Our results indicate that AtPAD4 overexpression in B. distachyon plants led to SA accumulation and induced PR gene expression that reduced the rate of colonisation by P. brachypodii. PMID- 28836327 TI - Serum sodium level within the normal range is associated with maximum voluntary tongue pressure against the palate among community-dwelling older Japanese men. AB - AIM: Recent geriatric studies have focused on maximum voluntary tongue pressure against the palate (MTP) as a diagnostic value for dysphagia, as dysphagia causes aspiration pneumonia. Dysphagia can also cause water intake difficulties, resulting in hypernatremia by indicating the presence of hyperosmotic dehydration. However, no studies have reported on a possible association between reduced MTP and serum sodium levels. METHODS: To evaluate hyperosmotic dehydration within the normal range as an indicator of reduced MTP, we carried out a cross-sectional study of 655 older Japanese community-dwelling men (age >=60 years) who undertook a general health check-up from 2015 to 2016. As a high concentration of glucose influences serum osmolarity, which might act as a strong confounding factor on this association, the additional analysis was limited to individuals without diabetes. Reduced MTP is defined as a tongue pressure at or under the 20th percentile of the study population (<=24.0 kPa). RESULTS: Independent of classical cardiovascular risk factors, the adjusted odds ratio of reduced MTP for a 1-standard deviation increment of serum sodium (2.21 mEq/L) was 1.29 (95% confidence interval 1.10-1.52). When the analysis was limited to individuals without diabetes, the association became slightly stronger, with an adjusted corresponding value of 1.59 (95% confidence interval 1.21-2.10). CONCLUSIONS: Serum sodium level within the normal range is independently associated with reduced MTP in older Japanese men. This finding suggests that measuring the MTP is clinically relevant for estimating the pathophysiological values (such as dysphagia risks and aspiration pneumonia risks) in daily clinical practice. Geriatr Gerontol Int 2018; 18: 183-186. PMID- 28836328 TI - The MNS glycophorin variant GP.Mur affects differential erythroid expression of Rh/RhAG transcripts. AB - BACKGROUND: The band 3 macrocomplex (also known as the ankyrin-associated complex) on the red cell membrane comprises two interacting subcomplexes: a band 3/glycophorin A subcomplex, and a Rh/RhAG subcomplex. Glycophorin B (GPB) is a component of the Rh/RhAG subcomplex that is also structurally associated with glycophorin A (GPA). Expression of glycophorin B-A-B hybrid GP.Mur enhances band 3 expression and is associated with lower levels of Rh-associated glycoprotein (RhAG) and Rh polypeptides. The goal of this study was to determine whether GP.Mur influenced erythroid Rh/RhAG expression at the transcript level. MATERIALS AND METHODS: GP.Mur was serologically determined in healthy participants from Taitung County, Taiwan. RNA was extracted from the reticulocyte-enriched fraction of peripheral blood, followed by reverse transcription and quantitative PCR for RhAG, RhD and RhCcEe. RESULTS: Quantification by real-time PCR revealed significantly fewer RhAG and RhCcEe transcripts in the reticulocytes from subjects with homozygous GYP*Mur. Independent from GYP.Mur, both RhAG and RhD transcript levels were threefold or higher than that of RhCcEe. Also, in GYP.Mur and the control samples alike, direct quantitative associations were observed between the transcript levels of RhAG and RhD, but not between that of RhAG and RhCcEe. CONCLUSION: Erythroid RhD and RhCcEe were differentially expressed at the transcript levels, which could be related to their different degrees of interaction or sensitivity to RhAG. Further, the reduction or absence of glycophorin B in GYP.Mur erythroid cells affected transcript expressions of RhAG and RhCcEe. Thus, GPB and GP.Mur differentially influenced Rh/RhAG expressions prior to protein translation. PMID- 28836329 TI - The effect of professional tooth cleaning or non-surgical periodontal therapy on oral halitosis in patients with periodontal diseases. A systematic review. AB - OBJECTIVE: The aim of this systematic review was to give the best available evidence on the impact of professional tooth cleaning (PTC) and scaling and root planing (SRP) on oral halitosis in patients with periodontal diseases. MATERIAL AND METHODS: Three databases were screened for relevant studies. Only randomized controlled trials (RCTs) or controlled clinical trials (CCT) were included. The primary outcome in all included studies was volatile sulphur compounds (VSC) measured by Halimeter or OralChroma and organoleptic scores as secondary outcome. Only studies investigating healthy adults except for periodontitis or gingivitis were included. The considered intervention strategies were professional tooth cleaning and non-surgical periodontal treatment. For both strategies, additional oral hygiene instructions (OHI) were possible. Two independent reviewers performed the study selection and quality assessment. SEARCH RESULTS: After abstract and title screening and subsequent full-text reading of potential papers, a placebo-controlled RCT could not be found. However, eight studies or particular arms used PTC or SRP as sole interventions and were included in this review. All trials or study arms included showed a positive effect on VSC levels or organoleptic scores after intervention. CONCLUSIONS: Based on best available evidence, PTC and SRP in combination with oral hygiene instructions reduced VSC values in patients with oral halitosis and/or periodontal diseases, independent of tongue cleaning and the use of mouth rinses. PMID- 28836330 TI - Actein alleviates 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated cellular dysfunction in osteoblastic MC3T3-E1 cells. AB - The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to affect bone metabolism. We evaluated the protective effects of the triterpene glycoside actein from the herb black cohosh against TCDD-induced toxicity in MC3T3-E1 osteoblastic cells. We found that TCDD significantly reduced cell viability and increased apoptosis and autophagy in MC3T3-E1 osteoblastic cells (P < .05). In addition, TCDD treatment resulted in a significant increase in intracellular calcium concentration, mitochondrial membrane potential collapse, reactive oxygen species (ROS) production, and cardiolipin peroxidation, whereas pretreatment with actein significantly mitigated these effects (P < .05). The effects of TCDD on extracellular signal-related kinase (ERK), aryl hydrocarbon receptor, aryl hydrocarbon receptor repressor, and cytochrome P450 1A1 levels in MC3T3-E1 cells were significantly inhibited by actein. The levels of superoxide dismutase, ERK1, and nuclear factor kappa B mRNA were also effectively restored by pretreatment with actein. Furthermore, actein treatment resulted in a significant increase in alkaline phosphatase (ALP) activity and collagen content, as well as in the expression of genes associated with osteoblastic differentiation (ALP, type I collagen, osteoprotegerin, bone sialoprotein, and osterix). This study demonstrates the underlying molecular mechanisms of cytoprotection exerted by actein against TCDD-induced oxidative stress and osteoblast damage. PMID- 28836331 TI - Coronary artery rotation in native and stented porcine coronary arteries. AB - INTRODUCTION: Coronary arteries are exposed to several complex biomechanical forces during the cardiac cycle. These biomechanical forces potentially contribute to both native coronary artery disease, development of atherosclerosis and eventual stent failure. The aim of the present study was to characterize and define coronary artery axial rotation and the effect of stent implantation on this biomechanical factor. METHODS: Intravascular ultrasound (IVUS) images were obtained from porcine coronary arteries and analyzed in ultrasound analysis software used to evaluate myocardial strain and torsion in echocardiography. In this study the software was utilized for a novel application to evaluate coronary artery rotation and time-to-peak (TTP) rotation in porcine coronary arteries. Clockwise (CW) and counterclockwise (CCW) rotation of coronary arteries during the cardiac cycle and (TTP) rotation were measured. RESULTS: A total of 11 (4 LAD, 4 LCX, 3 RCA) coronary artery segments were independently analyzed pre- and post-stent implantation for a total of 22 IVUS runs. CW and CCW rotation and TTP varied widely within coronary artery segments and between different coronary arteries. Stent implantation impacted degree, direction and TTP of coronary rotation. Measurement reliability was assessed and the intraclass correlation coefficient for maximum average CCW was 0.990 (95% confidence interval 0.980 0.996, P < 0.0001), indicating excellent agreement. CONCLUSIONS: Coronary arteries display wide spectrum of CW and CCW rotation during the cardiac cycle. Coronary stents impact the degree and direction of coronary artery rotation. The implications of these findings on development of atherosclerosis and stent failure require further investigation. PMID- 28836332 TI - A bidirectional relationship between eating disorder symptoms and quality of life supports a recovery focussed approach to treatment. PMID- 28836333 TI - A range of psycho-social and psychological interventions can support moderate improvements in negative symptoms in psychosis. PMID- 28836334 TI - The ethical conduct of research in occupational therapy. PMID- 28836335 TI - Authors' Reply to the Letter to the Editor: Reply to "Cognitive performance in women with fibromyalgia' by de Heredia-Torres and colleagues". PMID- 28836337 TI - Overexpansion of the 29 mm SAPIEN 3 transcatheter heart valve in patients with large aortic annuli (area > 683 mm2 ): A case series. AB - OBJECTIVES: To evaluate overexpanded 29 mm SAPIEN (S3) transcatheter heart valves in patients with aortic annuli area >683 mm2 . BACKGROUND: The largest valve area the 29 mm S3 is specified for is 683 mm2 . Valve overexpansion has been performed in patients with larger aortic annuli, but data are limited. Moreover, feasibility in areas >740 mm2 is unknown. METHODS: All 29 mm S3 transcatheter aortic valve replacements (TAVR) at a single center over 23-months were retrospectively reviewed. Patients with annulus areas >683 mm2 were included. Immediate post-TAVR hemodynamics and transthoracic echocardiography (TTE) findings on post-TAVR day-1 and day-30 were recorded. RESULTS: Of 81 29 mm S3 TAVR cases, 3 (3.7%) met inclusion criteria (patients 1, 2, and 3 had CT-scan derived areas of 748.1 mm2 , 793 mm2 , and 787 mm2 , respectively). Annular eccentricity index ranged from 0.12 to 0.25. All underwent transfemoral TAVR with 29 mm S3 valves overexpanded using +4 mL of contrast. Post-dilatation with +5 mL was performed in patient 2. The average valve shortening was 10.68 mm. On day 1, patients 1 and 2 had trace and mild paravalvular leak (PVL) (respectively), whereas, patient 3 had mild-moderate PVL. Patient 1 was also noted to have trace central AR on day 1. No other central AR was noted. Immediate post-procedure aortic regurgitation (AR) index in patients 1, 2, and 3 was 43, 34, and 33 respectively. At 30 days, AR was completely resolved in patient 1, whereas AR severity in patients 2 and 3 remained similar. No patients had > moderate AR at any point during follow-up. No valve migration or embolization occurred. Patient 1 required a permanent pacemaker. No other major complications were noted. All patients were clinically stable at 30 days. CONCLUSIONS: TAVR using overexpanded 29 mm S3 in valve areas >740 mm2 (up to 793 mm2 ) seemed to be safe and feasible in our small series. Further study in a larger series is needed to determine clinical outcomes in this patient population. PMID- 28836338 TI - Analysis of autonomic modulation of heart rate in patients with Parkinson's disease and elderly individuals submitted to game therapy training. AB - AIM: Elderly patients and individuals with Parkinson's disease have a reduction in autonomic heart rate modulation, which may influence the survival of these patients, and rehabilitation can minimize this event. We tested the hypothesis that rehabilitation protocol with game console would influence the cardiac autonomic modulation of patients with Parkinson's Disease. METHODS: Eight-seven volunteers were divided into two groups, control (n = 45) and Parkinson's (n = 42), they completed the study 40 volunteers in the control group (CG) and 31 patients in the Parkinson group (PG), and subjected to 24 sessions of game therapy physiotherapy, thrice a week. Analysis of autonomic HR modulation was conducted before and after the rehabilitation program using a Polar RS800CX HR sensor. For the analysis of heart rate variability the data were transferred to the Kubios HRV 2.2 program. Statistical analysis was performed in the Biostat 5.2 program, the comparison of the data by ANOVA followed by Tukey test, and the general characteristics by the chi-square test. The critical value for rejecting the null hypothesis was set at P < 0.05. RESULTS: HR variability in patients with PD exhibited higher influence on the sympathetic nervous system before protocol implementation and, following the protocol, patients did not attain the normality values of the control group, exhibiting a discreet improvement and maintenance of autonomic modulation of HR values. CONCLUSION: Subjects with PD exhibit less autonomic modulation of HR and the rehabilitation protocol with game therapy improved autonomic modulation of HR. Geriatr Gerontol Int 2018; 18: 20-25. PMID- 28836339 TI - Visual estimation versus different quantitative coronary angiography methods to assess lesion severity in bifurcation lesions. AB - OBJECTIVES: To compare visual estimation with different quantitative coronary angiography (QCA) methods (single-vessel versus bifurcation software) to assess coronary bifurcation lesions. BACKGROUND: QCA has been developed to overcome the limitations of visual estimation. Conventional QCA however, developed in "straight vessels," has proved to be inaccurate in bifurcation lesions. Therefore, bifurcation QCA was developed. However, the impact of these different modalities on bifurcation lesion severity classification is yet unknown METHODS: From a randomized controlled trial investigating a novel bifurcation stent (Clinicaltrials.gov NCT01258972), patients with baseline assessment of lesion severity by means of visual estimation, single-vessel QCA, 2D bifurcation QCA and 3D bifurcation QCA were included. We included 113 bifurcations lesions in which all 5 modalities were assessed. The primary end-point was to evaluate how the different modalities affected the classification of bifurcation lesion severity and extent of disease. RESULTS: On visual estimation, 100% of lesions had side branch diameter stenosis (%DS) >50%, whereas in 83% with single-vessel QCA, 27% with 2D bifurcation QCA and 26% with 3D bifurcation QCA a side-branch %DS >50% was found (P < 0.0001). With regard to the percentage of "true" bifurcation lesions, there was a significant difference between visual estimate (100%), single-vessel QCA (75%) and bifurcation QCA (17% with 2D bifurcation software and 13% with 3D bifurcation software, P < 0.0001). CONCLUSIONS: Our study showed that bifurcation lesion complexity was significantly affected when more advanced bifurcation QCA software were used. "True" bifurcation lesion rate was 100% on visual estimation, but as low as 13% when analyzed with dedicated bifurcation QCA software. PMID- 28836340 TI - Electronic alert system for improving appropriate thromboprophylaxis in hospitalized medical patients: a randomized controlled trial. AB - : Essentials Venous thromboembolism (VTE) prophylaxis in hospitalized medical patients remains inconsistent. We implemented an electronic alert system featuring a validated risk assessment model for VTE. In this randomized controlled study, the e-alert system did not improve VTE prophylaxis. Many electronic alerts were ignored by ordering physicians. SUMMARY: Background The use of thromboprophylaxis among acutely ill hospitalized medical patients remains inconsistent. Objective To improve thromboprophylaxis use by implementing a computer-based alert system combined with a Geneva Risk Score calculation tool in the electronic patient chart and order entry system. Patients/Methods Consecutive patients admitted to the general internal medicine wards of the University Hospital Bern, Switzerland were randomized to the alert group, in which an alert and the Geneva Risk Score calculation tool was issued in the electronic patient chart, or to the control group, in which no alert was issued. The primary endpoint was the rate of appropriate thromboprophylaxis during hospital stay. Results Overall, 1593 patients (alert group, 804; control group, 789) were eligible for analysis. The median age was 67 years (interquartile range, 53-79 years) and 47% were female. Appropriate thromboprophylaxis was administered to 536 (66.7%) patients from the alert group and to 526 (66.7%) patients from the control group. Among the 804 patients from the alert group, a total of 446 (55.5%) either had no score calculation by the physician in charge (n = 348) or had a calculated score result that was inconsistent with information from the patient chart (n = 98). Appropriate thromboprophylaxis was less often administered to patients with no score or an inconsistent score result than to 358 patients with a consistent score result (62.6% versus 71.8%). Conclusions The electronic alert (e-alert) system did not improve appropriate thromboprophylaxis, most likely because many e-alerts were ignored by ordering physicians. The use of appropriate thromboprophylaxis in the control group was higher than expected. PMID- 28836342 TI - Single trans-septal access technique for left atrial intracardiac echocardiography to guide left atrial appendage closure. AB - OBJECTIVE: This registry aimed to describe the safety and feasibility of a single trans-septal (TS) access technique for left intracardiac echocardiography (ICE) guidance of left-atrial appendage (LAA) closure procedure. BACKGROUND: LAA closure is currently accepted as an alternative to oral anticoagulation (OAC) in patients with non-valvular atrial fibrillation (NVAF) who are at high-risk for bleeding. Currently, LAA closure procedure is typically performed under trans esophageal echocardiogram (TEE) guidance. Although, ICE has the advantage of not requiring profound sedation/anesthesia, ICE-LAA imaging quality is often limited from the right atrium requiring double TS access. METHODS: Twenty-two patients with NVAF underwent LAA closure using the Amplatzer AmuletTM device (St Jude Medical) under ICE guidance from the left atrium. The ICE AcuNav catheter (Biosense Webster) and the Amulet delivery sheath were advanced into the LA through single TS puncture technique. RESULTS: The population was predominately male (59.1%) with a mean age of 74 +/- 9.3 years, at high-risk for stroke (mean CHADS2 score of 3.8 +/- 1.1) and bleeding (mean HAS BLED score of 3.5 +/- 1.3). The Amplatzer AmuletTM device was successfully implanted in all patients. No procedural related complications including device embolization were noted. No major cardiovascular events occurred and all patients were discharged alive. At 30-day follow-up all patients remained alive, free of ischemic stroke and with no residual leak or device thrombus on TEE. CONCLUSIONS: This initial experience suggests that LAA occlusion with the Amplatzer Amulet device using ICE guidance from the left atrium via a single trans-septal technique is feasible and safe. PMID- 28836341 TI - Effect of late prophylaxis in hemophilia on joint status: a randomized trial. AB - : Essentials High-quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy. SPINART was a 3-year randomized clinical trial of late/tertiary prophylaxis vs on-demand therapy. Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI. Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy. SUMMARY: Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives To describe 3-year bleeding, joint health and structure, health-related quality-of life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods Males aged 12-50 years with severe hemophilia A, >= 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible. PMID- 28836343 TI - Addressing barriers to maternal nutrition in low- and middle-income countries: A review of the evidence and programme implications. AB - Adequate maternal nutrition during the "first 1,000 days" window is critical from conception through the first 6 months of life to improve nutritional status and reduce the risk of poor birth outcomes, such as low birthweight and preterm birth. Unfortunately, many programmes have targeted implementation and monitoring of nutrition interventions to infants and young children, rather than to women during pregnancy or post-partum. A literature review was conducted to identify barriers to food choice and consumption during pregnancy and lactation and to examine how low- and middle-income countries have addressed maternal nutrition in programmes. A literature review of peer-reviewed and grey literature was conducted, and titles and abstracts reviewed by authors. Twenty-three studies were included in this review. Barriers to adequate nutrition during pregnancy included cultural beliefs related to knowledge of quantity of food to eat during pregnancy, amount of weight to gain during pregnancy, and "eating down" during pregnancy for fear of delivering a large baby. Foods considered inappropriate for consumption during pregnancy or lactation contributed to food restriction. Drivers of food choice were influenced by food aversions, economic constraints, and household food availability. Counselling on maternal diet and weight gain during pregnancy was seldom carried out. Programming to support healthy maternal diet and gestational weight gain during pregnancy is scant. Tailored, culturally resonant nutrition education and counselling on diet during pregnancy and lactation and weight gain during pregnancy, as well as monitoring of progress in maternal nutrition, are areas of needed attention. PMID- 28836344 TI - Insights on the role of hox genes in the emergence of the pentadactyl ground state. AB - Tetrapods are characterized by the presence of digits at the distal end of their limbs, which have emerged during the transition from fins to limbs. While variations in digit number are observed in extant tetrapods, most have five digits per limb and divergence from this pentadactyl ground state is always a reduction in digit number. Paleontological data revealed that stem-group tetrapods were polydactylous indicating that the evolution from fish fin to modern tetrapod limbs involved two major transitions; the emergence of digits and the shift from polydactyly to pentadactyly. The absence of living polydactyl tetrapod species is a major limitation in assessing the foundation of the pentadactyl constraint. Nonetheless, several genes having the capacity of modulating digit number have been identified and studying their functional and regulatory phylogeny will likely be critical in our comprehension of the emergence of the pentadactyl state. In this review, we provide an overview of the data obtained from mouse genetics that uncovered the role of Hox genes in controlling digit number and discuss regulatory changes that could have been implicated in the emergence of the pentadactyl ground state. PMID- 28836345 TI - Safety of shorter length of hospital stay for patients undergoing minimalist transcatheter aortic valve replacement. AB - OBJECTIVE: Determine the feasibility and predictors of early discharge after minimalist transcatheter aortic valve replacement (TAVR). BACKGROUND: Duration of hospitalization has a direct impact on overall cost of care, but the clinical impact of length of stay (LOS) in patients undergoing minimalist TAVR remains unclear. METHODS: We studied 268 patients who underwent minimalist TAVR. Short LOS (sLOS) was defined as post-procedural LOS <= 3 days and observed in 163 patients. Prolonged LOS (pLOS) was observed in 105 patients. Propensity score matching based on 39 variables yielded 54 pairs of patients in each group. We analyzed 30-day mortality, 30-day re-hospitalization and long-term survival data. Multivariate regression models were used to define predictors of sLOS. RESULTS: Thirty-day mortality was 0% versus 5.5% in the sLOS and pLOS groups, respectively (P = 0.08). Incidence of re-hospitalization was higher in pLOS (13% vs. 3.7%). sLOS was associated with lower odds ratio of minor vascular complication (OR 0.1 [95% CI: 0.01, 0.75], P = 0.05), any bleeding (OR 0.35 [95% CI: 0.14, 0.87], P = 0.02), blood transfusion (OR 0.27 [95% CI: 0.08, 0.81], P = 0.02), and new pacemaker implantation (OR 0.23 [95% CI: 0.1, 0.53], P < 0.001). Discharge to home had a significantly higher odd ratio for sLOS (OR 8.67 [95% CI: 3.59, 23.11], P < 0.001). CONCLUSION: In appropriately selected patients, sLOS following minimalist TAVR approach in an experienced and high volume center is feasible and safe. Implementing such a strategy may reduce medical costs with the potential clinical benefit of early re-habilitation for the elderly TAVR population. PMID- 28836346 TI - The trap and occlude technique for retrograde wire externalization during chronic total occlusion revascularization. AB - Different strategies of retrograde approach were introduced in recent years to improve the success rate of percutaneous coronary intervention for coronary chronic total occlusions. The aim of this report is to describe a new technique, called "Trap and Occlude Technique," for retrograde wire externalization during CTO percutaneous revascularization. This technique may save time and reduce radiation exposure and procedure-related bleeding. PMID- 28836347 TI - Oral Health Education and Promotion Programmes: Meta-Analysis of 17-Year Intervention. AB - OBJECTIVES: Oral Health Education and Promotion Interventions (OHEPIs) focus on improving knowledge, to adopt favourable oral health behaviours that can enhance oral health and clinical oral health. However, no meta-analyses exist that evaluate the effectiveness of OHEPI programmes. The aim of this meta-analysis was to determine the effectiveness of oral health education and promotion programmes. METHODS: The PubMed, EMBASE, Cochrane and ScienceDirect databases from years 2000 to 2016 were searched. Eleven studies based on Participant, Intervention, Comparison, Outcome Study (PICOs) and quality assessment criteria were selected for the systematic review and meta-analysis. Meta-analysis of the data was carried out using the Comprehensive Meta-Analysis V2.0 software. As the heterogeneity of subgroups was higher than 50%, an effect random model was used for the computation of average odds ratio. RESULTS: The heterogeneity of the studies was higher than 50% (I2 = 92%, P < .001); therefore, the random effect model was used to calculate the average odds ratio. 3 subgroups, (A) programme outcomes (long- and short-term outcomes), (B) age groups and (C) the follow-up periods after the intervention, were extracted for the intervention review. Overall, programme outcome and the 3-month subgroup follow-up were both significantly increased (OR = 2. 41, CI: 1.3, 4.7; P = .005) (OR = 1.14, CI: 1.01, 1.30; P = .03) in terms of odds effectiveness of the interventions. But the age subgroups showed no significance (OR = 0.93, CI: 0.74, 1.17; P = .52) in odds effectiveness of the interventions. CONCLUSIONS: This study found that past OHEPIs are effective and positive impacts on dental visits, attitudes, as well as brushing and flossing behaviours during 3 months post-intervention among children. PMID- 28836348 TI - Effects of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 on the IgA flow rate of saliva in elderly persons residing in a nursing home: A before-after non-randomised intervention study. AB - OBJECTIVE: The aim of this study was to investigate the alterations in the salivary IgA levels of elderly persons administered yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) OLL1073R-1, which has been reported to reduce the risk of colds. BACKGROUND: Salivary immunoglobulin (Ig)A plays an important role in the defence of the oral cavity mucous membrane against foreign antigens and pathogens. Accordingly, low levels of salivary IgA are associated with an increased risk of upper respiratory tract infection. Furthermore, salivary IgA secretion has been reported to decrease with age. Recently, several studies have reported that certain strains of Lactobacillus and their products can modulate the immune response, but there are currently few studies on the effects of on the IgA level in human saliva. MATERIALS AND METHODS: This was a before-after non-randomised intervention study. Thirty-seven elderly persons (mean age, 82.7 years) residing in a single nursing home ingested 112 g of the yogurt every morning for 12 weeks. The participants' saliva was collected before and after 4, 8 and 12 weeks of yogurt intake. RESULTS: Our results showed that yogurt intake affected the concentration of IgA in the saliva (P < .0001). Additionally, yogurt intake and the body weight of the participants affected the IgA flow rate of saliva (P = .0003 and .03, respectively). CONCLUSION: Continuous intake of yogurt fermented with L. bulgaricus OLL1073R-1 may help improve the mucosal immune function in elderly people with weakened immune systems. PMID- 28836349 TI - Variation in floral characters, particularly floral scent, in sapromyophilous Stemona species. AB - Flowers or inflorescences often deploy various signals, including visual, olfactory, and gustatory cues, that can be detected by their pollinators. In many plants, these cues and their functions are poorly understood. Deciphering the interactions between floral cues and pollinators is crucial for analyzing the reproductive success of flowering plants. In this study, we examined the composition of the fetid floral scents produced by several Stemona species, including nine S. tuberosa populations from across China, using dynamic headspace adsorption, gas chromatography, and mass spectrometry techniques. We compared variations in floral phenotype, including floral longevity, nectar rewards, pollinator behavior, and flower length and color among the Stemona species. Of the 54 scent compounds identified, the major compounds include fetid dimethyl disulfide, dimethyl trisulfide, 1-pyrroline, butyric acid, p-cresol, isoamyl alcohol, and indole. We detected striking differentiation in floral scent at both the species and population level, and even within a population of plants with different colored flowers. Floral characteristics related to sapromyophily and deceptive pollination, including flower color mimicking livor mortis and a lack of nectar, were found in five Stemona species, indicating that Stemona is a typical sapromyophilous taxon. Species of this monocot genus might employ evolutionary tactics to exploit saprophilous flies for pollination. PMID- 28836350 TI - Impaired peripheral insulin sensitivity in non-obese Japanese patients with type 2 diabetes mellitus and fatty liver. AB - AIMS/INTRODUCTION: Type two diabetes mellitus and fatty liver (FL) are not uncommon in Asians with normal body mass index. Previous studies reported a link between FL and insulin resistance. Thus, FL could coexist with insulin resistance in Asian type two diabetes mellitus patients with a normal body mass index. However, the clinical and metabolic features of such patients have not been characterized yet. MATERIALS AND METHODS: We recruited 29 non-obese (body mass index <25 kg/m2 ) Japanese patients with early type two diabetes mellitus. Based on intrahepatic lipid level measured by H-magnetic resonance spectroscopy, the participants were divided into the FL (intrahepatic lipid >=5%, n = 7) and non-FL groups (intrahepatic lipid <5%, n = 22). RESULTS: Peripheral insulin sensitivity measured by hyperinsulinemic euglycemic clamp was ~25% lower in the FL group than in the non-FL group, whereas hepatic insulin sensitivity was comparable between the two groups. The subcutaneous fat area was larger, free fatty acid level was higher, C-reactive protein was higher and high molecular weight adiponectin was lower in the FL group than the non-FL group. CONCLUSIONS: The present study showed that the metabolic features of non-obese Japanese type two diabetes patients with FL include impaired peripheral (mainly muscle) insulin sensitivity, fat accumulation and related metabolic disorders, such as elevated free fatty acid, low high molecular weight adiponectin and low-grade inflammation. PMID- 28836352 TI - Early intervention for bipolar disorder in adolescents: A psychosocial perspective. AB - AIM: Early intervention in bipolar disorder (BD) has received increasing attention in recent years. The identification of risk factors has improved, but researchers continue to struggle to find an effective treatment once the illness has become established. The aetiology of BD and feasibility of early intervention present a challenge, making it difficult to decide who to target, as well as how. METHODS: This essay seeks to address the lack of guidance for managing patients with a possible emerging bipolar illness, by presenting a rough roadmap to psychological care. The psychological techniques currently showing the most potential for this challenging group are reviewed. Markers of risk and supplementary clinical targets, such as anxiety and sleep disruption, are also discussed. RESULTS: While research in this group remains in its infancy, various avenues of enquiry show promise, such as family-based approaches, CBT that targets features beyond the core illness, psychoeducation, and interventions that consider physical health. However, clearer pathways for establishing the course and stage of the illness are required to inform the intensity and type of treatment. CONCLUSION: It is argued that treating early, indistinct symptoms of psychological distress, that may or may not signify prodromal BD, is valuable beyond its utility as an early intervention tool, as it has the capacity to improve help-seeking behaviour, quality of life and the likelihood of functional recovery in those who go on to develop the illness as adults. PMID- 28836351 TI - Efficacy and safety of once-weekly oral trelagliptin switched from once-daily dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: An open-label, phase 3 exploratory study. AB - INTRODUCTION: Trelagliptin, a novel once-weekly oral dipeptidyl peptidase-4 (DPP 4) inhibitor, has shown favorable efficacy and safety in type 2 diabetes mellitus patients. Trelagliptin was launched in Japan, and is expected to be initially used for switchover from a daily DPP-4 inhibitor in the clinical setting. Thus, the present study was carried out to explore the efficacy and safety of trelagliptin after a daily DPP-4 inhibitor was switched to it. MATERIALS AND METHODS: This was an open-label, phase 3 exploratory study to evaluate the efficacy and safety of trelagliptin in Japanese type 2 diabetes mellitus patients who had stable glycemic control on once-daily sitagliptin therapy. Eligible patients received trelagliptin 100 mg orally before breakfast once a week for 12 weeks. The primary end-point was blood glucose by the meal tolerance test, and additional end-points were glycemic control (efficacy) and safety. RESULTS: Altogether, 14 patients received the study drug. The blood glucose did not markedly change from baseline at major assessment points in the meal tolerance test, and a decrease in blood glucose was observed at several other assessment points. Adverse events were reported in 42.9% (6/14) of patients, but all adverse events were mild or moderate in severity, and most were not related to the study drug. No cases of death, serious adverse events or hypoglycemia were reported. DISCUSSION: It is considered possible to switch a once-daily DPP-4 inhibitor to trelagliptin in type 2 diabetes mellitus patients with stable glycemic control in combination with diet and exercise therapy without any major influences on glycemic control or safety. PMID- 28836353 TI - Epiandrosterone sulfate prolongs the detectability of testosterone, 4 androstenedione, and dihydrotestosterone misuse by means of carbon isotope ratio mass spectrometry. AB - In the course of investigations into the metabolism of testosterone (T) by means of deuterated T and hydrogen isotope ratio mass spectrometry, a pronounced influence of the oral administration of T on sulfoconjugated steroid metabolites was observed. Especially in case of epiandrosterone sulfate (EPIA_S), the contribution of exogenous T to the urinary metabolite was traceable up to 8 days after a single oral dose of 40 mg of T. These findings initiated follow-up studies on the capability of EPIA_S to extend the detection of T and T analogue misuse by carbon isotope ratio (CIR) mass spectrometry in sports drug testing. Excretion study urine samples obtained after transdermal application of T and after oral administration of 4-androstenedione, dihydrotestosterone, and EPIA were investigated regarding urinary concentrations and CIR. With each administered steroid, EPIA_S was significantly depleted and prolonged the detectability when compared to routinely used steroidal target compounds by a factor of 2 to 5. In order to simplify the sample preparation procedure for sulfoconjugated compounds, enzymatic cleavage by Pseudomonas aeruginosa arylsulfatase was tested and implemented into CIR measurements for the first time. Further simplification was achieved by employing multidimensional gas chromatography to ensure the required peak purity for CIR determinations, instead of sample purification strategies using liquid chromatographic fractionation. Taking into account these results that demonstrate the unique and broad applicability of EPIA_S for the detection of illicit administrations of T or T related steroids, careful consideration of how this steroid can be implemented into routine doping control analysis appears warranted. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28836354 TI - Dental care for the elderly through a Capped-fee funding model: Optimising outcomes for primary government dental services. AB - OBJECTIVE: The objectives of this study were to (i) compare a Capped Payment formula for adults, to the fee-for-service model and the New South Wales Government services payment model; (ii) identify the presenting oral health needs of a 65+ years of age cohort during the period January 2011 to March 2015. BACKGROUND DATA DISCUSSING THE PRESENT STATUS OF THE FIELD: Australia faces an ageing population with the vast majority accessing free market dental care, whilst the poor access Government services. This cohort retains most of their dentition increasing demand on Government services. MATERIALS AND METHODS: The analysis of New South Wales Government adult de-identified patients' record unit data was from 2011 to 2015, for the three payment models and undertaken in three stages; (i) development of the Capped Payment Model; (ii) evaluation of twenty (20) case studies of adults 65+ years of age; (iii) analyse the cost efficiency of the three payment models. RESULTS: This study found that the Government model was the most cost effective. The Capped-fee model performed less efficiently, particularly in the 75+ age group, with the fee-for-service model generally more costly. It was $2580 (85%) more costly for the 65-74 age cohort, and $4619 (66%) for the 75+ age cohort. CONCLUSION: Policy makers in partnership with Government and private service providers should seek to develop partnerships with Government, private services and universities, scope opportunities in applying a Capped-fee funding model, and one that helps address the oral needs of the elderly. PMID- 28836355 TI - What would Dr. James Parkinson think today? The role of genetics in Parkinson's disease. PMID- 28836356 TI - Model-Based Discovery and Development of Biopharmaceuticals: A Case Study of Mavrilimumab. AB - Drug development is a lengthy, costly process with low probability of success. Biopharmaceuticals are highly specific molecules, with efficacy and safety closely tied to target biology and pharmacology. The "learning-predicting confirming" continuum by translational and clinical modeling and simulation (M&S) was implemented at every decision point for mavrilimumab, a human monoclonal antibody in development for rheumatoid arthritis (RA). This tutorial uses mavrilimumab as an example to demonstrate rational discovery, preclinical development, clinical study design, and dose selection of biotherapeutics by M&S. PMID- 28836357 TI - Improvements to the APBS biomolecular solvation software suite. AB - The Adaptive Poisson-Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that have provided impact in the study of a broad range of chemical, biological, and biomedical applications. APBS addresses the three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this article, we discuss the models and capabilities that have recently been implemented within the APBS software package including a Poisson-Boltzmann analytical and a semi-analytical solver, an optimized boundary element solver, a geometry-based geometric flow solvation model, a graph theory-based algorithm for determining pKa values, and an improved web-based visualization tool for viewing electrostatics. PMID- 28836358 TI - Use of multiple-locus variable-number of tandem repeats analysis (MLVA) to investigate genetic diversity of Salmonella enterica subsp. enterica serovar Typhimurium isolates from human, food, and veterinary sources. AB - Salmonella enterica subspecies enterica serovar Typhimurium is the most common zoonotic pathogen in Bulgaria. To allow efficient outbreak investigations and surveillance in the food chain, accurate and discriminatory methods for typing are needed. This study evaluated the use of multiple-locus variable-number of tandem repeats analysis (MLVA) and compared results with antimicrobial resistance (AMR) determinations for 100 S. Typhimurium strains isolated in Bulgaria during 2008-2012 (50 veterinary/food and 50 human isolates). Results showed that isolates were divided into 80 and 34 groups using MLVA and AMR, respectively. Simpson's index of diversity was determined to 0.994 +/- 0.003 and 0.945 +/- 0.012. The most frequently encountered MLVA profiles were 3-11-9-NA-211 (n = 5); 3-12-9-NA-211 (n = 3); 3-12-11-21-311 (n = 3); 3-17-10-NA-311 (n = 3); 2-20-9-7 212 (n = 3); and 2-23-NA-NA-111 (n = 3). No clustering of isolates related to susceptibility/resistance to antimicrobials, source of isolation, or year of isolation was observed. Some MLVA types were found in both human and veterinary/food isolates, indicating a possible route of transmission. A majority (83%) of the isolates were found to be resistant against at least one antimicrobial and 44% against >=4 antimicrobials. Further studies are needed to verify MLVA usefulness over a longer period of time and with more isolates, including outbreak strains. PMID- 28836359 TI - The potential role and rationale for treatment of heart failure with sodium glucose co-transporter 2 inhibitors. AB - Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication: "32%" in the previous sentence was corrected to "38%"]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate. PMID- 28836360 TI - Polycystic ovarian syndrome: Social situation influences outcome. PMID- 28836361 TI - Goodbye Physicians' Desk Reference, hello Prescribers' Desk Reference! PMID- 28836362 TI - Coffee and kidney disease. PMID- 28836364 TI - Broader concepts of quality-of-life measurement, encompassing validation - AY Finlay. PMID- 28836363 TI - Improving pharmacotherapy outcomes in patients with hepatitis C virus infection treated with direct-acting antivirals: The GRUviC project. AB - BACKGROUND/OBJECTIVE: Pharmaceutical care is needed in hepatitis C virus (HCV) infected patients treated with direct-acting antivirals (DAA). We describe the implementation of a comprehensive pharmaceutical care programme (CPCP) for HCV infected patients treated with DAA in a tertiary-care hospital and provide data about health outcomes and costs. METHODS: Quasi-experimental study between 1 April 2015 and 30 June 2016. A group of hospital pharmacists collaborating on HCV infection implemented interventional measures for validation of drug prescriptions, detection of clinically relevant drug-drug interactions and adverse drug events (ADEs), and patient education. Quality, health and cost effectiveness outcomes were evaluated. RESULTS: A total of 1070 patients were enrolled. Pharmacists made 327 interventions that led to the prevention of 299 (91.4%) medication errors, 16 of which were grade G-H (NCC MERP classification). The main reasons for the pharmacist's intervention were management of 143 drug drug interactions. The overall sustained virologic response at week 12 posttreatment (SVR12) rate was 93.0% (95% CI 91.4-94.6). The SVR12 was higher than 90.0% in all populations, except in genotype 3 patients (86.0%, 95% CI 78.7 93.9), decompensated cirrhotic patients (81.1%, 95% CI 69.7-92.6) and transplant recipients (86.8%, 95% CI 76.7-96.9). ADEs occurred in 85.5% of the study patients, but only 1.0% (11 patients) experienced an ADE that led to premature discontinuation. The total cost of treatment was ?18 279 225 (?17 083 per patient). The most cost-effective treatment was selected in 93.1% of patients. CONCLUSIONS: The implementation of a CPCP developed by hospital pharmacists in patients treated with DAAs for HCV infection is an effective approach that improves patient safety and education. The active involvement of the pharmacist in improving adherence to local guidelines promoted the selection of the most cost-effective treatment in the majority of cases. PMID- 28836365 TI - Use of antidepressants in dentistry: A systematic review. AB - OBJECTIVE: Previous research has suggested that antidepressants can be used in oral health care. The aim of this systematic review was to search for scientific evidence of the efficacy of the use of antidepressants in dentistry. MATERIALS AND METHODS: The clinical question was as follows (PICO question): dentistry patients (Patients); antidepressants (Intervention); no use or placebo or other drug (Comparison); and efficacy in oral health problems (Outcome). An electronic search was conducted in seven databases, as well as a manual search without restriction regarding language and date of publication. Two independent reviewers selected studies based on eligibility criteria, extracted data and assessed methodological quality based on the PEDro scale. The PROSPERO record is number CRD42016037442. RESULTS: A total of 15 randomized controlled trials were associated with the use of antidepressants to control chronic or acute pain in dentistry, among other conditions such as bruxism and burning mouth syndrome. The most commonly used drug in clinical trials was amitriptyline (more than 50% of studies). CONCLUSIONS: Antidepressants may be effective in dentistry for acute and chronic pain, but there is a large amount of methodological heterogeneity among the evaluated studies. In summary, there is rationality for the indication of this class of medicine in dentistry in specific clinical situations. PMID- 28836367 TI - Re: Association between inadequate antenatal care utilisation and severe perinatal and maternal morbidity: an analysis in the PreCARE cohort: Antenatal care utilisation and severe perinatal/maternal morbidity in PreCARE cohort. PMID- 28836366 TI - Lipoteichoic acid upregulates plasminogen activator inhibitor-1 expression in parapneumonic effusions. AB - BACKGROUND AND OBJECTIVE: Parapneumonic effusion (PPE) is commonly caused by Gram positive bacteria (GPB) and often presents with pleural loculation, which is characterized by overproduction of plasminogen activator inhibitor (PAI)-1. Lipoteichoic acid (LTA), a surface adhesion molecule of GPB, binds to the pleural mesothelium and triggers inflammation. However, the effects of LTA on PAI-1 expression in PPE and underlying mechanisms remain unclear. METHODS: Thirty consecutive patients with PPE were enrolled, including uncomplicated culture negative (CN, n = 11), Gram-negative bacteria (GNB, n = 7) and GPB (n = 12) groups stratified by pleural fluid characteristics and bacteriology, and the effusion PAI-1 levels were measured. In addition, human pleural mesothelial cells (PMC) were treated with LTA and the expression of PAI-1 and activation of signalling pathways were assayed. RESULTS: The median levels of PAI-1 were significantly higher in GPB (160.5 ng/mL) and GNB (117.0 ng/mL) groups than in the uncomplicated CN (58.0 ng/mL) group. In human PMC, LTA markedly upregulated PAI-1 mRNA and protein expression and enhanced elaboration of Toll-like receptor 2 (TLR2). Furthermore, LTA increased c-Jun N-terminal kinase (JNK) phosphorylation, induced activating transcription factor 2 (ATF2)/c-Jun nuclear translocation and activated PAI-1 promoter activity. Pretreatment with TLR2 siRNA significantly inhibited LTA-induced JNK phosphorylation and PAI-1 protein expression. CONCLUSION: Culture-positive PPE, especially that caused by GPB, has a significantly higher level of PAI-1 than uncomplicated CN PPE. LTA upregulates PAI-1 expression through activation of TLR2/JNK/activator protein 1 (AP-1) pathway in human PMC. Better understanding of the modulation of PAI-1 synthesis by LTA in PPE may provide potential therapies for infected pleural effusions. PMID- 28836368 TI - An Asymmetric Pathway to Dendrobine by a Transition-Metal-Catalyzed Cascade Process. AB - An asymmetric pathway to the caged tetracyclic pyrrolidine alkaloid, dendrobine, is reported. The successful synthetic strategy features a one-pot, sequential palladium-catalyzed enyne cycloisomerization and rhodium-catalyzed diene-assisted pyrrolidine formation by allylic CH activation. The developed transition-metal catalyzed cascade process permits rapid access to the dendrobine core structure and circumvents the handling of labile intermediates. An intramolecular aldol condensation under carefully defined reaction conditions takes place with a concomitant detosylation, followed by reductive amine methylation, to afford a late-stage intermediate (previously identified by several prior dendrobine syntheses) in only 10 synthetic steps overall. PMID- 28836369 TI - Wide-scale comparative analysis of longevity genes and interventions. AB - Hundreds of genes, when manipulated, affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse) and thus can be defined as longevity associated genes (LAGs). A major challenge is to determine whether these LAGs are model-specific or may play a universal role as longevity regulators across diverse taxa. A wide-scale comparative analysis of the 1805 known LAGs across 205 species revealed that (i) LAG orthologs are substantially overrepresented, from bacteria to mammals, compared to the entire genomes or interactomes, and this was especially noted for essential LAGs; (ii) the effects on lifespan, when manipulating orthologous LAGs in different model organisms, were mostly concordant, despite a high evolutionary distance between them; (iii) LAGs that have orthologs across a high number of phyla were enriched in translational processes, energy metabolism, and DNA repair genes; (iv) LAGs that have no orthologs out of the taxa in which they were discovered were enriched in autophagy (Ascomycota/Fungi), G proteins (Nematodes), and neuroactive ligand receptor interactions (Chordata). The results also suggest that antagonistic pleiotropy might be a conserved principle of aging and highlight the importance of overexpression studies in the search for longevity regulators. PMID- 28836370 TI - An inquiry into the concept of infancy care based on the perspective of Islam. AB - All schools of thought believe that infancy is crucial to the formation and development of the human character. Nevertheless, a search of literature revealed the lack of a clear definition of the concept of 'infancy care based on an Islamic perspective' in nursing texts. As the lack of a clear definition of a concept conveys the inapplicability of that concept to its relevant field and community, this study was conducted to explore and determine the characteristic features of the concept of infancy care based on the perspective of Islam. Walker and Avant's (Strategies for theory construction in nursing. Prentice Hall, Boston, 2011) literary concept synthesis as the manner of concept development approach was conducted. Islamic documents were surveyed without any time limitation. Findings involved the extraction of six main concepts, including God as the Merciful Nurturer, mother as the symbol of the Creativity and Divinity of God, infant as a person with dignity and potential for excellence, parents as the nurture way paver, basic principles of nurturing, and holistic lifelong health promotion. The theoretical definition of each concept was presented. From the perspective of Islam, infant care is the nurturing of a human who has been conceived with dignity, certain rights, identity, and the capacity for development and excellence. PMID- 28836371 TI - Prior joint disease is associated with increased risk of periarticular histiocytic sarcoma in dogs. AB - Periarticular histiocytic sarcoma (PAHS) is the most common synovial tumour in dogs and is characterized by aggressive local disease with a high rate of distant metastasis. Previously, an association between PAHS and prior joint disease has been demonstrated in the Bernese Mountain Dog breed and suggested in the Rottweiler. We hypothesized that this association would be present in other breeds and investigated this via a retrospective, case-controlled analysis. Cases were dogs diagnosed with PAHS of the stifle or elbow. Controls were age, breed and sex-matched dogs without a diagnosis of histiocytic sarcoma. Diagnosis of prior joint disease was determined based on review of medical records and direct veterinarian and owner communications. Data were evaluated using logistic regression, 2-sampled t tests, and chi-squared analysis. Our study population consisted of 28 cases and 46 controls, including Flat-Coated, Golden and Labrador Retrievers, Rottweilers, English Bulldogs, Shih Tzus, Australian Shepherds, Staffordshire Terriers and mixed breed dogs. Dogs with PAHS were more likely to have prior joint disease in the tumour-affected joint compared with the control population (odds ratio [OR] = 13.42, P < .0001, 95% confidence interval [CI] = 4.33-48.63). A total of 88.2% of dogs with stifle PAHS had prior joint disease in their tumour-affected joint, most commonly cranial cruciate ligament rupture. This study confirms that the previously noted association between prior joint disease and PAHS in Bernese Mountain Dogs also applies to other breeds. Additional studies are needed to further investigate for a causal relationship. PMID- 28836372 TI - Aphid specialism as an example of ecological-evolutionary divergence. AB - Debate still continues around the definition of generalism and specialism in nature. To some, generalism is equated solely with polyphagy, but this cannot be readily divorced from other essential biological factors, such as morphology, behaviour, genetics, biochemistry, chemistry and ecology, including chemical ecology. Viewed in this light, and accepting that when living organisms evolve to fill new ecological-evolutionary niches, this is the primal act of specialisation, then perhaps all living organisms are specialist in the broadest sense. To illustrate the levels of specialisation that may be found in a group of animals, we here provide an overview of those displayed by a subfamily of hemipteran insects, the Aphididae, which comprises some 1600 species/subspecies in Europe alone and whose members are specialised in a variety of lifestyle traits. These include life cycle, host adaptation, dispersal and migration, associations with bacterial symbionts (in turn related to host adaptation and resistance to hymenopterous wasp parasitoids), mutualisms with ants, and resistance to insecticides. As with polyphagy, these traits cannot easily be separated from one another, but rather, are interconnected, often highly so, which makes the Aphididae a fascinating animal group to study, providing an informative, perhaps unique, model to illustrate the complexities of defining generalism versus specialism. PMID- 28836373 TI - Evaluation of a smartphone nutrition and physical activity application to provide lifestyle advice to pregnant women: The SNAPP randomised trial. AB - Our objective was to evaluate the impact of a smartphone application as an adjunct to face-to-face consultations in facilitating dietary and physical activity change among pregnant women. This multicentre, nested randomised trial involved pregnant women with a body mass index >=18.5 kg/m2 , with a singleton pregnancy between 10 and 20 weeks' gestation, and participating in 2 pregnancy nutrition-based randomised trials across metropolitan Adelaide, South Australia. All women participating in the SNAPP trial received a comprehensive dietary, physical activity, and behavioural intervention, as part of the GRoW or OPTIMISE randomised trials. Women were subsequently randomised to either the "Lifestyle Advice Only Group," where women received the above intervention, or the "Lifestyle Advice plus Smartphone Application Group," where women were additionally provided access to the smartphone application. The primary outcome was healthy eating index (HEI) assessed by maternal food frequency questionnaire completed at trial entry, and 28 and 36 weeks' gestation. Analyses were performed using intention-to-treat principles, with statistical significance at p = .05. One hundred sixty-two women participated: 77 allocated to the Lifestyle Advice plus Smartphone Application Group and 85 to the Lifestyle Advice Only Group. Mean difference in HEI score at 28 weeks of pregnancy was 0.01 (CI [-2.29, 2.62]) and at 36 weeks of pregnancy -1.16 (CI [-4.60, 2.28]). There was no significant additional benefit from the provision of the smartphone application in improving HEI score (p = .452). Although all women improved dietary quality across pregnancy, use of the smartphone application was poor. Our findings do not support addition of the smartphone application. PMID- 28836374 TI - Intramolecular Thioether Crosslinking to Increase the Proteolytic Stability of Affibody Molecules. AB - Protein therapeutics suffer from low oral bioavailability, mainly due to poor membrane permeability and digestion by gastrointestinal proteases. To improve proteolytic stability, intramolecular thioether crosslinks were introduced into a three-helix affibody molecule binding the human epidermal growth factor receptor (EGFR). Solid-phase peptide synthesis was used to produce an unmodified control protein domain and three different crosslinked protein domain variants: one with a thioether crosslink between the N-terminal lysine residue and a cysteine residue in the second loop region (denoted K4), a second with a crosslink between the C-terminal lysine residue and a cysteine residue in the first loop region (denoted K58), and a third with crosslinks in both positions (denoted K4K58). Circular dichroism (CD) and surface-plasmon-resonance-based (SPR-based) biosensor studies of the protein domains showed that the three-helix structure and high affinity binding to EGFR were preserved in the crosslinked protein domains. In vitro digestion by gastrointestinal proteases demonstrated that the crosslinked protein domains showed increased stability towards pepsin and towards a combination of trypsin and chymotrypsin. PMID- 28836375 TI - A brief motivational interviewing as an adjunct to periodontal therapy-A potential tool to reduce relapse in oral hygiene behaviours. A three-year study. AB - OBJECTIVES: To evaluate (ii) whether inclusion of a single motivational interviewing (MI) session, as an adjunct to periodontal therapy, might be beneficial for preventing relapse in oral hygiene behaviours among patients treated for chronic periodontitis and (ii) whether individual and clinical characteristics can be of predictive value for retention of sufficient oral hygiene behaviours. MATERIAL & METHODS: This 3-year follow-up of a previously reported randomized controlled trial (RCT) study of 6-month duration included 26 patients. Patients in the test group had received one MI session by a clinical psychologist before initiation of the periodontal treatment. Otherwise, all patients followed the same treatment protocol for conventional educational intervention and non-surgical periodontal therapy. Efficacy variables assessed for evaluation of the standard of self-performed periodontal infection control were marginal bleeding index (MBI; primary efficacy variable) and plaque score (PI). RESULTS: The patterns of change in MBI and PI scores were similar for test and control groups over the observation period. At 3 years, both groups showed a desirable mean full-mouth MBI of 15%, a figure that was comparable to that at the short-term evaluation after active periodontal treatment. The post-treatment MBI was the only variable identified as a predictor of retained adequate oral hygiene behaviours. CONCLUSION: A single MI session as an adjunct to conventional periodontal therapy could not be proven to be of long-term beneficial additive effect with regard to prevention of relapse in oral hygiene behaviour. Desirable standard of self-performed infection control after active periodontal treatment predicted the retention of sufficient oral hygiene behaviour over time. PMID- 28836376 TI - Negotiating the boundaries of psychosis: A qualitative study of the service provider perspective on treatment delay in community mental health. AB - AIM: Evidence shows that many patients are detected and treated late in their course of illness, and that substantial delay occurs even after entry to mental health services. Although several studies have examined the service user and carer perspectives on treatment delay, few have explored the issue from the service provider perspective. The aim of this study was to broaden our understanding of treatment delay by exploring the service provider perspective on reasons for treatment delay in community mental health services. METHODS: A qualitative study using data from focus group interviews with 33 healthcare professionals in community mental health care. Interview data were digitally recorded and transcribed verbatim, and analysed using a grounded theory approach. RESULTS: Service providers perceived divergent or conflicting perspectives as the main challenge in early psychosis. Clinical negotiation was chosen as the main term describing the interactions between patients and healthcare professionals: This was observed in 3 overlapping areas: (1) Negotiating the patients status as help-seeker; (2) Negotiating the place and conditions of treatment and (3) Negotiating the meaning of distressing experiences and the timing of treatment options. CONCLUSIONS: This study suggests that delay in initiation of treatment for psychosis in community mental health is related to clinical challenges of early disengagement from services and diagnostic uncertainty. Service providers found negotiating the therapeutic relationship and patient-centred flexibility more useful in ensuring engagement than an assertive outreach approach. Diagnostic uncertainty was resolved through watchful waiting using a distress overload conceptualization in assessing changes in mental state and service needs. PMID- 28836377 TI - Investigating service features to sustain engagement in early intervention mental health services. AB - AIM: To understand what service features would sustain patient engagement in early intervention mental health treatment. METHODS: Mental health patients, family members of individuals with mental illness and mental health professionals completed a survey consisting of 18 choice tasks that involved 14 different service attributes. Preferences were ascertained using importance and utility scores. Latent class analysis revealed segments characterized by distinct preferences. Simulations were carried out to estimate utilization of hypothetical clinical services. RESULTS: Overall, 333 patients and family members and 183 professionals (N = 516) participated. Respondents were distributed between a Professional segment (53%) and a Patient segment (47%) that differed in a number of their preferences including for appointment times, individual vs group sessions and mode of after-hours support. Members of both segments shared preferences for many of the service attributes including having crisis support available 24 h per day, having a choice of different treatment modalities, being offered help for substance use problems and having a focus on improving symptoms rather than functioning. Simulations predicted that 60% of the Patient segment thought patients would remain engaged with a Hospital service, while 69% of the Professional segment thought patients would be most likely to remain engaged with an E-Health service. CONCLUSIONS: Patients, family members and professionals shared a number of preferences about what service characteristics will optimize patient engagement in early intervention services but diverged on others. Providing effective crisis support as well as a range of treatment options should be prioritized in the future design of early intervention services. PMID- 28836378 TI - Ethyl pyruvate does not require microglia for mediating neuroprotection after excitotoxic injury. AB - AIMS: Ethyl pyruvate (EP) mediates protective effects after neuronal injury. Besides a direct conservation of damaged neurons, the modulation of indigenous glial cells has been suggested as one important mechanism for EP-related neuroprotection. However, the specific contribution of glial cells is still unknown. METHODS: Organotypic hippocampal slice cultures (OHSC) were excitotoxically lesioned by 50 MUmol/L N-methyl-D-aspartate (NMDA, for 4 hours) or left untreated. In an additional OHSC subset, microglia was depleted using the bisphosphonate clodronate (100 MUg/mL) before lesion. After removal of NMDA, EP containing culture medium (0.84 MUmol/L, 8.4 MUmol/L, 42 MUmol/L, 84 MUmol/L, 168 MUmol/L) was added and incubated for 72 hours. OHSC were stained with propidium iodide to visualize degenerating neurons and isolectin IB4 -FITC to identify microglia. Effects of EP at concentrations of 0.84, 8.4, and 84 MUmol/L (0-48 hours) were analyzed in the astrocytic scratch wound assay. RESULTS: EP significantly reduced neurodegeneration following induced excitotoxicity except for 168 MUmol/L. For 84 MUmol/L, a reduction in the microglia cells was observed. Microglia depletion did not affect neuronal survival after EP treatment. EP decelerated astrocytic wound closure at 48 hours after injury. CONCLUSION: EP mediated neuroprotection seems to be mediated by astrocytes and/or neurons. PMID- 28836379 TI - Home-based multidimensional survivorship programmes for breast cancer survivors. AB - BACKGROUND: The prognosis and survival rate of women with breast cancer have significantly improved worldwide. Effective home-based multidimensional programmes for breast cancer survivors have gained an ever greater emphasis in survivorship care to maximise women's quality of life for their successful transition to rehabilitation and normal life. It is important to summarise the best available evidence to evaluate the effects of home-based multidimensional survivorship programmes on quality of life in women within 10 years of the completion of surgery or adjuvant cancer therapy for breast cancer, or both. OBJECTIVES: To assess the effects of home-based, multidimensional survivorship (HBMS) programmes on maintaining or improving the quality of life in breast cancer survivors. SEARCH METHODS: In April 2016 we searched the Cochrane Breast Cancer Specialised Register, CENTRAL, PubMed, Embase, CINAHL Plus, PsycINFO, Web of Science, and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov. We also screened reference lists of all identified studies and contacted study authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of HBMS programmes in maintaining or improving quality of life in women with stages 0 to 3 breast cancer who completed primary cancer treatment (surgery or adjuvant cancer therapy, or both) up to 10 years earlier. We considered studies where the interventions included more than one of the following listed components: educational (such as information provision and self-management advice), physical (such as exercise training and resistance training) and psychological (such as counselling and cognitive therapies), to constitute a multidimensional programme. Interventions had to be allowed to be carried out at home. DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligible studies for inclusion, and performed quality assessment and extracted relevant data of the included studies. Quality of life was the primary outcome of the review. MAIN RESULTS: We included 22 RCTs and four quasi-RCTs on 2272 participants. We categorised the intervention components into four groups: educational and psychological; educational and physical; physical and psychological; and educational, physical and psychological. Most of the studies used usual care (routine medical follow-up services) as the comparator. A few studies used a lower level or different type of intervention (e.g. stress management or exercise) or attention control as the comparator.We used the Functional Assessment of Cancer Therapy-Breast (FACT B), European Organisation for Research and Treatment of Cancer Quality of Life C30 (EORTC C30), Quality of Life (QoL) Breast Cancer, and SF36 questionnaires to assess quality of life. HBMS programmes may increase breast cancer-specific quality of life and global quality of life immediately after the intervention, as measured by FACT-B and EORTC C30 (FACT-B: mean difference (MD) 4.55, 95% confidence interval (CI) 2.33 to 6.78, 7 studies, 764 participants; EORTC: MD 4.38, 95% CI 0.11 to 8.64, 6 studies; 299 participants; moderate-quality evidence). There was no evidence of a difference in quality of life as measured by QoL-Breast Cancer or SF-36 (QoL-Breast Cancer: MD 0.42, 95% CI -0.02 to 0.85, 2 studies, 111 participants, very low-quality evidence; physical composite score SF36: MD 0.55, 95% CI -3.52 to 4.63, 2 studies, 308 participants, low-quality evidence).We observed a similar pattern at one to three months after the intervention: FACT-B (MD 6.10, 95% CI 2.48 to 9.72, 2 studies, 426 participants), EORTC-C30 (MD 6.32, 95% CI 0.61 to 12.04, 2 studies; 172 participants) and QoL Breast Cancer (MD 0.45, 95% CI -0.19 to 1.09, 1 study, 61 participants). At four to six months and 12 months, there was no evidence of a difference in quality of life between groups (four to six months: EORTC - MD 0.08, 95% CI -7.28 to 7.44, 2 studies; 117 participants; SF-36 - MD -1.05, 95% CI -5.60 to 3.51, 2 studies, 308 participants; 12 months: EORTC - MD 2.04, 95% CI -9.91 to 13.99, 1 study; 57 participants).Functional status was incorporated into the quality of life subscale findings. HBMS programmes may decrease anxiety (MD of Hospital Anxiety and Depression Scale (HADS) -1.01, 95% CI -1.94 to -0.08, 5 studies, 253 participants, low-quality evidence) compared to control immediately after the intervention but the effect did not persist at four to six months. There was no evidence of improvements in depression immediately after HBMS (MD of HADS -1.36, 95% CI -2.94 to 0.22, 4 studies, 213 participants, low-quality evidence) or at follow-up. HBMS programmes may also decrease fatigue (MD -1.11, 95% CI -1.78 to 0.45, 3 studies, 127 participants; low-quality evidence) and insomnia (MD -1.81, 95% CI -3.34 to -0.27, 3 studies, 185 participants, low-quality evidence).None of the included studies reported service needs and utilisation and cost of care, and therefore the effect of HBMS programmes on healthcare utilisation and cost is unknown. Due to the variations in assessment methods of adherence among the eight studies, we could not combine the results for meta-analysis. We synthesised the results narratively, with the reported adherence rates of 58% to 100%. AUTHORS' CONCLUSIONS: The results of this systematic review and meta-analysis revealed that HBMS programmes in breast cancer survivors appear to have a short-term beneficial effect of improving breast cancer-specific quality of life and global quality of life as measured by FACT-B and EORTC-C30, respectively. In addition, HBMS programmes are associated with a reduction in anxiety, fatigue and insomnia immediately after the intervention. We assessed the quality of evidence across studies as moderate for some outcomes, meaning that we are fairly confident about the results, while we assessed other outcomes as being low-quality, meaning that we are uncertain about the result. PMID- 28836380 TI - Comparison of human umbilical cord blood processing with or without hydroxyethyl starch. AB - BACKGROUND: Umbilical cord blood (UCB) processing with hydroxyethyl starch (HES) is the most common protocol in the cord blood banks. The quality of UCB volume reduction was guaranteed by minimum manipulation of cord blood samples in the closed system. This study aimed to analyze and compare cell recovery and viability of UCB processed using the Sepax automated system in the presence and absence of HES. STUDY DESIGN AND METHODS: Thirty UCB bags with a total nucleated cell (TNC) count of more than 2.5 * 109 were divided in two bags with equal volume. HES solution was added to one bag and another was intact. Both bags were processed with the Sepax. To determine cell recovery, viability, and potential of colony-forming cells (CFCs), preprocessing, postprocessing, and thawing samples were analyzed. RESULTS: The mean TNC recovery after processing and after thaw was significantly better with the HES method (p < 0.01 for the postprocessing step and p < 0.05 for the postthaw step). There were no significant differences to mononucleated cells (MNCs) and CD34+ cell recovery between the two methods after processing and after thaw. TNC and MNC viability was significantly higher without HES after processing and after thaw (p < 0.01). The results of the CFC assay were similar for both methods after processing and after thaw. CONCLUSION: These results showed that processing of UCB using the Sepax system with the without-HES protocol due to the lower manipulation of samples could be used as an eligible protocol to reduce the volume of UCB. PMID- 28836381 TI - Time-dependent effects of tongue cleaning with mouthwash or mouth moisturising gel on the number of microbes on the tongue surface of elders with care needs. AB - OBJECTIVE: The purpose of this study was to investigate time-dependent change in the number of microbes on the tongue surface after tongue cleaning using a mouthwash or mouth moisturising gel for elders fed with a feeding tube and with care needs. MATERIALS AND METHODS: Twelve elders fed through a feeding tube and with care needs participated in this prospective crossover study. There were four kinds of tongue cleaning modes as follows: (i) tongue cleaning with a mouthwash; (ii) tongue cleaning with a mouth moisturising gel; (iii) tongue cleaning with water; (iv) no tongue cleaning as a negative control. The total number of microbes on the tongue surface was measured using a rapid oral bacteria detection device at baseline, immediately after cleaning, and at 1, 3 and 5 hours after cleaning to evaluate the time-dependent change for each tongue cleaning mode. RESULTS: There were no significant differences regarding microbial count on every measurement in negative control and tongue cleaning with water. There were significant decreases immediately after cleaning, and at 1, 3 and 5 hours after cleaning compared to baseline when the tongue was cleaned with a mouthwash. There was a significant decrease between baseline and immediately after cleaning when the tongue was cleaned with a mouth moisturising gel. CONCLUSION: Tongue cleaning with mouth moisturising gel decreased the number of microbes on the tongue surface immediately after cleaning, and tongue cleaning with mouthwash decreased it for 5 hours. PMID- 28836382 TI - Sodium appetite elicited by low-sodium diet is dependent on p44/42 mitogen activated protein kinase (extracellular signal-regulated kinase 1/2) activation in the brain. AB - Sodium appetite is regulated by several signalling molecules, among which angiotensin II (Ang II) serves as a key driver of robust salt intake by binding to Ang II type 1 receptors (AT1R) in several regions in the brain. The activation of these receptors recruits the mitogen-activated protein kinase (MAPK) pathway, which has previously been linked to Ang II-induced increases in sodium appetite. Thus, we addressed the involvement of MAPK signalling in the induction of sodium appetite after 4 days of low-sodium diet consumption. An increase in extracellular signal-regulated kinase (ERK) phosphorylation in the laminae terminalis and mediobasal hypothalamus was observed after low-sodium diet consumption. This response was reduced by i.c.v. microinjection of an AT1R antagonist into the laminae terminalis but not the hypothalamus. This result indicates that low-sodium diet consumption activates the MAPK pathway via Ang II/AT1R signalling on the laminae terminalis. On the other hand, activation of the MAPK pathway in the mediobasal hypothalamus after low-sodium diet consumption appears to involve another extracellular mediator. We also evaluated whether a low-sodium diet could increase the sensitivity for Ang II in the brain and activate the MAPK pathway. However, i.c.v. injection of Ang II increased ERK phosphorylation on the laminae terminalis and mediobasal hypothalamus; this increase achieved a response magnitude similar to those observed in both the normal and low-sodium diet groups. These data indicate that low-sodium diet consumption for 4 days is insufficient to change the ERK phosphorylation response to Ang II in the brain. To investigate whether the MAPK pathway is involved in sodium appetite after low-sodium diet consumption, we performed i.c.v. microinjections of a MAPK pathway inhibitor (PD98059). PD98059 inhibited both saline and water intake after low-sodium diet consumption. Thus, the MAPK pathway is involved in promoting the sodium appetite after low-sodium diet consumption. PMID- 28836383 TI - Reply. PMID- 28836384 TI - Re: Medical therapy for preventing recurrent endometriosis after conservative surgery: a cost-effectiveness analysis: Cost-effectiveness in recurrent endometriosis prevention. PMID- 28836385 TI - The time paradox of emergency medicine: Another inverted U curve. AB - Time is integral to emergency medicine, but the importance of time is over-rated. Media promotes a focus on time over suffering. Terms such as the 'golden hour' and 'time is muscle' are embedded into our language, but is language that corrupts thought. Time-based metrics for ED quality measures focus on speed over accuracy, reflecting another inverted U curve in our system of care. We often fail to understand the importance of heterogeneity, and the heterogeneity of treatment effect, for example, sicker patients are more likely to benefit from the intervention, whereas less sick patients do not benefit but are more likely to be harmed. This highlights the importance of nuanced judgements. We need to get into the Goldilocks zone of the 'just right' balance between speed and accuracy. This essay challenges us to focus more on the suffering human subject, rather than on time-based metrics that reflect our hope bias. PMID- 28836386 TI - Corrigendum. PMID- 28836387 TI - Genetic prediction of myopia: prospects and challenges. PMID- 28836388 TI - Sclera does not change its shape during accommodation. PMID- 28836389 TI - Optimal orientation for angularly segmented multifocal corrections. AB - PURPOSE: Evaluate the importance of orientation of multifocal lens designs with angular increments of addition. METHODS: Optical properties of one monofocal and three multifocal designs were analysed with the visual Strehl ratio (VSOTF) metric through-focus (-1 to 5 D). Designs were tested in combination with the higher-order aberrations (HOAs) of 782 subjects (1564 eyes). Simulations included one monofocal, one bifocal (eight orientations), one trifocal (four orientations), and a 4-foci design (four orientations). Monocular and binocular performances of all designs were assessed by computing the area under the through focus VSOTF plots, the through-focus range of acceptable optical performance, and, for binocular combinations, optical disparity between left and right eyes. RESULTS: Under monocular conditions, bifocal designs generated larger areas under the through focus VSOTF than trifocal designs and 4-foci designs. Specifically, bifocal designs divided vertically were optimal for 48% of eyes. Trifocal designs and 4-foci designs offered longer intervals of acceptable through-focus vision. Coma and spherical aberration values were correlated with the optimal orientation of multifocal corrections. The best binocular combination was achieved with a monofocal and a trifocal lens. The orientation of a multifocal design with angular areas affected the final optical properties of the combination (lens plus eye). CONCLUSIONS: The optical aberration distributions for our population of physiologically normal eyes demonstrated improved performance for some lens design orientations (i.e., left-right segments for 2-zone bifocals). Taking into account the HOAs of healthy patients, with special attention to coma and spherical aberration, will increase the optical quality of angularly divided multifocal solutions. PMID- 28836390 TI - Cochrane Risk of Bias : 'Your common man has no conception of the zeal that animates a scientific investigator, the fury of contradiction you can arouse in him'. PMID- 28836391 TI - Glaucoma progression detection with frequency doubling technology (FDT) compared to standard automated perimetry (SAP) in the Groningen Longitudinal Glaucoma Study. AB - PURPOSE: To determine the usefulness of frequency doubling perimetry (FDT) for progression detection in glaucoma, compared to standard automated perimetry (SAP). METHODS: Data were used from 150 eyes of 150 glaucoma patients from the Groningen Longitudinal Glaucoma Study. After baseline, SAP was performed approximately yearly; FDT every other year. First and last visit had to contain both tests. Using linear regression, progression velocities were calculated for SAP (Humphrey Field Analyzer) mean deviation (MD) and FDT MD and the number of test locations with a total deviation probability below p < 0.01 (TD). Progression velocity tertiles were determined and eyes were classified as slowly, intermediately, or fast progressing for both techniques. Comparison between SAP and FDT classifications were made using a Mantel Haenszel chi-square test. Longitudinal signal-to-noise ratios (LSNRs) were calculated, per patient and per technique, defined as progression velocity divided by the standard deviation of the residuals. RESULTS: Mean (SD) follow-up was 6.4 (1.7) years; median (interquartile range [IQR]) baseline SAP MD -6.6 (-14.2 to -3.6) dB. On average 8.2 and 4.5 tests were performed for SAP and FDT, respectively. Median (IQR) MD slope was -0.16 (-0.46 to +0.02) dB/year for SAP and -0.05 (-0.39 to +0.17) dB/year for FDT. Mantel Haenszel chi-squares of SAP MD vs FDT MD and TD were 12.5 (p < 0.001) and 15.8 (p < 0.001), respectively. LSNRs for SAP MD (median -0.17 yr 1 ) were better than those for FDT MD (-0.04 yr-1 ; p = 0.010). CONCLUSIONS: FDT may be a useful technique for monitoring glaucoma progression in patients who cannot perform SAP reliably. PMID- 28836392 TI - Author's Reply. PMID- 28836394 TI - Reduced Nrf2 activation in PI3K phosphorylation-impaired vitiliginous keratinocytes increases susceptibility to ROS-generating chemical-induced apoptosis. AB - Keratinocytes in affected epidermis of vitiligo patients are known to have impaired activation of the PI3K/AKT pathway. Based on critical roles of keratinocytes and oxidative stress in vitiligo development, this study examined whether keratinocytes with impaired PI3K activation were more vulnerable to apoptosis caused by oxidative stress from phenolic compounds, p-tert-butylphenol (4-TBP) and hydroquinone (HQ). Cell viability assay, FACS analysis, ELISA for TNF alpha or IL-1a, ROS assay, Western blot analysis for Nrf2 expression, and confocal microscopy with anti-Nrf2 and phospho-PI3K antibodies were done on primary cultured normal human keratinocytes with or without PI3K knockdown in the presence or absence of chemical treatment or antioxidant. Immunofluorescence staining using anti-Nrf2, phospho-PI3K, TNF-alpha, and IL-1alpha antibodies, ROS assay using dihydroethidium, and TUNEL assay were performed on sets of depigmented and normally pigmented skin from vitiligo patients. Results showed that 4-TBP or HQ treatment increased apoptosis and the expression levels of TNF alpha, IL-1alpha, and ROS in PI3K-knockdown keratinocytes which reduced Nrf2 nuclear translocation compared to control keratinocytes. These changes were significantly recovered by an antioxidant treatment. Depigmented epidermis of vitiligo patients also showed lower levels of Nrf2 and phospho-PI3K but higher levels of ROS, TNF-alpha, IL-1alpha, and ROS with more TUNEL-positive cells. Therefore, impaired PI3K activation in keratinocytes in depigmented epidermis of vitiligo patients are vulnerable to apoptosis caused by ROS-generating chemicals due to reduced Nrf2 activation. PMID- 28836395 TI - High novelty seeking as a predictor of antisocial behaviour in early adulthood. AB - OBJECTIVE: This study aimed to examine the association between novelty seeking (NS) and antisocial behaviours (age 18-35). METHOD: A New Zealand general population birth cohort was studied from 1977 to 2012. Sample sizes ranged from n = 962 (age 35) to n = 1025 (age 18). NS was measured at age 16 using the Tridimensional Personality Questionnaire. Perpetration of antisocial behaviours was ascertained by self-report at ages 18, 21, 25, 30 and 35. Generalized estimating equation models investigated the association between NS and antisocial behaviours net of individual factors and correlates of NS before age 16 and alcohol and substance use disorders at age 18-35. RESULTS: Higher NS scores were associated with a higher unadjusted incidence of all forms of antisocial behaviour. Assault, theft, property damage and dishonesty offending remained associated with NS after adjustment for individual factors and correlates of NS before age 16. After further adjustment for alcohol and substance use disorders, NS was not associated with any antisocial behaviour outcomes, suggesting those disorders mediate the association between NS and antisocial behaviours. CONCLUSION: Alcohol and substance use disorders mediate the association between NS and antisocial behaviours in early adulthood. NS may be a useful endophenotype for investigating the causation of externalizing behaviours. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28836393 TI - The microglial fractalkine receptor is not required for activity-dependent plasticity in the mouse visual system. AB - Microglia have recently been implicated as key regulators of activity-dependent plasticity, where they contribute to the removal of inappropriate or excess synapses. However, the molecular mechanisms that mediate this microglial function are still not well understood. Although multiple studies have implicated fractalkine signaling as a mediator of microglia-neuron communications during synaptic plasticity, it is unclear whether this is a universal signaling mechanism or whether its role is limited to specific brain regions and stages of the lifespan. Here, we examined whether fractalkine signaling mediates microglial contributions to activity-dependent plasticity in the developing and adolescent visual system. Using genetic ablation of fractalkine's cognate receptor, CX3 CR1, and both ex vivo characterization and in vivo imaging in mice, we examined whether fractalkine signaling is required for microglial dynamics and modulation of synapses, as well as activity-dependent plasticity in the visual system. We did not find a role for fractalkine signaling in mediating microglial properties during visual plasticity. Ablation of CX3 CR1 had no effect on microglial density, distribution, morphology, or motility, in either adolescent or young adult mice across brain regions that include the visual cortex. Ablation of CX3 CR1 also had no effect on baseline synaptic turnover or contact dynamics between microglia and neurons. Finally, we found that fractalkine signaling is not required for either early or late forms of activity-dependent visual system plasticity. These findings suggest that fractalkine is not a universal regulator of synaptic plasticity, but rather has heterogeneous roles in specific brain regions and life stages. PMID- 28836396 TI - Morphological and Molecular Aspects of In Vitro Culture of Preantral Follicles Derived from Vitrified Ovarian. AB - OBJECTIVE: This study aimed to evaluate the expression of the genes related to folliculogenesis after vitrification of mouse ovarian tissues using a two-step in vitro culture. MATERIALS AND METHODS: In this experimental study, vitrified and non-vitrified ovaries from 7- day old (neonate) female mice were cultured using alpha-Minimum Essential Medium (alpha-MEM) supplemented with 5% fetal bovine serum (FBS) for 7 days. Morphology, surface area of ovaries and percentage of normal follicles were evaluated and compared in both groups. After one-week culture, in non-vitrified group, preantral follicles of cultured ovaries were isolated and cultured in a three-dimensional alginate culture system for 12 days. Then, the collected metaphase (M) II oocytes were inseminated with capacitated spermatozoa derived from 7-8-week old (adult) male NMRI mice. Follicular diameter, oocyte maturation, fertilization, embryo development and the expression of genes related to follicular development (Pcna, Fshr and Cyp17a1,) using real time reverse transcription-polymerase chain reaction (RT-PCR) were assessed at the end of last culture period in both groups. RESULTS: The ovarian area in vitrified group (162468.20 703.78) was less than non-vitrified group (297211.40 6671.71), while the percentage of preantral follicles in vitrified group (18.40%) was significantly lower than those of non-vitrified group (24.50%) on day 7 of culture (P>0.05). There were no significant differences between the two groups in terms of follicular diameter, expression of genes related to development of follicles, oocyte maturation, fertilization, as well as embryo development (P>0.05). CONCLUSION: The results of this study showed that vitrification of ovarian tissue following in vitro culture had negative impact on the survival and development of follicles within the tissue. However, no significant alterations were observed in development, gene expression and hormonal production of in vitro culture of isolated follicles derived from vitrified ovarian tissues as compared to the non-vitrified samples. PMID- 28836397 TI - Stochastic Cell Fate and Longevity of Offspring. AB - OBJECTIVE: Cellular decision-making is a key process in which cells with similar geneticand environmental background make dissimilar decisions. This stochastic process, which happens in prokaryotic and eukaryotic cells including stem cells, causes cellular diversity and phenotypic variation. In addition, fitness predicts and describes changes in the genetic composition of populations throughout the evolutionary history. Fitness may thus be defined as the ability to adapt and produce surviving offspring. Here, we present a mathematical model to predict the fitness of a cell and to address the fundamental issue of phenotypic variation. We study a basic decision-making scenario where a bacteriophage lambda reproduces in E. coli, using both the lytic and the lysogenic pathways. In the lytic pathway, the bacteriophage replicates itself within the host bacterium. This fast replication overcrowds and in turn destroys the host bacterium. In the lysogenic pathway, however, the bacteriophage inserts its DNA into the host genome, and is replicated simultaneously with the host genome. MATERIALS AND METHODS: In this prospective study, a mathematical predictive model was developed to estimate fitness as an index of survived offspring. We then leverage experimental data to validate the predictive power of our proposed model. A mathematical model based on game theory was also generated to elucidate a rationale behind cell decision. RESULTS: Our findings indicate that a rational decision that is aimed to maximize life expectancy of offspring is almost identical to bacteriophage behavior reported based on experimental data. The results also showed that stochastic decision on cell fate maximizes the expected number of survived offspring. CONCLUSION: We present a mathematical framework for analyzing a basic phenotypic variation problem and explain how bacteriophages maximize offspring longevity based on this model. We also introduce a mathematical benchmark for other investigations of phenotypic variation that exists in eukaryotes including stem cell differentiation. PMID- 28836398 TI - VDR and CYP24A1 Expression Analysis in Iranian Relapsing-Remitting Multiple Sclerosis Patients. AB - OBJECTIVES: Multiple sclerosis (MS) is a common disease of the central nervous system.This disease may be initiated by either vitamin deficiency or triggered by abnormality in CYP24A1 and vitamin D receptor. MATERIALS AND METHODS: In this case-control study, the expression of genes encoding vitamin D receptor (VDR) and CYP24A1 in relapsing-remitting MS (RR-MS) patients was compared with normal individuals in the Iranian population. RNA from whole blood of 50 RR-MS patients (HLA-DRB1*15-negative and responders to interferonbeta with a normal vitamin D level) and 50 normal controls was extracted. The levels of CYP24A1 and VDR expression were measured using real-time quantitative polymerase chain reaction. RESULTS: The RR-MS group had a significantly more than 2 times higher expression level of VDR than the normal group (P=0.04). On the other hand, there was a 0.89 times decrease in the expression level of CYP24A1 in RR-MS patients which was not statistically significant. There was no linear correlation between the risk of expanded disability status scale of Kurtzke (EDSS) and the expression level of either CYP24A1 or VDR. In addition, the expression level of CYP24A1 or VDR was not correlated with the duration of the disease. CONCLUSIONS: Up-regulation of VDR is likely to happen in RR-MS patients in the Iranian population. We did not observe a gene expression-phenotype correlation for CYP24A1 which may be due to limited statistical power as a result of the small sample size. Although the individuals taking part in this study had normal levels of vitamin D, the increase in VDR expression levels may perhaps be a response to a defect in vitamin D processing. Another possibility is that despite an increase in VDR expression level, factors such as micro-RNAs may result in their deactivation while an increase in VDR expression level can be seen as a compensatory response. Of course, further studies are required to identify the mechanism of action of vitamin D by analyzing genes involved in its signaling pathway, particularly VDR and CYP24A1. PMID- 28836399 TI - Multiple Sclerosis Gene Therapy with Recombinant Viral Vectors: Overexpression of IL-4, Leukemia Inhibitory Factor, and IL-10 in Wharton's Jelly Stem Cells Used in EAE Mice Model. AB - OBJECTIVES: Immunotherapy and gene therapy play important roles in modern medicine. The aim of this study is to evaluate the overexpression of interleukin 4 (IL-4), IL-10 and leukemia inhibitory factor (LIF) in Wharton's jelly stem cells (WJSCs) in the experimental autoimmune encephalomyelitis (EAE) mice model. MATERIALS AND METHODS: In this experimental study, a DNA construction containing IL- 4, IL-10 and LIF was assembled to make a polycistronic vector (as the transfer vector). Transfer and control vectors were co-transfected into Human Embryonic Kidney 293 (HEK-293T) cells with helper plasmids which produced recombinant lentiviral viruses (rLV). WJSCs were transduced with rLV to make recombinant WJSC (rWJSC). In vitro protein and mRNA overexpression of IL-4, LIF, and IL-10 were evaluated using quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and western blot (WB) analysis. EAE was induced in mice by MOG-CFA and pertussis toxin. EAE mice were injected twice with 2*105 rWJSCs. The in vivo level of IL-4, LIF, IL-10 cytokines and IL-17 were measured by ELISA. Brain tissues were analyzed histologically for evaluation of EAE lesions. RESULTS: Isolated WJSCs were performed to characterize by in vitro differentiation and surface markers were analyzed by flow cytometry method. Cloning of a single lentiviral vector with five genes was done successfully. Transfection of transfer and control vectors were processed based on CaPO4 method with >90% efficiency. Recombinant viruses were produced and results of titration showed 2-3*107 infection-unit/ml. WJSCs were transduced using recombinant viruses. IL-4, IL-10 and LIF overexpression were confirmed by ELISA, WB and qPCR. The EAE mice treated with rWJSC showed reduction of Il-17, and brain lesions as well as brain cellular infiltration, in vivo. Weights and physical activity were improved in gene-treated group. CONCLUSIONS: These results showed that gene therapy using anti-inflammatory cytokines can be a promising approach against multiple sclerosis (MS). In addition, considering the immunomodulatory potential of WJSCs, an approach using a combination of WJSCs and gene therapy will enhance the treatment efficacy. PMID- 28836400 TI - The Expression of TLR2 and TLR3 in Sertoli Cells of Azoospermic Patients. AB - OBJECTIVES: Toll-like receptors (TLRs) on Sertoli cells are thought to have essential roles in sperm protection. This study was conducted to investigate the expression of TLR2 and TLR3 in Sertoli cells of men with azoospermia. MATERIALS AND METHODS: In this experimental study, testicular biopsies were taken from ten azoospermic men. Following enzymatic dissociation, the samples were moved to lectin coated petri dishes. After a few passages, all cells were cultivated and Seroli cells were sorted by flow cytometry. To confirm Sertoli cell purification, alkaline phosphatase activity (ALP) and immunohistochemistry assays were employed. The expression of TLR2 and TLR3 at the transcript and protein levels was examined with real-time quantitative reverse transcription-polymerase chain reaction (RT-QPCR) and western blot, respectively. RESULTS: Isolation, purification and cultivation of human Sertoli cells were performed successfully. Efficacy of purification of Sertoli cells by fluorescence-activated cell sorting (FACS) sorter was ~97%. The type of cultured cells was confirmed by vimentin and follicle-stimulating hormone (FSH) receptor markers. Furthermore, the existence of anti- Mullerian hormone in culture was confirmed. RT-PCR showed that both genes were expressed in Sertoli cells. Consistently, proteins of both were also expressed in Sertoli cells. Moreover, QPCR showed that the relative expression of TLR3 transcripts was significantly higher than TLR2 in Sertoli cells. Although both genes are expressed in fibroblast cells, their level of expression was significantly lower than in Sertoli cells. CONCLUSIONS: This study confirmed expression of TLR2 and TLR3 in human Sertoli cells. This may be an indicator of their roles in developing immunity against pathogens as well as allo- and auto antigens or viral antigens in seminiferous tubules. PMID- 28836401 TI - Purinergic Receptor Expression and Potential Association with Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Development. AB - OBJECTIVES: Due to recent progress in production of human embryonic stem cell derived oligodendrocyte progenitor cells (hESC-OPCs) for ameliorating myelin disease such as multiple sclerosis (MS) and the role of purinergic signaling in OPCs development, we avaluated the profile of purinergic receptors expression during development of OPCs from hESC. MATERIALS AND METHODS: In this experimental study, we used reverse transcription and quantitative polymerase chain reaction (RT-qPCR) to obtain more information about potential roles of purinergic receptors during in vitro production of hESC-OPCs. We first determined the expression level of different subtypes of purinergic receptors in hESCs, embryoid bodies (EBs), and hESC-OPCs. The effects of A1 adenosine receptor (A1AR) activation on hESC-OPCs development were subsequently examined. RESULTS: hESCs and OPCs had different mRNA expression levels of the AR subtypes. ARs mRNA were expressed in the EB stage, except for A2AAR. We observed expressions of several P2X (P2X1, 2, 3, 4, 5, 7) and P2Y (P2Y1, 2, 4, 6, 11-14) genes in hESCs. hESC OPCs expressed different subtypes of P2X (P2X1, 2, 3,4,5,7) and P2Y (P2Y1, 2, 4, 6, 11-14). Except for P2X1 and P2X6, all other P2X and P2Y purinergic receptor subtypes expressed in EBs. We also indicate that A1AR might be involved in modulating gene expression levels of cell cycle regulators in an agonist and/or dose-dependent manner. CONCLUSIONS: Elucidation of the expression pattern of purinergic receptors and the effects of different subtypes of these receptors in hESC-OPCs may have a promising role in future cell-based therapy or drug design for demyelinating disease. PMID- 28836402 TI - Umbilical Cord Blood Platelet Lysate as Serum Substitute in Expansion of Human Mesenchymal Stem Cells. AB - OBJECTIVES: The diverse clinical applications for human mesenchymal stem cells (hMSCs) in cellular therapy and regenerative medicine warrant increased focus on developing adequate culture supplements devoid of animal-derived products. In the present study, we have investigated the feasibility of umbilical cord blood platelet lysate (UCB-PL) as a standard substitute for fetal bovine serum (FBS) and human peripheral blood-PL (PB-PL). MATERIALS AND METHODS: In this experimental study, platelet concentrates (PC) from UCB and human PB donors were frozen, melted, and sterilized to obtain PL. Quality control included platelet cell counts, sterility testing (viral and microbial), total protein concentrations, growth factor levels, and PL stability. The effects of UCB-PL and PB-PL on hMSCs proliferation and differentiation into osteocytes, chondrocytes, and adipocytes were studied and the results compared with FBS. RESULTS: UCB-PL contained high levels of protein content, platelet-derived growth factor- AB (PDGF-AB), and transforming growth factor (TGF) compared to PB-PL. All growth factors were stable for at least nine months post-storage at -70C. hMSCs proliferation enhanced following treatment with UCB-PL. With all three supplements, hMSCs could differentiate into all three lineages. CONCLUSIONS: PB PL and UCB-PL both were potent in hMSCs proliferation. However, PB promoted osteoblastic differentiation and UCB-PL induced chondrogenic differentiation. Because of availability, ease of use and feasible standardization of UCB-PL, we have suggested that UCB-PL be used as an alternative to FBS and PB-PL for the cultivation and expansion of hMSCs in cellular therapy. PMID- 28836403 TI - Caffeine Augments The Instruction of Anti-Inflammatory Macrophages by The Conditioned Medium of Mesenchymal Stem Cells. AB - OBJECTIVES: Mesenchymal stem cells (MSCs) have been shown to produce adenosine, express adenosine receptors, and communicate with macrophages and other cells. However, there is no information about the role of caffeine, as a popular drink and adenosine antagonist, on the crosstalk between MSCs and immune cells. The aim of the current study is to evaluate the effects of the conditioned medium of MSCs treated with caffeine on macrophages. MATERIALS AND METHODS: In this experimental study, MSCs were isolated from bone marrow of rats and pulsed with different concentrations of caffeine (0, 0.1, 0.5 and 1 mM) for 72 hours. The conditioned medium of MSCs was collected after 24 hours, then incubated with macrophages for 24 hours. Finally, the functions of the macrophages were evaluated. RESULTS: Conditioned medium of MSCs treated with caffeine significantly enhanced phagocytosis and simultaneously regressed expression of reactive oxygen species (ROS) and nitric oxide (NO) as well as IL-12 by macrophages compared to the supernatants of MSCs alone. The conditioned medium of MSCs pulsed with caffeine at low to moderate concentrations preserved the neutral red uptake by macrophages and elevated IL-10 secretion by macrophages. A high concentration of caffeine could interfere with the two latter effects of supernatants of MSCs on the macrophages. CONCLUSIONS: Collectively, caffeine treatment of MSCs appeared to augment the instruction of anti-inflammatory macrophages by conditioned medium of MSCs. These findings might offer new insight into the potential mechanisms that underlie the immunomodulatory and anti-inflammatory effects of caffeine. PMID- 28836404 TI - Anti-Inflammatory Effects of Curcumin on Insulin Resistance Index, Levels of Interleukin-6, C-Reactive Protein, and Liver Histology in Polycystic Ovary Syndrome-Induced Rats. AB - OBJECTIVES: Curcumin protects the liver against injury and fibrosis through suppressing hepatic inflammation, attenuating hepatic oxidative stress (OS), and inhibiting hepatic stellate cells (HSCs) activation. Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are considered as common metabolic disorders. Low-grade chronic inflammation with different markers, such as elevated C-reactive protein (CRP) and interleukin-6 (IL-6) levels, play a crucial role in PCOS. This study aimed to evaluate the therapeutic effects of curcumin on IL-6 and CRP levels as well as insulin resistance (IR) index on liver function in PCOS rats. MATERIALS AND METHODS: In this experimental study, 90 adult Wistar rats were divided into control (n=18), sham (n=18), PCOS (n=18) and curcumin-treated PCOS groups (n=36). PCOS group was injected subcutaneously with 2 mg estradio-valerate (E2V). After 60 days, PCOS group was treated with curcumin [100 and 300 mg/kg body weight (BW)] for 14 days and anesthetized by chloroform. Blood and liver samples were collected for histological and serological analyses. Data were analyzed using In-Stat 3 via one-way analysis of variance (ANOVA). RESULTS: Histological and serological analyses showed a reduction in number of necrotic cells, IR index, as well as IL-6 and CRP levels in PCOS rats that were treated with various concentrations of curcumin. CONCLUSIONS: In this study, curcumin decreased liver inflammation by induction of insulin sensitivity and reduction of hepatic necrosis. Therefore, curcumin may be considered as protective factor against inflammatory state of PCOS. PMID- 28836405 TI - Assessment of The Dose-Response Relationship of Radiation-Induced Bystander Effect in Two Cell Lines Exposed to High Doses of Ionizing Radiation (6 and 8 Gy). AB - OBJECTIVES: The dose-response relationship of radiation-induced bystander effect (RIBE) is controversial at high dose levels. The aim of the present study is to assess RIBE at high dose levels by examination of different endpoints. MATERIALS AND METHODS: This experimental study used the medium transfer technique to induce RIBE. The cells were divided into two main groups: QU-DB cells which received medium from autologous irradiated cells and MRC5 cells which received medium from irradiated QU-DB cells. Colony, MTT, and micronucleus assays were performed to quantify bystander responses. The medium was diluted and transferred to bystander cells to investigate whether medium dilution could revive the RIBE response that disappeared at a high dose. RESULTS: The RIBE level in QU-DB bystander cells increased in the dose range of 0.5 to 4 Gy, but decreased at 6 and 8 Gy. The Micronucleated cells per 1000 binucleated cells (MNBN) frequency of QU-DB bystander cells which received the most diluted medium from 6 and 8 Gy QU-DB irradiated cells reached the maximum level compared to the MNBN frequency of the cells that received complete medium (P<0.0001). MNBN frequency of MRC5 cells which received the most diluted medium from 4 Gy QU-DB irradiated cells reached the maximum level compared to MNBN frequency of cells that received complete medium (P<0.0001). CONCLUSIONS: Our results showed that RIBE levels decreased at doses above 4 Gy; however, RIBE increased when diluted conditioned medium was transferred to bystander cells. This finding confirmed that a negative feedback mechanism was responsible for the decrease in RIBE response at high doses. Decrease of RIBE at high doses might be used to predict that in radiosurgery, brachytherapy and grid therapy, in which high dose per fraction is applied, normal tissue damage owing to RIBE may decrease. PMID- 28836406 TI - Subcellular Distribution of S-Nitrosylated H-Ras in Differentiated and Undifferentiated PC12 Cells during Hypoxia. AB - OBJECTIVES: Hypoxia or exposure to excessive reactive oxygen or nitrogen species could induce S-nitrosylation of various target proteins, including GTPases of the Ras-superfamily. Under hypoxic conditions, the Ras-protein is translocated to the cytosol and interacts with the Golgi complex, endoplasmic reticulum, mitochondria. The mobility/translocation of Ras depend on the cells oxidative status. However, the importance of relocated Snitrosylated- H-Ras (NO-H-Ras) in proliferation/differentiation processes is not completely understood. We have determined the content of soluble- and membrane-bound-NO-HRas in differentiated (D) and undifferentiated (ND) rat pheochromocytoma (PC12) cells under hypoxic and normoxic conditions. MATERIALS AND METHODS: In our experimental study, we analyzed NO-H-Ras levels under hypoxic/normoxic conditions in membrane and soluble fractions of ND and D PC12 cells with/without nitric oxide donor, sodium nitroprusside (SNP) treatment. Cells were analyzed by the S-nitrosylated kit, immunoprecipitation, and Western blot. We assessed the action of NO-H-Ras on oxidative metabolism of isolated mitochondria by determining mitochondrial hydrogen peroxide generation via the scopoletin oxidation method and ATPproduction as estimated by the luminometric method. RESULTS: Hypoxia did not influence nitrosylation of soluble H-Ras in ND PC12 cells. Under hypoxic conditions, the nitrosylation of soluble-H-Ras greatly decreased in D PC12 cells. SNP didn't change the levels of nitrosylation of soluble-H-Ras, in either hypoxic or normoxic conditions. On the other hand, hypoxia, per se, did not affect the nitrosylation of membrane-bound-H-Ras in D and ND PC12 cells. SNP-dependent nitrosylation of membrane-bound-H-Ras greatly increased in D PC12 cells. Both unmodified normal and mutated H-Ras enhanced the mitochondrial synthesis of ATP, whereas the stimulatory effects on ATP synthesis were eliminated after S nitrosylation of H-Ras. CONCLUSIONS: According to the results, it may be proposed that hypoxia can decrease S-nitrosylation of soluble-H-Ras in D PC12 cells and abolish the inhibitory effect of NO-HRas in mitochondrial oxidative metabolism. PMID- 28836407 TI - Administration of Selenium Decreases Lipid Peroxidation and Increases Vascular Endothelial Growth Factor in Streptozotocin Induced Diabetes Mellitus. AB - OBJECTIVES: The imbalance in oxidant/antioxidant status plays a pivotal role in diabetes mellitus (DM). Selenium is a integral component of the antioxidant enzyme glutathione peroxidase. Se treatment induces angiogenesis and improves endothelial function through increased expression of vascular endothelial growth factor (VEGF). The aim of this study is to investigate the effect of selenium on oxidative stress, VEGF, and endothelin 1 (ET1) in a DM rat model. MATERIALS AND METHODS: We performed an experimental animal study with 64 adult male Wistar Albino rats. Rats were divided into the following groups (n=8): control (C)7, C21, C+sodium selenite (Se)7, and C+Se21 (control rats), and DM7, DM21, DM+Se7, and DM+Se21 (diabetic rats). Diabetes was induced by 2-deoxy-2-(3-methyl-3 nitrosoureido)- D-glucopyranose [streptozotocin (STZ)]. Three weeks after STZ, DM+Se7 rats received intraperitoneal (i.p.) injections of 0.4 mg/kg Se for 7 days. The DM+Se21 rats received these injections for 21 days. The same dose/duration of Se was administered to the C+Se7 and C+Se21 groups. The remaining rats (C7, C21, DM7, DM21) received physiologic saline injections for 7 or 21 days. Ferric reducing antioxidant power (FRAP), malondialdehyde (MDA), advanced oxidation protein products (AOPP), and endothelial function markers (VEGF and ET1) in plasma samples were measured. RESULTS: Diabetic rats (DM7 and DM21) had significantly increased plasma FRAP (P=0.002, P=0.001), AOPP (P=0.024, P=0.01), MDA (P=0.004, P=0.001), and ET1 (P=0.028, P=0.003) levels compared with C7 and C21 control rats. VEGF (P=0.02, P=0.01) significantly decreased in DM7 and DM21 diabetic rats compared with their controls (C7, C21). Se administration reversed the increased MDA and decreased VEGF levels, and lowered plasma glucose levels in the DM+Se7 and DM+Se21 diabetic groups compared with diabetic rats (DM7, DM21). We observed positive correlations between FRAP-AOPP (r=0.460), FRAP ET1 (r=0.510), AOPP-MDA (r=0.270), and AOPP-ET1 (r=0.407), and a negative correlation between MDA-VEGF (r=-0.314). CONCLUSIONS: We observed accentuated oxidative stress and impaired endothelial function in diabetes. Se treatment reduced lipid peroxidation and hyperglycemia. Se probably improved endothelial dysfunction in diabetic rats because of the increased VEGF levels. PMID- 28836408 TI - Effects of Estradiol on Histological Parameters and Secretory Ability of Pituitary Mammotrophs in Ovariectomized Female Rats. AB - OBJECTIVES: Estrogen replacement therapy remains current as a therapeutic approach to treat menopausal symptoms and may significantly affect hormone producing cells in the female pituitaries. The aim of this study was to examine the histological parameters of pituitary mammotrophs and prolactin secretion after chronic estradiol treatment in ovariectomized adult female rats, reflecting premature menopause. MATERIALS AND METHODS: In this experimental study, adult female Wistar rats were divided into non-ovariectomized (C), ovariectomized (OVX) and estradiol-treated ovariectomized (OVX+E) groups. Estradiol dipropionate [0.625 mg/kg body mass per day] was administered for four weeks, while the C and OVX groups received vehicle alone. Mammotrophs were identified by the peroxidase antiperoxidase (PAP) immunohistochemical procedure, while prolactin concentrations were measured by the non-isotopic two-step assay (Delfia) method. Comparison of the differences between groups was performed using one-way analysis of variance (ANOVA) and Tukay (honest significant difference) HSD test. RESULTS: Ovariectomy caused significant (P<0.05) decreases in mammotroph optical density (OD), volume density (VV) and number per mm2 by 29, 27 and 34%, respectively, in comparison with the C females. In the OVX+E group, significant (P<0.05) increases in OD, cell volume, VV and number of mammotrophs per mm2 by 181, 15%, 5.8-fold and 5.2-fold, respectively, were observed when compared to OVX animals. The serum prolactin concentration in OVX females was significantly (P<0.05) decreased by 14% in comparison to the C group, while in OVX+E females, prolactin levels were significantly (P<0.05) increased by 53% compared to the OVX controls. CONCLUSIONS: Estradiol supplementation in ovariectomized females is followed by stimulatory histological and secretory changes of the mammotrophs. These results could serve as indicators of possible prolactinome development upon estradiol application in premature menopausal subjects. PMID- 28836409 TI - Cardio-Protective Role of Gingerol along with Prominent Anti-Diabetic Cardiomyopathy Action in A Streptozotocin-Induced Diabetes Mellitus Rat Model. AB - OBJECTIVES: Diabetic cardiomyopathy (DCM) is characterized as a coronary heart disease which expands during diabetes due to alterations in the myocardial function and structure. The currentstudy intends to elucidate the protective effect of gingerol on DCM in a streptozotocin (STZ)-induced diabetes mellitus (DM) rat model. MATERIALS AND METHODS: In this experimental study, the animals were divided into three groups: normal control, DM control, and DM+gingerol (10 mg/kg). The body weights of all rats were estimated at regular intervals. The myocardial profile, oxidative stress, and activities of metabolic enzymes were also scrutinized. The proinflammatory cytokine levels together with cellular protein expression connected with apoptosis were estimated via Western blot analysis. RESULTS: The rats that suffered from DCM exhibited abnormal levels of myocardial markers, aberrant metabolic enzymatic activity, elevated concentrations of inflammatory factors, and enhanced oxidative stress parameters along with increased cell death apoptosis. Whereas gingerol showed protective effects on the treated rats by an improved antioxidant defense system. CONCLUSIONS: The current findings suggested that gingerol is effective in the treatment of DCM by inhibition of inflammation and oxidative stress. PMID- 28836410 TI - Effect of Fetal Mouse Lung Tissue Co-Culture on In Vitro Maturation of Mouse Immature Oocytes. AB - OBJECTIVES: The aim of this study was to evaluate the fetal mouse lung tissue co culture on in vitro maturation (IVM) of mouse immature oocytes. MATERIALS AND METHODS: In this experimental study, germinal vesicle (GV) oocytes from ovaries of a group of 25 female mice, 6-8 weeks of age, were dissected after being stimulated by 7.5 IU pregnant mare serum gonadotropin (PMSG) through an intraperitoneal (IP) injection. The fetal lung tissues were then prepared and cultured individually. A total number of 300 oocytes were cultured in the following three groups for 24 hours: control group (n=100) containing only base medium, group I (n=100) containing base medium co-cultured with 11.5- to 12.5-day old fetal mouse lung tissues, and group II (n=100) containing base medium co cultured with 12.5- to 13.5-day old fetal mouse lung tissues. The proportion of GV and metaphase I (MI) oocytes matured into MII oocytes were compared among the three groups using analysis of variance (ANOVA). Correlation test were also used to evaluate the successful rate of IVM oocytes. RESULTS: The proportions of GV oocytes reaching MII stage were 46, 65, and 56%, in control, I and II groups, respectively (P<0.05). The percentage of the oocytes remaining at the GV stage were higher in control group as compared with two treatment groups (P<0.05). CONCLUSIONS: This study indicated that fetal mouse lung tissue co-culture method increased the percentage of GV oocytes reaching MII stage. PMID- 28836411 TI - Evidence of Oocyte Polarity in Bovine; Implications for Intracytoplasmic Sperm Injection and Somatic Cell Nuclear Transfer. AB - OBJECTIVES: We recently demonstrated spatial regionalization of maternal transcripts and proteins within unfertilized ovine oocyte. Here, we investigated the likelihood of oocyte polarity for the first time in bovine. MATERIALS AND METHODS: In this experimental study, in vitro matured bovine oocytes were used for manual bisection [into oocyte halve that were near-to (HNS) and far-from (FS) spindle] or trisection [into MII-spindle (S), the spindle-side half (NS), and the distal half unassociated with the spindle (FS)]. Prepared pools of oocyte substructures were used for comparative quantitative real-time polymerase chain reaction (RT-qPCR). To map the possible preferential sperm entry point (SEP), the spatial relationship between SEP and MII-spindle was measured 5 hours post fertilization. RESULTS: The proportional amount of maternal mRNA in S oocyte fragment was estimated to be 6 to 11-fold higher than NS and FS counterparts. The relative abundances of Nanog, Oct4, Fgf4 and Tead4 were significantly higher in HNS oocyte fragment compared t0 FS. The relative abundances of Ctnb, Carm1, Rex1, Sox2 and Cdx2 were comparable between HNS and NS oocyte fragments. FS oocyte fragment possessed significantly higher transcripts of Gata4 compared to HNS. The distribution of certain transcripts related to pluripotency and lineage commitment were different depending upon the region of the oocyte; either enriched at S (Tead4, Nanog, Ctnb and Sox2), NS (Oct4), or FS (Gata6). The SEP in almost (90%) fertilized oocytes was located in MII-hemisphere. CONCLUSIONS: The observation of spatial restriction of mRNAs and SEP within MII-oocyte may indicate that the principal forces of oocyte polarity are evolutionary conserved. This may in turn highlight the need for refinements in the methodology of intracytoplasmic sperm injection (where a sperm is injected far from the MII spindle) and somatic cell nuclear transfer (where a major amount of regulative mRNAs that are associated with MIIspindle is removed during enucleation). PMID- 28836412 TI - Comparison of Allotransplantation of Fresh and Vitrified Mouse Ovaries to The Testicular Tissue under Influence of The Static Magnetic Field. AB - OBJECTIVES: The aim of this study was to investigate the effects of static magnetic field (SMF) during transplantation of the ovarian tissue into the testis. MATERIALS AND METHODS: In this experimental study, ovaries of 6- to 8 week-old female Naval Medical Research Institute (NMRI) mice were randomly divided into four groups: i. Fresh ovaries were immediately transplanted into the testicular tissue (FOT group), ii. Fresh ovaries were exposed to the SMF for 10 minutes and then transplanted into the testicular tissue (FOT+ group), iii. Vitrified-warmed ovaries were transplanted into the testicular tissue (VOT group), and iv. Vitrified-warmed ovaries were transplanted into the testicular tissue and the transplantation site was then exposed to the SMF for 10 minutes (VOT+ group). RESULTS: The lowest percentages of morphologically dead primordial follicles and the highest percentages of morphologically intact primordial follicles were seen in the FOT+ group (4.11% +/- 2.88 and 41.26% +/- 0.54, respectively). Although the lowest significant percentage of maturation, embryonic development and fertility was observed in the VOT group as compared to the other groups, the difference in the fertility rate was not significant between the VOT and VOT+ groups. Estrogen and progesterone concentrations were significantly higher in the FOT+ group than those of the control mice. CONCLUSIONS: It is concluded that, exposure of the vitrified-warmed ovaries to SMF retains the structure of the graft similar to that of fresh ovaries. PMID- 28836413 TI - Determinants of The Grade A Embryos in Infertile Women; Zero-Inflated Regression Model. AB - OBJECTIVES: In assisted reproductive technology, it is important to choose high quality embryos for embryo transfer. The aim of the present study was to determine the grade A embryo count and factors related to it in infertile women. MATERIALS AND METHODS: This historical cohort study included 996 infertile women. The main outcome was the number of grade A embryos. Zero-Inflated Poisson (ZIP) regression and Zero-Inflated Negative Binomial (ZINB) regression were used to model the count data as it contained excessive zeros. Stata software, version 13 (Stata Corp, College Station, TX, USA) was used for all statistical analyses. RESULTS: After adjusting for potential confounders, results from the ZINB model show that for each unit increase in the number 2 pronuclear (2PN) zygotes, we get an increase of 1.45 times as incidence rate ratio (95% confidence interval (CI): 1.23-1.69, P=0.001) in the expected grade A embryo count number, and for each increase in the cleavage day we get a decrease 0.35 times (95% CI: 0.20-0.61, P=0.001) in expected grade A embryo count. CONCLUSIONS: There is a significant association between both the number of 2PN zygotes and cleavage day with the number of grade A embryos in both ZINB and ZIP regression models. The estimated coefficients are more plausible than values found in earlier studies using less relevant models. PMID- 28836414 TI - Taraxerol Induces Cell Apoptosis through A Mitochondria-Mediated Pathway in HeLa Cells. AB - OBJECTIVES: Taraxerol acetate has potent anti-cancer effects via the induction of apoptosis, autophagy, cell cycle arrest, and inhibition of cell migration. However, whether taraxerol induced apoptosis and its underlying mechanisms of action is not clear. In the present study, we assess the effects of taraxerol on the mitochondrial apoptotic pathway and determine the release of cytochrome c to the cytosol and activation of caspases. MATERIALS AND METHODS: In this experimental study, we mainly investigated the effect of taraxerol on HeLa cells. We tested cell viability by the MTT assay and morphologic changes, analyzed apoptosis by DAPI staining and flow cytometry. We also determined reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) using a Microplate Reader. In addition, the apoptotic proteins were tested by Western blot. RESULTS: Taraxerol enhanced ROS levels and attenuated the MMP (Deltapsim) in HeLa cells. Taraxerol induced apoptosis mainly via the mitochondrial pathway including the release of cytochrome c to the cytosol and activation of caspases 9 and 3, and anti-poly (ADPribose) polymerase (PARP). Taraxerol could induce the down regulation of the anti-apoptotic protein Bcl-2 and up-regulation of pro-apoptotic protein Bax. It suppressed the PI3K/ Akt signaling pathway. CONCLUSIONS: These results demonstrated that taraxerol induced cell apoptosis through a mitochondria mediated pathway in HeLa cells. Thus, taraxerol might be a potential anticervical cancer candidate. PMID- 28836415 TI - Protease sensing using nontoxic silicon quantum dots. AB - Herein is presented a proof-of-concept study of protease sensing that combines nontoxic silicon quantum dots (SiQDs) with Forster resonance energy transfer (FRET). The SiQDs serve as the donor and an organic dye as the acceptor. The dye is covalently attached to the SiQDs using a peptide linker. Enzymatic cleavage of the peptide leads to changes in FRET efficiency. The combination of interfacial design and optical imaging presented in this work opens opportunities for use of nontoxic SiQDs relevant to intracellular sensing and imaging. PMID- 28836416 TI - Automated classification of cell morphology by coherence-controlled holographic microscopy. AB - In the last few years, classification of cells by machine learning has become frequently used in biology. However, most of the approaches are based on morphometric (MO) features, which are not quantitative in terms of cell mass. This may result in poor classification accuracy. Here, we study the potential contribution of coherence-controlled holographic microscopy enabling quantitative phase imaging for the classification of cell morphologies. We compare our approach with the commonly used method based on MO features. We tested both classification approaches in an experiment with nutritionally deprived cancer tissue cells, while employing several supervised machine learning algorithms. Most of the classifiers provided higher performance when quantitative phase features were employed. Based on the results, it can be concluded that the quantitative phase features played an important role in improving the performance of the classification. The methodology could be valuable help in refining the monitoring of live cells in an automated fashion. We believe that coherence controlled holographic microscopy, as a tool for quantitative phase imaging, offers all preconditions for the accurate automated analysis of live cell behavior while enabling noninvasive label-free imaging with sufficient contrast and high-spatiotemporal phase sensitivity. PMID- 28836417 TI - Second-harmonic patterned polarization-analyzed reflection confocal microscope. AB - We introduce the second-harmonic patterned polarization-analyzed reflection confocal (SPPARC) microscope-a multimodal imaging platform that integrates Mueller matrix polarimetry with reflection confocal and second-harmonic generation (SHG) microscopy. SPPARC microscopy provides label-free three dimensional (3-D), SHG-patterned confocal images that lend themselves to spatially dependent, linear polarimetric analysis for extraction of rich polarization information based on the Mueller calculus. To demonstrate its capabilities, we use SPPARC microscopy to analyze both porcine tendon and ligament samples and find differences in both circular degree-of-polarization and depolarization parameters. Moreover, using the collagen-generated SHG signal as an endogenous counterstain, we show that the technique can be used to provide 3-D polarimetric information of the surrounding extrafibrillar matrix plus cells or EFMC region. The unique characteristics of SPPARC microscopy holds strong potential for it to more accurately and quantitatively describe microstructural changes in collagen-rich samples in three spatial dimensions. PMID- 28836418 TI - Evolocumab in Patients with Cardiovascular Disease. PMID- 28836419 TI - Evolocumab in Patients with Cardiovascular Disease. PMID- 28836420 TI - Evolocumab in Patients with Cardiovascular Disease. PMID- 28836421 TI - Adalimumab for Uveitis in Juvenile Idiopathic Arthritis. PMID- 28836422 TI - Adjuvant Capecitabine for Breast Cancer. PMID- 28836423 TI - Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. PMID- 28836424 TI - More on Co-Occurrence of COMT and BRCA1/2 Variants in a Population. PMID- 28836425 TI - Targeted Delivery System Based on Gemcitabine-Loaded Silk Fibroin Nanoparticles for Lung Cancer Therapy. AB - Here, a targeted delivery system was developed based on silk fibroin nanoparticles (SFNPs) for the systemic delivery of gemcitabine (Gem) to treat induced lung tumor in a mice model. For targeting the tumorigenic lung tissue, SP5-52 peptide was conjugated to Gem-loaded SFNPs. Different methods were used to characterize the structural and physicochemical properties of the SFNPs. The prepared nanoparticles (NPs) showed suitable characteristics in terms of size, zeta potential, morphology, and structural properties. Moreover, the targeted Gem loaded SFNPs showed higher cytotoxicity, cellular uptake, and accumulation in the lung tissue in comparison to the nontargeted SFNPs and control groups. Afterward, a mice model with induced lung tumor was developed by intratracheal injection of Lewis lung carcinoma (LL/2) cells into the lungs for assessing the therapeutic efficacy of the prepared drug delivery system. The histopathological assessments and single-photon-emission computed tomography-CT radiographs showed successful lung tumor induction. Moreover, the obtained results showed higher potential of targeted Gem-loaded SFNPs in treating induced lung tumor compared with that of the control groups. Higher survival rate, less mortality, and no sign of metastasis were also observed in those animals treated with targeted NPs based on the histological and radiological analyses. This study presented an effective anticancer drug delivery system for specific targeting of induced lung tumor that could be useful in treating malignant lung cancers in future. PMID- 28836426 TI - Controlling the Growth of Molecular Crystal Aggregates with Distinct Linear and Nonlinear Optical Properties. AB - Two novel donor-acceptor molecules, 2,7-diphenylbenzo[1,2-b:4,3-b']difuran-4,5 dicarbonitrile and 2,7-bis(4-methoxyphenyl)benzo[1,2-b:4,3-b']difuran-4,5 dicarbonitrile containing cyano group as the electron acceptor, were synthesized. Their single-crystal structures, molecular packing, and self-assembly behaviors were also investigated. By simple solvent evaporation techniques, these compounds self-assemble into various low-dimensional microstructures that demonstrate distinctive nonlinear optical properties depending on the orientations of their transition dipoles. This study highlights the importance of the transition dipole moment in the construction of low-dimensional molecular materials with highly efficient nonlinear optical properties. PMID- 28836427 TI - Embedded Triboelectric Active Sensors for Real-Time Pneumatic Monitoring. AB - Pneumatic monitoring sensors have great demands for power supply in cylinder systems. Here, we present an embedded sliding triboelectric nanogenerator (TENG) in air cylinder as active sensors for position and velocity monitoring. The embedded TENG is composed of a circular poly(tetrafluoroethylene) polymer and a triangular copper electrode. The working mechanism as triboelectric active sensors and electric output performance are systematically investigated. By integrating into the pneumatic system, the embedded triboelectric active sensors have been used for real-time air pressure/flow monitoring and energy storage. Air pressures are measured from 0.04 to 0.12 MPa at a step of 0.02 MPa with a sensitivity of 49.235 V/MPa, as well as airflow from 50 to 250 L/min at a step of 50 L/min with a sensitivity of 0.002 MUA.min/L. This work has first demonstrated triboelectric active sensors for pneumatic monitoring and may promote the development of TENG in intelligent pneumatic system. PMID- 28836428 TI - Salinity Effects on Iron Speciation in Boreal River Waters. AB - Previous studies report high and increasing iron (Fe) concentrations in boreal river mouths. This Fe has shown relatively high stability to salinity-induced aggregation in estuaries. The aim of this study was to understand how the speciation of Fe affects stability over salinity gradients. For Fe to remain in suspension interactions with organic matter (OM) are fundamental and these interactions can be divided in two dominant phases: organically complexed Fe, and colloidal Fe (oxy)hydroxides, stabilized by surface interactions with OM. The stability of these two Fe phases was tested using mixing experiments with river water and artificial seawater. Fe speciation of river waters and salinity-induced aggregates was determined by synchrotron-based extended X-ray absorption fine structure (EXAFS) spectroscopy. The relative contribution of the two Fe phases varied widely across the sampled rivers. Moreover, we found selective removal of Fe (oxy)hydroxides by aggregation at increasing salinity, while organically complexed Fe was less affected. However, Fe-OM complexes were also found in the aggregates, illustrating that the control of Fe stability is not explained by the prevalence of the respective Fe phases alone. Factors such as colloid size and the chemical composition of the OM may also impact the behavior of Fe species. PMID- 28836429 TI - Orienting the Microstructure Evolution of Copper Phthalocyanine as an Anode Interlayer in Inverted Polymer Solar Cells for High Performance. AB - Recent advances in the interfacial modification of inverted-type polymer solar cells (PSCs) have resulted from controlling the surface energy of the cathode modified layer (TiO2 or ZnO) to enhance the short-circuit current (Jsc) or optimizing the contact morphology of the cathode (indium tin oxide or fluorine doped tin oxide) and active layer to increase the fill factor. Herein, we report that the performance enhancement of PSCs is achieved by incorporating a donor macromolecule copper phthalocyanine (CuPc) as an anode modification layer. Using the approach based on orienting the microstructure evolution, uniformly dispersed island-shaped CuPc spot accumulations are built on the top of PTB7:PC71BM blend film, leading to an efficient spectral absorption and photogenerated exciton splitting. The best power conversion efficiency of PSCs is increased up to 9.726%. In addition to the enhanced light absorption, the tailored anode energy level alignment and optimized boundary morphology by incorporating the CuPc interlayer boost charge extraction efficiency and suppress the interfacial molecular recombination. These results demonstrate that surface morphology induction through molecular deposition is an effective method to improve the performance of PSCs, which reveals the potential implications of the interlayer between the organic active layer and the electrode buffer layer. PMID- 28836430 TI - Bistinospinosides A and B, Dimeric Clerodane Diterpene Glycosides from Tinospora sagittata. AB - Two dimeric clerodane diterpene glycosides, namely, bistinospinosides A (1) and B (2), were isolated from the roots of Tinospora sagittata. Their structures were elucidated by extensive spectroscopic data interpretation. The compounds feature an unusual 1,4-epoxycyclohexane ring in their structures and may be biosynthetically constructed via an intermolecular Diels-Alder [4+2] cycloaddition from the corresponding clerodane diterpene. The compounds were evaluated in a nitric oxide inhibitory assay using J774.1 macrophage-like cells. PMID- 28836431 TI - Structure-Dependent Antimicrobial Theranostic Functions of Self-Assembled Short Peptide Nanoagents. AB - Gadolinium (Gd[III])-based nanoaggregates are potential noninvasive magnetic resonance imaging (MRI) probes with excellent spatial and temporal resolution for cancer diagnosis. Peptides conjugated with Gd3+ can aid in supramolecular scaffolding for MRI nanoagents because of their inherent biocompatibility and degradability. We report here a strategy to tune the MR relaxivity of tumor cell targeted nanoagents and enhance the antimicrobial and anticancer activities of nanoagents based on rationally designed antimicrobial peptide (AMP) assembly. A tripeptide with glycyl-l-histidyl-l-lysine (GHK) capable of Gd3+ chelation was attached to short AMPs containing pyrazole amino acids that spontaneously assembled as a function of the number of hydrophobic amino acid residues and the peptide length of AMPs. Aqueous coassembly of GHK with tumor-targeting, cyclic arginine-glycine-aspartic acid (cRGD)-tagged AMPs resulted in the formation of micelles, fibrils, vesicles, sheets, and planar networks. Interestingly, the two dimensional planar network nanostructure showed less antibacterial activity and tumor cell cytotoxicity but greater drug loading/delivery and magnetic resonance signaling than micelles because of its intrinsic structural characteristics. This study can provide a rational approach for the design and fabrication of clinically useful nanoagents. PMID- 28836432 TI - Phase Effect of NixPy Hybridized with g-C3N4 for Photocatalytic Hydrogen Generation. AB - The use of noble metal-free nickel phosphides (NixPy) as suitable cocatalysts in photocatalytic hydrogen (H2) generation has gained a lot of interest. In this paper, for the first time, three different crystalline phases of nickel phosphides, Ni2P, Ni12P5, and Ni3P, were synthesized and then hybridized with g C3N4 to investigate the phase effect of NixPy on photocatalytic H2 generation. It has been found that all three phases of NixPy work as effective cocatalysts for the enhancement of visible light H2 generation with g-C3N4. The effective charge transfer between g-C3N4 and NixPy, demonstrated by photoelectrochemical properties, photoluminescence, and time-resolved diffused reflectance, contributes to the enhanced photocatalytic H2 generation performance. Interestingly, Ni2P/g-C3N4 showed the highest photocatalytic activity among the three NixPy/g-C3N4. NixPy with a higher ratio of phosphorus (Ni2P) can accelerate charge transfer and provide more Ni-P bonds, leading to a preferable H2 generation performance. PMID- 28836433 TI - Janus Silver/Silica Nanoplatforms for Light-Activated Liver Cancer Chemo/Photothermal Therapy. AB - Stimuli-triggered nanoplatforms have become attractive candidates for combined strategies for advanced liver cancer treatment. In this study, we designed a light-responsive nanoplatform with folic acid-targeting properties to surmount the poor aqueous stability and photostability of indocyanine green (ICG). In this Janus nanostructure, ICG was released on-demand from mesoporous silica compartments in response to near-infrared (NIR) irradiation, exhibiting predominant properties to convert light to heat in the cytoplasm to kill liver cancer cells. Importantly, the silver ions released from the silver compartment that were triggered by light could induce efficient chemotherapy to supplement photothermal therapy. Under NIR irradiation, ICG-loaded Janus nanoplatforms exhibited synergistic therapeutic capabilities both in vitro and in vivo compared with free ICG and ICG-loaded mesoporous silica nanoparticles themselves. Hence, our Janus nanoplatform could integrate ICG-based photothermal therapy and silver ion-based chemotherapy in a cascade manner, which might provide an efficient and safe strategy for combined liver cancer therapy. PMID- 28836434 TI - Liquid Chromatography-Tandem Mass Spectrometry Analysis of Biomarkers of Exposure to Phosphorus Flame Retardants in Wastewater to Monitor Community-Wide Exposure. AB - Phosphorus flame retardants and plasticizers (PFRs) are increasingly used in consumer goods, from which they can leach and pose potential threats to human health. Monitoring human exposure to these compounds is thus highly relevant. Current assessment of exposure through analysis of biological matrices is, however, tedious as well as logistically and financially demanding. Analysis of selected biomarkers of exposure to PFRs in wastewater could be a simple and complementary approach to monitoring, over space and time, exposure at the population level. An analytical procedure, based on solid-phase extraction (SPE) and liquid chromatography coupled to tandem mass spectrometry, was developed and validated to monitor the occurrence in wastewater of human exposure biomarkers of 2-ethylhexyldiphenyl phosphate (EHDPHP), tris(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP), tris(2-chloroisopropyl) phosphate (TCIPP), and tris(2 chloroethyl) phosphate (TCEP). Various SPE sorbents and extraction protocols were evaluated, and for the optimized method, absolute extraction recoveries ranged between 46% and 100%. Accuracy and precision were satisfactory for the selected compounds. Method detection limits ranged from 1.6 to 19 ng L-1. Biomarkers of exposure to PFRs were measured for the first time in influent wastewater. Concentrations in samples collected in Belgium ranged from below the limit of quantitation to 1072 ng L-1, with 2-ethylhexyl phenyl phosphate (EHPHP) and TCEP being the most abundant. Per capita loads of target biomarkers varied greatly, suggesting potential differences in exposure between the investigated communities. The developed method allowed implementation of the concepts of human biomonitoring at the community scale, opening the possibility to assess population-wide exposure to PFRs. PMID- 28836435 TI - Controlling Molecular Weight of Hyaluronic Acid Conjugated on Amine-rich Surface: Toward Better Multifunctional Biomaterials for Cardiovascular Implants. AB - The molecular weights (MWs) of hyaluronic acid (HA) in extracellular matrix secreted from both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) play crucial roles in the cardiovascular physiology, as HA with appropriate MW influences important pathways of cardiovascular homeostasis, inhibits VSMC synthetic phenotype change and proliferation, inhibits platelet activation and aggregation, promotes endothelial monolayer repair and functionalization, and prevents inflammation and atherosclerosis. In this study, HA samples with gradients of MW (4 * 103, 1 * 105, and 5 * 105 Da) were prepared by covalent conjugation to a copolymerized film of polydopamine and hexamethylendiamine (PDA/HD) as multifunctional coatings (PDA/HD-HA) with potential to improve the biocompatibility of cardiovascular biomaterials. The coatings immobilized with high-MW-HA (PDA/HD-HA-2: 1 * 105 Da; PDA/HD-HA-3: 5 * 105 Da) exhibited a remarkable suppression of platelet activation/aggregation and thrombosis under 15 dyn/cm2 blood flow and simultaneously suppressed the adhesion and proliferation of VSMC and the adhesion, activation, and inflammatory cytokine release of macrophages. In particular, PDA/HD-HA-2 significantly enhanced VEC adhesion, proliferation, migration, and functional factors release, as well as the captured number of endothelial progenitor cells under dynamic condition. The in vivo results indicated that the multifunctional surface (PDA/HD-HA-2) created a favorable microenvironment of endothelial monolayer formation and functionalization for promoting reendothelialization and reducing restenosis of cardiovascular biomaterials. PMID- 28836436 TI - Regioselective Synthesis of Methylene-Bridged Naphthalene Oligomers and Their Host-Guest Chemistry. AB - In this research, we report the regioselective synthesis of methylene-bridged naphthalene oligomers from 2,6-dialkoxyl naphthanene and paraformaldehyde by using p-TsOH as the catalyst and CH2Cl2 as the solvent. The structures were characterized by NMR spectroscopy and X-ray crystallography. Their host-guest chemistry with organic cations was studied, and optimal naphthalene numbers in the oligomers were revealed for different guests. In addition, the reason for the unsuccessful synthesis of methylene-bridged naphthalene macrocycles was discussed. PMID- 28836438 TI - A Metal-Free Approach to 1,2-Diamines via Visible Light-Driven Reductive Coupling of Imines with Perylene as a Photoredox Catalyst. AB - A simple, metal-free, and versatile approach to 1,2-diamines has been developed based on reductive coupling reactions of various imines, where perylene, an aromatic hydrocarbon, was used as a photoredox catalyst under visible light irradiation using a white light-emitting diode. The use of 1 mol % perylene enabled almost complete conversion of the imines, leading to the formation of their corresponding 1,2-diamines, which were isolated in good yields. The ratios between dl and meso diamines ranged from 31:69 to 82:18 depending on the substituents of the imines. PMID- 28836437 TI - Luxurious Nitrogen Fertilization of Two Sugar Cane Genotypes Contrasting for Lignin Composition Causes Changes in the Stem Proteome Related to Carbon, Nitrogen, and Oxidant Metabolism but Does Not Alter Lignin Content. AB - Sugar cane is an important crop for sugar and biofuel production. Its lignocellulosic biomass represents a promising option as feedstock for second generation ethanol production. Nitrogen fertilization can affect differently tissues and its biopolymers, including the cell-wall polysaccharides and lignin. Lignin content and composition are the most important factors associated with biomass recalcitrance to convert cell-wall polysaccharides into fermentable sugars. Thus it is important to understand the metabolic relationship between nitrogen fertilization and lignin in this feedstock. In this study, a large-scale proteomics approach based on GeLC-MS/MS was employed to identify and relatively quantify proteins differently accumulated in two contrasting genotypes for lignin composition after excessive nitrogen fertilization. From the ~1000 nonredundant proteins identified, 28 and 177 were differentially accumulated in response to nitrogen from IACSP04-065 and IACSP04-627 lines, respectively. These proteins were associated with several functional categories, including carbon metabolism, amino acid metabolism, protein turnover, and oxidative stress. Although nitrogen fertilization has not changed lignin content, phenolic acids and lignin composition were changed in both species but not in the same way. Sucrose and reducing sugars increased in plants of the genotype IACSP04-065 receiving nitrogen. PMID- 28836439 TI - A Naphtho-p-quinodimethane Exhibiting Baird's (Anti)Aromaticity, Broken Symmetry, and Attractive Photoluminescence. AB - We report a novel reductive desulfurization reaction involving pi-acidic naphthalene diimides (NDI) 1 using thionating agents such as Lawesson's reagent. Along with the expected thionated NDI derivatives 2-6, new heterocyclic naphtho-p quinodimethane compounds 7 depicting broken/reduced symmetry were successfully isolated and fully characterized. Empirical studies and theoretical modeling suggest that 7 was formed via a six-membered ring oxathiaphosphenine intermediate rather than the usual four-membered ring oxathiaphosphetane of 2-6. Aside from the reduced symmetry in 7 as confirmed by single-crystal XRD analysis, we established that the ground state UV-vis absorption of 7 is red-shifted in comparison to the parent NDI 1. This result was expected in the case of thionated polycyclic diimides. However, unusual low energy transitions originate from Baird 4npi aromaticity of compounds 7 in lieu of the intrinsic Huckel (4n + 2)pi aromaticity as encountered in NDI 1. Moreover, complementary theoretical modeling results also corroborate this change in aromaticity of 7. Consequently, photophysical investigations show that, compared to parent NDI 1, 7 can easily access and emit from its T1 state with a phosphorescence 3(7a)* lifetime of tauP = 395 MUs at 77 K indicative of the formation of the corresponding "aromatic triplet" species according to the Baird's rule of aromaticity. PMID- 28836440 TI - Palladium-Catalyzed Intermolecular Azidocarbonylation of Alkenes via a Cooperative Strategy. AB - A novel intermolecular beta-azidocarbonylation reaction of alkenes has been developed in which a combination of iodine(III)-mediated alkene activation and palladium-catalyzed carbonylation was demonstrated as an efficient strategy for the difunctionalization of alkenes. A variety of beta-azido carboxylic esters were obtained from mono- and 1,1-disubstituted terminal alkenes with excellent regioselectivities. In addition, the introduced azido group can be reduced to an amine group, providing a facile access to beta-amino acid derivatives from simple olefins. PMID- 28836441 TI - Synthesis of beta,beta-Disubstituted Indanones via the Pd-Catalyzed Tandem Conjugate Addition/Cyclization Reaction of Arylboronic Acids with alpha,beta Unsaturated Esters. AB - Under Pd catalysis with a newly synthesized electron-deficient heterocycle, 2 (4,5-dihydroimidazol-2-yl)pyrimidine (as the ligand), the reaction of alpha,beta unsaturated esters with arylboronic acids afforded a wide range of 3,3 disubstituted indan-1-ones bearing a quaternary carbon in high yields. Mechanistic studies revealed that the reaction involves a tandem conjugate addition/1,4-Pd shift followed by a cyclization. PMID- 28836443 TI - Examining the Synergistic Effects of Two Transdiagnostic Vulnerability Factors in Relation to Anxiety and Depressive Symptoms and Disorders Among Latinos in a Community Health Care Setting. AB - Latinos are one of the fastest growing racial/ethnic population in the United States yet they experience a substantial amount of mental health disparities, such as anxiety and depression, compared with non-Hispanic Whites. The current study examined the interactive effects of rumination and mindful attention on anxiety and depression symptoms among economically disadvantaged Latinos. Participants consisted of 391 Latinos (86.7% female; Mage = 38.8 years [ SD = 11.4]; 95.3% first language Spanish) who attended a community-based primary health care clinic. Results provided support for an interaction effect of rumination with mindful attention in relation to depressive, suicidal, social anxiety, and anxious arousal symptoms as well as number of mood and anxiety disorders. The pattern of findings was consistent across each of these continuous dependent measures such that the highest levels of each affective variable were found for those with a combination of higher rumination and lower mindful attention. Unexpectedly, there was no interaction in relation to the dichotomous outcome of presence of any mood/anxiety diagnosis. PMID- 28836442 TI - Boosting Intracellular Delivery of Lipid Nanoparticle-Encapsulated mRNA. AB - Intracellular delivery of mRNA holds great potential for vaccine1-3 and therapeutic4 discovery and development. Despite increasing recognition of the utility of lipid-based nanoparticles (LNPs) for intracellular delivery of mRNA, particle engineering is hindered by insufficient understanding of endosomal escape, which is believed to be a main limiter of cytosolic availability and activity of the nucleic acid inside the cell. Using a series of CRISPR-based genetic perturbations of the lysosomal pathway, we have identified that late endosome/lysosome (LE/Ly) formation is essential for functional delivery of exogenously presented mRNA. Lysosomes provide a spatiotemporal hub to orchestrate mTOR signaling and are known to control cell proliferation, nutrient sensing, ribosomal biogenesis, and mRNA translation. Through modulation of the mTOR pathway we were able to enhance or inhibit LNP-mediated mRNA delivery. To further boost intracellular delivery of mRNA, we screened 212 bioactive lipid-like molecules that are either enriched in vesicular compartments or modulate cell signaling. Surprisingly, we have discovered that leukotriene-antagonists, clinically approved for treatment of asthma and other lung diseases, enhance intracellular mRNA delivery in vitro (over 3-fold, p < 0.005) and in vivo (over 2 fold, p < 0.005). Understanding LNP-mediated intracellular delivery will inspire the next generation of RNA therapeutics that have high potency and limited toxicity. PMID- 28836444 TI - Optimizing the Treatment of Steroid-Induced Hyperglycemia. AB - OBJECTIVE: To review therapeutic strategies for the management of patients with steroid-induced hyperglycemia. DATA SOURCES: A literature search of MEDLINE/PubMed (1990 to June 2017) was conducted using the search terms steroid, glucocorticoid, corticosteroid, hyperglycemia, and diabetes as well via review of literature citations. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials and case studies focusing on pharmacological interventions in humans were reviewed for inclusion. Articles discussing islet cell transplant were excluded. DATA SYNTHESIS: Hyperglycemia is a predictable adverse effect of glucocorticoid therapy, which is associated with negative outcomes, including an odds ratio of 1.36 for developing new-onset diabetes. A variety of strategies have been utilized for managing patients who are at risk of complications caused by steroid induced hyperglycemia. Agents such as sulfonylureas, thiazolidinediones, meglitinides, metformin, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptidase-1 agonists, and insulin have been evaluated in case studies and small clinical trials with varying degrees of success. CONCLUSIONS: Since there are limited clinical data available to guide therapy, strategies that minimize the risk of adverse effects should be selected for the management of steroid-induced hyperglycemia. Therapies that may be safe and effective given current information include DPP-4 inhibitors, metformin, and weight-based neutral protamine Hagedorn insulin. PMID- 28836445 TI - Clinical correlates and prognostic value of different metastatic sites in metastatic renal cell carcinoma. AB - AIM: Real life data on the clinical correlates and prognostic value of metastatic sites in metastatic renal cell carcinoma (RCC) are needed. This parameter was assessed in RCC patients registered within the surveillance, epidemiology and end results (SEER) database. METHODS: Data were obtained from the National Cancer Institute-SEER database spanning 2010-2013; and it has been accessed through SEER*Stat program to determine the clinical correlates and prognosis of RCC patients with distant metastases according to the site of metastasis. Multivariate analyses were performed using Cox regression analysis to determine factors associated with improved overall and cancer-specific survival. Kaplan Meier curves and log-rank tests were used to calculate and compare survival estimates. RESULTS: A total of 5992 patients with metastatic RCC were identified in the period from 2010 to 2013. Patients with isolated liver metastases have worse survival outcomes compared with patients with other single organ sites of metastases. Pairwise p-values for cancer-specific survival: bone metastasis versus liver metastasis: p < 0.0001; lung metastasis versus liver metastasis: p = 0.002; distant lymph nodes versus liver metastasis: p = 0.006. Multivariate analysis revealed that younger age at diagnosis (p < 0.0001), single organ site of metastatic disease (p = 0.046), male gender (p = 0.001), earlier T stage (p < 0.0001), node negative status (p < 0.0001), clear cell histology (p = 0.001), local treatment to the primary tumor (p < 0.0001) and surgery to the metastatic disease (p < 0.0001) were associated with better overall survival. The same factors (except age) were associated with better cancer-specific survival. CONCLUSION: Metastatic RCC patients with liver metastases seem to have worse outcomes compared with patients with other sites of metastases. PMID- 28836446 TI - Modified Brostrom Procedure Using Distal Fibular Periosteal Flap Augmentation vs Anatomic Reconstruction Using a Free Tendon Allograft in Patients Who Are Not Candidates for Standard Repair. AB - BACKGROUND: The modified Brostrom procedure (MBP) is widely accepted as the primary operative treatment for chronic lateral ankle instability (CLAI). However, the MBP does not produce good clinical results in all patients, and anatomic reconstruction using a free tendon graft may be considered in those patients. The purpose of this study was to evaluate the efficacy of the MBP using distal fibular periosteal flap augmentation for CLAI in patients who were not candidates for standard repair. METHODS: Thirty-eight patients (39 ankles) who underwent surgery for CLAI were retrospectively analyzed. The patients were divided into 2 groups: an anatomic lateral ligament reconstruction group (reconstruction group) consisting of 17 ankles and an MBP group using distal fibular periosteal flap augmentation (augmentation group) consisting of 22 ankles. Preoperative and postoperative clinical evaluations were performed using the visual analog scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS), and Karlsson-Peterson (Karlsson) scores. RESULTS: The mean VAS, AOFAS, and Karlsson scores significantly improved from 4.0 to 1.8, 54.7 to 92.9, and 46.4 to 92.7, respectively, in the reconstruction group ( P < .001, P < .001, P < .001), and from 4.1 to 1.5, 60.1 to 94.9, and 52.6 to 94.1, respectively, in the augmentation group ( P < .001, P < .001, P < .001). There were no significant differences in the mean postoperative AOFAS and Karlsson scores between the groups ( P = .214, P = .299). CONCLUSION: The MBP using distal fibular periosteal flap augmentation was also an effective option for CLAI in cases of generalized ligament laxity, severe attenuation of the soft tissue, previous failed surgery, high demand activity, and obesity. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 28836447 TI - Associations Between Profiles of Communication About Aging and Quality of Life for Middle-Aged and Older American Adults. AB - The association between how middle-aged and older adults talk about aging and their quality of life was examined using latent profile analysis and regression techniques. Two-hundred eight-six adults with an average age of 52.82 (range: 45 77) completed an online questionnaire, which assessed participants' self-reported communication about aging, stress, health-related quality of life, and satisfaction with life. Controlling for social support and demographics, participants' profile of communication about aging was found to predict satisfaction with life, stress, and mental health but not general or physical health. PMID- 28836448 TI - Gender differences in posttraumatic stress symptoms among former prisoners of wars' adult offspring. AB - OBJECTIVES: The lifetime risk for posttraumatic stress disorder (PTSD) and PTSD symptoms (PTSS) among primary and secondary female victims is known to be higher than for male. This study assessed gender differences in PTSS among former prisoners of war's (ex-POWs) adult offspring and the associations with their fathers' and mothers' PTSS and the parental bonding with them. DESIGN: A correlative study. METHODS: A sample of 79 Israeli father-mother-offspring ex-POW triads from the 1973 Yom Kippur War completed self-report measures. Fathers were assessed in 2008, mothers were assessed in 2011 and their adult offspring took part in 2014. RESULTS: Sons of ex-POWs reported higher levels of PTSS as compared to daughters of ex-POWs. However, fathers' PTSS was positively related to daughters' PTSS, but not significantly related to sons' PTSS. Daughters' PTSS were also associated with both parents' lower care and higher overprotection, while sons' PTSS were associated only with fathers' lower care and higher overprotection. CONCLUSIONS: Among adult offspring of ex-POWs, sons are at greater risk for psychological distress in the form of PTSS. Nevertheless, the intergenerational transmission of captivity-related PTSS from both fathers and spouses to their offspring is more prominent among daughters of ex-POWs. PMID- 28836449 TI - Adjacent Joint Kinematics After Ankle Arthrodesis During Cadaveric Gait Simulation. AB - BACKGROUND: Arthrodesis is an effective and reliable treatment for end-stage ankle arthritis; however, many patients develop ipsilateral adjacent joint arthritis following surgery. The mechanism that drives adjacent joint arthritis remains uncertain. Cadaveric simulation permits direct investigation of the effects of both arthrodesis and movement strategy on adjacent joints during simulated walking. The objective of this study was to identify the isolated effect of ankle arthrodesis on adjacent joint kinematics during simulated walking. METHODS: Effects of ankle arthrodesis on adjacent joint kinematics were assessed in 8 cadaveric foot and ankle specimens using a robotic gait simulator. Gait parameters acquired from healthy adults and patients with ankle arthrodesis were used as inputs for simulations. Three-dimensional subtalar and talonavicular joint kinematics were directly measured before and after ankle arthrodesis, and healthy- and arthrodesis-gait parameters were applied to identify the isolated effect of the ankle arthrodesis on adjacent joint kinematics. RESULTS: Ankle arthrodesis increased subtalar and talonavicular joint motion during early and midstance independent of which gait parameters were used as inputs to the gait simulator. However, adjacent joint motions did not differ between the control and arthrodesis condition during late stance, when the healthy gait parameters were used as inputs. Conversely, adjacent joint motion decreased during late stance following arthrodesis when simulating gait using parameters typical in arthrodesis patients. CONCLUSIONS: Regardless of the gait parameter inputs, subtalar and talonavicular joint motions increased from normal kinematics, which likely increase the biomechanical burden placed on these adjacent joints and may lead to joint degeneration. CLINICAL RELEVANCE: Increased motion of the adjacent joints caused by ankle arthrodesis may explain the articular degeneration observed clinically. PMID- 28836450 TI - Validation of the Advanced Clinical Solutions Word Choice Test (WCT) in a Mixed Clinical Sample: Establishing Classification Accuracy, Sensitivity/Specificity, and Cutoff Scores. AB - This study examined the Word Choice Test's (WCT) utility as a performance validity test in a mixed clinical sample of veterans referred for neuropsychological evaluation. Participants completed Green's Word Memory Test (WMT), WCT, and Test of Memory Malingering (TOMM) Trial 1. Using the WMT as the criterion for valid performance, logistic regressions examined the WCT and TOMM's classification accuracy for those with and without cognitive impairment (CI). Receiver operating characteristic curves were used to establish cut scores which maximized the sensitivity/specificity of each measure. In those without CI, both tests showed good classification accuracy (86.7% and 85.0%, respectively). Among those with CI, the TOMM retained good classification accuracy (82.3%), while the WCT's decreased considerably (69.4%). Optimal WCT cut scores differed based on impairment status, with a higher sensitivity/specificity trade-off among those with CI. Successful performance on the WCT appeared to rely more heavily on cognitive processes unrelated to performance validity. PMID- 28836451 TI - HIV-1 reservoirs in elite controllers: clues for developing a functional cure? PMID- 28836452 TI - Using Peer-Mediated Literacy-Based Behavioral Interventions to Increase First Aid Safety Skills in Students With Developmental Disabilities. AB - Many adolescents with developmental disabilities do not learn the safety skills needed to maintain physical well-being in domestic and community environments. Literacy-based behavioral interventions (LBBIs) that combine print, pictures, and behavioral rehearsal are effective for promoting acquisition and maintenance of self-care skills, but have not been investigated as safety skill intervention. Also, LBBIs have primarily been implemented by teachers and other professionals. In this study, a peer partner was taught to deliver an LBBI story to students so they would learn to perform a basic first aid routine: cleaning and dressing a wound. Results showed that students' accuracy with the first aid routine increased after a peer delivered the LBBI instructional package, and maintained after the peer stopped delivering it. This study demonstrates the effectiveness of the LBBI instructional package for teaching first aid safety skills, and extends previous research showing the efficacy of peers in delivering this intervention. PMID- 28836453 TI - Readability of the Most Commonly Accessed Online Patient Education Materials Pertaining to Pathology of the Hand. AB - BACKGROUND: The American Medical Association (AMA) and National Institutes of Health (NIH) recommend that patient education materials be written at no higher than a sixth-grade reading level. METHODS: We examined 100 online educational materials for the 10 hand conditions most commonly treated by hand surgeons, as reported by the American Society for Surgery of the Hand. The listed conditions were carpal tunnel syndrome, basal joint arthritis of the thumb, de Quervain syndrome, Dupuytren's contracture, ganglion cysts, hand fractures, trigger finger, extensor tendon injuries, flexor tendon injuries, and mallet finger. Following a Google search for each condition, we analyzed the 10 most visited websites for each disorder utilizing the Flesch-Kincaid formula. RESULTS: The average grade reading level of the 100 websites studied was 9.49 with a reading ease of 53.03 ("fairly difficult high school"). Only 29% of the websites were at or below the national average of an eighth-grade reading level. Carpal tunnel syndrome had the highest average grade reading level at 10.32 (standard deviation: 1.52), whereas hand fractures had the lowest at 8.14 (2.03). Every hand condition in this study had an average readability at or above the ninth grade reading level. CONCLUSIONS: The most frequently accessed materials for common maladies of the hand exceed both the readability limits recommended by the AMA and NIH, and the average reading ability of most US adults. Therefore, the most commonly accessed websites pertaining to hand pathology may not be comprehended by the audience for which it is intended. PMID- 28836454 TI - A novel method: ionic liquid-based ultrasound-assisted extraction of polyphenols from Chinese purple yam. AB - Chinese purple yam is famous for therapeutic and nutritional values in lowering blood glucose, blood pressure and even preventing and treating cardiovascular diseases. However, traditional extraction techniques for the functional polyphenolic compounds mostly utilise unfriendly organic solvent and easily cause degradation of polyphenols. In this study, a novel ionic liquid-based ultrasound assisted extraction (IL-UAE) technique was utilised to obtain polyphenols. The optimal extraction condition included: solid-liquid ratio (0.05 g/mL), ionic liquid concentration (1.05 M), extraction temperature (67 degrees C) and ultrasonic time (37 min). The maximum free radical scavenging activity (86.21%) and total antioxidant activity (2.21 mM) were achieved and matched well with the predicted values, superior to that of the extract from regular ethanol-based UAE. IL-UAE could be a rapid and green technique for efficient extraction of polyphenols from purple yam with low solvent consumption and few structural deterioration, exhibiting application potential in food and pharmaceutical industries. PMID- 28836455 TI - Antagonist muscle co-contraction during a double-leg landing maneuver at two heights. AB - BACKGROUND: Knee injuries are common during landing activities. Greater landing height increases peak ground reaction forces (GRFs) and loading at the knee joint. As major muscles to stabilize the knee joint, Quadriceps and Hamstring muscles provide internal forces to attenuate the excessive GRF. Despite the number of investigations on the importance of muscle function during landing, the role of landing height on these muscles forces using modeling during landing is not fully investigated. METHODS: Participant-specific musculoskeletal models were developed using experimental motion analysis data consisting of anatomic joint motions and GRF from eight male participants performing double-leg drop landing from 30 and 60 cm. Muscle forces were calculated in OpenSim and their differences were analyzed at the instances of high risk during landing i.e. peak GRF for both heights. RESULTS: The maximum knee flexion angle and moments were found significantly higher from a double-leg landing at 60 cm compared to 30 cm. The results showed elevated GRF, and mean muscle forces during landing. At peak GRF, only quadriceps showed significantly greater forces at 60 cm. Hamstring muscle forces did not significantly change at 60 cm compared to 30 cm. CONCLUSIONS: Quadriceps and hamstring muscle forces changed at different heights. Since hamstring forces were similar in both landing heights, this could lead to an imbalance between the antagonist muscles, potentially placing the knee at risk of injury if combined with small flexion angles that was not observed at peak GRF in our study. Thus, enhanced neuromuscular training programs strengthening the hamstrings may be required to address this imbalance. These findings may contribute to enhance neuromuscular training programs to prevent knee injuries during landing. PMID- 28836456 TI - Responsiveness of EQ-5D in Patients With a Distal Radius Fracture. AB - BACKGROUND: The EuroQol Group 5-Dimension (EQ-5D) questionnaire is frequently used as an outcome measure of general patient-reported health-related quality of life (HRQoL). We evaluated the internal and external responsiveness of EQ-5D (specifically EQ-5Dindex score) in patients with a surgically treated distal radius fracture. METHODS: Within the context of a randomized controlled trial (RCT), 132 patients with a surgically treated distal radius fracture filled out EQ-5D and Patient-Rated Wrist Evaluation (PRWE-Swe) at baseline (preinjury state), and at 3 and 12 months. Internal responsiveness was evaluated by calculating mean change score and standardized response mean (SRM) of the EQ 5Dindex scores. External responsiveness was evaluated with PRWE-Swe as the external criterion. PRWE-Swe was used to define 4 subgroups of patients with different clinical outcomes. The ability of EQ-5Dindex change score to discriminate between these subgroups was analyzed with logistic regression, receiver operating characteristic (ROC) curves, and area under the ROC curves (AUROCs). Correlation analysis was made with Spearman's rho test. RESULTS: The mean change in EQ-5Dindex score from baseline to the 3-month follow-up was -16.1 and from the 3- to the 12-month follow-up was 7.6. The corresponding SRMs were large (0.93) and small to moderate (0.47). Analysis of external responsiveness displayed odds ratios >1 and AUROCs between 0.70 and 0.76 in all 4 subgroups. The proportion of patients correctly classified into the 4 subgroups by the EQ 5Dindex change scores was 78% to 94%. Spearman's rho was 0.35. CONCLUSION: EQ-5D displayed an overall acceptable to good responsiveness in patients with a distal radius fracture. It may thus be used as a measure of HRQoL in this patient group. PMID- 28836457 TI - Investigational drugs in phase II clinical trials for primary biliary cholangitis. AB - INTRODUCTION: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that may lead to biliary fibrosis, and eventually cirrhosis. The primary treatment for PBC is ursodeoxycholic acid (UDCA), which has favorably altered its natural history. However, up to 40% of patients have an inadequate response to UDCA, and are therefore at high risk of liver-related complications. Obeticholic acid has recently been approved for use in patients with PBC with inadequate response or who are intolerant to UDCA, but improvement in long-term outcomes has not yet been demonstrated. Alternative therapeutic options for PBC are needed. Areas covered: Recent advances in research including epidemiological, genetic and pre-clinical studies in animal models of PBC have yielded numerous agents currently at different stages of development for treatment of patients with PBC; in this review, we cover novel therapies that were recently or are recently being investigated in phase II clinical trials. Expert opinion: Despite the evolving landscape in PBC, the main challenges facing development of novel therapies remain the rarity of the disease and the limitations to design and conduct of controlled clinical trials in PBC, which are needed to determine the long-term effects of novel therapies on the clinical outcomes of PBC. PMID- 28836458 TI - Efficacy and safety of rosuvastatin versus atorvastatin in high-risk Chinese patients with hypercholesterolemia: a randomized, double-blind, active-controlled study. AB - OBJECTIVE: To evaluate and compare the efficacy and safety of rosuvastatin versus atorvastatin in a high-risk Chinese population with hypercholesterolemia. RESEARCH DESIGN AND METHODS: This 6 week, prospective, multicenter, double-blind, three-arm, parallel-group, active-controlled study randomized adult Chinese patients (low-density lipoprotein cholesterol [LDL-C] >= 130-<250 mg/dL statin naive and >=100-<160 mg/dL in statin treated) to receive rosuvastatin (5 mg or 10 mg) or atorvastatin 10 mg. Patients not achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C targets in the randomized phase were administered rosuvastatin 10 mg and 20 mg in the open-label phase. RESULTS: In total 414 patients (mean age: 59.5 +/- 9.51 years, 59.4% females, mean LDL-C: 4.242 +/- 0.676 mmol/L (rosuvastatin 5 mg), 4.13 +/- 0.682 mmol/L (rosuvastatin 10 mg) and 4.213 +/- 0.662 mmol/L (atorvastatin 10 mg) were analyzed. Compared with atorvastatin 10 mg, rosuvastatin 5 mg (-41.70% vs. 38.67%, p = .132) and rosuvastatin 10 mg showed greater LDL-C reduction (-46.28% vs. -38.67%, p = .0002). LDL-C target achievement rates with rosuvastatin 5 mg, rosuvastatin 10 mg and atorvastatin 10 mg were 61.0%, 79.1% and 58.3% in the randomized phase. In the open-label phase, LDL-C target achievement occurred in >40% with both doses of rosuvastatin. The rate of >=1 adverse event was similar with rosuvastatin 5 mg (12.4%), 10 mg (11.7%) and atorvastatin 10 mg (8.9%). CONCLUSION: Rosuvastatin 5 mg demonstrated non-inferiority and rosuvastatin 10 mg demonstrated superiority to atorvastatin 10 mg for lowering LDL-C in high-risk Chinese patients with dyslipidemia, which was maintained through the open-label phase. CLINICAL TRIAL REGISTRATION: NCT00683618. PMID- 28836459 TI - 3D printing of oral drugs: a new reality or hype? PMID- 28836460 TI - Effect of lumbar fasciae on the stability of the lower lumbar spine. AB - The biomechanical effect of tensioning the lumbar fasciae (LF) on the stability of the spine during sagittal plane motion was analysed using a validated finite element model of the normal lumbosacral spine (L4-S1). To apply the tension in the LF along the direction of the fibres, a local coordinate was allocated using dummy rigid beam elements that originated from the spinous process. Up to 10 Nm of flexion and 7.5 Nm of extension moment was applied with and without 20 N of lateral tension in the LF. A follower load of 400 N was additionally applied along the curvature of the spine. To identify how the magnitude of LF tension related to the stability of the spine, the tensioning on the fasciae was increased up to 40 N with an interval of 10 N under 7.5 Nm of flexion/extension moment. A fascial tension of 20 N produced a 59% decrease in angular motion at 2.5 Nm of flexion moment while there was a 12.3% decrease at 10 Nm in the L5-S1 segment. Its decrement was 53 and 9.6% at 2.5 Nm and 10 Nm, respectively, in the L4-L5 segment. Anterior translation was reduced by 12.1 and 39.0% at the L4-L5 and L5-S1 segments under 10 Nm of flexion moment, respectively. The flexion stiffness shows an almost linear increment with the increase in fascial tension. The results of this study showed that the effect of the LF on the stability of the spine is significant. PMID- 28836461 TI - A musculoskeletal model to estimate the relative changes in wrist strength due to interacting wrist and forearm postures. AB - Wrist rotations about one wrist axis (e.g. flexion/extension) can affect the strength about another wrist axis (e.g. radial/ulnar deviation). This study used a musculoskeletal model of the distal upper extremity, and an optimization approach, to quantify the interaction effects of wrist flexion/extension (FE), radial/ulnar deviation (RUD) and forearm pronation/supination (PS) on wrist strength. Regression equations were developed to predict the relative changes in strength from the neutral posture, so that the changes in strength, due to complex and interacting wrist and forearm rotation postures, can be incorporated within future ergonomics assessments of wrist strength. PMID- 28836462 TI - A Biomechanical Evaluation of a 2-Suture Anchor Repair Technique for Thumb Metacarpophalangeal Joint Ulnar Collateral Ligament Injuries. AB - BACKGROUND: A complete thumb ulnar collateral ligament (UCL) repaired with 1 suture anchor has been demonstrated to be significantly weaker compared with the intact UCL. The objective of this study is to test the biomechanical strength of a 2-anchor thumb UCL repair. METHODS: Nine paired fresh-frozen hands were used for this biomechanical analysis. One thumb from each pair was randomized to the control group and one to the repair group. In the control group, the UCL was loaded to failure in tension. In the repair group, the UCL was dissected off of the proximal phalanx, subsequently repaired with a 2-anchor technique, and then tested to failure. RESULTS: The mean yield load was 342 N (95% confidence interval [CI], 215-470 N) in the control group and 68 N (95% CI, 45-91 N) in the repair group. The mean maximum load at failure was 379 N (95% CI, 246-513 N) in the control group and 84 N (95% CI, 62-105 N) in the repair group. The mean stiffness was 72 N/m (95% CI, 48-96 N/m) in the control group and 17 N/m (95% CI, 13-21 N) in the repair group. The mean displacement at failure was 7.8 mm (95% CI, 7-9 mm) in the control group and 7.8 mm (95% CI, 7-9 mm) in the repair group. CONCLUSIONS: The 2-anchor repair technique we tested does not acutely reestablish the strength of the insertion of the native insertion of the UCL with this technique. PMID- 28836463 TI - Prevalence, Incidence, Trend, and Complications of Thalassemia in Iraq. AB - Globally, thalassemia is the most common hereditary hemoglobinopathy, and occurs in 4.4/10,000 live births. In the developing world, the majority of patients die before the age of 20 years. In Iraq, there is little data on the epidemiology and burden of thalassemia. The objectives of this study were to determine the prevalence, incidence, trend, and complications of thalassemia patients in Iraq. All thalassemia patients registered in the accessible 16 (of the 19) thalassemia centers in Iraq until December 31 2015, were included. Data were acquired from patients' files and the centers' registries. The total number of registered thalassemia patients was 11,165 representing 66.3% of all registered hereditary anemias in these centers. The prevalence of thalassemia had increased from 33.5/100,000 in 2010 to 37.1/100,000 in 2015, while the incidence rate had decreased from 72.4/100,000 live births to 34.6/100,000 live births between 2010 and 2015. beta-Thalassemia major (beta-TM) represented 73.9% of all types of thalassemia. About 66.0% of patients were under 15 years old; 78.8% were offspring of parents who were related, and 55.9% had at least one complication. Respectively, 13.5 and 0.4% of thalassemia patients were infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) at some point in their lives. No patients were infected with the human immune deficiency virus (HIV). In conclusion, the prevalence of thalassemia in Iraq is slightly increasing in spite of decreasing incidence. Screening for carriers, and intensified premarital screening and counseling programs, coupled with strong legislation can help in further decreasing incidence rate. PMID- 28836464 TI - Flow visualisation study of spiral flow in the aorta-renal bifurcation. AB - The aim of this study was to analyse the flow dynamics in an idealised model of the aorta-renal bifurcation using flow visualisation, with a particular focus on the effect of aorta-to-renal flow ratio and flow spirality. The recirculation length was longest when there was low flow in the renal artery and smaller in the presence of spiral flow. The results also indicate that patients without spiral flow or who have low flow in the renal artery due to the presence of stenosis may be susceptible to heightened development of atherosclerotic lesions. PMID- 28836466 TI - Effect of Acetaminophen on the Prevention of Acute Kidney Injury in Patients With Sepsis. AB - BACKGROUND: Acute kidney injury (AKI) commonly occurs in patients with sepsis. Acetaminophen (APAP) has been shown to inhibit lipid peroxidation and, thus, may be renal protective in patients with sepsis. OBJECTIVE: The objective of this study was to determine the effect of APAP on AKI in patients with sepsis. METHODS: This was a retrospective cohort study conducted at 2 affiliated academic medical centers in the United States. Adult patients who were admitted to the intensive care unit with a diagnosis of severe sepsis were included. Patients were categorized based on whether APAP was received within the first 7 days of hospitalization (APAP or no APAP groups). The primary outcome measure was occurrence or increase in AKI stage from admission. Multivariate logistic regression analyses were used to adjust for potential confounders. RESULTS: There were 238 patients who were included in the study cohort. Of these, 122 received APAP and 116 did not receive APAP. AKI or exacerbation occurred in 16.4% (n = 20) of patients in the APAP group and 19.8% (n = 23) of patients in the no APAP group ( P = 0.505). After adjusting for the most important confounders, there was no significant association between APAP use and AKI (odds ratio = 1.2; 95% CI = 0.6 2.4; P = 0.639). CONCLUSION: APAP use in critically ill patients with sepsis may not reduce the occurrence or exacerbation of AKI. PMID- 28836465 TI - Epidemiology and antifungal susceptibilities of yeast isolates causing invasive infections across urban Beijing, China. AB - AIM: To investigate the species distribution and antifungal susceptibility profiles of yeast isolates causing invasive infections across Beijing. MATERIALS & METHODS: A total of 1201 yeast isolates recovered from blood and other sterile body fluids were correctly identified by matrix-assisted laser desorption/ionization TOF MS supplemented by DNA sequencing. Antifungal susceptibility testing was performed according to the Clinical and Laboratory Standards Institute broth microdilution method. RESULTS: Candida (95.5%) remained the most common yeast species isolated; Candida albicans (38.8%) and Candida parapsilosis (22.6%) were the leading species of candidemia. Azole resistances were mainly observed in Candida glabrata and Candida tropicalis isolates. CONCLUSION: This study outlined the epidemiologic data of invasive yeast infections and highlighted the need for continuous monitoring of azole resistances among C. glabrata and C. tropicalis isolates in Beijing. PMID- 28836467 TI - Do psychosocial interventions improve rehabilitation outcomes after anterior cruciate ligament reconstruction? A systematic review. AB - OBJECTIVE: To examine the role of psychosocial interventions in improving patient reported clinical outcomes, including return to sport/activity, and intermediary psychosocial factors after anterior cruciate ligament reconstruction. METHODS: MEDLINE/PubMed, CINAHL, PsycINFO, and Web of Science were searched from each database's inception to March 2017 for published studies in patients after anterior cruciate ligament reconstruction. Studies were included if they reported on the effects of a postoperative psychosocial intervention on a patient-reported clinical measure of disability, function, pain, quality of life, return to sport/activity, or intermediary psychosocial factor. Data were extracted using a standardized form and summary effects from each article were compiled. The methodological quality of randomized trials was assessed using the Physiotherapy Evidence Database Scale and scores greater than 5/10 were considered high quality. RESULTS: A total of 893 articles were identified from the literature search. Of these, four randomized trials ( N = 210) met inclusion criteria. The four articles examined guided imagery and relaxation, coping modeling, and visual imagery as postoperative psychosocial interventions. Methodological quality scores of the studies ranged from 5 to 9. There were inconsistent findings for the additive benefit of psychosocial interventions for improving postoperative function, pain, or self-efficacy and limited evidence for improving postoperative quality of life, anxiety, or fear of reinjury. No study examined the effects of psychosocial interventions on return to sport/activity. CONCLUSION: Overall, there is limited evidence on the efficacy of postoperative psychosocial interventions for improving functional recovery after anterior cruciate ligament reconstruction. PMID- 28836468 TI - Effectiveness, Safety, and Costs of a Treatment Switch to Dolutegravir Plus Rilpivirine Dual Therapy in Treatment-Experienced HIV Patients. AB - BACKGROUND: Evidence about the use of dolutegravir (DTG) and rilpivirine (RPV) as an antiretroviral therapy (ART) in treatment-experienced patients is scarce. OBJECTIVE: To explore the effectiveness, safety, and costs of switching to a DTG plus RPV regimen in this population. METHODS: This observational, prospective study included all treatment-experienced patients who switched to DTG plus RPV between November 2014 and July 2016. Patients were excluded if resistance mutations to integrase inhibitors or RPV were found. The effectiveness endpoint was the proportion of patients who achieved virological suppression (viral load [VL] <50 copies/mL) at week 48 (W48). Safety (incidence of adverse events leading to discontinuation and laboratory abnormalities), adherence, and costs were analyzed. RESULTS: A total of 35 patients were included, and 91.4% were virologically suppressed at baseline. Patients were treated with ART for a median of 14 years (interquartile range = 7-20). At W48, 91.4% of patients were virologically suppressed (95% CI = 77.0-98.2). Two of the 3 patients not suppressed at baseline achieved undetectable VL at W48, and 2 patients discontinued DTG plus RPV (intolerance and a drug-drug interaction). None of the virologically suppressed patients at baseline showed virological rebound through W48. There were no significant changes in lipid, liver, and renal profiles. The proportion of patients with an ART adherence >90% increased from 65.6% to 93.8% ( P = 0.004). The annual per-patient ART costs dropped by ?665 ( P = 0.265). CONCLUSIONS: Switching to DTG plus RPV seems to be an effective and safe strategy. Significant improvements in patients' adherence and costs were achieved. PMID- 28836469 TI - Improved Killing of Ovarian Cancer Stem Cells by Combining a Novel Chimeric Antigen Receptor-Based Immunotherapy and Chemotherapy. AB - Ovarian cancer represents the most lethal gynecological cancer. Although cytoreductive chemotherapy and surgery lead to complete macroscopic tumor removal, most of the patients in advanced stages suffer from recurrent disease and subsequently die. This may be explained by the activity of cancer stem cells (CSC), which are a subpopulation of cells with an elevated chemoresistance and an increased capacity for self-renewal and metastatic spread. Specifically targeting these cells by adoptive immunotherapy represents a promising strategy to reduce the risk for recurrent disease. This study selected the widely accepted CSC marker CD133 as a target for a chimeric antigen receptor (CAR)-based immunotherapeutic approach to treat ovarian cancer. A lentiviral vector was generated encoding a third-generation anti-CD133-CAR, and clinically used NK92 cells were transduced. These engineered natural killer (NK) cells showed specific killing against CD133-positive ovarian cancer cell lines and primary ovarian cancer cells cultured from sequential ascites harvests. Additionally, specific activation of these engineered NK cells was demonstrated via interferon-gamma secretion assays. To improve clinical efficacy of ovarian cancer treatment, the effect of the chemotherapeutic agent cisplatin was evaluated together with CAR transduced NK cell treatment. It was demonstrated that NK cells remain cytotoxic and active under cisplatin treatment and, importantly, that sequential treatment with cisplatin followed by CAR-NK cells led to the strongest killing effect. The specific eradication of ovarian CSCs by anti-CD133-CAR expressing NK92 cells represents a promising strategy and, when confirmed in vivo, shall be the basis of future clinical studies with the aim to prevent recurrent disease. PMID- 28836470 TI - The Effectiveness of EMLA as a Primary Dressing on Painful Chronic Leg Ulcers: Effects on Wound Healing and Health-Related Quality of Life. AB - This study aimed to evaluate the effect of EMLA 5% cream applied to painful chronic leg ulcers (CLUs) as a primary dressing on wound healing and health related quality of life (HRQoL). A pilot, parallel-group, nonblinded, randomized controlled trial was conducted in 6 community nursing procedure clinics in New South Wales, Australia. A total of 60 participants with painful CLUs of varied etiology were randomly assigned to the intervention (EMLA daily for 4 weeks as a primary dressing, followed by usual care) or usual care only. Wound size and HRQoL were measured at baseline, end of the intervention period (week 4), and week 12. At baseline, wound sizes were similar for both the intervention and control groups. During the intervention period, there was no significant difference in wound sizes between groups (intervention group: median (cm2) = 2.4, IQR = 1.3-12.7; control group: median (cm2) = 5.0, IQR = 2.5-9.9; P = .05). Mean HRQoL scores for all subscales at baseline and weeks 4 and 12 were similar between groups except for Wellbeing, which was significantly higher in the intervention group at the end of the 4-week intervention period (intervention group: mean = 52.41, SD = 24.50; control group: mean = 38.15, SD = 21.25; P = .03; d = 0.62). The trial findings suggest that daily applications of EMLA as a primary dressing do not inhibit wound healing and may improve patient well-being. Studies with larger samples are required to more comprehensively evaluate the impact of this treatment on wound healing and HRQoL. PMID- 28836471 TI - Changes in antipsychotics and other psychotropic drugs during a 30-month lifestyle intervention among outpatients with schizophrenia. AB - BACKGROUND: Patients with schizophrenia have high risk of early death from diabetes and cardiovascular diseases, partly because of poor lifestyle and partly because of long-lasting exposure to antipsychotic treatment. AIMS: To investigate the influence of a lifestyle intervention program on changes in psychotropic medication in a non-selected cohort of patients with schizophrenia. METHODS: Observational study of outpatients in the Central Denmark Region during a 30 month lifestyle program. RESULTS: One hundred and thirty-six patients were enrolled and 130 were available for analysis. Median follow-up time was 15.9 months (range 1-31 months). Nineteen patients (15%) were not treated with antipsychotic drugs during the study period. 54% of the 111 patients exposed to antipsychotics were subject to monotherapy at index and at follow-up. The median defined daily dose (DDD) of antipsychotics was 1.33 at index (interquartile range (IQR) 0.67-2.00) and 1.07 at follow-up (IQR 0.40-1.50). 52% of the patients experienced a decrease in DDD during the study period (median change 0.33; IQR 1.00-0.43). There were no significant differences between the patients with decreased, stable or increased DDD with regard to age, sex, follow-up time and time since diagnosis. The number of prescriptions was significantly higher in the patients who decreased their DDD and the proportion of antipsychotic depot formulation was higher in those who increased their DDD. CONCLUSIONS: Most patients decreased or stabilized their total dose of antipsychotic medication during the study period. Many patients were subject to antipsychotic polypharmacy. The extent of participation in the lifestyle intervention program did not correlate with the changes in dosing of antipsychotic medication. PMID- 28836472 TI - The Finnish Clinical Outcome in Routine Evaluation Outcome Measure: psychometric exploration in clinical and non-clinical samples. AB - The Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM) is a 34 item self-report measure designed to monitor changes in psychiatric patients. It has been translated into 25 languages, including Finnish. This is the first psychometric exploration of Finnish CORE-OM data. The aim of the study is to examine acceptability, internal consistency and convergent validity of the Finnish CORE-OM scores. Translation of the CORE-OM from English to Finnish was undertaken according to recommended protocols. Psychometric exploration was conducted in two samples: psychiatric patients (N = 201) and non-clinical participants (N = 209). Participation was voluntary and involved completion of all scales. Convergent validity was tested in terms of the mean score differences between clinical and non-clinical samples and correlations against the Beck Depression Inventory (BDI) and the Symptom Checklist (SCL-90). Among the clinical sample, all domains showed good or acceptable internal reliability. In the non clinical sample, the alphas of domains were good or acceptable, with only the alphas of the Risk domain registering as low. There were no marked gender or age effects. CORE-OM scores correlated strongly with both the BDI and SCL-90, particularly in patients' data. Some possible effects of Finnish language were found. The Finnish translation of the CORE-OM is psychometrically sound and can be recommended for use in Finnish mental health and clinical settings. However, further investigation in larger and different samples will clarify the generalizability its psychometric properties. Clinical services are encouraged to contribute to the creation of a collaborative Finnish CORE practice research network. PMID- 28836473 TI - Use of Art-Making Intervention for Pain and Quality of Life Among Cancer Patients: A Systematic Review. AB - BACKGROUND: Although pain is one of the most prevalent symptoms among cancer patients, medications do not always result in sufficient pain relief. Furthermore, these medications only address the physical component of pain. Art making, a holistic approach, may distract the user's attention from pain and allow expression of the nonphysical (e.g., psychological, spiritual) components of pain. The purpose of this systematic review was to evaluate evidence for the efficacy of art-making interventions in reducing pain and improving health related quality of life (QoL) among cancer patients. METHOD: PubMed, Academic Search Premier, ProQuest, and CINAHL were searched from database inception to September 2016 using the following search terms: neoplasm, cancer, tumor, pain, pain management, quality of life (QoL), well-being, art therapy, painting, and drawing. RESULTS: Fourteen articles reporting 13 studies were reviewed. Some studies reported beneficial effects of art making on pain and QoL, but the evidence was weakened by poor study quality ratings, heterogeneity in art-making interventions and outcome measures, interventions including non-art-making components, and few randomized controlled studies. CONCLUSION: More rigorous research is needed to demonstrate the efficacy of art making in relieving cancer related pain and improving QoL. PMID- 28836474 TI - Positioning Children's Voice in Clinical Trials Research: A New Model for Planning, Collaboration, and Reflection. AB - Following the United Nations Convention on the Rights of the Child, there has been considerable growth in research with children about health and services that affect them. Creative methods to engage with children have also been developed. One area where progress has been slower is the inclusion of children's perspectives in qualitative research in the context of clinical trials or feasibility studies. Addressing this gap, this article discusses experiences of, and reflections on, the process of researching children's views as part of a clinical feasibility study. The article considers what worked well and highlights remaining dilemmas. A new continuum of children's engagement in research is presented, designed to assist researchers to make explicit the contingent demands on their research, and to suggest a range of techniques from within the broader fields of health, childhood studies, and education research that could be used to forward qualitative research in clinical contexts. PMID- 28836475 TI - Two Sides of the Same Coin: The Positive and Negative Impact of Spiritual Religious Coping on Quality of Life and Depression in Dialysis Patients. AB - BACKGROUND: Studies have shown that spiritual/religious beliefs are associated with mental health and health-related quality of life (HRQoL). However, few studies evaluated how spiritual/religious coping (SRC) could affect hemodialysis patients. OBJECTIVES: The present study investigated the role of SRC behaviors on HRQoL and depressive symptoms in hemodialysis patients. DESIGN AND PARTICIPANTS: This was cross-sectional study with 184 patients. Patients completed the Beck Depression Inventory, Brief SRC Scale, Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and a Sociodemographic and Health Characterization Questionnaire. RESULTS: From 218 patients, 184 (84.4%) were included (53.8% male with a median age of 55.9 years). Negative SRC, but not positive SRC, was associated with depressive symptoms. Positive SRC presented significant effects in SF-36 pain and physical and social functioning. On the other hand, negative SRC exhibited significant effects in SF-36 role emotional, energy/fatigue, pain, and physical functioning. CONCLUSION: SRC influences the mental health and HRQoL in Brazilian hemodialysis patients in two distinct ways. If used positively, it may have positive outcomes. However, if used negatively, it may lead to dysfunctional consequences such as greater depressive symptomatology and affect HRQoL. Health professionals must be aware of these "two sides of the same coin." PMID- 28836476 TI - The Mediating Effect of Self-Control on Parenting and Delinquency: A Gendered Approach With a Multinational Sample. AB - This study aims to clarify the relationships between parenting techniques, low self-control, and juvenile delinquency in Gottfredson and Hirschi's general theory of crime while controlling for alternative explanations of delinquency. We relied on a sample of 35,511 adolescent students from 31 countries from the International Self-Report Delinquency 2 Study. Results indicate that parenting exhibits a direct effect on adolescents' violence perpetration and property offending, and that while self-control weakens the strength of this relationship, it fails to fully mediate it. Males reported lower levels of self-control, exposure to poorer parenting techniques, and higher rates of violence perpetration and property offending. The relationship between parenting, self control, and juvenile delinquency was similar for females and males. These results provide evidence that parenting has important implications for adolescents' involvement in delinquency above and beyond its influence on their level of self-control. PMID- 28836477 TI - Antithrombocytopenic and immunomodulatory potential of metabolically characterized aqueous extract of Carica papaya leaves. AB - CONTEXT: Carica papaya Linn. (Caricaceae) leaf (CPL) juice has long been traditionally used in ethnomedicine for dengue fever. OBJECTIVE: The study examines the effects of standardized CPL aqueous extract (SCPLE) on platelet count, extramedullary haematopoiesis (EMH), and immunomodulation in cyclophosphamide (CP)-induced animal model of thrombocytopenia. MATERIALS AND METHODS: The extract was analyzed for myricetin, caffeic acid, trans-ferulic acid, and kaempferol using HPTLC for standardization followed by UPLC-qTOF/MS fingerprinting for metabolite signature. The effects of SCPLE (50 and 150 mg/kg p.o.) on proliferative response of platelet count and total leucocyte count (TLC) were observed up to 14 days in Wistar rat. However, delayed-type hypersensitivity (DTH), haemagglutination titre (HT), and in vivo carbon clearance were examined as immunomodulatory parameters in albino mice at 150 mg/kg p.o. against CP. RESULTS: The quantitative HPTLC estimation of SCPLE showed the presence of myricetin, caffeic acid, trans-ferulic acid, and kaempferol up to 280.16 +/- 5.99, 370.18 +/- 6.27, 1110.86 +/- 2.97, and 160.53 +/- 2.48 (MUg/g), respectively. Twenty-four metabolites were identified using UPLC-qTOF/MS. Oral administration of SCPLE (150 mg/kg) in thrombocytopenic rats exhibited significant (p < 0.01) increase in thrombocytes (1014.83 * 103 cells/mm3), DTH response (0.16 +/- 0.004), and phagocytic index (63.15% increase) as compared to CP-induced thrombocytopenia group. Histopathological studies showed minimal fibrosis in spleen histology. DISCUSSION AND CONCLUSIONS: Results suggest CPL can mediate the release of platelets providing the means for the treatment and prevention of dengue. PMID- 28836478 TI - The Clinical Research Associate Retention Study: A Report From the Children's Oncology Group. AB - Pediatric medicine often struggles to receive adequate research funding for its small, yet vulnerable population of patients. Remarkable discovery in pediatric oncology is credited in large part to the collaborative structure of its research community. The Children's Oncology Group conducts studies supported by the National Cancer Institute. The clinical research associate (CRA) discipline comprises professionals who support administrative duties, regulatory duties, subject management, and data collection at individual research sites. The purpose of this study was to identify factors associated with CRA retention, as the group continues to have high turnover and position vacancy. A cross-sectional survey design was used to characterize the most frequently cited reasons CRAs gave when considering leaving or staying within their position. Results suggest that low salary, unmanageable workload, lack of career advancement and professional development, and lack of research commitment from the medical team were associated with intent to leave CRA positions. The most frequently cited reasons for staying at their job were the meaningfulness and interest in the work, a supportive principal investigator, and enjoyment working with colleagues. CRAs reported serious but eminently solvable issues that can be addressed using practical and low-cost solutions to improve job satisfaction and retention. PMID- 28836479 TI - Male contraceptive efficacy of poly herbal formulation, contracept-TM, composed of aqueous extracts of Terminalia chebula fruit and Musa balbisiana seed in rat. AB - CONTEXT: Terminalia chebula Retz (Combretaceae) and Musa balbisiana Colla (Musaceae) have a traditional reputation as a male contraceptive. OBJECTIVE: To determine the hypo-testicular activity of aqueous extracts of Terminalia chebula (fruit) and Musa balbisiana (seed) separately, and in composite manner at the ratio of 1:1 named as 'Contracept-TM' compared to cyproterone acetate (CPA), for developing a polyherbal contraceptive. MATERIALS AND METHODS: The separate extract of above said plants or 'Contracept-TM' at the dose of 40 mg/100 g body weight of rat/day or CPA at 2 mg/100 g body weight of rat/day was administered for 28 days. Spermiological, androgenic and oxidative stress sensors, LD50 and ED50/100 g body weight values were measured. RESULTS: Treatment of individual, 'Contracept-TM' or CPA resulted significant decrease in the count of spermatogonia A (36.36-49.09%), pre-leptotene spermatocyte (19.11-55.30%), mid pachytene spermatocyte (28.65-47.28%) and step 7 spermatid (29.65-51.59%). Activities of testicular Delta5, 3beta (21.25-48.02%),17beta-hydroxysteroid dehydrogenases (29.75-55.08%), catalase (19.06-43.29%) and peroxidase (30.76 62.82%), levels of testosterone (28.15-63.44%), testicular cholesterol (19.61 49.33%), conjugated diene (29.69-84.99%) and thiobarbituric acid reactive substances (41.25-86.73%) were elevated compare to the control. The ED50 and LD50 values were 40 mg and 5.8 g (T. chebula), 48 mg and 6.3 g (M. bulbisiana), 40 mg and 6.0 g ('Contracept-TM'), respectively. DISCUSSION AND CONCLUSION: The said spermiological and androgenic sensors' levels were decreased significantly by 'Contracept-TM' than its constitutional individual plant extract and it may be comparable to standard anti-testicular drug like CPA. So, it may be concluded that above polyherbal formulation is potent for inducing hypo-testicular activity. PMID- 28836480 TI - Anxiety and depression in adolescents with ADHD and autism spectrum disorders; correlation between parent- and self-reports and with attention and adaptive functioning. AB - BACKGROUND: Adolescents with attention-deficit/hyperactive disorder (ADHD) or autism spectrum disorder (ASD) are at high risk of anxiety and depression. This is important to identify in the clinical assessment to understand its impact. AIMS: The aim of this study is to investigate the correlation between parent- and self-reports of anxiety and depression in adolescents with ADHD or ASD, as well as the correlation with adaptive functioning and performance on an attention test. METHOD: A total of 65 adolescents with an ADHD diagnosis (n = 24) or an ASD diagnosis (n = 41) filled out Beck Youth Inventories of Emotional and Social Impairment (BYI) to assess depression and anxiety and completed a Continuous Performance Test (QbTest) measuring ADHD symptoms. Parents of the participants completed the internalizing domain in the Five to Fifteen questionnaire (FTF), measuring symptoms of anxiety and depression, and the Vineland Adaptive Behavior Scales (VABS) about the adolescent's adaptive functioning. RESULTS: Approximately a third of the study group self-reported substantial internalizing mental symptoms not always recognized by parents, and not always obvious in adaptive function or performance at ADHD test. Correlations between BYI and FTF were low. The BYI depression inventory correlated negatively with VABS and positively with activity level in a subgroup medicated for ADHD. There was a stronger correlation between girls BYI and FTF results as compared with boys. CONCLUSIONS: The results highlight the need for identification of anxiety and depression, using both self- and parent report. Present anxiety and depression symptoms do not seem to affect the clinical assessment of ASD and ADHD. PMID- 28836481 TI - Empirical Antibiotic Treatment in Diabetic Foot Infection: A Study Focusing on the Culture and Antibiotic Sensitivity in a Population From Southern China. AB - Diabetic foot and subsequent diabetic ulcer infections are the most devastating complication of diabetes. This study was conducted to explore the bacterial spectrum, sensitivity of microbials, and analysis of the empirical antibiotic regimens in our health center. The study included patients with diabetic foot ulcer infection (DFI) seen from 2009 to 2014. The patients included had all information covering the physical examination, laboratory tests, and image examinations. We sent appropriately obtained specimens for culture prior to starting empirical antibiotic therapy in all participants. A total of 312 patients were included: 52, 112, 95 and 53 patients within uninfected, mild, moderate, and severe infection groups. The total percentages of Gram-positive cocci (GPCs) and Gram-negative rods (GNRs) were 54% and 48.8% ( P = 0.63). The most common GPC was Staphylococcus aureus (22.4%) and GNR was Pseudomonas aeruginosa (11.9%). Methicillin-resistant Staphylococcus aureus was isolated from 21 patients (6.7%). Even in the mild infection group, there was no significant difference between GPC and GNR infection, irrespective of recent antibiotic use ( P = 0.053). The most frequently used empirical antibiotics in our center were second-/third-generation cephalosporin +/- clindamycin, both in the mild and moderate/severe infection groups. In our center, the amoxicillin/clavulanate or ampicillin/sulbactam (beta-L-ase 1) and second-/third-generation cephalosporins were highly resistant to the common GNR (30%-60%). The ticarcillin/clavulanate, piperacillin/tazuobactam (beta-L-ase 2), fluoroquinolone, and group 2 carbapenem had good sensitivity. This study presents a comprehensive microbiological survey of diabetic foot ulcers in inpatients and provides reliable evidence of the local microbial epidemiology and sensitivity of antibiotics, which may help us improve clinical outcomes in DFI patients. PMID- 28836482 TI - Assessment of Needs: Differences between male and female patients with schizophrenia needs in psychiatric hospitals in Baghdad city. AB - BACKGROUND: Gender differences are one of the most important and crucial subjects in evaluating the nursing care as well as mental health care system for psychiatric patients especially patients with schizophrenia. AIMS: We aimed to identify differences in needs of male and female patients with schizophrenia in psychiatric hospitals in Baghdad city and its relationship with some variables. METHOD: A descriptive, analytical design that was carried out by using Camberwell needs assessment, short appraisal schedule, self-report version (CANSAS-P) after translating to Arabic. RESULTS: Results indicated that there were a lot of unmet needs of male and female patients with schizophrenia, according to the entire CANSAS-P domains especially psychological symptoms. Differences were found in types of needs as the majority of men have more social needs while females was found to be more occupied with their fears and need safety. CONCLUSION: there were differences in types of need between male and female patients with schizophrenia; needs were affected by some variables such as educational level, first 10 days of admission and family visiting. PMID- 28836483 TI - "It Can Promote an Existential Crisis": Factors Influencing Pap Test Acceptability and Utilization Among Transmasculine Individuals. AB - Transmasculine (i.e., female-to-male transgender) individuals have lower rates of cervical cancer screening than nontransgender women and often report negative experiences with the Pap test. Deciding to undergo screening and the test experience itself are characterized by the following processes: negotiating identity as the patient, provider, and insurance company wrestle with the degree of (in)congruence between a patient's masculine gender identity and their conception of the Pap test as feminine; bargaining for health as a Pap test may be required to obtain medical transition services or avoid undesired health outcomes; withstanding acute challenges during the Pap test to body, identity, and privacy; or reframing challenges as affirmation. The degree of distress triggered by the Pap test varied from "routine" to traumatic. Participants affirmed that a trusted, trans-competent health care provider could significantly reduce barriers to regular and satisfactory cervical cancer screening. Data are from 32 in-depth interviews conducted in Boston, Massachusetts, with transmasculine individuals; a modified grounded theory approach informed the analysis. PMID- 28836484 TI - The influence of crisis resolution treatment on employment: a retrospective register-based comparative study. AB - Crisis resolution treatment (CRT) is a short-term acute psychiatric home-based treatment offered as an alternative to hospitalization. The purpose of CRT is to support patient recovery by maintaining and improving competencies in relation to everyday life. Individuals with mental disorders are at increased risk of leaving the labor market, which is a central aspect of everyday life. Thus, a primary outcome of interest is whether CRT enables higher employment compared with traditional hospitalization. The aim of this study was to assess the effectiveness of CRT compared with hospitalization in relation to attempted or committed suicides, admissions, readmissions and employment. This study utilized register-based psychiatric data. The CRT intervention, which was carried out in a psychiatric center (N = 374), was matched to traditional hospitalization treatment in a corresponding area (N = 9460). The outcomes (suicide attempts, suicides, admissions and readmissions) were replicated by applying propensity score matching (PSM) to evaluate the general treatment effect of CRT. The effectiveness of CRT on employment was estimated by applying PSM combined with a difference-in-difference estimator to account for any time trends. Receiving CRT was associated with significantly more employment after 1 year compared with hospitalization. Furthermore, after 1 year, receiving CRT was associated with fewer suicide attempts, admissions and readmissions. The associations were not significant after two years. The results suggest that CRT patients retain a higher employment rate, which could indicate better recovery. Using CRT could lead to savings in the social security system owing to higher employment rates. PMID- 28836485 TI - The vascularization pattern of acellular nerve allografts after nerve repair in Sprague-Dawley rats. AB - OBJECTIVE: We have demonstrated that angiogenesis in acellular nerve allografts (ANAs) can promote neuroregeneration. The present study aimed to investigate the microvascular regeneration pattern of ANAs in Sprague-Dawley (SD) rats. METHODS: Sixty male SD rats were randomly divided into an autologous group and a rat acellular nerve allograft group (rANA), and 10-mm sciatic nerve defects were induced in these rats. On the 7th, 14th and 21st days after surgery, systemic perfusion with Evans Blue (EB) or lead oxide was performed on the rats through carotid intubation. Samples were then collected for gross observation, and the microvessels in the nerves were reconstructed through microscopic CT scans using MIMICS software. The vascular volume fraction (VF, %) and microvessel growth rate (V, mm/d) in both groups were then measured, and 1 month after surgery, NF-200 staining was performed to observe and compare the growth condition of the axons. RESULTS: Early post-operative perfusion with gelatin/EB showed EB permeation around the acellular nerve. Perfusion with gelatin/lead oxide showed that the blood vessels had grown into the allograft from both ends 7 days after the operation. Fourteen days after the operation, the microvessel growth rate of the autologous group was faster than that of the rANA group (0.39 +/- 0.17 mm/d vs. 0.26 +/- 0.14 mm/d, p < 0.05), and the vascular VF was also higher than that of the rANA group (8.92% +/- 1.54% vs. 6.31% +/- 1.21%, p < 0.05). Twenty-one days after the operation, the blood vessels at both ends of the allograft had connected to form a microvessel network. The growth rate was not significantly different between the two groups; however, the vascular VF of the autologous group was higher than that of the rANA group (12.18% +/- 2.27% vs. 9.92% +/- 0.84%, p < 0.05). One month after the operation, the NF-200 fluorescence (IOD) in the autologous group significantly increased compared with that of the rANA group (540,278 +/- 17,424 vs. 473,310 +/- 14,636, respectively, p < 0.05), suggesting that the results of the repair after nerve injury were significantly better in the autologous group than in the rANA group. CONCLUSION: Both the autologous nerve and ANAs rely on the permeation of tissue fluids to supply nutrients during the early stage, and microvessel growth mainly starts at both ends of the graft and enters the graft along the long axis. Compared to ANAs, the growth speed of revascularization in autologous nerve grafts was faster, leading to a better outcome in the autologous nerve group. PMID- 28836486 TI - Delayed In-Custody Death Involving Excited Delirium. AB - This case study presents a 37-year-old male who was experiencing excited delirium (ExD) and died in a county jail 4 days after being taken into custody. The male died in a jail observation cell without having been restrained and was not under the influence of a drug stimulant. The subject had a documented psychiatric history of bipolar disorder and schizophrenia and was known to consume marijuana, cocaine, and methamphetamines. This case illustrates the pernicious effects of ExD and how its lethality can be delayed when many cases involve drug use and use of force where subjects die shortly thereafter. Implications of ExD for correctional agencies and efforts of responding to it in correctional and law enforcement contexts are discussed. PMID- 28836488 TI - Developing and Using Vignettes to Explore the Relationship Between Risk Management Practice and Recovery-Oriented Care in Mental Health Services. AB - There is a lack of literature evaluating the development and use of vignettes to explore contested constructs in qualitative health care research where a conventional interview schedule might impose assumptions on the data collected. We describe the development and validation of vignettes in a study exploring mental health worker and service user understandings of risk and recovery in U.K. mental health services. Focus groups with mental health workers and service users explored study questions from experiential perspectives. Themes identified in the groups were combined with existing empirical literature to develop a set of vignettes. Feedback focus groups were conducted to validate and amend the vignettes. Following use in research interviews, results suggested that the vignettes had successfully elicited data on issues of risk and recovery in mental health services. Further research using creative, comparative methods is needed to fully understand how vignettes can best be used in qualitative health care research. PMID- 28836487 TI - DNA methylation as a marker of response in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a complex disease affecting approximately 0.5-1% of the population. While there are effective biologic therapies, in up to 40% of patients, disease activity remains inadequately controlled. Therefore, identifying factors that predict, prior to the initiation of therapy, which patients are likely to respond best to which treatment is a research priority and DNA methylation is increasingly being explored as a potential theranostic biomarker. DNA methylation is thought to play a role in RA disease pathogenesis and in mediating the relationship between genetic variants and patient outcomes. The role of DNA methylation has been most extensively explored in cancer medicine, where it has been shown to be predictive of treatment response. Studies in RA, however, are in their infancy and, while showing promise, further investigation in well-powered studies is warranted. PMID- 28836490 TI - Unawareness for Motor Impairment and Distorted Perception of Task Difficulty. AB - OBJECTIVES: Anosognosia for motor impairment is a complex syndrome that can manifest itself under different forms, guiding patients' behavior and task decisions. However, current diagnostic tools tend to evaluate only more explicit aspects of anosognosia (asking the patients about their motor abilities) and fail to address more subtle features of awareness. We have developed a new assessment measure, the ECT (Errand Choice Test), where patients are asked to judge task difficulty rather than estimate their own impairment. METHODS: We assessed awareness in a group of 73 unilateral left- and right-brain damaged (30 LBD and 43 RBD, respectively) patients by means of the VATAm, which explicitly requires them to evaluate their own motor abilities, and the ECT. A control group of 65 healthy volunteers was asked to perform the ECT under two conditions: Current condition (i.e., using both hands) and Simulated conditions (i.e., simulating hemiplegia). RESULTS: A total of 27% of the patients showed different performance on the VATAm and ECT, 21% of the patients showing lack of awareness only on VATAm and 6% only on ECT. Moreover, despite the ECT identified a higher frequency of anosognosia after RBD (33.3%) than LBD (27.6%), this hemispheric asymmetry was not significant. Remarkably, anosognosic patients performed very similarly to controls in the "current condition", suggesting that anosognosic patients' ability to perceive the complexity of each task per se is not altered. CONCLUSION: Different methods may be able to tackle different aspects of awareness and the ECT proved to be able to detect less evident forms of awareness. (JINS, 2018, 24, 45-56). PMID- 28836489 TI - Postdose 3 G1 serum neutralizing antibody as correlate of protection for pentavalent rotavirus vaccine. AB - Although clinical trials of the pentavalent rotavirus vaccine (RotaTeq(r), RV5) have demonstrated efficacy against RV gastroenteritis (RGE) in low and high income settings, a clear correlate of protection or a measure of immune response that could predict efficacy has yet to be identified. This is the first time that immunogenicity data with both serum neutralized antibody (SNA) titers and anti-RV IgA titers from several clinical efficacy trials were pooled to provide a unique context for evaluating the correlation between immunogenicity and RGE risk or efficacy of RV5. The correlation between immunogenicity and RGE risk is evaluated with data at the individual subject level. The analyses show that higher Postdose 3 (PD3) G1 SNA titers are associated with lower odds of contracting any RGE. The correlation between immunogenicity and efficacy is assessed using aggregated population level data, which shows higher efficacy associated with higher PD3 G1 SNA geometric mean titer (GMT) ratio (between RV5 and placebo) and PD3 serum anti RV IgA GMT ratio. Among high-income countries, efficacy plateaus over the range of PD3 G1 SNA GMT ratios and PD3 serum anti-RV IgA GMT ratios. From both individual- and population-level analyses, PD3 G1 SNA titers correlated most closely with the RGE risk or efficacy for RV5. PMID- 28836491 TI - The Effect of Participating in a Surgical Site Infection (SSI) Surveillance Network on the Time Trend of SSI Rates: A Systematic Review. AB - This systematic literature review reveals that participating in a surgical site infection (SSI) surveillance network is associated with short-term reductions in SSI rates: relative risk [RR] for year 2, 0.80 (95% confidence interval [CI], 0.79-0.82); year 3 RR, 0.92 (95% CI, 0.90-0.94); year 4 RR, 0.98 (95% CI, 0.96 1.00). Infect Control Hosp Epidemiol 2017;38:1364-1366. PMID- 28836492 TI - Association of vegetarian diet with inflammatory biomarkers: a systematic review and meta-analysis of observational studies. AB - OBJECTIVE: Vegetarian diets contain various anti-inflammatory components. We aimed to investigate the effects of vegetarianism on inflammatory biomarkers when compared with omnivores. DESIGN: Systematic review and meta-analysis. SETTING: Literature search was conducted in Science Direct, Proquest, MEDLINE and Google Scholar up to June 2016. Summary estimates and corresponding 95 % CI were derived via the DerSimonian and Laird method using random effects, subgroup analyses were run to find the source of heterogeneity and a fixed-effect model examined between subgroup heterogeneity. SUBJECTS: Studies were included if they evaluated effects of any type of vegetarianism compared with omnivores on circulating levels of inflammatory biomarkers. No restriction was made in terms of language or the date of study publications. RESULTS: Eighteen articles were included. Pooled effect size showed no difference in high-sensitivity C-reactive protein (hs-CRP) levels in vegetarians v. omnivores (Hedges' g=-0.15; 95 % CI -0.35, 0.05), with high heterogeneity (I 2=75.6 %, P<0.01). A subgroup analysis by minimum duration of vegetarianism showed that a minimum duration of 2 years vegetarianism was associated with lower hs-CRP levels v. omnivores (Hedges' g=-0.29; 95 % CI -0.59, 0.01), with moderate heterogeneity (I 2=68.9 %, P<0.01). No significant effect was found in studies using a minimum duration of 6 months of vegetarianism, with low heterogeneity. Vegetarianism was associated with increased IL-6 concentrations (0.21 pg/ml; 95 % CI 0.18, 0.25), with no heterogeneity (I 2=0.0 %, P=0.60). CONCLUSIONS: The meta-analysis provides evidence that vegetarianism is associated with lower serum concentrations of hs-CRP when individuals follow a vegetarian diet for at least 2 years. Further research is necessary to draw appropriate conclusions regarding potential associations between vegetarianism and IL-6 levels. A vegetarian diet might be a useful approach to manage inflammaging in the long term. PMID- 28836493 TI - Developing a multidisciplinary rehabilitation package following hip fracture and testing in a randomised feasibility study: Fracture in the Elderly Multidisciplinary Rehabilitation (FEMuR). AB - BACKGROUND: Proximal femoral fracture is a major health problem in old age, with annual UK health and social care costs of L2.3B. Rehabilitation has the potential to maximise functional recovery and maintain independent living, but evidence of clinical effectiveness and cost-effectiveness is lacking. OBJECTIVES: To develop an enhanced community-based rehabilitation package following surgical treatment for proximal femoral fracture and to assess acceptability and feasibility for a future definitive randomised controlled trial (RCT) and economic evaluation. DESIGN: Phase I - realist review, survey and focus groups to develop the rehabilitation package. Phase II - parallel-group, randomised (using a dynamic adaptive algorithm) feasibility study with focus groups and an anonymised cohort study. SETTING: Recruitment was from orthopaedic wards of three acute hospitals in the Betsi Cadwaladr University Health Board, North Wales. The intervention was delivered in the community following hospital discharge. PARTICIPANTS: Older adults (aged >= 65 years) who had received surgical treatment for hip fracture, lived independently prior to fracture, had mental capacity (assessed by the clinical team) and received rehabilitation in the North Wales area. INTERVENTIONS: Participants received usual care (control) or usual care plus an enhanced rehabilitation package (intervention). Usual care was variable and consisted of multidisciplinary rehabilitation delivered by the acute hospital, community hospital and community services depending on need and availability. The intervention was designed to enhance rehabilitation by improving patients' self efficacy and increasing the amount and quality of patients' practice of physical exercise and activities of daily living. It consisted of a patient-held information workbook, a goal-setting diary and six additional therapy sessions. MAIN OUTCOME MEASURES: The primary outcome measure was the Barthel Activities of Daily Living (BADL) index. The secondary outcome measures included the Nottingham Extended Activities of Daily Living (NEADL) scale, EuroQol-5 Dimensions, ICEpop CAPability measure for Older people, General Self-Efficacy Scale, Falls Efficacy Scale - International (FES-I), Self-Efficacy for Exercise scale, Hospital Anxiety and Depression Scale (HADS) and service use measures. Outcome measures were assessed at baseline and at 3-month follow-up by blinded researchers. RESULTS: Sixty-two participants were recruited (23% of those who were eligible), 61 were randomised (control, n = 32; intervention, n = 29) and 49 (79%) were followed up at 3 months. Compared with the cohort study, a younger, healthier subpopulation was recruited. There were minimal differences in most outcomes between the two groups, including the BADL index, with an adjusted mean difference of 0.5 (Cohen's d = 0.29). The intervention group showed a medium-sized improvement on the NEADL scale relative to the control group, with an adjusted mean difference between groups of 3.0 (Cohen's d = 0.63). There was a trend for greater improvement in FES-I and HADS in the intervention group, but with small effect sizes, with an adjusted mean difference of 4.2 (Cohen's d = 0.31) and 1.3 (Cohen's d = 0.20), respectively. The cost of delivering the intervention was L231 per patient. There was a possible small relative increase in quality adjusted life-years in the intervention group. No serious adverse events relating to the intervention were reported. CONCLUSIONS: Trial methods were feasible in terms of eligibility, recruitment and retention, although recruitment was challenging. The NEADL scale was more responsive than the BADL index, suggesting that the intervention could enable participants to regain better levels of independence compared with usual care. This should be tested in a definitive Phase III RCT. There were two main limitations of the study: the feasibility study lacked power to test for differences between the groups and a ceiling effect was observed in the primary measure. TRIAL REGISTRATION: Current Controlled Trials ISRCTN22464643. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 44. See the NIHR Journals Library for further project information. PMID- 28836494 TI - Fibrillar collagen injection for organ protection during thermal ablation of hepatic malignancies. AB - Percutaneous image-guided ablation is performed throughout many areas of the body for various pathologies including hepatic malignancies. Heat and cold-based ablative technologies are effective and well-tolerated with an acceptable safety profile. However, ablative therapies may be technically more challenging and cause collateral thermal injury if the targeted lesion is adjacent to critical organs. Previously, techniques including artificial ascites and pneumoperitoneum have been utilized to displace or insulate critical structures from the ablation zone. This technical innovation describes (10-30 mL) fibrillar collagen dissolved in fluid as a focal thermal insulation technique. Small volume fibrillar collagen instillation, and thermal ablation were technically successful in three cases without complication. Clinical follow-up and 3-month imaging confirmed complete ablation of all hepatic malignancies without collateral injury. PMID- 28836495 TI - Letter to the Editor Regarding "Assessment of Retinal Nerve Fiber Layer Thickness in Non-Diabetic Obese Children and Adolescents". PMID- 28836496 TI - Metachronous Synovial Sarcoma After Treatment of Mixed Germ Cell Tumor in a Child with Complete Gonadal Dysgenesis. AB - Patients with complete XY gonadal dysgenesis (GD) show a high predisposition to germ cell tumors (GCT). Patients with coexistence of GCT and GD have been reported previously. Here we present a 15-year-old girl with mixed GCT and GD who also developed an intra-abdominal synovial sarcoma one year after the treatment. This is the first report, to our knowledge, of synovial sarcoma associated with XY GD. PMID- 28836497 TI - Research on the effect of formononetin on photodynamic therapy in K562 cells. AB - At the present time, many cancer patients combine some forms of complementary and alternative medicine therapies with their conventional therapies. The most common choice of these therapies is the use of antioxidants. Formononetin is presented in different foods. It has a variety of biological activities including antioxidant and anti-cancer properties. On account of its antioxidant activity, formononetin might protect cancer cells from free radical damage in photodynamic therapy (PDT) during which reactive oxygen species (ROS) production was stimulated leading to irreversible tumor cell injury. In this study, the influence of formononetin on K562 cells in PDT was demonstrated. The results showed that formononetin supplementation alone did not affect the lipid peroxidation, DNA damage and apoptosis in K562 cells. It increases the lipid peroxidation, DNA damage and apoptosis in K562 cells induced by PDT. The singlet oxygen quencher sodium azide suppresses the apoptosis induced by PDT with formononetin. In conclusion, formononetin consumption during PDT increases the effectiveness of cancer therapy on malignant cells. The effect of antioxidants on PDT maybe was determined by its sensitization ability to singlet oxygen. PMID- 28836498 TI - Evaluation of liposomal carnosine in adjuvant arthritis. AB - Liposomal carnosine could overcome the problems associated with direct application of this peptide. Anti-inflammatory and antioxidant effects of liposomal and non-liposomal carnosine in adjuvant arthritis were compared. The experiments were done on healthy animals, untreated arthritic animals, arthritic animals with oral administration of carnosine, and with subcutaneous administration of liposomal carnosine, both administered in the same daily dose of 150 mg/kg b.w. during 28 days. Carnosine reduced hind paw volume on day 28. Both forms markedly decreased interleukin-1beta, matrix metalloproteinase-9 and monocyte chemoattractant protein-1 (MCP-1) in plasma on day 14. Only liposomal carnosine reduced significantly MCP-1. Malondialdehyde, 4-hydroxynonenal, resistance to Fe2+-induced oxidation and protein carbonyls were significantly corrected after administration of any form of carnosine. Liposomal carnosine corrected more effectively the oxidative stress in plasma than did carnosine. In brain tissue, our results showed protective ability of both forms of carnosine against oxidation of proteins and lipids. They also corrected the resistance to Fe2+-induced oxidation in arthritic animals. We found that only liposomal carnosine decreased the mRNA expression of inducible nitric oxide synthase in cartilage tissue. It can be concluded that the liposomal drug-delivery system is improving the pharmacological properties of carnosine administered in arthritis. PMID- 28836499 TI - Effects of extremely low frequency electromagnetic fields on morphine analgesia and tolerance in rats. AB - Several studies have demonstrated that the electromagnetic fields produce analgesic activity. The aim of this study was to investigate the effects of extremely low frequency (ELF) electromagnetic fields (EMF) on morphine analgesia and tolerance in rats. In the study, 78 adult male Wistar albino rats (approximately 240 +/- 12 g) were used. The application of 50 Hz magnetic field, each day the same times for 30 minutes for 15 days, and a total of four times every 15 minute intervals. To constitute morphine tolerance, high dose of morphine (50 mg/kg) were administered for 3 days in rats and tolerance was evaluated on day 4. Prior to analgesia tests, the effective dose (5 mg/kg) of morphine was injected into rats. In the statistical analyzes of the data, analysis of variance (two-way ANOVA) was used and the multiple comparison determined by Tukey tests. The maximum analgesic effect of the 5 mT magnetic field was determined on 7 days. Administration of morphine (5 mg/kg) in rats exposed to a magnetic field, the analgesic effect was significantly higher compared to the morphine group (p < 0.05). Morphine tolerant animals exposed to a magnetic field, the analgesic effect was found significantly higher than morphine tolerant group rats (p < 0.05). Analgesia test data demonstrated that application of ELF-EMFs to rats increases the morphine analgesia and reduces morphine tolerance. PMID- 28836500 TI - In vitro non-thermal oxidative stress response after 1800 MHz radiofrequency radiation. AB - In this study possible connection between radiofrequency exposure (RF) and development of oxidative stress was investigated by measuring impairment in cellular oxidation-reduction balance immediately after RF exposure. Fibroblast cells V79 were exposed for 10, 30 and 60 minutes to 1800 MHz RF radiation. Electric field strength was 30 V/m and specific absorption rate (SAR) was calculated to be 1.6 W/kg. Electromagnetic field was generated within Gigahertz Transversal Electromagnetic Mode cell (GTEM) equipped by signal generator, amplifier and modulator. Cell viability was determined by CCK-8 colorimetric assay and level of reactive oxygen species (ROS) was detected by dihydroethidium staining. Reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) were used to assess cell antioxidant activity while lipid oxidative damage was evaluated measuring concentration of malondialdehyde. Viability of V79 cells remained within normal physiological values regardless of exposure time. Increased level of superoxide radicals was detected after 60-min exposure. Significantly higher GSH level was observed immediately after 10-min exposure with higher but insignificant activity of GSH-Px. Lipid oxidative damage in exposed cell samples was not observed. Short-term RF exposure revealed transient oxidation-reduction imbalance in fibroblast cells following adaptation to applied experimental conditions. PMID- 28836501 TI - Effects of natural ligands and synthetic triorganotin compounds of nuclear retinoid X receptors in human MCF-7 breast cancer cell line. AB - In the present study, we analyzed in vitro effects of natural and synthetic triorganotin ligands of nuclear retinoid X receptors in human MCF-7 breast cancer cells. Our data has shown that all-trans retinoic acid significantly reduced expression of RXRalpha mRNA, Bcl2 and enhanced expression of BAX proteins. Tributyltin bromide markedly decreased mRNA level of RXRalpha and RXRbeta. Significantly reduced levels of both RXRs proteins were observed after treatment with tributyltin chloride (TBT-Cl) but not after treatment with triphenyltin chloride (TPT-Cl) for RXRbeta protein. Both RXRalpha and RXRbeta protein levels decrease was found also by combination ATRA+TBT-Cl/TPT-Cl. PMID- 28836503 TI - Enhancement effect of defect fluorescence of ZnSe quantum dots on a heterojuction of ZnSe quantum dots and gold nanoparticles. AB - We studied an enhancement effect of defect fluorescence of ZnSe quantum dots (QDs) on a heterojunction of ZnSe QDs and gold nanoparticles. The photoluminescence (PL) of Au/ZnSe heterojunction is excited by using a 150 nm diameter ultraviolet laser spot of a scanning near-field optical microscope. Owing to the charge transfer of photon-generated carriers from ZnSe QDs, the enhanced PL effect is observed, which results from the increase of the built-in electric field to hinder the electron transfer to gold nanoparticles and is trapped by the defect states of ZnSe QDs. The broadening of defect fluorescence spectra and the reduction of excitonic fluorescence in multi-heterojunction of ZnSe QDs and gold nanoparticles are also observed which is attributed to an increase of their contact areas. We believe that enhanced defect fluorescence method described in this paper have potential applications in forming uniform optoelectronic heterojunction in controlling and boosting fluorescent efficiency of weak PL devices. PMID- 28836502 TI - Inhibition of PDE4 by low doses of rolipram induces changes in lipid and protein components of mice heart. AB - There is significant increasing interest in phosphodiesterase-4 (PDE4) inhibition in treatment of cardiovascular diseases. Related with this, research has focused on cellular, biochemical, molecular and structural changes in heart tissue induced by PDE4s inhibitors. However, for their clinical applicability additional studies are still needed. Fourier transform infrared spectroscopy offers promising approach to contribute such issue due to its ability in detection the changes in biomolecules. By utilizing this method, we examined the effects of PDE4 inhibition by rolipram at 0.05 mg/kg and 0.1 mg/kg doses on content of lipids and proteins, and fluidity, order and packing of membranes in naive mice heart. In treated groups, there was a significant decrease in unsaturated, saturated lipids, cholesterol esters, fatty acids, phospholipids and triacylgylcerols obtained from CH2, C=O, olefinic=CH, and COO- areas, and CH2/lipid, C=O/lipid, olefinic=CH/lipid, and COO-/lipid ratios. Additionally, olefinic=CH area and olefinic=CH/lipid ratio may suggest decreased lipid peroxidation, confirmed by thiobarbituric acid assay. Also, a higher degree of membrane order, slight increase in membrane fluidity and differences in membrane packing were obtained. Amide I and II areas and RNA/protein ratios showed that variation in protein content is not correlated with applied concentration. Analysis of amide I mode predicted alterations in secondary structures like an increase in random coils and decrease in alpha-helices. Moreover, all groups were successfully discriminated by cluster analysis. The corresponding results may help to understand the potential effects of PDE4 inhibition by rolipram. PMID- 28836504 TI - Shape-controlled synthesis of vanadium diselenide. AB - VSe2 is a typical layered semimetal TMDC, and was thought to be difficult to synthesize for many years. By changing the concentration of precursors and reaction steps in the hydrothermal method, here we successfully synthesize three different shapes of VSe2: nano-hydrangea (NH), nano-dandelion (ND) and hexagonal disk (HD). The as-prepared VSe2 HDs have a single-crystalline structure compared with the poly-crystalline structure of NHs and NDs. The as-prepared VSe2 in these three shapes also demonstrates apparent differences and intrinsic properties both in the nitrogen adsorption-desorption characterizations and UV-vis absorption analysis. Possible growth processes and mechanisms are put forward in detail to further inspire shape-design in other nanoscale materials. PMID- 28836505 TI - ON-state evolution in lateral and vertical VO2 threshold switching devices. AB - We report the results of finite element simulations of the ON state characteristic of VO2-based threshold switching devices and compare the results with experimental data. The model is based on thermally induced threshold switching (thermal runaway) and successfully reproduces the I-V characteristics showing the formation and growth of the conductive filament in the ON state. Furthermore, we compare the I-V characteristics for two VO2 films with different electrical conductivities in the insulating and metallic phases as well as those based on TaO x and NbO x functional layers. PMID- 28836506 TI - Unintended and accidental medical radiation exposures in radiology: guidelines on investigation and prevention. AB - This paper sets out guidelines for managing radiation exposure incidents involving patients in diagnostic and interventional radiology. The work is based on collation of experiences from representatives of international and national organizations for radiologists, medical physicists, radiographers, regulators, and equipment manufacturers, derived from an International Atomic Energy Agency Technical Meeting. More serious overexposures can result in skin doses high enough to produce tissue reactions, in interventional procedures and computed tomography, most notably from perfusion studies. A major factor involved has been deficiencies in training of staff in operation of equipment and optimization techniques. The use of checklists and time outs before procedures commence, and dose alerts when critical levels are reached during procedures, can provide safeguards to reduce the risks of these effects occurring. However, unintended and accidental overexposures resulting in relatively small additional doses can take place in any diagnostic or interventional x-ray procedure and it is important to learn from errors that occur, as these may lead to increased risks of stochastic effects. Such events may involve the wrong examinations, procedural errors, or equipment faults. Guidance is given on prevention, investigation, and dose calculation for radiology exposure incidents within healthcare facilities. Responsibilities should be clearly set out in formal policies, and procedures should be in place to ensure that root causes are identified and deficiencies addressed. When an overexposure of a patient or an unintended exposure of a foetus occurs, the foetal, organ, skin, and/or effective dose may be estimated from exposure data. When doses are very low, generic values for the examination may be sufficient, but a full assessment of doses to all exposed organs and tissues may sometimes be required. The use of general terminology to describe risks from stochastic effects is recommended rather than the calculation of numerical values, as these are misleading when applied to individuals. PMID- 28836507 TI - Detection of atrial fibrillation using an earlobe photoplethysmographic sensor. AB - : Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world, associated with increased risk of thromboembolic events and an increased mortality rate. In addition, a significant portion of AF patients are asymptomatic. Current AF diagnostic methods, often including a body surface electrocardiogram or implantable loop recorder, are both expensive and invasive and offer limited access within the general community. OBJECTIVE: We tested the feasibility of the detection of AF using a photoplethysmographic signal acquired from an inexpensive, non-invasive earlobe photoplethysmographic sensor. This technology can be implemented into wearable devices and would enable continuous cardiac monitoring capabilities, greatly improving the rate of asymptomatic AF detection. APPROACH: We conducted a clinical study of patients going through electrical cardioversion for AF treatment. Photoplethysmographic recordings were taken from these AF patients before and after their cardioversion procedure, along with recordings from a healthy control group. Using these recordings, cardiac beats were identified and the inter-systolic interval was calculated. The inter-systolic interval was used to calculate four parameters to quantify the heart rate variability indicative of AF. Receiver operating characteristic curves were used to calculate discriminant thresholds between the AF and non-AF cohorts. MAIN RESULTS: The parameter with the greatest discriminant capability resulted in a sensitivity and specificity of 90.9%. These results are comparable to expensive ECG-based and invasive implantable loop recorder AF detection methods. SIGNIFICANCE: These results demonstrate that using a non-invasive earlobe photoplethysmographic signal is a viable and inexpensive alternative to ECG-based AF detection methods, and an alternative that could be invaluable in detecting subclinical AF. PMID- 28836508 TI - Circulating tumor cells and their role in prostate cancer. AB - Circulating tumor cells (CTC) have become an important biomarker in patients with advanced prostate cancer. CTC count has been demonstrated to be a prognostic factor for overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In localized prostate cancer, a clear correlation between CTC counts and clinicopathological risk parameters and outcome has not been observed. Currently, the focus of research is shifting from CTC enumeration towards molecular characterization of CTC leading to the discovery of markers predicting treatment response. The role of androgen receptor splice variants expressed by CTC as markers of resistance to abiraterone and enzalutamide has been assessed by various studies. The identification of CTC markers predicting treatment response represents a key step to guide the selection of treatment (e.g., abiraterone/enzalutamide vs taxanes), particularly in patients with mCRPC. As an alternative to CTC, the analysis of circulating tumor DNA has been shown to enable a noninvasive disease characterization having high potential to promote precision oncology. PMID- 28836509 TI - An annoying mass of the nail bed. PMID- 28836510 TI - Steroid-resistant erythroderma and alopecia in a newborn. PMID- 28836511 TI - An animal experimental study to assess the core tissue acquisition ability of endoscopic ultrasound-guided histology needles. AB - Background and Objectives: Acquisition of core tissue on endoscopic ultrasound (EUS)-guided fine-needle aspiration has been regarded as important for establishing an accurate histological diagnosis. Recently, a new 20-gauge histology needle with reverse bevel (ProCore needle) and a 22-gauge needle with 3 novel symmetric heels (Acquire needle) have been developed. The aims of this animal experimental study were to assess the core tissue acquisition (TA) abilities of these new histology needles by comparing them with those of conventional 22-gauge needles and to evaluate the efficacy of suction for these needles. Materials and Methods: Three experienced echoendoscopists performed EUS guided TA with and without suction using 43 types of needles. The amount of obtained tissue specimens and blood contamination was assessed using a scoring system, and the weight of the obtained tissue specimens was measured using an electronic balance. Results: The mean amount of core tissue score of the Acquire 22-gauge needle or ProCore 20-gauge needle was significantly higher than that of the conventional 22-gauge needles (Acquire 22-gauge needle vs. conventional 22 gauge needles: P = 0.024; ProCore 20-gauge needle vs. conventional 22-gauge needles: P = 0.001). There was no significant difference in the mean amount of core tissue score between the Acquire 22-gauge needle and the ProCore 20-gauge needle (P = 0.296). In the Acquire 22-gauge needle and ProCore 20-gauge needle, there was no significant difference between the mean amount of core tissue score with suction and that without suction (3.7 +/- 0.4 vs. 3.5 +/- 0.4, P = 0.734) although blood contamination increased (2.3 +/- 0.7 vs. 1.6 +/- 0.3, P = 0.061). Conclusion: The TA abilities of the ProCore 20-gauge needle and Acquire 22-gauge needle were better than those of the conventional 22-gauge needles. The efficacy of suction for the ProCore 20-gauge needle and Acquire 22-gauge needle was limited. PMID- 28836512 TI - A tertiary care hospital's 10 years' experience with rectal ultrasound in early rectal cancer. AB - Background and Objectives: Rectal endoscopic ultrasound (RUS) has become an essential tool in the management of rectal adenocarcinoma because of the ability to accurately stage lesions. The aim of this study was to identify the staging agreement of early RUS-staged rectal adenocarcinoma with surgical resected pathology and ultimately determine how this impacts the management of early rectal cancer (T1-T2). Methods: Retrospective chart review was performed from November 2002 to November 2013 to identify procedure indication, RUS staging data, surgical management, and postoperative surgical pathology data. Results: There were a total of 693 RUS examinations available for review and 282 of these were performed for a new diagnosis of rectal adenocarcinoma. There was staging agreement between RUS and surgical pathology in 19 out of 20 (95%) RUS-staged T1 cases. There was staging agreement between RUS and surgical pathology in 3 out of 9 (33%) RUS-staged T2 cases. There was significantly better staging agreement for RUS-staged T1 lesions compared to RUS staged T2 lesions (P = 0.002). Nearly 60% of T1N0 cancers were referred for transanal excisions (TAEs), and 78% of T2N0 cancers underwent low anterior resection. Conclusions: This study identified only a small number of T1-T2 adenocarcinomas. There was good staging agreement between RUS and surgical pathology among RUS-staged T1 lesions whereas poor staging agreement among RUS-staged T2 lesions. Although TAE is largely indicated by the staging of a T1 lesion, this approach may be less appropriate for T2 lesions due to high reported local recurrence. PMID- 28836513 TI - Large liver abscess after endoscopic ultrasound-guided fiducial placement. PMID- 28836514 TI - Ectopic pancreas in the upper gastrointestinal tract: Is endosonographic diagnosis reliable? Data from the German Endoscopic Ultrasound Registry and review of the literature. AB - Background: Ectopic pancreas (EP) belongs to the most frequent subepithelial lesions (SELs) of the upper gastrointestinal (GI) tract. In the majority of cases, it is detected incidentally. Differential diagnosis from mesenchymal subepithelial tumors may be difficult. Methods: Among 24,308 endosonographic examinations and interventions, which were prospectively enrolled in the database of the German Endoscopic Ultrasound (EUS) Registry from January 2009 to August 2013, 575 were performed for suspected SELs of the upper GI tract. Sixty three cases of EP of the upper GI tract (stomach, n = 53; duodenum, n = 10; esophagus, n = 0) were extracted and retrospectively reviewed. Results: In 65.1% of cases, radial echoendoscopes or radial miniprobes were used for examination. Nearly 84% of EP was found in the stomach, 16% in the duodenum, none in the esophagus. In 88.9% of cases, the EUS examination discerned the layer of origin. In 59% of cases EP was described as a heterogeneous, in 28.6% as a homogeneous-hypoechoic and in 7.9% as a homogeneous-echogenic subepithelial mass lesion. Mean diameter was 13.0 mm * 8.1 mm, the mean ratio between long and short axis diameter was 1.75. EUS-guided fine needle aspiration (EUS-FNA) was used to accomplish cytological or histological diagnosis in only 6.3% of cases. Conclusions: EP accounts for 11% of all EUS examinations performed for subepithelial lesions of the upper GI tract and prospectively enrolled in the German EUS registry. Rather than being an eyecatcher, EP is a chameleon with numerous differential diagnoses. In selected cases, EUS-FNA may help clarifying the diagnosis. PMID- 28836515 TI - Endoscopic ultrasound-guided antegrade metal stent placement using the stent-in stent technique in a patient with malignant hilar biliary obstruction. PMID- 28836517 TI - SpyGlass findings of mucinous cystic neoplasm by introducing the fiber-optic into the cyst through a 19-gauge needle during endoscopic ultrasound. PMID- 28836516 TI - Autoimmune pancreatitis: Imaging features. AB - Background and Objectives: Autoimmune pancreatitis (AIP) remains a difficult disease to diagnose before treatment, particularly if presenting as a focal mass lesion. The purpose of this multicenter retrospective study is to analyze imaging features of histologically confirmed AIP to determine the additional diagnostic value of contrast-enhanced ultrasound (CEUS), contrast-enhanced endoscopic ultrasound (CE-EUS), and elastography to B-mode features. Patients and Methods: We report on a retrospective data collection of 60 histologically confirmed cases of AIP in comparison to 16 patients with pancreatic adenocarcinomas (PDAC). All CE (-E) US examinations were assessed by two independent readers in consensus. The role of CEUS and CE-EUS for pancreatic evaluation was defined according to the 2011 European Federation of Societies for Ultrasound in Medicine and Biology guidelines. Results: After injection of ultrasound (US) contrast agents, most AIP lesions displayed focal or diffuse isoenhancement (86.6%) in the arterial phase, while most of the PDAC lesions (93.7%) were hypoenhancing (P < 0.01). During the late phase, most AIP lesions were hyper-(65%) or iso-enhancing (35%), while most PDAC lesions were hypoenhancing (93.7%). CE-EUS was performed in a subset of ten patients and showed hyperenhancement in all AIP cases. Most focal AIP lesions (n = 27, 79.4%) were stiffer than the surrounding pancreatic parenchyma. Conclusions: In this study, percutaneous and endoscopic contrast enhanced harmonic US techniques consistently revealed diffuse and focal types of AIP to have features consistent with vascularized lesions. Differentiation from the typically hypovascularized pancreatic adenocarcinoma was possible with CE (-E) US evaluation. PMID- 28836518 TI - Contrast-enhanced endoscopic ultrasonography features of a mucoepidermoid carcinoma of the pancreas. PMID- 28836519 TI - Direct puncture of the ampulla as a modified Endoscopic ultrasound-guided rendezvous technique. PMID- 28836520 TI - Performance of a new needle for endoscopic ultrasound-guided fine-needle biopsy in patients with pancreatic solid lesions: A retrospective multicenter study. AB - Background and Objectives: Procurement of tissue core biopsy samples may overcome some of the limitations of endoscopic ultrasound (EUS)-guided fine-needle aspiration. We aimed at assessing the safety, histological sample procurement yield, and diagnostic accuracy of a newly available histology needle. Materials and Methods: Data from consecutive patients with pancreatic solid lesions who underwent EUS-fine needle biopsy (EUS-FNB) using the 22-gauge AcquireTM needle were retrospectively retrieved from four tertiary care centers database. Results: Fifty-nine patients (mean age 68 +/- 12 years; male/female 29/30) with pancreatic solid lesions underwent EUS-FNB using the 22-gauge AcquireTM needle. The biopsy was done transgastrically in 22 (37.3%) patients and transduodenally in 37 (62.7%) cases. A mean of 2.8 +/- 0.45 needle passes per lesion site were performed, without any major complication. A tissue core biopsy sample for histological evaluation was obtained in 55 (93.2%) cases. In the additional four cases, the specimen obtained resulted adequate for cytological evaluation. Considering malignant versus nonmalignant disease, sensitivity, specificity, negative likelihood ratio, positive likelihood ratio, and diagnostic accuracy were 98.2% (95% confidence interval [CI], 90.6-99.7), 100% (95% CI, 43.6-100), 0.018 (95% CI, 0.003-0.125), 295.6 (95% CI, 0-9.3 * 1010), and 98.3% (95% CI, 94.9-100), respectively. Conclusions: EUS-FNB using the 22-gauge AcquireTM needle is able to reach a very high procurement yield and diagnostic accuracy. Large prospective studies are warranted to further evaluate the utility of this newly developed needle. PMID- 28836521 TI - A prospective study of endoscopic ultrasonography features, cyst fluid carcinoembryonic antigen, and fluid cytology for the differentiation of small pancreatic cystic neoplasms. AB - Background and Objectives: With improvements in imaging technologies, pancreatic cystic lesions (PCLs) have been increasingly identified in recent years. However, the imaging modalities used to differentiate the categories of pancreatic cysts remain limited, which may cause confusion when planning treatment. Due to progress in endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) technology, auxiliary diagnosis by the detection of cystic fluid has become a recent trend. Methods: From March 2015 to April 2016, 120 patients with PCLs were enrolled in this study. According to the results of EUS, cyst fluid carcinoembryonic antigen (CEA) analysis, and cystic fluid cytology, the patients were divided into two groups: a nonmucinous and a mucinous group. Of those, 61 patients who had undergone surgical resection were included in the analysis. The clinical features, biochemical and tumor markers of cyst fluid as well as the cytological test results of the patients were compared with histopathology results. Results: A cyst size of 4.0 cm was used as the boundary value; a cyst <=4.0 cm was defined as a small PCL. 87 (72.5%) lesions were <=4.0 cm, and 33 (27.5%) lesions were >4.0 cm. Regarding the analysis of CEA and carbohydrate antigens 19-9 (CA19-9), significant differences were found between the nonmucinous and mucinous groups (P < 0.05) according to nonparametric independent samples tests. The EUS, cystic fluid CEA, and cystic fluid cytology results were compared with the tissue pathology findings using McNemar's test (P < 0.05) and showed a sensitivity of 90% and a specificity of 84%. Conclusion: A diagnostic combination of EUS, cyst fluid CEA, and cystic fluid cytology could be used to differentiate small pancreatic cystic neoplasms. Cystic fluid cytology analysis is helpful for planning treatment for pancreatic cystic tumors that pose a surgical risk. PMID- 28836522 TI - From research to practice. PMID- 28836523 TI - Burden of oral diseases in India: Where are we? PMID- 28836524 TI - Qualitative analysis of connective tissue stroma in different grades of oral squamous cell carcinoma: A histochemical study. AB - BACKGROUND: Detection of oral cancer at an early stage is of utmost importance to decrease morbidity and mortality. Tumor stroma plays a critical role during carcinogenesis. There is lack of information regarding the characteristics of the stroma in relation to the invading malignant epithelial cells and the interdependence between stroma and tumor cells in different grades of oral squamous cell carcinoma (OSCC). AIM: The present study was aimed to analyze and compare the nature of stroma in the vicinity of invading tumor islands in different grades of OSCC, using a histochemical technique picrosirius polarization method. The present study also evaluated and correlated the possible role of inflammatory response in determining the nature of the stroma. SUBJECTS AND METHODS: The study included thirty cases of different grades of histologically diagnosed OSCC and ten sections of normal buccal mucosa as a control group. Nature of collagen was analyzed using picrosirius-polarization method, and intensity of inflammatory cell infiltrate was recorded using ImageJ software (1.42q, NIH, USA). The results were tabulated and analyzed statistically. RESULTS: Normal oral mucosa showed predominantly reddish birefringence. All cases of well-differentiated OSCC showed reddish-orange color. Nearly 70% moderately differentiated cases showed yellowish-orange (YO) and 60% of poorly differentiated cases, showed greenish-yellow (GY). The mean inflammatory cell count was highest in well-differentiated group. There was shift to YO and GY collagen when the cell differentiation and inflammatory cell count decreased in moderate and poorly differentiated cases. CONCLUSION: Both inflammatory cells and tumor cells have a role in determining the nature of the collagen fibers in tumor stroma of OSCC, probably with opposing effects on stromal behavior and hence both are significant in predicting prognosis. PMID- 28836525 TI - A study of complexity of oral mucosa using fractal geometry. AB - BACKGROUND: The oral mucosa lining the oral cavity is composed of epithelium supported by connective tissue. The shape of the epithelial-connective tissue interface has traditionally been used to describe physiological and pathological changes in the oral mucosa. AIM: The aim is to evaluate the morphometric complexity in normal, dysplastic, well-differentiated, and moderately differentiated squamous cell carcinoma (SCC) of the oral mucosa using fractal geometry. MATERIALS AND METHODS: A total of 80 periodic acid-Schiff stained histological images of four groups: normal mucosa, dysplasia, well-differentiated SCC, and moderately differentiated SCC were verified by the gold standard. These images were then subjected to fractal analysis. STATISTICAL ANALYSIS: ANOVA and post hoc test: Bonferroni was applied. RESULTS: Fractal dimension (FD) increases as the complexity increases from normal to dysplasia and then to SCC. Normal buccal mucosa was found to be significantly different from dysplasia and the two grades of SCC (P < 0.05). ANOVA of fractal scores of four morphometrically different groups of buccal mucosa was significantly different with F (3,76) = 23.720 and P< 0.01. However, FD of dysplasia was not significantly different from well-differentiated and moderately differentiated SCC (P = 1.000 and P = 0.382, respectively). CONCLUSION: This study establishes FD as a newer tool in differentiating normal tissue from dysplastic and neoplastic tissue. Fractal geometry is useful in the study of both physiological and pathological changes in the oral mucosa. A new grading system based on FD may emerge as an adjuvant aid in cancer diagnosis. PMID- 28836526 TI - Knowledge and attitude of Indian dentists regarding dental stem cells: A cross sectional descriptive survey. AB - BACKGROUND: Dental stem cells derived from tooth structures are adult stem cells that have received attention of researchers over the past decade. Dental stem cells can be used to regenerate dental tissues as well as non dental organs. These dental stem cells are readily accessible as compared to other sources of stem cells and can be obtained and stored for future use through minimally invasive procedures. Research in this field is growing at a fast pace and it is essential that awareness regarding the same should be present amongst professionals. AIM: This study was carried out to assess the knowledge and attitude of Indian dentists regarding dental stem cells. MATERIAL AND METHODS: A cross sectional descriptive, questionnaire based survey based on Knowledge, Attitude and Practice (KAP) was conducted and a total of 823 dentists from Maharashtra, India participated in the survey. The Pearson's Chi-Square Test and percentages of the total were used for statistical analysis. RESULTS AND CONCLUSION: A total of 823 dentists completed the questionnaire survey; out of which 396 were male and 427 were female. Maximum respondents (53%) were dental graduates, followed by post graduates (45%) and PhD (1.7%). Data from the study revealed that there is good awareness regarding stem cells in general. However; the awareness, knowledge regarding sources, applications, uses and clinical research guidelines regarding dental stem cells is lacking amongst most dentists. Despite this lack of knowledge, dentists are keen on updating their knowledge regarding dental stem cells. PMID- 28836527 TI - Evaluation of polymerization shrinkage, polymerization shrinkage stress, wear resistance, and compressive strength of a silorane-based composite: A finite element analysis study. AB - BACKGROUND: Understanding the mechanical properties is important in predicting the clinical behavior of composites. Finite element analysis (FEA) evaluates properties of materials replicating clinical scenario. AIM: This study evaluated polymerization shrinkage and stress, wear resistance (WR), and compressive strength (CS) of silorane in comparison with two methacrylate resins. SETTINGS AND DESIGN: This study design was a numerical study using FEA. MATERIALS AND METHODS: Three-dimensional (3D) models of maxillary premolar with Class I cavities (2 mm depth, 4 mm length, and 2.5 mm width) created and restored with silorane, nanohybrid, and microhybrid; Groups I, II, and III, respectively. Loads of 200-600 N were applied. Polymerization shrinkage was first determined by displacement produced in the X, Y, and Z planes. Maximum stress distribution due to shrinkage was calculated using AN SYS software. 3D cube models of composite resins were simulated with varying filler particle size. Similar loads were applied. WR and compressive stress were calculated: K W L/H and load/cross sectional area, respectively. Statistical analysis done using one-way ANOVA, Kruskal-Wallis, and Tukey's honestly significant difference test (P < 0.05). RESULTS: Polymerization shrinkage (0.99%) and shrinkage stress (233.21 Mpa) of silorane were less compared to microhybrid (2.14% and 472.43 Mpa) and nanohybrid (2.32% and 464.88 Mpa). Silorane (7.92*/1011 MUm/mm3) and nanohybrid (7.79*/1011) showed superior WR than microhybrid (1.113*/1017). There was no significant difference in compressive stress among the groups. CONCLUSION: Silorane exhibited less polymerization shrinkage and shrinkage stress compared to methacrylates. Silorane and nanohybrid showed greater WR compared to microhybrid. CS of all groups was similar. PMID- 28836528 TI - Low-level laser therapy: A novel therapeutic approach to temporomandibular disorder - A randomized, double-blinded, placebo-controlled trial. AB - AIMS AND OBJECTIVE: The objective of this study was to assess the effectiveness of low-level laser therapy (LLLT)/low intensity laser therapy (LILT) in the management of temporomandibular joint (TMJ) pain in a random and double-blind research design. MATERIALS AND METHODS: TMJ pain patients, randomly assigned into two groups: Group 1 (n = 20) and Group 2 (n = 20), received 2-3 treatments per week for 8 sessions of active LILT with diode laser (gallium aluminum arsenide, 810 nm, 0.1 W). Measures of TMJ pain during function were evaluated at baseline, after completion of 8 sessions of laser treatment, and 30 days after the final laser therapy. RESULTS: At the final treatment point, within-group, pain reduction was observed in both active LLLT and placebo groups at day 0 (P = 0.000), 8th session (P = 0.000), and 1 month (P = 0.001). Between the groups, there is no significant difference at day 0 (P = 0.214), 8th session (P = 0.806), and 1 month (P = 0.230). Significant increased mouth opening was observed in both Group 1 and Group 2 (P = 0.006 and P = 0.021, respectively) after treatment. However, no significant difference was found between the two groups (P = 0.330). Furthermore, significant improvement in clicking was recorded before and after treatment both in Group 1 (P = 0.000) and Group 2 (P = 0.001). CONCLUSION: The study suggests that LLLT is not better than placebo at reducing TMJ pain during function. It may be assumed that a more tailored application of LLLT should be developed to take into account the multifactorial aspect of the disorder. PMID- 28836529 TI - Correlation of periodontitis with mandibular radiomorphometric indices, serum calcium and serum estradiol in postmenopausal women: A case-control study. AB - BACKGROUND: Osteoporosis and periodontitis have several risk factors in common. The majority of studies evaluating periodontal bone loss and systemic bone mineral density have found that low bone mineral density systemically is significantly associated with an increase in loss of alveolar bone height and periodontal destruction. Hence, the purpose of the study was to determine the effect of periodontitis on mandibular radiomorphometric indices, serum calcium and serum estradiol levels in postmenopausal women. MATERIALS AND METHODS: Forty female patients in the age group of 35-55 years were included in the study. The participants were divided into two equal groups, i.e., control group A (twenty - postmenopausal women with healthy periodontium) and study group B (twenty - postmenopausal women with periodontitis). A thorough clinical examination of all the forty patients was carried out to detect the presence of periodontitis on the basis of clinical attachment level. Quantitative indices were measured on digital panoramic radiographs, and serum calcium and estradiol levels were estimated. RESULTS: No statistically significant correlation of periodontitis with any of the radiomorphometric indices, serum calcium and serum estradiol levels was observed in postmenopausal women. CONCLUSION: There is little evidence of correlation of serum estradiol, serum calcium levels, and morphometric indices with periodontitis and therefore detailed further research about this correlation is required. PMID- 28836530 TI - Sialic acid as a biomarker of oral potentially malignant disorders and oral cancer. AB - BACKGROUND: Carcinogenesis is a multistep process where a healthy cell has initially a precancerous stage and finally an early cancerous stage. The process of carcinogenesis can be divided into three stages of initiation, promotion, and progression. In this process, there is increased turnover, secretion, and/or shedding from malignant cells. Glycoproteins like sialic acid are expressed on the cell surface. In oral potentially malignant disorders (OPMDs) and oral cancer (OC), the sialic acid level is seen to increase due to high cell turnover and shedding of malignant cells which, in turn, results in the release of glycoproteins like sialic acid into circulation. Glycoproteins also form an important constituent of salivary mucins and hence due to the same mechanism, an increase in sialic acid level is also seen in saliva. OBJECTIVE: The aim is to estimate serum and salivary sialic acid levels in healthy controls, patients with OPMDs and patients with OC. MATERIALS AND METHODS: In this observational cross sectional study, serum and salivary sialic acid levels were estimated in thirty healthy controls, thirty patients with OPMDs and thirty patients with OC. RESULTS: Serum and salivary sialic acid levels obtained were subjected to statistical analysis. Post hoc Tukey test was used to compare the serum and salivary sialic acid levels of the two study groups to the control group. ANOVA test was used for the comparison of sialic acid levels between the groups. Pearson's correlation coefficient was used to assess correlation (P < 0.05 was considered statistically significant). The mean serum and salivary sialic acid levels were increased significantly in subjects with OPMDs and OC when compared to healthy controls. CONCLUSION: This study highlights the high expression of sialic acid on outer cell membranes, due to the significant increase in subjects with OPMDs and OC when compared to healthy controls. A significant increase in sialic acid level is also seen in saliva. Hence, it can be stated that saliva can be used as a reliable, noninvasive tool in diagnosis and management of OPMDs and OC. PMID- 28836531 TI - Efficacy of protaper instruments during endodontic retreatment. AB - INTRODUCTION: The effectiveness of ProTaper Universal and ProTaper Retreatment rotary instruments was compared to the Hedstrom files in the removal of filling material from root canals. MATERIALS AND METHODS: Thirty-six extracted human mandibular premolars with a single straight root canal were shaped and filled with gutta-percha and AH Plus. The specimens were stored for 6 months at 37 degrees C and at 100% relative humidity, and then randomly divided into three groups: PTU - removal of filling material performed with ProTaper Universal instruments; PTR - removal of filling material performed with ProTaper Retreatment instruments; HF - removal of filling material performed with Gates Glidden burs, Hedstrom files and solvent. After the filling material removal and diaphanization, the specimens were longitudinally sectioned and images of the canal surfaces were scanned. The remaining areas of filling material were measured (Image Tool 3.0), and data was analyzed statistically (Kruskal-Wallis and Dunn tests). The time required for filling removal in each group was also recorded (one-way ANOVA and Tukey's HSD test). RESULTS: All groups presented remnants of filling material; PTU had the smallest amount and HF group presented the highest mean value (P< 0.05) in all the thirds. The cervical third had the smallest amount of material when compared with the other thirds (P< 0.05). HF group required a longer mean time, presenting significant difference (P< 0.05). CONCLUSION: Considering the time required and the amount of the filling removal, ProTaper Retreatment were not superior to ProTaper Universal, but both rotary instruments were more effective and less time-consuming than Hedstrom manual files. PMID- 28836532 TI - Comparative study: Oral mucosal lesions, signs and symptoms in diabetes mellitus patients with end stage renal disease with analogous findings in diabetes mellitus patients with non-end stage renal disease. AB - AIM: The aim of this study is to compare oral signs, symptoms and oral lesions type and prevalence, in end stage renal disease (ESRD) with non-end stage renal disease (NESRD) in diabetes mellitus (DM) patients. METHODOLOGY: Two groups of DM patients were studied, Group 1 includes 100 patients with ESRD, who were under hemodialysis therapy, and Group 2 includes100 patients with NESRD whose serum creatinine level is <2.0 mg/dl. The DM status and other laboratory investigations were recorded, with the patients consent and thorough oral examination was performed and the findings were recorded. All the data were entered into Microsoft Excel sheets. Statistical analysis including Pearson's correlation analysis, Chi-square test, and t-test were done using SPSS software SYSTAT version 7.0. RESULTS: On thorough clinical examination, the prevalence of oral lesions was found to be higher in ESRD patients. The most common lesions such as saburral tongue (P <= 0.002), petechiae/ecchymoses (P <= 0.000), pale mucosa (P <= 0.000), stomatitis medicamentosa (P <= 0.043) fissured tongue, smooth tongue, candidiasis, dry and fissured lips, angular cheilitis, uremic stomatitis, signs such as uremic fetor (P <= 0.000), xerostomia and symptoms like burning tongue, unpleasant taste are noted. CONCLUSION: The high prevalence of uremic fetor, saburral tongue, pale mucosa, and petechiae/ecchymoses in ESRD patient group can be considered as a possible sign of undiagnosed advanced stage of renal disease in other diabetic patients. PMID- 28836533 TI - Application of liquid-based cytology preparation in micronucleus assay of exfoliated buccal epithelial cells in road construction workers. AB - BACKGROUND: Asphalts are bitumens that consist of complex of hydrocarbon mixtures and it is used mainly in road construction and maintenance. AIM: This study was undertaken to evaluate the micronucleus (MN) assay of exfoliated buccal epithelial cells in road construction workers using liquid-based cytology (LBC) preparation. MATERIALS AND METHODS: Three different stains (May-Grunwald Giemsa, hematoxylin and eosin, and Papanicolaou) were used to evaluate the frequency of MN in exfoliated buccal epithelial of 100 participants (fifty road construction workers and fifty administrative staff) using LBC preparation. Statistical analysis was performed with Student's t-test, and P< 0.05 was considered statistically significant. RESULTS: The mean frequency of MN for cases was significantly higher than that of controls (P = 0.001) regardless of staining method used and also cases with exposure period of more than 5 years had statistically significant difference (P < 0.05) than cases with Conclusion: The present study concluded that workers exposed to asphalts during road construction exhibit a higher frequency of MN in exfoliated buccal epithelial cells and they are under the significant risk of cytogenetic damage. LBC preparation has potential application for the evaluation of frequency of MN. This technique may be advocated in those who are occupationally exposed to potentially carcinogenic agents in view of improvement in the smear quality and visualization of cell morphology. PMID- 28836534 TI - Determination of p16 overexpression as an indicator of human papillomavirus infection in oral dysplasia and carcinoma. AB - CONTEXT: Oral and pharyngeal cancer, grouped together, is the sixth most common cancer in the world. In the past few years, human papillomavirus (HPV) infection has been suggested as a risk factor for oral cancer apart from traditional risk factors such as smoking, tobacco, and alcohol consumption. AIMS: The aim of this study was to determine HPV status of the tumors using polymerase chain reaction (HPV-DNA PCR) and p16 immunostaining and to correlate p16 overexpression as an indicator of HPV-associated oral dysplasia and carcinoma. SETTINGS AND DESIGN: A prospective study was conducted in fifty cases of suspected oral cancer. MATERIALS AND METHODS: PCR Amplification of extracted HPV-DNA was done for HPV DNA status in fresh tissue of suspected oral cancer cases. Histomorphological features of the cases were analyzed, and p16 immunohistochemistry was performed on the same specimen after making paraffin blocks to study p16 overexpression. STATISTICAL ANALYSIS USED: Chi-square test was used to analyze the differences between discrete variables. RESULTS: 5/6 (83.3%) HPV-DNA-positive cases were positive for p16 expression, whereas 26/44 (59.09%) p16-positive cases which were negative for HPV-DNA. Sensitivity and specificity of p16 as a surrogate marker for HPV-DNA were found to be 83.3% and 40%, respectively. CONCLUSIONS: p16 immunostaining is a good first-line assay for eliminating HPV-negative cases from additional analysis, but other causes of p16 overexpression in oral tumorigenesis related to tobacco consumption in keratinizing squamous cell carcinoma needs to be explored further. PMID- 28836535 TI - Prevalence and pattern of lobular capillary hemangioma in Eastern Madhya Pradesh, India: A clinicopathological analysis. AB - BACKGROUND: Lobular capillary hemangioma is a common benign vascular tumor seen in the oral cavity. It occurs in response to various stimuli such as low-grade local irritation, traumatic insult, and hormonal factors or as a response to a wide variety of drugs. MATERIALS AND METHODS: All patients presenting to the Department of Dentistry, Shyam Shah Medical College, Rewa, Madhya Pradesh during July 2014 to June 2016, who were diagnosed by histopathologic confirmation as oral lobular capillary hemangioma (OLCH), were evaluated for the area involved, clinicopathologic presentation, demographic features, and treatment. RESULTS: A total of 94 cases were identified as OLCH by histopathologic confirmation during this period. The lesion occurred most commonly in the age group of 21-30 years. A characteristic female predominance (female: male ratio of 2.24:1) was seen. Anterior maxillary labial gingiva was most frequently involved (34.04%) followed by posterior maxillary buccal gingiva (14.89%). CONCLUSION: The clinicopathologic picture of OLCH found in this study was similar to other studies conducted on same as well different ethnic and geographical populations. Poor oral-dental hygiene was observed in majority of patients (87.23%) dental health education should be an integral component of imparting oral health care by health providers. Surgical excision as a treatment modality renders good results with low recurrence rate. PMID- 28836536 TI - Lip response to incisor movement in operated cleft lip and palate patients. AB - BACKGROUND: Although the literature has shown that the lip response to maxillary incisor retraction varies, these studies have been done on a noncleft lip/palate sample. AIM: The aim of this study is to evaluate response of operated cleft lip to orthodontic tooth movement and to determine if there are any differences in the response between the operated cleft lip and the noncleft lip. SETTINGS AND DESIGN: This was a hospital-based retrospective study using radiographs. MATERIALS AND METHODS: Lip changes were evaluated using pre- and post-operative lateral cephalometric radiographs. The experimental group consisted of 12 patients with operated cleft lip while the control group consisted of 12 noncleft patients with dental and skeletal Class I malocclusion. STATISTICAL ANALYSIS: ANOVA was used for statistical analysis. RESULTS: The operated lip responded less to incisor movement than the noncleft group (P < 0.05). While the cleft group demonstrated an increase in upper lip thickness measurements at Point A and vermilion following incisor retraction, the control group showed a decrease in thickness of the upper lip at Point A and an increase at vermilion. CONCLUSION: The cleft team should be aware that the operated lip responds differently to incisor movement. This will enable them to better plan comprehensive treatment for the cleft lip and palate patient. PMID- 28836537 TI - Effect of organic solvents compared to sandblasting on the repair bond strength of nanohybrid and nanofilled composite resins. AB - BACKGROUND: This study evaluated the effect of different surface treatments on the repair bond strength of nanohybrid (Empress Direct) and nanofilled (Filtek Z350 XT) composite resins. MATERIALS AND METHODS: A total of 120 specimens of each material (7.5 x 4.5 x 3 mm) were prepared and polished with SiC paper. Half of the specimens were kept in water for seven days and the other half for six months; they were then divided into six groups according to the type of surface treatment: negative control (no treatment), Al2O3sandblasted, liquid acetone, acetone gel, liquid alcohol and alcohol gel. Following application of the silane coupling agent and the adhesive system, composite resin cylinders were fabricated on the specimens and light cured (20 seconds). The same composite resins were used for the repair. Additionally, ten intact specimens of each composite resin (without repair) were prepared (positive control). The specimens were then loaded to failure in the microshear mode. Three additional specimens were fabricated in each group, and the surface treatments were analyzed by atomic force microscopy, energy-dispersive X-ray spectroscopy (EDS) and scanning electron microscopy (SEM). RESULTS: The nanofilled composite resin showed higher cohesive strength and repair bond strength than the nanohybrid composite resin. The aging process affected the repair bond strength of the nanofilled composite resin. Al2O3sandblasting was more efficient for the nanofilled composite resin and promoted greater surface roughness in both materials. The solvents demonstrated higher efficacy for the nanohybrid composite resin. CONCLUSION: The strengths resulting from the solvents were material dependent, and Al2O3sandblasting resulted in superior repair bond strength in both materials. PMID- 28836538 TI - A comparative study to determine strength of autopolymerizing acrylic resin and autopolymerizing composite resin influenced by temperature during polymerization: An In Vitro study. AB - AIM: Temporary coverage of a prepared tooth is an important step during various stages of the fixed dental prosthesis. Provisional restorations should satisfy proper mechanical requirements to resist functional and nonfunctional loads. A few studies are carried out regarding the comparison of the effect of curing environment, air and water, on mechanical properties of autopolymerizing acrylic and composite resin. Hence, the aim of this study was to compare the transverse strength of autopolymerizing acrylic resin and autopolymerizing composite resin as influenced by the temperature of air and water during polymerization. MATERIALS AND METHODS: Samples of autopolymerizing acrylic resin and composite resin were prepared by mixing as per manufacturer's instructions and were placed in a preformed stainless steel mold. The mold containing the material was placed under different controlled conditions of water temperature and air at room temperature. Polymerized samples were then tested for transverse strength using an Instron universal testing machine. RESULTS: Alteration of curing condition during polymerization revealed a significant effect on the transverse strength. The transverse strength of acrylic resin specimens cured at 60 degrees C and composite resin specimens cured at 80 degrees C was highest. Polymerizing the resin in cold water at 10 degrees C reduced the mechanical strength. CONCLUSIONS: Polymerization of the resin in hot water greatly increased its mechanical properties. The method of placing resin restoration in hot water during polymerization may be useful for improving the mechanical requirements and obtaining long-lasting performance. PMID- 28836539 TI - Effects of two desensitizing dentifrices on dentinal tubule occlusion with citric acid challenge: Confocal laser scanning microscopy study. AB - BACKGROUND: Dentin hypersensitivity results when patent tubules are exposed to pain-inducing external stimuli. AIM: This study aims to compare the effects of two desensitizing dentifrices containing NovaMin and arginine on dentinal tubule occlusion with and without citric acid challenge in vitro using confocal laser scanning microscopy (CLSM). MATERIALS AND METHODS: Forty dentin discs were randomly divided into Groups I and II containing twenty specimens each, treated with NovaMin and arginine-containing dentifrices, respectively. Groups I and II were divided into subgroups A and B where IA and IIA underwent CLSM analysis to determine the percentage of tubule occlusion while IB and IIB underwent 0.3% citric acid challenge and CLSM analysis. A novel grading system was devised to categorize tubule occlusion. RESULTS: In Group II, the percentage of occluded tubules was highest for IIA (72.25% +/- 10.57%) and least for IIB (42.55% +/- 8.65%) having statistical significance (P < 0.0005). In Group I, the difference between IA (49.9% +/- 12.96%) and IB (43.15% +/- 12.43%) was statistically insignificant (P = 0.249). On the comparison between IB and IIB statistically indifferent result was obtained (P = 0.901), whereas the difference between IA and IIA was statistically significant (P < 0.001). The results of grading system were for IA 50% of samples belonged to Grade 2, for IIA 60% - Grade 3, and for IB 70% and for IIB 90% - Grade 2. CONCLUSION: Dentinal tubule occlusion with arginine-containing dentifrice was significantly higher than NovaMin. However, it could not resist citric acid challenge as effectively as NovaMin. The effects of NovaMin were more sustainable as compared to arginine-containing dentifrice, thus proving to be a better desensitizing agent. PMID- 28836540 TI - Gingival fibromatosis with hypertrichosis syndrome: Case series of rare syndrome. AB - Gingival fibromatosis with hypertrichosis syndrome is an extremely rare genetic condition characterized by profound overgrowth of hair and gums, as well as other variable features. Gingival fibromatosis is characterized by a large increase in the gingival dimension which extends above the dental crowns, covering them partially or completely. They were found to have a genetic origin, may also occur in isolation or be part of a syndrome, or acquired origin, due to specific drugs administered systemically. Congenital generalized hypertrichosis is a heterogeneous group of diseases with continuing excessive growth of terminal hair without androgenic stimulation. It has informally been called werewolf syndrome because the appearance is similar to that of a werewolf. Various syndromes have been associated with these features such as epilepsy, mental retardation, cardiomegaly, or osteochondrodysplasia. As so far very few cases have been reported in literature, we are reporting a series of three cases with management of the same. The excess gingival tissues, in these cases, were removed by conventional gingivectomy under general anesthesia. The postoperative result was uneventful and the patient's appearance improved significantly. Good esthetic result was achieved to allow patient to practice oral hygiene measures. Though this is not a serious condition clinically, psychosocial trauma cannot be neglected owing to the cosmetic disfigurement it produces. PMID- 28836541 TI - Laser-assisted multidisciplinary approach for closure and prevention of relapse of midline diastema. AB - Midline diastema, which occurs as spacing between the upper central incisors, is a common occurrence seen in the pediatric population. In the ugly duckling stage of development; no treatment is generally advocated as the diastema is a transient one. When diastemas occur due to other pathologies, they pose several problems in relation to esthetics and speech in a growing child. With the advent of time, patient's demand for esthetics has greatly increased. Along with this, a less time-consuming treatment option is a favorite. Proper diagnosis of the diastema, unfolding its etiology, helps in devising an adequate treatment plan. This eventually will lead to stability of the final result. The present case report presents a different and unique approach for the esthetic closure of midline diastema following frenectomy procedure. The approach proves to be a quick and simple option for closure of midline diastemas in cases with concomitant incisal edge irregularities. PMID- 28836542 TI - Adolescent tobacco menace: Attitudes, norms, and parental influence. AB - BACKGROUND: Adolescence is a very delicate and vulnerable age when children are exposed to the harmful and damaging culture of the society. Tobacco habits are increasingly becoming an annoying menace to the Indian society since the past few years. The teenage group is fast catching up the tobacco habits because of its easy availability in the local Indian markets. Thus, this study was envisaged to analyze the factors responsible for this adverse habit and to obtain an overview of the trends in tobacco habits in young children of North India. METHODS: Eight hundred and sixteen schoolchildren in the age group of 14-19 years of different schools of Meerut city were instructed to fill the prepared questionnaires. Results were formulated and statistical analysis was done. RESULTS: Chi-square analysis revealed significant difference between tobacco users and nonusers. Smokeless habit was more prevalent among adolescent boys. Peer pressure was the most cited reason for initiating the tobacco habit while parental influence helped the most in abstaining from this adverse addiction. CONCLUSION: Despite the existence of anti-tobacco regulations in India, tobacco dependence in adolescents raises an alarm for the Indian community and stringent steps are required to remove this menace. PMID- 28836543 TI - Allergy and Chronic Obstructive Pulmonary Disease. PMID- 28836544 TI - Multidrug-resistant Tuberculosis Burden among the New Tuberculosis Patients in Zhejiang Province: An Observational Study, 2009-2013. AB - BACKGROUND: Screening on multidrug-resistant tuberculosis (MDR-TB) has been limited to the serious TB subpopulations excluding the new TB patients. This study aimed to examine MDR-TB burden among the new TB patients. METHODS: We conducted a study in Zhejiang Province during 2009-2013 to screen for MDR-TB patients among the low MDR-TB risk patients and five subpopulations of high MDR TB risk patients. The number, prevalence, and trend of MDR-TB were compared while the logistic regression model was used to examine risk factors related to MDR-TB. RESULTS: A total of 200 and 791 MDR-TB cases were, respectively, identified from the 9830 new TB cases and 2372 high-risk suspects who took MDR-TB screening from 2009 to 2013. The MDR-TB rates went down in both of the new TB patients and five MDR-TB high-risk groups over the study time, but the percentage of MDR-TB patients identified from the new TB patients in all diagnosed MDR-TB cases kept stable from 28.3% in 2011 to 27.0% in 2012 to 26.0% in 2013. CONCLUSIONS: The study indicated that MDR-TB burden among new TB patients was high, thus screening for MDR-TB among the new TB patients should be recommended in China as well as in the similar situation worldwide. PMID- 28836545 TI - Characteristics of Proinflammatory Cytokines and Chemokines in Airways of Asthmatics: Relationships with Disease Severity and Infiltration of Inflammatory Cells. AB - BACKGROUND: Increased proinflammatory cytokines and chemokines might contribute to infiltration of inflammatory cells and remodeling in airways of asthma. Although these molecules may be associated with asthma, there is lack of systemic evidence showing which and how important these events are in the disease. We aimed to analyze the concentrations of these molecules in the airways and relationships with disease severity and with airway infiltration of inflammatory cells in a large cohort of asthmatics (n = 70, including 37 mild and 33 moderate/severe asthmatics) compared with controls (n = 30). METHODS: Meso scale discovery system and commercial ELISA kits were used to measure the concentrations of proinflammatory cytokines interleukin (IL)-1beta; tumor necrosis factor-alpha (TNF-alpha); IL-6; and IL-17 and CC and CXC chemokines CCL2, CCL4, CCL11, CCL13, CCL17, CCL22, and CCL26 and CXCL8, CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid of asthmatics and controls. RESULTS: The concentrations of IL-1, TNF-alpha, IL-6, CXCL8 and CXCL10, and CCL4, CCL11, CCL17, and CCL22 were significantly elevated in asthmatics compared with controls (P < 0.05). The concentrations of TNF-alpha and CXCL8, but not others, were negatively correlated with severity of disease (lung function forced expiratory volume in 1 s) (TNF-alpha vs. total: r = -0.359, P= 0.002 vs. moderate/severe: r= -0.541, P= 0.001; CXCL8 vs. total: r = -0.327, P= 0.006 vs. moderate/severe: r = 0.625, P= 0.0001, respectively). In addition, concentrations of these two molecules were also correlated with the absolute numbers of infiltrating eosinophils and neutrophils in asthmatic airways. CONCLUSIONS: Increased concentrations of TNF-alpha and CXCL8 are associated with pathogenesis of asthma. Targeting these molecules might provide an alternative therapeutic for this disease. PMID- 28836546 TI - Comparison of Space Glucose Control and Routine Glucose Management Protocol for Glycemic Control in Critically Ill Patients: A Prospective, Randomized Clinical Study. AB - BACKGROUND: The Space Glucose Control (SGC) system is a computer-assisted device combining infusion pumps with the enhanced Model Predictive Control algorithm to achieve the target blood glucose (BG) level safely. The objective of this study was to evaluate the efficacy and safety of glycemic control by SGC with customized BG target range of 5.8-8.9 mmol/L in the critically ill patients. METHODS: It is a randomized controlled trial of seventy critically ill patients with mechanical ventilation and hyperglycemia (BG >= 9.0 mmol/L). Thirty-six patients in the SGC group and 34 in the routine glucose management group were observed for three consecutive days. Target BG for both groups was 5.8-8.9 mmol/L. The primary outcome was the percentage time in the target range. RESULTS: The percentage time within BG target range in the SGC group (69 +/- 15%) was significantly higher than in the routine management group (52 +/- 24%; P< 0.01). No measurement was <=2.2 mmol/L, and there was only one episode of hypoglycemia (2.3-3.3 mmol/L) in each group. The average BG was significantly lower in the SGC group (7.8 +/- 0.7 mmol/L) than in the routine management group (9.1 +/- 1.6 mmol/L, P< 0.001). Target BG level was reached earlier in the SGC group than routine management group (2.5 +/- 2.9 vs. 12.1 +/- 15.3 h, P= 0.001). However, the SGC group performed worse for daily insulin requirement (59.8 +/- 39.3 vs. 28.4 +/- 36.7 U, P= 0.001) and sampling interval (2.0 +/- 0.5 vs. 3.7 +/- 0.5 h, P< 0.001) than the routine management group did. Multiple linear regression showed that the intervention group remained a significant individual predictor (P < 0.001) of the percentage time in target range. CONCLUSIONS: The SGC system, with a BG target of 5.8-8.9 mmol/L, resulted in effective and reliable glycemic control with few hypoglycemic episodes in critically ill patients with mechanical ventilation and hyperglycemia. However, the workload was increased. TRIAL REGISTRATION: http://www.clinicaltrials.gov, NCT 02491346; https://www.clinicaltrials.gov/ct2/show/NCT02491346?term=NCT02491346&cond=Hypergl cemia&cntry1=ES%3ACN&rank=1. PMID- 28836547 TI - Trends in Antimicrobial Resistance against Enterobacteriaceae Strains Isolated from Blood: A 10-year Epidemiological Study in Mainland China (2004-2014). AB - BACKGROUND: Antimicrobial resistance is a serious problem that compromises the empirical treatment of infections, resulting in a lack of effective antibiotics and high medical expenses. Here, we aimed to monitor the trends in antimicrobial resistance among Enterobacteriaceae isolated from blood samples in mainland China. METHODS: A total of 2240 Enterobacteriaceae isolates from blood were collected from hospitalized patients at 19 tertiary hospitals between October 2004 and June 2014. The minimum inhibitory concentrations of all isolates were determined using the agar dilution method according to the Clinical and Laboratory Standards Institute 2016 guidelines. RESULTS: The most commonly isolated bacteria were Escherichia coli, compromising 47.0% (1053/2240) of the total isolates, followed by Klebsiella spp. (26.3%), Salmonella spp. (10.4%), and Enterobacter spp. (9.2%). The detection rates of extended-spectrum beta lactamases (ESBLs) among E. coli were 68.9% (2004-2005), 73.2% (2007-2008), 67.9% (2009-2010), 72.6% (2011-2012), and 58.4% (2013-2014), whereas those in ESBL producing Klebsiella pneumoniae were slightly decreased (75.9%, 50.0%, 41.4%, 40.2%, and 43.0%, respectively). Carbapenems were the most potent agents against the Enterobacteriaceae isolates, followed by moxalactam, tigecycline, and amikacin. However, there was a decrease in the susceptibility rates for carbapenems in all species, particularly K. pneumoniae(decreased by 10.6% for imipenem) and Enterobacter aerogenes (decreased by 21.1% for imipenem). Reviving antibiotics (tigecycline and polymyxins) showed good in vitro activity against Enterobacteriaceae. CONCLUSIONS: The activity of antibiotics against Enterobacteriaceae isolated from blood was decreased overall. Large proportions of ESBL-producing isolates were identified among E. coli and Klebsiella spp. Carbapenem-resistant isolates have become a major challenge in the treatment of infections. PMID- 28836548 TI - Epidemiological Survey and Risk Factor Analysis of Recurrent Spontaneous Miscarriages in Infertile Women at Large Infertility Centers. AB - BACKGROUND: A higher frequency of spontaneous miscarriage has been observed in infertile couples, and there is a higher prevalence of infertility among patients with a history of recurrent spontaneous miscarriages (RSMs; >=2 miscarriages). This study aimed to determine the proportion of infertile patients with RSM and examine risk factors associated in patients with RSM being treated with assisted reproductive technologies. METHODS: This cross-sectional observational study was conducted at six reproductive medicine centers in three cities of China. Data of 751 patients with at least one spontaneous miscarriage were analyzed. Demographic data and etiological factors associated with infertility were compiled and compared between patients with a single spontaneous miscarriage (SSM) and those with RSM. RESULTS: Two hundred (26.6%, 95% confidence interval [CI]: 23.50 29.95%) patients experienced RSMs and 551 (73.4%) had a single miscarriage. The odds of RSM increased with increasing age (odds ratio [OR] = 1.06), uterine disorders (OR = 2.09), endocrine disorders (OR = 2.48), and immune disorders (OR = 2.98). Higher education level, masters or above, and a pelvic cavity disorder were associated with lower risk of RSM (OR = 0.27 and 0.46, respectively). Late spontaneous miscarriages were more frequent in patients with RSM than in those with a SSM (31.5% vs. 14.2%, respectively, P< 0.001) and were associated with a history of uterine cavity procedures (OR = 2.095) and cervical factors related to infertility (OR = 4.136, 95% CI: 1.012-16.90). CONCLUSIONS: Compared to patients with only a SSM, the conditions of patients with RSM are more complicated. To increase the success rate of assisted reproductive technology, factors including uterus cavity adhesion, cervical relaxation, endocrine disorders, and immune disorders should be treated before assisted reproduction is initiated. These data may provide treatment guidance for infertile patients with a history of RSM. PMID- 28836549 TI - Validation of the Pretreatment Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor in a Large Cohort of Chinese Patients with Upper Tract Urothelial Carcinoma. AB - BACKGROUND: The pretreatment neutrophil-to-lymphocyte ratio (NLR) has been reported to be a prognostic factor in various types of carcinomas. The aim of this study was to investigate the prognostic value of pretreatment NLR in a large cohort of Chinese patients with upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively analyzed the medical data of 656 UTUC patients who underwent radical nephroureterectomy (RNU) from 2001 to 2011 at Peking University First Hospital. Receiver operating characteristic (ROC) curve analysis was performed to calculate the optimal cutoff point of pretreatment NLR. Uni- and multi-variate analyses were used to identify the prognostic factors for cancer-specific survival (CSS) and intravesical recurrence-free survival (IVRFS). RESULTS: The optimal cutoff point of pretreatment NLR was 2.40 by ROC curves, by which patients with high NLR (NLR >=2.40) and low NLR (NLR <2.40) accounted for 314 (47.9%) and 342 (52.1%) patients, respectively. Patients with a high pretreatment NLR tended to have high tumor grades (chi2 = 15.725, P< 0.001), high tumor stages (chi2 = 25.416, P< 0.001), tumor sizes >5 cm (chi2 = 8.213, P= 0.005), ipsilateral hydronephrosis (chi2 = 4.624, P= 0.033), and concomitant carcinoma in situ(CIS) (chi2 = 9.517, P= 0.003). A high pretreatment NLR (hazard ratio [HR] = 1.820, P= 0.001), main tumor diameter >5 cm (HR = 1.789, P= 0.009), lymph node metastasis (HR = 1.863, P= 0.024), and high tumor stage (HR = 1.745, P< 0.001) independently predicted poor CSS after surgery, while only concomitant carcinoma in situ(CIS) (HR = 2.164, P= 0.034), ureteroscopy before surgery (HR = 1.701, P= 0.015), and high tumor grade (HR = 1.645, P= 0.018) were independent predictors of IVRFS after RNU. CONCLUSIONS: The pretreatment NLR was related to some adverse clinicopathological features and was an independent predictor of CSS, although not IVRFS, in Chinese UTUC patients. PMID- 28836550 TI - Predictive models of adjuvant chemotherapy for patients with stage ii colorectal cancer: A retrospective study. AB - BACKGROUND: It remains controversial whether patients with Stage II colorectal cancer would benefit from adjuvant chemotherapy after radical resection. The aim of this study was to establish two mathematical models to identify the suitable patients for adjuvant chemotherapy. METHODS: The current study comprised of two steps. In the first step, 353 patients with Stage II colorectal cancer who underwent surgical procedures at the Third Affiliated Hospital of Sun Yat-sen University between June 2006 and December 2015 were entered and followed up for 6 120 months. Their clinical data were collected and enrolled into the database. We established two mathematical models by univariate and multivariate Cox regression analysis to identify the target patients; in the second step, 230 patients under the same standard between January 2012 and December 2016 were entered and followed up for 3-62 months to verify the two models' validation. RESULTS: In the first step, totally 340 surgical patients with Stage II colorectal cancer were finally enrolled in this study. Statistical analysis showed that tumor differentiation (TD) (P < 0.001), lymphovascular invasion (LVI) (P < 0.001), uncertain or positive margins (UPM) (P < 0.001), and fewer lymph nodes (LNs) (<12) retrieved (P < 0.001) were correlated with the overall survival (OS) and disease free survival (DFS). We obtained two models: (1) OS risk score = 1.116 * TD + 2.202 * LVI + 3.676 * UPM + 1.438 * LN - 0.493; (2) DFS risk score = 0.789 * TD + 2.074 * LVI + 3.183 * UPM + 1.329 * LN - 0.432. According to the models and cutoff points [(0.07, 1.33) and (-0.04, 1.30), respectively], patients can be divided into three groups: low-risk, moderate-risk, and high-risk. Moreover, the high-risk group patients could benefit from adjuvant chemotherapy. In the second step, totally 221 patients were finally used to verify the models' validation. The results proved that the models were accurate and feasible (P< 0.05). CONCLUSIONS: According to the predictive models, patients with Stage II colorectal cancer in the high-risk group are strongly recommended for adjuvant chemotherapy, thus facilitating the individualized and precise treatment. PMID- 28836551 TI - Clinical Characteristics of Bloodstream Infections in Pediatric Acute Leukemia: A Single-center Experience with 231 Patients. AB - BACKGROUND: Acute leukemia is the most common pediatric hematological malignancy. Bloodstream infections (BSIs) are severe complications in these patients during chemotherapy. This study aimed to explore the clinical presentation and etiology of BSI, as well as the common sites of infection, and to provide a basis for the rational regarding antibiotic use. METHODS: We performed a retrospective chart review of all pediatric patients who had acute leukemia accompanied by a BSI in our hospital from December 2011 to September 2015. All patients were selected based on clinical presentation and had to have at least one positive blood culture for inclusion. The basic clinical characteristics, blood culture results, and antimicrobial susceptibilities were analyzed. RESULTS: All 231 patients had a fever; of them, 12 patients continued to have a fever. Twenty-five patients had nonremitting (NR) leukemia, and 206 patients achieved complete remission (CR). Differences in the duration of fever between the NR and CR groups were significant (9.6 +/- 7.9 vs. 5.1 +/- 3.8 days, P= 0.016). One hundred and eighty patients had agranulocytosis. Differences in fever duration between the agranulocytosis and nonagranulocytosis groups were significant (6.2 +/- 5.1 vs. 4.1 +/- 2.6 days, P= 0.001). The other sites of infection in these 231 patients were the lung, mouth, digestive tract, and rectum. Blood culture comprised 2635 samples. There were 619 samples, which were positive. Of the 619 positive blood culture samples, 59.9% had Gram-negative bacteria, 39.3% had Gram-positive bacteria, and 0.8% had fungus. The primary pathogens were Pseudomonas aeruginosa, Enterobactercloacae, Escherichia coli, and Klebsiella pneumoniae. Of these 231 patients, 217 patients were cured. The effective treatment ratio was 94%. CONCLUSIONS: Gram-negative bacteria were the main pathogenic bacteria in patients with acute leukemia in our center. NR primary illness, agranulocytosis, and drug resistant pathogenic bacteria were all risk factors for poor prognosis. PMID- 28836552 TI - Development and Initial Validation of the Novel Scale for Assessing Quality of Life of Prostate Cancer Patients Receiving Androgen Deprivation Therapy. AB - BACKGROUND: There has been no a specific scale to measure quality of life (QOL) for prostate cancer patients receiving androgen deprivation therapy (ADT) to date. This study aimed to develop and initially validate the scale to evaluate QOL for prostate cancer patients receiving ADT. METHODS: The scale was developed following international recommendations. Moreover, the items were all generated through literature review and referenced questionnaires. After being reviewed by expert panelists, the revised scale was formed and then completed by a convenience sample of 200 prostate cancer patients from our hospital. Explore factor analysis (EFA) was applied to test the construct validity, then split-half reliability, Cronbach's alpha, and test-retest reliability were applied to assess the reliability and stability of the scale. RESULTS: The revised scale contained 22 items and a total of 200 participants had completed the scale. One hundred participants were randomly selected from the total 200 participants to perform EFA with varimax rotation on the revised scale, and "hot flashes" item was deleted for low factor loading. We selected only 3 items from each factor, then, the final scale was formed with 18-items. We selected another 100 participants to perform the EFA again on the final scale. It was demonstrated that the structure with 6 factors explained 72.5% of total variance and factor loading value was above 0.40 in all items of the factors. Moreover, the split-half reliability coefficient, Cronbach's alpha, and test-retest reliability coefficient were calculated to be 0.74, 0.63, and 0.89, respectively, exhibiting good reliability on the whole. CONCLUSIONS: The scale was identified to be a valid and reliable instrument to measure QOL for prostate cancer patients receiving ADT. Moreover, further research is needed to overcome the potential drawbacks. PMID- 28836553 TI - Depression, anxiety, and quality of life in paroxysmal kinesigenic dyskinesia patients. AB - BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder characterized by recurrent dystonic or choreoathetoid attacks triggered by sudden voluntary movements. Under the condition of psychological burden, some patients' attacks may get worsened with longer duration and higher frequency. This study aimed to assess nonmotor symptoms and quality of life of patients with PKD in a large population. METHODS: We performed a cross-sectional survey in 165 primary PKD patients from August 2008 to October 2016 in Rui Jin Hospital, using Symptom Check List-90-Revised (SCL-90-R), World Health Organization Quality of Life-100 (WHOQoL-100), Self-Rating Depression Scale, and Self-Rating Anxiety Scale. We evaluated the differences of SCL-90-R and WHOQOL-100 scores in patients and Chinese normative data (taken from literature) by using the unpaired Student's t test. We applied multivariate linear regression to analyze the relationships between motor manifestations, mental health, and quality of life among PKD patients. RESULTS: Compared with Chinese normative data taken from literature, patients with PKD exhibited significantly higher (worse) scores across all SCL-90 R subscales (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism; P= 0.000 for all) and significantly lower (worse) scores of five domains in WHOQoL-100 (physical domain, psychological domain, independence domain, social relationship domain, and general quality of life; P= 0.000 for all). Nonremission of dyskinesia episodes (P = 0.011) and higher depression score (P = 0.000) were significantly associated with lower levels of quality of life. The rates of depression and anxiety in patients with PKD were 41.2% (68/165) and 26.7% (44/165), respectively. CONCLUSIONS: Depression, anxiety, and low levels of quality of life were prevalent in patients with PKD. Co-occurrence of depression and anxiety was common among these patients. Regular mental health interventions could set depression and anxiety as intervention targets. Considering that the motor episodes could be elicited by voluntary movements and sometimes also by emotional stress, and that symptoms may get worsened with longer duration and higher frequency when patients are stressed out, intervention or treatment of depression and anxiety might improve the motor symptoms and overall quality of life in PKD patients. PMID- 28836554 TI - Outcomes of Chimney and/or Periscope Techniques in the Endovascular Management of Complex Aortic Pathologies. AB - BACKGROUND: The chimney/periscope technique has been used to address complex aortic pathologies. This study aimed to report the outcomes and experiences of chimney and/or periscope grafts (CPGs) used in the endovascular management of complex aortic pathologies. METHODS: Twenty-two patients with complex aortic pathologies were retrospectively studied from January 2013 to August 2016 in two vascular centers of teaching hospitals. All patients were diagnosed using computed tomography angiography (CTA). The patients were followed up at postoperative 1, 3, 6, and 12 months and yearly thereafter with X-ray, ultrasound, and/or CTA. RESULTS: Twenty-two cases (17 males; mean age 60.7 +/- 16.3 years) with complex aortic pathologies were analyzed. Nineteen patients underwent CPGs only, and the other three cases underwent the simultaneous implantation of chimney/periscope and fenestrated/scallop grafts. Twenty-six arteries were managed with forty CPGs during the procedures. Complete angiographies revealed two Type I endoleaks, one Type III endoleak, and one Type IV endoleak. Other intraoperative complications included brachial thrombosis, external iliac artery rupture, and left renal stenosis. The 30-day mortality was 0. The mean follow-up was 26.1 +/- 10.1 months with a range of 2-39 months. During the follow-up, two Type I endoleaks and one Type IV endoleak were observed. One right renal stent occlusion occurred in the 5th month and turned patent after reintervention. Three patients died during the follow-up, one due to an aneurysm rupture as a Type I endoleak, and two due to myocardial infarction. The instant technical success was 96%. The primary and secondary patencies were 92% and 96%, respectively. The overall survival rates were 95%, 84%, and 84% at 12, 24, and 36 months, respectively. Stent migration was not observed in any patient. CONCLUSIONS: Chimney/periscope techniques could be used to tackle complex aortic pathologies, but the indications must be strictly controlled, and additional experiences are required. PMID- 28836555 TI - Upregulation of Interleukin 21 and Interleukin 21 Receptor in Patients with Dermatomyositis and Polymyositis. AB - BACKGROUND: The immunopathologic mechanism underlying dermatomyositis (DM) and polymyositis (PM) remains poorly understood. Many cytokines play a pathogenic role in DM and PM. Interleukin 21 (IL-21) has a pleiotropic effect on inflammation regulation. This study aimed to detect the serum IL-21 level and investigate the expression of IL-21 and IL-21 receptor (IL-21R) in muscle tissues of patients with DM and PM. METHODS: Biopsied muscle samples were obtained from 11 patients with DM, 12 with PM, and six controls; mRNA levels of IL-21 and IL 21R were analyzed by real-time quantitative reverse transcription-polymerase chain reaction; and immunohistochemical staining was used to evaluate the protein expression of IL-21 and IL-21R. Serum samples were obtained from 36 patients with DM, 19 with PM, and 20 healthy controls. The serum IL-21 level was detected by enzyme-linked immunosorbent assay. RESULTS: The expression of IL-21 was upregulated in patients with DM and PM. The IL-21 mRNA level was significantly increased in muscle tissues of patients with DM and PM (DM vs. control, P= 0.001; PM vs. control, P= 0.001), whereas IL-21R mRNA level in patients with DM/PM was not statistically different from that of healthy controls. Immunohistochemical staining showed both IL-21 and IL-21R were significantly expressed in the inflammatory cells in muscle tissues of patients with DM and PM. The serum IL-21 level was also significantly higher in patients with DM/PM than in controls (DM vs. control, 49.12 [45.28, 60.07] pg/ml vs. 42.54 [38.69, 48.85] pg/ml, P= 0.001; PM vs. control, 50.77 [44.19, 60.62] pg/ml vs. 42.54 [38.69, 48.85] pg/ml, P= 0.005). CONCLUSIONS: IL-21 expression is upregulated in patients with DM and PM in both muscle tissue and serum. In addition, IL-21R protein is highly expressed in affected muscle tissues of patients with DM and PM. IL-21 may play a pathogenic role through IL-21R in patients with DM and PM. PMID- 28836556 TI - Epinephrine in Out-of-hospital Cardiac Arrest: Helpful or Harmful? AB - OBJECTIVE: Epinephrine is the primary drug administered during cardiopulmonary resuscitation (CPR) to reverse cardiac arrest. The evidence for the use of adrenaline in out-of-hospital cardiac arrest (OHCA) and in-hospital resuscitation is inconclusive. We conducted a systematic review on the clinical efficacy of adrenaline in adult OHCA patients to evaluate whether epinephrine provides any overall benefit for patients. DATA SOURCES: The EMBASE and PubMed databases were searched with the key words "epinephrine," "cardiac arrest," and variations of these terms. STUDY SELECTION: Data from clinical randomized trials, meta analyses, guidelines, and recent reviews were selected for review. RESULTS: Sudden cardiac arrest causes 544,000 deaths in China each year, with survival occurring in <1% of cases (compared with 12% in the United States). The American Heart Association recommends the use of epinephrine in patients with cardiac arrest, as part of advanced cardiac life support. There is a clear evidence of an association between epinephrine and increased return of spontaneous circulation (ROSC). However, there are conflicting results regarding long-term survival and functional recovery, particularly neurological outcome, after CPR. There is currently insufficient evidence to support or reject epinephrine administration during resuscitation. We believe that epinephrine may have a role in resuscitation, as administration of epinephrine during CPR increases the probability of restoring cardiac activity with pulses, which is an essential intermediate step toward long-term survival. CONCLUSIONS: The administration of adrenaline was associated with improved short-term survival (ROSC). However, it appears that the use of adrenaline is associated with no benefit on survival to hospital discharge or survival with favorable neurological outcome after OHCA, and it may have a harmful effect. Larger placebo-controlled, double-blind, randomized control trials are required to definitively establish the effect of epinephrine. PMID- 28836557 TI - 18F-fluorodeoxyglucose Uptake with Expression of Excision Repair Cross complementary Group 1 and Ribonucleotide Reductase Subunit M1 in Non-small Cell Lung Cancer. PMID- 28836558 TI - Efficacy of the DumonTM Stent in the Treatment of Airway Gastric Fistula: A Case Series Involving 16 Patients. PMID- 28836559 TI - Early Treatment for Laser-induced Maculopathy. PMID- 28836560 TI - Imaging Features of Primary Cardiac Lymphoma. PMID- 28836561 TI - Castleman's Disease: A Rare Mass in the Pararenal Retroperitoneum that Mimics Other Tumors. PMID- 28836562 TI - A Novel Case of Pulmonary Nocardiosis with Secondary Hemophagocytic Lymphohistiocytosis. PMID- 28836563 TI - A Case of Inflammatory Fibroid Polyp with an Elongated Shape in Cecum. PMID- 28836565 TI - A Rare Case of Lupus Vulgaris with Papulonecrotic Tuberculid and Discoid Lupus Erythematosus. PMID- 28836564 TI - Pyoderma Gangrenosum as the Initial Manifestation of Small Cell Lung Cancer with Dermatomyositis. PMID- 28836566 TI - Atrial Premature Contractions Arising from the Right Atrial Appendage. PMID- 28836567 TI - Primary Small Intestinal Diffuse Large B-cell Lymphoma Masquerading as Crohn's Disease: A Case Report. PMID- 28836568 TI - Idiopathic Pulmonary Fibrosis: A Systemic Disease? PMID- 28836569 TI - Promising of Multidrug-resistant Tuberculosis Screening among New Tuberculosis Patients in China. PMID- 28836570 TI - Thirty-day Postoperative Complications following Primary Total Knee Arthroplasty: A Retrospective Study of Incidence and Risk Factors at a Single Center in China. AB - BACKGROUND: Total knee arthroplasty (TKA) may be associated with serious complications that adversely affect outcomes and increase the likelihood of disability. However, few studies with sufficient sample size have reported postoperative complications following TKA among Chinese patients. This study aimed to evaluate complications of TKA within 30 postoperative days and to identify the related risk factors. METHODS: A retrospective complication-based analysis of TKA using the arthroplasty registry between 2008 and 2013 was performed by summarizing complications of TKA within 30 postoperative days. Multivariate logistic regression was used to identify the predicting factors for complications 30 days after operation. RESULTS: A total of 1542 patients underwent 2254 primary TKA between January 2008 and December 2013. A total of 137 complications occurred within 30 days after operation with an incidence rate of 6.1%. The incidence rate of major systemic complications within postoperative 30 days was 2.3%, with cardiovascular and respiratory complications as the most common complications. The incidence rates of deep venous thrombosis (DVT) and local complications were 2.4% and 1.0%, respectively. The 30-day postoperative mortality rate was 0.1% (3/2254). Multivariate logistic regression analyses identified body mass index (BMI) of >=30.0 kg/m2 (odds ratio [OR]: 1.47) and age >=80 years (OR: 1.87) as significant risk factors for postoperative systemic complications. A BMI of >=30.0 kg/m2 was a significant risk factor for DVT (OR: 2.86) and other complications (OR: 2.11). The comorbidity of diabetes was a risk factor for postoperative mortality (OR: 19.20). CONCLUSIONS: This study highlighted complications with cardiac and respiratory origins as the most common complications within 30 postoperative days following primary TKA. The BMI of >=30.0 kg/m2 and age >=80 years were significant risk factors for 30-day postoperative complications. PMID- 28836571 TI - Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury. AB - Background:: Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kappaB) signaling pathway. Methods:: C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-kappaB were investigated by immunofluorescence double staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-kappaB expressions were also detected. Results:: In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-kappaB, functional and histologic results showed that the inhibition of TLR4 or NF-kappaB alleviated glycerol-induced renal damages (P < 0.01). CLI-095 or PDTC administration suppressed proinflammatory cytokine (TNF-alpha, IL-6, and IL-1beta) production and macrophage infiltration into the kidney (P < 0.01). Moreover, in an in vitro study, CLI-095 or PDTC suppressed myoglobin-induced expression of TLR4, NF-kappaB, and proinflammatory cytokine levels in macrophage RAW264.7 cells (P < 0.01). Conclusion:: The pharmacological inhibition of TLR4/NF kappaB exhibited protective effects on rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration. PMID- 28836572 TI - Elevated Levels of Very Low-density Lipoprotein Cholesterol Independently Associated with In-stent Restenosis in Diabetic Patients after Drug-eluting Stent Implantation. AB - BACKGROUND: High rate of in-stent restenosis (ISR) remained an unsolved clinical problem in clinical practice, especially among patients with diabetes mellitus (DM). Diabetic patients often had hypertriglyceridemia with elevated levels of very low-density lipoprotein cholesterol (VLDL-C). Increasing evidence suggested that VLDL-C was known as a significant risk factor for atherosclerosis and had been recommended as a treatment target by current dyslipidemia guidelines. However, the role of VLDL-C in the occurrence and development of ISR in coronary artery disease (CAD) patients with DM had not been studied. The aim of this study was to evaluate the association between the elevated levels of VLDL-C and the risk of ISR in CAD patients with DM. METHODS: A total of 1390 diabetic patients, who underwent coronary drug-eluting stent (DES) implantation at Beijing Anzhen Hospital and followed up by angiography within 6-24 months, were consecutively enrolled. Patients' demographic and clinical characteristics, including age, gender, CAD risk factors, family history, life style, medical history, and coronary angiographic information, were collected carefully at baseline percutaneous coronary intervention and follow-up angiography. Multivariate Cox's proportional hazards regression modeling using the step-wise method (entry, 0.05; removal, 0.05) was used to determine the independent risk associated with ISR in diabetic patients. RESULTS: Finally, 1206 of patients were included in this study. ISR occurred in 132/1206 diabetic patients (10.9%) by follow-up angiography. Patients with ISR had elevated median serum VLDL-C levels compared with those without ISR (0.65 mmol/L vs. 0.52 mmol/L, P = 0.030). The multivariate regression analysis showed that VLDL-C was significantly associated with the risk of ISR in diabetic CAD patients (hazard ratio [HR] = 1.15, 95% confidence interval [CI]: 1.03-1.29, P = 0.017). The HR for the risk of ISR associated with VLDL-C level >=0.52 mmol/L was 3.01 (95% CI: 1.24-7.34, P = 0.015). CONCLUSION: The elevated level of serum VLDL-C was a significant and independent risk factor for ISR in diabetic CAD patients after coronary DES implantation. PMID- 28836573 TI - Stress and stability: applying the Anna Karenina principle to animal microbiomes. AB - All animals studied to date are associated with symbiotic communities of microorganisms. These animal microbiotas often play important roles in normal physiological function and susceptibility to disease; predicting their responses to perturbation represents an essential challenge for microbiology. Most studies of microbiome dynamics test for patterns in which perturbation shifts animal microbiomes from a healthy to a dysbiotic stable state. Here, we consider a complementary alternative: that the microbiological changes induced by many perturbations are stochastic, and therefore lead to transitions from stable to unstable community states. The result is an 'Anna Karenina principle' for animal microbiomes, in which dysbiotic individuals vary more in microbial community composition than healthy individuals-paralleling Leo Tolstoy's dictum that "all happy families look alike; each unhappy family is unhappy in its own way". We argue that Anna Karenina effects are a common and important response of animal microbiomes to stressors that reduce the ability of the host or its microbiome to regulate community composition. Patterns consistent with Anna Karenina effects have been found in systems ranging from the surface of threatened corals exposed to above-average temperatures, to the lungs of patients suffering from HIV/AIDs. However, despite their apparent ubiquity, these patterns are easily missed or discarded by some common workflows, and therefore probably underreported. Now that a substantial body of research has established the existence of these patterns in diverse systems, rigorous testing, intensive time-series datasets and improved stochastic modelling will help to explore their importance for topics ranging from personalized medicine to theories of the evolution of host microorganism symbioses. PMID- 28836575 TI - Structural biology: Loading T4SS substrates. PMID- 28836576 TI - Marine microbiology: Roommates in space and time. PMID- 28836574 TI - Translational fidelity and mistranslation in the cellular response to stress. AB - Faithful translation of mRNA into the corresponding polypeptide is a complex multistep process, requiring accurate amino acid selection, transfer RNA (tRNA) charging and mRNA decoding on the ribosome. Key players in this process are aminoacyl-tRNA synthetases (aaRSs), which not only catalyse the attachment of cognate amino acids to their respective tRNAs, but also selectively hydrolyse incorrectly activated non-cognate amino acids and/or misaminoacylated tRNAs. This aaRS proofreading provides quality control checkpoints that exclude non-cognate amino acids during translation, and in so doing helps to prevent the formation of an aberrant proteome. However, despite the intrinsic need for high accuracy during translation, and the widespread evolutionary conservation of aaRS proofreading pathways, requirements for translation quality control vary depending on cellular physiology and changes in growth conditions, and translation errors are not always detrimental. Recent work has demonstrated that mistranslation can also be beneficial to cells, and some organisms have selected for a higher degree of mistranslation than others. The aims of this Review Article are to summarize the known mechanisms of protein translational fidelity and explore the diversity and impact of mistranslation events as a potentially beneficial response to environmental and cellular stress. PMID- 28836578 TI - Corrigendum: Phytosterol esters attenuate hepatic steatosis in rats with non alcoholic fatty liver disease rats fed a high-fat diet. AB - This corrects the article DOI: 10.1038/srep41604. PMID- 28836577 TI - Oxytocin Modulates Attention Switching Between Interoceptive Signals and External Social Cues. AB - Emotional experience involves an integrated interplay between processing of external emotional cues and interoceptive feedback, and this is impaired in a number of emotional disorders. The neuropeptide oxytocin (OT) enhances the salience of external social cues but its influence on interoception is unknown. The present pharmaco-fMRI study therefore investigated whether OT enhances interoceptive awareness and if it influences the interplay between interoceptive and salience processing. In a randomized, double-blind, between-subject, design study 83 subjects received either intranasal OT or placebo. In Experiment 1, subjects performed a heartbeat detection task alone, while in Experiment 2 they did so while viewing both neutral and emotional face stimuli. Interoceptive accuracy and neural responses in interoceptive and salience networks were measured. In Experiment 1, OT had no significant influence on interoceptive accuracy or associated activity in the right anterior insula (AI) and dorsal anterior cingulate cortex. However, in Experiment 2 when face stimuli were also presented, OT decreased interoceptive accuracy and increased right AI activation and its functional connectivity with the left posterior insula (PI), with the latter both being negatively correlated with accuracy scores. The present study provides the first evidence that while OT does not influence processing of interoceptive cues per se it may switch attention away from them towards external salient social cues by enhancing right AI responses and its control over the PI. Thus OT may help regulate the interplay between interoceptive and external salience processing within the insula and could be of potential therapeutic benefit for emotional disorders. PMID- 28836579 TI - Change advice on antibiotics with caution. PMID- 28836580 TI - BCR-ABL1-positive microvesicles malignantly transform human bone marrow mesenchymal stem cells in vitro. AB - The intercellular communication between leukemia cells and bone marrow mesenchymal stem cells (BM-MSCs) plays more important role in chronic myeloid leukemia (CML) than we previously understood. Recently, we found that microvesicles released from human leukemia cell line K562 (K562-MVs) containing BCR-ABL1 mRNA malignantly transformed normal hematopoietic transplants. Here, we investigated whether K562-MVs contribute to the transformation of human bone marrow mesenchymal stem cells (BM-MSCs). We showed that K562-MVs could be integrated into co-cultured normal BM-MSCs and dose-dependently enhanced the proliferation of BM-MSCs. Meanwhile, K562-MVs (400 ng/mL) significantly increased the expression of BCR-ABL1 in these BM-MSCs, accompanied by the enhanced secretion of TGF-beta1. These BM-MSCs in turn could trigger the TGF-beta1 dependent proliferation of K562 cells. Moreover, we confirmed the presence of BCR ABL1 in circulating MVs from 11 CML patients. Compared to the normal BM-MSCs, the BM-MSCs from CML patients more effectively increased the BCR-ABL1 expression and TGF-beta1 secretion in K562 cells as well as the proliferation of K562 cells. Our findings enrich the mechanisms involved in the interaction between leukemia cells and BM-MSCs and provide novel ways to monitor minimal residual disease and worthwhile approaches to treat CML. PMID- 28836581 TI - Ginsenosides synergize with mitomycin C in combating human non-small cell lung cancer by repressing Rad51-mediated DNA repair. AB - The use of ginseng extract as an adjuvant for cancer treatment has been reported in both animal models and clinical applications, but its molecular mechanisms have not been fully elucidated. Mitomycin C (MMC), an anticancer antibiotic used as a first- or second-line regimen in the treatment for non-small cell lung carcinoma (NSCLC), causes serious adverse reactions when used alone. Here, by using both in vitro and in vivo experiments, we provide evidence for an optimal therapy for NSCLC with total ginsenosides extract (TGS), which significantly enhanced the MMC-induced cytotoxicity against NSCLC A549 and PC-9 cells in vitro when used in combination with relatively low concentrations of MMC. A NSCLC xenograft mouse model was used to confirm the in vivo synergistic effects of the combination of TGS with MMC. Further investigation revealed that TGS could significantly reverse MMC-induced S-phase cell cycle arrest and inhibit Rad51 mediated DNA damage repair, which was evidenced by the inhibitory effects of TGS on the levels of phospho-MEK1/2, phospho-ERK1/2 and Rad51 protein and the translocation of Rad51 from the cytoplasm to the nucleus in response to MMC. In summary, our results demonstrate that TGS could effectively enhance the cytotoxicity of MMC against NSCLC cells in vitro and in vivo, thereby revealing a novel adjuvant anticancer mechanism of TGS. Combined treatment with TGS and MMC can significantly lower the required concentration of MMC and can further reduce the risk of side effects, suggesting a better treatment option for NSCLC patients. PMID- 28836582 TI - Influences of renal function descriptors on population pharmacokinetic modeling of vancomycin in Chinese adult patients. AB - Vancomycin, a glycopeptide antibiotic for the treatment of grampositive infections, is mainly eliminated via glomerular filtration. Thus, its therapeutic effects are affected predominantly by renal function. The aim of this study was to develop a population pharmacokinetic model of vancomycin for Chinese adult patients and to investigate the influence of different renal function descriptors on the predictability of the model. A retrospective analysis was performed based on the blood concentrations of vancomycin in 218 Chinese adult patients. Among these patients, the data from 160 were used to establish the population pharmacokinetic model, and the data from the remaining 58 patients were used for external model validation. A simulation was employed to determine the appropriate initial vancomycin dosage regimens in adult Chinese patients for reaching the target steady-state trough concentrations of 10-15 mg/L and 15-20 mg/L. We developed a one-compartment model with first-order absorption to characterize the concentration-time profile of vancomycin. There was a positive correlation between the body clearance of vancomycin and renal function; both creatinine clearance (CLCr) and age were the covariates that influenced the PK of vancomycin, and the excretion of vancomycin decreased as renal function diminishing with age. The typical clearance (CL) value was 2.829 L/h for 75-year old patients with CLCr values of 80 mL/min, and the rate constant of CL with the CLCr changing at 1 mL/min was 0.00842. The influence coefficient of age on CL was 0.08143. The external validation results revealed that the current different descriptors of renal function behaved similarly to the predicted performance of the models. In conclusion, the developed model is appropriate for Bayesian dose predictions of vancomycin concentrations in the population of Chinese adult patients. Furthermore, the simulation provides a reference for clinical optimized antibacterial therapy with vancomycin. PMID- 28836583 TI - Pharmacokinetic and metabolomic analyses of the neuroprotective effects of salvianolic acid A in a rat ischemic stroke model. AB - Salvianolic acid A (SAA), a water-soluble phenolic acid isolated from the root of Dan Shen, displays distinct antioxidant activity and effectiveness in protection against cerebral ischemia/reperfusion (I/R) damage. However, whether SAA can enter the central nervous system and exert its protective effects by directly targeting brain tissue remains unclear. In this study, we evaluated the cerebral protection of SAA in rats subjected to transient middle cerebral artery occlusion (tMCAO) followed by reperfusion. The rats were treated with SAA (5, 10 mg/kg, iv) when the reperfusion was performed. SAA administration significantly decreased cerebral infarct area and the brain water content, attenuated the neurological deficit and pathology, and enhanced the anti-inflammatory and antioxidant capacity in tMCAO rats. The concentration of SAA in the plasma and brain was detected using LC-MS/MS. A pharmacokinetic study revealed that the circulatory system exposure to SAA was equivalent in the sham controls and I/R rats, but the brain exposure to SAA was significantly higher in the I/R rats than in the sham controls (fold change of 9.17), suggesting that the enhanced exposure to SAA contributed to its cerebral protective effect. Using a GC/MS-based metabolomic platform, metabolites in the serum and brain tissue were extracted and profiled. According to the metabolomic pattern of the tissue data, SAA administration significantly modulated the I/R-caused perturbation of metabolism in the brain to a greater extent than that in the serum, demonstrating that SAA worked at the brain tissue level rather than the whole circulation system. In conclusion, a larger amount of SAA enters the central nervous system in ischemia/reperfusion rats to facilitate its protective and regulatory effects on the perturbed metabolism. PMID- 28836584 TI - Iron dysregulates APP processing accompanying with sAPPalpha cellular retention and beta-secretase inhibition in rat cortical neurons. AB - Amyloid precursor protein (APP) and iron both play pivotal roles in the central nervous system, but whether and how iron influences the processing of endogenous APP in neurons remain unclear. Here, we investigated the regulatory effects and underlying mechanisms of iron on non-amyloidogenic and amyloidogenic processing of APP in rat primary cortical neurons. Treatment of the neurons with ferric ammonium citrate (FAC, 100 MUmol/L) markedly facilitated the non-amyloidogenic processing of APP, as evidenced by a robust increase in alpha-secretase-derived carboxy-terminal fragment alpha (CTFalpha). Furthermore, the distribution of sAPPalpha was altered after iron treatment, and sAPPalpha remained in the cellular lysates instead of being secreted into the extracellular milieu. Moreover, the levels of APP amyloidogenic products, including sAPPbeta and Abeta were both decreased. We further revealed that FAC did not alter the expression of beta-secretase, but significantly suppressed its enzymatic activity in iron treated neurons. In a cell-free beta-secretase activity assay, FAC dose dependently inhibited the activity of purified beta-secretase with an IC50 value of 21.67 MUmol/L. Our data provide the first evidence that iron overload alters the neuronal sAPPalpha distribution and directly inhibits beta-secretase activity. These findings shed light on the regulatory mechanism of bio-metals on APP processing. PMID- 28836586 TI - Counterfeit reagents: Fake serum has telltale fingerprint. PMID- 28836585 TI - Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients. AB - Mycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group). Population pharmacokinetic data analysis was performed using the NONMEM software. The pharmacokinetics of MPA was best described by a two-compartment model with a first-order absorption rate with no lag time. Body weight and serum creatinine level were positively correlated with apparent clearance (CL/F). The polymorphism in uridine diphosphate glucuronosyltransferase gene, UGT2B7, significantly explained the interindividual variability in the initial volume of distribution (V1/F). The estimated population parameters (and interindividual variability) were CL/F 18.3 L/h (34.2%) and V1/F 27.9 L (21.3%). The interoccasion variability was 13.7%. These population pharmacokinetic data have significant clinical value for the individualization of MMF therapy in Chinese adult renal transplant patients. PMID- 28836587 TI - Gravitational waves: History of black holes revealed by their spin. PMID- 28836589 TI - Molecular magnetic hysteresis at 60 kelvin in dysprosocenium. AB - Lanthanides have been investigated extensively for potential applications in quantum information processing and high-density data storage at the molecular and atomic scale. Experimental achievements include reading and manipulating single nuclear spins, exploiting atomic clock transitions for robust qubits and, most recently, magnetic data storage in single atoms. Single-molecule magnets exhibit magnetic hysteresis of molecular origin-a magnetic memory effect and a prerequisite of data storage-and so far lanthanide examples have exhibited this phenomenon at the highest temperatures. However, in the nearly 25 years since the discovery of single-molecule magnets, hysteresis temperatures have increased from 4 kelvin to only about 14 kelvin using a consistent magnetic field sweep rate of about 20 oersted per second, although higher temperatures have been achieved by using very fast sweep rates (for example, 30 kelvin with 200 oersted per second). Here we report a hexa-tert-butyldysprosocenium complex-[Dy(Cpttt)2][B(C6F5)4], with Cpttt = {C5H2tBu3-1,2,4} and tBu = C(CH3)3-which exhibits magnetic hysteresis at temperatures of up to 60 kelvin at a sweep rate of 22 oersted per second. We observe a clear change in the relaxation dynamics at this temperature, which persists in magnetically diluted samples, suggesting that the origin of the hysteresis is the localized metal-ligand vibrational modes that are unique to dysprosocenium. Ab initio calculations of spin dynamics demonstrate that magnetic relaxation at high temperatures is due to local molecular vibrations. These results indicate that, with judicious molecular design, magnetic data storage in single molecules at temperatures above liquid nitrogen should be possible. PMID- 28836590 TI - Materials science: Magnetic molecules back in the race. PMID- 28836592 TI - Atmospheric science: Ancient ice and the global methane cycle. PMID- 28836595 TI - Distinguishing spin-aligned and isotropic black hole populations with gravitational waves. AB - The direct detection of gravitational waves from merging binary black holes opens up a window into the environments in which binary black holes form. One signature of such environments is the angular distribution of the black hole spins. Binary systems that formed through dynamical interactions between already-compact objects are expected to have isotropic spin orientations (that is, the spins of the black holes are randomly oriented with respect to the orbit of the binary system), whereas those that formed from pairs of stars born together are more likely to have spins that are preferentially aligned with the orbit. The best measured combination of spin parameters for each of the four likely binary black hole detections GW150914, LVT151012, GW151226 and GW170104 is the 'effective' spin. Here we report that, if the magnitudes of the black hole spins are allowed to extend to high values, the effective spins for these systems indicate a 0.015 odds ratio against an aligned angular distribution compared to an isotropic one. When considering the effect of ten additional detections, this odds ratio decreases to 2.9 * 10-7 against alignment. The existing preference for either an isotropic spin distribution or low spin magnitudes for the observed systems will be confirmed (or overturned) confidently in the near future. PMID- 28836593 TI - Minimal geological methane emissions during the Younger Dryas-Preboreal abrupt warming event. AB - Methane (CH4) is a powerful greenhouse gas and plays a key part in global atmospheric chemistry. Natural geological emissions (fossil methane vented naturally from marine and terrestrial seeps and mud volcanoes) are thought to contribute around 52 teragrams of methane per year to the global methane source, about 10 per cent of the total, but both bottom-up methods (measuring emissions) and top-down approaches (measuring atmospheric mole fractions and isotopes) for constraining these geological emissions have been associated with large uncertainties. Here we use ice core measurements to quantify the absolute amount of radiocarbon-containing methane (14CH4) in the past atmosphere and show that geological methane emissions were no higher than 15.4 teragrams per year (95 per cent confidence), averaged over the abrupt warming event that occurred between the Younger Dryas and Preboreal intervals, approximately 11,600 years ago. Assuming that past geological methane emissions were no lower than today, our results indicate that current estimates of today's natural geological methane emissions (about 52 teragrams per year) are too high and, by extension, that current estimates of anthropogenic fossil methane emissions are too low. Our results also improve on and confirm earlier findings that the rapid increase of about 50 per cent in mole fraction of atmospheric methane at the Younger Dryas Preboreal event was driven by contemporaneous methane from sources such as wetlands; our findings constrain the contribution from old carbon reservoirs (marine methane hydrates, permafrost and methane trapped under ice) to 19 per cent or less (95 per cent confidence). To the extent that the characteristics of the most recent deglaciation and the Younger Dryas-Preboreal warming are comparable to those of the current anthropogenic warming, our measurements suggest that large future atmospheric releases of methane from old carbon sources are unlikely to occur. PMID- 28836596 TI - Scientific journals: Rename the impact factor. PMID- 28836597 TI - Neurobiology: Diversity reaches the stars. PMID- 28836598 TI - Patrick Bateson (1938-2017). PMID- 28836600 TI - Reproducibility: Check your chemistry. PMID- 28836601 TI - UK regulations: Could fracking creep under the radar? PMID- 28836602 TI - Water management: Signing up to safe water for billions. PMID- 28836604 TI - Mysteries of turbulence unravelled. PMID- 28836605 TI - Ecologists protest Australia's plans to cut funding for environment-monitoring network. PMID- 28836603 TI - Epitaxy of advanced nanowire quantum devices. AB - Semiconductor nanowires are ideal for realizing various low-dimensional quantum devices. In particular, topological phases of matter hosting non-Abelian quasiparticles (such as anyons) can emerge when a semiconductor nanowire with strong spin-orbit coupling is brought into contact with a superconductor. To exploit the potential of non-Abelian anyons-which are key elements of topological quantum computing-fully, they need to be exchanged in a well-controlled braiding operation. Essential hardware for braiding is a network of crystalline nanowires coupled to superconducting islands. Here we demonstrate a technique for generic bottom-up synthesis of complex quantum devices with a special focus on nanowire networks with a predefined number of superconducting islands. Structural analysis confirms the high crystalline quality of the nanowire junctions, as well as an epitaxial superconductor-semiconductor interface. Quantum transport measurements of nanowire 'hashtags' reveal Aharonov-Bohm and weak-antilocalization effects, indicating a phase-coherent system with strong spin-orbit coupling. In addition, a proximity-induced hard superconducting gap (with vanishing sub-gap conductance) is demonstrated in these hybrid superconductor-semiconductor nanowires, highlighting the successful materials development necessary for a first braiding experiment. Our approach opens up new avenues for the realization of epitaxial three-dimensional quantum architectures which have the potential to become key components of various quantum devices. PMID- 28836606 TI - Correction. PMID- 28836607 TI - Supernova's messy birth casts doubt on reliability of astronomical yardstick. PMID- 28836608 TI - Theft of South African relics riles researchers. PMID- 28836609 TI - Head injuries in sport must be taken more seriously. PMID- 28836610 TI - Creeping earth could hold secret to deadly landslides. PMID- 28836611 TI - Oldest ice, censorship row and Yemen's cholera emergency. PMID- 28836612 TI - Magnetic antiparticle expands strange field of swirling science. PMID- 28836613 TI - How machine learning could help to improve climate forecasts. PMID- 28836614 TI - To reduce gender biases, acknowledge them. PMID- 28836615 TI - A long journey to reproducible results. PMID- 28836616 TI - Heart failure with reduced ejection fraction. AB - Heart failure is a global public health problem that affects more than 26 million people worldwide. The global burden of heart failure is growing and is expected to increase substantially with the ageing of the population. Heart failure with reduced ejection fraction accounts for approximately 50% of all cases of heart failure in the United States and is associated with substantial morbidity and reduced quality of life. Several diseases, such as myocardial infarction, certain infectious diseases and endocrine disorders, can initiate a primary pathophysiological process that can lead to reduced ventricular function and to heart failure. Initially, ventricular impairment is compensated for by the activation of the sympathetic nervous system and the renin-angiotensin aldosterone system, but chronic activation of these pathways leads to worsening cardiac function. The symptoms of heart failure can be associated with other conditions and include dyspnoea, fatigue, limitations in exercise tolerance and fluid accumulation, which can make diagnosis difficult. Management strategies include the use of pharmacological therapies and implantable devices to regulate cardiac function. Despite these available treatments, heart failure remains incurable, and patients have a poor prognosis and high mortality rate. Consequently, the development of new therapies is imperative and requires further research. PMID- 28836618 TI - Cardiac regeneration: Cardiomyocyte proliferation: a variable genetic trait? PMID- 28836617 TI - Hypertension as a cardiovascular risk factor in autoimmune rheumatic diseases. AB - Evidence for the increased risk of cardiovascular morbidity and mortality in patients with chronic inflammatory and systemic autoimmune diseases has accumulated during the past 15 years. In these patients, an interplay between several mechanisms, including premature acceleration of subclinical atherosclerotic damage, inflammation, and dysregulation of the immune system, is involved in the induction and progression of atherosclerosis. Moreover, traditional cardiovascular risk factors are also likely to contribute, at least in part, to the excess cardiovascular risk. Among traditional cardiovascular risk factors, hypertension is an important predictor of cardiovascular events in the general population and in patients with chronic inflammatory and autoimmune diseases. Evidence supports the idea that the pathogenic mechanisms underlying the increased blood pressure in these diseases are multifactorial and not only related to the mechanical injury of the arterial wall. In particular, chronic inflammation and immune-mediated mechanisms have been demonstrated to affect blood-pressure control in patients with systemic autoimmune disease. In this Review, we discuss the available evidence on the relationship between hypertension and autoimmune diseases, and describe the multiple factors that might affect blood-pressure control in patients with chronic inflammatory and systemic autoimmune diseases. We also discuss the effect of hypertension and antirheumatic therapies on cardiovascular outcome. PMID- 28836621 TI - Imaging: Perivascular fat - an unheralded informant of coronary inflammation. PMID- 28836620 TI - Future of transcatheter aortic valve implantation - evolving clinical indications. AB - Accumulating clinical experience and technological improvements have provided the basis for transcatheter aortic valve implantation (TAVI) to emerge as a well established means for treating patients with severe symptomatic aortic stenosis at high or prohibitive surgical risk. During this decade, TAVI has emerged as a valid alternative to surgical aortic valve replacement in patients at intermediate surgical risk, and several studies are currently being performed to evaluate the role of TAVI in patients at low surgical risk. Furthermore, promising, but preliminary, data are emerging on the efficacy of TAVI for treating patients with bicuspid aortic valve disease, as well as patients with pure aortic regurgitation. In this Perspectives article, we summarize the evolving indications for TAVI, and give our opinion on the future perspectives for this procedure. PMID- 28836619 TI - Beyond gut feelings: how the gut microbiota regulates blood pressure. AB - Hypertension is the leading risk factor for heart disease and stroke, and is estimated to cause 9.4 million deaths globally every year. The pathogenesis of hypertension is complex, but lifestyle factors such as diet are important contributors to the disease. High dietary intake of fruit and vegetables is associated with reduced blood pressure and lower cardiovascular mortality. A critical relationship between dietary intake and the composition of the gut microbiota has been described in the literature, and a growing body of evidence supports the role of the gut microbiota in the regulation of blood pressure. In this Review, we describe the mechanisms by which the gut microbiota and its metabolites, including short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides, act on downstream cellular targets to prevent or contribute to the pathogenesis of hypertension. These effects have a direct influence on tissues such as the kidney, the endothelium, and the heart. Finally, we consider the role of the gut microbiota in resistant hypertension, the possible intergenerational effect of the gut microbiota on blood pressure regulation, and the promising therapeutic potential of gut microbiota modification to improve health and prevent disease. PMID- 28836622 TI - Corrigendum: Pannexin1 channels dominate ATP release in the cochlea ensuring endocochlear potential and auditory receptor potential generation and hearing. AB - This corrects the article DOI: 10.1038/srep10762. PMID- 28836623 TI - Corrigendum: Demonstration of nanoimprinted hyperlens array for high-throughput sub-diffraction imaging. AB - This corrects the article DOI: 10.1038/srep46314. PMID- 28836624 TI - The generalized Sellmeier equation for air. AB - We present a compact, uniform generalized Sellmeier-equation (GSE) description of air refraction and its dispersion that remains highly accurate within an ultrabroad spectral range from the ultraviolet to the long-wavelength infrared. While the standard Sellmeier equation (SSE) for atmospheric air is not intended for the description of air refractivity in the mid-infrared and long-wavelength infrared, failing beyond, roughly 2.5 MUm, our generalization of this equation is shown to agree remarkably well with full-scale air-refractivity calculations involving over half a million atmospheric absorption lines, providing a highly accurate description of air refractivity in the range of wavelengths from 0.3 to 13 MUm. With its validity range being substantially broader than the applicability range of the SSE and its accuracy being at least an order of magnitude higher than the accuracy that the SSE can provide even within its validity range, the GSE-based approach offers a powerful analytical tool for the rapidly progressing mid- and long-wavelength-infrared optics of the atmosphere. PMID- 28836625 TI - Corrigendum: IL-33/ST2 immune responses to respiratory bacteria in pediatric asthma. AB - This corrects the article DOI: 10.1038/srep43426. PMID- 28836627 TI - Corrigendum: Male African elephants discriminate and prefer vocalizations of unfamiliar females. AB - This corrects the article DOI: 10.1038/srep46414. PMID- 28836628 TI - Corrigendum: Nitrogen-doped porous carbon monoliths from polyacrylonitrile (PAN) and carbon nanotubes as electrodes for supercapacitors. AB - This corrects the article DOI: 10.1038/srep40259. PMID- 28836629 TI - Viral pathogenesis: Unlocking Ebola persistence. PMID- 28836630 TI - Erratum: Arabidopsis thaliana dehydroascorbate reductase 2: Conformational flexibility during catalysis. AB - This corrects the article DOI: 10.1038/srep42494. PMID- 28836631 TI - Tuning the formation of reductive species of perylene-bisimide derivatives in DMF via aggregation matter. AB - Host-guest interaction and chemical modification are found to be effective in tuning the formation of reductive species of perylene-bisimide (PBI) derivatives in DMF. Moreover, some of the PBI derivatives as synthesized produce radical anions in the solvent without the need of a base. PMID- 28836632 TI - Quality components and antidepressant-like effects of GABA green tea. AB - Gamma (gamma)-aminobutyric acid (GABA) green tea, with high GABA content, is a kind of special green tea. The goals of this study are to analyze the changes in quality components of green tea during anaerobic treatment, and to investigate whether or not the extract of GABA present in green tea can prevent depression or improve the depressive state of animals. Results showed that GABA content in green tea had increased significantly after anaerobic treatment. The contents of tea polysaccharides, total free amino acids, and water extracts were also increased whereas tea polyphenols were reduced. More importantly, the extract of GABA green tea could alleviate mouse depression and stress from desperate environments through the forced swim test (FST), tail suspension test (TST), mRNA and protein expression levels of GABAA receptors. Therefore, these results indicate that GABA green tea may have a health effect on prevention and alleviation of depression, and it works on the GABAergic neurotransmission of mouse cerebral cortex via up-regulating expression of the GABAA receptor alpha1 subunit, thus ameliorating depression. PMID- 28836633 TI - Self-aggregation propensity of the Tat peptide revealed by UV-Vis, NMR and MD analyses. AB - By a combination of UV-Vis analyses, NMR-based diffusion measurements and MD simulations we have demonstrated for the first time that the HIV-1 Tat arginine rich peptide (Tat11) is able to self-aggregate in both its fluorescently labeled and unlabeled variants. We propose Tat11 dimerization as the dominant aggregation process and show that the associated equilibrium constant increases ten-fold by labeling with the standard TAMRA dye. Also, we extend similar conclusions to other cationic cell penetrating peptides (CPPs), such as Antennapedia (Ant) and nona-arginine (R9). PMID- 28836634 TI - Aggregation-induced emission in precursors to porous molecular crystals. AB - Trigonal fluorinated pyrazoles assemble into porous molecular crystals and show solid-state fluorescence. However, in a DMF/H2O mixed solvent system, the triazine-centered compound displays aggregation-induced emission, while its benzene-based counterpart does not. PMID- 28836635 TI - A catalytic asymmetric construction of a tetrahydroquinoline-based spirooxindole framework via a diastereo- and enantioselective decarboxylative [4+2] cycloaddition. AB - A catalytic asymmetric decarboxylative [4+2] cycloaddition of vinyl benzoxazinanones with methyleneindolinones has been established, which provided a series of chiral tetrahydroquinoline-based 3,3'-spirooxindoles in high yields (up to 96%) and with excellent diastereo- and enantioselectivities (all >95 : 5 d.r., up to 99% ee). This reaction not only represents the first example of catalytic enantioselective [4+2] cycloaddition between methyleneindolinones and Pd containing 1,4-dipoles, but also demonstrates the great practicability of catalytic asymmetric decarboxylative cycloadditions in the synthesis of enantio enriched polycyclic compounds. PMID- 28836636 TI - Boosting selective oxidation of cyclohexane over a metal-organic framework by hydrophobicity engineering of pore walls. AB - A porphyrinic metal-organic framework (MOF), PCN-222(Fe), was found to exhibit sound activity and selectivity to cyclohexanone and cyclohexanol (known as KA oil) toward cyclohexane oxidation. Remarkably, hydrophobicity engineering of the MOF pore walls led to significantly enhanced activity and selectivity to KA oil, far superior to that of the homogeneous porphyrin catalyst. PMID- 28836637 TI - NMR spectroscopic studies of a TAT-derived model peptide in imidazolium-based ILs: influence on chemical shifts and the cis/trans equilibrium state. AB - NMR spectroscopy was used to study systematically the impact of imidazolium-based ionic liquid (IL) solutions on a TAT-derived model peptide containing Xaa-Pro peptide bonds. The selected IL anions cover a wide range of the Hofmeister series of ions. Based on highly resolved one- and two-dimensional NMR spectra individual 1H and 13C peptide chemical shift differences were analysed and a classification of IL anions according to the Hofmeister series was derived. The observed chemical shift changes indicate significant interactions between the peptide and the ILs. In addition, we examined the impact of different ILs towards the cis/trans equilibrium state of the Xaa-Pro peptide bonds. In this context, the IL cations appear to be of exceptional importance for inducing an alteration of the native cis/trans equilibrium state of Xaa-Pro bonds in favour of the trans isomers. PMID- 28836638 TI - On-skin liquid metal inertial sensor. AB - A wireless on-skin inertial sensor based on free-moving liquid metal is introduced. The inertial sensor comprises a eutectic gallium-indium (eGaIn) droplet that modulates the capacitance between two electrodes. The capacitive output of the sensor is connected to a planar coil to form an LC resonator whose resonant frequency can be read out wirelessly. Liquid metal electrodes and the coil are fabricated on a 20 MUm thick silicone membrane, which can stretch up to 600%, using spray-deposition of eGaIn. The moving droplet is encapsulated on the opposite side of the membrane using spray-deposition of Dragon Skin 10 silicone. The output characteristics, electrical simulations of the capacitance, and dynamic characteristics of the sensor are shown. The sensor is used for measuring tilt angles and recording arm gestures. PMID- 28836639 TI - Titanium nanoparticles (TiO2)/graphene oxide nanosheets (GO): an electrochemical sensing platform for the sensitive and simultaneous determination of benzocaine in the presence of antipyrine. AB - An effective electrochemical sensing platform for the simultaneous determination of benzocaine (BEN) and antipyrine (ANT) based upon titanium dioxide nanoparticle (TiO2)/graphene oxide nanosheet (GO) bulk modified carbon paste electrodes (TiO2 GO/CPE) is reported. The TiO2-GO/CPE electrochemical sensing platform is found to exhibit linear ranges from 1.0 * 10-6 to 1.0 * 10-4 M and 1.2 * 10-8 to 8.0 * 10 5 M for BEN and ANT, respectively. The TiO2-GO/CPE sensor is explored towards the analysis of BEN and ANT in oral fluid (saliva) and pharmaceutical products. The synergy between the graphene oxide nanosheets and titanium dioxide nanoparticles results in a dramatic enhancement in the sensitivity of the sensor through a combination of increased surface area and improved electron transfer kinetics compared to other electrode alternatives. The fabricated TiO2-GO/CPE exhibits high sensitivity and good stability towards the sensing of BEN and ANT and has the potential to be utilised as a clinical assay and QA in pharmaceutical products. PMID- 28836640 TI - Assembly of donor-acceptor hybrid heterostructures based on iodoplumbates and viologen coordination polymers. AB - The insertion of electron-rich iodoplumbate nanowires and nanolayers into layered electron-deficient metal-viologen frameworks leads to two donor-acceptor hybrid structures, respectively, which exhibit interesting semiconductor behaviors. Due to the bicontinuous donor and acceptor components, both of them exhibit highly efficient photocatalytic degradation activities over organic dyes under visible light irradiation compared to those of other iodoplumbate hybrid materials. PMID- 28836641 TI - Magnetoelastoelectric coupling in core-shell nanoparticles enabling directional and mode-selective magnetic control of THz beam propagation. AB - Magnetoelastoelectric coupling in an engineered biphasic multiferroic nanocomposite enables a novel magnetic field direction-defined propagation control of terahertz (THz) waves. These core-shell nanoparticles are comprised of a ferromagnetic cobalt ferrite core and a ferroelectric barium titanate shell. An assembly of these nanoparticles, when operated in external magnetic fields, exhibits a controllable amplitude modulation when the magnetic field is applied antiparallel to the THz wave propagation direction; yet the same assembly displays an additional phase modulation when the magnetic field is applied along the propagation direction. While field-induced magnetostriction of the core leads to amplitude modulation, phase modulation is a result of stress-mediated piezoelectricity of the outer ferroelectric shell. PMID- 28836643 TI - Simple and rapid fabrication of pencil-on-paper triboelectric nanogenerators with enhanced electrical performance. AB - Paper and pencil have many advantages in triboelectric nanogenerators (TENGs) in terms of low-cost, light weight, and environment friendliness. In this work, a pencil-on-paper triboelectric nanogenerator (PP-TENG) with highly enhanced performance was introduced. In order to use paper as a friction layer and improve its triboelectric performance, a simple and rapid paper-coating process was utilized with polyvinylidene fluoride (PVDF), polyvinyledenedifluoride trifluoroethylene (PVDF-TrFE), and poly(methyl methacrylate) (PMMA) solutions. The fabrication process of the PP-TENG was completed within 10 minutes via pencil drawing of an electrode followed by a solution coating. With an optimized electrode shape, the PP-TENG showed a maximum power density of 64 mW m-2, which is more than 19 times higher than that of the uncoated paper TENG. The electrical performance of the PP-TENG was sufficient to drive a few hundred LEDs and charge various capacitors. It was maintained after the paper was folded or even crumpled. The proposed PP-TENG is expected to be utilized with other wearable electronic devices. PMID- 28836645 TI - Photodynamic inactivation of microorganisms sensitized by cationic BODIPY derivatives potentiated by potassium iodide. AB - The photodynamic inactivation mediated by 1,3,5,7-tetramethyl-8-[4-(N,N,N trimethylamino)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene 3 and 8-[4-(3 (N,N,N-trimethylamino)propoxy)phenyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene 4 was investigated on Staphylococcus aureus, Escherichia coli and Candida albicans. In vitro experiments indicated that BODIPYs 3 and 4 were rapidly bound to microbial cells at short incubation periods. Also, fluorescence microscopy images showed green emission of BODIPYs bound to microbial cells. Photosensitized inactivation improved with an increase of the irradiation time. Similar photoinactivation activities were found for both BODIPYs in bacteria. The photoinactivation induced by these BODIPYs was effective for both bacteria. However, the Gram-positive bacterium was inactivated sooner and with a lower concentration of a photosensitizer than the Gram-negative bacterium. After 15 min irradiation, the complete eradication of S. aureus was obtained with 1 MUM photosensitizer. A reduction of 4.5 log in the E. coli viability was found when using 5 MUM photosensitizer and 30 min irradiation. Also, the last conditions produced a decrease of 4.5 log in C. albicans cells treated with BODIPY 3, while 4 was poorly effective. On the other hand, the effect of the addition of KI on photoinactivation at different irradiation periods and salt concentrations was investigated. A smaller effect was observed in S. aureus because the photosensitizers alone were already very effective. In E. coli, photokilling potentiation was mainly found at longer irradiation periods. Moreover, the photoinactivation of C. albicans mediated by these BODIPYs was increased in the presence of KI. In solution, an increase in the formation of the BODIPY triplet states was observed with the addition of the salt, due to the effect of external heavy atoms. The greater intersystem crossing together with the formation of reactive iodine species induced by BODIPYs may be contributing to enhance the inactivation of microorganisms. Therefore, these BODIPYs represent interesting photosensitizers to inactivate microorganisms. In particular, BODIPY 3 in combination with KI was highly effective as a broad spectrum antimicrobial photosensitizer. PMID- 28836649 TI - A novel mechanism for red emission carbon dots: hydrogen bond dominated molecular states emission. AB - Carbon dots (CDs) have emerged as novel fluorescent probes due to their remarkable optical properties; however, red emission is still rare, has a relatively low efficiency, and its mechanism remains ambiguous. Herein, relatively efficient red-emission CDs based on p-phenylenediamine were prepared through various solvothermal means, where the highest quantum yield approached 41.1% in n-amyl alcohol, which was the most efficient quantum yield reported to date. Various structural characterizations were performed and confirmed that the red emission originated from the molecular states consisting of a nitrogen containing organic fluorophore. The CDs were dispersed in different organic solvents and showed tunable emission, evolving from green to orange-red in aprotic solvents and a red emission in protic solvents. Further solvent correlation studies indicated that the hydrogen bond effect between the CDs and solvents was the main mechanism leading to the spectral shift. Accordingly, solid state luminescent CDs-polymers were fabricated, which also demonstrated continuously tunable emission properties. This work opens a new window for recognizing the generation of tunable and red-emission CDs. PMID- 28836650 TI - What would it take to eliminate tuberculosis in the Eastern Mediterranean Region? PMID- 28836651 TI - Surveillance of communicable diseases for decisionmaking in Egypt: 2006-2013. AB - The Egyptian Ministry of Health and Population surveillance system provides data about notifiable communicable diseases. This study aimed to provide information for decision-making to reduce the burden of communicable diseases in Egypt by analysis of the surveillance data for 2006-2013 to identify trends in the incidence of the diseases by governorate, season, age and sex. Composite risk index scores were estimated to rank the 27 Egyptian governorates into 3 groups: high, medium and low risk. The 15 diseases with the highest incidence were food and waterborne diseases (5 diseases), vaccine-preventable diseases (7 diseases) and others, e.g. hepatitis C infection. Bloody diarrhoea and typhoid had the high incidence for 2006-2013. There were 11 high-risk governorates; Ismailia had the highest risk-index score. The findings suggest the need for specific interventions related to environmental sanitation and improving the childhood immunization programme, particularly in the high-risk governorates. PMID- 28836652 TI - The relation between pica and iron deficiency in children in Zanjan, Islamic Republic of Iran: a case-control study. AB - The aim of this case-control study was to determine the frequency of pica and its relationship with iron deficiency in children in Zanjan. We selected 872 children and determined the frequency of pica. We selected students who did not have pica of the same age and sex, and in the same class as our cases as a control group. Both groups were evaluated for iron deficiency anaemia. Among the 57 students (6.7%) who had pica, there was no significant relationship with sex (P > 0.05). The most common types of pica were soil (62.3%) and paper (31.2%). The frequency of anaemia among cases was greater than in controls, although the difference was not statistically significant. The serum iron/total iron binding capacity ratio <= 0.15 did not differ significantly between the 2 groups. We did not find any association between pica and anaemia and/or iron deficiency (P > 0.05). PMID- 28836653 TI - Disease and treatment-related factors associated with tuberculosis treatment default in Khartoum State, Sudan: a case-control study. AB - Defaulting on tuberculosis (TB) treatment remains a challenge to controlling TB. This case-control study aimed to identify determinants of treatment default among TB patients attending treatment clinics in Khartoum State from May to July 2011. Cases were TB patients who defaulted on treatment and controls were those who completed treatment. Of the 2727 TB patients attending the clinics, 328 (14%) had defaulted. Of these, 185 had resumed treatment before data collection and 143 had not and were eligible as cases. Of the 143, 27 could not be traced and 11 declined to participate. Thus, 105 cases and 210 controls were included and interviewed. The variables significantly associated with treatment default were: rural residence (OR: 2.68; 95% CI: 1.51-4.73), not being on a DOTS programme (OR: 2.53; 95% CI: 1.49-4.30), having side-effects from treatment (OR: 1.94; 95% CI: 1.14-3.29), and having a history of TB (relapse, multidrug-resistant TB or treatment failure) (OR: 5.11; 95% CI: 2.69-9.69). Attention should be paid to these groups at risk of defaulting to encourage treatment adherence and continuation. PMID- 28836654 TI - Health labour market requirements of health professional education in Yemen. AB - It is important to link health professional education to the health service needs of the private and public labour market so as to meet the plans of the health sector. Thus, the main focus of this study was to identify the present labour market requirements for the outcomes of health training institutes. A qualitative study was carried out among mixed healthcare professionals and various stakeholders in Sana'a City, Yemen. Six focus group discussions were formed for 42 graduates and 20 in-depth interviews were undertaken with health development partners and public and private employers. Outcomes of the health training institutes were still below the expectations of the health labour market, and did not fill the existing gaps in English-language proficiency and clinical skills. The survival of health professional education depends on future development to meet labour market demands through collaboration between key stakeholders, regular updating of the curriculum, and constant professional development of the teaching staff. PMID- 28836655 TI - Delays in diagnosis and treatment among children with cancer: Egyptian perspective. AB - Delayed diagnosis is one of the contributing factors to lower cure rates for cancer in low-income countries. This was a cross-sectional study of 138 children with cancer who were treated at the Pediatric Oncology Unit, Oncology Center of Mansoura University, Egypt. One hundred and sixteen patients were initially misdiagnosed. The median total delay was 37 days, including median patient/parent delay of 3 days and median physician delay of 28 days. The type of cancer significantly influenced the diagnostic delay. Patients' sex, level of parents' education, and residence did not significantly affect the median total delay, while patients aged < 5 years and those who had an initial provisional diagnosis of cancer had the shortest median total delay. We suggest implementation of continuing medical education programmes, improving access to diagnostic facilities, and facilitating referral to give priority to those with suspected cancer to shorten the time for cancer diagnosis. PMID- 28836656 TI - The impact of antimicrobial stewardship strategies on antibiotic appropriateness and prescribing behaviours in selected countries in the Middle East: a systematic review. AB - Antimicrobial resistance is a global health problem and antimicrobial stewardship is an essential component of hospital policies worldwide yet little is known regarding effective implementation strategies in the Middle East. We conducted a review of studies carried out in this region that deployed different antimicrobial stewardship strategies to assess antimicrobial appropriateness and prescribing behaviours. A search of MEDLINE, EMBASE, International Pharmaceutical Abstracts, Google and Google Scholar was conducted. Twenty articles met the inclusion criteria; 2 studies evaluated strategies including prospective audit with feedback, while 18 others evaluated strategies including benchmarking antimicrobial utilization against guidelines. Recommendations for implementation of stewardship in the Middle East highlighted the importance of developing and updating local antimicrobial prescribing policies and using collaborative interdisciplinary approaches for success. PMID- 28836657 TI - Determinants of caesarean birth on maternal demand in the Islamic Republic of Iran: a review. AB - The phenomenon of caesarean birth on demand has gained attention, particularly as a first caesarean birth appears to be strongly predictive of subsequent caesareans. Identification of reasons behind caesarean birth on demand is important for planning effective interventions. Therefore, this review reports the factors involved in the tendency of women to undergo caesarean birth, based on studies in the Islamic Republic of Iran. Several keywords including caesarean delivery, childbirth, causes, maternal request/demand, and patient choice were used to search Medline, PubMed, Ovid, Scientific Information Database, Magiran, Google and Google Scholar. The search was conducted on Persian and English language articles, with no time limitation. Using content analysis, the factors influencing caesarean section were divided into 3 categories: maternal, social and healthcare giver. According to the high prevalence of caesarean section, it is important to design and implement effective programmes and interventions with consideration of the key reasons that lead women to opt for unnecessary caesarean section. PMID- 28836658 TI - Governing the Lebanese health system: strengthening the national response to the burden of Syrian refugees. AB - Lebanon is providing sanctuary to an estimated 1.5 million Syrian refugees, with potential consequences for its health system. Here, we analyse how it has responded to this challenge, identify sensitive areas where a strong national governance system is needed and explore how it might be implemented. An effective response to the Syrian refugee crisis requires concerted international action. Nonetheless, geography dictates that the Lebanese health system must play a central role. We identify some areas where a strengthened stewardship role of the Ministry of Public Health is urgently required. We argue that the Ministry is well placed to take a lead, with its detailed knowledge of the Lebanese health system and its legitimacy to formulate a national health response. Finally, we suggest that this crisis could be a catalyst for the strengthening of the Lebanese health system, based on evidence-informed policies that would benefit refugees and the Lebanese population alike. PMID- 28836659 TI - Zonisamide for essential tremor. AB - BACKGROUND: Essential tremor (ET) is one of the most common movement disorders. The treatment is primarily based on pharmacological agents. Although primidone and propranolol are well established treatments in clinical practice, they can be ineffective in 25% to 55% of patients, and can produce serious adverse events in a large percentage of them. For these reasons, it may be worthwhile evaluating the treatment alternatives for ET. Zonisamide has been suggested as a potentially useful agent for the treatment of ET but there is uncertainty about its efficacy and safety. OBJECTIVES: To assess the effect on functional abilities and the safety profile of zonisamide in adults with essential tremor (ET). SEARCH METHODS: We carried out a systematic search, without language restrictions to identify all relevant trials. We searched CENTRAL, MEDLINE, Embase, NICE, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) to January 2017. We searched BIOSIS Citation Index (2000 to January 2017) for conference proceedings. We handsearched grey literature and examined the reference lists of identified studies and reviews. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of zonisamide versus placebo or any other treatment. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in patients presenting secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently collected and extracted data using a data collection form. We assessed the risk of bias and the quality of evidence.We used inverse variance methods for continuous outcomes and measurement scales. We compared differences between treatment groups as mean differences. We combined results for dichotomous outcomes using Mantel-Haenszel methods and obtained risk differences to compare treatment groups. We used Review Manager 5 software for data management and analysis. MAIN RESULTS: We only considered one study eligible for this review (20 participants). Assessments of risk of bias for most domains were unclear or low. Adverse events were only reported in participants from the zonisamide group, making it possible that they were aware of treatment group assignment. We are uncertain as to the effects of zonisamide on motor tasks (mean difference (MD) -0.00, 95% confidence interval (CI) -1.51 to 1.51, very low quality evidence) and functional disabilities (MD -0.30, 95% CI -1.23 to 0.63, very low-quality evidence) when compared with placebo. Three participants in the zonisamide group (30%) and two participants in the placebo group (20%) discontinued the treatment and withdrew from the study for any reason (very low quality evidence), however the increased risk of withdrawal in the zonisamide group was statistically non-significant (risk difference (RD) 0.1, 95% CI -0.28 to 0.48). Six participants in the zonisamide group (60%) and none of the participants in the placebo group (0%) developed adverse events (AEs), with a RD of 0.60 (95% CI 0.28 to 0.92; very low quality evidence). The most common AEs, experienced with zonisamide treatment, were headache, nausea, fatigue, sleepiness, and diarrhoea. Quality of life was not assessed in the study included. AUTHORS' CONCLUSIONS: Based on currently available data, there is insufficient evidence to assess the efficacy and safety of zonisamide treatment for ET. PMID- 28836660 TI - Smart Conformists: Children and Adolescents Associate Conformity With Intelligence Across Cultures. AB - The current study used a novel methodology based on multivocal ethnography to assess the relations between conformity and evaluations of intelligence and good behavior among Western (U.S.) and non-Western (Ni-Vanuatu) children (6- to 11 year-olds) and adolescents (13- to 17-year-olds; N = 256). Previous research has shown that U.S. adults were less likely to endorse high-conformity children as intelligent than Ni-Vanuatu adults. The current data demonstrate that in contrast to prior studies documenting cultural differences between adults' evaluations of conformity, children and adolescents in the United States and Vanuatu have a conformity bias when evaluating peers' intelligence and behavior. Conformity bias for good behavior increases with age. The results have implications for understanding the interplay of conformity bias and trait psychology across cultures and development. PMID- 28836662 TI - Health-related quality of life and emotional well-being after epilepsy surgery: A prospective, controlled, long-term follow-up. AB - OBJECTIVE: To evaluate health-related quality of life (HRQOL) and emotional well being in resective epilepsy surgery and nonoperated patients at long-term follow up. METHODS: This is a prospective cohort study where patients undergoing presurgical work-up during 1995-1998 completed the Short-Form Health Survey (SF 36) and the Hospital Anxiety and Depression scale (HAD) at baseline, and 2 and 14 years after resective surgery or presurgical evaluation (nonoperated patients). SF-36 scores were compared to a normative population. Proportions of patients reaching HRQOL changes of minimum clinically important difference (MCID) were calculated. RESULTS: At 14-year follow-up, operated patients scored equal to or better than the normative sample on all SF-36 domains except Social Functioning and Mental Health. Physical component summary (PCS) was better and mental component summary (MCS) was worse than for the normative sample. Nonoperated patients scored worse than the normative sample on five of eight domains, and on PCS and MCS. Change in seizure status from 2 to 14 years did not affect PCS or MCS means. Improvement reaching MCID from baseline to long-term was seen in 50% (PCS) and 47% (MCS) of operated and in 33% (PCS) and 38% (MCS) of nonoperated patients. Worsening was seen in 18% (PCS) and 22% (MCS) of operated and in 38% (PCS) and 38% (MCS) of nonoperated patients. Differences between groups were nonsignificant. HAD scores did not differ between groups, and the numbers of possible or probable cases were low. Patient satisfaction with surgery was higher in operated seizure-free patients. Only 5% of all operated patients considered surgery not to be overall beneficial. SIGNIFICANCE: At the group level, HRQOL was stable 14 years after surgery compared to after 2 years. Social Functioning and Mental Health were still below, but other domains were similar to the normative sample. Individual patterns did not follow seizure outcome changes, indicating that multiple factors are important for long-term HRQOL. PMID- 28836663 TI - Detection of Herpesvirus anguillae (AngHV-1) in European eel Anguilla anguilla (L.) originating from northern Poland-assessment of suitability of selected diagnostic methods. AB - The Community Action Plan requests EU member states to implement measures that ensure the recovery of the severely depleted European eel stocks. One of the main threats is posed by Anguillid herpesvirus 1 (AngHV-1) leading to increased mortality in both wild and farmed eels. Following recommendations of the OIE to minimize the risk of obtaining false-negative results, the main aim of the study was to optimize diagnostic methods for AngHV-1 detection using conventional PCR, nested PCR and in situ hybridization assay. While 53.3% of the individual organ samples were tested positive for AngHV-1 by PCR, the additional virus analysis via nested PCR revealed that the actual prevalence was 93.3%. In the cell cultivation passages, a cytopathic effect was hardly found in the first two rounds. In the third passage onto cell cultures, a lytic CPE was detected. The identification and confirmation of the viruses obtained from cell cultures as well as directly from the organ tissues were proceeded by PCR, nested PCR and sequencing of the PCR products. While no positive signal was detectable in the first round by PCR using samples from the third cell culture passages, the nested PCR provided weak but visible positive signals. PMID- 28836661 TI - Self-dsDNA in the pathogenesis of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic and poly-aetiological autoimmune disease characterized by the production of antibodies to autologous double stranded DNA (dsDNA) which serve as diagnostic and prognostic markers. The defective clearance of apoptotic material, together with neutrophil extracellular traps (NETs), provides abundant chromatin or self-dsDNA to trigger the production of anti-dsDNA antibodies, although the mechanisms remain to be elucidated. In SLE patients, the immune complex (IC) of dsDNA and its autoantibodies trigger the robust type I interferon (IFN-I) production through intracellular DNA sensors, which drives the adaptive immune system to break down self-tolerance. In this review, we will discuss the potential resources of self-dsDNA, the mechanisms of self-dsDNA-mediated inflammation through various DNA sensors and its functions in SLE pathogenesis. PMID- 28836664 TI - Inhibitory control and lexical alignment in children with an autism spectrum disorder. AB - BACKGROUND: Two experiments investigated the contribution of conflict inhibition to pragmatic deficits in children with autism spectrum disorder (ASD). Typical adults' tendency to reuse interlocutors' referential choices (lexical alignment) implicates communicative perspective-taking, which is regulated by conflict inhibition. We examined whether children with ASD spontaneously lexically aligned, and whether conflict inhibition mediated alignment. METHODS: Children with ASD and chronological- and verbal-age-matched typically developing controls played a picture-naming game. We manipulated whether the experimenter used a preferred or dispreferred name for each picture, and examined whether children subsequently used the same name. RESULTS: Children with ASD spontaneously lexically aligned, to the same extent as typically developing controls. Alignment was unrelated to conflict inhibition in both groups. CONCLUSIONS: Children with ASD's referential communication is robust to impairments in conflict inhibition under some circumstances. Their pragmatic deficits may be mitigated in a highly structured interaction. PMID- 28836665 TI - Evaluating the Guo-Campanella viscoelastic model. AB - : Biological materials are characterized by complex structures and compositions, leading to viscoelastic behavior. Their viscoelastic characterization is important for the evaluation, design, and optimization of processes to ensure high quality products. Proposals of methodologies of analysis and modeling are critical steps in studying the rheological properties of these materials. In this context, a new model, the Guo-Campanella Model, was recently proposed to describe the stress-relaxation behavior of biological material. This work is an independent and impartial evaluation of this new model. It considers 10 different samples, comprising in natura and processed foods, from both plant and animal bases. For comparison, a Generalized Maxwell Model and the Peleg Model were also evaluated. The Guo-Campanella Model fitted the stress-relaxation data of evaluated products well, demonstrating its validity for describing the viscoelastic behavior of biological materials with different structures, sources, and processing. Finally, the Guo-Campanella Model parameters were evaluated and their interpretations and possible uses described. It was shown that the Guo Campanella Model can be successfully used for future studies. PRACTICAL APPLICATIONS: The stress-relaxation assay is a common technique for characterizing the viscoelastic properties of biological materials. The results obtained are generally evaluated using such compound models as the Generalized Maxwell model. Although this approach is interesting from a fundamental point of view, it results in many parameters to evaluate, thus increasing the complexity and limiting the interpretation. In this sense, the Guo-Campanella Model has only two parameters, which facilitates interpretation, especially for practical applications. This work validated this model, also contributing to its interpretation by discussing the meaning of its parameters. Consequently, this is potentially useful for future studies on food properties and process design. PMID- 28836667 TI - Oxidative stress is associated with late-stage amoebic gill disease in farmed Atlantic salmon (Salmo salar L.). PMID- 28836666 TI - First detection of Edwardsiella ictaluri (Proteobacteria: Enterobacteriaceae) in wild Australian catfish. AB - The bacterium Edwardsiella ictaluri is considered to be one of the most significant pathogens of farmed catfish in the United States of America and has also caused mortalities in farmed and wild fishes in many other parts of the world. E. ictaluri is not believed to be present in wild fish populations in Australia, although it has previously been detected in imported ornamental fishes held in quarantine facilities. In an attempt to confirm freedom from the bacterium in Australian native fishes, we undertook a risk-based survey of wild catfishes from 15 sites across northern Australia. E. ictaluri was detected by selective culturing, followed by DNA testing, in Wet Tropics tandan (Tandanus tropicanus) from the Tully River, at a prevalence of 0.40 (95% CI 0.21-0.61). The bacterium was not found in fishes sampled from any of the other 14 sites. This is the first report of E. ictaluri in wild fishes in Australia. PMID- 28836668 TI - Blood-brain barrier breakdown and myeloperoxidase activity in silver catfish experimentally infected with Pseudomonas aeruginosa. AB - Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality, and microbial invasion of the blood-brain barrier (BBB) is considered a prerequisite for CNS infections, which contribute to behavioural abnormalities and disease pathogenesis. Based on this information, the aim of this study was to evaluate whether Pseudomonas aeruginosa causes disruption of the BBB, and to investigate the involvement of cerebral myeloperoxidase (MPO) activity in this process in experimentally infected silver catfish. The permeability of the BBB to Evans blue dye increased in the infected animals on days three and six post-infection (PI) compared to the control group. Moreover, cerebral MPO activity and reactive oxygen species (ROS) levels also increased in the infected animals on days three and six PI compared to the control group. Based on this evidence, we concluded that P. aaeruginosa causes a disruption of the BBB, which may contribute to disease pathogenesis in the CNS. Moreover, the increase in cerebral MPO activity and ROS levels may be considered a pathway involved in BBB breakdown, allowing the passage of bacteria to the CNS. PMID- 28836669 TI - Vacuolar processing enzyme 4 contributes to maternal control of grain size in barley by executing programmed cell death in the pericarp. AB - The angiosperm embryo and endosperm are limited in space because they grow inside maternal seed tissues. The elimination of cell layers of the maternal seed coat by programmed cell death (PCD) could provide space and nutrition to the filial organs. Using the barley (Hordeum vulgare L.) seed as a model, we elucidated the role of vacuolar processing enzyme 4 (VPE4) in cereals by using an RNAi approach and targeting the enzymatic properties of the recombinant protein. A comparative characterization of transgenic versus wild-type plants included transcriptional and metabolic profiling, flow cytometry, histology and nuclear magnetic imaging of grains. The recombinant VPE4 protein exhibited legumain and caspase-1 properties in vitro. Pericarp disintegration was delayed in the transgenic grains. Although the VPE4 gene and enzymatic activity was decreased in the early developing pericarp, storage capacity and the size of the endosperm and embryo were reduced in the mature VPE4-repressed grains. The persistence of the pericarp in the VPE4-affected grains constrains endosperm and embryo growth and leads to transcriptional reprogramming, perturbations in signalling and adjustments in metabolism. We conclude that VPE4 expression executes PCD in the pericarp, which is required for later endosperm filling, and argue for a role of PCD in maternal control of seed size in cereals. PMID- 28836670 TI - Epizootics of Streptococcus agalactiae infection in captive rays from Queensland, Australia. AB - The aim of this study was to describe two epizootics of high mortalities from infection with Streptococcus agalactiae, occurring in captive rays held in a marine display aquarium in south-east Queensland, Australia, in 2009 and 2010. Five different species of rays were affected, including mangrove whiprays (Himantura granulata), estuary rays (Dasyatis fluviorum), eastern shovelnose rays (Aptychotrema rostrata), white-spotted eagle rays (Aetobatus narinari) and blue spotted mask rays (Neotrygon kuhlii). This report describes the history of both epizootics including collection, quarantine and husbandry of rays, the disease epizootics, clinico-pathological features of the disease, antimicrobial therapy, autogenous vaccine production, and laboratory studies including clinical and histopathology, bacteriology, PCR, molecular serotyping and sequencing of the bacterium S. agalactiae. PMID- 28836671 TI - First description of a mortality event in adult Pacific oysters in Italy associated with infection by a Tenacibaculum soleae strain. AB - Summer mortality episodes in adult Pacific oysters have been described since the 1950s in various farming areas. Starting in 2012, a recrudescence of mortalities in commercial-sized oysters was first observed in France and then in Italy, with seasonality extension and translation later in the year. Moribund individuals collected during an event in Italy in December 2014 showed yellowish lesions of the mantle and adductor muscle. Histological examination revealed filamentous bacteria associated with necrotic areas. Quantitative PCRs targeting OsHV-1 and Vibrio aestuarianus detected only high loads of the pathogenic bacteria in tissues of symptomatic individuals. A lower diversity of the hemolymph microbiota was also evidenced in moribund individuals, with a predominance of Vibrio and Arcobacter species. A strain of Flavobacteriaceae was isolated from all the symptomatic individuals. Sequence analysis of the 16S rRNA gene identified the strain as Tenacibaculum soleae. When strain pathogenicity was tested by injection in adult individuals, it induced mortality rates of up to 45%, even in the absence of V. aestuarianus. As mortality occurred only 11 days post-infection, further investigation is needed to determine its effective virulence in natural conditions. This is the first description of a Tenacibaculum strain associated with bivalve mortalities. PMID- 28836672 TI - Whole grain cereals for the primary or secondary prevention of cardiovascular disease. AB - BACKGROUND: There is evidence from observational studies that whole grains can have a beneficial effect on risk for cardiovascular disease (CVD). Earlier versions of this review found mainly short-term intervention studies. There are now longer-term randomised controlled trials (RCTs) available. This is an update and expansion of the original review conducted in 2007. OBJECTIVES: The aim of this systematic review was to assess the effect of whole grain foods or diets on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible RCTs. SEARCH METHODS: We searched CENTRAL (Issue 8, 2016) in the Cochrane Library, MEDLINE (1946 to 31 August 2016), Embase (1980 to week 35 2016), and CINAHL Plus (1937 to 31 August 2016) on 31 August 2016. We also searched ClinicalTrials.gov on 5 July 2017 and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 6 July 2017. We checked reference lists of relevant articles and applied no language restrictions. SELECTION CRITERIA: We selected RCTs assessing the effects of whole grain foods or diets containing whole grains compared to foods or diets with a similar composition, over a minimum of 12 weeks, on cardiovascular disease and related risk factors. Eligible for inclusion were healthy adults, those at increased risk of CVD, or those previously diagnosed with CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies. Data were extracted and quality-checked by one review author and checked by a second review author. A second review author checked the analyses. We assessed treatment effect using mean difference in a fixed-effect model and heterogeneity using the I2 statistic and the Chi2 test of heterogeneity. We assessed the overall quality of evidence using GRADE with GRADEpro software. MAIN RESULTS: We included nine RCTs randomising a total of 1414 participants (age range 24 to 70; mean age 45 to 59, where reported) to whole grain versus lower whole grain or refined grain control groups. We found no studies that reported the effect of whole grain diets on total cardiovascular mortality or cardiovascular events (total myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, total stroke). All included studies reported the effect of whole grain diets on risk factors for cardiovascular disease including blood lipids and blood pressure. All studies were in primary prevention populations and had an unclear or high risk of bias, and no studies had an intervention duration greater than 16 weeks.Overall, we found no difference between whole grain and control groups for total cholesterol (mean difference 0.07, 95% confidence interval -0.07 to 0.21; 6 studies (7 comparisons); 722 participants; low-quality evidence).Using GRADE, we assessed the overall quality of the available evidence on cholesterol as low. Four studies were funded by independent national and government funding bodies, while the remaining studies reported funding or partial funding by organisations with commercial interests in cereals. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs of an effect of whole grain diets on cardiovascular outcomes or on major CVD risk factors such as blood lipids and blood pressure. Trials were at unclear or high risk of bias with small sample sizes and relatively short-term interventions, and the overall quality of the evidence was low. There is a need for well-designed, adequately powered RCTs with longer durations assessing cardiovascular events as well as cardiovascular risk factors. PMID- 28836674 TI - Effects of hydrocolloids as fat replacers on the physicochemical properties of produced Labneh. AB - : This study was undertaken to investigate the effects of hydrocolloids when used as fat replacers on the physicochemical properties of Labneh. Four combination sets of carboxymethylcellulose, Arabic gum, carrageenan, and xanthan were used in a three factor mixture response surface methodology. Labneh water holding capacity (WHC), viscosity parameters, texture and sensory attributes were assessed. WHC played the critical role in affecting produced Labneh physical properties. Hydrocolloids influenced Labneh WHC in the following order; xanthan > Arabic gum > carrageenan > carboxymethylcellulose. Furthermore, xanthan showed an antagonistic effect with carboxymethylcellulose that lead to the decrease in WHC. Usage of 17% xanthan and 66% Arabic gum resulted in an increase in WHC to 98.6% which indicates a mixture response effect of hydrocolloids in affecting WHC of produced Labneh. The increase in carrageenan from 17% to 66% resulted in an increase in WHC from 62.7 to 70.7%. Consumer testing showed a superior Labneh sensory attributed using various hydrocolloids combinations compared to a control. Hydrocolloids were successfully used in Labneh as fat replacers. The developed reduced fat Labneh with its texture and sensory attributed that exceeded the full fat Labneh attributed can provide a solution to consumers with restricting fat diets. PRACTICAL APPLICATIONS: Carbohydrate-based fat replacers are of growing interest because of their physicochemical, sensorial properties, and health characteristics. The used hydrocolloids suggest plausible texture and sensory attributes solution in low or reduced fat content products including dairy products. PMID- 28836673 TI - Evaluation of gene expression levels for cytokines in ocular toxoplasmosis. AB - This study evaluated levels for mRNA expression of 7 cytokines in ocular toxoplasmosis. Peripheral blood mononuclear cells (PBMC) of patients with ocular toxoplasmosis (OT Group, n = 23) and chronic toxoplasmosis individuals (CHR Group, n = 9) were isolated and stimulated in vitro with T. gondii antigen. Negative controls (NC) were constituted of 7 PBMC samples from individuals seronegative for toxoplasmosis. mRNA expression for cytokines was determined by qPCR. Results showed a significant increase in mRNA levels from antigen stimulated PBMCs derived from OT Group for expressing IL-6 (at P < .005 and P < .0005 for CHR and NC groups, respectively), IL-10 (at P < .0005 and P < .005 for CHR and NC groups, respectively) and TGF-beta (at P < .005) for NC group. mRNA levels for TNF-alpha and IL-12 were also upregulated in patients with OT compared to CHR and NC individuals, although without statistical significance. Additionally, mRNA levels for IL-27 and IFN-gamma in PBMC of patients with OT were upregulated in comparison with NC individuals. Differences between OT and NC groups were statistically significant at P < .05 and P < .0005, respectively. PMID- 28836675 TI - Commentary: The importance of exploring dose-dependent, subtype-specific, and age related effects of maltreatment on the HPA axis and the mediating link to psychopathology. A response to Fisher (2017). AB - We greatly appreciate Dr. Fisher's commentary that provides an excellent backdrop and well-considered perspective on our findings. We agree that our results mesh well with previous work documenting hypocortisolism among youth who experienced early adversity, especially neglect. Moreover, as also perceptively noted by Dr. Fisher, our cross-sectional data provide support for the notion that hypocortisolism is not simply a transient phenomenon, but, rather, a persistent pattern characterizing maltreated youth. Specifically, the consistency of the between group effect (from age 9.69 onwards) on a multimonth index of cumulative cortisol and the dose-dependent gradient of cortisol secretion within the maltreated group, which was related to the number of subtypes and the length of exposure to maltreatment, lend weight to this view. PMID- 28836676 TI - Commentary: Is there a there there in hair? A reflection on child maltreatment and hair cortisol concentrations in White et al. (2017). AB - Both chronic and acute stressors have typically been understood to produce elevations in cortisol, as a means to maintaining homeostatic balance. In the past two decades, however, individuals experiencing high levels of chronic early adversity have been shown to manifest an alternate profile involving blunted cortisol levels. In the context of this emerging evidence, a number of questions about diminished cortisol have remained unclear. The study by White et al. (2017) is the first to measure hair cortisol concentrations in the context of adversity, and provides validation for the stability of diminished cortisol in maltreated individuals, the association between neglect and low cortisol, and a mediating role for dysregulated hypothalamic-pituitary-adrenal axis activity in the association between early maltreatment and behavioral dysregulation. PMID- 28836677 TI - Erratum. PMID- 28836678 TI - Commentary: Lingering questions about the Social Responsiveness Scale short form. A commentary on Sturm et al. (2017). PMID- 28836679 TI - Commentary: A refresh for evidence-based psychological therapies - reflections on Marchette and Weisz (2017). AB - Is the introduction of evidence-based psychotherapy into mainstream child and adolescent mental health services (CAMHS) a breakthrough for a scientific approach to child mental health? Or are we still in the dark ages despite our best efforts to link evidence with practice (EBP)? PMID- 28836680 TI - Basic science and treatment innovation. AB - The idea of trans-diagnostic and modular treatments highlighted in this Editorial points the way beyond self-contained 'branded' therapies to a more flexible intervention science responsive to advances in basic science and relevant also to personalisation of therapies. For such approaches to be rigorous, there need to be empirically identified trans-diagnostic target mechanisms. The Editorial reviews two studies of potential mechanisms of this kind in the developmental neurobiology of stress response in children at risk from prenatal maternal stress and post natal neglect and maltreatment. A number of treatment trials are also reviewed illustrating the common method of digitally-aided therapy; a common theme is the difficult in sustaining adherence to such treatment delivery methods. Finally it reviews a useful independent investigation of a commonly used autism screening instrument, suggesting improvements for greater specificity. PMID- 28836681 TI - Recent developments in capillary and microchip electroseparations of peptides (2015-mid 2017). AB - The review brings a comprehensive overview of recent developments and applications of high performance capillary and microchip electroseparation methods (zone electrophoresis, isotachophoresis, isoelectric focusing, affinity electrophoresis, electrokinetic chromatography, and electrochromatography) to analysis, microscale isolation, purification, and physicochemical and biochemical characterization of peptides in the years 2015, 2016, and ca. up to the middle of 2017. Advances in the investigation of electromigration properties of peptides and in the methodology of their analysis (sample preseparation, preconcentration and derivatization, adsorption suppression and EOF control, and detection) are described. New developments in particular CE and CEC methods are presented and several types of their applications to peptide analysis are reported: qualitative and quantitative analysis, determination in complex (bio)matrices, monitoring of chemical and enzymatical reactions and physical changes, amino acid, sequence and chiral analysis, and peptide mapping of proteins. Some micropreparative peptide separations are shown and capabilities of CE and CEC methods to provide important physicochemical characteristics of peptides are demonstrated. PMID- 28836683 TI - Case of linear bullous aplasia cutis congenita. PMID- 28836682 TI - Millimeter-wave emissivity as a metric for the non-contact diagnosis of human skin conditions. AB - A half-space electromagnetic model of human skin over the band 30-300 GHz was constructed and used to model radiometric emissivity. The model showed that the radiometric emissivity rose from 0.4 to 0.8 over this band, with emission being localized to a layer approximately one millimeter deep in the skin. Simulations of skin with differing water contents associated with psoriasis, eczema, malignancy, and thermal burn wounds indicated radiometry could be used as a non contact technique to detect and monitor these conditions. The skin emissivity of a sample of 30 healthy volunteers, measured using a 95 GHz radiometer, was found to range from 0.2 to 0.7, and the experimental measurement uncertainty was +/ 0.002. Men on average were found to have an emissivity 0.046 higher than those of women, a measurement consistent with men having thicker skin than women. The regions of outer wrist and dorsal forearm, where skin is thicker, had emissivities 0.06-0.08 higher than the inner wrist and volar forearms where skin is generally thinner. Recommendations are made to develop a more sophisticated model of the skin and to collect larger data sets to obtain a deeper understanding of the signatures of human skin in the millimeter wave band. Bioelectromagnetics. 38:559-569, 2017. (c) 2017 The Authors. Bioelectromagnetics published by Wiley Periodicals, Inc. PMID- 28836684 TI - Usefulness of dual-energy computed tomography for the evaluation of early-stage psoriatic arthritis only accompanied by nail psoriasis. PMID- 28836686 TI - Wong-type dermatomyositis: A first report from Japan. PMID- 28836685 TI - Occupational styrene exposure and acquired dyschromatopsia: A systematic review and meta-analysis. AB - BACKGROUND: Styrene is a chemical used in the manufacture of plastic-based products worldwide. We systematically reviewed eligible studies of occupational styrene-induced dyschromatopsia, qualitatively synthesizing their findings and estimating the exposure effect through meta-analysis. METHODS: PubMed, EMBASE, and Web of Science databases were queried for eligible studies. Using a random effects model, we compared measures of dyschromatopsia between exposed and non exposed workers to calculate the standardized mean difference (Hedges'g). We also assessed between-study heterogeneity and publication bias. RESULTS: Styrene exposed subjects demonstrated poorer color vision than did the non-exposed (Hedges' g = 0.56; 95%CI: 0.37, 0.76; P < 0.0001). A non-significant Cochran's Q test result (Q = 23.2; P = 0.171) and an I2 of 32.2% (0.0%, 69.9%) indicated low to-moderate between-study heterogeneity. Funnel plot and trim-and-fill analyses suggested publication bias. CONCLUSIONS: This review confirms the hypothesis of occupational styrene-induced dyschromatopsia, suggesting a modest effect size with mild heterogeneity between studies. PMID- 28836687 TI - Neuroprotective potential of astroglia. AB - Astroglia are the homoeostatic cells of the central nervous system, which participate in all essential functions of the brain. Astrocytes support neuronal networks by handling water and ion fluxes, transmitter clearance, provision of antioxidants, and metabolic precursors and growth factors. The critical dependence of neurons on constant support from the astrocytes confers astrocytes with intrinsic neuroprotective properties. On the other hand, loss of astrocytic support or their pathological transformation compromises neuronal functionality and viability. Manipulating neuroprotective functions of astrocytes is thus an important strategy to enhance neuronal survival and improve outcomes in disease states. (c) 2017 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc. PMID- 28836689 TI - Acral lentiginous melanoma with dematiaceous fungal elements of Chaetomium globosum: A saprophytism or coexistence of superficial phaeohyphomycosis? PMID- 28836688 TI - Src kinase inhibition reduces inflammatory and cytoskeletal changes in DeltaF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy. AB - : Cystic fibrosis transmembrane conductance regulator (CFTR), the channel mutated in cystic fibrosis (CF), is expressed by the biliary epithelium (i.e., cholangiocytes) of the liver. Progressive clinical liver disease (CF-associated liver disease; CFLD) occurs in around 10% of CF patients and represents the third leading cause of death. Impaired secretion and inflammation contribute to CFLD; however, the lack of human-derived experimental models has hampered the understanding of CFLD pathophysiology and the search for a cure. We have investigated the cellular mechanisms altered in human CF cholangiocytes using induced pluripotent stem cells (iPSCs) derived from healthy controls and a DeltaF508 CFTR patient. We have devised a novel protocol for the differentiation of human iPSC into polarized monolayers of cholangiocytes. Our results show that iPSC-cholangiocytes reproduced the polarity and the secretory function of the biliary epithelium. Protein kinase A/cAMP-mediated fluid secretion was impaired in DeltaF508 cholangiocytes and negligibly improved by VX-770 and VX-809, two small molecule drugs used to correct and potentiate DeltaF508 CFTR. Moreover, DeltaF508 cholangiocytes showed increased phosphorylation of Src kinase and Toll like receptor 4 and proinflammatory changes, including increased nuclear factor kappa-light-chain-enhancer of activated B cells activation, secretion of proinflammatory chemokines (i.e., monocyte chemotactic protein 1 and interleukin 8), as well as alterations of the F-actin cytoskeleton. Treatment with Src inhibitor (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine) decreased the inflammatory changes and improved cytoskeletal defects. Inhibition of Src, along with administration of VX-770 and VX-809, successfully restored fluid secretion to normal levels. CONCLUSION: Our findings have strong translational potential and indicate that targeting Src kinase and decreasing inflammation may increase the efficacy of pharmacological therapies aimed at correcting the basic DeltaF508 defect in CF liver patients. These studies also demonstrate the promise of applying iPSC technology in modeling human cholangiopathies. (Hepatology 2018;67:972-988). PMID- 28836690 TI - Methotrexate, but not narrowband ultraviolet B radiation, suppresses interleukin 33 mRNA levels in psoriatic plaques and protein levels in serum of patients with psoriasis. AB - Interleukin (IL)-33 can function both as a conventional cytokine and as a nuclear factor regulating gene transcription. IL-33 expression is strongly upregulated in the nucleus of keratinocytes and serum of patients with psoriasis. However, the role of IL-33 in psoriasis is unclear, and IL-33 expression in the lesional psoriatic skin after conventional systemic treatments has not been investigated. In this study, we aimed to compare IL-33 mRNA in patients' lesional skin samples and IL-33 protein expression in patients' serum before and after treatment with methotrexate (MTX) and narrowband ultraviolet B (NB-UVB). IL-33 mRNA levels in lesional skin and IL-33 protein levels in serum were downregulated after treatment with MTX. Results revealed a significant decrease in IL-33 protein expression (P = 0.028). IL-33 expression increased after NB-UVB treatment. IL-33 production is associated with inflammatory skin in psoriasis, possibly through its cytokine function. However, high expression of IL-33 after NB-UVB treatment suggests the occurrence of unknown functions to alleviate psoriatic lesions without IL-33 involvement. PMID- 28836692 TI - Forced acoustic oscillations of biological cell. AB - This article considers the possibility of excitation of acoustic oscillations in a cell by electromagnetic waves. In this process, not only the frequency but also the length of a wave is of great importance. It is also reported that the pulse signal can be more effective than harmonic signal, and the pulse length is not essential. In accordance with this fact, it is possible to explain the biological effects of electromagnetic waves and to develop new medical electronic devices. Bioelectromagnetics. 38:613-617, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28836691 TI - Disseminated cutaneous Mycobacterium kansasii infection presenting with Rosai Dorfman disease-like histological features in a patient carrying anti-interferon gamma autoantibodies. AB - Typical cutaneous non-tuberculous mycobacteria (NTM) infections show a histopathology pattern of granulomas with admixed Langhans giant cells, and abscesses may be observed in acute lesions. Herein, we describe a patient carrying a high titer of autoantibodies to interferon (IFN)-gamma with disseminated Mycobacterium kansasii infection presenting with emperipolesis and Rosai-Dorfman disease (RDD)-like histopathological features characterized by remarkable, large, pale-staining "RD cells", which were CD68 and S100 positive and CD1a negative. The patient was misdiagnosed with RDD initially, but exhibited a poor response to all interventions. A re-biopsy revealed Langhans-type multinucleated giant cells; multiple definite acid-fast bacilli were also found. M. kansasii was isolated from cultured tissues. Anti-NTM treatment was initiated. After treatment, all lesions resolved almost completely within the following month. High-titer anti-IFN-gamma autoantibodies were detected during follow up, leading to the diagnosis of adult-onset immunodeficiency syndrome. In conclusion, patients carrying high-titer autoantibodies to IFN-gamma who also have a disseminated cutaneous M. kansasii infection may present with RDD-like histopathological features, which may be a pitfall in the diagnosis of disseminated cutaneous NTM infections. PMID- 28836693 TI - Case of diffuse panbronchiolitis developed in a patient with epidermodysplasia verruciformis. PMID- 28836694 TI - Elements of a sustainable, competent, and empathetic workforce to support patients with dementia during an acute hospital stay: A comprehensive literature review. AB - Internationally, there has been a focus on the development of acute hospital workforces to support and care for people with dementia. Recommendations and initiatives to improve person-centred care in acute hospitals have included: education and training, dementia-specific roles, clinical leads, and environment changes. The aim of this literature review is to understand the elements of a sustainable, competent, and empathetic acute hospital workforce providing person centred care for patients with dementia. The following databases were searched for literature published in English from January 1, 2006, to August 1, 2016: CINHAL, MEDLINE, PsychINFO, PubMed, and Science Direct. A thematic analysis was applied to develop a meta-synthesis of the data. A total of 12 papers with a range of methodological approaches from various countries were included. Emergent themes were as follows: understanding the current workforce, implementation and evaluation of training, and exploration of new and existing roles. An important element was the sustainability of acute hospital workforces competent in dementia care, as studies highlighted an ageing nursing population and a high turnover of staff. Dementia awareness training was sustainable, although there was a lack of consistency in the length, content, and delivery, which had a viable impact on the provision of empathetic and person-centred care. The lack of consistency of training and specialist dementia roles restricts recommendations from a robust evidence base. PMID- 28836696 TI - Transungual fibrokeratoma. PMID- 28836695 TI - Synthesis, binding ability, and cell cytotoxicity of fluorescent probes for l arginine detection based on naphthalene derivatives: Experiment and theory. AB - Inspired by biological related parts, Schiff base derivatives and functional groups of chemical modification can provide efficient detection method of amino acids. Therefore, we have designed and prepared 4 compounds based on Schiff base derivatives involving ?NO2 , ?OH, and naphthyl group. Results indicated that compound 4 containing 2 nitro groups showed strong sensitivity and high selectivity for arginine (Arg) among normal 18 kinds of standard amino acids (alanine, valine, leucine, isoleucine, methionine, aspartic acid, glutamic acid, arginine, glycine, serine, asparagine, phenylalanine, histidine, tryptophan, proline, lysine, glutamine, and cysteine). Theoretical investigation also approved the strong binding ability of compound 4 for Arg. In addition, compound 4 displayed high combining ability of Arg and low cytotoxicity of MCF-7 cell in the 0 to 150 MUg mL-1 of concentration range; it can be used for Arg in vivo detection of fluorescent probe. PMID- 28836697 TI - Visible-Light-Induced, Catalyst-Free Radical Arylations of Arenes and Heteroarenes with Aryldiazonium Salts. AB - In the absence of a photocatalyst and other additives, the radical arylation of diverse arenes and heteroarenes has been achieved with aryldiazonium salts under visible-light irradiation from a blue light-emitting diode (LED). Although the course of some reactions can be rationalized by the formation of strongly light absorbing charge-transfer (CT) complexes between the diazonium ion and the aromatic substrate, several further examples indicated that the simple presence of an aromatic substrate, showing only weak interactions to the diazonium ion, is fully sufficient to enable product formation. PMID- 28836698 TI - Re-evaluating the use of ultrasound to investigate first febrile urinary tract infections in childhood. PMID- 28836699 TI - C-H Bond Functionalization by Mechanochemistry. AB - The advances made in the mechanosynthesis of inorganic and organometallic complexes and the excellent past developments with metal-catalyzed cross-coupling reactions by high-speed ball milling have sufficienly laid the ground work for the merging of C-H functionalization and mechanochemical techniques. In recent years, the fast development of mechanochemical C-H activation have given us examples of metal-catalyzed olefinations, amidations, halogenations, and oxidative couplings, among others. This concept article will describe some of the events that led to the development of mechanochemical C-H activation, the current state-of-the-art, the present challenges of this merge, and some unique scenarios in which mechanochemistry could complement the traditional solution-based approaches. PMID- 28836700 TI - Rational Design Rules for Molecular Water Oxidation Catalysts based on Scaling Relationships. AB - Lowering the overpotential required for water oxidation is of paramount importance for the efficient production of carbon-neutral fuels. This article highlights the intrinsic influence of the water oxidation mechanism used by molecular catalysts on the theoretically achievable minimal overpotential, based on scaling relationships typically used for heterogeneous catalysts. Due to such scaling relationships, catalysts that operate through the water nucleophilic attack mechanism have a fundamental minimal overpotential of about 0.3 V, whereas those that follow the dinuclear radical oxo coupling mechanism should in principle be able to operate with a lower overpotential. Therefore, it is recommended to design catalysts operating through the latter mechanism to achieve very efficient water oxidation systems. PMID- 28836701 TI - BSACI guideline for the diagnosis and management of peanut and tree nut allergy. AB - Peanut nut and tree nut allergy are characterised by IgE mediated reactions to nut proteins. Nut allergy is a global disease. Limited epidemiological data suggest varying prevalence in different geographical areas. Primary nut allergy affects over 2% of children and 0.5% of adults in the UK. Infants with severe eczema and/or egg allergy have a higher risk of peanut allergy. Primary nut allergy presents most commonly in the first five years of life, often after the first known ingestion with typical rapid onset IgE-mediated symptoms. The clinical diagnosis of primary nut allergy can be made by the combination of a typical clinical presentation and evidence of nut specifc IgE shown by a positive skin prick test (SPT) or specific IgE (sIgE) test. Pollen food syndrome is a distinct disorder, usually mild, with oral/pharyngeal symptoms, in the context of hay fever or pollen sensitisation, which can be triggered by nuts. It can usually be distinguish clinically from primary nut allergy. The magnitude of a SPT or sIgE relates to the probability of clinical allergy, but does not relate to clinical severity. SPT of >= 8 mm or sIgE >= 15 KU/L to peanut is highly predictive of clinical allergy. Cut off values are not available for tree nuts. Test results must be interpreted in the context of the clinical history. Diagnostic food challenges are usually not necessary but may be used to confirm or refute a conflicting history and test result. As nut allergy is likely to be a long-lived disease, nut avoidance advice is the cornerstone of management. Patients should be provided with a comprehensive management plan including avoidance advice, patient specific emergency medication and an emergency treatment plan and training in administration of emergency medication. Regular re training is required. PMID- 28836702 TI - Results of a 36-year surveillance program for ulcerative colitis-associated neoplasia in the Japanese population. AB - BACKGROUND AND AIM: Surveillance colonoscopy has been carried out for patients with long-standing ulcerative colitis who have an increased risk for colorectal cancer. The aim of the present study was to determine the incidence of and the risk factors for neoplasia. METHODS: We evaluated 289 ulcerative colitis patients who underwent surveillance colonoscopy between January1979 and December 2014. Cumulative incidence of neoplasia and its risk factors were investigated. Clinical stage and overall survival were compared between the surveillance and non-surveillance groups. RESULTS: Cumulative risk of dysplasia was 3.3%, 12.1%, 21.8%, and 29.1% at 10, 20, 30 and 40 years after the onset of ulcerative colitis, respectively. Cumulative risk of colorectal cancer was 0.7%, 3.2%, 5.2%, and 5.2% at 10, 20, 30 and 40 years from the onset of ulcerative colitis, respectively. Total colitis was a risk factor for neoplasia (P = 0.015; hazard ratio, 2.96). CONCLUSIONS: Our surveillance colonoscopy program revealed the incidence and risk factors of ulcerative colitis-associated neoplasias in the Japanese population. Total colitis is a risk factor for neoplasia. PMID- 28836703 TI - Anoikis resistance and oncoviruses. AB - Anoikis is known as a special type of programmed cell death which occurs in response to loss of correct cell-extracellular matrix (ECM) connections. This process could be as pivotal event in normal development and tissue homeostasis and found as important mechanism in cancer invasiveness and metastasis. The persistent infection with oncoviruses including EBV (Epstein Bar virus), HPV (Human Papillomaviruses), HBV (Hepatitis B virus), KSHV (Human herpesvirus 8), HTLV-1 (Human T-lymphotropic virus-1), and HCV (Hepatitis C virus) accounted as one of main risk factor for cancer progression. Some of them play critical roles in metastasis, especially in anoikis resistance which could contribute to metastasis of tumor cells. The better understanding of effects of oncoviruses on anoikis could contribute to finding of effective therapeutic platforms for treatment of virus-associated cancers. This paper highlighted effects of these oncoviruses on anoikis protection in cancer. PMID- 28836705 TI - Survival and neurodevelopmental outcomes in extremely preterm infants 22-24 weeks of gestation born in Western Australia. AB - AIM: The management of births at borderline viability continues to present dilemmas for health professionals and parents. The aim of the study was to review local outcomes of infants born between 22 and 24 weeks of gestation between 2004 and 2010 in Western Australia (WA) to aid perinatal counselling. METHODS: Survival data for the study were sourced retrospectively from the Neonatal Clinical Care Unit and Department of Health records of births in WA. Neurodevelopmental follow-up outcomes were assessed using the most recent standardised assessment (Griffiths, Bayley-III and Wechsler Preschool and Primary Scale of Intelligence, 3rd Ed) and medical examination of infants/children 12 months to 8 years from follow-up clinic appointments. RESULTS: At these gestations, 159 survivors represented 72% of neonatal intensive care unit admissions, 53% of WA live births and 26% of WA live and still births; 5% of live births survived at 22 weeks, 46% at 23 weeks and 77% at 24 weeks. Of the 14 outborn/retrieved infants, 4 survived (29%). At a median age of 59 months, disabilities were severe in 13% of children (22-23w = 19%; 24w = 11%). The median test quotient was 90. Moderate and severe cognitive disability was found in 16%, cerebral palsy was found in 7% (n = 11), and 55% of children were free from impairment as defined in this study. CONCLUSION: At these gestations, survival figures varied markedly with the chosen population denominator. Regional data are essential for valid population comparison. While many developmental difficulties occurred in these children, 78% were free from moderate or severe impairment at ages 3-5 years. PMID- 28836704 TI - A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species. AB - Lipoate is an essential cofactor for enzymes that are important for central metabolism and other processes. In malaria parasites, scavenged lipoate from the human host is required for survival. The Plasmodium falciparum mitochondrion contains two enzymes (PfLipL1 and PfLipL2) that are responsible for activating mitochondrial proteins through the covalent attachment of lipoate (lipoylation). Lipoylation occurs via a novel redox-gated mechanism that remains poorly understood. We show that PfLipL1 functions as a redox switch that determines which downstream proteins will be activated. Based on the lipoate redox state, PfLipL1 either functions as a canonical lipoate ligase or as a lipoate activating enzyme which works in conjunction with PfLipL2. We demonstrate that PfLipL2 is a lipoyltransferase and is a member of a novel clade of lipoate attachment enzymes. We show that a LipL2 enzyme from Chlamydia trachomatis has similar activity, demonstrating conservation between intracellular pathogens from different phylogenetic kingdoms and supporting the hypothesis that an early ancestor of malaria parasites once contained a chlamydial endosymbiont. Redox-dependent lipoylation may regulate processes such as central metabolism and oxidative defense pathways. PMID- 28836706 TI - The utility of serial echocardiograms for organ procurement in brain death. AB - Heart transplantation rates are limited by a shortage of donor hearts, and left ventricular dysfunction is an important cause. We hypothesized that an early echocardiographic evaluation in severe brain injury (performed within 12 hours from ICU admission) could allow the detection of potentially reversible left ventricular (LV) abnormalities and thus the initiation of tailored treatment whose effects could be assessed at a second echocardiogram performed when brain death develops. We assessed this hypothesis in 49 patients with severe brain injury who were potential heart donors. A reduction in LV ejection fraction (LVEF) (<55%) was present in five patients (10.2%): diffuse hypokinesia in three patients (6.1%), segmental wall motion abnormalities in two (4.1%). Two patients showed apical ballooning (normal LVEF). The three patients with diffuse hypokinesia showed, at the echocardiogram performed 12 hours later, a complete recovery of wall motion and LVEF. Among patients with apical ballooning, a complete resolution was observed in both patients. Two patients were considered potentially eligible for heart donation, resulting in 20% increase in donor retrieval rate. In serious encephalic lesions, potentially evolving toward brain death, echocardiography performed after ICU admission allowed the identification of LV abnormalities, which could be specifically treated with complete resolution. PMID- 28836707 TI - Quantification of the Pyrrolizidine Alkaloid Jacobine in Crassocephalum crepidioides by Cation Exchange High-Performance Liquid Chromatography. AB - INTRODUCTION: Pyrrolizidine alkaloids (PAs) are secondary plant metabolites with considerable hepatoxic, tumorigenic and genotoxic potential. For separation, reversed phase chromatography is commonly used because of its excellent compatibility with detection by mass spectrometry. However, reversed phase chromatography has a low selectivity for PAs. OBJECTIVE: The objective of this work was to investigate the suitability of cation exchange chromatography for separation of PAs and to develop a rapid method for quantification of jacobine in Crassocephalum crepidioides that is suitable for analysis of huge sample numbers as required for mutant screening procedures. RESULTS: We demonstrate that cation exchange chromatography offers excellent selectivity for PAs allowing their separation from most other plant metabolites. Due to the high selectivity, plant extracts can be directly analysed after simple sample preparation. Detection with UV at 200 nm instead of mass spectrometry can be applied, which makes the method very simple and cost-effective. The recovery rate of the method exceeded 95%, the intra-day and inter-day standard deviations were below 7% and the limit of detection and quantification were 1 mg/kg and 3 mg/kg, respectively. CONCLUSION: The developed method is sufficiently sensitive for reproducible detection of jacobine in C. crepidioides. Simple sample preparation and rapid separation allows for quantification of jacobine in plant material in a high-throughput manner. Thus, the method is suitable for genetic screenings and may be applicable for other plant species, for instance Jacobaea maritima. In addition, our results show that C. crepidioides cannot be considered safe for human consumption. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28836708 TI - Tuning the pKa of Fluorescent Rhodamine pH Probes through Substituent Effects. AB - Rhodamine spirolactams (RSLs) have recently emerged as popular fluorescent pH probes due to their fluorescence turn-on capability and ease of functionalization at the spirolactam nitrogen. Design of RSLs is often driven by biological targeting or compatibility concerns, rather than the pH sensitivity of the probe, and the relationship between RSL structure and pKa is not well understood. To elucidate the relationship between pKa values and the properties of substituents attached to the spirolactam nitrogen, a series of 19 aniline-derived RSLs is presented. RSLs derived from di-ortho-substituted anilines exhibit pKa tunability across the moderately acidic region (ca. pH 4-6). Evaluation of pKa data using the Fujita-Nishioka model for ortho substituent effects reveals that both steric and electronic substituent properties influence RSL pH responsiveness, with pKa values increasing as substituent size and electron withdrawing character increase. These trends are attributed to changes in the RSL structure induced by large substituents, and to electronic influences on the protonated spirocyclic reaction intermediate. To demonstrate the practical applicability of these probes in completely aqueous environments, RSL-doped conjugated polymer nanoparticles that exhibit a ratiometric fluorescence response to changing pH levels are presented. PMID- 28836709 TI - Persistency of left atrial linear lesions after radiofrequency catheter ablation for atrial fibrillation: Data from an invasive follow-up electrophysiology study. AB - BACKGROUND: Data on the roof line (RL) and mitral isthmus line (MIL) reconnections after atrial fibrillation (AF) catheter ablation (CA) are scarce. OBJECTIVE: We studied the RL and MIL completeness and localization of reconnection sites in consecutive patients after their first-ever AF-CA. METHODS: We prospectively included 41 consecutive AF patients who underwent predefined lesion sets of two circumferential lines (CLs) for ipsilateral pulmonary vein isolation (PVI) combined with a RL and lateral MIL. Three months after CA, all patients underwent invasive follow-up procedure for line persistency evaluation, irrespective of clinical outcome. RESULTS: At the time of index ablation, PVI CLs, RL, and MIL was completed in 41 (100%), 39 (95%), and 34 (83%) of patients, respectively. At the 3-month follow-up procedure, reconnections of PVI-CLs, RL, and MIL were found in 61% (25/41), 28% (11/39), and 24% (8/34) of patients, respectively. The 3-month reconnections were located commonly in the anterior and posterior PVI-CL segments, and rarely in the right third of RL and in the posterior part of MIL. The 3-month reconnections were rarely seen at the sites of acute reconnections during index procedure (6%, 20%, and 25% of the PVI-CL segments, RL segments, and MIL segments, respectively). CONCLUSIONS: To our knowledge, this is the first study systematically investigating the reconnection of standardized left atrium linear lesions such as RL and MIL after RF-CA for AF in consecutive patients. The RL and MIL 3-month reconnection rates were relatively low (28% and 24%), with poor anatomical concordance between the sites with acute and 3-month reconnections. PMID- 28836710 TI - Airway plaque presenting after alteration of immunosuppression in a pediatric patient remote from heart transplantation. AB - Success after solid organ transplantation is dependent on the proper balance of immunosuppression to prevent rejection of the allograft while limiting the risk of developing infections and malignancy. We present a 9-year-old girl, remote from transplant, who presented with airway plaque after a change in immunosuppression to include the mTOR inhibitor sirolimus. Differential diagnosis included direct medication side effect, infection, and neoplasia. PMID- 28836711 TI - Delirium tremens and alcohol withdrawal nationally in the Veterans Health Administration. AB - BACKGROUND AND OBJECTIVES: Alcohol withdrawal-especially delirium tremens (DT)-is a potentially life-threatening condition. While short-term treatment regimens and factors that predispose to more severe symptomatology have been extensively studied, little attention has been paid to the clinical epidemiology and long term care of the chronic medical, addictive, psychiatric, and psychosocial problems faced by these patients. METHODS: National Veterans Health Administration data from fiscal year 2012 were examined to identify veterans diagnosed with DT; with withdrawal but not DT (WNDT); and with Alcohol Use Disorder (AUD) but neither DT nor WNDT. They were compared on sociodemographic characteristics, psychiatric and medical co-morbidities, and health service and psychotropic medication use, first with bivariate analyses and then multiple logistic regression. RESULTS: Among the 345,297 veterans diagnosed with AUD, 2,341 (0.7%) were diagnosed with DT and 6,738 (2.0%) with WNDT. Veterans diagnosed with either WNDT or DT were more likely to have been homeless, had more comorbid medical and psychiatric disorders, were more likely to be diagnosed with drug use disorders, utilized more health services, received more psychotropic medications, and were more likely to receive naltrexone. They were more likely to receive specialized legal, housing, vocational, and psychosocial rehabilitation services, as well as intensive case management. CONCLUSIONS: Adults with WNDT and DT suffer from multiple chronic conditions and long-term service models are needed to coordinate the work of multiple specialists and to assure continuity of care. SCIENTIFIC SIGNIFICANCE: This national study identifies sociodemographic characteristics, comorbidities, and service utilization patterns associated with WNDT and DT.(Am J Addict 2017;26:722-730). PMID- 28836713 TI - Doping Phosphorene with Holes and Electrons through Molecular Charge Transfer. AB - An important aspect of phosphorene, the novel two-dimensional semiconductor, is whether holes and electrons can both be doped in this material. Some reports found that only electrons can be preferentially doped into phosphorene. There are some theoretical calculations showing charge-transfer interaction with both tetrathiafulvalene (TTF) and tetracyanoethylene (TCNE). We have carried out an investigation of chemical doping of phosphorene by a variety of electron donor and acceptor molecules, employing both experiment and theory, Raman scattering being a crucial aspect of the study. We find that both electron acceptors and donors interact with phosphorene by charge-transfer, with the acceptors having more marked effects. All the three Raman bands of phosphorene soften and exhibit band broadening on interaction with both donor and acceptor molecules. First principles calculations establish the occurrence of charge-transfer between phosphorene with donors as well as acceptors. The absence of electron-hole asymmetry is noteworthy. PMID- 28836712 TI - Religious coping in patients with severe substance use disorders receiving acute inpatient detoxification. AB - BACKGROUND AND OBJECTIVES: Religious coping, one of the most widely studied components of spirituality among psychiatric populations, has rarely been addressed in patients with severe substance use disorders (SUD). The aim of our study was to elucidate whether religious coping is related to symptom expression and mutual-help participation. METHODS: Self-reported religious coping was assessed in individuals sequentially admitted to a private psychiatric hospital for inpatient detoxification. Target symptoms of SUD included severity of substance use prior to admission and craving during detoxification. Three hundred thirty-one patients (68.6% male) participated in the survey; mean age was 38.0 years, and primary presenting diagnosis was most commonly alcohol use disorder (n = 202; 61%), followed by opioid use disorder (n = 119; 36%). RESULTS: Positive religious coping was associated with significantly greater mutual-help participation, fewer days of drug use prior to admission, and was modestly, yet significantly associated with lower drug craving. Negative religious coping was associated with lower confidence in the ability to remain abstinent post discharge and higher drug craving. CONCLUSIONS: Consistent with hypotheses, greater positive religious coping was associated with greater mutual-help participation, lower severity of pre-admission drug use, and lower substance craving during detoxification. Use of positive religious coping may modify the course of SUD recovery by promoting engagement in mutual-help activities. SCIENTIFIC SIGNIFICANCE: The findings of this study suggest that positive and negative religious coping are linked with several key SUD recovery variables. Further research to replicate this finding and to assess mechanisms within this potential association is warranted. (Am J Addict 2017;26:744-750). PMID- 28836714 TI - Completion dissection or observation for sentinel-node metastasis in melanoma. PMID- 28836715 TI - Sorting nexin (MoVps17) is required for fungal development and plant infection by regulating endosome dynamics in the rice blast fungus. AB - Vps17 is a sorting nexin (SNX) and a component of the retromer, a protein complex mediating retrograde vesicle transport between endosomes and the trans-Golgi network. However, its role in the development and pathogenicity of filamentous fungi such as the rice blast fungus (Magnaporthe oryzae) remains unclear. We investigate the functional relationship between the SNX and the cargo-selective complex (CSC) of the fungal retromer by genetic analysis, live cell imaging and immunological assay. Our data show that the MoVps17 null mutation causes defects in growth, development and pathogenicity in M. oryzae. MoVps17 is localized to endosomes depending on the activity of phosphatidylinositol 3-kinase (PI3K), a key enzyme for fungal development and infection. Both PX and BAR domains of MoVps17 are essential for its endosomal localization and function. Furthermore, our yeast two-hybrid assays show that MoVps17 and MoVps5 can interact. Lastly, live cell imaging suggests that MoVps17 can regulate early endosome fusion and budding as well as endocytosis. Taken together, our results suggest that MoVps17 specifically functions as a retromer component with CSC and also plays a distinct role in the regulation of endosome dynamics during fungal development and plant infection. PMID- 28836716 TI - Education of the postprandial experience by a sensory-cognitive intervention. AB - BACKGROUND: Ingestion of a meal induces homeostasis-related sensations (satiety/fullness) that have a hedonic dimension (satisfaction/mood). We have previously shown that a previous physiological intervention, a meal preload, influences the responses to a subsequent meal, specifically: it increases satiety/fullness and decreases satisfaction. We now wished to determine the differential effects of education on the homeostatic and hedonic postprandial experience. METHODS: Randomized, parallel study comparing the effect of real vs sham education on the responses to a probe meal. In two groups of healthy subjects (n = 14 each), homeostatic (satiety, fullness) and hedonic sensations (digestive well-being, mood) in response to a probe meal (250 mL soup, 25 g bread) were measured on 2 separate days before and after a single sensory cognitive educational intervention (taste recognition test of supra- and sub threshold tastands for real and sham education, respectively). KEY RESULTS: Before education, in both groups the probe meal induced homeostatic sensations (satiety, fullness) with a positive hedonic dimension (increased digestive well being and mood). In contrast to sham education, real education enhanced both homeostatic and hedonic responses to the probe meal (P < .05 vs sham education for all). CONCLUSIONS AND INFERENCES: Education modifies the subjects' receptiveness and influences the responses to a meal, not only the hedonic postprandial experience, but also homeostatic sensations. Since homeostatic and hedonic responses are dissociable, education might be tailored to target different conditions. PMID- 28836717 TI - Transmission of Penicillium aurantiogriseum partiti-like virus 1 to a new fungal host (Cryphonectria parasitica) confers higher resistance to salinity and reveals adaptive genomic changes. AB - We attempted to transfect six recently characterized virus species to protoplasts of Penicillium janczewskii and Chryphonectria parasitica. None of the recovered P. janczewskii colonies was positive for the transfected viruses, but Penicillium aurantiogriseum partiti-like virus 1 (PaPLV1) was detected in three distinct regenerated C. parasitica colonies. We screened the phenotype of the infected strains in up to 45 different conditions combining different media, salinity and temperatures: our results show that the infected strains grow slower than the virus- free in most of the tested conditions with the exception of halophilic stress in a specific nutrient combination media. We proceeded to characterize molecularly the population of distinct isolates of PaPLV1 infected C. parasitica through RNAseq: comparison to the viral population present in the original host - P. auratiogriseum - showed that two isolates accumulated non-synonymous mutations suggesting adaptation to the new host. RNAseq analyses identified a second genomic RNA segment and northern blot of RNA extracted from purified virus suspensions allowed establishing that PaPLV1 is at least bipartite in nature and that it forms isometric virions of circa 36-38 nm in diameter. In light of these new acquisitions, we discuss the taxonomic placement of PaPLV1 inside the Partitiviridae. PMID- 28836718 TI - The personality of past, present and future speech-language pathology students. AB - BACKGROUND: As allied health professions change over time to keep up with and reflect a rapidly changing society, it is quite possible that the people attracted to the profession may also change. If this is the case, then knowing this could be critical for future workforce marketing, training and planning. AIMS: The aim was to investigate whether the personality of students entering a speech-language pathology (SLP) program had changed over time and whether there were generational differences in personality. METHODS & PROCEDURES: The study used the Big Five personality inventory to consider whether there were differences in the personality in speech-language pathology (SLP) students enrolled in the same regional university in Australia in 2005 and 2016. OUTCOMES & RESULTS: The results showed there were significant differences between the two groups on the Agreeableness and Extroversion scales. The students who were more Conscientious were also more Confident in their ability to perform as an SLP. Generational differences across the two cohorts were also considered. CONCLUSIONS & IMPLICATIONS: SLP is a dynamic profession that is reflected through an evolving scope of practice, increasing utilization of technology and specialization. As careers evolve it is logical that the people attracted to those careers may also shift; as demonstrated here via changes in the personality of SLP students. Understanding the personality of current SLP students and future Generation Z students may assist universities to identify specific skills and experiences students need to be successful in the workforce. PMID- 28836720 TI - Correction. PMID- 28836721 TI - Correction. PMID- 28836722 TI - Correction. PMID- 28836723 TI - Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy. AB - BACKGROUND: Rifaximin might decrease the risk of portal hypertension-related complications by controlling small intestinal bacterial overgrowth. AIM: To evaluate whether rifaximin was associated with the risk of death and cirrhotic complications. METHODS: We conducted a retrospective study that included 1042 patients experiencing hepatic encephalopathy (HE): 421 patients without hepatocellular carcinoma (HCC; the non-HCC cohort) and 621 patients with HCC (the HCC cohort). The primary endpoint was overall survival and secondary endpoints were recurrence of HE and the development of spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS) and variceal bleeding. RESULTS: In the non-HCC cohort, 145 patients received rifaximin plus lactulose (the rifaximin group) and 276 patients received lactulose alone (the control group). The multivariate analysis revealed that rifaximin was significantly associated with lower risk of death (adjusted hazard ratio [aHR], 0.697; P = .024) and reduced the risk of recurrent HE (aHR, 0.452; P < .001), SBP (aHR, 0.210; P < .001) and variceal bleeding (aHR, 0.425; P = .011) but not HRS (aHR, 0.598; P = .08). In the HCC cohort, 173 patients received rifaximin plus lactulose and 448 patients received lactulose. Rifaximin was not associated with the risk of death (aHR, 1.177; P = .121). Rifaximin was associated with lower risk of SBP (aHR, 0.323; P < .001) but not with variceal bleeding (aHR, 0.660; P = .104) or recurrent HE (aHR, 0.689; P = .057). The risk of Clostridium difficile-associated diarrhoea was not different between the groups (aHR, 0.028; P = .338). CONCLUSIONS: In patients without HCC, rifaximin treatment was significantly associated with prolonged overall survival and reduced risks of spontaneous bacterial peritonitis, variceal bleeding and recurrent hepatic encephalopathy. PMID- 28836725 TI - A Material Showing Colossal Positive and Negative Volumetric Thermal Expansion with Hysteretic Magnetic Transition. AB - It is an ongoing challenge to design and synthesize magnetic materials that undergo colossal thermal expansion and that possess potential applications as microscale or nanoscale actuators with magnetic functionality. A paramagnetic metallocyanate building block was used to construct a cyanide-bridged Fe-Co complex featuring both positive and negative colossal volumetric thermal expansion behavior. A detailed study revealed that metal-to-metal charge transfer between 180 and 240 K induced a volumetric thermal expansion coefficient of 1498 MK-1 accompanied with hysteretic spin transition. Rotation of the magnetic building blocks induced change of pi???pi interactions, resulting in a negative volume expansion coefficient of -489 MK-1 , and another hysteretic magnetic transition between 300 and 350 K. This work presents a strategy for incorporating both colossal positive and negative volumetric thermal expansion with shape and magnetic memory effects in a material. PMID- 28836727 TI - Organometallic Synthesis of CuO Nanoparticles: Application in Low-Temperature CO Detection. AB - A metal-organic approach has been employed for the preparation of anisotropic CuO nanoparticles. These nanostructures have been characterized by transmission and high resolution transmission electron microscopy, field-emission scanning electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The CuO nanoparticles have been deposited as gas-sensitive layers on miniaturized silicon devices. At an operating temperature of 210 degrees C, the sensors present an optimum response toward carbon monoxide correlated with a fast response (Rn) and short recovery time. A high sensitivity to CO (Rn~150 %, 100 ppm CO, RH 50 %) is achieved. These CuO nanoparticles serve as a very promising sensing layer for the fabrication of selective CO gas sensors working at a low temperature. PMID- 28836726 TI - Dynamic causal modeling in PTSD and its dissociative subtype: Bottom-up versus top-down processing within fear and emotion regulation circuitry. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with decreased top down emotion modulation from medial prefrontal cortex (mPFC) regions, a pathophysiology accompanied by hyperarousal and hyperactivation of the amygdala. By contrast, PTSD patients with the dissociative subtype (PTSD + DS) often exhibit increased mPFC top-down modulation and decreased amygdala activation associated with emotional detachment and hypoarousal. Crucially, PTSD and PTSD + DS display distinct functional connectivity within the PFC, amygdala complexes, and the periaqueductal gray (PAG), a region related to defensive responses/emotional coping. However, differences in directed connectivity between these regions have not been established in PTSD, PTSD + DS, or controls. METHODS: To examine directed (effective) connectivity among these nodes, as well as group differences, we conducted resting-state stochastic dynamic causal modeling (sDCM) pairwise analyses of coupling between the ventromedial (vm)PFC, the bilateral basolateral and centromedial (CMA) amygdala complexes, and the PAG, in 155 participants (PTSD [n = 62]; PTSD + DS [n = 41]; age-matched healthy trauma unexposed controls [n = 52]). RESULTS: PTSD was characterized by a pattern of predominant bottom-up connectivity from the amygdala to the vmPFC and from the PAG to the vmPFC and amygdala. Conversely, PTSD + DS exhibited predominant top down connectivity between all node pairs (from the vmPFC to the amygdala and PAG, and from the amygdala to the PAG). Interestingly, the PTSD + DS group displayed the strongest intrinsic inhibitory connections within the vmPFC. CONCLUSIONS: These results suggest the contrasting symptom profiles of PTSD and its dissociative subtype (hyper- vs. hypo-emotionality, respectively) may be driven by complementary changes in directed connectivity corresponding to bottom-up defensive fear processing versus enhanced top-down regulation. Hum Brain Mapp 38:5551-5561, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28836728 TI - RELAX-AHF, BLAST-AHF, TRUE-AHF, and other important truths in acute heart failure research. PMID- 28836724 TI - Sleeper cells: the stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle. AB - Infections with tick-transmitted Borreliella (Borrelia) burgdorferi, the cause of Lyme disease, represent an increasingly large public health problem in North America and Europe. The ability of these spirochetes to maintain themselves for extended periods of time in their tick vectors and vertebrate reservoirs is crucial for continuance of the enzootic cycle as well as for the increasing exposure of humans to them. The stringent response mediated by the alarmone (p)ppGpp has been determined to be a master regulator in B. burgdorferi. It modulates the expression of identified and unidentified open reading frames needed to deal with and overcome the many nutritional stresses and other challenges faced by the spirochete in ticks and animal reservoirs. The metabolic and morphologic changes resulting from activation of the stringent response in B. burgdorferi may also be involved in the recently described non-genetic phenotypic phenomenon of tolerance to otherwise lethal doses of antimicrobials and to other antimicrobial activities. It may thus constitute a linchpin in multiple aspects of infections with Lyme disease borrelia, providing a link between the micro ecological challenges of its enzootic life-cycle and long-term residence in the tissues of its animal reservoirs, with the evolutionary side effect of potential persistence in incidental human hosts. PMID- 28836730 TI - Iron deficiency in heart failure: Efficacy and safety of intravenous iron therapy. AB - AIM: To discuss the pathophysiology of iron metabolism in chronic heart failure (CHF) and the current knowledge of the efficacy of intravenous (IV) iron therapy in patients with CHF and identify points of controversy as well as highlight areas for future research. DISCUSSION: Iron deficiency is a recognized complication of many chronic conditions. Numerous studies have reported that iron deficiency is highly prevalent in patients with CHF and is associated with exercise intolerance, reduced quality of life, and increased risk of hospitalization and mortality. Several small studies have demonstrated IV iron to be associated with improvements in symptoms, exercise capacity, quality of life, renal function, New York Heart Association (NYHA) functional class and left ventricular ejection fraction (LVEF), and reduction in NT-pro-brain natriuretic peptide (NT-proBNP) in patients with CHF and iron deficiency. Two larger-scale trials confirming these results (FAIR-HF and CONFIRM-HF) have led to guideline recommendations that IV iron therapy should be considered in patients with CHF with reduced ejection fraction and iron deficiency (serum ferritin <100 MUg/L, or ferritin between 100 and 299 MUg/L with transferrin saturation <20%) to provide symptomatic relief and improve exercise capacity and quality of life. CONCLUSION: Intravenous iron therapy improves symptoms, exercise capacity, and quality of life, at least in the short-to-intermediate time. However, there are still currently no standardized criteria used to define iron deficiency and the underlying mechanism of iron deficiency in CHF remains incompletely understood. Further work is required to improve the ability to identify iron deficiency in patients with CHF and evaluate the effect of iron repletion on hard endpoints including hospitalization and mortality. PMID- 28836729 TI - Transient exposure to oxygen or nitrate reveals ecophysiology of fermentative and sulfate-reducing benthic microbial populations. AB - For the anaerobic remineralization of organic matter in marine sediments, sulfate reduction coupled to fermentation plays a key role. Here, we enriched sulfate reducing/fermentative communities from intertidal sediments under defined conditions in continuous culture. We transiently exposed the cultures to oxygen or nitrate twice daily and investigated the community response. Chemical measurements, provisional genomes and transcriptomic profiles revealed trophic networks of microbial populations. Sulfate reducers coexisted with facultative nitrate reducers or aerobes enabling the community to adjust to nitrate or oxygen pulses. Exposure to oxygen and nitrate impacted the community structure, but did not suppress fermentation or sulfate reduction as community functions, highlighting their stability under dynamic conditions. The most abundant sulfate reducer in all cultures, related to Desulfotignum balticum, appeared to have coupled both acetate- and hydrogen oxidation to sulfate reduction. We describe a novel representative of the widespread uncultured candidate phylum Fermentibacteria (formerly candidate division Hyd24-12). For this strictly anaerobic, obligate fermentative bacterium, we propose the name 'U Sabulitectum silens' and identify it as a partner of sulfate reducers in marine sediments. Overall, we provide insights into the function of fermentative, as well as sulfate-reducing microbial communities and their adaptation to a dynamic environment. PMID- 28836731 TI - Testing the metabolic theory of ecology with marine bacteria: different temperature sensitivity of major phylogenetic groups during the spring phytoplankton bloom. AB - Although temperature is a key driver of bacterioplankton metabolism, the effect of ocean warming on different bacterial phylogenetic groups remains unclear. Here, we conducted monthly short-term incubations with natural coastal bacterial communities over an annual cycle to test the effect of experimental temperature on the growth rates and carrying capacities of four phylogenetic groups: SAR11, Rhodobacteraceae, Gammaproteobacteria and Bacteroidetes. SAR11 was the most abundant group year-round as analysed by CARD-FISH, with maximum abundances in summer, while the other taxa peaked in spring. All groups, including SAR11, showed high temperature-sensitivity of growth rates and/or carrying capacities in spring, under phytoplankton bloom or post-bloom conditions. In that season, Rhodobacteraceae showed the strongest temperature response in growth rates, estimated here as activation energy (E, 1.43 eV), suggesting an advantage to outcompete other groups under warmer conditions. In summer E values were in general lower than 0.65 eV, the value predicted by the Metabolic Theory of Ecology (MTE). Contrary to MTE predictions, carrying capacity tended to increase with warming for all bacterial groups. Our analysis confirms that resource availability is key when addressing the temperature response of heterotrophic bacterioplankton. We further show that even under nutrient-sufficient conditions, warming differentially affected distinct bacterioplankton taxa. PMID- 28836732 TI - Concise Review: Mesenchymal Stem Cells in Cardiovascular Regeneration: Emerging Research Directions and Clinical Applications. AB - Experimental and early clinical data suggest that, due to several unique properties, mesenchymal stem cells (MSCs) may be more effective than other cell types for diseases that are difficult to treat or untreatable. Owing to their ease of isolation and culture as well as their secretory and immunomodulatory abilities, MSCs are the most promising option in the field of cell-based therapies. Although MSCs from various sources share several common characteristics, they also exhibit several important differences. These variations may reflect, in part, specific regional properties of the niches from which the cells originate. Moreover, morphological and functional features of MSCs are susceptible to variations across isolation protocols and cell culture conditions. These observations suggest that careful preparation of manufacturing protocols will be necessary for the most efficient use of MSCs in future clinical trials. A typical human myocardial infarct involves the loss of approximately 1 billion cardiomyocytes and 2-3 billion other (mostly endothelial) myocardial cells, leading (despite maximized medical therapy) to a significant negative impact on the length and quality of life. Despite more than a decade of intensive research, search for the "best" (safe and maximally effective) cell type to drive myocardial regeneration continues. In this review, we summarize information about the most important features of MSCs and recent discoveries in the field of MSCs research, and describe current data from preclinical and early clinical studies on the use of MSCs in cardiovascular regeneration. Stem Cells Translational Medicine 2017;6:1859-1867. PMID- 28836735 TI - When prevalence of infection may not directly reflect the burden of disease. PMID- 28836733 TI - Cognitive impairment and cardiovascular medication use: Results from wave 1 of The Irish Longitudinal Study on Ageing. AB - AIM: To explore the association between cardiovascular medication use and cognitive impairment in adults aged 50 years and over. METHOD: This cross sectional linked database study involved secondary quantitative analysis of 1903 participants from wave 1 of the Irish Longitudinal Study on Ageing with available pharmacy claims data. Cognitive impairment was assessed using a cut-off of <=23 on the Montreal Cognitive Assessment. Cardiovascular medication use was calculated using the proportion of days covered for antihypertensive, antithrombotic, and lipid-modifying medications. For each class of cardiovascular medication, participants were categorized as belonging to one of three medication use groups: (1) not dispensed any medications (reference); (2) poor adherence (proportion of days covered <80%); and (3) good adherence (proportion of days covered >=80%). RESULTS: Controlling for demographic and health variables, there was no evidence of an independent association between impaired cognitive function and use of antihypertensives [good adherence OR (95% CI): 1.16 (0.88, 1.52), poor adherence OR (95% CI): 1.39 (0.95, 2.04)]; antithrombotics [good adherence OR (95% CI): 1.26 (0.93, 1.70), poor adherence OR 95% CI): 1.13 (0.80, 1.59)]; or lipid-modifying agents [good adherence OR (95% CI): 0.95 (0.71, 1.25), poor adherence OR (95% CI): 0.88 (0.64, 1.22)]. CONCLUSION: We found no evidence of an association between cardiovascular medication use and cognitive function. Future studies should investigate the prospective associations between cognition and use of cardiovascular medications using longitudinal data. PMID- 28836736 TI - CCL2 recruits T cells into the brain in a CCR2-independent manner. AB - CCL2 is a chemokine that can be induced during neuroinflammation to recruit immune cells, but its role in the central nervous system (CNS) is unclear. Our aim was to better understand its role. We induced CCL2 in CNS of naive CCL2 deficient mice using intrathecally administered replication-defective adenovirus and examined cell infiltration by flow cytometry. CCL2 expression induced pronounced and unexpected recruitment of regulatory and IFNgamma-producing T cells to CNS from blood, possibly related to defective egress of monocytes from CCL2-deficient bone marrow. Infiltration also occurred in mice lacking CCR2, a receptor for CCL2. Expression of another receptor for CCL2, CCR4, and CXCR3, a receptor for CXCL10, which was also induced, were both increased in CCL2-treated CNS. CCR4 was expressed by neurons and astrocytes as well as CD4 T cells, and CXCR3 was expressed by CD4 and CD8 T cells. Chemokine-recruited T cells did not lead to CNS pathology. Our findings show a role for CCL2 in recruitment of CD4 T cells to the CNS and show that redundancy among chemokine receptors ensures optimal response. PMID- 28836737 TI - Hepatic artery and biliary complications in liver transplant recipients with radioembolization bridging treatment for hepatocellular carcinoma. AB - BACKGROUND: Locoregional bridging treatments are commonly applied in patients with hepatocellular carcinoma (HCC) prior to liver transplantation to prevent tumor progression during waiting time. It remains unknown whether pre-transplant radioembolization treatment may increase the prevalence of hepatic artery and biliary complications post-transplant. METHODS: We performed a retrospective review of 173 consecutive patients with HCC who underwent liver transplantation at our transplant center between January 2007 and December 2016. RESULTS: Radioembolization bridging treatment was applied in 42 patients while 131 patients received other or no forms of bridging treatment. The overall prevalence of intra-operative and early post-operative hepatic artery complications was 9.5% in the radioembolization group and 9.2% in the control group (P = 1.000). Biliary complications were significantly less frequent in the radioembolization group (4.8% vs 17.6%, P = .0442). In multivariable analysis, radioembolization was not significantly associated with an increased risk of arterial complications. Considering biliary complications, radioembolization bridging treatment was the only factor significantly associated with decreased odds (OR 0.187 (0.039, 0.892), P = .036). CONCLUSIONS: Radioembolization is not associated with higher odds of hepatic artery complications following liver transplantation. There may even be a protective effect regarding biliary complications. Radioembolization as a bridge to transplantation may effectively be applied without compromising successful liver transplantation. PMID- 28836738 TI - Concise Review: Bioprinting of Stem Cells for Transplantable Tissue Fabrication. AB - Bioprinting is a quickly progressing technology, which holds the potential to generate replacement tissues and organs. Stem cells offer several advantages over differentiated cells for use as starting materials, including the potential for autologous tissue and differentiation into multiple cell lines. The three most commonly used stem cells are embryonic, induced pluripotent, and adult stem cells. Cells are combined with various natural and synthetic materials to form bioinks, which are used to fabricate scaffold-based or scaffold-free constructs. Computer aided design technology is combined with various bioprinting modalities including droplet-, extrusion-, or laser-based bioprinting to create tissue constructs. Each bioink and modality has its own advantages and disadvantages. Various materials and techniques are combined to maximize the benefits. Researchers have been successful in bioprinting cartilage, bone, cardiac, nervous, liver, and vascular tissues. However, a major limitation to clinical translation is building large-scale vascularized constructs. Many challenges must be overcome before this technology is used routinely in a clinical setting. Stem Cells Translational Medicine 2017;6:1940-1948. PMID- 28836739 TI - Corrigendum. AB - Baiz, N., Chastang, J., Ibanez, G., & Annesi-Maesano I. (2016). Prenatal exposure to selenium may protect against wheezing in children by the age of 3. Immunity, Inflammation and Disease, 5 (1), 37-44. DOI: 10.1002/iid3.138. In the article "Prenatal exposure to selenium may protect against wheezing in children by the age of 3", it has been noted that the 'EDEN Mother-Child Cohort Study Group was omitted in error. The correct author list for the article is shown below. Nour Baiz1 , Julie Chastang1,2 , Gladys Ibanez1,2 , Isabella Annesi-Maesano1 and the EDEN Mother-Child Cohort Study Group3 . 3 Members of the EDEN Mother-Child Cohort Study Group includes the following members: I. Annesi-Maesano, J. Y. Bernard, J. Botton, M.A. Charles, P. Dargent-Molina, B. de Lauzon-Guillain, P. Ducimetiere, M. de Agostini, B. Foliguet, A. Forhan, X. Fritel, A. Germa, V. Goua, R. Hankard, B. Heude, M. Kaminski, B. Larroque, N. Lelong, J. Lepeule, G. Magnin, L. Marchand, C. Nabet, F. Pierre, R. Slama, M.J. Saurel-Cubizolles, M. Schweitzer, O. Thiebaugeorges. We apologize for any inconvenience caused. PMID- 28836740 TI - Incidence and costs of achalasia in The Netherlands. AB - BACKGROUND: Recent reports show increasing incidence of achalasia in some populations. The aim of this study was to estimate incidence, prevalence, and healthcare costs of achalasia in a large cohort in The Netherlands. METHODS: Data were obtained from the largest Dutch healthcare insurance company (+/-4.4 million insured). Adult achalasia patients were identified between 2006 and 2014 when having an achalasia diagnosis code registered. A total of 907 achalasia patients were identified and included in our database, along with 9068 control patients (non-achalasia patients), matched by age and gender. KEY RESULTS: The mean incidence over the 9-year period was 2.2 per 100 000 persons and the mean prevalence was 15.3 per 100 000 persons. Mean age of achalasia patients was 54 (range 18-98) years. Male to female ratio was 1:1. Socio-economic status distribution was similar in achalasia patients and controls. Prior to the diagnosis, 74% of achalasia patients received proton pump inhibitors and 26% received anti-emetic medication. The first year after diagnosis median total direct medical costs of achalasia patients were ?2283 (IQR 969-3044) per year. Patients above the 90th percentile of ?4717 were significantly older than other patients below the 90th percentile (mean age 63 vs 57); P = .005. CONCLUSION & INFERENCES: In this large study that used a database comprising about 25% of all inhabitants of The Netherlands, it is confirmed that achalasia affects individuals of both genders and all ages. The costs associated with diagnosis and treatment of new cases of achalasia increase with increasing age. PMID- 28836741 TI - Quantification and neurochemical coding of the myenteric plexus in humans: No regional variation between the distal colon and rectum. AB - BACKGROUND: It remains unclear whether regional variation exists in the human enteric nervous system (ENS) ie, whether intrinsic innervation varies along the gut. Recent classification of gastrointestinal neuropathies has highlighted inadequacies in the quantification of the human ENS. This study used paired wholemounts to accurately quantify and neurochemically code the hindgut myenteric plexus, comparing human distal colon and rectum. METHODS: Paired human descending colonic/rectal specimens were procured from 15 patients undergoing anterior resection. Wholemounts of myenteric plexi were triple-immunostained with anti Hu/NOS/ChAT antibodies. Images were acquired by motorized epifluorescence microscopy, allowing assessment of ganglionic density/size, ganglionic area density, and neuronal density. 'Stretch-corrected' values were calculated using stretched/relaxed tissue dimensions. KEY RESULTS: Tile-stitching created a collage with average area 99 300 000 MUm2 . Stretch-corrected ganglionic densities were similar (colon: median 510 ganglia/100 mm2 [range 386-1170], rectum: 585 [307-923]; P = .99), as were average ganglionic sizes (colon: 57 593 MUm2 [40 301-126 579], rectum: 54 901 [38 701-90 211], P = .36). Ganglionic area density (colon: 11.92 mm2 per 100 mm2 [7.53-18.64], rectum: 9.84 [5.80-17.19], P = .10) and stretch-corrected neuronal densities (colon: 189 neurons/mm2 [117 388], rectum: 182 [89-361], P = .31) were also similar, as were the neurochemical profiles of myenteric ganglia, with comparable proportions of NOS+ and ChAT+ neurons (P > .10). CONCLUSIONS AND INFERENCES: This study has revealed similar neuronal and ganglionic densities and neurochemical profiles in human distal colon and rectum. Further investigation of other components of the ENS, incorporating additional immunohistochemical markers are required to confirm that there is no regional variation in the human hindgut ENS. PMID- 28836742 TI - Thriving or surviving? Evaluating active microbial guilds in Baltic Sea sediment. AB - Microbial life in the deep subsurface biosphere is taxonomically and metabolically diverse, but it is vigorously debated whether the resident organisms are thriving (metabolizing, maintaining cellular integrity and expressing division genes) or just surviving. As part of Integrated Ocean Drilling Program Expedition 347: Baltic Sea Paleoenvironment, we extracted and sequenced RNA from organic carbon-rich, nutrient-replete and permanently anoxic sediment. In stark contrast to the oligotrophic subsurface biosphere, Baltic Sea Basin samples provided a unique opportunity to understand the balance between metabolism and other cellular processes. Targeted sequencing of 16S rRNA transcripts showed Atribacteria (an uncultured phylum) and Chloroflexi to be among the dominant and the active members of the community. Metatranscriptomic analysis identified methane cycling, sulfur cycling and halogenated compound utilization as active in situ respiratory metabolisms. Genes for cellular maintenance, cellular division, motility and antimicrobial production were also transcribed. This indicates that microbial life in deep subsurface Baltic Sea Basin sediments was not only alive, but thriving. PMID- 28836743 TI - Hydrography shapes community composition and diversity of amoA-containing Thaumarchaeota in the coastal waters off central Chile. AB - Thaumarchaea are often abundant in low oxygen marine environments, and recent kinetic studies indicate a capacity for aerobic ammonia oxidation at vanishingly low oxygen levels (nM). However, molecular diversity surveys targeting this group to high sequencing coverage are limited, and how these populations are coupled to changes in dissolved oxygen remains unknown. In this study, the ammonia monooxygenase subunit A (amoA) gene was sequenced from samples collected in the Chilean coast (36.5 degrees S), a system prone to recurrent seasonal hypoxia and anoxia, at several depths over one year, to read depths that saturated coverage statistics. Temperature, salinity and depth displayed a stronger impact on community composition than chemical and biological variables, such as dissolved oxygen. The Nitrosopumilus water-column A clade (WCA) displayed high proportional representation in all samples (42%-100% of all amoA OTUs). The two dominant WCA OTUs displayed differences in their distributions that were inversely correlated with one another, providing the first evidence for intra-subgroup specific differences in the distributions among closely related WCA Thaumarcheota. Nitrosopumilus water-column B (WCB) representatives displayed increased proportional abundances (42%) at deeper depths during the spring and summer, were highly coupled to decreased dissolved oxygen conditions and were non-detectable during the austral winter. The depth of sequencing also enabled observation of lower abundance taxa that are typically not observed in marine environments, such as members of the genus Nitrosotalea amid austral winter surface waters. This study highlights a strong coupling between Thaumarchaeal community diversity and hydrographic variables, is the first to highlight intra-subclade depth specific shifts in community diversity amongst members of the WCA clade, and links the WCB clade to upwelling conditions associated with seasonal oxygen depletion. PMID- 28836744 TI - Biosimilars in Rheumatology- Name Changers or Game Changers? PMID- 28836745 TI - Use of Biologics and Biosimilars in Rheumatology. AB - Prior to the availability of biologics, synthetic DMARDs (Disease modifying anti rheumatic drugs) were the mainstay of the treatment in rheumatology. With the introduction of biologics, the scenario is changing to become more promising. These drugs have innovative mechanism of action, based on the targeted inhibition of specific molecular or cellular targets directly involved in disease pathogenesis. The biosimilars are highly similar copies of originator biologics approved through pre-defined, stringent regulatory processes after rigorous physicochemical, non-clinical, and clinical evaluations. Low cost and resulting wider patient access as compared to innovators goes in favor of biosimilars. Regulatory guidelines for biosimilar development and approval are rigorous and undergoing constant refinement. Approval of several biosimilars in across the world in last few years bears testimony to the increased regulatory acceptance of these agents. This article addresses development of biosimilars, regulatory process, benefits and concerns about their usage in rheumatologic practice. PMID- 28836746 TI - Review of Biosimilars of Adalimumab. AB - A first fully humanized monoclonal antibody approved by US Food and Drug Administration (FDA) in 2002 was Adalimumab. Clinical efficacy and safety of adalimumab has been assessed in various trials in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, Crohn's Disease, and ulcerative colitis. It is one of the major sales success among biological and still one of the greatest blockbuster amongst monoclonal antibodies. With the advent of patent expiry of the parent drug HUMIRA, several potential biosimilars have debuted in various markets worldwide. Present article will discuss current situation of molecules that are front-runners to become adalimumab biosimilars with particular stress on Indian market and ZRC3197 (Adalimumab Biosimilar). PMID- 28836747 TI - Clinical use of ZRC3197 (Adalimumab Biosimilar) in Patients with Inflammatory Arthritis: A Real-life Experience. AB - We present our real-life clinical experience of ZRC3197 (Adalimumab Biosimilar) in Indian patients with inflammatory arthritis [spondyloarthropathy (SPA) and rheumatoid arthritis (RA)]. Medical records of these patients were retrospectively retrieved and analysed at our single centre. All the patients had received biosimilar Adalimumab 40 mg every 15 days for initial 3 months. Post 3 months, an 'on-demand modified dosing approach' was followed, wherein BASDAI/DAS28-guided dose reduction or discontinuation of treatment was done. Dose reduction was primarily done by increasing the dosing interval for biosimilar Adalimumab. The 3, 6 and 12 months' follow-up data revealed a significant reduction in disease activity scores (BASDAI/DAS28). At 3 months, BASDAI50% was achieved in 91% and BASDAI 70% was achieved in 45% of SPA patients. At 3 months, 88% showed a reduction in DAS28 > 1.2 from baseline. At 12 months, 94% of the evaluable SPA patients and 58% of evaluable RA patients showed clinical remission or low disease activity. BASDAI/DAS28 score-guided dose reduction led to significantly lesser requirement of biosimilar Adalimumab doses. Biosimilar Adalimumab was well-tolerated with no serious or unexpected side effects. Our analysis suggests that disease activity-guided modified dosing may serve as an effective strategy for patients with inflammatory arthritis, leading to a lower dose requirement for the treatment. Despite the modified dosing, the clinical response following biosimilar Adalimumab was comparable to the published data for the standard Adalimumab treatment in such patients. PMID- 28836748 TI - Switching from Other Biologics to ZRC3197 (Adalimumab Biosimilar) in Patients with Spondyloarthropathy: A Prospective Evaluation from Real-Life Clinical Practice. AB - Tumour necrosis factor inhibitors (TNFi) like Infliximab, Etarnacept and Adalimumab have been successfully studied in controlled clinical trials and are currently recommended in the treatment of patients with spondyloarthropathy (SPA). Significant proportion of patients in clinical studies have, however, failed to achieve a desired clinical response, or, are discontinued from the therapy due to secondary inefficacy or side effects. Therefore, owing to the different molecular structures and routes of administration, switching from one TNFi to another is considered as in important option in SPA patients eligible to receive TNFi therapy. We report here our experience of switching Indian patients with SPA with inadequate response to other TNFi to ZRC 3197(Adalimumab Biosimilar) treatment available in India. PMID- 28836749 TI - Real-life Safety Profile of ZRC3197 (Adalimumab Biosimilar) in Indian Patients with Common Rheumatic Diseases. AB - The advent of biologic therapies has brought in significant improvement in the outcome of patients suffering from chronic inflammatory arthritis. High costs and unavailability have however, limited their utility in some parts of the world. These limitations have been overcome to a good extent by the introduction of biosimilar versions of original products, which are gaining momentum, of late. Adalimumab (Humira(r)), a TNF-alpha inhibitor has been successfully used in patients with inflammatory arthritis for more than a decade now. ZRC3197 (Adalimumab Biosimilar) was developed in India and approved for use since 2014. Ongoing evaluation of safety in real-world setting outside the context of controlled clinical trials is pivotal in ensuring long-term safety of such biologic therapies. We share the real-life safety profile of biosimilar Adalimumab in patients with chronic inflammatory arthritis and other autoimmune conditions from a tertiary care centre in south India. PMID- 28836750 TI - Emergency management of renal and genitourinary trauma: best practices update [digest]. AB - In up to 10% of patients who experience abdominal trauma, renal and urogenital systems will be involved. In polytrauma patients with other potentially life threatening injuries, renal and genitourinary trauma may be overlooked initially, but a delayed or missed diagnosis of these injuries may result in preventable complications. This review provides a best-practice approach to the diagnosis and management of renal and genitourinary injuries, with an emphasis on the systematic approach needed to identify subtle injuries and avoid long-term urinary sequelae such as hypertension, incontinence, erectile dysfunction, chronic kidney disease, and nephrectomy. [Points & Pearls is a digest of Emergency Medicine Practice.]. PMID- 28836751 TI - Reducing Racial and Ethnic Disparities in Access to Care: Has the Affordable Care Act Made a Difference? AB - ISSUE: Prior to the Affordable Care Act (ACA), blacks and Hispanics were more likely than whites to face barriers in access to health care. GOAL: Assess the effect of the ACA's major coverage expansions on disparities in access to care among adults. METHODS: Analysis of nationally representative data from the American Community Survey and the Behavioral Risk Factor Surveillance System. FINDINGS AND CONCLUSIONS: Between 2013 and 2015, disparities with whites narrowed for blacks and Hispanics on three key access indicators: the percentage of uninsured working-age adults, the percentage who skipped care because of costs, and the percentage who lacked a usual care provider. Disparities were narrower, and the average rate on each of the three indicators for whites, blacks, and Hispanics was lower in both 2013 and 2015 in states that expanded Medicaid under the ACA than in states that did not expand. Among Hispanics, disparities tended to narrow more between 2013 and 2015 in expansion states than nonexpansion states. The ACA's coverage expansions were associated with increased access to care and reduced racial and ethnic disparities in access to care, with generally greater improvements in Medicaid expansion states. PMID- 28836752 TI - Highly Flexible, Multipixelated Thermosensitive Smart Windows Made of Tough Hydrogels. AB - In a cold night, a clear window that will become opaque while retaining the indoor heat is highly desirable for both privacy and energy efficiency. A thermally responsive material that controls both the transmittance of solar radiance (predominantly in the visible and near-infrared wavelengths) and blackbody radiation (mainly in the mid-infrared) can realize such windows with minimal energy consumption. Here, we report a smart coating made from polyampholyte hydrogel (PAH) that transforms from a transparency state to opacity to visible radiation and strengthens opacity to mid-infrared when lowering the temperature as a result of phase separation between the water-rich and polymer rich phases. To match a typical temperature fluctuation during the day, we fine tune the phase transition temperature between 25 and 55 degrees C by introducing a small amount of relatively hydrophobic monomers (0.1 to 0.5 wt % to PAH). To further demonstrate an actively controlled, highly flexible, and high-contrast smart window, we build in an array of electric heaters made of printed elastomeric composite. The multipixelated window offers rapid switching, ~70 s per cycle, whereas the device can withstand high strain (up to 80%) during operations. PMID- 28836753 TI - Potency and Cytotoxicity of a Novel Gallium-Containing Mesoporous Bioactive Glass/Chitosan Composite Scaffold as Hemostatic Agents. AB - Chitosan-based hemostats are promising candidates for immediate hemorrhage control. However, they have some disadvantages and require further improvement to achieve the desired hemostatic efficiency. Here, a series of 1% Ga2O3-containing mesoporous bioactive glass-chitosan composite scaffolds (Ga-MBG/CHT) were constructed by the lyophilization process and the effect of various concentrations of Ga-MBG (10, 30, and 50 wt %) on the hemostatic function of the CHT scaffold was assessed as compared to that of Celox Rapid gauze (CXR), a current commercially available chitosan-coated hemostatic gauze. The prepared scaffolds exhibited >79% porosity and showed increased water uptake compared to that in CXR. The results of coagulation studies showed that pure CHT and composite scaffolds exhibited increased hemostatic performance with respect to CXR. Furthermore, the composite scaffold with the highest Ga-MBG content (50 wt %) had increased capability to enhancing thrombus generation, blood clotting, and platelet adhesion and aggregation than that of the scaffold made of pure CHT. The antibacterial efficacy and biocompatibility of the prepared scaffolds were also assessed by a time-killing assay and an Alamar Blue assay, respectively. Our results show that the antibacterial effect of 50% Ga-MBG/CHT was more pronounced than that of CHT and CXR. The cell viability results also demonstrated that Ga MBG/CHT composite scaffolds had good biocompatibility, which facilitates the spreading and proliferation of human dermal fibroblast cells even with 50 wt % Ga MBG loading. These results suggest that Ga-MBG/CHT scaffolds could be a promising hemostatic candidate for improving hemostasis in critical situations. PMID- 28836755 TI - Remediation Performance and Mechanism of Heavy Metals by a Bottom Up Activation and Extraction System Using Multiple Biochemical Materials. AB - Soil contamination with heavy metals has caused serious environmental problems and increased the risks to humans and biota. Herein, we developed an effective bottom up metals removal system based on the synergy between the activation of immobilization metal-resistant bacteria and the extraction of bioaccumulator material (Stropharia rugosoannulata). In this system, the advantages of biochar produced at 400 degrees C and sodium alginate were integrated to immobilize bacteria. Optimized by response surface methodology, the biochar and bacterial suspension were mixed at a ratio of 1:20 (w:v) for 12 h when 2.5% sodium alginate was added to the mixture. Results demonstrated that the system significantly increased the proportion of acid soluble Cd and Cu and improved the soil microecology (microbial counts, soil respiration, and enzyme activities). The maximum extractions of Cd and Cu were 8.79 and 77.92 mg kg-1, respectively. Moreover, details of the possible mechanistic insight into the metal removal are discussed, which indicate positive correlation with the acetic acid extractable metals and soil microecology. Meanwhile, the "dilution effect" in S. rugosoannulata probably plays an important role in the metal removal process. Furthermore, the metal-resistant bacteria in this system were successfully colonized, and the soil bacteria community were evaluated to understand the microbial diversity in metal-contaminated soil after remediation. PMID- 28836754 TI - Cell Lysate-Based AlphaLISA Deubiquitinase Assay Platform for Identification of Small Molecule Inhibitors. AB - The deubiquitinases, or DUBs, are associated with various human diseases, including neurological disorders, cancer, and viral infection, making them excellent candidates for pharmacological intervention. Drug discovery campaigns against DUBs require enzymatic deubiquitination assays amenable for high throughput screening (HTS). Although several DUB substrates and assays have been developed in recent years, they are largely limited to recombinantly purified DUBs. Many DUBs are large multidomain proteins that are difficult to obtain recombinantly in sufficient quantities for HTS. Therefore, an assay that obviates the need of recombinant protein generation and also recapitulates a physiologically relevant environment is highly desirable. Such an assay will open doors for drug discovery against many therapeutically relevant, but currently inaccessible, DUBs. Here, we report a cell lysate DUB assay based on AlphaLISA technology for high throughput screening. This assay platform uses a biotin tagged ubiquitin probe and a HA-tagged DUB expressed in human cells. The assay was validated and adapted to a 1536-well format, which enabled a screening against UCHL1 as proof of principle using a library of 15 000 compounds. We expect that the new platform can be readily adapted to other DUBs to allow the identification of more potent and selective small molecule inhibitors and chemical probes. PMID- 28836756 TI - Colloidal Mesoporous Silica Nanoparticles as Strong Adhesives for Hydrogels and Biological Tissues. AB - Sub-100 nm colloidal mesoporous silica (CMS) nanoparticles are evaluated as an adhesive for hydrogels or biological tissues. Because the adhesion energy is proportional to the surface area of the nanoparticles, the CMS nanoparticles could provide a stronger adhesion between two hydrogels than the nonporous silica nanoparticles. In the case of 50 nm CMS nanoparticles with a pore diameter of 6.45 nm, the maximum adhesion energy was approximately 35.0 J/m2 at 3.0 wt %, whereas the 10 wt % nonporous silica nanoparticle solution showed only 7.0 J/m2. Moreover, the CMS nanoparticle solution had an adhesion energy of 22.0 J/m2 at 0.3 wt %, which was 11 times higher than that of the nonporous nanoparticles at the same concentration. Moreover, these CMS nanoparticles are demonstrated for adhering incised skin tissues of mouse, resulting in rapid healing even at a lower nanoparticle concentration. Finally, the CMS nanoparticles had added benefit of quick degradation in biological media because of their porous structure, which may prevent unwanted accumulation in tissues. PMID- 28836757 TI - Renewable Formate from C-H Bond Formation with CO2: Using Iron Carbonyl Clusters as Electrocatalysts. AB - As a society, we are heavily dependent on nonrenewable petroleum-derived fuels and chemical feedstocks. Rapid depletion of these resources and the increasingly evident negative effects of excess atmospheric CO2 drive our efforts to discover ways of converting excess CO2 into energy dense chemical fuels through selective C-H bond formation and using renewable energy sources to supply electrons. In this way, a carbon-neutral fuel economy might be realized. To develop a molecular or heterogeneous catalyst for C-H bond formation with CO2 requires a fundamental understanding of how to generate metal hydrides that selectively donate H- to CO2, rather than recombining with H+ to liberate H2. Our work with a unique series of water-soluble and -stable, low-valent iron electrocatalysts offers mechanistic and thermochemical insights into formate production from CO2. Of particular interest are the nitride- and carbide-containing clusters: [Fe4N(CO)12]- and its derivatives and [Fe4C(CO)12]2-. In both aqueous and mixed solvent conditions, [Fe4N(CO)12]- forms a reduced hydride intermediate, [H Fe4N(CO)12]-, through stepwise electron and proton transfers. This hydride selectively reacts with CO2 and generates formate with >95% efficiency. The mechanism for this transformation is supported by crystallographic, cyclic voltammetry, and spectroelectrochemical (SEC) evidence. Furthermore, installation of a proton shuttle onto [Fe4N(CO)12]- facilitates proton transfer to the active site, successfully intercepting the hydride intermediate before it reacts with CO2; only H2 is observed in this case. In contrast, isoelectronic [Fe4C(CO)12]2- features a concerted proton-electron transfer mechanism to form [H-Fe4C(CO)12]2-, which is selective for H2 production even in the presence of CO2, in both aqueous and mixed solvent systems. Higher nuclearity clusters were also studied, and all are proton reduction electrocatalysts, but none promote C-H bond formation. Thermochemical insights into the disparate reactivities of these clusters were achieved through hydricity measurements using SEC. We found that only [H Fe4N(CO)12]- and its derivative [H-Fe4N(CO)11(PPh3)]- have hydricities modest enough to avoid H2 production but strong enough to make formate. [H-Fe4C(CO)12]2- is a stronger hydride donor, theoretically capable of making formate, but due to an overwhelming thermodynamic driving force and the increased electrostatic attraction between the more negative cluster and H+, only H2 is observed experimentally. This illustrates the fundamental importance of controlling thermochemistry when designing new catalysts selective for C-H bond formation and establishes a hydricity range of 15.5-24.1 or 44-49 kcal mol-1 where C-H bond formation may be favored in water or MeCN, respectively. PMID- 28836758 TI - Suppression of Myogenic Differentiation of Mammalian Cells Caused by Fluidity of a Liquid-Liquid Interface. AB - There is growing evidence to suggest that the prevailing physical microenvironment and mechanical stress regulate cellular functions, including adhesion, proliferation, and differentiation. Moreover, the physical microenvironment determines the stem-cell lineage depending on stiffness of the substrate relative to biological tissues as well as the stress relaxation properties of the viscoelastic substrates used for cell culture. However, there is little known regarding the biological effects of a fluid substrate, where viscoelastic stress is essentially absent. Here, we demonstrate the regulation of myogenic differentiation on fluid substrates by using a liquid-liquid interface as a scaffold. C2C12 myoblast cells were cultured using water-perfluorocarbon (PFC) interfaces as the fluid microenvironment. We found that, for controlled in vitro culture at water-PFC interfaces, expression of myogenin, myogenic regulatory factors (MRF) family gene, is remarkably attenuated even when myogenic differentiation was induced by reducing levels of growth factors, although MyoD was expressed at the usual level (MyoD up-regulates myogenin under an elastic and/or viscoelastic environment). These results strongly suggest that this unique regulation of myogenic differentiation can be attributed to the fluid microenvironment of the interfacial culture medium. This interfacial culture system represents a powerful tool for investigation of the mechanisms by which physical properties regulate cellular adhesion and proliferation as well as their differentiation. Furthermore, we successfully transferred the cells cultured at such interfaces using Langmuir-Blodgett (LB) techniques. The combination of the interfacial culture system with the LB approach enables investigation of the effects of mechanical compression on cell functions. PMID- 28836759 TI - High-Throughput Single-Particle Analysis of Metal-Enhanced Fluorescence in Free Solution Using Ag@SiO2 Core-Shell Nanoparticles. AB - Metal-enhanced fluorescence (MEF) based on localized surface plasmon resonance (LSPR) is an effective strategy to increase the detection sensitivity in biotechnology and biomedicine. Because plasmonic nanoparticles are intrinsically heterogeneous, high-throughput single-particle analysis of MEF in free solution are highly demanded for the mechanistic understanding and control of this nanoscale process. Here, we report the application of a laboratory-built high sensitivity flow cytometer (HSFCM) to investigate the fluorescence-enhancing effect of individual plasmonic nanoparticles on nearby fluorophore molecules. Ag@SiO2 core-shell nanoparticles were used as the model system which comprised a silver core, a silica shell, and an FITC-doped thin layer of silica shell. FITC doped silica nanoparticles of the same particle size but without silver core were used as the counterparts. Both the side scattering and fluorescence signals of single nanoparticles in suspension were measured simultaneously by the HSFCM at a speed of thousands of particles per minute. The roles of silver core size (40-100 nm) and fluorophore-metal distance (5-30 nm) were systematically examined. Fluorescence enhancement factor exceeding 30 was observed at silver core size of 70 nm and silica shell thickness of 5 nm. Compared with ensemble-averaged spectrofluorometric measurements, our experimental observation at the single particle level was well supported by the finite difference time domain (FDTD) calculation. It allows us to achieve a fundamental understanding of MEF, which is important to the design and control of plasmonic nanostructures for efficient fluorescence enhancement. PMID- 28836760 TI - Glucose and Lactate Miniaturized Biosensors for SECM-Based High-Spatial Resolution Analysis: A Comparative Study. AB - With the aim of developing miniaturized enzymatic biosensors suitable for in vitro diagnostic applications, such as monitoring of metabolites at single cell level, glucose and lactate biosensors were fabricated by immobilizing enzymes (glucose oxidase and lactate oxidase, respectively) on 10 MUm Pt ultramicroelectrodes. These electrodes are meant to be employed as probes for scanning electrochemical microscopy (SECM), which is a unique technique for high spatial-resolution electrochemical-based analysis. The use of enzymatic moieties improves sensitivity, time scale response, and information content of the microprobes; however, protein immobilization is a key step in the biosensor preparation that greatly affects the overall performance. A crucial aspect is the miniaturization of the sensing, preserving their sensitivity. In this work, we investigated the most common enzyme immobilization techniques. Several fabrication routes are reported and the main figures of merit, such as sensitivity, detection limit, response time, reproducibility, spatial resolution, biosensor efficiency, permeability, selectivity, and the ability to block electro active interfering species, are investigated and compared. With the intent of using the microprobes for in vitro functional imaging of single living cells, we carefully evaluate the spatial resolution achieved by our modified electrodes on 2D SECM imaging. Metabolic activity of single MCF10A cells were obtained by monitoring the glucose concentrations in close proximity of single living cell, using the UME-based biosensor probes prepared. A voltage-switch approach was implemented to disentangle the topographical contribution of the cells enabling quantitative measurements of cellular uptakes. PMID- 28836762 TI - High Performance Poly(viologen)-Graphene Nanocomposite Battery Materials with Puff Paste Architecture. AB - Four linear poly(viologens) (PV1, PV2: phenylic, PV3: benzylic, and PV4: aliphatic) in tight molecular contact with reduced graphene oxide (rGO), that is, PV@rGO, were prepared and used as anodic battery materials. These composites show exceptionally high, areal, volumetric, and current densities, for example, PV1@rGO composites (with 15 wt % rGO, corresponding to 137 mAh g-1) show 13.3 mAh cm-2 at 460 MUm and 288 mAh cm-3 with 98% Coulombic efficiency at current densities up to 1000 A g-1, better than any reported organic materials. These remarkable performances are based on (i) molecular self-assembling of PVs on individual GO sheets yielding colloidal PV@GO and (ii) efficient GO/rGO transformation electrocatalyzed by PVs. Ion breathing during charging/discharging was studied by electrochemical quartz crystal microbalance and electrochemical atomic force microscopy revealing an absolute reversible and strongly anisotropic thickness oscillation of PV1@rGO at a right angle to the macroscopic current collector. It is proposed that such stress-free breathing is the key property for good cyclability of the battery material. The anisotropy is related to a puff paste architecture of rGO sheets parallel to the macroscopic current collector. A thin graphite sheet electrode with an areal capacity of 1.23 mAh cm-2 is stable over 200 bending cycles, making the material applicable for wearable electronics. The polymer acts as a lubricant between the rGO layers if shearing forces are active. PMID- 28836761 TI - High-Speed "4D" Computational Microscopy of Bacterial Surface Motility. AB - Bacteria exhibit surface motility modes that play pivotal roles in early-stage biofilm community development, such as type IV pili-driven "twitching" motility and flagellum-driven "spinning" and "swarming" motility. Appendage-driven motility is controlled by molecular motors, and analysis of surface motility behavior is complicated by its inherently 3D nature, the speed of which is too fast for confocal microscopy to capture. Here, we combine electromagnetic field computation and statistical image analysis to generate 3D movies close to a surface at 5 ms time resolution using conventional inverted microscopes. We treat each bacterial cell as a spherocylindrical lens and use finite element modeling to solve Maxwell's equations and compute the diffracted light intensities associated with different angular orientations of the bacterium relative to the surface. By performing cross-correlation calculations between measured 2D microscopy images and a library of computed light intensities, we demonstrate that near-surface 3D movies of Pseudomonas aeruginosa translational and rotational motion are possible at high temporal resolution. Comparison between computational reconstructions and detailed hydrodynamic calculations reveals that P. aeruginosa act like low Reynolds number spinning tops with unstable orbits, driven by a flagellum motor with a torque output of ~2 pN MUm. Interestingly, our analysis reveals that P. aeruginosa can undergo complex flagellum-driven dynamical behavior, including precession, nutation, and an unexpected taxonomy of surface motility mechanisms, including upright-spinning bacteria that diffuse laterally across the surface, and horizontal bacteria that follow helicoidal trajectories and exhibit superdiffusive movements parallel to the surface. PMID- 28836763 TI - High-Flow-Rate Impinger for the Study of Concentration, Viability, Metabolic Activity, and Ice-Nucleation Activity of Airborne Bacteria. AB - The study of airborne bacteria relies on a sampling strategy that preserves their integrity and in situ physiological state, e.g. viability, cultivability, metabolic activity, and ice-nucleation activity. Because ambient air harbors low concentrations of bacteria, an effective bioaerosol sampler should have a high sampling efficiency and a high airflow. We characterize a high-flow-rate impinger with respect to particle collection and retention efficiencies in the range 0.5 3.0 MUm, and we investigated its ability to preserve the physiological state of selected bacterial species and seawater bacterial community in comparison with four commercial bioaerosol samplers. The collection efficiency increased with particle size and the cutoff diameter was between 0.5 and 1 MUm. During sampling periods of 120-300 min, the impinger retained the cultivability, metabolic activity, viability, and ice-nucleation activity of investigated bacteria. Field studies in semiurban, high-altitude, and polar environments included periods of low bacterial air concentrations, thus demonstrating the benefits of the impinger's high flow rate. In conclusion, the impinger described here has many advantages compared with other bioaerosol samplers currently on the market: a potential for long sampling time, a high flow rate, a high sampling and retention efficiency, low costs, and applicability for diverse downstream microbiological and molecular analyses. PMID- 28836764 TI - Intrinsic Differences in Backbone Dynamics between Wild Type and DNA-Contact Mutants of the p53 DNA Binding Domain Revealed by Nuclear Magnetic Resonance Spectroscopy. AB - Mutations in p53's DNA binding domain (p53DBD) are associated with 50% of all cancers, making it an essential system to investigate and understand the genesis and progression of cancer. In this work, we studied the changes in the structure and dynamics of wild type p53DBD in comparison with two of its "hot-spot" DNA contact mutants, R248Q and R273H, by analysis of backbone amide chemical shift perturbations and 15N spin relaxation measurements. The results of amide chemical shift changes indicated significantly more perturbations in the R273H mutant than in wild type and R248Q p53DBD. Analysis of 15N spin relaxation rates and the resulting nuclear magnetic resonance order parameters suggests that for most parts, the R248Q mutant exhibits limited conformational flexibility and is similar to the wild type protein. In contrast, R273H showed significant backbone dynamics extending up to its beta-sandwich scaffold in addition to motions along the DNA binding interface. Furthermore, comparison of rotational correlation times between the mutants suggests that the R273H mutant, with a higher correlation time, forms an enlarged structural fold in comparison to the R248Q mutant and wild type p53DBD. Finally, we identify three regions in these proteins that show conformational flexibility to varying degrees, which suggests that the R273H mutant, in addition to being a DNA-contact mutation, exhibits properties of a conformational mutant. PMID- 28836765 TI - Dimensional Control and Morphological Transformations of Supramolecular Polymeric Nanofibers Based on Cofacially-Stacked Planar Amphiphilic Platinum(II) Complexes. AB - Square-planar platinum(II) complexes often stack cofacially to yield supramolecular fiber-like structures with interesting photophysical properties. However, control over fiber dimensions and the resulting colloidal stability is limited. We report the self-assembly of amphiphilic Pt(II) complexes with solubilizing ancillary ligands based on polyethylene glycol [PEGn, where n = 16, 12, 7]. The complex with the longest solubilizing PEG ligand, Pt-PEG16, self assembled to form polydisperse one-dimensional (1D) nanofibers (diameters <5 nm). Sonication led to short seeds which, on addition of further molecularly dissolved Pt-PEG16 complex, underwent elongation in a "living supramolecular polymerization" process to yield relatively uniform fibers of length up to ca. 400 nm. The fiber lengths were dependent on the Pt-PEG16 complex to seed mass ratio in a manner analogous to a living covalent polymerization of molecular monomers. Moreover, the fiber lengths were unchanged in solution after 1 week and were therefore "static" with respect to interfiber exchange processes on this time scale. In contrast, similarly formed near-uniform fibers of Pt-PEG12 exhibited dynamic behavior that led to broadening of the length distribution within 48 h. After aging for 4 weeks in solution, Pt-PEG12 fibers partially evolved into 2D platelets. Furthermore, self-assembly of Pt-PEG7 yielded only transient fibers which rapidly evolved into 2D platelets. On addition of further fiber-forming Pt complex (Pt-PEG16), the platelets formed assemblies via the growth of fibers selectively from their short edges. Our studies demonstrate that when interfiber dynamic exchange is suppressed, dimensional control and hierarchical structure formation are possible for supramolecular polymers through the use of kinetically controlled seeded growth methods. PMID- 28836766 TI - Implications of Bioremediation of Polycyclic Aromatic Hydrocarbon-Contaminated Soils for Human Health and Cancer Risk. AB - Bioremediation uses soil microorganisms to degrade polycyclic aromatic hydrocarbons (PAHs) into less toxic compounds and can be performed in situ, without the need for expensive infrastructure or amendments. This review provides insights into the cancer risks associated with PAH-contaminated soils and places bioremediation outcomes in a context relevant to human health. We evaluated which bioremediation strategies were most effective for degrading PAHs and estimated the cancer risks associated with PAH-contaminated soils. Cancer risk was statistically reduced in 89% of treated soils following bioremediation, with a mean degradation of 44% across the B2 group PAHs. However, all 180 treated soils had postbioremediation cancer risk values that exceeded the U.S. Environmental Protection Agency (USEPA) health-based acceptable risk level (by at least a factor of 2), with 32% of treated soils exceeding recommended levels by greater than 2 orders of magnitude. Composting treatments were most effective at biodegrading PAHs in soils (70% average reduction compared with 28-53% for the other treatment types), which was likely due to the combined influence of the rich source of nutrients and microflora introduced with organic compost amendments. Ultimately, bioremediation strategies, in the studies reviewed, were unable to successfully remove carcinogenic PAHs from contaminated soils to concentrations below the target cancer risk levels recommended by the USEPA. PMID- 28836767 TI - Transition State Analogue Inhibitors of 5'-Deoxyadenosine/5'-Methylthioadenosine Nucleosidase from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis 5'-deoxyadenosine/5'-methylthioadenosine nucleosidase (Rv0091) catalyzes the N-riboside hydrolysis of its substrates 5' methylthioadenosine (MTA) and 5'-deoxyadenosine (5'-dAdo). 5'-dAdo is the preferred substrate, a product of radical S-adenosylmethionine-dependent enzyme reactions. Rv0091 is characterized by a ribocation-like transition state, with low N-ribosidic bond order, an N7-protonated adenine leaving group, and an activated but weakly bonded water nucleophile. DADMe-Immucillins incorporating 5' substituents of the substrates 5'-dAdo and MTA were synthesized and characterized as inhibitors of Rv0091. 5'-Deoxy-DADMe-Immucillin-A was the most potent among the 5'-dAdo transition state analogues with a dissociation constant of 640 pM. Among the 5'-thio substituents, hexylthio-DADMe-Immucillin-A was the best inhibitor at 87 pM. The specificity of Rv0091 for the Immucillin transition state analogues differs from those of other bacterial homologues because of an altered hydrophobic tunnel accepting the 5'-substituents. Inhibitors of Rv0091 had weak cell growth effects on M. tuberculosis or Mycobacterium smegmatis but were lethal toward Helicobacter pylori, where the 5'-methylthioadenosine nucleosidase is essential in menaquinone biosynthesis. We propose that Rv0091 plays a role in 5' deoxyadenosine recycling but is not essential for growth in these Mycobacteria. PMID- 28836769 TI - Elaborating the History of Our Cementing Societies: An in-Use Stock Perspective. AB - Modern cities and societies are built fundamentally based on cement and concrete. The global cement production has risen sharply in the past decades due largely to urbanization and construction. Here we deployed a top-down dynamic material flow analysis (MFA) model to quantify the historical development of cement in-use stocks in residential, nonresidential, and civil engineering sectors of all world countries. We found that global cement production spreads unevenly among 184 countries, with China dominating the global production and consumption after the 1990s. Nearly all countries have shown an increasing trend of per capita cement in-use stock in the past century. The present per capita cement in-use stocks vary from 10 to 40 tonnes in major industrialized and transiting countries and are below 10 tonnes in developing countries. Evolutionary modes identified from historical patterns suggest that per capita in-use cement stock growth generally complies with an S-shape curve and relates closely to affluence and urbanization of a country, but more in-depth and bottom-up investigations are needed to better understand socioeconomic drivers behind stock growth. These identified in-use stock patterns can help us better estimate future demand of cement, explore strategies for emissions reduction in the cement industry, and inform CO2 uptake potentials of cement based products and infrastructure in service. PMID- 28836768 TI - A Single Active Site Mutation in the Pikromycin Thioesterase Generates a More Effective Macrocyclization Catalyst. AB - Macrolactonization of natural product analogs presents a significant challenge to both biosynthetic assembly and synthetic chemistry. In the preceding paper , we identified a thioesterase (TE) domain catalytic bottleneck processing unnatural substrates in the pikromycin (Pik) system, preventing the formation of epimerized macrolactones. Here, we perform molecular dynamics simulations showing the epimerized hexaketide was accommodated within the Pik TE active site; however, intrinsic conformational preferences of the substrate resulted in predominately unproductive conformations, in agreement with the observed hydrolysis. Accordingly, we engineered the stereoselective Pik TE to yield a variant (TES148C) with improved reaction kinetics and gain-of-function processing of an unnatural, epimerized hexaketide. Quantum mechanical comparison of model TES148C and TEWT reaction coordinate diagrams revealed a change in mechanism from a stepwise addition-elimination (TEWT) to a lower energy concerted acyl substitution (TES148C), accounting for the gain-of-function and improved reaction kinetics. Finally, we introduced the S148C mutation into a polyketide synthase module (PikAIII-TE) to impart increased substrate flexibility, enabling the production of diastereomeric macrolactones. PMID- 28836770 TI - Highly Stable and Efficient Light-Emitting Electrochemical Cells Based on Cationic Iridium Complexes Bearing Arylazole Ancillary Ligands. AB - A series of bis-cyclometalated iridium(III) complexes of general formula [Ir(ppy)2(N?N)][PF6] (ppy- = 2-phenylpyridinate; N?N = 2-(1H-imidazol-2 yl)pyridine (1), 2-(2-pyridyl)benzimidazole (2), 1-methyl-2-pyridin-2-yl-1H benzimidazole (3), 2-(4'-thiazolyl)benzimidazole (4), 1-methyl-2-(4' thiazolyl)benzimidazole (5)) is reported, and their use as electroluminescent materials in light-emitting electrochemical cell (LEC) devices is investigated. [2][PF6] and [3][PF6] are orange emitters with intense unstructured emission around 590 nm in acetonitrile solution. [1][PF6], [4][PF6], and [5][PF6] are green weak emitters with structured emission bands peaking around 500 nm. The different photophysical properties are due to the effect that the chemical structure of the ancillary ligand has on the nature of the emitting triplet state. Whereas the benzimidazole unit stabilizes the LUMO and gives rise to a 3MLCT/3LLCT emitting triplet in [2][PF6] and [3][PF6], the presence of the thiazolyl ring produces the opposite effect in [4][PF6] and [5][PF6] and the emitting state has a predominant 3LC character. Complexes with 3MLCT/3LLCT emitting triplets give rise to LEC devices with luminance values 1 order higher than those of complexes with 3LC emitting states. Protecting the imidazole N-H bond with a methyl group, as in complexes [3][PF6] and [5][PF6], shows that the emissive properties become more stable. [3][PF6] leads to outstanding LECs with simultaneously high luminance (904 cd m-2), efficiency (9.15 cd A-1), and stability (lifetime over 2500 h). PMID- 28836771 TI - Barium Sulfide under Pressure: Discovery of Metastable Polymorphs and Investigation of Electronic Properties on ab Initio Level. AB - Barium sulfide (BaS) is an important precursor to other barium compounds with applications from ceramics and flame retardants to luminous paints and additives, and recent research shows potential technological applications in electrical and optical devices. Under normal conditions, BaS crystallizes in the NaCl type of structure, and with the increase in pressure BaS undergoes a structural phase transition to a CsCl type modification. This study presents modeling of barium sulfide under pressure with special focus on structural aspects and electronic properties. We predict metastable BaS polymorphs which have not yet been observed in the experiment or in previous calculations, and we investigated their vibrational and thermodynamical properties. Furthermore, we investigate the electronic properties of experimentally known structures as well as novel predicted modifications of BaS on ab initio level using Hartree-Fock, GGA-PBE, and the hybrid B3LYP functional. In this way, we address new possibilities of synthesizing BaS and possible band gap tuning which can have great applications in optoelectrical technologies. PMID- 28836772 TI - Identification of a Thioesterase Bottleneck in the Pikromycin Pathway through Full-Module Processing of Unnatural Pentaketides. AB - Polyketide biosynthetic pathways have been engineered to generate natural product analogs for over two decades. However, manipulation of modular type I polyketide synthases (PKSs) to make unnatural metabolites commonly results in attenuated yields or entirely inactive pathways, and the mechanistic basis for compromised production is rarely elucidated since rate-limiting or inactive domain(s) remain unidentified. Accordingly, we synthesized and assayed a series of modified pikromycin (Pik) pentaketides that mimic early pathway engineering to probe the substrate tolerance of the PikAIII-TE module in vitro. Truncated pentaketides were processed with varying efficiencies to corresponding macrolactones, while pentaketides with epimerized chiral centers were poorly processed by PikAIII-TE and failed to generate 12-membered ring products. Isolation and identification of extended but prematurely offloaded shunt products suggested that the Pik thioesterase (TE) domain has limited substrate flexibility and functions as a gatekeeper in the processing of unnatural substrates. Synthesis of an analogous hexaketide with an epimerized nucleophilic hydroxyl group allowed for direct evaluation of the substrate stereoselectivity of the excised TE domain. The epimerized hexaketide failed to undergo cyclization and was exclusively hydrolyzed, confirming the TE domain as a key catalytic bottleneck. In an accompanying paper , we engineer the standalone Pik thioesterase to yield a thioesterase (TES148C) and module (PikAIII-TES148C) that display gain-of-function processing of substrates with inverted hydroxyl groups. PMID- 28836773 TI - Mass Spectrometry of Aliphatic Macrolides, Important Semiochemicals or Pheromones. AB - Macrolides are a relatively common structural motif prevalent in Nature. However, the structures of these large ring lactones have been relatively difficult to elucidate via NMR spectroscopy due to the minute amounts of compounds that are sometimes obtainable from natural sources. Thus, GC-MS analysis of individual macrolactones has become the method of choice for the structural identification of these compounds. Here we discuss the mass spectrometric behavior of aliphatic macrolides, evaluating spectra from numerous compounds of various ring size, including derivatives containing methyl branches as well as double bonds. The specific fragmentation of these macrolactones under electron impact conditions allows for the development of a general rule set aimed at the identification of similar compounds by mass spectrometry. In addition, the mass spectra of dimethyl disulfide adducts of unsaturated macrolides are discussed. The mass spectra of almost 50 macrolides are presented. PMID- 28836774 TI - New Titanium Borylimido Compounds: Synthesis, Structure, and Bonding. AB - We report a combined experimental and computational study of the synthesis and electronic structure of titanium borylimido compounds. Three new synthetic routes to this hitherto almost unknown class of Group 4 imide are presented. The double deprotonation reaction of the borylamine H2NB(NAr'CH)2 (Ar' = 2,6-C6H3iPr2) with Ti(NMe2)2Cl2 gave Ti{NB(NAr'CH)2}Cl2(NHMe2)2, which was easily converted to Ti{NB(NAr'CH)2}Cl2(py)3. This compound is an entry point to other borylimides, for example, reacting with Li2N2pyrNMe to form Ti(N2pyrNMe){NB(NAr'CH)2}(py)2 and with 2 equiv of NaCp to give Cp2Ti{NB(NAr'CH)2}(py) (23). Borylamine-tert butylimide exchange between H2NB(NAr'CH)2 and Cp*Ti(NtBu)Cl(py) under forcing conditions afforded Cp*Ti{NB(NAr'CH)2}Cl(py), which could be further substituted with guanidinate or pyrrolide-amine ligands to give Cp*Ti(hpp){NB(NAr'CH)2} (16) and Cp*Ti(NpyrNMe2){NB(NAr'CH)2} (17). The Ti-Nim distances in compounds with the NB(NAr'CH)2 ligand were comparable to those of the corresponding arylimides. Dialkyl- or diaryl-substituted borylamines do not undergo the analogous double deprotonation or imide-amine exchange reactions. Reaction of (Cp"2Ti)2(MU2:eta1,eta1-N2) with N3BMes2 gave the base-free, diarylborylimide Cp"2Ti(NBMes2) (26) by an oxidative route; this compound has a relatively long Ti Nim bond and large Cp"-Ti-Cp" angle. Reaction of 16 with H2NtBu formed equilibrium mixtures with H2NB(NAr'CH)2 and Cp*Ti(hpp)(NtBu) (DeltarG = -1.0 kcal mol-1). In contrast, the dialkylborylimide Cp*Ti{MeC(NiPr)2}(NBC8H14) (2) reacted quantitatively with H2NtBu to give the corresponding tert-butylimide and borylamine. The electronic structures and imide-amine exchange reactions of half sandwich and sandwich titanium borylimides have been evaluated using density functional theory (DFT), supported by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis, and placed more generally in context with the well-established alkyl- and arylimides and hydrazides. The calculations find that Ti-Nim bonds for borylimides are stronger and more covalent than in their organoimido or hydrazido analogues, and are strongest for alkyl- and arylborylimides. Borylamine-tert-butylimide exchange reactions fail for H2NBR2 (R = hydrocarbyl) but not for H2NB(NAr'CH)2 because the increased strength of the new Ti-Nim bond for the former is outweighed by the increased net H-N bond strengths in the borylamine. Variation of the Ti-Nim bond length over short distances is dominated by pi-interactions with any appropriate orbital on the Nim atom organic substituent. However, over the full range of imides and hydrazides studied, overall bond energies do not correlate with bond length but with the Ti-Nim sigma-bond character and the orthogonal pi-interaction. PMID- 28836775 TI - Identification of alpha-Fe in High-Silica Zeolites on the Basis of ab Initio Electronic Structure Calculations. AB - alpha-Fe is the precursor of the reactive FeIV?O core responsible for methane oxidation in Fe-containing zeolites. To get more insight into the nature and stability of alpha-Fe in different zeolites, the binding of Fe(II) at six membered-ring cation exchange sites (6MR) in ZSM-5, zeolite beta, and ferrierite was investigated using DFT and multireference ab initio methods (CASSCF/CASPT2). CASPT2 ligand field (LF) excitation energies of all sites were compared with the experimental DR-UV-vis spectra reported by Snyder et al. From this comparison it is concluded that the 16000 cm-1 band of alpha-Fe, observed in all three zeolites, can uniquely be assigned to a high-spin square-planar (SP) Fe(II) located at a 6MR with an Al-Si-Si-Al sequence, where the Al atoms are positioned opposite in the ring and as close to each other as possible. The stability of such conformations is also confirmed by the binding energies obtained from DFT. The bands at 10000 cm-1 in the experimental spectra, assigned to spectator Fe(II), are attributed to six-coordinated trigonal-prismatic Fe(II) species, as calculated for the gamma-site in ZSM-5. The entatic effect of the zeolite lattice on the stability of the SP sites was investigated by making use of the unconstrained Fe(II) model complex FeL2 (with L = [Al(OH)4]-). The SP conformer is approximately 2 kcal/mol more stable than the tetrahedral form, indicating that the SP coordination environment of alpha-Fe is not imposed by the zeolite lattice but rather electronically preferred by Fe(II) in the environment of four O ligands. A significant contribution to the stability of the SP conformer is provided by mixing of the doubly occupied 3dz2 orbital with the higher lying 4s. PMID- 28836776 TI - Mechanistic Insight into Reversible Core Structural Changes of Dinuclear MU Hydroxoruthenium(II) Complexes with a 2,8-Di-2-pyridyl-1,9,10-anthyridine Backbone Prior to Water Oxidation Catalysis. AB - proximal,proximal-(p,p)-[RuII2(tpy)2LXY]n+ (tpy = 2,2';6',2"-terpyridine, L = 5 phenyl-2,8-di-2-pyridyl-1,9,10-anthyridine, and X and Y = other coordination sites) yields the structurally and functionally unusual RuII(MU-OH)RuII core, which is capable of catalyzing water oxidation with key water insertion to the core (Inorg. Chem. 2015, 54, 7627). Herein, we studied a sequence of bridging ligand substitution among p,p-[Ru2(tpy)2L(MU-Cl)]3+ (Ru2(MU-Cl)), p,p [Ru2(tpy)2L(MU-OH)]3+ (Ru2(MU-OH)), p,p-[Ru2(tpy)2L(OH)(OH2)]3+ (Ru2(OH)(OH2)), and p,p-[Ru2(tpy)2L(OH)2]2+ (Ru2(OH)2) in aqueous solution. Ru2(MU-Cl) converted slowly (10-4 s-1) to Ru2(MU-OH), and further Ru2(MU-OH) converted very slowly (10 6 s-1) to Ru2(OH)(OH2) by the insertion of water to reach equilibrium at pH 8.5 12.3. On the basis of density functional theory (DFT) calculations, Ru2(OH)(OH2) was predicted to be thermodynamically stable by 13.3 kJ mol-1 in water compared to Ru2(MU-OH) because of the specially stabilized core structure by multiple hydrogen-bonding interactions involving aquo, hydroxo, and L backbone ligands. The observed rate from Ru2(MU-OH) to Ru2(OH)2 by the insertion of an OH- ion increased linearly with an increase in the OH- concentration from 10 to 100 mM. The water insertion to the core is very slow (~10-6 s-1) in aqueous solution at pH 8.5-12.3, whereas the insertion of OH- ions is accelerated (10-5-10-4 s-1) above pH 13.4 by 2 orders of magnitude. The kinetic data including activation parameters suggest that the associative mechanism for the insertion of water to the RuII(MU-OH)RuII core of Ru2(MU-OH) at pH 8.5-12.3 alters the interchange mechanism for the insertion of an OH- ion to the core above pH 13.4 because of relatively stronger nucleophilic attack of OH- ions. The hypothesized p,p [Ru2(tpy)2L(MU-OH2)]4+ and p,p-[Ru2(tpy)2L(OH2)2]4+ formed by protonation from Ru2(MU-OH) and Ru2(OH)(OH2) were predicted to be unstable by 71.3 and 112.4 kJ mol-1 compared to Ru2(MU-OH) and Ru2(OH)(OH2), respectively. The reverse reactions of Ru2(MU-OH), Ru2(OH)(OH2), and Ru2(OH)2 to Ru2(MU-Cl) below pH 5 could be caused by lowering the core charge by protonation of the MU-OH- or OH- ligand. PMID- 28836777 TI - Iodine-Catalyzed Regioselective Synthesis of Multisubstiuted Pyrrole Polyheterocycles Free from Rotamers and Keto-Enol Tautomers. AB - A highly regioselective iodine-mediated cascade reaction for the synthesis of multifunctional polyheterocyclic systems is developed by employing 3-(2-oxo-2 arylethylidene)oxindoles and 1,4-benzoxazinone as starting materials. The polyheterocycles are skillfully embraced with oxindole, pyrrole, and coumarin scaffolds, which are well-known for their enriched biological activity. The current approach worked under mild reaction conditions. The reaction afforded a single product, and no rotameric and keto-enol isomeric products are formed. The method is environmentally benign and atom-economical, and the only side product of this reaction is water. This protocol obviates the purification techniques such as column chromatography for the isolation of the products. The products were isolated by decantation of the solvent or by recrystallization. The reaction proceeds through inter- and intramolecular C-C and C-N bond formation. PMID- 28836778 TI - Dipolar NLO Chromophores Bearing Diazine Rings as pi-Conjugated Linkers. AB - The synthesis of a series of push-pull derivatives bearing triphenylamine electron-donating group, cyclopenta[c]thiophen-4,6-dione electron acceptor and various pi-linkers including (hetero)aromatic fragments is reported. All target chromophores with systematically varied pi-linker structure were further investigated by electrochemistry, absorption measurements, and EFISH experiments in conjunction with DFT calculations. Based on electrochemical and photophysical measurements, when a polarizable 2,5-thienylene moiety is embedded into the chromophore pi-backbone the highest intramolecular charge transfer (ICT) is observed. Benzene, pyrimidine, and pyridazine derivatives exhibit lower polarizability and extent of the ICT across these pi-linkers. The elongation of the pi-conjugated system via additional ethenylene linker results in a significant reduction of the HOMO-LUMO gap and an enhancement of the NLO response. Whereas it does not significantly influence electrochemical and linear optical properties, the orientation of the pyrimidine ring seems to be a key parameter on the MUbeta value due to significant variation of the dipolar moment (MU) value. In 2a and 2c, pyrimidine is oriented to behave as an acceptor and thus generate dipolar molecule with MU above 5 D, whereas in 2b and 2d ground state dipole moment is significantly reduced. This study seems to indicate a high aromaticity of pyrimidine and pyridazine derivatives, close to the benzene analogues and significantly higher than thiophene analogues. PMID- 28836779 TI - M8MgSc(PO4)7:xDy3+ (M = Ca/Sr) Single-Phase Full-Color Phosphor with High Thermal Emission Stability. AB - Two series of phosphors of Ca8MgSc(PO4)7:Dy3+ and Sr8MgSc(PO4)7:Dy3+ single-phase white-emitting phosphors with high thermal emission stability are synthesized by the high-temperature solid-state reaction. The crystal structure, photoluminescence (PL), PL excitation (PLE), and thermal PL quenching spectra of Ca8MgSc(PO4)7:xDy3+ and Sr8MgSc(PO4)7:xDy3+ were investigated and compared in detail. Upon excitation at 387 nm, M8MgSc(PO4)7:xDy3+ (M = Ca/Sr) showed white emission centered at 480, 571, 660, and 754 nm. The white-emitting Dy-phosphor Ca8MgSc(PO4)7:Dy3+ (CMSP:Dy) had good terminal stability. The emission intensity of Ca8MgSc(PO4)7:Dy3+ still remained 95.2% of that at room temperature at 160 degrees C, and remained 77.3% at 300 degrees C under 387 nm excitation. PMID- 28836780 TI - B(C6F5)3-Catalyzed C-Si/Si-H Cross-Metathesis of Hydrosilanes. AB - The substituent redistribution of hydrosilanes on silicon through C-Si and Si-H bond cleavage and reformation is of great interest and importance, but this transformation is usually difficult to achieve in a selective fashion. By using electron-rich aromatic hydrosilanes, we have achieved for the first time the selective C-Si/Si-H bond homo- and cross-metathesis of a series of hydrosilanes in the presence of a boron catalyst B(C6F5)3. This protocol features simple reaction conditions, high chemoselectivity, wide substrate scope, and high functionality tolerance, offering a new pathway for the synthesis of multisubstituted functional silanes. PMID- 28836781 TI - Molecular Dynamics Simulations on the Behaviors of Hydrophilic/Hydrophobic Cyclic Peptide Nanotubes at the Water/Hexane Interface. AB - In this work, nine kinds of amino acid residues, i.e., alanine (A), leucine (L), valine (V), isoleucine (I), tryptophan (W), glutamine (Q), threonine (T), serine (S), and cysteine (C), were selected to construct seven cyclic peptide nanotubes (CPNTs) with diverse hydrophilic/hydrophobic external surfaces, which were further separately inserted at the water/hexane interface to investigate their microstructures and interfacial properties. Molecular dynamics (MD) simulations reveal that all the CPNTs except the QT- and VL-CPNTs have different degrees of tilt, fracture, and shedding at the interface. The end-CPs are more susceptible to the effect of the surroundings than the mid-CPs. The interactions of individual CP subunits with the neighborings disclose the firmness of the mid-CPs and the dissociation of the end-CPs. The results indicate that a hydrophobic CPNT is prone to stay at the interface, while a hydrophilic CPNT easily enters the water phase, resulting in many H-bonds with water. Results in this work enrich the dynamic properties of a hydrophilic/hydrophobic CPNT at the biphase interface at the atomic level. PMID- 28836782 TI - Stabilization of 2,6-Diarylanilinum Cation by Through-Space Cation-pi Interactions. AB - Energetically favorable cation-pi interactions play important roles in numerous molecular recognition processes in chemistry and biology. Herein, we present synergistic experimental and computational physical-organic chemistry studies on 2,6-diarylanilines that contain flanking meta/para-substituted aromatic rings adjacent to the central anilinium ion. A combination of measurements of pKa values, structural analyses of 2,6-diarylanilinium cations, and quantum chemical analyses based on the quantitative molecular orbital theory and a canonical energy decomposition analysis (EDA) scheme reveal that through-space cation-pi interactions essentially contribute to observed trends in proton affinities and pKa values of 2,6-diarylanilines. PMID- 28836783 TI - Controlled Energy Transfer from a Ligand to an EuIII Ion: A Unique Strategy To Obtain Bright-White-Light Emission and Its Versatile Applications. AB - A new diphenylamine-functionalized ancillary-ligand-coordinated europium(III) beta-diketonate complex showed incomplete photoexcitation energy transfer from a ligand to a EuIII ion. A solvatochromism study led to a balancing of the primary colors to obtain single-molecule white-light emission. Thermal-sensing analysis of the europium complex was executed. The europium complex, conjugated with a near-UV-light-emitting diode (395 nm), showed appropriate white-light-emission CIE color coordinates (x = 0.34 and y = 0.33) with a 5152 K correlated color temperature. PMID- 28836784 TI - Metal Effects on the Sensitivity of Isostructural Metal-Organic Frameworks Based on 5-Amino-3-nitro-1H-1,2,4-triazole. AB - Two energetic metal-organic frameworks (MOFs), Co-ANTA and Zn-ANTA, are synthesized from 5-amino-3-nitro-1H-1,2,4-triazole (ANTA) and exhibit superior oxygen balance, density, and thermal stability compared to ANTA. The superior oxygen balance is achieved through a combination of hydroxide ligands and deprotonated linkers. Although the materials are isostructural and have similar density, oxygen balance, and sensitivity to heat, their impact sensitivities are significantly different. Similar to ANTA, Zn-ANTA is fairly insensitive to impact. By contrast, the impact sensitivity of ANTA is increased significantly after coordination polymerization with cobalt. The disparate impact sensitivities of the compounds might be attributed to the different electronic configurations of the metal ions constituting the frameworks. PMID- 28836785 TI - Synthesis of Zintl Triads Comprising Extended Conjugated pi-Electronic Systems: [RGe9-CH?CH-CH?CH-Ge9R]4- (R = -CH?CH2, -C(CH3)?CH-CH?N(CH2)2NH2). AB - Triads with extended conjugated pi-electronic systems between polyhedral cage molecules possess promising electronic properties. In contrast to the known fullerene-bridge-fullerene triads, fewer synthetic procedures are known for the related homoatomic deltahedral cage molecules of the heavier homologues of carbon. The synthesis of the organo-Zintl triads [RGe9-CH?CH-CH?CH-Ge9R]4- with R = -CH?CH2 (R1), -C(CH3)?CH-CH?N(CH2)2NH2 ((2Z,4E)-7-amino-5-azahepta-2,4-dien-2 yl) (R2) is reported, in which the deltahedral Ge9 cages carry an additional functional group, allowing for further connections. Both anionic cage entities bear a butadiene-1,4-diyl bridge which is formed by reacting the Zintl ion [Ge9]4 with 1,4-bis(trimethylsilyl)butadiyne in ethylenediamine. The organic tethers can be attached by nucleophilic attack of the Ge9 clusters at the bis(trimethylsilyl)acetylene and (3Z/3E)-7-amino-1-(trimethylsilyl)-5-azahepta-3 en-1-yne, respectively, in ethylenediamine, and the products cis/trans-[R1Ge9 CH?CH-CH?CH-Ge9R1]4- and cis/cis-[R2Ge9-CH?CH-CH?CH-Ge9R2]4- have been isolated as [A(2,2,2-crypt)]+ salts with A = K, Rb, respectively. Crystals containing the novel anions [RGe9-CH?CH-CH?CH-Ge9R]4- have been structurally characterized by X ray diffraction methods, and the compounds have been investigated by 1H and 13C NMR as well as by Raman spectroscopy. The cis/cis configurational isomer of [R1Ge9-CH?CH-CH?CH-Ge9R1]4- was characterized by means of NMR spectroscopy. Via in situ NMR measurements, we shed some light on the formation of the Zintl triads [RGe9-CH?CH-CH?CH-Ge9R]4- bearing supplemental organic tethers. PMID- 28836786 TI - Sesteralterin and Tricycloalterfurenes A-D: Terpenes with Rarely Occurring Frameworks from the Marine-Alga-Epiphytic Fungus Alternaria alternata k21-1. AB - A new sesterterpene, sesteralterin (1), four new meroterpenes, tricycloalterfurenes A-D (2-5), and a known meroterpene, TCA-F (6), were obtained from the culture extract of an Alternaria alternata strain (k21-1) isolated from the surface of the marine red alga Lomentaria hakodatensis. The structures and relative/absolute configurations of these compounds were identified by spectroscopic analyses, mainly including 1D/2D NMR, ECD, and mass spectra and quantum chemical calculations. Compound 1 represents the first nitidasane sesterterpene naturally produced by fungi, and 2-5 feature a tetrahydrofuran unit rarely occurring in tricycloalternarenes. Compounds 1-6 were assayed for inhibition of the growth of four marine plankton and one marine alga-pathogenic bacterium. PMID- 28836787 TI - Self-Healing Superhydrophobic Materials Showing Quick Damage Recovery and Long Term Durability. AB - Superhydrophobic coatings/materials are important for a wide variety of applications, but the majority of these man-made coatings/materials still suffer from poor durability because of their lack of self-healing ability. Here, we report novel superhydrophobic materials which can quickly self-heal from various severe types of damage. In this study, we used poly(dimethylsiloxane) (PDMS) infused with two liquids: trichloropropylsilane, which reacts with ambient moisture to self-assemble into grass-like microfibers (named silicone micro/nanograss) on the surfaces and low-viscosity silicone oil (SO), which remains within the PDMS matrices and acts as a self-healing agent. Because of the silicone micro/nanograss structures on the PDMS surfaces and the effective preserve/protection system of a large quantity of SO within the PDMS matrices, our superhydrophobic materials showed quick superhydrophobic recovery under ambient conditions (within 1-2 h) even after exposure to plasma (24 h), boiling water, chemicals, and outside environments. Such an ability is superior to the best self-healing superhydrophobic coatings/materials reported so far. PMID- 28836788 TI - Emulsion Solvent Evaporation-Induced Self-Assembly of Block Copolymers Containing pH-Sensitive Block. AB - A simple yet efficient method is developed to manipulate the self-assembly of pH sensitive block copolymers (BCPs) confined in emulsion droplets. Addition of acid induces significant variation in morphological transition (e.g., structure and surface composition changes) of the polystyrene-block-poly(4-vinylpyridine) (PS-b P4VP) assemblies, due to the hydrophobic-hydrophilic transition of the pH sensitive P4VP block via protonation. In the case of pH > pKa(P4VP) (pKa (P4VP) = 4.8), the BCPs can self-assemble into pupa-like particles because of the nearly neutral wetting of PS and P4VP blocks at the oil/water interface. As expected, onion-like particles obtained when pH is slightly lower than pKa(P4VP) (e.g., pH = 3.00), due to the interfacial affinity to the weakly hydrophilic P4VP block. Interestingly, when pH was further decreased to ~2.5, interfacial instability of the emulsion droplets was observed, and each emulsion droplet generated nanoscale assemblies including vesicles, worm-like and/or spherical micelles rather than a nanostructured microparticle. Furthermore, homopolymer with different molecular weights and addition ratio are employed to adjust the interactions among copolymer blocks. By this means, particles with hierarchical structures can be obtained. Moreover, owing to the kinetically controlled processing, we found that temperature and stirring speed, which can significantly affect the kinetics of the evaporation of organic solvent and the formation of particles, played a key role in the morphology of the assemblies. We believe that manipulation of the property for the aqueous phase is a promising strategy to rationally design and fabricate polymeric assemblies with desirable shapes and internal structures. PMID- 28836789 TI - Synthesis of N,N-Dioxopyridazines. AB - Despite many efforts, one of the smallest heterocycles containing two nitrogen atoms, pyridazine, could not be converted to its N,N-dioxide (see, however, Nakadate et al. Chem. Pharm. Bull. 1970 , 18 , 1211 - 1218 ). HOF.CH3CN, made easily from diluted fluorine, was able to accomplish this task in a fast reaction with good yields. PMID- 28836790 TI - Stabilizing Unstable Amorphous Menthol through Inclusion in Mesoporous Silica Hosts. AB - The amorphization of the readily crystallizable therapeutic ingredient and food additive, menthol, was successfully achieved by inclusion of neat menthol in mesoporous silica matrixes of 3.2 and 5.9 nm size pores. Menthol amorphization was confirmed by the calorimetric detection of a glass transition. The respective glass transition temperature, Tg = -54.3 degrees C, is in good agreement with the one predicted by the composition dependence of the Tg values determined for menthol:flurbiprofen therapeutic deep eutectic solvents (THEDESs). Nonisothermal crystallization was never observed for neat menthol loaded into silica hosts, which can indicate that menthol rests as a full amorphous/supercooled material inside the pores of the silica matrixes. Menthol mobility was probed by dielectric relaxation spectroscopy, which allowed to identify two relaxation processes in both pore sizes: a faster one associated with mobility of neat-like menthol molecules (alpha-process), and a slower, dominant one due to the hindered mobility of menthol molecules adsorbed at the inner pore walls (S-process). The fraction of molecular population governing the alpha-process is greater in the higher (5.9 nm) pore size matrix, although in both cases the S-process is more intense than the alpha-process. A dielectric glass transition temperature was estimated for each alpha (Tg,dielc(alpha)) and S (Tg,dielc(S)) molecular population from the temperature dependence of the relaxation times to 100 s. While Tg,dielc(alpha) agrees better with the value obtained from the linearization of the Fox equation assuming ideal behavior of the menthol:flurbiprofen THEDES, Tg,dielc(S) is close to the value determined by calorimetry for the silica composites due to a dominance of the adsorbed population inside the pores. Nevertheless, the greater fraction of more mobile bulk-like molecules in the 5.9 nm pore size matrix seems to determine the faster drug release at initial times relative to the 3.2 nm composite. However, the latter inhibits crystallization inside pores since its dimensions are inferior to menthol critical size for nucleation. This points to a suitability of these composites as drug delivery systems in which the drug release profile can be controlled by tuning the host pore size. PMID- 28836791 TI - Core-Shell-Corona Silica Hybrid Nanoparticles Templated by Spherical Polyelectrolyte Brushes: A Study by Small Angle X-ray Scattering. AB - Core-shell-corona silica/polymer hybrid nanoparticles with narrow size distribution were prepared in the template of spherical polyelectrolyte brushes (SPB) which consist of a solid polystyrene (PS) core densely grafted with linear poly(acrylic acid) (PAA) chains. The microstructure of obtained hybrid nanoparticles was studied by small-angle X-ray scattering (SAXS) and in combination with dynamic light scattering (DLS) and transmission electron microscopy (TEM). The generation of silica shell within the brush is confirmed by the significant increase of the electron density in the shell, and the silica shell showed a unique inner-loose-outer-dense structure, whose thickness is pH sensitive but is insensitive to ionic strength as revealed by fitting SAXS data. After dissolving the PS core, hollow silica nanoparticles were obtained and determined by SAXS, which should be ideal carriers for pH-triggered drug delivery. SAXS is confirmed to be a powerful method to characterize the core shell-corona silica/polymer hybrid and hollow silica nanoparticles. PMID- 28836792 TI - Galactose-Anchored Gelatin Nanoparticles for Primaquine Delivery and Improved Pharmacokinetics: A Biodegradable and Safe Approach for Effective Antiplasmodial Activity against P. falciparum 3D7 and in Vivo Hepatocyte Targeting. AB - Primaquine phosphate (PQ) is mainly used as a radical cure therapy to eradicate relapse of malaria at the liver stage, which is particularly caused by P. falciparum and P. vivax. In the present study, PQ-loaded galactosylated gelatin nanoparticles (Gel-LA-PQ-NPs) were formulated using a one-step desolvation technique. The mean particle size of Gel-LA-PQ-NPs was found to be 93.48 +/- 6.36 nm with a zeta potential of 4.80 +/- 0.20 mV having 69.90 +/- 1.53% encapsulation efficiency. Electron microscopy demonstrated that the NPs were spherical in shape and uniformly distributed without any cluster formation. The in vitro release of PQ from Gel-LA-PQ-NPs has been facilitated in sustained manner, and the release was three times slower than the naive drug. The prepared nanoparticles (Gel-LA-PQ NPs) were significantly (p < 0.0001) less hemolytic than the pure drug PQ. The hematological ex vivo study further supported that the developed Gel-LA-PQ-NPs were safer than PQ. The in vitro antiplasmodium assay revealed that the IC50 value against the blood stage of asexual P. falciparum 3D7 strains was significantly (p < 0.01) less (2.862 +/- 0.103 MUM) for Gel-LA-PQ-NPs than naive PQ (3.879 +/- 0.655 MUM). In vivo pharmacokinetic parameters of Gel-LA-PQ-NPs such as half-life and AUC were significantly higher for Gel-LA-PQ-NPs, i.e., with higher bioavailability. Galactosylation of the NPs led to liver targeting of the PQ in animal studies. Approximately eight-fold higher accumulation of PQ was observed in liver compared to pure drug (i.e., PQ). Conclusively, the prepared galactosylated gelatin nanocarrier holds the promising potential and hepatic targetability of an antimalarial, maintaining its safety and biocompatibility. PMID- 28836793 TI - Construction of the [6,5,7,5] Tetracyclic Core of Calyciphylline A Type Alkaloids via a Tandem Semipinacol Rearrangement/Nicholas Reaction. AB - A novel and efficient approach toward the assembly of the synthetically challenging tetracyclic [6,5,7,5] core structure of calyciphylline A-type alkaloids is developed. The synthetic route features a tandem semipinacol rearrangement/Nicholas reaction that has been devised strategically to construct the spirocyclic A/B ring and the sterically congested vicinal all-carbon quaternary carbon centers in high diastereoselectivity. Late-stage installation of the hydropyrrole ring and the strained 7-membered ring via a double-reductive amination and ring-closing metathesis, respectively, has also been realized. PMID- 28836794 TI - Molecular Dynamics Simulations as a Tool for Accurate Determination of Surfactant Micelle Properties. AB - Molecular dynamics (MD) simulations were used to characterize the equilibrium size, shape, hydration, and self-assembly of dodecylphosphocholine (DPC) and dodecyl-beta-D-maltoside (DDM) micelles. We show that DPC molecules self-assemble to form micelles with sizes within the range reported in the experimental literature. The equilibrium shape of DPC and DDM micelles as well as associated micellar radii are in agreement with small-angle X-ray scattering (SAXS) experiments and theoretical packing parameters. In addition, we show that hydration of the micelle interior is limited; however, flexibility of the acyl chains leads to dynamic encounters with the solvated outer shell of the micelle, providing an explanation for long-standing differences in models of micelle hydration. Altogether, our results provide fundamental understanding of physical characteristics of micelles that can be utilized to study other types of detergents and proteomicelle complexes. PMID- 28836795 TI - Correction to "CO2-Reactive Ionic Liquid Surfactants for the Control of Colloidal Morphology". PMID- 28836797 TI - An illness by any other name: The effect of renaming gout on illness and treatment perceptions. AB - OBJECTIVE: Inaccurate lay views of an illness can lead to the adoption of unhelpful coping strategies and treatments. Gout is an example of an illness where the popular view of the condition conflicts with a modern understanding of the illness by overemphasizing the role of diet and alcohol in the development and management of the disease. In this study we investigated the effect of renaming gout as urate crystal arthritis on the perceptions of the illness. METHOD: One-hundred and 89 supermarket shoppers participated in a study examining the perceptions of different types of arthritis. Participants completed a questionnaire that either used the term "urate crystal arthritis" (UCA) or "gout" for the label and a description of the disease. Participants rated likely causal factors, illness perceptions and the usefulness of various management strategies. RESULTS: Gout was perceived as being more likely caused by the patient's own behavior through poor diet and overconsumption of alcohol, while UCA was attributed to aging. The UCA-labeled illness was also viewed as a more chronic and serious condition, while the gout-labeled illness was seen as being more socially embarrassing and more under the patient's personal control. Management for the gout-labeled illness centered on dietary interventions, while the UCA labeled illness was perceived as requiring long-term medication. CONCLUSION: Changing an illness label can have a significant effect on causal beliefs, illness perceptions, and management strategies. Changing illness labels may be useful where the lay perceptions of an illness are not aligned with a current understanding of the condition. (PsycINFO Database Record PMID- 28836796 TI - Analyzing components of Community Reinforcement and Family Training (CRAFT): Is treatment entry training sufficient? AB - Community Reinforcement and Family Training (CRAFT) assists family members with a treatment-resistant loved one. The most consistent outcome of CRAFT is increased treatment entry of the identified treatment-resistant person (IP). This led us to question whether all 6 components of CRAFT are necessary. In a randomized clinical trial, 115 concerned significant others (CSOs) of an IP received 12-14 sessions of the full CRAFT intervention, 4-6 sessions focused on Treatment Entry Training (TEnT), or 12-14 sessions of Al-Anon/Nar-Anon Facilitation (ANF). We monitored treatment entry, attendance, and substance use of the IP and the CSO's mood and functioning. Data were collected at baseline and 4, 6, and 9 months after the baseline. We found significant reductions in time to treatment entry (chi(2)2 = 8.89, p = .01) and greater treatment entry rates for CRAFT (62%; odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1-6.9) and TEnT (63%; OR = 2.9, 95% CI = 1.2-7.5) compared with ANF (37%), but CRAFT and TEnT did not differ significantly from each other (OR = 1.1, 95% CI = 0.4-2.7). No between-group differences in IP drug use were reported by CSOs, but days of drug use decreased over time for all groups (F(3, 277) = 13.47, p < .0001). Similarly, CSO mood and functioning did not differ between the 3 conditions but improved over time (p < .0001 for all significant measures). We replicated the results of previous trials demonstrating that CRAFT produces greater treatment entry rates than ANF and found similar treatment entry rates for CRAFT and TEnT. This suggests that treatment entry training is sufficient for producing the best established outcome of CRAFT. (PsycINFO Database Record PMID- 28836798 TI - Affective associations as predictors of health behavior in urban minority youth. AB - OBJECTIVE: Affective associations are key predictors of health-relevant action that can mediate the relationships between cognitive variables and health behavior. Little data, however, has examined affective associations in high-risk groups, the individuals with the greatest need for intervention. Further, few studies have examined the unique predictive ability of positive and negative affective associations. METHODS: The present study assessed positive affective associations, negative affective associations, cognitive beliefs, subjective norms, and reports of 4 obesity-related behaviors (physical activity, fruit consumption, vegetable consumption, and soft drink consumption) across a cross sectional (n = 1,499) and a longitudinal sample (n = 104) of predominantly African American adolescents of low socioeconomic status from the inner city of urban Detroit. RESULTS: In both samples, positive (not negative) affective associations were the strongest and most consistent predictor of health behavior. Analyses also suggested that positive affective associations mediate the relationships between cognitive beliefs, subjective norms, and health behavior. Interaction tests revealed no evidence that the link between positive affective associations and health behavior is moderated by negative affective associations, cognitive beliefs, subjective norms, sex, or age. CONCLUSIONS: The results are consistent with affective association research and support the development of health interventions for urban minority youth aimed at changing positive (rather than negative) affective associations. The consistency across behaviors and the lack of reliable interactive effects suggests that changing positive affective associations may benefit urban youth regardless of behavior domain, age, sex, negative affective associations, subjective norm, and cognitive beliefs. (PsycINFO Database Record PMID- 28836799 TI - Leadership and member voice in action teams: Test of a dynamic phase model. AB - Voice is an important way that members contribute to effective team functioning. And yet, the existing literature provides divergent guidance as to how leaders can promote member voice in action teams-a dynamic team context where eliciting voice may be difficult, due to different task demands encountered in the preparation and action phases of task performance, among members who may have little history of working together. Drawing on the employee voice and team leadership literatures, we focus on three leader behaviors-directing, coaching, and supporting-and employ a functional leadership perspective to assess whether certain leader behaviors enhance voice in one phase of the performance episode versus the other. We also assess whether these leadership-voice relationships are further contingent on team members' prior familiarity with one another. Observation and survey data from 105 surgical team episodes revealed that leader directing promoted voice in both the preparation and action phases. Coaching also facilitated voice in both phases, especially in the action phase for more familiar teams. Surprisingly, supporting did not enhance voice in either phase, and in fact exhibited negative effects on voice in the preparation phase of more familiar teams. Theoretical and practical implications around how leaders can elicit voice in action teams are discussed. (PsycINFO Database Record PMID- 28836801 TI - Need satisfaction at work, job strain, and performance: A diary study. AB - We performed a daily diary study to examine the mediating role of autonomy need satisfaction and competence need satisfaction in the relationships between job characteristics (i.e., job resources, challenge and hindrance demands) and strain and performance. For 10 consecutive working days, 194 employees reported on their daily job resources, challenge and hindrance demands, task performance, strain level, and satisfaction of the needs for competence and autonomy. Multilevel path modeling demonstrated that the within-person relationships between job resources, challenge and hindrance demands, and strain are mediated by autonomy need satisfaction, but not by competence need satisfaction. However, the relationships between job resources and hindrance demands, and performance are mediated by both competence and autonomy need satisfaction. Our findings show that organizations may benefit from designing jobs that provide employees with the opportunity to satisfy their basic needs for competence and autonomy. (PsycINFO Database Record PMID- 28836802 TI - What inverted U can do for your country: A curvilinear relationship between confidence in the social system and political engagement. AB - We examined the link between political engagement and the tendency to justify the sociopolitical system. On one hand, confidence in the system should be negatively related to political engagement, insofar as it entails reduced desire for social change; on the other hand, system confidence should also be positively related to political engagement to the extent that it carries an assumption that the system is responsive to citizens' political efforts. Because of the combination of these 2 opposing forces, the motivation for political engagement should be highest at intermediate levels of system confidence. Five studies revealed a negative quadratic relationship between system confidence and normative political engagement. In 2 representative surveys, Polish participants with moderate levels of system confidence were more likely to vote in political elections (Study 1) and to participate in solidarity-based collective action (Study 2). Two field studies demonstrated a negative quadratic relationship between system confidence and actual participation in political demonstrations (gender equality and teachers' protests in Poland; Studies 3 and 4). This pattern of results was further corroborated by analyses of data from 50 countries drawn from the World Value Survey: we observed negative quadratic relationships between system confidence and collective action as well as voting. These relationships were stronger in democratic (vs. nondemocratic) regimes (Study 5). Our results suggest that some degree of system confidence might be useful to stimulate political engagement within the norms of the system. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28836800 TI - Does college alcohol consumption impact employment upon graduation? Findings from a prospective study. AB - [Correction Notice: An Erratum for this article was reported in Vol 103(1) of Journal of Applied Psychology (see record 2017-44578-001). In the article, the authors incorrectly used the term "probability" instead of the term "odds" when relating to the impact of drinking in college on post-graduation employment. The abstract should note "a roughly 10% reduction in the odds...", and in the 2nd paragraph of the Discussion section, (a) "a roughly 10% lower probability" should be "a roughly 10% lower odds", and (b) "their probability of full-time employment upon graduation is roughly 6% lower than..." should be "their odds of full-time employment upon graduation is roughly 6% lower than..." All versions of this article have been corrected.] Although scholars have extensively studied the impact of academic and vocational factors on college students' employment upon graduation, we still know little as to how students' health-related behaviors influence such outcomes. Focusing on student alcohol use as a widely prevalent, health-related behavior, in the current study, we examined the employment implications of student drinking behavior. Drawing from literature examining the productivity effects of drinking and research on job search, we posited that modal quantity and frequency of alcohol consumption, as well as the frequency of heavy episodic drinking (HED) adversely impact the probability of employment upon graduation. Using data from 827 graduating seniors from 4 geographically diverse universities in the United States collected in the context of a prospective study design, we found modal alcohol consumption to have no adverse effect on the likelihood of employment upon graduation. However, we did find a significant adverse effect for the frequency of heavy drinking, with the data suggesting a roughly 10% reduction in the odds of employment upon graduation among college seniors who reported engaging in the average level of HED. The theoretical and practical implications of these findings are discussed. (PsycINFO Database Record PMID- 28836803 TI - Reducing Defensive Responses to Thoughts of Death: Meditation, Mindfulness, and Buddhism. AB - Three studies investigated the effects of meditation on responses to reminders of death. Study 1 took a quasi-experimental approach, comparing defensive responses to mortality salience (MS) of South Korean participants with varying levels of experience with Buddhism and meditation. Whereas non-Buddhists without meditation showed the typical increase in worldview defense after mortality salience (MS), this effect was not found among non-Buddhists immediately after an initial meditation experience, nor among lay Buddhists who meditated regularly or Buddhist monks with intensive meditation experience. Study 2, a fully randomized experiment, showed that MS increased worldview defense among South Koreans at a meditation training who were assessed before meditating but not among participants assessed after their first meditation experience. Study 3 showed that whereas American students without prior meditation experience showed increased worldview defense and suppression of death-related thoughts after MS, these effects were eliminated immediately after an initial meditation experience. Death thought accessibility mediated the effect of MS on worldview defense without meditation, but meditation eliminated this mediation. (PsycINFO Database Record PMID- 28836805 TI - Pediatric rehabilitation psychology: Rehabilitating a moving target. AB - The current special section includes manuscripts focusing on four aspects of pediatric rehabilitation psychology that are unique to this practice area. The first domain addressed is natural developmental progression in the context of a disability (i.e., habilitation). The next domain addressed in this special section is pediatric rehabilitation; pediatric rehabilitation psychology addresses the reacquisition of previously attained skills and abilities within the context of the natural developmental milieu. This special section also highlights the inherently interdisciplinary and transdisciplinary nature of pediatric rehabilitation psychology given the complex environment in which children exist. Finally, the special section includes illustrations of the crucial role pediatric rehabilitation psychologists play in facilitating transitions through major milestones, particularly from pediatrics to adulthood when living with a disability. (PsycINFO Database Record PMID- 28836804 TI - Patient SWAP-200 personality dimensions and FFM traits: Do they predict therapist responses? AB - The main aim of this study was to examine the relationship between therapists' emotional responses and patients' personality evaluated by 3 dimensional diagnostic approaches empirically derived from the Shedler-Westen Assessment Procedure-200 (SWAP-200; Westen & Shedler, 1999a, 1999b): Two of these rely on the 5-factor model (FFM) domains, that were assessed with different SWAP-200 FFM versions developed by Shedler and Westen (SW-FFM scales; 2004) and McCrae, Lockenhoff, and Costa (MLC-FFM scales; 2005); the third approach is based on a multifaceted model of personality syndromes (SWAP personality dimension scales; see Shedler & Westen, 2004). A national sample of psychiatrists and psychologists (N = 166) of various theoretical orientations completed the Therapist Response Questionnaire (TRQ; Zittel Conklin & Westen, 2003) to identify patterns of therapist response, and the SWAP-200 to assess personality regarding a patient currently in their care. The findings showed good levels of construct validity between the SW-FFM and MLC-FFM scales, with the exception of the Openness trait. Moreover, specific SW-FFM and MLC-FFM scales were significantly associated with distinct SWAP personality dimension scales according in a conceptually meaningful nomological network. Although there were significant, theoretically coherent, and systematic relationships between therapists' responses and patients' personality features, overall the contribution of the SW-FFM and MLC-FFM traits in predicting therapists' responses was less sizable than the SWAP personality dimensions. These results seem to confirm the diagnostic and therapeutic value of countertransference as an essential tool in understanding psychological traits/dimensions that underlie the patients' psychopathology, both from within and outside of the FFM. (PsycINFO Database Record PMID- 28836806 TI - The Kennedy Krieger Independence Scales-Sickle Cell Disease: Executive components of transition readiness. AB - PURPOSE/OBJECTIVE: Youth with sickle cell disease (SCD) are at an increased risk for executive dysfunction and simultaneously have increased self-management needs compared to typical adolescents. This unique combination may contribute, in part, to difficulties during transition to young adulthood. Current measures assessing adaptive skills do not assess the executive components (e.g., initiation, prospective memory) of SCD-related self-care tasks. Modeled on the KKIS-Spina Bifida (Jacobson et al., 2013), the Kennedy Krieger Independence Scales-Sickle Cell Disease (KKIS-SCD) is a new caregiver-report measure that assesses independence with self-management of SCD-specific demands as well as routine daily activities in adolescents with SCD. Research Method/Design: Thirty-three youth with SCD and their caregivers participated in this preliminary validation study examining the construct validity of the KKIS-SCD total and composite scores (Initiation of Routines, Prospective Memory) and exploring relationships of this measure with intellectual functioning, demographic factors, illness severity, and age. RESULTS: The KKIS-SCD exhibited generally good internal consistency (Cronbach's alpha = .733 to .803), and demonstrated evidence for construct and discriminant validity when compared to an existing measure of adaptive function. The KKIS-SCD was significantly associated with caregiver-report of executive behaviors but not with intellectual functioning, demographic factors, illness severity, or age. CONCLUSIONS/IMPLICATIONS: Results provide preliminary support for the KKIS-SCD as a reliable and valid tool for the assessment of executive components of self-care management skills for youth with SCD. Identifying specific weaknesses in executive function related to self-care management skills might assist in guiding intervention and individualizing transition planning in these at-risk youth. (PsycINFO Database Record PMID- 28836807 TI - Health self-management, transition readiness and adaptive behavior in persons with cerebral palsy or myelomeningocele. AB - PURPOSE/OBJECTIVE: This study was conducted to examine the associations between generic and condition-specific health self-management and levels of adaptive behavior in 2 groups of transition-age youth with congenital neurodevelopmental conditions. METHOD: The sample included 43 adolescents/young adults diagnosed with cerebral palsy (CP) and 36 with spina bifida/myelomeningocele (SBM), ages 13 29, mean age 18.96 (4.77), 51.9% female. Health self-management was assessed with the Transition Readiness Assessment Questionnaire (TRAQ) completed by the child, and the Kennedy Krieger Independence Scales-Spina Bifida (KKIS-SB) completed by the parent/guardian. The Adaptive Behavior Assessment System (ABAS-II) completed by the parent/guardian was used to assess levels of adaptive behavior. RESULTS: There were significant group differences in condition-specific health self management, including lower KKIS-SB Initiation of Routines and KKIS-SB Prospective Memory scores in the group with SBM. Those differences were no longer significant when scoring was modified to account for item applicability. Group differences in generic health self-management and adaptive behavior were not significant. There were significant differences in the correlations between health self-management instruments and ABAS-II composite scores. CONCLUSIONS: For youth with congenital neurodevelopmental conditions who are in the transition to adulthood, there are important condition-specific self-management needs that are not captured by measuring generic transition readiness or adaptive behavior. Findings highlight the need for clinicians to assess health self-management needs from multiple perspectives, utilizing generic and condition-specific measures that can inform targeted interventions and supports for optimal independence. (PsycINFO Database Record PMID- 28836808 TI - Social-cognitive predictors of vocational outcomes in transition youth with epilepsy: Application of social cognitive career theory. AB - OBJECTIVE: This study examined the utility of social-cognitive career theory (SCCT; Lent, Brown, & Hackett, 1994) as a framework to investigate career self efficacy, outcome expectations, goals, and contextual supports and barriers as predictors of choice actions among transition-age individuals with epilepsy. Moreover, these SCCT constructs are offered as an operational definition of work participation in this population. METHOD: Using a quantitative descriptive research design and hierarchical regression analysis (HRA), 90 transition-age individuals with epilepsy, age 18-25, were recruited from affiliates of the Epilepsy Foundation and invited to complete an online survey comprised of a series of self-report social-cognitive measures. RESULTS: The HRA findings indicated that self-efficacy, outcome expectations, and environmental supports were significant predictors of work participation in youth and young adults with epilepsy. The final model accounted for 58% of the variance in work participation, which is considered a large effect size. CONCLUSIONS: The research findings provide support for the use of the SCCT framework to identify predictors of work participation and to provide guidance for designing customized vocational rehabilitation services and career development interventions for individuals with epilepsy in the transition from adolescence to adulthood. (PsycINFO Database Record PMID- 28836809 TI - Teen online problem solving for teens with traumatic brain injury: Rationale, methods, and preliminary feasibility of a teen only intervention. AB - PURPOSE/OBJECTIVE: To describe the Teen Online Problem Solving-Teen Only (TOPS TO) intervention relative to the original Teen Online Problem Solving-Family (TOPS-F) intervention, to describe a randomized controlled trial to assess intervention efficacy, and to report feasibility and acceptability of the TOPS-TO intervention. Research method and design: This is a multisite randomized controlled trial, including 152 teens (49 TOPS-F, 51 TOPS-TO, 52 IRC) between the ages of 11-18 who were hospitalized for a moderate to severe traumatic brain injury in the previous 18 months. Assessments were completed at baseline, 6 months post baseline, and 12-months post baseline. Data discussed include adherence and satisfaction data collected at the 6-month assessment (treatment completion) for TOPS-F and TOPS-TO. RESULTS: Adherence measures (sessions completed, dropout rates, duration of treatment engagement, and rates of program completion) were similar across treatment groups. Overall, teen and parent reported satisfaction was high and similar across groups. Teens spent a similar amount of time on the TOPS website across groups, and parents in the TOPS-F spent more time on the TOPS website than those in the TOPS-TO group (p = .002). Parents in the TOPS-F group rated the TOPS website as more helpful than those in the TOPS TO group (p = .05). CONCLUSIONS/IMPLICATIONS: TOPS-TO intervention is a feasible and acceptable intervention approach. Parents may perceive greater benefit from the family based intervention. Further examination is required to understand the comparative efficacy in improving child and family outcomes, and who is likely to benefit from each approach. (PsycINFO Database Record PMID- 28836810 TI - A review of the literature on pediatric concussions and return-to-learn (RTL): Implications for RTL policy, research, and practice. AB - OBJECTIVE: While reintegration of concussed youth back into sports has been increasingly studied over the past decade, a noticeably lacking yet growing body of research has begun to focus on issues surrounding return to academics or "return-to-learn" (RTL). The objective of this article was to conduct a comprehensive literature review to identify the full range of themes and gaps in the current body of RTL research. STUDY DESIGN: Researchers analyzed PubMed, PsycINFO, and ERIC databases to identify all recent (January 2000 through May 2016) empirical publications on the RTL process following youth concussions. In addition to the database searches, bibliographies of selected manuscripts were hand-searched for additional sources. RESULTS: A total of 35 articles met inclusion criteria. Key themes identified from the RTL literature centered on academic outcomes, physician recommendations, length of time to complete RTL, concussion-related symptom difficulties, and academic accommodations/guidelines. Across these areas, the research was fairly inconsistent in terms of providing clear conclusions, likely because of the small number of studies conducted within these areas as well as variability in methodology and terminology. Gaps in the research include a lack of the following: consensus on RTL protocols, agreement on prescription of cognitive rest, guidance for RTL legislation, understanding of communication between systems of care, concussion-related education for systems of care, evidence-based programs or interventions for RTL, and the impact on RTL outcomes. CONCLUSIONS: Given the inconsistencies in RTL literature, more rigorous research is needed to inform concussion policy and practice to assist with pediatric concussion management. (PsycINFO Database Record PMID- 28836811 TI - Clinical utility and psychometric properties of the Disability Rating Scale with individuals with traumatic brain injury. AB - This Rehabilitation Measures Database summary provides a review of the psychometric properties of the Disability Rating Scale (DRS) which is an observer rated instrument designed to measure general functional disability in individuals with traumatic brain injury. A full review of the DRS as well as reviews of over 300 other instruments can be found at www.rehabmeasures.org. (PsycINFO Database Record PMID- 28836813 TI - The trip of a lifetime: hallucinogen persisting perceptual disorder. AB - OBJECTIVES: The differential diagnosis of psychotic symptoms is broad and extends beyond primary psychotic and affective disorders. We aim to illustrate that the chronology and phenomenological nature of hallucinatory symptoms may provide clues towards alternative diagnoses, such as hallucinogen persisting perceptual disorder (HPPD). We describe the resurgence of visual pseudo-hallucinations in a young woman in the context of previous substance-induced hallucinatory symptoms and a prior diagnosis of occipital lobe epilepsy. She presented a diagnostic challenge, saw several emergency and specialist doctors and attracted stigmatising diagnoses leading to anxiety and depressive symptoms. Her symptoms were finally recognised as HPPD, and she was treated appropriately with lamotrigine. CONCLUSIONS: Patients with perceptual disturbance can present in various clinical settings, and HPPD is an under-recognised diagnostic possibility. Delayed or misdiagnosis prolongs profound functional impairment and social decline, and predisposes the patient to the development of anxiety and depression and related increased risk of suicide. PMID- 28836814 TI - 'Not quite out of the woods': potential for misdiagnosis of delayed neurologic syndrome of carbon monoxide poisoning as relapse of mental illness. AB - OBJECTIVE: The aim of this paper is to provide an overview of the delayed neurologic syndrome of carbon monoxide poisoning and its clinical importance in psychiatric settings. METHOD: A brief review of carbon monoxide poisoning is presented with a focus on the delayed neurologic syndrome and a case of deliberate self- poisoning is described. RESULTS: As in the case described, the delayed manifestations of carbon monoxide poisoning can resemble a relapse of psychiatric illness. CONCLUSIONS: In cases of carbon monoxide poisoning it is important to consider the delayed neurologic syndrome as misdiagnosis could lead to inappropriate treatment and worsened outcome. PMID- 28836815 TI - Oversight of Genomic Data Sharing: What Roles for Ethics and Data Access Committees? AB - Discussions regarding responsible genomic data sharing often center around ethical and legal issues such as the consent, privacy, and confidentiality of individuals, families, and communities. To ensure the ethical grounds of genomic data sharing, oversight by both research ethics and Data Access Committees (DACs) across the research lifecycle is warranted. In this article, we review these oversight practices and argue that they reveal a compelling need to clarify the scope of ethical considerations by oversight bodies and to delineate core elements such as "objectionable" data uses. Ethical oversight of genomic data sharing would be considerably improved if the relevant ethical considerations by research ethics and DACs were coordinated. We therefore suggest several mechanisms to achieve greater clarification of ethical considerations by these committees, as well as greater communication and coordination between both to ensure robust and sustained ethical oversight of genomic data sharing. PMID- 28836816 TI - Comparative effects of traditional Chinese and Western migraine medicines in an animal model of nociceptive trigeminovascular activation. AB - Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine. PMID- 28836817 TI - High frequency of methicillin-resistant Staphylococcus aureus (MRSA) with SCCmec type III and spa type t030 in Karaj's teaching hospitals, Iran. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has been one of the most important antibiotic-resistant pathogen in many parts of the world over the past decades. This cross-sectional study was conducted to investigate MRSA isolated between July 2013 and July 2014 in Karaj, Iran. All tested isolates were collected in teaching hospitals from personnel, patients, and surfaces and each MRSA was analyzed by SCCmec and spa typing. Antibiotic susceptibility testing was accomplished by disk diffusion method. Out of 49 MRSA isolates from the Karaj's teaching hospitals, 82%, 10%, and 6% of the isolates were SCCmec types III, II, and I, respectively. The main spa type in this study was spa t030 with frequency as high as 75.5% from intensive care unit (ICU) of the hospitals and high rate of resistance to rifampicin (53%) was found in MRSA isolates. In conclusion, high frequency of spa t030 with SCCmec type III and MRSA phenotype illustrated circulating of one of the antibiotic-resistant strains in ICU of Karaj's teaching hospitals and emphasizes the need for ongoing molecular surveillance, antibiotic susceptibility monitoring, and infection control. PMID- 28836818 TI - Experimentally Testing Hydrothermal Vent Origin of Life on Enceladus and Other Icy/Ocean Worlds. AB - We review various laboratory strategies and methods that can be utilized to simulate prebiotic processes and origin of life in hydrothermal vent systems on icy/ocean worlds. Crucial steps that could be simulated in the laboratory include simulations of water-rock chemistry (e.g., serpentinization) to produce hydrothermal fluids, the types of mineral catalysts and energy gradients produced in vent interfaces where hydrothermal fluids interface with the surrounding seawater, and simulations of biologically relevant chemistry in flow-through gradient systems (i.e., far-from-equilibrium experiments). We describe some examples of experimental designs in detail, which are adaptable and could be used to test particular hypotheses about ocean world energetics or mineral/organic chemistry. Enceladus among the ocean worlds provides an ideal test case, since the pressure at the ocean floor is more easily simulated in the lab. Results for Enceladus could be extrapolated with further experiments and modeling to understand other ocean worlds. Key Words: Enceladus-Ocean worlds-Icy worlds Hydrothermal vent-Iron sulfide-Gradient. Astrobiology 17, 820-833. PMID- 28836819 TI - An audit of patient aggression in an adult psychiatric unit: 2013-2014. AB - OBJECTIVES: The aim of this study was to determine the rates of patient aggression in a psychiatric unit over 12 months and to determine underlying causes, notably the role of substances. METHODS: A retrospective file audit was undertaken of all patients admitted to St Vincent's psychiatric unit (Melbourne, Australia) in the first half of 2013 and 2014 involved in an aggressive incident. Patient information included demographics, psychiatric, substance and aggression history. The setting and context of aggression and associated mental state findings were also reviewed. RESULTS: There were 26 aggressive incidents in 2013 and 63 in 2014, perpetrated by 11 and 34 patients respectively. No significant differences were found between the groups' baseline demographics. The 2014 cohort was significantly more likely to have substance use history (odds ratio (OR) 4.83) and have made threats to staff (OR 4.07) but significantly less likely to be distracted by internal stimuli (OR 0.05). There were also (not statistically significant) trends for the 2014 cohort; they were more likely to report a history of alcohol use (OR 3.9); be accompanied to emergency department by police (OR 2.95) and have leave prior to aggression ( chi2 = 7.37). CONCLUSIONS: Aggressive incidents more than doubled over 12 months. Substance use appeared to be a major factor associated with aggression. These findings have implications for service provision and training. Further research is needed to better understand and manage substances in psychiatric settings. PMID- 28836820 TI - The Science of Breastfeeding and Brain Development. PMID- 28836821 TI - Nutritional Assessment of Ethiopian Children: The Role of Breastfeeding. PMID- 28836822 TI - A review of ECG and QT interval measurement use in a public psychiatric inpatient setting. AB - OBJECTIVES: There is an increased rate of sudden cardiac death (SCD) in mental health patients. Some antipsychotic medications are known to prolong the QT interval, thus increasing a patient's risk of SCD via the arrhythmia, torsades de pointes (TdP). Our aim was to evaluate assessment for QT prolongation within a public inpatient mental health facility by auditing electrocardiograph (ECG) use. METHODS: We reviewed records of all mental health inpatient admissions to a public emergency mental health inpatient unit between 1 January 2016 and 11 February 2016. ECG availability was noted and QT interval was manually measured and assessed for risk of TdP using the QT nomogram when present. Demographic information and medication use was collected. RESULTS: Of 263 mental health inpatient admissions, 50 (19%) presentations had an ECG. A total of four (8%) had a prolonged QT interval. Of the 50 patients with an ECG, 12 (24%) were taking medication known to prolong the QT interval. CONCLUSIONS: There was very limited risk assessment for QT prolongation in a public hospital psychiatric inpatient unit, with less than 20% of patients having an ECG performed. Our study supports an association between QT-prolonging drugs and a clinically significant prolonged QT interval; however, a larger study with routine ECG screening is required. PMID- 28836823 TI - Abstracts for the 23rd Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28836826 TI - Amelioration of mild and moderate depression through Pranic Healing as adjuvant therapy: randomised double-blind controlled trial. AB - OBJECTIVES: Depression is a mental disorder, affecting the quality of life. Our study explores the efficacy of Pranic Healing (PH), as an adjuvant therapy in treating depression Methods: In this randomised double-blind controlled trial, 52 participants with a mean age of 34.4 years, with mild to moderate depression were assessed using the Hamilton Depression Rating (HAM-D) scale during the 5-week study. Both Medication + PH (MedPH) and Medication + Mock PH (MedMockPH) groups comprising 26 members received Pranic and mock healing lasting 20 minutes per session respectively once a week for 4 weeks, along with the antidepressant drug. RESULTS: The average decrease in HAM-D score in MedPH was median 11 (Interquartile Range (IQR) 7-12) and was significantly higher compared with the MedMockPH group median 6.5 (IQR 3-9). At pre-assessment, both groups had 8 cases of mild and 18 cases of moderate depression. At post-assessment, HAM-D showed that the improvement in depression category was seen in 69.2% of participants in the MedMockPH group and 100% in MedPH group. CONCLUSIONS: These results give first the evidence that PH can aid as an adjuvant therapy for depressed people. PMID- 28836827 TI - Analyzing the LncRNA, miRNA, and mRNA Regulatory Network in Prostate Cancer with Bioinformatics Software. AB - Information processing tools and bioinformatics software have significantly advanced researchers' ability to process and analyze biological data. Molecular data from human and model organism genomes help researchers identify topics for study, which, in turn, improves predictive accuracy, facilitates the identification of relevant genes, and simplifies the validation of laboratory data. The objective of this study was to explore the regulatory network constituted by long noncoding RNA (lncRNA), miRNA, and mRNA in prostate cancer (PCa). Microarray data of PCa were downloaded from The Cancer Genome Atlas database and DESeq package in R language were used to identify the differentially expressed genes (DEGs) between PCa and normal samples. Gene ontology enrichment analysis of DEGs was conducted using the Database for Annotation, Visualization, and Integrated Discovery. TargetScan, microcosm, miRanda, miRDB, and PicTar were used to predict target genes. LncRNA associated with PCa was exploited in the lncRNASNP database, and the LncRNA-miRNA-mRNA regulatory network was visualized using Cytoscape. Our study identified 57 differentially expressed miRNAs and 1252 differentially expressed mRNAs; of these, 691 were downregulated genes primarily involved in focal adhesion, vascular smooth muscle contraction, calcium signaling pathway, and so on. The remaining 561 were upregulated genes principally involved in systemic lupus erythematosus, progesterone-mediated oocyte maturation, oocyte meiosis, and so on. Through the integrated analysis of correlation and target gene prediction, our studies identified 1214 miRNA:mRNA pairs, including 52 miRNAs and 395 mRNAs, and screened out 455 lncRNA-miRNA pairs containing 52 miRNAs. Therefore, owing to the interrelationship of lncRNAs and miRNAs with mRNAs, our study screened out 19,075 regulatory relationships. Our data provide a comprehensive bioinformatics analysis of genes, functions, and pathways that may be involved in the pathogenesis of PCa. PMID- 28836828 TI - Navigating the social synapse: the neurobiology of bedside manner. AB - OBJECTIVES: This paper seeks to explore the application of neurobiology to further understanding the importance of developing, refining and modelling good bedside manner in psychiatry. The concept of a social synapse is used as a framework to understand the impact of verbal and non-verbal information that crosses between two attuned individuals. Research shows that widely distributed cortical and subcortical networks are involved in processing of social information and the perception of safety. CONCLUSIONS: Good bedside manner is proposed as the ability of a clinician to navigate the social synapse and make a patient feel at ease. Findings from neurobiology suggest that good bedside manner needs to be a more considered component of effective psychiatric health care. PMID- 28836829 TI - Autologous Transplantation of Amniotic Fluid-Derived Mesenchymal Stem Cells into Sheep Fetuses. AB - Long-term engraftment and phenotype correction has been difficult to achieve in humans after in utero stem cell transplantation mainly because of allogeneic rejection. Autologous cells could be obtained during gestation from the amniotic fluid with minimal risk for the fetus and the mother. Using a sheep model, we explored the possibility of using amniotic fluid mesenchymal stem cells (AFMSCs) for autologous in utero stem cell/gene therapy. We collected amniotic fluid (AF) under ultrasound-guided amniocentesis in early gestation pregnant sheep ( n = 9, 58 days of gestation, term = 145 days). AFMSCs were isolated and expanded in all sampled fetal sheep. Those cells were transduced using an HIV vector encoding enhanced green fluorescent protein (GFP) with 63.2% (range 38.3-96.2%) transduction efficiency rate. After expansion, transduced AFMSCs were injected into the peritoneal cavity of each donor fetal sheep at 76 days under ultrasound guidance. One ewe miscarried twin fetuses after amniocentesis. Intraperitoneal injection was successful in the remaining 7 fetal sheep giving a 78% survival for the full procedure. Tissues were sampled at postmortem examination 2 weeks later. PCR analysis detected GFP-positive cells in fetal tissues including liver, heart, placenta, membrane, umbilical cord, adrenal gland, and muscle. GFP protein was detected in these tissues by Western blotting and further confirmed by cytofluorimetric and immunofluorescence analyses. This is the first demonstration of autologous stem cell transplantation in the fetus using AFMSCs. Autologous cells derived from AF showed widespread organ migration and could offer an alternative way to ameliorate prenatal congenital disease. PMID- 28836830 TI - Functional Recovery after the Transplantation of Neurally Differentiated Mesenchymal Stem Cells Derived from Bone Marrow in a Rat Model of Spinal Cord Injury. AB - This study was designed to investigate functional recovery after the transplantation of mesenchymal stem cells (MSCs) or neurally differentiated MSCs (NMSCs) derived from bone marrow in a rat model of spinal cord injury (SCI). Sprague-Dawley rats were subjected to incomplete SCI using an NYU impactor to create a free drop contusion at the T9 level. The SCI rats were then classified into three groups; MSCs, NMSCs, and phosphate-buffered saline (PBS)-treated groups. The cells or PBS were administrated 1 week after SCI. Basso-Beattie Bresnahan (BBB) locomotor rating scores were measured at 1-week intervals for 9 weeks. Somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) were also recorded 8 weeks after transplantation. While transplantation of MSCs led to a clear tendency of motor recovery, NMSC-treated rats had significantly improved BBB scores and showed significantly shortened initial latency, N1 latency, and P1 latency of the SSEPs compared to PBS controls. In addition, 5 bromo-2-deoxyuridine (BrdU)-prelabeled MSCs costained for BrdU and glial fibrillary acidic protein (GFAP) or myelin basic protein (MBP) were found rostrally and caudally 5 mm each from the epicenter of the necrotic cavity 4 weeks after transplantation. These results suggest that neurally differentiated cells might be an effective therapeutic source for functional recovery after SCI. PMID- 28836832 TI - Abstracts for the 22nd Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28836831 TI - A Simple, Rapid, and Efficient Method for Isolating Mesenchymal Stem Cells from the Entire Umbilical Cord. AB - Several reports have been published on the isolation, culture, and identification of mesenchymal stem cells (MSCs) from different anatomical regions of the umbilical cord (UC). UC is suitable for standardizing methods of MSC isolation because it is a uniform source with high MSC numbers. Although the UC is considered a medical waste after childbirth, ethical issues for its use must be considered. An increased demand for MSCs in regenerative medicine has made scientists prioritize the development of MSC isolation methods. Several research groups are attempting to provide a large number of high-quality MSCs. In this study, we present a modulated explant/enzyme method (MEEM) to isolate the maximum number of MSCs from the entire UC. This method was established for the isolation of MSCs from different anatomical regions of the UC altogether. We could retrieve 6 to 10 million MSCs during 8 to 10 days of primary culture. After three passages, we could obtain 8-10 * 108 cells in 28-30 days. MSCs isolated by this method express CD73, CD90, CD105, and CD44, but they do not express hematopoietic markers CD34 and CD45 or the endothelial marker CD31. The genes SOX2, OCT4, and NANOG are expressed in isolated MSCs. The capacity of these MSCs to differentiate into adipocytes and osteocytes highlights their application in regenerative medicine. This method is simple, reproducible, and cost efficient. Moreover, this method is suitable for the production of a large number of high-quality MSCs from an UC in less than a month, to be used for cell therapy in an 80-kg person. PMID- 28836833 TI - Continuous Glucose Monitoring in Patients with Type 1 Diabetes and Impaired Awareness of Hypoglycemia: Also Effective in Patients with Psychological Distress? AB - The aim of this study was to evaluate whether psychological distress modifies the effect of continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D) and impaired awareness of hypoglycemia. Fifty-two patients with T1D and impaired awareness of hypoglycemia participated in an earlier reported randomized crossover trial with two 16-week intervention periods comparing CGM with self monitoring of blood glucose (SMBG). During the CGM phase, time spent in euglycemia (4-10 mmol/L), the primary outcome, was 9.6% higher compared with the SMBG phase (P < 0.0001). Psychological distress was operationalized as low emotional well-being (World Health Organization Well-being Index 5 [WHO-5] < 50), high diabetes-related distress (Problem Areas in Diabetes 5 [PAID-5] >= 8), and/or high fear of hypoglycemia (Hypoglycemia Fear Survey [HFS] Worry > mean HFS Worry score +1 standard deviation). Modifying effects were assessed by analyzing psychological distress score * intervention-interaction effects. Results showed that both the low emotional well-being group and normal emotional well-being group had equal glycemic outcomes during the CGM phase. High diabetes distress and elevated fear of hypoglycemia did not result in significant interaction effects for glycemic outcomes. This study demonstrated that CGM is equally effective in terms of glycemic improvements in high versus low distressed patients with T1D and impaired awareness of hypoglycemia. PMID- 28836836 TI - Leveraging TSP Solver Complementarity through Machine Learning. AB - The Travelling Salesperson Problem (TSP) is one of the best-studied NP-hard problems. Over the years, many different solution approaches and solvers have been developed. For the first time, we directly compare five state-of-the-art inexact solvers-namely, LKH, EAX, restart variants of those, and MAOS-on a large set of well-known benchmark instances and demonstrate complementary performance, in that different instances may be solved most effectively by different algorithms. We leverage this complementarity to build an algorithm selector, which selects the best TSP solver on a per-instance basis and thus achieves significantly improved performance compared to the single best solver, representing an advance in the state of the art in solving the Euclidean TSP. Our in-depth analysis of the selectors provides insight into what drives this performance improvement. PMID- 28836837 TI - Effects of changes in analytic variables and contrast medium on estimation of glomerular filtration rates by computed tomography in healthy dogs. AB - OBJECTIVE To investigate effects of changes in analytic variables and contrast medium osmolality on glomerular filtration rate estimated by CT (CT-GFR) in dogs. ANIMALS 4 healthy anesthetized Beagles. PROCEDURES GFR was estimated by inulin clearance, and dogs underwent CT-GFR with iodinated contrast medium (iohexol or iodixanol) in a crossover-design study. Dynamic renal CT scanning was performed. Patlak plot analysis was used to calculate GFR with the renal cortex or whole kidney selected as the region of interest. The renal cortex was analyzed just prior to time of the second cortical attenuation peak. The whole kidney was analyzed 60, 80, 100, and 120 seconds after the appearance of contrast medium. Automated GFR calculations were performed with preinstalled perfusion software including 2 noise reduction levels (medium and strong). The CT-GFRs were compared with GFR estimated by inulin clearance. RESULTS There was no significant difference in CT-GFR with iohexol versus iodixanol in any analyses. The CT-GFR at the renal cortex, CT-GFR for the whole kidney 60 seconds after appearance of contrast medium, and CT-GFR calculated by perfusion software with medium noise reduction did not differ significantly from GFR estimated by inulin clearance. The CT-GFR was underestimated at >= 80 seconds after contrast medium appearance (whole kidney) and when strong noise reduction was used with perfusion CT software. CONCLUSIONS AND CLINICAL RELEVANCE Selection of the renal cortex as region of interest or use of the 60-second time point for whole-kidney evaluation yielded the best CT-GFR results. The perfusion software used produced good results with appropriate noise reduction. IMPACT FOR HUMAN MEDICINE The finding that excessive noise reduction caused underestimation of CT-GFR suggests that this factor should also be considered in CT-GFR examination of human patients. PMID- 28836839 TI - Antinociceptive efficacy of intramuscular administration of morphine sulfate and butorphanol tartrate in tegus (Salvator merianae). AB - OBJECTIVE To evaluate the antinociceptive efficacy of IM morphine sulfate or butorphanol tartrate administration in tegus (Salvator merianae). ANIMALS 6 healthy juvenile (12- to 24-month-old) tegus (mean +/- SD body weight, 1,484 +/- 473 g). PROCEDURES In a crossover study design, tegus were randomly assigned to treatment order, with a minimum washout period of 15 days between treatments. Each of 5 treatments was administered IM in a forelimb: saline (0.9% NaCl) solution (0.5 mL), morphine sulfate (5 or 10 mg/kg), or butorphanol tartrate (5 or 10 mg/kg). A withdrawal latency test was used to evaluate antinociception, with a noxious thermal stimulus applied to the plantar surface of the hind limb before (0 hours; baseline) and 0.5, 1, 2, 3, 4, 6, 12, and 24 hours after each treatment. Observers were unaware of treatment received. RESULTS With saline solution, mean hind limb withdrawal latencies (interval to limb withdrawal from the thermal stimulus) remained constant, except at 12 hours. Tegus had higher than baseline mean withdrawal latencies between 0.5 and 1 hour and at 12 hours with morphine at 5 mg/kg and between 1 and 12 hours with morphine at 10 mg/kg. With butorphanol at 5 and 10 mg/kg, tegus maintained withdrawal responses similar to baseline at all assessment points. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that morphine, but not butorphanol, provided antinociception at 5 and 10 mg/kg in tegus as measured by thermal noxious stimulus testing. These data supported the hypothesis that MU-opioid (but not kappa-opioid) receptor agonists provide antinociception in reptiles. PMID- 28836840 TI - Computed tomographic findings in dogs with head trauma and development of a novel prognostic computed tomography-based scoring system. AB - OBJECTIVE To characterize CT findings and outcomes in dogs with head trauma and design a prognostic scale. ANIMALS 27 dogs admitted to the Koret School Veterinary Teaching Hospital within 72 hours after traumatic head injury that underwent CT imaging of the head. PROCEDURES Data were extracted from medical records regarding dog signalment, history, physical and neurologic examination findings, and modified Glasgow coma scale scores. All CT images were retrospectively evaluated by a radiologist unaware of dog status. Short-term (10 days after trauma) and long-term (>= 6 months after trauma) outcomes were determined, and CT findings and other variables were analyzed for associations with outcome. A prognostic CT-based scale was developed on the basis of the results. RESULTS Cranial vault fractures, parenchymal abnormalities, or both were identified via CT in 24 of 27 (89%) dogs. Three (11%) dogs had only facial bone fractures. Intracranial hemorrhage was identified in 16 (59%) dogs, cranial vault fractures in 15 (56%), midline shift in 14 (52%), lateral ventricle asymmetry in 12 (44%), and hydrocephalus in 7 (26%). Hemorrhage and ventricular asymmetry were significantly and negatively associated with short- and long-term survival, respectively. The developed 7-point prognostic scale included points for hemorrhage, midline shift or lateral ventricle asymmetry, cranial vault fracture, and depressed fracture (1 point each) and infratentorial lesion (3 points). CONCLUSIONS AND CLINICAL RELEVANCE The findings reported here may assist in determining prognoses for other dogs with head trauma. The developed scale may be useful for outcome assessment of dogs with head trauma; however, it must be validated before clinical application. PMID- 28836841 TI - Fluoroscopic evaluation of diaphragmatic excursion during spontaneous breathing in healthy Beagles. AB - OBJECTIVE To evaluate dynamic movement of the diaphragm of clinically normal dogs by use of fluoroscopy and to obtain quantitative data of diaphragmatic excursion during spontaneous breathing. ANIMALS 8 healthy male Beagles with no history of respiratory tract disease. PROCEDURES Fluoroscopy was performed during stabilized respiratory conditions. The beam center was located at the level of the diaphragm, and diaphragmatic motion was recorded during 3 respiratory cycles in dogs positioned in left lateral, right lateral, and dorsal recumbency. Extent of excursion of the diaphragmatic cupula and both crura, difference in excursion between the left and right crura, and ratios of the excursions of the diaphragmatic cupula and left and right crura to the length of the eighth thoracic vertebra were determined. RESULTS Diaphragmatic crural excursion was symmetric for dogs in right lateral recumbency, and the crural excursion was approximately three-quarters of the vertebral length; however, crural excursion appeared to be asymmetric for dogs in left lateral recumbency. Mean +/- SD difference in excursion between the right and left crura was 22.68 +/- 8.68% for left lateral recumbency, 16.63 +/- 9.22% for right lateral recumbency, and 18.11 +/- 12.96% for dorsal recumbency. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the fluoroscopic view of a dog positioned in right lateral recumbency may allow better evaluation of the symmetry of diaphragmatic excursion, compared with results for other recumbency positions. This study provided quantitative data on the excursion of diaphragmatic movement observed by use of fluoroscopy in clinically normal Beagles. PMID- 28836842 TI - Evaluation of the effect of serum antibody abundance against bovine coronavirus on bovine coronavirus shedding and risk of respiratory tract disease in beef calves from birth through the first five weeks in a feedlot. AB - OBJECTIVE To evaluate the effect of serum antibody abundance against bovine coronavirus (BCV) on BCV shedding and risk of bovine respiratory disease (BRD) in beef calves from birth through the first 5 weeks in a feedlot. ANIMALS 890 natural-service crossbred beef calves from 4 research herds. PROCEDURES Serial blood samples for measurement of serum anti-BCV antibody abundance by an ELISA and nasal swab specimens for detection of BCV and other viral and bacterial BRD pathogens by real-time PCR methods were collected from all calves or subsets of calves at predetermined times from birth through the first 5 weeks after feedlot entry. Test results were compared among herds, over time, and between calves that did and did not develop BRD. The associations of various herd and calf factors with test results were also evaluated. RESULTS At the calf level, serum anti-BCV antibody abundance was not associated with BCV shedding, but BCV shedding was positively associated with BRD incidence before and after weaning. The mean serum anti-BCV antibody abundance at weaning for a group of calves was inversely related with the subsequent incidence of BRD in that group; however, the serum anti-BCV antibody abundance at weaning for individual calves was not predictive of which calves would develop BRD after feedlot entry. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that serum anti-BCV antibody abundance as determined with ELISA were not associated with BCV shedding or risk of BRD in individual beef calves from birth through the first 5 weeks after feedlot entry. PMID- 28836843 TI - Evaluation of two methods for topical application of contrast medium to the pharyngeal and laryngeal region of horses. AB - OBJECTIVE To determine the pharyngeal and laryngeal distribution of radiopaque contrast medium administered orally or via nasopharyngeal catheter to standing horses. ANIMALS 5 healthy adult horses. PROCEDURES A crossover study was conducted. Radiopaque contrast medium (12 mL) was administered orally and via nasopharyngeal catheter to each horse. Pharyngeal and laryngeal distribution of contrast medium was determined by examination of radiographs obtained immediately after administration of contrast medium, compared with those obtained before administration. Regional distribution of contrast medium was graded. Endoscopic examination of the nasopharynx, laryngopharynx, and larynx was performed to confirm radiographic results. RESULTS Examination of radiographs obtained after nasopharyngeal administration revealed contrast medium in the nasopharynx (n = 5), oropharynx (2), laryngopharynx (3), and larynx (5) of the 5 horses. Examination of radiographs obtained after oral administration revealed contrast medium in the oropharynx (n = 4) and larynx (1) of the 5 horses. Endoscopic examination confirmed radiographic findings and was found to be sensitive for detection of contrast medium in the laryngopharynx, whereby detection rates were higher for both administration methods. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that medication administered by use of a nasopharyngeal catheter will result in topical distribution within the nasopharynx, including the dorsal surface of the soft palate, and larynx, although distribution should be evaluated in horses with clinical airway disease to confirm these findings. Oral administration did not result in consistently detectable topical laryngeal distribution but could be used for selected conditions (eg, palatitis). PMID- 28836844 TI - Behavioral and physiologic changes in Holstein steers experimentally infected with Mannheimia haemolytica. AB - OBJECTIVE To evaluate changes in behavior and surfactant protein (SP) A and D concentrations in serum and bronchoalveolar lavage fluid (BALF) samples of calves experimentally infected with Mannheimia haemolytica. ANIMALS Twelve 4- to 5-month old Holstein steers. PROCEDURES Calves were divided into 2 treatment groups and instrumented with a data logger to collect behavioral data. After 10 days of acclimation, calves were experimentally inoculated with 3 * 109 CFUs to 5 * 109 CFUs of M haemolytica suspended in approximately 5 mL of PBS solution (infected calves; n = 6) or 5 mL of PBS solution without M haemolytica (control calves; 6) through a catheter into the right accessory lung lobe. Calves were clinically evaluated twice daily for 7 days after inoculation. Blood and BALF samples were collected from all calves at predetermined times for determination of serum and BALF SP-A and SP-D concentrations. Serum and BALF concentrations of SP-A and SP-D and behavioral data were evaluated over time and between treatment groups. RESULTS Compared with control calves, infected calves spent more time lying in general and more time lying on the right side during the 24 hours and 6 days after inoculation, respectively. Mean rectal temperature for infected calves (41.3 degrees C) was significantly greater than that for control calves (39.2 degrees C) 12 hours after inoculation. Mean respiratory rate for infected calves (52.5 breaths/min) was significantly greater than that for control calves (45.4 breaths/min) throughout the observation period. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated continuous behavioral monitoring may improve detection of calves with respiratory tract disease. PMID- 28836845 TI - Repeatability of gait pattern variables measured by use of extremity-mounted inertial measurement units in nonlame horses during trotting. AB - OBJECTIVE To determine repeatability of gait variables measured by use of extremity-mounted inertial measurement units (IMUs) in nonlame horses during trotting under controlled conditions of treadmill exercise. ANIMALS 10 horses. PROCEDURES Six IMUs were strapped to the metacarpal, metatarsal, and distal tibial regions of each horse. Data were collected in a standardized manner (3 measurements/d on 3 d/wk over a 3-week period) while each horse was trotted on a treadmill. Every measurement consisted of a minimum of 20 strides from which a minimum of 10 strides was selected for analysis. Spatial and temporal variables were derived from the IMUs. Repeatability coefficients based on the within subject SD were computed for each gait analysis variable at each week. RESULTS Most of the temporal and spatial variables had high repeatability (repeatability coefficients < 10), and the repeatability coefficients were consistent among the 3 weeks of data collection. Some spatial variables, specifically the symmetry variables (which were calculated from other variables), had somewhat higher repeatability coefficients (ie, lower repeatability) only in the last week. CONCLUSIONS AND CLINICAL RELEVANCE With the exceptions of some symmetry variables, which may reflect individual variations during movement, the extremity mounted IMUs provided data with high repeatability for nonlame horses trotting under controlled conditions of treadmill exercise. Repeatability was achieved for each instrumented limb segment with regard to the spatial relationship between 2 adjacent segments (joint angles) and the temporal relationship among all segments (limb phasing). Extremity-mounted IMUs could have the potential to become a method for gait analysis in horses. PMID- 28836846 TI - A technique of needle redirection at a single craniolateral site for injection of three compartments of the equine stifle joint. AB - OBJECTIVE To determine accuracy for a technique of needle redirection at a single craniolateral site for injection of 3 compartments of the equine stifle joint, describe the external needle position, and identify the location of the needle tip within each joint compartment. SAMPLE 24 equine cadaver stifle joints. PROCEDURES Stifle joints were placed in a customized stand. After the needle was placed, external needle position was measured and recorded. Each joint compartment (medial and lateral compartments of the femorotibial joint and the femoropatellar joint) was injected with a solution containing iodinated contrast medium, water, and dye. Radiography, assessment of intra-articular location of the needle tip, and gross dissection were performed to determine success of entering each joint compartment. Student t tests and an ANOVA were used to compare mean values. RESULTS Overall accuracy was 19 of 24 (79.1%), and accuracy for individual joint compartments was at least 21 of 24 (87.5%). Mean depth of needle insertion to access each compartment of the stifle joint was 5.71 cm. Mean angle of insertion (relative to the long axis of the tibia) was 82.1 degrees , 80.3 degrees , and 18.5 degrees for the medial compartment of the femorotibial joint, lateral compartment of the femorotibial joint, and femoropatellar joint, respectively, and 28 degrees medial, 7.3 degrees lateral, and 1.3 degrees lateral for the medial compartment of the femorotibial joint, lateral compartment of the femorotibial joint, and femoropatellar joint, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results supported that this was an accurate technique for successful injection of the 3 equine stifle joint compartments. PMID- 28836848 TI - Evaluation of a portable media device for use in determining postural stability in standing horses. AB - OBJECTIVE To determine the ability of an accelerometer within a commercially available portable media device (PMD) to measure changes in postural stability of standing horses during various stance conditions and to compare these results with data obtained by use of a stationary force platform. ANIMALS 7 clinically normal horses. PROCEDURES A PMD was mounted on a surcingle; the surcingle was placed immediately caudal to the highest point of the shoulders (withers). Each horse was examined while standing on a stationary force platform system in a normal square stance, forelimb base-narrow stance, and normal square stance at 5 and 10 minutes after sedation induced by IV administration of xylazine hydrochloride. A minimum of 5 trials were conducted for each stance condition. Ranges of craniocaudal and mediolateral motion as well as SDs were collected for the PMD and force platform system. Analyses were performed with mixed-model ANOVAs, and correlation coefficients were calculated. RESULTS Stance condition significantly altered craniocaudal accelerations measured by use of the PMD, all craniocaudal and mediolateral displacements of the center of pressure, and velocities measured by use of the stationary force platform. For both the PMD and force platform, SDs were significantly affected by stance condition in both craniocaudal and mediolateral directions. Correlation coefficients between the systems for all variables were low to moderate (r = 0.18 to 0.58). CONCLUSIONS AND CLINICAL RELEVANCE Body-mounted PMDs should be investigated for use in assessment of postural stability in horses with neuromuscular abnormalities. PMID- 28836847 TI - Evaluation of a modified infraorbital approach for a maxillary nerve block for rhinoscopy with nasal biopsy of dogs. AB - OBJECTIVE To determine whether a maxillary nerve block via a modified infraorbital approach, applied before rhinoscopy and nasal biopsy of dogs, would decrease procedural nociception, minimize cardiorespiratory anesthetic effects, and improve recovery quality. ANIMALS 8 healthy adult hound-type dogs PROCEDURES In a crossover study, dogs received 0.5% bupivacaine (0.1 mL/kg) or an equivalent volume of saline (0.9% NaCl) solution as a maxillary nerve block via a modified infraorbital approach. A 5-cm, 20-gauge over-the-needle catheter was placed retrograde within each infraorbital canal, and bupivacaine or saline solution was administered into each pterygopalatine region. Rhinoscopy and nasal biopsy were performed. Variables monitored included heart rate, systolic arterial blood pressure (SAP), mean arterial blood pressure (MAP), diastolic arterial blood pressure (DAP), plasma cortisol and norepinephrine concentrations, purposeful movement, and pain scores. After a 14-day washout period, the other treatment was administered on the contralateral side, and rhinoscopy and nasal biopsy were repeated. RESULTS SAP, MAP, and DAP were significantly higher for the saline solution treatment than for the bupivacaine treatment, irrespective of the time point. Plasma cortisol concentrations after saline solution treatment were significantly higher 5 minutes after nasal biopsy than at biopsy. Heart rate, norepinephrine concentration, purposeful movement, and pain score were not significantly different between treatments. CONCLUSIONS AND CLINICAL RELEVANCE Maxillary nerve block via a modified infraorbital approach prior to rhinoscopy and nasal biopsy reduced procedural nociception as determined on the basis of blood pressures and plasma cortisol concentrations during anesthesia. These findings warrant further evaluation in dogs with nasal disease. PMID- 28836849 TI - Body weight, blood pressure, and systemic changes following low-dosage prednisolone administration in dogs. AB - OBJECTIVE To investigate systemic changes following low-dosage prednisolone administration in dogs. ANIMALS 4 healthy purpose-bred adult male Beagles. PROCEDURES Dogs were administered prednisolone PO at a dosage of 2 mg/kg/d for 2 weeks, 1 mg/kg/d for 4 weeks, and 0.5 mg/kg/d for 3 weeks. Body weight, blood pressure, hepatic size and echogenicity, percentage of vacuolated hepatocytes, serum hepatic enzyme activities and glucose concentration, adrenal gland size, and pancreatic echogenicity were evaluated weekly for 9 weeks. RESULTS The only significant change identified was an increase in hepatic echogenicity, assessed by measuring liver-kidney contrast on ultrasonographic images. Increases in hepatic size and percentage of vacuolated hepatocytes were identified, but values did not differ from baseline values. Similarly, serum hepatic enzyme activities increased, but changes were mild and not significantly different from baseline values. Body weight, pancreatic echogenicity, and serum glucose concentration did not show noticeable changes. Mild systemic hypertension was seen, but blood pressure was not significantly different from the baseline value. Similarly, adrenal gland size steadily decreased during the first 6 weeks and increased again after the prednisolone dosage was decreased to 0.5 mg/kg/d. However, mean adrenal gland size was not significantly different from the baseline value at any time. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that in dogs, administration of prednisolone at a low dosage was associated with minimal systemic effects. PMID- 28836850 TI - HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo. AB - The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite combination antiretroviral therapy (cART). There is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non nucleoside reverse transcriptase inhibitor efavirenz (EFV) has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6J mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV. PMID- 28836851 TI - Provitamin A-biofortified maize consumption increases serum xanthophylls and 13C natural abundance of retinol in Zambian children. AB - Plants that undergo C4 photosynthesis, such as maize, are enriched in the stable isotope of carbon (13C) compared with other dietary plants and foods. Consumption of maize that has been biofortified to contain elevated levels of provitamin A carotenoids (orange maize) increased the abundance of 13C in serum retinol of Mongolian gerbils. We evaluated this method in humans to determine if it has potential for further use in intervention effectiveness studies. A random subset of samples from a two-month randomized controlled feeding trial of rural three- to five-year old Zambian children were used to determine the impact of orange maize intake on serum carotenoid concentrations ( n = 88) and 13C-natural abundance in serum retinol ( n = 77). Concentrations of beta-cryptoxanthin (a xanthophyll provitamin A carotenoid) and the dihydroxy xanthophylls lutein and zeaxanthin, which do not have vitamin A activity, were elevated in children consuming orange maize compared with those consuming a white maize control ( P < 0.001), while beta-carotene was not different ( P > 0.3). Furthermore, 13C natural abundance was higher after two months' intervention in the orange maize group compared with the white maize group ( P = 0.049). Predictions made from equations developed in the aforementioned gerbil study estimated that maize provided 11% (2-21%, 95% confidence interval) of the recent dietary vitamin A to these children. These results demonstrate that orange maize is efficacious at providing retinol to the vitamin A pool in children through provitamin A carotenoids, as monitored by the change in 13C enrichment, which was not reflected in serum beta-carotene concentrations. Further effectiveness studies in countries who have adopted orange maize should consider determining differences in retinol 13C-enrichment among target groups in addition to profiling serum xanthophyll carotenoids with specific emphasis on zeaxanthin. Impact statement Maize biofortified with provitamin A carotenoids (orange) has been released in some African markets. Responsive and sensitive methods to evaluate dissemination effectiveness are needed. This study investigated methods to evaluate effectiveness of orange maize consumption using serum from Zambian children fed orange maize for two months. Many varieties of orange maize contain higher amounts of the xanthophyll carotenoids in addition to beta-carotene compared with typical varieties. This study uniquely showed higher concentrations of the maize xanthophylls lutein, zeaxanthin, and beta-cryptoxanthin in children who consumed orange maize compared with white. Furthermore, maize is a C4 plant and is therefore naturally enriched with 13C. Higher 13C was detected in the serum retinol of the orange maize consumers with no change in serum beta-carotene concentration suggesting preferential bioconversion to retinol. The combined analyses of serum zeaxanthin specifically and 13C-natural abundance of retinol could prove useful in effectiveness studies between orange maize adopters and non adopters. PMID- 28836852 TI - Do the expressions of epithelial-mesenchymal transition proteins, periostin, integrin-alpha4 and fibronectin correlate with clinico-pathological features and prognosis of metastatic castration-resistant prostate cancer? AB - Development of metastatic castration-resistant prostate cancer is a result of the lack of an apoptotic response by the tumor cells and loss of the ability to stick to adjacent cells through epithelial-mesenchymal transition. Although there are several strongly recommended biomarkers for determining prognosis of metastatic castration-resistant prostate cancer, only few of them may help decide the selection of the optimal treatment option. The mode of treatment sequencing in metastatic castration-resistant prostate cancer will be based on the individual characteristics of the patient. In this study, we aimed to explain the correlation between the expression characteristics of periostin, integrin-alpha4, and fibronectin in metastatic castration-resistant prostate cancer patients and their clinico-pathological data comprising Gleason score, PSA levels, and metastatic sites in the process of epithelial-mesenchymal transition. We evaluated by using Western blotting, periostin, integrin-alpha4, and fibronectin expressions in peripheral blood samples of metastatic castration-resistant prostate cancer patients ( n = 40), benign prostatic hyperplasia patients ( n = 20), and the healthy control group ( n = 20). Associations between changes in the protein expressions and clinico-pathological parameters were also analyzed in the metastatic castration-resistant prostate cancer group. When comparing BPH and healthy groups with the metastatic castration-resistant prostate cancer group, a reduced expression of integrin-alpha4 was found in metastatic patients, albeit being statistically insignificant ( P > 0.05). Protein expressions of periostin and fibronectin in the metastatic castration-resistant prostate cancer group were higher than those in the BPH and heathy groups ( P < 0.001). Increased periostin expression in metastatic patients was significantly associated with bone metastasis ( P < 0.05). Elevated periostin and fibronectin levels in metastatic castration-resistant prostate cancer patients may be appropriate targets of therapeutic intervention in the future. Impact statement Prostate cancer is the third most common cancer in the world and the most common cancer among men. Development of metastatic castration-resistant prostate cancer (mCRPC) is a result of the lack of an apoptotic response by the tumor cells and loss of the ability to stick to adjacent cells through epithelial-mesenchymal transition (EMT). The present study analyzes for the first time the expressions of EMT marker proteins - periostin, integrin alpha4, fibronectin - in mCRPC and in benign prostatic hyperplasia (BPH) with the aim to determine the clinical relevance of changes in these three proteins vis-a-vis the PCa aggressive phenotype. In doing so, it sheds light on the molecular mechanism underlying the disease. We concluded that elevated periostin and fibronectin levels in mCRPC patients may be appropriate targets of therapeutic intervention in the future; hence, adopting methods that target these proteins may help treat prostate cancer effectively. PMID- 28836853 TI - MicroRNA-31 inhibits RhoA-mediated tumor invasion and chemotherapy resistance in MKN-45 gastric adenocarcinoma cells. AB - microRNAs are small single-stranded non-coding RNA molecules which modify gene expression by silencing potential target genes. The aberrant expression of RhoA, a small GTPase protein of Rho family, is involved in gastric cancer tumorigenesis. Since miR-31 is a pleomorphic molecule, we evaluated the miR 31/RhoA axis in inducing the malignant phenotype of gastric cancer cells MKN-45. Also, the clinicopathological significance of RhoA was investigated in a well defined collection of gastric carcinomas which were embedded in tissue microarray blocks. Induction of miR-31 in MKN-45 followed by suppression of RhoA expression resulted in increased sensitivity to 5-fluorouracil, inhibition of cell proliferation, and invasion compared to the control groups. Immunohistochemical analysis in gastric adenocarcinoma patients' samples showed significantly higher expression of RhoA in diffuse versus intestinal subtype tumors ( P = 0.009), poorly differentiated versus well and moderately differentiated tumors ( P = 0.03) and the presence of vascular invasion versus the absence of vascular invasion ( P = 0.04). Our findings suggest a critical role for miR-31, as a tumor suppressor gene, in gastric cancer tumorigenesis by targeting the RhoA. Impact statement Gastric cancer ranks as the third leading cause of cancer-associated deaths worldwide. The RhoA gene encodes a small GTPase protein of Rho family (RhoA) that its dysregulation is associated with cell motility and invasion. A strong line of evidence supports the regulation of RhoA by a number of miRs, including miR-31 in tumors. Our findings revealed that miR-31 is involved in gastric cancer tumorigenesis as a tumor suppressor gene. Through down-regulation of RhoA, miR-31 decreased cell proliferation, migration, and invasion in gastric cancer cells. In addition, induction of miR-31 increased sensitivity to 5-FU; thus, increasing its tissue concentrations could be a potential target for treatment of gastric cancer in the future. PMID- 28836854 TI - An update on the developing mitotic inhibitors for the treatment of non-small cell carcinoma. AB - INTRODUCTION: Mitosis is necessary to sustain life and is followed immediately by cell division into two daughter cells. Microtubules play a key role in the formation of the mitotic spindle apparatus and cytokinesis at the end of mitosis. Various anti-microtubule agents such as taxanes and vinca alkaloids are widely used in the treatment of advanced non-small cell lung cancer (NSCLC) but their use is associated with hematologic toxicity profile, acquired resistance and hypersensitivity reactions. Areas covered: The Nab-paclitaxels are the more recent antimitotic agents approved in NSCLC showing a better tolerability and activity when compared to previous ones. Despite this, the outcome of patients with advanced non-small cell lung cancer is poor. Due to the key role of mitosis, research is focused on the identification of new mitotic drug targets other than microtubule inhibitors, such as cell cycle targets, aurora kinases and Polo-like kinases. Expert opinion: Despite improvements in chemotherapeutic choices and supportive care, the majority of patients experience a deteriorating quality of life and significant toxicities associated to a poor outcome. Thus, the therapeutic management of patients with advanced NSCLC represents an ongoing challenge and novel agents targeting mitosis are under investigation. PMID- 28836855 TI - Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-alpha-tocopherol polyethylene glycol 1000 succinate and copovidone. AB - CONTEXT: Low bioavailability of oral manidipine (MDP) is due to its low water solubility. OBJECTIVE: The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d alpha-tocopherol polyethyleneglycol-1000-succinate and copovidone. METHODS: In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated. RESULTS AND DISCUSSION: The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo. CONCLUSIONS: The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique. PMID- 28836856 TI - The role of mast cells and macrophages in amiodarone induced pulmonary fibrosis and the possible attenuating role of atorvastatin. AB - Amiodarone (AM) is an effective anti-arrhythmic drug. We investigated the role of mast cells and macrophages on AM induced pulmonary fibrosis and the action of atorvastatin on this fibrosis. Rats were allocated into four groups; negative control (1), positive control (2), 30 mg/kg body weight/day AM (3) and AM + 10 mg/kg/day atorvastatin (4). Lungs were harvested and prepared for histology and immunohistochemistry. Hematoxylin and eosin stained sections of group 3 exhibited disorganized lung architecture. We found cellular debris in the lumen of both intrapulmonary bronchi and bronchioles with partial disruption of the thickened epithelial lining and mononuclear cellular infiltration into the lamina propria. We also observed thickening of the epithelial lining and the smooth muscle layer. Congested, dilated and thickened blood capillaries and thickened inter-alveolar septa were observed with mononuclear cellular infiltrates in the lung of group 3. Most alveoli were collapsed, but some dilated ones were detected. In some alveoli, type II pneumocytes were increased, while type I cells were decreased. We observed significant increases in the amount of collagen in the thickened inter-alveolar septa, around bronchioles and around blood capillaries in sections from group 3. We found a significant increase in mast cells and alveolar macrophages in group 3 compared to group 1. Mast cells and macrophages appear to play important roles in AM induced pulmonary fibrosis. Atorvastatin appears to attenuate this condition. PMID- 28836857 TI - Uric acid and incident chronic kidney disease in dyslipidemic individuals. AB - BACKGROUND: Elevated uric acid (UA) is a recognized risk factor for chronic kidney disease (CKD). This study aimed to investigate whether this association exists in dyslipidemic patients receiving multifactorial treatment. METHODS: An observational study conducted in Greece including 1,269 dyslipidemic individuals followed-up in a lipid clinic for >=3 years. Estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI equation and CKD was defined as <=60 mL/min/1.73 m2. The correlation was assessed between UA levels and the CKD risk after adjusting for potential confounding factors, after defining the following UA quartiles: Q1: < 4, Q2: 4-5, Q3: 5-6, and Q4: > 6 mg/dL. RESULTS: After excluding patients with baseline eGFR <60 mL/min/1.73 m2, gout and those taking UA-lowering drugs, 1,095 individuals were eligible; of those, 91% and 69% were treated with statins and anti-hypertensive drugs, respectively. During their follow-up (6 years; IQR = 4-10), 11.9% of the subjects developed CKD, whereas the median annual eGFR decline was 0.69 mL/min/1.73 m2 (IQR = 0.45-2.33). Multivariate analysis showed that baseline UA levels (HR = 1.26; 95% CI = 1.09-1.45, p = .001), female gender (HR = 1.74; 95% CI = 1.14-2.65, p = .01), age (HR = 1.10; 95% CI = 1.07-1.12, p < .001), diabetes (HR = 1.67; 95% CI = 1.05-2.65, p = .03), cardiovascular disease (HR = 1.62; 95% CI = 1.02-2.58, p = .04), decreased baseline renal function (eGFR <90 mL/min/1.73 m2) (HR = 2.38; 95% CI = 1.14-4.81, p = .02), and low-density lipoprotein cholesterol reduction (HR = 0.995; 95% CI = 0.991-0.998, p = .01) were associated with incident CKD. Additionally, patients with UA >=6 mg/dL exhibited a higher risk of incident CKD compared with those in the lowest UA quartile (HR = 2.01; 95% CI = 1.11-3.65, p = .02). CONCLUSION: Higher UA levels are correlated with a higher risk of incident CKD in dyslipidemic individuals taking multifactorial treatment. PMID- 28836858 TI - Investigational anabolic agents for the treatment of osteoporosis: an update on recent developments. AB - INTRODUCTION: Teriparatide, a PTH analogue, was the first anabolic agent to be approved for the treatment of osteoporosis in 2002. Abaloparatide was also recently approved by the FDA. The need for other anabolic agents is still unmet. Areas covered: In this review, we discuss target molecules and recent advances in the field of anabolic therapy for osteoporosis. PTH and PTHrP analogues binding to the PTH receptor and different routes of administration of teriparatide to avoid the burden of daily subcutaneous injections are discussed. We also review antibodies targeting suppressors of the Wnt pathway such as sclerostin and Dickopff-1. Expert opinion: The development of alternative ways of administering PTH receptor ligands is a promising field, especially via the transdermal route. Other more promising molecules are still at very early stages of development. FDA recently requested more data on Romosozumab. PMID- 28836859 TI - An update on the validation of whole slide imaging systems following FDA approval of a system for a routine pathology diagnostic service in the United States. AB - Pathologists have used light microscopes and glass slides to interpret the histologic appearance of normal and diseased tissues for more than 150 years. The quality of both microtomes used to cut tissue sections and microscopes has improved significantly during the past few decades, but the process of rendering diagnoses has changed little. By contrast, major advances in digital technology have occurred since the introduction of hand held electronic devices, including the development of whole slide imaging (WSI) systems with software packages that can convert microscope images into virtual (digital) slides that can be viewed on computer monitors and via the internet. To date, however, these technological developments have had minimal impact on the way pathologists perform their daily work, with the exception of using computers to access electronic medical records and scholarly web sites for pertinent information to assist interpretation of cases. Traditional practice is likely to change significantly during the next decade, especially since the Federal Drug Administration in the USA has approved the first WSI system for routine diagnostic practice. I review here the development and slow acceptance of WSI by pathology departments. I focus on recent advances in validation of WSI systems that is required for routine diagnostic reporting of pathology cases using this technology. PMID- 28836860 TI - Enhancement or inhibition of PLCgamma2 expression in rat hepatocytes by recombinant adenoviral vectors that contain full-length gene or siRNA. AB - We investigated the effects of recombinant adenovirus vectors that overexpress or silence PLCgamma2 on the expression of this gene during hepatocyte proliferation. Hepatocytes were isolated, identified by immunofluorescent cytochemical staining and infected by previously constructed Ad-PLCgamma2 and Ad-PLCgamma2 siRNA1, siRNA2 and siRNA3. Green fluorescent protein (GFP) expression was observed by fluorescence microscopy. Infection percentage was calculated by flow cytometry. mRNA and protein levels of PLCgamma2 were detected by quantitative reverse transcription-PCR (qRT-PCR) and western blotting, respectively. The viability of the infected hepatocytes was measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay. We found that nearly 97% of cells were positive for the hepatocyte marker, CK18. After infection of Ad-PLCgamma2 and Ad PLCgamma2 siRNA, more than 99% of hepatocytes expressed GFP significantly, and mRNA and protein expression of PLCgamma2 was up-regulated significantly in Ad PLCgamma2 infected hepatocytes, but down-regulated in Ad-PLCgamma2 siRNA2 infected cells. The cell proliferation rate decreased in PLCgamma2-overexpressing cells, while the rate increased in PLCgamma2-silencing cells. We verified that recombinant Ad-PLCgamma2 and Ad-PLCgamma2 siRNA2 were constructed successfully. These two recombinant vectors promoted or decreased the expression of PLCgamma2 in rat hepatocytes and affected the cell proliferation rate, which provides a useful tool for further investigation of the role of PLCgamma2 in hepatocyte apoptosis. PMID- 28836861 TI - Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy. AB - BACKGROUND: Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM. METHODS: Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov. RESULTS: Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia. CONCLUSIONS: The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal plus or basal-bolus insulin). PMID- 28836862 TI - Impact of uterine fibroid symptoms on health-related quality of life of US women: evidence from a cross-sectional survey. AB - BACKGROUND: Uterine fibroids (UF) are associated with significant health-related quality of life (HRQL) impact. This study examined the impact of UF symptoms on HRQL. METHODS: An online cross-sectional survey of 18 to 49 year old US women was conducted and collected demographics, UF prevalence, symptoms, and HRQL using the UFS-QOL. Descriptive statistics were used to examine the impact of symptom presence, severity, bothersomeness, and number of UF symptoms on HRQL. Analyses were weighted to match the US female population distribution. Multivariate regressions were performed with each subscale as a dependent variable to examine the impact of individual UF symptoms on HRQL. RESULTS: A total of 59,411 (15.5%) panel members completed the prevalence screener; 4848 met inclusion criteria; 955 had UF and no hysterectomy. Mean age was 40.3; 58% were white; 63% were married/civil union. Common UF symptoms were: lower back pain (65%), fatigue/weariness (63%), bloating (61%), pelvic pain/cramping during menses (63%), and heavy bleeding during menses (54%). Mean UFS-QoL subscale scores were significantly (p < .05) worse among women with a UF symptom versus women without the symptom. Women who rated their UF symptoms as severe had significantly (p < .001) worse UFS-QoL scores than women with mild or moderate symptoms. UFS-QoL subscale scores worsened as the number of symptoms increased. In the regressions, the presence of bleeding and non-bleeding symptoms were related to worse UFS-QoL subscale scores. CONCLUSION: HRQL among women with UF was significantly impacted by UF-related symptoms. Greater impact was observed as the number and severity of symptoms increased. PMID- 28836863 TI - The De Novo Synthesis of Horsepox Virus: Implications for Biosecurity and Recommendations for Preventing the Reemergence of Smallpox. AB - In March 2017, the American biotech company Tonix announced that a Canadian scientist had synthesized horsepox virus as part of a project to develop a safer vaccine against smallpox. The first de novo synthesis of an orthopoxvirus, a closely related group of viruses that includes horsepox and the variola virus that causes smallpox, crosses an important Rubicon in the field of biosecurity. The synthesis of horsepox virus takes the world one step closer to the reemergence of smallpox as a threat to global health security. That threat has been held at bay for the past 40 years by the extreme difficulty of obtaining variola virus and the availability of effective medical countermeasures. The techniques demonstrated by the synthesis of horsepox have the potential to erase both of these barriers. The primary risk posed by this research is that it will open the door to the routine and widespread synthesis of other orthopoxviruses, such as vaccinia, for use in research, public health, and medicine. The normalization and globalization of orthopoxvirus synthesis for these beneficial applications will create a cadre of laboratories and scientists that will also have the capability and expertise to create infectious variola virus from synthetic DNA. Unless the safeguards against the synthesis of variola virus are strengthened, the capability to reintroduce smallpox into the human population will be globally distributed and either loosely or completely unregulated, providing the foundation for a disgruntled or radicalized scientist, sophisticated terrorist group, unscrupulous company, or rogue state to recreate one of humanity's most feared microbial enemies. The reemergence of smallpox because of a laboratory accident or an intentional release-would be a global health disaster. International organizations, national governments, the DNA synthesis industry, and the synthetic biology community all have a role to play in devising new approaches to preventing the reemergence of smallpox. PMID- 28836864 TI - Detection of MET mRNA in gastric cancer in situ. Comparison with immunohistochemistry and sandwich immunoassays. AB - Determination of predictive biomarkers by immunohistochemistry (IHC) relies on antibodies with high selectivity. RNA in situ hybridization (RNA ISH) may be used to confirm IHC and may potentially replace it if suitable antibodies are not available or are insufficiently selective to discriminate closely related protein isoforms. We validated RNA ISH as specificity control for IHC and as a potential alternative method for selecting patients for treatment with MET inhibitors. MET, the HGF receptor, is encoded by the MET proto-oncogene that may be activated by mutation or amplification. MET expression and activity were tested in a panel of control cell lines. MET could be detected in formalin fixed paraffin, embedded (FFPE) samples by IHC and RNA ISH, and this was confirmed by sandwich immunoassays of fresh frozen samples. Gastric cancer cell lines with high MET expression and phosphorylation of tyrosine-1349 respond to the MET inhibitor, BAY 853474. High expression and phosphorylation of MET is a predictive biomarker for response to MET inhibitors. We then analyzed MET expression and activity in a matched set of FFPE vs. fresh frozen tumor samples consisting of 20 cases of gastric cancer. Two of 20 clinical samples investigated exhibited high MET expression with RNA ISH and IHC. Both cases were shown by sandwich immunoassays to exhibits strong functional activity. Expression levels and functional activity in these two cases were in a range that predicted response to treatment. Our findings indicate that owing to its high selectivity, RNA ISH can be used to confirm findings obtained by IHC and potentially may replace IHC for certain targets if no suitable antibodies are available. RNA ISH is a valid platform for testing predictive biomarkers for patient selection. PMID- 28836865 TI - The cost-effectiveness and monetary benefits of dabigatran in the prevention of arterial thromboembolism for patients with non-valvular atrial fibrillation in the Netherlands. AB - BACKGROUND: Atrial fibrillation (AF) causes a significant health and economic burden to the Dutch society. Dabigatran was proven to have at least similar efficacy and a similar or better safety profile when compared to vitamin K antagonists (VKAs) in preventing arterial thromboembolism in patients with AF. OBJECTIVE: To evaluate the cost-effectiveness and monetary benefit of dabigatran vs VKAs in Dutch patients with non-valvular AF. Value-based pricing considerations and corresponding negotiations on dabigatran will be explicitly considered. METHODS: The base case economic analysis was conducted from the societal perspective. Health effects and costs were analysed using a Markov model. The main model inputs were derived from the RE-LY trial and Dutch observational data. Univariate, probabilistic sensitivity, and various scenario analyses were performed. RESULTS: Dabigatran was cost saving compared to VKAs. A total of 4,552 QALYs were gained, and ?13,892,288 was saved in a cohort of 10,000 AF patients. The economic value of dabigatran was strongly related to the costs of VKA control that are averted. Notably, dabigatran was cost saving compared to VKAs if annual costs of VKA control exceeded ?159 per person, or dabigatran costs were below ?2.81 per day. CONCLUSION: Dabigatran was cost saving compared to VKAs for the prevention of atrial thromboembolism in patients with non-valvular AF in the Netherlands. This result appeared robust in the sensitivity analysis. Furthermore, volume based reduction of the price in the Netherlands will further increase the monetary benefits of dabigatran. PMID- 28836866 TI - Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. AB - In this prospective trial, the efficacy of azacitidine in lower-risk myelodysplastic syndromes (LR-SMD) lacking del(5q) was compared to best supportive care (BSC) at 1:1. The primary endpoint was the achievement of erythroid hematologic improvement (HI-E) after nine cycles. Thirty-six patients received at least >=1 cycle. HI-E was confirmed 44.4% randomized to Aza and in 5.5% of patients receiving BSC (p < .01). After entry in Aza extension period, transfusion independence was achieved in all Aza responders with a median duration of 50 weeks (range: 17-231). No significant differences were observed in secondary endpoints. Importantly, variant allele frequency (VAF) of some mutated genes (RET, SF3B1, ASXL1) decreased after 9 months of treatment in Aza-responder patients. In conclusion, LR-MDS patients lacking del5q and resistant to ESAs, who receive 5 days Aza, achieve TI in a substantial proportion of cases and results in modifications in mutational landscape. PMID- 28836867 TI - Effects of ciprofloxacin on fetal rat liver during pregnancy and protective effects of quercetin. AB - Urinary tract infections are common in pregnant women and ciprofloxacin frequently is used as a broad spectrum antibiotic. It has been suggested that ciprofloxacin causes liver damage in fetuses. Quercetin is a flavonoid with antioxidant properties. We investigated the efficacy of quercetin treatment for preventing fetal liver damage caused by ciprofloxacin. Pregnant rats were divided into four groups: untreated control group (C), 20 mg/kg quercetin for 21 days group (Q), 20 mg/kg twice/day ciprofloxacin for 10 days group (CP), and 20 mg/kg, ciprofloxacin + quercetin for 21 days group (CP + Q). Fetal livers were removed on day 21 of gestation to measure antioxidants and for histological observation. Malondialdehyde (MDA) and glutathione (GSH) levels, and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities were measured in tissue samples. GSH-Px, SOD and CAT activities were significantly lower in the CP group compared to group C. A significant increase in MDA was observed in the CP group compared to group C. There was no significant difference in GSH levels in any group. MDA levels were lower and CAT, SOD and GSH-Px enzyme activities were higher in the CP + Q group compared to group CP. Liver samples of the CP group exhibited central vein dilation, portal vein congestion, pyknotic nuclei and cytoplasmic vacuolization in some hepatocytes. Histological changes were less prominent in the rats treated with quercetin. Use of ciprofloxacin during pregnancy caused oxidative damage in fetal liver tissue. Oxidative stress was ameliorated by quercetin. Quercetin supports the antioxidant defense mechanism and it is beneficial for treating fetal liver damage caused by ciprofloxacin. PMID- 28836868 TI - High expression of INHBA is an adverse prognostic factor for de novo acute myeloid leukemia. AB - Inhibin-beta A (INHBA) is a ligand of the transforming growth factor beta superfamily and associated with tumorigenesis and tumor progression in solid tumors. In this study, we investigated the expression levels and clinical significance of INHBA in acute myeloid leukemia (AML). The results showed that high expression of INHBA was significantly correlated with elderly age (>60 years) (p = .038), adverse cytogenetic risks (p = .034), negative NPM1 mutation (p = .016), positive FLT3 internal tandem duplications (p = .011), and low hemoglobin levels (<60 g/dL) (p = .04). Patients with high levels of INHBA had poor responses to therapies as indicated by lower complete remission rate (p = .004), higher early death rate (p = .018), and shorter relapse-free survival (p = .04) and overall survival (p = .003). Moreover, multivariate analysis showed that high expression of INHBA was an independent adverse prognostic factor for AML. Taken together, our study suggested that high expression of INHBA was an adverse prognostic factor for de novo AML. PMID- 28836869 TI - Renin-angiotensin system as a potential target for new therapeutic approaches in Parkinson's disease. AB - INTRODUCTION: Currently, available therapies for Parkinson's disease (PD) are symptomatic. Therefore, the search for neuroprotective drugs remains a top priority. Areas covered: In this review, the potential symptomatic or disease modifying effect of drugs targeting the Renin-Angiotensin System (RAS) in PD will be explored. Expert opinion: The importance of nigrostriatal local RAS has only begun to be unraveled in the last decades. On one hand, there is a complex feedback cycle between RAS and dopamine (DA). On the other hand, RAS affects dopaminergic neurons vulnerability. Neuroprotective effects in animal PD models have been shown for the angiotensin-converting enzyme (ACE) inhibitors captopril and perindopril, and the AT1 receptor antagonists losartan, candesartan and telmisartan. These effects appear to be mediated by a reduction in the overproduction of reactive oxygen species. In a proof-of-concept, randomized, double-blind, crossover study in PD patients, perindopril enhanced the effect of levodopa without inducing dyskinesias. There has not been any clinical trial exploring the neuroprotective effect of RAS drugs, but one cohort study in hypertensive patients suggested a protective effect of ACE inhibitors on PD risk. RAS is a promising target for symptomatic and neuroprotective therapies in PD. Further studies in PD animal models and patients are warranted. PMID- 28836870 TI - Phytotherapy as an alternative to conventional antimicrobials: combating microbial resistance. AB - INTRODUCTION: In the modern antimicrobial era, the rapid spread of resistance to antibiotics and introduction of new and mutating viruses is a global concern. Combating antimicrobial resistant microbes (AMR) requires coordinated international efforts that incorporate new conventional antibiotic development as well as development of alternative drugs with antimicrobial activity, management of existing antimicrobials, and rapid detection of AMR pathogens. Areas covered: This manuscript discusses some conventional strategies to control microbial resistance. The main purpose of the manuscript is to present information on specific herbal medicines that may serve as good treatment alternatives to conventional antimicrobials for infections sensitive to conventional as well as resistant strains of microorganisms. Expert commentary: Identification of potential new antimicrobials is challenging; however, one source for potential structurally diverse and complex antimicrobials are natural products. Natural products may have advantages over other post-germ theory antimicrobials. Many antimicrobial herbal medicines possess simultaneous antibacterial, antifungal, antiprotozoal and/or antiviral properties. Herbal products have the potential to boost host resistance to infections, particularly in immunocompromised patients. Antimicrobial broad-spectrum activity in conjunction with immunostimulatory properties may help to prevent microbial resistance to herbal medicine. As part of the efforts to broaden use of herbal medicines to treat microbial infections, pre-clinical and clinical testing guidelines of these compounds as a whole should be implemented to ensure consistency in formulation, efficacy and safety. PMID- 28836871 TI - Effectiveness of Smartphone Devices in Promoting Physical Activity and Exercise in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review. AB - The objectives of this systematic review were to analyse existing evidence on the efficacy of smartphone devices in promoting physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) and to identify the validity and precision of their measurements. A systematic review was undertaken across nine electronic databases: WOS Core Collection, PubMed, CINAHL, AMED, Academic Search Complete, Cochrane Central Register of Controlled Trials, SciELO, LILACS and ScienceDirect. Randomized and non-randomized controlled clinical trials were identified. To obtain additional eligible articles, the reference lists of the selected studies were also checked. Eligibility criteria and risk of bias were assessed by two independent authors. A total of eight articles met eligibility criteria. The studies were focused on promoting PA (n = 5) and the precision of device measurements (n = 3). The effectiveness of smartphones in increasing PA level (steps/day) at short and long term is very limited. Mobile-based exercise programs reported improvements in exercise capacity (i.e. incremental Shuttle Walk-Test) at short and long term (18.3% and 21%, respectively). The precision of device measurements was good-to-excellent (r = 0.69-0.99); however, these data should be interpreted with caution due to methodological limitations of studies. The effectiveness of smartphone devices in promoting PA levels in patients with COPD is scarce. Further high-quality studies are needed to evaluate the effectiveness of smartphone devices in promoting PA levels. Registration number: CRD42016050048. PMID- 28836872 TI - A comparative study on the raft chemical properties of various alginate antacid raft-forming products. AB - OBJECTIVE: Research to measure the chemical characterization of alginate rafts for good raft performance and ascertain how formulation can affect chemical parameters. SIGNIFICANCE: A selection of alginate formulations was investigated all claiming to be proficient raft formers with significance between products established and ranked. METHODS: Procedures were selected which demonstrated the chemical characterization allowing rafts to effectively impede the reflux into the esophagus or in severe cases to be refluxed preferentially into the esophagus and exert a demulcent effect, with focus of current research on methods which complement previous studies centered on physical properties. The alginate content was analyzed by a newly developed HPLC method. Methods were used to determine the neutralization profile and the acid neutralization within the raft determined along with how raft structure affects neutralization. RESULTS: Alginate content of Gaviscon Double Action (GDA) within the raft was significantly superior (p < .0001) to all competitor products. The two products with the highest raft acid neutralization capacity were GDA and Rennie Duo, the latter product not being a raft former. Raft structure was key and GDA had the right level of porosity to allow for longer duration of neutralization. CONCLUSION: Alginate formulations require three chemical reactions to take place simultaneously: transformation to alginic acid, sodium carbonate reacting to form carbon dioxide, calcium releasing free calcium ions to bind with alginic acid providing strength to raft formation. GDA was significantly superior (p <.0001) to all other comparators. PMID- 28836873 TI - Adaptive invention: independence and mobility through modifications. AB - BACKGROUND: Stroke is a leading cause of disability that limits everyday activities and reduces social participation. Provision of assistive devices helps to achieve independence and social inclusion. However, due to limited resources or a lack of suited objects for their needs, individuals with disabilities in low and middle income countries (LMIC) often do not have access to assistive devices. This has resulted in the creation of purpose built innovative solutions. Methodology and case content: This paper uses a single case derived from a larger ethnographic study of stroke survivors in rural Malaysia to demonstrate the role of assistive devices in shaping stroke recovery and how existing structures can be modified. Second, the concept of affordances in relation to structures within the environment, issues of affordability and accessibility of assistive devices for individuals in LMIC are discussed. FINDINGS AND CONCLUSIONS: Stroke recovery involves adapting to new limitations and discovering the support necessary to live life. These changes are influenced by a range of environmental factors. Healthcare professionals need to support stroke patients in identifying challenges and work to find innovative ways to address them. Stroke survivors may benefit from the use of an assistive device beyond its clinical function to participate purposefully in activities of daily living. Implications for Rehabilitation Stroke is a cause of disability that limits everyday activities and reduces social participation. Assistive devices help achieve independence, social inclusion and shape stroke recovery. Individuals with disabilities in low and middle income countries often do not have access to assistive devices and resort to innovative solutions that are purpose built. Stroke recovery involves adapting to new limitations and discovering the support necessary to live life as best as possible. PMID- 28836875 TI - A novel nucleotide oligomerisation domain 2 mutation in a family with Blau syndrome: Phenotype and function. AB - Mutations in the nucleotide binding domain of the PRR, NOD2, are associated with the autoinflammatory diseases Blau syndrome and early-onset sarcoidosis. Current theories suggest that constitutive activation of the NOD2 pathway may be responsible for pathogenesis of these diseases. Here, we report the phenotype of a kindred with Blau syndrome caused by a novel NOD2 mutation (p.E383D). Signaling protein and cytokine expression were examined, and the results of these experiments challenge current theories of constitutive NOD2 activation in the pathophysiology of Blau syndrome. PMID- 28836874 TI - Anti-fibrosis effect for Hirsutella sinensis mycelium based on inhibition of mTOR p70S6K phosphorylation. AB - Hirsutella sinensis, cultured in vitro, is an attractive substitute for Cordyceps sinensis as health supplement. The aim of this study was to demonstrate whether H. sinensis mycelium (HSM) attenuates murine pulmonary fibrosis induced by bleomycin and to explore the underlying molecular mechanisms. Using lung fibrosis modle induced by intratracheal instillation of bleomycin (BLM; 4 mg/kg), we observed that the administration of HSM reduced HYP, TGF-beta1 and the production of several pro-fibrosis cytokines (alpha-smooth muscle actin, fibronectin and vimentin) in fibrotic mice lung sections. Histopathological examination of lung tissues also demonstrated that HSM improved BLM-induced pathological damage. Concurrently, HSM supplementation markedly reduced the chemotaxis of alveolar macrophages and potently suppressed the expression of inflammatory cytokines. Also, HSM influenced Th1/Th2 and Th17/Treg imbalance and blocked the phosphorylation of mTOR pathway in vivo. Alveolar epithelial A549 cells acquired a mesenchymal phenotype and an increased expression of myofibroblast markers of differentiation (vimentin and fibronectin) after treatment with TGF-beta1. HSM suppressed these markers and blocked the phosphorylation of mTOR pathway in vitro. The results provide evidence supporting the use of HSM in the intervention of pulmonary fibrosis and suggest that HSM is a potential therapeutic agent for lung fibrosis. PMID- 28836876 TI - The Limits of Autonomy: Ideals in Care for People with Learning Disabilities. AB - In the Netherlands, autonomy is a key ideal in visions of care for people with learning disability. This ideal can lead to tension when clients, in the opinion of their caregivers, overuse alcohol or drugs. In this article, we analyze how professional caregivers understand the ideal of autonomy in care for people with learning disability, and articulate the tacit attempts of caregivers to provide "good care," which can be understood as care for relationships. This relational view includes caregivers, care recipients, and their networks and infrastructures in the vision of care. PMID- 28836877 TI - Management of hyperglycemia in the neurosurgery patient. AB - Hyperglycemia is associated with adverse outcomes in patients who are candidates for or underwent neurosurgical procedures. Specific concerns and settings that relate to these patients are preoperative glycemic control, intraoperative control, management in the neurological intensive care unit (NICU), and postoperative control. In each of these settings, physicians have to ensure appropriate glycemic control to prevent or minimize adverse events. The glycemic control is usually managed by a neurohospitalist in co-management with the neurosurgery team pre- and post-operatively, and by the neurocritical care team in the setting of NICU. In this review article, we outline current standards of care for neurosurgery patients with diabetes mellitus and/or and hyperglycemia and discuss results of most recent clinical trials. We highlight specific concerns with regards to glycemic controls in these patients including enteral tube feeding and parenteral nutrition, the issues of the transition to the outpatient care, and management of steroid-induced hyperglycemia. We also note lack of evidence in some important areas, and the need for more research addressing these gaps. Where possible, we provide suggestions how to manage these patients when there is no underlying guideline. PMID- 28836878 TI - Role of 'shared epitope' and other citrullination-sites in rheumatoid arthritis and in melanoma. PMID- 28836879 TI - Outcome of the Sauve-Kapandji procedure for distal radioulnar joint disorder with rheumatoid arthritis or osteoarthritis: Results of one-year follow-up. AB - OBJECTIVES: We performed the Sauve-Kapandji procedure for treating disorders of the distal radioulnar joint (DRUJ) in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). This study aimed to compare and clarify the results of the SK procedure between RA and OA patients. We report the one-year follow-up results of patients who underwent the SK procedure to correct the DRUJ disorder caused by RA or OA. METHODS: The study included 22 wrists of 19 patients with RA and 10 wrists of nine patients with OA. Pain, grip strength and range of motion of the wrist were examined clinically. For the evaluation of the stability of the carpus, ulnar stump and bone union, parameters were measured using radiographs. Shortened disabilities of the arm, shoulder and hand questionnaire (QuickDASH) was used for functional evaluation. RESULTS: Wrist pain reduced in all cases, and bone union was achieved in all wrists. The QuickDASH score significantly improved in both patients with RA and OA. In patients with RA, the range of motion increased significantly with regard to supination but decreased significantly with regard to palmar flexion. Carpal alignment and ulnar stump stability were maintained well at one-year follow-up. CONCLUSION: The Sauve-Kapandji procedure for treating disorders of the distal radioulnar joint DRUJ showed good results clinically and radiographically, irrespective of RA or OA. PMID- 28836880 TI - Long-Term Intravitreal Dexamethasone Treatment in Eyes with Pretreated Chronic Diabetic Macular Edema. AB - PURPOSE: The aim of this study is to assess the effect of repeated injections of dexamethasone implants in patients with persistent diabetic macular edema (DME) despite prior therapies. METHODS: This retrospective interventional study involved 47 DME-afflicted eyes, which were administered >=2 intravitreal injections of dexamethasone. Group 1 (34 eyes) received a dexamethasone monotherapy, whereas group 2 (13 eyes) received a combination therapy with intravitreal antivascular endothelial growth factor as needed. The duration of dexamethasone effect until retreatment and the change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were defined as outcome measures. RESULTS: A total of 197 injections of dexamethasone were administered in group 1 and 52 in group 2 during a mean follow-up of 23 +/- 10 and 24 +/- 13 months, respectively. Mean time to reinjection was 4.6 +/- 0.5 (group 1) and 5.3 +/- 1.0 months (group 2; P = 0.17). Reinjection intervals did not shorten over time for up to 10 dexamethasone injections per eye in group 1 and BCVA improved from before 1 month after the first implantation, 7.0 letters (P = 0.04). In group 2, there was no significant improvement in BCVA at any time point. CRT decreased from 534 +/- 208 and 529 +/- 215 MUm to 287 +/- 115 and 371 +/- 78 MUm at 3 months and increased to 460 +/- 186 MUm and 547 +/- 175 MUm before reinjection (groups1 and 2, respectively). The maximal CRT before each implantation remained stable over time. CONCLUSIONS: In eyes with chronic DME that respond incompletely to prior therapy or require frequent reinjections, dexamethasone shows promising long-term anatomic and functional improvement. The absence of a treatment effect reduction over time argues against a relevant rebound phenomenon. PMID- 28836881 TI - Segmented Forefoot Plate in Basketball Footwear: Does it Influence Performance and Foot Joint Kinematics and Kinetics? AB - This study examined the effects of shoes' segmented forefoot stiffness on athletic performance and ankle and metatarsophalangeal joint kinematics and kinetics in basketball movements. Seventeen university basketball players performed running vertical jumps and 5-m sprints at maximum effort with 3 basketball shoes of various forefoot plate conditions (medial plate, medial + lateral plates, and no-plate control). One-way repeated measures ANOVAs were used to examine the differences in athletic performance, joint kinematics, and joint kinetics among the 3 footwear conditions (alpha = .05). Results indicated that participants wearing medial + lateral plates shoes demonstrated 2.9% higher jump height than those wearing control shoes (P = .02), but there was no significant differences between medial plate and control shoes (P > .05). Medial plate shoes produced greater maximum plantar flexion velocity than the medial + lateral plates shoes (P < .05) during sprinting. There were no significant differences in sprint time. These findings implied that inserting plates spanning both the medial and lateral aspects of the forefoot could enhance jumping, but not sprinting performances. The use of a medial plate alone, although induced greater plantar flexion velocity at the metatarsophalangeal joint during sprinting, was not effective in improving jump heights or sprint times. PMID- 28836882 TI - Erratum: Lin and Karduna (2017). AB - In the article by Lin Y-L and Karduna A, "Errors in Shoulder Joint Position Sense Mainly Come from the Glenohumeral Joint," in J Appl Biomech. 33(1):32-38, https://doi.org/10.1123/jab.2016-0034 , Figure 3c was a duplicate of Figure 3b and was therefore incorrect. The online version of this article has been corrected; we apologize for this error. PMID- 28836883 TI - Review on Sustained Relief of Osteoarthritis Symptoms with a Proprietary Extract from Pine Bark, Pycnogenol. AB - This review summarizes the effects of the standardized proprietary bark extract of the French maritime pine (Pycnogenol(r)) in mild osteoarthritis (OA), stage 1 and 2. The extract exerts antioxidative, anti-inflammatory, and chondroprotective effects in vitro and in vivo. Its phenolic acids as well as catechin and taxifolin are quickly absorbed. Active metabolites, produced by gut microbiota in the intestinal tract from oligomeric procyanidins, appear in blood 6 h following ingestion and remain for at least 14 h, providing a long-lasting flow of anti inflammatory substances for relief of OA symptoms. These constituents of Pycnogenol could be detected in serum, blood cells, and synovial fluid of OA patients. The resulting inhibition of cartilage-destructing proteases and pain producing cyclo-oxygenases provides the basis for relief from pain, improvement of stiffness, enhanced mobility, and well-being in three clinical studies with the pine bark extract as an adjunct supplement. Sparing the use of nonsteroidal anti-inflammatory drugs, supplementation with the pine bark extract reduced gastric complications and hospital admissions of OA patients. Because of its favorable safety profile and sustained anti-inflammatory action, Pycnogenol represents an option as an add-on supplement for OA patients. PMID- 28836884 TI - Identifying Barriers and Pathways to Success for New Occupational Therapy Faculty Members: A Pilot Survey. AB - Research suggests new health care professional faculty members benefit from assistance and support in the transition from the clinic to academia; however, few recent studies have been conducted to determine if this is true for occupational therapy. This descriptive pilot study explores the barriers that may face new occupational therapy faculty members and suggests strategies to assist new faculty members in their transition to academia. Through an electronic survey, identified barriers, challenges, and potential resolutions for the transitioning of new faculty members are highlighted. The results suggest the need for enhanced preparations for a career in academia; as well as new faculty member orientations that include instruction on professional development, classroom management, academic culture, scholarship, and mentoring. PMID- 28836885 TI - Clinical Characteristics and Outcomes Among Older Women with HIV. AB - OBJECTIVES: To inform the development of HIV care strategies for older women with HIV infection, an understudied group, we compared the psychosocial, behavioral, and clinical characteristics of HIV-positive women aged >=50 (older women) with those aged 18-49 (younger women). METHODS: We examined factors among HIV-positive women in care using data from the 2009 through 2013 cycles of a nationally representative sample of HIV-positive adults in care (Medical Monitoring Project). We compared psychosocial, clinical, and behavioral factors among women aged >=50 years at interview versus those aged <50 years. We calculated weighted frequency estimates and performed logistic regression to compute adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) for the comparison of characteristics among women aged >=50 versus <50 years. RESULTS: Of 22,145 participants, 6186 were women; 40.7% (CI 39.1-42.3) were >=50 years, and 32.7% of older women reported being sexually active. Compared with women <50 years, women aged >=50 years were more likely to be dose adherent (aPR = 1.19; CI 1.07-1.33), prescribed antiretroviral therapy and have sustained viral load suppression (aPR = 1.03; CI 1.00-1.18), and were less likely to report any depression (aPR = 0.92; CI 0.86-0.99), to report condomless sex with a negative or unknown partner if sexually active (aPR = 0.56; CI 0.48-0.67), and to have received HIV/sexually transmitted infection (STI) prevention counseling from a healthcare provider (aPR = 0.82; CI 0.76-0.88). CONCLUSIONS: These data suggest that older women in HIV care have more favorable outcomes in some clinical areas, but may warrant increased HIV/STI prevention counseling from their care providers, especially if sexually active. PMID- 28836886 TI - Subacute and Chronic Left Ventricular Myocardial Scar: Accuracy of Texture Analysis on Nonenhanced Cine MR Images. AB - Purpose To test whether texture analysis (TA) allows for the diagnosis of subacute and chronic myocardial infarction (MI) on noncontrast material-enhanced cine cardiac magnetic resonance (MR) images. Materials and Methods In this retrospective, institutional review board-approved study, 120 patients who underwent cardiac MR imaging and showed large transmural (volume of enhancement on late gadolinium enhancement [LGE] images >20%, n = 72) or small (enhanced volume <=20%, n = 48) subacute or chronic ischemic scars were included. Sixty patients with normal cardiac MR imaging findings served as control subjects. Regions of interest for TA encompassing the left ventricle were drawn by two blinded, independent readers on cine images in end systole by using a freely available software package. Stepwise dimension reduction and texture feature selection based on reproducibility, machine learning, and correlation analyses were performed for selecting features, enabling the diagnosis of MI on nonenhanced cine MR images by using LGE imaging as the standard of reference. Results Five independent texture features allowed for differentiation between ischemic scar and normal myocardium on cine MR images in both subgroups: Teta1, Perc.01, Variance, WavEnHH.s-3, and S(5,5)SumEntrp (in patients with large MI: all P values < .001; in patients with small MI: Teta1 and Perc.01, P < .001; Variance, P = .026; WavEnHH.s-3, P = .007; S[5,5]SumEntrp, P = .045). Multiple logistic regression models revealed that combining the features Teta1 and Perc.01 resulted in the highest accuracy for diagnosing large and small MI on cine MR images, with an area under the curve of 0.93 and 0.92, respectively. Conclusion This proof-of-concept study indicates that TA of nonenhanced cine MR images allows for the diagnosis of subacute and chronic MI with high accuracy. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28836887 TI - Sequential Stereotype Priming: A Meta-Analysis. AB - Psychological interest in stereotype measurement has spanned nearly a century, with researchers adopting implicit measures in the 1980s to complement explicit measures. One of the most frequently used implicit measures of stereotypes is the sequential priming paradigm. The current meta-analysis examines stereotype priming, focusing specifically on this paradigm. To contribute to ongoing discussions regarding methodological rigor in social psychology, one primary goal was to identify methodological moderators of the stereotype priming effect whether priming is due to a relation between the prime and target stimuli, the prime and target response, participant task, stereotype dimension, stimulus onset asynchrony (SOA), and stimuli type. Data from 39 studies yielded 87 individual effect sizes from 5,497 participants. Analyses revealed that stereotype priming is significantly moderated by the presence of prime-response relations, participant task, stereotype dimension, target stimulus type, SOA, and prime repetition. These results carry both practical and theoretical implications for future research on stereotype priming. PMID- 28836888 TI - Pain, Bullying Involvement, and Mental Health Problems Among Children and Adolescents With ADHD in Taiwan. AB - OBJECTIVE: The aim of this study was to examine the relationships of pain and pain-induced functional impairment with bullying involvement, as well as the relationships between pain and mental health problems among 474 children and adolescents with ADHD. METHOD: The levels of pain, pain-induced functional impairment, involvement in bullying, depression, anxiety, ADHD symptoms, and sleep quality were assessed. RESULTS: Both victims of verbal and relational bullying and victims of physical bullying were more likely to have pain and pain induced functional impairment than nonvictims. The perpetrators of verbal and relational bullying were more likely to have pain than the nonperpetrators. Participants with pain and pain-induced functional impairment experienced more severe depression and anxiety and worse sleep quality than did those without pain or pain-induced functional impairment. CONCLUSION: Clinical and educational professionals should consider the possibility of involvement in bullying and comorbid depression, anxiety, and poor sleep quality among ADHD children and adolescents with pain problems. PMID- 28836889 TI - Candida Vulvovaginitis and Vulvodynia: The Mystery Continues. PMID- 28836890 TI - Hip Abductor Fatigability and Recovery Are Related to the Development of Low Back Pain During Prolonged Standing. AB - A prolonged standing exposure can identify asymptomatic adults who have a higher risk of developing clinical low back pain later in life. Hip abductor cocontraction differences can predict low back pain development during standing exposures. This study's purpose was to determine if hip abductor strength, fatigability, and recovery during prolonged standing were related to standing induced low back pain. Forty young, asymptomatic adults (50% female) performed two 2-hour standing sessions; a fatiguing hip abductor exercise was performed prior to 1 of the 2 standing sessions. Hip abductor strength and surface electromyography of gluteus medius and tensor fascia latae were measured. Self reported low back pain differentiated low back pain developing (PD) and nonpain developing (NPD) groups. The PD group hip abductors fatigued before the NPD group, with similar perceived effort and force losses. Mean power frequency decreases with fatigue were similar between pain groups for all muscles measured after the fatiguing exercise. Unlike NPDs, PDs did not recover force losses after 120 minutes of standing. Hip abductor fatigability may be related to the development of low back pain in this population. PMID- 28836892 TI - 2017 European guidelines for the management of genital herpes. AB - Genital herpes is one of the commonest sexually transmitted infections worldwide. Using the best available evidence, this guideline recommends strategies for diagnosis, management, and follow-up of the condition as well as for minimising transmission. Early recognition and initiation of therapy is key and may reduce the duration of illness or avoid hospitalisation with complications, including urinary retention, meningism, or severe systemic illness. The guideline covers a range of common clinical scenarios, such as recurrent genital herpes, infection during pregnancy, and co-infection with human immunodeficiency virus. PMID- 28836893 TI - Systemic Juvenile Xanthogranuloma Involving the Bone Marrow, Multiple Bones, and the Skin That Developed During Treatment of Acute Lymphoblastic Leukemia in Remission State. AB - Juvenile xanthogranuloma (JXG) is a rare benign disorder classified as non Langerhans cell histiocytosis, with unclear etiology and pathogenesis. JXG is generally characterized by solitary or multiple cutaneous nodules that resolve spontaneously over a few years. JXG rarely presents as extracutaneous lesions that progress to a symptomatic systemic disorder through multiple organ involvement. We encountered a systemic JXG case involving the bone marrow, multiple bones, and the skin during acute lymphoblastic leukemia (ALL) treatment. A 16-year-old boy undergoing ALL treatment experienced unexplained prolonged fever and scalp, hip joint, and right knee joint pain for 2 weeks during interim maintenance chemotherapy. Bone marrow pathologic findings revealed no evidence of leukemia relapse but showed diffuse infiltration of histiocytes with several Touton-type giant cells; the stains were positive for CD68 and negative for CD1a and S100 protein. Bone and skin biopsies confirmed the findings. Symptoms have resolved since maintenance chemotherapy, which included vincristine, dexamethasone, 6-mercaptopurine, and methotrexate. Bone marrow involvement of JXG is very rare, occurring only in patients less than 1 year of age; however, this case was reported in an adolescent during ALL treatment. PMID- 28836894 TI - A novel mutation of MIP in a Chinese family with congenital nuclear cataract identified by whole-exome sequencing. PMID- 28836895 TI - Correlations Between Clinical Trial Outcomes Based on Symptoms, Functional Impairments, and Quality of Life in Children and Adolescents With ADHD. AB - OBJECTIVE: To assess relationships between treatment-associated changes in measures of ADHD symptoms, functional impairments, and health-related quality of life in children and adolescents with ADHD. METHOD: Pearson correlation coefficients were calculated post hoc for changes from baseline to endpoint in outcomes of one randomized, placebo- and active-controlled trial of lisdexamfetamine (osmotic-release methylphenidate reference) and one of guanfacine extended-release (atomoxetine reference). RESULTS: Changes in ADHD Rating Scale IV (ADHD-RS-IV) total score generally correlated moderately with changes in Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE:PRF) Achievement and Risk Avoidance ( r ~ .4), but weakly with Resilience, Satisfaction, and Comfort ( r ~ .2); and moderately with Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) total score ( r ~ .5). CHIP CE: PRF Achievement and Risk Avoidance correlated moderately to strongly with WFIRS-P total score ( r ~ .6). CONCLUSION: The ADHD-RS-IV, CHIP-CE:PRF, and WFIRS P capture distinct but interconnected aspects of treatment response in individuals with ADHD. PMID- 28836896 TI - Factors Underlying the Relationship Between Parent and Child Grief. AB - The death of a parent in a child's life is a significant risk factor for later mental and physical health problems. While much has been written about the surviving parent's functioning and its effects on their bereaved children, little work has been done to look into factors underlying this effect such as how the parent copes. The present study recruited 38 parent-child dyads from a community based grief support center. Parent and child, independently, completed various measures of emotional functioning, including grief symptoms and coping such as social support and locus of control. The results indicated that parental coping did have an impact on children's grief symptoms. This represents a unique view of adaptation in bereaved children: Parental coping strategies can have an impact on the child, independent of the child's coping strategies. By focusing on parent coping, we have highlighted another possible pathway through which parental functioning affects children's grief. PMID- 28836897 TI - Genomic Characterization of Crimean-Congo Hemorrhagic Fever Virus in Hyalomma Tick from Spain, 2014. AB - Crimean-Congo hemorrhagic fever (CCHF) is a severe tick-borne disease caused by CCHF virus (CCHFV). Ticks in the genus Hyalomma are the main vectors and reservoirs of CCHFV. In Spain, CCHFV was first detected in Hyalomma ticks from Caceres in 2010. Subsequently, two autochthonous CCHF cases were reported in August 2016. In this study, we describe the characterization of the CCHFV genome directly from Hyalomma lusitanicum collected in Caceres in 2014. Phylogenetic analyses reveal a close relationship with clade III strains from West Africa, with an estimated divergence time of 50 years. The results of this work suggest that CCHFV has been circulating in Spain for some time, and most likely originated from West Africa. PMID- 28836898 TI - Recognizing, reporting, and responding to abuse, neglect, and self-neglect of vulnerable adults: an evaluation of the re:act adult protection worker basic curriculum. AB - Abuse and neglect of vulnerable adults are significant problems, the identification and management of which is increasingly being made the legal responsibility of healthcare professionals. In response, some jurisdictions have developed training to assist professionals in these duties. This study evaluates the re:act Adult Protection Worker Basic Curriculum training from British Columbia, Canada. One hundred and fifty-seven participants, 109 training completers and 48 non-completers, answered a survey evaluating their confidence, knowledge, and applied knowledge in identifying, reporting, and investigating cases of suspected abuse, neglect, and self-neglect of vulnerable adults. Comparisons of training completers to non-completers showed significant gains in completers' perceived confidence and knowledge, but no improvement in applied knowledge. The type of healthcare professional being trained and the length of training did not impact learner improvement. The results suggest ways in which both training and evaluation can be improved (e.g., supervised practice) to increase and detect gains in knowledge and practice. PMID- 28836899 TI - Association Between BKPyV Serotype I Antibody Level and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. AB - To determine the association between BK polyomavirus (BKPyV) types 1 and 4 capsid antibody and natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS), serum samples were obtained from 10 natalizumab-associated PML cases and 130 control MS patients treated with natalizumab, and 82 control MS patients never exposed to natalizumab. In a sex- and age-adjusted regression model, BKPyV serotype 1 antibody levels were significantly higher in natalizumab-treated controls (p = 0.009) compared with cases, and were higher in controls never treated with natalizumab compared with cases, but the difference did not reach statistical significance (p = 0.158). There was no association between BKPyV serotype 4 antibody and PML. We hypothesize that a robust immune response to BKPyV may be protective against the development of PML. PMID- 28836901 TI - A clinical review of early outcomes from contemporary flow modulation versus open, fenestrated and branch technologies in the management of thoracoabdominal aortic aneurysm. AB - Traditional therapeutic options for complex thoracoabdominal aneurysm include open repair, hybrid repair or endovascular repair (involving fenestrated or branched endografts). The Streamliner Multilayer Flow Modulator has been available for treatment of thoracoabdominal aneurysms since 2010. Its design permits blood flow to perfuse through the mesh in a modus that preserves collateral branch patency, while modulating turbulent to laminar flow within the device. The flow then stagnates over time within the surrounding aneurysm sac. Significant complications, including paraplegia, renal failure and cerebrovascular accident, are much lower with Streamliner Multilayer Flow Modulator treatment. Application of the Streamliner Multilayer Flow Modulator to complex aortic pathologies presents a novel solution to an, as of yet, unmet clinical need, and has resulted in promising clinical outcomes when compared to existing solutions. The Streamliner Multilayer Flow Modulator offers potential for treatment of thoracoabdominal aortic pathologies in patients and is not just confined to those with complexity that dictates no other management options. While current literature illustrates that there is a decreased risk of mortality and associated complications when this new disruptive technology is utilised, there is still a need for prospective, long-term clinical trials, as well as comparative trials to accurately assess outcomes of Streamliner Multilayer Flow Modulator treatment that are both precise and reproducible. This article is a review of current clinical literature regarding contemporary flow modulating technology compared with open, branched and fenestrated managements, presenting early outcomes. PMID- 28836902 TI - Telepsychotherapy and the Therapeutic Relationship: Principles, Advantages, and Case Examples. AB - OBJECTIVE: As the use of technology continues to expand within our mental healthcare system, there has been an increasing interest in conducting psychotherapy online using videoconferencing. Literature pertaining to telepsychotherapy has explored possible drawbacks of this modality on the therapeutic relationship, although several studies have shown that the efficacy of online psychotherapy is equivalent to in-person approaches. Little is written about the potential advantages to the psychotherapeutic relationship when psychotherapy is carried out over videoconferencing. METHODS: The available literature was reviewed, as were the general principles of telepsychotherapy and the therapeutic relationship, followed by a more in-depth consideration of patient populations for whom telepsychotherapy may offer distinct advantages. RESULTS: The current literature, as well as our own clinical experience, suggests that telepsychotherapy may be effective for a broad range of patients, and it may offer distinct advantages in the building of a trusting psychotherapeutic relationship. CONCLUSION: Telepsychotherapy offers a novel way to reach and form strong psychotherapeutic relationships with many different types of patients, and it may foster therapeutic intimacy in ways that in-person psychotherapy cannot. More research is needed to further explore this unique modality. PMID- 28836900 TI - A nationwide analysis of 30-day readmissions related to critical limb ischemia. AB - Objectives There is paucity of information regarding critical limb ischemia related readmission rates in patients admitted with critical limb ischemia. We studied 30-day critical limb ischemia-related readmission rate, its predictors, and clinical outcomes using a nationwide real-world dataset. Methods We did a secondary analysis of the 2013 Nationwide Readmissions Database. We included all patients with a primary diagnosis of extremity rest pain, ulceration, and gangrene secondary to peripheral arterial disease. From this group, all patients readmitted with similar diagnosis within 30 days were recorded. Results Of the total 25,111 index hospitalization for critical limb ischemia, 1270 (5%) were readmitted with a primary diagnosis of critical limb ischemia within 30 days. The readmission rate was highest (9.5%) for the group that did not have any intervention (revascularization or major amputation) and was lowest for surgical revascularization and major amputation groups (2.6% and 1.3%, P value <0.001 for all groups). Severity of critical limb ischemia at index admission was associated with a significantly higher rate of 30-day readmission. Critical limb ischemia related readmission was associated with a higher rate of major amputation (29.6% vs. 16.2%, P<0.001), a lower rate of any revascularization procedure (46% vs. 62.6%, P<0.001), and a higher likelihood of discharge to a skilled nursing facility (43.2% vs. 32.2%, P<0.001) compared to index hospitalization. Conclusions In patients with primary diagnosis of critical limb ischemia, 30-day critical limb ischemia-related readmission rate was affected by initial management strategy and the severity of critical limb ischemia. Readmission was associated with a significantly higher rate of amputation, increased length of stay, and a more frequent discharge to an alternate care facility than index admission and thus may serve as a useful quality of care metric in critical limb ischemia patients. PMID- 28836903 TI - Breast Microcalcifications and Their Implications for Risk Assessment. A Brief Review. PMID- 28836904 TI - Kikuchi Disease. AB - Kikuchi disease is a rare, idiopathic, self-limited disorder affecting the cervical lymph nodes. PMID- 28836905 TI - All-Cause Mortality for Life Insurance Applicants with a History of Breast Cancer. AB - Breast cancer is the most commonly diagnosed cancer worldwide. Breast cancer is also the second leading cause of cancer death among women in the United States after lung cancer with over 40,000 breast cancer deaths occurring each year. The purpose of this research was to determine the all-cause mortality of applicants diagnosed with breast cancer currently or at some time in the past. Life insurance applicants with reported breast cancer were extracted from data covering United States residents between November 2007 and November 2014. Information about these applicants was matched to the Social Security Death Master (SSDMF) file for deaths occurring from 2007 to 2011 and to another commercially available death source file (Other Death Source, ODS) for deaths occurring from 2007 to 2014 to determine vital status. If there was a death from the other death source, then the SSDMF was searched to verify the death. The study had approximately 561,000 person-years of exposure. Actual-to-expected (A/E) mortality ratios were calculated using the Society of Actuaries 2008 Valuation Basic Table (2008VBT), select and ultimate table (age last birthday) and the 2010 US population as expected mortality ratios. Since the A/Es presented in this paper were known to be an underestimate due to the exclusion of the recent SSDMF deaths, comparative analysis of the mortality ratios was done. Since there was no smoking status information in this study, all expected bases were not smoker distinct. Overall, the 35-44 age group had 6.3 times the relative mortality ratio than those in the 65-75 age group. The relative mortality ratio for the 35-44 age group applicants, when cancer severity was accounted for in combination with 3 or more nodes of cancer involvement, was 29.3 times that when compared to those in the 65-75 age group having localized cancer, where no nodes are involved. The 35-44 age group applicants who were diagnosed with cancer within the last year had over 10-fold increase in relative mortality ratios compared to the 65-75 age group, who were over 10 years from diagnosis. Taking the severity of cancer along with time from diagnosis showed over a 12 times relative mortality ratio between the low rate of over 10 years from diagnosis and localized involvement to those diagnosed within the last year having 3 or more nodes with cancer. Applicant age, time since diagnosis and cancer severity were the most significant variables to predict the relative mortality ratios. PMID- 28836906 TI - The Medical Underwriting of Transgender Individuals. AB - As more transgender individuals apply for life insurance, it is important to understand the many health issues that are particular to this population. This article reviews the pathophysiology, diagnosis and treatment of gender dysphoria- the dominant medical problem of transgender individuals. It also reviews the frequent co-morbidities in the transgender population and finishes with a review of the small number of studies that have examined long-term mortality. PMID- 28836907 TI - JIM Reading List. PMID- 28836908 TI - A "Full Monty" Issue of the Journal. PMID- 28836909 TI - Random Forest. AB - For the task of analyzing survival data to derive risk factors associated with mortality, physicians, researchers, and biostatisticians have typically relied on certain types of regression techniques, most notably the Cox model. With the advent of more widely distributed computing power, methods which require more complex mathematics have become increasingly common. Particularly in this era of "big data" and machine learning, survival analysis has become methodologically broader. This paper aims to explore one technique known as Random Forest. The Random Forest technique is a regression tree technique which uses bootstrap aggregation and randomization of predictors to achieve a high degree of predictive accuracy. The various input parameters of the random forest are explored. Colon cancer data (n = 66,807) from the SEER database is then used to construct both a Cox model and a random forest model to determine how well the models perform on the same data. Both models perform well, achieving a concordance error rate of approximately 18%. PMID- 28836910 TI - Regular Expressions: Mixed Effects Models. PMID- 28836911 TI - Infarction or Pseudo-infarction? AB - An applicant with a history of paroxysmal atrial fibrillation is found to have QS waves in leads III and AVF suggestive of a prior inferior wall myocardial infarction. Using the relationship between Q wave and T wave vectors in the inferior leads, an alternative explanation is explored. PMID- 28836912 TI - Noise pollution in the hospital environment of a developing country: A case study of Lahore (Pakistan). AB - The present study investigates the noise pollution levels in public- and private sector hospitals of Lahore. The noise pollution parameters were investigated from 20 public and 10 private hospitals. We observed that the equivalent continuous sound level (Leq) values varied significantly in different departments of the hospitals as well as at different times of the day. The public-sector hospitals had significantly higher noise pollution compared to the private-sector hospitals. The Wilcoxon Mann-Whitney two-sample rank-sum test revealed significant difference between noise levels in intensive care unit (ICU) during morning and in emergency, waiting area, intensive care unit (ICU), and reception during daytimes. However, no significant differences were found for any department during the evening. The Leq values were found to be higher than the international norms (WHO standards) for all hospitals, higher than USEPA for 29 hospitals and higher than local standards for 27 hospitals. Overall, significantly lower sound levels were always observed in private hospitals. PMID- 28836913 TI - Correction to: Thyroid 2017;27:315-389. DOI: 10.1089/thy.2016.0457. PMID- 28836914 TI - Interactions Between Chronic Viral Infections and the Host Immune System. PMID- 28836915 TI - A Cross-Cultural Study in Germany, Russia, and China: Are Resilient and Social Supported Students Protected Against Depression, Anxiety, and Stress? AB - This study cross-culturally investigated resilience and social support as possible protective factors for mental health. The values of depression, anxiety, and stress symptoms, resilience and social support were collected from German (N = 4433), Russian (N = 3774), and Chinese students (N = 4982). The samples were split (two-thirds vs. one-third) to cross-validate the results. In all samples, resilience and social support were significantly negatively associated with depression, anxiety, and stress symptoms. While in Germany those associations were stronger for social support, in Russia and in China stronger associations were found for resilience. Furthermore, in all samples, resilience was found to mediate the association between social support and the negative mental health variables significantly. In conclusion, resilience and social support are universal interrelated protective factors for mental health independently of historical, cultural, social, and geographical conditions of a country. PMID- 28836916 TI - The Use of Acceptance and Commitment Therapy in Oncology Settings: A Narrative Review. AB - Various psychotherapeutic approaches have been developed to address the psychosocial stressors and distress associated with cancer diagnosis and treatment. One such approach, Acceptance and Commitment Therapy (ACT), may be particularly well suited to people with cancer as it offers a model of healthy adaptation to difficult circumstances. This paper provides a description and theoretical rationale for using ACT in psychosocial oncology care that emphasizes emotional distress and cancer-related pain and provides a narrative review of the current state of evidence for this setting. Six studies met eligibility criteria for inclusion in the review. The research designs included one case study, three pre-post cohort studies, and two randomized controlled trials. Cancer diagnoses of patients included breast cancer, ovarian cancer, colorectal cancer, and mixed cancer populations at various stages of disease progression or recovery. ACT interventions demonstrated significant improvements in symptoms including quality of life and psychological flexibility as well as reductions in symptoms including distress, emotional disturbances, physical pain, and traumatic responses. Overall, although there is limited published research currently available, there is some evidence to support ACT as an effective psychotherapeutic approach for cancer patients. Further research is needed for different cancer populations across the illness trajectory. Barriers to implementation are discussed. PMID- 28836918 TI - Foreword. PMID- 28836917 TI - Multiple Group Confirmatory Factor Analysis of the DASS-21 Depression and Anxiety Scales: How Do They Perform in a Cancer Sample? AB - The DASS-21 is a public domain instrument that is commonly used to evaluate depression and anxiety in psychiatric and community populations; however, the factor structure of the measure has not previously been examined in oncologic settings. Given that the psychometric properties of measures of distress may be compromised in the context of symptoms related to cancer and its treatment, the present study evaluated the psychometric properties of the DASS-21 Depression and Anxiety scales in cancer patients ( n = 376) as compared to noncancer control participants ( n = 207). Cancer patients ranged in age from 21 to 84 years (mean = 58.3, standard deviation = 10.4) and noncancer control participants ranged in age from 18 to 81 years (mean = 45.0, standard deviation = 11.7). Multiple group confirmatory factor analysis supported the structural invariance of the DASS-21 Depression and Anxiety scales across groups; the factor variance/covariance invariance model was the best fit to the data. Cronbach's coefficient alpha values demonstrated acceptable internal consistency reliability across the total sample as well as within subgroups of cancer patients and noncancer control participants. Expected relationships of DASS-21 Depression and Anxiety scale scores to measures of suicidal ideation, quality of life, self-rated health, and depressed mood supported construct validity. These results support the psychometric properties of the DASS-21 Depression and Anxiety scales when measuring psychological distress in cancer patients. PMID- 28836919 TI - Dopaminergic and Serotonergic Genotypes and the Subjective Experiences of Hypnosis. AB - Hypnotizability is related to the Val158Met polymorphism of the COMT gene. The authors' aim was to find associations between candidate genes and subjective dimensions of hypnosis; 136 subjects participated in hypnosis and noninvasive DNA sampling. The phenomenological dimensions were tapped by the Archaic Involvement Measure (AIM), the Phenomenology of Consciousness Inventory (PCI), and the Dyadic Interactional Harmony Questionnaire (DIH). The main results were that the "Need of dependence" subscale of AIM was associated with the COMT genotypes. The GG subgroup showed higher scores, whereas AA had below average scores on the majority of the subjective measures. An association between the 5-HTTLPR polymorphism and the intimacy scores on the DIH was also evident. The effects are discussed in the social-psychobiological model of hypnosis. PMID- 28836920 TI - Feasibility of Music and Hypnotic Suggestion to Manage Chronic Pain. AB - The authors investigated the feasibility and possible effects of hypnotic suggestion and music for chronic pain. Ten people completed the 2-week intervention that consisted of daily listening to hypnotic suggestions combined with music. Averaged subjective pain intensity, pain bothersomeness, overall distress, anxiety, and depression decreased from baseline to endpoint. Participants rated pre- and postlistening pain intensity and pain bothersomeness decreased for each session. Information provided during end-of-study interviews indicated all participants were satisfied with treatment and felt they benefited from being in the study. Means and standard deviations are reported for outcome measures and a case study is provided. This preliminary study supports the use of a combined hypnotic suggestion and music intervention for chronic pain. PMID- 28836921 TI - The Pioneering Work of Enrico Morselli (1852-1929) in Light of Modern Scientific Research on Hypnosis and Suggestion. AB - This article examines research on hypnosis and suggestion, starting with the nineteenth-century model proposed by Enrico Morselli (1852-1929), an illustrious Italian psychiatrist and psychologist. The authors conducted an original psychophysiological analysis of hypnosis, distancing the work from the neuropathological concept of the time and proposing a model based on a naturalistic approach to investigating mental processes. The issues investigated by Morselli, including the definition of hypnosis and analysis of specific mental processes such as attention and memory, are reviewed in light of modern research. From the view of modern neuroscientific concepts, some problems that originated in the nineteenth century still appear to be present and pose still-open questions. PMID- 28836922 TI - A Neutral Control Condition for Hypnosis Experiments: "Wiki" Text. AB - A new control condition called Wiki is introduced. Key themes of each test suggestion of the Stanford Hypnotic Susceptibility Scale, Form C, were matched by a corresponding extract from Wikipedia.org. The authors compared phenomenological reports of participants across 4 conditions: hypnosis split into high and low hypnotizable subgroups, music, and Wiki condition, using the Phenomenology of Consciousness Inventory. High hypnotizables undergoing hypnosis reported higher altered experience and altered states of awareness than individuals in the Wiki condition, supporting the authors' hypothesis that the Wiki condition does not evoke an altered state of consciousness (internal dialogue, volitional control, and self-awareness did not differ). Wiki might be a viable control condition in hypnosis research given further examination. PMID- 28836923 TI - Hypnotizability and the Peripersonal Space. AB - High hypnotizability is associated with left-sided cerebral asymmetry, which could influence measurement of the Peripersonal Space (PPS). Right-handed participants with high (highs, n = 20), medium (mediums, n = 9), and low hypnotizability scores (lows, n = 20) performed the line bisection test on a computer screen automatically displaced at distances of 30, 60, and 90 cm from the subjects' eyes. Highs' results showed rightward bias of the bisection (Relative Error, RE) for all presentation distances. In contrast, in lows RE was displaced leftward at 30 cm and exhibited a progressive rightward shift at 60 and 90 cm, as occurs in the general population. Mediums' RE values were intermediate between highs' and lows' values. Bisection Times (BT) were significantly longer in highs/mediums than in lows. Findings indicate that the highs' bisection identifies PPS as if it was extrapersonal, but further studies should assess its functional characteristics. The highs/mediums longer BT suggest less efficient sensorimotor performance. PMID- 28836924 TI - Preputial mucosal graft for urethral repair. AB - Urethral stricture disease is the commonest cause of morbidity in urology practice in sub-Saharan Africa. In contrast, prostate disease is commonly cited as the leading cause of urological disease in most urology practices in developed countries. In Africa, the aetiology of urethral stricture disease is compounded by a high prevalence of sexually transmitted infections (STIs), increasing levels of urethral trauma and over-stretched urological services. Thus, patients with prostate disease are treated with long-stay urethral catheters for periods often up to two years. This increases the risk of urethral stricture. The predominant aetiological factor is sexually transmitted infection due to gonococcus or chlamydia. This frequently leads to long severe strictures with spongiofibrosis, especially in the anterior urethra where the periurethral glands are located. These strictures respond poorly to urethral dilatation, optical urethrotomy or primary anastomosis. The majority of strictures in Africa are best treated by open substitution urethroplasty. The gold standard has been the use of buccal mucosa graft for this substitution procedure. This procedure poses a great challenge in most centres with limited resources. In these settings, we have found that the use of a dorsal onlay free preputial graft is easy to perform and gives good results. PMID- 28836925 TI - Tuberculosis in healthcare workers, Scotland. AB - In an attempt to explore healthcare worker acquisition of tuberculosis infection, we conducted population-based surveillance of all cases recorded as healthcare workers reported to Enhanced Surveillance of Mycobacterial Infection from 2000 to 2015. Over the study period, the mean incidence rate of tuberculosis among all healthcare workers was 15.4 per 100,000 healthcare workers. However, the incidence rate of tuberculosis amongst those healthcare workers born outside the UK was 164.8 per 100,000 compared with 5.0 per 100,000 UK-born healthcare workers. Fifty-seven per cent of all non-UK-born healthcare workers were diagnosed within five years of their arrival in the UK and would have been new entrants to the NHS. An effective new entrant occupational health screening programme for latent tuberculosis infection may have prevented some of these active cases of infection. PMID- 28836926 TI - Platypnoea-orthodeoxia syndrome in the elderly: A difficult-to-make diagnosis of intracardiac right-to-left shunt. AB - Introduction Platypnea-orthodeoxia syndrome is a combination of positional dyspnoea and hypoxemia; it is caused by several cardiac, pulmonary and hepatic diseases. Case presentation In this study, we describe a 77-year-old female affected by unexplained dizziness and hypoxia that exacerbated in upright position. After diagnosing platypnea-orthodeoxia syndrome and excluding all possible causes (liver cirrhosis, acute and chronic pulmonary diseases and arteriovenous malformations), the origin of the syndrome was individuated in the presence of a patent foramen ovale with right-to-left shunt. Endovascular patent foramen ovale closure permitted the resolution of symptoms and disappearance of platypnea-orthodeoxia syndrome. Conclusion Although patent foramen ovale may be present since birth without giving clinical signs, it may represent a common enough cause of platypnea-orthodeoxia syndrome and other vascular complications in the elderly. PMID- 28836927 TI - Statin usage, vascular diagnosis and vascular risk factors in Parkinson's disease. AB - Background and aims Vascular disease is a common comorbidity in Parkinson's disease patients. Statins are potentially neuroprotective for Parkinson's disease through non-vascular mechanisms. We investigated prevailing statin use in a Parkinson's disease cohort. Methods and results Data on diagnostic indication for statins, anti-Parkinson therapy, vascular risk factors, and statin prescription, were obtained from electronic medical record review for consecutive Parkinson's disease patients. The ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network system was used to calculate future cardiovascular risk and identify those warranting statin use. Of 441 patients included, 59.9% were male, with a mean age of 68.9 years (standard deviation 10.3). One hundred and seventy four (39.5%) patients had at least one diagnostic indication for statin use, of whom 136 (78.2%) were prescribed a statin. In the 267 (60.5%) cases without a diagnostic indication, 54 (20.2%) were excluded owing to age limitations defined in ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network. Of the remaining 213, 62 (29.1%) had an ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network score in the recommended range for statin therapy, of whom 15 (24.1%) were prescribed statins. Conclusion There is suboptimal implementation of statin therapy in Parkinson's disease patients. Given the possible neuroprotective effects of statins in Parkinson's disease in addition to reducing cardiovascular risk, reasons for suboptimal implementation warrant further investigation. PMID- 28836928 TI - Delays in diagnosis are associated with poorer outcomes in adult hip dysplasia. AB - Background and Aims Developmental dysplasia of the hip is a common cause of osteoarthritis. Periacetabular osteotomy can restore femoral head coverage; however, it is reserved for patients with minimal articular degeneration. We examined the relationship between delays in diagnosis and outcomes. Methods We identified patients presenting to a hip specialist with a new diagnosis of hip dysplasia. The time taken between patients presenting to their general practitioner and attending the young adult hip clinic was established. Patients were stratified into Early, Moderate and Late Referral groups. Hip and SF-12 questionnaires were completed. Radiographs were graded according to the Tonnis classification system and the outcome following hip specialist review documented. Results Fifty-one patients were identified. Mean time from attending a general practitioner to review at the young adult hip clinic was 40.4 months. Lower hip and SF-12 scores, and higher radiological osteoarthritis grades were found in the Moderate and Late Referral groups. A higher proportion of the Moderate and Late Referral group underwent total hip arthroplasty rather than periacetabular osteotomy. Conclusion Delays in referring a patient to a hip specialist are associated with poorer outcomes. We propose pelvic radiographs are requested early by general practitioners to allow prompt diagnosis and referral to a hip specialist. PMID- 28836929 TI - Comparing Female- and Male-Perpetrated Child Sexual Abuse: A Mixed-Methods Analysis. AB - This mixed-methods study compares experiences of female- and male-perpetrated child sexual abuse using self-report data from a correctional subsample of 26 women and 25 men currently incarcerated for a sex crime against a child. First, we use bivariate and logistic regression analyses to determine whether there are differences in offender, victim, and offense characteristics between women and men who commit child sexual abuse. Second, we examine participants' open-ended responses eliciting details about their offenses. Quantitative results reveal some differences between women and men in victim characteristics, presence of a co-offender, and adulthood experiences with violence but no differences between women and men in experiences of childhood adversity, including prior child sexual abuse victimization. Qualitative results, however, suggest marked differences in the way women and men characterize their offenses. Overall, findings indicate that women and men report unique experiences with child sexual abuse perpetration and therefore would benefit from gender-specific treatment. PMID- 28836930 TI - The Fears and Futures of Boy Victims of Sexual Abuse: An Analysis of Narratives. AB - Qualitative analysis of boys' narratives about child sexual abuse revealed several themes, including memories of the abuse, the disclosure and subsequent events, the healing journey, and a meta-theme titled "fear and safety." In this article, boys' (N = 19) experiences related to fear and safety and the healing journey are explored. The narratives provided a unique look at boys' road to recovery, perceptions of counseling, and hopes for their futures. Recommendations for counseling boy victims are discussed. PMID- 28836931 TI - Liver Stiffness Measurements Using Acoustic Radiation Force Impulse in Recipients of Living-Donor and Deceased-Donor Orthotopic Liver Transplant. AB - OBJECTIVES: The aim of this study was to evaluate the diagnostic efficiency of the acoustic radiation force impulse (Siemens Medical Solutions, Erlangen, Germany) elastography in assessment of fibrosis in orthotopic liver transplant patients. MATERIALS AND METHODS: We enrolled 28 orthotopic liver transplant patients (deceased and living donors), whose biopsy decision had been prospectively given clinically. Ten acoustic radiation force impulse elastographic measurements were applied before the biopsy or within 3 days after the biopsy by 2 radiologists. After the core tissue needle biopsy, specimens of all patients were analyzed according to the modified Ishak scoring system. Measurements of acoustic radiation force impulse elastography and pathology specimen results were compared. RESULTS: From 28 biopsies, fibrosis scores of 4 biopsies were evaluated as F0 (14.3%), 16 as F1 (57.1%), 4 as F2 (14.3%), and 4 as F3 (14.3%). Mean results of acoustic radiation force impulse measurements were calculated as 1.4 +/- 0.07 in F0, 1.74 +/- 0.57 in F1, 2.19 +/- 0.7 in F2, and 2.18 +/- 0.35 in F3. There were no significant correlations of mean acoustic radiation force impulse values between the F0 versus F1 (P = .956) and F0 versus F2 stages (P = .234). A statistically significant correlation of mean acoustic radiation force impulse values was found between the F0 and F3 fibrosis stages (P = .046). CONCLUSIONS: Acoustic radiation force impulse imaging is a promising screening test for detecting significant liver fibrosis (>= F3 in modified Ishak) in living-donor or deceased-donor orthotopic liver transplant recipients. PMID- 28836932 TI - A Better Journey for Patients, a Better Deal for the NHS: The Successful Implementation of an Enhanced Recovery Program After Renal Transplant Surgery. AB - OBJECTIVES: Our aim was to apply the principles of enhanced recovery in renal transplant recipients and to assess the changes in the quality of patient care and patient satisfaction. MATERIALS AND METHODS: Our study included 286 consecutive renal transplant patients. Of these, 135 patients went through the enhanced recovery program and 151 patients had traditional recovery. Patient education and discharge planning were commenced on admission. For enhanced recovery, prolonged preoperative fasting was avoided by carbohydrate loading. Goal-directed fluid management was aided by transesophageal Doppler to avoid central line insertion. Intrathecal diamorphine and ultrasonography-guided transversus abdominis plane blocks were used to achieve adequate analgesia. Patients started oral intake a few hours postoperatively. The urinary catheter was removed 2 to 4 days after transplant. RESULTS: The postoperative patient controlled analgesia requirement for morphine was significantly reduced in the enhanced recovery versus traditional recovery group (median of 9.5 vs 47 mg; P < 0.001). The length of stay was significantly reduced for living-donor (median 5 vs 7 days; P < .001) and for deceased-donor transplant recipients (median 5 vs 8.5 days; P < 0.001) with enhanced recovery versus recipients who had traditional recovery. Implementing enhanced recovery saves L2160 per living-donor transplant and L3078 per deceased-donor transplant. In the enhanced recovery group, readmission within 10 days after transplant was 5%. CONCLUSIONS: Our service evaluation demonstrated that enhanced recovery benefits both types of renal transplant (living and deceased grafts) procedures, with excellent patient satisfaction and reduction of hospital length of stay. PMID- 28836933 TI - Intracerebral Hemorrhage Related With Penicillium Species Following Deceased Donor Liver Transplant. AB - Early or late posttransplant opportunistic infections are among the leading complications after liver transplant. The source of early posttransplant opportunistic infections is usually the patient, the implantation of an infected graft, contamination during a surgical procedure, or invasive interventions performed at the intensive care unit. A 10-year-old male patient with Wilson disease (Pediatric End-Stage Liver Disease Score of 42, Child-Pugh score of 12, total bilirubin 40 mg/dL, platelet count 55?000/mL, hemoglobin level 6.3 g/dL, albumin level 1.7 g/dL, urinary copper level 4305 MU/24 h) was closely monitored in the pediatric intensive care unit of our liver transplantation center for care of a worsened general status. A deceased-donor liver transplant was performed using a right lobe liver graft (ex vivo split) obtained through the national organ sharing network. The patient developed rightward deviation of eyes and altered consciousness after the procedure and underwent cranial magnetic resonance imaging and computerized tomography examinations. The cranial magnetic resonance image, taken on the third postoperative day, revealed lesions consistent with embolic infarction, and the computed tomography scan, taken on the eighth day, showed intracerebral hemorrhage. Decompressive craniotomy, which included hematoma drainage and catheter placement, was performed. Culture and histopathologic examinations of the hematoma material revealed a Penicillium species of fungi. However, the patient died before a definitive diagnosis was made. The aim of this report is to raise awareness on early posttransplant opportunistic infections of the central nervous system presenting with intracranial hemorrhage following liver transplant. PMID- 28836934 TI - Sirolimus Associated with Tacrolimus at Low Doses in Elderly Kidney Transplant Patients: A Prospective Randomized Controlled Trial. AB - OBJECTIVES: There is no consensus on the best immunosuppressive regimen for elderly renal transplant recipients. The objective of this study was to assess cytomegalovirus infection incidence and kidney transplant outcomes in elderly recipients treated with mammalian target of rapamycin inhibitors sirolimus/ tacrolimus at low doses compared with those receiving tacrolimus/mycophenolate sodium. MATERIALS AND METHODS: In this single-center prospective randomized study (Trial Registration No. NCT02683291), kidney transplant recipients over 60 years of age were randomly allocated into 2 groups: tacrolimus-sirolimus (21 patients) and tacrolimus-mycophenolate (23 patients). Cytomegalovirus infection rate and patient survival, biopsy-proven acute rejection, and renal function at 12 months were assessed. RESULTS: Cytomegalovirus infection rate was higher in the mycophenolate group (60.9%) than in the sirolimus group (16.7%; P = .004). The rates of biopsy-proven acute rejection, patient survival, graft survival, and estimated glomerular filtration rate over 12 months did not significantly differ between groups. CONCLUSIONS: The incidence of cytomegalovirus infection was significantly lower in the sirolimus group. The use of tacrolimus combined with sirolimus in elderly kidney transplant recipients is safe. PMID- 28836935 TI - MicroRNA-mediated responses to long-term magnesium-deficiency in Citrus sinensis roots revealed by Illumina sequencing. AB - BACKGROUND: Magnesium (Mg)-deficiency occurs most frequently in strongly acidic, sandy soils. Citrus are grown mainly on acidic and strong acidic soils. Mg deficiency causes poor fruit quality and low fruit yield in some Citrus orchards. For the first time, we investigated Mg-deficiency-responsive miRNAs in 'Xuegan' (Citrus sinensis) roots using Illumina sequencing in order to obtain some miRNAs presumably responsible for Citrus Mg-deficiency tolerance. RESULTS: We obtained 101 (69) miRNAs with increased (decreased) expression from Mg-starved roots. Our results suggested that the adaptation of Citrus roots to Mg-deficiency was related to the several aspects: (a) inhibiting root respiration and related gene expression via inducing miR158 and miR2919; (b) enhancing antioxidant system by down-regulating related miRNAs (miR780, miR6190, miR1044, miR5261 and miR1151) and the adaptation to low-phosphorus (miR6190); (c) activating transport-related genes by altering the expression of miR6190, miR6485, miR1044, miR5029 and miR3437; (d) elevating protein ubiquitination due to decreased expression levels of miR1044, miR5261, miR1151 and miR5029; (e) maintaining root growth by regulating miR5261, miR6485 and miR158 expression; and (f) triggering DNA repair (transcription regulation) by regulating miR5176 and miR6485 (miR6028, miR6190, miR6485, miR5621, miR160 and miR7708) expression. Mg-deficiency-responsive miRNAs involved in root signal transduction also had functions in Citrus Mg-deficiency tolerance. CONCLUSIONS: We obtained several novel Mg-deficiency-responsive miRNAs (i.e., miR5261, miR158, miR6190, miR6485, miR1151 and miR1044) possibly contributing to Mg-deficiency tolerance. These results revealed some novel clues on the miRNA-mediated adaptation to nutrient deficiencies in higher plants. PMID- 28836936 TI - Protective effects of heme oxygenase-1 against severe acute pancreatitis via inhibition of tumor necrosis factor-alpha and augmentation of interleukin-10. AB - BACKGROUND: Heme oxygenase-1 (HO-1) is an inducible defense gene which plays a significant role in inflammation. HO-1 protects cells and tissues through the mechanism of anti-oxidation, maintaining microcirculation and anti-inflammation. The aim of the current study is to investigate the role of HO-1 on systemic inflammatory response in severe acute pancreatitis (SAP). METHODS: Forty male Sprague-Dawley (SD) rats were randomly assigned into four groups: control group (n = 10); SAP group (n = 10), SAP model was induced by retrograde injection of 3% sodium taurocholate through pancreatic duct; HO-1 stimulation group (n = 10), SD rats were injected 75 MUg/kg hemin intraperitoneally 30 min after induction of SAP; HO-1 inhibition group (n = 10), SD rats were injected 20 MUg/kg Zinc porphyrin (Zn-PP) intraperitoneally 30 min after induction of SAP. After 24 h of SAP establishment, tissues were collected for HO-1, tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) mRNA expression, and blood samples were collected for cytokines and biochemical measurements. Meanwhile, the histopathological changes of pancreas and liver tissues were observed. RESULTS: The expression of HO-1 mRNA and protein were significantly induced by SAP in rat pancreas and liver. Hemin treatment significantly decreased oxidative stress and TNF-alpha in plasma and tissues, while the IL-10 was significantly increased. Pancreas and liver injury induced by SAP was markedly attenuated by Hemin treatment. Moreover, inhibition of HO-1 expression by Zn-PP administration aggravated the injury caused by SAP. CONCLUSIONS: Induction of HO-1 in early SAP may modulate systemic inflammatory response and prevent pancreas and nearby organs such as liver injury through inhibition of TNF-alpha and augmentation of IL-10. PMID- 28836937 TI - Identifying highly informative genetic markers for quantification of ancestry proportions in crossbred sheep populations: implications for choosing optimum levels of admixture. PMID- 28836938 TI - Identifying pleiotropic genes in genome-wide association studies from related subjects using the linear mixed model and Fisher combination function. AB - BACKGROUND: A multivariate genome-wide association test is proposed for analyzing data on multivariate quantitative phenotypes collected from related subjects. The proposed method is a two-step approach. The first step models the association between the genotype and marginal phenotype using a linear mixed model. The second step uses the correlation between residuals of the linear mixed model to estimate the null distribution of the Fisher combination test statistic. RESULTS: The simulation results show that the proposed method controls the type I error rate and is more powerful than the marginal tests across different population structures (admixed or non-admixed) and relatedness (related or independent). The statistical analysis on the database of the Study of Addiction: Genetics and Environment (SAGE) demonstrates that applying the multivariate association test may facilitate identification of the pleiotropic genes contributing to the risk for alcohol dependence commonly expressed by four correlated phenotypes. CONCLUSIONS: This study proposes a multivariate method for identifying pleiotropic genes while adjusting for cryptic relatedness and population structure between subjects. The two-step approach is not only powerful but also computationally efficient even when the number of subjects and the number of phenotypes are both very large. PMID- 28836941 TI - Reasons for missed appointments linked to a public-sector intervention targeting patients with stable chronic conditions in South Africa: results from in-depth interviews and a retrospective review of medical records. AB - BACKGROUND: Missed appointments serve as a key indicator for adherence to therapy and as such, identifying patient reasons for this inconsistency could assist in developing programmes to improve health outcomes. In this article, we explore the reasons for missed appointments linked to a centralised dispensing system in South Africa. This system dispenses pre-packed, patient-specific medication parcels for clinically stable patients to health facilities. However, at least 8% 12% of about 300,000 parcels are not collected each month. This article aims to establish whether missed appointments for collection of medicine parcels are indicative of loss-to-follow-up and also to characterise the patient and health system factors linked to missed appointments. METHODS: We applied an exploratory mixed-methods design in two overlapping research phases. This involved in-depth interviews to yield healthcare practitioners' and patients' experiences and medical record reviews. Data collection was conducted during the period 2014 2015. Qualitative data were analysed through a hybrid process of inductive and deductive thematic analysis which integrated data-driven and theory-driven codes. Data from medical records (N = 89) were analysed in MS excel using both descriptive statistics and textual descriptions. RESULTS: Review of medical records suggests that the majority of patients (67%) who missed original appointments later presented voluntarily to obtain medicines. This could indicate a temporal effect of some barriers. The remaining 33% revealed a range of CDU implementation issues resulting from, among others, erroneous classification of patients as defaulters. Interviews with patients revealed the following reasons for missed appointments: temporary migration, forgetting appointments, work commitments and temporary switch to private care. Most healthcare practitioners confirmed these barriers to collection but perceived that some were beyond the scope of health services. In addition, healthcare practitioners also identified a lack of patient responsibility, under-utilisation of medicines and use of plural healthcare sources (e.g. traditional healers) as contributing to missed appointments. CONCLUSION: We suggest developing a patient care model reflecting the local context, attention to improving CDU's implementation processes and strengthening information systems in order to improve patient monitoring. This model presents lessons for other low-and-middle income countries with increasing need for dispensing of medicines for chronic illnesses. PMID- 28836942 TI - Erratum to: Identification of endonuclease domain-containing 1 as a novel tumor suppressor in prostate cancer. PMID- 28836939 TI - Genetic influences on the human oral microbiome. AB - BACKGROUND: The human oral microbiome is formed early in development. Its composition is influenced by environmental factors including diet, substance use, oral health, and overall health and disease. The influence of human genes on the composition and stability of the oral microbiome is still poorly understood. We studied both environmental and genetic characteristics on the oral microbiome in a large twin sample as well as in a large cohort of unrelated individuals. We identify several significantly heritable features of the oral microbiome. The heritability persists in twins even when their cohabitation changes. The heritability of these traits correlates with the cumulative genetic contributions of over half a million single nucleotide sequence variants measured in a different population of unrelated individuals. Comparison of same-sex and opposite sex cotwins showed no significant differences. We show that two new loci on chromosomes 7 and 12 are associated with the most heritable traits. RESULTS: An analysis of 752 twin pairs from the Colorado Twin Registry, shows that the beta-diversity of monozygotic twins is significantly lower than for dizygotic or unrelated individuals. This is independent of cohabitation status. Intraclass correlation coefficients of nearly all taxa examined were higher for MZ than DZ twin pairs. A comparison of individuals sampled over 2-7 years confirmed previous reports that the oral microbiome remains relatively more stable in individuals over that time than to unrelated people. Twin modeling shows that a number of microbiome phenotypes were more than 50% heritable consistent with the hypothesis that human genes influence microbial populations. To identify loci that could influence microbiome phenotypes, we carried out an unbiased GWAS analysis which identified one locus on chromosome 7 near the gene IMMPL2 that reached genome wide significance after correcting for multiple testing. Another locus on chromosome 12 near the non-coding RNA gene INHBA-AS1 achieved genome-wide significance when analyzed using KGG4 that sums SNP significance across coding genes. DISCUSSION: Using multiple methods, we have demonstrated that some aspects of the human oral microbiome are heritable and that with a relatively small sample we were able to identify two previously unidentified loci that may be involved. PMID- 28836940 TI - Genome-wide identification of novel intergenic enhancer-like elements: implications in the regulation of transcription in Plasmodium falciparum. AB - BACKGROUND: The molecular mechanisms of transcriptional regulation are poorly understood in Plasmodium falciparum. In addition, most of the genes in Plasmodium falciparum are transcriptionally poised and only a handful of cis-regulatory elements are known to operate in transcriptional regulation. Here, we employed an epigenetic signature based approach to identify significance of previously uncharacterised intergenic regions enriched with histone modification marks leading to discovery of enhancer-like elements. RESULTS: We found that enhancer like elements are significantly enriched with H3K4me1, generate unique non-coding bi-directional RNAs and majority of them can function as cis-regulators. Furthermore, functional enhancer reporter assay demonstrates that the enhancer like elements regulate transcription of target genes in Plasmodium falciparum. Our study also suggests that the Plasmodium genome segregates functionally related genes into discrete housekeeping and pathogenicity/virulence clusters, presumably for robust transcriptional control of virulence/pathogenicity genes. CONCLUSIONS: This report contributes to the understanding of parasite regulatory genomics by identification of enhancer-like elements, defining their epigenetic and transcriptional features and provides a resource of functional cis-regulatory elements that may give insights into the virulence/pathogenicity of Plasmodium falciparum. PMID- 28836943 TI - An efficient unified model for genome-wide association studies and genomic selection. AB - BACKGROUND: A quantitative trait is controlled both by major variants with large genetic effects and by minor variants with small effects. Genome-wide association studies (GWAS) are an efficient approach to identify quantitative trait loci (QTL), and genomic selection (GS) with high-density single nucleotide polymorphisms (SNPs) can achieve higher accuracy of estimated breeding values than conventional best linear unbiased prediction (BLUP). GWAS and GS address different aspects of quantitative traits, but, as statistical models, they are quite similar in their description of the genetic mechanisms that underlie quantitative traits. METHODS: Here, we propose a stepwise linear regression mixed model (StepLMM) to unify GWAS and GS in a single statistical model. First, the variance components of the genomic-BLUP (GBLUP) model are estimated. Then, in the SNP selection step, the linear mixed model (LMM) for GWAS is equivalently transformed into a simple linear regression to improve computation speed, and the most significant SNP is selected and included into the evaluation model. In the SNP dropping step, the SNPs in the evaluation model are tested according to the standard errors of their estimated effects. If non-significant SNPs are present, the least significant one is dropped from the model and variance components are re-estimated. We used extended Bayesian information criteria (eBIC) to evaluate the model optimization, i.e. the model with the smallest eBIC is the final one and includes only significant SNPs. RESULTS: We simulated scenarios with different heritabilities with 100 QTL. StepLMM estimated heritability accurately and mapped QTL precisely. Genomic prediction accuracy was much higher with StepLMM than with GBLUP. The comparison of StepLMM with other GWAS and GS methods based on a dataset from the 16th QTLMAS Workshop showed that StepLMM had medium mapping power, the lowest rate of false positives for QTL mapping, and the highest accuracy for genomic prediction. CONCLUSIONS: StepLMM is a combination of GWAS and GBLUP. GWAS and GBLUP are beneficial to each other in a single statistical model, GWAS improves genomic prediction accuracy, while GBLUP increases mapping precision and decreases the rate of false positives of GWAS. StepLMM has a high performance in both GWAS and GS and is feasible for agricultural breeding programs and human genetic studies. PMID- 28836944 TI - Simultaneous fitting of genomic-BLUP and Bayes-C components in a genomic prediction model. AB - BACKGROUND: The rapid adoption of genomic selection is due to two key factors: availability of both high-throughput dense genotyping and statistical methods to estimate and predict breeding values. The development of such methods is still ongoing and, so far, there is no consensus on the best approach. Currently, the linear and non-linear methods for genomic prediction (GP) are treated as distinct approaches. The aim of this study was to evaluate the implementation of an iterative method (called GBC) that incorporates aspects of both linear [genomic best linear unbiased prediction (G-BLUP)] and non-linear (Bayes-C) methods for GP. The iterative nature of GBC makes it less computationally demanding similar to other non-Markov chain Monte Carlo (MCMC) approaches. However, as a Bayesian method, GBC differs from both MCMC- and non-MCMC-based methods by combining some aspects of G-BLUP and Bayes-C methods for GP. Its relative performance was compared to those of G-BLUP and Bayes-C. METHODS: We used an imputed 50 K single nucleotide polymorphism (SNP) dataset based on the Illumina Bovine50K BeadChip, which included 48,249 SNPs and 3244 records. Daughter yield deviations for somatic cell count, fat yield, milk yield, and protein yield were used as response variables. RESULTS: GBC was frequently (marginally) superior to G-BLUP and Bayes-C in terms of prediction accuracy and was significantly better than G BLUP only for fat yield. On average across the four traits, GBC yielded a 0.009 and 0.006 increase in prediction accuracy over G-BLUP and Bayes-C, respectively. Computationally, GBC was very much faster than Bayes-C and similar to G-BLUP. CONCLUSIONS: Our results show that incorporating some aspects of G-BLUP and Bayes C in a single model can improve accuracy of GP over the commonly used method: G BLUP. Generally, GBC did not statistically perform better than G-BLUP and Bayes C, probably due to the close relationships between reference and validation individuals. Nevertheless, it is a flexible tool, in the sense, that it simultaneously incorporates some aspects of linear and non-linear models for GP, thereby exploiting family relationships while also accounting for linkage disequilibrium between SNPs and genes with large effects. The application of GBC in GP merits further exploration. PMID- 28836945 TI - Awareness and knowledge of glaucoma and associated factors among adults: a cross sectional study in Gondar Town, Northwest Ethiopia. AB - BACKGROUND: Raising public awareness and knowledge about glaucoma is a key for early case identification and prevention of blindness. However, awareness and knowledge about glaucoma is unknown at community level, making provision of interventions difficult. This study was intended to assess the awareness and knowledge of adults about glaucoma and the factors affecting it in Gondar town, Northwest Ethiopia. METHODS: Community based cross - sectional study was conducted on 701 adults 35 and above years in Gondar from April 12-30, 2016. Multistage sampling technique was used to select study participants. Interviewer administered pretested structured questionnaire was used to collect data after verbal informed consent. Data were entered into EpiData version 3.1 and analyzed by Statistical Package for Social Sciences version 20. Bivariate and multivariate logistic regression models and Odds ratio with 95% interval were used to identify factors. P-value <0.05 was considered statistically significant. RESULTS: Seven hundred one adults age 35 and above years were participated with a response rate of 99.3%. The male to female ratio was 1:1.6 with median age of 48 years with interqurtile range of 20. The proportion of awareness was 35.1% (95% CI: 31.5%, 38.6%). Good knowledge was demonstrated in 49.6% (95%CI: 43.3%, 55%) of glaucoma aware participants. Education (primary [AOR: 3.21; 1.73, 5.95], secondary [AOR: 4.34; 2.30, 8.22]; college and above [AOR: 9.82; 4.27, 22.60]) and having eye examination [AOR: 2.78; 1.86, 4.15] were positively associated with awareness of glaucoma whereas older age (65 -74 years [AOR: 0.31(0.21, 0.76]) was inversely related. Level of Education (primary[AOR:2.83;1.04,7.71],secondary[AOR:3.45;1.33,9.41],college and above [AOR: 4.86;1.82,12,99] and having eye examination [AOR: 2.61;1.53,4.45] were significantly associated with knowledge. CONCLUSION: The study has indicated higher level of awareness and knowledge about glaucoma in urban communities than previous studies. It has also identified educational status, eye examination at least once in life are related with better awareness and knowledge. The present awareness and knowledge should be enhanced through public oriented glaucoma education via mass media and incorporating eye check up as a routine in older people. PMID- 28836946 TI - Persistence with antihypertensives in uncomplicated treatment-naive very elderly patients: a nationwide population-based study. AB - BACKGROUND: Limited studies have evaluated the medication-taking behavior in very elderly hypertensive patients. The aim of this study was to evaluate the persistence and adherence with antihypertensive agents in treatment-naive patients, along with other related factors, according to age. METHODS: Adult (19 64 years), elderly (65-79 years), and very elderly (>=80 years) uncomplicated hypertensive patients starting antihypertensive monotherapy were identified from the National Health Insurance claims database. The first-year treatment persistence and adherence rates measured using the medication possession ratio were assessed and compared in these three age cohorts. RESULTS: After propensity score matching, three age cohorts with 6689 patients each were assembled from 228,925 uncomplicated hypertensive patients who began antihypertensive monotherapy in 2012. The treatment persistence and adherence rates over the first year were the lowest in the very elderly (59.5% and 62.8%, respectively) and highest in the elderly (65.2% and 67.9%, respectively) patients among the three age cohorts (p < 0.001). The adjusted risk for treatment non-persistence was significantly higher in the very elderly (adjusted hazard ratio, 1.20; 95% confidence interval, 1.13-1.27) compared with the elderly. Having more comorbidities, being a beneficiary of medical aid, and having a diagnosis of dementia were unique positive predictors for treatment persistence in the very elderly, along with common predictors such as female sex, dyslipidemia, and an initially chosen antihypertensive therapeutic class other than beta blockers and thiazide diuretics. CONCLUSIONS: Very elderly patients were less likely to continue antihypertensive therapy over the first year compared with their younger counterparts. Our findings suggest that a low comorbidity index and lack of medical aid support negatively affect the treatment persistence in this population. PMID- 28836947 TI - Country and regional variations in purchase prices for essential cancer medications. AB - BACKGROUND: Accessibility to essential cancer medications in low- and middle income countries is threatened by insufficient availability and affordability. The objective of this study is to characterize variation in transactional prices for essential cancer medications across geographies, medication type, and time. METHODS: Drug purchase prices for 19 national and international buyers (representing 29 total countries) between 2010 and 2014 were obtained from Management Sciences for Health. Median values for drug pricing were computed, to address outliers in the data. For comparing purchase prices across geographic units, medications, and over time; Mann-Whitney U tests were used to compare two groups, Kruskal Wallis H tests were used to compare more than two groups, and linear regression was used to compare across continuous independent variables. RESULTS: During the five-year data period examined, the median price paid for a package of essential cancer medication was $12.63. No significant differences in prices were found based on country-level wealth, country-level disease burden, drug formulation, or year when medication was purchased. Statistical tests found significant differences in prices paid across countries, regions, individual medications, and medication categories. Specifically, countries in the Africa region appeared to pay more for a package of essential cancer medication than countries in the Latin America region, and cancer medications tended to be more expensive than anti-infective medications and cardiovascular medications. CONCLUSIONS: Though preliminary, our study found evidence of variation in prices paid by health systems to acquire essential cancer medications. Primarily, variations in pricing based on geographic location and cancer medication type (including when comparing to essential medicines that treat cardiovascular and infectious diseases) indicate that these factors may impact availability, affordability and access to essential cancer drugs. These factors should be taken into consideration when countries assess formulary decisions, negotiate drug procurement terms, and when formulating health and cancer policy. PMID- 28836948 TI - IL-8 and IP-10 expression from human bronchial epithelial cells BEAS-2B are promoted by Streptococcus pneumoniae endopeptidase O (PepO). AB - BACKGROUND: The bronchial epithelium serves as the first defendant line of host against respiratory inhaled pathogens, mainly through releasing chemokines (e.g. interleukin-8 (IL-8), interferon-induced protein 10 (IP-10) etc.) responsible for neutrophil or lymphocyte recruitment to promote the clearance of inhaled pathogens including Streptococcus pneumoniae (S. pneumoniae). Previous studies have shown that IL-8 expression is induced by pneumococcal virulence factors (e.g. pneumolysin, peptidoglycan-polysaccharides, pneumococcal surface protein A (PspA) etc.), which contributes to the pathogenesis of pneumonia. Whether other pneumococcal virulence factors are involved in inducing chemokines expression in epithelium is still unknown. RESULTS: We studied the effect of PepO, a widely expressed and newly discovered pneumococcal virulence protein, on the release of proinflammatory cytokines, IL-8 and IP-10, from human bronchial epithelial cell line BEAS-2B and identified the relevant signaling pathways. Incubation of BEAS 2B with PepO resulted in increased synthesis and release of IL-8 and IP-10 in a dose and time independent manner. We also detected the increased and sustained expression of TLR2 and TLR4 transcripts in BEAS-2B stimulated by PepO. PepO activation leaded to the phosphorylation of MAPKs, Akt and p65. Pharmacologic inhibitors of MAPKs, PI3K and IkappaB-alpha phosphorylation attenuated IL-8 release, while IP-10 production was just suppressed by inhibitors of IkappaB alpha phosphorylation, PI3K and P38 MAPK. CONCLUSION: These results suggest that PepO enhances IL-8 and IP-10 production in BEAS-2B in a MAPKs-PI3K/Akt-p65 dependent manner, which may play critical roles in the pathogenesis of pneumonia. PMID- 28836949 TI - 2-Dimensional Speckle Tracking Echocardiography predicts severe coronary artery disease in women with normal left ventricular function: a case-control study. AB - BACKGROUND: Women who have coronary artery disease (CAD) often present with atypical symptoms that may lead to misdiagnosis. We assessed strain, systolic strain rate and left ventricular dyssynchrony with 2- dimensional- speckle tracking echocardiography to evaluate its use as a non-invasive method for detecting CAD in women with normal ejection fraction compared with healthy women controls with a normal angiogram. METHODS: We included 35 women with CAD confirmed by coronary angiography and a positive exercise stress echocardiography and 35 women in a control group with a low pretest probability of CAD, normal angiogram and a normal stress echocardiography with normal EF. RESULTS: Statistically significant 2D-STE findings for the CAD vs control groups were as follows for the mean of: global circumferential strain (CS) (-19.4% vs -22.4%, P = .02); global radial S (49% vs 34%, P = .03); global radial SR (2.4 s-1 vs 1.9 s 1, P = .05); global longitudinal LV S (GLS) (-14.3% vs -17.2%, P < .001). For mechanical dyssynchrony, SD of the GLS time-to-peak (TTP) was computed (99 vs 33 ms, P < .001). The receiver operating characteristic and area under the curve (AUC) were calculated. A cutoff value of 45 ms for 1 SD of the longitudinal S TTP had 97% sensitivity and 89% specificity (AUC, 0.96). GLS cutoff value of -15.87% had 71% sensitivity and 74% specificity; AUC, 0.74 in differentiating CAD and control groups. The combined GLS, CS, and SD of the longitudinal S TTP had an AUC of 0.96 (sensitivity 97%, specificity 86%). Interclass correlations of the GLS segment and GLS TTP measurements were 0.49 (95% CI, 0.227-0.868) and 0.74 (95% CI, 0.277-0.926), respectively. CONCLUSION: In women with a normal echocardiogram and LVEF, CAD can be identified by dyssynchrony and abnormal strain values, as evidenced by 2D-STE. PMID- 28836950 TI - Concurrent chemoradiotherapy with or without cetuximab for stage II to IVb nasopharyngeal carcinoma: a case-control study. AB - BACKGROUND: This study aimed to evaluate the long-term outcome and toxicities in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by concurrent chemoradiotherapy (CCRT) with/without adding cetuximab. METHODS: A total of 62 patients treated with CCRT plus cetuximab were matched with 124 patients treated with CCRT alone by age, sex, pathological type, T category, N category, disease stage, radiotherapy (RT) technique, Epstein-Barr virus (EBV) DNA levels, and Eastern Cooperative Oncology Group (ECOG). Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method and log-rank test. Treatment toxicities were clarified and compared between two groups. RESULTS: A total of 186 well-balanced stage II to IV NPC patients were retrospectively analyzed (median follow-up, 76 months). Compared to CCRT alone, adding cetuximab resulted in more grade 3 to 4 radiation mucositis (51.6% vs. 23.4%; P < 0.001). No differences were found between the CCRT + cetuximab group and the CCRT group in 5-year OS (89.7% vs. 90.7%, P = 0.386), 3 year PFS (83.9% vs. 88.7%, P = 0.115), the 3-year LRFS (95.0% vs. 96.7%, P = 0.695), and the 3-year DMFS (88.4% vs 91.9%, P = 0.068). Advanced disease stage was the independent prognostic factor predicting poorer OS and PFS. CONCLUSION: Adding cetuximab to CCRT did not significantly improve benefits in survival in stage II to IV NPC and exacerbated acute mucositis and acneiform rash. Further investigations are warranted. PMID- 28836951 TI - Hospitalizations realted to herpes zoster infection in the Canary Islands, Spain (2005-2014). AB - BACKGROUND: Herpes zoster is an important problem of public health especially among the elderly in Spain. METHODS: A population-based retrospective epidemiological study to estimate the burden of herpes zoster requiring hospitalization in the Canary Islands, Spain was conducted by using data from the national surveillance system for hospital data, Conjunto Minimo Basico de Datos. Records of all patients admitted to hospital with a diagnosis of herpes zoster in any position and cases of primary diagnosis (ICD-9-MC codes 053.0-053.9) during a 10-year period (2005-2014), were selected. RESULTS: A total of 1088 hospitalizations with a primary or secondary diagnosis of herpes zoster were identified during the study period. Annually there were 6.99 hospitalizations by herpes zoster per 100,000 population. It increases with age reaching a maximum in persons >=85 years of age (43.98 admissions per 100,000). Average length of hospitalization was 16 days and 73 patients died, with a case-fatality rate of 4.03%. In 22% of the cases hospitalized, herpes zoster was the primary diagnosis. CONCLUSION: The hospitalization burden of herpes zoster in adults in the Canary Islands was still important during the last decade and justify the implementation of preventive measures, like vaccination in the elderly or other high risk groups to reduce the most severe cases of the disease. PMID- 28836952 TI - PR interval prolongation in coronary patients or risk equivalent: excess risk of ischemic stroke and vascular pathophysiological insights. AB - BACKGROUND: Whether PR prolongation independently predicts new-onset ischemic events of myocardial infarction and stroke was unclear. Underlying pathophysiological mechanisms of PR prolongation leading to adverse cardiovascular events were poorly understood. We investigated the role of PR prolongation in pathophysiologically-related adverse cardiovascular events and underlying mechanisms. METHODS: We prospectively investigated 597 high-risk cardiovascular outpatients (mean age 66 +/- 11 yrs.; male 67%; coronary disease 55%, stroke 22%, diabetes 52%) for new-onset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and cardiovascular death. Vascular phenotype was determined by carotid intima-media thickness (IMT). RESULTS: PR prolongation >200 ms was present in 79 patients (13%) at baseline. PR prolongation >200 ms was associated with significantly higher mean carotid IMT (1.05 +/- 0.37 mm vs 0.94 +/- 0.28 mm, P = 0.010). After mean study period of 63 +/- 11 months, increased PR interval significantly predicted new-onset ischemic stroke (P = 0.006), CHF (P = 0.040), cardiovascular death (P < 0.001), and combined cardiovascular endpoints (P < 0.001) at cut-off >200 ms. Using multivariable Cox regression, PR prolongation >200 ms independently predicted new onset ischemic stroke (HR 8.6, 95% CI: 1.9-37.8, P = 0.005), cardiovascular death (HR 14.1, 95% CI: 3.8-51.4, P < 0.001) and combined cardiovascular endpoints (HR 2.4, 95% CI: 1.30-4.43, P = 0.005). PR interval predicts new-onset MI at the exploratory cut-off >162 ms (C-statistic 0.70, P = 0.001; HR: 8.0, 95% CI: 1.65 38.85, P = 0.010). CONCLUSIONS: PR prolongation strongly predicts new-onset ischemic stroke, MI, cardiovascular death, and combined cardiovascular endpoint including CHF in coronary patients or risk equivalent. Adverse vascular function may implicate an intermediate pathophysiological phenotype or mediating mechanism. PMID- 28836954 TI - Randomized controlled trial to evaluate the effects of personalized prediction and adaptation tools on treatment outcome in outpatient psychotherapy: study protocol. AB - BACKGROUND: Psychotherapy is successful for the majority of patients, but not for every patient. Hence, further knowledge is needed on how treatments should be adapted for those who do not profit or deteriorate. In the last years prediction tools as well as feedback interventions were part of a trend to more personalized approaches in psychotherapy. Research on psychometric prediction and feedback into ongoing treatment has the potential to enhance treatment outcomes, especially for patients with an increased risk of treatment failure or drop-out. METHODS/DESIGN: The research project investigates in a randomized controlled trial the effectiveness as well as moderating and mediating factors of psychometric feedback to therapists. In the intended study a total of 423 patients, who applied for a cognitive-behavioral therapy at the psychotherapy clinic of the University Trier and suffer from a depressive and/or an anxiety disorder (SCID interviews), will be included. The patients will be randomly assigned either to one therapist as well as to one of two intervention groups (CG, IG2). An additional intervention group (IG1) will be generated from an existing archival data set via propensity score matching. Patients of the control group (CG; n = 85) will be monitored concerning psychological impairment but therapists will not be provided with any feedback about the patients assessments. In both intervention groups (IG1: n = 169; IG2: n = 169) the therapists are provided with feedback about the patients self-evaluation in a computerized feedback portal. Therapists of the IG2 will additionally be provided with clinical support tools, which will be developed in this project, on the basis of existing systems. Therapists will also be provided with a personalized treatment recommendation based on similar patients (Nearest Neighbors) at the beginning of treatment. Besides the general effectiveness of feedback and the clinical support tools for negatively developing patients, further mediating and moderating variables on this feedback effect should be examined: treatment length, frequency of feedback use, therapist effects, therapist's experience, attitude towards feedback as well as congruence of therapist's and patient's evaluation concerning the progress. Additional procedures will be implemented to assess treatment adherence as well as the reliability of diagnosis and to include it into the analyses. DISCUSSION: The current trial tests a comprehensive feedback system which combines precision mental health predictions with routine outcome monitoring and feedback tools in routine outpatient psychotherapy. It also adds to previous feedback research a stricter design by investigating another repeated measurement CG as well as a stricter control of treatment integrity. It also includes a structured clinical interview (SCID) and controls for comorbidity (within depression and anxiety). This study also investigates moderators (attitudes towards, use of the feedback system, diagnoses) and mediators (therapists' awareness of negative change and treatment length) in one study. TRIAL REGISTRATION: Current Controlled Trials NCT03107845 . Registered 30 March 2017. PMID- 28836953 TI - Efficacy and safety of transcatheter aortic valve replacement in aortic stenosis patients at low to moderate surgical risk: a comprehensive meta-analysis. AB - BACKGROUND: Recently, transcatheter aortic valve replacement (TAVR) has become the procedure of choice in high surgical risk patients with aortic stenosis (AS). However, its value is still debated in operable AS cases. We performed this meta analysis to compare the safety and efficacy of TAVR to surgical aortic valve replacement (SAVR) in low-to-moderate surgical risk patients with AS. METHODS: A systematic search of five authentic databases retrieved 11 eligible studies (20,056 patients). Relevant Data were pooled as risk ratios (RRs) or standardized mean differences (SMD), with their 95% confidence interval, using Comprehensive Meta-Analysis and RevMan software for windows. RESULTS: At one-year of follow-up, the pooled effect-estimates showed no significant difference between TAVR and SAVR groups in terms of all-cause mortality (RR 1.02, 95% CI [0.83, 1.26], stroke (RR 0.83, 95%CI [0.56, 1.21]), myocardial infarction (RR 0.82, 95% CI [0.57, 1.19]), and length of hospital stay (SMD -0.04, 95% CI [-0.34, 0.26]). The incidence of major bleeding (RR 0.45, 95% CI [0.24, 0.86]) and acute kidney injury (RR 0.52, 95% CI [0.30, 0.88]) was significantly lower in the TAVR group, compared to the SAVR group. However, TAVR was associated with a higher risk of permanent pacemaker implantation (RR 2.57, 95% CI [1.36, 4.86]), vascular-access complications at 1 year (RR 1.99, 95%CI [1.04, 3.80]), and paravalvular aortic regurgitation at 30 days (RR 3.90, 95% CI [1.25, 12.12]), compared to SAVR. CONCLUSIONS: Due to the comparable mortality rates in SAVR and TAVR groups and the lower risk of life-threatening complications in the TAVR group, TAVR can be an acceptable alternative to SAVR in low-to-moderate risk patients with AS. However, larger trials with longer follow-up periods are required to compare the long-term outcomes of both techniques. PMID- 28836955 TI - Prevalence of hepatitis B in people living with HIV/AIDS in Latin America and the Caribbean: a systematic review and meta-analysis. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major cause of chronic liver disease worldwide. In immunocompromised patients, the chronicity rates of HBV infection are higher, but the rates of hepatitis Be antigen (HBeAg) and HBsAg loss and seroconversion to anti-HBe and anti-HBs are lower than those in immunocompetent subjects. This study aimed to evaluate articles on the prevalence of HBsAg in people living with human immunodeficiency virus (HIV) /AIDS (PLWHA) in Latin America and the Caribbean (LAC). METHODS: We searched the PubMed, Latin American and Caribbean Health Sciences, and Embase databases for studies up to November 2016 on infection with HIV and HBV in LAC without period or language restrictions. We did not include case reports, case series, review articles, comments, or studies with a sample size smaller than 100. We also evaluated the quality of the articles using a list of criteria totaling 21 items. RESULTS: Of the 28 selected articles (n = 18,457) published from 1999 to 2016, 18 studies (64.3%) were from Brazil, 3 (10.7%) were from Argentina, 2 (7.1%) were from Chile, 2 (7.1%) were from Cuba, 1 (3.6%) was from Colombia, 1 (3.6%) was from Venezuela, and 1 (3.6%) was from Jamaica. The mean score for the assessment of the study quality was 11.6 (range: 8-16). The estimated pooled prevalence of HBsAg among PLWHA in the selected studies was 7.0% (95% CI 7.0-7.0%). The pooled prevalence of HBsAg was 8.0% (95% CI 8.0-9.0%) in the studies published from 1999 to 2006 and 6.0% (95% CI 5.0-6.0%) in the studies published during the later timeframe. CONCLUSIONS: The results of this review indicate the need to increase the investment in preventive measures against hepatitis B, particularly when the impact of adequate vaccination in this population is considered. Future studies with larger sample sizes are needed in LAC to determine the true prevalence of hepatitis B throughout the region and to clarify and address the risk factors associated with the acquisition of infection. PMID- 28836956 TI - Comparison of astigmatism prediction error taken with the Pentacam measurements, Baylor nomogram, and Barrett formula for toric intraocular lens implantation. AB - BACKGROUND: To evaluate and compare the astigmatism prediction errors taken with the Pentacam measurements, Baylor nomogram, and Barrett formula for toric intraocular lens (IOL) implantation. METHODS: Phacoemulsification with toric Precizon IOL implantation was performed in 41 eyes with corneal astigmatism (range, 1 to 5 diopters (D)) determined by IOLMaster and SimK on Pentacam. Preoperative corneal astigmatism measurements were obtained from IOLMaster readings (IOLMaster, Baylor-IOLMaster, and Barrett-IOLMaster) and Pentacam readings (SimK, Baylor-SimK, Barrett-SimK, wavefront, true net power, total corneal refractive power, and vector derived by manual vector summation using corneal front and back astigmatism). Prediction error and intraclass correlation coefficient (ICC) between the measured (or calculated) astigmatism by IOLMaster and Pentacam and the estimated corneal astigmatism estimated by IOL toricity power and residual astigmatism were determined. RESULTS: The centroid errors in prediction error with IOLMaster, SimK, Baylor-IOLMaster, Baylor-SimK, Barrett IOLMaster, Barrett-SimK, wavefront, true net power, total corneal refractive power, and vector were 0.59@103, 0.61 @103, 0.37@161, 0.41@162, 0.24@171, 0.36@162, 0.42@106, 0.04@8, 0.07@82, and 0.03@82, respectively, in with-the-rule (WTR) astigmatism eyes at postoperative 3-month. They were 0.22@87, 0.20@74, 0.16@21, 0.54@10, 0.43@3, 0.33@19, 0.51@25, 0.31@58, 0.29@50, and 0.14@50 in against-the-rule (ATR) astigmatism eyes. Of the ten modalities, vector showed the lowest WTR astigmatism prediction error and the highest ICC between the predicted and the estimated corneal astigmatism for both WTR and ATR eyes. CONCLUSION: Vector summation using anterior and posterior corneal surface power taken with the Pentacam yields the least astigmatism prediction error and is a promising tool for determining toric IOL cylinder power. PMID- 28836957 TI - The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. AB - BACKGROUND: Schizophrenia is a chronic and debilitating neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. Cariprazine is a potent dopamine D3 and D2 receptor partial agonist that is FDA-approved in the US for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults; the recommended dose range is 1.5-6 mg/d. METHODS: To further characterize the long-term safety of cariprazine, data from two 48-week open-label, flexible-dose extension studies were pooled for post hoc analyses. Outcomes were evaluated in the pooled safety population (patients who received >=1 dose of cariprazine during an open-label extension period); findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5-3, 4.5-6, and 9 mg/d). RESULTS: Of the 679 patients in the overall cariprazine safety population, 40.1% completed the study. The only adverse events (AEs) leading to discontinuation of >=2% of patients in any dose group were akathisia, worsening of schizophrenia, and psychotic disorder. Treatment-emergent AEs (TEAEs) of akathisia, insomnia, weight increased, and headache were reported in >=10% of the overall population. Mean prolactin levels decreased in all dose groups (overall, 15.4 ng/mL). Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed; no dose-response relationship was observed across groups. Mean total (-5.3 mg/dL), low-density lipoprotein (-3.5 mg/dL), and high-density lipoprotein (-0.8 mg/dL) cholesterol levels decreased; no dose response relationship was observed for metabolic parameters. Mean change in body weight was 1.58 kg; body weight increase and decrease >=7% occurred in 27% and 11% of patients, respectively. Mean changes in cardiovascular parameters, including blood pressure and pulse, were generally not considered clinically significant. EPS-related TEAEs that occurred in >=5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder. CONCLUSION: In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/d for schizophrenia. CLINICAL TRIALS REGISTRATION: NCT01104792, NCT00839852. PMID- 28836958 TI - Day2day: investigating daily variability of magnetic resonance imaging measures over half a year. AB - BACKGROUND: Most studies of brain structure and function, and their relationships to cognitive ability, have relied on inter-individual variability in magnetic resonance (MR) images. Intra-individual variability is often ignored or implicitly assumed to be equivalent to the former. Testing this assumption empirically by collecting enough data on single individuals is cumbersome and costly. We collected a dataset of multiple MR sequences and behavioural covariates to quantify and characterize intra-individual variability in MR images for multiple individuals. METHODS AND DESIGN: Eight participants volunteered to undergo brain scanning 40-50 times over the course of 6 months. Six participants completed the full set of sessions. T1-weighted, T2*-weighted during rest, T2 weighted high-resolution hippocampus, diffusion-tensor imaging (DTI), and proton magnetic resonance spectroscopy sequences were collected, along with a rich set of stable and time-varying physical, behavioural and physiological variables. Participants did not change their lifestyle or participated in any training programs during the period of data collection. CONCLUSION: This imaging dataset provides a large number of MRI scans in different modalities for six participants. It enables the analysis of the time course and correlates of intra individual variability in structural, chemical, and functional aspects of the human brain. PMID- 28836959 TI - Strategies for improving approximate Bayesian computation tests for synchronous diversification. AB - BACKGROUND: Estimating the variability in isolation times across co-distributed taxon pairs that may have experienced the same allopatric isolating mechanism is a core goal of comparative phylogeography. The use of hierarchical Approximate Bayesian Computation (ABC) and coalescent models to infer temporal dynamics of lineage co-diversification has been a contentious topic in recent years. Key issues that remain unresolved include the choice of an appropriate prior on the number of co-divergence events (Psi), as well as the optimal strategies for data summarization. METHODS: Through simulation-based cross validation we explore the impact of the strategy for sorting summary statistics and the choice of prior on Psi on the estimation of co-divergence variability. We also introduce a new setting (beta) that can potentially improve estimation of Psi by enforcing a minimal temporal difference between pulses of co-divergence. We apply this new method to three empirical datasets: one dataset each of co-distributed taxon pairs of Panamanian frogs and freshwater fishes, and a large set of Neotropical butterfly sister-taxon pairs. RESULTS: We demonstrate that the choice of prior on Psi has little impact on inference, but that sorting summary statistics yields substantially more reliable estimates of co-divergence variability despite violations of assumptions about exchangeability. We find the implementation of beta improves estimation of Psi, with improvement being most dramatic given larger numbers of taxon pairs. We find equivocal support for synchronous co divergence for both of the Panamanian groups, but we find considerable support for asynchronous divergence among the Neotropical butterflies. CONCLUSIONS: Our simulation experiments demonstrate that using sorted summary statistics results in improved estimates of the variability in divergence times, whereas the choice of hyperprior on Psi has negligible effect. Additionally, we demonstrate that estimating the number of pulses of co-divergence across co-distributed taxon pairs is improved by applying a flexible buffering regime over divergence times. This improves the correlation between Psi and the true variability in isolation times and allows for more meaningful interpretation of this hyperparameter. This will allow for more accurate identification of the number of temporally distinct pulses of co-divergence that generated the diversification pattern of a given regional assemblage of sister-taxon-pairs. PMID- 28836960 TI - The feasibility and benefit of a brief psychosocial intervention in addition to early palliative care in patients with advanced cancer to reduce depressive symptoms: a pilot randomized controlled clinical trial. AB - BACKGROUND: The aim of this study was to assess the feasibility and potential benefit of a brief psychosocial intervention based on cognitive-behavioral therapy performed in addition to early palliative care (PC) in the reduction of depressive symptoms among patients with advanced cancer. METHODS: An open-label randomized phase II clinical trial with two intervention arms and one control group. Patients with advanced cancer starting palliative chemotherapy and who met the selection criteria were included. The participants were randomly allocated to three arms: arm A, five weekly sessions of psychosocial intervention combined with early PC; arm B, early PC only; and arm C, standard cancer treatment. Feasibility was investigated by calculating rates (%) of inclusion, attrition, and contamination (% of patients from Arm C that received PC). Scores of depression (primary aim), anxiety, and quality of life were measured at baseline and 45, 90, 120, and 180 days after randomization. RESULTS: From the total of 613 screened patients (10.3% inclusion rate), 19, 22, and 22 patients were allocated to arms A, B, and C, respectively. Contamination and attrition rates (180 days) were 31.8% and 38.0%, respectively. No interaction between the arms and treatments were found. Regarding effect sizes, there was a moderate benefit in arm A over arms B and C in emotional functioning (-0.66 and -0.61, respectively) but a negative effect of arm A over arm C in depression (-0.74). CONCLUSIONS: Future studies to be conducted with this population group need to revise the eligibility criteria and make them less restrictive. In addition, the need for arm C is questioned due to high contamination rate. The designed psychosocial intervention was not able to reduce depressive symptoms when combined with early PC. Further studies are warrant to evaluate the intervention on-demand and in subgroups of high risk of anxiety/depression. TRIAL REGISTRATION: Clinical Trials identifier NCT02133274 . Registered May 6, 2014. PMID- 28836961 TI - Visual outcome following bilateral non-arteritic anterior ischemic optic neuropathy: a systematic review and meta-analysis. AB - BACKGROUND: Many patients who suffer unilateral non-arteritic anterior ischemic optic neuropathy (NAION) will eventually develop the same condition in their other eye, worrying them about losing vision in both eyes. The purpose of this meta-analysis is to determine whether it is possible to predict the visual outcome of the consecutive NAION event based on initial presentation and to compare mean visual loss of firstly versus secondly affected eyes. METHODS: A systematic review and meta-analysis of studies published between January 1st 1966 and May 31st 2016 reporting on visual acuity and/or visual field loss of both affected eyes, measured either at presentation or follow-up following bilateral NAION. RESULTS: Ten studies were included in the meta- analysis of visual acuity, including 9 retrospective reports and one randomized clinical trial, and five retrospective studies were included in visual field meta-analysis. A significant correlation exists for visual acuity (R = 0.387, P < 0.001) in both eyes of the same patient following bilateral NAION, and also for visual field loss (R = 0.445, P < 0.001) in the two eyes. The calculated coefficient of determination (R2) of 0.149 for visual acuity, and 0.198 for visual field loss indicates that for any given individual suffering from unilateral NAION only 15% of visual acuity and 20% of visual field loss in the secondly affected eye can be explained by these outcomes in the first eye. In addition, there was no difference in mean visual outcome of the first versus second NAION events (standardized mean differences of visual acuity 0.008, P = 0.890; and visual field loss, -0.019, P = 0.819). CONCLUSION: Even though a weak connection exists between visual outcome in both eyes following bilateral NAION it is still impossible to predict with certainty the visual outcome of a sequential contralateral NAION event based on the severity of visual loss in the first affected eye. Measures often taken after the first event are ineffective in improving the visual outcome of a second event should it occur. PMID- 28836962 TI - MicroRNA expression profiling of porcine mammary epithelial cells after challenge with Escherichia coli in vitro. AB - BACKGROUND: Coliform mastitis is a symptom of postpartum dysgalactia syndrome (PDS), a multifactorial infectious disease of sows. Our previous study showed gene expression profile change after bacterial challenge of porcine mammary epithelial cells (PMECs). These mRNA expression changes may be regulated through microRNAs (miRNAs) which play critical roles in biological processes. Therefore, miRNA expression profile was investigated in PMECs. RESULTS: PMECs were isolated from three lactating sows and challenged with heat-inactivated potential mastitis causing pathogen Escherichia coli (E. coli) for 3 h and 24 h, in vitro. At 3 h post-challenge with E. coli, target gene prediction identified a critical role of miRNAs in regulation of host immune responses and homeostasis of PMECs mediated by affecting pathways including cytokine binding (miR-202, miR-3277, miR-4903); IL-10/PPAR signaling (miR-3277, miR-4317, miR-548); and NF-KB/TNFR2 signaling (miR-202, miR-2262, miR-885-3p). Target genes of miRNAs in PMECs at 24 h were significantly enriched in pathways associated with interferon signaling (miR-210, miR-23a, miR-1736) and protein ubiquitination (miR-125, miR-128, miR-1280). CONCLUSIONS: This study provides first large-scale miRNA expression profiles and their predicted target genes in PMECs after contact with a potential mastitis causing E. coli strain. Both, highly conserved miRNAs known from other species as well as novel miRNAs were identified in PMECs, representing candidate predictive biomarkers for PDS. Time-dependent pathogen clearance suggests an important role of PMECs in inflammatory response of the first cellular barrier of the porcine mammary gland. PMID- 28836964 TI - Evaluation of a peer-delivered, transitional and post-discharge support program following psychiatric hospitalisation. AB - BACKGROUND: The time following discharge from psychiatric hospitalisation is a high risk period. Rates of hospital readmission are high and there is increased risk for homelessness and suicide. Transitional and post-discharge support programs have demonstrated positive results in terms of enhanced wellbeing, improved connection with community-based services and, in some cases, reductions in hospital re-admission. This paper reports on the outcomes of a peer-delivered post-discharge support program. METHODS: The program involved peer workers (individuals with their own lived experience of mental illness and recovery) providing individualised practical and emotional support to individuals for six to eight weeks following discharge from an inpatient psychiatric unit. Outcomes measures included self-reported mental health recovery, personal wellness and self-reported re-admission rates. Process and satisfaction measures were also collected and semi-structured follow-up interviews were completed with consenting participants. RESULTS: The program provided support for a total of 64 individuals, 38 of whom consented to participate in the evaluation. Participants reported improvements in terms of functional and clinical recovery and in the areas of intellectual, social and psychological wellness. Participants self report of hospital readmissions suggested that there was a reduction in hospital bed days following engagement with the program. Themes from the follow up interviews included: Easing the transition to the "real world"; Practical and individualised support; Someone to talk to; Positive qualities of the worker, Workers' lived experience was a positive thing, and It wasn't long enough. CONCLUSION: Overall, evaluation data suggest that the program supported positive outcomes for participants in terms of recovery, wellbeing and hospital avoidance. Participant feedback suggested that the use of support workers with their own lived experience of mental illness was a particularly powerful aspect of the program. PMID- 28836963 TI - Bioinformatics comparisons of RNA-binding proteins of pathogenic and non pathogenic Escherichia coli strains reveal novel virulence factors. AB - BACKGROUND: Pathogenic bacteria have evolved various strategies to counteract host defences. They are also exposed to environments that are undergoing constant changes. Hence, in order to survive, bacteria must adapt themselves to the changing environmental conditions by performing regulations at the transcriptional and/or post-transcriptional levels. Roles of RNA-binding proteins (RBPs) as virulence factors have been very well studied. Here, we have used a sequence search-based method to compare and contrast the proteomes of 16 pathogenic and three non-pathogenic E. coli strains as well as to obtain a global picture of the RBP landscape (RBPome) in E. coli. RESULTS: Our results show that there are no significant differences in the percentage of RBPs encoded by the pathogenic and the non-pathogenic E. coli strains. The differences in the types of Pfam domains as well as Pfam RNA-binding domains, encoded by these two classes of E. coli strains, are also insignificant. The complete and distinct RBPome of E. coli has been established by studying all known E. coli strains till date. We have also identified RBPs that are exclusive to pathogenic strains, and most of them can be exploited as drug targets since they appear to be non-homologous to their human host proteins. Many of these pathogen-specific proteins were uncharacterised and their identities could be resolved on the basis of sequence homology searches with known proteins. Detailed structural modelling, molecular dynamics simulations and sequence comparisons have been pursued for selected examples to understand differences in stability and RNA-binding. CONCLUSIONS: The approach used in this paper to cross-compare proteomes of pathogenic and non pathogenic strains may also be extended to other bacterial or even eukaryotic proteomes to understand interesting differences in their RBPomes. The pathogen specific RBPs reported in this study, may also be taken up further for clinical trials and/or experimental validations. PMID- 28836965 TI - Predictors of high healthcare costs in elderly patients with liver cancer in end of-life: a longitudinal population-based study. AB - BACKGROUND: Studies have indicated a pervasive pattern of decreasing healthcare costs during elderly patients' last year of life. The aim of this study was to explore the predictors of high healthcare costs (HC) in elderly liver cancer patients in Taiwan during their last month of life (LML). METHODS: Costs of hospitalization, outpatient visits, aggressiveness of care, and associated costs for elderly (age >= 65 y) patients with liver cancer in the LML were analyzed using a national insurance database. An HC was defined as being greater than the 90th percentile (US $5093) in the LML, amounting to 38.95% of total healthcare costs. RESULTS: We enrolled 2121 subjects who died during 1997-2011. Mean healthcare costs per person in their LML were US $8042 +/- 3477 in the HC group and US $1407 +/- 1464 in the non-HC group (p < 0.001). For patients receiving aggressive end-of-life (EOL) cancer care (e.g. intensive care, cardiopulmonary resuscitation, anticancer treatment, and a high number of admission days), comorbidities of chronic kidney disease, esophageal bleeding, and receiving opioids in the LML, were significantly independent positive predictors of HCs; but admission times, comorbidities of ascites, and hypertension were negative predictors. CONCLUSION: These findings could inform healthcare providers by avoiding aggressive treatments during EOL for elderly patients with liver cancer and to save on healthcare costs. Shorter admission days and more admission times in the last month of life could decrease healthcare costs. PMID- 28836966 TI - Impact of midfoot and Hindfoot involvement on functional disability in Korean patients with rheumatoid arthritis. AB - BACKGROUND: Foot involvement in rheumatoid arthritis (RA) patients has been reported to severely affect functional capacity and quality of life. We aimed to determine the impact of midfoot and hindfoot involvement on functional disability in Korean patients with RA. METHODS: We evaluated the RA involvement and deformity of three regions of the foot (forefoot, midfoot and hindfoot) and ankle using conventional radiography in Korean patients with RA. We compared the clinical features between RA patients with and without foot or ankle involvement. Using multivariable logistic regression analyses, the impact of midfoot or hindfoot involvement on functional disability in RA patients was evaluated. RESULTS: Overall, 120 patients with a median age of 48.0 [interquartile range (IQR), 37-56] years and median disease duration of 58.0 (IQR, 10-89) months were included. The prevalence of foot or ankle RA involvement was 74 (61.7%). The number of patients with forefoot, midfoot, hindfoot and ankle involvement was 32 (43.2%), 24 (32.4%), 46 (62.2%) and 4 (5.4%), respectively. Compared to patients without foot or ankle involvement those with such involvement had greater disease activity and functional disability, more of them were treated with biologic agents, and they had a lower health-related quality of life. After adjusting for potential confounders, hindfoot involvement was associated with a higher degree of functional disability. However, walking difficulty was more associated with midfoot involvement rather than with involvement in other regions. CONCLUSIONS: In Korean patients with RA, hindfoot involvement is associated with functional disability and midfoot involvement affects walking. PMID- 28836967 TI - Erratum to: The impact of hip fracture on mortality in Estonia: a retrospective population-based cohort study. PMID- 28836968 TI - Infrarenal high intra-abdominal testis: fusion of T2-weighted and diffusion weighted magnetic resonance images and pathological findings. AB - BACKGROUND: Several recent reports have demonstrated that the preoperative sensitivity and accuracy of identifying and locating non-palpable testes increases with the use of conventional MRI, in addition to diffusion-weighted imaging (DWI). Therefore, pre-operative prediction of the presence and location of testes using imaging techniques may guide management of intra-abdominal testis. Fowler-Stephens orchiopexy is effective for treating patients with intra abdominal testis; however, long-term testicular function after this procedure has not been clarified. We present a case of a high intra-abdominal testis located below the kidney, and discuss the usefulness of fusion view with T2-weighted and DWI images to make a diagnosis of high intra-abdominal testis and the pathological findings to predict future fertility potential. CASE PRESENTATION: A 10-month-old boy was referred to the urology department for the management of non palpable testis. We employed not only conventional MRI, but also DWI, to improve the diagnostic accuracy of non-palpable testes by MRI examination. The high intensity mass-like structure below the kidney on the T2-weighted image and the markedly high signal intensity mass on the DWI image completely matched, which suggested that the mass below the kidney was the right testis. The patient underwent diagnostic and therapeutic laparoscopy. A testis was found under the ascending colon, 1 cm below the right kidney. We performed 2-stage Fowler Stephens orchiopexy. The testis could be delivered to the scrotum without any tension. We examined expression patterns of the stem cell marker, undifferentiated embryonic cell transcription factor 1 (UTF1) in the testicular biopsy sample, and demonstrated that the UTF1-positive Ad spermatogonia / negative Ad spermatogonia ratio was lower in this patient than in boys his age with descended and inguinal undescended testes, indicating that spermatogonial stem cell activity may decrease remarkably in this boy. CONCLUSIONS: Fusion view with T2-weighted and DWI images may be a useful diagnostic modality for high intra-abdominal testes. Fowler-Stephens orchiopexy may provide blood supply to the testis but that might not be enough to achieve spermatogenesis. PMID- 28836969 TI - The application of a novel integrated rigid and flexible Nephroscope in percutaneous nephrolithotomy for renal staghorn stones. AB - BACKGROUND: Renal staghorn stones are challenging for urologists to ensure maximum stone clearance and minimal morbidity. Percutaneous nephrolithotomy (PCNL) has become the gold standard treatment for renal staghorn stones. To assess the safety and efficacy of a novel integrated rigid and flexible percutaneous nephroscope(Rigi-flex nephroscope) in PCNL for renal staghorn stones.We present our initial experience with this new technique. METHODS: From March to July 2016, a prospective analysis of 3 patients with staghorn stones treated with Rigi-flex nephroscope in PCNLunder totally ultrasound guidance by paravertebral block (PVB) anesthesia was done. PCNL was performed with the rigid section of a 13-Fr Rigi-flex nephroscope firstly and the stones were disintegrated into fragments by holmium laser.Then the stones were removed by active flushout, followed by a search for residual stones in other inaccessible calyces with the flexible section. Finally, the residual stones were disintegrated into small fractions by holmium laser in situ or repositioned with a set of disposable retrieval baskets to pelvic or other accessible areas. The whole procedure was accomplished via only one nephrostomy tract. The operating time, stone-free rates (SFR), postoperative hemoglobin drop, complications, length of hospitalization, were recorded. RESULTS: The operation time were 89, 62 and 45 min, respectively, the postoperative hemoglobin drop was 1, 0.8 and 0.9 mg/dl, respectively.The postoperative Kidney-Ureter-Bladder (KUB) radiograph of the three patients showed no residual fragment >3 mm. No patients needed blood transfusion and suffered significant complications. The length of hospitalization was 9, 6 and 4 days, respectively. No patient needed multiple tracts PCNL or staged auxiliary measures one month after the operation. CONCLUSIONS: The application of Rigi-flex nephroscope in PCNL under ultrasound guidance for staghorn stones has its unique advantages as monotherapy with increasing procedural stone free rate (SFR) via single nephrostomy tract, hence there is less morbidity as it does not require additional tracts dilation and staged auxiliary procedures combination. However, SFR should also be evaluated at a longer follow-up, particularly for staghorn stone, further large-scale multicenter prospective clinical trial are needed to verify its feasibility. PMID- 28836970 TI - Comprehensive comparison of three different animal models for systemic inflammation. AB - BACKGROUND: To mimic systemic inflammation in humans, different animal models have been developed. Since these models are still discussed controversially, we aimed to comparatively evaluate the most widely used models with respect to the systemic effects, the influence on organ functions and to the underlying pathophysiological processes. METHODS: Systemic inflammation was induced in C57BL/6N mice with lipopolysaccharide (LPS) treatment, peritoneal contamination and infection (PCI), or cecal ligation and puncture (CLP). Blood glucose and circulating cytokine levels were evaluated at 0, 2, 4, 6, 12, 24, 48, and 72 h after induction of inflammation. Additionally, oxidative stress in various organs and liver biotransformation capacity were determined. Markers for oxidative stress, apoptosis, infiltrating immune cells, as well as cytokine expression patterns, were assessed in liver and spleen tissue by immunohistochemistry. RESULTS: Treating mice with LPS and PCI induced a very similar course of inflammation; however, LPS treatment elicited a stronger response. In both models, serum pro-inflammatory cytokine levels rapidly increased whereas blood glucose decreased. Organs showed early signs of oxidative stress, and apoptosis was increased in splenic cells. In addition, liver biotransformation capacity was reduced and there was pronounced immune cell infiltration in both the liver and spleen. Mice exposed to either LPS or PCI recovered after 72 h. In contrast, CLP treatment induced comparatively fewer effects, but a more protracted course of inflammation. CONCLUSIONS: The LPS model of systemic inflammation revealed to be most suitable when being interested in the impact of new therapies for acute inflammation. When using the CLP model to mimic human sepsis more closely, a longer time course should be employed, as the treatment induces delayed development of systemic inflammation. PMID- 28836971 TI - Which patient-specific and surgical characteristics influence postoperative pain after THA in a fast-track setting? AB - BACKGROUND: In our hospital a fast-track setting including a multimodal pain protocol is used for total hip arthroplasty (THA). Despite this multimodal pain protocol there is still a large range in reported postoperative pain between patients, which hinders mobilization and rehabilitation postoperatively. The goal of this study was to identify which patient-specific and surgical characteristics influence postoperative pain after THA in a fast-track setting. METHODS: All 74 patients with osteoarthritis of the hip who underwent primary THA procedure by anterior supine intermuscular approach between November 2012 and January 2014 were included in this prospective cohort study. The protocol for pain medication was standardized. Postoperative pain determined with the Numeric Rating Score was collected at 17 standardized moments. Linear mixed models were used to examine potential patient-specific and surgical factors associated with increased postoperative pain. RESULTS: Pain patterns differed substantially across individuals. Adjusted for other variables in the model, preoperative use of pain medication (regression coefficient 0.78 (95% CI 0.28-1.26); p = 0.005) and preoperative neuropathic pain scored by DN4 (regression coefficient 0.68 (95% CI 0.15-1.20); p = 0.02) were the only factors significantly associated with higher postoperative pain scores. CONCLUSIONS: The knowledge of which factors are associated with higher postoperative pain scores after THA in a fast-track setting may help optimizing perioperative postoperative pain management and preoperative education of these patients. TRIAL REGISTRATION: The study was retrospectively registered in the ISRCTN registry under identifier ISRCTN15422220 (date of registration: July 25, 2017). PMID- 28836972 TI - Access to medicines and diagnostic tests integral in the management of diabetes mellitus and cardiovascular diseases in Uganda: insights from the ACCODAD study. AB - BACKGROUND: Despite the burgeoning burden of diabetes mellitus (DM) and cardiovascular diseases (CVD) in low and middle income countries (LMIC), access to affordable essential medicines and diagnostic tests for DM and CVD still remain a challenge in clinical practice. The Access to Cardiovascular diseases, Chronic Obstructive pulmonary disease, Diabetes mellitus and Asthma Drugs and diagnostics (ACCODAD) study aimed at providing contemporary information about the availability, cost and affordability of medicines and diagnostic tests integral in the management of DM and CVD in Uganda. METHODS: The study assessed the availability, cost and affordability of 37 medicines and 19 diagnostic tests in 22 public hospitals, 23 private hospitals and 100 private pharmacies in Uganda. Availability expressed as a percentage, median cost of the available lowest priced generic medicine and the diagnostic tests and affordability in terms of the number of days' wages it would cost the least paid public servant to pay for one month of treatment and the diagnostic tests were calculated. RESULTS: The availability of the medicines and diagnostic tests in all the study sites ranged from 20.1% for unfractionated heparin (UFH) to 100% for oral hypoglycaemic agents (OHA) and from 6.8% for microalbuminuria to 100% for urinalysis respectively. The only affordable tests were blood glucose, urinalysis and serum ketone, urea, creatinine and uric acid. Parenteral benzathine penicillin, oral furosemide, glibenclamide, bendrofluazide, atenolol, cardiac aspirin, digoxin, metformin, captopril and nifedipine were the only affordable drugs. CONCLUSION: This study demonstrates that the majority of medicines and diagnostic tests essential in the management of DM and CVD are generally unavailable and unaffordable in Uganda. National strategies promoting improved access to affordable medicines and diagnostic tests and primary prevention measures of DM and CVD should be prioritised in Uganda. PMID- 28836973 TI - Comparison and analysis of reoperations in two different treatment protocols for trochanteric hip fractures - postoperative technical complications with dynamic hip screw, intramedullary nail and Medoff sliding plate. AB - BACKGROUND: In treatment of unstable trochanteric fractures dynamic hip screw and Medoff sliding plate devices are designed to allow secondary fracture impaction, whereas intramedullary nails aim to maintain fracture alignment. Different treatment protocols are used by two similar Swedish regional emergency care hospitals. Dynamic hip screw is used for fractures considered as stable within the respective treatment protocol, whereas one treatment protocol (Medoff sliding plate/dynamic hip screw) uses biaxial Medoff sliding plate for unstable pertrochanteric fractures and uniaxial Medoff sliding plate for subtrochanteric fractures, the second (intramedullary nail/dynamic hip screw) uses intramedullary nail for subtrochanteric fractures and for pertrochanteric fractures with intertrochanteric comminution or subtrochanteric extension. All orthopedic surgeries are registered in a regional database. METHODS: All consecutive trochanteric fracture operations during 2011-2012 (n = 856) and subsequent technical reoperations (n = 40) were derived from the database. Reoperations were analysed and classified into the categories adjustment (percutaneous removal of the locking screw of the Medoff sliding plate or the intramedullary nail, followed by fracture healing) or minor, intermediate (reosteosynthesis) or major (hip joint replacement, Girdlestone or persistent nonunion) technical complications. RESULTS: The relative risk of intermediate or major technical complications was 4.2 (1.2-14) times higher in unstable pertrochanteric fractures and 4.6 (1.1-19) times higher in subtrochanteric fractures with treatment protocol: intramedullary nail/dynamic hip screw, compared to treatment protocol: Medoff sliding plate/dynamic hip screw. Overall rates of intermediate and major technical complications in unstable pertrochanteric and subtrochanteric fractures were with biaxial Medoff sliding plate 0.68%, with uniaxial Medoff sliding plate 1.4%, with dynamic hip screw 3.4% and with intramedullary nail 7.2%. CONCLUSIONS: The treatment protocol based on use of biaxial Medoff sliding plate for unstable pertrochanteric and uniaxial Medoff sliding plate for subtrochanteric fractures reduced the risk of severe technical complications compared to using the treatment protocol based on dynamic hip screw and intramedullary nail. PMID- 28836974 TI - Insulin prices, availability and affordability: a cross-sectional survey of pharmacies in Hubei Province, China. AB - BACKGROUND: Poor access to affordable insulin results in serious and needless complications and premature deaths for those with diabetes who need this essential medicine. To help address this issue, we assessed insulin availability, prices, affordability and price components in Hubei Province as China has the heaviest burden of diabetes globally. METHODS: In 2016, insulin availability and price data was collected in the capital and five other cities. A total of 30 public sector outlets (hospitals and primary care institutions) and 30 private pharmacies were sampled, using an adaptation of the World Health Organization/Health Action International methodology, Data was collected for all human and analogue insulins in stock, then analyzed by type (prandial, basal or pre-mixed) and duration of action. Prices were expressed as Median Price Ratios (MPRs) to Australian PBS prices. Price components were tracked for five insulin products in two cities.. Affordability was assessed as the number of days' wages of the lowest paid unskilled government worker needed to purchase 10 ml 100 IU/ml (approximately 30 days' supply). RESULTS: Mean availability was highest in public hospitals for prandial (70%), basal (80%) and pre-mixed insulin (90%). In primary care institutions and private pharmacies mean availability ranged from 10% to 33%. Median prices of all insulin types were higher that Australian PBS prices in all three sectors for human and analogue insulins (ranging from1.36-2.59 times). Patients have to pay 4 to 16 days' wages to purchase a month's treatment depending on the insulin type and sector. The largest component of the patient price was the manufacturers' selling price (60%). Taxes in the form of import duties and VAT are applied in some sectors. CONCLUSIONS: The availability of insulin in primary care institutions and private retail pharmacies was very low in Hubei. Only public hospitals had good insulin availability. Insulin prices were high in all sectors making this life-saving medicine unaffordable, especially for those on low incomes. Governments should consider using its bargaining power to reduce prices, abolish taxes on essential medicines such as insulin, and develop strategies for more equitable access to insulin. PMID- 28836975 TI - Antioxidant capacity and fatty acids characterization of heat treated cow and buffalo milk. AB - BACKGROUND: Antioxidant capacity of milk is largely due to vitamins A, E, carotenoids, zinc, selenium, superoxide dismutase, catalase, glutathione peroxidase and enzyme systems. Cow milk has antioxidant capacity while the antioxidant capacity of buffalo milk has been studied in a limited way. The information regarding the effect of pasteurization and boiling on antioxidant capacity of cow and buffalo milk is also scared. METHODS: Cow and buffalo milk was exposed to two different heat treatments i.e. 65 degrees C for 30 min and boiling for 1 min. After heat treatments, milk samples were cooled down to 4 degrees C packaged in transparent 250 ml polyethylene PET bottles and stored at 4 degrees C for 6 days. Milk composition, total flavonoid content, total antioxidant capacity, reducing power, DPPH free radical scavenging activity, antioxidant activity in linoleic acid, vitamin C, A, E, selenium, Zinc, fatty acid profile, peroxide value and sensory characteristics were studied in raw, pasteurized and boiled cow and buffalo milk at 0, 3 and 6 days of storage period. RESULTS: Total antioxidant capacity (TAC) of raw, pasteurized and boiled milk for cow (42.1, 41.3 and 40.7%) and buffalo (58.4, 57.6 and 56.5%) samples was found, respectively. Reducing power (RP) of raw cow and buffalo milk was 6.74 and 13.7 while pasteurization and boiling did not showed significant effect on RP of both cow and buffalo milk. DPPH activity of raw, pasteurized and boiled milk for cow (24.3, 23.8 and 23.6%) and buffalo (31.8, 31.5 and 30.4%) samples was noted, respectively. Storage period up to 3 days was non-significant while DPPH assay after 6 days of storage period indicated significant decline in antioxidant activity of milk samples. Antioxidant activity in linoleic acid (AALA) of buffalo and cow milk were recorded 11.7 and 17.4%, respectively. Pasteurization and boiling did not showed any impact on antioxidant capacity of cow and buffalo milk. The Loss of vitamin C in pasteurization (40 and 42%) and boiling (82 and 61%) of cow and buffalo milk was recorded, respectively. Concentration of vitamin A and E in pasteurized cow and buffalo milk was not significantly different from raw milk samples of cow and buffalo. Concentration of selenium and zinc was not influenced by the heat treatment in both cow and buffalo milk samples. After 3 days of refrigerated storage, antioxidant capacity of both cow and buffalo milk decreased. Concentrations of short-chain and medium-chain fatty acids increased in pasteurized and boiled cow and buffalo milk, while long-chain fatty acids decreased in pasteurized and boiled cow and buffalo milk, with no effect on colour and flavor score. Peroxide value of pasteurized and boiled cow and buffalo milk was not influenced by the storage up to 3 days. CONCLUSIONS: These results suggest that buffalo milk had a higher antioxidant capacity than cow milk and pasteurized milk should be consumed within 3 days of refrigerated storage for better antioxidant perspectives. PMID- 28836976 TI - Impact of nutritional status in the era of FOLFOX/FIRI-based chemotherapy. AB - BACKGROUND: The nutritional status plays a pivotal role during anticancer therapy. This study analyzed whether nutritional status influences the outcomes in the era of FOLFOX/FIRI therapy. METHODS: The patients were divided into two groups according to whether the nutritional status was well (serum albumin level >= 3.8 g/dL or a >= 1.0 g/dL increase as compared with the value before chemotherapy) or not before and 2 and 6 months after the start of chemotherapy. Chemotherapy-related adverse events (AE), treatment effect, and compliance were evaluated according to the nutritional status. The progression-free survival (PFS) and overall survival (OS) were assessed based on the nutritional status at 6 months. RESULTS: Between 2010 and 2013, data on 108 consecutive patients were analyzed. At 2 months after chemotherapy, the hematotoxicic AE and the value of tumor markers did not differ significantly. The non-hematotoxic AE were less frequent in patients in the well-nourished group (grade 2, 15.9 vs. 38.5%, p < 0.01). Based on the nutritional status at 6 months after chemotherapy, the hematotoxicic AE (grade 3, 9 vs. 19.5%, p = 0.03) and non-hematotoxic AE (grade 2, 31.3 vs. 51.2%, p = 0.04; grade 3, 6.0 vs. 24.4%, p < 0.01) were less frequent, and the median CEA value (5.3 vs. 27.75 mg/L, p < 0.01) was significantly lower in the well-nourished group. The median PFS (364 vs. 233 days, p < 0.01) and 5-year OS (26.5 vs. 11.1%, p = 0.01) are significantly better in the well-nourished group. CONCLUSIONS: The well-nourished at initial 6 months may predict a better treatment response and fewer adverse events in FOLFOX/FIRI chemotherapy. PMID- 28836977 TI - 2-Butanone as a carbon dioxide mimic in attractant blends for the Afrotropical malaria mosquitoes Anopheles gambiae and Anopheles funestus. AB - BACKGROUND: Most odour baits designed to attract host-seeking mosquitoes contain carbon dioxide (CO2), which enhances trap catches, given its role as a mosquito flight activator. However, the use of CO2 is expensive and logistically demanding for prolonged area-wide use. METHODS: This study explored the possibility of replacing organically-produced CO2 with 2-butanone in odour blends targeting host seeking malaria mosquitoes. During semi-field and field experiments MM-X traps were baited with a human odour mimic (MB5 blend) plus CO2 or 2-butanone at varying concentrations. Unbaited traps formed a control. The attraction of Anopheles gambiae s.s., Anopheles arabiensis and Anopheles funestus to these differently baited traps was measured and mean catch sizes were compared to determine whether 2-butanone could form a viable replacement for CO2 for these target species. RESULTS: Under semi-field conditions significantly more female An. gambiae mosquitoes were attracted to a reference attractant blend (MB5 + CO2) compared to MB5 without CO2 (P < 0.001), CO2 alone (P < 0.001), or a trap without a bait (P < 0.001). Whereas MB5 + CO2 attracted significantly more mosquitoes than its variants containing MB5 plus different dilutions of 2-butanone (P = 0.001), the pure form (99.5%) and the 1.0% dilution of 2-butanone gave promising results. In the field mean indoor catches of wild female An. gambiae s.l. in traps containing MB5 + CO2 (5.07 +/- 1.01) and MB5 + 99.5% 2-butanone (3.10 +/- 0.65) did not differ significantly (P = 0.09). The mean indoor catches of wild female An. funestus attracted to traps containing MB5 + CO2 (3.87 +/- 0.79) and MB5 + 99.5% 2-butanone (3.37 +/- 0.70) were also similar (P = 0.635). Likewise, the mean outdoor catches of An. gambiae and An. funestus associated with MB5 + CO2 (1.63 +/- 0.38 and 0.53 +/- 0.17, respectively) and MB5 + 99.5% 2-butanone (1.33 +/- 0.32 and 0.40 +/- 0.14, respectively) were not significantly different (P = 0.544 and P = 0.533, respectively). CONCLUSION: These results demonstrate that 2-butanone can serve as a good replacement for CO2 in synthetic blends of attractants designed to attract host-seeking An. gambiae s.l. and An. funestus mosquitoes. This development underscores the possibility of using odour-baited traps (OBTs) for monitoring and surveillance as well as control of malaria vectors and potentially other mosquito species. PMID- 28836978 TI - Diurnal variation of NMR based blood metabolites in calves fed a high plane of milk replacer: a pilot study. AB - BACKGROUND: Blood profiles have been used to monitor herd health status, diagnose disorders, and predict the risk of diseases in cattle and calves. Characterizing plasma metabolites in dairy calves could provide further insight into daily metabolic variations and the mechanisms that lead to metabolic diseases. In addition, by understanding physiological ranges of plasma metabolites relative to meal and the time of feeding in healthy animals, veterinarians can accurately diagnose abnormalities with a blood test. For diagnostic purposes, nuclear magnetic resonance (NMR) spectroscopy shows promise as a new and reliable method to determine a large number of blood metabolites simultaneously. RESULTS: Results demonstrated that the concentration of specific metabolites in plasma (i.e., lysine, isoleucine, leucine, tyrosine, glutamine, creatine, and 1 methylhistidine) fluctuated around meal times, while others (i.e., glutamic acid, methanol, formic acid, and acetic acid) maintained a stable temporal concentration. In addition to temporal changes in concentration, results also characterized differences for overall plasma metabolite concentrations; for example, methionine had the lowest (38 MUM) while glutamine had the highest concentration (239 MUM) amongst plasma AA. This is the first report describing how the plasma metabolome changes during 24-h period in young calves fed an elevated plane of milk replacer twice daily. CONCLUSIONS: Data from this pilot study will help to establish reference standards for future metabolic diagnostics in dairy calves. In addition, this pilot study illustrated that feeding milk replacer may influence plasma metabolite concentrations. With the rapid implementation of blood metabolomics in monitoring animal health, it is then important to consider the time of feeding during the day when interpreting metabolomics analysis results. PMID- 28836979 TI - Facilitators and barriers of change toward an elder-friendly surgical environment: perspectives of clinician stakeholder groups. AB - BACKGROUND: Current acute care surgical practices do not focus on the unique needs of older adults. Adverse outcomes in older patients result from a complex interrelationship between baseline vulnerability and insults experienced during hospitalization. The purpose of this study is to assess the organizational readiness and the barriers and facilitators for the implementation of elder friendly interventions in the acute care of unplanned abdominal surgery patients. METHODS: This cross-sectional mixed methods study included a convenience sample of clinician stakeholder groups. Eight focus groups were conducted with 33 surgical team members including: 10 health care aides, 6 licensed practical nurses, 6 registered nurses, 4 nurse managers and 7 surgeons, to identify barriers and facilitators to the implementation of an elder-friendly surgical unit. Audio recordings of the focus groups were transcribed verbatim and analysed using interpretive description techniques. Transcripts were coded along with explanatory memos to generate a detailed description of participant experiences. Themes were identified followed by refining the codes. Participants also completed the Organizational Readiness for Implementing Change questionnaire. Differences in organizational readiness scores across clinician stakeholder groups were assessed using Kruskal-Wallice tests. Mann-Whitney tests (Bonferroni's corrections for multiple comparisons) were conducted to assess pair wise relationships. RESULTS: The focus group data were conceptualized to represent facilitators and barriers to change at two levels of care delivery. Readiness to change at the organizational level was evident in five categories that reflected the barriers and facilitators to implementing an elder-friendly surgical unit. These included education, environment, staffing, policies and other research projects. At the individual level barriers and facilitators were apparent in staff members' acceptance of new roles and duties with other staff, family and patients. Examples of these included communication, teamwork and leadership. The mean change commitment and change efficacy scores on the Organizational Readiness for Implementing Change Questionnaire were 3.7 (0.8) and 3.5 (0.9) respectively. No statistically significant differences were detected between the stakeholder groups. CONCLUSIONS: Staff are interested in contributing to improved care for elderly surgical patients; however, opportunities were identified to enhance facilitators and reduce barriers in advance of implementing the elder-friendly surgical unit intervention. PMID- 28836980 TI - Fractional esterification rate of cholesterol in high-density lipoprotein associates with risk of coronary heart disease. AB - BACKGROUND: Fractional esterification rate of cholesterol in high-density lipoprotein (FERHDL) has been found to be closely correlated with atherosclerotic dyslipidemia, especially lipoprotein distributions, and is a potentially useful predictor for coronary heart disease (CHD). The associations of FERHDL, measured by the simple and precise HPLC method, with angiographically defined CHD and its related risk factors in Chinese patients were evaluated. METHODS: Two hundred and fifty eight Chinese patients who had indications for angiography were enrolled in this study. Coronary angiograms were obtained by the standard techniques. FERHDL was determined by the HPLC method. Cholesterol levels in serum HDL, LDL and subfractions were measured by ultracentrifugation/HPLC method. Associations between FERHDL and CHD and CHD risk factors were analyzed. RESULTS: FERHDL was correlated with almost all the CHD risk factors. Compared with the non-CHD group, the CHD patients had higher values of FERHDL (20.9 +/- 7.9%/h vs 17.7 +/- 7.1%/h, p = 0.001). FERHDL was found to be independently and positively correlated with log TG (beta = 0.386, P < 0.001) and log (LDLb-C) (beta = 0.165, P = 0.020), respectively, and negatively correlated with log (HDL2-C)(beta = -0.351, P < 0.001). Logistic regression analysis demonstrated that age, diabetes mellitus, smoking and FERHDL (OR = 1.056-1.080, p < 0.05) were independent risk factors for CHD. CONCLUSION: FERHDL significantly correlated with both HDL2-C and LDLb-C, and therefore, is the predictor of lipoprotein distributions. In addition, after correcting for the presence of classic risk factors, FERHDL was independently associated with the presence of angiographically defined CHD. PMID- 28836981 TI - Safe medication management in specialized home healthcare - an observational study. AB - BACKGROUND: Medication management is a complex, error-prone process. The aim of this study was to explore what constitutes the complexity of the medication management process (MMP) in specialized home healthcare and how healthcare professionals handle this complexity. The study is theoretically based in resilience engineering. METHOD: Data were collected during the MMP at three specialized home healthcare units in Sweden using two strategies: observation of workplaces and shadowing RNs in everyday work, including interviews. Transcribed material was analysed using grounded theory. RESULTS: The MMP in home healthcare was dynamic and complex with unclear boundaries of responsibilities, inadequate information systems and fluctuating work conditions. Healthcare professionals adapted their everyday clinical work by sharing responsibility and simultaneously being authoritative and preserving patients' active participation, autonomy and integrity. To promote a safe MMP, healthcare professionals constantly re prioritized goals, handled gaps in communication and information transmission at a distance by creating new bridging solutions. Trade-offs and workarounds were necessary elements, but also posed a threat to patient safety, as these interim solutions were not systematically evaluated or devised learning strategies. CONCLUSIONS: To manage a safe medication process in home healthcare, healthcare professionals need to adapt to fluctuating conditions and create bridging strategies through multiple parallel activities distributed over time, space and actors. The healthcare professionals' strategies could be integrated in continuous learning, while preserving boundaries of safety, instead of being more or less interim solutions. Patients' and family caregivers' as active partners in the MMP may be an underestimated resource for a resilient home healthcare. PMID- 28836982 TI - Food consumption patterns of adolescents aged 14-16 years in Kolkata, India. AB - BACKGROUND: The nutrition transition has brought about rapid changes in the structure of the Indian diet. The replacement of traditional home-cooked meals with ready-to-eat, processed foods has contributed to an increased risk of chronic diseases in urban Indians. Improving the nutrition of Indians by promoting healthy food consumption in early life and in adolescence would help to reduce these health risks. However, little is known about the quality and quantity of foods and beverages consumed by urban Indian adolescents. Therefore, the aim of this study was to describe the food consumption patterns in a sample of urban Indian adolescents. METHODS: A self-administered, semi-quantitative, 59 item meal-based food frequency questionnaire (FFQ) was developed to assess the dietary intake of adolescents over the previous day. A total of 1026 students (aged 14-16 years) attending private, English-speaking schools in Kolkata, India completed the survey. RESULTS: Overall, the adolescents reported poor dietary intakes; over one quarter (30%) reported no consumption of vegetables and 70% reported eating three or more servings of energy-dense snacks, on the previous day. Nearly half of the respondents (45%) did not consume any servings of fruits and 47% reported drinking three or more servings of energy-dense beverages. The mean consumption of food groups in serves/day varied from 0.88 (SD = 1.36) for pulses and legumes to 6.25 (SD = 7.22) for energy-dense snacks. In general, girls had more nutritious dietary intakes than boys. CONCLUSIONS: The Indian adolescents reported poor food consumption patterns, and these findings highlight the need to design effective nutrition promotion strategies to encourage healthy eating in adolescence and targeting food supply and availability. PMID- 28836983 TI - Family-based childhood obesity prevention interventions: a systematic review and quantitative content analysis. AB - BACKGROUND: A wide range of interventions has been implemented and tested to prevent obesity in children. Given parents' influence and control over children's energy-balance behaviors, including diet, physical activity, media use, and sleep, family interventions are a key strategy in this effort. The objective of this study was to profile the field of recent family-based childhood obesity prevention interventions by employing systematic review and quantitative content analysis methods to identify gaps in the knowledge base. METHODS: Using a comprehensive search strategy, we searched the PubMed, PsycIFO, and CINAHL databases to identify eligible interventions aimed at preventing childhood obesity with an active family component published between 2008 and 2015. Characteristics of study design, behavioral domains targeted, and sample demographics were extracted from eligible articles using a comprehensive codebook. RESULTS: More than 90% of the 119 eligible interventions were based in the United States, Europe, or Australia. Most interventions targeted children 2-5 years of age (43%) or 6-10 years of age (35%), with few studies targeting the prenatal period (8%) or children 14-17 years of age (7%). The home (28%), primary health care (27%), and community (33%) were the most common intervention settings. Diet (90%) and physical activity (82%) were more frequently targeted in interventions than media use (55%) and sleep (20%). Only 16% of interventions targeted all four behavioral domains. In addition to studies in developing countries, racial minorities and non-traditional families were also underrepresented. Hispanic/Latino and families of low socioeconomic status were highly represented. CONCLUSIONS: The limited number of interventions targeting diverse populations and obesity risk behaviors beyond diet and physical activity inhibit the development of comprehensive, tailored interventions. To ensure a broad evidence base, more interventions implemented in developing countries and targeting racial minorities, children at both ends of the age spectrum, and media and sleep behaviors would be beneficial. This study can help inform future decision-making around the design and funding of family-based interventions to prevent childhood obesity. PMID- 28836984 TI - Effects of parents training on parents' knowledge and attitudes about adolescent sexuality in Accra Metropolis, Ghana. AB - BACKGROUND: Attitudes of parents about discussing sexuality issues with adolescents may or may not be influenced by their level of knowledge on such issues. This study seeks to examine parents' training and its effects on parent knowledge and attitudes about sexuality in Accra Metropolis, Ghana. METHODS: This was an intervention study consisting of 145 parents who were recruited through their wards from 12 public junior high schools in Accra Metropolis. Parents were randomized equally into intervention and control groups and the intervention group received a 4 weeks training on adolescent sexuality topics. At pre intervention and 3 months after parent training, parents answered questions on knowledge and attitudes about adolescent sexuality. Changes in baseline and follow-up within and between groups were compared using the difference- in difference model and logistic regression. RESULTS: The ages of the parents ranged from 26 to 63 years and 44.1% of them completed middle school. There were 69.9% and 59.7% mothers in the intervention and control groups respectively. At pre intervention, 21.9% of parents in the intervention group had very good knowledge but this increased significantly to 60% three months after the training. Knowledge about sexuality increased to a lesser degree from 18.1% to 34.7% in the control group. Parents' positive attitudes towards adolescents' sexuality increased by 50% in the intervention group compared to 20% in the control group. There were significant differences in knowledge on adolescent sexuality as parents in the intervention group had a greater positive effect than parents in the control group (28.7%, p-value = <0.001). Regarding attitudes of parents towards allowing adolescents to use family planning services (FPS), there was a greater positive effect on parents in the intervention group compared to those in the control group (37.4%; p- value = <0.001). Being part of the intervention group increased the odds of parent knowledge on adolescent sexuality by 16-fold (p-value = <0.001), whilst being in the intervention group increased the likelihood of parents' attitudes towards allowing adolescents to use FPS by four fold (p-value = 0.039). CONCLUSION: Training parents for a relatively short period of time can positively impact parents' knowledge and attitudes about adolescent sexuality. This may have beneficial effects on adolescent reproductive health. PMID- 28836985 TI - Providing guidance for genomics-based cancer treatment decisions: insights from stakeholder engagement for post-prostatectomy radiation therapy. AB - BACKGROUND: Despite the emergence of genomics-based risk prediction tools in oncology, there is not yet an established framework for communication of test results to cancer patients to support shared decision-making. We report findings from a stakeholder engagement program that aimed to develop a framework for using Markov models with individualized model inputs, including genomics-based estimates of cancer recurrence probability, to generate personalized decision aids for prostate cancer patients faced with radiation therapy treatment decisions after prostatectomy. METHODS: We engaged a total of 22 stakeholders, including: prostate cancer patients, urological surgeons, radiation oncologists, genomic testing industry representatives, and biomedical informatics faculty. Slides were at each meeting to provide background information regarding the analytical framework. Participants were invited to provide feedback during the meeting, including revising the overall project aims. Stakeholder meeting content was reviewed and summarized by stakeholder group and by theme. RESULTS: The majority of stakeholder suggestions focused on aspects of decision aid design and formatting. Stakeholders were enthusiastic about the potential value of using decision analysis modeling with personalized model inputs for cancer recurrence risk, as well as competing risks from age and comorbidities, to generate a patient-centered tool to assist decision-making. Stakeholders did not view privacy considerations as a major barrier to the proposed decision aid program. A common theme was that decision aids should be portable across multiple platforms (electronic and paper), should allow for interaction by the user to adjust model inputs iteratively, and available to patients both before and during consult appointments. Emphasis was placed on the challenge of explaining the model's composite result of quality-adjusted life years. CONCLUSIONS: A range of stakeholders provided valuable insights regarding the design of a personalized decision aid program, based upon Markov modeling with individualized model inputs, to provide a patient-centered framework to support for genomic-based treatment decisions for cancer patients. The guidance provided by our stakeholders may be broadly applicable to the communication of genomic test results to patients in a patient-centered fashion that supports effective shared decision-making that represents a spectrum of personal factors such as age, medical comorbidities, and individual priorities and values. PMID- 28836986 TI - Robotic versus laparoscopic Gastrectomy for gastric cancer: a systematic review and updated meta-analysis. AB - BACKGROUND: Advanced minimally invasive techniques including robotic surgery are being employed with increasing frequency around the world, primarily in order to improve the surgical outcomes of laparoscopic gastrectomy (LG). We conducted a systematic review and meta-analysis to evaluate the feasibility, safety and efficacy of robotic gastrectomy (RG). METHODS: Studies, which compared surgical outcomes between LG and RG, were retrieved from medical databases before May 2017. Outcomes of interest were estimated as weighted mean difference (WMD) or risk ratio (RR) using the random-effects model. The software Review Manage version 5.1 was used for all calculations. RESULTS: Nineteen comparative studies with 5953 patients were included in this analysis. Compared with LG, RG was associated with longer operation time (WMD = -49.05 min; 95% CI: -58.18 ~ -39.91, P < 0.01), less intraoperative blood loss (WMD = 24.38 ml; 95% CI: 12.32 ~ 36.43, P < 0.01), earlier time to oral intake (WMD = 0.23 days; 95% CI: 0.13 ~ 0.34, P < 0.01), and a higher expense (WMD = -3944.8 USD; 95% CI: -4943.5 ~ -2946.2, P < 0.01). There was no significant difference between RG and LG regarding time to flatus, hospitalization, morbidity, mortality, harvested lymph nodes, and cancer recurrence. CONCLUSIONS: RG can be performed as safely as LG. However, it will take more effort to decrease operation time and expense. PMID- 28836987 TI - Benefits of different intensity of aerobic exercise in modulating body composition among obese young adults: a pilot randomized controlled trial. AB - BACKGROUND: The aim of present study was to compare the effects of different aerobic exercise intensities and energy expenditures on the body composition of sedentary obese college students in Taiwan. METHODS: Forty-eight obese participants [body mass index (BMI) >= 27 kg/m2, age 18-26 years] were randomized into four equal groups (n = 12): light-intensity training group (LITG), 40%-50% heart rate reserve (HRR); middle-intensity training group (MITG), 50%-70% HRR; high-intensity training group (HITG), 70%-80% HRR; and control group (CG). The aerobic exercise training program was conducted for 60 min per day on a treadmill 3 days per week for 12 weeks. All participant anthropometric data, blood biochemical parameters, and health-related physical fitness components were measured at baseline and after 12 weeks. RESULTS: At baseline, the anthropometric indices did not differ significantly among the four groups (p > 0.05). After 12 week exercise intervention, the HITG and MITG had significantly more changes in body weight, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to height ratio (WHtR) than the LITG. The changes in BMI and body fat percentage differed among all four groups (p < 0.05). CONCLUSIONS: A 12-week high-intensity exercise intervention with high energy expenditure can considerably reduce body weight, body fat, WC, WHR, and WHtR, whereas a light-intensity exercise intervention can significantly reduce body weight and body fat. TRIAL REGISTRATION: Current Controlled Trials TPECTR09831410900 , registered on 24th Dec 2009. PMID- 28836988 TI - Does antithrombotic therapy improve survival with colorectal cancer? AB - BACKGROUND: The study aimed to evaluate the prognosis for patients with colorectal cancer who underwent surgery while receiving antithrombotic therapy (ATT) across all disease stages and for patients at disease stages 0-III. METHODS: This retrospective cohort study included 710 Japanese patients who underwent surgery for colorectal cancer between January 2009 and November 2015 at our institution. Approximately 35% of these patients received ATT. Of these, 199 (28.0%) received antiplatelet therapy, and 76 (10.7%) received anticoagulant therapy. We investigated the prognosis among patients with colorectal cancer receiving ATT, antiplatelet therapy, or anticoagulant therapy in all-stage and stage 0-III cancers. RESULTS: For all disease stages combined, no benefit was observed for ATT, antiplatelet therapy, and anticoagulant therapy groups in the overall survival rates (ATT: 87.8 vs. 78.4%, P = 0.23; antiplatelet therapy: 87.8 vs. 78.6%, P = 0.25; and anticoagulant therapy: 92.2 vs. 80.2%, P = 0.26). However, overall survival rates of patients with stage 0-III colorectal cancer undergoing ATT, antiplatelet therapy, and anticoagulant therapy significantly improved. (ATT: 98.5 vs. 92.7%, P = 0.01; antiplatelet therapy: 98.3 vs. 91.1%, P = 0.02; and anticoagulant therapy: 100 vs. 92.1%, P = 0.00). CONCLUSION: Receiving ATT significantly improves overall survival rates in patients with stage 0-III colorectal cancer. PMID- 28836989 TI - Experience of maintaining tooth brushing for children born with a cleft lip and/or palate. AB - BACKGROUND: Children with a Cleft Lip and/or Palate (CL/P) have been reported to have poorer oral health than those without the condition. The consequences for these children can be particularly problematic due to implications for future treatments. Tooth brushing is an important behaviour contributing to children's oral health, but is under researched in the CL/P population. The aim of the study is to explore the experience of maintaining tooth brushing among children in the United Kingdom (UK) with a CL/P and their parents. METHODS: Semi-structured interviews were carried out with twenty-two parents and sixteen children with a CL/P (5-11 years), recruited at a cleft centre in the UK. Thematic analysis was used for data analysis. RESULTS: Three key themes were drawn from the qualitative data: first, parents of children with a CL/P generally had strong motivation to look after their children's teeth but children's motivation was inconsistent. Second, parents were primary enablers of children's tooth brushing behaviour, often employing approaches adapted to their child's characteristics to encourage tooth brushing. Third, a range of obstacles were encountered by parents and children in maintaining regular tooth brushing behaviours. They reported obstacles such as issues related to CL/P, 'forgetting' and childhood illness. CONCLUSIONS: The paper suggests that parents of children with a CL/P need support to enact their intention to maintain regular tooth brushing and prioritise tooth brushing within the context of demanding and dynamic family life. PMID- 28836990 TI - Wound healing effect of Euphorbia hirta linn. (Euphorbiaceae) in alloxan induced diabetic rats. AB - BACKGROUND: Euphorbia hirta linn., is a species of Euphorbiaceae family. They are known as asthma plant, barokhervi. The plant E. hirta is famous for its medicinal importance among the tribal population. It is a common practice to use the whole to heal wounds. Several pharmacological properties including antiseptic, anti inflammatory, antidibetic, antispasmodic, antibacterial, antiviral, antifungal, anticonvulsant, nootropic, antifertility and aphrodisiac properties have already been reported for this plant. The aim of present work was to evaluate the wound healing property in diabetic animals by oral and topical administration of ethanolic extract of E. hirta whole plant. METHODS: The ethanolic extract of E. hirta was subjected to determine the total phenolic content and total flavonoid content using galic acid and quercetin, respectively as standard. A single injection of alloxan monohydrate (120 mg/kg, i.p.) prepared in normal saline was administered to produce diabetes in rats, after overnight fasting. For analyzing the rate of contraction of wound, excision wounds sized 4.90cm2 and of 2 mm depth were used. Oral (100, 200 and 400 mg/kg/day; p.o.) and topical treatment with the extract (5% and 10% ointment 50 mg/kg/day) and standard (5% povidone iodine ointment 50 mg/kg/day) was started on the day of induction of wound and continued up to 16 days. The means of wound area measurement between groups at different time intervals were compared using ANOVA and Dunnet's test. The diabetic wound healing mechanism was studied by measuring the plasma level of glucose, malondialdehyde (MDA) and nitric oxide (NO) in both control and treated groups. For the confirmation of activity, histopathology of the wounds tissues from excision wound model was performed. RESULTS: Phytochemical investigations showed the presence of various phytoconstituents (carbohydrates, saponins, alkaloids, glycosides, steroids, flavonoids, tannins). In the ethanolic extract of E. hirta the total phenol content was 285 +/- 3.22 mg/g whereas the total flavonoid content was 118.46 +/- 1.85 mg/g. In the present study, E. hirta caused significant wound closer both orally (35.92%, 44.69% and 61.42% at the doses of 100, 200 and 400, respectively) and topically (32.86% and 36.32% at the doses of 5% and 10%) treated groups as compared to diabetic control. However, the orally treated groups showed more significant effect than the topically treated groups. Moreover, oral administration of E. hirta ethanolic extract significantly reduced the blood glucose levels in diabetic wound rats (p < 0.01) on day 8 and day 16 as compared to the diabetic wound control (p < 0.01). On the other hand, topical application of E. hirta did not influence the blood glucose levels in diabetic rats (p > 0.05). It also demonstrated a significant decrease in the plasma levels of lipid malondialdehyde and nitric oxide. The results of biochemical parameters were further supported by the histopathological changes of different organs (liver, pancrease, kidney, heart and skin from wound area) which were evidenced through a decrease in inflammatory cell infiltration. CONCLUSION: The present study demonstrates that E. hirta whole plant extract promotes healing of wounds more significantly as compared to diabetic control rats, where healing is otherwise delayed. PMID- 28836992 TI - Real-life prevalence of resistance-associated variants against non-structural protein 5A inhibitors and efficiency of Daclatasvir + Asunaprevir therapy in Korean patients with genotype 1b hepatitis C. AB - BACKGROUND: Direct-acting antivirals (DAAs) for chronic hepatitis C (CHC) treatment are tolerable and highly effective in a shorter period of time than before. However, resistance-associated variants (RAVs) can affect the efficacy of DAAs. The aim of this study was to investigate the real-life prevalence of RAVs against non-structural protein 5A (NS5A) inhibitors in Korean patients with genotype 1b chronic hepatitis C. METHODS: All consecutive patients with CHC genotype 1b who underwent a RAV test at a single referral hospital were enrolled. RESULTS: A total of 142 patients (male 53, female 89) were tested for RAVs. The average age of the patients was 58 years. Liver cirrhosis was found in 34.5% (49/142) of patients, and 19.0% (29/142) of patients had previously undergone interferon-based treatment. Twenty-nine patients (20.4%) had RAVs (Y93 or L31). Y93H, L31, or Y93H with L31 were detected in 22 (15.5%), 8 (5.6%), and 1 (0.7%) patients, respectively. The presence of RAV was not affected by previous interferon-based treatment or by the existence of liver cirrhosis. Among 113 patients without baseline NS5A RAVs, 72 patients started daclatasvir (DCV) + asunaprevir (ASV) treatment and 95% (68/72) patients achieved virologic response at week 4. Virologic response at end of treatment and sustained virologic response at 12 weeks after treatment were achieved by 94% (68/72) and 94% (68/72), respectively. CONCLUSIONS: In Korean patients with genotype 1b CHC, 20.4% (29 of 142) of patients showed RAVs against NS5A inhibitors. Patient without RAVs who received treatment with DCV + ASV showed high virologic response rates in Korea. PMID- 28836993 TI - The Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial: update to the study protocol and detailed statistical analysis plan (SAP). AB - BACKGROUND: Cellulitis is a painful, potentially serious, infectious process of the dermal and subdermal tissues and represents a significant disease burden. The statistical analysis plan (SAP) for the Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial is described here. The PEDOCELL trial is a multicentre, randomised, parallel-arm, double-blinded, non inferiority clinical trial comparing the efficacy of flucloxacillin (monotherapy) with combination flucloxacillin/phenoxymethylpenicillin (dual therapy) for the outpatient treatment of cellulitis in the emergency department (ED) setting. To prevent outcome reporting bias, selective reporting and data-driven results, the a priori-defined, detailed SAP is presented here. METHODS/DESIGN: Patients will be randomised to either orally administered flucloxacillin 500 mg four times daily and placebo or orally administered 500 mg of flucloxacillin four times daily and phenoxymethylpenicillin 500 mg four times daily. The trial consists of a 7-day intervention period and a 2-week follow-up period. Study measurements will be taken at four specific time points: at patient enrolment, day 2-3 after enrolment and commencing treatment (early clinical response (ECR) visit), day 8 10 after enrolment (end-of-treatment (EOT) visit) and day 14-21 after enrolment (test-of-cure (TOC) visit). The primary outcome measure is investigator determined clinical response measured at the TOC visit. The secondary outcomes are as follows: lesion size at ECR, clinical treatment failure at each follow-up visit, adherence and persistence of trial patients with orally administered antibiotic therapy at EOT, health-related quality of life (HRQoL) and pharmacoeconomic assessments. The plan for the presentation and comparison of baseline characteristics and outcomes is described in this paper. DISCUSSION: This trial aims to establish the non-inferiority of orally administered flucloxacillin monotherapy with orally administered flucloxacillin/phenoxymethylpenicillin dual therapy for the ED-directed outpatient treatment of cellulitis. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. The SAP for the PEDOCELL trial was developed a priori in order to minimise analysis bias. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT number: 2016-001528-69). Registered on 5 April 2016. ClinicalTrials.gov, ID: NCT02922686 . Registered on 9 August 2016. PMID- 28836994 TI - The Spanish version of the Patient-Rated Wrist Evaluation outcome measure: cross cultural adaptation process, reliability, measurement error and construct validity. AB - BACKGROUND: The Patient-Rated Wrist Evaluation (PRWE) is a widely used measure of patient-reported disability and pain related to wrist disorders. We performed cross-cultural adaptation of the PRWE into Spanish (Spain) and assessed reliability and construct validity in patients with distal radius fracture. METHODS: Adaptation of the English version to Spanish (Spain) was performed using translation/back translation methodology. The measurement properties of the PRWE Spanish were assessed in a sample of 40 consecutive patients (31 women), mean age 58 (SD 19) years, with extra-articular distal radius fractures treated with closed reduction and cast. The patients completed the PRWE-Spanish and the standard Spanish versions of the 11-item Disabilities of the Arm, Shoulder and Hand (QuickDASH) and EQ-5D questionnaires at baseline (health status before fracture) and at 8, 9, 12, and 13 weeks after treatment. Internal-consistency reliability was assessed with the Cronbach alpha coefficient and test-retest reliability with the intraclass correlation coefficient (ICC) comparing responses at 8 and 9 weeks and responses at 12 and 13 weeks. Cross-sectional precision was analyzed with the Standard Error of the Measurement (SEM). Longitudinal precision for test-retest reliability coefficient was analyzed with the Standard Error of the Measurement difference (SEMdiff) and the Minimal Detectable Change at 90% (MDC90) and 95% (MDC95) confidence levels. For assessing construct validity we hypothesized that the PRWE-Spanish (lower score indicates less disability and pain) would have strong positive correlation with the QuickDASH (lower score indicates less disability) and moderate negative correlation with the EQ-5D Index (higher score indicates better health); Spearman correlation coefficient (r) was used. RESULTS: For the PRWE total score, Cronbach alpha was 0.98 (SEM = 2.67) at baseline and 0.96 (SEM = 4.37) at 8 weeks. For test-retest reliability ICC was 0.94 (8 and 9 weeks) and 0.96 (12 and 13 weeks) with SEMdiff 7.61 and 6.18 and MDC95 13.74 and 12.11, respectively. The PRWE-Spanish scores had strong positive correlation with the QuickDASH scores at baseline (r = 0.71) and at 8 weeks (r = 0.79) and moderate negative correlation with the EQ-5D Index (r = -0.44 and r = 0.40, respectively). CONCLUSIONS: The PRWE-Spanish showed high internal consistency and test-retest reliability and good construct validity in patients with distal radius fracture. PMID- 28836995 TI - Glycemic effects of quinine infusion in healthy volunteers. AB - BACKGROUND: We aimed to quantify the glycemic effects of quinine in healthy individuals. METHODS: We evaluated the glycemic profile in response to 4 h infusion of 500 ml of 0.9% saline versus 5% glucose solution with and without quinine at therapeutic dose (500 mg) in ten healthy volunteers (8 men) aged 28 +/ 9 years. The order of the fourth explorations was randomly assigned. During these explorations, we measured blood glucose every 15 min for 4 h and compared the mean and glycemic fluctuations for each test. A resting ECG was performed before and after quinine infusion in each participant. RESULTS: The mean glycemic level during the 4-h infusion was 83 +/- 5 mg/dl without quinine versus 74 +/- 5 mg/dl with quinine (p < 0.001) using saline solute versus 92 +/- 7 mg/dl without quinine versus 82 +/- 5 mg/dl with quinine (p < 0.001) when associated with the glucose solute. In isotonic dirty solute, quinine induces a cumulative glycemic decrease of 17.5% (p = 0.01) characterized by a nadir estimated at -26.5% at the 60th minute (65 +/- 23 mg/dl), p <0.001 followed by a gradual increase until the 4th hour. There were no signs of hypoglycemia or significant prolongation of the QT interval at the ECG. Overall, quinine did not induce a significant change in blood glucose with glucose compared to saline. CONCLUSION: The intravenous infusion of quinine at a therapeutic dose induces a light drop in blood glucose with a significant nadir at the 60th minute in the healthy subject without hypoglycemia. This suggests the need for close monitoring in patients at risk of hypoglycemia such as those with severe malaria especially during the first hour of quinine infusion. PMID- 28836996 TI - Random or predictable?: Adoption patterns of chronic care management practices in physician organizations. AB - BACKGROUND: Theories, models, and frameworks used by implementation science, including Diffusion of Innovations, tend to focus on the adoption of one innovation, when often organizations may be facing multiple simultaneous adoption decisions. For instance, despite evidence that care management practices (CMPs) are helpful in managing chronic illness, there is still uneven adoption by physician organizations. This exploratory paper leverages this natural variation in uptake to describe inter-organizational patterns in adoption of CMPs and to better understand how adoption choices may be related to one another. METHODS: We assessed a cross section of national survey data from physician organizations reporting on the use of 20 CMPs (5 each for asthma, congestive heart failure, depression, and diabetes). Item response theory was used to explore patterns in adoption, first considering all 20 CMPs together and then by subsets according to disease focus or CMP type (e.g., registries, patient reminders). Mokken scale analysis explored whether adoption choices were linked by disease focus or CMP type and whether a consistent ordering of adoption choices was present. RESULTS: The Mokken scale for all 20 CMPs demonstrated medium scalability (H = 0.43), but no consistent ordering. Scales for subsets of CMPs sharing a disease focus had medium scalability (0.4 < H < 0.5), while subsets sharing a CMP type had strong scalability (H > 0.5). Scales for CMP type consistently ranked diabetes CMPs as most adoptable and depression CMPs as least adoptable. Within disease focus scales, patient reminders were ranked as the most adoptable CMP, while clinician feedback and patient education were ranked the least adoptable. CONCLUSIONS: Patterns of adoption indicate that innovation characteristics may influence adoption. CMP dissemination efforts may be strengthened by encouraging traditionally non-adopting organizations to focus on more adoptable practices first and then describing a pathway for the adoption of subsequent CMPs. Clarifying why certain CMPs are "less adoptable" may also provide insights into how to overcome CMP adoption constraints. PMID- 28836997 TI - Ethnomedicinal plants used by local inhabitants of Jakholi block, Rudraprayag district, western Himalaya, India. AB - BACKGROUND: Ethnomedicinal knowledge of the Indian Himalayas is very interesting because of the wide range of medicinal plants used in traditional medical practice. However, there is a danger of knowledge being lost because the knowledge sharing is very limited and passed on orally. The present study is the first ethnomedicinal study in Jakholi area of Rudraprayag district of Northwestern India. The aim of present study was to identify traditional medicinal plants used by the inhabitants to treat different ailments and document the associated knowledge of these medicinal plants. METHODS: An ethnomedicinal survey was carried out in 72 of 133 villages and alpine pastures of Jakholi block (800-4000 m asl). Door to door surveys and group discussions, applying semi structured questionnaires were conducted with traditional healers and villagers in local language (Garhwali). Informant Consensus Factor (ICF) was computed to analyse collected ethnomedicinal data. RESULTS: A total of 78 species (Gymnosperms 3 species, Monocotyledons 12 and 63 Dicotyledons) belonging to 73 genera in 46 families were identified to treat 14 different ailments categories. Most dominant family is Asteraceae (5 species). In disease treated categories, Diseases of the skin (DE) have the highest proportion (29.55%) followed by Gastro intestinal disorder (GA) (25.89%). The most life form of plants used was herb (56%) followed by tree (23%) while root was the most frequently used part of the plants and the traditional preparation was mainly applied in the form of paste (37%). The highest ICF value (0.99) was found for hair ailments (HA) followed ophthalmologic complaints (OP) and mental afflictions (MA) (0.98). CONCLUSIONS: The present study provides valuable information about traditional knowledge of medicinal plants of Jakholi Block in the Northwestern Himalaya, India. Local communities still possess large traditional knowledge of plants and their therapeutic uses and that the link of that traditional knowledge to modern research could be of importance for the isolation of new phytotherapeutic compounds leading to the development of novel therapeutic active agents. Some of the ethnomedicinal plants are facing high threats and are becoming rare, and conservation initiatives are needed to conserve them for sustainable management in the region. PMID- 28836991 TI - Modeling DNA damage-induced pneumopathy in mice: insight from danger signaling cascades. AB - Radiation-induced pneumonitis and fibrosis represent severe and dose-limiting side effects in the radiotherapy of thorax-associated neoplasms leading to decreased quality of life or - as a consequence of treatment with suboptimal radiation doses - to fatal outcomes by local recurrence or metastatic disease. It is assumed that the initial radiation-induced damage to the resident cells triggers a multifaceted damage-signalling cascade in irradiated normal tissues including a multifactorial secretory program. The resulting pro-inflammatory and pro-angiogenic microenvironment triggers a cascade of events that can lead within weeks to a pronounced lung inflammation (pneumonitis) or after months to excessive deposition of extracellular matrix molecules and tissue scarring (pulmonary fibrosis).The use of preclinical in vivo models of DNA damage-induced pneumopathy in genetically modified mice has helped to substantially advance our understanding of molecular mechanisms and signalling molecules that participate in the pathogenesis of radiation-induced adverse late effects in the lung. Herein, murine models of whole thorax irradiation or hemithorax irradiation nicely reproduce the pathogenesis of the human disease with respect to the time course and the clinical symptoms. Alternatively, treatment with the radiomimetic DNA damaging chemotherapeutic drug Bleomycin (BLM) has frequently been used as a surrogate model of radiation-induced lung disease. The advantage of the BLM model is that the symptoms of pneumonitis and fibrosis develop within 1 month.Here we summarize and discuss published data about the role of danger signalling in the response of the lung tissue to DNA damage and its cross-talk with the innate and adaptive immune systems obtained in preclinical studies using immune-deficient inbred mouse strains and genetically modified mice. Interestingly we observed differences in the role of molecules involved in damage sensing (TOLL-like receptors), damage signalling (MyD88) and immune regulation (cytokines, CD73, lymphocytes) for the pathogenesis and progression of DNA damage-induced pneumopathy between the models of pneumopathy induced by whole thorax irradiation or treatment with the radiomimetic drug BLM. These findings underline the importance to pursue studies in the radiation model(s) if we are to unravel the mechanisms driving radiation-induced adverse late effects.A better understanding of the cross-talk of danger perception and signalling with immune activation and repair mechanisms may allow a modulation of these processes to prevent or treat radiation-induced adverse effects. Vice-versa an improved knowledge of the normal tissue response to injury is also particularly important in view of the increasing interest in combining radiotherapy with immune checkpoint blockade or immunotherapies to avoid exacerbation of radiation-induced normal tissue toxicity. PMID- 28836998 TI - Towards comprehensive and effective strategies to address sexual health. AB - Sexual health is an important global public health concern. Planning effective strategies to improve sexual health requires a high degree of attention to the local epidemiological trends and cultural context where the strategy is to be implemented. The paper by Chemtob et al. describes the process to develop a plan that aims to reduce the burden of Sexually Transmitted Infections in Israel by 2025. This commentary argues that increased attention to planning and implementation of sexual health policy is required in order to address the real burden of disease. Sexual health should not be merely addressed from a communicable disease control perspective but should comprehensively address health and wellbeing of all population groups through a positive approach in line with the WHO current definition of sexual health. As even traditionally culturally conservative societies are experiencing rapid changes in attitudes and practices towards sexual lifestyles, the challenge is to ensure that sexual health strategies combine evidence-informed measures and good practices with culturally appropriate communication and implementation approaches. PMID- 28836999 TI - Erratum to: SuperTranscripts: a data driven reference for analysis and visualisation of transcriptomes. PMID- 28837000 TI - MAGE-specific T cells detected directly ex-vivo correlate with complete remission in metastatic breast cancer patients after sequential immune-endocrine therapy. AB - Studies suggest that conventional cancer therapies given after immunotherapy (IT) can boost antitumor immunity and possibly improve response rates and progression free survival. We report two cases of metastatic breast cancer with durable complete responses (CRs) after sequential IT and endocrine therapy. Immune analyses of these long-term disease-free breast cancer patients previously treated with imiquimod (IMQ) suggest in-situ vaccination is achieved by topical application of the TLR-7 agonist directly onto tumors. Furthermore, IT-induced antigen-specific T cells were expanded by subsequent endocrine therapy and correlated with response, persisting > 2 years. Our findings therefore suggest that the induction/boosting of polyfunctional tumor antigen-specific T in response to sequential immune endocrine therapy and detected directly ex-vivo can serve as a peripheral blood biomarker for true clinical benefit. PMID- 28837001 TI - New skin for the old RNA-Seq ceremony: the age of single-cell multi-omics. AB - New methods for simultaneously quantifying protein and gene expression at the single-cell level have the power to identify cell types and to classify cell populations. PMID- 28837002 TI - Early gut mycobiota and mother-offspring transfer. AB - BACKGROUND: The fungi in the gastrointestinal tract, the gut mycobiota, are now recognised as a significant part of the gut microbiota, and they may be important to human health. In contrast to the adult gut mycobiota, the establishment of the early gut mycobiota has never been described, and there is little knowledge about the fungal transfer from mother to offspring. METHODS: In a prospective cohort, we followed 298 pairs of healthy mothers and offspring from 36 weeks of gestation until 2 years of age (1516 samples) and explored the gut mycobiota in maternal and offspring samples. Half of the pregnant mothers were randomised into drinking probiotic milk during and after pregnancy. The probiotic bacteria included Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis subsp. lactis Bb-12 and Lactobacillus acidophilus La-5. We quantified the fungal abundance of all the samples using qPCR of the fungal internal transcribed spacer (ITS)1 segment, and we sequenced the 18S rRNA gene ITS1 region of 90 high-quantity samples using the MiSeq platform (Illumina). RESULTS: The gut mycobiota was detected in most of the mothers and the majority of the offspring. The offspring showed increased odds of having detectable faecal fungal DNA if the mother had detectable fungal DNA as well (OR = 1.54, p = 0.04). The fungal alpha diversity in the offspring gut increased from its lowest at 10 days after birth, which was the earliest sampling point. The fungal diversity and fungal species showed a succession towards the maternal mycobiota as the child aged, with Debaryomyces hansenii being the most abundant species during breast-feeding and Saccharomyces cerevisiae as the most abundant after weaning. Probiotic consumption increased the gut mycobiota abundance in pregnant mothers (p = 0.01). CONCLUSION: This study provides the first insight into the early fungal establishment and the succession of fungal species in the gut mycobiota. The results support the idea that the fungal host phenotype is transferred from mother to offspring. TRIAL REGISTRATION: Clinicaltrials.gov NCT00159523. PMID- 28837005 TI - Sphingomonas crusticola sp. nov., isolated from biological soil crusts. AB - A yellow-pigmented, Gram-stain-negative, short-rod-shaped bacterial strain, MIMD3T, was isolated from biological soil crusts collected in Liangcheng, north western China. Cell growth could be observed at 10-37 degrees C (optimum 25 degrees C), at pH 5-8 (optimum 6.6) and in the presence of 1 % (w/v) NaCl (optimum 0 %). The genomic DNA G+C content was 65.0 mol%. Analysis of 16S rRNA gene sequences showed that strain MIMD3T shared the highest similarity with Sphingomonas vulcanisoli KCTC 42454T (95.1 %), Sphingomonas oligophenolica JCM 12082T (94.8 %), Sphingomonas mali IFO 15500T (94.5 %), Sphingomonas. leidyi ATCC 15260T (94.4 %) and Sphingomonas formosensis CC-Nfb-2T (94.3 %). The strain had Q 10 as the predominant respiratory quinone, and sym-homospermidine as the major polyamine. The major fatty acids of the strain were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), C19 : 0 cyclo omega8c, C14 : 0 2-OH and C16 : 0. The main polar lipids of strain MIMD3T were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and sphingoglycolipid. Based on phenotypic, chemotaxonomic and phylogenetic characteristics, it is concluded that strain MIMD3T represents a novel species of the genus Sphingomonas, for which the name Sphingomonas crusticola sp. nov. is proposed. The type strain is MIMD3T (=KCTC 42801T=MCCC 1K01310T). PMID- 28837006 TI - The Delivery of Palliative and End-of-Life Care in Ontario. AB - Healthcare use in the year prior to death represents a large portion of healthcare spending by older adults. While Canada is considered to have advanced integration of palliative care services within our healthcare system, much of this care is still delivered in hospitals and with varying levels of access according to cause of death trajectory and geography. Results presented in a series of studies from the Institute for Clinical Evaluative Sciences (ICES) unveil gaps in current palliative care delivery and offer directions for future research and policy development. PMID- 28837004 TI - Antibiotic exposure and risk of weight gain and obesity: protocol for a systematic review. AB - BACKGROUND: The prevalence of obesity is increasing worldwide, and there is growing interest in better delineating the role of the human gut microbiome in this phenomenon. Obesity-specific gut microbiome features have been observed in both human and animal studies, and these variations appear to play a causative role in increasing body weight. There is evidence that antibiotics can modify the composition and diversity of the gut microbiome and that this may contribute to body weight changes. The primary objective of the proposed systematic review is to evaluate and synthesize the existing evidence evaluating the possible association between antibiotic use, weight gain, and obesity. METHODS: A comprehensive search of the MEDLINE and EMBASE databases will be performed. Both randomized and non-randomized studies (excluding case reports) in neonates, children, adults, and pregnant women will be included. The exposure of interest is antibiotics of any type, duration, and route given for any indication. All included studies must have a comparator group. The primary outcomes are the development of overweight and obesity. Secondary outcomes are percent weight change from baseline and change in body mass index or waist circumference. Additional secondary outcomes in pregnant women are gestational weight gain, postpartum weight retention, offspring birth weight, childhood weight, and obesity. Risk of bias of included trials will be performed. Two reviewers will screen and perform data extraction independently. DISCUSSION: This systematic review will summarize the existing evidence evaluating the association between antibiotic use, weight gain, and obesity and facilitate the identification of important gaps and uncertainties in the literature. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017069177. PMID- 28837008 TI - In Conversation with Mark Hundert. PMID- 28837007 TI - New Tools for Measuring and Improving Patient Safety in Canadian Hospitals. AB - The Canadian Institute for Health Information (CIHI) and the Canadian Patient Safety Institute (CPSI) have collaborated on a new measure of patient safety, along with a resource of evidence-informed practices. This measure captures four broad categories of harm in acute care hospitals, consisting of 31 clinical groups selected by clinicians. Analysis showed that harm was experienced in 1 of 18 hospital stays in Canada in 2014?2015 and that no single category accounted for the majority of harmful events. Although CIHI and CPSI continue to work with hospitals and experts to further refine the methodology, the measure and associated Improvement Resource are useful new tools for monitoring and identifying harm, and have the potential to improve patient safety. PMID- 28837009 TI - Public and Professional Insights on End-of-Life Care: Results of the 2016 Health Care in Canada Survey. AB - A new dimension has been added to Canadian Medicare ? exemption from prosecution for physicians, nurse practitioners and assistants providing medical assistance in dying for competent and informed adult patients with a grievous and irremediable medical condition causing intolerable physical or psychological suffering, irreversible decline in capabilities and reasonably foreseeable natural death. To define stakeholders' perceptions on all contemporary end-of life care options, we analyzed data from the 2016 Health Care in Canada Survey comprising representative samples of the adult public (n = 1,500), physicians (n = 102), nurses (n = 102), pharmacists (n = 100), administrators (n = 100) and allied health professionals (n = 100). Among the public, enhanced pain management, hospice/palliative care and home/family care were all supported at, or above, the 80th percentile; medically assisted death was supported by 70%. Among all professionals, hospice/palliative care, pain management and home care garnered >90% support; support for medically assisted death ranged from 58% (physicians) to 79% (allied professionals). In terms of priority to implement available options, medically assisted death was rated first by 46% of the public, overall, and by 69% of the sub-group who strongly supported it, followed by enhanced pain management (45%) and home care (42%). Among professionals, top implementation priorities (range: 57?61%) were: enhanced pain management, hospice/palliative care and home care support. Priority for medically assisted death ranged between 25% and 41%, although among professionals who strongly supported it, it was their top priority (52%). When asked to balance patients' right to access assisted death, versus some professionals' reluctance to provide it, 42% of the public and the majority of professionals thought providers should be allowed to opt out if they referred patients to another willing provider. And many professionals perceive some risk of either legal or regulatory reprisal if they assist in patients' deaths. In summary, there is substantial contemporary support for all components of end-of-life care among all stakeholders. However, non-lethal care modalities remain generally preferred, perhaps, at least in part, because medical professionals have a pervasive concern of going in harm's way by participating in assisted death, or by refusing. Things can be better. PMID- 28837010 TI - Second Medical Opinions in End-of-Life Disputes in Critical Care: An Ethics-Based Approach. AB - Requests for a second medical opinion (SMO) by patients or substitute decision makers (SDMs) can arise during end-of-life disputes in critical care. Such disagreements between patients or SDMs and physicians often pertain to specific elements of the decision-making process related to withholding or withdrawing of life-sustaining treatments. When these disputes occur in the critical care setting in Canada, practicalities and policy barriers prevent an SDM from obtaining an SMO without support from healthcare providers; moreover, in a majority of these cases the SDM will require the facilitation of a physician who is often the same individual with whom they are in conflict. Institutional and a national society's policy statements propose SMOs as an important component of a conflict resolution process for end-of-life disputes (Bosslet et al. 2015; Singer et al. 2001). However, these policies do not provide specific guidance to physicians on how to fairly consider SMO requests. Given the vulnerable position of patients and their SDMs in the critical care context and in order to promote fairness, physicians should apply consistent standards in deciding whether to facilitate a request for an SMO. To guide physicians' decision-making and inform future policy development, we propose three ethical principles for considering SDM requests for an SMO in critical care at the end of life. PMID- 28837011 TI - A Survey of Hospital Ethics Structures in Ontario. AB - In response to the growing recognition of the prevalence of ethical issues in clinical care, hospitals in Canada began forming ethics committees in the 1980s. Studies showed significant growth in the prevalence of ethics committees over the ensuing decade. Although the limited studies available suggest that ethics committees have become very prevalent in Canadian hospitals, hospital ethics services have evolved in recent years to include a wider range of structures. In some cases, these structures may work in conjunction with an ethics committee, but in other cases they may replace ethics committees. They include on-staff ethicists, external ethics consultants, "hub-and-spokes" structures and regional ethics programs. What is not known, however, is how prevalent these other structures are and whether ethics committees continue to function as the main delivery mechanism for ethics services in Canadian hospitals. This paper reports on the results of a survey of hospitals in Ontario to answer those questions. PMID- 28837012 TI - Persistent and Non-Persistent High-Users of Acute Care Resources: A Deeper Dive into the Patient and System Factors. AB - A small population of patients are responsible for the majority of Ontario's acute healthcare costs ? high-users of acute care. At our institution, high-users were divided into those who persisted in their high use across more than six months and those who did not. Persistent users were more likely to live alone, have more than three comorbidities, take more than five medications and be admitted for chronic diseases. In a survey of their family physicians, 58% believed no interventions could have prevented readmissions; however, useful strategies such as patient education, surgical rapid access clinics and increased mental health supports were proposed. PMID- 28837013 TI - Six Change Ideas that Significantly Minimize Alternate Level of Care (ALC) Days in Acute Care Hospitals. AB - A significant issue affecting the healthcare system across Ontario is the number of patients admitted to hospitals that are then subsequently being designated alternate level of care (ALC). In 2016, 14.5% of Ontario in-patient beds were occupied by ALC-designated patients. Contributing to this phenomenon are ethical errors that can affect decision-making around discharge. Since 2012, William Osler Health System has redesigned their discharge process to eliminate ethical errors and align more fully with the Health Care Consent Act (HCCA) and the Public Hospitals Act (PHA). Through quality improvement processes including the use of scripting, education, checklists, mentoring and role clarity, Osler's ALC days are currently the lowest in the province of Ontario. The elimination of such errors also decreased patient confusion and improved the discharge experience. PMID- 28837014 TI - Leading Practices in Alternate Level of Care (ALC) Avoidance: A Standardized Approach. AB - Providers across the healthcare system want to provide the right care, in the right place, in a timely manner. Patients listed as alternate level of care (ALC) are often not in the right place to receive the necessary care. In 2014, using a standardized approach, the Toronto Central Community Care Access Centre (CCAC), now Toronto Central Local Health Integration Network (LHIN), set out to reduce the number of ALC beds in hospitals to ensure that more people received the most appropriate level and type of care. Case studies cited in this article will highlight the successes that CCAC and its various partners have realized in developing and implementing strategies. PMID- 28837015 TI - Conserving Quality of Life through Community Paramedics. AB - The Economic Value of Community Paramedicine Programs Study was a randomized controlled trial in two Eastern Ontario communities ? one urban and one rural ? to determine whether community paramedicine services (the intervention through home visits) would have a positive economic impact through influencing self perceived quality of life and determining a monetized value. A total of 200 clients who were high-users of healthcare services and had one or more of five chronic diseases (congestive heart failure, chronic obstructive pulmonary disease, hypertension, stroke and diabetes) were recruited in early 2015. These participants were randomly assigned to either the intervention group (receiving community paramedicine services for 12 months) or the control group (receiving conventional treatment). Study results suggest that although quality of life scores decreased for all groups, those receiving community paramedicine services demonstrated significantly less reduction in their scores. Suggestions to further increase cost efficiency of this novel service are given. PMID- 28837016 TI - Medication Incidents Involving Antiepileptic Drugs in Canadian Hospitals: A Multi Incident Analysis. AB - Medication errors involving antiepileptic drugs (AEDs) are not well studied but have the potential to cause significant harm. We investigated the occurrence of medication incidents in Canadian hospitals that involve AEDs, their severity and contributing factors by analyzing data from two national databases. Our multi incident analysis revealed that while medication errors were rarely fatal, errors do occur of which some are serious. Medication incidents were most commonly caused by dose omissions, the dose or its frequency being incorrect and the wrong AED being given. Our analysis could augment quality-improvement initiatives by medication safety administrators to reduce AED medication incidents in hospitals. PMID- 28837017 TI - Sustainable Benefits of a Community Hospital-Based Paediatric Asthma Clinic. AB - In 2011, we reported that our paediatric asthma clinic (PAC) appeared to significantly reduce the burden of paediatric asthma in our community. Supported by these results, the PAC underwent a gradual threefold expansion while maintaining the same model of care. We now report on the outcome of that expansion and demonstrate that our PAC continues to significantly reduce the burden of paediatric asthma in our community. As previously, newly enrolled PAC patients continue to show a 12-month reduction in asthma-related emergency department (ED) visits and admissions exceeding 60% and 80%, respectively. This consistent short-term benefit, coupled with clinic expansion, has contributed to a significant improvement in our rate of paediatric asthma-related ED visits or hospitalizations when compared to other Ontario hospitals. PMID- 28837018 TI - Strategic Change in Surgical Quality Improvement: The Ottawa Hospital (TOH) Comprehensive Unit-Based Safety Program (CUSP) Experience. AB - Strategic change principles are widely cited in business and healthcare management literature, but not in the surgical quality improvement literature despite the need for effective change management skills to successfully enable quality improvement projects. The Ottawa Hospital (TOH) Comprehensive Unit-Based Safety Program (CUSP) model within the Division of General Surgery applied strategic change management principles to support the development and implementation of surgical quality improvement initiatives. Using the TOH CUSP experience, we aim to provide insight and a practical example for surgeons seeking to drive quality improvement within their practice environment. PMID- 28837019 TI - Medial thalamic stroke and its impact on familiarity and recollection. AB - Models of recognition memory have postulated that the mammillo-thalamic tract (MTT)/anterior thalamic nucleus (AN) complex would be critical for recollection while the Mediodorsal nucleus (MD) of the thalamus would support familiarity and indirectly also be involved in recollection (Aggleton et al., 2011). 12 patients with left thalamic stroke underwent a neuropsychological assessment, three verbal recognition memory tasks assessing familiarity and recollection each using different procedures and a high-resolution structural MRI. Patients showed poor recollection on all three tasks. In contrast, familiarity was spared in each task. No patient had significant AN lesions. Critically, a subset of 5 patients had lesions of the MD without lesions of the MTT. They also showed impaired recollection but preserved familiarity. Recollection is therefore impaired following MD damage, but familiarity is not. This suggests that models of familiarity, which assign a critical role to the MD, should be reappraised. PMID- 28837021 TI - Single, successful lady is looking for... a baby. PMID- 28837020 TI - Modelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan Africa. AB - Rapid diagnostic tests (RDTs) have transformed malaria diagnosis. The most prevalent P. falciparum RDTs detect histidine-rich protein 2 (PfHRP2). However, pfhrp2 gene deletions yielding false-negative RDTs, first reported in South America in 2010, have been confirmed in Africa and Asia. We developed a mathematical model to explore the potential for RDT-led diagnosis to drive selection of pfhrp2-deleted parasites. Low malaria prevalence and high frequencies of people seeking treatment resulted in the greatest selection pressure. Calibrating our model against confirmed pfhrp2-deletions in the Democratic Republic of Congo, we estimate a starting frequency of 6% pfhrp2 deletion prior to RDT introduction. Furthermore, the patterns observed necessitate a degree of selection driven by the introduction of PfHRP2-based RDT guided treatment. Combining this with parasite prevalence and treatment coverage estimates, we map the model-predicted spread of pfhrp2-deletion, and identify the geographic regions in which surveillance for pfhrp2-deletion should be prioritised. PMID- 28837022 TI - Comments on the paper "The new Portuguese law on surrogacy - The story of how a promising law does not really regulate surrogacy arrangements". PMID- 28837023 TI - Assisted reproductive techniques in Latin America: The Latin American Registry, 2014. AB - Multinational data on assisted reproduction techniques undertaken in 2014 were collected from 159 institutions in 15 countries in Latin America. Treatments included IVF/ ICSI, FET, OD, PGD and fertility preservation (FP). 41.34% of IVF/ICSI cycles were performed in women aged 35 to 39 years and 23.35% in women aged 40 and older. After removing cases with total freezing, delivery rate per oocyte retrieval was 25.05% for ICSI and 27.41% for IVF. Multiple births included 20.78% twins and 0.92 % triplets and over. In OD, twins reached 28.93% and triplets 1.07 %. Preterm deliveries reached 16.4% in singletons, 55.02% in twins and 76% in triplets. Perinatal mortality in 18,162 births was 23 per 1000 in singletons, 35 per 1000 in twins, and 36 per 1000 in high-order multiples. Elective single embryo transfer (eSET) represented only 2.63 % of fresh transfers, with a delivery rate of 32.15% per transfer. Elective double embryo transfer (eDET) represented 23.74% of transfers, with a delivery rate of 41.03% per transfer. Among babies born during this period 11,373 (62.6%) were singletons; 6,398 (35.2%) twins, and 391 (2.2%), triplets and more. Given the effect of multiple births on prematurity, morbidity and perinatal mortality, reinforcing the existing trend of reducing the number of embryos transferred is mandatory. PMID- 28837024 TI - The predictive value of serum concentrations of anti-Mullerian hormone for oocyte quality, fertilization, and implantation. AB - OBJECTIVE: This study aimed to identify a possible correlation between serum levels of anti-Mullerian hormone (AMH) and oocyte quality, embryo developmental competence, and implantation potential. METHODS: 4488 oocytes obtained from 408 patients undergoing ICSI cycles were evaluated. Oocyte dimorphisms, embryo quality on days two and three, blastocyst formation competence, fertilization rates, implantation rates, and pregnancy rates were correlated with serum levels of AMH using Pearson's correlation coefficient and regression analysis. RESULTS: A positive correlation was observed between serum levels of AMH and number of retrieved oocytes (CC: 0.600, p<0.001), fertilization rate (CC:0.595, p=0.048), and number of obtained embryos (CC:0.495, p<0.001). AMH did not affect the quality of cleavage stage embryos or the chance of blastocyst formation. However, AMH levels affected oocyte quality (OR:0.75, CI 0.44-0.96, p<0.001), and implantation (CC:0,116, p=0.031) and pregnancy (OR:1.22, CI:1.03-1.53, p<0.001) rates. CONCLUSION: Serum levels of AMH are a useful predictor of ovarian response to COS, oocyte quality, and fertilization. However, AMH levels may also compromise clinical outcomes; lower AMH levels did not impair embryo development. PMID- 28837025 TI - Comparison of two different dosage of GnRH agonist as ovulation trigger in oocyte donors: a randomized controled trial. AB - OBJECTIVE: To compare the results obtained with two different GnRH agonist dosages: 0.3mg versus 0.4mg to trigger ovulation in oocyte donor cycles. METHODS: Experimental controlled randomized trial including 40 patients from a private practice center. The patients were randomized into two groups. Group A received a single dose of Triptorelin 0.3mg (Decapeptyl(r)) 36hours before pick-up. Group B patients received Triptorelin 0.4mg (Decapeptyl(r)) before pick-up to final oocyte maturation. We evaluated the total number of oocytes collected, the number of mature oocytes and total days of ovarian stimulation. RESULTS: The average of total collected oocytes were 16 (Group A) versus 15 (Group B), and the mean number of mature oocytes were 13 versus 12 respectively. The only variable showing a difference was the percentage of mature oocytes, which was greater in Group A, resulting in 84.6%, in contrast with those treated with 0.4mg of Triptorelin (78.6%), although these differences were not statistical significant (p=0.35). Days of stimulation did not differ between groups. No cases of empty follicle syndrome were reported. CONCLUSIONS: We found that an increase from 0.3 to 0.4mg of triptorelin in an oocyte donation program might not improve outcomes. Nevertheless, more studies might be necessary, not only in oocyte donors but in sterile women as well, to evaluate how GnRH agonist dosage could affect the results among other factors. PMID- 28837026 TI - A comparison between a new vitrification protocol and the slow freezing method in the cryopreservation of prepubertal testicular tissue. AB - OBJECTIVE: This study aimed to compare a new vitrification protocol with reduced cryoprotectant exposure to the slow freezing method in the cryopreservation of prepubertal rat testicular tissue. METHODS: Five sexually immature male Wistar rats were submitted to bilateral orchiectomy. Tissue samples from each testicle were fragmented into small pieces and randomly assigned to three groups: Group A, fresh tissue (control); Group B, slow programmable freezing (SPF); and Group C (vitrification). Frozen/thawed, vitrified/warmed, and fresh testicular tissue were histologically compared. A pathologist blinded to the procedures assessed the morphology (cell differentiation, nuclei, and epithelium) of 10 seminiferous tubules from each testicle (100 tubules per Group). RESULTS: Sertoli and spermatogonial stem cells were easily differentiated, and the nucleoli were easily viewed in the tubules assessed in all three groups. Small alterations in tissue architecture were observed in the control group as a result of tissue handling. Moderate alterations of the epithelium with the formation of small gaps and cell detachment from the basement membrane were observed in 28% of the frozen and 9% of the vitrified tubules. Condensed nuclei involving a small proportion of cells were observed in six and three tubules of the frozen and vitrified group, respectively. Despite the alterations, 97% of the frozen and 99% of the vitrified tubules were considered well preserved. CONCLUSIONS: The findings indicate that the vitrification protocol tested in this study adequately preserved the morphological integrity of prepubertal testicular tissue in a rat model. Further studies are required to confirm testicular tissue function after grafting. PMID- 28837027 TI - Expression of PGR, HBEGF, ITGAV, ITGB3 and SPP1 genes in eutopic endometrium of infertile women with endometriosis during the implantation window: a pilot study. AB - OBJECTIVE: Alterations in endometrial receptivity may be involved in the etiopathogenesis of endometriosis-related infertility. The literature has suggested that patients with endometriosis present progestin resistance, which could affect embryo implantation. We question the presence of alterations in the expression of the progesterone receptor gene (PGR) and the genes related to endometrium-embryo interaction regulated by progesterone. This pilot study compared the expression of PGR, HBEGF, ITGAV, ITGB3, and SPP1 genes in eutopic endometrium during the implantation window (IW) in infertile women with endometriosis with that observed in the endometrium of fertile and infertile controls. METHODS: In this prospective case-control study, endometrial biopsies were performed during the IW in patients aged between 18 and 45 years old, with regular cycles and without endocrine/systemic dysfunctions, divided into endometriosis (END), infertile control (IC) and fertile control (FC) groups. Total RNA extraction, cDNA synthesis, and gene expression analysis by Real-Time PCR were performed. We assessed the size of the difference that our series was powered to detect. RESULTS: From the 687 patients who underwent diagnostic videolaparoscopy or tubal ligation at the University Hospital, 130 were eligible. Of these, 32 had endometrial samples collected, with 17 confirmed in the IW. Fifteen samples (5 END, 5 IC and 5 FC) were analyzed. There was no significant difference in the expression of any studied gene. Our sample size allowed us to identify or discard large differences (two standard deviations) among the groups. CONCLUSION: Endometriosis doesn't cause large changes in the endometrial expression of PGR, HBEGF, ITGAV, ITGB3 and SPP1 during the IW. PMID- 28837028 TI - Chromosomal analysis of blastocyst derived from monopronucleated ICSI zygotes: approach by double trophectoderm biopsy. AB - OBJECTIVE: This study aims to increase the knowledge about monopronucleated ICSI derived blastocysts, analyzing trophectoderm biopsies by aCGH and FISH to evaluate their chromosome constitution. METHODS: Fifteen monopronucleated ICSI derived blastocysts were studied. Double trophectoderm biopsy was performed and analyzed by FISH and aCGH. The blastocysts were classified according to chromosome constitution. Disagreements between the two techniques were assessed. RESULTS: Results obtained after FISH and aCGH analyses showed the following: 20% (3/15) and 60% (9/15) diploid females, respectively; 26.7% (4/15) and 26.7% (4/15) diploid males, respectively; and 53.3% (8/15) and 13.3% (2/15) mosaics, respectively. No mosaic male embryos were found using FISH or aCGH. There were disagreements in 40% (6/15) of the cases due to the higher detection of mosaicism by FISH compared to aCGH. CONCLUSIONS: The combination of FISH and aCGH has been shown to be a suitable approach to increase the knowledge about monopronucleated ICSI-derived embryos. FISH analysis of blastocysts derived from monopronucleated ICSI zygotes enabled us to conclude that aCGH underestimates haploidy. Some diploid embryos diagnosed by aCGH are in fact mosaic. In cases where these embryos would be used for reproductive purposes, extra analysis of parental genome origin is recommended. PMID- 28837029 TI - Zika Virus Outbreak - Should assisted reproduction patients avoid pregnancy? AB - OBJECTIVE: To discuss the requirement from the National Health Surveillance Agency (ANVISA), for assisted reproduction treatment patients to undergo laboratory tests for ZIKV detection, and if the public health authorities and government leaders' recommendations to women simply avoid pregnancy is prudent. METHODS: This study was performed in a university-affiliated in vitro fertilization center in Brazil. We present a critical discussion on the risk of microcephaly due to ZIKV infection and the prevalence of other harmful pathogens to vulnerable pregnant women and infants. We assessed, 954 patients undergoing intracytoplasmic sperm injection cycles (ICSI), between April and November of 2016, concerning the results of ZIKV test, according to different regions in Brazil. RESULTS: Patients undergoing ICSI cycles were split into groups, according to their region of origin: 28 (3.0%) were from the North, 27 (2.8%) were from the Northeast, 40 (4.2%) were from the Midwest, 830 (87.2%) were from the Southeast, and 29 (3.0%) were from the South. Concerning the diagnosis, 112 samples had a positive or inconclusive result for ZIKV, by chromatography immunoassay. These samples were re-analyzed by ELISA and no result was positive. All positive results were from the Southeast region and none from the Northeast or Midwest regions, which are considered endemic regions. CONCLUSION: ZIKV test before the onset of assisted reproduction treatments does not rule out the risk of the infection during pregnancy. In addition, although ZIKV infection risk is extremely high, the microcephaly risk due to ZIKV is not higher than the risk of miscarriage and birth defects due to other recognized pathogens. PMID- 28837030 TI - The adverse effect of overweight in assisted reproduction treatment outcomes. AB - OBJECTIVE: To assess Body Mass Index (BMI) effects on the results obtained from ICSI cycles. METHODS: We studied 266 ICSI cycles performed between January 2014 and December 2016. The patients were grouped according to their BMI in: Normal (18.5-24.9), Overweight (25.0-29.9) and Obese (>30). We compared the following variables between the groups: number of antral follicles, ovarian stimulation length, gonadotropin dose used, maximum estradiol level, follicles developed/antral follicles, retrieved oocytes/developed follicles and mature/retrieved oocytes, normal fertilization rate, embryo achieved/normal fertilized oocytes, clinical pregnancy and implantation rates. We used the Kruskal-Wallis and the Chi square tests. p<0.05 was considered significant. RESULTS: Normal, Overweight and Obese patients presented comparable values for number of antral follicles (11.6+/-5.4, 12.5+/-5.5, 12.2+/-5.7), ovarian stimulation length (7.5+/-1.4, 7.6+/-1.1, 7.8+/-1.3) and gonadotropin dose used (2043+/-489, 1940+/-536, 2109+/-605). Obese patients had lower values of estradiol (1560+/-610, 1511+/-635, 1190+/-466; p=0.018), developed follicles (81%, 76%, 70%; p<0.0001), and retrieved oocytes (91%, 90%, 84%; p=0.0017); and not significantly lower values of mature oocytes (82%, 82%, 77%; p=0.26). The groups had comparable fertilization rates (72%, 73%, 69%) and embryo achieved rates (67%, 63%, 72%). The normal group had higher, but not significantly higher pregnancy and implantation rates (43%, 40%, 38%, p=0.53; and 33%, 26%, 23%; p=0.11), and significantly higher ongoing pregnancy rates (37%, 33%, 33%, p=0.042). CONCLUSION: Increased BMI patients had impaired ovarian response and lower pregnancy rates in ICSI cycles. PMID- 28837031 TI - Can ovarian double-stimulation in the same menstrual cycle improve IVF outcomes? AB - OBJECTIVE: To evaluate the double-stimulation protocol efficacy over conventional ovarian stimulation in recovering a more adequate number of oocytes and increase the number of embryos to be transferred or to be genetically analyzed. METHODS: A retrospective and comparative study with 13 patients who underwent unsuccessful in vitro fertilization (IVF) cycles with a conventional antagonist ovarian stimulation protocol and repeat the attempt with a double stimulation protocol. The following variables were analyzed: number of oocytes collected, mature oocytes collected, fertilization rate, blastocyst rate, biopsied blastocyst rate and euploidy rate. RESULTS: The double stimulation protocol had a significant higher number of oocytes collected (p=0.007) and mature oocytes to be injected (p=0.01). There was no statistically significant difference in fertilization (p=0.78) and blastocyst (p=0.59) rates. CONCLUSION: Double stimulation favors patients who are at risk of incurring several attempts of IVF to achieve pregnancy. PMID- 28837032 TI - Blastocyst classification systems used in Latin America: is a consensus possible? AB - OBJECTIVE: To identify different blastocyst classification systems used by embryologists in Latin American countries and evaluate the possibility of establishing a consensus among these countries. METHODS: An E-mail survey was carried out through the Latin American Network of Assisted Reproduction (REDLARA) aimed at embryologists from assisted reproduction centers in Latin countries. RESULTS: Sixty surveys were collected from 12 Latin American countries, of which 66.7% had >10years of professional practice as embryologists. Seven different blastocyst classification systems were reported, of which 5 have previously been described in the literature. CONCLUSION: Although the group of embryologists surveyed use different blastocyst classification systems, most in this group consider that the embryo score system should be unified in their countries as well as in the region. PMID- 28837033 TI - The new Portuguese law on surrogacy - The story of how a promising law does not really regulate surrogacy arrangements. AB - Since 2006, surrogacy arrangements have been expressly forbidden within the Portuguese legal order, in any one of its forms, and in some situations, it has even been criminalised. However, since August 2016, surrogacy has been allowed under certain restrictive scenarios, providing it follows several prerequisites. In spite of this progress, the 2016 amendment to the law has not been immune to criticism. One of its most debatable aspects is the lack of the surrogate's right to regret, although it is doubtful that surrogacy contracts will be enforced against a surrogate's wishes. But the weakest point of the new law is its failure to address some of the nuclear issues of surrogacy contracts, leaving solutions either to general contract law or to the clauses stipulated by the parties. Furthermore, it is unclear which clauses are allowed and which are forbidden under the law. This study describes the content of the new Portuguese surrogacy law, exposes its main fragilities and suggests solutions for matters not covered by the law. The conclusion is that a law full of promise fails regarding the issues it is supposed to regulate. PMID- 28837034 TI - Single versus sequential culture medium: which is better at improving ongoing pregnancy rates? A systematic review and meta-analysis. AB - This study aimed to evaluate if single medium is better than sequential medium at improving ongoing pregnancy rates in patients undergoing assisted reproductive technology (ART) procedures. The data featured in this meta-analysis were extracted from four randomized controlled trials yielded from a systematic search carried out on electronic databases. The primary endpoint was ongoing pregnancy rate. Secondary endpoints included clinical pregnancy and miscarriage rates. The endpoints for ongoing pregnancy rate were also analyzed based on the time at which the embryo transfers were performed: cleavage stage (day 2/3) and/or blastocyst stage (day 5/6). There were no significant differences between single and sequential medium for clinical pregnancy (RR=1.09; 95%CI=0.83-1.44; p=0.53), ongoing pregnancy (RR=1.11; 95%CI=0.87-1.40; p=0.39), or miscarriage rates (RR=0.89; 95%CI=0.44-1.81; p=0.74). No significant difference was found for ongoing pregnancy rate (RR=1.29; 95%CI=0.93-1.78; p=0.12) between single and sequential medium when only trials in which embryos were transferred at the blastocyst stage were included. In conclusion, the choice of embryo culture approach - single or sequential medium - did not affect the ongoing pregnancy rates of patients undergoing ART cycles. PMID- 28837035 TI - Estradiol use in the luteal phase and its effects on pregnancy rates in IVF cycles with GnRH antagonist: a systematic review. AB - For all the steps of in vitro fertilization to occur successfully, factors such as the quality of retrieved oocytes and endometrial receptivity to the embryo must be ensured. Current studies have shown that endometrial receptivity can be optimized using dedicated exogenous progesterone for luteal phase support in assisted reproduction cycles. But it has not yet been established the benefits of additional use of estradiol in this support. Analyzing pituitary suppression protocols that employ GnRH antagonists, this review will address literature publications between the years 2000-2016, shedding light on this issue to answer questions about the benefits of supplementation. PMID- 28837036 TI - Are children born from singleton pregnancies conceived by ICSI at increased risk for congenital malformations when compared to children conceived naturally? A systematic review and meta-analysis. AB - Since 1992, the development of intra-cytoplasmic sperm injection (ICSI) has allowed infertile couples and couples affected by severe male factor infertility in particular, many of which with a history of failed traditional IVF, to become parents. This has generated considerable controversy over the safety of the procedure for the offspring. This systematic review seeks to determine whether evidence indicates that the use of ICSI increases the risk of congenital malformation in children born from singleton pregnancies versus naturally conceived children. Twenty-one of the 104 publications listed in the literature search were included in the analysis. Observational studies reported mostly an increased risk for congenital malformation; the risk of congenital malformations is 7.1% in ICSI and 4.0% in the general population (OR 1.99 (95% CI [1.87 - 2.11]). However, attributing higher risk solely to ICSI might seem far-fetched, as in vitro and simulation procedures, patient diseases, and ICSI indication may also be associated with higher risk of malformation. PMID- 28837039 TI - Abstracts of the 21th Annual Congress of the SBRA, Sao Paulo/SP, 02-5 August 2017. PMID- 28837038 TI - Abstracts of the 21st Annual Congress of the SBRA, Sao Paulo/SP, 02-5 August 2017. PMID- 28837037 TI - Fresh embryos versus freeze-all embryos - transfer strategies: Nuances of a meta analysis. AB - OBJECTIVE: The present meta-analysis aimed to evaluate whether the freeze-all strategy (Freeze/All-ET) could bring about improvements in the clinical assisted reproductive technique (ART) outcomes when compared with the fresh embryo transfer strategy (Fresh-ET) in patients undergoing an ART cycle in accordance with the mean number of oocytes collected. METHODS: A systematic review based on electronic searches in databases (PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials) was carried out to identify randomized controlled trails (RCTs) comparing ART outcomes between fresh-embryo transfers versus elective frozen-embryo transfers up to February of 2017. Four reviewers independently evaluated abstracts, validity assessment and data extraction. Odds Ratio (OR) values with a 95% confidence interval (CI), and heterogeneity were evaluated. RESULTS: Five RCTs were included as targets for data extraction and meta-analysis purposes. The results of this meta-analysis were divided into two parts (Freeze/All-ET versus Fresh-ET): Part I- All trials in which the mean number of collected oocytes was >12 and <21 for ongoing pregnancy rate (OR=1.24; 95%CI=1.06-1.44), clinical pregnancy rate (OR=1.19; 95%CI=0.98-1.43), live birth rate (OR= 1.39; 95%CI=0.99-1.95), and miscarriage rate (OR=0.68; 95%CI=0.46-1.00); Part II- Three studies where the mean number of oocytes retrieved was >12 and <15 for ongoing pregnancy rate (OR=1.17; 95%CI=1.00 1.38), clinical pregnancy rate (OR=1.34; 95%CI=0.79-2.28), live birth rate (OR= 1.24; 95%CI=1.00-1.55), and miscarriage rate (RR=0.68; 95%CI=0.46-1.02). CONCLUSIONS: The freeze-all strategy could be favorable when high numbers of oocytes are collected, signaling an association between higher ovarian stimulation and consequent impairment of endometrial receptivity. However, when the mean number of oocytes collected is <15, the freeze-all strategy does not appear to be advantageous. PMID- 28837040 TI - Green bioprinting: extrusion-based fabrication of plant cell-laden biopolymer hydrogel scaffolds. AB - Plant cell cultures produce active agents for pharmaceuticals, food and cosmetics. However, up to now process control for plant cell suspension cultures is challenging. A positive impact of cell immobilization, such as encapsulation in hydrogel beads, on secondary metabolites production has been reported for several plant species. The aim of this work was to develop a method for bioprinting of plant cells in order to allow fabrication of free-formed three dimensional matrices with defined internal pore architecture for in depth characterization of immobilization conditions, cell agglomeration and interactions. By using extrusion-based 3D plotting of a basil cell-laden hydrogel blend consisting of alginate, agarose and methylcellulose (alg/aga/mc), we could demonstrate that bioprinting is applicable to plant cells. The majority of the cells survived plotting and crosslinking and the embedded cells showed high viability and metabolic activity during the investigated cultivation period of 20 d. Beside its compatibility with the plant cells, the novel alg/aga/mc blend allowed fabrication of defined 3D constructs with open macropores both in vertical and horizontal direction which were stable under culture conditions for several weeks. Thus, Green Bioprinting, an additive manufacturing technology processing live cells from the plant kingdom, is a promising new immobilization tool for plant cells that enables the development of new bioprocesses for secondary metabolites production as well as monitoring methods. PMID- 28837041 TI - Laser processing of protein films as a method for accomplishment of cell patterning at the microscale. AB - In this study, we propose a photostructuring approach for protein films based on a treatment with nanosecond pulses of a KrF excimer laser. As a model protein we used an amyloid fibril-forming protein. Laser treatment induced a foaming of the sample surface exhibiting an interconnected fibrous mesh with a high degree of control and precision. The surface foaming was well characterized by scanning electron microscopy, atomic force microscopy, laser induced fluorescence and contact angle measurements. The laser irradiated areas of the protein films acquired new morphological and physicochemical properties that could be exploited to fulfill unmet challenges in the tissue engineering field. In this context we subsequently evaluated the response of NIH/3T3 fibroblast cell line on the processed film. Our results show a strong and statistically significant preference for adhesion and proliferation of cells on the irradiated areas compared to the non-irradiated ones. We propose that this strategy can be followed to induce selective cell patterning on protein films at the microscale. PMID- 28837042 TI - High mobility 2-dimensional electron gas at LaAlO3/SrTiO3 interface prepared by spin coating chemical methods. AB - Highly mobile 2-dimensional electron gases (2DEGs) at the (001), (011) and (111) oriented LaAlO3/SrTiO3 (LAO/STO) interfaces are obtained using spin coating chemical method, which is a gentle technique without plasma bombardment of the pulsed laser deposition. As revealed by x-ray diffraction spectrum and x-ray reflectivity analysis, the LAO over layer is epitaxially grown, and has a uniform thickness of ~15 nm, ~20 nm and ~26 nm for (001), (011) and (111) orientations, respectively. The interfaces are well metallic down to 2 K. The carrier mobilities are ~28 000 cm2 V-1 s-1, ~22 000 cm2 V-1 s-1 and ~8300 cm2 V-1 s-1 at 2 K for the (001), (011) and (111) LAO/STO interfaces, respectively, and ~8 cm2 V 1 s-1, ~4 cm2 V-1 s-1 and ~4 cm2 V-1 s-1 at room temperature. The present work shows that the spin coating chemical method is a feasible approach to get high quality 2DEG at both the polar/non-polar and polar/polar interfaces. PMID- 28837043 TI - A 3D printed microfluidic perfusion device for multicellular spheroid cultures. AB - The advent of 3D printing technologies promises to make microfluidic organ-on chip technologies more accessible for the biological research community. To date, hydrogel-encapsulated cells have been successfully incorporated into 3D printed microfluidic devices. However, there is currently no 3D printed microfluidic device that can support multicellular spheroid culture, which facilitates extensive cell-cell contacts important for recapitulating many multicellular functional biological structures. Here, we report a first instance of fabricating a 3D printed microfluidic cell culture device capable of directly immobilizing and maintaining the viability and functionality of 3D multicellular spheroids. We evaluated the feasibility of two common 3D printing technologies i.e. stereolithography (SLA) and PolyJet printing, and found that SLA could prototype a device comprising of cell immobilizing micro-structures that were housed within a microfluidic network with higher fidelity. We have also implemented a pump-free perfusion system, relying on gravity-driven flow to perform medium perfusion in order to reduce the complexity and footprint of the device setup, thereby improving its adaptability into a standard biological laboratory. Finally, we demonstrated the biological performance of the 3D printed device by performing pump-free perfusion cultures of patient-derived parental and metastatic oral squamous cell carcinoma tumor and liver cell (HepG2) spheroids with good cell viability and functionality. This paper presents a proof-of-concept in simplifying and integrating the prototyping and operation of a microfluidic spheroid culture device, which will facilitate its applications in various drug efficacy, metabolism and toxicity studies. PMID- 28837044 TI - Estimation of lung shunt fraction from simultaneous fluoroscopic and nuclear images. AB - : Radioembolisation with yttrium-90 (90Y) is increasingly used as a treatment of unresectable liver malignancies. For safety, a scout dose of technetium-99m macroaggregated albumin (99mTc-MAA) is used prior to the delivery of the therapeutic activity to mimic the deposition of 90Y. One-day procedures are currently limited by the lack of nuclear images in the intervention room. To cope with this limitation, an interventional simultaneous fluoroscopic and nuclear imaging device is currently being developed. The purpose of this simulation study was to evaluate the accuracy of estimating the lung shunt fraction (LSF) of the scout dose in the intervention room with this device and compare it against current clinical methods. METHODS: A male and female XCAT phantom, both with two respiratory profiles, were used to simulate various LSFs resulting from a scout dose of 150 MBq 99mTc-MAA. Hybrid images were Monte Carlo simulated for breath hold (5 s) and dynamic breathing (10 frames of 0.5 s) acquisitions. Nuclear images were corrected for attenuation with the fluoroscopic image and for organ overlap effects using a pre-treatment CT-scan. For comparison purposes, planar scintigraphy and mobile gamma camera images (both 300 s acquisition time) were simulated. Estimated LSFs were evaluated for all methods and compared to the phantom ground truth. RESULTS: In the clinically relevant range of 10-20% LSF, hybrid imaging overestimated LSF with approximately 2 percentage points (pp) and 3 pp for the normal and irregular breathing phantoms, respectively. After organ overlap correction, LSF was estimated with a more constant error. Errors in planar scintigraphy and mobile gamma camera imaging were more dependent on LSF, body shape and breathing profile. CONCLUSION: LSF can be estimated with a constant minor error with a hybrid imaging device. Estimated LSF is highly dependent on true LSF, body shape and breathing pattern when estimated with current clinical methods. The hybrid imaging device is capable of accurately estimating LSF within a few seconds in an interventional setting. PMID- 28837045 TI - Subject-specific bone attenuation correction for brain PET/MR: can ZTE-MRI substitute CT scan accurately? AB - In brain PET/MR applications, accurate attenuation maps are required for accurate PET image quantification. An implemented attenuation correction (AC) method for brain imaging is the single-atlas approach that estimates an AC map from an averaged CT template. As an alternative, we propose to use a zero echo time (ZTE) pulse sequence to segment bone, air and soft tissue. A linear relationship between histogram normalized ZTE intensity and measured CT density in Hounsfield units ([Formula: see text]) in bone has been established thanks to a CT-MR database of 16 patients. Continuous AC maps were computed based on the segmented ZTE by setting a fixed linear attenuation coefficient (LAC) to air and soft tissue and by using the linear relationship to generate continuous MU values for the bone. Additionally, for the purpose of comparison, four other AC maps were generated: a ZTE derived AC map with a fixed LAC for the bone, an AC map based on the single-atlas approach as provided by the PET/MR manufacturer, a soft-tissue only AC map and, finally, the CT derived attenuation map used as the gold standard (CTAC). All these AC maps were used with different levels of smoothing for PET image reconstruction with and without time-of-flight (TOF). The subject specific AC map generated by combining ZTE-based segmentation and linear scaling of the normalized ZTE signal into [Formula: see text] was found to be a good substitute for the measured CTAC map in brain PET/MR when used with a Gaussian smoothing kernel of [Formula: see text] corresponding to the PET scanner intrinsic resolution. As expected TOF reduces AC error regardless of the AC method. The continuous ZTE-AC performed better than the other alternative MR derived AC methods, reducing the quantification error between the MRAC corrected PET image and the reference CTAC corrected PET image. PMID- 28837046 TI - Association between pathology and texture features of multi parametric MRI of the prostate. AB - The role of multi-parametric (mp)MRI in the diagnosis and treatment of prostate cancer has increased considerably. An alternative to visual inspection of mpMRI is the evaluation using histogram-based (first order statistics) parameters and textural features (second order statistics). The aims of the present work were to investigate the relationship between benign and malignant sub-volumes of the prostate and textures obtained from mpMR images. The performance of tumor prediction was investigated based on the combination of histogram-based and textural parameters. Subsequently, the relative importance of mpMR images was assessed and the benefit of additional imaging analyzed. Finally, sub-structures based on the PI-RADS classification were investigated as potential regions to automatically detect maligned lesions. Twenty-five patients who received mpMRI prior to radical prostatectomy were included in the study. The imaging protocol included T2, DWI, and DCE. Delineation of tumor regions was performed based on pathological information. First and second order statistics were derived from each structure and for all image modalities. The resulting data were processed with multivariate analysis, using PCA (principal component analysis) and OPLS-DA (orthogonal partial least squares discriminant analysis) for separation of malignant and healthy tissue. PCA showed a clear difference between tumor and healthy regions in the peripheral zone for all investigated images. The predictive ability of the OPLS-DA models increased for all image modalities when first and second order statistics were combined. The predictive value reached a plateau after adding ADC and T2, and did not increase further with the addition of other image information. The present study indicates a distinct difference in the signatures between malign and benign prostate tissue. This is an absolute prerequisite for automatic tumor segmentation, but only the first step in that direction. For the specific identified signature, DCE did not add complementary information to T2 and ADC maps. PMID- 28837047 TI - Lung respiration motion modeling: a sparse motion field presentation method using biplane x-ray images. AB - Respiration-introduced tumor location uncertainty is a challenge in the precise lung biopsy for lung lesions. Current statistical modeling approaches hardly capture the complex local respiratory motion information. In this study, we formulate a statistical respiratory motion model using biplane x-ray images to improve the accuracy of motion field estimation by efficiently preserving local motion details for specific patients. Given CT data sets of 18 healthy subjects at end-expiratory and end-inspiratory breathing phases, the respiratory motion field is constructed based on deformation vector fields which are extracted from these CT data sets, and a lung contour motion repository respiratory is generated dependent on displacements of boundary control points. By varying the sparse weight coefficients of the statistical sparse motion field presentation (SMFP) method, the newly-input motion field is approximately presented by a sparse linear combination of a subset of the motion repository. The SMFP method is employed twice in the coefficient optimization process. Finally, these non-zero coefficients are fine-tuned to maximize the similarity between the projection image of reconstructed volumetric images and the current x-ray image. We performed the proposed method for estimating respiratory motion field on ten subject datasets and compared the result with the PCA method. The maximum average target registration error of the PCA-based and the SMFP-based respiratory motion field estimation are 3.1(2.0) and 2.9(1.6) mm, respectively. The maximum average symmetric surface distance of two methods are 2.5(1.6) and 2.4(1.3) mm, respectively. PMID- 28837048 TI - Evaluation of motion correction for clinical dynamic contrast enhanced MRI of the liver. AB - Motion correction of 4D dynamic contrast enhanced MRI (DCE-MRI) series is required for diagnostic evaluation of liver lesions. The registration, however, is a challenging task, owing to rapid changes in image appearance. In this study, two different registration approaches are compared; a conventional pairwise method applying mutual information as metric and a groupwise method applying a principal component analysis based metric, introduced by Huizinga et al (2016). The pairwise method transforms the individual 3D images one by one to a reference image, whereas the groupwise registration method computes the metric on all the images simultaneously, exploiting the temporal information, and transforms all 3D images to a common space. The performance of the two registration methods was evaluated using 70 clinical 4D DCE-MRI series with the focus on the liver. The evaluation was based on the smoothness of the time intensity curves in lesions, lesion volume change after deformation and the smoothness of spatial deformation. Furthermore, the visual quality of subtraction images (pre-contrast image subtracted from the post contrast images) before and after registration was rated by two observers. Both registration methods improved the alignment of the DCE-MRI images in comparison to the non-corrected series. Furthermore, the groupwise method achieved better temporal alignment with smoother spatial deformations than the pairwise method. The quality of the subtraction images was graded satisfactory in 32% of the cases without registration and in 77% and 80% of the cases after pairwise and groupwise registration, respectively. In conclusion, the groupwise registration method outperforms the pairwise registration method and achieves clinically satisfying results. Registration leads to improved subtraction images. PMID- 28837049 TI - On the diffraction pattern of bundled rare-earth silicide nanowires on Si(0 0 1). AB - Motivated by the complex diffraction pattern observed for bundled rare-earth silicide nanowires on the Si(0 0 1) surface, we investigate the influence of the width and the spacing distribution of the nanowires on the diffraction pattern. The diffraction pattern of the bundled rare-earth silicide nanowires is analyzed by the binary surface technique applying a kinematic approach to diffraction. Assuming a categorical distribution for the (individual) nanowire size and a Poisson distribution for the size of the spacing between adjacent nanowire bundles, we are able to determine the parameters of these distributions and derive an expression for the distribution of the nanowire-bundle size. Additionally, the comparison of our simulations to the experimental diffraction pattern reveal that a (1 * 1)-periodicity on top of the nanowires has to be assumed for a good match. PMID- 28837050 TI - Edge absorption and pure spin current in a 2D topological insulator in the Volkov Pankratov model. AB - Light absorption due to transitions between the edge and two-dimensional (2D) states of a 2D topological insulator (TI) is considered in the Volkov-Pankratov model. It is shown that the transitions are allowed only for the in-plane electric field orthogonal to the TI edge. It is found that the absorption is accompanied by pure spin photocurrent along the TI edge. A possibility of spin current measurement using polarized luminescence from 2D TI quantum dots is discussed. PMID- 28837051 TI - Area-selective atomic layer deposition of Ru on electron-beam-written Pt(C) patterns versus SiO2 substratum. AB - Area selectivity is an emerging sub-topic in the field of atomic layer deposition (ALD), which employs opposite nucleation phenomena to distinct heterogeneous starting materials on a surface. In this paper, we intend to grow Ru exclusively on locally pre-defined Pt patterns, while keeping a SiO2 substratum free from any deposition. In a first step, we study in detail the Ru ALD nucleation on SiO2 and clarify the impact of the set-point temperature. An initial incubation period with actually no growth was revealed before a formation of minor, isolated RuO x islands; clearly no continuous Ru layer formed on SiO2. A lower temperature was beneficial in facilitating a longer incubation and consequently a wider window for (inherent) selectivity. In a second step, we write C-rich Pt micro-patterns on SiO2 by focused electron-beam-induced deposition (FEBID), varying the number of FEBID scans at two electron beam acceleration voltages. Subsequently, the localized Pt(C) deposits are pre-cleaned in O2 and overgrown by Ru ALD. Already sub-nanometer-thin Pt(C) patterns, which were supposedly purified into some form of Pt(O x ), acted as very effective activation for the locally restricted, thus area-selective ALD growth of a pure, continuous Ru covering, whereas the SiO2 substratum sufficiently inhibited towards no growth. FEBID at lower electron energy reduced unwanted stray deposition and achieved well-resolved pattern features. We access the nucleation phenomena by utilizing a hybrid metrology approach, which uniquely combines in-situ real-time spectroscopic ellipsometry, in-vacuo x-ray photoelectron spectroscopy, ex-situ high-resolution scanning electron microscopy, and mapping energy-dispersive x-ray spectroscopy. PMID- 28837052 TI - Bismuth subsalicylate nanoparticles with anaerobic antibacterial activity for dental applications. AB - In recent years, nanomaterials have been used in the medical-dental field as new alternative antimicrobial agents. Bismuth subsalicylate (BSS) has been used as an antimicrobial agent, but the effect of BSS in the form of nanoparticles (BSS nano) as a potential antimicrobial agent has not been tested, in specific against bacteria responsible for periodontal disease. The aim of this study was to evaluate the antibacterial effect of BSS-nano against oral anaerobic bacteria and to assess the safety of BSS-nano by evaluating their cytotoxicity in human gingival fibroblast (HGF-1) cells. BSS-nano were synthesized by laser ablation and were previously physico-chemically characterized using in vitro assays. The antibacterial activity was measured using the tetrazolium-based XTT assay, and cytotoxicity was determined using lactate dehydrogenase (LDH) and MTS assays in HGF-1 cells. Transmission electron microscopy of HGF-1 exposed to BSS-nano was also performed. BSS-nano was shown to have a primary size of 4-22 nm and a polygonal shape. Among the tested bacterial strains, those with a greater sensitivity to BSS-nano (highest concentration of 21.7 MUg ml-1) were A. actinomycetemcomitans, C. gingivalis, and P. gingivalis. BSS-nano at a concentration of 60 MUg ml-1 showed low cytotoxicity (6%) in HFG-1 cells and was mainly localized intracellularly in acidic vesicles. Our results indicate that the concentration of BSS-nano used as an effective antibacterial agent does not induce cytotoxicity in mammalian cells; thus, BSS-nano can be applied as an antibacterial agent in dental materials or antiseptic solutions. PMID- 28837053 TI - A multi-controlled drug delivery system based on magnetic mesoporous Fe3O4 nanopaticles and a phase change material for cancer thermo-chemotherapy. AB - Herein a novel multi-controlled drug release system for doxorubicin (DOX) was developed, in which monodisperse mesoporous Fe3O4 nanoparticles were combined with a phase change material (PCM) and polyethylene glycol 2000 (PEG2000). It is found that the PCM/PEG/DOX mixture containing 20% PEG could be dissolved into water at 42 degrees C. The mesoporous Fe3O4 nanoparticles prepared by the solvothermal method had sizes of around 25 nm and exhibited a mesoporous microstructure. A simple solvent evaporation process was employed to load the PCM/PEG/DOX mixture on the mesoporous Fe3O4 nanoparticles completely. In the Fe3O4@PCM/PEG/DOX system, the pores of the Fe3O4 nanoparticles were observed to be filled with the mixture of PCM/PEG/DOX. The Fe3O4@PCM/PEG/DOX system showed a saturation magnetization value of 50.0 emu g-1, lower than 71.1 emu g-1 of the mesoporous Fe3O4 nanoparticles, but it was still high enough for magnetic targeting and hyperthermia application. The evaluation on drug release performance indicated that the Fe3O4@PCM/PEG/DOX system achieved nearly zero release of DOX in vitro in body temperature, while around 80% of DOX could be released within 1.5 h at the therapeutic threshold of 42 degrees C or under the NIR laser irradiation for about 4 h. And a very rapid release of DOX was achieved by this system when applying an alternating magnetic field. By comparing the systems with and without PEG2000, it is revealed that the presence of PEG2000 makes DOX easy to be released from 1-tetradecanol to water, owing to its functions of increasing the solubility of DOX in 1-tetradecanol as well as decreasing the surface tension between water and 1-tetradecanol. The novel drug release system shows great potential for the development of thermo-chemotherapy of cancer treatment. PMID- 28837054 TI - Universal spectral signatures in pnictides and cuprates: the role of quasiparticle-pair coupling. AB - Understanding the physical properties of a large variety of high-T c superconductors (SC), the cuprate family as well as the more recent iron-based superconductors, is still a major challenge. In particular, these materials exhibit the 'peak-dip-hump' structure in the quasiparticle density of states (DOS). The origin of this structure is explained within our pair-pair interaction (PPI) model: The non-superconducting state consists of incoherent pairs, a 'Cooper-pair glass' which, due to the PPI, undergoes a Bose-like condensation below T c to the coherent SC state. We derive the equations of motion for the quasiparticle operators showing that the DOS 'peak-dip-hump' is caused by the coupling between quasiparticles and excited pair states, or 'super quasiparticles'. The renormalized SC gap function becomes energy-dependent and non retarded, reproducing accurately the experimental spectra of both pnictides and cuprates, despite the large difference in gap value. PMID- 28837055 TI - Intraoperative Molecular Imaging: The Surgical Oncologist's North Star. PMID- 28837056 TI - Reply. PMID- 28837058 TI - Development of a Handheld Line Information Reader and Generator for Efficient Management of Optical Communication Lines. AB - A handheld line information reader and a line information generator were developed for the efficient management of optical communication lines. The line information reader consists of a photo diode, trans-impedance amplifier, voltage amplifier, microcontroller unit, display panel, and communication modules. The line information generator consists of a laser diode, laser driving circuits, microcontroller unit, and communication modules. The line information reader can detect the optical radiation field of the test line by bending the optical fiber. To enhance the sensitivity of the line information reader, an additional lens was used with a focal length of 4.51 mm. Moreover, the simulation results obtained through BeamPROP(r) software from Synopsys, Inc. demonstrated a stronger optical radiation field of the fiber due to a longer transmission wavelength and larger bending angle of the fiber. Therefore, the developed devices can be considered as useful tools for the efficient management of optical communication lines. PMID- 28837057 TI - The Natural Fungal Metabolite Beauvericin Exerts Anticancer Activity In Vivo: A Pre-Clinical Pilot Study. AB - Recently, in vitro anti-cancer properties of beauvericin, a fungal metabolite were shown in various cancer cell lines. In this study, we assessed the specificity of this effect by comparing beauvericin cytotoxicity in malignant versus non-malignant cells. Moreover, we tested in vivo anticancer effects of beauvericin by treating BALB/c and CB-17/SCID mice bearing murine CT-26 or human KB-3-1-grafted tumors, respectively. Tumor size and weight were measured and histological sections were evaluated by Ki-67 and H/E staining as well as TdT mediated-dUTP-nick-end (TUNEL) labeling. Beauvericin levels were determined in various tissues and body fluids by LC-MS/MS. In addition to a more pronounced activity against malignant cells, we detected decreased tumor volumes and weights in beauvericin-treated mice compared to controls in both the allo- and the xenograft model without any adverse effects. No significant differences were detected concerning percentages of proliferating and mitotic cells in tumor sections from treated and untreated mice. However, a significant increase of necrotic areas within whole tumor sections of beauvericin-treated mice was found in both models corresponding to an enhanced number of TUNEL-positive, i.e., apoptotic, cells. Furthermore, moderate beauvericin accumulation was detected in tumor tissues. In conclusion, we suggest beauvericin as a promising novel natural compound for anticancer therapy. PMID- 28837059 TI - Novel Drug Delivery Systems Tailored for Improved Administration of Glucocorticoids. AB - Glucocorticoids (GC) are one of the most popular and versatile classes of drugs available to treat chronic inflammation and cancer, but side effects and resistance constrain their use. To overcome these hurdles, which are often related to the uniform tissue distribution of free GC and their short half-life in biological fluids, new delivery vehicles have been developed including PEGylated liposomes, polymeric micelles, polymer-drug conjugates, inorganic scaffolds, and hybrid nanoparticles. While each of these nanoformulations has individual drawbacks, they are often superior to free GC in many aspects including therapeutic efficacy when tested in cell culture or animal models. Successful application of nanomedicines has been demonstrated in various models of neuroinflammatory diseases, cancer, rheumatoid arthritis, and several other disorders. Moreover, investigations using human cells and first clinical trials raise the hope that the new delivery vehicles may have the potential to make GC therapies more tolerable, specific and efficient in the future. PMID- 28837060 TI - Synthesis and Characterization of Tissue Plasminogen Activator-Functionalized Superparamagnetic Iron Oxide Nanoparticles for Targeted Fibrin Clot Dissolution. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted great attention in many biomedical fields and are used in preclinical/experimental drug delivery, hyperthermia and medical imaging. In this study, biocompatible magnetite drug carriers, stabilized by a dextran shell, were developed to carry tissue plasminogen activator (tPA) for targeted thrombolysis under an external magnetic field. Different concentrations of active tPA were immobilized on carboxylated nanoparticles through carbodiimide-mediated amide bond formation. Evidence for successful functionalization of SPIONs with carboxyl groups was shown by Fourier transform infrared spectroscopy. Surface properties after tPA immobilization were altered as demonstrated by dynamic light scattering and zeta potential measurements. The enzyme activity of SPION-bound tPA was determined by digestion of fibrin-containing agarose gels and corresponded to about 74% of free tPA activity. Particles were stored for three weeks before a slight decrease in activity was observed. tPA-loaded SPIONs were navigated into thrombus-mimicking gels by external magnets, proving effective drug targeting without losing the protein. Furthermore, all synthesized types of nanoparticles were well tolerated in cell culture experiments with human umbilical vein endothelial cells, indicating their potential utility for future therapeutic applications in thromboembolic diseases. PMID- 28837061 TI - Molecular Structure and Phylogenetic Analyses of Complete Chloroplast Genomes of Two Aristolochia Medicinal Species. AB - The family Aristolochiaceae, comprising about 600 species of eight genera, is a unique plant family containing aristolochic acids (AAs). The complete chloroplast genome sequences of Aristolochia debilis and Aristolochia contorta are reported here. The results show that the complete chloroplast genomes of A. debilis and A. contorta comprise circular 159,793 and 160,576 bp-long molecules, respectively and have typical quadripartite structures. The GC contents of both species were 38.3% each. A total of 131 genes were identified in each genome including 85 protein-coding genes, 37 tRNA genes, eight rRNA genes and one pseudogene (ycf1). The simple-sequence repeat sequences mainly comprise A/T mononucletide repeats. Phylogenetic analyses using maximum parsimony (MP) revealed that A. debilis and A. contorta had a close phylogenetic relationship with species of the family Piperaceae, as well as Laurales and Magnoliales. The data obtained in this study will be beneficial for further investigations on A. debilis and A. contorta from the aspect of evolution, and chloroplast genetic engineering. PMID- 28837062 TI - Size Controlled Copper (I) Oxide Nanoparticles Influence Sensitivity of Glucose Biosensor. AB - Copper (I) oxide (Cu2O) is an appealing semiconducting oxide with potential applications in various fields ranging from photovoltaics to biosensing. The precise control of size and shape of Cu2O nanostructures has been an area of intense research. Here, the electrodeposition of Cu2O nanoparticles is presented with precise size variations by utilizing ethylenediamine (EDA) as a size controlling agent. The size of the Cu2O nanoparticles was successfully varied between 54.09 nm to 966.97 nm by changing the concentration of EDA in the electrolytic bath during electrodeposition. The large surface area of the Cu2O nanoparticles present an attractive platform for immobilizing glucose oxidase for glucose biosensing. The fabricated enzymatic biosensor exhibited a rapid response time of <2 s. The limit of detection was 0.1 MUM and the sensitivity of the glucose biosensor was 1.54 mA/cm2. mM. The Cu2O nanoparticles were characterized by UV-Visible spectroscopy, scanning electron microscopy and X-ray diffraction. PMID- 28837063 TI - Daytime-Dependent Changes of Cannabinoid Receptor Type 1 and Type 2 Expression in Rat Liver. AB - The present study was performed to investigate the diurnal expression pattern of cannabinoid receptor type 1 (CB1) and type 2 (CB2) in liver tissue of 12- and 51 week-old normoglycemic Wistar rats. By using real-time RT-PCR, daytime dependent changes in both age groups and, for both, hepatic Cnr1 and Cnr2 receptor mRNA levels were measured. Highest amount of mRNA was detected in the light period (ZT3, ZT6, and ZT9) while the lowest amount was measured in the dark period (ZT18 and ZT21). Diurnal transcript expression pattern was accompanied by comparable changes of protein level for CB1, as shown by Western blotting. The current results support the conclusion that expression pattern of cannabinoid receptors are influenced by light/dark cycle and therefore seems to be under the control of a diurnal rhythm. These findings might explain the differences in the efficacy of cannabinoid receptor agonists or antagonists. In addition, investigation of liver of streptozotocin (STZ)-treated 12- and 51-week-old rats show alterations in the diurnal profile of both receptors Cnr1 and Cnr2 compared to that of normoglycemic Wistar rats. This suggests an influence of diabetic state on diurnal expression levels of cannabinoid receptors. PMID- 28837064 TI - Hepatocyte Growth Factor Mediates Enhanced Wound Healing Responses and Resistance to Transforming Growth Factor-beta1-Driven Myofibroblast Differentiation in Oral Mucosal Fibroblasts. AB - Oral mucosal wounds are characterized by rapid healing with minimal scarring, partly attributable to the "enhanced" wound healing properties of oral mucosal fibroblasts (OMFs). Hepatocyte growth factor (HGF) is a pleiotropic growth factor, with potential key roles in accelerating healing and preventing fibrosis. HGF can exist as full-length or truncated (HGF-NK), NK1 and NK2 isoforms. As OMFs display elevated HGF expression compared to dermal fibroblasts (DFs), this study investigated the extent to which HGF mediates the preferential cellular functions of OMFs, and the influence of pro-fibrotic, transforming growth factor-beta1 (TGF beta1) on these responses. Knockdown of HGF expression in OMFs by short interfering RNA (siHGF) significantly inhibited OMF proliferative and migratory responses. Supplementation with exogenous TGF-beta1 also significantly inhibited proliferation and migration, concomitant with significantly down-regulated HGF expression. In addition, knockdown abrogated OMF resistance to TGF-beta1-driven myofibroblast differentiation, as evidenced by increased alpha-smooth muscle actin (alpha-SMA) expression, F-actin reorganisation, and stress fibre formation. Responses were unaffected in siHGF-transfected DFs. OMFs expressed significantly higher full-length HGF and NK1 levels compared to patient-matched DFs, whilst NK2 expression was similar in both OMFs and DFs. Furthermore, NK2 was preferentially expressed over NK1 in DFs. TGF-beta1 supplementation significantly down-regulated full-length HGF and NK1 expression by OMFs, while NK2 was less affected. This study demonstrates the importance of HGF in mediating "enhanced" OMF cellular function. We also propose that full-length HGF and HGF-NK1 convey desirable wound healing properties, whilst fibroblasts preferentially expressing more HGF-NK2 readily undergo TGF-beta1-driven differentiation into myofibroblasts. PMID- 28837066 TI - Fibre Bragg Gratings in Embedded Microstructured Optical Fibres Allow Distinguishing between Symmetric and Anti-Symmetric Lamb Waves in Carbon Fibre Reinforced Composites. AB - Conventional contact sensors used for Lamb wave-based ultrasonic inspection, such as piezo-electric transducers, measure omnidirectional strain and do not allow distinguishing between fundamental symmetric and anti-symmetric modes. In this paper, we show that the use of a single fibre Bragg grating created in a dedicated microstructured optical fibre allows one to directly make the distinction between these fundamental Lamb wave modes. This feature stems from the different sensitivities of the microstructured fibre to axial and transverse strain. We fabricated carbon fibre-reinforced polymer panels equipped with embedded microstructured optical fibre sensors and experimentally demonstrated the strain waves associated with the propagating Lamb waves in both the axial and transverse directions of the optical fibre. PMID- 28837065 TI - Arabidopsis E3 Ubiquitin Ligases PUB22 and PUB23 Negatively Regulate Drought Tolerance by Targeting ABA Receptor PYL9 for Degradation. AB - Drought causes osmotic stress and rapidly triggers abscisic acid (ABA) accumulation in plants. The roles of various ABA receptors in drought tolerance and molecular mechanisms regulating ABA receptor stability needs to be elucidated. Here, we report that Arabidopsis plants overexpressing PYL9, one of the 14 pyrabactin resistance (PYR)/pyrabactin resistance-like (PYL)/regulatory component of ABA receptors (RCAR) family ABA receptors, gained drought tolerance trait. Osmotic stress induced accumulation of the PYL9 protein, which was regulated by the 26S proteasome. PYL9 interacted with two highly homologous plant U-box E3 ubiquitin ligases PUB22 and PUB23. In the cell-free degradation assay, the degradation of GST-PYL9 was accelerated in protein extract from plants overexpressing PUB22 but slowed down in protein extract from the pub22 pub23 double mutant. The in vivo decay of Myc-PYL9 was significantly reduced in the pub22 pub23 double mutant as compared with the wild-type. Additionally, PUB22 also interacted with other ABA receptors such as PYL5, PYL7 and PYL8. Considering the improved drought tolerance in the pub22 pub23 double mutant in previous studies, our results suggest that PUB22 and PUB23 negatively regulate drought tolerance in part by facilitating ABA receptors degradation. PMID- 28837067 TI - IonchanPred 2.0: A Tool to Predict Ion Channels and Their Types. AB - Ion channels (IC) are ion-permeable protein pores located in the lipid membranes of all cells. Different ion channels have unique functions in different biological processes. Due to the rapid development of high-throughput mass spectrometry, proteomic data are rapidly accumulating and provide us an opportunity to systematically investigate and predict ion channels and their types. In this paper, we constructed a support vector machine (SVM)-based model to quickly predict ion channels and their types. By considering the residue sequence information and their physicochemical properties, a novel feature extracted method which combined dipeptide composition with the physicochemical correlation between two residues was employed. A feature selection strategy was used to improve the performance of the model. Comparison results of in jackknife cross-validation demonstrated that our method was superior to other methods for predicting ion channels and their types. Based on the model, we built a web server called IonchanPred which can be freely accessed from http://lin.uestc.edu.cn/server/IonchanPredv2.0. PMID- 28837068 TI - Probability-Based Recognition Framework for Underwater Landmarks Using Sonar Images ?. AB - This paper proposes a probability-based framework for recognizing underwater landmarks using sonar images. Current recognition methods use a single image, which does not provide reliable results because of weaknesses of the sonar image such as unstable acoustic source, many speckle noises, low resolution images, single channel image, and so on. However, using consecutive sonar images, if the status-i.e., the existence and identity (or name)-of an object is continuously evaluated by a stochastic method, the result of the recognition method is available for calculating the uncertainty, and it is more suitable for various applications. Our proposed framework consists of three steps: (1) candidate selection, (2) continuity evaluation, and (3) Bayesian feature estimation. Two probability methods-particle filtering and Bayesian feature estimation-are used to repeatedly estimate the continuity and feature of objects in consecutive images. Thus, the status of the object is repeatedly predicted and updated by a stochastic method. Furthermore, we develop an artificial landmark to increase detectability by an imaging sonar, which we apply to the characteristics of acoustic waves, such as instability and reflection depending on the roughness of the reflector surface. The proposed method is verified by conducting basin experiments, and the results are presented. PMID- 28837069 TI - A Preliminary Investigation of the Interactions between the Brood Parasite Chalcoela iphitalis and Its Polistine Wasp Hosts. AB - The life history of Chalcoela iphitalis-a common brood parasite of social wasps has been described in previous literature, but critical information regarding oviposition behavior and possible differential host parasitism remain cryptic. Here we report on infestation levels of this moth in field populations of paper wasps in Polistes and Mischocyttarus, as well as the oviposition behavior of the moths under a laboratory setting. We found evidence for differential parasitism between paper wasp genera in the field, with almost 50% nest infestation in P. bellicosus and no occurrences of moth infestation in M. mexicanus. Laboratory results revealed that oviposition occurs only at night and is stimulated by contact with the wasp nest or adult wasps. In this setting, eggs were laid largely on the substrate above or adjacent to the host nest, but not on the nest itself. PMID- 28837071 TI - Autonomous Landmark Calibration Method for Indoor Localization. AB - Machine-generated data expansion is a global phenomenon in recent Internet services. The proliferation of mobile communication and smart devices has increased the utilization of machine-generated data significantly. One of the most promising applications of machine-generated data is the estimation of the location of smart devices. The motion sensors integrated into smart devices generate continuous data that can be used to estimate the location of pedestrians in an indoor environment. We focus on the estimation of the accurate location of smart devices by determining the landmarks appropriately for location error calibration. In the motion sensor-based location estimation, the proposed threshold control method determines valid landmarks in real time to avoid the accumulation of errors. A statistical method analyzes the acquired motion sensor data and proposes a valid landmark for every movement of the smart devices. Motion sensor data used in the testbed are collected from the actual measurements taken throughout a commercial building to demonstrate the practical usefulness of the proposed method. PMID- 28837070 TI - Mechanisms of Antimicrobial Action of Cinnamon and Oregano Oils, Cinnamaldehyde, Carvacrol, 2,5-Dihydroxybenzaldehyde, and 2-Hydroxy-5-Methoxybenzaldehyde against Mycobacterium avium subsp. paratuberculosis (Map). AB - The antimicrobial modes of action of six naturally occurring compounds, cinnamon oil, cinnamaldehyde, oregano oil, carvacrol, 2,5-dihydroxybenzaldehyde, and 2 hydroxy-5-methoxybenzaldehyde, previously found to inhibit the growth of Mycobacterium avium subsp. paratuberculosis (Map) reported to infect food animals and humans and to be present in milk, cheese, and meat, were investigated. The incubation of Map cultures in the presence of all six compounds caused phosphate ions to leak into the extracellular environment in a time- and concentration dependent manner. Cinnamon oil and cinnamaldehyde decreased the intracellular adenosine triphosphate (ATP) concentration of Map cells, whereas oregano oil and carvacrol caused an initial decrease of intracellular ATP concentration that was restored gradually after incubation at 37 degrees C for 2 h. Neither 2,5 dihydroxybenzaldehyde nor 2-hydroxy-5-methoxybenzaldehyde had a significant effect on intracellular ATP concentration. None of the compounds tested were found to cause leakage of ATP to the extracellular environment. Monolayer studies involving a Langmuir trough apparatus revealed that all anti-Map compounds, especially the essential oil compounds, altered the molecular packing characteristics of phospholipid molecules of model membranes, causing fluidization. The results of the physicochemical model microbial membrane studies suggest that the destruction of the pathogenic bacteria might be associated with the disruption of the bacterial cell membrane. PMID- 28837072 TI - Understanding the Epilepsy in POLG Related Disease. AB - Epilepsy is common in polymerase gamma (POLG) related disease and is associated with high morbidity and mortality. Epileptiform discharges typically affect the occipital regions initially and focal seizures, commonly evolving to bilateral convulsive seizures which are the most common seizure types in both adults and children. Our work has shown that mtDNA depletion-i.e., the quantitative loss of mtDNA-in neurones is the earliest and most important factor of the subsequent development of cellular dysfunction. Loss of mtDNA leads to loss of mitochondrial respiratory chain (MRC) components that, in turn, progressively disables energy metabolism. This critically balanced neuronal energy metabolism leads to both a chronic and continuous attrition (i.e., neurodegeneration) and it leaves the neurone unable to cope with increased demand that can trigger a potentially catastrophic cycle that results in acute focal necrosis. We believe that it is the onset of epilepsy that triggers the cascade of damage. These events can be identified in the stepwise evolution that characterizes the clinical, Electroencephalography (EEG), neuro-imaging, and neuropathology findings. Early recognition with prompt and aggressive seizure management is vital and may play a role in modifying the epileptogenic process and improving survival. PMID- 28837073 TI - Two Archaeal RecJ Nucleases from Methanocaldococcus jannaschii Show Reverse Hydrolysis Polarity: Implication to Their Unique Function in Archaea. AB - Bacterial nuclease RecJ, which exists in almost all bacterial species, specifically degrades single-stranded (ss) DNA in the 5' to 3' direction. Some archaeal phyla, except Crenarchaea, also encode RecJ homologs. Compared with bacterial RecJ, archaeal RecJ exhibits a largely different amino acid sequence and domain organization. Archaeal RecJs from Thermococcus kodakarensis and Pyrococcus furiosus show 5'->3' exonuclease activity on ssDNA. Interestingly, more than one RecJ exists in some Euryarchaeota classes, such as Methanomicrobia, Methanococci, Methanomicrobia, Methanobacteria, and Archaeoglobi. Here we report the biochemical characterization of two RecJs from Methanocaldococcus jannaschii, the long RecJ1 (MJ0977) and short RecJ2 (MJ0831) to understand their enzymatic properties. RecJ1 is a 5'->3' exonuclease with a preference to ssDNA; however, RecJ2 is a 3'->5' exonuclease with a preference to ssRNA. The 5' terminal phosphate promotes RecJ1 activity, but the 3' terminal phosphate inhibits RecJ2 nuclease. Go-Ichi-Ni-San (GINS) complex does not interact with two RecJs and does not promote their nuclease activities. Finally, we discuss the diversity, function, and molecular evolution of RecJ in archaeal taxonomy. Our analyses provide insight into the function and evolution of conserved archaeal RecJ/eukaryotic Cdc45 protein. PMID- 28837074 TI - Remembering Dr. Rex Munday. AB - Rex Munday was a scientist working for AgResearch Ltd. in New Zealand. He was a leading figure in the area of marine toxin toxicity. His passing in July 2017 marked a loss for his family, as well as for colleagues who knew him as a dedicated professional, and a lively scientist with a great sense of humor. PMID- 28837075 TI - Botulinum Toxin for the Treatment of Neuropathic Pain. AB - Botulinum toxin (BoNT) has been used as a treatment for excessive muscle stiffness, spasticity, and dystonia. BoNT for approximately 40 years, and has recently been used to treat various types of neuropathic pain. The mechanism by which BoNT acts on neuropathic pain involves inhibiting the release of inflammatory mediators and peripheral neurotransmitters from sensory nerves. Recent journals have demonstrated that BoNT is effective for neuropathic pain, such as postherpetic neuralgia, trigeminal neuralgia, and peripheral neuralgia. The purpose of this review is to summarize the experimental and clinical evidence of the mechanism by which BoNT acts on various types of neuropathic pain and describe why BoNT can be applied as treatment. The PubMed database was searched from 1988 to May 2017. Recent studies have demonstrated that BoNT injections are effective treatments for post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, and intractable neuropathic pain, such as poststroke pain and spinal cord injury. PMID- 28837076 TI - iTRAQ-Based Proteomics Analysis and Network Integration for Kernel Tissue Development in Maize. AB - Grain weight is one of the most important yield components and a developmentally complex structure comprised of two major compartments (endosperm and pericarp) in maize (Zea mays L.), however, very little is known concerning the coordinated accumulation of the numerous proteins involved. Herein, we used isobaric tags for relative and absolute quantitation (iTRAQ)-based comparative proteomic method to analyze the characteristics of dynamic proteomics for endosperm and pericarp during grain development. Totally, 9539 proteins were identified for both components at four development stages, among which 1401 proteins were non redundant, 232 proteins were specific in pericarp and 153 proteins were specific in endosperm. A functional annotation of the identified proteins revealed the importance of metabolic and cellular processes, and binding and catalytic activities for the tissue development. Three and 76 proteins involved in 49 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were integrated for the specific endosperm and pericarp proteins, respectively, reflecting their complex metabolic interactions. In addition, four proteins with important functions and different expression levels were chosen for gene cloning and expression analysis. Different concordance between mRNA level and the protein abundance was observed across different proteins, stages, and tissues as in previous research. These results could provide useful message for understanding the developmental mechanisms in grain development in maize. PMID- 28837077 TI - Electroacupuncture Promotes Recovery of Motor Function and Reduces Dopaminergic Neuron Degeneration in Rodent Models of Parkinson's Disease. AB - Parkinson's disease (PD) is a common neurodegenerative disease. The pathological hallmark of PD is a progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta in the brain, ultimately resulting in severe striatal dopamine deficiency and the development of primary motor symptoms (e.g., resting tremor, bradykinesia) in PD. Acupuncture has long been used in traditional Chinese medicine to treat PD for the control of tremor and pain. Accumulating evidence has shown that using electroacupuncture (EA) as a complementary therapy ameliorates motor symptoms of PD. However, the most appropriate timing for EA intervention and its effect on dopamine neuronal protection remain unclear. Thus, this study used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model (systemic-lesioned by intraperitoneal injection) and the 1-methyl-4 phenylpyridinium (MPP+)-lesioned rat model (unilateral-lesioned by intra-SN infusion) of PD, to explore the therapeutic effects and mechanisms of EA at the GB34 (Yanglingquan) and LR3 (Taichong) acupoints. We found that EA increased the latency to fall from the accelerating rotarod and improved striatal dopamine levels in the MPTP studies. In the MPP+ studies, EA inhibited apomorphine induced rotational behavior and locomotor activity, and demonstrated neuroprotective effects via the activation of survival pathways of Akt and brain-derived neurotrophic factor (BDNF) in the SN region. In conclusion, we observed that EA treatment reduces motor symptoms of PD and dopaminergic neurodegeneration in rodent models, whether EA is given as a pretreatment or after the initiation of disease symptoms. The results indicate that EA treatment may be an effective therapy for patients with PD. PMID- 28837078 TI - Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree. AB - Retinitis pigmentosa (RP) causes progressive photoreceptor loss resulting from mutations in over 80 genes. This study identified the genetic cause of RP in three members of a non-consanguineous pedigree. Detailed ophthalmic evaluation was performed in the three affected family members. Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed in the three affected and the two unaffected family members and variants were filtered to detect rare, potentially deleterious variants segregating with disease. WES and WGS did not identify potentially pathogenic variants shared by all three affected members. However, WES identified a previously reported homozygous nonsense mutation in KIZ (c.226C>T, p.Arg76*) in two affected sisters, but not in their affected second cousin. WGS revealed a novel 1.135 kb homozygous deletion in a retina transcript of C21orf2 and a novel 30.651 kb heterozygous deletion in CACNA2D4 in the affected second cousin. The sisters with the KIZ mutation carried no copies of the C21orf2 or CACNA2D4 deletions, while the second cousin with the C21orf2 and CACNA2D4 deletions carried no copies of the KIZ mutation. This study identified two independent, homozygous mutations in genes previously reported in autosomal recessive RP in a non-consanguineous family, and demonstrated the value of WGS when WES fails to identify likely disease-causing mutations. PMID- 28837079 TI - Electrostatic Assembly of Platinum Nanoparticles along Electrospun Polymeric Nanofibers for High Performance Electrochemical Sensors. AB - A novel polyacrylonitrile (PAN) nanofibrous membrane conjugated with platinum nanoparticles (PtNPs) was fabricated by electrospinning and electrostatic assembly techniques. In this procedure, PAN was electrospun with 3 aminopropyltriethoxysilane (APS) together as precursor materials. First, amine groups were introduced onto PAN nanofibers, and then the as-prepared negative charged platinum nanoparticles (PtNPs) were conjugated onto the surface of the amino-modified PAN nanofibers uniformly by the electrostatic interaction-mediated assembly. The fabricated PAN-PtNPs hybrid nanofibrous membrane was further utilized to modify the glassy carbon electrodes and was used for the fabrication of a non-enzymatic amperometric sensor to detect hydrogen peroxide (H2O2). The electrochemical results indicated that, due to the uniform dispersion of PtNPs and the electrostatic interaction between amine groups and PtNPs, the fabricated PAN-PtNPs nanofibrous membrane-based electrochemical sensor showed excellent electrocatalytic activity toward H2O2, and the chronoamperometry measurements illustrated that the fabricated sensor had a high sensitivity for detecting H2O2. It is anticipated that the strategies used in this work will not only guide the design and fabrication of functional polymeric nanofiber-based biomaterials and nanodevices, but also extend their potential applications in energy storage, cytology, and tissue engineering. PMID- 28837081 TI - A Simple and Selective Fluorescent Sensor Chip for Indole-3-Butyric Acid in Mung Bean Sprouts Based on Molecularly Imprinted Polymer Coatings. AB - In this paper, we report the preparation of molecularly imprinted polymer coatings on quartz chips for selective solid-phase microextraction and fluorescence sensing of the auxin, indole-3-butyric acid. The multiple copolymerization method was used to prepare polymer coatings on silylated quartz chips. The polymer preparation conditions (e.g., the solvent, monomer, and cross linker) were investigated systemically to enhance the binding performance of the imprinted coatings. Direct solid-phase fluorescence measurements on the chips facilitated monitoring changes in coating performance. The average binding capacity of an imprinted polymer coated chip was approximately 152.9 ug, which was higher than that of a non-imprinted polymer coated chip (60.8 ug); the imprinted coatings showed the highest binding to IBA among the structural analogues, indicating that the coatings possess high selectivity toward the template molecule. The developed method was used for the determination of the auxin in mung bean extraction, and the recovery was found to be in the range of 91.5% to 97.5%, with an RSD (n = 3) of less than 7.4%. Thus, the present study provides a simple method for fabricating a fluorescent sensor chip for selective analysis. PMID- 28837080 TI - Activation of Matrix Hyaluronan-Mediated CD44 Signaling, Epigenetic Regulation and Chemoresistance in Head and Neck Cancer Stem Cells. AB - Head and neck squamous cell carcinoma (HNSCC) is a solid tumor composed by a genotypically and phenotypically heterogeneous population of neoplastic cells types. High recurrence rate and regional metastases lead to major morbidity and mortality. Recently, many studies have focused on cellular and molecular mechanisms of tumor progression that can help to predict prognosis and to choose the best therapeutic approach for HNSCC patients. Hyaluronan (HA), an important glycosaminoglycan component of the extracellular matrix (ECM), and its major cell surface receptor, CD44, have been suggested to be important cellular mediators influencing tumor progression and treatment resistance in head and neck cancer. HNSCC contains a small subpopulation of cells that exhibit a hallmark of CD44 expressing cancer stem cell (CSC) properties with self-renewal, multipotency, and a unique potential for tumor initiation. HA has been shown to stimulate a variety of CSC functions including self-renewal, clone formation and differentiation. This review article will present current evidence for the existence of a unique small population of CD44v3highALDHhigh-expressing CSCs in HNSCC. A special focus will be placed on the role of HA/CD44-induced oncogenic signaling and histone methyltransferase, DOT1L activities in regulating histone modifications (via epigenetic changes) and miRNA activation. Many of these events are essential for the CSC properties such as Nanog/Oct4/Sox2 expression, spheroid/clone formation, self-renewal, tumor cell migration/invasion, survival and chemotherapeutic drug resistance in HA-activated head and neck cancer. These newly-discovered HA/CD44 mediated oncogenic signaling pathways delineate unique tumor dynamics with implications for defining the drivers of HNSCC progression processes. Most importantly, the important knowledge obtained from HA/CD44-regulated CSC signaling and functional activation could provide new information regarding the design of novel drug targets to overcome current therapeutic drug resistance which will have significant treatment implications for head and neck cancer patients. PMID- 28837082 TI - RNA Interference and BMP-2 Stimulation Allows Equine Chondrocytes Redifferentiation in 3D-Hypoxia Cell Culture Model: Application for Matrix Induced Autologous Chondrocyte Implantation. AB - As in humans, osteoarthritis (OA) causes considerable economic loss to the equine industry. New hopes for cartilage repair have emerged with the matrix-associated autologous chondrocyte implantation (MACI). Nevertheless, its limitation is due to the dedifferentiation occurring during the chondrocyte amplification phase, leading to the loss of its capacity to produce a hyaline extracellular matrix (ECM). To enhance the MACI therapy efficiency, we have developed a strategy for chondrocyte redifferentiation, and demonstrated its feasibility in the equine model. Thus, to mimic the cartilage microenvironment, the equine dedifferentiated chondrocytes were cultured in type I/III collagen sponges for 7 days under hypoxia in the presence of BMP-2. In addition, chondrocytes were transfected by siRNA targeting Col1a1 and Htra1 mRNAs, which are overexpressed during dedifferentiation and OA. To investigate the quality of the neo-synthesized ECM, specific and atypical cartilage markers were evaluated by RT-qPCR and Western blot. Our results show that the combination of 3D hypoxia cell culture, BMP-2 (Bone morphogenetic protein-2), and RNA interference, increases the chondrocytes functional indexes (Col2a1/Col1a1, Acan/Col1a1), leading to an effective chondrocyte redifferentiation. These data represent a proof of concept for this process of application, in vitro, in the equine model, and will lead to the improvement of the MACI efficiency for cartilage tissue engineering therapy in preclinical/clinical trials, both in equine and human medicine. PMID- 28837084 TI - Consumption of Low-Calorie Sweetened Beverages Compared to Water Is Associated with Reduced Intake of Carbohydrates and Sugar, with No Adverse Relationships to Glycemic Responses: Results from the 2001-2012 National Health and Nutrition Examination Surveys. AB - Although the 2015 Dietary Guidelines Advisory Committee concluded that there was moderate evidence that substituting sugar-containing sweeteners with low-calorie sweeteners (LCS) reduces calorie intake and weight, dietary recommendations encourage substituting only water for sugar-sweetened beverages during weight management. This cross-sectional study evaluated the relation of water and no- and low-calorie sweetened beverage (LCSB) intake with nutrient intakes and prediabetes criteria using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2012 in 25,817 adults that were free of diabetes. Although linear trends were observed with both beverages, higher LCSB intake was associated with significantly lower consumption of carbohydrates (-9.1 g/day vs. -1.4 g/day), total sugars (-10.9 g/day vs. -2.2 g/day), and added sugars (-2.0 tsp eq vs. -0.8 tsp eq) than those associated with higher water intake. Higher intake of both beverages was significantly associated with lower insulin levels (p < 0.01); however, higher intake of LCSB was also associated with lower hemoglobin A1c (HbA1c) and lower homeostatic model assessment of insulin resistance (HOMA-IR) (p < 0.01). We observed lower odds ratios for elevated HbA1c (adjusted odds ratio [OR] 0.79, 95% CI 0.64-0.98), HOMA-IR (0.68, 0.53-0.87), and insulin levels (0.63, 0.49-0.80) in LCSB among the higher (2+ servings) intake group compared to the lowest (<1 serving) intake group. Contrary to conventional wisdom, LCSB consumption was associated with equal, if not better, dietary intake and glycemic response than water consumption. Although observational in nature, these results contribute to the growing body of evidence from human studies suggesting that in addition to water, LCSBs can also be sensible choices for reducing sugars and carbohydrate intake, with no adverse associations to measures of glycemic response. PMID- 28837083 TI - Resveratrol as a Natural Autophagy Regulator for Prevention and Treatment of Alzheimer's Disease. AB - Alzheimer's disease (AD) is one of the most common neurodegenerative disorders over the age of 65 years old. Although several underlying mechanisms for explaining the pathogenesis of AD are elucidated, the effective supplements or drugs for the intervention of AD are still limited. Recently, impaired autophagy associated with miRNA dysfunction has been reported to involve in aging and aging related neurodegenerative diseases. Thus, the activation of autophagy through effectively regulating miRNAs may become a potential target for the prevention or treatment of AD. Mounting evidence from in vitro and in vivo AD models has demonstrated that resveratrol, one of polyphenolic compounds, can exert neuroprotective role in neurodegenerative diseases especially AD. In this review, the regulation of miRNAs and autophagy using resveratrol during the prevention and treatment of AD are systematically discussed, which will be beneficial to establish a target for the direct link between pharmacological intervention and AD in the future. PMID- 28837085 TI - Consumption of Energy Drinks among Undergraduate Students in Taiwan: Related Factors and Associations with Substance Use. AB - Background: This study aimed to investigate the consumption of energy drinks and associated factors among undergraduate students in Taiwan. Methods: Data came from a cross-sectional survey conducted in 2015. Eligible participants completed a self-administered questionnaire assessing use and perceptions of energy drinks, tobacco, alcohol, and betel nut. Results: Among 606 surveyed undergraduate students, 24.8% reported consuming energy drinks in the past 30 days. The major reasons for use included keeping alert at work (48.7%), being curious about the products (32.0%), enjoying the flavor (31.3%), or preparing for school exams (26.7%). Among energy drink users, half have never read the nutrition label, and 15.3% reported that they had ever mixed energy drinks with alcohol. Most participants showed negative attitudes toward using tobacco, alcohol, or betel nut, while 54.1% reported positive attitudes toward consuming energy drinks. Being male, living away from parents' home, tobacco use, alcohol use, and positive perceptions of energy drink's effects significantly predicted energy drink consumption. Conclusions: In addition to exploring motivations of energy drink consumption in undergraduate students in Taiwan, the study findings indicated that energy drink consumption might relate to the use of tobacco and alcohol, which should be taken into account in substance use prevention programs. PMID- 28837086 TI - Discrepancy between Knowledge and Perceptions of Dietary Omega-3 Fatty Acid Intake Compared with the Omega-3 Index. AB - Little is known about the relationship between perceptions of nutrient adequacy and biomarkers of nutrition status. This cross-sectional study of U.S. and German adults (n = 200; 18-80 years) compared dietary practices, knowledge, and beliefs of omega-3 fatty acids (O3-FA) with the omega-3 index (O3-I), an erythrocyte based biomarker associated with cardiovascular disease (CVD) risk. More than half of adults believed that O3-FAs are beneficial for heart and brain health and could correctly identify the food sources of O3-FA. However, the mean O3-I in the U.S. (4.3%) and Germany (5.5%) puts the majority of adults sampled (99%) in intermediate or high CVD-risk categories. More Americans were considered at high CVD-risk (40%) when compared with Germans (10%). In the U.S., but not Germany, women had a significantly higher O3-I than men (4.8% vs. 3.8%, p < 0.001). In the intermediate CVD-risk group, about one-third of adults in both countries (30% in the U.S. and 27% in Germany) believed their diet was adequate in O3-FA. Notably, mean O3-I concentrations did not significantly differ with dietary perceptions of adequacy. More adults in Germany (26%) than in the U.S. (10%) believed that dietary supplements are needed to achieve a balanced diet. In spite of adequate knowledge about food sources and a consistent belief that O3-FA are important for health, very few participants had O3-I concentrations in the range for CVD protection. PMID- 28837087 TI - Ginseng Extract G115 Attenuates Ethanol-Induced Depression in Mice by Increasing Brain BDNF Levels. AB - The decrease of brain-derived neurotrophic factor (BDNF) has been reported in alcohol use disorder and major depression. The effective treatment of these comorbid diseases remains undiscovered. Nutraceutical products are therefore proposed as an alternative approach to overcome this challenge. Ginseng extract G115, the standardized extract of Panax ginseng, is a widely-used nutraceutical that is beneficial for various central nervous system disorders. This study aimed to determine the antidepressant effect of ginseng extract G115 in ethanol-treated mice models. Mice received either water, amitriptyline, or various doses of G115 (p.o.) followed by water or ethanol (i.p.) for 8 days. The antidepressant activity was evaluated using forced swimming test. BDNF levels were measured from hippocampal and prefrontal cortex tissues. The results demonstrated that the increase of immobility time in depressant mice induced by ethanol was reversed by both G115 and amitriptyline treatment. A significant increase of BDNF levels in the hippocampus and prefrontal cortex was observed in ethanol-treated mice receiving G115. Taken together, this study provides scientific information on the use of G115 as an antidepressant that could be further used as a dietary supplement in comorbid alcohol use and major depressive disorders. PMID- 28837088 TI - Modulatory Effect of Methanol Extract of Piper guineense in CCl4-Induced Hepatotoxicity in Male Rats. AB - This study seeks to investigate the possible protective role of the methanol extract of Piper guineense seeds against CCl4-induced hepatotoxicity in an animal model. Hepatotoxicity was induced by administering oral doses of CCl4 (1.2 g/kg bw) three times a week for three weeks. Group 1 (Control) and Group 2 (CCl4) were left untreated; Piper guineense (PG; 400 mg/kg bw) was administered to Group 3 (T1) by oral gavage for 14 days prior to the administration of CCl4 and simultaneously with CCl4; PG (400 mg/kg bw) was administered simultaneously with CCl4 in Group 4 (T2); and Livolin forte (20 mg/kg bw) was administered simultaneously with CCl4 in Group 5 (T3), the standard drug group. The administration of CCl4 induces histopathological alteration in the liver, with concomitant increased activities of serum hepatic marker enzymes associated with increased levels of lipid peroxidation. Similarly, there was decrease in non enzymatic (reduced glutathione) and enzymatic antioxidants (glutathione S transferase), superoxide dismutase, and catalase. An elevation in serum triglyceride and total cholesterol levels was noticed along with decreased levels of serum total protein. Treatment with PG 400 mg/kg bw exhibited excellent modulatory activity with respect to the different parameters studied by reversing all the above-mentioned biochemical changes significantly in the experimental animals. These results suggest that PG offered protection comparable to that of Livolin forte with better efficacy when pre-treated with 400 mg/kg bw 14 days prior to CCl4-exposure. PMID- 28837089 TI - Heterologous Expression, Purification and Immunoreactivity of the Antigen 5 from Polybia paulista Wasp Venom. AB - Polybia paulista (Hymenoptera: Vespidae) is responsible for a high number of sting accidents and anaphylaxis events in Southeast Brazil, Argentina and Paraguay. The specific detection of allergy to the venom of this wasp is often hampered by the lack of recombinant allergens currently available for molecular diagnosis. Antigen 5 (~23 kDa) from P. paulista venom (Poly p 5) is a highly abundant and glycosylated allergenic protein that could be used for development of component-resolved diagnosis (CRD). Here, we describe the cloning and heterologous expression of the antigen 5 (rPoly p 5) from P. paulista venom using the eukaryotic system Pichia pastoris. The expression as a secreted protein yielded high levels of soluble rPoly p 5. The recombinant allergen was further purified to homogeneity (99%) using a two-step chromatographic procedure. Simultaneously, the native form of the allergen (nPoly p 5) was purified from the wasp venom by Ion exchange chromatography. The rPoly p 5 and nPoly p 5 were then submitted to a comparative analysis of IgE-mediated immunodetection using sera from patients previously diagnosed with sensitization to wasp venoms. Both rPoly p 5 and nPoly p 5 were recognized by specific IgE (sIgE) in the sera of the allergic individuals. The high levels of identity found between nPoly p 5 and rPoly p 5 by the alignment of its primary sequences as well as by 3-D models support the results obtained in the immunoblot. Overall, we showed that P. pastoris is a suitable system for production of soluble rPoly p 5 and that the recombinant allergen represents a potential candidate for molecular diagnosis of P.paulista venom allergy. PMID- 28837090 TI - A Vote for School Lunches: School Lunches Provide Superior Nutrient Quality than Lunches Obtained from Other Sources in a Nationally Representative Sample of US Children. AB - Childhood obesity is an ongoing public health program. As such, a major public health research objective is to identify potential targets for intervention; one such area is school lunches (SL). The National School Lunch Program (NSLP) serves over 31 million children each day; the National Health and Nutrition Examination Survey (NHANES) is uniquely positioned to allow researchers to assess diet quality in federal nutrition assistance programs. The objective of the study was to investigate whether lunches provided by schools provide different nutritional value than lunches obtained elsewhere. In a nationally representative sample of 2190 children, consumption of a school-provided lunch (SL) was associated with greater nutritional quality compared to lunches obtained elsewhere across both age and income categories. Children who were eligible for no-cost school lunch, but did not participate in the NSLP consumed approximately 60% more energy, 58% more total fat, 60% more saturated fat, 50% more solid fat, 61% more sodium, double the amount of added sugars and less than half the amount of fruit than NSLP participants (all p < 0.001). The results of this study suggest that though widely criticized, school lunches provide superior nutrient quality than lunches obtained from other sources, particularly for low-income children. PMID- 28837091 TI - Comment on: Macronutrient Intake and Risk of Crohn's Disease: Systematic Review and Dose-Response: Meta-Analysis of Epidemiological Studies, Nutrients 2017, 9, 500. AB - We read with great interest the article by Zeng et al. recently published in Nutrients [1].[...]. PMID- 28837094 TI - An Energy-Aware Runtime Management of Multi-Core Sensory Swarms. AB - In sensory swarms, minimizing energy consumption under performance constraint is one of the key objectives. One possible approach to this problem is to monitor application workload that is subject to change at runtime, and to adjust system configuration adaptively to satisfy the performance goal. As today's sensory swarms are usually implemented using multi-core processors with adjustable clock frequency, we propose to monitor the CPU workload periodically and adjust the task-to-core allocation or clock frequency in an energy-efficient way in response to the workload variations. In doing so, we present an online heuristic that determines the most energy-efficient adjustment that satisfies the performance requirement. The proposed method is based on a simple yet effective energy model that is built upon performance prediction using IPC (instructions per cycle) measured online and power equation derived empirically. The use of IPC accounts for memory intensities of a given workload, enabling the accurate prediction of execution time. Hence, the model allows us to rapidly and accurately estimate the effect of the two control knobs, clock frequency adjustment and core allocation. The experiments show that the proposed technique delivers considerable energy saving of up to 45%compared to the state-of-the-art multi-core energy management technique. PMID- 28837092 TI - Incorporating Oxygen-Enhanced MRI into Multi-Parametric Assessment of Human Prostate Cancer. AB - Hypoxia is associated with prostate tumor aggressiveness, local recurrence, and biochemical failure. Magnetic resonance imaging (MRI) offers insight into tumor pathophysiology and recent reports have related transverse relaxation rate (R2*) and longitudinal relaxation rate (R1) measurements to tumor hypoxia. We have investigated the inclusion of oxygen-enhanced MRI for multi-parametric evaluation of tumor malignancy. Multi-parametric MRI sequences at 3 Tesla were evaluated in 10 patients to investigate hypoxia in prostate cancer prior to radical prostatectomy. Blood oxygen level dependent (BOLD), tissue oxygen level dependent (TOLD), dynamic contrast enhanced (DCE), and diffusion weighted imaging MRI were intercorrelated and compared with the Gleason score. The apparent diffusion coefficient (ADC) was significantly lower in tumor than normal prostate. Baseline R2* (BOLD-contrast) was significantly higher in tumor than normal prostate. Upon the oxygen breathing challenge, R2* decreased significantly in the tumor tissue, suggesting improved vascular oxygenation, however changes in R1 were minimal. R2* of contralateral normal prostate decreased in most cases upon oxygen challenge, although the differences were not significant. Moderate correlation was found between ADC and Gleason score. ADC and R2* were correlated and trends were found between Gleason score and R2*, as well as maximum-intensity-projection and area under-the-curve calculated from DCE. Tumor ADC and R2* have been associated with tumor hypoxia, and thus the correlations are of particular interest. A multi parametric approach including oxygen-enhanced MRI is feasible and promises further insights into the pathophysiological information of tumor microenvironment. PMID- 28837093 TI - An Overview on Recent Progress in Electrochemical Biosensors for Antimicrobial Drug Residues in Animal-Derived Food. AB - Anti-microbial drugs are widely employed for the treatment and cure of diseases in animals, promotion of animal growth, and feed efficiency. However, the scientific literature has indicated the possible presence of antimicrobial drug residues in animal-derived food, making it one of the key public concerns for food safety. Therefore, it is highly desirable to design fast and accurate methodologies to monitor antimicrobial drug residues in animal-derived food. Legislation is in place in many countries to ensure antimicrobial drug residue quantities are less than the maximum residue limits (MRL) defined on the basis of food safety. In this context, the recent years have witnessed a special interest in the field of electrochemical biosensors for food safety, based on their unique analytical features. This review article is focused on the recent progress in the domain of electrochemical biosensors to monitor antimicrobial drug residues in animal-derived food. PMID- 28837095 TI - Editorial of the Special Issue: Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer. AB - Oncolytic viruses (OVs), either occurring naturally or through genetic engineering, can selectively infect, replicate in, and kill cancer cells, while leaving normal cells (almost) unharmed [...]. PMID- 28837096 TI - A Mobile Outdoor Augmented Reality Method Combining Deep Learning Object Detection and Spatial Relationships for Geovisualization. AB - The purpose of this study was to develop a robust, fast and markerless mobile augmented reality method for registration, geovisualization and interaction in uncontrolled outdoor environments. We propose a lightweight deep-learning-based object detection approach for mobile or embedded devices; the vision-based detection results of this approach are combined with spatial relationships by means of the host device's built-in Global Positioning System receiver, Inertial Measurement Unit and magnetometer. Virtual objects generated based on geospatial information are precisely registered in the real world, and an interaction method based on touch gestures is implemented. The entire method is independent of the network to ensure robustness to poor signal conditions. A prototype system was developed and tested on the Wuhan University campus to evaluate the method and validate its results. The findings demonstrate that our method achieves a high detection accuracy, stable geovisualization results and interaction. PMID- 28837097 TI - Exploring the Effects of Argon Plasma Treatment on Plasmon Frequency and the Chemiresistive Properties of Polymer-Carbon Nanotube Metacomposite. AB - Metacomposites, composite materials exhibiting negative permittivity, represent an opportunity to create materials with depressed plasmon frequency without the need to create complex structural geometries. Although many reports exist on the synthesis and characterizations of metacomposites, very few have ventured into exploring possible applications that could take advantage of the unique electrical properties of these materials. In this article, we report on the chemiresistive properties of a polymer-CNT metacomposite and explore how these are affected by Argon plasma treatment. PMID- 28837098 TI - Optical CAD Utilization for the Design and Testing of a LED Streetlamp. AB - The design and testing of LED lamps are vital steps toward broader use of LED lighting for outdoor illumination and traffic signalling. The characteristics of LED sources, in combination with the need to limit light pollution and power consumption, require a precise optical design. In particular, in every step of the process, it is important to closely compare theoretical or simulated results with measured data (obtained from a prototype). This work examines the various possibilities for using an optical CAD (Lambda Research TracePro) to design and check a LED lamp for outdoor use. This analysis includes the simulations and testing on a prototype as an example; data acquired by measurement are inserted into the same simulation software, making it easy to compare theoretical and actual results. PMID- 28837099 TI - Enhanced Cycleability of Amorphous MnO2 by Covering on alpha-MnO2 Needles in an Electrochemical Capacitor. AB - An allomorph MnO2@MnO2 core-shell nanostructure was developed via a two-step aqueous reaction method. The data analysis of Scanning Electron Microscopy, Transmission Electron Microscopy, X-Ray Diffraction and N2 adsorption-desorption isotherms experiments indicated that this unique architecture consisted of a porous layer of amorphous-MnO2 nano-sheets which were well grown onto the surface of alpha-MnO2 nano-needles. Cyclic voltammetry experiments revealed that the double-layer charging and Faradaic pseudo-capacity of the MnO2@MnO2 capacitor electrode contributed to a specific capacitance of 150.3 F.g-1 at a current density of 0.1 A.g-1. Long cycle life experiments on the as-prepared MnO2@MnO2 sample showed nearly a 99.3% retention after 5000 cycles at a current density of 2 A.g-1. This retention value was found to be significantly higher than those reported for amorphous MnO2-based capacitor electrodes. It was also found that the remarkable cycleability of the MnO2@MnO2 was due to the supporting role of alpha-MnO2 nano-needle core and the outer amorphous MnO2 layer. PMID- 28837101 TI - Novel Approach in the Use of Plasma Spray: Preparation of Bulk Titanium for Bone Augmentations. AB - Thermal plasma spray is a common, well-established technology used in various application fields. Nevertheless, in our work, this technology was employed in a completely new way; for the preparation of bulk titanium. The aim was to produce titanium with properties similar to human bone to be used for bone augmentations. Titanium rods sprayed on a thin substrate wire exerted a porosity of about 15%, which yielded a significant decrease of Young's modulus to the bone range and provided rugged topography for enhanced biological fixation. For the first verification of the suitability of the selected approach, tests of the mechanical properties in terms of compression, bending, and impact were carried out, the surface was characterized, and its compatibility with bone cells was studied. While preserving a high enough compressive strength of 628 MPa, the elastic modulus reached 11.6 GPa, thus preventing a stress-shielding effect, a generally known problem of implantable metals. U-2 OS and Saos-2 cells derived from bone osteosarcoma grown on the plasma-sprayed surface showed good viability. PMID- 28837100 TI - Homoisoflavonoids and Chalcones Isolated from Haematoxylum campechianum L., with Spasmolytic Activity. AB - Haematoxylum campechianum is a medicinal plant employed as an astringent to purify the blood and to treat stomach problems such as diarrhea and dysentery. A bio-guided chemical fractionation of the methanolic extract obtained from this plant allowed for the isolation of five compounds: two chalcones known as sappanchalcone (1); 3-deoxysappanchalcone (2); three homoisoflavonoids known as hematoxylol A (3); 4-O-methylhematoxylol (4); and, hematoxin (5). The spasmolytic activity was determined in an in vitro model (electrically induced contractions of guinea pig ileum), and allowed to demonstrate that the methanolic extract (EC50 = 62.11 +/- 3.23) fractions HcF7 (EC50 = 61.75 +/- 3.55) and HcF9 (EC50 = 125.5 +/- 10.65) and compounds 1 (EC50 = 16.06 +/- 2.15) and 2 (EC50 = 25.37 +/- 3.47) of Haematoxylum campechianum present significant relaxing activity as compared to papaverine (EC50 = 20.08 +/- 2.0) as a positive control. PMID- 28837102 TI - Dietary Sources of High Sodium Intake in Turkey: SALTURK II. AB - Previous research has shown daily salt intakes in Turkey to be far above the recommended limits. Knowing the sources of dietary salt could form a basis for preventive strategies aimed towards salt reduction. This study aimed to investigate dietary sources of salt in Turkey. A sub-group (n = 657) was selected from the PatenT2 study population, which represented the urban and rural areas of 4 major cities (Ankara, Istanbul, Izmir, and Konya). A questionnaire inquiring about sociodemographic characteristics, medical histories, detailed histories of diet, and salt consumption was completed. Participants were asked to collect a 24 h urine sample and to record their food intake (dietary recall) on the same day. Of 925 participants selected, 657 (71%) provided accurate 24-h urine collections, based on creatinine excretion data. The mean daily 24-h urinary sodium excretion was 252.0 +/- 92.2 mmol/day, equal to daily salt intake of 14.8 +/- 5.4 g. Of the 657 participants with accurate 24-h urine collections, 464 (70%) provided fully completed dietary recalls. Among these 464 participants, there was a significant difference between the 24-h urinary sodium excretion-based salt intake estimation (14.5 +/- 5.1 g/day) and the dietary recall-based salt intake estimation (12.0 +/ 7.0 g/day) (p < 0.001). On the other hand, a positive correlation was obtained between the dietary recall-based daily salt intake and 24-h urinary sodium excretion-based daily salt intake (r = 0.277, p < 0.001). Bread was the main source of salt (34%) followed by salt added during cooking and preparing food before serving (30%), salt from various processed foods (21%), and salt added at the table during food consumption (11%). Conclusively, this study confirmed a very high salt intake of the adult population in four major cities in Turkey. The present findings support the emerging salt reduction strategy in Turkey by promoting lower salt content in baked bread, and less salt use in habitual food preparation and during food consumption in the home. PMID- 28837103 TI - Activities, Participation and Quality of Life Concepts in Children and Adolescents with Celiac Disease: A Scoping Review. AB - Celiac disease (CD) is a food-related chronic condition and adherence to a strict gluten-free diet is the only available treatment. Adherence to the restrictive diet is challenging among children, especially adolescents. The aim was to describe existing knowledge about food-related activities, participation, and quality of life in daily life among children and adolescents with CD and to illuminate gaps in knowledge. The scoping review methodology was applied and literature searches were conducted in electronic databases. Twenty-three articles met the inclusion criteria. Food-related activities were identified, classified, and coded under the International Classification of Functioning, Disability, and Health adapted for children and youth (ICF-CY) concepts of activities and participation. A wide variety of study populations, objectives, methods, and tools involving 55 different food-related activities were found. Incorporation of the ICF-CY concepts and quality of life captures new insights into everyday challenges. Reviewing the CD literature using this different lens reveals areas yet to receive sufficient attention. Further research can deepen the understanding of daily functioning of children with CD and the underlying skills required to participate in daily food-related activities while adhering to the diet. This can lead to the development of standardized disease-specific assessment tools and suitable intervention programs. PMID- 28837104 TI - The Lipid Raft Proteome of African Trypanosomes Contains Many Flagellar Proteins. AB - Lipid rafts are liquid-ordered membrane microdomains that form by preferential association of 3-beta-hydroxysterols, sphingolipids and raft-associated proteins often having acyl modifications. We isolated lipid rafts of the protozoan parasite Trypanosoma brucei and determined the protein composition of lipid rafts in the cell. This analysis revealed a striking enrichment of flagellar proteins and several putative signaling proteins in the lipid raft proteome. Calpains and intraflagellar transport proteins, in particular, were found to be abundant in the lipid raft proteome. These findings provide additional evidence supporting the notion that the eukaryotic cilium/flagellum is a lipid raft-enriched specialized structure with high concentrations of sterols, sphingolipids and palmitoylated proteins involved in environmental sensing and cell signaling. PMID- 28837105 TI - A Behaviour Monitoring System (BMS) for Ambient Assisted Living. AB - Unusual changes in the regular daily mobility routine of an elderly person at home can be an indicator or early symptom of developing health problems. Sensor technology can be utilised to complement the traditional healthcare systems to gain a more detailed view of the daily mobility of a person at home when performing everyday tasks. We hypothesise that data collected from low-cost sensors such as presence and occupancy sensors can be analysed to provide insights on the daily mobility habits of the elderly living alone at home and to detect routine changes. We validate this hypothesis by designing a system that automatically learns the daily room-to-room transitions and permanence habits in each room at each time of the day and generates alarm notifications when deviations are detected. We present an algorithm to process the sensors' data streams and compute sensor-driven features that describe the daily mobility routine of the elderly as part of the developed Behaviour Monitoring System (BMS). We are able to achieve low detection delay with confirmation time that is high enough to convey the detection of a set of common abnormal situations. We illustrate and evaluate BMS with synthetic data, generated by a developed data generator that was designed to mimic different user's mobility profiles at home, and also with a real-life dataset collected from prior research work. Results indicate BMS detects several mobility changes that can be symptoms of common health problems. The proposed system is a useful approach for learning the mobility habits at the home environment, with the potential to detect behaviour changes that occur due to health problems, and therefore, motivating progress toward behaviour monitoring and elder's care. PMID- 28837106 TI - Positive Rates and Factors Associated with Abnormal Lung Function of Greenhouse Workers in China: A Cross-Sectional Study. AB - Since the number of greenhouse workers are increasing in China, this observational cross-sectional study was designed to evaluate lung function and discuss the potential risk factors, to provide evidence in the surveillance of greenhouse workers' health. 678 greenhouse workers in Gansu Province, China were enrolled. A questionnaire which included demographic and occupational information was used. Vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1:FVC ratios (FEV1/FVC), maximal expiratory flow after 50% of the FVC has not been exhaled (MEF50), maximal expiratory flow after 25% of the FVC has not been exhaled (MEF25) and maximal mid-expiratory flow curve (MMEF) were measured as lung function indicators. The mean values and standard deviations (SDs) of VC% predicted, FVC% predicted, FEV1% predicted and FEV1/FVC ratio were 106.07 +/- 13.36, 107.60 +/- 13.95, 97.19 +/- 14.80 and 89.76 +/- 10.78 respectively. The positive rates of above four and abnormal lung ventilation function were 2.9%, 2.8%, 11.2%, 4.6% and 6.5% respectively. Gender, age, BMI and number of greenhouses owned were influence factors of lung ventilation function (p < 0.05). The mean values and SDs of MEF50% predicted, MEF25% predicted and MMEF% predicted were 69.63 +/- 24.95, 54.04 +/- 24.94 and 66.81 +/- 24.53. The positive rates of above three and abnormal small airway function were 45.0%, 72.1%, 47.2% and 49.4% respectively. Age, education and number of greenhouses owned were influence factors for small airway function (p < 0.05). Working in a greenhouse might influence lung function of the workers. Small airway function indicators could be used as priority indicators for the surveillance of greenhouse workers' health. PMID- 28837107 TI - The Influence of Lead on Generation of Signalling Molecules and Accumulation of Flavonoids in Pea Seedlings in Response to Pea Aphid Infestation. AB - The aim of this study was to investigate the effect of an abiotic factor, i.e., lead at various concentrations (low causing a hormesis effect and causing high toxicity effects), on the generation of signalling molecules in pea (Pisum sativum L. cv. Cysterski) seedlings and then during infestation by the pea aphid (Acyrthosiphon pisum Harris). The second objective was to verify whether the presence of lead in pea seedling organs and induction of signalling pathways dependent on the concentration of this metal trigger defense responses to A. pisum. Therefore, the profile of flavonoids and expression levels of genes encoding enzymes of the flavonoid biosynthesis pathway (phenylalanine ammonialyase and chalcone synthase) were determined. A significant accumulation of total salicylic acid (TSA) and abscisic acid (ABA) was recorded in the roots and leaves of pea seedlings growing on lead-supplemented medium and next during infestation by aphids. Increased generation of these phytohormones strongly enhanced the biosynthesis of flavonoids, including a phytoalexin, pisatin. This research provides insights into the cross-talk between the abiotic (lead) and biotic factor (aphid infestation) on the level of the generation of signalling molecules and their role in the induction of flavonoid biosynthesis. PMID- 28837108 TI - Isolation, Characterization and Bioactivities of an Extracellular Polysaccharide Produced from Streptomyces sp. MOE6. AB - A Streptomyces strain was isolated from soil and the sequence of 1471 nucleotides of its 16S rDNA showed 99% identity to Streptomyces sp. HV10. This newly isolated Streptomyces strain produced an extracellular polysaccharide (EPS) composed mainly of glucose and mannose in a ratio of 1:4.1, as was characterized by Fourier transform infrared spectroscopy (FTIR), HPLC and 1H-NMR. The antioxidant activities of the partially purified MOE6-EPS were determined by measuring the hydroxyl free radical scavenging activity and the scavenging of 2,2-diphenyl-2 picryl-hydrazyl (DPPH) radicals. In addition, the partially purified MOE6-EPS showed high ferrous ion (Fe2+) chelation activity which is another antioxidant activity. Interestingly, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays that were colorimetric assays for NAD(P)H-dependent cellular oxidoreductases and a proxy of the number of viable cells, showed that the partially purified MOE6-EPS inhibited the proliferation of the human breast cancer cells (MDA-MB-231). The scratch wound assay showed that MOE6-EPS reduced the migration of mouse breast cancer cells (4T1). This study reports the production of EPS from Streptomyces species with promising antioxidant, metal chelating and mammalian cell inhibitory activities. PMID- 28837109 TI - Comparative Degradation of a Thiazole Pollutant by an Advanced Oxidation Process and an Enzymatic Approach. AB - Organic pollutants, especially those found in water bodies, pose a direct threat to various aquatic organisms as well as humans. A variety of different remediation approaches, including chemical and biological methods, have been developed for the degradation of various organic pollutants. However, comparative mechanistic studies of pollutant degradation by these different systems are almost non-existent. In this study, the degradation of a model thiazole pollutant, thioflavin T (ThT), was carried out in the presence of either an advanced oxidation process (ultraviolet (UV) + H2O2) or a chloroperoxidase enzyme system (CPO + H2O2). The degradation was followed both spectrophotometrically and using liquid chromatography-mass spectroscopy (LC-MS), and the products formed were identified using tandem liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS). The results show that the two remediation approaches produced different sets of intermediates, with only one common species (a demethylated form of ThT). This suggests that different degradation schemes were operating in the two systems. Interestingly, one of the major intermediates produced by the CPO + H2O2 system was a chlorinated form of thioflavin. Phytotoxicity studies showed that the CPO + H2O2-treated ThT solution was significantly (p <0.05) less toxic than the UV + H2O2-treated ThT solution. This is the first time that a comparative mechanistic study showing in detail the intermediates generated in chemical and biological remediation methods has been presented. Furthermore, the results show that different remediation systems have very different degradation schemes and result in products having different toxicities. PMID- 28837110 TI - Phytochemistry, Pharmacology and Traditional Uses of Plants from the Genus Trachelospermum L. AB - This paper is intended to review advances in the botanical, phytochemical, traditional uses and pharmacological studies of the genus Trachelospermum. Until now, 138 chemical constituents have been isolated and characterized from these plants, particularly from T. asiaticum and T. jasminoides. Among these compounds, lignans, triterpenoids, and flavonoids are the major bioactive constituents. Studies have shown that plants from the genus Trachelospermum exhibit an extensive range of pharmacological properties both in vivo and in vitro, including anti-inflammatory, analgesic, antitumor, antiviral and antibacterial activities. In Traditional Chinese Medicine (TCM) culture, drugs that include T. jasminoides stems have been used to cure rheumatism, gonarthritis, backache and pharyngitis, although there are few reports concerning the clinical use and toxicity of these plants. Further attention should be paid to gathering information about their toxicology data, quality-control measures, and the clinical value of the active compounds from genus Trachelospermum. PMID- 28837111 TI - Longitudinal Impact of Hurricane Sandy Exposure on Mental Health Symptoms. AB - Hurricane Sandy hit the eastern coast of the United States in October 2012, causing billions of dollars in damage and acute physical and mental health problems. The long-term mental health consequences of the storm and their predictors have not been studied. New York City and Long Island residents completed questionnaires regarding their initial Hurricane Sandy exposure and mental health symptoms at baseline and 1 year later (N = 130). There were statistically significant decreases in anxiety scores (mean difference = -0.33, p < 0.01) and post-traumatic stress disorder (PTSD) scores (mean difference = 1.98, p = 0.001) between baseline and follow-up. Experiencing a combination of personal and property damage was positively associated with long-term PTSD symptoms (ORadj 1.2, 95% CI [1.1-1.4]) but not with anxiety or depression. Having anxiety, depression, or PTSD at baseline was a significant predictor of persistent anxiety (ORadj 2.8 95% CI [1.1-6.8], depression (ORadj 7.4 95% CI [2.3 24.1) and PTSD (ORadj 4.1 95% CI [1.1-14.6]) at follow-up. Exposure to Hurricane Sandy has an impact on PTSD symptoms that persists over time. Given the likelihood of more frequent and intense hurricanes due to climate change, future hurricane recovery efforts must consider the long-term effects of hurricane exposure on mental health, especially on PTSD, when providing appropriate assistance and treatment. PMID- 28837112 TI - Comparative Evaluation of Background Subtraction Algorithms in Remote Scene Videos Captured by MWIR Sensors. AB - Background subtraction (BS) is one of the most commonly encountered tasks in video analysis and tracking systems. It distinguishes the foreground (moving objects) from the video sequences captured by static imaging sensors. Background subtraction in remote scene infrared (IR) video is important and common to lots of fields. This paper provides a Remote Scene IR Dataset captured by our designed medium-wave infrared (MWIR) sensor. Each video sequence in this dataset is identified with specific BS challenges and the pixel-wise ground truth of foreground (FG) for each frame is also provided. A series of experiments were conducted to evaluate BS algorithms on this proposed dataset. The overall performance of BS algorithms and the processor/memory requirements were compared. Proper evaluation metrics or criteria were employed to evaluate the capability of each BS algorithm to handle different kinds of BS challenges represented in this dataset. The results and conclusions in this paper provide valid references to develop new BS algorithm for remote scene IR video sequence, and some of them are not only limited to remote scene or IR video sequence but also generic for background subtraction. The Remote Scene IR dataset and the foreground masks detected by each evaluated BS algorithm are available online: https://github.com/JerryYaoGl/BSEvaluationRemoteSceneIR. PMID- 28837113 TI - Orally Delivered Scorpion Antimicrobial Peptides Exhibit Activity against Pea Aphid (Acyrthosiphon pisum) and Its Bacterial Symbionts. AB - Aphids are severe agricultural pests that damage crops by feeding on phloem sap and vectoring plant pathogens. Chemical insecticides provide an important aphid control strategy, but alternative and sustainable control measures are required to avoid rapidly emerging resistance, environmental contamination, and the risk to humans and beneficial organisms. Aphids are dependent on bacterial symbionts, which enable them to survive on phloem sap lacking essential nutrients, as well as conferring environmental stress tolerance and resistance to parasites. The evolution of aphids has been accompanied by the loss of many immunity-related genes, such as those encoding antibacterial peptides, which are prevalent in other insects, probably because any harm to the bacterial symbionts would inevitably affect the aphids themselves. This suggests that antimicrobial peptides (AMPs) could replace or at least complement conventional insecticides for aphid control. We fed the pea aphids (Acyrthosiphon pisum) with AMPs from the venom glands of scorpions. The AMPs reduced aphid survival, delayed their reproduction, displayed in vitro activity against aphid bacterial symbionts, and reduced the number of symbionts in vivo. Remarkably, we found that some of the scorpion AMPs compromised the aphid bacteriome, a specialized organ that harbours bacterial symbionts. Our data suggest that scorpion AMPs holds the potential to be developed as bio-insecticides, and are promising candidates for the engineering of aphid-resistant crops. PMID- 28837115 TI - Improved Spatial Differencing Scheme for 2-D DOA Estimation of Coherent Signals with Uniform Rectangular Arrays. AB - This paper proposes an improved spatial differencing (ISD) scheme for two dimensional direction of arrival (2-D DOA) estimation of coherent signals with uniform rectangular arrays (URAs). We first divide the URA into a number of row rectangular subarrays. Then, by extracting all the data information of each subarray, we only perform difference-operation on the auto-correlations, while the cross-correlations are kept unchanged. Using the reconstructed submatrices, both the forward only ISD (FO-ISD) and forward backward ISD (FB-ISD) methods are developed under the proposed scheme. Compared with the existing spatial smoothing techniques, the proposed scheme can use more data information of the sample covariance matrix and also suppress the effect of additive noise more effectively. Simulation results show that both FO-ISD and FB-ISD can improve the estimation performance largely as compared to the others, in white or colored noise conditions. PMID- 28837114 TI - Polydeoxyribonucleotide Ameliorates Lipopolysaccharide-Induced Lung Injury by Inhibiting Apoptotic Cell Death in Rats. AB - Lung injury is characterized by diffuse lung inflammation, alveolar-capillary destruction, and alveolar flooding, resulting in respiratory failure. Polydexyribonucleotide (PDRN) has an anti-inflammatory effect, decreasing inflammatory cytokines, and suppressing apoptosis. Thus, we investigated its efficacy in the treatment of lung injury, which was induced in rats using lipopolysaccharide (LPS). Rats were randomly divided into three groups according to sacrifice time, and each group split into control, lung injury-induced, and lung injury-induced + PDRN-treated groups. Rats were sacrificed 24 h and 72 h after PDRN administration, according to each group. Lung injury was induced by intratracheal instillation of LPS (5 mg/kg) in 0.2 mL saline. Rats in PDRN treated groups received a single intraperitoneal injection of 0.3 mL distilled water including PDRN (8 mg/kg), 1 h after lung injury induction. Percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive, cleaved caspase-3-, -8-, and -9-positive cells, the ratio of Bcl-2 associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2), and expressions of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6) were decreased by PDRN treatment in the LPS-induced lung injury rats. Therefore, treatment with PDRN reduced lung injury score. This anti-apoptotic effect of PDRN can be ascribed to the enhancing effect of PDRN on adenosine A2A receptor expression. Based on these results, PDRN might be considered as a new therapeutic agent for the treatment of lung injury. PMID- 28837116 TI - Looking Back, Looking Forward at Halogen Bonding in Drug Discovery. AB - Halogen bonding has emerged at the forefront of advances in improving ligand: receptor interactions. In particular the newfound ability of this extant non covalent-bonding phenomena has revolutionized computational approaches to drug discovery while simultaneously reenergizing synthetic approaches to the field. Here we survey, via examples of classical applications involving halogen atoms in pharmaceutical compounds and their biological hosts, the unique advantages that halogen atoms offer as both Lewis acids and Lewis bases. PMID- 28837117 TI - Preclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic Infection Imaging Agent. AB - The study assessed a radiolabeled depsipeptide conjugate (68Ga-DOTA-TBIA101) for its potential as an imaging agent targeting infection or infection-associated inflammation. 68Ga-labeled DOTA-TBIA101 imaging was performed in (NZR1) healthy rabbits; (NZR2) rabbits bearing muscular sterile inflammation and Staphylococcus aureus (SA) infection; and (NZR3) rabbits infected with Mycobacterium tuberculosis (MTB) combined with a subcutaneous scruff infection of SA in the same animal. All animals were imaged using a PET/CT scanner at 5 and 60 min post injection. Images showed elevated accumulation of 68Ga-DOTA-TBIA101 in the sterile muscular inflammation site (T/NT ratio = 2.6 +/- 0.37 (5 min) and 2.8 +/- 2.3 (60 min)) and muscles infected with MTB (T/NT ratio = 2.6 +/- 0.35 (5 min) and 2.8 +/- 0.16 (60 min)). The findings suggest that 68Ga-DOTA-TBIA101-PET/CT may detect MTB-associated inflammation, although more foundational studies need to be performed to rationalize the diagnostic value of this technique. PMID- 28837118 TI - Building Extraction Based on an Optimized Stacked Sparse Autoencoder of Structure and Training Samples Using LIDAR DSM and Optical Images. AB - In this paper, a building extraction method is proposed based on a stacked sparse autoencoder with an optimized structure and training samples. Building extraction plays an important role in urban construction and planning. However, some negative effects will reduce the accuracy of extraction, such as exceeding resolution, bad correction and terrain influence. Data collected by multiple sensors, as light detection and ranging (LIDAR), optical sensor etc., are used to improve the extraction. Using digital surface model (DSM) obtained from LIDAR data and optical images, traditional method can improve the extraction effect to a certain extent, but there are some defects in feature extraction. Since stacked sparse autoencoder (SSAE) neural network can learn the essential characteristics of the data in depth, SSAE was employed to extract buildings from the combined DSM data and optical image. A better setting strategy of SSAE network structure is given, and an idea of setting the number and proportion of training samples for better training of SSAE was presented. The optical data and DSM were combined as input of the optimized SSAE, and after training by an optimized samples, the appropriate network structure can extract buildings with great accuracy and has good robustness. PMID- 28837120 TI - Fuzzy Modelling for Human Dynamics Based on Online Social Networks. AB - Human mobility mining has attracted a lot of attention in the research community due to its multiple implications in the provisioning of innovative services for large metropolises. In this scope, Online Social Networks (OSN) have arisen as a promising source of location data to come up with new mobility models. However, the human nature of this data makes it rather noisy and inaccurate. In order to deal with such limitations, the present work introduces a framework for human mobility mining based on fuzzy logic. Firstly, a fuzzy clustering algorithm extracts the most active OSN areas at different time periods. Next, such clusters are the building blocks to compose mobility patterns. Furthermore, a location prediction service based on a fuzzy rule classifier has been developed on top of the framework. Finally, both the framework and the predictor has been tested with a Twitter and Flickr dataset in two large cities. PMID- 28837119 TI - Toward the Selection of Cell Targeting Aptamers with Extended Biological Functionalities to Facilitate Endosomal Escape of Cargoes. AB - Over the past decades there have been exciting and rapid developments of highly specific molecules to bind cancer antigens that are overexpressed on the surfaces of malignant cells. Nanomedicine aims to exploit these ligands to generate nanoscale platforms for targeted cancer therapy, and to do so with negligible off target effects. Aptamers are structured nucleic acids that bind to defined molecular targets ranging from small molecules and proteins to whole cells or viruses. They are selected through an iterative process of amplification and enrichment called SELEX (systematic evolution of ligands by exponential enrichment), in which a combinatorial oligonucleotide library is exposed to the target of interest for several repetitive rounds. Nucleic acid ligands able to bind and internalize into malignant cells have been extensively used as tools for targeted delivery of therapeutic payloads both in vitro and in vivo. However, current cell targeting aptamer platforms suffer from limitations that have slowed their translation to the clinic. This is especially true for applications in which the cargo must reach the cytosol to exert its biological activity, as only a small percentage of the endocytosed cargo is typically able to translocate into the cytosol. Innovative technologies and selection strategies are required to enhance cytoplasmic delivery. In this review, we describe current selection methods used to generate aptamers that target cancer cells, and we highlight some of the factors that affect productive endosomal escape of cargoes. We also give an overview of the most promising strategies utilized to improve and monitor endosomal escape of therapeutic cargoes. The methods we highlight exploit tools and technologies that can potentially be incorporated in the SELEX process. Innovative selection protocols may identify aptamers with extended biological functionalities that allow effective cytosolic translocation of therapeutics. This in turn may facilitate successful translation of these platforms into clinical applications. PMID- 28837122 TI - Highlights From the XVII International Workshop on Chronic Lymphocytic Leukemia. PMID- 28837123 TI - Highlights From the XVII International Workshop on Chronic Lymphocytic Leukemia: Commentary. PMID- 28837124 TI - Highlights in Aggressive Non-Hodgkin Lymphoma From the 2017 American Society of Clinical Oncology Annual Meeting. PMID- 28837125 TI - Highlights in Aggressive Non-Hodgkin Lymphoma From the 2017 American Society of Clinical Oncology Annual Meeting: Commentary. PMID- 28837121 TI - Diagnostic Approach to Pulmonary Hypertension in Premature Neonates. AB - Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease in premature infants following respiratory distress at birth. With increasing survival of extremely low birth weight infants, alveolar simplification is the defining lung characteristic of infants with BPD, and along with pulmonary hypertension, increasingly contributes to both respiratory morbidity and mortality in these infants. Growth restricted infants, infants born to mothers with oligohydramnios or following prolonged preterm rupture of membranes are at particular risk for early onset pulmonary hypertension. Altered vascular and alveolar growth particularly in canalicular and early saccular stages of lung development following mechanical ventilation and oxygen therapy, results in developmental lung arrest leading to BPD with pulmonary hypertension (PH). Early recognition of PH in infants with risk factors is important for optimal management of these infants. Screening tools for early diagnosis of PH are evolving; however, echocardiography is the mainstay for non-invasive diagnosis of PH in infants. Cardiac computed tomography (CT) and magnetic resonance are being used as imaging modalities, however their role in improving outcomes in these patients is uncertain. Follow-up of infants at risk for PH will help not only in early diagnosis, but also in appropriate management of these infants. Aggressive management of lung disease, avoidance of hypoxemic episodes, and optimal nutrition determine the progression of PH, as epigenetic factors may have significant effects, particularly in growth-restricted infants. Infants with diagnosis of PH are managed with pulmonary vasodilators and those resistant to therapy need to be worked up for the presence of cardio-vascular anomalies. The management of infants and toddlers with PH, especially following premature birth is an emerging field. Nonetheless, combination therapies in a multi-disciplinary setting improves outcomes for these infants. PMID- 28837127 TI - Highlights in Ovarian Cancer From the 2017 American Society of Clinical Oncology Annual Meeting: Commentary. PMID- 28837126 TI - Highlights in Ovarian Cancer From the 2017 American Society of Clinical Oncology Annual Meeting. PMID- 28837128 TI - Unveiling bifidobacterial biogeography across the mammalian branch of the tree of life. AB - Internally transcribed spacer (ITS) rRNA profiling is a novel tool for detailed analysis of microbial populations at low taxonomic ranks. Here we exploited this approach to explore species-level biogeography of the Bifidobacterium genus across 291 adult mammals. These include humans and 13 other primates, domesticated animals, such as dogs, cats, cows, sheep, goats, horses and pigs, and 46 additional species. The collected profiles revealed the presence of 89 putative novel bifidobacterial taxa in addition to 45 previously described species. Remarkably, in contrast to what is currently known for many gut commensals, we did not observe host-specialization among bifidobacterial species but rather their widespread distribution across mammals. Moreover, ITS rRNA profiling of wild relatives of domesticated dogs, rabbits and pigs clearly indicates that domestication and close contact with humans have impacted on the composition of the fecal bifidobacterial population. These data were complemented by analysis of bifidobacterial communities in milk of eight mammalian families, showing that bifidobacteria represent prototypical early gut microbiota members which are inherited by newborns from their lactating mother. Thus this study highlights the role of bifidobacteria as pioneering gut colonizers of a wide range of mammals. PMID- 28837129 TI - Large-scale comparative metagenomics of Blastocystis, a common member of the human gut microbiome. AB - The influence of unicellular eukaryotic microorganisms on human gut health and disease is still largely unexplored. Blastocystis spp. commonly colonize the gut, but its clinical significance and ecological role are currently unsettled. We have developed a high-sensitivity bioinformatic pipeline to detect Blastocystis subtypes (STs) from shotgun metagenomics, and applied it to 12 large data sets, comprising 1689 subjects of different geographic origin, disease status and lifestyle. We confirmed and extended previous observations on the high prevalence the microrganism in the population (14.9%), its non-random and ST-specific distribution, and its ability to cause persistent (asymptomatic) colonization. These findings, along with the higher prevalence observed in non-westernized individuals, the lack of positive association with any of the disease considered, and decreased presence in individuals with dysbiosis associated with colorectal cancer and Crohn's disease, strongly suggest that Blastocystis is a component of the healthy gut microbiome. Further, we found an inverse association between body mass index and Blastocystis, and strong co-occurrence with archaeal organisms (Methanobrevibacter smithii) and several bacterial species. The association of specific microbial community structures with Blastocystis was confirmed by the high predictability (up to 0.91 area under the curve) of the microorganism colonization based on the species-level composition of the microbiome. Finally, we reconstructed and functionally profiled 43 new draft Blastocystis genomes and discovered a higher intra subtype variability of ST1 and ST2 compared with ST3 and ST4. Altogether, we provide an in-depth epidemiologic, ecological, and genomic analysis of Blastocystis, and show how metagenomics can be crucial to advance population genomics of human parasites. PMID- 28837130 TI - ADP-ribose-specific chromatin-affinity purification for investigating genome-wide or locus-specific chromatin ADP-ribosylation. AB - Protein ADP-ribosylation is a structurally heterogeneous post-translational modification (PTM) that influences the physicochemical and biological properties of the modified protein. ADP-ribosylation of chromatin changes its structural properties, thereby regulating important nuclear functions. A lack of suitable antibodies for chromatin immunoprecipitation (ChIP) has so far prevented a comprehensive analysis of DNA-associated protein ADP-ribosylation. To analyze chromatin ADP-ribosylation, we recently developed a novel ADP-ribose-specific chromatin-affinity purification (ADPr-ChAP) methodology that uses the recently identified ADP-ribose-binding domains RNF146 WWE and Af1521. In this protocol, we describe how to use this robust and versatile method for genome-wide and loci specific localization of chromatin ADP-ribosylation. ADPr-ChAP enables bioinformatic comparisons of ADP-ribosylation with other chromatin modifications and is useful for understanding how ADP-ribosylation regulates biologically important cellular processes. ADPr-ChAP takes 1 week and requires standard skills in molecular biology and biochemistry. Although not covered in detail here, this technique can also be combined with conventional ChIP or DNA analysis to define the histone marks specifically associated with the ADP-ribosylated chromatin fractions and dissect the molecular mechanism and functional role of chromatin ADP-ribosylation. PMID- 28837131 TI - Detection of nucleic acid-protein interactions in plant leaves using fluorescence lifetime imaging microscopy. AB - DNA-binding proteins (DNA-BPs) and RNA-binding proteins (RNA-BPs) have critical roles in living cells in all kingdoms of life. Various experimental approaches exist for the study of nucleic acid-protein interactions in vitro and in vivo, but the detection of such interactions at the subcellular level remains challenging. Here we describe how to detect nucleic acid-protein interactions in plant leaves by using a fluorescence resonance energy transfer (FRET) approach coupled to fluorescence lifetime imaging microscopy (FLIM). Proteins of interest (POI) are tagged with a GFP and transiently expressed in plant cells to serve as donor fluorophore. After sample fixation and cell wall permeabilization, leaves are treated with Sytox Orange, a nucleic acid dye that can function as a FRET acceptor. Upon close association of the GFP-tagged POI with Sytox-Orange-stained nucleic acids, a substantial decrease of the GFP lifetime due to FRET between the donor and the acceptor can be monitored. Treatment with RNase before FRET-FLIM measurements allows determination of whether the POI associates with DNA and/or RNA. A step-by-step protocol is provided for sample preparation, data acquisition and analysis. We describe how to calibrate the equipment and include a tutorial explaining the use of the FLIM software. To illustrate our approach, we provide experimental procedures to detect the interaction between plant DNA and two proteins (the AeCRN13 effector from the oomycete Aphanomyces euteiches and the AtWRKY22 defensive transcription factor from Arabidopsis). This protocol allows the detection of protein-nucleic acid interactions in plant cells and can be completed in <2 d. PMID- 28837132 TI - Massively parallel and multiparameter titration of biochemical assays with droplet microfluidics. AB - Biochemical systems in which multiple components take part in a given reaction are of increasing interest. Because the interactions between these different components are complex and difficult to predict from basic reaction kinetics, it is important to test for the effect of variations in the concentration for each reagent in a combinatorial manner. For example, in PCR, an increase in the concentration of primers initially increases template amplification, but large amounts of primers result in primer-dimer by-products that inhibit the amplification of the template. Manual titration of biochemical mixtures rapidly becomes costly and laborious, forcing scientists to settle for suboptimal concentrations. Here we present a droplet-based microfluidics platform for mapping of the concentration space of up to three reaction components followed by detection with a fluorescent readout. The concentration of each reaction component is read through its internal standard (barcode), which is fluorescent but chemically orthogonal. We describe in detail the workflow, which comprises the following: (i) production of the microfluidics chips, (ii) preparation of the biochemical mixes, (iii) their mixing and compartmentalization into water-in-oil emulsion droplets via microfluidics, (iv) incubation and imaging of the fluorescent barcode and reporter signals by fluorescence microscopy and (v) image processing and data analysis. We also provide recommendations for choosing the appropriate fluorescent markers, programming the pressure profiles and analyzing the generated data. Overall, this platform allows a researcher with a few weeks of training to acquire ~10,000 data points (in a 1D, 2D or 3D concentration space) over the course of a day from as little as 100-1,000 MUl of reaction mix. PMID- 28837134 TI - Clinician performed ultrasound in fetal growth restriction: fetal, neonatal and pediatric aspects. AB - Fetal growth restriction (FGR) affects 7-10% pregnancies. Conventional and tissue Doppler imaging has noted cardiac compromise during fetal and early neonatal periods in this cohort. In this article, we discuss the use of salient ultrasound parameters across age groups. During fetal life, certain feto-placental sonographic parameters have been linked to adverse perinatal outcomes and are predictive of later life hypertension. During the early postnatal period altered morphometry (hypertrophied and globular hearts) with sub-clinical impairment of cardiac function has been noted in both term and preterm infants with FGR. Vascular imaging has noted thickened and stiffer arteries in association with significantly elevated blood pressure. Similar findings in the pediatric age groups indicate persistence of these alterations, and have formed the basis of intervention studies. Assessment methodology and clinical relevance of these parameters, especially in designing and monitoring of intervention strategies is discussed. Frontline care givers (obstetricians and neonatologists) are increasingly using point of care ultrasound to discern these manifestations of FGR during the sub-clinical phase. PMID- 28837135 TI - Identifying a quality improvement project. AB - An important step on the roadmap to a successful quality improvement (QI) project is careful selection of topics and aims to be addressed by QI projects. Using information from a variety of data monitoring systems as well as individual events and experiences, leaders of neonatal units and QI teams should first identify quality and safety gaps in their unit. They should then use an explicit, formal process for selecting the best projects to which their limited time and resources should be allocated. Priority should be given to projects that address a quality gap of high magnitude and impact, have a high likelihood of success, have a champion, fit with the unit's state of readiness for change, have organizational support and align with organizational priorities. The scope of the project should also match the experience and expertise of the QI team. PMID- 28837133 TI - Construction of an aerolysin nanopore in a lipid bilayer for single oligonucleotide analysis. AB - Nanopore techniques offer the possibility to study biomolecules at the single molecule level in a low-cost, label-free and high-throughput manner. By analyzing the level, duration and frequency of ionic current blockades, information regarding the structural conformation, mass, length and concentration of single molecules can be obtained in physiological conditions. Aerolysin monomers assemble into small pores that provide a confined space for effective electrochemical control of a single molecule interacting with the pore, which significantly improves the temporal resolution of this technique. In comparison with other reported protein nanopores, aerolysin maintains its functional stability in a wide range of pH conditions, which allows for the direct discrimination of oligonucleotides between 2 and 10 nt in length and the monitoring of the stepwise cleavage of oligonucleotides by exonuclease I (Exo I) in real time. This protocol describes the process of activating proaerolysin using immobilized trypsin to obtain the aerolysin monomer, the construction of a lipid membrane and the insertion of an individual aerolysin nanopore into this membrane. A step-by-step description is provided of how to perform single oligonucleotide analyses and how to process the acquired data. The total time required for this protocol is ~3 d. PMID- 28837136 TI - Cord blood neutropenia is an independent predictor of early sepsis. AB - OBJECTIVE: The significance of cord blood neutropenia as a screening tool for early-onset sepsis (EOS) is unclear. The objectives were to define reference values for cord blood neutrophil count and to determine the sensitivity and positive likelihood ratio of cord neutropenia for the detection of EOS. STUDY DESIGN: This retrospective observational cohort study included all mother-infant pairs with deliveries between 2009 and 2014 for whom cord neutrophil counts were routinely done. EOS cases were identified by interrogation of electronic charts. Maternal and perinatal factors were assessed to determine reference values of cord neutrophil. The diagnostic value of neutropenia for detecting EOS was assessed. A nested case-control design was used to measure the value of neutropenia in the detection of EOS in comparison with other risk factors. RESULTS: A total of 8,590 mother-infant pairs were included. We identified 84 sepsis cases. The neutrophil count was strongly associated with gestational age. Neutropenia adjusted for gestational age was strongly associated with EOS and had good specificity but poor sensitivity. The addition of neutropenia to other EOS risk factors increased sensitivity without decreasing specificity. CONCLUSION: Cord blood neutropenia was significantly associated with EOS and the addition of cord neutropenia to current EOS risk factors increased the detection rate of EOS. PMID- 28837137 TI - Maternal and neonatal demographics of macrosomic infants admitted to the neonatal intensive care unit. AB - OBJECTIVE: The objective of this study is to determine the incidence, significance, associated demographics and impact of macrosomic infants (?4 kg) admitted to the Neonatal Intensive Care Unit (NICU) on NICU census and resources. STUDY DESIGN: A retrospective cohort review was performed from 2010 to 2015. Descriptive statistical analyses were used. RESULTS: Of 19 308 deliveries, 1823 were infants ?4000 g and 213 were admitted to the NICU. Cesarean delivery occurred in 70% of the admitted infants, most (74.1%) were Grade 1 macrosomia and male (63%). Preterm birth occurred in 4%. The incidence of maternal diabetes was 25%. Primary admitting diagnoses were respiratory distress, suspected sepsis, hypoglycemia and perinatal depression. The average length of stay was 8+/-6 days for all macrosomic infants admitted, increased to 22+/-13 days for infants with Grade 3 macrosomia. CONCLUSION: Macrosomic infants are a growing population, who increase the demand on existing NICU resources. A larger multi-centered study is needed to determine the overall relevance of these findings in other populations. PMID- 28837138 TI - In vivo assessment of placental and brain volumes in growth-restricted fetuses with and without fetal Doppler changes using quantitative 3D MRI. AB - OBJECTIVE: The relationship between placental and fetal brain growth is poorly understood and difficult to assess. The objective of this study was to interrogate placental and fetal brain growth in healthy pregnancies and those complicated by fetal growth restriction (FGR). STUDY DESIGN: In a prospective, observational study, pregnant women with normal pregnancies or pregnancies complicated by FGR underwent fetal magnetic resonance imaging (MRI). Placental, global and regional brain volumes were calculated. RESULTS: A total of 114 women (79 controls and 35 FGR) underwent MRI (median gestational age (GA) 30 weeks, range 18 to 39). All measured volumes increased exponentially with advancing GA. Placental, total brain, cerebral and cerebellar volumes were smaller in FGR compared with controls (P<0.05). Increasing placental volume was associated with increasing cerebral and cerebellar volumes (P<0.05). CONCLUSION: Quantitative fetal MRI can accurately detect decreased placental and brain volumes in pregnancies with FGR and may provide insight into the timing and mechanisms of brain injury in FGR. PMID- 28837139 TI - Apelin involved in progression of diabetic nephropathy by inhibiting autophagy in podocytes. AB - Podocyte autophagy dysfunction has been reported to be responsible for the progression of diabetic nephropathy (DN), however, the factors contributed to autophagy dysfunction in type 2 diabetes are not fully understood. Among promoting factors in DN, an adipokine, apelin, had been showed to trigger podocyte dysfunction. Therefore, it is hypothesized that apelin, which is increased in plasma in type 2 diabetes, lead to podocyte apoptosis through inhibiting podocyte autophagy, which resulted in podocyte dysfunction followed by DN. KkAy mice (diabetic mice) and cultured podocytes (MPC5 cells and native podocytes) were treated with high glucose (HG) and apelin or its antagonist F13A. Renal function, podocyte autophagy, podocyte apoptosis and corresponding cell signaling pathways in podocytes were detected. The results showed that apelin aggravated the renal dysfunction and foot process injuries in kkAy mice, which is positively correlated to podocyte apoptosis and negatively correlated to podocyte autophagy. Apelin induced podocyte apoptosis and inhibited podocyte autophagy in both normal glucose and HG conditions while F13A reversed these effects. Investigations by western blot found that apelin inhibits podocyte autophagy through ERK-, Akt- and mTOR-dependent pathways. In conclusion, increased apelin concentration in plasma inhibited podocyte autophagy, which would lead to podocyte apoptosis and renal dysfunction in diabetes. These effects would contribute to the progression of DN. PMID- 28837140 TI - MET/SMAD3/SNAIL circuit mediated by miR-323a-3p is involved in regulating epithelial-mesenchymal transition progression in bladder cancer. AB - Bladder cancer (BCa) is the one of the most common cancers with high incidence, occurrence and low 5-year survival rate. Emerging evidence indicates that DLK1 DIO3 genomic region especially the miRNA cluster in this region is involved in several pathologic processes and various cancers, and miR-323a-3p is a member of this miRNA cluster. In this study, we investigate the function and regulatory network of miR-323a-3p in BCa. miR-323a-3p is frequently downregulated in BCa tissues and three cell lines compared with adjacent non-tumorous tissues and bladder normal cell line (SV-HUC-1). Besides, downregulation of miR-323a-3p is significantly associated with poor overall survival rate of BCa. Methylation of DLK1-MEG3 intergenic DMR (IG-DMR) contributes to the reduction of miR-323a-3p. Overexpression of miR-323a-3p significantly inhibits the epithelial-mesenchymal transition (EMT) progression of BCa. Both upregulated MET and SMAD3 are direct targets of miR-323a-3p, and the knockdown of MET and SMAD3 also represses the EMT progression consistently with overexpression of miR-323a-3p. SNAIL is detected in the last targeted confocal protein of both MET and SMAD3 signaling that trigger EMT consequently. Hence, a miR-323a-3p/MET/SMAD3/SNAIL circuit is established to regulate the EMT progression of BCa. And a mutual regulatory mechanism between miR-323a-3p/miR-433/miR-409 and MET also participates in this circuit. In conclusion, our study demonstrates a novel regulatory mechanism of the miR-323a 3p/MET/SMAD3/SNAIL circuit that is involved in the EMT regulation of BCa, which may be a potential therapy target for BCa. PMID- 28837141 TI - Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF beta1/STAT3 axis-regulated EMT. AB - Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide. We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT. Furthermore, based on the effect of metformin on the activation of STAT3 and expression of TGF-beta1, we propose that metformin exerts its effects by targeting the TGF-beta1/STAT3 axis. These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy for the treatment of castration-resistant prostate cancer. PMID- 28837142 TI - Microenvironment inflammatory infiltrate drives growth speed and outcome of hepatocellular carcinoma: a prospective clinical study. AB - In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-beta1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial-mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast growing HCCs are associated with TGF-beta signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFbeta1 signaling in a general background of long-standing and permanent inflammatory state. PMID- 28837143 TI - Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. AB - Neuroendocrine neoplasms (NENs) are rare, heterogeneous and ubiquitous tumors commonly localized in the gastrointestinal tract, lung, and pancreas. The clinical behavior of NEN is highly unpredictable; in fact, low-grade cases can unexpectedly be associated with metastases. Currently, the 2010 WHO NEN classification employs histological differentiation and the proliferation index for grading tumors but fails to provide reliable prognostic and therapeutic indications. Therefore, there is an urgent need for a better characterization of G2/G3 NENs. Similar to several other tumors, NENs possess immune-escape mechanisms, but very little has yet been done to characterize this crucial aspect. There are no available data describing PD-L1 expression in these tumors. Here we provide, for the first time, evidence of PD-L1 tissue expression in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). PD-L1 expression was significantly associated with a high-grade WHO classification (G3) (P<0.001) but not with gender, primary site, or lymph node status. The PD-L1 positivity rate and signal intensity are directly correlated (P<0.001) with a grade increase from G1 to G3. In particular in G3 cases, we observed a dichotomy between the morphology (WD- and PD-NENs) and Ki67. Moreover, our study demonstrated a significant association with the grade and PD-L1 expression levels in immune infiltrating cells (P<0.001). In particular, G3 tumors are characterized by strong PD-L1 expression in both the tumor and infiltrating immune cells (P<0.001), reflecting an unfavorable environment for T-cell-mediated tumor aggression. These findings suggest that NENs might acquire resistance to immune surveillance by upregulating PD-L1 and inhibiting peritumoral and intratumoral infiltrating lymphocytes. Here we demonstrate that PD-L1 is currently the best known biomarker for G3 NENs, becoming the new gold standard for G3 NEN discrimination. Furthermore, pharmacological approaches using anti-PD-1 antibodies may become the logical choice for the treatment of G3 cases with a poor prognosis. PMID- 28837145 TI - Discovery of (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone through upregulating hTERT induces cell apoptosis and ERS. AB - Dominant-negative mutants of telomerase hTERT were demonstrated to have selective effects in tumor cells. However, no any effective and highly selective hTERT inhibitor has been developed so far. We focused on developing new hTERT modulators and synthesized a small molecular compound, named (4-bromophenyl)(3 hydroxy-4-methoxyphenyl)methanone. Our in vitro studies found that title compound showed high inhibitory activity against telomerase, had high antiproliferative capacity on SMMC-7721 cells with IC50 value 88 nm, and had no obvious toxic effect on human normal hepatocyte cells with IC50 value 10 MUM. Our in vivo studies showed that this compound significantly inhibited tumor growth in xenograft tumor models. The further molecular mechanisms of title compound inhibition SMMC-7721 cell proliferation by modulating hTERT were explored; the results showed that endoplasmic reticulum stress (ERS) through ER over response (EOR) activates the expression of hTERT, and then induces ERS, which is believed to be intricately associated with oxidative stress and mitochondrial dysfunction, resulting in apoptotic cell death, thereby modulating the expression of downstream signaling molecules including CHOP (CAAT/enhancer-binding protein homologous protein)) and mitochondrion pathway of apoptosis, leading to inhibition of cell proliferation. PMID- 28837144 TI - Long noncoding RNA XIST expedites metastasis and modulates epithelial-mesenchymal transition in colorectal cancer. AB - Tumor progression and metastasis is the main cause of death in colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer. In this study, we found that lncRNA XIST was overexpressed in CRC cell lines and tissues. High expression of lncRNA XIST was associated with adverse overall survival in CRC patients. Knockdown of lncRNA XIST remarkably inhibited CRC cell proliferation, invasion, epithelial mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and metastasis in vivo. Further study indicated that knockdown of lncRNA XIST markedly increased the expression of microRNA-200b-3p (miR-200b-3p) that has been found to be downregulated in CRC tissues and cell lines, and luciferase activity assay indicated that lncRNA XIST could bind directly with miR 200b-3p. Moreover, knockdown of lncRNA XIST significantly reduced the expression of ZEB1, which was the direct target of miR-200b-3p, and the tumor suppressive effects caused by knockdown of lncRNA XIST could be rescued by re-expression of ZEB1 in CRC cells. Overall, our study demonstrated how lncRNA XIST regulates CRC progression and metastasis by competing for miR-200b-3p to modulate the expression of ZEB1. lncRNA XIST may be used as a biomarker to predict prognosis in CRC patients. PMID- 28837146 TI - Adropin deficiency worsens HFD-induced metabolic defects. AB - The limited efficacy of current treatment methods and increased type 2 diabetes mellitus (T2DM) incidence constitute an incentive for investigating how metabolic homeostasis is maintained, to improve treatment efficacy and identify novel treatment methods. We analyzed a three-generation family of Chinese origin with the common feature of T2DM attacks and fatty pancreas (FP), alongside 19 unrelated patients with FP and 58 cases with T2DM for genetic variations in Enho, serum adropin, and relative Treg amounts. Functional studies with adropin knockout (AdrKO) in C57BL/6J mice were also performed. It showed serum adropin levels were significantly lower in FP and T2DM patients than in healthy subjects; relative Treg amounts were also significantly decreased in FP and T2DM patients, and positively associated with adropin (r=0.7220, P=0.0001). Sequencing revealed that the patients shared a Cys56Trp mutation in Enho. In vivo, adropin-deficiency was associated with increased severity of glucose homeostasis impairment and fat metabolism disorder. AdrKO mice exhibited reduced endothelial nitric oxide synthase (eNOS) phosphorylation (Ser1177), impaired glycosphingolipid biosynthesis, adipocytes infiltrating, and loss of Treg, and developed FP and T2DM. Adropin-deficiency contributed to loss of Treg and the development of FP disease and T2DM. PMID- 28837147 TI - Doxorubicin upregulates CXCR4 via miR-200c/ZEB1-dependent mechanism in human cardiac mesenchymal progenitor cells. AB - Doxorubicin (DOXO) treatment is limited by its cardiotoxicity, since it causes cardiac-progenitor-cell depletion. Although the cardioprotective role of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF1/CXCR4) axis is well established, its involvement during DOXO-induced cardiotoxicity has never been investigated. We showed that in a mouse model of DOXO-induced cardiomyopathy, CXCR4+ cells were increased in response to DOXO, mainly in human cardiac mesenchymal progenitor cells (CmPC), a subpopulation with regenerative potential. Our in vitro results showed a CXCR4 induction after 24 h of DOXO exposure in CmPC. SDF1 administration protected from DOXO-induced cell death and promoted CmPC migration. CXCR4 promoter analysis revealed zinc finger E-box binding homeobox 1 (ZEB1) binding sites. Upon DOXO treatment, ZEB1 binding decreased and RNA-polymerase-II increased, suggesting a DOXO-mediated transcriptional increase in CXCR4. Indeed, DOXO induced the upregulation of miR 200c, that directly targets ZEB1. SDF1 administration in DOXO-treated mice partially reverted the adverse remodeling, decreasing left ventricular (LV) end diastolic volume, LV ejection fraction and LV anterior wall thickness in diastole, recovering LV end systolic pressure and reducing+/-dP/dt. Moreover, in vivo administration of SDF1 partially reverted DOXO-induced miR-200c and p53 protein upregulation in mouse hearts. In addition, downmodulation of ZEB1 mRNA and protein by DOXO was significantly increased by SDF1. In keeping, p21 mRNA, that is induced by p53 and inhibited by ZEB1, is induced by DOXO treatment and is decreased by SDF1 administration. This study showed new players of the DOXO induced cardiotoxicity, that can be exploited to ameliorate DOXO-associated cardiomyopathy. PMID- 28837148 TI - Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. AB - The cure rate of osteosarcoma has not improved in the past 30 years. The search for new treatments and drugs is urgently needed. Apatinib is a high selectivity inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, exerting promising antitumoral effect in various tumors. The antitumor effect of Apatinib in human osteosarcoma has never been reported. We investigated the effects of Apatinib in osteosarcoma in vitro and in vivo. Osteosarcoma patients with high levels of VEGFR2 have poor prognosis. Apatinib can inhibit cell growth of osteosarcoma cells. In addition to cycle arrest and apoptosis, Apatinib induces autophagy. Interestingly, inhibition of autophagy increased Apatinib-induced apoptosis in osteosarcoma cells. Immunoprecipitation confirmed direct binding between VEGFR2 and signal transducer and activator of transcription 3 (STAT3). Downregulation of VEGFR2 by siRNA resulted in STAT3 inhibition in KHOS cells. VEGFR2 and STAT3 are inhibited by Apatinib in KHOS cells, and STAT3 act downstream of VEGFR2. STAT3 and BCL-2 were downregulated by Apatinib. STAT3 knockdown by siRNA reinforced autophagy and apoptosis induced by Apatinib. BCL-2 inhibits autophagy and was apoptosis restrained by Apatinib too. Overexpression of BCL-2 decreased Apatinib-induced apoptosis and autophagy. Apatinib repressed the expression of STAT3 and BCL-2 and suppressed the growth of osteosarcoma in vivo. To sum up, deactivation of VEGFR2/STAT3/BCL-2 signal pathway leads to Apatinib-induced growth inhibition of osteosarcoma. PMID- 28837149 TI - IDH3 mediates apoptosis of alveolar epithelial cells type 2 due to mitochondrial Ca2+ uptake during hypocapnia. AB - In adult respiratory distress syndrome (ARDS) pulmonary perfusion failure increases physiologic dead-space (VD/VT) correlating with mortality. High VD/VT results in alveolar hypocapnia, which has been demonstrated to cause edema formation, atelectasis, and surfactant depletion, evoked, at least in part, by apoptosis of alveolar epithelial cells (AEC). However, the mechanism underlying the hypocapnia-induced AEC apoptosis is unknown. Here, using fluorescent live cell imaging of cultured AEC type 2 we could show that in terms of CO2 sensing the tricarboxylic acid cycle enzyme isocitrate dehydrogenase (IDH) 3 seems to be an important player because hypocapnia resulted independently from pH in an elevation of IDH3 activity and subsequently in an increase of NADH, the substrate of the respiratory chain. As a consequence, the mitochondrial transmembrane potential (DeltaPsi) rose causing a Ca2+ shift from cytosol into mitochondria, whereas the IDH3 knockdown inhibited these responses. Furthermore, the hypocapnia induced mitochondrial Ca2+ uptake resulted in reactive oxygen species (ROS) production, and both the mitochondrial Ca2+ uptake and ROS production induced apoptosis. Accordingly, we provide evidence that in AEC type 2 hypocapnia induces elevation of IDH3 activity leading to apoptosis. This finding might give new insight into the pathogenesis of ARDS and may help to develop novel strategies to reduce tissue injury in ARDS. PMID- 28837150 TI - Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance. AB - Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g., via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here we show that both static 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D-grown cells are substantially different from those of 3D-grown cells and tumor tissue. Autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models more closely mimic tumor (patho-)physiology, including the upregulation of tumor relevant pathways, such as autophagy. PMID- 28837151 TI - Mycobacterium abscessus glycopeptidolipids inhibit macrophage apoptosis and bacterial spreading by targeting mitochondrial cyclophilin D. AB - Mycobacterium abscessus (MAB) is a species of nontuberculous mycobacteria (NTM) and a major causative pathogen of pulmonary diseases especially in patients with cystic fibrosis. MAB infection is notoriously difficult to treat because of its intrinsic or inducible resistance to most antibiotics. The rough (R) morphotype of MAB, lacking cell surface glycopeptidolipids (GPLs), is associated with more severe and persistent infection than the smooth (S) type; however, the mechanisms underlying the R type's virulence and the relation with GPLs remain unclear. In this study, we found that R-type MAB is much more proapoptotic than the S type, as a result of GPL-mediated inhibition of macrophage apoptosis. Polar GPLs inhibited an apoptotic response (induced by proapoptotic stimuli) by suppressing ROS production and the cytochrome c release and by preserving mitochondrial transmembrane potential. Furthermore, GPLs were found to be targeted to mitochondria and interacted with cyclophilin D; their acetylation was essential for this interaction. Finally, GPLs inhibited the intracellular growth and bacterial spreading of R-type MAB among macrophages via apoptosis inhibition. These findings suggest that GPLs limit MAB virulence by inhibiting apoptosis and the spread of bacteria and therefore provide a novel insight into the mechanism underlying virulence of MAB. PMID- 28837152 TI - Lysosomotropism depends on glucose: a chloroquine resistance mechanism. AB - There has been long-standing interest in targeting pro-survival autophagy as a combinational cancer therapeutic strategy. Clinical trials are in progress testing chloroquine (CQ) or its derivatives in combination with chemo- or radiotherapy for solid and haematological cancers. Although CQ has shown efficacy in preclinical models, its mechanism of action remains equivocal. Here, we tested how effectively CQ sensitises metastatic breast cancer cells to further stress conditions such as ionising irradiation, doxorubicin, PI3K-Akt inhibition and serum withdrawal. Contrary to the conventional model, the cytotoxic effects of CQ were found to be autophagy-independent, as genetic targeting of ATG7 or the ULK1/2 complex could not sensitise cells, like CQ, to serum depletion. Interestingly, although CQ combined with serum starvation was robustly cytotoxic, further glucose starvation under these conditions led to a full rescue of cell viability. Inhibition of hexokinase using 2-deoxyglucose (2DG) similarly led to CQ resistance. As this form of cell death did not resemble classical caspase dependent apoptosis, we hypothesised that CQ-mediated cytotoxicity was primarily via a lysosome-dependent mechanism. Indeed, CQ treatment led to marked lysosomal swelling and recruitment of Galectin3 to sites of membrane damage. Strikingly, glucose starvation or 2DG prevented CQ from inducing lysosomal damage and subsequent cell death. Importantly, we found that the related compound, amodiaquine, was more potent than CQ for cell killing and not susceptible to interference from glucose starvation. Taken together, our data indicate that CQ effectively targets the lysosome to sensitise towards cell death but is prone to a glucose-dependent resistance mechanism, thus providing rationale for the related compound amodiaquine (currently used in humans) as a better therapeutic option for cancer. PMID- 28837153 TI - Cardioprotective effects of fibroblast growth factor 21 against doxorubicin induced toxicity via the SIRT1/LKB1/AMPK pathway. AB - Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Fibroblast growth factor 21 (FGF21), as a well-known regulator of glucose and lipid metabolism, was recently shown to exert cardioprotective effects. The aim of this study was to investigate the possible protective effects of FGF21 against DOX-induced cardiomyopathy. We preliminarily established DOX induced cardiotoxicity models in H9c2 cells, adult mouse cardiomyocytes, and 129S1/SyImJ mice, which clearly showed cardiac dysfunction and myocardial collagen accumulation accompanying by inflammatory, oxidative stress, and apoptotic damage. Treatment with FGF21 obviously attenuated the DOX-induced cardiac dysfunction and pathological changes. Its effective anti-inflammatory activity was revealed by downregulation of inflammatory factors (tumor necrosis factor-alpha and interleukin-6) via the IKK/IkappaBalpha/nuclear factor-kappaB pathway. The anti-oxidative stress activity of FGF21 was achieved via reduced generation of reactive oxygen species through regulation of nuclear transcription factor erythroid 2-related factor 2 transcription. Its anti-apoptotic activity was shown by reductions in the number of TUNEL-positive cells and DNA fragments along with a decreased ratio of Bax/Bcl-2 expression. In a further mechanistic study, FGF21 enhanced sirtuin 1 (SIRT1) binding to liver kinase B1 (LKB1) and then decreased LKB1 acetylation, subsequently inducing AMP-activated protein kinase (AMPK) activation, which improved the cardiac inflammation, oxidative stress, and apoptosis. These alterations were significantly prohibited by SIRT1 RNAi. The present work demonstrates for the first time that FGF21 obviously prevented DOX-induced cardiotoxicity via the suppression of oxidative stress, inflammation, and apoptosis through the SIRT1/LKB1/AMPK signaling pathway. PMID- 28837155 TI - ZOMES: the intriguing interplay of PCI complexes and the ubiquitin in protein homeostasis. PMID- 28837154 TI - AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells. AB - DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells. We show that treatment of cells with CDT or IR increased the levels of the autophagy marker LC3B-II. Consistently, an enhanced formation of autophagosomes and a decrease of the autophagy substrate p62 were observed. Both CDT and IR concomitantly suppressed mTOR signaling and stimulated the autophagic flux. DSBs were demonstrated as the primary trigger of autophagy using a DNase I-defective CDT mutant, which neither induced DSBs nor autophagy. Genetic abrogation of p53 and inhibition of ATM signaling impaired the autophagic flux as revealed by LC3B-II accumulation and reduced formation of autophagic vesicles. Blocking of DSB-induced apoptotic cell death by the pan-caspase inhibitor Z-VAD stimulated autophagy. In line with this, pharmacological inhibition of autophagy increased cell death, while ATG5 knockdown did not affect cell death after DSB induction. Interestingly, both IR and CDT caused AKT activation, which repressed DSB-triggered autophagy independent of the cellular DNA-PK status. Further knockdown and pharmacological inhibitor experiments provided evidence that the negative autophagy regulation was largely attributable to AKT2. Finally, we show that upregulation of CDT-induced autophagy upon AKT inhibition resulted in lower apoptosis and increased cell viability. Collectively, the findings demonstrate that DSBs trigger pro-survival autophagy in an ATM- and p53-dependent manner, which is curtailed by AKT2 signaling. PMID- 28837156 TI - CHAC2, downregulated in gastric and colorectal cancers, acted as a tumor suppressor inducing apoptosis and autophagy through unfolded protein response. AB - Tumor suppressor genes play a key role in cancer pathogenesis. Through massive expression profiling we identified CHAC2 as a frequently downregulated gene in gastric and colorectal cancers. Immunohistochemistry and western blot revealed that CHAC2 was downregulated in most tumor tissues, and 3-year survival rate of patients with high CHAC2 expression was significantly higher than that of patients with low CHAC2 expression (P<0.001 and P=0.001, respectively). The data of univariate analysis and multivariate analysis suggested that CHAC2 could serve as an independent prognostic marker. Our results showed for the first time that CHAC2 was degraded by the ubiquitin-proteasome pathway and CHAC2 expression inhibited tumor cell growth, proliferation, migration in vitro and in vivo. Mechanistic study showed that CHAC2 induced mitochondrial apoptosis and autophagy through unfolded protein response. So in gastric and colorectal cancer CHAC2 acted as a tumor suppressor and might have therapeutic implication for patients. PMID- 28837157 TI - Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia. AB - PurposeMutations in genes involved in Fanconi anemia (FA)/BRCA DNA repair pathway cause cancer susceptibility diseases including familial breast cancer and Fanconi anemia (FA). A single FA patient with biallelic FANCM mutations was reported in 2005 but concurrent FANCA pathogenic mutations precluded assignment of FANCM as an FA gene. Here we report three individuals with biallelic FANCM truncating mutations who developed early-onset cancer and toxicity to chemotherapy but did not present congenital malformations or any hematological phenotype suggestive of FA.MethodsChromosomal breakages, interstrand crosslink sensitivity, and FANCD2 monoubiquitination were assessed in primary fibroblasts. Mutation analysis was achieved through Sanger sequencing. Genetic complementation of patient-derived cells was performed by lentiviral mediated transduction of wild-type FANCM complementary DNA followed by functional studies.ResultsPatient-derived cells exhibited chromosomal fragility, hypersensitivity to interstrand crosslinks, and impaired FANCD2 monoubiquitination. We identified two homozygous mutations (c.2586_2589del4; p.Lys863Ilefs*12 and c.1506_1507insTA; p.Ile503*) in FANCM as the cause of the cellular phenotype. Patient-derived cells were genetically complemented upon wild-type FANCM complementary DNA expression.ConclusionLoss-of function mutations in FANCM cause a cancer predisposition syndrome clinically distinct from bona fide FA. Care should be taken with chemotherapy and radiation treatments in these patients due to expected acute toxicity. PMID- 28837158 TI - High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. AB - PurposeMosaicism probably represents an underreported cause of genetic disorders due to detection challenges during routine molecular diagnostics. The purpose of this study was to evaluate the frequency of mosaicism detected by next-generation sequencing in genes associated with epilepsy-related neurodevelopmental disorders.MethodsWe conducted a retrospective analysis of 893 probands with epilepsy who had a multigene epilepsy panel or whole-exome sequencing performed in a clinical diagnostic laboratory and were positive for a pathogenic or likely pathogenic variant in one of nine genes (CDKL5, GABRA1, GABRG2, GRIN2B, KCNQ2, MECP2, PCDH19, SCN1A, or SCN2A). Parental results were available for 395 of these probands.ResultsMosaicism was most common in the CDKL5, PCDH19, SCN2A, and SCN1A genes. Mosaicism was observed in GABRA1, GABRG2, and GRIN2B, which previously have not been reported to have mosaicism, and also in KCNQ2 and MECP2. Parental mosaicism was observed for pathogenic variants in multiple genes including KCNQ2, MECP2, SCN1A, and SCN2A.ConclusionMosaic pathogenic variants were identified frequently in nine genes associated with various neurological conditions. Given the potential clinical ramifications, our findings suggest that next-generation sequencing diagnostic methods may be utilized when testing these genes in a diagnostic laboratory. PMID- 28837159 TI - Inferred inheritance of MorbidMap genes without OMIM clinical synopsis. AB - PurposeThe Genomic Oligoarray and SNP Array Evaluation Tool 3.0 matches candidate genes within regions of homozygosity with a patient's phenotype, by mining OMIM for gene entries that contain a Clinical Synopsis. However, the tool cannot identify genes/disorders whose OMIM entries lack a descriptor of the mode of (Mendelian) inheritance. This study aimed to improve the tool's diagnostic power by building a database of autosomal recessive diseases not diagnosable through OMIM.MethodsWe extracted a list of all genes in OMIM that produce disease phenotypes but lack Clinical Synopses or other statements of mode of inheritance. We then searched PubMed for literature regarding each gene in order to infer its inheritance pattern.ResultsWe analyzed 1,392 genes. Disorders associated with 372 genes were annotated as recessive and 430 as dominant. Autosomal genes were ranked from 1 to 3, with 3 indicating the strongest evidence behind the inferred mode of inheritance. Of 834 autosomal genes, 158 were ranked as 1, 228 as 2, and 448 as 3.ConclusionThe 372 genes associated with recessive disorders will be contributed to the SNP array tool, and the entire database to OMIM. We anticipate that these findings will be useful in rare disease diagnostics. PMID- 28837160 TI - Loss-of-function mutations in TDRD7 lead to a rare novel syndrome combining congenital cataract and nonobstructive azoospermia in humans. AB - PurposeComorbid familial nonobstructive azoospermia (NOA) and congenital cataract (CC) have not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose was to uncover novel human mutations and genes causing familial NOA and CC.MethodsWe performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7.ResultsTwo novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and c.688_689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient's seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome.ConclusionWe identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.GENETICS in MEDICINE advance online publication, 24 August 2017; doi:10.1038/gim.2017.130. PMID- 28837161 TI - Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay. AB - PURPOSE: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability. METHODS: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software. RESULTS: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein. CONCLUSION: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans. PMID- 28837164 TI - Supported liquid metal catalysts: Popping up to the surface. PMID- 28837162 TI - Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility. AB - PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features. PMID- 28837163 TI - A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells. AB - The self-propagation of misfolded conformations of tau underlies neurodegenerative diseases, including Alzheimer's. There is considerable interest in discovering the minimal sequence and active conformational nucleus that defines this self-propagating event. The microtubule-binding region, spanning residues 244-372, reproduces much of the aggregation behaviour of tau in cells and animal models. Further dissection of the amyloid-forming region to a hexapeptide from the third microtubule-binding repeat resulted in a peptide that rapidly forms fibrils in vitro. We show that this peptide lacks the ability to seed aggregation of tau244-372 in cells. However, as the hexapeptide is gradually extended to 31 residues, the peptides aggregate more slowly and gain potent activity to induce aggregation of tau244-372 in cells. X-ray fibre diffraction, hydrogen-deuterium exchange and solid-state NMR studies map the beta-forming region to a 25-residue sequence. Thus, the nucleus for self-propagating aggregation of tau244-372 in cells is packaged in a remarkably small peptide. PMID- 28837167 TI - Organometallic mechanisms: Measuring up with the early metals. PMID- 28837165 TI - Visible-light excitation of iminium ions enables the enantioselective catalytic beta-alkylation of enals. AB - Chiral iminium ions-generated upon condensation of alpha,beta-unsaturated aldehydes and amine catalysts-are used extensively by chemists to make chiral molecules in enantioenriched form. In contrast, their potential to absorb light and promote stereocontrolled photochemical processes remains unexplored. This is despite the fact that visible-light absorption by iminium ions is a naturally occurring event that triggers the mechanism of vision in higher organisms. Herein we demonstrate that the direct excitation of chiral iminium ions can unlock unconventional reaction pathways, enabling enantioselective catalytic photochemical beta-alkylations of enals that cannot be realized via thermal activation. The chemistry uses readily available alkyl silanes, which are recalcitrant to classical conjugate additions, and occurs under illumination by visible-light-emitting diodes. Crucial to success was the design of a chiral amine catalyst with well-tailored electronic properties that can generate a photo active iminium ion while providing the source of stereochemical induction. This strategy is expected to offer new opportunities for reaction design in the field of enantioselective catalytic photochemistry. PMID- 28837166 TI - Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. AB - Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCF2H), an inexpensive, abundant and widely used industrial raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CF2H) from ClCF2H into aromatics has not been reported. Here, we describe a direct palladium-catalysed difluoromethylation method for coupling ClCF2H with arylboronic acids and esters to generate difluoromethylated arenes with high efficiency. The reaction exhibits a remarkably broad substrate scope, including heteroarylboronic acids, and was used for difluoromethylation of a range of pharmaceuticals and biologically active compounds. Preliminary mechanistic studies revealed that a palladium difluorocarbene intermediate is involved in the reaction. Although numerous metal-difluorocarbene complexes have been prepared, the catalytic synthesis of difluoromethylated or difluoromethylenated compounds involving metal-difluorocarbene complexes has not received much attention. This new reaction therefore also opens the door to understand metal-difluorocarbene complex catalysed reactions. PMID- 28837168 TI - Quantifying ligand effects in high-oxidation-state metal catalysis. AB - Catalysis by high-valent metals such as titanium(IV) impacts our lives daily through reactions like olefin polymerization. In any catalysis, optimization involves a careful choice of not just the metal but also the ancillary ligands. Because these choices dramatically impact the electronic structure of the system and, in turn, catalyst performance, new tools for catalyst development are needed. Understanding ancillary ligand effects is arguably one of the most critical aspects of catalyst optimization and, while parameters for phosphines have been used for decades with low-valent systems, a comparable system does not exist for high-valent metals. A new electronic parameter for ligand donation, derived from experiments on a high-valent chromium species, is now available. Here, we show that the new parameters enable quantitative determination of ancillary ligand effects on catalysis rate and, in some cases, even provide mechanistic information. Analysing reactions in this way can be used to design better catalyst architectures and paves the way for the use of such parameters in a host of high-valent processes. PMID- 28837169 TI - Peaceful berkelium. PMID- 28837171 TI - The bottom line. PMID- 28837170 TI - Solvent-switchable continuous-breathing behaviour in a diamondoid metal-organic framework and its influence on CO2 versus CH4 selectivity. AB - Understanding the behaviour of flexible metal-organic frameworks (MOFs)-porous crystalline materials that undergo a structural change upon exposure to an external stimulus-underpins their design as responsive materials for specific applications, such as gas separation, molecular sensing, catalysis and drug delivery. Reversible transformations of a MOF between open- and closed-pore forms a behaviour known as 'breathing'-typically occur through well-defined crystallographic transitions. By contrast, continuous breathing is rare, and detailed characterization has remained very limited. Here we report a continuous breathing mechanism that was studied by single-crystal diffraction in a MOF with a diamondoid network, (Me2NH2)[In(ABDC)2] (ABDC, 2-aminobenzene-1,4 dicarboxylate). Desolvation of the MOF in two different solvents leads to two polymorphic activated forms with very different pore openings, markedly different gas-adsorption capacities and different CO2 versus CH4 selectivities. Partial desolvation introduces a gating pressure associated with CO2 adsorption, which shows that the framework can also undergo a combination of stepped and continuous breathing. PMID- 28837172 TI - Incipient class II mixed valency in a plutonium solid-state compound. AB - Electron transfer in mixed-valent transition-metal complexes, clusters and materials is ubiquitous in both natural and synthetic systems. The degree to which intervalence charge transfer (IVCT) occurs, dependent on the degree of delocalization, places these within class II or III of the Robin-Day system. In contrast to the d-block, compounds of f-block elements typically exhibit class I behaviour (no IVCT) because of localization of the valence electrons and poor spatial overlap between metal and ligand orbitals. Here, we report experimental and computational evidence for delocalization of 5f electrons in the mixed-valent PuIII/PuIV solid-state compound, Pu3(DPA)5(H2O)2 (DPA = 2,6 pyridinedicarboxylate). The properties of this compound are benchmarked by the pure PuIII and PuIV dipicolinate complexes, [PuIII(DPA)(H2O)4]Br and PuIV(DPA)2(H2O)3.3H2O, as well as by a second mixed-valent compound, PuIII[PuIV(DPA)3H0.5]2, that falls into class I instead. Metal-to-ligand charge transfer is involved in both the formation of Pu3(DPA)5(H2O)2 and in the IVCT. PMID- 28837173 TI - Iterative assembly line synthesis of polypropionates with full stereocontrol. AB - The polypropionate motif is ubiquitous, being characteristic of the most important family of natural products for human health, the polyketides. Numerous strategies have been devised to construct these molecules with high stereocontrol, but certain stereoisomers remain challenging to prepare. We now describe the development of an iterative assembly line strategy for the construction of polypropionates. An assembly line strategy for the synthesis of deoxypolypropionates has already been described. However, the introduction of carbinol units required the development of new building blocks and new reaction conditions. This has been achieved by the use of enantioenriched lithiated alpha chlorosilanes [1-((2'-lithiochloromethyldimethylsilyl)-methyl)-2-(methoxymethyl) pyrrolidine], thus enabling the programmed synthesis of polypropionates in a fully stereocontrolled manner, including the stereochemically challenging anti anti isomers. The versatility of the approach is exemplified in its extension to the synthesis of 1,3-related polyols. The methodology now allows access to a much wider family of polyketide natural products with stereochemistry being dialled in at will. PMID- 28837174 TI - Stereochemical plasticity modulates cooperative binding in a CoII12L6 cuboctahedron. AB - Biomolecular receptors are able to process information by responding differentially to combinations of chemical signals. Synthetic receptors that are likewise capable of multi-stimuli response can form the basis of programmable molecular systems, wherein specific input sequences create distinct outputs. Here we report a pseudo-cuboctahedral assembly capable of cooperatively binding anionic and neutral guest species. The binding of pairs of fullerene guests was observed to effect the all-or-nothing cooperative templation of an S6-symmetric host stereoisomer. This bis-fullerene adduct exhibits different cooperativity in binding pairs of anions from the fullerene-free parent: in one case, positive cooperativity is observed, while in another all binding affinities are enhanced by an order of magnitude, and in a third the binding events are only minimally perturbed. This intricate modulation of binding affinity, and thus cooperativity, renders our new cuboctahedral receptor attractive for incorporation into systems with complex, programmable responses to different sets of stimuli. PMID- 28837175 TI - The structure and binding mode of citrate in the stabilization of gold nanoparticles. AB - Elucidating the binding mode of carboxylate-containing ligands to gold nanoparticles (AuNPs) is crucial to understand their stabilizing role. A detailed picture of the three-dimensional structure and coordination modes of citrate, acetate, succinate and glutarate to AuNPs is obtained by 13C and 23Na solid-state NMR in combination with computational modelling and electron microscopy. The binding between the carboxylates and the AuNP surface is found to occur in three different modes. These three modes are simultaneously present at low citrate to gold ratios, while a monocarboxylate monodentate (1kappaO1) mode is favoured at high citrate:gold ratios. The surface AuNP atoms are found to be predominantly in the zero oxidation state after citrate coordination, although trace amounts of Audelta+ are observed. 23Na NMR experiments show that Na+ ions are present near the gold surface, indicating that carboxylate binding occurs as a 2e- L-type interaction for each oxygen atom involved. This approach has broad potential to probe the binding of a variety of ligands to metal nanoparticles. PMID- 28837176 TI - Elucidating bonding preferences in tetrakis(imido)uranate(VI) dianions. AB - Actinyl species, [AnO2]2+, are well-known derivatives of the f-block because of their natural occurrence and essential roles in the nuclear fuel cycle. Along with their nitrogen analogues, [An(NR)2]2+, actinyls are characterized by their two strong trans-An-element multiple bonds, a consequence of the inverse trans influence. We report that these robust bonds can be weakened significantly by increasing the number of multiple bonds to uranium, as demonstrated by a family of uranium(VI) dianions bearing four U-N multiple bonds, [M]2[U(NR)4] (M = Li, Na, K, Rb, Cs). Their geometry is dictated by cation coordination and sterics rather than by electronic factors. Multiple bond weakening by the addition of strong pi donors has the potential for applications in the processing of high valent actinyls, commonly found in environmental pollutants and spent nuclear fuels. PMID- 28837177 TI - Chelation and stabilization of berkelium in oxidation state +IV. AB - Berkelium (Bk) has been predicted to be the only transplutonium element able to exhibit both +III and +IV oxidation states in solution, but evidence of a stable oxidized Bk chelate has so far remained elusive. Here we describe the stabilization of the heaviest 4+ ion of the periodic table, under mild aqueous conditions, using a siderophore derivative. The resulting Bk(IV) complex exhibits luminescence via sensitization through an intramolecular antenna effect. This neutral Bk(IV) coordination compound is not sequestered by the protein siderocalin-a mammalian metal transporter-in contrast to the negatively charged species obtained with neighbouring trivalent actinides americium, curium and californium (Cf). The corresponding Cf(III)-ligand-protein ternary adduct was characterized by X-ray diffraction analysis. Combined with theoretical predictions, these data add significant insight to the field of transplutonium chemistry, and may lead to innovative Bk separation and purification processes. PMID- 28837179 TI - Bonding with actinides. PMID- 28837178 TI - Tyrosine sulfation modulates activity of tick-derived thrombin inhibitors. AB - Madanin-1 and chimadanin are two small cysteine-free thrombin inhibitors that facilitate blood feeding in the tick Haemaphysalis longicornis. Here, we report a post-translational modification-tyrosine sulfation-of these two proteins that is critical for potent anti-thrombotic and anticoagulant activity. Inhibitors produced in baculovirus-infected insect cells displayed heterogeneous sulfation of two tyrosine residues within each of the proteins. One-pot ligation desulfurization chemistry enabled access to homogeneous samples of all possible sulfated variants of the proteins. Tyrosine sulfation of madanin-1 and chimadanin proved crucial for thrombin inhibitory activity, with the doubly sulfated variants three orders of magnitude more potent than the unmodified inhibitors. The three-dimensional structure of madanin-1 in complex with thrombin revealed a unique mode of inhibition, with the sulfated tyrosine residues binding to the basic exosite II of the protease. The importance of tyrosine sulfation within this family of thrombin inhibitors, together with their unique binding mode, paves the way for the development of anti-thrombotic drug leads based on these privileged scaffolds. PMID- 28837180 TI - Gallium-rich Pd-Ga phases as supported liquid metal catalysts. AB - A strategy to develop improved catalysts is to create systems that merge the advantages of heterogeneous and molecular catalysis. One such system involves supported liquid-phase catalysts, which feature a molecularly defined, catalytically active liquid film/droplet layer adsorbed on a porous solid support. In the past decade, this concept has also been extended to supported ionic liquid-phase catalysts. Here we develop this idea further and describe supported catalytically active liquid metal solutions (SCALMS). We report a liquid mixture of gallium and palladium deposited on porous glass that forms an active catalyst for alkane dehydrogenation that is resistant to coke formation and is thus highly stable. X-ray diffraction and X-ray photoelectron spectroscopy, supported by theoretical calculations, confirm the liquid state of the catalytic phase under the reaction conditions. Unlike traditional heterogeneous catalysts, the supported liquid metal reported here is highly dynamic and catalysis does not proceed at the surface of the metal nanoparticles, but presumably at homogeneously distributed metal atoms at the surface of a liquid metallic phase. PMID- 28837181 TI - Avelumab for the treatment of metastatic Merkel cell carcinoma. AB - Avelumab is a promising new therapeutic agent for patients with metastatic Merkel cell carcinoma, a rare and aggressive type of neuroendocrine tumor of the skin. Until the recent approval of avelumab (Bavencio), no therapies were approved by the U.S. Food and Drug Administration for the treatment of metastatic Merkel cell carcinoma. In a recent trial, avelumab, an anti-programmed death ligand-1 antibody, demonstrated an objective response in 28 of 88 patients (31.8% [95.9% CI, 21.9-43.1]) with advanced, chemotherapy-refractory Merkel cell carcinoma. Overall, avelumab was well tolerated at a dose of 10 mg/kg administered intravenously every 2 weeks. Serious treatment-related adverse events were reported in 5 patients (6%), but no grade 4 adverse events or treatment-related deaths were reported. Preliminary data evaluating avelumab in chemotherapy-naive patients is also encouraging. PMID- 28837182 TI - Bezlotoxumab for the treatment of Clostridium difficile-associated diarrhea. AB - Diarrhea caused by Clostridium difficile is one of the major emerging threats to modern healthcare systems worldwide. Although C. difficile spores are present in the gut innocuously, because of repeated broad-spectrum antibiotic therapy, the spores germinate with concomitant release of exotoxin A and B, resulting in mild to severe diarrhea. Antibiotic therapy is augmented by addition of the humanized antibodies actoxumab and bezlotoxumab to prevent the action of exotoxins A and B, respectively, since they provide passive immunity. Bezlotoxumab, a fully humanized monoclonal antibody developed against C. difficile toxin B, was approved by the U.S. Food and Drug Administration in 2016 to prevent the recurrence of C. difficile infections (CDI) in patients above 18 years of age who are receiving antibiotics for CDI and are at a higher risk of recurrence. PMID- 28837184 TI - Checkpoint inhibitors: a cutting edge in oncology. AB - The checkpoint inhibitor field, and indeed the whole of immuno-oncology, is fast paced and fascinating, with huge clinical and commercial potential. The challenge in the coming years will be to define the best type and combination of immunotherapy, and the best target population to receive it. Keytruda's ground breaking approval for a biomarker-based rather than location-based indication is a solid step in this direction, and is likely to be followed by other such approvals. As the field develops, it is to be hoped that immuno-oncology therapeutics will continue to deliver the significant improvements in patient outcome that have been seen so far. PMID- 28837183 TI - Keratitis in association with herpes zoster and varicella vaccines. AB - The objective of this review was to collect reports of keratitis in association with herpes zoster virus (HZV) or varicella zoster virus (VZV) vaccines. HZV vaccination is intended for at-risk adult populations and VZV vaccination is intended for all pediatric patients. We reviewed the literature and reports of keratitis in association with herpes zoster or varicella vaccine from the National Registry of Drug-Induced Ocular Side Effects and the World Health Organization. Twenty-four cases of unilateral keratitis in association with VZV vaccines were collected from the adverse reaction databases and literature. In most cases, the onset of keratitis occurred within days of vaccination and resolved with topical steroid eye drops and oral acyclovir. Data suggest that keratitis in association with herpes zoster or varicella vaccine is rare, is usually self-limited or resolves with treatment. The mechanism may be the persistence of viral antigens in the cornea after VZV vaccination or herpes zoster ophthalmicus. This reaction is probable, given the plausible biological mechanism, the temporal relationship between vaccination and keratitis, and overall patterns of presentation after vaccination. PMID- 28837186 TI - Raman endoscopy for monitoring the anticancer drug treatment of colorectal tumors in live mice. AB - A miniaturized Raman endoscope (mRE) system was employed to study the effects of anticancer treatment on colorectal tumors in a live murine model. The endoscope is narrow enough to observe the inside of the mouse colon under anesthesia. It has a channel for a ball lens mounted on a hollow fiber Raman probe (BHRP) to measure any targeted point under the visual control of the endoscope. Colorectal cancer tissue was observed to study the alterations of the tissue in response to anticancer drug treatment. Three anticancer drugs, 5-fluorouracil (5-FU), cisplatin (CDDP), and docetaxel, were employed. Although no alteration was recognized in the endoscopic visual observations at 2 weeks after the drug treatment, the Raman spectra obtained in the live mouse colon indicated that molecular changes of lipids and proteins were observed. This study demonstrates that in situ Raman analysis is highly sensitive for detecting the effects of anticancer drugs. PMID- 28837185 TI - American Diabetes Association - 77th Scientific Sessions (June 9-13, 2017 - San Diego, California, USA). AB - The 77th American Diabetes Association (ADA) Sci-entific Sessions took place in San Diego, California. The meeting brought together scientists and professionals from a wide range of disciplines in the field of diabetes and provided a platform for networking, allowing experts and researchers to share ideas and learn about the significant advances in diabetes research, treatment and care. Over the course of the 5 days, participants received exclusive access to more than 2,500 original research presentations. PMID- 28837187 TI - Promoting photocatalytic H2 evolution by tuning cation deficiency in La and Cr co doped SrTiO3. AB - Cation defects in La and Cr co-doped SrTiO3 have been specifically studied for elucidating correlations between defect concentration, electronic properties, structural properties and photocatalytic activity for H2 production. A moderate cation deficiency can promote the photocatalytic activity by ca. 3 fold, which can be mainly linked to the enhancement of the charge carrier mobility. PMID- 28837188 TI - Radiolysis of N2-rich astrophysical ice by swift oxygen ions: implication for space weathering of outer solar system bodies. AB - In order to investigate the role of medium mass cosmic rays and energetic solar particles in the processing of N2-rich ice on frozen moons and cold objects in the outer solar system, the bombardment of an N2 : H2O : NH3 : CO2 (98.2 : 1.5 : 0.2 : 0.1) ice mixture at 16 K employing 15.7 MeV 16O5+ was performed. The changes in the ice chemistry were monitored and quantified by Fourier transformed infrared spectroscopy (FTIR). The results indicate the formation of azide radicals (N3), and nitrogen oxides, such as NO, NO2, and N2O, as well as the production of CO, HNCO, and OCN-. The effective formation and destruction cross sections are roughly on the order of 10-12 cm2 and 10-13 cm2, respectively. From laboratory molecular analyses, we estimated the destruction yields for the parent species and the formation yields for the daughter species. For N2, this value was 9.8 * 105 molecules per impact of ions, and for the most abundant new species (N3), it was 1.1 * 105 molecules per impact of ions. From these yields, an estimation of how many species are destroyed or formed in a given timescale (108 years) in icy bodies in the outer solar system was calculated. This work reinforces the idea that such physicochemical processes triggered by cosmic rays, solar wind, and magnetospheric particles (medium-mass ions) in nitrogen-rich ices may play an important role in the formation of molecules (including pre-biotic species precursors such as amino acids and other "CHON" molecules) in very cold astrophysical environments, such as those in the outer region of the solar system (e.g. Titan, Triton, Pluto, and other KBOs). PMID- 28837189 TI - Underpotential deposition of Cu on Au(111) from neutral chloride containing electrolyte. AB - The structure of a chloride terminated copper monolayer electrodeposited onto Au(111) from a CuSO4/KCl electrolyte was investigated ex situ by three complementary experimental techniques (scanning tunneling microscopy (STM), photoelectron spectroscopy (PES), X-ray standing wave (XSW) excitation) and density functional theory (DFT) calculations. STM at atomic resolution reveals a stable, highly ordered layer which exhibits a Moire structure and is described by a (5 * 5) unit cell. The XSW/PES data yield a well-defined position of the Cu layer and the value of 2.16 A above the topmost Au layer suggests that the atoms are adsorbed in threefold hollow sites. The chloride exhibits some distribution around a distance of 3.77 A in agreement with the observed Moire pattern due to a higher order commensurate lattice. This structure, a high order commensurate Cl overlayer on top of a commensurate (1 * 1) Cu layer with Cu at threefold hollow sites, is corroborated by the DFT calculations. PMID- 28837190 TI - Acceptor-type hydroxide graphite intercalation compounds electrochemically formed in high ionic strength solutions. AB - The intercalation of hydroxide ions (OH-) into graphite formed graphite intercalation compounds (GICs) in high ionic strength solutions. GICs of solvated OH- anions with two water molecules (OH-.2H2O) in alkaline aqueous solutions and GICs of only OH- anions in a molten NaOH-KOH salt solution were electrochemically synthesized. PMID- 28837191 TI - Highlights from the 52nd EUCHEM conference on stereochemistry, Burgenstock, Switzerland, May 2017. PMID- 28837192 TI - [Cd(H2O)6]@{Cd6Cl4(nico)12[Hg(Tab)2(MU-Cl)]2}: a heterometallic host-guest icosidodecahedron cage via hierarchical assembly. AB - Complexation of a preformed complex [Hg(Tab)2](PF6)2 (1) with nicotinic acid in the presence of Et3N afforded a mononuclear complex [Hg(Tab)2(nico)]2(PF6)2 (2) (nico = nicotinate, Tab = 4-(trimethylammonio)benzenethiolate) which, upon subsequent treatment with one or three equiv. of CdCl2.2.5H2O, gave rise to an unprecedented heterometallic cage complex [Cd(H2O)6]@{Cd6Cl4(nico)12[Hg(Tab)2(MU Cl)]2} (3) or a simple salt of [Hg(Tab)2][CdCl4] (4). PMID- 28837193 TI - Co-assembly behaviour of Janus nanoparticles and amphiphilic block copolymers in dilute solution. AB - Nanoparticles can co-assemble with amphiphilic block copolymers (ABPs) in solution to generate nanoaggregates with unique properties, yet the mechanism of such a co-assembly behaviour for Janus nanoparticles (JPs) and ABPs remains unclear. Here, the self-assembly behaviour of JP/ABP mixtures in dilute solution was studied via theoretical simulations. Two kinds of ABPs with different volume fractions fA of hydrophilic blocks were considered: one is symmetric copolymers with fA = 0.5, and the other is asymmetric ABPs with fA = 0.3. In the first case, mixtures of spheres and rods, connected networks and vesicles were formed sequentially as the volume fraction cJP of nanoparticles increases. In the second case, vesicles were constantly formed. For both cases, at lower cJP values, the nanoparticles were located at the core-corona interfaces. By contrast, at higher particle loadings, a large number of particles were involved in clusters embedded in the vesicle walls. Based on the simulation results, a morphological diagram in the space of cJP and fA was constructed to indicate the stability regions of different nanostructures. Specifically, it was found that the vesicles formed by JPs and ABPs with short hydrophilic blocks are stimuli-responsive. By changing the interaction parameters between hydrophobic blocks, controllable pores in the vesicle walls could be created. Our findings not only provide insights into the co-assembly behaviour of Janus nanoparticles and amphiphilic block copolymers in solution, but also offer a novel strategy to prepare nanoreactors with permeable membranes. PMID- 28837194 TI - A modular trigger for the development of selective superoxide probes. AB - We report here a new bioinspired copper-based strategy of superoxide sensing and the development of sensitive (>90-fold fluorescence turn-on) and selective superoxide probes for imaging variations in the endogenous superoxide level in various live mammalian cells (HEK293T, HeLa and A431). PMID- 28837195 TI - Extra-high short-circuit current for bifacial solar cells in sunny and dark-light conditions. AB - We present here a symmetrically structured bifacial solar cell tailored by two fluorescent photoanodes and a platinum/titanium/platinum counter electrode, yielding extra-high short-circuit current densities as high as 28.59 mA cm-2 and 119.9 MUA cm-2 in simulated sunlight irradiation (100 mW cm-2, AM1.5) and dark light conditions, respectively. PMID- 28837196 TI - Inkjet fabrication of highly efficient luminescent Eu-doped ZrO2 nanostructures. AB - We have demonstrated for the first time an inkjet fabrication of highly efficient luminescent structures based on Eu-doped ZrO2 nanocrystals (3.4 +/- 0.3 nm), with a refractive index close to the one of the bulk materials. The nanoparticles were synthesised using a nonhydrolytic method in benzyl alcohol where the particles were post treated using acetic acid, leading to the formation of a stable colloid. It was shown that the non-polar methyl group of the acetic acid is responsible for its penetration through the hydrophobic layer all the way through to the surface of the ZrO2, leading to the cleavage of the Zr-OCH2C6H5 bond and the formation of surface acetate species and a concomitant decomposition of the zirconia superlattice. Hereby we show a new and efficient universal ink production through a multi-step process - starting from solvothermal synthesis, dispersion of nanocrystals in water, and adaptation of the rheological parameters of the resulting sols. Eventually, we were able to obtain inks that we used for the production of optical coatings, monolayer luminescent-protected holography and anti-counterfeiting printing. These structures, obtained at room temperature through inkjet printing, present dense xerogel structures with high optical transparency, a high refractive index and more efficient luminescence compared with the non-homogeneous structures produced as a mixture of rare-earth elements and nanocrystals. PMID- 28837197 TI - Novel mononuclear Ln complexes with pyrazine-2-carboxylate and acetylacetonate co ligands: remarkable single molecule magnet behavior of a Yb derivative. AB - A series of novel isomorphic mononuclear complexes [Ln(PyrCOO)(acac)2(H2O)2] (Ln = Eu (1), Gd (2), Tb (3), Dy (4), Ho (5), Er (6), Tm (7), Yb (8), Y(9); acac- - acetylacetonate (pentane-2,4-dionate) anion, PyrCOOH is pyrazine-2-carboxylic acid) were prepared. Slow magnetic relaxation indicating SMM behavior was found in complexes 3, 4, 6 and 8. For 4 (Dy), the anisotropy barrier is Deltaeff/kB = 77 K under a dc field of 1500 Oe. For 8 (Yb), the anisotropy barrier is Deltaeff/kB = 54 K under a dc field of 2000 Oe which is the highest presently known value for molecular Yb carboxylate complexes and for Yb molecular complexes in general. PMID- 28837198 TI - Long-range surface plasmon resonance and surface-enhanced Raman scattering on X shaped gold plasmonic nanohole arrays. AB - A multilayered architecture including a thin Au film supporting an X-shaped nanohole array and a thick continuous Au film separated by a Cytop dielectric layer is reported in this work. Long-range surface plasmon resonance (LR-SPR) was generated at the top Au/water interface, which also resulted in a long-range surface-enhanced Raman scattering (LR-SERS) effect. LR-SPR originates from the coupling of surface plasmons (SPs) propagating along the opposite sides of the thin Au film embedded in a symmetric refractive index environment with Cytop (n = 1.34) and water (n = 1.33). The finite-difference time-domain (FDTD) simulation method was used to investigate the optimal dimensions of the substrate by studying the reflectance spectra and electric field profiles. The calculated optimal structure was then fabricated via electron beam lithography, and its LR SERS performance was demonstrated by detecting rhodamine 6G and 4-mercaptobenzoic acid in the refractive index-matched environment. We believe that this structure as a LR-SPR or LR-SERS substrate can have broad applications in biosensing. PMID- 28837199 TI - Orientation dependent interlayer stacking structure in bilayer MoS2 domains. AB - We have studied the atomic structure of small secondary domains that nucleate on monolayer MoS2 grown by chemical vapour deposition (CVD), which form the basis of bilayer MoS2. The small secondary bilayer domains have a faceted geometry with three-fold symmetry and adopt two distinct orientations with 60 degrees rotation relative to an underlying monolayer MoS2 single crystal sheet. The two distinct orientations are associated with the 2H and 3R stacking configuration for bilayer MoS2. Atomic resolution images have been recorded using annular dark field scanning transmission electron microscopy (ADF-STEM) that show the edge termination, lattice orientation and stacking sequence of the bilayer domains relative to the underlying monolayer MoS2. These results provide important insights that bilayer MoS2 growth from 60 degrees rotated small nuclei on the surface of monolayer MoS2 could lead to defective boundaries when merged to form larger continuous bilayer regions and that pure AA' or AB bilayer stacking may be challenging unless from a single seed. PMID- 28837200 TI - Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited. AB - As part of an ongoing effort to discover inhibitors of caspase-1 with an optimized selectivity and biopharmaceutical profile, acylsulfonamides were explored as carboxylate isosteres for caspase inhibitors. Acylsulfonamide analogues of the clinically investigated caspase-1 inhibitor VRT-043198 and of the pan-caspase inhibitor Z-VAD-CHO were synthesized. The isostere-containing analogues with an aldehyde warhead had inhibitory potencies comparable to the carboxylate references. In addition, the conformational and tautomeric characteristics of these molecules were determined using 1H- and 13C-based NMR. The propensity of acylsulfonamides with an aldehyde warhead to occur in a ring closed conformation at physiological pH significantly increases the sensitivity to hydrolysis of the acylsulfonamide moiety, yielding the parent carboxylate containing inhibitors. These results indicate that the acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 might have potential as a novel type of prodrug for the latter. Finally, inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages was found to correlate with the potencies of the compounds in enzymatic assays. PMID- 28837201 TI - Palladium-catalyzed regioselective C-H bond arylations at the C3 position of ortho-substituted fluorobenzenes. AB - The influence of an ortho-substituent on fluorobenzene derivatives for palladium catalyzed C-H bond arylation has been explored. In the presence of 2-bromo, 2 chloro and 2-methoxy substituents, the reaction proceeds nicely using a diphosphine-palladium catalyst and potassium acetate/dimethylacetamide (PivOK/DMA) as the catalytic system. In all cases, a regioselective arylation at the other ortho-position to the fluorine atom (C3) was observed. A variety of electron-withdrawing substituents on the aryl bromide coupling partner, such as formyl, nitro, nitrile, and also heteroaryl bromides, was tolerated. Moreover, tri(hetero)aryl derivatives containing a fluorobenzene as the central unit have been prepared from 2-bromofluorobenzene through palladium-catalyzed-successive C H bond (hetero)arylations. PMID- 28837202 TI - Porous double network gels with high toughness, high stretchability and fast solvent-absorption. AB - Using the freeze-drying method, we fabricated porous double network gels with high toughness, high stretchability and fast solvent-absorption. When the freezing temperature was -20 degrees C and the freezing time was 24 hours, pores with diameters around 300 MUm could form in the gel. When the freezing temperature was lowered to -196 degrees C and the freezing time was reduced to 10 minutes, monodisperse pores with diameters around 15 MUm could form in the gel. We found out that both porous gels fabricated under different conditions could absorb solvent much more and much faster than a nonporous gel. Furthermore, we found that the rupturing strain, stiffness and strength of the porous double network gels were all comparable to the nonporous double network gel when containing the same amount of solvent. The unique combination of the mechanical properties of the porous double network gels might motivate new explorations of gels in practical applications. PMID- 28837203 TI - Pinning susceptibility: a novel method to study growth of amorphous order in glass-forming liquids. AB - The existence and growth of amorphous order in supercooled liquids approaching glass transition is a subject of intense research. Even after decades of work, there is still no clear consensus on the molecular mechanisms that lead to a rapid slowing down of liquid dynamics approaching this putative transition. The existence of a correlation length associated with amorphous order has recently been postulated and has also been estimated using multi-point correlation functions which cannot be calculated easily in experiments. Thus the study of growing amorphous order remains mostly restricted to systems like colloidal glasses and simulations of model glass-forming liquids. In this work, we propose an experimentally realizable yet simple susceptibility to study the growth of amorphous order. We then demonstrate the validity of this approach for a few well studied model supercooled liquids and obtain results which are consistent with other conventional methods. PMID- 28837204 TI - Inducing heat shock protein 70 expression provides a robust antithrombotic effect with minimal bleeding risk. AB - Antithrombotic medications target coagulation factors. Their use is associated with an increased bleeding risk. Safer drugs are needed. The heat shock protein 70 (Hsp70) exhibits antithrombotic properties that do not influence bleeding. By using murine models, we aimed to test the hypothesis that overexpressing Hsp70 with CM-695, a first in class dual inhibitor of HDAC6 and phosphodiesterase 9, protects against thrombosis while leaves bleeding tendency unaltered. CM-695 was used to induce Hsp70 overexpression. Hsp70 overexpressing mice were submitted to three thrombosis-triggering procedures. The ferric chloride carotid artery model was used to compare the antithrombotic role of CM-695 and rivaroxaban, a direct oral anticoagulant. The mouse tail transection model was used to compare the bleeding tendency upon CM-695 or rivaroxaban administration. Intraperitoneal (i. p.) 20 mg/kg CM-695 increased Hsp70 expression markedly in the murine aortic tissue. This treatment delayed thrombosis in the collagen/epinephrine [p=0.04 (Log-Rank test), n=10], Rose Bengal/laser [median vessel occlusion time (OT): 58.6 vs 39.0 minutes (min) in the control group (CG), p=0.008, n>=10] and ferric chloride (OT: 14.7 vs 9.2 min in the CG, p=0.032, n>=10) models. I.p. 80 mg/kg CM 695 (n>=9) and intravenous 3 mg/kg rivaroxaban (n>=8) significantly delayed thrombosis. CM-695 did not induce bleeding [median bleeding time (BT): 8.5 vs 7.5 min in the CG, n>=10]. However, BT was dramatically increased by rivaroxaban (30.0 vs 13.7 min in the CG, p=0.001, n=10). In conclusion, CM-695 is a new antithrombotic small molecule devoid of bleeding risk that may be envisioned as a useful clinical tool. PMID- 28837205 TI - Triggering Receptor Expressed on Myeloid cells-1: a new player in platelet aggregation. AB - Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is an immunoreceptor initially known to be expressed on neutrophils and monocytes/macrophages. TREM-1 acts as an amplifier of the inflammatory response during both infectious and aseptic inflammatory diseases. Another member of the TREM family, The Triggering receptor expressed on myeloid cells Like Transcript-1 (TLT-1) is exclusively expressed in platelets and promotes platelet aggregation. As the gene that encodes for TLT-1 is located in the TREM-1 gene cluster, this prompted us to investigate the expression of TREM-1 on platelets. Here we show that TREM-1 is constitutively expressed in alpha-granules and mobilised at the membrane upon platelet activation. Pharmacologic inhibition of TREM-1 reduces platelet activation as well as platelet aggregation induced by collagen, ADP, and thrombin in human platelets. Aggregation is similarly impaired in platelets from Trem-1-/- mice. In vivo, TREM-1 inhibition decreases thrombus formation in a carotid artery model of thrombosis and protects mice during pulmonary embolism without excessive bleeding. These findings suggest that TREM-1 inhibition could be useful adducts in antiplatelet therapies. PMID- 28837206 TI - Neutrophil extracellular traps are increased in patients with acute ischemic stroke: prognostic significance. AB - Neutrophil extracellular traps (NETs) are networks of DNA, histones, and proteolytic enzymes produced by activated neutrophils through different mechanisms. NET formation is promoted by activated platelets and can in turn activate platelets, thus favoring thrombotic processes. NETs have been detected in venous and arterial thrombosis, but data in stroke are scarce. The aim of this study was to evaluate NETs in the plasma of patients with acute ischemic stroke and their potential association with baseline clinical characteristics, stroke severity, and one-year clinical outcomes. The study included 243 patients with acute ischemic stroke. Clinical and demographic data and scores of stroke severity (NIHSS and mRs) at onset and discharge were recorded. Markers of NETs (cell-free DNA, nucleosomes, and citrullinated histone 3 (citH3)), were determined in plasma. Patients were followed-up for 12 months after the ischemic event. NETs were significantly elevated in the plasma of patients with acute ischemic stroke when compared to healthy subjects. NETs were increased in patients who were over 65 years of age and in those with a history of atrial fibrillation (AF), cardioembolic stroke, high glucose levels, and severe stroke scores at admission and discharge. In multivariate analysis, elevated levels of citH3, the most specific marker of NETs, at onset were independently associated with AF and all-cause mortality at one-year follow-up. NETs play a role in the pathophysiology of stroke and are associated with severity and mortality. In conclusion, citH3 may constitute a useful prognostic marker and therapeutic target in patients with acute stroke. PMID- 28837207 TI - Apixaban and dalteparin in active malignancy associated venous thromboembolism. The ADAM VTE Trial. AB - Currently, low molecular weight heparin (LMWH) is the guideline endorsed treatment of patients with cancer associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, there are limited data supporting its use in cancer patients. The rationale and design of this investigator initiated Phase IV, multicenter, randomized, open label, superiority trial assessing the safety of apixaban versus dalteparin for cancer associated VTE is provided (ADAM-VTE; NCT02585713). The main aim of the ADAM-VTE trial is to test the hypothesis that apixaban is associated with a significantly lower rate of major bleeding compared to dalteparin in the treatment of cancer patients with acute VTE. The primary safety outcome is rate of major bleeding. Secondary efficacy objective is to assess the rates of recurrent VTE or arterial thromboembolism. Cancer patients with acute VTE (n=300) are randomized to receive apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily thereafter) or dalteparin (200 IU/Kg daily for 30 days followed by 150 IU/kg daily thereafter) for 6 months. Stratification factors used for randomization include cancer stage and cancer specific risk of venous thromboembolism using the Khorana score. Participating centers are chosen from the Academic and Community Cancer Research United (ACCRU) consortium comprised of 90 oncology practices in the United States and Canada. Based on the hypothesis to be tested, we anticipate that these trial results will provide evidence supporting apixaban as an effective treatment of cancer associated VTE at lower rates of major bleeding compared to LMWH. PMID- 28837208 TI - Platelet count recovery and seroreversion in immune HIT despite continuation of heparin: further observations and literature review. AB - One of the standard distinctions between type 1 (non-immune) and type 2 (immune mediated) heparin-induced thrombocytopenia (HIT) is the transience of thrombocytopenia: type 1 HIT is viewed as early-onset and transient thrombocytopenia, with platelet count recovery despite continuing heparin administration. In contrast, type 2 HIT is viewed as later-onset (i. e., 5 days or later) thrombocytopenia in which it is generally believed that platelet count recovery will not occur unless heparin is discontinued. However, older reports of type 2 HIT sometimes did include the unexpected observation that platelet counts could recover despite continued heparin administration, although without information provided regarding changes in HIT antibody levels in association with platelet count recovery. In recent years, some reports of type 2 HIT have confirmed the observation that platelet count recovery can occur despite continuing heparin administration, with serological evidence of waning levels of HIT antibodies ("seroreversion"). We now report two additional patient cases of type 2 HIT with platelet count recovery despite ongoing therapeutic-dose (1 case) or prophylactic-dose (1 case) heparin administration, in which we demonstrate concomitant waning of HIT antibody levels. We further review the literature describing this phenomenon of HIT antibody seroreversion and platelet count recovery despite continuing heparin administration. Our observations add to the concept that HIT represents a remarkably transient immune response, including sometimes even when heparin is continued. PMID- 28837209 TI - Erythrocyte-heme proteins and STEMI: implications in prognosis. AB - The role of erythrocytes in thrombus formation has been often neglected, but some studies have highlighted their active role in thrombotic events. Free-haemoglobin (Hb) has shown to induce oxidative-stress damage. Herein we have investigated the coordinated changes in heme-related proteins in patients with acute-coronary syndromes (ACS), their association to ongoing thrombosis and their impact on patients' prognosis. The serum proteome of STEMI-patients (N=27) within the first 6h after event-onset and 3d after were compared to controls (N=60). Changes in heme-metabolism were characterized in a second STEMI-group by a dual proteomic approach analyzing in-vivo aspirated coronary thrombi at PCI (N=24) and the associated peripheral-blood changes (N=10). A third STEMI-group (N=132) was studied to analyze the impact of the observed changes in prognosis at 6-months follow-up. The haptoglobin/hemopexin(Hpg/Hpx)-scavenging-system revealed a time dependent response after STEMI with an early increase in Hpg circulating levels in the acute phase (P=0.01) and a late increase in Hpx levels 3d after (P=0.045). Beta-Hb content in coronary thrombi was directly correlated with systemic beta-Hb and Hpg (R=0.804,P=0.0029; R=0.859,P=0.0007) levels. The presence of a fully occlusive thrombus was associated to higher circulating levels of beta-Hb (P=0.03) and unbound-Hpg (P=0.03). ELISA validation demonstrated a decreased survival rate at 6-months follow-up in STEMI-patients with lower Hpg plasma levels at admission (P=0.027). Our results show active Hb-release form erythrocytes in ACS. This release is followed by a systemic early increase in Hpg levels and a late increase in Hpx levels that can co-ordinately help to prevent systemic pro-oxidative effects. The Hb-scavenging ability of haptoglobin is related to patients' prognosis. PMID- 28837210 TI - Derivation and validation of a novel bleeding risk score for elderly patients with venous thromboembolism on extended anticoagulation. AB - Existing clinical scores do not perform well in predicting bleeding in elderly patients with acute venous thromboembolism (VTE). We sought to derive an easy-to use clinical score to help physicians identify elderly patients with VTE who are at high-risk of bleeding during extended anticoagulation (>3 months). Our derivation sample included 743 patients aged >=65 years with VTE who were enrolled in a prospective multicenter cohort study. All patients received extended anticoagulation with vitamin K antagonists. We derived our score using competing risk regression, with the time to a first major bleeding up to 36 months of extended anticoagulation as the outcome, and 17 candidate variables as predictors. We used bootstrapping methods for internal validation. Sixty-six (9 %) patients suffered major bleeding. The clinical score is based on seven clinical factors (previous bleeding, active cancer, low physical activity, anemia, thrombocytopenia, antiplatelet drugs/NSAIDs, and poor INR control). Overall, 48 % of patients were classified as low-risk, 37 % as moderate-risk, and 15 % as high-risk of bleeding. The rate of major bleeding was 1.4 events in low risk, 5.0 events in moderate-risk, and 12.2 events per 100 patient-years in high risk patients. The c-statistic was 0.78 at 3 months and 0.71 at 36 months of extended anticoagulation. Model calibration was excellent (p=0.93). Internal validation showed similar results. This simple clinical score accurately identified elderly patients with VTE who are at high risk of major bleeding and who may not benefit from extended anticoagulation. Further validation of the score is important before its implementation into practice. The study is registered to https://clinicaltrials.gov as NCT00973596. PMID- 28837211 TI - Special Topic Interoperability and EHR: Combining openEHR, SNOMED, IHE, and Continua as approaches to interoperability on national eHealth. AB - OBJECTIVES: The main aims of the paper comprise the characterization and examination of the potential approaches regarding interoperability. This includes openEHR, SNOMED, IHE, and Continua as combined interoperability approaches, possibilities for their incorporation into the eHealth environment, and identification of the main success factors in the field, which are necessary for achieving required interoperability, and consequently, for the successful implementation of eHealth projects in general. METHODS: The paper represents an in-depth analysis regarding the potential application of openEHR, SNOMED, IHE and Continua approaches in the development and implementation process of eHealth in Slovenia. The research method used is both exploratory and deductive in nature. The methodological framework is grounded on information retrieval with a special focus on research and charting of existing experience in the field, and sources, both electronic and written, which include interoperability concepts and related implementation issues. RESULTS: The paper will try to answer the following inquiries that are complementing each other: 1. Scrutiny of the potential approaches, which could alleviate the pertinent interoperability issues in the Slovenian eHealth context. 2. Analyzing the possibilities (requirements) for their inclusion in the construction process for individual eHealth solutions. 3. Identification and charting the main success factors in the interoperability field that critically influence development and implementation of eHealth projects in an efficient manner. CONCLUSIONS: Provided insights and identified success factors could serve as a constituent of the strategic starting points for continuous integration of interoperability principles into the healthcare domain. Moreover, the general implementation of the identified success factors could facilitate better penetration of ICT into the healthcare environment and enable the eHealth-based transformation of the health system especially in the countries which are still in an early phase of eHealth planning and development and are often confronted with differing interests, requirements, and contending strategies. PMID- 28837212 TI - Barriers to Achieving Economies of Scale in Analysis of EHR Data. A Cautionary Tale. AB - Signed in 2009, the Health Information Technology for Economic and Clinical Health Act infused $28 billion of federal funds to accelerate adoption of electronic health records (EHRs). Yet, EHRs have produced mixed results and have even raised concern that the current technology ecosystem stifles innovation. We describe the development process and report initial outcomes of a chronic kidney disease analytics application that identifies high-risk patients for nephrology referral. The cost to validate and integrate the analytics application into clinical workflow was $217,138. Despite the success of the program, redundant development and validation efforts will require $38.8 million to scale the application across all multihospital systems in the nation. We address the shortcomings of current technology investments and distill insights from the technology industry. To yield a return on technology investments, we propose policy changes that address the underlying issues now being imposed on the system by an ineffective technology business model. PMID- 28837213 TI - Antithrombotic potency of ticagrelor versus clopidogrel in type-2 diabetic patients with cardiovascular disease. AB - Type-2 Diabetes Mellitus [T2DM] is associated with increased platelet reactivity and hypo-response to antiplatelet drugs. Ticagrelor, with its faster and more potent antiplatelet effects, was shown to reduce adverse events more than clopidogrel in the overall CAD patient population of PLATO trial, but the benefits did not reach statistical significance in the T2DM subgroup. To better understand these findings, we compared the antithrombotic effects of ticagrelor versus with clopidogrel in T2DM patients with cardiovascular disease. In a randomized, 2 treatment-sequence, crossover-design, T2DM patients (n=20, 57+/-8 years, 60 % male) received a loading-dose [LD] plus one week of daily-therapy [DT] of clopidogrel or ticagrelor. Treatment effects were assessed by measuring thrombus formation (Badimon Chamber) and platelet aggregation (Multiple Electrode Aggregometry (MEA) Analyzer and VerifyNow(r)) at 2- and 6-hour post-LD and on Day 7 of DT, in comparison with pre-treatment baseline. After 2 weeks of washout, patients switched to the second treatment under identical testing conditions. Ticagrelor significantly reduced thrombus formation versus baseline at 2- and 6 hour post-LD and Day-7 of DT (33 %, 40 % and 31 %, respectively, p<0.01 for all) whereas thrombus reductions with clopidogrel were much lower and significant only at 6-hour post-LD (16 %, 20 % and 17 %, respectively). Antithrombotic effect of ticagrelor at 6-hour was significantly stronger than clopidogrel (p<0.05). Platelet aggregation (MEA and VerifyNow(r)) was inhibited by both treatments but effects of ticagrelor were significantly stronger at each time-point. Ticagrelor exhibits a faster and more potent antithrombotic effect than clopidogrel in T2DM patients with cardiovascular disease, supporting its use in this population. PMID- 28837215 TI - Extremity of Externalizing Behavior and Young Adult Outcomes. AB - Data from the National Child Development Study were used to explore the relationship between extremity of externalizing behavior problems during childhood and employment-related outcomes in young adulthood. Analyses focused on four heuristic dimensions of extremity (age at onset, density, persistence, and pervasiveness) and three outcomes (school-leaving age, level of qualifications at labor force entry, and social class of job al age 23). Persistence was associated with the most substantial deficits across all outcomes, and temporal proximity was more influential than early onset. The data suggest that school-based and home-based situational behavior problems should not be combined into a single nonpervasive category. PMID- 28837214 TI - Combined genotypes of the MBL2 gene related to low mannose-binding lectin levels are associated with vaso-occlusive events in children with sickle cell anemia. AB - Sickle cell anemia (SCA) presents heterogenous clinical manifestations that cannot be explained solely by alterations to hemoglobin (Hb); other components such as endothelial adhesion, thrombosis and inflammation may be involved. The mannose-binding lectin (MBL) has an important role in innate immunity and inflammatory diseases. In this report, we describe an association between MBL2 polymorphism related to low production of serum MBL and the frequency of vasoocclusive events (FVOE) in children <= 5 years old with SCA (p = 0.0229; OR 5.55; CI 1.11-27.66). Further studies are needed to explore the role of low MBL2 in the pathophysiology of vasoocclusive events in SCA. PMID- 28837216 TI - The Orphans of Eritrea: A Comparison Study. AB - The social-emotional state and cognitive development was compared between a group of 74 4-7-year-old Eritrean orphans and refugee children living in families. Both groups had been exposed to the chronic stresses of war and drought and the orphans had, in addition, lost both parents to the violence of war, and were living in an overcrowded orphanage- Contrary to expectations, there were relatively few clinically significant differences between comparison groups. The orphans showed more behavioral symptoms of emotional distress, but performed at a more advanced level on cognitive and language performance measures. The findings suggest that when group care is child-centered, it can under some circumstances be a viable solution for unaccompanied children in countries where adoption and foster care are not realistic alternatives. PMID- 28837218 TI - Second malignancies in Ewing sarcoma survivors. PMID- 28837217 TI - A 340/380 nm light-emitting diode illuminator for Fura-2 AM ratiometric Ca2+ imaging of live cells with better than 5 nM precision. AB - We report the first demonstration of a fast wavelength-switchable 340/380 nm light-emitting diode (LED) illuminator for Fura-2 ratiometric Ca2+ imaging of live cells. The LEDs closely match the excitation peaks of bound and free Fura-2 and enables the precise detection of cytosolic Ca2+ concentrations, which is only limited by the Ca2+ response of Fura-2. Using this illuminator, we have shown that Fura-2 acetoxymethyl ester (AM) concentrations as low as 250 nM can be used to detect induced Ca2+ events in tsA-201 cells and while utilising the 150 MUs switching speeds available, it was possible to image spontaneous Ca2+ transients in hippocampal neurons at a rate of 24.39 Hz that were blunted or absent at typical 0.5 Hz acquisition rates. Overall, the sensitivity and acquisition speeds available using this LED illuminator significantly improves the temporal resolution that can be obtained in comparison to current systems and supports optical imaging of fast Ca2+ events using Fura-2. PMID- 28837219 TI - A systematic review and meta-analysis of nonpharmacological adjuvant interventions for patients undergoing assisted reproductive technology treatment. AB - BACKGROUND: Assisted reproductive technology (ART) is not always successful, yet places a high psychological burden on individuals. OBJECTIVES: To assess whether nonpharmacological adjuvant interventions could improve outcomes among patients receiving ART. SEARCH STRATEGY: Electronic databases were searched from inception to March 2017, using keywords such as "fertility treatment," "emotional distress," and "clinical pregnancy." SELECTION CRITERIA: Reports of randomized controlled trials investigating the impact of nonpharmacological interventions on emotional disorders and the pregnancy rate in patients receiving ART published in any language were included. DATA COLLECTION AND ANALYSIS: Data were extracted into a predesigned form. Psychological ratings were pooled using standardized mean differences (SMDs). Heterogeneity was assessed. The primary outcome measures were psychological ratings at baseline and after intervention. MAIN RESULTS: Overall, 34 randomized controlled trials, with a total of 7213 patients, met the inclusion criteria. Nonpharmacological interventions reduced anxiety when compared with control interventions (SMD 0.25, 95% confidence interval 0.08-0.42; I2 =85%), but they had no significant effects on depression and infertility distress. CONCLUSIONS: Nonpharmacological interventions could improve the psychological outcomes of patients undergoing ART treatment. PMID- 28837220 TI - Reply to Second malignancies in Ewing sarcoma survivors. PMID- 28837221 TI - Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. AB - BACKGROUND: Asthma severity and control can be measured both subjectively and objectively. Sputum analysis for evaluation of percentage of sputum eosinophilia directly measures airway inflammation, and is one method of objectively monitoring asthma. Using sputum analysis to adjust or tailor asthma medications is potentially superior to traditional methods based on symptoms and spirometry. OBJECTIVES: To evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to traditional methods (usually symptom-based with or without spirometry/peak flow) for asthma-related outcomes in children and adults. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trials' registries, and reference lists of articles. The last search was conducted in February 2017. SELECTION CRITERIA: All randomised controlled comparisons of adjustment of asthma therapy based on sputum eosinophils compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. In this update, two reviewers selected relevant studies, independently assessed trial quality and extracted the data. We contacted authors for further information when relevant. We analysed data as 'treatment received' and performed sensitivity analyses. MAIN RESULTS: Three new studies were added in this update, resulting in a total of six included studies (five in adults and one involving children/adolescents). These six studies were clinically and methodologically heterogeneous (use of medications, cut-off for percentage of sputum eosinophils and definition of asthma exacerbation). Of 374 participants randomised, 333 completed the trials. In the meta-analysis, there was a significant reduction in the occurrence of any exacerbations when treatment was based on sputum eosinophil counts, compared to that based on clinical symptoms with or without lung function; pooled odds ratio (OR) was 0.57 (95% confidence interval (CI) 0.38 to 0.86). The risk of having one or more exacerbations over 16 months was 82% in the control arm and 62% (95% CI 49% to 74%) in the sputum strategy arm, resulting in a number needed to treat to benefit (NNTB) of 6 (95% CI 4 to 13).There were also differences between the groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids and hospitalisations: the risk of one or more hospitalisations over 16 months was 24% in controls compared to 8% (95% CI 3% to 21%) in the sputum arm. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was also similar in both groups. However sputum induction was not always possible. The included studies did not record any adverse events.One study was not blinded and thus was considered to have a high risk of bias. However, when this study was removed in a sensitivity analysis, the difference between the groups for the primary outcome (exacerbations) remained statistically significant between groups. The GRADE quality of the evidence ranged from moderate (for the outcomes 'Occurrence of any exacerbation' and 'Hospitalisation' ) to low (for the outcome 'Mean dose of inhaled corticosteroids per person per day') due to the inconsistency in defining exacerbations and the small number of hospital admissions. AUTHORS' CONCLUSIONS: In this updated review, tailoring asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. Adults with frequent exacerbations and severe asthma may derive the greatest benefit from this additional monitoring test, although we were unable to confirm this through subgroup analysis. There is insufficient data available to assess tailoring asthma medications based on sputum eosinophilia in children.Further robust RCTs need to be undertaken and these should include participants with different underlying asthma severities and endotypes. PMID- 28837223 TI - Editorial. PMID- 28837222 TI - Ablation of the Cbeta2 subunit of PKA in immune cells leads to increased susceptibility to systemic inflammation in mice. AB - Protein kinase A (PKA) is a holoenzyme composed of a regulatory subunit dimer and two catalytic subunits and regulates numerous cellular functions including immune cell activity. There are two major catalytic subunit genes, PRKACA and PRKACB encoding the catalytic subunits Calpha and Cbeta. The PRKACB gene encodes several splice variants including Cbeta2, which is enriched in T-, B- and natural killer cells. Cbeta2 is significantly larger (46 kDa) than any other C splice variant. In this study we characterized mice ablated for the Cbeta2 protein demonstrating a significantly reduced cAMP-induced catalytic activity of PKA in the spleenocytes, lymphocytes and thymocytes. We also observed a significantly increased number of CD62L-expressing CD4+ and CD8+ T cells in LNs, accompanied by increased susceptibility to systemic inflammation by the Cbeta2 ablated mice. The latter was reflected in an elevated sensitivity to collagen-induced arthritis (CIA), as well as higher concentration of TNF-alpha and lower concentration of IL 10 in response to LPS challenges. We suggest a role of Cbeta2 in regulating innate as well as adaptive immune sensitivity in vivo. PMID- 28837224 TI - A framework based on hidden Markov trees for multimodal PET/CT image co segmentation. AB - PURPOSE: The purpose of this study was to investigate the use of a probabilistic quad-tree graph (hidden Markov tree, HMT) to provide fast computation, robustness and an interpretational framework for multimodality image processing and to evaluate this framework for single gross tumor target (GTV) delineation from both positron emission tomography (PET) and computed tomography (CT) images. METHODS: We exploited joint statistical dependencies between hidden states to handle the data stack using multi-observation, multi-resolution of HMT and Bayesian inference. This framework was applied to segmentation of lung tumors in PET/CT datasets taking into consideration simultaneously the CT and the PET image information. PET and CT images were considered using either the original voxels intensities, or after wavelet/contourlet enhancement. The Dice similarity coefficient (DSC), sensitivity (SE), positive predictive value (PPV) were used to assess the performance of the proposed approach on one simulated and 15 clinical PET/CT datasets of non-small cell lung cancer (NSCLC) cases. The surrogate of truth was a statistical consensus (obtained with the Simultaneous Truth and Performance Level Estimation algorithm) of three manual delineations performed by experts on fused PET/CT images. The proposed framework was applied to PET-only, CT-only and PET/CT datasets, and were compared to standard and improved fuzzy c means (FCM) multimodal implementations. RESULTS: A high agreement with the consensus of manual delineations was observed when using both PET and CT images. Contourlet-based HMT led to the best results with a DSC of 0.92 +/- 0.11 compared to 0.89 +/- 0.13 and 0.90 +/- 0.12 for Intensity-based HMT and Wavelet-based HMT, respectively. Considering PET or CT only in the HMT led to much lower accuracy. Standard and improved FCM led to comparatively lower accuracy than HMT, even when considering multimodal implementations. CONCLUSIONS: We evaluated the accuracy of the proposed HMT-based framework for PET/CT image segmentation. The proposed method reached good accuracy, especially with pre-processing in the contourlet domain. PMID- 28837225 TI - Toward image quality assessment in mammography using model observers: Detection of a calcification-like object. AB - PURPOSE: Model observers (MOs) are of interest in the field of medical imaging to assess image quality. However, before procedures using MOs can be proposed in quality control guidelines for mammography systems, we need to know whether MOs are sensitive to changes in image quality and correlations in background structure. Therefore, as a proof of principle, in this study human and model observer (MO) performance are compared for the detection of calcification-like objects using different background structures and image quality levels of unprocessed mammography images. METHOD: Three different phantoms, homogeneous polymethyl methacrylate, BR3D slabs with swirled patterns (CIRS, Norfolk, VA, USA), and a prototype anthropomorphic breast phantom (Institute of Medical Physics and Radiation Protection, Technische Hochschule Mittelhessen, Germany) were imaged on an Amulet Innovality (FujiFilm, Tokyo, Japan) mammographic X-ray unit. Because the complexities of the structures of these three phantoms were different and not optimized to match the characteristics of real mammographic images, image processing was not applied in this study. In addition, real mammograms were acquired on the same system. Regions of interest (ROIs) were extracted from each image. In half of the ROIs, a 0.25-mm diameter disk was inserted at four different contrast levels to represent a calcification-like object. Each ROI was then modified, so four image qualities relevant for mammography were simulated. The signal-present and signal-absent ROIs were evaluated by a non-pre-whitening model observer with eye filter (NPWE) and a channelized Hotelling observer (CHO) using dense difference of Gaussian channels. The ROIs were also evaluated by human observers in a two alternative forced choice experiment. Detectability results for the human and model observer experiments were correlated using a mixed-effect regression model. Threshold disk contrasts for human and predicted human observer performance based on the NPWE MO and CHO were estimated. RESULTS: Global trends in threshold contrast were similar for the different background structures, but absolute contrast threshold levels differed. Contrast thresholds tended to be lower in ROIs from simple phantoms compared with ROIs from real mammographic images. The correlation between human and model observer performance was not affected by the range of image quality levels studied. CONCLUSIONS: The correlation between human and model observer performance does not depend on image quality. This is a promising outcome for the use of model observers in image quality analysis and allows for subsequent research toward the development of MO-based quality control procedures and guidelines. PMID- 28837226 TI - A reference range of fetal abdominal circumference growth velocity between 20 and 36 weeks' gestation. AB - OBJECTIVE: To create a single equation and reference range for abdominal circumference growth velocity (ACGV) between 20 and 36 weeks in singleton pregnancies. METHOD: Observational study of pregnant women having routine scans for abdominal circumference (AC) at 20 and 36 weeks' gestation. Exclusion criteria were multiple pregnancy, abnormal karyotype, major fetal abnormalities, and absent data on first-trimester dating. Scan image quality and AC measurement reliability were assessed according to INTERGROWTH-21st criteria. Regression models for the AC mean and standard deviation were fitted separately at 20 and 36 weeks, and z scores were calculated. Abdominal circumference growth velocity was defined as the z score difference between 20 and 36 weeks divided by the interval in days and multiplied by 100. RESULTS: The study population included 3334 fetuses. The equation for ACGV is (((AC36 - 53.090 - 1.081*GA36 )/(0.057638*GA36 + 0.622741)) - ((AC20 + 68.349 - 1.571*GA20 )/(0.06265*GA20 - 2.55361)))*100/(GA36 - GA20 ), where AC is expressed in millimeters and GA is gestational age in days. The 3rd, 5th, 10th, 50th, 90th, 95th, and 97th centiles are -1.8997, -1.6785, -1.3091, -0.0069, 1.3255, 1.7279, 1.9973, respectively. CONCLUSION: We have defined ACGV between 20 and 36 weeks, and we have established its reference range. Further studies are needed to evaluate the clinical significance of growth patterns in the tail ends of this distribution. PMID- 28837228 TI - Nursing voices on government decision-making tables. PMID- 28837227 TI - Enrichment and Cytotoxic Activity of Curcuminoids from Turmeric Using Macroporous Resins. AB - Curcuminoids are functional secondary metabolites abundant in turmeric. In the present study, a simple and efficient method for enrichment of curcuminoids from turmeric was developed using macroporous resin. Eight different types of macroporous resins were examined by static adsorption/desorption properties and the type of XDA-7 was selected as the optimum one. Under the optimized conditions, the final contents of refined extract excluded 84.2% of impurities, by comparison with crude extract in a scale-up experiment. Meanwhile, 8 representative curcuminoids including 4 dihydro- and tetrahydro-curcuminoids were enriched, isolated, and identified by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) data. In addition, the individual curcuminoids were prepared to evaluate their cytotoxic activity toward HeLa tumor cell lines. All compounds, especially the trace amount of curcuminoids, demonstrated notable cytotoxic activity. The results supported that those trace amount of curcuminoids can be good candidates for drug development as anticancer agents. The purification process was simple and efficient, which could afford a potential method to enrich and concentrate not only the major curcuminoids, but also the trace amount of ones from turmeric raw materials for industrial applications. PMID- 28837229 TI - TOGETHER - the watchword I have chosen for my term in office. PMID- 28837230 TI - The nursing profession in Sri Lanka: time for policy changes. AB - AIM: We address issues and challenges in nursing in Sri Lanka with the aim of identifying where and how policy changes need to be made. BACKGROUND: Increased global interconnectivity calls for professional leadership, research, education, and policy reform in nursing as these are identified as enhancing health workforce performance and professionalization, thereby improving health systems. SOURCES OF EVIDENCE: We draw on first-hand knowledge of health care and nursing in Sri Lanka and a recent survey of nurses at a large urban government hospital in Sri Lanka, followed by discussion and proposed action on themes identified through analysis of published and unpublished literature about the nursing profession. DISCUSSION: Policy and action are needed to: (a) establish mandatory nurse licensure in the public and private healthcare sectors; (b) implement realistic policies to further develop nursing education; (c) develop a professionalization process to support nursing autonomy and voice; and (d) promote systematic processes for educational accreditation, curriculum revision, continuing professional development, evidence-based practice, research, leadership, and information systems. CONCLUSION: There is a policy vacuum that requires careful analysis and strategic planning by formal nurse leaders. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Implementing change will require political and professional power and strategic, innovative, and evolutionary policy initiatives as well as organizational infrastructure modifications best achieved through committed multidisciplinary collaboration, augmented research capacity, bolstered nursing leadership, and promotion of partnerships with policy makers. PMID- 28837231 TI - Physical activity, quality of life and successful ageing among community-dwelling older adults. AB - AIM: To identify the relationships between physical activity, quality of life and successful ageing among community-dwelling older adults in South Korea. BACKGROUND: With increasing numbers of financially stable and active older adults, it has become imperative to understand successful ageing to promote well being in this population. METHODS: Questionnaire data were collected from senior welfare centres from August to November 2013. Participants were adults aged 65 years or older living in urban areas. Participants were asked to complete self report questionnaires assessing physical activity, quality of life and successful ageing. Data from 212 participants were analysed using descriptive statistics, independent t-tests, ANOVAs with Scheffe tests and ordinary least square and quantile regression models using STATA 12.0. FINDINGS: In the ordinary least square model, the association between physical activity and successful ageing was not statistically significant, whereas quantile regression revealed significant associations within the 75th and 90th percentiles of successful ageing scores. Quality of life was significantly associated with successful ageing in the ordinary least square model and with the median and 75th percentiles of successful ageing in quantile regressions. CONCLUSION: Results suggested that physical activity and quality of life were both in part significantly associated with successful ageing among Korean older adults. IMPLICATIONS FOR NURSING AND HEALTH POLICIES: Physical activity and quality of life play an important role in enhancing successful ageing. The development of an effective exercise programme advertised towards community-dwelling older adults may be essential for maintaining their successful ageing. PMID- 28837232 TI - International Council of Nurses' 2017 Congress hits record numbers of participants. PMID- 28837233 TI - Real-time tomosynthesis for radiation therapy guidance. AB - PURPOSE: Fluoroscopy has been a tool of choice for monitoring treatments or interventions because of its extremely fast imaging times. However, the contrast obtained in fluoroscopy may be insufficient for certain clinical applications. In stereotactic ablative radiation therapy of the lung, fluoroscopy often lacks sufficient contrast for gating treatment. The purpose of this work is to describe and assess a real-time tomosynthesis design that can produce sufficient contrast for guidance of lung tumor treatment within a small field of view. METHODS: Previous tomosynthesis designs in radiation oncology have temporal resolution on the order of seconds. The proposed system design uses parallel acquisition of multiple frames by simultaneously illuminating the field of view with multiple sources, enabling a temporal resolution of up to 30 frames per second. For a small field of view, a single flat-panel detector could be used if different sectors of the detector are assigned to specific sources. Simulated images were generated by forward projection of existing clinical datasets. The authors varied the number of tubes and the power of each tube in order to determine the impact on tumor visualization. RESULTS: Visualization of the tumor was much clearer in tomosynthesis than in fluoroscopy. Contrast generally improved with the number of sources used, and a minimum of four sources should be used. The high contrast of the lung allows very low system power, and in most cases, less than 1 mA was needed. More power is required in the lateral direction than the AP direction. CONCLUSIONS: The proposed system produces images adequate for real-time guidance of radiation therapy. The additional hardware requirements are modest, and the system is capable of imaging at high frame rates and low dose. Further development, including a prototype system and a dosimetry study, is needed to further evaluate the feasibility of this device for radiation therapy guidance. PMID- 28837235 TI - Papers Recently Accepted for Publication. PMID- 28837234 TI - A precision 3D conformal treatment technique in rats: Application to whole-brain radiotherapy with hippocampal avoidance. AB - PURPOSE: To develop and validate three-dimensional (3D) conformal hippocampal sparing whole-brain radiation therapy (HA-WBRT) for Wistar rats utilizing precision 3D-printed immobilization and micro-blocks. This technique paves the way for future preclinical studies investigating brain treatments that reduce neurotoxicity. METHODS AND MATERIALS: A novel preclinical treatment planning and delivery process was developed to enable precision 3D conformal treatment and hippocampal avoidance capability for the Xrad 225cx small animal irradiator. A range of conformal avoidance plans were evaluated consisting of equiangularly spaced coplanar axial beams, with plans containing 2, 4, 7, and 8 fields. The hippocampal sparing and coverage of these plans were investigated through Monte Carlo dose calculation (SmART-Plan Xrad 225cx planning system). Treatment delivery was implemented through a novel process where hippocampal block shapes were computer generated from an MRI rat atlas which was registered to on-board cone beam CT of the rat in treatment position. The blocks were 3D printed with a tungsten-doped filament at lateral resolution of 80 MUm. Precision immobilization was achieved utilizing a 3D-printed support system which enabled angled positioning of the rat head in supine position and bite block to improve coverage of the central diencephalon. Treatment delivery was verified on rodent-morphic Presage(r) 3D dosimeters optically scanned at 0.2-mm isotropic resolution. Biological verification of hippocampal avoidance was performed with immunohistologic staining. RESULTS: All simulated plans spared the hippocampus while delivering high dose to the brain (22.5-26.2 Gy mean dose to brain at mean hippocampal dose of 7 Gy). No significant improvement in hippocampal sparing was observed by adding beams beyond four fields. Dosimetric sparing of hippocampal region of the four-field plan was verified with the Presage(r) dosimeter (mean dose = 9.6 Gy, D100% = 7.1 Gy). Simulation and dosimeter match at distance-to agreement of 2 mm and dose difference of +/-3% at 91.7% gamma passing rate (passing criteria of gamma < 1). Agreement is less at 1 mm and +/-5% at 69.0% gamma passing rate. The four-field plan was further validated with immunohistochemistry and showed a significant reduction in DNA double-strand breaks within the spared region compared with whole-brain irradiated groups (P = 0.021). However, coverage of the whole brain was low at 48.5-57.8% of the volume receiving 30Gy at 7Gy mean hippocampal dose in simulation and 46.7-52.5% in dosimetric measurements. This can be attributed to the shape of the rat hippocampus and the inability of treatment platform to employ non-coplanar beams. CONCLUSION: A novel approach for conformal microradiation therapy using 3D printing technology was developed, implemented, and validated. A workflow was developed to generate accurate 3D-printed blocks from registered high-resolution rat MRI atlas structures. Although hippocampus was spared with this technique, whole-brain target coverage was suboptimal, indicating that non-coplanar beams and IMRT capability may be required to meet stringent dose criteria associated with current human RTOG trials. PMID- 28837236 TI - Renal NUT carcinoma: a case report. PMID- 28837237 TI - Pseudodominant inheritance pattern in a family with CMT2 caused by GDAP1 mutations. AB - We report a family in which an autosomal dominantly inherited Charcot-Marie-Tooth (CMT) disease type 2 was suspected. The affected family members (proband, sister, father, and paternal aunt) showed intrafamilial clinical variability. The proband needed walking aids since adolescence because of generalized muscle weakness. The sister showed the same symptoms although to a lesser extent. The father and paternal aunt had foot deformity and atrophy of lower legs. A homozygous GDAP1 mutation was found in the proband and in the sister. Further testing showed compound heterozygous GDAP1 mutations in the father and paternal aunt. In this CMT2 family with a pseudodominant inheritance pattern DNA-diagnostics revealed the presence of both homozygous and compound heterozygous GDAP1 mutations. We recommend including multiple family members in genetic studies on CMT families. PMID- 28837238 TI - Increase of n-NOS and i-NOS in Rat Colon After Sacral Neuromodulation. AB - OBJECTIVE: Sacral neuromodulation (SNM) is proposed to treat different anorectal dysfunctions but its mechanism of action is not yet known. Our previous study demonstrated how SNM can significantly increase neuronal nitric oxide synthase NOS (n-NOS) and inducible NOS (i-NOS) expression in the anus and rectum of rats. There are no reports regarding the relation between SNM and NOS in colonic cells: our aim was to assess NOS expression in colonic rat model after SNM. MATERIALS AND METHODS: Twenty-six female Sprangue-Dawley rats were considered: group I, normal control rats; group II, sham treatment rats, in whom electrodes for electrical stimulation were placed in S1 foramen bilaterally and left in place, without performing neuromodulation; group III, rats in whom SNM was performed. After 14 days, the rats were sacrificed and we evaluated n-NOS and i-NOS in colonic specimens by immunohistochemistry and Western Blot analysis. RESULTS: Western Blot analysis showed that levels of n-NOS and i-NOS were higher in colon of the III group rats respect to the others; in particular, immunohistochemistry revealed that, after neuromodulation, n-NOS expression in the muscle cells and i NOS expression in glandular epithelium and nervous cells were highly represented (p < 0.05). CONCLUSION: Our study showed that in colon, SNM is able to influence NO synthesis, activating n-NOS expression in muscle cells and i-NOS expression in glandular epithelium and nervous cells. Our study showed a complex colonic response to SNM. This experimental model could be applied to better understand the mechanism of action of SNM in bowel dysfunction. PMID- 28837239 TI - The role of S-acylation in protein trafficking. AB - Protein S-acylation, also known as palmitoylation, consists of the addition of a lipid molecule to one or more cysteine residues through a thioester bond. This modification, which is widespread in eukaryotes, is thought to affect over 12% of the human proteome. S-acylation allows the reversible association of peripheral proteins with membranes or, in the case of integral membrane proteins, modulates their behavior within the plane of the membrane. This review focuses on the consequences of protein S-acylation on intracellular trafficking and membrane association. We summarize relevant information that illustrates how lipid modification of proteins plays an important role in dictating precise intracellular movements within cells by regulating membrane-cytosol exchange, through membrane microdomain segregation, or by modifying the flux of the proteins by means of vesicular or diffusional transport systems. Finally, we highlight some of the key open questions and major challenges in the field. PMID- 28837241 TI - The Design of a New Cobalt Sulfide Nanoparticle Implanted Porous Organic Polymer Nanohybrid as a Smart and Durable Water-Splitting Photoelectrocatalyst. AB - Development of an inexpensive, efficient and robust nanohybrid catalyst as a substitute for platinum in photoelectrocatalytic hydrogen production has been considered intriguing and challenging. In this study, the design and sequential synthesis of a novel cobalt sulfide nanoparticle grafted Porous Organic Polymer nanohybrid (CoSx @POP) is reported and used as an active and durable water splitting photoelectrocatalyst in the hydrogen evolution reaction (HER). The specific textural and relevant chemical properties of as-synthesised nanohybrid materials (Co3 O4 @POP &CoSx @POP) were investigated by means of XRD, XPS, FTIR, 13 C CP MAS NMR, spectroscopy, HR-TEM, HAADF-STEM with the corresponding elemental mapping, FE-SEM and nitrogen physisorption studies. CoSx @POP has been evaluated as a superior photoelectrocatalyst in HER, achieving a current density of 6.43 mA cm-2 at 0 V versus the reversible hydrogen electrode (RHE) in a 0.5 m Na2 SO4 electrolyte which outperforms its Co3 O4 @POP analogue. It was found that the nanohybrid CoSx @POP catalyst exhibited a substantially enhanced catalytic performance of 1.07 MUmol min-1 cm-2 , which is considered to be ca. 10 and 1.94 times higher than that of pristine POP and CoSx , respectively. Remarkable photoelectrocatalytic activity of CoSx @POP compared to Co3 O4 @POP toward H2 evolution could be attributed to intrinsic synergistic effect of CoSx and POP, leading to the formation of a unique CoSx @POP nanoarchitecture with high porosity, which permits easy diffusion of electrolyte and efficient electron transfer from POP to CoSx during hydrogen generation with a tunable bandgap, that straddles between the reduction and oxidation potential of water. PMID- 28837242 TI - Characterization of patients with suspected hypersensitivity to cervicovaginal fluid. AB - BACKGROUND: Allergic reaction to seminal plasma was described decades ago. In USA, only tens of thousands women are estimated to be affected. Not only seminal plasma but also cervicovaginal fluid contains sex-restricted antigens, yet allergy to cervicovaginal fluid has never been reported in medical literature. We came to a suspicion that because immunologic tests required to prove such a diagnosis, allergy to cervicovaginal fluid has never been reported yet it is not uncommon. OBJECTIVE: The objective of this study was to use an Internet-based questionnaire to characterize the population of men with suspected hypersensitivity to cervicovaginal fluid. METHODS: A questionnaire designed to cover localized and systemic symptoms of hypersensitivity reaction was made available via the Internet. Respondents with postcoital adverse reactions were invited to participate. Only respondents who presented with at least two symptoms suggestive to hypersensitivity to seminal plasma or cervicovaginal fluid and were negative for STI, and known hypersensitivity reactions such as latex allergy were a subject for further analysis. Board-certified dermatologists were surveyed for seeing bona fide cases of cervicovaginal fluid hypersensitivity. RESULTS: We have identified 52 cases of suspected hypersensitivity to cervicovaginal fluid (CVF). Both localized and systemic types of hypersensitivity were identified. A substantial number of dermatologists admitted to witnessing cases of hypersensitivity to CVF. CONCLUSION: Based on data from affected individuals as well as the opinions of dermatologists worldwide, we believe that allergic reaction to cervicovaginal fluid is at least as common as seminal plasma allergy. However, remains unreported due to technical difficulties in diagnosis and dermatologists' disbelief in its actual existence. PMID- 28837243 TI - Clinical accuracy of abnormal cell-free fetal DNA results for the sex chromosomes. AB - OBJECTIVE: To investigate factors associated with abnormal cell-free DNA (cfDNA) results for sex chromosomes (SCs). STUDY DESIGN: This is a retrospective cohort study of abnormal cfDNA results for SC at a referral practice from March 2013 to July 2015. Cell-free DNA results were abnormal if they were positive for SC aneuploidy (SCA), inconclusive, or discordant with ultrasound (US) findings. Primary outcome was concordance with karyotype or postnatal evaluation. RESULTS: Of 50 abnormal cfDNA results for SC, 31 patients (62%) were positive for SCA, 13 (26%) were inconclusive, and 6 (12%) were sex discordant on US. Of SCA results, 19 (61%) were reported as 45,X and 12 (39%) were SC trisomy. Abnormal karyotypes were confirmed in 8/23 (35%) of SC aneuploidy and 1/5 (20%) of inconclusive results. Abnormal SC cfDNA results were associated with in vitro fertilization (P = .001) and twins (P < .001). Sex discordance between cfDNA and US was associated with twin gestation (P < .001). CONCLUSIONS: In our cohort, abnormal SC cfDNA results were associated with in vitro fertilization and twins. Our results indicate cfDNA for sex prediction in twins of limited utility. Positive predictive value and sensitivity for SC determination were lower than previously reported. PMID- 28837244 TI - Conjugated Gold-Porphyrin Monolayers Assembled on Inorganic Surfaces. AB - Gold nanoparticles show important properties owing to their electronic structures. A limitation of some gold nanoparticles is that they either show surface plasmons or luminescence. The increase in size of the gold nanoparticles, and the appearance of the surface plasmons may result in the disappearance of luminescence. The aim of our study is the nanoscale assembly of Au nanoparticles on a monolayer of porphyrin molecules anchored to functionalized inorganic surfaces. This functional architecture not only exhibits a strong surface plasmon due to the gold nanoparticles, but also a strong luminescence signal from the porphyrin molecules. Finally we observed a long-range order in the Au nanoparticles conjugated to the porphyrin monolayer. PMID- 28837245 TI - Revealing the Activity of pi-Acid Catalysts using a 7-Alkynyl Cycloheptatriene. AB - A compound that isomerizes into distinct products depending on the particular Lewis acid or Bronsted acid catalyst used is disclosed. One product can only be obtained with the softest pi-acids, such as Au, Pt, Ga, or In complexes. Another is formed only with harder pi-acids incorporating Ag or Cu salts. The formation of the third category requires even harder pi-acids or protons. This simple benchmark reaction allows for prediction of the category of transformations that can be catalyzed by a new complex. It also informs whether protons have been unintentionally generated in the reaction mixture. PMID- 28837247 TI - Highlights from the 2017 meeting of the Society for Neural Control of Movement (Dublin, Ireland). PMID- 28837246 TI - c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice. AB - Pancreatic ductal adenocarcinoma (PDAC) is a life-threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c-Jun N terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1aCre/+ ;KrasG12D/+ mice with JNK1-/- mice to generate Ptf1aCre/+ ;KrasG12D/+ ;JNK1-/- (Kras;JNK1-/- ) mice. Tumor weight was significantly lower in Kras;JNK1-/- mice than in Kras;JNK1+/- mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 s.c. into WT and JNK1 /- mice. Tumor diameters were significantly smaller in JNK1-/- mice. Phosphorylated JNK (p-JNK) was activated in alpha-smooth muscle actin (SMA) positive cells in tumor stroma, and mPC-conditioned medium activated p-JNK in tumor-associated fibroblasts (TAF) in vitro. Relative expression of Ccl20 was downregulated in stimulated TAF. Ccl20 is an important chemokine that promotes CD8+ T-cell infiltration by recruitment of dendritic cells, and the number of CD8+ T cells was decreased in Kras;JNK1+/- mice compared with Kras;JNK1-/- mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8+ T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD8+ T cells, which would be expected to enhance antitumor immunity. PMID- 28837248 TI - Stillbirth and neonatal mortality in pregnancies complicated by major congenital anomalies: Findings from a large European cohort. AB - OBJECTIVE: To provide prognostic information to help parents to reach an informed decision about termination or continuation of the pregnancy and to shape peripartum policy based on a large European cohort. METHOD: Thirteen registries from the European Surveillance of Congenital Anomalies (EUROCAT) network contributed data from January 1, 1998, to December 31, 2011. Terminations for fetal anomalies were excluded. Chromosomal anomalies, syndromes and isolated anomaly groups were distinguished according to EUROCAT guidelines. Perinatal mortality, stillbirths, and early and late neonatal mortality rates (NMRs) were analyzed by anomaly group and gestational age. RESULTS: Among 73 337 cases, perinatal mortality associated with congenital anomaly was 1.27 per 1000 births (95% confidence interval, 1.23-1.31). Average stillbirth rate was 2.68% (range 0% 51.2%). Early and late NMR were 2.75% (range 0%-46.7%) and 0.97% (range 0% 17.9%), respectively. Chromosomal anomalies and syndromes, and most isolated anomalies, had significant differences regarding timing of fetal demise compared to the general population. Chromosomal and central nervous system anomalies had higher term stillbirth rates. CONCLUSIONS: We found relevant differences between anomalies regarding rates of stillbirth, NMR, and timing by gestational age. Our data can help parents to decide about their unborn child with a congenital anomaly and help inform maternal-fetal medicine specialists regarding peripartum management. PMID- 28837249 TI - Hospital-level balloon tamponade use is associated with increased mortality for all patients presenting with acute variceal haemorrhage. AB - BACKGROUND & AIMS: Balloon tamponade (BT) can bridge patients to salvage therapy for uncontrollable acute variceal haemorrhage (AVH). However, data are limited regarding the reasons for, rate of and outcomes associated with Balloon tamponade use. METHODS: First, we performed an single-centre cohort study of all patients (N = 139) with oesophageal acute variceal haemorrhage from 01/2009 to 10/2015. Associations between Balloon tamponade use and adherence to four quality metrics (endoscopy within 12 hours, band-ligation, pre-endoscopy antibiotics and octreotide) were evaluated. Second, we analysed the National Inpatient Sample (2005-2011) to determine the association between in-hospital mortality for patients and their hospital's Balloon tamponade-utilization to acute variceal haemorrhage volume ratio. RESULTS: In the national cohort, 5.5% of 140 521 acute variceal haemorrhage admissions required Balloon tamponade utilization. Adjusting for patient- and hospital-level confounders, the rate of Balloon tamponade use per acute variceal haemorrhage managed at any given hospital was associated with increased mortality for all-comers with acute variceal haemorrhage. Compared to the lowest tertile, acute variceal haemorrhage admissions in the highest Balloon tamponade utilizers were associated with increased mortality of (OR1.17 95%CI (1.01-1.37). In the single-centre cohort, 14 (10.1%) patients required Balloon tamponade. Balloon tamponade utilization was significantly associated with alcohol abuse (50.4% vs 21.4%, P = .04), hepatocellular carcinoma (35.7% vs 8.8%, P = .01), higher median model for end-stage liver disease (MELD) score (26.3vs15.5, P = .002) and active bleeding during endoscopy (64.3% vs 27.5%, P = .01). Failure to provide all quality metrics was associated with a higher model for end-stage liver disease-adjusted risk of Balloon tamponade use: OR 16.7 95% CI(4.17-100.0, P < .0001). CONCLUSION: Balloon tamponade use is associated with severity of bleeding but may also implicate deficits in processes of care. Even for patients who did not need Balloon tamponade, presentation to hospitals with high Balloon tamponade utilization increases their odds of dying from acute variceal haemorrhage. PMID- 28837250 TI - Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer. AB - This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1-21 with carboplatin (area under the concentration-time curve 6 mg/mL*min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8 and 15 every 3 weeks for up to 6 21 day cycles. Dose escalation followed a 3 + 3 design to determine dose-limiting toxicities, maximum tolerated dose and the recommended phase 2 dose. Nine patients (median age 62 [range 27-72] years) received a median of 5 (range 3-6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose-limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer. PMID- 28837251 TI - Elevated expression of JAM-A promotes neoplastic properties of lung adenocarcinoma. AB - A cell-cell adhesion protein, junctional adhesion molecule-A (JAM-A), has been shown to be involved in neoplasia of various organs. However, the fundamental role of JAM-A in tumorigenesis is still under debate because dysregulated expression of this protein has distinct effects, playing opposite roles in carcinogenesis depending on the target tissues. In the present study, we found elevated levels of JAM-A expression in lung adenocarcinoma and its preinvasive lesions, including atypical adenomatous hyperplasia and adenocarcinoma in situ by immunohistochemistry. We also showed that suppression of constitutive JAM-A expression conferred target cells with increased susceptibility to apoptosis in lung adenocarcinoma cells. Consequently, inhibition of JAM-A activity decreased colony-forming capability in vitro and tumorigenicity in vivo. The transformed phenotype following suppression of JAM-A expression was sufficient to reduce motile and invasive capacities. Importantly, knockout of JAM-A had striking effects on cells. Our observations suggest that increased expression of JAM-A promotes neoplasia of lung adenocarcinoma. In addition, an anti-JAM-A antibody efficiently reduced cell proliferation and provoked apoptosis, indicating the potential feasibility of JAM-A-inhibitory cancer therapy. PMID- 28837252 TI - Chromobox homolog 8 is a predictor of muscle invasive bladder cancer and promotes cell proliferation by repressing the p53 pathway. AB - Chromobox homolog 8 (CBX8), also known as human polycomb 8, is a repressor that maintains the transcriptionally repressive state in various cellular genes, and has been reported to promote tumorigenesis. In the present study, we examined CBX8 expression in eight pairs of muscle invasive bladder cancer tissues and adjacent non-tumor tissues, and found that CBX8 was frequently upregulated in muscle invasive bladder cancer tissues when compared to adjacent non-tumor tissues. Analysis showed that high expression of CBX8 in 152 muscle invasive bladder cancer specimens was associated with progression of the T, N, and M stages (P = 0.004, 0.005, <0.001, respectively). Furthermore, Kaplan-Meier survival analysis and log-rank test showed that muscle invasive bladder cancer patients with high CBX8 expression had a poor rate of overall survival (P < 0.001) and 5-year recurrence-free survival (P < 0.001) compared to patients with low CBX8 expression. High CBX8 expression predicted poor overall survival and 5 year recurrence-free survival in T and N stages of muscle invasive bladder cancer patients. Moreover, knockdown of CBX8 inhibited cell proliferation of urothelial carcinoma of the bladder both in vitro and in vivo. In addition, CBX8 depletion resulted in cell cycle delay of urothelial carcinoma cells of the bladder at the G2/M phase by the p53 pathway. The data suggest that high expression of CBX8 plays a critical oncogenic role in aggressiveness of urothelial carcinoma cells of the bladder through promoting cancer cell proliferation by repressing the p53 pathway, and CBX8 could be used as a novel predictor for muscle invasive bladder cancer patients. PMID- 28837254 TI - Polyaspartates as Thermoresponsive Enantiodifferentiating Helically Chiral Alignment Media for Anisotropic NMR Spectroscopy. AB - Lyotropic liquid crystalline phases of poly-beta-phenethylaspartates are presented as new helically chiral enantiodifferentiating alignment media with thermoresponsive properties. In addition to displaying the highest enantiodifferentiation observed for homopolypeptides, the alignment media undergo a temperature induced helix reversal without perturbing the nematic phase. This offers the opportunity to measure residual dipolar couplings (RDCs) in high and low temperature helix conformation (P- and M-helix) in one polymer. Thus different mean orientations of a chiral analyte can be determined within the same sample. Furthermore, we investigated whether the resulting media are diastereomeric and whether we are able to obtain information about the alignment process. PMID- 28837253 TI - Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. AB - In cancer cells the small compounds erastin and RSL3 promote a novel type of cell death called ferroptosis, which requires iron-dependent accumulation of lipid reactive oxygen species. Here we assessed the contribution of lipid peroxidation activity of lipoxygenases (LOX) to ferroptosis in oncogenic Ras-expressing cancer cells. Several 12/15-LOX inhibitors prevented cell death induced by erastin and RSL3. Furthermore, siRNA-mediated silencing of ALOX15 significantly decreased both erastin-induced and RSL3-induced ferroptotic cell death, whereas exogenous overexpression of ALOX15 enhanced the effect of these compounds. Immunofluorescence analyses revealed that the ALOX15 protein consistently localizes to cell membrane during the course of ferroptosis. Importantly, treatments of cells with ALOX15-activating compounds accelerated cell death at low, but not high doses of erastin and RSL3. These observations suggest that tumor ferroptosis is promoted by LOX-catalyzed lipid hydroperoxide generation in cellular membranes. PMID- 28837255 TI - Role of the Chalcogen (S, Se, Te) in the Oxidation Mechanism of the Glutathione Peroxidase Active Site. AB - The oxidation by H2 O2 of the human phospholipid hydroperoxide glutathione peroxidase (GPx4), used as a model peroxidase selenoenzyme, as well as that of its cysteine (Cys) and tellurocysteine (Tec) mutants, was investigated in silico through a combined classic and quantum mechanics approach to assess the role of the different chalcogens. To perform this analysis, new parameters for selenocysteine (Sec) and tellurocysteine (Tec) were accurately derived for the AMBER ff14SB force field. The oxidation represents the initial step of the antioxidant activity of GPx, which catalyzes the reduction of H2 O2 and organic hydroperoxides by glutathione (GSH). A mechanism involving a charge-separation intermediate is feasible for the Cys and Sec enzymes, leading from the initial thiol/selenol form to sulfenic/selenenic acid, whereas for the Tec mutant a direct oxidation pathway is proposed. Activation strain analyses, performed for Cys-GPx and Sec-GPx, provided insight into the rate-accelerating effect of selenium as compared to sulfur and the role of specific amino acids other than Cys/Sec that are typically conserved in the catalytic pocket. PMID- 28837256 TI - On the Role of Chirality in Guiding the Self-Assembly of Peptides. AB - Homochirality in peptides is crucial in sustaining "like-like" intermolecular interactions that allow the formation of assemblies and aggregates and is ultimately responsible for the resulting material properties. With the help of a series of stereoisomers of the tripeptide F-F-L, we demonstrate the critical role that peptide stereochemistry plays in the self-assembly of peptides, guided by molecular recognition, and for self-sorting. Homochiral self-assemblies are thermally and mechanically more robust compared to heterochiral self-assemblies. Morphological studies of the multicomponent peptide systems showed that aggregates formed from homochiral peptides possessed a uniform nano-fibrous structure, whereas heterochiral systems resulted in self-sorted systems with a heterogeneous morphology. In essence, homochiral peptides form the stronger aggregates, which may be one of reasons why homochirality is preferred in living systems. PMID- 28837257 TI - Platinum Nanoparticle Impacts at a Liquid|Liquid Interface. AB - Single nanoparticle (NP) electrochemistry detection at a micro liquid|liquid interface (LLI) is exploited using the catalyzed oxygen reduction reaction (ORR). In this way, current spikes reminiscent of nanoimpacts were recorded, which corresponded to electrocatalytic enhancement of the ORR by Pt NPs. The nature of the LLI allows exploration of new phenomena in single NP electrochemistry. The recorded impacts result from a bipolar reaction occurring at the Pt NP straddling the LLI. O2 reduction takes place in the aqueous phase, while ferrocene hydride (Fc-H+ ; a complex generated upon facilitated interfacial proton transfer by Fc) is oxidized in the organic phase. Ultimately, the role of reactant partitioning, NP bouncing, or the ability of NPs to induce Marangoni effects, is demonstrated. PMID- 28837259 TI - Adaptation despite gene flow? Low recombination helps. AB - About 15,000 years earlier, the Northern half of Europe and North America was buried under a few kilometres of ice. Since then, many organisms have colonized and rapidly adapted to the new, vacant habitats. Some, like the threespine stickleback fish, have done so more successfully than others: from the sea, stickleback have adapted to a multitude of lake and stream habitats with a vast array of complex phenotypes and life histories. Previous studies showed that most of these "ecotypes" differ in multiple divergently selected genes throughout the genome. But how are well-adapted ecotypes of one habitat protected from maladaptive gene flow from ecotypes of another, adjacent habitat? According to a From the Cover meta-analysis in this issue of Molecular Ecology (Samuk et al., 2017), low recombination rate regions in the genome offer such protection. While inversions have often been highlighted as an efficient way to maintain linkage disequilibrium among sets of adaptive variants in the face of gene flow, Samuk et al. (2017) show that variation in recombination rate across the genome may perform a similar role in threespine stickleback. With this study, theoretical predictions for the importance of low recombination regions in adaptation are for the first time tested with a highly replicated population genomic data set. The findings from this study have implications for the adaptability of species, speciation and the evolution of genome architecture. PMID- 28837258 TI - Diagnostic and prognostic role of urinary collagens in primary human bladder cancer. AB - Collagen type 4 alpha 1 (COL4A1) and collagen type 13 alpha 1 (COL13A1) produced by urothelial cancer cells support the vital oncogenic property of tumor invasion. We investigated the diagnostic and prognostic capability of COL4A1 and COL13A1 in voided urine and compared the observed values with those of fragments of cytokeratin-19 (CYFRA21-1), nuclear matrix protein 22 (NMP-22), and voided urine cytology in bladder cancer (BCa). We collected voided urine samples from 154 patients newly diagnosed with BCa, before surgery and from 61 control subjects. Protein levels of COL4A1, COL13A1, CYFRA21-1, and NMP-22 in urine supernatants were measured using enzyme-linked immunosorbent assays. Diagnostic performance and optimal cut-off values were determined by receiver operating characteristic analysis. Urine levels of COL4A1, COL13A1, the combined values of COL4A1 and COL13A1 (COL4A1 + COL13A1), and CYFRA21-1 were significantly elevated in urine from patients with BCa compared to the controls. Among these biomarkers, the optimal cut-off value of COL4A1 + COL13A1 at 1.33 ng/mL resulted in 57.4%, 83.7%, 56.1%, 80.7%, and 91.7% sensitivity for low-grade tumors, high-grade tumors, Ta, T1, and muscle invasive disease, respectively. We evaluated the prognostic value of preoperative urine levels in 130 non-muscle invasive BCa samples after the initial transurethral surgery. A high urinary COL4A1 + COL13A1 was found to be an independent risk factor for intravesical recurrence. Although these data need to be externally validated, urinary COL4A1 and COL13A1 could be a potential diagnostic and prognostic biomarker for BCa. This easy-to-use urinary signature identifies a subgroup of patients with a high probability of recurrence and progression in non-muscle invasive and muscle invasive BCa. PMID- 28837260 TI - A Selective Biligand Inhibitor of CK2 Increases Caspase-3 Activity in Cancer Cells and Inhibits Platelet Aggregation. AB - Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5 yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a Kd value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub micromolar concentrations (EC50 =0.3 MUm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development. PMID- 28837261 TI - Detection of free oxygen and water vapor in fertilized and unfertilized eggs by diode laser spectroscopy-Exploration of diagnostics possibilities. AB - Nonintrusive methods for characterizing food products are of increasing interest related to the greater awareness of food safety issues. Hen eggs are an important part in food consumption in most parts of the world. We have investigated an optical method utilizing tunable diode lasers for monitoring free gas in eggs. We show that oxygen signals, recorded around 760 nm, increase steadily as eggs become older. Further, we investigated fertilized eggs, which show a quite different temporal behavior during the hatching time. The oxygen signal decreases here with time, while water vapor, recorded around 937 nm, shows a steady increase. Conclusions regarding the size of the air cell and the oxygen availability in fertilized eggs are drawn. The technique might be developed for automatic control of egg freshness, as well as for assessing if eggs are fertilized or not. PMID- 28837262 TI - Evaluating the potential for weed seed dispersal based on waterfowl consumption and seed viability. AB - BACKGROUND: Migratory waterfowl have often been implicated in the movement of troublesome agronomic and wetland weed species. However, minimal research has been conducted to investigate the dispersal of agronomically important weed species by waterfowl. The two objectives for this project were to determine what weed species are being consumed by ducks and snow geese, and to determine the recovery rate and viability of 13 agronomic weed species after passage through a duck's digestive system. RESULTS: Seed recovered from digestive tracts of 526 ducks and geese harvested during a 2-year field study had 35 020 plants emerge. A greater variety of plant species emerged from ducks each year (47 and 31 species) compared to geese (11 and 3 species). Viable seed from 11 of 13 weed species fed to ducks in a controlled feeding study were recovered. Viability rate and gut retention times indicated potential dispersal up to 2900 km from the source depending on seed characteristics and variability in waterfowl dispersal distances. CONCLUSIONS: Study results confirm that waterfowl are consuming seeds from a variety of agronomically important weed species, including Palmer amaranth, which can remain viable after passage through digestive tracts and have potential to be dispersed over long distances by waterfowl. (c) 2017 Society of Chemical Industry. PMID- 28837263 TI - Magnetic micro-solid-phase extraction based on magnetite-MCM-41 with gas chromatography-mass spectrometry for the determination of antidepressant drugs in biological fluids. AB - A new facile magnetic micro-solid-phase extraction coupled to gas chromatography and mass spectrometry detection was developed for the extraction and determination of selected antidepressant drugs in biological fluids using magnetite-MCM-41 as adsorbent. The synthesized sorbent was characterized by several spectroscopic techniques. The maximum extraction efficiency for extraction of 500 MUg/L antidepressant drugs from aqueous solution was obtained with 15 mg of magnetite-MCM-41 at pH 12. The analyte was desorbed using 100 MUL of acetonitrile prior to gas chromatography determination. This method was rapid in which the adsorption procedure was completed in 60 s. Under the optimized conditions using 15 mL of antidepressant drugs sample, the calibration curve showed good linearity in the range of 0.05-500 MUg/L (r2 = 0.996-0.999). Good limits of detection (0.008-0.010 MUg/L) were obtained for the analytes with good relative standard deviations of <8.0% (n = 5) for the determination of 0.1, 5.0, and 500.0 MUg/L of antidepressant drugs. This method was successfully applied to the determination of amitriptyline and chlorpromazine in plasma and urine samples. The recoveries of spiked plasma and urine samples were in the range of 86.1-115.4%. Results indicate that magnetite micro-solid-phase extraction with gas chromatography and mass spectrometry is a convenient, fast, and economical method for the extraction and determination of amitriptyline and chlorpromazine in biological samples. PMID- 28837266 TI - Covalent dimerization of interleukin-like epithelial-to-mesenchymal transition (EMT) inducer (ILEI) facilitates EMT, invasion, and late aspects of metastasis. AB - The interleukin-like epithelial-to-mesenchymal transition (EMT) inducer (ILEI)/FAM3C is a member of the highly homologous FAM3 family and is essential for EMT and metastasis formation. It is upregulated in several cancers, and its altered subcellular localization strongly correlates with poor survival. However, the mechanism of ILEI action, including the structural requirements for ILEI activity, remains elusive. Here, we show that ILEI formed both monomers and covalent dimers in cancer cell lines and in tumors. Using mutational analysis and pulse-chase experiments, we found that the four ILEI cysteines, conserved throughout the FAM3 family and involved in disulfide bond formation were essential for extracellular ILEI accumulation in cultured cells. Modification of a fifth cysteine (C185), unique for ILEI, did not alter protein secretion, but completely inhibited ILEI dimerization. Wild-type ILEI monomers, but not C185A mutants, could be converted into covalent dimers extracellularly upon overexpression by intramolecular-to-intermolecular disulfide bond isomerization. Incubation of purified ILEI with cell culture medium showed that dimerization was triggered by bovine serum in a dose- and time-dependent manner. Purified ILEI dimers induced EMT and trans-well invasion of cancer cells in vitro. In contrast, ILEI monomers and the dimerization-defective C185A mutant affected only cell motility as detected by scratch assays and cell tracking via time-lapse microscopy. Importantly, tumor cells overexpressing wild-type ILEI caused large tumors and lung metastases in nude mice, while cells overexpressing the dimerization-defective C185A mutant behaved similar to control cells. These data show that covalent ILEI self-assembly is essential for EMT induction, elevated tumor growth, and metastasis. PMID- 28837267 TI - Sequence identification, serological reactivity and family genetics of a novel HLA allele, HLA-A*26:82. AB - HLA-A*26:82 was identified by sequence-based typing and showed the serological specificity of A26. PMID- 28837264 TI - RNA on the brain: emerging layers of post-transcriptional regulation in cerebral cortex development. AB - Embryonic development is a critical period during which neurons of the brain are generated and organized. In the developing cerebral cortex, this requires complex processes of neural progenitor proliferation, neuronal differentiation, and migration. Each step relies upon highly regulated control of gene expression. In particular, RNA splicing, stability, localization, and translation have emerged as key post-transcriptional regulatory nodes of mouse corticogenesis. Trans regulators of RNA metabolism, including microRNAs (miRs) and RNA-binding proteins (RBPs), orchestrate diverse steps of cortical development. These trans-factors function either individually or cooperatively to influence RNAs, often of similar classes, termed RNA regulons. New technological advances raise the potential for an increasingly sophisticated understanding of post-transcriptional control in the developing neocortex. Many RNA-binding factors are also implicated in neurodevelopmental diseases of the cortex. Therefore, elucidating how RBPs and miRs converge to influence mRNA expression in progenitors and neurons will give valuable insights into mechanisms of cortical development and disease. WIREs Dev Biol 2018, 7:e290. doi: 10.1002/wdev.290 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory RNA Nervous System Development > Vertebrates: Regional Development Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease. PMID- 28837265 TI - Exposure to BMAA mirrors molecular processes linked to neurodegenerative disease. AB - The goal of this study is to investigate the molecular pathways perturbed by in vitro exposure of beta-methylamino-L-alanine (BMAA) to NSC-34 cells via contemporary proteomics. Our analysis of differentially regulated proteins reveals significant enrichment (p < 0.01) of pathways related to ER stress, protein ubiquitination, the unfolded protein response, and mitochondrial dysfunction. Upstream regulator analysis indicates that exposure to BMAA induces activation of transcription factors (X-box binding protein 1; nuclear factor 2 erythroid like 2; promyelocytic leukemia) involved in regulation of the UPR, oxidative stress, and cellular senescence. Furthermore, the authors examine the hypothesis that BMAA causes protein damage via misincorporation in place of L Serine. The authors are unable to detect misincorporation of BMAA into protein via analysis of cellular protein, secreted protein, targeted detection of BMAA after protein hydrolysis, or through the use of in vitro protein translation kits. PMID- 28837268 TI - Core-needle biopsy of breast cancer is associated with a higher rate of distant metastases 5 to 15 years after diagnosis than FNA biopsy. AB - BACKGROUND: The literature offers discordant results regarding whether diagnostic biopsy is associated with the dissemination of cancer cells, resulting in local and/or distant metastasis. The long-term outcomes of patients with breast cancer were compared between those who were diagnosed using either fine-needle aspiration biopsy (FNAB) or core-needle biopsy (CNB) during 2 decades: the 1970s and 1990s. METHODS: In the 1970s, the only diagnostic needle biopsy method used for breast cancer in Sweden was FNAB. CNB was introduced 1989 and became established in Stockholm Gotland County in the early 1990s. The authors compared the clinical outcomes of patients diagnosed using FNAB from 1971 to 1976 (n = 354) versus those of patients diagnosed using CNB from 1991 to 1995 (n = 1729). Adjusting for differences in various treatment modalities, mammography screening, tumor size, DNA ploidy, and patient age between the 2 decades, 2 strictly matched samples representing FNAB (n = 181) and CNB (n = 203) were selected for a 15-year follow-up study. RESULTS: In a comparison of the rates of distant metastasis in the strictly matched patient groups from the FNAB and CNB cohorts, significantly higher rates of late-appearing (5-15 years after diagnosis) distant metastasis were observed among the patients who were diagnosed on CNB compared with those who were diagnosed on FNAB. No significant difference in local metastasis was observed between the 2 groups. CONCLUSIONS: At 5 to 15 years after diagnosis of the primary tumor, CNB-diagnosed patients had significantly higher rates of distant metastases than FNAB-diagnosed patients. Cancer Cytopathol 2017;125:748 56. (c) 2017 American Cancer Society. PMID- 28837269 TI - Primum Non Nocere. PMID- 28837270 TI - Nanoscale imaging and sensing for biomedical applications. PMID- 28837271 TI - CYTO 2017 Award Recipients. PMID- 28837272 TI - Corrigendum to Quantification Methods for Human and Large Animal Leukocytes Using DNA Dyes by Flow Cytometry. doi:10.1002/cyto.a.22874, Cytometry Part A 2016; 89A (6): 565-574. PMID- 28837273 TI - PNL2: an adjunctive biomarker for renal angiomyolipomas and perivascular epithelioid cell tumours. AB - AIMS: Renal angiomyolipoma (AML) and perivascular epithelioid cell tumour (PEComa) are members of the microphthalmia-associated transcription factor (MiTF) family of tumours. Traditionally, HMB45 and melan-A have been used to diagnose these lesions; however, low sensitivity can make interpretation difficult. PNL2 is a sensitive and specific biomarker for epithelioid melanoma, and immunoreactivity has also been shown in small series of PEComas. This study was aimed at determining the utility of PNL2 in MiTF and non-MiTF renal tumours. METHODS AND RESULTS: PNL2 immunostaining was performed on 196 tumours, including 40 MiTF renal tumours [AMLs, epithelioid AMLs, sclerosing PEComas, malignant PEComas, and Xp11.2 renal cell carcinomas (RCCs)] and 156 non-MiTF renal tumours. HMB45, melan-A and cathepsin K were also evaluated in a subset of MiTF tumours. Overall, 85% of AMLs and PEComas were positive for PNL2, as compared with 81%, 76% and 95% that were positive for HMB45, melan-A, and cathepsin K, respectively. In 55% of cases, PNL2 stained more extensively than HMB45. PNL2 staining was more frequent than HMB45 (78%) and melan-A (38%) staining in sclerosing and malignant PEComas (89%). All remaining renal tumours, except one melanocytic Xp11.2 RCC, were negative for PNL2. CONCLUSIONS: PNL2 has high sensitivity and specificity for AML and PEComas as compared with non-MiTF renal tumours, and PNL2 appears to be a more useful biomarker for sclerosing and malignant PEComas. For cases that are limited in tissue quantity (i.e. core biopsies) and/or are morphologically suspicious for AML/PEComa, but negative or focally positive for HMB45 and melan A, PNL2 may be a useful adjunctive biomarker. PMID- 28837274 TI - Association Between Bone Mineral Density and Depressive Symptoms in a Population Based Sample. AB - OBJECTIVE: This analysis was conducted to determine the relationship between bone mineral density (BMD) and depressive symptoms in a population-based cohort. METHODS: Data were extracted from the second phase of the Dallas Heart Study (DHS 2), a large, multiethnic population sample in Dallas County, Texas, from September 1, 2007, to December 31, 2009. Depressive symptom severity was measured with the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS SR16), which is derived from DSM-IV major depressive disorder criteria. BMD was measured using dual-energy x-ray absorptiometry. Multiple linear regressions examined the relationship between QIDS-SR16 score and BMD controlling for age, body mass index, sex, ethnicity, smoking status, alcohol use status, serum 25 hydroxyvitamin D concentration, antidepressant use, and physical activity as measured by total vigorous and moderate metabolic equivalents. Subgroup analyses explored differences related to age. RESULTS: QIDS-SR16 score was not a significant predictor of either lumbar spine or total hip T-score (beta = -0.01, P = .61 and beta = -0.02, P = .39) in the overall population (n = 2,285). There was a significant negative interaction term between age and QIDS-SR16 group (beta = -0.01, P = .01). In participants aged 60 years or older (n = 465), QIDS-SR16 score was a significant predictor of BMD at the lumbar spine and total hip (beta = -0.14, P = .003 and beta = -0.12, P = .006, respectively). CONCLUSIONS: QIDS SR16 score did not significantly predict BMD in the overall DHS-2 sample. There was, however, a significant association observed in participants aged >= 60 years. Results suggest that diagnosis and treatment of depressive symptoms may be of clinical importance in older individuals, a subgroup at high risk for osteoporosis and fractures. PMID- 28837275 TI - ? PMID- 28837276 TI - [Why to treat a total chronic coronary occlusion?] AB - Despite an incidence of about 15% of the patients undergoing coronary angiography, total chronic occlusions (CTO) are rarely revascularized by percutaneous angioplasty (PCI). Nevertheless, current evidence suggest that successful CTO-PCI improve symptoms, quality of live and long-term survival. During the last years, improvement of specific techniques for these complexes procedures and increasing experience of operators allow actually to obtain success and complications rates almost equivalent to non-CTO lesions angioplasty. This review focus on the clinical benefits of CTO revascularization and on appropriate patient selection. PMID- 28837277 TI - [DPP-4 or SGLT2 inhibitor added to metformin alone in type 2 diabetes]. AB - After failure of a monotherapy with metformin, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium-glucose cotransporters type 2 (gliflozins) offer an alternative to the add-on of a sulphonylurea, especially in diabetic patients at risk of hypoglycaemia. The choice between a gliptin and a gliflozin may be guided by the individual patient characteristics : rather a gliptin in a patient without obesity or severe hyperglycaemia, in an elderly patient, with a frailty profile or with renal impairment; rather a gliflozin in an obese patient, with hypertension, hyperuricaemia, antecedents of cardiovascular disease (especially heart failure), without advanced renal insufficiency and with a low risk of urinary/genital infections or events linked to dehydration such as hypotension. PMID- 28837278 TI - [Therapeutic options for a type 2 diabetic patient not well controlled with metformin plus basal insulin]. AB - In a patient with type 2 diabetes not well controlled with a basal insulin - metformin combination, several therapeutic options may be considered: intensifying insulin therapy with different schemes (appropriate titration using a more favourable basal insulin analogue, adding one, two or three rapid-acting insulin analogues, shift to two or three premix insulin injections), adding a dipeptidyl peptidase-4 inhibitor (gliptin) or an inhibitor of sodium-glucose cotransporters type 2 (gliflozin), or combining a glucagon-like peptide-1 receptor agonist with basal insulin. The choice should be made according the individual profile and preference of the patient, in a personalized approach, taking into account the advantages and disadvantages of each therapeutic solution. PMID- 28837279 TI - [Cardiorenal protection with SGLT2 inhibitors (gliflozins) : from EMPA-REG OUTCOME to CANVAS]. AB - The cardiovascular (CV) and renal protection reported with empagliflozin in EMPA REG OUTCOME is now confirmed with canagliflozin in CANVAS in patients with type 2 diabetes and high cardiovascular risk: similar and significant reductions in major CV events (-14 vs. -14%), in hospitalisations for heart failure (-35 vs. 33%) and in renal events (-39 vs. -40%). The greater reduction in CV mortality ( 38 vs. - 13%) and all-cause mortality (-32 vs. -13%) in EMPA-REG OUTCOME than in CANVAS may be explained by the greater proportion of patients with CV disease (secondary prevention : 99 vs. 65%). In contrast to EMPA-REG OUTCOME, CANVAS did not show an increase in stroke (-10%, NS), but reported a higher rate of fractures and amputations with canagliflozin. Overall, these results support a class effect for the cardiorenal protection by inhibitors of sodium-glucose type 2 (SGLT2) cotransporters. PMID- 28837280 TI - [Proton-pump inhibitors and risk of kidney disease]. AB - Regarded as safe and effective for management of upper peptic ulcer disease due to gastric acid secretion, the proton pump inhibitors are among the most commonly prescribed drugs. Their use, however, is not without concerns. Acute kidney injury, mainly due to acute interstitial nephritis, could happen 1.5 to 2 times more frequently when using these drugs. Moreover, a risk for chronic kidney disease has also be noted with proton pump inhibitor use (1.15 to 1.8 increased risk), although biases may exist due to confounding factors related to the observational nature of the studies. So, caution is required before available results from good prospective randomized studies are available. Renal function should be checked when using these medications and timely cessation should be advised when there is no more clear indication for use. PMID- 28837282 TI - [2017 vaccination guidelines update and practical review of vaccination schedule for practitioners]. AB - This article presents the 2017 revised immunization schedule published by the Swiss Federal Office of Public Health focusing notably on 1) acellular pertussis vaccinations before each pregnancy, 2) acellular pertussis booster every 10 years for all adults in regular contact with infants under 6 months, 3) DTPa-IPV booster with reduced diphtheria and pertussis antigen content possible from 4 years of age, when the combined DTPa-IPV vaccinations are not available. This paper also includes the main vaccination guideline updates published in recent years, for use by general practitioners, gynecologists, pediatricians and all other healthcare professionals involved in spreading information on vaccination guidelines. We also review the different vaccination information supports available for general practitioners and the public at large. PMID- 28837281 TI - [Interest of confocal endomicroscopy for the management of chronic inflammatory bowel disease]. AB - Inflammatory bowel diseases are chronic diseases whose long-term evolution depends on the depth of remission. Their clinical and endoscopic evaluation is imperfect. The development of confocal endomicroscopy allows microscopic images to be obtained in vivo. These microscopic data are correlated with the activity of the disease. They predict a possible relapse of the disease and also predict the response to treatment with a biological agent, which allows to modify the therapy before the relapse or to make a rational choice between the different biological agents before introducing a new treatment. PMID- 28837283 TI - ? PMID- 28837285 TI - ? PMID- 28837284 TI - ? PMID- 28837287 TI - ? PMID- 28837286 TI - ? PMID- 28837288 TI - ? PMID- 28837289 TI - ? PMID- 28837290 TI - ? PMID- 28837291 TI - [Prehospital misconceptions]. AB - We confronted some of the most prevalent prehospital misconceptions with the available literature. We found that: the diminution of a retrosternal pain following nitrate administration is not predictive of a cardiac origin of the pain ; survival of traumatic cardiac arrest may not be as bad as usually believed ; peripheral venous administration of vasopressors through proximal catheters during short times may be considered as a safe temporary alternative to central venous access ; using the pulse palpation usually lead to an under-estimation of the systolic blood pressure ; applying a pelvic belt at the level of the iliac crests doesn't aggravate an open-book fracture; there is no 90 mmHg threshold values below which mortality increases in traumatic brain injuries. PMID- 28837292 TI - [Position of a patient in emergency situations : lots of experiences, few evidences]. AB - In emergency situations, regularly trained technical skills return as automatisms. This is so with the positioning of our critical patients. According to their signs and symptoms (e.g. respiratory distress, unconsciousness, hypotension), they will be installed immediately in a semi-sitting position, in the recovery position, in the Trendelenburg position or with raised legs. But are these gestures repeated and transmitted to successive generations of caregivers really effective and safe? Do we understand the original context and purpose in which these positions were invented? Here we review three of the most common positions in emergency medicine, reminding ourselves of their contextual origin, as well as existing evidence and limits to their use. It is up to you to judge whether they remain relevant in your clinical practice. PMID- 28837293 TI - [" Golden hour " and the Sellick manoeuvre in emergency care: we must not throw out the baby with the bathwater]. AB - This article evaluates 3 controversial subjects of pre-hospital emergency care : 1) The concept of the " Golden hour " predicates an increased morbidity and mortality for injured patients, if pre-hospital care exceeds 1 hour. In the subgroup of patients presenting with severe hemorrhagic injuries or penetrating trauma to the torso, a transport of 60 minutes or less decreases mortality ; 2) The Sellick manoeuvre is used to decrease the risk of bronchoaspiration in patients undergoing an emergency intubation. In view of the low incidence of bronchoaspiration and the inherent risks of cricoid pressure, it should be used only in selected patients ; 3) Improvised cricothyroidotomy using non-medical devices may be feasible if a knife to perform an incision in the cricothyroid membrane and an endotracheal tube of sufficient diameter are available. PMID- 28837294 TI - [Emergency medecine : myths in hospital care]. AB - Many of our medical procedures are conditioned by beliefs or experiences by our mentors, which we pass on to the younger, for example: gradually emptying a full bladder to avoid hypotension or haemorrhage, hydrating the alcoholic so that the blood alcohol level decreases faster, always obtaining an arterial blood gas instead of a venous one and not injecting iodinated intravenous contrast in patients allergic to shellfish. PMID- 28837295 TI - [Cutaneous surgery myths and traditions in the Emergency Department]. AB - Traditions and myths die hard in many fields of medicine but especially in the field of cutaneous surgical emergencies. In a few selected paragraphs, we set out to undo some of these myths with the aim of a less ritualized approach to daily gestures. PMID- 28837296 TI - [Astronomical bodies, disasters and superstitions]. AB - The belief that a full moon or Friday the 13th or some specific doctors are associated with busier shifts in the emergency room is still widespread among caregivers. Although such a topic may seem anecdotal, even folkloric, it has been the subject of several studies that have shown that there is no association between these factors and the number of emergency room admissions or type of pathology. It is not certain that an evidence-based approach is sufficient to eliminate such beliefs because their existence also responds to an attempt to put some semblance of meaning into the chaotic and stressful activity of emergencies. PMID- 28837298 TI - ? PMID- 28837297 TI - [Paradoxical vocal fold motion, a real breathing problem : diagnosis and treatment]. AB - The paradoxical vocal fold motion (PVFM) is a temporary total inability to breathe, which is important to rule out from other more or less important breathing difficulties encountered in asthma. Overtreatment for asthma instead of treatment for PVFM can lead to iatrogenic complications which can be averted by early and correct diagnosis. This article presents a list of symptoms and related disorders, enabling to more easily diagnose PVFM, as well as its specifics treatments and a " Block-unblock maneuver " not yet described in the literature, allowing the patient to respond to the crisis and to prevent future crises. PMID- 28837299 TI - ? PMID- 28837300 TI - ? PMID- 28837301 TI - ? PMID- 28837302 TI - ? PMID- 28837303 TI - ? PMID- 28837308 TI - Human African trypanosomiasis diagnosis by peripheral blood smear review in a Spanish traveler PMID- 28837309 TI - Systemic AL amyloidosis associated with Waldenstrom macroglobulinemia: an unusual presenting complication PMID- 28837310 TI - Lymphocytic variant of hypereosinophilic syndrome mimicking peripheral T-cell lymphoma in a young woman PMID- 28837311 TI - Boron-Doped Graphite for High Work Function Carbon Electrode in Printable Hole Conductor-Free Mesoscopic Perovskite Solar Cells. AB - Work function of carbon electrodes is critical in obtaining high open-circuit voltage as well as high device performance for carbon-based perovskite solar cells. Herein, we propose a novel strategy to upshift work function of carbon electrode by incorporating boron atom into graphite lattice and employ it in printable hole-conductor-free mesoscopic perovskite solar cells. The high-work function boron-doped carbon electrode facilitates hole extraction from perovskite as verified by photoluminescence. Meanwhile, the carbon electrode is endowed with an improved conductivity because of a higher graphitization carbon of boron-doped graphite. These advantages of the boron-doped carbon electrode result in a low charge transfer resistance at carbon/perovskite interface and an extended carrier recombination lifetime. Together with the merit of both high work function and conductivity, the power conversion efficiency of hole-conductor-free mesoscopic perovskite solar cells is increased from 12.4% for the pristine graphite electrode-based cells to 13.6% for the boron-doped graphite electrode-based cells with an enhanced open-circuit voltage and fill factor. PMID- 28837312 TI - Compound Specific Stable Chlorine Isotopic Analysis of Volatile Aliphatic Compounds Using Gas Chromatography Hyphenated with Multiple Collector Inductively Coupled Plasma Mass Spectrometry. AB - Stable chlorine isotope analysis is increasingly used to characterize sources, transformation pathways, and sinks of organic aliphatic compounds, many of them being priority pollutants in groundwater and the atmosphere. A wider use of chlorine isotopes in environmental studies is still inhibited by limitations of the different analytical techniques such as high sample needs, offline preparation, confinement to few compounds and mediocre precision, respectively. Here we present a method for the delta37Cl determination in volatile aliphatic compounds using gas chromatography coupled with multiple-collector inductively coupled plasma mass spectrometry (GC-MC-ICPMS), which overcomes these limitations. The method was evaluated by using a suite of five previously offline characterized in-house standards and eight chlorinated methanes, ethanes, and ethenes. Other than in previous approaches using ICP methods for chlorine isotopes, isobaric interference of the 36ArH dimer with 37Cl was minimized by employing dry plasma conditions. Samples containing 2-3 nmol Cl injected on column were sufficient to achieve a precision (sigma) of 0.1 mUr (1 milliurey = 0.001 = 10/00) or better. Long-term reproducibility and accuracy was always better than 0.3 mUr if organics were analyzed in compound mixtures. Standardization is carried out by using a two-point calibration approach. Drift, even though very small in this study, is corrected by referencing versus an internal standard. The presented method offers a direct, universal, and compound specific procedure to measure the delta37Cl of a wide array of organic compounds overcoming limitations of previous techniques with the benefits of high sensitivity and accuracy comparable to the best existing approaches. PMID- 28837313 TI - Artificial Synapses with Short- and Long-Term Memory for Spiking Neural Networks Based on Renewable Materials. AB - Emulation of biological synapses that perform memory and learning functions is an essential step toward realization of bioinspired neuromorphic systems. Artificial synaptic devices have been developed based mostly on inorganic materials and conventional semiconductor device fabrication processes. Here, we propose flexible biomemristor devices based on lignin by a simple solution process. Lignin is one of the most abundant organic polymers on Earth and is biocompatible, biodegradable, as well as environmentally benign. This memristor emulates several essential synaptic behaviors, including analog memory switching, short-term plasticity, long-term plasticity, spike-rate-dependent plasticity, and short-term to long-term transition. A flexible lignin-based artificial synapse device can be operated without noticeable degradation under mechanical bending test. These results suggest lignin can be a promising key component for artificial synapses and flexible electronic devices. PMID- 28837314 TI - Thieno[3,2-b]pyrrolo-Fused Pentacyclic Benzotriazole-Based Acceptor for Efficient Organic Photovoltaics. AB - A novel nonfullerene small molecular acceptor (BZIC) based on a ladder-type thieno[3,2-b]pyrrolo-fused pentacyclic benzotriazole core (dithieno[3,2 b]pyrrolobenzotriazole, BZTP) and end-capped with 1,1-dicyanomethylene-3-indanone (INCN) has been first reported in this work. Through introducing multifused benzotriazole and INCN, BZIC could maintain a high-lying lowest unoccupied molecular orbital (LUMO) energy level of -3.88 eV. Moreover, BZIC shows a low optical bandgap of 1.45 eV with broad and efficient absorption band from 600 to 850 nm due to increased pi-pi interactions by the covalently locking thiophene and benzotriazole units. A power conversion efficiency of 6.30% is delivered using BZIC as nonfullerene acceptor and our recently synthesized hexafluoroquinoxaline-based polymer HFQx-T as donor. This is the first time to synthesize mutifused benzotriazole-based molecules as nonfullerene electron acceptor up to date. The preliminary results demonstrate that the mutifused benzotriazole derivatives hold great potential for efficient photovoltaics. PMID- 28837315 TI - Diketopyrrolopyrrole-Based Photosensitizers Conjugated with Chemotherapeutic Agents for Multimodal Tumor Therapy. AB - For synergistic cancer therapy, it is highly desirable to devise a single multifunctional agent to combine photodynamic therapy (PDT), photothermal therapy (PTT), and chemotherapy, which is soluble and excitable at low irradiation, as well as able to selectively target tumors and achieve high efficacy. Toward this ambition, here the chemotherapy drugs chlorambucil (Cb), and all trans retinoic acid (ATRA) are covalently conjugated onto a small dye molecule diketopyrrolopyrrole (DPP-Cb and DPP-ATRA). The soluble nanoparticles (NPs) of DPP-Cb and DPP-ATRA formed by reprecipitation can selectively accumulate in tumors, release chemotherapy drugs under acidic conditions, and exhibit efficient reactive oxygen species (ROS) generation and photothermal conversion under the irradiation of a low power xenon lamp (40 mW/cm2). We show in vitro and in vivo that both NPs can effectively kill cancer cells and suppress cancer growth at a low dose (0.4 mg/kg). PMID- 28837316 TI - Size Controllable, Transparent, and Flexible 2D Silver Meshes Using Recrystallized Ice Crystals as Templates. AB - Ice templates have been widely utilized for the preparation of porous materials due to the obvious advantages, such as environmentally benign and applicable to a wide range of materials. However, it remains a challenge to have controlled pore size as well as dimension of the prepared porous materials with the conventional ice template, since it often employs the kinetically not-stable growing ice crystals as the template. For example, there is no report so far for the preparation of 2D metal meshes with tunable pore size based on the ice template, although facile and eco-friendly prepared metal meshes are highly desirable for wearable electronics. Here, we report the preparation of 2D silver meshes with tunable mesh size employing recrystallized ice crystals as templates. Ice recrystallization is a kinetically stable process; therefore, the grain size of recrystallized ice crystals can be easily tuned, e.g., by adding different salts and changing the annealing temperature. Consequently, the size and line width of silver meshes obtained after freeze-drying can be easily adjusted, which in turn varied the conductivity of the obtained 2D silver film. Moreover, the silver meshes are transparent and display stable conductivity after the repeated stretching and bending. It can be envisioned that this approach for the preparation of 2D conducting films is of practical importance for wearable electronics. Moreover, this study provides a generic approach for the fabrication of 2D meshes with a controllable pore size. PMID- 28837317 TI - Designing Pd-N-Heterocyclic Carbene Complexes for High Reactivity and Selectivity for Cross-Coupling Applications. AB - Over the past decade, the use of Pd-NHC complexes in cross-coupling applications has blossomed, and reactions that were either not previously possible or possible only under very forcing conditions (e.g., > 100 degrees C, strong base) are now feasible under mild conditions (e.g., room temperature, weak base). Access to tools such as computational chemistry has facilitated a much greater mechanistic understanding of catalytic cycles, which has enabled the design of new NHC ligands and accelerated advances in cross-coupling. With these elements of rational design, highly reactive Pd-NHC complexes have been invented to catalyze the selective formation of single products in a variety of transformations that have the potential to afford multiple compounds (e.g., isomers). Pd-NHC catalysts may be prepared as stable Pd(II) precatalysts that are readily reduced to the active Pd(0) species in the presence of an organometallic cross-coupling partner or nucleophile possessing beta-hydrogens. It has been found from computational and experimental results that Pd-NHC complexes bearing a single bulky NHC ligand are well-suited to tackle challenging cross-coupling reactions. N-Aryl substituted imidazole-2-ylidenes with branched alkyl chains at the ortho positions of the aryl group are effective for the challenging couplings of hindered biaryls, secondary alkyl organozincs, electron-deficient anilines, alpha amino esters, primary alkylamines, and ammonia. The bulk of the NHC has been tuned by increasing the size of the alkyl groups at the ortho positions and substituting the NHC core with chlorine substituents. All of the cross-coupling transformations studied benefit from the increased bulk when the ortho groups are changed from methyl to 2-propyl to 3-pentyl. However, there is a limit to the positive effect of steric bulk, as some reactions do not benefit from the increased size of the 4-heptyl group compared with 3-pentyl. Thus, there is an optimum size for the NHC ligand that depends upon whether reactivity (turnover frequency and turnover number), selectivity, or both are needed to obtain the desired reaction outcome. In the cases that we have studied, reactivity and selectivity increase together (i.e., the fastest catalyst is also the most selective), allowing cross-couplings to be carried out under mild conditions to obtain one product with high selectivity. This Account focuses on seminal literature reports that have disclosed new Pd-NHC complexes that have led to significant breakthroughs in efficacy for challenging couplings while demonstrating high selectivity for the desired target. These catalysts have been used widely in materials science, pharmaceutical, and agrochemical applications. PMID- 28837318 TI - Rapid Isolation of Centromeres from Scheffersomyces stipitis. AB - Centromeres (CENs) are the chromosomal regions promoting kinetochore formation for faithful chromosome segregation. In yeasts, CENs have been recognized as the essential elements for extra-chromosomal DNA stabilization. However, the epigeneticity of CENs makes their localization on individual chromosomes very challenging, especially in many not well-studied nonconventional yeast species. Previously, we applied a stepwise method to identify a 500-bp CEN5 from Scheffersomyces stipitis chromosome 5 and experimentally confirmed its critical role on improving plasmid stability. Here we report a library-based strategy that integrates in silico GC3 chromosome scanning and high-throughput functional screening, which enabled the isolation of all eight S. stipitis centromeres with a 16 000-fold reduction in sequence very efficiently. Further identification of a 125-bp CEN core sequence that appears multiple times on each chromosome but all in the unique signature GC3-valley indicates that CEN location might be accurately discerned by their local GC3 percentages in a subgroup of yeasts. PMID- 28837320 TI - Persistent Luminescence Nanophosphor Involved Near-Infrared Optical Bioimaging for Investigation of Foodborne Probiotics Biodistribution in Vivo: A Proof-of Concept Study. AB - Probiotics has attracted great attention in food nutrition and safety research field, but thus far there are limited analytical techniques for visualized and real-time monitoring of the probiotics when they are ingested in vivo. Herein, the optical bioimaging technique has been introduced for investigation of foodborne probiotics biodistribution in vivo, employing the near-infrared (NIR) emitting persistent luminescence nanophosphors (PLNPs) of Cr3+-doped zinc gallogermanate (ZGGO) as the contrast nanoprobes. The ultrabrightness, super long afterglow, polydispersed size, low toxicity, and excellent photostability and biocompatibility of PLNPs were demonstrated to be qualified as a tracer for labeling probiotics via antibody (anti-Gram positive bacteria LTA antibody) recognition as well as contrast agent for long-term bioimaging the probiotics. In vivo optical bioimaging assay showed that the LTA antibody functionalized ZGGO nanoprobes that could be efficiently tagged to the probiobics were successfully applied for real-time monitoring and nondamaged probing of the biodistribution of probiotics inside the living body after oral administration. This work presents a proof-of-concept that exploited the bioimaging methodology for real-time and nondamaged researching the foodborne probiotics behaviors in vivo, which would open up a novel way of food safety detection and nutrition investigation. PMID- 28837319 TI - Hydrogen Bond Directed Photocatalytic Hydrodefluorination: Overcoming Electronic Control. AB - The photocatalytic C-F functionalization of highly fluorinated arenes is a powerful method for accessing functionalized multifluorinated arenes. The decisive step in the determining regioselectivity in fluorine functionalization is fluoride fragmentation from the radical anion of the multifluorinated arene. To date, the availability of regioisomers has been dictated by the innate electronics of the fluorinated arene, limiting the synthetic utility of the chemistry. This study investigates the remarkable ability of a strategically located hydrogen bond to transcend the normal regioselectivity of the C-F functionalization event. A significant rate acceleration is additionally observed for hydrodefluorination of fluorines that can undergo intramolecular hydrogen bonds that form 5-8-membered cycles with moderately acidic N-H's. The hydrogen bond is expected to facilitate the fragmentation not only by bending the C-F bond of the radical anion out of planarity but also by increasing the exothermicity of the fluoride extrusion step through protonation of the naked fluoride. Finally, the synthetic utility of the method is demonstrated in an expedited synthesis of the trifluorinated alpha-phenyl acetic acid derivative required for the commercial synthesis of Januvia, an antidiabetic drug. This represents the first synthesis of a commercially important multifluorinated arene via a defluorination strategy and is significantly shorter than the current strategy. PMID- 28837321 TI - Seed Treatment Combined with a Spot Application of Clothianidin Granules Prolongs the Efficacy of Controlling Piercing-Sucking Insect Pests in Cotton Fields. AB - Seed treatments can directly protect cotton from early season piercing-sucking insect Aphis gossypii Glover but hardly provide long-term protection against Apolygus lucorum (Meyer-Dur). Therefore, the efficacy of clothianidin seed treatments combined with spot applications of clothianidin granules at the bud stage of cotton was evaluated to control piercing-sucking pests during the entire cotton growing season. Clothianidin seed treatments (at the rate of 4 g ai/kg seed) combined with a clothianidin granular treatment (even at low rate of 0.9 kg ai/ha) at the bud stage can effectively suppress A. gossypii and A. lucorum infestations throughout the seedling and blooming stages after planting and can improve cotton yield. The spot application of clothianidin granules also reduced the population densities of Bemisia tabaci (Gennadius). The dynamic changes of clothianidin residues demonstrated that the control efficacy of clothianidin against A. gossypii and A. lucorum might be related to the residues of this neonicotinoid in cotton leaves. This pest management practice provided long-term protection against cotton piercing-sucking pests for the entire growing season of cotton plants and could supplement the short-term control efficiency of clothianidin used as a seed treatment. PMID- 28837322 TI - Intraligand Charge Transfer Sensitization on Self-Assembled Europium Tetrahedral Cage Leads to Dual-Selective Luminescent Sensing toward Anion and Cation. AB - Luminescent supramolecular lanthanide edifices have many potential applications in biology, environments, and materials science. However, it is still a big challenge to improve the luminescent performance of multinuclear lanthanide assemblies in contrast to their mononuclear counterparts. Herein, we demonstrate that combination of intraligand charge transfer (ILCT) sensitization and coordination-driven self-assembly gives birth to bright EuIII tetrahedral cages with a record emission quantum yield of 23.1%. The ILCT sensitization mechanism has been unambiguously confirmed by both time-dependent density functional theory calculation and femtosecond transient absorption studies. Meanwhile, dual responsive sensing toward both anions and cations has been demonstrated making use of the ILCT transition on the ligand. Without introduction of additional recognition units, high sensitivity and selectivity are revealed for the cage in both turn-off luminescent sensing toward I- and turn-on sensing toward Cu2+. This study offers important design principles for the future development of luminescent lanthanide molecular materials. PMID- 28837323 TI - Tubular Monolayer Superlattices of Hollow Mn3O4 Nanocrystals and Their Oxygen Reduction Activity. AB - Self-assembled nanocrystal (NC) superlattices are emerging as an important class of materials with rationally modulated properties. Engineering the nanoscale structure of constituent building blocks as well as the mesoscale morphology of NC superlattices is a crucial step in widening their range of applications. Here, we report a template-assisted epitaxial assembly strategy, enabling growth of freestanding, carbon-coated tubular monolayer superlattices (TMSLs). Specifically, we design and construct TMSLs of hollow Mn3O4 NCs (h-Mn3O4-TMSLs) by exploiting structural evolution of MnO NCs. The tubular superlattices obtained possess a number of unique and advantageous structural features unavailable in conventional NC superlattices, rendering them particularly attractive for energy conversion applications. We demonstrate this by employing h-Mn3O4-TMSLs as electrocatalysts for oxygen reduction, the catalytic performance of which is comparable to that of state-of-the-art Pt/C catalysts and superior to that of most manganese oxide-based catalysts reported. PMID- 28837324 TI - Total Synthesis of Pseudomonas aeruginosa 1244 Pilin Glycan via de Novo Synthesis of Pseudaminic Acid. AB - Pseudaminic acid (Pse) is a nonulosonic acid unique to bacterial species, found as a component of important cell surface glycans and glycoproteins in various pathogenic species, such as the critical hospital threat Pseudomonas aeruginosa. Herein we present the development of a facile and scalable de novo synthesis of Pse and its functionalized derivatives from easily available Cbz-l-allo-threonine methyl ester (16 steps in 11% yield). The key reactions in our de novo synthesis involve the diastereoselective glycine thioester isonitrile-based aldol-type reaction to create the 1,3-anti-diamino skeleton, followed by the Fukuyama reduction and the indium-mediated Barbier-type allylation. Moreover, we have studied the glycosylation of the Pse glycosyl donors and identified the structural determinants for its glycosylation diastereoselectivity, which enabled us to complete the total synthesis of P. aeruginosa 1244 pilin trisaccharide alpha-5NbetaOHC47NFmPse-(2->4)-beta-Xyl-(1->3)-FucNAc. PMID- 28837325 TI - Combinatorial Evolution of Fast-Conducting Highly Selective K+-Channels via Modularly Tunable Directional Assembly of Crown Ethers. AB - We describe here a modularly tunable molecular strategy for construction and combinatorial optimization of highly efficient K+-selective channels. In our strategy, a highly robust supramolecular H-bonded 1D ensemble was used to order the appended crown ethers in such a way that they roughly stack on top of each other to form a channel for facilitated ion transport across the membrane. Among 15 channels that all prefer K+ over Na+ ions, channel molecule 5F8 shows the most pronounced optimum for K+ while disfavoring all other biologically important cations (e.g., Na+, Ca2+ and Mg2+). With a K+/Na+ selectivity of 9.8 and an EC50 value of 6.2 MUM for K+ ion, 5F8 is clearly among the best synthetic potassium channels developed over the past decades. PMID- 28837326 TI - Bidentate Phosphine-Assisted Synthesis of an All-Alkynyl-Protected Ag74 Nanocluster. AB - Determining the total structure of metal nanoparticles is vital to understand their properties. In this work, the first all-alkynyl-protected Ag nanocluster, Ag74(C=CPh)44, was synthesized and structurally characterized by single crystal diffraction. Ag atoms are arranged in a Ag4@Ag22@Ag48 three shell structure and all 44 phenylethynyl ligands coordinated with Ag in a MU3 mode. In spite of being absent in nanocluster, 31P NMR study reveals that bidentate phosphine first reacts with Ag(I) to form a dinuclear complex, from which Ag atoms are then released to phenylethynyl ligands. This phosphine mediated strategy may find general application in synthesis of alkynyl-protected Ag nanoclusters. PMID- 28837327 TI - Vapor-Enabled Propulsion for Plasmonic Photothermal Motor at the Liquid/Air Interface. AB - This paper explores a new propulsion mechanism that is based on the ejection of hot vapor jet to propel the motor at the liquid/air interface. For conventional photothermal motors, which mostly are driven by Marangoni effect, it is challenging to propel those motors at the surfaces of liquids with low surface tension due to the reduced Marangoni effect. With this new vapor-enabled propulsion mechanism, the motors can move rapidly at the liquid/air interface of liquids with a broad range of surface tensions. A design that can accumulate the hot vapor is further demonstrated to enhance both the propulsion force as well as the applicable range of liquids for such motors. This new propulsion mechanism will help open up new opportunities for the photothermal motors with desired motion controls at a wide range of liquid/air interfaces where hot vapor can be generated. PMID- 28837328 TI - Direct Detection of Dilute Solid Chemicals with Responsive Lateral Organic Diodes. AB - Organic field-effect transistors (OFETs) have emerged as promising sensors targeting chemical analytes in vapors and liquids. However, the direct detection of solid chemicals by OFETs has not been achieved. Here for the first time, we describe the direct detection of solid chemical analytes by organic electronics. An organic diode structure based on a horizontal side-by-side p-n junction was adopted and shown to be superior to OFETs for this purpose. The diodes showed more than 40% current decrease upon exposure to 1 ppm melamine powders. The estimated detection limit to melamine can potentially reach the ppb range. This is the first demonstration of an electronic signal from an interaction between a solid and an organic p-n junction directly, which suggests that our lateral organic diodes are excellent platforms for the development of future sensors when direct detection of solid chemicals is needed. The approach developed here is general and can be extended to chemical sensors targeting various analytes, opening unprecedented opportunities for the development of low-cost and high performance solid chemical sensors. PMID- 28837329 TI - Self-Templated Formation of Interlaced Carbon Nanotubes Threaded Hollow Co3S4 Nanoboxes for High-Rate and Heat-Resistant Lithium-Sulfur Batteries. AB - Lithium-sulfur batteries (Li-S) have attracted soaring attention due to the particularly high energy density for advanced energy storage system. However, the practical application of Li-S batteries still faces multiple challenges, including the shuttle effect of intermediate polysulfides, the low conductivity of sulfur and the large volume variation of sulfur cathode. To overcome these issues, here we reported a self-templated approach to prepare interconnected carbon nanotubes inserted/wired hollow Co3S4 nanoboxes (CNTs/Co3S4-NBs) as an efficient sulfur host material. Originating from the combination of three dimensional CNT conductive network and polar Co3S4-NBs, the obtained hybrid nanocomposite of CNTs/Co3S4-NBs can offer ultrahigh charge transfer properties, and efficiently restrain polysulfides in hollow Co3S4-NBs via the synergistic effect of structural confinement and chemical bonding. Benefiting from the above advantages, the S@CNTs/Co3S4-NBs cathode shows a significantly improved electrochemical performance in terms of high reversible capacity, good rate performance, and long-term cyclability. More remarkably, even at an elevated temperature (50 degrees C), it still exhibits high capacity retention and good rate capacity. PMID- 28837330 TI - Development of a Drug Delivery System Based on Chitosan Nanoparticles for Oral Administration of Interferon-alpha. AB - Despite the good clinical efficacy of interferon-alpha (IFNalpha) to treat some types of cancer and viral infections, this biological drug is underused given its severe adverse effects and high dosing parenteral regimens. Aiming to achieve a breakthrough in therapy with IFNalpha, this work reports for the first time on the design and full characterization of a novel nanomedicine of IFNalpha-2b loaded chitosan nanoparticles (IFN-CT NPs) for oral delivery. IFN-CT NPs produced by ionotropic gelation, encapsulating approximately 100% of the drug, showed a size of 36 +/- 8 nm, zeta potential of +30 mV (dynamic light scattering), and spherical morphology (transmission electron microscopy). The antiviral activity of IFN-CT NPs in vitro was comparable to that of commercial IFNalpha. Remarkably, both treatments stimulated the expression of IFN response genes to a similar extent in both noninfected and infected cells with Human Lymphotropic-T Virus type 1. Finally, oral administration of IFN-CT NPs (0.3 MIU) to CF1 mice showed detectable levels of IFNalpha in plasma after 1 h, whereas no IFNalpha was detected with a commercial formulation. These results are encouraging and open a new avenue for the administration of this biological drug in a minimally invasive, safer, and more patient-compliant way. PMID- 28837331 TI - Magnetophoretic Mole-Ratio Method. AB - The principle of the mole-ratio method utilizing magnetophoretic velocimetry was demonstrated for the first time. The feasibility of the magnetophoretic mole ratio method was studied for the determination of the stoichiometry of the complexes formed between a hydrophobic phosphate ligand adsorbed in mesoporous hydrophobic silica particles and paramagnetic metal ions of Co(II), Tb(III), and Dy(III) in aqueous solutions. The present method is a nonspectroscopic method and carried out by a simple magnetic device. PMID- 28837333 TI - An Acidity Scale of Triazolium-Based NHC Precursors in DMSO. AB - An acidity scale of triazolium-based N-heterocyclic carbene precursors was established by measuring 25 compounds' (10a-15b) equilibrium acidities in dimethyl sulfoxide (DMSO) solution using overlapping indicator method. The pKa values ranged from 12.08 to 15.5, responding not only to the N-aryl motif, but also to the core structure. Excellent correlation was observed between the pKa values and the Hammett substituent constants (sigmap). PMID- 28837332 TI - Discovery of a Novel HIV-1 Integrase/p75 Interacting Inhibitor by Docking Screening, Biochemical Assay, and in Vitro Studies. AB - Protein-protein interaction between lens epithelium-derived growth factor (LEDGF/p75) and HIV-1 integrase becomes an attractive target for anti-HIV drug development. The blockade of this interaction by small molecules could potentially inhibit HIV-1 replication. These small molecules are termed as LEDGINs; and several newly identified LEDGINs have been reported to significantly reduce HIV-1 replication. Through this project, we have finished the docking screening of the Maybridge database against the p75 binding site of HIV-1 integrase using both DOCK and Autodock Vina software. Finally, we have successfully identified a novel scaffold LEDGINs inhibitor DW-D-5. Its antiviral activities and anticatalytic activity of HIV-1 integrase are similar to other LEDGINs under development. We demonstrated that the combination of DW-D-5 and FDA approved anti-HIV drugs resulted in additive inhibitory effects on HIV-1 replication, indicating that DW-D-5 could be an important component of combination pills for clinic use in HIV treatment. PMID- 28837334 TI - Microporous Metal-Organic Framework Based on Ligand-Truncation Strategy with High Performance for Gas Adsorption and Separation. AB - By using the ligand-truncation strategy, a microporous metal-organic framework (1) with high surface area was designedly synthesized. MOF 1 shows a new (4, 4) connected net with a Schlafli symbol of (44.62)(43.62.8)2(42.82.102) and exhibits a high H2 capture capacity (193 cm3 g-1 at 1 atm and 77 K) and selectivities for CO2 over N2 and CH4 at low pressure. PMID- 28837335 TI - Tulongicin, an Antibacterial Tri-Indole Alkaloid from a Deep-Water Topsentia sp. Sponge. AB - Antibacterial-guided fractionation of an extract of a deep-water Topsentia sp. marine sponge led to the isolation of two new indole alkaloids, tulongicin A (1) and dihydrospongotine C (2), along with two known analogues, spongotine C (3) and dibromodeoxytopsentin (4). Their planar structures were determined by NMR spectroscopy. Their absolute configurations were determined through a combination of experimental and computational analyses. Tulongicin (1) is the first natural product to contain a di(6-Br-1H-indol-3-yl)methyl group linked to an imidazole core. The coexistence of tri-indole 1 and bis-indole alcohol 2 suggests a possible route to 1. All of the compounds showed strong antimicrobial activity against Staphylococcus aureus. PMID- 28837337 TI - Correction to Next-Generation Magnetic Resonance Imaging Contrast Agents. PMID- 28837338 TI - Practical Density Functionals beyond the Overdelocalization-Underbinding Zero-Sum Game. AB - Density functional theory (DFT) uses a density functional approximation (DFA) to add electron correlation to mean-field electronic structure calculations. Standard strategies (generalized gradient approximations GGAs, meta-GGAs, hybrids, etc.) for building DFAs, no matter whether based on exact constraints or empirical parametrization, all face a zero-sum game between overdelocalization (fractional charge error, FC) and underestimation of covalent bonding (fractional spin error, FS). This work presents an alternative strategy. Practical "Rung 3.5" ingredients are used to implement insights from hyper-GGA DFAs that reduce both FS and FC errors. Prototypes of this strategy qualitatively improve FS and FC error over 40 years of standard DFAs while maintaining low cost and practical evaluation of properties. Numerical results ranging from transition metal thermochemistry to absorbance peaks and excited-state geometry optimizations highlight this strategy's promise and indicate areas requiring further development. PMID- 28837339 TI - Environmental Benefit Assessment for the Carbonation Process of Petroleum Coke Fly Ash in a Rotating Packed Bed. AB - A high-gravity carbonation process was deployed at a petrochemical plant using petroleum coke fly ash and blowdown wastewater to simultaneously mineralized CO2 and remove nitrogen oxides and particulate matters from the flue gas. With a high gravity carbonation process, the CO2 removal efficiency was found to be 95.6%, corresponding to a capture capacity of 600 kg CO2 per day, at a gas flow rate of 1.47 m3/min under ambient temperature and pressure. Moreover, the removal efficiency of nitrogen oxides and particulate matters was 99.1% and 83.2%, respectively. After carbonation, the reacted fly ash was further utilized as supplementary cementitious materials in the blended cement mortar. The results indicated that cement with carbonated fly ash exhibited superior compressive strength (38.1 +/- 2.5 MPa at 28 days in 5% substitution ratio) compared to the cement with fresh fly ash. Furthermore, the environmental benefits for the high gravity carbonation process using fly ash were critically assessed. The energy consumption of the entire high-gravity carbonation ranged from 80 to 169 kWh/t CO2 (0.29-0.61 GJ/t-CO2). Compared with the scenarios of business-as-usual and conventional carbon capture and storage plant, the economic benefit from the high gravity carbonation process was approximately 90 and 74 USD per ton of CO2 fixation, respectively. PMID- 28837336 TI - Resistance of Echovirus 11 to ClO2 Is Associated with Enhanced Host Receptor Use, Altered Entry Routes, and High Fitness. AB - Waterborne viruses can exhibit resistance to common water disinfectants, yet the mechanisms that allow them to tolerate disinfection are poorly understood. Here, we generated echovirus 11 (E11) with resistance to chlorine dioxide (ClO2) by experimental evolution, and we assessed the associated genotypic and phenotypic traits. ClO2 resistance emerged after E11 populations were repeatedly reduced (either by ClO2-exposure or by dilution) and then regrown in cell culture. The resistance was linked to an improved capacity of E11 to bind to its host cells, which was further attributed to two potential causes: first, the resistant E11 populations possessed mutations that caused amino acid substitutions from ClO2 labile to ClO2-stable residues in the viral proteins, which likely increased the chemical stability of the capsid toward ClO2. Second, resistant E11 mutants exhibited the capacity to utilize alternative cell receptors for host binding. Interestingly, the emergence of ClO2 resistance resulted in an enhanced replicative fitness compared to the less resistant starting population. Overall this study contributes to a better understanding of the mechanism underlying disinfection resistance in waterborne viruses, and processes that drive resistance development. PMID- 28837340 TI - Highly Sensitive Bifunctional Probe for Colorimetric Cyanide and Fluorometric H2S Detection and Bioimaging: Spontaneous Resolution, Aggregation, and Multicolor Fluorescence of Bisulfide Adduct. AB - A 4-methylbenzothiazole linked maleimide-based single molecular bifunctional probe 1 has been synthesized for the colorimetric and fluorometric detection of highly competitive H2S and cyanide ion in aqueous DMSO media. The probe 1 selectively detected CN- under the UV-vis spectroscopy through the rapid appearance of deep pink color. The bright pink color developed due to ICT in the moderately stable cyano substituted enolate intermediate. The absorbance titration of 1 with CN- revealed a new band at 540 nm and the nonlinear curve fitting analysis showed good fit with 1:1 model. In fluorescence channel, 1 was found to be highly selective to H2S in 50% aqueous buffer (pH 7). It exhibited ~16-fold fluorescence intensity enhancement at 435 nm after reaction with 1 equiv of H2S due to the inhibition of PET. The 1-SH adduct showed TICT phenomenon and behaved like molecular rotor. It further displayed aggregation behavior at higher concentration and excitation wavelength dependent multicolor emission properties. Most interestingly, the spontaneous resolution of chiral S-isomer of the 1-SH adduct occurred during crystallization. The cell imaging study revealed the staining of the cell and multicolor emission in the presence of H2S. PMID- 28837341 TI - Correction to "Boron Dipyridylmethene (DIPYR) Dyes: Shedding Light on Pyridine Based Chromophores". PMID- 28837343 TI - Novel Milrinone Nanoformulation for Use in Cardiovascular Diseases: Preparation and in Vitro Characterization. AB - Cardiovascular diseases are the leading causes of mortality across the globe. Over the years, various drug formulations and delivery methods have been tested for cardiac repair. Milrinone (MRN) is a widely known cardiac inotrope drug used for the treatment of congestive heart failure in patients, however, its efficacy is limited. This study is the first to report the design of a novel MRN nanoformulation using human serum albumin nanoparticles (HSA-NPs). The HSA-NPs exhibit promising drug delivery characteristics, such as target specificity, nonimmunogenicity, biocompatibility, and enhanced bioavailability. This article describes a MRN-nanoformulation design for in vitro drug release, cellular uptake, biocompatibility, and other features. The MRN-nanoformulation was prepared by the ethanol desolvation technique and key parameters were optimized to obtain a desired particle size of 154.2 +/- 5.8 nm, zeta potential of -29.5 +/ 2.9 mV, and a drug encapsulation efficiency of 41.1 +/- 1.7%. Molecular docking studies have revealed that MRN binds in the hydrophobic cavity of HSA, which has also been indicated by circular dichroism and enzyme-mediated drug release studies in the presence of trypsin, pepsin, proteinase K, protease, and cathepsin D. The intracellular uptake of fluorescently tagged MRN-HSA-NPs using HUVEC and H9c2 cells was evaluated by flow cytometry. The nanoparticle toxicity results indicated that MRN-HSA-NPs show significantly lower cytotoxicity and higher cell viability ( P < 0.0001) as compared to the MRN-lactate drug in HUVEC (61.6 +/- 3.7% vs 36.2 +/- 2.9%) and H9c2 (58.8 +/- 5.7% vs 18.8 +/- 4.9%) cells. These studies indicate that the novel MRN-nanoformulation offers better drug delivery procedures than currently used methods and has potential in treatment of congestive heart failure and other cardiovascular diseases. PMID- 28837342 TI - Cyperaceae Species Are Potential Sources of Natural Mammalian Arginase Inhibitors with Positive Effects on Vascular Function. AB - The inhibition of arginase is of substantial interest for the treatment of various diseases of public health interest including cardiovascular diseases. Using an ex vivo experiment on rat aortic rings and an in vitro assay with liver bovine purified arginase, it was demonstrated that several polyphenolic extracts from Cyperus and Carex species possess vasorelaxant properties and mammalian arginase inhibitory capacities. Phytochemical studies performed on these species led to the identification of eight compounds, including monomers, dimers, trimers, and tetramers of resveratrol. The potential of these stilbenes as inhibitors of mammalian arginase was assessed. Five compounds, scirpusin B (5), epsilon-viniferin (4), cyperusphenol B (6), carexinol A (7), and the new compound virgatanol (1), showed significant inhibition of arginase, with percentage inhibition ranging from 70% to 95% at 100 MUg/mL and IC50 values between 12.2 and 182.1 MUM, confirming that these stilbenes may be useful for the development of new pharmaceutical products. PMID- 28837344 TI - Role of Macromolecular Crowding on Stability and Iron Release Kinetics of Serum Transferrin. AB - The macromolecular crowding influences the structural stability and functional properties of transferrin (Tf). The equilibrium as well as kinetic studies of Tf at different concentrations of crowding agents (dextran 40, dextran 70, and ficoll 70) and at a fixed concentration of dextran 40 under different concentrations of NaCl at pH 7.4 and 5.6 (+/-1) revealed that (i) the crowder environment increases the diferric-Tf (Fe2Tf) stability against iron loss and overall denaturation of the protein, (ii) both in the absence and presence of crowder, the presence of salt promotes the loss of iron and overall denaturation of Fe2Tf which is due to ionic screening of electrostatic interactions, (iii) the crowder environment retards iron release from monoferric N-lobe of Tf (FeNTf) by increasing enthalpic barrier, (iv) the retardation of iron release by crowding is enthalpically dominated than the entropic one, (v) both in the absence and presence of crowder, the presence of salt accelerates the iron release from FeNTf due to ionic screening of electrostatic interactions and anion binding to KISAB sites, and (vi) the crowders environment is unable to diminish (a) the salt induced destabilization of Fe2Tf against the loss of iron and overall denaturation and (b) the anion effect and ionic screening of diffusive counterions responsible to promote iron release from FeNTf. PMID- 28837345 TI - Gas-Phase Reaction of Methyl n-Propyl Ether with OH, NO3, and Cl: Kinetics and Mechanism. AB - Rate constants at room temperature (293 +/- 2 K) and atmospheric pressure for the reaction of methyl n-propyl ether (MnPE), CH3OCH2CH2CH3, with OH and NO3 radicals and the Cl atom have been determined in a 100 L FEP-Teflon reaction chamber in conjunction with gas chromatography-flame ionization detector (GC-FID) as the detection technique. The obtained rate constants k (in units of cm3 molecule-1 s 1) are (9.91 +/- 2.30) * 10-12, (1.67 +/- 0.32) * 10-15, and (2.52 +/- 0.14) * 10 10 for reactions with OH, NO3, and Cl, respectively. The products of these reactions were investigated by gas chromatography-mass spectrometry (GC-MS), and formation mechanisms are proposed for the observed reaction products. Atmospheric lifetimes of the studied ether, calculated from rate constants of the different reactions, reveal that the dominant loss process for MnPE is its reaction with OH, while in coastal areas and in the marine boundary layer, MnPE loss by Cl reaction is also important. PMID- 28837346 TI - Genetic Manipulation of the COP9 Signalosome Subunit PfCsnE Leads to the Discovery of Pestaloficins in Pestalotiopsis fici. AB - By deleting the COP9 signalosome subunit PfcsnE from Pestalotiopsis fici, seven compounds that were newly produced by the mutant could be characterized, including five new structures, pestaloficins A-E (1 and 3-6). Pestaloficin A (1) represents a new type of dimeric cyclohexanone derivative linked through an unprecedented pentacyclic spiral ring. PMID- 28837347 TI - Carbon-Carbon Bond Formation by Reaction of Rhodium Azavinylcarbenes with Secondary Amides: Access to Indigo Analogues from Isatins. AB - A novel protocol for the synthesis of unsymmetrical indigo-like (E)-alpha-amino enaminones by rhodium-catalyzed transformations of isatins with 1-tosyl-1,2,3 triazoles has been developed. A plausible reaction mechanism is proposed to account for the formation of structurally important unsymmetrical indigo analogues, which represents a new strategy for C-C bond formation based on the transformations of secondary amides and rhodium azavinylcarbenes. PMID- 28837348 TI - Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic alpha-Chiral Side Chains. AB - Peptoids that are oligomers of N-substituted glycines represent a class of peptide mimics with great potential in areas ranging from medicinal chemistry to biomaterial science. Controlling the equilibria between the cis and trans conformations of their backbone amides is the major hurdle to overcome for the construction of discrete folded structures, particularly for the development of all-cis polyproline type I (PPI) helices, as tools for modulating biological functions. The prominent role of backbone to side chain electronic interactions (n -> pi*) and side chains bulkiness in promoting cis-amides was essentially investigated with peptoid aromatic side chains, among which the chiral 1 naphthylethyl (1npe) group yielded the best results. We have explored for the first time the possibility to achieve similar performances with a sterically hindered alpha-chiral aliphatic side chain. Herein, we report on the synthesis and detailed conformational analysis of a series of (S)-N-(1-tert butylethyl)glycine (Ns1tbe) peptoid homo-oligomers. The X-ray crystal structure of an Ns1tbe pentamer revealed an all-cis PPI helix, and the CD curves of the Ns1tbe oligomers also resemble those of PPI peptide helices. Interestingly, the CD data reported here are the first for any conformationally homogeneous helical peptoids containing only alpha-chiral aliphatic side chains. Finally we also synthesized and analyzed two mixed oligomers composed of NtBu and Ns1tbe monomers. Strikingly, the solid state structure of the mixed oligomer Ac-(tBu)2 (s1tbe)4-(tBu)2-COOtBu, the longest to be solved for any linear peptoid, revealed a PPI helix of great regularity despite the presence of only 50% of chiral side chain in the sequence. PMID- 28837349 TI - Amino Acid-Directed Strategy for Inducing the Marine-Derived Fungus Scedosporium apiospermum F41-1 to Maximize Alkaloid Diversity. AB - By feeding various amino acids to the marine fungus Scedosporium apiospermum F41 1, 22 diverse alkaloids, including 14 new compounds, were obtained. Scedapins A-E (1-5) possess a rare skeleton of a pyrazinoquinazolinedione and an imidazoindolone/indolone linked by a tetrahydrofuran ring. Scedapin C (3) is the first example of fumiquinazoline that contains an aminosulfonyl group. Their structures were determined by HRMS, NMR, ECD calculations and X-ray single crystal diffraction analysis. The biosynthetic pathways of fumiquinazolines 1-18 were proposed. Scedapin C (3) and scequinadoline D (8) displayed significant antiviral activity against hepatitis C. PMID- 28837350 TI - vic-Diphosphination of Alkenes with Silylphosphine under Visible-Light-Promoted Photoredox Catalysis. AB - An Ir(ppy)3-catalyzed vic-diphosphination of styrenes with Me3Si-PPh2 and NFSI proceeds under blue LED irradiation to afford the corresponding bis(diphenylphosphino)ethane derivatives without any formation of hydrophosphination byproducts, which are inevitable and problematic under the previous Cu/NHC catalysis. Additionally, the visible-light-promoted photoredox catalysis enables the diphosphination of relatively challenging aliphatic alkenes and beta-substituted styrene. PMID- 28837351 TI - Accessing 1,3-Dienes via Palladium-Catalyzed Allylic Alkylation of Pronucleophiles with Skipped Enynes. AB - An unprecedented palladium-catalyzed allylic alkylation of pronucleophiles with unactivated skipped enynes has been developed. This method provides a straightforward access to a wide array of 1,3-dienes without the need to preinstall leaving groups or employ extra oxidants. The reaction exhibited high atom economy, good functional group tolerance, excellent regioselectivities, and scalability. With D2O as cosolvent, deuterium could be incorporated in high efficiency. PMID- 28837352 TI - A Linear-Time Algorithm for the Copy Number Transformation Problem. AB - Problems of genome rearrangement are central in both evolution and cancer. Most evolutionary scenarios have been studied under the assumption that the genome contains a single copy of each gene. In contrast, tumor genomes undergo deletions and duplications, and thus, the number of copies of genes varies. The number of copies of each segment along a chromosome is called its copy number profile (CNP). Understanding CNP changes can assist in predicting disease progression and treatment. To date, questions related to distances between CNPs gained little scientific attention. Here we focus on the following fundamental problem, introduced by Schwarz et al.: given two CNPs, u and v, compute the minimum number of operations transforming u into v, where the edit operations are segmental deletions and amplifications. We establish the computational complexity of this problem, showing that it is solvable in linear time and constant space. PMID- 28837354 TI - Society of Biomolecular Imaging and Informatics 4th Annual Meeting September 13 15, 2017. PMID- 28837353 TI - The Psychological Effects of Playing Exergames: A Systematic Review. AB - Successful exergames should lead players not only to achieve enough level of energy expenditure but also to engage in the play itself. The aim of this study is to review studies that explored the psychological effects of playing exergames, from the viewpoint of player engagement. Peer-reviewed journal articles in English collected via database search (Science Direct, Web of Science, ACM Digital Library) from 2011 to 2015 were considered, and 45 experimental studies were selected out of 911 studies. The results show that a variety of psychological effects of engagement including enjoyment, immersion, and flow were measured in the exergame studies. In addition, physiological variables (e.g., energy expenditure), feedback modality (e.g., auditory and tactile), and play modes (e.g., solitary or group play mode) are related to psychological effects of playing exergames. Finally, salient methodological issues (e.g., validated measurement, sample size calculation) in the studies are identified and discussed. PMID- 28837355 TI - Society of Biomolecular Imaging and Informatics Special Issue. PMID- 28837356 TI - Phenotypic Assays for Characterizing Compound Effects on Induced Pluripotent Stem Cell-Derived Cardiac Spheroids. AB - Development of more complex, biologically relevant, and predictive cell-based assays for compound screening is a major challenge in drug discovery. The focus of this study was to establish high-throughput compatible three-dimensional (3D) cardiotoxicity assays using human induced pluripotent stem cell-derived cardiomyocytes. Using both high-content imaging and fast kinetic fluorescence imaging, the impact of various compounds on the beating rates and patterns of cardiac spheroids was monitored by changes in intracellular Ca2+ levels with calcium-sensitive dyes. Advanced image analysis methods were implemented to provide multiparametric characterization of the Ca2+ oscillation patterns. In addition, we used confocal imaging and 3D analysis methods to characterize compound effects on the morphology of 3D spheroids. This phenotypic assay allows for the characterization of parameters such as beating frequency, amplitude, peak width, rise and decay times, as well as cell viability and morphological characteristics. A set of 22 compounds, including a number of known cardioactive and cardiotoxic drugs, was assayed at different time points, and the calculated EC50 values for compound effects were compared between 3D and two-dimensional (2D) model systems. A significant concordance in the phenotypes was observed for compound effects between the two models, but essential differences in the concentration responses and time dependencies of the compound-induced effects were observed. Together, these results indicate that 3D cardiac spheroids constitute a functionally distinct biological model system from traditional flat 2D cultures. In conclusion, we have demonstrated that phenotypic assays using 3D model systems are enabled for screening and suitable for cardiotoxicity assessment in vitro. PMID- 28837357 TI - Improving Comprehension Efficiency of High Content Screening Data Through Interactive Visualizations. AB - In this study, an experiment is conducted to measure the performance in speed and accuracy of interactive visualizations. A platform for interactive data visualizations was implemented using Django, D3, and Angular. Using this platform, a questionnaire was designed to measure a difference in performance between interactive and noninteractive data visualizations. In this questionnaire consisting of 12 questions, participants were given tasks in which they had to identify trends or patterns. Other tasks were directed at comparing and selecting algorithms with a certain outcome based on visualizations. All tasks were performed on high content screening data sets with the help of visualizations. The difference in time to carry out tasks and accuracy of performance was measured between a group viewing interactive visualizations and a group viewing noninteractive visualizations. The study shows a significant advantage in time and accuracy in the group that used interactive visualizations over the group that used noninteractive visualizations. In tasks comparing results of different algorithms, a significant decrease in time was observed in using interactive visualizations over noninteractive visualizations. PMID- 28837358 TI - The gallbladder polypoid-lesions conundrum: moving forward with controversy by looking back. AB - INTRODUCTION: Gallbladder polypoid-lesions (GPs) are found in 5-10% of the general population. Although the majority of GPs are asymptomatic and benign in nature, some of them can develop into cancer, which carries a poor prognosis. Currently, the risk factors, natural history and classification of GPs remain unclear, differentiation of benign from malignant or premalignant GPs based on available diagnostic modalities and/or features of patients and GPs remain difficult, and there are still no evidence-based guidelines to dictate when and how GPs of varying sizes and subtypes should be managed. All of these facts have left GPs in uncertainty. Areas covered: A literature search was performed using the terms 'gallbladder polyps' AND 'polypoid lesion of gallbladder' in the PubMed database from January 2000 to September 2016. Original and review articles on almost all aspects of GPs in humans, especially diagnosis, treatment and surveillance, were reviewed and analyzed. Reference lists of reviews and original articles were also examined for relevant publications. Expert commentary: The present article summarizes almost all aspects of GPs, analyzes the controversies, and outlines our data and comments. It is the authors' purpose that this article be beneficial for scientific, accurate and appropriate management of GPs. PMID- 28837359 TI - Young females' attention toward road safety images: An ERP study of the revised reinforcement sensitivity theory. AB - OBJECTIVE: This study examined whether reward and punishment sensitivities, as conceptualized by Gray and McNaughton's revised reinforcement sensitivity theory (RST), influenced young female drivers' attention toward a series of positive and negative antispeeding advertisement images. Young females' increasing crash risk is associated with their engagement in risky behaviors, which, in turn, has been associated with a stronger behavioral approach system (BAS; sensitive to rewards). It was predicted that individuals with a stronger BAS would elicit larger N100 and N200 mean amplitudes (reflecting greater attention) toward the positive images. Similar associations were predicted in relation to the fight flight-freeze system (FFFS; sensitive to punishments) for negative images. METHOD: Twenty-four female drivers (17-25 years; final N = 16) completed Corr Cooper's RST-Personality Questionnaire, prior to undergoing an event-related potential computerized visual task (i.e., oddball paradigm) that included positive, negative, and neutral images as targets against checkerboard image distractors. RESULTS: Contrary to expectations, individuals with a stronger BAS (Reward Reactivity and Impulsivity) demonstrated significantly larger N200 mean amplitudes at the Cz electrode site on presentation of the negative images than those with a weaker BAS. No other significant RST effects were found. CONCLUSIONS: These findings provide some preliminary objective support for the use of negative emotion-based road safety advertisements for young females. Further, this study provides support for using psychophysiological measures to enhance understanding of traffic injury persuasion. PMID- 28837360 TI - Assessment of needs, psychological impact and quality of life in families of patients with locked-in syndrome. AB - OBJECTIVE: Family needs of patients with acquired brain injuries have been studied for about three decades. In this study, we assessed the needs, the quality of life and the psychological state of relatives of patients with locked in syndrome (LIS). DESIGN: A survey was carried out using the family needs' questionnaire (FNQ). SUBJECTS AND METHODS: Thirty relatives of patients with LIS fully completed the FNQ. RESULTS: The most important need reported by families corresponded to the need for medical information. The highest percentage of satisfaction (66%) was also observed for this need. Among the needs for information, specifically, the most important for LIS' relatives was to know that the patient's needs and wishes were respected by the professional staff, which were fulfilled in 93% of the sample. The need for emotional support was the least important and had the lowest percentage of satisfaction (55%). The number of met/unmet needs correlated with the quality of life of the families. Most of the relatives reported anxiety feelings and depressive thoughts. CONCLUSIONS: Receiving accurate medical information is the most important need for family of patients with LIS and their quality of life is correlated with the fulfilment of their needs. PMID- 28837361 TI - Role of Honey in Topical and Systemic Bacterial Infections. AB - BACKGROUND: The development of bacterial resistance to antibiotics has made it more difficult and expensive to treat infections. Honey is getting worldwide attention as a topical therapeutic agent for wound infections and potential future candidate for systemic infections. OBJECTIVES: The purpose of this review was to summarise different antibacterial bio-active compounds in honey, their synergistic interaction and their clinical implications in topical and systemic infections. In addition, contemporary testing methods for evaluating peroxide and non-peroxide antibacterial activity of honey were also critically appraised. DESIGN: MEDLINE, EMBASE, Cochrane Library, Pub Med, reference lists and databases were used to review the literature. RESULTS: Honey contains several unique antibacterial components. These components are believed to act on diverse bacterial targets, are broad spectrum, operate synergistically, prevent biofilm formation, and decrease production of virulence factors. Moreover, honey has the ability to block bacterial communication (quorum sensing), and therefore, it is unlikely that bacteria develop resistance against honey. Bacterial resistance against honey has not been documented so far. Unlike conventional antibiotics, honey only targets pathogenic bacteria without disturbing the growth of normal gastrointestinal flora when taken orally. It also contains prebiotics, probiotics, and zinc and enhances the growth of beneficial gut flora. The presence of such plethora of antibacterial properties in one product makes it a promising candidate not only in wound infections but also in systemic and particularly for gastrointestinal infections. Agar diffusion assay, being used for evaluating antibacterial activity of honey, is not the most appropriate and sensitive assay as it only detects non-peroxide activity when present at a higher level. Therefore, there is a need to develop more sensitive techniques that may be capable of detecting and evaluating different important components in honey as well as their synergistic interaction. CONCLUSIONS: Keeping in view the current guidelines for treatment of diarrhea, honey is considered one of the potential candidates for treatment of diarrhea because it contains a natural combination of probiotics, prebiotics, and zinc. Therefore, it would be worthwhile if such a combination is tested in RCTs for treatment of diarrhea. PMID- 28837362 TI - Investigation of hit-and-run crash occurrence and severity using real-time loop detector data and hierarchical Bayesian binary logit model with random effects. AB - OBJECTIVE: Most of the extensive research dedicated to identifying the influential factors of hit-and-run (HR) crashes has utilized typical maximum likelihood estimation binary logit models, and none have employed real-time traffic data. To fill this gap, this study focused on investigating factors contributing to HR crashes, as well as the severity levels of HR. METHODS: This study analyzed 4-year crash and real-time loop detector data by employing hierarchical Bayesian models with random effects within a sequential logit structure. In addition to evaluation of the impact of random effects on model fitness and complexity, the prediction capability of the models was examined. Stepwise incremental sensitivity and specificity were calculated and receiver operating characteristic (ROC) curves were utilized to graphically illustrate the predictive performance of the model. RESULTS: Among the real-time flow variables, the average occupancy and speed from the upstream detector were observed to be positively correlated with HR crash possibility. The average upstream speed and speed difference between upstream and downstream speeds were correlated with the occurrence of severe HR crashes. In addition to real-time factors, other variables found influential for HR and severe HR crashes were length of segment, adverse weather conditions, dark lighting conditions with malfunctioning street lights, driving under the influence of alcohol, width of inner shoulder, and nighttime. CONCLUSIONS: This study suggests the potential traffic conditions of HR and severe HR occurrence, which refer to relatively congested upstream traffic conditions with high upstream speed and significant speed deviations on long segments. The above findings suggest that traffic enforcement should be directed toward mitigating risky driving under the aforementioned traffic conditions. Moreover, enforcement agencies may employ alcohol checkpoints to counter driving under the influence (DUI) at night. With regard to engineering improvements, wider inner shoulders may be constructed to potentially reduce HR cases and street lights should be installed and maintained in working condition to make roads less prone to such crashes. PMID- 28837363 TI - Beyond stuttering: Speech disfluencies in normally fluent French-speaking children at age 4. AB - The aim of this study was to establish normative data on the speech disfluencies of normally fluent French-speaking children at age 4, an age at which stuttering has begun in 95% of children who stutter (Yairi & Ambrose, 2013). Fifty monolingual French-speaking children who do not stutter participated in the study. Analyses of a conversational speech sample comprising 250-550 words revealed an average of 10% total disfluencies, 2% stuttering-like disfluencies and around 8% non-stuttered disfluencies. Possible explanations for these high speech disfluency frequencies are discussed, including explanations linked to French in particular. The results shed light on the importance of normative data specific to each language. PMID- 28837364 TI - To which extent can we decrease antibiotic duration in critically ill patients? AB - INTRODUCTION: Inadequate empirical antibiotic therapy is associated with higher mortality in critically ill patients with severe infections. Nevertheless, prolonged duration of antibiotic treatment is also potentially harmful. Development of new infections with more resistant pathogens is one of the arguments against the administration of prolonged courses of antibiotics. Areas covered: We aim to describe the optimal duration of antimicrobial therapy in the most common infections affecting critically ill patients. A literature search was performed to identify all clinical trials, observational studies, meta-analysis, and reviews about this topic from PubMed. Expert commentary: Diverse observational studies have reported a poor outcome in critically ill patients without a documented infection who receive prolonged antibiotic therapy. We summarize the available information about the optimal duration of antimicrobial therapy in critically ill patients with severe infections including community acquired pneumonia, intra-abdominal infections, bacteremia, meningitis and urinary-tract infections as well as the clinical consequences of short antimicrobial courses in certain severe infections. The utility of procalcitonin to reduce the duration of antibiotics is also discussed. Finally, we give clear recommendations about the length of treatment for the most common infections in critically ill patients. PMID- 28837366 TI - Uterine leiomyomata: the snowball effect. PMID- 28837365 TI - Oxymetazoline hydrochloride cream for facial erythema associated with rosacea. AB - INTRODUCTION: Rosacea is a chronic skin condition characterized by transient and persistent erythema of the central face. The symptom of persistent erythema can be particularly frustrating for both patients and physicians as it is difficult to treat. Areas covered: Current treatment options for the treatment of rosacea include metronidazole, azelaic acid, sodium sulfacetamide-sulfur, and brimonidine. Until recently, brimonidine gel was the only option approved specifically for the treatment of facial erythema. However, oxymetazoline hydrochloride 1% cream is a newly FDA approved topical medication for adult rosacea patients. A primarily alpha-1a agonist, oxymetazoline hydrochloride (HCl) is thought to diminish erythema through vasoconstriction. Our paper seeks to evaluate evidence for topical oxymetazoline HCl with respect to its efficacy and safety for its approved indication of treating the persistent erythema associated with rosacea. Expert commentary: While assessment of available clinical trial data indicates that the medication is as effective as other available treatment for controlling rosacea-associated erythema with minimal risk of adverse effects, studies of long-term duration and direct comparison will be necessary to establish its place in treatment guidelines and clinical practice. As further evidence becomes available, the real-world clinical potential of topical oxymetazoline cream will become clearer. PMID- 28837367 TI - Advances in immunopathogenesis of macrophage activation syndrome during rheumatic inflammatory diseases: toward new therapeutic targets? AB - INTRODUCTION: Macrophage activation syndrome (MAS) is a severe, hyperinflammatory life-threatening syndrome, generally complicating different rheumatic diseases. Despite the severity of the disease, little is known about the pathogenic mechanisms and, thus, possible targeted therapies in the management of these patients. Areas covered: In this review, we aimed to update the current pathogenic knowledge of MAS, during rheumatic diseases, focusing mainly on immunologic abnormalities and on new possible therapeutic strategies. Expert commentary: The difficult pathogenic scenario of MAS, in which genetic defects, predisposing diseases, and triggers are mixed together with the high mortality rate, make it difficult to manage these patients. Although most efforts have been focused on investigating the disease in children, in recent years, several studies are trying to elucidate the possible pathogenic mechanism in adult MAS patients. In this context, genetic and immunological studies might lead to advances in the knowledge of pathogenic mechanisms and possible new therapeutic targets. In the future, the results of ongoing clinical trials are awaited in order to improve the management and, thus, the survival of these patients. PMID- 28837369 TI - Surgical Treatment of Distal Biceps Tendon Ruptures: An Analysis of Complications in 784 Surgical Repairs. AB - BACKGROUND: Distal biceps brachii tendon ruptures lead to substantial deficits in elbow flexion and supination; surgical repair restores muscle strength and endurance. PURPOSE: To examine clinical and surgical outcomes for distal biceps tendon repairs in a large, multispecialty, integrated health care system. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Retrospective cohort study of distal biceps tendon repairs performed between January 1, 2008, and December 31, 2015. The repair methods were classified as double-incision approach using bone tunnel-suture fixation or anterior single-incision approach. Anterior single incisions were further classified according to the fixation method: cortical button alone, cortical button and interference screw, or suture anchors alone. Patient demographics, surgeon characteristics, range of motion, and complications were analyzed for all repair types. RESULTS: Of the 784 repairs that met the inclusion criteria, 639 (81.5%) were single-incision approaches. When comparing double-incision and single-incision repairs, there was a significantly higher rate of posterior interosseous nerve palsy (3.4% vs 0.8%, P = .010), heterotopic bone formation (7.6% vs 2.7%, P = .004), and reoperation (8.3% vs 2.3%, P < .001). The most common nerve complication encountered was a lateral antebrachial cutaneous nerve palsy (n = 162), which was significantly more common in the single-incision repairs than in the double-incision repairs (24.4% vs 4.1%, P < .001). When excluding lateral antebrachial cutaneous nerve palsies, there was no significant difference in the overall nerve palsies between single-incision and double-incision (5.8% vs 6.9%, P = .612). The overall rate of tendon rerupture was 1.9% (single incision, 1.6%; double incision, 2.8%; P = .327). The overall rate of postoperative wound infection was 1.5% (single incision, 1.3%; double incision, 2.8%; P = .182). The average time from surgery to release from medical care was 14.4 weeks (single incision, 14 weeks; double incision, 16 weeks; P = .286). Patients treated with cortical button plus interference screw were released significantly sooner than were patients with other single-incision repair types (13.1 +/- 8.01 weeks, P = .011). There were no significant differences in rates of motor neurapraxia, infection, rerupture, and reoperation with regard to surgeon's years of practice, fellowship training, or case volume. CONCLUSION: The surgical repair of distal biceps tendon ruptures has an overall low rate of serious complications, regardless of approach or technique. However, the double-incision technique has a higher rate of posterior interosseous nerve palsy, heterotopic bone formation, and reoperation rate. Surgeon's years of practice, fellowship training, and case volume do not affect the rate of major complications. PMID- 28837370 TI - Drug-delivering endovascular treatment versus angioplasty in artery occlusion diseases: a systematic review and meta-analysis. AB - OBJECTIVE: The best management of patients with femoropopliteal and infrapopliteal artery occlusion disease is not clear. This study aimed to compare the efficacy of drug-coated balloons (DCBs) and drug-eluting stents (DESs) with percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal or infrapopliteal arterial occlusive disease. METHODS: Medline, Cochrane, Embase, and Google Scholar databases were searched for randomized controlled trials from 1 January 2000 until 30 June 2016. RESULTS: Compared with PTA, significant benefits in favor of DCB and DES were found for target lesion revascularization (TLR) (OR = 0.38, 95% CI = 0.22 to 0.66, p = .001 for DCB; OR = 0.51, 95% CI = 0.32 to 0.81, p < .001 for DES). Primary patency rate was greater with DCB (p = .001) and DES (p < .001) than PTA. Compared with PTA, a significant reduction in mortality was observed in the DCB group (p = .039) but not in the DES group. Subgroup analysis found a lower rate of TLR and a higher rate of primary patency in the active group (DCB and DES) compared with the control group (PTA) in patients with femoropopliteal arterial occlusion (p <= .016) but not in patients with infrapopliteal arterial occlusion (p >= .063). Mortality was similar between active replacement and control groups both in the femoropopliteal arterial occlusion and the infrapopliteal arterial occlusion subgroups (all p > .05). CONCLUSIONS: Significantly better TLR and primary patency rate were found in the drug-delivering endovascular treatments compared with the PTA group for patients with femoropopliteal arterial occlusion but not for patients with infrapopliteal arterial occlusion. PMID- 28837371 TI - BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function. AB - As a member of the bromodomain and extraterminal (BET) family, BRD4 (bromodomain containing 4) can bind to acetylated histones and transcription factors, and is also able to recruit various transcriptional regulators. Previous studies have shown that BRD4 mainly plays a positive role in cell growth and cell cycle progression. In a recent study conducted by Sakamaki et al., the authors found that BRD4 acts as a transcriptional repressor in regulating macroautophagy/autophagy and lysosome gene expression, via binding to the histone lysine methyltransferase EHMT2/G9a. The oncoprotein BRD4-NUTM1/NUT also helps block autophagy and lysosome functions. A knockdown of BRD4 allows the retention of MTOR activity during starvation and significantly undermines starvation induced cell death. However, BRD4 repression only contributes to stimulus dependent autophagy and aggrephagy, and is not involved in other types of selective autophagy. Taken together, the newly reported repressive role of BRD4 in autophagy adds to our understanding of how autophagy and lysosome functions are regulated at the transcriptional level. PMID- 28837368 TI - Advances in the local and targeted delivery of anti-infective agents for management of osteomyelitis. AB - INTRODUCTION: Osteomyelitis, a common and debilitating invasive infection of bone, is a frequent complication following orthopedic surgery and causes pathologic destruction of skeletal tissues. Bone destruction during osteomyelitis results in necrotic tissue, which is poorly penetrated by antibiotics and can serve as a nidus for relapsing infection. Osteomyelitis therefore frequently necessitates surgical debridement procedures, which provide a unique opportunity for targeted delivery of antimicrobial and adjunctive therapies. Areas covered: Following surgical debridement, tissue voids require implanted materials to facilitate the healing process. Antibiotic-loaded, non-biodegradable implants have been the standard of care. However, a new generation of biodegradable, osteoconductive materials are being developed. Additionally, in the face of widespread antimicrobial resistance, alternative therapies to traditional antibiotic regimens are being investigated, including bone targeting compounds, antimicrobial surface modifications of orthopedic implants, and anti-virulence strategies. Expert commentary: Recent advances in biodegradable drug delivery scaffolds make this technology an attractive alternative to traditional techniques for orthopedic infection that require secondary operations for removal. Advances in novel treatment methods are expanding the arsenal of viable antimicrobial treatment strategies in the face of widespread drug resistance. Despite a need for large scale clinical investigations, these strategies offer hope for future treatment of this difficult invasive disease. PMID- 28837372 TI - Update upon efficacy and safety of etanercept for the treatment of spondyloarthritis and juvenile idiopathic arthritis. AB - TNF-alpha inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis (AS), psoriasis (Ps) and/or psoriatic arthritis (PsA) and may be administered off-label to treat disseminated granuloma annulare, systemic lupus erythematosus and systemic sclerosis. There are several TNF-alpha inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. In this article, we discuss the efficacy and safety of etanercept in the treatment of spondyloarthritis and juvenile idiopathic arthritis (JIA). Etanercept is effective in the treatment of PsA, AS, JIA and uveitis. Independent predictors of achieving a sustained clinical improvement or MDA in children with JIA include shorter disease duration, no concurrent oral corticosteroid use, history of chronic anterior uveitis and age <9 years. IBD incidence was lower in patients receiving etanercept plus MTX. Intra-articular administration of etanercept seems to favor a prompt target joint improvement without serious adverse events. Etanercept improve endothelial function reducing the risk of acute cardiovascular and/or cerebrovascular events. The most commonly reported adverse events were nasopharyngitis, epidermal and dermal conditions, upper respiratory tract infection, cough, headache and fatigue. PMID- 28837374 TI - Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update Summary. PMID- 28837373 TI - Informed Consent and Decision Making Among Participants in Novel-Design Phase I Oncology Trials. AB - BACKGROUND: Although phase I clinical trials are the gateway to progress in cancer therapies, this setting poses ethical challenges to ensure that patients provide consent free from misunderstandings of therapeutic intent or unrealistic expectations of benefit. The design of phase I oncology trials has evolved rapidly over time and today includes more targeted agents and combinations of experimental drugs with standard drugs, which may further complicate how patients understand phase I research participation. METHODS: We conducted semistructured interviews regarding motivations, decision making, and understanding of trial purpose nested within a phase I clinical trial of a novel PI3kinase inhibitor combined with a standard oral chemotherapy in 18 participants. RESULTS: Fewer than half of patients correctly identified the safety and dosing objectives. The inclusion of a targeted agent was attractive to participants and was perceived as an indicator of less toxic or more efficacious therapy, with less appreciation for added risks. The significance of a cellular drug target, without a known predictive biomarker of response, was unclear to patients. The inclusion of a standard drug in the regimen attracted patients with more treatment options than traditional first-in-human participants. Patients frequently expressed a realistic understanding of prognosis and uncertainty of benefit, but simultaneous hopes for extraordinary outcomes. CONCLUSION: Novel phase I oncology trial designs may attract patients with less constrained treatment options, but the inclusion of targeted drugs and combinations including standard chemotherapies is likely to complicate understanding of safety and dosing objectives and likelihood of personal benefit for purposes of informed consent. PMID- 28837376 TI - "I Have a Lot of Pills in My Bag, You Know": Institutional Norms in the Provision of Hope in Phase I Clinical Cancer Trials. PMID- 28837375 TI - Hematology-Oncology Fellows' Training in Geriatrics and Geriatric Oncology: Findings From an American Society of Clinical Oncology-Sponsored National Survey. AB - PURPOSE: Older adults compose the majority of patients with cancer in the United States; however, it is unclear how well geriatrics or geriatric oncology training is being incorporated into hematology-oncology (hem-onc) fellowships. METHODS: A convenience sample of hem-onc fellows completed a (written or electronic) survey assessing their education, clinical experiences, and perceived proficiency in geriatric oncology during training; knowledge base in geriatric oncology; confidence in managing older adults with cancer; and general attitudes toward geriatric oncology principles. RESULTS: Forty-five percent of respondents (N = 138) were female, 67% were based in the United States, and most (60%) were past their first year of training. Most fellows rated geriatric oncology as important or very important (84%); however, only 25% reported having access to a geriatric oncology clinic and more than one half (53%) reported no lectures in geriatric oncology. Fellows reported fewer educational experiences in geriatric oncology than in nongeriatric oncology. For example, among procedure-based activities, 12% learned how to perform a geriatric assessment but 78% learned how to perform a bone marrow biopsy ( P < .05). Of those completing the knowledge-based items, 41% were able to identify correctly the predictors of chemotherapy toxicity in older adults with cancer. CONCLUSION: Despite the prevalence of cancer in older adults, hem-onc fellows report limited education in or exposure to geriatric oncology. The high value fellows place on geriatric oncology suggests that they would be receptive to additional training in this area. PMID- 28837378 TI - In praise of M. Anselmier who first used the term "autophagie" in 1859. AB - A Google search for the combined terms "de Duve, autophagy, 1963" will reveal over 45,000 hits, most of them referring to the idea that the term autophagy was coined by the brilliant Christian de Duve on the sidelines of a symposium on lysosomes that took place in 1963. However, the first use of the term "autophagy" actually took place a century earlier. PMID- 28837377 TI - Economic evaluation of rituximab in addition to standard of care chemotherapy for adult patients with acute lymphoblastic leukemia. AB - AIMS: Acute lymphoblastic leukemia (ALL) is an aggressive form of leukemia with a poor prognosis in adult patients. The addition of the monoclonal antibody rituximab to standard chemotherapy has been shown to improve survival in adults with ALL. However, it is unknown whether the addition of rituximab is cost effective. The objective was to determine the economic impact of rituximab in addition to standard of care (SOC) chemotherapy vs SOC alone in newly-diagnosed Philadelphia chromosome-negative, CD20-positive, B-cell precursor ALL. METHODS: A decision analytic model was constructed, based upon the Canadian healthcare system. It included the following health states over a lifetime horizon (max ~60 years): event-free survival (EFS), relapsed/resistant disease, cure, and death. SOC was either hyper-CVAD or the Dana Farber Cancer Institute (DFCI) ALL consortium. EFS, overall survival, and serious adverse event (SAE) rates were derived from a large randomized controlled trial. Costs of the model included: first-line treatment and administration, disease management, second-line and third-line treatment and administration, palliative care, and SAE-related treatments. Inputs were sourced from provincial and national public data, the literature, and cancer agency input. RESULTS: Quality-adjusted life-years (QALYs) increased by 2.20 QALYs with rituximab in addition to SOC. The resulting mean Incremental Cost-Effectiveness Ratio (ICER) was C$21,828/QALY. At a willingness to-pay threshold of C$100,000/QALY, the probability of being cost-effective was 98%. Decision outcomes were robust to the probabilistic and deterministic sensitivity analyses, including the SOC backbone as either hyper-CVAD or DFCI. LIMITATIONS: The results of this analysis are limited by generalizability of the chemotherapy backbone to Canadian practice. CONCLUSIONS: For adults with ALL, rituximab in addition to SOC was found to be a cost-effective intervention, compared to SOC alone. The addition of rituximab is associated with increased life years and increased QALYs at a reasonable incremental cost. PMID- 28837379 TI - Hypolipidemic Effect of Red Gram (Cajanus cajan L.) Prebiotic Oligosaccharides in Wistar NIN Rats. AB - The hypolipidemic effect of red gram prebiotics of raffinose family oligosaccharides was studied in Wistar National Institute of Nutrition male rat strain. The study consisted of 36 rats randomly divided into three groups of 12 rats each. For 16 weeks, Group I was fed with the control diet; Group II was fed with a diet containing 3% standard raffinose as the reference group; Group III received the diet containing 3% red gram prebiotics. The results showed that the gain in body weight was low in the red gram prebiotics-supplemented group followed by the control group; highest increase of body weight was seen in the raffinose standard-fed group. Serum glucose levels of the red gram prebiotic-fed group decreased 14.92% compared to the control group and increased 2.07% compared to the reference group. The decrease in serum triglycerides (TG) levels of the red gram prebiotic-fed groups was 32.76% compared to the control group and 33.64% compared to the reference group. Decrease in the serum TC of the red gram-fed animals was 18.51% and 4.63% compared to the control group and the reference group, respectively. Increase in the level of serum high-density lipoprotein cholesterol (HDL-C) in the red gram-fed animals was 18.51% compared to the control group and 4.63% compared to the reference group. The present study can be a proof for the use of prebiotics as a preventive measure for overweight and obesity in humans, and legume prebiotics can be explored as a novel prebiotic product in the consumer market. PMID- 28837381 TI - Dermal filler-associated malar edema: Treatment of a persistent adverse effect. AB - A 72-year-old Caucasian female presented for evaluation of bilateral lower eyelid "fluid filled" bags that had been present and slowly worsening for 7 years. She reported a history of lower eyelid blepharoplasty in her 40s, as well as hyaluronic acid tear trough fillers 8 years prior to presentation. Her malar edema completely resolved following injection of hyaluronidase. To our knowledge, this is the longest reported interval for presentation and treatment of hyaluronic acid associated malar edema. PMID- 28837380 TI - CaV2 channel subtype expression in rat sympathetic neurons is selectively regulated by alpha2delta subunits. AB - Type two voltage gated calcium (CaV2) channels are the primary mediators of neurotransmission at neuronal presynapses, but their function at neural soma is also important in regulating excitability. 1 Mechanisms that regulate CaV2 channel expression at synapses have been studied extensively, which motivated us to perform similar studies in the soma. Rat sympathetic neurons from the superior cervical ganglion (SCG) natively express CaV2.2 and CaV2.3. 2 We noted previously that heterologous expression of CaV2.1 but not CaV2.2 results in increased calcium current in SCG neurons. 3 In the present study, we extended these observations to show that both CaV2.1 and CaV2.3 expression resulted in increased calcium currents while CaV2.2 expression did not. Further, CaV2.1 could displace native CaV2.2 channels, but CaV2.3 expression could not. Heterologous expression of the individual accessory subunits alpha2delta-1, alpha2delta-2, alpha2delta-3, or beta4 alone failed to increase current density, suggesting that the calcium current ceiling when CaV2.2 was over-expressed was not due to lack of these subunits. Interestingly, introduction of recombinant alpha2delta subunits produced surprising effects on displacement of native CaV2.2 by recombinant channels. Both alpha2delta-1 and alpha2delta-2 seemed to promote CaV2.2 displacement by recombinant channel expression, while alpha2delta-3 appeared to protect CaV2.2 from displacement. Thus, we observe a selective prioritization of CaV channel functional expression in neurons by specific alpha2delta subunits. These data highlight a new function for alpha2delta subtypes that could shed light on subtype selectivity of CaV2 membrane expression. PMID- 28837382 TI - National estimates of 30-day readmissions among children hospitalized for asthma in the United States. AB - OBJECTIVE: Previous single-center studies have reported that up to 40% of children hospitalized for asthma will be readmitted. The study objectives are to investigate the prevalence and timing of 30-day readmissions in children hospitalized with asthma, and to identify factors associated with 30-day readmissions. METHODS: Data (n = 12,842) for children aged 6-18 years hospitalized for asthma were obtained from the 2013 Nationwide Readmission Database (NRD). The primary study outcome was time to readmission within 30 days after discharge attributable to any cause. Several predictors associated with the risk of admission were included: patient (age, sex, median household income, insurance type, county location, and pediatric chronic complex condition), admission (type, day, emergency services utilization, length of stay (LOS), and discharge disposition), and hospital (ownership, bed size, and teaching status). Cox's proportional hazards model was used to identify predictors. RESULTS: Of 12,842 asthma-related index hospitalizations, 2.5% were readmitted within 30-days post-discharge. Time to event models identified significantly higher risk of readmission among asthmatic children aged 12-18 years, those who resided in micropolitan counties, those with >4-days LOS during index hospitalization, those who were hospitalized in an urban hospital, who had unfavorable discharge (hazard ratio 2.53, 95% confidence interval 1.33-4.79), and those who were diagnosed with a pediatric complex chronic condition, respectively, than children in respective referent categories. CONCLUSION: A multi-dimensional approach including effective asthma discharge action plans and follow-up processes, home-based asthma education, and neighborhood/community-level efforts to address disparities should be integrated into the routine clinical care of asthma children. PMID- 28837383 TI - Autophagy is required for gamete differentiation in the moss Physcomitrella patens. AB - Autophagy, a major catabolic process in eukaryotes, was initially related to cell tolerance to nutrient depletion. In plants autophagy has also been widely related to tolerance to biotic and abiotic stresses (through the induction or repression of programmed cell death, PCD) as well as to promotion of developmentally regulated PCD, starch degradation or caloric restriction important for life span. Much less is known regarding its role in plant cell differentiation. Here we show that macroautophagy, the autophagy pathway driven by engulfment of cytoplasmic components by autophagosomes and its subsequent degradation in vacuoles, is highly active during germ cell differentiation in the early diverging land plant Physcomitrella patens. Our data provide evidence that suppression of ATG5 mediated autophagy results in reduced density of the egg cell-mediated mucilage that surrounds the mature egg, pointing toward a potential role of autophagy in extracellular mucilage formation. In addition, we found that ATG5- and ATG7 mediated autophagy is essential for the differentiation and cytoplasmic reduction of the flagellated motile sperm and hence for sperm fertility. The similarities between the need of macroautophagy for sperm differentiation in moss and mouse are striking, strongly pointing toward an ancestral function of autophagy not only as a protector against nutrient stress, but also in gamete differentiation. PMID- 28837384 TI - Adverse Health Outcomes and Associations with Self-Reported General Health in Childhood Lymphoma Survivors. AB - BACKGROUND: The increased incidence of physical and psychosocial adverse health outcomes (AHOs) in childhood lymphoma survivors (CLSs) is well known, but these AHOs' association with self-reported general health is rarely described. AIM: We explored this association among long-term CLSs. METHODS: In 124 CLSs (Hodgkin: 81; non-Hodgkin: 43; median age: 33 years), physical AHOs were graded based on slightly modified common toxicity criteria for adverse effects (CTCAE)-4 recommendations (Grade 0-3). Psychosocial AHOs (pain, work inability, fatigue, and mental distress) were mainly assessed by validated patient-reported questionnaires (Grade 0-2). The results were related to contemporary self reported general health. Statistical significance: p < 0.01. RESULTS: At least one physical AHO was found in 120 CLSs, being of Grades 1, 2, and 3, respectively, in 43, 43, and 34 survivors. The prevalence of psychosocial AHOs (Grades 1 or 2) was 63%, being Grade 2 in 62 CLSs. The CLSs described their general health as significantly reduced compared with controls, with the greatest reduction for survivors in whom physical AHOs were combined with moderate to severe psychosocial AHOs. CONCLUSION: Psychosocial more than physical AHOs impact on CLSs' current self-reported general health. Clinicians responsible for follow up of CLSs should be aware of the strong reduction of contemporary general health by Grade 2 psychosocial AHOs. The study challenges the use of the physician assessed CTCAE-4 categories in long-term cancer survivors and emphasizes the need to develop instruments, which reflect both physical and psychosocial AHOs in these individuals. PMID- 28837386 TI - Crosstalk between translation and the aggresome-autophagy pathway. AB - Many neurodegenerative disorders feature the presence of misfolded polypeptide containing intracellular inclusion bodies biochemically and morphologically analogous to cellular aggresomes. However, it is largely unknown how misfolded polypeptides form aggresomes and are eventually cleared by the aggresome macroautophagy/autophagy pathway, so-called aggrephagy. Our recent study revealed that when the ubiquitin-proteasome system is impaired, the accumulated misfolded polypeptides are selectively recognized and transported to the aggresome by a CED complex. This complex is composed of CTIF, originally identified as a specific factor for nuclear cap-binding protein complex (a heterodimer of NCBP1/CBP80 and NCBP2/CBP20)-dependent translation (CT), and its associated factors EEF1A1 and DCTN1. Aggresomal targeting of a misfolded polypeptide via the CED complex is accompanied by CTIF release from the CT complex and thereby inhibits CT efficiency. Therefore, our study provides new mechanistic insights into the crosstalk between translational inhibition and aggresome formation under the influence of a misfolded polypeptide. PMID- 28837387 TI - CRMP2 is necessary for Neurofibromatosis type 1 related pain. AB - Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases, affecting roughly 1 in 3000 individuals. As a multisystem disorder, it affects cognitive development, as well as bone, nerve and muscle constitution. Peripheral neuropathy in NF1 constitutes a potentially severe clinical complication and is associated with increased morbidity and mortality. The discovery of effective therapies for Neurofibromatosis type 1 (NF1) pain depends on mechanistic understanding that has been limited, in part, by the relative lack of availability of animal models relevant to NF1 pain. We have used intrathecal targeted editing of Nf1 in rats to provide direct evidence of a causal relationship between neurofibromin and pain responses. We demonstrated that editing of neurofibromin results in functional remodeling of peripheral nociceptors characterized by enhancement of interactions of the tetrodotoxin sensitive (TTX-S) Na+ voltage-gated sodium channel (NaV1.7) and the collapsin response mediator protein 2 (CRMP2). Collectively, these peripheral adaptations increase sensory neuron excitability and release of excitatory transmitters to the spinal dorsal horn to establish and maintain a state of central sensitization reflected by hyperalgesia to mechanical stimulation of the hindpaw. The data presented here shows that CRMP2 inhibition is sufficient to reverse the dysregulations of voltage-gated ion channels and neurotransmitter release observed after Nf1 gene editing. The concordance in normalization of ion channel dysregulation by a CRMP2-directed strategy and of hyperalgesia supports the translational targeting of CRMP2 to curb NF1-related pain. PMID- 28837388 TI - Vitamin and Mineral Supplement Use by Community-Dwelling Adults Living in Canada and the United States: A Scoping Review. AB - Vitamin and mineral supplements can assist a person in meeting recommended intakes but excessive use can pose risks. Knowing prevalence of supplement use is the first step toward gauging risk-benefit. This scoping review sought to determine the prevalence of vitamin and mineral supplement use among community dwelling Canadian and American adults. Medline and Embase were searched using keywords and MeSH headings that encapsulated both vitamin and mineral supplements and community-dwelling adults in Canada and the United States. Search limits were set for study participants over the age of 18, English language articles, and a publication date from the year 2000 to June of 2016. Of the 181 articles originally identified, 30 were deemed relevant for this scoping review. Eleven studies reported on vitamin and mineral supplement use in general, without specifying the prevalence of use for any particular supplement(s). Prevalence of general vitamin and mineral supplement use reported in these studies ranged from 7-85%. Twenty-two studies reported the prevalence of consumption for specific vitamins and minerals; although three of these studies also reported on overall supplement use. Calcium and vitamin D were widely reported, with 10 of 22 studies focusing on these key nutrients. Multivitamin/mineral supplements were also widely studied with 8 of 22 articles reporting their prevalence of consumption. Results from this scoping review indicate that data on the quantity and combination of supplement use is lacking in Canada and United States. These data are key for identifying intake amounts and combinations that have the potential to cause adverse effects. PMID- 28837385 TI - Mechanisms and models of cardiac sodium channel inactivation. AB - Shortly after cardiac Na+ channels activate and initiate the action potential, inactivation ensues within milliseconds, attenuating the peak Na+ current, INa, and allowing the cell membrane to repolarize. A very limited number of Na+ channels that do not inactivate carry a persistent INa, or late INa. While late INa is only a small fraction of peak magnitude, it significantly prolongs ventricular action potential duration, which predisposes patients to arrhythmia. Here, we review our current understanding of inactivation mechanisms, their regulation, and how they have been modeled computationally. Based on this body of work, we conclude that inactivation and its connection to late INa would be best modeled with a "feet-on-the-door" approach where multiple channel components participate in determining inactivation and late INa. This model reflects experimental findings showing that perturbation of many channel locations can destabilize inactivation and cause pathological late INa. PMID- 28837389 TI - Basaloid adenocarcinoma of the lacrimal sac: A rare entity and approach to management. AB - Presented is a rare case of basaloid adenocarcinoma of the lacrimal sac. Low grade features of this malignancy permitted a conservative surgical approach to maximize functional and cosmetic outcomes. This is retrospective case description of a single 77-year-old-female patient who underwent a dacryocystorhinostomy with silicone tubes at an outside hospital for epiphora, but was referred to the Wills Eye Hospital Oculoplastics Department for a lacrimal sac biopsy showing low-grade carcinoma with basaloid features. She was treated with complete excision of the mass, common canaliculus and distal canaliculi, and the nasolacrimal duct. The associated maxillary, lacrimal, and ethmoidal bones were similarly excised. Frozen sections were sent of the surrounding periosteum, orbital fat, nasal and sinus mucosa, and soft tissues, and all were negative. Reconstruction of the lacrimal system was performed with silicone tube intubation and the defect was closed with large glabellar and mid-facial flaps. One year post-operatively she maintained a normal ocular examination, and her eyelids and silicone tubes were well positioned. Systemic evaluation remained unrevealing. Basaloid adenocarcinoma of the lacrimal sac is relatively rare, and we highlight the role of a more conservative surgical intervention given the high rates of survival and low incidence of progression to metastatic disease when treating this rare malignancy. PMID- 28837390 TI - Genome-wide gene expression analysis of amphioxus (Branchiostoma belcheri) following lipopolysaccharide challenge using strand-specific RNA-seq. AB - Amphioxus is the closest living proxy for exploring the evolutionary origin of the immune system in vertebrates. To understand the immune responses of amphioxus to lipopolysaccharide (LPS), 5 ribosomal RNA (rRNA)-depleted libraries of amphioxus were constructed, including one control (0 h) library and 4 treatment libraries at 6, 12, 24, and 48 h post-injection (hpi) with LPS. The transcriptome of Branchiostoma belcheri was analyzed using strand-specific RNA sequencing technology (RNA-seq). A total of 6161, 6665, 7969, and 6447 differentially expressed genes (DEGs) were detected at 6, 12, 24, and 48 hpi, respectively, compared with expression levels at 0 h. We identified amphioxus genes active during the acute-phase response to LPS at different time points after stimulation. Moreover, to better visualize the resolution phase of the immune process during immune response, we identified 6057 and 5235 DEGs at 48 hpi by comparing with 6 and 24 hpi, respectively. Through real-time quantitative PCR (qRT-PCR) analysis of 12 selected DEGs, we demonstrated the accuracy of the RNA seq data in this study. Functional enrichment analysis of DEGs demonstrated that most terms were related to defense and immune responses, disease and infection, cell apoptosis, and metabolism and catalysis. Subsequently, we identified 1330, 485, 670, 911, and 1624 time-specific genes (TSGs) at 0, 6, 12, 24, and 48 hpi. Time-specific terms at each of 5 time points were primarily involved in development, immune signaling, signal transduction, DNA repair and stability, and metabolism and catalysis, respectively. As this is the first study to report the transcriptome of an organism with primitive immunity following LPS challenge at multiple time points, it provides gene expression information for further research into the evolution of immunity in vertebrates. PMID- 28837392 TI - When Self-Interest Contradicts Ideology: A Reply to Hoffarth and Jost (2017). PMID- 28837391 TI - Naive B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1-/- mice. AB - IgM and B-1 cell deficient mice exhibit early C. neoformans dissemination from lungs to brain, but a definitive role for B cells in conferring resistance to C. neoformans dissemination has not been established. To address this question, we developed an intranasal (i.n.) C. neoformans infection model in B and T cell deficient Rag1-/- mice and found they also exhibit earlier fungal dissemination and higher brain CFU than wild-type C57Bl/6 (wild-type) mice. To probe the effect of B cells on fungal dissemination, Rag1-/- mice were given splenic (intravenously) or peritoneal (intraperitoneally) B cells from wild-type mice and infected i.n. with C. neoformans 7 d later. Mice that received B cells had lung histopathology resembling wild type mice 14 d post-infection, and B-1, not B-2 or T cells in their lungs, and serum and lung IgM and IgG 21 d post-infection. Lung CFU were comparable in wild-type, Rag1-/-, and Rag1-/- mice that received B cells 21 d post-infection, but brain CFU were significantly lower in mice that received B cells than Rag1-/- mice that did not. To determine if natural antibody can promote immunity in our model, we measured alveolar macrophage phagocytosis of C. neoformans in Rag1-/- mice treated with naive wild-type IgM-sufficient or sIgM-/- IgM-deficient sera before infection. Compared to IgM-deficient sera, IgM sufficient sera significantly increased phagocytosis. Our data establish B cells are able to reduce early C. neoformans dissemination in mice and suggest natural IgM may be a key mediator of early antifungal immunity in the lungs. PMID- 28837394 TI - Corrigendum. PMID- 28837393 TI - Claudins in morphogenesis: Forming an epithelial tube. AB - The claudin family of tetraspan transmembrane proteins is essential for tight junction formation and regulation of paracellular transport between epithelial cells. Claudins also play a role in apical-basal cell polarity, cell adhesion and link the tight junction to the actin cytoskeleton to exert effects on cell shape. The function of claudins in paracellular transport has been extensively studied through loss-of-function and gain-of-function studies in cell lines and in animal models, however, their role in morphogenesis has been less appreciated. In this review, we will highlight the importance of claudins during morphogenesis by specifically focusing on their critical functions in generating epithelial tubes, lumens, and tubular networks during organ formation. PMID- 28837396 TI - Research and proposal on selective catalytic reduction reactor optimization for industrial boiler. AB - : The advanced computational fluid dynamics (CFD) software STAR-CCM+ was used to simulate a denitrification (De-NOx) project for a boiler in this paper, and the simulation result was verified based on a physical model. Two selective catalytic reduction (SCR) reactors were developed: reactor 1 was optimized and reactor 2 was developed based on reactor 1. Various indicators, including gas flow field, ammonia concentration distribution, temperature distribution, gas incident angle, and system pressure drop were analyzed. The analysis indicated that reactor 2 was of outstanding performance and could simplify developing greatly. Ammonia injection grid (AIG), the core component of the reactor, was studied; three AIGs were developed and their performances were compared and analyzed. The result indicated that AIG 3 was of the best performance. The technical indicators were proposed for SCR reactor based on the study. IMPLICATIONS: Flow filed distribution, gas incident angle, and temperature distribution are subjected to SCR reactor shape to a great extent, and reactor 2 proposed in this paper was of outstanding performance; ammonia concentration distribution is subjected to ammonia injection grid (AIG) shape, and AIG 3 could meet the technical indicator of ammonia concentration without mounting ammonia mixer. The developments above on the reactor and the AIG are both of great application value and social efficiency. PMID- 28837395 TI - Nightshift work, chronotype, and genome-wide DNA methylation in blood. AB - Molecular mechanisms underlying the negative health effects of shift work are poorly understood, which remains a barrier to developing intervention strategies to protect the long-term health of shift workers. We evaluated genome-wide differences in DNA methylation (measured in blood) between 111 actively employed female nightshift and 86 actively employed female dayshift workers from the Seattle metropolitan area. We also explored the effect of chronotype (i.e., measure of preference for activity earlier or later in the day) on DNA methylation among 110 of the female nightshift workers and an additional group of 131 male nightshift workers. Methylation data were generated using the Illumina Infinium HumanMethylation450 BeadChip (450K) Array. After applying the latest methylation data processing methods, we compared methylation levels at 361,210 CpG loci between the groups using linear regression models adjusted for potential confounders and applied the false-discovery rate (FDR) <= 0.05 to account for multiple comparisons. No statistically significant associations at the genome wide level were observed with shift work or chronotype, though based on raw P values and absolute effect sizes, there were suggestive associations in genes that have been previously linked with cancer (e.g., BACH2, JRK, RPS6KA2) and type 2 diabetes (e.g., KCNQ1). Given that our study was underpowered to detect moderate effects, examining these suggestive results in well-powered independent studies or in pooled data sets may improve our understanding of the pathways underlying the negative health effects of shift work and the influence of personal factors such as chronotype. Such an approach may help identify potential interventions that can be used to protect the long-term health of shift workers. PMID- 28837397 TI - When Ideology Contradicts Self-Interest: Conservative Opposition to Same-Sex Marriage Among Sexual Minorities-A Commentary on Pinsof and Haselton (2016). PMID- 28837399 TI - Enhancement of cell wall protein SRPP expression during emergent root hair development in Arabidopsis. AB - SRPP is a protein expressed in seeds and root hairs and is significantly induced in root hairs under phosphate (Pi)-deficient conditions. Root hairs in the knockout mutant srpp-1 display defects, i.e., suppression of cell growth and cell death. Here, we analyzed the expression profile of SRPP during cell elongation of root hairs and compared the transcript levels in several mutants with short root hairs. The mRNA level was increased in wild-type plants and decreased in mutants with short root hairs. Induction of SRPP expression by Pi starvation occurred one or two days later than induction of Pi-deficient sensitive genes, such as PHT1 and PHF1. These results indicate that the expression of SRPP is coordinated with root hair elongation. We hypothesize that SRPP is essential for structural robustness of the cell walls of root hairs. PMID- 28837400 TI - PKC SUMOylation inhibits the binding of 14-3-3tau to GluK2. AB - Phosphorylation and SUMOylation of the kainate receptor (KAR) subunit GluK2 have been shown to regulate KAR surface expression, trafficking and synaptic plasticity. In addition, our previous study has shown that a phosphorylation dependent interaction of 14-3-3tau and GluK2a-containing receptors contributes to the slow decay kinetics of native KAR-EPSCs. However, it is unknown whether SUMOylation participates in the regulation of the interaction between 14-3-3tau and GluK2a-containing receptors. Here we report that SUMOylation of PKC, but not GluK2, represses the binding of 14-3-3tau to GluK2a via decreasing the phosphorylation level of GluK2a. These results suggest that PKC SUMOylation is an important regulator of the 14-3-3 and GluK2a protein complex and may contribute to regulate the decay kinetics of KAR-EPSCs. PMID- 28837398 TI - The long noncoding RNA Malat1: Its physiological and pathophysiological functions. AB - Recent studies suggest that in humans, DNA sequences responsible for protein coding regions comprise only 2% of the total genome. The rest of the transcripts result in RNA transcripts without protein-coding ability, including long noncoding RNAs (lncRNAs). Different from most members in the lncRNA family, the metastasis-associated lung adenocarcinoma transcript 1 (Malat1) is abundantly expressed and evolutionarily conserved throughout various mammalian species. Malat1 is one of the first identified lncRNAs associated with human disease, and cumulative studies have indicated that Malat1 plays critical roles in the development and progression of various cancers. Malat1 is also actively involved in various physiologic processes, including alternative splicing, epigenetic modification of gene expression, synapse formation, and myogenesis. Furthermore, extensive evidences show that Malat1 plays pivotal roles in multiple pathological conditions as well. In this review, we will summarize latest findings related to the physiologic and pathophysiological processes of Malat1 and discuss its therapeutic potentials. PMID- 28837401 TI - Complex roles of myoglianin in regulating adult performance and lifespan. AB - Myoglianin, the Drosophila homolog of the secreted vertebrate proteins Myostatin and GDF-11, is an important regulator of neuronal modeling, and synapse function and morphology. While Myoglianin suppression during development elicits positive effects on the neuromuscular system, genetic manipulations of myoglianin expression levels have a varied effect on the outcome of performance tests in aging flies. Specifically, Myoglianin preserves jumping ability, has no effect on negative geotaxis, and negatively regulates flight performance in aging flies. In addition, Myoglianin exhibits a tissue-specific effect on longevity, with myoglianin upregulation in glial cells increasing the median lifespan. These findings indicate complex role for this TGF-beta-like protein in governing neuromuscular signaling and consequent behavioral outputs and lifespan in adult flies. PMID- 28837402 TI - tRNAPyl: Structure, function, and applications. AB - Pyrrolysine is the 22nd proteinogenic amino acid encoded into proteins in response to amber (TAG) codons in a small number of archaea and bacteria. The incorporation of pyrrolysine is facilitated by a specialized aminoacyl-tRNA synthetase (PylRS) and its cognate tRNA (tRNAPyl). The secondary structure of tRNAPyl contains several unique features not found in canonical tRNAs. Numerous studies have demonstrated that the PylRS/tRNAPyl pair from archaea is orthogonal in E. coli and eukaryotic hosts, which has led to the widespread use of this pair for the genetic incorporation of non-canonical amino acids. In this brief review we examine the work that has been done to elucidate the structure of tRNAPyl, its interaction with PylRS, and survey recent progress on the use of tRNAPyl as a tool for genetic code expansion. PMID- 28837403 TI - Environmentally realistic exposure to weathered North Sea oil: Sublethal effects in Atlantic cod (Gadus morhua) and turbot (Scophthalmus maximus). AB - With increasing oil and gas activities and transport in the Arctic, there is a need to understand how operational or accidental releases of substances affect marine organisms from a pristine environment. The aim of the current study was to describe and compare the responses of two marine fish species, Atlantic cod (Gadus morhua) and turbot (Scophthalmus maximus), following exposure to three levels (low, medium, high) of the water-soluble fraction of a North Sea crude oil for 16 days. The exposure system simulated environmental exposure by allowing clean seawater to percolate through gravel covered in weathered oil before being introduced to aquaria. Both polycyclic aromatic hydrocarbon (PAH) metabolite bile concentrations and cytochrome P4501A (CYP1A) levels and activity increased markedly in comparison with controls in both species, but there were no significant differences between the three exposures. Turbot possessed 4-5-fold higher concentrations of two PAH bile metabolites compared to Atlantic cod by day 8. In contrast, hepatic CYP1A activity in cod was consistently 2-6-fold higher than in turbot with increasing differences over the experimental period. Baseline DNA strand breaks in lymphocytes and kidney cells were low in both species, but was elevated for all treatments by day two. There were no marked indications of the treatments affecting immune functions in either species. This investigation demonstrated that there may be significant differences in responses between species receiving identical exposures and that DNA strand breaks in lymphocytes and kidney cells are sensitive to confinement stress. Data also indicate that some species, such as turbot, may adapt to treatments within days and weeks. PMID- 28837405 TI - Safety and Antitumor Activity of Pembrolizumab in Patients With Programmed Death Ligand 1-Positive Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. AB - Purpose To establish the safety profile and antitumor activity of the anti programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade >= 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC. PMID- 28837407 TI - A dynamic energy-based model to analyze sublethal effects of chronic gamma irradiation in the nematode Caenorhabditis elegans. AB - Understanding how toxic contaminants affect wildlife species at various levels of biological organization (subcellular, histological, physiological, organism, and population levels) is a major research goal in both ecotoxicology and radioecology. A mechanistic understanding of the links between different observed perturbations is necessary to predict the consequences for survival, growth, and reproduction, which are critical for population dynamics. In this context, experimental and modeling studies were conducted using the nematode Caenorhabditis elegans. A chronic exposure to external gamma radiation was conducted under controlled conditions. Results showed that somatic growth and reproduction were reduced with increasing dose rate. Modeling was used to investigate whether radiation effects might be assessed using a mechanistic model based upon the dynamic energy budget (DEB) theory. A DEB theory in toxicology (DEB-tox), specially adapted to the case of gamma radiation, was developed. Modelling results demonstrated the suitability of DEB-tox for the analysis of radiotoxicity and suggested that external gamma radiation predominantly induced a direct reduction in reproductive capacity in C. elegans and produced an increase in costs for growth and maturation, resulting in a delay in growth and spawning observed at the highest tested dose rate. PMID- 28837404 TI - Human Papillomavirus Vaccination Rates in Young Cancer Survivors. AB - Purpose Cancer survivors are at high risk for human papillomavirus (HPV)-related morbidities; we estimated the prevalence of HPV vaccine initiation in cancer survivors versus the US population and examined predictors of noninitiation. Methods Participants included 982 cancer survivors (9 to 26 years of age; 1 to 5 years postcompletion of therapy); we assessed HPV vaccine initiation, sociodemographic and clinical characteristics, and vaccine-specific health beliefs; age-, sex-, and year-matched US population comparisons were from the National Immunization Survey-Teen and the National Health Interview Survey (2012 2015). Results The mean age at the time of the study was 16.3 +/- 4.7 years; the mean time off therapy was 2.7 +/- 1.2 years; participants were 55% male and 66% non-Hispanic white; 59% had leukemia/lymphoma. Vaccine initiation rates were significantly lower in cancer survivors versus the general population (23.8%; 95% CI, 20.6% to 27.0% v 40.5%; 95% CI, 40.2% to 40.7%; P < .001); survivors were more likely to be HPV vaccine-naive than general population peers (odds ratio [OR], 1.72; 95% CI, 1.41 to 2.09; P < .001). Initiation in adolescent survivors (ages 13 to 17 years) was 22.0% (95% CI, 17.3% to 26.7%), significantly lower than population peers (42.5%; 95% CI, 42.2% to 42.8%; P < .001). Initiation in young adult survivors and peers (ages 18 to 26 years) was comparably low (25.3%; 95% CI, 20.9% to 29.7% v 24.2%; 95% CI, 23.6% to 24.9%). Predictors of noninitiation included lack of provider recommendation (OR, 10.8; 95% CI, 6.5 to 18.0; P < .001), survivors' perceived lack of insurance coverage for HPV vaccine (OR, 6.6; 95% CI, 3.9 to 11.0; P < .001), male sex (OR, 2.9; 95% CI, 1.7 to 4.8; P < .001), endorsement of vaccine-related barriers (OR, 2.7; 95% CI, 1.6 to 4.6; P < .001), and younger age (9 to 12 years; OR, 3.7; 95% CI, 1.8-7.6; P < .001; comparison, 13 to 17 years). Conclusion HPV vaccine initiation rates in cancer survivors are low. Lack of provider recommendation and barriers to vaccine receipt should be targeted in vaccine promotion efforts. PMID- 28837406 TI - Evaluation of waste isoflurane gas exposure during rodent surgery in an Australian university. AB - Biomedical researchers use of inhalational anesthetics has increased in recent years. Use of isoflurane as an inhalational anesthetic may result in human exposure to waste anesthetic gas. Potential health effects from exposure include genotoxic and hepatotoxic effects with some evidence of teratogenic and reproductive effects. Research suggests that exposure to waste anesthetic gas within human hospital settings has improved substantially but exposures to biomedical researchers and veterinarians still requires improvement. A number of biomedical research facilities are located at The University of Queensland, Australia, where researchers and animal handlers are potentially exposed to waste isoflurane gas. There is limited published data on the exposures received by biomedical researchers performing routine procedures. This project aimed to assess isoflurane exposure received during routine rodent anesthetic protocols performed at the university. Atmospheric concentrations of isoflurane were assessed via two methods-personal active gas sampling using sorbent tubes and direct readings using infrared spectroscopy. Total procedure and isoflurane exposure times ranged from 135-268 min. Personal sorbent tube sampling detected isoflurane levels from below detectable limits (<0.01 ppm) to a Time Weighted Average for the task (TWA-Task) of 6.20 ppm (0.73 +/- 9.13). Participants were not exposed to isoflurane outside of the sampling period during the remainder of the workday. TWA-8 hr adjusted levels ranged from below the limit of detection to 1.76 ppm isoflurane (0.69 ppm +/- 0.61 ppm). The infrared spectroscopy readings taken in the breathing zone of participants ranged from 0.1-68 ppm. Results indicate that if adequately controlled through good room ventilation, effective active gas scavenging and well constructed anesthetic equipment, waste anesthetic exposures are minimal. However, where industry standards are not met exposures may occur, including some high peak exposures. PMID- 28837409 TI - Use of a gas chromatography-mass spectrometry organic aerosol monitor for in field detection of fine particulate organic compounds in source apportionment. AB - : A study was conducted on the Brigham Young University campus during January and February 2015 to identify winter-time sources of fine particulate material in Utah Valley, Utah. Fine particulate mass and components and related gas-phase species were all measured on an hourly averaged basis. Light scattering was also measured during the study. Included in the sampling was the first-time source apportionment application of a new monitoring instrument for the measurement of fine particulate organic marker compounds on an hourly averaged basis. Organic marker compounds measured included levoglucosan, dehydroabietic acid, stearic acid, pyrene, and anthracene. A total of 248 hourly averaged data sets were available for a positive matrix factorization (PMF) analysis of sources of both primary and secondary fine particulate material. A total of nine factors were identified. The presence of wood smoke emissions was associated with levoglucosan, dehydroabietic acid, and pyrene markers. Fine particulate secondary nitrate, secondary organic material, and wood smoke accounted for 90% of the fine particulate material. Fine particle light scattering was dominated by sources associated with wood smoke and secondary ammonium nitrate with associated modeled fine particulate water. IMPLICATIONS: The identification of sources and secondary formation pathways leading to observed levels of PM2.5 (particulate matter with an aerodynmaic diameter <2.5 MUm) is important in making regulatory decisions on pollution control. The use of organic marker compounds in this assessment has proven useful; however, data obtained on a daily, or longer, sampling schedule limit the value of the information because diurnal changes associated with emissions and secondary aerosol formation cannot be identified. A new instrument, the gas chromtography-mass spectrometry (GC-MS) organic aerosol monitor, allows for the determination on these compounds on an hourly averaged basis. The demonstrated potential value of hourly averaged data in a source apportionment analysis indicates that significant improvement in the data used for making regulatory decisions is possible. PMID- 28837408 TI - Intestinal surfactant permeation enhancers and their interaction with enterocyte cell membranes in a mucosal explant system. AB - Intestinal permeation enhancers (PEs) are agents aimed to improve oral delivery of therapeutic drugs with poor bioavailability. The main permeability barrier for oral delivery is the intestinal epithelium, and PEs act to increase the paracellular and/or transcellular passage of drugs. Transcellular passage can be achieved by cell membrane permeabilization and/or by endocytic uptake and subsequent transcytosis. One broad class of PEs is surfactants which act by inserting into the cell membrane, thereby perturbing its integrity, but little is known about how the dynamics of the membrane are affected. In the present work, the interaction of the surfactants lauroyl-L-carnitine, 1-decanoyl-rac-glycerol, and nonaethylene glycol monododecyl ether with the intestinal epithelium was studied in organ cultured pig jejunal mucosal explants. As expected, at 2 mM, these agents rapidly permeabilized the enterocytes for the fluorescent polar tracer lucifer yellow, but surprisingly, they all also blocked both constitutive and receptor-mediated pathways of endocytosis from the brush border, indicating a complete arrest of apical membrane trafficking. At the ultrastructural level, the PEs caused longitudinal fusion of brush border microvilli. Such a membrane fusogenic activity could also explain the observed formation of vesicle-like structures and large vacuoles along the lateral cell membranes of the enterocytes induced by the PEs. We conclude that the surfactant action of the PEs selected in this study not only permeabilized the enterocytes, but profoundly changed the dynamic properties of their constituent cell membranes. PMID- 28837410 TI - New insights into artemisinin regulation. AB - Artemisinin is a sesquiterpene lactone coming from the traditional Chinese herb Artemisia annua L. Artemisinin combination therapies (ACTs) are the main recommended treatment of malaria. Transcription factors regulation of artemisinin belong to different families including AP2/ERF, bHLH, MYB and WRKY. Plant hormones jasmonic acid (JA), abscisic acid (ABA), salicylic acid (SA) and gibberellins (GA) have been described as positively affecting artemisinin biosynthesis in A. annua. Transporter and miRNA open up new possibilities for the biosynthesis of high value artemisinin. We review recently major developments regarding regulator which play a center role in artemisinin biosynthesis, and provide suggestion for further studies. PMID- 28837411 TI - Regulation of autophagy, mitochondrial dynamics, and cellular bioenergetics by 4 hydroxynonenal in primary neurons. AB - The production of reactive species contributes to the age-dependent accumulation of dysfunctional mitochondria and protein aggregates, all of which are associated with neurodegeneration. A putative mediator of these effects is the lipid peroxidation product 4-hydroxynonenal (4-HNE), which has been shown to inhibit mitochondrial function, and accumulate in the postmortem brains of patients with neurodegenerative diseases. This deterioration in mitochondrial quality could be due to direct effects on mitochondrial proteins, or through perturbation of the macroautophagy/autophagy pathway, which plays an essential role in removing damaged mitochondria. Here, we use a click chemistry-based approach to demonstrate that alkyne-4-HNE can adduct to specific mitochondrial and autophagy related proteins. Furthermore, we found that at lower concentrations (5-10 MUM), 4-HNE activates autophagy, whereas at higher concentrations (15 MUM), autophagic flux is inhibited, correlating with the modification of key autophagy proteins at higher concentrations of alkyne-4-HNE. Increasing concentrations of 4-HNE also cause mitochondrial dysfunction by targeting complex V (the ATP synthase) in the electron transport chain, and induce significant changes in mitochondrial fission and fusion protein levels, which results in alterations to mitochondrial network length. Finally, inhibition of autophagy initiation using 3-methyladenine (3MA) also results in a significant decrease in mitochondrial function and network length. These data show that both the mitochondria and autophagy are critical targets of 4-HNE, and that the proteins targeted by 4-HNE may change based on its concentration, persistently driving cellular dysfunction. PMID- 28837412 TI - Recurrence of Colonic Diverticulitis: Identifying Predictive CT Findings Retrospective Cohort Study. AB - Purpose To identify computed tomographic (CT) findings that are predictive of recurrence of colonic diverticulitis. Materials and Methods Institutional review board approval was obtained for this HIPAA-compliant, retrospective cohort study. Six abdominal fellowship-trained radiologists reviewed the CT studies of 440 consecutive subjects diagnosed with acute colonic diverticulitis between January 2004 and May 2008 to determine the involved segments, maximum wall thickness in the inflamed segment, severity of diverticulosis, presence of complications (abscess, fistula, stricture, or perforation), and severity of the inflammation. Electronic medical records were reviewed for a 5-year period after the patients' first CT study to determine clinical outcomes. Predictors of diverticulitis recurrence were assessed with univariate and multiple Cox proportional hazard regression models. Results Colonic diverticulitis most commonly involved the rectosigmoid (70%, 309 of 440) and descending (30%, 133 of 440) colon segments. Complicated diverticulitis was present in 22% (98 of 440) of patients. On the basis of the results of univariate analysis, significant predictors of diverticulitis recurrence were determined to be maximum colonic wall thickness in the inflamed segment (hazard ratio [HR], 1.07 per every millimeter of increase in wall thickness; P < .001), presence of a complication (HR, 1.75; P = .002), and subjective severity of inflammation (HR, 1.36 for every increase in severity category; P value for linear trend = .003). The difference in maximum wall thickness in the inflamed segment (HR, 1.05 per millimeter; P = .016) and subjective inflammation severity (HR, 1.29 per category; P = .018)remained statistically significant in a Cox multiple regression model. Conclusion Maximum colonic wall thickness and subjective severity of acute diverticulitis allow prediction of recurrent diverticulitis and may be useful for stratifying patients according to the need for elective partial colectomy. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28837414 TI - Lateral tarsal strip plus skin-muscle flap excision in the treatment of lower eyelid involutional entropion. AB - This article examines the effectiveness of skin-muscle flap excision in conjunction with a lateral tarsal strip for the treatment of involutional entropion. Ninety-six eyelids in 83 consecutive patients with involutional entropion were treated using a standardized surgical procedure. All patients underwent lower eyelid tightening with a lateral tarsal strip, dissection of a skin-muscle flap inferiorly through a subciliary incision and excision of redundant skin as well as orbicularis muscle. Follow-up data was obtained by retrospective chart review and telephone interviews. 80 patients were included in this study. The only exclusion criteria was failure to attend the 1 week follow up appointment, n = 3. There was only one recurrence which was mild and revised under local anesthesia. Two patients had overcorrection with mild ectropion but did not require additional surgery. In those that completed their initial post operative visit, the average time follow-up time was 502 days. Excision of a skin muscle flap is a useful addition to lateral tarsal strip surgery in the treatment of involutional entropion and is a quick procedure producing excellent functional and cosmetic results. To our knowledge, this is the first cohort of patients to be reported using this technique where all patients had a standardized surgical approach. Additional studies are needed to compare long-term outcomes of this technique against other surgical treatments. PMID- 28837413 TI - Radiologic Features of Small Pulmonary Nodules and Lung Cancer Risk in the National Lung Screening Trial: A Nested Case-Control Study. AB - Purpose To extract radiologic features from small pulmonary nodules (SPNs) that did not meet the original criteria for a positive screening test and identify features associated with lung cancer risk by using data and images from the National Lung Screening Trial (NLST). Materials and Methods Radiologic features in SPNs in baseline low-dose computed tomography (CT) screening studies that did not meet NLST criteria to be considered a positive screening examination were extracted. SPNs were identified for 73 incident case patients who were given a diagnosis of lung cancer at either the first or second follow-up screening study and for 157 control subjects who had undergone three consecutive negative screening studies. Multivariable logistic regression was used to assess the association between radiologic features and lung cancer risk. All statistical tests were two sided. Results Nine features were significantly different between case patients and control subjects. Backward elimination followed by bootstrap resampling identified a reduced model of highly informative radiologic features with an area under the receiver operating characteristic curve of 0.932 (95% confidence interval [CI]: 0.88, 0.96), a specificity of 92.38% (95% CI: 52.22%, 84.91%), and a sensitivity of 76.55% (95% CI: 87.50%, 95.35%) that included total emphysema score (odds ratio [OR] = 1.71; 95% CI: 1.39, 2.01), attachment to vessel (OR = 2.41; 95% CI: 0.99, 5.81), nodule location (OR = 3.25; 95% CI: 1.09, 8.55), border definition (OR = 7.56; 95% CI: 1.89, 30.8), and concavity (OR = 2.58; 95% CI: 0.89, 5.64). Conclusion A set of clinically relevant radiologic features were identified that that can be easily scored in the clinical setting and may be of use to determine lung cancer risk among participants with SPNs. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28837415 TI - The efficacy of abatacept focusing on anti-CCP antibody in Japanese patients with rheumatoid arthritis for 104 weeks. PMID- 28837416 TI - Evaluation of alternative filter media for particulate matter emission testing of residential wood heating devices. AB - : The performance of Teflon-coated glass fiber filter media (Pallflex Emfab TX40) is evaluated for particulate matter (PM) sampling of residential wood heating devices in a dilution tunnel. Thirty samples of varying duration and PM loading and concentration were collected from an U.S. Environmental Protection Agency (EPA) Method 28 dilution tunnel using dual Method 5G sample trains with untreated glass fiber and Emfab filters. Filters were weighed soon after the end of sampling and again the next day after equilibration at 35% relative humidity (RH). PM concentrations from both types of filters agreed very well with 1-day equilibration, demonstrating that Emfab filters are appropriate for use in measuring PM from residential wood burning appliances in a dilution tunnel and have performance equal to or better than the glass fiber filter media. Agreement between filter media without equilibration was erratic, with PM from glass fiber filter samples varying from slightly less than the Emfab samples to as much as 2.8 times higher. Some of the glass fiber filters lost substantial mass with equilibration, with the highest percent loss at lower filter mass loadings. Mass loss for Emfab samples was a small percentage of the mass and very consistent across the range of mass loadings. Taken together, these results may indicate water uptake on the glass fiber media that is readily removed with 1-day equilibration at moderate RH conditions. IMPLICATIONS: EPA regulations now allow the use of either glass fiber or Teflon filter media for wood appliance PM emission testing. Teflon filter media minimizes the potential for acid-gas PM artifacts on glass fiber filters; this is important as EPA moves toward the use of locally sourced cordwood for testing that may have higher sulfur content. This work demonstrates that the use of Teflon-coated glass fiber filters can give similar PM measurement results to glass fiber filters after 1 day of equilibration. With no equilibration, measured PM from glass fiber filters was usually higher than from Teflon-coated glass fiber filters. PMID- 28837417 TI - Baseline and oxidative DNA damage in marine invertebrates. AB - Anthropogenic pollutants produce oxidative stress in marine organisms, directly or following generation of reactive oxygen species (ROS), potentially resulting in increased accumulation of DNA strand breaks quantified. The aim of this study is to quantify baseline levels of DNA strand breaks in marine species from four phyla and to assess relative sensitivity to oxidative stress as well as ability to recover. DNA strand breaks were determined using a formamidopyrimidine DNA glycosylase (Fpg)-amended comet assay in circulating cells from blue mussel (Mytilus edulis), shore crab (Carcinus maenas), sea star (Asterias rubens), and vase tunicate (Ciona intestinalis). Lymphocytes from Atlantic cod (Gadus morhua) were used as a reference. In addition to immediate analysis, cells from all species were exposed ex vivo to two concentrations of hydrogen peroxide (H2O2) at 25 or 250 MUM prior to assay. Mean baseline DNA strand breaks were highest for cells from sea star (34%) followed by crab (25%), mussel (22%), tunicate (17%), and cod (14%). Circulating cells from invertebrates were markedly more sensitive to oxidative stress compared to cod lymphocytes. DNA strand breaks exceeded 80% for sea star, crab, and mussel cells following exposure to the lowest H2O2 concentration. There was no recovery for cells from any species following 1 hr in buffer. This study provides an in-depth analysis of DNA integrity for ecologically important species representing 4 phyla. Data indicate that circulating cells from invertebrates are more sensitive to oxidative stress than cells from fish as evidenced by DNA strand breaks. Future studies need to address the extent to which DNA strand breaks may exert consequences for body maintenance costs in marine invertebrates. PMID- 28837418 TI - The National Elder Mistreatment Study: An 8-year longitudinal study of outcomes. AB - OBJECTIVES: To conduct an 8-year follow-up of the National Elder Mistreatment Study (NEMS) and specify risk ratios for negative outcomes of elder abuse, including DSM-5 defined depression, generalized anxiety disorder (GAD), post traumatic stress disorder (PTSD), and poor self-reported health. METHODS: Attempts were made to re-contact, via Computer Assisted Telephone Interview, all 752 NEMS participants who reported mistreatment since age 60 at Wave I, as well as a randomly selected sample of non-mistreated NEMS participants Results: 183 NEMS Wave I elder abuse victims and 591 non-victims provided data. In bivariate analyses, elder mistreatment 8 years earlier increased risk of negative outcomes by 200-700%. However, multivariate analyses revealed that Current (Wave II) social support was highly protective against most negative outcomes (excepting PTSD), and even appeared to nullify effects of mistreatment on GAD and poor self reported health. CONCLUSIONS: Outcomes of elder mistreatment have not been studied prospectively in a national sample. The NEMS 8-year follow-up findings indicate a strong relationship between elder mistreatment at Wave I and negative emotional and physical health 8 years later. Fortunately, current (Wave II) social support appears to be both consistently and powerfully protective against most negative outcomes. PMID- 28837420 TI - Relationship between childhood bullying and addictive and anti-social behaviors among adults in Saudi Arabia: a cross-sectional national study. AB - Background Bullying is a widespread public health problem among youth with potentially far reaching negative implications. Objective To determine the prevalence of childhood bullying and its association with addictive and anti social behaviors among adults. Subjects Adults (n = 10,156) aged >=18 years were invited to participate. Methods A cross-sectional, national study utilizing Adverse Childhood Experiences International Questionnaire (ACE-IQ) was conducted in Saudi Arabia (SA). Odds ratios (OR) and 95% confidence intervals (CIs) were calculated for bullying in relation to the outcome. Results Participant's mean age was 34.3 +/- 11.3 years and 52% were male. Thirty-nine percent of the participants reported being bullied. Significant gender differences were found in terms of prevalence of different types of bullying. Men reported higher prevalence of physical (40% vs. 33%, p < 0.01) and sexual (19% vs. 10%, p < 0.01) types of bullying. In contrast, women tend to report higher prevalence of psychological (16% vs. 9%, p < 0.01) and social (14% vs. 10%, p < 0.01) types of bullying. Bullying victims were 1.8 (95% CI 1.6-2.1) times more likely to smoke, 2.3 (95% CI 1.9-2.7) times more likely to drink alcohol, 2.9 (95% CI 2.4-3.4) times more likely to use drugs, 2.1 (95% CI 1.8-2.4) times more likely to have ever had out of wedlock sexual relations, and 2.5 (95% CI 2.1-3.0) times more likely to have suicidal thoughts compared to those who were not bullied. Conclusion Childhood bullying increases the chances of risky behaviors among adults in SA. Prevention of bullying should be in the national agenda of the Ministry of Education. PMID- 28837421 TI - Comparison of different volumes of high intensity interval training on cardiac autonomic function in sedentary young women. AB - Purpose The present study was conducted to compare the effects of low volume of high intensity interval training (LVHIIT) and high volume of high intensity interval training (HVHIIT) on heart rate variability (HRV) as a primary outcome measure, and on maximum oxygen consumption (VO2max), body composition, and lower limb muscle strength as secondary outcome measures, in sedentary young women. Methods Thirty-six participants were recruited in this study. The LVHIIT group (n = 17) performed one 4-min bout of treadmill running at 85%-95% maximum heart rate (HRmax), followed by 3 min of recovery by running at 70% HRmax, three times per week for 6 weeks. The HVHIIT group (n = 15) performed four times 4-min bouts of treadmill running at 85%-95% HRmax, interspersed with 3-min of recovery by running at 70% HRmax, 3 times per week for 6 weeks. All criterion measures were measured before and after training in both the groups. Results Due to attrition of four cases, data of 32 participants was used for analysis. A significant increase in high frequency (HF) power (p < 0.001) and decrease in the ratio of low frequency to high frequency power (LF/HF) ratio (p < 0.001) in HRV parameters, was observed post-HVHIIT, whereas, these variables did not change significantly (HF: p = 0.92, LF/HF ratio: p = 0.52) in LVHIIT group. Nevertheless, both the interventions proved equally effective in improving aerobic capacity (VO2max), body composition, and muscle strength. Conclusion The study results suggest that both LVHIIT and HVHIIT are equally effective in improving VO2max, body composition, and muscle strength, in sedentary young women. However, HVHIIT induces parasympathetic dominance as well, as measured by HRV. PMID- 28837419 TI - Impairments in laterodorsal tegmentum to VTA projections underlie glucocorticoid triggered reward deficits. AB - Ventral tegmental area (VTA) activity is critical for reward/reinforcement and is tightly modulated by the laterodorsal tegmentum (LDT). In utero exposure to glucocorticoids (iuGC) triggers prominent motivation deficits but nothing is known about the impact of this exposure in the LDT-VTA circuit. We show that iuGC rats have long-lasting changes in cholinergic markers in the LDT, together with a decrease in LDT basal neuronal activity. Interestingly, upon LDT stimulation, iuGC animals present a decrease in the magnitude of excitation and an increase in VTA inhibition, as a result of a shift in the type of cells that respond to the stimulus. In agreement with LDT-VTA dysfunction, we show that iuGC animals present motivational deficits that are rescued by selective optogenetic activation of this pathway. Importantly, we also show that LDT-VTA optogenetic stimulation is reinforcing, and that iuGC animals are more susceptible to the reinforcing properties of LDT-VTA stimulation. PMID- 28837422 TI - Decreasing screen time and/or increasing exercise only helps in certain situations for young adults. AB - There seems to be a lack of consensus about whether greater screen time is highly correlated to greater body mass index (BMI) (and lower physical exercise). What has been proven is that the vast majority of children and adolescents spend a "lot of time" indulging in screen-based leisure. The aim of this study was to investigate, among young adults, screen time and physical activity/fitness. A questionnaire was developed and circulated to young adults via media networks (i.e. email, social media platforms, etc.). There was no geographic restriction, and the survey was designed in English. Two people did not consent to the study, while 262 consented and completed the survey. The vast majority of participants resided in Canada, with a noticeable minority living in the United Kingdom and the United States. Of the participants, 46% were 18 or 19 years old, 30% were between the ages of 20 and 22 years and the remaining 24% were split evenly between the age cohorts of under 18 years and over 22 years. Four of 262 (2%) participants did not disclose their sex, 66% reported as female and 32% noted they were male. The BMI ranged from 14.4525 to 39.5325, and had a mean of 22.8155 and standard deviation of 4.1939. Among people who spent less than 4 h of exercise a week, those who spent more than 5 h on screen time based activities had a higher BMI (p = 0.0032) of 23.8151 vs. 21.7879 for those who spent less than 5 h. There was no relation between screen time and BMI among people who spent more than 4 h of exercise a week (p = 0.6209). Between exercise groups who spent less than 5 h of screen time a day, there was no relation between hours of exercise and BMI (p = 0.1242). There seems to exist a trend that among those who spend more than 5 h of screen time a day, less exercise is related to higher BMI (p = 0.0510) - 23.8151 vs. 22.4361. Healthy lifestyle choices such as fewer screen time hours and more exercise can be beneficial to young adults. Among certain groups, such as those who spend a lot of time on screens and those who do not exercise regularly, the benefits of more exercise and less screen time, respectively, are much more noticeable. PMID- 28837424 TI - Visual evoked potentials in women with and without preeclampsia during pregnancy and postpartum. AB - OBJECTIVE: Preeclampsia is a severe hypertensive disorder of pregnancy which may lead to brain complications such as eclampsia. Visual symptoms are present in ~25% of preeclamptic women suggesting the visual cortex to be altered during preeclampsia. Visual evoked potentials (VEPs) measure the functional neuronal integrity of the visual pathway from retina to the occipital cortex of the brain. The objective of this study was to compare neurophysiological changes in women with preeclampsia and other hypertensive disorders of pregnancy, using VEPs. We hypothesized that women with preeclampsia and other hypertensive disorders of pregnancy develop abnormal latency and amplitude of VEPs as compared with normotensive pregnant women. METHODS: We performed a prospective observational study in 15 women with mild preeclampsia, 33 with severe preeclampsia (sPE), eight women with chronic hypertension, nine with pregnancy-induced hypertension, and 29 normotensive pregnant women. VEP measurements were made at four different time points of gestation (12-14 weeks, 26-28 weeks, 32-34 weeks, 36-40 weeks) and 6-8 weeks postpartum. RESULTS: We defined reference values for normotensive pregnant women. Normotensive pregnant women had a shorter latency during pregnancy compared to their postpartum value (P = 0.005). Women with sPE had a prolonged latency of VEPs compared with normotensive pregnant women (P = 0.006), a difference that disappeared postpartum. CONCLUSION: Our study showed neurophysiological adaptation to pregnancy of the visual cortex in normotensive pregnant women, that seemed to be absent in women with sPE. The study groups of women with chronic hypertension and pregnancy-induced hypertension were to small to draw any conslusions from. PMID- 28837423 TI - A novel healthy blood pressure phenotype in the Long Life Family Study. AB - BACKGROUND: Hypertension tends to run in families and has both genetic and environmental determinants. We assessed the hypothesis that a novel healthy blood pressure (BP) phenotype is also familial and sought to identify its associated factors. METHODS: We developed a healthy BP phenotype in the Long Life Family Study, a cohort of two-generation families selected for longevity. Participants from the offspring generation (n = 2211, ages 32-88) were classified as having healthy BP if their age-adjusted and sex-adjusted SBP z-score was between -1.5 and -0.5. Offspring on antihypertensive medications were classified as not having healthy BP. Families with at least two offspring (n = 419 families) were defined as meeting the healthy BP phenotype if at least two and at least 50% of their offspring had healthy BP. RESULTS: Among 2211 offspring, 476 (21.5%) met the healthy BP phenotype. When examining the 419 families, only 44 (10.5%) families met the criteria for the healthy BP phenotype. Both offspring and probands from families with healthy BP performed better on neuropsychological tests that place demands on complex attention and executive function when compared with offspring and probands from remaining families. Among families with the healthy BP phenotype compared with families without, a higher proportion of offspring met the American Heart Association definition of ideal cardiovascular health (10.8 versus 3.8%, respectively; driven by BP, smoking status, and BMI components). CONCLUSION: In this cohort of familial longevity, few families had a novel healthy BP phenotype in multiple members. Families with this healthy BP phenotype may represent a specific pathway to familial longevity. PMID- 28837425 TI - Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. AB - PURPOSE OF REVIEW: The aim of this study was to provide clinically relevant findings from the DRCR.net Protocol T, a multicentre randomized clinical trial comparing intravitreous aflibercept, repackaged (compounded) bevacizumab and ranibizumab for vision-impairing centre-involved diabetic macular oedema (DME). RECENT FINDINGS: At 1 year, all three antivascular endothelial growth factor (anti-VEGF) drugs, on average, improved visual acuity. There was no difference among drugs in mean change in visual acuity from baseline among eyes with baseline Snellen equivalent visual acuity of 20/32 to 20/40, whereas aflibercept yielded superior vision outcomes among eyes with baseline visual acuity of 20/50 to 20/320. At 2 years, aflibercept remained superior, on average, to bevacizumab, but not ranibizumab, among eyes with baseline visual acuity of 20/50 to 20/320. Over 2 years, in post-hoc area-under-the-curve analysis, aflibercept vision outcomes were superior to bevacizumab or ranibizumab among these eyes. All three drugs had comparable ocular and systemic safety profiles. The substantial cost differential between aflibercept and bevacizumab raises challenges when safety and efficacy are at odds with cost-effectiveness results. SUMMARY: When initial visual acuity loss is mild, there are no apparent differences, on average, among aflibercept, bevacizumab and ranibizumab for treating DME. When visual acuity loss is moderate or worse, aflibercept is more likely to improve visual acuity. PMID- 28837426 TI - Factorial Validity and Measurement Invariance of the Test of Preschool Early Literacy-Phonological Awareness Test Among Deaf and Hard-of-Hearing Children and Hearing Children. AB - OBJECTIVES: Emerging evidence suggests that early phonological awareness in deaf and hard-of-hearing (DHH) children with functional hearing is significantly related to their reading acquisition, and the assessment of phonological awareness can play a critical role in preventing reading difficulties. Validation of the scores obtained from standardized assessments when used with DHH students is crucial to support the assessments' intended interpretations and implications of test scores. Using archival data sets, the aim of this study was twofold: (a) to establish the factorial validity of the item scores on the Test of Preschool Early Literacy-Phonological Awareness (TOPEL-PA) for DHH children with functional hearing and hearing children and (b) to test measurement invariance across these groups. Our archival data sets included assessments of DHH children, hearing children from low socioeconomic status (SES) backgrounds, and hearing children from a range of SES backgrounds. We hypothesized that a second-order unifying ability, Phonological Awareness, along with four first-order subtest factors would explain inter-item associations among the 27 items on the TOPEL-PA. We further hypothesized that patterns of associations among the item scores would be similar across groups and that the individual items would function similarly across groups. DESIGN: Seven hundred and thirty-three children from three samples participated in the study; 171 were DHH children (Mage = 58.7 months old, SDage = 12.5 months old), 195 were low-SES hearing children (Mage = 55.5 months old, SDage = 3.5 months old), and 367 were diverse-SES hearing children (Mage = 53.4 months old, SDage = 8.9 months old). All DHH children were able to identify the referent of monosyllabic spoken words on the Early Speech Perception Test. RESULTS: Test of confirmatory item factor analyses of the hypothesized second order factor structure revealed that a second-order unifying ability along with four first-order subtest factors well explained associations among the item scores for all groups. This aligned with the scoring structure of the TOPEL-PA, providing strong evidence for factorial validity of the item scores for DHH children as well as for hearing children groups. The measurement invariance test results provided evidence that the vast majority of TOPEL-PA items functioned similarly for hearing children and DHH children with speech perception abilities, suggesting that the utility of the assessment scores obtained from DHH children is consistent with the scores obtained from hearing children. CONCLUSION: Results of our study suggest that researchers and practitioners can use the TOPEL-PA to assess DHH children with functional hearing. It also suggests that the two skills measured on the TOPEL-PA (blending and elision) are qualitatively similar for DHH and hearing children, but the latent mean score obtained from the DHH children significantly differed from those of the hearing groups, suggesting a quantitative difference. PMID- 28837427 TI - Suicidal Ideation Among Medical Students: Prevalence and Predictors. AB - Suicide is one of the leading causes of death among medical students, second to car accidents. We investigated the prevalence and predictors of suicidal ideation (SI) among medical students in Brazil. This is a cross-sectional study with 475 medical students of a public university. The research protocol included data on sociodemographics and academic life, and structured instruments to assess social support and psychopathological symptoms, including the Beck Depression Inventory (BDI). The outcome was evaluated using the BDI suicide item. Bivariate analyses were followed by logistic regression. SI was present in 34 participants (7.2%). In the logistic regression, SI remained associated with living alone, thoughts of abandoning the course, moderate or severe depressive symptoms, and probable obsessive-compulsive disorder. SI is frequent among medical students and can be identified with a simple screening question. Special attention should be given to students living alone, with thoughts of abandoning the course, and relevant depressive or obsessive-compulsive symptoms. PMID- 28837428 TI - In Their Own Words: Perspectives on Nonsuicidal Self-Injury Disorder Among Those With Lived Experience. AB - Nonsuicidal self-injury (NSSI) is included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a condition warranting further study. Although potential advantages and disadvantages regarding this prospect have been documented, no study has examined the perspectives of those who self-injure. The goal of the current study was to give voice to these views. Seventy-six participants with an NSSI history completed quantitative and qualitative measures assessing perspectives about NSSI being included as a DSM disorder. Findings revealed mixed views overall. Thematic analysis of open-ended responses highlighted several unique advantages (i.e., enhanced understanding of NSSI, validation of the NSSI experience, facilitation of NSSI treatment, encouragement of NSSI help-seeking, reduction of NSSI stigma) and disadvantages (i.e., exacerbation of NSSI stigma, diminishment of underlying concerns). These findings speak to the need to consider the perceptions of those with lived NSSI experience; future directions and implications are discussed. PMID- 28837429 TI - Severe Burnout Is Common Among Critical Care Physician Assistants. AB - OBJECTIVES: To determine the prevalence of and risk factors for burnout among critical care medicine physician assistants. DESIGN: Online survey. SETTINGS: U.S. ICUs. SUBJECTS: Critical care medicine physician assistant members of the Society of Critical Care Medicine coupled with personal contacts. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used SurveyMonkey to query critical care medicine physician assistants on demographics and the full 22-question Maslach Burnout Inventory, a validated tool comprised of three subscales-emotional exhaustion, depersonalization, and achievement. Multivariate regression was performed to identify factors independently associated with severe burnout on at least one subscale and higher burnout scores on each subscale and the total inventory. From 431 critical care medicine physician assistants invited, 135 (31.3%) responded to the survey. Severe burnout was seen on at least one subscale in 55.6%-10% showed evidence of severe burnout on the "exhaustion" subscale, 44% on the "depersonalization" subscale, and 26% on the "achievement" subscale. After multivariable adjustment, caring for fewer patients per shift (odds ratio [95% CI]: 0.17 [0.05-0.57] for 1-5 vs 6-10 patients; p = 0.004) and rarely providing futile care (0.26 [0.07-0.95] vs providing futile care often; p = 0.041) were independently associated with having less severe burnout on at least one subscale. Those caring for 1-5 patients per shift and those providing futile care rarely also had a lower depersonalization scores; job satisfaction was independently associated with having less exhaustion, less depersonalization, a greater sense of personal achievement, and a lower overall burnout score. CONCLUSIONS: Severe burnout is common in critical care medicine physician assistants. Higher patient-to-critical care medicine physician assistant ratios and provision of futile care are risk factors for severe burnout. PMID- 28837431 TI - Monotherapy Is Adequate for Septic Shock Due to Gram-Negative Organisms. PMID- 28837432 TI - A Floating Object in the Left Atrium. PMID- 28837430 TI - The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level-One Trauma Centers. AB - OBJECTIVE: To determine the incidence and risk factors of chronic critical illness after severe blunt trauma. DESIGN: Prospective observational cohort study (NCT01810328). SETTING: Two level-one trauma centers in the United States. PATIENTS: One hundred thirty-five adult blunt trauma patients with hemorrhagic shock who survived beyond 48 hours after injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chronic critical illness was defined as an ICU stay lasting 14 days or more with evidence of persistent organ dysfunction. Three subjects (2%) died within the first 7 days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to chronic critical illness. Patients who developed chronic critical illness were older (55 vs 44-year-old; p = 0.01), had more severe shock (base deficit, -9.2 vs -5.5; p = 0.005), greater organ failure severity (Denver multiple organ failure score, 3.5 +/- 2.4 vs 0.8 +/- 1.1; p < 0.0001) and developed more infectious complications (84% vs 35%; p < 0.0001). Chronic critical illness patients were more likely to be discharged to a long term care setting (56% vs 34%; p = 0.008) than to a rehabilitation facility/home. At 4 months, chronic critical illness patients had higher mortality (16.0% vs 1.9%; p < 0.05), with survivors scoring lower in general health measures (p < 0.005). Multivariate analysis revealed age greater than or equal to 55 years, systolic hypotension less than or equal to 70 mm Hg, transfusion greater than or equal to 5 units packed red blood cells within 24 hours, and Denver multiple organ failure score at 72 hours as independent predictors of chronic critical illness (area under the receiver operating curve, 0.87; 95% CI, 0.75-0.95). CONCLUSIONS: Although early mortality is low after severe trauma, chronic critical illness is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity, and persistent organ dysfunction are predictive of chronic critical illness. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype. PMID- 28837433 TI - Right Atrial Myxoma with Cannon A Waves. PMID- 28837434 TI - Images in Anesthesiology: Tracheopharyngeal Fistula from Treated Hypopharyngeal Carcinoma. PMID- 28837436 TI - Are Anesthesia and Surgery during Infancy Associated with Decreased White Matter Integrity and Volume during Childhood? AB - BACKGROUND: Anesthetics have neurotoxic effects in neonatal animals. Relevant human evidence is limited. We sought such evidence in a structural neuroimaging study. METHODS: Two groups of children underwent structural magnetic resonance imaging: patients who, during infancy, had one of four operations commonly performed in otherwise healthy children and comparable, nonexposed control subjects. Total and regional brain tissue composition and volume, as well as regional indicators of white matter integrity (fractional anisotropy and mean diffusivity), were analyzed. RESULTS: Analyses included 17 patients, without potential confounding central nervous system problems or risk factors, who had general anesthesia and surgery during infancy and 17 control subjects (age ranges, 12.3 to 15.2 yr and 12.6 to 15.1 yr, respectively). Whole brain white matter volume, as a percentage of total intracranial volume, was lower for the exposed than the nonexposed group, 37.3 +/- 0.4% and 38.9 +/- 0.4% (least squares mean +/- SE), respectively, a difference of 1.5 percentage points (95% CI, 0.3 to 2.8; P = 0.016). Corresponding decreases were statistically significant for parietal and occipital lobes, infratentorium, and brainstem separately. White matter integrity was lower for the exposed than the nonexposed group in superior cerebellar peduncle, cerebral peduncle, external capsule, cingulum (cingulate gyrus), and fornix (cres) and/or stria terminalis. The groups did not differ in total intracranial, gray matter, and cerebrospinal fluid volumes. CONCLUSIONS: Children who had anesthesia and surgery during infancy showed broadly distributed, decreased white matter integrity and volume. Although the findings may be related to anesthesia and surgery during infancy, other explanations are possible. PMID- 28837437 TI - Nursing Students and Service Learning: Research From a Symbiotic Community Partnership With Local Schools and Special Olympics. AB - This research is an example of a service learning partnership between a prelicensure nursing program and local school district. Through this partnership, students participated in a thoughtfully organized project that met the needs of a community and promoted the humanizing of health care education. Nursing students, under the guidance of faculty, performed required physical examinations for Special Olympics athletes who represented a wide range of age, physical, social, and intellectual levels. Research findings indicated an increase in nursing students' affective and cognitive development after this activity. PMID- 28837438 TI - Assessment of a Competency-Based Undergraduate Course on Genetics and Genomics. AB - In response to new demands in the nursing profession, an innovative undergraduate genetics course was designed based on the Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics. Reflective journaling and storytelling were used as major pedagogies, alongside more traditional approaches. Thematic content analysis of student reflections revealed transformational learning as the major theme emerging from genomic and genetic knowledge acquisition. Quantitative analyses of precourse/postcourse student self assessments of competencies revealed significant findings. PMID- 28837439 TI - Enhancing Communication With the Deaf Through Simulation. PMID- 28837440 TI - Delayed Onset Cranial Nerve Palsies After Endovascular Coil Embolization of Direct Carotid-Cavernous Fistulas. AB - BACKGROUND: Late recurrence of visual symptoms associated with carotid-cavernous fistula (CCF), including diplopia, is uncommon and raises concern for new or recurrent fistula formation. METHODS: We report 2 patients with traumatic CCFs, where cranial nerve paresis resolved after endovascular CCF treatment only to reappear years later. RESULTS: No evidence of recurrent or new fistula formation was found. Both were treated successfully with strabismus surgery. CONCLUSIONS: Although the cause of delayed onset diplopia after successful treatment is still unknown, theories include late compression of cranial nerves within the cavernous sinus due to coil mass that can cause chronic ischemia, delayed inflammation due to a thrombophilic nidus created by the coil mass, or injury to the cranial nerves that manifests later due to decompensated strabismus. PMID- 28837441 TI - Gorham-Stout Disease Presenting as Acute Unilateral Proptosis. AB - Gorham-Stout disease (GSD) is a rare angiomatous disorder characterized by osteolysis. We report the case of a 66-year-old woman who developed sudden left eye proptosis and facial pain. Neuroimaging demonstrated a destructive mass involving the roof and lateral wall of the left orbit with adjacent abnormal orbital soft tissue. An initial biopsy of the soft tissue was nondiagnostic; however, transcranial biopsy of the orbital roof revealed an intraosseous cavernous angioma, with infiltration of orbital fat by angiomatous tissue. Despite resection of the orbital roof and lateral wall, the orbital lesion continued to expand, leading to signs of a compressive optic neuropathy. The patient then reported severe back pain, prompting imaging that demonstrated disseminated bony involvement of the axial skeleton, eventually leading to the diagnosis of GSD. The patient was treated with a bisphosphonate and a vascular endothelial growth factor inhibitor with stabilization of disease. PMID- 28837442 TI - Diagnosis, follow-up and treatment of cystic fibrosis-related liver disease. AB - PURPOSE OF REVIEW: To provide an insight and overview of the challenges in the diagnosis, follow-up and treatment of cystic fibrosis-related liver disease (CFLD). RECENT FINDINGS: The variable pathophysiology of CFLD complicates its diagnosis and treatment. A 'gold standard' for CFLD diagnosis is lacking. Over the past years, new techniques to diagnose features of CFLD, such as transient elastography, have been investigated. Although most of these tests confirm cystic fibrosis-related liver involvement (CFLI), they are, however, not suitable to distinguish various phenotypical presentations or predict progression to clinically relevant cirrhosis or portal hypertension. A combined initiative from the European and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has been started, aimed to obtain consensus on CFLD criteria and definitions. Currently, only ursodeoxycholic acid is used in CFLD treatment, although it has not been convincingly demonstrated to change the natural course of the disease. Drugs that directly target cystic fibrosis transmembrane conductance regulator protein dysfunction show promising results; however, more long-term follow-up and validation studies are needed. SUMMARY: CFLD is an umbrella term referring to a wide variety of liver manifestations with variable clinical needs and consequences. CFLD with portal hypertension is the most severe form of CFLD due to its significant implications on morbidity and mortality. The clinical relevance of other CFLI is uncertain. Consensus on CFLD definitions is essential to validate new diagnostic tools and therapeutic outcome measures. PMID- 28837444 TI - Small Hepatocellular Carcinoma With Low Tumor Marker Expression Benefits More From Anatomical Resection Than Tumors With Aggressive Biology. AB - OBJECTIVE: We assessed prognostic advantage of anatomical resection (AR) over nonanatomical resection (NAR) for hepatocellular carcinoma (HCC) according to multiplication of alpha-fetoprotein, des-gamma-carboxyprothrombin, and tumor volume (ADV) scores. BACKGROUND: Superiority of AR over NAR is debated. ADV score is surrogate marker of postresection prognosis for solitary HCC. METHODS: This study included 1572 patients who underwent curative resection for solitary HCC of 2.0 to 5.0 cm between 2006 and 2014. RESULTS: Preoperative patient profiles were not statistically different between AR and NAR groups. In 1324 naive patients without preoperative treatment, AR group showed lower recurrence rates (P = 0.003) and higher patient survival rates (P = 0.012) than NAR group. AR group showed lower recurrence rates in patients with ADV <=5 log (P <= 0.046). ADV scores >4 log and >3 log were independent risk factors for tumor recurrence and patient survival in treatment-naive patients, respectively. In treatment-naive group with preserved hepatic functional reserve, AR group showed lower recurrence rates in patients with ADV <=4 log (P = 0.026). Absence of microvascular invasion also showed lower recurrence rates (P = 0.007) in AR group. In 248 patients with preoperative treatment, AR group showed lower recurrence rates (P = 0.001) and higher patient survival rates (P = 0.006). AR group showed lower recurrence rates in patients with ADV <=4 log (P < 0.001) and higher survival rates in patients with ADV <=5 log (P <= 0.043). CONCLUSIONS: Prognostic benefit of AR was evident in patients with ADV score <=4 log or absence of microvascular invasion. Patients with less aggressive tumor biology benefit more from AR than NAR, thus being reasonably indicated for AR. PMID- 28837443 TI - Effect of Transcranial Direct Current Stimulation on Severely Affected Arm-Hand Motor Function in Patients After an Acute Ischemic Stroke: A Pilot Randomized Control Trial. AB - OBJECTIVE: The aim of this article was to determine whether cathodal transcranial direct current stimulation (c-tDCS) to unaffected primary motor cortex (PMC) plus conventional occupational therapy (OT) improves functional motor recovery of the affected arm hand in patients after an acute ischemic stroke compared with sham transcranial direct current stimulation plus conventional OT. DESIGN: In this prospective, randomized, double-blinded, sham-controlled trial of 16 severe, acute ischemic stroke patients with severe arm-hand weakness were randomly assigned to either experimental (c-tDCS plus OT; n = 8) or control (sham transcranial direct current stimulation plus OT; n = 8) groups. All patients received a standard 3-hr in-patient rehabilitation therapy, plus an additional ten 30-min sessions of tDCS. During each session, 1 mA of cathodal stimulation to the unaffected PMC is performed followed by the patient's scheduled OT. The primary outcome measure was change in Action Research Arm Test (ARAT) total and subscores on discharge. RESULT: Application of c-tDCS to unaffected PMC resulted in a clinically relevant 10-point improvement in the affected arm-hand function based on ARAT total score compared with a 2-point improvement in the control group. CONCLUSIONS: Application of 30-min of c-tDCS to the unaffected PMC showed a 10-point improvement in the ARAT score. This corresponds to a large effect size in improvement of affected arm-hand function in patients with severe, acute ischemic stroke. Although not statistically significant, this suggests that larger studies, enrolling at least 25 patients in each group, and with a longer follow-up are warranted. PMID- 28837445 TI - Characteristics of Effective Mentorship for Academic Surgeons: A Grounded Theory Model. AB - OBJECTIVE: The authors sought to describe characteristics of effective mentoring relationships in academic surgery based upon lived experiences of mid-career and senior female academic surgeons. BACKGROUND: Prior qualitative work describes characteristics of successful mentoring relationships. However, no model exists of effective mentorship that is specific to academic surgery. METHODS: The authors conducted in-depth interviews with mid-career and senior female US academic surgeons about the impact of mentoring on professional development during 2014 and 2015. Purposive selection aimed to maximize institutional, specialty, years in career, and racial diversity. Grounded theory method was used to generate a conceptual model of effective mentoring relationships. Data saturation occurred following 15 interviews. RESULTS: Interviewees described the need for multiple mentors over time with each mentor addressing a unique domain. Interviewees suggested that mentees should seek mentors who will serve as strategic advisors, who will be unselfish, and who engage with diverse mentees. CONCLUSIONS: This study identified a need for multiple mentors across time and disciplines, and identified 3 key characteristics of effective mentoring relationships in academic surgery. Future work in this area should generate an operational definition of mentorship that supports quantitative evaluation of mentor and mentoring panel performance. PMID- 28837446 TI - Letter to the Editor for "Low Versus Standard Urine Output Targets in Patients Undergoing Major Abdominal Surgery". PMID- 28837447 TI - Surgical Video in the Age of Big Data. PMID- 28837448 TI - Response to Comment: RE: ) Exploring the Relationship Between Working Memory, Compressor Speed, and Background Noise Characteristics, Ear Hear 37, 137-143. PMID- 28837450 TI - Identifying Persistent Asthma in Children: A Comparison of Healthcare Effectiveness Data and Information Set Criteria and National Heart, Lung, and Blood Institute Guidelines. AB - Persistent asthma requires a daily controller medication. National Heart, Lung, and Blood Institute (NHLBI) guidelines and Healthcare Effectiveness Data and Information Set (HEDIS) quality measures are used to identify persistent asthma, the former method used by clinicians, and the latter by managed care organizations (MCOs). This study aims to determine the degree of agreement between these criteria in classifying pediatric persistent asthma. Asthmatic patients aged 5-18 years old in a university pediatric practice who were continuously enrolled with one MCO from January 1, 2012 to December 31, 2013 (Cohort 1: 329 patients) and January 1, 2013 to December 31, 2014 (Cohort 2: 212 patients) were identified. Subjects with at least one asthma visit were included. Independence of NHLBI and HEDIS criteria was determined by the McNemar test. Agreement was determined by confusion matrix analysis and Cohen kappa statistic with continuity correction. Agreement in controller assignment was 82% in Cohort 1 and 88% in Cohort 2. Agreement was fair in Cohort 1 (Cohen kappa = 0.364; 95% confidence interval [CI] = 0.217-0.511) and moderate in Cohort 2 (Cohen kappa = 0.447; 95% CI = 0.247-0.646). The HEDIS misclassified persistent asthma by 16.4% (95% CI: 11.5-21.2%) and 11.8% (95% CI: 6.8-16.7%) in Cohorts 1 and 2, respectively. NHLBI and HEDIS criteria show fair to moderate agreement; however, the HEDIS consistently misclassified persistent asthma, suggesting that it is a poor measure of practice performance. PMID- 28837449 TI - Uses and Limitations of Claims-based Performance Feedback Reports: Lessons From the Comprehensive Primary Care Initiative. AB - BACKGROUND: Performance feedback is central to data-driven models of quality improvement, but the use of claims-based data for feedback has received little attention. PURPOSE: To examine the challenges, uses, and limitations of quarterly Medicare claims-based performance feedback reports generated for practices participating in the Comprehensive Primary Care (CPC) initiative from 2012 to 2015. METHODS: Mixed methods study of nearly 500 CPC practices in seven regions, combining pilot testing; systematic monitoring; surveys; in-depth interviews; user feedback; and input from data feedback team. RESULTS: Designing reports required addressing issues about timing, data completeness and reliability, variations in patient risk across practices, and use of benchmarks and metrics understandable to users. Practices' ability to use reports constructively depended on their experience, analytic resources, expectations, and perceptions about the role of primary care in improving reported outcomes. CONCLUSIONS: Generating claims-based feedback reports that support practices' quality improvement efforts requires a significant investment of analytic expertise, time, resources, continuous improvement, and technical assistance. IMPLICATIONS: Claims-based performance feedback can provide insight into patterns of patients' care across provider settings and opportunities for improvement, but practices need data from other sources to manage patients in real time or assess the short term effects of specific changes in care delivery. PMID- 28837451 TI - Within-Hospital Variation in 30-Day Adverse Events: Implications for Measuring Quality. AB - Novel measures of hospital quality are needed. Because quality improvement efforts seek to reduce variability in processes and outcomes, hospitals with higher variability in adverse events may be delivering poorer quality care. We sought to evaluate whether within-hospital variability in adverse events after a procedure might function as a quality metric that is correlated with facility level mortality rates. We analyzed all percutaneous coronary interventions (PCIs) performed in the Veterans Health Administration (VHA) system from 2007 to 2013 to evaluate the correlation between within-hospital variability in 30-day postdischarge adverse events (readmission, emergency department visit, and repeat revascularization), and facility-level mortality rates, after adjustment for patient demographics, comorbidities, PCI indication, and PCI urgency. The study cohort included 47,567 patients at 48 VHA hospitals. The overall 30-day adverse event rate was 22.0% and 1-year mortality rate was 4.9%. The most variable sites had relative changes of 20% in 30-day rates of adverse events period-to-period. However, within-hospital variability in 30-day events was not correlated with 1 year mortality rates (correlation coefficient = .06; p = .66). Thus, measuring within-hospital variability in postdischarge adverse events may not improve identification of low-performing hospitals. Evaluation in other conditions, populations, and in relationship with other quality metrics may reveal stronger correlations with care quality. PMID- 28837452 TI - JAAOS at 25 Years. PMID- 28837453 TI - Marfan Syndrome: A Clinical Update. AB - Marfan syndrome is a connective tissue disorder that can affect many organ systems. Affected patients present with orthopaedic manifestations of the syndrome during all phases of life. Pain caused by musculoskeletal abnormalities often requires definitive orthopaedic treatment. Orthopaedic surgeons must understand the phenotypes of Marfan syndrome so they can recognize when screening is warranted and can appropriately address the skeletal manifestations. Through medical advancements, patients with Marfan syndrome are living longer and more active lives. Knowledge of the latest diagnostic criteria for the disorder, as well as of advances in understanding the skeletal phenotype, clinical trials of medication therapy, and lifestyle considerations is important for orthopaedic surgeons who treat these patients because these clinicians often are the first to suspect Marfan syndrome and recommend screening. PMID- 28837454 TI - Posterior Glenohumeral Instability: Evidence-based Treatment. AB - Posterior glenohumeral instability is an increasingly important clinical finding in athletic patients. Over the last decade, basic and clinical research has improved our understanding of the pathoanatomy and biomechanics of this challenging disorder, as well as our ability to diagnose and appropriately treat it. Although recurrent posterior shoulder instability is not as common as anterior instability, it is prevalent among specific populations, including football and rugby players, and may be overlooked by clinicians who are unaware of the typical physical examination and radiographic findings. PMID- 28837455 TI - Revision Total Knee Arthroplasty for the Management of Periprosthetic Fractures. AB - Periprosthetic fractures after total knee arthroplasty (TKA) can present reconstructive challenges. Not only is the procedure technically complex, but patients with these fractures may have multiple comorbidities, making them prone to postoperative complications. Early mobilization is particularly beneficial in patients with multiple comorbidities. Certain patient factors and fracture types may make revision TKA the ideal management option. Periprosthetic fractures around the knee implant occur most frequently in the distal femur, followed by the tibia and the patella. Risk factors typically are grouped into patient factors (eg, osteoporosis, obesity) and surgical factors (eg, anterior notching, implant malposition). Surgical options for periprosthetic fractures that involve the distal femur or proximal tibia include reconstruction of the bone stock with augments or metal cones or replacement with an endoprosthesis. PMID- 28837456 TI - Temporal Healing of Achilles Tendons After Injury in Rodents Depends on Surgical Treatment and Activity. AB - INTRODUCTION: Achilles tendon ruptures affect 15 of 100,000 women and 55 of 100,000 men each year. Controversy continues to exist regarding optimal treatment and rehabilitation protocols. The objective of this study was to investigate the temporal effects of surgical repair and immobilization or activity on Achilles tendon healing and limb function after complete transection in rodents. METHODS: Injured tendons were repaired (n = 64) or left nonrepaired (n = 64). The animals in both cohorts were further randomized into groups immobilized in plantar flexion for 1, 3, or 6 weeks that later resumed cage and treadmill activity for 5, 3, or 0 weeks, respectively (n = 36 for each regimen), which were euthanized at 6 weeks after injury, or into groups immobilized for 1 week and then euthanized (n = 20). RESULTS: At 6 weeks after injury, the groups that had 1 week of immobilization and 5 weeks of activity had increased range of motion and decreased ankle joint toe stiffness compared with the groups that had 3 weeks of immobilization and 3 weeks of activity. The groups with 6 weeks of immobilization and no activity period had decreased tendon cross-sectional area but increased tendon echogenicity and collagen alignment. Surgical treatment dramatically decreased fatigue cycles to failure in repaired tendons from groups with 1 week of immobilization and 5 weeks of activity. Normalized comparisons between 1-week and 6-week postinjury data demonstrated that changes in tendon healing properties (area, alignment, and echogenicity) were maximized by 1 week of immobilization and 5 weeks of activity, compared with 6 weeks of immobilization and no activity period. DISCUSSION: This study builds on an earlier study of Achilles tendon fatigue mechanics and functional outcomes during early healing by examining the temporal effects of different immobilization and/or activity regimens after initial postinjury immobilization. CONCLUSION: This study demonstrates how the temporal postinjury healing response of rodent Achilles tendons depends on both surgical treatment and the timing of immobilization/activity timing. The different pattern of healing and qualities of repaired and nonrepaired tendons suggest that two very different healing processes may occur, depending on the chosen immobilization/activity regimen. PMID- 28837457 TI - Hallux Rigidus Grade Does Not Correlate With Foot and Ankle Ability Measure Score. AB - INTRODUCTION: Classification systems for hallux rigidus imply that, as radiographic changes progress, symptoms will concurrently increase in severity. However, symptom intensity and radiographic severity can be discordant for many patients. We studied the correlation between hallux rigidus grades and the Foot and Ankle Ability Measure (FAAM) scores to better understand this relationship. METHODS: We retrospectively reviewed weight-bearing radiographs of the foot and FAAM Activities of Daily Living (ADL) questionnaires for 84 patients with hallux rigidus. The Spearman rank coefficient was used to correlate clinical radiographic hallux rigidus grade with FAAM ADL scores. RESULTS: In 84 patients, the clinical-radiographic grade for hallux rigidus showed no relationship with FAAM ADL score (r = -0.10; P = 0.36) but did show moderate correlation with patient age (r = 0.63; P < 0.001). DISCUSSION: Advancing radiographic changes in hallux rigidus did not correspond with patient symptoms as measured via FAAM ADL scores. CONCLUSION: The reliability and validity of current grading criteria for hallux rigidus may require further exploration. LEVEL OF EVIDENCE: Level III. PMID- 28837458 TI - Early Lessons on Bundled Payment at an Academic Medical Center. AB - INTRODUCTION: Orthopaedic care is shifting to alternative payment models. We examined whether New York University Langone Medical Center achieved savings under the Centers for Medicare and Medicaid Services Bundled Payments for Care Improvement initiative. METHODS: This study was a difference-in-differences study of Medicare fee-for-service patients hospitalized from April 2011 to June 2012 and October 2013 to December 2014 for lower extremity joint arthroplasty, cardiac valve procedures, or spine surgery (intervention groups), or for congestive heart failure, major bowel procedures, medical peripheral vascular disorders, medical noninfectious orthopaedic care, or stroke (control group). We examined total episode costs and costs by service category. RESULTS: We included 2,940 intervention episodes and 1,474 control episodes. Relative to the trend in the control group, lower extremity joint arthroplasty episodes achieved the greatest savings: adjusted average episode cost during the intervention period decreased by $3,017 (95% confidence interval [CI], -$6,066 to $31). For cardiac procedures, the adjusted average episode cost decreased by $2,999 (95% CI, -$8,103 to $2,105), and for spinal fusion, it increased by $8,291 (95% CI, $2,879 to $13,703). Savings were driven predominantly by shifting postdischarge care from inpatient rehabilitation facilities to home. Spinal fusion index admission costs increased because of changes in surgical technique. DISCUSSION: Under bundled payment, New York University Langone Medical Center decreased total episode costs in patients undergoing lower extremity joint arthroplasty. For patients undergoing cardiac valve procedures, evidence of savings was not as strong, and for patients undergoing spinal fusion, total episode costs increased. For all three conditions, the proportion of patients referred to inpatient rehabilitation facilities upon discharge decreased. These changes were not associated with an increase in index hospital length of stay or readmission rate. CONCLUSION: Opportunities for savings under bundled payment may be greater for lower extremity joint arthroplasty than for other conditions. PMID- 28837459 TI - The Crankshaft Phenomenon. AB - The crankshaft phenomenon, a progressive rotational and angular spinal deformity that can occur after posterior spinal surgery, has been reported in pediatric patients with idiopathic, congenital, and neuromuscular scoliosis. In the skeletally immature patient, the crankshaft phenomenon is thought to occur secondary to continued growth of the anterior elements of the spine after solid posterior spinal fusion. The condition has also been reported in the setting of newer, so-called growth-friendly posterior distraction-based spinal instrumentation. The clinical evidence of crankshaft phenomenon is often subtle, whereas radiographic findings are usually more apparent. However, objective measurement of radiographic signs may be complicated by instrumentation and postoperative changes. Treatment options for patients with the crankshaft phenomenon are limited; in those with problematic deformity and/or risk of progression, additional surgery may be indicated. PMID- 28837460 TI - Normal Palmar Anatomy and Variations That Impact Median Nerve Decompression. AB - Annually, carpal tunnel release is one of the most commonly executed orthopaedic procedures. Despite the frequency of the procedure, complications may occur as a result of anatomic variations. Understanding both normal and variant anatomy, including anomalies in neural, vascular, tendinous, and muscular structures about the carpal tunnel, is fundamental to achieving both safe and efficacious surgery. Reviewing and aggregating this information reveals certain principles that may lead to the safest possible surgical approach. Although it is likely that no true internervous plane or so-called safe zone exists during the approach for carpal tunnel release, the long-ring web space axis does appear to pose the lowest risk to important structures. PMID- 28837461 TI - Management of Lower Extremity Long-bone Fractures in Spinal Cord Injury Patients. AB - The AO classification system, used as a guide for modern fracture care and fixation, follows a basic philosophy of care that emphasizes early mobility and return to function. Lower extremity long-bone fractures in patients with spinal cord injury often are pathologic injuries that present unique challenges, to which the AO principles may not be entirely applicable. Optimal treatment achieves healing without affecting the functional level of the patient. These injuries often result from low-energy mechanisms in nonambulatory patients with osteopenic bone and a thin, insensate soft-tissue envelope. The complication rate can be high, and the outcomes can be catastrophic without proper care. Satisfactory results can be obtained through various methods of immobilization. Less frequently, internal fixation is applied. In certain cases, after discussion with the patient, amputation may be suitable. Prevention strategies aim to minimize bone loss and muscle atrophy. PMID- 28837462 TI - Welcoming the Class of 2021: Prepare for Uncharted Waters. AB - By the time they graduate, nursing roles and settings may be vastly different. PMID- 28837463 TI - A New Charter on Professionalism and Health Care Organizations. AB - Nurses should embrace and share this ethical framework. PMID- 28837464 TI - The Human Microbiome. PMID- 28837465 TI - Critical Thinking During Time-Out Protocols. PMID- 28837466 TI - Critical Thinking During Time-Out Protocols. PMID- 28837467 TI - Helping Pregnant Smokers Quit. PMID- 28837468 TI - Natural Disasters and Resilience Training. PMID- 28837469 TI - Keeping Assessment Skills Sharp. PMID- 28837470 TI - Gun Violence and Children. AB - A grim picture persists, exacerbated by scant research. PMID- 28837471 TI - How Long Should Routine Health Screening Continue? AB - Guidelines differ, but a new study guides patient discussions. PMID- 28837473 TI - Two Studies Suggest Fewer Opioids Could Be Prescribed After Cesarean Sections. AB - Shared decision making cuts the number of pills prescribed. PMID- 28837475 TI - Trends in U.S. Health Care. PMID- 28837479 TI - Will Rural Community Hospitals Survive? AB - Low patient volume and reimbursement issues drive closures. PMID- 28837482 TI - Vitamin A Supplementation for the Prevention of Morbidity and Mortality in Infants. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. For more information, see http://nursingcare.cochrane.org. PMID- 28837483 TI - New Indication for Cancer Drug Based on Biomarkers. PMID- 28837484 TI - Diabetes Drug Receives Boxed Warning for Increased Risk of Leg and Foot Amputations. PMID- 28837488 TI - Six Things You Can Do Today to Prevent Hospital-Onset C. difficile Tomorrow. AB - Some lesser-known advice on keeping patients safe. PMID- 28837489 TI - Lessons Learned from Litigation: Legal and Ethical Consequences of Social Media. AB - Editor's note: To the surprise of many, a Canadian nurse's Facebook post complaining about the medical care a family member had received resulted in disciplinary action by the licensing board. We asked our legal and ethical contributing editors to provide some insight on the issues of this case. PMID- 28837490 TI - Number of U.S. Women Taking Maternity Leave Remains Static. PMID- 28837491 TI - NSAIDs Increase the Risk of AMI. PMID- 28837492 TI - Routine Glucose Self-Monitoring Unnecessary for Non-Insulin-Treated Patients with Type 2 Diabetes. PMID- 28837493 TI - Proton Pump Inhibitors may Reduce Bleeding Risk in Older Patients on Antiplatelet Therapy. PMID- 28837494 TI - Supporting Adjunct Clinical Faculty. AB - This article is one in a series on the roles of adjunct clinical faculty and preceptors, who teach nursing students and new graduates to apply knowledge in clinical settings. In this article, the author discusses ways to promote learning among adjunct clinical faculty as well as strategies for creating closer connections between these teachers and the schools of nursing that employ them. PMID- 28837495 TI - Those Who Comfort Us. AB - Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely-and often more personal perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to draw the attention of AJN readers to posts we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com. PMID- 28837496 TI - Palliative Care in the Acute Care Setting. AB - This series on palliative care is developed in collaboration with the Hospice and Palliative Nurses Association (HPNA; http://hpna.advancingexpertcare.org). The HPNA aims to guide nurses in preventing and relieving suffering and in giving the best possible care to patients and families, regardless of the stage of disease or the need for other therapies. The HPNA offers education, certification, advocacy, leadership, and research. PMID- 28837497 TI - Empowering Nurses Across the Globe. AB - As the largest part of the health care workforce, it's nurses, says Leslie Mancuso, who will make the difference. PMID- 28837498 TI - The Squeeze. AB - Why is the experience of violence a commonality in nursing? PMID- 28837499 TI - Robot ZORA in rehabilitation and special education for children with severe physical disabilities: a pilot study. AB - The aim of this study was to explore the potential of ZORA robot-based interventions in rehabilitation and special education for children with severe physical disabilities. A two-centre explorative pilot study was carried out over a 2.5-month period involving children with severe physical disabilities with a developmental age ranging from 2 to 8 years. Children participated in six sessions with the ZORA robot in individual or in group sessions. Qualitative and quantitative methods were used to collect data on aspects of feasibility, usability, barriers and facilitators for the child as well as for the therapist and to obtain an indication of the effects on playfulness and the achievement of goals. In total, 17 children and seven professionals participated in the study. The results of this study show a positive contribution of ZORA in achieving therapy and educational goals. Moreover, sessions with ZORA were indicated as playful. Three main domains were indicated to be the most promising for the application of ZORA: movement skills, communication skills and cognitive skills. Furthermore, ZORA can contribute towards eliciting motivation, concentration, taking initiative and improving attention span of the children. On the basis of the results of the study, it can be concluded that ZORA has potential in therapy and education for children with severe physical disabilities. More research is needed to gain insight into how ZORA can be applied best in rehabilitation and special education. PMID- 28837500 TI - The role of collective labor contracts and individual characteristics on job satisfaction in Tuscan nursing homes. AB - BACKGROUND: The role played by remuneration strategies in motivating health care professionals is one of the most studied factors. Some studies of nursing home (NH) services, while considering wages and labor market characteristics, do not explicitly account for the influence of the contract itself. PURPOSE: This study investigates the relationship between the labor contracts applied in 62 Tuscan NHs and NH aides' job satisfaction with two aims: to investigate the impact of European contracts on employee satisfaction in health care services and to determine possible limitations of research not incorporating these contracts. METHODOLOGY: We apply a multilevel model to data gathered from a staff survey administered in 2014 to all employees of 62 NHs to analyze two levels: individual and NH. Labor contracts were introduced into the model as a variable of NH. RESULTS: Findings show that the factors influencing nursing aides' satisfaction occur at both the individual and NH levels. Organizational characteristics explain 16% of the variation. For individual characteristics, foreign and temporary workers emerge as more satisfied than others. For NH variables, results indicate that the labor contract with the worst conditions is not associated with lower workers' satisfaction. CONCLUSION: Although working conditions play a relevant role in the job satisfaction of aides, labor contracts do not seem to affect it. Interestingly, aides of the NHs with the contract having the best conditions register a significantly lower level of satisfaction compared to the NHs with the worst contract conditions. This suggests that organizational factors such as culture, team work, and other characteristics, which were not explicitly considered in this study, may be more powerful sources of worker satisfaction than labor contracts. PRACTICE IMPLICATIONS: Our analysis has value as a management tool to consider alternative sources as well as the labor contract for employee incentives.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 28837501 TI - Social identity and the prison health worker: Implications for practitioner satisfaction and turnover intentions. AB - BACKGROUND: Delivering health care within the prison walls poses distinct and arduous challenges to the practitioner. Correctional health workers regularly face issues of overcrowding, increased prevalence of infectious disease, advancing age, deteriorating conditions, and patients with an inclination for violence. Still, regardless of the sizeable workforce, costs, and impact on community well-being, correctional health is often overlooked in health services delivery research. PURPOSE: The aim of this study was to better understand the unique nature of delivering services in the prison context through the lens of social identity theory and further explore practitioner satisfaction and retention. METHODOLOGY/APPROACH: A survey design was used in this study, sampling clinicians in a state department of corrections in the United States. Using the data from 317 respondents, the study explored the relationship between professional identification and perceived organizational support as they impact job satisfaction and turnover intention and while controlling for burnout. RESULTS: Using nested ordinary least squares regression and nested logistic regression, the results showed that professional identification and perceived organizational support were positively associated with job satisfaction. Perceived organizational support was negatively and significantly related to turnover intentions. CONCLUSION: This article adds originality and value to the literature by using social identity theory to address the occupational perceptions of a large, yet often underrepresented and underexplored, subsector of the health workforce. PRACTICE IMPLICATIONS: The results highlight several areas where health care managers, whether from correctional or noncorrectional environments, could implement policy and procedure changes to further engage and retain the clinical workforce. To engage and retain the health worker population, managers must consider identification-reinforcing interventions that align with the self-concept and visibly display gestures of organizational support. PMID- 28837502 TI - Let's be civil: Elaborating the link between civility climate and hospital performance. AB - BACKGROUND: The importance of interpersonal behavior at the workplace is increasingly recognized in the health care industry and related literature. An unresolved issue in the existing health care research is how a climate of courteous interpersonal behavior may form the foundation for strong hospital care performance. PURPOSE: The aim of this study was to test the link between a climate of courteous interpersonal behavior, termed "civility climate," and hospital care performance. We conceptualize a multidimensional model of care performance by contrasting two dimensions: performance as perceived by employees and performance as perceived by patients. Furthermore, for both performance perspectives, we test an intermediate variable (error orientation climate) that may explain the relationship between civility climate and hospital care performance. METHODOLOGY: The 2011 study sample comprised responses from 6,094 nurses and 38,627 patients at 123 Veterans Health Administration acute care inpatient hospitals in the United States. We developed and empirically tested a theoretical model using regression modeling, and we used a bootstrap method to test for mediation. RESULTS: The results indicate a direct effect of civility climate on employee perceptions of care performance and an indirect effect mediated by error orientation climate. With regard to patient perceptions of care performance, the analyses reveal a direct effect of civility climate. The indirect effect mediated by error orientation climate was not supported. PRACTICE IMPLICATIONS: Our findings point to the importance of strengthening interpersonal interactions for ensuring and improving both employees' and patients' perceptions of care, which constitute key success factors in the increasingly competitive hospital market. The insights may further stimulate discussion regarding interventions to foster a strong civility climate in hospitals. PMID- 28837504 TI - Efficacy and safety of bazedoxifene in postmenopausal Latino women with osteoporosis. AB - OBJECTIVE: Bazedoxifene (BZA) reduces fractures and bone turnover in postmenopausal women with osteoporosis. This report evaluates safety and efficacy of BZA in Latin American women in the global trial. METHODS: In the 3-year, phase 3, randomized, double-blind trial, postmenopausal women with osteoporosis (N = 7,492) received BZA 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. Outcomes included vertebral fractures, bone mineral density, bone turnover markers, and safety. This post hoc analysis included 3,036 Latin American women. RESULTS: Incidence of vertebral fractures at month 36 with BZA 20 mg, BZA 40 mg, raloxifene, and placebo was 1.87%, 1.90%, 1.43%, and 2.83%, respectively (differences not significant). Adjusted mean percentage increases in bone mineral density were 2.49%, 2.79%, 3.18%, and 1.26% for lumbar spine, and 0.40%, 0.95%, 1.11%, and -0.41% for total hip (P < 0.001 for BZA 20/40 mg vs placebo). Adjusted median percentage reductions in osteocalcin at month 12 were -43.0%, -44.1%, 46.9%, and -27.0%, and C-telopeptide were -50.7%, -53.4%, -57.6%, and -32.1% (P < 0.001 for BZA 20/40 mg vs placebo). Common adverse events included pain and flu syndrome. CONCLUSIONS: BZA significantly improved bone mineral density and reduced bone turnover, and numerically reduced fractures, compared with placebo in postmenopausal Latin American women with osteoporosis. Results were similar to the global trial. PMID- 28837503 TI - Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component. AB - Neuropathic pain is an integral component of several chronic pain conditions and poses a major health problem worldwide. Despite emerging understanding of mechanisms behind neuropathic pain, the available treatment options are still limited in efficacy or associated with side effects, therefore making it necessary to find viable alternatives. In a genetic screen, we recently identified SerpinA3N, a serine protease inhibitor secreted in response to nerve damage by the dorsal root ganglion neurons and we showed that SerpinA3N acts against induction of neuropathic pain by inhibiting the T-cell- and neutrophil derived protease, leucocyte elastase (LE). In the current study, via detailed in vivo pharmacology combined with analyses of evoked- and spontaneous pain-related behaviors in mice, we report that on systemic delivery, a single dose of 3 independent LE inhibitors can block established nociceptive hypersensitivity in early and late phases in the spared nerve injury model of traumatic neuropathic pain in mice. We further report the strong efficacy of systemic LE inhibitors in reversing ongoing pain in 2 other clinically relevant mouse models-painful diabetic neuropathy and cancer pain. Detailed immunohistochemical analyses on the peripheral tissue samples revealed that both T-Lymphocytes and neutrophils are the sources of LE on peripheral nerve injury, whereas neutrophils are the primary source of LE in diabetic neuropathic conditions. In summary, our results provide compelling evidence for a strong therapeutic potential of generic LE inhibitors for the treatment of neuropathic pain and other chronic pain conditions harboring a neuropathic pain component. PMID- 28837505 TI - Diagnostic Criteria of Pediatric Intestinal Myopathies. AB - The authors aim to identify criteria for the diagnosis of intestinal visceral myopathy (IVM); results were compared with ultrastructural studies. Six IVM patients and 7 pediatric control cases (without gastrointestinal diseases) were studied. One case was a typical megacystis-microcolon-intestinal hypoperistalsis syndrome. The diagnostic path included: rectal suction biopsy, one-trocar transumbilical laparoscopic intestinal full-thickness biopsy technique. Pathological analysis included anti-alpha smooth muscle actin staining, and US study of intestinal biopsies. IVM histological examination demonstrated thinning of longitudinal muscle layer. The ratio of circular/longitudinal thickness was evaluated in all samples; in cases, this ratio presented as a mean value of 2.91, and in controls, a mean value of 1.472 (P = 0.0002). Ultrastructural diagnosis revealed variable myofibrils density in smooth muscle cells, irregularity of sarcolemma membranes, interstitial fibrosis, and myofiber disarray. The authors concluded that in IVM, circular/longitudinal thickness ratio and alpha smooth muscle actin staining can be used as significant tools to address the diagnosis. PMID- 28837506 TI - Coagulopathy in Children With Liver Disease. AB - It was thought that a high international normalized ratio predicted bleeding in patients with chronic liver disease (CLD) and patients were "autoanticoagulated." Contrary to this belief, while patients with CLD experienced bleeding, they also developed thromboses. In the last decade, the prevailing literature challenged the idea that an elevated international normalized ratio increased bleeding risk. The global assays of coagulation such as thromboelastography (TEG)/rotational thromboelastometry and thrombin generation assays provide additional insight into coagulation processes. It has become apparent that a parallel reduction of procoagulant and anticoagulant factors leave patients in a new "balanced" state, albeit a fragile one, where the balance can be easily disrupted. The inherent differences in coagulation between children and adults such as differences in levels of procoagulant and anticoagulant factors, underlying liver disease, and the paucity of studies in children make extrapolation of these findings to the pediatric population problematic. Ultimately, this is an area that requires further investigation to avoid inappropriate use of blood products and medication. PMID- 28837507 TI - Intestinal Rehabilitation Programs in the Management of Pediatric Intestinal Failure and Short Bowel Syndrome. AB - Intestinal failure is a rare, debilitating condition that presents both acute and chronic medical management challenges. The condition is incompatible with life in the absence of the safe application of specialized and individualized medical therapy that includes surgery, medical equipment, nutritional products, and standard nursing care. Intestinal rehabilitation programs are best suited to provide such complex care with the goal of achieving enteral autonomy and oral feeding with or without intestinal transplantation. These programs almost all include pediatric surgeons, pediatric gastroenterologists, specialized nurses, and dietitians; many also include a variety of other medical and allied medical specialists. Intestinal rehabilitation programs provide integrated interdisciplinary care, more discussion of patient management by involved specialists, continuity of care through various treatment interventions, close follow-up of outpatients, improved patient and family education, earlier treatment of complications, and learning from the accumulated patient databases. Quality assurance and research collaboration among centers are also goals of many of these programs. The combined and coordinated talents and skills of multiple types of health care practitioners have the potential to ameliorate the impact of intestinal failure and improve health outcomes and quality of life. PMID- 28837508 TI - Every-other-day Dosing of Oral Viscous Budesonide Is not Effective in the Management of Eosinophlic Esophagitis. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized histologically by esophageal eosinophilia. Oral viscous budesonide (OVB) is an effective treatment with remission rates reported between 55% and 87%; however, topical corticosteroids are associated with increased risk of candidal esophagitis and adrenal suppression. Attempts to decrease the daily dose of topical steroids have resulted in disease relapse. The objective of this study was to determine whether or not reducing the frequency of OVB administration would be effective in controlling esophageal eosinophilia in children and adolescents. METHODS: Data were obtained by retrospective chart review of patients at Boston Children's Hospital diagnosed with EoE, based on endoscopic findings of >15 eosinophils per high power field (eos/HPF) on esophageal biopsies while on acid blockade. Patients with histologic evidence of response (<15 eos/HPF) while on daily OVB had been offered the option of maintenance therapy based on a Monday-Wednesday-Friday (MWF) dosing regimen. Changes in peak esophageal eosinophil counts over time were examined. RESULTS: Eight male patients ages 5 to 18 years attained clinical response while receiving daily OVB and were subsequently maintained on a MWF OVB dosing regimen for 3 to 7 months. All 8 patients showed an increase in peak esophageal eosinophils, with 7 of 8 (88%) experiencing disease relapse. In fact, the distribution of peak esophageal eosinophils after MWF dosing was not statistically different from peak levels at diagnosis (P = 0.95). CONCLUSIONS: An MWF dosing regimen of OVB was not effective at maintaining histologic response in children and adolescents with EoE. Larger prospective studies are warranted to confirm these results. PMID- 28837509 TI - A Rare Phenotype of Alpha-1-Antitrypsin Deficiency Owing to PI*IS in a Newborn With Liver Disease. PMID- 28837510 TI - Use of Fully Covered Self-expanding Metal Biliary Stents in Pediatrics: A Case Series. AB - OBJECTIVES: Endoscopic retrograde cholangiopancreatography is used to manage biliary pathology in pediatric patients. Plastic biliary stents have been used in this population for obstructive lesions and bile leaks; however, they are sometimes not effective due to migration, occlusion, or ineffective sealing. Fully covered self-expanding metal stents (FCSEMS) have larger diameters making them more suitable for some situations. Their use in pediatrics has, however, not been defined. The aim of the present study is to describe our experience with FCSEMS at our institution. METHODS: We present a series of all patients who underwent FCSEMS placement at Children's Hospital Colorado including 3 adolescents and 1 young adult with complex medical needs. RESULTS: Patient age range was 12 to 24 years and the weight ranged between 36 and 75 kg. All patients underwent previous endoscopic retrograde cholangiopancreatography and 1 or more rounds of plastic stenting without adequate clinical response before consideration of FCSEMS placement. Indications included recalcitrant biliary anastomotic stricture after liver transplant, persistent bile leak after needle perforation, recurrent obstructive choledocholithiasis after cholecystectomy, and malignant biliary stricture. Sizes of FCSEMS depended on patient bile duct size and biliary pathology. Dwell time was 6 to 8 weeks. Three patients had resolution of biliary pathology after FCSEMS therapy. One patient had distal migration of FCSEMS necessitating repeat stenting. There were no adverse events from FCSEMS placement or removal. CONCLUSIONS: FCSEMS therapy should be considered in appropriate pediatric patients when plastic biliary stents are not effective. Further studies are needed to evaluate the safety and efficacy of FCSEMS in the pediatric age group. PMID- 28837511 TI - Functional Gastrointestinal Disorders and Joint Hypermobility: A School-based Study. AB - The aim of the study was to assess the prevalence of joint hypermobility (JH) among school children with and without functional gastrointestinal disorders (FGIDs). School children completed validated Rome III questionnaires to diagnose FGID. Each child diagnosed with an FGID was matched for age and sex with a healthy control. The prevalence of JH in both groups was compared. A total of 654 school children participated in the study. One hundred forty-eight (22.6%) children were diagnosed with an FGID. Data from 136 FGIDs and 136 healthy controls were analyzed. Joint laxity was assessed to establish the Beighton score (>=4 was considered JH). There was no significant difference in JH between children with and without diagnoses of FGIDs odds ratio (OR) 1.03 (95% confidence interval [CI]: 0.59-1.81, P = 0.89). Multivariate analysis showed that younger age OR 2.31 (95% CI: 1.30-4.10, P = 0.004) and female sex OR 2.27 (95% CI: 1.22 4.24, P = 0.009) were significantly associated with JH. JH is equally prevalent in school children with and without FGIDs. PMID- 28837513 TI - Prospective Study of Gastrointestinal Symptoms in School Children of South America. AB - OBJECTIVES: The aim of the study was to establish the prevalence of abdominal pain (AP) in school children in Pasto (Colombia) and determine the effect of AP on their daily activities; and compare the prevalence of AP and other gastrointestinal symptoms between school children from Pasto and Chicago. METHODS: Fourth- and fifth-grade students from a public school and a private school in Colombia were invited to participate in a prospective study using the same methods and questionnaires (Spanish version) as a previous study conducted in Chicago schools. Children completed weekly confidential surveys for 8 consecutive weeks. RESULTS: A total of 332 children participated in the study (40% girls, mean age 9.97 years, median 10, range 8-12 years): public school (288), private school (44). A total of 2425 surveys were analyzed. Out of 2656 possible weekly surveys (332 children * 8 weeks), 91.3% were completed. Overall weekly prevalence of gastrointestinal symptoms: AP (39%), nausea (29.5%), constipation (14%), diarrhea (10.5%), vomiting (9%). Children with AP reported interference with activities: gym (21.9%), school (17.3%), difficulty sleeping (13.7%), and social activities (12.6%). Out of all children, 8.4% sought medical attention for AP during the study period. CONCLUSIONS: Gastrointestinal symptoms are common in school-aged children in Colombia and interfere with both daily activities and school attendance. The prevalence of AP, diarrhea, and vomiting found in the present study was similar to published prevalence of American children using similar methods. PMID- 28837514 TI - Fatal Central Nervous System Post-Transplant Lymphoproliferative Disease in a Patient Who Underwent Liver Transplantation for Hepatoblastoma. PMID- 28837515 TI - Dietary Polyphenols in the Aetiology of Crohn's Disease and Ulcerative Colitis-A Multicenter European Prospective Cohort Study (EPIC). AB - BACKGROUND: Oxidative stress may be involved in the aetiology of inflammatory bowel disease and whether dietary polyphenols, which possess antioxidants properties, prevent its development is unknown. METHODS: A total of 401,326 men and women aged 20 to 80 years from 8 countries were recruited between 1991 and 1998 and at baseline completed validated food frequency questionnaires. Dietary polyphenol intake was measured using Phenol-Explorer, a database with information on the content of 502 polyphenols. Incident cases of Crohn's diseases (CD) and ulcerative colitis (UC) were identified during the follow-up period of up to December 2010. A nested case-control study using conditional logistic regression estimated the odds ratios (ORs), and 95% confidence intervals, for polyphenol intake (categories based on quartiles) and developing CD or UC. RESULTS: In total, 110 CD (73% women) and 244 UC (57% women) cases were identified and matched to 440 and 976 controls, respectively. Total polyphenol intake was not associated with CD (P trend = 0.17) or UC (P trend = 0.16). For flavones and CD, there were reduced odds for all quartiles, which were statistically significant for the third (OR3rd versus 1st quartile = 0.33; 95% confidence interval, 0.15 0.69) and there was an inverse trend across quartiles (P = 0.03). Similarly, for resveratrol, there was an inverse association with CD (OR4th versus 1st quartile = 0.40; 95% confidence interval, 0.20-0.82) with an inverse trend across quartiles (P = 0.02). No significant associations between subtypes of polyphenols and UC were found. Effect modification by smoking in CD was documented with borderline statistical significance. CONCLUSIONS: The data supports a potential role of flavones and resveratrol in the risk of developing CD; future aetiological studies should investigate these dietary components and further examine the potential for residual confounding. PMID- 28837516 TI - Inflammatory Bowel Diseases in Children and Young Adults with Celiac Disease. A Multigroup Matched Comparison. AB - BACKGROUND: Celiac disease (CD) has been linked to inflammatory bowel disease (IBD) but previous reports have been inconsistent and may have been affected by surveillance bias. METHODS: Matched birth cohort study in Friuli-Venezia Giulia Region, Italy. We identified 1294 individuals with CD aged 0 to 23 years at diagnosis using pathology reports, hospital discharge records, or copayment exemptions. Each CD individual was matched with up to 5 general population reference individuals from the regional Medical Birth Register in Friuli-Venezia Giulia (n = 5681). As secondary comparison groups, we used individuals undergoing small intestinal biopsy but not having villous atrophy (either Marsh 0-1-2 or exclusively Marsh 0). Individuals with IBD were identified through hospital discharge records or copayment exemptions. Conditional logistic regression was used to estimate odds ratios (ORs) for having IBD among CD individuals (before or after CD diagnosis) compared with their matched references. RESULTS: Overall 35 individuals with IBD were identified (29 with CD and 6 general population controls). This corresponded to an increased risk of IBD in CD (OR = 24.17; 95% CI, 10.03-58.21). However, compared with individuals with Marsh 0-1-2 the OR decreased to 1.41 (95% CI, 0.91-2.18) and restricting our comparison group to individuals with Marsh 0, the OR was 1.28 (95% CI, 0.61-2.70). CONCLUSIONS: In conclusion, this article found a highly increased risk of IBD in individuals with CD when comparing with the general population. Bias is the likely explanation for the very high risk increase for IBD in CD because the excess risk was substantially lower when we used individuals with a small intestinal biopsy without villous atrophy as our reference. PMID- 28837517 TI - Concomitant Therapy with Immunomodulator Enhances Infliximab Durability in Pediatric Inflammatory Bowel Disease. AB - BACKGROUND: Data on long-term durability of infliximab (IFX) and outcomes of concomitant therapy with immunomodulator in pediatric inflammatory bowel disease are limited. METHODS: Children with inflammatory bowel disease who received IFX +/- immunomodulator were retrospectively reviewed. Predictors of induction response were assessed using a binary logistic regression model and long-term outcomes evaluated by Cox proportional hazards model. Propensity score matching examined long-term efficacy of concomitant therapy in patients with Crohn's disease (CD). RESULTS: Among 148 patients (113 CD, 35 ulcerative colitis; median age at IFX initiation 14.09 years [interquartile range 12.16-15.65]), 91% experienced response to induction therapy; patients with CD were more likely to respond (95% versus 77%, odds ratio = 2.63, 95% confidence interval, 1.01-6.85, P = 0.048). Despite dose optimization, secondary loss of response occurred at a rate of 9.01% and 8.33% per year for patients with CD and ulcerative colitis, respectively. A Cox proportional hazards model showed that concomitant therapy >6 months significantly lowered the risk of secondary loss of response in CD (hazard ratio = 0.39, 95% confidence interval, 0.17-0.88, P = 0.025). The same trend was observed in ulcerative colitis but did not reach significance. A higher proportion of patients on IFX monotherapy stopped IFX because of loss of response or infusion reactions (55% versus 21%, P < 0.001). Propensity score analysis of patients with CD showed significantly higher steroid-free remission rates for concomitant versus monotherapy at 1 year (78% versus 54%, P = 0.020) and 2 years (68% versus 46%, P = 0.044), and durability of response (P = 0.022). CONCLUSIONS: These data demonstrate sustained efficacy of IFX in a cohort of pediatric patients with inflammatory bowel disease with durability of response enhanced by concomitant therapy. PMID- 28837518 TI - Increased Rate of Venous Thromboembolism in Hospitalized Inflammatory Bowel Disease Patients with Clostridium Difficile Infection. AB - BACKGROUND: Risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD) is well established; however, there is paucity of data on the potential added risk of VTE in patients with IBD with Clostridium difficile infection (CDI). We sought to study the difference in VTE rates in hospitalized patients with IBD with CDI compared to those without CDI. METHODS: We queried Nationwide Inpatient Sample from year 2011 to identify patients >=18 years of age with a discharge diagnosis of IBD (i.e., Crohn's disease and ulcerative colitis) based on ICD-9-CM codes 555.xx and 556.xx, respectively. Patients were further divided into 2 groups: those with and without CDI. To adjust and control for potential baseline differences between groups, 1:1 propensity matching was performed. Multivariate regression analysis was used to evaluate the difference in VTE rates in 2 groups. RESULTS: Of 312,147 patients with the discharge diagnosis of IBD, 12,560 (4%) had CDI. VTE was present 6% in group with CDI versus 3% in group without CDI (P < 0.001). On performing multivariate analysis after propensity-score matching, CDI was significantly associated with VTE (adjusted odds ratio 1.7, 95% confidence interval 1.4-2.2, P < 0.001). On subgroup analysis, Crohn's disease with CDI had a higher association with VTE compared with Crohn's disease only. Similarly, ulcerative colitis with CDI had a higher association with VTE compared with ulcerative colitis only. CONCLUSIONS: Rate of VTE was higher in hospitalized patients with IBD with CDI compared with those without CDI, necessitating extra vigilance in this patient population. PMID- 28837519 TI - Patients with Crohn's Disease with High Body Mass Index Present More Frequent and Rapid Loss of Response to Infliximab. AB - BACKGROUND: Infliximab (IFX) is effective in inducing and maintaining remission in patients with luminal and anoperineal Crohn's disease (CD). However, treatment failure within 12 months after initiating IFX is observed in a significant proportion of patients. The aim of the present study was to determine whether the body mass index (BMI) affects response to IFX during the first year of treatment in patients with CD. METHODS: All patients with luminal CD who began IFX between January 2010 and May 2014 were prospectively included. BMI was calculated before IFX treatment was begun, and patients were divided into 3 groups: normal BMI (BMI < 25 kg/m), overweight patients (BMI of 25.0-30 kg/m), and obese patients (BMI > 30.0 kg/m). The primary outcome was to evaluate the rate and delay of IFX optimization during the first year of treatment among normal weight, overweight, and obese patients. RESULTS: One hundred forty patients were included. Demographic and clinical characteristics at IFX initiation were comparable among the 3 groups. Within 12 months after the initiation of IFX, the rate of IFX optimization was significantly higher in overweight and obese patients than in the normal BMI group: 52%, 56%, and 20%, respectively (P = 0.0002). The median time until optimization of IFX was significantly shorter in overweight and obese patients than in the normal BMI group: 7, 7, and 10 months, respectively (P = 0.03). A BMI >25 kg/m was significantly associated with IFX optimization within 12 months on multivariate analysis. CONCLUSION: This is the first study to show that optimization of IFX is more frequent and faster in obese and overweight patients with CD and occurs within 12 months after beginning IFX, suggesting that an induction regimen with higher doses of IFX and a tight control of IFX concentrations may be needed in these patients. PMID- 28837520 TI - Findings of Retrograde Contrast Study Through Double-balloon Enteroscopy Predict the Risk of Bowel Resections in Patients with Crohn's Disease with Small Bowel Stenosis. AB - BACKGROUND: Patients with Crohn's disease (CD) with small bowel strictures are at risk of surgery. Double-balloon enteroscopy (DBE) can evaluate the status of the small intestine, and retrograde contrast through the scope enables the surgeon to obtain information beyond the reach of the scope. This study aimed to examine whether a retrograde contrast study through DBE could be used as a predictor of subsequent surgery in patients with CD with small intestinal strictures. METHODS: The findings of DBE with retrograde contrast in 48 patients CD with small bowel strictures were examined. RESULTS: Of the 48 patients, 14 (29%) underwent surgery for small intestinal strictures during a median observation period of 2.4 years (interquartile range: 1.4-3.7 yr). According to the results of the multivariate analysis, a maximum length of strictures >=20 mm and the ratio of the maximum diameter of prestenotic dilations to the diameter of the normal small intestine >=1.4 were independent risk factors of surgery for small intestinal strictures (risk ratio = 7.6 [95% confidence interval, 1.8-42.0], P = 0.006; and risk ratio = 52.0 [95% confidence interval, 3.5-2485.1], P = 0.002, respectively). The latter predicted subsequent surgery with 92% sensitivity and 88% specificity. Cumulative surgery-free rates were discriminated significantly according to the presence or absence of these 2 risk factors (log-rank test: P < 0.001). CONCLUSIONS: Findings of retrograde contrast through DBE are helpful to predict risk of surgery in patients with CD with small intestinal strictures. PMID- 28837521 TI - Premedication Use in Preventing Acute Infliximab Infusion Reactions in Patients with Inflammatory Bowel Disease: A Single Center Cohort Study. AB - BACKGROUND: Infliximab (IFX) is commonly used in patients with inflammatory bowel disease. One common side effect of IFX is an acute infusion reaction. Despite the lack of evidence supporting their use, clinicians use various premedications to prevent acute reactions. We evaluated the effectiveness of premedications in the prevention of acute IFX infusion reactions. METHODS: A retrospective cohort study was performed identifying patients with a diagnosis of inflammatory bowel disease who received IFX at our institution. Information about each IFX infusion was recorded, including the dose, infusion rate, use of premedications, and any reactions. Infusions were stratified into low and high risk. In the high- and low risk groups, the relative risk was calculated for each premedication combination used in our institution. RESULTS: Seven hundred seventy-three patients were identified; 578 patients (7090 infusions) met inclusion criteria and were included for analysis. Nine hundred eighty-six high-risk infusions were isolated; 620 (62.8%) of these infusions were administered with premedications (diphenhydramine and/or hydrocortisone) and 53 (5.4%) reactions occurred. Six thousand one hundred four low-risk infusions were identified; 2253 (36.9%) of these infusions had premedications and 61 (1.0%) reactions occurred. In both groups, none of the premedications used resulted in a significantly lower reaction rate compared with no premedication use. CONCLUSIONS: In both the high- and low-risk cohorts in this study, premedication use was not effective in reducing the rate of acute IFX reactions. Given this, routine premedication use is not recommended without future randomized control trials to demonstrate efficacy. PMID- 28837522 TI - Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma and this risk may increase with use of anti-tumor necrosis factor (TNF) therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients. This study aims to (1) identify risk factors for melanoma development in patients with IBD, (2) compare clinical characteristics of melanoma in patients with IBD to the general population, and (3) assess the influence of immunosuppressive medication on survival. METHODS: We retrospectively searched the Dutch Pathology Database to identify all Dutch patients with IBD with cutaneous melanoma between January 1991 and December 2011. We then performed 2 case-control studies. To identify risk factors for melanoma development in IBD, we compared patients with IBD with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. RESULTS: We included 304 patients with IBD with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; P < 0.01; Crohn's disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; P = 0.02). Despite a lower Nodes (N)-stage in patients with IBD (N1+ 8.3% versus 18.2%; P < 0.01) with comparable Tumor (T) and Metastasis (M) stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. CONCLUSIONS: This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in patients with IBD, we could not confirm impaired survival after melanoma in patients with IBD, regardless of anti-TNF and/or thiopurine use. PMID- 28837523 TI - Predictors of Early Readmission in Hospitalized Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Readmissions are being increasingly used as an indicator of quality of care. We sought to identify risk factors for 30-day readmission in hospitalized patients with inflammatory bowel disease. METHODS: Patients with inflammatory bowel disease hospitalized between 2004 and 2013 at the University of Maryland were identified. Demographic and clinical information were extracted from the medical record for each admission. Multivariate logistic regression was performed to determine the association between these variables and readmission. RESULTS: One thousand two hundred thirteen admissions were identified in 498 patients; 232 (19.1%) index admissions were followed by a 30-day readmission. Mean age was 39.4 +/- 14.5 years. Approximately 70% of the population was white, 60% were women, and 67.5% had Crohn's disease. Concurrent congestive heart failure and chronic obstructive pulmonary disease, history of steroid use, diverting ileostomy, subtotal colectomy, or a thromboembolic event during index admission, and IV antibiotics or restricted diet at discharge were associated with readmission. After adjustment, patients with congestive heart failure or chronic obstructive pulmonary disease were more likely to be readmitted (aOR 4.06 and 2.86, respectively). Underweight or obese patients were nearly twice as likely to be readmitted (aOR 1.81 and 1.72, respectively). Those with past steroid use, new ileostomy, or those who were discharged on hyperalimentation were twice as likely to be readmitted (aOR 1.90, 2.04, and aOR 1.97, respectively). CONCLUSIONS: Nineteen percentage of patients with inflammatory bowel disease treated at a referral center are readmitted within 30 days. Our results suggest that patients with comorbid medical conditions, malnutrition or obesity, a new ileostomy, past steroid use, or those discharged on hyperalimentation are at increased risk for readmission. Research is needed to determine if targeted interventions for high-risk patients decreases readmissions. PMID- 28837524 TI - The Association Between Drug Levels and Endoscopic Recurrence in Postoperative Patients with Crohn's Disease Treated with Tumor Necrosis Factor Inhibitors. AB - BACKGROUND: Endoscopic recurrence is associated with a risk of clinical recurrence in patients with Crohn's disease after ileocecal or small bowel resection. Drug levels and presence of antidrug antibodies are associated with important clinical and endoscopic outcomes in patients with Crohn's disease treated with tumor necrosis factor inhibitors, such association was not evaluated for endoscopic postsurgical recurrence. METHODS: Consecutive patients with Crohn's disease treated with anti-tumor necrosis factors after surgery were identified in the databases of the participating centers. Anti-tumor necrosis factor levels and antidrug antibodies were correlated with Rutgeerts score on colonoscopy performed >=6 months postoperatively. Significant endoscopic recurrence (SER) was defined as Rutgeerts score >2. RESULTS: Seventy-three consecutive patients (32-infliximab, 41-adalimumab) were included in the study. The colonoscopies were performed after a median of 15 (7-43) months after surgery and 8 (6-15) months from treatment onset. SER was demonstrated in 26/73 (35.6%) of the patients. The need for dose optimization, as well as trough infliximab levels (2.4 MUg/mL [0.45-4.1] versus 1.1 (0-0.6), P = 0.008) and presence of antidrug antibodies (1/18 [5.6%] versus 10/14 [71.4%], P = 0.0001) were significantly associated with a risk of SER. The optimal cutoff infliximab level for prediction of SER was 1.8 MUg/mL. No association between adalimumab levels and antiadalimumab antibodies was demonstrated. PMID- 28837525 TI - Combination Therapy in Pediatric Inflammatory Bowel Disease: Yes, No, Maybe. PMID- 28837526 TI - Mitochondrial DNA is Released in Urine of SIRS Patients With Acute Kidney Injury and Correlates With Severity of Renal Dysfunction. AB - Systemic inflammatory response syndrome (SIRS) is characterized by the activation of the innate immune system resulting in stimulation of inflammatory responses, coagulation, and platelet activation that may contribute to complication such as the development of acute kidney injury (AKI). AKI importantly worsens the outcome of SIRS, implying the existence of a detrimental cross talk via systemic messages. Mitochondria are a source of damage-associated molecular patterns (DAMPs) and are thought to form a molecular link between tissue injury and stimulation of innate immunity. The role of mitochondrial DNA (mtDNA) in the cross talk between the onset of SIRS and subsequent development of AKI is unknown. Hence, we performed a case control study in critically ill patients with SIRS diagnosed with or without AKI, in which we determined mtDNA levels in plasma and urine, and correlated these to markers of renal impairment, inflammation, coagulation, and platelet activation. In addition, we exposed mice, primary renal tubular epithelial cells (TECs), and platelets to mtDNA or purified mitochondrial ligands, and measured their response to elucidate underlying pathophysiological mechanisms. Our data reveal that increased systemic mtDNA levels in SIRS patients do not correlate with systemic inflammation and renal disease activity. Moreover, AKI does not have an additional effect on circulating mtDNA levels. In contrast, we found that urinary mtDNA levels correlate with an elevated albumin creatinine ratio (ACR) as well as with increased urinary markers of inflammation, coagulation, and platelet activation. Both renal TECs and platelets respond to mtDNA and mtDNA ligands, leading to increased expression of, respectively, inflammatory cytokines and P-selectin. Moreover, activation of platelets results in mtDNA release. Together, these data suggest that circulating mtDNA is probably not important in the detrimental cross talk between SIRS and AKI, whereas renal mtDNA accumulation may be related to intrarenal inflammation, coagulation processes, and renal dysfunction in the pathophysiology of SIRS. PMID- 28837527 TI - Prestained and Preloaded DMEK Grafts: An Evaluation of Tissue Quality and Stain Retention. AB - PURPOSE: To examine endothelial cell damage and stain retention of prestained preloaded Descemet membrane endothelial keratoplasty (DMEK) grafts. METHODS: DMEK grafts were stained with trypan blue or left unstained before loading into a Straiko modified Jones tube. A protocol to stain preloaded grafts inside the modified Jones tube and resulting cell loss was also examined. Endothelial cell loss was determined by vital dye staining after 3 days of cold storage and compared between the 3 groups. Eight additional grafts were stained, loaded, and shipped from Oregon to New York to assess stain stability. Stain retention and the ability to successfully inject and open these "prestained preloaded" grafts in cadaveric donor eyes were also evaluated. RESULTS: Unstained preloaded DMEK grafts showed an overall cell loss of 15% +/- 3% [95% confidence interval (CI), 11%-18%]. Prestained grafts had a cell loss of 16% +/- 4% (95% CI, 10%-22%) and were not significantly different from unstained grafts (P = 1). Grafts stained while inside the modified Jones tubes had an average cell loss of 18% +/- 2% (95% CI, 16%-20%, Pprestained = 0.15, Punstained = 0.09). All grafts shipped across the country and examined 3 days after preparation showed a decrease in stain intensity but were still deemed suitable for transplantation by an experienced DMEK surgeon. CONCLUSIONS: It is possible to prestain and preload DMEK grafts without inducing additional endothelial cell loss. Consideration should be given to the interval between staining and surgery because stain can fade. PMID- 28837528 TI - Minimizing Graft Preparation Failure in Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To report the failure rate of 2 graft preparation techniques for Descemet membrane endothelial keratoplasty (DMEK) and to evaluate how to minimize graft preparation failure. METHODS: Retrospective, nonrandomized study at an eye bank specialized in graft preparation for lamellar keratoplasty. For 1416 donor corneas, the DMEK graft preparation failure rate was evaluated for 2 different techniques, technique I: "Standardized traditional technique" (n = 341) and technique II: "Standardized no-touch technique" (n = 933), and for grafts that were converted from technique II to technique I during preparation (n = 142). RESULTS: The overall failure rate averaged 3.9% (55/1416): 7.0% (24/341) for technique I and 2.9% (31/1075) for technique II (P < 0.05). Tissue preparations which were converted from technique II to technique I failed in 13.4% (19/142), whereas for grafts that were entirely prepared by technique II, the failure rate was only 1.3% (12/933). The endothelial cell density decrease (before compared with after preparation) did not differ for both techniques (1.1% vs. 0.2%, P > 0.05). CONCLUSIONS: Various DMEK graft preparation techniques may provide failure rates of <4%. A "no-touch preparation" approach (technique II) may combine good graft quality (completely intact endothelial cell layer, ie, negligible preparation-induced endothelial cell density decrease) with low risk of dissection failure, leaving the possibility of conversion to "traditional preparation" (technique I) as a backup method. PMID- 28837529 TI - Corneal Tomographic Changes After UV Cross-Linking for Corneal Ectasia (1-Year Results). AB - PURPOSE: To evaluate changes in maximum keratometry (Kmax), corneal higher-order aberrations (HOAs), and densitometry (backscattered light) up to 1 year after UV cross-linking and their possible relation with changes in the visual outcome. METHODS: Retrospective cohort study on 18 eyes of 16 patients, who underwent UV cross-linking after the Dresden protocol for progressive keratoconus or ectasia after laser-assisted in situ keratomileusis. Corrected distance visual acuity (CDVA), Scheimpflug-based corneal tomography, mean image brightness (corneal densitometry) from the anterior 120 MUm of the midcornea, and posterior 60 MUm of the central 6 mm of the cornea, and HOAs were evaluated. RESULTS: Kmax at 1 month (59.7 +/- 6.0D) after UV cross-linking resembled preoperative Kmax (59.3 +/- 6.4D, P = 0.368), decreased until 3 months postoperatively (58.3 +/- 6.3D, P = 0.002), and stabilized thereafter (P > 0.227). All postoperative corneal densitometry values were higher than preoperative values in all measured depths (P < 0.05). One-month anterior and total corneal HOAs (4.28 +/- 1.64 MUm and 3.87 +/- 1.62 MUm, respectively) resembled preoperative values (4.10 +/- 1.70 MUm and 3.67 +/- 1.62 MUm, respectively; P > 0.221) and then decreased until 12 months postoperatively (3.86 +/- 1.84 MUm and 3.40 +/- 1.80 MUm, respectively; P < 0.005). Thinnest point thickness decreased from before (442 +/- 25 MUm) to 3 months postoperatively (427 +/- 25 MUm, P < 0.001), with no difference at 12 months postoperatively compared with preoperative values (437 +/- 29 MUm, P = 0.149). CDVA and endothelial cell density remained unchanged (P > 0.345 and P > 0.257, respectively). No relations were found between CDVA and the evaluated parameters (P > 0.05). CONCLUSIONS: One year after UV cross-linking, the observation of stable CDVA and thinnest point thickness, together with reduced Kmax suggests no ectasia progression within the study period in these cases. Although HOAs showed a trend toward improvement, corneal densitometry remained elevated. PMID- 28837530 TI - Visual Outcomes After SMILE, LASEK, and LASEK Combined With Corneal Cross-Linking for High Myopic Correction. PMID- 28837531 TI - Preoperative Opioid Use is a Predictor of Poor Return to Work in Workers' Compensation Patients After Lumbar Diskectomy. AB - STUDY DESIGN: A retrospective cohort. OBJECTIVE: The aim of this study was to determine the impact of preoperative opioid use in workers' compensation (WC) patients undergoing lumbar diskectomy (LD). SUMMARY OF BACKGROUND DATA: The prevalence of back pain among opioid users approached 60%. Long-term opioid dependence in spine surgery patients is roughly 20%. Despite pervasive use, there is no evidence to support long-term opioid analgesic use for back pain. METHODS: Ten thousand five hundred ninety-two patients received compensation from the Ohio Bureau of Workers' Compensation for a lumbar disc herniation between 2005 and 2012. Patients with spine comorbidities, smoking history, or multilevel surgery were excluded. Preoperatively, 566 patients had no opioid use, 126 had short-term opioid use (STO), 315 had moderate opioid use (MTO), and 279 had long-term opioid use (LTO). The primary outcome was whether subjects returned to work (RTW). RESULTS: Seven hundred twelve (55.4%) patients met our RTW criteria. There was a significant difference in RTW rates among the no opioid (64.1%), MTO (52.7%), and LTO (36.9%) populations. Multivariate logistic regression analysis found several covariates to be independent negative predictors of RTW status: preoperative opioid use [P < 0.01; odds ratio (OR) = 0.54], time to surgery (P < 0.01; OR = 0.98 per month), legal representation (P < 0.01; OR = 0.57), and psychiatric comorbidity (P = 0.02; OR = 0.36). Patients in the LTO group had higher medical costs (P < 0.01), rates of psychiatric comorbidity (P < 0.01), incidence of failed back surgery syndrome (FBSS) (P < 0.01), and postoperative opioid use (P < 0.01) compared with the STO and no opioid groups. CONCLUSION: Preoperative opioid use was determined to be a negative predictor of RTW rates after LD in WC patients. In addition, long-term preoperative opioid use was associated with higher medical costs, psychiatric illness, FBSS, and postoperative opioid use. Even a short or moderate course of preoperative opioids was associated with worse outcomes compared with no use. For WC patients undergoing LD, judicious use of preoperative opioid analgesics may improve clinical outcomes and reduce the opioid burden. LEVEL OF EVIDENCE: 3. PMID- 28837532 TI - Hyperbaric Oxygen Therapy After Acute Thoracic Spinal Cord Injury: Improvement of Locomotor Recovery in Rats. AB - STUDY DESIGN: A controlled laboratory study. OBJECTIVE: The aim of this study was to analyze the effectiveness of hyperbaric therapy (HT) using mild and moderate models of spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: SCI can cause permanent impairment with socioeconomic consequences. The motor deficit occurs by two mechanisms: destruction of neuronal cells and local inflammatory response, resulting in hypoxia. HT acts by increasing oxygen in the injured area. METHODS: Thoracic laminectomy was performed in 72 female Wistar rats. The MASCIS impactor was used at 12.5 mm (n = 35) and 25 mm (n = 35) of height to perform, respectively, mild and moderate SCI. Muscle strength was assessed through the Basso, Beattie, and Bresnahan scale (BBB) on days 1, 7, 14, 21, and 28 after SCI. The animals were randomized into five subgroups with seven animals each: (1) control group had SCI without HT; (2) HT 30 minutes after SCI; (3) HT 30 minutes after SCI and daily for 7 days; (4) HT 12 hours after SCI; and (5) HT 12 hours after SCI and daily for 7 days. HT was performed at 2.5 atm for 1 hour. RESULTS: There was a linear relationship between injury severity and motor deficit until day 21, with similar BBB scores on day 28. A pattern of uniform lesions was observed in the mild SCI, with lower variation of BBB when compared with moderate SCI. All animals that underwent HT had significant improvement in motor function and histology when compared with control group. Regardless of the injury model, animals submitted to 7-day protocols had an early improvement in motor function and a smaller area of histological injury. CONCLUSION: The present study reported that the sooner HT is begun after mild and moderate SCI and the larger the number of sessions, the greater and earlier is the motor recovery and smaller is the tissue injury. LEVEL OF EVIDENCE: N/A. PMID- 28837533 TI - Ewing Sarcoma of the Spine: Prognostic Variables for Survival and Local Control in Surgically Treated Patients. AB - STUDY DESIGN: Multicenter, ambispective observational study. OBJECTIVE: To quantify mortality and local recurrence after surgical treatment of spinal Ewing sarcoma (ES) and to determine whether an Enneking appropriate procedure and surgical margins (en bloc resection with wide/marginal margins) are associated with improved prognosis. SUMMARY OF BACKGROUND DATA: Treatment of primary ES of the spine is complex. Ambiguity remains regarding the role and optimal type of surgery in the treatment of spinal ES. METHODS: The AOSpine Knowledge Forum Tumor developed a multicenter database including demographics, diagnosis, treatment, mortality, and recurrence rate data for spinal ES. Patients were stratified based on surgical margins and Enneking appropriateness. Survival and recurrence were analyzed using Kaplan-Meier curves and log-rank tests. RESULTS: Fifty-eight patients diagnosed with primary spinal ES underwent surgery. Enneking appropriateness of surgery was known for 55 patients; 24 (44%) treated Enneking appropriately (EA) and 31 (56%) treated Enneking inappropriately (EI). A statistically significant difference in favor of EA-treated patients was found with regards to survival (P = 0.034). Neoadjuvant and postoperative chemotherapy was significantly associated with increased survival (P = 0.008). Local recurrence occurred in 22% (N = 5) of patients with an EA procedure versus 38% (N = 11) of patients with an EI procedure. The timing of chemotherapy treatment was significantly different between the Enneking cohorts (P < 0.001) and all EA treated patients received chemotherapy treatment. Although, local recurrence was not significantly different between Enneking cohorts (P = 0.140), intralesional surgical margins and patients who received a previous spine tumor operation were associated with increased local recurrence (P = 0.025 and P = 0.018, respectively). CONCLUSION: Surgery should be undertaken when an en bloc resection with wide/marginal margins is feasible. An EA surgery correlates with improved survival, but the impact of other prognostic factors needs to be evaluated. En bloc resection with wide/marginal margins is associated with local control. LEVEL OF EVIDENCE: 3. PMID- 28837534 TI - SEX STEROIDS AND MACULAR TELANGIECTASIA TYPE 2. AB - PURPOSE: To investigate the relationship between macular telangiectasia Type 2 and systemic levels of sex steroids or their antagonization. METHODS: In a prospective single-center study, 90 patients with macular telangiectasia Type 2 were investigated. Female patients were evaluated for previous surgical (e.g., ovariectomy) and/or pharmacological (e.g., aromatase inhibitors, tamoxifen) therapy resulting in reduced action of sex steroids. In males, free serum testosterone levels were assessed in patients and controls. RESULTS: Fourteen of 49 (29%) female patients had a history of pharmacological suppression of sex steroids and/or ovariectomy. These patients were younger at disease onset when compared with those without such medical history (mean +/- SD: 47.1 +/- 7.8, range: 38-59, versus 60.1 +/- 7.6, range: 45-76; P < 0.0001). Male patients showed significantly lower free serum testosterone levels compared with controls at younger age (P < 0.0001 and 0.04 in the first and second age quartiles, respectively), as opposed to nonsignificant differences in older patients. In men <= 60 years of age, a biochemical hypogonadism (free serum testosterone < 0.05 ng/mL) was present in 53% (8/15) and 4% (2/49) of patients and controls, respectively (P < 0.0001). CONCLUSION: The results indicate that steroidal sex hormones might be involved in the presumably multifactorial pathophysiology of macular telangiectasia Type 2. PMID- 28837535 TI - OPTICAL COHERENCE TOMOGRAPHY ANALYSIS OF OUTER RETINAL TUBULATIONS: Sequential Evolution and Pathophysiological Insights. AB - PURPOSE: To describe the sequential evolution of outer retinal tubulations (ORTs) in patients diagnosed with choroidal neovascularization and/or retinal pigment epithelium atrophy. METHODS: Retrospective evaluation of spectral domain optical coherence tomography of a consecutive cohort of patients with various retinal conditions. RESULTS: We reviewed the clinical findings of 238 eyes of 119 consecutive patients (54 men and 65 women) with a mean age of 76.2 +/- 14.2 years (range: 57-90) and a mean follow-up of 3 +/- 1.6 years (range 1-7). Over the follow-up period, ORTs were diagnosed in 67 of 238 eyes (28.1%), 9 of which were imaged with sequential, eye-tracked spectral domain optical coherence tomography dating from the beginning of ORT formation. The presence of geographic atrophy and subretinal hyperreflective material at baseline were found to be risk factors for ORT development (P < 0.001 and P < 0.001, respectively). Outer retinal tubulations were divided into forming versus formed morphologies. The latter was comprised open and closed ORTs of which the open subtype was the most common. The formation of ORTs was significantly associated with microcystic macular lesions in the inner nuclear layer and the downward displacement of the outer plexiform layer, referred to as the outer plexiform layer subsidence sign (P < 0.001). CONCLUSION: Outer retinal tubulation is a frequent optical coherence tomography finding in eyes with choroidal neovascularization and geographic atrophy. Open ORTs with progressive scrolled edges and shortened diameter were significantly associated with microcystic macular lesions in the inner nuclear layer and the outer plexiform layer subsidence sign. PMID- 28837536 TI - Evolving Role of Regional Depot Corticosteroids in Management of Diabetic Macular Edema. PMID- 28837537 TI - Characterization of hypoalbuminemia following temporary abdominal closure. AB - BACKGROUND: The purpose of this study was to characterize associations among serum proteins, negative-pressure wound therapy (NPWT) fluid loss, and primary fascial closure (PFC) following emergent laparotomy and temporary abdominal closure (TAC). We hypothesized that high levels of C-reactive protein (CRP) and NPWT output would be associated with hypoalbuminemia and failure to achieve PFC. METHODS: We performed a retrospective analysis of 233 patients managed with NPWT TAC. Serum proteins and resuscitation indices were assessed on admission, initial laparotomy, and then at 48 hours, 96 hours, 7 days, and discharge. Correlations were assessed by Pearson coefficient. Multivariable regression was performed to identify predictors of PFC with cutoff values for continuous variables determined by Youden index. RESULTS: Patients who failed to achieve PFC (n = 55) had significantly higher CRP at admission (249 vs. 148 mg/L, p = 0.003), initial laparotomy (237 vs. 154, p = 0.002), and discharge (124 vs. 72, p = 0.003), as well as significantly lower serum albumin at 7 days (2.3 vs. 2.5 g/dL, p = 0.028) and discharge (2.5 vs. 2.8, p = 0.004). Prealbumin (in milligrams per deciliter) was similar between groups at each time point. There was an inverse correlation between nadir serum albumin and total milliliters of NPWT output (r = -0.33, p < 0.001). Exogenous albumin administration (in grams per day) correlated with higher serum albumin levels at each time point: 48 hours: r = 0.26 (p = 0.002), 96 hours: r = 0.29 (p = 0.002), 7 days: r = 0.40 (p < 0.001). Albumin of less than 2.6 g/dL was an independent predictor of failure to achieve PFC (odds ratio, 2.59; 95% confidence interval, 1.02-6.61) in a multivariate model including abdominal sepsis, body mass index of greater than 40 kg/m, and CRP of greater than 250 mg/L. CONCLUSIONS: Early and persistent systemic inflammation and high NPWT output were associated with hypoalbuminemia, which was an independent predictor of failure to achieve PFC. The utility of exogenous albumin following TAC requires further study. LEVEL OF EVIDENCE: Prognostic study, level III; Therapeutic study, level IV. PMID- 28837539 TI - Developing a risk calculator for mortality following emergency general surgery. PMID- 28837538 TI - Human neutrophil elastase mediates fibrinolysis shutdown through competitive degradation of plasminogen and generation of angiostatin. AB - BACKGROUND: A subset of trauma patients undergo fibrinolysis shutdown rather than pathologic hyperfibrinolysis, contributing to organ failure. The molecular basis for fibrinolysis shutdown in trauma is incompletely understood. Elastase released from primed/activated human neutrophils (HNE) has historically been described as fibrin(ogen)olytic. However, HNE can also degrade plasminogen (PLG) to angiostatin (ANG), retaining the kringle domains but not the proteolytic function, and could thereby compete for generation of active plasmin by tissue plasminogen activator (tPA). We hypothesized that HNE can drive fibrinolysis shutdown rather than fibrinolysis. METHODS: Turbidometry was performed using light scatter (lambda = 620 nm) in a purified fibrinogen + PLG system and in healthy citrate plasma clotted with Ca/thrombin +/- tPA, +/-HNE, and +/-ANG to evaluate HNE effects on fibrinolysis, quantified by time to transition midpoint (Tm). DeltaTm from control is reported as percent of control +/-95% CI. Purified HNE coincubated with PLG or tPA was analyzed by western blot to identify cleavage products. Exogenous HNE was mixed ex vivo with healthy volunteer blood (n = 7) and used in TEG +/- tPA to evaluate effects on fibrinolysis. RESULTS: HNE did not cause measurable fibrinolysis on fibrin clots, clotted plasma, or whole blood as assessed by turbidometry or TEG in the absence of tPA. Upon tPA treatment, all three methods of evaluating fibrinolysis showed delays and decreases in fibrinolysis caused by HNE relative to control: fibrin clot turbidometry DeltaTm = 110.7% (CI 105.0-116.5%), clotted citrate plasma (n = 6 healthy volunteers) DeltaTm = 126.1% (CI 110.4-141.8%), and whole blood native TEG (n = 7 healthy volunteers) with DeltaLY30 = 28% (p = 0.043). Western blot analysis of HNE-PLG co incubation confirmed that HNE generates angiostatin K1-3, and plasma turbidity assays treated with angiostatin K1-3 delayed fibrinolysis. CONCLUSION: HNE degrades PLG and generates angiostatin K1-3, which predominates over HNE cleavage of fibrin(ogen). These findings suggest that neutrophil release of elastase may underlie trauma-induced fibrinolytic shutdown. PMID- 28837540 TI - Multi-institutional analysis of neutrophil-to-lymphocyte ratio (NLR) in patients with severe hemorrhage: A new mortality predictor value. AB - BACKGROUND: The neutrophil/lymphocyte ratio (NLR) has been associated as a predictor for increased mortality in critically ill patients. We sought to determine the relationship between NLR and outcomes in adult trauma patients with severe hemorrhage requiring the initiation of massive transfusion protocol (MTP). We hypothesized that the NLR would be a prognostic indicator of mortality in this population. METHODS: This was a multi-institutional retrospective cohort study of adult trauma patients (>=18 years) with severe hemorrhage who received MTP between November 2014 and November 2015. Differentiated blood cell counts obtained at days 3 and 10 were used to obtain NLR. Receiver operating characteristic (ROC) curve analysis assessed the predictive capacity of NLR on mortality. To identify the effect of NLR on survival, Kaplan-Meier (KM) survival analysis and Cox regression models were used. RESULTS: A total of 285 patients with severe hemorrhage managed with MTP were analyzed from six participating institutions. Most (80%) were men, 57.2% suffered blunt trauma. Median (IQR) age, Injury Severity Score, and Glasgow Coma Scale were 35 (25-47), 25 (16-36), and 9 (3-15), respectively. Using ROC curve analysis, optimal NLR cutoff values of 8.81 at day 3 and 13.68 at day 10 were calculated by maximizing the Youden index. KM curves at day 3 (p = 0.05) and day 10 (p = 0.02) revealed an NLR greater than or equal to these cutoff values as a marker for increased in-hospital mortality. Cox regression models failed to demonstrate an NLR over 8.81 as predictive of in hospital mortality at day 3 (p = 0.056) but was predictive for mortality if NLR was greater than 13.68 at day 10 (p = 0.036). CONCLUSIONS: NLR is strongly associated with early mortality in patients with severe hemorrhage managed with MTP. Further research is needed to focus on factors that can ameliorate NLR in this patient population. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 28837541 TI - Behcet disease: a rare systemic vasculitis in Poland. AB - INTRODUCTION Behcet disease (BD) is an immune-mediated small-vessel systemic vasculitis, which is rarely seen in Poland. OBJECTIVES The aim of this study was to evaluate the incidence and prevalence of BD, as well as to assess the sex and geographical distribution of BD in Poland during a 7-year follow-up. To our knowledge, this is the first evaluation of this rare disease in Poland, based on a hospital morbidity database. PATIENTS AND METHODS We analyzed population based administrative data obtained from a national hospital morbidity study conducted between January 2008 and December 2014 by the National Institute of Public Health in Poland. The annual incidence rates and point prevalence of BD were calculated using the number of patients with BD and corresponding census data for the overall Polish population. RESULTS Data included 316 hospitalization records. The final study sample comprised 130 patients (54 men [42%] and 76 women [58%]) with first-time hospitalizations for BD. The mean (SD) age was 41.6 (18.7) years (95% confidence interval [CI], 38.3-44.8; range, 5-85 years). The incidence rate of BD was estimated at 0.5 per million persons per year (95% CI, 0.35-0.61). The point prevalence at the end of 2014 was 3.4 per million persons. The incidence rate of BD did not vary significantly between more urban and more rural regions, and BD was observed more often in women than in men. CONCLUSIONS BD is endemic in Eastern and Central Asian countries, but is also seen in Poland. However, its incidence and prevalence rates are lower in Poland than in other European countries. PMID- 28837542 TI - Professors of internal diseases at Polish universities in 1918-1939. AB - The article outlines the achievements of Polish professors who specialized in the treatment of internal diseases. The analysis concerns the scientists who held professorial chairs between 1918 and 1939. The findings were presented in the context of university medical departments. In Poland, in the interwar period, a total of 13 professors held chairs of internal medicine: Zdzislaw Gorecki, Wladyslaw Antoni Gluzinski, Aleksander Januszkiewicz, Walery Jaworski, Wincenty Jezierski, Jerzy Latkowski, Jan Henryk Lubieniecki, Witold Orlowski, Zenon Orlowski, Roman Rencki, Kazimierz Rzetkowski, Tadeusz Tempka, and Edward Zebrowski. Some of them had been awarded their chairs before 1918. Most of them were successful researchers. Professors Antoni Gluzinski and Witold Orlowski were particularly recognized in the scientific world. Gluzinski held chairs at Jagiellonian University and then at the University of Warsaw. Orlowski worked at Jan Kazimierz University in Lviv and then moved to the University of Warsaw. In the interwar period, Polish departments of medicine were one of the largest when compared with other departments. Consequently, internal medicine units (assigned to such chairs) were the largest within the departments of medicine in terms of the staff employed. For this reason, most universities decided to divide such units into 2 independent ones. In the years 1918-1939, the field of internal medicine had flourished in Warsaw, Krakow, Poznan, Lviv, and Vilnius; however, the outbreak of World War II would change this forever. After 1945, Lviv and Vilnius were no longer within the territory of Poland, and Polish professors based in those cities moved to join professorial staff at Polish universities. PMID- 28837543 TI - Treatment and outcomes of patients under 40 years of age with acute myocardial infarction in Poland in 2009-2013: an analysis from the PL-ACS registry. AB - INTRODUCTION Patients under the age of 40 years represent from 1% to 6% of all patients with acute myocardial infarction (AMI). OBJECTIVES We aimed to analyze the recent trends in the clinical presentation, treatment, and both the in-hospital and 12-month outcomes of patients under 40 years of age with ST segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI), treated from 2009 to 2013. PATIENTS AND METHODS The study included 1639 young patients with AMI under the age of 40 years included in the PL-ACS registry (1.3% of all patients with AMI). Trends in the period from 2009 to 2010 (643 patients) and from 2012 to 2013 (676 patients) were analyzed. RESULTS The percentage of admissions for STEMI decreased (71.7% vs 63.9%; P = 0.002), while that of admissions for NSTEMI increased (28.3% vs 36.1%; P = 0.002) over the years. There was no difference in the in-hospital mortality (1.7% vs 1.6%; P = 1.0). The percentage of patients treated invasively increased from 90.7% in the period 2009 2010 to 95.7% in the period 2012-2013 (P = 0.0003). There was no difference between the groups in the incidence of death (2.5% vs 2.8%; P = 0.72) or the rate of the composite endpoint of death, recurrent AMI, or stroke within 1 year of the index hospitalization (5.3% vs 5.6%, P = 0.80). CONCLUSIONS There was no significant difference in the in-hospital and 12-month outcomes between the patients under 40 years of age with STEMI and NSTEMI hospitalized in the years 2009-2010 and those treated in the years 2012-2013. The relative percentage of patients with NSTEMI and those treated invasively increased significantly over the years. PMID- 28837544 TI - An update on the management of latent tuberculosis infection and active disease in patients with chronic kidney disease. AB - In 2010, the British Thoracic Society published guidelines on the management of tuberculosis (TB) infection and disease in patients with chronic kidney disease (CKD), in response to physicians' concerns about the challenges encountered in treating this complex patient group. Later, in 2010, we summarized the main messages from these guidelines for readers of this journal. The purpose of this review is an update on the current management of latent and active Mycobacterium tuberculosis infection in patients with CKD. Patients with CKD have an increased risk of both infection and disease with Mycobacterium tuberculosis, and practice varies between renal units. Since 2010, the majority of published data have focused on screening for TB infection in immunosuppressed patients, including those with CKD and transplant recipients. While there is currently no perfect screening test, the evidence suggests that we should be using the available interferon-gamma release assays, with or without the tuberculin skin test, to try and reduce the undoubted risk of active TB in these patients. While we are not aware of any new evidence to change the recommended treatment regimens, we have reiterated some of the important recommendations outlined in the original guidelines. PMID- 28837546 TI - National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years - United States, 2016. AB - The Advisory Committee on Immunization Practices (ACIP) recommends that adolescents routinely receive tetanus, diphtheria, and acellular pertussis vaccine (Tdap), meningococcal conjugate vaccine (MenACWY), and human papillomavirus (HPV) vaccine (1) at age 11-12 years. ACIP also recommends catch up vaccination with hepatitis B vaccine, measles, mumps, and rubella (MMR) vaccine, and varicella vaccine for adolescents who are not up to date with childhood vaccinations. ACIP recommends a booster dose of MenACWY at age 16 years (1). In December 2016, ACIP updated HPV vaccine recommendations to include a 2 dose schedule for immunocompetent adolescents initiating the vaccination series before their 15th birthday (2). To estimate adolescent vaccination coverage in the United States, CDC analyzed data from the 2016 National Immunization Survey Teen (NIS-Teen) for 20,475 adolescents aged 13-17 years.* During 2015-2016, coverage increased for >=1 dose of Tdap (from 86.4% to 88.0%) and for each HPV vaccine dose (from 56.1% to 60.4% for >=1 dose). Among adolescents aged 17 years, coverage with >=2 doses of MenACWY increased from 33.3% to 39.1%. In 2016, 43.4% of adolescents (49.5% of females; 37.5% of males) were up to date with the HPV vaccination series, applying the updated HPV vaccine recommendations retrospectively.? Coverage with >=1 HPV vaccine dose varied by metropolitan statistical area (MSA) status and was lowest (50.4%) among adolescents living in non-MSA areas and highest (65.9%) among those living in MSA central cities.S Adolescent vaccination coverage continues to improve overall; however, substantial opportunities exist to further increase HPV-associated cancer prevention. PMID- 28837545 TI - IL-17A Inhibits Osteogenic Differentiation of Bone Mesenchymal Stem Cells via Wnt Signaling Pathway. AB - BACKGROUND Interleukin-17A (IL-17A) is not only an important modulator of inflammatory reactions, but also affects bone metabolism, which is involved in osteogenic differentiation of stem cells. However, the role and mechanism of IL 17A in osteogenic differentiation of bone mesenchymal stem cells (BMSCs) are not fully understood. In this study, we investigated the role and mechanism of IL-17A in osteogenic differentiation of BMSCs. MATERIAL AND METHODS The osteogenic differentiation of BMSCs was induced by osteoblast-induction medium with IL-17A or without IL-17A. The osteogenic differentiation of BMSCs was confirmed by the alkaline phosphatase and alizarin red staining. The lentiviral plasmid was used to construct the sFRP1-shRNA expression vector. The associated osteogenic differentiation marks (RUNX2, ALP, OPN), Wnt signaling pathway inhibitor (sFRP1), and modulators of Wnt signaling pathway (Wnt3, Wnt6) were detected by qRT-PCR and Western blot method. RESULTS The results showed that the addition of IL-17A inhibited osteogenic differentiation of BMSCs. IL-17A induced up-regulated expression of sFRP1 and down-regulated expression of Wnt3 and Wnt6 in BMSCs. In addition, sFRP1-shRNA abolished the inhibition effect of IL-17A in osteogenic differentiation of BMSCs and induced up-regulated expression of Wnt3 and Wnt6 in the Wnt signaling pathway in BMSCs. CONCLUSIONS Our findings show that IL-17A inhibits osteogenic differentiation of bone mesenchymal stem cells via the Wnt signaling pathway. PMID- 28837547 TI - HIV Testing Among Transgender Women and Men - 27 States and Guam, 2014-2015. AB - Transgender persons are at high risk for human immunodeficiency virus (HIV) infection; in a recent analysis of the results of over nine million CDC funded HIV tests, transgender women* had the highest percentage of confirmed positive results (2.7%) of any gender category (1). Transgender men,? particularly those who have sex with cisgenderS men, are also at high risk for infection (2). HIV testing is critical for detecting and treating persons who are infected and delivering preventive services to those who are uninfected. CDC recommends that persons at high risk for HIV infection be screened for HIV at least annually, although transgender persons are not specified in the current recommendations. CDC analyzed data from the Behavioral Risk Factor Surveillance System (BRFSS) to describe HIV testing among transgender women and men and two cisgender comparison groups in 27 states and Guam. After adjusting for demographic characteristics, transgender women and men had a lower prevalence of ever testing and past year testing for HIV (35.6% and 31.6% ever, and 10.0% and 10.2% past year, respectively) compared with cisgender gay and bisexual men (61.8% ever and 21.6% past year) and instead reported testing at levels comparable to cisgender heterosexual men and women (35.2% ever, and 8.6% past year). This finding suggests that transgender women and men might not be sufficiently reached by current HIV testing measures. Tailoring HIV testing activities to overcome the unique barriers faced by transgender women and men might increase rates of testing among these populations. PMID- 28837548 TI - CDC Grand Rounds: Newborn Screening for Hearing Loss and Critical Congenital Heart Disease. AB - Newborn screening is a public health program that benefits 4 million U.S. infants every year by enabling early detection of serious conditions, thus affording the opportunity for timely intervention to optimize outcomes (1). States and other U.S. jurisdictions decide whether and how to regulate newborn screening practices. Most newborn screening is done through laboratory analyses of dried bloodspot specimens collected from newborns. Point-of-care newborn screening is typically performed before discharge from the birthing facility. The Recommended Uniform Screening Panel includes two point-of-care conditions for newborn screening: hearing loss and critical congenital heart disease (CCHD). The objectives of point-of-care screening for these two conditions are early identification and intervention to improve neurodevelopment, most notably language and related skills among infants with permanent hearing loss, and to prevent death or severe disability resulting from delayed diagnosis of CCHD. Universal screening for hearing loss using otoacoustic emissions or automated auditory brainstem response was endorsed by the Joint Committee on Infant Hearing in 2000 and 2007* and was incorporated in the first Recommended Uniform Screening Panel in 2005. Screening for CCHD using pulse oximetry was recommended by the Advisory Committee on Heritable Disorders in Newborns and Children in 2010 based on an evidence review? and was added to the Recommended Uniform Screening Panel in 2011.S. PMID- 28837550 TI - QuickStats: Percentage* of Adults Who Ever Used an E-cigarette? and Percentage Who Currently Use E-cigarettes,S by Age Group - National Health Interview Survey, United States, 2016 . PMID- 28837549 TI - Use of Outpatient Cardiac Rehabilitation Among Heart Attack Survivors - 20 States and the District of Columbia, 2013 and Four States, 2015. AB - Heart disease is the leading cause of death in the United States (1). Each year, approximately 790,000 adults have a myocardial infarction (heart attack), including 210,000 that are recurrent heart attacks (2). Cardiac rehabilitation (rehab) includes exercise counseling and training, education for heart-healthy living, and counseling to reduce stress. Cardiac rehab provides patients with education regarding the causes of heart attacks and tools to initiate positive behavior change, and extends patients' medical management after a heart attack to prevent future negative sequelae (3). A systematic review has shown that after a heart attack, patients using cardiac rehab were 53% (95% confidence interval [CI] = 41%-62%) less likely to die from any cause and 57% (95% CI = 21%-77%) less likely to experience cardiac-related mortality than were those who did not use cardiac rehab (3). However, even with long-standing national recommendations encouraging use of cardiac rehab (4), the intervention has been underutilized. An analysis of 2005 Behavioral Risk Factor Surveillance System (BRFSS) data found that only 34.7% of adults who reported a history of a heart attack also reported subsequent use of cardiac rehab (5). To update these estimates, CDC used the most recent BRFSS data from 2013 and 2015 to assess the use of cardiac rehab among adults following a heart attack. Overall use of cardiac rehab was 33.7% in 20 states and the District of Columbia (DC) in 2013 and 35.5% in four states in 2015. Cardiac rehab use was underutilized overall and differences were evident by sex, age, race/ethnicity, level of education, cardiovascular risk status, and by state. Increasing use of cardiac rehab after a heart attack should be encouraged by health systems and supported by the public health community. PMID- 28837551 TI - Notes from the Field: Fatal Pneumonic Tularemia Associated with Dog Exposure - Arizona, June 2016. PMID- 28837553 TI - Data driven flexible backbone protein design. AB - Protein design remains an important problem in computational structural biology. Current computational protein design methods largely use physics-based methods, which make use of information from a single protein structure. This is despite the fact that multiple structures of many protein folds are now readily available in the PDB. While ensemble protein design methods can use multiple protein structures, they treat each structure independently. Here, we introduce a flexible backbone strategy, FlexiBaL-GP, which learns global protein backbone movements directly from multiple protein structures. FlexiBaL-GP uses the machine learning method of Gaussian Process Latent Variable Models to learn a lower dimensional representation of the protein coordinates that best represent backbone movements. These learned backbone movements are used to explore alternative protein backbones, while engineering a protein within a parallel tempered MCMC framework. Using the human ubiquitin-USP21 complex as a model we demonstrate that our design strategy outperforms current strategies for the interface design task of identifying tight binding ubiquitin variants for USP21. PMID- 28837554 TI - "We are survivors and not a virus:" Content analysis of media reporting on Ebola survivors in Liberia. AB - BACKGROUND: The Ebola virus disease epidemic between 2013 and 2016 in West Africa was unprecedented. It resulted in approximately 28.000 cases and 10.000 Ebola survivors. Many survivors face social, economic and health-related predicaments and media reporting is crucially important in infectious disease outbreaks. However, there is little research on reporting of the social situation of Ebola survivors in Liberia. METHODS: The study used a mixed methods approach and analysed media reports from the Liberian Daily Observer (DOL), a daily newspaper available online in English. We were interested to know how the situation of Ebola survivors was portrayed; in what way issues such as stigma and discrimination were addressed; and which stigma reduction interventions were covered and how. We included all articles on the situation of Ebola survivors in the quantitative and in-depth qualitative analysis published between April 2014 and March 2016. RESULTS: The DOL published 148 articles that portrayed the social situation of Ebola survivors between the 24 months observation period. In these articles, Ebola survivors were often defined beyond biological terms, reflecting on a broader social definition of survivorship. Survivorship was associated with challenges such as suffering from after-effects, social and economic consequences and psychological distress. Almost 50% of the articles explicitly mentioned stigmatisation in their reporting on Ebola survivors. This was contextualised in untrustworthiness towards international responses and the local health care system and inconclusive knowledge on cures and transmission routes. In the majority of DOL articles stigma reduction and engaging survivors in the response was reported as crucially important. DISCUSSION: Reporting in the DOL was educational-didactical and well-balanced in terms of disseminating available medical knowledge and reflecting the social situation of Ebola survivors. While the articles contextualised factors contributing to stigmatisation throughout the reporting, journalistic scrutiny regarding effectiveness of interventions by government and NGOs was missing. PMID- 28837555 TI - Spread of hospital-acquired infections: A comparison of healthcare networks. AB - Hospital-acquired infections (HAIs), including emerging multi-drug resistant organisms, threaten healthcare systems worldwide. Efficient containment measures of HAIs must mobilize the entire healthcare network. Thus, to best understand how to reduce the potential scale of HAI epidemic spread, we explore patient transfer patterns in the French healthcare system. Using an exhaustive database of all hospital discharge summaries in France in 2014, we construct and analyze three patient networks based on the following: transfers of patients with HAI (HAI specific network); patients with suspected HAI (suspected-HAI network); and all patients (general network). All three networks have heterogeneous patient flow and demonstrate small-world and scale-free characteristics. Patient populations that comprise these networks are also heterogeneous in their movement patterns. Ranking of hospitals by centrality measures and comparing community clustering using community detection algorithms shows that despite the differences in patient population, the HAI-specific and suspected-HAI networks rely on the same underlying structure as that of the general network. As a result, the general network may be more reliable in studying potential spread of HAIs. Finally, we identify transfer patterns at both the French regional and departmental (county) levels that are important in the identification of key hospital centers, patient flow trajectories, and regional clusters that may serve as a basis for novel wide scale infection control strategies. PMID- 28837557 TI - Altruism by age and social proximity. AB - This study evaluates the extent to which an individual's stated altruistic sentiments can be influenced by context-most importantly, by the age and social proximity of the other person and by the nature of what is being sacrificed. We measure willingness to sacrifice own health for another person's health and willingness to sacrifice own wealth for another person's wealth. To evaluate these sentiments, two surveys were administered to representative samples of Americans which contained hypothetical scenarios with context randomly assigned; the first survey posed a dictator game question and the second survey was designed to elicit marginal rates of substitution between own and other's health/wealth. As expected, we find less altruism towards those who are more socially distant (e.g., strangers relative to family). We find individuals are more health altruistic towards young children and more wealth altruistic towards adults, and health altruism tends to be lowest for survey respondents near retirement age. We find no relationship between levels of altruism and the distance between the respondent's state of birth and state of current residence. These findings improve society's understanding of situational altruism and kinship and reciprocity as motivations for altruism, and they have practical implications concerning the economic valuation of human lives used to guide public policy-making. PMID- 28837556 TI - From homeostasis to behavior: Balanced activity in an exploration of embodied dynamic environmental-neural interaction. AB - In recent years, there have been many computational simulations of spontaneous neural dynamics. Here, we describe a simple model of spontaneous neural dynamics that controls an agent moving in a simple virtual environment. These dynamics generate interesting brain-environment feedback interactions that rapidly destabilize neural and behavioral dynamics demonstrating the need for homeostatic mechanisms. We investigate roles for homeostatic plasticity both locally (local inhibition adjusting to balance excitatory input) as well as more globally (regional "task negative" activity that compensates for "task positive", sensory input in another region) balancing neural activity and leading to more stable behavior (trajectories through the environment). Our results suggest complementary functional roles for both local and macroscale mechanisms in maintaining neural and behavioral dynamics and a novel functional role for macroscopic "task-negative" patterns of activity (e.g., the default mode network). PMID- 28837558 TI - The prevalence and incidence of active syphilis in women in Morocco, 1995-2016: Model-based estimation and implications for STI surveillance. AB - BACKGROUND: Evolving health priorities and resource constraints mean that countries require data on trends in sexually transmitted infections (STI) burden, to inform program planning and resource allocation. We applied the Spectrum STI estimation tool to estimate the prevalence and incidence of active syphilis in adult women in Morocco over 1995 to 2016. The results from the analysis are being used to inform Morocco's national HIV/STI strategy, target setting and program evaluation. METHODS: Syphilis prevalence levels and trends were fitted through logistic regression to data from surveys in antenatal clinics, women attending family planning clinics and other general adult populations, as available post 1995. Prevalence data were adjusted for diagnostic test performance, and for the contribution of higher-risk populations not sampled in surveys. Incidence was inferred from prevalence by adjusting for the average duration of infection with active syphilis. RESULTS: In 2016, active syphilis prevalence was estimated to be 0.56% in women 15 to 49 years of age (95% confidence interval, CI: 0.3%-1.0%), and around 21,675 (10,612-37,198) new syphilis infections have occurred. The analysis shows a steady decline in prevalence from 1995, when the prevalence was estimated to be 1.8% (1.0-3.5%). The decline was consistent with decreasing prevalences observed in TB patients, fishermen and prisoners followed over 2000 2012 through sentinel surveillance, and with a decline since 2003 in national HIV incidence estimated earlier through independent modelling. CONCLUSIONS: Periodic population-based surveys allowed Morocco to estimate syphilis prevalence and incidence trends. This first-ever undertaking engaged and focused national stakeholders, and confirmed the still considerable syphilis burden. The latest survey was done in 2012 and so the trends are relatively uncertain after 2012. From 2017 Morocco plans to implement a system to record data from routine antenatal programmatic screening, which should help update and re-calibrate next trend estimations. PMID- 28837559 TI - High anti-human cytomegalovirus antibody levels are associated with the progression of essential hypertension and target organ damage in Han Chinese population. AB - Human cytomegalovirus (CMV) infection is associated with hypertension and has been linked with the pathogenesis of increased arterial blood pressure (BP). Currently, whether CMV infection is associated with the progression of hypertension and hypertensive target organ damage (TOD) remains to be identified. We aimed to examine the relationship between CMV infection and the progression of hypertension and hypertensive TOD, which could provide clues on the possible mediating mechanisms, in the Han Chinese population. A total of 372 patients with hypertension and 191 healthy controls (Han participants from Xinjiang, China) were included in the study. Enzyme-linked immunosorbent assay (ELISA) and qPCR were used to detect CMV infection. C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) titers were also analyzed using an ELISA kit. Moreover, cardiovascular disease markers were evaluated by echocardiography, carotid ultrasonography, and tomographic scans. Essential hypertension (EH) patients exhibited a marked increase in CMV IgG antibody, CRP, TNF-alpha, and IL-6 levels. Higher grade of hypertension and hypertensive TOD had higher CMV IgG antibody and CRP levels. The CMV IgG antibody titers were positively correlated with arterial BP, greater grade of hypertension and hypertensive TOD, and CRP and IL-6 levels. The higher quartile of CMV IgG titer and CRP level were associated with the incidence of hypertension and the progression of hypertension and hypertensive TOD. In the Han Chinese population, high CMV IgG titers are associated with the progression of hypertension and hypertensive TOD. CMV IgG titer >4.25 U could be an independent predictor of hypertension and progression of hypertension, while that >4.85 U could be an independent risk factor for hypertensive TOD. The underlying mechanism may be largely mediated by chronic inflammation. PMID- 28837560 TI - Wnt/beta-catenin signaling pathway inhibits the proliferation and apoptosis of U87 glioma cells via different mechanisms. AB - The Wnt signaling pathway is necessary for the development of the central nervous system and is associated with tumorigenesis in various cancers. However, the mechanism of the Wnt signaling pathway in glioma cells has yet to be elucidated. Small-molecule Wnt modulators such as ICG-001 and AZD2858 were used to inhibit and stimulate the Wnt/beta-catenin signaling pathway. Techniques including cell proliferation assay, colony formation assay, Matrigel cell invasion assay, cell cycle assay and Genechip microarray were used. Gene Ontology Enrichment Analysis and Gene Set Enrichment Analysis have enriched many biological processes and signaling pathways. Both the inhibiting and stimulating Wnt/beta-catenin signaling pathways could influence the cell cycle, moreover, reduce the proliferation and survival of U87 glioma cells. However, Affymetrix expression microarray indicated that biological processes and networks of signaling pathways between stimulating and inhibiting the Wnt/beta-catenin signaling pathway largely differ. We propose that Wnt/beta-catenin signaling pathway might prove to be a valuable therapeutic target for glioma. PMID- 28837561 TI - Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation. AB - Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype. PMID- 28837562 TI - Interventions to address unequal gender and power relations and improve self efficacy and empowerment for sexual and reproductive health decision-making for women living with HIV: A systematic review. AB - BACKGROUND: Many women living with HIV experience gendered power inequalities, particularly in their intimate relationships, that prevent them from achieving optimal sexual and reproductive health (SRH) and exercising their rights. We assessed the effectiveness of interventions to improve self-efficacy and empowerment of women living with HIV to make SRH decisions through a systematic review. METHODS AND FINDINGS: We included peer-reviewed articles indexed in PubMed, PsycINFO, CINAHL, Embase, and Scopus published through January 3, 2017, presenting multi-arm or pre-post intervention evaluations measuring one of the following outcomes: (1) self-efficacy, empowerment, or measures of SRH decision making ability, (2) SRH behaviors (e.g., condom use, contraceptive use), or (3) SRH outcomes (e.g., sexually transmitted infections [STIs]). Twenty-one studies evaluating 11 intervention approaches met the inclusion criteria. All were conducted in the United States or sub-Saharan Africa. Two high-quality randomized controlled trials (RCTs) showed significant decreases in incident gonorrhea and chlamydia. Sixteen studies measuring condom use generally found moderate increases associated with the intervention, including in higher-quality RCTs. Findings on contraceptive use, condom self-efficacy, and other empowerment measures (e.g., sexual communication, equitable relationship power) were mixed. Studies were limited by small sample sizes, high loss to follow-up, and high reported baseline condom use. CONCLUSIONS: While more research is needed, the limited existing evidence suggests that these interventions may help support the SRH and rights of women living with HIV. This review particularly highlights the importance of these interventions for preventing STIs, which present a significant health burden for women living with HIV that is rarely addressed holistically. Empowerment-based interventions should be considered as part of a comprehensive package of STI and other SRH services for women living with HIV. PMID- 28837563 TI - Demographic, clinical and behavioural determinants of HIV serostatus non disclosure to sex partners among HIV-infected pregnant women in the Eastern Cape, South Africa. AB - OBJECTIVES: Drawing from a baseline sample of a cohort study, the study examines the extent and correlates of serostatus non-disclosure to sex partners and family members, and reasons for non-disclosure among HIV-infected pregnant women in the Eastern Cape Province, South Africa. METHODS: This longitudinal cohort study recruited 1709 pregnant women living with HIV who attended three of the largest maternity centres in the Eastern Cape, South Africa, for delivery between September 2015 and May 2016. Relevant items on demographics, serostatus awareness, disclosure to sex partners and family members, and lifestyle behaviours were obtained using structured interviews. Age-stratified binary logistic regression models were used to determine the significant correlates of non-disclosure among the participants. RESULTS: A higher rate of HIV serostatus non-disclosure to sex partners (25.6%) in comparison to family members (20%) was reported by the participants. Younger age, not living with partners and alcohol use were significantly associated with non-disclosure of HIV serostatus to sex partners. Non-disclosure of HIV serostatus to sex partners was significantly (p<0.05) associated with poor adherence to the highly active anti-retroviral therapy (HAART), failure to keep clinic appointments and high viral load at the delivery of the baby. Perceived fear of intimate partner violence, fear of rejection, guilt of not disclosing at the onset of the relationship, sex partner's non-disclosure of HIV serostatus, and guilt of unfaithfulness were some of the reasons for non-disclosure of HIV serostatus to sex partners. CONCLUSIONS: Non-disclosure of HIV serostatus is a public health concern with serious implications for both mother-to-child transmission, as well as horizontal transmission, in our setting. Strategic efforts toward ending the epidemic of HIV and AIDS in South Africa should address the sociocultural and behavioural determinants of non-disclosure. PMID- 28837564 TI - Impact of meningitis on intelligence and development: A systematic review and meta-analysis. AB - BACKGROUND: We undertook a systematic review and meta-analysis to address the question "what is the impact of meningitis on IQ and development." METHODS: Search: conducted using standardized search terms across Medline, PsychInfo and EMBASE to 06/2014. Eligibility: human studies of any infectious aetiology of meningitis reporting IQ or infant developmental age or stage outcomes. Quality: Centre for Evidence Based Medicine, Oxford, quality tools. Analysis: random effects meta-analysis by organism. RESULTS: 39 studies were included in the review, 34 providing data on IQ (2015 subjects) and 12 on developmental delay (382 subjects). Across all bacterial organisms, meningitis survivors had a mean IQ 5.50 (95% CI: -7.19, -3.80; I2 = 47%, p = 0.02) points lower than controls. IQ was significantly lower than controls for Neisseria meningitides (NM: 5 points) and Haemophilus influenzae b (Hib: 6 points) but not in viral meningitis, with only single studies included for Streptococcus pneumoniae (SP) and group B streptococcus (GBS). The pooled relative risk (RR) for low IQ (IQ<70) in survivors of bacterial meningitis compared with controls was 4.99 (95% CI: 3.17, 7.86) with no significant heterogeneity (I2 = 49%, p = 0.07). Developmental delay of approximately 0.5SD was reported in studies of bacterial meningitis but no delay in the only study of viral meningitis. CONCLUSIONS: We found moderate evidence that surviving bacterial meningitis has a deleterious impact on IQ and development but no evidence that viral meningitis had meaningful cognitive impacts. Survivors of bacterial meningitis should be routinely offered screening for cognitive deficits and developmental delay in addition to hearing loss. PMID- 28837566 TI - Determinants of user acceptance of a specific social platform for older adults: An empirical examination of user interface characteristics and behavioral intention. AB - The use of the Internet and social applications has many benefits for the elderly, but numerous investigations have shown that the elderly do not perceive online social networks as a friendly social environment. Therefore, TreeIt, a social application specifically designed for the elderly, was developed for this study. In the TreeIt application, seven mechanisms promoting social interaction were designed to allow older adults to use social networking sites (SNSs) to increase social connection, maintain the intensity of social connections and strengthen social experience. This study's main objective was to investigate how user interface design affects older people's intention and attitude related to using SNSs. Fourteen user interface evaluation heuristics proposed by Zhang et al. were adopted as the criteria to assess user interface usability and further grouped into three categories: system support, user interface design and navigation. The technology acceptance model was adopted to assess older people's intention and attitude related to using SNSs. One hundred and one elderly persons were enrolled in this study as subjects, and the results showed that all of the hypotheses proposed in this study were valid: system support and perceived usefulness had a significant effect on behavioral intention; user interface design and perceived ease of use were positively correlated with perceived usefulness; and navigation exerted an influence on perceived ease of use. The results of this study are valuable for the future development of social applications for the elderly. PMID- 28837565 TI - Leishmania infection and blood food sources of phlebotomines in an area of Brazil endemic for visceral and tegumentary leishmaniasis. AB - The aims of the study were to determine the blood feeding preferences of sandflies and to identify species of Leishmania that infected phlebotomines in Caxias, Maranhao, Brazil, an area that is highly endemic for leishmaniasis. Sandflies were captured in light traps located in the peridomiciliary environments of randomly selected houses in urban and rural settings between 1800 and 0600 hours on new moon days between March 2013 and February 2015. DNA extracts from 982 engorged female sandflies were submitted to fragment length polymorphism analysis to identify infecting species of Leishmania, and blood sources were identified for 778 of these specimens. Infection by Leishmania infantum was detected in Lutzomyia longipalpis, Lu. whitmani and Lu. termitophila; L. infantum/L. braziliensis in Lu. longipalpis, Lu. whitmani and Lu. trinidadensis; L. shawi in Lu. longipalpis; L. mexicana in Lu. longipalpis; L. braziliensis in Lu. longipalpis and Lu. whitmani; L. guyanensis in Lu. longipalpis and Lu. termitophila; L. amazonensis in Lu. longipalpis and L. lainsoni or L. naiffi in Lu. longipalpis, while Lu. longipalpis and Lu. trinidadensis were infected with unidentified Leishmania sp. Blood sources were identified in 573 individual phlebotomines and the preferred hosts were, in decreasing order, chicken, dog, rodent and human with lower preferences for pig, horse, opossum and cattle. Lu. longipalpis and Lu. whitmani performed mixed feeding on man, dog and rodent, while Lu. longipalpis was the most opportunistic species, feeding on the blood of all hosts surveyed, but preferably on dog/chicken, dog/rodent and rodent/chicken. Our findings reveal the concomitant circulation of Leishmania species that cause visceral leishmaniasis and tegumentary leishmaniasis in the study area, and explain the occurrence of autochthonous human cases of both clinical forms of leishmaniasis in Caxias, Maranhao. The results support our hypothesis that, in the municipality of Caxias, transmission of Leishmania occurs in close proximity to humans. PMID- 28837567 TI - Genetic architecture of atherosclerosis dissected by QTL analyses in three F2 intercrosses of apolipoprotein E-null mice on C57BL6/J, DBA/2J and 129S6/SvEvTac backgrounds. AB - Quantitative trait locus (QTL) analyses of intercross populations between widely used mouse inbred strains provide a powerful approach for uncovering genetic factors that influence susceptibility to atherosclerosis. Epistatic interactions are common in complex phenotypes and depend on genetic backgrounds. To dissect genetic architecture of atherosclerosis, we analyzed F2 progeny from a cross between apolipoprotein E-null mice on DBA/2J (DBA-apoE) and C57BL/6J (B6-apoE) genetic backgrounds and compared the results with those from two previous F2 crosses of apolipoprotein E-null mice on 129S6/SvEvTac (129-apoE) and DBA-apoE backgrounds, and B6-apoE and 129-apoE backgrounds. In these round-robin crosses, in which each parental strain was crossed with two others, large-effect QTLs are expected to be detectable at least in two crosses. On the other hand, observation of QTLs in one cross only may indicate epistasis and/or absence of statistical power. For atherosclerosis at the aortic arch, Aath4 on chromosome (Chr)2:66 cM follows the first pattern, with significant QTL peaks in (DBAx129)F2 and (B6xDBA)F2 mice but not in (B6x129)F2 mice. We conclude that genetic variants unique to DBA/2J at Aath4 confer susceptibility to atherosclerosis at the aortic arch. A similar pattern was observed for Aath5 on chr10:35 cM, verifying that the variants unique to DBA/2J at this locus protect against arch plaque development. However, multiple loci, including Aath1 (Chr1:49 cM), and Aath2 (Chr1:70 cM) follow the second type of pattern, showing significant peaks in only one of the three crosses (B6-apoE x 129-apoE). As for atherosclerosis at aortic root, the majority of QTLs, including Ath29 (Chr9:33 cM), Ath44 (Chr1:68 cM) and Ath45 (Chr2:83 cM), was also inconsistent, being significant in only one of the three crosses. Only the QTL on Chr7:37 cM was consistently suggestive in two of the three crosses. Thus QTL analysis of round-robin crosses revealed the genetic architecture of atherosclerosis. PMID- 28837568 TI - Progranulin gene delivery reduces plaque burden and synaptic atrophy in a mouse model of Alzheimer's disease. AB - Progranulin (PGRN) is a multifunctional protein that is widely expressed throughout the brain, where it has been shown to act as a critical regulator of CNS inflammation and also functions as an autocrine neuronal growth factor, important for long-term neuronal survival. PGRN has been shown to activate cell signaling pathways regulating excitoxicity, oxidative stress, and synaptogenesis, as well as amyloidogenesis. Together, these critical roles in the CNS suggest that PGRN has the potential to be an important therapeutic target for the treatment of various neurodegenerative disorders, particularly Alzheimer's disease (AD). AD is the leading cause of dementia and is marked by the appearance of extracellular plaques consisting of aggregates of amyloid-beta (Abeta), as well as neuroinflammation, oxidative stress, neuronal loss and synaptic atrophy. The ability of PGRN to target multiple key features of AD pathophysiology suggests that enhancing its expression may benefit this disease. Here, we describe the application of PGRN gene transfer using in vivo delivery of lentiviral expression vectors in a transgenic mouse model of AD. Viral vector delivery of the PGRN gene effectively enhanced PGRN expression in the hippocampus of Tg2576 mice. This elevated PGRN expression significantly reduced amyloid plaque burden in these mice, accompanied by reductions in markers of inflammation and synaptic atrophy. The overexpression of PGRN was also found to increase activity of neprilysin, a key amyloid beta degrading enzyme. PGRN regulation of neprilysin activity could play a major role in the observed alterations in plaque burden. Thus, PGRN may be an effective therapeutic target for the treatment of AD. PMID- 28837569 TI - Transferrin receptor-1 and ferritin heavy and light chains in astrocytic brain tumors: Expression and prognostic value. AB - Astrocytic brain tumors are the most frequent primary brain tumors. Treatment with radio- and chemotherapy has increased survival making prognostic biomarkers increasingly important. The aim of the present study was to investigate the expression and prognostic value of transferrin receptor-1 (TfR1) as well as ferritin heavy (FTH) and light (FTL) chain in astrocytic brain tumors. A cohort of 111 astrocytic brain tumors (grade II-IV) was stained immunohistochemically with antibodies against TfR1, FTH, and FTL and scored semi-quantitatively. Double immunofluorescence stainings were established to determine the phenotype of cells expressing these markers. We found that TfR1, FTH, and FTL were expressed by tumor cells in all grades. TfR1 increased with grade (p<0.001), but was not associated with prognosis in the individual grades. FTH and FTL were expressed by tumor cells and cells with microglial/macrophage morphology. Neither FTH nor FTL increased with malignancy grade, but low FTH expression by both tumor cells (p = 0.03) and microglia/macrophages (p = 0.01) correlated with shorter survival in patients anaplastic astrocytoma. FTL-positive microglia/macrophages were frequent in glioblastomas, and high FTL levels correlated with shorter survival in the whole cohort (p = 0.01) and in patients with anaplastic astrocytoma (p = 0.02). Double-immunofluorescence showed that TfR1, FTH, and FTL were co-expressed to a limited extent with the stem cell-related marker CD133. FTH and FTL were also co expressed by IBA-1-positive microglia/macrophages. In conclusion, TfR1 was highly expressed in glioblastomas and associated with shorter survival in the whole cohort, but not in the individual malignancy grades. Low levels of FTH-positive tumor cells and microglia/macrophages were associated with poor survival in anaplastic astrocytomas, while high amounts of FTL-positive microglia/macrophages had a negative prognostic value. The results suggest that regulation of the iron metabolism in astrocytic brain tumors is complex involving both autocrine and paracrine signaling. PMID- 28837571 TI - A latent transition analysis of bullying and victimization in Chinese primary school students. AB - Bullying is a social phenomenon that impacts a large number of children and young people, worldwide. This study aimed to longitudinally examine the development of bullying and victimization in Chinese students in grades 4, 5, and 6. We used latent class analysis to empirically identify groups of youth with different bullying and victimization patterns, and then used latent transition analysis to explore the movement of children between these latent classes over time. Results showed that: (1) across the three time points, students could be classified into four classes: bullies, victims, bully-victims, and non-involved children; and (2) students in the non-involved class tended to remain in that class when moving to higher grades, students in the bully and victims classes tended to transition to the non-involved class, while students in the bully-victims class tended to transition to the bullies class. Thus, future intervention should be implemented to prevent bully-victims from bullying behaviors. PMID- 28837570 TI - Assessment of the influence of direct tobacco smoke on infection and active TB management. AB - BACKGROUND: Smoking is a risk factor for tuberculosis (TB) infection and disease progression. Tobacco smoking increases susceptibility to TB in a variety of ways, one of which is due to a reduction of the IFN-gamma response. Consequently, an impaired immune response could affect performance of IFN-gamma Release Assays (IGRAs). OBJECTIVE: In the present study, we assess the impact of direct tobacco smoking on radiological manifestations, sputum conversion and immune response to Mycobacterium tuberculosis, analyzing IFN-gamma secretion by IGRAs. METHODS: A total of 525 participants were studied: (i) 175 active pulmonary TB patients and (ii) 350 individuals coming from contact tracing studies, 41 of whom were secondary TB cases. Clinical, radiological and microbiological data were collected. T-SPOT.TB and QFN-G-IT were processed according manufacturer's instructions. RESULTS: In smoking patients with active TB, QFN-G-IT (34.4%) and T SPOT.TB (19.5%) had high frequencies of negative results. In addition, by means of an unconditional logistic regression, smoking was a main factor associated with IGRAs' false-negative results (aOR: 3.35; 95%CI:1.47-7.61; p<0.05). Smoking patients with active TB presented a high probability of having cavitary lesions (aOR: 1.88; 95%CI:1.02-3.46;p<0.05). Mean culture negativization (months) +/- standard deviation (SD) was higher in smokers than in non-smokers (2.47+/-1.3 versus 1.69+/-1.4). Latent TB infection (LTBI) was favored in smoking contacts, being a risk factor associated with infection (aOR: 11.57; 95%CI:5.97-22.41; p<0.00005). The IFN-gamma response was significantly higher in non-smokers than in smokers. Smoking quantity and IFN-gamma response analyzed by IGRAs were dose dependent related. CONCLUSIONS: Smoking had a negative effect on radiological manifestations, delaying time of sputum conversion. Our data establish a link between tobacco smoking and TB due to a weakened IFN-gamma response caused by direct tobacco smoke. PMID- 28837572 TI - Efficient and stable production of Modified Vaccinia Ankara virus in two-stage semi-continuous and in continuous stirred tank cultivation systems. AB - One important aim in cell culture-based viral vaccine and vector production is the implementation of continuous processes. Such a development has the potential to reduce costs of vaccine manufacturing as volumetric productivity is increased and the manufacturing footprint is reduced. In this work, continuous production of Modified Vaccinia Ankara (MVA) virus was investigated. First, a semi continuous two-stage cultivation system consisting of two shaker flasks in series was established as a small-scale approach. Cultures of the avian AGE1.CR.pIX cell line were expanded in the first shaker, and MVA virus was propagated and harvested in the second shaker over a period of 8-15 days. A total of nine small scale cultivations were performed to investigate the impact of process parameters on virus yields. Harvest volumes of 0.7-1 L with maximum TCID50 titers of up to 1.0*109 virions/mL were obtained. Genetic analysis of control experiments using a recombinant MVA virus containing green-fluorescent-protein suggested that the virus was stable over at least 16 d of cultivation. In addition, a decrease or fluctuation of infectious units that may indicate an excessive accumulation of defective interfering particles was not observed. The process was automated in a two-stage continuous system comprising two connected 1 L stirred tank bioreactors. Stable MVA virus titers, and a total production volume of 7.1 L with an average TCID50 titer of 9*107 virions/mL was achieved. Because titers were at the lower range of the shake flask cultivations potential for further process optimization at large scale will be discussed. Overall, MVA virus was efficiently produced in continuous and semi-continuous cultivations making two-stage stirred tank bioreactor systems a promising platform for industrial production of MVA derived recombinant vaccines and viral vectors. PMID- 28837574 TI - Beyond form and functioning: Understanding how contextual factors influence village health committees in northern India. AB - Health committees are a common strategy to foster community participation in health. Efforts to strengthen committees often focus on technical inputs to improve committee form (e.g. representative membership) and functioning (e.g. meeting procedures). However, porous and interconnected contextual spheres also mediate committee effectiveness. Using a framework for contextual analysis, we explored the contextual features that facilitated or hindered Village Health, Sanitation and Nutrition Committee (VHSNC) functionality in rural north India. We conducted interviews (n = 74), focus groups (n = 18) and observation over 1.5 years. Thematic content analysis enabled the identification and grouping of themes, and detailed exploration of sub-themes. While the intervention succeeded in strengthening committee form and functioning, participant accounts illuminated the different ways in which contextual influences impinged on VHSNC efficacy. Women and marginalized groups navigated social hierarchies that curtailed their ability to assert themselves in the presence of men and powerful local families. These dynamics were not static and unchanging, illustrated by pre-existing cross caste problem solving, and the committee's creation of opportunities for the careful violation of social norms. Resource and capacity deficits in government services limited opportunities to build relationships between health system actors and committee members and engendered mistrust of government institutions. Fragmented administrative accountability left committee members bearing responsibility for improving local health without access to stakeholders who could support or respond to their efforts. The committee's narrow authority was at odds with widespread community needs, and committee members struggled to involve diverse government services across the health, sanitation, and nutrition sectors. Multiple parallel systems (political decentralization, media and other village groups) presented opportunities to create more enabling VHSNC contexts, although the potential to harness these opportunities was largely unmet. This study highlights the urgent need for supportive contexts in which people can not only participate in health committees, but also access the power and resources needed to bring about actual improvements to their health and wellbeing. PMID- 28837573 TI - Spontaneous mutation rate is a plastic trait associated with population density across domains of life. AB - Rates of random, spontaneous mutation can vary plastically, dependent upon the environment. Such plasticity affects evolutionary trajectories and may be adaptive. We recently identified an inverse plastic association between mutation rate and population density at 1 locus in 1 species of bacterium. It is unknown how widespread this association is, whether it varies among organisms, and what molecular mechanisms of mutagenesis or repair are required for this mutation-rate plasticity. Here, we address all 3 questions. We identify a strong negative association between mutation rate and population density across 70 years of published literature, comprising hundreds of mutation rates estimated using phenotypic markers of mutation (fluctuation tests) from all domains of life and viruses. We test this relationship experimentally, determining that there is indeed density-associated mutation-rate plasticity (DAMP) at multiple loci in both eukaryotes and bacteria, with up to 23-fold lower mutation rates at higher population densities. We find that the degree of plasticity varies, even among closely related organisms. Nonetheless, in each domain tested, DAMP requires proteins scavenging the mutagenic oxidised nucleotide 8-oxo-dGTP. This implies that phenotypic markers give a more precise view of mutation rate than previously believed: having accounted for other known factors affecting mutation rate, controlling for population density can reduce variation in mutation-rate estimates by 93%. Widespread DAMP, which we manipulate genetically in disparate organisms, also provides a novel trait to use in the fight against the evolution of antimicrobial resistance. Such a prevalent environmental association and conserved mechanism suggest that mutation has varied plastically with population density since the early origins of life. PMID- 28837575 TI - Development of a tool for prediction of ovarian cancer in patients with adnexal masses: Value of plasma fibrinogen. AB - OBJECTIVE: To develop a tool for individualized risk estimation of presence of cancer in women with adnexal masses, and to assess the added value of plasma fibrinogen. STUDY DESIGN: We performed a retrospective analysis of a prospectively maintained database of 906 patients with adnexal masses who underwent cystectomy or oophorectomy. Uni- and multivariate logistic regression analyses including pre-operative plasma fibrinogen levels and established predictors were performed. A nomogram was generated to predict the probability of ovarian cancer. Internal validation with split-sample analysis was performed. Decision curve analysis (DCA) was then used to evaluate the clinical net benefit of the prediction model. RESULTS: Ovarian cancer including borderline tumours was found in 241 (26.6%) patients. In multivariate analysis, elevated plasma fibrinogen, elevated CA-125, suspicion for malignancy on ultrasound, and postmenopausal status were associated with ovarian cancer and formed the basis for the nomogram. The overall predictive accuracy of the model, as measured by AUC, was 0.91 (95% CI 0.87-0.94). DCA revealed a net benefit for using this model for predicting ovarian cancer presence compared to a strategy of treat all or treat none. CONCLUSION: We confirmed the value of plasma fibrinogen as a strong predictor for ovarian cancer in a large cohort of patients with adnexal masses. We developed a highly accurate multivariable model to help in the clinical decision-making regarding the presence of ovarian cancer. This model provided net benefit for a wide range of threshold probabilities. External validation is needed before a recommendation for its use in routine practice can be given. PMID- 28837576 TI - Space-time variations in child mortality in a rural South African population with high HIV prevalence (2000-2014). AB - OBJECTIVE: The aim of the study was to identify the key determinants of child mortality 'hot-spots' in space and time. METHODS: Comprehensive population-based mortality data collected between 2000 and 2014 by the Africa Centre Demographic Information System located in the UMkhanyakude District of KwaZulu-Natal Province, South Africa, was analysed. We assigned all mortality events and person time of observation for children <5 years of age to an exact homestead of residence (mapped to <2m accuracy as part of the DSA platform). Using these exact locations, both the Kulldorff and Tango spatial scan statistics for regular and irregular shaped cluster detection were used to identify clusters of childhood mortality events in both space and time. FINDINGS: Of the 49 986 children aged < 5 years who resided in the study area between 2000 and 2014, 2010 (4.0%) died. Childhood mortality decreased by 80% over the period from >20 per 1000 person years in 2001-2003 to 4 per 1000 person-years in 2014. The two scanning spatial techniques identified two high-risk clusters for child mortality along the eastern border of the study site near the national highway, with a relative risk of 2.10 and 1.91 respectively. CONCLUSIONS: The high-risk communities detected in this work, and the differential risk factor profile of these communities, can assist public health professionals to identify similar populations in other parts of rural South Africa. Identifying child mortality hot-spots will potentially guide policy interventions in rural, resource-limited settings. PMID- 28837577 TI - Reduced genetic diversity and alteration of gene flow in a fiddler crab due to mangrove degradation. AB - The fiddler crab Austruca occidentalis is a dominant species in mangrove forests along the East African coast. It enhances soil aeration and, through its engineering activities, makes otherwise-inaccessible food available for other marine organisms. Despite its importance, the habitat of A. occidentalis is threatened by human activities. Clearing the mangroves for salt farming and selective logging of mangroves trees continue to jeopardise mangrove ecosystems in the Western Indian Ocean. This study aims to use partial mitochondrial COI gene sequences and nuclear microsatellites to determine whether salt farming activities in mangroves have a negative impact on the genetic diversity and gene flow of A. occidentalis collected along the Tanzania coast. The level of genetic diversity for both mitochondrial DNA and nuclear microsatellites are relatively lower in samples from salt ponds compared to natural mangrove sites. Analysis of molecular variance (AMOVA) among all populations showed low but significant differentiation (COI: Fst = 0.022, P < 0.05; microsatellites: Fst = 0.022, P < 0.001). A hierarchical AMOVA indicates lower but significant genetic differentiation among populations from salt ponds and natural mangroves sites (COI: Fct = 0.033, P < 0.05; microsatellites: Fct = 0.018, P = < 0.01). These results indicate that salt farming has a significant negative impact on the genetic diversity of A. occidentalis. Since higher genetic diversity contributes to a stable population, restoring the cleared habitats might be the most effective measures for the conservation of genetic diversity and hence adaptive potential to environmental change in this species. PMID- 28837578 TI - Atopic children and use of prescribed medication: A comprehensive study in general practice. AB - PURPOSE: A comprehensive and representative nationwide general practice database was explored to study associations between atopic disorders and prescribed medication in children. METHOD: All children aged 0-18 years listed in the NIVEL Primary Care Database in 2014 were selected. Atopic children with atopic eczema, asthma and allergic rhinitis (AR) were matched with controls (not diagnosed with any of these disorders) within the same general practice on age and gender. Logistic regression analyses were performed to study the differences in prescribed medication between both groups by calculating odds ratios (OR); 93 different medication groups were studied. RESULTS: A total of 45,964 children with at least one atopic disorder were identified and matched with controls. Disorder-specific prescriptions seem to reflect evidence-based medicine guidelines for atopic eczema, asthma and AR. However, these disorder-specific prescriptions were also prescribed for children who were not registered as having that specific disorder. For eczema-related medication, about 3.7-8.4% of the children with non-eczematous atopic morbidity received these prescriptions, compared to 1.4-3.5% of the non-atopic children. The same pattern was observed for anti-asthmatics (having non-asthmatic atopic morbidity: 0.8-6.2% vs. controls: 0.3-2.1%) and AR-related medication (having non-AR atopic morbidity: 4.7-12.5% vs. controls: 2.8-3.1%). Also, non-atopic related medication, such as laxatives and antibiotics were more frequently prescribed for atopic children. CONCLUSIONS: The present study shows that atopic children received more prescriptions, compared to non-atopic children. Non-atopic controls frequently received specific prescriptions for atopic disorders. This indicates that children with atopic disorders need better monitoring by their GP. PMID- 28837580 TI - Driving style recognition method using braking characteristics based on hidden Markov model. AB - Since the advantage of hidden Markov model in dealing with time series data and for the sake of identifying driving style, three driving style (aggressive, moderate and mild) are modeled reasonably through hidden Markov model based on driver braking characteristics to achieve efficient driving style. Firstly, braking impulse and the maximum braking unit area of vacuum booster within a certain time are collected from braking operation, and then general braking and emergency braking characteristics are extracted to code the braking characteristics. Secondly, the braking behavior observation sequence is used to describe the initial parameters of hidden Markov model, and the generation of the hidden Markov model for differentiating and an observation sequence which is trained and judged by the driving style is introduced. Thirdly, the maximum likelihood logarithm could be implied from the observable parameters. The recognition accuracy of algorithm is verified through experiments and two common pattern recognition algorithms. The results showed that the driving style discrimination based on hidden Markov model algorithm could realize effective discriminant of driving style. PMID- 28837579 TI - Identification of a discriminative metabolomic fingerprint of potential clinical relevance in saliva of patients with periodontitis using 1H nuclear magnetic resonance (NMR) spectroscopy. AB - Periodontitis is characterized by the loss of the supporting tissues of the teeth in an inflammatory-infectious context. The diagnosis relies on clinical and X-ray examination. Unfortunately, clinical signs of tissue destruction occur late in the disease progression. Therefore, it is mandatory to identify reliable biomarkers to facilitate a better and earlier management of this disease. To this end, saliva represents a promising fluid for identification of biomarkers as metabolomic fingerprints. The present study used high-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy coupled with multivariate statistical analysis to identify the metabolic signature of active periodontitis. The metabolome of stimulated saliva of 26 patients with generalized periodontitis (18 chronic and 8 aggressive) was compared to that of 25 healthy controls. Principal Components Analysis (PCA), performed with clinical variables, indicated that the patient population was homogeneous, demonstrating a strong correlation between the clinical and the radiological variables used to assess the loss of periodontal tissues and criteria of active disease. Orthogonal Projection to Latent Structure (OPLS) analysis showed that patients with periodontitis can be discriminated from controls on the basis of metabolite concentrations in saliva with satisfactory explained variance (R2X = 0.81 and R2Y = 0.61) and predictability (Q2Y = 0.49, CV-AUROC = 0.94). Interestingly, this discrimination was irrespective of the type of generalized periodontitis, i.e. chronic or aggressive. Among the main discriminating metabolites were short chain fatty acids as butyrate, observed in higher concentrations, and lactate, gamma-amino butyrate, methanol, and threonine observed in lower concentrations in periodontitis. The association of lactate, GABA, and butyrate to generate an aggregated variable reached the best positive predictive value for diagnosis of periodontitis. In conclusion, this pilot study showed that 1H-NMR spectroscopy analysis of saliva could differentiate patients with periodontitis from controls. Therefore, this simple, robust, non-invasive method, may offer a significant help for early diagnosis and follow-up of periodontitis. PMID- 28837581 TI - Fetal exposure to maternal human platelet antigen-1a does not induce tolerance. An analytical observational study. AB - Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that may cause severe bleeding complications with risk of perinatal death or lifelong disability. The main cause of FNAIT is maternal antibodies against human platelet antigen (HPA)-1a. Both fetomaternal bleeding and transplacental trafficking of fetal cells during pregnancy could be the cause of alloimmunization. Persistence of fetal cells in the mother (fetal microchimerism) and maternal cells in the child (maternal microchimerism) are well-recognized phenomena. Thus, it could be envisaged that fetal exposure to the HPA-1a antigen could tolerize an HPA-1a negative female fetus and prevent production of anti-HPA-1a antibodies later in life if she becomes pregnant with an HPA-1a positive fetus. The objective of the current study was to assess if the risk of producing anti-HPA-1a antibodies and the severity of neonatal thrombocytopenia in HPA-1a negative women with HPA-1a positive mothers (i.e. the mother is HPA-1a/b), was lower than in HPA-1a negative women with HPA-1a negative mothers. HPA-1a negative women with HPA-1a antibodies, identified from a Norwegian screening study (1996-2004), where HPA-1 genotype of their mothers was available, were included in the study. The frequency of HPA-1a positive mothers to HPA-1a immunized daughters were compared to the calculated frequency in the general population. We did not find any difference in the frequency of HPA-1ab among mothers to daughters with HPA-1a antibodies as compared with the general population. Furthermore, acknowledging sample-size limitations, we neither found an association between the mothers' HPA type and their daughters' anti-HPA-1a antibody levels or any difference between the two groups of mothers (HPA-1ab vs HPA-1bb), with respect to frequency of thrombocytopenia in the children of their daughters with HPA-1a antibodies. Hence, there was no indication of tolerance against fetal HPA-1a antigen in HPA 1bb women who had been exposed to HPA-1a antigen during fetal development. PMID- 28837582 TI - A bottom-up approach to assess verbal therapeutic techniques. Development of the Psychodynamic Interventions List (PIL). AB - OBJECTIVE: Knowing which specific verbal techniques "good" therapists use in their daily work is important for training and evaluation purposes. In order to systematize what is being practiced in the field, our aim was to empirically identify verbal techniques applied in psychodynamic sessions and to differentiate them according to their basic semantic features using a bottom-up, qualitative approach. METHOD: Mixed-Method-Design: In a comprehensive qualitative study, types of techniques were identified at the level of utterances based on transcribed psychodynamic therapy sessions using Qualitative Content Analysis (4211 utterances). The definitions of the identified categories were successively refined and modified until saturation was achieved. In a subsequent quantitative study, inter-rater reliability was assessed both at the level of utterances (n = 8717) and at the session level (n = 38). The convergent validity of the categories was investigated by analyzing associations with the Interpretive and Supportive Technique Scale (ISTS). RESULTS: The inductive approach resulted in a classification system with 37 categories (Psychodynamic Interventions List, PIL). According to their semantic content, the categories can be allocated to three dimensions: form (24 categories), thematic content (9) and temporal focus (4). Most categories showed good or excellent inter-rater reliability and expected associations with the ISTS were predominantly confirmed. The rare use of the residual category "Other" suggests that the identified categories might comprehensively describe the breadth of applied techniques. CONCLUSIONS: The atheoretical orientation and the clear focus on overt linguistic features should enable the PIL to be used without intensive training or prior theoretical knowledge. The PIL can be used to investigate the links between verbal techniques derived from practice and micro-outcomes (at the session level) as well as the overall therapeutic outcomes. This approach might enable us to determine to what extent the outcome of therapy is due to unintended or non-theoretically relevant techniques. PMID- 28837583 TI - Single-cell profiling of dynamic cytokine secretion and the phenotype of immune cells. AB - Natural killer (NK) cells are a highly heterogeneous population of innate lymphocytes that constitute our first line of defense against several types of tumors and microbial infections. Understanding the heterogeneity of these lymphocytes requires the ability to integrate their underlying phenotype with dynamic functional behaviors. We have developed and validated a single-cell methodology that integrates cellular phenotyping and dynamic cytokine secretion based on nanowell arrays and bead-based molecular biosensors. We demonstrate the robust passivation of the polydimethylsiloxane (PDMS)-based nanowells arrays with polyethylene glycol (PEG) and validated our assay by comparison to enzyme-linked immunospot (ELISPOT) assays. We used numerical simulations to optimize the molecular density of antibodies on the surface of the beads as a function of the capture efficiency of cytokines within an open-well system. Analysis of hundreds of individual human peripheral blood NK cells profiled ex vivo revealed that CD56dimCD16+ NK cells are immediate secretors of interferon gamma (IFN-gamma) upon activation by phorbol 12-myristate 13-acetate (PMA) and ionomycin (< 3 h), and that there was no evidence of cooperation between NK cells leading to either synergistic activation or faster IFN-gamma secretion. Furthermore, we observed that both the amount and rate of IFN-gamma secretion from individual NK cells were donor-dependent. Collectively, these results establish our methodology as an investigational tool for combining phenotyping and real-time protein secretion of individual cells in a high-throughput manner. PMID- 28837584 TI - Adaptive ultrasound temperature imaging for monitoring radiofrequency ablation. AB - Radiofrequency ablation (RFA) has been widely used as an alternative treatment modality for liver tumors. Monitoring the temperature distribution in the tissue during RFA is required to assess the thermal dosage. Ultrasound temperature imaging based on the detection of echo time shifts has received the most attention in the past decade. The coefficient k, connecting the temperature change and the echo time shift, is a medium-dependent parameter used to describe the confounding effects of changes in the speed of sound and thermal expansion as temperature increases. The current algorithm of temperature estimate based on echo time shift detection typically uses a constant k, resulting in estimation errors when ablation temperatures are higher than 50 degrees C. This study proposes an adaptive-k algorithm that enables the automatic adjustment of the coefficient k during ultrasound temperature monitoring of RFA. To verify the proposed algorithm, RFA experiments on in vitro porcine liver samples (total n = 15) were performed using ablation powers of 10, 15, and 20 W. During RFA, a clinical ultrasound system equipped with a 7.5-MHz linear transducer was used to collect backscattered signals for ultrasound temperature imaging using the constant- and adaptive-k algorithms. Concurrently, an infrared imaging system and thermocouples were used to measure surface temperature distribution of the sample and internal ablation temperatures for comparisons with ultrasound estimates. Experimental results demonstrated that the proposed adaptive-k method improved the performance in visualizing the temperature distribution. In particular, the estimation errors were also reduced even when the temperature of the tissue is higher than 50 degrees C. The proposed adaptive-k ultrasound temperature imaging strategy has potential to serve as a thermal dosage evaluation tool for monitoring high-temperature RFA. PMID- 28837585 TI - A two dimensional electromechanical model of a cardiomyocyte to assess intra cellular regional mechanical heterogeneities. AB - Experimental studies on isolated cardiomyocytes from different animal species and human hearts have demonstrated that there are regional differences in the Ca2+ release, Ca2+ decay and sarcomere deformation. Local deformation heterogeneities can occur due to a combination of factors: regional/local differences in Ca2+ release and/or re-uptake, intra-cellular material properties, sarcomere proteins and distribution of the intracellular organelles. To investigate the possible causes of these heterogeneities, we developed a two-dimensional finite-element electromechanical model of a cardiomyocyte that takes into account the experimentally measured local deformation and cytosolic [Ca2+] to locally define the different variables of the constitutive equations describing the electro/mechanical behaviour of the cell. Then, the model was individualised to three different rat cardiac cells. The local [Ca2+] transients were used to define the [Ca2+]-dependent activation functions. The cell-specific local Young's moduli were estimated by solving an inverse problem, minimizing the error between the measured and simulated local deformations along the longitudinal axis of the cell. We found that heterogeneities in the deformation during contraction were determined mainly by the local elasticity rather than the local amount of Ca2+, while in the relaxation phase deformation was mainly influenced by Ca2+ re uptake. Our electromechanical model was able to successfully estimate the local elasticity along the longitudinal direction in three different cells. In conclusion, our proposed model seems to be a good approximation to assess the heterogeneous intracellular mechanical properties to help in the understanding of the underlying mechanisms of cardiomyocyte dysfunction. PMID- 28837586 TI - NAMPT serum levels are selectively elevated in acute infectious disease and in acute relapse of chronic inflammatory diseases in children. AB - Nicotinamide phosphoribosyl transferase (NAMPT) is an inflammatory adipocytokine shown to interact in immune modulation in chronic inflammatory diseases, acute respiratory distress syndrome, sepsis, cancer and obesity in adulthood. It is, however, not clear whether this association reflects a chronic elevation or acute inflammatory response. We analyzed NAMPT concentrations in distinct states of inflammation in 102 children and found consistently significantly increased NAMPT levels in subjects with acute infections. NAMPT concentrations in children with stable chronic inflammatory diseases were not significantly different, whereas in patients with acute relapse of chronic disease NAMPT was significantly higher than in children in remission or healthy controls. In states of low-grade inflammation (children with atopic disease or obesity) we did not detect alterations in NAMPT serum levels. NAMPT correlated positively with inflammatory markers such as CRP. The most predictive factor for NAMPT serum concentrations was leucocyte count and therein the neutrophil count. Furthermore, systemic circulating NAMPT levels were closely associated with NAMPT release from corresponding cultured PBMCs. In conclusion, NAMPT is selectively increased in states of acute but not chronic inflammation in children. The close relationship between systemic circulating NAMPT with leucocyte counts and release indicate that leucocytes most probably are the source of inflammation related NAMPT levels. PMID- 28837587 TI - The current status of syphilis prevention and control in Jiangsu province, China: A cross-sectional study. AB - OBJECTIVE: To analyze the midterm evaluation data from the National Syphilis Prevention and Control Plan (2010-2020) and evaluate the current status of syphilis prevention and control in Jiangsu province, China. METHODS: We collected data via (1) field surveys conducted in 2015 and (2) data recorded in existing syphilis surveillance systems. We conducted descriptive statistical analysis to evaluate the current landscape of syphilis control initiatives and their potential effect in syphilis control. RESULTS: The incidence of all cases of syphilis decreased from 2010 (32.3 per 100,000) to 2015 (30.1 per 100,000), with an annual growth of -1.17% (x2trend = -7.52, P<0.001) in Jiangsu province. The incidence of primary and secondary syphilis and congenital syphilis both decreased significantly from 2010 to 2015. The average awareness rate of syphilis knowledge among professional personnel was 95.4% (3781/3963). Rural residents had the lowest awareness rate (83.5%, 1875/2245) and commercial sex workers had the highest awareness rate (92.1%, 7804/8474) in 2015. Only 47.8% (33908/70894) of patients received provider-initiated syphilis counseling and testing (PISTC) services in sexually transmitted disease (STD) clinics, but 94.5% (87927/93020) of all syphilis patients received free testing for syphilis. Overall, 97.2% (9378/9648) of syphilis reported cases of syphilis at medical institutions were confirmed to be accurate, and 92.2% (5850/6345) of patients diagnosed with syphilis at medical institutions received treatment with penicillin. CONCLUSION: The syphilis incidence rate in Jiangsu has decreased in recent years, but remains at a high level. It is essential to promote PISTC services to improve knowledge of syphilis and rates of testing and treatment in Jiangsu province. PMID- 28837588 TI - Culture-induced recurrent epigenetic aberrations in human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) are an important player in disease modeling and regenerative medicine. Nonetheless, multiple studies uncovered their inherent genetic instability upon prolonged culturing, where specific chromosomal aberrations provide cells with a growth advantage. These positively selected modifications have dramatic effects on multiple cellular characteristics. Epigenetic aberrations also possess the potential of changing gene expression and altering cellular functions. In the current study we assessed the landscape of DNA methylation aberrations during prolonged culturing of hPSCs, and defined a set of genes which are recurrently hypermethylated and silenced. We further focused on one of these genes, testis-specific Y-encoded like protein 5 (TSPYL5), and demonstrated that when silenced, differentiation-related genes and tumor suppressor genes are downregulated, while pluripotency- and growth promoting genes are upregulated. This process is similar to the hypermethylation-mediated inactivation of certain genes during tumor development. Our analysis highlights the existence and importance of recurrent epigenetic aberrations in hPSCs during prolonged culturing. PMID- 28837589 TI - A decrease in serum creatinine after ICU admission is associated with increased mortality. AB - BACKGROUND: The elevation of serum creatinine (SCr), acute kidney injury (AKI), is associated with an increase of mortality in critically ill patients. However, it is uncertain whether a decrease in SCr in the intensive care unit (ICU) has an effect on outcomes. METHODS: In a retrospective study, we enrolled 486 patients who had been admitted to an urban tertiary center ICU between Jan 2014 and Dec 2014. The effect of changes in SCr after ICU admission on 90 day mortality was analyzed. Patients were classified into 3 groups based on change in SCr after ICU admission: a stable SCr group (Delta SCr < 0.3mg/dL during ICU stay), a decreased SCr group (Delta SCr >= -0.3 mg/dL during ICU stay) and an increased SCr group with criteria based on the KDIGO AKI criteria. RESULTS: In total, 486 patients were identified. SCr decreased in 123 (25.3%) patients after ICU admission. AKI developed in 125 (24.4%) patients. The overall 90-day mortality rate was 29.0%. In a Kaplan-Meyer analysis, the mortality of the AKI group was higher than that of other groups (p<0.0001). Patients with a decrease in SCr had a higher mortality rate than those with stable SCr (p<0.0001). A Cox analysis showed that both a decrease in SCR (HR, 3.56; 95% CI, 1.59-7.97; p = 0.002) and an increase in SCr (AKI stage 1, HR, 9.35; 95% CI, 4.18-20.9; p<0.0001; AKI stage 2, HR, 11.82; 95% CI, 3.85-36.28; p<0.0001; AKI stage 3, HR, 17.41; 95% CI, 5.50-55.04; p<0.0001) were independent risk factors for death compared to stable SCr. CONCLUSION: Not only an increase in SCr, but also a decrease in SCr was associated with mortality in critically ill patients. PMID- 28837590 TI - Environmental drivers of spatial patterns of topsoil nitrogen and phosphorus under monsoon conditions in a complex terrain of South Korea. AB - Nitrogen (N) and phosphorus (P) in topsoils are critical for plant nutrition. Relatively little is known about the spatial patterns of N and P in the organic layer of mountainous landscapes. Therefore, the spatial distributions of N and P in both the organic layer and the A horizon were analyzed using a light detection and ranging (LiDAR) digital elevation model and vegetation metrics. The objective of the study was to analyze the effect of vegetation and topography on the spatial patterns of N and P in a small watershed covered by forest in South Korea. Soil samples were collected using the conditioned latin hypercube method. LiDAR vegetation metrics, the normalized difference vegetation index (NDVI), and terrain parameters were derived as predictors. Spatial explicit predictions of N/P ratios were obtained using a random forest with uncertainty analysis. We tested different strategies of model validation (repeated 2-fold to 20-fold and leave-one-out cross validation). Repeated 10-fold cross validation was selected for model validation due to the comparatively high accuracy and low variance of prediction. Surface curvature was the best predictor of P contents in the organic layer and in the A horizon, while LiDAR vegetation metrics and NDVI were important predictors of N in the organic layer. N/P ratios increased with surface curvature and were higher on the convex upper slope than on the concave lower slope. This was due to P enrichment of the soil on the lower slope and a more even spatial distribution of N. Our digital soil maps showed that the topsoils on the upper slopes contained relatively little P. These findings are critical for understanding N and P dynamics in mountainous ecosystems. PMID- 28837591 TI - Modulation of nutrient composition of black soldier fly (Hermetia illucens) larvae by feeding seaweed-enriched media. AB - Black soldier fly (Hermetia illucens) larvae are a promising source of protein and lipid for animal feeds. The nutritional composition of the BSF larvae depend partly on the composition of the feeding medium. The BSF lipid profile in part mimics the feeding media lipid profile, and micronutrients, like minerals and vitamins, can readily accumulate in black soldier fly larvae. However, investigative studies on bioconversion and accumulation of nutrients from media to black soldier fly larvae are scarce. Here we show that inclusion of the brown algae Ascophyllum nodosum in the substrate for black soldier fly larvae can introduce valuable nutrients, commonly associated with the marine environment, into the larvae. The omega-3 fatty acid eicosapentaenoic acid (20:5n-3), iodine and vitamin E concentrations increased in the larvae when more seaweed was included in the diet. When the feeding media consisted of more than 50% seaweed, the larvae experienced poorer growth, lower nutrient retention and lower lipid levels, compared to a pure plant based feeding medium. Our results confirm the plasticity of the nutritional make-up of black soldier fly larvae, allowing it to accumulate both lipid- and water-soluble compounds. A broader understanding of the effect of the composition of the feeding media on the larvae composition can help to tailor black soldier fly larvae into a nutrient profile more suited for specific feed or food purposes. PMID- 28837592 TI - Development and validation of a set of six adaptable prognosis prediction (SAP) models based on time-series real-world big data analysis for patients with cancer receiving chemotherapy: A multicenter case crossover study. AB - BACKGROUND: We aimed to develop an adaptable prognosis prediction model that could be applied at any time point during the treatment course for patients with cancer receiving chemotherapy, by applying time-series real-world big data. METHODS: Between April 2004 and September 2014, 4,997 patients with cancer who had received systemic chemotherapy were registered in a prospective cohort database at the Kyoto University Hospital. Of these, 2,693 patients with a death record were eligible for inclusion and divided into training (n = 1,341) and test (n = 1,352) cohorts. In total, 3,471,521 laboratory data at 115,738 time points, representing 40 laboratory items [e.g., white blood cell counts and albumin (Alb) levels] that were monitored for 1 year before the death event were applied for constructing prognosis prediction models. All possible prediction models comprising three different items from 40 laboratory items (40C3 = 9,880) were generated in the training cohort, and the model selection was performed in the test cohort. The fitness of the selected models was externally validated in the validation cohort from three independent settings. RESULTS: A prognosis prediction model utilizing Alb, lactate dehydrogenase, and neutrophils was selected based on a strong ability to predict death events within 1-6 months and a set of six prediction models corresponding to 1,2, 3, 4, 5, and 6 months was developed. The area under the curve (AUC) ranged from 0.852 for the 1 month model to 0.713 for the 6 month model. External validation supported the performance of these models. CONCLUSION: By applying time-series real-world big data, we successfully developed a set of six adaptable prognosis prediction models for patients with cancer receiving chemotherapy. PMID- 28837593 TI - Relationship between response to aripiprazole once-monthly and paliperidone palmitate on work readiness and functioning in schizophrenia: A post-hoc analysis of the QUALIFY study. AB - Schizophrenia is a chronic disease with negative impact on patients' employment status and quality of life. This post-hoc analysis uses data from the QUALIFY study to elucidate the relationship between work readiness and health-related quality of life and functioning. QUALIFY was a 28-week, randomized study (NCT01795547) comparing the treatment effectiveness of aripiprazole once-monthly 400 mg and paliperidone palmitate once-monthly using the Heinrichs-Carpenter Quality-of-Life Scale as the primary endpoint. Also, patients' capacity to work and work readiness (Yes/No) was assessed with the Work Readiness Questionnaire. We categorized patients, irrespective of treatment, by work readiness at baseline and week 28: No to Yes (n = 41), Yes to Yes (n = 49), or No at week 28 (n = 118). Quality-of-Life Scale total, domains, and item scores were assessed with a mixed model of repeated measures. Patients who shifted from No to Yes in work readiness showed robust improvements on Quality-of-Life Scale total scores, significantly greater than patients not ready to work at week 28 (least squares mean difference: 11.6+/-2.6, p<0.0001). Scores on Quality-of-Life Scale instrumental role domain and items therein-occupational role, work functioning, work levels, work satisfaction-significantly improved in patients shifting from No to Yes in work readiness (vs patients No at Week 28). Quality-of-Life Scale total scores also significantly predicted work readiness at week 28. Overall, these results highlight a strong association between improvements in health-related quality of life and work readiness, and suggest that increasing patients' capacity to work is an achievable and meaningful goal in the treatment of impaired functioning in schizophrenia. PMID- 28837594 TI - Cost-effectiveness of inactivated seasonal influenza vaccination in a cohort of Thai children <=60 months of age. AB - BACKGROUND: Vaccination is the best measure to prevent influenza. We conducted a cost-effectiveness evaluation of trivalent inactivated seasonal influenza vaccination, compared to no vaccination, in children <=60 months of age participating in a prospective cohort study in Bangkok, Thailand. METHODS: A static decision tree model was constructed to simulate the population of children in the cohort. Proportions of children with laboratory-confirmed influenza were derived from children followed weekly. The societal perspective and one-year analytic horizon were used for each influenza season; the model was repeated for three influenza seasons (2012-2014). Direct and indirect costs associated with influenza illness were collected and summed. Cost of the trivalent inactivated seasonal influenza vaccine (IIV3) including promotion, administration, and supervision cost was added for children who were vaccinated. Quality-adjusted life years (QALY), derived from literature, were used to quantify health outcomes. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in the expected total costs between the vaccinated and unvaccinated groups divided by the difference in QALYs for both groups. RESULTS: Compared to no vaccination, IIV3 vaccination among children <=60 months in our cohort was not cost-effective in the introductory year (2012 season; 24,450 USD/QALY gained), highly cost-effective in the 2013 season (554 USD/QALY gained), and cost effective in the 2014 season (16,200 USD/QALY gained). CONCLUSION: The cost effectiveness of IIV3 vaccination among children participating in the cohort study varied by influenza season, with vaccine cost and proportion of high-risk children demonstrating the greatest influence in sensitivity analyses. Vaccinating children against influenza can be economically favorable depending on the maturity of the program, influenza vaccine performance, and target population. PMID- 28837595 TI - Novel axolotl cardiac function analysis method using magnetic resonance imaging. AB - The salamander axolotl is capable of complete regeneration of amputated heart tissue. However, non-invasive imaging tools for assessing its cardiac function were so far not employed. In this study, cardiac magnetic resonance imaging is introduced as a non-invasive technique to image heart function of axolotls. Three axolotls were imaged with magnetic resonance imaging using a retrospectively gated Fast Low Angle Shot cine sequence. Within one scanning session the axolotl heart was imaged three times in all planes, consecutively. Heart rate, ejection fraction, stroke volume and cardiac output were calculated using three techniques: (1) combined long-axis, (2) short-axis series, and (3) ultrasound (control for heart rate only). All values are presented as mean +/- standard deviation. Heart rate (beats per minute) among different animals was 32.2+/-6.0 (long axis), 30.4+/-5.5 (short axis) and 32.7+/-4.9 (ultrasound) and statistically similar regardless of the imaging method (p > 0.05). Ejection fraction (%) was 59.6+/-10.8 (long axis) and 48.1+/-11.3 (short axis) and it differed significantly (p = 0.019). Stroke volume (MUl/beat) was 133.7+/-33.7 (long axis) and 93.2+/-31.2 (short axis), also differed significantly (p = 0.015). Calculations were consistent among the animals and over three repeated measurements. The heart rate varied depending on depth of anaesthesia. We described a new method for defining and imaging the anatomical planes of the axolotl heart and propose one of our techniques (long axis analysis) may prove useful in defining cardiac function in regenerating axolotl hearts. PMID- 28837597 TI - Can crabs kill like a keystone predator? A field-test of the effects of crab predation on mussel mortality on a northeast Pacific rocky shore. AB - Predation can strongly influence community structure and ecosystem function, so the loss of key predators can have dramatic ecological consequences, unless other predatory species in the system are capable of playing similar ecological roles. In light of the recent outbreak of sea star wasting disease (SSWD) and subsequent depletion of west coast sea star populations, including those of the keystone predator Pisaster ochraceus, we examined whether large mobile crabs could play a role as predators on mussels (Mytilus californianus) on a rocky shore in Northern California. Using a combination of sea star removal and predator exclusion cages we found that mussel mortality was 43-294 times greater in uncaged treatments versus caged treatments. Mortality on uncaged mussels at low tidal elevations was due to predation by large mobile crabs (Cancer productus and Romaleon antennarium); confirmed by the presence of mussel shell fragments and documented attacks on wax snail replicas. Laboratory feeding assays indicated that crabs, on a per unit biomass basis, can consume almost twenty-five times as many mussels per day than sea stars, which together with the results of our field experiment, suggest that large predatory crabs could play an important role in maintaining ecosystem function through their predation on mussels on rocky shores where P. ochraceus are rare, absent, or have been depleted by SSWD. PMID- 28837596 TI - Membrane-active macromolecules kill antibiotic-tolerant bacteria and potentiate antibiotics towards Gram-negative bacteria. AB - Chronic bacterial biofilms place a massive burden on healthcare due to the presence of antibiotic-tolerant dormant bacteria. Some of the conventional antibiotics such as erythromycin, vancomycin, linezolid, rifampicin etc. are inherently ineffective against Gram-negative bacteria, particularly in their biofilms. Here, we report membrane-active macromolecules that kill slow dividing stationary-phase and antibiotic tolerant cells of Gram-negative bacteria. More importantly, these molecules potentiate antibiotics (erythromycin and rifampicin) to biofilms of Gram-negative bacteria. These molecules eliminate planktonic bacteria that are liberated after dispersion of biofilms (dispersed cells). The membrane-active mechanism of these molecules forms the key for potentiating the established antibiotics. Further, we demonstrate that the combination of macromolecules and antibiotics significantly reduces bacterial burden in mouse burn and surgical wound infection models caused by Acinetobacter baumannii and Carbapenemase producing Klebsiella pneumoniae (KPC) clinical isolate respectively. Colistin, a well-known antibiotic targeting the lipopolysaccharide (LPS) of Gram-negative bacteria fails to kill antibiotic tolerant cells and dispersed cells (from biofilms) and bacteria develop resistance to it. On the contrary, these macromolecules prevent or delay the development of bacterial resistance to known antibiotics. Our findings emphasize the potential of targeting the bacterial membrane in antibiotic potentiation for disruption of biofilms and suggest a promising strategy towards developing therapies for topical treatment of Gram-negative infections. PMID- 28837598 TI - Accelerometer-assessed sedentary work, leisure time and cardio-metabolic biomarkers during one year: Effectiveness of a cluster randomized controlled trial in parents with a sedentary occupation and young children. AB - BACKGROUND: It is unknown whether reducing sedentary time at work and during leisure time is possible and effective during one year. METHODS: Office workers with young children were recruited for this one-year cluster-randomized controlled trial through kindergartens and primary schools from 7 clusters in the city of Jyvaskyla, Finland. After a lecture, face-to-face tailored counseling was used to set contractually binding goals regarding reducing and breaking up sitting periods and increasing light intensity physical activity during work and leisure time. Primary outcomes of total, work and leisure sedentary time (<100 counts/min, cpm), light activity time (<2020 cpm), moderate-to-vigorous activity time (MVPA) and breaks/sedentary hour were assessed with a waist-worn Alive accelerometer for 7 days, 5 times during the year. Anthropometrics (DXA), fasting biomarkers and self-reported diet were assessed as secondary outcomes. Data were collected between 2011-2013 and analyzed between 2013-2016 with a linear mixed effects model fit by REML using likelihood ratio test and intention-to-treat principle. RESULTS: Participants from intervention (N = 71) and control (N = 62) regions were assessed at baseline and 117 completed the study. Sedentary leisure time decreased [-21.2 (95% CI -37.3 to -5.1) min/8 hours, likelihood ratio P<0.001] and light activity time [13.4 (-2.2 to 29.0) min/8 hours, P = 0.008] and breaks per sedentary hour [1.0 (-0.2 to 2.2), P = 0.010] increased in the intervention group as compared to controls at 3 months. The decrease in sedentary leisure time was maintained throughout the year [-7.9 (-24.0 to 8.3) min/8 hours, P = 0.029]. Small decreases in the control group's work and leisure MVPA were observed mostly at 3 months. Small favorable intervention effects were observed for fasting plasma glucose at 3 months and for leg lean mass and apoB/apoA-1 ratio at 12 months, with no changes in other outcomes. CONCLUSIONS: Behavioral counseling induced a small decline in sedentary leisure time throughout one year in parents with a sedentary occupation and young children. Small concurrent changes in different biomarkers suggest that reducing sedentary leisure time during one year may be beneficial. TRIAL REGISTRATION: ISRCTN28668090, registered 30 November 2011. PMID- 28837599 TI - HSF-1 is a regulator of miRNA expression in Caenorhabditis elegans. AB - The ability of an organism to sense and adapt to environmental stressors is essential for proteome maintenance and survival. The highly conserved heat shock response is a survival mechanism employed by all organisms, including the nematode Caenorhabditis elegans, upon exposure to environmental extremes. Transcriptional control of the metazoan heat shock response is mediated by the heat shock transcription factor HSF-1. In addition to regulating global stress responsive genes to promote stress-resistance and survival, HSF-1 has recently been shown to regulate stress-independent functions in controlling development, metabolism, and longevity. However, the indirect role of HSF-1 in coordinating stress-dependent and -independent processes through post-transcriptional regulation is largely unknown. MicroRNAs (miRNAs) have emerged as a class of post transcriptional regulators that control gene expression through translational repression or mRNA degradation. To determine the role of HSF-1 in regulating miRNA expression, we have performed high-throughput small RNA-sequencing in C. elegans grown in the presence and absence of hsf-1 RNAi followed by treatment with or without heat shock. This has allowed us to uncover the miRNAs regulated by HSF-1 via heat-dependent and -independent mechanisms. Integrated miRNA/mRNA target-prediction analyses suggest HSF-1 as a post-transcriptional regulator of development, metabolism, and longevity through regulating miRNA expression. This provides new insight into the possible mechanism by which HSF-1 controls these processes. We have also uncovered oxidative stress response factors and insulin like signaling factors as a common link between processes affected by HSF-1 regulated miRNAs in stress-dependent and -independent mechanisms, respectively. This may provide a role for miRNAs in regulating cross-talk between various stress responses. Our work therefore uncovers an interesting potential role for HSF-1 in post-transcriptionally controlling gene expression in C. elegans, and suggests a mechanism for cross-talk between stress responses. PMID- 28837600 TI - Recombinant human collagen-based microspheres mitigate cardiac conduction slowing induced by adipose tissue-derived stromal cells. AB - BACKGROUND: Stem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may also increase the risk of arrhythmias by providing an arrhythmogenic substrate. We previously showed that porcine adipose tissue-derived-stromal cells (pASC) induce conduction slowing through paracrine actions, whereas rat ASC (rASC) and human ASC (hASC) induce conduction slowing by direct coupling. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling. AIM: To investigate the modulation of ASC-loaded recombinant human collagen-based microspheres, on the electrophysiological behavior of neonatal rat ventricular myocytes (NRVM). METHOD: Unipolar extracellular electrograms, derived from microelectrode arrays (8x8 electrodes) containing NRVM, co-cultured with ASC or ASC loaded microspheres, were used to determine conduction velocity (CV) and conduction heterogeneity. Conditioned medium (Cme) of (co)cultures was used to assess paracrine mechanisms. RESULTS: Microspheres did not affect CV in control (NRVM) monolayers. In co-cultures of NRVM and rASC, hASC or pASC, CV was lower than in controls (14.4+/-1.0, 13.0+/ 0.6 and 9.0+/- 1.0 vs. 19.5+/-0.5 cm/s respectively, p<0.001). Microspheres loaded with either rASC or hASC still induced conduction slowing compared to controls (13.5+/-0.4 and 12.6+/-0.5 cm/s respectively, p<0.001). However, pASC loaded microspheres increased CV of NRVM compared to pASC and NRMV co-cultures (16.3+/-1.3 cm/s, p< 0.001) and did not differ from controls (p = NS). Cme of pASC reduced CV in control monolayers of NRVM (10.3+/-1.1 cm/s, p<0.001), similar to Cme derived from pASC-loaded microspheres (11.1+/-1.7 cm/s, p = 1.0). The presence of microspheres in monolayers of NRVM abolished the CV slowing influence of Cme pASC (15.9+/-1.0 cm/s, p = NS vs. control). CONCLUSION: The application of recombinant human collagen-based microspheres mitigates indirect paracrine conduction slowing through interference with a secondary autocrine myocardial factor. PMID- 28837601 TI - Age- and severity-adjusted treatment of proximal humerus fractures in children and adolescents-A systematical review and meta-analysis. AB - BACKGROUND: Fractures of the proximal humerus in patients under the age of 18 years show a low incidence; existing clinical studies only comprise small patient numbers. Different treatment methods are mentioned in the literature but a comparison of the outcome of these methods is rarely made. Up to now, no evidence based algorithm for conservative and operative treatment is available. The aim of this systematic review with meta-analysis was therefore to gather the best evidence of different treatment methods and their associated functional outcome, complication rates, rates of limb length discrepancies and radiological outcome. METHODS AND FINDINGS: The OVID database was systematically searched on September 30th in 2016 in order to find all published clinical studies on the subject of proximal humerus fractures of patients <=18 years. Exclusion criteria were previously defined. The Coleman Methodology Score was used to evaluate the quality of the single studies. 886 studies have been identified by the search strategy. 19 studies with a total of 643 children (mean age: 11.8 years) were included into the meta-analysis with a mean Coleman Methodology Score of 71 +/- 7.4 points. 18 of the 19 studies eligible for inclusion were retrospective ones, of the best quality available (mean follow-up >= 1 year, mean follow-up rate >= 65%). 56% of the patients were male. Proximal humerus fractures were treated conservatively in 41% and surgically in 59% of the cases (Elastic Stable Intramedullary Nailing (ESIN): 31%; K-wires: 20%; 8% other methods, e.g. plate osteosynthesis, olecranon traction). The overall success rate (good/excellent outcome) for all treatment methods was 93%. The success rate of ESIN (98%) and of K- wire fixation (95%) was significantly higher (p = 0.01) than the success rate of conservative treatment options (91%). A subgroup analysis of severely displaced fractures (Neer grade III/IV, angulation >= 20 degrees ) resulted in a change of success rates, to the disadvantage of conservative treatment methods (conservative treatment 82%, ESIN 98%, K-wires 95%; p < 0.001). Complication rates did not differ to a significant extent. 9% of the complications occurred in the patients treated by K-wire fixation, 8% if a conservative treatment option was chosen and 7% in the fractures that were stabilized by ESIN. A change from a one-nail technique to a two-nail technique reduced the complication rate of ESIN significantly. Follow-up X- rays without residual deformity could be found in 96% of the patients treated by ESIN, a rate which was higher than in the patients treated conservatively (93%) or by K-wire fixation (88%). The rate of arm length discrepancies at final follow- up was lower if the fractures were stabilized by ESIN (4%) than if they were treated conservatively (9%) or by K-wires (19%). An evaluation of age-dependent treatment options was performed. CONCLUSIONS: By performing this meta-analysis an evidence-based treatment algorithm could be introduced to treat the fractures according to the severity of displacement and according to the patient's age. For severely displaced fractures ESIN is the method of choice, with the best clinical and radiological outcome. PMID- 28837602 TI - Insights on correlation dimension from dynamics mapping of three experimental nonlinear laser systems. AB - BACKGROUND: We have analysed large data sets consisting of tens of thousands of time series from three Type B laser systems: a semiconductor laser in a photonic integrated chip, a semiconductor laser subject to optical feedback from a long free-space-external-cavity, and a solid-state laser subject to optical injection from a master laser. The lasers can deliver either constant, periodic, pulsed, or chaotic outputs when parameters such as the injection current and the level of external perturbation are varied. The systems represent examples of experimental nonlinear systems more generally and cover a broad range of complexity including systematically varying complexity in some regions. METHODS: In this work we have introduced a new procedure for semi-automatically interrogating experimental laser system output power time series to calculate the correlation dimension (CD) using the commonly adopted Grassberger-Proccacia algorithm. The new CD procedure is called the 'minimum gradient detection algorithm'. A value of minimum gradient is returned for all time series in a data set. In some cases this can be identified as a CD, with uncertainty. FINDINGS: Applying the new 'minimum gradient detection algorithm' CD procedure, we obtained robust measurements of the correlation dimension for many of the time series measured from each laser system. By mapping the results across an extended parameter space for operation of each laser system, we were able to confidently identify regions of low CD (CD < 3) and assign these robust values for the correlation dimension. However, in all three laser systems, we were not able to measure the correlation dimension at all parts of the parameter space. Nevertheless, by mapping the staged progress of the algorithm, we were able to broadly classify the dynamical output of the lasers at all parts of their respective parameter spaces. For two of the laser systems this included displaying regions of high-complexity chaos and dynamic noise. These high-complexity regions are differentiated from regions where the time series are dominated by technical noise. This is the first time such differentiation has been achieved using a CD analysis approach. CONCLUSIONS: More can be known of the CD for a system when it is interrogated in a mapping context, than from calculations using isolated time series. This has been shown for three laser systems and the approach is expected to be useful in other areas of nonlinear science where large data sets are available and need to be semi automatically analysed to provide real dimensional information about the complex dynamics. The CD/minimum gradient algorithm measure provides additional information that complements other measures of complexity and relative complexity, such as the permutation entropy; and conventional physical measurements. PMID- 28837603 TI - Proteomic analysis of protein phosphatase Z1 from Candida albicans. AB - Protein phosphatase Z is a "novel type" fungus specific serine/threonine protein phosphatase. Previously our research group identified the CaPPZ1 gene in the opportunistic pathogen Candida albicans and reported that the gene deletion had several important physiological consequences. In order to reveal the protein targets and the associated mechanisms behind the functions of the phosphatase a proteomic method was adopted for the comparison of the cappz1 deletion mutant and the genetically matching QMY23 control strain. Proteins extracted from the control and deletion mutant strains were separated by two-dimensional gel electrophoresis and the protein spots were stained with RuBPS and Pro-Q Diamond in order to visualize the total proteome and the phosphoproteome, respectively. The alterations in spot intensities were determined by densitometry and were analysed with the Delta2D (Decodon) software. Spots showing significantly different intensities between the mutant and control strains were excised from the gels and were digested with trypsin. The resulting peptides were identified by LC-MS/MS mass spectrometry. As many as 15 protein spots were found that exhibited significant changes in their intensity upon the deletion of the phosphatase and 20 phosphoproteins were identified in which the level of phosphorylation was modified significantly in the mutant. In agreement with previous findings we found that the affected proteins function in protein synthesis, oxidative stress response, regulation of morphology and metabolism. Among these proteins we identified two potential CaPpz1 substrates (Eft2 and Rpp0) that may regulate the elongation step of translation. RT-qPCR experiments revealed that the expression of the genes coding for the affected proteins was not altered significantly. Thus, the absence of CaPpz1 exerted its effects via protein synthesis/degradation and phosphorylation/dephosphorylation. In addition, our proteomics data strongly suggested a role for CaPpz1 in biofilm formation, was confirmed experimentally. Thus our unbiased proteomic approach lead to the discovery of a novel function for this phosphatase in C. albicans. PMID- 28837604 TI - Colouration in amphibians as a reflection of nutritional status: The case of tree frogs in Costa Rica. AB - Colouration has been considered a cue for mating success in many species; ornaments in males often are related to carotenoid mobilization towards feathers and/or skin and can signal general health and nutrition status. However, there are several factors that can also link with status, such as physiological blood parameters and body condition, but there is not substantial evidence which supports the existence of these relationships and interactions in anurans. This study evaluated how body score and blood values interact with colouration in free range Agalychnis callidryas and Agalychnis annae males. We found significant associations between body condition and plasmatic proteins and haematocrit, as well as between body condition and colour values from the chromaticity diagram. We also demonstrated that there is a significant relation between the glucose and plasmatic protein values that were reflected in the ventral colours of the animals, and haematocrit inversely affected most of those colour values. Significant differences were found between species as well as between populations of A. callidryas, suggesting that despite colour variation, there are also biochemical differences within animals from the same species located in different regions. These data provide information on underlying factors for colouration of male tree frogs in nature, provide insights about the dynamics of several nutrients in the amphibian model and how this could affect the reproductive output of the animals. PMID- 28837605 TI - Regio- and enantioselective microbial hydroxylation and evaluation of cytotoxic activity of beta-cyclocitral-derived halolactones. AB - Three beta-cyclocitral-derived halolactones, which exhibit antifeedant activity towards storage product pests, were subjected to microbial transformation processes. Among the thirty tested strains of filamentous fungi and yeast, the most effective biocatalysts were Absidia cylindrospora AM336, Mortierella isabellina AM212 and Mortierella vinaceae AM149. As a result of regio- and enantioselective hydroxylation four new oxygenated derivatives were obtained. Regardless of the biocatalyst applied, the delta-iodo- and delta-bromo-gamma lactones were hydroxylated in an inactivated position C-5 of cyclohexane ring. The analogous transformation of chlorolactone was observed in Mortierella isabellina AM212 culture but in the case of two other biocatalysts the hydroxy group was introduced at C-3 position. All obtained hydroxylactones were enantiomerically pure (ee = 100%) or enriched (ee = 50%). The highest enantioselectivity of hydroxylation was observed for M. isabellina AM212. The cytotoxic activity of halolactones was also examined by WST-1 assay wherein tested compounds did not exhibit significant effect on the viability of tumor HeLa and normal CHO-K1 cells. PMID- 28837606 TI - Maintenance of influenza A viruses and antibody response in mallards (Anas platyrhynchos) sampled during the non-breeding season in Alaska. AB - Prevalence of influenza A virus (IAV) infections in northern-breeding waterfowl has previously been reported to reach an annual peak during late summer or autumn; however, little is known about IAV infection dynamics in waterfowl populations persisting at high-latitude regions such as Alaska, during winter. We captured mallards (Anas platyrhynchos) throughout the non-breeding season (August April) of 2012-2015 in Fairbanks and Anchorage, the two largest cities in Alaska, to assess patterns of IAV infection and antibody production using molecular methods and a standard serologic assay. In addition, we used virus isolation, genetic sequencing, and a virus microneutralization assay to characterize viral subtypes and to evaluate the immune response of mallards captured on multiple occasions through time. We captured 923 mallards during three successive sampling years: Fairbanks in 2012/13 and 2013/14, and Anchorage in 2014/15. Prevalence varied by age, season, and year/site with high and relatively stable estimates throughout the non-breeding season. Infected birds were detected in all locations/seasons except early-winter in Fairbanks during 2013/14. IAVs with 17 combinations of hemagglutinin (H1-5, H7-9, H11, H12) and neuraminidase (N1-6, N8, N9) subtypes were isolated. Antibodies to IAVs were detected throughout autumn and winter for all sampling locations and years, however, seroprevalence was higher among adults and varied among years. Mallards exhibited individual heterogeneity with regard to immune response, providing instances of both seroconversion and seroreversion to detected viral subtypes. The probability that an individual transitioned from one serostatus to another varied by age, with juvenile mallards having higher rates of seroconversion and seroreversion than adults. Our study provides evidence that a diversity of IAVs circulate in populations of mallards wintering at urban locations in Alaska, and we suggest waterfowl wintering at high-latitudes may play an important role in maintenance of viruses across breeding seasons. PMID- 28837607 TI - A validated LC-MS/MS method for cellular thyroid hormone metabolism: Uptake and turnover of mono-iodinated thyroid hormone metabolites by PCCL3 thyrocytes. AB - Tyrosine and phenolic ring de-iodination of thyroid hormones (TH) is crucial for regulating their physiological activity. Furthermore, reactions such as de carboxylation to thyronamines (TAM) and de-amination to thyroacetic acids (TAc) produce TH metabolites (THM) with distinct biological properties. This needs to be considered when studying effects of TH and THM. The accurate and precise quantitative analysis of TH and THM in cell culture supernatants and cell lysates are key procedures required for studying the in vitro metabolism of TH. We report here the development of a liquid-liquid extraction/isotope dilution-liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) method for the quantification of 9 thyronines (TN) and 6 TAM in human hepatocellular carcinoma Hep G2 cell lysate extracts. In addition, we adapted the method to quantify TH, TAM and TAc, in cell lysates of FBS-depleted rat thyroid epithelium PCCL3 cells. The methods for both cell lines were validated by rigorous assessment of linearity, limits of quantification and detection (LLOQ and LLOD respectively), intra- and inter-day accuracy, precision, process efficiency (PE), matrix effect (ME) and relative recovery (RE). Calibration curves covering 11 concentrations (based on 400 MUl of lysate) were linear in the range 0.016-50 nM and 0.010-50 nM for Hep G2 and PCCL3 cells respectively. The lower limits of quantification were in the range 0.031 to 1 nM. We applied the PCCL3 version of the LC-MS/MS method to the analysis of lysed cell extracts from PCCL3 cells that had been incubated with 3-iodo-L-thyronine (T1), 3-iodothyronamine (3-T1AM) and 3-iodothyroacetic acid (3-T1Ac). Over the course of 30 minutes incubation 3-T1AM was de-iodinated to 4-[4-(2-aminoethylphenoxy)]phenol (thyronamine, T0AM) and de-aminated to 3 T1Ac respectively, whilst T1 underwent de-iodination to T0. This data indicates avid metabolism of these mono-iodinated compounds and the utility of LC-MS/MS to quantify such cellular metabolism. PMID- 28837608 TI - Reduced statherin in acquired enamel pellicle on eroded teeth compared to healthy teeth in the same subjects: An in-vivo study. AB - The aim of this in-vivo study was to compare total protein and four key salivary proteins present in the acquired enamel pellicle (AEP) on eroded and non-eroded surfaces in participants with erosive tooth wear. Participants with erosive tooth wear of dietary non-intrinsic origin, present on the occlusal surfaces of the lower first molars and an unaffected posterior occlusal surface in the same quadrant were recruited from restorative dental clinics at King's College London Dental Institute (n = 29, REC ref 14/EM/1171). Following removal of the salivary film, AEP samples were collected from the eroded occlusal surfaces (EP, n = 29) and the non-eroded occlusal surfaces (NP, n = 29) using 0.5% sodium dodecyl sulfate (SDS) soaked filter papers. Total protein concentration was analysed using bicinchoninic acid assay (BCA). Protein fractions were separated using SDS PAGE and immunoblotted against: mucin5b, albumin, carbonic anhydrase VI (CA VI) and statherin antibodies. Amounts were quantified using ImageLab software against purified protein standards of known concentration. ANOVA followed by paired t test and Wilcoxon's matched-pair signed-rank test were used to test statistical significance. The difference was considered to be significant at a P value < 0.05. The total protein on eroded surfaces was significantly lower compared to the total protein on non-eroded surfaces [0.41mg/mL (0.04) and 0.61 mg/mL (0.11)] respectively (p< 0.05). The median (min, max) amount of statherin was also significantly lower on eroded occlusal surfaces [84.1 (20.0, 221.8) ng] compared to AEP from non-eroded teeth in the same subjects [97.1(30.0, 755.6) ng] (p = 0.002). No statistical differences were observed for mucin 5b, albumin or CA VI. The total protein and statherin in the in-vivo AEP were different between eroded and non-eroded tooth surfaces of the same patient. PMID- 28837610 TI - Potential effects of incorporating fertility control into typical culling regimes in wild pig populations. AB - Effective management of widespread invasive species such as wild pigs (Sus scrofa) is limited by resources available to devote to the effort. Better insight of the effectiveness of different management strategies on population dynamics is important for guiding decisions of resource allocation over space and time. Using a dynamic population model, we quantified effects of culling intensities and time between culling events on population dynamics of wild pigs in the USA using empirical culling patterns and data-based demographic parameters. In simulated populations closed to immigration, substantial population declines (50-100%) occurred within 4 years when 20-60% of the population was culled annually, but when immigration from surrounding areas occurred, there was a maximum of 50% reduction, even with the maximum culling intensity of 60%. Incorporating hypothetical levels of fertility control with realistic culling intensities was most effective in reducing populations when they were closed to immigration and when intrinsic population growth rate was too high (> = 1.78) to be controlled by culling alone. However, substantial benefits from fertility control used in conjunction with culling may only occur over a narrow range of net population growth rates (i.e., where net is the result of intrinsic growth rates and culling) that varies depending on intrinsic population growth rate. The management implications are that the decision to use fertility control in conjunction with culling should rely on concurrent consideration of achievable culling intensity, underlying demographic parameters, and costs of culling and fertility control. The addition of fertility control reduced abundance substantially more than culling alone, however the effects of fertility control were weaker than in populations without immigration. Because these populations were not being reduced substantially by culling alone, fertility control could be an especially helpful enhancement to culling for reducing abundance to target levels in areas where immigration can't be prevented. PMID- 28837609 TI - A qualitative study assessing patient perspectives in the process of decision making on disease modifying therapies (DMT's) in multiple sclerosis (MS). AB - BACKGROUND: Physicians commonly advise patients to begin disease modifying therapies (DMT's) shortly after the establishment of a diagnosis of Multiple Sclerosis (MS) to prevent further relapses and disease progression. However, little is known about the meaning for patients going through the process of the diagnosis of MS and of making decisions on DMT's in early MS. OBJECTIVE: To explore the patient perspective on using DMT's for MS. Methods: Ten participants with a recent (< 2 years) relapsing-remitting MS diagnosis were interviewed. Seven of them were using DMT's at the time of the interview. All interviews were transcribed and analyzed using a hermeneutical-phenomenological approach. RESULTS: The analysis revealed the following themes: (1) Constant confrontation with the disease, (2) Managing inevitable decline, (3) Hope of delaying the progression of the disease, and, (4) The importance of social support. The themes show that patients associate the recommendation to begin DMT's (especially injectable DMT's) with views about their bodies as well as their hopes about the future. Both considering and adhering to treatment are experienced by patients as not only matters of individual and rational deliberation, but also as activities that are lived within a web of relationships with relatives and friends. CONCLUSION: From the patient perspective, the use of DMT's is not a purely rational and individual experience. More attention to the use of DMT's as relational and lived phenomena will improve the understanding of the process of decision-making for DMT's in MS. PMID- 28837611 TI - Rooibos (Aspalathus linearis) extract enhances boar sperm velocity up to 96 hours of semen storage. AB - Rooibos (Aspalathus linearis) is a native shrub from South African fynbos and has become very popular in the last decades for its antioxidant and medicinal attributes. Several studies have shown its beneficial properties in numerous cell lines, but to date, the in vitro effects of rooibos extract on sperm cells are still unknown. In this study, boar semen was supplemented with four concentrations both of fermented and unfermented rooibos extracts during 96 h of liquid storage at 17 degrees C. The effects of rooibos extracts on sperm velocity, membrane integrity, and acrosomal status were evaluated at 2 h, 48 h, and 96 h of semen storage. Overall our results indicate that rooibos extract enhances sperm velocity, protects the acrosome structure, and tends to preserve the membrane integrity during semen storage. Although the unfermented rooibos showed higher total polyphenol content and total antioxidant capacity than the fermented one, the latter had better effects on sperm velocity leading to, for instance, an increase of 30% in the rectilinear velocity (VSL) at 48 h compared to the control group. Taking into account the different storage times, we established a suitable range of extracts concentrations to be used in boar semen. The rooibos extract ought to be considered as a powerful and natural source of antioxidants for the preservation of boar semen. PMID- 28837612 TI - Shared features of cryptic plasmids from environmental and pathogenic Francisella species. AB - The Francisella genus includes several recognized species, additional potential species, and other representatives that inhabit a range of incredibly diverse ecological niches, but are not closely related to the named species. Francisella species have been obtained from a wide variety of clinical and environmental sources; documented species include highly virulent human and animal pathogens, fish pathogens, opportunistic human pathogens, tick endosymbionts, and free living isolates inhabiting brackish water. While more than 120 Francisella genomes have been sequenced to date, only a few contain plasmids, and most of these appear to be cryptic, with unknown benefit to the host cell. We have identified several putative cryptic plasmids in the sequenced genomes of three Francisella novicida and F. novicida-like strains (TX07-6608, AZ06-7470, DPG_3A IS) and two new Francisella species (F. frigiditurris CA97-1460 and F. opportunistica MA06-7296). These plasmids were compared to each other and to previously identified plasmids from other Francisella species. Some of the plasmids encoded functions potentially involved in replication, conjugal transfer and partitioning, environmental survival (transcriptional regulation, signaling, metabolism), and hypothetical proteins with no assignable functions. Genomic and phylogenetic comparisons of these new plasmids to the other known Francisella plasmids revealed some similarities that add to our understanding of the evolutionary relationships among the diverse Francisella species. PMID- 28837613 TI - Impact of sheath diameter of different sheath types on vascular complications and mortality in transfemoral TAVI approaches using the Proglide closure device. AB - OBJECTIVE: Evaluation of the impact of the sheath diameter on vascular complications and mortality in transfemoral aortic valve implantation. METHOD: Between 2012 and 2014, 183 patients underwent the procedure using a sheath diameter of 18-24 F. This collective was divided into two groups: group 1, with a sheath diameter of 18F (G1, n = 94), consisted of patients with 18F Medtronic Sentrant and 18 F Direct Flow sheaths, and group 2 with a sheath diameter of 19 24 F (G2, n = 89) consisted of patients with Edwards expandable e-sheath and Solopath sheaths. Perclose-Proglide(r) was used as a closure device in all patients. RESULTS: G1 had significantly more female patients (64.9% vs. 46.1% in G2, p = 0.01) and the average BMI was lower (26 +/- 4.5% vs. 27.4 +/- 4.7%, p = 0.03). There was no significant difference in the incidence of major and minor vascular complications (G1: 12.8% vs. G2: 12.4%, p = 0.9). 30-day mortality was similar in both groups (G1: 6.4 +/- 2.5% [95% CI: 0.88-0.98], G2: 3.7 +/- 1.9% [95% CI: 0.92-0.99]. The Kaplan Meier analysis of survival revealed no significant differences either. CONCLUSION: The difference in sheath diameter had no effect on either incidence or severity of vascular complications. There was no impact on mortality either. PMID- 28837614 TI - Mice deficient in the anti-haemophilic coagulation factor VIII show increased von Willebrand factor plasma levels. AB - Von Willebrand factor (VWF) is the carrier protein of the anti-haemophilic Factor VIII (FVIII) in plasma. It has been reported that the infusion of FVIII concentrate in haemophilia A patients results in lowered VWF plasma levels. However, the impact of F8-deficiency on VWF plasma levels in F8-/y mice is unresolved. In order to avoid confounding variables, we back-crossed F8-deficient mice onto a pure C57BL/6J background and analysed VWF plasma concentrations relative to C57BL/6J WT (F8+/y) littermate controls. F8-/y mice showed strongly elevated VWF plasma concentrations and signs of hepatic inflammation, as indicated by increased TNF-alpha, CD45, and TLR4 transcripts and by elevated macrophage counts in the liver. Furthermore, immunohistochemistry showed that expression of VWF antigen was significantly enhanced in the hepatic endothelium of F8-/y mice, most likely resulting from increased macrophage recruitment. There were no signs of liver damage, as judged by glutamate-pyruvate-transaminase (GPT) and glutamate-oxalacetate-transaminase (GOT) in the plasma and no signs of systemic inflammation, as white blood cell subsets were unchanged. As expected, impaired haemostasis was reflected by joint bleeding, prolonged in vitro clotting time and decreased platelet-dependent thrombin generation. Our results point towards a novel role of FVIII, synthesized by the liver endothelium, in the control of hepatic low-grade inflammation and VWF plasma levels. PMID- 28837615 TI - Exploring virus release as a bottleneck for the spread of influenza A virus infection in vitro and the implications for antiviral therapy with neuraminidase inhibitors. AB - Mathematical models (MMs) have been used to study the kinetics of influenza A virus infections under antiviral therapy, and to characterize the efficacy of antivirals such as neuraminidase inhibitors (NAIs). NAIs prevent viral neuraminidase from cleaving sialic acid receptors that bind virus progeny to the surface of infected cells, thereby inhibiting their release, suppressing infection spread. When used to study treatment with NAIs, MMs represent viral release implicitly as part of viral replication. Consequently, NAIs in such MMs do not act specifically and exclusively on virus release. We compared a MM with an explicit representation of viral release (i.e., distinct from virus production) to a simple MM without explicit release, and investigated whether parameter estimation and the estimation of NAI efficacy were affected by the use of a simple MM. Since the release rate of influenza A virus is not well-known, a broad range of release rates were considered. If the virus release rate is greater than ~0.1 h-1, the simple MM provides accurate estimates of infection parameters, but underestimates NAI efficacy, which could lead to underdosing and the emergence of NAI resistance. In contrast, when release is slower than ~0.1 h 1, the simple MM accurately estimates NAI efficacy, but it can significantly overestimate the infectious lifespan (i.e., the time a cell remains infectious and producing free virus), and it will significantly underestimate the total virus yield and thus the likelihood of resistance emergence. We discuss the properties of, and a possible lower bound for, the influenza A virus release rate. PMID- 28837616 TI - A novel device for collecting and dispensing fingerstick blood for point of care testing. AB - The increased world-wide availability of point-of-care (POC) tests utilizing fingerstick blood has led to testing scenarios in which multiple separate fingersticks are performed during a single patient encounter, generating cumulative discomfort and reducing testing efficiency. We have developed a device capable of a) collection of up to 100 MUL of fingerstick blood from a single fingerstick by capillary action, and b) dispensing this blood in variable increments set by the user. We tested the prototype device both in a controlled laboratory setting and in a fingerstick study involving naive device users, and found it to have accuracy and precision similar to a conventional pipettor. The users also found the device to be easy to use, and recommended minor ergonomic improvements. Our device would allow performance of multiple POC tests from a single fingerstick blood sample, thus providing a novel functionality that may be of use in many testing settings worldwide. PMID- 28837617 TI - Structural characterisation of TNRC6A nuclear localisation signal in complex with importin-alpha. AB - The GW182/TNRC6 family of proteins are central scaffolds that link microRNA associated Argonaute proteins to the cytoplasmic decay machinery for targeted mRNA degradation processes. Although nuclear roles for the GW182/TNRC6 proteins are unknown, recent reports have demonstrated nucleocytoplasmic shuttling activity that utilises the importin-alpha and importin-beta transport receptors for nuclear translocation. Here we describe the structure of mouse importin-alpha in complex with the TNRC6A nuclear localisation signal peptide. We further show that the interactions observed between TNRC6A and importin-alpha are conserved between mouse and human complexes. Our results highlight the ability of monopartite cNLS sequences to maximise contacts at the importin-alpha major binding site, as well as regions outside the main binding cavities. PMID- 28837618 TI - Therapeutic benefits of intravenous cardiosphere-derived cell therapy in rats with pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive condition characterized by occlusive pulmonary arteriopathy, in which survival remains poor despite pharmacologic advances. The aim of this study was to evaluate the ability of cardiosphere-derived cells (CDCs), cardiac progenitor cells with potent anti inflammatory and immunomodulatory properties, to attenuate hemodynamic and morphometric remodeling of the right ventricle (RV) and pulmonary arterioles in rats with established monocrotaline (MCT)-induced PAH. Animals were divided into 3 groups: 1) Control (CTL), 2) PAH in which CDCs were centrally infused (CDC) and 3) PAH in which saline was given (Sham). Significant increments in RV systolic pressure (RVSP) and RV hypertrophy were noted in Sham animals compared to CTL. In CDC rats at day 35, RSVP fell (- 38%; p< 0.001) and RV hypertrophy decreased ( 26%; p< 0.01). TAPSE and cardiac output were preserved in all 3 groups at day 35. Pulmonary arteriolar wall thickness was greater in Sham rats compared to CTL, and reduced in CDC animals for vessels 20-50 MUm (P<0.01; back to CTL levels) and 50 80MUm (P<0.01) in diameter. The macrophage population was increased in Sham animals compared to CTL (P< 0.001), but markedly reduced in CDC rats. In conclusion, infusion of CDCs markedly attenuated several key pathophysiologic features of PAH. As adjunctive therapy to PAH-specific agents, CDCs have the potential to impact on the pathobiology of adverse pulmonary arteriolar remodeling, by acting on multiple mechanisms simultaneously. PMID- 28837619 TI - LL-37 causes cell death of human nasal epithelial cells, which is inhibited with a synthetic glycosaminoglycan. AB - LL-37 is an immune peptide that regulates innate and adaptive immune responses in the upper airways. Elevated levels of LL-37 have been linked to cell death and inflammatory diseases, such as chronic rhinosinusitis (CRS). Glycosaminoglycans (GAGs) are polysaccharides that are found on respiratory epithelial cells and serve important roles in mucosal surface repair. Recent findings suggest that a synthetic glycosaminoglycan (GM-0111) can protect against LL-37-induced sinonasal mucosal inflammation and cell death in a murine model of acute RS. Herein, we elucidated the mechanisms by which LL-37 causes sinonasal inflammation and how GM 0111 can prevent these mechanisms. When challenged with LL-37, human nasal epithelial cells (HNEpCs) and mouse macrophages (J774.2) demonstrated increased release of adenosine triphosphate (ATP) and interleukin (IL)-6 and -8, as well as cell death and lysis. These cellular responses were all blocked dose-dependently by pre-treatment with GM-0111. We identified that LL-37-induced cell death is associated with caspase-1 and -8 activation, but not activation of caspase-3/7. These responses were again blocked by GM-0111. Our data suggest that LL-37 causes cellular death of HNEpCs and macrophages through the pro-inflammatory necrotic and/or pyroptotic pathways rather than apoptosis, and that a GM-0111 is capable of inhibiting these pro-inflammatory cellular events. PMID- 28837620 TI - Extranodal spread of primary and secondary metastatic nodes: The dominant risk factor of survival in patients with head and neck squamous cell carcinoma. AB - Extranodal spread (ENS) in patients with head and neck squamous cell carcinoma (HNSCC) can greatly influence the prognostic outcomes. However, the relative risks of ENS in the primary (1st) and secondary (2nd) metastatic nodes (mets) are not well documented. We retrospectively analyzed the hazard ratios (HRs) of ENS in the 1st and 2nd mets from 516 HNSCC patients who had undergone primary tumor excision. The impact of clinically and/or histologically confirmed ENS-positive mets on prognosis in terms of cancer-specific survival was analyzed. Cox proportional hazard regression analysis indicated that ENS-positive 1st met (adjusted HR = 3.15; 95% CI, 1.40-7.56; p = 0.006) and ENS-positive 2nd met (adjusted HR = 4.03; 95% CI, 1.41-16.96; p = 0.007) significantly and independently predicted poor prognosis; however, other variables including primary site, met size or numbers, and met location in the contralateral side of the primary lesion, did not. Cumulative incidence function and Cox analyses indicated that differences in ENS profiles of 1st and 2nd mets stratified HNSCC patients with varying risks of poor outcome; HRs relative to patients with ENS positive 1st met (-)/ENS-positive 2nd met (-) were 4.02 (95% CI, 1.78-8.24; p = 0.002), 8.29 (95% CI, 4.58-14.76; p <0.001), and 25.80 (95% CI, 10.15-57.69; p <0.001) for patients with ENS-positive 1st met (+)/ENS-positive 2nd met (-), ENS positive 1st met (-)/ENS-positive 2nd met (+), and ENS-positive 1st met (+)/ENS positive 2nd met (+) patients, respectively. Kaplan-Meier analysis indicated that the 2nd met that appeared in the neck side with a history of 1st met and neck dissection had a higher risk of ENS than the 2nd met in the neck side without the history (p = 0.003). These results suggested that ENS is a dominant prognostic predictor of HNSCC patients, with double-positive ENS in the 1st and 2nd mets predicting the most devastating outcome. PMID- 28837621 TI - Predicting the preferences for involvement in medical decision making among patients with mental disorders. AB - BACKGROUND: The involvement of patients in medical decision making has been investigated widely in somatic diseases. However, little is known about the preferences for involvement and variables that could predict these preferences in patients with mental disorders. OBJECTIVE: This study aims to determine what roles mentally ill patients actually want to assume when making medical decisions and to identify the variables that could predict this role, including patients' self-efficacy. METHOD: Demographic and clinical data of 798 patients with mental disorders from three psychotherapeutic units in Germany were elicited using self report questionnaires. Control preference was measured using the Control Preferences Scale, and patients' perceived self-efficacy was assessed using the Self-Efficacy Scale. Bivariate and multivariate regression analyses were conducted to investigate the associations between patient variables and control preference. RESULTS: Most patients preferred a collaborative role (57.5%), followed by a semi passive (21.2%), a partly autonomous (16.2%), an autonomous (2.8%) and a fully passive (2.3%) role when making medical decisions. Age, sex, diagnosis, employment status, medical pretreatment and perceived self-efficacy were associated with the preference for involvement in the multivariate logistic model. CONCLUSION: Our results confirm the preferences for involvement in medical decisions of mentally ill patients. We reconfirmed previous findings that older patients prefer a shared role over an autonomous role and that subjects with a high qualification prefer a more autonomous role over a shared role. The knowledge about predictors may help strengthen treatment effectiveness because matching the preferred and actual role preferences has been shown to improve clinical outcome. PMID- 28837622 TI - Lef1-dependent hypothalamic neurogenesis inhibits anxiety. AB - While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/beta-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species. PMID- 28837623 TI - Multidimensional pooled shRNA screens in human THP-1 cells identify candidate modulators of macrophage polarization. AB - Macrophages are key cell types of the innate immune system regulating host defense, inflammation, tissue homeostasis and cancer. Within this functional spectrum diverse and often opposing phenotypes are displayed which are dictated by environmental clues and depend on highly plastic transcriptional programs. Among these the 'classical' (M1) and 'alternative' (M2) macrophage polarization phenotypes are the best characterized. Understanding macrophage polarization in humans may reveal novel therapeutic intervention possibilities for chronic inflammation, wound healing and cancer. Systematic loss of function screening in human primary macrophages is limited due to lack of robust gene delivery methods and limited sample availability. To overcome these hurdles we developed cell autonomous assays using the THP-1 cell line allowing genetic screens for human macrophage phenotypes. We screened 648 chromatin and signaling regulators with a pooled shRNA library for M1 and M2 polarization modulators. Validation experiments confirmed the primary screening results and identified OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) as a novel mediator of M2 polarization in human macrophages. Our approach offers a possible avenue to utilize comprehensive genetic tools to identify novel candidate genes regulating macrophage polarization in humans. PMID- 28837624 TI - Rare variants in genes encoding the cardiac sodium channel and associated compounds and their impact on outcome of catheter ablation of atrial fibrillation. AB - AIM: Rare variants of genes encoding the cardiac sodium channel and associated compounds have been linked with atrial fibrillation (AF). Nevertheless, current expert consensus does not support genetic testing in AF, which is in part based on the fact that "there is no therapeutic impact derived from AF genetic test results". However, there are no studies available supporting this recommendation. Consequently, this study analyzed the impact of rare variants affecting the cardiac sodium channel on rhythm outcome of AF catheter ablation. METHODS AND RESULTS: In 137 consecutive patients with lone AF enrolled in the Leipzig Heart Center AF ablation registry, screening for mutations in SCN5A, SCN1B - 4B, CAV3, GPD1L, SNTA1 and MOG1 was performed. We identified 3 rare non-synonymous variants in SCN5A, 5 in SCN1B, 1 in SCN4B, 1 in CAV3, 6 in GPD1L, 3 in SNTA1 and 3 in MOG1 (16%). Variant carriers were otherwise comparable with non-variant carriers. Analysis of AF recurrence rates after radiofrequency AF catheter ablation by serial 7-day Holter ECG monitoring between 3 and 12 months revealed no difference between groups, i.e. 45% in variant carriers vs. 49% in non-variant carriers. CONCLUSIONS: Rare variants in genes encoding the cardiac sodium channel and associated compounds are frequently found in lone AF but were not found to impact the outcome of AF catheter ablation. This finding supports current recommendations not to screen for rare variants for the ablation outcome in AF. Nevertheless, it may at least be helpful for understanding AF mechanisms and larger studies are needed to further explore the possible association between genotype and response to AF therapies. PMID- 28837625 TI - Extraction optimization and influences of drying methods on antioxidant activities of polysaccharide from cup plant (Silphium perfoliatum L.). AB - Response surface methodology (RSM) was used to investigate the extraction condition of polysaccharide from cup plant (Silphium perfoliatum L.) (named CPP). Water to raw material ratio (10-30 mL/g), extraction time (40-80 min) and extraction temperature (60-100 degrees C) were set as the 3 independent variables, and their effects on the extraction yield of CPP were measured. In addition, the effects of drying methods including hot air drying (HD), vacuum drying (VD) and freeze drying (FD) on the antioxidant activities of CPP were evaluated. The results showed that the optimal condition to extract CPP was: water to raw material ratio (15 mL/g), extraction time (61 min), and extraction temperature (97 degrees C), a maximum CPP yield of 6.49% was obtained under this condition. CPP drying with FD method showed stronger reducing power (0.943 at 6 mg/mL) and radical scavenging capacities against DPPH radical (75.71% at 1.2 mg/mL) and ABTS radical (98.06 at 1.6 mg/mL) than CPP drying with HD and VD methods. Therefore, freeze drying served as a good method for keeping the antioxidant activities of polysaccharide from cup plant. The polysaccharide from cup plant has potential to use as a natural antioxidant. PMID- 28837626 TI - Trehalose improves traumatic brain injury-induced cognitive impairment. AB - Traumatic brain Injury (TBI) is a significant cause of death and long-term disability for which there are currently no effective pharmacological treatment options. In this study then, we utilized a mouse model of TBI to assess the therapeutic potential of the stable disaccharide trehalose, which is known to protect against oxidative stress, increase levels of chaperone molecules and enhance autophagy. Furthermore, trehalose has demonstrated neuroprotective properties in numerous animal models and has been proposed as a potential treatment for neurodegeneration. As TBI (and associated neurodegenerative disorders) is complicated by a sudden and dramatic change in brain metal concentrations, including iron (Fe) and zinc (Zn), the collective accumulation and translocation of which has been hypothesized to contribute to the pathogenesis of TBI, then we also sought to determine whether trehalose modulated the metal dyshomeostasis associated with TBI. In this study three-month-old C57Bl/6 wildtype mice received a controlled cortical impact TBI, and were subsequently treated for one month with trehalose. During this time animals were assessed on multiple behavioral tasks prior to tissue collection. Results showed an overall significant improvement in the Morris water maze, Y-maze and open field behavioral tests in trehalose-treated mice when compared to controls. These functional benefits occurred in the absence of any change in lesion volume or any significant modulation of biometals, as assessed by laser ablation inductively coupled plasma mass spectrometry. Western blot analysis, however, revealed an upregulation of synaptophysin, doublecortin and brain derived neurotrophic factor protein in trehalose treated mice in the contralateral cortex. These results indicate that trehalose may be efficacious in improving functional outcomes following TBI by a previously undescribed mechanism of action that has relevance to multiple disorders of the central nervous system. PMID- 28837627 TI - Sequence-structure relationships, expression profiles, and disease-associated mutations in the paralogs of phosphoglucomutase 1. AB - The key metabolic enzyme phosphoglucomutase 1 (PGM1) controls glucose homeostasis in most human cells. Four proteins related to PGM1, known as PGM2, PGM2L1, PGM3 and PGM5, and referred to herein as paralogs, are encoded in the human genome. Although all members of the same enzyme superfamily, these proteins have distinct substrate preferences and different functional roles. The recent association of PGM1 and PGM3 with inherited enzyme deficiencies prompts us to revisit sequence structure and other relationships among the PGM1 paralogs, which are understudied despite their importance in human biology. Using currently available sequence, structure, and expression data, we investigated evolutionary relationships, tissue-specific expression profiles, and the amino acid preferences of key active site motifs. Phylogenetic analyses indicate both ancient and more recent divergence between the different enzyme sub-groups comprising the human paralogs. Tissue-specific protein and RNA expression profiles show widely varying patterns for each paralog, providing insight into function and disease pathology. Multiple sequence alignments confirm high conservation of key active site regions, but also reveal differences related to substrate specificity. In addition, we find that sequence variants of PGM2, PGM2L1, and PGM5 verified in the human population affect residues associated with disease-related mutants in PGM1 or PGM3. This suggests that inherited diseases related to dysfunction of these paralogs will likely occur in humans. PMID- 28837628 TI - Septic shock and the use of norepinephrine in an intermediate care unit: Mortality and adverse events. AB - BACKGROUND: Septic shock is associated with high mortality. Aged and multimorbid patients are not always eligible for intensive care units. Norepinephrine is an accepted treatment for hypotension in septic shock. It is unknown whether norepinephrine has a place in treatment outside an intensive care unit and when given peripherally. OBJECTIVES: To describe mortality, Acute Physiology And Chronic Health Evaluation (APACHE-II), time to mean arterial pressure >65 mmHg, and adverse events in patients with septic shock receiving norepinephrine peripherally in an intermediate care unit. METHODS: From a retrospective chart review of 91 patients with septic shock treated with norepinephrine for hypotension, ward mortality, 30-, 60- and 90-day mortality, standardized mortality ratio (SMR) and adverse events (necrosis and arrhythmia) were analysed. Administration route via peripheral venous catheter or central venous catheter was registered. RESULTS: Median age was 81 (43-96) years and median APACHE-II score was 26 (12-42). Observed ward mortality was 27.5% (SMR 0.443, 95% CI: 0.287 0.654), and 30-day and 90-day mortality were 47.2% and 58.2%, respectively. CONCLUSIONS: Elderly patients with septic shock treated with norepinephrine displayed a better survival in the ward and at 30 days than expected. Our retrospective study did not indicate frequent complications when administering norepinephrine via a peripheral venous catheter. PMID- 28837629 TI - Effects of subconjunctival administration of anti-high mobility group box 1 on dry eye in a mouse model of Sjogren's syndrome. AB - PURPOSE: Extracellular high mobility group box 1 (HMGB1) acts as a damage associated molecular pattern molecule through the Toll-like receptor to promote autoreactive B cell activation, which may be involved in the pathogenesis of Sjogren's syndrome. The aim of this study was to investigate the effect of subconjunctival administration of anti-HMGB1 on dry eye in a mouse model of Sjogren's syndrome. METHODS: Ten weeks-old NOD.B10.H2b mice were subconjunctivally injected with 0.02 to 2 MUg of anti-HMGB1 antibodies or PBS twice a week for two consecutive weeks. Tear volume and corneal staining scores were measured and compared between before- and after-treatment. Goblet cell density was counted in PAS stained forniceal conjunctiva and inflammatory foci score (>50 cells/focus) was measured in extraorbital glands. Flow cytometry was performed to evaluate the changes in BrdU+ cells, IL-17-, IL-10-, or IFNgamma secreting cells, functional B cells, and IL-22 secreting innate lymphoid cells (ILC3s) in cervical lymph nodes. The level of IL-22 in intraorbital glands was measured by ELISA. RESULTS: Injection of 2 MUg or 0.02 MUg anti-HMGB1 attenuated corneal epithelial erosions and increased tear secretion (p<0.05). Goblet cell density was increased in 0.2 MUg and 2 MUg anti-HMGB1-treated-mice with marginal significance. The inflammatory foci score, and the number of BrdU+ cells, IL-17-, IL-10-, IFNgamma-secreting cells, and functional B cells did not significantly change following anti-HMGB1 treatment. Surprisingly, the percentage of ILC3s was significantly increased in the draining lymph nodes (p<0.05), and the expression of IL-22 was significantly increased in the intraorbital glands (p<0.05) after administration of 2 MUg anti-HMGB1. CONCLUSION: This study shows that subconjunctival administration of anti-HMGB1 attenuates clinical manifestations of dry eye. The improvement of dry eye may involve an increase of ILC3s, rather than modulation of B or plasma cells, as shown using a mouse model of Sjogren's syndrome. PMID- 28837630 TI - Influence of electrode array stiffness and diameter on hearing in cochlear implanted guinea pig. AB - During cochlear implantation, electrode array translocation and trauma should be avoided to preserve residual hearing. The aim of our study was to evaluate the effect of physical parameters of the array on residual hearing and cochlear structures during insertion. Three array prototypes with different stiffnesses or external diameters were implanted in normal hearing guinea pigs via a motorized insertion tool carried on a robot-based arm, and insertion forces were recorded. Array prototypes 0.4 and 0.4R had 0.4 mm external diameter and prototype 0.3 had 0.3 mm external diameter. The axial stiffness was set to 1 for the 0.4 prototype and the stiffnesses of the 0.4R and 0.3 prototypes were calculated from this as 6.8 and 0.8 (relative units), respectively. Hearing was assessed preoperatively by the auditory brainstem response (ABR), and then at day 7 and day 30 post implantation. A study of the macroscopic anatomy was performed on cochleae harvested at day 30 to examine the scala location of the array. At day 7, guinea pigs implanted with the 0.4R array had significantly poorer hearing results than those implanted with the 0.3 array (26+/-17.7, 44+/-23.4, 33+/-20.5 dB, n = 7, vs 5+/-8.7, 1+/-11.6, 12+/-11.5 dB, n = 6, mean+/-SEM, respectively, at 8, 16 and 24 kHz, p<0.01) or those implanted with the 0.4 array (44+/-23.4 dB, n = 7, vs 28+/ 21.7 dB, n = 7, at 16 kHz, p<0.05). Hearing remained stable from day 7 to day 30. The maximal peak of insertion force was higher with the 0.4R array than with the 0.3 array (56+/-23.8 mN, n = 7, vs 26+/-8.7 mN, n = 6). Observation of the cochleae showed that an incorrectly positioned electrode array or fibrosis were associated with hearing loss >=40 dB (at 16 kHz). An optimal position in the scala tympani with a flexible and thin array and prevention of fibrosis should be the primary objectives to preserve hearing during cochlear implantation. PMID- 28837631 TI - WRKY70 and its homolog WRKY54 negatively modulate the cell wall-associated defenses to necrotrophic pathogens in Arabidopsis. AB - Previous studies have identified the Arabidopsis thaliana transcription factor WRKY70 as a node of convergence for salicylic acid (SA) and jasmonic acid (JA) mediated defense signal pathways and, together with its closest homolog WRKY54, as a negative regulator of SA biosynthesis. Here, we demonstrate that WRKY70 together with WRKY54 negatively affect the response of Arabidopsis to the necrotrophic pathogens Pectobacterium carotovorum and Botrytis cinerea, but not to the hemibiotroph Pseudomonas syringae pv tomato (Pst) DC3000, as revealed by mutants studies. Unstressed wrky54wrky70 double mutants exhibited increased levels of SA, accumulation of hydrogen peroxide (H2O2) and up-regulated expression of both SA and JA/ethylene (ET) responsive defense related genes. Additionally, protein cross-linking in cell wall was promoted by endogenous SA, suggesting involvement of wall-associated defenses against necrotrophs. This response to necrotrophs was compromised by introducing the sid2-1 allele impairing SA biosynthesis and leading to reduction of H2O2 content and of defense gene expression. The data suggest that the elevated SA level in the wrky54wrky70 double mutant results in moderate accumulation of H2O2, in promoting cell wall fortification and consequently enhanced resistance to necrotrophs but is not sufficient to trigger hypersensitive reaction (HR)-like cell death and resistance to biotrophs/hemibiotrophs like Pst DC3000. PMID- 28837633 TI - Towards a model of resilience for transnational families of Filipina domestic workers. AB - Many Filipinos experience poverty and poor employment opportunities. In order to alleviate poverty and provide sufficient resources for their families, numerous mothers leave the Philippines to become domestic workers. The present study aimed to build a model of family resilience for transnational families. A total of 33 participants consisting of Filipino transnational families, domestic workers, and key informants participated in a series of focus group discussions and interviews. A new model of resilience among transnational families of Filipina domestic helpers was created using a constructivist grounded theory approach. The model highlighted how temporal and spatial elements are embedded in collective migration experiences. Family narratives begin with the sacrifice of separation, where mothers leave their families for a chance to solve economic problems. To successfully adapt to their separation, the families undergo five relational processes. First, families communicate across space using technology to bridge relational distance. Second, families restructure across space through role sharing and the validation of each other's efforts in their family roles. Third, families rebuild ties through temporary family reunification that bridge physical and relational distance. Fourth, families have the collective goal of permanent family reunification by ending migration to become complete again. Fifth, they strive to commit to their families by prioritizing them instead of succumbing to difficulties. Family resilience for transnational migrants is a collectivistic process, negotiated by each family member. PMID- 28837632 TI - Green fluorescent genetically encoded calcium indicator based on calmodulin/M13 peptide from fungi. AB - Currently available genetically encoded calcium indicators (GECIs) utilize calmodulins (CaMs) or troponin C from metazoa such as mammals, birds, and teleosts, as calcium-binding domains. The amino acid sequences of the metazoan calcium-binding domains are highly conserved, which may limit the range of the GECI key parameters and cause undesired interactions with the intracellular environment in mammalian cells. Here we have used fungi, evolutionary distinct organisms, to derive CaM and its binding partner domains and design new GECI with improved properties. We applied iterative rounds of molecular evolution to develop FGCaMP, a novel green calcium indicator. It includes the circularly permuted version of the enhanced green fluorescent protein (EGFP) sandwiched between the fungal CaM and a fragment of CaM-dependent kinase. FGCaMP is an excitation-ratiometric indicator that has a positive and an inverted fluorescence response to calcium ions when excited at 488 and 405 nm, respectively. Compared with the GCaMP6s indicator in vitro, FGCaMP has a similar brightness at 488 nm excitation, 7-fold higher brightness at 405 nm excitation, and 1.3-fold faster calcium ion dissociation kinetics. Using site-directed mutagenesis, we generated variants of FGCaMP with improved binding affinity to calcium ions and increased the magnitude of FGCaMP fluorescence response to low calcium ion concentrations. Using FGCaMP, we have successfully visualized calcium transients in cultured mammalian cells. In contrast to the limited mobility of GCaMP6s and G-GECO1.2 indicators, FGCaMP exhibits practically 100% molecular mobility at physiological concentrations of calcium ion in mammalian cells, as determined by photobleaching experiments with fluorescence recovery. We have successfully monitored the calcium dynamics during spontaneous activity of neuronal cultures using FGCaMP and utilized whole-cell patch clamp recordings to further characterize its behavior in neurons. Finally, we used FGCaMP in vivo to perform structural and functional imaging of zebrafish using wide-field, confocal, and light-sheet microscopy. PMID- 28837634 TI - Factors associated with readmission to the hospital within 30 days in patients with inflammatory bowel disease. AB - BACKGROUND: Management of inpatients with inflammatory bowel disease (IBD) requires increasing resources. We aimed to identify factors associated with hospital readmissions among individuals with IBD. MATERIALS & METHODS: We collected data from the Healthcare Cost and Utilization Project Nationwide Readmissions Database 2013. We identified individuals with index hospitalizations for IBD. Patient-specific factors, comorbidities and hospitalization characteristics were extracted for the index hospitalization. We performed logistic regression modeling to create adjusted odds ratios (ORs) for 30-day hospital readmission. Subgroup analysis was performed based on disease type and performance of surgery. RESULTS: We analyzed a total of 55,942 index hospital discharges; 3037 patients (7.0%) were readmitted to the hospital within 30 days. Increasing patient age (> 65: OR: 0.45; 95% CI 0.39-0.53) was associated with a decreased risk of readmission, while a diagnosis of Crohn's disease (OR: 1.09; 95% CI 1.00-1.18) and male sex (OR: 1.16; 95% CI 1.07-1.25) were associated with an increased risk of readmission. The comorbidities of smoking (OR: 1.09; 95% CI 1.00-1.19), anxiety (OR: 1.17; 95% CI 1.01-1.36) and opioid dependence (OR: 1.40; 95% CI 1.06-1.86) were associated with an increased risk of 30-day readmission. Individual hospitalization characteristics and disease complications were significantly associated with readmission. Performance of a surgery during the index admission was associated with a decreased risk of readmission (OR: 0.57; 95% CI 0.33-0.96). CONCLUSION: Analyzing data from a US publicly available all payer inpatient healthcare database, we identified patient and hospitalization risk factors associated with 30-day readmission. Identifying patients at high risk for readmission may allow for interventions during or after the index hospitalization to decrease this risk. PMID- 28837635 TI - Maternal detection of neonatal jaundice during birth hospitalization using a novel two-color icterometer. AB - BACKGROUND: Mothers are frequently the first to observe the onset of jaundice in their newborn infants before the decision to seek treatment. However, simple-to use tools that could facilitate early detection of jaundice and assist mothers to seek professional care, especially after hospital discharge, are rare. This study therefore, set out to evaluate the performance of a -two-color icterometer (BilistripTM) as a possible screening tool for detecting significant jaundice by mothers or care-givers in the first week of life. METHODS: Prior to discharge, mothers in a maternity hospital were trained to use the BilistripTM on the blanched skin of their baby's nose to ascertain absence (Light Yellow) or presence (Dark Yellow) of significant jaundice. Their babies had transcutaneous bilirubin (TcB) measurements independently, along with total serum bilirubin (TSB) if indicated. The reliability of BilistripTM as a screening test for significant jaundice was determined at different TcB and TSB thresholds. The predictive performance of BilistripTM was also evaluated with multivariable logistic regression. RESULTS: Some 2492 mother-infant pairs were enrolled over 15 months, of which 347 (13.9%) chose Dark Yellow. The mean TcB for Dark Yellow (10mg/dL) was significantly higher (p<0.001) than for Light Yellow (6.1mg/dL). BilistripTM showed increasing sensitivity (47.0% - 92.6%) and negative predictive value (NPV) (91.4% - 99.9%) for selected TcB thresholds (>=10mg/dL, >=12mg/dL, >=15mg/dL, and >=17mg/dL). Among neonates with TSB measurements (n = 124), BilistripTM was associated also with increasing sensitivity (86.8% - 100%) and NPV (62.5% - 100%). The sensitivity and NPV for detecting neonates requiring phototherapy were 95.8% respectively. Only one of the 24 neonates who required phototherapy was missed by the BilistripTM. CONCLUSIONS: BilistripTM is a potential decision-making tool for empowering mothers to detect neonates with clinically significant jaundice that may require close monitoring or treatment, and neonates not requiring treatment for jaundice in the first week of life. PMID- 28837636 TI - Tetrodotoxin-insensitive electrical field stimulation-induced contractions on Crotalus durissus terrificus corpus cavernosum. AB - Reptiles are the first amniotes to develop an intromitent penis, however until now the mechanisms involved in the electrical field stimulation-induced contraction on corpora cavernosa isolated from Crotalus durissus terrificus were not investigated. Crotalus and rabbit corpora cavernosa were mounted in 10 mL organ baths for isometric tension recording. Electrical field stimulation (EFS) induced contractions were performed in presence/absence of phentolamine (10 MUM), guanethidine (30 MUM), tetrodotoxin (1 MUM and 1mM), A-803467 (10 MUM), 3-iodo-L Tyrosine (1 mM), salsolinol (3 MUM) and a modified Krebs solution (equimolar substitution of NaCl by N-methyl-D-glucamine). Immuno-histochemistry for tyrosine hydroxylase was also performed. Electrical field stimulation (EFS; 8 Hz and 16 Hz) caused contractions in both Crotalus and rabbit corpora cavernosa. The contractions were abolished by previous incubation with either phentolamine or guanethidine. Tetrodotoxin (1 MUM) also abolished the EFS-induced contractions of rabbit CC, but did not affect EFS-induced contractions of Crotalus CC. Addition of A-803467 (10 MUM) did not change the EFS-induced contractions of Crotalus CC but abolished rabbit CC contractions. 3-iodo-L-Tyrosine and salsolinol had no effect on EFS-induced contractions of Crotalus CC and Rabbit CC. Replacement of NaCl by N- Methyl-D-glucamine (NMDG) abolished EFS-induced contractions of rabbit CC, but did not affect Crotalus CC. The presence of tyrosine hydroxylase was identified in endothelial cells only of Crotalus CC. Since the EFS-induced contractions of Crotalus CC is dependent on catecholamine release, insensitive to TTX, insensitive to A803467 and to NaCl replacement, it indicates that the source of cathecolamine is unlikely to be from adrenergic terminals. The finding that tyrosine hydroxylase is present in endothelial cells suggests that these cells can modulate Crotalus CC tone. PMID- 28837637 TI - GSTM1/GSTT1 double-null genotype increases risk of treatment-resistant schizophrenia: A genetic association study in Brazilian patients. AB - BACKGROUND: The role of oxidative stress in schizophrenia has been demonstrated, particularly in subjects with treatment-resistant schizophrenia (TRS). In such patients, the decreased levels of antioxidants in conjunction with the increased generation of reactive oxygen species in the brain exposes the neurons to a higher risk of damage. METHODS AND FINDINGS: We evaluated the association of deletion polymorphisms of two genes of the antioxidant Glutathione S-Transferase family, GSTT1 and GSTM1, with susceptibility to TRS. A total of 54 TRS patients (mean age 38.7 years) and 78 healthy control subjects (mean age 39.0 years) were enrolled in this study. The subjects were matched by sex, age, and smoking and alcohol consumption habits. In the case group, the frequencies of GSTT1-null and GSTM1-null genotypes were 24.1 and 51.9%, respectively, whereas for the control group, the frequencies were 12.8 and 46.2%, respectively. Analysis performed with respect to the risk of developing TRS associated with the GSTT1 and GSTM1 deletion polymorphisms, resulted in odds ratio (OR) values of 2.1 and 1.2, respectively. However, the association was not found to be significant (p = 0.1229 and p = 0.5916, respectively). The analysis performed with respect to the combined genotypes of GSTT1 and GSTM1 revealed that the double-null genotype confers a 4.6-fold increased risk of developing TRS (p = 0.0412). CONCLUSION: The results of the present study indicate that a combination of GST deficiencies may play a role in enhanced susceptibility to TRS, and the present genotype of one of these genes may buffer the deficiency caused by the lack (null genotype) of the other. The results suggest that combined deletion polymorphisms of GSTT1 and GSTM1 can have implications in the prediction of the clinical course of the disease. PMID- 28837638 TI - NTFP harvesters as citizen scientists: Validating traditional and crowdsourced knowledge on seed production of Brazil nut trees in the Peruvian Amazon. AB - Understanding the factors that underlie the production of non-timber forest products (NTFPs), as well as regularly monitoring production levels, are key to allow sustainability assessments of NTFP extractive economies. Brazil nut (Bertholletia excelsa, Lecythidaceae) seed harvesting from natural forests is one of the cornerstone NTFP economies in Amazonia. In the Peruvian Amazon it is organized in a concession system. Drawing on seed production estimates of >135,000 individual Brazil nut trees from >400 concessions and ethno-ecological interviews with >80 concession holders, here we aimed to (i) assess the accuracy of seed production estimates by Brazil nut seed harvesters, and (ii) validate their traditional ecological knowledge (TEK) about the variables that influence Brazil nut production. We compared productivity estimates with actual field measurements carried out in the study area and found a positive correlation between them. Furthermore, we compared the relationships between seed production and a number of phenotypic, phytosanitary and environmental variables described in literature with those obtained for the seed production estimates and found high consistency between them, justifying the use of the dataset for validating TEK and innovative hypothesis testing. As expected, nearly all TEK on Brazil nut productivity was corroborated by our data. This is reassuring as Brazil nut concession holders, and NTFP harvesters at large, rely on their knowledge to guide the management of the trees upon which their extractive economies are based. Our findings suggest that productivity estimates of Brazil nut trees and possibly other NTFP-producing species could replace or complement actual measurements, which are very expensive and labour intensive, at least in areas where harvesters have a tradition of collecting NTFPs from the same trees over multiple years or decades. Productivity estimates might even be sourced from harvesters through registers on an annual basis, thus allowing a more cost efficient and robust monitoring of productivity levels. PMID- 28837639 TI - Neural responses to feedback information produced by self-generated or other generated decision-making and their impairment in schizophrenia. AB - Several studies of self-monitoring dysfunction in schizophrenia have focused on the sense of agency to motor action using behavioral and psychophysiological techniques. So far, no study has ever tried to investigate whether the sense of agency or causal attribution for external events produced by self-generated decision-making is abnormal in schizophrenia. The purpose of this study was to investigate neural responses to feedback information produced by self-generated or other-generated decision-making in a multiplayer gambling task using even related potentials and electroencephalogram synchronization. We found that the late positive component and theta/alpha synchronization were increased in response to feedback information in the self-decision condition in normal controls, but that these responses were significantly decreased in patients with schizophrenia. These neural activities thus reflect the self-reference effect that affects the cognitive appraisal of external events following decision-making and their impairment in schizophrenia. PMID- 28837640 TI - Whole-brain background-suppressed pCASL MRI with 1D-accelerated 3D RARE Stack-Of Spirals readout. AB - Arterial Spin Labeled (ASL) perfusion MRI enables non-invasive, quantitative measurements of tissue perfusion, and has a broad range of applications including brain functional imaging. However, ASL suffers from low signal-to-noise ratio (SNR), limiting image resolution. Acquisitions using 3D readouts are optimal for background-suppression of static signals, but can be SAR intensive and typically suffer from through-plane blurring. In this study, we investigated the use of accelerated 3D readouts to obtain whole-brain, high-SNR ASL perfusion maps and reduce SAR deposition. Parallel imaging was implemented along the partition encoding direction in a pseudo-continuous ASL sequence with background suppression and 3D RARE Stack-Of-Spirals readout, and its performance was evaluated in three small cohorts. First, both non-accelerated and two-fold accelerated single-shot versions of the sequence were evaluated in healthy volunteers during a motor-photic task, and the performance was compared in terms of temporal SNR, GM-WM contrast, and statistical significance of the detected activation. Secondly, single-shot 1D-accelerated imaging was compared to a two shot accelerated version to assess benefits of SNR and spatial resolution for applications in which temporal resolution is not paramount. Third, the efficacy of this approach in clinical populations was assessed by applying the single-shot 1D-accelerated version to a larger cohort of elderly volunteers. Accelerated data demonstrated the ability to detect functional activation at the subject level, including cerebellar activity, without loss in the perfusion signal temporal stability and the statistical power of the activations. The use of acceleration also resulted in increased GM-WM contrast, likely due to reduced through-plane partial volume effects, that were further attenuated with the use of two-shot readouts. In a clinical cohort, image quality remained excellent, and expected effects of age and sex on cerebral blood flow could be detected. The sequence is freely available upon request for academic use and could benefit a broad range of cognitive and clinical neuroscience research. PMID- 28837641 TI - Intra-individual comparison between abdominal virtual mono-energetic spectral and conventional images using a novel spectral detector CT. AB - OBJECTIVES: To quantitatively and qualitatively assess abdominal arterial and venous phase contrast-enhanced spectral detector computed tomography (SDCT) virtual mono-energetic (MonoE) datasets in comparison to conventional CT reconstructions provided by the same system. MATERIALS AND METHODS: Conventional and MonoE images at 40-120 kilo-electron volt (keV) levels with a 10 keV increment as well as 160 and 200 keV were reconstructed in abdominal SDCT datasets of 55 patients. Attenuation, image noise, and contrast- / signal-to noise ratios (CNR, SNR) of vessels and solid organs were compared between MonoE and conventional reconstructions. Two readers assessed contrast conditions, detail visualization, overall image quality and subjective image noise with both, fixed and adjustable window settings. RESULTS: Attenuation, CNR and SNR of vessels and solid organs showed a stepwise increase from high to low keV reconstructions in both contrast phases while image noise stayed stable at low keV MonoE reconstruction levels. Highest levels were found at 40 keV MonoE reconstruction (p<0.001), respectively. Solid abdominal organs showed a stepwise decrease from low to high energy levels in regard to attenuation, CNR and SNR with significantly higher values at 40 and 50 keV, compared to conventional images. The 70 keV MonoE was comparable to conventional poly-energetic reconstruction (p>=0.99). Subjective analysis displayed best image quality for the 70 keV MonoE reconstruction level in both phases at fixed standard window presets and at 40 keV if window settings could be adjusted. CONCLUSION: SDCT derived low keV MonoE showed markedly increased CNR and SNR values due to constantly low image noise values over the whole energy spectrum from 40 to 200 keV. PMID- 28837643 TI - Source attribution of human campylobacteriosis at the point of exposure by combining comparative exposure assessment and subtype comparison based on comparative genomic fingerprinting. AB - Human campylobacteriosis is a common zoonosis with a significant burden in many countries. Its prevention is difficult because humans can be exposed to Campylobacter through various exposures: foodborne, waterborne or by contact with animals. This study aimed at attributing campylobacteriosis to sources at the point of exposure. It combined comparative exposure assessment and microbial subtype comparison with subtypes defined by comparative genomic fingerprinting (CGF). It used isolates from clinical cases and from eight potential exposure sources (chicken, cattle and pig manure, retail chicken, beef, pork and turkey meat, and surface water) collected within a single sentinel site of an integrated surveillance system for enteric pathogens in Canada. Overall, 1518 non-human isolates and 250 isolates from domestically-acquired human cases were subtyped and their subtype profiles analyzed for source attribution using two attribution models modified to include exposure. Exposure values were obtained from a concurrent comparative exposure assessment study undertaken in the same area. Based on CGF profiles, attribution was possible for 198 (79%) human cases. Both models provide comparable figures: chicken meat was the most important source (65 69% of attributable cases) whereas exposure to cattle (manure) ranked second (14 19% of attributable cases), the other sources being minor (including beef meat). In comparison with other attributions conducted at the point of production, the study highlights the fact that Campylobacter transmission from cattle to humans is rarely meat borne, calling for a closer look at local transmission from cattle to prevent campylobacteriosis, in addition to increasing safety along the chicken supply chain. PMID- 28837642 TI - Hot-spot identification on a broad class of proteins and RNA suggest unifying principles of molecular recognition. AB - Chemically diverse fragments tend to collectively bind at localized sites on proteins, which is a cornerstone of fragment-based techniques. A central question is how general are these strategies for predicting a wide variety of molecular interactions such as small molecule-protein, protein-protein and protein-nucleic acid for both experimental and computational methods. To address this issue, we recently proposed three governing principles, (1) accurate prediction of fragment macromolecule binding free energy, (2) accurate prediction of water-macromolecule binding free energy, and (3) locating sites on a macromolecule that have high affinity for a diversity of fragments and low affinity for water. To test the generality of these concepts we used the computational technique of Simulated Annealing of Chemical Potential to design one small fragment to break the RecA RecA protein-protein interaction and three fragments that inhibit peptide deformylase via water-mediated multi-body interactions. Experiments confirm the predictions that 6-hydroxydopamine potently inhibits RecA and that PDF inhibition quantitatively tracks the water-mediated binding predictions. Additionally, the principles correctly predict the essential bound waters in HIV Protease, the surprisingly extensive binding site of elastase, the pinpoint location of electron transfer in dihydrofolate reductase, the HIV TAT-TAR protein-RNA interactions, and the MDM2-MDM4 differential binding to p53. The experimental confirmations of highly non-obvious predictions combined with the precise characterization of a broad range of known phenomena lend strong support to the generality of fragment-based methods for characterizing molecular recognition. PMID- 28837644 TI - Prickle1 regulates neurite outgrowth of apical spiral ganglion neurons but not hair cell polarity in the murine cochlea. AB - In the mammalian organ of Corti (OC), the stereocilia on the apical surface of hair cells (HCs) are uniformly organized in a neural to abneural axis (or medial laterally). This organization is regulated by planar cell polarity (PCP) signaling. Mutations of PCP genes, such as Vangl2, Dvl1/2, Celsr1, and Fzd3/6, affect the formation of HC orientation to varying degrees. Prickle1 is a PCP signaling gene that belongs to the prickle / espinas / testin family. Prickle1 protein is shown to be asymmetrically localized in the HCs of the OC, and this asymmetric localization is associated with loss of PCP in Smurf mutants, implying that Prickle1 is involved in HC PCP development in the OC. A follow-up study found no PCP polarity defects after loss of Prickle1 (Prickle1-/-) in the cochlea. We show here strong Prickle1 mRNA expression in the spiral ganglion by in situ hybridization and beta-Gal staining, and weak expression in the OC by beta-Gal staining. Consistent with this limited expression in the OC, cochlear HC PCP is unaffected in either Prickle1C251X/C251X mice or Prickle1f/f; Pax2-cre conditional null mice. Meanwhile, type II afferents of apical spiral ganglion neurons (SGN) innervating outer hair cells (OHC) have unusual neurite growth. In addition, afferents from the apex show unusual collaterals in the cochlear nuclei that overlap with basal turn afferents. Our findings argue against the role of Prickle1 in regulating hair cell polarity in the cochlea. Instead, Prickle1 regulates the polarity-related growth of distal and central processes of apical SGNs. PMID- 28837645 TI - Identification of burden hotspots and risk factors for cholera in India: An observational study. AB - BACKGROUND: Even though cholera has existed for centuries and many parts of the country have sporadic, endemic and epidemic cholera, it is still an under recognized health problem in India. A Cholera Expert Group in the country was established to gather evidence and to prepare a road map for control of cholera in India. This paper identifies cholera burden hotspots and factors associated with an increased risk of the disease. METHODOLOGY/PRINCIPLE FINDINGS: We acquired district level data on cholera case reports of 2010-2015 from the Integrated Disease Surveillance Program. Socioeconomic characteristics and coverage of water and sanitation was obtained from the 2011 census. Spatial analysis was performed to identify cholera hotspots, and a zero-inflated Poisson regression was employed to identify the factors associated with cholera and predicted case count in the district. 27,615 cholera cases were reported during the 6-year period. Twenty-four of 36 states of India reported cholera during these years, and 13 states were classified as endemic. Of 641 districts, 78 districts in 15 states were identified as "hotspots" based on the reported cases. On the other hand, 111 districts in nine states were identified as "hotspots" from model-based predicted number of cases. The risk for cholera in a district was negatively associated with the coverage of literate persons, households using treated water source and owning mobile telephone, and positively associated with the coverage of poor sanitation and drainage conditions and urbanization level in the district. CONCLUSIONS/SIGNIFICANCE: The study reaffirms that cholera continues to occur throughout a large part of India and identifies the burden hotspots and risk factors. Policymakers may use the findings of the article to develop a roadmap for prevention and control of cholera in India. PMID- 28837646 TI - Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants. AB - BACKGROUND: Recent experimental and epidemiological studies have suggested that osteoprotegerin, a key regulator in bone metabolism, may be involved in vascular calcification and atherosclerosis. Our aim was to reliably quantify the associations of osteoprotegerin concentration and incidence of first-ever cardiovascular disease outcomes in the general population. METHODS: Using the electronic databases MEDLINE, EMBASE and Web of Science (January 1975 and April 2017, no language restrictions), nine relevant studies were identified involving a total of 26,442 participants recruited from the general population. Over a mean follow-up of 8.5 years, 2,160 cardiovascular disease, 2,123 coronary heart disease, and 1,102 stroke outcomes were recorded. Study-specific risk ratios were combined with random-effects meta-analysis. RESULTS: When comparing individuals in the top with those in the bottom third of osteoprotegerin concentration, the combined risk ratio was 1.83 (95% confidence interval: 1.46, 2.30; P<0.001; I2 = 76.8%) for cardiovascular disease, 1.72 for coronary heart disease (1.26, 2.37; P = 0.001; I2 = 83.5%), and 1.58 for stroke (1.18, 2.12; P = 0.002; I2 = 65.2%). Associations appeared stronger at younger age (P = 0.018 for cardiovascular disease), in studies that did not employ statistical adjustment (P = 0.023 for cardiovascular disease and 0.018 for coronary heart disease), and potentially in studies that measured osteoprotegerin in plasma rather than in serum (P = 0.005 for cardiovascular disease and 0.018 for coronary heart disease). Magnitudes of associations did not differ according to the proportion of males, geographical region, or osteoprotegerin assay manufacturer. There was no evidence for publication bias for any of the outcomes assessed (all P>0.05). CONCLUSIONS: Elevated osteoprotegerin concentration is associated with an increased risk of incident cardiovascular disease in the general population. The mechanisms underlying this observation deserve further investigation. PMID- 28837647 TI - Nitrogen uptake and assimilation in proliferating embryogenic cultures of Norway spruce-Investigating the specific role of glutamine. AB - Somatic embryogenesis is an in vitro system employed for plant propagation and the study of embryo development. Nitrogen is essential for plant growth and development and, hence, the production of healthy embryos during somatic embryogenesis. Glutamine has been shown to increase plant biomass in many in vitro applications, including somatic embryogenesis. However, several aspects of nitrogen nutrition during somatic embryogenesis remain unclear. Therefore, we investigated the uptake and assimilation of nitrogen in Norway spruce pro embryogenic masses to elucidate some of these aspects. In our study, addition of glutamine had a more positive effect on growth than inorganic nitrogen. The nitrogen uptake appeared to be regulated, with a strong preference for glutamine; 67% of the assimilated nitrogen in the free amino acid pool originated from glutamine-nitrogen. Glutamine addition also relieved the apparently limited metabolism (as evidenced by the low concentration of free amino acids) of pro embryogenic masses grown on inorganic nitrogen only. The unusually high alanine concentration in the presence of glutamine, suggests that alanine biosynthesis was involved in alleviating these constraints. These findings inspire further studies of nitrogen nutrition during the somatic embryogenesis process; identifying the mechanism(s) that govern glutamine enhancement of pro-embryogenic masses growth is especially important in this regard. PMID- 28837648 TI - Enhanced rhamnolipid production by Pseudomonas aeruginosa overexpressing estA in a simple medium. AB - A modified Pseudomonas aeruginosa strain capable of overexpressing the estA gene, an encoding gene for a membrane-bound esterase, was constructed and its rhamnolipid (RML) production was studied. Fermentations using wild-type (WT) and modified P. aeruginosa strains were conducted until exhaustion of glycerol in Medium Salt Production, using two different C/N ratios. At a C/N of 83.2, the modified strain produced up to 3.9 times more RMLs than the WT, yielding a maximum concentration of 14.62 g/L RML when measured by HPLC and 22 g/L by the orcinol assay. Cell-free supernatant from the modified strain reduced surface tension to 29.4 mN/m and had a CMC of 240 mg/L and CMD of 56.05. This is the first report on the construction of an estA-based recombinant strain for RML production. PMID- 28837649 TI - Integrative analysis for the discovery of lung cancer serological markers and validation by MRM-MS. AB - Non-small-cell lung cancer (NSCLC) constitutes approximately 80% of all diagnosed lung cancers, and diagnostic markers detectable in the plasma/serum of NSCLC patients are greatly needed. In this study, we established a pipeline for the discovery of markers using 9 transcriptome datasets from publicly available databases and profiling of six lung cancer cell secretomes. Thirty-one out of 312 proteins that overlapped between two-fold differentially expressed genes and identified cell secretome proteins were detected in the pooled plasma of lung cancer patients. To quantify the candidates in the serum of NSCLC patients, multiple-reaction-monitoring mass spectrometry (MRM-MS) was performed for five candidate biomarkers. Finally, two potential biomarkers (BCHE and GPx3; AUC = 0.713 and 0.673, respectively) and one two-marker panel generated by logistic regression (BCHE/GPx3; AUC = 0.773) were identified. A validation test was performed by ELISA to evaluate the reproducibility of GPx3 and BCHE expression in an independent set of samples (BCHE and GPx3; AUC = 0.630 and 0.759, respectively, BCHE/GPx3 panel; AUC = 0.788). Collectively, these results demonstrate the feasibility of using our pipeline for marker discovery and our MRM-MS platform for verifying potential biomarkers of human diseases. PMID- 28837650 TI - Structure and properties of virions and virus-like particles derived from the coat protein of Alternanthera mosaic virus. AB - Plant viruses and their virus-like particles (VLPs) have a lot of advantages for biotechnological applications including complete safety for humans. Alternanthera mosaic virus (AltMV) is a potentially promising object for design of novel materials. The 3D structures of AltMV virions and its VLPs were obtained by single particle EM at ~13A resolution. The comparison of the reconstructions and a trypsin treatment revealed that AltMV CPs possesses a different fold in the presence (virions) and absence of viral RNA (VLPs). For the first time, the structure of morphologically similar virions and virus-like particles based on the coat protein of a helical filamentous plant virus is shown to be different. Despite this, both AltMV virions and VLPs are stable in a wide range of conditions. To provide a large amount of AltMV for biotechnology usage the isolation procedure was modified. PMID- 28837651 TI - Difference of polymorphism VEGF-gene rs699947 in Indonesian chronic liver disease population. AB - BACKGROUND: The VEGF gene polymorphism rs699947 related to clinical pathology, mortality, and recurrence of HCC. Few studies mentioned an association between VEGF gene polymorphisms with illness progression in chronic liver disease. We aimed to explore differences of VEGF gene polymorphism rs699947 in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma patients in Indonesian population. METHODS: A cross-sectional study with consecutive sampling and without matching was performed during a 3 years period (2011-2014) at Dr. Sardjito General Hospital Yogyakarta, Indonesia. Blood DNA was sequenced from 123 subjects with chronic liver diseases [39 chronic hepatitis (CH), 39 liver cirrhosis (LC), and 45 hepatocellular carcinoma (HCC)]. 59 healthy subjects also participated. Using isolated VEGF genes for specific primers for rs699947, blood samples were examined by targeting DNA sequences with Applied Bio systems. All data were analyzed using STATA version 11.0 with significance level at P<0.05. RESULTS: The mean of age in HCC and LC subjects were older than in CH and healthy (P value <0.05); there were more males in LC, HCC and the healthy groups but not in CH (P>0.05). HBV was the dominant etiology in HCC, LC, and CH besides HCV and non HBV-HCV (P<0.05). There were significant differences in the SNP -2578 distributions of allele C compared to allele A in all subjects (healthy vs. LC, and HCC; LC vs. CH (P<0.05), but no significant difference A>C vs. C>C, and genotypes distribution. Proportion of SNP -2578 A>C vs. C>C CH 1.8:1; HCC 1.4:1; healthy 1.7:1; but its proportion in LC was inversed (1:1.2). Genotype A was low in all subjects (5%-11%). Significant difference of allele distribution was found in healthy vs. LC, and HCC; CH vs. LC. Based on HWE analyses, distribution of allele C was dominant. There were not significant differences in deletion, insertion-deletion at -2547 until -2526, and haplotype (Ht) CCGACCCC (P>0.05). The OR analyses of allele and SNP showed that allele A can be a predictor of disease progression in LC to HCC (OR 2.26) and healthy to LC (OR 1.65); and SNP A>C also can be a predictor in healthy to HCC (OR 1.41) and CH (OR 1.14). CONCLUSION: The occurrence of allele A and SNP A>C VEGF gene (-2578) might predict illness progression from healthy to CH, LC or HCC and LC to HCC. PMID- 28837652 TI - An infrared optical pacing system for screening cardiac electrophysiology in human cardiomyocytes. AB - Human cardiac myocytes derived from pluripotent stem cells (hCM) have invigorated interest in genetic disease mechanisms and cardiac safety testing; however, the technology to fully assess electrophysiological function in an assay that is amenable to high throughput screening has lagged. We describe a fully contactless system using optical pacing with an infrared (IR) laser and multi-site high fidelity fluorescence imaging to assess multiple electrophysiological parameters from hCM monolayers in a standard 96-well plate. Simultaneous multi-site action potentials (FluoVolt) or Ca2+ transients (Fluo4-AM) were measured, from which high resolution maps of conduction velocity and action potential duration (APD) were obtained in a single well. Energy thresholds for optical pacing were determined for cell plating density, laser spot size, pulse width, and wavelength and found to be within ranges reported previously for reliable pacing. Action potentials measured using FluoVolt and a microelectrode exhibited the same morphology and rate of depolarization. Importantly, we show that this can be achieved accurately with minimal damage to hCM due to optical pacing or fluorescence excitation. Finally, using this assay we demonstrate that hCM exhibit reproducible changes in repolarization and impulse conduction velocity for Flecainide and Quinidine, two well described reference compounds. In conclusion, we demonstrate a high fidelity electrophysiological screening assay that incorporates optical pacing with IR light to control beating rate of hCM monolayers. PMID- 28837653 TI - Computational investigation of Amyloid-beta-induced location- and subunit specific disturbances of NMDAR at hippocampal dendritic spine in Alzheimer's disease. AB - In Alzheimer's disease (AD), dysregulation of intracellular Ca2+ signalling has been observed as an early event prior to the presence of clinical symptoms and is believed to be a crucial factor contributing to AD pathogenesis. Amyloid-beta oligomers (AbetaOs) disturb the N-methyl-D-aspartate receptor (NMDAR)-mediated postsynaptic Ca2+ signalling in response to presynaptic stimulation by increasing the availability of extracellular glutamate as well as directly disturbing the NMDARs. The abnormal Ca2+ response can further lead to impairments in long-term potentiation (LTP), an important process in memory formation. In this study, we develop a mathematical model of a CA1 pyramidal dendritic spine and conduct computational experiments. We use this model to mimic alterations by AbetaOs under AD conditions to investigate how they are involved in the Ca2+ dysregulation in the dendritic spine. The alterations in glutamate availability, as well as NMDAR availability and activity, are studied both individually and globally. The simulation results suggest that alterations in glutamate availability mostly affect the synaptic response and have limited effects on the extrasynaptic receptors. Moreover, overactivation of extrasynaptic NMDARs in AD is unlikely to be induced by presynaptic stimulation, but by upregulation of the resting level of glutamate, possibly resulting from these alterations. Furthermore, internalisation of synaptic NR2A-NMDAR shows greater damage to the postsynaptic Ca2+ response in comparison with the internalisation of NR2B-NMDARs; thus, the suggested neuroprotective role of the latter is very limited during synaptic transmission in AD. We integrate a CaMKII state transition model with the Ca2+ model to further study the effects of alterations of NMDARs in the CaMKII state transition, an important downstream event in the early phase of LTP. The model reveals that cooperation between NR2A- and NR2B-NMDAR is required for LTP induction. Under AD conditions, internalisation of membrane NMDARs is suggested to be the cause of the loss of synapse numbers by disrupting CaMKII NMDAR formation. PMID- 28837654 TI - Immune characterization of the HBHA-specific response in Mycobacterium tuberculosis-infected patients with or without HIV infection. AB - INTRODUCTION: RD1-based Interferon-gamma Release Assays (IGRAs) cannot distinguish latent from active tuberculosis (TB) disease. Conversely, a positive response to heparin-binding haemagglutinin (HBHA)-based IGRAs, among TB-infected subjects, correlates with Mycobacterium tuberculosis (Mtb) containment and low risk of TB progression. The aim of this study was to characterize HBHA-immune responses in HIV-infected and uninfected subjects with active TB or latent TB infection (LTBI). METHODS: 49 subjects were prospectively enrolled: 22 HIV uninfected (13 TB, 9 LTBI) and 27 HIV-infected (12 HIV-TB, 15 HIV-LTBI). Whole blood and peripheral blood mononuclear cells were stimulated with HBHA and RD1 antigens. Interferon (IFN)gamma release was evaluated by ELISA whereas cytokine profile [IFNgamma, tumor necrosis (TNF)alpha, interleukin (IL)2] and phenotype (CD45RA, CCR7) by flow cytometry. RESULTS: Among LTBI individuals, HBHA stimulation induced IFNgamma release in all the HIV-uninfected, while, only 4/15 HIV-infected responded. Within the active TB, only 5/13 HIV-uninfected and 1/12 HIV-TB patients responded. Interestingly, by cytometry we showed that CD4+ T cells response to HBHA was significantly impaired in the HIV-infected subjects with TB or LTBI compared to the HIV-uninfected subjects. The phenotype of HBHA specific CD4 T-cells showed a predominantly central memory (CM) and effector memory (EM) phenotype without differences among the groups. Differently, HBHA specific CD8+ T-cells, showed mainly a CM and naive phenotype in LTBI group while TB, HIV-LTBI and HIV-TB groups were characterized by EM or terminally differentiated phenotypes. Interestingly, differently than what observed for RD1, the cytokine profile of HBHA-specific T-cells evaluated by cytometry showed that the CD4+ T-cells were mostly monofunctional. Conversely, CD8-specific T-cells were mostly monofunctional for both HBHA and RD1 stimulations. CONCLUSIONS: These results characterize the impact of HIV infection in CD4- and CD8-specific response to HBHA in both LTBI and TB patients. HIV infection impairs the CD4 response to HBHA and likely this may lead to an impairment of TB control. PMID- 28837655 TI - Northeast African genomic variation shaped by the continuity of indigenous groups and Eurasian migrations. AB - Northeast Africa has a long history of human habitation, with fossil-finds from the earliest anatomically modern humans, and housing ancient civilizations. The region is also the gate-way out of Africa, as well as a portal for migration into Africa from Eurasia via the Middle East and the Arabian Peninsula. We investigate the population history of northeast Africa by genotyping ~3.9 million SNPs in 221 individuals from 18 populations sampled in Sudan and South Sudan and combine this data with published genome-wide data from surrounding areas. We find a strong genetic divide between the populations from the northeastern parts of the region (Nubians, central Arab populations, and the Beja) and populations towards the west and south (Nilotes, Darfur and Kordofan populations). This differentiation is mainly caused by a large Eurasian ancestry component of the northeast populations likely driven by migration of Middle Eastern groups followed by admixture that affected the local populations in a north-to-south succession of events. Genetic evidence points to an early admixture event in the Nubians, concurrent with historical contact between North Sudanese and Arab groups. We estimate the admixture in current-day Sudanese Arab populations to about 700 years ago, coinciding with the fall of Dongola in 1315/1316 AD, a wave of admixture that reached the Darfurian/Kordofanian populations some 400-200 years ago. In contrast to the northeastern populations, the current-day Nilotic populations from the south of the region display little or no admixture from Eurasian groups indicating long-term isolation and population continuity in these areas of northeast Africa. PMID- 28837657 TI - Mycetoma laboratory diagnosis: Review article. AB - Mycetoma is a unique neglected tropical disease caused by a substantial number of microorganisms of fungal or bacterial origins. Identification of the causative organism and the disease extension are the first steps in the management of the affected patients and predicting disease treatment outcome and prognosis. Different laboratory-based diagnostic tools and techniques were developed over the years to determine and identify the causative agents. These include direct microscopy and cytological, histopathological, and immunohistochemical techniques in addition to the classical grain culture. More recently, various molecular based techniques have joined the mycetoma diagnostic armamentarium. The available mycetoma diagnostic techniques are of various specificity and sensitivity rates. Most are invasive, time consuming, and operator dependent, and a combination of them is required to reach a diagnosis. In addition, they need a well-equipped laboratory and are therefore not field friendly. This review aims to provide an update on the laboratory investigations used in the diagnosis of mycetoma. It further aims to assist practising health professionals dealing with mycetoma by outlining the guidelines developed by the Mycetoma Research Centre, University of Khartoum, WHO collaborating centre on mycetoma following a cumulative experience of managing more than 7,700 mycetoma patients. PMID- 28837656 TI - In silico analysis of protein toxin and bacteriocins from Lactobacillus paracasei SD1 genome and available online databases. AB - Lactobacillus paracasei SD1 is a potential probiotic strain due to its ability to survive several conditions in human dental cavities. To ascertain its safety for human use, we therefore performed a comprehensive bioinformatics analysis and characterization of the bacterial protein toxins produced by this strain. We report the complete genome of Lactobacillus paracasei SD1 and its comparison to other Lactobacillus genomes. Additionally, we identify and analyze its protein toxins and antimicrobial proteins using reliable online database resources and establish its phylogenetic relationship with other bacterial genomes. Our investigation suggests that this strain is safe for human use and contains several bacteriocins that confer health benefits to the host. An in silico analysis of protein-protein interactions between the target bacteriocins and the microbial proteins gtfB and luxS of Streptococcus mutans was performed and is discussed here. PMID- 28837658 TI - Dorsal root ganglia hypertrophy as in vivo correlate of oxaliplatin-induced polyneuropathy. AB - PURPOSE: To investigate in vivo morphological and functional correlates of oxaliplatin-induced peripheral neuropathy (OXA-PNP) by magnetic resonance neurography (MRN). METHODS: Twenty patients (7 female, 13 male, 58.9+/-10.0 years) with mild to moderate OXA-PNP and 20 matched controls (8 female, 12 male, 55.7+/-15.6 years) were prospectively enrolled. All patients underwent a detailed neurophysiological examination prior to neuroimaging. A standardized imaging protocol at 3.0 Tesla included the lumbosacral plexus and both sciatic nerves and their branches using T2-weighted fat-saturated sequences and diffusion tensor imaging. Quantitative assessment included volumetry of the dorsal root ganglia (DRG), sciatic nerve normalized T2 (nT2) signal and caliber, and fractional anisotropy (FA), mean diffusivity (MD), axial (AD) and radial diffusivity (RD). Additional qualitative evaluation of sciatic, peroneal, and tibial nerves evaluated the presence, degree, and distribution of nerve lesions. RESULTS: DRG hypertrophy in OXA-PNP patients (207.3+/-47.7mm3 vs. 153.0+/-47.1mm3 in controls, p = 0.001) was found as significant morphological correlate of the sensory neuronopathy. In contrast, peripheral nerves only exhibited minor morphological alterations qualitatively. Quantitatively, sciatic nerve caliber (27.3+/-6.7mm2 vs. 27.4+/-7.4mm2, p = 0.80) and nT2 signal were not significantly changed in patients (1.32+/-0.22 vs. 1.22+/-0.26, p = 0.16). AD, RD, and MD showed a non significant decrease in patients, while FA was unchanged. CONCLUSION: OXA-PNP manifests with morphological and functional correlates that can be detected in vivo by MRN. We report hypertrophy of the DRG that stands in contrast to experimental and postmortem studies. DRG volume should be further investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies. PMID- 28837659 TI - In vivo cloning of up to 16 kb plasmids in E. coli is as simple as PCR. AB - The precise assembly of defined DNA sequences into plasmids is an essential task in bioscience research. While a number of molecular cloning techniques have been developed, many methods require specialized expensive reagents or laborious experimental procedure. Not surprisingly, conventional cloning techniques based on restriction digestion and ligation are still commonly used in routine DNA cloning. Here, we describe a simple, fast, and economical cloning method based on RecA- and RecET-independent in vivo recombination of DNA fragments with overlapping ends using E. coli. All DNA fragments were prepared by a 2 consecutive PCR procedure with Q5 DNA polymerase and used directly for transformation resulting in 95% cloning accuracy and zero background from parental template plasmids. Quantitative relationships were established between cloning efficiency and three factors-the length of overlapping nucleotides, the number of DNA fragments, and the size of target plasmids-which can provide general guidance for selecting in vivo cloning parameters. The method may be used to accurately assemble up to 5 DNA fragments with 25 nt overlapping ends into relatively small plasmids, and 3 DNA fragments into plasmids up to 16 kb in size. The whole cloning procedure may be completed within 2 days by a researcher with little training in cloning. The combination of high accuracy and zero background eliminates the need for screening a large number of colonies. The method requires no enzymes other than Q5 DNA polymerase, has no sequence restriction, is highly reliable, and represents one of the simplest, fastest, and cheapest cloning techniques available. Our method is particularly suitable for common cloning tasks in the lab where the primary goal is to quickly generate a plasmid with a pre-defined sequence at low costs. PMID- 28837660 TI - A recombinant multi-antigen vaccine with broad protection potential against avian pathogenic Escherichia coli. AB - Chickens are a major source of protein worldwide, yet infectious diseases continue to threaten the poultry industry. Avian pathogenic Escherichia coli (APEC), a subgroup of extraintestinal pathogenic E. coli (ExPEC), causes colibacillosis in chickens resulting in economic loss because of treatment, condemnation of products, and death. In this study, we evaluated a recombinant antigens (rAg) vaccine combining common ExPEC surface proteins EtsC, OmpA, OmpT, and TraT for broad protective potential against APEC infections in chickens. The specific objectives were to evaluate antibody (serum) and cytokines (lymphoid organs) responses to vaccination; in vitro bactericidal ability of serum and splenocytes against multiple APEC serotypes; and in vivo protection against APEC challenge in chickens. Groups of four-day old chickens (N = 10) were vaccinated twice (two-week interval) subcutaneously with rAgs alone or in combination and CpG adjuvant or PBS (control). IgY antibody in the serum and mRNA expression of IL-1beta, IL-6, IL-18, IFN-gamma, IL-4, IFN-beta, and IL-8 in bursa, spleen, and thymus were measured using ELISA and RT-qPCR, respectively. Serum and splenocytes were tested for their bactericidal ability in vitro against multiple APEC isolates. Vaccinated and non-vaccinated chickens were challenged with 108 CFU of APEC-O2 via air sac at 31 days post first vaccination. Vaccine protection was determined by the decrease of bacterial loads in blood and organs (lung, heart, spleen, and liver), as well as gross colibacillosis lesion scores in air sac, heart, and liver. Vaccination significantly (P < 0.05) elicited IgY against specific antigens, induced immune related mRNA expression in the spleen and bursa, reduced in vitro growth of multiple APEC serotypes, and decreased bacterial loads in the heart and spleen, and gross lesion scores of the air sac, heart and liver in chickens. The vaccine reported may be used to provide broad protection against APEC strains, increasing animal welfare and food production. PMID- 28837662 TI - Mass drug administration for the prevention human strongyloidiasis should consider concomitant treatment of dogs. PMID- 28837661 TI - Contrasting effects of copper limitation on the photosynthetic apparatus in two strains of the open ocean diatom Thalassiosira oceanica. AB - There is an intricate interaction between iron (Fe) and copper (Cu) physiology in diatoms. However, strategies to cope with low Cu are largely unknown. This study unveils the comprehensive restructuring of the photosynthetic apparatus in the diatom Thalassiosira oceanica (CCMP1003) in response to low Cu, at the physiological and proteomic level. The restructuring results in a shift from light harvesting for photochemistry-and ultimately for carbon fixation-to photoprotection, reducing carbon fixation and oxygen evolution. The observed decreases in the physiological parameters Fv/Fm, carbon fixation, and oxygen evolution, concomitant with increases in the antennae absorption cross section (sigmaPSII), non-photochemical quenching (NPQ) and the conversion factor (phie:C/etaPSII) are in agreement with well documented cellular responses to low Fe. However, the underlying proteomic changes due to low Cu are very different from those elicited by low Fe. Low Cu induces a significant four-fold reduction in the Cu-containing photosynthetic electron carrier plastocyanin. The decrease in plastocyanin causes a bottleneck within the photosynthetic electron transport chain (ETC), ultimately leading to substantial stoichiometric changes. Namely, 2 fold reduction in both cytochrome b6f complex (cytb6f) and photosystem II (PSII), no change in the Fe-rich PSI and a 40- and 2-fold increase in proteins potentially involved in detoxification of reactive oxygen species (ferredoxin and ferredoxin:NADP+ reductase, respectively). Furthermore, we identify 48 light harvesting complex (LHC) proteins in the publicly available genome of T. oceanica and provide proteomic evidence for 33 of these. The change in the LHC composition within the antennae in response to low Cu underlines the shift from photochemistry to photoprotection in T. oceanica (CCMP1003). Interestingly, we also reveal very significant intra-specific strain differences. Another strain of T. oceanica (CCMP 1005) requires significantly higher Cu concentrations to sustain both its maximal and minimal growth rate compared to CCMP 1003. Under low Cu, CCMP 1005 decreases its growth rate, cell size, Chla and total protein per cell. We argue that the reduction in protein per cell is the main strategy to decrease its cellular Cu requirement, as none of the other parameters tested are affected. Differences between the two strains, as well as differences between the well documented responses to low Fe and those presented here in response to low Cu are discussed. PMID- 28837663 TI - Combining FMEA with DEMATEL models to solve production process problems. AB - Failure mode and effects analysis (FMEA) is an analysis tool for identifying and preventing flaws or defects in products during the design and process planning stage, preventing the repeated occurrence of problems, reducing the effects of these problems, enhancing product quality and reliability, saving costs, and improving competitiveness. However, FMEA can only analyze one influence factor according to its priority, rendering this method ineffective for systems containing multiple FMs whose effects are simultaneous or interact with one another. Accordingly, when FMEA fails to identify the influence factors and the factors being influenced, the most crucial problems may be placed in lower priority or remain unresolved. Decision-Making Trial and Evaluation Laboratory (DEMATEL) facilitates the determination of cause and effect factors; by identifying the causal factors that should be prioritized, prompt and effective solutions to core problems can be derived, thereby enhancing performance. Using the photovoltaic cell manufacturing industry in China as the research target, the present study combined FMEA with DEMATEL to amend the flaws of FMEA and enhance its effectiveness. First, FMEA was used to identify items requiring improvement. Then, DEMATEL was employed to examine the interactive effects and causal relationships of these items. Finally, the solutions to the problems were prioritized. The proposed method effectively combined the advantages of FMEA and DEMATEL to facilitate the identification of core problems and prioritization of solutions in the Chinese photovoltaic cell industry. PMID- 28837664 TI - The unbearable emptiness of tweeting-About journal articles. AB - Enthusiasm for using Twitter as a source of data in the social sciences extends to measuring the impact of research with Twitter data being a key component in the new altmetrics approach. In this paper, we examine tweets containing links to research articles in the field of dentistry to assess the extent to which tweeting about scientific papers signifies engagement with, attention to, or consumption of scientific literature. The main goal is to better comprehend the role Twitter plays in scholarly communication and the potential value of tweet counts as traces of broader engagement with scientific literature. In particular, the pattern of tweeting to the top ten most tweeted scientific dental articles and of tweeting by accounts is examined. The ideal that tweeting about scholarly articles represents curating and informing about state-of-the-art appears not to be realized in practice. We see much presumably human tweeting almost entirely mechanical and devoid of original thought, no evidence of conversation, tweets generated by monomania, duplicate tweeting from many accounts under centralized professional management and tweets generated by bots. Some accounts exemplify the ideal, but they represent less than 10% of tweets. Therefore, any conclusions drawn from twitter data is swamped by the mechanical nature of the bulk of tweeting behavior. In light of these results, we discuss the compatibility of Twitter with the research enterprise as well as some of the financial incentives behind these patterns. PMID- 28837665 TI - The effectiveness of computerised decision support on antibiotic use in hospitals: A systematic review. AB - BACKGROUND: Inappropriate antimicrobial use has been shown to be an important determinant of the emergence of antimicrobial resistance (AMR). Health information technology (HIT) in the form of Computerised Decision Support (CDS) represents an option for improving antimicrobial prescribing and containing AMR. OBJECTIVES: To evaluate the evidence for CDS in improving quantitative and qualitative measures of antibiotic prescribing in inpatient hospital settings. METHODS: A systematic literature search was conducted of articles published from inception to 20th December 2014 using eight electronic databases: MEDLINE, EMBASE, PUBMED, Web of Science, CINAHL, Cochrane Library, HMIC and PsychINFo. An updated systematic literature search was conducted from January 1st 2015 to October 1st 2016 using PUBMED. The search strategy used combinations of the following terms: (electronic prescribing) OR (clinical decision support) AND (antibiotic or antibacterial or antimicrobial) AND (hospital or secondary care or inpatient). Studies were evaluated for quality using a 10-point rating scale. RESULTS: Eighty-one studies were identified matching the inclusion criteria. Seven outcome measures were evaluated: adequacy of antibiotic coverage, mortality, volume of antibiotic usage, length of stay, antibiotic cost, compliance with guidelines, antimicrobial resistance, and CDS implementation and uptake. Meta-analysis of pooled outcomes showed CDS significantly improved the adequacy of antibiotic coverage (n = 13; odds ratio [OR], 2.11 [95% CI, 1.67 to 2.66, p <= 0.00001]). Also, CDS was associated with marginally lowered mortality (n = 20; OR, 0.85 [CI, 0.75 to 0.96, p = 0.01]). CDS was associated with lower antibiotic utilisation, increased compliance with antibiotic guidelines and reductions in antimicrobial resistance. Conflicting effects of CDS on length of stay, antibiotic costs and system uptake were also noted. CONCLUSIONS: CDS has the potential to improve the adequacy of antibiotic coverage and marginally decrease mortality in hospital-related settings. PMID- 28837666 TI - Tumor necrosis factor-alpha blockade treatment decreased CD154 (CD40-ligand) expression in rheumatoid arthritis. AB - CONTEXTS: CD154 (commonly referred to as CD40-ligand) is a critical T cell factor that participates in the pathogenesis of autoimmune and is over-expressed in rheumatoid arthritis (RA). TNF-alpha blockade treatment had dramatic efficacy in RA. OBJECTIVE: To investigate whether TNF-alpha blockade treatment can inhibit CD154 expression in RA. METHODS: Blood samples were collected from 33 patients with rheumatoid arthritis before and 3 months after TNF-alpha blockade treatment. Clinical serological data determined by standard assays and T cell CD154 expression levels determined by flow cytometry were statistically analyzed for these two time points. RESULTS: The percentage of CD154 expression on gated CD4+ T cells of PBMCs from RA patients after 3 months TNF-alpha blockade treatment was significantly lower than before treatment (2.94 +/- 3.21% vs. 7.21 +/- 5.64%; p = 0.0001). The disease activity and anti-CCP antibody levels were also significantly reduced after TNF-alpha blockade treatment. The CD154 expression levels were positively correlated with disease activity index DAS28, and CRP. The post-stimulated CD154 expression percentage of purified CD4+ T cells between baseline and after TNF-alpha blockade treatment was not significantly different (p = 0.221). Baseline CD154 levels were positively correlated with treatment induced changes in DAS28 (p = 0.014; r2 = 0.187). CONCLUSIONS: TNF-alpha blockade treatment significantly decreased the CD154 expression on CD4+ T cells, disease activity and anti-CCP antibody simultaneously in RA patients. However TNF-alpha blockade did not impair T cell capacity to express CD154 after stimulation. These results suggest that decreased CD154 expression after TNF-alpha blockade may be due to decreased RA disease activity but not direct inhibition of CD154 responsiveness of T cells. PMID- 28837667 TI - Influenza NS1 directly modulates Hedgehog signaling during infection. AB - The multifunctional NS1 protein of influenza A viruses suppresses host cellular defense mechanisms and subverts other cellular functions. We report here on a new role for NS1 in modifying cell-cell signaling via the Hedgehog (Hh) pathway. Genetic epistasis experiments and FRET-FLIM assays in Drosophila suggest that NS1 interacts directly with the transcriptional mediator, Ci/Gli1. We further confirmed that Hh target genes are activated cell-autonomously in transfected human lung epithelial cells expressing NS1, and in infected mouse lungs. We identified a point mutation in NS1, A122V, that modulates this activity in a context-dependent fashion. When the A122V mutation was incorporated into a mouse adapted influenza A virus, it cell-autonomously enhanced expression of some Hh targets in the mouse lung, including IL6, and hastened lethality. These results indicate that, in addition to its multiple intracellular functions, NS1 also modifies a highly conserved signaling pathway, at least in part via cell autonomous activities. We discuss how this new Hh modulating function of NS1 may influence host lethality, possibly through controlling cytokine production, and how these new insights provide potential strategies for combating infection. PMID- 28837668 TI - Prominent features of the amino acid mutation landscape in cancer. AB - Cancer can be viewed as a set of different diseases with distinctions based on tissue origin, driver mutations, and genetic signatures. Accordingly, each of these distinctions have been used to classify cancer subtypes and to reveal common features. Here, we present a different analysis of cancer based on amino acid mutation signatures. Non-negative Matrix Factorization and principal component analysis of 29 cancers revealed six amino acid mutation signatures, including four signatures that were dominated by either arginine to histidine (Arg>His) or glutamate to lysine (Glu>Lys) mutations. Sample-level analyses reveal that while some cancers are heterogeneous, others are largely dominated by one type of mutation. Using a non-overlapping set of samples from the COSMIC somatic mutation database, we validate five of six mutation signatures, including signatures with prominent arginine to histidine (Arg>His) or glutamate to lysine (Glu>Lys) mutations. This suggests that our classification of cancers based on amino acid mutation patterns may provide avenues of inquiry pertaining to specific protein mutations that may generate novel insights into cancer biology. PMID- 28837669 TI - Comparison of antibiotic supplementation versus a yeast-based prebiotic on the cecal microbiome of commercial broilers. AB - Prebiotics are defined as fermentable food ingredients that selectively stimulate beneficial bacteria in the lower gastrointestinal tract of the host. The purpose of this study was to assess growth performance of broilers and the cecal microbial populations of an antibiotic, BMD50, supplemented birds compared to broiler chickens fed the prebiotic, Biolex(r) MB40. Weight response data including feed conversion ratios (FCR), carcasses without giblets (WOG), wing, skin, white meat were collected during processing. Extracted DNA from cecal contents was utilized for microbiome analysis via an Illumina Miseq. In conclusion, white meat yield of Biolex(r) MB40 supplemented group exhibited significant improvement compared to both negative control (NC) and BMD50 supplemented groups. In addition, antibiotic significantly decreased level of Lactobacillus in 2 wk compared to other groups. A significantly higher percentage of Campylobacter was observed from the 4 wk old birds treated with antibiotic BMD50 compared to the NC and prebiotic group. Retention of broiler performance and improvement of white meat yield suggest that the prebiotic MB40 appears to be a potential alternative to replace the antibiotic growth promoter. PMID- 28837670 TI - Investigation of potential targets of Porphyromonas CRISPRs among the genomes of Porphyromonas species. AB - The oral bacterial species Porphyromonas gingivalis, a periodontal pathogen, has plastic genomes that may be driven by homologous recombination with exogenous deoxyribonucleic acid (DNA) that is incorporated by natural transformation and conjugation. However, bacteriophages and plasmids, both of which are main resources of exogenous DNA, do not exist in the known P. gingivalis genomes. This could be associated with an adaptive immunity system conferred by clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated (cas) genes in P. gingivalis as well as innate immune systems such as a restriction-modification system. In a previous study, few immune targets were predicted for P. gingivalis CRISPR/Cas. In this paper, we analyzed 51 P. gingivalis genomes, which were newly sequenced, and publicly available genomes of 13 P. gingivalis and 46 other Porphyromonas species. We detected 6 CRISPR/Cas types (classified by sequence similarity of repeat) in P. gingivalis and 12 other types in the remaining species. The Porphyromonas CRISPR spacers with potential targets in the genus Porphyromonas were approximately 23 times more abundant than those with potential targets in other genus taxa (1,720/6,896 spacers vs. 74/6,896 spacers). Porphyromonas CRISPR/Cas may be involved in genome plasticity by exhibiting selective interference against intra- and interspecies nucleic acids. PMID- 28837671 TI - Development of acute hydrocephalus does not change brain tissue mechanical properties in adult rats, but in juvenile rats. AB - INTRODUCTION: Regional changes in brain stiffness were previously demonstrated in an experimental obstructive hydrocephalus juvenile rat model. The open cranial sutures in the juvenile rats have influenced brain compression and mechanical properties during hydrocephalus development and the extent by which closed cranial sutures in adult hydrocephalic rat models affect brain stiffness in-vivo remains unclear. The aims of this study were to determine changes in brain tissue mechanical properties and brain structure size during hydrocephalus development in adult rat with fixed cranial volume and how these changes were related to brain tissue deformation. METHODS: Hydrocephalus was induced in 9 female ten weeks old Sprague-Dawley rats by injecting 60 MUL of a kaolin suspension (25%) into the cisterna magna under anaesthesia. 6 sham-injected age-matched female SD rats were used as controls. MR imaging (9.4T, Bruker) was performed 1 day before and then at 3 days post injection. T2-weighted anatomical MR images were collected to quantify ventricle and brain tissue cross-sectional areas. MR elastography (800 Hz) was used to measure the brain stiffness (G*, shear modulus). RESULTS: Brain tissue in the adult hydrocephalic rats was more compressed than the juvenile hydrocephalic rats because the skulls of the adult hydrocephalic rats were unable to expand like the juvenile rats. In the adult hydrocephalic rats, the cortical gray matter thickness and the caudate-putamen cross-sectional area decreased (Spearman, P < 0.001 for both) but there were no significant changes in cranial cross-sectional area (Spearman, P = 0.35), cortical gray matter stiffness (Spearman, P = 0.24) and caudate-putamen (Spearman, P = 0.11) stiffness. No significant changes in the size of brain structures were observed in the controls. CONCLUSIONS: This study showed that although brain tissue in the adult hydrocephalic rats was severely compressed, their brain tissue stiffness did not change significantly. These results are in contrast with our previous findings in juvenile hydrocephalic rats which had significantly less brain compression (as the brain circumference was able to stretch with the cranium due to the open skull sutures) and had a significant increase in caudate putamen stiffness. These results suggest that change in brain mechanical properties in hydrocephalus is complex and is not solely dependent on brain tissue deformation. Further studies on the interactions between brain tissue stiffness, deformation, tissue oedema and neural damage are necessary before MRE can be used as a tool to track changes in brain biomechanics in hydrocephalus. PMID- 28837672 TI - Cardiac transcriptome profiling of diabetic Akita mice using microarray and next generation sequencing. AB - Although diabetes mellitus (DM) causes cardiomyopathy and exacerbates heart failure, the underlying molecular mechanisms for diabetic cardiomyopathy/heart failure are poorly understood. Insulin2 mutant (Ins2+/-) Akita is a mouse model of T1DM, which manifests cardiac dysfunction. However, molecular changes at cardiac transcriptome level that lead to cardiomyopathy remain unclear. To understand the molecular changes in the heart of diabetic Akita mice, we profiled cardiac transcriptome of Ins2+/- Akita and Ins2+/+ control mice using next generation sequencing (NGS) and microarray, and determined the implications of differentially expressed genes on various heart failure signaling pathways using Ingenuity pathway (IPA) analysis. First, we validated hyperglycemia, increased cardiac fibrosis, and cardiac dysfunction in twelve-week male diabetic Akita. Then, we analyzed the transcriptome levels in the heart. NGS analyses on Akita heart revealed 137 differentially expressed transcripts, where Bone Morphogenic Protein-10 (BMP10) was the most upregulated and hairy and enhancer of split related (HELT) was the most downregulated gene. Moreover, twelve long non-coding RNAs (lncRNAs) were upregulated. The microarray analyses on Akita heart showed 351 differentially expressed transcripts, where vomeronasal-1 receptor-180 (Vmn1r180) was the most upregulated and WD Repeat Domain 83 Opposite Strand (WDR83OS) was the most downregulated gene. Further, miR-101c and H19 lncRNA were upregulated but Neat1 lncRNA was downregulated in Akita heart. Eleven common genes were upregulated in Akita heart in both NGS and microarray analyses. IPA analyses revealed the role of these differentially expressed genes in key signaling pathways involved in diabetic cardiomyopathy. Our results provide a platform to initiate focused future studies by targeting these genes and/or non coding RNAs, which are differentially expressed in Akita hearts and are involved in diabetic cardiomyopathy. PMID- 28837673 TI - Top-down influence on gaze patterns in the presence of social features. AB - Visual saliency maps reflecting locations that stand out from the background in terms of their low-level physical features have proven to be very useful for empirical research on attentional exploration and reliably predict gaze behavior. In the present study we tested these predictions for socially relevant stimuli occurring in naturalistic scenes using eye tracking. We hypothesized that social features (i.e. human faces or bodies) would be processed preferentially over non social features (i.e. objects, animals) regardless of their low-level saliency. To challenge this notion, we included three tasks that deliberately addressed non social attributes. In agreement with our hypothesis, social information, especially heads, was preferentially attended compared to highly salient image regions across all tasks. Social information was never required to solve a task but was regarded nevertheless. More so, after completing the task requirements, viewing behavior reverted back to that of free-viewing with heavy prioritization of social features. Additionally, initial eye movements reflecting potentially automatic shifts of attention, were predominantly directed towards heads irrespective of top-down task demands. On these grounds, we suggest that social stimuli may provide exclusive access to the priority map, enabling social attention to override reflexive and controlled attentional processes. Furthermore, our results challenge the generalizability of saliency-based attention models. PMID- 28837674 TI - Fleet behavior is responsive to a large-scale environmental disturbance: Hypoxia effects on the spatial dynamics of the northern Gulf of Mexico shrimp fishery. AB - The northwestern Gulf of Mexico shelf experiences one of the largest seasonal hypoxic zones in the western hemisphere. Hypoxia (dissolved oxygen, DO <= 2.0 mg.L-1) is most severe from May to August during the height of the Gulf shrimp fishery, but its effects on the fishery are not well known. Prior studies indicate that hypoxia alters the spatial dynamics of shrimp and other species through habitat loss and aggregation in nearby oxygenated refuge habitats. We hypothesized that hypoxia-induced changes in the distribution of shrimp also alter the spatial dynamics of the Gulf shrimp fleet. We integrated data on the geographic distribution of shrimp tows and bottom DO to evaluate the effects of hypoxia on spatial patterns in shrimping effort. Our analyses indicate that shrimping effort declines in low DO waters on both the Texas and Louisiana shelf, but that considerable effort still occurs in low DO waters off Louisiana, likely because riverine nutrients fuel both benthic production and low bottom DO in the same general regions. The response of the shrimp fleet to hypoxia on the Louisiana shelf was complex with shifts in effort inshore, offshore, westward, and eastward of the hypoxic zone, as well as to an oxygenated area between two hypoxia regimes associated with the Mississippi and the Atchafalaya River outflows. In contrast, effort on the Texas shelf mostly shifted offshore in response to low DO but also shifted inshore in some years. Spatial patterns in total shrimping effort were driven primarily by the number of shrimp tows, consistent with aggregation of the fleet outside of hypoxic waters, though tow duration also declined in low DO waters. Overall, our results demonstrate that hypoxia alters the spatial dynamics of the Gulf shrimp fishery with potential consequences for harvest interactions and the economic condition of the fishery. PMID- 28837675 TI - The interplay between maze complexity, colony size, learning and memory in ants while solving a maze: A test at the colony level. AB - Central-place foragers need to explore their immediate habitat in order to reach food. We let colonies of the individually foraging desert ant Cataglyphis niger search for a food reward in a maze. We did so for three tests per day over two successive days and an additional test after a time interval of 4-20 days (seven tests in total). We examined whether the colonies reached the food reward faster, consumed more food and changed the number of workers searching over time, within and between days. Colonies' food-discovery time shortened within and between days, indicating that some workers learnt and became more efficient in moving through the maze. Such workers, however, also forgot and deteriorated in their food-discovery time, leveling off back to initial performance after about two weeks. We used mazes of increasing complexity levels, differing in the potential number of wrong turns. The number of workers searching increased with colony size. Food-discovery time also increased with colony size in complex mazes but not in simple ones, perhaps due to the more frequent interactions among workers in large colonies having to move through narrow routes. Finally, the motivation to solve the maze was probably not only the food reward, because food consumption did not change over time. PMID- 28837676 TI - ALK signaling cascade confers multiple advantages to glioblastoma cells through neovascularization and cell proliferation. AB - Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Here we examined the functional role of the ALK gene in glioblastomas (GBMs). In clinical samples of GBMs, high ALK expression without gene rearrangements or mutations was frequently observed in perivascular lesions, in contrast to the relatively low expression in the perinecrotic areas, which was positively correlated with N-myc and phosphorylated (p) Stat3 scores and Ki-67 labeling indices. ALK immunoreactivity was also found to be associated with neovascular features including vascular co-option and vascular mimicry. In astrocytoma cell lines, cells stably overexpressing full-length ALK showed an increase in expression of pStat3 and pAkt proteins, as well as hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor-A (VEGF-A) mRNAs, in contrast to cells with knockdown of endogenous ALK which showed decreased expression of these molecules. Transfection of the constitutively active form of Stat3 induced an increase in HIF-1alpha promoter activity, and the overexpression of HIF-1alpha in turn resulted in enhancement of VEGF-A promoter activity. In addition, cells with overexpression or knockdown of ALK also showed a tendency toward increased and decreased proliferation, respectively, through changes in expression of pAkt and pStat3. Finally, ALK promoter was significantly activated by transfection of Sox4 and N-myc, which are known to contribute to neuronal properties. These findings therefore suggest that N-myc/Sox4-mediated ALK signaling cascades containing Stat3, Akt, HIF-1alpha, and VEGF-A confer multiple advantages to tumor growth through alterations in neovascularization and cell proliferation in GBMs. PMID- 28837677 TI - Characterization of lincRNA expression in the human retinal pigment epithelium and differentiated induced pluripotent stem cells. AB - Long intervening non-coding RNAs (lincRNAs) are increasingly being implicated as important factors in many aspects of cellular development, function, and disease, but remain poorly understood. In this study, we examine the human retinal pigment epithelium (RPE) lincRNA transcriptome using RNA-Seq data generated from human fetal RPE (fRPE), RPE derived from human induced pluripotent stem cells (iPS RPE), and undifferentiated iPS (iPS). In addition, we determine the suitability of iPS-RPE, from a transcriptome standpoint, as a model for use in future studies of lincRNA structure and function. A comparison of gene and isoform expression across the whole transcriptome shows only minimal differences between all sample types, though fRPE and iPS-RPE show higher concordance than either shows with iPS. Notably, RPE signature genes show the highest degree of fRPE to iPS-RPE concordance, indicating that iPS-RPE cells provide a suitable model for use in future studies. An analysis of lincRNAs demonstrates high concordance between fRPE and iPS-RPE, but low concordance between either RPE and iPS. While most lincRNAs are expressed at low levels (RPKM < 10), there is a high degree of concordance among replicates within each sample type, suggesting the expression is consistent, even at levels subject to high variability. Finally, we identified and annotated 180 putative novel genes in the fRPE samples, a majority of which are also expressed in the iPS-RPE. Overall, this study represents the first characterization of lincRNA expression in the human RPE, and provides a model for studying the role lincRNAs play in RPE development, function, and disease. PMID- 28837678 TI - Clinical utility of the UCSD Performance-Based Skills Assessment-Brief (UPSA-B) in adults living with HIV: Associations with neuropsychological impairment and patient-reported everyday functioning difficulties. AB - OBJECTIVE: Requiring only 10-15 minutes to complete, the UCSD Performance-Based Skills Assessment (UPSA-B) has high clinical utility as a brief measure of functional capacity. This study aimed to validate the UPSA-B in adults living with HIV/AIDS (HIV+), and identify whether the UPSA-B can be used as an indicator of functional dependence in this population. METHOD: One hundred and three HIV+ adults and 91 HIV- adults completed a comprehensive neuropsychological and neuromedical battery, including a self-report measure of functional status (IADL Dependence vs. IADL Independence), an objective measure of functional capacity (UPSA-B), and a self-report measure of mood states including a subscale related to cognitive difficulties (Profile of Mood States [POMS]-Confusion/Bewilderment subscale). RESULTS: HIV+ participants had significantly lower UPSA-B scores than their HIV- counterparts (p = 0.02), although this fell to a trend (p = 0.08) when including covariates. Among the HIV+ group, higher UPSA-B scores were related to better neuropsychological ability, but unrelated to self-reported functional independence. Conversely, UPSA-B scores were unrelated to participant-reported cognitive difficulties on the POMS Confusion/Bewilderment subscale. An ROC curve was generated to determine the optimal UPSA-B value for discriminating between normal neuropsychological functioning versus neuropsychological impairment, with results indicating an optimal cutoff of 79. The UPSA-B identified HIV+ persons with cognitive impairment with 70.9% accuracy. CONCLUSIONS: The UPSA-B was able to differentiate neuropsychological impairment from no impairment among HIV+ participants and holds promise as a clinical screening tool in this population. However, indicators of functional disability among adults living with HIV is still not well understood and is likely multifactorial in nature. These data highlight the complex interplay between objective functional capacity, neurocognitive ability, subjective cognitive symptoms, and functional dependence. PMID- 28837679 TI - Influence of coronary architecture on the variability in myocardial infarction induced by coronary ligation in rats. AB - It has been shown that the size of myocardial infarction in rats created by coronary ligation technique is not uniform, varying from 4% to 65%. We hypothesized that infarct size variability induced by coronary artery ligation might be caused by coronary artery branching pattern. Coronary artery angiography was performed in 50 normal Lewis rats and in chronic myocardial infarction models in which coronary artery was ligated immediately below the left atrial appendage or 2mm distal to the left atrial appendage (n = 25 for each), followed by histological analysis. Unlike the human, the rats had a single major septal artery arising from the proximal part of the left coronary artery (n = 30) or right coronary artery (n = 20). There were three branching patterns of left circumflex artery (LCX): 33 (66%) had LCX branching peripherally from a long left main coronary artery (LMCA), while the remainder 17 (34%) had the LCX branching from the proximal part of the septal artery or a short LMCA. The rats with distal coronary ligation presented myocardial infarction localized to an anterior territory irrespective of LCX branching pattern. In the rats with proximal coronary ligation, 64% (n = 16) had broad myocardial infarction involving the anterior and lateral territories, while the remainder (36%, n = 9) had myocardial infarction localized to an anterior territory with the intact LCX arising proximally from a short LMCA. The interventricular septum was spared from infarction in all rats because of its anatomical location. Infarct size variations were caused not only by ligation site but also by varying LCX branching patterns. There are potential risks to create different sizes of myocardial infarction, particularly when targeting a broad range of myocardial infarction. The territory of the septal artery always appears to be spared from myocardial infarction induced by the coronary ligation technique. PMID- 28837680 TI - The prevalence of discrimination across racial groups in contemporary America: Results from a nationally representative sample of adults. AB - A large body of social science research is devoted to understanding the causes and correlates of discrimination. Comparatively less effort has been aimed at providing a general prevalence estimate of discrimination using a nationally representative sample. The current study is intended to offer such an estimate using a large sample of American respondents (N = 14,793) while also exploring perceptions regarding why respondents felt they were discriminated against. The results provide a broad estimate of self-reported discrimination experiences-an event that was only reported by about one-quarter of all sample members-across racial and ethnic categories. PMID- 28837681 TI - Bispecific T cell engager (BiTE(r)) antibody constructs can mediate bystander tumor cell killing. AB - For targets that are homogenously expressed, such as CD19 on cells of the B lymphocyte lineage, immunotherapies can be highly effective. Targeting CD19 with blinatumomab, a CD19/CD3 bispecific antibody construct (BiTE(r)), or with chimeric antigen receptor T cells (CAR-T) has shown great promise for treating certain CD19-positive hematological malignancies. In contrast, solid tumors with heterogeneous expression of the tumor-associated antigen (TAA) may present a challenge for targeted therapies. To prevent escape of TAA-negative cancer cells, immunotherapies with a local bystander effect would be beneficial. As a model to investigate BiTE(r)-mediated bystander killing in the solid tumor setting, we used epidermal growth factor receptor (EGFR) as a target. We measured lysis of EGFR-negative populations in vitro and in vivo when co-cultured with EGFR positive cells, human T cells and an EGFR/CD3 BiTE(r) antibody construct. Bystander EGFR-negative cells were efficiently lysed by BiTE(r)-activated T cells only when proximal to EGFR-positive cells. Our mechanistic analysis suggests that cytokines released by BiTE(r)-activated T-cells induced upregulation of ICAM-1 and FAS on EGFR-negative bystander cells, contributing to T cell-induced bystander cell lysis. PMID- 28837682 TI - Cardiac computed tomography-derived epicardial fat volume and attenuation independently distinguish patients with and without myocardial infarction. AB - BACKGROUND AND OBJECTIVE: Epicardial adipose tissue (EAT) volume is associated with coronary plaque burden and adverse events. We aimed to determine, whether CT derived EAT attenuation in addition to EAT volume distinguishes patients with and without myocardial infarction. METHODS AND RESULTS: In 94 patients with confirmed or suspected coronary artery disease (aged 66.9+/-14.7years, 61%male) undergoing cardiac CT imaging as part of clinical workup, EAT volume was retrospectively quantified from non-contrast cardiac CT by delineation of the pericardium in axial images. Mean attenuation of all pixels from EAT volume was calculated. Patients with type-I myocardial infarction (n = 28) had higher EAT volume (132.9 +/- 111.9ml vs. 109.7 +/- 94.6ml, p = 0.07) and CT-attenuation (-86.8 +/- 5.8HU vs. -89.0 +/- 3.7HU, p = 0.03) than patients without type-I myocardial infarction, while EAT volume and attenuation were only modestly inversely correlated (r = -0.24, p = 0.02). EAT volume increased per standard deviation of age (18.2 [6.2-30.2] ml, p = 0.003), BMI (29.3 [18.4-40.2] ml, p<0.0001), and with presence of diabetes (44.5 [16.7-72.3] ml, p = 0.0002), while attenuation was higher in patients with lipid-lowering therapy (2.34 [0.08-4.61] HU, p = 0.04). In a model containing volume and attenuation, both measures of EAT were independently associated with the occurrence of type-I myocardial infarction (OR [95% CI]: 1.79 [1.10-2.94], p = 0.02 for volume, 2.04 [1.18-3.53], p = 0.01 for attenuation). Effect sizes remained stable for EAT attenuation after adjustment for risk factors (1.44 [0.77-2.68], p = 0.26 for volume; 1.93 [1.11-3.39], p = 0.02 for attenuation). CONCLUSION: CT-derived EAT attenuation, in addition to volume, distinguishes patients with vs. without myocardial infarction and is increased in patients with lipid-lowering therapy. Our results suggest that assessment of EAT attenuation could render complementary information to EAT volume regarding coronary risk burden. PMID- 28837683 TI - Birth preparedness and complication readiness among the women beneficiaries of selected rural primary health centers of Dakshina Kannada district, Karnataka, India. AB - INTRODUCTION: Birth preparedness and complication readiness (BPCR) is a strategy to promote timely use of skilled maternal and neonatal care during childbirth. According to World Health Organization, BPCR should be a key component of focused antenatal care. Dakshina Kannada, a coastal district of Karnataka state, is categorized as a high-performing district (institutional delivery rate >25%) under the National Rural Health Mission. However, a substantial proportion of women in the district experience complications during pregnancy (58.3%), childbirth (45.7%), and postnatal (17.4%) period. There is a paucity of data on BPCR practice and the factors associated with it in the district. Exploring this would be of great use in the evidence-based fine-tuning of ongoing maternal and child health interventions. OBJECTIVE: To assess BPCR practice and the factors associated with it among the beneficiaries of two rural Primary Health Centers (PHCs) of Dakshina Kannada district, Karnataka, India. METHODS: A facility-based cross-sectional study was conducted among 217 pregnant (>28 weeks of gestation) and recently delivered (in the last 6 months) women in two randomly selected PHCs from June -September 2013. Exit interviews were conducted using a pre-designed semi-structured interview schedule. Information regarding socio-demographic profile, obstetric variables, and knowledge of key danger signs was collected. BPCR included information on five key components: identified the place of delivery, saved money to pay for expenses, mode of transport identified, identified a birth companion, and arranged a blood donor if the need arises. In this study, a woman who recalled at least two key danger signs in each of the three phases, i.e., pregnancy, childbirth, and postpartum (total six) was considered as knowledgeable on key danger signs. Optimal BPCR practice was defined as following at least three out of five key components of BPCR. OUTCOME MEASURES: Proportion, Odds ratio, and adjusted Odds ratio (adj OR) for optimal BPCR practice. RESULTS: A total of 184 women completed the exit interview (mean age: 26.9+/-3.9 years). Optimal BPCR practice was observed in 79.3% (95% CI: 73.5 85.2%) of the women. Multivariate logistic regression revealed that age >26 years (adj OR = 2.97; 95%CI: 1.15-7.7), economic status of above poverty line (adj OR = 4.3; 95%CI: 1.12-16.5), awareness of minimum two key danger signs in each of the three phases, i.e., pregnancy, childbirth, and postpartum (adj OR = 3.98; 95%CI: 1.4-11.1), preference to private health sector for antenatal care/delivery (adj OR = 2.9; 95%CI: 1.1-8.01), and woman's discussion about the BPCR with her family members (adj OR = 3.4; 95%CI: 1.1-10.4) as the significant factors associated with optimal BPCR practice. CONCLUSION: In this study population, BPCR practice was better than other studies reported from India. Healthcare workers at the grassroots should be encouraged to involve women's family members while explaining BPCR and key danger signs with a special emphasis on young (<26 years) and economically poor women. Ensuring a reinforcing discussion between woman and her family members may further enhance the BPCR practice. PMID- 28837684 TI - Association of peptic ulcer disease with obesity, nutritional components, and blood parameters in the Korean population. AB - OBJECTIVES: Peptic ulcer disease (PUD) is a common disorder, but whether an association exists between PUD and anthropometric indicators remains controversial. Furthermore, no studies on the association of PUD with anthropometric indices, blood parameters, and nutritional components have been reported. The aim of this study was to assess associations of anthropometrics, blood parameters, nutritional components, and lifestyle factors with PUD in the Korean population. METHODS: Data were collected from a nationally representative sample of the South Korean population using the Korea National Health and Nutrition Examination Survey. Logistic regression was used to examine associations of anthropometrics, blood parameters and nutritional components among patients with PUD. RESULTS: Age was the factor most strongly associated with PUD in women (p = <0.0001, odds ratio (OR) = 0.770 [0.683-0.869]) and men (p = <0.0001, OR = 0.715 [0.616-0.831]). In both crude and adjusted analyses, PUD was highly associated with weight (adjusted p = 0.0008, adjusted OR = 1.251 [95%CI: 1.098-1.426]), hip circumference (adjusted p = 0.005, adjusted OR = 1.198 [1.056-1.360]), and body mass index (adjusted p = 0.0001, adjusted OR = 1.303 [1.139-1.490]) in women and hip circumference (adjusted p = 0.0199, adjusted OR = 1.217 [1.031-1.435]) in men. PUD was significantly associated with intake of fiber (adjusted p = 0.0386, adjusted OR = 1.157 [1.008-1.328], vitamin B2 (adjusted p = 0.0477, adjusted OR = 1.155 [1.001-1.333]), sodium (adjusted p = 0.0154, adjusted OR = 1.191 [1.034-1.372]), calcium (adjusted p = 0.0079, adjusted OR = 1.243 [1.059-1.459]), and ash (adjusted p = 0.0468, adjusted OR = 1.152 [1.002-1.325] in women but not in men. None of the assessed blood parameters were associated with PUD in women, and only triglyceride level was associated with PUD in men (adjusted p = 0.0169, adjusted OR = 1.227 [1.037 1.451]). DISCUSSION: We found that obesity was associated with PUD in the Korean population; additionally, the association between nutritional components and PUD was greater in women than in men. PMID- 28837685 TI - Species distribution models: A comparison of statistical approaches for livestock and disease epidemics. AB - In livestock industries, reliable up-to-date spatial distribution and abundance records for animals and farms are critical for governments to manage and respond to risks. Yet few, if any, countries can afford to maintain comprehensive, up-to date agricultural census data. Statistical modelling can be used as a proxy for such data but comparative modelling studies have rarely been undertaken for livestock populations. Widespread species, including livestock, can be difficult to model effectively due to complex spatial distributions that do not respond predictably to environmental gradients. We assessed three machine learning species distribution models (SDM) for their capacity to estimate national-level farm animal population numbers within property boundaries: boosted regression trees (BRT), random forests (RF) and K-nearest neighbour (K-NN). The models were built from a commercial livestock database and environmental and socio-economic predictor data for New Zealand. We used two spatial data stratifications to test (i) support for decision making in an emergency response situation, and (ii) the ability for the models to predict to new geographic regions. The performance of the three model types varied substantially, but the best performing models showed very high accuracy. BRTs had the best performance overall, but RF performed equally well or better in many simulations; RFs were superior at predicting livestock numbers for all but very large commercial farms. K-NN performed poorly relative to both RF and BRT in all simulations. The predictions of both multi species and single species models for farms and within hypothetical quarantine zones were very close to observed data. These models are generally applicable for livestock estimation with broad applications in disease risk modelling, biosecurity, policy and planning. PMID- 28837686 TI - Concurrency and other sexual partnership patterns reported in a survey of young people in rural Northern Tanzania. AB - African adolescents and young adults remain at substantial risk of infection with HIV and other sexually transmitted infections (STIs), and AIDS is the leading cause of death among African adolescents (10-19 years). Sexual partnership patterns influence transmission risk of sexually transmitted infections. We describe patterns reported by youth (15-30y) in a community-based survey in Tanzania. Among participants reporting multiple partners, we investigated factors associated with reported concurrency. Female (N = 6513) and male (N = 7301) participants had median ages of 21 and 22 years, respectively. Most participants (92%) reported having previously been sexually active, of whom 15% of males and <1% of females reported >=4 partners in the past year. The point prevalence of concurrency was 2.3% (95%CI 1.9-2.9) for females and 10.6% (95%CI 9.3-12.1) for males. High levels of multiple and concurrent partnerships were reported by those previously married. Females were more likely than males to report having spousal/regular partners and longer partnership lengths. Compared to males, the partnerships reported by females were less likely to be new partnerships, and more likely to be defined by the respondent as still 'ongoing'. Females reporting younger sexual debut were more likely to report concurrent sexual partners. Far fewer young women reported multiple and concurrent partnerships, but we cannot definitively conclude that concurrency was uncommon for women, because stigma towards women's multiple sexual partnerships might contribute to substantial under-reporting, as was found in extensive qualitative research in the study population. This study provides one of the most comprehensive quantitative descriptions of partnership patterns of young people in an African setting. Interventions addressing sexual risk among youth should involve male partners, empower women to protect themselves within different types of partnerships, and encourage a greater openness about young people's sexual relationships. PMID- 28837687 TI - The spliceosome-associated protein Mfap1 binds to VCP in Drosophila. AB - Posttranscriptional regulation of gene expression contributes to many developmental transitions. Previously, we found that the AAA chaperone Valosin Containing Protein (VCP) regulates ecdysone-dependent dendrite pruning of Drosophila class IV dendritic arborization (c4da) neurons via an effect on RNA metabolism. In a search for RNA binding proteins associated with VCP, we identified the spliceosome-associated protein Mfap1, a component of the tri-snRNP complex. Mfap1 is a nucleolar protein in neurons and its levels are regulated by VCP. Mfap1 binds to VCP and TDP-43, a disease-associated RNA-binding protein. via distinct regions in its N- and C-terminal halfs. Similar to vcp mutations, Mfap1 overexpression causes c4da neuron dendrite pruning defects and mislocalization of TDP-43 in these cells, but genetic analyses show that Mfap1 is not a crucial VCP target during dendrite pruning. Finally, rescue experiments with a lethal mfap1 mutant show that the VCP binding region is not essential for Mfap1 function, but may act to increase its stability or activity. PMID- 28837688 TI - Lost in translation: The challenge of adapting integrated approaches for worker health and safety for low- and middle-income countries. AB - OBJECTIVES: To describe the process of adapting an intervention integrating occupational safety and health (OSH) and health promotion for manufacturing worksites in India and the challenges faced in implementing it; and explore how globalization trends may influence the implementation of these integrated approaches in India and other low- and middle-income countries (LMICs). METHODS: This study-conducted in 22 manufacturing worksites in Mumbai, India-adapted and implemented an evidence-based intervention tested in the U.S. that integrated OSH and tobacco control. The systematic adaptation process included formative research and pilot testing, to ensure that the tested intervention was tailored to the local setting. We used qualitative methods and process evaluation to assess the extent to which this intervention was implemented, and to explore barriers to implementation. RESULTS: While participating worksites agreed to implement this intervention, not all components of the adapted intervention were implemented fully in the 10 worksites assigned to the intervention condition. We found that the OSH infrastructure in India focused predominantly on regulatory compliance, medical screening (secondary prevention) and the treatment of injuries. We observed generally low levels of leadership support and commitment to OSH, evidenced by minimal management participation in the intervention, reluctance to discuss OSH issues with the study team or workers, and little receptivity to recommendations resulting from the industrial hygienist's reports. CONCLUSION: India presents one example of a LMIC with a rising burden of non communicable diseases and intensified exposures to both physical and organizational hazards on the job. Our experiences highlight the importance of national and global trends that shape workers' experiences on the job and their related health outcomes. Beyond a singular focus on prevention of non communicable diseases, coordinated national and international efforts are needed to address worker health outcomes in the context of the conditions of work that clearly shape them. PMID- 28837689 TI - Type 2 diabetes and in-hospital complications after revision of total hip and knee arthroplasty. AB - PURPOSE: To assess the effect of type 2 diabetes (T2DM) on hospital outcomes such as in hospital postoperative complications (IHPC), length of hospital stay (LOHS) and in-hospital mortality (IHM) after the revision of total hip arthroplasty (RHA) and total knee arthroplasty (RKA) and to identify factors associated with IHPC among T2DM patients undergoing these procedures. METHODS: We performed a retrospective study using the Spanish National Hospital Discharge Database, 2005 2014. We included patients who were >=40 years old that had undergone RHA and RKA. For each T2DM patient, we selected a year-, gender-, age- and Charlson Comorbidity Index-matched non-diabetic patient. RESULTS: We identified 44,055 and 39,938 patients who underwent RHA (12.72% with T2DM) and RKA (15.01% with T2DM). We matched 4,700 and 5,394 couples with RHA and RKA, respectively. Any IHPC was more frequent among patients with T2DM than among non-T2DM patients (19% vs. 15.64% in the RHA cohort and 12.94% vs. 11.09% in the RKA cohort, respectively). For patients who underwent RHA, postoperative infection (4.51% vs. 2.94%, p<0.001), acute post-hemorrhagic anemia (9.53% vs. 7.70%, p<0.001), mean LOHS and IHM were significantly higher in patients with T2DM. Among RKA patients, the incidence of acute posthemorrhagic anemia (7.21% vs. 5.62%; p = 0.001) and urinary tract infection (1.13% vs. 0.72%; p = 0.029) was significantly higher in patients with diabetes. Older age, obesity, infection due to internal joint prosthesis, myocardial infarction, congestive heart failure, mild liver disease and renal disease and emergency room admission were significantly associated with a higher risk of IHPC in T2DM patients. IHPC decreased over time only in T2DM patients who underwent RHA (OR 0.94, 95%CI 0.89-0.98). CONCLUSIONS: Patients with T2DM who underwent RHA and RKA procedures had more IHPC after controlling for the effects of possible confounders. LOHS and IHM were also higher among RHA patients with diabetes. Older age, comorbidity, obesity and emergency room admission were strong predictors of IHPC in diabetic patients. PMID- 28837690 TI - Getting the flu: 5 key facts about influenza virus evolution. PMID- 28837691 TI - Population genetic structure of Guiana dolphin (Sotalia guianensis) from the southwestern Atlantic coast of Brazil. AB - Sotalia guianensis is a small dolphin that is vulnerable to anthropogenic impacts. Along the Brazilian Atlantic coast, this species is threatened with extinction. A prioritized action plan for conservation strategies relies on increased knowledge of the population. The scarcity of studies about genetic diversity and assessments of population structure for this animal have precluded effective action in the region. Here, we assessed, for the first time, the genetic differentiation at 14 microsatellite loci in 90 S. guianensis specimens stranded on the southeastern Atlantic coast of the State of Espirito Santo, Brazil. We estimated population parameters and structure, measured the significance of global gametic disequilibrium and the intensity of non-random multiallelic interallelic associations and constructed a provisional synteny map using Bos taurus, the closest terrestrial mammal with a reference genome available. All microsatellite loci were polymorphic, with at least three and a maximum of ten alleles each. Allele frequencies ranged from 0.01 to 0.97. Observed heterozygosity ranged from 0.061 to 0.701. The mean inbreeding coefficient was 0.103. Three loci were in Hardy-Weinberg disequilibrium even when missing genotypes were inferred. Although 77 of the 91 possible two-locus associations were in global gametic equilibrium, we unveiled 13 statistically significant, sign-based, non-random multiallelic interallelic associations in 10 two-locus combinations with either coupling (D' values ranging from 0.782 to 0.353) or repulsion (D' values -0.517 to -1.000) forces. Most of the interallelic associations did not involve the major alleles. Thus, for either physically or non-physically linked loci, measuring the intensity of non-random interallelic associations is important for defining the evolutionary forces at equilibrium. We uncovered a small degree of genetic differentiation (FST = 0.010; P-value = 0.463) with a hierarchical clustering into one segment containing members from the southern and northern coastal regions. The data thus support the scenario of little genetic structure in the population of S. guianensis in this geographic area. PMID- 28837692 TI - Assessing the accuracy of predictive models for numerical data: Not r nor r2, why not? Then what? AB - Assessing the accuracy of predictive models is critical because predictive models have been increasingly used across various disciplines and predictive accuracy determines the quality of resultant predictions. Pearson product-moment correlation coefficient (r) and the coefficient of determination (r2) are among the most widely used measures for assessing predictive models for numerical data, although they are argued to be biased, insufficient and misleading. In this study, geometrical graphs were used to illustrate what were used in the calculation of r and r2 and simulations were used to demonstrate the behaviour of r and r2 and to compare three accuracy measures under various scenarios. Relevant confusions about r and r2, has been clarified. The calculation of r and r2 is not based on the differences between the predicted and observed values. The existing error measures suffer various limitations and are unable to tell the accuracy. Variance explained by predictive models based on cross-validation (VEcv) is free of these limitations and is a reliable accuracy measure. Legates and McCabe's efficiency (E1) is also an alternative accuracy measure. The r and r2 do not measure the accuracy and are incorrect accuracy measures. The existing error measures suffer limitations. VEcv and E1 are recommended for assessing the accuracy. The applications of these accuracy measures would encourage accuracy improved predictive models to be developed to generate predictions for evidence informed decision-making. PMID- 28837693 TI - Alternative vaccine administration by powder injection: Needle-free dermal delivery of the glycoconjugate meningococcal group Y vaccine. AB - Powder-injectors use gas propulsion to deposit lyophilised drug or vaccine particles in the epidermal and sub epidermal layers of the skin. We prepared dry powder (Tg = 45.2 +/- 0.5 degrees C) microparticles (58.1 MUm) of a MenY-CRM197 glyconjugate vaccine (0.5% wt.) for intradermal needle-free powder injection (NFPI). SFD used ultrasound atomisation of the liquid vaccine-containing excipient feed, followed by lyophilisation above the glass transition temperature (Tg' = - 29.9 +/- 0.3 degrees C). This resulted in robust particles (density~ 0.53 +/-0.09 g/cm3) with a narrow volume size distribution (mean diameter 58.1 MUm, and span = 1.2), and an impact parameter (rhovr ~ 11.5 kg/m.s) sufficient to breach the Stratum corneum (sc). The trehalose, manitol, dextran (10 kDa), dextran (150 kDa) formulation, or TMDD (3:3:3:1), protected the MenY-CRM197 glyconjugate during SFD with minimal loss, no detectable chemical degradation or physical aggregation. In a capsular group Y Neisseria meningitidis serum bactericidal assay (SBA) with human serum complement, the needle free vaccine, which contained no alum adjuvant, induced functional protective antibody responses in vivo of similar magnitude to the conventional vaccine injected by hypodermic needle and syringe and containing alum adjuvant. These results demonstrate that needle-free vaccination is both technically and immunologically valid, and could be considered for vaccines in development. PMID- 28837694 TI - Multikingdom microscale models. PMID- 28837695 TI - A physiological model for interpretation of arterial spin labeling reactive hyperemia of calf muscles. AB - To characterize and interpret arterial spin labeling (ASL) reactive hyperemia of calf muscles for a better understanding of the microcirculation in peripheral arterial disease (PAD), we present a physiological model incorporating oxygen transport, tissue metabolism, and vascular regulation mechanisms. The model demonstrated distinct effects between arterial stenoses and microvascular dysfunction on reactive hyperemia, and indicated a higher sensitivity of 2-minute thigh cuffing to microvascular dysfunction than 5-minute cuffing. The recorded perfusion responses in PAD patients (n = 9) were better differentiated from the normal subjects (n = 7) using the model-based analysis rather than characterization using the apparent peak and time-to-peak of the responses. The analysis results suggested different amounts of microvascular disease within the patient group. Overall, this work demonstrates a novel analysis method and facilitates understanding of the physiology involved in ASL reactive hyperemia. ASL reactive hyperemia with model-based analysis may be used as a noninvasive microvascular assessment in the presence of arterial stenoses, allowing us to look beyond the macrovascular disease in PAD. A subgroup who will have a poor prognosis after revascularization in the patients with critical limb ischemia may be associated with more severe microvascular diseases, which may potentially be identified using ASL reactive hyperemia. PMID- 28837696 TI - The macrophage cytoskeleton acts as a contact sensor upon interaction with Entamoeba histolytica to trigger IL-1beta secretion. AB - Entamoeba histolytica (Eh) is the causative agent of amebiasis, one of the major causes of dysentery-related morbidity worldwide. Recent studies have underlined the importance of the intercellular junction between Eh and host cells as a determinant in the pathogenesis of amebiasis. Despite the fact that direct contact and ligation between Eh surface Gal-lectin and EhCP-A5 with macrophage alpha5beta1 integrin are absolute requirements for NLRP3 inflammasome activation and IL-1beta release, many other undefined molecular events and downstream signaling occur at the interface of Eh and macrophage. In this study, we investigated the molecular events at the intercellular junction that lead to recognition of Eh through modulation of the macrophage cytoskeleton. Upon Eh contact with macrophages key cytoskeletal-associated proteins were rapidly post translationally modified only with live Eh but not with soluble Eh proteins or fragments. Eh ligation with macrophages rapidly activated caspase-6 dependent cleavage of the cytoskeletal proteins talin, Pyk2 and paxillin and caused robust release of the pro-inflammatory cytokine, IL-1beta. Macrophage cytoskeletal cleavages were dependent on Eh cysteine proteinases EhCP-A1 and EhCP-A4 but not EhCP-A5 based on pharmacological blockade of Eh enzyme inhibitors and EhCP-A5 deficient parasites. These results unravel a model where the intercellular junction between macrophages and Eh form an area of highly interacting proteins that implicate the macrophage cytoskeleton as a sensor for Eh contact that leads downstream to subsequent inflammatory immune responses. PMID- 28837697 TI - Herpesviruses shape tumour microenvironment through exosomal transfer of viral microRNAs. AB - Metabolic changes within the cell and its niche affect cell fate and are involved in many diseases and disorders including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). KSHV latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, these miRNAs are responsible for inducing the Warburg effect in infected cells. Here we identify a novel mechanism enabling KSHV to manipulate the metabolic nature of the tumour microenvironment. We demonstrate that KSHV infected cells specifically transfer the virus-encoded microRNAs to surrounding cells via exosomes. This flow of genetic information results in a metabolic shift toward aerobic glycolysis in the surrounding non-infected cells. Importantly, this exosome-mediated metabolic reprogramming of neighbouring cells supports the growth of infected cells, thereby contributing to viral fitness. Finally, our data show that this miRNA transfer-based regulation of cell metabolism is a general mechanism used by other herpesviruses, such as EBV, as well as for the transfer of non-viral onco-miRs. This exosome-based crosstalk provides viruses with a mechanism for non-infectious transfer of genetic material without production of new viral particles, which might expose them to the immune system. We suggest that viruses and cancer cells use this mechanism to shape a specific metabolic niche that will contribute to their fitness. PMID- 28837698 TI - Differences in pathogenicity of three animal isolates of Mycobacterium species in a mouse model. AB - Animal mycobacterioses are among the most important zoonoses worldwide. These are generally caused by either Mycobacterium tuberculosis (MTB), M. bovis (MBO) or M. avium (MAV). To test the hypothesis that different species of pathogenic mycobacteria isolated from varied anatomic locations or animal species differ in virulence and pathogenicity, we performed experiments with three mycobacteria strains (NTSE-3(MTB), NTSE-4(MBO) and NTSE-5 (MAV)) obtained from animal species. Spoligotyping analysis was used to confirm both MTB and MBO strains while the MAV strain was confirmed by 16s rDNA sequencing. BALB/c mice were intranasally infected with the three strains at low and high CFU doses to evaluate variations in pathogenicity. Clinical and pathological parameters were assessed. Infected mice were euthanized at 80 days post-inoculation (dpi). Measures of lung and body weights indicated that the MBO infected group had higher mortality, more weight loss, higher bacterial burden and more severe lesions in lungs than the other two groups. Cytokine profiles showed higher levels of TNF-alpha for MBO versus MTB, while MAV had the highest amounts of IFN-beta in vitro and in vivo. In vitro levels of other cytokines such as IL-1beta, IL-10, IL-12, IL-17, and IFN-beta showed that Th1 cells had the strongest response in MBO infected mice and that Th2 cells were inhibited. We found that the level of virulence among the three isolates decreased in the following order MBO>MTB>MAV. PMID- 28837699 TI - Talking to fewer people leads to having more malleable linguistic representations. AB - We learn language from our social environment. In general, the more sources we have, the less informative each of them is, and the less weight we should assign it. If this is the case, people who interact with fewer others should be more susceptible to the influence of each of their interlocutors. This paper tests whether indeed people who interact with fewer other people have more malleable phonological representations. Using a perceptual learning paradigm, this paper shows that individuals who regularly interact with fewer others are more likely to change their boundary between /d/ and /t/ following exposure to an atypical speaker. It further shows that the effect of number of interlocutors is not due to differences in ability to learn the speaker's speech patterns, but specific to likelihood of generalizing the learned pattern. These results have implications for both language learning and language change, as they suggest that individuals with smaller social networks might play an important role in propagating linguistic changes. PMID- 28837700 TI - Risk of pneumonia in patients with gastroesophageal reflux disease: A population based cohort study. AB - PURPOSE: The prevalence of gastroesophagel reflux disease (GERD) has steadily increased. However, the association between GERD itself and the risk of pneumonia remains unclear. This study aimed to investigate the association between GERD and long-term risk of pneumonia and to identify the major risk factors for pneumonia in GERD patients. METHODS: Using the Taiwan National Health Insurance Research Database, we identified patients who were newly diagnosed with GERD and treated with proton pump inhibitors (PPIs) from January 1, 2004 through December 31, 2010. Two groups comprising 15,715 GERD cases and 15,715 non-GERD matched controls were generated using propensity score matching, thereby making the differences in basic demographics, concomitant medication use, and comorbidities between the two groups inconsiderable. RESULTS: Cumulative incidence of pneumonia was significantly higher in the patients with GERD than that in the non-GERD matched controls, with an adjusted HR of 1.48 (95% confidence interval [CI] = 1.31-1.67; P < 0.001) within 6-year follow-ups. Multivariate stratified analyses revealed similar results in many subgroups, with a highest risk in individuals younger than 40 years of age (HR = 2.17, 95% CI = 1.48-3.19). Crucially, patients with GERD using PPIs longer than 4 months were at a significantly increased risk of pneumonia than those who did not use PPIs or took PPIs less than 4 months. CONCLUSIONS: GERD was significantly associated with long-term risk of pneumonia, especially in GERD with PPI use longer than 4 months or in the young population. Further prospective longitudinal studies should be conducted for validation and implementing clinical practice guidelines. PMID- 28837702 TI - Imidacloprid transport and sorption nonequilibrium in single and multilayered columns of Immokalee fine sand. AB - Imidacloprid (IMD) is a neonicotinoid pesticide soil-drenched to many crops to control piercing-sucking insects such as the Asian citrus psyllid (ACP). Neonicotinoids are persistent in the environment and transport analyses are helpful estimate leaching potential from soils that could result in groundwater pollution. The objective of this study was to analyze IMD breakthrough under saturated water flow in soil columns packed with three horizons (A, E, Bh) of Immokalee Fine Sand (IFS). Also, we used the dimensionless form of the convective dispersive model (CD-Model) to compare the optimized transport parameters from each column experiment (retardation factor, R; fraction of instantaneous-to-total retardation, beta; and mass transfer coefficient, omega) with the parameters obtained from sorption batch equilibria and sorption kinetics. The tracer (Cl-) breakthrough curves (BTCs) were symmetrical and properly described by the CD Model. IMD BTCs from A, Bh, and multilayered [A+E+Bh] soil columns showed steep fronts and tailing that were well described by the one-site nonequilibrium (OSNE) model, which was an evidence of non-ideal transport due to IMD mass transfer into the soil organic matter. In general, IMD was weakly-sorbed in the A and Bh horizons (R values of 3.72 +/- 0.04 and 3.08 +/- 0.07, respectively), and almost no retardation was observed in the E horizon (R = 1.20 +/- 0.02) due to its low organic matter content (0.3%). Using the HYDRUS-1D package, optimized parameters (R, beta, omega) from the individual columns successfully simulated IMD transport in a multilayered column mimicking an IFS soil profile. These column studies and corresponding simulations agreed with previous findings from batch sorption equilibria and kinetics experiments, where IMD showed one-site kinetic mass transfer between soil surfaces and soil solution. Ideally, sandy soils should be maintained unsaturated by crop irrigation systems and rainfall monitoring during and after soil-drench application. The unsaturated soil will increase IMD retardation factors and residence time for plant uptake, lowering leaching potential from soil layers with low sorption capacity, such as the E horizon. PMID- 28837701 TI - Lissencephaly-1 dependent axonal retrograde transport of L1-type CAM Neuroglian in the adult drosophila central nervous system. AB - Here, we established the Drosophila Giant Fiber neurons (GF) as a novel model to study axonal trafficking of L1-type Cell Adhesion Molecules (CAM) Neuroglian (Nrg) in the adult CNS using live imaging. L1-type CAMs are well known for their importance in nervous system development and we previously demonstrated a role for Nrg in GF synapse formation. However, in the adult they have also been implicated in synaptic plasticity and regeneration. In addition, to its canonical role in organizing cytoskeletal elements at the plasma membrane, vertebrate L1CAM has also been shown to regulate transcription indirectly as well as directly via its import to the nucleus. Here, we intend to determine if the sole L1CAM homolog Nrg is retrogradley transported and thus has the potential to relay signals from the synapse to the soma. Live imaging of c-terminally tagged Nrg in the GF revealed that there are at least two populations of retrograde vesicles that differ in speed, and either move with consistent or varying velocity. To determine if endogenous Nrg is retrogradely transported, we inhibited two key regulators, Lissencephaly-1 (Lis1) and Dynactin, of the retrograde motor protein Dynein. Similar to previously described phenotypes for expression of poisonous subunits of Dynactin, we found that developmental knock down of Lis1 disrupted GF synaptic terminal growth and that Nrg vesicles accumulated inside the stunted terminals in both mutant backgrounds. Moreover, post mitotic Lis1 knock down in mature GFs by either RNAi or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) induced mutations, resulted in normal length terminals with fully functional GF synapses which also exhibited severe accumulation of endogenous Nrg vesicles. Thus, our data suggests that accumulation of Nrg vesicles is due to failure of retrograde transport rather than a failure of terminal development. Together with the finding that post mitotic knock down of Lis1 also disrupted retrograde transport of tagged Nrg vesicles in GF axons, it demonstrates that endogenous Nrg protein is transported from the synapse to the soma in the adult central nervous system in a Lis1-dependent manner. PMID- 28837704 TI - Long-term spatial distributions and trends of the latent heat fluxes over the global cropland ecosystem using multiple satellite-based models. AB - Estimating cropland latent heat flux (LE) from continental to global scales is vital to modeling crop production and managing water resources. Over the past several decades, numerous LE models were developed, such as the moderate resolution imaging spectroradiometer LE (MOD16) algorithm, revised remote sensing based Penman-Monteith LE algorithm (RRS), the Priestley-Taylor LE algorithm of the Jet Propulsion Laboratory (PT-JPL) and the modified satellite-based Priestley Taylor LE algorithm (MS-PT). However, these LE models have not been directly compared over the global cropland ecosystem using various algorithms. In this study, we evaluated the performances of these four LE models using 34 eddy covariance (EC) sites. The results showed that mean annual LE for cropland varied from 33.49 to 58.97 W/m2 among the four models. The interannual LE slightly increased during 1982-2009 across the global cropland ecosystem. All models had acceptable performances with the coefficient of determination (R2) ranging from 0.4 to 0.7 and a root mean squared error (RMSE) of approximately 35 W/m2. MS-PT had good overall performance across the cropland ecosystem with the highest R2, lowest RMSE and a relatively low bias. The reduced performances of MOD16 and RRS, with R2 ranging from 0.4 to 0.6 and RMSEs from 30 to 39 W/m2, might be attributed to empirical parameters in the structure algorithms and calibrated coefficients. PMID- 28837703 TI - Combinatorial effects of zinc deficiency and arsenic exposure on zebrafish (Danio rerio) development. AB - Zinc deficiency and chronic low level exposures to inorganic arsenic in drinking water are both significant public health concerns that affect millions of people including pregnant women. These two conditions can co-exist in the human population but little is known about their interaction, and in particular, whether zinc deficiency sensitizes individuals to arsenic exposure and toxicity, especially during critical windows of development. To address this, we utilized the Danio rerio (zebrafish) model to test the hypothesis that parental zinc deficiency sensitizes the developing embryo to low-concentration arsenic toxicity, leading to altered developmental outcomes. Adult zebrafish were fed defined zinc deficient and zinc adequate diets and were spawned resulting in zinc adequate and zinc deficient embryos. The embryos were treated with environmentally relevant concentrations of 0, 50, and 500 ppb arsenic. Arsenic exposure significantly reduced the amount of zinc in the developing embryo by ~7%. The combination of zinc deficiency and low-level arsenic exposures did not sensitize the developing embryo to increased developmental malformations or mortality. The combination did cause a 40% decline in physical activity of the embryos, and this decline was significantly greater than what was observed with zinc deficiency or arsenic exposure alone. Significant changes in RNA expression of genes that regulate zinc homeostasis, response to oxidative stress and insulin production (including zip1, znt7, nrf2, ogg1, pax4, and insa) were found in zinc deficient, or zinc deficiency and arsenic exposed embryos. Overall, the data suggests that the combination of zinc deficiency and arsenic exposure has harmful effects on the developing embryo and may increase the risk for developing chronic diseases like diabetes. PMID- 28837705 TI - Changes in the pattern of plasma extracellular vesicles after severe trauma. AB - BACKGROUND: Extracellular vesicles (EV) released into the circulation after traumatic injury may influence complications. We thus evaluated the numbers of EV in plasma over 28 days after trauma and evaluated their pro-coagulant and inflammatory effects. METHODS AND FINDINGS: 37 patients suffering trauma with an injury severity score >15 were studied along with 24 healthy controls. Plasma samples were isolated by double centrifugation (2000g 20min; 13000g 2min) from blood collected from within an hour up to 28 days after injury. Plasma EV were counted and sized using nanoparticle tracking analysis (NTA); counts and cellular origins were also determined by flow cytometry (FC) using cell-specific markers. Functional effects were tested in a procoagulant phospholipid assay and in flow based, leukocyte adhesion assay after endothelial cells (EC) were treated with EV. We found that EV concentrations measured by NTA were significantly increased in trauma patients compared to healthy controls, and remained elevated over days. In addition, or FC showed that patients with trauma had higher numbers of EV derived from platelets (CD41+), leukocytes (CD45+) and endothelial EC (CD144+). The increases were evident throughout the 28-day follow-up. However, the FC count represented <1% of the count detected by NTA, and only 1-2% of EV identified using NTA had a diameter >400nm. The procoagulant phospholipid activity assay showed that patient plasma accelerated coagulation on day 1 and day 3 after trauma, with coagulation times correlated with EV counts. Furthermore, treatment of EC for 24 hours with plasma containing EV tended to increase the recruitment of peripheral flowing blood mononuclear cells. CONCLUSIONS: EV counted by FC represent a small sub-population of the total load detected by NTA. Both methods however indicate a significant increase in plasma EV after severe traumatic injury that have pro-coagulant and pro-inflammatory effects that may influence outcomes. PMID- 28837706 TI - A DNA inducing VLP vaccine designed for HIV and tested in mice. AB - We developed a DNA vaccine that induces the formation of a VLP in vivo. This VLP was designed to elicit neutralizing antibodies, to induce better T-cell responses and to activate the innate immune system. Overall, 5 groups of 10 mice were electroporated with the following constructs: pVLP-LTR-GagPro [full], pVLP-GagPro [VLP wihout RNA], pVLP-LTR-Gag [VLP immature], pVLP-Gag and pVLP-EnvBG505 [regular DNA vaccine] and a mock group. We performed ICS on the mouse spleens and performed ELISA for ENV antibodies and a Luminex assay for inflammatory cytokines. The VLP showed good binding to the neutralizing antibodies. The percentage of CD4 cells producing cytokines was 0.1% [IFNg], 0.15%[IL-2] and 0.2% [TNFa] for the construct pVLP-LTR-GagPro. The percentage of CD8 cells producing cytokines was 0.3%[IFNg], 0.2%[IL-2] and 0.25%[TNFa]. All pVLP constructs induced more antibodies for EnvBG505 than the regular DNA vaccine Env. The pVLP-LTR GagPro induced more IL-1B than the other constructs 24 hours post-vaccination. PMID- 28837708 TI - Partial Costal Cartilage Harvest for Rhinoplasty. PMID- 28837707 TI - Epidemiology of a Rare Event: The Singapore Epidemiology of Eye Disease Study. PMID- 28837710 TI - Hearing Loss and Patient-Physician Communication: The Role of an Otolaryngologist. PMID- 28837709 TI - Age-Related Hearing Loss and Communication Breakdown in the Clinical Setting. PMID- 28837711 TI - Repair of Lateral Wall Insufficiency. AB - Importance: Lateral wall insufficiency (LWI) is classified by the zone in which it occurs. Multiple techniques for treating LWI are described in the literature and are used, but no treatment approach has been widely adopted. Objective: To establish an algorithm for treatment of LWI by evaluating subjective and objective outcomes of patients who underwent LWI repair and comparing these results with those of a control group who received no specific LWI repair. Design, Setting, and Participants: This case-control study was conducted in a tertiary referral center. In group 1, there were 44 patients who underwent septorhinoplasty to repair LWI between February 1, 2014, and May 31, 2016. In group 2, there were 44 age- and sex-matched patients who underwent cosmetic septorhinoplasty without LWI repair. Data analysis was conducted from February 1, 2014, to May 31, 2016. Intervention: Open septorhinoplasty. Main Outcomes and Measures: Nasal Obstruction Symptom Evaluation (NOSE) scores and LWI grades. Results: Forty-four patients (8 men and 36 women, with a mean [SD] age of 46 [16] years) who underwent open septorhinoplasty to repair LWI and 44 age- and sex matched patients (composed of 8 men and 36 women, with a mean [SD] age of 41 [12] years) were included in the study. The mean (SD) preoperative NOSE scores were 69.4 (22) in group 1 and 20.5 (20.8) in group 2 (P < .001). The NOSE scores in both groups significantly improved after surgery (44.7 [95% CI, -28.9 to -49.9; P < .001] and -14.5 [95% CI, -2.7 to -18.5; P = .02]), although the improvement in group 2 was not clinically significant. The mean preoperative LWI grades were higher in group 1 than in group 2 for each zone (P < .001 and P = .001) but were similar between groups for each zone after surgery. Postoperative LWI scores significantly decreased in group 1 to levels similar to that of group 2. A positive linear correlation was noted between NOSE scores and LWI grades, with the strongest correlation between preoperative zone 1 LWI grades and NOSE scores (R = 0.68). Lateral crural strut grafts were used for zone 1 LWI and alar rim grafts were used for zone 2 LWI. Conclusions and Relevance: The LWI grading system enables surgeons to localize LWI, tailor the surgical treatment to the patient, and monitor improvements in the postoperative period. Level of Evidence: 3. PMID- 28837712 TI - The Hereditary Paraganglioma-Pheochromocytoma Syndrome: No Time to Waste-Reply. PMID- 28837713 TI - The Hereditary Paraganglioma-Pheochromocytoma Syndrome: No Time to Waste. PMID- 28837714 TI - Change in Pattern of Secondary Cancers After Kaposi Sarcoma in the Era of Antiretroviral Therapy. AB - Importance: Studies performed in the 1980s and early 1990s have shown that people who develop Kaposi sarcoma (KS) are at higher risk of developing other cancers. The demographics of those affected with human immunodeficiency virus (HIV)/AIDS and KS have changed, and individuals with HIV/AIDS and KS now live longer. Objectives: To test the hypothesis that the secondary cancers developing in patients with KS have changed in recent years and to assess the risk of secondary cancers after KS in different periods. Design, Setting, and Participants: Longitudinal data from 9 cancer registries in the Surveillance, Epidemiology, and End Results (SEER) database were used to identify cases of KS diagnosed from January 1973 to December 2013. The dates of the analysis were November 2016 to February 2017. Main Outcomes and Measures: The primary outcome was the development of secondary cancers in individuals with KS. Secondary cancers were considered only if diagnosed 2 months after a diagnosis of KS. Standardized incidence ratios (SIRs) were calculated for the development of new secondary cancers in the pre-AIDS era (1973-1979), pre-highly active antiretroviral therapy (HAART) era (1980-1995), and HAART era (1996-2013). Stratified analysis was then performed on a subset of the cases diagnosed from 1996 to 2013 based on age at diagnosis (<65 and >=65 years), latency period between KS and the development of secondary cancers (1 year, 2-5 years, >5 to 10 years, and >10 years), and registries with higher vs lower reported rates of HIV/AIDS. Results: Among 14 905 individuals with diagnosed KS, 13 721 (92.1%) were younger than 65 years at the time of diagnosis, and 14 356 (96.3%) were male. From 1980 to 1995, SIRs were 2.01 (95% CI, 1.00-3.60) for cancer of the rectum, 49.70 (95% CI, 33.53-70.94) for cancer of the anus, 4.98 (95% CI, 2.79-8.22) for cancer of the liver, 13.70 (95% CI, 2.82-40.03) for cancer of the cervix, 6.40 (95% CI, 2.76-12.60) for Hodgkin lymphoma, and 48.97 (95% CI, 44.85-53.36) for non-Hodgkin lymphoma. From 1996 to 2013, cancer of the anus, Hodgkin lymphoma, non-Hodgkin lymphoma, and cancer of the liver remained associated with KS, with the addition of the following significant SIRs: 6.99 (95% CI, 3.20-13.27) for cancer of the tongue, 10.28 (95% CI, 1.24-37.13) for cancer of the penis, and 17.62 (95% CI, 3.63 51.49) for acute lymphocytic leukemia. The SIR of developing any tumor after KS decreased significantly from 3.36 to 1.94 from the pre-HAART era to the HAART era. Conclusions and Relevance: There has been a significant decline in the overall risk of secondary cancers after KS. Certain cancers, including acute lymphocytic leukemia, cancer of the tongue, and cancer of the penis, are increasingly becoming more common in the HAART era compared with the pre-HAART era. Close monitoring and screening for these secondary cancers is desirable in patients with KS. PMID- 28837715 TI - Ocular Surface Squamous Neoplasia in a Patient With Hepatitis C. PMID- 28837716 TI - The Rest of Them. PMID- 28837717 TI - Nonvoluntary Psychiatric Treatment Is Distinct From Involuntary Psychiatric Treatment. PMID- 28837718 TI - Adjuvant Chemotherapy vs Observation for Patients With Adverse Pathologic Features at Radical Cystectomy Previously Treated With Neoadjuvant Chemotherapy. AB - Importance: Despite existing evidence of a benefit associated with cisplatin based adjuvant chemotherapy (AC) after radical cystectomy (RC) for chemotherapy naive patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder (UCB), to our knowledge, no studies have addressed the effectiveness of AC in those who received neoadjuvant chemotherapy (NAC) before surgery. Objective: To assess the comparative effectiveness of AC vs observation for patients with pT3/T4 and/or pN+ UCB previously treated with NAC and RC. Design, Setting, and Participants: This observational cohort study used the National Cancer Data Base (January 1, 2006, through December 31, 2012) to identify individuals who received NAC and RC followed by AC or observation for pT3/T4 and/or pN+ UCB. Main Outcomes and Measures: After multiple imputation was used to handle missing data, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox proportional hazards regression analyses were performed with a 6-month conditional landmark to compare overall survival (OS) among patients who received NAC and RC followed by AC vs observation. In addition, exploratory analyses were conducted to examine the heterogeneity of the treatment effect according to age (continuous), sex (female vs male), Charlson comorbidity index (>=1 vs 0), pT/N stage (pT3/T4N0 vs pTanyN+), and surgical margin status (positive vs negative) by testing interaction terms within the IPTW-adjusted Cox proportional hazards regression model. Results: Of the 788 patients with pT3/T4 and/or pN+ UCB (mean [SD] age, 65.3 [9.4] years; 603 [76.5%] male and 185 [23.5%] female), 184 (23.4%) received NAC and RC followed by AC and 604 (76.6%) received NAC and RC followed by observation. The 6-month conditional landmark, IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for NAC and RC followed by AC (29.9 months; interquartile range, 15.1-85.4 months) vs NAC and RC followed by observation (24.2 months; interquartile range, 12.9-58.9 months) (P = .046). The 5-year IPTW-adjusted rates of OS were 36.8% for NAC and RC followed by AC vs 24.7% for NAC and RC followed by observation. In the IPTW-adjusted Cox proportional hazards regression analysis, NAC and RC followed by AC was associated with a significant OS benefit (hazard ratio, 0.78; 95% CI, 0.61-0.99; P = .046). Interaction term analyses indicated that the OS benefit of NAC and RC followed by AC decreased significantly with age (hazard ratio, 0.97; 95% CI, 0.95 0.99; P = .02), whereas no significant interaction was observed with sex (P = .82), Charlson comorbidity index (P = .51), pT/N stage (P = .95), and surgical margin status (P = .29). Conclusions and Relevance: This study found that AC after NAC and RC may be associated with an OS benefit for patients with pT3/T4 and/or pN+ UCB. The present findings should be considered as preliminary evidence to conduct a randomized clinical trial to address this association. PMID- 28837720 TI - Errors in Tables. PMID- 28837719 TI - Modeling the Pathophysiology of Phonotraumatic Vocal Hyperfunction With a Triangular Glottal Model of the Vocal Folds. AB - Purpose: Our goal was to test prevailing assumptions about the underlying biomechanical and aeroacoustic mechanisms associated with phonotraumatic lesions of the vocal folds using a numerical lumped-element model of voice production. Method: A numerical model with a triangular glottis, posterior glottal opening, and arytenoid posturing is proposed. Normal voice is altered by introducing various prephonatory configurations. Potential compensatory mechanisms (increased subglottal pressure, muscle activation, and supraglottal constriction) are adjusted to restore an acoustic target output through a control loop that mimics a simplified version of auditory feedback. Results: The degree of incomplete glottal closure in both the membranous and posterior portions of the folds consistently leads to a reduction in sound pressure level, fundamental frequency, harmonic richness, and harmonics-to-noise ratio. The compensatory mechanisms lead to significantly increased vocal-fold collision forces, maximum flow-declination rate, and amplitude of unsteady flow, without significantly altering the acoustic output. Conclusion: Modeling provided potentially important insights into the pathophysiology of phonotraumatic vocal hyperfunction by demonstrating that compensatory mechanisms can counteract deterioration in the voice acoustic signal due to incomplete glottal closure, but this also leads to high vocal-fold collision forces (reflected in aerodynamic measures), which significantly increases the risk of developing phonotrauma. PMID- 28837722 TI - Drug Development at the Portfolio Level Is Important for Policy, Care Decisions and Human Protections. PMID- 28837721 TI - Visual Function in Asymptomatic Patients With Homozygous Sickle Cell Disease and Temporal Macular Atrophy. AB - Importance: Temporal macular involvement in sickle cell disease can now easily be detected by optical coherence tomography (OCT). However, while recent studies have demonstrated its high prevalence, little is known about its potential consequences on visual function. Objective: To assess the visual function of patients with sickle cell disease with no visual symptoms despite temporal macular atrophy. Design, Setting, and Participants: This retrospective case series included data collection and explorations made in a single referral center for sickle cell disease in 2016. Three patients with sickle cell disease exhibiting preserved visual acuity but showing temporal macular retinal atrophy were included. Exposures: Patients underwent the following explorations: best corrected distance and near visual acuity evaluation; dilated fundus examination; OCT with 12 * 6-mm thickness map; horizontal, vertical, and en face sections; OCT angiography of the 6 * 6-mm perifoveal retina; 30 degrees and 12 degrees central visual fields; Lanthony 15-hue color vision test; automated static contrast sensitivity test; and global electroretinography. Main Outcomes and Measures: The OCT thickness maps were checked for areas of retinal thinning, appearing as blue patches. When present, these areas were compared with the areas of superficial and deep capillary flow loss on OCT angiography and with the scotomas on visual fields. Contrast sensitivity and color vision loss were quantified. Results: All 3 patients included had homozygous sickle cell disease. They presented with a 20/20 distance visual acuity, and Parinaud 1,5 near visual acuity in both eyes. They were all followed up for a severe cerebral vasculopathy related to sickle cell disease. The areas of atrophy involved the inner retinal layers and were associated with an absence of signal in the deep capillary plexuses in OCT angiography. These patches of retinal thinning were also matching with scotomas in the automated visual fields. Color vision ability and contrast sensitivity were impaired in all patients. Global electroretinography findings were normal. Conclusions and Relevance: Temporal macular atrophy in sickle cell disease may have direct consequences on visual function, including in children, even when visual acuity is preserved. Optical coherence tomographic imaging may be warranted when evaluating patients with sickle cell disease, even if asymptomatic with 20/20 visual acuity. PMID- 28837724 TI - Typographical Data Error in Abstract. PMID- 28837723 TI - Orientation of the Temporal Nerve Fiber Raphe in Healthy and in Glaucomatous Eyes. AB - Purpose: To determine the normal variation in orientation of the temporal nerve fiber raphe, and the accuracy with which it may be predicted or approximated in lieu of direct measurement. Methods: We previously described an algorithm for automatic measurement of raphe orientation from optical coherence tomography, using the intensity of vertically oriented macular cubes. Here this method was applied in 49 healthy participants (age 19-81 years) and 51 participants with primary open angle glaucoma (age 51-80 years). Results: Mean fovea-disc-raphe angle was 173.5 degrees +/- 3.2 degrees (range = 166 degrees -182 degrees ) and 174.2 degrees +/- 3.4 degrees (range = 166 degrees -184 degrees ) in healthy and glaucoma patients, respectively. Differences between groups were not significant. Fovea-disc-raphe angle was not correlated with age or axial length (P > 0.4), showed some symmetry between eyes in glaucoma (R2 = 0.31, P < 0.001), and little symmetry in the healthy group (P = 0.06). Fovea-disc angle was correlated with fovea-raphe angle (R2 = 0.27, P = 0.0001), but was not a good predictor for raphe orientation (average error = 6.8 degrees ). The horizontal axis was a better predictor (average error = 3.2 degrees ; maximum error = 9.6 degrees ), but still gave approximately twice the error previously reported for direct measurement from macular cubes. Conclusions: There is substantial natural variation in temporal nerve fiber raphe orientation, which cannot be predicted from age, axial length, relative geometry of the disc and fovea, or the contralateral eye. For applications to which the orientation of the raphe is considered important, it should be measured directly. PMID- 28837725 TI - Comparison of Output Volume Thresholds for Drain Removal After Selective Lateral Neck Dissection: A Randomized Clinical Trial. PMID- 28837726 TI - Respiratory and Laryngeal Changes With Vocal Loading in Younger and Older Individuals. AB - Purpose: The objective of the current study was to investigate the effects of age and vocal loading on the respiratory and laryngeal systems. Method: Fourteen younger (M = 20 years) and 13 older (M = 75 years) healthy individuals participated in a 40-min vocal loading challenge in the presence of 70-dB background noise. Respiratory kinematic and laryngeal measurements were obtained before and after the challenge. Results: Following the loading challenge, participants in both groups reported greater speaking effort. Sound pressure level increased in the older group and decreased in the younger group after loading. Younger adults, but not older adults, used lower lung volume initiations and higher lung volume terminations after loading. Cepstral peak prominence increased with loading in both groups, but this change was of small magnitude and not clinically significant. Conclusions: The negative effects of loading were observed in respiratory and laryngeal measures, although the pattern of changes differed across the groups. These data increase our knowledge of underlying respiratory and laryngeal physiological changes following a loading challenge and may reflect some of the physiologic mechanisms underlying vocal fatigue. PMID- 28837727 TI - Short-Term Effect of Two Semi-Occluded Vocal Tract Training Programs on the Vocal Quality of Future Occupational Voice Users: "Resonant Voice Training Using Nasal Consonants" Versus "Straw Phonation". AB - Purpose: The purpose of this study was to determine the short-term effect of 2 semi-occluded vocal tract training programs, "resonant voice training using nasal consonants" versus "straw phonation," on the vocal quality of vocally healthy future occupational voice users. Method: A multigroup pretest-posttest randomized control group design was used. Thirty healthy speech-language pathology students with a mean age of 19 years (range: 17-22 years) were randomly assigned into a resonant voice training group (practicing resonant exercises across 6 weeks, n = 10), a straw phonation group (practicing straw phonation across 6 weeks, n = 10), or a control group (receiving no voice training, n = 10). A voice assessment protocol consisting of both subjective (questionnaire, participant's self-report, auditory-perceptual evaluation) and objective (maximum performance task, aerodynamic assessment, voice range profile, acoustic analysis, acoustic voice quality index, dysphonia severity index) measurements and determinations was used to evaluate the participants' voice pre- and posttraining. Groups were compared over time using linear mixed models and generalized linear mixed models. Within group effects of time were determined using post hoc pairwise comparisons. Results: No significant time * group interactions were found for any of the outcome measures, indicating no differences in evolution over time among the 3 groups. Within-group effects of time showed a significant improvement in dysphonia severity index in the resonant voice training group, and a significant improvement in the intensity range in the straw phonation group. Conclusions: Results suggest that the semi-occluded vocal tract training programs using resonant voice training and straw phonation may have a positive impact on the vocal quality and vocal capacities of future occupational voice users. The resonant voice training caused an improved dysphonia severity index, and the straw phonation training caused an expansion of the intensity range in this population. PMID- 28837729 TI - Analyzing and Predicting Visual Acuity Outcomes of Anti-VEGF Therapy by a Longitudinal Mixed Effects Model of Imaging and Clinical Data. AB - Purpose: We develop a longitudinal statistical model describing best-corrected visual acuity (BCVA) changes in anti-VEGF therapy in relation to imaging data, and predict the future BCVA outcome for individual patients by combining population-wide trends and initial subject-specific time points. Methods: Automatic segmentation algorithms were used to measure intraretinal (IRF) and subretinal (SRF) fluid volume on monthly spectral-domain optical coherence tomography scans of eyes with central retinal vein occlusion (CRVO) receiving standardized anti-VEGF treatment. The trajectory of BCVA over time was modeled as a multivariable repeated-measure mixed-effects regression model including fluid volumes as covariates. Subject-specific BCVA trajectories and final treatment outcomes were predicted using a population-wide model and individual observations from early follow-up. Results: A total of 193 eyes (one per patient, 12-month follow-up, 2420 visits) were analyzed. The population-wide mixed model revealed that the impact of fluid on BCVA is highest for IRF in the central millimeter around the fovea, with -31.17 letters/mm3 (95% confidence interval [CI], -39.70 to -23.32), followed by SRF in the central millimeter, with -17.50 letters/mm3 ( 31.17 to -4.60) and by IRF in the parafovea, with -2.87 letters/mm3 (-4.71 to 0.44). The influence of SRF in the parafoveal area was -1.24 letters/mm3 (-3.37 1.05). The conditional R2 of the model, including subject-specific deviations, was 0.887. The marginal R2 considering the population-wide trend and fluid changes was 0.109. BCVA at 1 year could be predicted for an individual patient after three visits with a mean absolute error of six letters and a predicted R2 of 0.658 using imaging information. Conclusions: The mixed-effects model revealed that retinal fluid volumes and population-wide trend only explains a small proportion of the variation in BCVA. Individual BCVA outcomes after 1 year could be predicted from initial BCVA and fluid measurements combined with the population-wide model. Accounting for fluid in the predictive model increased prediction accuracy. PMID- 28837730 TI - A Novel Potentially Causative Variant of NDUFAF7 Revealed by Mutation Screening in a Chinese Family With Pathologic Myopia. AB - Purpose: Pathologic myopia described as myopia accompanied by severe deformation of the eye besides excessive elongation of eye, is usually a genetic heterogeneous disorder characterized by extreme, familial, early-onset vision loss. However, the exact pathogenesis of pathologic myopia remains unclear. In this study, we screened a Han Chinese family with pathologic myopia to identify the causative mutation and explore the possible pathogenic mechanism based on evaluation of the biological functions of the mutation. Methods: We identified the mutations in a family with pathologic myopia by single nucleotide polymorphism array combined with short tandem repeat microsatellite marker analysis and exome sequencing. Mutations were validated among family members by direct Sanger sequencing. The subcellular localization of the protein variant was investigated by immunofluorescence, and the stability of the mutant protein was determined by immunoblotting. Intracellular levels of adenosine triphosphate and reactive oxygen species and complex I activity were measured by traditional biochemical methods to determine the functional role of the disease-associated mutation. Results: The novel missense mutation: c.798C>G (p.Asp266Glu) in NDUFAF7, cosegregated with the disease and the resulting amino acid substitution affected a highly conserved residue in its protein. The mutation D266E in NDUFAF7 impaired complex I activity, which resulted in decreased ATP levels in cultured cells. Conclusions: We propose that the heterozygous mutation (c.798C>G) in NDUFAF7 may contribute to the pathogenesis of pathologic myopia, possibly by interfering with the phototransduction cascade. Mitochondrial dysfunction during eye development may lead to pathologic myopia. PMID- 28837728 TI - How Stuttering Develops: The Multifactorial Dynamic Pathways Theory. AB - Purpose: We advanced a multifactorial, dynamic account of the complex, nonlinear interactions of motor, linguistic, and emotional factors contributing to the development of stuttering. Our purpose here is to update our account as the multifactorial dynamic pathways theory. Method: We review evidence related to how stuttering develops, including genetic/epigenetic factors; motor, linguistic, and emotional features; and advances in neuroimaging studies. We update evidence for our earlier claim: Although stuttering ultimately reflects impairment in speech sensorimotor processes, its course over the life span is strongly conditioned by linguistic and emotional factors. Results: Our current account places primary emphasis on the dynamic developmental context in which stuttering emerges and follows its course during the preschool years. Rapid changes in many neurobehavioral systems are ongoing, and critical interactions among these systems likely play a major role in determining persistence of or recovery from stuttering. Conclusion: Stuttering, or childhood onset fluency disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; American Psychiatric Association [APA], 2013), is a neurodevelopmental disorder that begins when neural networks supporting speech, language, and emotional functions are rapidly developing. The multifactorial dynamic pathways theory motivates experimental and clinical work to determine the specific factors that contribute to each child's pathway to the diagnosis of stuttering and those most likely to promote recovery. PMID- 28837731 TI - Quantitative Characterization of Autoimmune Uveoretinitis in an Experimental Mouse Model. AB - Purpose: To accurately evaluate the autoimmune inflammation, we aim to develop three quantitative measurements to monitor the inflammatory changes in the retina: retinal-choroidal thickness, major retinal vessel diameter, and electroretinography amplitudes. Methods: During a 21-day experimental period, eyes were examined by confocal scanning laser ophthalmoscopy, optical coherence tomography, fundus fluorescein angiography, and electroretinography in living mice, which were then subsequently killed for histologic assessments. Results: On day 21 postimmunization, inflammation was observed both in vivo and in vitro. Fold change of retinal-choroidal thickness and major retinal vessel diameter in experimental autoimmune uveoretinitis mice were significantly greater than controls (P < 0.001). Both scotopic and photopic electroretinography amplitudes were significantly attenuated when compared with control mice (P < 0.01). Our results showed that these three quantifiable indicators provided an objective and accurate evaluation of autoimmune inflammation, which are in good correlations with the reported clinical and histopathologic scoring systems (P < 0.05). Conclusions: These three indicators will be useful to detect the small but significant differences in the severity of experimental autoimmune uveoretinitis for future longitudinally therapeutic studies. PMID- 28837732 TI - Candida Species From Eye Infections: Drug Susceptibility, Virulence Factors, and Molecular Characterization. AB - Purpose: To determine the type of Candida species in ocular infections and to investigate the relationship of antifungal susceptibility profile to virulence factors. Methods: Fifty isolates of yeast-like fungi from patients with keratitis, endophthalmitis, and orbital cellulitis were identified by Vitek-2 compact system and DNA sequencing of ITS1-5.8S-ITS2 regions of the rRNA gene, followed by phylogenetic analysis for phenotypic and genotypic identification, respectively. Minimum inhibitory concentration of six antifungal drugs was determined by E test/microbroth dilution methods. Phenotypic and genotypic methods were used to determine the virulence factors. Results: Phylogenetic analysis showed the clustering of all isolates into eight distinct groups with a major cluster formed Candida parapsilosis (n = 21), which was the most common species by both Vitek 2 and DNA sequencing. Using chi2 test no significant difference was noted between the techniques except that Vitek 2 did not identify C. viswanathii, C. orthopsilosis, and two non-Candida genera. Of 43 tested Candida isolates high susceptibility to amphotericin B (39/43, 90.6%) and natamycin (43/43, 100%) was noted. While none of the isolates produced coagulase, all produced esterase and catalase. The potential to form biofilm was detected in 23/43 (53.4%) isolates. Distribution of virulence factors by heat map analysis showed difference in metabolic activity of biofilm producers from nonbiofilm producers. Conclusions: Identified by Vitek 2 and DNA sequencing methods C. parapsilosis was the most common species associated with eye infections. Irrespective of the virulence factors elaborated, the Candida isolates were susceptible to commonly used antifungal drugs such as amphotericin B and natamycin. PMID- 28837734 TI - Error in Author Name and Affiliations. PMID- 28837733 TI - Erratum. PMID- 28837735 TI - Partial Costal Cartilage Harvest for Rhinoplasty. PMID- 28837736 TI - Prevalence and Associations of Retinal Emboli With Ethnicity, Stroke, and Renal Disease in a Multiethnic Asian Population: The Singapore Epidemiology of Eye Disease Study. AB - Importance: To our knowledge, population-based data on retinal emboli are limited in Asia. Besides its associations with traditional cardiovascular risk factors and stroke, associations between retinal emboli and renal disease and function remain unclear. Objective: To examine the prevalence of and risk factors for retinal emboli in a large, contemporary, multiethnic Asian population. Design, Setting, and Participants: This population-based cross-sectional study was conducted from 2004 to 2011 and included a total of 10 033 Chinese, Malay, and Indian persons aged 40 to 80 years residing in the general communities of Singapore. Analyses were performed from November 2016 to February 2017. Interventions or Exposures: Retinal emboli were ascertained from retinal photographs obtained from both eyes of all participants according to a standardized protocol. Age-standardized prevalence of retinal emboli was calculated using the 2010 Singapore adult population. Risk factors were assessed from comprehensive systemic and ophthalmic examinations, interviews, and laboratory investigations. Main Outcomes and Measures: Retinal emboli. Results: Of the 10 033 participants, 9978 (99.5%) had gradable retinal photographs. Of these, 5057 (50.7%) were female, and 3375 (33.8%) were Indian. We identified 88 individuals (0.9%) with retinal emboli; the overall person-specific, age standardized prevalence of retinal emboli was 0.75% (95% CI, 0.60-0.95), with the highest prevalence seen in the Indian cohort (0.98%), followed by the Chinese (0.73%) and Malay (0.44%) cohorts (P = .03). In multivariable-adjusted analysis, factors associated with prevalent retinal emboli included older age (per 5-year increase; odds ratio [OR], 1.22; 95% CI, 1.05-1.41), Indian ethnicity (compared with Malay ethnicity; OR, 3.58; 95% CI, 1.95-6.60), hypertension (OR, 1.95; 95% CI, 1.03-3.70), chronic kidney disease (OR, 2.05; 95% CI, 1.15-3.64), creatinine level (per SD increase; OR, 1.13; 95% CI, 1.05-1.21), glomerular filtration rate (per SD increase; OR, 0.67; 95% CI, 0.51-0.86), and history of stroke (OR, 3.45; 95% CI, 1.70-6.99). Conclusions and Relevance: Based on 88 individuals among 9978 participants of 3 major Asian ethnic populations, retinal emboli were most commonly seen in Indian persons and associated with conventional cardiovascular risk factors, stroke, and chronic kidney disease. Therefore, its presence may signal vascular embolic event and damage not only in the brain but also in the kidneys. If these data are confirmed in longitudinal studies, they would suggest that persons with retinal emboli may require both general cardiovascular and renal assessment. PMID- 28837737 TI - Comparison of W-Plasty and Straight-Line Trichophytic Closure on Aesthetic Outcomes of Occipital Hairline Scars in Rhytidectomy. AB - Importance: Incision placement and design in rhytidectomy is critical for patient satisfaction. Objective: To evaluate the aesthetic outcome of W-plasty vs traditional straight-line (SL) trichophytic closure techniques on posterior occipital hairline scars in rhytidectomy. Design, Setting, and Participants: A retrospective cohort study was conducted at the Buckingham Center for Facial Plastic Surgery. Clinical history and operative reports were reviewed for 46 patients who underwent rhytidectomy (23 using W-plasty and 23 using SL technique) between June 1, 2014 and August 31, 2015. Blinded photographic analysis of 1-year postoperative photographs was performed. Interventions: The posterior occipital hairline incision was primarily closed with either a W-plasty or SL trichophytic technique. Main Outcomes and Measures: Standard photographs of the posterior occipital incision site obtained after the 1-year postoperative mark were reviewed and scored in a blinded fashion by 3 nonphysician medical staff members using a modified Manchester Scar Scale (MSS: from 0 [best possible outcome] to 24 [worst possible outcome]). Interrater reliability was assessed via Cronbach alpha testing. Results: There were 23 patients in each group. The W-plasty and SL groups were similar in terms of age (mean [SD] age, 59.6 [6.3] years and 64.1 [7.3] years, respectively), sex (21 [91%] and 21 [91%] women, respectively), race ethnicity, and absence of risk factors (smoking and diabetes) predisposing to poor wound healing (0 and 0 smoking/diabetes, respectively). Mean (SD) follow-up times for the W-plasty and SL groups were 388 (38.8) and 475 (100.1) days, respectively. No statistical difference was demonstrated in the mean aggregate MSS scores from all evaluators between the W-plasty group and the SL group (reviewer 1: 5.69 vs 5.86, P = .60; reviewer 2: 10.09 vs 9.56, P = .65; and reviewer 3: 5.30 vs 6.17, P = .08). Overall interrater reliability for the MSS scores was 0.56. Conclusion and Relevance: Primary W-plasty and SL trichophytic closures in the posterior occipital hairline appear to yield highly acceptable and similar cosmetic outcomes under objective blinded evaluation. These techniques can be used with success to help minimize conspicuous scarring after rhytidectomy. Level of Evidence: 3. PMID- 28837738 TI - A Man With Bilateral Peripheral Visual Field Loss. PMID- 28837739 TI - Animal Model for Retinopathy of Prematurity Laser Surgery Training. AB - Peripheral retinal laser ablation for high-risk retinopathy of prematurity (ROP) improves visual outcomes. Some pediatric ophthalmology fellows receive little exposure to this procedure. The authors identified and evaluated an animal teaching model that simulates peripheral retinal laser ablation in human infants with ROP. [J Pediatr Ophthalmol Strabismus. 2017;54:e47-e49.]. PMID- 28837740 TI - Managing Hypoplasia of the Inferior Rectus Muscle by Inferior Oblique Anterior Transposition in Children. AB - Congenital hypoplasia or aplasia of the inferior rectus muscle is an uncommon condition. The authors present two pediatric patients with hypoplasia of the inferior rectus muscle treated by inferior oblique anterior transposition. The long-term follow-up outcomes of eye position and stereopsis acuity development were favorable. [J Pediatr Ophthalmol Strabismus. 2017;54:e50-e53.]. PMID- 28837741 TI - Torpedo Maculopathy in a 6-Month-Old Infant: Early Clinical and Optical Coherence Tomography Findings. AB - A 6-month-old male infant presented for routine ophthalmologic examination. Indirect ophthalmoscopy revealed a flat, oval, hypopigmented lesion located in the temporal macula in the right eye with the tip pointing toward the fovea, which was compatible with torpedo maculopathy. Optical coherence tomography (OCT) was performed at the time of diagnosis. OCT scans of the lesion revealed slight retinal pigment epithelium hyperreflectivity. This case serves as the earliest OCT finding of the youngest patient diagnosed as having torpedo maculopathy in the literature. [J Pediatr Ophthalmol Strabismus. 2017;54:e54-e57.]. PMID- 28837742 TI - Fast separation of enantiomers by capillary electrophoresis using a combination of two capillaries with different internal diameters. AB - The combination of capillaries with different internal diameters was used to accelerate the separation of enantiomers in capillary electrophoresis. Separation of R,S-1,1'-binaphthalene-2,2'-diyl hydrogen phosphate using isopropyl derivative of cyclofructan 6 was studied as a model system. The best separation conditions included 500 mM sodium borate pH 9.5 with 60 mM concentration of the chiral selector. Separation lasted approx. 1.5 min using the combination of 50 and 100 MUm id capillaries of 9.7 cm and 22.9 cm, respectively. It allowed approx. 12 fold acceleration in comparison to the traditional long-end separation mainly due to the higher electroosmotic flow generated in the connected capillaries. PMID- 28837743 TI - Oxidation-Responsive Aliphatic Polycarbonates from N-Substituted Eight-Membered Cyclic Carbonate: Synthesis and Degradation Study. AB - Oxidation-responsive aliphatic polycarbonates represent a promising branch of functional biodegradable polymers. This paper reports the synthesis and ring opening polymerization (ROP) of an eight-membered cyclic carbonate possessing phenylboronic pinacol ester (C3) and the H2 O2 -triggered degradation of its polymer (PC3). C3 is prepared from the inexpensive and readily available diethanolamine with a moderate yield and undergoes the well-controlled anionic ROP with a living character under catalysis of 1,8-diazabicyclo[5.4.0]undec-7 ene. It can also be copolymerized with l-lactide, trimethylene carbonate, and 5 ter-butyloxycarbonylamino trimethylene carbonate, affording the copolymers with a varied distribution of the repeating units. To clearly demonstrate the oxidative degradation mechanism of PC3, this paper first investigates the H2 O2 -induced decomposition of small-molecule model compounds by proton nuclear magnetic resonance (1 H NMR). It is found that the adduct products formed by the in-situ generated secondary amines and p-quinone methide (QM) are thermodynamically unstable and can decompose slowly back to QM and the amines. On this basis, this paper further studies the H2 O2 -accelerated degradation of PC3 nanoparticles that are prepared by the o/w emulsion method. A sequential process of oxidation of the phenylboronic ester, 1,6-elimination of the in-situ-generated phenol, releasing CO2 and intramolecular cyclization or isomerization is proposed as the degradation mechanism of PC3. PMID- 28837744 TI - An arthropod survival strategy in a frequently burned forest. PMID- 28837745 TI - Advanced Photonic Processes for Photovoltaic and Energy Storage Systems. AB - Solar-energy harvesting through photovoltaic (PV) conversion is the most promising technology for long-term renewable energy production. At the same time, significant progress has been made in the development of energy-storage (ES) systems, which are essential components within the cycle of energy generation, transmission, and usage. Toward commercial applications, the enhancement of the performance and competitiveness of PV and ES systems requires the adoption of precise, but simple and low-cost manufacturing solutions, compatible with large scale and high-throughput production lines. Photonic processes enable cost efficient, noncontact, highly precise, and selective engineering of materials via photothermal, photochemical, or photophysical routes. Laser-based processes, in particular, provide access to a plethora of processing parameters that can be tuned with a remarkably high degree of precision to enable innovative processing routes that cannot be attained by conventional approaches. The focus here is on the application of advanced light-driven approaches for the fabrication, as well as the synthesis, of materials and components relevant to PV and ES systems. Besides presenting recent advances on recent achievements, the existing limitations are outlined and future possibilities and emerging prospects discussed. PMID- 28837746 TI - Hepatitis C virus-related symptoms, but not quality of life, were improved by treatment with direct-acting antivirals. AB - AIM: Direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection have a significantly high sustained virologic response rate after a short treatment course and do not have any severe adverse effects. Patient reported outcomes (PROs) have become increasingly important to assess the total impact of a chronic disease. We aimed to evaluate the changes in symptoms of patients with HCV infection treated with DAAs by using PROs. METHODS: A total of 107 patients with chronic HCV infection were treated with DAAs. Daclatasvir/asunaprevir or sofosbuvir/ledipasvir was used for HCV 1B infection, and sofosbuvir/ribavirin for HCV 2A/2B infection. The PROs measured at the start of treatment and 1 year after the start of treatment were cirrhosis-related symptom score (CSS), presence of restless legs syndrome (RLS), Epworth sleepiness scale (ESS), Pittsburg sleep quality index (PSQI), Kessler 6 score (K-6), and the SF-36 to measure quality of life (QOL). All patients had a sustained virologic response rate of 24. RESULTS: The CSS, PSQI, K-6, and RLS scores were improved 1 year after beginning treatment. However, QOL had not recovered. Changes in total CSS were correlated with HCV genotype, sex, hypertensive drug use, serum low density lipoprotein, and ESS at the start of treatment and RLS 1 year after the start of treatment. The factors that contributed to worsening of CSS were HCV genotype 2B and RLS 1 year after the start of treatment. CONCLUSION: Treatment with DAAs eliminated HCV-RNA and improved most symptoms, but QOL did not recover. PMID- 28837747 TI - Model for end-stage liver disease exceptions: A common problem. PMID- 28837748 TI - Tuning the response of osteoblast-like cells to the porous-alumina-assisted mixed oxide nano-mound arrays. AB - Nanostructuring of biomaterials is used to create an appropriate interfacial layer that promotes stable cellular adhesion, proliferation, and differentiation on orthopedic and dental implants. Here, we synthesize self-organized arrays of composite-oxide nano-mounds through anodizing Al/Ta bilayers sputtered on substrates to cover the "missing" smallest size range of 10-40 nm for structuring an advanced inorganic biomaterial-Al2 O3 -doped Ta2 O5 films. The osteoblast-like cells appear to be able to recognize the finest differences in the film nano morphologies. In the absence of serum proteins, the adhesion and cell growth are substantially enhanced on the 20 and 40 nm nanoarrays while in complete medium the cells show better initial adhesion on the 10 nm nanoarrays. The proliferation assay reveals a significant rise in cell number on the 20 and 40 nm nanoarrays during the first 7 days. A remarkable increase in the alkaline phosphatase activity is noticed on the 40 nm nanoarray. Immunostaining of cells adhered to the nano-mound surfaces shows that the cells are well spread over all the nanostructured films with organized actin fibers. The larger surface areas and improved focal contacts are again associated with the 20 and 40 nm nanoarrays. The findings help improve compatibility of living cells with the metal-oxide nanostructured surfaces developed for tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1645-1654, 2018. PMID- 28837749 TI - Vaccination to prevent de novo hepatitis B: Are there patients who do not need antiviral prophylaxis? PMID- 28837750 TI - Smart Electrochemical Energy Storage Devices with Self-Protection and Self Adaptation Abilities. AB - Currently, with booming development and worldwide usage of rechargeable electrochemical energy storage devices, their safety issues, operation stability, service life, and user experience are garnering special attention. Smart and intelligent energy storage devices with self-protection and self-adaptation abilities aiming to address these challenges are being developed with great urgency. In this Progress Report, we highlight recent achievements in the field of smart energy storage systems that could early-detect incoming internal short circuits and self-protect against thermal runaway. Moreover, intelligent devices that are able to take actions and self-adapt in response to external mechanical disruption or deformation, i.e., exhibiting self-healing or shape-memory behaviors, are discussed. Finally, insights into the future development of smart rechargeable energy storage devices are provided. PMID- 28837751 TI - Qualitative and quantitative determination of YiXinShu Tablet using ultra high performance liquid chromatography with Q Exactive hybrid quadrupole orbitrap high resolution accurate mass spectrometry. AB - To clarify and quantify the chemical profile of YiXinShu Tablet rapidly, a feasible and accurate strategy was developed by applying ultra high performance liquid chromatography with Q Exactive hybrid quadrupole orbitrap high-resolution accurate mass spectrometry. A total of 105 components were identified, including 25 phenanthraquinones, 11 lactones, 19 lignans, 24 acids, and 26 other compounds. Among them, 26 major compounds were unambiguously detected by comparing with reference standards. And 19 of these compounds in three batches of YiXinShu Tablet were selected for quantitative determination. (Z)-Ligustilide, salvianic acid A, salvianolic acid A, salvianolic acid B, and rosmarinic acid were abundant in these three batches with contents over 1 mg/g. The established analysis methods were examined to be accurate and feasible. The results show that the ultra high performance liquid chromatography with Q Exactive hybrid quadrupole orbitrap high-resolution accurate mass spectrometry method has a powerful qualitative ability and promising quantitative application. PMID- 28837752 TI - Enhancing surface properties of breast implants by using electrospun silk fibroin. AB - In the present study, a new electrospun silk fibroin coating of silicone breast implants with improved biocompatibility and mechanical properties was obtained. Fibrous scaffolds were produced by electrospinning a solution containing silk fibroin, derived from Bombyx mori cocoons, and polyethylene oxide (PEO) to be used as a coating of breast implants. A randomly oriented structure of fibroin/PEO was electrospun on implants as assessed by SEM analysis, roughness measurements and ATR-FTIR spectroscopy. The scaffold showed 0.25 um diameter fibres, 0.76 um size superficial pores, arithmetic roughness of 0.632 +/- 0.12 um and texture aspect ratio of 0.893 +/- 0.04. ATR-FTIR spectroscopy demonstrates the presence of PEO and fibroin in the coating. The mechanical characterisation of the implants before and after being coated with fibroin/PEO demonstrated that the fibroin/PEO scaffold contributes to the increase in the elastic modulus from 0.392 +/- 0.02 to 0.560 +/- 0.03 MPa and to a more elastic behaviour of the breast implants. Using the fibroin/PEO coating, human fibroblasts seeded on this matrix increased viability up to 30% compared to conventional breast implants. Electrospun silk fibroin could represent a clinically compatible, viable form to coat breast implants. Low cytotoxicity by the fibroin coating and its physico chemical and mechanical properties may find application in improving breast implants biocompatibility. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1655-1661, 2018. PMID- 28837753 TI - Functional outcomes and quality of life after total laryngectomy with noncircumferential radial forearm free tissue transfer. AB - BACKGROUND: The purpose of this study was to compare long-term functional and quality of life (QOL) outcomes after total laryngectomy with primary closure and those who underwent reconstruction with noncircumferential radial free forearm tissue transfer (RFFTT). METHODS: Sixty-seven patients were identified by chart review and underwent long-term follow-up using QOL surveys and standardized interviews. RESULTS: The RFFTT group had significantly higher rates of chemotherapy, gastric tube (G-tube) at surgery, and postoperative stricture. At follow-up, most patients (88%) had a tracheoesophageal prosthesis (TEP) and were using it as their primary communication method. Diet and swallowing outcomes were comparable and no one had a G-tube. Device life and TEP complications did not differ significantly. Only voice-related QOL differed significantly between the RFFTT group and those who had undergone total laryngectomy without adjuvant treatment. CONCLUSION: Despite more extensive treatment, the reconstructed group achieved comparable outcomes to those who had undergone total laryngectomy with adjuvant treatment. PMID- 28837754 TI - Monitoring quality consistency of Liuwei Dihuang Pill by integrating the ultraviolet spectroscopic fingerprint, a multi-wavelength fusion fingerprint method, and antioxidant activities. AB - Liuwei Dihuang Pill, a classical traditional Chinese medicine, has been widely used to treat kidney yin deficiency in China for hundreds of years. Little attention, however, has been paid to quality control methods for this formulation. In the present study, we aimed to establish a comprehensive and practical quality evaluation system for Liuwei Dihuang Pill. Thus, ultraviolet spectroscopic fingerprints and multi-wavelength fusion fingerprints have been proposed for quality consistency evaluation of the popular patent. The similarity analysis of Liuwei Dihuang Pill samples was evaluated by systematic quantitative fingerprint method from qualitative and quantitative perspectives. The results showed that 26 batches of samples were classified into five grades for fusion fingerprints and three grades for ultraviolet spectroscopic fingerprints. Moreover, the fingerprint-efficacy correlation was also established and confirmed through the partial least squares model to visualize the antioxidant activity of Liuwei Dihuang Pill in vitro. In conclusion, these results indicated that integrating ultraviolet spectroscopic fingerprints and multi-wavelength fusion fingerprints coupled with antioxidant activities provide a rapid and effective approach to monitor the quality consistency of Liuwei Dihuang Pill. PMID- 28837755 TI - Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti-Hyperlipidemic and Antioxidant Agents. AB - Hyperlipidemia and oxidative stress have been implicated as contributing factors to the development of atherosclerosis and cardiovascular diseases (CVDs). Currently, a large number of antihyperlipidemic medications are conveniently available in the market. Nonetheless, the majority of antihyperlipidemics lack the desired safety and efficacy. Thus, the present study was undertaken to evaluate the potential effect of novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives in controlling hyperlipidemia and oxidative stress using the Triton WR-1339-induced hyperlipidemic rat model for antihyperlipidemic activity and the DPPH radical scavenging assay for antioxidant activity. This study revealed the antihyperlipidemic activities of some of the newly synthesized, novel carboxamide derivatives, mainly C4 and C12 (p < 0.05). The majority of the compounds displayed a relatively low or no DPPH radical scavenging effect, with C20 possessing the best radical scavenging effect (22%) among all. This research opens the door for new potential antihyperlipidemic compounds derived from isonicotinic acid. N-(3-Benzoylphenyl)pyridine-4-carboxamide (C4) was found to have promising lipid-lowering and antioxidant effects, which may create a protective effect against CVDs, by reducing the LDL-C levels and diminishing the generation of reactive oxygen species. PMID- 28837756 TI - Scalable Manufacturing of Solderable and Stretchable Physiologic Sensing Systems. AB - Methods for microfabrication of solderable and stretchable sensing systems (S4s) and a scaled production of adhesive-integrated active S4s for health monitoring are presented. S4s' excellent solderability is achieved by the sputter-deposited nickel-vanadium and gold pad metal layers and copper interconnection. The donor substrate, which is modified with "PI islands" to become selectively adhesive for the S4s, allows the heterogeneous devices to be integrated with large-area adhesives for packaging. The feasibility for S4-based health monitoring is demonstrated by developing an S4 integrated with a strain gauge and an onboard optical indication circuit. Owing to S4s' compatibility with the standard printed circuit board assembly processes, a variety of commercially available surface mount chip components, such as the wafer level chip scale packages, chip resistors, and light-emitting diodes, can be reflow-soldered onto S4s without modifications, demonstrating the versatile and modular nature of S4s. Tegaderm integrated S4 respiration sensors are tested for robustness for cyclic deformation, maximum stretchability, durability, and biocompatibility for multiday wear time. The results of the tests and demonstration of the respiration sensing indicate that the adhesive-integrated S4s can provide end users a way for unobtrusive health monitoring. PMID- 28837757 TI - Systemic antibiotics for treating malignant wounds. AB - BACKGROUND: Malignant wounds are a devastating complication of cancer. They usually develop in the last six months of life, in the breast, chest wall or head and neck regions. They are very difficult to treat successfully, and the commonly associated symptoms of pain, exudate, malodour, and the risk of haemorrhage are extremely distressing for those with advanced cancer. Treatment and care of malignant wounds is primarily palliative, and focuses on alleviating pain, controlling infection and odour from the wound, managing exudate and protecting the surrounding skin from further deterioration. In malignant wounds, with tissue degradation and death, there is proliferation of both anaerobic and aerobic bacteria. The aim of antibiotic therapy is to successfully eliminate these bacteria, reduce associated symptoms, such as odour, and promote wound healing. OBJECTIVES: To assess the effects of systemic antibiotics for treating malignant wounds. SEARCH METHODS: We searched the following electronic databases on 8 March 2017: the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library, 2017, Issue 3), Ovid MEDLINE, Ovid Embase and EBSCO CINAHL Plus. We also searched the clinical trial registries of the World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch) and ClinicalTrials.gov on 20 March 2017; and OpenSIGLE (to identify grey literature) and ProQuest Dissertations & Theses Global (to retrieve dissertation theses related to our topic of interest) on 13 March 2017. SELECTION CRITERIA: Randomised controlled trials that assessed the effects of any systemic antibiotics on malignant wounds were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected trials for inclusion, assessed risk of bias and extracted study data. A third reviewer checked extracted data for accuracy prior to analysis. MAIN RESULTS: We identified only one study for inclusion in this review. This study was a prospective, double-blind cross-over trial that compared the effect of systemic metronidazole with a placebo on odour in malignant wounds. Nine participants with a fungating wound and for whom the smell was troublesome were recruited and six of these completed both the intervention and control (placebo) stages of the trial. Each stage lasted fourteen days, with a fourteen day gap (washout period) between administration of the metronidazole and the placebo.The study, in comparing metronidazole and placebo, reported on two of this review's pre-specified primary outcomes (malodour and adverse effects of the treatment) and on none of the review's pre-specified secondary outcomes.MalodourThe mean malodour (smell) scores for the metronidazole group was 1.17 (standard deviation (SD) 1.60) and the mean for the placebo group was 3.33 (SD 0.82). It is unclear if systemic antibiotics were associated with a difference in malodour (1 study with 6 participants; MD -2.16, 95% CI -3.6 to 0.72) as the quality of the evidence (GRADE) was very low for this outcome. The study was downgraded due to high risk of attrition bias (33% loss to follow-up) and very serious imprecision due to the small sample size.Adverse effectsNo adverse effects of the treatment were reported in either the intervention or control group by the trial authors. AUTHORS' CONCLUSIONS: It is uncertain whether systemic metronidazole leads to a reduction in malodour in patients with malignant wounds. This is because we were only able to include a single study at high risk of bias with a very small sample size, which focused only on patients with breast cancer. More research is needed to substantiate these findings and to investigate the effects of systemic metronidazole and other antibiotics on quality of life, pain relief, exudate and tumour containment in patients with malignant wounds. PMID- 28837758 TI - Natural development of dermal ectopic bone in the american alligator (Alligator mississippiensis) resembles heterotopic ossification disorders in humans. AB - Heterotopic ossification (HO) occurs when soft tissues are inappropriately converted to bony tissue. Several human diseases result in HO with few reliable treatment options. Animal models that naturally produce dermal ectopic bone (i.e., osteoderms), such as crocodilians, have never been utilized as models for studying these disorders in humans. Here, a histological evaluation and staging criteria for osteoderm development is described for the first time in the American alligator (Alligator mississipiensis). Differential staining and immunohistochemistry of alligator scales depict a progressive change during development, where woven bone forms from the differentiated dermis. Bone formation proceeds via intramembranous ossification, which is initiated in part by endothelial cell precursors that undergo endothelial-to-mesenchymal transition and eventually acquire an osteoblast phenotype. As such, the development of osteoderms in the American alligator bears morphological and mechanistic similarities to HO in humans, presenting a potential model for future study of soft tissue mineralization pathologies and providing insight into the morphological and molecular development of osteoderms in other vertebrate lineages. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 301:56-76, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28837759 TI - Nanocarbons for Catalytic Desulfurization. AB - Nanocarbon catalysts are green and sustainable alternatives to metal-based catalysts for numerous catalytic transformations. The application of nanocarbons for environmental catalysis is an emerging research discipline and has undergone rapid development in recent years. In this focus review, we provide a critical analysis of state-of-the-art nanocarbon catalysts for three different catalytic desulfurization processes. In particular, we focus on the advantages and limitations as well as the reaction mechanisms of the nanocarbon catalysts at the molecular level. PMID- 28837760 TI - Bifunctional Initiators as Tools to Track Chain Transfer during the CROP of 2 Oxazolines. AB - Detailed kinetic studies during the cationic ring-opening polymerization (CROP) of 2-ethyl-2-oxazoline (EtOx) are conducted using four bifunctional bromo-type initiators in N,N-dimethylformamide (DMF) at 140 degrees C. Serving as models to quantify chain transfer to monomer occurring during the CROP initiated by monofunctional initiators, size exclusion chromatography (SEC) resolves a second molar mass distribution with lower molar mass at initial [monomer] to [initiation site] ratios ([M]0 /[I]0 ) of 25, while the resolution is insufficient at [M]0 /[I]0 of 10. Slightly slow initiation is revealed at [M]0 /[I]0 = 25, which prohibits the derivation of chain transfer rates by fitting of the size exclusion chromatography (SEC) data. Although conventional kinetic plots give no indication of significant amounts of chain transfer, the molar mass distributions resolved by SEC can unambiguously be identified as such by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) in both the high as well as the low m/z regions of the mass spectra. PMID- 28837761 TI - Diversification and convergence of aposematic phenotypes: truncated receptors and cellular arrangements mediate rapid evolution of coloration in harlequin poison frogs. AB - Aposematic signals represent one of the classical systems to study evolution and, as such, they have received considerable empirical and theoretical investigation. Despite the extensive literature on aposematic coloration, much uncertainty remains about genetic changes responsible for the repeated evolution of similar signals in multiple lineages. Here, we study the diversification and convergence of coloration among lineages of aposematic harlequin poison frogs (Oophaga histrionica complex). Our results suggest that different background phenotypes, showing different color and/or luminance contrast, have evolved independently at least twice in this group. We suggest that cellular arrangements are behind the striking diversity of color and patterns in this group and propose that differences in dorsal background color may be related to either or both, the presence/absence of xanthophores and the dispersion of melanosomes. Our genetic analyses support a role for the melanocortin receptor MC1R in melanosome aggregation, and we show evidence that two different mutations (?433 and C432A) are responsible for the darker phenotypes that may display a more detectable, easier to learn, aposematic signal. PMID- 28837762 TI - Young Children's Self-Concepts Include Representations of Abstract Traits and the Global Self. AB - There is debate about the abstractness of young children's self-concepts specifically, whether they include representations of (a) general traits and abilities and (b) the global self. Four studies (N = 176 children aged 4-7) suggested these representations are indeed part of early self-concepts. Studies 1 and 2 reexamined prior evidence that young children cannot represent traits and abilities. The results suggested that children's seemingly immature judgments in previous studies were due to peculiarities of the task context not the inadequacy of children's self-concepts. Similarly, Studies 3 and 4 revealed that, contrary to claims of immaturity in reasoning about the global self, young children update their global self-evaluations in flexible, context-sensitive ways. This evidence suggests continuity in the structure of self-concepts across childhood. PMID- 28837763 TI - Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells. AB - Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8 nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8 nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles. PMID- 28837764 TI - Novel Cell Model for Tauopathy Induced by a Cell-Permeable Tau-Related Peptide. AB - In the present study, a cell penetrating peptide (CPP)-amyloid conjugate was prepared (T-peptide), where the amyloid-forming sequence was homologous to a nucleating sequence from human Tau protein (306VQIVYK311). Kinetic and biophysical studies showed the peptide formed long-lived oligomers which were taken up by endocytosis and localized in perinuclear vesicles and in the cytoplasm of murine hippocampal neuroblastoma cells and human HeLa cells. Thioflavin S (ThS) staining of amyloid colocalized with pathological phosphorylated Tau, suggesting that the peptide was able to seed endogenous wild type Tau. Subsequent experiments showed that aggregates present in the lysosomes mediated lysosome membrane permeability (LMP). We observed a decrease in total Tau, irrespective of phosphorylation state, consistent with Tau fragmentation by lysosomal proteases. We found cytotoxicity of T-peptide could be abrogated by inhibitors of lysosomal hydrolases and caspases, consistent with a model where Tau fragments processed by the lysosome leak into the cytoplasm and induce toxicity in subsequent downstream steps. It is our hope that the T-peptide system may prove amenable to the evaluation of small molecule inhibitors of cytotoxicity, especially those which target either Tau aggregation or the lysosomal/autophagy system. PMID- 28837765 TI - Intracellular Assembly of Nuclear-Targeted Gold Nanosphere Enables Selective Plasmonic Photothermal Therapy of Cancer by Shifting Their Absorption Wavelength toward Near-Infrared Region. AB - Despite the important applications of near-infrared (NIR) absorbing nanomaterials in plasmonic photothermal therapy (PPT), their high yield synthesis and nonspecific heating during the active- and passive-targeted cancer therapeutic strategies remain challenging. In the present work, we systematically demonstrate that in situ aggregation of typical non-NIR absorbing plasmonic nanoparticles at the nuclear region of the cells could translate them into an effective NIR photoabsorber in plasmonic photothermal therapy of cancer due to a significant shift of the plasmonic absorption band to the NIR region. We evaluated the potential of nuclear-targeted AuNSs as photoabsorber at various stages of endocytosis by virtue of their inherent in situ assembling capabilities at the nuclear region of the cells, which has been considered as one of the most thermolabile structures within the cells, to selectively destruct cancer cells with minimal damage to healthy cells. Various plasmonic nanoparticles such as rods and cubes have been exploited to elucidate the role of plasmonic field coupling in assembled nanoparticles and their subsequent killing efficiency. The NIR absorbing capabilities of aggregated AuNSs have been further demonstrated both experimentally and theoretically using discrete dipolar approximation (DDA) techniques, which was in concordance with the observed results in plasmonic photothermal therapeutic studies. While the current work was able to demonstrate the utility of non-NIR absorbing plasmonic nanoparticles as a potential alternative for plasmonic photothermal therapy by inducing localized plasmonic heating at the nuclear region of the cells, these findings could potentially open up new possibilities in developing more efficient nanoparticles for efficient cancer treatment modalities. PMID- 28837767 TI - Excitonic Coupling Modulated by Mechanical Stimuli. AB - Understanding energy transfer is of vital importance in a diverse range of applications from biological systems to photovoltaics. The ability to tune excitonic coupling in any of these systems, however, is generally limited. In this work, we have simulated a new class of single-molecule spectroscopy in which force microscopy is used to control the excitonic coupling between chromophores. Here we demonstrate that the excitonic coupling can be controlled by mechanical manipulation of the molecule (perylenediimide dimers and terrylenediimide perylenediimide heterodimers) and can be tuned over a broad range of values (0.02 0.15 eV) that correspond to different regimes of exciton dynamics going from the folded to the elongated structure of the dimer. In all of the systems considered here, the switching from high to low coupling takes place simultaneously with the mechanical deformation detected by a strong increase and subsequent decay of the force. These simulations suggest that single-molecule force spectroscopy can be used to understand and eventually aid the design of excitonic devices. PMID- 28837766 TI - Palladium-Catalyzed Intermolecular Exchange between C-C and C-Si sigma-Bonds. AB - A palladium-isocyanide complex opens the two four-membered rings of benzocyclobutenone and silacyclobutane to merge them into an eight-membered ring skeleton. The present reaction provides a unique example of an intermolecular cross metathesis-type reaction between covalent sigma-bonds of low polarity. PMID- 28837768 TI - Identification and Quantitation of C?C Location Isomers of Unsaturated Fatty Acids by Epoxidation Reaction and Tandem Mass Spectrometry. AB - Unsaturated fatty acids (FAs) serve as nutrients, energy sources, and signaling molecules for organisms, which are the major components for a large variety of lipids. However, structural characterization and quantitation of unsaturated FAs by mass spectrometry remain an analytical challenge. Here, we report the coupling of epoxidation reaction of the C?C in unsaturated FAs and tandem mass spectrometry (MS) for rapid and accurate identification and quantitation of C?C isomers of FAs in a shotgun lipidomics approach. Epoxidation of the C?C leads to the production of an epoxide which, upon collision induced dissociation (CID), produces abundant diagnostic ions indicative of the C?C location. The total intensity of the same set of diagnostic ions for one specific FA C?C isomer was also used for its relative and absolute quantitation. The simple experimental setup, rapid reaction kinetics (<2 min), high reaction yield (>90% for monounsaturated FAs), and easy-to-interpret tandem MS spectra enable a promising methodology particularly for the analysis of unsaturated FAs in complex biological samples such as human plasma and animal tissues. PMID- 28837769 TI - The Potency of Diarylamine Radical-Trapping Antioxidants as Inhibitors of Ferroptosis Underscores the Role of Autoxidation in the Mechanism of Cell Death. AB - Two aromatic amines (ferrostatin-1 and liproxstatin-1) were recently identified from high-throughput screening efforts to uncover potent inhibitors of ferroptosis, the necrotic-like cell death induced by inhibition of glutathione peroxidase 4 (GPX4), deletion of the corresponding gpx4 gene, or starvation of GPX4 of its reducing cosubstrate, glutathione (GSH). We have since demonstrated that these two aromatic amines are highly effective radical-trapping antioxidants (RTAs) in lipid bilayers, suggesting that they subvert ferroptosis by inhibiting lipid peroxidation (autoxidation) and, thus, that this process drives the execution of ferroptosis. Herein, we show that diarylamine RTAs used to protect petroleum-derived products from autoxidation can be potent inhibitors of ferroptosis. The diarylamines investigated include representative examples of additives to engine oils, greases and rubber (4,4'-dialkyldiphenylamines), core structures of dyes and pharmaceuticals (phenoxazines and phenothiazines), and aza analogues of these three classes of compounds that we have recently shown can be modified to achieve much greater reactivity. We find that regardless of how ferroptosis is induced (GPX4 inhibition, gpx4 deletion or GSH depletion), compounds which possess good RTA activity in organic solution (kinh > 105 M-1 s 1) and lipid bilayers (kinh > 104 M-1 s-1) are generally potent inhibitors of ferroptosis (in mouse embryonic fibroblasts). Likewise, structural analogs that do not possess RTA activity are devoid of antiferroptotic activity. These results further support the argument that lipid peroxidation (autoxidation) plays a major role in the mechanism of cell death induced by either GPX4 inhibition, gpx4 deletion, or GSH depletion. Moreover, it offers clear direction that ongoing medicinal chemistry efforts on liproxstatin and ferrostatin derivatives, which have been proposed as lead compounds for the treatment and/or prevention of ischemia/reperfusion injury, renal failure, and neurodegeneration, can be widened to include other aminic RTAs. To aid in these efforts, some relevant structure reactivity relationships are discussed. PMID- 28837770 TI - Background Nutrients Affect the Biotransformation of Tetracycline by Stenotrophomonas maltophilia as Revealed by Genomics and Proteomics. AB - Certain bacteria are resistant to antibiotics and can even transform antibiotics in the environment. It is unclear how the molecular mechanisms underlying the resistance and biotransformation processes vary under different environmental conditions. The objective of this study is to investigate the molecular mechanisms of tetracycline resistance and biotransformation by Stenotrophomonas maltophilia strain DT1 under various background nutrient conditions. Strain DT1 was exposed to tetracycline for 7 days with four background nutrient conditions: no background (NB), peptone (P), peptone plus citrate (PC), and peptone plus glucose (PG). The biotransformation rate follows the order of PC > P > PG > NB ~ 0. Genomic analysis showed that strain DT1 contained tet(X1), a gene encoding an FAD-binding monooxygenase, and eight peroxidase genes that could be relevant to tetracycline biotransformation. Quantitative proteomic analyses revealed that nodulation protein transported tetracycline outside of cells; hypoxanthine guanine phosphoribosyltransferase facilitated the activation of the ribosomal protection proteins to prevent the binding of tetracycline to the ribosome and superoxide dismutase and peroxiredoxin-modified tetracycline molecules. Comparing different nutrient conditions showed that the biotransformation rates of tetracycline were positively correlated with the expression levels of superoxide dismutase. PMID- 28837771 TI - Predicting Catalytic Activity of Nanoparticles by a DFT-Aided Machine-Learning Algorithm. AB - Catalytic activities are often dominated by a few specific surface sites, and designing active sites is the key to realize high-performance heterogeneous catalysts. The great triumphs of modern surface science lead to reproduce catalytic reaction rates by modeling the arrangement of surface atoms with well defined single-crystal surfaces. However, this method has limitations in the case for highly inhomogeneous atomic configurations such as on alloy nanoparticles with atomic-scale defects, where the arrangement cannot be decomposed into single crystals. Here, we propose a universal machine-learning scheme using a local similarity kernel, which allows interrogation of catalytic activities based on local atomic configurations. We then apply it to direct NO decomposition on RhAu alloy nanoparticles. The proposed method can efficiently predict energetics of catalytic reactions on nanoparticles using DFT data on single crystals, and its combination with kinetic analysis can provide detailed information on structures of active sites and size- and composition-dependent catalytic activities. PMID- 28837772 TI - Thermal Stability of Co-Pt and Co-Au Core-Shell Structured Nanoparticles: Insights from Molecular Dynamics Simulations. AB - Co-Pt and Co-Au core-shell nanoparticles were heated by molecular dynamics simulations to investigate their thermal stability. Two core structures, that is, hcp Co and fcc Co, have been addressed. The results demonstrate that the hcp-fcc phase transition happens in the hcp-Co-core/fcc-Pt-shell nanoparticle, while it is absent in the hcp-Co-core/fcc-Au-shell one. The stacking faults appear in both Pt and Au shells despite different structures of the Co core. The Co core and Pt shell concurrently melt and present an identical melting point in both Co-Pt core shell nanoparticles. However, typical two-stage melting occurs in both Co-Au core shell nanoparticles. Furthermore, the Au shell in the hcp-Co-core/fcc-Au-shell nanoparticle exhibits a lower melting point than that in the fcc-Co-core/fcc-Au shell one, while the melting points are closely equal for both hcp and fcc Co cores. All of these observations suggest that their thermal stability strongly depends on the structure of the core and the element of the shell. PMID- 28837773 TI - Wearable Electrocardiogram Monitor Using Carbon Nanotube Electronics and Color Tunable Organic Light-Emitting Diodes. AB - With the rapid advances in wearable electronics, the research on carbon-based and/or organic materials and devices has become increasingly important, owing to their advantages in terms of cost, weight, and mechanical deformability. Here, we report an effective material and device design for an integrative wearable cardiac monitor based on carbon nanotube (CNT) electronics and voltage-dependent color-tunable organic light-emitting diodes (CTOLEDs). A p-MOS inverter based on four CNT transistors allows high amplification and thereby successful acquisition of the electrocardiogram (ECG) signals. In the CTOLEDs, an ultrathin exciton block layer of bis[2-(diphenylphosphino)phenyl]ether oxide is used to manipulate the balance of charges between two adjacent emission layers, bis[2-(4,6 difluorophenyl)pyridinato-C2,N](picolinato)iridium(III) and bis(2-phenylquinolyl N,C(2'))iridium(acetylacetonate), which thereby produces different colors with respect to applied voltages. The ultrathin nature of the fabricated devices supports extreme wearability and conformal integration of the sensor on human skin. The wearable CTOLEDs integrated with CNT electronics are used to display human ECG changes in real-time using tunable colors. These materials and device strategies provide opportunities for next generation wearable health indicators. PMID- 28837774 TI - Graphene-Anchored p-Type CuBO2 Nanocrystals for a Transparent Cold Cathode. AB - CuBO2 nanostructures were synthesized by employing a low-cost hydrothermal technique to combine into the CuBO2-RGO nanocomposite for the first time using chemically prepared graphene sheets. The nanohybrid samples were characterized for structural information using X-ray diffraction (XRD) that revealed the proper crystalline phase formation of CuBO2 unaltered by composite formation with graphene. Raman spectroscopic studies were employed to confirm the presence of graphene. A morphological study with field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) suggested the proper wrapping of RGO sheets over CuBO2 nanocubes. Moreover, the close proximity of lattice planes of CuBO2 and RGO to each other was observed in high-resolution TEM studies that were correlated with the Raman spectroscopic studies. Finally, the samples were characterized to study the field emission (FE) properties of the same using a laboratory-made high-vacuum field-emission setup. Finite-element-based theoretical simulation studies were carried out to explain and compare the field emission properties with the experimental results. The FE properties of the composite samples were found to be tuned by the nature of wrapping the RGO sheets over the CuBO2 nanocubes, which was typically dependent upon the spiky morphology of the nanocubes. PMID- 28837775 TI - Photosensitization of Fluorofuroxans and Its Application to the Development of Visible Light-Triggered Nitric Oxide Donor. AB - Nitric oxide (NO) is an endogenous signaling molecule used in multiple biochemical processes. The development of switchable NO donors that deliver an NO payload under spatiotemporal control harbors many medicinal benefits. Previously, 4-fluorofuroxans were found to function as a UV light-induced NO donor under physiological conditions based on the photoinduced isomerization mechanism; however, the isomerization of fluorofuroxans with longer wavelength light is desired for further application into living systems. Herein, we report the use of photosensitizers in the photochemical isomerization of fluorofuroxan, enabling the use of visible light to induce isomerization. Among the tried photosensitizers, anthraquinone derivatives showed a good sensitizing ability to isomerize 4-fluorofuroxan to 3-fluorofuroxan using visible light. This new phenomenon was applied to the synthesis of a water-soluble anthraquinone fluorofuroxan all-in-one molecule, which demonstrated promising NO-releasing ability using 400-500 nm irradiation. A high level of control is displayed with "on" and "off" NO-release functionality suggesting that photosensitizer-furoxan hybrids would make valuable donors. Furthermore, unlike most furoxans, NO is released in the absence of thiol cofactor. PMID- 28837776 TI - Morphology and Structural Properties of Novel Short Linear Glucan/Protein Hybrid Nanoparticles and Their Influence on the Rheological Properties of Starch Gel. AB - Starch nanoparticles were potential texture modifiers. However, they have strong tendency to aggregate and poor water dispersibility, which limited their application. The interaction between glucan (prepared from starch by enzymatic modification) and protein could significantly improve the dispersity of starch nanoparticles and, thus, enhance the rheological properties of food gels. In this work, glucan/protein hybrid nanoparticles were successfully developed for the first time using short linear glucan (SLG) and edible proteins [soy protein isolate (SPI), rice protein (RP), and whey protein isolate (WPI)]. The results showed that the SLG/SPI hybrid nanoparticles exhibited hollow structures, of which the smallest size was approximately 10-20 nm when the SLG/SPI ratio was 10:5. In contrast, SLG/RP nanoparticles displayed flower-like superstructures, and SLG/WPI nanoparticles presented stacked lamellar nanostructures with a width of 5-10 nm and a length of 50-70 nm. In comparison to bare SLG nanoparticles, SLG/SPI and SLG/WPI hybrid nanoparticles had higher melting temperatures. The addition of all nanoparticles greatly increased the storage modulus of corn starch gels and decreased loss tangent values. Importantly, the G' value of starch gels increased by 567% with the addition of flower-like SLG/RP superstructures. PMID- 28837778 TI - Unilateral High-Altitude Pulmonary Edema. PMID- 28837777 TI - Arsenite Binds to the Zinc Finger Motif of TIP60 Histone Acetyltransferase and Induces Its Degradation via the 26S Proteasome. AB - Arsenic is a ubiquitous environmental contaminant with widespread public health concern. Epidemiological studies have revealed that chronic human exposure to arsenic in drinking water is associated with the prevalence of skin, lung, and bladder cancers. Aberrant histone modifications (e.g., methylation, acetylation, and ubiquitination) were previously found to be accompanied by arsenic exposure; thus, perturbation of epigenetic pathways is thought to contribute to arsenic carcinogenesis. Arsenite is known to interact with zinc finger motifs of proteins, and zinc finger motif is present in and indispensable for the enzymatic activities of crucial histone-modifying enzymes especially the MYST family of histone acetyltransferases (e.g., TIP60). Hence, we reasoned that trivalent arsenic may target the zinc finger motif of these enzymes, disturb their enzymatic activities, and alter histone acetylation. Herein, we found that As3+ could bind directly to the zinc-finger motif of TIP60 in vitro and in cells. In addition, exposure to As3+ could lead to a dose-dependent decrease in TIP60 protein level via the ubiquitin-proteasome pathway. Thus, the results from the present study revealed, for the first time, that arsenite may target cysteine residues in the zinc-finger motif of the TIP60 histone acetyltransferase, thereby altering the H4K16Ac histone epigenetic mark. Our results also shed some new light on the mechanisms underlying the arsenic-induced epigenotoxicity and carcinogenesis in humans. PMID- 28837779 TI - Portal vein ligation alters coding and noncoding gene expression in rat livers. AB - Portal vein occlusion increases the resectability of initially unresectable liver cancer by inducing hypertrophy in non-occluded liver lobes. However, the mechanisms of how portal vein occlusion induces hepatic hypertrophy remain unclear. A cDNA microarray was used to identify the gene expression signatures of ligated (LLLs) and nonligated liver lobes (NLLLs) at different time points after portal vein ligation (PVL). The results of a bioinformatics analysis revealed that LLLs and NLLLs displayed different gene expression profiles. Moreover, the expression levels of both coding and noncoding RNA were different between LLLs and NLLLs at different time points after PVL. A series test of cluster analysis revealed that the No. 22 and No. 5 expression patterns, which showed altered expression at 24 h and maintained this altered expression over the following 14 days, had the lowest P values and the highest number of differentially expressed genes in both the LLLs and NLLLs. The results of a GO analysis showed the activation of hypoxia pathways in LLLs and the activation of cell proliferation and cell-cycle pathways in NLLLs, suggesting the involvement of these pathways in PVL-induced hepatic hypertrophy and regeneration. These results provide insight into the molecular mechanisms underlying hepatic hypertrophy and regeneration induced by portal vein occlusion, and they identify potential targeting pathways that can promote the clinical application of PVL in liver cancer therapy. PMID- 28837781 TI - Reply: Unilateral Pulmonary Edema after Visiting High Altitude. PMID- 28837780 TI - Development of MAST: A Microscopy-Based Antimicrobial Susceptibility Testing Platform. AB - Antibiotic resistance is compromising our ability to treat bacterial infections. Clinical microbiology laboratories guide appropriate treatment through antimicrobial susceptibility testing (AST) of patient bacterial isolates. However, increasingly, pathogens are developing resistance to a broad range of antimicrobials, requiring AST of alternative agents for which no commercially available testing methods are available. Therefore, there exists a significant AST testing gap in which current methodologies cannot adequately address the need for rapid results in the face of unpredictable susceptibility profiles. To address this gap, we developed a multicomponent, microscopy-based AST (MAST) platform capable of AST determinations after only a 2 h incubation. MAST consists of a solid-phase microwell growth surface in a 384-well plate format, inkjet printing-based application of both antimicrobials and bacteria at any desired concentrations, automated microscopic imaging of bacterial replication, and a deep learning approach for automated image classification and determination of antimicrobial minimal inhibitory concentrations (MICs). In evaluating a susceptible strain set, 95.8% were within +/-1 and 99.4% were within +/-2, twofold dilutions, respectively, of reference broth microdilution MIC values. Most (98.3%) of the results were in categorical agreement. We conclude that MAST offers promise for rapid, accurate, and flexible AST to help address the antimicrobial testing gap. PMID- 28837782 TI - Production of inbred offspring by intracytoplasmic sperm injection of oocytes from juvenile female mice. AB - The aim of the present study was to determine whether the use of oocytes from juvenile female mice would improve the efficiency of intracytoplasmic sperm injection (ICSI). In the present study, 15 adult and 14 juvenile C57BL6/J female mice were superovulated, with 17.8 oocytes per mouse harvested from adults, significantly lower than the 40.2 harvested from juveniles (P<0.01). Sixty and 233 oocytes were harvested from C57BL/6J adult and juvenile mice respectively, activated in 10mM SrCl2+5MUgmL-1 cytochalasin B for 5-6h and cultured in potassium simplex optimisation medium (KSOM) for 3.5 days, with no differences in morula and blastocyst rates between groups (91.7% vs 96.6%; P>0.05). Twelve hours after injection of human chorionic gonadotrophin, oocytes were harvested from C57BL/6J juvenile mice into KSOM, randomly divided into groups and activated with the same method mentioned above at 0, 2, 4 or 6h and then cultured in KSOM for 3.5 days. There was no significant difference in morula and blastocyst rates among the different groups (P>0.05). Oocytes from juvenile mice activated in 10mM SrCl2 for 2h were subjected to ICSI and the rates of pronuclear formation and Day 1 cleavage were significantly improved compared with the control group (P<0.01). ICSI combined with activation of oocytes from inbred mouse strains (C57BL/6J, C57BL/6N and 129Svev) successfully produced pups. The fertility of some these mice resulting from ICSI was tested, and the animals proved fertile. In conclusion, superovulated juvenile mice can yield more useable oocytes than adult mice, but additional activation is essential for full development of ICSI oocytes harvested from juvenile inbred mice. PMID- 28837783 TI - Synthesis of novel aryl brassinosteroids through alkene cross-metathesis and preliminary biological study. AB - A series of phenyl analogues of brassinosteroids was prepared via alkene cross metathesis using commercially available styrenes and 24-nor-5alpha-chola-2,22 dien-6-one. All derivatives were successfully docked into the active site of BRI1 using AutoDock Vina. Plant growth promoting activity was measured using the pea inhibition biotest and Arabidopsis root sensitivity assay and then was compared with naturally occuring brassinosteroids. Differences in the production of plant hormone ethylene were also observed in etiolated pea seedlings after treatment with the new and also five known brassinosteroid phenyl analogues. Antiproliferative activity was also studied using normal human fibroblast and human cancer cell lines. PMID- 28837784 TI - Relevance of bone marrow transplantation nursing training program at King Faisal Specialist Hospital and Research Centre for national and regional nurses. PMID- 28837785 TI - Canagliflozin prevents scopolamine-induced memory impairment in rats: Comparison with galantamine hydrobromide action. AB - Canagliflozin (CAN) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated to improve glycemic control in adults with type 2 diabetes mellitus. There is a little information about its effect on the cholinergic system that proposed mechanism for memory improvement occurring by SGLT2 drugs. This study aimed to estimate the effect of CAN as compared to galantamine (GAL) treatments for two weeks on scopolamine hydrobromide (SCO)-induced memory dysfunction in experimental rats. Animals divided into six groups; control (CON), CAN, GAL, SCO, SCO + CAN and SCO + GAL. Results indicated significant decrease in body weights of the CAN groups as compared to control values. Moreover, in the SCO + CAN and SCO + GAL the number of arm entry and number of correct alternation in Y maze task increased and showed improvement in the water maze task, acetylcholinesterase (AChE) activities decreased significantly, while monoamines levels significantly increased compared with the SCO group values. Results also recorded acetylcholine M1 receptor (M1 mAChR) in SCO + CAN or SCO + GAL groups in comparison with the SCO group. The study suggested that canagliflozin might improve memory dysfunction induced by scopolamine hydrobromide via cholinergic and monoamines system. PMID- 28837786 TI - Time-dependent peristaltic analysis in a curved conduit: Application to chyme movement through intestine. AB - A theoretical model of time-dependent peristaltic viscous fluid flow through a curved channel in the presence of an applied magnetic field is investigated. The results for stream function, pressure distribution and mechanical efficiency are obtained under the assumptions of long wavelength and low Reynolds number approximation. Pressure fluctuations due to an integral and a non-integral number of waves along the channel length are discussed under influence of channel curvature and magnetic parameter. Two inherent characteristics of peristaltic flow regimes (trapping and reflux) are discussed numerically. The mechanical efficiency of curved magnetohydrodynamic peristaltic pumping is also examined. The magnitude of pressure increases with an increasing channel curvature and magnetic parameter. Reflex phenomenon is analyzed in the Lagrangian frame of reference. It is observed that reflex in the curved channel is higher than in the straight channel. The trapped fluid in a curved channel is studied in the Eulerian frame of reference and it contains two asymmetric boluses. The size of the lower bolus grows and the upper bolus decreases with increasing effect of magnetic strength. Pumping efficiency of the peristaltic pump is low for curved channel flow than for straight channel flow. Also, the pumping efficiency is comparatively low at the high effect of the magnetic parameter. PMID- 28837787 TI - Proteomic analysis of Taenia hydatigena cyst fluid reveals unique internal microenvironment. AB - Taenia hydatigena is a parasitic flatworm that is widely distributed around the world. Using MS/MS, the proteome of T. hydatigena cyst fluid (CF) was profiled and a total of 520 proteins were identified, 430 of which were of sheep origin. T. hydatigena shared 37 parasite-origin and 109 host-origin CF proteins with Echinococcus granulosus. Compared with E. granulosus, T. hydatigena had much more CF proteins associated with amino acid synthesis and complement cascades. In addition, glutamate metabolism and anti-oxidative reactions were identified as relatively more important events. These results suggest that T. hydatigena metacestodes have internal microenvironment with special immune and oxidative conditions. PMID- 28837788 TI - Regulation of the corticosteroid signalling system in rainbow trout HPI axis during confinement stress. AB - This study aims to shed light on corticosteroid regulation of stress in teleost fish with focus on the corticosteroid signalling system. The role of the mineralocorticoid-like hormone 11-deoxycorticosterone (DOC) in fish is still enigmatic, as is the function of the mineralocorticoid receptor, MR. Low plasma DOC levels and ubiquitous tissue distribution of MR question the physiological relevance of the mineralocorticoid-axis. Furthermore, the particular purpose of each of the three corticosteroid receptors in fish, the glucocorticoid receptors, GR1 and GR2, and the MR, is still largely unknown. Therefore we investigate the regulation of cortisol and DOC in plasma and mRNA levels of MR, GR1 and GR2 in the HPI-axis tissues (hypothalamus, pituitary and interrenal gland) during a detailed confinement stress time-course. Here we show a sustained up-regulation of plasma DOC levels during a confinement stress time-course. However, the low DOC levels compared to cortisol measured in the plasma do not favour an activity of DOC through MR receptors. Furthermore, we show differential contribution of the CRs in regulation and control of HPI axis activity following confinement stress. Judged by the variation of mRNA levels negative feedback regulation of cortisol release occurs on the level of the pituitary via MR and on the level of the interrenal gland via GR2. Finally, asa significant effect of confinement stress on CR expressions was observed in the pituitary gland, we completed this experiment by demonstrating that corticosteroid receptors (GR1, GR2 and MR) are co-expressed in the ACTH cells located in the adenohypophysis. Overall, these data suggest the involvement of these receptors in the regulation of the HPI axis activity by cortisol. PMID- 28837789 TI - Repertoire of bone morphogenetic proteins and growth/differentiation factors in ovary of the Indian wall lizard (Hemidactylus flaviviridis) with emphasis on differential expression and gonadotropic regulation of bmp15 and gdf9. AB - Analysis of ovarian transcriptome of Indian wall lizard demonstrates the existence of several bone morphogenetic proteins (bmp1, 2, 3, 3b, 7, 8, 15) and growth/differentiation factors (gdf5, 9) for the first time in reptilian ovary. The characterization of putative full-length/partial protein sequences of BMPs (BMP2, 3, 3b, 7, 15) and GDF9 showed high homology of their TGF-beta domain with that of other vertebrates while BMP1 bore homology to zinc-dependent metalloprotease. Phylogenetic analyses showed clustering of BMPs and GDF9 from wall lizards with that of squamates lying in close proximity to chelonia, crocodilia and aves. This study also correlates the expression of ovarian bmp15 and gdf9 with folliculogenesis. Level of bmp15 dramatically increased with the onset of follicular growth in early recrudescence and attained peak during late recrudescence whereas gdf9 sharply decreased during recrudescence as compared to regression. Nonetheless, expression of these growth factors decreased appreciably with the formation of vitellogenic follicle during breeding phase. Ovarian expression of bmp15 and gdf9 appeared to be regulated by gonadotropin as bmp15 considerably increased while gdf9 decreased in parallel to follicular development after administration of 3 injections of FSH. Expression of both the growth factors declined with the prolongation of treatment that led to formation of early/late vitellogenic follicle. Our in vitro study revealed stimulatory effect of FSH on expression of bmp15 and gdf9 in early growing, previtellogenic and early vitellogenic follicles. In light of in vitro results, FSH-induced in vivo decline in gene expression seems to be due to some other FSH-induced factor. PMID- 28837790 TI - Disorganization of the Retinal Inner Layers as a Predictor of Visual Acuity in Eyes With Macular Edema Secondary to Vein Occlusion. AB - PURPOSE: To determine whether spectral-domain optical coherence tomography (SD OCT) disorganization of the retinal inner layers (DRIL) is predictive of best corrected visual acuity (BCVA) in retinal vein occlusion macular edema (RVO-ME). DESIGN: Retrospective cohort study. METHODS: Setting: Two tertiary centers. PATIENTS: Treatment-naive RVO-ME receiving monthly intravitreal bevacizumab. OBSERVATION PROCEDURES: Spectral-domain optical coherence tomography (SD-OCT) images from baseline, 4-month, and 8-month visits. The DRIL extent and additional parameters were evaluated in the 1-mm-wide foveal centered area. MAIN OUTCOME MEASURES: BCVA at each visit. RESULTS: A total of 136 eyes were included in this study. Greater DRIL extent at baseline correlated with worse baseline BCVA (point estimate, 0.04; 95% CI, 0.01-0.07 per 100 MUm, P = .003). In multivariate analysis extent of DRIL (P = .03) and ellipsoid zone disruption (P < .001) correlated with baseline BCVA. Four-month DRIL reduction was associated with 8 month BCVA improvement (point estimate, 0.02; 95% CI, 0.01-0.04, P = .01), with only DRIL remaining significant in multivariate analysis (P = .02). Baseline DRIL predicted 8-month improvement in BCVA (point estimate, 0.03; 95% CI, 0.01-0.05, P = .04), with only DRIL remaining significant in multivariate analysis (P = .006). Eight-month DRIL change was associated with 8-month BCVA change (point estimate, 0.03, 95% CI 0.01-0.05, P = .001), with only DRIL remaining significant in multivariate analysis (P = .002). CONCLUSIONS: The change of the DRIL extent following the first 3 monthly injections identifies eyes with a high likelihood of subsequent BCVA improvement or decline. Therefore, the extent of DRIL before and after treatment is an additional SD-OCT parameter that may serve as a biomarker for patients with RVO-ME. PMID- 28837791 TI - Morphologic and Functional Retinal Vessel Changes in Branch Retinal Vein Occlusion: An Optical Coherence Tomography Angiography Study. AB - PURPOSE: The present study aimed to investigate the morphology of the retinal vasculature in eyes with branch retinal vein occlusion (BRVO) using optical coherence tomography (OCT) angiography. DESIGN: Observational case series. METHODS: Fluorescein angiography (FA) and OCT angiography were used to examine macular area and the retinal vasculature at the affected arteriovenous (AV) crossing in 46 patients with BRVO. RESULTS: FA revealed that the affected AV crossing pattern involved arterial overcrossing in 23 eyes (50.0%) and venous overcrossing in 11 eyes (23.9%). However, FA failed to detect the crossing pattern in 10 eyes (21.7%). OCT angiography was significantly more effective for identification of the AV crossing pattern than FA (44 eyes; 95.7%; P = .013). The number of eyes with venous overcrossing detected via OCT angiography (20 eyes, 43.5%) was also higher than that detected via FA (P = .047). OCT angiography revealed that venous narrowing (25.5 +/- 21.1 MUm) was significantly greater in instances of venous overcrossing than in those of arterial overcrossing (46.4 +/- 23.7 MUm, P = .005). Macular nonperfusion areas (NPAs) were larger in eyes with venous overcrossing than in those with arterial overcrossing (P = .011 for superficial plexus, P = .049 for deep plexus). The peripheral NPA was significantly larger in eyes with venous overcrossing (65.1 +/- 35.3 disc area [DA]) than in those with arterial overcrossing (17.2 +/- 24.1 DA; P < .001). CONCLUSIONS: Our findings suggest that BRVO characterized by venous overcrossing may be more prevalent than previously reported, and that there is a significant association between NPA size and AV crossing pattern. PMID- 28837792 TI - Lipids of Dietzia sp. A14101. Part II: A study of the dynamics of the release of surface active compounds by Dietzia sp. A14101 into the medium. AB - Dietzia sp. A14101 isolated from an oil reservoir model column was found to induce a strong decrease of the interfacial tension (IFT) in hydrocarbon-water mixtures in the presence of the intact bacterial cells (Kowalewski et al., 2005). The strain was shown to be able to degrade a wide range of hydrocarbon substrates (Bodtker et al., 2009). Further studies showed that the surface-active compounds tentatively identified as glycolipids were produced by Dietzia sp. A14101 on non- and water-immiscible -hydrocarbon substrates, Part I (Hvidsten et al., 2017). The results suggested that biosurfactant (BS) was a mixture of several isomers. The study presented here is aimed to investigate whether BS are secreted into the aqueous medium, and if so, then at which phase of the culture growth and in which amounts - the dynamics of the BS release in incubations on water-immiscible hydrocarbons. Two methods of BS extraction from the medium were attempted and compared: a liquid-liquid extraction (LLE) and precipitation by acid. For qualitative and semi-quantitative assessment, gas chromatography-mass spectrometry (GC/MS), thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LC-MS), surface tension measurements (SFT), emulsification (E24) and oil-spreading tests were employed. The results indicated that BS only partially were secreted into the medium. Detectable amounts of glycolipids in media were first identified during the exponential growth phase. However, only a slight decrease of SFT was observed in the cell-free medium. The emulsification index values of the sampled material were lower than those reported for related strains. The results suggested that most of the BS produced by Dietzia sp. A14101 remains cell-bound during the culture development in a batch mode and only a narrow range of the BS isomers can be detected in small amounts in media. PMID- 28837793 TI - Inducing rat brain CYP2D with nicotine increases the rate of codeine tolerance; predicting the rate of tolerance from acute analgesic response. AB - Repeated opioid administration produces analgesic tolerance, which may lead to dose escalation. Brain CYP2D metabolizes codeine to morphine, a bioactivation step required for codeine analgesia. Higher brain, but not liver, CYP2D is found in smokers and nicotine induces rat brain, but not liver, CYP2D expression and activity. Nicotine induction of rat brain CYP2D increases acute codeine conversion to morphine, and analgesia, however the role of brain CYP2D on the effects of repeated codeine exposure and tolerance is unknown. Rats were pretreated with nicotine (brain CYP2D inducer; 1mg/kg subcutaneously) or vehicle (saline; 1ml/kg subcutaneously). Codeine (40-60mg/kg oral-gavage) or morphine (20 30mg/kg oral-gavage) was administered daily and analgesia was assessed daily using the tail-flick reflex assay. Nicotine (versus saline) pretreatment increased acute codeine analgesia (1.32-fold change in AUC0-60min; p<0.05) and the rate of loss of peak analgesia (11.42%/day versus 4.20%; p<0.006) across the first four days of codeine administration (time to negligible analgesia). Inducing brain CYP2D with nicotine did not alter acute morphine analgesia (1.03 fold; p>0.8), or the rate of morphine tolerance (8.1%/day versus 7.6%; p>0.9). The rate of both codeine and morphine tolerance (loss in peak analgesia from day 1 to day 4) correlated with initial analgesic response on day 1 (R=0.97, p<001). Increasing brain CYP2D altered initial analgesia and subsequent rate of tolerance. Variation in an individual's initial response to analgesic (e.g. high initial dose, smoking) may affect the rate of tolerance, and thereby the risk for dose escalation and/or opioid dependence. PMID- 28837794 TI - A short cross-linker activates human P-glycoprotein missing a catalytic carboxylate. AB - P-glycoprotein (P-gp) is an ATP-dependent drug pump that protects us from toxic agents and confers multidrug resistance. It has a tweezer-like structure with each arm consisting of a transmembrane domain (TMD) and a nucleotide-binding domain (NBD). Drug substrates bind to sites within the TMDs to activate ATPase activity by promoting a tweezer-like closing of the gap between the NBDs. The catalytic carboxylates may be critical for NBD movements because the E556Q(NBD1) or E1201Q(NBD2) mutation inhibited drug-stimulated ATPase activity. If the catalytic carboxylates were components of the mechanism to bring the NBDs together, then we predicted that insertion of a flexible cross-linker between the arms would increase ATPase activity of the mutants. We found that cross-linking (between L175C(TMD1) and N820C(TMD2)) with a short flexible cross-linker (7.8A maximum) restored high levels of drug-stimulated ATPase activity of the E556Q or E1201Q mutants. Cross-linking with a longer cross-linker (22A maximum) however, did not restore activity. Cross-linking could not rescue all ATPase deficient mutants. For example, cross-linking L175C/N820C with short or long cross-linkers did not activate the H-loop mutants H587A or H1232A or the Walker A K433M or K1076M mutants. The results suggest that the E556 and E1201 catalytic carboxylates are part of a spring-like mechanism that is required to facilitate movements between the open and closed conformations of P-gp during ATP hydrolysis. PMID- 28837795 TI - Unconventional Surgical Strategies for the Obstructed Megaureter-What are the Options and When Should We Use Them? PMID- 28837796 TI - Videothoracoscopic surgery before and after chest tube drainage for children with complicated parapneumonic effusion. AB - OBJECTIVES: To evaluate the effectiveness of videothoracoscopic surgery in the treatment of complicated parapneumonic pleural effusion and to determine whether there is a difference in the videothoracoscopic surgery outcome before or after the chest tube drainage. METHODS: The medical records of 79 children (mean age 35 months) undergoing videothoracoscopic surgery from January 2000 to December 2011 were retrospectively reviewed. The same treatment algorithm was used in the management of all patients. Patients were divided into two groups: in group 1, videothoracoscopic surgery was performed as the initial procedure; in group 2, videothoracoscopic surgery was performed after previous chest tube drainage. RESULTS: Videothoracoscopic surgery was effective in 73 children (92.4%); the other six (7.6%) needed another procedure. Sixty patients (75.9%) were submitted directly to videothoracoscopic surgery (group 1) and 19 (24%) primarily underwent chest tube drainage (group 2). Primary videothoracoscopic surgery was associated with a decrease of hospital stay (p=0.05), time to resolution (p=0.024), and time with a chest tube (p<0.001). However, there was no difference between the groups regarding the time until fever resolution, time with a chest tube, and the hospital stay after videothoracoscopic surgery. No differences were observed between groups regarding the need for further surgery and the presence of complications. CONCLUSIONS: Videothoracoscopic surgery is a highly effective procedure for treating children with complicated parapneumonic pleural effusion. When videothoracoscopic surgery is indicated in the presence of loculations (stage II or fibrinopurulent), no difference were observed in time of clinical improvement and hospital stay among the patients with or without chest tube drainage before videothoracoscopic surgery. PMID- 28837797 TI - Ocular/adnexal lymphoma: dissimilar to systemic lymphoma. AB - Ocular adnexal lymphoma and intraocular lymphoma, whether occurring simultaneously or sequentially, are often similar to associated systemic lymphoma. We describe 4 cases of ocular adnexal lymphoma or intraocular lymphoma with a dissimilar systemic lymphoma. Two of the cases represent Richter transformation of chronic lymphocytic leukemia/small-cell lymphoma into diffuse large B-cell lymphoma. In the third patient, conjunctival extranodal marginal zone lymphoma developed following treatment for Hodgkin lymphoma. The fourth patient had a remote history of systemic diffuse large B-cell lymphoma with a subsequent diagnosis of orbital extranodal marginal zone lymphoma. Clinical pathological correlation is reported for all cases in addition to pertinent review of the literature. PMID- 28837798 TI - Lymphotoxins Promote the Progression of Human Lymphatic Malformation by Enhancing Lymphatic Endothelial Cell Proliferation. AB - Formation of inflammation-related tertiary lymphoid organs promotes human lymphatic malformation (LM) development. However, the role of lymphotoxins (LTs) and LT-related inducible ligand, the crucial mediators for tertiary lymphoid organ formation, is undetermined in LMs. Herein, we show that LTs and LT-related inducible ligand promote LM development by enhancing lymphatic endothelial cell (LEC) proliferation via activating NF-kappaB pathways. The expression of LTs and their receptors was increased in LMs, especially the infected ones, when compared with normal skins. Nuclear translocation of p65, p52, and RelB in the LECs of LMs indicated the activation of classic and alternative NF-kappaB pathways. Pearson's correlation and cluster analysis suggested the close relationship between LEC proliferation and NF-kappaB activation. Moreover, in vitro data demonstrated LTs accelerated the proliferation of human dermal LECs (HdLECs) through activation of NF-kappaB. In addition, lipopolysaccharide (LPS) up-regulated LT receptor expression in HdLECs, leading to increased sensitivity to LTs. Suppression of LT receptors hampered LPS-enhanced HdLEC proliferation, indicating the crucial role of LT pathways in inflammatory lymphangiogenesis. Besides, evidence from the LM rat models demonstrated LTalpha and LPS enhanced LEC proliferation, therefore promoting LM development. Blocking LT pathways by neutralizing antibodies against LTalpha and lymphotoxin beta receptor may decelerate the growth of the disease. In summary, our present study demonstrated activation of LT signaling pathways in LECs contributed to the progression of LMs. PMID- 28837799 TI - Essential Role of IL-12 in Angiogenesis in Type 2 Diabetes. AB - Recently, IL-12 emerged as a critical player in type 2 diabetes complications. We previously reported that ischemia-induced angiogenesis is compromised in type 2 diabetic mice. In this study, we determined that IL-12 disruption rescued angiogenesis and arteriogenesis in type 2 diabetic mice. To induce type 2 diabetes, wild-type (WT), p40IL-12-/- (p40-/-), and p35IL-12-/- (p35-/-) mice were fed a high-fat diet (HFD) for 12 weeks. Body weight, glucose test tolerance, and insulin test tolerance were assessed. After 12 weeks of an HFD, the femoral artery was ligated and blood flow recovery was measured every week for 4 weeks. WT, p40-/-, and p35-/- mice fed an HFD become obese after 12 weeks and exhibit glucose intolerance and insulin resistance. Blood flow recovery was fully restored in 2 to 3 weeks after femoral artery ligation in all groups of mice fed a normal diet. However, after 12 weeks of an HFD, blood flow recovery was compromised in WT mice, whereas it was fully recovered in p40-/- and p35-/- mice. The mechanism of blood flow recovery involves an increase in capillary/arteriole density, endothelial nitric oxide synthase/Akt/vascular endothelial growth factor receptor 2 signaling, and a reduction in oxidative stress and inflammation. The disruption of IL-12 promotes angiogenesis and increases blood flow recovery in obese type 2 diabetic mice by an endothelial nitric oxide synthase/Akt/vascular endothelial growth factor receptor 2/oxidative stress-inflammation-dependent mechanism. PMID- 28837802 TI - Transcriptional Termination Enhances Protein Expression in Human Cells. PMID- 28837800 TI - Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy. AB - Inhibition of monocyte chemotactic protein-1 (MCP-1) with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Because the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx-degrading enzyme heparanase. Four weeks of treatment of diabetic Apoe knockout mice with the mouse-specific NOX-E36 attenuated albuminuria without any change in systemic hemodynamics, despite persistent loss of podocyte function. MCP-1 inhibition, however, increased glomerular endothelial glycocalyx coverage, with preservation of heparan sulfate. Mechanistically, both glomerular cathepsin L and heparanase expression were reduced. MCP-1 inhibition resulted in reduced CCR2-expressing Ly6Chi monocytes in the peripheral blood, without affecting overall number of kidney macrophages at the tissue level. However, the CD206+/Mac3+ cell ratio, as an index of presence of anti-inflammatory macrophages, increased in diabetic mice after treatment. Functional analysis of isolated renal macrophages showed increased release of IL 10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mouse-specific NOX-E36 treatment. We show that MCP-1 inhibition restores glomerular endothelial glycocalyx and barrier function and reduces tissue inflammation in the presence of ongoing diabetic injury, suggesting a therapeutic potential for NOX-E36 in diabetic nephropathy. PMID- 28837803 TI - ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1. PMID- 28837804 TI - Structural Basis for the Activation and Inhibition of the UCH37 Deubiquitylase. PMID- 28837805 TI - MiR-361 targets Yes-associated protein (YAP) mRNA to suppress cell proliferation in lung cancer. AB - Yes-associated protein (YAP) contributes to the development of multiple tumors, but the post-transcription modulation of YAP remains unexplored. Here, we present a new regulatory microRNA of YAP, miR-361, which directly targets YAP to inhibit cell proliferation in lung cancer. We used bioinformatics to predict that miR-361 could target 3'-untranslated region (3'UTR) of YAP mRNA. Luciferase reporter gene assays demonstrated that miR-361 could decrease the luciferase activities of 3'UTR vector of YAP. Furthermore, YAP expression was obviously abated by miR-361 using RT-PCR and immunoblotting in lung cancer A549 cells. In terms of function, MTT and colony formation analysis showed that ectopic miR-361 expression significantly suppressed cell proliferation in lung cancer. Notably, overexpressed YAP accelerated miR-361-bated proliferation of lung cancer cells. MiR-361 inhibitor promoted cell proliferation in lung cancer, but YAP RNA interference reversed miR-361 inhibitor-driven cell proliferation. Interestingly, miR-361 was capable of affecting the cell cycle in lung cancer progression. Finally, the negative correlation of miR-361 with YAP was found in clinical human lung cancer tissues. In conclusion, miR-361 targets 3'UTR of YAP mRNA to depress the proliferation of lung cancer cells. PMID- 28837801 TI - Pharmacologic and Nonpharmacologic Treatment for Acute Cough Associated With the Common Cold: CHEST Expert Panel Report. AB - BACKGROUND: Acute cough associated with the common cold (CACC) causes significant impairment in quality of life. Effective treatment approaches are needed for CACC. We conducted a systematic review on the management of CACC to update the recommendations and suggestions of the CHEST 2006 guideline on this topic. METHODS: This systematic review of randomized controlled trials (RCTs) asked the question: Is there evidence of clinically relevant treatment effects for pharmacologic or nonpharmacologic therapies in reducing the duration/severity of acute CACC? Studies of adults and pediatric patients with CACC were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on using the American College of Chest Physicians organization methodology. RESULTS: Six systematic reviews and four primary studies identified from updated literature searches for each of the reviews or from hand searching were included and reported data on 6,496 participants with CACC who received one or more of a variety of interventions. The studies used an assortment of descriptors and assessments to identify CACC. CONCLUSIONS: The evidence supporting the management of CACC is overall of low quality. This document provides treatment suggestions based on the best currently available evidence and identifies gaps in our knowledge and areas for future research. PMID- 28837806 TI - Rhodospirillum rubruml-asparaginase targets tumor growth by a dual mechanism involving telomerase inhibition. AB - Rhodospirillum rubruml-asparaginase mutant RrA E149R, V150P, F151T (RrA) was previously identified to down-regulate telomerase activity along with catalyzing the hydrolysis of l-asparagine. The aim of this study was to define the effect of prolonged RrA exposure on telomerase activity, maintenance of telomeres and proliferation of cancer cells in vitro and in vivo. RrA could inhibit telomerase activity in SCOV-3, SkBr-3 and A549 human cancer cell lines due to its ability to down-regulate the expression of telomerase catalytic subunit hTERT. Telomerase activity in treated cells did not exceeded 29.63 +/- 12.3% of control cells. Continuous RrA exposure of these cells resulted in shortening of telomeres followed by cell death in vitro. Using real time PCR we showed that length of telomeres in SCOV-3 cells has been gradually decreasing from 10105 +/- 2530 b.p. to 1233 +/- 636 b.p. after 35 days of cultivation. RrA treatment of xenograft models in vivo showed slight inhibition of tumor growth accompanied with 49.5 53.3% of decrease in hTERT expression in the all tumors. However down-regulation of hTERT expression, inhibition of telomerase activity and the loss of telomeres was significant in response to RrA administration in xenograft models. These results should facilitate further investigations of RrA as a potent therapeutic protein. PMID- 28837807 TI - WITHDRAWN: Schisandrin B suppresses NLRP3 inflammasome activation to alleviate myocardial ischemia reperfusion injury via maintaining mitochondrial autophagy. AB - This article has been retracted at the request of the authors. The Editor in Chief has agreed to retract this article and the publisher supports the decision. The authors have indicated that their initial results were not reproducible when conducted by their colleagues. They indicated that the levels of autophagy were significantly different in the MI/R mice model in the respective results. The authors of this article would like to apologize to all affected parties. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28837808 TI - Elevated expression of microRNA-873 facilitates Th17 differentiation by targeting forkhead box O1 (Foxo1) in the pathogenesis of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, and its pathogenesis remains mostly unknown. MicroRNAs (miRs) has drawn much attention as a crucial regulator of autoimmune diseases. In this study, we demonstrated that miR-873 expression was significantly up-regulated in patients with SLE, and its expression was positively associated with the disease severity. CD4+ T cells, especially the Th17 subset, were found to be the major source of miR-873 expression. Using gain- and loss-of-function approaches, we further showed that miR-873 could facilitate the differentiation of CD4+ T cells into Th17 lineage. Moreover, forkhead box O1 (Foxo1), one member of the Foxo family, was identified as a novel target gene of miR-873, and Foxo1 has been known as an inhibitor of Th17 cell differentiation. Foxo1 was observed to be markedly decreased in PBMC of patients with SLE. Notably, in vivo lentivirus-mediated inhibition of miR-873 significantly alleviated the disease severity of spontaneous SLE in MRL/lpr mice, with down-regulated levels of autoantibodies, proteinuria, and IL-17A. Our data reveal a novel mechanism in which the elevated miR-873 in PBMC of SLE promotes Th17 cell differentiation through down-regulation of Foxo1. In vivo blockade of miR-873 may serve as a novel therapeutic approach in the treatment of SLE. PMID- 28837810 TI - Defining Human Tyrosine Kinase Phosphorylation Networks Using Yeast as an In Vivo Model Substrate. AB - Systematic assessment of tyrosine kinase-substrate relationships is fundamental to a better understanding of cellular signaling and its profound alterations in human diseases such as cancer. In human cells, such assessments are confounded by complex signaling networks, feedback loops, conditional activity, and intra kinase redundancy. Here we address this challenge by exploiting the yeast proteome as an in vivo model substrate. We individually expressed 16 human non receptor tyrosine kinases (NRTKs) in Saccharomyces cerevisiae and identified 3,279 kinase-substrate relationships involving 1,351 yeast phosphotyrosine (pY) sites. Based on the yeast data without prior information, we generated a set of linear kinase motifs and assigned ~1,300 known human pY sites to specific NRTKs. Furthermore, experimentally defined pY sites for each individual kinase were shown to cluster within the yeast interactome network irrespective of linear motif information. We therefore applied a network inference approach to predict kinase-substrate relationships for more than 3,500 human proteins, providing a resource to advance our understanding of kinase biology. PMID- 28837812 TI - Considering and Reconsidering Peer Review. PMID- 28837811 TI - Fast, Quantitative and Variant Enabled Mapping of Peptides to Genomes. AB - Current tools for visualization and integration of proteomics with other omics datasets are inadequate for large-scale studies and capture only basic sequence identity information. Furthermore, the frequent reformatting of annotations for reference genomes required by these tools is known to be highly error prone. We developed PoGo for mapping peptides identified through mass spectrometry to overcome these limitations. PoGo reduced runtime and memory usage by 85% and 20%, respectively, and exhibited overall superior performance over other tools on benchmarking with large-scale human tissue and cancer phosphoproteome datasets comprising ~3 million peptides. In addition, extended functionality enables representation of single-nucleotide variants, post-translational modifications, and quantitative features. PoGo has been integrated in established frameworks such as the PRIDE tool suite and OpenMS, as well as a standalone tool with user friendly graphical interface. With the rapid increase of quantitative high resolution datasets capturing proteomes and global modifications to complement orthogonal genomics platforms, PoGo provides a central utility enabling large scale visualization and interpretation of transomics datasets. PMID- 28837809 TI - Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States. AB - The systematic sequencing of the cancer genome has led to the identification of numerous genetic alterations in cancer. However, a deeper understanding of the functional consequences of these alterations is necessary to guide appropriate therapeutic strategies. Here, we describe Onco-GPS (OncoGenic Positioning System), a data-driven analysis framework to organize individual tumor samples with shared oncogenic alterations onto a reference map defined by their underlying cellular states. We applied the methodology to the RAS pathway and identified nine distinct components that reflect transcriptional activities downstream of RAS and defined several functional states associated with patterns of transcriptional component activation that associates with genomic hallmarks and response to genetic and pharmacological perturbations. These results show that the Onco-GPS is an effective approach to explore the complex landscape of oncogenic cellular states across cancers, and an analytic framework to summarize knowledge, establish relationships, and generate more effective disease models for research or as part of individualized precision medicine paradigms. PMID- 28837813 TI - Principles of Systems Biology, No. 20. AB - This month: RNA nanodevices that compute (Yin), self-organizing skin follicles (Shyer), cancer drivers identified by network hitting time (Sahinalp), single cell microfluidics breaks the Poisson barrier (Abate). PMID- 28837814 TI - Navigating the Cancer Transcriptome by Decoding Divergent Oncogenic States. AB - A new approach decomposes aberrant signaling mediated by an oncogenic mutation into underlying core cellular states that may be more permissive to available therapeutic options. PMID- 28837815 TI - When Seeing Isn't Believing: How Math Can Guide Our Interpretation of Measurements and Experiments. AB - Mathematical thought experiments probe the meaning and pitfalls of experimental measurements and demonstrate that caution is in order when measuring heterogeneity. PMID- 28837816 TI - Identification and segmentation of myelinated nerve fibers in a cross-sectional optical microscopic image using a deep learning model. AB - BACKGROUND: The morphometric analysis of myelinated nerve fibers of peripheral nerves in cross-sectional optical microscopic images is valuable. Several automated methods for nerve fiber identification and segmentation have been reported. This paper presents a new method that uses a deep learning model of a convolutional neural network (CNN). We tested it for human sural nerve biopsy images. METHODS: The method comprises four steps: normalization, clustering segmentation, myelinated nerve fiber identification, and clump splitting. A normalized sample image was separated into individual objects with clustering segmentation. Each object was applied to a CNN deep learning model that labeled myelinated nerve fibers as positive and other structures as negative. Only positives proceeded to the next step. For pretraining the model, 70,000 positive and negative data each from 39 samples were used. The accuracy of the proposed algorithm was evaluated using 10 samples that were not part of the training set. A P-value of <0.05 was considered statistically significant. RESULTS: The total true-positive rate (TPR) for the detection of myelinated fibers was 0.982, and the total false-positive rate was 0.016. The defined total area similarity (AS) and area overlap error of segmented myelin sheaths were 0.967 and 0.068, respectively. In all but one sample, there were no significant differences in estimated morphometric parameters obtained from our method and manual segmentation. COMPARISON WITH EXISTING METHODS: The TPR and AS were higher than those obtained using previous methods. CONCLUSIONS: High-performance automated identification and segmentation of myelinated nerve fibers were achieved using a deep learning model. PMID- 28837817 TI - Polymorphisms associated with resistance to protease inhibitors in naive patients infected with hepatitis C virus genotype 1 in Argentina: Low prevalence of Q80K. AB - Incorporation of direct acting antivirals (DAA) in the treatment of Hepatitis C Virus (HCV) significantly increases sustained virologic response rates. However, despite the greater potency offered by these antivirals, drug resistance plays a key role in patients with failure to DAA. Nevertheless, there is no information about the prevalence of resistance-associated substitutions (RASs) in Argentina. The aim of this study was to analyze HCV variants resistant to protease inhibitors (PI) in naive patients infected with HCV genotype 1 from Argentina. In this retrospective cross-sectional study, 103 patients infected with HCV-1 were included. Eighteen positions related with RASs were analyzed by Sanger at baseline and phylogenetic analysis was performed to determine the diversification of this samples. The analyzed RASs were present in 38 out of 103 patients (36.9%) infected with HCV-1. Patients infected with subtype HCV-1b had higher prevalence of baseline RASs than patients infected with HCV-1a [51.6% vs. 12.8%, respectively (p<0.001)]. The Q80K polymorphism was not found in HCV-1a samples, even when 51% of them belonged to cluster 1, which is associated with a high frequency of Q80K. Phylogenetic analysis showed that Argentinean samples were intermingled with sequences from other geographic regions. RASs to PI were highly prevalent and subtype dependent in treatment-naive Argentinean patients. Surprisingly, Q80K polymorphism was not detected in our study population. The phylogenetic analysis showed no relationship between our samples and other samples from Brazil which also present a low prevalence of Q80K. This study supports the need for surveillance of resistance in patients who will be treated with DAA in each particular country since the observed RASs have very different prevalence worldwide. PMID- 28837818 TI - Current strategies to improve the safety of chimeric antigen receptor (CAR) modified T cells. AB - Adoptive immunotherapy adopting chimeric antigen receptor (CAR) modified T cells has arisen attention as a hard-hitting therapy for numerous cancers. CARs are genetically engineered receptors that could stimulate tumor cytotoxicity once binding to the specific tumor epitopes. In spite of current noteworthy achievements in hematologic malignancies, the safety problems have aroused public awareness. In this review, we will focus on recent potential strategies to improve the security of CAR modified T cells. PMID- 28837819 TI - Visual exposure and categorization performance positively influence 3- to 6-year old children's willingness to taste unfamiliar vegetables. AB - The present research focuses on the effectiveness of visual exposure to vegetables in reducing food neophobia and pickiness among young children. We tested the hypotheses that (1) simple visual exposure to vegetables leads to an increase in the consumption of this food category, (2) diverse visual exposure to vegetables (i.e., vegetables varying in color are shown to children) leads to a greater increase in the consumption of this food category than classical exposure paradigms (i.e. the same mode of presentation of a given food across exposure sessions) and (3) visual exposure to vegetables leads to an increase in the consumption of this food category through a mediating effect of an increase in ease of categorization. We recruited 70 children aged 3-6 years who performed a 4 week study consisting of three phases: a 2-week visual exposure phase where place mats with pictures of vegetables were set on tables in school cafeterias, and pre and post intervention phases where willingness to try vegetables as well as cognitive performances were assessed for each child. Results indicated that visual exposure led to an increased consumption of exposed and non-exposed vegetables after the intervention period. Nevertheless, the exposure intervention where vegetables varying in color were shown to children was no more effective. Finally, results showed that an ease of categorization led to a larger impact after the exposure manipulation. The findings suggest that vegetable pictures might help parents to deal with some of the difficulties associated with the introduction of novel vegetables and furthermore that focusing on conceptual development could be an efficient way to tackle food neophobia and pickiness. PMID- 28837821 TI - pH fluctuations imperil the robustness of C. glutamicum to short term oxygen limitation. AB - The presence of complex gradients for, e.g., nutrients, oxygen or pH in industrial scale fed batch processes are a major challenge for process performance. To consider such impact of scale-up during laboratory scale process development, scale-down bioreactor simulation, i.e. mimicking inhomogeneous conditions, became the method of choice. However, most scale-down studies simulate combined inhomogeneities of more than one parameter, so that the impact of the individual parameters remains unclear. The presented scale down study addresses this challenge by separating the influence of glucose, pH and oxygen fluctuations in terms of their specific impact in a well-established two compartment scale down device. This was carried out for an 1,5-diaminopentane production process using the industrial production host Corynebacterium glutamicum. Strikingly, oxygen depletion alone showed no effect on the process performance while changes of only one pH unit in acidic as well as alkaline direction reduced the biomass and product formation. Even more pronounced phenotypes up to -13% of MU and -39% of YX/S were observed, when an oscillatory acidic pH shift was combined with dissolved oxygen fluctuations. These losses are accompanied by a missing regulation of fermentative pathways. In conclusion, large-scale C. glutamicum processes seem to be most sensitive to pH variation. PMID- 28837820 TI - An experiment assessing effects of personalized feedback about genetic susceptibility to obesity on attitudes towards diet and exercise. AB - As increasing attention is paid to possible genetic influences on susceptibility to obesity, recent studies have examined how genetic attributions can impact laypeople's weight-related attitudes and eating behavior. Little consideration, however, has been devoted to understanding the potential effects of learning that one does not have a genetic predisposition to obesity. The present study investigated the possibility that such feedback might bring about negative consequences by making people feel invulnerable to weight gain, which is termed a genetic invincibility effect. After conducting a saliva test disguised as genetic screening, participants were randomly assigned to be told that there was either a very high or very low chance that they carried genes known to increase one's risk of developing obesity. Participants who were told that they were not genetically predisposed to obesity judged the efficacy of healthy diet and exercise habits to be significantly lower than did those who were told that they were genetically predisposed and those who did not receive any genetic feedback. When prompted to select a meal from a menu of options, participants who were told that they were not genetically predisposed to obesity were also more likely than others to select unhealthy foods. These findings demonstrate the existence of a genetic invincibility effect, suggesting that personalized feedback indicating the absence of a genetic liability could have negative psychological consequences with substantial health-related implications. PMID- 28837822 TI - Tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates overcome doxorubicin resistance in cancer therapy. AB - Nanomedicines hold promise in overcoming drug resistance in cancer therapy, but the in vivo therapeutic efficacy is limited by their inefficient tumor targeting, poor tumor penetration, low cellular uptake and insufficient drug release. Here we report tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates for overcoming doxorubicin resistance. These nanoconjugates show accelerated cellular uptake and doxorubicin release and thus enhanced cytotoxicity to doxorubicin-resistant cancer cells when exposed to ultrasound. In a doxorubicin-resistant breast cancer mouse model, they exhibited improved tumor accumulation and penetration following exposure to ultrasound. More importantly, they displayed significantly improved in vivo anticancer efficacy without appreciable side effects post ultrasound irradiation. These findings suggest that these nanoconjugates are promising as a new class of intelligent nanomedicines for overcoming drug resistance in cancer therapy. PMID- 28837823 TI - Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia. AB - Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are potential therapies for various diseases, but their angiogenic mechanisms of therapeutic efficacy remain unclear. Here, we describe how MSC-EVs, activates VEGF receptors and downstream angiogenesis pathways. Mouse MSC-EVs were isolated from cell culture medium and characterized using transmission electron microscopy, nanoparticle analysis, and western blotting. In vitro migration, proliferation, and tube formation assays using endothelial cells were used to assess the angiogenic potential of MSC-EVs, and revealed higher levels of cellular migration, proliferation, and tube formation after treatment. qRT-PCR and western blotting (WB) revealed higher protein and mRNA expression of the angiogenic genes VEGFR1 and VEGFR2 in mouse SVEC-4 endothelial cells after MSC EVs treatment. Additionally, other vital pro-angiogenic pathways (SRC, AKT, and ERK) were activated by in vitro MSC-EV treatment. WB and qRT-PCR revealed enriched presence of VEGF protein and miR-210-3p in MSC-EV. The hindlimb ischemia mouse model was established and MSC-EVs with or without Matrigel (EV-MSC+Gel) were injected into the ischemic area and blood reperfusion was monitored using molecular imaging techniques. The in vivo administration of MSC-EVs increased both blood reperfusion and the formation of new blood vessels in the ischemic limb, with the addition of matrigel enhancing this effect further by releasing EVs slowly. MSC-EVs enhance angiogenesis in ischemic limbs, most likely via the overexpression of VEGFR1 and VEGFR2 in endothelial cells. These findings reveal a novel mechanism of activating receptors by MSC-EVs influence the angiogenesis. PMID- 28837824 TI - Chicken TBK1 interacts with STING and is involved in IFN-beta signaling regulation. AB - TANK-binding kinase 1 (TBK1) is an essential serine/threonine-protein kinase required for the Toll-like receptor (TLR)- and retinoic acid-inducible gene I (RIG-I) -mediated induction of type I IFN. Through endogenous Co-IP and LC-MS/MS, we identified chicken TBK1 (chTBK1) as a chSTING-interactive protein. Through exogenous Co-IP assay in transfected cells, we confirmed the interaction between chSTING and chTBK1. To better understand the biological role of chTBK1 in the chSTING-mediated IFN pathway, we cloned the chTBK1 and investigated its biological functions. Quantitative RT-PCR showed that chTBK1 mRNA was widely expressed in different tissues. The overexpression of chTBK1 in DF-1 cells induced the expression of IFN-beta and ISGs and inhibited AIV viral replication. We identified indispensable domains of chTBK1 on IFN-beta production via the generation of various chTBK1 mutant forms. Together, we identified the chTBK1 as a chSTING interactive protein and concluded that chTBK1 is involved in chSTING triggered IFN-beta signaling in chicken cells. PMID- 28837825 TI - Renal effects of Bunodosoma caissarum crude extract: Prostaglandin and endothelin involvement. AB - Sea anemones contain a variety of interesting biologically active compounds, including some potent toxins. PLA2 from Bunodosoma caissarum, a sea anemone endemic in the Brazilian southern coast, has shown renal alterations on isolated kidney. The aim of this study was to evaluate the renal and vascular effects of B. caissarum crude extract (BcE) on isolated perfused kidney and arteriolar mesenteric bed, as well the involvement of prostaglandins and endothelin. BcE did not show any effect on arteriolar mesenteric bed, but increased perfusion pressure, renal vascular resistance, urinary flow, glomerular filtration rate and decreased the percentage of sodium tubular transport on isolated perfused kidney. Indomethacin blocked the renal effects induced by BcE and tezosentan only partially blocked these effects. These results demonstrate the effects of BcE on kidney in situ, suggesting the involvement of prostaglandins and endothelin. PMID- 28837826 TI - Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections. AB - The aim of this article is to provide a review of the use of injections of botulinum toxin in the management of selected symptoms and signs of Parkinson's disease and other forms of parkinsonism. Sialorrhea is defined as inability to control oral secretions, resulting in excessive saliva in the oropharynx. There is a high level of evidence for the treatment of sialorrhea in parkinsonism with injections of different forms of botulinum toxin type A as well as botulinum toxin type B. Tremor can be improved by the use of botulinum toxin injections but improved tremor control often leads to concomitant motor weakness, limiting its use. Levodopa induced dyskinesias are difficult to treat with botulinum toxin injections because of their variable frequency and direction. Apraxia of eyelid opening, a sign more commonly seen in progressive supranuclear palsy and other tauopathies, often improves after botulinum toxin injections. Recent data suggest that regardless of the underlying mechanism, pain in parkinsonism can be alleviated by botulinum toxin injections. Finally, freezing of gait, camptocormia and Pisa syndrome in parkinsonism almost invariably fail to respond to botulinum toxin injections. PMID- 28837827 TI - Pharmacotherapy of emotional dysregulation in adults with ADHD: A systematic review and meta-analysis. AB - : Emotional dysregulation (ED) is a dysfunction in modifying an emotional state in an adaptive and goal oriented way, with excitability, ease anger, and mood lability. It is present in up to 70% of adults with ADHD, regardless of other comorbidities, and substantially worsens the psychosocial outcomes of the disorder. Besides fronto-parietal circuits mediating top-down control, brain regions involved in bottom-up processes (e.g., amygdala, orbitofrontal cortex, and ventral striatum) are implicated in ED. We performed a systematic review/meta analysis of double-blind randomized controlled trials of ADHD medications to assess their effects on ED in adults with ADHD. We searched an extensive set of databases, international trials registries, and contacted study authors/drug companies for unpublished data. We retained 21 trials. We found small-to-moderate effects (methylphenidate: SMD=0.34, 95% CI=0.23-0.45; atomoxetine: SMD=0.24, 95% CI=0.15-0.34; lisdexamfetamine: SMD=0.50, 95% CI=0.21-0.8). We suggest that, whilst ADHD medications are effective on ADHD core symptoms, they may be less effective on bottom-up mechanisms underlying ED. Further research on novel pharmacological and non-pharmacological strategies for ED in adults with ADHD is warranted. PROSPERO: CRD42017068426. PMID- 28837828 TI - Brain structural changes in late-life generalized anxiety disorder. AB - Late-life Generalized Anxiety Disorder (GAD) is relatively understudied and the underlying structural and functional neuroanatomy has received little attention. In this study, we compare the brain structural characteristics in white and gray matter in 31 non-anxious older adults and 28 late-life GAD participants. Gray matter indices (cortical thickness and volume) were measured using FreeSurfer parcellation and segmentation, and mean diffusivity was obtained through Diffusion Tensor Imaging (DTI). We assessed both macroscopic white matter changes [using white matter hyperintensity (WMH) burden] and microscopic white matter integrity [using fractional anisotropy (FA)]. No differences in macro- or microscopic white matter integrity were found between GAD and non-anxious controls (HC). GAD participants had lower cortical thickness in the orbitofrontal cortex (OFC), inferior frontal gyrus, and pregenual anterior cingulate cortex (ACC). Higher worry severity was associated with gray matter changes in OFC, ACC and the putamen. The results did not survive the multiple comparison correction, but the effect sizes indicate a moderate effect. The study suggests that late life GAD is associated with gray matter changes in areas involved in emotion regulation, more so than with white matter changes. We conclude that anxiety related chronic hypercortisolemia may have a dissociative effect on gray and white matter integrity. PMID- 28837830 TI - Between-litter variation in developmental studies of hormones and behavior: Inflated false positives and diminished power. AB - Developmental studies of hormones and behavior often include littermates-rodent siblings that share early-life experiences and genes. Due to between-litter variation (i.e., litter effects), the statistical assumption of independent observations is untenable. In two literatures-natural variation in maternal care and prenatal stress-entire litters are categorized based on maternal behavior or experimental condition. Here, we (1) review both literatures; (2) simulate false positive rates for commonly used statistical methods in each literature; and (3) characterize small sample performance of multilevel models (MLM) and generalized estimating equations (GEE). We found that the assumption of independence was routinely violated (>85%), false positives (alpha=0.05) exceeded nominal levels (up to 0.70), and power (1-beta) rarely surpassed 0.80 (even for optimistic sample and effect sizes). Additionally, we show that MLMs and GEEs have adequate performance for common research designs. We discuss implications for the extant literature, the field of behavioral neuroendocrinology, and provide recommendations. PMID- 28837831 TI - Effect of low-dose zearalenone exposure on reproductive capacity of male mice. AB - Zearalenone (ZEA), a kind of nonsteroidal mycotoxin with estrogenic effects, can influence animal reproductive capacity through interfering with estrogen signaling pathway. Previous studies have shown exposure to ZEA at high doses (higher than No-Observed Effect Level, NOEL) had a significant impact on mouse sperm quality and pregnant rate, but little is known about the effect of exposure to ZEA at low doses (lower than NOEL) on mouse reproductive capacity. This study evaluated the effects of exposure to low-dose ZEA on mouse spermatogenesis and semen quality. Male mice (CD-1) of 21days were exposed to ZEA at 20, or 40MUg/kg body weight for 14, 28 or 42days. After exposure to ZEA for 14days, the spermatogenic cells in seminiferous tubules were declined dose-independently; however in groups treated by ZEA for 28days, the spermatogenic cells were declined dose-dependently. Moreover, after treatment for 28days or 42days, the DNA double stand break (DSB) in spermatogenic cells were increased in a dose dependent manner in treated groups. Compared with the control group, the sperm concentration, viability, motility, and hyperactive rate in treated groups were decreased dose-dependently and time-dependently. Meanwhile, deformity and mortality rate of sperm in treated groups were increased remarkably dose dependently too. In conclusion, low dose ZEA impaired male reproductive capacity especially in spermatogenesis and semen quality of mouse. PMID- 28837829 TI - Precuneus abnormalities in middle-aged to older adults with depressive symptoms: An analysis of BDI-II symptom dimensions. AB - We recently reported age-related increases in left precuneus cortical thickness (CT) in older adults with elevated total depressive symptoms. However, it is unclear whether abnormalities in precuneus surface area (SA) are also evident and whether specific symptom dimensions of depression moderated age effects on these measurements. Seventy-three adults completed the Beck Depression Inventory - 2nd edition (BDI-II) and underwent structural neuroimaging. Measures of CT and SA were extracted from the right and left precuneus via FreeSurfer. Regression models included regions of interest as dependent variables, with age, BDI-II subscale scores (e.g., affective, cognitive, and somatic symptoms), and their interactions as independent variables, controlling for mean hemispheric thickness (for CT) or total intracranial volume (for SA). A significant age * somatic symptom interaction was found for left precuneus CT, such that elevated levels of somatic symptoms were significantly associated with age-related cortical thinning. No depressive symptom dimensions moderated the relationship between age and SA, suggesting that CT may be a more sensitive measure of brain abnormalities in middle-aged to older adults with depressive symptoms. PMID- 28837832 TI - Factors associated with adverse pregnancy outcomes in women with antiphospholipid syndrome: A multicenter study. AB - The aim of this study was to understand the clinical features of antiphospholipid syndrome (APS)-complicated pregnancies and evaluate risk factors for the adverse pregnancy outcomes. This multicenter study evaluated live-birth rates according to therapy modality for APS and risk factors of pregnancy loss in 81 pregnancies. Risk factors for pregnancy complications, including premature delivery before 34 gestational weeks, hypertensive disorders of pregnancy, thrombocytopenia, and light-for-date neonate, were evaluated in 51 women who received low dose aspirin (LDA) plus unfractionated heparin (UFH) and delivered after 24 GW. The live-birth rate in APS pregnancies with LDA+UFH therapy was 92.6%. A multiple logistic regression analysis demonstrated that LDA+UFH therapy decreased the risk of pregnancy loss (OR 0.13, 95%CI 0.03-0.62), and that a history of pregnancy loss despite LDA+UFH therapy increased the risk of pregnancy loss (OR 8.74, 95%CI 1.69 45.2). LDA therapy prior to pregnancy decreased the risk of premature delivery (OR 0.14, 95%CI 0.03-0.69). Positive tests for two or more anti-phospholipid antibodies increased the risks of premature delivery (OR 9.61, 95%CI 1.78-51.8) and thrombocytopenia (OR 4.90, 95%CI 1.11-21.7). Laboratory findings of low complements increased the risk of hypertensive disorders of pregnancy (OR 12.1, 95%CI 1.61-91.0). Standard therapy yielded high live-birth rates. Positive tests for two or more anti-phospholipid antibodies and low complements were associated with adverse pregnancy outcomes. These results have important implications for clinicians. PMID- 28837834 TI - Progress towards molecular patient stratification of hepatocellular carcinoma: Lost in translation? PMID- 28837833 TI - Sequencing of transporter genes in cholestasis: We are still learning. PMID- 28837835 TI - Prospective validation of transient elastography for staging liver fibrosis in patients undergoing hepatectomy and liver transplantation. PMID- 28837836 TI - Meta-analysis of the effect of road work zones on crash occurrence. AB - There is strong evidence that work zones pose increased risk of crashes and injuries. The two most common risk factors associated with increased crash frequencies are work zone duration and length. However, relevant research on the topic is relatively limited. For that reason, this paper presents formal meta analyses of studies that have estimated the relationship between the number of crashes and work zone duration and length, in order to provide overall estimates of those effects on crash frequencies. All studies presented in this paper are crash prediction models with similar specifications. According to the meta analyses and after correcting for publication bias when it was considered appropriate, the summary estimates of regression coefficients were found to be 0.1703 for duration and 0.862 for length. These effects were significant for length but not for duration. However, the overall estimate of duration was significant before correcting for publication bias. Separate meta-analyses on the studies examining both duration and length was also carried out in order to have rough estimates of the combined effects. The estimate of duration was found to be 0.953, while for length was 0.847. Similar to previous meta-analyses the effect of duration after correcting for publication bias is not significant, while the effect of length was significant at a 95% level. Meta-regression findings indicate that the main factors influencing the overall estimates of the beta coefficients are study year and region for duration and study year and model specification for length. PMID- 28837837 TI - Coming back into the loop: Drivers' perceptual-motor performance in critical events after automated driving. AB - This driving simulator study, conducted as part of the EU AdaptIVe project, investigated drivers' performance in critical traffic events, during the resumption of control from an automated driving system. Prior to the critical events, using a between-participant design, 75 drivers were exposed to various screen manipulations that varied the amount of available visual information from the road environment and automation state, which aimed to take them progressively further 'out-of-the-loop' (OoTL). The current paper presents an analysis of the timing, type, and rate of drivers' collision avoidance response, also investigating how these were influenced by the criticality of the unfolding situation. Results showed that the amount of visual information available to drivers during automation impacted on how quickly they resumed manual control, with less information associated with slower take-over times, however, this did not influence the timing of when drivers began a collision avoidance manoeuvre. Instead, the observed behaviour is in line with recent accounts emphasising the role of scenario kinematics in the timing of driver avoidance response. When considering collision incidents in particular, avoidance manoeuvres were initiated when the situation criticality exceeded an Inverse Time To Collision value of ~0.3s-1. Our results suggest that take-over time and timing and quality of avoidance response appear to be largely independent, and while long take-over time did not predict collision outcome, kinematically late initiation of avoidance did. Hence, system design should focus on achieving kinematically early avoidance initiation, rather than short take-over times. PMID- 28837838 TI - Single nucleotide variations in cultured cancer cells: Effect of mismatch repair. AB - We assessed single nucleotide variations (SNVs) between individual cells in two cancer cell lines; DU145, from brain metastasis of prostate tumor with deficient mismatch repair; and HT1080, a fibrosarcoma cell line. Clones of individual cells were isolated, and sequenced using Ion Ampliseq comprehensive cancer panel that covered the exomes of 409 oncogenes and tumor suppressor genes. Five clones of DU145 and four clones of HT1080 cells were analyzed. We found from 7 to 12 unique SNVs between DU145 clones, while HT1080 clones showed no more than one unique SNV. We then sub-cloned individual cells from some of these isolated clones of DU145 and HT1080 cells. The sub-clones were expanded from a single cell to approximately one million cells after about 20 cell divisions. The sub-clones of DU145 cells had from one to four new unique SNVs within the sequenced regions. No unique SNVs were found between sub-clones of HT1080 cells. Our data demonstrate that the extent of genetic variation at the single nucleotide level in cultured cancer cells is significantly affected by the status of the DNA mismatch repair system. PMID- 28837839 TI - Genetic and structural elucidation of capsular polysaccharides from Streptococcus pneumoniae serotype 23A and 23B, and comparison to serotype 23F. AB - Streptococcus pneumoniae is a globally important encapsulated human pathogen with approximately 100 different serotypes recognized. Serogroup 23 consists of serotype 23F, present in licensed vaccines, and emerging serotypes 23A and 23B. Here, we report the previously unknown structures of the pneumococcal capsular polysaccharides serotype 23A and 23B determined using genetic analysis, NMR spectroscopy, composition and linkage analysis and Smith degradation (of polysaccharide 23A). The structure of the serotype 23A capsular polysaccharide is: ->4)-beta-D-Glcp-(1->3)-[[alpha-L-Rhap-(1->2)]-[Gro-(2->P->3)]-beta-D-Galp-(1 >4)]-beta-L-Rhap-(1->. This structure differs from polysaccharide 23F as it features a disaccharide backbone and the di-substituted beta-Gal is linked to beta-Rha as a side chain. This is due to the different polymerization position catalysed by the unusually divergent repeat unit polymerase Wzy in the 23A cps biosynthesis locus. Steric crowding in 23A, confirmed by molecular models, causes the NMR signal for H-1 of the di-substituted 2,3-beta-Gal to resonate in the alpha-anomeric region. The structure of the serotype 23B capsular polysaccharide is the same as 23F, but without the terminal alpha-Rha: ->4)-beta-D-Glcp-(1->4) [Gro-(2->P->3)]-beta-D-Galp-(1->4)-beta-L-Rhap-(1->. The immunodominant terminal alpha-Rha of 23F is more sterically crowded in 23A and absent in 23B. This may explain the reported typing cross reactions for serotype 23F: slight with 23A and none with 23B. PMID- 28837840 TI - Development of a recombinant yellow fever vector expressing a HIV clade C founder envelope gp120. AB - Development of a HIV-1 vaccine is a major global priority. The yellow fever virus (YFV) attenuated vaccine 17D is among the most effective of currently used vaccines. However, the stability of the YFV17D vector when carrying non flavivirus genes has been problematic. We have constructed and expressed HIV-1 Env in YFV17D with either single transmembrane (STM) or double transmembrane (DTM) YFV E protein domains for the development of anti-HIV antibodies. Here we describe modifications of the YFV17D vector such that HIV-1 Env gp120 is expressed in up to 5 passages in Vero cells. Immunization with recombinant YFV17D vector prime followed by HIV-1 CH505 TF gp120 protein boosts were able to induce neutralizing antibodies for a HIV-1 tier 1 isolate in mice. This modified YFV vector may be a starting point for constructing HIV-1 vaccine candidate priming vectors. PMID- 28837841 TI - Development and validation of a TaqMan probe-based real-time PCR method for the differentiation of wild type lumpy skin disease virus from vaccine virus strains. AB - Lumpy skin disease (LSD) is a transboundary viral disease of cattle with severe economic impact. Immunization of cattle with homologous live attenuated vaccines poses a number of diagnostic problems, as it has been associated with adverse reactions resembling disease symptoms. The latter hampers clinical diagnosis and poses challenges in virus identification. To this end, a duplex quantitative real time PCR method targeting the GPCR gene was developed and validated, for the concurrent detection and differentiation of wild type and vaccine Lumpy skin disease virus (LSDV) strains. The method was evaluated in three laboratories. The evaluation included a panel of 38 poxvirus isolates/strains and the analytical characteristics of the method were determined. Amplification efficiencies were 91.3% and 90.7%, for wild type and vaccine LSDV, respectively; the limit of detection was 8 DNA copies for both targets and the inter-assay CV was 0.30% for wild type and 0.73% for vaccine LSDV. The diagnostic performance was assessed using 163 LSDV-positive samples, including field specimens and samples from experimentally vaccinated/infected animals. The method is able to confirm diagnosis in suspect cases, it differentiates infected from vaccinated animals (DIVA) and can be regarded as an important tool for effective LSD surveillance and eradication during vaccination campaigns. PMID- 28837842 TI - Defining the relative performance of isothermal assays that can be used for rapid and sensitive detection of foot-and-mouth disease virus. AB - This study describes the first multiway comparison of portable isothermal assays for the detection of foot-and-mouth disease virus (FMDV), benchmarked against real-time reverse transcription RT-PCR (rRT-PCR). The selected isothermal chemistries included reverse transcription loop-mediated isothermal amplification (RT-LAMP) and reverse transcription recombinase polymerase amplification (RT RPA). The analytical sensitivity of RT-LAMP was comparable to rRT-PCR (101 RNA copies), while RT-RPA was one log10 less sensitive (102 RNA copies). Diagnostic performance was evaluated using a panel of 35 samples from FMDV-positive cattle and eight samples from cattle infected with other vesicular viruses. Assay concordance for RT-LAMP and RT-RPA was 86-98% and 67-77%, respectively, when compared to rRT-PCR, with discordant samples consistently having high rRT-PCR cycle threshold values (no false-positives were detected for any assay). In addition, a hierarchy of sample preparation methods, from robotic extraction to simple dilution of samples, for epithelial suspensions, serum and oesophageal pharyngeal (OP) fluid were evaluated. Results obtained for RT-LAMP confirmed that FMDV RNA can be detected in the absence of RNA extraction. However, simple sample preparation methods were less encouraging for RT-RPA, with accurate results only obtained when using RNA extraction. Although the evaluation of assay performance is specific to the conditions tested in this study, the compatibility of RT-LAMP chemistry with multiple sample types, both in the presence and absence of nucleic acid extraction, provides advantages over alternative isothermal chemistries and alternative pen-side diagnostics such as antigen-detection lateral-flow devices. These characteristics of RT-LAMP enable the assay to be performed over a large diagnostic detection window, providing a realistic means to rapidly confirm positive FMD cases close to the point of sampling. PMID- 28837843 TI - Positive influence of partial resection on overall survival of patients with overlapping glioblastomas. AB - OBJECTIVES: Patients with overlapping glioblastomas (former known as gliomatosis cerebri according to the 2007 WHO classification) have a poor prognosis. Most of the patients undergo biopsy to confirm histopathological diagnosis. Treatment comprises chemotherapy, radiation and combination of both. We determined whether resection of the contrast enhancing tumor parts leads to a prolonged survival. PATIENTS AND METHODS: We performed a retrospective analysis and included 31 patients with overlapping glioblastomas (OG) who showed WHO IV in the initial histopathological examination. All patients fulfilled criteria of overlapping glioblastomas in the MRI according to WHO criteria (3 or more lobes were affected). We evaluated Karnofsky performance score (KPS), gender, age, IDH 1_R132H status, MGMT promotor methylation status, proliferation index, postoperative therapy, biopsy vs. partial resection and extent of resection as possible factors affecting overall survival (OAS). A matched pair analysis was performed between the biopsy and resection group on basis of age, KPS and combined radio-chemotherapy. RESULTS: 10 Patients underwent resection of the contrast enhancing tumor parts, 21 patients underwent stereotactic biopsy. All included patients showed contrast enhancing lesions in the MRI. Median age was 61 years in the biopsy-group and 53 in the partial resection (PR) group. We found a significant correlation between OAS and age <50 (p=0.02). Median KPS was 80 in the STX group vs. 100 in the PR group. KPS above 80 was significantly associated with longer OAS (p=0.02). Median survival was 174days in the STX group compared to 446days in the PR group (p=0.05). Also the matched pair analysis showed significant p-values for resection. CONCLUSION: Partial resection might have a positive impact on overall survival of patients with overlapping glioblastomas (former known as gliomatosis cerebri), although the prognosis remains limited. PMID- 28837844 TI - A wheat NBS-LRR gene TaRGA19 participates in Lr19-mediated resistance to Puccinia triticina. AB - Wheat leaf rust, caused by Puccinia triticina (Pt), is one of the most severe fungal diseases on wheat globally. Rational utilization of wheat leaf rust resistance (Lr) genes is still the best choice for control this disease. Wheat seedlings carrying Lr19 showed a high resistance phenotype to all Pt races in China. So far, all the cloned seedling Lr genes including Lr1, Lr10 and Lr21, encode protein with NBS-LRR domain. In this study, a wheat gene with NBS-LRR domain from previously established Lr19-resistance-related cDNA library was cloned and designated as TaRGA19. Full length of this gene was amplified by rapid amplification of cDNA ends (RACE). By blast against IWGSC wheat genome database, we have noticed that TaRGA19 was located on chromosome 2DS, which was different from Lr19 located on chromosome 7DL. Compared with susceptible Thatcher line, expression level of TaRGA19 was upregulated in wheat isogenic lines carrying Lr19 (TcLr19) after inoculation of Pt race THTS. By particle bombardment, TaRGA19-GFP fused protein was localized on plasma membrane of epidermal cells. Using virus induced gene silencing (VIGS), TaRGA19-knockdown plants of TcLr19 showed reduced resistance and few sporulation phenotype upon Pt challenge. Further histological observation indicated that Pt hyphal growth at the infection sites was less suppressed in the TaRGA19-knockdown plants. In conclusion, we speculate this TaRGA19 gene was involved in the Lr19-mediated resistance to wheat leaf rust along with other components. PMID- 28837845 TI - The senescent bystander effect is caused by ROS-activated NF-kappaB signalling. AB - Cell senescence is an important driver of the ageing process. The accumulation of senescent cells in tissues is accelerated by stress signals from senescent cells that induce DNA damage and ultimately senescence in bystander cells. We examine here the interplay of senescence-associated mitochondrial dysfunction (SAMD) driven production of reactive oxygen species (ROS) and senescence-associated secretory phenotype (SASP) in causing the bystander effect. We show that in various modes of fibroblast senescence ROS are necessary and sufficient to activate the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), which facilitates a large part of the SASP. This ROS-NF-kappaB axis causes the DNA damage response in bystander cells. Cytokines IL-6 and IL-8 are major components of the pro-inflammatory SASP in senescent fibroblasts. However, their activation in senescence is only partially controlled by NF-kappaB, and they are thus not strong candidates as intercellular mediators of the bystander effect as mediated by the ROS-NF-kappaB axis. PMID- 28837846 TI - Synthesis of Aloevera/Acrylonitrile based Nanoparticles for targeted drug delivery of 5-Aminosalicylic acid. AB - Aloevera (AV) polysaccharide/acrylonitrile (AN) nanoparticles (AVANp4 of ~50nm size) have been crafted via free radical polymerization method using persulfate/ascorbic acid (KPS/AA) and methylenebisacrylamide (MBA) as the redox initiator and crosslinker respectively. AVANp4 was extensively characterized using FTIR, SEM, TEM, XRD, and Thermal analysis (TGA & DTG). Inclusion of AN in AV polysaccharide has been evidenced by nitrile stretching peak at 2244cm-1 in FTIR spectrum of AVANp4. Colon specific targeted in-vitro release of 5 Aminosalicylic acid from AVANp4 has been studied in pH 1.2 and pH 7.4 buffer solutions at 37 degrees C. The controlled release was witnessed up to 48h for AVANp4 in contrast to AV for which the release exhausted within 7-8h in both the buffers. The delayed release of the drug from AVANp4 is attractive since it can allow the drug to reach colon rather than being released in the upper part of the gastrointestinal tract. PMID- 28837847 TI - Renoprotective effect of Chinese chive polysaccharides in adenine-induced chronic renal failure. AB - In this work, we investigated the effect of Chinese chive polysaccharides (CCP) on renal function in mice with adenine-induced chronic renal failure (CRF). Results exhibited that adenine treatment caused serious renal pathological damages and elevation of serum creatinine and blood urea nitrogen of mice. However, these changes could be significantly reversed by the administration of CCP in a dose-dependent manner. When CCP dosage reached 200mg/kg/day, the area of renal pathological damage was decreased by 59.2%, and the levels of serum creatinine and blood urea nitrogen were decreased by 23.9% and 34.7% compared to those of model group. Moreover, it was found that renal oxidative damage, inflammation and fibrosis of adenine-induced CRF mice could also be significantly inhibited by CCP. These results suggested that CCP could improve the kidney functions of adenine-induced CRF mice and the renoprotective effect might be associated with its antioxidant, anti-inflammatory and anti-fibrosis activities. PMID- 28837848 TI - Interaction of the red pigment-concentrating hormone of the crustacean Daphnia pulex, with its cognate receptor, Dappu-RPCHR: A nuclear magnetic resonance and modeling study. AB - The primary sequence of the red pigment-concentrating hormone (RPCH) receptor of the water flea, Daphnia pulex, was used in homology modeling to construct the first 3D model of a crustacean G-protein coupled receptor, Dappu-RPCHR. This receptor was found to belong to the class A subfamily of GPCRs with a disulfide bridge between Cys72 and Cys150 and an ionic lock between Arg97 and Thr224 and Thr220. NMR restrained molecular dynamics was used to determine the structure of an agonist, Dappu-RPCH, in a membrane-mimicking environment. The agonist was found to be flexible but has two main conformations in solution, both having beta turns. Docking of the predominant structure was used to find a binding pocket on the receptor. The pocket's spatial location was similar to that of the AKH receptor of Anopheles gambiae. The binding affinity was -69kcalmol-1 with the N terminus of Dappu-RPCH inserted between helices 4 and 6, and the C-terminus interacting with extra-cellular loop, ECL2. Upon binding, H-bonding to the peptide may activate the receptor. This development of the first Dappu-RPCH/Dappu RPCHR model could be useful for understanding ligand-receptor interactions in crustaceans. PMID- 28837849 TI - Isolation and molecular cloning of hepatocyte growth factor from guinea pig (gHGF), and expression of truncated variant of gHGF with improved anti-fibrotic activity in Escherichia coli. AB - Hepatocyte growth factor (HGF) is an attractive target for anti-fibrotic therapy because it attenuates excessive transforming growth factor-beta1 (TGF-beta1) which plays an important role in hepatic fibrosis. In the study, we reported on the isolation and molecular cloning of the open reading frame (ORF) of guinea pig HGF (gHGF), encoding a protein of 729 amino acids, with an apple-like (hairpin) domain, four kringle domains and a trypsin-like serine protease domain. Moreover, the truncated variant of gHGF (a double mutant of N-terminal hairpin and first kringle domains of gHGF, K132E and G134E, gmNK1) protein fused with His6 tag, the molecular weight of which was about 20.0kDa, which was expressed in Escherichia coli BL21 (DE3) and purified with Ni2+-affinity chromatography. Furthermore, gmNK1 inhibited protein expression levels of fibrosis-related type I collagen (Col I) and alpha-smooth muscle actin (alpha-SMA) genes in TGF-beta1-activated HSC-T6 cells and CCl4-induced liver fibrosis in rat. In addition, gmNK1 ameliorated liver morphology and fibrotic responses in fibrosis animal. Taken together, we first reported on the sequence of HGF from guinea pig and determined the anti-fibrotic activity of gmNK1 in hepatic fibrosis, which will be helpful for investigations into the biological roles of gHGF in this important animal model. PMID- 28837850 TI - Ca2+-induced stabilization of the nucleoside 2'- deoxyribosyltransferase from Lactobacillus hilgardii ZJS01: Characteristics and application in nucleosides synthesis. AB - A novel nucleoside 2'-deoxyribosyltransferase (LhNDT) from Lactobacillus hilgardii ZJS01 was cloned and expressed in Escherichia coli BL21 (DE3). The amino acid sequence of LhNDT displayed the highest identity of 26% to other reported NDTs. LhNDT was a monomer as revealed by gel filtration chromatography with or without addition of Ca2+ in elution buffer. This enzyme showed a high activity and stability over a broad pH range and was sensitive to temperature. With the addition of 15mM Ca2+, the thermostability of LhNDT was greatly promoted by 63 times and 46 times at 30 degrees C and 35 degrees C, respectively. With the use of 2'-deoxyuridine as sugar donor at an economic molar ratio of 1:1, 5-aza-2' deoxycytidine (46%) and 5-fluoro-2'- deoxycytidine (58%) were efficiently synthesized from 5-azacytosine and 5-fluorocytosine, respectively, by LhNDT for 2h. PMID- 28837851 TI - Photo-producible and photo-degradable starch/TiO2 bionanocomposite as a food packaging material: Development and characterization. AB - In current study, starch/TiO2 bionanocomposites were produced by photochemical reactions as a biodegradable food packaging material. Physical, mechanical, thermal and water-vapor permeability properties were investigated. Then, the photo-degradation properties of nanocomposite films were studied. This is the first report of the photo-producible and photo-degradable bionanocomposite as a food packaging material. Film-forming solutions were exposed to ultraviolet A (UV A) for different times. Our results showed that UV-A irradiation increased the hydrophobicity of starch films. With increasing UV-A exposure time, tensile strength and Young's modulus of the specimens were decreased. On the other hand, elongation at break of the films was increased with increasing UV-A irradiation. The glass transition temperature and melting point of the films were increased by increasing UV-A exposure time. Nevertheless, the results showed that photo degradation properties of photo-produced starch/TiO2 nanocomposite were significantly higher than virgin starch and virgin starch/TiO2 films. According to obtain results and bibliography a schema was developed to describe the mechanism of photo-production and photo-degradation of starch/TiO2 by UV-A ray. It can be concluded, the modification of starch based biopolymer by UV-A and nano TiO2, is an easy and accessible process to improve the packaging properties and photo-degradability of biopolymer based films. PMID- 28837852 TI - Bactericidal and fungistatic activity of peptide derived from GH18 domain of prawn chitinase 3 and its immunological functions during biological stress. AB - Chitinases play a vital role during the pathogenic invasion and immunosuppression in various organisms including invertebrates and vertebrates. In this study, we have investigated the participation of MrChit-3 (Macrobrachium rosenbergii Chitinase-3) during host-pathogenic interaction in freshwater prawn, M. rosenbergii. Quantitative real-time PCR analysis showed that the expression of MrChit-3 was up-regulated during bacterial, viral and laminarin challenge. Moreover, to understand the antimicrobial role of the GH18 domain, a putative membrane-targeting antimicrobial peptide (MrVG) was identified from the GH18 domain region of the protein and it was chemically synthesized. Physico-chemical features of the GH18 derived antimicrobial peptide (AMP) was assessed by various in silico tools and the antimicrobial property of the peptide was confirmed from in vitro studies. The membrane targeting mechanism of the peptide was determined by flow cytometry (FACS) and scanning electron microscope (SEM) analysis. Interestingly, the peptide was able to inhibit the growth of a chitinolytic fungal pathogen, Aspergillus niger, which was isolated from the shells of M. rosenbergii. The toxicity studies such as hemolysis activity on human blood erythrocytes and cell viability assay with primary kidney cells, HEK293 of MrVG revealed that the peptide was not involved in inducing any toxicity. PMID- 28837853 TI - Finger millet arabinoxylan protects mice from high-fat diet induced lipid derangements, inflammation, endotoxemia and gut bacterial dysbiosis. AB - Arabinoxylan (AX), a non-starch polysaccharide extracted from cereals such as wheat, rice and millets, is known to impart various health promoting effects. Our earlier study suggested that finger millet (FM) could ameliorate high fat diet (HFD)-induced metabolic derangements. The present study is aimed to evaluate the effect of FM-AX supplementation, a key bioactive from finger millet, on HFD induced metabolic and gut bacterial derangements. Male Swiss albino mice were fed with normal chow diet (NPD) or HFD (60%kcal from fat) for 10 weeks. FM-AX was orally supplemented at doses of 0.5 and 1.0g/kg bodyweight on every alternate day for 10 weeks. Glucose tolerance, serum hormones, hepatic lipid accumulation and inflammation, white adipose tissue marker gene expression, adipocyte size and inflammation; metagenomic alterations in cecal bacteria; cecal short chain fatty acids and colonic tight junction gene expressions were studied. FM-AX supplementation prevented HFD-induced weight gain, alerted glucose tolerance and serum lipid profile, hepatic lipid accumulation and inflammation. Hepatic and white adipose tissue gene expressions were beneficially modulated. Further, AX supplementation prevented metagenomic alterations in cecum; improved ileal and colonic health and overall prevented metabolic endotoxemia. Present work suggests that AX from finger millet can be developed as a nutraceutical for the management of HFD- induced obesity. PMID- 28837854 TI - North, East, South, West: mapping vascular tissues onto the Arabidopsis root. AB - The Arabidopsis root has provided an excellent model for understanding patterning processes and cell fate specification. Vascular patterning represents an especially interesting process, as new positional information must be generated to transform an approximately radially symmetric root pole into a bisymmetric structure with a single xylem axis. This process requires both growth of the embryonic tissue alongside the subsequent patterning. Recently researchers have identified a series of transcription factors that modulate cell divisions to control vascular tissues growth. Spatial regulation in the signalling of two hormones, auxin and cytokinin, combine with other transcription factors to pattern the xylem axis. We are now witnessing the discovery of increasingly complex interactions between these hormones that can be interpreted through the use of mathematical models. PMID- 28837855 TI - Use it or average it: stochasticity in plant development. AB - A process that is stochastic has a probabilistic or randomly determined outcome. At the molecular level, all processes are stochastic; but development is highly reproducible, suggesting that plants and other multicellular organisms have evolved mechanisms to ensure robustness (achieving correct development despite stochastic and environmental perturbations). Mechanisms of robustness can be discovered through isolating mutants with increased variability in phenotype; such mutations do not necessarily change the average phenotype. Surprisingly, some developmental robustness mechanisms actually exploit stochasticity as a useful source of variation. For example, gene expression is stochastic and can be utilized to create subtle differences between identical cells that can initiate the patterning of specialized cell types. Stochasticity can also be used to promote robustness through spatiotemporal averaging-stochasticity can be averaged out across space and over time. Thus, organisms often harness stochasticity to ensure robust development. PMID- 28837856 TI - Secure and robust cloud computing for high-throughput forensic microsatellite sequence analysis and databasing. AB - Next-generation Sequencing (NGS) is a rapidly evolving technology with demonstrated benefits for forensic genetic applications, and the strategies to analyze and manage the massive NGS datasets are currently in development. Here, the computing, data storage, connectivity, and security resources of the Cloud were evaluated as a model for forensic laboratory systems that produce NGS data. A complete front-to-end Cloud system was developed to upload, process, and interpret raw NGS data using a web browser dashboard. The system was extensible, demonstrating analysis capabilities of autosomal and Y-STRs from a variety of NGS instrumentation (Illumina MiniSeq and MiSeq, and Oxford Nanopore MinION). NGS data for STRs were concordant with standard reference materials previously characterized with capillary electrophoresis and Sanger sequencing. The computing power of the Cloud was implemented with on-demand auto-scaling to allow multiple file analysis in tandem. The system was designed to store resulting data in a relational database, amenable to downstream sample interpretations and databasing applications following the most recent guidelines in nomenclature for sequenced alleles. Lastly, a multi-layered Cloud security architecture was tested and showed that industry standards for securing data and computing resources were readily applied to the NGS system without disadvantageous effects for bioinformatic analysis, connectivity or data storage/retrieval. The results of this study demonstrate the feasibility of using Cloud-based systems for secured NGS data analysis, storage, databasing, and multi-user distributed connectivity. PMID- 28837857 TI - Removal of nutrients in saline wastewater using constructed wetlands: Plant species, influent loads and salinity levels as influencing factors. AB - This study aims to evaluate how plant species, influent loads and salinity levels affect the removal of nutrients from saline wastewater using constructed wetlands (CWs). CWs planted with Canna indica showed the greatest removal percentages among the four tested species for nitrogen (N) (~100%) at both low and high influent loads, and ~100% and 93.8% for phosphorus (P) at low and high influent loads, respectively at an electrical conductivity (EC) of 7 mS/cm (25 degrees C). The influence of different salinity levels on plant assimilation of N and P varied with their respective concentrations; salinity (e.g., EC at 7, 10 and 15 mS/cm) even enhanced plant absorption of N and P under specific conditions. In conclusion, CWs planted with selected species can be used for the removal of N and P under a range of different salinity levels (e.g., EC at 7, 10 and 15 mS/cm, 25 degrees C). PMID- 28837859 TI - Systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in Europe. AB - Community-acquired pneumonia (CAP) is an important respiratory disease and the fifth leading cause of mortality in Europe. The development of molecular diagnostic tests has highlighted the contributions of respiratory viruses to the aetiology of CAP, suggesting the incidence of viral pneumonia may have been previously underestimated. We performed a systematic review and meta-analysis to describe the overall identification of respiratory viruses in adult patients with CAP in Europe, following PRISMA guidelines (PROSPERO; CRD42016037233). We searched EMBASE, MEDLINE, CINAHL, WHOLIS, COCHRANE library and grey literature sources for relevant studies, and screened these against protocol eligibility criteria. Two researchers performed data extraction and risk of bias assessments, independently, using a piloted form. Results were synthesised narratively, and random effects meta-analyses performed to calculate pooled estimates of effect; heterogeneity was quantified using I2. Twenty-eight studies met inclusion criteria of which 21 were included in the primary meta-analysis. The pooled proportion of patients with identified respiratory viruses was 22.0% (95% CI: 18.0%-27.0%), rising to 29.0% (25.0%-34.0%) in studies where polymerase chain reaction (PCR) diagnostics were performed. Influenza virus was the most frequently detected virus in 9% (7%-12%) of adults with CAP. Respiratory viruses make a substantial contribution to the aetiology of CAP in adult patients in Europe; one or more respiratory viruses are detected in about one quarter of all cases. PMID- 28837858 TI - Risk factors for herpes simplex virus-1/2 viremia and clinical outcomes following unmanipulated haploidentical haematopoietic stem cell transplantation. AB - BACKGROUND: Herpes simplex virus (HSV)-1/2 can still be reactivated after allogeneic haematopoietic stem cell transplantation (allo-HSCT) even when the prophylactic acyclovir is used. However, the risk factors for HSV-1/2 viremia and the clinical outcomes following unmanipulated haploidentical HSCT remain unknown. OBJECTIVES AND STUDY DESIGN: Nineteen patients with HSV-1/2 viremia and fifty seven patients without HSV-1/2 viremia which were selected using the case-pair method after undergoing haploidentical HSCT were enrolled. We analysed the risk factors for HSV-1/2 viremia and compared the clinical outcomes between the two groups. RESULTS: The risk factors for HSV-1/2 viremia included HLA disparity >=2 loci (p=0.049) and cytomegalovirus (CMV) reactivation (p=0.028). The incidences of platelet engraftment, oral mucositis and severe haemorrhagic cystitis (HC) in patients with and without HSV-1/2 viremia were 77% and 94% (p=0.003), 78% and 13% (p=0.000), and 25% and 6% (p=0.04), respectively. Moreover, the median time to platelet engraftment in patients with and without HSV-1/2 viremia was +25days (range, +11-+80) and +17days (range, +8-+67) (p=0.004), respectively. According to the multivariate analyses, HSV-1/2 viremia was associated with delayed platelet engraftment (p=0.038), a higher incidence of oral mucositis (p=0.000) and severe HC (p=0.038). However, HSV-1/2 viremia was not associated with non relapse mortality (34.0% vs. 31.5%, p=0.26), leukaemia-free survival (60.9% vs. 57.9%, p=0.46) and overall survival (61.2% vs. 60.7%, p=0.37). CONCLUSIONS: Based on our study results, we recommend that HSV-1/2 PCR should be performed upon clinical suspicion of HSV-1/2 infection. PMID- 28837860 TI - Pomegranate peel extract attenuates D-galactose-induced oxidative stress and hearing loss by regulating PNUTS/PP1 activity in the mouse cochlea. AB - Oxidative stress is considered to be a major contributor to age-related hearing loss (ARHL). Here, we investigated whether pomegranate peel extract (PPE) protected against hearing loss by decreased oxidative stress in the cochlea of D galactose-induced accelerated aging mice. The aging mice exhibited an increase in hearing threshold shifts and hair cells loss, which were improved in the PPE treated aging mice. The aging mice also exhibited an increase in 4 hydroxynonenal, the expression of protein phosphatase 1 nuclear targeting subunit (PNUTS), p53 and caspase-3, and a decrease in protein phosphatase 1 (PP1) and MDM2 in the cochlea. PPE treatment reversed the changes in aforementioned molecules. Our results suggested that PPE can protect against ARHL, the underlying mechanisms may involve in the inhibition of oxidative damage of cochlea, possibly by regulating PNUTS/PP1 pathway. The results from the present study provide a new therapeutic strategy to use PPE for prevention of ARHL. PMID- 28837861 TI - Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss. AB - Although the absence of the age-regulating klotho protein causes klotho-deficient mice to rapidly develop cognitive impairment and increasing klotho enhances hippocampal-dependent memory, the cellular effects of klotho that mediate hippocampal-dependent memory function are unknown. Here, we show premature aging of the klotho-deficient hippocampal neurogenic niche as evidenced by reduced numbers of neural stem cells, decreased proliferation, and impaired maturation of immature neurons. Klotho-deficient neurospheres show reduced proliferation and size that is rescued by supplementation with shed klotho protein. Conversely, 6 month-old klotho-overexpressing mice exhibit increased numbers of neural stem cells, increased proliferation, and more immature neurons with enhanced dendritic arborization. Protection from normal age-related loss of object location memory with klotho overexpression and loss of spatial memory when klotho is reduced by even half suggests direct, local effects of the protein. Together, these data show that klotho is a novel regulator of postnatal neurogenesis affecting neural stem cell proliferation and maturation sufficient to impact hippocampal-dependent spatial memory function. PMID- 28837863 TI - Increased alcohol use after Hurricane Ike: The roles of perceived social cohesion and social control. AB - Hurricane Ike, the third costliest hurricane in US history, made landfall in the Galveston Bay Area in September, 2008. Existing literature postulates that maladaptive behavior such as increased alcohol use is often exhibited by disaster survivors in coping with both disaster-related traumatic events and post-disaster stressful events. In addition, it has also been postulated that survivors' perceptions of social cohesion and social control can potentially serve to moderate such behavior. The purpose of this paper is to study such hypotheses for Hurricane Ike. In particular, we investigate the following four hypotheses: (H1) There is an increase of alcohol use by survivors of Hurricane Ike in the Galveston Bay Area; (H2) There are positive associations between both Ike-related trauma and post-Ike stress events and the increase in alcohol use; (H3) There are negative associations between both perceived social cohesion and social control and the increase in alcohol use following Ike; and finally that (H4) perceived social cohesion and social control serve to moderate the associations between both Ike-related trauma and post-Ike stress events and increased alcohol use after Ike. Using public use survey-weighted data from the Galveston Bay Recovery Study (GBRS) of Ike survivors (N = 658), we tested these hypotheses using logistic regressions controlling for other key socioeconomic variables. Our results confirm H1 and H2. Hypotheses H3 and H4 are partially confirmed with respect to social control, but show that (i) there is a positive association between perceived social cohesion and the increase in alcohol use following Ike, and that (ii) while perceived social cohesion and social control do moderate the association between post-Ike stress events and increased alcohol use, they have no effect on the association between Ike-related trauma and increased alcohol use. PMID- 28837862 TI - Childhood deprivation and later-life cognitive function in a population-based study of older rural South Africans. AB - RATIONALE: Little research has evaluated the life course drivers of cognitive aging in South Africa. OBJECTIVES: We investigated the relationships of self rated childhood health and father's occupation during childhood with later-life cognitive function score and whether educational attainment mediated these relationships among older South Africans living in a former region of Apartheid era racial segregation. METHODS: Data were from baseline assessments of "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community" (HAALSI), a population-based study of 5059 men and women aged >=40 years in 2015 in rural Agincourt sub-district, South Africa. Childhood health, father's occupation during childhood, and years of education were self-reported in study interviews. Cognitive measures assessed time orientation, numeracy, and word recall, which were included in a z-standardized latent cognitive function score variable. Linear regression models adjusted for age, sex, and country of birth were used to estimate the total and direct effects of each childhood risk factor, and the indirect effects mediated by years of education. RESULTS: Poor childhood health predicted lower cognitive scores (total effect = -0.28; 95% CI = -0.35, -0.21, versus good); this effect was not mediated by educational attainment. Having a father in a professional job during childhood, while rare (3% of sample), predicted better cognitive scores (total effect = 0.25; 95% CI = 0.10, 0.40, versus unskilled manual labor, 29% of sample). Half of this effect was mediated by educational attainment. Education was linearly associated with later-life cognitive function score (0.09; 95% CI = 0.09, 0.10 per year achieved). CONCLUSION: In this post-Apartheid, rural South African context, older adults with poor self-reported childhood health or whose father worked in unskilled manual labor had relatively poor cognitive outcomes. Educational attainment strongly predicted cognitive outcomes, and appeared to be, in part, a mechanism of social stratification in later-life cognitive health in this context. PMID- 28837864 TI - The political economy of diagnosis-related groups. AB - A well-established political economic literature has shown as multi-level governance affects the inefficiency of public expenditures. Yet, this expectation has not been empirically tested on health expenditures. We provide a political economy interpretation of the variation in the prices of 6 obstetric DRGs using Italy as a case study. Italy offers a unique institutional setting since its 21 regional governments can decide whether to adopt the national DRG system or to adjust/waive it. We investigate whether the composition and characteristics of regional governments do matter for the average DRG level and, if so, why. To address both questions, we first use a panel fixed effects model exploiting the results of 66 elections between 2000 and 2013 (i.e., 294 obs) to estimate the link between DRGs and the composition and characteristics of regional governments. Second, we investigate these results exploiting the implementation of a budget constraint policy through a difference-in-differences framework. The incidence of physicians in the regional government explains the variation of DRGs with low technological intensity, such as normal newborn, but not of those with high technological intensity, as severely premature newborn. We also observe a decrease in the average levels of DRGs after the budget constraint implementation, but the magnitude of this decrease depends primarily on the presence of physicians among politicians and the political alignment between the regional and the national government. To understand which kind of role the relevance of the political components plays (i.e., waste vs. better defined DRGs), we check whether any of the considered political economy variables have a positive impact on the quality of regional obstetric systems finding no effect. These results are a first evidence that a system of standardized prices, such as the DRGs, is not immune to political pressures. PMID- 28837865 TI - Valproic acid sensitizes breast cancer cells to hydroxyurea through inhibiting RPA2 hyperphosphorylation-mediated DNA repair pathway. AB - It was reported that valproic acid (VPA, a histone deacetylase inhibitor) can sensitize cancer cells to hydroxyurea (HU, a ribonucleotide reductase inhibitor) for chemotherapy, although the mechanism of VPA-induced HU sensitization is unclear. In this study, we systematically characterized VPA-induced HU sensitization of breast cancer cells. Multiple breast cancer cell models were employed to investigate whether the safe concentration of 0.5mM VPA and 2mM HU can result in DNA double-strand breaks (DSBs) and impact cell survival. Furthermore, the underlying mechanism was explored through cell biology assays, including clonogenic survival, homologous recombination (HR) activity, immunoblot and immunofluorescence. We found that VPA and HU cooperatively suppressed cancer cell survival. VPA resulted in the accumulation of more DNA double-strand breaks (DSBs) in response to HU-induced replication arrest and was able to block HU stimulated homologous recombination (HR) through inhibiting the activity of two key HR repair proteins by hyperphosphorylation of replication protein A2 (RPA2-p) and recombinase Rad51. However, apoptosis was not detected under this condition. In addition, the results from the survival fraction in the cells expressing defective RPA2-p showed that VPA disrupted the HU-induced RPA2-p-Rad51-mediated HR pathway. Importantly, these findings were further supported by analyzing primary-culture cells from the tissue of chemical carcinogen (DMBA)-induced breast cancer in rats. Thus, our data demonstrated that VPA and HU synergistically suppressed tumor cells via disturbing RPA2-p-mediated DNA repair pathway, which provides a new way for combining chemotherapeutic drugs to sensitize breast cancer cells. PMID- 28837866 TI - Protective effect of aspirin-triggered resolvin D1 on hepatic ischemia/reperfusion injury in rats: The role of miR-146b. AB - PURPOSE: Inflammatory responses play an important role in the tissue injury during liver ischemia/reperfusion (I/R). We previously reported that resolvin D1 (RvD1) administrated prior to hepatic I/R attenuates liver injury through inhibition of inflammatory response. In this study, we investigated the effects of the aspirin-triggered resolvin D1 (AT-RvD1) on hepatic I/R and the role of miR 146b in this process. METHODS: Partial warm ischemia was performed in the left and middle hepatic lobes of Sprague-Dawley rats for 1h, followed by 6h of reperfusion. Rats received either AT-RvD1 (5MUg/kg), vehicle, or AT-RvD1+miR-146b antagomir by intravenous injection 30min before ischemia. Blood and tissue samples of the rats were collected after 6-h reperfusion. RESULTS: Pretreatment with AT-RvD1 significantly diminished I/R-induced elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and significantly blunted the histological injury of the liver. Moreover, AT-RvD1 significantly inhibited inflammatory response, as indicated by attenuations of TNF-alpha and myeloperoxidase levels. Reduced apoptosis, and increased survival rate were observed in the AT-RvD1 group compared with the control I/R group. AT-RvD1 pretreatment increased miR-146b expression in the liver of the rats with hepatic I/R. Administration of miR-146b antagomir impaired the effects of AT-RvD1 on hepatic I/R injury in rats. Downregulation of miR-146b inhibited TRAF6 and NF kappaB expression in liver. CONCLUSIONS: Pre-administration of AT-RvD1 attenuates hepatic I/R injury partly through modulation of miR-146b. PMID- 28837867 TI - The inhibition of inducible nitric oxide synthase and oxidative stress by agmatine attenuates vascular dysfunction in rat acute endotoxemic model. AB - : Vascular dysfunction leading to hypotension is a major complication in patients with septic shock. Inducible nitric oxide synthase (iNOS) together with oxidative stress play an important role in development of vascular dysfunction in sepsis. Searching for an endogenous, safe and yet effective remedy was the chief goal for this study. The current study investigated the effect of agmatine (AGM), an endogenous metabolite of l-arginine, on sepsis-induced vascular dysfunction induced by lipopolysaccharides (LPS) in rats. AGM pretreatment (10mg/kg, i.v.) 1h before LPS (5mg/kg, i.v.) prevented the LPS-induced mortality and elevations in serum creatine kinase-MB isoenzyme (CK-MB) activity, lactate dehydrogenase (LDH) activity, C-reactive protein (CRP) level and total nitrite/nitrate (NOx) level after 24h from LPS injection. The elevation in aortic lipid peroxidation illustrated by increased malondialdehyde (MDA) content and the decrease in aortic glutathione (GSH) and superoxide dismutase (SOD) were also ameliorated by AGM. Additionally, AGM prevented LPS-induced elevation in mRNA expression of iNOS, while endothelial NOS (eNOS) mRNA was not affected. Furthermore AGM prevented the impaired aortic contraction to KCl and phenylephrine (PE) and endothelium dependent relaxation to acetylcholine (ACh) without affecting endothelium independent relaxation to sodium nitroprusside (SNP). IN CONCLUSION: AGM may represent a potential endogenous therapeutic candidate for sepsis-induced vascular dysfunction through its inhibiting effect on iNOS expression and oxidative stress. PMID- 28837868 TI - Removal of atrazine and its by-products from water using electrochemical advanced oxidation processes. AB - Atrazine (ATZ) is one of the most common pesticides detected in surface water in Quebec (Canada). The present study was mainly focused on the degradation of ATZ and its by-products using electrochemical advanced oxidation processes such as photo-electro-Fenton (PEF), electro-Fenton (EF) and anodic-oxidation with simultaneous H2O2 formation (AO - H2O2). The comparison of these processes showed that PEF process was found to be the most effective process in removing ATZ and its by-products from both synthetic solution (ATZ0 = 100 MUg L-1) and real agricultural surface water enriched with ATZ (ATZ0 = 10 MUg L-1). Different operating parameters, including wavelength of the light, pH, current density and the presence of natural organic matter (humic acids) were investigated for PEF process using boron-doped diamond (BDD) anode and graphite cathode. The current density and the wavelength of the light were the most important parameters in the ATZ degradation efficiency. The best operating conditions were recorded for the synthetic samples at a current density of 18.2 mA cm-2, a pH of 3.0 and treatment time of 45 min. Results showed that atrazine-desethyl-desisopropyl (DEDIA) was the most important by-product recorded. More than 99% of ATZ oxidation was recorded after 15 min of treatment and all the concentrations of major by products were less than the limit of detection after 45 min of treatment. The PEF process was also tested for real surface water contaminated by ATZ: i) with and without addition of iron; ii) without pH adjustment (pH ~ 6.7) and with pH adjustment (pH ~ 3.1). In spite of the presence of radical scavenger and iron complexation the PEF process was more effective to remove ATZ from real surface water when the pH value was adjusted near to 3.0. The ATZ removal was 96.0% with 0.01 mM of iron (kapp = 0.13 min-1) and 100% with 0.1 mM of iron (kapp = 0.17 min 1). PMID- 28837869 TI - Silver perchlorate in the mobile phase for rapid separation and determination of a pair of positional isomers in Inula racemosa Hook.f. with RP-HPLC. AB - Alantolactone and isoalantolactone isolated from many species of plants are a pair of positional isomers of CC bond. Previously, alantolactone and isoalantolactone have been proved to be good lead compounds for future anticancer agent development. Similarity of their molecular structures increases the separation difficulty for these two isomers on a conventional C18 column. Silver perchlorate (AgClO4) as mobile phase additives with RP-HPLC for improving the separation was developed for rapid determination of the positional isomers in Inula racemosa Hook.f. The effects of the concentration of silver perchlorate on the separation of the analytes were investigated. The composition of acetonitrile and water containing 5.0% silver perchlorate in a 65:35 (v/v) ratio was used as mobile phase, in which they were well separated within a short period of time on the C18 column. The method was successfully applied to determine them in an extract of Inula racemosa Hook.f. root. Silver perchlorate in mobile phase can efficiently improve the separation of the positional isomers and could be applied to rapidly determinate their content in this plant. PMID- 28837870 TI - Factors associated with the disposition of frozen embryos after a live birth through IVF treatment in China. AB - OBJECTIVE: To investigate infertility patients' attitudes towards frozen embryos and the factors that influence patients' decisions. STUDY DESIGN: This is a cross sectional quantitative observational study conducted between 1 April 2010 and 1 April 2015. Patients underwent IVF with embryo cryopreservation and successfully delivered at least one baby were called to complete a questionnaire regarding decisions about embryo disposition and reasons for their preferred option. The chi-square test was used to compare the attitudes about embryo disposition between subgroups. A multinomial logistic regression was performed to examine the effects of various individual characteristics on the decision. The effects were presented by adjusted odds ratios (OR) and their 95% confidence interval (95% CI). SETTING: Guangzhou Women and Children's Hospital. RESULTS: Among 769 interviewed couples, 718 couples (93.4%) completed the questionnaire. A total of 462 couples (64.3%) continued to store embryos. Among the participants who discontinued storage, 214 couples (83.6%) chose to discard embryos, and 42 couples (16.4%) agreed to donate embryos for research. Having no college education and longer storage duration were associated with an increase in the likelihood of discontinuing storage. The couples having twins from IVF were more likely to discontinue storage (OR=6.33, 95%CI: 4.37-9.39) compared to those having only one child. Regarding the choice of discarding or donation for research among those who decided to discontinue frozen embryos, females aged 30 or above were more willing to donate their embryos for research (OR=2.85, 95%CI:1.12-7.23). CONCLUSION: The preference for embryo disposition was associated with the number of children, storage duration, and the couple's education. Chinese patients generally chose to store cryopreserved embryos and were less receptive to the concept of embryo research compared with patients in other developed countries. PMID- 28837871 TI - Adsorption of caffeine on mesoporous activated carbon fibers prepared from pineapple plant leaves. AB - The present work reports the preparation of activated carbon fibers (ACFs) from pineapple plant leaves, and its application on caffeine (CFN) removal from aqueous solution. The preparation procedure was carried out using the H3PO4 as activating agent and slow pyrolysis under N2 atmosphere. The characterization of materials was performed from the N2 adsorption and desorption isotherms, scanning electron microscopy (SEM), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Raman spectroscopy, Boehm titration and pHpzc method. ACFs showed high BET surface area value (SBET = 1031m2 g-1), well-developed mesoporous structure (mesopore volume of 1.27cm3 g-1) and pores with average diameter (DM) of 5.87nm. Additionally, ACFs showed features of fibrous material with predominance of acid groups on its surface. Adsorption studies indicated that the pseudo-second order kinetic and Langmuir isotherm models were that best fitted to the experimental data. The monolayer adsorption capacity was found to be 155.50mgg-1. thermodynamic studies revealed that adsorption process is spontaneous, exothermic and occurs preferably via physisorption. The pineapple leaves are an efficient precursor for preparation of ACFs, which were successful applied as adsorbent material for removal of caffeine from the aqueous solutions. PMID- 28837872 TI - Pollution potential leaching index as a tool to assess water leaching risk of arsenic in excavated urban soils. AB - Leaching of hazardous trace elements from excavated urban soils during construction of cities has received considerable attention in recent years in Japan. A new concept, the pollution potential leaching index (PPLI), was applied to assess the risk of arsenic (As) leaching from excavated soils. Sequential leaching tests (SLT) with two liquid-to-solid (L/S) ratios (10 and 20Lkg-1) were conducted to determine the PPLI values, which represent the critical cumulative L/S ratios at which the average As concentrations in the cumulative leachates are reduced to critical values (10 or 5ugL-1). Two models (a logarithmic function model and an empirical two-site first-order leaching model) were compared to estimate the PPLI values. The fractionations of As before and after SLT were extracted according to a five-step sequential extraction procedure. Ten alkaline excavated soils were obtained from different construction projects in Japan. Although their total As contents were low (from 6.75 to 79.4mgkg-1), the As leaching was not negligible. Different L/S ratios at each step of the SLT had little influence on the cumulative As release or PPLI values. Experimentally determined PPLI values were in agreement with those from model estimations. A five-step SLT with an L/S of 10Lkg-1 at each step, combined with a logarithmic function fitting was suggested for the easy estimation of PPLI. Results of the sequential extraction procedure showed that large portions of more labile As fractions (non-specifically and specifically sorbed fractions) were removed during long-term leaching and so were small, but non-negligible, portions of strongly bound As fractions. PMID- 28837873 TI - Chemical and toxicological assessment of arsenic sorption onto Fe-sericite composite powder and beads. AB - Batch sorption and leaching of arsenic (1-30mgL-1) on Fe-sericite composite powder and beads were investigated in this study. Fe-sericite composite powder was made from natural sericite modified with iron, and alginate was used to transform the powder into beads. The maximum sorption capacities of the Fe sericite composite powder (15.04 and 13.21mgg-1 for As(III) and As(V), respectively) were higher than those of the corresponding beads (9.02 and 7.11mgg 1 for As(III) and As(V), respectively) owing to the higher specific surface area of the powder. In addition, the leaching amounts of As(III) from Fe-sericite composite beads (<= 15.03%) were higher than those of the corresponding powder (<= 5.71%). However, acute toxicity of As(III)-sorbed Fe-sericite composite beads toward Daphnia magna was not significantly different from that of the corresponding powder (p > 0.05). Considering higher uptake of the powder particles by the daphnids, Fe-sericite composite beads seem to be a more appropriate and safer sorbent for arsenic removal in practical application. Based on Fe content, Fe-sericite composite beads had similar or higher maximum sorption capacities (71.19 and 56.11mgg-1 Fe for As(III) and As(V), respectively) than those of previously reported sorbents. PMID- 28837874 TI - Long term growth of crop plants on experimental plots created among slag heaps. AB - Suppression of plant growth is a common problem in post-mining reclaimed areas, as coarse texture of soils may increase nitrate leaching. Assessing feasibility of using solid waste (precipitated solid matter) produced by water and sewage treatment processes in field conditions is very important in mine soil reclamation. Our work investigated the possibility of plant growth in a degraded site covered with sewage-derived sludge material. A test area (21m * 18m) was established on a mine soil heap. Experimental plant species included Camelina sativa, Helianthus annuus, Festuca rubra, Miscanthus giganteus, Amaranthus cruentus, Brassica napus, Melilotus albus, Beta vulgaris, and Zea mays. ANOVA showed sufficient water content and acceptable physical properties of the soil in each year and layer in a multi-year period, indicating that these species were suitable for phytoremediation purposes. Results of trace elements assays indicated low degree of contamination caused by Carbocrash waste material and low potential ecological risk for all plant species. Detrended correspondence analysis revealed that total porosity and capillary porosity were the most important variables for the biosolids among all water content related properties. Overall, crop plants were found useful on heavily degraded land and the soil benefited from their presence. An addition of Carbocrash substrate to mine soil improved the initial stage of soil reclamation and accelerated plant growth. The use of this substrate in phytoremediation helped to balance the content of nutrients, promoted plant growth, and increased plant tolerance to salinity. Sewage sludge-amended biosolids may be applied directly to agricultural soil, not only in experimental conditions. PMID- 28837875 TI - The intensity of tyrosine nitration is associated with selenite and selenate toxicity in Brassica juncea L. AB - Selenium phytotoxicity involves processes like reactive nitrogen species overproduction and nitrosative protein modifications. This study evaluates the toxicity of two selenium forms (selenite and selenate at 0uM, 20uM, 50uM and 100uM concentrations) and its correlation with protein tyrosine nitration in the organs of hydroponically grown Indian mustard (Brassica juncea L.). Selenate treatment resulted in large selenium accumulation in both Brassica organs, while selenite showed slight root-to-shoot translocation resulting in a much lower selenium accumulation in the shoot. Shoot and root growth inhibition and cell viability loss revealed that Brassica tolerates selenate better than selenite. Results also show that relative high amounts of selenium are able to accumulate in Brassica leaves without obvious visible symptoms such as chlorosis or necrosis. The more severe phytotoxicity of selenite was accompanied by more intense protein tyrosine nitration as well as alterations in nitration pattern suggesting a correlation between the degree of Se forms-induced toxicities and nitroproteome size, composition in Brassica organs. These results imply the possibility of considering protein tyrosine nitration as novel biomarker of selenium phytotoxicity, which could help the evaluation of asymptomatic selenium stress of plants. PMID- 28837876 TI - Partial recovery from alloxan-induced diabetes by sodium phthalhydrazide in rats. AB - In the commonly used experimental model of diabetes, a cytotoxic glucose analogue alloxan can selectively destruct pancreatic beta-cells, with characteristics similar to the type-1 diabetes (T1D) in humans. Treatment of diabetic rats with sodium phthalhydrazide partially reversed diabetogenic pathology in the alloxan induced diabetes. The alloxan-treated rats with permanent hyperglycemia, which further received i.p. twenty daily doses 2mg/kg b.w. phthalhydrazide, showed at 60days of the experiment a significant amelioration of the diabetes status. Hyperglycemia was decreased by 52%, glycated haemoglobin HbA1c returned to control value, insulin concentration significantly increased from 45,4% (alloxan group) to 59,5% (alloxan+phthalhydrazide) of the control values. Importantly, phthalhydrazide treatment of alloxan-treated diabetic rats markedly decreased the concentrationof interleukin-6 (IL-6) and corticosterone level. Morphometric analysis revealed a marked increase in the number of pancreatic islets/mm2, and a number of cells/mm2 in the pancreatic islets. These changes, including 3-fold increase in the number of insulin-producing cells and 2-fold decrease in blood glucose levels, correlated with the increased proliferative activity of pancreatic beta-cells in the diabetic phthalhydrazide-treated animals. Interestingly, the number of CD68+ cells/macrophages in the pancreatic islets, which was relatively high in the alloxan group (63,9+- 16.4/mm2), markedly decreased after the phthalhydrazide treatment (23,6+-7,2/mm2). Taking together with the previous data on the phthalhydrazide-related macrophage silencing, restriction of macrophage quantity in the alloxan-affected pancreatic islets can be possibly one of important events leading to the partial recovery from the beta cell disruption. PMID- 28837877 TI - CTGF secreted by mesenchymal-like hepatocellular carcinoma cells plays a role in the polarization of macrophages in hepatocellular carcinoma progression. AB - M2 macrophages play critical roles in the progression of hepatocellular carcinoma (HCC), and they are associated with poor outcomes. TGF-beta-induced epithelial mesenchymal transition (EMT) has been shown to be critically important to cancer cell dissemination in HCC. However, the relationship between stromal-like HCC cells and M2 macrophages formation is not clear. Here, we interrogated the molecular link between mesenchymal-like HCC cells and the formation of M2 macrophages. We demonstrated that mesenchymal-like HCC cells secrete connective tissue growth factor (CTGF) to polarized macrophages. Reciprocally, Chemokine ligand 18 (CCL18) from M2 macrophages promotes HCC progression. Furthermore, CTGF and CCL18 were increased significantly in HCC compared to adjacent normal liver tissues. In summary, our study discovered a positive feedback loop between CTGF and CCL18 in HCC metastasis. Targeting CTGF or CCL18 might provide beneficial effects for the clinical treatment of HCC. PMID- 28837878 TI - miR-367 regulation of DOC-2/DAB2 interactive protein promotes proliferation, migration and invasion of osteosarcoma cells. AB - Recently, miR-367 is reported to exert either oncogenic or tumor suppressive effects in human malignancies. Recent study reports that miR-367 is up-regulated in OS tissues and cell lines, and abrogates adriamycin-induced apoptosis. The clinical significance of miR-367 and its function in OS need further investigation. In our study, miR-367 expression in OS was markedly elevated compared with corresponding non-tumor tissues. High miR-367 expression was associated with malignant clinical features and poor prognosis of OS patients. In accordance, the levels of miR-367 were dramatically up-regulated in OS cells. Loss of miR-367 expression in Saos-2 cells obviously inhibited the proliferation, migration and invasion of cancer cells in vitro. Meanwhile, miR-367 restoration promoted these malignant behaviors of MG-63 cells. Mechanistically, miR-367 negatively regulated DOC-2/DAB2 interactive protein (DAB2IP) abundance in OS cells. Hereby, DAB2IP was recognized as a direct target gene of miR-367 in OS. DAB2IP mRNA level was down-regulated and inversely correlated with miR-367 expression in OS specimens. DAB2IP overexpression prohibited proliferation, migration and invasion in Saos-2 cells, while DAB2IP knockdown showed promoting effects on proliferation, migration and invasion of MG-63 cells. Furthermore, the role of miR-367 might be mediated by DAB2IP-regulated phosphorylation of ERK and AKT in OS cells. To conclude, miR-367 may function as a biomarker for prediction of prognosis and a target for OS therapy. PMID- 28837879 TI - Telmisartan ameliorates adipoR1 and adipoR2 expression via PPAR-gamma activation in the coronary artery and VSMCs. AB - The effects of telmisartan on insulin-resistant properties and expression of adiponectin receptors (AdipoRs) were investigated. A diabetic rat model was established using a high-fat diet and streptozotocin (25mg/kg) and primary rat coronary vascular smooth muscle cells (VSMCs) were used to elucidate the underlying mechanisms. The diabetic rats were insulin-resistant and exhibited weight gain, elevated blood pressures, and increased plasma triglyceride levels. These manifestations were ameliorated by elmisartan treatment. Four-week telmisartan therapy increased plasma adiponectin and decreased TNF-alpha expression in the coronary artery. Moreover, telmisartan significantly decreased AdipoR1 and AdipoR2 expression. Using high glucose-treated rat coronary VSMCs, telmisartan and PPAR-gamma agonist GW1929 prominently stimulated PPAR-gamma and decreased TNF-alpha expression. Interestingly, telmisartan or GW1929 also prevented hyperglycemia-induced downregulation of AdipoR1 and AdipoR2 expression. Additionally, GW9662 (PPAR-gamma antagonist) significantly decreased the effects of telmisartan on AdipoR1 and AdipoR2 expression. These results demonstrated that telmisartan effectively ameliorated coronary insulin resistance and inflammation in diabetic rats and upregulated AdipoR1/R2 expression via activation of PPAR gamma in the coronary artery and VSMCs. PMID- 28837880 TI - Administration of antioxidant compounds affects the lens chaperone activity and prevents the onset of cataracts. AB - To prevent lens opacification and cataract formation, the lens contains alpha crystallin, which has been shown to function as a molecular chaperone that maintains the correct folding of other proteins. Oxidative stress is known to be an important factor in the initiation and progression of a cataract. So far, several antioxidant compounds have been reported to prevent cataracts in vivo and in vitro. This stress also triggers alpha-crystallin modifications and alters its chaperone activity. However, few studies have examined the relationship between the consumption of antioxidant compounds and lens chaperone activity. To elucidate the effect of antioxidants on lens chaperone activity, antioxidants were administered to a selenite-induced cataract model of rats. The chaperone activity in lens water-soluble fraction was measured using aldehyde dehydrogenase. All antioxidant treatment groups, except decaffeinated coffee treatment, had less severe central opacities and lower stage cataracts than control groups. The chaperone activity was weaker in lens of selenite cataract rats, but antioxidant compounds and coffee treatment can prevent the chaperone activity decreasing, but not decaffeinated coffee. These results suggested that the treatment with antioxidant compounds could prevent cataract formation by the maintenance of the chaperone activity in water-soluble lens proteins. Thus, this study describes the development of an anticataract drug target for lens chaperone activity. PMID- 28837881 TI - Mechanochemical destruction of DDTs with Fe-Zn bimetal in a high-energy planetary ball mill. AB - Mechanochemical destruction has been proposed as a promising, non-combustion technology for the disposal of toxic, halogenated, organic pollutants. In the study presented, additives including Fe, Zn, Fe-Zn bimetal, CaO and Fe2O3 were tested for their effectiveness to remove DDTs by MC. The results showed that Fe Zn bimetal was the most efficient additive, with 98% of DDTs removed after 4h. The Fe-Zn mass ratio was optimized to avoid possible spontaneous combustion of the ground sample during subsample collection. Inorganic water-soluble chloride in the ground sample increased by 91% after 4h of grinding, which indicated dechlorination during destruction of DDTs. In addition, relationships were established between the rate constant and the rotation speed or the charge ratio. Discrete Element Method (DEM) modeling was used to simulate the motion of the grinding ball and calculate both total impact energy and normal impact energy. The latter expressed a stronger, linear correlation with the rate constant. Therefore, normal impact energy is proposed to be the main driving force in the MC destruction of DDTs. PMID- 28837883 TI - Environmental exposure to a major urban wastewater effluent: Effects on the energy metabolism of northern pike. AB - Municipal wastewater effluents (MWWEs) consist of dynamic and complex mixtures of chemical and biological compounds that can alter the health of exposed aquatic organisms. Disturbance of energy metabolism has been reported in fish exposed to MWWEs. However, there is a scarcity of knowledge on the physiological events leading to perturbation of energy balance and thyroid regulation, and associated lipid metabolism. The objective of the present study was to use a set of biomarkers, from gene transcription to body condition, to investigate the effects of a chronic environmental exposure to a major primary MWWE on fatty acid metabolism and thyroid hormone levels in northern pike (Esox lucius) collected from the St. Lawrence River near Montreal (QC, Canada). The exposure of pike to MWWE was examined through determination of a suite of persistent and bioaccumulative halogenated flame retardants in liver as this effluent is a known regional source for these chemicals. Greater hepatic concentrations of polybrominated diphenyl ethers (PBDEs, range: 29.6-465ng/g w.w. and 88.8-823ng/g w.w. in females and males, respectively) and other halogenated flame retardants (e.g., dechlorane-related compounds) were determined in fish collected downstream of the MWWE's point of discharge relative to the upstream site. This exposure in male pike was associated with decreased acyl-coA oxidase (acox1) and fatty acid synthase (fasn) mRNA levels as well as a decreased acyl-coA oxidase (ACOX) activity in liver. In female pike, MWWE exposure was associated with lower circulating free and total triiodothyronine (T3) levels and a tendency for greater total lipid percentages in liver. Present findings provide evidence that chronic exposure of a top predator fish to MWWE can be related to gender-specific effects on fatty acid metabolism and thyroid hormone homeostasis, and highlight the need for further investigation. PMID- 28837882 TI - A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration. AB - Mitochondrial fragmentation due to fission/fusion imbalance has often been linked to mitochondrial dysfunction and apoptosis in neurodegeneration. Conventionally, it is believed that once mitochondrial morphology shifts away from its physiological tubular form, mitochondria become defective and downstream apoptotic signaling pathways are triggered. However, our study shows that beta amyloid (Abeta) induces morphological changes in mitochondria where they become granular-shaped and are distinct from fragmented mitochondria in terms of both morphology and functions. Accumulation of mitochondrial reactive oxygen species triggers granular mitochondria formation, while mitoTEMPO (a mitochondria targeted superoxide scavenger) restores tubular mitochondrial morphology within Abeta-treated neurons. Interestingly, modulations of mitochondria fission and fusion by genetic and pharmacological tools attenuated not only the induction of granular mitochondria, but also mitochondrial superoxide levels in Abeta-treated neurons. Our study shows a reciprocal relationship between mitochondrial dynamics and reactive oxygen species and provides a new potential therapeutic target at early stages of neurodegenerative disease pathogenesis. PMID- 28837884 TI - Macrophages induce EMT to promote invasion of lung cancer cells through the IL-6 mediated COX-2/PGE2/beta-catenin signalling pathway. AB - Infiltration of macrophages plays a critical role in the connection between inflammation and cancer invasion; however, the molecular mechanism that enables this crosstalk remains unclear. This paper investigates a molecular link between infiltration of macrophages and metastasis of lung cancer cells. In this study, the macrophage density and cyclooxygenase-2 (COX-2) protein were examined in surgical specimens by immunohistochemistry (IHC), and the prostaglandin E2 (PGE2) levels were determined in the blood of 30 non-small cell lung cancer (NSCLC) patients using enzyme-linked immunosorbent assay (ELISA). We demonstrated that macrophage infiltration was significantly associated with elevated tumour COX-2 expression and serum PGE2 levels in NSCLC patients. Interestingly, the COX-2 and PGE2 levels as well as macrophages were poor predictors of NSCLC patient survival. THP-1-derived macrophages were co-cultured in vitro with A549 and H1299 lung cancer cells. In the co-culture process, interleukin-6 (IL-6) induced the COX-2/PGE2 pathway in lung cancer cells, which subsequently promoted beta-catenin translocation from the cytoplasm to the nucleus, resulting in epithelial mesenchymal transition (EMT) and lung cancer cell invasion. Our findings show that the IL-6-dependent COX-2/PGE2 pathway induces EMT to promote invasion of tumour cells through beta-catenin activation during the interaction between macrophages and lung cancer cells, which suggests that inhibition of COX-2/PGE2 or macrophages has the potential to suppress metastasis of lung cancer cells. PMID- 28837886 TI - Recovery and identification of human remains in post-conflict environments: A comparative study of the humanitarian forensic programs in Cyprus and Kosovo. AB - This study follows the humanitarian forensic programs in Cyprus and Kosovo over a ten-year period with an emphasis on the role of local capacity building. It begins by providing an in-depth historical account of forensic activities, followed by a comparison of the rate of excavations, exhumations and identifications. Through this analysis, a repeated pattern emerges whereby forensic activities in Kosovo start with a surge in values, which drop drastically in the first few years of operations, followed by a steadily declining productivity curve. By contrast, in Cyprus, activities begin modestly, with lower values allowing for some modest growth. Close observation of the two programs provides indications as to the factors that may influence the development of forensic programs as well as the elements that need to be set in place to create an environment conducive to greater sustainability through local ownership and responsibility. PMID- 28837885 TI - Effect of insulin glargine on recreational physical activity and TV viewing: Analysis of the randomised ORIGIN trial. AB - AIMS: To quantify whether insulin therapy, and concomitant weight gain, affects recreational physical activity and TV viewing time using data from the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial. METHODS: 12,537 insulin-naive individuals with dysglycaemia were randomised to receive either basal insulin glargine or standard care and followed for a median of 6.2years. Complete recreational physical activity and TV viewing time questionnaires across baseline, 2year follow-up and study end were available for 8954 participants. Differences between groups at follow-up were assessed by analysis of covariance. RESULTS: At follow-up, there was no difference in physical activity or TV viewing time between those taking insulin glargine and those receiving standard care, despite body weight increasing by 1.66 (7.56) kg in the insulin glargine group and reducing by -0.65 (7.90) kg in the standard care group (P<0.001). The dose of insulin glargine was not associated with changes in physical activity. CONCLUSIONS: Despite modest weight gain, insulin glargine did not adversely impact recreational physical activity levels within an international cohort with dysglyaemia. ORIGIN ClinicalTrials.gov number: NCT00069784. PMID- 28837887 TI - Synthesis, molecular docking studies of coumarinyl-pyrazolinyl substituted thiazoles as non-competitive inhibitors of mushroom tyrosinase. AB - A series of coumarinyl-pyrazolinyl substituted thiazoles derivatives were synthesized and their inhibitory effects on the DPPH and mushroom tyrosinase were evaluated. The results showed that all of the synthesized compounds exhibited significant mushroom tyrosinase inhibitory activities. In particular, 3-(5-(4 (benzyloxy)-3-methoxyphenyl)-1-(4-(4-bromophenyl)thiazol-2-yl)-4,5-dihydro-1H pyrazol-3-yl)-2H-chromen-2-one (7j) exhibited the most potent tyrosinase inhibitory activity with IC50 value 0.00458+/-0.00022MUM compared with the IC50 value of kojic acid is 16.84+/-0.052MUM. The inhibition mechanism analyzed by Lineweaver-Burk plots revealed that the type of inhibition of compound 7j on tyrosinase was noncompetitive. The docking study against tyrosinase enzyme was also performed to determine the binding affinity of the compounds. The compound 7a showed the highest binding affinity (-10.20kcal/mol) with active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that compound 7j may serve asa structural template for the design and development of novel tyrosinase inhibitors. PMID- 28837888 TI - Retroviruses of the RDR superinfection interference group: ancient origins and broad host distribution of a promiscuous Env gene. AB - Due to recombination, different regions of a retrovirus genome can have distinct phylogenetic histories. The RD114-and-D-type-retrovirus (RDR) interference group provides an extreme example: the RDR group comprises a variety of taxonomically distinct retroviruses, isolated from diverse mammalian and avian hosts, that share a homologous env gene and use the same cell-surface entry receptor. RDR env homologs are also found among ancient endogenous retrovirus (ERV) sequences, including the syncytin genes of humans and rabbits, indicating that RDR Env glycoproteins have likely mediated endogenization on multiple occasions in diverse vertebrate lineages. The distribution of RDR env among exogenous and endogenous retroviruses indicates that it has been swapped between viruses many times, and that it likely facilitated multiple cross-species transmission events spanning millions of years of vertebrate evolution. PMID- 28837889 TI - Humanized mouse models for Epstein Barr virus infection. AB - It is essential for the human immune system to control Epstein Barr virus (EBV), because this common human gamma-herpesvirus efficiently spreads through the human population with more than 90% being persistently infected after 20 years of age even in developed countries. Moreover, it threatens each host with its potent growth transforming properties, readily immortalizing human B cells into persistently growing lymphoma cell lines. Since this virus only infects humans, mice with reconstituted human immune system components provide an informative in vivo model to study EBV infection, the associated tumor formation and immune control thereof. They recapitulate the different infection programs in human B cells, allow modeling EBV driven lymphoma formation and interrogation of the key cytotoxic lymphocyte responses that are also required to control this pathogen in humans. The respective lessons that were taught by these investigations will be discussed in this review as well as the challenges in the future to address the whole portfolio of EBV associated diseases and how they could be prevented by EBV specific immunotherapies. PMID- 28837890 TI - Fragment analysis represents a suitable approach for the detection of hotspot c.7541_7542delCT NOTCH1 mutation in chronic lymphocytic leukemia. AB - The hotspot c.7541_7542delCT NOTCH1 mutation has been proven to have a negative clinical impact in chronic lymphocytic leukemia (CLL). However, an optimal method for its detection has not yet been specified. The aim of our study was to examine the presence of the NOTCH1 mutation in CLL using three commonly used molecular methods. Sanger sequencing, fragment analysis and allele-specific PCR were compared in the detection of the c.7541_7542delCT NOTCH1 mutation in 201 CLL patients. In 7 patients with inconclusive mutational analysis results, the presence of the NOTCH1 mutation was also confirmed using ultra-deep next generation sequencing. The NOTCH1 mutation was detected in 15% (30/201) of examined patients. Only fragment analysis was able to identify all 30 NOTCH1 mutated patients. Sanger sequencing and allele-specific PCR showed a lower detection efficiency, determining 93% (28/30) and 80% (24/30) of the present NOTCH1 mutations, respectively. Considering these three most commonly used methodologies for c.7541_7542delCT NOTCH1 mutation screening in CLL, we defined fragment analysis as the most suitable approach for detecting the hotspot NOTCH1 mutation. PMID- 28837891 TI - Characterization of trapped charges distribution in terms of mirror plot curve. AB - Accumulation of charges (electrons) at the specimen surface in scanning electron microscope (SEM) lead to generate an electrostatic potential. By using the method of image charges, this potential is defined in the chamber's space of such apparatus. The deduced formula is expressed in terms a general volumetric distribution which proposed to be an infinitesimal spherical extension. With aid of a binomial theorem the defined potential is expanded to a multipolar form. Then resultant formula is adopted to modify a novel mirror plot equation so as to detect the real distribution of trapped charges. Simulation results reveal that trapped charges may take a various sort of arrangement such as monopole, quadruple and octuple. But existence of any of these arrangements alone may never be take place, rather are some a formations of a mix of them. Influence of each type of these profiles depends on the distance between the incident electron and surface of a sample. Result also shows that trapped charge's amount of trapped charges can refer to a threshold for failing of point charge approximation. PMID- 28837892 TI - Gas effect on the emission and detection of the backscattered electrons in a VP SEM at low energy. AB - The effect of the electron beam skirting on the emission and detection of the backscattered electrons (BSE) in a low vacuum scanning electron microscope is investigated at low energy regime. Monte Carlo computed dependencies of the BSE distribution on the water vapor and air pressure shown a significant increase of the extent of the BSE exit zone. The pressure variation has however a little effect when helium gas is used. A new approach based on the comparison between the sizes of the skirt and the BSE exit zone on the specimen surface provides a useful tool to determine the operating pressure range that ensures minimal degradation of the lateral resolution in BSE imaging mode. PMID- 28837893 TI - A quantitative method for determining a representative detection limit of the forensic luminol test for latent bloodstains. AB - The luminol test has been used for over 60 years by forensic investigators for presumptive identification of blood and visualization of blood splatter patterns. Multiple studies have estimated the limit of detection (LD) for bloodstains when luminol is employed, with results ranging from 100* to 5,000,000* dilute. However, these studies typically have not identified and controlled important experimental variables which may affect the luminol LD for bloodstains. Without control of experimental parameters in the laboratory, variables which affect the potential of presumptive bloodstain test methods remain largely unknown, and comparisons required to establish new, more powerful detection methods are simply impossible. We have developed a quantitative method to determine the relationship between the amount of blood present and its reaction with luminol by measuring, under controlled conditions, the resulting chemiluminescent intensity with a video camera, combined with processing of the digital intensity data. The method resulted in an estimated LD for bloodstains on cotton fabric at ~200,000* diluted blood with a specific luminol formulation. Although luminol is the focus of this study, the experimental protocol used could be modified to study effects of variables using other blood detection reagents. PMID- 28837894 TI - Polyelectrolyte multi-layers assembly of SiCHA nanopowders and collagen type I on aminolysed PLA films to enhance cell-material interactions. AB - This paper presents a new approach in assembling bone extracellular matrix components onto PLA films, and investigates the most favourable environment which can be created using the technique for cell-material interactions. Poly (lactic acid) (PLA) films were chemically modified by covalently binding the poly(ethylene imine) (PEI) as to prepare the substrate for immobilization of polyelectrolyte multilayers (PEMs) coating. Negatively charged polyelectrolyte consists of well-dispersed silicon-carbonated hydroxyapatite (SiCHA) nanopowders in hyaluronic acid (Hya) was deposited onto the modified PLA films followed by SiCHA in collagen type I as the positively charged polyelectrolyte. The outermost layer was finally cross-linked by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrocholoride and N-hydroxysulfosuccinimide sodium salt (EDC/NHS) solutions. The physicochemical features of the coated PLA films were monitored via X-ray Photoelectron Spectroscopy (XPS) and Atomic Force Microscope (AFM). The amounts of calcium and collagen deposited on the surface were qualitatively and quantitatively determined. The surface characterizations suggested that 5-BL has the optimum surface roughness and highest amounts of calcium and collagen depositions among tested films. In vitro human mesenchymal stem cells (hMSCs) cultured on the coated PLA films confirmed that the coating materials greatly improved cell attachment and survival compared to unmodified PLA films. The cell viability, cell proliferation and Alkaline Phosphatase (ALP) expression on 5-BL were found to be the most favourable of the tested films. Hence, this newly developed coating materials assembly could contribute to the improvement of the bioactivity of polymeric materials and structures aimed to bone tissue engineering applications. PMID- 28837895 TI - Immunoliposomes: A review on functionalization strategies and targets for drug delivery. AB - Nanoparticles, especially liposomes, have gained prominence in the field of drug delivery for the treatment of human diseases, particularly cancer; they provide several advantages, including controlled drug release, protection of the drug against degradation, improved pharmacokinetics, long circulation, and passive targeting to tumors and inflammatory sites due to the enhanced permeability and retention effect. The functionalization of liposomes with monoclonal antibodies or antibody fragments to generate immunoliposomes has emerged as a promising strategy for targeted delivery to and uptake by cells overexpressing the antigens to these antibodies, with a consequent reduction in side effects. In this review, we address functionalization strategies for the non-covalent and covalent attachment of monoclonal antibodies and their fragments to liposomal surfaces. The main reaction occurs between the sulfhydryl groups of thiolated antibodies and maleimide-containing liposomes. Furthermore, we explore the main targeting possibilities with these ligands for the treatment of a variety of pathologies, including HER2- and EGFR-positive cancers, inflammatory and cardiovascular diseases, infectious diseases, and autoimmune and neurodegenerative diseases, which have not previously been reviewed together. Overall, many studies have shown selective delivery of immunoliposomes to target cells, with promising in vivo results, particularly for cancer treatment. Although clinical trials have been conducted, immunoliposomes have not yet received clinical approval. However, immunoliposomes are promising formulations that are expected to become available for therapeutic use after clinical trials prove their safety and efficacy, and after scaling issues are resolved. PMID- 28837896 TI - Formation and enzymatic degradation of poly-l-arginine/fucoidan multilayer films. AB - A polyelectrolyte multilayer (PEM) system based on biopolymers has been constructed and studied in its formation and enzymatic breakdown. The multilayer is composed of fucoidan (a proven antimicrobial/anti-inflammatory seaweed-based polysaccharide) and poly-l-arginine (a polypeptide that can be readily degraded with trypsin to yield arginine, a known NO donor), thus making the multilayer a potential dual action surface treatment for wound dressings. Studies on the formation of the multilayer revealed that the film built-up in the expected stepwise manner with consistent reversal of the zeta potential upon the adsorption of each subsequent polyion. The completed film (8 bilayers) was seen to have low hydration (30% water), as determined by H2O/D2O solvent replacement studies using the quartz crystal microbalance, with an adsorbed mass (without hydration water) of approx. 4.8MUgcm-2, as determined by quantitative attenuated total reflectance Fourier transform infrared (ATR FTIR) spectroscopy. The enzymatic breakdown of the film in response to exposure to trypsin was also investigated, and the film was seen to release both polymers over time, with a projected complete film removal period of approximately 24h. Critically, this information was determined using ATR FTIR spectroscopy experiments, which allowed unambiguous deconvolution of the removal rates of the two polyions, which is information that cannot be obtained from other methodologies used to study enzymatic breakdown of surface films. PMID- 28837897 TI - Effects of ABCB1, ABCC2, UGT2B7 and HNF4alpha genetic polymorphisms on oxcarbazepine concentrations and therapeutic efficacy in patients with epilepsy. AB - PURPOSE: The aim of the study is to investigate the effects of ABCB1, ABCC2, UGT2B7 and HNF4alpha genetic polymorphisms on plasma oxcarbazepine (OXC) concentrations and therapeutic efficacy in Han Chinese patients with epilepsy. METHODS: We recruited 116 Han Chinese patients with epilepsy who were receiving OXC monotherapy. Blood samples were taken and OXC levels were measured. The polymorphisms of ABCB1 rs1045642, ABCC2 rs2273697, UGT2B7 rs7439366, and HNF4alpha rs2071197 were determined. The therapeutic efficacy of OXC at the 1 year time-point was assessed. Data analysis was performed using IBM SPSS Statistics 22.0. RESULTS: The genetic polymorphism of ABCB1 rs1045642 was found to be associated with normalized OXC concentration and therapeutic efficacy in patients with epilepsy (P<0.05). As for UGT2B7 rs7439366, the allele polymorphism exhibited a correlation with treatment outcome, but not OXC concentration. The polymorphisms of ABCC2 rs2273697 and HNF4alpha rs2071197 was not associated with OXC concentrations and therapeutic efficacy. CONCLUSION: These results suggested that ABCB1 rs1045642 and UGT2B7 rs7439366 may affect OXC pharmacokinetics and therapeutic efficacy in Han Chinese patients with epilepsy. However, further studies in larger populations and other ethnic groups are required. PMID- 28837898 TI - Patterns of intrahemispheric propagation in pediatric photoparoxysmal response. AB - PURPOSE: The photoparoxysmal response (PPR) is the most important EEG indication of photosensitivity (PS). It may be elicited by intermittent photic stimulation (IPS). PS mostly affects young individuals, with adolescent females at greatest risk. The diagnosis of PS is based on visual EEG assessment. To date, no objective test of PS has been established. METHOD: Here we describe 89 individuals of both sexes, aged 5-18 years, epileptic and non-epileptic, in whom a PPR was elicited by IPS during a standard EEG procedure. The distribution of amplitude and intrahemispheric coherence indices were analyzed and, in each case, revealed a unique pattern of PPR propagation. RESULTS: A lateral (occipito temporo-frontal) track was found in 52% of recordings, and 55% of individuals tested showed symmetric patterns. A bilateral pattern dominated in all age groups, all grades of PS, and across epileptic and non-epileptic groups. CONCLUSION: A symmetric, bilateral pattern is the most common type of PPR across genders and all ages, regardless of grade of PS and the presence of epilepsy. The results of this study show the current PPR classification in a new light and provide a basis for the concept of PPR lateralization based on objective, quantitative findings. PMID- 28837899 TI - The proximal-to-distal sequence in upper-limb motions on multiple levels and time scales. AB - The proximal-to-distal sequence is a phenomenon that can be observed in a large variety of motions of the upper limbs in both humans and other mammals. The mechanisms behind this sequence are not completely understood and motor control theories able to explain this phenomenon are currently incomplete. The aim of this narrative review is to take a theoretical constraints-led approach to the proximal-to-distal sequence and provide a broad multidisciplinary overview of relevant literature. This sequence exists at multiple levels (brain, spine, muscles, kinetics and kinematics) and on multiple time scales (motion, motor learning and development, growth and possibly even evolution). We hypothesize that the proximodistal spatiotemporal direction on each time scale and level provides part of the organismic constraints that guide the dynamics at the other levels and time scales. The constraint-led approach in this review may serve as a first onset towards integration of evidence and a framework for further experimentation to reveal the dynamics of the proximal-to-distal sequence. PMID- 28837900 TI - "Which pass is better?" Novel approaches to assess passing effectiveness in elite soccer. AB - Passing behaviour is a key property of successful performance in team sports. Previous investigations however have mainly focused on notational measurements like total passing frequencies which provide little information about what actually constitutes successful passing behaviour. Consequently, this has hampered the transfer of research findings into applied settings. Here we present two novel approaches to assess passing effectiveness in elite soccer by evaluating their effects on majority situations and space control in front of the goal. Majority situations are assessed by calculating the number of defenders between the ball carrier and the goal. Control of space is estimated using Voronoi-diagrams based on the player's positions on the pitch. Both methods were applied to position data from 103 German First division games from the 2011/2012, 2012/2013 and 2014/2015 seasons using a big data approach. The results show that both measures are significantly related to successful game play with respect to the number of goals scored and to the probability of winning a game. The results further show that on average passes from the mid-field into the attacking area are most effective. The presented passing efficiency measures thereby offer new opportunities for future applications in soccer and other sports disciplines whilst maintaining practical relevance with respect to tactical training regimes or game performances analysis. PMID- 28837901 TI - The effect of PRR ligands on the membrane potential of intestinal epithelial cells. AB - BACKGROUND: Disproportionate signaling through intestinal epithelial pattern recognition receptors (PRR) plays a role in IBD (inflammatory bowel disease) pathophysiology. Diarrhea is a clinical trademark of IBD and altered activity of K+ channels (KC) may contribute to the low sodium absorption state. Here we sought to study the impact of PRR activation on the membrane potential of human intestinal epithelial cells and the role of KC in it. METHODS: All assays were performed in cultured HT-29 cells. KC activity was assessed by spectrofluorometry, measuring changes in cell membrane potential (MP) with the anionic fluorophore DiBAC4(3). PRRs were activated by specific ligands (MDP, LTA, MPLA, flagellin, loxoribine and ODN2216). KC modulators employed were BaCl2, pinacidil, noxiustoxin and AMP-PNP. RESULTS: Activation of NOD2, TLR5, TLR7 and TLR9 hyperpolarized the membrane (at 103ng/ml, the normalized AUC of the fluorescence intensity variation from the control were respectively (mean+/-SEM): -725.3+/-111.5; -1517.4+/-95.0; -857.8+/-61.1 and -995.6+/-53.6), while TLR2 and TLR4 stimulation induced membrane depolarization (1110.4+/-73.1 and 3890.3+/ 342.7 at 103ng/ml, respectively). MPD effect on MP was abolished by BaCl2, partially reversed by AMP-PNP (aKATP channel inhibitor) and insensitive to noxiustoxin (a voltage-gated KC inhibitor). CONCLUSION: It was shown for the first time that PRR activation affects MP in human intestinal epithelial cells. KC appear to be important mediators in this phenomenon; in particular, KATP channels may partake in NOD2-derived effects. PMID- 28837902 TI - Estimating daily minimum, maximum, and mean near surface air temperature using hybrid satellite models across Israel. AB - Meteorological stations measure air temperature (Ta) accurately with high temporal resolution, but usually suffer from limited spatial resolution due to their sparse distribution across rural, undeveloped or less populated areas. Remote sensing satellite-based measurements provide daily surface temperature (Ts) data in high spatial and temporal resolution and can improve the estimation of daily Ta. In this study we developed spatiotemporally resolved models which allow us to predict three daily parameters: Ta Max (day time), 24h mean, and Ta Min (night time) on a fine 1km grid across the state of Israel. We used and compared both the Aqua and Terra MODIS satellites. We used linear mixed effect models, IDW (inverse distance weighted) interpolations and thin plate splines (using a smooth nonparametric function of longitude and latitude) to first calibrate between Ts and Ta in those locations where we have available data for both and used that calibration to fill in neighboring cells without surface monitors or missing Ts. Out-of-sample ten-fold cross validation (CV) was used to quantify the accuracy of our predictions. Our model performance was excellent for both days with and without available Ts observations for both Aqua and Terra (CV Aqua R2 results for min 0.966, mean 0.986, and max 0.967; CV Terra R2 results for min 0.965, mean 0.987, and max 0.968). Our research shows that daily min, mean and max Ta can be reliably predicted using daily MODIS Ts data even across Israel, with high accuracy even for days without Ta or Ts data. These predictions can be used as three separate Ta exposures in epidemiology studies for better diurnal exposure assessment. PMID- 28837903 TI - The association of e-cigarette use with exposure to nickel and chromium: A preliminary study of non-invasive biomarkers. AB - BACKGROUND: Nickel (Ni) and chromium (Cr) are components of e-cigarette heating coils. Whether e-cigarettes increase metal internal dose, however, is unknown. We assessed the association of e-cigarette use patterns and of e-liquid and aerosol metal concentrations with Ni and Cr biomarker levels in e-cigarette users from Maryland. METHODS: We recruited 64 e-cigarette users from December 2015 to March 2016. We collected urine, saliva, and exhaled breath condensate (EBC), data on e cigarette use, and samples from their e-cigarette device (dispenser e-liquid, aerosol, and tank e-liquid). RESULTS: Median Ni and Cr levels were 0.73 and 0.39MUg/g creatinine in urine, 2.25 and 1.53MUg/L in saliva, and 1.25 and 0.29MUg/L in EBC. In adjusted models, tertiles 2 and 3 of aerosol Ni concentrations were associated with 16% and 72% higher urine Ni and 202% and 321% higher saliva Ni compared to the lowest tertile. Tertile 3 of aerosol Cr levels were associated with 193% higher saliva Cr. An earlier time to first vape in the morning and more frequent coil change were associated with higher urine Ni. Tertile 2 of e-liquid consumption per week and voltage were associated with higher saliva Ni levels than tertile 1. CONCLUSION: Positive associations of Ni and Cr aerosol concentrations with corresponding Ni and Cr biomarker levels indicate e-cigarette emissions increase metal internal dose. Increased e cigarette use and consumption were also associated with higher Ni biomarker levels. Metal level standards are needed to prevent involuntary metal exposure among e-cigarette users. PMID- 28837904 TI - Residential proximity to agricultural land and risk of brain tumor in the general population. AB - The effect of pesticides on human health is still controversial, particularly as regards long-term health effects like cancer. The literature does suggest, however, that they could be involved in the occurrence of brain tumors, although the results concerning residential exposure are scarce. Our objective was to investigate the association between residential proximity to agricultural pesticides and brain tumors among adults in France by using a geographical information system. CERENAT is a population-based case-control study carried out in France in 2004-2006. We used two geographical data sources on agricultural land use to create exposure scores based on crop surface areas near the residence, for open field crops, vineyards and orchards. Conditional logistic regression for matched sets was used to estimate Odds Ratios (ORs) and 95% confidence intervals (95%CI). We found a significant association between meningioma and proximity to open field crops above the 75th percentile (OR 2.30 95%CI 1.04-5.10). Non-significant associations were also found with proximity of vineyards above the 95th percentile (OR 1.90 95%CI 0.41-8.69) and orchards above the 95th percentile (OR 5.50, 95%CI 0.49-61.94). No significant association was found between glioma and proximity to agricultural land. Further investigations are needed, particularly to improve the quality and availability of geographical data on agricultural land use. PMID- 28837905 TI - Interictal epileptiform discharge characteristics underlying expert interrater agreement. AB - OBJECTIVE: The presence of interictal epileptiform discharges (IED) in the electroencephalogram (EEG) is a key finding in the medical workup of a patient with suspected epilepsy. However, inter-rater agreement (IRA) regarding the presence of IED is imperfect, leading to incorrect and delayed diagnoses. An improved understanding of which IED attributes mediate expert IRA might help in developing automatic methods for IED detection able to emulate the abilities of experts. Therefore, using a set of IED scored by a large number of experts, we set out to determine which attributes of IED predict expert agreement regarding the presence of IED. METHODS: IED were annotated on a 5-point scale by 18 clinical neurophysiologists within 200 30-s EEG segments from recordings of 200 patients. 5538 signal analysis features were extracted from the waveforms, including wavelet coefficients, morphological features, signal energy, nonlinear energy operator response, electrode location, and spectrogram features. Feature selection was performed by applying elastic net regression and support vector regression (SVR) was applied to predict expert opinion, with and without the feature selection procedure and with and without several types of signal normalization. RESULTS: Multiple types of features were useful for predicting expert annotations, but particular types of wavelet features performed best. Local EEG normalization also enhanced best model performance. As the size of the group of EEGers used to train the models was increased, the performance of the models leveled off at a group size of around 11. CONCLUSIONS: The features that best predict inter-rater agreement among experts regarding the presence of IED are wavelet features, using locally standardized EEG. Our models for predicting expert opinion based on EEGer's scores perform best with a large group of EEGers (more than 10). SIGNIFICANCE: By examining a large group of EEG signal analysis features we found that wavelet features with certain wavelet basis functions performed best to identify IEDs. Local normalization also improves predictability, suggesting the importance of IED morphology over amplitude-based features. Although most IED detection studies in the past have used opinion from three or fewer experts, our study suggests a "wisdom of the crowd" effect, such that pooling over a larger number of expert opinions produces a better correlation between expert opinion and objectively quantifiable features of the EEG. PMID- 28837906 TI - Comparison of visual evoked potential monitoring during spine surgeries under total intravenous anesthesia versus balanced general anesthesia. AB - OBJECTIVE: To determine the comparison of its clinical utility and safety profile for visual evoked potential (VEP) monitoring during prone spine surgeries under total intravenous anesthesia (TIVA) versus balanced general anesthesia using the SightSaverTM visual stimulator. METHODS: The protocol was designed asa pilot, single center, prospective, randomized, and double-arm study. Subjects were randomized to receive either TIVA or balanced general anesthesia. Following induction and intubation, 8 electrodes were placed subcutaneously to collect VEP recordings. The SightSaverTM visual stimulator was placed on the subject's scalp before prone positioning. VEP waveforms were recorded every 30min and assessed by a neurophysiologist throughout the length of surgery. RESULTS: A total of 19 subjects were evaluated and VEP waveforms were successfully collected. TIVA group showed higher amplitude and lower latency than balanced anesthesia. CONCLUSIONS: Our data suggested that TIVA is associated with higher VEP amplitude and shorter latencies than balanced general anesthesia; therefore, TIVA could be the most efficient anesthesia regimen for VEP monitoring. SIGNIFICANCE: The findings help to better understand the effect of different anesthesia regimens on intra operative VEP monitoring. PMID- 28837907 TI - Electroencephalogram dynamics in children during different levels of anaesthetic depth. AB - OBJECTIVE: Anaesthesia-induced dynamics in EEG are dependent on age and level of anaesthesia, but distinct characterisation in children is incomplete. Here we analyse EEG dynamics in children related to age and level of anaesthesia. METHODS: Frontal EEG recordings were obtained from 93 children (0-19years) during routine clinical anaesthesia. EEG segments were selected at four different levels of anaesthesia: emergence, light anaesthesia, deep anaesthesia, and very deep anaesthesia. RESULTS: Total power differed significantly over age at deep (R2=0.314; p<0.0001) and very deep anaesthesia (R2=0.403; p<0.0001). Relative beta band power at light anaesthesia increased linearly with age (R2=0.239; p<0.0001). Level of anaesthesia caused significant differences for relative delta band power (increasing with anaesthetic depth), for relative beta band power and for spectral edge frequency (decreasing with anaesthetic depth) for all children (p<0.0001). CONCLUSIONS: EEG parameterin children were primary dependent on anaesthetic depth, where beta band power, delta band power and spectral edge frequency showed a linear relation. Age-dependency during anaesthesia procedure were only seen for single EEG parameters. SIGNIFICANCE: Different levels of anaesthesia can be identified by relative beta band power, relative delta band power and spectral edge frequency irrespective of the children's age. PMID- 28837908 TI - Motor unit remodelling in multifocal motor neuropathy: The importance of axonal loss. AB - OBJECTIVE: To estimate the degree of axonal loss in patients diagnosed with multifocal motor neuropathy (MMN) using a novel assessment of motor unit numbers and size. METHODS: Automated motor unit number estimation using a compound muscle action potential (CMAP) scan was undertaken in median nerves with conduction block. Results were compared with 30 age-matched healthy controls. RESULTS: Compared with healthy controls, MMN patients had fewer motor units (MMN: 33+/ 11vs HC: 93+/-36 [mean+/-SD]; p<0.0001) and larger 'size of the largest unit' (MMN: 1.2+/-0.5mVvs HC: 0.4+/-0.1mV; p<0.0001), despite having normal distal CMAP amplitudes (MMN: 7.6+/-1.8mVvs HC: 8.7+/-2.5mV; p=0.24). CONCLUSIONS: MMN is associated with marked axonal loss which may be masked by striking re-innervation resulting in preservation of distal CMAP amplitudes. SIGNIFICANCE: Assessment of motor unit properties should be incorporated into assessment of disease progression in MMN, given that nerve conduction studies are insensitive to motor unit remodelling. PMID- 28837909 TI - Age, sex, and gonadal hormones differently influence anxiety- and depression related behavior during puberty in mice. AB - Anxiety and depression symptoms increase dramatically during adolescence, with girls showing a steeper increase than boys after puberty onset. The timing of the onset of this sex bias led us to hypothesize that ovarian hormones contribute to depression and anxiety during puberty. In humans, it is difficult to disentangle direct effects of gonadal hormones from social and environmental factors that interact with pubertal development to influence mental health. To test the role of gonadal hormones in anxiety- and depression-related behavior during puberty, we manipulated gonadal hormones in mice while controlling social and environmental factors. Similar to humans, we find that mice show an increase in depression-related behavior from pre-pubertal to late-pubertal ages, but this increase is not dependent on gonadal hormones and does not differ between sexes. Anxiety-related behavior, however, is more complex during puberty, with differences that depend on sex, age, behavioral test, and hormonal status. Briefly, males castrated before puberty show greater anxiety-related behavior during late puberty compared to intact males, while pubertal females are unaffected by ovariectomy or hormone injections in all assays except the marble burying test. Despite this sex-specific effect of pubertal hormones on anxiety related behavior, we find no sex differences in intact young adults, suggesting that males and females use separate mechanisms to converge on a similar behavioral phenotype. Our results are consistent with anxiolytic effects of testicular hormones during puberty in males but are not consistent with a causal role for ovarian hormones in increasing anxiety- and depression-related behavior during puberty in females. PMID- 28837910 TI - Shadow prices of emerging pollutants in wastewater treatment plants: Quantification of environmental externalities. AB - Conventional wastewater treatment plants (WWTPs) are designed to remove mainly the organic matter, nitrogen and phosphorus compounds and suspended solids from wastewater but are not capable of removing chemicals of human origin, such as pharmaceutical and personal care products (PPCPs). The presence of PPCPs in wastewater has environmental effects on the water bodies receiving the WWTP effluents and renders the effluent as unsuitable as a nonconventional water source. Considering PPCPs as non-desirable outputs, the shadow prices methodology has been implemented using the output distance function to measure the environmental benefits of removing five PPCPs (acetaminophen, ibuprofen, naproxen, carbamazepine and trimethoprim) from WWTP effluents discharged to three different ecosystems (wetland, river and sea). Acetaminophen and ibuprofen show the highest shadow prices of the sample for wetland areas. Their values are 128.2 and 11.0 ?/mg respectively. These results represent a proxy in monetary terms of the environmental benefit achieved from avoiding the discharge of these PPCPs in wetlands. These results suggest which PPCPs are urgent to remove from wastewater and which ecosystems are most vulnerable to their presence. The findings of this study will be useful for the plant managers in order to make decisions about prioritization in the removal of different pollutants. PMID- 28837911 TI - Evaluating the attractiveness and effectiveness of artificial coral reefs as a recreational ecosystem service. AB - Artificial reefs are increasingly being used around the globe to attract recreational divers, for both environmental and commercial reasons. This paper examines artificial coral reefs as recreational ecosystem services (RES) by evaluating their attractiveness and effectiveness and by examining divers' attitudes toward them. An online survey targeted at divers in Israel (n = 263) indicated that 35% of the dives in Eilat (a resort city on the shore of the Red Sea) take place at artificial reefs. A second study monitored divers' behavior around the Tamar artificial reef, one of the most popular submerged artificial reefs in Eilat, and juxtaposed it with divers' activities around two adjacent natural reefs. Findings show that the average diver density at the artificial reef was higher than at the two nearby natural knolls and that the artificial reef effectively diverts divers from natural knolls. A third study that examined the attitudes towards natural vs. artificial reefs found that the artificial reefs are considered more appropriate for training, but that divers feel less relaxed around them. By utilizing the RES approach as a framework, the study offers a comprehensive methodology that brings together the aesthetic, behavioral, and attitudinal aspects in terms of which artificial reefs can be evaluated. PMID- 28837912 TI - The global palm oil sector must change to save biodiversity and improve food security in the tropics. AB - Most palm oil currently available in global markets is sourced from certified large-scale plantations. Comparatively little is sourced from (typically uncertified) smallholders. We argue that sourcing sustainable palm oil should not be determined by commercial certification alone and that the certification process should be revisited. There are so-far unrecognized benefits of sourcing palm oil from smallholders that should be considered if genuine biodiversity conservation is to be a foundation of 'environmentally sustainable' palm oil production. Despite a lack of certification, smallholder production is often more biodiversity-friendly than certified production from large-scale plantations. Sourcing palm oil from smallholders also alleviates poverty among rural farmers, promoting better conservation outcomes. Yet, certification schemes - the current measure of 'sustainability' - are financially accessible only for large-scale plantations that operate as profit-driven monocultures. Industrial palm oil is expanding rapidly in regions with weak environmental laws and enforcement. This warrants the development of an alternative certification scheme for smallholders. Greater attention should be directed to deforestation-free palm oil production in smallholdings, where production is less likely to cause large scale biodiversity loss. These small-scale farmlands in which palm oil is mixed with other crops should be considered by retailers and consumers who are interested in promoting sustainable palm oil production. Simultaneously, plantation companies should be required to make their existing production landscapes more compatible with enhanced biodiversity conservation. PMID- 28837913 TI - Concentration levels of new-generation fungicides in throughfall released by foliar wash-off from vineyards. AB - The presence of agricultural pesticides in the environment and their effects on ecosystems are major concerns addressed in a significant number of articles. However, limited information is available on the pesticide concentrations released from crops. This study reports losses of new-generation fungicides by foliar wash-off from vineyards and their potential impact on the concentrations of their main active substances (AS) in surface waters. Two experimental plots devoted to vineyards were treated with various combinations of commercial new generation fungicide formulations. Then, up to sixteen throughfall collectors were installed under the canopy. Concentrations of sixteen different AS in throughfall were determined along nine rainfall episodes. Concentrations in throughfall far exceeded the maximum permissible levels for drinking water established by the European Union regulations. Dynamics of fungicide release indicated a first-flush effect in the wash-off founding the highest concentrations of AS in the first rain episodes after application of the fungicides. This article shows that foliar spray application of commercial formulations of new-generation fungicides does not prevent the release of their AS to soil or the runoff. Concentration data obtained in this research can be valuable in supporting the assessment of environmental effects of new-generation fungicides and modeling their environmental fate. PMID- 28837914 TI - What works in delivering dementia education or training to hospital staff? A critical synthesis of the evidence. AB - BACKGROUND: The quality of care delivered to people with dementia in hospital settings is of international concern. People with dementia occupy up to one quarter of acute hospital beds, however, staff working in hospitals report lack of knowledge and skills in caring for this group. There is limited evidence about the most effective approaches to training hospital staff on dementia. OBJECTIVE: The purpose of this literature review was to examine published evidence on the most effective approaches to dementia training and education for hospital staff. DESIGN AND REVIEW METHODS: The review was conducted using critical synthesis and included qualitative, quantitative and mixed/multi- methods studies. Kirkpatrick's four level model for the evaluation of training interventions was adopted to structure the review. DATA SOURCES: The following databases were searched: MEDLINE, PsycINFO, CINAHL, AMED, British Education Index, Education Abstracts, ERIC (EbscoHost), The Cochrane Library-Cochrane reviews, Economic evaluations, CENTRAL (Wiley), HMIC (Ovid), ASSIA, IBSS (Proquest), Conference Proceedings Citation Indexes (Web of Science), using a combination of keyword for the following themes: Dementia/Alzheimer's, training/education, staff knowledge and patient outcomes. RESULTS: A total of 20 papers were included in the review, the majority of which were low or medium quality, impacting on generalisability. The 16 different training programmes evaluated in the studies varied in terms of duration and mode of delivery, although most employed face-to-face didactic techniques. Studies predominantly reported on reactions to training and knowledge, only one study evaluated outcomes across all of the levels of the Kirkpatrick model. Key features of training that appeared to be more acceptable and effective were identified related to training content, delivery methods, practicalities, duration and support for implementation. CONCLUSIONS: The review methodology enabled inclusion of a broad range of studies and permitted common features of successful programmes to be identified. Such features may be used in the design of future dementia training programmes, to increase their potential for effectiveness. Further research on the features of effective dementia training for hospital staff is required. PMID- 28837915 TI - A late unusual complication after an open cholecystectomy: Amputation neuroma of the CBD causing obstructive jaundice. AB - INTRODUCTION: Cholecystectomy is one of the most frequently done procedures in general surgery. There are few reports of amputation neuromas following this procedure. This presentation describes a case of obstructive jaundice due to amputation neuroma in a patient with a history of cholecystectomy. CASE PRESENTATION: We report about a 53 y o lady who presented with obstructive jaundice, 8 years following open cholecystectomy. Paraclinical investigations were in favor of cholangicarcinoma, however the final pathology revealed an amputation neuroma of the CBD. DISCUSSION: Amputation neuromas are rarely seen in the era of laparoscopic cholecystectomy. They are benign reparative lesions of the CBD following surgery or manipulation of the extra hepatic biliary tree. It is very difficult to diagnose them pre-operatively. Surgical resection is the first choice of treatment. CONCLUSION: Traumatic neuromas should always be among the differential diagnosis, when assessing a CBD mass in patients with a previous history of open cholecystectomy or surgery to the gastrointestinal tract. PMID- 28837916 TI - Chylopericardium following thoracoscopic resection of a mediastinal cyst: A case report. AB - INTRODUCTION: Thoracic duct cysts are very rare, and diagnosis is often difficult. We report a rare case of chylopericardium following thoracic duct cyst resection. There are no established guidelines on the management of such cases. We reviewed the literature on postoperative complications after thoracic duct cyst resection, and conducted the first thorough review of the etiology and management of chylopericardium in surgical cases. PRESENTATION OF CASE: A 54-year old male presented with cardiac tamponade due to chylopericardium. He had undergone resection of a thoracic duct cyst 2 years previously, which was complicated by postoperative chylothorax. Chyle accumulation resolved with conservative treatment. DISCUSSION: Chylothorax is a frequent complication following thoracic duct cyst resection, especially in cases where no intraoperative diagnosis is reached. Diagnosis may be difficult due to anomalous location of the cyst, as in our case. Chylopericardium is rarely reported, and may have occurred in our case because of prior pleurodesis. Chyle accumulation can reportedly be managed with diet restrictions in over half of reported cases, especially in cases of lung or mediastinal tumor resection. CONCLUSION: The most important points highlighted by this rare case of chylopericardium secondary to thoracic duct cyst resection are: 1) pedicles should be ligated in cyst resections, regardless of location; 2) careful assessment in the initial surgery may help identify the point of leakage; 3) low-fat diet is the first choice in the initial management of postoperative chylopericardium, but surgical repair may be considered in cases with no response after>2 weeks of conservative treatment. PMID- 28837917 TI - Aging effect on step adjustments and stability control in visually perturbed gait initiation. AB - Gait adaptability is essential for fall avoidance during locomotion. It requires the ability to rapidly inhibit original motor planning, select and execute alternative motor commands, while also maintaining the stability of locomotion. This study investigated the aging effect on gait adaptability and dynamic stability control during a visually perturbed gait initiation task. A novel approach was used such that the anticipatory postural adjustment (APA) during gait initiation were used to trigger the unpredictable relocation of a foot-size stepping target. Participants (10 young adults and 10 older adults) completed visually perturbed gait initiation in three adjustment timing conditions (early, intermediate, late; all extracted from the stereotypical APA pattern) and two adjustment direction conditions (medial, lateral). Stepping accuracy, foot rotation at landing, and Margin of Dynamic Stability (MDS) were analyzed and compared across test conditions and groups using a linear mixed model. Stepping accuracy decreased as a function of adjustment timing as well as stepping direction, with older subjects exhibited a significantly greater undershoot in foot placement to late lateral stepping. Late adjustment also elicited a reaching like movement (i.e. foot rotation prior to landing in order to step on the target), regardless of stepping direction. MDS measures in the medial-lateral and anterior-posterior direction revealed both young and older adults exhibited reduced stability in the adjustment step and subsequent steps. However, young adults returned to stable gait faster than older adults. These findings could be useful for future study of screening deficits in gait adaptability and preventing falls. PMID- 28837918 TI - Biomechanical analysis of gait waveform data: exploring differences between shod and barefoot running in habitually shod runners. AB - The aim of this study was to utilise one-dimensional statistical parametric mapping to compare differences between biomechanical and electromyographical waveforms in runners when running in barefoot or shod conditions. Fifty habitually shod runners were assessed during overground running at their current 10-km race running speed. Electromyography, kinematics and ground reaction forces were collected during these running trials. Joint kinetics were calculated using inverse dynamics. One-dimensional statistical parametric mapping one sample t test was conducted to assess differences over an entire gait cycle on the variables of interest when barefoot or shod (p<0.05). Only sagittal plane differences were found between barefoot and shod conditions at the knee during late stance (18-23% of the gait cycle) and swing phase (74-90%); at the ankle early stance (0-6%), mid-stance (28-38%) and swing phase (81-100%). Differences in sagittal plane moments were also found at the ankle during early stance (2, 4 5%) and knee during early stance (5-11%). Condition differences were also found in vertical ground reaction force during early stance between (3-10%). An acute bout of barefoot running in habitual shod runners invokes temporal differences throughout the gait cycle. Specifically, a co-ordinative responses between the knee and ankle joint in the sagittal plane with a delay in the impact transient peak; onset of the knee extension and ankle plantarflexion moment in the shod compared to barefoot condition was found. This appears to affect the delay in knee extension and ankle plantarflexion during late stance. This study provides a glimpse into the co-ordination of the lower limb when running in differing footwear. PMID- 28837919 TI - Reporting reactive cellular changes on smears among women who undergo cervical cancer screening: results of a cohort study after seven years of follow-up. AB - OBJECTIVE: To identify whether women presenting with reactive cellular changes (RCC) on their cervical smear face an increased risk for developing high grade cervical intraepithelial neoplasia (CIN2-3) or cancer as compared with women with an entirely normal smear. STUDY DESIGN: French data from the association in charge of organized cervical cancer screening in Bas-Rhin administrative region were used to establish a cohort of 96,215 women presenting with a smear classified as entirely normal or with RCC during the year 2001. The Kaplan-Meyer method was used to calculate the probabilities of CIN2-3 and cancer at seven years of follow-up. Univariate and multivariate survival analyses were performed using Cox proportional hazard models. RESULTS: Among the 95,559 women included in the final analysis, 32.2% presented a smear with RCC. After seven years of follow up, 441 women developed a CIN2-3 and 35 a cancer. Probability of CIN2-3 was increased in the RCC group as compared with the group of women with a normal smear (0.7% versus 0.5%, p=0.002). Multivariate analyses showed that, compared with a normal cervical smear, RCC were associated with a significant 37% increased risk of CIN2-3 (HR=1.37 CI95 [1.13-1.66]). However, the risk of cancer was not significantly increased (HR=1.11 CI95 [0.55-2.23]). CONCLUSION: This study showed that, at seven years, women with RCC on their cervical smear face an increased risk of CIN2-3 but no significant increased risk of cancer. The distinction between entirely normal and RCC cervical smears should therefore not lead to specific clinical management. PMID- 28837920 TI - Prodrug strategy for cancer cell-specific targeting: A recent overview. AB - The increasing development of targeted cancer therapy provides extensive possibilities in clinical trials, and numerous strategies have been explored. The prodrug is one of the most promising strategies in targeted cancer therapy to improve the selectivity and efficacy of cytotoxic compounds. Compared with normal tissues, cancer cells are characterized by unique aberrant markers, thus inactive prodrugs targeting these markers are excellent therapeutics to release active drugs, killing cancer cells without damaging normal tissues. In this review, we explore an integrated view of potential prodrugs applied in targeted cancer therapy based on aberrant cancer specific markers and some examples are provided for inspiring new ideas of prodrug strategy for cancer cell-specific targeting. PMID- 28837921 TI - Discovery of BAZ2A bromodomain ligands. AB - The bromodomain adjacent to zinc finger domain protein 2A (BAZ2A) is implicated in aggressive prostate cancer. The BAZ2A bromodomain is a challenging target because of the shallow pocket of its natural ligand, the acetylated side chain of lysine. Here, we report the successful screening of a library of nearly 1500 small molecules by high-throughput docking and force field-based binding-energy evaluation. For seven of the 20 molecules selected in silico, evidence of binding to the BAZ2A bromodomain is provided by ligand-observed NMR spectroscopy. Two of these compounds show a favorable ligand efficiency of 0.42 kcal/mol per non hydrogen atom in a competition-binding assay. The crystal structures of the BAZ2A bromodomain in complex with four fragment hits validate the predicted binding modes. The binding modes of compounds 1 and 3 are compatible with ligand growing for optimization of affinity for BAZ2A and selectivity against the close homologue BAZ2B. PMID- 28837923 TI - Structural transition of solvated H-Ras/GTP revealed by molecular dynamics simulation and local network entropy. AB - The state transitions of solvated H-Ras protein with GTP were theoretically analyzed through molecular dynamics (MD) simulations. To accelerate the structural changes associated with the locations of two switch regions (I and II), the Parallel Cascade Selection MD (PaCS-MD) method was employed in this study. The interconversions between the State 1 and State 2 were thus studied in atomic details, leading to a reasonable agreement with experimental observations and consequent scenarios concerning the transition mechanism that would be essential for the development of Ras inhibitors as anti-cancer agents. Furthermore, the state-transition-based local network entropy (SNE) was calculated for the transition process from State 1 to State 2, by which the temporal evolution of information entropy associated with the dynamical behavior of hydrogen bond network composed of hydration water molecules was described. The calculated results of SNE thus proved to provide a good indicator to detect the dynamical state transition of solvated Ras protein system (and probably more general systems) from a viewpoint of nonequilibrium statistical thermodynamics. PMID- 28837922 TI - Development of GLUT4-selective antagonists for multiple myeloma therapy. AB - Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue. Basally retained within the cell, GLUT4 traffics to the plasma membrane (PM) in response to insulin and exercise-stimulation. The plasma cell malignancy multiple myeloma (MM) exhibits increased constitutive expression of GLUT4 on the PM, co-opting use of GLUT4 for survival and proliferation. GLUT4 inhibition by knockdown or treatment with the FDA-approved HIV protease inhibitor ritonavir leads to cytostatic and/or cytotoxic and chemosensitizing effects in tumor cells both in vitro and in vivo. We recently reported our generation of GLUT4 homology models and virtual high-throughput screening (vHTS) to identify multiple series of novel GLUT4 antagonists. In this report, we describe our initial hit-to-lead optimization to synthesize new analogs with improved potency and selectivity for GLUT4, and the biological characterization of these compounds in a variety of assays. We show that our lead compound (compound 20) decreases glucose uptake and cell proliferation as well as inhibits the expression of pro-survival MCL-1 in MM similar to the effect observed via knockdown of GLUT4 expression. Compound 20 is also effective at chemosensitizing multiple myeloma cell lines and patient samples to venetoclax, dexamethasone and melphalan. In sum, we report development of selective GLUT4 inhibitors lacking inhibitory activity against GLUT1 and GLUT8. We show that selective pharmacological inhibition of GLUT4 is feasible and this may represent a novel strategy for the treatment and chemosensitization of multiple myeloma to standard therapeutics. PMID- 28837924 TI - Efficient in situ growth of enzyme-inorganic hybrids on paper strips for the visual detection of glucose. AB - A visual colorimetric microfluidic paper-based analytical device (MUPAD) was constructed following the direct synthesis of enzyme-inorganic hybrid nanomaterials on the paper matrix. An inorganic solution of MnSO4 and KH2PO4 containing a diluted enzyme (glucose oxidase, GOx) was subsequently pipetted onto cellulose paper for the in situ growth of GOx@Mn3(PO4)2 hybrid functional materials. The characterization of the morphology and chemical composition validated the presence of hybrid materials roots in the paper fiber, while the Mn3(PO4)2 of the hybrid provided both a surface for enzyme anchoring and a higher peroxidase-like catalytic activity as compared to the Mn3(PO4)2 crystal that was synthesized without enzyme modulation. This new approach for the in situ growth of an enzyme-inorganic hybrid on a paper matrix eliminates centrifugation and the dry process by casting the solution on paper. The sensing material loading was highly reproducible because of the accuracy and stability of pipetting, which eventually contributed to the reliability of the MUPAD. The self-assembled natural and artificial enzyme hybrid on the MUPADs specifically detected glucose from a group of interferences, which shows great specificity using this method. Moreover, the colorimetric signal exhibited detection limitation for glucose is 0.01mM, which lies in the physiological range of glucose in biological samples. PMID- 28837925 TI - Recent advances in signal amplification strategy based on oligonucleotide and nanomaterials for microRNA detection-a review. AB - MicroRNAs (MiRNAs) play multiple crucial regulating roles in cell which can regulate one third of protein-coding genes. MiRNAs participate in the developmental and physiological processes of human body, while their aberrant adjustment will be more likely to trigger diseases such as cancers, kidney disease, central nervous system diseases, cardiovascular diseases, diabetes, viral infections and so on. What's worse, for the detection of miRNAs, their small size, high sequence similarity, low abundance and difficult extraction from cells impose great challenges in the analysis. Hence, it's necessary to fabricate accurate and sensitive biosensing platform for miRNAs detection. Up to now, researchers have developed many signal-amplification strategies for miRNAs detection, including hybridization chain reaction, nuclease amplification, rolling circle amplification, catalyzed hairpin assembly amplification and nanomaterials based amplification. These methods are typical, feasible and frequently used. In this review, we retrospect recent advances in signal amplification strategies for detecting miRNAs and point out the pros and cons of them. Furthermore, further prospects and promising developments of the signal amplification strategies for detecting miRNAs are proposed. PMID- 28837926 TI - Triclosan (TCS) and triclocarban (TCC) induce systemic toxic effects in a model organism the nematode Caenorhabditis elegans. AB - The broad application of triclosan (TCS) and triclocarban (TCC) as antimicrobials in household and personal care products has led to the concerns regarding their human health risk and environmental impact. Although many studies have examined the toxicological effects of these compounds to a wide range of aquatic organisms from algae to fish, their potential toxicity to an important model organism the nematode Caenorhabditis elegans has never been systematically investigated. Here we assessed the toxicological effects of TCS and TCC in C. elegans using endpoints from organismal to molecular levels, including lethality, reproduction, lifespan, hatching, germline toxicity, and oxidative stress. L4 stage or young adult worms were exposed to TCS or TCC and examined using above-mentioned endpoints. Both TCS and TCC showed acute toxicity to C. elegans, with 24-h LC50s of 3.65 (95% CI: 3.15, 4.3) mg/L and 0.91 (95% CI: 0.47, 1.53) mg/L, respectively. TCS at 0.1-2 mg/L and TCC at 0.01-0.5 mg/L, respectively, induced concentration dependent reduction in the worm's reproduction, lifespan, and delay in hatching. Using a DAF-16:GFP transgenic strain, we found both compounds induced oxidative stress in the worm, indicated by the relocalization of DAF 16:GFP from cytoplasm to the nucleus upon exposure. Germline toxicity of the two compounds was also demonstrated using a xol-1:GFP transgenic strain. These findings suggest that TCS and TCC induce systemic toxic effects in C. elegans. Further studies are needed to elucidate the potential mechanisms of toxicity of these antimicrobials in the model organism, especially their potential endocrine disruption effects. PMID- 28837927 TI - Parental transfer of microcystin-LR induced transgenerational effects of developmental neurotoxicity in zebrafish offspring. AB - Microcystin-LR (MCLR) has been reported to cause developmental neurotoxicity in zebrafish, but there are few studies on the mechanisms of MCLR-induced transgenerational effects of developmental neurotoxicity. In this study, zebrafish were exposed to 0, 1, 5, and 25 MUg/L MCLR for 60 days. The F1 zebrafish embryos from the above-mentioned parents were collected and incubated in clean water for 120 h for hatching. After examining the parental zebrafish and F1 embryos, MCLR was detected in the gonad of adults and F1 embryos, indicating MCLR could potentially be transferred from parents to offspring. The larvae also showed a serious hypoactivity. The contents of dopamine, dihydroxyphenylacetic acid (DOPAC), serotonin, gamma-aminobutyric acid (GABA) and acetylcholine (ACh) were further detected, but only the first three neurotransmitters showed significant reduction in the 5 and 25 MUg/L MCLR parental exposure groups. In addition, the acetylcholinesterase (AChE) activity was remarkably decreased in MCLR parental exposure groups, while the expression levels of manf, bdnf, ache, htr1ab, htr1b, htr2a, htr1aa, htr5a, DAT, TH1 and TH2 genes coincided with the decreased content of neurotransmitters (dopamine, DOPAC and serotonin) and the activity of AChE. Neuronal development related genes, alpha1-tubulin, syn2a, mbp, gfap, elavl3, shha and gap43 were also measured, but gap43 was the gene only up regulated. Our results demonstrated MCLR could be transferred to offspring, and subsequently induce developmental neurotoxicity in F1 zebrafish larvae by disturbing the neurotransmitter systems and neuronal development. PMID- 28837928 TI - Bulimic symptoms and interpersonal functioning among college students. AB - Integrating interpersonal theory and the stress generation hypothesis, two studies investigated the association between bulimic symptoms and interpersonal distress and the mechanism underlying this association. In Study 1, 36 pairs of female roommates completed self-report questionnaires in a laboratory while Study 2 recruited 539 undergraduate men and women to participate in a longitudinal online study by completing self-report measures at two time points. Multilevel modeling revealed that targets' bulimic symptoms predicted roommates' intention to continue living with them in Study 1. Greater bulimic symptoms predicted lower intention. In Study 2, bulimic symptoms had a direct and an indirect effect on interpersonal distress, with reassurance-seeking as a mediator in the indirect effect. Findings replicated previous studies showing that bulimic symptoms generate further distress and, in our studies, interpersonal distress specifically. Moreover, reassurance-seeking was a newly identified mechanism underlying this association. These findings provide support for the usefulness of interpersonal theory and the stress generation hypothesis as a framework for understanding bulimic symptomatology. Clinicians may find it useful to target reassurance-seeking behaviors during the treatment of bulimic symptoms in order to improve treatment outcomes. PMID- 28837929 TI - Sleep-related problems and minor psychiatric disorders among Brazilian shift workers. AB - The aim of this study was to explore the association between sleep-related problems with the occurrence of minor psychiatric disorders in shift workers of southern Brazil. A cross-sectional study with 1202 workers (785 females) aged 18 50 years was carried out. Minor psychiatric disorders were assessed using the Self-Reporting Questionnaire (SRQ-20), and four sleep problems were collected and analyzed: sleep deprivation (<= 5h), difficulty falling asleep, waking up during sleep, and sleep medication use. Results show that the overall prevalence of minor psychiatric disorders was 26.8%, but it was more prevalent among females than males (30.2% vs. 20.4%). Nightshift work was significantly associated with the occurrence of sleep-related problems. After adjusting for confounding factors, the number of sleep-related problems showed a positive linear trend with psychiatric disorders in both sexes. Having two or more sleep-related problems was associated with increased probability of psychiatric disorders approximately three-fold among males and two-fold among females, when compared with those without sleep problems. In conclusion, this study demonstrated that sleep-related problems have a strong and independent association with psychiatric disorders among shift workers. Furthermore, the prevalence of both conditions was higher among females than males; however, the strength of these associations was higher in males. PMID- 28837930 TI - The indirect assessment of social anhedonia in Chinese adolescents: Preliminary findings. AB - Nearly all self-report measures of anhedonia have been developed for use in adults. Recently we developed an age and developmentally appropriate measure of social/interpersonal pleasure for adolescents (ACIPS-A), whereby lower scores are indicative of social anhedonia. However the scale had not been administered to Eastern samples. The adolescent version of the Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS-A) was administered to a general, community derived Chinese adolescent sample of 442 students, including 186 males (44%), who ranged in age from 12 to 18 years old. The 20-item Chinese Temporal Experience of Pleasure (TEPS) was also administered to the sample. Exploratory factor analysis revealed that three factors (Casual bonding, Close relationships, and Shared interests) accounted for nearly 69% of the variance. The total ACIPS-A showed excellent internal consistency, with ordinal alpha = 0.94. Scores on the adolescent version of the ACIPS were positively and significantly associated with total scores on the four Chinese TEPS subscales. The ACIPS-A is a sufficiently robust measure to be useful and valid in Chinese samples as well as in Western (i.e. European and U.S.) samples. PMID- 28837932 TI - Quality of life in individuals with attenuated psychotic symptoms: Possible role of anxiety, depressive symptoms, and socio-cognitive impairments. AB - Individuals with Clinical High-Risk state for Psychosis (CHR-P) are reported to exhibit impaired quality of life (QOL) similar to that observed in schizophrenia, but its determinants remain unclear. We investigated the QOL of 33 subjects with CHR-P, 45 patients with schizophrenia, and 63 healthy subjects using the Quality of Life Scale (QLS). The CHR-P and schizophrenia groups were administered the Brief Assessment of Cognition in Schizophrenia (BACS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Social and Occupational Functioning Assessment Scale (SOFAS) for socio-cognitive functions; and the Positive and Negative Syndrome Scale (PANSS) and the State-Trait Anxiety Inventory for clinical symptoms. The CHR-P group was also assessed using the Beck Depression Inventory. The CHR-P and schizophrenia groups had a significantly lower QLS score to the same degree compared with controls, which was predominantly associated with the SOFAS, SCoRS, and PANSS negative/general scores. For the CHR-P, the severity of anxiety and depressive symptoms was also correlated with a lower QLS score. Regression analyses demonstrated that the QLS score was predicted by SOFAS (for both groups) and SCoRS (for CHR-P) scores. Our findings suggest the importance of addressing socio-cognitive dysfunctions as well as anxiety and depressive symptoms for better QOL in CHR-P. PMID- 28837931 TI - Modifiable cardiometabolic risk factors in youth with at-risk mental states: A cross-sectional pilot study. AB - Young people experiencing psychotic illness engage in low amounts of physical activity have poor fitness levels and poor sleep quality. This study aimed to determine the prevalence of these modifiable cardiometabolic risk factors among individuals with at-risk mental states (ARMS), who are at increased risk of developing psychosis. A cross-sectional study was conducted in a community-based youth mental health service. Thirty participants (23%?, 21.3 +/- 1.7 years old) were recruited, 10 with ARMS, 10 with first-episode psychosis (FEP) and 10 healthy volunteers. Physical activity levels were assessed using self-report and objective measures. Aerobic capacity, upper body strength, hamstring flexibility, forearm grip strength and core endurance were assessed. Sleep quality, depression and anxiety were measured by self-report questionnaire. The ARMS group did not differ significantly on anthropometric measures from FEP or healthy volunteers. They engaged in significantly less physical activity (p < 0.05) and had poorer sleep quality (p < 0.05) than healthy volunteers. Our results are consistent with other studies that found that youth with ARMS are at greater cardiometabolic risk. Interventions aimed at improving these modifiable risk factors may assist with preventing the decline in physical health associated with the development of psychiatric illness. PMID- 28837933 TI - When the human spirit helps? The moderating role of somatization on the association between Olympic game viewing and the will-to-live. AB - This study examined whether participants with low somatization (no bodily manifestations of anxiety) who are assumed to identify with- and be inspired- by the Olympic-Games-spirit will present a stronger association between their Olympic-game viewing hours and their will-to-live, than persons with high somatization. One hundred and thirty seven participants reported their daily Olympic-game viewing hours, somatization and will-to-live levels. Results show that while among those with low somatization symptoms level, the relationships between Olympic game viewing hours and will-to-live was positive, the opposite was found among those with high somatization symptoms level. Viewing the Olympic Games may be beneficial for individuals with low somatization level but less so to individuals with higher somatization. PMID- 28837934 TI - Maternal alcohol use disorders and depression in emerging adulthood: Examining the relevance of social ties, childhood adversity, and socioeconomic status. AB - A number of recent studies have found that alcohol use disorders (AUDs) among parents are associated with higher levels of depression in their adult children. However, these studies have not considered whether several important social conditions in childhood help explain this association. Using a large sample of young adults from the National Longitudinal Surveys of Youth 1979 Children and Young Adults (NLSY79-CY), this study examines changes in the relationship between maternal AUDs and depression in emerging adulthood after controlling for three clusters of variables related to childhood social ties, adversity, and socioeconomic status. After models adjust for these factors, the association is reduced, but maternal AUDs remain a robust predictor of depression in emerging adulthood. These findings highlight the intergenerational consequences of AUDs and the need to develop interventions that supplement children's social support and economic circumstances. PMID- 28837935 TI - Suicidal behavior in the context of disrupted rhythmicity in bipolar disorder Complementary research of clock genes with suicide risks factors and course of disease. AB - Former findings indicate that suicidal behavior in bipolar disorder is associated with clock genes. Additionally, numerous non-genetic risk factors are potentially associated with suicidal behavior. Therefore, we conducted an analysis of the relationship between clock genes (as distal risk factors) with clinical characteristics and the course of bipolar disorder. We also tried to obtain a predictive model for suicide attempts based on clinical and genetic data. We found associations between selected polymorphisms and. PMID- 28837936 TI - Violent crimes in a community and quality of life for its inhabitants: Results of a multi-level study in South Korea. AB - Violent crimes have gradually been increasing in number in South Korea, and this increase is expected to affect quality of life (QOL). In this study, we investigated the relationship between a community's crime rates and its QOL that little attention has been paid. We used Community Health Survey, e-provincial indicators, and Official Crime Statistics during 2008-2012. We performed a multi level analysis adjusting for both individual- and community-level variables to examine the relationships. Among 234,485 participants, 46.8% were males and 53.2% were females. From the multi-level analysis, statistically significant higher homicide and rape rates showed an inverse relationship with the QOL of inhabitants in the community for both males and females. Additionally, strong inverse relationship were shown among individuals living in detached houses compared with individuals living in apartments. The relationships were more significant in females than males. In conclusions, increases in violent crimes, such as intentional homicide and rape, in the community appears to decrease the QOL of its inhabitants. Improved strategies are needed to address mental health issues related to community crime rates. PMID- 28837937 TI - Differences in responses to the Rorschach test between patients with dementia with Lewy bodies and Alzheimer's disease -from the perspective of visuoperceptual impairment. AB - Patients with Dementia with Lewy bodies (DLB) tend to perform worse in tasks on visuoperception than patients with Alzheimer's disease (AD). The Rorschach inkblot test has its utility for assessing perceptual and visuospatial abilities. In this study, we examined the differences in responses to the Rorschach test between patients with DLB and those with AD in terms of visuoperception, and investigated the utility of the test for assessing visuoperceptual impairment in DLB. Using the comprehensive system of Rorschach test, six variables were significantly higher, and three variables were significantly lower in DLB patients compared to AD patients. Among those variables, PTI showed high sensitivity and specificity for differentiating DLB from AD. Furthermore, when the PTI score was combined with the Dd score and a number of times a patient saw an eye in a shading part of an inkblot, the sensitivity and specificity reached 90.6% and 73.1%, respectively. These results indicate that the patients with DLB perceive objects in the inkblot differently from patients with AD, and suggest that some variables of the Rorschach test could assist with neuropsychological examinations when differentiating DLB from AD. PMID- 28837938 TI - The relations between inadequate parent-child boundaries and borderline personality disorder in adolescence. AB - Borderline Personality Disorder (BPD) is a severe mental illness that onsets in adolescence. Research has demonstrated the central role of parent-child relationships for the development and maintenance of BPD although more research is necessary to clarify the specific dynamics that relate to BPD during adolescence. Based on preliminary research establishing the importance of parent child boundaries for adolescent BPD, this study sought to evaluate the relations between different forms of inadequate boundaries and BPD in adolescence using a multi-method approach. To that end, 301 adolescents (65.1% female; ages 12-17) inpatients were recruited; parents and adolescents completed questionnaire- and interview-based measures of BPD features in adolescent children and a questionnaire-based measure of parent-child boundaries. Relations were found between parental guilt induction and psychological control with children's BPD features above and beyond relations with psychiatric severity and gender. Relations between parent reports of triangulation (when children are recruited to mediate parental marital conflict) and children's BPD were contingent on the level of children's perceptions of triangulation. Findings confirm previous research suggesting the relevance of inadequate parent-child boundaries to children's BPD features and have important implications for understanding the dynamics in families with adolescents with BPD, representing a relevant treatment target. PMID- 28837939 TI - Measurement Invariance of the Internet Gaming Disorder Scale-Short-Form (IGDS9 SF) between the United States of America, India and the United Kingdom. AB - The Internet Gaming Disorder Scale-Short-Form (IGDS9-SF) has been extensively used worldwide to assess Internet Gaming Disorder (IGD) behaviors. Therefore, investigating cultural limitations and implications in its applicability is necessary. The cross-cultural feasibility of a test can be psychometrically evaluated with measurement invariance analyses. Thus, the present study used Multigroup Confirmatory Factor Analysis (MGCFA) to examine the IGDS9-SF measurement invariance across gamers from the United States of America (USA), India, and the United Kingdom (UK). A total of 1013 gamers from the USA (n = 405), India (n = 336), and the UK (n = 272) were recruited. Although the one factor structure of the IGD construct was supported, cross-country variations were demonstrated considering the way that this was reflected on items assessing preoccupation/salience, tolerance, deception, gaming escapism/mood modification, as well as daily activities' impairment related to gaming. Furthermore, the same scores on items assessing withdrawal symptoms, tolerance, lack of control over gaming engagement, escapism/mood modification and daily activities impairment associated to gaming, have been found to reflect various levels of IGD severity across the three groups. The implications of these results are further discussed in the context of existing evidence regarding the assessment of IGD. PMID- 28837940 TI - "Geographical predisposition to a mania-predominant course of bipolar disorder in Asia". PMID- 28837941 TI - Delayed galactorrhea after discontinuation of risperidone in a schizophrenia patient. PMID- 28837942 TI - Obsessive-compulsive disorder presenting with gender incongruence obsessions. PMID- 28837943 TI - Low post-traumatic stress disorder rate in Chinese in Beijing, China. AB - OBJECT: There have been significantly fewer community-based, epidemiological studies focusing on PTSD and its socio-demographic correlates among the Chinese than Western populations. METHOD: The multistage household cluster random sampling method was used to select participants from18 districts and counties in Beijing; a total of 16,032 participants were assessed; face-to-face interviews and data collection was conducted using the semi-structured clinical interview for DSM-IV-TR Axis I Disorders-Patient Edition (SCID-I/P). RESULT: The lifetime PTSD prevalence was 0.3%. Older age, low educational level, low personal monthly income, urban living, unemployment and being a farmer were all significantly associated with an increased risk of PTSD. Multivariate analysis showed that farmers and the unemployed were significantly associated with a higher risk for PTSD. CONCLUSIONS: The prevalence rates of PTSD in Beijing were low compared with that of Western countries. Farming occupation and unemployment were independent risk factors for PTSD. PMID- 28837944 TI - Underground metabolism: network-level perspective and biotechnological potential. AB - A key challenge in molecular systems biology is understanding how new pathways arise during evolution and how to exploit them for biotechnological applications. New pathways in metabolic networks often evolve by recruiting weak promiscuous activities of pre-existing enzymes. Here we describe recent systems biology advances to map such 'underground' activities and to predict and analyze their contribution to new metabolic functions. Underground activities are prevalent in cellular metabolism and can form novel pathways that either enable evolutionary adaptation to new environments or provide bypass to genetic lesions. We also illustrate the potential of integrating computational models of underground metabolism and experimental approaches to study the evolution of novel metabolic phenotypes and advance the field of biotechnology. PMID- 28837945 TI - Creating plant molecular factories for industrial and nutritional isoprenoid production. AB - Chemical refining is a highly efficient process that has driven industrialisation and globalisation. However, dwindling fuel reserves and climatic fluctuation are now imposing key societal and economic challenges to health and welfare provision, agriculture, manufacturing outputs and energy. Plants are potentially exploitable 'green' chemical factories, with vast chemical diversity that can be used for the discovery and production of food, feed, medicines and biomaterials. Despite notable advances, plant based production under real-life scenarios remains, in most cases, economically uncompetitive when compared to inherently non-sustainable petrochemical based processes. In the present review the strategies available and those emerging will be described. Furthermore, how can the new evolving molecular tools such as genome editing be utilised to create a new paradigm of plant-based production? To illustrate the present status quo, we have chosen the isoprenoids as the class of natural products. These compounds display vast chemical diversity and have been used across multiple industrial sectors as medicines, supplements in food and feedstuffs, colourants and fragrances. PMID- 28837946 TI - Insights into the link between drug use and criminality: Lifetime offending of criminally-active opiate users. AB - BACKGROUND: We test whether the offending trajectory of those who test positive for opiates is greater than test-negative controls and whether the relationship is constant both prior to, and post, opiate initiation. We consider whether these relationships differ according to gender and offence type. METHODS: The study provides an analysis of historical offending records in adults linked to test results for opiate and cocaine metabolites. Those testing positive for opiates were linked to treatment records to retrieve data on age of opiate initiation. Rate ratios (RR) were calculated to compare opiate positive testers to opiate and cocaine negative controls, separately by gender and adjusting for age and birth cohort. Age of opiate initiation was included in a second model as a time dependent variable. Within-subject clustering was accounted for using generalised estimating equations. RESULTS: Opiate-positive cases had higher rates of offending than test-negative controls, both prior to, and post, opiate initiation. Initiation of opiate use increased the RR by 16% for males but doubled it for females. The RR increase in non-serious acquisitive crime was greater than that seen in serious crime. For males only, opiate initiation narrowed the difference in violent offending rate between cases and controls. A larger offending increase was associated with opiate initiation in female, compared to male, users. CONCLUSIONS: For most crime categories, the difference between groups is exacerbated by opiate initiation. The findings indicate that opiate prevention initiatives might be effective in reducing offending, particularly among females. PMID- 28837947 TI - Context-dependent effects of rimonabant on ethanol-induced conditioned place preference in female mice. AB - BACKGROUND: The CB1 receptor antagonist rimonabant has been previously found to prevent behavioral effects of drugs of abuse in a context-dependent manner, suggesting an important role of endocannabinoid signaling in drug-induced environmental conditioning. The aim of the present study was to evaluate the effects of rimonabant on ethanol-induced conditioned place preference (CPP) in female mice. METHODS: Animals were conditioned with saline or ethanol (1.8g/kg) during 8 sessions, and subsequently treated with either saline or rimonabant (1 or 10mg/kg) in the CPP environment previously associated with saline (unpaired) or ethanol (paired) for 6 consecutive days. Animals were then challenged with ethanol (1.8g/kg) in the ethanol-paired environment and ethanol-induced CPP was quantified on the following day. RESULTS: While treatment with 1mg/kg rimonabant in the saline-associated environment had no effects on the subsequent expression of ethanol-induced CPP, it blocked the expression of CPP to ethanol when paired to the ethanol-associated environment. When given in the ethanol-paired environment, 10mg/kg rimonabant induced aversion to the ethanol-associated environment. The same aversion effect was observed for 10mg/kg rimonabant when given in the saline-associated environment, thereby potentiating the expression of ethanol-induced CPP. Importantly, rimonabant did not induce CPP or conditioned place aversion on its own. Controlling for the estrous cycle phase showed no influences of hormonal cycle on the development and expression of ethanol-induced CPP. CONCLUSIONS: Our data suggest that rimonabant reduces the rewarding properties of ethanol by abolishing drug-environment conditioning in the CPP paradigm in a context-dependent manner. PMID- 28837948 TI - Coping strategies as mediators in relation to resilience and posttraumatic stress disorder. AB - BACKGROUND: Resilience has been shown to protect against the development of posttraumatic stress disorder (PTSD) in the aftermath of trauma. However, it remains unclear how coping strategies influence resilience and PTSD development in the acute aftermath of trauma. The current prospective, longitudinal study investigated the relationship between resilience, coping strategies, and the development of chronic PTSD symptoms. METHODS: A sample of patients was recruited from an emergency department following a Criterion A trauma. Follow-up assessments were completed at 1-, 3-, and 6-months post-trauma to assess PTSD symptom development (N = 164). RESULTS: Resilience at 1-month positively correlated with the majority of active coping strategies (all p < .05) and negatively correlated with the majority of avoidant coping strategies (all p < .05), as well as future PTSD symptoms (p < .001). Additionally, all avoidant coping strategies, including social withdrawal, positively correlated with future PTSD symptoms (all p < .01). After controlling for demographic and clinical variables, social withdrawal at 3-months fully mediated the relationship between resilience at 1-month and PTSD symptoms at 6-months. LIMITATIONS: Limitations include participant drop out and the conceptual overlap between avoidant coping and PTSD. CONCLUSIONS: These data suggest that resilience and social withdrawal may be possible therapeutic targets for mitigating the development of chronic PTSD in the aftermath of trauma. PMID- 28837949 TI - Adult attachment predicts the seven-year course of recurrent depression in primary care. AB - BACKGROUND: Attachment theory posits that attachment has a persistent, long-term impact on depression. Empirical data on associations between adult attachment and the long-term course of depression is, however, scarce. The present study addresses this omission. METHOD: Primary care patients with a history of depression (n = 103) completed the Experiences in Close Relationships questionnaire measuring adult attachment dimensions (avoidance and anxiety) and styles (secure, preoccupied, dismissing and fearful). The subsequent seven-year course of depression was assessed with the face-to-face administered Composite International Diagnostic Interview (CIDI) and a life-chart interview based on the Longitudinal Interval Follow-up Evaluation (LIFE). At the end of the seven-year follow-up severity of depression was additionally measured with the Beck Depression Inventory (BDI). RESULTS: The attachment dimensions avoidance and anxiety both showed significant associations during the seven-year course with lower proportions of depressive symptom-free time and higher severity of depression (LIFE and BDI). The secure style predicted compared to preoccupied attachment a significantly higher proportion of symptom-free time (4.97 vs. 1.10 years), compared to dismissing attachment a higher proportion of symptom-free time (4.97 vs. 2.20 years) and lower severity of depression (LIFE: 1.65 vs. 2.14; BDI 6.04 vs. 9.52), and compared to fearful attachment a lower relapse/recurrence rate (45.7% vs. 76.9%), higher proportions of depression diagnosis-free time (7.31 vs. 6.65 years) and symptom-free time (4.97 vs. 0.29 years), and lower severity of depression (LIFE: 1.65 vs. 2.19; BDI 6.04 vs. 15.54). LIMITATIONS: Sample size was restricted. CONCLUSION: Insecure attachment predicts an unfavorable course of depression over a seven-year period. PMID- 28837950 TI - Meta-analytic review of the effects of a single dose of intranasal oxytocin on threat processing in humans. AB - BACKGROUND: Heightened threat sensitivity is a transdiagnostic feature in several psychiatric disorders. The neuropeptide oxytocin has been shown to reduce fear related behaviours and facilitated fear extinction in animals. These findings have led to increasing interest to explore the effects of intranasal oxytocin on threat processing in humans. METHODS: The review included 26 studies (N = 1173), nine of which included clinical populations (N = 234). The clinical groups included were people with borderline personality disorder (BPD), anorexia nervosa, bulimia nervosa, depression, anxiety, and alcohol dependence disorder. We examined the effects of a single dose of intranasal oxytocin on startle response, attentional responses, and behavioural responses to threat. RESULTS: A single dose of intranasal oxytocin significantly increased the physiological startle response to threat in healthy people with a small effect size. However, oxytocin did not have significant effects on attentional bias towards social or disorder-specific threat, fixation towards threatening stimuli among healthy or clinical populations, or on threat related behavioural approach or avoidance responses. LIMITATIONS: No studies investigated the effects of oxytocin on the startle response to threat among clinical populations. Additionally, only one of the reviewed studies had sufficient power to detect at least a moderate effect of oxytocin according to our criterion. DISCUSSION: The synthesis of literature suggest that oxytocin may influence the salience of threatening stimuli among healthy individuals, increasing the startle response to threat. It would be of interest to investigate the effects of oxytocin on the startle response to threat among clinical populations. PMID- 28837951 TI - Latent classes of trait affect and cognitive affective regulation strategies are associated with depression, non-suicidal self-injury, and well-being. AB - BACKGROUND: The present study sought to better understand the unique profiles of late adolescents' affective functioning by exploring patterns of trait affect and cognitive affective regulation strategies. The study also examined whether these unique profiles significantly predicted depressive symptoms, non-suicidal self injury (NSSI), and well-being outcomes. METHODS: Data from a sample of 590 late adolescents were examined (M = 19.14 years, SD = 1.41, 63% Female, 62% Caucasian, 38% African American/Biracial). Participants were followed for an average of 14 months (SD = 2.53) and completed measures of trait affect, cognitive affective regulation, depression, NSSI, and well-being. Data were examined using latent class analysis. RESULTS: Five subgroups with unique patterns of affective functioning were identified. Late adolescents who reported above average levels of negative affect, dampening of positive affect, brooding, and reflection, coupled with below average levels of positive affect and positive rumination, were more likely to report having higher levels of depressive symptoms and greater engagement in NSSI during the one-year period prior to baseline. Similarly, the late adolescents fitting this profile also reported lower levels of well-being and were more likely to report engaging in NSSI at the follow-up. LIMITATIONS: Limitations include a narrow exploration of affective regulation strategies and the addition of key variables after the initiation of the larger study. CONCLUSIONS: These findings shed light on affective regulation factors relevant to the experience of depressive symptoms and NSSI, and the promotion of well-being. PMID- 28837952 TI - Association of obesity with cognitive function and brain structure in patients with major depressive disorder. AB - BACKGROUND: Obesity has been implicated in the pathophysiology of major depressive disorder (MDD), which prompted us to examine the possible association of obesity with cognitive function and brain structure in patients with MDD. METHODS: Three hundred and seven patients with MDD and 294 healthy participants, matched for age, sex, ethnicity (Japanese), and handedness (right) were recruited for the study. Cognitive function was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). Gray and white matter structures were analyzed using voxel-based morphometry and diffusion tensor imaging in a subsample of patients (n = 114) whose magnetic resonance imaging (MRI) data were obtained using a 1.5 T MRI system. RESULTS: Verbal memory, working memory, motor speed, attention, executive function, and BACS composite scores were lower for the MDD patients than for the healthy participants (p < 0.05). Among the patient group, working memory, motor speed, executive function, and BACS composite scores were lower in obese patients (body mass index >= 30, n = 17) than in non-obese patients (n = 290, p < 0.05, corrected). MRI determined frontal, temporal, thalamic, and hippocampal volumes, and white matter fractional anisotropy values in the internal capsule and left optic radiation were reduced in obese patients (n = 7) compared with non-obese patients (n = 107, p < 0.05, corrected). LIMITATIONS: Sample size for obese population was not very large. CONCLUSIONS: Obesity is associated with decreased cognitive function, reduced gray matter volume, and impaired white matter integrity in cognition-related brain areas in patients with MDD. PMID- 28837953 TI - Temperaments in psychotic and major affective disorders. AB - BACKGROUND: Assessment of affective temperaments with the extensively validated, 110-item TEMPS-A autoquestionnaire has been used to characterize patients with mood disorders, and its scores have been associated consistently with suicidal behavior. Much less has been reported about comparisons of characteristics of such assessments in psychotic and other psychiatric disorders. METHODS: We analyzed results of TEMPS-A assessments in 1081 psychiatrically hospitalized patients in Rome and compared subscale scores (anxious [anx], cyclothymic [cyc], depressive [dep], irritable [irr], hyperthymic [hyp]) and a composite score (anx+cyc+dep+irr - hyp) among diagnoses and subjects with vs. without a suicide attempt. RESULTS: TEMPS-A subscale scores differed significantly among diagnoses and were higher with major affective than psychotic or other disorders. Suicide attempts were 1.5-times more frequent among women than men and with affective versus nonaffective disorders, ranking: bipolar-II > major depression > bipolar-I > other disorders > psychotic disorders. TEMPS-A subscores were significantly higher among suicidal subjects (ranking: anx >= cyc >= dep > irr) except hyp (lower), but the composite score differed most (1.37-fold higher). Multivariable logistic regression modeling indicated that suicide attempt was significantly and independently associated with: TEMPS-A composite score > female sex > affective disorder > older age. CONCLUSIONS: TEMPS-A scores, particularly a composite score (anx+cyc+dep+irr - hyp) may help effectively evaluate suicidal risk in association with nonaffective as well as affective disorders. PMID- 28837954 TI - Is parity status associated with bipolar disorder clinical features, severity or evolution? AB - OBJECTIVE: To assess prospectively the association of the number of past pregnancies on the evolution of bipolar disorder (BD). METHODS: Data were drawn from the 2 waves of the National Epidemiologic Study of Alcohol and Related Conditions (NESARC), a representative sample of the US population of 34,653 participants. All women diagnosed with BD were included. The number of children and BD's characteristics, i.e. BD type, age of onset, hospitalization and suicide attempt, and lifetime psychiatrics comorbidity were assessed at wave 1. Mood episode and BD's characteristics were also assessed at wave 2. RESULTS: In the sample of 1190 women with BD, 27% had no child, 17% had one, 25% had two 31% had three children or more. Women with at least two children were more likely to have BD I, to report hypomania and suicide attempt during the follow-up than women without child. Parity was not associated with other characteristics of BD, nor with the severity and course of the illness. LIMITATIONS: Not provide information on pregnancies not ending to a delivery. CONCLUSION: Parity is associated with a higher incidence of hypomania and suicide attempt during a 3-years follow-up in women with BD. PMID- 28837955 TI - Social inhibition, sense of belonging and vulnerability to internalizing problems. AB - BACKGROUND: The aim of this study was to provide a conceptual test of how social inhibition, sense of belonging and internalizing problems are related, and whether sense of belonging moderates or mediates the relation between social inhibition and internalizing problems. METHODS: Data were used from two waves of the Dutch internet cohort LISS (Longitudinal Internet Studies of the Social Sciences; N = 511, M age = 52.09 years). Social inhibition was measured using the DS14 in 2012, sense of belonging (i.e., feeling cut off and having people to really talk to) was measured with the General Social Exclusion Index in 2012 and internalizing problems with the MHI-5 in 2015. RESULTS: Social inhibition was related to a lower sense of belonging and more internalizing problems. A low sense of belonging was related to more internalizing problems. Results indicated no moderation. However, evidence was found for partial mediation. That is, feeling cut off and having people to really talk to explained part of the link between social inhibition and internalizing problems. All analyses were controlled for sex, age and income. LIMITATIONS: The items used to measure sense of belonging only cover part of the construct. The study was not fully prospective, as such, no conclusions can be drawn regarding causality. CONCLUSIONS: Low sense of belonging is a key factor to consider when aiming at understanding individual differences in internalizing psychopathology related to social inhibition. PMID- 28837956 TI - Physiological mechanisms of prosociality. AB - Psychophysiological perspectives can provide unique insights into the nature and motivations of children's prosociality and inform our understanding of individual differences. Here, I review current research on prosociality involving some of the most common physiological measures in developmental psychology, including cortisol, various sympathetic nervous system measures, and high-frequency heart rate variability. The literature has been quite mixed, in part because the link between physiology and prosociality is context-dependent and person-dependent. However, recent advances are refining our understanding of the basic physiological mechanisms of prosociality. Resting physiology that contributes to a balance of regulation and vigilance prepares children to effectively cope with future social challenges, like noticing and attending to the needs of others. Experiencing some arousal is an important aspect of empathy-related responding, but physiological patterns of both heightened and hypoarousal can undermine prosociality. Physiological flexibility in response to others' needs may support emotional and behavioral flexibility important for prosociality. PMID- 28837957 TI - Positive feelings reward and promote prosocial behavior. AB - Humans are extraordinarily prosocial. What inspires and reinforces a willingness to help others? Here we focus on the role of positive feelings. Drawing on functional accounts of positive emotion, which suggest that positive emotional states serve to alert actors to positive experiences and encourage similar action in the future, we summarize evidence demonstrating that positive feelings promote and reward prosocial behavior throughout development. Specifically, we highlight new and classic evidence from both child and adult research showing first, that various positive states prompt prosocial behavior, and second, prosocial action leads to positive states. We also consider the possibility of a positive feedback loop, wherein the emotional rewards of giving promote future prosociality. PMID- 28837958 TI - Terminating the criminal collaboration in pancreatic cancer: Nanoparticle-based synergistic therapy for overcoming fibroblast-induced drug resistance. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a dismal overall prognosis mainly unchanged over the past decades. PDAC is generally refractory to conventional treatments, and thus novel therapies are urgently needed. Recently, accumulating evidence has indicated that human pancreatic stellate cells (PSCs) facilitate PDAC development and drug resistance through paracrine activation of hedgehog pathway. Here, we report that smart SN38 (active metabolite of irinotecan) polymeric prodrug-based nanoparticles effectively encapsulate the commercial hedgehog pathway inhibitor GDC-0449 for co-delivery. More intriguingly, we obtained size-tunable nanoparticles with increased GDC-0449 loading efficiency by simply extending the chain length of the hydrophobic SN38 block. To better evaluate the efficacy and investigate the synergistic mechanisms, we immortalized human PSCs and established fibroblast-containing models in vitro and in vivo. In PSCs, BxPC-3 cells and MIA PaCa-2 cells, GDC-0449 suppressed the co-culture induced up-regulations of the two drug resistance contributors: sonic hedgehog transcription factor glioma-associated protein1 (GLI 1) and UGT1A glucuronosyltransferase. Importantly, the nanoparticle-mediated co delivery system exhibited potent antitumor efficacy with enhanced apoptosis and reduced collagen, alpha-SMA and GLI-1 expression in tumor tissues. These findings reveal a potential strategy to utilize nanoparticle-mediated drug co-delivery platform as an effective combination therapy for fibroblast-enriched PDAC. PMID- 28837959 TI - Europium-doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent. AB - Although much research has gone into the design of nanomaterials, inflammatory response still impedes the capacity of nanomaterial-induced tissue regeneration. In-situ incorporation of nutrient elements in silica-based biomaterials has emerged as a new option to endow the nanomaterials modulating biological reactions. In this work, europium-doped mesoporous silica nanospheres (Eu-MSNs) were successfully synthesized via a one-pot method. The nanospheres (size of 280 300 nm) possess uniformly spherical morphology and mesoporous structure, and well distributed Eu elements. The nanospheres show distinct fluorescent property at 615 nm for potential bio-labeling. Noticeably, the Eu-MSNs stimulate pro inflammatory response of macrophages and induce a modulated immune microenvironment, which further activates the osteogenic differentiation of bone marrow stromal cells (BMSCs) as well as angiogenic activity of human umbilical vein endothelial cells (HUVECs). During the process, osteogenesis-related genes (e.g. ALP, OCN, OPN and COL-I) of BMSCs, and angiogenesis-related genes (e.g. CD31, MMP9, VEGFR1/2, and PDGFRalpha/beta) of HUVECs were significantly upregulated by Eu-MSNs modulating immune environment of macrophages. The in vivo study further demonstrated that the Eu-MSNs could not only stimulate osteogenesis by accelerating the new bone formation at critical-sized cranial defect site, but also support the blood vessel formation as well as collagen deposition and re epithelialization at chronic skin wound sites, showing an improved angiogenesis activity when comparing with MSNs alone. Given the easy handling characteristics and extensive application potential, the results suggest that Eu-MSNs could be used as immunity-modulated osteogenesis/angiogenesis agent for skin and bone regeneration. PMID- 28837960 TI - Prodrug-embedded angiogenic vessel-targeting nanoparticle: A positive feedback amplifier in hypoxia-induced chemo-photo therapy. AB - Photodynamic therapy (PDT) induced hypoxia can significantly upregulate the expression of vascular endothelial growth factor (VEGF) at the tumor-stromal interface, resulting in a promoted angiogenesis. Thus, an angiogenesis vessel targeting nanoparticle (AVT-NP) consisting of photosensitizer, angiogenic vessel targeting peptide, and bioreductive prodrug is developed for a chemo-photo synergistic cancer therapy, with which anti-cancer effect is achieved first by PDT and immediately followed with hypoxia-activated cytotoxic free radicals. With targeting capability, the AVT-NPs can effectively accumulate at the tumor site due to the promoted angiogenesis in response to PDT-induced hypoxia. The more nanoparticles delivered to the tumor tissue, the higher efficacy of PDT can be achieved, resulting in a more severe hypoxia and increased angiogenesis. Therefore, the prodrug embedded AVT-NP functions as a positive feedback amplifier in the combinational chemo-photo treatment and indeed achieves an enhanced anti tumor effect in both in vitro and in vivo studies. PMID- 28837961 TI - Motion-based super-resolution in the peripheral visual field. AB - Improvements in foveal acuity for moving targets have been interpreted as evidence for the ability of the visual system to combine information over space and time, in order to reconstruct the image at a higher resolution (super resolution). Here, we directly test whether this occurs in the peripheral visual field and discuss its potential for improving functional capacity in ocular disease. The effect of motion on visual acuity was first compared under conditions in which performance was limited either by natural undersampling in the retinal periphery or by the presence of overlaid masks with opaque elements to simulate retinal loss. To equate the information content of moving and static sequences, we next manipulated the dynamic properties of the masks. Finally, we determined the dependence of motion-related improvements on the object of motion (target or mask) and its trajectory (smooth or jittered). Motion improved visual acuity for masked but not unmasked peripheral targets. Equating the information content of moving and static conditions removed some but not all of this benefit. Residual motion-related improvements were largest in conditions in which the target moved along a consistent and predictable path. Our results show that motion can improve peripheral acuity in situations in which performance is limited by abnormal undersampling. These findings are consistent with the operation of a super-resolution system and could have important implications for any pathology that alters the regular sampling properties of the retinal mosaic. PMID- 28837963 TI - Comparing averaging limits for social cues over space and time. AB - Observers are able to extract summary statistics from groups of faces, such as their mean emotion or identity. This can be done for faces presented simultaneously and also from sequences of faces presented at a fixed location. Equivalent noise analysis, which estimates an observer's internal noise (the uncertainty in judging a single element) and effective sample size (ESS; the effective number of elements being used to judge the average), reveals what limits an observer's averaging performance. It has recently been shown that observers have lower ESSs and higher internal noise for judging the mean gaze direction of a group of spatially distributed faces compared to the mean head direction of the same faces. In this study, we use the equivalent noise technique to compare limits on these two cues to social attention under two presentation conditions: spatially distributed and sequentially presented. We find that the differences in ESS are replicated in spatial arrays but disappear when both cue types are averaged over time, suggesting that limited peripheral gaze perception prevents accurate averaging performance. Correlation analysis across participants revealed generic limits for internal noise that may act across stimulus and presentation types, but no clear shared limits for ESS. This result supports the idea of some shared neural mechanisms b in early stages of visual processing. PMID- 28837962 TI - Perisaccadic visual perception. AB - Primates use frequent, rapid eye movements to sample their visual environment. This is a fruitful strategy to make the best use of the highly sensitive foveal part of the retina, but it requires neural mechanisms to bind the rapidly changing visual input into a single, stable percept. Studies investigating these neural mechanisms have typically assumed that perisaccadic perception in nonhuman primates matches that of humans. We tested this assumption by performing identical experiments in human and nonhuman primates. Our data confirm that perisaccadic visual perception of macaques and humans is qualitatively similar. Specifically, we found a reduction in detectability and mislocalization of targets presented at the time of saccades. We also found substantial differences between human and nonhuman primates. Notably, in nonhuman primates, localization that requires knowledge of eye position was less precise, nonhuman primates detected fewer perisaccadic stimuli, and perisaccadic compression was not towards the saccade target. The qualitative similarities between species support the view that the nonhuman primate is ideally suited to study aspects of brain function such as those relying on foveal vision-that are uniquely developed in primates. The quantitative differences, however, demonstrate the need for a reassessment of the models purportedly linking neural response changes at the time of saccades with the behavioral phenomena of perisaccadic reduction of detectability and mislocalization. PMID- 28837964 TI - Global processing of random-phase radial frequency patterns but not modulated lines. AB - Previously, researchers have used circular contours with sinusoidal deformations of the radius (radial frequency [RF] patterns) to investigate the underlying processing involved in simple shape perception. On finding that the rapid improvement in sensitivity to deformation as more cycles of modulation were added was greater than expected from probability summation across sets of local independent detectors, they concluded that global integration of contour information was occurring. More recently, this conclusion has been questioned by researchers using a method of calculating probability summation derived from signal detection theory (Baldwin, Schmidtmann, Kingdom, & Hess, 2016). They could not distinguish between global integration and probability summation. Furthermore, it has been argued that RF patterns and lines are processed in a similar manner (Mullen, Beaudot, & Ivanov, 2011; Schmidtmann & Kingdom, 2017). The current study investigates these claims using fixed-phase (in which the local elements have spatial certainty) and random-phase (in which the local elements have spatial uncertainty) RF patterns and modulated lines. Thresholds were collected from eight naive observers and compared to probability summation estimates calculated using methods derived from both high threshold theory and signal detection theory. The results indicate global processing of random-phase RF patterns and evidence for an interaction between local and global cues for fixed-phase RF patterns. They also show no evidence of global integration with modulated line stimuli. The results provide further evidence for the global processing of random-phase RF patterns and indicate that RF patterns and modulated lines are processed differently. PMID- 28837965 TI - Short-term adaptation of saccades does not affect smooth pursuit eye movement initiation. AB - Scrutiny of the visual environment requires saccades that shift gaze to objects of interest. In case the object should be moving, smooth pursuit eye movements (SPEM) try to keep the image of the object within the confines of the fovea in order to ensure sufficient time for its analysis. Both saccades and SPEM can be adaptively changed by the experience of insufficiencies, compromising the precision of saccades or the minimization of object image slip in the case of SPEM. As both forms of adaptation rely on the cerebellar oculomotor vermis (OMV), most probably deploying a shared neuronal machinery, one might expect that the adaptation of one type of eye movement should affect the kinematics of the other. In order to test this expectation, we subjected two monkeys to a standard saccadic adaption paradigm with SPEM test trials at the end and, alternatively, the same two monkeys plus a third one to a random saccadic adaptation paradigm with interleaved trials of SPEM. In contrast to our expectation, we observed at best marginal transfer which, moreover, had little consistency across experiments and subjects. The lack of consistent transfer of saccadic adaptation decisively constrains models of the implementation of oculomotor learning in the OMV, suggesting an extensive separation of saccade- and SPEM-related synapses on P cell dendritic trees. PMID- 28837966 TI - L-/M-cone opponency in visual evoked potentials of human cortex. AB - L and M cones send their signals to the cortex using two chromatic (parvocellular and blue-yellow koniocellular) and one luminance (magnocellular) pathways. These pathways contain ON and OFF subpathways that respond to excitation increments and decrements respectively. Here, we report on visually evoked potentials (VEP) recordings that reflect L- and M-cone driven increment (LI and MI) and decrement (LD and MD) activity. VEP recordings were performed on 12 trichromats and four dichromats (two protanopes and two deuteranopes). We found that the responses to LI strongly resembled those to MD, and that LD and MI responses were very similar. Moreover, the lack of a photoreceptor type (L or M) in the dichromats led to a dominance of the ON pathway of the remaining photoreceptor type. These results provide electrophysiological evidence that antagonistic L/M signal processing, already present in the retina and the lateral geniculate nucleus (LGN), is also observed at the visual cortex. These data are in agreement with results from human psychophysics where MI stimuli lead to a perceived brightness decrease whereas LI stimuli resulted in perceived brightness increases. VEP recording is a noninvasive tool that can be easily and painlessly applied. We propose that the technique may provide information in the diagnosis of color vision deficiencies. PMID- 28837967 TI - Stereovision for action reflects our perceptual experience of distance and depth. AB - Binocular vision is widely recognized as the most reliable source of 3D information within the peripersonal space, where grasping takes place. Since grasping is normally successful, it is often assumed that stereovision for action is accurate. This claim contradicts psychophysical studies showing that observers cannot estimate the 3D properties of an object veridically from binocular information. In two experiments, we compared a front-to-back grasp with a perceptual depth estimation task and found that in both conditions participants consistently relied on the same distorted 3D representation. The subjects experienced (a) compression of egocentric distances: objects looked closer to each other along the z-axis than they were, and (b) underconstancy of relative depth: closer objects looked deeper than farther objects. These biases, which stem from the same mechanism, varied in magnitude across observers, but they equally affected the perceptual and grasping task of each subject. In a third experiment, we found that the visuomotor system compensates for these systematic errors, which are present at planning, through online corrections allowed by visual and haptic feedback of the hand. Furthermore, we hypothesized that the two phenomena would give rise to estimates of the same depth interval that are geometrically inconsistent. Indeed, in a fourth experiment, we show that the landing positions of the grasping digits differ systematically depending on whether they result from absolute distance estimates or relative depth estimates, even when the targeted spatial locations are identical. PMID- 28837968 TI - Feature-based attentional tuning during biological motion detection measured with SSVEP. AB - Performance in detection tasks can be improved by directing attention to task relevant features. In this study, we evaluate the direction tuning of selective attention to motion features when observers detect point-light biological motion in noise. Feature-based attention strategy is assessed by capitalizing on the sensitivity of unattended steady-state visual-evoked potential (SSVEP) to the spreading of feature-based attention to unattended regions of space. Participants monitored for the presence of a point-light walker embedded in uniform dynamic noise in the center of the screen. We analyzed the phase-locked electroencephalogram response to a flickering random-dot kinematogram (RDK) in an unattended peripheral annulus for the 1 s prior to the onset of the target. We found the highest SSVEP power to originate from electrodes over posterior parietal cortex (PPC), with power modulated by the direction of motion in the unattended annulus. The SSVEP was strongest on trials in which the unattended motion was opposite the facing direction of the walker, consistent with the backstroke of the feet and with the global direction of perceived background motion from a translating walker. Coherence between electrodes over PPC and other brain regions successfully predicted individual participant's d-prime, with the highest regression coefficients at electrodes over ventrolateral prefrontal cortex (VLPFC). The findings are evidence that functional connectivity between frontal and parietal cortex promote perceptual feature-based attention, and subsequent perceptual sensitivity, when segregating point-light figures from masking surround. PMID- 28837969 TI - Intrinsic position uncertainty impairs overt search performance. AB - Uncertainty regarding the position of the search target is a fundamental component of visual search. However, due to perceptual limitations of the human visual system, this uncertainty can arise from intrinsic, as well as extrinsic, sources. The current study sought to characterize the role of intrinsic position uncertainty (IPU) in overt visual search and to determine whether it significantly limits human search performance. After completing a preliminary detection experiment to characterize sensitivity as a function of visual field position, observers completed a search task that required localizing a Gabor target within a field of synthetic luminance noise. The search experiment included two clutter conditions designed to modulate the effect of IPU across search displays of varying set size. In the Cluttered condition, the display was tiled uniformly with feature clutter to maximize the effects of IPU. In the Uncluttered condition, the clutter at irrelevant locations was removed to attenuate the effects of IPU. Finally, we derived an IPU-constrained ideal searcher model, limited by the IPU measured in human observers. Ideal searchers were simulated based on the detection sensitivity and fixation sequences measured for individual human observers. The IPU-constrained ideal searcher predicted performance trends similar to those exhibited by the human observers. In the Uncluttered condition, performance decreased steeply as a function of increasing set size. However, in the Cluttered condition, the effect of IPU dominated and performance was approximately constant as a function of set size. Our findings suggest that IPU substantially limits overt search performance, especially in crowded displays. PMID- 28837970 TI - Foveal to peripheral extrapolation of brightness within objects. AB - Peripheral viewing is characterized by poor resolution and distortions as compared to central viewing; nevertheless, when we move our gaze around, the visual scene does not appear to change. One possible mechanism leading to perceptual uniformity would be that peripheral appearance is extrapolated based on foveal information. Here we investigate foveal-to-peripheral extrapolation in the case of the perceived brightness of an object's surface. While fixating a spot on the rendered object, observers were asked to adjust the brightness of a disc to match a peripherally viewed target area on the surface of the same object. Being forced to fixate a better illuminated point led to brighter matches as compared to fixating points in the shadow, indicating that foveal brightness information was extrapolated. When observers fixated additional points outside of the object on the scene's background, fixated brightness had no effect on the brightness match. Results indicate that our visual system uses the brightness of the foveally viewed surface area to estimate the brightness of areas in the periphery. However, this mechanism is selectively applied within an object's boundary. PMID- 28837971 TI - Mortality and its Causes in a German Cohort with Diabetes Mellitus Type 1 after 20 Years of Follow-Up: The JEVIN Trial. AB - BACKGROUND: The JEVIN trial started as a cross-sectional study in 1989/90 in Jena. After a follow-up of more than 20 years, the mortality incidence of JEVIN participants with type 1 diabetes was surveyed. METHODS: 103 (78.6%) of the 131 JEVIN patients participating at baseline could be examined. 38 persons (36.9%) had deceased. All JEVIN survey data and routine examinations documented in the electronic patient record EMIL(r) of surviving and deceased participants were used for analyses. We compared the data of the surviving with the deceased participants (follow-up time: 2,166 person-years). RESULTS: The incidence rate of death was 1.75/100 person-years. Median observation time for all patients was 23.1 years (range 0.61-26.6 years). Mean age at death was 58.5 years (34.2-78.4 years), and diabetes duration 35 years (3.5-68.5 years). Most frequent causes of death were: cardiovascular diseases (48.2%, n=13) and infections (25.9%, n=7). There were no differences in age (p=0.302), diabetes duration (p=0.371), BMI (p=0.535), blood pressure (p=0.622/0.820), gender (p=0.566), and smoking status (p=0.709) between surviving and deceased persons. The mean HbA1c of the last year before death or last visit was higher in the deceased than surviving persons (7.5% vs. 7.0%; p=0.010). 57.4% of the surviving and 87.0% of the deceased participants had nephropathy (p=0.012), 79.7% vs. 89.7% retinopathy (p=0.241) and 61.4% vs. 63.3% neuropathy (p=0.860), but only nephropathy was significantly associated with increased mortality risk (HR=4.208, CI:1.226-14.440; HR=2.360, CI:0.696-8.004; HR=0.944, CI:0.436-2.043). CONCLUSIONS: In the JEVIN population with diabetes mellitus type 1 only, diabetic nephropathy was associated with higher mortality risk. PMID- 28837972 TI - Excessive Catecholamine Secretion and the Activation of the Renin-Angiotensin Aldosterone-System in Patients with Pheochromocytoma: A Single Center Experience and Overview of the Literature. AB - Catecholamines stimulate renin-secretion in the juxtaglomerular cells of the kidney and a number of case reports suggest an association between pheochromocytoma and activation of the RAAS. Therefore, it could be asked whether patients suffering from pheochromocytoma with high concentrations of circulating catecholamines present with oversecretion of renin and aldosterone. We identified twelve patients with excessive catecholamine secretion due to pheochromocytoma and compared them to a group of twelve patients with essential hypertension (EH) with regard to the activation of the renin-angiotensin-aldosterone-system (RAAS). The PubMed database was screened for studies that investigate the association between pheochromocytoma and activation of the RAAS. The plasma concentrations of metanephrines (19.9-fold) and normetanephrines (29.5-fold) were significantly higher in the pheochromocytoma group than in the EH group. Renin and aldosterone levels were 1.3-fold and 1.6-fold higher, respectively, as compared to the EH group, whereas the differences were not statistically significant. There was no significant correlation between plasma metanephrine or normetanephrine levels and the plasma renin concentration (rs=0.077, rs=0.049, respectively) in our patients. The data from our institution and from review of literature suggest that an association between pheochromocytoma in the context of high plasma catecholamine levels and activation of the RAAS is present. However, results have not been consistent. Thus, other causes of RAAS-activation should be considered also in the presence of pheochromocytoma or reinvestigation for aldosteronism should be offered to such patients after removal of the catecholamine-producing tumour. PMID- 28837973 TI - Arthrosonographic Reference Values of the Shoulder Joint in Healthy Children and Adolescents: A Cross-Sectional Multicentre Ultrasound Study. AB - : Background Defining of gray scale ultrasound standard reference values of the shoulder joint in childhood and adolescence during maturation. PATIENTS: We examined 445 healthy girls and boys between 1 year and 18 years of age. Method A cross-sectional multicentre grey-scale ultrasound study was performed to examine the shoulder joint on both sides. The children were divided according to their gender and were further classified into six age groups, which constituted three year age ranges, to record anatomical development changes. We measured the capsule-bone distance (BCD) as a representation of the intracapsular cavity, as well as the thickness of the joint capsule and joint cartilage. Values were expressed in mean+/-standard deviation (SD) and minimum-maximum (min-max). The shape of the joint capsule and capsule-bone junction zone was qualitatively analysed. Results The joint cartilage thickness decreased with increasing age in all joints independently from sex and body side. However, the BCD and the capsule thickness increased with age. There was no intraarticular fluid visible. The joint capsule had a predominantly concave form, whereas the capsule-bone junction was mostly sharp. Discussion This study is the first describing age-related normal values of the intracapsular cavity, joint capsule and cartilage thickness as well as their respective shape in a large cohort of healthy children. Conclusion The findings could be helpful to differentiate between physiological and pathological joint conditions and thereby distinguishing age-related variations from alterations caused by inflammation. PMID- 28837974 TI - Klebsiella Oxytoca Bacteremia Induced Septic Shock following Platelet Transfusion. PMID- 28837975 TI - [Required Framework for the Collection of Real-life Data: An Example from University Eye Hospital Munich]. AB - Background The importance of evaluating real-life data is constantly increasing. Currently available computer systems better allow for analyses of data, as more and more data is available in a digital form. Before a project for real-life data analyses is started, technical considerations and staff, legal, and data protection procedures need to be addressed. In this manuscript, experiences made at the University Eye Hospital in Munich will be shared. Materials and Methods Legal requirements, as found in laws and guidelines governing documentation and data privacy, are highlighted. Technical requirements for information technology infrastructure and software are defined. A survey conducted by the German Ophthalmological Society, among German eye hospitals investigating the current state of digitalization, was conducted. Also, staff requirements are outlined. Results A database comprising results of 330,801 patients was set up. It includes all diagnoses, procedures, clinical findings and results from diagnostic devices. This database was approved by the local data protection officer. In less than half of German eye hospitals (n = 21) that participated in the survey (n = 54), a complete electronic documentation is done. Fourteen institutions are completely paper-based, and the remainder of the hospitals used a mixed system. Conclusion In this work, we examined the framework that is required to develop a comprehensive database containing real-life data from clinics. In future, these databases will become increasingly important as more and more innovation are made in decision support systems. The base for this is comprehensive and well-curated databases. PMID- 28837976 TI - [Patient-Reported Treatment Satisfaction with Stereotactic Radiotherapy in Neovascular Age-Related Macular Degeneration]. AB - Background Stereotactic radiotherapy (SRT) in conjunction with the common intravitreal injections (IVI) is a new adjuvant approach in neovascular age related macular degeneration (AMD) patients. The aim of our study was to investigate factors influencing patient satisfaction one year after SRT. Methods A questionnaire was administered to 35 AMD patients who had consecutively undergone SRT using the IRay(r)-device at the Department of Ophthalmology, University of Lubeck. In addition to descriptive statistics, responses were evaluated by correlation analysis. Moreover, subgroup analyses were performed, using a classification of IVI responders (annual injection rate after SRT <= 3), visual acuity (VA) responders (VA improvement >= 0.2 logMAR) and double responders (annual injection rate after SRT <= 3 as well as VA improvement >= 0.2 logMAR). Results The response rate was 86%. With respect to their treatment expectations, twice as many patients hoped to receive less injections instead of a better vision. Those hoping for less injections were significantly more satisfied with their clinical outcome. In addition, IVI-responders were significantly more satisfied than IVI-non-responders, while VA-responders were not, compared to VA-non-responders. Conclusions Patient satisfaction seems to depend on patients' comprehension of how SRT affects their disease and what kinds of expectations were set. It is of utmost importance to provide the patients with adequate and comprehensible education and to define realistic goals prior to SRT. PMID- 28837977 TI - [Static Retinal Vessel Analysis in Population-based Study SHIP-Trend]. AB - Background Interdisciplinary investigations of possible connections between general diseases and ophthalmological changes are difficult to perform in the clinical environment. But they are gaining in importance as a result of the age related increase in chronic diseases. The collection of health-related parameters in the Study of Health in Pomerania (SHIP) project allows to derive conclusions for the general population. Methods The population-based SHIP trend study was conducted between 2008 and 2012 in Greifswald. The baseline cohort included 4420 subjects (response 50.1%) at the age of 20 to 84 years. The pre-existence of arterial hypertension, diabetes mellitus and smoking status were questioned in a standardized questionnaire, the blood pressure and the HbA1c were determined by the laboratory. The vascular diameter of retinal arterioles and venules were determined by means of non-mydriatic fundus images and the retinal arterial (CRAE) and venous equivalent (CRVE) were calculated therefrom. The association of diabetes mellitus, HbA1c, smoking status and blood pressure with the retinal vascular parameters was tested for age and sex with linear regression models. Results In 3218 subjects with evaluable standardized fundus photographs, significant associations of elevated HbA1c (> 6.5%), smoking status and systolic and diastolic blood pressure were found with the retinal vessel widths CRAE and CRVE. Anamnestic diabetes mellitus, on the other hand, was not associated with any of the vascular parameters. Conclusion This research study reveals a relevant correlation between general diseases and the retinal blood flow in the eye. Therefore, general diseases can induce ophthalmological changes and eye examination can provide information for the assessment of general diseases. PMID- 28837978 TI - [Do We Perform Glaucoma Surgery too Late?] AB - As glaucoma specialists, we often ask ourselves why patients are referred so late for surgery. Usually the patient is referred in a far advanced stage of the disease after long-term conventional treatment with topical medications. By that time, substantial morphologic damage is present and the patient is disabled by far advanced visual field defects. In addition, decompensated intraocular pressure, despite maximal tolerated medical treatment, is seen. Delayed surgery due to late diagnosis is rather a rare event. Various reasons may be responsible for this late referral. Improved IOP-lowering medications (i.e., fixed combinations), personal aversion (fear and knowledge of lack of improvement in visual acuity) against surgery, and imperfect glaucoma procedures may play an important role. A retrospective review of the last 274 cases referred for filtering glaucoma surgery is used to describe and analyze criteria for adequate timing of glaucoma surgery. This study reveals that almost 3/4 of patients are referred rather late for glaucoma surgery. Criteria for adequate timing of glaucoma surgery are given for non-glaucoma specialists in particular. They apply for all types of glaucoma surgery, and the pros and cons are discussed in detail. Trabeculectomy is still regarded as the gold standard of glaucoma surgery. Because trabeculectomy may not be an ideal glaucoma procedure, there is hope that the modern less-invasive glaucoma procedures (MIGS) will be able to extend indications for glaucoma surgery. This may also lower the hurdle of referral for glaucoma surgery for both patients and non-glaucoma specialist doctors. PMID- 28837979 TI - [Causes, Diagnosis and Therapy of Negative Dysphotopsia]. AB - Negative Dysphotopsia (ND) is a dark, sometimes rounded bar or shadow in the temporal visual field after uncomplicated cataract surgery that may lead to great patient discomfort. R. Olson called it "the number one troublesome complaint after uneventful cataract surgery". The origin of this phenomena remains uncertain and is discussed conversely in literature. We have found evidence that it may be caused by a slight difference in magnification caused by the new IOL compared to the old crystalline lens. This may lead to a minimal shift of the object space corresponding the blind spot and the larger central vessels so they become visible for a short time after surgery. Until now, no definitive criteria have been published for a proper diagnosis of ND. Based on our experience with 55 patients (77 eyes) with ND, out of 6,031 cataract procedures during the last two years, the following aspects seems to be important: ND is always 1) a disturbing dark shadow in the temporal visual field after cataract surgery and lens implantation. 2) No pathology of the eye can be found to explain this shadow. 3) In most cases, the following points exist in descending order of importance: The patients feel that the ND-shadow is far in the periphery of the visual field, mostly between 60 degrees and 90 degrees ; using objective criteria, the shadow is, in reality, mostly between 10 degrees and 25 degrees in the temporal visual field; ND is variable; temporal illumination diminish ND in most patients; the correction of even the smallest refraction diminishes ND in most patients; if the hands of the examiner are placed alongside the patient's head-like blinders-ND will diminish in most cases; in monocular examination ND may diminish. Before surgery, each patient must be informed about dysphotopsia. Therapy is gradually phased in three steps: 1) ND should be explained by showing an image of the retina, saying, that the shadow is not the border of the IOL, but probably the border of the optic nerve and that all patients get used to that within a few weeks. This calms all patients. 2) If ND lasts too long from the point of view of patients, glasses should be tried, even with very moderate refraction, until ND disappears. 3) If patients do not wish to wear glasses, even for a little while, occlusion for some weeks causes ND to disappear. Only 2 of our 77 eyes with ND out of 6,031 cataract procedures required occlusion therapy, revision surgery was not necessary in any case. PMID- 28837980 TI - [Chances and Risks of Telemedicine in Orthopaedics and Trauma Surgery]. AB - BACKGROUND: The use of information technology (IT) in health care has continuously increased. This includes software solutions for digitalisation, data storage and innovative approaches in diagnostics. The facilitation of the access to specific information, even by the patient, has changed daily clinical work. Patients inform themselves about symptoms, diagnostic methods and treatment options. This urge for information and the wish for the best treatment is summarised in the expression "patient empowerment". In some countries, the gap between do-it-yourself diagnosis and telemedicine via the telephone has already been closed. A sophisticated telemedical hotline may help to improve consultation and treatment of patients living in remote regions or rural communities. Traumatology telemedicine may also be used in trauma environments, such as disasters or mass casualties. Therefore, the purpose of this study was to assess the demand for e-health solutions among patients seeking the help of the emergency department in a trauma hospital. METHODS: A total of 255 patients (age range 18 - 75 years) were included in the study and were surveyed with the use of a questionnaire. As regards personal data, the questionnaire asked the patient about their Internet habits and about interesting topics they had researched in the world wide web. However, the questionnaire was specifically designed to ask for potential benefits and the patient's expectations for e-health solutions. Expected weaknesses and procedures for telemedical services were also included in a subsection. RESULTS: 43.5% of the patient cohort were woman and 56.5% men. The average distance to the hospital was 39.86 km. 223 patients were insured by the governmental health service providers and 32 had private insurance coverage. Aside from online shopping and online banking, the search for health topics was most frequent. The greatest fear was the lack of personal contact to the doctor (71.2%). Patients were also concerned about the safety of individual health data in privately run databanks (54.3%). On the other hand, patients were neutral towards the web-based scheduling of medical appointments. Automatic reminders for such appointments were desired via e-mail (68.8%) or SMS (66.5%). CONCLUSION: Patients are demanding mobile solutions for scheduling medical appointments, including reminders of these. Patients are keen to be involved in the communications and would like to receive overall information about their health status. Online chats or video calls with physicians are not their first choice but might be a possibility until personal presentation. PMID- 28837981 TI - [Structured Outpatient Care in a New Orthopaedic Healthcare Program: Patients' Experiences as Criterion for Quality]. AB - Background In 2015 a survey was conducted in Baden-Wurttemberg (Germany) among patients treated by orthopaedic specialists participating in a medical specialists' contract between doctors and statutory health insurance funds, in accordance with S 73c of the German Social Code, Book V (SGB V). This contract aims to improve orthopaedic care by structured cooperation between orthopaedic specialists and general practitioners, who are the central coordinators of care, and refer patients to a specialist if necessary. The program is intended to achieve patient-centred care by taking into account the physical, psychological and social aspects of the patients' orthopaedic complaints, as well as informing and motivating patients for self-management and health promoting activities. The survey was intended to receive feedback on the quality of care from the patients enrolled in this medical specialists' program, particularly concerning the specific aims of the program. A feedback report with individual results and a comparison with the overall results of all participating medical practices was sent out to those practices that provided at least 20 analysable questionnaires. Material and Methods The anonymous survey was conducted using a questionnaire specifically developed for the project. Participating practices handed out questionnaires to up to 100 patients who were enrolled in the program and consulted their orthopaedic or surgical specialist within 3 months of the start of the survey. Completed questionnaires were collected and sent to the research institute for data analysis in a sealed box. Results A total of 10,010 patients from 267 practices took part in the survey. Data analysis (including an anonymous comparison of the results of participating practices) was conducted on the basis of patients' responses from 183 practices that had obtained at least 20 completed questionnaires (8,988 patients, response rate 49.1%). Survey results are presented on doctor-patient communication, scheduling appointments, waiting times, cooperation with general practitioner, referral and treatment. On the whole, patients were satisfied with the care provided by their orthopaedic or surgical specialist. The comparison between the practices revealed significant differences in the patients' sociodemographic features and their feedback on the medical care received. Patients' evaluation of information and the counselling received from their orthopaedic/surgical specialist showed the strongest correlation with overall satisfaction. Referral by their general practitioner had a positive influence on patients' intentions to consult their orthopaedic/surgical specialist again. From the patients' point of view, doctors' information and counselling on self-help activities (e.g. eating habits, physical activity) had the largest potential for improvement. Conclusions The survey's results confirm the objectives of this new orthopaedic health care program, especially motivational counselling on adequate physical activity and self management. They provide a basis for the further development of the quality of care, in accordance with both the contractual aims and the patients' needs. PMID- 28837982 TI - Erratum: Neurological Manifestations in Familial Mediterranean Fever: Results of 22 Children from a Reference Center in Kayseri, an Urban Area in Central Anatolia, Turkey. PMID- 28837984 TI - Jeffrey M. Ellenbogen, MD. PMID- 28837985 TI - Sleep Medicine. PMID- 28837987 TI - Sleep and Epilepsy. PMID- 28837988 TI - Sleep in Autism. PMID- 28837989 TI - TBI and Sleep-Wake Disorders: Pathophysiology, Clinical Management, and Moving towards the Future. PMID- 28837990 TI - Chronic Insomnia. PMID- 28837986 TI - Sleep Disturbance, Cognitive Decline, and Dementia: A Review. PMID- 28837991 TI - The Role of Iron in Pediatric Restless Legs Syndrome and Periodic Limb Movements in Sleep. PMID- 28837992 TI - Diagnosis and Management of Narcolepsy. PMID- 28837993 TI - Clinical Overview of REM Sleep Behavior Disorder. PMID- 28837994 TI - Emergency Sleep Medicine. PMID- 28837995 TI - Microscopic and Phytochemical Comparison of the Three Leonurus Species L. cardiaca, L. japonicus, and L. sibiricus. AB - At least three Leonurus species, Leonurus cardiaca, Leonurus japonicus, and Leonurus sibiricus, are used in various traditional medicinal systems for different therapeutic purposes. The plant names "L. sibiricus" and "L. japonicus" are often used as synonyms, which causes confusion in literature and implies that several studies may be based on improperly identified plant material. To avoid further confusion, the current status of the identification of these three species is illustrated. Characteristics for their unequivocal identification are presented using stereo and light microscopy as well as HPTLC.The establishment of the species-specific anatomical, morphological, and phytochemical characters was based on reference specimens in comparison with wild collected or commercially obtained material. Morphologically, the species differed in shape and length ratio of the upper and lower lip of the corolla. Differentiating anatomical characters involve the presence, density, and dimension of trichomes on different organs. Detailed anatomical descriptions of the leaves and corollae of L. japonicus and L. sibiricus are given and compared to L. cardiaca. These three sets of characters facilitate fast and reliable identification. Complementary HPTLC fingerprints show type-specific patterns that allow the differentiation of L. japonicus from the other two species. For the distinction of L. cardiaca and L. sibiricus, flower morphology has to be considered.The presented data contribute to the quality control of the three Leonurus species and additionally meet a definite and timely need regarding the introduction of L. japonicus to the European Pharmacopoeia in addition to the already existing monograph of L. cardiaca. PMID- 28837996 TI - A Single-Center Experience with Very Low Birth Weight Infants and Focal Intestinal Perforation: Comparison of Primary Anastomosis versus Stoma Opening. AB - INTRODUCTION: We present a single-center experience with very low birth weight (VLBW) infants with focal intestinal perforation (FIP), comparing the results of primary anastomosis (PA) and stoma opening (SO). MATERIALS AND METHODS: Clinical records of VLBW infants with FIP who underwent surgery between 2006 and 2015 were reviewed. Patients were divided into two groups according to the procedure performed: limited bowel resection and PA or SO. Patients with gastric perforation or patients who underwent clip and drop were excluded. Information regarding birth weight (BW), gestational age (GA), weight at surgery (WS), number of abdominal reoperations, duration of parenteral nutrition (PN), and demise was recorded. RESULTS: In this study, 40 patients were included: 22 in PA group and 18 in SO group. BW was 865 g in PA and 778 in SO (p-value: 0.2). GA was 26.1 weeks in PA and 25.6 in SO (p-value: 0.3). WS was 1,014 g in PA and 842 in SO (p value: 0.09). Duration of surgery was 115 minutes in PA and 122 in SO (p-value: 0.67). Five patients (23%) belonging to PA group developed complications and required SO. Five patients (23%) demised in PA group and six (33%) in SO (p value: 0.2). Seventeen abdominal reoperations were performed in PA group and 22 in SO group (p-value: 0.08). CONCLUSION: Both procedures appear to be safe. When possible, PA should be performed as it reduces the number of abdominal reinterventions. PMID- 28837997 TI - Initiation of Enteral Feeding After Necrotizing Enterocolitis. AB - INTRODUCTION: Management of necrotizing enterocolitis (NEC) consists of cessation of enteral feeding, intravenous antibiotic administration, and supportive treatment. There is no evidence-based recommendation regarding when to restart feeding after a NEC episode. We performed a systematic review and meta analysis to examine the effect of timing of enteral feeding reinitiation on NEC recurrence. METHODS: MEDLINE, Embase, Google scholar, and Cochrane databases were searched. Human studies evaluating enteral feeding timing with a primary outcome of NEC recurrence were included. A total of 2,257 titles or abstracts were screened, and 47 full-text articles were analyzed. A systematic review and meta-analysis comparing NEC recurrence and other associated outcomes between early (<5 days after NEC diagnosis) and delayed (>5 days) initiation of enteral feeding after NEC were performed according to the PRISMA statement. The meta analysis data were analyzed using RevMan 5.3 to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Two retrospective observational studies met the inclusion criteria, comprising 56 cases in which enteral feeding was started early and 35 cases of delayed enteral feeding initiation. There were no randomized controlled trials (RCTs). The recurrence rates of NEC were unchanged between early (5.4%) and delayed (8.6%) enteral feeding groups (pooled OR = 0.61; 95% CI: 0.12-3.16; p = 0.56; I2 = 0%). Catheter-related sepsis (pooled OR = 0.20; 95% CI: 0.01-3.29; p = 0.26; I2 = 67%) and post-NEC stricture (pooled OR = 0.28; 95% CI: 0.07-1.18; p = 0.08; I2 = 23%) rates were not different between early and delayed enteral feeding groups. CONCLUSION: Initiating early enteral feeding, within 5 days of NEC diagnosis, is not associated with adverse outcomes, including NEC recurrence. In addition, catheter-related sepsis and post-NEC stricture rates were unchanged between early and delayed enteral feeding groups after NEC. However, the quality of the evidence from the review of literature is suboptimal. A further RCT is needed to confirm these results. PMID- 28837998 TI - Understanding Experiences of Youth Growing Up with Anorectal Malformation or Hirschsprung's Disease to Inform Transition Care: A Qualitative In-Depth Interview Study. AB - INTRODUCTION: The impact of anorectal malformation (ARM) or Hirschsprung's disease (HD) in children continues into adulthood despite early surgical correction. We aimed to explore the physical, social, and emotional impacts of these conditions on youth to inform best transition care strategies. MATERIALS AND METHODS: Eligible participants were those aged between 14 and 21 years who had undergone surgery for ARM/HD in our institution. We conducted one-on-one in depth interviews to saturation using a question guide developed from literature review and clinician expertise. Deidentified transcripts were coded by four coders (two pediatric surgeons, one psychiatrist, and one qualitative expert) for major themes using a constant comparison approach. A theoretical model for understanding the transition experience was developed using grounded theory. RESULTS: Out of 120 patients identified as eligible, 11 youth (6 males) participated in the study. Interviews lasted from 50 to 60 minutes. Four major themes emerged: (1) social support (subthemes: family as core, friends as outer support), (2) cognitive and emotional change (subthemes: realization/recognition of illness, matching emotional response), (3) impact of physical symptoms (subthemes: adverse effects of abnormal bowel habits, gaining bowel continence control leading to overall feeling of control, need to keep disease private), and (4) healthcare providers (viewed as important information sources). Themes did not differ by gender. CONCLUSION: Our model suggests that participants' understanding of bowel disease evolved over time with a "lightbulb" moment in preteens or early teens accompanied by increasing disease ownership and self management. Clinicians should independently engage with patients in late childhood to address evolving emotional and information needs and encourage increasing autonomy. Future studies should explore communication approaches to meet transition needs of patients. PMID- 28837999 TI - Protective Effects of Hypericum perforatum and Quercetin in a Rat Model of Ischemia/Reperfusion Injury of Testes. AB - PURPOSE: This study aimed to compare the protective effects of Hypericum perforatum (Hp) and quercetin, a flavonoid, against ischemia/reperfusion (I/R) injury in rat testes. MATERIALS AND METHODS: This study included 28 male Wistar albino rats that were divided into four groups. Except for the sham group, torsion was created by rotating both testes at an angle of 720 degrees clockwise for 2 hours. The Hp and quercetin groups received 25 mg/kg Hp and quercetin intraperitoneally 30 minutes before detorsion, respectively. Orchiectomy was performed for the measurement of markers of oxidative stress and histopathological examination. RESULTS: In the Hp and quercetin groups, malondialdehyde (MDA) and nitric oxide (NO) levels and total oxidant capacity were significantly lower, the glutathione level and total antioxidant status were significantly higher, and Johnsen's testis biopsy scores were significantly higher than in the torsion/detorsion group (p ? 0.001). The markers of oxidative injury were significantly lower (p ? 0.001) and total antioxidant status was significantly higher (p ? 0.001), except for glutathione (p = 0.62) in the Hp group than in the quercetin group. Johnsen's score between Hp and quercetin groups was not significantly different (p = 0.80). CONCLUSION: Both Hp and quercetin have protective effects against I/R injury of the testes, but the protective effect of Hp was found to be stronger than that of quercetin. PMID- 28838000 TI - Histological and Biochemical Evaluation of Urethral Scar following Three Different Hypospadias Repairs: An Experimental Study in Rabbits. AB - INTRODUCTION: Several urethroplasties have been employed in the surgical treatment of hypospadias. Neourethral strictures are among the most common postoperative complications that often require reoperation. MATERIALS AND METHODS: We created a hypospadias model in New Zealand white male rabbits through a hypospadias-like defect and acute repair. A total of 24 animals were randomly allocated into three groups: tubularized incised-plate urethroplasty (TIPU) group (8), perimeatal-based flap urethroplasty (Mathieu) group (8), onlay island flap urethroplasty (onlay) group (8), and corresponding surgical procedures were immediately performed to reconstruct neourethra. The rabbits were killed postoperatively at 5 days, 2 weeks, 6 weeks, and 3 months, respectively. The penile tissue was harvested for histological and biochemical investigations to evaluate the expressions of transforming growth factor beta1 (TGF-beta1) and alpha-smooth muscle actin (alpha-SMactin) in all groups. RESULTS: All rabbits were operated on uneventfully. The amount of collagen content was increased in the Mathieu and onlay groups than in the TIPU group (p < 0.05). Biochemical analysis showed that the expression of TGF-beta1 in the TIPU group was decreased compared with the two other groups at 2 or 6 weeks postoperatively (p < 0.01). The expression pattern regarding alpha-SMactin was similar at 6 weeks or 3 months postoperatively (p < 0.01). CONCLUSION: The neourethra repaired by TIPU was practically resumed to normal anatomy and scarring was less apparent than the two other groups. Therefore, TIPU is considered as a relatively rational approach for hypospadias repair. The activity of fibroblasts has been increased in the long term, which may be the pathogenesis of neourethral stricture following hypospadias repair. PMID- 28838001 TI - Postnatal Germ Cell Development in the Cryptorchid Testis: The Key to Explain Why Early Surgery Decreases the Risk of Malignancy. AB - PURPOSE: Cryptorchidism is a risk factor for testicular malignancy and surgical treatment lowers this risk. This study aimed to investigate the germ cell behavior in prepubertal cryptorchid testes using immunohistochemical markers for germ cell malignancy to understand how early orchiopexy may possibly prevent cancer developing. MATERIALS AND METHODS: Histology sections from 1,521 consecutive testicular biopsies from 1,134 boys aged 1 month to 16.5 years operated for cryptorchidism were incubated with antibodies including antiplacental-like alkaline phosphatase (PLAP), anti-Oct3/4, anti-C-kit, and anti D2-40. RESULTS: Oct3/4 and D2-40-positive germ cells are found throughout the first 2 years of life, with declining frequency thereafter. After 2 years, they should have disappeared and may indicate neoplasia. PLAP-positive cells were seen in 57 to 82% and C-kit-positive cells in 5 to 21% of cryptorchid testes between 4 and 13 years. Not until puberty did PLAP and C-kit-positive undifferentiated spermatogonial stem cells vanish. Only 0.3% of the present material had obvious prepubertal intratubular germ cell neoplasia (ITGCN) and they all had syndromic cryptorchidism. An additional three boys (0.3%) older than 2 years had weak Oct3/4 expression in undescended testes, but all cases were D2-40 negative. CONCLUSION: Prepubertal ITGCN was rare and mostly seen in syndromic cryptorchidism. In nonsyndromic cryptorchidism PLAP-positive undifferentiated spermatogonial stem cells persisted in a significant proportion of nontreated undescended testes and they will be especially sensitive to long-lasting abnormally high temperature that may be the single most important cause facilitating the accumulation of mutations during cell replication and the development of ITGCN to be prevented by orchiopexy. PMID- 28838002 TI - Pediatric Intestinal Rehabilitation and Transplantation Registry: Initial Report from a European Collaborative Registry. AB - INTRODUCTION: Short bowel syndrome (SBS) is the main cause of intestinal failure (IF) in the pediatric population. To promote the standardization of care of these patients, the registry of Pediatric Intestinal Rehabilitation and Transplantation (PIRAT) has been established. The aim of this study is to describe patients with IF using PIRAT database. MATERIALS AND METHODS: Data from two tertiary care European referral Centers registered in PIRAT (https://www.studeon.eu/pirat) were analyzed (1994-2015). Neonatal SBS-related IF was defined as need for parenteral nutrition (PN) to sustain life and growth for more than 75 days, after extensive bowel resection during neonatal period. Data included patient demographics, disease at birth, residual small intestine, and intestinal autonomy (PN on/off). RESULTS: In this study, 114 children with SBS-related IF were identified (male 60%). Median gestational age was 35.3 weeks (interquartile range [IQR]: 33.0 38.0); median birth weight was 2,440 g (IQR: 1,700-2,990). The main causes of SBS were intestinal atresia in 31 (27%), midgut volvulus in 29 (25%), necrotizing enterocolitis in 23 (20%), and gastroschisis in 12 (11%). Nine (7.9%) patients died on PN (six sepsis, two IF-associated liver disease, and one multiorgan failure). Median residual small bowel length was 46 cm (IQR: 13.0-92.5). Ileocecal valve was resected in 48 patients (42%). Intestinal autonomy was achieved in 68% patients. CONCLUSION: We present the web-based registry PIRAT and the first results of patients with IF registered from two European Centers. PIRAT could give the opportunity to create a dedicated international network (IF net) to standardize, improve, and spread the therapeutic paths for the rare and heterogeneous condition of SBS-related IF. PMID- 28838003 TI - Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death? AB - OBJECTIVE: The aim was to compare survival of patients with septic shock receiving or not hydrocortisone (HC) and to analyze the hemodynamic response to HC. STUDY DESIGN: It is a retrospective study of 62 premature neonates with septic shock (confirmed bacteremia) and/or necrotizing enterocolitis (NEC) stage 2 and above receiving inotropes with or without HC. We analyzed survival and hemodynamic response to HC. RESULTS: Thirty-nine (63%) premature neonates received HC and were compared with 23 (37%) who only received inotropes. Vasoactive index score (VAI) decreased and blood pressure, urine output, and oxygen requirements improved significantly following HC. Despite receiving more inotropes (VAI of 33 [20-53] vs 10 [8-20], p < 0.001), being more premature (26 +/- 2 vs 27 +/- 2 weeks, p = 0.02) and more frequently having NEC (64 vs 26%, p = 0.004), patients who received HC had similar survival from septic episode (death: 22% vs 41%, p = 0.12). However, patients receiving HC during their sepsis were less likely to survive at their 1-year postmenstrual age follow-up when accounted for gestational age (GA) at birth and duration of inotropes (hazard ratio 6.08 p = 0.01). CONCLUSION: HC was used in infants with increased inotropic support. HC during septic shock was associated with similar survival from episode, but with decreased survival at 1-year postmenstrual age. PMID- 28838005 TI - Implementation of Quantification of Blood Loss Does Not Improve Prediction of Hemoglobin Drop in Deliveries with Average Blood Loss. AB - OBJECTIVE: The National Partnership for Maternal Safety released a postpartum hemorrhage bundle in 2015 recommending quantification of blood loss (QBL) for all deliveries. We sought to determine whether QBL more accurately predicts hemoglobin (Hb) drop than visually estimated blood loss (EBL). STUDY DESIGN: This is a prospective observational study. Preintervention data (PRE) were collected on all deliveries between October 15, 2013 and December 15, 2013. Deliveries were included if EBL, admission Hb, and 12-hour postpartum Hb (12hrCBC) were available. QBL was implemented in July 2015. Postintervention data (POST) were collected between October 20, 2015 and December 20, 2015. A total of 500 mL EBL was predicted to result in 1 g/dL Hb drop at 12hrCBC. Student's t-test was used to compare the means. RESULTS: A total of 592 of 626 (95%) PRE and 583 of 613 (95%) POST deliveries were included. Overall, 278 (48%) POST deliveries had QBL recorded. In both PRE and POST, actual Hb drop differed from predicted by 0.6 g/dL in both groups of deliveries. When evaluating deliveries with EBL > 1,000 mL, QBL in POST was slightly better at predicting Hb drop versus EBL in PRE, although not statistically significant (0.2 vs. 0.5 g/dL, p = 0.17). CONCLUSION: In all deliveries, QBL does not predict Hb drop more accurately than EBL. The decision to perform QBL needs to balance accuracy with a resource intense measurement process. PMID- 28838004 TI - Polyhydramnios or Excessive Fetal Growth Are Markers for Abnormal Perinatal Outcome in Euglycemic Pregnancies. AB - OBJECTIVE: This study aims to investigate the perinatal outcome of fetuses with polyhydramnios and/or accelerated growth among women with a normal oral glucose challenge test (oGCT). METHODS: Singleton, nonanomalous pregnancies with an oGCT(< 130 mg/dL) at 24 to 28 weeks, who subsequently demonstrate polyhydramnios (amniotic fluid index > 24 cm or maximum vertical pocket > 8 cm) and/or accelerated growth (abdominal circumference > 95th percentile) on two-third trimester examinations were studied. Maternal demographics, delivery, and neonatal information were recorded. Cases were compared with a reference group (normal oGCT with neither abnormal third-trimester growth nor polyhydramnios). RESULTS: A total of 282 pregnancies were in the study group, and 663 were in the reference group. Deliveries in the study group were at a higher risk for birth weight (BW)% > 90%, standard deviation, and postpartum hemorrhage when compared with the reference group (adjusted odds ratio: 2.3-5.6). Pregnancies complicated by both polyhydramnios and accelerated fetal growth were significantly more likely to result in a BW% > 90% (odds ratio [OR]: 18.5; 95% confidence interval [CI]: 8.9-38.6) and PPH (OR: 4.2; 95% CI: 2.4-7.6). CONCLUSION: Pregnancies with normal oGCT that develop polyhydramnios and accelerated growth are at higher risk for maternal and neonatal complications. Isolated polyhydramnios without accelerated growth increases the risk for delivery complications but not neonatal morbidity. PMID- 28838006 TI - Perioperative Antibiotic Choice in Labored versus Unlabored Cesareans and Risk of Postcesarean Infectious Morbidity. AB - OBJECTIVE: This study aims to estimate postcesarean infectious morbidity in women receiving perioperative beta-lactam versus non-beta-lactam antibiotics. METHODS: We conducted a retrospective cohort analysis of the Maternal-Fetal Medicine Unit Cesarean Registry. The exposure was beta-lactam perioperative antibiotics versus non-beta-lactam regimens at cesarean delivery (CD). We stratified by labored versus unlabored CD. The primary composite outcome included wound infection, seroma, hematoma, endometritis, readmission due to wound complication, or debridement. Multivariable logistic regression estimated odds of wound complication by antibiotic regimen after adjusting for relevant confounders. RESULTS: Our analysis included 43,735 women who delivered via CD, 48% following labor. In both groups, 95% of women received beta-lactam antibiotics. In the labored CD group (n = 20,860), there was no significant difference in primary outcome by beta-lactam versus non-beta-lactam antibiotics (10.5 vs. 9.9%, p = 0.53). In the unlabored CD group (n = 22,875), women receiving non-beta-lactam antibiotics were more likely to experience a wound complication compared with those in the beta-lactam group (6.2 vs. 4.7%, p = 0.02, adjusted odds ratio: 1.39, 95% confidence interval: 1.08-1.80) after adjustment for clinical confounders. CONCLUSION: In unlabored CD, non-beta lactam antibiotics have a higher risk of wound complications compared with beta lactam regimens. Further study to optimize antibiotic prophylaxis for beta-lactam allergic women undergoing unlabored CD is warranted. PMID- 28838007 TI - Role of Early Pulmonary Hypertension as a Risk Factor for Late Pulmonary Hypertension in Extremely Preterm Infants. AB - OBJECTIVE: The evidence on the role of early pulmonary vascular disease (PVD) in the development of late pulmonary hypertension (PH) in the extremely preterm infants is limited. Objectives were to determine the incidence of early and late PH in extreme preterm infants and to evaluate the role of early PH as a risk factor for development of clinically detected late PH. METHODS: It was a retrospective analysis of early echocardiograms (day of life 5-14) in preterm infants, 22 to 27 weeks' gestation, admitted to the University of Iowa NICU between July 01, 2012 to June 30, 2015. Late echocardiograms performed for clinical suspicion of PH were also analyzed. RESULTS: A total of 154 infants were included in the study. Early PH was diagnosed in 31 (20%) infants. Twenty four (16%) infants were evaluated for clinically suspected PH. Eight (5%) infants were diagnosed with late PH. Infants with early PH had echocardiograms performed earlier than infants without the evidence of early PH. Early PH was not associated with the development of late PH (p = 0.99). CONCLUSION: Early PH is common among extremely preterm infants (20%). Five percent of infants had clinically detected late PH. Infants with early PH had echocardiograms performed earlier than infants without the evidence of early PH. Early PH was not associated with the development of clinically detected late PH. PMID- 28838008 TI - Maternal and Neonatal Outcomes of Induction of Labor Compared with Planned Cesarean Delivery in Women with Preeclampsia at 34 Weeks' Gestation or Longer. AB - OBJECTIVE: This study aims to compare outcomes of induction with planned cesarean in women with preeclampsia. STUDY DESIGN: A retrospective cohort study, including women with singleton pregnancies, preeclampsia (mild, severe, and superimposed), and without previous cesarean at >= 34 weeks' gestation was conducted. Outcomes included primary outcome (intensive care unit [ICU] admission, thromboembolism, transfusion, and hysterectomy), composite severe neonatal outcome (asphyxia, arterial cord pH < 7.0, hypoxic-ischemic encephalopathy, and 5-minute Apgar score < 5), neonatal ICU (NICU) admission, transient tachypnea of newborn (TTN), and respiratory distress syndrome (RDS). Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated, controlling for confounders. RESULTS: Of 5,506 women with preeclampsia at >= 34 weeks' gestation, 5,104 (92.7%) women underwent induction. Induction compared with planned cesarean was not associated with an increased risk of the primary outcome but was related to increased risks of ICU admission (aOR: 3.29; 95% CI: 1.02-10.64), and linked to decreased risks of composite neonatal outcome (aOR: 0.32; 95% CI: 0.10-0.99), NICU admission (aOR: 0.60; 95% CI: 0.43-0.84), TTN (aOR: 0.38; 95% CI: 0.22-0.64), and RDS (aOR: 0.44; 95% CI: 0.22-0.86). CONCLUSION: Induction was not associated with an increased risk of the primary outcome but was associated with an increased risk of ICU admission and decreased risks of neonatal outcomes. PMID- 28838009 TI - Maternal-Fetal Medicine Physician and Fellow Perceptions of Business in Medicine. AB - OBJECTIVE: Principles of practice management provide a foundation for clinical success and performance improvement. Scant data exist regarding maternal-fetal medicine (MFM) physicians' knowledge of these topics. We hypothesize that physicians enter practice with inadequate education in practice management. STUDY DESIGN: Surveys were emailed to members of the Society for Maternal-Fetal Medicine rating their knowledge and capabilities in practice management topics, and respondents assessed their current institution's business in the medical curriculum. RESULTS: A total of 325 (14.4%) physicians responded: 63 fellows in training and 262 MFM physician subspecialists. Practicing physicians reported learning most of their knowledge "in practice after fellowship" (85%) or "never at all" (10%). Only 3% of respondents had adequate business education during fellowship, and only 5% felt prepared to teach business principles. However, 85% of those surveyed agreed that this material should be taught during the fellowship. Among MFM subspecialists and fellows in training at institutions with fellowships, 60% reported no current curriculum for practice management, and those with current curricula reported it had "limited" or "no value" (76%). CONCLUSION: There is a significant desire for practice management curricula during MFM fellowship, and current training is insufficient. With many MFM physicians ill-prepared to teach these principles, professional education from other financial fields, and standardized education in practice management from current expert sources is needed. PMID- 28838010 TI - Supplemental Oxygen Study: A Randomized Controlled Study on the Effect of Maternal Oxygen Supplementation during Planned Cesarean Delivery on Umbilical Cord Gases. AB - OBJECTIVE: The aim was to determine the fetal umbilical blood gas effects of supplemental maternal oxygenation compared with room air (RA) during term planned cesarean delivery. METHODS: This is a prospective randomized controlled study of singleton planned cesarean deliveries randomized to receive supplemental oxygen (O2) at 10 L per minute (L/min) via facemask or RA. Umbilical cord gases were collected. The primary outcome was umbilical arterial pH level. Secondary outcomes included umbilical cord values and maternal and neonatal outcomes. Data were expressed as median +/- interquartile range (IQR). RESULTS: Seventy subjects in total were enrolled, with 65 subjects available for analysis. The median umbilical arterial pO2 was significantly increased in the supplemental O2 group (18 [13.5-20.5] mm Hg) versus RA group (16 [12-18] mm Hg), p = 0.04). The median umbilical venous pO2 was significantly increased in the supplemental O2 group (32 [26.5-36.0] mm Hg) versus RA group (28.5 [22-34.3] mm Hg), p = 0.04). There were no significant differences with other umbilical blood gas values and composite maternal or neonatal complications. CONCLUSION: Subjects with term singleton gestations receiving O2 at 10 L/min during cesarean delivery compared with RA demonstrated no significant change in umbilical cord pH values. There was a significant increase in umbilical cord arterial and venous O2 levels in those receiving O2. PMID- 28838012 TI - ? PMID- 28838011 TI - [Bio-Psycho-Social Characteristics and Therapeutic Aspects of Methamphetamine Dependent Women - Gender Specific Results of a Systematic Literature Search]. AB - SUBJECT: Compared to other illicit drugs Methamphetamine (MethA) is used more frequently by women than by men. Assuming the biopsychosocial etiology model, the dependency is based on several factors in which women and men differ significantly. Systematic gender-differentiated knowledge is missing until today. METHOD: Based on a database research (PUBMED) the review examines biological, social and psychological as well as therapeutic aspects in MethA-dependent women. RESULTS: MethA-induced cognitive disturbance appear to have severer manifestations in women than in men. MethA-addicted women's lifestyle is often characterized by active and passive (sexualized) violence. They show an increased risk behavior; i. e. unprotected sexual intercourse with several partners. Their psychological comorbidities seem to be more pronounced and especially affect anxiety disorders and depressive syndromes. CONCLUSION AND CLINICAL RELEVANCE: In women, abuse and dependence of MethA are determined by psychological as well as social factors. However, further research is needed to improve prevention, counseling and therapy. PMID- 28838013 TI - ? PMID- 28838014 TI - ? PMID- 28838015 TI - ? PMID- 28838016 TI - ? PMID- 28838017 TI - ? PMID- 28838018 TI - [Laparoscopic Resection of Urachal Cysts]. AB - Objective This video is a step-by-step description of the laparoscopic technique for the resection of urachal cysts. Indication The urachus is an embryonic extraperitoneal structure between the urinary bladder and the umbilicus. Failure of the allantois to obliterate in utero leads to urachal anomalies such as fistulas or cysts. Because of the risk of infection and malignant degeneration later in life, urachal fistulas or cysts are usually removed by surgical excision. Method The procedure is performed in supine position with 3 mm trocars in the epigastric angle, the left upper abdomen and the left middle abdomen. During the operation, the trocar in the epigastric angle will be upsized to 5 mm in order to introduce a 5 mm polymer clip applier. We use a 5 mm 30 degrees optic and a 3 mm monopolar hook for dissection. Conclusion This laparoscopic approach to removing urachal remnants allows for the involved structures to be clearly identified and accurately dissected. A complete resection of urachal remnants is facilitated by direct visualization of the entire anomaly down to the bladder dome. PMID- 28838019 TI - ? PMID- 28838020 TI - [The Relevance of Surgeon-performed Ultrasound For the Detection of Acute Appendicitis: a Review of the Literature and a Practical Diagnostic Algorithm]. AB - Background The relevance of ultrasound (US) in diagnosing acute appendicitis is controversial. The validity of US in comparison with other imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), is unclear, as is the difference between surgeon-performed ultrasound (SPUS) and radiologist-performed ultrasound (RPUS). On the basis of a review of current literature, our study aimed to develop a US-based algorithm to simplify the choice between additional diagnostic measures and surgery. Methods MEDLINE (PubMed(r)) was searched for literature published between 2010 and 2016. A total of 53 relevant full-text articles were eventually evaluated. Results Ultrasound (US) is an established part of algorithms used to diagnose acute appendicitis and has already replaced CT as the imaging technique of choice. The differences between SPUS and RPUS with regard to sensitivity, specificity, and positive and negative predictive values (PPV, NPV) are not statistically significant. The benefit of SPUS over RPUS is the simultaneous clinical assessment of the patient by the surgeon while the sonogram is performed (sonopalpation), which can increase diagnostic accuracy even further. Radiation exposure as a result of CT could be avoided or significantly reduced through the routine use of US, which is increasingly being used and is widely available. Conclusions SPUS should be the first imaging technique used to diagnose patients with suspected appendicitis. Additional diagnosis using CT or MRI is only recommended if sonographic imaging of the appendix is impossible in combination with specific clinical and laboratory criteria. A structured diagnostic approach with obligatory use of (SP)US, as described in the diagnostic algorithm, should be used for detection of acute appendicitis. PMID- 28838021 TI - [Management of Thoracic Trauma]. AB - Patients with a thoracic trauma are commonly treated by large bore chest tube thoracostomy and appropriate analgesia. The initial treatment is determined by the assessment of the emergency doctor and/or trauma surgeon. Severe intrathoracic lesions in polytrauma patients are rare. However, such injuries may be acutely life-threating. After primary stabilisation of the patients, imaging studies should be performed to assess the extent of the injuries and determine the treatment of choice. Assessment of such injuries should always be performed in a multidisciplinary team of anaesthesiologists, general surgeons, trauma surgeons and thoracic surgeons. For this reason, patients with thoracic traumas should always be treated in specialised centers. This approach reduces overall mortality and shortens the length of hospital stay. PMID- 28838022 TI - [Characteristics and Treatment Strategies for Penetrating Injuries on the Example of Gunshot and Blast Victims without Ballistic Body Armour in Afghanistan (2009 - 2013)]. AB - Much like other countries, Germany has recently seen terrorist attacks being planned, executed or prevented at the last minute. This highlights the need for expertise in the treatment of penetrating torso traumas by bullets or explosions. Data on the treatment of firearm injuries and, even more so, blast injuries often stems from crises or war regions. However, it is difficult to compare injuries from such regions with injuries from civilian terrorist attacks due to the ballistic body protection (protective vests, body armour) worn by soldiers. Methods An analysis was performed based on data from patients who were treated in the German Military Hospital Mazar-e Sharif for gunshots or injuries from explosions in the years 2009 to 2013. The data selection was based on patients with penetrating injuries to the thorax and/or abdomen. For better comparability with civilian attack scenarios, this study only included civilian patients without ballistic body protection (body armour, protective vests). Results Out of 117 analysed patients, 58 were affected by firearms and 59 by explosive injuries of the thorax or abdomen. 60% of patients had a thoracic injury, 69% had an abdominal injury, and 25.6% had combined thoracic-abdominal injuries. Blast injury patients were significantly more affected by thoracic trauma. As regards abdominal injuries, liver, intestinal, and colonic lesions were leading in number. Patients with blast injuries had significantly more injured organs and a significantly higher ISS averaging 29. 26% of the shot patients and 41% of the blast wounded patients received Damage Control Surgery (DCS). Despite a lower ISS, gunshot victims did not have a lower total number of operations per patient. Overall mortality was 13.7% (10.3% gunshot wounds, 16.7% blast injury). The highest mortality rate (25.7%) was recorded for patients with combined thoracoabdominal injuries (vs. 8.3% for thoracic and 8.7% for abdominal injuries). The ISS of deceased patients was significantly higher at 32.9%. Conclusion Patients without ballistic protection of the torso have high mortality rates, especially when suffering thoracoabdominal blast injuries. Blast injuries frequently lead to the DCS indication. The care of firearm and blast injury patients requires knowledge and competence in the damage control procedures for thorax and abdomen. PMID- 28838023 TI - [Interventional Radiological Treatment of Intercostal Artery Bleedings - a Retrospective Analysis]. AB - Background Intercostal artery bleedings are potentially fatal injuries. Apart from conservative and surgical treatment options, emergency interventional radiological treatment can also be performed. We report our experience with emergency intercostal artery embolisation. Materials and Methods Patients with acute arterial bleedings from the intercostal artery who were treated interventionally over a period of 7 years were identified retrospectively. Technical and clinical success, clinical and procedural parameters as well as overall survival were analysed. Results Between 2010 and 2017, a total of 27 embolisation procedures was performed in 24 patients (14 male, mean age 65.7 +/- 13.9 years). The majority of patients suffered from iatrogenic intercostal artery bleedings (n = 17; 70.1%; especially after thoracocentesis). In five cases, thoracoscopic surgery was attempted prior to intervention but was unsuccessful. Primary technical success was obtained in 25/27 interventions. In two cases, there was re-bleeding via collateral arteries so that re-intervention became necessary (secondary technical success). In 15 cases, secondary surgery after successful interventional treatment was necessary to evacuate the haematoma/haemothorax. Intercostal artery embolisation was clinically successful in 23/24 patients. One patient died despite technically successful embolisation, due to extensive haemothorax. One case of spinal ischaemia was observed as a major complication. Conclusion Intercostal artery embolisation is an effective interventional radiological emergency measure in patients with acute bleeding and is an alternative to surgical treatment even after attempted, unsuccessful surgery. Because of potentially severe complications, the interventional procedure should be performed by an experienced interventionalist. PMID- 28838024 TI - [Vascular Complications and Emergencies within Oncologic Abdominal Surgery - What Knowledge and Skills Are Essential for the Visceral Surgeon]. AB - Background Continuous improvements in perioperative and neoadjuvant therapy concepts nowadays permit more extensive tumor resections with curative intention. In patients with arterial or venous tumour involvement in preoperative imaging, physicians with expertise in vascular surgery should be involved in the planning phase of the operation. Unexpected vascular complications during abdominal surgery demand prompt management by the oncological surgeon. However, skills in vascular surgery are still not obligatory for the visceral surgeon in training. This topic is controversial and is therefore the focus of the present study. Patients and Methods From 2010 - 2015, a total of 126 patients underwent visceral operations involving vascular surgical interventions. Of these, 30 operations were performed as radical tumour resections. Retrospective data acquisition was performed with a minimum follow-up of 12 months. Aside from comprehensive characterisation of patients and their diseases, an outcome analysis was conducted. Furthermore, visceral surgery training programs in accordance with all 17 German federal medical associations were analysed and compared with respect to vascular surgery teaching. Results Vascular surgery was necessary in most patients, due to lesions of the mesentericoportal venous system (n = 11; 37%) and visceral arteries (n = 14; 47%). Techniques involved were mostly vascular sutures, reanastomosis or patch plastic surgery (n = 19; 63%) and venous thrombectomy/arterial embolectomy (n = 18; 60%). Hospital mortality was 3%. During follow-up, 33% of oncological patients died, whereas solely venous injury was an independent adverse prognostic variable (arterial vs. venous complications: HR 0.028; 95%-CI 0.002 - 0.442; p = 0.01). Skills in vascular surgery are optional for up to 12 months within visceral surgery training. Conclusions Intraoperative vascular complications in visceral surgical oncology are rare but pose severe risks for the patients. Their management requires basic knowledge and skills in vascular anatomy, preparation and skills to ensure immediate safe control of bleeding, as well as suture techniques and interposition grafts. Current training and specialisation in visceral surgery does not include obligatory vascular surgery teaching, so that this issue needs reevaluation. PMID- 28838025 TI - [Basic Statistical Measures for Dichotomous Data Formats: Risk, Odds, Logits, Relative Risk, Odds Ratio]. AB - In rehabilitation science dichotomous data formats are frequently used to indicate or analyze patient characteristics. Although underlying information may be more fine graded, dichotomous or dichotomized data formats like 'yes vs. no', 'salient vs. not salient' or 'capable to work vs. not capable to work' are often adequate information formats for communication or decision making purposes. Definitions and properties of risk, odds and logits - typically applied in rehabilitation research - are outlined as frequency measures of occurrence. The association of two variables can be characterized by relative risk, risk reduction, logit reduction, odds ratio and ln(odds ratio). As odds ratio is independent from base rates it reflects association strength unambiguously. Hence, important correlational measures are defined as functions of odds ratio. It will be illustrated that statistical aspects as well as aspects regarding comprehensibility of the represented information are decisive to select appropriate measures and present data information appropriately. PMID- 28838027 TI - N-Butyl-4-hydroxy-1,8-naphthalimide: A new matrix for small molecule analysis by matrix-assisted laser desorption/ionization mass spectrometry. AB - RATIONALE: The matrix plays an essential role in defining detection limits and ionization yields of analytes in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) analysis. Small molecule MALDI-MS analyses commonly suffer from the high background interference generated from matrices. Moreover, the inhomogeneous crystallization of some matrices, such as 2,5-dihydroxybenzoic acid (DHB), is to the detriment of the quality or repeatability of detection. We have found that N-butyl-4-hydroxy-1,8-naphthalimide (BHN) can provide improved performance as a matrix for small molecule analysis. METHODS: BHN was evaluated in the low-mass region for its ionization efficiency, repeatability and background interference using O-acetyl-L-carnitine hydrochloride, Abeta35-40, Abeta35-42, and oxytocin as the model analytes. In addition, the modification effects of BHN on DHB were investigated for the in situ analysis of endogenous compounds in rat brain slices using Fourier transform ion cyclotron resonance (FTICR)-MS. RESULTS: BHN is capable of ionizing small molecules, including O acetyl-L-carnitine hydrochloride and peptides, with high repeatability and low background interference signals. A low concentration of BHN (3 mM) modifies the crystallization state of DHB but still retains its ionization performance. The determination of small molecules desorbed from tissue slices was significantly improved by using a binary matrix of DHB and BHN, yielding superior signal-to noise ratio and signal intensities. CONCLUSIONS: The new matrix BHN has exhibited suitability for the analysis of small molecules. Compared with the conventional matrices, CHCA and DHB, BHN provides a clean background in the low-mass region. In combination with DHB, the ability of BHN to form highly homogenous crystalline particles shows the clear beneficial effects of BHN for the reproducibility of MS detection. PMID- 28838026 TI - [Acute Care Rehabilitation is the First Link in a Chain of Rehabilitation Interventions]. AB - An early, intensive rehabilitative therapy accelerates the recovery of the functions of patients. It contributes to a reduction in the complication rate as well as an improvement in physical and social functioning/participation in the long-term follow-up. Early rehabilitation must be strengthened on the basis of the existing structures: the creation and maintenance of adequately qualified early-stage rehabilitation facilities, at least in hospitals with priority and maximum supply contracts. Patients with long-term intensive care and polytrauma must be rehabilitated as soon as possible (intensive medical rehabilitation).Specialists in physical and rehabilitative medicine, rehabilitative geriatrists, neurologists, orthopaedists and accident surgeons and other regional physicians must cooperate in a targeted manner. Exclusion criteria using corresponding OPS codes must be canceled. Additional specialist physician groups (anesthetists and intensive care physicians, general practitioners, accident and thoracic surgeons, internists) must be sensitized to the importance of early rehabilitation.In the case of more than 500,000 hospital beds, 25,000 beds should be identified as age- and diagnosis-independent early-care beds in the country-specific bed-care plans. A cost-covering financing of the different, personal and cost-intensive early rehabilitation must be ensured. A phase model similar to the BAR guidelines for neurological-neurosurgical early rehabilitation is to be considered for other disease entities.In order to make the rehabilitation process as successful as possible, medical (acute) treatment, medical rehabilitation, occupational integration and social integration have to be understood as a holistic event and are effectively interrelated, as a continuous process which accompanies the entire disease phase-wise. For this purpose, a continuous case management or a rehabilitation guidance has to be established. PMID- 28838028 TI - Distinct in vivo target occupancy by bivalent- and induced-fit-like binding drugs. AB - BACKGROUND AND PURPOSE: Optimal drug therapy often requires long-lasting target occupancy While this attribute was usually linked to the drug's pharmacokinetic properties, the dissociation rate is now increasingly recognized to contribute as well. Nearly all the earlier pharmacokinetic-pharmacodynamic (PK-PD) simulations encompassed single-step binding drugs and focused on koff . However, 'micro'-PK mechanisms and more complex binding mechanisms like bivalent- and induced-fit binding may contribute as well. Corresponding binding models are presently explored. EXPERIMENTAL APPROACH: We compared the 24 h in vivo occupancy over time profiles of prototype bivalent- and induced-fit-like binding drugs (A and B) after one or repeated daily dosings, both without and with rebinding. Special attention was focused on the effect of each of the microscopic rate constants on the occupancy profiles and on the metrics to represent those profiles. KEY RESULTS: Although both models can be represented by the same mathematical formulation, drugs A and B display quite different occupancy profiles, even though they have the same potency. These differences can be attributed to the different effects of their microscopic rate constants on their composite koff and also on their susceptibility to experience rebinding. This also affects how the occupancy profiles of bivalent- and induced-fit-like binders progress when repeating the dosings and by changing the dosage. CONCLUSIONS AND IMPLICATIONS: Closer attention should be paid to more complex binding models in PK-PD simulations. This may help pharmacologists and medicinal chemists to improve the translation of in vitro kinetic measurements from preclinical screening programmes into clinical efficiency. PMID- 28838029 TI - Radionuclide synovectomy/synoviorthesis (RS) in patients with bleeding disorders: A review of patient and procedure demographics and functional outcomes in the ATHNdataset. AB - INTRODUCTION: Radionuclide synovectomy/synoviorthesis (RS) to manage proliferative synovitis in persons with bleeding disorders has been utilized for decades; however, aggregate US results are limited. AIM: To determine the prevalence of RS utilization, patient and procedure related demographics and functional outcomes in United States haemophilia treatment centres (HTCs). The ATHNdataset includes US patients with bleeding disorders who have authorized the sharing of their demographic and clinical information for research. METHODS: We performed a multi-institutional, observational cohort study utilizing this dataset through 2010. Cases treated with RS procedure were compared to controls within the dataset. Standard template for data collection included patient and procedure related demographics as well as functional outcomes including range of motion (ROM) of the affected joint. Normative age- and sex-matched control ROM was obtained from published data. RESULTS: In the ATHNdataset there were 19 539 control-patients and 196 case-patients treated with RS. Patients with severe haemophilia were more likely to have had RS compared to those with mild/moderate haemophilia, although the proportion of RS performed was similar between severe HA and HB. Inhibitory antibodies, HIV and hepatitis C infection were significantly more common in cases. There were 362 RS procedures captured with 94 cases having >1 RS procedures. CONCLUSIONS: Right-sided joint procedures were more prevalent than left-sided procedures. Overall, case-patients had worse joint ROM compared to control-patients and published normative values. Geographically, there was regional variation in RS utilization, as the Southeast region had the largest percent of case-patients. PMID- 28838030 TI - Digest: A replication of sexual dimorphisms in size and longevity in a simulated baboon population. PMID- 28838031 TI - Interventions for the management of CMV-associated anterior segment inflammation. AB - BACKGROUND: Cytomegalovirus (CMV) is a virus that usually affects people with reduced immunity. In recent years, this virus has been thought to cause repeated inflammation in the eye, in otherwise healthy people. This form of inflammation can cause damage to the cornea (the outer layer of the eye) or to the optic nerve by causing secondary glaucoma, or to both, leading to visual loss. OBJECTIVES: Our primary objective was to assess the effects of drug therapies for the treatment of CMV-associated anterior segment inflammation.Our secondary objective was to determine the optimal dose and duration of treatment with respect to recurrence and adverse effects. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 2), MEDLINE Ovid (1946 to 21 March 2017), Embase Ovid (1947 to 21 March 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 21 March 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 21 March 2017, and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 21 March 2017. We did not use any date or language restrictions in the electronic searches for trials. Two review authors independently reviewed the titles and abstracts. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) on the management of CMV-associated anterior segment inflammation. DATA COLLECTION AND ANALYSIS: We planned to have two review authors independently extract data from reports of included studies and analyse data based on methods expected by Cochrane. MAIN RESULTS: We did not identify any RCTs that met our inclusion criteria. AUTHORS' CONCLUSIONS: There is currently no good-quality evidence on the management of CMV-associated anterior segment inflammation. Ideally, a well-designed RCT is needed to evaluate the effectiveness of different anti-CMV medications as well as the optimal dose and duration. PMID- 28838032 TI - Orthogonal strategy development using reversed macroporous resin coupled with hydrophilic interaction liquid chromatography for the separation of ginsenosides from ginseng root extract. AB - Ginsenosides have been widely conceded as having various biological activities and are considered to be the active ingredient of ginseng. Nowadays, preparative high-performance liquid chromatography is considered to be a highly efficient method for ginseng saponins purification and preparation. However, in the process of practical application, due to the complex and varied composition of natural products and relatively simple pretreatment process, it is likely to block the chromatographic column and affect the separation efficiency and its service life. In this work, an orthogonal strategy was developed; in the first-dimension separation, reverse-phase macroporous resin was applied to remove impurities in ginseng crude extracts and classified ginseng extracts into protopanaxatriol and protopanaxadiol fractions. In the second-dimension separation, the obtained fractions were further separated by a preparative hydrophilic column, and finally yielded 11 pure compounds. Eight of them identified as ginsenoside Rh1 , Rg2 , Rd, Rc, Rb2 , Rb1 , Rg1 , and Re by standards comparison and electrospray ionization mass spectrometry. The purity of these ginsenosides was assessed by high-performance liquid chromatography with UV detection. PMID- 28838033 TI - Chemotherapy versus Best Supportive Care in Advanced Biliary Tract Carcinoma: A Multi-institutional Propensity Score Matching Analysis. AB - Purpose: Although chemotherapy is recommended by various guidelines for advanced biliary tract cancer (BTC), the evidence supporting its use over best supportive care (BSC) is limited. The aim of this study was to investigate the survival benefit of chemotherapy over that of BSC in advanced BTC patients. Materials and Methods: Advanced BTC patientswith a good performance status (Eastern CooperativeOncologyGroup [ECOG] 0-2) were eligible for the study. Data were retrospectively collected from four tertiary cancer centers and analyzed using propensity score matching (PSM). Of the 604 patients enrolled, 206 received BSC and 398 received chemotherapy. PSM analysis was performed using the following variables: age, ECOG status, carcinoembryonic antigen (CEA) level, white blood cell level, albumin level, total bilirubin level, and aspartate aminotransferase level. The sample size of each group was 164 patients after PSM. Median survival was compared between the two groups by using the Kaplan-Meier method, and prognostic factors were investigated using Cox proportional regression analysis. Results: In post-PSM analysis, the respective median survival for the chemotherapy and BSC groups was dependent on the following prognostic factors: total population, 12.0 months vs. 7.5 months (p=0.001); locally advanced disease, 16.7 months vs. 13.4 months (p=0.490); cancer antigen 19-9 <= 100 IU/mL, 12.7 months vs. 10.6 months (p=0.330); and CEA <= 3.4 ng/mL, 17.1 months vs. 10.6 months (p=0.052). Conclusion: Chemotherapy improved overall survival of patients with advanced BTC who had a good performance status. However, this survival benefit was not observed in BTC patients with locally advanced disease or with lower tumor marker. Individualized approach is needed for initiation of palliative chemotherapy in advanced BTC. PMID- 28838034 TI - Fate and effects of silver nanoparticles on early life-stage development of zebrafish (Danio rerio) in comparison to silver nitrate. AB - The use of silver nanomaterials in everyday products, such as cosmetics, textiles, certain types of packaging, etc. is increasing, leading to their release into the environment, including aquatic ecosystems. This last point initiated this investigation on the toxicological effects of Ag nanoparticles (Ag NPs) in the aquatic model organism Danio rerio. For this purpose, zebrafish larvae were exposed to 20nm bare Ag NPs at different concentrations and AgNO3, used as a positive control for Ag+ ions toxicity, at the beginning of their foraging behaviour to determine adverse effects on fitness parameters. We used secondary ion mass spectrometry (SIMS) to determine the localization of Ag and transcriptomics (microarray) to determine the toxicity at the level of gene expression in fish larvae. Exposure to Ag NPs did not result in adverse effects on survival and growth of the fish. However, SIMS analysis showed that Ag NPs mainly concentrate around liver blood vessels and in the interstitial tissue between the intestine and the liver. Gene expression profiles revealed that AgNO3 and Ag NPs impacted common pathways, suggesting similar targets, such as the phototransduction system. However, the Ag NPs showed a broader set of genes impacted following the exposure, including the circadian clock regulation and the photoreception, suggesting specific particle-related effects in addition to those induced by ions. PMID- 28838035 TI - Spatiotemporal variation of hand-foot-mouth disease in relation to socioecological factors: A multiple-province analysis in Vietnam. AB - BACKGROUND: Hand-foot-and-mouth disease (HFMD) is a significant public health issue in Asia-pacific countries. Numerous studies have examined the relationship between socio-ecological factors and HFMD however the research findings were inconsistent. This study examined the association between socio-ecologic factors and HFMD in multiple provinces across Vietnam. METHODS: We applied a spatial autoregressive model using a Bayesian framework to examine the relationship between HFMD and socio-demographic factors. We used a Generalized Linear Model (GLD) with Poisson family to examine the province-specific association between monthly HFMD and climatic factors while controlling for spatial lag, seasonality and long-term trend of HFMD. Then, we used a random-effect meta-analysis to generate pooled effect size of climate-HFMD association for regional and country scale. RESULTS: One percent increase in newborn breastfed within 1h of birth, households with permanent houses, and households accessed to safe water resulted in 1.57% (95% CI: -2.25, -0.93), 0.96% (-1.66, -0.23), and 1.13% (-2.16, -0.18) reduction in HFMD incidence, respectively. At the country-level, HFMD increased 7% (RR: 1.07; 95%CI: 1.052-1.088) and 3.1% (RR: 1.031, 95%CI: 1.024-1.039) for 1 degrees C increase in monthly temperature above 26 degrees C and 1% increase in monthly humidity above 76%. Whereas, HFMD decreased 3.1% associated with 1mm increase in monthly cumulative rainfalls. The climate-HFMD relationship was varied by regions and provinces across the country. CONCLUSIONS: The findings reflect an important implication for the climate change adaptation strategies and public-health decision, of which development of weather-based early warning systems should be considered to strengthen communicable disease prevention system. PMID- 28838036 TI - Quantification of volatile fatty acids from cattle manure via non-catalytic esterification for odour indication. AB - This report proposes a new approach to evaluate the odour nuisance of cattle manure samples from three different cattle breeds (i.e., native cattle, beef cattle, and milk cow) by means of quantification and speciation of volatile fatty acids (VFAs). To this end, non-catalytic esterification thermally induced in the presence of a porous material (silica) was undertaken, and the optimal operational parameters such as the derivatizing temperature (330 degrees C) for the maximum yield (>=99+/-0.4%) of volatile fatty acid methyl esters (VFAMEs) were established. Among the VFA species in cattle manure based on quantification of VFAs, the major species were acetic, butyric and valeric acid. Considering the odour threshold of each VFA, our experimental results suggested that the major contributors to odour nuisance were C4-5 VFA species (i.e., butyric and valeric acid). Hydrothermal treatment was performed at 150 degrees C for 0-40min to correlate the formation of VFAs with different types of cattle feed formulations. Our experimental data demonstrated that the formation of total VFAs is linearly proportional to the hydrothermal treatment duration and the total content of VFAs in native cattle, beef cattle, and milk cow manure samples reached up to ~1000, ~3200, and ~2800ppm, respectively. Thus, this study demonstrated that the degree of VFA formation is highly dependent on cattle feed formulations, which rely significantly on the protein content. Furthermore, the hydrothermal treatment provides a favourable condition for generating more VFAs. In this context, producing cattle manure into refused derived fuel (RDF) via a hydrothermal treatment is not a viable option to control odour. PMID- 28838037 TI - The superior effect of nature based solutions in land management for enhancing ecosystem services. AB - The rehabilitation and restoration of land is a key strategy to recover services goods and resources- ecosystems offer to the humankind. This paper reviews key examples to understand the superior effect of nature based solutions to enhance the sustainability of catchment systems by promoting desirable soil and landscape functions. The use of concepts such as connectivity and the theory of system thinking framework allowed to review coastal and river management as a guide to evaluate other strategies to achieve sustainability. In land management NBSs are not mainstream management. Through a set of case studies: organic farming in Spain; rewilding in Slovenia; land restoration in Iceland, sediment trapping in Ethiopia and wetland construction in Sweden, we show the potential of Nature based solutions (NBSs) as a cost-effective long term solution for hydrological risks and land degradation. NBSs can be divided into two main groups of strategies: soil solutions and landscape solutions. Soil solutions aim to enhance the soil health and soil functions through which local eco-system services will be maintained or restored. Landscape solutions mainly focus on the concept of connectivity. Making the landscape less connected, facilitating less rainfall to be transformed into runoff and therefore reducing flood risk, increasing soil moisture and reducing droughts and soil erosion we can achieve the sustainability. The enhanced eco-system services directly feed into the realization of the Sustainable Development Goals of the United Nations. PMID- 28838038 TI - Removal of lead from aqueous solution using superparamagnetic palygorskite nanocomposite: Material characterization and regeneration studies. AB - A palygorskite-iron oxide nanocomposite (Pal-IO) was synthesized in situ by embedding magnetite into the palygorskite structure through co-precipitation method. The physico-chemical characteristics of Pal-IO and their pristine components were examined through various spectroscopic and micro-analytical techniques. Batch adsorption experiments were conducted to evaluate the performance of Pal-IO in removing Pb(II) from aqueous solution. The surface morphology, magnetic recyclability and adsorption efficiency of regenerated Pal IO using desorbing agents HCl (Pal-IO-HCl) and ethylenediaminetetraacetic acid disodium salt (EDTA-Na2) (Pal-IO-EDTA) were compared. The nanocomposite showed a superparamagnetic property (magnetic susceptibility: 20.2 emu g-1) with higher specific surface area (99.8 m2 g-1) than the pristine palygorskite (49.4 m2 g-1) and iron oxide (72.6 m2 g-1). Pal-IO showed a maximum Pb(II) adsorption capacity of 26.6 mg g-1 (experimental condition: 5 g L-1 adsorbent loading, 150 agitations min-1, initial Pb(II) concentration from 20 to 500 mg L-1, at 25 degrees C) with easy separation of the spent adsorbent. The adsorption data best fitted to the Langmuir isotherm model (R2 = 0.9995) and pseudo-second order kinetic model (R2 = 0.9945). Pb(II) desorption using EDTA as the complexing agent produced no disaggregation of Pal-IO crystal bundles, and was able to preserve the composite's magnetic recyclability. Pal-IO-EDTA exhibited almost 64% removal capacity after three cycles of regeneration and preserved the nanocomposite's structural integrity and magnetic properties (15.6 emu g-1). The nanocomposite holds advantages as a sustainable material (easily separable and recyclable) for potential application in purifying heavy metal contaminated wastewaters. PMID- 28838039 TI - Bisphenol A and alternatives in thermal paper receipts - a German market analysis from 2015 to 2017. AB - Bisphenol A (BPA) was commonly used as color developer for thermal paper such as cash register receipts, labels or tickets. Therefore, thermal paper was considered by the European Food Safety Authority (EFSA) as the main source of human exposure to BPA beside epoxy based food contact materials. In this study, a German market analysis on the use of BPA and alternative color developers in thermal paper receipts is provided for the years 2015, 2016 and 2017.114 (2015), 98 (2016) and 99 (2017) samples were randomly collected and analyzed by HPLC-DAD. In summary, BPA was still the most frequently found color developer (48.2% in 2015, 46.9% in 2016 and 52.5% in 2017). The most commonly used alternative was the phenol-free substance Pergafast(r) 201 (34.2%, 33.7%, 40.4%). The bisphenol analogs bisphenol S (BPS; 11.4%, 9.2%, 6.1%) and D8 (6.1%, 7.1%, 1.0%) were less common. Another phenol-free substituent, a urea urethane compound (UU), was also detected (3.1% in 2016). Concentrations of color developers in thermal paper ranged from 1.4 to 32.4 mg/g (median values between 2.5 and 15.9 mg/g). Concentrations of BPA were found to be highest followed by BPS, UU, Pergafast(r) 201 and D8. In addition, two pharmacologically active substances, dapsone (6.0 mg/g) and tolbutamide (5.5 mg/g), were detected in a non-marketed thermal paper, that was supposed to use ascorbic acid as initial color developer. Different release experiments of the detected color developers were performed. Sensitizers 1,2-diphenoxy-ethane, 1-phenylmethoxy-naphthalene and diphenylsulfone, used frequently in the thermal paper processes, were quantified. PMID- 28838040 TI - Partition kinetics of chlorobenzenes in a sediment-water system. AB - The partition kinetics of chlorobenzenes (CBs) in a sediment-water system were studied to provide a basis for understanding the compounds' behaviour in the natural aquatic environment. A series of chlorobenzenes (CBs) 1,4-dichlorobenzene (DCB), 1,3,5-trichlorobenzene (TCB), 1,2,4,5-tetrachlorobenzene (TeCB), pentachlorobenzene (QCB), and hexachlorobenzene (HCB) were spiked to the sediment, and the concentrations of CBs both in sediment and water were measured at six different mixing time periods (0.17, 1, 4, 12, 24 and 48 h). A partition kinetics model was developed to determine kinetics rate constants. Adsorption rate constants increased (DCB 15.3; HCB 26.3 L kg-1 h-1) while desorption rate constants decreased (DCB 0.41; HCB 0.01 h-1) with KOW values. The times to reach equilibrium in the system were between 6.7 h (HCB) and 14.3 h (TeCB), with no specific pattern related to the KOW values of CBs. The kinetics of CBs were fitted to a first-order kinetics with a single-compartment model. QSAR analysis showed strong linear relationships between kinetics rate constants and physicochemical properties. PMID- 28838043 TI - Further insight into transcatheter and surgical aortic bioprosthetic valve thrombosis. PMID- 28838041 TI - The role of mineralocorticoid receptor signaling in the cross-talk between adipose tissue and the vascular wall. AB - Vascular dysfunction and impaired endothelial mediated relaxation are powerful underlying abnormalities in the pathogenesis of hypertension, coronary heart disease, and stroke. Obesity, type 2 diabetes mellitus, and other metabolic abnormalities are associated with activation of mineralocorticoid receptor (MRs) in the vasculature and adipose tissue. While MR signaling is involved in the normal physiological differentiation and maturation of adipocyte, enhanced activation of MRs also contributes to increase oxidative stress, release of pro inflammatory adipokines, and dysregulation of adipocyte autophagy. This, in turn, increases the maladaptive expansion of subcutaneous, visceral and perivascular adipose tissue, resulting in systemic and cardiovascular (CV) insulin resistance and increased CV stiffness and impaired vascular and cardiac relaxation. This review summarizes the normal role of MR activation in adipose tissues and explores the mechanisms by which excessive MR activation mediates adipose tissue inflammation and vascular dysfunction. Potential preventative and therapeutic strategies directed in the prevention of MR activation and CV disease are also discussed. PMID- 28838045 TI - Andreas R Gruntzig 40th Anniversary CP Issue. PMID- 28838044 TI - Natural history of subclinical leaflet thrombosis affecting motion in bioprosthetic aortic valves. AB - Aims: Four-dimensional volume-rendered computed tomography (4DCT) has demonstrated instances of hypo-attenuating leaflet thickening (HALT) with or without hypo-attenuation affecting motion (HAM) after transcatheter and surgical aortic valve implantation (TAVI, SAVR). The temporal pattern of evolution of these phenomena is uncertain. Methods and results: The SAVORY registry enrolled patients treated by TAVI (n = 75) or SAVR (n = 30) with two 4DCT scans fully interpretable for HALT and HAM as well as unchanged anti-thrombotic medication between the scans. Logistic regression analysis was performed to examine the evolution of HALT and HAM while accounting for demographic and baseline variables, timing of both CT scans, valve type and antithrombotic therapy. The analysis population consisted of 84 patients, in whom first and second CT scans were performed at 140 +/- 152 days and 298 +/- 141 days after valve implantation, respectively. Hypo-attenuating leaflet thickening was noted in 32 patients (38.1%), with HAM in 17 (20.2%). Both findings were dynamic, showing progression in 13 (15.5%) and regression and 9 (10.7%) patients. Compared with antiplatelet therapy, progression was less likely among patients on oral anticoagulation with vitamin-K antagonists or non-VKA oral anticoagulants (odds ratio: 0.014, P = 0.036). Maintenance on chronic oral anticoagulation was not a significant predictor of regression. These findings were similar for both transcatheter and surgical bioprosthetic aortic valves. No patients developed symptoms of valve dysfunction and leaflet thickening was not clearly associated with any clinical events. Conclusions: Subclinical leaflet thrombosis is a common finding after TAVI and SAVR, and may progress from normal leaflet over HALT to the more severe HAM. The phenomenon can develop and regress at variable intervals after valve implantation. Anticoagulants may have a protective effect against the development of HALT, but HALT can also regress without anticoagulation therapy. Registered at ClinicalTrials.gov: NCT02426307. PMID- 28838047 TI - Andreas Roland Gruntzig, the man. PMID- 28838046 TI - 40 Years on. PMID- 28838048 TI - My early days with Andreas Roland Gruntzig. PMID- 28838049 TI - The first PTCAs in Zurich, in 1977. PMID- 28838042 TI - The role of infiltrating immune cells in dysfunctional adipose tissue. AB - Adipose tissue (AT) dysfunction, characterized by loss of its homeostatic functions, is a hallmark of non-communicable diseases. It is characterized by chronic low-grade inflammation and is observed in obesity, metabolic disorders such as insulin resistance and diabetes. While classically it has been identified by increased cytokine or chemokine expression, such as increased MCP-1, RANTES, IL-6, interferon (IFN) gamma or TNFalpha, mechanistically, immune cell infiltration is a prominent feature of the dysfunctional AT. These immune cells include M1 and M2 macrophages, effector and memory T cells, IL-10 producing FoxP3+ T regulatory cells, natural killer and NKT cells and granulocytes. Immune composition varies, depending on the stage and the type of pathology. Infiltrating immune cells not only produce cytokines but also metalloproteinases, reactive oxygen species, and chemokines that participate in tissue remodelling, cell signalling, and regulation of immunity. The presence of inflammatory cells in AT affects adjacent tissues and organs. In blood vessels, perivascular AT inflammation leads to vascular remodelling, superoxide production, endothelial dysfunction with loss of nitric oxide (NO) bioavailability, contributing to vascular disease, atherosclerosis, and plaque instability. Dysfunctional AT also releases adipokines such as leptin, resistin, and visfatin that promote metabolic dysfunction, alter systemic homeostasis, sympathetic outflow, glucose handling, and insulin sensitivity. Anti-inflammatory and protective adiponectin is reduced. AT may also serve as an important reservoir and possible site of activation in autoimmune-mediated and inflammatory diseases. Thus, reciprocal regulation between immune cell infiltration and AT dysfunction is a promising future therapeutic target. PMID- 28838050 TI - Andreas Roland Gruntzig in Atlanta. PMID- 28838051 TI - Andreas Roland Gruntzig's forgotten legacy. PMID- 28838052 TI - The Stent Story: how it all started.... PMID- 28838054 TI - Mitral interventions, another heritage from Andreas Gruntzig's pioneering work. PMID- 28838053 TI - Standards defining a 'Heart Valve Centre': ESC Working Group on Valvular Heart Disease and European Association for Cardiothoracic Surgery Viewpoint. PMID- 28838055 TI - TAVI the frontier of interventional cardiology 40 years after the first ballon angioplasty. PMID- 28838056 TI - Rhythm for Life, in Germany. PMID- 28838057 TI - EuroPrevent 2017. PMID- 28838058 TI - Denise Hilfiker-Kleiner PhD. PMID- 28838059 TI - CABG in the era of modern PCI. PMID- 28838060 TI - Cardiac patients and electronic anti-theft systems. PMID- 28838061 TI - Congenital heart disease: some progress, but still the challenge of a lifetime! PMID- 28838062 TI - The Validity of Predictive Equations to Estimate 24-Hour Sodium Excretion: The MESA and CARDIA Urinary Sodium Study. AB - We examined the population distribution of urinary sodium concentrations and the validity of existing equations predicting 24-hour sodium excretion from a single spot urine sample among older adults with and without hypertension. In 2013, 24 hour urine collections were obtained from 554 participants in the Multi-Ethnic Study of Atherosclerosis and the Coronary Artery Risk Development in Young Adults study, who were aged 45-79 years and of whom 56% were female, 58% were African American, and 54% had hypertension, in Chicago, Illinois. One-third provided a second 24-hour collection. Four timed (overnight, morning, afternoon, and evening) spot urine specimens and the 24-hour collection were analyzed for sodium and creatinine concentrations. Mean 24-hour sodium excretion was 3,926 (standard deviation (SD), 1,623) mg for white men, 2,480 (SD, 1,079) mg for white women, 3,454 (SD, 1,651) mg for African-American men, and 3,397 (SD, 1,641) mg for African-American women, and did not differ significantly by hypertensive status. Mean bias (difference) in predicting 24-hour sodium excretion from the timed spot urine specimens ranged from -182 (95% confidence interval: -285, -79) to 1,090 (95% confidence interval: 966, 1,213) mg/day overall. Although the Tanaka equation using the evening specimen produced the least bias overall, no single equation worked well across subgroups of sex and race/ethnicity. A single spot urine sample is not a valid indicator of individual sodium intake. New equations are needed to accurately estimate 24-hour sodium excretion for older adults. PMID- 28838063 TI - Body Mass Index Development and Asthma Throughout Childhood. AB - Several studies have found an association between overweight and asthma, yet the temporal relationship between their onsets remains unclear. We investigated the development of body mass index (BMI) from birth to adolescence among 2,818 children with and without asthma from a Swedish birth cohort study, the BAMSE (a Swedish acronym for "children, allergy, milieu, Stockholm, epidemiology") Project, during 1994-2013. Measured weight and height were available at 13 time points throughout childhood. Asthma phenotypes (transient, persistent, and late onset) were defined by timing of onset and remission. Quantile regression was used to analyze percentiles of BMI, and generalized estimating equations were used to analyze the association between asthma phenotypes and the risk of high BMI. Among females, BMI development differed between children with and without asthma, with the highest BMI being seen among females with persistent asthma. The difference existed throughout childhood but increased with age. For example, females with persistent asthma had 2.33 times' (95% confidence interval: 1.21, 4.49) greater odds of having a BMI above the 85th percentile at age >=15 years than females without asthma. Among males, no clear associations between asthma and BMI were observed. In this study, persistent asthma was associated with high BMI throughout childhood among females, whereas no consistent association was observed among males. PMID- 28838064 TI - A Comparison of Agent-Based Models and the Parametric G-Formula for Causal Inference. AB - Decision-making requires choosing from treatments on the basis of correctly estimated outcome distributions under each treatment. In the absence of randomized trials, 2 possible approaches are the parametric g-formula and agent based models (ABMs). The g-formula has been used exclusively to estimate effects in the population from which data were collected, whereas ABMs are commonly used to estimate effects in multiple populations, necessitating stronger assumptions. Here, we describe potential biases that arise when ABM assumptions do not hold. To do so, we estimated 12-month mortality risk in simulated populations differing in prevalence of an unknown common cause of mortality and a time-varying confounder. The ABM and g-formula correctly estimated mortality and causal effects when all inputs were from the target population. However, whenever any inputs came from another population, the ABM gave biased estimates of mortality and often of causal effects even when the true effect was null. In the absence of unmeasured confounding and model misspecification, both methods produce valid causal inferences for a given population when all inputs are from that population. However, ABMs may result in bias when extrapolated to populations that differ on the distribution of unmeasured outcome determinants, even when the causal network linking variables is identical. PMID- 28838065 TI - Microvesicles derived from normal and multiple myeloma bone marrow mesenchymal stem cells differentially modulate myeloma cells' phenotype and translation initiation. AB - Multiple myeloma (MM) cells' interaction with the bone marrow (BM) microenvironment critically hinders disease therapy. Previously, we showed that MM co-culture with BM-mesenchymal stem cells (MSCs) caused co-modulation of translation initiation (TI) and cell phenotype and implicated secreted components, specifically microvesicles (MVs). Here, we studied the role of the BM MSCs [normal donors (ND) and MM] secreted MVs in design of MM cells' phenotype, TI and signaling. BM-MSCs' MVs collected from BM-MSCs (MM/ND) cultures were applied to MM cell lines. After MVs uptake confirmation, the MM cells were assayed for viability, cell count and death, proliferation, migration, invasion, autophagy, TI status (factors, regulators, targets) and MAPKs activation. The interdependence of MAPKs, TI and autophagy was determined (inhibitors). ND-MSCs MVs' treated MM cells demonstrated a rapid (5 min) activation of MAPKs followed by a persistent decrease (1-24 h), while MM-MSCs MVs' treated cells demonstrated a rapid and continued (5 min-24 h) activation of MAPKs and TI (?25-200%, P < 0.05). Within 24 h, BM-MSCs MVs were internalized by MM cells evoking opposite responses according to MVs origin. ND-MSCs' MVs decreased viability, proliferation, migration and TI (?15-80%; P < 0.05), whereas MM-MSCs' MVs increased them (?10-250%, P < 0.05). Inhibition of MAPKs in MM-MSCs MVs treated MM cells decreased TI and inhibition of autophagy elevated cell death. These data demonstrate that BM-MSCs MVs have a fundamental effect on MM cells phenotype in accordance with normal or pathological source implemented via TI modulation. Future studies will aim to elucidate the involvement of MVs-MM receptor ligand interactions and cargo transfer in our model. PMID- 28838067 TI - Zebrafish Models of Human Disease: Gaining Insight into Human Disease at ZFIN. AB - The Zebrafish Model Organism Database (ZFIN; https://zfin.org) is the central resource for genetic, genomic, and phenotypic data for zebrafish (Danio rerio) research. ZFIN continuously assesses trends in zebrafish research, adding new data types and providing data repositories and tools that members of the research community can use to navigate data. The many research advantages and flexibility of manipulation of zebrafish have made them an increasingly attractive animal to model and study human disease.To facilitate disease-related research, ZFIN developed support to provide human disease information as well as annotation of zebrafish models of human disease. Human disease term pages at ZFIN provide information about disease names, synonyms, and references to other databases as well as a list of publications reporting studies of human diseases in which zebrafish were used. Zebrafish orthologs of human genes that are implicated in human disease etiology are routinely studied to provide an understanding of the molecular basis of disease. Therefore, a list of human genes involved in the disease with their corresponding zebrafish ortholog is displayed on the disease page, with links to additional information regarding the genes and existing mutations. Studying human disease often requires the use of models that recapitulate some or all of the pathologies observed in human diseases. Access to information regarding existing and published models can be critical, because they provide a tractable way to gain insight into the phenotypic outcomes of the disease. ZFIN annotates zebrafish models of human disease and supports retrieval of these published models by listing zebrafish models on the disease term page as well as by providing search interfaces and data download files to access the data. The improvements ZFIN has made to annotate, display, and search data related to human disease, especially zebrafish models for disease and disease associated gene information, should be helpful to researchers and clinicians considering the use of zebrafish to study human disease. PMID- 28838068 TI - Rat Genome and Model Resources. AB - Rats remain a major model for studying disease mechanisms and discovery, validation, and testing of new compounds to improve human health. The rat's value continues to grow as indicated by the more than 1.4 million publications (second to human) at PubMed documenting important discoveries using this model. Advanced sequencing technologies, genome modification techniques, and the development of embryonic stem cell protocols ensure the rat remains an important mammalian model for disease studies. The 2004 release of the reference genome has been followed by the production of complete genomes for more than two dozen individual strains utilizing NextGen sequencing technologies; their analyses have identified over 80 million variants. This explosion in genomic data has been accompanied by the ability to selectively edit the rat genome, leading to hundreds of new strains through multiple technologies. A number of resources have been developed to provide investigators with access to precision rat models, comprehensive datasets, and sophisticated software tools necessary for their research. Those profiled here include the Rat Genome Database, PhenoGen, Gene Editing Rat Resource Center, Rat Resource and Research Center, and the National BioResource Project for the Rat in Japan. PMID- 28838066 TI - Mouse Genome Informatics (MGI) Resource: Genetic, Genomic, and Biological Knowledgebase for the Laboratory Mouse. AB - The Mouse Genome Informatics (MGI) Resource supports basic, translational, and computational research by providing high-quality, integrated data on the genetics, genomics, and biology of the laboratory mouse. MGI serves a strategic role for the scientific community in facilitating biomedical, experimental, and computational studies investigating the genetics and processes of diseases and enabling the development and testing of new disease models and therapeutic interventions. This review describes the nexus of the body of growing genetic and biological data and the advances in computer technology in the late 1980s, including the World Wide Web, that together launched the beginnings of MGI. MGI develops and maintains a gold-standard resource that reflects the current state of knowledge, provides semantic and contextual data integration that fosters hypothesis testing, continually develops new and improved tools for searching and analysis, and partners with the scientific community to assure research data needs are met. Here we describe one slice of MGI relating to the development of community-wide large-scale mutagenesis and phenotyping projects and introduce ways to access and use these MGI data. References and links to additional MGI aspects are provided. PMID- 28838070 TI - The Role of the IACUC in the Design and Conduct of Animal Experiments that Contribute to Translational Success. AB - Institutional Animal Care and Use Committees (IACUCs) have a mandated role under the Animal Welfare Act and under Public Health Service Policy to assure the ethical and humane use of research animals in experiments conducted in the United States. The IACUC by virtue of its mandated functions is well positioned to help nurture an institutional culture of optimized animal use since this Committee is often responsible in large part for the culture of animal use that evolves within an institution. In addition to fostering a culture of humane care for research animals and a culture of working with the concepts of the 3Rs (refinement, reduction, replacement), the IACUC can help foster a culture of optimized animal use that encourages high quality reproducible studies that contribute to translational success. In part this is achieved when the IACUC is successful in encouraging interdisciplinary collaboration early and often within the animal use community it serves. Unfortunately in some instances the institutional research community may envisage the IACUC as a bureaucratic burden, regulatory necessity, and compliance tool more than a group that enhances the methodology and quality of animal experiments. A well-functioning IACUC should strive to nurture an institutional culture that places value in enhancing the scientific quality of research to help assure the reproducibility of animal studies and translational success of animal models. This is integral to both high quality science as well as excellence in the supporting animal care and use. PMID- 28838069 TI - Genomic Tools for the Use of Nonhuman Primates in Translational Research. AB - Nonhuman primates (NHPs) are important preclinical models for understanding the etiology of human diseases and for developing therapies and vaccines to cure or eliminate disease. Most human diseases have genetic components. Therefore, to be of maximal utility, the NHP species used for translational science should be as well characterized in regard to their genome and transcriptome as possible. This article reviews the current status of genomic information for the five NHP species used most often in translational research: rhesus macaque, cynomolgus macaque, vervet (African green) monkey, baboon, and marmoset NHP. These species have published whole genome sequences (with the exception of the baboon) and relatively well-characterized transcriptomes. Some have also been characterized in regard to specific genetic loci that are particularly related to translational concerns, such as the major histocompatability complex and the cytochrome P40 genes. Genomic resources to aid in stratifying captive populations in regard to genetic and phenotypic characteristics have been developed as an aid to enhancing reproducibility and facilitating more efficient use of animals. Taken together, the current genomic resources and numerous studies currently underway to improve them should enhance the value of NHPs as preclinical models of human disease. PMID- 28838071 TI - Informatics Support for Basic Research in Biomedicine. AB - Informatics methodologies exploit computer-assisted techniques to help biomedical researchers manage large amounts of information. In this paper, we focus on the biomedical research literature (MEDLINE). We first provide an overview of some text mining techniques that offer assistance in research by identifying biomedical entities (e.g., genes, substances, and diseases) and relations between them in text.We then discuss Semantic MEDLINE, an application that integrates PubMed document retrieval, concept and relation identification, and visualization, thus enabling a user to explore concepts and relations from within a set of retrieved citations. Semantic MEDLINE provides a roadmap through content and helps users discern patterns in large numbers of retrieved citations. We illustrate its use with an informatics method we call "discovery browsing," which provides a principled way of navigating through selected aspects of some biomedical research area. The method supports an iterative process that accommodates learning and hypothesis formation in which a user is provided with high level connections before delving into details.As a use case, we examine current developments in basic research on mechanisms of Alzheimer's disease. Out of the nearly 90 000 citations returned by the PubMed query "Alzheimer's disease," discovery browsing led us to 73 citations on sortilin and that disorder. We provide a synopsis of the basic research reported in 15 of these. There is wide-spread consensus among researchers working with a range of animal models and human cells that increased sortilin expression and decreased receptor expression are associated with amyloid beta and/or amyloid precursor protein. PMID- 28838072 TI - Mycoplasma genitalium: Accurate Diagnosis Is Necessary for Adequate Treatment. AB - Background: Mycoplasma genitalium is very difficult to grow in culture but has been more able to be studied for disease associations since the advent of research molecular amplification assays. Polymerase chain reaction (PCR) and other molecular assays have demonstrated an association with adverse disease outcomes, such as urethritis or nongonococcal urethritis in men and adverse reproductive sequelae in women-for example, cervicitis, endometritis, and pelvic inflammatory disease (PID), including an association with risk for human immunodeficiency virus. The lack of commercially available diagnostic assays has limited widespread routine testing. Increasing reports of high rates of resistance to azithromycin detected in research studies have heightened the need available commercial diagnostic assays as well as standardized methods for detecting resistance markers. This review covers available molecular methods for the diagnosis of M. genitalium and assays to predict the antibiotic susceptibility to azithromycin. Methods: A PubMed (US National Library of Medicine and National Institutes of Health) search was conducted for literature published between 2000 and 2016, using the search terms Mycoplasma genitalium, M. genitalium, diagnosis, and detection. Results: Early PCR diagnostic tests focused on the MPa adhesion gene and the 16S ribosomal RNA gene. Subsequently, a transcription-mediated amplification assay targeting ribosomes was developed and widely used to study the epidemiology of M. genitalium. Newer methods have proliferated and include quantitative PCR for organism load, AmpliSens PCR, PCR for the pdhD gene, a PCR-based microarray for multiple sexually transmitted infections, and multiplex PCRs. None yet are cleared by the Food and Drug Administration in the United States, although several assays are CE marked in Europe. As well, many research assays, including PCR, gene sequencing, and melt curve analysis, have been developed to detect the 23S ribosomal RNA gene mutations that confer resistance to azithromycin. One recently developed assay can test for both M. genitalium and azithromycin resistance mutations at the same time. Conclusions: It is recommended that more commercial assays to both diagnose this organism and guide treatment choices should be developed and made available through regulatory approval. Research is needed to establish the cost effectiveness of routine M. genitalium testing in symptomatic patients and screening in all individuals at high risk of acquiring and transmitting sexually transmitted infections. PMID- 28838073 TI - New Horizons in Mycoplasma genitalium Treatment. AB - Mycoplasmagenitalium is an important sexually transmitted pathogen responsible for both male and female genital tract disease. Appreciation of its significance in human disease has been hampered by its slow growth in culture, difficulty in isolating it, and lack of commercial molecular-based tests for rapid detection. Comparatively few in vitro data on antimicrobial susceptibility are available due to the scarcity of clinical isolates and difficulty in performing susceptibility tests to determine minimum inhibitory concentrations for M. genitalium. Antimicrobial agents that inhibit protein synthesis such as macrolides, along with fluoroquinolones that inhibit DNA replication, have been the treatments of choice for M. genitalium infections. Even though international guidelines recommend azithromycin as first-line treatment, rapid spread of macrolide resistance as well as emergence of quinolone resistance has occurred. Increasing rates of treatment failure have resulted in an urgent need for new therapies and renewed interest in other classes such as aminocyclitols, phenicols, and streptogramins as treatment alternatives. Limited data for new investigational antimicrobials such as the ketolide solithromycin suggest that this drug may eventually prove useful in management of some resistant M. genitalium infections, although it is not likely to achieve cure rates >80% in macrolide-resistant strains, in a similar range as recently reported for pristinamycin. However, agents with completely new targets and/or mechanisms that would be less likely to show cross-resistance with currently available drugs may hold the greatest promise. Lefamulin, a pleuromutilin, and new nonquinolone topoisomerase inhibitors are attractive possibilities that require further investigation. PMID- 28838075 TI - Mycoplasma genitalium From Basic Science to Public Health: Summary of the Results From a National Institute of Allergy and Infectious Disesases Technical Consultation and Consensus Recommendations for Future Research Priorities. AB - This article lays out the research priorities for Mycoplasma genitalium research agreed upon by the participants in a 2016 National Institutes of Allergy and Infectious Diseases-funded Technical Consultation focused on this organism. The state of current knowledge concerning the microbiology, epidemiology, clinical manifestations of infection, treatment, and public health significance of M. genitalium reviewed at the meeting is described in detail in the individual articles included in this supplemental edition of the Journal of Infectious Diseases. Here we summarize the points made in these articles most relevant to the formulation of the research priorities listed in this article. The most important recommendation resulting from this Technical Consultation is the initiation of clinical trials designed to determine definitively whether screening for and treatment of M. genitalium infections in women and their sexual partners improve reproductive health in women and/or prevent human immunodeficiency virus transmission. PMID- 28838074 TI - Mycoplasma genitalium Infection in Men. AB - Mycoplasmagenitalium is one of the major causes of nongonococcal urethritis (NGU) worldwide but an uncommon sexually transmitted infection (STI) in the general population. The risk of sexual transmission is probably lower than for Chlamydia trachomatis. Infection in men is usually asymptomatic and it is likely that most men resolve infection without developing disease. The incubation period for NGU caused by Mycoplasma genitalium is probably longer than for NGU caused by C. trachomatis. The clinical characteristics of symptomatic NGU have not been shown to identify the pathogen specific etiology. Effective treatment of men and their sexual partner(s) is complicated as macrolide antimicrobial resistance is now common in many countries, conceivably due to the widespread use of azithromycin 1 g to treat STIs and the limited availability of diagnostic tests for M. genitalium. Improved outcomes in men with NGU and better antimicrobial stewardship are likely to arise from the introduction of diagnostic M. genitalium nucleic acid amplification testing including antimicrobial resistance testing in men with symptoms of NGU as well as in their current sexual partner(s). The cost effectiveness of these approaches needs further evaluation. The evidence that M. genitalium causes epididymo-orchitis, proctitis, and reactive arthritis and facilitates human immunodeficiency virus transmission in men is weak, although biologically plausible. In the absence of randomized controlled trials demonstrating cost effectiveness, screening of asymptomatic men cannot be recommended. PMID- 28838076 TI - Mycoplasma genitalium From Basic Science to Public Health Implications: Results of a National Institute of Allergy and Infectious Diseases Technical Consultation. PMID- 28838077 TI - The Unique Microbiology and Molecular Pathogenesis of Mycoplasma genitalium. AB - Mycoplasma genitalium is increasingly appreciated as a common cause of sexually transmitted disease syndromes, including urethritis in men and cervicitis, endometritis, pelvic inflammatory disease, and possibly preterm birth, tubal factor infertility, and ectopic pregnancy in women. Despite these disease associations, which parallel those of Chlamydia trachomatis and Neisseria gonorrhoeae, the mechanisms by which this pathogen elicits inflammation, causes cellular damage, and persists in its only natural host (humans) are unique and are not fully understood. The purpose of this review is to briefly provide a historical background on the discovery, microbiology, and recognition of M. genitalium as a pathogen, and then summarize the recent advances in our understanding of the molecular biology and pathogenesis of this unique urogenital organism. Collectively, the basic scientific discussions herein should provide a framework for understanding the clinical and epidemiological outcomes described in the accompanying articles in this supplemental issue. PMID- 28838078 TI - Mycoplasma genitalium in Women: Current Knowledge and Research Priorities for This Recently Emerged Pathogen. AB - Health consequences of sexually transmitted diseases disproportionately affect women, making it important to determine whether newly emerged pathogens cause sequelae. Although the pathogenic role of Mycoplasma genitalium in male urethritis is clear, fewer studies have been conducted among women to determine its pathogenic role in the female reproductive tract. Pelvic inflammatory disease (PID) is an important cause of infertility and ectopic pregnancy, and Chlamydia trachomatis and Neisseria gonorrhoeae are recognized microbial causes. Emerging data demonstrate an association between M. genitalium and PID, and limited data suggest associations with infertility and preterm birth, yet the attributable risk for female genital tract infections remains to be defined. Further investigations are needed to better define the impact of M. genitalium on women's reproductive health. Importantly, prospective studies evaluating whether screening programs and targeted treatment of M. genitalium improve reproductive outcomes in women are necessary to guide public health policy for this emerging pathogen. PMID- 28838079 TI - Developing a Public Health Response to Mycoplasma genitalium. AB - Although Mycoplasma genitalium is increasingly recognized as a sexually transmitted pathogen, at present there is no defined public health response to this relatively newly identified sexually transmitted infection. Currently available data are insufficient to justify routinely screening any defined population for M. genitalium infection. More effective therapies, data on acceptability of screening and its impact on clinical outcomes, and better information on the natural history of infection will likely be required before the value of potential screening programs can be adequately assessed. Insofar as diagnostic tests are available or become available in the near future, clinicians and public health agencies should consider integrating M. genitalium testing into the management of persons with sexually transmitted infection (STI) syndromes associated with the infection (ie urethritis, cervicitis, and pelvic inflammatory disease) and their sex partners. Antimicrobial-resistant M. genitalium is a significant problem and may require clinicians and public health authorities to reconsider the management of STI syndromes in an effort to prevent the emergence of ever more resistant M. genitalium infections. PMID- 28838080 TI - Core Themes in Music Therapy Clinical Improvisation: An Arts-Informed Qualitative Research Synthesis. AB - Background: Although clinical improvisation continues to be an important focus of music therapy research and practice, less attention has been given to integrating qualitative research in this area. As a result, this knowledge base tends to be contained within specific areas of practice rather than integrated across practices and approaches. Objective: This qualitative research synthesis profiles, integrates, and re-presents qualitative research focused on the ways music therapists and clients engage in, and make meaning from, clinical improvisation. Further, as a conduit for broadening dialogues, opening up this landscape fully, and sharing our response to the analysis and interpretation process, we present an arts-informed re-presentation of this synthesis. Methods: Following an eight-step methodological sequence, 13 qualitative studies were synthesized. This included reciprocal and refutational processes associated with synthesizing the primary studies, and additional steps associated with an arts informed representation. Findings: Three themes, professional artistry, performing self, and meaning-making, are presented. Each theme is explored and exemplified through the selected articles, and discussed within a larger theoretical framework. An artistic re-presentation of the data is also presented. Conclusions: Music therapists use complex frameworks through which to engage clients in, and make meaning from, improvisational experiences. Artistic representation of the findings offers an added dimension to the synthesis process, challenging our understanding of representation, and thereby advancing synthesis methodology. PMID- 28838081 TI - US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K. AB - Vitamin K plays important biological roles in maintaining normal blood coagulation, bone mineralization, soft tissue physiology, and neurological development. Menaquinone-7 is a form of vitamin K2 that occurs naturally in some animal-derived and fermented foods. It is also available as an ingredient of dietary supplements. Menaquinone-7 has greater bioavailability than other forms of vitamin K, which has led to increasing sales and use of menaquinone-7 supplements. This special article reviews the chemistry, nomenclature, dietary sources, intake levels, and pharmacokinetics of menaquinones, along with the nonclinical toxicity data available and the data on clinical outcomes related to safety (adverse events). In conclusion, the data reviewed indicate that menaquinone-7, when ingested as a dietary supplement, is not associated with any serious risk to health or with other public health concerns. On the basis of this conclusion, US Pharmacopeia monographs have been developed to establish quality standards for menaquinone-7 as a dietary ingredient and as a dietary supplement in various dosage forms. PMID- 28838082 TI - Effect of school wellness policies and the Healthy, Hunger-Free Kids Act on food consumption behaviors of students, 2006-2016: a systematic review. AB - Context: Federal regulation mandates that the US National School Lunch Program nutrition standards align with the Dietary Guidelines for Americans. As students consume a substantial proportion of their nutrition during school lunch, increasing access to healthy foods is proposed to improve student dietary outcomes. The purpose of this review is to assess whether policy changes impacted food-consumption behaviors of students during periods when (1) school wellness policies were implemented (2006-2007); (2) the Healthy, Hunger-Free Kids Act was passed (2010-2012); and (3) the Healthy, Hunger-Free Kids Act was implemented (2012-present). PubMed, Web of Science, and Science Direct were searched for primary research studies. Policy evaluations and interventions implemented from 2006 to 2016 were included. A total of 31 studies evaluating plate waste, dietary intake, food selection, and/or purchasing patterns were identified and reviewed. Fourteen of 19 intervention and longitudinal observation studies reported improved food-consumption behaviors (increased selection, intake, and sales of healthy foods, and decreased plate waste). Only 2 of 12 one-time observation studies reported food-consumption behaviors meeting target nutrition standards. The majority of studies indicated that increasing access to healthy foods during school lunch improved students' dietary intakes. Challenges related to study design, adaptation period, quality of foods, and policy implementation likely affect a school lunch program's ability to impact students' food-consumption behaviors. Ongoing evaluation of these programs is warranted. PMID- 28838083 TI - Health impact of childhood and adolescent soy consumption. AB - Soyfoods have been intensely researched, primarily because they provide such abundant amounts of isoflavones. Isoflavones are classified as both plant estrogens and selective estrogen receptor modulators. Evidence suggests that these soybean constituents are protective against a number of chronic diseases, but they are not without controversy. In fact, because soyfoods contain such large amounts of isoflavones, concerns have arisen that these foods may cause untoward effects in some individuals. There is particular interest in understanding the effects of isoflavones in young people. Relatively few studies involving children have been conducted, and many of those that have are small in size. While the data are limited, evidence suggests that soy does not exert adverse hormonal effects in children or affect pubertal development. On the other hand, there is intriguing evidence indicating that when soy is consumed during childhood and/or adolescence, risk of developing breast cancer is markedly reduced. Relatively few children are allergic to soy protein, and most of those who initially are outgrow their soy allergy by 10 years of age. The totality of the available evidence indicates that soyfoods can be healthful additions to the diets of children, but more research is required to allow definitive conclusions to be made. PMID- 28838084 TI - Comparative analysis of recurrent events after presentation with an index myocardial infarction or ischaemic stroke. AB - Aims: Acute myocardial infarction (AMI) and stroke are important causes of mortality and morbidity. Our aims are to determine the comparative epidemiology of AMI and ischaemic stroke; and examine the differences in cardiovascular outcomes or mortality occurring after an AMI or stroke. Methods and results: The Singapore National Registry of Diseases Office collects countrywide data on AMI, stroke, and mortality. Index events of AMI and ischaemic stroke between 2007 and 2012 were identified. Patients were then matched for occurrences of subsequent AMI, stroke, or death within 1-year of the index event. There were 33 222 patients with first-ever AMI and 20 982 with first-ever stroke. AMI patients were significantly more likely to be men (66.3% vs. 56.9%), non-Chinese (32.1% vs. 24.1%), and smokers (43.1% vs. 38.6%), but less likely to have hypertension (65.6% vs. 79%) and hyperlipidaemia (61.1% vs. 65.5%), compared with stroke patients. In total 6.8% of the AMI patients had recurrent AMI, whereas 4.8% of the stroke patients had recurrent stroke within 1 year; 31.7% of the AMI patients died, whereas 17.1% of the ischaemic stroke patients died within 1 year. Older age, Malay ethnicity, and diabetes mellitus were statistically significant risk factors for all-cause mortality and for the composite endpoint of AMI, stroke, and all-cause mortality, at 1 year. Conclusions: Risk profiles of patients with AMI and stroke are significantly different. Patients suffer recurrent events in vascular territories similar to the index event. Age and diabetes mellitus are significant predictors of recurrent vascular events and mortality. PMID- 28838085 TI - Long-term survival and fate of the leg in de novo intermittent claudication. AB - Aims: The long-term life expectancy and fate of the leg, including progression rate to critical limb ischaemia (CLI), were analysed in de novo patients with intermittent claudication (IC). Methods and results: A prospective cohort study was performed in 1107 patients with de novo IC. The endpoints were overall survival (OS), freedom from major adverse cardiovascular events (MACE), freedom from major adverse cardiovascular and limb events (MACLE), and fate of the leg. The 5-, 10-, 15-, and 20-year rates were 73.3, 47.8, 28.1, and 14.9% for OS, and 63.0, 35.6, 18.5, and 5.7% for freedom from MACE, respectively. In Cox multivariable analysis, body mass index, diabetes, haemodialysis, and C-reactive protein (CRP) level were correlated with OS (P < 0.05). Ankle brachial pressure index, diabetes, coronary artery disease, haemodialysis, and CRP level were independently correlated with freedom from MACE and MACLE. Statins improved mortality, MACE, and MACLE (P < 0.05). Revascularization did not improve mortality and MACE, and femoropopliteal revascularization increased MACLE (P < 0.05). There was no deterioration of claudication in 881 patients (79.6%). Worsening claudication was noted in 211 patients (14.8% per 5 years), and 15 patients (1.1% per 5 years) worsened to CLI. Diabetes and haemodialysis were independent predictors of CLI. A history of cerebral infarction and femoropopliteal revascularization tended to increase CLI. Conclusions: Life expectancy in patients with IC was poor, but the rate of IC progression to CLI was low. Statins improved mortality and morbidity, revascularization did not improve mortality and MACE, and femoropopliteal revascularization reduced freedom from MACLE with a risk of CLI. PMID- 28838087 TI - Quality of life following coronary artery bypass graft surgery vs. percutaneous coronary intervention in diabetics with multivessel disease: a five-year registry study. AB - Aims: The aim of this study is to investigate the long-term relationship between revascularization technique and health status in diabetics with multivessel disease. Methods and results: Using the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry, we captured 1319 diabetics with multivessel disease requiring revascularization for an acute coronary syndrome (January 2009-December 2012) and reported health status using the Seattle Angina Questionnaire (SAQ) at baseline, 1, 3 and 5-years [599 underwent coronary artery bypass grafting (CABG); 720 underwent percutaneous coronary intervention (PCI)]. Adjusted analyses were performed using a propensity score-matching technique. After adjustment (including baseline SAQ domain scores), 1-year mean (95% CI) SAQ scores (range 0-100 with higher scores reflecting improved health status) were significantly greater in selected domains for CABG compared to PCI (exertional capacity: 81.7 [79.5-84.0] vs. 78.8 [76.5 81.0], P = 0.07; angina stability: 83.1 [80.4-85.9] vs. 75.0 [72.3-77.8], P < 0.001]; angina frequency 93.2 [91.6-95.0] vs. 90.0 [87.8-91.3], P = 0.003; treatment satisfaction: 93.6 [92.2-94.9] vs. 90.8 [89.2-92.0], P = 0.003; quality of life [QOL]: 83.8 [81.7-85.8] vs. 77.2 [75.2-79.2] P < 0.001). At 3-years, these benefits were attenuated (exertional capacity: 79.3 [76.9-81.7] vs. 78.7 [76.3-81.1], P = 0.734; angina stability 79.3 [76.3-82.3] vs. 75.5 [72.5-78.5], P = 0.080; angina frequency: 93.2 [91.3-95.1] vs. 90.9 [89.0-92.8], P = 0.095; treatment satisfaction: 92.5 [91.0-94.0] vs. 91.5 [90.0-93.0] P = 0.382; QOL: 83.2 [81.1-85.2] vs. 80.3 [78.2-82.4], P = 0.057). At 5-years, majority of domains were similar (exertional capacity: 77.8 [75.0-80.6] vs. 76.3 [73.2-79.3], P = 0.482; angina stability: 78.0 [74.8-81.2] vs. 74.8 [71.4-78.2], P = 0.175; angina frequency: 94.2 [92.3-96.0] vs. 90.9 [89.0-92.9], P = 0.018; treatment satisfaction: 93.7 [92.2-95.1] vs. 92.2 [90.6-93.7], P = 0.167; QOL: 84.1 [82.0 86.3] vs. 81.1 [78.8-83.4], P = 0.058). Majority in both groups remained angina free at 5-years (75.0% vs. 70.3%, P = 0.15). Conclusion: Improvements in health status with CABG compared with PCI were not sustained long-term. This temporal sequence should be considered when contemplating a revascularization strategy in diabetics with multivessel disease. PMID- 28838086 TI - Incidence of myocardial infarction in pregnancy: a systematic review and meta analysis of population-based studies. AB - Aims: Cardiac disease is one of the leading causes of indirect maternal death, and myocardial infarction (MI) is one of its most common aetiologies. The objectives of this systematic review and meta-analysis were to characterize the incidence of pregnancy-associated MI (PAMI), as well as the maternal mortality and the case-fatality rates due to PAMI. Methods and results: Articles were obtained by searching electronic databases, bibliographies and conference proceedings with no language or date restrictions. Two reviewers independently selected population-based cohort and case-control studies reporting on incidence, mortality and case-fatality rates for pregnancy-associated MI. Meta-analysis was performed to estimate pooled maternal incidence, mortality and case-fatality rates. Meta-regression was performed to explore heterogeneity. Based on 17 included studies, the pooled incidence of PAMI and maternal mortality from PAMI were 3.34 (2.09-4.58) and 0.20 (0.10-0.29) per 100 000 pregnancies, respectively. The case-fatality rate was 5.03% (3.78-6.27%). Country/region (meta-regression P = 0.006) and years of study (meta-regression P = 0.04) were potential explanations for the observed heterogeneity in the pooled incidence estimates of maternal MI and its associated mortality, with more recent studies and those conducted in the USA revealing the highest rates. Conclusion: This article provides a global estimate of the incidence, mortality rate, and case fatality rate of pregnancy-associated MI. We identified higher rates of PAMI in the USA (relative to Canada and European countries) and rising rates over time. Further research regarding this population is needed, especially given rising maternal age and the increasing prevalence of cardiovascular risk factors. PMID- 28838088 TI - Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry. AB - Aims: The presence of cancer can complicate treatment choices for patients with atrial fibrillation (AF) increasing both the risk of thrombotic and bleeding events. Methods and results: Using data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we aimed to characterize AF patients with cancer, to describe their management and to assess the association between cancer and cardiovascular (CV) outcomes. Among 9749 patients, 23.8% had history of cancer (57% solid malignancy, 1.3% leukaemia, 3.3% lymphoma, 40% other type, and 2.2% metastatic cancer). Patients with history of cancer were older, more likely to have CV disease, CV risk factors, and prior gastrointestinal bleeding. No difference in antiarrhythmic and antithrombotic therapy was observed between those with and without cancer. Patients with history of cancer had a significantly higher risk of death (7.8 vs. 4.9 deaths per 100 patient-years follow-up, P = 0.0003) mainly driven by non-CV death (4.2 vs. 2.4 per 100 patient years follow-up; P = 0.0004) and higher risk of major bleeding (5.1 vs. 3.5 per 100 patient-years follow-up; P = 0.02) compared with non-cancer patients; no differences were observed in risks of strokes/non-central nervous system embolism (1.96 vs. 1.48, P = 0.74) and CV death (2.89 vs. 2.07, P = 0.35) between the two groups. Conclusion: A history of cancer is common among AF patients with up to one in four patients having both. Antithrombotic therapy, rates of cerebrovascular accident, other thrombotic events and cardiac death were similar in AF patients with or without a history of cancer. Patients with cancer, however, were at higher risk of major bleeding and non-CV death. PMID- 28838089 TI - Cancer and heart disease: new bedfellows in the cardiovascular landscape. PMID- 28838090 TI - Are there sex differences following treatment of left ventricular outflow tract obstruction in adults with hypertrophic cardiomyopathy? PMID- 28838091 TI - Myocardial infarction in pregnancy: how frequent, how fatal? PMID- 28838093 TI - Sex differences in post-traumatic stress disorder in cardiovascular patients after the Great East Japan Earthquake: a report from the CHART-2 Study. AB - Aims: The temporal changes and sex differences in post-traumatic stress disorder (PTSD) after natural disasters remain unclear. Therefore, we examined the prevalence, prognostic impacts, and determinant factors of PTSD after the Great East Japan Earthquake (GEJE) of 11 March 2011 in cardiovascular (CV) patients registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-2 Study (n = 10 219), with a special reference to sex. Methods and results: By self-completion questionnaires of the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J), the prevalence of PTSD, defined as IES-R-J score >=25, was 14.8, 15.7, 7.4, and 7.5% in 2011, 2012, 2013, and 2014, respectively. The PTSD rate was higher in women than in men in all years (all P < 0.01). During a median 3.5-year follow-up period, the patients with PTSD in 2011 more frequently experienced a composite of all-cause death and hospitalization for acute myocardial infarction, stroke, and heart failure than those without PTSD [adjusted hazard ratio (aHR) 1.27, P < 0.01]. Importantly, the prognostic impacts of PTSD on all-cause death (aHR 2.10 vs. 0.87, P for interaction = 0.03) and CV death (aHR 3.43 vs. 0.90, P for interaction = 0.02) were significant in women but not in men. While insomnia medication was a prominent determinant factor of PTSD in both sexes during 2011-14, economic poverty was significantly associated with PTSD only in men. Conclusion: After the GEJE, marked sex differences existed in the prevalence, prognostic impacts, and determinant factors of PTSD, suggesting the importance of sex-sepcific mental stress care in disaster medicine. PMID- 28838092 TI - Percutaneous coronary intervention vs. coronary artery bypass grafting for left main revascularization: an updated meta-analysis. AB - Aims: The optimal revascularization strategy for left main coronary artery disease (LMD) remains controversial, especially with two recent randomized controlled trials showing conflicting results. We sought to address this controversy with our analysis. Methods and results: Comprehensive literature search was performed. We compared percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for LMD revascularization using standard meta-analytic techniques. A 21% higher risk of long-term major adverse cardiac and cerebrovascular event [MACCE; composite of death, myocardial infarction (MI), stroke, and repeat revascularization] was observed in patients undergoing PCI in comparison with CABG [risk ratio (RR) 1.21, 95% confidence interval (CI) 1.05 1.40]. This risk was driven by higher rate of repeat revascularization in those undergoing PCI (RR 1.61, 95% CI 1.34-1.95). On the contrary, MACCE rates at 30 days were lower in PCI when compared with CABG (RR 0.55, 95% CI 0.39-0.76), which was driven by lower rates of stroke in the PCI arm (RR 0.41, 95% CI 0.17-0.98). At 1 year, lower stroke rates (RR 0.21, 95% CI 0.08-0.59) in the PCI arm were balanced by higher repeat revascularization rates in those undergoing PCI (RR 1.78, 95% CI 1.33-2.37), resulting in a clinical equipoise in MACCE rates between the two revascularization strategies. There was no difference in death or MI between PCI when compared with CABG at any time point. Conclusion: Outcomes of CABG vs. PCI for LMD revascularization vary over time. Therefore, individualized decisions need to be made for LMD revascularization using the heart team approach. PMID- 28838094 TI - The obesity paradox, extreme obesity, and long-term outcomes in older adults with ST-segment elevation myocardial infarction: results from the NCDR. AB - Aims: To investigate the obesity paradox and association of extreme obesity with long-term outcomes among older ST-segment elevation myocardial infarction (STEMI) patients. Methods and results: Nineteen thousand four hundred and ninety-nine patients >=65 years with STEMI surviving to hospital discharge in NCDR ACTION Registry-GWTG linked to Centers for Medicare and Medicaid Services outcomes between 2007 and 2012 were stratified by body mass index (BMI) (kg/m2) into normal weight (18.5-24.9), overweight (25-29.9), class I (30-34.9), class II (35 39.9), and class III/extreme obese (>=40) categories. Multivariable-adjusted associations were evaluated between BMI categories and mortality by Cox proportional hazards models, and days alive and out of hospital (DAOH) by generalized estimating equations, within 3 years after discharge. Seventy percent of patients were overweight/obese and 3% extremely obese. Normal weight patients were older and more likely to smoke; while extremely obese patients were younger and more likely to be female and black, with lower socioeconomic status and more comorbidity (P <= 0.001). A U-shaped association was observed between BMI categories and mortality: patients with class I obesity were at lowest risk, while normal weight [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.15 1.47] and extremely obese patients (HR 1.33, 95% CI 1.02-1.74) had higher mortality. Normal weight [odds ratio (OR) 0.79, 95% CI 0.68-0.90] and extremely obese (OR 0.73, 95% CI 0.54-0.99) individuals also had lower odds of DAOH. Conclusion: Mild obesity is associated with lower long-term risk in older STEMI patients, while normal weight and extreme obesity are associated with worse outcomes. These findings highlight hazards faced by an increasing number of older individuals with normal weight or extreme obesity and cardiovascular disease. PMID- 28838095 TI - Regional differences in coronary revascularization procedures and outcomes: a nationwide 11-year observational study. AB - Aims: The study investigated whether regional differences in choice of coronary revascularization affected outcomes in Sweden. Methods and results: We conducted a prospective nationwide study of outcome in patients undergoing coronary artery bypass grafting (CABG, n = 47 065) or percutaneous coronary intervention (PCI, n = 140 945) from 2001 through 2011, tracked for a median of 5 years. During this period, the proportion of CABG in revascularization procedures decreased nationwide from an average of 38% to 18%e. Three-vessel disease and left main stem coronary artery stenosis were more common among CABG patients than in PCI patients. In both males and females, all-cause mortality was higher in CABG patients than in PCI patients, while repeat PCI was performed more frequently in the PCI group. CABG proportions in 21 counties ranged from 13% to 42% in females and males. The combined outcomes of repeat revascularization, non-fatal acute myocardial infarction, and death during the tracking period was recorded in 151 936 patients without ST-elevation myocardial infarction after PCI (n = 37 820, 36%) and CABG (n = 18 903, 40%). The multivariable adjusted risk of combined outcomes was higher after both PCI and CABG in both females and males in the three quartiles of counties with a smaller proportion of CABG than in the quartile of counties with the highest proportion of CABG. Similar patterns persisted after including only mortality in the analyses. Conclusion: There are subgroups of patients who have prognostic benefits of CABG in addition to symptomatic improvement that is well documented with both PCI and CABG. PMID- 28838097 TI - Corrigendum. PMID- 28838096 TI - Revsacularization for unprotected left main coronary artery disease: has stenting caught up with bypass surgery? PMID- 28838098 TI - The obesity paradox and obesity severity in elderly STEMI patients. PMID- 28838099 TI - Innovations and technologies in thoracic surgery. PMID- 28838100 TI - Long-term results of the Mitroflow aortic pericardial bioprosthesis in over 800 patients: limited durability and mechanisms of dysfunction. AB - OBJECTIVES: The Mitroflow aortic pericardial bioprosthesis was widely employed in the past. However, some authors have recently reported early structural valve deterioration (SVD) of the Mitroflow LA/LXA model. Thus, we reviewed our experience with the Mitroflow bioprosthesis and studied the risk factors for SVD and mortality. METHODS: Records of patients who underwent aortic valve replacement with a Mitroflow bioprosthesis between November 2005 and January 2015 were retrospectively evaluated with Kaplan-Meier, Cox-regression and multistate analysis. Only patients with a complete clinical follow-up were included in the study. Average follow-up was 45 months and ended on 1 April 2016. RESULTS: Between November 2005 and January 2015, among the 916 patients undergoing aortic valve replacement with the Mitroflow prosthesis at our Institution, the 832 (90.8%) patients with follow-up information were included into the study. Fifty two (6.2%) patients developed SVD (stenosis, n = 38; regurgitation, n = 7; mixed, n = 7). Freedom from SVD was 95.4% and 67.9%, at 5 and 9 years, respectively, without differences after stratification according to the prosthesis model ( P = 0.87) and prosthesis size ( P = 0.70). At the multivariable analysis, increasing age was identified as a protective factor against SVD (hazard ratio = 0.94, P < 0.001). Twenty (38.4%) patients with SVD underwent redo aortic valve replacement. At 5 and 9 years, survival was 64.5% and 43.1%, repectively. According to the multistate analysis, the fraction of patients living with degenerated valves at 9 years was 10.0%; 7.1% died following degeneration. CONCLUSIONS: The LA/LXA Mitroflow model showed limited long-term durability. Degenerated prostheses showed more stenosis than regurgitation. Patient age played an important role in the development of SVD. PMID- 28838101 TI - Valve-sparing David I procedure in acute aortic type A dissection: a 20-year experience with more than 100 patients. AB - OBJECTIVES: The aortic valve-sparing David procedure has been applied to the elective treatment of patients with aortic aneurysms with excellent results. The use of this technique in patients with acute aortic dissection type A (AADA) is still a matter of debate. We present our long-term experience with 109 patients with AADA who had the valve-sparing David I procedure. METHODS: Between July 1993 and October 2015, 109 patients with AADA had the valve-sparing David I procedure at our centre. We conducted a retrospective review with follow-up. RESULTS: The mean age was 54 +/- 12 years; 78 (72%) patients were men. Marfan syndrome was present in 6 (5%) patients and bicuspid aortic valve in 3 (3%). Only 4 (4%) patients received the isolated David procedure; 50 (46%) underwent additional proximal, 13 (12%) subtotal and 42 (39%) total aortic arch replacement. The in hospital mortality rate was 11% ( n = 12). Intraoperative/discharge echocardiography showed aortic insufficiency <= I degrees in 93 of 97 patients (96%). Mean follow-up time was 8.3 +/- 5.7 years. The survival rate after discharge at 1, 5 and 10 years was 94%, 90% and 78%, respectively. Thirteen percent ( n = 13) of patients underwent valve-related reoperation. Freedom from valve-related reoperation at 1, 5 and 10 years was 96%, 88% and 85%, respectively. Compared to patients who underwent the David I procedure for any reason other than AADA, there were no significant differences in long-term survival rates ( P = 0.29) and freedom from a valve-related reoperation ( P = 0.39). CONCLUSIONS: The valve-sparing David I procedure has acceptable long-term results even in emergent operations for AADA and is not inferior when performed in elective settings. PMID- 28838103 TI - Spotlight on recently published ICVTS articles. PMID- 28838102 TI - David operation for type A aortic dissection: risks and rewards. PMID- 28838104 TI - Approaching the Atrium Through the Intraparietal Sulcus: Mapping the Sulcal Morphology and Correlating the Surgical Corridor to Underlying Fiber Tracts. AB - BACKROUND: Although the operative corridor used during the intraparietal transsulcal approach to the atrium has been previously investigated, most anatomical studies focus on its relationship to the optic radiations. OBJECTIVE: To study the intraparietal sulcus (IPS) morphology and to explore the subcortical anatomy with regard to the surgical trajectory used during the intraparietal transsulcal tranventricular approach. METHODS: Twenty-five adult, formalin fixed, cerebral hemispheres were investigated. Fifteen underwent the Klingler procedure and were dissected in a lateromedial direction using the fiber microdissection technique. The trajectory of the dissection resembled that of real operative settings. The remaining 10 hemispheres were cut along the longitudinal axis of the sulcus in order to correlate its surface anatomy to corresponding parts of the ventricular system. RESULTS: IPS demonstrated an interrupted course in 36% of the specimens while its branching pattern was variable. The sulcus anterior half was found to overly the atrium in all occasions. Four discrete, consecutive white matter layers were identified en route to the atrium, ie, the arcuate fibers, the arcuate segment of the superior longitudinal fasciculus, the corona radiata and tapetum, with the arcuate segment being near to the dissection trajectory. CONCLUSION: Given the angle of brain transgression during the intraparietal approach, we found the optimal dissection area to be the very middle of the sulcus. The IPS-postcentral sulcus meeting point, in contrast to previous thought, proved to risk potential injury to the arcuate segment of the superior longitudinal fasciculus, thus affecting surgical outcome. PMID- 28838105 TI - Letter: Endoscopic and Gravity-Assisted Resection of Medial Temporo-occipital Lesions Through a Supracerebellar Transtentorial Approach: Technical Notes With Case Illustrations. PMID- 28838106 TI - Subgaleal Retention Sutures: Internal Pressure Dressing Technique for Dolenc Approach. AB - BACKGROUND: Extradural approach to the cavernous sinus, the "Dolenc" approach recognizing its developing Dr. Vinko Dolenc, is a critically important skull base approach. However, resection of the lateral wall of the cavernous sinus, most commonly for cavernous sinus meningiomas, results commonly in a defect that often cannot be reconstructed in a water-tight fashion. This may result in troublesome pseudomeningocele postoperatively. OBJECTIVE: To describe a technique designed to mitigate the development of pseudomeningocele. METHODS: We found the Dolenc approach critical for resection of cavernous lesions. However, a number of pseudomeningoceles were managed with prolonged external pressure wrapping in the early cohort. Therefore, we incorporated subgaleal to muscular sutures, which were designed to close this potential space and retrospectively analyzed our results. RESULTS: Twenty-one patients treated with a Dolenc approach and resection of the lateral wall of the cavernous sinus over a 2-year period were included. Prior to incorporation of this technique, 12 patients were treated and 3 (25%) experienced postoperative pseudomeningoceles requiring multiple clinic visits and frequent dressing. After incorporation of subgaleal retention sutures, no patient (0%) experienced this complication. CONCLUSION: Although basic, subgaleal to temporalis muscle retention sutures likely aid in eliminating this potential dead space, thereby preventing patient distress postoperatively. This technique is simple and further emphasizes the importance of dead space elimination in complex closures. PMID- 28838107 TI - Contralateral Anterior Interhemispheric Approach to Medial Frontal Arteriovenous Malformations: Surgical Technique and Results. AB - BACKGROUND: Medial frontal arteriovenous malformations (AVMs) require opening the interhemispheric fissure and are traditionally accessed through an ipsilateral anterior interhemispheric approach (IAIA). The contralateral anterior interhemispheric approach (CAIA) flips the positioning with the midline still positioned horizontally for gravity retraction, but with the AVM on the upside and the approach from the contralateral, dependent side. OBJECTIVE: To determine whether the perpendicular angle of attack associated with the IAIA converts to a more favorable parallel angle of attack with the CAIA. METHODS: The CAIA was used in 6 patients with medial frontal AVMs. Patients and AVM characteristics, as well as pre- and postoperative clinical and radiographic data, were reviewed retrospectively. RESULTS: Four patients presented with unruptured AVMs, with 5 AVMs in the dominant, left hemisphere. The lateral margin was off-midline in all cases, and average nidus size was 2.3 cm. All AVMs were resected completely, as confirmed by postoperative catheter angiography. All patients had good neurological outcomes, with either stable or improved modified Rankin Scores at last follow-up. CONCLUSIONS: This study demonstrates that the CAIA is a safe alternative to the IAIA for medial frontal AVMs that extend 2 cm or more off midline into the deep frontal white matter. The CAIA aligns the axis of the AVM nidus parallel to the exposure trajectory, brings its margins in view for circumferential dissection, allows gravity to deliver the nidus into the interhemispheric fissure, and facilitates exposure of the lateral margin for the final dissection, all without resecting or retracting adjacent normal cortex. PMID- 28838108 TI - The Infrazygomatic Segment of the Superficial Temporal Artery: Anatomy and Technique for Harvesting a Better Interposition Graft. AB - BACKGROUND: The superficial temporal artery (STA) is underutilized as an interposition graft because current techniques expose and harvest STA above the level of the zygoma. This technique yields a diminutive arterial segment in both length and diameter, which limits its use for extracranial-intracranial bypass. OBJECTIVE: To introduce a safe and efficient technique for harvesting of the infrazygomatic segment of the STA. METHODS: Scalp layers, STA, and the facial nerve were studied in 18 specimens. The length of the STA segment harvested below the superior border of the zygomatic arch was measured. Safety of this technique was assessed by measuring the distance between the facial nerve and the STA. RESULTS: The galea and subgaleal fat pad were the only anatomical planes found between the facial nerve and the STA below the zygomatic arch. A dense subcutaneous band of galea contained the STA and allowed proximal dissection of the artery without exposing the facial nerve. The average length of the artery harvested between the zygomatic arch and the parotid gland was 20 mm. CONCLUSION: Subcutaneous dissection within the galea below the level of the zygomatic arch and preservation of the dense subcutaneous band surrounding the STA avoids transecting the facial nerve branches while providing increased STA exposure. This anatomical knowledge may increase the use of STA as an interposition graft in cerebrovascular bypass procedures and reduce the need to harvest grafts through additional incisions at remote sites. PMID- 28838109 TI - Endoscopic Endonasal Interdural Middle Fossa Approach to the Maxillary Nerve: Anatomic Considerations and Surgical Relevance. AB - BACKGROUND: The maxillary nerve (V2) can be approached via the open middle fossa approach. OBJECTIVE: To delineate the anatomy of V2 and its specific segments with respect to the endonasal landmarks. We present the endoscopic endonasal interdural middle fossa approach to V2 and its potential application for the treatment of perineural spread in sinonasal/skull base tumors. METHODS: Five human head silicon-injected specimens underwent bilateral endoscopic endonasal transpterygoid approaches. V2 prominence and the maxillary strut were identified in the lateral recess along with paraclival carotid protruberance. The regions superior and inferior to V2 corresponding to the anteromedial and anterolateral triangles of the middle fossa were exposed. RESULTS: V2 can be classified into 3 segments: interdural (from the Gasserian ganglion to the proximal part of the maxillary strut), intracanalicular (corresponding to the anteroposterior length of the maxillary strut), and pterygopalatine (distal to the maxillary strut and the site of its divisions). Endonasally, the average length of the interdural and the intracanalicular segments were approximately 9 and 4.4 mm, respectively. V2, following its division distal to the maxillary strut, was successfully dissected off the middle fossa dura and transected just distal to the Gasserian ganglion. CONCLUSION: Endonasally, the interdural segment can be safely mobilized between the periosteal and meningeal dural layers while ensuring the integrity of the middle fossa dura. This allows transection of infiltrated V2 to facilitate tumor resection without entering the intradural/arachnoidal space. Posteriorly, this is limited by the Gasserian ganglion and superomedially by the dural envelope surrounding the cavernous sinus and the paraclival carotid artery. PMID- 28838110 TI - Subpectoral Implantation of Internal Pulse Generators for Deep Brain Stimulation: Technical Note for Improved Cosmetic Outcomes. AB - BACKGROUND: Deep brain stimulation is increasingly used to treat a variety of disorders. As the prevalence of this technology increases, greater demands are placed on neurosurgical practitioners to improve cosmetic results, maximize patient comfort, and minimize complication rates. We have increasingly employed subpectoral implantation of internal pulse generators (IPGs) to improve patient satisfaction. OBJECTIVE: To determine the complication rates of subpectorally placed IPGs as compared to those placed in a subcutaneous location. METHODS: We reviewed a series of 301 patients from a single institution. Complication rates including infection, hematoma, and lead fracture were recorded. Rates were compared for subcutaneously and subpectorally located devices. RESULTS: Of the records reviewed, we found 301 patients who underwent 308 procedures for initial IPG implantation. Of these, 275 were subpectoral IPG implantation, 19 were infraclavicular subcutaneous implantation, and 14 were subcutaneous implantation in the abdomen. A total of 6 IPG pocket infections occurred, 2 subpectoral and 4 infraclavicular subcutaneous. Of the IPG infections, 2 of the infraclavicular subcutaneous devices had associated erosions. Two patients had their devices relocated from a subpectoral pocket to a subcutaneous pocket in the abdomen due to discomfort. Two patients in the subpectoral group suffered from hematoma requiring evacuation. Two patients in the infraclavicular subcutaneous group had lead fracture occur. CONCLUSIONS: Subpectoral implantation of deep brain stimulation IPGs is a viable alternative with a low complication rate. This technique may offer a lower rate of infection and wound erosion. PMID- 28838111 TI - Functional Outcome After Resection of Von Hippel-Lindau Disease-Associated Cauda Equina Hemangioblastomas: An Observational Cohort Study. AB - BACKGROUND: Cauda equina hemangioblastomas in von Hippel-Lindau (VHL) disease can cause significant neurological signs and symptoms. Despite their associated morbidity, the management of these tumors remains incompletely defined. OBJECTIVE: To determine optimal management, we analyzed the functional outcomes after resection of these tumors. METHODS: VHL patients who underwent surgical resection of cauda equina hemangioblastomas at the National Institutes of Health and the University of Virginia were included. Clinical and radiological follow-up was performed at 6- to 12-month intervals after surgery. RESULTS: Fifteen patients underwent 18 operations for 21 cauda equina hemangioblastomas (median follow-up 5.9 years). Patients often presented with multiple symptoms, including pain (67%), numbness (50%), urinary complaints (33%), and weakness (11%). Median preoperative tumor volume was 1.2 cm 3 . Four tumors at 3 operations were not resected due to a motor nerve root origin. Gross total resection was achieved in 14 surgeries (93% of operations when resection was attempted). New mild (non function limiting) neurological symptoms were noted after 11 operations (61%), which most often (64%) resolved within 2 weeks of surgery. At 6-month follow-up, 15 patients (83%) were stable, 2 (11%) were improved, and 1 (6%) was worse. Histological analysis revealed that all tumors originated from within the involved nerve fascicle. CONCLUSIONS: VHL-associated cauda equina hemangioblastomas have an intrafascicular origin and require interruption of the rootlet of origin for complete resection. Motor nerve root involvement may preclude complete resection but strategies including bony decompression and/or interruption of vascular supply may provide a therapeutic option. Nevertheless, most VHL patients with symptom-producing lesions improve with resection. PMID- 28838112 TI - Endoscopic Endonasal Surgery for Cranial Base Chondrosarcomas. AB - BACKGROUND: Microsurgical resection via open approaches is considered the main treatment modality for cranial base chondrosarcomas (CBCs). The use of endoscopic endonasal approaches (EEAs) has been rarely reported. OBJECTIVE: To present the endoscopic endonasal experience with CBCs at our institution. METHODS: Retrospective review of the medical records of 35 consecutive patients who underwent EEA for CBC resection between January 2004 and April 2013. Surgical outcomes and variables that might affect extent of resection, complications, and recurrence were analyzed. RESULTS: Forty-eight operations were performed (42 EEAs and 6 open approaches). Gross-total resection was achieved in 22 patients (62.9%), near total (>=90% tumor resection) in 11 (31.4%). Larger tumors were associated with incomplete resection in univariate and multivariate analysis ( P = .004, .015, respectively). In univariate analysis, tumors involving the lower clivus and cerebellopontine angle were associated with increased number of complications, especially postoperative cerebrospinal fluid leak ( P = .015) and new cranial neuropathy ( P = .037), respectively. Other major complications included 2 cases of meningitis and deep venous thrombosis, and 1 case of hydrocephalus and carotid injury. Involvement of the lower clivus, parapharyngeal space, and cervical spine required a combination of approaches to maximize tumor resection ( P = .017, .044, .017, respectively). No predictors were significantly associated with increased risk of recurrence. The average follow-up time was 44.6 +/- 31 months. CONCLUSIONS: EEAs may be considered a good option for managing CBCs without significant posterolateral extension beyond the basal foramina and can be used in conjunction with open approaches for maximal resection with acceptable morbidity. PMID- 28838113 TI - Indocyanine Green Videoangiography for Surgery of a Ruptured Dissecting Aneurysm in the Precommunicating Anterior Cerebral Artery: A Technical Case Report. AB - BACKGROUND AND IMPORTANCE: Indocyanine green videoangiography (ICG-VA) is an important intraoperative adjunct for saccular aneurysm surgery, but its efficacy in surgery for dissecting aneurysms has rarely been reported. The authors describe the usefulness of preclipping ICG-VA in a rare case of a ruptured dissecting aneurysm located at the precommunicating (A1) segment of the anterior cerebral artery. CLINICAL PRESENTATION: A 52-year-old woman, with no history of connective tissue diseases or vascular disorders, presented with sudden headache and convulsion. The CT scan showed that the patient had subarachnoid hemorrhage. Angiography showed a dissecting aneurysm in the left A1 segment of the anterior cerebral artery. Thus, the patient underwent trapping of the dissecting aneurysm. ICG-VA was used as an intraoperative adjunct before and after clipping. The preclipping ICG-VA showed the heterogeneously bright dissecting aneurysm and branching arteries even in the presence of hematoma. CONCLUSION: Preclipping ICG VA may enhance the advantage of direct surgery for dissecting aneurysm by allowing visualization of the extent of the dissected vascular wall and the related branching arteries. ICG-VA can be an indispensable adjunct to minimize the compromise from the surgical treatment for intracranial dissecting aneurysms. PMID- 28838114 TI - Endovascular Treatment of Large and Giant Carotid Aneurysms with Flow-Diverter Stents Alone or in Combination with Coils: A Multicenter Experience and Long-Term Follow-up. AB - BACKGROUND: Although flow diverters (FDs) have been widely accepted by neurointerventionists, their safety has yet to be fully defined. Stratification by aneurysm size and location is essential for correct evaluation of treatment outcomes and risks of flow diversion. OBJECTIVE: To compare neurological and anatomic outcomes and evaluate the risk of complications after endovascular treatment of large or giant internal carotid artery (ICA) aneurysms with FD/FDs alone or together with coil embolization. METHODS: We reviewed all patients with large or giant, ruptured or unruptured ICA aneurysms who underwent endovascular treatment with flow diversion alone (group A) or with concomitant coiling (group B) in 4 international institutions between 2010 and 2015. Anatomic outcome was evaluated using the Byrne scale on digital subtraction angiography and/or angioMRI and/or angioCT scans 3, 6, 12, and 24 months postoperatively. RESULTS: We collected 44 patients with large or giant ICA aneurysms. Four patients (9%) presented with aneurysmal subarachnoid hemorrhage (SAH). FD/FDs were used alone in 26 patients and in combination with coil embolization in the 18 remaining patients. The mortality rate due to procedure-related and/or neurological complications was 2.2%. Twelve months after the procedure, 88.6% (n = 39) of patients had a favorable neurological outcome. One year after the procedure, the aneurysm was completely occluded in 72.7% of patients: 61.5% (16/18) in group A and 88.9% (16/26) in group B. CONCLUSION: Clinical outcomes and rates of intraoperative and postoperative complications did not differ significantly between the groups. Better anatomic results using FD/FDs combined with coils were documented 6 months after the procedure; this option seems to provide a higher aneurysm occlusion rate and reduce the need for retreatment. PMID- 28838115 TI - Endoscopic Endonasal Approach to the Ventral Jugular Foramen: Anatomical Basis, Technical Considerations, and Clinical Series. AB - BACKGROUND: Surgical exposure of the jugular foramen (JF) is challenging given its complex regional anatomy and proximity to critical neurovascular structures. OBJECTIVE: To describe the anatomical basis, surgical technique, and outcomes of a group of patients who underwent the endoscopic endonasal approach to the JF. METHODS: Five silicon-injected anatomical specimens were prepared for dissection. Additionally, a chart review was conducted through our patient database, searching for endonasal exposure of the JF. Demographic data, clinical presentation, pathological findings, extent of resection in the JF, and occurrence of complications were analyzed. RESULTS: The endonasal exposure of the JF requires 3 sequential steps: a transpterygoid, a "far-medial," and an "extreme medial" approach. Mobilization or transection of the cartilaginous portion of the eustachian tube (ET) is necessary. In the clinical series, cranial neuropathies were the presenting symptoms in 16 patients (89%). Eighteen tumors (10 chondrosarcomas, 7 chordomas, 1 adenocarcinoma) extended secondarily into the JF. Total tumor resection was achieved in 10 patients (56%), near total (>=90%) in 6 (33%), and subtotal (<90%) in 2 (11%). ET dysfunction (75% of cases), transient palatal numbness (17%), cerebrospinal fluid leakage (17%), and lower cranial nerve palsy (17%) were the most common postoperative complications. There were no carotid artery or jugular vein injuries. CONCLUSION: The endoscopic endonasal approach to the JF requires mobilization or transection of the cartilaginous portion of the ET. This maneuver provides a safe infrapetrosal surgical route to the JF. It may be considered a valid option, in well-selected cases, for resection of malignant and recurrent cranial base tumors. PMID- 28838116 TI - Surgery After Primary Radiation Treatment for Sporadic Vestibular Schwannomas: Case Series. AB - BACKGROUND: As radiation has become an increasingly popular primary treatment option for sporadic vestibular schwannomas, there is a minority of tumors that do not respond favorably to radiation. Data on repeat radiosurgery are emerging, and salvage surgery has been associated with increased technical difficulty and poor facial nerve outcomes. OBJECTIVE: To review the current literature and report our results with surgical resection of sporadic vestibular schwannomas that have failed primary radiation treatment. METHODS: This is a retrospective, single surgeon case series of patients with sporadic vestibular schwannomas who failed primary radiation treatment and underwent subsequent surgical resection. We analyze demographics, clinical information, and intraoperative findings, focusing on facial nerve functional outcomes and extent of resection. RESULTS: Between 2006 and 2015, 10 patients with sporadic vestibular schwannomas whose only prior treatment was radiation underwent microsurgical resection. Eight of 10 patients had a postoperative House-Brackmann score of 1 at a median follow-up of 14 months, while 2 patients had House-Brackmann score of 4. Gross total resection was achieved in 7 of 10 cases. Near total resection was achieved in 2 cases, and only subtotal resection was achieved in 1 case. CONCLUSION: Salvage surgery is a safe and effective option after failure of primary radiation and may offer benefits over repeat radiosurgery. PMID- 28838117 TI - Technique for Mini-open Decompression of Chiari Type I Malformation in Adults. AB - BACKGROUND: The technique for decompression of Chiari type I malformation relies on open exposure of craniocervical junction for suboccipital craniectomy and upper cervical laminectomy with or without duraplasty. There is no detailed technical report of a minimally invasive approach for Chiari decompression in adults. OBJECTIVE: To describe a mini-open technique for decompression of Chiari type I malformation (including duraplasty) in adults. METHODS: Six consecutive adult patients with symptomatic Chiari type I malformation underwent decompression through a 3 to 4 cm midline incision via a speculum retractor. All patients underwent a limited suboccipital craniectomy and C1 laminectomy with an ultrasonic bone scalpel. All patients underwent duraplasty with a synthetic dural substitute. In the 2 patients with syringomyelia, the arachnoid was opened and intradural dissection was carried out. In the remaining 4 patients, the arachnoid was left intact. RESULTS: All operations were completed successfully through the mini-open exposure. Mean surgery time, blood loss, and length of stay were 114 min, 55 mL, and 1.3 days, respectively. Mean follow-up was 13.2 months (range 9 18). All patients had excellent clinical outcomes as defined by scores of 15 (3 patients) or 16 (3 patients) on Chicago Chiari Outcome Scale. There were no neurological complications or cerebrospinal fluid leaks. Postop computed tomography revealed good boney decompression. In the 2 patients with syringomyelia, MRI at 6 months revealed resolution of the syrinx. CONCLUSION: Decompression of Chiari type I malformation in adults can be performed safely and effectively through the mini-open exposure described in this report. PMID- 28838118 TI - Efficacy of Endoscopic Fluorescein Video Angiography in Aneurysm Surgery-Novel and Innovative Assessment of Vascular Blood Flow in the Dead Angles of the Microscope. AB - BACKGROUND: In aneurysm surgery, assessment of the blood flow around the aneurysm is crucial. Recently, intraoperative fluorescence video angiography has been widely adopted for this purpose. However, the observation field of this procedure is limited to the microscopic view, and it is difficult to visualize blood flow obscured by the skull base anatomy, parent arteries, and aneurysm. OBJECTIVE: To demonstrate the efficacy of a new small-caliber endoscopic fluorescence video angiography system employing sodium fluorescein in aneurysm surgery for the first time. METHODS: Eighteen patients with 18 cerebral aneurysms were enrolled in this study. Both microscopic fluorescence angiography and endoscopic fluorescein video angiography were performed before and after clip placement. RESULTS: Endoscopic fluorescein video angiography provided bright fluorescence imaging even with a 2.7-mm-diameter endoscope and clearly revealed blood flow within the vessels in the dead angle areas of the microscope in all 18 aneurysms. Consequently, it revealed information about aneurysmal occlusion and perforator patency in 15 aneurysms (83.3%) that was not obtainable with microscopic fluorescence video angiography. Furthermore, only endoscopic video angiography detected the incomplete clipping in 2 aneurysms and the occlusion of the perforating branches in 3 aneurysms, which led to the reapplication of clips in 2 aneurysms. CONCLUSION: The innovative endoscopic fluorescein video angiography system we developed features a small-caliber endoscope and bright fluorescence images. Because it reveals blood flow in the dead angle areas of the microscope, this novel system could contribute to the safety and long-term effectiveness of aneurysm surgery even in a narrow operative field. PMID- 28838119 TI - Letter: Prepackaged Instrument Kit for Percutaneous Balloon Compression Rhizotomy for the Treatment of Trigeminal Neuralgia: Improvised Solution for an Unexpected National Supply Shortage. PMID- 28838120 TI - The Supracerebellar-Transtentorial Approach to Vascular Lesions in the Inferomedial Temporal Lobe: 3-Dimensional Operative Video. PMID- 28838121 TI - Clip Reconstruction of a Recurrent Giant Anterior Communicating Artery Aneurysm After Endovascular Coiling: 3-Dimensional Operative Video. PMID- 28838122 TI - Flow Diversion for the Treatment of an Unruptured Paraclinoid Carotid Artery Aneurysm. PMID- 28838123 TI - Microsurgical Management of Large, Fusiform, Partially Thrombosed Middle Cerebral Artery (M2) Aneurysm with End-to-End M2 Anastomosis: 3-Dimensional Operative Video. PMID- 28838124 TI - Minimally Invasive Transpalpebral ''Eyelid'' Approach to Unruptured Middle Cerebral Artery Aneurysms. AB - BACKGROUND: Although recent technological advances have led to successful endovascular treatment, middle cerebral artery (MCA) aneurysms are still prone to surgery. Because minimally invasive options are limited and possess several functional and cosmetic drawbacks, a transpalpebral approach is proposed as a new alternative. OBJECTIVES: To describe and assess surgical results of the minimally invasive transpalpebral approach in patients with MCA aneurysms. METHODS: The data of 25 patients with unruptured MCA aneurysms from 2013 to 2016 were included in a cohort prospective database. We describe modifications of the approach and technique for MCA aneurysm clipping, in a step-by-step manner. The outcome was based on complications, procedural morbidity and mortality, and clinical and angiographic outcomes. RESULTS: All procedures were successfully performed in a standardized way, and no major complications related to the new approach were observed. Twenty-two patients were discharged the day after surgery (88%). The majority of aneurysms were 5 to 6 mm in diameter (mean, 7 mm; range 4-21 mm). All patients underwent postoperative angiographic control, which showed no significant residual neck. A 3-mo follow-up was sufficient to show no visible scars with excellent cosmetic results. The mean duration of follow-up was 16 mo. CONCLUSION: The transpalpebral approach comes as a minimally invasive, safe, definitive, and cosmetically adequate solution for MCA aneurysms at the present time. PMID- 28838125 TI - HOTHEAD-Like HTH1 is Involved in Anther Cutin Biosynthesis and is Required for Pollen Fertility in Rice. AB - The cuticle covering the outer surface of anthers is essential for male reproductive development in plants. However, the mechanism underlying the synthesis of these lipidic polymers remains unclear. HOTHEAD (HTH) in Arabidopsis thaliana is a presumptive glucose-methanol-choline (GMC) oxidoreductase involved in the biosynthesis of long-chain alpha-,omega-dicarboxylic fatty acids. In this study, we characterized the function of an anther-specific gene HTH1 in rice. HTH1 contains a conserved GMC oxidoreductase-like domain, and the sequence of HTH1 was highly similar to that of HTH in A. thaliana. Quantitative real-time PCR (qRT-PCR) and in situ hybridization analyses showed that HTH1 was highly expressed in epidermal cells of anthers. Rice plants with HTH1 suppression through CRISPR (clustered regularly interspaced short palindromic repeats) and RNA interference (RNAi) displayed defective anther wall and aborted pollen. Disorganized cuticle layers in anthers and shriveled pollen grains were observed in HTH1-RNAi lines. The total amounts of long-chain fatty acids and cutin monomers in anthers of HTH1-RNAi lines were significantly reduced compared with the wild type. Our results suggested that HTH1 is involved in cutin biosynthesis and is required for anther development and pollen fertility in rice. PMID- 28838126 TI - The MIEL1 E3 Ubiquitin Ligase Negatively Regulates Cuticular Wax Biosynthesis in Arabidopsis Stems. AB - Cuticular wax is an important hydrophobic layer that covers the plant aerial surface. Cuticular wax biosynthesis is shaped by multiple layers of regulation. In particular, a pair of R2R3-type MYB transcription factors, MYB96 and MYB30, are known to be the main participants in cuticular wax accumulation. Here, we report that the MYB30-INTERACTING E3 LIGASE 1 (MIEL1) E3 ubiquitin ligase controls the protein stability of the two MYB transcription factors and thereby wax biosynthesis in Arabidopsis. MIEL1-deficient miel1 mutants exhibit increased wax accumulation in stems, with up-regulation of wax biosynthetic genes targeted by MYB96 and MYB30. Genetic analysis reveals that wax accumulation of the miel1 mutant is compromised by myb96 or myb30 mutation, but MYB96 is mainly epistatic to MIEL1, playing a predominant role in cuticular wax deposition. These observations indicate that the MIEL1-MYB96 module is important for balanced cuticular wax biosynthesis in developing inflorescence stems. PMID- 28838127 TI - Sensors Make Sense of Signaling. PMID- 28838128 TI - Hypoxia Sensing in Plants: On a Quest for Ion Channels as Putative Oxygen Sensors. AB - Over 17 million km2 of land is affected by soil flooding every year, resulting in substantial yield losses and jeopardizing food security across the globe. A key step in resolving this problem and creating stress-tolerant cultivars is an understanding of the mechanisms by which plants sense low-oxygen stress. In this work, we review the current knowledge about the oxygen-sensing and signaling pathway in mammalian and plant systems and postulate the potential role of ion channels as putative oxygen sensors in plant roots. We first discuss the definition and requirements for the oxygen sensor and the difference between sensing and signaling. We then summarize the literature and identify several known candidates for oxygen sensing in the mammalian literature. This includes transient receptor potential (TRP) channels; K+-permeable channels (Kv, BK and TASK); Ca2+ channels (RyR and TPC); and various chemo- and reactive oxygen species (ROS)-dependent oxygen sensors. Identified key oxygen-sensing domains (PAS, GCS, GAF and PHD) in mammalian systems are used to predict the potential plant counterparts in Arabidopsis. Finally, the sequences of known mammalian ion channels with reported roles in oxygen sensing were employed to BLAST the Arabidopsis genome for the candidate genes. Several plasma membrane and tonoplast ion channels (such as TPC, AKT and KCO) and oxygen domain-containing proteins with predicted oxygen-sensing ability were identified and discussed. We propose a testable model for potential roles of ion channels in plant hypoxia sensing. PMID- 28838129 TI - Reduced Tolerance to Night Shift in Chronic Shift Workers: Insight From Fractal Regulation. AB - Study Objectives: Healthy physiology is characterized by fractal regulation (FR) that generates similar structures in the fluctuations of physiological outputs at different time scales. Perturbed FR is associated with aging and age-related pathological conditions. Shift work, involving repeated and chronic exposure to misaligned environmental and behavioral cycles, disrupts circadian coordination. We tested whether night shifts perturb FR in motor activity and whether night shifts affect FR in chronic shift workers and non-shift workers differently. Methods: We studied 13 chronic shift workers and 14 non-shift workers as controls using both field and in-laboratory experiments. In the in-laboratory study, simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and the sleep-wake cycles (ie, circadian misalignment) while environmental conditions and food intake were controlled. Results: In the field study, we found that FR was robust in controls but broke down in shift workers during night shifts, leading to more random activity fluctuations as observed in patients with dementia. The night shift effect was present even 2 days after ending night shifts. The in-laboratory study confirmed that night shifts perturbed FR in chronic shift workers and showed that FR in controls was more resilience to the circadian misalignment. Moreover, FR during real and simulated night shifts was more perturbed in those who started shift work at older ages. Conclusions: Chronic shift work causes night shift intolerance, which is probably linked to the degraded plasticity of the circadian control system. PMID- 28838131 TI - Erratum. PMID- 28838132 TI - Erratum. PMID- 28838130 TI - Validation of Photoplethysmography-Based Sleep Staging Compared With Polysomnography in Healthy Middle-Aged Adults. AB - Study Objectives: To compare the accuracy of automatic sleep staging based on heart rate variability measured from photoplethysmography (PPG) combined with body movements measured with an accelerometer, with polysomnography (PSG) and actigraphy. Methods: Using wrist-worn PPG to analyze heart rate variability and an accelerometer to measure body movements, sleep stages and sleep statistics were automatically computed from overnight recordings. Sleep-wake, 4-class (wake/N1 + N2/N3/REM) and 3-class (wake/NREM/REM) classifiers were trained on 135 simultaneously recorded PSG and PPG recordings of 101 healthy participants and validated on 80 recordings of 51 healthy middle-aged adults. Epoch-by-epoch agreement and sleep statistics were compared with actigraphy for a subset of the validation set. Results: The sleep-wake classifier obtained an epoch-by-epoch Cohen's kappa between PPG and PSG sleep stages of 0.55 +/- 0.14, sensitivity to wake of 58.2 +/- 17.3%, and accuracy of 91.5 +/- 5.1%. kappa and sensitivity were significantly higher than with actigraphy (0.40 +/- 0.15 and 45.5 +/- 19.3%, respectively). The 3-class classifier achieved a kappa of 0.46 +/- 0.15 and accuracy of 72.9 +/- 8.3%, and the 4-class classifier, a kappa of 0.42 +/- 0.12 and accuracy of 59.3 +/- 8.5%. Conclusions: The moderate epoch-by-epoch agreement and, in particular, the good agreement in terms of sleep statistics suggest that this technique is promising for long-term sleep monitoring, although more evidence is needed to understand whether it can complement PSG in clinical practice. It also offers an improvement in sleep/wake detection over actigraphy for healthy individuals, although this must be confirmed on a larger, clinical population. PMID- 28838133 TI - The Burden of Human Metapneumovirus and Respiratory Syncytial Virus Infections in Hospitalized Norwegian Children. AB - Background: The burden of severe human metapneumovirus (HMPV) respiratory tract infections (RTIs) in European children has not been clarified. We assessed HMPV in Norwegian children and compared hospitalization rates for HMPV and respiratory syncytial virus (RSV). Methods: We prospectively enrolled children (<16 years old) hospitalized with RTI and asymptomatic controls (2006-2015). Nasopharyngeal aspirate samples were analyzed with polymerase chain reaction (PCR) tests for HMPV, RSV, and 17 other pathogens. We genotyped HMPV-positive samples and assessed shedding time in 32 HMPV-infected children. Results: In children with RTI, HMPV was detected in 7.3% (267 of 3650) and RSV in 28.7% (1048 of 3650). Among controls, 2.1% (7 of 339) had low HMPV levels detected by PCR, but all were culture negative. HMPV primarily occurred from January to April and in regular epidemics. At least 2 HMPV subtypes occurred each season. The average annual hospitalization rates in children <5 years old with lower RTI were 1.9/1000 (HMPV) and 10.4/1000 (RSV). Among children with RTI, the median HMPV shedding time by PCR was 13 days (range, 6-28 days), but all were culture negative (noninfectious) after 13 days. Conclusions: HMPV appears in epidemics in Norwegian children, with a hospitalization rate 5 times lower than RSV. Low levels of HMPV are rarely detected in healthy children. PMID- 28838135 TI - Reply to Brooks et al. PMID- 28838136 TI - Malaria in an Internally Displaced Persons Camp in the Democratic Republic of the Congo. PMID- 28838137 TI - Erratum. PMID- 28838138 TI - Systematic Characterization of Autophagy in Gestational Diabetes Mellitus. AB - Autophagy is a dynamic process that degrades and recycles cellular organelles and proteins to maintain cell homeostasis. Alterations in autophagy occur in various diseases; however, the role of autophagy in gestational diabetes mellitus (GDM) is unknown. In the present study, we characterized the roles and functions of autophagy in GDM patient samples and extravillous trophoblasts cultured with glucose. We found significantly enhanced autophagy in GDM patients. Moreover, high glucose levels enhanced autophagy and cell apoptosis, reducing proliferation and invasion, and these effects were ameliorated through knockdown of ATG5. Genome-wide 5-hydroxymethylcytosine data analysis further revealed the epigenomic regulatory circuitry underlying the induced autophagy and apoptosis in GDM and preeclampsia. Finally, RNA sequencing was performed to identify gene expression changes and critical signaling pathways after silencing of ATG5. Our study has demonstrated the substantial functions of autophagy in GDM and provides potential therapeutic targets for the treatment of GDM patients. PMID- 28838139 TI - Mutation of foxl2 or cyp19a1a Results in Female to Male Sex Reversal in XX Nile Tilapia. AB - It is well accepted that Forkhead box protein L2 (Foxl2) and aromatase (Cyp19a1; the enzyme responsible for estrogen synthesis) are critical for ovarian development in vertebrates. Knockouts of Foxl2 and Cyp19a1 in goat, mouse, and zebrafish have revealed similar but not identical functions across species. Functional analyses of these two genes in other animals are needed to elucidate their conserved roles in vertebrate sexual development. In this study, we established foxl2 and cyp19a1a mutant lines in Nile tilapia. Both foxl2-/- and cyp19a1a-/- XX fish displayed female-to-male sex reversal. Sf1, Dmrt1, and Gsdf were upregulated in the foxl2-/- and the cyp19a1a-/- XX gonads. Downregulation of Cyp19a1a and serum estradiol-17beta level, and upregulation of Cyp11b2 and serum 11-ketotestosterone level were observed in foxl2-/- XX fish. The mutant phenotype of foxl2-/- XX individuals could be rescued by 17beta-estradiol treatment from 5 to 30 days after hatching (dah). Upregulation of Star1, the enzyme involved in androgen production in tilapia, was also observed in the foxl2-/- XX gonad at 30 and 90 dah. In vitro promoter analyses consistently demonstrated that Foxl2 could suppress the transcription of star1 in a dose-dependent manner. In addition, compared with the control XX gonad, fewer germ cells were detected in the foxl2-/ XX, cyp19a1a-/- XX, and control XY gonads 10 dah. These results demonstrate that Foxl2 promotes ovarian development by upregulating Cyp19a1a expression and repressing male pathway gene expression. These results extend the study of Foxl2 and Cyp19a1a loss of function to a commercially important fish species. PMID- 28838140 TI - Corrigendum for "Ovariectomy Alters Gene Expression of the Hippocampal Formation in Middle-Aged Rats". PMID- 28838141 TI - FOX01 Is the Headline Akt Regulating Hepatic Glucose Metabolism. PMID- 28838142 TI - Placental Transfer of Maternal Obesity: Identifying the Gatekeeper. PMID- 28838143 TI - Cervical Spine Deformity-Part 1: Biomechanics, Radiographic Parameters, and Classification. AB - Cervical spine deformities can have a significant negative impact on the quality of life by causing pain, myelopathy, radiculopathy, sensorimotor deficits, as well as inability to maintain horizontal gaze in severe cases. Many different surgical options exist for operative management of cervical spine deformities. However, selecting the correct approach that ensures the optimal clinical outcome can be challenging and is often controversial. We aim to provide an overview of cervical spine deformity in a 3-part series covering topics including the biomechanics, radiographic parameters, classification, treatment algorithms, surgical techniques, clinical outcome, and complication avoidance with a review of pertinent literature. PMID- 28838144 TI - Reviews in Spinal Surgery: The Quest for Balance. PMID- 28838145 TI - Valganciclovir for the Suppression of Epstein-Barr Virus Replication. AB - Epstein-Barr virus (EBV) causes infectious mononucleosis and can lead to lymphoproliferative diseases. We evaluated the effects of valganciclovir on oral EBV shedding in a randomized, double-blind, placebo-controlled study. Twenty-six men received oral valganciclovir or daily placebo for 8 weeks, followed by a 2 week "washout period" and then 8 weeks of the alternative treatment. Valganciclovir reduced the proportion of days with EBV detected from 61.3% to 17.8% (relative risk, 0.28; 95% confidence interval [CI], .21-.41; P < .001), and quantity of virus detected by 0.77 logs (95% CI, .62-.91 logs; P < .001). Further investigations into the impact of valganciclovir on EBV-associated diseases are needed. PMID- 28838146 TI - Prolonged Shedding of Human Coronavirus in Hematopoietic Cell Transplant Recipients: Risk Factors and Viral Genome Evolution. AB - Background: Recent data suggest that human coronavirus (HCoV) pneumonia is associated with significant mortality in hematopoietic cell transplant (HCT) recipients. Investigation of risk factors for prolonged shedding and intrahost genome evolution may provide critical information for development of novel therapeutics. Methods: We retrospectively reviewed HCT recipients with HCoV detected in nasal samples by polymerase chain reaction (PCR). HCoV strains were identified using strain-specific PCR. Shedding duration was defined as time between first positive and first negative sample. Logistic regression analyses were performed to evaluate factors for prolonged shedding (>=21 days). Metagenomic next-generation sequencing (mNGS) was conducted when >=4 samples with cycle threshold values of <28 were available. Results: Seventeen of 44 patients had prolonged shedding. Among 31 available samples, 35% were OC43, 32% were NL63, 19% were HKU1, and 13% were 229E; median shedding duration was similar between strains (P = .79). Bivariable logistic regression analyses suggested that high viral load, receipt of high-dose steroids, and myeloablative conditioning were associated with prolonged shedding. mNGS among 5 subjects showed single nucleotide polymorphisms from OC43 and NL63 starting 1 month following onset of shedding. Conclusions: High viral load, high-dose steroids, and myeloablative conditioning were associated with prolonged shedding of HCoV in HCT recipients. Genome changes were consistent with the expected molecular clock of HCoV. PMID- 28838147 TI - Specific Biomarkers Associated With Neurological Complications and Congenital Central Nervous System Abnormalities From Zika Virus-Infected Patients in Brazil. AB - Background: Zika virus (ZIKV) infections have been linked to different levels of clinical outcomes, ranging from mild rash and fever to severe neurological complications and congenital malformations. Methods: We investigated the clinical and immunological response, focusing on the immune mediators profile in 95 acute ZIKV-infected adult patients from Campinas, Brazil. These patients included 6 pregnant women who later delivered during the course of this study. Clinical observations were recorded during hospitalization. Levels of 45 immune mediators were quantified using multiplex microbead-based immunoassays. Results: Whereas 11.6% of patients had neurological complications, 88.4% displayed mild disease of rash and fever. Several immune mediators were specifically higher in ZIKV infected patients, and levels of interleukin 10, interferon gamma-induced protein 10 (IP-10), and hepatocyte growth factor differentiated between patients with or without neurological complications. Interestingly, higher levels of interleukin 22, monocyte chemoattractant protein 1, TNF-alpha, and IP-10 were observed in ZIKV-infected pregnant women carrying fetuses with fetal growth-associated malformations. Notably, infants with congenital central nervous system deformities had significantly higher levels of interleukin 18 and IP-10 but lower levels of hepatocyte growth factor than those without such abnormalities born to ZIKV-infected mothers. Conclusions: This study identified several key markers for the control of ZIKV pathogenesis. This will allow a better understanding of the molecular mechanisms of ZIKV infection in patients. PMID- 28838148 TI - Serum C-Reactive Protein and Congestive Heart Failure as Significant Predictors of Herpes Zoster Vaccine Response in Elderly Nursing Home Residents. AB - Background: Elderly long-term care residents often exhibit a myriad of risk factors for immune dysfunction, including chronic inflammation and multiple comorbid conditions, which undoubtedly contribute to their enhanced susceptibility to infection. Hence, understanding the factors required for optimal vaccine responsiveness is critical. Methods: We examined 187 elderly nursing home residents (aged 80-102 years) and 50 community-dwelling seniors (aged 60-75 years) immunized with the live-attenuated varicella-zoster virus (VZV) vaccine. Specifically, we examined whether vaccine responsiveness was associated with serum C-reactive protein (CRP), tumor necrosis factor, interleukin 1beta, 6, and 10, leukocyte telomere length, chronic disease status, and frailty. Results: Elderly participants had significantly higher levels of CRP, tumor necrosis factor, and interleukin 6 and shorter leukocyte telomere length. Vaccine responsiveness was inversely related to the CRP level in elderly participants, but not seniors, and those with congestive heart failure were less likely to achieve a 2-fold response (odds ratio, 0.08). The latter relationship is probably due to immunosenescence, because heart failure was associated with increased senescent CD4+ T cells, and reduced naive and effector and central memory CD8+ T cells. Conclusions: In summary, these data improve our understanding of vaccine responsiveness for those in long-term care, suggesting that certain risk factors are associated with a greater likelihood of vaccine failure. PMID- 28838149 TI - Human Immunodeficiency Virus Type 1 Persistence Following Systemic Chemotherapy for Malignancy. AB - Background: Systemic chemotherapies for various malignancies have been shown to significantly, yet transiently, decrease numbers of CD4+ T lymphocytes, a major reservoir for human immunodeficiency virus type 1 (HIV-1) infection. However, little is known about the impact of cytoreductive chemotherapy on HIV-1 reservoir dynamics, persistence, and immune responses. Methods: We investigated the changes in peripheral CD4+ T-cell-associated HIV-1 DNA and RNA levels, lymphocyte activation, viral population structure, and virus-specific immune responses in a longitudinal cohort of 15 HIV-1-infected individuals receiving systemic chemotherapy or subsequent autologous stem cell transplantation for treatment of hematological malignancies and solid tumors. Results: Despite a transient reduction in CD4+ T cells capable of harboring HIV-1, a 1.7- and 3.3-fold increase in mean CD4+ T-cell-associated HIV-1 RNA and DNA, respectively, were observed months following completion of chemotherapy in individuals on antiretroviral therapy. We also observed changes in CD4+ T-cell population diversity and clonal viral sequence expansion during CD4+ T-cell reconstitution following chemotherapy cessation. Finally, HIV-1 DNA was preferentially, and in some cases exclusively, detected in cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-responsive CD4+ T cells following chemotherapy. Conclusions: Expansion of HIV-infected CMV/EBV-specific CD4 + T cells may contribute to maintenance of the HIV DNA reservoir following chemotherapy. PMID- 28838150 TI - Genital Chlamydia trachomatis Infections Clear More Slowly in Men Than Women, but Are Less Likely to Become Established. AB - Background: Rigorous estimates for clearance rates of untreated chlamydia infections are important for understanding chlamydia epidemiology and designing control interventions, but were previously only available for women. Methods: We used data from published studies of chlamydia-infected men who were retested at a later date without having received treatment. Our analysis allowed new infections to take one of 1, 2, or 3 courses, each clearing at a different rate. We determined which of these 3 models had the most empirical support. Results: The best-fitting model had 2 courses of infection in men, as was previously found for women: "slow-clearing" and "fast-clearing." Only 68% (57%-78%) (posterior median and 95% credible interval [CrI]) of incident infections in men were slow clearing, vs 77% (69%-84%) in women. The slow clearance rate in men (based on 6 months' follow-up) was 0.35 (.05-1.15) year-1 (posterior median and 95% CrI), corresponding to mean infection duration 2.84 (.87-18.79) years. This compares to 1.35 (1.13-1.63) years in women. Conclusions: Our estimated clearance rate is slower than previously assumed. Fewer infections become established in men than women but once established, they clear more slowly. This study provides an improved description of chlamydia's natural history to inform public health decision making. We describe how further data collection could reduce uncertainty in estimates. PMID- 28838151 TI - High Time to Start Human Immunodeficiency Virus Type 1-Infected Patients on Integrase Inhibitors in Sub-Saharan Africa. PMID- 28838153 TI - First description of a Brugada phenocopy in the inferior leads in the context of an acute inferior myocardial infarction. PMID- 28838152 TI - Etiology of Severe Acute Watery Diarrhea in Children in the Global Rotavirus Surveillance Network Using Quantitative Polymerase Chain Reaction. AB - Background: The etiology of acute watery diarrhea remains poorly characterized, particularly after rotavirus vaccine introduction. Methods: We performed quantitative polymerase chain reaction for multiple enteropathogens on 878 acute watery diarrheal stools sampled from 14643 episodes captured by surveillance of children <5 years of age during 2013-2014 from 16 countries. We used previously developed models of the association between pathogen quantity and diarrhea to calculate pathogen-specific weighted attributable fractions (AFs). Results: Rotavirus remained the leading etiology (overall weighted AF, 40.3% [95% confidence interval {CI}, 37.6%-44.3%]), though the AF was substantially lower in the Americas (AF, 12.2 [95% CI, 8.9-15.6]), based on samples from a country with universal rotavirus vaccination. Norovirus GII (AF, 6.2 [95% CI, 2.8-9.2]), Cryptosporidium (AF, 5.8 [95% CI, 4.0-7.6]), Shigella (AF, 4.7 [95% CI, 2.8 6.9]), heat-stable enterotoxin-producing Escherichia coli (ST-ETEC) (AF, 4.2 [95% CI, 2.0-6.1]), and adenovirus 40/41 (AF, 4.2 [95% CI, 2.9-5.5]) were also important. In the Africa Region, the rotavirus AF declined from 54.8% (95% CI, 48.3%-61.5%) in rotavirus vaccine age-ineligible children to 20.0% (95% CI, 12.4% 30.4%) in age-eligible children. Conclusions: Rotavirus remained the leading etiology of acute watery diarrhea despite a clear impact of rotavirus vaccine introduction. Norovirus GII, Cryptosporidium, Shigella, ST-ETEC, and adenovirus 40/41 were also important. Prospective surveillance can help identify priorities for further reducing the burden of diarrhea. PMID- 28838154 TI - Lessons Learned From the Introduction of Inactivated Poliovirus Vaccine in Bangladesh. AB - Background: We assessed programmatic adaptations and infants' uptake of inactivated poliovirus vaccine (IPV) after its introduction into the routine immunization schedule in Bangladesh. Methods: Using convenience and probability sampling, we selected 23 health facilities, 36 vaccinators, and 336 caregivers, within 5 districts and 3 city corporations. We collected data during August October 2015 by conducting interviews, reviewing vaccination records, and observing activities. Results: Knowledge about IPV was high among vaccinators (94%). No problems with IPV storage, transport, or waste disposal were detected, but shortages were reported in 20 health facilities (87%). Wastage per 5-dose vaccine vial was above the recommended 30% in 20 health facilities (87%); all were related to providing <5 doses per open vial. Among eligible infants, 87% and 86% received the third dose of pentavalent and oral poliovirus vaccine, respectively, but only 65% received IPV at the same visit. Among 73 infants not vaccinated with IPV, 58% of caregivers reported that vaccine was unavailable. Conclusions: Bangladesh successfully introduced IPV, but shortages related to insufficient global supply and high vaccine wastage in small outreach immunization sessions might reduce its impact on population immunity. Minimizing wastage and use of a 2-dose fractional-IPV schedule could extend IPV immunization to more children. PMID- 28838155 TI - Use of Dedicated Mobile Teams and Polio Volunteer Community Mobilizers to Increase Access to Zero-Dose Oral Poliovirus Vaccine and Routine Childhood Immunizations in Settlements at High Risk for Polio Transmission in Northern Nigeria. AB - Background: The Polio Eradication Initiative in Nigeria, which started >20 years ago, faced many challenges, including initial denial, resistance from communities, and prolonged regional safety concerns. These challenges led into the structuring of the response including the development of the National Emergency Action Plan, improved partner coordination and government engagement, and the establishment of a Polio Emergency Operations Centre. Although monthly supplementary immunization activities (SIAs) continued, the targeting of settlements at high risk for polio transmission with routine immunization (RI) and other selected primary healthcare (PHC) services using dedicated mobile teams and volunteer community mobilizers (VCMs) became a key strategy for interrupting polio transmission in the high-risk areas. These efforts could have contributed to the wild poliovirus-free 2-year period between 24 July 2014 and 11 August 2016, when 2 cases of the virus were reported from Borno State, Northern Nigeria. Methods: A narrative analysis of polio-related program and other official documents was conducted to identify the relevant human resources and their role in the Polio Eradication Initiative and in RI. The data used in the article was obtained from United Nations Children's Fund (UNICEF) and World Health Organization project reports and a draft evaluation report of the dedicated mobile teams approach in Northern Nigeria. Results: The data from 6 of the states that commenced the provision of polio, RI, and other selected PHC services using the dedicated mobile teams approach in 2014 showed an overall increase in the percentage of children aged 12-23 months in the settlements at high risk for polio transmission with a RI card seen, from 23% to 56%, and an overall increase in fully immunized children aged 12-23 months, from 19% to 55%. The number of newborns given the first dose of oral poliovirus vaccine (OPV) according to the RI schedule and the number of children given zero-dose OPV with the assistance of the VCMs similarly increased between 2013 and 2015. In 2015, VCMs helped track 167 092 newborns and also linked 156 537 infants aged <1 year to RI services in the 6 states. Conclusions: The analysis illustrates that polio personnel in Northern Nigeria are used in increasing access to zero-dose OPV, RI, and selected PHC services. The increase in the services generated represented the increasing role of the dedicated mobile teams and polio VCMs in strengthening RI. PMID- 28838156 TI - Succeeding in New Vaccine Introduction: Lessons Learned From the Introduction of Inactivated Poliovirus Vaccine in Cameroon, Kenya, and Nigeria. AB - Introducing a new vaccine is a large-scale endeavor that can face many challenges, resulting in introduction delays and inefficiencies. The development of national task teams and tools, such as prelaunch trackers, for the introduction of new vaccines (hereafter, "new vaccine introductions" [NVIs]) can help countries implement robust project management systems, front-load critical preparatory activities, and ensure continuous communication around vaccine supply and financing. In addition, implementing postlaunch assessments to take rapid corrective action accelerates the uptake of the new vaccines. NVIs can provide an opportunity to strengthen routine immunization, through strengthening program management systems or by reinforcing local immunization managers' abilities, among others. This article highlights key lessons learned during the introduction of inactivated poliovirus vaccine in 3 countries that would make future NVIs more successful. The article concludes by considering how the Immunization Systems Management Group of the Global Polio Eradication Initiative has been useful to the NVI process and how such global structures could be further enhanced. PMID- 28838157 TI - Placing Human Behavior at the Center of the Fight to Eradicate Polio: Lessons Learned and Their Application to Other Life-Saving Interventions. AB - Today, acceptance of oral polio vaccine is the highest ever. Reaching this level of acceptance has depended on decades of engaging with communities, building trust amid extraordinary social contexts, and responding to the complex variables that trigger behavioral and social change. Drawing on both the successes and setbacks in the 28 years of the Global Polio Eradication Initiative (GPEI), this article articulates what happened when the GPEI began to pay more attention to the dynamics of human and social behavior change. Three particular lessons for other health and immunization programs can be drawn from the experience of GPEI: change begins from within (ie, success needs institutional recognition of the importance of human behavior), good data are not enough for good decision-making, and health workers are important agents of behavior change. These lessons should be harnessed and put into practice to build demand and trust for the last stages of polio eradication, as well as for other life-saving health interventions. PMID- 28838158 TI - Routine Immunization Service Delivery Through the Basic Package of Health Services Program in Afghanistan: Gaps, Challenges, and Opportunities. AB - Background: The Basic Package of Health Services (BPHS) program has increased access to immunization services for children living in rural Afghanistan. However, multiple surveys have indicated persistent immunization coverage gaps. Hence, to identify gaps in implementation, an assessment of the BPHS program was undertaken, with specific focus on the routine immunization (RI) component. Methods: A cross-sectional survey was conducted in 2014 on a representative sample drawn from a sampling frame of 1858 BPHS health facilities. Basic descriptive analysis was performed, capturing general characteristics of survey respondents and assessing specific RI components, and chi2 tests were used to evaluate possible differences in service delivery by type of health facility. Results: Of 447 survey respondents, 27% were health subcenters (HSCs), 30% were basic health centers, 32% were comprehensive health centers, and 12% were district hospitals. Eighty-seven percent of all respondents offered RI services, though only 61% of HSCs did so. Compared with other facility types, HSCs were less likely to have adequate stock of vaccines, essential cold-chain equipment, or proper documentation of vaccination activities. Conclusions: There is an urgent need to address manpower and infrastructural deficits in RI service delivery through the BPHS program, especially at the HSC level. PMID- 28838159 TI - A Supply and Demand Management Perspective on the Accelerated Global Introductions of Inactivated Poliovirus Vaccine in a Constrained Supply Market. AB - A total of 105 countries have introduced IPV as of September 2016 of which 85 have procured the vaccine through UNICEF. The Global Eradication and Endgame Strategic Plan 2013-2018 called for the rapid introduction of at least one dose of IPV into routine immunization schedules in 126 all OPV-using countries by the end of 2015. At the time of initiating the procurement process, demand was estimated based on global modeling rather than individual country indications. In its capacity as procurement agency for the Global Polio Eradication Initiative and Gavi, the Vaccine Alliance, UNICEF set out to secure access to IPV supply for around 100 countries. Based on offers received, sufficient supply was awarded to two manufacturers to meet projected routine requirements. However, due to technical issues scaling up vaccine production and an unforecasted demand for IPV use in campaigns to interrupt wild polio virus and to control type 2 vaccine derived polio virus outbreaks, IPV supplies are severely constrained. Activities to stretch supplies and to suppress demand have been ongoing since 2014, including delaying IPV introduction in countries where risks of type 2 reintroduction are lower, implementing the multi-dose vial policy, and encouraging the use of fractional dose delivered intradermally. Despite these efforts, there is still insufficient IPV supply to meet demand. The impact of the supply situation on IPV introduction timelines in countries are the focus of this article, and based on lessons learned with the IPV introductions, it is recommended for future health programs with accelerated scale up of programs, to take a cautious approach on supply commitments, putting in place clear allocation criteria in case of shortages or delays and establishing a communication strategy vis a vis beneficiaries. PMID- 28838160 TI - Rotary's PolioPlus Program: Lessons Learned, Transition Planning, and Legacy. AB - Hundreds of thousands of Rotary volunteers have provided support for polio eradication activities and continue to this day by making financial contributions to the Rotary PolioPlus program, participating in national immunization days, assisting with surveillance, working on local, national, and international advocacy programs for polio eradication, assisting at immunization posts and clinics, and mobilizing their communities for immunization activities (including poliovirus and other vaccines) and other health benefits. Rotary has contributed more than $1.61 billion for the global eradication of polio and has committed to provide an additional $35 million each year until 2018 (all dollar amounts represent US dollars). Its unwavering commitment to eradicate polio has been vital to the success of the program. Rotary is providing additional support for routine immunization and healthcare. When polio is finally gone, we will have the knowledge from the lessons learned with PolioPlus, such as the value of direct involvement by local Rotarians, the program for emergency funding, innovative tactics, and additional approaches for tackling other global issues, even those beyond public health. Rotary has already transitioned its grants program to include 6 areas of focus: disease prevention and treatment, water and sanitation, maternal and child health, basic education and literacy, economic and community development, and peace and conflict prevention/resolution. Funding for these grants in 2015-2016 was $71 million. The legacy of the polio program will be the complete eradication of poliovirus and the elimination of polio for all time. PMID- 28838161 TI - Systematization of the Introduction of IPV and Switch from tOPV to bOPV in the Americas. AB - The synchronized introduction of the inactivated polio vaccine (IPV) and the switch from trivalent oral polio vaccine (tOPV) to bivalent oral polio vaccine (bOPV) has constituted an effort without precedents, and with astonishing results. Within the established time frame, all countries in our region managed to carry out the decision, planning, and introduction of this vaccine and subsequent switch to their national immunization schedules.The purpose of this article is to systematize the process of IPV introduction and switch in Latin America and the Caribbean, which constitutes an important piece in the documentation of the polio legacy in the Americas. Regional level as well as country perspectives and viewpoints are described. Analyzing and summarizing the lessons learned from the introduction of IPV and the switch from tOPV to bOPV can be useful for the introduction of new vaccines in the Pan American Health Organization (PAHO) region and in other regions of the world, and to help our own region successfully carry out another synchronized vaccine introduction in the future, if necessary. PMID- 28838162 TI - Monitoring and Validation of the Global Replacement of tOPV with bOPV, April-May 2016. AB - The phased withdrawal of oral polio vaccine (OPV) associated with the Polio Eradication and Endgame Strategic Plan 2013-2018 began with the synchronized global replacement of trivalent OPV (tOPV) with bivalent OPV (bOPV) during April May 2016, a transition referred to as the "switch." The World Health Organization's (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization recommended conducting this synchronized switch in all 155 OPV-using countries and territories (which collectively administered several hundred million doses of tOPV each year via several hundred thousand facilities) to reduce risks of re emergence of vaccine-derived polioviruses. Safe execution of this switch required implementation of an associated independent monitoring strategy, the primary objective of which was verification that tOPV was no longer available for administration post-switch. This strategy had to be both practical and rigorous such that tOPV withdrawal could be reasonably employed and confirmed in all countries and territories within a discreet timeframe. Following these principles, WHO recommended that designated monitors in each of the 155 countries and territories visit all vaccine stores as well as a 10% sample of highest-risk health facilities within two weeks of the national switch date, removing any tOPV vials found. National governments were required to provide the WHO with formal validation of execution and monitoring of the switch. In practice, all countries reported cessation of tOPV by 12 May 2016 and 95% of countries and territories submitted detailed monitoring data to WHO. According to these data, 272 out of 276 (99%) national stores, 3,741 out of 3.968 (94%) regional stores, 16,144 out of 22,372 (72%) district level stores, and 143,050 out of 595,401 (24%) of health facilities were monitored. These data, along with field reports suggest that monitoring and validation of the switch was efficient and effective, and that the strategies used during the process could be adapted to future stages of OPV withdrawal. PMID- 28838163 TI - Using the Stop Transmission of Polio (STOP) Program to Develop a South Sudan Expanded Program on Immunization Workforce. AB - In 2009, the international Stop Transmission of Polio (STOP) program began supporting the Global Polio Eradication Initiative in the Republic of South Sudan to address shortages of human resources and strengthen acute flaccid paralysis surveillance. Workforce capacity support is provided to the South Sudan Expanded Program on Immunization by STOP volunteers, implementing partners, and non governmental organizations. In 2013, the Polio Technical Advisory Group recommended that South Sudan transition key technical support from external partners to national staff as part of the Polio Eradication and Endgame Strategic Plan, 2013-2018. To assist in this transition, the South Sudan Expanded Program on Immunization human resources development project was launched in 2015. This 3 year project aims to build national workforce capacity as a legacy of the STOP program by training 56 South Sudanese at national and state levels with the intent that participants would become Ministry of Health staff on their successful completion of the project. PMID- 28838164 TI - Regulatory Aspects of Sabin Type 2 Withdrawal From Trivalent Oral Poliovirus Vaccine: Process and Lessons Learned. AB - Withdrawal of type 2 oral poliovirus vaccine (OPV) in OPV-using countries required regulatory approval for use of inactivated poliovirus vaccine and bivalent OPV in routine immunization. Worldwide, a variety of mechanisms were used by member states, with some differences in approach observed between inactivated poliovirus vaccine and bivalent OPV. These included acceptance for use of World Health Organization (WHO) prequalified vaccines, registration and licensure pathways, participation in WHO-convened joint reviews of licensing dossiers, as well as pragmatic application of alternatively available mechanisms, when appropriate. Simple but effective tools were used to monitor progress and to record, authenticate, and share information. Essential to achievement of regulatory targets was ongoing communication with key stakeholders, including switch-country national regulatory authorities, vaccine manufacturers, partner organizations, and relevant units within WHO. Understanding of the regulatory environment gained through the OPV switch can be helpful in supporting further stages of the polio end game and other time-sensitive vaccine introduction programs. PMID- 28838165 TI - Contribution of Global Polio Eradication Initiative-Funded Personnel to the Strengthening of Routine Immunization Programs in the 10 Focus Countries of the Polio Eradication and Endgame Strategic Plan. AB - Background: The Polio Eradication and Endgame Strategic Plan (PEESP) established a target that at least 50% of the time of personnel receiving funding from the Global Polio Eradication Initiative (GPEI) for polio eradication activities (hereafter, "GPEI-funded personnel") should be dedicated to the strengthening of immunization systems. This article describes the self-reported profile of how GPEI-funded personnel allocate their time toward immunization goals and activities beyond those associated with polio, the training they have received to conduct tasks to strengthen routine immunization systems, and the type of tasks they have conducted. Methods: A survey of approximately 1000 field managers of frontline GPEI-funded personnel was conducted by Boston Consulting Group in the 10 focus countries of the PEESP during 2 phases, in 2013 and 2014, to determine time allocation among frontline staff. Country-specific reports on the training of GPEI-funded personnel were reviewed, and an analysis of the types of tasks that were reported was conducted. Results: A total of 467 managers responded to the survey. Forty-seven percent of the time (range, 23%-61%) of GPEI-funded personnel was dedicated to tasks related to strengthening immunization programs, other than polio eradication. Less time was spent on polio-associated activities in countries that had already interrupted wild poliovirus (WPV) transmission, compared with findings for WPV-endemic countries. All countries conducted periodic trainings of the GPEI-funded personnel. The types of non-polio-related tasks performed by GPEI-funded personnel varied among countries and included surveillance, microplanning, newborn registration and defaulter tracing, monitoring of routine immunization activities, and support of district immunization task teams, as well as promotion of health behaviors, such as clean water use and good hygiene and sanitation practices. Conclusion: In all countries, GPEI-funded personnel perform critical tasks in the strengthening of routine immunization programs and the control of measles and rubella. In certain countries with very weak immunization systems, GPEI-funded personnel provide critical support for the immunization programs, and sudden discontinuation of their employment would potentially disrupt the immunization programs in their countries and create a setback in capacity and effectiveness that would put children at higher risk for vaccine-preventable diseases. PMID- 28838166 TI - Acceptance of the Administration of Multiple Injectable Vaccines in a Single Immunization Visit in Albania. AB - Background: Albania introduced inactivated polio vaccine (IPV) into its immunization system in May 2014, increasing the maximum recommended number of injectable vaccines given in a single visit from 2 to 3. Methods: Health-care providers and caregivers were interviewed at 42 health facilities in Albania to assess knowledge, attitudes, and practices regarding injectable vaccine administration. Immunization register data were abstracted from December 2014 to July 2015 at the same facilities to explore the number of injectable vaccines children received during their 2- and 4-month visits. Results: The majority of children (87%) identified in the record review at either their 2- or 4-month immunization visit received all 3 injectable vaccines in a single visit. Almost all children who did not receive the vaccines in a single visit were subsequently fully immunized, most within a 2-week period. Over half of caregivers whose children got 3 or more injectable vaccines in a single visit reported being only comfortable with 1 or 2 injectable vaccines in a single visit. Conclusions: Despite most caregivers expressing hesitation regarding children receiving multiple injectable vaccines in a single visit, most children received vaccines according to the recommended schedule. Almost all children eventually received all recommended vaccines. PMID- 28838167 TI - Managing the Planned Cessation of a Global Supply Market: Lessons Learned From the Global Cessation of the Trivalent Oral Poliovirus Vaccine Market. AB - The Polio Eradication and Endgame Strategic Plan 2013-2018 calls for the phased withdrawal of OPV, beginning with the globally synchronized cessation of tOPV by mid 2016. From a global vaccine supply management perspective, the strategy provided two key challenges; (1) the planned cessation of a high volume vaccine market; and (2) the uncertainty of demand leading and timeline as total vaccine requirements were contingent on epidemiology. The withdrawal of trivalent OPV provided a number of useful lessons that could be applied for the final OPV cessation. If carefully planned for and based on a close collaboration between programme partners and manufacturers, the cessation of a supply market can be undertaken with a successful outcome for both parties. As financial risks to manufacturers increase even further with OPV cessation, early engagement from the cessation planning phase and consideration of production lead times will be critical to ensure sufficient supply throughout to achieve programmatic objectives. As the GPEI will need to rely on residual stocks including with manufacturers through to the last campaign to achieve its objectives, the GPEI should consider to decide on and communicate a suitable mechanism for co-sharing of financial risks or other financial arrangement for the outer years. PMID- 28838168 TI - Disposing of Excess Vaccines After the Withdrawal of Oral Polio Vaccine. AB - Until recently, waste management for national immunization programs was limited to sharps waste, empty vaccine vials, or vaccines that had expired or were no longer usable. However, because wild-type 2 poliovirus has been eradicated, the World Health Organization's (WHO's) Strategic Advisory Group of Experts on Immunization deemed that all countries must simultaneously cease use of the type 2 oral polio vaccine and recommended that all countries and territories using oral polio vaccine (OPV) "switch" from trivalent OPV (tOPV; types 1, 2, and 3 polioviruses) to bivalent OPV (bOPV; types 1 and 3 polioviruses) during a 2-week period in April 2016. Use of tOPV after the switch would risk outbreaks of paralysis related to type 2-circulating vaccine-derived poliovirus (cVDPV2). To minimize risk of vaccine-derived polio countries using OPV were asked to dispose of all usable, unexpired tOPV after the switch to bOPV. In this paper, we review the rationale for tOPV disposal and describe the global guidelines provided to countries for the safe and appropriate disposal of tOPV. These guidelines gave countries flexibility in implementing this important task within the confines of their national regulations, capacities, and resources. Steps for appropriate disposal of tOPV included removal of all tOPV vials from the cold chain, placement in appropriate bags or containers, and disposal using a recommended approach (ie, autoclaving, boiling, chemical inactivation, incineration, or encapsulation) followed by burial or transportation to a designated waste facility. This experience with disposal of tOPV highlights the adaptability of national immunization programs to new procedures, and identifies gaps in waste management policies and strategies with regard to disposal of unused vaccines. The experience also provides a framework for future policies and for developing programmatic guidance for the ultimate disposal of all OPV after the eradication of polio. PMID- 28838169 TI - Exceptional Financial Support for Introduction of Inactivated Polio Vaccine in Middle-Income Countries. AB - In May 2012, the World Health Assembly declared the completion of poliovirus eradication a programmatic emergency for global public health and called for a comprehensive polio endgame strategy. The Polio Eradication and Endgame Strategic Plan 2013-2018 was developed in response to this call and demands that all countries using Oral Polio Vaccine (OPV) only introduce at least 1 dose of Inactivated Polio Vaccine (IPV) into routine immunization schedules by the end of 2015. In November 2013, the Board of Gavi (the Vaccine Alliance) approved the provision of support for IPV introduction in the 72 Gavi-eligible countries. Following analytical work and stakeholder consultations, the IPV Immunization Systems Management Group (IMG) presented a proposal to provide exceptional financial support for IPV introduction to additional OPV-only using countries not eligible for Gavi support and that would otherwise not be able to mobilize the necessary financial resources within the Polio Eradication and Endgame Strategic Plan timelines. In June 2014, the Polio Oversight Board (POB) agreed to make available a maximum envelope of US $45 million toward supporting countries not eligible for Gavi funding. This article describes the design of the funding mechanism that was developed, its implementation and the lessons learned through this process. PMID- 28838170 TI - Experience With Inactivated Polio Vaccine Introduction and the "Switch" From Trivalent to Bivalent Oral Polio Vaccine in the World Health Organization's Western Pacific Region. AB - The World Health Organization (WHO) Western Pacific Region (WPR) has maintained its polio-free status since 2000. The emergence of vaccine-derived polioviruses (VDPVs), however, remains a risk, as oral polio vaccine (OPV) is still used in many of the region's countries, and pockets of unimmunized or underimmunized children exist in some countries. From 2014 to 2016, the region participated in the globally coordinated efforts to introduce inactivated polio vaccine (IPV) into all countries that did not yet include it in their national immunization schedules, and to "switch" from trivalent OPV (tOPV) to bivalent OPV (bOPV) in all countries still using OPV in 2016.As of September 2016, 15 of 17 countries and areas that did not use IPV by the end of 2014 had introduced IPV. Introduction in the remaining 2 countries has been delayed because of the global shortage of IPV, making it unavailable to select lower-risk countries until the fourth quarter of 2017. All 16 countries using OPV as of 2016 successfully withdrew tOPV during the globally synchronized switch from April to May 2016, and 15 of 16 countries introduced bOPV at the same time, with the remaining country introducing it within 30 days. While countries were primarily responsible for self-funding these activities, additional support was provided.The main challenges encountered in the Western Pacific Region with both IPV introduction and the tOPV-bOPV switch were related to overcoming regulatory policies and challenges with vaccine procurement. As a result, substantial lead time was needed to resolve procurement and regulatory issues before the introductions of IPV and bOPV. As the global community prepares for the full removal of all OPV from immunization programs, this need for lead time and consideration of the impact on national policies should be considered. PMID- 28838171 TI - Financial Support to Eligible Countries for the Switch From Trivalent to Bivalent Oral Polio Vaccine-Lessons Learned. AB - The global switch from trivalent oral polio vaccine (tOPV) to bivalent oral polio vaccine (bOPV) ("the switch") presented an unprecedented challenge to countries. In order to mitigate the risks associated with country-level delays in implementing the switch, the Global Polio Eradication Initiative provided catalytic financial support to specific countries for operational costs unique to the switch. Between November 2015 and February 2016, a total of approximately US$19.4 million in financial support was provided to 67 countries. On average, country budgets allocated 20% to human resources, 23% to trainings and meetings, 8% to communications and advocacy, 9% to logistics, 15% to monitoring, and 5% to waste management. All 67 funded countries successfully switched from tOPV to bOPV during April-May 2016. This funding provided target countries with the necessary catalytic support to facilitate the execution of the switch on an accelerated timeline, and the mechanism offers a model for similar support to future global health efforts, such as the eventual global withdrawal of bOPV. PMID- 28838172 TI - National, Regional and Global Certification Bodies for Polio Eradication: A Framework for Verifying Measles Elimination. AB - The Global Certification Commission (GCC), Regional Certification Commissions (RCCs), and National Certification Committees (NCCs) provide a framework of independent bodies to assist the Global Polio Eradication Initiative (GPEI) in certifying and maintaining polio eradication in a standardized, ongoing, and credible manner. Their members meet regularly to comprehensively review population immunity, surveillance, laboratory, and other data to assess polio status in the country (NCC), World Health Organization (WHO) region (RCC), or globally (GCC). These highly visible bodies provide a framework to be replicated to independently verify measles and rubella elimination in the regions and globally. PMID- 28838173 TI - Cold-Chain Adaptability During Introduction of Inactivated Polio Vaccine in Bangladesh, 2015. AB - Background: Introduction of inactivated polio vaccine creates challenges in maintaining the cold chain for vaccine storage and distribution. Methods: We evaluated the cold chain in 23 health facilities and 36 outreach vaccination sessions in 8 districts and cities of Bangladesh, using purposive sampling during August-October 2015. We interviewed immunization and cold-chain staff, assessed equipment, and recorded temperatures during vaccine storage and transportation. Results: All health facilities had functioning refrigerators, and 96% had freezers. Temperature monitors were observed in all refrigerators and freezers but in only 14 of 66 vaccine transporters (21%). Recorders detected temperatures >8 degrees C for >60 minutes in 5 of 23 refrigerators (22%), 3 of 6 cold boxes (50%) transporting vaccines from national to subnational depots, and 8 of 48 vaccine carriers (17%) used in outreach vaccination sites. Temperatures <2 degrees C were detected in 4 of 19 cold boxes (21%) transporting vaccine from subnational depots to health facilities and 14 of 48 vaccine carriers (29%). Conclusions: Bangladesh has substantial cold-chain storage and transportation capacity after inactivated polio vaccine introduction, but temperature fluctuations during vaccine transport could cause vaccine potency loss that could go undetected. Bangladesh and other countries should strive to ensure consistent and sufficient cold-chain storage and monitor the cold chain during vaccine transportation at all levels. PMID- 28838174 TI - Polio Endgame: Lessons Learned From the Immunization Systems Management Group. AB - The Immunization Systems Management Group (IMG) was established to coordinate and oversee objective 2 of the Polio Eradication and Endgame Strategic Plan 2013 2018, namely, (1) introduction of >=1 dose of inactivated poliovirus vaccine in all 126 countries using oral poliovirus vaccine (OPV) only as of 2012, (2) full withdrawal of OPV, starting with the withdrawal of its type 2 component, and (3) using polio assets to strengthen immunization systems in 10 priority countries. The IMG's inclusive, transparent, and partnership-focused approach proved an effective means of leveraging the comparative and complementary strengths of each IMG member agency. This article outlines 10 key factors behind the IMG's success, providing a potential set of guiding principles for the establishment and implementation of other interagency collaborations and initiatives beyond the polio sphere. PMID- 28838175 TI - Using Acute Flaccid Paralysis Surveillance as a Platform for Vaccine-Preventable Disease Surveillance. AB - Surveillance for acute flaccid paralysis (AFP) is a fundamental cornerstone of the global polio eradication initiative (GPEI). Active surveillance (with visits to health facilities) is a critical strategy of AFP surveillance systems for highly sensitive and timely detection of cases. Because of the extensive resources devoted to AFP surveillance, multiple opportunities exist for additional diseases to be added using GPEI assets, particularly because there is generally 1 district officer responsible for all disease surveillance. For this reason, integrated surveillance has become a standard practice in many countries, ranging from adding surveillance for measles and rubella to integrated disease surveillance for outbreak-prone diseases (integrated disease surveillance and response). This report outlines the current level of disease surveillance integration in 3 countries (Nepal, India, and Nigeria) and proposes that resources continue for long-term maintenance in resource-poor countries of AFP surveillance as a platform for surveillance of vaccine-preventable diseases and other outbreak-prone diseases. PMID- 28838176 TI - The Role of National Immunization Technical Advisory Groups (NITAGs) in the Introduction of Inactivated Polio Vaccine: Experience of the Indonesia and Uganda NITAGs. AB - Background: National Immunization Technical Advisory Groups (NITAGs) are established by national authorities to provide them with independent, bias-free, objective, and evidence-based advice on vaccines and immunization challenges. As of December 2015, 125 countries have reported having set up an NITAG. The Health Policy and Institutional Development Center at the Agence de Medecine Preventive, a World Health Organization (WHO) Collaborative Center for evidence-informed immunization, through its Supporting Independent Immunization and Vaccine Advisory Committees (SIVAC) Initiative project, provides assistance to low- and middle-income countries in the establishment and strengthening of their NITAGs. The Indonesian NITAG (ITAGI) was formed in December 2006 and Uganda's (UNITAG) was formed in November 2014. Both Uganda and Indonesia have introduced inactivated polio vaccine (IPV) as part of the Global Polio Eradication and Endgame Strategic Plan (the Endgame plan). The authors reflect on the process and the role played by NITAGs in the introduction of IPV in the routine immunization program and the lessons learned. Methods: This commentary is a reflection of the authors' experience on NITAG's role as observed in 2 particular local settings and applied to a global public health issue, the polio eradication Endgame plan. The reflection is backed up by the relevant (policy and technical) documents on polio eradication, along with minutes and reports from countries' ministries of health, immunization programs, WHO, and NITAGs. Results: NITAGs are valuable tools for ministries of health to ensure sustainable, evidence-informed immunization policies that are trusted and accepted by their communities. Early engagement with NITAGs also ensures that the adoption of strategies addressing global public health threats at the country level reinforces the national immunization programs. On the other end, when NITAGs are proactive and forward thinking, they can contribute to a smooth and effective introduction of the above mentioned strategies. Time and resources are key factors to ensure optimal performance of NITAGs. PMID- 28838177 TI - The Switch From Trivalent to Bivalent Oral Poliovirus Vaccine in the South-East Asia Region. AB - This analysis describes an innovative and successful approach to risk identification and mitigation in relation to the switch from trivalent to bivalent oral polio vaccine (OPV) in the 11 countries of the World Health Organization's (WHO's) South-East Asia Region (SEAR) in April 2016.The strong commitment of governments and immunization professionals to polio eradication and an exemplary partnership between the WHO, United Nations Children's Fund (UNICEF), and other partners and stakeholders in the region and globally were significant contributors to the success of the OPV switch in the SEAR. Robust national switch plans were developed and country-specific innovations were planned and implemented by the country teams. Close monitoring and tracking of the activities and milestones through dashboards and review meetings were undertaken at the regional level to ensure that implementation time lines were met, barriers identified, and solutions for overcoming challenges were discussed and implemented.The SEAR was the first WHO Region globally to complete the switch and declare the successful withdrawal of trivalent OPV from all countries on 17 May 2016.A number of activities implemented during the switch process are likely to contribute positively to existing immunization practices and to similar initiatives in the future. These activities include better vaccine supply chain management, improved mechanisms for disposal of vaccination-related waste materials, and a closer collaboration with drug regulators, vaccine manufacturers, and the private sector for immunization-related initiatives. PMID- 28838178 TI - Introduction of Inactivated Poliovirus Vaccine and Trivalent Oral Polio Vaccine/Bivalent Oral Polio Vaccine Switch in the African Region. AB - The Polio Eradication and Endgame Strategic plan outlines the phased removal of oral polio vaccines (OPVs), starting with type 2 poliovirus-containing vaccine and introduction of inactivated polio vaccine in routine immunization to mitigate against risk of vaccine-associated paralytic polio and circulating vaccine derived poliovirus. The objective includes strengthening routine immunization as the primary pillar to sustaining high population immunity. After 2 years without reporting any wild poliovirus (July 2014-2016), the region undertook the synchronized switch from trivalent OPV (tOPV) to bivalent OPV (bOPV) as recommended by the Strategic Advisory Group of Experts on Immunization. Consequently the 47 countries of the World Health Organization (WHO) African Region switched from the use of tOPV to bOPV within the stipulated period of April 2016. Planning started early, routine immunization was strengthened, and technical and financial support was provided for vaccine registration, procurement, destruction, logistics, and management across countries by WHO in collaboration with the United Nations Children's Fund (UNICEF) and partners. National commitment and ownership, as well as strong coordination and collaboration between UNICEF and WHO and with partners, ensured success of this major, historic public health undertaking. PMID- 28838179 TI - Implementing the Synchronized Global Switch from Trivalent to Bivalent Oral Polio Vaccines-Lessons Learned From the Global Perspective. AB - In 2015, the Global Commission for the Certification of Polio Eradication certified the eradication of type 2 wild poliovirus, 1 of 3 wild poliovirus serotypes causing paralytic polio since the beginning of recorded history. This milestone was one of the key criteria prompting the Global Polio Eradication Initiative to begin withdrawal of oral polio vaccines (OPV), beginning with the type 2 component (OPV2), through a globally synchronized initiative in April and May 2016 that called for all OPV using countries and territories to simultaneously switch from use of trivalent OPV (tOPV; containing types 1, 2, and 3 poliovirus) to bivalent OPV (bOPV; containing types 1 and 3 poliovirus), thus withdrawing OPV2. Before the switch, immunization programs globally had been using approximately 2 billion tOPV doses per year to immunize hundreds of millions of children. Thus, the globally synchronized withdrawal of tOPV was an unprecedented achievement in immunization and was part of a crucial strategy for containment of polioviruses. Successful implementation of the switch called for intense global coordination during 2015-2016 on an unprecedented scale among global public health technical agencies and donors, vaccine manufacturers, regulatory agencies, World Health Organization (WHO) and United Nations Children's Fund (UNICEF) regional offices, and national governments. Priority activities included cessation of tOPV production and shipment, national inventories of tOPV, detailed forecasting of tOPV needs, bOPV licensing, scaling up of bOPV production and procurement, developing national operational switch plans, securing funding, establishing oversight and implementation committees and teams, training logisticians and health workers, fostering advocacy and communications, establishing monitoring and validation structures, and implementing waste management strategies. The WHO received confirmation that, by mid May 2016, all 155 countries and territories that had used OPV in 2015 had successfully withdrawn OPV2 by ceasing use of tOPV in their national immunization programs. This article provides an overview of the global efforts and challenges in successfully implementing this unprecedented global initiative, including (1) coordination and tracking of key global planning milestones, (2) guidance facilitating development of country specific plans, (3) challenges for planning and implementing the switch at the global level, and (4) best practices and lessons learned in meeting aggressive switch timelines. Lessons from this monumental public health achievement by countries and partners will likely be drawn upon when bOPV is withdrawn after polio eradication but also could be relevant for other global health initiatives with similarly complex mandates and accelerated timelines. PMID- 28838180 TI - Monitoring Results in Routine Immunization: Development of Routine Immunization Dashboard in Selected African Countries in the Context of the Polio Eradication Endgame Strategic Plan. AB - Background: To monitor immunization-system strengthening in the Polio Eradication Endgame Strategic Plan 2013-2018 (PEESP), the Global Polio Eradication Initiative identified 1 indicator: 10% annual improvement in third dose of diphtheria- tetanus-pertussis-containing vaccine (DTP3) coverage in polio high-risk districts of 10 polio focus countries. Methods: A multiagency team, including staff from the African Region, developed a comprehensive list of outcome and process indicators measuring various aspects of the performance of an immunization system. Results: The development and implementation of the dashboard to assess immunization system performance allowed national program managers to monitor the key immunization indicators and stratify by high-risk and non-high-risk districts. Discussion: Although only a single outcome indicator goal (at least 10% annual increase in DTP3 coverage achieved in 80% of high-risk districts) initially existed in the endgame strategy, we successfully added additional outcome indicators (eg, decreasing the number of DTP3-unvaccinated children) as well as program process indicators focusing on cold chain, stock availability, and vaccination sessions to better describe progress on the pathway to raising immunization coverage. Conclusion: When measuring progress toward improving immunization systems, it is helpful to use a comprehensive approach that allows for measuring multiple dimensions of the system. PMID- 28838181 TI - Mapping for Health in Cameroon: Polio Legacy and Beyond. AB - During the poliovirus outbreak in Cameroon from October 2013 to April 2015, the Ministry of Public Health's Expanded Program on Immunization requested technical support to improve mapping of health district boundaries and health facility locations for more effective planning and analysis of polio program data. In December 2015, teams collected data on settlements, health facilities, and other features using smartphones. These data, combined with high-resolution satellite imagery, were used to create new health area and health district boundaries, providing the most accurate health sector administrative boundaries to date for Cameroon. The new maps are useful to and used by the polio program as well as other public health programs within Cameroon such as the District Health Information System and the Emergency Operations Center, demonstrating the value of the Global Polio Eradication Initiative's legacy. PMID- 28838182 TI - Polio Legacy in Action: Using the Polio Eradication Infrastructure for Measles Elimination in Nigeria-The National Stop Transmission of Polio Program. AB - From 2012 to date, Nigeria has been the focus of intensified polio eradication efforts. Large investments made by multiple partner organizations and the federal Ministry of Health to support strategies and resources, including personnel, for increasing vaccination coverage and improved performance monitoring paid off, as the number of wild poliovirus (WPV) cases detected in Nigeria were reduced significantly, from 122 in 2012 to 6 in 2014. No WPV cases were detected in Nigeria in 2015 and as at March 2017, only 4 WPV cases had been detected. Given the momentum gained toward polio eradication, these resources seem well positioned to help advance other priority health agendas in Nigeria, particularly the control of vaccine-preventable diseases, such as measles. Despite implementation of mass measles vaccination campaigns, measles outbreaks continue to occur regularly in Nigeria, leading to high morbidity and mortality rates for children <5 years of age. The National Stop Transmission of Polio (NSTOP) program was collaboratively established in 2012 to create a network of staff working at national, state, and district levels in areas deemed high risk for vaccine preventable disease outbreaks. As an example of how the polio legacy can create long-lasting improvements to public health beyond polio, the Centers for Disease Control and Prevention will transition >180 NSTOP officers to provide technical experience to improve measles surveillance, routine vaccination coverage, and outbreak investigation and response in high-risk areas. PMID- 28838183 TI - Transition Planning For After Polio Eradication. AB - The Global Polio Eradication Initiative (GPEI) has been in operation since 1988, now spends $1 billion annually, and operates through thousands of staff and millions of volunteers in dozens of countries. It has brought polio to the brink of eradication. After eradication is achieved, what should happen to the substantial assets, capabilities, and lessons of the GPEI? To answer this question, an extensive process of transition planning is underway. There is an absolute need to maintain and mainstream some of the functions, to keep the world polio-free. There is also considerable risk-and, if seized, substantial opportunity-for other health programs and priorities. And critical lessons have been learned that can be used to address other health priorities. Planning has started in the 16 countries where GPEI's footprint is the greatest and in the program's 5 core agencies. Even though poliovirus transmission has not yet been stopped globally, this planning process is gaining momentum, and some plans are taking early shape. This is a complex area of work-with difficult technical, financial, and political elements. There is no significant precedent. There is forward motion and a willingness on many sides to understand and address the risks and to explore the opportunities. Very substantial investments have been made, over 30 years, to eradicate a human pathogen from the world for the second time ever. Transition planning represents a serious intent to responsibly bring the world's largest global health effort to a close and to protect and build upon the investment in this effort, where appropriate, to benefit other national and global priorities. Further detailed technical work is now needed, supported by broad and engaged debate, for this undertaking to achieve its full potential. PMID- 28838184 TI - The Public Health Legacy of Polio Eradication in Africa. AB - The legacy of polio in Africa goes far beyond the tragedies of millions of children with permanent paralysis. It has a positive side, which includes the many well-trained polio staff who have vaccinated children, conducted surveillance, tested stool specimens in the laboratories, engaged with communities, and taken care of polio patients. This legacy also includes support for routine immunization services and vaccine introductions and campaigns for other diseases. As polio funding declines, it is time to take stock of the resources made available with polio funding in Africa and begin to find ways to keep some of the talented staff, infrastructure, and systems in place to work on new public health challenges. The partnerships that helped support polio eradication will need to consider funding to maintain and to strengthen routine immunization services and other maternal, neonatal, and child health programs in Africa that have benefitted from the polio eradication infrastructure. PMID- 28838185 TI - Intradermal Administration of Fractional Doses of Inactivated Poliovirus Vaccine: A Dose-Sparing Option for Polio Immunization. AB - A fractional dose of inactivated poliovirus vaccine (fIPV) administered by the intradermal route delivers one fifth of the full vaccine dose administered by the intramuscular route and offers a potential dose-sparing strategy to stretch the limited global IPV supply while further improving population immunity. Multiple studies have assessed immunogenicity of intradermal fIPV compared with the full intramuscular dose and demonstrated encouraging results. Novel intradermal devices, including intradermal adapters and disposable-syringe jet injectors, have also been developed and evaluated as alternatives to traditional Bacillus Calmette-Guerin needles and syringes for the administration of fIPV. Initial experience in India, Pakistan, and Sri Lanka suggests that it is operationally feasible to implement fIPV vaccination on a large scale. Given the available scientific data and operational feasibility shown in early-adopter countries, countries are encouraged to consider introducing a fIPV strategy into their routine immunization and supplementary immunization activities. PMID- 28838186 TI - Assessing Inactivated Polio Vaccine Introduction and Utilization in Kano State, Nigeria, April-November 2015. AB - Background: Kano State, Nigeria, introduced inactivated polio vaccine (IPV) into its routine immunization (RI) schedule in March 2015 and was the pilot site for an RI data module for the National Health Management Information System (NHMIS). We determined factors impacting IPV introduction and the value of the RI module on monitoring new vaccine introduction. Methods: Two assessment approaches were used: (1) analysis of IPV vaccinations reported in NHMIS, and (2) survey of 20 local government areas (LGAs) and 60 associated health facilities (HF). Results: By April 2015, 66% of LGAs had at least 20% of HFs administering IPV, by June all LGAs had HFs administering IPV and by July, 91% of the HFs in Kano reported administering IPV. Among surveyed staff, most rated training and implementation as successful. Among HFs, 97% had updated RI reporting tools, although only 50% had updated microplans. Challenges among HFs included: IPV shortages (20%), hesitancy to administer 2 injectable vaccines (28%), lack of knowledge on multi dose vial policy (30%) and age of IPV administration (8%). Conclusion: The introduction of IPV was largely successful in Kano and the RI module was effective in monitoring progress, although certain gaps were noted, which should be used to inform plans for future vaccine introductions. PMID- 28838187 TI - Experiences and Lessons From Polio Eradication Applied to Immunization in 10 Focus Countries of the Polio Endgame Strategic Plan. AB - Nine polio areas of expertise were applied to broader immunization and mother, newborn and child health goals in ten focus countries of the Polio Eradication Endgame Strategic Plan: policy & strategy development, planning, management and oversight (accountability framework), implementation & service delivery, monitoring, communications & community engagement, disease surveillance & data analysis, technical quality & capacity building, and partnerships. Although coverage improvements depend on multiple factors and increased coverage cannot be attributed to the use of polio assets alone, 6 out of the 10 focus countries improved coverage in three doses of diphtheria tetanus pertussis containing vaccine between 2013 and 2015. Government leadership, evidence-based programming, country-driven comprehensive operational annual plans, community partnership and strong accountability systems are critical for all programs and polio eradication has illustrated these can be leveraged to increase immunization coverage and equity and enhance global health security in the focus countries. PMID- 28838188 TI - Administering Multiple Injectable Vaccines During a Single Visit-Summary of Findings From the Accelerated Introduction of Inactivated Polio Vaccine Globally. AB - Background: In 2013, the World Health Organization's (WHO's) Strategic Advisory Group of Experts (SAGE) recommended that all 126 countries using only oral polio vaccine (OPV) introduce at least 1 dose of inactivated polio vaccine (IPV) into their routine immunization schedules by the end of 2015. In many countries, the addition of IPV would necessitate delivery of multiple injectable vaccines (hereafter, "multiple injections") during a single visit, with infants receiving IPV alongside pentavalent vaccine (which covers diphtheria, tetanus, and whole cell pertussis; hepatitis B; and Haemophilus influenzae type b) and pneumococcal vaccine. Unanticipated concerns emerged from countries over acceptability of multiple injections, sites of administration, and safety. We contextualized the issues surrounding multiple injections by documenting concerns associated with administration of >=3 injections, existing evidence in the published literature, and findings of a systematic review on administration practices and techniques. Methods: Concerns associated with multiple-injection visits were documented from meetings and personal communications with immunization program managers. Published literature on the acceptability of multiple injections by providers and caregivers was summarized, and a systematic review of the literature on administration practices was completed on the following topics: spacing between injection sites (ie, vaccine spacing), site of injection, route of injection, and procedural preparedness. WHO and United Nations Children's Fund data from 2013 2015 were used to assess multiple-injection visits included in national immunization schedules. Results: Healthcare provider and caregiver attitudes and practices indicated concerns about infant pain, potential adverse effects, and uncertainty about vaccine effectiveness with multiple-injection visits. Published literature reinforced the record of safety and acceptance of the recommended schedule of IPV by the SAGE, but the evidence was largely from developed countries. Parental acceptance of multiple injections was associated with a positive provider recommendation to the caregiver. Findings of the systematic review identified that the intramuscular route is preferred over the subcutaneous route for vaccine administration and that the vastus lateralis muscle is preferred over the deltoid muscle for intramuscular injections. Recommendations on vaccine spacing and procedural preparedness were based on practical necessities, but comparative evidence was not identified. During 2013-2015, 85 countries added IPV to their immunization schedules, 46 (55%) of which adopted a schedule resulting in 3 injectable vaccines being administered in a single visit. Conclusion: The multiple-injection experience identified gaps in guidance for future vaccine introductions. Global partner organizations quickly mobilized to assess, document, and communicate the existing global experience on multiple injection visits. This evidence-based approach provided reassurance to opinion leaders, health workers, and professional societies, thus encouraging uptake of IPV as a second or third injection in an accelerated manner globally. PMID- 28838189 TI - Communications, Immunization, and Polio Vaccines: Lessons From a Global Perspective on Generating Political Will, Informing Decision-Making and Planning, and Engaging Local Support. AB - The requirements under objective 2 of the Polio Eradication and Endgame Strategic Plan 2013-2018-to introduce at least 1 dose of inactivated poliomyelitis vaccine (IPV); withdraw oral poliomyelitis vaccine (OPV), starting with the type 2 component; and strengthen routine immunization programs-set an ambitious series of targets for countries. Effective implementation of IPV introduction and the switch from trivalent OPV (containing types 1, 2, and 3 poliovirus) to bivalent OPV (containing types 1 and 3 poliovirus) called for intense global communications and coordination on an unprecedented scale from 2014 to 2016, involving global public health technical agencies and donors, vaccine manufacturers, World Health Organization and United Nations Children's Fund regional offices, and national governments. At the outset, the new program requirements were perceived as challenging to communicate, difficult to understand, unrealistic in terms of timelines, and potentially infeasible for logistical implementation. In this context, a number of core areas of work for communications were established: (1) generating awareness and political commitment via global communications and advocacy; (2) informing national decision-making, planning, and implementation; and (3) in-country program communications and capacity building, to ensure acceptance of IPV and continued uptake of OPV. Central to the communications function in driving progress for objective 2 was its ability to generate a meaningful policy dialogue about polio vaccines and routine immunization at multiple levels. This included efforts to facilitate stakeholder engagement and ownership, strengthen coordination at all levels, and ensure an iterative process of feedback and learning. This article provides an overview of the global efforts and challenges in successfully implementing the communications activities to support objective 2. Lessons from the achievements by countries and partners will likely be drawn upon when all OPVs are completely withdrawn after polio eradication, but also may offer a useful model for other global health initiatives. PMID- 28838190 TI - Legacy of Polio-Use of India's Social Mobilization Network for Strengthening of the Universal Immunization Program in India. AB - The Social Mobilization Network (SMNet) has been lauded as one of the most successsful community engagement strategies in public health for its role in polio elimination in India. The UNICEF-managed SMNet was created as a strategy to eradicate polio by engaging >7000 frontline social mobilizers to advocate for vaccination in some of the most underserved, marginalized, and at-risk communities in India. This network focused initially on generating demand for polio vaccination but later expanded its messaging to promote routine immunization and other health and sanitation interventions related to maternal and children's health. As an impact of the network's interventions, in collaboration with other eradication efforts, these high-risk pockets witnessed an increase in full routine immunization coverage. The experience of the SMNet offers lessons for health-system strengthening for social mobilization and promoting positive health behaviors for other priority health programs like the Universal Immunization Program. PMID- 28838191 TI - Expansion of Surveillance for Vaccine-preventable Diseases: Building on the Global Polio Laboratory Network and the Global Measles and Rubella Laboratory Network Platforms. AB - Laboratory networks were established to provide accurate and timely laboratory confirmation of infections, an essential component of disease surveillance systems. The World Health Organization (WHO) coordinates global laboratory surveillance of vaccine-preventable diseases (VPDs), including polio, measles and rubella, yellow fever, Japanese encephalitis, rotavirus, and invasive bacterial diseases. In addition to providing high-quality laboratory surveillance data to help guide disease control, elimination, and eradication programs, these global networks provide capacity-building and an infrastructure for public health laboratories. There are major challenges with sustaining and expanding the global laboratory surveillance capacity: limited resources and the need for expansion to meet programmatic goals. Here, we describe the WHO-coordinated laboratory networks supporting VPD surveillance and present a plan for the further development of these networks. PMID- 28838192 TI - The Global Polio Laboratory Network as a Platform for the Viral Vaccine Preventable and Emerging Diseases Laboratory Networks. AB - The Global Polio Laboratory Network (GPLN) began building in the late 1980s on a 3-tiered structure of 146 laboratories with different and complementary technical and support capacities (poliovirus isolation, molecular strain characterization including sequencing, quality assurance, and research). The purpose of this network is to provide timely and accurate laboratory results to the Global Polio Eradication Initiative. Deeply integrated with field case-based surveillance, it ultimately provides molecular epidemiological data from polioviruses used to inform programmatic and immunization activities. This network of global coverage requires substantial investments in laboratory infrastructure, equipment, supplies, reagents, quality assurance, staffing and training, often in resource limited settings. The GPLN has not only developed country capacities, but it also serves as a model to other global laboratory networks for vaccine-preventable diseases that will endure after the polio eradication goal is achieved. Leveraging lessons learned during past 27 years, the authors discuss options for transitioning GPLN assets to support control of other viral vaccine-preventable, emerging, and reemerging diseases. PMID- 28838193 TI - Considerations for the Full Global Withdrawal of Oral Polio Vaccine After Eradication of Polio. AB - Eliminating the risk of polio from vaccine-derived polioviruses is essential for creating a polio-free world, and eliminating that risk will require stopping use of all oral polio vaccines (OPVs) once all types of wild polioviruses have been eradicated. In many ways, the experience with the global switch from trivalent OPV (tOPV) to bivalent OPV (bOPV) can inform the eventual full global withdrawal of OPV. Significant preparation will be needed for a thorough, synchronized, and full withdrawal of OPV, and such preparation would be aided by setting a reasonably firm date for OPV withdrawal as far in advance as possible, ideally at least 24 months. A shorter lead time would provide valuable flexibility for decisions about when to stop use of OPV in the context of uncertainty about whether or not all types of wild polioviruses had been eradicated, but it might increase the cost of OPV withdrawal. PMID- 28838194 TI - Lessons From the Polio Endgame: Overcoming the Failure to Vaccinate and the Role of Subpopulations in Maintaining Transmission. AB - Background: Recent detections of circulating serotype 2 vaccine-derived poliovirus in northern Nigeria (Borno and Sokoto states) and Pakistan (Balochistan Province) and serotype 1 wild poliovirus in Pakistan, Afghanistan, and Nigeria (Borno) represent public health emergencies that require aggressive response. Methods: We demonstrate the importance of undervaccinated subpopulations, using an existing dynamic poliovirus transmission and oral poliovirus vaccine evolution model. We review the lessons learned during the polio endgame about the role of subpopulations in sustaining transmission, and we explore the implications of subpopulations for other vaccine-preventable disease eradication efforts. Results: Relatively isolated subpopulations benefit little from high surrounding population immunity to transmission and will sustain transmission as long as they do not attain high vaccination coverage. Failing to reach such subpopulations with high coverage represents the root cause of polio eradication delays. Achieving and maintaining eradication requires addressing the weakest links, which includes immunizing populations in insecure areas and/or with disrupted or poor-performing health systems and managing the risks of individuals with primary immunodeficiencies who can excrete vaccine-derived poliovirus long-term. Conclusions: Eradication efforts for vaccine-preventable diseases need to create performance expectations for countries to immunize all people living within their borders and maintain high coverage with appropriate interventions.Keywords. Polio; eradication; transmission; heterogeneity. PMID- 28838195 TI - Transitioning Lessons Learned and Assets of the Global Polio Eradication Initiative to Global and Regional Measles and Rubella Elimination. AB - The Global Polio Eradication Initiative has built an extensive infrastructure with capabilities and resources that should be transitioned to measles and rubella elimination efforts. Measles continues to be a major cause of child mortality globally, and rubella continues to be the leading infectious cause of birth defects. Measles and rubella eradication is feasible and cost saving. The obvious similarities in strategies between polio elimination and measles and rubella elimination include the use of an extensive surveillance and laboratory network, outbreak preparedness and response, extensive communications and social mobilization networks, and the need for periodic supplementary immunization activities. Polio staff and resources are already connected with those of measles and rubella, and transitioning existing capabilities to measles and rubella elimination efforts allows for optimized use of resources and the best opportunity to incorporate important lessons learned from polio eradication, and polio resources are concentrated in the countries with the highest burden of measles and rubella. Measles and rubella elimination strategies rely heavily on achieving and maintaining high vaccination coverage through the routine immunization activity infrastructure, thus creating synergies with immunization systems approaches, in what is termed a "diagonal approach." PMID- 28838197 TI - Individually Linked Household and Health Facility Vaccination Survey in 12 At risk Districts in Kinshasa Province, Democratic Republic of Congo: Methods and Metadata. AB - Health facility (HF) and household (HH) data can complement each other to provide a better understanding of the factors that contribute to vaccination status. In 12 zones with low vaccination coverage within Kinshasa Province, Democratic Republic of Congo, we conducted 2 surveys: (1) a linked HH and HF survey among 6 11-month-old infants, and (2) a HH survey among 12-23-month-old children. Linked survey objectives were to identify factors associated with vaccination status and to explore methodological considerations for linked survey implementation. To provide linked HH and HF data, we enrolled 6-11-month-old infants in HH clusters in each zone and then surveyed HFs located within the 12 zones and cited by caregivers of the enrolled infants as the most recent HF visited for vaccination or curative care. To provide vaccination coverage estimates for the 12-zone area, we enrolled 12-23-month-old children in every fourth HH. Of the HHs with a child aged 6-23 months, 16% were ineligible because they had resided in the neighborhood for <3 months or were unavailable to be interviewed, 4% refused, and 80% were eligible and participated. Of 1224 enrolled infants 6-11 months of age, records of 879 (72%) were linked to one of the 182 surveyed HFs. For the coverage survey, 710 children aged 12-23 months participated. Home-based vaccination cards were available for 1210 of 1934 children (63%) surveyed. The surveys were successful in assessing HH information for 2 age groups, documenting written vaccination history for a large proportion of 6-23-month-old children, linking the majority of infants with their most recently visited HF, and surveying identified HFs. The implementation of the individually linked survey also highlighted the need for a comprehensive list of HFs and an analysis plan that addresses cross-classified clusters with only 1 child. PMID- 28838196 TI - Addressing the Challenges and Opportunities of the Polio Endgame: Lessons for the Future. AB - The Global Commission for the Certification of the Eradication of Poliomyelitis certified the eradication of type 2 poliovirus in September 2015, making type 2 poliovirus the first human pathogen to be eradicated since smallpox. The eradication of type 2 poliovirus, the absence of detection of type 3 poliovirus worldwide since November 2012, and cornering type 1 poliovirus to only a few geographic areas of 3 countries has enabled implementation of the endgame of polio eradication which calls for a phased withdrawal of oral polio vaccine beginning with the type 2 component, introduction of inactivated poliovirus vaccine, strengthening of routine immunization in countries with extensive polio resources, and initiating activities to transition polio resources, program experience, and lessons learned to other global health initiatives. This supplement focuses on efforts by global partners to successfully launch polio endgame activities to permanently secure and sustain the enormous gains of polio eradication forever. PMID- 28838198 TI - Lessons From Globally Coordinated Cessation of Serotype 2 Oral Poliovirus Vaccine for the Remaining Serotypes. AB - Background: Comparing model expectations with the experience of oral poliovirus vaccine (OPV) containing serotype 2 (OPV2) cessation can inform risk management for the expected cessation of OPV containing serotypes 1 and 3 (OPV13). Methods: We compare the expected post-OPV2-cessation OPV2-related viruses from models with the evidence available approximately 6 months after OPV2 cessation. We also model the trade-offs of use vs nonuse of monovalent OPV (mOPV) for outbreak response considering all 3 serotypes. Results: Although too early to tell definitively, the observed die-out of OPV2-related viruses in populations that attained sufficiently intense trivalent OPV (tOPV) use prior to OPV2 cessation appears consistent with model expectations. As expected, populations that did not intensify tOPV use prior to OPV2 cessation show continued circulation of serotype 2 vaccine-derived polioviruses (VDPVs). Failure to aggressively use mOPV to respond to circulating VDPVs results in a high risk of uncontrolled outbreaks that would require restarting OPV. Conclusions: Ensuring a successful endgame requires more aggressive OPV cessation risk management than has occurred to date for OPV2 cessation. This includes maintaining high population immunity to transmission up until OPV13 cessation, meeting all prerequisites for OPV cessation, and ensuring sufficient vaccine supply to prevent and respond to outbreaks. PMID- 28838199 TI - Introduction of Inactivated Polio Vaccine, Withdrawal of Type 2 Oral Polio Vaccine, and Routine Immunization Strengthening in the Eastern Mediterranean Region. AB - The Global Polio Eradication Initiative has reduced the global incidence of polio by 99% and the number of countries with endemic polio from 125 to 3 countries. The Polio Eradication and Endgame Strategic Plan 2013-2018 (Endgame Plan) was developed to end polio disease. Key elements of the endgame plan include strengthening immunization systems using polio assets, introducing inactivated polio vaccine (IPV), and replacing trivalent oral polio vaccine with bivalent oral polio vaccine ("the switch"). Although coverage in the Eastern Mediterranean Region (EMR) with the third dose of a vaccine containing diphtheria, tetanus, and pertussis antigens (DTP3) was >=90% in 14 countries in 2015, DTP3 coverage in EMR dropped from 86% in 2010 to 80% in 2015 due to civil disorder in multiple countries. To strengthen their immunization systems, Pakistan, Afghanistan, and Somalia developed draft plans to integrate Polio Eradication Initiative assets, staff, structure, and activities with their Expanded Programmes on Immunization, particularly in high-risk districts and regions. Between 2014 and 2016, 11 EMR countries introduced IPV in their routine immunization program, including all of the countries at highest risk for polio transmission (Afghanistan, Pakistan, Somalia, and Yemen). As a result, by the end of 2016 all EMR countries were using IPV except Egypt, where introduction of IPV was delayed by a global shortage. The switch was successfully implemented in EMR due to the motivation, engagement, and cooperation of immunization staff and decision makers across all national levels. Moreover, the switch succeeded because of the ability of even the immunization systems operating under hardship conditions of conflict to absorb the switch activities. PMID- 28838200 TI - Lessons Learned and Legacy of the Stop Transmission of Polio Program. AB - In 1988, the by the World Health Assembly established the Global Polio Eradication Initiative, which consisted of a partnership among the World Health Organization (WHO), Rotary International, the Centers for Disease Control and Prevention (CDC), and the United Nations Children's Fund. By 2016, the annual incidence of polio had decreased by >99.9%, compared with 1988, and at the time of writing, only 3 countries in which wild poliovirus circulation has never been interrupted remain: Afghanistan, Nigeria, and Pakistan. A key strategy for polio eradication has been the development of a skilled and deployable workforce to implement eradication activities across the globe. In 1999, the Stop Transmission of Polio (STOP) program was developed and initiated by the CDC, in collaboration with the WHO, to train and mobilize additional human resources to provide technical assistance to polio-endemic countries. STOP has also informed the development of other public health workforce capacity to support polio eradication efforts, including national STOP programs. In addition, the program has diversified to address measles and rubella elimination, data management and quality, and strengthening routine immunization programs. This article describes the STOP program and how it has contributed to polio eradication by building global public health workforce capacity. PMID- 28838201 TI - Impact of an Intervention to Use a Measles, Rubella, and Polio Mass Vaccination Campaign to Strengthen Routine Immunization Services in Nepal. AB - Background: The potential to strengthen routine immunization (RI) services through supplementary immunization activities (SIAs) is an important benefit of global measles and rubella elimination and polio eradication strategies. However, little evidence exists on how best to use SIAs to strengthen RI. As part the 2012 Nepal measles-rubella and polio SIA, we developed an intervention package designed to improve RI processes and evaluated its effect on specific RI process measures. Methods: The intervention package was incorporated into existing SIA activities and materials to improve healthcare providers' RI knowledge and practices throughout Nepal. In 1 region (Central Region) we surveyed the same 100 randomly selected health facilities before and after the SIA and evaluated the following RI process measures: vaccine safety, RI planning, RI service delivery, vaccine supply chain, and RI data recording practices. Data collection included observations of vaccination sessions, interviews with the primary healthcare provider who administered vaccines at each facility, and administrative record reviews. Pair-matched analytical methods were used to determine whether statistically significant changes in the selected RI process measures occurred over time. Results: After the SIA, significant positive changes were measured in healthcare provider knowledge of adverse events following immunization (11% increase), availability of RI microplans (+17%) and maps (+12%), and awareness of how long a reconstituted measles vial can be used before it must be discarded (+14%). For the SIA, 42% of providers created an SIA high-risk villages list, and >50% incorporated this information into RI outreach session site planning. Significant negative changes occurred in correct knowledge of measles vaccination contraindications (-11%), correct definition for a measles outbreak (-21%), and how to treat a child with a severe adverse event following immunization (-10%). Twenty percent of providers reported cancelling >=1 RI sessions during the SIA. Many RI process measures were at high proportions (>90%) before the SIA and remained high afterward, including proper vaccine administration techniques, proper vaccine waste management, and availability of vaccine carriers and vaccine registers. Conclusions: Focusing on activities that are easily linked between SIAs and RI services, such as using SIA high-risk village list to strengthen RI microplanning and examining ways to minimize the impact of an SIA on RI session scheduling, should be prioritized when implementing SIAs. PMID- 28838202 TI - Approaches to Vaccination Among Populations in Areas of Conflict. AB - Vaccination is an important and cost-effective disease prevention and control strategy. Despite progress in vaccine development and immunization delivery systems worldwide, populations in areas of conflict (hereafter, "conflict settings") often have limited or no access to lifesaving vaccines, leaving them at increased risk for morbidity and mortality related to vaccine-preventable disease. Without developing and refining approaches to reach and vaccinate children and other vulnerable populations in conflict settings, outbreaks of vaccine-preventable disease in these settings may persist and spread across subnational and international borders. Understanding and refining current approaches to vaccinating populations in conflict and humanitarian emergency settings may save lives. Despite major setbacks, the Global Polio Eradication Initiative has made substantial progress in vaccinating millions of children worldwide, including those living in communities affected by conflicts and other humanitarian emergencies. In this article, we examine key strategic and operational tactics that have led to increased polio vaccination coverage among populations living in diverse conflict settings, including Nigeria, Somalia, and Pakistan, and how these could be applied to reach and vaccinate populations in other settings across the world. PMID- 28838203 TI - Lessons Learned From Managing the Planning and Implementation of Inactivated Polio Vaccine Introduction in Support of the Polio Endgame. AB - The Immunization Systems Management Group (IMG) was established as a time-limited entity, responsible for the management and coordination of Objective 2 of the Polio Eradication and Endgame Strategic Plan. This objective called for the introduction of at least 1 dose of inactivated polio vaccine (IPV) into the routine immunization programs of all countries using oral polio vaccine (OPV) only. Despite global vaccine shortages, which limited countries' abilities to access IPV in a timely manner, 105 of 126 countries using OPV only introduced IPV within a 2.5-year period, making it the fastest rollout of a new vaccine in history. This achievement can be attributed to several factors, including the coordination work of the IMG; high-level engagement and advocacy across partners; the strong foundations of the Expanded Programme on Immunization at all levels; Gavi, the Vaccine Alliance's vaccine introduction experiences and mechanisms; innovative approaches; and proactive communications. In many ways, the IMG's work on IPV introduction can serve as a model for other vaccine introductions, especially in an accelerated context. PMID- 28838204 TI - Resource Needs for the Trivalent Oral Polio to Bivalent Oral Polio Vaccine Switch in Indonesia. AB - Background: We present an empirical economic cost analysis of the April 2016 switch from trivalent (tOPV) to bivalent (bOPV) oral polio vaccine at the national-level and 3 provinces (Bali, West Sumatera and Nusa Tenggara) for Indonesia's Expanded Program on Immunization. Methods: Data on the quantity and prices of resources used in the 4 World Health Organization guideline phases of the switch were collected at the national-level and in each of the sampled provinces, cities/districts, and health facilities. Costs were calculated as the sum of the value of resources reportedly used in each sampled unit by switch phase. Results: Estimated national-level costs were $46 791. Costs by health system level varied from $9062 to $34 256 at the province-level, from $4576 to $11 936 at the district-level , and from $3488 to $29 175 at the city-level. Estimated national costs ranged from $4 076 446 (Bali, minimum cost scenario) to $28 120 700 (West Sumatera, maximum cost scenario). Conclusions: Our findings suggest that the majority of tPOV to bOPV switch costs were borne at the subnational level. Considerable variation in reported costs among health system levels surveyed indicates a need for flexibility in budgeting for globally synchronized public health activities. PMID- 28838206 TI - Discovery and development of novel therapies in advanced breast cancer: rapid development of ribociclib. PMID- 28838205 TI - A new role for FBP21 as regulator of Brr2 helicase activity. AB - Splicing of eukaryotic pre-mRNA is carried out by the spliceosome, which assembles stepwise on each splicing substrate. This requires the concerted action of snRNPs and non-snRNP accessory proteins, the functions of which are often not well understood. Of special interest are B complex factors that enter the spliceosome prior to catalytic activation and may alter splicing kinetics and splice site selection. One of these proteins is FBP21, for which we identified several spliceosomal binding partners in a yeast-two-hybrid screen, among them the RNA helicase Brr2. Biochemical and biophysical analyses revealed that an intrinsically disordered region of FBP21 binds to an extended surface of the C terminal Sec63 unit of Brr2. Additional contacts in the C-terminal helicase cassette are required for allosteric inhibition of Brr2 helicase activity. Furthermore, the direct interaction between FBP21 and the U4/U6 di-snRNA was found to reduce the pool of unwound U4/U6 di-snRNA. Our results suggest FBP21 as a novel key player in the regulation of Brr2. PMID- 28838207 TI - Gonadotropin-releasing hormone analogs for ovarian function protection during chemotherapy in young early breast cancer patients: the last piece of the puzzle? PMID- 28838208 TI - Diffuse pseudoprogression in a patient with metastatic non-small-cell lung cancer treated with Nivolumab. PMID- 28838209 TI - Precision, complexity and stigma in advanced prostate cancer terminology: it is time to move away from 'castration-resistant' prostate cancer. PMID- 28838211 TI - CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 'gene desert', serve as important prognostic biomarkers in colorectal cancer. AB - Background: 8q24.21 is a frequently amplified genomic region in colorectal cancer (CRC). This region is often referred to as a 'gene desert' due to lack of any important protein-coding genes, highlighting the potential role of noncoding RNAs, including long noncoding RNAs (lncRNAs) located around the proto-oncogene MYC. In this study, we have firstly evaluated the clinical significance of altered expression of lncRNAs mapped to this genomic locus in CRC. Patients and methods: A total of 300 tissues, including 280 CRC and 20 adjacent normal mucosa specimens were evaluated for the expression of 12 lncRNAs using qRT-PCR assays. We analyzed the associations between lncRNA expression and various clinicopathological features, as well as with recurrence free survival (RFS) and overall survival (OS) in two independent cohorts. Results: The expression of CCAT1, CCAT1-L, CCAT2, PVT1, and CASC19 were elevated in cancer tissues (P = 0.039, <0.001, 0.018, <0.001, 0.002, respectively). Among these, high expression of CCAT1 and CCAT2 was significantly associated with poor RFS (P = 0.049 and 0.022, respectively) and OS (P = 0.028 and 0.015, respectively). These results were validated in an independent patient cohort, in which combined expression of CCAT1 and CCAT2 expression was significantly associated with a poor RFS (HR:2.60, 95% confidence interval [CI]: 1.04-6.06, P = 0.042) and a poor OS (HR:8.38, 95%CI: 2.68-37.0, P < 0.001). We established a RFS prediction model which revealed that combined expression of CCAT1, CCAT2, and carcinoembryonic antigen was a significant determinant for efficiently predicting RFS in stage II (P = 0.034) and stage III (P = 0.001) CRC patients. Conclusions: Several lncRNAs located in 8q24.21 locus are highly over-expressed in CRC. High expression of CCAT1 and CCAT2 significantly associates with poor RFS and OS. The expression of these two lncRNAs independently, or in combination, serves as important prognostic biomarkers in CRC. PMID- 28838210 TI - De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. AB - The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world. PMID- 28838213 TI - The potential use of lncRNAs found in the 8q24 region as biomarkers for colon cancer. PMID- 28838212 TI - Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database. AB - Background: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. Patients and methods: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. Results: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. Conclusion: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation. PMID- 28838214 TI - Prognostic significance of PD-L1 expression on circulating tumor cells in patients with head and neck squamous cell carcinoma. AB - Background: Successful application of programmed death 1 (PD1) checkpoint inhibitors in the clinic may ultimately benefit from appropriate patient selection based upon predictive biomarkers. Molecular characterization of circulating tumor cells (CTC) is crucial for the investigation of molecular targeted therapies while predictive biomarkers for response to PD1 checkpoint inhibitors are lacking. We sought to assess whether overexpression of PD-L1 in CTCs could be detected at baseline and at different timepoints during treatment in a prospective cohort of head and neck squamous cell carcinoma (HNSCC) patients and used to predict clinical outcome after treatment with curative intent. Patients and methods: We developed a highly sensitive, specific and robust RT qPCR assay for PD-L1 mRNA expression in EpCAM(+) CTCs. In a prospective cohort of 113 locally advanced HNSCC patients treated with curative intent we evaluated PD L1 expression in the EpCAM(+) CTC fraction at baseline, after 2 cycles of induction chemotherapy (week 6) and at the end of concurrent chemoradiotherapy (week 15). Results: PD-L1 overexpression was found in 24/94 (25.5%) patients at baseline, 8/34 (23.5%) after induction chemotherapy and 12/54 (22.2%) patients at the end of treatment. Patients with CTCs overexpressing PD-L1 at end of treatment had shorter progression-free survival (P = 0.001) and overall survival (P < 0.001). Multivariate analysis revealed that PD-L1 overexpression at end of treatment was independent prognostic factor for progression-free survival and overall survival. The absence of PD-L1 overexpression at the end of treatment was strongly associated with complete response with an odds ratio = 16.00 (95% CI = 2.76-92.72, P = 0.002). Conclusions: We demonstrate that detection of CTCs overexpressing PD-L1 is feasible and may provide important prognostic information in HNSCC. Our results suggest that adjuvant PD1 inhibitors deserve evaluation in HNSCC patients in whom PD-L1(+) CTCs are detected at the end of curative treatment. PMID- 28838215 TI - Reply to the letter to the editor 'Specific QOL scales that reflect toxicity induced impairment are needed in RCTs'. PMID- 28838216 TI - BET inhibitors: a novel epigenetic approach. AB - Epigenetics has been defined as 'the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.' Currently, several classes of anticancer drugs function at the epigenetic level, including inhibitors of DNA methyltransferase, histone deacetylase (HDAC), lysine-specific demethylase 1, zeste homolog 2, and bromodomain and extra-terminal motif (BET) proteins.BET proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation. In recent years, inhibitors of BET proteins have been developed as anticancer agents. These inhibitors exhibit selectivity for tumor cells by preferentially binding to superenhancers, noncoding regions of DNA critical for the transcription of genes that determine a cell's identity. Preclinical research on BET inhibitors has identified them as a potential means of targeting MYC.Early clinical trials with BET inhibitors have had mixed results, with few responses in both hematologic and solid tumors that tend to be short-lived. Toxicities have included severe, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea; GI side-effects, fatigue, and low-grade dysgeusia have limited compliance. However, preclinical data suggest that BET inhibitors may have a promising future in combination with other agents. They appear to be able to overcome resistance to targeted agents and have strong synergy with immune checkpoint inhibitors as well as with multiple epigenetic agents, particularly HDAC inhibitors. In many instances, BET and HDAC inhibitors were synergistic at reduced doses, suggesting a potential means of avoiding the overlapping toxicities of the two drug classes.BET inhibitors provide a novel approach to epigenetic anticancer therapy. However, to date they appear to have limited efficacy as single agents. A focus on BET inhibitors in combination with other drugs such as targeted and/or as other epigenetic agents is warranted, due to limited monotherapy activity, including pharmacodynamic correlatives differential activity amongst select drug combinations. PMID- 28838218 TI - News From the Foundation for Physical Therapy. PMID- 28838219 TI - The new why when designing mandatory medical examinations. PMID- 28838217 TI - Diagnosis of Upper Quadrant Lymphedema Secondary to Cancer: Clinical Practice Guideline From the Oncology Section of the American Physical Therapy Association. AB - The Oncology Section of the American Physical Therapy Association (APTA) developed a clinical practice guideline to aid the clinician in diagnosing secondary upper quadrant cancer-related lymphedema. Following a systematic review of published studies and a structured appraisal process, recommendations were written to guide the physical therapist and other health care clinicians in the diagnostic process. Overall clinical practice recommendations were formulated based on the evidence for each diagnostic method and were assigned a grade based on the strength of the evidence for different patient presentations and clinical utility. In an effort to maximize clinical applicability, recommendations were based on the characteristics as to the location and stage of a patient's upper quadrant lymphedema. PMID- 28838220 TI - Global occupational health. PMID- 28838221 TI - Occupational skin cancer: sweeping the path to prevention. PMID- 28838222 TI - Effects of Increased NADPH Concentration by Metabolic Engineering of the Pentose Phosphate Pathway on Antibiotic Production and Sporulation in Streptomyces lividans TK24. AB - Most of the biosynthetic pathways for secondary metabolites are influenced by carbon metabolism and supply of cytosolic NADPH. We engineered carbon distribution to the pentose phosphate pathway (PPP) and redesigned the host to produce high levels of NADPH and primary intermediates from the PPP. The main enzymes producing NADPH in the PPP, glucose 6-phosphate dehydrogenase (encoded by zwf1 and zwf2) and 6-phosphogluconate dehydrogenase (encoded by zwf3), were overexpressed with opc encoding a positive allosteric effector essential for Zwf activity in various combinations in Streptomyces lividans TK24. Most S. lividans transformants showed better cell growth and higher concentration of cytosolic NADPH than those of the control, and S. lividans TK24/pWHM3-Z23O2 containing zwf2+zwf3+opc2 showed the highest NADPH concentration but poor sporulation in R2YE medium. S. lividans TK24/pWHM3-Z23O2 in minimal medium showed the maximum growth (6.2 mg/ml) at day 4. Thereafter, a gradual decrease of biomass and a sharp increase of cytosolic NADPH and sedoheptulose 7-phosphate between days 2 and 4 and between days 1 and 3, respectively, were observed. Moreover, S. lividans TK24/pWHM3-Z23O2 produced 0.9 times less actinorhodin but 1.8 times more undecylprodigiosin than the control. These results suggested that the increased NADPH concentration and various intermediates from the PPP specifically triggered undecylprodigiosin biosynthesis that required many precursors and NADPH-dependent reduction reaction. This study is the first report on bespoke metabolic engineering of PPP routes especially suitable for producing secondary metabolites that need diverse primary precursors and NADPH, which is useful information for metabolic engineering in Streptomyces. PMID- 28838223 TI - Determination and Variation of Core Bacterial Community in a Two-Stage Full-Scale Anaerobic Reactor Treating High-Strength Pharmaceutical Wastewater. AB - Knowledge on the functional characteristics and temporal variation of anaerobic bacterial populations is important for better understanding of the microbial process of two-stage anaerobic reactors. However, owing to the high diversity of anaerobic bacteria, close attention should be prioritized to the frequently abundant bacteria that were defined as core bacteria and putatively functionally important. In this study, using MiSeq sequencing technology, the core bacterial community of 98 operational taxonomic units (OTUs) was determined in a two-stage upflow blanket filter reactor treating pharmaceutical wastewater. The core bacterial community accounted for 61.66% of the total sequences and accurately predicted the sample location in the principal coordinates analysis scatter plot as the total bacterial OTUs did. The core bacterial community in the first-stage (FS) and second-stage (SS) reactors were generally distinct, in that the FS core bacterial community was indicated to be more related to a higher-level fermentation process, and the SS core bacterial community contained more microbes in syntrophic cooperation with methanogens. Moreover, the different responses of the FS and SS core bacterial communities to the temperature shock and influent disturbance caused by solid contamination were fully investigated. Co-occurring analysis at the Order level implied that Bacteroidales, Selenomonadales, Anaerolineales, Syneristales, and Thermotogales might play key roles in anaerobic digestion due to their high abundance and tight correlation with other microbes. These findings advance our knowledge about the core bacterial community and its temporal variability for future comparative research and improvement of the two stage anaerobic system operation. PMID- 28838224 TI - Specific Expression of Interferon-gamma Induced by Synergistic Activation Mediator-Derived Systems Activates Innate Immunity and Inhibits Tumorigenesis. AB - The synergistic activation mediator (SAM) system can robustly activate endogenous gene expression by a single-guide RNA. This transcriptional modulation has been shown to enhance gene promoter activity and leads to epigenetic changes. Human interferon-gamma is a common natural glycoprotein involved in antiviral effects and inhibition of cancer cell growth. Large quantities of high-purity interferon gamma are important for medical research and clinical therapy. To investigate the possibility of employing the SAM system to enhance endogenous human interferon gamma with normal function in innate immunity, we designed 10 single-guide RNAs that target 200 bp upstream of the transcription start sites of the interferon gamma genome, which could significantly activate the interferon-gamma promoter reporter. We confirmed that the system can effectively and highly activate interferon-gamma expression in several humanized cell lines. Moreover, we found that the interferon-gamma induced by the SAM system could inhibit tumorigenesis. Taken together, our results reveal that the SAM system can modulate epigenetic traits of non-immune cells through activating interferon-gamma expression and triggering JAK-STAT signaling pathways. Thus, this strategy could offer a novel approach to inhibit tumorigenesis without using exogenous interferon-gamma. PMID- 28838225 TI - Role of alpha-Actinin 2 in Cytoadherence and Cytotoxicity of Trichomonas vaginalis. AB - Trichomonas vaginalis is a pathogen that triggers severe immune responses in hosts. T. vaginalis alpha-actinin 2 (Tvalpha-actinin 2) has been used to diagnose trichomoniasis. Tvalpha-actinin 2 was dissected into three parts; the N-terminal, central, and C-terminal portions of the protein (#1, #2, and #3, respectively). Western blot of these Tvalpha-actinin 2 proteins with pooled patients' sera indicated that #2 and #3, but not #1, reacted with those sera. Immunofluorescence assays of two different forms of T. vaginalis (trophozoites and amoeboid forms), using anti-Tvalpha-actinin 2 antibodies, showed localization of Tvalpha-actinin 2 close to the plasma membranes of the amoeboid form. Fractionation experiments indicated the presence of Tvalpha-actinin 2 in cytoplasmic, membrane, and secreted proteins of T. vaginalis. Binding of fluorescence-labeled Trichomonas to vaginal epithelial cells and prostate cells was decreased in the antibody blocking experiment using anti-Tvalpha-actinin 2 antibodies. Pretreatment of T. vaginalis with anti-rTvalpha-actinin 2 antibodies also resulted in reduction in its cytotoxicity. Flow cytometry, ligand-binding immunoblotting assay, and observation by fluorescence microscopy were used to detect the binding of recombinant Tvalpha-actinin 2 to human epithelial cell lines. Specifically, the truncated N-terminal portion of Tvalpha-actinin 2, Tvalpha-actinin 2 #1, was shown to bind directly to vaginal epithelial cells. These data suggest that alpha actinin 2 is one of the virulence factors responsible for the pathogenesis of T. vaginalis by serving as an adhesin to the host cells. PMID- 28838226 TI - Intradialytic exercise improves physical function and reduces intradialytic hypotension and depression in hemodialysis patients. AB - Background/Aims: As numbers of maintenance hemodialysis patients are growing, debilitating conditions of muscle wasting and atrophy are becoming some of the greatest concerns in end-stage renal disease patients. Exercise training has various potential benefits in terms of prevention of a sustained decline in functional status. This study aimed to evaluate the physical, psychological, laboratory, and dialysis-related effects of intradialytic exercise. Methods: We enrolled 22 patients from a hemodialysis center for a 6-month non-randomized prospective trial. Combination of aerobic exercise with bicycle ergometer and anaerobic exercise with elastic bands was conducted during hemodialysis. Data including physical fitness test results, dialysis-related measurements, and biochemical laboratory results were collected at baseline, 3, and 6 months. Depression and quality of life were assessed using Beck Depression Inventory and Short Form-36 health survey. Results: After exercise completion, there were significant improvements in back muscle power, forward and backward trunk flexibility, vertical jump, elbow flexion, sit to stand test, and 6-minute walk test (p < 0.05). No significant changes were observed in dry weight, blood pressure, Kt/V, and biochemical variables, except for intradialytic hypotension (p < 0.05). For depression, Beck Depression Inventory showed statistically significant enhancement (p < 0.05). Scores of Short Form-36 health survey did not show significant increase in each domain, except for bodily pain (p < 0.05). Conclusions: Combined aerobic and anaerobic exercise training during dialysis was found to be effective on physical health status, intradialytic hypotension, and depression in terms of mental health. Therefore, the findings of the current study may provide an appropriate guidance for encouraging exercise by nephrologists. PMID- 28838227 TI - Aromatase inhibitor use is a risk factor of carotid plaque presence in endocrine responsive breast cancer patients. AB - Background/Aims: The aromatase inhibitors (AIs) are well known anti-hormonal therapy in endocrine-responsive breast cancer patients. It can lead to dyslipidemia and be the risk factor of cardiovascular disease due to low estrogen level. However, some recent studies comparing AIs with placebo have shown controversial results. The aim of this study was to investigate lipid profiles, measurement of carotid intima-media thickness (IMT) and the presence of plaque among endocrine-responsive breast cancer treated with AIs compared to ones that were not treated with AIs. Methods: A total of 85 postmenopausal women, who underwent breast cancer surgery during the age of 50 to 64 without history of statin use were included. There were 42 patients who were treated with AIs over 1 year (group 1) and 43 patients without AIs use (group 2). Serum total cholesterol, high density lipoprotein cholesterol, triglycerides, fasting blood glucose, carotid IMT, and presence of plaque were assessed. Results: The baseline characteristics were similar between two groups and there was no significant difference in carotid IMT irrespective of AIs administration. However, ultrasonographic evaluation of carotid artery revealed that the presence of plaque in AI users was significantly higher than in non-AI users (66.7% vs. 41.9%, p = 0.02; odds ratio, 4.21 in adjusted model; p = 0.01). History of diabetes was also the significant risk factor for the plaque formation. Conclusions: There was no significant difference in lipid profile itself between two groups, but more importantly the presence of the plaque was much higher indicating possible detrimental effect of AI on cardiovascular system. PMID- 28838228 TI - Red blood cell distribution width is useful in discriminating adult onset Still's disease and sepsis within 24 hours after hospitalization. AB - BACKGROUND/AIMS: Red blood cell distribution width (RDW) is a value representing the heterogeneity in the size of red blood cell, and it is usually used in distinguishing types of anaemia. Recently, it was reported that it could reflect the burden of inflammation in diverse diseases and their prognosis. Hence, in this study, we investigated whether RDW may contribute to discriminating adult onset Still's disease (AOSD) from sepsis in serious febrile patients within 24 hours after hospitalization. METHODS: We reviewed the medical records and enrolled 21 AOSD patients, 27 sepsis patients and 30 matched healthy controls. We collected at least two laboratory results of variables including RDW within 24 hours after hospitalization, and we calculated their mean values. RESULTS: Sepsis patients showed the significantly increased median white blood cell count, compared to AOSD patients (14,390.0/mm3 vs. 12,390.0/mm3 , p = 0.010). The median RDW in sepsis patients was higher than that in AOSD patients (15.0% vs. 13.3%, p = 0.001), and furthermore, the median RDW in both patient-groups was significantly higher than that in healthy controls. In contrast, the median ferritin level in sepsis patients was lower than that in AOSD patients (544.0 mg/dL vs. 3,756.6 mg/dL, p = 0.001). In multivariate analysis, RDW >= 14.8% (odds ratio, 17.549) and ferritin < 2,251.0 mg/dL (odds ratio, 32.414) independently suggested sepsis more than AOSD in patients initially presenting with fever requiring hospitalization. CONCLUSION: RDW might be a rapid and helpful marker for a differential diagnosis between AOSD from sepsis at an early phase. PMID- 28838229 TI - Expression of Prostaglandin E2 Receptors in Acquired Middle Ear Cholesteatoma. AB - OBJECTIVES: To investigate the expression of prostaglandin E2 receptor subtypes, E-prostanoid (EP) 1-4 receptors, in acquired cholesteatoma and its possible role in the pathologic process of this disorder. METHODS: Specimens of human acquired cholesteatoma were obtained from 29 patients and 19 skin biopsies of normal external auditory canal were as controls. The mRNA and protein expression of EP receptors was assessed by quantitative real-time polymerase chain reaction, immunohistochemistry and Western blot. RESULTS: In acquired cholesteatoma, EP1 EP4 receptors were mainly expressed on squamous epithelium and subepithelial infiltrated inflammatory cells. In external auditory canal skin, EP1-EP4 receptors were mainly expressed on squamous epithelium and glandular epithelium. The expression of EP4 receptor on mRNA and protein levels were significant lower in acquired cholesteatoma compared with controls. EP1-EP3 receptors had no significant difference between the experimental and control group. CONCLUSION: Low expression of EP4 may play a crucial role in the pathologic process of inflammation reaction and bone destruction in acquired cholesteatoma, but not EP1, EP2, or EP3 receptors. PMID- 28838230 TI - Control of Multiple Exciton Generation and Electron-Phonon Coupling by Interior Nanospace in Hyperstructured Quantum Dot Superlattice. AB - The possibility of precisely manipulating interior nanospace, which can be adjusted by ligand-attaching down to the subnanometer regime, in a hyperstructured quantum dot (QD) superlattice (QDSL) induces a new kind of collective resonant coupling among QDs and opens up new opportunities for developing advanced optoelectric and photovoltaic devices. Here, we report the first real-time dynamics simulations of the multiple exciton generation (MEG) in one-, two-, and three-dimensional (1D, 2D, and 3D) hyperstructured H-passivated Si QDSLs, accounting for thermally fluctuating band energies and phonon dynamics obtained by finite-temperature ab initio molecular dynamics simulations. We computationally demonstrated that the MEG was significantly accelerated, especially in the 3D QDSL compared to the 1D and 2D QDSLs. The MEG acceleration in the 3D QDSL was almost 1.9 times the isolated QD case. The dimension-dependent MEG acceleration was attributed not only to the static density of states but also to the dynamical electron-phonon couplings depending on the dimensionality of the hyperstructured QDSL, which is effectively controlled by the interior nanospace. Such dimension-dependent modifications originated from the short-range quantum resonance among component QDs and were intrinsic to the hyperstructured QDSL. We propose that photoexcited dynamics including the MEG process can be effectively controlled by only manipulating the interior nanospace of the hyperstructured QDSL without changing component QD size, shape, compositions, ligand, etc. PMID- 28838231 TI - Separation of Silver Nanoparticles with Different Coatings by Capillary Electrophoresis Coupled to ICP-MS in Single Particle Mode. AB - The possibility of separating mixtures of Ag nanoparticles (NPs) with similar sizes but different surface coatings using capillary electrophoresis coupled to single particle inductively coupled mass-spectrometry (CE-SP-ICP-MS) was investigated. In two-component mixtures, it was possible to separate 40 nm sized polyvinylpirrolidone (PVP)- and citrate-coated NPs, 40 nm sized polyethylene glycol (PEG)- and citrate-coated NPs, and 60 nm sized PVP- and citrate-coated NPs. The separation of a more complex mixture containing NPs with the different coatings and sizes was successful, and each component, namely, 20, 40, and 60 nm sized citrate-coated and 40 and 60 nm sized PVP-coated NPs, could be distinguished. The theoretically expected migration order was confirmed by experimental results with selected Ag NPs. On the basis of the experimental observations, a separation mechanism that considers the effect of stable vs displaceable coatings during NP migration in CE is suggested. The ICP-MS was equipped with a prototype data acquisition system (MUsDAQ) that provided 5 MUs time resolution. PMID- 28838232 TI - Lipid Accumulation Mechanisms in Auto- and Heterotrophic Microalgae. AB - Microalgae lipids have attracted great attention in the world as a result of their potential use for biodiesel productions. Microalgae are cultivated in photoautotrophic conditions in most cases, but several species are able to grow under heterotrophic conditions, in which microalgae are cultivated in the dark where the cell growth and reproduction are supported by organic carbons. This perspective is covering the related studies concerning the difference between hetero- and autotrophic cultivation of microalgae. The auto- and heterotrophic central carbon metabolic pathways in microalgae are described, and the catalyzing reactions of several key metabolic enzymes and their corresponding changes in the protein level are summarized. Under adverse environmental conditions, such as nutrient deprivation, microalgae have the ability to highly store energy by forming triacylglycerol (TAG), the reason for which is analyzed. In addition, the biosynthesis of fatty acids and TAGs and their difference between auto- and heterotrophic conditions are compared at the molecular level. The positive regulatory enzymes, such as glucose transporter protein, fructose-1,6 bisphosphate aldolase, and glycerol-3-phosphate dehydrogenase, and the negative regulation enzymes, such as triose phosphate isomerase, played a crucial role in the lipid accumulation auto- and heterotrophic conditions. PMID- 28838233 TI - Intraorgan Targeting of Gold Conjugates for Precise Liver Cancer Treatment. AB - Intraorgan targeting of chemical drugs at tumor tissues is essential in the treatment of solid tumors that express the same target receptor as normal tissues. Here, asialoglycoprotein receptor (ASGP-R)-targeting paclitaxel conjugated gold nanoparticles (Gal/PTX-GNPs) are fabricated as a demonstration to realize the precise treatment of liver cancer. The enhanced biological specificity and therapeutic performance of drugs loaded on nanoparticles not only rely on the ligands on carriers for receptor recognition but are also determined by the performance of gold conjugates with designed structure. The tumor cell selectivity of the designed conjugates in liver tumor (HepG2) cells is close to six times of that incubated with control conjugates without galactose modification in liver normal (L02) cells. The drug level in tumor versus liver of Gal/PTX-GNPs is 121.0% at 8 h post injection, a 15.7-fold increase in the tumor specificity compared to that of GNPs conjugated with PTX only. This intraorgan targeting strategy results in a considerable improvement of performance in treating both Heps heterotopic and orthotopic xenograft tumor models, which is expected to be used for the enhanced antitumor efficacy and reduced hepatotoxicity in liver cancer treatment. PMID- 28838234 TI - Structural Characterization of Intact Glycoconjugates by Tandem Mass Spectrometry Using Electron-Induced Dissociation. AB - Characterizing the structures of glycoconjungates is important because of glycan heterogeneity and structural complexity of aglycon. The presence of relatively weak glycosidic linkages leads to preferential cleavages that limit the acquisition of structural information under typical mass spectrometry dissociation conditions, such as collision-induced dissociation (CID) and infrared multiphoton dissociation. In this paper, we explored the dissociation behaviors of different members of glycoconjugates, including glycopeptides, glycoalkaloids, and glycolipids, under electron-induced dissociation (EID) conditions. Using CID spectra as references, we found that EID is not only a complementary method to CID, but also a method that can generate extensive fragment ions for the structural characterization of all intact glycoconjugates studied. Furthermore, isomeric ganglioside species can be differentiated, and the double bond location in the ceramide moiety of the gangliosides can be identified through the MS3 approach involving sequential CID and EID processes. PMID- 28838235 TI - Initial Reactivity of Linkages and Monomer Rings in Lignin Pyrolysis Revealed by ReaxFF Molecular Dynamics. AB - The initial conversion pathways of linkages and their linked monomer units in lignin pyrolysis were investigated comprehensively by ReaxFF MD simulations facilitated by the unique VARxMD for reaction analysis. The simulated molecular model contains 15 920 atoms and was constructed on the basis of Adler's softwood lignin model. The simulations uncover the initial conversion ratio of various linkages and their linked aryl monomers. For linkages and their linked monomer aryl rings of alpha-O-4, beta-O-4 and alpha-O-4 & beta-5, the Calpha/Cbeta ether bond cracking dominates the initial pathway accounting for at least up to 80% of their consumption. For the linkage of beta-beta & gamma-O-alpha, both the Calpha O ether bond cracking and its linked monomer aryl ring opening are equally important. Ring-opening reactions dominate the initial consumption of other 4-O 5, 5-5, beta-1, beta-2, and beta-5 linkages and their linked monomers. The ether bond cracking of Calpha-O and Cbeta-O occurs at low temperature, and the aryl ring-opening reactions take place at relatively high temperature. The important intermediates leading to the stable aryl ring opening are the phenoxy radicals, the bridged five-membered and three-membered rings and the bridged six-membered and three-membered rings. In addition, the reactivity of a linkage and its monomer aryl ring may be affected by other linkages. The ether bond cracking of alpha-O-4 and beta-O-4 linkages can activate its neighboring linkage or monomer ring through the formed phenoxy radicals as intermediates. The important intermediates revealed in this article should be of help in deepening the understanding of the controlling mechanism for producing aromatic chemicals from lignin pyrolysis. PMID- 28838236 TI - Biopolymer-Drug Conjugate Nanotheranostics for Multimodal Imaging-Guided Synergistic Cancer Photothermal-Chemotherapy. AB - Some of the biomedical polymer-drug conjugates are being translated into clinical trials; however, they intrinsically lack photothermal and multi-imaging capabilities, hindering them from imaging-guided precision cancer therapy and complete tumor regression. We introduce a new concept of all-in-one biopolymer drug conjugate nanotheranostics and prepare a kind of intracellular pH-sensitive polydopamine-doxorubicin (DOX) conjugate nanoparticles (PDCNs) under mild conditions. Significantly, this strategy integrates polymeric prodrug-induced chemotherapy (CT), near-infrared (NIR) light-mediated photothermal therapy (PT), and triple modalities including DOX self-fluorescence, photothermal, and photoacoustic (PA) imaging into one conjugate nanoparticle. The PDCNs present excellent photothermal property, dual stimuli-triggered drug release behavior, and about 12.4-fold blood circulation time compared to free DOX. Small animal fluorescent imaging technique confirms that PDCNs have preferential tumor accumulation effect in vivo, giving a 12.8-fold DOX higher than the control at 12 h postinjection. Upon NIR laser irradiation (5 min, 808 nm, and 2 W.cm-2), the PDCN-mediated photothermal effect can quickly elevate the tumor over 50 degrees C, exhibiting good photothermal and PA imaging functions, of which the PA amplitude is 3.6-fold greater than the control. In vitro and in vivo assays persuasively verify that intravenous photothermal-CT of PDCNs produces synergistic antitumor activity compared to single PT or CT, achieving complete tumor ablation during the evaluation period. PMID- 28838237 TI - Competitive Inhibition of the Enzyme-Mimic Activity of Gd-Based Nanorods toward Highly Specific Colorimetric Sensing of l-Cysteine. AB - Gd-based nanomaterials offer interesting magnetic properties and have been heavily investigated for magnetic resonance imaging. The applicability of these materials beyond biomedical imaging remains limited. The current study explores the applicability of these rare-earth nanomaterials as nanozyme-mediated catalysts for colorimetric sensing of l-cysteine, an amino acid of high biomedical relevance. We show a facile solution-based strategy to synthesize two Gd-based nanomaterials viz. Gd(OH)3 and Gd2O3 nanorods. We further establish the catalytic peroxidase-mimic nanozyme activity of these Gd(OH)3 and Gd2O3 nanorods. This catalytic activity was suppressed specifically in the presence of l-cysteine that allowed us to develop a colorimetric sensor to detect this biologically relevant molecule among various other contaminants. This suppression, which could either be caused due to catalyst poisoning or enzyme inhibition, prompted extensive investigation of the kinetics of this catalytic inhibition in the presence of cysteine. This revealed a competitive inhibition process, a mechanism akin to those observed in natural enzymes, bringing nanozymes a step closer to the biological systems. PMID- 28838238 TI - Fabrication of Noncoplanar Molecule Aggregates with Inherent Porous Structures for Electrochemiluminescence Signal Amplification. AB - A simple and time-saving strategy was developed for the amplification of electrochemiluminescence (ECL) by dropping the noncoplanar tetraphenylethylene (TPE) solution on the surface of gold electrode. The self-assembled TPE aggregates exhibited inherent porous structures, endowing them with high specific surface area and oxygen adsorption capability. Therefore, the fabricated porous structures could lead to a 50-fold increase in the ECL signal of luminol in neutral aqueous solution, in comparison to that on the bare electrode. In contrast, the aggregates of the two typical coplanar polycyclic aromatic hydrocarbons (PAHs), perylene and pyrene, gave a weaker ECL enhancement, owing to their disc-like molecular structure and densely packed layers under aggregated conditions. The proposed ECL system has been successfully applied for the detection of hydrogen peroxide (H2O2) in the linear range of 0.25-1000 MUM with a detection limit (S/N = 3) of 0.1 MUM. Our findings provide inspiration for revealing the role of inherent molecular structure in the aggregate configuration, and they provide attractive perspectives for the usage of noncoplanar molecules in analytical applications. PMID- 28838239 TI - Automated Programmable Preparation of Carbonate-Bicarbonate Eluents for Ion Chromatography with Pressurized Carbon Dioxide. AB - We introduce a novel carbonate-bicarbonate eluent generation system in which CO2 is introduced using programmable CO2 pressures across a membrane into a flowing solution of electrodialytically generated high purity KOH. Many different gradient types are possible, including situations where gradients are run both on the [KOH] and the CO2 pressure. The system is more versatile than current electrodialytic carbonate eluent generators and can easily generate significantly higher eluent concentrations (at least to 40 mM carbonate), paving the way for future higher capacity columns. Demonstrably purer carbonate-bicarbonate eluent systems are possible compared to manually prepared carbonate-bicarbonate eluents and with considerable savings in time. Performance in different modes is examined. The dissolved CO2 is removed by a carbon dioxide removal device prior to detection. Best case noise levels are within a factor of 2-3 of best case suppressed hydroxide eluent operation. The eluent system allows particular latitude in controlling elution order/time of polyprotic acid analytes. Although CO2 introduction is possible prior to hydroxide eluent generation, this configuration causes complications because of electroreduction of CO2 to formate. PMID- 28838240 TI - Low-Temperature Molecular Layer Deposition Using Monofunctional Aromatic Precursors and Ozone-Based Ring-Opening Reactions. AB - Molecular layer deposition (MLD) is an increasingly used deposition technique for producing thin coatings consisting of purely organic or hybrid inorganic-organic materials. When organic materials are prepared, low deposition temperatures are often required to avoid decomposition, thus causing problems with low vapor pressure precursors. Monofunctional compounds have higher vapor pressures than traditional bi- or trifunctional MLD precursors, but do not offer the required functional groups for continuing the MLD growth in subsequent deposition cycles. In this study, we have used high vapor pressure monofunctional aromatic precursors in combination with ozone-triggered ring-opening reactions to achieve sustained sequential growth. MLD depositions were carried out by using three different aromatic precursors in an ABC sequence, namely with TMA + phenol + O3, TMA + 3-(trifluoromethyl)phenol + O3, and TMA + 2-fluoro-4 (trifluoromethyl)benzaldehyde + O3. Furthermore, the effect of hydrogen peroxide as a fourth step was evaluated for all studied processes resulting in a four precursor ABCD sequence. According to the characterization results by ellipsometry, infrared spectroscopy, and X-ray reflectivity, self-limiting MLD processes could be obtained between 75 and 150 degrees C with each of the three aromatic precursors. In all cases, the GPC (growth per cycle) decreased with increasing temperature. In situ infrared spectroscopy indicated that ring-opening reactions occurred in each ABC sequence. Compositional analysis using time-of flight elastic recoil detection indicated that fluorine could be incorporated into the film when 3-(trifluoromethyl)phenol and 2-fluoro-4 (trifluoromethyl)benzaldehyde were used as precursors. PMID- 28838242 TI - Real-Time Multiplex Kinase Phosphorylation Sensors in Living Cells. AB - Phosphorylation is an important post-translational modification implicated in cellular signaling and regulation. However, current methods to study protein phosphorylation by various kinases lack spatiotemporal resolution or the ability to simultaneously observe in real time the activity of multiple kinases in live cells. We present a peptide biosensor strategy with time correlated single photon counting-fluorescence lifetime imaging (TCSPC-FLIM) to interrogate the spatial and temporal dynamics of VEGFR-2 and AKT phosphorylation activity in real time in live 2D and 3D cell culture models at single cell resolution. By recording the increase in fluorescence lifetime due to a change in the solvatochromic environment of the sensor upon phosphorylation, we demonstrate that spatiotemporal maps of protein kinase activity can be obtained. Our results suggest that fluorescence lifetime imaging of peptide biosensors can be effectively and specifically used to monitor and quantify phosphorylation of multiple kinases in live cells. PMID- 28838243 TI - August 2017: Two Years of Submissions. PMID- 28838241 TI - Mechanism and Origins of Ligand-Controlled Stereoselectivity of Ni-Catalyzed Suzuki-Miyaura Coupling with Benzylic Esters: A Computational Study. AB - Nickel catalysts have shown unique ligand control of stereoselectivity in the Suzuki-Miyaura cross-coupling of boronates with benzylic pivalates and derivatives involving C(sp3)-O cleavage. The SIMes ligand (1,3-dimesityl-4,5 dihydroimidazol-2-ylidene) produces the stereochemically inverted C-C coupling product, while the tricyclohexylphosphine (PCy3) ligand delivers the retained stereochemistry. We have explored the mechanism and origins of the ligand controlled stereoselectivity with density functional theory (DFT) calculations. The oxidative addition determines the stereoselectivity with two competing transition states, an SN2 back-side attack type transition state that inverts the benzylic stereogenic center and a concerted oxidative addition through a cyclic transition state, which provides stereoretention. The key difference between the two transition states is the substrate-nickel-ligand angle distortion; the ligand controls the selectivity by differentiating the ease of this angle distortion. For the PCy3 ligand, the nickel-ligand interaction involves mainly sigma donation, which does not require a significant energy penalty for the angle distortion. The facile angle distortion with PCy3 ligand allows the favorable cyclic oxidative addition transition state, leading to the stereoretention. For the SIMes ligand, the extra d-p back-donation from nickel to the coordinating carbene increases the rigidity of the nickel-ligand bond, and the corresponding angle distortion is more difficult. This makes the concerted cyclic oxidative addition unfavorable with SIMes ligand, and the back-side SN2-type oxidative addition delivers the stereoinversion. PMID- 28838245 TI - The Nutritive Value of Organic and Conventional White Cabbage (Brassica Oleracea L. Var. Capitata) and Anti-Apoptotic Activity in Gastric Adenocarcinoma Cells of Sauerkraut Juice Produced Therof. AB - White cabbage is one of the most important vegetables grown both in Poland and worldwide. Cabbage contains considerable amounts of bioactive compounds such as glucosinolates, vitamin C, carotenoids, and polyphenols. Some experiments indicate that vegetables from organic production contain more bioactive compounds than those from conventional production, however, only a few studies have been conducted on cruciferous plants. The presented study has proved that organic fresh cabbage, compared to the conventional one, contained significantly less total flavonoids in both years of experiments (3.95 +/- 0.21 mg/100 g FW and 3.71 +/- 0.33 mg/100 g FW), several flavonoid compounds, total chlorophylls (1.51 +/- 0.17 mg/100 g FW and 1.30 +/- 0.22 mg/100 g FW) carotenoids, nitrites (0.55 +/- 0.04 mg/kg FW and 0.45 +/- 0.02 mg/kg FW), and nitrates (0.50 +/- 0.13 g/kg FW and 0.47 +/- 0.11 g/kg FW). The organic sauerkraut juice, compared to the conventional one, contained significantly more total polyphenols (5.39 +/- 0.22 mg/100 g FW and 9.05 +/- 1.10 mg/100 g FW) as well as several flavonoids. Only CONV sauerkraut juice produced with the highest N level of fertilization induced a statistical significant increase of the level of necrosis of human stomach gastric adenocarcinoma cell line AGS. PMID- 28838246 TI - Demographic and rural-urban variations in dental service utilization in Taiwan. AB - INTRODUCTION: This study assesses whether demographic and rural-urban variations in dental care service utilization still exist in Taiwan after 15 years of the implementation of universal health insurance coverage, which largely reduces financial barriers to dental care. METHODS: The data analysed in this cohort study were based on a random sample of one million beneficiaries retrieved from Taiwan's National Health Insurance Research Database (NHIRD) in 2005. The follow up was made between 2005 and 2010. Poisson regression models were used to explore the associations of dental service utilization rates with urbanization and demographic characteristics. RESULTS: The highest and lowest rates of preventive dental care were obtained in people aged 55-64 years (579.2/1000 person-years) and <15 years (178.6/1000 person-years). The corresponding figures for curative care were 1592.0/1000 person-years (<15 years) and 757.2/1000 person-years (35-44 years). Compared with the people living in the least urbanized areas, those from the most urbanized areas presented significantly higher rates of preventive and curative dental services; a greater estimated rate ratio was noted for preventive services than for curative services (1.57 vs 1.42). CONCLUSIONS: The urban-rural disparity in dental care service utilization still exists after 15 years of the implementation of the national health insurance in Taiwan, suggesting that factors other than affordability may play roles in such disparity. PMID- 28838247 TI - The auditory and vestibular toxicities induced by antiepileptic drugs. AB - INTRODUCTION: Epilepsy is a chronic medical disease in one third of patients and is associated with comorbid adverse somatic conditions due to epilepsy itself or its long-term treatment with antiepileptic drugs (AEDs). Data from experimental, cross-sectional and prospective studies have evidence for the deleterious effect of some AEDs on the auditory and vestibular systems. These abnormalities may be reversible or irreversible. Areas covered: This article review the evidence that long-term treatment with some antiepileptic drugs (AEDs) [e.g. carbamazepine, phenytoin, valproate, lamotrigine, gabapentin, vigabatrin and oxcarbazepine] (even in therapeutic drug doses) may result in tinnitus, phonophobia, sensorineural hearing loss, dizziness, ataxia, disequilibrium, imbalance, nystagmus, abnormalities in saccadic and pursuit eye movements and delayed conduction within the cochlea, auditory nerve and brainstem auditory pathways evidenced by abnormalities in Brainstem auditory evoked potentials and nystagmography recordings indicating auditory and central and/or peripheral vestibular dysfunctions. Expert opinion: Identification of monitoring of patients at high risk for developing audio-vestibular manifestations is necessary for appropriate preventive and therapeutic measures. PMID- 28838249 TI - Filgotinib for the treatment of rheumatoid arthritis. AB - INTRODUCTION: Biologics were the first targeted therapies for rheumatoid arthritis (RA), having in common high clinical efficacy. Being proteins, they are administered parenterally. The first oral targeted small molecules approved for RA are competitive inhibitors of the Janus kinase (JAK) enzyme family which mediate signalling for a cytokine subset important in RA pathogenesis. Areas covered: Several JAK inhibitors have been developed with differing selectivity for the four JAK enzymes with a view to generating oral, multi-cytokine inhibitors. Here we review the pharmacology and clinical trial data for efficacy and safety of filgotinib, an investigational selective JAK1 inhibitor. We contextualise the contemporary approach to RA management and substantial unmet needs that remain. Expert opinion: The selectivity of filgotinib for JAK1 may have theoretical advantages in terms of limiting toxicity. However, establishing whether this is so before larger numbers of patients are exposed in phase III and beyond in the real word setting, will be difficult. Filgotinib clinical trial data to date has been encouraging with rapid, sustained efficacy with promising safety and tolerability. We are likely to see an expanding choice of approved JAK inhibitors in the clinic but it may not be straightforward to distinguish safety and efficacy differences. PMID- 28838248 TI - The relevance of personality traits in impulsivity-related disorders: From substance use disorders and gambling disorder to bulimia nervosa. AB - Background and aims The main aim of this study was to analyze and describe the clinical characteristics and shared personality traits in different impulsivity compulsivity spectrum disorders: substance use disorders (SUD), gambling disorder (GD), and bulimia nervosa (BN). The specific aims were to compare personality differences among individuals with pure SUD, BN with and without SUD, and GD with and without SUD. In addition, we assessed the differential predictive capacity of clinical and personality variables in relation to diagnostic subtype. Methods The sample comprised 998 subjects diagnosed according to DSM-IV-TR criteria: 101 patients were diagnosed with SUD, 482 with GD, 359 with BN, 11 with GD + SUD, and 45 patients with BN + SUD. Various assessment instruments were administered, as well as other clinical measures, to evaluate their predictive capacity. Results Marked differences in personality traits were observed between groups. Novelty seeking, harm avoidance, self-directedness, cooperation, and self-transcendence best differentiated the groups. Notably, novelty seeking was significantly higher in the two dual pathology subgroups. Patients with dual pathology showed the most dysfunctional personality profiles. Discussion and conclusion Our results indicate the existence of shared dysfunctional personality traits among the groups studied, especially in novelty seeking and self-directedness. PMID- 28838250 TI - An update on drug design strategies to prevent acquired sensorineural hearing loss. AB - INTRODUCTION: Acute sensorineural hearing loss is a dramatic event for the patient. Different pathologies might result in acute sensorineural hearing loss, such as sudden hearing loss, exposure to medications/drugs or loud sound. Current therapeutic approaches include steroids and hyperbaric oxygen in addition to other methods. Research activities of the past have shed light on the molecular mechanisms involved in damage to hair cells, the synapses at the hair cell spiral ganglion junction and the stria vascularis. Molecular events and signaling pathways which underlie damage to these structures have been discovered. Areas covered: This paper summarizes current research efforts involved in investigating the molecular mechanisms involved in acute sensorineural hearing loss. Expert opinion: While progress has been made in unraveling basic mechanisms involved in acute sensorineural hearing loss, it is difficult to translate basic concepts to the clinic. There are often conflicting data in animal and human studies on the effect of a given intervention. There is also a lack of high quality clinical trials (double blind, placebo controlled and high powered). However, this author is confident that research efforts will pay out and that some of these efforts will translate into new therapeutic options for patients with acute hearing loss. PMID- 28838251 TI - Increased Risk of Smoking in Female Adolescents Who Had Childhood ADHD. AB - OBJECTIVE: This study examined the effects of childhood attention deficit hyperactivity disorder (ADHD) symptoms, both inattention and hyperactivity impulsivity, on the development of smoking in male and female adolescents. METHOD: Twin difference methods were used to control for shared genetic and environmental confounders in three population-based, same-sex twin samples (N=3,762; 64% monozygotic). One cohort oversampled female adolescents with ADHD beginning in childhood. Regressions of childhood inattentive and hyperactive impulsive symptoms were conducted to predict smoking outcomes by age 17. ADHD effects were divided into those shared between twins in the pair and those nonshared, or different within pairs. RESULTS: Adolescents who had more severe ADHD symptoms as children were more likely to initiate smoking and to start smoking younger. The association of ADHD symptoms with daily smoking, number of cigarettes per day, and nicotine dependence was greater in females than in males. Monozygotic female twins with greater attentional problems than their co-twins had greater nicotine involvement, consistent with possible causal influence. These effects remained when co-occurring externalizing behaviors and stimulant medication were considered. Hyperactivity-impulsivity, while also more strongly related to smoking for female adolescents, appeared primarily noncausal. CONCLUSIONS: Smoking initiation and escalation are affected differentially by ADHD subtype and gender. The association of inattention with smoking in female adolescents may be causal, whereas hyperactivity-impulsivity appears to act indirectly, through shared propensities for both ADHD and smoking. PMID- 28838252 TI - NanoMIL-100(Fe) containing docetaxel for breast cancer therapy. AB - Metal-organic frameworks, such as MIL-100, have been recently introduced as promising drug carriers due to their notable characteristics such as stability, biocompatibility and owning large porosity which may admit a broad range of drugs with different molecular sizes. In this study, we firstly proposed an accessible top-down approach using ultrasound method to prepare nanoMIL-100 and secondly, evaluated its potentials as an anticancer nanocarrier. This is the first report that docetaxel (DTX) as a highly hydrophobic anticancer drug was encapsulated in nanoMIL-100 with the drug payload of 57.2 wt%. Characterizations of the prepared nanoMIL-100 and DTX-loaded nanoMIL-100 were performed by PXRD, FT-IR, N2 adsorption, DLS and FE-SEM. Moreover, the drug loading and release processes were quantified by HPLC. The in vitro release of DTX from the prepared nanocarrier was investigated in two pH values, 7.4 and 5.5. The toxic effect of DTX-loaded nanoMIL-100 was examined on human breast cancer cell line, MCF-7, and a significant decrease was observed in IC50 value (0.198 MUg/mL) at the first 24 h in comparison with the free drug (4.9908 MUg/mL). This nanocarrier may, thus offer promising potentials as a novel cytotoxic drug delivery system. PMID- 28838253 TI - 70% Ethanol for Decontamination of Central Venous Lines Exposed to Calcineurin Inhibitors. AB - BACKGROUND: Tacrolimus, commonly used for graft versus host disease prophylaxis is usually administered via a dedicated central venous line (CVL) and trough levels drawn from the unexposed lumen. Being an oil-based medication, it may be adsorbed to the inner lumen of the CVL and result in falsely high levels drawn from an inadvertently exposed lumen. There is no treatment for decontamination of such CVLs, and natural decay occurs over months before the CVL can be used to draw reliable trough levels. OBJECTIVE: The primary objective of the study was to estimate the effectiveness of 70% ethanol locks for decontaminating CVLs exposed to tacrolimus. METHODS: We studied the efficacy of 70% ethanol lock in decontaminating CVLs exposed to tacrolimus in patients during transplant. Trough tacrolimus levels were drawn from the exposed and unexposed (control) lumens at 8:00 am, followed by a 2-mL 70% ethanol lock instilled for a 2-hour dwell into the exposed (intervention) lumen. Trough tacrolimus levels were again drawn from both lumens at 8:00 pm and levels compared for efficacy. RESULTS: All 20 sets showed a high 8 am trough level in the exposed intervention arm (median = 30 ng/mL), significantly greater ( P < 0.0001) than that in the control arm (median = 9.05 ng/mL), and were contaminated. After the 2-hour ethanol lock, 65% of the lumens were decontaminated. The difference between the control and intervention arms was no longer found to be statistically significant ( P = 0.0826). CONCLUSION: A 2-hour 70% ethanol lock is effective for decontamination of CVLs exposed to tacrolimus. PMID- 28838256 TI - Comparative study of different polymeric coatings for the next-generation magnesium-based biodegradable stents. AB - Development of next-generation bioabsorbable stents based on magnesium alloys is gaining lots of attention. However, finding an appropriate coating in order to enhance its corrosion resistance along with preserving other requirements is still a challenge. In this study, three FDA-approved polymers, namely poly(lactic acid), polycaprolactone and poly(lactic-co-glycolic acid), have been investigated as potential coatings for magnesium-based stents to enhance their corrosion resistance, biocompatibility and haemocompatibility. Potentiodynamic and electrochemical impedance spectroscopy results demonstrated that PLA and PLGA coating performed better in improving corrosion resistance in comparison with uncoated and other coated samples. Although all coated and bare samples displayed desirable results of haemocompatibility assays, PLA-coated samples showed better outcome in terms of biocompatibility. The results revealed that PLA can be considered as a potential coating material to enhance the main characteristics of magnesium-based bioabsorbable stents. PMID- 28838257 TI - Advanced patient age at diagnosis of diffuse large B-cell lymphoma is associated with molecular characteristics including ABC-subtype and high expression of MYC. AB - The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age being patient age at diagnosis an adverse prognostic factor. However, elderly patients are often underrepresented in common studies. To investigate the effect between age and biological characteristics in DLBCL, we analyzed data of 1534 patients encompassing all adult age groups, enriched for the age >=75 years. Follicular lymphoma (FL) grade 3B with histopathological characteristics of DLBCLs were included. Gender, centroblastic cytology, FL grade 3B morphology, CD10 expression, and ABC/non-GCB-subtype were significantly associated with age after correction for multiple testing and after adjusting for cohorts. Analysis of a subgroup points towards an association of MYC expression with age. Our data indicate that biological features of DLBCL and FL grade 3B are associated with increasing age among adult patients. The prevalence of the ABC/non-GCB-subtype in elderly patients suggests that therapies targeting this molecular subtype should be specifically explored in this subgroup. PMID- 28838258 TI - The protective effects of bone morphogenetic protein-7 against epithelial injury and matrix metalloproteases upregulation induced by silica in vitro. AB - OBJECTIVE: We investigate the effects of bone morphogenetic protein-7 (BMP-7) on models with silica-induced and macrophage-mediated fibrosis and its possible mechanisms in vitro. METHODS: Rat alveolar II epithelial (RLE-6TN) cells were incubated with the supernatant of mouse macrophage-like cells (RAW264.7) and treated with 0, 25, 50, and 100 MUg/mL silica. Using Western blotting, the epithelial markers (surfactant proteins-C and E-cadherin) and the mesenchymal markers (fibronectin (FN) and viminten (Vim)) were detected. After neutralizing the BMP-7, the progress of fibrosis was assessed by the content of hydroxyproline (Hyp) and collagen I, III protein levels as well as the Smad signaling pathway proteins, including phosphorylated Smad1/5(P-Smad1/5) and phosphorylated Smad2/3(P-Smad2/3). Collagen I was also identified by immunofluorescence and pretreated with SB-431542, LDN-193189, or anti-BMP-7-neutralizing antibody. In addition, the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected using Western blotting. RESULTS: The model of RLE-6TN cells was established successfully, the expressions of Vim, FN, MMP-2, and MMP-9 were upregulated, while the concentration of silica is increased. Neutralizing BMP-7 stimulated the decrease of P-Smad1/5 and the increase of P-Smad2/3, as well as the collagen I, collagen III, FN, and Hyp via Smad signaling pathway. Furthermore, pretreated with LDN-193189 or anti-BMP-7-neutralizing antibody, the expression of collagen I was increased, yet it was decreased with SB-431542 intervention. CONCLUSION: The activated BMP/Smad and suppressed transforming growth factor-beta/Smad pathways could suppress silica-induced fibrosis via a MMP dependent mechanism. BMP-7 is expected to be the optimized strategy of delaying the interstitial changes. PMID- 28838259 TI - A study on the safety evaluation of buphrenorphine administered through an autoinjector compared with manual injection using haematological and biochemical variables in rats. AB - Buprenorphine drug cartridge was made for autoinjector device for use in emergency and critical situations to reduce the morbidity and mortality. Water filled cartridges were prepared and buprenorphine was injected aseptically in the cartridge, to make 0.05 and 0.10 mg/mL. Rats were injected intraperitoneally, buprenorphine (0.3 and 0.6 mg/kg), repeatedly with the autoinjector and compared with manual injection (7 days and 14 days) using various haematological and biochemical parameters. No significant change was observed in the body weight, organ to body weight ratio and haematological variables in any of the experimental groups compared with the control group. Except serum urea and aspartate aminotransferase, no significant change was observed in glucose, cholesterol, triglycerides, bilirubin, protein, albumin, creatinine, uric acid, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase. The autoinjectors deliver the drugs with spray effect and force for faster absorption. In the present study, the autoinjector meant for intramuscular injection was injected intraperitoneally in rats, and the drug was delivered with force on the vital organs. No significant difference was observed in the autoinjector group compared to the manual group showing tolerability and safety of the buphrenorphine autoinjector. This study shows that buprenorphine autoinjector can be considered for further research work. PMID- 28838260 TI - Development and psychometric evaluation of the Thirst Distress Scale for patients with heart failure. AB - BACKGROUND: Patients with heart failure can experience thirst distress. However, there is no instrument to measure this in patients with heart failure. The aim of the present study was to develop the Thirst Distress Scale for patients with Heart Failure (TDS-HF) and to evaluate psychometric properties of the scale. METHODS AND RESULTS: The TDS-HF was developed to measure thirst distress in patients with heart failure. Face and content validity was confirmed using expert panels including patients and healthcare professionals. Data on the TDS-HF was collected from patients with heart failure at outpatient heart failure clinics and hospitals in Sweden, the Netherlands and Japan. Psychometric properties were evaluated using data from 256 heart failure patients (age 72+/-11 years). Concurrent validity of the scale was assessed using a thirst intensity visual analogue scale. Patients did not have any difficulties answering the questions, and time taken to answer the questions was about five minutes. Factor analysis of the scale showed one factor. After psychometric testing, one item was deleted. For the eight item TDS-HF, a single factor explained 61% of the variance and Cronbach's alpha was 0.90. The eight item TDS-HF was significantly associated with the thirst intensity score ( r=0.55, p<0.001). Regarding test-retest reliability, the intraclass correlation coefficient was 0.88, and the weighted kappa values ranged from 0.29-0.60. CONCLUSION: The eight-item TDS-HF is valid and reliable for measuring thirst distress in patients with heart failure. PMID- 28838261 TI - Baseline serum bicarbonate levels independently predict short-term mortality in critically ill patients with ischaemic cardiogenic shock. AB - BACKGROUND: Cardiogenic shock is a feared complication of acute myocardial infarction with high mortality rates. Data on the predictive role of acid base dysregulation in this clinical setting are sparse. We therefore embarked on investigating the predictive role of serum bicarbonate in critically ill intensive care unit (ICU) patients with cardiogenic shock. METHODS: A total of 165 ischaemic cardiogenic shock patients (118 men, aged 68.4 years (interquartile range 59.0-77.4), APACHE II score 26.0 (interquartile range 21.0-29.0), after percutaneous coronary intervention were included in a single-centre analysis. Percutaneous coronary intervention-related data such as left ventricular ejection fraction and laboratory indices were recorded and routine clinical follow-up was obtained at hospital discharge and at one year. All-cause mortality was assessed and data were analysed using univariate and multivariate models. RESULTS: All cause mortality was highest (17%) during the first 48 hours following ICU admission (28-day mortality rate 43%). In a multiple regression model, age (hazard ratio (HR) 1.035, 95% confidence interval (CI) 1.011-1.059, P=0.004), APACHE II score (HR 1.036, 95% CI 1.002-1.072, P=0.037) and baseline serum bicarbonate levels (HR 0.93, 95% CI 0.866-0.998, P=0.046) independently predicted 28-day mortality (overall model fit chi2 22.9, P<0.0001). The HR for patients in the lowest baseline serum bicarbonate tertile for 365-day mortality was HR 2.06 (95% CI 1.20-3.53). CONCLUSIONS: In a large cohort of consecutive cardiogenic shock patients hospitalised in the ICU, low serum bicarbonate levels at admission independently predicted mortality. Given the widespread availability of blood gas analysers in ICUs, we propose baseline serum bicarbonate levels as an additional biomarker for identification and stratification of cardiogenic shock patients at risk. PMID- 28838262 TI - Editor's presentation. PMID- 28838263 TI - Evaluation of oxidative stress via protein expression of glutathione S transferase and cytochrome p450 (CYP450) isoenzymes in psoriasis vulgaris patients treated with methotrexate. AB - INTRODUCTION: Oxidative stress is the imbalance between oxidant-antioxidant systems and may play a major role in the psoriasis pathogenesis. Cytochrome (CYP) is a family of enzymes that are responsible for the metabolism of various endogenous and exogenous substances such as drug metabolism. Most importantly, the antioxidant system is the glutathione S-transferases (GST), which decrease oxidative stress by reducing oxidative products. AIM: We aimed to evaluate the expressions of isoenzymes of GST and CYP families and the beneficial role of metotrexate (MTX) in this process. MATERIAL AND METHODS: This study included 21 patients with psoriasis and 22 healthy subjects. We treated all the patients with 10-15 mg/week of MTX for minimum 12 weeks. Expressions of GST and CYP enzymes were assessed by immunohistochemical staining. RESULTS: GSTK1, GSTM1 and GSTT1 expressions were significantly higher in the psoriasis tissues than in the control tissues (p < 0.05; p < 0.05; p < 0.05, respectively). In the psoriasis patients, GSTO1 expression was similar the control group. CYP1B1 and CYP2E1 expressions were significantly higher in the pre-treatment and post-treatment psoriasis tissues than in the control tissues (p < 0.05; p < 0.05; p < 0.05; p < 0.05, respectively). CONCLUSION: We found a significant increase in the tissue levels of, either expression of GST, or CYP, which has important role in drug metabolism and oxidative stress. MTX treatment resulted in marked clinical improvement, yet we found that MTX did not have any significant effect on these parameters. CYP2E1 is especially the most important enzyme for MTX metabolism since it is the primarily responsible of the toxic metabolism of various drugs. The other experimental studies involving greater number of patients and other different drug are needed to enlighten the role of oxidant and antioxidant systems and the other possible mechanisms for the pathogenesis of psoriasis. PMID- 28838264 TI - Comparative genomic analysis of PML and RARA breakpoints in paired diagnosis/relapse samples of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. PMID- 28838265 TI - Ninety-day post-operative morbidity and mortality using the National Cancer Institute's common terminology criteria for adverse events better describe post operative outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: The post-operative morbidity and mortality after CRS-HIPEC has been widely evaluated. However, there is a major discrepancy between rates reported due to different metrics and time of analysis used. OBJECTIVE: To evaluate the legitimacy of 90-day morbidity and mortality based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 classification as criteria of quality for cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: A prospective database of all patients undergoing CRS-HIPEC for peritoneal carcinomatosis between 2004 and 2015 was queried for 90-day morbidity and mortality and survival. RESULTS: Among 881 patients, the 90-day major complication rate based on NCI-CTCAE classification and Clavien-Dindo's classification were 51% (n = 447 patients) and 25% (n = 222 patients), respectively. Among patients who presented with a 90-day complication based on the NCI-CTCAE classification, 50% (n = 225 patients) presented a medical complication not reported by Clavien-Dindo's classification. After surgery, 24 patients (2.7%) died of post-operative complications, for only 10 (42%) of them the death occurred within 30-day after surgery. Occurrence of major complication based on either NCI-CTCAE classification, Clavien-Dindo's classification or the medical complication not reported by Clavien-Dindo's classification all negatively impacts the overall survival. CONCLUSION: Among commonly reported morbidity's classification, 90-day morbidity based on NCI-CTCAE classification represents a legitimate metric of CRS HIPEC quality. Post-operative morbidity after CRS-HIPEC should be reported using 90-day NCI-CTCAE classification. PMID- 28838266 TI - Recurrence of extreme serum analytes in consecutive pregnancies and association with obstetrical outcomes. AB - OBJECTIVE: To evaluate if presence of extreme maternal serum biochemical analytes recurs in consecutive pregnancies. We hypothesized that presence of >1 extreme analyte in prior pregnancy is associated with increased risk of adverse pregnancy outcome in subsequent pregnancy. METHODS: Retrospective cohort study of singleton pregnancies evaluated and delivered in 2 consecutive pregnancies (2011-2015). Adverse outcomes were defined as indicated preterm delivery before 37 completed weeks due to preeclampsia, fetal growth restriction or other complications. RESULTS: First and second trimester maternal serum analytes were assessed in 1434 patients in 2 consecutive pregnancies. The presence of >1 extreme serum analyte in prior pregnancy significantly increased likelihood of >1 extreme analyte in subsequent pregnancy. The likelihood increased as number of prior extreme markers increased. In patients with normal outcomes and 2 or more extreme serum analytes in prior pregnancy, there was an increased incidence of adverse pregnancy outcomes in subsequent pregnancy with relative risk (RR) of 5.42 [95% CI 1.6 18.3]. CONCLUSIONS: The presence of more than 1 extreme serum marker in one pregnancy increases likelihood of recurrence in subsequent pregnancies. Risk of adverse outcomes in subsequent pregnancy can be evaluated based on biochemistry results as well as prior pregnancy outcomes. PMID- 28838268 TI - Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies. AB - Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways. Many of these strategies involve downregulation of Mcl-1, a pro-survival Bcl-2 family member that is not targeted by venetoclax, and which often confers resistance to this agent. Given encouraging clinical results involving venetoclax in both lymphoid and myeloid malignancies, it is likely that such combination approaches will be incorporated into the therapeutic armamentarium for multiple hematologic malignancies in the near future. PMID- 28838269 TI - alpha0-Thalassemia Due to a 90.7 kb Deletion (- -NFLD). AB - We report an alpha0-thalassemia (alpha0-thal) trait in Newfoundlanders caused by a novel 90.7 kb deletion. The deletion, designated the Newfoundland deletion (- NFLD), removes both the HBA2 and HBA1 genes, while leaving the HBZ gene intact. The 5' deletion endpoint is within the HBAP1 pseudogene, approximately 3.7 kb upstream of the HBA2 gene. The 3' deletion endpoint is approximately 82.5 kb downstream of the HBA1 gene, within the second intervening sequence (IVS-II) of the FAM234A gene. This is the second alpha0-thal deletion reported in Newfoundland families of northern European descent. PMID- 28838270 TI - Surgical outcome evaluation of perforated gastric cancer: from the aspects of both acute care surgery and surgical oncology. AB - BACKGROUND: Perforated gastric cancer (PGC) is a rare condition of gastric cancer (GC). In this study, we sought to assess the outcome of PGC from the aspects of both acute care surgery and surgical oncology at a single institute, Chang Gung Memorial Hospital (CGMH). METHODS: From 1997 to 2013, 6864 patients were diagnosed with GC and 2738 were diagnosed with gastroduodenal perforation at CGMH. In total, 29 patients with PGC were identified. Immediate surgical and long term oncologic outcomes were evaluated after an appropriate matching process was performed. RESULTS: The immediate surgical outcome of PGC, i.e., the hospital mortality rate within 30 d after surgery, did not significantly differ from that of non-cancer related gastroduodenal perforation. The long-term oncologic outcome, with matching by age, gender, year of surgery and AJCC 7th stage grouping, also did not significantly differ from that of GC without perforation. CONCLUSIONS: Aggressive surgical treatment, including an initial emergency procedure for containing peritonitis and radical surgery for GC, may benefit PGC patients in terms of both the immediate and oncologic outcomes. PMID- 28838271 TI - An update on biomarkers for kinase inhibitor response in non-small-cell lung cancer. AB - INTRODUCTION: The discovery of activating genetic and their use as predictive biomarkers for targeted therapy, such as tyrosine kinase inhibitors (TKIs), has changed the treatment paradigm of non-small cell lung cancer (NSCLC). As a result, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) TKIs have become the standard first-line treatment. Since then, other kinds of targetable oncogenic alterations have been identified in NSCLC. Several novel, molecularly-targeted TKIs have now achieved regulatory approval, while many others are currently in early- or late-phase clinical trial testing. These TKIs have significantly impacted and changed clinical outcomes for advanced NSCLC. Areas covered: In this review, the authors discuss recent evidence and progress in targeted therapies, especially small molecular tyrosine kinase inhibitors, matched with their biomarkers for the treatment of advanced NSCLC. Expert commentary: Although targeted therapies dramatically improve the outcome of patients with NSCLC harboring specific oncogenic alterations, molecular and clinical resistance almost invariably develops. New TKIs specifically active in molecular subgroups of NSCLC or the resistance setting have now been developed. The development of additional TKIs and rational combinations may further improve outcomes of NSCLC. PMID- 28838267 TI - Immunogenicity and efficacy of DNA/MVA HIV vaccines in rhesus macaque models. AB - INTRODUCTION: Despite 30 years of research on HIV, a vaccine to prevent infection and limit disease progression remains elusive. The RV144 trial showed moderate, but significant protection in humans and highlighted the contribution of antibody responses directed against HIV envelope as an important immune correlate for protection. Efforts to further build upon the progress include the use of a heterologous prime-boost regimen using DNA as the priming agent and the attenuated vaccinia virus, Modified Vaccinia Ankara (MVA), as a boosting vector for generating protective HIV-specific immunity. Areas covered: In this review, we summarize the immunogenicity of DNA/MVA vaccines in non-human primate models and describe the efficacy seen in SIV infection models. We discuss immunological correlates of protection determined by these studies and potential approaches for improving the protective immunity. Additionally, we describe the current progress of DNA/MVA vaccines in human trials. Expert commentary: Efforts over the past decade have provided the opportunity to better understand the dynamics of vaccine induced immune responses and immune correlates of protection against HIV. Based on what we have learned, we outline multiple areas where the field will likely focus on in the next five years. PMID- 28838272 TI - Molecular mechanisms and clinical implications of miRNAs in drug resistance of esophageal cancer. AB - INTRODUCTION: With the increasing incidence of esophageal cancer, drug resistance is becoming a major obstacle to successful cancer therapy since chemotherapy is regarded as a curative approach to inhibit cancer cell proliferation. Despite the great progress in anticancer treatment achieved during the last decades, the mechanisms of multidrug resistance have not been completely elucidated. Recently, accumulating studies and pre-clinical reports highlighted the role of miRNAs in the drug resistance of esophageal cancer. Areas covered: In this review, we mainly summarized the current advances of miRNAs in esophageal cancer and the mechanisms underlying drug resistance. We also reviewed the potential role of miRNAs as biomarkers for predicting drug response and prognosis. Finally, we envisaged the future orientation and challenges in translating the existing knowledge of drug resistance related miRNAs into clinical applications. Expert commentary: Based on the current knowledge of certain miRNAs, we believe that miRNAs would be helpful to overcome the drug resistance and provide personalized treatment for patients with esophageal cancer. The aims of this study were to provide a comprehensive summary on the emerging role of miRNAs in the drug resistance of esophageal cancer and attract broad attention of more researchers on this field. PMID- 28838273 TI - Switching maintenance infliximab therapy to biosimilar infliximab in inflammatory bowel disease patients. AB - BACKGROUND: Clinical use of biosimilar infliximab (CT-P13) in inflammatory bowel diseases (IBDs) is based on extrapolation of indication from clinical studies performed in rheumatological diseases. Only few data exist of behaviour of infliximab trough levels (TLs) and anti-drug antibodies (ADAs) during switching. AIM: The objective of this study was to evaluate changes in TLs, ADA formation and disease activity after switching from originator infliximab to biosimilar one. METHODS: All our IBD patients receiving maintenance infliximab therapy were switched to biosimilar infliximab. TLs and ADAs were measured before the last originator infusion and before the third biosimilar infusion. Laboratory values, disease activity indices (partial Mayo score and Harvey-Bradshaw index) and demographic data were collected from patient records. RESULTS: A total of 62 patients were included in the final analysis (32 Crohn's disease, 30 ulcerative colitis (UC) or IBD-unclassified). No significant changes in median TLs before (5.5 mg/l) and after switching (5.5 mg/l, p = .05) occurred in the entire study group or in the Crohn's disease (CD) subgroup (5.75 and 6.5 mg/l, p = .68). However, in the subgroup of ulcerative colitis, the change in median TL was significantly different (from 5.2 to 4.25 mg/l, p = .019). Two patients developed ADAs after switching. No changes in disease activity were detected during switching and no safety concerns occurred. CONCLUSIONS: Switching from originator to biosimilar infliximab resulted in statistically significant differences in infliximab TLs in patients with UC but not in patients with Crohn's disease. The clinical significance for this difference is doubtful and in neither group changes in disease activity occurred. PMID- 28838274 TI - Catheter and laryngeal mask endotracheal surfactant therapy: does the mannequin count? PMID- 28838275 TI - The role of cell-free DNA in predicting colorectal cancer prognosis. AB - INTRODUCTION: Colorectal cancer is a cancer of the digestive system with poor prognosis. Cell-free DNA has received much attention with its unique predominance, especially in colorectal cancer. Areas covered: This study has summarized recent advancements and challenges regarding cell-free DNA in predicting CRC prognosis. Furthermore, the authors make predictions on the potential developments concerning cell-free DNA in future prognosis prediction techniques. Expert commentary: Cell-free DNA has the value of predicting CRC prognosis as an important biomarke. Further clinical trials should be performed to promote translating cell-free DNA into clinical applications. PMID- 28838276 TI - Real life experience with frontline azacitidine in a large series of older adults with acute myeloid leukemia stratified by MRC/LRF score: results from the expanded international E-ALMA series (E-ALMA+). AB - Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA. PMID- 28838277 TI - Tolerable delay for speech production and perception: effects of hearing ability and experience with hearing aids. AB - OBJECTIVE: Processing delay is one of the important factors that limit the development of novel algorithms for hearing devices. In this study, both normal hearing listeners and listeners with hearing loss were tested for their tolerance of processing delay up to 50 ms using a real-time setup for own-voice and external-voice conditions based on linear processing to avoid confounding effects of time-dependent gain. DESIGN: Participants rated their perceived subjective annoyance for each condition on a 7-point Likert scale. STUDY SAMPLE: Twenty normal-hearing participants and twenty participants with a range of mild to moderate hearing losses. RESULTS: Delay tolerance was significantly greater for the participants with hearing loss in two out of three voice conditions. The average slopes of annoyance ratings were negatively correlated with the degree of hearing loss across participants. A small trend of higher tolerance of delay by experienced users of hearing aids in comparison to new users was not significant. CONCLUSION: The increased tolerance of processing delay for speech production and perception with hearing loss and reduced sensitivity to changes in delay with stronger hearing loss may be beneficial for novel algorithms for hearing devices but the setup used in this study differed from commercial hearing aids. PMID- 28838278 TI - Time to response and survival in hypomethylating agent-treated acute myeloid leukemia. PMID- 28838279 TI - Do resettlement variables predict psychiatric treatment outcomes in a sample of asylum-seeking survivors of torture? AB - PURPOSE: Mental health clinicians who work with asylum seekers provide services to patients who face stressful everyday living conditions. However, little is known about how these problems potentially impact psychiatric treatment within these populations. The purpose of this study was thus to examine whether resettlement factors predict outcomes of a mental health intervention for a sample of asylum-seeking survivors of torture. METHODS: The study included data from a US outpatient clinic that specialized in treating asylum-seeking survivors of torture. Patients (primarily from Iraq, Afghanistan and African Countries) were evaluated on demographic factors at intake and psychiatric symptoms throughout the course of treatment. RESULTS: Patients experienced significant reductions in depression, anxiety and trauma symptoms, although symptoms still remained near or above clinical thresholds. Stable, uncrowded housing conditions significantly predicted lower depression, anxiety and trauma symptoms at follow up. CONCLUSION: These findings support the hypotheses that individuals seeking asylum within the United States who have survived torture can benefit from psychiatric treatment and emphasize the importance of stable living conditions in improving treatment effectiveness. This suggests the need for further research on social predictors of treatment outcomes, as well as the need for clinicians and policymakers to target improved housing as a potentially important tool to reduce psychiatric problems related to torture and forced migration. PMID- 28838280 TI - Neuroendocrine regulation of energy balance: Implications on the development and surgical treatment of obesity. AB - INTRODUCTION: Obesity, a serious public health problem, occurs mainly when food consumption exceeds energy expenditure. Therefore, energy balance depends on the regulation of the hunger-satiety mechanism, which involves interconnection of the central nervous system and peripheral signals from the adipose tissue, pancreas and gastrointestinal tract, generating responses in short-term food intake and long-term energy balance. Increased body fat alters the gut- and adipose-tissue derived hormone signaling, which promotes modifications in appetite-regulating hormones, decreasing satiety and increasing hunger senses. With the failure of conventional weight loss interventions (dietary treatment, exercise, drugs and lifestyle modifications), bariatric surgeries are well-accepted tools for the treatment of severe obesity, with long-term and sustained weight loss. Bariatric surgeries may cause weight loss due to restriction/malabsorption of nutrients from the anatomical alteration of the gastrointestinal tract that decreases energy intake, but also by other physiological factors associated with better results of the surgical procedure. OBJECTIVE: This review discusses the neuroendocrine regulation of energy balance, with description of the predominant hormones and peptides involved in the control of energy balance in obesity and all currently available bariatric surgeries. CONCLUSIONS: According to the findings of our review, bariatric surgeries promote effective and sustained weight loss not only by reducing calorie intake, but also by precipitating changes in appetite control, satiation and satiety, and physiological changes in gut-, neuro- and adipose-tissue-derived hormone signaling. PMID- 28838281 TI - Utility of estimated glomerular filtration rate based on cystatin C in patients receiving combination antiretroviral therapy including dolutegravir. PMID- 28838282 TI - A retrospective analysis comparing APCEDEN(r) dendritic cell immunotherapy with best supportive care in refractory cancer. AB - AIM: A retrospective survival benefit analysis of APCEDEN(r), APAC BIOTECH Pvt Ltd 69, Jacranda Marg, DLF PHASE II, Gurugram, Haryana, India, an autologous dendritic cell-based product for management of refractory solid malignancies, was performed in comparison with a control group. METHODS: Subjects (retrospective data) whose survival data, geographical region, age, gender, ECOG performance status and stage of disease that could be matched with the treatment group were considered for analysis. RESULTS: The analysis suggests a significant survival benefit of 199 days for the APCEDEN therapy treatment group when compared with the control group (356 vs 157 days). The event-free survival time of APCEDEN therapy was 439 days in patients who demonstrated an objective response at first evaluation as per immune-related response criteria. CONCLUSION: APCEDEN demonstrated highly convincing survival benefits when compared with the control group. PMID- 28838283 TI - Exocrine pancreatic insufficiency is common in people living with HIV on effective antiretroviral therapy. AB - OBJECTIVES: The primary aim of this prospective study was to determine the prevalence of exocrine pancreatic insufficiency (EPI) in people living with HIV (PLHIV) on suppressive antiretroviral therapy (ART). METHODS: PLHIV >=18 years of age and on ART for >6 months and with HIV RNA <50 copies/mL plasma were included. Faecal elastase-1 measurement was performed on a single stool sample, serum markers of malnutrition were collected, and participants answered a short questionnaire about gastrointestinal symptoms. Participants with EPI and symptoms were offered pancreatic enzyme replacement therapy (PERT), and the result of this therapy was also evaluated. RESULTS: Of 100 participants, 32% had EPI (faecal elastase-1 < 200 MUg/g) and 20% severe EPI (faecal elastase-1 < 100 MUg/g). We did not find any correlation between self-reported symptoms and degree of EPI. Twelve out of the 32 participants with EPI accepted to start PERT. Nine out of 12 (75%) reported improvement or became asymptomatic within 14 days. CONCLUSION: EPI is common in PLHIV on effective ART. We could, however, not find a correlation between gastrointestinal symptoms and the presence of EPI. Assessment of pancreatic exocrine function could be considered in PLHIV particularly in those with gastrointestinal discomfort, since there is a possible gain in treating them with relief of symptoms and improved quality of life. The effects of PERT in PLHIV on effective ART need further study. PMID- 28838285 TI - A review on golimumab in the treatment of psoriatic arthritis. AB - Psoriatic arthritis (PsA) causes inflammation in and around the joints and usually affects people who already have psoriasis. However, some patients develop the joint problems before the psoriasis. Currently, there are five anti-TNF-alpha agents licensed for use in patients with PsA: adalimumab, certolizumab pegol, etanercept, golimumab and infliximab. Golimumab, a human monoclonal antibody, has been approved by the US FDA for the treatment of PsA and is targeted against the pro-inflammatory molecule TNF-alpha. The Phase III GO-REVEAL study confirmed this drug was well tolerated and showed significant improvement in disease activity compared with placebo. PMID- 28838284 TI - Enhancing the radiation response of tumors but not early or late responding normal tissues using a vascular disrupting agent. AB - INTRODUCTION: Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant normal tissues. MATERIAL AND METHODS: Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm3 foot implanted C3H mammary carcinomas was assessed using percent tumor control at 90 days. Normal tissue effects were evaluated using early responding skin (development of moist desquamation in the foot at 11-30 days), and late responding bladder (50% reduction in reservoir function estimated by cystometry up to 9 months after treatment), and lung (20% increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p < .05). RESULTS: The radiation dose controlling 50% of irradiated tumors was 52 Gy. This significantly decreased to 45 Gy with CA4P. The radiation doses inducing a change in skin, bladder and lung response in 50% of mice were 31 Gy, 14 Gy and 12 Gy, respectively. CA4P had no significant effect on the radiation response of any of these normal tissues. CONCLUSIONS: VDAs significantly enhance tumor radiation response, but had absolutely no effect on the radiation response of early or late responding normal tissues. PMID- 28838286 TI - Self-reported history of seizure and baseline neurocognitive test performance in student-athletes: an initial investigation. AB - OBJECTIVES: Baseline neurocognitive assessment data can be critical in return to play (RTP) decision-making following a sport-related concussion (SRC). The literature indicates that many modifying factors of SRC have been studied empirically; however, there has been little investigation into the effect of a self-reported history of seizure(s) on baseline neurocognitive test data. The objective of this investigation was to determine whether a self-reported history of seizure(s) is associated with differences in baseline Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) performance. METHODS: A retrospective analysis of 18,245 adolescent and young adult athletes' ImPACT scores was performed. After application of inclusion and exclusion criteria, 7,391 participants were dichotomized into groups based on the presence or absence of a self-reported history of seizure. Participants reporting a history of seizure (n = 60) were matched on multiple variables in a 1:3 ratio with controls (n = 180) without a history of self-reported seizure. Baseline ImPACT composite scores were then compared between groups using either a 2-tailed t-test or a Mann Whitney U-Test. RESULTS: A significant between-group difference was observed in ImPACT visual motor speed composite scores (35.28 vs. 37.64, p = 0.029, Hedge's g = 0.327), with the group self-reporting a history of seizure performing at inferior average scores. No significant between-group differences were detected in verbal memory, visual memory, reaction time, impulse control, or total symptom scores. CONCLUSION: Athletes with a history of self-reported seizure scored significantly lower on ImPACT visual motor speed compared to matched controls. As a solitary finding with a small effect size, the clinical significance of this difference is unclear. Apart from the decrease in visual-motor speed, this preliminary analysis suggests that athletes with a history of seizure might not have significantly different neurocognitive baseline test scores when compared with matched controls. Further empirical investigation is warranted to determine if a history of seizure is a modifying factor for SRC. PMID- 28838287 TI - Introduction of second-generation tyrosine kinase inhibitors may reduce the prognostic impact of high-risk patients, according to the European treatment and outcome study (EUTOS) score. AB - Our study aims to highlight the critical role of the introduction of second generation tyrosine kinase inhibitors (2nd TKIs) on the prognosis of patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP), as determined by European Treatment and Outcome Study (EUTOS) system. Patients who were diagnosed with CML-CP before March 2009 were classified into the imatinib group, and those diagnosed after April 2009 were classified into the 2nd TKI group. EUTOS high risk patients exhibited significantly worse outcomes in terms of event-free survival (EFS), progression-free survival (PFS), and CML-associated death than those considered to be low-risk. Risk stratification by EUTOS score was predictive of risk-associated clinical outcomes in patients classified into the imatinib group; however, the EUTOS score failed to predict the outcomes of patients classified into the 2nd TKI group. Our data suggest that the introduction of 2nd TKIs might have improved treatment outcomes, particularly in EUTOS high-risk patients. PMID- 28838288 TI - Overexpression of Drosophila frataxin triggers cell death in an iron-dependent manner. AB - Friedreich ataxia (FRDA) is the most important autosomal recessive ataxia in the Caucasian population. FRDA patients display severe neurological and cardiac symptoms that reflect a strong cellular and axonal degeneration. FRDA is caused by a loss of function of the mitochondrial protein frataxin which impairs the biosynthesis of iron-sulfur clusters and in turn the catalytic activity of several enzymes in the Krebs cycle and the respiratory chain leading to a diminished energy production. Although FRDA is due to frataxin depletion, overexpression might also be very helpful to better understand cellular functions of frataxin. In this work, we have increased frataxin expression in neurons to elucidate specific roles that frataxin might play in these tissues. Using molecular, biochemical, histological and behavioral methods, we report that frataxin overexpression is sufficient to increase oxidative phosphorylation, modify mitochondrial morphology, alter iron homeostasis and trigger oxidative stress-dependent cell death. Interestingly, genetic manipulation of mitochondrial iron metabolism by silencing mitoferrin successfully improves cell survival under oxidative-attack conditions, although enhancing antioxidant defenses or mitochondrial fusion failed to ameliorate frataxin overexpression phenotypes. This result suggests that cell degeneration is directly related to enhanced incorporation of iron into the mitochondria. Drosophila frataxin overexpression might also provide an alternative approach to identify processes that are important in FRDA such as changes in mitochondrial morphology and oxidative stress induced cell death. PMID- 28838289 TI - Emotional cascade theory and non-suicidal self-injury: the importance of imagery and positive affect. AB - Grounded in Emotional Cascade Theory, we explored whether rumination and multisensory imagery-based cognitions moderated the relationships between affect and both odds of non-suicidal self-injury (NSSI), and frequency of the behaviour. A sample of 393 university students completed self-report questionnaires assessing the constructs of interest. Contrary to expectations, rumination did not emerge as a significant moderator of the affect-NSSI relationship. However, the relationship between affect and frequency of NSSI was moderated by the use of imagery. Further, the relationship between negative affect and NSSI was moderated by positive affect, underscoring the need to consider both negative and positive affect in models of NSSI. Most youth who self-injured reported thinking in images while the urge to self-injure was strong, with 53% thinking in images at least half the time. Future work is needed to explore how positive and negative affect work in concert to govern NSSI, and how imagery might either exacerbate or reduce risk of NSSI. PMID- 28838290 TI - A randomized study on the effect of modified behavioral activation treatment for depressive symptoms in rural left-behind elderly. AB - OBJECTIVE: To evaluate the effectiveness of a modified behavioral activation treatment (MBAT) intervention on reducing depressive symptoms in rural left behind elderly. METHOD: This is a randomized study registered in Chinese Clinical Trial Registry (ChiCTR-IOR-17011289). Eighty rural left-behind elderly people who had a Geriatric Depression Scale (GDS) score between 11 and 25 were randomly assigned to the intervention (n = 40) and control group (n = 40). The intervention group received both MBAT and regular treatment for 8 weeks while the control group received regular treatment. Both groups were assessed with the GDS, Beck Anxiety Inventory (BAI), and Oxford Happiness Questionnaire (OHQ) at baseline, immediately post-intervention, and at 3 months post-intervention. RESULTS: There were a total of 73 participants that completed the intervention. The scores of GDS and BAI decreased significantly, but the scores of OHQ increased significantly in the intervention group after 8 sessions of MBAT (P < .01). The reduction in depression symptoms after the intervention was maintained at the 3-month follow-up. Significant differences in GDS, BAI, and OHQ scores were observed between the intervention group and the control group (P < .01). CONCLUSION: MBAT produced a significantly greater reduction in depressive symptoms than regular care in rural left-behind elderly. PMID- 28838291 TI - Zero-valent iron supported on nitrogen-doped carbon xerogel as catalysts for the oxidation of phenol by fenton-like system. AB - Nitrogen-free and nitrogen-doped carbon xerogel materials, from urea and melamine precursors, were prepared at different pH and evaluated as adsorbents/catalysts in the removal of phenol. Then, zero-valent iron (ZVI) was supported on these carbon xerogel materials and its activity was again evaluated for phenol removal by adsorption and catalytic wet peroxide oxidation (CWPO). The prepared samples were characterized by N2 adsorption at -196 degrees C, pH at the point of zero charge (pHPZC) and elemental analysis. The textural properties of the N-free and N-doped carbon xerogels are strongly influenced by pH of the preparation solution and precursor used. The presence of ZVI on all carbon xerogel supports improved the phenol removal efficiency. ZVI supported on urea- and melamine-doped carbon xerogels show a good performance, reaching above 87% phenol conversion after 60 min of CWPO. On the contrary, pure adsorption and CWPO using the same materials without the presence of ZVI gives low phenol removal efficiency. A correlation was found between the activity of ZVI catalysts in CWPO and the N-content of the supports. PMID- 28838293 TI - Is lack of breakfast contributing to nutrient deficits and poor nutritional indicators among adolescent girls? AB - BACKGROUND: Breakfast is considered the first and most important meal of the day. Missing the first meal may result in significant nutritional deficits, if not compensated in subsequent meals. AIM: To describe the nutrient intake through breakfast and to study its association with nutritional indicators among adolescent girls. METHODS: A cross-sectional study among adolescent girls ( n = 565) 16-18 years was carried out in urban slums of Pune, Maharashtra, India. Haemoglobin was assessed by cyanmethemoglobin method. Nutritional status was assessed through anthropometry and three 24-hours diet recall. Z scores, independent sample test, and linear logistic regression were used to assess undernutrition, to compare means of nutrient intake and to associate nutrient intake with nutritional status, respectively. RESULTS: Almost 50% did not consume solid food for breakfast and 99% of the participants consumed inadequate breakfast (<610 kcal). Two types of breakfast emerged: I (bakery products + beverage) and II (traditional breakfast + beverage). Although the mean energy intake of type II breakfast (235+/-100.55 kcal) and the mean micronutrient intake was significantly higher than type I (micronutrients: vitamin C and folate ( p = 0.001), iron ( p = 0.01)) it did not meet the adequacy norms for breakfast. Among nutritional indicators breakfast intake was not directly associated with body mass index. However, mean intake of nutrients such as energy, protein and iron through the day were significantly lesser ( p = 0.001, p = 0.01 and p = 0.01 respectively) among anaemic adolescents. Linear regression showed significant association between energy, fat intake and BAZ scores. CONCLUSIONS: Compensating dietary deficits that arise in the first meal would directly address the day's nutrient deficit. The results highlight the need for a food-based approach to address undernutrition among adolescent girls in resource-poor settings. PMID- 28838292 TI - Balancing the cost of leaving with the cost of living: drivers of long-term retention of health workers: an explorative study in three rural districts in Eastern Uganda. AB - BACKGROUND: Health worker retention in rural and underserved areas remains a persisting problem in many low and middle income countries, and this directly affects the quality of health services offered. OBJECTIVE: This paper explores the drivers of long-term retention and describes health worker coping mechanisms in rural Uganda. METHODS: A descriptive qualitative study explored the factors that motivated health workers to stay, in three rural districts of Uganda: Kamuli, Pallisa, and Kibuku. In-depth interviews conducted among health workers who have been retained for at least 10 years explored factors motivating the health workers to stay within the district, opportunities, and the benefits of staying. RESULTS: Twenty-one health workers participated. Ten of them male and 11 female with the age range of 33-51 years. The mean duration of stay among the participants was 13, 15, and 26 years for Kamuli, Kibuku, and Pallisa respectively. Long-term retention was related to personal factors, such as having family ties, community ties, and opportunities to invest. The decentralization policy and pension benefits also kept workers in place. Opportunities for promotion or leadership motivated long stay only if they came with financial benefits. Workload reportedly increased over the years, but staffing and emoluments had not increased. Multiple job, family support, and community support helped health workers cope with the costs of living, and holding a secure pensionable government job was valued more highly than seeking uncertain job opportunities elsewhere. CONCLUSION: The interplay between the costs of leaving and the benefit of staying is demonstrated. Family proximity, community ties, job security, and pension enhance staying, while higher costs of living and an unpredictable employment market make leaving risky. Health workers should be able to access investment opportunities in order to cope with inadequate remuneration. Promotions and leadership opportunities only motivate if accompanied by financial benefits. PMID- 28838295 TI - News & Views. PMID- 28838294 TI - Feline leprosy due to Candidatus 'Mycobacterium lepraefelis': Further clinical and molecular characterisation of eight previously reported cases and an additional 30 cases. AB - OBJECTIVES: This paper, the last in a series of three on 'feline leprosy', provides a detailed description of disease referable to the previously unnamed species, Candidatus 'Mycobacterium lepraefelis', a close relative of the human pathogens Mycobacterium leprae and Mycobacterium lepromatosis. METHODS: Cases were sourced retrospectively and prospectively for this observational study, describing clinical, geographical and molecular microbiological data for cats definitively diagnosed with Candidatus 'M lepraefelis' infection. RESULTS: A total of 145 cases of feline leprosy were scrutinised; 114 'new' cases were sourced from the Victorian Infectious Diseases Reference Laboratory (VIDRL) records, veterinary pathology laboratories or veterinarians, and 31 cases were derived from six published studies. Thirty-eight cats were definitively diagnosed with Candidatus 'M lepraefelis' infection. Typically, cats tended to be middle aged or older when first infected, with a male predilection. Affected cats typically had widespread cutaneous lesions, in some cases after initially localised disease. Advanced cases were often systemically unwell. All cats had outdoor access. The histological picture was lepromatous in the majority of patients, although two cases had tuberculoid disease. In one case that underwent necropsy, lesions were evident in the liver, spleen and lungs. Treatment was varied, although most cats received a combination of oral clarithromycin and rifampicin. Prognosis for recovery was variable, but typically poor. CONCLUSIONS AND RELEVANCE: Candidatus 'M lepraefelis' typically causes high bacterial index (lepromatous) feline leprosy that in some cases progresses to systemic mycobacteriosis. The disease has a variable clinical course and prognosis. Many cases either died or were euthanased due to the infection. Multilocus sequence analysis reveals a heterogeneous picture and further analysis of draft genome sequencing may give clues to the taxonomy and epidemiology of this organism. Prospective treatment trials and/or additional drug susceptibility testing in specialised systems would further inform treatment recommendations. Comparative aspects: This paper finishes with a discussion of comparative aspects of infection caused by the three feline leproid disease agents that have been the subject of this series: Candidatus 'Mycobacterium tarwinense', Mycobacterium lepraemurium and Candidatus 'M lepraefelis'. PMID- 28838296 TI - Leprosy - we've much left to learn, but are looking to squirrels, cows and cats for insights. PMID- 28838297 TI - Clinical/research abstracts accepted for presentation at the World Feline Congress 2017. PMID- 28838298 TI - Skin as a marker of general feline health: Cutaneous manifestations of systemic disease. AB - Practical relevance: Although most skin lesions occur due to diseases primarily affecting the skin, some reflect important systemic diseases. Such lesions may relate directly to the systemic disease, or may occur due to secondary skin diseases that develop because of immunosuppression. Early recognition of skin changes as a marker of systemic disease will maximise patient outcomes. Clinical challenges: In older or clearly debilitated cats presenting with skin disease, the potential for underlying systemic disease is often readily apparent. Similarly, cats presenting with severe ulcerative or multifocal nodular skin lesions, or with concurrent signs of systemic illness, will more instinctively prompt systemic evaluation. More challenging is the cat presenting with alopecic, scaling, erythemic and/or mildly crusted skin disease, with or without pruritus; hypersensitivities and infectious dermatoses are the most common considerations, but occasionally systemic disease underlies the skin changes. Knowing when screening laboratory testing, body imaging or other systemic diagnostics are indicated is not always straightforward. Evidence base: This article reviews cutaneous presentations of systemic diseases reported in the veterinary literature, and discusses important differential diagnoses. The author draws on clinical experience, published data on disease prevalence and case evaluations, and expert opinions on approach to common systemic problems to provide guidance on when investigation for underlying systemic disease is most appropriate. PMID- 28838299 TI - Peculiarities of feline hyperadrenocorticism: Update on diagnosis and treatment. AB - Practical relevance: Hyperadrenocorticism (HAC) is a relatively uncommon endocrinopathy of older cats, with a mean age at diagnosis of 10 years. In addition to pituitary-dependent and adrenal-dependent hypercortisolism, clinical signs of HAC can result from adrenal sex steroid-producing tumours. Clinical challenges: While HAC in cats has many similarities to canine HAC, there are key differences in presentation, diagnosis and response to therapy. Most, but not all, cats with HAC have concurrent diabetes mellitus, which is often insulin resistant. Up to a third of cats with HAC have extreme skin fragility and are at high risk of debilitating iatrogenic skin tears during diagnostic or therapeutic interventions. Infections of the skin and nail beds, and urinary, respiratory and gastrointestinal tract, secondary to cortisol-induced immune suppression, are also common. Cats respond differently to dogs to adrenal function tests including adrenocorticotropic hormone (ACTH) stimulation and dexamethasone suppression tests; a 10-fold higher dose of dexamethasone is recommended in cats to screen for HAC. Curative treatment options include adrenalectomy or transsphenoidal hypophysectomy. Radiation or medical treatment may improve clinical signs. The response to mitotane therapy is poor. While trilostane is the medical treatment of choice based on retrospective studies, investigations into the pharmacokinetics of this drug in cats are lacking. Global importance: Feline HAC occurs worldwide and is not associated with any purebreed predisposition. Although uncommon, adrenal sex steroid-producing tumours have a higher prevalence in cats than in dogs. Evidence base: The information in this review is drawn from over 180 reported cases of feline HAC. Reports investigating clinical presentation, clinicopathological findings and treatment outcomes are observational, retrospective multiple case series (EBM grade III) or single case reports (EBM grade IV). While most endocrine testing studies for diagnosis are cohort controlled analytical studies (EBM grade III), prospective, randomised, placebo-controlled studies have been performed (EBM grade I). PMID- 28838300 TI - Supporting global health goals with information and communications technology. AB - The objective of this study is to critically assess the possible roles of information and communications technology (ICT) in supporting global health goals. This is done by considering privilege and connectibility. In short, ICT can contribute by providing health information via four different kinds of access, each with its own history and prospective future. All four are analyzed here, in two perspectives: business-as-usual and disruptive. Health data analytics is difficult since the digital representation of past, current, and future health information is lacking. The flow of analytics that may prove beneficial to the individual and not just meet abstract population-level goals or ambitions is analyzed in detail. Sensemaking is also needed, to meet the minimum requirement of making prospective future services understandable to policymakers. Drivers as well as barriers for areas in which policy decisions have the potential to drive positive developments for meeting the Sustainable Development Goals are identified. PMID- 28838301 TI - The digital age. PMID- 28838302 TI - Integrating mHealth at point of care in low- and middle-income settings: the system perspective. AB - While the field represents a wide spectrum of products and services, many aspects of mHealth have great promise within resource-poor settings: there is an extensive range of cheap, widely available tools which can be used at the point of care delivery. However, there are a number of conditions which need to be met if such solutions are to be adequately integrated into existing health systems; we consider these from regulatory, technological and user perspectives. We explore the need for an appropriate legislative and regulatory framework, to avoid 'work around' solutions, which threaten patient confidentiality (such as the extensive use of instant messaging services to deliver sensitive clinical information and seek diagnostic and management advice). In addition, we will look at other confidentiality issues such as the need for applications to remove identifiable information (such as photos) from users' devices. Integration is dependent upon multiple technological factors, and we illustrate these using examples such as products made available specifically for adoption in low- and middle-income countries. Issues such as usability of the application, signal loss, data volume utilization, need to enter passwords, and the availability of automated or in-app context-relevant clinical advice will be discussed. From a user perspective, there are three groups to consider: experts, front-line clinicians, and patients. Each will accept, to different degrees, the use of technology in care - often with cultural or regional variation - and this is central to integration and uptake. For clinicians, ease of integration into daily work flow is critical, as are familiarity and acceptability of other technology in the workplace. Front-line staff tend to work in areas with more challenges around cell phone signal coverage and data availability than 'back-end' experts, and the effect of this is discussed. PMID- 28838303 TI - Policymakers and mHealth: roles and expectations, with observations from Ethiopia, Ghana and Sweden. AB - The rapid increase in mobile phone use and other telecommunication technologies in health care during the past decade has paved the way for optimism. mHealth (mobile health) initiatives need to be integrated into national health systems and priorities and fit into the system that the country has already invested in. Partnership between government, regional governments, health care systems, Community Health Workers, the private sector and universities is considered as a precondition for success. In turn, this requires strategic and integrative policy decisions on the national/regional level to be defined in the action plans as concrete steps. Decision makers are calling for scale-up plans to be in place even in the pilot phases. Hope is expressed that the initial joy and curiosity that new technology generates in the implementation phase will be transferred to routine work. Standards and a common technical architecture that enables interoperability and upscaling are key issues. Based on publications on policy and national strategies, this paper highlights some key areas for decision makers' role and expectations with regard to mHealth. The paper will also report some mHealth experiences from Ethiopia, Ghana and Sweden. PMID- 28838304 TI - Viral mHealth. AB - Thousands of mHealth applications are developed every year, but few of these spread or 'go viral'. Even clinical applications that provide health benefits and social value often linger after an initial pilot phase. An examination of common hindrances in low-income countries suggests that more subsidies and education of health care personnel are insufficient solutions. Instead we propose better a priori screening of mHealth applications based on four criteria that may largely determine whether an mHealth application will spread. Further, we illustrate how using these criteria forms a good basis for involving 'impact investors' in the development of mHealth applications. This can reduce risks for public health care providers and increase the likelihood of success. PMID- 28838305 TI - Point-of-care mobile digital microscopy and deep learning for the detection of soil-transmitted helminths and Schistosoma haematobium. AB - BACKGROUND: Microscopy remains the gold standard in the diagnosis of neglected tropical diseases. As resource limited, rural areas often lack laboratory equipment and trained personnel, new diagnostic techniques are needed. Low-cost, point-of-care imaging devices show potential in the diagnosis of these diseases. Novel, digital image analysis algorithms can be utilized to automate sample analysis. OBJECTIVE: Evaluation of the imaging performance of a miniature digital microscopy scanner for the diagnosis of soil-transmitted helminths and Schistosoma haematobium, and training of a deep learning-based image analysis algorithm for automated detection of soil-transmitted helminths in the captured images. METHODS: A total of 13 iodine-stained stool samples containing Ascaris lumbricoides, Trichuris trichiura and hookworm eggs and 4 urine samples containing Schistosoma haematobium were digitized using a reference whole slide scanner and the mobile microscopy scanner. Parasites in the images were identified by visual examination and by analysis with a deep learning-based image analysis algorithm in the stool samples. Results were compared between the digital and visual analysis of the images showing helminth eggs. RESULTS: Parasite identification by visual analysis of digital slides captured with the mobile microscope was feasible for all analyzed parasites. Although the spatial resolution of the reference slide-scanner is higher, the resolution of the mobile microscope is sufficient for reliable identification and classification of all parasites studied. Digital image analysis of stool sample images captured with the mobile microscope showed high sensitivity for detection of all helminths studied (range of sensitivity = 83.3-100%) in the test set (n = 217) of manually labeled helminth eggs. CONCLUSIONS: In this proof-of-concept study, the imaging performance of a mobile, digital microscope was sufficient for visual detection of soil-transmitted helminths and Schistosoma haematobium. Furthermore, we show that deep learning-based image analysis can be utilized for the automated detection and classification of helminths in the captured images. PMID- 28838306 TI - Are mobile health applications useful for supporting shared decision making in diagnostic and treatment decisions? AB - Mobile health (mHealth) applications intended to support shared decision making in diagnostic and treatment decisions are increasingly available. In this paper, we discuss some recent studies on mHealth applications with relevance to shared decision making. We discuss the potential advantages and disadvantages of using mHealth in shared decision making in various contexts, and suggest some directions for future research in this quickly expanding field. PMID- 28838307 TI - Image-based mHealth for remote diagnostic assistance a means to promote equity in quality care. PMID- 28838308 TI - Medical mobile technologies - what is needed for a sustainable and scalable implementation on a global scale? AB - Current advances within medical technology show great potential from a global health perspective. Inexpensive, effective solutions to common problems within diagnostics, medical procedures and access to medical information are emerging within almost all fields of medicine. The innovations can benefit health care both in resource-limited and in resource-rich settings. However, there is a big gap between the proof-of-concept stage and implementation. This article will give examples of promising solutions, with special focus on mobile image- and sensor based diagnostics. We also discuss how technology and frugal innovations could be made sustainable and widely available. Finally, a list of critical factors for success is presented, based on both our own experiences and the literature. PMID- 28838309 TI - Institutionalizing human-computer interaction for global health. AB - Digitalization is the societal change process in which new ICT-based solutions bring forward completely new ways of doing things, new businesses and new movements in the society. Digitalization also provides completely new ways of addressing issues related to global health. This paper provides an overview of the field of human-computer interaction (HCI) and in what way the field has contributed to international development in different regions of the world. Additionally, it outlines the United Nations' new sustainability goals from December 2015 and what these could contribute to the development of global health and its relationship to digitalization. Finally, it argues why and how HCI could be adopted and adapted to fit the contextual needs, the need for localization and for the development of new digital innovations. The research methodology is mostly qualitative following an action research paradigm in which the actual change process that the digitalization is evoking is equally important as the scientific conclusions that can be drawn. In conclusion, the paper argues that digitalization is fundamentally changing the society through the development and use of digital technologies and may have a profound effect on the digital development of every country in the world. But it needs to be developed based on local practices, it needs international support and to not be limited by any technological constraints. Particularly digitalization to support global health requires a profound understanding of the users and their context, arguing for user-centred systems design methodologies as particularly suitable. PMID- 28838310 TI - A roadmap for the implementation of mHealth innovations for image-based diagnostic support in clinical and public-health settings: a focus on front-line health workers and health-system organizations. AB - BACKGROUND: Diagnostic support for clinicians is a domain of application of mHealth technologies with a slow uptake despite promising opportunities, such as image-based clinical support. The absence of a roadmap for the adoption and implementation of these types of applications is a further obstacle. OBJECTIVES: This article provides the groundwork for a roadmap to implement image-based support for clinicians, focusing on how to overcome potential barriers affecting front-line users, the health-care organization and the technical system. METHODS: A consensual approach was used during a two-day roundtable meeting gathering a convenience sample of stakeholders (n = 50) from clinical, research, policymaking and business fields and from different countries. A series of sessions was held including small group discussions followed by reports to the plenary. Session moderators synthesized the reports in a number of theme-specific strategies that were presented to the participants again at the end of the meeting for them to determine their individual priority. RESULTS: There were four to seven strategies derived from the thematic sessions. Once reviewed and prioritized by the participants some received greater priorities than others. As an example, of the seven strategies related to the front-line users, three received greater priority: the need for any system to significantly add value to the users; the usability of mHealth apps; and the goodness-of-fit into the work flow. Further, three aspects cut across the themes: ease of integration of the mHealth applications; solid ICT infrastructure and support network; and interoperability. CONCLUSIONS: Research and development in image-based diagnostic pave the way to making health care more accessible and more equitable. The successful implementation of those solutions will necessitate a seamless introduction into routines, adequate technical support and significant added value. PMID- 28838311 TI - A smartphone-based consultation system for acute burns - methodological challenges related to follow-up of the system. AB - BACKGROUND: A smartphone-based consultation system for acute burns is currently being implemented in the Western Cape, South Africa. Even though studies indicate that similar systems for burns tend to support valid diagnosis and influence patient management, the evidence is still sparse. There is a need for more in depth evaluations, not least in resource-constrained settings where mHealth projects are increasing. OBJECTIVE: This article describes the consultation system and assessments in relation to its implementation with a special focus on methodological challenges. METHODS: A number of evaluations and assessments have been conducted, are ongoing or planned for in relation to the implementation of the teleconsultation system. Initial assessments showed that size and depth of burns could be assessed at least as well using photographs as at bedside and that the image quality of handheld devices can be used as well as computers. Studies on system usability are currently being done with a mixed-methods approach. A historical cohort design will be applied to assess the potential health impact of the system. Patients with burn injuries where the doctor at point of care has used the app to receive diagnostic support from a burns expert will be considered as exposed and patients with burn injuries where the app has not been used will be considered as non-exposed. CONCLUSIONS: Smartphone-based consultation systems have the potential to strengthen the assessment of burn injury in many settings. However, ethically and methodologically sound evaluations are needed to find the best systems and solutions. This article identifies challenges and suggests potential assessments in relation to the implementation of such a system. PMID- 28838313 TI - Trade-off between benefits, harms and economic efficiency of low-dose CT lung cancer screening: a microsimulation analysis of nodule management strategies in a population-based setting. AB - BACKGROUND: In lung cancer screening, a nodule management protocol describes nodule assessment and thresholds for nodule size and growth rate to identify patients who require immediate diagnostic evaluation or additional imaging exams. The Netherlands-Leuvens Screening Trial and the National Lung Screening Trial used different selection criteria and nodule management protocols. Several modelling studies have reported variations in screening outcomes and cost effectiveness across selection criteria and screening intervals; however, the effect of variations in the nodule management protocol remains uncertain. This study evaluated the effects of the eligibility criteria and nodule management protocols on the benefits, harms and cost-effectiveness of lung screening scenarios in a population-based setting in Germany. METHODS: We developed a modular microsimulation model: a biological module simulated individual histories of lung cancer development from carcinogenesis onset to death; a screening module simulated patient selection, screening-detection, nodule management protocols, diagnostic evaluation and screening outcomes. Benefits included mortality reduction, life years gained and averted lung cancer deaths. Harms were costs, false positives and overdiagnosis. The comparator was no screening. The evaluated 76 screening scenarios included variations in selection criteria and thresholds for nodule size and growth rate. RESULTS: Five years of annual screening resulted in a 9.7-12.8% lung cancer mortality reduction in the screened population. The efficient scenarios included volumetric assessment of nodule size, a threshold for a volume of 300 mm3 and a threshold for a volume doubling time of 400 days. Assessment of volume doubling time is essential for reducing overdiagnosis and false positives. Incremental cost-effectiveness ratios of the efficient scenarios were 16,754-23,847 euro per life year gained and 155,287-285,630 euro per averted lung cancer death. CONCLUSIONS: Lung cancer screening can be cost-effective in Germany. Along with the eligibility criteria, the nodule management protocol influences screening performance and cost-effectiveness. Definition of the thresholds for nodule size and nodule growth in the nodule management protocol should be considered in detail when defining optimal screening strategies. PMID- 28838312 TI - Docosahexaenoic acid-containing choline phospholipid modulates LPS-induced neuroinflammation in vivo and in microglia in vitro. AB - BACKGROUND: Neuroinflammatory processes are considered a double-edged sword, having both protective and detrimental effects in the brain. Microglia, the brain's resident innate immune cells, are a key component of neuroinflammatory response. There is a growing interest in developing drugs to target microglia and control neuroinflammatory processes. In this regard, docosahexaenoic acid (DHA), the brain's n-3 polyunsaturated fatty acid, is a promising molecule to regulate pro-inflammatory microglia and cytokine production. Several works reported that the bioavailability of DHA to the brain is higher when DHA is acylated to phospholipid. In this work, we analyzed the anti-inflammatory activity of DHA phospholipid, either acetylated at the sn-1 position (AceDoPC, a stable form thought to have superior access to the brain) or acylated with palmitic acid at the sn-1 position (PC-DHA) using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo. METHODS: In vivo, adult C57Bl6/J mice were injected intravenously (i.v.) with either AceDoPC or PC-DHA 24 h prior to LPS (i.p.). For in vitro studies, immortalized murine microglia cells BV-2 were co-incubated with DHA forms and LPS. AceDoPC and PC-DHA effect on brain or BV-2 PUFA content was assessed by gas chromatography. LPS-induced pro inflammatory cytokines interleukin IL-1beta, IL-6, and tumor necrosis factor (TNF) alpha production were measured by quantitative PCR (qPCR) or multiplex. IL 6 receptors and associated signaling pathway STAT3 were assessed by FACS analysis and western-blot in vitro. RESULTS: In vivo, a single injection of AceDoPC or PC DHA decreased LPS-induced IL-6 production in the hippocampus of mice. This effect could be linked to their direct effect on microglia, as revealed in vitro. In addition, AceDoPC or PC-DHA reduced IL-6 receptor while only AceDoPC decreased IL 6-induced STAT3 phosphorylation. CONCLUSIONS: These results highlight the potency of administered DHA-acetylated to phospholipids-to rapidly regulate LPS-induced neuroinflammatory processes through their effect on microglia. In particular, both IL-6 production and signaling are targeted by AceDoPC in microglia. PMID- 28838314 TI - Lack of association between AKAP2 and the susceptibility of adolescent idiopathic scoliosis in the Chinese population. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a well characterized spinal deformity that affects millions of children world-wide. The role of genetic factor in the development of AIS has been of great interest, since obvious hereditary trend has been observed in AIS families. In a recent study of Chinese population, a novel mutation of AKAP2 was observed in a family with AIS, which was believed to play a role in the aetiopathogenesis of AIS. The purpose of this study was to investigate whether genetic variants of AKAP2 are associated with the susceptibility of AIS in Chinese population. METHODS: SNV c.2645A > C of AKAP2 was genotyped in 1254 AIS patients and 1232 normal controls using allelic specific multiple ligase detection reactions. SNPs located within 5' untranslated regions (UTR) and 3' UTR of AKAP2 gene were selected using Haploview (v2.6). The GWAS database composed of 961 AIS patients and 1499 controls was referred to for the genotyping information. Relative mRNA expression of AKAP2 in peripheral blood was analyzed for 33 patients and 18 age-matched controls. Comparison between the cases and controls were performed using the Student's t test. PLINK (v1.90) was used to calculate the association of each SNP with the disease by Cochran Armitage trend test. RESULTS: All the patients and the controls presented a genotype of AA in c.2645A > C of AKAP2, and there was no case of mutation in any subject. A total of 116 SNPs covering AKAP2 were analyzed, and none of these SNPs was found to have significantly different allele frequency between the cases and the controls. The mRNA expression of AKAP2 in patients was comparable with that in the controls (1.9 +/- 0.8 vs. 1.8 +/- 0.7, p = 0.66). CONCLUSIONS: Our large scale replication study of the variants in AKAP2 gene did not support its association with the susceptibility of AIS in the Chinese population. In future study, functional studies of the previously reported rare variant are warranted to clarify whether the variant can regulate the expression of AKAP2. The whole AKAP2 gene can be sequenced in larger AIS cohorts to identify potentially missing mutations. PMID- 28838315 TI - Erratum to: Incorporation of causative quantitative trait nucleotides in single step GBLUP. PMID- 28838316 TI - Evaluation of PDQ-8 and its relationship with PDQ-39 in China: a three-year longitudinal study. AB - BACKGROUND: Parkinson's disease is characterized by motor and non-motor symptoms with wide ranging impacts on the health-related quality of life. The 39-item Parkinson's disease Questionnaire (PDQ-39) is the most widely used PD-specific health-related quality-of-life questionnaire. The short-form 8-item Parkinson's disease Questionnaire (PDQ-8) was found to produce results similar to that of the PDQ-39 cross-culturally. However, there is no evaluation of the PDQ-8 in the mainland of China. METHODS: In this longitudinal study, 283 patients with Parkinson's disease were recruited. The PDQ-39, the PDQ-8 and other scales were administered. Patients attended the clinic once annually for three years to complete the scales. RESULTS: The PDQ-8 was found to have good validity and reliability. There was a strong correlation between the summary indices of the PDQ-8 and the PDQ-39 (r=0.93, P<0.001). Results suggested that the PDQ-8 was also associated with other clinical scales of mobility, depression and cognition. The convergent validity and discriminant validity of the PDQ-8 were demonstrated by item-to-dimension correlations. There was acceptable internal consistency of the PDQ-8 (Cronbach's alpha: 0.80; Item-scale correlation efficient: 0.56-0.72). The PDQ-8 replicated the results of the PDQ-39 well at all follow-up time points (intraclass correlation coefficient: 0.96-0.98). In addition, there was good test retest reliability of the PDQ-8. CONCLUSION: The PDQ-8 is a valid and reliable instrument assessing health-related quality of life for PD patients in the mainland of China. PMID- 28838317 TI - Applying next generation sequencing with microdroplet PCR to determine the disease-causing mutations in retinal dystrophies. AB - BACKGROUND: Inherited Retinal dystrophy (IRD) is a broad group of inherited retinal disorders with heterogeneous genotypes and phenotypes. Next generation sequencing (NGS) methods have been broadly applied for analyzing patients with IRD. Here we report a novel approach to enrich the target gene panel by microdroplet PCR. METHODS: This assay involved a primer library which targeted 3071 amplicons from 2078 exons comprised of 184 genes involved in retinal function and/or retinal development. We amplified the target regions using the RainDance target enrichment PCR method and sequenced the products using the MiSeq NGS platform. RESULTS: In this study, we analyzed 82 samples from 67 families with IRD. Bioinformatics analysis indicated that this procedure was able to reach 99% coverage of target sequences with an average sequence depth of reads at 119*. The variants detected by this study were filtered, validated, and prioritized by pathogenicity analysis. Genotypes and phenotypes were correlated by determining a consistent relationship in 38 propands (56.7%). Pathogenic variants in genes related to retinal function were found in another 11 probands (16.4%), but the clinical correlations showed inconsistencies and insufficiencies in these patients. CONCLUSIONS: The application of NGS in IRD clinical molecular diagnosis provides a powerful approach to exploring the etiology and pathology in patients. It is important for the clinical laboratory to interpret the molecular findings in the context of patient clinical presentations because accurate interpretation of pathogenic variants is critical for delivering solid clinical molecular diagnosis to clinicians and patients and improving the standard care of patients. PMID- 28838318 TI - Anesthetic management during adenotonsillectomy for twins with congenital insensitivity to pain with anhidrosis: two case reports. AB - BACKGROUND: Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive disorder characterized by hyperpyrexia, anhidrosis, pain insensitivity, self-inflicted injuries, and intellectual disability. The anesthetic management of these patients is challenging owing to the high risk of perioperative complications resulting from their autonomic dysfunction, such as hyperthermia, hypotension, and bradycardia, which result from autonomic nervous system dysfunction. CASE PRESENTATION: Two 3-year-old Han Chinese identical male twins (weighing 13.5 kg and measuring 93 cm tall) were previously diagnosed as having congenital insensitivity to pain with anhidrosis based on clinical features and genetic screening. According to the presence of loud snoring and heavy breathing during sleep and neck radiograph findings, they were diagnosed as having tonsil and adenoid hypertrophy and needed adenotonsillectomy. Because of innate analgesia, some reports suggested that patients with congenital insensitivity to pain with anhidrosis do not require perioperative pain control. Accordingly, our patients did not receive opiates. We describe the general anesthetic management of these patients using sevoflurane and propofol, but without opiates, for adenotonsillectomy. Remarkable tachycardia and hypertension occurred during airway manipulation and when the surgical stimuli increased, and their temperatures increased from 36 degrees C and 36.8 degrees C to 37.8 degrees C and 38.5 degrees C, respectively. Patients with congenital insensitivity to pain with anhidrosis lack pain sensation, but they may have tactile hyperesthesia. Surgical noxious stimuli may therefore produce a stress response and unpleasant sensations, leading to hemodynamic fluctuation and temperature increase. CONCLUSIONS: On the basis of these findings, we suggest that careful intraoperative opiate titration may be justified to blunt the surgical stress response and promote hemodynamic and temperature stability in similar patients; we also recommend the preparation of warming and cooling devices and continuous temperature monitoring in these patients. Since anesthetic management of these patients is not simple, careful attention is required. PMID- 28838320 TI - Does Value Stream Mapping affect the structure, process, and outcome quality in care facilities? A systematic review. AB - BACKGROUND: Quality improvement within health and social care facilities is needed and has to be evidence-based and patient-centered. Value Stream Mapping, a method of Lean management, aims to increase the patients' value and quality of care by a visualization and quantification of the care process. The aim of this research is to examine the effectiveness of Value Stream Mapping on structure, process, and outcome quality in care facilities. METHODS: A systematic review is conducted. PubMed, EBSCOhost, including Business Source Complete, Academic Search Complete, PSYCInfo, PSYNDX, SocINDEX with Full Text, Web of Knowledge, and EMBASE ScienceDirect are searched in February 2016. All peer-reviewed papers evaluating Value Stream Mapping and published in English or German from January 2000 are included. For data synthesis, all study results are categorized into Donabedian's model of structure, process, and outcome quality. To assess and interpret the effectiveness of Value Stream Mapping, the frequencies of the results statistically examined are considered. RESULTS: Of the 903 articles retrieved, 22 studies fulfill the inclusion criteria. Of these, 11 studies are used to answer the research question. Value Stream Mapping has positive effects on the time dimension of process and outcome quality. It seems to reduce non-value-added time (e.g., waiting time) and length of stay. All study designs are before and after studies without control, and methodologically sophisticated studies are missing. CONCLUSIONS: For a final conclusion about Value Stream Mapping's effectiveness, more research with improved methodology is needed. Despite this lack of evidence, Value Stream Mapping has the potential to improve quality of care on the time dimension. The contextual influence has to be investigated to make conclusions about the relationship between different quality domains when applying Value Stream Mapping. However, for using this review's conclusion, the limitation of including heterogeneous and potentially biased results has to be considered. PMID- 28838319 TI - Genome-wide association studies dissect the genetic networks underlying agronomical traits in soybean. AB - BACKGROUND: Soybean (Glycine max [L.] Merr.) is one of the most important oil and protein crops. Ever-increasing soybean consumption necessitates the improvement of varieties for more efficient production. However, both correlations among different traits and genetic interactions among genes that affect a single trait pose a challenge to soybean breeding. RESULTS: To understand the genetic networks underlying phenotypic correlations, we collected 809 soybean accessions worldwide and phenotyped them for two years at three locations for 84 agronomic traits. Genome-wide association studies identified 245 significant genetic loci, among which 95 genetically interacted with other loci. We determined that 14 oil synthesis-related genes are responsible for fatty acid accumulation in soybean and function in line with an additive model. Network analyses demonstrated that 51 traits could be linked through the linkage disequilibrium of 115 associated loci and these links reflect phenotypic correlations. We revealed that 23 loci, including the known Dt1, E2, E1, Ln, Dt2, Fan, and Fap loci, as well as 16 undefined associated loci, have pleiotropic effects on different traits. CONCLUSIONS: This study provides insights into the genetic correlation among complex traits and will facilitate future soybean functional studies and breeding through molecular design. PMID- 28838321 TI - A review on plant importance, biotechnological aspects, and cultivation challenges of jojoba plant. AB - Jojoba is considered a promising oil crop and is cultivated for diverse purposes in many countries. The jojoba seed produces unique high-quality oil with a wide range of applications such as medical and industrial-related products. The plant also has potential value in combatting desertification and land degradation in dry and semi-dry areas. Although the plant is known for its high-temperature and high-salinity tolerance growth ability, issues such as its male-biased ratio, relatively late flowering and seed production time hamper the cultivation of this plant. The development of efficient biotechnological platforms for better cultivation and an improved production cycle is a necessity for farmers cultivating the plant. In the last 20 years, many efforts have been made for in vitro cultivation of jojoba by applying different molecular biology techniques. However, there is a lot of work to be done in order to reach satisfactory results that help to overcome cultivation problems. This review presents a historical overview, the medical and industrial importance of the jojoba plant, agronomy aspects and nutrient requirements for the plant's cultivation, and the role of recent biotechnology and molecular biology findings in jojoba research. PMID- 28838322 TI - Erratum to: Factors associated with malaria infection in Honde valley, Mutasa district, Zimbabwe, 2014: a case control study. PMID- 28838323 TI - Use of an endotracheal tube for surgical abortion complicated by a leiomyomatous uterus: a case report. AB - BACKGROUND: Abnormal uterine anatomy, especially leiomyomas, can significantly impact the difficulty and potential morbidity of surgical uterine evacuation. To avoid hysterotomy and/or hysterectomy, limited evidence exists to guide surgical uterine evacuation when pregnancy tissue is inaccessible with routine instruments. CASE PRESENTATION: A 41-year-old G4P1021 African American woman at 14 4/7 weeks' gestation was referred for surgical-induced abortion in the setting of an enlarged leiomyomatous uterus. Two large opposing leiomyomas at the internal cervical os rendered pregnancy tissue inaccessible with routine gynecologic surgical instruments. With ultrasound guidance, an endotracheal tube was connected to routine electric suction and utilized to complete uterine evacuation. CONCLUSIONS: With distorted or markedly enlarged uterine anatomy rendering pregnancy tissue inaccessible with routine surgical instruments, the minimally invasive use of an endotracheal tube may aid completion of uterine evacuation for surgical uterine evacuation. PMID- 28838324 TI - Microbial regulation of microRNA expression in the amygdala and prefrontal cortex. AB - BACKGROUND: There is growing evidence for a role of the gut microbiome in shaping behaviour relevant to many psychiatric and neurological disorders. Preclinical studies using germ-free (GF) animals have been essential in contributing to our current understanding of the potential importance of the host microbiome for neurodevelopment and behaviour. In particular, it has been repeatedly demonstrated that manipulation of the gut microbiome modulates anxiety-like behaviours. The neural circuits that underlie anxiety- and fear-related behaviours are complex and heavily depend on functional communication between the amygdala and prefrontal cortex (PFC). Previously, we have shown that the transcriptional networks within the amygdala and PFC of GF mice are altered. MicroRNAs (miRNAs) act through translational repression to control gene translation and have also been implicated in anxiety-like behaviours. However, it is unknown whether these features of host post-transcriptional machinery are also recruited by the gut microbiome to exert control over CNS transcriptional networks. RESULTS: We conducted Illumina(r) next-generation sequencing (NGS) in the amygdala and PFC of conventional, GF and germ-free colonized mice (exGF). We found a large proportion of miRNAs to be dysregulated in GF animals in both brain regions (103 in the amygdala and 31 in the PFC). Additionally, colonization of GF mice normalized some of the noted alterations. Next, we used a complementary approach to GF by manipulating the adult rat microbiome with an antibiotic cocktail to deplete the gut microbiota and found that this strategy also impacted the expression of relevant miRNAs. CONCLUSION: These results suggest that the microbiome is necessary for appropriate regulation of miRNA expression in brain regions implicated in anxiety-like behaviours. PMID- 28838325 TI - A study on the safety and efficacy of reveglucosidase alfa in patients with late onset Pompe disease. AB - BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. RESULTS: Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (-0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. CONCLUSIONS: Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late onset Pompe disease. TRIAL REGISTRATION: ISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011. PMID- 28838326 TI - "Take me seriously and do something!" - a qualitative study exploring patients' perceptions and expectations of an upcoming orthopaedic consultation. AB - BACKGROUND: Patients' perceptions of care is an important factor in evaluation of health care, in quality assessment, and in improvement efforts. Expectations of assessments or procedures such as surgery have been found to be related to perceptions of outcome as well as satisfaction, and are therefore of interest to both clinicians and researchers. Increased understanding of these patient views is important so that orthopaedic assessments, regardless of who performs them, can be further developed and patient-centred to better meet patients' needs. The purpose of this study was therefore to explore patients' perceptions and expectations of an upcoming orthopaedic consultation. METHODS: This was an explorative qualitative study with an inductive approach. Thirteen patients who were referred for orthopaedic consultation were included using a purposeful sampling strategy. Patients participated in individual, semi-structured interviews that were recorded, transcribed verbatim and analysed with qualitative content analysis. RESULTS: The participants' expressed perceptions and expectations of the upcoming orthopaedic surgeon consultation were classified into 5 categories: Hoping for action, Meeting an expert, A respectful meeting, Participating in the consultation, and A belief that hard facts make evidence. Across the categories, an overarching theme was formulated: Take me seriously and do something! The participants emphasised a desire to be taken seriously and for something to happen, both during the consultation itself and as a result of the orthopaedic consultation. They described a trust in the expertise of the orthopaedic surgeon and stressed the importance of the surgeon's attitude, but still expected to participate in the consultation as well as in the decision making process. CONCLUSIONS: The study findings illuminate aspects that are important for patients in an orthopaedic consultation. The descriptions of patients' perceptions and expectations can serve to improve patient-clinician relationships as well as to inform the development of new models of care, and a greater understanding of these aspects may improve the patient experience. PMID- 28838327 TI - The relationship between exclusion from school and mental health: a secondary analysis of the British Child and Adolescent Mental Health Surveys 2004 and 2007. AB - BACKGROUND: Children with poor mental health often struggle at school. The relationship between childhood psychiatric disorder and exclusion from school has not been frequently studied, but both are associated with poor adult outcomes. We undertook a secondary analysis of the British Child and Adolescent Mental Health Surveys from 2004 and its follow-up in 2007 to explore the relationship between exclusion from school and psychopathology. We predicted poorer mental health among those excluded. METHOD: Psychopathology was measured using the Strengths and Difficulties Questionnaire, while psychiatric disorder was assessed using the Development and Well-Being Assessment and applying Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM IV) criteria. Exclusion from school and socio-demographic characteristics were reported by parents. Multi variable regression models were used to examine the impact of individual factors on exclusion from school or psychological distress. RESULTS: Exclusion from school was commoner among boys, secondary school pupils and those living in socio economically deprived circumstances. Poor general health and learning disability among children and poor parental mental health were also associated with exclusion. There were consistently high levels of psychological distress among those who had experienced exclusion at baseline and follow-up. CONCLUSIONS: We detected a bi-directional association between psychological distress and exclusion. Efforts to identify and support children who struggle with school may therefore prevent both future exclusion and future psychiatric disorder. PMID- 28838328 TI - Backing into the future: pharmacological approaches to the management of resistant depression. AB - Pragmatic studies indicate that a substantial number of depressed patients do not remit with current first-line antidepressant treatments and after two failed treatment steps the chance of remission with subsequent therapies is around 15%. This paper focuses on current evidence for pharmacological treatments in resistant depression as well as possible future developments. For patients who have failed to respond to two antidepressant trials, augmentation with atypical antipsychotic drugs, specifically quetiapine and aripiprazole, has the best evidence for efficacy, though older treatments such as lithium and triiodothyronine still have utility. The striking antidepressant effect of ketamine in resistant depression has stimulated research into glutamatergic compounds; however, capturing the efficacy of ketamine with drugs suitable for continuous use has proved challenging. Growing knowledge of the pathophysiological role of inflammation in depression offers great opportunities for future treatment in terms of repurposing anti-inflammatory agents from general medicine and pre-treatment stratification of those depressed patients in whom such interventions are likely to be beneficial. Finally an older drug, the dopamine receptor agonist pramipexole, if used carefully may well improve the prospects of depressed patients who are refractory to current approaches. PMID- 28838329 TI - Using an Education Intervention to Increase Preparedness Among Pet Owners: Results of a Pilot Study. AB - OBJECTIVES: Households with pets are considered a high-risk population, presenting many challenges to response and recovery efforts. Research indicates that households with pets are less likely to evacuate during disasters, and pets left behind pose a health risk to relief workers and the general public. This pilot study explores a brief education intervention targeting households with pets as a method of increasing general household preparedness, with the purpose of facilitating evacuation and protective behaviors in this population. METHODS: A convenience sample of households with pets was recruited to participate in a one-group pre- and post-survey design evaluating the impact of a brief education intervention on increasing pet-specific and general household preparedness levels. RESULTS: Results suggest that the sample population was below national estimates in basic household preparedness before the intervention. Post-survey results indicate an increase in completion of some preparedness tasks after the intervention. There was a statistically significant increase in overall pet preparedness at the P=0.10 level; however, that difference did not translate into general household preparedness. CONCLUSION: The findings from this study are consistent with those from previous literature suggesting that persons often place the needs of their pets above their own; however, the use of a brief education intervention may be successful in increasing pet-specific preparedness levels, which may be useful in successful evacuation and pet well-being. (Disaster Med Public Health Preparedness. 2018;12:441-445). PMID- 28838330 TI - Cognitive Behaviour Therapy for Health Anxiety: A Systematic Review and Meta Analysis - CORRIGENDUM. PMID- 28838331 TI - Quantification of Hexavalent Chromium in Surface Water Samples by a Selective Electrochemical Method. AB - The current study aimed to develop a robust, selective, and sensitive voltammetric method for hexavalent chromium (CrVI) at a chemically modified carbon paste electrode. For the preparation of the electrode, a micropipet tip was packed with modified carbon paste mainly consisting of graphite powder and diphenylcarbazone (5 + 1, w/w). Voltammetric mode, type of electrolyte, pH, volume of electrolytes, accumulation time, accumulation potential, and stirring rate were studied in detail. The current response was linearly dependent on the concentration of CrVI from 0.20 to 2.60 umol/L. The reproducible results were obtained for replicate analyses (n = 11) of three proposed electrodes of the same composition with RSDs of <2.0%. The LODs and LOQs were found to be 0.052 and 0.174 umol/L, respectively. The noticeable electrode surface passivation was not observed for the detection of CrVI. The proposed methods were successfully applied for CrVI in different surface waters in Sindh, Pakistan. PMID- 28838332 TI - Oncolytic E1B 55KDa-deleted adenovirus replication is independent of p53 levels in cancer cells. AB - Oncolytic adenoviruses represent a new approach for cancer therapy due to its tumor specificity. E1B 55kDa-deleted adenovirus type 5 (Ad5dlE1B 55kDa) is a promising therapeutic agent that can selectively replicate in and lyse p53 defective cancer cells. However, the overall efficacy has shown varying degrees of success with raised doubts about the correlation between p53 status and E1B deleted adenovirus replication ability. In this study, we investigated the relationship between the efficiency of Ad5dlE1B 55kDa replication and p53 levels in cancer cells. Five transient p53 expression vectors were engineered to expresses different p53 levels in transfected cells. Then, the effect of the variable p53 levels and cellular backgrounds on the replication efficiency of oncolytic Ad5dlE1B 55kDa was evaluated in H1299 and HeLa cell lines. We found that the replication efficiency of these oncolytic viruses is dependent on the status, but not the expression levels, of p53. Ad5dlE1B 55kDa was shown to have selective replication activity in H1299 cells (p53-null) and decreased viral replication in HeLa cells (p53-positive), relative to the wild-type adenovirus in both cell lines. Our findings suggest that there is a relation between the E1B deleted adenovirus replication and the presence as well as the activity of p53, independent of its quantity. PMID- 28838333 TI - Hypoxia stimulates neural stem cell proliferation by increasing HIF-1alpha expression and activating Wnt/beta-catenin signaling. AB - Evidence indicates that after brain injury, neurogenesis is enhanced in regions such as hippocampus, striatum, and cortex. To study the role of hypoxia-inducible factor-1 (HIF-1alpha) and Wnt signaling in cerebral ischemia/hypoxia-induced proliferation of neural stem cells (NSCs), we investigated the proliferation of NSCs, expression of HIF-1alpha, and activation of Wnt signaling under conditions of pathologic hypoxia in vitro. NSCs were isolated from 30-day-old Sprague-Dawley rats and subjected to 0.3% oxygen in a microaerophilic incubation system. Cell proliferation was evaluated by measuring the diameter of neurospheres and by bromodeoxyuridine incorporation assays. Real-time quantitative PCR and Western blotting were used to detect mRNA and protein levels of HIF-1alpha, beta-catenin, and cyclin D1 in the NSCs. The results showed that hypoxia increased NSC proliferation and the levels of HIF-1alpha, beta-catenin, and cyclin D1 (p < 0.05). Blockade of the Wnt signaling pathway decreased hypoxia-induced NSC proliferation, whereas activation of this pathway increased hypoxia-induced NSC proliferation (p < 0.05). Knockdown of HIF-1alpha with HIF-1alpha siRNA decreased beta-catenin nuclear translocation and cyclin D1 expression, and inhibited proliferation of NSCs (p < 0.05). These findings indicate that pathologic hypoxia stimulates NSC proliferation by increasing expression of HIF-1alpha and activating the Wnt/beta-catenin signaling pathway. The data suggest that Wnt/beta catenin signaling may play a key role in NSC proliferation under conditions of pathologic hypoxia. PMID- 28838334 TI - Effects of curcumin plus Soy oligosaccharides on intestinal flora of rats with ulcerative colitis. AB - To explore the therapeutic effect of curcumin (Cur) and soybean oligosaccharides (SBOS) on ulcerative colitis (UC) through testing the intestinal flora and ulcerative colitis (UC). 80 male SD rats were selected divided into four groups with 20 rats in each group: normal group, sulfasalazine (SASP) group, model group and group of curcumin plus soy oligosaccharide. All animals were treated for 4 weeks. In the fifth week rats were decapitated. Macroscopic damage scores of colonic mucosa were calculated. A 4mL blood sample was taken to detect the contents of serum tumor necrosis factor -alpha (TNF-alpha) and interleukin 8 (IL 8) by the double antibody sandwich ABC-ELISA method (enzyme-linked immunosorbent assay). Colonic tissues with the most obvious lesions were obtained using a surgical scissor. A routine hematoxylin-eosin (HE) staining method was used to stain pathological specimens and images of staining results were obtained. Histological injury scores of colonic mucosa were calculated. Ulcerative colitis model rats had the highest macroscopic damage scores and histological injury scores of colonic mucosa. After treatment the contents of TNF-alpha and IL-8 decreased significantly in the group of curcumin plus soy oligosaccharide compared with the model group with statistical significance (P <0.01) while the contents were close to those in the SASP group. There was no statistical significance (P> 0.05). The treatment could decrease TNF-alpha and IL- 8 expression and reduce colonic mucosa inflammation and tissue damage. PMID- 28838335 TI - Comparative determination of ventilatory efficiency from constant load and incremental exercise testing. AB - The analysis of the relationships between minute ventilation (VE) to CO2 output (VCO2), referred to as ventilatory efficiency, in response to incremental exercise testing, is considered a useful index for assessing the presence and severity of cardiopulmonary and metabolic diseases. The effects of constant load exercise testing performed at work intensity associated with anaerobic threshold (AT) and respiratory compensation points (RCP), on the accurate measurements of ventilatory efficiency are not well known. The aim of this present study was to investigate the reliability of the VE/VCO2 ratio obtained from constant load exercise tests performed with two important metabolic rates (at the AT and RCP) and compare it to that of those of incremental exercise tests. A total of 20 young male (20.8+/-0.4 yr) subjects initially performed an incremental exercise test and then two constant load exercise tests, on different days. Respiratory and pulmonary gas exchange variables were used to estimate AT and RCP. A paired t test was used to analyse data. AT and RCP (average) occurred the at 60% and at 71% of peak O2 uptake, respectively. The lowest VE/VCO2 ratio recorded within the first 2 minutes of constant load exercise tests with a work load of AT (26.4+/ 0.3) and RCP (26.7+/-0.5) was not statistically different from the lowest ratio obtained from the incremental exercise tests (26.0+/-0.7). In the constant load exercise test, despite the different metabolic rates, the increase in ventilation corresponded closely with the increase in CO2 production, reflecting an optimal ventilation and perfusion ratio. Clinicians should consider the constant load exercise test work load associated with AT and RCP as it provides a meaningful lowest value for ventilatory efficiency. PMID- 28838336 TI - Effect of Cdc42 on myocardial ischemia-reperfusion of rats. AB - To investigate the effects and their possible mechanisms of cell division cycle 42 (Cdc42) to neonatal rat myocardial cells subjected to the ischemia-repefusion. Neonatal rat cardiomyocytes were cultured and then subjected to the ischemia reperfusion. Experimental groups 1. Control group; 2. Ischemia-repefusion group (I/R group); 3. Oligofectamine group (Oli group); 4. Oligofectamine and antisense oligodeoxynucleotide (AS-ODN) group (As group); 5. Oligofectamine and missense oligodeoxynucleotide (MS-ODN) group (Ms group); 6. SP600125 and Oligofectamine and AS-ODN group (SP600125/As group); 7. SP600125 and Oligofectamine and MS-ODN group (SP600125/Ms group). The cardiacmyocyte apoptosis rate was detected by AnnexinV/PI with flow cytometry. Cdc42, JNK, p-JNK, Bax and Bcl-2 were detected by western blot. In comparison with control group, Cdc42, the cardiacmyocyte apoptosis rate and phosphorylation of JNK were increased and the ratio of Bcl 2/Bax was reduced in the I/R group; Cdc42, the cardiacmyocyte apoptosis rate and phosphorylation of JNK in As group was lower than the I/R group, Oli group and the Ms group, and the ratio of Bcl-2/Bax was the highest in the four groups; Cdc42, cardiacmyocyte apoptosis rate, phosphorylation of JNK and the ratio of Bcl 2/Bax showed no differences in the I/R group, Oli group and the Ms group. Compared with As group, phosphorylation of JNK was lower in the SP600125/As group, phosphorylation of JNK in SP600125/Ms group was lower than the Ms group, and it showed no differences between the SP600125 & As group and the SP600125 & Ms group. Cdc42 in myocardial I/R can promote cardiacmyocyte apoptosis rate. AS ODN of Cdc42 can decrease the cardiacmyocyte apoptosis rate in I/R. Cdc42 may played a role in myocardial I/R via JNK , Bcl-2 and Bax signal pathway. PMID- 28838337 TI - Mass spectrometric identification of diagnostic markers for chronic prostatitis in seminal plasma by analysis of seminal plasma protein clinical samples. AB - There are few specific diagnostic markers for chronic prostatitis. Therefore, we used mass spectrometry to evaluate differences in seminal plasma protein expression among patients with prostatitis and young and middle-aged healthy controls. We analysed pooled seminal plasma protein samples from four prostatitis patients (two pools), three young controls (one pool), and three middle-aged controls (one pool). The samples were analysed by liquid chromatography-tandem mass spectrometry. Of the 349 proteins identified, 16 were differentially expressed between the two control pools. Five proteins were up- or down-regulated in both of the prostatitis pools compared to middle-aged controls but not between young and middle-aged pools. Progestagen-associated endometrial protein (PAEP) was over-expressed in prostatitis samples compared to young and middle-aged controls. Our findings and those of previous studies indicate that PAEP is a potential seminal plasma marker for chronic prostatitis. In conclusion, we found age-related changes in seminal plasma protein expression. PAEP expression in seminal plasma should be investigated further to evaluate its potential as a diagnostic marker for chronic prostatitis. PMID- 28838338 TI - Ghrelin and NUCB2/Nesfatin-1 expression in unilateral testicular torsion-induced rats with and without N-acetylcysteine. AB - Testicular torsion (TT) is a common urological problem in the field of pediatric surgery. The degree and duration of torsion determines the degree of testicular damage; however, its effects on the expression of octanoylated ghrelin and nucleobindin 2 (NUCB2) /nesfatin-1 synthetized from testicular tissue remain unclear. We explored the effects of experimentally induced unilateral TT on serum and contralateral testicular tissue ghrelin and NUCB2/nesfatin-1 levels, and determined whether N-acetyl cysteine (NAS) treatment had any effects on their expression. A total of 42 Wistar Albino strain rats were divided into 7 groups: Group (G) I control, GII sham, GIII 12-hour torsion, GIV 12-hour torsion + detorsion + 100 mg/kg NAS, GV 24-hour torsion, GVI 24-hour torsion + detorsion + 100 mg/kg NAS, and GVII 100 mg/kg NAS. Octanoylated ghrelin and NUCB2/nesfatin-1 concentrations were evaluated in serum using the ELISA method and in testicular tissue with immunohistochemical methods. Immunoreactivity of octanoylated ghrelin significantly increased in GI compared to GIII, GV, and GVI (p<0.05). NUCB2/nesfatin-1 immunoreactivity increased in GV and GVIII relative to GI (p<0.05). In the 12-hour torsion group, a significant decrease in octanoylated ghrelin levels with NAS treatment was observed; however, in the 24-hour torsion group, a significant decrease was not observed. In the 12-hour torsion + NAS treatment group, a significant change was not observed in NUCB2/nesfatin-1 expression. Following 24-hour torsion, an increase in NUCB2/nesfatin-1 levels was observed, and NAS treatment did not reverse this increase. It was determined that increases in the expression of octanoylated ghrelin and NUCB2/nesfatin-1, the latter of which was a result of TT, reflect damage in this tissue. Importantly, NAS treatment could prevent this damage. Thus, there may be a clinical application for the combined use of NAS and octanoylated ghrelin in preventing TT related infertility. PMID- 28838339 TI - Histologic analyses of different concentrations of TritonX-100 and Sodium dodecyl sulfate detergent in lung decellularization. AB - Pulmonary diseases cusecs a large portion of mortality in the world. There is no more cure for pulmonary diseases and many approaches are needed for finding ways to cure. Nowadays, implantation and drugs are only ways for curing those people who are facing with these diseases. Tissue engineering and regenerative medicine have been appeared as multidisciplinary field and also, they presents new therapeutic approaches for pulmonary diseases. One of these therapeutic approaches is decellularization which removes cellular but leaves intact important extracellular matrix (ECM) proteins and three-dimensional (3D) architecture and also, this approach has been studied for in-vitro and ex-vivo. In this study, we aimed to investigate a comparison of different concentrations of Triton X-100 and Sodium dodecyl sulfate detergents in lung decellularization in order to evaluate the effects of different concentrations and times of mentioned detergents on three dimensional and ECM proteins lung. Two detergents (Triton-X100 and Sodium dodecyl sulfat) were used with different concentrations for decellularizing rat lungs for maintaining of three-dimensional lung architecture and ECM protein compositions which have significant roles in differentiation and migration of stem cells. Results showed that SDS 0.05%, 0.1% and Triton-X100 0.1% could maintain 3D, elastin and collagen better than other concentrations in 24 and 48 h- decellularization. We concluded that these approaches can help to achieve three-dimensional architecture and extracellular matrix of lung with minimum destruction for next step such as recellularization and in-vivo study. PMID- 28838340 TI - Isolation, identification and characterization of Morganella morganii from Naja naja atra in Beijing, China. AB - Morganella morganii is an important opportunistic human pathogen and belongs to the family of Enterobacteriaceae. Although it is widely distribution, it only be considered a rare cause of human infections. We report the isolate of M. morganii from Naja naja atra following infections of heart, lung and liver. Seven strains were confirmed using 16S rDNA amplified and sequences. Antimicrobial susceptibility testing of M. morganii isolates demonstrated ubiquitous resistance to ampicillin, amoxicillin/clavulanic acid, cefazolin, cephalothin, sulfamethoxazole/trimethoprim, sulfamethoxazole et al. However, M. morganii ubiquitous susceptible to piperacillin, ampicillin/sulbactam, piperacillin/tazobactam, cefixime et al. Further investigate display gyr B and Sul2 genes presence in all M. morganii isolates. AAC(3)-II was found in E2, E3 and E6 M. morganii. gyrA and qnrB expression in M3 and M6 M. morganii. This is the first description in M. morganii carrying AAC(3)-II, gyrB, gyrA, qnrB, and Sul2 genes from Naja naja atra, which suggests the increasing risk of pathogen transmission between humans and wildlife. PMID- 28838341 TI - Chicken egg-white extracts promote OCT4 and NANOG expression and telomeres growth in 293T cells. AB - It will have broad applications in cell biology if one of egg cell extracts has the roles to promote cell proliferation and reprogramming. It will provide a new method for easier reprogramming somatic cells and promote cell proliferation. We found chicken egg-white extracts have roles to promote cell proliferation and reprogramming. The different ingredients were then assessed for cell proliferation activity and somatic cell reprogramming. Chicken egg-white extract ingredients that were less than 3 kDa (LT3K) promoted cell proliferation. Those ingredients that were greater than 3 kDa (GT3K) promoted the increased expression of pluripotency factors in somatic cells and promote telomeres growth in 293T cells. Chicken egg-whites can be separated into ingredients of LT3K, which act to promote cell proliferation, and GT3K, which can be used to promote somatic cell reprogramming. PMID- 28838342 TI - The association between PAI-1 -675 4G/5G polymorphism and type 2 diabetes mellitus. AB - In this study, we aimed to analyze the association between plasminogen activator inhibitor 1 (PAI-1) -675 4G/5G polymorphism and type 2 diabetes mellitus (T2DM) risk. We included in 187 T2DM patients and 186 heathy controls between 2014 and 2017 from Tianjin Gong An Hospital, China. All patients and controls were ethnically Chinese Han population. The primers and polymerase chain reaction (PCR) conditions were performed. Results from this case-control study suggested that PAI-1 -675 4G/5G polymorphism was not associated with T2DM risk in four genetic models. Additionally, PAI-1 -675 4G/5G polymorphism was not associated with clinical and laboratory characteristics, such as age, gender, body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, and HbA1c. In conclusion, this case-control study suggested that PAI-1 -675 4G/5G polymorphism was not associated with T2DM risk in this population. PMID- 28838343 TI - In vitro evaluation of cytotoxic, anti-proliferative, anti-oxidant, apoptotic, and anti-microbial activities of Cladonia pocillum. AB - The aim of this study was to investigate the anti-proliferative, apoptotic, cytotoxic, and anti-oxidant effects of extracts from the lichen Cladonia pocillumon human breast cancer cells (MCF-7), and to characterize the anti microbial features. MCF-7 cells were treated with methanolic C. pocillum extract for 24h. The cytotoxicity of the extract was tested with MTT. Moreover, its anti proliferative effects were examined with immunocytochemical method. Apoptosis and biochemical parameters were detected in MCF-7. The methanol and chloroform extracts of the lichen were tested for anti-microbial activity against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans using the disc diffusion method and calculation of minimal inhibitory concentrations. Although BrdU incorporation was not observed in MCF-7 cells treated with methanol extract at a concentration above 0.2 mg/mL, a significant decrease was observed int he percentage of PCNA immunoreactive cells in groups treated with 0.2, 0.4, 06, and 0.8 mg/mL methanol extracts of C.pocillum (49+/-6.3, 44+/-5.2, 23+/-2.5, 0, respectively) compared to that of control (85+/-4.5). The percentage of apoptotic cells significantly increased in groups treated with 0.2, 0.4, 0.6, and 0.8 mg/mL extracts of the C.pocillum (54+/-3.5, 76+/-2.6, 77+/-1.8, 82+/-4.2, respectively) compared with that of control group (3.9+/-1.5).The half-maximal inhibitory concentration of the methanol extract against MCF-7 cells was 0.802 mg/mL .Although the chloroform extract showed more effective anti-microbial activity overall, the methanol extract showed higher anti-fungal activity. Collectively, the results of our study indicate that C.pocillum extracts have strong anti-microbial and apoptotic effects. This lichen therefore shows potential for development as a natural anti microbial, anti-oxidant, and apoptotic agent. PMID- 28838344 TI - Inflammatory and immune responses to a 3-day period of downhill running in active females. AB - Exercise-induced muscle damage (EIMD) is accompanied by inflammatory and immune responses. However, due to the repeated bout effect, there will probably be less EIMD. Hence, the purpose was to investigate inflammatory and immune responses over a three-day period of downhill running in active females. Eleven moderately trained healthy females performed three 60-minute bouts of downhill running in 13.5% grade, separated by 24 hours, at a speed eliciting 70-80% of their VO2peak on level grade. Delayed onset muscle soreness (DOMS), range of motion (ROM) and maximum knee isotonic strength (1RM) were measured pre- and two-hour post every bout. Blood variables, including CBC, serum lactate dehydrogenase (LDH), creatine kinase (CK), myoglobin (Mb), IL-10, IL-6 and Monocyte chemoattractant protein-1 (MCP-1) were measured at 1 hour before the first bout and two hours after every bout. Data was analysed by repeated measure ANOVA (P<0.05). Although CK, LDH, Mb, IL-10, IL-6, MCP-1, total leukocyte count, monocytes and neutrophils increased significantly following the first bout, CK, LDH, Mb, IL-10, monocytes and neutrophils were only significantly higher following the third bout compared to the baseline (all P<0.05). Moreover, IL-10 and IL-6 decreased following the second and third bouts compared to the first bout (P<0.05). In comparison with the baseline, lymphocytes decreased after the second bout, DOMS increased following the second and third bouts, 1RM decreased following the first and second bouts (all P<0.05). ROM showed no significant difference. The three-day period of downhill running did not exacerbate EIMD and inflammatory response was partly attenuated. PMID- 28838345 TI - Prediction of G gene epitopes of viral hemorrhagic septicemia virus and eukaryotic expression of major antigen determinant sequence. AB - This study aims to express fish Viral hemorrhagic septicemia virus (VHSV) G main antigen domain by using Bac-to-bac expression system. Using bioinformatics tools, B cell epitope of VHSV G gene was predicted, and G main antigen domain was optimized. GM gene was inserted into pFastBac1 vector, then transferred recombinant plasmid into DH10Bac to get recombinant rBacmid-GM. Obtained shuttle plasmid rBacmid-GM was transfected into sf9 cells. GM expression was examined using by PCR and western-blot. Results indicated that G main antigen domain gene of VHSV was successfully cloned and sequenced which contains 1209 bp. PCR proved that shuttle plasmid rBacmid-GM was constructed correctly. SDS-PAGE electrophoresis analysis detected a band of protein about 45kD in expression product of G gene. Obtained recombinant G protein reacted with VHSV-positive serum that was substantiated by western-blot analysis. In conclusion, the main antigen domain of VHSV G was successfully expressed in the Bac-to-Bac baculovirus system. PMID- 28838346 TI - Molecular effects of leptin on peroxisome proliferator activated receptor gamma (PPAR-gamma) mRNA expression in rat's adipose and liver tissue. AB - Leptin is a 16-kDa peptide hormone secreted by adipose tissue that participates in the regulation of energy homeostasis. The aim of this study was to determine the effect of leptin injection on mRNA expression of peroxisome proliferator activated receptor gamma (PPAR-gamma) and comparison of PPAR-gamma mRNA expression in rat's adipose and liver tissue. Twenty adult male rats were divided into the following groups: Group 1asa control (n=10) that did not receive any treatment. Group 2as a treatment (n=10) that received leptin (30 ug / kg BW) intraperitoneally (ip) for two successive days. Blood samples were taken before and one day after second leptin injection for triglyceride (TG), Free Fatty Acid (FFA), HLD-cholesterol, and LDL-cholesterol measurement. Total RNA was extractedfrom the adipose tissue and liver tissues of rats. Adipose and liver tissue cells' cDNA was synthesized to characterize the expression of PPAR-gamma. Gene expression of PPAR-gamma mRNA was tested by RT- PCR technique. Results show leptin decreases expression of PPAR-gamma on rat. Low levels of PPAR-gamma mRNA were detected in adipose and liver tissues of treatment rats in comparison to control group. In treatment group, the level of PPAR-gamma mRNA in liver tissue was very lower than the adipose tissue. The levels of HDL and FFA in treatment rats were increased whereas serum levels TG, VLDL and LDL were not changed. It is concluded that leptin signal with suppressing of PPAR-gamma mRNA expression in rat's adipose and liver tissues can result in lipolysis instead of lipogenesis. PMID- 28838347 TI - Synaptosomal and mitochondrial oxidative damage followed by behavioral impairments in streptozotocin induced diabetes mellitus: restoration by Malvastrum tricuspidatum. AB - Synaptosomal and mitochondrial impairments in the brain of diabetic individual manifest metabolic risk factors that most likely affect the brain functions. Diabetes is associated with the structural and functional alterations of the brain and neuronal loss leading to cognitive and other behavioral impairments, thus reducing the quality of life. The biochemical mechanisms underlying the diabetes-associated behavioral decline are poorly understood. In the present study, we examined the effects of hyperglycemia on the oxidative stress and behavioral functions in streptozotocin-induced diabetic mice. Our results showed the increase in oxidative stress in synaptosomes and brain mitochondria marked by an increase in lipid peroxidation and protein carbonyl content and decline in reduced glutathione in mice treated with streptozotocin. The oxidative damage in synaptosomes and brain mitochondria further caused impairment in locomotor and memory behavioral functions. Furthermore, we examined the protective effects of plant extract derived from Malvastrum tricuspidatum against STZ induced oxidative stress and behavioural impairments. For the first time we showed that this plant extract attenuate synaptosomal and mitochondrial oxidative stress and behavioral impairments in mice treated with streptozotocin. We suggest that streptozotocin caused impairments in synaptosomes and brain mitochondria and altered behavioral functions via increase in the oxidative stress and decrease in the antioxidant defense system. These impairments in synaptosomes and brain mitochondria and alterations in behavioral functions are significantly prevented by supplementation of Malvastrum tricuspidatum extract. PMID- 28838348 TI - Effect of salinity on gene expression, morphological and biochemical characteristics of stevia rebaudiana Bertoni under in vitro conditions. AB - Stevia rebaudiana Bertoni is a famous medicinal plant for its low calorific value compounds which are named steviol glycosides (SGs) and they are 150-300 times sweeter than sugar. Among various SGs, stevioside and rebaudioside A considered to be the main sweetening compounds. Soil salinity is one of the most essential stress in the world. Salinity affects the survival and yield of crops. In current study the effects of salinity and osmotic stress caused by different concentration of NaCl (0, 20, 40, 60 and 80 mM) on morphological traits, genes expressionand amount of both stevioside and rebaudioside Aunder in vitro conditions has been investigated. The morphological traits such as bud numbers, root numbers, shoot length (after 15 and 30 days) were evaluated. With increasing salinity, the values of all studied morphological traits decreased. To investigation of UGT74G1 and UGT76G1 genes expression that are involved in the synthesis of SGs, RT-PCR was done and there were significant differences between all media. The highest expression of both genes was observed in plantlets grown on MS media (with NaCl-free). Also, the lowest amounts of gene expression of the both genes were seen in MS+ 60 mM NaCl. Based on HPLC results, the highest amount of both stevioside and rebaudioside A were observed in plantlets grown in MS media (with NaCl-free). Finally, it can be concluded that stevia can survive under salt stress, but it has the best performance in the lower salinity. PMID- 28838349 TI - Effect of KH2PO4 on gene expression, morphological and biochemical characteristics of stevia rebaudiana Bertoni under in vitro conditions. AB - Stevia rebaudiana is one of the most important biologically sourced and low calorie sweeteners Bertoni that has a lot of steviol glycosides. Tissue culture is the best for propagation of stevia and micro nutrients can affect both morphological traits and steviol glycosides production. Therefore, the effect of different concentrations of KH2PO4on stevia growth factors and gene expression had been studied by tissue culture methods, RT-PCR and HPLC. According the results, bud numbers had increased significantly in MS + 0.034 mMKH2PO4 media and the highest measured length was seen in plants grown under MS + 0.034 mM KH2PO4 treatment. Also, the highest growth rate (1.396 mm/d) was observed in MS + 0.034 mMKH2PO4.The best concentration of KH2PO4 for expression of UGT74G1 was 0.00425mMand the best one for UGT76G1 expression was 0.017mM. Interestingly, the best media for both stevioside and rebaudioside A accumulation was 0.017mM KH2PO4containing media. There was positive correlation between the best media for gene expression and the best one for steviol glycosides production. PMID- 28838350 TI - Molecular identification of drug resistant mutations to tetracycline in Mycoplasma spp. isolated from patients with multiple sclerosis. AB - Bacterial infections play a significant role in causing or intensifying the attacks in MS and there are reports based on the interference of Mycoplasma with a global distribution. Mycoplasma causes autoimmune attacks by imitating the host cell membrane, which is a way of resistance to antibiotics. The purpose of this study was to evaluate the molecular identification of mutations causing resistance to tetracycline in Mycoplasma isolated from MS patients. A total number of 32 cerebrospinal fluid samples and 48 urinal fluid samples were collected from MS patients. The samples were enriched in 7 PPLO broth for one night and continuous cultivation in agar PPLO and PPLO broth for one week. DNA was extracted, and then nested PCR and Doublex PCR were used for bacteria genus identification and the presence of potential tetracycline-resistant alleles (rrs4 and rrs3), respectively. A total number of 12 samples created colonies. However, only 5 samples (1 cerebrospinal fluid and 4 urinal samples) were detected to be Mycoplasma. The urinal samples showed the desired alleles and were tetracycline resistant. By sequencing the PCR products, it was shown that these alleles have mutated in various points. Based on the results it seems that the resistant mutated Mycoplasma can be detected in MS patients in our population and may be considered as a risk factor for the disease. PMID- 28838351 TI - Transgender HIV and sexually transmissible infections. AB - Transgender women across a range of different populations and settings have a high prevalence of HIV infection. There are fewer and often poorer quality studies of sexually transmissible infection (STI) prevalence. There are fewer studies in transgender men and, in general, the prevalence of HIV and STIs is lower than that of transgender women. Susceptibility to HIV and STI infection is inextricably linked to the increased vulnerability of transgender populations, a consequence of a lack of legal and social recognition that results in reduced access to educational and employment opportunities, which can result in high rates of transactional sex. Other measures of disadvantage, such as substance abuse and mental health problems, also increase the risk of HIV and STIs and have an effect on access to health care, highlighting the need for transgender friendly multidisciplinary services offering individualised risk assessment, prevention advice and testing for STI and HIV. PMID- 28838353 TI - Epidemiology of gender dysphoria and transgender identity. AB - This review provides an update on the epidemiology of gender dysphoria and transgender identity in children, adolescents and adults. Although the prevalence of gender dysphoria, as it is operationalised in the fifth edtion of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), remains a relatively 'rare' or 'uncommon' diagnosis, there is evidence that it has increased in the past couple of decades, perhaps reflected in the large increase in referral rates to specialised gender identity clinics. In childhood, the sex ratio continues to favour birth-assigned males, but in adolescents, there has been a recent inversion in the sex ratio from one favouring birth-assigned males to one favouring birth-assigned females. In both adolescents and adults, patterns of sexual orientation vary as a function of birth-assigned sex. Recent studies suggest that the prevalence of a self-reported transgender identity in children, adolescents and adults ranges from 0.5 to 1.3%, markedly higher than prevalence rates based on clinic-referred samples of adults. The stability of a self reported transgender identity or a gender identity that departs from the traditional male-female binary among non-clinic-based populations remains unknown and requires further study. PMID- 28838352 TI - Syndromic management of sexually transmissible infections in resource-poor settings: a systematic review with meta-analysis of the abnormal vaginal discharge flowchart for Neisseria gonorrhoea and Chlamydia trachomatis. AB - BACKGROUND: Syndromic management of sexually transmissible infections is commonly used in resource-poor settings for the management of common STIs; abnormal vaginal discharge (AVD) flowcharts are used to identify and treat cervical infection including Neisseria gonorrhoea and Chlamydia trachomatis. A systematic review and meta-analysis was undertaken to measure the diagnostic test performance of AVD flowcharts, including both World Health Organization (WHO)- and locally-adapted AVD flowcharts. METHODS: A systematic search of multiple electronic databases was conducted to locate eligible studies published between 1991 and 2014. Flowcharts were categorised into one of 14 types based on: 1) use of WHO guidelines or locally-adapted versions; 2) use of risk assessment, clinical examination or both; and 3) symptomatic entry. Summary diagnostic performance measures calculated included summary sensitivity, summary specificity and diagnostic odds ratio. RESULTS: Thirty-six studies, including data on 99 flowcharts, were included in the review. Summary sensitivity estimates for WHO flowcharts ranged from 41.2 to 43.6%, and for locally adapted flowcharts from 39.5 to 74.8%. Locally adapted flowcharts performed slightly better than the WHO flowcharts. A difference in performance was not observed between use of risk assessment or clinical examination. The AVD flowchart performed slightly better when it was not restricted to symptomatic women only. CONCLUSIONS: There was considerable variation in the performance of the AVD flowchart but overall it was a poor diagnostic tool regardless of whether risk assessment or clinical examination was included, or whether the flowchart was WHO or locally developed. Many women were treated unnecessarily and many women with cervical infection were not detected. We caution against their continued use for management of cervical infection. PMID- 28838354 TI - The medical care of the neovagina of transgender women: a review. AB - For transgender women, genital adjustment surgery involves removal of the natal reproductive organs and creation of a neovagina, vulva and clitoris. We conducted a review of the medical literature in order to summarise the issues that can affect the health of the neovagina in the long term, and to make recommendations on how to manage these issues. PMID- 28838355 TI - Sixteen Years of Meiotic Silencing by Unpaired DNA. AB - The filamentous fungus Neurospora crassa possesses a process called meiotic silencing by unpaired DNA (MSUD). MSUD has a remarkable ability to scan homologous chromosomes for unpaired DNA during meiosis. After unpaired DNA is identified, MSUD silences all RNA from the unpaired DNA along with any RNA transcribed from homologous sequences at other locations in the genome, regardless of their pairing state. The mechanism by which unpaired DNA is detected is unknown. Unpaired DNA segments can be as short as 1.3kb, if not shorter, and DNA sequences with only a small level of polymorphism (6%) can be considered unpaired by MSUD. MSUD research has identified nine proteins required for full efficiency of the process, three of which are homologs of the canonical RNA interference (RNAi) proteins Dicer, Argonaute, and RNA-dependent RNA polymerase. Most MSUD proteins, including the RNAi homologs, appear to dock outside of the nuclear envelope during early stages of meiosis. Only two have been observed inside the nucleus, a low number given that the identification of unpaired DNA and the triggering of silencing must begin within this location. These two proteins may participate in the unpaired DNA detection process. Recent evidence indicates that the search for unpaired DNA is spatially constrained, possibly because of restrictions on the arrangement of chromatin loops during or after homolog pairing. This review attempts to provide a complete analysis of past, present, and future directions of MSUD research, starting with its discovery during a search for a conserved regulator of fungal development and ending with some benefits the process may provide to MSUD capable organisms. PMID- 28838356 TI - Sleeping Beauty? Developmental Timing, Sleep, and the Circadian Clock in Caenorhabditis elegans. AB - The genetics toolkit is pretty successful in drilling down into minutiae. The big challenge is to integrate the information from this specialty as well as those of biochemistry, physiology, behavior, and anatomy to explain how fundamental biological processes really work. Sleep, the circadian clock and development all qualify as overarching processes that encompass levels from molecule to behavior as part of their known mechanisms. They overlap each other, such that understanding the mechanisms of one can lead to insights into one of the others. In this essay, we consider how the experimental approaches and findings relating to Caenorhabditis elegans development and lethargus on one hand, and to the circadian clock and sleep in higher organisms on the other, could complement and enhance one another. PMID- 28838357 TI - Integrated Genomic Medicine: A Paradigm for Rare Diseases and Beyond. AB - Individualized medicine, or the tailoring of therapeutic interventions to a patient's unique genetic, biochemical, physiological, exposure and behavioral profile, has been enhanced, if not enabled, by modern biomedical technologies such as high-throughput DNA sequencing platforms, induced pluripotent stem cell assays, biomarker discovery protocols, imaging modalities, and wireless monitoring devices. Despite successes in the isolated use of these technologies, however, it is arguable that their combined and integrated use in focused studies of individual patients is the best way to not only tailor interventions for those patients, but also shed light on treatment strategies for patients with similar conditions. This is particularly true for individuals with rare diseases since, by definition, they will require study without recourse to other individuals, or at least without recourse to many other individuals. Such integration and focus will require new biomedical scientific paradigms and infrastructure, including the creation of databases harboring study results, the formation of dedicated multidisciplinary research teams and new training programs. We consider the motivation and potential for such integration, point out areas in need of improvement, and argue for greater emphasis on improving patient health via technological innovations, not merely improving the technologies themselves. We also argue that the paradigm described can, in theory, be extended to the study of individuals with more common diseases. PMID- 28838359 TI - Reinforcing the Links in the Chain of Survival. PMID- 28838358 TI - Coronary Artery Disease in Patients With Out-of-Hospital Refractory Ventricular Fibrillation Cardiac Arrest. AB - BACKGROUND: The prevalence of coronary artery disease (CAD) among patients with refractory out-of-hospital (OH) ventricular fibrillation (VF)/ventricular tachycardia (VT) cardiac arrest is unknown. OBJECTIVES: The goal of this study was to describe the prevalence and complexity of CAD and report survival to hospital discharge in patients experiencing refractory VF/VT cardiac arrest treated with a novel protocol of early transport to a cardiac catheterization laboratory (CCL) for extracorporeal life support (ECLS) and revascularization. METHODS: Between December 1, 2015, and December 1, 2016, consecutive adult patients with refractory OH VF/VT cardiac arrest requiring ongoing cardiopulmonary resuscitation were transported by emergency medical services to the CCL. ECLS, coronary angiography, and percutaneous coronary intervention were performed, as appropriate. Functionally favorable survival to hospital discharge (Cerebral Performance Category 1 or 2) was determined. Outcomes in a historical comparison group were also evaluated. RESULTS: Sixty-two (86%) of 72 transported patients met emergency medical services transport criteria. Fifty-five (89%) of the 62 patients met criteria for continuing resuscitation on CCL arrival; 5 had return of spontaneous circulation, 50 received ECLS, and all 55 received coronary angiography. Forty-six (84%) of 55 patients had significant CAD, 35 (64%) of 55 had acute thrombotic lesions, and 46 (84%) of 55 had percutaneous coronary intervention with 2.7 +/- 2.0 stents deployed per patient. The mean SYNTAX score was 29.4 +/- 13.9. Twenty-six (42%) of 62 patients were discharged alive with Cerebral Performance Category 1 or 2 versus 26 (15.3%) of 170 in the historical comparison group (odds ratio: 4.0; 95% confidence interval: 2.08 to 7.7; p < 0.0001). CONCLUSIONS: Complex but treatable CAD was prevalent in patients with refractory OH VF/VT cardiac arrest who also met criteria for continuing resuscitation in the CCL. A systems approach using ECLS and reperfusion seemed to improve functionally favorable survival. PMID- 28838361 TI - Transcatheter Mitral Valve Replacement When Mitral Surgery Fails: 10 Years Later. PMID- 28838360 TI - Transcatheter Mitral Valve Replacement for Degenerated Bioprosthetic Valves and Failed Annuloplasty Rings. AB - BACKGROUND: Limited data exist regarding transcatheter mitral valve replacement (TMVR) for patients with failed mitral valve replacement and repair. OBJECTIVES: This study sought to evaluate the outcomes of TMVR in patients with failed mitral bioprosthetic valves (valve-in-valve [ViV]) and annuloplasty rings (valve-in-ring [ViR]). METHODS: From the TMVR multicenter registry, procedural and clinical outcomes of mitral ViV and ViR were compared according to Mitral Valve Academic Research Consortium criteria. RESULTS: A total of 248 patients with mean Society of Thoracic Surgeons score of 8.9 +/- 6.8% underwent TMVR. Transseptal access and the balloon-expandable valve were used in 33.1% and 89.9%, respectively. Compared with 176 patients undergoing ViV, 72 patients undergoing ViR had lower left ventricular ejection fraction (45.6 +/- 17.4% vs. 55.3 +/- 11.1%; p < 0.001). Overall technical and device success rates were acceptable, at 92.3% and 85.5%, respectively. However, compared with the ViV group, the ViR group had lower technical success (83.3% vs. 96.0%; p = 0.001) due to more frequent second valve implantation (11.1% vs. 2.8%; p = 0.008), and lower device success (76.4% vs. 89.2%; p = 0.009) due to more frequent reintervention (16.7% vs. 7.4%; p = 0.03). Mean mitral valve gradients were similar between groups (6.4 +/- 2.3 mm Hg vs. 5.8 +/- 2.7 mm Hg; p = 0.17), whereas the ViR group had more frequent post procedural mitral regurgitation moderate or higher (19.4% vs. 6.8%; p = 0.003). Furthermore, the ViR group had more frequent life-threatening bleeding (8.3% vs. 2.3%; p = 0.03), acute kidney injury (11.1% vs. 4.0%; p = 0.03), and subsequent lower procedural success (58.3% vs. 79.5%; p = 0.001). The 1-year all-cause mortality rate was significantly higher in the ViR group compared with the ViV group (28.7% vs. 12.6%; log-rank test, p = 0.01). On multivariable analysis, failed annuloplasty ring was independently associated with all-cause mortality (hazard ratio: 2.70; 95% confidence interval: 1.34 to 5.43; p = 0.005). CONCLUSIONS: The TMVR procedure provided acceptable outcomes in high-risk patients with degenerated bioprostheses or failed annuloplasty rings, but mitral ViR was associated with higher rates of procedural complications and mid-term mortality compared with mitral ViV. PMID- 28838363 TI - Appropriate and Appropriate Use: What Do These Words Really Mean? PMID- 28838362 TI - Improving the Appropriate Use of Transthoracic Echocardiography: The Echo WISELY Trial. AB - BACKGROUND: Appropriate use criteria (AUC) have defined transthoracic echocardiogram (TTE) indications for which there is a clear lack of benefit as rarely appropriate (rA). OBJECTIVES: This study sought to investigate the impact of an AUC-based educational intervention on outpatient TTE ordering by cardiologists and primary care providers. METHODS: The authors conducted a prospective, investigator-blinded, multicenter, randomized controlled trial of an AUC-based educational intervention aimed at reducing rA outpatient TTEs. The study was conducted at 8 hospitals across 2 countries. The authors randomized cardiologists and primary care providers to receive either intervention or control (no intervention). The primary outcome measure was the proportion of rA TTEs. RESULTS: One hundred and ninety-six physicians were randomized, and 179 were included in the analysis. From December 2014 to April 2016, the authors assessed 14,697 TTEs for appropriateness, of which 99% were classifiable using the 2011 AUC. The mean proportion of rA TTEs was significantly lower in the intervention versus the control group (8.8% vs. 10.1%; odds ratio [OR]: 0.75; 95% confidence interval [CI]: 0.57 to 0.99; p = 0.039). In physicians who ordered, on average, at least 1 TTE per month, there was a significantly lower proportion of rA TTEs in the intervention versus the control group (8.6% vs. 11.1%; OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.047). There was no difference in the TTE ordering volume between the intervention and control groups (mean 77.7 +/- 89.3 vs. 85.4 +/- 111.4; p = 0.83). CONCLUSIONS: An educational intervention reduced the number of rA TTEs ordered by attending physicians in a variety of ambulatory care environments. This may prove to be an effective strategy to improve the use of imaging. (A Multi-Centered Feedback and Education Intervention Designed to Reduce Inappropriate Transthoracic Echocardiograms [Echo WISELY]; NCT02038101). PMID- 28838365 TI - Insights Into Spontaneous Coronary Artery Dissection: Can Recurrence Be Prevented? PMID- 28838364 TI - Spontaneous Coronary Artery Dissection: Clinical Outcomes and Risk of Recurrence. AB - BACKGROUND: Spontaneous coronary artery dissection (SCAD) is underdiagnosed and an important cause of myocardial infarction (MI), especially in young women. Long term cardiovascular outcomes, including recurrent SCAD, are inadequately reported. OBJECTIVES: This study sought to describe the acute and long-term cardiovascular outcomes and assess the predictors of recurrent SCAD. METHODS: Nonatherosclerotic SCAD patients were prospectively followed at Vancouver General Hospital systematically to ascertain baseline, predisposing and precipitating stressors, angiographic features, revascularization, use of medication, and in hospital and long-term cardiovascular events. Clinical predictors for recurrent de novo SCAD were tested using univariate and multivariate Cox regression models. RESULTS: The authors prospectively followed 327 SCAD patients. Average age was 52.5 +/- 9.6 years, and 90.5% were women (56.9% postmenopausal). All presented with MI; 25.7% had ST-segment elevation MI, 74.3% had non-ST-segment elevation MI, and 8.9% had ventricular tachycardia/ventricular fibrillation. Precipitating emotional stressors were reported in 48.3% and physical stressors in 28.1%. Fibromuscular dysplasia was present in 62.7%, connective tissue disorder in 4.9%, and systemic inflammatory disease in 11.9%. The majority (83.1%) were initially treated medically, with only 16.5% or 2.2% undergoing in-hospital percutaneous coronary intervention or coronary artery bypass graft surgery, respectively. The majority of SCAD patients were taking aspirin and beta-blocker therapy at discharge and at follow-up. Median hospital stay was 3.0 days, and the overall major adverse event rate was 7.3%. Median long-term follow-up was 3.1 years, and overall major adverse cardiac event rate was 19.9% (death rate: 1.2%; recurrent MI: 16.8%; stroke/transient ischemic attack: 1.2%; revascularization: 5.8%). Recurrent SCAD occurred in 10.4% of patients. In multivariate modeling, only hypertension increased (hazard ratio: 2.46; p = 0.011) and beta-blocker use diminished (hazard ratio: 0.36; p = 0.004) recurrent SCAD. CONCLUSIONS: In our large prospectively followed SCAD cohort, long-term cardiovascular events were common. Hypertension increased the risk of recurrent SCAD, whereas beta-blocker therapy appeared to be protective. PMID- 28838367 TI - Managing Patients With Homozygous Familial Hypercholesterolemia. PMID- 28838366 TI - Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations. AB - BACKGROUND: Homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder, is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerotic cardiovascular disease. Statin treatment starts at diagnosis, but no statin has been formally evaluated in, or approved for, HoFH children. OBJECTIVES: The authors sought to assess the LDL-C efficacy of rosuvastatin versus placebo in HoFH children, and the relationship with underlying genetic mutations. METHODS: This was a randomized, double-blind, 12-week, crossover study of rosuvastatin 20 mg versus placebo, followed by 12 weeks of open-label rosuvastatin. Patients discontinued all lipid-lowering treatment except ezetimibe and/or apheresis. Clinical and laboratory assessments were performed every 6 weeks. The relationship between LDL C response and genetic mutations was assessed by adding children and adults from a prior HoFH rosuvastatin trial. RESULTS: Twenty patients were screened, 14 randomized, and 13 completed the study. The mean age was 10.9 years; 8 patients were on ezetimibe and 7 on apheresis. Mean LDL-C was 481 mg/dl (range: 229 to 742 mg/dl) on placebo and 396 mg/dl (range: 130 to 700 mg/dl) on rosuvastatin, producing a mean 85.4 mg/dl (22.3%) difference (p = 0.005). Efficacy was similar regardless of age or use of ezetimibe or apheresis, and was maintained for 12 weeks. Adverse events were few and not serious. Patients with 2 defective versus 2 negative LDL receptor mutations had mean LDL-C reductions of 23.5% (p = 0.0044) and 14% (p = 0.038), respectively. CONCLUSIONS: This first-ever pediatric HoFH statin trial demonstrated safe and effective LDL-C reduction with rosuvastatin 20 mg alone or added to ezetimibe and/or apheresis. The LDL-C response in children and adults was related to underlying genetic mutations. (A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia [HYDRA]; NCT02226198). PMID- 28838368 TI - Cerebral Amyloid Angiopathy: Diagnosis, Clinical Implications, and Management Strategies in Atrial Fibrillation. AB - With an aging population, clinicians are more frequently encountering patients with atrial fibrillation who are also at risk of intracerebral hemorrhage due to cerebral amyloid angiopathy, the result of beta-amyloid deposition in cerebral vessels. Cerebral amyloid angiopathy is common among elderly patients, and is associated with an increased risk of intracerebral bleeding, especially with the use of anticoagulation. Despite this association, this entity is absent in current risk-benefit analysis models, which may result in underestimation of the chance of bleeding in the subset of patients with this disease. Determining the presence and burden of cerebral amyloid angiopathy is particularly important when planning to start or restart anticoagulation after an intracerebral hemorrhage. Given the lack of randomized trial data to guide management strategies, we discuss a heart-brain team approach that includes clinician-patient shared decision making for the use of pharmacologic and nonpharmacologic approaches to diminish stroke risk. PMID- 28838370 TI - ACC Tackling Prior Authorization. PMID- 28838369 TI - Computer-Interpreted Electrocardiograms: Benefits and Limitations. AB - Computerized interpretation of the electrocardiogram (CIE) was introduced to improve the correct interpretation of the electrocardiogram (ECG), facilitating health care decision making and reducing costs. Worldwide, millions of ECGs are recorded annually, with the majority automatically analyzed, followed by an immediate interpretation. Limitations in the diagnostic accuracy of CIE were soon recognized and still persist, despite ongoing improvement in ECG algorithms. Unfortunately, inexperienced physicians ordering the ECG may fail to recognize interpretation mistakes and accept the automated diagnosis without criticism. Clinical mismanagement may result, with the risk of exposing patients to useless investigations or potentially dangerous treatment. Consequently, CIE over-reading and confirmation by an experienced ECG reader are essential and are repeatedly recommended in published reports. Implementation of new ECG knowledge is also important. The current status of automated ECG interpretation is reviewed, with suggestions for improvement. PMID- 28838372 TI - Issues With Estimating "Diastolic Function" and Left Ventricular Filling Pressure Using the New Guidelines. PMID- 28838371 TI - Target Vessel Revascularization and Territory of Myocardial Ischemia in Patients With Chronic Total Occlusions. PMID- 28838373 TI - Reply: Issues With Estimating "Diastolic Function" and Left Ventricular Filling Pressure Using the New Guidelines. PMID- 28838374 TI - Ezetimibe, Risk Stratification, and Secondary Prevention. PMID- 28838375 TI - Reply: Ezetimibe, Risk Stratification, and Secondary Prevention. PMID- 28838376 TI - Correction. PMID- 28838377 TI - A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia. AB - INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP. METHODS: Previously treated, inoperable NSCLC patients with mild IIP were enrolled. Mild IIP was defined as having a predicted vital capacity >=80% and a possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on chest high-resolution computed tomography. Patients received nivolumab at a dose of 3mg/kg biweekly. RESULTS: Six patients were enrolled in this trial between April 2016 and December 2016. None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 3 had experienced a partial response. CONCLUSIONS: Nivolumab therapy may be feasible in NSCLC patients with mild IIP. (Trial registration number: UMIN000022037). PMID- 28838378 TI - Tobacco use and motivation to stop smoking among long-term smokers who are ineligible for lung cancer screening. AB - BACKGROUND: The importance of smoking cessation interventions in lung cancer screening participants has been highlighted. This study aimed to describe the smoking habits of individuals who were ineligible for lung cancer screening and to investigate whether this encounter may represent an opportunity to reduce tobacco use. METHODS: Ever smokers between the ages of 55 and 80 and >=1.5% lung cancer risk over 6 years or having smoked >=30 pack-years and with no more than 15 years of smoking abstinence were eligible to participate in the Alberta Lung Cancer Screening Program (ALCSP). A baseline questionnaire exploring tobacco use was administered to all interested individuals as part of the eligibility determination for the program. RESULTS: Among 504 individuals, 254 (50.4%) met the criteria for the ALCSP and 250 (49.6%) were non-eligible for screening. Non eligible individuals were slightly younger (mean=60.2 vs. 63.1 years, p-value <0.001), and less likely to be current smokers (26.0% vs. 48.8%, p-value <0.001). Non-eligible smokers had a lower degree of addiction compared to eligible group, as measured by the Fagerstrom Test of Nicotine Dependence (Median=4.0 vs 6.0, p value=0.001), but still in the "moderately dependent" range for this test. There were no significant differences in motivation to quit (98.5% vs. 97.6%, p value=0.689), or motivation to receive help with their quit attempt (89.2% vs. 90.3%, p-value=0.813) between these two groups. Only 7.7% of non-eligible and 2.4% of eligible current smokers were currently in a smoking cessation program. CONCLUSION: A significant proportion of individuals applying to, but not qualifying for a lung cancer screening program are active smokers with significant nicotine dependence. Very few are currently participating in active smoking cessation programs but almost all are interested in quitting and in receiving help with quit attempts. Future studies need to investigate the most effective approaches for smoking cessation in this substantial group of older, long-term smokers, capitalizing on their motivation to receive cessation assistance. PMID- 28838379 TI - Phase II study of olaratumab with paclitaxel/carboplatin (P/C) or P/C alone in previously untreated advanced NSCLC. AB - BACKGROUND: In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRalpha monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC. MATERIALS AND METHODS: Patients received up to six 21-day cycles of P 200mg/m2 and C AUC 6 (day 1)+/-olaratumab 15mg/kg (days 1 and 8). Primary endpoint was PFS. Olaratumab was continued in the olaratumab+P/C arm until disease progression. RESULTS: 131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86-1.93]; p=0.21). Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68-1.57]; p=0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive. CONCLUSIONS: The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway. PMID- 28838380 TI - Frequent silencing of RASSF1A by DNA methylation in thymic neuroendocrine tumours. AB - OBJECTIVES: Aberrant methylation of promoter CpG islands (CGIs) of tumour suppressor genes is a common epigenetic mechanism underlying cancer pathogenesis. The methylation patterns of thymic tumours have not been studied in detail since such tumours are rare. Herein, we sought to identify genes that could serve as epigenetic targets for thymic neuroendocrine tumour (NET) therapy. MATERIALS AND METHODS: Genome-wide screening for aberrantly methylated CGIs was performed in three NET samples, seven thymic carcinoma (TC) samples, and eight type-B3 thymoma samples. The methylation status of thymic epithelial tumours (TETs) samples was validated by pyrosequencing in a larger cohort. The expression status was analysed by quantitative polymerase chain reaction (PCR) and immunohistochemistry. RESULTS: We identified a CGI on a novel gene, RASSF1A, which was strongly hypermethylated in NET, but not in thymic carcinoma or B3 thymoma. RASSF1A was identified as a candidate gene statistically and bibliographically, as it showed frequent CGI hypermethylation in NET by genome wide screening. Pyrosequencing confirmed significant hypermethylation of a RASSF1A CGI in NET. Low-grade NET tissue was more strongly methylated than high grade NET. Quantitative PCR and immunohistochemical staining revealed that RASSF1A mRNA and protein expression levels were negatively regulated by DNA methylation. CONCLUSIONS: RASSF1A is a tumour suppressor gene epigenetically dysregulated in NET. Aberrant methylation of RASSF1A has been reported in various tumours, but this is the first report of RASSF1A hypermethylation in TETs. RASSF1A may represent an epigenetic therapeutic target in thymic NET. PMID- 28838381 TI - Full circle: Extranodal marginal zone B-cell lymphoma of the trachea. PMID- 28838382 TI - Assessing the prognostic impact of the International Association for the Study of Lung Cancer proposed definitions of complete, uncertain, and incomplete resection in non-small cell lung cancer surgery. AB - OBJECTIVE: The aim of this study was to assess the prognostic impact of the definitions of complete, uncertain, and incomplete resection in non-small cell lung cancer (NSCLC) surgery, as proposed by the International Association for the Study of Lung Cancer (IASLC). PATIENTS AND METHODS: Single institution retrospective study of consecutive patients undergoing surgery for NSCLC between 1998 and 2007. Complete resection was defined by absence of gross and microscopic residual disease; systematic nodal dissection; no extracapsular extension in distal lymph nodes; and negativity of the highest mediastinal node removed. An uncertain resection was defined by free resection margins, but one of the following applied: lymph node evaluation less rigorous than systematic nodal dissection; positivity of the highest mediastinal node removed; presence of carcinoma in situ at the bronchial margin; positive pleural lavage cytology. A resection was defined incomplete by presence of residual disease; extracapsular extension in distal lymph nodes; positive cytology of pleural or pericardial effusions. Follow-up was complete and all patients were followed up until death or for a minimum period of 5 years. Overall survival (OS) was analyzed using Kaplan-Meier method, log rank test, and Cox proportional hazards model. RESULTS: A total of 1277 patients were identified. One thousand and three patients (78.5%) underwent complete resection, 185 (14.5%) underwent uncertain resection, and 89 (7.0%) underwent incomplete resection. Both uncertain and incomplete resection were associated with significantly worse OS when compared with complete resection (hazard ratio: 1.69 and 3.18, respectively; both p=0.0001). Median OS and 5-year survival rate were 80.1, 39.9, 17.3 months and 58.8%, 37.3%, 15.7% in patients undergoing complete, uncertain, and incomplete resection, respectively. CONCLUSION: The present analysis suggests that in patients undergoing surgery for NSCLC, the IASLC definitions of complete, uncertain, and incomplete resection are associated with statistically significant differences in survival. PMID- 28838383 TI - Uniform and blinded cause of death verification of the NELSON lung cancer screening participants. AB - Primary outcome of the Dutch-Belgian lung cancer screening trial (NELSON) is lung cancer-specific mortality. Accurate assessment of the cause of death (CoD) is crucial. As death certificates regarding the CoD can be inaccurate, a clinical expert committee (CEC) was formed to assign the CoD. In this study, the medical files of deceased lung cancer patients were reviewed and the outcomes were compared with official death certificates. The first 266 completed medical files of Dutch deceased participants who were diagnosed with lung cancer during the study or of those with lung cancer on the death certificate were selected and blinded towards arms and patients identity. The end product of the review process consisted of six possible categories which defined the graduation of certainty that lung cancer was the primary CoD. The percentage agreement and the Cohen's kappa statistics between the two CEC-memberswere calculated. The sensitivity and specificity of the official death certificates were determined. The results indicated that, the overall concordance and the Cohen's kappa between the CEC memberswere 86.1% and 0.57(0.45-0.69, p<0.001), respectively. This level increased with the numbers of cases evaluated. The sensitivity and the specificity of the official death certificate were 92.6% and 98.8%; 6.5% cases were reclassified to lung cancer specific death, which is lower than in the National Lung Screening trial(22.0%). Concluding, each death should be reviewed by at least two members. So far, in the NELSON trial, possible biases related to lung cancer death seem relatively small. PMID- 28838384 TI - Cell-free circulating tumor DNA supplementing tissue biopsies for identification of targetable mutations: Implications for precision medicine and considerations for reconciling results. AB - Cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is emerging as a noninvasive technique for detecting targetable mutations. We describe two lung adenocarcinoma cases that show the clinical utility of supplementing tumor biopsy molecular interrogation with ctDNA NGS. For both cases, ctDNA NGS identified actionable mutations that were previously not reported by molecular interrogation of tissue. Explanations are provided for the observed differences between ctDNA and tumor biopsy genomic results along with considerations for reconciling findings. Case 1 consisted of a patient with multiple lesions in the left and right lung that was initially suspected to be related to malignancy. A tumor biopsy was positive for EGFR-mutated lung cancer. ctDNA NGS reported an activating KRAS mutation, which was unexpected given the rare occurrence of EGFR/KRAS co-mutations. Radiologic imaging and ctDNA NGS resulted in the diagnoses of synchronous EGFR-mutated left lung cancer and KRAS mutated right lung cancer. The second case describes a patient who was negative for RET rearrangements by tissue interrogation, but positive for a RET-KIF5B fusion by ctDNA NGS. Further tissue analysis demonstrated heterogeneity was the cause of differing results. We demonstrate that supplementing tumor biopsies with ctDNA NGS has a crucial role in patient care. Understanding the causes of differing ctDNA and tumor biopsy genomic results is essential for reconciling findings and application to precision medicine management. PMID- 28838385 TI - Chest ultrasonography in health surveillance of asbestos related pleural disease. AB - High resolution computed tomography, (HRCT), is currently considered the diagnostic gold standard to diagnose early stage malignant pleural mesothelioma and other non-malignant pleural conditions, but it is expensive and exposes the patient to radiation dose. In a screening and population medicine perspective, Thoracic Ultrasounds may become a valuable alternative because it can detect minimal changes in pleural surface, is widely available and safe. On these bases, we therefore validated thoracic US in subjects with history of exposure to asbestos, having HRCT as the reference standard. One hundred-fifty subjects were screened and 117 were recruited. Pleural abnormalities at US and/or HRCT were detected in 66 out of 117 subjects (prevalence=57%), and their prevalence was unrelated to both mansion and smoking habit, while mean age and mean length of exposure were higher in those having pleural abnormalities (age=47+/-5 vs 44+/ 6years, p<0.05;years of exposure=20+/-7 vs 17+/-5, p<0.05). Thirteen out of 19 subjects with pleural abnormalities at HRCT were also identified by thoracic US, whereas 47 participants had lesions seen at US, but not at the HRCT scan. Positive and negative percent agreement were 66.6% and 51.8%, respectively; the McNemar's test for equality showed a p-value <0.001. In conclusion, chest US might complement HRCT in the health surveillance of asbestos exposed population to detect earlier lesions or to follow up US approachable lesions. Further research is needed to clarify whether this approach may enhance early recognition of pleural mesothelioma and ameliorate prognosis. PMID- 28838386 TI - Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project. AB - INTRODUCTION: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome. METHODS: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio>=2 (with average MET GCN>=4), high MET GCN as CGN>=5 and MET IHC+ as >=2+ intensity in >=50% of tumor cells. A total of 182 MET IHC+ and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation. RESULTS: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN>=5 in 4.1% of 1572 patients. MET amplification and MET GCN>=5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p<0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC+ WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR. CONCLUSION: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice. PMID- 28838387 TI - TR3 is involved in hypoxia-induced apoptosis resistance in lung cancer cells downstream of HIF-1alpha. AB - OBJECTIVES: Lung cancer is the leading cause of cancer death worldwide. Like in all solid tumors, hypoxia is common in lung cancer and contributes to apoptosis, and thus chemotherapy resistance. However, the underlying mechanisms are not entirely clear. TR3 (NR4A1, Nur77) is an orphan nuclear receptor that induces apoptosis and may mediate chemotherapy-induced apoptosis in cancer cells. MATERIALS AND METHODS: We used A549, H23 and H1299 cell lines to investigate how TR3-mediated apoptosis is affected by hypoxia in non-small cell lung cancer (NSCLC) cells. Cell culture, western blot analysis, apoptosis assay, and siRNA mediated gene silencing were performed in this study. RESULTS AND CONCLUSION: The TR3 activator cytosporone B was used to investigate TR3-mediated apoptosis in NSCLC cells under normoxic and hypoxic conditions. Cytosporone B induced apoptosis in a concentration-dependent manner. Chronic moderate hypoxia induced a significant down-regulation of TR3. Accordingly, the cytosporone B effect was reduced under these conditions. Hypoxia-induced down-regulation of TR3 was mediated by hypoxia-inducible factor 1alpha. Our immunoblotting analysis and expression data from a public dataset suggest that TR3 is downregulated in NSCLC. In conclusion, our findings suggest that hypoxia-induced down-regulation of TR3 might play an important role for hypoxia-induced apoptosis resistance in NSCLC. PMID- 28838388 TI - Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature Part 4: Neurological paraneoplastic syndromes, involving the peripheral nervous system and the neuromuscular junction and muscles. AB - The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the fourth of a series of five and deals mainly with neurological paraneoplastic syndromes involving the peripheral nervous system and the neuromuscular junction and muscles. PMID- 28838389 TI - Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 5: Neurological auto-antibodies, discussion, flow chart, conclusions. AB - The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the last of a series of five and deals mainly with onconeural antibodies involved in neurological paraneoplastic syndromes and provides the final discussion. PMID- 28838390 TI - Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. AB - OBJECTIVES: Immunotherapy with the programmed death receptor-1 (PD-1) antibody nivolumab has changed the field of metastatic non-small cell lung cancer (NSCLC) treatment. Nivolumab shows better outcome compared to standard second line chemotherapy, but reliable prognostic markers are lacking. High neutrophil-to lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation and associated with worse overall survival (OS) in several tumor types, but have not been analysed extensively in lung cancer in the era of immunotherapy. METHODS: Patients with metastatic NSCLC treated with nivolumab were enrolled. Pre-treatment NLR and PLR were calculated by division of neutrophils and platelets by lymphocytes measured in peripheral blood. Cox regression analyses were conducted to study the prognostic role of NLR and PLR on OS and progression free survival (PFS). Logistic regression was used to study the association of NLR and PLR. The combined impact of NLR and other known prognostic factors was explored with multivariable regression. RESULTS: Fifty-two patients were included. Elevated NLR was associated with worse OS (HR for log(NLR)=3.64, 95% CI 1.78-7.46, p<0.001) and lower response rates (OR for log(NLR)=0.17, 95% CI 0.04-0.68, p=0.013). There was no significant association with PFS (HR for log(NLR)=1.46, 95% CI=0.91-2.34, p=0.114). The AUC for the prediction of 10-month survival using log(NLR) was 0.738, the AUC for the prediction of response to nivolumab was 0.776. Relationships with PLR were similar. NLR and PLR didn't correlate with other known prognostic factors (i.e histology, tobacco use, ECOG performance status,) in our cohort. Inclusion of NLR in multivariable models with these other factors significantly improved the prediction of OS. CONCLUSION: Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors. PMID- 28838391 TI - Programmed death-ligand 1 expression and T790M status in EGFR-mutant non-small cell lung cancer. AB - BACKGROUND: Differential biology and prognosis between T790M+ and T790M- populations imply immunological differences also. METHODS: We retrospectively analyzed programmed death-ligand 1 (PD-L1) expression and T790M status in rebiopsied samples of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). PD-L1 immunohistochemistry was performed using the SP142 antibody for tumour cell (TC) and tumour-infiltrating immune cell (IC) and the 28-8 antibody for TC. PD-L1+ was defined as TC or IC >=1%. RESULTS: We investigated 67 available rebiopsied histologic samples in 47 patients. Using the SP142, prevalence of PD-L1 any+, moderate+, and strong+ in T790M+ vs. T790M- samples were 31% vs. 61%, 8% vs. 15%, and 0% vs. 2%, respectively, representing PD-L1+ prevalence of T790M+ samples was significantly lower than that of T790M- (p=0.0149). Prevalence of any TC+/IC+ in T790M+ vs. T790M- samples were TC: 31% vs. 51% (p=0.0997) and IC: 8% vs. 27% (p=0.0536), respectively. Using the 28-8, median percentage of PD-L1+ in T790M+ samples was 1.9 (range, 0-27.2), whereas T790M- was 4.1 (range, 0-89.8) (p=0.0801). Prevalence of PD-L1+ >=1%, >=5%, and >=10% in T790M+ vs. T790M- samples were 77% vs. 83% (p=0.5476), 31% vs. 49% (p=0.1419), and 12% vs. 27% (p=0.1213), respectively. In 9 of 11 patients receiving multiple rebiopsies, T790M and/or PD-L1 expression revealed temporal dynamism. Survival curves according to PD-L1 expression/T790M status suggested better prognosis in PD-L1-/T790M+ population. CONCLUSIONS: T790M+ status was correlated to lower PD-L1 expression. PD-L1 expression might have a prognostic value and interaction with T790M mutation in EGFR-mutant NSCLC. PMID- 28838393 TI - Prognostic and predictive effects of TP53 co-mutation in patients with EGFR mutated non-small cell lung cancer (NSCLC). AB - INTRODUCTION: TP53 mutations are common in non-small cell lung cancer (NSCLC) and have been reported as prognostic of poor outcome. The impact of TP53 co-mutations in epidermal growth factor receptor (EGFR)-mutated NSCLC is unclear. MATERIALS AND METHODS: Tissue from 105 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre was analyzed by next-generation or Sanger sequencing to determine TP53 mutational status. Associations between TP53 status and baseline patient and tumor characteristics, treatments and outcomes (relapse-free survival [RFS] after surgical resection, overall survival [OS], overall response rate [ORR] and progression-free survival [PFS] on EGFR tyrosine kinase inhibitors [TKIs]), were investigated. RESULTS: Dual TP53/EGFR mutations were found in 43/105 patients (41%). Among 76 patients who underwent surgical resection, neither RFS (HR 0.99, CI 0.56-1.75, p=0.96) nor OS (HR 1.39, CI 0.70-2.77; p=0.35) was associated with TP53 status. Sixty patients (24 TP53 MUT; 36 TP53 WT) received first-generation EGFR TKIs for advanced disease. ORR was not significantly different (TP53 MUT 54%, WT 66%, p=0.42). There was a non significant trend towards shorter PFS on EGFR TKIs with TP53 mutation (HR 1.74, CI 0.98-3.10, p=0.06). When limited to TP53 missense mutations (n=17), PFS was significantly shorter (HR 1.91, CI 1.01-3.60, p=0.04). Among 11 evaluable patients treated with T790M inhibitors, ORR was not significantly different (TP53 MUT 3/3 [100%], WT 7/8 [88%]). CONCLUSIONS: Patients with dual TP53/EGFR mutations, especially missense mutations, had marginally lower response rates and shorter PFS when treated with EGFR TKI therapy. Larger datasets are required to validate these observations. PMID- 28838392 TI - Detection of epidermal growth factor receptor gene T790M mutation in cytology samples using the cobas(r) EGFR mutation test. AB - OBJECTIVE: Detection of epidermal growth factor receptor (EGFR) gene mutations is essential in deciding therapeutic strategy in non-small cell lung cancer (NSCLC) patients at initial diagnosis. Moreover, in EGFR mutation-positive (EGFRm) NSCLC patients, re-biopsy at disease progression to clarify resistance mechanisms is also important. However, collecting histology samples is often difficult because of inaccessibility and invasiveness. In some cases, only cytology samples can be collected, and studies have reported that cytology samples are appropriate for EGFR gene mutation testing. The cobas(r) EGFR Mutation Test (Roche Molecular Systems Inc., Branchburg, New Jersey, USA) is approved as a companion diagnostic for osimertinib, a third-generation EGFR-tyrosine kinase inhibitor approved in Japan. However, it is not clear whether the EGFR T790M mutation can be detected in cytology samples using this test. The primary objective of this study was to assess concordance of EGFR T790M gene mutation detection between histology and matched cytology samples using the cobas(r) EGFR Mutation Test. MATERIALS AND METHODS: We conducted a multicenter, observational study in Japan. Overall, 41 EGFRm NSCLC patients who had both histology and cytology samples collected at the same time at re-biopsy and with the results of EGFR mutation test using histology samples were enrolled. The EGFR mutation status of both sample types was tested using the cobas(r) EGFR Mutation Test and the concordance rates were calculated. RESULTS: The EGFR T790M mutation detection rate in histology and cytology samples was 42.5% and 37.5%, respectively. The overall percent agreement between the histology and cytology samples was 91.7%. CONCLUSIONS: These data demonstrate that the cobas(r) EGFR Mutation Test can detect the EGFR T790M mutation in both cytology and histology samples. PMID- 28838394 TI - Molecular profiling in Italian patients with advanced non-small-cell lung cancer: An observational prospective study. AB - OBJECTIVES: Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs. MATERIALS AND METHODS: This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients' outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2). RESULTS AND CONCLUSION: Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR, 53% for ALK, 27% for KRAS, 16% for ROS1, 14% for BRAF, 5% for HER2, 4% for MET and 1% for FGFR. The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62-10.0), median PFS1 was 4.61 months (95%CI 4.31-4.84) and median PFS2 was 2.76 months (95%CI 2.57-3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line. PMID- 28838395 TI - Randomized phase II study of carboplatin plus irinotecan versus carboplatin plus amrubicin in patients with chemo-naive extensive-stage small-cell lung cancer: North Japan Lung Cancer Study Group (NJLCG) 0901. AB - OBJECTIVE: Carboplatin-based regimens are the standard regimens for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, the efficacies of these regimens are unsatisfactory. We previously identified carboplatin plus irinotecan (CI) and carboplatin plus amrubicin (CA) as promising new carboplatin based regimens. Accordingly, we conducted a randomized phase II study to identify the appropriate regimen for future phase III trials. MATERIALS AND METHODS: Chemotherapy-naive patients with ES-SCLC were randomly assigned to receive 4-6 cycles of carboplatin [area under the curve (AUC) 5.0, day 1] plus irinotecan (70mg/m2, days 1 and 8) every 3 weeks (CI arm) or carboplatin (AUC 4.0, day 1) plus amrubicin (35mg/m2, days 1-3) every 3 weeks (CA arm). The primary endpoint was the overall response rate (ORR). The secondary endpoints were the progression free survival (PFS), overall survival (OS) and toxicity. RESULTS: Between December 2009 and March 2013, 71 patients were enrolled. One patient in each arm did not receive any protocol treatment due to rapid disease progression. The characteristics of the treated patients were as follows: median age, 70 years (range 51-84 years); proportion of males, 84%. The ORRs were 79% and 89% in the CI and CA arms, respectively. The median PFS values were 5.1 and 6.2 months in the CI and CA arms, respectively [CA; hazard ratio (HR)=0.59, 95% confidence interval (CI): 0.35-0.98, P=0.042]. The grade 3 or higher toxicity severities were neutropenia (CI, 53% and CA, 89%), anemia (CI, 26% and CA, 20%), thrombocytopenia (CI, 18% and CA, 14%), and febrile neutropenia (CI, 12% and CA, 29%). No treatment-related deaths were observed. CONCLUSION: CA was numerically more effective than CI, with acceptable toxicity, in chemo-naive ES-SCLC patients. CA could be selected for future phase III trials. PMID- 28838396 TI - Assessment of interfering factors and clinical risk associated with discontinuation of pemetrexed maintenance therapy in advanced non-squamous non small cell lung cancer. AB - OBJECTIVES: Pemetrexed continuation maintenance therapy after induction with platinum-based chemotherapy is a standard treatment option for non-squamous non small cell lung cancer (NSCLC) patients. However, discontinuation of maintenance therapy is still a challenge in clinical practice. We aimed to investigate interfering factors and clinical risk associated with discontinuation of pemetrexed maintenance therapy (PMT). MATERIALS AND METHODS: Data of patients with locally advanced or metastatic non-squamous NSCLC who received PMT between December 2011 and October 2015 were retrospectively analyzed. Patients' characteristics, performance status (PS), response and toxicity evaluation were collected. The reasons for PMT discontinuation were summarized. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and Cox proportional hazard model. RESULTS: Of the 220 patients included for final analysis, 132 patients (60.0%) continued PMT until disease progression. The patients over 60 years old (p=0.021), the patients with PS 2 at the initiation of PMT (p=0.005) and the patients experienced grade 3/4 toxicity during PMT (p<0.001) had a higher discontinuation rate. The reasons for PMT discontinuation were the regarding toxicity (39.8%), high intensity of hospital visit (17.0%), treatment cost (13.6%), patients' preference (26.1%) and failure of pain control (3.4%). In univariate analysis, PS 0-1 at the initiation of PMT (5.6 versus 4.3 months, p=0.022) and PMT continuation (5.6 versus 4.3 months, p<0.001) were associated with improved PFS. And PMT continuation was associated with improved OS (19.2 versus 16.8 months, p=0.003) along with actionable mutations and PS 0-1 at the initiation of PMT. In multivariate analysis, PMT continuation (hazard ratio: 1.486; 95% CI: 1.050-2.104; p=0.025) was an independent prognostic factor regarding OS benefit assessed by Cox proportional hazard model. CONCLUSION: Discontinuation of PMT is common in clinical practice. The survival benefit suggests that fit patients should be encouraged to continue PMT until disease progression. PMID- 28838397 TI - Management of ceritinib therapy and adverse events in patients with ALK rearranged non-small cell lung cancer. AB - Anaplastic lymphoma kinase rearrangement (ALK+) occurs in approximately 2-7% of patients with non-small cell lung cancer (NSCLC), contributing to a considerable number of patients with ALK+ NSCLC worldwide. Ceritinib is a next generation ALK inhibitor (ALKi), approved by the European Medicines Agency in 2015. In the first in-human, phase I study, ceritinib demonstrated rapid and durable responses in ALK patients previously treated with a different ALKi and in those who were ALKi naive. As ceritinib is starting to be used routinely for the treatment of patients with ALK+ NSCLC, experience is growing with regard to ideal therapy management. In this review we provide a brief background to the development of ceritinib. The optimal treatment management and adverse events associated with ceritinib in clinical trials and in clinical practice are then discussed in detail, and where applicable, an expert consensus on specific recommendations are made. In clinical trials, the most common adverse events related to ceritinib are nausea, vomiting, and diarrhea. However, the majority of these are mild and, in the opinion of the authors, can be effectively managed with dose modifications. Based on clinical data, ceritinib has demonstrated efficacy as a first-line therapy and in patients who have relapsed on crizotinib, including those with brain metastases at baseline. Unfortunately, at some point, all patients experience progressive disease, with the central nervous system being a common site of metastases. Recommendations are made for continuing treatment beyond disease progression as long as a clinical benefit to patients is observed. Here, we review management of ceritinib treatment and adverse events and make recommendations on optimal management of patients. PMID- 28838398 TI - Peritoneal recurrence of thymoma treated by surgery and hyperthermic intraperitoneal chemotherapy. AB - Thymomas are rare (1,5 cases/million) and typically occur in adults with a median age of 50 years old. Thymomas are indolent with a 10-year overall survival for resected stage II thymomas of 70%. Late relapses occur in 20% of the cases, and distant metastasis from thymoma is rare. Peritoneal recurrence of thymoma treated with surgery associated with hyperthermic intraperitoneal chemotherapy (HIPEC) has not been described in the literature. This report manages peritoneal recurrence of thymoma with HIPEC, suggesting that aggressive therapies may decrease the risk of recurrence. PMID- 28838399 TI - Phase I clinical trials in patients with advanced non-small cell lung cancer treated within a Drug Development Unit: What have we learnt? AB - OBJECTIVES: Despite advances in novel drug development for patients with advanced non-small cell lung cancer (NSCLC), there are still only a limited number of approved treatments. We therefore evaluated the clinical outcomes of patients with advanced NSCLC referred to a dedicated phase I clinical trials unit assessed baseline clinical factors associated with successful enrollment onto phase I trials. MATERIAL AND METHODS: We conducted a retrospective study involving patients with advanced NSCLC referred to the Drug Development Unit at the RMH between January 2005 and December 2013. RESULTS: 257 patients with advanced NSCLC were referred for consideration of phase I trials, of which only 89 (35%) patients successfully commenced phase I trials. The commonest reasons for not entering study included poor ECOG performance status and rapid disease progression. A multivariate analysis identified that ECOG performance status (0 1) and RMH prognostic score (0-1) were associated with successful enrollment onto phase I trials (p<0.001). Single agent therapies included novel agents against the phosphatidylinositol-3 kinase pathway, insulin growth factor-1 receptor and pan-HER family tyrosine kinases. These trial therapies were well tolerated and mainly associated with grade 1-2 adverse events, with a minority experiencing grade 3 toxicities. Nine (10%) patients, 4 with known EGFR or KRAS mutations, achieved RECIST partial responses. Median time to progression was 2.6 months and median overall survival was 8.1 months for patients enrolled. CONCLUSIONS: Phase I trial therapies were generally well tolerated with potential antitumor benefit for patients with advanced NSCLC. Early referral to drug development units at time of disease progression should be considered to enhance the odds of patient participation in these studies. PMID- 28838400 TI - Emergence of FGFR3-TACC3 fusions as a potential by-pass resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR mutated NSCLC patients. AB - Resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancers (NSCLCs) with activating EGFR mutations generally involve development of acquired secondary or tertiary EGFR mutations, such as T790M or C797S. However, case reports have demonstrated that actionable receptor tyrosine kinase fusions such as EML4-ALK, CCDC6-RET, and FGFR3-TACC3 can potentially confer resistance to EGFR TKIs. We seeked to identify the prevalence of FGFR3-TACC3 fusion transcripts as resistance mechanism to EGFR TKIs. Hybrid-capture based genomic profiling was performed on FFPE tissue samples and circulating tumor DNA isolated from peripheral whole blood in the course of clinical care. We performed a comprehensive survey of 17,319 clinical NSCLC samples (14,170 adenocarcinomas and 3149 NSCLC not otherwise specified (NOS)) and identified 5 cases of FGFR3-TACC3 containing the intact kinase domain of FGFR3 and the coiled-coil domain of TACC3 emerging after treatment with EGFR TKIs, including one previously reported index case. Of the 4 novel cases of FGFR3-TACC3, one emerged after erlotinib, one after afatinib, one after osimertinib, and one after ASP8273. These 5 cases of FGFR3 TACC3 fusions acquired post-EGFR TKI, while rare, indicate that FGFR3-TACC3 is a recurrent resistance mechanism, which can bypass EGFR blockade by all generations of EGFR TKIs in NSCLC. Routine re-biopsy and genomic profiling using platforms capable of detecting kinase fusions has the potential to inform new therapeutic strategies for patients with EGFR-mutant NSCLC progressing on TKIs. PMID- 28838401 TI - Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer. AB - Small cell transformation is a rare but well recognised mechanism of acquired resistance to EGFR-TKI therapy in EGFR-mutated NSCLC, but optimal drug therapy thereof is unknown. Nivolumab has demonstrated activity in relapsed de novo small cell lung cancer in early phase trials. Here, we report a case of transformed EGFR-mutant SCLC treated with nivolumab with no benefit. PMID- 28838402 TI - Ipsilateral pleural recurrence after diagnostic transthoracic needle biopsy in pathological stage I lung cancer patients who underwent curative resection. AB - OBJECTIVES: The relationship between transthoracic needle biopsy (TTNB) and pleural recurrence of cancer after curative lung resection remains unclear. We aimed to assess whether TTNB increases the ipsilateral pleural recurrence (IPR) rate and identify other potential risk factors for pleural recurrence after surgery. MATERIALS AND METHODS: This retrospective study included 392 patients with p-stage I non-small cell lung cancer with solid or part-solid nodules after curative lung resection in 2009-2010. Imbalances among the characteristics were adjusted using an inverse probability-weighted method based on propensity scoring. Multivariate Cox's regression analysis and the Kaplan-Meier method were used to determine independent risk factors for IPR. RESULTS: A total of 243 (62%) patients received TTNB, while 149 (38%) underwent an alternate, or no, diagnostic technique. IPR was significantly more frequent in the TTNB group (p=0.004), while total recurrence was similar between the groups (p=0.098). After applying the weighted model, diagnostic TTNB (hazard ratio [HR], 5.27; 95% confidence interval [CI], 1.49-18.69; p=0.010), microscopic visceral pleural invasion (HR, 2.76; 95% CI, 1.08-7.01; p=0.033) and microscopic lymphatic invasion (HR, 3.25; 95% CI, 1.30-8.10; p=0.012) were associated with an increased frequency of IPR. Among patients who received TTNB, microscopic lymphatic invasion was a risk factor for IPR (HR, 2.74; 95% CI, 1.10-6.79; p=0.030). CONCLUSIONS: The diagnostic TTNB procedure is associated with pleural recurrence but may be unrelated to overall recurrence-free survival in early lung cancer. Moreover, microscopic lymphatic invasion could be a risk factor for pleural recurrence. TTNB should be carefully considered before lung resection and close follow-up to detect if pleural recurrence is needed. PMID- 28838403 TI - Pathological complete response in malignant pleural mesothelioma patients following induction chemotherapy: Predictive factors and outcomes. AB - A small proportion of patients with malignant pleural mesothelioma (MPM) achieve pathological complete response (CR) following treatment with current practice induction chemotherapy. Our analysis of 58 patients with MPM treated with platinum-based chemotherapy showed 4 patients (7%) attained pathological CR at subsequent extrapleural pneumonectomy (EPP). Patient and tumour factors such as age, gender, smoking habit, histological subtype, and clinical stage were not found to be associated with pathological CR. Patients with pathological CR had longer disease-free survival (29.2 vs. 13.8 months; p=0.08) and overall survival (76.4 vs. 23.4 months; p=0.06) but this did not reach statistical significance. Our study suggests that patients who achieve pathological CR after chemotherapy may have improved survival in MPM. PMID- 28838404 TI - Validation of ALK/ROS1 Dual Break Apart FISH Probe probe in non-small-cell lung cancer. AB - BACKGROUND: ALK and ROS1 gene rearrangements are distinct molecular subsets of non-small-cell lung cancer (NSCLC), and they are strong predictive biomarkers of response to ALK/ROS1 inhibitors, such as crizotinib. Thus, it is clinically important to develop an effective screening strategy to detect patients who will benefit from such treatment. In this study, we aimed to validate analytical performance of Vysis ALK/ROS1 Dual Break Apart Probe Kit (RUO) in NSCLC. METHODS: Study population composed of three patient cohorts with histologically confirmed lung adenocarcinoma (patients with ALK rearrangement, patients with ROS1 rearrangement and patients with wild-type ALK and ROS1). Specimens consisted of 12 ALK-positive, 8 ROS1-positive and 21 ALK/ROS1-wild type formalin-fixed paraffin-embedded samples obtained from surgical resection or excisional biopsy. ALK rearrangement was previously assessed by Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Abbot Park, IL, USA) and ROS1 rearrangement was previously assessed by ZytoLight(r) SPEC ROS1 Break Apart Probe (ZytoVision, GmbH). All specimens were re-evaluated by Vysis ALK/ROS1 Dual Break Apart Probe Kit. FISH images were scanned on BioView AllegroPlus system and interpreted via BioView SoloWeb remotely. RESULTS: For a total of 41 patient samples, the concordance of the results by Vysis ALK/ROS1 Dual Break Apart Probe Kit was evaluated and compared to the known ALK and ROS1 rearrangement status of the specimen. Of the 12 ALK-positive cases, hybridization with Vysis ALK/ROS1 Dual Break Apart Probe Kit was successful in 10 cases (success rate 10/12, 83%) and of these 10 cases, all showed ALK rearrangement (100% concordance with the results of Vysis ALK Break Apart FISH Probe Kit). Two of the ALK+ cases were excluded due to weak ROS1 signals that could not be enumerated. Of the 8 ROS1-positive cases, 6 cases were successfully evaluated using Vysis ALK/ROS1 Dual Break Apart Probe Kit. The success rate was 75% (6/8), and of these 6 cases, all showed ROS1 rearrangement, giving a 100% concordance with ZytoLight(r) SPEC ROS1 Break Apart Probe. Two of the cases were excluded due to weak ROS1 gold signal or high background. In the cohort of 21 wild-type cases, the success rate using Vysis ALK/ROS1 Dual Break Apart FISH Probe Kit was 85% (18/21) and the concordance with ALK and ROS1 probe kit was 100% (18/18). CONCLUSION: Vysis ALK/ROS1 Dual Break Apart Probe Kit (RUO) can detect ALK and ROS1 rearrangement simultaneously in NSCLC. PMID- 28838405 TI - Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib. AB - Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR driven lung adenocarcinoma in patients who had progressed on osimertinib treatment. This study demonstrates the importance of both tissue and blood based hybrid-capture based genomic profiling at disease progression to identifying novel resistance mechanisms in the clinic. PMID- 28838406 TI - Clinical significance of preoperative serum albumin level for prognosis in surgically resected patients with non-small cell lung cancer: Comparative study of normal lung, emphysema, and pulmonary fibrosis. AB - OBJECTIVES: This study was performed to clarify whether preoperative serum albumin level is related to the prognosis of non-small cell lung cancer patients undergoing surgical resection, and the relationships between serum albumin level and clinicopathological characteristics of lung cancer patients with emphysema or pulmonary fibrosis. MATERIALS AND METHODS: We retrospectively evaluated 556 patients that underwent surgical resection for non-small cell lung cancer. The correlation between preoperative serum albumin level and survival was evaluated. Patients were divided into three groups according to the findings on chest high resolution computed tomography (normal lung, emphysema, and pulmonary fibrosis), and the relationships between serum albumin level and clinicopathological characteristics, including prognosis, were evaluated. RESULTS: The cut-off value of serum albumin level was set at 4.2g/dL. Patients with low albumin levels (albumin <4.2) had significantly poorer prognosis than those with high albumin levels (albumin >=4.2) with regard to both overall survival and recurrence-free survival. Serum albumin levels in the emphysema group (n=48) and pulmonary fibrosis group (n=45) were significantly lower than that in the normal lung group (n=463) (p=0.009 and <0.001, respectively). Low serum albumin level was a risk factor in normal lung and pulmonary fibrosis groups, but not in the emphysema group. CONCLUSION: Preoperative serum albumin level was an important prognostic factor for overall survival and recurrence-free survival in patients with resected non-small cell lung cancer. Divided into normal lung, emphysema, and pulmonary fibrosis groups, serum albumin level showed no influence only in patients in the emphysema group. PMID- 28838407 TI - Lung cancer in renal transplant recipients: A case-control study. AB - INTRODUCTION: Solid organ transplant patients are at heightened risk of several cancers compared to the general population. Secondary to a higher number of procedures and better survival after transplantation, cancer is a rising health concern in this situation. Limited data exist for lung cancer (LC) after renal transplantation. We report here the most important series of renal transplant recipients with lung cancer. METHODS: Retrospective study of all cases of LC diagnosed in three French Renal Transplant Units from 2003 to 2012. A control group consisted of non-transplant patients with LC matched with the cases for age (<30; 30-50; 50-65; >65 years), gender and diagnosis date. We recruited two controls for each case. RESULTS: Thirty patients (median age 60 years; range 29 85; male/female ratio 80/20%) with LC were analysed. LC incidence was 1.89/1000 person-years over the period 2008-2012. All patients were former or active smokers (median 30 pack-years). Transplanted patients had significantly more comorbidities, mainly cardiovascular disease. The median interval of time from kidney transplantation (KT) to diagnosis of LC was 7 years (range 0.5-47 years). LC was incidentally diagnosed in 40%. Most patients (70%) had advanced LC (stage III or IV) disease. Stage of LC at diagnosis was similar in cases and controls. Surgery and chemotherapy were proposed to the same proportion of patients. In cases, mortality was cancer related in 87% and median survival time after diagnosis was 24 months. Survival was not significantly different between the 2 groups. CONCLUSION: Despite frequent medical and radiological examinations, diagnosis of LC is usually made at an advanced stage and the overall prognosis remains poor. PMID- 28838408 TI - Crohn's Disease: Genetics Update. AB - Since the discovery of the first Crohn's disease (CD) gene NOD2 in 2001, 140 genetic loci have been found in whites using high-throughput genome-wide association studies. Several genes influence the CD subphenotypes and treatment response. With the observations of increasing prevalence in Asia and developing countries and the incomplete explanation of CD variance, other underexplored areas need to be integrated through novel methodologies. Algorithms that incorporate specific genetic risk alleles with other biomarkers will be developed and used to predict CD disease course, complications, and response to specific therapies, allowing precision medicine to become real in CD. PMID- 28838410 TI - The Microbiome in Crohn's Disease: Role in Pathogenesis and Role of Microbiome Replacement Therapies. AB - Individuals with a genetic predisposition to Crohn's disease develop aberrant immune responses to environmental triggers. The gastrointestinal microbiota is increasingly recognized to play an important role in the development of Crohn's disease. Decrease in global gut microbial diversity and specific bacterial alterations have been implicated in Crohn's disease. Advances in sequencing techniques and bioinformatics and correlation with host genetics continue to improve insight into the structure and function of the microbial community and interactions with the host immune system. This article summarizes the existing literature on the role of the gut microbiome and its manipulation in the development and management of Crohn's disease. PMID- 28838409 TI - Epidemiology, Natural History, and Risk Stratification of Crohn's Disease. AB - Crohn's disease (CD) is a chronic condition that can result in significant morbidity and disability. By studying the association between demographics and initial clinical features and subsequent natural history, one may be able to stratify patients by their risks of clinical relapse, hospitalization, and surgery. Understanding the potential environmental risk factors and natural history of CD in a given patient guides the physician when counseling the patient and selecting a treatment strategy. In this review, updated data regarding the incidence and prevalence of CD, important environmental risk factors, natural history of the disease, and important prognostic factors are discussed. PMID- 28838411 TI - Endoscopic and Radiographic Assessment of Crohn's Disease. AB - Crohn's disease is a chronic inflammatory disorder that can progress to obstructive and penetrating complications. Although clinical symptoms are an important component of therapy, they correlate poorly with objective measures of inflammation. The treatment targets have evolved from clinical improvement only to the addition of more objective measures, such as endoscopic mucosal healing and radiologic response, which have been associated with favorable long-term outcomes, including reduced hospitalizations, surgeries, and need for corticosteroids. There are multiple endoscopic and radiologic scoring systems that can aid in quantifying disease activity and response to therapy. These modalities and scoring tools are discussed in this article. PMID- 28838412 TI - Intestinal and Nonintestinal Cancer Risks for Patients with Crohn's Disease. AB - Crohn's disease (CD) is a chronic inflammatory disease that confers a higher risk of cancer than in the general population. New, large, population-based studies in the past decade show that patients with CD are at higher risk of colorectal, small bowel, melanoma, and cervical cancer. Patients who use thiopurines are at additional risk of development of lymphoma and nonmelanoma skin cancer. Preventive surveillance for cancers of the colorectum, skin, and uterine cervix is advised. PMID- 28838413 TI - Sexuality, Fertility, and Pregnancy in Crohn's Disease. AB - Many factors influence the sexual health of people with Crohn's disease, but active disease and depression play key roles. The fertility rate in nonoperated patients with inflammatory bowel disease with quiescent disease is similar to that in the general population. Crohn's disease can increase the risk for adverse pregnancy outcomes, but being in remission on a stable, steroid-free medication regimen for at least 3 months before conception and adhering to the treatment throughout pregnancy can improve outcomes. Infants with intrauterine exposure to anti-tumor necrosis factor medications should avoid live vaccines for the first 9 months or until drug concentrations are undetectable. PMID- 28838414 TI - Interdisciplinary Management of Perianal Crohn's Disease. AB - Perianal disease is a common manifestation of Crohn disease (CD) that results in significant morbidity and decreased quality of life. Despite several medical and surgical options, complex perianal CD remains difficult to treat. Before the advent of biologic therapy, antibiotics were the mainstay of medical treatment. Infliximab remains the most well-studied medical therapy for perianal disease. Surgical interventions are limited by the risk of nonhealing wounds and potential incontinence. When treatment options fail, fecal diversion or proctectomy may be necessary. Stem cell therapies may offer improved results and seem to be safe, but are not yet widely used. PMID- 28838415 TI - Management of Crohn's Disease After Surgical Resection. AB - Approximately 25% to 35% of patients with Crohn's disease (CD) who undergo surgery require repeat surgery. Active smoking, multiple prior surgeries, and penetrating or perianal disease are risk factors for recurrence of CD after surgical resection. Early initiation of prophylactic therapy is effective in decreasing the risk of recurrence. Active colonoscopic surveillance for the early detection of endoscopic recurrence within 6 to 12 months of surgery is recommended. In symptomatic patients without evidence of endoscopic recurrence, noninflammatory causes should be sought. PMID- 28838416 TI - Targeting Specific Immunologic Pathways in Crohn's Disease. AB - Understanding the immunologic pathways in intestinal inflammation is crucial for the development of new therapies that can maximize patient response and minimize toxicity. Targeting integrins and cytokines is intended to control leukocyte migration to effector sites or inhibit the action of proinflammatory cytokines. New approaches to preventing leukocyte migration may target integrin receptors expressed on the intestinal vascular endothelium. The interleukin (IL)-12/IL-23 pathway has been a therapeutic target of interest in controlling active Crohn's disease (CD). New therapeutic approaches in CD may involve the enhancement of anti-inflammatory cytokine pathways and modulation of cellular responses and intranuclear signals associated with intestinal inflammation. PMID- 28838417 TI - Use of Anti-Tumor Necrosis Factors and Anti-Integrins in the Treatment of Crohn's Disease. AB - In patients with Crohn's disease (CD), anti-tumor necrosis factor (TNF) therapy is efficacious for the induction and maintenance of clinical remission, mucosal healing, reducing rates of surgery and hospitalizations, and improving health related quality of life. The decision between anti-TNFs and anti-integrins as first-line treatment in CD depends on disease severity, safety concerns, and prescription coverage. Given the existing data on long-term outcomes and safety, anti-TNFs are often preferred to anti-integrins. Additional clinical experience and preferably prospective, head-to-head studies will be important to determine whether vedolizumab should be considered more often for first-line therapy in CD. PMID- 28838418 TI - Ustekinumab and Anti-Interleukin-23 Agents in Crohn's Disease. AB - This article reviews the available data regarding the efficacy of ustekinumab across published randomized clinical trials and open-label experience from tertiary medical centers, safety data, including in pregnancy, and its use in patients who have failed tumor necrosis factor (TNF) antagonists as well as patients who have not failed TNF antagonists. We have proposed an algorithm for positioning the use of ustekinumab among other agents (TNF antagonists, vedolizumab) in moderate-severe Crohn's disease. The article also enumerates drugs that are specific interleukin-23 blockers, including brazikumab (MEDI2070), risankizumab, LY3074828, tildrakizumab, and guselkumab, and the current status of their clinical trials. PMID- 28838420 TI - Update on Therapeutic Drug Monitoring in Crohn's Disease. AB - In patients with Crohn's disease on biologic medications, the use of therapeutic drug monitoring leads to a personalized approach to optimize treatment. Using an algorithmic approach, measurement of drug concentrations and anti-drug antibodies can be used to improve treatment outcomes. Therapeutic drug concentrations and absence of antibodies are associated with improved clinical and endoscopic outcomes. In clinical practice, therapeutic drug monitoring has been shown to be clinically useful and cost-effective in patients experiencing a loss of response to treatment. This review highlights the available data on therapeutic drug monitoring in the treatment of patients with Crohn's disease on biologic medications. PMID- 28838419 TI - Janus Kinase Antagonists and Other Novel Small Molecules for the Treatment of Crohn's Disease. AB - There is an ongoing, unmet need for effective therapies for Crohn's disease. Treatments for Crohn's disease continue to evolve from the traditional biologics to novel small molecules, with targeted mechanisms directed toward pathways that are dysregulated in Crohn's disease. There are multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1 phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies for Crohn's disease. PMID- 28838421 TI - The Evolution of Treatment Paradigms in Crohn's Disease: Beyond Better Drugs. AB - Despite advances in care, most patients with Crohn's disease (CD) develop complications, such as fistulas, or require surgery. Given the recent advances in drug therapy, an opportunity exists to optimize the management of this chronic disease through early use of effective therapies, clear definition of treatment targets, and application of the principles of personalized medicine. In this article, the authors discuss the evolution of treatment algorithms for CD to incorporate these strategies. PMID- 28838422 TI - Crohn's Disease: Etiology, Complications, Assessment, Therapy, and Management. PMID- 28838423 TI - Comment on: Impact of pneumococcal conjugate vaccine in children morbidity and mortality in Peru: Time series analysis. PMID- 28838424 TI - Response to comment on: Impact of pneumococcal conjugate vaccine in children morbidity and mortality in Peru: Time series analyses. PMID- 28838426 TI - Acridone Alkaloids. AB - There have been substantial developments in the chemistry and biology of the acridone alkaloids in the 16years since the topic was last reviewed in this series of monographs (2000). The present survey covers the literature from mid 1999 to 2016. A brief overview of the biosynthesis of acridone alkaloids is followed by details of the occurrence and characterization of known alkaloids from new sources, and of novel alkaloids. The classes covered include simple acridone alkaloids, C-prenylacridones, furo[3,2-b]- and furo[2,3-c]acridones, pyrano[3,2-b]- and pyrano[2,3-c]acridones, and dimeric alkaloids containing acridone moieties. Syntheses of acridone alkaloids and certain analogs reported during the review period are comprehensively covered. The final section summarizes aspects of their bioactivity, including cytotoxicity and anticancer activity, antimicrobial and antiparasitic properties, and enzyme inhibition. The chapter concludes with a brief description of important bioactive synthetic analogs. PMID- 28838425 TI - Lymph node ratio relationship to regional failure and distant metastases in oral cavity cancer. AB - BACKGROUND: We aimed to investigate the impact of lymph node ratio (LNR, number of positive nodes/total number of excised nodes) on regional-only-failure, distant-only-failure and overall survival (OS) in oral squamous cell carcinoma (OSCC). METHODS: Retrospective review of pN0-2 OSCC-patients (1994-2012) treated with curative-surgery with neck dissection+/-postoperative radiotherapy (PORT)+/ concurrent chemotherapy. LNR was subjected to multivariable analysis (MVA) of regional-only-failure, distant-only-failure and OS. RESULTS: Overall 914 patients were identified; median follow-up: 51months (1-189); pN0: 482 (52.7%), pN1: 128 (14%), pN2a: 6 (0.7%); pN2b: 225 (24.6%); pN2c: 73 (8%); median number of dissected nodes: 36 (6-125); median number of pN+: 2 (1-49); median LNR for pN+ patients: 6%; extranodal extension: 187 (20.5%). Bilateral neck dissection: 368 (40.3%); PORT: 452 (49.5%); and concurrent chemotherapy: 80 (8.8%). High grade, lymphovascular invasion perineural invasion and pT3-4 were associated with high LNR. On MVA, LNR was associated with regional-only-failure (HR=1.06; 95%CI: 1.04 1.08; p<0.001), distant-only-failure (HR=1.03; 95%CI: 1.02-1.05; p=0.004) and lower OS (HR=1.03; 95%CI: 1.02-1.05; p<0.001). Similarly, in pN2-subgroup: LNR was associated with regional-only-failure (HR=1.04; 95%CI: 1.02-1.06; p<0.001), distant-only-failure (HR=1.03; 95%CI: 1.01-1.06; p=0.045) and lower OS (HR=1.03; 95%CI: 1.02-1.04; p<0.001). CONCLUSION: High LNR is associated with higher regional-only-failure/distant-only-failure and lower OS. LNR should be assessed in future prospective trials for selection of adjuvant therapy. PMID- 28838427 TI - Galbulimima Alkaloids. AB - This chapter provides a comprehensive overview of recent achievements in the area of Galbulimima alkaloids. Following a discussion of the isolation of Galbulimima alkaloids and structural features of members of this fascinating family of secondary metabolites, biological properties of selected compounds are briefly discussed. Furthermore, the proposed biosynthetic routes toward Galbulimima alkaloids are outlined. The main section of the chapter is devoted to a detailed discussion and comparison of all total syntheses of Galbulimima alkaloids published to date. PMID- 28838428 TI - Total Synthesis of Lundurine and Related Alkaloids: Synthetic Approaches and Strategies. AB - This review focuses on the total synthesis of lundurines A-C. Their main structural feature is a unique cyclopropa[b]indole core that has been found only in these alkaloids. In addition to this characteristic structure, the biological activity makes them as attractive synthetic targets. However, almost two decades passed from their isolation and structural determination in 1995 to their first total synthesis. The first part of this review summarizes the synthetic approaches to the tri- and tetracyclic ring systems of lundurine as well as an inter- and intramolecular cyclopropanation strategy that gives the cyclopropa[b]indole core. The second part presents a detailed description of four total syntheses that were reported from 2014 to 2016. In addition, the asymmetric total synthesis of the related alkaloids grandilodine C and lapidilectine B is described. PMID- 28838429 TI - Cephalotaxus Alkaloids. AB - Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs. PMID- 28838430 TI - Breakthrough in the Transplantation of Thoracic Organs in Hungary. AB - In 2016 the focus was, by all means, on the transplantation on thoracic organs. More than 50 heart transplantations were performed in this year. With this achievement, the Hungarian Heart Transplantation Program became one of the leading programs in the world. In the Thoracic Surgery Unit of the National Institute of Oncology and the Thoracic Surgery Department of Semmelweis University the first successful lung transplantation was carried out on December 12, 2015 when the Hungarian Lung Transplantation Program was launched. PMID- 28838431 TI - Patient Attitudes Toward Transplantation as Preferred Treatment Modality in Different Stages of Renal Disease. AB - OBJECTIVE: Kidney transplantation is generally considered to be the best treatment for end-stage renal disease. Not every patient can be operated, but many of suitable patients refuse this possibility. We aimed to explore the attitudes of patients with chronic kidney disease towards renal replacement therapies to recognize motives, thoughts, and feelings concerning accepting or refusing the treatment. We studied the attitudes towards the illness and the treatment, the appearance of depression, and the disease burden during different stages of the disease. METHODS: For this study we implemented a questionnaire that we developed (which has been described in an earlier publication of this journal) with 99 pre-dialysis patients, 99 dialysis patients, and 87 transplantation patients. We completed the attitude questionnaire designed by our team to include disease burden and depression questionnaires. RESULTS: We used discriminant analysis to describe different stages of the disease. There was a significant difference in the following factors between the three patient groups: accepting the new kidney, lack of confidence in transplantation therapy, fear of surgery, accepting self-responsibility in recovery, dependency on the transplanted kidney, confidence in recovery, subjective burden of dialysis, and denial of personal responsibility in maintaining the transplanted kidney. Significant differences were also detected in these three groups regarding the level of depression and disease burden: we measured the highest value among the dialysis patients, and the lowest value among the pre-dialysis patients. Comparing patients accepting and refusing transplantation, we found a correlation between the refusal of transplantation and the attitudes towards the illness and treatment. CONCLUSIONS: Most patients remain unmotivated to change treatment modality and refuse transplantation. Misbelief about transplantation shows a correlation with the motive of refusal. Dissemination of information may facilitate a change in the situation. PMID- 28838432 TI - Autosomal Dominant Polycystic Kidney Disease Transplant Recipients After Kidney Transplantation: A Single-center Experience. AB - Kidney transplantation is indicated for end-stage renal disease. Autosomal dominant polycystic kidney disease (ADPKD) causes structural degeneration of the kidney and eventually becomes end-stage renal disease. ADPKD patients usually have several renal and nonrenal complications. We analyzed our kidney transplantation activities between 1991 and 2010 regarding ADPKD. We followed up with patients to December 31, 2016. Data were collected as patient and graft survival rates, the prevalence of polycystic manifestation of the gastrointestinal tract and other organs, and the attendance of urinary tract infection. Among the 734 kidney transplantations, 10.9% (n = 80) had an ADPKD. Four patients (5%) had diverticulum perforation. The prevalence of post transplantation urinary tract infection was higher in ADPKD patients (55.9%) compared to non-ADPKD patients (44.1%). The 1-, 3-, and 5-year overall survival rates in ADPKD recipients versus non-ADPKD patients are 77.5%, 70.0%, and 67.5% versus 86.4%, 83.0%, and 80.1%, respectively. Patients with ADPKD were transplanted at an elder age compared to others (median: 47.5 years vs. 39.9 years). Female patients had longer graft survival times than males. ADPKD implies multiple cystic degeneration of the kidneys; however, it can cause structural degeneration in other organs. It is typical for ADPKD patients to have an acute abdominal-like syndrome. Immunosuppressive drugs can hide the clinical picture, which makes early diagnosis difficult. PMID- 28838433 TI - Ophthalmic Findings in Patients After Renal Transplantation. AB - The aim of the study was to perform complete ophthalmic examinations in patients after renal transplantation to determine ocular alterations and condition of the eyes. Moreover, ophthalmic findings were correlated with certain clinical characteristics related to transplantation such as post-operative renal functions and immunosuppressive regimen. The study was performed on 84 eyes of 42 patients who had received a renal transplant at least 6 months earlier. All patients underwent a complete ophthalmologic examination. In addition, in 33 (78.6%) patients peripapillary retinal nerve fiber layer (RNFL) thickness was determined using optical coherence tomography (Stratus OCT, Zeiss, Germany), which is a unique finding among renal transplantation patients. Recipients received immunosuppressive therapy consisting of tacrolimus, mycophenolate mofetil, and corticosteroid. Of 42 patients, 19 (45%) were women and 23 (55%) were men. The age of the patients ranged from 26 to 74 years, the mean age was 53.4 years. At least one ocular abnormality could be detected in 37 patients (88%), including impaired visual acuity (n = 31, 74%), keratoconjunctivitis sicca (n = 6, 14.3%), pinguecula (n = 3, 7.1%), arcus lipoides (n = 1, 2.4%), cataracts (n = 24, 57.1%), glaucoma (n = 2, 5%), retinal drusen (n = 6, 14.3%), and hypertensive or atherosclerotic retinopathy (n = 22, 52.4%). Twenty-five patients (75.8%) have reduced RNFL thickness. Cataract formation was positively correlated with age and usage of methylprednisolone. Moreover, RNFL thickness loss was correlated with transplantation duration and postoperative infections. Our study suggests that ocular disorders are frequent among renal transplantation patients. Besides immunosuppression and postoperative infection, aging is a high-risk factor in such cases. PMID- 28838434 TI - Management of Portal Hypertension After Liver Transplantation. AB - INTRODUCTION: Post-transplantation portal hypertension has severe complications, such as esophageal varix bleeding, therapy refractory ascites, extreme splenomegaly, and graft dysfunction. The aim of our study was to analyze the effectiveness of the therapeutic strategies and how to visualize the procedure. METHODS: A retrospective study involving liver transplantation patients from the Semmelweis University Department of Transplantation and Surgery was performed between 2005 and 2015. The prevalence, etiology, and leading complications of the condition were determined. The applied interventions' effects on the patients' ascites volume, splenic volume, and the occurrence of variceal bleeding were determined. Mean portal blood flow velocity and congestion index values were calculated using Doppler ultrasonography. RESULTS: The prevalence of post transplantation portal hypertension requiring intervention was 2.8%. The most common etiology of the disease was portal anastomotic stenosis. The most common complications were esophageal varix bleeding and therapy refractory ascites. The patients' ascites volume decreased significantly (2923.3 +/- 1893.2 mL vs. 423.3 +/- 634.3 mL; P < .05), their splenic volume decreased markedly. After the interventions, only one case of recurrent variceal bleeding was reported. The calculated Doppler parameters were altered in the opposite direction in cases of pre-hepatic versus intra- or post-hepatic portal hypertension. After the interventions, these parameters shifted towards the physiologic ranges. CONCLUSION: The interventions performed in our clinic were effective in most cases. The patients' ascites volume, splenic volume, and the prevalence of variceal bleeding decreased after the treatment. Doppler ultrasonography has proved to be a valuable imaging modality in the diagnosis and the follow-up of post-transplantation portal hypertension. PMID- 28838435 TI - Launching the Hungarian Lung Transplantation Program. AB - The first successful lung transplantation was done in 1963 by James Hardy in the United States. The Vienna Lung Transplant program was launched in 1989 by Professor Walter Klepetko, and in 1996 lung transplantation became available in this center also for Hungarian patients. By 2013, conditions for full-scale Hungarian lung transplantation program were ripe. The Hungarian government invested 3 million Euros for infrastructural developments that made the operation and the perioperative care available. Besides funding, the professional training of medical personnel was also essential for this program to start. Hungarian specialists have had internship opportunities to study all aspects of lung transplantation at the Thoracic Surgery Department in Vienna. After successful preparations, the first lung transplantation in Hungary was performed on December 12, 2015. PMID- 28838436 TI - Early Postoperative Problems After Lung Transplantation: First-Year Experiences in Light of the Newly Established National Hungarian Lung Transplantation Program. AB - Until December 2015, Hungarian patients' lung transplantations (LTXs) were done at the Medical University of Vienna. After several years of preparation, the National Hungarian Lung Transplantation Program was launched and the first milestone LTX was performed in Budapest on December 12, 2015. During the first 12 months, 18 lung transplantations took place in Hungary, including the first one. Data were retrospectively collected to analyze the early postoperative problems of the first 18 LTX patients of the newly launched Hungarian National Lung Transplantation Program. No patients with primary pulmonary hypertension and no children were transplanted during this period. We found that the postoperative problems of LTX differ from those of other huge thoracic surgeries both in a quantitative and a qualitative manner. We also reveal problems that are not present with other thoracic surgeries. The wide variety of problems during the early postoperative period after LTX can be managed by a highly organized and coordinated interdisciplinary teamwork. PMID- 28838437 TI - Urgent Lung Transplantation in Severe Acute Respiratory Failure Based on Rapidly Progressive Interstitial Lung Disease: A Case Report. AB - Lung transplantation (LUTX) became a worldwide accepted standard therapy for certain well-defined chronic end-stage lung diseases. Until recently, patients on mechanical ventilation or extracorporeal life support techniques were hardly eligible for LUTX because of the inferior short-term results. However, a paradigm shift has occurred, and now these techniques represent bridging options to LUTX for listed patients. In the current practice, transplantation from the intensive care unit (ICU) is not extraordinary in patients on the waiting list. On the other hand, transplantation of an ICU patient who has previously been healthy without any chronic lung disease is still exceptional. Here we report a unique case of a 37-year-old woman without any relevant medical history who developed acute lung failure based on a cryptogenic organizing pneumonia. Her condition rapidly deteriorated and she required mechanical support, then she was bridged to transplantation on venovenous extracorporeal membrane oxygenation. She was listed for LUTX, and despite elevated panel-reactive antibody values, positive crossmatch LUTX was performed. Induction therapy, alemtuzumab, plasmapheresis, and intravenous immunoglobulin were administered. Her recovery was slow but finally she could be discharged from hospital in stable condition. After 2 months at home, she was readmitted to the hospital with respiratory failure from combined antibody-mediated rejection and infection. Before December 2015, the launch of Hungarian National Lung Transplantation Program, Hungarian patients were transplanted in Vienna. This case presents an exceptional example of national and international teamwork that aimed to save a young woman's life. PMID- 28838438 TI - Donor-Derived Metastatic Melanoma and Checkpoint Inhibition. AB - Donor-derived malignancy, particularly melanoma, is a rare but known complication of organ transplantation. Here we describe a case of metastatic melanoma in a deceased-donor kidney transplant recipient. After diagnosis, the patient was successfully treated with cessation of immunosuppression, explantation of the renal allograft, and novel melanoma therapies, including the mutation-targeted agents dabrafenib and trametinib and the immune checkpoint inhibitor nivolumab. These 2 new classes of melanoma therapy have revolutionized the course of metastatic melanoma, altering it from one of nearly certain mortality to one of potential cure. This case reviews the mechanisms of action of these therapies and reports our experience with them in the rare setting of donor-derived melanoma in a dialysis-dependent patient. PMID- 28838439 TI - Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report. AB - A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient. PMID- 28838440 TI - Ganciclovir Dosing Strategies and Development of Cytomegalovirus Resistance in a Kidney Transplant Recipient: A Case Report. AB - In renal transplant recipients, delayed graft function and accompanying renal impairment may lead to therapeutic underexposure of valganciclovir. We describe a case of a cytomegalovirus (CMV)-seronegative kidney transplant recipient from a CMV-seropositive donor, whose course was complicated during valganciclovir prophylaxis by CMV disease, ultimately progressing to ganciclovir, foscarnet, and cidofovir resistance. Assessments and adjustments for renal dysfunction, according to both Cockgroft-Gault and Modification of Diet in Renal Disease study equations, are described. Therapy was complicated by outpatient parenteral therapy with pump-administered antiviral therapy, which may have led to drug underexposure and the fostering of antiviral resistance. Suppression was ultimately achieved in conjunction with reduction in immunosuppressive therapy, CMV immunoglobulin, and initiation of leflunomide. At-risk recipients may benefit from 24 hour creatinine clearance assessments, direct creatinine clearance measurement, or therapeutic drug monitoring. Optimal dosing strategies in recipients with impaired kidney function remain undefined, with limited pharmacokinetic data to date. PMID- 28838441 TI - Long-term Graft Survival After Kidney Allograft Torsion: Rapid Diagnosis and Surgical Management Key to Reversibility of Injury. AB - INTRODUCTION: Kidney allograft torsion (KAT) is a rare complication of kidney transplantation (KT) that occurs when the transplanted kidney rotates around its vascular pedicle, which may result in a catastrophic compromise of the graft's blood supply, deterioration of kidney function, and eventually premature graft death. CASE REPORT: We report the case of a patient who had an acute kidney injury (AKI) episode from KAT. Her diagnosis was ascertained expeditiously and she had prompt surgical management. Five years after the KAT event, her baseline creatinine (Cr) stabilized around 1.6 mg/dL and she has achieved >8-year graft survival. DISCUSSION: This case illustrates the reversibility of injury that can occur after a KAT event with a commensurate return to baseline kidney function when KAT is promptly diagnosed and treated. A high index of suspicion of this uncommon but catastrophic complication of KT must be maintained to achieve desirable long-term outcomes. A diagnosis of KAT must be considered when routine etiologies of an acute deterioration of kidney allograft function have been excluded. Finally, prophylactic nephropexy must be strongly considered with intraperitoneal placement of a kidney allograft to avoid KAT. PMID- 28838442 TI - Late-Onset Allograft Aspergillosis in an HIV-Positive Renal Transplant Recipient: A Case Report. AB - Aspergillus infection of the allograft in renal transplant patients is rare and associated with a high mortality. We report a case of a 21-year-old, human immunodeficiency virus-positive, deceased-donor kidney recipient who presented 1 year after transplant with oliguric kidney injury. A nuclear medicine renal scan revealed absence of flow to the transplanted kidney, and a urine fungal culture was positive for Aspergillus flavus. The diagnosis was confirmed with the presence of fungal hyphae along with thrombosis in the vascular structures in renal allograft pathology. We found no evidence of disseminated aspergillosis or involvement of any other organ in the patient. To our knowledge, this case is the first reported in the literature of late-onset non-disseminated renal-limited aspergillosis in a human immunodeficiency virus-positive renal transplant patient. PMID- 28838443 TI - First Treatment of Relapsing Rapidly Progressive IgA Nephropathy With Eculizumab After Living Kidney Donation: A Case Report. AB - BACKGROUND: IgA nephropathy (IGAN) rarely can present as a crescent and progressive form leading to end-stage renal disease (ESRD) in a short period of time. Recurrence of IGAN after kidney transplantation is frequent, and complement components such as C3, C4d, and C5 seem to be involved. We present a case of a young male patient with ESRD caused by rapidly progressive IGAN and who demonstrated rapid recurrence of crescentic IGAN after kidney donation. CASE REPORT: In September 2014, a 28-year-old male patient was hospitalized due to IGAN with 60% of crescents. Cyclophosphamide, steroids, and plasmapheresis did not prevent ESRD. After 8 months of peritoneal dialysis, the patient received a blood group-compatible living donor kidney from his 57-year-old mother. Immunosuppression consisted of tacrolimus, mycophenolic acid, and steroids without induction therapy. Acute graft failure occurred 2 months later, and graft biopsy results revealed recurrence of crescentic IGAN. Cyclophosphamide was added to tacrolimus and steroid treatment, but graft function could not be restored despite viable kidney tissue in repeated biopsy specimens. Rescue therapy with 4 single doses of eculizumab was introduced while hemodialysis had already been initiated. After a cumulative dose of 1800 mg of eculizumab, kidney function did not recover. CONCLUSIONS: In this case, eculizumab was not effective in treating IGAN recurrence after transplantation. Therapy was started late when hemodialysis had already been initiated; an earlier start of therapy might be more effective. PMID- 28838444 TI - An Unusual Case of Acute Myeloid Leukemia Cell Infiltration of the Renal Allograft: A Case Report and Review of Literature. AB - Kidney transplant recipients are at a high risk for developing malignancies with dermatologic cancers and lymphomas making up the bulk of these. Leukemia is rare in this cohort of patients. Kidney infiltration by leukemic cells is seen in about 34% of native kidneys based on autopsy studies. But leukemia infiltration of the kidney allograft has not been described much in the literature. Here we discuss the case of a 59-year-old kidney transplant recipient with acute myeloid leukemia (AML) who presented with acute kidney injury and his transplant kidney biopsy showed leukemic cell infiltration of the renal cortex. We also present a comprehensive literature review of post-kidney transplantation AML. PMID- 28838445 TI - Blastomyces dermatitidis in a Renal Transplant Recipient: A Case Report. AB - Fungal infections have an important role in organ transplant recipients, and in some cases can be lethal. Blastomycosis is rare in kidney transplantation. We present a case of cutaneous blastomycosis in a kidney transplant recipient in Tunisia, a country outside the known endemic countries. This case, with the very uncommon and unexpected diagnosis of blastomycosis, demonstrates the diversity of infections in transplant recipients and reflects the importance of histologic and serologic tests in the immunocompromised patient. PMID- 28838446 TI - A Case Report: Organs From a Donor With Highly Virulent Zoonotic Outbreak Strain of Streptococcus agalactiae Serotype III, Multilocus Sequence Type 283 Infective Endocarditis Did Not Result in Transmission With Adequate Prophylactic Antibiotic Cover. AB - In 2015, an outbreak involving a highly virulent zoonotic outbreak strain of Streptococcus agalactiae serotype III, multilocus sequence type 283 occurred in Singapore with increased neurologic complications, septic arthritis, and spinal infections in healthier patients. We report a case of a successful dual kidney transplant from a deceased donor with infective endocarditis and disseminated infection with the same strain of S agalactiae and we review the current literature. PMID- 28838447 TI - Case Report of Salmonella gallinarum Urinary Tract Infection in a Renal Allograft Recipient. AB - Urinary tract infections (UTIs) caused by nontyphoidal Salmonella in a renal allograft recipient are a rare occurrence. Although there is some existing literature on Salmonella typhi bacteriuria and non-typhoidal bacteriuria, none of the cases has been reported in a renal transplant patient. This case report describes a rare instance in which group D Salmonella was isolated from a renal allograft recipient's urine culture and the patient was successfully treated with antibiotics. PMID- 28838448 TI - Inguinal Bladder Hernia With Acute Ureteral Obstruction 14 Years After Kidney Transplantation: A Case Report. AB - An 82-year-old man with a history of renal transplantation 14 years earlier presented with acute obstructive renal failure secondary to inguinal herniation of the urinary bladder complicated by ureteroneocystostomy entrapment. After percutaneous nephrostomy tube and endoscopic stent placement, the bladder was reduced and the hernia repaired with the use of a preperitoneal mesh. The postoperative course was uneventful and the renal function returned to normal. Inguinal herniation of the transplant ureter is a rare cause of hydronephrosis, but it has been described in the literature. Bladder hernias do usually not cause urologic complications in the nontransplanted patient, but they can present as an emergency after renal transplantation. PMID- 28838449 TI - Successful Blood Transfusion Management of a Living Donor Liver Transplant Recipient in the Presence of Anti-Jra: A Case Report. AB - A 48-year-old Japanese woman was diagnosed with Budd-Chiari syndrome and transferred for possible living donor liver transplantation (LDLT). Examinations before LDLT revealed that the recipient had anti-Jra and preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA). Rituximab was administrated at 16 days prior to the patient's scheduled LDLT for the prophylaxis of antibody mediated rejection by DSA. The clinical significance of anti-Jra has not been clearly established because of the rarity of this antibody, so we discussed blood transfusion strategy with the Department of Blood Transfusion Service and prepared for Jra-negative packed red blood cells (RBCs). Intraoperative blood salvage was used during LDLT procedures to reduce the use of packed RBCs. Although post-transplantation graft function was excellent, a total of 44 U of Jra-negative RBCs were transfused during the entire perioperative period. Because sufficient amounts of Jra-negative packed RBCs were supplied, Jra mismatched blood transfusion was avoided. The patient was discharged from our hospital on postoperative day 102 without clinical evidence of any blood transfusion-related adverse events. Although there are some controversies of blood transfusion related to anti-Jra antibodies, the current strategies of blood transfusion for liver transplantation with anti-Jra are as follows: (1) sufficient supply and transfusion of Jra-negative matched packed RBCs and (2) application of intraoperative blood salvage to reduce the total amount of rare blood type RBCs. These strategies may be changed when the mechanism of anti-Jra alloimmunization is fully understood in the future. PMID- 28838450 TI - Living-Donor Liver Transplantation With the Use of a Left-Lobe Graft From a Donor With Anomalous Biliary Anatomy in Which B4 Joins the Right Anterior Sectional Duct: A Case Report. AB - When there is an anatomic anomaly in the biliary tract of the donor for living donor liver transplantation, the risk of postoperative biliary tract complications increases in both the donor and the recipient. We studied a case of living-donor liver transplantation with a left hepatic lobe graft that had anatomic anomalies, in which the medial segmental branch (B4) joined the anterior segmental branch and the posterior segmental branch formed a common trunk with the lateral segmental branch. A 40-year-old man visited our institution as a candidate organ donor for his mother, who had end-stage liver failure. An anomaly of B4 connecting the anterior segmental branch was suspected on magnetic resonance cholangiopancreatography. On intraoperative cholangiography, confluence of B4 with the anterior segmental branch and connection of the posterior and lateral segmental branches forming a common trunk were confirmed. Accordingly, individual anastomoses of the lateral segmental branch and B4 with the recipient jejunum were planned, and a left-lobe graft was excised. The postoperative recovery was smooth, and the donor was discharged with no complications. Even when an anatomic anomaly is present in the donor bile duct, in urgent cases, accurate evaluation through the use of various modalities may enable living-donor liver transplantation with the use of a graft with an anatomic anomaly. PMID- 28838451 TI - Hepatic Artery Reconstruction Using 3-in-1 Segmental Resection in Pediatric Living Donor Liver Transplantation: A Case Report and Literature Review. AB - We report a transplant of the left lateral liver segments with 3 arteries for a pediatric recipient from a living donor. A 6-month-old female infant was diagnosed with liver cirrhosis secondary to biliary atresia and scheduled for living donor liver transplantation (LDLT; mother as donor). Left lateral hepatectomy was performed at the donor site. The dissection of the left hepatic artery (HA), which was divided immediately after its origin, showed 3 branches for segments II, III, and IV. The arteries for segment II, segment III, and segment IV were anastomosed to the recipient HA. No postoperative complications were observed. The outcome of this case demonstrates that left lateral segments with 3 arteries can be successfully used if proper surgical techniques are applied. From this experience we can recommend "3-in-1 segmental resection" in the donor can be safely done by skilled microvascular surgeons and this technique should be considered for selected cases where multiple tiny arteries supply the graft. PMID- 28838452 TI - Utilization of the Iliac Artery as Inflow in the Morbidly Obese During Orthotopic Liver Transplantation: A Case Report. AB - Arterial conduits are a well-recognized technique used in liver transplantation to achieve allograft arterial inflow when conventional hepatic arterial inflow is compromised. Indications for ectopic inflow include native arterial disease at the time of initial transplantation, as well as reconstruction in the setting of thrombotic complications. Although supraceliac or infrarenal aortic reconstructions are preferred approaches, the right common iliac artery represents a viable alternative. We present the case of a morbidly obese patient with occlusive atheromatous plaque at the celiac origin not amenable to preoperative angioplasty who underwent reconstruction with a donor iliac artery conduit to the recipient right common iliac artery. His hepatic arterial inflow remained patent postoperatively with no thrombotic or hemorrhagic complications. PMID- 28838453 TI - Cholestasis After Pediatric Liver Transplantation-Recurrence of a Progressive Familial Intrahepatic Cholestasis Phenotype as a Rare Differential Diagnosis: A Case Report. AB - INTRODUCTION: Nonobstructive cholestasis after pediatric liver transplantation is a common diagnostic and therapeutic dilemma. We describe a girl with neonatal cholestasis because of progressive familial intrahepatic cholestasis 2 (PFIC-2) and presence of a homozygous splice site mutation in the ABCB11 gene. Liver transplantation was performed because of end-stage liver disease at the age of 6. Cholestasis with normal gamma-glutamyl transferase (GGT) developed 8 years after liver transplantation. A liver biopsy showed canalicular cholestasis and giant cell hepatitis without evidence of rejection, mimicking PFIC-2. Immunofluorescence staining of normal human liver sections with patient's serum revealed reactivity toward a canalicular epitope, which could be identified as bile salt export pump (BSEP) using BSEP-yellow fluorescent protein (YFP) transfected cells. Our patient developed a recurrence of a PFIC-2 phenotype due to production of antibodies against BSEP (alloimmune BSEP disease [AIBD]). Intensification of immunosuppressive therapy as well as antibody treatment with plasmapheresis and Rituximab were initiated, leading to stabilization of the clinical condition and depletion of anti-BSEP antibodies in serum. However, after 1 year liver transplantation was necessary again because of end-stage liver insufficiency. Afterward, immunomodulatory treatment consisted of tacrolimus, mycophenolate mofetil, prednisone, immunoadsorption, and high-dose immunoglobulin therapy (1 g/kg/d). CONCLUSION: Cholestasis after liver transplantation may indicate an AIBD with a PFIC-2 phenotype. Besides enhancement of immunosuppressive therapy, an antibody depletion with plasmapheresis, immunoadsorption, immunoglobulins, and B-cell depletion represents a therapeutic option. PMID- 28838454 TI - Acute Graft Rejection and Formation of De Novo Donor-Specific Antibodies Triggered by Low Cyclosporine Levels and Interferon Therapy for Recurrent Hepatitis C Infection After Liver Transplantation: A Case Report. AB - BACKGROUND: We report a case of acute rejection of a liver graft, together with the occurrence of de novo donor-specific antibodies (DSAs), in a 53-year-old Japanese man who had undergone deceased-donor liver transplantation. METHODS: The graft rejection was triggered by low cyclosporine levels and pegylated interferon treatment for the recurrence of hepatitis C virus (HCV) infection 18 months after transplantation. Although the graft was ABO-compatible, pre-formed DSA B51 was detected; therefore, total plasma exchange was performed and intravenous rituximab (500 mg/body) was administered before transplantation. RESULTS: DSA was absent 6 months after transplantation. HCV recurrence was treated with pegylated interferon-alpha-2a. Renal function deteriorated with this anti-HCV therapy, with serum cyclosporine levels decreasing to 50 ng/mL. A rapid virologic response was achieved, but liver function deteriorated after 3 months of anti-HCV therapy, with histologic evidence of acute cellular rejection and formation of de novo DSAs. Anti-thymocyte globulin was administered for 5 days, which led to immediate improvement in liver function. However, renal function declined, warranting hemodialysis. The patient recovered 2 months after acute rejection, although de novo DSAs persisted. CONCLUSIONS: Careful immunologic monitoring may be required for patients receiving interferon therapy for HCV infection to maintain sufficient blood levels of immunosuppressive agents and to prevent acute liver graft rejection. PMID- 28838455 TI - An Unusual Posttransplant T-cell Lymphoma After Liver Transplantation: A Case Report. AB - Posttransplantation lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities ranging from benign lymphocytic proliferations to high grade malignant lymphomas. The majority of PTLDs are associated with reactivation of Epstein-Barr virus (EBV), which induces B-cell proliferation and occurs in the setting of severe immune suppression after solid organ or bone marrow transplantation. T-cell/natural killer cell PTLDs are relatively rare, constituting ~15% of all cases. T-cell PTLDs are usually aggressive, and outcomes are poor. This article describes an unusual case of T-cell PTLD with a favorable outcome. The patient is a 57-year-old man who underwent a liver transplantation due to hepatitis C cirrhosis. He developed graft-versus-host disease with skin and gastrointestinal involvement and generalized lymphadenopathy 4 months after transplantation. Histologic sections of an excised axillary lymph node showed atypical medium and larger T-lymphocytes that were positive for CD3, CD5, CD43, and CD8 but were negative for B-cell antigens, CD56, and in situ hybridization for EBV-encoded RNA. Polymerase chain reaction analysis revealed monoclonal T cell receptor gamma chain gene rearrangement. A diagnosis of high-grade T-cell PTLD was made. The patient was treated with 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone and is currently in remission, 4 years after therapy. The rapid presentation of an EBV-negative T-cell PTLD with a nonaggressive course and complete response to treatment is an unusual presentation of posttransplantation T-cell lymphoma, which is usually associated with a high mortality rate. PMID- 28838456 TI - Successful Treatment of Stricture of Duct-to-Duct Biliary Anastomosis After Living-Donor Liver Transplantation of the Left Lobe: A Case Report. AB - Biliary complications, such as stricture or obstruction, after living-donor liver transplantation (LDLT) remain major problems to be solved. Magnetic compression anastomosis (MCA) is a minimally invasive method of biliary anastomosis without surgery in patients with biliary stricture or obstruction. A 66-year-old woman had undergone LDLT for end-stage liver disease for primary biliary cholangitis 20 months previously at another hospital. Computerized tomography showed dilation of the intrahepatic bile duct (B2). Because B2 was invisible with the use of endoscopic retrograde cholangiopancreatography, percutaneous transhepatic biliary drainage (PTBD) was performed for treatment of cholangitis. The rendezvous technique failed because a guidewire could not pass through the biliary stricture. Therefore, we decided to perform MCA. A parent magnet was endoscopically placed distally in the common bile duct of the stricture, and a daughter magnet attached to a guidewire was inserted proximally through the fistula tract of the PTBD. Both magnets were positioned across the stricture, and the 2 magnets were pulled to each other by magnetic power, to sandwich the stricture. By 14 days after MCA, a fistula between B2 and the common bile duct was created. At 28 days after MCA, the magnets were removed distally and a 16 French tube was placed across the fistula. At 7 months after MCA, that tube was removed. In conclusion, when a conventional endoscopic or percutaneous approach including the rendezvous technique fails, MCA is a good technique for biliary stricture after LDLT. PMID- 28838457 TI - Coexistent End-stage Nonalcoholic Steatohepatitis and Colon Cancer: Should We Do Liver Transplantation? AB - BACKGROUND: Colon cancer accompanying decompensated liver cirrhosis is a rare clinical condition. Usually, treatment of colon cancer is prioritized, with cirrhosis dealt with later. CASE REPORT: We present a case of end-stage liver disease due to nonalcoholic steatohepatitis evaluated for living donor liver transplant. During the pretransplant examination, an ascending colon cancer was detected. Liver function was too poor to perform colon resection first. Simultaneous living donor liver transplant and colonic resection were carried out. The patient developed left lung metastasis at 2 different times during the first postoperative year, and both of them were resected. The patient received the standard chemoradiotherapy. Now, the patient is alive at 42 months postprocedure and recurrence-free at 31 months postoperatively. CONCLUSION: Simultaneous liver transplantation and colon resection are possible with acceptable long-term outcomes. Immunosuppressive therapy after transplantation increases the risk for cancer recurrence. So the patient should undergo close surveillance. PMID- 28838458 TI - Successful Simultaneous Pancreas-Kidney Re-transplantation in a Highly Human Leukocyte Antigen-Sensitized Patient. AB - BACKGROUND: The waiting time for re-transplantation for sensitized patients is greatly prolonged, given the lack of transplants that are available for this group and additional immunologic barriers. We report the case of a successful re transplantation in a patient with very high levels of panel reactive antibodies ([PRA] >85%). METHODS: A 45-year-old woman had repetitive rejections after simultaneous pancreas-kidney transplantation, with consequent loss of function of both transplanted organs. Because of a symptomatic episode of kidney rejection, additional removal of the transplanted kidney was performed 6 years later. Because our patient had a very high PRA level, she was enrolled in a desensitization protocol. The regimen was based on an initial single dose of rituximab, followed by repetitive plasmapheresis/immune-absorption sessions and intravenous substitution of immunoglobulin. Eight cycles were required, until a cross-match test was negative (PRA level <50%). The protocol included prednisolone and weight-adapted thymoglobulin. The basic immunosuppressive medication consisted of prednisolone, tacrolimus, and mycophenolate mofetil. The patient's postoperative course was uneventful. RESULTS: Preoperative treatment is essential for sensitized patients. There are no prospective, randomized trials comparing all suggested desensitization protocols. The main tenets of every approach are plasmapheresis and intravenous substitution of immunoglobulin, which appear to have a strong immunomodulatory effect. In the case of re transplantation, the clinical surgeon not only faces special technical and surgical challenges but also must confront immunologic barriers. CONCLUSIONS: Pancreas-kidney transplantation in patients with high PRA levels is feasible and can be performed successfully with novel desensitization protocols. PMID- 28838459 TI - Thromboembolism Induced by Umbilical Cord Mesenchymal Stem Cell Infusion: A Report of Two Cases and Literature Review. AB - OBJECTIVE: To investigate the thromboembolism induced by blood-mediated inflammatory reactions against infused cells during the clinical application of stem cells. METHODS: Two patients with renal transplantation and chronic kidney disease, respectively, experienced thromboembolism after umbilical cord mesenchymal stem cell (UCMSC) infusion. The clinical manifestations and the laboratory test results were collected and analyzed. RESULTS: The patients received stem cell infusion through the peripheral veins and presented with a swollen and painful forearm postinfusion. Doppler ultrasound showed venous clots at the proximal end of the puncture site. Urokinase and warfarin were used for thrombolytic therapy. The swelling and pain were relieved and cured. CONCLUSION: Safety concerns are still a primary hurdle for stem cell therapy, and thromboembolism as a critical complication should be prevented appropriately. PMID- 28838460 TI - 91-Year-Old Allograft: Oldest Surviving Donor Heart Still Going: A Case Report. AB - For patients with end-stage heart failure, heart transplantation remains one of the most successful therapies with excellent long-term survival rates. However, over the past few decades, there has been a worsening supply/demand mismatch given the rising epidemic of heart failure and the relatively fixed availability of donor hearts. In this case report, we describe the case of a 30-year-old woman who underwent transplantation with a 68-year-old donor heart and who has survived for 23 years without any major cardiac problems. To our knowledge, this patient has one of the oldest surviving donor hearts (91-year-old heart). Review of the latest guidelines and recent studies have demonstrated a gradual expansion of donor criteria to meet this critical shortage of donor organs. PMID- 28838461 TI - Fever, Malaise, and Dyspnea in a Diabetic Heart Transplant Patient: A Case Report. AB - Patients with solid-organ transplants usually present at the emergency department with nonspecific symptoms. The physician should consider a great variety of syndromes and diseases, given the greater risk that solid-organ transplant patients carry because of immunosuppression and transplant-related conditions. Myocardial infarction caused by cardiac allograft vasculopathy must be always suspected and ruled out, even when initial symptoms do not orientate in that direction. We present a case that conjugates signs that can be present in different pathologies. It shows that fever is not always related to infection or rejection but could also appear in acute cardiac allograft vasculopathy. It emphasizes the need of a multi-disciplinary team led by a heart transplant specialist when dealing with this sort of clinical case. PMID- 28838462 TI - Drug-Eluting Balloons-A New Tool in the Treatment of Cardiac Allograft Vasculopathy: A Case Series. AB - Percutaneous coronary intervention in patients with cardiac allograft vasculopathy is burdened with a lot of difficulties. Although they have allowed significant progress in comparison with plain balloon angioplasty and bare metal stents, drug-eluting stents have not fully overcome problems of diffuse lesions and small-vessel disease that are so common in transplant coronary artery disease. There is growing evidence that drug-eluting balloons might be a better choice for patients with small vessel atherosclerotic coronary disease and yet there is no experience with this technology in patients with cardiac allograft vasculopathy. Herein we report a case series of successful percutaneous coronary interventions in patients with cardiac allograft vasculopathy. PMID- 28838463 TI - Beware Cold Agglutinins in Organ Donors! Ex Vivo Lung Perfusion From an Uncontrolled Donation After Circulatory-Determination-of-Death Donor With a Cold Agglutinin: A Case Report. AB - BACKGROUND: We began to recover lungs from uncontrolled donation after circulatory determination of death to assess for transplant suitability by means of ex vivo lung perfusion (EVLP) and computerized tomographic (CT) scan. Our first case had a cold agglutinin with an interesting outcome. CASE REPORT: A 60 year-old man collapsed at home and was pronounced dead by Emergency Medical Services personnel. Next-of-kin consented to lung retrieval, and the decedent was ventilated and transported. Lungs were flushed with cold Perfadex, removed, and stored cold. The lungs did not flush well. Medical history revealed a recent hemolytic anemia and a known cold agglutinin. Warm nonventilated ischemia time was 51 minutes. O2-ventilated ischemia time was 141 minutes. Total cold ischemia time was 6.5 hours. At cannulation for EVLP, established clots were retrieved from both pulmonary arteries. At initiation of EVLP with Steen solution, tiny red aggregates were observed initially. With warming, the aggregates disappeared and the perfusate became red. After 1 hour, EVLP was stopped because of florid pulmonary edema. The lungs were cooled to 20 degrees C; tiny red aggregates formed again in the perfusate. Ex vivo CT scan showed areas of pulmonary edema and a pyramidal right middle lobe opacity. Dissection showed multiple pulmonary emboli-the likely cause of death. However, histology showed agglutinated red blood cells in the microvasculature in pre- and post-EVLP biopsies, which may have contributed to inadequate parenchymal preservation. CONCLUSIONS: Organ donors with cold agglutinins may not be suitable owing to the impact of hypothermic preservation. PMID- 28838465 TI - Erratum. PMID- 28838464 TI - Clearance of Hepatitis C Virus Prior to Lung Transplantation: A Case Report. AB - Hepatitis C virus (HCV) continues to be considered a relative contraindication to lung transplantation due to concerns of progression of liver disease with the introduction of immunosuppression. Since the recent introduction of effective antiviral therapy for HCV, new approaches in the management of the HCV-positive recipient are being utilized in liver transplantation to clear HCV pre- and post transplant. Herein, we report use of ledipasvir/sofosbuvir for HCV clearance prior to lung transplantation in a patient with usual interstitial pneumonia. Listing for transplant was delayed until completion of HCV treatment, and he subsequently required extracorporeal membrane oxygenation as a bridge to transplantation due to progressive hypoxia. With antiviral cure rates exceeding 90%, HCV should no longer be considered a relative contraindication to lung transplant, and timing of antiviral treatment should consider the progressive nature of the recipient's lung disease. PMID- 28838466 TI - Theory-Based Computational Psychiatry. PMID- 28838467 TI - A Formal Valuation Framework for Emotions and Their Control. AB - Computational psychiatry aims to apply mathematical and computational techniques to help improve psychiatric care. To achieve this, the phenomena under scrutiny should be within the scope of formal methods. As emotions play an important role across many psychiatric disorders, such computational methods must encompass emotions. Here, we consider formal valuation accounts of emotions. We focus on the fact that the flexibility of emotional responses and the nature of appraisals suggest the need for a model-based valuation framework for emotions. However, resource limitations make plain model-based valuation impossible and require metareasoning strategies to apportion cognitive resources adaptively. We argue that emotions may implement such metareasoning approximations by restricting the range of behaviors and states considered. We consider the processes that guide the deployment of the approximations, discerning between innate, model-free, heuristic, and model-based controllers. A formal valuation and metareasoning framework may thus provide a principled approach to examining emotions. PMID- 28838468 TI - Computational Dysfunctions in Anxiety: Failure to Differentiate Signal From Noise. AB - BACKGROUND: Differentiating whether an action leads to an outcome by chance or by an underlying statistical regularity that signals environmental change profoundly affects adaptive behavior. Previous studies have shown that anxious individuals may not appropriately differentiate between these situations. This investigation aims to precisely quantify the process deficit in anxious individuals and determine the degree to which these process dysfunctions are specific to anxiety. METHODS: One hundred twenty-two subjects recruited as part of an ongoing large clinical population study completed a change point detection task. Reinforcement learning models were used to explicate observed behavioral differences in low anxiety (Overall Anxiety Severity and Impairment Scale score <= 8) and high anxiety (Overall Anxiety Severity and Impairment Scale score >= 9) groups. RESULTS: High anxiety individuals used a suboptimal decision strategy characterized by a higher lose-shift rate. Computational models and simulations revealed that this difference was related to a higher base learning rate. These findings are better explained in a context-dependent reinforcement learning model. CONCLUSIONS: Anxious subjects' exaggerated response to uncertainty leads to a suboptimal decision strategy that makes it difficult for these individuals to determine whether an action is associated with an outcome by chance or by some statistical regularity. These findings have important implications for developing new behavioral intervention strategies using learning models. PMID- 28838470 TI - Computational Psychiatry: Embracing Uncertainty and Focusing on Individuals, Not Averages. PMID- 28838469 TI - The Unpredictive Brain Under Threat: A Neurocomputational Account of Anxious Hypervigilance. AB - BACKGROUND: Anxious hypervigilance is marked by sensitized sensory-perceptual processes and attentional biases to potential danger cues in the environment. How this is realized at the neurocomputational level is unknown but could clarify the brain mechanisms disrupted in psychiatric conditions such as posttraumatic stress disorder. Predictive coding, instantiated by dynamic causal models, provides a promising framework to ground these state-related changes in the dynamic interactions of reciprocally connected brain areas. METHODS: Anxiety states were elicited in healthy participants (n = 19) by exposure to the threat of unpredictable, aversive shocks while undergoing magnetoencephalography. An auditory oddball sequence was presented to measure cortical responses related to deviance detection, and dynamic causal models quantified deviance-related changes in effective connectivity. Participants were also administered alprazolam (double blinded, placebo-controlled crossover) to determine whether the cortical effects of threat-induced anxiety are reversed by acute anxiolytic treatment. RESULTS: Deviant tones elicited increased auditory cortical responses under threat. Bayesian analyses revealed that hypervigilant responding was best explained by increased postsynaptic gain in primary auditory cortex activity as well as modulation of feedforward, but not feedback, coupling within a temporofrontal cortical network. Increasing inhibitory gamma-aminobutyric acidergic action with alprazolam reduced anxiety and restored feedback modulation within the network. CONCLUSIONS: Threat-induced anxiety produced unbalanced feedforward signaling in response to deviations in predicable sensory input. Amplifying ascending sensory prediction error signals may optimize stimulus detection in the face of impending threats. At the same time, diminished descending sensory prediction signals impede perceptual learning and may, therefore, underpin some of the deleterious effects of anxiety on higher-order cognition. PMID- 28838472 TI - Too Hot? Too Cold? When Is it "Just Right" to Stop Dual Antiplatelet Therapy After PCI With DES? PMID- 28838471 TI - Risk of Early Adverse Events After Clopidogrel Discontinuation in Patients Undergoing Short-Term Dual Antiplatelet Therapy: An Individual Participant Data Analysis. AB - OBJECTIVES: The study sought to evaluate the presence of a clinically relevant rebound phenomenon after dual antiplatelet therapy (DAPT) discontinuation in randomized trials. BACKGROUND: It is currently unknown whether clopidogrel discontinuation after short-term DAPT is associated with an early hazard of ischemic events. METHODS: The authors performed an individual participant data analysis and aggregate meta-analysis. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of cardiac death, myocardial infarction (MI), or stroke. RESULTS: The study included 11,473 PCI patients with individual participant data from 6 randomized trials comparing short-term DAPT (3 or 6 months) versus long-term DAPT (12 months or more). During the first 90 days following clopidogrel discontinuation, there was no significant increase in the risk of MACCE between patients randomized to short-term DAPT compared with long-term DAPT (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.71 to 1.98; p = 0.52; absolute risk difference 0.10%; 95% CI: -0.16% to 0.36%). The risk of MI or stent thrombosis was similar among patients randomized to short-term DAPT versus long-term DAPT (HR: 0.93; 95% CI: 0.46 to 1.90; p = 0.85). In the aggregate data meta-analysis of 11 trials including 38,919 patients, a higher risk of early MACCE was observed after long-term (>=12 months) DAPT duration (HR: 2.28; 95% CI: 1.69 to 3.09; p < 0.001) but not short-term (<12 months) DAPT duration (HR: 1.08; 95% CI: 0.67 to 1.74; p for interaction = 0.036). CONCLUSIONS: Among patients undergoing PCI with predominantly new generation DES, discontinuation of clopidogrel after 3 or 6 months DAPT duration was not associated with an early increase in adverse clinical events. An early increase in MACCE was observed after long-term (>=12 months) DAPT exposure. PMID- 28838474 TI - Percutaneous Coronary Interventions in Patients Requiring Long-Term Oral Anticoagulation: Is the Drug-Coated Stent a Potential Game Changer? PMID- 28838473 TI - Safety and Efficacy of Polymer-Free Biolimus A9-Coated Versus Bare-Metal Stents in Orally Anticoagulated Patients: 2-Year Results of the LEADERS FREE Oral Anticoagulation Substudy. AB - OBJECTIVES: The aim of this study was to compare the performance of drug-coated stents (DCS) versus bare-metal stents (BMS) in patients who are candidates for long-term oral anticoagulation (OAC) after percutaneous coronary interventions. BACKGROUND: The randomized controlled LEADERS FREE (A Randomized Clinical Evaluation of the BioFreedomTM Stent) trial demonstrated the superior safety and efficacy of a polymer-free biolimus A9 DCS compared with a similar BMS used with 1 month of dual antiplatelet therapy in 2,466 patients at high bleeding risk. METHODS: The 2 stents were compared in a pre-specified analysis of the 879 LEADERS FREE patients (35.6%) scheduled to remain on OAC after percutaneous coronary intervention. The primary safety endpoint was a composite of cardiac death, myocardial infarction, and stent thrombosis. The primary efficacy endpoint was the incidence of clinically driven target lesion revascularization. RESULTS: Baseline characteristics of 448 DCS and 431 BMS recipients were similar, 78.8% had histories of atrial fibrillation, and 21% presented with acute coronary syndromes. Four hundred patients in the DCS group and 376 in the BMS group were discharged on OAC after percutaneous coronary intervention. At 2 years, for the DCS and BMS recipients, respectively, the incidence of clinically driven target lesion revascularization was 7.5% versus 11.2% (hazard ratio: 0.63; 95% confidence interval: 0.40 to 1.01; p = 0.0514), the safety endpoint was reached by 14.4% and 15.0% (p = NS), and the rates of major bleeding events (Bleeding Academic Research Consortium 3 to 5) were 10.7% and 12.9% (p = NS). CONCLUSIONS: The efficacy advantage of DCS over BMS up to 2 years appears confirmed in patients on long-term OAC. Despite the very short course of dual antiplatelet therapy, both the DCS and BMS groups experienced similarly high rates of major bleeding. (A Randomized Clinical Evaluation of the BioFreedomTM Stent [Leaders Free]; NCT01623180). PMID- 28838475 TI - Comparison of Ticagrelor Versus Prasugrel for Inflammation, Vascular Function, and Circulating Endothelial Progenitor Cells in Diabetic Patients With Non-ST Segment Elevation Acute Coronary Syndrome Requiring Coronary Stenting: A Prospective, Randomized, Crossover Trial. AB - OBJECTIVES: This study compared adenosine-associated pleiotropic effects of the 2 P2Y12 receptor antagonists on vascular function, systemic inflammation, and circulating endothelial progenitor cells (EPCs). BACKGROUND: Both ticagrelor and prasugrel have potent antiplatelet effects. However, only ticagrelor inhibits cellular uptake of adenosine. METHODS: Using a randomized, crossover design with 10-week follow-up ticagrelor or prasugrel was administered to type 2 diabetic patients with non-ST-segment elevation acute coronary syndrome requiring stent implantation. A total of 62 patients underwent randomization in a 1:1 ratio to receive ticagrelor or prasugrel for 5 weeks followed by a direct cross over to the alternative treatment for 5 additional weeks. Brachial artery flow-mediated dilation, inflammatory markers, and number of circulating EPCs were compared. RESULTS: Improvement in brachial artery flow-mediated dilation was greater in the ticagrelor group (0.15 +/- 0.19 mm vs. -0.03 +/- 0.18 mm; p < 0.001). Moreover, ticagrelor compared with prasugrel decreased interleukin 6 (-0.58 +/- 0.43 pg/ml vs. -0.05 +/- 0.24 pg/ml; p < 0.001), tumor necrosis factor alpha (-5.62 +/- 4.40 pg/ml vs. -0.42 +/- 2.64 pg/ml; p < 0.001), and increased adiponectin (2.31 +/- 2.00 MUg/ml vs. 0.08 +/- 1.50 MUg/ml; p < 0.001) during 10-week follow-up. Other inflammatory cytokines like high-sensitivity C-reactive protein and soluble vascular cell adhesion molecule-1 were decreased in both groups. Ticagrelor compared with prasugrel significantly increased absolute numbers of circulating EPCs CD34+/KDR+ (42.5 +/- 37.8 per MUl vs. -28.2 +/- 23.7 per MUl; p < 0.001), CD34+/CD117+ (51.9 +/- 77.2 per MUl vs. -66.3 +/- 45.2 per MUl; p < 0.001), and CD34+/CD133+ (55.2 +/- 69.2 per MUl vs. -28.0 +/- 34.1 per MUl; p < 0.001). CONCLUSIONS: Compared with prasugrel, ticagrelor significantly decreased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha and increased circulating EPCs, contributing to improved arterial endothelial function in diabetic non-ST-segment elevation acute coronary syndrome patients. Thus, data support that pleiotropic effects of ticagrelor beyond its potent antiplatelet effects could contribute to additional clinical benefits. (Comparison of Ticagrelor vs. Prasugrel on Inflammation, Arterial Stiffness, Endothelial Function, and Circulating Endothelial Progenitor Cells in Diabetic Patients With Non-ST Elevation Acute Coronary Syndrome [NSTE-ACS] Requiring Coronary Stenting; NCT02487732). PMID- 28838476 TI - More Evidence for Non-P2Y12-Mediated Effects of Ticagrelor. PMID- 28838477 TI - Transcatheter Mitral Valve Implantation Using the HighLife System. AB - OBJECTIVES: This study is the first report of 2 cases of HighLife (HighLife, Paris, France) implantation in humans. BACKGROUND: Transcatheter mitral valve implantation represents a promising approach to treating mitral regurgitation in patients at increased risk of perioperative mortality. The HighLife transcatheter mitral valve is a 2-component system. The valve is implanted in the mitral position and is anchored by interacting and then reaching an equilibrium position with a previously positioned subannular implant. METHODS: The procedures were successfully performed in a 69-year-old man and a 65-year-old woman with severe functional mitral regurgitation. Both patients were in New York Heart Association functional class IV heart failure with depressed left ventricular ejection fraction and additional comorbidities. RESULTS: The valve was implanted uneventfully in both patients. General anesthesia was used. The subannular implant was deployed through the transfemoral access, whereas the transcatheter mitral valve was released using the transapical access. Patients maintained hemodynamically stable. There were no intraoperative complications. Acutely, post procedural echocardiograms demonstrated excellent prosthetic valve function with a low transvalvular gradient and no paravalvular leak and left ventricular outflow tract obstruction. Both patients had mild intraprosthetic regurgitation. Patient #1 survived at 5-months follow-up in New York Heart Association functional class II with excellent prosthesis performance. Patient #2 expired 4 days after a technically successful procedure, because the left ventricle did not tolerate the reduction of mitral regurgitation and despite a high dose of inotropic agents the left ventricular function rapidly deteriorated. CONCLUSIONS: Transcatheter mitral valve implantation using the 2-component HighLife system is technically feasible and can be performed safely. Early hemodynamic performance of the prosthesis was excellent. PMID- 28838479 TI - Transcatheter Mitral Valve Replacement: Maintaining Future Focus Despite Present Uncertainty. PMID- 28838478 TI - 2-Year Outcomes After Transcatheter Mitral Valve Replacement. AB - OBJECTIVES: This study sought to determine late (2-year) outcomes following transcatheter mitral valve replacement (TMVR) with the FORTIS valve (Edwards Lifesciences, Irvine, California). BACKGROUND: No data exist on long-term clinical outcomes following TMVR in patients with severe native mitral regurgitation (MR). METHODS: This multicenter registry included consecutive patients with severe MR who underwent TMVR with the FORTIS valve under a compassionate clinical use program. Clinical and echocardiographic data were collected at baseline, 30-day, and 1- and 2-year follow-up. RESULTS: Thirteen patients (71 +/- 8 years, 10 men, logistic European System for Cardiac Operative Risk Evaluation score = 23.7 +/- 12.1%) with severe MR were included. MR was of ischemic origin in most (76.9%) patients, and the mean left ventricular ejection fraction was 34 +/- 9%. Technical success was achieved in 10 patients (76.9%), and 5 patients (38.5%) died within the 30 days following the procedure. At 30-day follow-up, mean transmitral gradient was 3 +/- 1 mm Hg, and there were no cases of moderate-severe residual MR or left ventricular outflow tract obstruction. Two patients died during the follow-up period due to terminal heart failure, leading to an all-cause mortality rate of 54% at 2-year follow-up. At 2-year follow-up, all patients but 1 were in New York Heart Association functional class II, and there were no cases of valve malfunction (increasing gradients or MR recurrence). Computed tomography exams performed at 2-year follow-up in 3 patients showed no valve prosthesis fractures or displacement. CONCLUSIONS: TMVR with the FORTIS valve was feasible. MR reduction after TMVR was maintained at 2-year follow-up and no late device-related events were observed. PMID- 28838481 TI - Stent Selection in the Iliac Arteries: Don't Fall Through the ICE! PMID- 28838482 TI - Cangrelor Use in Cardiogenic Shock: A Single-Center Real-World Experience. PMID- 28838480 TI - Self-Expanding Versus Balloon-Expandable Stents for Iliac Artery Occlusive Disease: The Randomized ICE Trial. AB - OBJECTIVES: Atherosclerosis of iliac arteries is widespread. As inflow vessels, they are of great clinical significance and increasingly being treated by endovascular means. Most commonly, stents are implanted. BACKGROUND: So far, due to a lack of comparative data, no guideline recommendations on the preferable stent type, balloon-expandable stent (BE) or self-expanding stent (SE), have been issued. METHODS: In this randomized, multicenter study, patients with moderate to severe claudication from common or external iliac artery occlusive disease were assigned 1:1 to either BE or SE. The primary endpoint was binary restenosis at 12 months as determined by duplex ultrasound. Key secondary endpoints were walking impairment, freedom from target lesion revascularization (TLR), hemodynamic success, target limb amputation, and all-cause death. RESULTS: Six hundred sixty patients with 660 lesions were enrolled at 18 German and Swiss sites over a period of 34 months; 24.8% of the patients had diabetes and 57.4% were current smokers. The common iliac artery was affected in 58.9%. One hundred nine (16.5%) lesions were totally occluded and 25.6% heavily calcified. Twelve-month incidence of restenosis was 6.1% after SE implantation and 14.9% after BE implantation (p = 0.006). Kaplan-Meier estimate of freedom from TLR was 97.2% and 93.6%, respectively (p = 0.042). There was no between-group difference in walking impairment, hemodynamic success, amputation rate, all-cause death, or periprocedural complications. CONCLUSIONS: The treatment of iliac artery occlusive disease with SE as compared with BE resulted in a lower 12-month restenosis rate and a significantly reduced TLR rate. No safety concerns arose in both groups. (Iliac, Common and External [ICE] Artery Stent Trial; NCT01305174). PMID- 28838483 TI - Stent Fracture and Hypersensitivity: What Happens First? PMID- 28838484 TI - Be Careful What You Read and the Company You Keep. PMID- 28838485 TI - Statistical Commentary. PMID- 28838486 TI - Evaluation of a Novel Cryoprobe for Atrial Ablation in a Chronic Ovine Model. AB - PURPOSE: Cryoablation is used in the treatment of atrial fibrillation and other cardiac arrhythmias. This study evaluated a novel 10-cm flexible nitrous oxide cryoprobe in an ovine model of atrial ablation. DESCRIPTION: Six sheep were anesthetized, underwent a left thoracotomy, and were placed on cardiopulmonary bypass. A left atriotomy was performed, and the cryoprobe was applied endocardially for 120 seconds at less than -40 degrees C to 4 sites on the left atrium. The atrium was closed and the animals were allowed to recover. After 30 days, the animals were euthanized. Transmurality was evaluated in 5-mm sections of each lesion using 2,3,5-triphenyltetrazolium chloride (TTC) and Masson's trichrome staining. EVALUATION: All animals survived. One hundred four of 106 sections (98%) were transmural by TTC; 103 of 106 (97%) sections were transmural by trichrome staining. There was no late atrial perforation, intraluminal thrombus, or thromboembolism. CONCLUSIONS: The device reliably produced transmural lesions in a chronic ovine model. Its performance was equivalent to that of other nitrous oxide cryoablation systems. PMID- 28838487 TI - Cardioscopically Guided Beating Heart Surgery: Paravalvular Leak Repair. AB - PURPOSE: There remains a paucity of direct visualization techniques for beating heart intracardiac procedures. To address this need, we evaluated a novel cardioscope in the context of aortic paravalvular leaks (PVLs) localization and closure. DESCRIPTION: A porcine aortic PVL model was created using a custom-made bioprosthetic valve, and PVL presence was verified by epicardial echocardiography. Transapical delivery of occlusion devices guided solely by cardioscopy was attempted 13 times in a total of three pigs. Device retrieval after release was attempted six times. Echocardiography, morphologic evaluation, and delivery time were used to assess results. EVALUATION: Cardioscopic imaging enabled localization of PVLs via visualization of regurgitant jet flow in a paravalvular channel at the base of the prosthetic aortic valve. Occluders were successfully placed in 11 of 13 attempts (84.6%), taking on average 3:03 +/- 1:34 min. Devices were cardioscopically removed successfully in three of six attempts (50%), taking 3:41 +/- 1:46 min. No damage to the ventricle or annulus was observed at necropsy. CONCLUSIONS: Cardioscopy can facilitate intracardiac interventions by providing direct visualization of anatomic structures inside the blood-filled, beating-heart model. PMID- 28838488 TI - Invited Commentary. PMID- 28838489 TI - About the Decision-Making Process for Mitral Valve Repair. PMID- 28838491 TI - Reply. PMID- 28838490 TI - Careful Indications for Intentional Segmentectomy in cT1aN0 Non-Small Cell Lung Cancer. PMID- 28838492 TI - Carotid Doppler Before Aortic Valve Replacement and Perioperative Management. PMID- 28838493 TI - Reply. PMID- 28838494 TI - Socioeconomic Factors and Readmission in Patients With Early-Stage Lung Cancer After Lobectomy. PMID- 28838495 TI - Reply. PMID- 28838496 TI - Advanced Age Is a Risk Factor in Aortic Arch Surgery. PMID- 28838497 TI - Reply. PMID- 28838498 TI - We Cannot Compare "Apples and Oranges". PMID- 28838499 TI - Could Tumor Stage Be Conditioned by Surgical Technique Adopted? PMID- 28838500 TI - Carotid Doppler Assessment in Patients With Severe Aortic Stenosis. PMID- 28838501 TI - Video-Assisted Thoracic Surgery Utilizing Local Anesthesia and Sedation: How I Teach It. PMID- 28838502 TI - Invited Commentary. PMID- 28838503 TI - Invited Commentary. PMID- 28838504 TI - Invited Commentary. PMID- 28838505 TI - Invited Commentary. PMID- 28838506 TI - Invited Commentary. PMID- 28838507 TI - Magnetic Twin Stent for Short-Term Palliation of Acquired Nonmalignant Tracheoesophageal Fistula. AB - Through a tracheostomy with a rigid esophagoscope in the esophagus, the authors simultaneously placed self-made magnetic twin stents in a critically ill patient with high tracheoesophageal fistula. The operation took 17 minutes. Oral nutrition was started immediately. The stents were checked and changed after the months 3, 7, and 14. At 18 months, a tracheal resection and esophageal reconstruction through a partial median sternotomy was completed successfully. The magnetic twin stent technique can temporize critically ill patients with an acquired nonmalignant tracheoesophageal fistula until they become operable. PMID- 28838508 TI - Postpneumonectomy Bronchopleural Fistula Closure With Biologic Mesh and Diaphragm Flap. AB - A 77-year-old man with clinical stage II squamous cell carcinoma underwent right intrapericardial pneumonectomy. After an initially uneventful course he was readmitted with right-sided empyema, bronchopleural fistula, and pulmonary embolus. This was managed with initial resuscitation and anticoagulant agents, followed by debridement and closure of the fistula with biologic mesh reinforced with a pedicled diaphragm muscle flap. PMID- 28838509 TI - Initial Experience With Lung Cancer Resection After Treatment With T-Cell Checkpoint Inhibitors. AB - T-cell checkpoint inhibitors targeting the programmed death receptor-1 (PD-1) and its ligand (PD-L1) have recently been approved for the treatment of metastatic non-small cell lung cancer (NSCLC), but their safety and efficacy as neoadjuvant therapy are still undefined. Autoimmune toxicities, notably pneumonitis, are a particular concern in the perioperative setting. This series of 5 cases describes for the first time the safety and technical issues relating to pulmonary resection after checkpoint inhibitor therapy. PMID- 28838510 TI - Giant Aortic Thrombus in the Ascending Aorta and Perforation of Bowel Associated With Cocaine Use. AB - A floating giant aortic thrombus is a rare finding in the absence of any coagulation disorder. Patients usually remain asymptomatic until the development of embolic complications. Our report highlights cocaine abuse as a potential cause of aortic thrombus and bowel perforation. Clinicians should have a high index of suspicion when treating patients with a history of illicit cocaine use with signs and symptoms of arterial ischemia. The risks of cardiovascular and abdominal complications related to cocaine use should not be underestimated. Prompt diagnosis is required to circumvent potentially life-threatening complications. PMID- 28838511 TI - Repair of Tricuspid Valve Leaflet With CardioCel Patch After Traumatic Tricuspid Regurgitation. AB - Posttraumatic tricuspid valve regurgitation (TR) is a rare entity and is almost always associated with blunt chest trauma. It is usually identified by transthoracic echocardiography after the manifestation of clinical symptoms of heart failure. Treatment varies from long-term medical therapy and observation to surgical correction with tricuspid valve replacement or repair. We describe the case of a 26-year-old man who was involved in a major road traffic accident and was referred for surgical repair a year later because of severe posttraumatic TR. The tricuspid valve was successfully reconstructed with a CardioCel patch, Gore Tex neochordae, and a tricuspid ring. The patient recovered well. PMID- 28838512 TI - Severe Tricuspid Regurgitation After Percutaneous Removal of a Swan-Ganz Catheter Caught by Suture. AB - Swan-Ganz catheter entrapment in the heart, vena cava, or pulmonary artery is rare but may lead to life-threatening events. We report a case of severe tricuspid regurgitation resulting from papillary muscle rupture during percutaneous removal of a Swan-Ganz catheter (SCG) caught by a surgical suture. We performed urgent tricuspid valve repair by suturing the ruptured papillary muscle. This report highlights preventive measures to avoid suture-related entrapment and raises a word of caution regarding percutaneous removal of accidentally entrapped SCGs. PMID- 28838513 TI - Hybrid Arch Frozen Elephant Trunk for Persistent Endoleak After Thoracic Endovascular Aortic Repair. AB - Aneurysms of the distal aortic arch and proximal descending thoracic aorta remain challenging to treat. Whereas thoracic endovascular aortic repair (TEVAR) with arch debranching has provided a more minimally invasive option for patients with such aneurysms, recurrent type Ia endoleaks can be difficult or impossible to treat with further endovascular intervention. We report the successful use of a hybrid arch and frozen elephant trunk graft for the treatment of a patient with a recurrent type Ia endoleak after TEVAR and arch debranching. PMID- 28838514 TI - Primary Cardiac Leiomyoma Causing Right Ventricular Obstruction and Tricuspid Regurgitation. AB - We report the unique case of a primary cardiac leiomyoma originating from the right ventricle and involving the tricuspid valve in a 43-year-old woman. Echocardiography showed a giant mass causing severe pulmonary stenosis and tricuspid valve regurgitation. The patient underwent surgical excision and histologic examination revealed a primary cardiac leiomyoma. To the best of our knowledge only three cases of primary cardiac leiomyoma have so far been reported, and this is the first case of primary cardiac leiomyoma involving the tricuspid valve apparatus. PMID- 28838515 TI - Surgical Repair of Cervical Aortic Arch With Brain Circulation Anomaly Through Clamshell Incision. AB - We report the successful surgical repair of a cervical aortic arch and diverticulum with a brain circulation anomaly through a clamshell incision. Because of the reliability of selective antegrade cerebral perfusion and superior exposure, we chose an approach through a clamshell incision. We describe the utility of this approach for treating a cervical aortic arch with a diverticulum. PMID- 28838516 TI - Cardiac Regeneration in the Human Left Ventricle After CorMatrix Implantation. AB - CorMatrix is an organic extracellular matrix (ECM) derived from porcine small intestine submucosa and is used for pericardial closure and cardiac tissue repair. During explantation of a HeartMate II (Thoratec Corp, Pleasanton, CA) left ventricular assist device (LVAD) because of infection, CorMatrix was used to repair the left ventricular apex and aorta. Three months later, a HeartWare HVAD (HeartWare International, Inc, Framingham, MA) was implanted for recurrent heart failure. Excised apical CorMatrix samples showed cardiac tissue remodeling with viable cardiomyoblasts similar to native myocardium. Excised CorMatrix from the aorta showed organization of collagen and elastin similar to native aortic tissue. PMID- 28838517 TI - Ruptured Papillary Muscles After Chordae-Preserving Bioprosthetic Mitral Valve Replacement. AB - Bioprosthetic valve-associated masses in the perioperative period are rare. This report describes the case of a 68-year-old man with perivalvular masses that were initially discovered on a routine postoperative transthoracic echocardiogram 7 days after chordae-preserving mitral valve replacement and coronary artery bypass grafting. An intraoperative transesophageal echocardiogram demonstrated ruptured papillary muscles. This case report describes the differential diagnosis and surgical management of this rare finding. PMID- 28838518 TI - Midventricular Obstruction Caused by Abnormal Intra-Left Ventricular Septum and Papillary Muscles. AB - Abnormal papillary muscle is a rare cause of midventricular obstruction. In this case report, hypertrophied abnormal papillary muscles and abnormal tissue growth from the septal wall formed an intra-left ventricular septum with a small hole and resulted in severe midventricular obstruction. Radical resection of both papillary muscles and the intra-left ventricular septum was performed along with mitral valve replacement to relieve the obstruction. PMID- 28838519 TI - Unusual Cause of Life-Threatening Hemoptysis During Cardiac Operation: Surgical Management Revisited. AB - The surgical management of life-threatening perioperative hemoptysis has been vastly replaced by radiologic embolization. In some situations, surgical therapy can prove useful. This case report describes life-threatening hemoptysis of an unusual cause during coronary artery bypass grafting, managed through an original technique of temporary pulmonary vascular exclusion by thoracotomy. PMID- 28838520 TI - Surgical Repair for the Treatment of Pulmonary Vein Stenosis After Radiofrequency Ablation. AB - Radiofrequency ablation procedures for atrial fibrillation are occasionally associated with pulmonary vein stenosis (PVS). A common treatment for PVS is catheter intervention; however, because of the high restenosis rate, it is not suitable for young patients. The case presented herein is of a young male patient with severe bilateral PVS who underwent successful surgical pulmonary vein repair by sutureless technique. The stenotic lesions of the pulmonary veins were dissected and were covered using autologous pericardium. An enhanced computed tomographic scan revealed that all the pulmonary veins were widely patent after 6 months from the operation. PMID- 28838521 TI - Aortic Valve Replacement as a Trigger of Atypical Hemolytic Uremic Syndrome. AB - Mechanical hemolysis is a frequent but usually harmless complication of aortic valve replacement. The most common reason is valvular leakage. This report presents atypical hemolytic uremic syndrome (aHUS) as an alternative cause of mechanical hemolysis after this procedure. aHUS is a complement-mediated disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. It necessitates immediate specific treatment including plasma exchange or complement inhibition to avoid an adverse outcome. The present case identifies aortic valve replacement as a trigger of aHUS and shows that this disease must be taken into account in the differential diagnosis of hemolysis after valve surgery. PMID- 28838522 TI - Resection of a Giant Cardiac Lymphovenous Malformation Involving the Right Atrioventricular Groove. AB - Lymphovenous malformations of the heart are rare, and optimal management is uncertain. We present a case of a 39-year-old gentleman with a giant symptomatic lymphovenous malformation involving the right atrium, ventricle, and coronary artery. Radical resection was performed with replacement of the tricuspid valve and bovine pericardial reconstruction of the atrium and ventricle. Additional coronary artery bypass grafting was performed to the acute marginal and distal right coronary artery. Radical resection for this benign process is feasible and may be considered given the possibility of recurrence seen with lymphatic malformations of other parts of the body. PMID- 28838523 TI - Novel Surgical Technique for Coronary Fistulas With Proximal Origin. AB - Postoperative residual shunting is a significant concern in patients with coronary arteriovenous fistulas, especially in fistulas originating from the proximal left coronary artery, because of the limited surgical field. We report a case of fistulas originating from the proximal coronary artery in a 63-year-old woman in whom the ascending aorta and pulmonary artery were transected to obtain good surgical exposure. After complete transection of both great arteries, fistulas arising from the left main trunk were ligated externally, and their intracardiac openings were closed internally. Postoperative examination revealed no residual shunt flow. PMID- 28838524 TI - Aborted Sudden Cardiac Death After Unroofing of Anomalous Left Coronary Artery. AB - We describe a patient with anomalous left coronary artery with a short intramural course and a previously unrecognized myocardial bridge who presented with a recurrent episode of aborted sudden cardiac death. Intravascular ultrasound and fractional flow reserve showed significant compression at the left coronary artery ostium by the intercoronary pillar and at the myocardial bridge. Intravascular ultrasound and fractional flow reserve were normal after coronary translocation and unroofing of the myocardial bridge. All potential anatomic culprits should be addressed when operating on patients with anomalous coronaries. PMID- 28838525 TI - Surgical Angioplasty of Stenotic Left Main Coronary Artery 15 Years After ALCAPA Repair. AB - Studies regarding long-term results after repair of anomalous left main coronary artery from the pulmonary artery (ALCAPA) have mainly focused on survival rates, left ventricular function, and mitral valve function. The development of left main coronary stenosis following repair has been infrequently reported and its incidence unknown. Optimal therapy is also not known. Here we report the use of surgical angioplasty to achieve revascularization of a stenotic left main coronary artery in a patient with ALCAPA who had undergone coronary transfer 15 years earlier. PMID- 28838526 TI - Congenital Left Ventricular Diverticulum Complicated by Ventricular Fibrillation. AB - Congenital left ventricular diverticulum (CLVD) is a rare congenital anomaly and may be associated with fatal adverse events. A previously healthy 20-year-old man collapsed as a result of sudden ventricular fibrillation (VF). Despite intractable VF, he had return of spontaneous circulation with cardiopulmonary resuscitation and subsequent introduction of venoarterial extracorporeal membrane oxygenation (ECMO). After ECMO was discontinued, cardiac magnetic resonance imaging revealed CLVD at the posterolateral wall of the left ventricle. Given the risk of recurrent VF and left ventricular rupture, he underwent surgical repair for CLVD and implantation of a subcutaneous implantable cardioverter defibrillator. PMID- 28838527 TI - Aortic Dissection After the Hybrid Stage 1 Procedure: Diagnosis and Management Strategy. AB - Hybrid Norwood palliation is gaining acceptance as an alternative to open Norwood palliation in high-risk neonates with hypoplastic left heart syndrome. Aortic dissection after hybrid Norwood palliation is a rare but ominous complication that has not been reported. PMID- 28838528 TI - Cardiac Lymphangioma Encasing Right Coronary Artery in an Infant. AB - Cardiac lymphangioma is a rare primary benign tumor of the heart. We report a 3 year-old with cystic lymphangioma encasing the right coronary artery. Cardiac magnetic resonance imaging confirmed a intra-pericardial heterogeneous mass measuring 2.6 * 2.4 * 3.9 cm and situated right anterolateral to the ascending aorta and extending into the right atrioventricular groove. Furthermore, the right coronary artery traversed through the center of the mass. Surgical resection, on cardiopulmonary bypass, consisted of excision by skeletonizing the right coronary artery along the length of the mass. The pathology report was consistent with a lymphatic malformation. The postoperative course was uneventful without recurrence at follow-up. PMID- 28838529 TI - Primary Mediastinal Undifferentiated Carcinoma Mimicking Type B Aortic Intramural Hematoma. PMID- 28838530 TI - Isolated Infective Endocarditis of the Left Ventricular Outflow Tract and Multiple Septic Embolisms. PMID- 28838531 TI - Ascending Aortic Pseudoaneurysm as an Unusual Cause of Superior Vena Cava Syndrome. PMID- 28838532 TI - Repair of Partial Pulmonary Artery Sling in a Symptomatic Adolescent. PMID- 28838533 TI - Surgical Management of Caseous Calcification of the Mitral Annulus. AB - Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annular calcification; it can manifest with conduction abnormalities or systemic embolization. It typically involves the posterior mitral annulus, and surgery is indicated for severe mitral valve dysfunction, for embolic complications or when the diagnosis is not certain. We describe a structured approach to the surgical management of CCMA using bovine pericardium to repair the defect. PMID- 28838534 TI - True Lumen Perfusion Technique for Extensive Aortic Dissections Involving the Neck and Femoral Vessels. AB - Cannulation and perfusion in extensive aortic dissection involving the neck and femoral vessels is challenging in view of false lumen cannulation and attendant malperfusion syndromes. Although a number of methods have been described, our technique of cannulation and perfusion through right atrial-to-left atrial bypass and innominate artery transection ensures adequate brain perfusion and visceral organ true lumen perfusion during the entire duration of cardiopulmonary bypass. This procedure can be applied to all varieties of extensive type A aortic dissections involving the neck and femoral vessels. A step-by-step of how to do it has been described. PMID- 28838535 TI - Zone 2 Arch Replacement and Staged Thoracic Endovascular Aortic Repair for Acute Type A Aortic Dissection. AB - Potential benefits of extending the distal extent of repair for acute type A aortic dissection beyond hemiarch has prompted the exploration of various total arch repair approaches. A zone 2 arch is advocated by some surgeons but the nomenclature and technique have not been described. PMID- 28838536 TI - Transcatheter Valve Implantation in Mitral Annular Calcification During Open Surgery: Extended Collar Technique. AB - We describe an improvised technique during open surgery of inserting a transcatheter heart valve in the mitral position under very challenging circumstances. This is the first described use of the "extended collar" technique, which allowed implantation of a transcatheter heart valve in severe mitral valve annular calcification, into which a surgical valve could not safely be implanted. We believe that this technique is reproducible and may be helpful to other surgeons when faced with similar difficult circumstances. PMID- 28838537 TI - Regulation of Autophagy by MiRNAs and Their Emerging Roles in Tumorigenesis and Cancer Treatment. AB - Autophagy is a conserved catabolic process for the degradation and recycling of cytosolic components or organelles through a lysosome-dependent pathway. Autophagy can be induced in response to multiple stress conditions, such as nutrient deprivation, hypoxia, energy depletion, etc. As a result, autophagy can regulate many biological processes, including cell survival, metabolism, differentiation, senescence, and cell death. MicroRNAs (MiRNAs) are small noncoding molecules that regulate gene expression by silencing mRNA targets. MiRNA dysregulation exhibits great regulatory potential during organismal development, hematopoiesis, immunity, cell proliferation and death, and autophagy. Recently, increasing studies have linked MiRNAs to autophagic regulation during cancer initiation and development. Although the relationship between MiRNAs and autophagy is quite complicated and has not been well elucidated, MiRNAs may underlie key aspects of autophagy and cancer biology. Increasing evidence shows that MiRNAs play important roles as both oncogenic MiRNAs and tumor suppressive MiRNAs in cancer initiation and development. Thus, understanding the novel relationship between MiRNAs and autophagy may allow us to develop promising cancer biomarkers and therapeutic targets. PMID- 28838538 TI - Senescence-Associated MicroRNAs. AB - Senescent cells arise as a consequence of cellular damage and can have either a detrimental or advantageous impact on tissues and organs depending on the specific cell type and metabolic state. As senescent cells accumulate in tissues with advancing age, they have been implicated in many age-related declines and diseases. The major facets of senescence include two pathways responsible for establishing and maintaining a senescence program, p53/CDKN1A(p21) and CDKN2A(p16)/RB, as well as the senescence-associated secretory phenotype. Numerous MicroRNAs influence senescence by modulating the abundance of key senescence regulatory proteins, generally by lowering the stability and/or translation of mRNAs that encode such factors. Accordingly, understanding the molecular mechanisms by which MicroRNAs influence senescence will enable diagnostic and therapeutic opportunities directed at senescent cells. Here, we review senescence-associated (SA)-MicroRNAs and discuss their implications in senescence-relevant pathologies. PMID- 28838539 TI - MiRNA Deregulation in Cardiac Aging and Associated Disorders. AB - The prevalence of age-related diseases is increasing dramatically, among which cardiac disease represents the leading cause of death. Aging of the heart is characterized by various molecular and cellular hallmarks impairing both cardiomyocytes and noncardiomyocytes, and resulting in functional deteriorations of the cardiac system. The aging process includes desensitization of beta adrenergic receptor (betaAR)-signaling and decreased calcium handling, altered growth signaling and cardiac hypertrophy, mitochondrial dysfunction and impaired autophagy, increased programmed cell death, low-grade inflammation of noncanonical inflammatory cells, and increased ECM deposition. MiRNAs play a fundamental role in regulating the processes underlying these detrimental changes in the cardiac system, indicating that MiRNAs are crucially involved in aging. Among others, MiR-34, MiR-146a, and members of the MiR-17-92 cluster, are deregulated during senescence and drive cardiac aging processes. It is therefore suggested that MiRNAs form possible therapeutic targets to stabilize the aged failing myocardium. PMID- 28838540 TI - MicroRNA Dysregulation in Aging and Pathologies of the Skeletal Muscle. AB - Skeletal muscle is one of the biggest organs of the body with important mechanistic and metabolic functions. Muscle homeostasis is controlled by environmental, genetic, and epigenetic factors. Indeed, MiRNAs, small noncoding RNAs robust regulators of gene expression, have and have been shown to regulate muscle homeostasis on several levels: through controlling myogenesis, muscle growth (hypertrophy) and atrophy, as well as interactions of muscle with other tissues. Given the large number of MiRNA target genes and the important role of MiRNAs in most physiological processes and various diseases, MiRNAs may have an enormous potential as therapeutic targets against numerous disorders, including pathologies of muscle. The purpose of this review is to present the current knowledge of the role of MiRNAs in skeletal muscle homeostasis and pathologies and the potential of MiRNAs as therapeutics for skeletal muscle wasting, with particular focus on the age- and disease-related loss of muscle mass and function. PMID- 28838541 TI - Molecular Regulation of Cellular Senescence by MicroRNAs: Implications in Cancer and Age-Related Diseases. AB - Cellular senescence is a tumor suppressor response that acts as a barrier to cancer development and progression. In normal cells, diverse stimuli, including excessive mitogenic signaling, DNA damage or telomere shortening, trigger a senescence response characterized by stable growth arrest. Cellular senescence is orchestrated by tumor suppressor pathways, which have to be inactivated in order to impair the establishment of senescence and promote cancer. Consequently, by overcoming or bypassing this cellular response, cancer cells evade cell cycle checkpoint control leading to genomic instability and uncontrolled proliferation. MicroRNAs (MiRs) have emerged as essential factors contributing to or preventing cellular senescence. Here we detail the molecular mechanisms underlying the fine tuning of cellular senescence signals by MiRs, and how the senescence response itself contributes to modulation of MiR expression, with a special focus on cancer and pathologies associated with aging. PMID- 28838542 TI - MicroRNAs in Neurodegenerative Diseases. AB - MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level in a sequence-specific manner. After their discovery in 1993, mounting data have provided compelling evidence for their causal involvement in several human diseases, such as cancer and disorders of the brain. MicroRNAs have been described as the main regulator of homeostasis in neurons, and their dysregulation results in pathological conditions in the brain. In this review, we will focus on the role of MicroRNAs as novel drug targets and biomarkers of the three main neurodegenerative disorders (Alzheimer's disease, Parkinson's diseases, and Huntington's disease) and their role in other neurological disorders including traumatic brain injury and status epilepticus. PMID- 28838544 TI - Arrhythmias in the History: Lovesickness. AB - Lovesickness has been termed a real disorder, with a specific cause, pathogenesis, and cure: it has been attested to in the medical literature since classical times and may still have a place in current medicine in the frame of psychiatry and humoral disorders. Although in different cultures there is a general agreement on the symptoms, including fever, agitation, loss of appetite, headache, rapid breathing, and palpitations, the treatments vary greatly in the various cultural contexts. PMID- 28838545 TI - General Introduction, Classification, and Electrocardiographic Diagnosis of Cardiac Arrhythmias. AB - The conduction system includes a primary pacemaker, the internodal tracts, the atrioventricular node, and the His bundle with the right and left branches. In "emergency" conditions, accessory pacemakers may be triggered. The conduction system produces very low-intensity currents; a surface electrocardiogram (ECG) detects only the big myocardial masses. Electrogenetic mechanisms are reduced automaticity and/or impaired conduction at the base of bradycardias. An increased automaticity and/or reentry phenomenon are at the base of ectopic beats and tachycardias. A "wide QRS" is a ventricular activation time of 120 milliseconds or more. The "laddergram" helps in the fast and reliable ECG interpretation. PMID- 28838546 TI - P Wave and the Substrates of Arrhythmias Originating in the Atria. AB - The sinus node is the primary cardiac pacemaker from which the wavefront of activation proceeds through bundles of atrial fibers to the atrioventricular node. Left atrial activation proceeds along the Bachmann bundle and lower right atrium, determining P-wave morphology. Electrocardiogram reveals ectopic or retrograde atrial activation, wandering pacemaker activity, or artificial pacemaker-mediated atrial depolarization. Vectorcardiography and transesophageal recording are complementary methods. Atrial anatomic structure and automatic cells outside the sinus node constitute the mechanisms of focal and reentrant atrial arrhythmias. Arrhythmias with specific arrhythmogenic mechanisms correspond to precise electrocardiographic morphology for accurate diagnosis. PMID- 28838547 TI - Arrhythmias Originating in the Atria. AB - Atrial flutter, atrial tachycardias, and atrial fibrillation are the main sustained atrial tachycardias. Reentry, increased automaticity, and triggered activity are atrial arrhythmia's main mechanisms. Atrial flutter is the clinical and theoretical model of reentry. Its classification is based on the atrial chamber involved and the arrhythmia's anatomic path. Ablative procedures for atrial fibrillation have created several new reentrant tachycardias. Electrocardiography (ECG) identifies the site of origin of focal atrial tachycardias and the mechanism of these arrhythmias. ECG is fundamental in the diagnosis of atrial fibrillation and often allows understanding of its mechanism of origin and maintenance. PMID- 28838548 TI - PR Interval and Junctional Zone. AB - The atrioventricular junction is a pivotal component of the cardiac conduction system, a key electrical relay site between the atria and the ventricles. The sophisticated functions carried out by the atrioventricular junction are possible for the presence of a complex apparatus made of specialized anatomic structures, cells with specific ion-channel expression, a well-organized spatial distribution of intercellular junctions (connexins), cells with intrinsic automatism, and a rich autonomic innervation. This article reviews the main anatomic and electrophysiologic features of the atrioventricular junction, with a focus on cardiac preexcitation. PMID- 28838549 TI - Arrhythmias Involving the Atrioventricular Junction. AB - The atrioventricular junction has a central role in electrophysiology, responsible for reentrant and automatic forms of supraventricular tachycardia. During atrioventricular nodal reentry tachycardia, the circuit involves 2 electrophysiologically separate pathways located in the vicinity of the atrioventricular node. Atrioventricular reentry tachycardia is caused by the presence of an accessory pathway located almost anywhere along the atrioventricular groove; the macroreentrant circuit involves the atrioventricular node, the accessory pathway and necessarily portions of atria and ventricles. Junctional tachycardia is a rare form of nonparoxysmal supraventricular tachycardia, secondary to enhanced automaticity or triggered activity. By analyzing a 12-lead electrocardiogram during sinus rhythm and tachycardia, it is possible to accurately diagnose the specific type of supraventricular tachycardia. PMID- 28838550 TI - The QRS Complex: Normal Activation of the Ventricles. AB - The ventricular conduction system starts below the His bundle, where it bifurcates into the right and left bundle branches that taper out to the subendocardial Purkinje network, which activates the ventricular myocardium. This system is responsible for the synchronized and almost simultaneous activation of both ventricles. On the surface electrocardiogram, the ventricular conduction system lies in the terminal portion of the PR interval, whereas the QRS complex composed of the electrical currents originating from ventricular depolarization. This article reviews the main electroanatomic features of the ventricular conduction system and the effects of its delay on the QRS. PMID- 28838551 TI - General Approach to a Wide QRS Complex. AB - Wide QRS complex is present when the normal activation pattern is modified by various mechanisms and clinical conditions. Correct interpretation is crucial for appropriate decision making. When approaching an electrocardiogram (ECG) with wide complex tachycardia, one must differentiate between ventricular tachycardia and supraventricular tachycardia conducted with aberrancy. ECG criteria are used and algorithms developed to aid in differential diagnosis. They are based on finding ECG signs of ventriculoatrial dissociation and QRS morphologies inconsistent with classic bundle branch block. The conditions able to modify structurally the normal activation of the heart may alter spontaneous ventricular activation during supraventricular tachycardia, creating differential diagnosis problems. PMID- 28838543 TI - A Macro View of MicroRNAs: The Discovery of MicroRNAs and Their Role in Hematopoiesis and Hematologic Disease. AB - MicroRNAs (MiRNAs) are a class of endogenously encoded ~22 nucleotide, noncoding, single-stranded RNAs that contribute to development, body planning, stem cell differentiation, and tissue identity through posttranscriptional regulation and degradation of transcripts. Given their importance, it is predictable that dysregulation of MiRNAs, which target a wide variety of transcripts, can result in malignant transformation. In this review, we explore the discovery of MiRNAs, their mechanism of action, and the tools that aid in their discovery and study. Strikingly, many of the studies that have expanded our understanding of the contributions of MiRNAs to normal physiology and in the development of diseases have come from studies in the hematopoietic system and hematologic malignancies, with some of the earliest identified functions for mammalian MiRNAs coming from observations made in leukemias. So, with a special focus on the hematologic system, we will discuss how MiRNAs contribute to differentiation of stem cells and how dysregulation of MiRNAs contributes to the development of malignancy, by providing examples of specific MiRNAs that function as oncogenes or tumor suppressors, as well as of defects in MiRNA processing. Finally, we will discuss the promise of MiRNA-based therapeutics and challenges for the future study of disease-causing MiRNAs. PMID- 28838552 TI - Normal Ventricular Repolarization and QT Interval: Ionic Background, Modifiers, and Measurements. AB - The QT interval on surface electrocardiogram represents the sum of depolarization and repolarization process of the ventricles. The ventricular recovery process, reflected by ST segment and T wave, mainly depends on the transmembrane outward transport of potassium ions to reestablish the endocellular electronegativity. Outward potassium channels represent a heterogeneous family of ionic carriers, whose global kinetics is modulated by heart rate and autonomic nervous activity. Several cardiac and noncardiac drugs and disease conditions, and several mutations of genes encoding ionic channels, generating distinct genetic channellopathies, may affect the ventricular repolarization, provoke QT interval prolongation and shortening, and increase the susceptibility to ventricular arrhythmias. PMID- 28838553 TI - On the Shoulder of Giants. PMID- 28838554 TI - Normal Electrophysiology, Substrates, and the Electrocardiographic Diagnosis of Cardiac Arrhythmias. PMID- 28838555 TI - Distinct effects of dietary flax compared to fish oil, soy protein compared to casein, and sex on the renal oxylipin profile in models of polycystic kidney disease. AB - Oxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFA) that are important regulators of kidney function and health. Targeted lipidomic analyses of renal oxylipins from four studies of rodent models of renal disease were performed to investigate the differential effects of dietary flax compared to fish oil, soy protein compared to casein, and sex. Across all studies, dietary fish oil was more effective than flax oil in reducing n-6 PUFA derived oxylipins and elevating eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived oxylipins, whereas dietary flax oil resulted in higher alpha-linolenic acid (ALA) oxylipins. Dietary soy protein compared to casein resulted in higher linoleic acid (LA) derived oxylipins. Kidneys from females had higher levels of arachidonic acid (AA) oxylipins, but similar or lower levels of oxylipins from other PUFA. Modulation of the oxylipin profile by diet and sex may help elucidate their effects on renal physiology and health. PMID- 28838556 TI - Eicosapentaenoic acid (EPA) vs. Docosahexaenoic acid (DHA): Effects in epididymal white adipose tissue of mice fed a high-fructose diet. AB - BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated to be beneficial for many diseases, including those associated with the metabolic syndrome (e.g. insulin resistance and hypertension). Nevertheless, not only their actions are not entirely understood, but also their only effects were not yet elucidated. Therefore, we aimed to compare the effects of EPA and DHA, alone or in combination, on the epididymal white adipose tissue (WAT) metabolism in mice fed a high-fructose diet. METHODS: 3-mo-old C57Bl/6 mice were fed a control diet (C) or a high-fructose diet (HFru). After three weeks on the diets, the HFru group was subdivided into four new groups for another five weeks: HFru, HFru+EPA, HFru+DHA, and HFru-EPA+DHA (n=10/group). Besides evaluating biometric and metabolic parameters of the animals, we measured the adipocyte area and performed molecular analyses (inflammation and lipolysis) in the epididymal WAT. RESULTS: The HFru group showed adipocyte hypertrophy, inflammation, and uncontrolled lipolysis. The treated animals showed a reversion of adipocyte hypertrophy, inhibition of inflammation with activation of anti-inflammatory mediators, and regularization of lipolysis. Overall, the beneficial effects were more marked with DHA than EPA. CONCLUSION: Although the whole-body metabolic effects were similar between EPA and DHA, DHA appeared to be the central actor in WAT metabolism, modulating pro and anti-inflammatory pathways and alleviating adipocytes abnormalities. Therefore, when considering fructose-induced adverse effects in WAT, the most prominent actions were observed with DHA. PMID- 28838557 TI - Fads3 modulates docosahexaenoic acid in liver and brain. AB - Fatty acid desaturase 3 (FADS3) is the third member of the FADS gene cluster. FADS1 and FADS2 code for enzymes required for highly unsaturated fatty acid (HUFA) biosynthesis, but FADS3 function remains elusive. We generated the first Fads3 knockout (KO) mouse with an aim to characterize its metabolic phenotype and clues to in vivo function. All mice (wild type (WT) and KO) were fed facility rodent chow devoid of HUFA. No differences in overt phenotypes (survival, fertility, growth rate) were observed. Docosahexaenoic acid (DHA, 22:6n-3) levels in the brain of postnatal day 1 (P1) KO mice were lower than the WT (P < 0.05). The ratio of docosapentaenoic acid (DPA, 22:5n-3) to DHA in P1 KO liver was higher than in WT suggesting lower desaturase activity. Concomitantly, 20:4n-6 was lower but its elongation product 22:4n-6 was greater in the liver of P1 KO mice. P1 KO liver Fads1 and Fads2 mRNA levels were significantly downregulated whereas expression levels of elongation of very long chain 2 (Elovl2) and Elovl5 genes were upregulated compared to age-matched WT. No Delta13-desaturation of vaccenic acid was observed in liver or heart in WT mice expressing FADS3 as was reported in vitro. Taken together, the fatty acid compositional results suggest that Fads3 enhances liver-mediated 22:6n-3 synthesis to support brain 22:6n-3 accretion before and during the brain growth spurt. PMID- 28838558 TI - Reply to: Late-Life Depression, Cortisol, and the Hippocampus: On the Need to Consider Depressive, Hippocampal, and Pharmacological Complexities. PMID- 28838559 TI - Late-Life Depression, Cortisol, and the Hippocampus: On the Need to Consider Depressive, Hippocampal, and Pharmacological Complexities. PMID- 28838560 TI - Skin Tumors Arising on Chronic Lymphedema. PMID- 28838561 TI - Psoriasis-Arthritis Units: Three Years on. PMID- 28838562 TI - Disseminate recurrent folliculitis as the presenting picture of hidradenitis suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) has a polymorphous clinical presentation. Herein we report two cases of HS revealed by disseminate recurrent folliculitis. PATIENTS AND METHODS CASE 1: A 31-year-old woman consulted for disseminate recurrent folliculitis on the trunk and proximal segments of the limbs that had been ongoing for several years. No other cutaneous lesions were seen, particularly in the classic area for HS lesions. Weight loss and treatment with azithromycin 500mg/day resulted in complete remission, but relapse occurred on dosage reduction. CASE 2: The elder sister of patient 1, who was also obese and 10 years her senior, presented a similar clinical history, although in addition, she was presenting lesions characteristic of HS on her armpits and inguinal folds; further, she had undergone an operation 3 years earlier for pilonidal sinus. Three months of combined treatment with rifampicin and clindamycin 900 mg/day followed by long-term doxycycline 200mg/day resulted in marked improvement. DISCUSSION: Disseminate folliculitis is not infrequent during the course of HS; it forms part of the clinical picture and is particularly common in the follicular phenotypic variant; however, it is not part of the diagnostic criteria as defined consensually by the Hidradenitis Suppurativa Foundation. The cases we report suggest that a setting of disseminate recurrent folliculitis may constitute the mode of presentation of HS, and may even represent an atypical monosymptomatic form of HS. CONCLUSION: Disseminate recurrent folliculitis constitutes part of the clinical picture of HS; if it is isolated, screening should be performed for personal or familial signs of HS. PMID- 28838563 TI - A volumetric technique for fossil body mass estimation applied to Australopithecus afarensis. AB - Fossil body mass estimation is a well established practice within the field of physical anthropology. Previous studies have relied upon traditional allometric approaches, in which the relationship between one/several skeletal dimensions and body mass in a range of modern taxa is used in a predictive capacity. The lack of relatively complete skeletons has thus far limited the potential application of alternative mass estimation techniques, such as volumetric reconstruction, to fossil hominins. Yet across vertebrate paleontology more broadly, novel volumetric approaches are resulting in predicted values for fossil body mass very different to those estimated by traditional allometry. Here we present a new digital reconstruction of Australopithecus afarensis (A.L. 288-1; 'Lucy') and a convex hull-based volumetric estimate of body mass. The technique relies upon identifying a predictable relationship between the 'shrink-wrapped' volume of the skeleton and known body mass in a range of modern taxa, and subsequent application to an articulated model of the fossil taxa of interest. Our calibration dataset comprises whole body computed tomography (CT) scans of 15 species of modern primate. The resulting predictive model is characterized by a high correlation coefficient (r2 = 0.988) and a percentage standard error of 20%, and performs well when applied to modern individuals of known body mass. Application of the convex hull technique to A. afarensis results in a relatively low body mass estimate of 20.4 kg (95% prediction interval 13.5-30.9 kg). A sensitivity analysis on the articulation of the chest region highlights the sensitivity of our approach to the reconstruction of the trunk, and the incomplete nature of the preserved ribcage may explain the low values for predicted body mass here. We suggest that the heaviest of previous estimates would require the thorax to be expanded to an unlikely extent, yet this can only be properly tested when more complete fossils are available. PMID- 28838564 TI - Psychiatric Emergencies for Clinicians: Emergency Department Management of Cocaine-Related Presentations. PMID- 28838565 TI - A Case of Methemoglobinemia Successfully Treated with Hyperbaric Oxygenation Monotherapy. AB - BACKGROUND: Methylene blue is the first-line therapy for methemoglobinemia, but it can be intermittently unavailable due to production issues. For this clinical scenario, alternative treatment options need to be explored. Hyperbaric oxygenation (HBO) is conventionally applied as an adjunctive therapy during the systemic administration of methylene blue. Currently, little is known regarding the effects of HBO monotherapy in methemoglobinemia. We report a case of methemoglobinemia that was successfully treated with HBO monotherapy. CASE REPORT: A 41-year-old man presented to the Emergency Department with dyspnea and dizziness subsequent to smoking in a garage filled with motor vehicle exhaust gas. There were no abnormal heart or lung sounds. While administering oxygen flowing at 15 L/min via a mask with a reservoir bag, blood tests revealed high methemoglobin (MetHb) levels at 59.6%. He was treated with HBO monotherapy, and sequential tests showed that the MetHb level decreased significantly to 34.0%, 12.8%, 6.2%, and eventually, 3.5%. He was discharged with stable vital signs the next day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: HBO monotherapy is an effective alternative treatment for methemoglobinemia when methylene blue is not available. PMID- 28838566 TI - Missing grafts and the potential for inappropriate revascularization. AB - The best outcome for coronary intervention in coronary artery bypass graft patients requires knowledge of prior coronary anatomy. This information is not always available as many cases present acutely, especially in ST-elevation myocardial infarction. We present three cases in which bypass grafts were documented as occluded but follow-up angiograms for other reasons revealed that the grafts were still patent. This presents the potential for inappropriate revascularizations. PMID- 28838567 TI - Brief psychological intervention in patients admitted after acute coronary syndrome: Essential or secondary? PMID- 28838568 TI - Risk stratification in acute coronary syndromes: Graced by a new score? PMID- 28838569 TI - #PACHA6. PMID- 28838570 TI - (Dis)integrated Care: Barriers to Health Care Utilization for Trans Women Living With HIV. AB - Transgender (trans) women have been particularly impacted by HIV. To seek insights into the dynamics of health service utilization, interviews were conducted with trans women living with HIV (n = 14) as part of the Trans PULSE community-based research project in Ontario, Canada. Service providers (n = 10) were also interviewed to provide additional details about communication between trans women, social service providers, and clinicians. Results highlight how both problematic interactions with individuals and health systems navigation challenges affect access to services and impede the development of trans-specific HIV supports. Participants described discrimination, identified strategies for navigating a dysfunctional system, and outlined specific ways in which health and social services may be failing trans women living with HIV. Findings support the importance of coordinating HIV services and transition-related care, and providing training for service providers. PMID- 28838572 TI - Here/In This Issue and There/Abstract Thinking: The Growing, and Changing, Landscape of Child and Adolescent Mental Healthcare Delivery. PMID- 28838573 TI - "Dude-Me, Too!": The Importance of Wellness Mentorship From Day One. PMID- 28838574 TI - Teen Suicide: Fanning the Flames of a Public Health Crisis. PMID- 28838575 TI - Moving Beyond the Basics of the Binary: Addressing Mental Health Needs and Suicidality Among Transgender Youth. PMID- 28838576 TI - Understanding the Costs of Autism Services. PMID- 28838577 TI - The Effect of Physical Activity Interventions on Children's Cognition and Metacognition: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The objective was twofold: to assess the effect of physical activity (PA) interventions on children's and adolescents' cognition and metacognition; and to determine the characteristics of individuals and PA programs that enhance the development of cognitive and metacognitive functions. METHOD: We systematically searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and PsycINFO databases from their inception to October 16, 2016. Intervention studies aimed at examining the exercise-cognition interaction at a developmental age were included in this systematic review and meta-analysis. Random-effects models were used to calculate pooled effect size (ES) values and their corresponding 95% CIs. Subgroup analyses were conducted to examine the effect of participants' and PA programs' characteristics. RESULTS: A total of 36 studies were included in this systematic review and meta-analysis. Pooled ES estimations were as follows: nonexecutive cognitive functions 0.23 (95% CI = 0.09-0.37); core executive functions 0.20 (95% CI = 0.10-0.30), including working memory (0.14 [95% CI = 0.00-0.27]), selective attention-inhibition (0.26 [95% CI = 0.10-0.41]), and cognitive flexibility (0.11 [95% CI = -0.10 to 0.32]); and metacognition 0.23 (95% CI = 0.13-0.32), including higher-level executive functions (0.19 [95% CI = 0.06-0.31]) and cognitive life skills (0.30 [95% CI = 0.15-0.45]). CONCLUSION: PA benefits several domains of cognition and metacognition in youth. Curricular physical education interventions and programs aimed at increasing daily PA seem to be the most effective. PMID- 28838578 TI - Prevalence and Correlates of Suicidal Ideation Among Transgender Youth in California: Findings From a Representative, Population-Based Sample of High School Students. AB - OBJECTIVE: No representative population-based studies of youth in the United States exist on gender identity-related disparities in suicidal ideation or on factors that underlie this disparity. To address this, this study examined gender identity-related disparities in the prevalence of suicidal ideation; evaluated whether established psychosocial factors explained these disparities; and identified correlates of suicidal ideation among all youth and stratified by gender identity. METHOD: Data were derived from the 2013 to 2015 California Healthy Kids Survey (CHKS; N = 621,189) and a weighted subsample representative of the Californian student population (Biennial Statewide California Student Survey [CSS], N = 28,856). RESULTS: Prevalence of past 12-month self-reported suicidal ideation was nearly twice as high for transgender compared with non transgender youth (33.73% versus 18.85%; chi2 = 35.48, p < .001). In fully adjusted models within the representative sample, transgender youth had 2.99 higher odds (95% CI 2.25-3.98) of reporting past-year suicidal ideation compared with non-transgender youth. Among transgender youth, only depressive symptoms (adjusted odds ratio 5.44, 95% CI 1.81-16.38) and victimization (adjusted odds ratio 2.66, 95% CI 1.26-5.65) remained significantly associated with higher odds of suicidal ideation in fully adjusted models. In multiple mediation analyses, depression attenuated the association between gender identity and suicidal ideation by 17.95% and victimization by 14.71%. CONCLUSION: This study uses the first representative population-based sample of youth in the United States that includes a measurement of gender identity to report on gender identity-related disparities in suicidal ideation and to identify potential mechanisms underlying this disparity in a representative sample. PMID- 28838579 TI - National Trends in Substance Use and Use Disorders Among Youth. AB - OBJECTIVE: To examine trends in the 12-month prevalence of patterns of substance use and substance use disorders (SUDs) among US youth during 2002 through 2014. METHOD: Data were from 288,300 persons 12 to 17 years old who participated in the 2002 to 2014 National Surveys on Drug Use and Health. Descriptive analyses and bivariable and multivariable logistic regressions were applied. RESULTS: During 2002 through 2014, among US youth, the 12-month prevalence of any substance use decreased by 27.1% (from 43.2% to 31.5%); among youth users, the 12-month prevalence of SUDs decreased by 28.9% (from 27.0% to 19.2%), and the ratio of substance dependence to abuse decreased from 2.2 to 1.6. Multiple substance use was common and was associated with SUDs. During 2002 through 2014, the prevalence of using marijuana and alcohol only, using marijuana only, and having marijuana use disorders only increased, whereas most other trends were downward. Increases in age at first substance use were associated with downward trends in any substance use. Upward trends in age at first substance use, youth and parental strong disapproval of cigarette use, and youths' seatbelt-wearing prevalence and downward trends in substance use patterns were associated with the downward trend in SUDs among youth users. CONCLUSION: The 12-month prevalence of any substance use among youth and SUDs among youth users decreased during 2002 through 2014. Postponing age at first use of any substance is critical among youth in the United States. Future research is needed to better understand the interrelations between specific risk and protective factors, age at first substance use, substance use patterns, and SUDs among youth users. PMID- 28838581 TI - Cross-Domain Symptom Development Typologies and Their Antecedents: Results From the UK Millennium Cohort Study. AB - OBJECTIVE: Typologies of symptom development have been used to identify individuals with different symptom development in the externalizing and internalizing domains of child psychopathology separately despite the domains' high comorbidity and shared common etiologic risk. This study identified typologies of development jointly across the 2 symptom domains in childhood and investigated their associated antecedents with a specific focus on the comparisons between overall severity of symptoms and symptom expression in one or the other domain. METHOD: Latent class analysis identified groups based on emotional and behavioral symptoms assessed at 3, 5, 7, and 11 years in the UK Millennium Cohort Study (N = 15,439). Different sociodemographic, family structure and environment, birth, infancy, and early childhood antecedents were examined. RESULTS: Five groups were identified: 1. low symptoms (57%), 2. moderate behavioral (21%), 3. moderate emotional (12.5%), 4. high emotional and moderate behavioral (5.5%), and 5. high behavioral and moderate emotional (4%). Higher symptoms were predicted by larger numbers of antecedents and risk factors compared with the low symptom group and compared with moderate and high levels of symptoms in either domain (groups 5 versus 2 and 4 versus 3). Comparisons of groups with similar overall symptom levels but different dominant symptom domain (groups 2 versus 3 and 4 versus 5) indicated that apart from gender and ethnicity, there were few unique antecedents of whether children mainly internalize or externalize their symptoms. CONCLUSION: It is possible and useful to define groupings or typologies jointly across externalizing and internalizing symptom development in childhood. Although numerous antecedents predict the experience of symptoms, there are few unique antecedents that differentiate individuals with similarly high levels of psychopathology expressed mainly as internalizing or externalizing symptoms. Identification of at-risk children and delivery of early intervention might benefit from a decreased focus on symptom domain with possible downstream effects through the life course for most common psychiatric disorders. PMID- 28838580 TI - Trauma Exposure and Externalizing Disorders in Adolescents: Results From the National Comorbidity Survey Adolescent Supplement. AB - OBJECTIVE: Exposure to violence and other forms of potentially traumatic events (PTEs) are common among youths with externalizing psychopathology. These associations likely reflect both heightened risk for the onset of externalizing problems in youth exposed to PTEs and elevated risk for experiencing PTEs among youth with externalizing disorders. In this study, we disaggregate the associations between exposure to PTEs and externalizing disorder onset in a population-representative sample of adolescents. METHOD: We analyzed data from 13 to 18-year-old participants in the National Comorbidity Survey Replication Adolescent Supplement (NCS-A) (N = 6,379). Weighted survival models estimated hazard ratios (HRs) for onset of oppositional defiant disorder (ODD), conduct disorder (CD), and substance use disorders (SUDs) associated with PTEs, and for exposure to PTEs associated with prior-onset externalizing disorders. Multiplicative interaction terms tested for effect modification by sex, race/ethnicity, and household income. RESULTS: All types of PTEs were associated with higher risk for SUD (HRs = 1.29-2.21), whereas only interpersonal violence (HR = 2.49) was associated with onset of CD and only among females. No associations were observed for ODD. Conversely, ODD and CD were associated with elevated risk for later exposure to interpersonal violence and other/nondisclosed events (HRs = 1.45-1.75). CONCLUSION: Externalizing disorders that typically begin in adolescence, including SUDs and CD, are more likely to emerge in adolescents with prior trauma. ODD onset, in contrast, is unrelated to trauma exposure but is associated with elevated risk of experiencing trauma later in development. CD and interpersonal violence exposure exhibit reciprocal associations. These findings have implications for interventions targeting externalizing and trauma-related psychopathology. PMID- 28838582 TI - Cost Offset Associated With Early Start Denver Model for Children With Autism. AB - OBJECTIVE: To determine the effect of the Early Start Denver Model (ESDM) for treatment of young children with autism on health care service use and costs. METHOD: We used data from a randomized trial that tested the efficacy of the ESDM, which is based on developmental and applied behavioral analytic principles and delivered by trained therapists and parents, for 2 years. Parents were interviewed about their children's service use every 6 months from the onset of the intervention to follow-up (age 6 years). The sample for this study consisted of 39 children with autism who participated in the original randomized trial at age 18 to 30 months, and were also assessed at age 6 years. Of this sample, 21 children were in the ESDM group, and 18 children were in the community care (COM) group. Reported services were categorized and costed by applying unit hourly costs. Annualized service use and costs during the intervention and post intervention for the two study arms were compared. RESULTS: During the intervention, children who received the ESDM had average annualized total health related costs that were higher by about $14,000 than those of children who received community-based treatment. The higher cost of ESDM was partially offset during the intervention period because children in the ESDM group used less applied behavior analysis (ABA)/early intensive behavioral intervention (EIBI) and speech therapy services than children in the comparison group. In the postintervention period, compared with children who had earlier received treatment as usual in community settings, children in the ESDM group used less ABA/EIBI, occupational/physical therapy, and speech therapy services, resulting in significant cost savings in the amount of about $19,000 per year per child. CONCLUSION: Costs associated with ESDM treatment were fully offset within a few years after the intervention because of reductions in other service use and associated costs. CLINICAL TRIAL REGISTRATION INFORMATION: Early Characteristics of Autism; http://clinicaltrials.gov/; NCT0009415. PMID- 28838584 TI - Selfies. PMID- 28838583 TI - Oral Aripiprazole as Maintenance Treatment in Adolescent Schizophrenia: Results From a 52-Week, Randomized, Placebo-Controlled Withdrawal Study. AB - OBJECTIVE: To evaluate the efficacy, safety, and tolerability of aripiprazole, a dopamine D2 receptor partial agonist, as maintenance treatment in adolescent outpatients with schizophrenia. METHOD: This was a multicenter, double-blind, placebo-controlled, randomized withdrawal design trial. Participants 13 to 17 years of age with a diagnosis of schizophrenia (DSM-IV-TR) were first cross titrated from their other oral antipsychotic(s) (4-6 weeks), then stabilized (7 21 weeks) on oral aripiprazole 10 to 30 mg/d, and finally randomized 2:1 to continuation of oral aripiprazole or to placebo in a double-blind maintenance phase (<=52 weeks). The primary endpoint was time from randomization to exacerbation of psychotic symptoms/impending relapse. Safety and tolerability were assessed. RESULTS: Of 201 enrolled participants, 146 were randomized to aripiprazole (n = 98) or placebo (n = 48) in the double-blind maintenance phase. Treatment with aripiprazole was associated with a significantly longer time to exacerbation of psychotic symptoms/impending relapse compared with placebo (hazard ratio, 0.46 [95% CI = 0.24-0.88]; p = .016). Aripiprazole was associated with lower rates of serious treatment-emergent adverse events (TEAEs) versus placebo (3.1% versus 12.5%; p = .059) and severe TEAEs (2.0% versus 10.4%; p = .039). The rate of discontinuation due to TEAEs was lower with aripiprazole versus placebo (20.4% versus 39.6%, p = .014; number-needed-to-harm = 5.1). The incidences of extrapyramidal symptoms, weight gain, and somnolence were similar or lower with aripiprazole than with placebo, and no TEAEs related to elevated serum prolactin were reported. Based on Tanner staging, 27.6% of participants treated with aripiprazole and 16.7% of those who received placebo progressed one or two stages from baseline. CONCLUSION: Aripiprazole was observed to be safe and effective for the maintenance treatment of adolescents with schizophrenia. CLINICAL TRIAL REGISTRATION INFORMATION: Efficacy and Safety Study of Oral Aripiprazole in Adolescents With Schizophrenia; http://clinicaltrials.gov/; NCT01149655. PMID- 28838585 TI - Erratum. PMID- 28838586 TI - From the Editor's perspective.... PMID- 28838587 TI - "Intermittent claudication a real pain in the calf"-Patient experience of diagnosis and treatment with a supervised exercise program. AB - Intermittent claudication (IC) is a common condition which has severe impacts on quality of life, physical function, and mental health. Supervised exercise is the recommended first-line treatment for patients with this condition; however, these are not always feasible or accessible to patients. As the proportion of patients who have this treatment remains suboptimal, it is important to better understand the perception of exercise in this population. A gap in the literature exists about the barriers and facilitators to exercise in patients completing, dropping out of, or declining an exercise program. A qualitative analysis was undertaken to understand this further. Twenty-five patients were interviewed face to face, 10 who had completed exercise, 10 who had declined, and 5 who had dropped out of an exercise program. Three major themes emerged from the data, IC, and perception to exercise and experience or beliefs of the exercise program.Addressing the barriers and facilitators to exercise in patients with IC is crucial in optimizing the delivery and uptake of exercise programs. More education or time investment is needed with these patients during initial diagnostic to help overcome perceived barriers and emphasis healthy behavioral changes. PMID- 28838588 TI - Service provision for stroke: The Greek paradox. AB - Stroke remains a leading cause of mortality, as well as of subsequent serious long-term physical and mental morbidity. This places special demands for updated clinical excellence and optimum organization of stroke care services. Stroke units have been shown to improve patient outcomes. Thus, many western countries have developed and implemented sophisticated stroke facilities and corresponding public awareness strategies. These cannot be easily "translated" in Greece due to special features on the hospital administration system such as a unique rotation system for acute admissions and long-standing austerity. Yet, despite adverse conditions, clinicians within the Greek health care system have been exceeding themselves in their attempt to provide optimum care outcomes. An example of such efforts is the improvisation of stroke bays (SBs) as part of a medical or neurology ward, providing sophisticated treatments. New centralized policy decisions are now needed in order to improve stroke services nationwide. These should be tailored to the country's geography and health care mapping especially as there is already considerable technical knowhow and local efforts in place. A pragmatic solution would be to create a "grid" of services for stroke, by providing a comprehensive stroke centers in each of the two major cities and SBs at a prefectural level. Once these are established, more efforts should be taken to educate the public on stroke recognition and subsequently on facilities available. PMID- 28838589 TI - Early mobilization reduces the atelectasis and pleural effusion in patients undergoing coronary artery bypass graft surgery: A randomized clinical trial. AB - Atelectasis and pleural effusion are common after coronary artery bypass graft surgery (CABG). Longer stay in the bed is one of the most important contributing factors in pulmonary complications. Some studies confirm the benefits of early mobilization (EM) in critically ill patients, but the efficacy of EM on pulmonary complications after CABG is not clear. This study was designed to examine the effect of EM on the incidence of atelectasis and pleural effusion in patients undergoing CABG. In a single-blinded randomized clinical trial, 100 patients who were undergoing coronary artery bypass graft surgery were randomly assigned into two groups each consisted of 50 patients. Patients in the experimental group were enrolled in a mobilization protocol consisting of the mobilization from the bed in the first 3 days after surgery in the morning and evening. Patients in the control group were mobilized from bed in third postoperation day, according to the hospital routine. Arterial blood gases, pleural effusion, and atelectasis were compared between groups. Atelectasis and pleural effusion was reduced in experimental group. The partial pressure of oxygen in arterial blood in third postoperative day and the percentage of arterial oxygen saturation in the fourth postoperative day were higher in the intervention group (P value < .05). EM from bed could be an effective intervention in reducing atelectasis and pleural effusion in patients undergoing CABG. PMID- 28838590 TI - Infrainguinal wound infections in vascular surgery: An antiquated challenge without a modern solution. AB - Surgical site infections (SSIs) have always complicated recovery after surgery, being associated with increased cost of hospitalization, length of stay, and mortality. The most significant measure to reduce the incidence of SSI was the standardization of prophylactic antibiotic administration in patients undergoing surgical procedures. Since then, countless measures have been proposed to improve rates of SSI and patient outcome, but few have been as efficacious as prophylactic antibiotics. Therefore, SSI continues to plague clinicians and patients in modern health care. This review focuses on current and future efforts at SSI control. PMID- 28838591 TI - Effects of serum phosphorus on vascular calcification in a healthy, adult population: A systematic review. AB - Cardiovascular disease has been associated with elevated serum phosphorus levels, which have been associated with cardiovascular mortality. This is commonly seen in the chronic kidney disease (CKD) population where studies have shown that high phosphorus levels cause coronary artery calcification. Although studies have independently associated vascular stiffness and serum phosphorus in those with and without CKD, there are fewer data in individuals without CKD. Therefore, the aim of this systematic review was to analyze whether serum phosphorus levels are associated with cardiovascular calcification in healthy individuals. A systematic review of the literature that was conducted revealed 10 articles, all cross sectional studies, that met eligibility criteria. These criteria were peer reviewed studies on a healthy, adult population written in the English language. Studies lacking data on serum phosphorus and measured to assess its association with vascular calcification were excluded. Studies on subjects with CKD, other chronic diseases, or on children were also excluded. Of the 10 studies located, 8 indicated an association between serum phosphorus and vascular calcification. One study did not indicate an association. One study indicated a statistically significant association between serum phosphorus and vascular calcification prevalence, but not incidence. Studies were limited since no randomized controlled trials were available. This systematic review generates gaps in research. Due to considerable amounts of phosphorus additives in the food supply, there may be a connection to dietary phosphorus and vascular calcification. Additionally, phosphorus binders may assist in the prevention of vascular calcification but have not been studied in a healthy population. Further study on both dietary phosphorus restriction and phosphorus binders is needed. While 8 out of 10 cross-sectional studies found an association in this systematic review, the topic of vascular calcification and serum phosphorus needs further study if a cause and effect relationship is to be detected. PMID- 28838592 TI - Review of article: Feasibility and pilot efficacy of a brief smoking cessation intervention delivered by vascular surgeons in the Vascular Physician Offer and Report (VAPOR) trial. Goodney PP, Spangler EL, Newhall K, Brooke BS, Schanzer A, Tan T-W, Beck AW, Hallett JH, MacKenzie TA, Edelen MO, Hoel AW, Rigotti NA, Farber A. J Vasc Surg 2017; 65: 1152-60. PMID- 28838594 TI - Diabetes and disasters. PMID- 28838593 TI - Scientific Autobiography. PMID- 28838595 TI - Variations in hospital costs after traffic injuries: The importance of sociodemographic aspects and comorbidities. AB - OBJECTIVE: The impact of sociodemographic aspects and comorbidities on the inpatient hospital care costs of traffic victims are not clear. The main goal of this study is to provide insights into the sociodemographic characteristics and clinical conditions (including comorbidities) of the victims that result in higher hospital costs. PARTICIPANTS: For the period 2009-2011, people admitted to a hospital as a result of a road traffic crash (N=64,304) were identified in the national Minimal Hospital Dataset, after which they were linked to their respective claims data from the sickness funds. METHODS: A generalized linear model was used to analyse hospital costs controlling for roadway user categories, demographics (gender, age, individual socioeconomic status (SES)), and clinical factors (the nature, location, and severity of injury, and comorbidities). RESULTS: The median hospital cost was ? 2801 (IQR ? 1510-? 7175, 2015 Euros). There was no significant difference between gender. Low SES inpatients incurred 16% (95% CI: 14%-18%) higher hospital costs than inpatients of high SES. The presence of comorbidities was associated with an increased hospital cost, however with varying magnitude. For example traffic victims suffering from dementia incur significantly higher hospital costs than those who were not (49% higher, 95% CI: 44%-53%), whereas diabetes was associated with a smaller increase in costs compared to non-diabetics (13%, 95% CI: 10%-16%). CONCLUSION: Comorbidities and low SES are associated with higher hospital costs for traffic victims, notwithstanding their age, and the nature and the severity of their injury. The broad variability of hospital costs among trauma inpatients should be accounted for when reconsidering financing models. Furthermore, the strong predictive value of some comorbidities and SES on hospital costs should be considered when projections of future health care utilisation in traffic safety scenarios are prepared. PMID- 28838596 TI - Nonlinearity and asymptotic behaviours: Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida and Nisrine Outada. PMID- 28838597 TI - Myofascial force transmission in the lower limb: An in vivo experiment. AB - Anatomical studies have shown structural continuity between the lumbopelvic region and the lower limb. The present study aimed to verify how simultaneous changes on knee/hip positions modify the ankle's resting position and passive torque. Thirty-seven subjects underwent an isokinetic assessment of ankle passive torque. The relationship between the absolute values of ankle passive resistance torque and the ankle angular position was used to calculate the dependent variables: ankle resting position (position in which the passive resistance torque is zero); and ankle passive torque at 0 degrees (torque at the neutral position of the ankle in the sagittal plane). These measures were carried out under three test conditions: 0 degrees at knee and 0 degrees at hip (0 degrees /0 degrees ); 90 degrees at knee and 90 degrees at hip (90 degrees /90 degrees ); and, 135 degrees at knee and 120 degrees at hip (135 degrees /120 degrees ). The results demonstrated that the ankle resting position shifted towards dorsiflexion when knee/hip position changed from 0 degrees /0 degrees to 90 degrees /90 degrees and shifted towards plantar flexion when knee/hip position changed from 90 degrees /90 degrees to 135 degrees /120 degrees , achieving values close to the ones at the position 0 degrees /0 degrees . Similarly, passive torque reduced when knee/hip position changed from 0 degrees /0 degrees to 90 degrees /90 degrees , but it increased when knee/hip position changed from 90 degrees /90 degrees to 135 degrees /120 degrees . The unexpected changes observed in ankle passive torque and resting position due to changes in knee and hip from 90 degrees /90 degrees to 135 degrees /120 degrees , cannot be explained exclusively by forces related to tissues crossing the knee and ankle. This result supports the existence of myofascial force transmission among lower limb joints. PMID- 28838598 TI - Additional tools to improve the follow up after bariatric surgery. PMID- 28838600 TI - Social and Emotional Learning. PMID- 28838599 TI - Geospatial risk assessment and trace element concentration in reef associated sediments, northern part of Gulf of Mannar biosphere reserve, Southeast Coast of India. AB - Fifty two surface sediments were collected from the northern part of the Gulf of Mannar biosphere reserve to assess the geospatial risk of sediments. We found that distribution of organic matter and CaCO3 distributions were locally controlled by the mangrove litters and fragmented coral debris. In addition, Fe and Mn concentrations in the marine sediments were probably supplied through the riverine input and natural processes. The Geo-accumulation of elements fall under the uncontaminated category except Pb. Lead show a wide range of contamination from uncontaminated-moderately contaminated to extremely contaminated category. The sediment toxicity level of the elements revealed that the majority of the sediments fall under moderately to highly polluted sediments (23.07-28.84%). The grades of potential ecological risk suggest that predominant sediments fall under low to moderate risk category (55.7-32.7%). The accumulation level of trace elements clearly suggests that the coral reef ecosystem is under low to moderate risk. PMID- 28838601 TI - Fetal Alcohol Spectrum Disorders: What Pediatric Providers Need to Know. AB - Prenatal alcohol exposure is the cause of fetal alcohol spectrum disorders (FASDs), the prevalence of which is similar to that of other developmental disabilities like Down syndrome and autism. Children, adolescents, and adults who live with the disabilities associated with prenatal alcohol exposure face extraordinary challenges throughout their lives. Pediatric providers need to be able to identify patients with FASD because early recognition and intervention is known to improve life outcomes for affected individuals. The purposes of this continuing education activity are to report what is known about the prevalence of FASDs; to detail the spectrum of problems experienced by affected individuals; and to suggest specific strategies for preventing, identifying, and managing FASDs in clinical practice. PMID- 28838602 TI - Impact of Cigarette Smoking and Smoking Cessation on Stent Changes as Determined by Optical Coherence Tomography After Sirolimus Stent Implantation. AB - There is debate regarding whether smoking results in microstructural changes after stenting. The aim of this study was to evaluate the microstructural changes after stenting in patients with different smoking statuses. We retrospectively identified 220 sirolimus-eluting stents in 179 patients who underwent follow-up optical coherence tomography examination 12 months after sirolimus stenting. Subjects were classified as current smokers (CS, n = 31), smoking cessation <=1 year (n = 36), smoking cessation >1 year (SC > 1Y, n = 27), and never smokers (NS, n = 85). The neointimal hyperplasia (NIH) area was larger in CS than in NS (1.04 +/- 0.72 mm2 vs 0.96 +/- 0.68 mm2; p = 0.04). The incidence of lipid-laden neointima was lower in SC > 1Y patients (1.6%) than in all other patients (NS: 3.9%, p = 0.002; CS: 3.0%, p = 0.073; SC1Y: 5.0%, p <0.001). Smoking cessation level was negatively correlated with NIH (B = -0.154; 95% confidential interval 0.187, -0.121; p <0.001) and independently associated with the presence of homogeneous neointima (odds ratio: 1.414; 95% confidential interval 1.145, 1.745; p = 0.001). The incidence of malapposed struts was higher in CS than in NS (3.2% vs 1.6%; p = 0.004). However, smoking cessation patients showed a decreased trend in the incidence of malapposed struts (p = 0.0003). In conclusion, continued smoking increases NIH and the incidence of malapposed struts. However, smoking cessation slows down NIH progression and decreases the incidence of malapposed struts. Smoking cessation promotes vascular healing after stenting. PMID- 28838603 TI - Effect of Shorter Door-to-Balloon Times Over 20 Years on Outcomes of Patients With Anterior ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. AB - Cardiovascular disease remains the most common cause of mortality. We studied the change in outcomes for anterior ST-elevation myocardial infarction (STEMI) between 1995 and 2014. Over the past 20 years, 1,658 patients presenting to our center with anterior STEMI underwent primary percutaneous coronary intervention within 12 hours of presentation. We divided these into 4 quartiles, 1995 to 1999 (n = 312), 2000 to 2004 (n = 408), 2005 to 2009 (n = 428), and 2010 to 2014 (n = 510). Across the 4 quartiles, mean age decreased (64.4, 62, 60.3, and 60 years, p <0.01). In all groups, there was a significant rise in prevalence of smoking, hypertension, and obesity. The median length of hospital stay decreased (6, 4.4, 4.2, and 3.6 days, p <0.01), as did the median door-to-balloon time (DBT) (217, 194, 135, and 38 minutes, p <0.01). Thirty-day and 1-year mortality improved over time (14.4%, 11.8%, 8.4%, and 7.8%; and 20.5%, 16.4%, 15.9%, and 13.9%) (p = 0.01 both). Also, 3-year mortality improved (25.3%, 21.6%, 21.3%, and 16.5%, p = 0.02). After adjusting for age, gender, co-morbidities, ejection fraction, clinical shock, and mitral regurgitation, shorter DBT was associated with lower long-term mortality (compared with DBT <60 minutes; 60 to 90 minutes hazard ratio [HR] 1.67, 95% confidence interval [CI] 0.93 to 3.00, p = 0.084; 90 to 120 minutes, HR 1.74, 95% CI 1.02 to 2.95, p = 0.04; >120 minutes, HR 1.91, 95% CI 1.23 to 2.96, p = 0.004). In conclusion, over the past 2 decades, long-term outcomes improved in patients presenting with anterior STEMI associated with shortening of DBT. PMID- 28838604 TI - A Scientific Analysis of the 100 Citation Classics of Valvular Heart Disease. AB - Bibliometric analyses can help researchers and research funding agencies determine which areas of medicine need appropriate research attention. Citation classics of several specialties and subspecialties have been published; however, a literature search did not turn up any in the field of valvular heart disease (VHD). The main objective of this analysis was to overcome this paucity by identifying the top 100 cited articles in VHD and to assess their characteristics. We chose Scopus as our database, from where relevant articles were extracted after a thorough search by 2 independent researchers. A list of the top 100 cited articles was prepared, after which a detailed analysis of the list was conducted. The top-cited articles were published in the 63-year era starting from 1951, with the most articles published in the 10-year interval of 2001 to 2010. The citations of the articles ranged from 438 to 2,717 with a median of 609.5. Manuscripts from our top-cited list originated from 25 different countries. Most of the articles in the top 100 list were published in high-impact journals, with about a third of the articles published in Circulation (n = 27). Our study also reveals that the current focus of researchers in the field is on transcatheter aortic valve replacement, and therefore, funding in this area is likely to result in impactful studies. In conclusion, our study highlights the characteristics of high-impact articles in the field of VHD, and this information may be useful for investigators planning to conduct studies in this area of medicine in the future. PMID- 28838606 TI - [Vascular renal abnormalities]. PMID- 28838605 TI - Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold. AB - BACKGROUND AND PURPOSE: Due to the long life expectancy after treatment, the risk of late effects after radiotherapy (RT) is of particular importance for patients with Hodgkin lymphoma (HL). Both deep inspiration breath hold (DIBH) and proton therapy have been shown to reduce the dose to normal tissues for mediastinal HL, but the impact of these techniques in combination is unknown. The purpose of this study was to compare the life years lost (LYL) attributable to late effects after RT for mediastinal HL using intensity modulated radiation therapy (IMRT) in free breathing (FB) and DIBH, and proton therapy in FB and DIBH. MATERIALS AND METHODS: Plans for each technique were created for 22 patients with HL. Doses were extracted and the risk of late effects and LYL were estimated. RESULTS: We found that the use of DIBH, proton therapy, and the combination significantly reduced the LYL compared to IMRT in FB. The lowest LYL was found for proton therapy in DIBH. However, when IMRT in DIBH was compared to proton therapy in FB, no significant difference was found. CONCLUSIONS: Patient-specific plan comparisons should be used to select the optimal technique when comparing IMRT in DIBH and proton therapy in FB. PMID- 28838607 TI - Structural and biochemical characterization of ligand recognition by CysB, the master regulator of sulfate metabolism. AB - CysB, a member of LysR-type transcriptional regulators, up-regulates the expression of genes associated with sulfate metabolism and cysteine biosynthesis. CysB is activated under sulfur limiting conditions by O-acetylserine (OAS) and N acetylserine (NAS), but the activation mechanism of CysB remain unknown. Here, we report four crystal structures of ligand binding domains of CysB (CysB-LBD) in apo form and in complex with sulfate, OAS, and NAS. Our results show that CysB has two distinct allosteric ligand binding sites; a sulfate and NAS specific site 1 and a second, NAS and OAS specific site-2. All three ligands bind through the induced-fit mechanism. Surprisingly, OAS remodels the site-1 by binding to site 2, suggesting that site-1 and site-2 are coupled allosterically. Using DNA binding and site-directed mutagenesis approach, we show that OAS enhances NAS mediated activation and mutation at site-1 has no effect on site-2 mediated OAS activation. Results indicate that inducer binding triggered signals from OAS Specific site-2 are relayed to DBD through site-1. Together, results presented here suggest that induced-fit binding and allosteric coupling between two ligand binding sites and DBD underlie the key feature of CysB activation. Further, this study provides first structural glimpse into recognition of inducer ligands by CysB and provides a general framework to understand how LTTR family regulators respond to dual activators. PMID- 28838608 TI - Development of a thermal-stable structure-switching cocaine-binding aptamer. AB - We have developed a new cocaine-binding aptamer variant that has a significantly higher melt temperature when bound to a ligand than the currently used sequence. Retained in this new construct is the ligand-induced structure-switching binding mechanism that is important in biosensing applications of the cocaine-binding aptamer. Isothermal titration calorimetry methods show that the binding affinity of this new sequence is slightly tighter than the existing cocaine-binding aptamer. The improved thermal performance, a Tm increase of 4 degrees C for the cocaine-bound aptamer and 9 degrees C for the quinine-bound aptamer, was achieved by optimizing the DNA sequence in stem 2 of the aptamer to have the highest stability based on the nearest neighbor thermodynamic parameters and confirmed by UV and fluorescence spectroscopy. The sequences in stem 1 and stem 3 were unchanged in order to retain the structure switching and ligand binding functions. The more favorable thermal stability characteristics of the OR3 aptamer should make it a useful construct for sensing applications employing the cocaine-binding aptamer system. PMID- 28838609 TI - A quantitative weight of evidence assessment of confidence in modes-of-action and their human relevance. AB - A quantitative weight of evidence (QWoE) methodology was developed to assess confidence in postulated mode(s) of action for adverse effects in animal toxicity studies. The QWoE is appropriate for assessing adverse effects as relevant endpoints for classification and labeling purposes. The methodology involves definition of mode of actions and scoring supporting data for all key steps using predefined criteria for quality and relevance/strength of effects. Scores for all key steps are summarized, and the summary score is compared to the maximal achievable score for the mode of action. The ratio of the summary score to the maximal achievable scores gives an indication of confidence in a specific mode of action in animals. The mode of action in animals with highest confidence is then taken forward to assess appropriateness to humans. If one of the key steps cannot occur in humans, the mode of action is not relevant to humans. The methodology developed is applied to four case studies. PMID- 28838611 TI - Reply to Kawada letter to editor about "Dairy intake and risk of type 2 diabetes". PMID- 28838610 TI - Toxicological profile of IQG-607 after single and repeated oral administration in minipigs: An essential step towards phase I clinical trial. AB - IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in vitro and in vivo. Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220 mg/kg) to female and male minipigs did not result in any morbidity or mortality. No gross lesions were observed in the minipigs at necropsy. Repeated administration of IQG 607 (65, 30, or 15 mg/kg), given orally, for 90 days, in both male and female animals did not cause any mortality and no significant body mass alteration. Diarrhea and alopecia were the clinical signs observed in animals dosed with IQG-607 for 90 days. Long-term treatment with IQG 607 did not induce evident alterations of blood cell counts or any hematological parameters. Importantly, the repeated schedule of administration of IQG-607 resulted in increased cholesterol levels, increased glucose levels, decrease in the globulin levels, and increased creatinine levels over the time. Most necropsy and histopathological alterations of the organs from IQG-607-treated groups were also observed for the untreated group. In addition, pharmacokinetic parameters were evaluated. IQG-607 represents a potential candidate molecule for anti tuberculosis drug development programs. Its promising in vivo activity and mild to moderate toxic events detected in this study suggest that IQG-607 represents a candidate for clinical development. PMID- 28838612 TI - Fasting and surgical performance: potential source of harm? PMID- 28838613 TI - Impact of dysfunction of the facial nerve after superficial parotidectomy: a prospective study. AB - To evaluate the impact of dysfunction of the facial nerve after superficial parotidectomy for pleomorphic adenoma of the superficial lobe, we prospectively analysed the data of 79 patients using the Facial Disability Index (FDI) and the Short-Form 36-Item (SF-36) questionnaires up to 12 months postoperatively. The function of the facial nerve was grading on the House-Brackmann Scale. Results at 1 week and 1, 3, 6, and 12 months were compared with preoperative (baseline) measurement. The maximum reduction in FDI scores coincided with the highest facial paresis values at one week. Physical values on the FDI significantly decreased during the first three months (p=.039 at 3 months) and psychosocial values improved significantly from then onwards (p=.001 at 12 months). At 12 months, there were signs of full recovery compared with the preoperative baseline, and it was even exceeded in some psychosocial items. The SF-36 questionnaire showed no significant differences at any time during the study. The FDI was a useful instrument with which to understand the impact of facial disability and wellbeing associated with physical, social, and emotional aspects after superficial parotidectomy. Unlike the SF-36 questionnaire, the FDI offers clinicians a tool with which to counsel patients and better inform them about the anticipated results of operation before superficial parotidectomy. PMID- 28838614 TI - Implementation of Preoperative Screening Criteria Lowers Infection and Complication Rates Following Elective Total Hip Arthroplasty and Total Knee Arthroplasty in a Veteran Population. AB - BACKGROUND: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are common procedures with a risk of complications. Attempting to minimize complications, our institution implemented preoperative screening criteria for patients undergoing elective total joint replacement. Our study aimed to determine if screening criteria lowered total complications and/or surgical site infections (SSI). METHODS: Two groups of consecutive patients undergoing TKA and THA at a single Veterans Affairs facility were evaluated prior to and after implementation of screening criteria, 520 and 475 respectively. Screening criteria included hemoglobin A1c <=7, hemoglobin >=11, body mass index <=35, and albumin >=3.5. Groups were analyzed for demographics, preoperative comorbidities, and postoperative complications. Rates of total complications and SSI were compared. Average follow-up was at least 2 years with minimum of 1 year. RESULTS: Demographics and comorbidities outside the screening criteria were similar. Total complication rate was reduced from 35.4% to 14.8% (P < .01) after implementation of screening criteria. For TKA, total complications were reduced from 33.1% to 15.0% (P < .01) and for THA they were reduced from 42.4% to 14.2% (P < .01). SSI rates for combined TKA and THA were reduced from 4.4% to 1.3% (P < .01). For knees, SSI was reduced from 4.6% to 1.3% (P = .01) and was statistically significant. For THA, SSI decreased from 3.8% to 1.2% (P < .05). CONCLUSION: Our institution saw a statistically significant decrease in both SSI and total complications following implementation of preoperative screening criteria for elective TKA and THA. PMID- 28838615 TI - Malignant solitary fibrous tumour of the kidney with lymph node and liver metastases: beware of STAT6 expression in dedifferentiated liposarcoma with a solitary fibrous tumour-like morphology: author reply. PMID- 28838617 TI - The skin as sensor and effector organ orchestrating cutaneous and systemic disease. PMID- 28838616 TI - Molecular analysis of immunoglobulin variable genes supports a germinal center experienced normal counterpart in primary cutaneous diffuse large B-cell lymphoma, leg-type. AB - BACKGROUND: Immunophenotype of primary cutaneous diffuse large B-cell lymphoma, leg-type (PCLBCL-LT) suggests a germinal center-experienced B lymphocyte (BCL2+ MUM1+ BCL6+/-). OBJECTIVES: As maturation history of B-cell is "imprinted" during B-cell development on the immunoglobulin gene sequence, we studied the structure and sequence of the variable part of the genes (IGHV, IGLV, IGKV), immunoglobulin surface expression and features of class switching in order to determine the PCLBCL-LT cell of origin. METHODS: Clonality analysis with BIOMED2 protocol and VH leader primers was done on DNA extracted from frozen skin biopsies on retrospective samples from 14 patients. The clonal DNA IGHV sequence of the tumor was aligned and compared with the closest germline sequence and homology percentage was calculated. Superantigen binding sites were studied. Features of selection pressure were evaluated with the multinomial Lossos model. RESULTS: A functional monoclonal sequence was observed in 14 cases as determined for IGHV (10), IGLV (2) or IGKV (3). IGV mutation rates were high (>5%) in all cases but one (median:15.5%), with superantigen binding sites conservation. Features of selection pressure were identified in 11/12 interpretable cases, more frequently negative (75%) than positive (25%). Intraclonal variation was detected in 3 of 8 tumor specimens with a low rate of mutations. Surface immunoglobulin was an IgM in 12/12 cases. FISH analysis of IGHM locus, deleted during class switching, showed heterozygous IGHM gene deletion in half of cases. The genomic PCR analysis confirmed the deletions within the switch MU region. IGV sequences were highly mutated but functional, with negative features of selection pressure suggesting one or more germinal center passage(s) with somatic hypermutation, but superantigen (SpA) binding sites conservation. Genetic features of class switch were observed, but on the non functional allele and co-existing with primary isotype IgM expression. CONCLUSION: These data suggest that cell-of origin is germinal center experienced and superantigen driven selected B-cell, in a stage between germinal center B-cell and plasma cell. PMID- 28838618 TI - Microbe-mitochondrion crosstalk and health: An emerging paradigm. AB - Human mitochondria are descendants of microbes and altered mitochondrial function has been implicated in processes ranging from ageing to diabetes. Recent work has highlighted the importance of gut microbial communities in human health and disease. While the spotlight has been on the influence of such communities on the human immune system and the extraction of calories from otherwise indigestible food, an important but less investigated link between the microbes and mitochondria remains unexplored. Microbial metabolites including short chain fatty acids as well as other molecules such as pyrroloquinoline quinone, fermentation gases, and modified fatty acids influence mitochondrial function. This review focuses on the known direct and indirect effects of microbes upon mitochondria and speculates regarding additional links for which there is circumstantial evidence. Overall, while there is compelling evidence that a microbiota-mitochondria link exists, explicit and holistic mechanistic studies are warranted to advance this nascent field. PMID- 28838619 TI - Functional redundancy ensures performance robustness in 3-stage PHA-producing mixed cultures under variable feed operation. AB - Polyhydroxyalkanoates (PHA) are biopolymers that can be produced by mixed microbial cultures using wastes or industrial by-products, which represent an economical and environmental advantage over pure culture processes. The use of alternate feedstocks enables using seasonal by-products, providing that the process is resilient to transient conditions. The mixed microbial communities of a 3-stage PHA producing system fed initially with molasses and then cheese whey were investigated through amplicon sequencing of the 16S rRNA gene. The transition in feedstock resulted in an adaptation of the acidogenic community, where Actinobacteria dominated with sugarcane molasses (up to 93% of the operational taxonomic units) and Firmicutes, with cheese whey (up to 97%). The resulting fermentation products profile also changed, with a higher fraction of HV precursors obtained with molasses than cheese whey (7.1+/-0.5 and 1.7+/-0.7 gCOD/L, respectively). As for the PHA storing culture, the genera Azoarcus, Thauera and Paracoccus were enriched with fermented molasses (average 89% of Bacteria). Later, fermented cheese whey fostered a higher diversity, including some less characterised PHA-storers such as the genera Paenibacillus and Lysinibacillus. Although the microbial community structure was significantly affected by the feedstock shift, the acidogenic and PHA storing performance of the 3-stage system was very similar once a pseudo steady state was attained, showing that a reliable level of functional redundancy was attained in both mixed cultures. PMID- 28838621 TI - Ki-67 and the Chromosome Periphery Compartment in Mitosis. AB - The chromosome periphery is a complex network of proteins and RNA molecules (many derived from nucleoli) that covers the outer surface of chromosomes and whose function remains mysterious. Although it was first described over 130 years ago, technological advances and the recent discovery that Ki-67 acts as an organiser of this region have allowed the chromosome periphery to be dissected in previously unattainable detail, leading to a revival of interest in this obscure chromosomal compartment. Here, we review the most recent advances into the composition, structure and function of the chromosome periphery, discuss possible roles of Ki-67 during mitosis and consider why this structure is likely to remain the focus of ongoing attention in the future. PMID- 28838622 TI - Defining Hand Stereotypies in Rett Syndrome: A Movement Disorders Perspective. AB - INTRODUCTION: Hand stereotypies (HS) are a primary diagnostic criterion for Rett syndrome (RTT) but are difficult to characterize and quantify systematically. METHODS: We collected video on 27 girls (2-12 years of age) with classic RTT who participated in a mecasermin trial. The present study focused exclusively on video analyses, by reviewing two five-minute windows per subject to identify the two most common HS. Three raters with expertise in movement disorders independently rated the five-minute windows using standardized terminology to determine the level of agreement. We iteratively refined the protocol in three stages to improve descriptive accuracy, categorizing HS as "central" or "peripheral," "simple" or "complex," scoring each hand separately. Inter-rater agreement was analyzed using Kappa statistics. RESULTS: In the initial protocol evaluating HS by video, inter-rater agreement was 20.7%. In the final protocol, inter-rater agreement for the two most frequent HS was higher than the initial protocol at 50%. CONCLUSION: Phenotypic variability makes standardized evaluation of HS in RTT a challenge; we achieved only 50% level of agreement and only for the most frequent HS. Therefore, objective measures are needed to evaluate HS. PMID- 28838623 TI - [Quality of life in adult patient (Tunisian) with severe OSA]. AB - INTRODUCTION: The negative impact of obstructive sleep apnea (OSA) on quality of life of affected individuals is a central consequence of this disease. The recognition of the quality of life as a therapeutic target is a relatively new concept. OBJECTIVES: To evaluate the quality of life and its determinants in patients with OSA. MATERIALS AND METHODS: We conducted a cross-sectional study during the period from 1st July 2012 to 30th June 2013. The target population was patients with OSA and in employment examined in consultations of pneumology in the teaching hospital Farhat-Hached in Sousse (Tunisia). This study was based on a generic questionnaire (SF-36) to assess the quality of life. RESULTS: The study population included 103 cases with a mean age of 55.15+/-11.4years and a sex ratio of 0.71. Our patients were obese in 95.1 % of cases with an average BMI of 39.13+/-7.19kg/m2. The majority of our patients had an impaired quality of life with an average score of 44.76 (SF36) and extremes of 22 and 70. There was a positive linear relationship between physical and mental components of the SF-36 and gender, age, BMI, and anxiety and depressive disorders. CONCLUSION: The OSA is a demanding disease whose impact on the quality of life seems important and requires special attention. The management of this disease should not be limited to controlling the disease but aspire to overall patient satisfaction. PMID- 28838624 TI - [Systemic inflammatory profile of smokers with and without COPD]. AB - INTRODUCTION: Studies comparing the systemic inflammatory profiles of smokers with and without COPD present discordant findings. AIM: To compare the systemic inflammatory profile of smokers with and without COPD. METHODS: This is a cross sectional comparative study. Two groups of active smokers of more than 10 pack years were included: 56 consecutives stable COPD (postbronchodilator FEV1/FVC<0.70) and 32 consecutives non-COPD (postbronchodilator FEV1/FVC>=0.70). Smoking and clinical, anthropometric and spirometric data were noted. The following blood biomarkers were identified: leukocytes, hemoglobin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR). According to the levels (normal/abnormal) of these markers, two groups of smokers were formed. Quantitative and qualitative data were expressed, respectively, as means+/-SD and percentages. RESULTS: Compared to the non-COPD group, the COPD group was older (56+/-12 vs. 65+/-8 years) and had a higher smoking consumption (30+/-18 vs. 52+/ 31 pack-years). Compared to the non-COPD group, the COPD group had higher values of CRP (2.06+/-1.24 vs. 11.32+/-11.03mg/L), of ESR (9.59+/-8.29 vs. 15.96+/ 11.56), of IL-6 (9.28+/-4.69 vs. 20.27+/-5.31ng/L) and of TNF-alpha (18.38+/ 7.98ng/L vs. 8.62+/-3.72ng/L). Compared to the non-COPD group, the COPD group included higher percentages of smokers with elevated CRP (0 % vs. 32 %), with leukocytosis (6 % vs. 16 %), with higher levels of IL-6 (81 % vs. 98 %) or TNF alpha (91 % vs. 100 %). CONCLUSION: Smokers with COPD, compared to smokers free from COPD, have a marked systemic inflammation. PMID- 28838620 TI - Emerging Roles for the Lysosome in Lipid Metabolism. AB - Precise regulation of lipid biosynthesis, transport, and storage is key to the homeostasis of cells and organisms. Cells rely on a sophisticated but poorly understood network of vesicular and nonvesicular transport mechanisms to ensure efficient delivery of lipids to target organelles. The lysosome stands at the crossroads of this network due to its ability to process and sort exogenous and endogenous lipids. The lipid-sorting function of the lysosome is intimately connected to its recently discovered role as a metabolic command-and-control center, which relays multiple nutrient cues to the master growth regulator, mechanistic target of rapamycin complex (mTORC)1 kinase. In turn, mTORC1 potently drives anabolic processes, including de novo lipid synthesis, while inhibiting lipid catabolism. Here, we describe the dual role of the lysosome in lipid transport and biogenesis, and we discuss how integration of these two processes may play important roles both in normal physiology and in disease. PMID- 28838625 TI - [Which surgery for mediastinum tumor: Experience of the Department of thoracic surgery of CHU Hassan II of Fes]. AB - INTRODUCTION: Tumors of the mediastinum are a heterogeneous group of dysembryoplatic and neoplastic diseases essentially with different prognoses and therapeutic. These tumors develop slowly and remain long asymptomatic in 40-50% of cases. The purpose of our work is to bring the result of surgical management in diagnostic and therapeutic of principal mediastinum tumors framework. PATIENTS AND METHOD: We reviewed retrospectively the records of 68 patients in our training, between January 2009 and December 2013, for tumor of the mediastinum in the diagnostic framework and or therapy. RESULTS: There were 37 men and 31 women with a mean age of 37 years with extremes ranging from 11 to 73 years and 77.94% had an age between 11 and 50. In 39 patients, surgery had a diagnostic purpose (2 benign tumors and 37 malignancies including 27 cases of lymphomas). Curative surgery was performed in 34 patients, dominated by the tumors of thymic origin in 15 cases. Conventional surgery had involved 32 patients. The surgical approach was a total vertical sternotomy in 14 patients, in 17 patients was posterolateral thoracotomy and a left anterior thoracotomy in 1 patient. Video assisted thoracic surgery had been done in 3 patients under resection of a pleuropericardique cyst. Overall mortality was 4.41 percent. It is a death at D17 of the postoperative (thymoma with myasthenia) following a myasthenic crisis requiring a tracheotomy. A patient operated on for invasive thymoma developed myopathy and died at D44 of the postoperative following a difficulty of weaning. Another patient had a thymoma B3 benefited from 6 courses of neoadjuvant chemotherapy and then a thymectomy had presented a respiratory distress with bilateral pleural effusion, death at D10 of the postoperative by septic shock following a nosocomial infection. CONCLUSION: Tumors of the mediastinum are infrequent, discovered more often by chance. The main prognostic factor is the completeness of tumor resection without taking the break. Conventional surgery always keeps a place in our context, despite the advent of minimally invasive surgery. PMID- 28838626 TI - Are pressure injuries related to skin failure in critically ill patients? AB - BACKGROUND: Pressure injuries contribute significantly to patient morbidity and healthcare costs. Critically ill patients are a high risk group for pressure injury development and may suffer from skin failure secondary to hypoperfusion. The aim of this study was to report hospital acquired pressure injury incidence in intensive care and non-intensive care patients; and assess the clinical characteristics and outcomes of ICU patients reported as having a hospital acquired pressure injury to better understand patient factors associated with their development in comparison to ward patients. METHODS: The setting for this study was a 630 bed, government funded, tertiary referral teaching hospital. A secondary data analysis was undertaken on all patients with a recorded PI on the hospital's critical incident reporting systems and admitted patient data collection between July 2006 to March 2015. RESULTS: There were a total of 5280 reports in 3860 patients; 726 reports were intensive care patients and 4554 were non-intensive care patients, with severe hospital acquired PI reported in 22 intensive care patients and 54 non-intensive care patients. Pressure injury incidence increased in intensive care patients and decreased in non-intensive care patients over the study period. There were statistically significant differences in the anatomical location of severe hospital acquired pressure injuries between these groups (p=0.008). CONCLUSION: Intensive care patients have greater than 10-fold higher hospital acquired pressure injury incidence rates compared to other hospitalised patients. The predisposition of critically ill patients leaves them susceptible to pressure injury development despite implementation of pressure injury prevention strategies. Skin failure appears to be a significant phenomenon in critically ill patients and is associated with the use of vasoactive agents and support systems such as extra corporeal membrane oxygenation and mechanical ventilation. PMID- 28838627 TI - Adherence to standard medication infusion concentrations and its impact on paediatric intensive care patient outcomes. AB - AIM: To review compliance with the DERS, and to evaluate the impact on daily fluid balances as a standard outcome in paediatric intensive care. METHOD: A prospective audit of patients admitted to our tertiary level PICU over a 10day period. The audit tool collated information on patient's weight, diagnosis, medication infusions, whether standard concentrations were selected, daily fluid balance, target fluid balance, and renal support including use of diuretics. RESULTS: Seventy-seven (84%) of patients weighed less than 10kg. On average, there were seven medication infusions per patient and 98% of the medication infusions adhered to standard concentrations for medication infusions and DERS. In 2% of medication infusions staff opted not to use the DERS, or selected non standard concentration, and 2% of patients had no labels on the syringe. 90% of patients had a minimal positive balance of 0.5mL/kg/h, averaged over 24h; 48% of patients received renal support and 16% of patients were 24h post cardiac surgery, where a negative fluid balance was recorded. It is standard practice post cardiac surgery to receive diuretics. Standard concentrations did not have a significant impact on patients' daily fluid balance. CONCLUSIONS: The use of standard concentrations and short infusions in PICU using DERS is feasible & achievable as demonstrated by high compliance, and does not have a negative impact on patient outcome, especially fluid balance. PMID- 28838629 TI - In vitro antifungal activity of cassia fistula extracts against fluconazole resistant strains of Candida species from HIV patients. AB - BACKGROUND: Candida species is the fourth common cause of blood stream infections all over the world which is life threatening. Invasive candidiasis leads to increased mortality and morbidity especially in immunosuppressed. The antifungal resistance pattern in high-risk patients is major concern. PURPOSE: The present study was to access the anticandidal activity of leaves, bark and seeds of Cassia fistula against fluconazole resistant Candida species, C. albicans, C. glabrata, C. krusei, C. tropicalis, C. kefyr and C. parapsilosis isolated from HIV patients. The predominant phytochemical component responsible for fungicidal activity was to be accessed. MATERIAL AND METHODS: Ethanol, chloroform, petroleum ether and aqueous extracts of leaves, bark and seeds of C. fistula linn. was evaluated against Microbial type culture collection (MTCC) Candida strains and 21 fluconazole resistant clinical isolates. Antifungal activity was evaluated by agar diffusion and broth dilution techniques. The active phytochemical component present in the ethanol extract of seeds was accessed by high performance thin layer chromatography. The docking study was done with lanosterol 14-alpha demethylase, the azole drug target with the predominant phytochemical from the extract having antifungal activity. RESULTS: All the extracts of C. fistula showed excellent anticandidal activity. Ethanol extract of C. fistula seed exhibited the most inhibitory activity. C. krusei and C. parapsilosis were the most inhibited and C. kefyr was the least inhibited species. The predominant phytochemical active component of the ethanol extract of seed was gallic acid. Gallic acid showed excellent binding with lanosterol 14-alpha demethylase. CONCLUSION: The present study reports the antifungal activity of various extracts of Cassia fistula for the first time against fluconazole resistant Candida isolates. We can conclude that the polyphenolic compound gallic acid is a potent natural antifungal agent. Further research is needed to assess the pharmacokinetic property. PMID- 28838628 TI - The study of the tear as example of translation: From the bench to the clinic. PMID- 28838630 TI - Treatment decision-making in chronic diseases: What are the family members' roles, needs and attitudes? A systematic review. AB - OBJECTIVE: This systematic review aims to examine the roles of family members (FMs) in treatment decision-making for adult patients without cognitive or psychiatric disorders affecting their ability to participate in decision-making. METHODOLOGY: A comprehensive, systematic search of the Cochrane Library, PsycINFO, PubMed and ScienceDirect databases, with relevant keywords, was conducted. Two authors evaluated the eligibility of the studies independently, then cross-checked for accuracy. The quality of included studies were assessed using standardized criteria. RESULTS: Out of the 12.137 studies identified, 40 were included. Results highlighted the different roles and influences FMs have in the decision-making process. Moreover, several factors ranging from personal to cultural and family-related factors influence their level of involvement. Regardless of the illness, some similarities in family influence exist (e.g., social support). However, the type of family involvement varies according to the illness, the treatment choice and the patients' culture. CONCLUSION: FMs have an important role in the decision-making process. In fact, the final decision is often made by the patients after consulting their families. FMs can support both patients and medical teams, and thus facilitate the process. PRACTICE IMPLICATIONS: Physicians should include FMs in treatment decision-making when the patients and their FMs wish to be included. PMID- 28838631 TI - True communication skills assessment in interdepartmental OSCE stations: Standard setting using the MAAS-Global and EduG. AB - BACKGROUND: Comparing outcome of clinical skills assessment is challenging. This study proposes reliable and valid comparison of communication skills (1) assessment as practiced in Objective Structured Clinical Examinations (2). The aim of the present study is to compare CS assessment, as standardized according to the MAAS Global, between stations in a single undergraduate medical year. METHODS: An OSCE delivered in an Irish undergraduate curriculum was studied. We chose the MAAS-Global as an internationally recognized and validated instrument to calibrate the OSCE station items. The MAAS-Global proportion is the percentage of station checklist items that can be considered as 'true' CS. The reliability of the OSCE was calculated with G-Theory analysis and nested ANOVA was used to compare mean scores of all years. RESULTS: MAAS-Global scores in psychiatry stations were significantly higher than those in other disciplines (p<0.03) and above the initial pass mark of 50%. The higher students' scores in psychiatry stations were related to higher MAAS-Global proportions when compared to the general practice stations. CONCLUSION: Comparison of outcome measurements, using the MAAS Global as a standardization instrument, between interdisciplinary station checklists was valid and reliable. PRACTICE IMPLICATIONS: The MAAS-Global was used as a single validated instrument and is suggested as gold standard. PMID- 28838633 TI - The challenges of centralization with HPB resectional surgery. PMID- 28838632 TI - The TRIANGLE operation - radical surgery after neoadjuvant treatment for advanced pancreatic cancer: a single arm observational study. AB - BACKGROUND: Neoadjuvant therapy is an important strategy for locally advanced pancreatic cancer (PDAC) as resection rates increase with modern chemotherapy regimens even in patients with arterial tumor encasement. The aim of this study is the description of technique and initial outcomes of a new type of radical and arterial-sparing resection after neoadjuvant treatment for locally advanced PDAC. METHODS: The surgical technique and perioperative results of a new type of operation are described, comprising radical tumor removal by sharp dissection along the celiac axis and the superior mesenteric artery with complete dissection of all soft tissue between both - arteries and superior mesenteric/portal vein (TRIANGLE operation). RESULTS: 15 patients underwent artery-preserving tumor removal without mortality, 7/15 patients showed postoperative complications and an R0 resection was achieved in 6/15 patients. Functional outcome was good in 11/15 patients despite the extended approach of dissection. CONCLUSION: After neoadjuvant therapy for locally advanced PDAC, surgical exploration should be attempted in patients with stable disease or remission to clarify true vascular infiltration. In case of absent viable tumor, the described technique allows to perform radical surgery without arterial resection in this subgroup of patients. PMID- 28838634 TI - Geographic disparities in surgical treatment recommendation patterns and survival for pancreatic adenocarcinoma. AB - BACKGROUND: Previous studies have described pessimistic attitudes of physicians toward recommending surgery for early-stage pancreatic adenocarcinoma. However, the impact of geographic region on recommendation patterns of surgical treatment for potentially resectable pancreatic cancer is unknown. METHODS: The SEER registry was used to identify patients with early-stage pancreatic adenocarcinoma (AJCC I-II) [2004-2013]. The exposure of interest was geographic region of diagnosis: Midwest, West, Southeast or Northeast. The endpoints of interest were recommendation of no surgery, and overall survival. RESULTS: A total of 24,408 patients were identified [Midwest - 10.6%, West - 50.1%, Southeast - 21.7% and Northeast - 17.6%]. Overall, 38% of patients had a recommendation of no surgery by their provider. On univariate analysis, the likelihood of having a recommendation of no surgery was lowest in the NE [OR: Northeast (0.8), West (1.6), Southeast (1.3), and Midwest (Ref); p < 0.05 for all]. This association persisted following risk adjustment. Geographic region was an independent predictor of mortality, irrespective of resection status. CONCLUSION: Significant disparities in surgical treatment recommendation patterns and survival for early stage pancreatic cancer exist based on geographic location. Improved adherence to guideline-driven treatment recommendations, standardization of care processes, and regionalization may help stem the existing variability in care and outcomes. PMID- 28838635 TI - Editorial. PMID- 28838636 TI - Mechanistic Fermentation Models for Process Design, Monitoring, and Control. AB - Mechanistic models require a significant investment of time and resources, but their application to multiple stages of fermentation process development and operation can make this investment highly valuable. This Opinion article discusses how an established fermentation model may be adapted for application to different stages of fermentation process development: planning, process design, monitoring, and control. Although a longer development time is required for such modeling methods in comparison to purely data-based model techniques, the wide range of applications makes them a highly valuable tool for fermentation research and development. In addition, in a research environment, where collaboration is important, developing mechanistic models provides a platform for knowledge sharing and consolidation of existing process understanding. PMID- 28838637 TI - Calcification Volume Reduces Stretch Capability and Predisposes Plaque to Rupture in an in vitro Model of Carotid Artery Stenting. AB - OBJECTIVE/BACKGROUND: Carotid artery stenting (CAS) in calcified arteries carries a higher peri-operative risk. This study investigates the relationship between the stretching limits of carotid plaque samples and calcification in order to determine a stretch tolerance criterion for endovascular intervention. METHODS: Seventeen carotid plaque samples were acquired from standard endarterectomy procedures. The maximum stretch capability of the global plaque was determined by circumferentially extending the tissue to complete failure. Quantitative assessment of calcification was performed using high resolution computed tomography, including measures of percent calcification volume fraction (%CVF) and calcification configuration. Maximum stretch properties were then related to calcification measures in order to evaluate the predictive power of calcification for determining plaque stretching limits. RESULTS: A strong negative correlation was found between %CVF and stretch ratio with respect to specific calcification configuration types. All plaques with < 70% stenosis superseded the minimum required stretch threshold. Severe stenosis (> 70%) warrants a stretch of at least 2.33 during revascularisation and only plaques containing concentric calcifications with < 20% CVF successfully reached this minimum required stretch threshold. CONCLUSION: The addition of calcification measures to the stenosis classification may help in guiding endovascular intervention techniques to achieve a balance between an acceptable residual patency level while avoiding plaque rupture in calcified carotid plaques. PMID- 28838638 TI - Zika virus infection in semen: effect on human reproduction. PMID- 28838639 TI - Effect of acute Zika virus infection on sperm and virus clearance in body fluids: a prospective observational study. AB - BACKGROUND: Evidence of human sexual transmission during Zika virus emergence is a matter of concern, particularly in procreation, but to date, kinetics of seminal shedding and the effects of infection on human reproductive function have not been described. To investigate the effects of Zika virus infection on semen and clearance of Zika virus from semen and body fluids, we aimed to study a cohort of Zika virus-infected men. METHODS: This prospective observational study recruited men presenting with acute Zika virus infection at Pointe-a-Pitre University Hospital in Guadeloupe, French Caribbean, where a Zika virus outbreak occurred between April and November, 2016. Blood, urine, and semen were collected at days 7, 11, 20, 30, 60, 90, and 120 after symptom onset, and semen characteristics, such as total sperm count, sperm motility, vitality, and morphology, and reproductive hormone concentrations, such as testosterone, inhibin, follicle-stimulating hormone, and luteinising hormone, were assessed. At days 7, 11, and 20, semen was processed to isolate motile spermatozoa. Zika virus RNA was detected by RT-PCR using whole blood, serum, urine, seminal plasma, semen cells, and motile spermatozoa fractions. Zika virus was isolated from different sperm fractions on Vero E6 cultures. FINDINGS: 15 male volunteers (mean age 35 years [SD 5; range 25-44) with acute Zika virus infection and positive Zika virus RNA detection in blood or urine were enrolled. Total sperm count was decreased from median 119 * 106 spermatozoa (IQR 22-234) at day 7 to 45.2 * 106 (16.5-89.6) at day 30 and 70 * 106 (28.5-81.4) at day 60, respectively, after Zika virus infection. Inhibin values increased from 93.5 pg/mL (IQR 55-162) at day 7 to 150 pg/mL (78-209) at day 120 when total sperm count recovered. In motile spermatozoa obtained after density gradient separation, Zika virus RNA was found in three of 14 patients at day 7, four of 15 at day 11, and four of 15 at day 20, and replication-competent virus was found in the tested patient. Seminal shedding kinetics seemed heterogeneous among patients. Whole blood was the fluid most frequently positive for Zika virus RNA (62 of 92 samples) and three patients remained positive at day 120. INTERPRETATION: Semen alterations early after acute Zika virus infection might affect fertility and could be explained by virus effects on the testis and epididymis. Frequency of shedding and high viral load in semen, together with the presence of replicative virus in a motile spermatozoa fraction, can lead to Zika virus transmission during sexual contact and assisted reproduction procedures. Whole blood seems to be the best specimen for Zika virus RNA detection, diagnosis, and follow-up. FUNDING: Agence de la Biomedecine/Agence Regionale de Sante de la Guadeloupe/Inserm-REACTing. PMID- 28838640 TI - Emerging Role of Three-Dimensional Printing in Simulation in Otolaryngology. AB - Simulation is rapidly expanding across medicine as a valuable component of trainee education. For procedural simulation, development of low-cost simulators that allow a realistic, haptic experience for learners to practice maneuvers while appreciating anatomy has become highly valuable. Otolaryngology has seen significant advancements in development of improved, specialty-specific simulators with the expansion of three-dimensional (3D) printing. This article highlights the fundamental components of 3D printing and the multitude of subspecialty simulators that have been developed with the assistance of 3D printing. It briefly discusses important considerations such as cost, fidelity, and validation where available in the literature. PMID- 28838642 TI - Genetic polymorphisms of 15 autosomal STR loci in 3962 individuals from the Han population of Jiangxi, Southeast China. PMID- 28838643 TI - The paradigm shift in DNA profile interpretation. PMID- 28838646 TI - Corrigendum to "High sensitivity HPLC method for analysis of in vivo extracellular GABA using optimized fluorescence parameters for o-phthalaldehyde (OPA)/sulfite derivatives" [J. Chromatogr. B 1055-1056 (2017) 1-7]. PMID- 28838645 TI - Systematic screening and characterization of multiple constituents in Guizhi Fuling capsule and metabolic profiling of bioactive components in rats using ultra-high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - Guizhi Fuling capsule (GFC), a prestigious traditional Chinese medicinal (TCM) prescription, is efficiently used to treat primary dysmenorrhea in the clinical practice. It's significant to explore the metabolic fate of multiple components in vivo which are responsible for the pharmacological effects but not fully investigated. A rapid and high-throughput method using ultra performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS/MS) was established for systematic investigation on GFC, including GFC chemical compositions, and their absorption and metabolism in rat plasma, urine, uterus and brain after oral administration of GFC. A total of 102 nonvolatile GFC phytochemistry components were identified based on the accurately measured mass value, fragmentation pattern and retention behavior. Compared to the previous GFC study, additional 47 different GFC components were detected. Furthermore 21, 9, 4 and 3 prototype compounds were separately observed in plasma, urine, uterus and brain samples with the support of in vitro GFC study. While 29, 33, 10 and 8 metabolites were also identified with the assistance of the MetaboLynx tool in these biological samples. The result indicated that the developed method was suitable for the components identification even in the complex matrix. The chemical and metabolic profiling of GFC provided an abundant substance foundation for the extensive GFC research, especially for the pharmacodynamic mechanisms research. PMID- 28838644 TI - Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial. AB - BACKGROUND: Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. METHODS: In this randomised controlled, open label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18-80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). FINDINGS: Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178.1 (95% CI 171.1-185.0) in the resection group versus 172.0 (164.3-179.6) in the infliximab group (mean difference 6.1 points, 95% CI 4.2 to 16.4; p=0.25). At 12 months, the mean SF-36 total score was 112.1 (95% CI 108.0-116.2) in the resection group versus 106.5 (102.1-110.9) in the infliximab group (mean difference 5.6, 95% CI -0.4 to 11.6), the mean physical component score was 47.7 (45.7-49.7) versus 44.6 (42.5-46.8; mean difference 3.1, 4.2 to 6.0), and the mean mental component score was 49.5 (47.0-52.1) versus 46.1 (43.3 48.9; mean difference 3.5, -0.3 to 7.3). Mean numbers of days of sick leave were 3.4 days (SD 7.1) in the resection group versus 1.4 days (4.7) in the infliximab group (p<0.0001), days not able to take part in social life were 1.8 days (6.3) versus 1.1 days (4.5; p=0.20), days of scheduled hospital admission were 6.5 days (3.8) versus 6.8 days (3.2; p=0.84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0.68). Body-image scale mean scores in the patients who had resection were 16.0 (95% CI 15.2-16.8) at baseline versus 17.8 (17.1-18.4) at 12 months, and cosmetic scale mean scores were 17.6 (16.6-18.6) versus 18.6 (17.6-19.6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2-6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF. INTERPRETATION: Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy. FUNDING: Netherlands Organisation for Health Research and Development. PMID- 28838641 TI - Mitochondrial toxicity of tobacco smoke and air pollution. PMID- 28838647 TI - From Nonclinical Research to Clinical Trials and Patient-registries: Challenges and Opportunities in Biomedical Research. AB - The most important challenge faced by human beings is health. The only way to provide better solutions for health care is innovation, true innovation. The only source of true innovation is research, good research indeed. The pathway from a basic science study to a randomized clinical trial is long and not free of bumps and even landmines. These are all the obstacles and barriers that limit the availability of resources, entangle administrative-regulatory processes, and restrain investigators' initiatives. There is increasing demand for evidence to guide clinical practice but, paradoxically, biomedical research has become increasingly complex, expensive, and difficult to integrate into clinical care with increased barriers to performing the practical aspects of investigation. We face the challenge of increasing the volume of biomedical research and simultaneously improving the efficiency and output of this research. In this article, we review the main stages and methods of biomedical research, from nonclinical studies with animal and computational models to randomized trials and clinical registries, focusing on their limitations and challenges, but also providing alternative solutions to overcome them. Fortunately, challenges are always opportunities in disguise. PMID- 28838648 TI - Salvage brachytherapy for recurrent prostate cancer after definitive radiation therapy: A comparison of low-dose-rate and high-dose-rate brachytherapy and the importance of prostate-specific antigen doubling time. AB - BACKGROUND: Salvage brachytherapy is a treatment option for patients with locally recurrent prostate cancer after primary radiation therapy. We reviewed our experience using low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy to compare the outcome and toxicity profiles of each approach in the salvage brachytherapy setting. METHODS AND MATERIALS: Ninety-eight patients with biopsy proven locally recurrent prostate cancer who underwent salvage brachytherapy (LDR = 37; HDR = 61) following an initial course of definitive radiotherapy between 4/2003 and 4/2015 were retrospectively reviewed. All patients underwent salvage brachytherapy using LDR or HDR. Androgen deprivation therapy was used in 45% of the patients. Prostate-specific antigen (PSA) failure was determined using the Phoenix (nadir+2) definition. Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and patient-reported questionnaires. RESULTS: Median followup was 31 months. The 3-year PSA relapse-free survival (RFS) was 60.1% (95% CI, 49.6-72.5%). There was no difference between LDR and HDR brachytherapy in terms of PSA RFS (p = 0.84 by log-rank test). On multivariate analysis, only prostate-specific antigen doubling time (PSADT) <12 months was significantly associated with PSA relapse. The 3-year PSA RFS for patients with a PSADT <12 months was 39% compared with 73% for PSADT >=12 months (p = 0.002 by long-rank test). There were no statistically significant differences in toxicity between LDR and HDR brachytherapy. There was a higher peak in urinary symptoms in LDR patients; however by 24-36 months, most patients in both groups returned to baseline. CONCLUSIONS: Both LDR and HDR salvage brachytherapy are an excellent treatment options for appropriately selected patients with comparable outcome and toxicity. Patients with a PSADT < 12 months seem to have worse outcomes. PMID- 28838649 TI - Brachytherapy attains abscopal effects when combined with immunostimulatory monoclonal antibodies. AB - PURPOSE/OBJECTIVES: Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lesions and on tumors at distant, nonirradiated sites. We have recently reported that external beam radiotherapy achieves abscopal effects when combined with antagonist anti-PD1 mAbs and agonist anti-CD137 (4-1BB) mAbs. The goal of this work is to study the abscopal effects of radiotherapy instigated by brachytherapy techniques. METHODS AND MATERIALS: Mice bearing a subcutaneous colorectal carcinoma, MC38 (colorectal cancer), in both flanks were randomly assigned to receive brachytherapy or not (8 Gy * three fractions) to only one of the two grafted tumors, in combination with intraperitoneal immunostimulatory monoclonal antibodies (anti-PD1, anti-CD137, and/or their respective isotype controls). To study the abscopal effects of brachytherapy, we established an experimental set up that permits irradiation of mouse tumors sparing a distant site resembling metastasis. Such second nonirradiated tumor was used as indicator of abscopal effect. Tumor size was monitored every 2 days. RESULTS: Abscopal effects on distant nonirradiated subcutaneous tumor lesions of transplanted MC38-derived tumors only took place when brachytherapy was combined with immunostimulatory anti-PD1 and/or anti-CD137 mAbs. CONCLUSIONS: Our results demonstrate that immunotherapy-potentiated abscopal effects can be attained by brachytherapy. Accordingly, immunotherapy plus brachytherapy combinations are suitable for clinical translation. PMID- 28838650 TI - Incomplete septal cirrhosis: An uncommon condition. PMID- 28838651 TI - Mass defect filtering-oriented classification and precursor ions list-triggered high-resolution mass spectrometry analysis for the discovery of indole alkaloids from Uncaria sinensis. AB - Discovery of new natural compounds is becoming increasingly challenging because of the interference from those known and abundant components. The aim of this study is to report a dereplication strategy, by integrating mass defect filtering (MDF)-oriented novelty classification and precursor ions list (PIL)-triggered high-resolution mass spectrometry analysis, and to validate it by discovering new indole alkaloids from the medicinal herb Uncaria sinensis. Rapid chromatographic separation was achieved on a Kinetex(r) EVO C18 column (<16min). An in-house MDF algorithm, developed based on the informed phytochemistry information and molecular design, could more exactly screen the target alkaloids and divide them into three novelty levels: Known (KN), Unknown-but-Predicted (UP), and Unexpected (UN). A hybrid data acquisition method, namely PIL-triggered collision-induced dissociation-MS2 and high-energy C-trap dissociation-MS3 with dynamic exclusion on a linear ion trap/Orbitrap mass spectrometer, facilitated the acquisition of diverse product ions sufficient for the structural elucidation of both indole alkaloids and the N-oxides. Ultimately, 158 potentially new alkaloids, including 10 UP and 108 UN, were rapidly characterized from the stem, leaf, and flower of U. sinensis. Two new alkaloid compounds thereof were successfully isolated and identified by 1D and 2D NMR analyses. The varied ring E and novel alkaloid acylquinic acid conjugates were first reported from the whole Uncaria genus. Conclusively, it is a practical chemical dereplication strategy that can enhance the efficiency and has the potential to be a routine approach for the discovery of new natural compounds. PMID- 28838652 TI - Calibration and performance of synchronous SIM/scan mode for simultaneous targeted and discovery (non-targeted) analysis of exhaled breath samples from firefighters. AB - Traditionally, gas chromatography-mass spectrometry (GC/MS) analysis has used a targeted approach called selected ion monitoring (SIM) to quantify specific compounds that may have adverse health effects. Due to method limitations and the constraints of preparing duplicate samples, the information that could be obtained from separately collecting the full scan chromatogram of the sample has often been sacrificed. However, the hybrid technique called synchronous SIM/scan mode alternates between the two acquisition modes, maintaining the accuracy and sensitivity of SIM for targeted analysis while also providing the full scan chromatogram for discovery of non-target compounds. This technology was assessed using calibration data and real-world breath samples from a joint EPA/NIOSH collaboration that investigated the safety of firefighters' protective gear during controlled structure burns. Collecting field samples is costly and must be performed strategically to ensure that time points and replicates are accurate and representative of the intended population. This is difficult to accomplish with firefighters who are working under volatile conditions. The synchronous SIM/scan method decreases the number of field samples that need to be collected by half and reduces error in trying to recreate time points since a breath sample from a single sorbent tube can be used to collect both the SIM and scan data simultaneously. As a practical demonstration of the method, we investigate thirty six firefighter breath samples, document organic compounds of interest, and identify additional non-target compounds. PMID- 28838653 TI - Comment on "Bioflocculation management through high-rate contact stabilization: A promising technology to recover organic carbon from low-strength wastewater by Rahman, A., Meerburg, F.A., Ravadagundhi, S., Wett, B., Jimenez, J., Bott, C., Al Omari, A., Riffat, R., Murthy, S. and De Clippeleir, H. [Water Research 104 (2016) 485-496]". PMID- 28838654 TI - Physalis alkekengi L. var. franchetii (Mast.) Makino: An ethnomedical, phytochemical and pharmacological review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino (Physalis Calyx seu Fructus), have been widely used in traditional and indigenous Chinese medicines for the therapy of cough, excessive phlegm, pharyngitis, sore throat, dysuria, pemphigus, eczema, and jaundice with a long history. AIM OF THE REVIEW: The present review aims to achieve a comprehensive and up-to-date investigation in ethnomedical uses, phytochemistry, pharmacology, and toxicity of P. alkekengi var. franchetii, particularly its calyxes and fruits. Through analysis of these findings, evidences supporting their applications in ethnomedicines are illustrated. Possible perspectives and opportunities for the future research are analyzed to highlight the gaps in our knowledge that deserves further investigation. MATERIAL AND METHODS: Information on P. alkekengi var. franchetii was collected via electronic search of major scientific databases (e.g. Web of Science, SciFinder, Google Scholar, Pubmed, Elsevier, SpringerLink, Wiley online and China Knowledge Resource Integrated) for publications on this medicinal plant. Information was also obtained from local classic herbal literature on ethnopharmacology. RESULTS: About 124 chemical ingredients have been characterized from different parts of this plant. Steroids (particularly physalins) and flavonoids are the major characteristic and bioactive constituents. The crude extracts and the isolated compounds have demonstrated various in vitro and in vivo pharmacological functions, such as anti-inflammation, inhibition of tumor cell proliferation, antimicrobial activity, diuretic effect, anti-diabetes, anti-asthma, immunomodulation, and anti-oxidation. CONCLUSIONS: P. alkekengi var. franchetii is an important medicinal plant for the ethnomedical therapy of microbial infection, inflammation, and respiratory diseases (e.g. cough, excessive phlegm, pharyngitis). Phytochemical and pharmacological investigations of this plant definitely increased in the past half century. The chemical profiles, including ingredients and structures, have been adequately verified. Modern pharmacological studies supported its uses in the traditional and folk medicines, however, the molecular mechanisms of purified compounds remained unclear and were worth of further exploration. Therefore, the researchers should be paid more attention to a better utilization of this plant. PMID- 28838655 TI - Identification and characterization of lipid metabolism-related microRNAs in the liver of genetically improved farmed tilapia (GIFT, Oreochromis niloticus) by deep sequencing. AB - MicroRNAs (miRNAs) play vital roles in modulating diverse metabolic processes in the liver, including lipid metabolism. Genetically improved farmed tilapia (GIFT, Oreochromis niloticus), an important aquaculture species in China, is susceptible to hepatic steatosis when reared in intensive culture systems. To investigate the miRNAs involved in GIFT lipid metabolism, two hepatic small RNA libraries from high-fat diet-fed and normal-fat diet-fed GIFT were constructed and sequenced using high-throughput sequencing technology. A total of 204 known and 56 novel miRNAs were identified by aligning the sequencing data with known Danio rerio miRNAs listed in miRBase 21.0. Six known miRNAs (miR-30a-5p, miR-34a, miR-145-5p, miR-29a, miR-205-5p, and miR-23a-3p) that were differentially expressed between the high-fat diet and normal-fat diet groups were validated by quantitative real time PCR. Bioinformatics tools were used to predict the potential target genes of these differentially expressed miRNAs, and Gene Ontology enrichment analysis indicated that these miRNAs may play important roles in diet-induced hepatic steatosis in GIFT. Our results provide a foundation for further studies of the role of miRNAs in tilapia lipid homeostasis regulation, and may help to identify novel targets for therapeutic interventions to reduce the occurrence of fatty liver disease in farmed tilapia. PMID- 28838656 TI - Functions of the Prion Protein. AB - Although initially disregarded compared to prion pathogenesis, the functions exerted by the cellular prion protein PrPC have gained much interest over the past two decades. Research aiming at unraveling PrPC functions started to intensify when it became appreciated that it would give clues as to how it is subverted in the context of prion infection and, more recently, in the context of Alzheimer's disease. It must now be admitted that PrPC is implicated in an incredible variety of biological processes, including neuronal homeostasis, stem cell fate, protection against stress, or cell adhesion. It appears that these diverse roles can all be fulfilled through the involvement of PrPC in cell signaling events. Our aim here is to provide an overview of our current understanding of PrPC functions from the animal to the molecular scale and to highlight some of the remaining gaps that should be addressed in future research. PMID- 28838657 TI - Structural Modeling of Human Prion Protein's Point Mutations. AB - Prion diseases, or transmissible spongiform encephalopathies, are a group of rare fatal neurodegenerative maladies that affect humans and animals. The main event in disease progression is the posttranslational conversion of the ubiquitously expressed cellular form of the prion protein (PrPC) into its misfolded and pathogenic isoform, known as prion or PrPSc. In the presence of specific disease linked mutations, the conversion may occur spontaneously. Molecular simulation studies on human PrPC wild-type and variants from several research groups, including ours, have provided a consistent picture of the effect of such mutations. In particular, the calculations have pinpointed "hot spots" for the conversion across several disease-linked variants. They have also identified a region of the protein containing two helices (Helix 2 and Helix 3) as a key structural element most prone to the conversion, consistently with a wealth of experimental data. Some of these findings are summarized here. PMID- 28838658 TI - Prion Protein and Genetic Susceptibility to Diseases Caused by Its Misfolding. AB - Early genetic studies on scrapie, an infectious neurodegenerative disease of sheep that was adapted to mice, provided evidence in support of the hypothesis that the agent was a slow virus with a nucleic acid genome independent of the host. Particularly compelling support for an independent genome came from the existence of strains of scrapie agent, some of which were true breeding, while others appeared to mutate under selective pressure. Kuru, a neurodegenerative disease in the remote highlands of Papua New Guinea, had pathological changes similar to those in scrapie and also proved to be transmissible. Genetic studies with the tools of molecular biology and transgenic mice forced a reevaluation of earlier work and supported the prion hypothesis of a novel pathogen devoid of nucleic acid. In this chapter, I discuss the contributions of classical and molecular genetics to understanding PrP prion diseases and to determining that heritable information is enciphered in protein conformation. PMID- 28838659 TI - The Prion Concept and Synthetic Prions. AB - Transmissible spongiform encephalopathies or prion diseases are a group of fatal neurodegenerative diseases caused by unconventional infectious agents, known as prions (PrPSc). Prions derive from a conformational conversion of the normally folded prion protein (PrPC), which acquires pathological and infectious features. Moreover, PrPSc is able to transmit the pathological conformation to PrPC through a mechanism that is still not well understood. The generation of synthetic prions, which behave like natural prions, is of fundamental importance to study the process of PrPC conversion and to assess the efficacy of therapeutic strategies to interfere with this process. Moreover, the ability of synthetic prions to induce pathology in animals confirms that the pathological properties of the prion strains are all enciphered in abnormal conformations, characterizing these infectious agents. PMID- 28838660 TI - Gene Targeted Transgenic Mouse Models in Prion Research. AB - The production of transgenic mice expressing different forms of the prion protein (PrP) or devoid of PrP has enabled researchers to study the role of PrP in the infectious process of a prion disease and its normal function in the healthy individual. A wide range of transgenic models have been produced ranging from PrP null mice, normal expression levels to overexpression models, models expressing different species of the Prnp gene and different mutations and polymorphisms within the gene. Using this range of transgenic models has allowed us to define the influence of PrP expression on disease susceptibility and transmission, assess zoonotic potential, define strains of human prion diseases, elucidate the function of PrP, and start to unravel the mechanisms involved in chronic neurodegeneration. This chapter focuses mainly on the use of the gene targeted transgenic models and summarizes the ways in which they have allowed us to study the role of PrP in prion disease and the insights they have provided into the mechanisms of neurodegenerative diseases. PMID- 28838661 TI - Transmission and Replication of Prions. AB - Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal diseases that affect the nervous system of many mammals including humans. The key molecular event in the pathogenesis of TSEs is the conversion of the cellular prion protein PrPC into a disease-associated isoform PrPSc. The "protein-only hypothesis" argues that PrPSc itself is the infectious agent. In effect, PrPSc can adopt several structures that represent different prion strains. The interspecies transmission of TSEs is difficult because of differences between the host and donor primary PrP sequence. However, transmission is not impossible as this occurred when bovine spongiform encephalopathy spread to humans causing variant Creutzfeldt-Jakob disease (vCJD). This event determined a need for a thorough understanding of prion replication and transmission so that we could be one step ahead of further threats for human health. This chapter focuses on these concepts and on new insights gained into prion propagation mechanisms. PMID- 28838662 TI - Immunology of Prion Protein and Prions. AB - Many natural prion diseases are acquired peripherally, such as following the oral consumption of contaminated food or pasture. After peripheral exposure many prion isolates initially accumulate to high levels within the host's secondary lymphoid tissues. The replication of prions within these tissues is essential for their efficient spread to the brain where they ultimately cause neurodegeneration. This chapter describes our current understanding of the critical tissues, cells, and molecules which the prions exploit to mediate their efficient propagation from the site of exposure (such as the intestine) to the brain. Interactions between the immune system and prions are not only restricted to the secondary lymphoid tissues. Therefore, an account of how the activation status of the microglial in the brain can also influence progression of prion disease pathogenesis is provided. Prion disease susceptibility may also be influenced by additional factors such as chronic inflammation, coinfection with other pathogens, and aging. Finally, the potential for immunotherapy to provide a means of safe and effective prophylactic or therapeutic intervention in these currently untreatable diseases is considered. PMID- 28838663 TI - Phenotypical Variability in Bovine Spongiform Encephalopathy: Epidemiology, Pathogenesis, and Diagnosis of Classical and Atypical Forms. AB - After thirty years, bovine spongiform encephalopathy (BSE) still represents the biggest crisis in the field of food safety. Initially detected in the United Kingdom in 1986, BSE spread to many other countries all over the world, involving approximately 200,000 cattle. The origin of BSE is uncertain, but epidemiological studies suggest that the source was cattle feed prepared from prion-infected animal tissues. The implementation of the drastic measures, including the ban of meat and bone meal from livestock feed and the removal of specified risk material from the food chain, has eventually resulted in a significant decline of the epidemic. For many years, it was believed that the disease was caused by transmission of a single prion strain. However, since 2004 two types of BSE, with distinct phenotypical characteristics, have been detected in Italy and France. These atypical types are characterized by distinct Western Blot profiles of abnormal protease-resistant prion protein, named high-type (H-BSE) and low-type (L-BSE). At present, there is no comprehensive information about the origin of the atypical BSEs (sporadic vs. acquired), and data about the pathogenesis of both atypical forms are very limited as compared to the classical type (C-BSE). This chapter will provide a well-organized overview of what is known about classical and atypical BSE. It will review information on the main epidemiological features, pathogenesis, and the criteria for routine diagnosis based on rapid tests, histological, immunohistochemical, and Western blot analysis. Furthermore, a brief overview about the most recently in vitro techniques will be also provided. PMID- 28838664 TI - Scrapie, CWD, and Transmissible Mink Encephalopathy. AB - Transmissible spongiform encephalopathies (TSEs), or prions, are neurodegenerative diseases that affect a variety of animal species, including humans. Cruetzfeldt-Jakob disease (CJD) in humans, sheep and goat scrapie, chronic wasting disease (CWD) of cervids, and transmissible mink encephalopathy (TME) of mink are classified as TSEs. According to the "protein-only" hypothesis (Prusiner, 1982),1 prions are devoid of nucleic acids and consist of assemblies of misfolded host-encoded normal protein, the prion protein (PrPC). Prion propagation is thought to occur by a templating mechanism during which PrPC is recruited, converted to a disease-associated isoform (PrPD), and assembled onto the growing amyloid fibril. This fibular assembly is infectious, with ability to initiate disease processes similar to other pathogenic agents. Evidence indicates that scrapie, CWD, and TME disease processes follow this rule. PMID- 28838665 TI - Infectious and Sporadic Prion Diseases. AB - Prion diseases are progressive fatal encephalopathies characterized by a neurodegenerative pathology, the tissue deposition of abnormally folded prion protein and, in general, potential transmissibility. Creutzfeldt-Jakob disease (CJD) is the commonest human prion disease and occurs in three principal forms: sporadic (idiopathic), acquired (infectious), and inherited (genetic). This chapter concerns the sporadic and acquired forms. Sporadic CJD occurs worldwide and affects mainly the middle aged and elderly. There are recognized genetic risk factors-most importantly the PRNP-129 polymorphism. The acquired forms of CJD consist of iatrogenic CJD (accidental transmission of CJD via medical or surgical procedures) and variant CJD (vJCD) (which originated as a zoonosis via bovine spongiform encephalopathy (BSE)-contamination of human food). The main causes of iatrogenic CJD are cadaveric-derived human growth hormone treatment and dura mater surgical grafts. The PRNP-129 polymorphism has important effects on iatrogenic infection, including overall susceptibility and incubation period. vCJD, resulting from dietary exposure to BSE, has affected mostly the United Kingdom, followed by France. All tested cases were originally PRNP-129MM, although two MV cases have been identified recently (one possible; one definite). vCJD has been secondarily transmitted via blood transfusion and a blood product. There is continuing concern over secondary transmission since there is evidence from lymphoreticular tissue studies-of extensive subclinical infection in the UK general population, although a further recent study has caused uncertainty over the significance of the previous studies. While definitive diagnosis of CJD is pathological, recent developments in protein amplification and detection have led to significantly better clinical diagnosis. PMID- 28838666 TI - Neuropathology of Human Prion Diseases. AB - The human prion diseases comprise sporadic, genetic, and acquired disorders. These are rare conditions with a heterogeneous clinicopathologic phenotype, which can make diagnosis challenging. A combined clinical, genetic, neuropathologic and biochemical approach to diagnosis is therefore essential. Since prion infectivity is the highest in tissues from the central nervous system, special laboratory precautions are required for the safe handling of these tissues. Neuropathologic assessment is generally performed following autopsy, when the fixed brain should be adequately sampled and studied by conventional stains and immunohistochemistry for the abnormal form of the prion protein. Frozen brain tissue is also required for DNA extraction for prion protein gene sequencing and for Western blot analysis of protease-resistant prion protein. The microscopic assessment of the nature and degree of spongiform change, neuronal loss, gliosis, and abnormal prion protein deposition in the brain can be used to determine the major categories of human prion disease. This information can be combined with clinical, genetic data, and biochemical data to allow an accurate diagnosis of a human prion disease and facilitates subclassification into recognized disease subtypes, for example in sporadic Creutzfeldt-Jakob disease. The spectrum of human prion diseases continues to expand and neuropathology will play a key role in the recognition and understanding of any further novel entities or disease variants that may emerge in the future. PMID- 28838667 TI - The Structure of the Infectious Prion Protein and Its Propagation. AB - The prion diseases, which include Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids (i.e., deer, elk, moose, and reindeer), bovine spongiform encephalopathy in cattle, as well as sheep and goat scrapie, are caused by the conversion of the cellular prion protein (PrPC) into a disease causing conformer (PrPSc). PrPC is a regular, GPI-anchored protein that is expressed on the cell surface of neurons and many other cell types. The structure of PrPC is well studied, based on analyses of recombinant PrP, which is thought to mimic the structure of native PrPC. The mature protein contains an N-terminal, unfolded domain and a C-terminal, globular domain that consists of three alpha helices and only a small, two-stranded beta-sheet. In contrast, PrPSc was found to contain predominantly beta-structure and to aggregate into a variety of quaternary structures, such as oligomers, amorphous aggregates, amyloid fibrils, and two-dimensional crystals. The tendency of PrPSc to aggregate into these diverse forms is also responsible for our incomplete knowledge about its molecular structure. Nevertheless, the repeating nature of the more regular PrPSc aggregates has provided informative insights into the structure of the infectious conformer, albeit at limited resolution. These data established a four-rung beta solenoid architecture as the main element of its structure. Moreover, the four rung beta-solenoid architecture provides a molecular framework for an autocatalytic propagation mechanism, which could explain the conversion of PrPC into PrPSc. PMID- 28838668 TI - Copper- and Zinc-Promoted Interdomain Structure in the Prion Protein: A Mechanism for Autoinhibition of the Neurotoxic N-Terminus. AB - The function of the cellular prion protein (PrPC), while still poorly understood, is increasingly linked to its ability to bind physiological metal ions at the cell surface. PrPC binds divalent forms of both copper and zinc through its unstructured N-terminal domain, modulating interactions between PrPC and various receptors at the cell surface and ultimately tuning downstream cellular processes. In this chapter, we briefly discuss the molecular features of copper and zinc uptake by PrPC and summarize evidence implicating these metal ions in PrP-mediated physiology. We then focus our review on recent biophysical evidence revealing a physical interaction between the flexible N-terminal and globular C terminal domains of PrPC. This interdomain cis interaction is electrostatic in nature and is promoted by the binding of Cu2+ and Zn2+ to the N-terminal octarepeat domain. These findings, along with recent cellular studies, suggest a mechanism whereby NC interactions serve to regulate the activity and/or toxicity of the PrPC N-terminus. We discuss this potential mechanism in relation to familial prion disease mutations, lethal deletions of the PrPC central region, and neurotoxicity induced by certain globular domain ligands, including bona fide prions and toxic amyloid-beta oligomers. PMID- 28838669 TI - Protein Misfolding Cyclic Amplification of Infectious Prions. AB - Transmissible spongiform encephalopathies, or prion diseases, are a group of incurable disorders caused by the accumulation of an abnormally folded prion protein (PrPSc) in the brain. According to the "protein-only" hypothesis, PrPSc is the infectious agent able to propagate the disease by acting as a template for the conversion of the correctly folded prion protein (PrPC) into the pathological isoform. Recently, the mechanism of PrPC conversion has been mimicked in vitro using an innovative technique named protein misfolding cyclic amplification (PMCA). This technology represents a great tool for studying diverse aspects of prion biology in the field of basic research and diagnosis. Moreover, PMCA can be expanded for the study of the misfolding process associated to other neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and frontotemporal lobar degeneration. PMID- 28838670 TI - Amplified Detection of Prions and Other Amyloids by RT-QuIC in Diagnostics and the Evaluation of Therapeutics and Disinfectants. AB - Among the most sensitive, specific and practical of methods for detecting prions are the real-time quaking-induced conversion (RT-QuIC) assays. These assays exploit the fundamental self-propagating activity of prions to amplify the presence of prion seeds by as much as a trillion-fold. The reactions can detect most of the known mammalian prion diseases, often with sensitivities greater than those of animal bioassays. RT-QuIC assays are performed in multiwell plates with fluorescence detection and have now reached the sensitivity and practicality required for routine prion disease diagnostics. Some key strains of prions within particular host species, e.g., humans, cattle, and sheep, can be discriminated by comparison of RT-QuIC responses with different recombinant prion protein substrates. The most thoroughly validated diagnostic application of RT-QuIC is in the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) using cerebrospinal fluid. Diagnostic sensitivities as high as 96% can be achieved in less than 24h with specificities of 98%-100%. The ability, if needed, to also test nasal swab samples can increase the RT-QuIC sensitivity for sCJD to virtually 100%. In addition to diagnostic applications, RT-QuIC has also been used in the testing of prion disinfectants and potential therapeutics. Mechanistically related assays are also now being developed for other protein misfolding diseases. PMID- 28838671 TI - Biochemical Characterization of Prions. AB - Prion disease or transmissible spongiform encephalopathies are characterized by the presence of the abnormal form of the prion protein (PrPSc). The pathological and transmissible properties of PrPSc are enciphered in its secondary and tertiary structures. Since it's well established that different strains of prions are linked to different conformations of PrPSc, biochemical characterization of prions seems a preliminary but reliable approach to detect, analyze, and compare prion strains. Experimental biochemical procedures might be helpful in distinguishing PrPSc physicochemical properties and include resistance to proteinase K (PK) digestion, insolubility in nonionic detergents, PK-resistance under denaturing conditions and sedimentation properties in sucrose gradients. This biochemical approach has been extensively applied in human prion disorders and subsequently expanded for PrPSc characterization in animals. In particular, in sporadic Creutzfedlt-Jakob disease (sCJD) PrPSc is characterized by two main glycotypes conventionally named Type 1 and Type 2, based on the apparent gel migration at 21 and 19kDa of the PrPSc PK-resistant fragment. An additional PrPSc type was identified in sCJD characterized by an unglycosylated dominant glycoform pattern and in 2010 a variably protease-sensitive prionopathy (VPSPr) was reported showing a PrPSc with an electrophoretic ladder like pattern. Additionally, the presence of PrPSc truncated fragments completes the electrophoretic characterization of different prion strains. By two-dimensional (2D) electrophoretic analysis additional PrPSc pattern was identified, since this procedure provides information about the isoelectric point and the different peptides length related to PK cleavage, as well as to glycosylation extent or GPI anchor presence. We here provide and extensive review on PrPSc biochemical analysis in human and animal prion disorders. Further, we show that PrPSc glycotypes observed in CJD share similarities with PrPSc in bovine spongiform encephalopathy forms (BSE). PMID- 28838672 TI - Omics of Prion Diseases. AB - Prion diseases are unique neurodegenerative pathologies that can occur with sporadic, genetic, and acquired etiologies. Human and animal prion diseases can be recapitulated in laboratory animals with good reproducibility providing highly controlled models for studying molecular mechanisms of neurodegeneration. In this chapter the overall area of omics research in prion diseases is described. The term omics includes all fields of studies that employ a comprehensive, unbiased, and high-throughput approach to areas of research such as functional genomics, transcriptomics, and proteomics. These kind of approaches can be extremely helpful in identifying disease susceptibility factors and pathways that are dysregulated upon the onset and the progression of the disease. Herein, the most important research about the various forms of prion pathologies in human and in models of prion diseases in animals is presented and discussed. PMID- 28838673 TI - Therapeutic Approaches to Prion Diseases. AB - Therapy of prion diseases represents an extremely challenging effort for scientists working in the field. These challenges are epitomized by 20 years of failures in clinical trials and preclinical investigations. However, the discovery that misfolded proteins involved in other neurodegenerative diseases show a prion-like mechanism of spreading, is positively impacting the prion drug discovery field. Herein, we describe those efforts that have contributed to strengthen the drug discovery process in prion diseases. Accordingly, we analyze the historical course of clinical trials that have assessed the efficacy of several chemically unrelated repositioned drugs. Unfortunately, none of them resulted successful. Thus, alternative approaches aiming at identifying innovative drugs with a completely new mechanism of action, have been recently pursued. In this respect, the multifactorial nature of prion diseases provides a strong foundation to the development of small molecules directed to two or multiple pathological targets, critically involved in the intricate disease pathogenesis (i.e., multitarget compounds). Second, the fact that misfolded proteins can be considered not only as therapeutic target, but also as neuropathological hallmark, lends support to the development of theranostics, i.e., single molecules with concomitant therapeutic and diagnostic properties. Although nobody knows whether these innovative tools will be brought to clinical trials, and the process is certainly time-consuming and demanding, the rewards are well worth the effort. PMID- 28838674 TI - Biosafety of Prions. AB - Prions are the infectious agents that cause devastating and untreatable disorders known as Transmissible Spongiform Encephalopathies (TSEs). The pathologic events and the infectious nature of these transmissible agents are not completely understood yet. Due to the difficulties in inactivating prions, working with them requires specific recommendations and precautions. Moreover, with the advent of innovative technologies, such as the Protein Misfolding Cyclic Amplification (PMCA) and the Real Time Quaking-Induced Conversion (RT-QuIC), prions could be amplified in vitro and the infectious features of the amplified products need to be carefully assessed. PMID- 28838676 TI - Understanding the Effect of Disease-Related Mutations on Human Prion Protein Structure: Insights From NMR Spectroscopy. AB - Prion diseases or transmissible spongiform encephalopathies constitute a group of fatal neurodegenerative diseases that can be of sporadic, genetic, or acquired origin. The central molecular event of prion diseases is the conformational conversion of the physiological cellular prion protein, PrPC, into a disease associated form known as prion or PrPSc. Spontaneous generation of prions in genetic prion diseases is caused by mutations in the human prion protein gene (PRNP). Understanding of the earliest conformational changes during misfolding of PrPC in genetic forms of prion diseases may benefit from detailed structural characterization of various human (Hu) PrP variants. Nuclear magnetic resonance (NMR) spectroscopy offers unique opportunities to obtain detailed atomic-level structure information. In this chapter we present an overview of high-resolution NMR studies on several HuPrPs with disease-associated mutations at mildly acidic and physiological pH conditions that provided valuable insights into possible key structural determinants underlying the formation of prions. PMID- 28838675 TI - Cell Biology of Prion Protein. AB - Cellular prion protein (PrPC) is a mammalian glycoprotein which is usually found anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. The precise function of PrPC remains elusive but may depend upon its cellular localization. PrPC misfolds to a pathogenic isoform PrPSc, the causative agent of neurodegenerative prion diseases. Nonetheless some forms of prion disease develop in the apparent absence of infectious PrPSc, suggesting that molecular species of PrP distinct from PrPSc may represent the primary neurotoxic culprits. Indeed, in some inherited cases of human prion disease, the predominant form of PrP detectable in the brain is not PrPSc but rather CtmPrP, a transmembrane form of the protein. The relationship between the neurodegeneration occurring in prion diseases involving PrPSc and that associated with CtmPrP remains unclear. However, the different membrane topology of the PrP mutants, as well as the presence of the GPI anchor, could influence both the function and the intracellular localization and trafficking of the protein, all being potentially very important in the pathophysiological mechanism that ultimately causes the disease. Here, we review the latest findings on the fundamental aspects of prions biology, from the PrPC biosynthesis, function, and structure up to its intracellular traffic and analyze the possible roles of the different topological isoforms of the protein, as well as the GPI anchor, in the pathogenesis of the disease. PMID- 28838677 TI - Preface. PMID- 28838678 TI - Critical care polyneuropathy in burn injuries: An integrative review. AB - Polyneuropathy is a debilitating condition which may be associated with large burns. The aim of this integrative review is to identify factors that contribute to the development of critical care polyneuropathy in patients admitted to an intensive care unit with a severe burn injury. PubMed, Scopus, CINHAL and EMBASE were searched up until July 2016. Studies/case reports focusing on critical care polyneuropathy for burn injured patients were included. The ten studies, included a total of 2755 burns subjects and identified 128 critical care polyneuropathy patients with an incidence of 4.4%. Three case reports identified prolonged ventilation and development of critical care neuropathy. Overall, factors identified as contributing to the development of critical care polyneuropathy in burn injured patients included prolonged ventilation (>7 days), large and deep total body surface area burns (mean TBSA 40%), and sepsis. Critical care polyneuropathy in burn patients remains challenging to diagnose and treat. To date, there is a lack of long term studies describing the impact of critical care polyneuropathy on functional performance or participation in activities of daily living in the burns population and this is consistent with the general literature addressing the lack of follow up assessments and long term consequences of persistent muscle weakness. PMID- 28838680 TI - On the identity of the 'Upland seal' with comments on the paper by Salis et al. (2016). PMID- 28838679 TI - Polyols and remineralisation of enamel subsurface lesions. AB - : Sugar-free chewing gum containing polyols has been demonstrated to reduce caries experience in randomised controlled clinical trials. A range of polyols (mannitol, sorbitol, xylitol and maltitol) can be found in sugar-free gums and it has been claimed that they can facilitate calcium uptake into enamel subsurface lesions promoting remineralisation. OBJECTIVES: The aim of this study was to compare the effect of polyols on remineralisation of enamel subsurface lesions in vitro by artificial saliva (AS) and by AS containing the salivary biomimetic casein phosphopeptide amorphous calcium phosphate (CPP-ACP). METHODS: The polyols (12.6% w/v) and CPP-ACP (0.376% w/v) were used at physiologically relevant concentrations approximating those released into saliva during chewing a CPP ACP/polyol chewing gum. Enamel subsurface lesions were exposed to one of the polyols (xylitol, sorbitol, maltitol, mannitol) in AS or AS containing CPP-ACP for 7days at 37 degrees C with a change of solution each day. Remineralisation of the enamel subsurface lesions was measured by transverse microradiography. RESULTS: A statistical test for equivalence showed there was no difference in remineralisation between the AS solutions with or without any of the polyols. The AS+CPP-ACP solution substantially promoted remineralisation over AS alone independently of any polyol added. CONCLUSION: This controlled in vitro study showed that polyols at physiologically relevant concentrations did not promote remineralisation of enamel subsurface lesions by facilitating calcium uptake into the lesion. PMID- 28838681 TI - Adherence to anticoagulant treatment with apixaban and rivaroxaban in a real environment. PMID- 28838682 TI - Is atrial fibrillation another manifestation of organ damage in diabetes? PMID- 28838683 TI - Risk of atrial fibrillation in people with type 1 diabetes compared with matched controls from the general population: a prospective case-control study. AB - BACKGROUND: Type 1 diabetes is associated with an increased risk of developing several cardiovascular complications. To our knowledge, the independent association between type 1 diabetes and atrial fibrillation has not been studied. METHODS: We did a prospective case-control study of individuals with type 1 diabetes in the Swedish National Diabetes Registry who were each matched with five controls for age, sex, and county of residence who were randomly selected from the Swedish Population Register. Cases of atrial fibrillation were obtained from the Swedish National Patient Registry. FINDINGS: We followed up 36 258 patients with type 1 diabetes and 179 980 controls between Jan 1, 2001, and Dec 31, 2013. Median follow-up was 9.7 years (IQR 5.2-13.0) for patients and 10.2 years (5.7-13.0) for controls. 749 (2%) individuals with type 1 diabetes and 2882 (2%) controls were diagnosed with atrial fibrillation, with an adjusted hazard ratio (HR) of 1.13 (95% CI 1.01-1.25; p=0.029) in men and 1.50 (1.30-1.72; p<0.0001) in women (p=0.0019 for interaction). The excess risk of atrial fibrillation in individuals with type 1 diabetes increased with worsening glycaemic control and renal complications. Among individuals with normoalbuminuria, no excess risk of atrial fibrillation was noted in men with type 1 diabetes who had HbA1c lower than 9.7% (<83 mmol/mol) or in women with type 1 diabetes who had HbA1c lower than 8.8% (<73 mmol/mol). INTERPRETATION: Compared with the general population, the risk of atrial fibrillation in men with type 1 diabetes was slightly raised, whereas for female patients it was 50% higher. The risk of atrial fibrillation in people with type 1 diabetes increased with renal complications and poor glycaemic control. FUNDING: Novo Nordisk Foundation, Swedish State (ALF agreement), Swedish Research Council (SIMSAM), Swedish Heart and Lung Foundation, Swedish Diabetes Foundation, Diabetes Wellness. PMID- 28838684 TI - Exaggerated hypertensive response to exercise and myocardial ischaemia in patients with known or suspected coronary artery disease. AB - OBJECTIVES: The association between an exaggerated hypertensive response to exercise (EHRE) and the probability of ischaemia in stress tests is controversial. Our purpose was to determine the possible association between an EHRE and the development of chest pain and electrocardiographic or echocardiographic ischaemia with exercise. PATIENTS AND METHODS: A retrospective observational study was conducted of 10,047 patients with known or suspected coronary artery disease referred for exercise echocardiography. A logistic regression analysis assessed the effect of developing an EHRE (defined as a maximum systolic blood pressure with exercise >=220mmHg) and the onset of chest pain and electrocardiographic and echocardiographic changes suggestive of ischaemia. RESULTS: A total of 402 patients developed an EHRE. The rates of angina, electrocardiographic ischaemia and echocardiographic ischaemia among the patients with an EHRE were 8.2, 16.2 and 22.6% versus 13.8, 14.7 and 27.5%, respectively, for patients without an EHRE (p=.001, p=.4, p=.032). After a multivariate fit, EHRE was associated with a lower probability of exercise induced angina (OR, 0.44; 95% CI 0.30-0.65; p<.001) and echocardiographic ischaemia (OR, 0.63; 95% CI 0.48-0.83; p=.001) but not with the onset of electrocardiographic ischaemia. CONCLUSIONS: EHRE is associated with a lower prevalence of angina and echocardiographic ischaemia in patients with known or suspected coronary artery disease. PMID- 28838685 TI - Efficacy and safety of glycopyrrolate/eFlow(r) CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: Results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials. AB - BACKGROUND: SUN-101 is a combination of glycopyrrolate delivered through an innovative, electronic nebulizer, intended for the treatment of patients with COPD. The objective of this study was to assess the efficacy and safety of this new drug device combination. METHODS: Replicate Phase III randomized, double blind, placebo-controlled studies were conducted to evaluate the efficacy and safety of glycopyrrolate solution administered by an investigational eFlow(r) Closed System (eFlow(r) CS) nebulizer in subjects with moderate-to-very-severe COPD, including those with continued background use of a long-acting beta2 agonist +/- inhaled corticosteroid and/or history of cardiovascular (CV) disease. Subjects were randomized in a 1:1:1 ratio to receive placebo or glycopyrrolate (25 MUg or 50 MUg twice daily [BID]) for 12 weeks. The primary efficacy endpoint was the change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 12 compared with placebo. Secondary endpoints included change from baseline in forced vital capacity (FVC) after 12 weeks, change from baseline in health status measured by St George's Respiratory Questionnaire (SGRQ) at 12 weeks/end of study (EOS), and change in rescue medication use, as well as change from baseline in FEV1 area under the curve from 0 to 12 h after 12 weeks in the GOLDEN 3 sub-study. Daytime and night-time symptoms were recorded using an electronic diary. Safety was monitored throughout the study, including major adverse cardiovascular events. RESULTS: A total of 653 subjects were randomized in GOLDEN 3 and 641 in GOLDEN 4. Treatment with glycopyrrolate 25 MUg BID and 50 MUg BID resulted in statistically significant and clinically important changes from baseline in trough FEV1 compared with placebo at Week 12 (GOLDEN 3: 0.105 L and 0.126 L; p <= 0.0001; GOLDEN 4: 0.084 L and 0.082 L; p <= 0.0001). Nebulized glycopyrrolate 25 MUg BID and 50 MUg BID also resulted in improvements in FVC change from baseline versus placebo at Week 12 (GOLDEN 3: 0.149 L and 0.167 L, p < 0.001; GOLDEN 4: 0.130 L and 0.113 L, p < 0.01), and in SGRQ change from baseline score versus placebo at Week 12/EOS (GOLDEN 3: -3.072 [p < 0.05] and 1.848; GOLDEN 4: -3.585 and -3.557, p < 0.01). LS mean change from baseline in EXACT-respiratory symptoms total score at Week 12 for placebo and nebulized glycopyrrolate 25 and 50 MUg BID were -0.936, -1.903 and -1.502 for GOLDEN 3 and 0.376, -1.647 and -1.532 for GOLDEN 4. Rescue medication use was unchanged. Nebulized glycopyrrolate was well tolerated at both doses based on the incidence of adverse events and CV events. CONCLUSIONS: The results of these studies demonstrated statistically significant and clinically important improvements in pulmonary function and patient-reported health outcomes, with an acceptable safety profile, support the use of glycopyrrolate/eFlow(r) CS as a potential maintenance treatment for moderate-to-very-severe COPD. PMID- 28838686 TI - Use of high b value diffusion-weighted magnetic resonance imaging in acute encephalopathy/encephalitis during childhood. AB - AIM: To determine the use of high b value diffusion-weighted imaging (DWI) in the diagnosis and assessment of acute febrile encephalopathy/encephalitis in childhood. SUBJECTS AND METHODS: We enrolled 22 children, for whom we examined DWI with b=1000s/mm2, DWI with b=3000s/mm2, and apparent diffusion coefficient (ADC) map with b=1000 during the acute phase of febrile encephalopathy/encephalitis. Clinical diagnoses included acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n=6), clinically mild encephalopathy/encephalitis with a reversible splenial lesion (MERS; n=6), and herpes simplex virus encephalitis (HSE; n=3), unclassified acute encephalopathy/acute encephalitis (n=2); acute encephalitis with refractory, repetitive partial seizures (AERRPS; n=1); other encephalopathy (n=1); infarction (n=1); head injury (n=1); or mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (n=1). The diagnostic quality of brain lesions was compared between b=1000 and b=3000 DWI images by visual inspection. In addition, we attempted a quantitative assessment using apparent diffusion coefficient (ADC) value and an index of signal intensity (SI) ratio, defined as the mean SI at the affected lesion divided by the mean SI at the pons. RESULTS: High intensity lesions were either visible only on b=3000 DWI (n=5; 2 AESD, 1 MERS, 1 HSE, and 1 unclassifiable encephalopathy) or more effectively identified on b=3000 DWI than on b=1000 DWI (n=17). The outcome of the former five subjects was favorable, without motor or intellectual sequelae. The mean SI ratio of b=3000 was significantly greater than that of b=1000 in AESD and MERS subgroups as well as in all 22 subjects. Mean ADC values were lower in the AESD and MERS than that in the HSE subgroups. CONCLUSION: We concluded that b=3000 DWI was superior to b=1000 DWI in detecting abnormal lesions in acute encephalopathy/encephalitis during childhood. PMID- 28838687 TI - Understanding nitrate uptake, signaling and remobilisation for improving plant nitrogen use efficiency. AB - The majority of terrestrial plants use nitrate as their main source of nitrogen. Nitrate also acts as an important signalling molecule in vital physiological processes required for optimum plant growth and development. Improving nitrate uptake and transport, through activation by nitrate sensing, signalling and regulatory processes, would enhance plant growth, resulting in improved crop yields. The increased remobilisation of nitrate, and assimilated nitrogenous compounds, from source to sink tissues further ensures higher yields and quality. An updated knowledge of various transporters, genes, activators, and microRNAs, involved in nitrate uptake, transport, remobilisation, and nitrate-mediated root growth, is presented. An enhanced understanding of these components will allow for their orchestrated fine tuning in efforts to improving nitrogen use efficiency in plants. PMID- 28838688 TI - Evaluation of tetraether lipid-based liposomal carriers for encapsulation and retention of nucleoside-based drugs. AB - Although liposomal nanoparticles are one of the most versatile class of drug delivery systems, stable liposomal formulation of small neutral drug molecules still constitutes a challenge due to the low drug retention of current lipid membrane technologies. In this study, we evaluate the encapsulation and retention of seven nucleoside analog-based drugs in liposomes made of archaea-inspired tetraether lipids, which are known to enhance packing and membrane robustness compared to conventional bilayer-forming lipids. Liposomes comprised of the pure tetraether lipid generally showed improved retention of drugs (up to 4-fold) compared with liposomes made from a commercially available diacyl lipid. Interestingly, we did not find a significant correlation between the liposomal leakage rates of the molecules with typical parameters used to assess lipophilicity of drugs (such logD or topological polar surface area), suggesting that specific structural elements of the drug molecules can have a dominant effect on leakage from liposomes over general lipophilic character. PMID- 28838689 TI - Efficient synthesis of the GABAA receptor agonist trans-4-aminocrotonic acid (TACA). AB - Investigations into the pharmacology of different types of cys-loop GABA receptor have relied for years on the chemical modification of GABA-like compounds. The GABA metabolite GABOB is an attractive molecule to modify due to its convenient chemical structure. In the process of developing new GABA-mimic compounds from GABOB as a starting compound three small molecule GABA derivatives were synthesized using a variety of chemical transformations. Amongst these, a new and reliable method to synthesize TACA (trans-4-aminocrotonic acid) is reported. PMID- 28838690 TI - Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates. AB - A series of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04MUM, respectively, which were comparable to that of Ninnanmycin (6.78MUM) and even better than that of Ribavirin (99.25MUM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC50 values of 33.66, 33.97, 33.87 and 30.57ug/mL, respectively, which were comparable to that of Ningnanmycin (36.85ug/mL) and superior to that of Ribavirin (88.52ug/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results. PMID- 28838691 TI - Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and alpha-glucosidase. AB - A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and alpha glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC50: 1.79-10.71nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against alpha-glucosidase (IC50=0.14, 0.09 and 0.25uM, respectively) were obvious higher than that of miglitol (IC50=2.43uM), a clinical using alpha-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFRwt tyrosine kinase (IC50=1.79nM), also to alpha-glucosidase (IC50=0.39uM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or alpha glucosidase. PMID- 28838692 TI - Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer activity against breast cancer cell lines. AB - Forskolin C1-isoxazole derivatives (3,5-regioisomers) (11a-e, 14, 15a-h and 15, 16a-g) were synthesized regioselectively by adopting 1,3-dipolar cycloadditions. These derivatives were tested using estrogen receptor positive breast cancer cell lines MCF-7 and BT-474. Majority of the compounds exhibited activity against the p53-positive MCF-7 breast cancer cells but not against the p53-negative BT-474 breast cancer cells. Among forskolin derivatives, compounds 11a, 11c, 14a, 14f, 14g, 14h, 15b, 16g and 17b exhibited higher anti-cancer activity against MCF-7 cell line with an IC50<=1uM. The derivative 14f exhibited highest activity in both p53-positive (MCF-7) and p53-negative (BT-474) breast cancer cell lines with an IC50 of 0.5uM. PMID- 28838694 TI - Synthesis and electronic properties of ester substituted 1,4 dicyanodibenzodioxins and evaluation of anti-proliferative activity of all isomeric 1,2-, 2,3- and 1,4-dicyanodibenzodioxins against HeLa cell line. AB - 1,4-Dicyanodibenzodioxins bearing carboxy methyl ester groups were synthesized using our established one-step SNAr coupling reaction between ortho- and meta ester substituted catechols and perfluorinated terephthalonitrile. These are the first examples of 1,4-dicyanodibenzodioxins substituted at both the benzene moieties. Optical spectra were similar to the earlier examples reported, with a marginal blue shift for the ester dibenzodioxins. Theoretical analysis of the molecular orbitals reveals modest destabilization of the frontier molecular orbitals of one carboxy methyl ester isomer over the other and overall higher HOMO-LUMO gap for both isomers when compared to the earlier published 1,4 dicyanodibenzodioxins. In vitro cytotoxicity against human cervical cancer HeLa cell line was evaluated for these two compounds and all other previously published dibenzodioxins from our laboratory (1,4-dicyano, 1,2-dicyano and 2,3 dicyano variants). A number of derivatives showed anti-tumor activity in MUM ranges and also exhibited no cytotoxicity against normal HEK 293 cell line. Mechanistic investigation of cell death pathways indicated high levels of reactive oxygen species (ROS) in the dibenzodioxin treated tumor cell lines along with cellular nuclear fragmentation, both of which are markers of the apoptotic cell death pathway. PMID- 28838695 TI - Design, synthesis and preliminary antiproliferative activity studies of new diheteroaryl thioether derivatives. AB - A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC50) values below 10MUM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well asarrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers. PMID- 28838693 TI - Design, synthesis, and biological activity of 5'-phenyl-1,2,5,6-tetrahydro-3,3' bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors. AB - Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridines (3a 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5 positions, respectively, and then subsequent modifications were made on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist, which is highly selective for alpha3beta4 nAChR (Ki=123nM) over the alpha4beta2 and alpha7 receptors. PMID- 28838696 TI - Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators. AB - We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3mg/kg, q.d.). PMID- 28838697 TI - Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents. AB - The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2) were selected as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then, chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be considered as promising compounds for colon and prostatic cancer adjuvant therapy. PMID- 28838698 TI - Pyrazole C-region analogues of 2-(3-fluoro-4 methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists. AB - A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3 chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP)=0.1nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360. PMID- 28838699 TI - Efficacious cellular codelivery of doxorubicin and EGFP siRNA mediated by the composition of PLGA and PEI protected gold nanoparticles. AB - This study reports the simultaneous delivery of EGFP siRNA and the chemotherapeutic drug, doxorubicin by means of the composition that results from the electrostatic interaction between positively charged siRNA-complexes of gold nanoparticles (AuNPs) capped with PEI, 25kDa (P25-AuNPs) and negatively charged carboxymethyl cellulose formulated PLGA nanoparticles loaded with doxorubicin. The nanoparticles and their facile interaction were studied by means of dynamic light scattering (DLS), zeta potential, transmission electron microscopic (TEM) measurements. The flow cytometric and confocal microscopic analysis evidenced the simultaneous internalization of both labelled siRNA and doxorubin into around 55% of the HeLa cancer cell population. Fluorescence microscopic studies enabled the visual analysis of EGFP expressing HeLa cells which suggested that the composition mediated codelivery resulted in a substantial downregulation of EGFP expression and intracellular accumulation of doxorubicin. Interestingly, codelivery treatment resulted in an increased cellular delivery of doxorubicin when compared to PLGA-DOX alone treatment. On the other hand, the activity of siRNA complexes of PEI-AuNPs was completely retained even when they were part of composition. The results suggest that this formulation can serve as promising tool for delivery applications in combinatorial anticancer therapy. PMID- 28838700 TI - Surgical approaches in neck dissection: Comparing functional, oncologic and aesthetic aspects of transverse cervicotomy to Paul Andre's approach. AB - BACKGROUND: Surgical approaches in neck dissection: comparing functional, oncologic and aesthetic aspects of transverse cervicotomy to Paul Andre's approach. METHODS: This single-center retrospective study compares a new transverse incision for cervicotomy to the classical approach described by Paul Andre in neck dissections. The evaluation criteria were: number of lymph nodes analyzed, operative time, complications, patient satisfaction and aesthetic aspects of the scar. RESULTS: A total of 34 patients were included in this study, from September 2009 until January 2015. The number of lymph nodes analyzed is not affected by this new approach compared to the classical one (P=0.9). The scar has a significantly more discreet appearance in the transverse cervicotomy group (P=0.023) likewise; patient satisfaction is higher in this group (P=0.006). CONCLUSIONS: Aesthetic and functional impairment can be reduced using this new transverse cervical approach hidden in the natural creases of the neck described by Langer. PMID- 28838701 TI - [Conclusions: An "up-to-date" neck-and face-lift?] PMID- 28838702 TI - Long-term outlook for transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) revolutionized the treatment of severe symptomatic aortic stenosis (AS). TAVR is increasingly offered for lower risk patients. The role and place of TAVR in the future treatment of AS is not clear yet. In this review, we discuss the long-term outlook for TAVR, its challenges and its relationship to conventional surgical aortic valve replacement. PMID- 28838703 TI - PacBio Sequencing Reveals Transposable Elements as a Key Contributor to Genomic Plasticity and Virulence Variation in Magnaporthe oryzae. PMID- 28838704 TI - Contact pressure of the coracoacromial arch in shoulders with joint contracture: A cadaveric study. AB - BACKGROUNDS: There have been many reports describing that the capsular fibrosis of the shoulder joint is the main cause of frozen shoulder, whereas others reported the significance of subacromial impingement as an etiological factor. The purpose of this study was to investigate the contact pressure between the coracoacromial arch and the rotator cuff tendons to clarify the contact phenomenon in shoulders with joint contracture. METHODS: Fourteen fresh-frozen cadaveric shoulders were used. Specimens were divided into two groups: normal group (8 shoulders, definition: more than 61 degrees of flexion and abduction and more than 21 degrees of external rotation) and joint contracture group (6 shoulders, definition: less than 60 degrees of flexion and abduction and less than 20 degrees of external rotation). Contact pressure and area beneath the coracoacromial arch were measured by a flexible force sensor during flexion, abduction, internal and external rotation in adduction and abduction, extension and horizontal extension motions. RESULTS: The peak contact pressure under the acromion was observed at 90 degrees in flexion and abduction in the normal group, whereas that in the contracture group was observed at 30 degrees in flexion (P = 0.037) and at 30 degrees in abduction (P = 0.041). Contact pressure in the contracture group was significantly higher than that in the normal group at 20 degrees and 30 degrees of abduction (P = 0.043, P = 0.041, respectively). There were no significant differences of contact pressure during other motions. Although no significant differences of contact pressure beneath the coracoacromial ligament were observed, contact area significantly increased in extension and horizontal extension motion. CONCLUSION: The contact between the acromion and the rotator cuff was observed in lower angles of flexion and abduction in shoulders with contracture than in those without. When treating patients with shoulder contracture, we need to perform rehabilitation taking such an abnormal movement into consideration. PMID- 28838706 TI - Evaluation of an Information Pamphlet for Women Considering Epidural Analgesia in Labour. AB - OBJECTIVE: This study sought to assess change in knowledge and preference for epidural use associated with use of an information pamphlet and to explore women's decision-making and information needs regarding pain relief in labour. METHODS: Six focus groups with women who were pregnant or had given birth during the past 12 months were conducted in three northern communities in British Columbia. Following completion of a 10-item knowledge pretest, women were randomly assigned to read either a short version or a detailed version of the pamphlet and then complete a post-test. After reading the alternate pamphlet they participated in a moderated discussion. Pretest and post-test knowledge scores were compared, and a thematic analysis of focus group data was conducted. RESULTS: Knowledge scores increased (2.12 points out of a possible total of 10; standard deviation 2.38; 95% CI 1.38 to 2.87). There was no difference in knowledge change or epidural preferences according to which version participants read first. Women preferred the detailed version and indicated that its information was more balanced. Four themes related to decision-making and information needs arose from the focus groups: making an informed choice, being open-minded, wanting comprehensive information, and experiencing pressure to have/not have an epidural. CONCLUSION: An illustrated information pamphlet can significantly increase women's knowledge of benefits and risks of epidural analgesia, but it is not associated with change of preference. Women prefer to receive comprehensive information prenatally to support informed choices in labour. PMID- 28838705 TI - Comparison of outcomes between partially healed and acute metaphyseally malaligned distal radial fracture treated by palmar locking plate fixation. AB - BACKGROUND: The purpose of this study was to determine whether a partially healed (surgical delay of 2-6 weeks) metaphyseally malaligned distal radius fracture (DRF) treated using the extended palmar approach with palmar locking plate fixation has poorer clinical or radiological outcomes than those of acute (surgical delay of <=2 weeks) metaphyseally unstable DRF treated by palmar locking plate fixation. METHODS: We identified 24 patients (Group A) who were treated with palmar locking plate for a partially healed (surgical delay of 2-6 weeks) metaphyseally malaligned DRF. We selected 48 patients (Group B) who were treated with palmar locking plate among the acute (surgical delay of <=2 weeks) metaphyseally unstable DRF to be individually matched in a 1:2 ratio for sex, age, and fracture type. The two study groups were compared with respect to clinical and radiological parameters. The clinical parameters examined were; wrist range of motion (flexion, extension, supination, and pronation), grip strength, and Disabilities of Arm, Shoulder and Hand (DASH) scores. Radiological measurements included radial inclination, palmar angulation, and ulnar variance. RESULTS: The wrist flexion and grip strength were significantly greater in group B than group A at 3 months postoperatively. However, wrist ranges of motion, grip strengths, and DASH scores were not significantly different at 1 year postoperatively. Radiographic evaluation demonstrated no intergroup difference in terms of radial inclination, palmar angulation, or ulnar variance at 1 year postoperatively. CONCLUSIONS: Partially healed metaphyseally malaligned healed DRFs had inferior clinical outcomes to acute metaphyseally unstable DRFs in an early postoperative period, however, achieved similar clinical outcomes at 1 year postoperatively when treated using palmar locking plate fixation. PMID- 28838707 TI - The Journal of Thoracic Oncology Achieves a New Benchmark. PMID- 28838708 TI - Local Therapy for Pulmonary Oligometastases: Is SABR a New Champion? PMID- 28838709 TI - Optimal Treatment of Stage IIIA-N2 Non-Small Cell Lung Cancer: A Neverending Story? PMID- 28838710 TI - Fast, Food and Ceritinib in ALK-Positive NSCLC. PMID- 28838711 TI - Prophylactic Cranial Irradiation in Resected Small Cell Lung Cancer: Comprehensive Staging, Adjuvant Chemotherapy, and Strict Stratification of Pathological Stage Play a Role. PMID- 28838712 TI - T790M EGFR Mutation Detection in Cerebrospinal Fluid and Response to Osimertinib in a Lung Cancer Patient with Meningeal Carcinomatosis. PMID- 28838713 TI - Liver Metastasis Is Associated with Poor Progression-Free Survival in Patients with Non-Small Cell Lung Cancer Treated with Nivolumab. PMID- 28838714 TI - Malignant Pleural Mesothelioma Harboring Both G719C and S768I Mutations of EGFR Successfully Treated with Afatinib. PMID- 28838715 TI - Abscopal Effect of Nivolumab in a Patient with Primary Lung Cancer. PMID- 28838716 TI - Atypical Pleuropulmonary Tuberculosis Mimicking a Malignant Disease. PMID- 28838717 TI - To Treat or Not to Treat: Role of Immunotherapy in Patients with Concomitant Diagnosis of Advanced-Stage Non-Small Cell Lung Cancer and Psoriasis. PMID- 28838718 TI - The Influence of Body Mass Index on Overall Survival following Surgical Resection of Non-Small Cell Lung Cancer: Methodological Issues. PMID- 28838719 TI - Reply to "Influence of Body Mass Index on Overall Survival Following Surgical Resection of Non-Small Cell Lung Cancer: Methodological Issues". PMID- 28838720 TI - More Health Outcomes Analysis from More Representative Population Data Is Necessary prior to Bronchial Genomic Classifier Application in Real Practice. PMID- 28838721 TI - Response to Lee et al. PMID- 28838723 TI - On homogeneity approximation in calibration of gamma-spectrometry assessment of bulk samples. AB - The effect of the intrinsic inhomogeneity of a sample on the efficiency for the measurement of the sample by gamma-ray spectrometry is studied. The difference between the efficiency for the inhomogeneous sample and the efficiency for a sample made from the equivalent homogeneous matrix is evaluated. PMID- 28838722 TI - Different iron deposition patterns in early- and middle-late-onset Parkinson's disease. AB - BACKGROUND: Iron deposition may contribute to the clinical symptoms in Parkinson's disease (PD). With partial different clinical manifestations, the iron deposition patterns between patients with early-onset Parkinson's disease (EOPD) and middle-late-onset Parkinson's disease (M-LOPD) are still unclear. This study was designed to investigate the patterns of iron deposition and their clinical relevance in EOPD and M-LOPD patients, using quantitative susceptibility mapping technique. MATERIALS AND METHODS: Thirty-five EOPD patients and 24 matched young controls, 33 M-LOPD patients and 22 matched older controls were recruited in the study. The iron content in the deep grey matter nuclei in the basal ganglia and midbrain were measured, and compared between patients and their corresponding controls. The correlations of regional iron content and clinical features were explored in patient groups. RESULTS: Both M-LOPD and EOPD patients showed increased iron content in the substantia nigra (SN) pars compacta and SN pars reticulata. Increased iron content in the putamen was only observed in M LOPD patients. The relationship between the increased iron content and disease severity (H&Y stages, UPDRS II scores and UPDRS III scores) was observed in M LOPD patients, but not in EOPD patients. CONCLUSION: Our study suggested that the iron deposition pattern was greatly influenced by the age of PD onset, which increases our understanding of the different pathological underpinnings of EOPD and M-LOPD patients. PMID- 28838724 TI - A method for the complete analysis of NORM building materials by gamma-ray spectrometry using HPGe detectors. AB - A methodology including software tools for analysing NORM building materials and residues by low-level gamma-ray spectrometry has been developed. It comprises deconvolution of gamma-ray spectra using the software GALEA with focus on the natural radionuclides and Monte Carlo simulations for efficiency and true coincidence summing corrections. The methodology has been tested on a range of building materials and validated against reference materials. PMID- 28838725 TI - Characterisation of an ultra low-background point contact HPGe well-detector for an underground laboratory. AB - Since a few years there are well-type HPGe-detectors with a small, point-like, anode contacts available commercially. This paper describes the characterisation of the first ultra low-background, so-called, SAGeTM well detector with regards to resolution and background performance. Inside a passive lead/copper shield in the underground laboratory HADES a background count rate of 690 +/- 6d-1 (268 +/- 3d-1 per kg Ge) was recorded 19 months after taking it underground. PMID- 28838726 TI - Moving Beyond "Abstinence-Only" Messaging to Reduce Sleep-Related Infant Deaths. PMID- 28838727 TI - Primary Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome: The Importance of Timely Clinical Differentiation. PMID- 28838728 TI - Perioperative Use of Coagulation Factor Concentrates in Patients Undergoing Cardiac Surgery. AB - Coagulopathy and bleeding are common in patients undergoing cardiac surgery, with a perioperative transfusion rate in excess of 50%. The mechanism of coagulopathy associated with cardiac surgery using cardiopulmonary bypass is multifactorial. Historically, coagulation factor-mediated bleeding in such instances has been treated with allogeneic plasma transfusion. Coagulation factor concentrate use for treatment of hemophilia, congenital factor deficiencies and, more recently, emergency warfarin reversal is common. Formulations of factor concentrates include single and multifactor concentrates and both human and recombinant derived products. Off-label use of factor concentrates for coagulopathy and bleeding associated with cardiac surgery has been described for decades; however, sound clinical research with regard to this practice is limited. This review highlights the literature discussing the use of factor concentrates in patients undergoing cardiac surgery and provides an overview of reasonable uses or lack thereof for factor concentrates in clinical practice. PMID- 28838729 TI - Healthcare-Associated Mycobacterium chimaera Infection Subsequent to Heater Cooler Device Exposure During Cardiac Surgery. AB - A SERIES of reports in the United States and Europe have linked Mycobacterium chimaera infections to contaminated heater-cooler devices used during cardiac surgery. Heater-cooler devices commonly are used for cardiopulmonary bypass during cardiac surgery. M. chimaera is a slow-growing nontuberculous mycobacterium that has been shown to cause cardiac complications that can lead to fatal disease following cardiac surgery. Given that more than 250,000 cardiothoracic surgical procedures requiring cardiopulmonary bypass take place each year in the United States, the estimated number of patient exposures to M. chimaera has prompted a public health crisis. The goal of this review is to summarize the present status of the M. chimaera outbreak and provide cardiothoracic surgeons, cardiac anesthesiologists, and other clinicians with current approaches to patient management and to discuss risk mitigation. PMID- 28838730 TI - Selective Reporting: Silent Atrial Fibrillation and Cryptogenic Strokes. PMID- 28838731 TI - The Reply. PMID- 28838732 TI - It Takes More than Just a Finger to Determine Emergency Room Disposition for Possible Gastrointestinal Bleeding. PMID- 28838733 TI - The Reply. PMID- 28838734 TI - The Reply. PMID- 28838735 TI - Prognosis in Patients with Different Types of Myocardial Infarction and Presence of Obstructive Coronary Artery Disease. PMID- 28838736 TI - The Reply. PMID- 28838737 TI - What About Pharmacologic Therapy? PMID- 28838738 TI - The Reply. PMID- 28838739 TI - Chronic Lyme Disease: An Unresolved Controversy. PMID- 28838740 TI - The Reply. PMID- 28838741 TI - When and Why Statins Fail to Save Lives. PMID- 28838742 TI - [Trends in the level of control of patients with type 2 diabetes from 2010 to 2015]. AB - INTRODUCTION: Aim: To examine the trend in the level of control of glycated haemoglobin (HbA1c), blood pressure (BP), and LDL-cholesterol (LDL) in patients with type 2 diabetes mellitus between 2010 and 2015. METHODS: Setting: 3 cut-offs in the years 2010, 2013, and 2015. Southeast area of Madrid. DESIGN: Descriptive and cross-sectional epidemiological study. PARTICIPANTS: Patients diagnosed and registered with type 2 diabetes. N=41,096 (2010), n=49,658 (2013), n=6,674 (2015) MAIN MEASUREMENTS: Measurement or not in the last year of HbA1c, BP, and LDL. Control of HbA1c (<7% individual targeting), BP (<140/90mmHg), and LDL (<100mg/dL, if cardiovascular disease <70mg/dL). Data were collected from electronic records of clinical history. The Chi-square test was used. RESULTS: The percentages of patients with each parameter measured in 2010, 2013 and 2015 were: HbA1c: 36.4%, 37.0%, 62.0% (P<.001); BP: 33.2%, 43.3%, 65.0% (P<.001); LDL: 32.9%, 33.2%, 43.5% (P<.001). The percentages of patients with each parameter measured and controlled in 2010, 2013, and 2015 were: HbA1c: 59.6%, 59.1%, 79.6% (P<.001); BP: 74.9%, 67.4%, 79.2% (P<.001); LDL: 41.8%, 58.3%, 58.8% (P<.001) CONCLUSION: In the 2010-2015 period, a sustained but insufficient trend of better control of HbA1c, BP and LDL was observed in patients with diabetes. The frequency of the measurements of these parameters improved more than the control of them. It seems that efforts to improve care for the patient with diabetes pay off, but they still have to be maintained. PMID- 28838743 TI - Total serum bilirubin and 8-year incident type 2 diabetes mellitus: The Korean Genome and Epidemiology Study. AB - AIM: In this study, the impact of serum bilirubin on new-onset type 2 diabetes mellitus (T2DM) in Korean adults was investigated. METHODS: Data were obtained from the Korean Genome and Epidemiology Study (KoGES), a population-based prospective cohort study. The study enrolled 8650 adults (4015 men and 4635 women), aged 40 to 69 years, who underwent a mean follow-up of 8.4 years. The study population was divided into quartiles (Q) of serum bilirubin levels, with cut-off points at 0.46, 0.61 and 0.82mg/dL for men, and 0.35, 0.47 and 0.61mg/dL for women. T2DM was defined based on the following data: fasting blood glucose>=7.0mmol/L, HbA1c level>=6.5% or 2-h plasma glucose>=11.1mmol/L during a 75-g oral glucose tolerance test. RESULTS: Over the mean 8.4-year follow-up, 786 participants (9.1%) developed T2DM. Compared with Q1, the odds ratios (ORs) and 95% confidence intervals (CIs) for T2DM incidence were 0.52 (0.36-0.74) in men and 0.56 (0.38-0.83) in women aged >=50 years, respectively, in the highest Q group after adjusting for possible confounding factors. These significant results persisted in those with impaired glucose tolerance and impaired fasting glucose. CONCLUSION: The results of this study reveal a protective role for serum total bilirubin on new-onset T2DM in Korean men and women. In addition, serum total bilirubin had favourable effects on new-onset T2DM in those with impaired glucose tolerance and impaired fasting glucose. PMID- 28838745 TI - The Pulmonologist-Patient Relationship After the Lung Cancer Committee Decision. PMID- 28838744 TI - Mitochondrial DNA analysis of Tunisians reveals a mosaic genetic structure with recent population expansion. AB - Tunisia is a country of great interest for human population genetics due to its strategic geographic position and rich human settlement history. These factors significantly contributed to the genetic makeup of present-day Tunisians harbouring components of diverse geographic origins. Here, we investigated the genetic structure of Tunisians by performing a mitochondrial DNA (mtDNA) comparison of 15 Tunisian population groups, in order to explore their complex genetic landscape. All Tunisian data were also analysed against 40 worldwide populations. Statistical results (Tajima's D and Fu's FS tests) suggested recent population expansion for the majority of studied populations, as well as showed (AMOVA test) that all populations were significantly different from each other, which is evidence of population structure even if it is not guided by geographic and ethnic effects. Gene flow analysis revealed the assignment of Tunisians to multiple ancestries, which agrees with their genetic heterogeneity. The resulting picture for the mtDNA pool confirms the evidence of a recent expansion of the Tunisian population and is in accordance with a mosaic structure, composed by North African, Middle Easterner, European and Sub-Saharan lineages, resulting from a complex settlement history. PMID- 28838746 TI - Lymphomatoid Granulomatosis: A Rare Tumor with Poor Prognosis. PMID- 28838747 TI - Neurofibromatosis Type I With Pulmonary Involvement. PMID- 28838748 TI - How Technology Is Changing News and Our Culture: Lessons From Elections 2016 and Davos 2017: Tech, Media, and the Newsroom of the Future. PMID- 28838749 TI - Worldwide Implementation of Radiology Quality and Safety Programs. PMID- 28838750 TI - Improving Novice Radiology Trainees' Perception Using Fine Art. AB - PURPOSE: To determine if fine art perception training improved performance in novice radiology trainees. METHODS: On the first day of their residency, 15 radiology residents underwent a basic radiology perception test in which they were shown 15 different radiographs that each had a significant abnormality. This was followed by a focused session of interpretation training at a local art gallery where art experts taught the trainees how to thoroughly analyze a painting. After this fine art session, the residents were once again shown 15 different radiographs and asked, in the same manner as before, to identify the location of the abnormality. The results of both radiograph assessments were then compared. RESULTS: The 15 residents correctly identified the areas of abnormality on 35 of 225 cases pre-art training with a mean score of 2.33 and a SD of 1.4. After art training, the figure for correctly identifying the area of abnormality rose to 94 of 225 cases with a mean score of 6.27 and a SD of 1.79 (P < .0001). CONCLUSION: The implementation of a focused teaching session on perception improved first-year residents' ability to localize imaging abnormalities. This improvement was significant (P < .0001). Most errors in radiology occur due to failures of perception rather than failures to correctly interpret a finding and, as such, it behooves the profession to ensure that perception training is adequately addressed as part of a radiology training curriculum. Using an art gallery may be a novel, effective transitional starting point for novice radiology trainees. PMID- 28838751 TI - Effects of a Parenting Program Among Women Who Began Childbearing as Adolescents and Young Adults. AB - PURPOSE: The purpose of the study was to examine whether access to an at-scale, group-based parenting education program ("Educacion Inicial") had differential effects on parenting behaviors and child cognitive development according to mother's age at the birth of her first child, with a focus on adolescent mothers in rural Mexico. METHODS: This was a secondary analysis of a cluster-randomized controlled trial (n = 728 households, n = 106 communities). We conducted intent to-treat analyses and examined the interaction between treatment group and mother's age at first birth. The primary outcomes were parenting behaviors (Family Care Indicators) and children's cognitive development (McCarthy Scales of Children's Abilities) at ages 3-5 years. RESULTS: We found that children of mothers who began childbearing in adulthood (20-30 years) scored higher on tests of cognitive development when randomized to weekly parenting support than their counterparts in the comparison group. Whereas, the children of mothers who began childbearing in adolescence (<=16 years) did not have higher scores associated with the parenting program (difference in magnitude of associations: Verbal = 8.19; 95% CI = -15.50 to -.88; p = .03; Memory = -7.22; 95% CI = -14.31 to -.14; p = .05). The higher scores among the children of mothers who began childbearing in adulthood were only significant when Educacion Inical was supported by Prospera, the conditional cash transfer program. CONCLUSIONS: Our study results suggest that the Educacion Inicial parenting intervention did not adequately address the needs of women who began childbearing in adolescence. One reason may be that adolescent mothers are more socially marginalized and less able to benefit from parenting programs. PMID- 28838753 TI - We Commend the Effort: 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. PMID- 28838752 TI - Child and Adolescent Mortality Across Malaysia's Epidemiological Transition: A Systematic Analysis of Global Burden of Disease Data. AB - PURPOSE: A rapid epidemiological transition in developing countries in Southeast Asia has been accompanied by major shifts in the health status of children and adolescents. In this article, mortality estimates in Malaysian children and adolescents from 1990 to 2013 are used to illustrate these changes. METHODS: All cause and cause-specific mortality estimates were obtained from the 2013 Global Burden of Disease Study. Data were extracted from 1990 to 2013 for the developmental age range from 1 to 24 years, for both sexes. Trends in all-cause and cause-specific mortality for the major epidemiological causes were estimated. RESULTS: From 1990 to 2013, all-cause mortality decreased in all age groups. Reduction of all-cause mortality was greatest in 1- to 4-year-olds (2.4% per year reduction) and least in 20- to 24-year-olds (.9% per year reduction). Accordingly, in 2013, all-cause mortality was highest in 20- to 24-year-old males (129 per 100,000 per year). In 1990, the principal cause of death for 1- to 9 year boys and girls was vaccine preventable diseases. By 2013, neoplasms had become the major cause of death in 1-9 year olds of both sexes. The major cause of death in 10- to 24-year-old females was typhoid in 1990 and neoplasms in 2013, whereas the major cause of death in 10- to 24-year-old males remained road traffic injuries. CONCLUSIONS: The reduction in mortality across the epidemiological transition in Malaysia has been much less pronounced for adolescents than younger children. The contribution of injuries and noncommunicable diseases to adolescent mortality suggests where public health strategies should focus. PMID- 28838754 TI - Sleep respiratory problems in children: Diagnosis and contribution of the orthodontist. AB - Obstructive sleep apnea/hypopnea syndrome (OSAS) is still not widely diagnosed in children as its clinical signs are extremely variable. The diagnosis is based on recognition of the nocturnal and diurnal clinical symptoms of the syndrome, but above all on analysis of a sleep recording revealing abnormal respiratory phenomena. This recording makes it possible to determine an Apnea/Hypopnea Index (AHI) for each hour of sleep. The abnormality threshold is 1.5AHI/h for children and 5AHI/h for adults. The higher the index, the more severe the OSAS. The consequences of this syndrome are far from negligible, leading possibly to learning difficulties, mood problems, growth abnormalities and delayed neurocognitive development; it may even have an impact on metabolism. The orthodontist, as a health specialist frequently in contact with young patients, needs to be able to detect OSAS by launching a dialogue on the question of sleep so as to refer the patient to a specialist who can confirm the diagnosis. Through observation of the patient, it is possible to identify children at risk. Potential OSAS can then be prevented or cured by increasing the volume of the upper airways thanks to orthodontic treatment. Management of patients suffering from OSAS is multidisciplinary, under the direction of the sleep specialist. PMID- 28838755 TI - ? PMID- 28838756 TI - ? PMID- 28838757 TI - A genetic heritage; the same yet different: A comparative study in twins. AB - Since the 19th century, and in every field of medicine, monozygotic twins have been studied to assess the involvement of genetic and environmental factors in phenotypic expression. The phenotype/genotype relationship remains the leading problem in contemporary biology. In dentofacial orthopedics, this relationship is of relevance in the three-dimensional approach to the face, in both diagnosis and treatment. The present study of two monozygotic twins presenting skeletal class III malocclusions which were genetic yet different is a clear illustration of the interaction of genotype and epigenetic factors with environmental influences. We will demonstrate that treatment can reduce phenotypic differences. PMID- 28838758 TI - Active subsite properties, subsite residues and targeting to lysosomes or midgut lumen of cathepsins L from the beetle Tenebrio molitor. AB - Cathepsins L are the major digestive peptidases in the beetle Tenebrio molitor. Two digestive cathepsins L (TmCAL2 and TmCAL3) from it had their 3D structures solved. The aim of this paper was to study in details TmCAL3 specificity and properties and relate them to its 3D structure. Recombinant TmCAL3 was assayed with 64 oligopeptides with different amino acid replacements in positions P2, P1, P1' and P2'. Results showed that TmCAL3 S2 specificity differs from the human enzyme and that its specificities also explain why on autoactivation two propeptide residues remain in the enzyme. Data on free energy of binding and of activation showed that S1 and S2' are mainly involved in substrate binding, S1' acts in substrate binding and catalysis, whereas S2 is implied mainly in catalysis. Enzyme subsite residues were identified by docking with the same oligopeptide used for kinetics. The subsite hydrophobicities were calculated from the efficiency of hydrolysis of different amino acid replacements in the peptide and from docking data. The results were closer for S1 and S2' than for S1' and S2, indicating that the residue subsites that were more involved in transition state binding are different from those binding the substrate seen in docking. Besides TmCAL1-3, there are nine other cathepsins L, most of them more expressed at midgut. They are supposed to be directed to lysosomes by a Drosophila-like Lerp receptor and/or motifs in their prodomains. The mannose 6-phosphate lysosomal sorting machinery is absent from T. molitor transcriptome. Cathepsin L direction to midgut contents seems to depend on overexpression. PMID- 28838759 TI - Chitosan-based mucoadhesive gel for oral mucosal toluidine blue O delivery: The influence of a non-ionic surfactant. AB - Photodynamic therapy (PDT) has been successfully employed in the treatment of oral cancer. Toluidine blue O (TBO) is a photosensitizer (PS) that has exhibited remarkable photocytotoxicity in a variety of tumour cells; however, its physicochemical properties, as well as the physicochemical properties of oral mucosa, prevent the drug from reaching the target site at a therapeutic concentration. The aim of this study was to evaluate the influence of Tween 80(r) (TW), which has shown potential as a penetration enhancer, on the mucosal retention of TBO for the PDT of oral cancer. 4% Chitosan-based mucoadhesive gels (CH gels) containing or not 5%TW were prepared (both containing 1%TBO), and their physicochemical properties (pH, rheology and mucoadhesion), TBO in vitro release profiles and TBO in vitro mucosal retention were evaluated. In vivo mucosal penetration studies of TBO followed by laser exposition were also carried out. The results showed that 4%CH gels containing 5%TW and 1%TBO have adequate mucoadhesive and rheological properties for oral mucosa use, although they present a slightly acid pH. TBO release studies showed that TW reduces TBO release, but it prolongs TBO release and increases TBO retention in the mucosa. In vivo studies showed that 4%CH gels containing 5%TW and 1%TBO cause an increase in the number of apoptotic cell, after laser exposition. In summary, 4%CH gels containing 5%TW may be a promising vehicle to optimize the penetration of TBO in oral mucosa and to improve the PDT response for the treatment of oral cancer. PMID- 28838760 TI - In vitro assessment of anti-tumorigenic mechanisms and efficacy of NanoALA, a nanoformulation of aminolevulic acid designed for photodynamic therapy of cancer. AB - BACKGROUND: The development of nanocarriers is an important approach to increase the bioavailability of hydrophilic drugs in target cells. In this work, we evaluated the anti-tumorigenic mechanisms and efficacy of NanoALA, a novel nanoformulation of aminolevulic acid (ALA) based on poly(lactide-co-glycolide) (PLGA) nanocapsules designed for anticancer photodynamic therapy (PDT). METHODS: For this purpose, physicochemical characterization, prodrug incorporation kinetics, biocompatibility and photocytotoxicity tests, analysis of the cell death type and mitochondrial function, measurement of the intracellular reactive oxygen species production and DNA fragmentation were performed in murine mammary carcinoma (4T1) cells. RESULTS: NanoALA formulation, stable over a period of 90days following synthesis, presented hydrodynamic diameter of 220+/-8.7nm, zeta potential of -30.6mV and low value of polydispersity index (0.28). The biological assays indicated that the nanostructured product promotes greater ALA uptake by 4T1 cells and consequently more cytotoxicity in the PDT process. For the first time in the scientific literature, there is a therapeutic efficacy report of approximately 80%, after only 1h of incubation with 100MUgmL-1 prodrug (0.6mM ALA equivalent). The mitochondria are probably the initial target of treatment, culminating in energy metabolism disorders and cell death by apoptosis. CONCLUSIONS: NanoALA emerges as a promising strategy for anticancer PDT. Besides being effective against a highly aggressive tumor cell line, the treatment may be economically advantageous because it allows a reduction in the dose and frequency of application compared to free ALA. PMID- 28838761 TI - Impact of genotypic and phenotypic differences in sarcoma models on the outcome of photochemical internalization (PCI) of bleomycin. AB - The low curative response to current treatment regimens for most soft tissue sarcomas indicates a strong need for alternative treatment strategies and predictive markers for treatment outcome. PCI (photochemical internalization) is a novel treatment strategy to translocate drugs into cytosol that otherwise would have been degraded in lysosomes. Two highly geno-and phenotypically different uterine and vulvar leiomyosarcoma cell lines, MES-SA and SK-LMS-1, were treated with bleomycin (BLM) activated by PCI (PCIBLM). The MES-SA cells were much more sensitive to PCIBLM than the SK-LMS-1 cells and the treatment induced a 7-8 fold higher increase in DNA double-strand breaks at the same dose of light as measure by gammaH2AX staining. A 3-fold higher induction of apoptosis and stronger activation of Bax and p21 was also measured in the P53WT MES-SA cells, compared to the P53mut SK-LMS-1 cells. The basal formation of reactive oxygen species (ROS) was 3-fold higher in SK-LMS-1 cells than in the MES-SA cells and SK-LMS-1 cells expressed glutathione peroxidase 1 (GPx1) and more superoxide dismutase 2 (SOD2) than the MES-SA cells. Glutathione depletion with the glutathione synthetase inhibitor buthionine sulfoximine increased the cytotoxic effect of the photochemical treatment (PDT) most strongly in the SK-LMS-1 cells, and reduced PCIBLM-induced H2AX activation in the MES-SA cells, but not in the SK-LMS-1 cells. The results indicate PCIBLM as a potential novel treatment strategy for soft tissue sarcomas, with antioxidant enzymes, in particular GPx1, and the P53 status as potential predictive markers for response to PCIBLM. PMID- 28838762 TI - Really malaria-free Europe? PMID- 28838764 TI - Prenatal Growth and CKD in Older Adults: Longitudinal Findings From the Helsinki Birth Cohort Study, 1924-1944. AB - BACKGROUND: According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, several noncommunicable diseases, including hypertension, type 2 diabetes, and coronary heart disease, have their origins in early life. Chronic kidney disease (CKD) has traditionally been assumed to develop as the result of an interaction between genetic and environmental factors, although more recently, the importance of factors present early in life has been recognized. STUDY DESIGN: Longitudinal birth cohort study. SETTING & PARTICIPANTS: 20,431 people born in 1924 to 1944 in Helsinki, Finland, who were part of the Helsinki Birth Cohort Study were followed up through their life course from birth until death or age 86 years. PREDICTOR: Prenatal growth and socioeconomic factors. OUTCOMES: Death or hospitalization for CKD. RESULTS: Smaller body size at birth was associated with increased risk for developing CKD. Each standard deviation higher birth weight was associated with an HR for CKD of 0.82 (95% CI, 0.74-0.91; P<0.001). Associations with ponderal index at birth, placental weight, and birth length were also statistically significant (P<0.001, P<0.001, and P=0.002, respectively), but only among men. Prematurity also predicted increased risk for CKD. LIMITATIONS: The study was restricted to people who were born in Helsinki in 1924 to 1944. CONCLUSIONS: Smaller body size at birth was associated with increased risk for developing CKD in men. Prematurity was also associated with increased risk for CKD in women. These findings in the Helsinki Birth Cohort Study support the importance of early life factors in the development of CKD. PMID- 28838763 TI - CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation? AB - CD11c+ T-bet+ B cells have now been detected and characterized in different experimental and clinical settings, in both mice and humans. Whether such cells are monolithic, or define subsets of B cells with different functions is not yet known. Our studies have identified CD11c+ IgM+ CD19hi splenic IgM memory B cells that appear at approximately three weeks post-ehrlichial infection, and persist indefinitely, during low-level chronic infection. Although the CD11c+ T-bet+ B cells we have described are distinct, they appear to share many features with similar cells detected under diverse conditions, including viral infections, aging, and autoimmunity. We propose that CD11c+ T-bet+ B cells as a group share characteristics of memory B cells that are maintained under conditions of inflammation and/or low-level chronic antigen stimulation. In some cases, these cells may be advantageous, by providing immunity to re-infection, but in others may be deleterious, by contributing to aged-associated autoimmune responses. PMID- 28838765 TI - Adherence to the Mediterranean Dietary Pattern and Incidence of Nephrolithiasis in the Seguimiento Universidad de Navarra Follow-up (SUN) Cohort. AB - BACKGROUND: Diet plays an important role in the pathogenesis of nephrolithiasis. Limited data are available to investigate the association between a Mediterranean dietary pattern and risk for nephrolithiasis. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 16,094 men and women without a history of nephrolithiasis who participated in the Seguimiento Universidad de Navarra Follow up (SUN) Project. PREDICTORS: A validated 136-item food frequency questionnaire was used to assess baseline adherence to a Mediterranean dietary pattern that is high in fruits, vegetables, nuts, fish, and legumes, but moderate in alcohol and low in meats, saturated fats, and sugars. A Mediterranean dietary pattern score was calculated and categorized into 3 groups (0-3, 4-6, and 7-9 points). Additional factors included in statistical models were sex, age, body mass index, smoking, physical activity, time spent watching television, following a medical nutritional therapy, water and energy intake, calcium and vitamin D supplementation, and history of hypertension or diabetes. OUTCOMES: Incidence of nephrolithiasis. Participants were classified as having incident nephrolithiasis if they reported a physician-made diagnosis of nephrolithiasis during follow-up. RESULTS: After a mean follow-up of 9.6 years, 735 new cases of nephrolithiasis were identified. The multivariable HRs of nephrolithiasis for the 2 highest categories of adherence to the Mediterranean dietary pattern, using the lowest category as the reference, were 0.93 (95% CI, 0.79-1.09) and 0.64 (95% CI, 0.48 0.87); P for trend=0.01. The risk for nephrolithiasis was lower with greater consumption of dairy products and vegetables and greater with higher monounsaturated fatty acid to saturated fatty acid ratio. LIMITATIONS: No information for kidney stone composition. CONCLUSIONS: Greater adherence to a Mediterranean dietary pattern was associated with reduced risk for incident nephrolithiasis. Additional longitudinal studies are needed. PMID- 28838766 TI - Concentrations of Trace Elements in Hemodialysis Patients: A Prospective Cohort Study. AB - BACKGROUND: Low concentrations and excessive concentrations of trace elements have been commonly reported in hemodialysis patients, but available studies have several important limitations. STUDY DESIGN: Random sample of patients drawn from a prospective cohort. SETTING & PARTICIPANTS: 198 incident hemodialysis patients treated in 3 Canadian centers. MEASUREMENTS: We used mass spectrometry to measure plasma concentrations of the 25 elements at baseline, 6 months, 1 year, and 2 years following enrollment in the cohort. We focused on low concentrations of zinc, selenium, and manganese and excessive concentrations of lead, arsenic, and mercury; low and excessive concentrations of the other 19 trace elements were treated as exploratory analyses. Low and excessive concentrations were based on the 5th and 95th percentile plasma concentrations from healthy reference populations. RESULTS: At all 4 occasions, low zinc, selenium, and manganese concentrations were uncommon in study participants (<=5.1%, <=1.8%, and <=0.9% for zinc, selenium, and manganese, respectively) and a substantial proportion of participants had concentrations that exceeded the 95th percentile (>=65.2%, >=74.2%, and >=19.7%, respectively). Almost all participants had plasma lead concentrations above the 95th percentile at all time points. The proportion of participants with plasma arsenic concentrations exceeding the 95th percentile was relatively constant over time (9.1%-9.8%); the proportion with plasma mercury concentrations that exceeded the 95th percentile varied between 15.2% and 29.3%. Low arsenic, platinum, tungsten, and beryllium concentrations were common (>50%), as were excessive cobalt, manganese, zinc, vanadium, cadmium, selenium, barium, antimony, nickel, molybdenum, lead, and chromium concentrations. CONCLUSIONS: There was no evidence that low zinc, selenium, or manganese concentrations exist in most contemporary Canadian hemodialysis patients. Some patients have excessive plasma arsenic and mercury concentrations, and excessive lead concentrations were common. These findings require further investigation. PMID- 28838768 TI - Brazilian guidelines for the diagnosis and treatment of postmenopausal osteoporosis. AB - Osteoporosis is the leading cause of fractures in the population older than 50 years. This silent disease affects primarily postmenopausal women and the elderly, and the morbidity and mortality rates are high. The main goal of treating osteoporosis is the prevention of fractures. The identification of populations at risk through early diagnosis and treatment is essential. The last Brazilian guideline for the treatment of postmenopausal osteoporosis was elaborated in 2002. Since then, new strategies for diagnosis and risk stratification have been developed, and drugs with novel action mechanisms have been added to the therapeutic arsenal. The Osteoporosis and Osteometabolic Diseases Committee of the Brazilian Society of Rheumatology, in conjunction with the Brazilian Medical Association and other Societies, has developed this update of the guidelines for the treatment of postmenopausal osteoporosis according to the best scientific evidence available. This update is intended for professionals in many medical and health specialties involved in the treatment of osteoporosis, for physicians in general and for health-related organizations. PMID- 28838767 TI - C4 Nephritic Factors in C3 Glomerulopathy: A Case Series. AB - BACKGROUND: C3 glomerulopathy (C3G) defines a group of rare complement-mediated kidney diseases with a shared underlying pathophysiology: dysregulation of complement in the fluid phase and glomerular microenvironment. Dysregulation can be driven by autoantibodies to C3 and C5 convertases. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 168 patients with C3G (dense deposit disease, 68; C3 glumerulonephritis, 100) selected from our C3G biobank. OUTCOMES: Patient purified immunoglobulin Gs were tested for C4 nephritic factors (C4NeFs). These autoantibodies recognize C4b2a, the C3 convertase of the classical pathway of complement. MEASUREMENTS: C4NeFs were detected using a modified hemolytic assay. RESULTS: C4NeFs were identified in 5 patients, 4 of whom had C3 glomerulonephritis. C4NeFs were associated with dysregulation of C3 and C5 convertases, and they appear to stabilize these convertases in a dose-dependent manner. C4NeFs also appear to protect C4b2a from decay mediated by soluble CR1 and C4 binding protein. The stabilizing activity of the autoantibodies was further demonstrated by using heat treatment to inactivate complement. C4NeFs were not detected in 150 patients with another complement-mediated kidney disease, atypical hemolytic uremic syndrome. They were also absent in 300 apparently healthy controls. LIMITATIONS: In addition to C4NeFs, 2 patients had positive findings for other autoantibodies: one patient also had autoantibodies to factor H; the other patient also had autoantibodies to C3bBb (C3NeFs). CONCLUSIONS: The finding of C4NeFs in a small percentage of patients with C3G highlights the challenge in identifying autoantibodies that drive complement dysregulation and underscores the complexity of the autoantibody repertoire that can be identified in these patients. PMID- 28838769 TI - Evaluation of the rotary drum reactor process as pretreatment technology of municipal solid waste for thermophilic anaerobic digestion and biogas production. AB - Municipal solid waste (MSW) contains a large fraction of biodegradable organic materials. When disposed in landfills, these materials can cause adverse environmental impact due to gaseous emissions and leachate generation. This study was performed with an aim of effectively separating the biodegradable materials from a Mechanical Biological Treatment (MBT) facility and treating them in well controlled anaerobic digesters for biogas production. The rotary drum reactor (RDR) process (a sub-process of the MBT facilities studied in the present work) was evaluated as an MSW pretreatment technology for separating and preparing the biodegradable materials in MSW to be used as feedstock for anaerobic digestion. The RDR processes used in six commercial MSW treatment plants located in the USA were surveyed and sampled. The samples of the biodegradable materials produced by the RDR process were analyzed for chemical and physical characteristics as well as anaerobically digested in the laboratory using batch reactors under thermophilic conditions. The moisture content, TS, VS and C/N of the samples varied between 64.7 and 44.4%, 55.6 to 35.3%, 27.0 to 41.3% and 24.5 to 42.7, respectively. The biogas yield was measured to be between 533.0 and 675.6 mL g 1VS after 20 days of digestion. Approximately 90% of the biogas was produced during the first 13 days. The average methane content of the biogas was between 58.0 and 59.9%. The results indicated that the biodegradable materials separated from MSW using the RDR processes could be used as an excellent feedstock for anaerobic digestion. The digester residues may be further processed for compost production or further energy recovery by using thermal conversion processes such as combustion or gasification. PMID- 28838770 TI - A modified nasolabial flap for reconstruction of transfixing alar wing defects. AB - Reconstruction of an entire alar wing is a frequently encountered reconstructive challenge in onco-dermatologic surgery. The aim of this technical note was to describe a surgical technique total for reconstruction of the alar wing, with a modified nasolabial flap with an inferior pedicle associated with a cartilaginous graft. This rapid procedure seems to be a well alternative for elderly people and patients who do not want a forehead flap. The aesthetic and functional outcomes of the donor and recipient sites were satisfactory. PMID- 28838771 TI - Bluish sub-mucosal alveolar swelling: A diagnostic dilemma. PMID- 28838772 TI - Bilateral nasolabial cyst. AB - Nasolabial cyst is an uncommon non-odontogenic extraosseous cyst located in the nasolabial fold. Bilateral nasolabial cysts are rarer and only few cases have been reported. We describe a case of two asymptomatic masses of the nasal ala areas, which prove to be nasolabial cysts in a 30-year-old Moroccan woman. PMID- 28838773 TI - Spasmodic torticollis after orthognathic surgery. AB - The treatment of malocclusions can involve orthognathic surgery. Although orthognathic surgery is a safe surgical procedure, low incidences of many complications have been reported such as infections, hemorrhage, nerve injuries, temporomandibular disorders (TMDs), and psychological problems. There are no reports in the literature of orthognathic surgery being associated with postural disorders although the link between dental occlusion and postural disorders is highlighted in numerous recent publications. This report describes the case of a young, healthy patient who presented with sustained spasmodic torticollis following orthognathic surgery. In addition, the physiopathological aspects of this atypical condition are discussed. PMID- 28838774 TI - The role of hyperbaric oxygen therapy in the prevention and management of radiation-induced complications of the head and neck - a systematic review of literature. AB - Radiation therapy for the treatment of head and neck cancer can injure normal tissues and have devastating side effects. Hyperbaric oxygen (HBO) is known to reduce the severity of radiation-induced injury by promoting wound healing. While most of the research in literature has focused on its efficacy in osteonecrosis, HBO has other proven benefits as well. The aim of this review was to identify the various benefits of hyperbaric oxygen therapy in patients who have undergone radiation for head and neck cancer. An electronic database search was carried out to identify relevant articles and selected articles were reviewed in detail. The quality of evidence for each benefit, including preserving salivary gland function, preventing osteonecrosis, dental implant success, and overall quality of life, was evaluated. Evidence showed that HBO was effective in improving subjective symptoms of xerostomia, swallowing, speech and overall quality of life. There was no conclusive evidence to show that HBO improved implant survival, prevented osteonecrosis, or improved salivary gland function. The high costs and accessibility of HBO therapy must be weighed against the potential benefits to each patient. PMID- 28838775 TI - Clear cell odontogenic carcinoma. A review. AB - INTRODUCTION: Clear cell odontogenic carcinoma (CCOC) is described as an exceptional and hard to diagnose malignant tumor which was first reported by Hansen in 1985. The purpose of this review article is to show that CCOC is a not that rare entity and to discuss its various aspects in order to enhance the diagnosis. MATERIAL AND METHODS: A search in the English language literature was performed using the Scopus, ScienceDirect, PubMed and Medline databases between 1985 and 2016. Data were collected on epidemiologic, clinical, radiographic, histological, immunohistochemistrical, cytogenetic, management, follow-up and prognosis features of CCOC. RESULTS: Sixty-five studies from which a total of 95 case reports were included in the review. CCOC was generally seen in the fifth decade and the most common site was mandibular. The most frequently found symptoms were swelling, tooth mobility and pain. Radiologically, the image was radiolucent and could look like a cyst or a periodontal lesion. In situ hybridization techniques frequently expressed a gene fission of EWSR1. The treatment was mostly a radical surgical excision of the tumor with or without adjuvant radiotherapy or chemotherapy. CCOC showed high rates of recurrence and mortality related with the presence of distance metastasis. DISCUSSION: Fission of EWSR1 gene could be the main element it the diagnosis of CCOC. A multidisciplinary approach, including a radiologist, pathologist and an oral & maxillofacial surgeon may be helpful in the evaluation and management of these lesions. With 95 reports found in English literature, we cannot say that CCOC is extremely rare anymore. PMID- 28838776 TI - The effect of lopinavir/ritonavir and lopinavir/ritonavir loaded PLGA nanoparticles on experimental toxoplasmosis. AB - A marked reduction has been achieved in the incidence and clinical course of toxoplasmic encephalitis after the introduction of protease inhibitors within the treatment regimen of HIV (HIV-PIs). This work was undertaken to study for the first time, the efficacy of HIV-PIs, lopinavir/ritonavir (L/R), as a therapeutic agent in acute experimental toxoplasmosis. Lopinavir/ritonavir (L/R) were used in the same ratio present in aluvia, a known HIV-PIs drug used in the developing countries in the treatment regimens of AID's patient. Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as a delivery system to L/R therapy. L/R alone or after its encapsulation on PLGA were given to Swiss strain albino mice that were infected with RH virulent toxoplasma strain. Both forms caused parasitological improvement in both mortality rate and parasite count. The higher efficacy was achieved by using L/R PLGA together with minimizing the effective dose. There was significant reduction in the parasite count in the peritoneal fluid and the liver. Parasite viability and infectivity were also significantly reduced. The anti-toxoplasma effect of the drug was attributed to the morphological distortion of the tachyzoites as evident by the ultrastructure examination and suppressed the egress of tachyzoites. L/R also induced changes that suggest apoptosis and autophagy of tachyzoites. The parasitophorous vacuole membrane was disrupted and vesiculated. The nanotubular networks inside the parasitophorous vacuole were disrupted. Therefore, the present work opens a new possible way for the approved HIV-PIs as an alternative treatment against acute toxoplasmosis. Furthermore, it increases the list of the opportunistic parasites that can be treated by this drug. The successful in vivo effect of HIV-PIs against Toxoplasma gondii suggests that this parasite may be a target in HIV treated patients, thus decrease the possibility of toxoplasmic encephalitis development. PMID- 28838777 TI - Pyelonephritis in Japan caused by Salmonella enterica subspecies arizonae. AB - Salmonella enterica subsp. arizonae is a bacteria commonly found in the gut of reptiles. In humans, infections caused by this organism are rare. Most cases originate from southwestern United States, where rattlesnake products are often used in traditional medicine. In Asia, only a few cases have been described. This case report documents a case involving a 64-year-old woman with pyelonephritis caused by S. arizonae in Japan. She had no history of contact with reptiles or foreign travel. The likely route of transmission is unclear. She was treated with cephalosporins for 14 days and the pyelonephritis appeared to be resolved; however recurrence occurred twice -after two weeks and then after one month. Prolonged antibiotic therapy with amoxicillin resolved the infection. This case demonstrates that pyelonephritis associated with S. arizonae can be found outside of the typical geographic region and may not be associated with typical animal hosts. PMID- 28838778 TI - Outbreaks of influenza B infection and pneumococcal pneumonia at a mental health facility in Japan. AB - BACKGROUND: Japan has an aging population and an increasing number of patients who reside in long-term care and mental health facilities. Both pneumococcal pneumonia and influenza B infection outbreaks have been observed in these populations, although no reports have described concurrent outbreaks of pneumococcal pneumonia and influenza B infection in these facilities. CASE PRESENTATION: Six patients and two staffs were initially diagnosed with influenza B infection at a mental health facility on March 14, 2015. By March 21, influenza B infection was diagnosed in 26 patients and 10 staff; all individuals received anti-influenza drugs. On March 19, two patients were diagnosed with pneumococcal pneumonia, and seven patients had developed pneumococcal pneumonia by March 24. Six of these seven patients also had influenza B infection. All individuals who developed pneumococcal pneumonia were hospitalized and treated using ampicillin/sulbactam at our hospital, and their symptoms subsequently subsided. Among the seven pneumococcal strains that were frozen and stored, two strains were type 3 and five strains were type 11A/E. Pulsed-field gel electrophoresis testing revealed that each of the serum types were from the same clone. CONCLUSION: It appears that an outbreak of influenza B infection was followed by the spread of multi-clone pneumococcal pneumonia among elderly patients at a mental health facility. Therefore, it may be prudent to use vaccinations to prevent the spread of pneumococcal pneumonia among elderly patients and this diagnosis should be actively considered during outbreaks of influenza infection at elder care facilities. PMID- 28838779 TI - Predictors of emergency department attendance by people with dementia in their last year of life: Retrospective cohort study using linked clinical and administrative data. AB - INTRODUCTION: A fall in hospital deaths in dementia has been interpreted as indicating an improvement in end-of-life care. Whether other indicators of quality of end-of-life care, such as emergency department (ED) attendance, show a similar trend is unclear. METHODS: Retrospective cohort study using electronic medical records from a large mental health care provider, linked to national mortality and hospital use data (2008-2013). RESULTS: Of 4867 patients, 78.6% (3824) had at least one ED attendance during their last year of life (mean 2.13, standard deviation 2.34, range 0-54). ED attendance increased over the time period (incidence rate ratio 1.62, 95% confidence interval 1.46-1.80 for 2012 2013 compared with 2008-2009). DISCUSSION: ED attendance in the last year of life for people with dementia is common and is increasing. Policy makers must pay attention to a broader range of indicators of poor end-of-life care alongside the place of death. PMID- 28838780 TI - Reply to letter: Neurocognitive and behavioural outcomes in a nearly drowned child with cardiac arrest and hypothermia resuscitated after 43 min of no flow time: A case study. PMID- 28838782 TI - Rebirth of the Incretin Concept: Its conception and early development. AB - This paper describes the resurrection of the Incretin Concept in the early 1960s. It began with the more or less simultaneous discovery by three groups working independently in London. Dupre demonstrated that secretin given intravenously with glucose increased its rate of disappearance from the blood, McIntyre and co workers established that hyperglycaemia evoked by oral glucose stimulated more insulin secretion than comparable hyperglycaemia produced by intravenous glucose and Marks and Samols established the insulinotropic properties of glucagon. The concept evolved with the discovery by Samols and co-workers that oral glucose stimulated the release of immunoreactive glucagon-like substances from the gut mucosa and the subsequent isolation of glucagon immunoreactive compounds, most notably oxyntomodulin and glicentin, and of gastic inhibitory polypetide (GIP). It concluded with the isolation and characterisation of glucagon-like peptide 1 (7-36) amide. PMID- 28838781 TI - A comparison of pediatric airway management techniques during out-of-hospital cardiac arrest using the CARES database. AB - OBJECTIVE: To compare odds of survival to hospital discharge among pediatric out of-hospital cardiac arrest (OHCA) patients receiving either bag-valve-mask ventilation (BVM), supraglottic airway (SGA) or endotracheal intubation (ETI), after adjusting for the propensity to receive a given airway intervention. METHODS: Retrospective cohort study using the Cardiac Arrest Registry to Enhance Survival (CARES) database from January 1 201-December 31, 2015. The CARES registry includes data on cardiac arrests from 17 statewide registries and approximately 55 additional US cities. We included patients less than18 years of age who suffered a non-traumatic OHCA and received a resuscitation attempt by Emergency Medical Services (EMS). The key exposure was the airway management strategy (BVM, ETI, or SGA). The primary outcome was survival to hospital discharge. RESULTS: Of the 3793 OHCA cases included from 405 EMS agencies, 1724 cases were analyzed after limiting the analysis to EMS agencies that used all 3 devices. Of the 1724, 781 (45.3%) were treated with BVM only, 727 (42.2%) ETI, and 215 (12.5%) SGA. Overall, 20.7% had ROSC and 10.9% survived to hospital discharge. After using a propensity score analysis, the odds ratio for survival to hospital discharge for ETI compared to BVM was 0.39 (95%CI 0.26-0.59) and for SGA compared to BVM was 0.32 (95% CI 0.12-0.84). These relationships were robust to the sensitivity analyses including complete case, EMS-agency matched, and age stratified. CONCLUSIONS: BVM was associated with higher survival to hospital discharge compared to ETI and SGA. A large randomized clinical trial is needed to confirm these findings. PMID- 28838783 TI - Esophageal Adenocarcinoma 10 Years After Surgical Resection of Barrett's Esophagus: Unusual Presentation as Subepithelial Tumor. PMID- 28838784 TI - Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. METHODS: We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sensp) and specificity (specp) values were determined using the Meta Analysis Package for R (metafor). RESULTS: In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sensp, 63.5% and specp, 74.4%) within routine biochemical tests, adiponectin (sensp, 72.0% and specp, 75.7%) within inflammatory markers, CK18-M30 (sensp, 68.4% and specp, 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sensp, 69.0% and specp, 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sensp and 95.3% specp) and the GlycoNASH test (67.1% sensp and 63.8% specp). CONCLUSION: In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (>=80%). However, some blood markers, when included in scoring systems in single studies, identified patients with NASH with >=80% sensitivity and specificity. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from simple steatosis. PMID- 28838785 TI - External Validation of a Thiopurine Monitoring Algorithm on the SONIC Clinical Trial Dataset. PMID- 28838786 TI - Improved Outcomes in HCV Patients Following Liver Transplantation During the Era of Direct-Acting Antiviral Agents. PMID- 28838788 TI - Anolyte recycling enhanced bioelectricity generation of the buffer-free single chamber air-cathode microbial fuel cell. AB - Anolyte acidification is an inevitable restriction for the bioelectricity generation of buffer-free microbial fuel cells (MFCs). In this work, acidification of the buffer-free KCl anolyte has been thoroughly eliminated through anolyte recycling. The accumulated HCO3- concentration in the recycled KCl anolyte was above 50mM, which played as natural buffer and elevated the anolyte pH to above 8. The maximum power density (Pmax) increased from 322.9mWm-2 to 527.2mWm-2, which is comparable with the phosphate buffered MFC. Besides Geobacter genus, the gradually increased anolyte pH and conductivity induced the growing of electrochemically active Geoalkalibacter genus, in the anode biofilm. Anolyte recycling is a feasible strategy to strengthen the self-buffering capacity of buffer-free MFCs, thoroughly eliminate the anolyte acidification and prominently enhance the electric power. PMID- 28838787 TI - Surgical Interventions and the Use of Device-Aided Therapy for the Treatment of Fecal Incontinence and Defecatory Disorders. AB - The purpose of this clinical practice update expert review is to describe the key principles in the use of surgical interventions and device-aided therapy for managing fecal incontinence (FI) and defecatory disorders. The best practices outlined in this review are based on relevant publications, including systematic reviews and expert opinion (when applicable). Best Practice Advice 1: A stepwise approach should be followed for management of FI. Conservative therapies (diet, fluids, techniques to improve evacuation, a bowel training program, management of diarrhea and constipation with diet and medications if necessary) will benefit approximately 25% of patients and should be tried first. Best Practice Advice 2: Pelvic floor retraining with biofeedback therapy is recommended for patients with FI who do not respond to the conservative measures indicated above. Best Practice Advice 3: Perianal bulking agents such as intra-anal injection of dextranomer may be considered when conservative measures and biofeedback therapy fail. Best Practice Advice 4: Sacral nerve stimulation should be considered for patients with moderate or severe FI in whom symptoms have not responded after a 3-month or longer trial of conservative measures and biofeedback therapy and who do not have contraindications to these procedures. Best Practice Advice 5: Until further evidence is available, percutaneous tibial nerve stimulation should not be used for managing FI in clinical practice. Best Practice Advice 6: Barrier devices should be offered to patients who have failed conservative or surgical therapy, or in those who have failed conservative therapy who do not want or are not eligible for more invasive interventions. Best Practice Advice 7: Anal sphincter repair (sphincteroplasty) should be considered in postpartum women with FI and in patients with recent sphincter injuries. In patients who present later with symptoms of FI unresponsive to conservative and biofeedback therapy and evidence of sphincter damage, sphincteroplasty may be considered when perianal bulking injection and sacral nerve stimulation are not available or have proven unsuccessful. Best Practice Advice 8: The artificial anal sphincter, dynamic graciloplasty, may be considered for patients with medically refractory severe FI who have failed treatment or are not candidates for barrier devices, sacral nerve stimulation, perianal bulking injection, sphincteroplasty and a colostomy. Best Practice Advice 9: Major anatomic defects (eg, rectovaginal fistula, full thickness rectal prolapse, fistula in ano, or cloaca-like deformity) should be rectified with surgery. Best Practice Advice 10: A colostomy should be considered in patients with severe FI who have failed conservative treatment and have failed or are not candidates for barrier devices, minimally invasive surgical interventions, and sphincteroplasty. Best Practice Advice 11: A magnetic anal sphincter device may be considered for patients with medically refractory severe FI who have failed or are not candidates for barrier devices, perianal bulking injection, sacral nerve stimulation, sphincteroplasty, or a colostomy. Data regarding efficacy are limited and 40% of patients had moderate or severe complications. Best Practice Advice 12: For defecatory disorders, biofeedback therapy is the treatment of choice. Best Practice Advice 13: Based on limited evidence, sacral nerve stimulation should not be used for managing defecatory disorders in clinical practice. Best Practice Advice 14: Anterograde colonic enemas are not effective in the long term for management of defecatory disorders. Best Practice Advice 15: The stapled transanal rectal resection and related procedures should not be routinely performed for correction of structural abnormalities in patients with defecatory disorders. PMID- 28838789 TI - Long-term memory deficits in temporal lobe epilepsy. AB - Memory complaints and deficits are common in patients with epilepsy, especially temporal lobe epilepsy (TLE), where memory-related brain structures are directly involved in the epileptic process. In recent years, substantial progress has been made in delineating memory impairment in TLE, challenging the traditional neuropsychological approach of the disorder. In particular, several lines of evidence have suggested that, beyond the apparent deficit demonstrable by standardized neuropsychological evaluations, TLE may also negatively interact with long-term memory, producing considerable loss of information of the patient's autobiographical history and an inability to maintain newly acquired information over a period of time. These observations have led to the development of innovative assessment techniques, and prompted a new domain of investigation focused on the relationships between interictal epileptiform activities and the integrity of anatomo-functional systems. The present paper reviews the available evidence for long-term memory deficits in TLE with respect to remote and very long-term memory, and discusses their putative pathophysiological mechanisms and the developing potential strategies to improve memory functioning. PMID- 28838790 TI - Impact of spontaneous intracerebral hemorrhage on cognitive functioning: An update. AB - Intracerebral hemorrhage (ICH) accounts for 15% of all strokes and approximately 50% of stroke-related mortality and disability worldwide. Patients who have experienced ICH are at high risk of negative outcome, including stroke and cognitive disorders. Vascular cognitive impairment are frequently seen after brain hemorrhage, yet little is known about them, as most studies have focused on neuropsychological outcome in ischemic stroke survivors, using well-documented acute and chronic cognitive scores. However, recent evidence supports the notion that ICH and dementia are closely related and each increases the risk of the other. The location of the lesion also plays a significant role as regards the neuropsychological profile, while the pathophysiology of ICH can indicate a specific pattern of dysfunction. Several cognitive domains may be affected, such as language, memory, executive function, processing speed and gnosis. PMID- 28838791 TI - Causality and complex disease: The example of multiple sclerosis. PMID- 28838792 TI - Vascular cognitive impairment: Advances and trends. AB - The presence of vascular neurocognitive impairment (whatever the severity) is always associated with a functional impact and increased risk of dependency and institutionalization. However, vascular cognitive impairment remains underdiagnosed, and the mechanisms underlying post-stroke cognitive disorders are still poorly understood. However, the advent of new criteria and a standardized international neuropsychological battery is expected to lead to improved diagnosis and management, and the development of novel techniques (such as brain imaging and amyloid PET) should improve our understanding of the mechanisms underlying vascular cognitive impairment and help to identify potential targets for therapy. PMID- 28838793 TI - The Impact of Glottal Configuration on Speech Breathing. AB - OBJECTIVE: The purpose of this study was to examine whether changes in respiratory patterns occurred in response to volitional changes in glottal configuration. METHODS: Twelve vocally healthy participants read a passage while wearing the Inductotrace respiratory inductive plethysmograph, which measures the excursions of the rib cage and abdomen. Participants read the passage 5 times in a typical speaking voice (baseline phase), 10 times in an experimental voice, which was similar to a breathy vocal quality (experimental phase), and 5 times again in a typical speaking voice (return phase). Kinematic estimates of lung volume (LV) initiation, LV termination, and LV excursion were collected for each speech breath. RESULTS: Participants spoke with larger LV excursions during the experimental phase, characterized by increased LV initiation and decreased LV termination compared with the baseline phase. CONCLUSION: In response to volitional changes in glottal configuration, healthy individuals spoke with increased LV excursion. They both responded to changes (decreasing LV termination) and planned for more efficient future utterances (increasing LV initiation) during the experimental phase. This study demonstrated that respiratory patterns change in response to changes in glottal configuration; future work will examine these patterns in individuals with voice disorders. PMID- 28838794 TI - [Pay for performance in dental care: A systematic narrative review of quality P4P models in dental care]. AB - BACKGROUND: Pay for performance (P4P) links reimbursement to the achievement of quality objectives. Experiences with P4P instruments and studies on their effects are available for the inpatient sector. A systematic narrative review brings together findings concerning the use and the effects of P4P, especially in dental care. METHODS: A systematic literature search in PubMed and the Cochrane Library for reimbursement models using quality indicators provided 77 publications. Inclusion criteria were: year of publication not older than 2007, dental sector, models of quality-oriented remuneration, quality of care, quality indicators. 27 publications met the inclusion criteria and were evaluated with regard to the instruments and effects of P4P. The database search was supplemented by a free search on the Internet as well as a search in indicator databases and portals. The results of the included studies were extracted and summarized narratively. RESULTS: 27 studies were included in the review. Performance-oriented remuneration is an instrument of quality competition. In principle, P4P is embedded in an existing remuneration system, i.e., it does not occur in isolation. In the United States, England and Scandinavia, models are currently being tested for quality-oriented remuneration in dental care, based on quality indicators. The studies identified by the literature search are very heterogeneous and do not yield comparable endpoints. Difficulties are seen in the reproducibility of the quality of dental care with regard to certain characteristics which still have to be defined as quality-promoting properties. Risk selection cannot be ruled out, which may have an impact on structural quality (access to care, coordination). CONCLUSION: There were no long-term effects of P4P on the quality of care. In the short and medium term, adverse effects on the participants' motivation as well as shifting effects towards the private sector are described. A prerequisite for the functioning of P4P is the definition of clear targets and measuring parameters. Furthermore, evidence-based quality indicators have to be developed that validly depict quality differences. It is yet unknown whether P4P will have long-term effects or whether the quality of dental care will increase. PMID- 28838795 TI - Weight Status and Weight Perception in Relation to Mental Distress and Psychosocial Protective Factors Among Adolescents. AB - OBJECTIVE: To measure how weight status and weight perception relate to mental distress and psychosocial protective factors in adolescents. METHODS: Adolescents in 8th, 9th, and 11th grade participating in the 2013 Minnesota Student Survey (N = 122,180) were classified on the basis of weight perception (overweight or not overweight) and weight status (not overweight, overweight, obese). Bivariate tests were used to assess the relationship of weight status and weight perception with internal mental distress, and generalized linear models were used to measure the association between weight status and weight perception with psychosocial protective factors including parent, school, and friend connectedness, social competency, and positive identity. Logistic regressions measured the relationship between psychosocial protective factors and internal mental distress. RESULTS: Prevalence of internal mental distress ranged from 14.5% for overweight boys who perceived themselves as not overweight to 55.0% for girls who were not overweight but self-perceived as overweight. Across all weight-status categories, adolescents who perceived themselves as overweight, compared to those who did not, had higher internal mental distress and lower mean levels of psychosocial protective factors. All psychosocial protective factors were related to lower odds of internal mental distress, with significant small differences by weight status and weight perception. CONCLUSIONS: Weight status and weight perception affected both mental distress and psychosocial protective factors. Those who perceived themselves as overweight, regardless of weight status, had the highest prevalence of mental distress and the lowest levels of psychosocial protective factors. Health care providers should consider screening for weight perception to provide a tailored approach to adolescent care. PMID- 28838796 TI - NK cell-based immunotherapy for cancer. AB - Natural killer (NK) cells can induce an antigen-independent immune response against malignant cells. A growing number of scientific reports and clinical studies have shown promising anti-tumor effects when using NK cell-based immunotherapy. Currently, various approaches are being used to enhance the number and function of NK cells. One approach uses cytokines to selectively boost both the number as well as the efficacy of anti-tumor functions of NK cells. Another emerging approach focuses on checkpoint inhibitors targeting the NK cell receptor. Furthermore, bi-specific and tri-specific engagers have been developed to enhance the specific immune response by cross-linking specific tumor antigens to effector cells. In addition, NK cell adoptive transfer therapies have shown promising prospects. Among the various sources of adoptive transfer NK cells, allogeneic haploidentical NK cells that have undergone short- or long-term activation or expansion have also demonstrated effective anti-tumor effects with a low rate of rejection and side effects. CAR-NKs, derived from a new type of genetic modification, show enhanced NK cell cytotoxicity, specificity, and targeting. These NK cell-based therapies have exhibited promising results in clinical trials with malignant tumors. In this review, the current progress on NK cell-based therapeutic approaches, NK cell manufacturing techniques and tumor therapy outcomes are discussed. PMID- 28838797 TI - Thread-based microfluidics: Flow patterns in homogeneous and heterogeneous microfiber bundles. AB - Thread-based microfluidics has recently seen considerable developments in the domain of portable diagnostic systems, smart bandages and tissue engineering. Similarly to paper-based microfluidics, thread-based microfluidics uses the wicking of fibers to move fluids. It has the advantage of confining and guiding the fluid along the yarns in a one, two or three dimensional space. A global approach to the motion of fluids in yarns and fiber bundles has already been reported in the literature based on the Lucas-Washburn-Rideal law. However no detailed investigation of the flow pattern inside the bundle has been conducted, depending on the internal structure of the bundle. Especially when the bundle possesses heterogeneous wetting properties, such as two different wetting regions interior and exterior, different flow patterns may exist. In this work, we perform a theoretical and numerical analysis of the different flow regimes for homogenous and heterogeneous fiber bundles. It is demonstrated that a limited number of fibers is sufficient for thread-based capillary flows, and that a caging of the flow can be achieved by realizing a lyophobic envelope. PMID- 28838799 TI - The potential contribution of 16S ribosomal RNA polymerase chain reaction to antimicrobial stewardship in culture-negative infection. AB - Empiric broad-spectrum antimicrobial therapy frequently results in culture negative specimens making rationalization of therapy difficult. We retrospectively reviewed 16S rRNA polymerase chain reaction (PCR) results from 78 specimens in 60 patients. 16S rRNA was detected in 28 (47%) patients with de escalation of therapy in five (21%). Microbial DNA was not detected in 32 (53%) patients with antimicrobials discontinued in two (8%). Neurosurgical patients had a higher proportion of positive results (53% vs 34%) and treatment rationalizations (17% vs 12%). In specific patient groups, 16s rRNA PCR is a useful antimicrobial stewardship tool for targeting antimicrobial therapy. PMID- 28838798 TI - Red blood cell (RBC) suspensions in confined microflows: Pressure-flow relationship. AB - Microfluidic-based assays have become increasingly popular to explore microcirculation in vitro. In these experiments, blood is resuspended to a desired haematocrit level in a buffer solution, where frequent choices for preparing RBC suspensions comprise notably Dextran and physiological buffer. Yet, the rational for selecting one buffer versus another is often ill-defined and lacks detailed quantification, including ensuing changes in RBC flow characteristics. Here, we revisit RBC suspensions in microflows and attempt to quantify systematically some of the differences emanating between buffers. We measure bulk flow rate (Q) of RBC suspensions, using PBS- and Dextran-40, as a function of the applied pressure drop (DeltaP) for two hematocrits (~0% and 23%). Two distinct microfluidic designs of varying dimensions are employed: a straight channel larger than and a network array similar to the size of individual RBCs. Using the resulting pressure-flow curves, we extract the equivalent hydrodynamic resistances and estimate the relative viscosities. These efforts are a first step in rigorously quantifying the influence of the 'background' buffer on RBC flows within microfluidic devices and thereby underline the importance of purposefully selecting buffer suspensions for microfluidic in vitro assays. PMID- 28838800 TI - Using a vanA polymerase chain reaction to detect environmental contamination during a vancomycin-resistant enterococci outbreak. PMID- 28838801 TI - Optimization of infobutton design and Implementation: A systematic review. AB - OBJECTIVE: Infobuttons are clinical decision tools embedded in the electronic health record that attempt to link clinical data with context sensitive knowledge resources. We systematically reviewed technical approaches that contribute to improved infobutton design, implementation and functionality. METHODS: We searched databases including MEDLINE, EMBASE, and the Cochrane Library database from inception to March 1, 2016 for studies describing the use of infobuttons. We selected full review comparative studies, usability studies, and qualitative studies examining infobutton design and implementation. We abstracted usability measures such as user satisfaction, impact, and efficiency, as well as prediction accuracy of infobutton content retrieval algorithms and infobutton adoption/interoperability. RESULTS: We found 82 original research studies on infobuttons. Twelve studies met criteria for detailed abstraction. These studies investigated infobutton interoperability (1 study); tools to help tailor infobutton functionality (1 study); interventions to improve user experience (7 studies); and interventions to improve content retrieval by improving prediction of relevant knowledge resources and information needs (3 studies). In-depth interviews with implementers showed the Health Level Seven (HL7) Infobutton standard to be simple and easy to implement. A usability study demonstrated the feasibility of a tool to help medical librarians tailor infobutton functionality. User experience studies showed that access to resources with which users are familiar increased user satisfaction ratings; and that links to specific subsections of drug monographs increased information seeking efficiency. However, none of the user experience improvements led to increased usage uptake. Recommender systems based on machine learning algorithms outperformed hand crafted rules in the prediction of relevant resources and clinicians' information needs in a laboratory setting, but no studies were found using these techniques in clinical settings. Improved content indexing in one study led to improved content retrieval across three health care organizations. CONCLUSION: Best practice technical approaches to ensure optimal infobutton functionality, design and implementation remain understudied. The HL7 Infobutton standard has supported wide adoption of infobutton functionality among clinical information systems and knowledge resources. Limited evidence supports infobutton enhancements such as links to specific subtopics, configuration of optimal resources for specific tasks and users, and improved indexing and content coverage. Further research is needed to investigate user experience improvements to increase infobutton use and effectiveness. PMID- 28838802 TI - Literature Based Discovery: Models, methods, and trends. AB - OBJECTIVES: This paper provides an introduction and overview of literature based discovery (LBD) in the biomedical domain. It introduces the reader to modern and historical LBD models, key system components, evaluation methodologies, and current trends. After completion, the reader will be familiar with the challenges and methodologies of LBD. The reader will be capable of distinguishing between recent LBD systems and publications, and be capable of designing an LBD system for a specific application. TARGET AUDIENCE: From biomedical researchers curious about LBD, to someone looking to design an LBD system, to an LBD expert trying to catch up on trends in the field. The reader need not be familiar with LBD, but knowledge of biomedical text processing tools is helpful. SCOPE: This paper describes a unifying framework for LBD systems. Within this framework, different models and methods are presented to both distinguish and show overlap between systems. Topics include term and document representation, system components, and an overview of models including co-occurrence models, semantic models, and distributional models. Other topics include uninformative term filtering, term ranking, results display, system evaluation, an overview of the application areas of drug development, drug repurposing, and adverse drug event prediction, and challenges and future directions. A timeline showing contributions to LBD, and a table summarizing the works of several authors is provided. Topics are presented from a high level perspective. References are given if more detailed analysis is required. PMID- 28838803 TI - Author's Reply. PMID- 28838804 TI - Castor oil as a natural alternative to labor induction: A retrospective descriptive study. AB - AIM: To describe birthing outcomes among women who consumed castor oil cocktail as part of a freestanding birth center labor induction protocol. METHODS: De identified data from birth logs and electronic medical records were entered into SPSS Statistics 22.0 for analysis for all women who received the castor oil cocktail (n=323) to induce labor between January 2008 and May 2015 at a birth center in the United States. Descriptive statistics were analyzed for trends in safety and birthing outcomes. RESULTS: Of the women who utilized the castor oil cocktail to stimulate labor, 293 (90.7%) birthed vaginally at the birth center or hospital. The incidence of maternal adverse effects (e.g., nausea, vomiting, extreme diarrhea) was less than 7%, and adverse effects of any kind were reported in less than 15% of births. An independent sample t-test revealed that parous women were more likely to birth vaginally at the birth center after using the castor oil cocktail than their nulliparous counterparts (p<.010), while gestational age (p=.26), woman's age (p=.23), and body mass index (p=.28) were not significantly associated. CONCLUSIONS: Nearly 91% of women in the study who consumed the castor oil cocktail to induce labor were able to give birth vaginally with little to no maternal or fetal complications. Findings indicate further research is needed to compare the safety and effectiveness of natural labor induction methodologies, including castor oil, to commonly used labor induction techniques in a prospective study or clinical trial. PMID- 28838805 TI - Monitoring postpartum haemorrhage in Australia: Opportunities to improve reporting. AB - PROBLEM: The rate and severity of postpartum haemorrhage (PPH) are increasing, according to research reports and clinical anecdote, causing a significant health burden for Australian women giving birth. However, reporting a national Australian rate is not possible due to inconsistent reporting of PPH. BACKGROUND: Clinician concerns about the incidence and severity of PPH are growing. Midwives contribute perinatal data on every birth, yet published population-based data on PPH seems to be limited. What PPH information is contributed? What data are publicly available? Do published data reflect the PPH concerns of clinicians? AIM: To examine routine public reporting on PPH across Australia. METHODS: We systematically analysed routine, publicly reported data on PPH published in the most recent perinatal data for each state, territory and national report (up to and including October 2016). We extracted PPH data on definitions, type and method of data recorded, markers of severity, whether any analyses were done and whether any trends or concerns were noted. FINDINGS: PPH data are collected by all Australian states and territories however, definitions, identification method and documentation of data items vary. Not all states and territories published PPH rates; those that did ranged from 3.3% to 26.5% and were accompanied by minimal reporting of severity and possible risk factors. Whilst there are plans to include PPH as a mandatory reporting item, the timeline is uncertain. CONCLUSIONS: Routinely published PPH data lack nationally consistent definitions and detail. All states and territories are urged to prioritise the adoption of nationally recommended PPH items. PMID- 28838806 TI - Evaluation of marker gene expression as a potential predictive marker of leukopenic toxicity for inactivated influenza vaccines. AB - The leukopenic toxicity test (LTT) is used to evaluate the safety and lot-to-lot consistency of influenza hemagglutinin split vaccine (HAv) and is included in the Japanese Minimum Requirements for Biological Products. LTT assesses the reduced leukocyte levels in murine peripheral blood after HAv administration. However, they require large numbers of animals, and therefore it would be beneficial to develop a more accurate and sensitive alternative method. In this study, we selected biomarkers of leukocyte reduction from 18 previously identified marker genes that were associated with an abnormal toxicity test (ATT). Among these 18 genes, the expressions of 15 marker genes were strongly associated with leukocyte reduction levels. A stepwise single addition multiple regression analysis was used to further extract the genes responsible for leukocyte reduction, with significant (p < 0.25) regression coefficients. The expression of 7 genes significantly predicted the leukocyte reduction. The prediction accuracy of this approach was approximately >90% (mean) for the direct measurement of leukocyte numbers. These results indicate that the expression of these 18 previously identified genes can provide information for both ATT and LTT. PMID- 28838807 TI - Skeletal health in breast cancer survivors. AB - Although some risk factors for breast cancer might be protective for osteoporosis, several cross-sectional studies have reported, nevertheless, that patients with breast cancer have a lower bone mass and potentially a higher incidence of fractures than expected. In any case, it appears that patients with breast cancer are not protected from osteoporosis, which provides further support for the recommendation that bone health is assessed after a diagnosis of breast cancer. Most adjuvant therapies will lead to increased bone loss and a higher fracture rate. Among the adjuvant therapy options for premenopausal patients with breast cancer, endocrine therapy (ovarian suppression) and chemotherapy can result in cancer treatment-induced bone loss (CTIBL) of up to 10% at the lumbar spine after one year. Antiresorptive therapies prevent CTIBL in premenopausal women with breast cancer. Most of the evidence demonstrating the efficacy of bisphosphonates in the prevention of CTIBL is derived from clinical trials with zoledronic acid. The addition of zoledronic acid 4mg per six months to adjuvant endocrine therapy maintained and even increased bone mass during a 3-year treatment period and significantly improved disease-free survival in a population of young women who underwent menopause due to the adjuvant treatment. The major contributor to bone loss in the adjuvant treatment of breast cancer in postmenopausal women is the use of aromatase inhibitors (AIs). Oncology trials have underestimated the fracture risk in the setting of AI-induced bone loss. In the ABCSG-18 study, the only trial in which fracture incidence was the primary endpoint, the rate of clinical fractures was close to 10% after 3 years in the placebo group on AIs only. Bisphosphonates and denosumab at osteoporosis treatment doses can counteract AI-induced bone loss. In the ABCSG-18 trial, treatment with denosumab 60mg injection every 6 months reduced the risk of first clinical fracture relative to placebo by 50%. Current guidelines recommend antiresorptive therapy in patients with a baseline T score of <-2.0 or with two or more clinical risk factors for fracture. These recent guidelines will need to be updated, as similar significant protective effects were seen in women with either normal or low bone mass. Moreover, a formal meta-analysis of individual patient data from more than 18,000 women in 26 randomized trials of adjuvant zoledronic acid or clodronate treatment for early breast cancer revealed that bisphosphonates significantly reduced the risk of first distant recurrence in bone and the risk of breast cancer mortality, at least in postmenopausal women. Even though the increased risk of fracture during adjuvant treatment for breast cancer in postmenopausal women is notable, an enhanced risk of fracture in long term survivors of breast cancer remains under debate. The most recent studies suggest that Caucasian breast cancer survivors do not have a significantly increased risk of osteoporotic fracture over the long term. PMID- 28838809 TI - What is the optimal distribution of myelin along a single axon? AB - The myelin sheath that insulates some axons in the central nervous system allows for faster signal conduction. Previously, axons were thought to be either unmyelinated or fully myelinated. Recent experimental work has discovered a new pattern of myelination (intermittent myelination) along axons in the mouse brain, in which long unmyelinated axon segments are followed by myelinated segments of comparable length. We use a computational model to explore how myelin distribution (in particular intermittent myelination) affects conduction velocity. We find that although fully myelinated axons minimize conduction velocity, varying the spatial distribution of a fixed amount of myelin along a partially myelinated axon leads to considerable variation in the conduction velocity for action potentials. Whether sodium ion channel number or sodium ion channel density is held constant as the area of the unmyelinated segments increases has a strong influence on the optimal pattern of myelin and the conduction velocity. PMID- 28838810 TI - The activation of NMDA receptors alters the structural dynamics of the spines of hippocampal interneurons. AB - N-Methyl-d-Aspartate receptors (NMDARs) are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play a key role in the structural plasticity of excitatory neurons, but to date little is known about their influence on the remodeling of interneurons. Among hippocampal interneurons, the somatostatin expressing cells in the CA1 stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change their density in response to different stimuli. In order to understand the role of NMDAR activation on the structural dynamics of the spines of somatostatin expressing interneurons in the CA1 stratum oriens, we have studied entorhino-hippocampal organotypic cultures obtained from mice in which this interneuronal subpopulation expresses constitutively EGFP, and have imaged them in real-time. We have acutely infused the cultures with NMDA, a strong NMDAR agonist, and have analyzed the structural dynamics of somatostatin expressing interneurons, prior and after its administration. The appearance and disappearance rates of their dendritic spines increased 24h after the NMDA infusion and returned to baseline levels 48h afterwards. By contrast, their stability rate decreased 24h after the infusion and also returned to control levels 48h later. The relative density of the dendritic spines remained unaltered throughout the assay. Altogether, our results show that the activation of NMDARs can influence the structural dynamics of interneurons. This is especially important because of the involvement of these receptors in neuronal potentiation/depression and their putative role in the etiopathology of certain neuropsychiatric disorders, such as schizophrenia. PMID- 28838808 TI - Characterization of structurally novel G protein biased CB1 agonists: Implications for drug development. AB - The human cannabinoid subtype 1 receptor (hCB1R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant derived and synthetic cannabinoids. Unfortunately, acute use of hCB1R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in beta-arrestin knockout mice suggest that interaction of certain GPCRs, including MU-, delta-, kappa-opioid and hCB1Rs, with beta arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to beta-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB1Rs might be improved by development of G-protein biased hCB1R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB1 receptors. Our studies found that a novel IQD-derived hCB1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non biased hCB1R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no beta-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to beta-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced beta-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB1Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Delta9-THC. Finally, studies of a structurally similar analog PNR- 4-02 show that it is also a G protein biased hCB1R agonist. It is predicted that cannabinoid agonists that bias hCB1R activation toward G protein, relative to beta-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically. PMID- 28838811 TI - Mitochondrial calcium imbalance in Parkinson's disease. AB - Multiple factors are involved in the mechanism(s) of neuronal loss in neurodegenerative disorders whilst mitochondria are thought to play a central role in neurodegeneration of Parkinson's disease. Mitochondria are vital to cellular functions by supplying energy in form of ATP and affect cell physiology via calcium, ROS and signalling proteins. Changes in mitochondrial calcium homeostasis and ROS overproduction can induce cell death by triggering mitochondrial permeability transition pore opening. One of the major triggers for PTP is mitochondrial calcium overload. Mitochondrial Ca2+ homeostasis is regulated by electrogenic calcium uptake (via Ca2+ uniporter MCU) and efflux (in excitable cells via Na+/Ca2+ exchanger NCLX). NCLX inhibition has been described in a familial form of Parkinson's disease where PINK-1 deficiency leads to a delayed calcium efflux and mitochondrial Ca2+ overload in response to physiological Ca2+ stimulation. Overexpression of NCLX in PINK-1 deficient neurons not only protects against mitochondrial calcium overload and calcium induced cell death but also restores mitochondrial bioenergetics in these neurons. Mitochondrial NCLX might therefore play an important role in the mechanism(s) of neurodegeneration in a variety of neurodegenerative disorders and activation of this exchanger may offer a novel therapeutic target. PMID- 28838813 TI - On study designs and hypotheses for clinical trials with predictive biomarkers. AB - Recent interest in conducting clinical trials with predictive biomarkers has generated research in comparing relative efficiency of different trial designs. We find these comparisons of efficiency mostly misleading since they are based on different hypotheses. In this paper, we discuss several commonly used trial designs and consider the hypotheses that each design is capable to address. We first consider the ideal situation of no classification errors, then the more realistic situation where marker assay's sensitivity, specificity and the rule of classification are imperfect. We pay special attention to the differences between treatment utility versus absolute treatment effect, and marker by treatment interaction versus marker utility. PMID- 28838812 TI - Polyphasic characterization of bacteria obtained from upland rice cultivated in Cerrado soil. AB - This work aimed to characterize 20 isolates obtained from upland rice plants, based on phenotypic (morphology, enzymatic activity, inorganic phosphate solubilization, carbon source use, antagonism), genotypic assays (16S rRNA sequencing) and plant growth promotion. Results showed a great morphological, metabolic and genetic variability among bacterial isolates. All isolates showed positive activity for catalase and protease enzymes and, 90% of the isolates showed positive activity for amylase, catalase and, nitrogenase. All isolates were able to metabolize sucrose and malic acid in contrast with mannitol, which was metabolized only by one isolate. For the other carbon sources, we observed a great variability in its use by the isolates. Most isolates showed antibiosis against Rhizoctonia solani (75%) and Sclerotinia sclerotiorum (55%) and, 50% of them showed antibiosis against both pathogens. Six isolates showed simultaneous ability of antibiosis, inorganic phosphate solubilization and protease activity. Based on phylogenetic analysis of the 16S rRNA gene all the isolates belong to Bacillus genus. Under greenhouse conditions, two isolates (S4 and S22) improved to about 24%, 25%, 30% and 31% the Total N, leaf area, shoot dry weight and root dry weight, respectively, of rice plants, indicating that they should be tested for this ability under field conditions. PMID- 28838814 TI - Lifestyle intervention program benefits children with overweigh compared to children with obesity. AB - BACKGROUND: Lifestyle weight loss interventions represent the mainstay of treating children with obesity. Long-term follow-up studies of intervention programs are scarce. This study assessed the long-term effects and identified factors associated with significant weight loss. METHODS: This prospective, observational study involved 165 children with body mass index (BMI) z-score >=1.5 who participated in after-school intervention program. MAIN OUTCOME MEASURE: change in BMI z-scores; decreased BMI z-score >=0.5 units was defined as clinically significant. RESULTS: At baseline, 55/165 (33.3%) had BMI z-score 1.5 2 and 98 (59.4%) had BMI z-score >2. At follow-up (mean 5.4+/-1.4 years), 80 (48.5%) had a clinically significant reduction in BMI z-score, while 56 (33.9%) reported a mildly decrease in BMI z-score of 0-0.5 and 29 (17.6%) reported increased BMI z-score. Lower BMI z-score at baseline and participation in sport activity at follow-up were associated with long-term decrease in BMI z-score. Participation in additional post-intervention weight control programs was correlated with weight gain. CONCLUSIONS: Intervention program was associated with long-term improvement in weight control, especially in children with mild obesity. Physical activity was related to long-term success. Participation in an additional intervention program was associated with failure of weight control. PMID- 28838816 TI - Reply to "Axonal hyperexcitability due to Schwann cell involvement in chronic progressive external ophthalmoplegia". PMID- 28838815 TI - Standardized computer-based organized reporting of EEG: SCORE - Second version. AB - Standardized terminology for computer-based assessment and reporting of EEG has been previously developed in Europe. The International Federation of Clinical Neurophysiology established a taskforce in 2013 to develop this further, and to reach international consensus. This work resulted in the second, revised version of SCORE (Standardized Computer-based Organized Reporting of EEG), which is presented in this paper. The revised terminology was implemented in a software package (SCORE EEG), which was tested in clinical practice on 12,160 EEG recordings. Standardized terms implemented in SCORE are used to report the features of clinical relevance, extracted while assessing the EEGs. Selection of the terms is context sensitive: initial choices determine the subsequently presented sets of additional choices. This process automatically generates a report and feeds these features into a database. In the end, the diagnostic significance is scored, using a standardized list of terms. SCORE has specific modules for scoring seizures (including seizure semiology and ictal EEG patterns), neonatal recordings (including features specific for this age group), and for Critical Care EEG Terminology. SCORE is a useful clinical tool, with potential impact on clinical care, quality assurance, data-sharing, research and education. PMID- 28838817 TI - 3D Fiber Orientation in Atherosclerotic Carotid Plaques. AB - Atherosclerotic plaque rupture is the primary trigger of fatal cardiovascular events. Fibrillar collagen in atherosclerotic plaques and their directionality are anticipated to play a crucial role in plaque rupture. This study aimed assessing 3D fiber orientations and architecture in atherosclerotic plaques for the first time. Seven carotid plaques were imaged ex-vivo with a state-of-the-art Diffusion Tensor Imaging (DTI) technique, using a high magnetic field (9.4Tesla) MRI scanner. A 3D spin-echo sequence with uni-polar diffusion sensitizing pulsed field gradients was utilized for DTI and fiber directions were assessed from diffusion tensor measurements. The distribution of the 3D fiber orientations in atherosclerotic plaques were quantified and the principal fiber orientations (circumferential, longitudinal or radial) were determined. Overall, 52% of the fiber orientations in the carotid plaque specimens were closest to the circumferential direction, 34% to the longitudinal direction, and 14% to the radial direction. Statistically no significant difference was measured in the amount of the fiber orientations between the concentric and eccentric plaque sites. However, concentric plaque sites showed a distinct structural organization, where the principally longitudinally oriented fibers were closer to the luminal side and the principally circumferentially oriented fibers were located more abluminally. The acquired unique information on 3D plaque fiber direction will help understanding pathobiological mechanisms of atherosclerotic plaque progression and pave the road to more realistic biomechanical plaque modeling for rupture assessment. PMID- 28838818 TI - X-ray diffraction measurement of cosolvent accessible volume in rhombohedral insulin crystals. AB - X-ray crystallographic measurement of the number of solvent electrons in the unit cell of a protein crystal equilibrated with aqueous solutions of different densities provides information about preferential hydration in the crystalline state. Room temperature and cryo-cooled rhombohedral insulin crystals were equilibrated with 1.2M trehalose to study the effect of lowered water activity. The native and trehalose soaked crystals were isomorphous and had similar structures. Including all the low resolution data, the amplitudes of the structure factors were put on an absolute scale (in units of electrons per asymmetric unit) by constraining the integrated number of electrons inside the envelope of the calculated protein density map to equal the number deduced from the atomic model. This procedure defines the value of F(000), the amplitude at the origin of the Fourier transform, which is equal to the total number of electrons in the asymmetric unit (i.e. protein plus solvent). Comparison of the F(000) values for three isomorphous pairs of room temperature insulin crystals, three with trehalose and three without trehalose, indicates that 75+/-12 electrons per asymmetric unit were added to the crystal solvent when soaked in 1.2M trehalose. If all the water in the crystal were available as solvent for the trehalose, 304 electrons would have been added. Thus, the co-solvent accessible volume is one quarter of the total water in the crystal. Determination of the total number of electrons in a protein crystal is an essential first step for mapping the average density distribution of the disordered solvent. PMID- 28838819 TI - Pediatric idiopathic intracranial hypertension - Is the fixed threshold value of elevated LP opening pressure set too high? AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) in children is a rare condition of unknown etiology and various clinical presentations. The primary aim of this study was to evaluate if our pediatric IIH study group fulfilled the revised diagnostic criteria for IIH published in 2013, particularly with regard to clinical presentation and threshold value of an elevated lumbar puncture opening pressure. Additionally we investigated the potential utilization of MR based and fundoscopic methods of estimating intracranial pressure for improved diagnosis. PATIENTS AND METHODS: Clinical data were collected retrospectively from twelve pediatric patients diagnosed with IIH between 2008 and 2012 and revised diagnostic criteria were applied. Comparison with non-invasive methods for measuring intracranial pressure, MRI-based measurement (MR-ICP) and venous ophthalmodynamometry was performed. RESULTS: Only four of the twelve children (33%) fulfilled the revised diagnostic criteria for a definite diagnosis of IIH. Regarding noninvasive methods, MR-ICP (n = 6) showed a significantly higher mean of intracranial pressure compared to a healthy age- and sex-matched control group (p = 0.0043). Venous ophthalmodynamometry (n = 4) showed comparable results to invasive lumbar puncture. CONCLUSION: The revised diagnostic criteria for IIH may be too strict especially in children without papilledema. MR-ICP and venous ophthalmodynamometry are promising complementary procedures for monitoring disease progression and response to treatment. PMID- 28838820 TI - Safe zone in anterior mandible related to the genial tubercle for implant osteotomy in a Chinese-Malaysian population: A CBCT study. AB - STATEMENT OF PROBLEM: The genial tubercle is a clinically palpable landmark in the mandible and can be identified in cone beam computed tomography (CBCT). Its location can be used to measure the safe zone in the interforaminal region of the mandible. These measurements may be helpful for implant treatment planning in patients with complete edentulism. PURPOSE: The purpose of this clinical study was to evaluate the safe distance in the interforaminal region of the mandible measured from the genial tubercle level for implant osteotomy in a Chinese Malaysian population. MATERIAL AND METHODS: A total of 201 Digital Imaging and Communications in Medicine (DICOM) files were selected for the study from the CBCTs of dentate or edentulous Chinese-Malaysian adult patients with ongoing or completed treatments. Measurements were made with implant planning software. The anatomy of the whole mandible was assessed in the coronal cross-sectional, horizontal view and in panoramic view. Measurements were obtained in millimeters on one side by locating and marking a genial tubercle and then marking the mesial margin of the mental foramen and the anterior loop of the inferior alveolar nerve. The corresponding points of these landmarks were identified on the crest of the mandibular ridge to measure the linear distances. All the measurement steps were repeated on the other side. The linear distance of 2 mm was deducted from the total distance between the genial tubercle and the anterior loop separately for left and right side measurements to identify the safe zone. The mixed 2-way analysis of variance (ANOVA) test was used to analyze side and sex related variations. RESULTS: The mean safe zone measured at the crestal level from the genial tubercle site on the left side of the mandible was 21.12 mm and 21.67 mm on the right side. A statistically significant (P<.05) difference was found between the left and right sides of the safe zone measurements in both men and women. No statistically significant differences were found in the safe zone between men and women on either the left or right side (P=.655). The minimum distance from the genial tubercle to the right side safe zone in women was 12.82 mm and 14.99 mm in men; however, on the left side, the minimum distance was observed to be 14.81 mm in women and 15.54 mm in men. CONCLUSIONS: The safe zone related to the genial tubercle was 21.12 mm on the left side and 21.67 mm on the right side, with no significant sex-related variations. Within the same individuals, a significant difference was found in the safe zone between the left and right side. PMID- 28838821 TI - Effect of annealing procedure on the bonding of ceramic to cobalt-chromium alloys fabricated by rapid prototyping. AB - STATEMENT OF PROBLEM: An annealing procedure is a heat treatment process to improve the mechanical properties of cobalt-chromium (Co-Cr) alloys. However, information is lacking about the effect of the annealing process on the bonding ability of ceramic to Co-Cr alloys fabricated by rapid prototyping. PURPOSE: The purpose of this in vitro study was to evaluate the effects of the fabrication techniques and the annealing procedure on the shear bond strength of ceramic to Co-Cr alloys fabricated by different techniques. MATERIAL AND METHODS: Ninety-six cylindrical specimens (10-mm diameter, 10-mm height) made of Co-Cr alloy were prepared by casting (C), milling (M), direct process powder-bed (LaserCUSING) with and without annealing (CL+, CL), and direct metal laser sintering (DMLS) with annealing (EL+) and without annealing (EL). After the application of ceramic to the metal specimens, the metal-ceramic bond strength was assessed using a shear force test at a crosshead speed of 0.5 mm/min. Shear bond strength values were statistically analyzed by 1-way ANOVA and Tukey multiple comparison tests (alpha=.05). RESULTS: Although statistically significant differences were found among the 3 groups (M, 29.87 +/-2.06; EL, 38.92 +/-2.04; and CL+, 40.93 +/-2.21; P=.002), no significant differences were found among the others (P>.05). The debonding surfaces of all specimens exhibited mixed failure mode. CONCLUSIONS: These results showed that the direct process powder-bed method is promising in terms of metal-ceramic bonding ability. The manufacturing technique of Co-Cr alloys and the annealing process influence metal-ceramic bonding. PMID- 28838822 TI - A multidisciplinary approach to the management of a maxillary midline diastema: A clinical report. AB - A maxillary midline diastema (MMD) is a common complaint of dental patients. An MMD can be closed with treatment from different disciplines, including operative dentistry and orthodontics. A comprehensive smile analysis is also a necessity before beginning treatment. This article highlights the closure of a 3-mm MMD by using a combination of orthodontics and direct composite resin restorations. PMID- 28838823 TI - Radiological findings in autosomal recessive infantile osteopetrosis. PMID- 28838824 TI - Phlebectasia in a finger in a case of microscopic polyangiitis with peripheral polyneuropathy. AB - The patient was a 56-year-old man with microscopic polyangiitis and symmetrical peripheral polyneuropathy of the extremities who was positive for p-ANCA, EMG pattern of mononeuritis multiplex and skin biopsy showing the presence of nonspecific vasculitis. He had phlebectasia with plethora and tortuous vessels on dorsum of the fingers on both hands, paresis and hypoesthesia of fingers and toes with functional limitations. The administration of prednisone, azathioprine and a cyclophosphamide pulse achieved rapid improvement in the general symptoms, but the changes in the neuropathy occurred very slowly. After 47 months of treatment, he had mild phlebectasia in fingers and slight hypoesthesia in hands and feet, with normal laboratory tests. Phlebectasia was probably the result of an autonomic dysfunction due to vasculitis of the vasa nervorum and could be a sign to look for in similar cases. PMID- 28838825 TI - Coexistence of Sarcoidosis and Gouty Arthritis. AB - Sarcoidosis is an inflammatory disease with unknown cause characterized by non caseating granuloma formations. It may present with bilateral hilar lymphadenopathy, skin lesions, the involvement of eye and symptoms on the locomotor system. Gouty arthritis is an autoinflammatory disease characterized by hyperuricemia, recurrent arthritis attacks and the deposition of monosodium urate crystals in the joints and the surrounding tissues. We reported the coexistence of sarcoidosis and gouty arthritis in this paper. PMID- 28838826 TI - Dental injury associated with anaesthesia: An 8-year database analysis of 592 claims from a major French insurance company. AB - INTRODUCTION: Dental injury is the most common incident associated with anaesthesia. Regarding recent recommendations on informed consent and changes in airway management practices, a large series of claims related to dental injury has not been recently described. The aim of this study was to analyse a recent database in order to describe the characteristics of dental injury in France. METHODS: A database that prospectively collected claims reported to Le Sou Medical-MACSF between January 2003 and December 2010, was analysed. Five hundred and ninety-two cases were reported. The following characteristics were analysed: number and type of teeth injured, mechanism of injury, anaesthetic procedure, risk factors and dental outcome after injury. RESULTS: Amongst the 1514 claims related to anaesthesia, 592 (39.2%) were classified as dental damage. Preoperative informed consent concerning possible perioperative dental injury was documented in only 34.8% of patients. Only one tooth was affected in 65.2% of patients, dental bridge injury in 12.8% of cases and damage to two or more teeth in 14% of patients. Incisors were involved in 50% of cases. Fracture was the most common type of injury (64.2%). Poor dentition was the most common risk factor (23.1%) followed by difficult intubation (15.4%). Both risks were combined in only 7.6% of cases. Tracheal intubation was the highest risk procedure (41.6%). CONCLUSION: Dental injury remains the most common anaesthesia-related claim. Dental examination and documentation in patient medical files requires improvement and better informed consent on dental injury risk needs to be provided to patients. PMID- 28838827 TI - Racial Difference in Cerebral Microbleed Burden among Ischemic Stroke Patients. AB - BACKGROUND AND AIMS: Data on the epidemiology of cerebral microbleeds (CMBs) among patients with ischemic stroke are limited. This study compared the number, associated factors, and topography of CMBs between African American and Caucasian ischemic stroke patients in the Mid-South United States. METHOD: We evaluated consecutive ischemic stroke patients admitted to our tertiary stroke center, University of Tennessee Health Science Center, Memphis, Tennessee, in a two-year period. We analyzed T2*-weighted magnetic resonance images for the number, location, and topography of CMBs, as well as patients' demographic and clinical information. RESULTS: Among 760 ischemic stroke patients who were included (mean age was 62.1 +/- 13.9 years, 51.4% men), 450 (59.2%) were African American. In comparison with Caucasians, African Americans were about five years younger (P = .000) and had a higher rate of hypertension (80.9% vs. 74.5%, P = .036). Similarly, African Americans had a higher prevalence of diabetes mellitus (P = .001). There was no significant difference between African-Americans and Caucasians in terms of CMBs presence and location. African Americans had a higher number of CMBs in comparison with Caucasians, but the difference was not significant. African Americans were more likely to have CMBs >=5 (P = .047). Although African American stroke patients had a higher rate of large confluent white matter lesions, there was no significant racial difference regarding the rate and severity of deep white matter lesions. CONCLUSION: We did not observe any differences between African American and Caucasian patients with ischemic stroke patients regarding the presence, number, and location of CMBs. However, our results suggested that the prevalence of multiple CMBs (CMBs >=5) might be higher among African American stroke patients. PMID- 28838828 TI - Huge Free-Floating Thrombus in the Internal Carotid Artery. AB - Free-floating thrombus in the carotid artery is extremely rare. A 70-year-old male patient with pre-existing Crohn's disease admitted to our clinic with recurrent transient ischemic attacks. Angiography showed a huge thrombus in internal carotid artery. He responded to anticoagulation treatment and delayed endovascular intervention. PMID- 28838829 TI - Childhood and adolescent obesity definitions as related to BMI, evaluation and management options. AB - In North America, 30% of children are overweight or obese. Child obesity is a precursor to adult health risks. Diagnosis of childhood obesity is difficult. The best measurement is BMI percentile charts. Obesity in children and adolescents can be treated by diet and activity changes. Family involvement in healthy lifestyle changes is best for weight loss and prevention. PMID- 28838830 TI - Synthesis and biological evaluation of 8-aryl-2-morpholino-7-O-substituted benzo[e][1,3]oxazin-4-ones against DNA-PK, PI3K, PDE3A enzymes and platelet aggregation. AB - A series of 40 7-(O-substituted)-2-morpholino-8-aryl-4H-benzo[e][1,3]oxazin-4-one derivatives was synthesized. They were prepared via synthesis of a key precursor, 8-bromo-7-hydroxy-2-morpholino-4H-benzo[e][1,3]oxazin-4-one 13 which was amenable to ether synthesis at the 7-position and Suzuki coupling at the 8-position. The 2 protons of 7-OCH2 in compounds 18g, 18h, 18i, 18l and 18m prove to be magnetically non-equivalent, atropisomerism (axial chirality), as result of sterically hindered rotation of the bulky 8-aryl-substituent. The products were evaluated for their activities against PI3K isoforms, DNA-PK and PDE3. The results showed that this substitution pattern has a deleterious effect on PI3K activities, which may arise from steric hindrance in the active site. PI3Kdelta was somewhat more tolerant of this substitution particularly where 8-(4 methoxylphenyl) substituents were present (IC50s~2-3MUM). Good activities against PDE3 were also obtained for compounds, with particular members of the 7-(2 pyridinyl) methoxy series 19 showing good inhibition (IC50s~2-3MUM), comparable to previously described analogues. A piperazinyl derivative 26a effectively inhibited ADP-induced platelet aggregation with an IC50 of 8MUM. PMID- 28838831 TI - Conjugates of 18beta-glycyrrhetinic acid derivatives with 3-(1H-benzo[d]imidazol 2-yl)propanoic acid as Pin1 inhibitors displaying anti-prostate cancer ability. AB - Twenty-six conjugates of 18beta-glycyrrhetinic acid derivatives with 3-(1H benzo[d]imidazol-2-yl)propanoic acid were designed and synthesized as Pin1 inhibitors. Most of these semi-synthetic compounds showed improved Pin1 inhibitory activity and anti-proliferative effects against prostate cancer cells as compared to 3-(1H-benzo[d]imidazol-2-yl)propanoic acid and GA. Compounds 10a and 12i were the most potent to inhibit growth of prostate cancer PC-3 with GI50 values of 7.80MUM and 3.52MUM, respectively. The enzyme inhibition ratio of nine compounds at 10MUM was over 90%. Structure-activity relationships indicated that both appropriate structure at ring C of GA and suitable length of linker between GA skeleton and benzimidazole moiety had significant impact on improving activity. Western blot assay revealed that 10a decreased the level of cell cycle regulating protein cyclin D1. Thus, these compounds might represent a novel anti proliferative agent working through Pin1 inhibition. PMID- 28838832 TI - Synthesis and evaluation of radioiodinated 1-{2-[5-(2-methoxyethoxy)-1H benzo[d]imidazol-1-yl]quinolin-8-yl}piperidin-4-amine derivatives for platelet derived growth factor receptor beta (PDGFRbeta) imaging. AB - Platelet-derived growth factor receptor beta (PDGFRbeta) is a transmembrane tyrosine kinase receptor and it is upregulated in various malignant tumors. Radiolabeled PDGFRbeta inhibitors can be a convenient tool for the imaging of tumors overexpressing PDGFRbeta. In this study, [125I]-1-{5-iodo-2-[5-(2 methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinoline-8-yl}piperidin-4-amine ([125I]IIQP) and [125I]-N-3-iodobenzoyl-1-{2-[5-(2-methoxyethoxy)-1H benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([125I]IB-IQP) were designed and synthesized, and their potential as PDGFRbeta imaging agents was evaluated. In cellular uptake experiments, [125I]IIQP and [125I]IB-IQP showed higher uptake by PDGFRbeta-positive cells than by PDGFRbeta-negative cells, and the uptake in PDGFRbeta-positive cells was inhibited by co-culture with PDGFRbeta ligands. The biodistribution of both radiotracers in normal mice exhibited hepatobiliary excretion as the main route. In mice inoculated with BxPC3-luc (PDGFRbeta-positive), the tumor uptake of radioactivity at 1h after the injection of [125I]IIQP was significantly higher than that after the injection of [125I]IB IQP. These results indicated that [125I]IIQP can be a suitable PDGFRbeta imaging agent. However, further modification of its structure will be required to obtain a more appropriate PDGFRbeta-targeted imaging agent with a higher signal/noise ratio. PMID- 28838834 TI - Response to a commentary on the study entitled "Prevalence of intestinal helminthic infections and malnutrition among schoolchildren of the Zegie Peninsula, northwestern Ethiopia". PMID- 28838833 TI - Using GoPro to Give Video-Assisted Operative Feedback for Surgery Residents: A Feasibility and Utility Assessment. AB - OBJECTIVE: As an adjunct to simulation-based teaching, laparoscopic video-based surgical coaching has been an effective tool to augment surgical education. However, the wide use of video review in open surgery has been limited primarily due to technological and logistical challenges. The aims of our study were to (1) evaluate perceptions of general surgery (GS) residents on video-assisted operative instruction and (2) conduct a pilot study using a head-mounted GoPro in conjunction with the operative performance rating system to assess feasibility of providing video review to enhance operative feedback during open procedures. DESIGN: GS residents were anonymously surveyed to evaluate their perceptions of oral and written operative feedback and use of video-based operative resources. We then conducted a pilot study of 10 GS residents to assess the utility and feasibility of using a GoPro to record resident performance of an arteriovenous fistula creation with an attending surgeon. Categorical variables were analyzed using the chi-square test. SETTING: Academic, tertiary medical center. PARTICIPANTS: GS residents and faculty. RESULTS: A total of 59 GS residents were anonymously surveyed (response rate = 65.5%). A total of 40% (n = 24) of residents reported that structured evaluations rarely or never provided meaningful feedback. When feedback was received, 55% (n = 32) residents reported that it was only rarely or sometimes in regard to their operative skills. There was no significant difference in surveyed responses among junior postgraduate year (PGY 1-2), senior (PGY 3-4), or chief residents (PGY-5). A total of 80% (n = 8) of residents found the use of GoPro video review very or extremely useful for education; they also deemed video review more useful for operative feedback than written or communicative feedback. An overwhelming majority (90%, n = 9) felt that video review would lead to improved technical skills, wanted to review the video with the attending surgeon for further feedback, and desired expansion of this tool to include additional procedures. CONCLUSIONS: Although there has been progress toward improving operative feedback, room for further improvement remains. The use of a head-mounted GoPro is a dynamic tool that provides high quality video for operative review and has the potential to augment the training experience of GS residents. Future studies exploring a wide array of open procedures involving a greater number of trainees will be needed to further define the use of this resource. PMID- 28838835 TI - Biomechanical evaluation of a novel hybrid reconstruction plate for mandible segmental defects: A finite element analysis and fatigue testing. AB - PURPOSE: This study develops a novel hybrid (NH) reconstruction plate that can provide load-bearing strength, secure the bone transplant at the prosthesis favored position, and also maintain the facial contour in a mandibular segmental defect. A new patient-match bending technique which uses a three-dimensional printing (3DP) stamping process is developed to increase the interfacial fit between the reconstruction plate and mandibular bone. MATERIALS AND METHODS: The NH reconstruction plate was designed to produce a continuous profile with non uniform thickness and triangular cross-screw patterns with a locking-screw feature at the plate base. Two mandible segmental defect finite element models including the NH reconstruction plate to secure a bone flap for occlusal requirement and the commercial straight (CS) reconstruction plate to secure a bone flap along the lower mandible border were generated for biomechanical fatigue testing. RESULTS: The simulated results showed that the maximum von Mises stresses of the reconstruction plate for CS secured model are about 4.5 times more than the NH secured model. The bone strains around the fixation screws showed that the CS secured model was meaningfully higher than that of the NH secured model and exceeded the bone limit value. No fracture of any component was found in any sample in the fatigue testing. CONCLUSION: In conclusion, the newly developed NH reconstruction plate can secure the transplant position in accordance to the individual occlusal requirements without sacrificing the maintenance of facial contour. Finite element-based biomechanical evaluation demonstrates superior mechanical strength compared to commercial standard plates. PMID- 28838836 TI - Relevant factors for treatment outcome and time to healing in medication-related osteonecrosis of the jaws - A retrospective cohort study. AB - BACKGROUND: Risk factors for medication-related osteonecrosis of the jaw (MRONJ) are well known, although few studies evaluate the factors that influence treatment outcomes in MRONJ and whether discontinuing antiresorptive medication influences healing. PURPOSE: (1) Describe the characteristics of a population of patients with MRONJ. (2) Identify the factors associated with favourable outcomes. (3) Identify a temporal correlation between discontinuation of antiresorptives and healing time. METHODS: A retrospective longitudinal cohort study was carried out, including 77 patients with MRONJ treated between 2004 and 2016. Primary outcome was defined as healed/improved vs. worse/stable. Time to healing was set as the secondary outcome. Statistical significance was defined as p < 0.05. RESULTS: Primary disease, route of administration, lesion location, and development of complications influenced the outcome of treatment. Significant differences in outcomes according to primary disease (p < 0.05) were found when staging, gender, and lesion location were held constant. Time to healing was longer for patients who discontinued medication more than 3 months after diagnosis than for those who discontinued at diagnosis or before - respectively, 36, 9, and 7 months (p = 0.01). CONCLUSIONS: The outcome of MRONJ treatment may be influenced by primary disease and route of administration of antiresorptives. Antiresorptive medication discontinuation contributes to reduce healing time in MRONJ. PMID- 28838837 TI - Osteomyocutaneous fibular flap harvesting: Computer-assisted planning of perforator vessels using Computed Tomographic Angiography scan and cutting guide. AB - INTRODUCTION: Mandibular reconstruction performed after virtual planning has become more common during recent years. The gold standard for extensive mandibular reconstruction is of course a fibular free flap. In designing an osteomyocutaneous fibula flap, poor planning, aberrant anatomy and/or inadequate perforator vessels are the most frequent causes of complications and may force the surgeon to modify the flap design, explore the contralateral leg or harvest an additional microvascular flap. The goal of our study was to pre-operatively evaluate the vascular anatomy of the fibula and localize the cutaneous perforator vessels, so to create the fibular cutting guide based on the position of the cutaneous perforator and safely harvest the reconstructive flap. MATERIALS AND METHODS: Twenty consecutive patients who were candidates for mandibular reconstruction using a fibular microvascular free flap were enrolled in this study between January 2016 and August 2016. The patients were preoperatively assessed with a Computed Tomographic scan of head and neck and with a Computed Tomographic Angiography (CTA) scan of the lower limbs to evaluate the vascular anatomy of the fibula. Virtual planning was carried out for all patients. The fibular cutting guide was based on the position of the perforator cutaneous vessels, which were used to harvest the cutaneous part of the flap. Preoperative CT measurements were performed in order to identify the cutaneous perforators on the patients' skin. Intraoperative checking was performed to evaluate the accuracy of the perforators' position and the reproducibility of the virtual planning. RESULTS: In 5 patients out of 20 (25%), anatomical anomalies were discovered, without clinical evidence. The perforator vessels were localized in all patients. The average difference between the CTA and the intraoperative perforator localization was 1 mm (range 0-2 mm). Fibular cutting guide was positioned and fitted the anatomy of the patients in all treated patients. This allowed us to perform the planned segmentation of the fibula, obtaining the correct number of segments. In all cases, flap insetting was carried out and skin paddle was positioned as preoperatively planned. Neither donor site complications nor flap complications occurred. CONCLUSIONS: Preoperative evaluation of the legs using CTA, in patients who undergo an osteomyocutaneous fibular free flap for mandibular reconstruction, is a valuable approach to reduce altered-anatomy related complications and to improve the accuracy and outcomes of the reconstruction, especially in reconstructions of complex defects. In these cases, a soft tissue-based cutting guide can be planned based on the perforator vessels of the skin paddle, minimizing the harvesting risks of vascular lesions. Further studies and longer follow-ups are needed to evaluate the long-term outcomes and advantages of this procedure. PMID- 28838838 TI - Microbiology and antibiotic sensitivity of head and neck space infections of odontogenic origin. Differences in inpatient and outpatient management. AB - INTRODUCTION: The microbial flora of infections of the orofacial region of odontogenic origin is typically polymicrobial. Shortly after mass production of the first antibiotics, antibiotic resistant microorganisms were observed. METHODS: A 28-months retrospective study evaluated hospital records of 107 patients that were treated for head and neck infections of odontogenic origin. All patients underwent surgical incision and drainage. RESULTS: There were 65 male (61%) and 42 female (39%) patients ranging in age from 5 to 91 years, with a mean age of 48 years (SD = 21). 52 patients underwent outpatient management and 55 patients inpatient management. A total of 92 bacterial strains were isolated from 107 patients, accounting for 0.86 isolates per patient. Overall 46 bacterial strains were isolated from patients that underwent outpatient and 34 bacterial strains that underwent inpatient treatment. 32.6% of the strains, isolated from outpatient treated individuals showed resistances against one or more of the tested antibiotics. Isolated strains of inpatient treated individuals showed resistances in 52.9%. DISCUSSION: According to this study's data, penicillin continues to be a highly effective antibiotic to be used against viridans streptococci, group C Streptococci and prevotella, whereas clindamycin was not shown to be effective as an empirical drug of choice for most odontogenic infections. CONCLUSION: Microorganisms that show low susceptibility to one or more of the standard antibiotic therapy regimes have a significantly higher chance of causing serious health problems, a tendency of spreading and are more likely to require an inpatient management with admission of IV antibiotics. Penicillin continues to be a highly effective antibiotic to be used against viridans streptococci, group C Streptococci and prevotella, whereas clindamycin could not be shown to be effective as an empirical drug of choice for a high number of odontogenic infections. PMID- 28838839 TI - Effect of computed tomographic venography on donor selection in submandibular gland transplantation in patients with severe dry eye. AB - BACKGROUND: A reliable anterior facial vein (AFV, donor vein) is cardinal for the success of submandibular gland (SMG) transplantation. This study determined the impact of computed tomographic (CT) venography in identifying AFV variations for SMG transplantation. METHODS: CT venography was performed in consecutive patients with severe dry eye prior to SMG transplantation in order to identify disadvantageous AFV variations for vascular anastomosis, namely, AFVs that did not drain the SMG and those that did not match the superficial temporal vein (STV, recipient vein; AFV:STV caliber ratio, >=3). The CT results were compared with the intraoperative findings for the diagnostic accuracy. RESULTS: Forty-two donors were included. Compared with the intraoperative findings, the CT results accurately identified AFV-STV caliber mismatches (P = 1.00; sensitivity and specificity, 100%). In the identification of AFVs not draining the SMG, CT showed 94.7% sensitivity and 100% specificity (P = 0.25). According to the CT findings, 10 contralateral SMGs with AFVs (23.8%), instead of ipsilateral donors, were selected for transplantations (conventionally ipsilateral donor was the first choice). The surgical success rate was 95.2% (40/42). CONCLUSION: CT venography is valuable in determining disadvantageous AFV variations for anastomosis and choosing a reliable donor for SMG transplantation. PMID- 28838840 TI - [Hand eczema in children. Clinical and epidemiological study of the population referred to a tertiary hospital]. AB - INTRODUCTION: Hand eczema is a frequent disease in adults. Diagnosing the cause of hand eczema is difficult due to different classifications. There is lack of evidence on hand eczema and its causes in children. MATERIAL AND METHOD: A total of 389 children between 0 and 16 years were identified between 1996 and 2016, from whom 42 (10.8%) with exclusively hand eczema were selected. In all cases a standard battery of epicutaneous patch tests was performed, as well as additional batteries depending on the clinical suspicion. The clinical and epidemiological features of these children were recorded and compared against children with eczema in other locations. RESULTS: The 42 children with hand eczema included 25 (60.5%) girls, and 17 (40.5%) boys, with a mean age of 10.6 +- 3.9 years, and did not differ from that of children with eczema in other locations. The definitive diagnosis after patch-testing was Atopic Dermatitis in 15 cases, Allergic Contact Dermatitis in 14 patients, Endogenous Vesiculous Eczema in 6 cases, Endogenous Hyperkeratotic Eczema in 5 cases, and Irritant Contact Dermatitis in 2 cases. The most frequent allergens detected were thiomersal (9 cases), nickel (5 cases), mercury (5 cases), and cobalt (4 cases). CONCLUSION: Hand eczema is a common condition in children. The most common cause is atopic dermatitis, although cases of allergic contact dermatitis manifesting as hand eczema are not uncommon. Any child with eczema of hands in whom an allergic cause is suspected should be referred for patch- testing. PMID- 28838841 TI - Mitochondria as pharmacological targets in Down syndrome. AB - Mitochondria play a pivotal role in cellular energy-generating processes and are considered master regulators of cell life and death fate. Mitochondrial function integrates signalling networks in several metabolic pathways controlling neurogenesis and neuroplasticity. Indeed, dysfunctional mitochondria and mitochondrial-dependent activation of intracellular stress cascades are critical initiating events in many human neurodegenerative or neurodevelopmental diseases including Down syndrome (DS). It is well established that trisomy of human chromosome 21 can cause DS. DS is associated with neurodevelopmental delay, intellectual disability and early neurodegeneration. Recently, molecular mechanisms responsible for mitochondrial damage and energy deficits have been identified and characterized in several DS-derived human cells and animal models of DS. Therefore, therapeutic strategies targeting mitochondria could have great potential for new treatment regimens in DS. The purpose of this review is to highlight recent studies concerning mitochondrial impairment in DS, focusing on alterations of the molecular pathways controlling mitochondrial function. We will also discuss the effects and molecular mechanisms of naturally occurring and chemically synthetized drugs that exert neuroprotective effects through modulation of mitochondrial function and attenuation of oxidative stress. These compounds might represent novel therapeutic tools for the modulation of energy deficits in DS. PMID- 28838842 TI - Ellagic acid antagonizes Bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes. AB - The Bcl-2 protein Bnip3 is crucial for provoking oxidative injury to mitochondria following anthracycline treatment or ischemia-reperfusion injury. Herein, we investigate the effects of the polyphenolic compound ellagic acid (EA) on Bnip3 mediated mitochondrial injury and necrotic cell death in cardiac myocytes. In contrast to vehicle treated cardiomyocytes, Bnip3 was highly enriched in mitochondrial fractions of cardiac myocytes treated with the anthracycline doxorubicin or in cells subjected to hypoxia (HPX). Mitochondrial associated Bnip3 was accompanied by mPTP opening and loss of ?Psim. The dynamin related fission protein Drp-1 was phosphorylated (Drp1616) and coincided with excessive mitochondrial fragmentation, mitophagy and necrosis in cardiac myocytes treated with doxorubicin or subjected to hypoxia. Moreover, knock-down of Bnip3 was sufficient to prevent mitochondrial fission and doxorubicin-induced cell death supporting the involvement of Bnip3 in doxorubicin cardiotoxity. Interestingly, mitochondrial associated Bnip3 in cells treated with doxorubicin was markedly reduced by EA. This resulted in significantly less mitochondrial fission and cell death. Notably, EA similarly suppressed mitochondrial injury and cell death induced by hypoxia or Bnip3 over-expression. Herein, we identify a novel signaling axis that operationally links EA and Bnip3 for suppression of cardiac cell death. We provide compelling new evidence that EA suppresses mitochondrial injury and necrotic cell death of cardiac myocytes by functionally abrogating Bnip3 activity. Hence, by suppressing mitochondrial injury induced by Bnip3, EA may provide a therapeutic advantage in reducing oxidative injury and cardiac dysfunction in cancer patients undergoing anthracycline treatment or individuals with ischemic cardiac stress. PMID- 28838843 TI - Targeted antitumor therapy mediated by prodrug-activating mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) were introduced as tumor-targeted vehicles suitable for delivery of the gene-directed enzyme/prodrug therapy more than 10 years ago. Over these years key properties of tumor cells and MSCs, which are crucial for the treatment efficiency, were examined; and there are some critical issues to be considered for the maximum antitumor effect. Moreover, engineered MSCs expressing enzymes capable of activating non-toxic prodrugs achieved long term curative effect even in metastatic and hard-to-treat tumor types in pre clinical scenario(s). These gene-modified MSCs are termed prodrug-activating MSCs throughout the text and represent promising approach for further clinical application. This review summarizes major determinants to be considered for the application of the prodrug-activating MSCs in antitumor therapy in order to maximize therapeutic efficiency. PMID- 28838844 TI - Comment on response to "Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer," Cancer Lett. 2017 Mar 1; 388(2017): 208-219. PMID- 28838845 TI - Inflammation fires up cancer metastasis. AB - Metastatic disease is the major challenge of cancer that accounts for over 90% of total cancer lethality. Mounting clinical and preclinical data now indicate that inflammation, a potent immune and repair response, is indispensable for metastasis. In this review we describe our current understanding of how major inflammatory cells contribute to metastatic cascade with a focus on the primary tumour. We also discuss exciting new directions for future research and novel therapeutic approaches to tackle metastatic disease through targeting inflammation. PMID- 28838847 TI - Scleral lenses (are) special. PMID- 28838846 TI - Safety of coronary CT angiography and functional testing for stable chest pain in the PROMISE trial: A randomized comparison of test complications, incidental findings, and radiation dose. AB - BACKGROUND: Coronary computed tomography angiography (CTA) and functional testing strategies for stable chest pain yield similar outcomes; one aspect that may guide test choice is safety. METHODS: We compared test safety (test complications, incidental findings, and effective radiation dose) between CTA and functional testing as-tested in PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain). In the subgroup whose physicians intended nuclear stress over other functional tests if randomized to the functional arm, we compared radiation dose of CTA versus nuclear stress and identified characteristics associated with dose. RESULTS: Of 9470 patients, none had major and <1% had minor complications (CTA: 0.8% [37/4633] vs. functional: 0.6% [27/4837]). CTA identified more incidental findings (11.6% [539/4633] vs. 0.7% [34/4837], p < 0.001), most commonly pulmonary nodules (9.4%, 437/4633). CTA had similar 90-day cumulative radiation dose to functional testing. However, in the subgroup whose physicians intended nuclear stress (CTA 3147; nuclear 3203), CTA had lower median index test (8.8 vs. 12.6 mSv, p < 0.001) and 90-day cumulative (11.6 vs. 13.1 mSv, p < 0.001) dose, independent of patient characteristics. The lowest nuclear doses employed 1-day Tc-99m protocols (12.2 mSv). The lowest CTA doses were at sites performing >=500 CTAs/year (6.9 mSv) and with advanced (latest available) CT scanners (5.5 mSv). CONCLUSION: Complications were negligibly rare for both CTA and functional testing. CTA detects more incidental findings. Compared to nuclear stress testing, CTA's lower radiation dose, independent of patient characteristics, makes it an attractive test choice. Radiation dose varies with imaging protocol, indicating opportunities to further reduce dose. (ClinicalTrials.gov number, NCT01174550). PMID- 28838848 TI - Omega-3 polyunsaturated fatty acids reduce vascular tone and inflammation in human saphenous vein. AB - Dietary intake of omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been reported to have beneficial cardiovascular effects. However, little is known about the effect of EPA and DHA on human vascular tone. Therefore, the aim of this study is to evaluate the effect of EPA and DHA on vascular tone of the human saphenous vein (SV) obtained from patients undergoing coronary bypass operation under normal and inflammatory conditions. Moreover, we aimed to investigate the effect of EPA and DHA on the release of inflammatory mediators from SV. Pretreatment of SV with EPA and DHA (100MUM, 18h) decreased the contractile response of SV to norepinephrine (NE) under normal and inflammatory conditions. Moreover, EPA and DHA pretreatment diminished increased Monocyte Chemoattractant Protein-1 (MCP-1) and Tumor Necrosis Factor-alpha (TNF-alpha) release from SV under inflammatory conditions. In conclusion, our results suggest that EPA and DHA pretreatment may be beneficial to counteract graft vasospasm and vascular inflammation in SV which are important factors in graft failure development. Therefore, dietary intake of EPA and DHA may have potential clinical applications in improving coronary bypass graft patency. PMID- 28838849 TI - One health education for future physicians in the pan-epidemic "Age of Humans". AB - We propose the term "pan-epidemic Anthropocene" to refer to multifocal infectious disease epidemics related to human-caused (anthropogenic) forces such as urbanization, globalization, industrialization and the growing populations of humans and animals. The integrated framework of One Health (human, animal, and environmental health) helps both to understand why epidemics occur when and where they do, and also how to respond, mitigate, and sometimes prevent them. We suggest a collaborative mechanism for increasing One Health in medical education to create a synergy of strengths between the growing number of contributing One Health organizations in the US and internationally. PMID- 28838850 TI - Safety and efficacy of stereotactic aspiration with fibrinolysis for deep-seated spontaneous intracerebral hemorrhages: A single-center experience. AB - OBJECTIVE: The aim of this study was to evaluate feasibility and safety of stereotactic aspiration with fibrinolysis of deep-seated intracerebral hemorrhages (ICH). MATERIALS AND METHODS: From March 1995 until December 2016, 58 adult patients (34 men and 24 women; mean age of 56.8+/-11.8 years) presenting with deep-seated spontaneous supratentorial ICH were treated using a minimally invasive technique. Intracerebral hematomas were aspirated until obvious resistance to free-hand suction and subsequent clot fibrinolysis was done using either streptokinase or recombinant tissue-type plasminogen activator. CT scans were performed at intervals ranging from 24 to 72h. At discharge, functional outcomes were evaluated using the Glasgow outcome scale (GOS). The 30-day mortality rate was evaluated in all patients. RESULTS: The average ICH volume on initial CT scan was 34.7+/-11.1cm3 (range, 20-90cm3). Mean residual hematoma volume after the treatment was 8.0+/-5.1cm3 (range, 3-32cm3). There was statistically significant reduction of ICH volume after the treatment (P<0.001). Median ICH reduction rate was 5cm3/d (range, 1.5-16.0cm3/d) and 17.2%/d (range, 5.27-40.0%/d). Median discharge GOS score was 3 (range, 1-4). Six (10.9%) patients died during the 30-day follow-up period. Treatment related complications were observed in three (5.5%) patients. In two patients asymptomatic increase of ICH volume occurred and one patient was diagnosed with CNS infection. CONCLUSIONS: Stereotactic clot aspiration with subsequent fibrinolytic therapy is safe and feasible treatment procedure associated with significant hematoma resolution rates and acceptable patient outcomes. PMID- 28838852 TI - Correction to Lancet Glob Health 2017; 5: e849-50. PMID- 28838851 TI - Platelet indices and glucose control in type 1 and type 2 diabetes mellitus: A case-control study. AB - BACKGROUND AND AIMS: The relationship between platelet indices and glucose control may differ in type 1 (T1DM) and type 2 (T2DM) diabetes. We aimed to investigate differences in mean platelet volume (MPV), platelet count, and platelet mass between patients with T1DM, T2DM, and healthy controls and to explore associations between these platelet indices and glucose control. METHODS AND RESULTS: A total of 691 T1DM and 459 T2DM patients and 943 control subjects (blood donors) were included. HbA1c was measured in all subjects with diabetes and 36 T1DM patients further underwent 24 h-continuous glucose monitoring to estimate short-term glucose control (glucose mean and standard deviation). Adjusting for age and sex, platelet count was higher and MPV lower in both T1DM and T2DM patients vs control subjects, while platelet mass (MPV * platelet count) resulted higher only in T2DM. Upon further adjustment for HbA1c, differences in platelet count and mass were respectively 19.5 * 109/L (95%CI: 9.8-29.3; p < 0.001) and 101 fL/nL (12-191; p = 0.027) comparing T2DM vs T1DM patients. MPV and platelet count were significantly and differently related in T2DM patients vs both T1DM and control subjects; this difference was maintained also accounting for HbA1c, age, and sex. Platelet mass and the volume-count relationship were significantly related to HbA1c only in T1DM patients. No associations were found between platelet indices and short-term glucose control. CONCLUSION: By accounting for confounders and glucose control, our data evidenced higher platelet mass and different volume-count kinetics in subjects with T2DM vs T1DM. Long-term glucose control seemed to influence platelet mass and the volume-count relationship only in T1DM subjects. These findings suggest different mechanisms behind platelet formation in T1DM and T2DM patients with long-term glycaemic control being more relevant in T1DM than T2DM. PMID- 28838853 TI - Successful treatment of a hepatic-hemangioendothelioma infant presenting with hypothyroidism and tetralogy of Fallot. PMID- 28838854 TI - Colistin resistance among blood culture isolates at a tertiary care centre in Hungary. AB - OBJECTIVES: The emergence of colistin resistance has been detected worldwide in recent years. Whilst colistin susceptibility has been tested in carbapenem resistant Enterobacteriaceae as well as multidrug-resistant Pseudomonas spp. and Acinetobacter spp. during routine laboratory practice, the overall rate of colistin resistance was unknown in our centre. The aim of this retrospective study was to reveal the prevalence of colistin resistance among clinically significant blood culture isolates in two different periods (2010-2011 and 2016) in our laboratory. METHODS: Consecutive non-duplicate strains (n=776) were screened for colistin resistance using agar plates containing 4mg/L colistin. Strains cultured on colistin-containing plates were further examined. Minimum inhibitory concentrations (MICs) of colistin-tolerant subcultures and original cultures were determined in parallel by the broth microdilution method. Screening for mcr-1-mediated colistin resistance was performed by PCR. RESULTS: The rate of colistin resistance was 0.6%, 1.3% and 2.6% in Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp., respectively; colistin-resistant subpopulations were found in 17%, 27% and 20% of isolates, respectively, with low frequency. Seven colistin-resistant strains were found, among which was an mcr-1-positive Escherichia coli isolated from a blood sample of a haemato-oncology patient in 2011. All Stenotrophomonas maltophilia isolates were resistant to colistin. CONCLUSIONS: The low prevalence of colistin resistance was in accordance with European data. The prevalence of heteroresistance was significantly higher, but the clinical significance of the phenomenon is unclear. We have identified the first mcr-1-positive E. coli strain in Hungary. mcr-1 has been in Hungary since 2011 but has not yet expanded. PMID- 28838856 TI - Blood transfusion in burn patients: Triggers of transfusion in a referral burn center in Iran. AB - OBJECTIVES: Blood and its derivatives are one of the most lifesaving products in the modern medicine practice. However, it is not an absolutely safe prescription. Many adverse effects such as infection, transfusion-related acute lung injury, immunosuppression, multi-organ dysfunction, acute respiratory syndrome, transfusion errors, transmission of infectious agents such as HIV, HBV, HCV are attributable to blood transfusion. The aim of this study was to describe how and when blood products were transfused in a referral burn center. PATIENTS AND METHODS: This cross-sectional study was performed on medical records of all admitted patients in the Department of Burns and Reconstructive Surgery of Imam Reza Hospital, Mashhad, Iran during September 2014 up to August 2015. Transfusion measures such as Hb, Hct and demographic data were extracted from patient records. SPSS version 11.5 was used for data analysis. RESULTS: During the study period, 701 acute burnt patients were admitted with the mean age of 25.5+/-20.5 years. Sixty-four percent were male and burnt percentage of total body surface area (TBSA) was 30.9+/-24.3%. About one third (240) of patients received at least one blood product. Mean of the transfused packed red blood cell was 274.1+/ 674.6mL per patient and 8.85mL per 1% of burnt TBSA. Anemia was the most common transfusion trigger. CONCLUSION: Mortality in burnt patients who received blood products was two folds more than patients who did not receive any blood products. We prescribed less blood products compared with other reviewed burn centers. However, following a written blood transfusion protocol by all clinicians may reduce blood transfusion in unnecessary situations even more significantly. PMID- 28838855 TI - Exosomes, DAMPs and miRNA: Features of Stress Physiology and Immune Homeostasis. AB - Psychological/physical stressors and local tissue damage increase inflammatory proteins in tissues and blood in humans and animals, in the absence of pathogenic disease. Stress-evoked cytokine/chemokine responses, or sterile inflammation, can facilitate host survival and/or negatively affect health, depending on context. Recent evidence supports the hypothesis that systemic stress-evoked sterile inflammation is initiated by the sympathetic nervous system, resulting in the elevation of exosome-associated immunostimulatory endogenous danger/damage associated molecular patterns (DAMPs) and a reduction in immunoinhibitory miRNA, which are carried in the circulation to tissues throughout the body. We propose that sterile inflammation should be considered an elemental feature of the stress response and that circulating exosomes transporting immunomodulatory signals, may play a role fundamental role in immune homeostasis. PMID- 28838857 TI - Value of physical tests in diagnosing cervical radiculopathy: a systematic review. AB - BACKGROUND CONTEXT: In clinical practice, the diagnosis of cervical radiculopathy is based on information from the patient's history, physical examination, and diagnostic imaging. Various physical tests may be performed, but their diagnostic accuracy is unknown. PURPOSE: This study aimed to summarize and update the evidence on diagnostic performance of tests carried out during a physical examination for the diagnosis of cervical radiculopathy. STUDY DESIGN: A review of the accuracy of diagnostic tests was carried out. STUDY SAMPLE: The study sample comprised diagnostic studies comparing results of tests performed during a physical examination in diagnosing cervical radiculopathy with a reference standard of imaging or surgical findings. OUTCOME MEASURES: Sensitivity, specificity, likelihood ratios are presented, together with pooled results for sensitivity and specificity. METHODS: A literature search up to March 2016 was performed in CENTRAL, PubMed (MEDLINE), Embase, CINAHL, Web of Science, and Google Scholar. The methodological quality of studies was assessed using the QUADAS-2. RESULTS: Five diagnostic accuracy studies were identified. Only Spurling's test was evaluated in more than one study, showing high specificity ranging from 0.89 to 1.00 (95% confidence interval [CI]: 0.59-1.00); sensitivity varied from 0.38 to 0.97 (95% CI: 0.21-0.99). No studies were found that assessed the diagnostic accuracy of widely used neurological tests such as key muscle strength, tendon reflexes, and sensory impairments. CONCLUSIONS: There is limited evidence for accuracy of physical examination tests for the diagnosis of cervical radiculopathy. When consistent with patient history, clinicians may use a combination of Spurling's, axial traction, and an Arm Squeeze test to increase the likelihood of a cervical radiculopathy, whereas a combined results of four negative neurodynamics tests and an Arm Squeeze test could be used to rule out the disorder. PMID- 28838858 TI - Predictive and concurrent validity of cartilage thickness change as a marker of knee osteoarthritis progression: data from the Osteoarthritis Initiative. AB - OBJECTIVE: To investigate the predictive and concurrent validity of magnetic resonance imaging (MRI)-based cartilage thickness change between baseline (BL) and year-two (Y2) follow-up (predictive validity) and between Y2 and Y4 follow-up (concurrent validity) for symptomatic and radiographic knee osteoarthritis (OA) progression during Y2->Y4. METHODS: 777 knees from 777 Osteoarthritis Initiative (OAI) participants (age: 61.3 +/- 9.0 years, BMI: 30.1 +/- 4.8 kg/m2) with Kellgren Lawrence (KL) grade 1-3 at Y2 (visit before progression interval) had cartilage thickness measurements from 3T MRI at BL, Y2 (n = 777), and Y4 (n = 708). Analysis of covariance and logistic regression were used to assess the association of pain progression (>=9 WOMAC units [scale 0-100], n = 205/572 with/without progression) and radiographic progression (>=0.7 mm minimum joint space width (mJSW) loss, n = 166/611 with/without progression) between Y2 and Y4 with preceding (BL->Y2) and concurrent (Y2->Y4) change in central medial femorotibial (cMFTC) compartment cartilage thickness. RESULTS: Symptomatic progression was associated with concurrent (Y2->Y4: -305 +/- 470 MUm vs -155 +/- 346 MUm, Odds ratios (OR) = 1.5 [1.2, 1.7]) but not with preceding cartilage thickness loss in cMFTC (-150 +/- 276 MUm vs -151 +/- 299 MUm, OR = 0.9 95% CI: [0.8, 1.1]). Radiographic progression, in contrast, was significantly associated with both concurrent (-542 +/- 550 MUm vs -98 +/- 255 MUm, OR = 3.4 [2.6, 4.3]) and preceding cMFTC thickness loss (-229 +/- 355 MUm vs -130 +/- 270 MUm, OR = 1.3 [1.1, 1.5]). CONCLUSIONS: These results extend previous reports that did not discern predictive vs concurrent associations of cartilage thickness loss with OA progression. The observed predictive and concurrent validity of cartilage thickness loss for radiographic progression and observed concurrent validity for symptomatic progression provide an important step in qualifying cartilage thickness loss as a biomarker of knee OA progression. CLINICALTRIALS. GOV IDENTIFICATION: NCT00080171. PMID- 28838859 TI - Transmural variation in elastin fiber orientation distribution in the arterial wall. AB - The complex three-dimensional elastin network is a major load-bearing extracellular matrix (ECM) component of an artery. Despite the reported anisotropic behavior of arterial elastin network, it is usually treated as an isotropic material in constitutive models. Our recent multiphoton microscopy study reported a relatively uniform elastin fiber orientation distribution in porcine thoracic aorta when imaging from the intima side (Chow et al., 2014). However it is questionable whether the fiber orientation distribution obtained from a small depth is representative of the elastin network structure in the arterial wall, especially when developing structure-based constitutive models. To date, the structural basis for the anisotropic mechanical behavior of elastin is still not fully understood. In this study, we examined the transmural variation in elastin fiber orientation distribution in porcine thoracic aorta and its association with elastin anisotropy. Using multi-photon microscopy, we observed that the elastin fibers orientation changes from a relatively uniform distribution in regions close to the luminal surface to a more circumferential distribution in regions that dominate the media, then to a longitudinal distribution in regions close to the outer media. Planar biaxial tensile test was performed to characterize the anisotropic behavior of elastin network. A new structure-based constitutive model of elastin network was developed to incorporate the transmural variation in fiber orientation distribution. The new model well captures the anisotropic mechanical behavior of elastin network under both equi- and nonequi-biaxial loading and showed improvements in both fitting and predicting capabilities when compared to a model that only considers the fiber orientation distribution from the intima side. We submit that the transmural variation in fiber orientation distribution is important in characterizing the anisotropic mechanical behavior of elastin network and should be considered in constitutive modeling of an artery. PMID- 28838860 TI - Comparison of local anesthetic infusion pump bupivacaine versus transversus abdominis plane (TAP) block liposomal bupivacaine for pain management after bilateral deep inferior epigastric perforator free flap reconstruction. PMID- 28838861 TI - Maintaining quality of life for patients with neuroendocrine tumours. PMID- 28838863 TI - Vulvar Arteriovenous Malformation in a 16-Year-Old Girl. AB - BACKGROUND: Congenital arteriovenous malformations (AVMs) are infrequent but represent a serious medical challenge because of their unpredictable progression and high hemodynamic activity. CASE: We report on the treatment of a voluminous vulvar AVM in a 16-year-old girl. After failure of medical therapy, we performed a radical surgical resection with preliminary embolization and flap reconstruction. SUMMARY AND CONCLUSION: A multidisciplinary approach is required for AVM management. Early intervention and complete surgical resection combined with preliminary embolization represents the ideal therapy. PMID- 28838862 TI - Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. METHODS: RADIANT-4 is a multicentre, randomised, double-blind, placebo controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged >=18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (+/- 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (>=7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11.27 months (95% CI 9.27-19.35) with everolimus and 9.23 months (5.52-not estimable) with placebo (adjusted hazard ratio 0.81, 95% CI 0.55 1.21; log-rank p=0.31). INTERPRETATION: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. FUNDING: Novartis Pharmaceuticals. PMID- 28838864 TI - Pelvic Abscess Secondary to Mycoplasma Hominis after Vaginal Laceration. AB - BACKGROUND: Mycoplasma hominis frequently colonizes the urogenital and respiratory tracts of healthy individuals. It has also been associated with genitourinary tract and extragenital syndromes. CASE: We present a 14-year-old girl who developed a pelvic abscess secondary to M. hominis after a vaginal laceration during sexual intercourse. Despite drainage and broad-spectrum antimicrobial therapy, the patient remained symptomatic until M. hominis was identified and specific therapy instituted. SUMMARY AND CONCLUSION: Health care providers need to be aware of the potential for M. hominis as a causal agent in patients who present with pelvic abscesses after vaginal trauma. This case highlights the challenges that exist in the diagnosis and treatment of M. hominis, because bacterial cultures are often negative and empiric antimicrobial agents do not provide adequate antimicrobial coverage. PMID- 28838865 TI - Microperforate Hymen and Pyocolpos: A Case Report and Review of the Literature. AB - BACKGROUND: Microperforate hymen is a rare congenital anomaly characterized by a small pinpoint opening in the hymen; girls with this anomaly are prone to develop ascending pelvic infections and recurrent urinary tract infections. CASE: We report the case of a 3-year-old girl who presented with fevers, abdominal pain, recurrent vaginitis, and dysuria. She was found to have a microperforate hymen and pyocolpos. She was treated with intravenous antibiotics and underwent hymenotomy and drainage of 150 cc of purulent fluid. SUMMARY AND CONCLUSION: This case highlights the need to perform thorough genital inspection and to consider hymenal anomalies in the differential diagnosis of girls who present with recurrent dysuria, vaginitis, fevers, and abdominal pain. Early intervention might prevent the development of pyocolpos and other sequelae associated with this anomaly. PMID- 28838867 TI - Prevalence of binge drinking during pregnancy by country and World Health Organization region: Systematic review and meta-analysis. AB - The objective was to obtain the first ever estimates of the prevalence of binge drinking (defined as four or more standard drinks per occasion) during pregnancy among the general population by country and World Health Organization region. A comprehensive systematic literature search was conducted, followed by country specific random-effects meta-analyses for those countries with two or more empirical studies. For the remaining countries, the prevalence was predicted via a multilevel fractional response regression model, using country-specific indicators. Regional averages were then estimated. Lastly, the proportion of pregnant women who binge drank during pregnancy out of all women who used any amount of alcohol during pregnancy was estimated for each country. The African Region was estimated to have the highest prevalence of binge drinking during pregnancy, while the Western Pacific Region had the lowest estimated prevalence. The findings indicate that a large portion of pregnancies that are alcohol exposed are being exposed to the most detrimental pattern of drinking - binge drinking. PMID- 28838866 TI - Stability of Symptom Clusters in Patients With Breast Cancer Receiving Chemotherapy. AB - CONTEXT: Patients with breast cancer who undergo chemotherapy (CTX) experience between 10 and 32 concurrent symptoms. An evaluation of how these symptoms cluster together and how these symptom clusters change over time may provide insights into how to treat these multiple co-occurring symptoms. OBJECTIVES: The purposes of this study were to determine the occurrence rates and severity ratings for 38 common symptoms, evaluate for differences in the number and types of symptom clusters, and evaluate for changes over time in these symptom clusters (i.e., before CTX, the week after CTX, and two weeks after CTX). METHODS: At each of the assessments, a modified version of the Memorial Symptom Assessment Scale was used to assess the occurrence and severity of the 38 symptoms. Exploratory factor analyses were used to extract the symptom clusters. RESULTS: Although across the two symptom dimensions (i.e., occurrence and severity) and the three assessments, eight distinct symptom clusters were identified, only five were relatively stable across both dimensions and across time (i.e., psychological, hormonal, nutritional, gastrointestinal, and epithelial). Two of the additional clusters varied by time but not by symptom dimension (i.e., sickness behavior and weight change). The CTX neuropathy cluster was identified only at the assessment performed in the week after CTX. CONCLUSION: These findings provide insights into the most common symptom clusters in patients undergoing CTX for breast cancer. In addition, the most common symptoms within each cluster appear to be relatively stable across the two dimensions, as well as across time. PMID- 28838868 TI - Online Surgeon Ratings and Outcomes in Hernia Surgery: An Americas Hernia Society Quality Collaborative Analysis. AB - BACKGROUND: Online surgeon ratings are viewed as a measure of physician quality by some consumers. Nevertheless, the correlation between online surgeon ratings and surgeon quality metrics remains unknown. The purpose of this study was to investigate the association between online surgeon ratings and hernia-specific quality metrics. STUDY DESIGN: The Americas Hernia Society Quality Collaborative (AHSQC) is recognized by the Centers for Medicaid and Medicare as a Quality Clinical Data Registry (QCDR) that reports risk-adjusted quality metrics for hernia surgeons. All surgeons who input at least 10 patients into the AHSQC and had both a HealthGrades.com and Vitals.com rating were included in the analysis. The association of surgeons' average, risk-adjusted QCDR quality score with their online ratings was investigated using a linear regression model. RESULTS: A total of 70 surgeons met inclusion criteria. The median number of evaluations each surgeon received on HealthGrades.com was 7; the median number of evaluations each surgeon received on Vitals.com was 3. There was a statistically significant correlation between the ratings surgeons received on HealthGrades.com and those that they received on Vitals.com (p < 0.0001). However, there was no correlation between surgeon ratings on either HealthGrades.com or Vitals.com and surgeon QCDR quality scores (p = 0.37 and p = 0.18, respectively). CONCLUSIONS: Online physician rating systems correlate with one another, but they do not accurately reflect physician quality. The development of specialty-specific, risk-adjusted quality measures and appropriate public dissemination of this information may help patients make more informed decisions about their health care. PMID- 28838869 TI - Evolution of Laparoscopic Liver Surgery from Innovation to Implementation to Mastery: Perioperative and Oncologic Outcomes of 2,238 Patients from 4 European Specialized Centers. AB - BACKGROUND: First seen as an innovation for select patients, laparoscopic liver resection (LLR) has evolved since its introduction, resulting in worldwide use. Despite this, it is still limited mainly to referral centers. The aim of this study was to evaluate a large cohort undergoing LLR from 2000 to 2015, focusing on the technical approaches, perioperative and oncologic outcomes, and evolution of practice over time. STUDY DESIGN: The demographics and indications, intraoperative, perioperative, and oncologic outcomes of 2,238 patients were evaluated. Trends in practice and outcomes over time were assessed. RESULTS: The percentage of LLR performed yearly has increased from 5% in 2000 to 43% in 2015. Pure laparoscopy was used in 98.3% of cases. Wedge resections were the most common operation; they were predominant at the beginning of LLR and then decreased and remained steady at approximately 53%. Major hepatectomies were initially uncommon, then increased and reached a stable level at approximately 16%. Overall, 410 patients underwent resection in the posterosuperior segments; these were more frequent with time, and the highest percentage was in 2015 (26%). Blood loss, operative time, and conversion rate improved significantly with time. The 5-year overall survival rates were 73% and 54% for hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM), respectively. The 5-year, recurrence-free survival rates were 50% and 37% for HCC and CRLM, respectively. CONCLUSIONS: Since laparoscopy was introduced, a long implementation process has been necessary to allow for standardization and improvement in surgical care, mastery of the technique, and the ability to obtain good perioperative results with safe oncologic outcomes. PMID- 28838870 TI - Effect of Surgeon and Hospital Volume on Emergency General Surgery Outcomes. AB - BACKGROUND: Emergency general surgery (EGS) contributes to half of all surgical mortality nationwide, is associated with a 50% complication rate, and has a 15% readmission rate within 30 days. We assessed associations between surgeon and hospital EGS volume with these outcomes. STUDY DESIGN: Using Maryland's Health Services Cost Review Commission database, we identified nontrauma EGS procedures performed by general surgeons among patients 20 years or older, who were admitted urgently or emergently, from July 2012 to September 2014. We created surgeon and hospital volume categories, stratified EGS procedures into simple (mortality <= 0.5%) and complex (>0.5%) procedures, and assessed postoperative mortality, complications, and 30-day readmissions. Multivariable logistic regressions both adjusted for clinical factors and accounted for clustering by individual surgeons. RESULTS: We identified 14,753 procedures (61.5% simple EGS, 38.5% complex EGS) by 252 (73.3%) low-volume surgeons (<=25 total EGS procedures/year), 63 (18.3%) medium-volume surgeons (26 to 50/year), and 29 (8.4%) high-volume surgeons (>50/year). Low-volume surgeons operated on one-third (33.1%) of all patients. For simple procedures, the very low rate of death (0.2%) prevented a meaningful regression with mortality; however, there were no associations between low-volume surgeons and complications (adjusted odds ratio [aOR] 1.07; 95% CI 0.81 to 1.41) or 30-day readmissions (aOR 0.80; 95% CI 0.64 to 1.01) relative to high-volume surgeons. Among complex procedures, low-volume surgeons were associated with greater mortality (aOR 1.64; 95% CI 1.12 to 2.41) relative to high-volume surgeons, but not complications (aOR 1.06; 95% CI 0.85 to 1.32) or 30 day readmission (aOR 0.99; 95% CI 0.80 to 1.22). Low-volume hospitals (<=125 total EGS procedures/year) relative to high-volume hospitals (>250/year) were not associated with mortality, complications, or 30-day readmissions for simple or complex procedures. CONCLUSIONS: We found evidence that surgeon EGS volume was associated with outcomes. Developing EGS-specific services, mentorship opportunities, and clinical pathways for less-experienced surgeons may improve outcomes. PMID- 28838871 TI - Optimism in the face of uncertainty supported by a statistically-designed multi armed bandit algorithm. AB - The principle of optimism in the face of uncertainty is known as a heuristic in sequential decision-making problems. Overtaking method based on this principle is an effective algorithm to solve multi-armed bandit problems. It was defined by a set of some heuristic patterns of the formulation in the previous study. The objective of the present paper is to redefine the value functions of Overtaking method and to unify the formulation of them. The unified Overtaking method is associated with upper bounds of confidence intervals of expected rewards on statistics. The unification of the formulation enhances the universality of Overtaking method. Consequently we newly obtain Overtaking method for the exponentially distributed rewards, numerically analyze it, and show that it outperforms UCB algorithm on average. The present study suggests that the principle of optimism in the face of uncertainty should be regarded as the statistics-based consequence of the law of large numbers for the sample mean of rewards and estimation of upper bounds of expected rewards, rather than as a heuristic, in the context of multi-armed bandit problems. PMID- 28838872 TI - The Value of Short-Term Pain Relief in Predicting the Long-Term Outcome of Lumbar Transforaminal Epidural Steroid Injections. AB - BACKGROUND: A previous report demonstrated predictive power of short-term leg pain relief after lumbar transforaminal epidural steroid injections for 1-month treatment response. The question whether the long-term response could be similarly predicted remained unanswered. METHODS: A prospective cohort of 57 patients who underwent a transforaminal epidural steroid injection for sciatica secondary to a lumbar disc herniation was followed for 24 months. Leg and back pain on the visual analog scale, health-related quality of life using the 12-Item Short Form Survey, and functional outcome using the Oswestry Disability Index were assessed. Responders were defined as not receiving any additional invasive treatment after a single injection. Patients who underwent a second injection or surgery were defined as treatment failures (nonresponders). RESULTS: At 24 months, 31 (54.4%) patients were responders, and 26 (45.6%) were nonresponders. Nonresponders left follow-up at 1 month (n = 9), 3 months (n = 9), 6 months (n = 6) and 12 months (n = 2). No patients were injected again or operated on between the 12- and 24-month follow-up. Responders at 24 months had significantly lower visual analog scale leg pain (P < 0.05) than nonresponders starting from the second week after TFESI and better 12-Item Short Form Survey scores and less disability on the Oswestry Disability Index. CONCLUSIONS: Most patients with a symptomatic lumbar disc herniation who opt for a second injection or surgery do so within the first 6 months. Reliable prediction of the long-term treatment response based on short-term pain relief is not possible. PMID- 28838873 TI - The Management of Patients with Chronic Subdural Hematoma Treated with Low-Dose Acetylsalicylic Acid: An International Survey of Practice. AB - BACKGROUND: The aim of this international survey was to investigate the current management of patients undergoing surgery for chronic subdural hematoma (cSDH) treated with low-dose acetylsalicylic acid (ASA). METHODS: We administered a survey via e-mail to neurosurgeons with questions relating to the surgical treatment of cSDH, emphasizing their practices with patients treated with low dose ASA. RESULTS: We received 157 responses, with a response rate of 22.4%. Almost 80% of the responders discontinue ASA treatment at least 5 days before surgery and 80.7% resume treatment after 5 days or more, and 27.6% discontinue treatment for at least 30 days. The main factor influencing ASA resumption time is the indication for ASA (54.5%), and postoperative imaging is concluded in 71.7%, Postoperative thrombosis prophylaxis is administered by 60% of the responders, and 50% apply it 24 hours after surgery. Almost 95% of the responders believe that better evidence is needed for the management of patients with cSDH treated with ASA. Guidelines for these patients exist in only 24.3% of the institutes. CONCLUSIONS: Most neurosurgeons discontinue ASA treatment for at least 7 days in the perioperative period of surgical evacuation of cSDH, even though recent studies show that early ASA resumption might be safe. Thrombosis prophylaxis is administered by only 60%, even though patients with cSDH are at high risk of developing thromboembolic complications. Better evidence and guidelines are warranted because the incidence of patients with cSDH under the treatment of ASA is increasing. PMID- 28838874 TI - Outcomes After Endoscopic Endonasal Resection of Craniopharyngiomas in the Pediatric Population. AB - BACKGROUND: Craniopharyngiomas have traditionally been treated via open transcranial approaches. More recently, endoscopic transsphenoidal approaches have been increasingly used; however, few case series exist in the pediatric population. METHODS: A retrospective review of patients (aged <18 years) undergoing endoscopic transsphenoidal resection of craniopharyngiomas between 1995 and 2016 was performed. Preoperative data included presenting symptoms, tumor size, location, and components. Postoperative outcomes included symptom resolution, visual outcomes, endocrine outcomes, disease recurrence, and major complications. RESULTS: Sixteen pediatric patients with mean age of 11.0 years (range, 5-15 years) were included. The median follow-up time was 56.2 months. Mean maximal tumor diameter was 3.98 cm. Most of the tumors had suprasellar (93.8%) and intrasellar (68.8%) components. The gross total resection rate was 93.8%. The most common presenting symptoms were vision changes (81.3%) and increased intracranial pressure (56.3%). Most patients (66.7%) had their presenting symptoms resolved by their first postoperative visit. Vision improved or remained normal in 69.2% of patients. Postoperatively, new incidence of panhypopituitarism or diabetes insipidus developed in 63.6% and 46.7% of patients, respectively. New hypothalamic obesity developed in 28.6% of patients. The postoperative cerebrospinal fluid leak rate was 18.8%. One patient died of intraventricular hemorrhage postoperatively. The major complication rate was 12.5%. Disease recurrence occurred in 1 patient with gross total resection (6.3%). CONCLUSIONS: Endoscopic transsphenoidal resection for craniopharyngiomas can achieve high rates of total resection with low rates of disease recurrence in larger tumors than previously described. However, hypothalamic-pituitary dysfunction and cerebrospinal fluid leak remain significant postoperative morbidities. PMID- 28838875 TI - Comparison of Porcine and Bovine Collagen Dural Substitutes in Posterior Fossa Decompression for Chiari I Malformation in Adults. AB - BACKGROUND: Posterior fossa decompression surgeries for Chiari malformations are susceptible to postoperative complications such as pseudomeningocele, external cerebrospinal fluid (CSF) leak, and meningitis. Various dural substitutes have been used to improve surgical outcomes. OBJECTIVE: This study examined whether the collagen matrix dural substitute type correlated with the incidence of postoperative complications after posterior fossa decompression in adult patients with Chiari I malformations. METHODS: A retrospective cohort study was conducted of 81 adult patients who underwent an elective decompressive surgery for treatment of symptomatic Chiari I malformations, with duraplasty involving a dural substitute derived from either bovine or porcine collagen matrix. Demographics and treatment characteristics were correlated with surgical outcomes. RESULTS: A total of 81 patients were included in the study. Compared with bovine dural substitute, porcine dural substitute was associated with a significantly higher risk of pseudomeningocele occurrence (odds ratio, 5.78; 95% confidence interval, 1.65-27.15; P = 0.01) and a higher overall complication rate (odds ratio, 3.70; 95% confidence interval, 1.23-12.71; P = 0.03) by univariate analysis. There was no significant difference in the rate of meningitis, repeat operations, or overall complication rate between the 2 dural substitutes. In addition, estimated blood loss was a significant risk factor for meningitis (P = 0.03). Multivariate analyses again showed that porcine dural substitute was associated with pseudomeningocele occurrence, although the association with higher overall complication rate did not reach significance. CONCLUSIONS: Dural substitutes generated from porcine collagen, compared with those from bovine collagen, were associated with a higher likelihood of pseudomeningocele development in adult patients undergoing Chiari I malformation decompression and duraplasty. PMID- 28838876 TI - Ventriculoscopic Approach for Intraventricular Neurocysticercosis: A Single Neurosurgical Center's Experience. AB - OBJECTIVE: To retrospectively analyze patients with intraventricular neurocysticercosis (NCC) who underwent a ventriculoscopic approach at a single neurosurgical center and assess the efficacy of this treatment in patients with intraventricular NCC. METHODS: Patients with intraventricular NCC patients who underwent surgery via a ventriculoscopic approach between January 2008 and March 2014 at Beijing Tiantan Hospital were analyzed. RESULTS: A total of 21 patients with intraventricular NCC (15 men and 6 women; mean age, 38.0 +/- 16.8 years; range, 9-65 years) were enrolled in the study. Ten of the patients underwent complete resection. The median progression-free survival (PFS) was 53.7 months (95% confidence interval, 31.7-75.6 months). On univariate analysis, PFS was better in the patients who underwent total NCC resection compared with those who underwent nontotal resection (P < 0.05). CONCLUSIONS: The ventriculoscopic approach to NCC resection is an effective technique with unique advantages for intraventricular NCC. Radical resection is necessary for intraventricular NCC. Combined application of rigid and flexible endoscopes can improve the total removal rate of intraventricular NCC. PMID- 28838877 TI - Progression-Free Survival and Factors Associated with Postoperative Recurrence in 126 Patients with Atypical Intracranial Meningioma. AB - OBJECTIVE: Atypical meningioma has a higher recurrence rate than benign meningioma. The mainstay of treatment is surgery with or without radiation therapy (RT). The objective of this study was to investigate progression-free survival (PFS) and factors associated with postoperative recurrence in patients with atypical meningioma. METHODS: Patients with diagnoses of atypical menigioma who underwent surgery at Siriraj Hospital during the 2004 to 2014 study period were included. Features potentially associated with PFS and tumor recurrence from clinical records, operative records, and neuroimaging studies were evaluated and analyzed. RESULTS: One hundred twenty-six patients (mean age, 55 years) were included. The median PFS was 55 months. The 5-year and 10-year PFS rates were 72.5% and 32%, respectively. The median follow-up duration was 52 months. In multivariate analysis, tumor location (convexity, parasagittal/falcine, intraventricular, skull base) (P = 0.003), and pial invasion (hazard ratio [HR]: 2.02; P = 0.045) were significantly associated with tumor recurrence. Postoperative RT was associated with reduction in tumor recurrence in both univariate (odds ratio: 0.48; P = 0.039) and multivariate analysis (HR: 0.42; P = 0.005). CONCLUSIONS: Tumor location and pial invasion were significantly correlated with increased incidence of tumor recurrence, and postoperative RT was found to be significantly associated with decreased tumor progression and recurrence. PMID- 28838878 TI - The Role of Antibiotic Prophylaxis in Shunt Surgery. AB - OBJECTIVE: To determine whether antibiotic prophylaxis (AP) can reduce the postoperative infection rate and identify the risk factors for postoperative infection in shunt surgery. DATA AND METHODS: In this study, we retrospectively collected information for each patient who underwent shunt surgery at Tianjin Huanhu Hospital from January 2011 to December 2016. According to whether prophylactic antibiotics were administered, the cases were divided into antibiotic prophylaxis (AP) and no antibiotic prophylaxis (N-AP) groups to evaluate whether there is a significant difference between the 2 groups. The risk factors for infection after shunt surgery were analyzed with the use of logistic regression analysis to identify independent risk factors. RESULTS: A total of 570 shunt surgery cases were included. The AP group comprised 321 surgical cases, including 21 cerebrospinal fluid (CSF) shunt infections and 2 incision infections, whereas the N-AP group consisted of 249 surgical cases, including 11 CSF shunt infections and 0 incision infections (P = 0.170). Bacterial cultures indicated that the CSF shunt infections in the AP group included 23 cases, of which 12 (12/23, 52%) were culture-positive, and that the CSF shunt infections in the N-AP group included 11 cases, of which 10 (10/11, 91%) were culture-positive (P = 0.029). There was a significant difference between the group with a time gap <6 months and the group with a time gap >=6 months (P = 0.038). A logistic regression analysis showed that a history of brain infection (P = 0.032; odds ratio 2.588; 95% confidence interval 1.088-6.158) and previous ventriculostomy (P = 0.049; odds ratio 2.426; 95% confidence interval 1.004-5.866) were independent risk factors for postoperative infection in shunt surgery. CONCLUSIONS: In our study, a preventive effect of AP on postoperative infection was not observed in shunt surgery. However, AP reduced the rate of positive bacterial cultures. A logistic regression analysis demonstrated that a history of brain infection and previous ventriculostomy were independent risk factors for postoperative infection and that AP was a nonprotective factor. PMID- 28838879 TI - Transvenous Endovascular Treatment for Scalp Arteriovenous Fistulas: Results with Combined Use of Onyx and Coils. AB - BACKGROUND: Scalp arteriovenous fistulas (AVFs) are rare lesions that may occur spontaneously or secondary to head trauma. A standard treatment strategy for these lesions has not been established to date. We present 3 cases of successful treatment of scalp AVFs using a combination of Onyx-18 and coils via a transvenous approach. METHODS: The patient database at Huashan Hospital, Fudan University, Shanghai, China was reviewed, and patients with scalp AVFs treated with Onyx-18 and coils via a transvenous approach were identified for analysis. RESULTS: Between 2014 and 2016, 3 consecutive patients with scalp AVFs were treated transvenously with Onyx embolization in combination with coil placement at our hospital. No procedure-related complications were noted. Postembolization angiography demonstrated successful and complete occlusion of the AVFs immediately after treatment. Clinical follow-up showed resolution of symptoms. CONCLUSIONS: The technique of transvenous "armored concrete" embolization using a combination of coils and Onyx is an effective treatment modality for scalp AVFs, particularly in type C cases. PMID- 28838880 TI - Innervation of the Anterior Sacroiliac Joint. AB - OBJECTIVE: Sacroiliac joint pain can be disabling and recalcitrant to medical therapy. The innervation of this joint is poorly understood, especially its anterior aspect. Therefore, the present cadaveric study was performed to better elucidate this anatomy. METHODS: Twenty-four cadaveric sides underwent dissection of the anterior sacroiliac joint, with special attention given to any branches from regional nerves to this joint. RESULTS: No femoral, obturator, or lumbosacral trunk branches destined to the anterior sacroiliac joint were identified in the 24 sides. In 20 sides, one or two small branches (less than 0.5 mm in diameter) were found to arise from the L4 ventral ramus (10%), the L5 ventral ramus (80%), or simultaneously from both the L4 and L5 ventral rami (10%). The length of the branches ranged from 5 to 31 mm (mean, 14 mm). All these branches arose from the posterior part of the nerves and traveled to the anterior surface of the sacroiliac joint. No statistical significance was found between sides or sexes. CONCLUSIONS: An improved knowledge of the innervation of the anterior sacroiliac joint might decrease suffering in patients with chronic sacroiliac joint pain. PMID- 28838881 TI - The effect of mild acute stress during memory consolidation on emotional recognition memory. AB - Stress during consolidation improves recognition memory performance. Generally, this memory benefit is greater for emotionally arousing stimuli than neutral stimuli. The strength of the stressor also plays a role in memory performance, with memory performance improving up to a moderate level of stress and thereafter worsening. As our daily stressors are generally minimal in strength, we chose to induce mild acute stress to determine its effect on memory performance. In the current study, we investigated if mild acute stress during consolidation improves memory performance for emotionally arousing images. To investigate this, we had participants encode highly arousing negative, minimally arousing negative, and neutral images. We induced stress using the Montreal Imaging Stress Task (MIST) in half of the participants and a control task to the other half of the participants directly after encoding (i.e. during consolidation) and tested recognition 48h later. We found no difference in memory performance between the stress and control group. We found a graded pattern among confidence, with responders in the stress group having the least amount of confidence in their hits and controls having the most. Across groups, we found highly arousing negative images were better remembered than minimally arousing negative or neutral images. Although stress did not affect memory accuracy, responders, as defined by cortisol reactivity, were less confident in their decisions. Our results suggest that the daily stressors humans experience, regardless of their emotional affect, do not have adverse effects on memory. PMID- 28838882 TI - Histamine regulates memory consolidation. AB - Recent findings have reasserted the role of histamine in the regulation of memory consolidation first proposed in 1986 in an inhibitory avoidance task in rats. They indicate that histamine is indeed a major regulator of memory consolidation in various tasks, through H2 receptors in the dorsal hippocampus and through H3 receptors in the basolateral amygdala, depending on the task. In the object recognition task, the memory enhancing effect is mediated by the three receptors (H1, H2, H3) in the dorsal hippocampus. In social recognition, the consolidation effect is mediated by H2 receptors in both amygdala and dorsal hippocampus. Data have suggested, in addition, influences on retrieval; this has been best studied in the dorsal hippocampus in step-down inhibitory avoidance task. Depending on the recent history of the conditioned stimulus (i.e., whether it has been recently reinforced or not), histamine acts on hippocampal H1 receptors, facilitating retrieval, or on H2 receptors, inhibiting it. PMID- 28838883 TI - Evaluation of Sampling Recommendations From the Influenza Virologic Surveillance Right Size Roadmap for Idaho. AB - BACKGROUND: The Right Size Roadmap was developed by the Association of Public Health Laboratories and the Centers for Disease Control and Prevention to improve influenza virologic surveillance efficiency. Guidelines were provided to state health departments regarding representativeness and statistical estimates of specimen numbers needed for seasonal influenza situational awareness, rare or novel influenza virus detection, and rare or novel influenza virus investigation. OBJECTIVE: The aim of this study was to compare Roadmap sampling recommendations with Idaho's influenza virologic surveillance to determine implementation feasibility. METHODS: We calculated the proportion of medically attended influenza-like illness (MA-ILI) from Idaho's influenza-like illness surveillance among outpatients during October 2008 to May 2014, applied data to Roadmap provided sample size calculators, and compared calculations with actual numbers of specimens tested for influenza by the Idaho Bureau of Laboratories (IBL). We assessed representativeness among patients' tested specimens to census estimates by age, sex, and health district residence. RESULTS: Among outpatients surveilled, Idaho's mean annual proportion of MA-ILI was 2.30% (20,834/905,818) during a 5-year period. Thus, according to Roadmap recommendations, Idaho needs to collect 128 specimens from MA-ILI patients/week for situational awareness, 1496 influenza-positive specimens/week for detection of a rare or novel influenza virus at 0.2% prevalence, and after detection, 478 specimens/week to confirm true prevalence is <=2% of influenza-positive samples. The mean number of respiratory specimens Idaho tested for influenza/week, excluding the 2009-2010 influenza season, ranged from 6 to 24. Various influenza virus types and subtypes were collected and specimen submission sources were representative in terms of geographic distribution, patient age range and sex, and disease severity. CONCLUSIONS: Insufficient numbers of respiratory specimens are submitted to IBL for influenza laboratory testing. Increased specimen submission would facilitate meeting Roadmap sample size recommendations. PMID- 28838884 TI - Conventional Cognitive Behavioral Therapy Facilitated by an Internet-Based Support System: Feasibility Study at a Psychiatric Outpatient Clinic. AB - BACKGROUND: Cognitive behavioral therapies have been shown to be effective for a variety of psychiatric and somatic disorders, but some obstacles can be noted in regular psychiatric care; for example, low adherence to treatment protocols may undermine effects. Treatments delivered via the Internet have shown promising results, and it is an open question if the blend of Internet-delivered and conventional face-to-face cognitive behavioral therapies may help to overcome some of the barriers of evidence-based treatments in psychiatric care. OBJECTIVE: We evaluated the feasibility of an Internet-based support system at an outpatient psychiatric clinic in Sweden. For instance, the support system made it possible to send messages and share information between the therapist and the patient before and after therapy sessions at the clinic. METHODS: Nine clinical psychologists participated and 33 patients were enrolled in the current study. We evaluated the usability and technology acceptance after 12 weeks of access. Moreover, clinical data on common psychiatric symptoms were assessed before and after the presentation of the support system. RESULTS: In line with our previous study in a university setting, the Internet-based support system has the potential to be feasible also when delivered in a regular psychiatric setting. Notably, some components in the system were less frequently used. We also found that patients improved on common outcome measures for depressive and anxious symptoms (effect sizes, as determined by Cohen d, ranged from 0.20-0.69). CONCLUSIONS: This study adds to the literature suggesting that modern information technology could be aligned with conventional face-to-face services. PMID- 28838885 TI - Text Messaging Interventions on Cancer Screening Rates: A Systematic Review. AB - BACKGROUND: Despite high-quality evidence demonstrating that screening reduces mortality from breast, cervical, colorectal, and lung cancers, a substantial portion of the population remains inadequately screened. There is a critical need to identify interventions that increase the uptake and adoption of evidence-based screening guidelines for preventable cancers at the community practice level. Text messaging (short message service, SMS) has been effective in promoting behavioral change in various clinical settings, but the overall impact and reach of text messaging interventions on cancer screening are unknown. OBJECTIVE: The objective of this systematic review was to assess the effect of text messaging interventions on screening for breast, cervical, colorectal, and lung cancers. METHODS: We searched multiple databases for studies published between the years 2000 and 2017, including PubMed, EMBASE, and the Cochrane Library, to identify controlled trials that measured the effect of text messaging on screening for breast, cervical, colorectal, or lung cancers. Study quality was evaluated using the Cochrane risk of bias tool. RESULTS: Our search yielded 2238 citations, of which 31 underwent full review and 9 met inclusion criteria. Five studies examined screening for breast cancer, one for cervical cancer, and three for colorectal cancer. No studies were found for lung cancer screening. Absolute screening rates for individuals who received text message interventions were 0.6% to 15.0% higher than for controls. Unadjusted relative screening rates for text message recipients were 4% to 63% higher compared with controls. CONCLUSIONS: Text messaging interventions appear to moderately increase screening rates for breast and cervical cancer and may have a small effect on colorectal cancer screening. Benefit was observed in various countries, including resource-poor and non-English-speaking populations. Given the paucity of data, additional research is needed to better quantify the effectiveness of this promising intervention. PMID- 28838889 TI - Mapping Out Cancer Dependencies. AB - Through large-scale RNAi screens, two groups of researchers have documented, in depth, the molecular players essential for tumor cell viability. Their cancer "dependency maps," which are publicly accessible, should aid drug discovery efforts by pinpointing therapeutic targets that merit developmental focus. PMID- 28838888 TI - Cancer Self-Defense: An Immune Stealth. AB - The hurdles in realizing successful cancer immunotherapy stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment/secretion of a "decoy flare," for example, anomalous cancer-associated antigens by the tumor cells. The cancer secretome, which resembles the parent cell make-up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs, etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents, resulting in a "cancer stealth" effect. Immunotherapy, or any treatment that relies on antigens' expression/function, could be improved by the understanding of the properties of the cancer secretome, as its clinical evaluation may change the therapeutic landscape. Cancer Res; 77(20); 5441-4. (c)2017 AACR. PMID- 28838886 TI - Smartphone-Enabled Health Coaching Intervention (iMOVE) to Promote Long-Term Maintenance of Physical Activity in Breast Cancer Survivors: Protocol for a Feasibility Pilot Randomized Controlled Trial. AB - BACKGROUND: Although physical activity has been shown to contribute to long-term disease control and health in breast cancer survivors, a majority of breast cancer survivors do not meet physical activity guidelines. Past research has focused on promoting physical activity components for short-term breast cancer survivor benefits, but insufficient attention has been devoted to long-term outcomes and sustained exercise adherence. We are assessing a health coach intervention (iMOVE) that uses mobile technology to increase and sustain physical activity maintenance in initially inactive breast cancer survivors. OBJECTIVE: This pilot randomized controlled trial (RCT) is an initial step in evaluating the iMOVE intervention and will inform development of a full-scale pragmatic RCT. METHODS: We will enroll 107 physically inactive breast cancer survivors and randomly assign them to intervention or control groups at the University Health Network, a tertiary cancer care center in Toronto, Canada. Participants will be women (age 18 to 74 years) stratified by age (55 years and older/younger than 55 years) and adjuvant hormone therapy (AHT) exposure (AHT vs no AHT) following breast cancer treatment with no metastases or recurrence who report less than 60 minutes of preplanned physical activity per week. Both intervention and control groups receive the 12-week physical activity program with weekly group sessions and an individualized, progressive, home-based exercise program. The intervention group will additionally receive (1) 10 telephone-based health coaching sessions, (2) smartphone with data plan, if needed, (3) supportive health tracking software (Connected Wellness, NexJ Health Inc), and (4) a wearable step-counting device linked to a smartphone program. RESULTS: We will be assessing recruitment rates; acceptability reflected in selective, semistructured interviews; and enrollment, retention, and adherence quantitative intervention markers as pilot outcome measures. The primary clinical outcome will be directly measured peak oxygen consumption. Secondary clinical outcomes include health-related quality of life and anthropometric measures. All outcome measures are administered at baseline, after exercise program (month 3), and 6 months after program (month 9). CONCLUSIONS: This pilot RCT will inform full-scale RCT planning. We will assess pilot procedures and interventions and collect preliminary effect estimates. TRIAL REGISTRATION: ClinicalTrials.gov NCT02620735; https://clinicaltrials.gov/ct2/show/NCT02620735 (Archived by WebCite at https://clinicaltrials.gov/ct2/show/NCT02620735). PMID- 28838887 TI - The Use of Mobile Apps and SMS Messaging as Physical and Mental Health Interventions: Systematic Review. AB - BACKGROUND: The initial introduction of the World Wide Web in 1990 brought around the biggest change in information acquisition. Due to the abundance of devices and ease of access they subsequently allow, the utility of mobile health (mHealth) has never been more endemic. A substantial amount of interactive and psychoeducational apps are readily available to download concerning a wide range of health issues. mHealth has the potential to reduce waiting times for appointments; eradicate the need to meet in person with a clinician, successively diminishing the workload of mental health professionals; be more cost effective to practices; and encourage self-care tactics. Previous research has given valid evidence with empirical studies proving the effectiveness of physical and mental health interventions using mobile apps. Alongside apps, there is evidence to show that receiving short message service (SMS) messages, which entail psychoeducation, medication reminders, and links to useful informative Web pages can also be advantageous to a patient's mental and physical well-being. Available mHealth apps and SMS services and their ever improving quality necessitates a systematic review in the area in reference to reduction of symptomology, adherence to intervention, and usability. OBJECTIVE: The aim of this review was to study the efficacy, usability, and feasibility of mobile apps and SMS messages as mHealth interventions for self-guided care. METHODS: A systematic literature search was carried out in JMIR, PubMed, PsychINFO, PsychARTICLES, Google Scholar, MEDLINE, and SAGE. The search spanned from January 2008 to January 2017. The primary outcome measures consisted of weight management, (pregnancy) smoking cessation, medication adherence, depression, anxiety and stress. Where possible, adherence, feasibility, and usability outcomes of the apps or SMS services were evaluated. Between-group and within-group effect sizes (Cohen d) for the mHealth intervention method group were determined. RESULTS: A total of 27 studies, inclusive of 4658 participants were reviewed. The papers included randomized controlled trials (RCTs) (n=19), within-group studies (n=7), and 1 within-group study with qualitative aspect. Studies show improvement in physical health and significant reductions of anxiety, stress, and depression. Within-group and between-group effect sizes ranged from 0.05-3.37 (immediately posttest), 0.05 3.25 (1-month follow-up), 0.08-3.08 (2-month follow-up), 0.00-3.10 (3-month follow-up), and 0.02-0.27 (6-month follow-up). Usability and feasibility of mHealth interventions, where reported, also gave promising, significant results. CONCLUSIONS: The review shows the promising and emerging efficacy of using mobile apps and SMS text messaging as mHealth interventions. PMID- 28838890 TI - Pregnancies in patients with inherited bone marrow failure syndromes in the NCI cohort. PMID- 28838891 TI - Interaction effects among IFN-gamma+874, IL-2-330, IL-10-1082, IL-10-592 and IL-4 589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus: a retrospective nested case-control study. AB - BACKGROUND: The natural outcomes of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections vary considerably among individuals The infection may heal naturally, or patients may succumb to chronic liver diseases, including chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The mechanism is not fully understood. OBJECTIVES: To evaluate the interaction among four single nucleotide polymorphisms (SNPs) and their influence on different clinical outcomes. METHODS: 277 individuals infected with HBV and/or HCV, including 81 patients with chronic hepatitis B and C, 122 asymptomatic HBV and/or HCV carriers and 74 controls who cleared HBV and HCV spontaneously, were involved in this study. The SNPs of four genes (rs2069762/-330 G/T of IL-2, rs2430561/+874A>T of IFN-gamma, rs1800896/-1082G>A and rs1800872/-592C>A of IL-10 and rs2243250/ 589C>T of IL-4) were analysed using restriction fragment length polymorphism polymerase chain reaction or sequence-specific primer PCR. The gene-gene interactions were assessed using the multifactor-dimensionality reduction method. RESULTS: Interleukin (IL)-10-592 AC and IL-4-589 CC/CT showed a synergistic effect on liver inflammatory injury (p<0.01), whereas interferon (IFN)-gamma+874 AA and IL-2-330 TT had a synergistic impact (p<0.05). IFN-gamma+874 AA and IL-10 1082 AA had an antagonistic effect (p<0.01) on the clinical progression, including asymptomatic HBV and HCV carriers and chronic hepatitis. IL-2-330 TT and IL-10-1082 AA synergistically influenced the clinical outcome (p<0.05). IFN gamma+874 AA, IL-2-330 TT and IL-10-1082 AA interactively affected the clinical outcome including asymptomatic HBV and HCV carriers and chronic hepatitis (p<0.05). CONCLUSIONS: Interactions among polymorphisms of IFN-gamma+874 AA, IL-2 330 TT, IL-10-1082 AA, IL10--592 AC and IL-4-589 CC/CT significantly influenced the clinical progression of the subjects with HBV and/or HCV infection. PMID- 28838892 TI - Concurrent validity, discriminatory power and feasibility of the instrument for Identification of Parents At Risk for child Abuse and Neglect (IPARAN). AB - OBJECTIVES: To determine the feasibility, concurrent validity and discriminatory power of the instrument for Identification of Parents At Risk for child Abuse and Neglect (IPARAN) among Dutch parents with a newborn child. SETTING: Community paediatrics. PARTICIPANTS: Data from a controlled trial were used. In total, 2659 Dutch parents with a newborn child were invited to participate. Of the 2659 parents, 759 parents filled in the consent form and participated in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Concurrent validity was determined by calculating correlations-using the Pearson's correlation (r)-between the IPARAN score and related constructs from the following instruments: the Empowerment Questionnaire 2.0, the Family Functioning Questionnaire and the Parenting Stress Questionnaire. Discriminatory power was determined by calculating receiver operating characteristic (ROC) curves between high-risk mothers and low-risk mothers according to their scores on the related constructs. Feasibility was determined by examining the percentage of missing answers. RESULTS: In terms of concurrent validity, we found that 3 out of 12 correlations between the IPARAN score and related constructs were strong (ie, r>0.50) and 4 out of 12 were medium (ie, r=0.30-0.49). In terms of discriminatory power, mothers with a score in the borderline/clinical range or lowest 10 percent (P10) range of the related constructs (high-risk mothers) had a higher IPARAN score than mothers with a score in the normal range or highest 90 percent (P90) range of the related constructs (low-risk mothers). Effect sizes varied from d=0.37 to d=1.93, and the area under the ROC curve varied from 0.62 to 0.93. Regarding feasibility, the part of the IPARAN filled in by the mother had on average 0.7% missing answers, whereas the part of the IPARAN filled in by the father had on average 1.7% missing answers. CONCLUSION: The results of this study support the concurrent validity, discriminatory power and feasibility of the IPARAN among a population of Dutch parents with a newborn child. PMID- 28838893 TI - Impact of family-friendly prison policies on health, justice and child protection outcomes for incarcerated mothers and their dependent children: a cohort study protocol. AB - INTRODUCTION: Female imprisonment has numerous health and social sequelae for both women prisoners and their children. Examples of comprehensive family friendly prison policies that seek to improve the health and social functioning of women prisoners and their children exist but have not been evaluated. This study will determine the impact of exposure to a family-friendly prison environment on health, child protection and justice outcomes for incarcerated mothers and their dependent children. METHODS AND ANALYSIS: A longitudinal retrospective cohort design will be used to compare outcomes for mothers incarcerated at Boronia Pre-release Centre, a women's prison with a dedicated family-friendly environment, and their dependent children, with outcomes for mothers incarcerated at other prisons in Western Australia (that do not offer this environment) and their dependent children. Routinely collected administrative data from 1985 to 2013 will be used to determine child and mother outcomes such as hospital admissions, emergency department presentations, custodial sentences, community service orders and placement in out-of home care. The sample consists of all children born in Western Australia between 1 January 1985 and 31 December 2011 who had a mother in a West Australian prison between 1990 and 2012 and their mothers. Children are included if they were alive and aged less than 18 years at the time of their mother's incarceration. The sample comprises an exposed group of 665 women incarcerated at Boronia and their 1714 dependent children and a non-exposed comparison sample of 2976 women incarcerated at other West Australian prisons and their 7186 dependent children, creating a total study sample of 3641 women and 8900 children. ETHICS AND DISSEMINATION: This project received ethics approval from the Western Australian Department of Health Human Research Ethics Committee, the Western Australian Aboriginal Health Ethics Committee and the University of Western Australia Human Research Ethics Committee. PMID- 28838894 TI - Breast cancer mortality and associated factors in Sao Paulo State, Brazil: an ecological analysis. AB - OBJECTIVE: Identify the factors associated with the age-standardised breast cancer mortality rate in the municipalities of State of Sao Paulo (SSP), Brazil, in the period from 2006 to 2012. DESIGN: Ecological study of the breast cancer mortality rate standardised by age, as the dependent variable, having each of the 645 municipalities in the SSP as the unit of analysis. SETTINGS: The female resident population aged 15 years or older, by age group and municipality, in 2009 (mid-term), obtained from public dataset (Informatics Department of the Unified Health System). PARTICIPANTS: Women 15 years or older who died of breast cancer in the SSP were selected for the calculation of the breast cancer mortality rate, according to the municipality and age group, from 2006 to 2012. MAIN OUTCOME MEASURES: Mortality rates for each municipality calculated by the direct standardisation method, using the age structure of the population of SSP in 2009 as the standard. RESULTS: In the final linear regression model, breast cancer mortality, in the municipal level, was directly associated with rates of nulliparity (p<0.0001), mammography (p<0.0001) and private healthcare (p=0.006). CONCLUSIONS: The findings that mammography ratio was associated, in the municipal level, with increased mortality add to the evidence of a probable overestimation of benefits and underestimation of risks associated with this form of screening. The same paradoxical trend of increased mortality with screening was found in recent individual-level studies, indicating the need to expand informed choice for patients, primary prevention actions and individualised screening. Additional studies should be conducted to explore if there is a causality link in this association. PMID- 28838895 TI - Associations of fibroblast growth factor 23, vitamin D and parathyroid hormone with 5-year outcomes in a prospective primary care cohort of people with chronic kidney disease stage 3. AB - OBJECTIVES: Vitamin D deficiency, elevated fibroblast growth factor 23 (FGF23) and elevated parathyroid hormone (PTH) have each been associated with increased mortality in people with chronic kidney disease (CKD). Previous studies have focused on the effects of FGF23 in relatively advanced CKD. This study aims to assess whether FGF23 is similarly a risk factor in people with early CKD, and how this risk compares to that associated with vitamin D deficiency or elevated PTH. DESIGN: Prospective cohort study. SETTING: Thirty-two primary care practices. PARTICIPANTS: One thousand six hundred and sixty-four people who met Kidney Disease: Improving Global Outcomes (KDIGO) definitions for CKD stage 3 (two measurements of estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 at least 90 days apart) prior to study recruitment. OUTCOME MEASURES: All-cause mortality over the period of study follow-up and progression of CKD defined as a 25% fall in eGFR and a drop in GFR category, or an increase in albuminuria category. RESULTS: Two hundred and eighty-nine participants died during the follow-up period. Vitamin D deficiency (HR 1.62, 95% CI 1.01 to 2.58) and elevated PTH (HR 1.42, 95% CI 1.09 to 1.84) were independently associated with all-cause mortality. FGF23 was associated with all-cause mortality in univariable but not multivariable analysis. Fully adjusted multivariable models of CKD progression showed no association with FGF23, vitamin D status or PTH. CONCLUSIONS: In this cohort of predominantly older people with CKD stage 3 and low risk of progression, vitamin D deficiency and elevated PTH were independent risk factors for all-cause mortality but elevated FGF23 was not. While FGF23 may have a role as a risk marker in high-risk populations managed in secondary care, our data suggest that it may not be as important in CKD stage 3, managed in primary care. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632. PMID- 28838896 TI - Priorities for research in miscarriage: a priority setting partnership between people affected by miscarriage and professionals following the James Lind Alliance methodology. AB - OBJECTIVES: To identify and prioritise important research questions for miscarriage. DESIGN: A priority setting partnership using prospective surveys and consensus meetings following methods advocated by the James Lind Alliance. SETTING: UK. PARTICIPANTS: Women and those affected by miscarriage working alongside healthcare professionals. RESULTS: In the initial survey, 1093 participants (932 women who have experienced miscarriage, 8 partners, 17 family members, friends or colleagues, 104 healthcare professionals and eight charitable organisations) submitted 3279 questions. A review of existing literature identified a further 64. Non-questions were removed, and the remaining questions were categorised and summarised into 58 questions. In an interim electronic survey, 2122 respondents chose their top 10 priorities from the 58 summary questions. The 25 highest ranked in the survey were prioritised at a final face to-face workshop. In summary, the top 10 priorities were ranked as follows: research into preventative treatment, emotional aspects in general, investigation, relevance of pre-existing medical conditions, emotional support as a treatment, importance of lifestyle factors, importance of genetic and chromosomal causes, preconception tests, investigation after different numbers of miscarriage and male causal factors. CONCLUSIONS: These results should be the focus of future miscarriage research. Presently, studies are being conducted to address the top priority; however, many other priorities, especially psychological and emotional support, are less well researched areas. We hope our results will encourage both researchers and funders to focus on these priorities. PMID- 28838897 TI - Rethinking exercise identity: a qualitative study of physically inactive cancer patients' transforming process while undergoing chemotherapy. AB - OBJECTIVE: To explore physically inactive breast and colon cancer patients' prediagnosis exercise history and attitudes to physical activity (PA) and experiences in initiating PA while undergoing adjuvant chemotherapy. DESIGN: An explorative qualitative study guided the interpretive analysis of semistructured, open-ended interviews conducted at initiation of chemotherapy and after 12 weeks. The study was embedded in a pilot randomised controlled trial. SETTING: Participants were recruited from the Oncological Department at a hospital in Copenhagen, Denmark. PARTICIPANTS: 33 patients with cancer, median age 49 years: 25 patients with breast cancer and 8 with colon cancer, 72% with a low cardiac respiratory fitness level and the majority with a high level of education. Patients received adjuvant chemotherapy, oncologist's PA recommendation and exercise, cancer nurse specialist's counselling prior to allocation to PA interventions or waitlist control group. RESULTS: Prediagnosis exercise had been excluded from patients' daily lives due to perceptions of exercise as boring, lack of discipline and stressful work conditions for both genders. Recommendations from oncologists and nurses inspired the patients to reconsider their attitudes and behaviour by accepting recruitment and participation in PA interventions during chemotherapy. Despite extensive side effects, most patients adhered to their PA commitment due to their perception of the bodily, emotional and social benefits and support of healthcare professionals, peers and family. CONCLUSION: The patients' attitude towards exercise transformed from having no priority in patients' daily lives prediagnosis to being highly prioritised. This study identified four important phases in the exercise transformation process during the patients' treatment trajectory of relevance to clinicians in identifying, motivating and supporting physically inactive patients with cancer at long-term risk. Clinicians should address young, highly educated patients with cancer at onset of adjuvant chemotherapy due to their specific risk of a sedentary lifestyle resulting from being in stressful, ambitious careers. TRIAL REGISTRATION NUMBER: Current Controlled Trials (ISRCTN24901641), Stage: Qualitative results. PMID- 28838898 TI - Protocol for a pilot randomised controlled trial of metformin in pre-diabetes after kidney transplantation: the Transplantation and Diabetes (Transdiab) study. AB - INTRODUCTION: Post-transplant diabetes mellitus (PTDM) is a common complication of kidney transplantation and is associated with significant morbidity and mortality. In the general population, metformin has been used for diabetes prevention in high-risk individuals. Improving insulin sensitivity is one of many proven favourable effects of metformin. Despite the high incidence of PTDM in kidney transplant recipients, there is a lack of evidence for the role of metformin in the prevention of diabetes in this setting. METHODS AND ANALYSIS: Transplantation and Diabetes (Transdiab) is a single-centre, unblinded, pilot randomised controlled trial assessing the feasibility, tolerability and efficacy of metformin after renal transplantation in patients with impaired glucose tolerance (IGT). Participants will undergo an oral glucose tolerance test in the 4-12 weeks post-transplantation; those with IGT will be randomised to standard care or standard care and metformin 500 mg twice daily, and followed up for 12 months. The primary outcomes of the study will be the feasibility of recruitment, the tolerability of metformin assessed using the Gastrointestinal Symptom Rating Scale at 3 and 12 months, and the efficacy of metformin assessed by morning glucose and glycated haemoglobin at 3, 6, 9 and 12 months. ETHICS AND DISSEMINATION: Despite the significant morbidity and mortality of PTDM, there are currently no randomised clinical trials assessing pharmacological interventions for its prevention after kidney transplantation. The Transdiab trial will thus provide important data on the feasibility, safety, tolerability and efficacy of metformin after renal transplantation in patients with IGT; this will facilitate undertaking larger multicentre trials of interventions to reduce the incidence or severity of diabetes after kidney transplantation. This study has been approved by the Northern B Health and Disability Ethics Committee of the Ministry of Health in New Zealand. On study completion, results are expected to be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry Number: ACTRN12614001171606. PMID- 28838899 TI - Combining parenthood with a medical career: questionnaire survey of the UK medical graduates of 2002 covering some influences and experiences. AB - OBJECTIVES: To report the self-assessed views of a cohort of medical graduates about the impact of having (or wanting to have) children on their specialty choice and the extent to which their employer was supportive of doctors with children. SETTING: United Kingdom (UK). PARTICIPANTS: UK medical graduates of 2002 surveyed by post and email in 2014. RESULTS: The response rate was 64.2% (2057/3205). Most respondents were living with a spouse or partner (86%) and, of these, 49% had a medical spouse. Having children, or wanting to have children, had influenced specialty choice for 47% of respondents; for 56% of doctors with children and 29% of doctors without children; for 59% of women and 28% of men; and for 78% of general practitioners compared with 27% of hospital doctors and 18% of surgeons. 42% of respondents regarded the National Health Service as a family-friendly employer, and 64% regarded their specialty as family-friendly. More general practitioners (78%) than doctors in hospital specialties (56%) regarded their specialty as family-friendly, while only 32% of surgeons did so.Of those who had taken maternity/paternity/adoption leave, 49% rated the level of support they had received in doing so as excellent/good, 32% said it was acceptable and 18% said the support had been poor/very poor. CONCLUSIONS: Having children is a major influence when considering specialty choice for many doctors, especially women and general practitioners. Surgeons are least influenced in their career choice by the prospect of parenthood. Almost half of doctors in hospital specialties regard their specialty as family-friendly. PMID- 28838900 TI - A patient cohort on long-term sequelae of sepsis survivors: study protocol of the Mid-German Sepsis Cohort. AB - INTRODUCTION: An increasing number of patients survive sepsis; however, we lack valid data on the long-term impact on morbidity from prospective observational studies. Therefore, we designed an observational cohort to quantify mid-term and long-term functional disabilities after intensive care unit (ICU)-treated sepsis. Ultimately, findings for the Mid-German Sepsis Cohort (MSC) will serve as basis for the implementation of follow-up structures for patients with sepsis and help to increase quality of care for sepsis survivors. METHODS AND ANALYSIS: All patients surviving ICU-treated sepsis are eligible and are recruited from five study centres in Germany (acute care hospital setting in Jena, Halle/Saale, Leipzig, Bad Berka, Erfurt; large long-term acute care hospital and rehabilitation setting in Klinik Bavaria Kreischa). Screening is performed by trained study nurses. Data are collected on ICU management of sepsis. On written informed consent provided by patients or proxies, follow-up is carried out by trained research staff at 3, 6 and 12 months and yearly thereafter. The primary outcome is functional disability as assessed by (instrumental) activities of daily living. Other outcomes cover domains like mortality, cognitive, emotional and physical impairment, and resource use. The estimated sample size of 3000 ICU survivors is calculated to allow detection of relevant changes in the primary outcome in sepsis survivors longitudinally. ETHICS AND DISSEMINATION: The study is conducted according to the current version of the Declaration of Helsinki and has been approved by four local/federal responsible institutional ethics committees and by the respective federal data protection commissioners. Results of MSC will be fed back to the patients and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry DRKS00010050. PMID- 28838901 TI - The association between vertebrobasilar insufficiency and the risk of dementia: a nationwide register-based retrospective cohort study in Taiwan. AB - OBJECTIVES: Neurodegenerative disorders are reportedly characterised by decreased regional cerebral blood flow. However, the association between vertebrobasilar insufficiency (VBI) and dementia remains unclear. In this nationwide, population based, retrospective cohort study, we explored the potential association between VBI and dementia. DESIGN: Nationwide population-based cohort study. SETTING: Patients with VBI were newly diagnosed between 2000 and 2005 from the Taiwan National Health Insurance Research Database. PARTICIPANTS: We included 3642 subjects as the VBI group. The control cohort included 14 568 randomly selected age-matched and sex-matched VBI-free individuals. OUTCOME MEASURES: All subjects were followed until the diagnosis of dementia, death or the end of 2010. Patients with VBI, dementia (viz, vascular and non-vascular, including Alzheimer's) subtypes and other confounding factors were identified according to the International Classification of Diseases Clinical Modification Codes. Cox proportional hazards regression analysis was employed to examine adjusted HRs after adjusting for confounding factors. RESULTS: Patients with VBI had a 1.807 fold (95% CI 1.643 to 1.988, p<0.001) higher risk to develop all-cause dementia than individuals without VBI. The risk was significantly higher in the VBI group than in the non-VBI group regardless of age (<65 years: HR: 2.997, 95% CI 1.451 to 6.454, p<0.001; >=65 years: HR: 1.752, 95% CI 1.584 to 1.937, p<0.001). The VBI group had a higher risk of all-cause dementia than the non-VBI group regardless of sex and follow-up time intervals (<1 year, 1-2 years and>=2 years). CONCLUSION: Patients with VBI appear to have an increased risk of developing dementia. Further research is needed to investigate the underlying pathophysiology. PMID- 28838902 TI - What is the impact of giant cell arteritis on patients' lives? A UK qualitative study. AB - OBJECTIVES: Clinical management of giant cell arteritis (GCA) involves balancing the risks and burdens arising from the disease with those arising from treatment, but there is little research on the nature of those burdens. We aimed to explore the impact of giant cell arteritis (GCA) and its treatment on patients' lives. METHODS: UK patients with GCA participated in semi-structured telephone interviews. Inductive thematic analysis was employed. RESULTS: 24 participants were recruited (age: 65-92 years, time since diagnosis: 2 months to >6 years). The overarching themes from analysis were: ongoing symptoms of the disease and its treatment; and 'life-changing' impacts. The overall impact of GCA on patients' lives arose from a changing combination of symptoms, side effects, adaptations to everyday life and impacts on sense of normality. Important factors contributing to loss of normality were glucocorticoid-related treatment burdens and fear about possible future loss of vision. CONCLUSIONS: The impact of GCA in patients' everyday lives can be substantial, multifaceted and ongoing despite apparent control of disease activity. The findings of this study will help doctors better understand patient priorities, legitimise patients' experiences of GCA and work with patients to set realistic treatment goals and plan adaptations to their everyday lives. PMID- 28838903 TI - Prevalence of depression and depressive symptoms among outpatients: a systematic review and meta-analysis. AB - OBJECTIVES: Depression and depressive symptoms are common mental disorders that have a considerable effect on patients' health-related quality of life and satisfaction with medical care, but the prevalence of these conditions varies substantially between published studies. The aim of this study is to conduct a systematic review and meta-analysis to provide a precise estimate of the prevalence of depression or depressive symptoms among outpatients in different clinical specialties. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND ELIGIBILITY CRITERIA: The PubMed and PsycINFO, EMBASE and Cochrane Library databases were searched to identify observational studies that contained information on the prevalence of depression and depressive symptoms in outpatients. All studies included were published before January 2016. Data characteristics were extracted independently by two investigators. The point prevalence of depression or depressive symptoms was measured using validated self report questionnaires or structured interviews. Assessments were pooled using a random-effects model. Differences in study-level characteristics were estimated by meta-regression analysis. Heterogeneity was assessed using standard chi2 tests and the I2 statistic. The study protocol has been registered with PROSPERO under number CRD42017054738. RESULTS: Eighty-three cross-sectional studies involving 41 344 individuals were included in this study. The overall pooled prevalence of depression or depressive symptoms was 27.0% (10 943/41 344 individuals; 95% CI 24.0% to 29.0%), with significant heterogeneity between studies (p<0.0001, tau2=0.3742, I2=96.7%). Notably, a significantly higher prevalence of depression and depressive symptoms was observed in outpatients than in the healthy controls (OR 3.16, 95% CI 2.66 to 3.76, I2=72.0%, chi 2 =25.33). The highest depression/depressive symptom prevalence estimates occurred in studies of outpatients from otolaryngology clinics (53.0%), followed by dermatology clinics (39.0%) and neurology clinics (35.0%). Subgroup analyses showed that the prevalence of depression and depressive symptoms in different specialties varied from 17.0% to 53.0%. The prevalence of depression and depressive symptoms was higher among outpatients in developing countries than in outpatients from developed countries. Moreover, the prevalence of depression and depressive symptoms in outpatients slightly decreased from 1996 to 2010. Regarding screening instruments, the Beck Depression Inventory led to a higher estimate of the prevalence of depression and depressive symptoms (1316/4702, 36.0%, 95% CI 29.0% to 44.0%, I2=94.8%) than the Hospital Anxiety and Depression Scale (1003/2025, 22.0%, 95% CI 12.0% to 35.0%, I2=96.6%). CONCLUSION: Our study provides evidence that a significant proportion of outpatients experience depression or depressive symptoms, highlighting the importance of developing effective management strategies for the early identification and treatment of these conditions among outpatients in clinical practice. The substantial heterogeneity between studies was not fully explained by the variables examined. PMID- 28838904 TI - Managing the transition (ManTra): a resource for persons with secondary progressive multiple sclerosis and their health professionals: protocol for a mixed-methods study in Italy. AB - INTRODUCTION: 15 years after clinical onset, about 50% of patients with relapsing remitting multiple sclerosis convert to secondary progressive multiple sclerosis (SPMS). Notwithstanding the importance of this transition, knowledge of the experiences and needs of patients and carers is fragmentary, and targeted interventions are not available. Managing the Transition to SPMS (ManTra) is a mixed methodology project to develop and test a user-led resource for newly diagnosed patients with SPMS. Here, we describe the developmental phase, consisting of a literature review and a new research study involving key stakeholders, in which we construct the resource. METHODS AND ANALYSIS: Round 1: The literature review and study will be conducted in parallel. The latter will identify patient needs using a qualitative approach consisting of: personal semistructured interviews with >15 recently diagnosed patients with SPMS; three focus group meetings (one with significant others of patients, one with neurologists and one with other health professionals caring for patients with SPMS). An online survey (>200 recently diagnosed Italian patients with SPMS) will follow to verify needs in a larger independent sample. An expert panel will outline a set of candidate resources/interventions that aim to satisfy the needs thus identified. Round 2: Consensus on the final resource will be obtained in a 1 day meeting of recently diagnosed patients with SPMS, significant others, health professionals and other stakeholders, using the nominal group technique. The expert panel will refine the resource, identify the outcome measures to assess its efficacy and ascertain the most suitable comparator (ManTra Phase 2, not part of this protocol). ETHICS AND DISSEMINATION: The study protocol was approved by the ethics committees of each of the involved centres: Foundation IRCCS Neurological Institute C Besta, Milan ; G D'Annunzio University of Chieti-Pescara and the Aldo Moro University of Bari. The results will be published in peer reviewed journals, presented at conferences and a lay summary sent to participants. PMID- 28838905 TI - Exploring the enablers and barriers to implementing the Medication Appropriateness Tool for Comorbid Health conditions during Dementia (MATCH-D) criteria in Australia: a qualitative study. AB - OBJECTIVES: The Medication Appropriateness Tool for Comorbid Health conditions in Dementia (MATCH-D) criteria provide expert consensus guidance about medication use for people with dementia. This study aimed to identify enablers and barriers to implementing the criteria in practice. SETTING: Participants came from both rural and metropolitan communities in two Australian states. PARTICIPANTS: Focus groups were held with consumers, general practitioners, nurses and pharmacists. OUTCOMES: data were analysed thematically. RESULTS: Nine focus groups were conducted. Fifty-five participants validated the content of MATCH-D, appraising them as providing patient-centred principles of care. Participants identified potential applications (including the use of MATCH-D as a discussion aid or educational tool for consumers about medicines) and suggested supporting resources. CONCLUSION: Participants provided insights into applying MATCH-D in practice and suggested resources to be included in an accompanying toolkit. These data provide external validation of MATCH-D and an empiric basis for their translation to practice. Following resource development, we plan to evaluate the feasibility and efficacy of implementation in practice. PMID- 28838906 TI - The Diagnostic Accuracy of Contrast-Enhanced CT of the Neck for the Investigation of Sialolithiasis. AB - BACKGROUND AND PURPOSE: Sialolithiasis is a common benign pathology affecting the salivary glands but it is unclear if contrast-enhanced CT, which is commonly used for investigation of head and neck pathology, can identify calculi as accurately as noncontrast CT. The aim of this study was to assess the diagnostic accuracy of contrast-enhanced CT of the neck in the diagnosis of sialolithiasis compared with noncontrast CT of the neck used as the criterion standard. MATERIALS AND METHODS: This was a retrospective, case-control study of 92 consecutive cases in 90 patients who underwent both noncontrast CT of the neck and contrast-enhanced CT of the neck in 2 tertiary referral centers from January 2011 to December 2015 for investigation of sialolithiasis. Axial 3-mm-section images were assessed by a fellowship-trained diagnostic neuroradiologist and diagnostic neuroradiology fellow in consensus. Blinded assessment of the contrast-enhanced CT of the neck was performed first, followed by noncontrast CT of the neck after a 2-week interval. The presence or absence of a stone and stone location and size were documented. Statistical analysis was undertaken to assess the agreement between CT protocols and calculate the sensitivity and specificity of contrast-enhanced CT of the neck. RESULTS: Fifty calculi were identified on noncontrast CT of the neck in 31 cases; and 48 calculi, in 31 cases on contrast-enhanced CT of the neck. No calculi were identified in the remaining 61 cases. The sensitivity and specificity of contrast-enhanced CT of the neck in the detection of sialolithiasis was 96% (95% CI, 86.3%-99.5%) and 100% (95% CI, 94.1%-100%), respectively. The positive predictive value of contrast-enhanced CT of the neck was 100% (95% CI, 92.6%-100%), and the negative predictive value was 96.8% (95% CI, 89%-99.6%). The accuracy of contrast-enhanced CT of the neck in diagnosing the presence or absence of salivary calculi was 98%. CONCLUSIONS: Contrast enhanced CT of the neck is accurate in the detection of sialolithiasis, with no difference in diagnostic accuracy compared with noncontrast CT of the neck. PMID- 28838907 TI - Torgny Greitz, MD, PhD, FACR, Professor of Neuroradiology, Emeritus. PMID- 28838908 TI - ERRATUM. PMID- 28838909 TI - Volume of Structures in the Fetal Brain Measured with a New Semiautomated Method. AB - BACKGROUND AND PURPOSE: Measuring the volume of fetal brain structures is challenging due to fetal motion, low resolution, and artifacts caused by maternal tissue. Our aim was to introduce a new, simple, Matlab-based semiautomated method to measure the volume of structures in the fetal brain and present normal volumetric curves of the structures measured. MATERIALS AND METHODS: The volume of the supratentorial brain, left and right hemispheres, cerebellum, and left and right eyeballs was measured retrospectively by the new semiautomated method in MR imaging examinations of 94 healthy fetuses. Four volume ratios were calculated. Interobserver agreement was calculated with the intraclass correlation coefficient, and a Bland-Altman plot was drawn for comparison of manual and semiautomated method measurements of the supratentorial brain. RESULTS: We present normal volumetric curves and normal percentile values of the structures measured according to gestational age and of the ratios between the cerebellum and the supratentorial brain volume and the total eyeball and the supratentorial brain volume. Interobserver agreement was good or excellent for all structures measured. The Bland-Altman plot between manual and semiautomated measurements showed a maximal relative difference of 7.84%. CONCLUSIONS: We present a technologically simple, reproducible method that can be applied prospectively and retrospectively on any MR imaging protocol, and we present normal volumetric curves measured. The method shows results like manual measurements while being less time-consuming and user-dependent. By applying this method on different cranial and extracranial structures, anatomic and pathologic, we believe that fetal volumetry can turn from a research tool into a practical clinical one. PMID- 28838910 TI - Assessment of Iron Deposition in the Brain in Frontotemporal Dementia and Its Correlation with Behavioral Traits. AB - BACKGROUND AND PURPOSE: Brain iron deposition has been implicated as a major culprit in the pathophysiology of neurodegeneration. However, the quantitative assessment of iron in behavioral variant frontotemporal dementia and primary progressive aphasia brains has not been performed, to our knowledge. The aim of our study was to investigate the characteristic iron levels in the frontotemporal dementia subtypes using susceptibility-weighted imaging and report its association with behavioral profiles. MATERIALS AND METHODS: This prospective study included 46 patients with frontotemporal dementia (34 with behavioral variant frontotemporal dementia and 12 with primary progressive aphasia) and 34 age-matched healthy controls. We performed behavioral and neuropsychological assessment in all the subjects. The quantitative iron load was determined on SWI in the superior frontal gyrus and temporal pole, precentral gyrus, basal ganglia, anterior cingulate, frontal white matter, head and body of the hippocampus, red nucleus, substantia nigra, insula, and dentate nucleus. A linear regression analysis was performed to correlate iron content and behavioral scores in patients. RESULTS: The iron content of the bilateral superior frontal and temporal gyri, anterior cingulate, putamen, right hemispheric precentral gyrus, insula, hippocampus, and red nucleus was higher in patients with behavioral variant frontotemporal dementia than in controls. Patients with primary progressive aphasia had increased iron levels in the left superior temporal gyrus. In addition, right superior frontal gyrus iron deposition discriminated behavioral variant frontotemporal dementia from primary progressive aphasia. A strong positive association was found between apathy and iron content in the superior frontal gyrus and disinhibition and iron content in the putamen. CONCLUSIONS: Quantitative assessment of iron deposition with SWI may serve as a new biomarker in the diagnostic work-up of frontotemporal dementia and help distinguish frontotemporal dementia subtypes. PMID- 28838911 TI - Anterior Mesencephalic Cap Dysplasia: Novel Brain Stem Malformative Features Associated with Joubert Syndrome. AB - In Joubert syndrome, the "molar tooth" sign can be associated with several additional supra- and infratentorial malformations. Here we report on 3 subjects (2 siblings, 8-14 years of age) with Joubert syndrome, showing an abnormal thick bulging of the anterior profile of the mesencephalon causing a complete obliteration of the interpeduncular fossa. DTI revealed that the abnormal tissue consisted of an ectopic white matter tract with a laterolateral transverse orientation. Tractographic reconstructions support the hypothesis of impaired axonal guidance mechanisms responsible for the malformation. The 2 siblings were compound heterozygous for 2 missense variants in the TMEM67 gene, while no mutations in a panel of 120 ciliary genes were detected in the third patient. The name "anterior mesencephalic cap dysplasia," referring to the peculiar aspect of the mesencephalon on sagittal MR imaging, is proposed for this new malformative feature. PMID- 28838912 TI - Anatomic Location of Tumor Predicts the Accuracy of Motor Function Localization in Diffuse Lower-Grade Gliomas Involving the Hand Knob Area. AB - BACKGROUND AND PURPOSE: The accuracy of preoperative blood oxygen level-dependent fMRI remains controversial. This study assessed the association between the anatomic location of a tumor and the accuracy of fMRI-based motor function mapping in diffuse lower-grade gliomas. MATERIALS AND METHODS: Thirty-five patients with lower-grade gliomas involving motor areas underwent preoperative blood oxygen level-dependent fMRI scans with grasping tasks and received intraoperative direct cortical stimulation. Patients were classified into an overlapping group and a nonoverlapping group, depending on the extent to which blood oxygen level-dependent fMRI and direct cortical stimulation results concurred. Tumor location was quantitatively measured, including the shortest distance from the tumor to the hand knob and the deviation distance of the midpoint of the hand knob in the lesion hemisphere relative to the midline compared with the normal contralateral hemisphere. RESULTS: A 4-mm shortest distance from the tumor to the hand knob value was identified as optimal for differentiating the overlapping and nonoverlapping group with the receiver operating characteristic curve (sensitivity, 84.6%; specificity, 77.8%). The shortest distances from the tumor to the hand knob of <=4 mm were associated with inaccurate fMRI-based localizations of the hand motor cortex. The shortest distances from the tumor to the hand knob were larger (P = .002), and the deviation distances for the midpoint of the hand knob in the lesion hemisphere were smaller (P = .003) in the overlapping group than in the nonoverlapping group. CONCLUSIONS: This study suggests that the shortest distance from the tumor to the hand knob and the deviation distance for the midpoint of the hand knob on the lesion hemisphere are predictive of the accuracy of blood oxygen level dependent fMRI results. Smaller shortest distances from the tumor to the hand knob and larger deviation distances for the midpoint of hand knob on the lesion hemisphere are associated with less accuracy of motor cortex localization with blood oxygen level-dependent fMRI. Preoperative fMRI data for surgical planning should be used cautiously when the shortest distance from the tumor to the hand knob is <=4 mm, especially for lower-grade gliomas anterior to the central sulcus. PMID- 28838914 TI - Reply. PMID- 28838913 TI - Age, Sex, and Racial Differences in Neuroimaging Use in Acute Stroke: A Population-Based Study. AB - BACKGROUND AND PURPOSE: Limited information is available regarding differences in neuroimaging use for acute stroke work-up. Our objective was to assess whether race, sex, or age differences exist in neuroimaging use and whether these differences depend on the care center type in a population-based study. MATERIALS AND METHODS: Patients with stroke (ischemic and hemorrhagic) and transient ischemic attack were identified in a metropolitan, biracial population using the Greater Cincinnati/Northern Kentucky Stroke Study in 2005 and 2010. Multivariable regression was used to determine the odds of advanced imaging use (CT angiography/MR imaging/MR angiography) for race, sex, and age. RESULTS: In 2005 and 2010, there were 3471 and 3431 stroke/TIA events, respectively. If one adjusted for covariates, the odds of advanced imaging were higher for younger (55 years or younger) compared with older patients, blacks compared with whites, and patients presenting to an academic center and those seen by a stroke team or neurologist. The observed association between race and advanced imaging depended on age; in the older age group, blacks had higher odds of advanced imaging compared with whites (odds ratio, 1.34; 95% CI, 1.12-1.61; P < .01), and in the younger group, the association between race and advanced imaging was not statistically significant. Age by race interaction persisted in the academic center subgroup (P < .01), but not in the nonacademic center subgroup (P = .58). No significant association was found between sex and advanced imaging. CONCLUSIONS: Within a large, biracial stroke/TIA population, there is variation in the use of advanced neuroimaging by age and race, depending on the care center type. PMID- 28838916 TI - Association of Epicardial Adipose Tissue and High-Risk Plaque Characteristics: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Epicardial adipose tissue (EAT) is hypothesized to alter atherosclerotic plaque composition, with potential development of high-risk plaque (HRP). EAT can be measured by volumetric assessment (EAT-v) or linear thickness (EAT-t). We performed a systematic review and random-effects meta analysis to assess the association of EAT with HRP and whether this association is dependent on the measurement method used. METHODS AND RESULTS: Electronic databases were systematically searched up to October 2016. Studies reporting HRP by computed tomography or intracoronary imaging and studies measuring EAT-v or EAT-t were included. Odds ratios were extracted from multivariable models reporting the association of EAT with HRP and described as pooled estimates with 95% confidence intervals (CIs). Analysis was stratified by EAT measurement method. Nine studies (n=3772 patients) were included with 7 measuring EAT-v and 2 measuring EAT-t. Increasing EAT was significantly associated with the presence of HRP (odds ratio: 1.26 [95% CI, 1.11-1.43]; P<0.001). Patients with HRP had higher EAT-v than those without (weighted mean difference: 28.3 mL [95% CI, 18.8-37.8 mL]; P<0.001). EAT-v was associated with HRP (odds ratio: 1.19 [95% CI, 1.06 1.33]; P<0.001); however, EAT-t was not (odds ratio: 3.09 [95% CI, 0.56-17]; P=0.2). Estimates remained significant when adjusted for small-study effect bias (odds ratio: 1.13 [95% CI, 1.03-1.28]; P=0.04). CONCLUSIONS: Increasing EAT is associated with the presence of HRP, and patients with HRP have higher quantified EAT-v. The association of EAT-v with HRP is significant compared with EAT-t; however, a larger scale study is still required, and further evaluation is needed to assess whether EAT may be a potential therapeutic target for novel pharmaceutical agents. CLINICAL TRIAL REGISTRATION: URL: https://www.crd.york.ac.uk/. Unique identifier: CRD42017055473. PMID- 28838915 TI - Radial Artery and Ulnar Artery Occlusions Following Coronary Procedures and the Impact of Anticoagulation: ARTEMIS (Radial and Ulnar ARTEry Occlusion Meta AnalysIS) Systematic Review and Meta-Analysis. AB - BACKGROUND: Incidence of radial artery occclusions (RAO) and ulnar artery occclusions (UAO) in coronary procedures, factors predisposing to forearm arteries occlusion, and the benefit of anticoaggulation vary significantly in existing literature. We sought to determine the incidence of RAO/UAO and the impact of anticoagulation intensity. METHODS AND RESULTS: Meta-analysis of 112 studies assessing RAO and/or UAO (N=46 631) were included. Overall, there was no difference between crude RAO and UAO rates (5.2%; 95% confidence interval [CI], 4.4-6.0 versus 4.0%; 95% CI, 2.8-5.8; P=0.171). The early occlusion rate (in hospital or within 7 days after procedure) was higher than the late occlusion rate. The detection rate of occlusion was higher with vascular ultrasonography compared with clinical evaluation only. Low-dose heparin was associated with a significantly higher RAO rate compared with high-dose heparin (7.2%; 95% CI, 5.5 9.4 versus 4.3%; 95% CI, 3.5-5.3; Q=8.81; P=0.003). Early occlusions in low-dose heparin cohorts mounted at 8.0% (95% CI, 6.1-10.6). The RAO rate was higher after diagnostic angiographies compared with coronary interventions, presumably attributed to the higher intensity of anticoagulation in the latter group. Hemostatic techniques (patent versus nonpatent hemostasis), geography (US versus non-US cohorts) and sheath size did not impact on vessel patency. CONCLUSIONS: RAO and UAO occur with similar frequency and in the order of 7% to 8% when evaluated early by vascular ultrasonography following coronary procedures. More intensive anticoagulation is protective. Late recanalization occurs in a substantial minority of patients. PMID- 28838918 TI - Patients are positive about accessing their records. PMID- 28838917 TI - Association Between Smoking and Serum GlycA and High-Sensitivity C-Reactive Protein Levels: The Multi-Ethnic Study of Atherosclerosis (MESA) and Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: Inflammation is suggested to be a central feature of atherosclerosis, particularly among smokers. We studied whether inflammatory biomarkers GlycA and high-sensitivity C-reactive protein are associated with cigarette smoking. METHODS AND RESULTS: A total of 11 509 participants, 6774 from the MESA (Multi Ethnic Study of Atherosclerosis) and 4735 from ELSA-Brasil (The Brazilian Longitudinal Study of Adult Health) were included. We evaluated the cross sectional association between multiple measures of smoking behavior and the inflammatory biomarkers, GlycA and high-sensitivity C-reactive protein, using regression models adjusted for demographic, anthropometric, and clinical characteristics. Participants were 57.7+/-11.1 years old and 46.4% were men. Never, former, and current smokers comprised 51.7%, 34.0%, and 14.3% of the population, respectively. Multivariable-adjusted mean absolute difference in GlycA levels (MUmol/L) with 95% confidence interval (CI) were higher for former (4.1, 95% CI, 1.7-6.6 MUmol/L) and current smokers (19.9, 95% CI, 16.6-23.2 MUmol/L), compared with never smokers. Each 5-unit increase in pack-years of smoking was associated with higher GlycA levels among former (0.7, 95% CI, 0.3 1.1 MUmol/L) and current smokers (1.6, 95% CI, 0.8-2.4 MUmol/L). Among former smokers, each 5-year increase in time since quitting smoking was associated with lower GlycA levels (-1.6, 95% CI, -2.4 to -0.8 MUmol/L) and each 10-unit increase in number of cigarettes/day was associated with higher GlycA among current smokers (2.8, 95% CI, 0.5-5.2 MUmol/L). There were similar significant associations between all measures of smoking behavior, and both log-transformed GlycA and high-sensitivity C-reactive protein. CONCLUSIONS: Acute and chronic exposure to tobacco smoking is associated with inflammation, as quantified by both GlycA and high-sensitivity C-reactive protein. These biomarkers may have utility for the study and regulation of novel and traditional tobacco products. PMID- 28838919 TI - Lipoprotein(a) and Risk of Myocardial Infarction and Death in Chronic Kidney Disease: Findings From the CRIC Study (Chronic Renal Insufficiency Cohort). AB - OBJECTIVE: To investigate the effect of LPA gene variants and renal function on lipoprotein(a) [Lp(a)] levels in people with chronic kidney disease and determine the association between elevated Lp(a) and myocardial infarction and death in this setting. APPROACH AND RESULTS: The CRIC Study (Chronic Renal Insufficiency Cohort) is an ongoing prospective study of 3939 participants with chronic kidney disease. In 3635 CRIC participants with genotype data, carriers of the rs10455872 or rs6930542 variants had a higher median Lp(a) level (mg/dL) compared with noncarriers (73 versus 23; P<0.001 and 56 versus 22; P<0.001, respectively). The 3744 participants (55% male and 41% non-Hispanic White) with available baseline Lp(a) levels were stratified into quartiles of baseline Lp(a) (mg/dL): <9.8, 9.8 to 26.0, 26.1 to 61.3, and >61.3. There were 315 myocardial infarctions and 822 deaths during a median follow-up of 7.5 years. The second quartile had the lowest event rate. After adjusting for potential confounders and using a Cox proportional hazards model, the highest quartile of Lp(a) was associated with increased risk of myocardial infarction (hazard ratio, 1.49; 95% confidence interval, 1.05-2.11), death (hazard ratio, 1.28; 95% confidence interval, 1.05 1.57), and the composite outcome (hazard ratio, 1.29; 95% confidence interval, 1.07-1.56) compared with the second quartile of Lp(a). CONCLUSIONS: Among adults with chronic kidney disease, elevated Lp(a) is independently associated with myocardial infarction and death. Future studies exploring pharmacological Lp(a) reduction in this population are warranted. PMID- 28838920 TI - CRISPR-Cas9 Genome Editing for Treatment of Atherogenic Dyslipidemia. AB - Although human genetics has resulted in the identification of novel lipid-related genes that can be targeted for the prevention of atherosclerotic vascular disease, medications targeting these genes or their protein products have short term effects and require frequent administration during the course of the lifetime for maximal benefit. Genome-editing technologies, such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated 9) have the potential to permanently alter genes in the body and produce long-term and even lifelong protection against atherosclerosis. In this review, we discuss recent advances in genome-editing technologies and early proof-of-concept studies of somatic in vivo genome editing in mice that highlight the potential of genome editing to target disease-related genes in patients, which would establish a novel therapeutic paradigm for atherosclerosis. PMID- 28838922 TI - Hepatic artery aneurysm: an unusual cause of upper gastrointestinal bleed. AB - An 86-year-old woman presented to hospital with melaena. This was her third presentation with the same symptom. There was no obvious source of bleeding on her oesophagogastroduodenoscopy; however, it did show a previously clipped Dieulafoy lesion. CT angiography showed an aneurysm arising from the hepatic artery. Selective coeliac artery angiogram showed aneurysmal dilatation of the distal part of the coeliac trunk and confirmed the presence of the common hepatic artery aneurysm. The aneurysm was coiled by the interventional radiologist. Final angiogram showed good flow through the hepatic artery with obliteration of the inferior patch. The procedure was uncomplicated and the patient was discharged shortly afterwards. PMID- 28838921 TI - Tortuous Microvessels Contribute to Wound Healing via Sprouting Angiogenesis. AB - OBJECTIVE: Wound healing is accompanied by neoangiogenesis, and new vessels are thought to originate primarily from the microcirculation; however, how these vessels form and resolve during wound healing is poorly understood. Here, we investigated properties of the smallest capillaries during wound healing to determine their spatial organization and the kinetics of formation and resolution. APPROACH AND RESULTS: We used intravital imaging and high-resolution microscopy to identify a new type of vessel in wounds, called tortuous microvessels. Longitudinal studies showed that tortuous microvessels increased in frequency after injury, normalized as the wound healed, and were closely associated with the wound site. Tortuous microvessels had aberrant cell shapes, increased permeability, and distinct interactions with circulating microspheres, suggesting altered flow dynamics. Moreover, tortuous microvessels disproportionately contributed to wound angiogenesis by sprouting exuberantly and significantly more frequently than nearby normal capillaries. CONCLUSIONS: A new type of transient wound vessel, tortuous microvessels, sprout dynamically and disproportionately contribute to wound-healing neoangiogenesis, likely as a result of altered properties downstream of flow disturbances. These new findings suggest entry points for therapeutic intervention. PMID- 28838923 TI - Primary renal echinococcosis with gross hydatiduria. AB - Renal echinococcosis is a rare disease. It is usually asymptomatic but may present with pain, lump or in rare cases hydatiduria. Diagnosis is mainly by imaging but serology is usually false negative. We present a patient of renal echinococcosis who presented with passing of grape skin like structures in urine and was diagnosed to be a case of renal echinococcosis on the basis of positive serology, ultrasonographic and CT findings. The patient underwent a nephroureterectomy and was given albendazole preoperatively and postoperatively. PMID- 28838924 TI - Elephantiasis nostras verrucosa secondary to recurrent erysipelas. PMID- 28838925 TI - Case of steroid-responsive encephalopathy from hypoglycaemia. AB - Hypoglycaemic encephalopathy is a feared complication in the management of patients with diabetes mellitus. We report on a 73-year-old woman with type 1 diabetes managed with an insulin pump who presented unresponsive after an inappropriate insulin bolus. The patient had minimal improvement in her neurological status over 8 days. After administration of 1 g intravenous methylprednisolone, she had dramatic neurological improvement including successful extubation and discharge from the intensive care unit. Steroid responsive encephalopathy is increasingly recognised in practice and literature. However, to the best of our knowledge, this is the first case of hypoglycaemic encephalopathy that responded to high-dose steroids. PMID- 28838927 TI - Sedentary lifestyle is putting middle aged health at risk, PHE warns. PMID- 28838926 TI - A Comprehensive Functional Assessment of Carboxylesterase 1 Nonsynonymous Polymorphisms. AB - Carboxylesterase 1 (CES1) is the predominant human hepatic hydrolase responsible for the metabolism of many clinically important medications. CES1 expression and activity vary markedly among individuals; and genetic variation is a major contributing factor to CES1 interindividual variability. In this study, we comprehensively examined the functions of CES1 nonsynonymous single nucleotide polymorphisms (nsSNPs) and haplotypes using transfected cell lines and individual human liver tissues. The 20 candidate variants include CES1 nsSNPs with a minor allele frequency >0.5% in a given population or located in close proximity to the CES1 active site. Five nsSNPs, including L40Ter (rs151291296), G142E (rs121912777), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), were loss-of-function variants for metabolizing the CES1 substrates clopidogrel, enalapril, and sacubitril. In addition, A158V (rs202121317), R199H (rs2307243), E220G (rs200707504), and T290M (rs202001817) decreased CES1 activity to a lesser extent in a substrate-dependent manner. Several nsSNPs, includingL40Ter (rs151291296), G147C (rs146456965), Y170D (rs148947808), and R171C (rs201065375), significantly reduced CES1 protein and/or mRNA expression levels in the transfected cells. Functions of the common nonsynonymous haplotypes D203E-A269S and S75N-D203E-A269S were evaluated using cells stably expressing the haplotypes and a large set of the human liver. Neither CES1 expression nor activity was affected by the two haplotypes. In summary, this study revealed several functional nsSNPs with impaired activity on the metabolism of CES1 substrate drugs. Clinical investigations are warranted to determine whether these nsSNPs can serve as biomarkers for the prediction of therapeutic outcomes of drugs metabolized by CES1. PMID- 28838929 TI - Debating the future of the NHS: Hawking versus Hunt. PMID- 28838930 TI - Electronic palliative care coordination system (EPaCCS): Interoperability is a problem. PMID- 28838931 TI - End-of-life prescribing of aspirin in patients with breast or colorectal cancer. AB - OBJECTIVES: The aim of this study was to evaluate the influence of an approaching cancer death on end-of-life aspirin use, a frequently prescribed medication for cardiovascular disease prevention. METHODS: This study was conducted using linked cancer registry and prescribing data. Breast (n=1151) and colorectal (n=1859) cancer decedents were matched to cancer survivors and the probability of either initiating aspirin, or continuing established aspirin use, was estimated in consecutive periods over the 5 years approaching a cancer-specific death (decedents) or matched index date (survivors). RESULTS: Using the linked data sets, we identified patients who died of their cancer (decedents) between 1 January 2001 and 31 December 2009. In the 5 years prior to death, we compared (1) the probability of initiating aspirin use for the first time, and (2) the probability of continuing aspirin use. In comparison to matched cancer survivors, an approaching cancer death was not associated with a reduction in aspirin initiation by breast or colorectal cancer decedents. However, the probability of continuing established aspirin use declined considerably in the 24 months approaching death and at the time of a death was significantly lower for breast (risk difference (RD) -0.26, 95% CI -0.33 to -0.20) and colorectal (RD -0.38, 95% CI -0.46 to -0.30) cancer decedents versus matched survivors. CONCLUSION: A significant proportion of patients discontinue their aspirin in the time approaching a breast or colorectal cancer-specific death. The safety and benefits of this are unclear and empirical data are needed to guide decisions about aspirin use in the end of life. PMID- 28838932 TI - Consultation for total pain in high-risk obstetrics. AB - Palliative care (PC) consultation rarely takes place in the clinical setting of high-risk obstetrics, where 'total pain' may be undermanaged. Here, we present a case of a young woman carrying twins and hospitalised for acute abdominal pain. Workup for her pain revealed non-viable fetal tissue positioned in the uterine horn; the remaining fetus was viable. Initial attempts to control the patient's pain with strong parenteral opioids by the obstetrics team and the acute pain service failed. The PC service was consulted to assist. Applying a customary interdisciplinary approach in a novel PC clinical setting, the PC service was able to identify and attend to the patient's physical, psychosocial and spiritual pain, resulting in an overall decrease in reported pain scores, decreased opioid requirement and a plan for preservation of the viable fetus. PMID- 28838933 TI - Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure. AB - BACKGROUND: Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls. METHODS: Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls. RESULTS: In the screening stage, we detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy (false discovery corrected P<=0.05), with 3 of them reaching epigenome-wide significance at P<=5*10-8. Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure. CONCLUSIONS: The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach. PMID- 28838934 TI - Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association. AB - For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes. PMID- 28838935 TI - Noise in a phosphorelay drives stochastic entry into sporulation in Bacillus subtilis. AB - Entry into sporulation in Bacillus subtilis is governed by a phosphorelay in which phosphoryl groups from a histidine kinase are successively transferred via relay proteins to the response regulator Spo0A. Spo0A~P, in turn, sets in motion events that lead to asymmetric division and activation of the cell-specific transcription factor sigmaF, a hallmark for entry into sporulation. Here, we have used a microfluidics-based platform to investigate the activation of Spo0A and sigmaF in individual cells held under constant, sporulation-inducing conditions. The principal conclusions were that: (i) activation of sigmaF occurs with an approximately constant probability after adaptation to conditions of nutrient limitation; (ii) activation of sigmaF is tightly correlated with, and preceded by, Spo0A~P reaching a high threshold level; (iii) activation of Spo0A takes place abruptly just prior to asymmetric division; and (iv) the primary source of noise in the activation of Spo0A is the phosphorelay. We propose that cells exhibit a constant probability of attaining a high threshold level of Spo0A~P due to fluctuations in the flux of phosphoryl groups through the phosphorelay. PMID- 28838937 TI - Daratumumab combinations: what can we learn? PMID- 28838936 TI - Redox regulation of plant stem cell fate. AB - Despite the importance of stem cells in plant and animal development, the common mechanisms of stem cell maintenance in both systems have remained elusive. Recently, the importance of hydrogen peroxide (H2O2) signaling in priming stem cell differentiation has been extensively studied in animals. Here, we show that different forms of reactive oxygen species (ROS) have antagonistic roles in plant stem cell regulation, which were established by distinct spatiotemporal patterns of ROS-metabolizing enzymes. The superoxide anion (O2.-) is markedly enriched in stem cells to activate WUSCHEL and maintain stemness, whereas H2O2 is more abundant in the differentiating peripheral zone to promote stem cell differentiation. Moreover, H2O2 negatively regulates O2.- biosynthesis in stem cells, and increasing H2O2 levels or scavenging O2.- leads to the termination of stem cells. Our results provide a mechanistic framework for ROS-mediated control of plant stem cell fate and demonstrate that the balance between O2.- and H2O2 is key to stem cell maintenance and differentiation. PMID- 28838938 TI - NR4A proteins and neutrophil lifespan. PMID- 28838939 TI - Syk TKIs "strengthen" RBCs against malaria. PMID- 28838940 TI - Chromosomally integrated HHV-6: a new piece of the puzzle. PMID- 28838941 TI - Intracellular light chain crystals in myeloma. PMID- 28838943 TI - Zaimoku Y, Takamatsu H, Hosomichi K, et al. Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia. Blood. 2017;129(21):2908-2916. PMID- 28838942 TI - Red cheeks to red cell aplasia: parvovirus B19 in a heart transplant patient. PMID- 28838944 TI - Infographic: Effects of specific injury prevention programmes in football. PMID- 28838945 TI - Medical Care Cost of Oropharyngeal Cancer among Texas Patients. AB - Background: The incidence of oropharyngeal cancer is rising rapidly, with the majority of cases being attributable to human papillomavirus (HPV). Despite the availability of a vaccine, rates of HPV vaccination among Texas youth are low. The healthcare cost of oropharyngeal cancer in Texas is unknown. The aims of this study were to estimate the first 2-year cost of treating new cases of oropharyngeal cancer and determine the predictors of oropharyngeal cancer treatment cost in Texas.Methods: This study included a retrospective cohort of 467 Texas patients with commercial insurance claims data with oropharyngeal cancer diagnosed from 2011 to 2014 and a control group of 467 noncancer patients obtained with propensity score matching. Total healthcare cost during the first 2 years after the index date was measured. A generalized linear model was used to identify predictors of monthly cost during the 2 years after the index date.Results: The mean differential adjusted healthcare cost for oropharyngeal cancer cases was $139,749 in the first 2 years. The mean adjusted monthly cost in the first 2 years was $6,693 for cases and $870 for controls. Age, comorbidity, mental health, prediagnostic healthcare cost, and time index were significant predictors of monthly cost.Conclusions: Medical care cost was about $140,000 in the first 2 years after diagnosis of oropharyngeal cancer among commercially insured patients in Texas.Impact: The cost estimates provide important parameters for development of decision-analytic models to inform decision makers about the potential value of initiatives for increasing the HPV immunization rate in the state. Cancer Epidemiol Biomarkers Prev; 26(9); 1443-9. (c)2017 AACR. PMID- 28838947 TI - Key signaling pathways in thyroid cancer. AB - Whole genome sequencing approaches have provided unprecedented insights into the genetic lesions responsible for the onset, progression and dedifferentiation of various types of thyroid carcinomas. Through these efforts, the MAPK and PI3K signaling cascades have emerged as the main activation pathways implicated in thyroid tumorigenesis. The nature of these essential pathways is highly complex, with hundreds of components, multiple points of crosstalk, different subcellular localizations and with the ability to potentially regulate many cellular processes. Small-molecule inhibitors targeting key kinases of these pathways hold great promise as novel therapeutics and several have reached clinical trials. However, while some remarkable responses have been reported, the development of resistance remains a matter of concern and limits the benefit for patients. In this review, we discuss the latest findings on the major components of the MAPK and PI3K pathways, including their mechanisms of activation in physiological and pathological contexts, their genetic alterations with respect to the different types of thyroid carcinomas and the more relevant drugs designed to block their activity. PMID- 28838948 TI - Pediatric Training Faculty and Resident Perceptions on Teaching High-Value, Cost Conscious Care: A Multi-Institutional Study. AB - BACKGROUND AND OBJECTIVES: High-value, cost-conscious care (HVCCC) is care that promotes optimal patient outcomes while reducing unnecessary costs. Teaching to promote HVCCC is essential, yet little research has assessed the dual perspectives of residents and faculty on this topic. Our aim was to investigate pediatric resident and faculty perspectives of HVCCC training and role modeling to more effectively promote curriculum and faculty development on this subject. METHODS: Pediatric residents and teaching faculty in 2 academic medical centers were surveyed during the 2015-2016 academic year. Questions addressed comfort with HVCCC, current teaching practices, barriers to teaching HVCC, and desired curriculum. Descriptive statistics were used to summarize data, and Fisher's exact or chi2 tests were used to assess for associations between responses. Institutional review board approval was obtained at both participating institutions. RESULTS: We received responses from 51% of faculty (128 of 249) and 60% of residents (73 of 123). Most faculty and residents agreed that HVCCC training is important, but only 26% of residents (18 of 69) felt comfortable practicing HVCCC. Faculty and residents identified lack of training or knowledge (50%, 61 of 121 and 53%, 37 of 70, respectively) and lack of hospital support (73%, 88 of 121 and 69%, 47 of 68, respectively) as the largest barriers. Of residents, >85% (60 of 69) reported a lack of attending physician role modeling. Most faculty (83%, 102 of 123) desired faculty development. CONCLUSIONS: Residents and faculty agree that HVCCC is important and that training institutions have a responsibility to address it. However, most residents were not comfortable with HVCCC. Faculty development in HVCCC as well as hospital support for access to pricing data will be key for programs to develop effective resident training in this area. PMID- 28838946 TI - Histone locus regulation by the Drosophila dosage compensation adaptor protein CLAMP. AB - The conserved histone locus body (HLB) assembles prior to zygotic gene activation early during development and concentrates factors into a nuclear domain of coordinated histone gene regulation. Although HLBs form specifically at replication-dependent histone loci, the cis and trans factors that target HLB components to histone genes remained unknown. Here we report that conserved GA repeat cis elements within the bidirectional histone3-histone4 promoter direct HLB formation in Drosophila In addition, the CLAMP (chromatin-linked adaptor for male-specific lethal [MSL] proteins) zinc finger protein binds these GA repeat motifs, increases chromatin accessibility, enhances histone gene transcription, and promotes HLB formation. We demonstrated previously that CLAMP also promotes the formation of another domain of coordinated gene regulation: the dosage compensated male X chromosome. Therefore, CLAMP binding to GA repeat motifs promotes the formation of two distinct domains of coordinated gene activation located at different places in the genome. PMID- 28838949 TI - Structural insights into the substrate specificity of a glycoside hydrolase family 5 lichenase from Caldicellulosiruptor sp. F32. AB - Glycoside hydrolase (GH) family 5 is one of the largest GH families with various GH activities including lichenase, but the structural basis of the GH5 lichenase activity is still unknown. A novel thermostable lichenase F32EG5 belonging to GH5 was identified from an extremely thermophilic bacterium Caldicellulosiruptor sp. F32. F32EG5 is a bi-functional cellulose and a lichenan-degrading enzyme, and exhibited a high activity on beta-1,3-1,4-glucan but side activity on cellulose. Thin-layer chromatography and NMR analyses indicated that F32EG5 cleaved the beta 1,4 linkage or the beta-1,3 linkage while a 4-O-substitued glucose residue linked to a glucose residue through a beta-1,3 linkage, which is completely different from extensively studied GH16 lichenase that catalyses strict endo-hydrolysis of the beta-1,4-glycosidic linkage adjacent to a 3-O-substitued glucose residue in the mixed-linked beta-glucans. The crystal structure of F32EG5 was determined to 2.8 A resolution, and the crystal structure of the complex of F32EG5 E193Q mutant and cellotetraose was determined to 1.7 A resolution, which revealed that the exit subsites of substrate-binding sites contribute to both thermostability and substrate specificity of F32EG5. The sugar chain showed a sharp bend in the complex structure, suggesting that a substrate cleft fitting to the bent sugar chains in lichenan is a common feature of GH5 lichenases. The mechanism of thermostability and substrate selectivity of F32EG5 was further demonstrated by molecular dynamics simulation and site-directed mutagenesis. These results provide biochemical and structural insights into thermostability and substrate selectivity of GH5 lichenases, which have potential in industrial processes. PMID- 28838950 TI - Medicaid Managed Care Structures and Care Coordination. AB - BACKGROUND: Child enrollment in Medicaid managed care (MMC) has expanded dramatically, primarily through state mandates. Care coordination is a key metric in MMC evaluation because it drives much of the proposed cost savings and may be associated with improved health outcomes and utilization. We evaluated the relationships between enrollment in 2 MMC structures, primary care case management (PCCM) and health maintenance organization (HMO) and access to and receipt of care coordination by children. METHODS: Using data from the 2011/2012 National Survey of Children's Health and the Medicaid Statistical Information System state data mart, we conducted a retrospective, cross-sectional analysis of the relationships between fee-for-service, PCCM or HMO enrollment, and access to and receipt of care coordination. State-level univariate analyses and individual and state multilevel multivariable analyses evaluated correlations between MMC enrollment and care coordination, controlling for demographic characteristics and state financing levels. RESULTS: In univariate and multilevel multivariable analyses, the PCCM penetration rate was significantly associated with increased access to care coordination (adjusted odds ratio: 1.23, P = .034) and receipt of care coordination (adjusted odds ratio: 1.37, P = .02). The HMO penetration rate was significantly associated with lower access to care coordination (adjusted odds ratio: 0.85, P = .05) and receipt of care coordination (adjusted odds ratio: 0.71, P < .001). Fee-for-service served as the referent. CONCLUSIONS: State utilization of MMC varied widely. These data suggest that care coordination may be more effective in PCCM than HMO structures. States should consider care coordination outcomes when structuring their Medicaid programs. PMID- 28838951 TI - Incentivizing Care Coordination in Managed Care. PMID- 28838953 TI - Bioenergetics of Monoterpenoid Essential Oil Biosynthesis in Nonphotosynthetic Glandular Trichomes. AB - The commercially important essential oils of peppermint (Mentha * piperita) and its relatives in the mint family (Lamiaceae) are accumulated in specialized anatomical structures called glandular trichomes (GTs). A genome-scale stoichiometric model of secretory phase metabolism in peppermint GTs was constructed based on current biochemical and physiological knowledge. Fluxes through the network were predicted based on metabolomic and transcriptomic data. Using simulated reaction deletions, this model predicted that two processes, the regeneration of ATP and ferredoxin (in its reduced form), exert substantial control over flux toward monoterpenes. Follow-up biochemical assays with isolated GTs indicated that oxidative phosphorylation and ethanolic fermentation were active and that cooperation to provide ATP depended on the concentration of the carbon source. We also report that GTs with high flux toward monoterpenes express, at very high levels, genes coding for a unique pair of ferredoxin and ferredoxin-NADP+ reductase isoforms. This study provides, to our knowledge, the first evidence of how bioenergetic processes determine flux through monoterpene biosynthesis in GTs. PMID- 28838952 TI - CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors. AB - Effective targeting of cancer stem cells (CSCs) requires neutralization of self renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non-CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors. PMID- 28838954 TI - The Genetic Basis of Plant Architecture in 10 Maize Recombinant Inbred Line Populations. AB - Plant architecture is a key factor affecting planting density and grain yield in maize (Zea mays). However, the genetic mechanisms underlying plant architecture in diverse genetic backgrounds have not been fully addressed. Here, we performed a large-scale phenotyping of 10 plant architecture-related traits and dissected the genetic loci controlling these traits in 10 recombinant inbred line populations derived from 14 diverse genetic backgrounds. Nearly 800 quantitative trait loci (QTLs) with major and minor effects were identified as contributing to the phenotypic variation of plant architecture-related traits. Ninety-two percent of these QTLs were detected in only one population, confirming the diverse genetic backgrounds of the mapping populations and the prevalence of rare alleles in maize. The numbers and effects of QTLs are positively associated with the phenotypic variation in the population, which, in turn, correlates positively with parental phenotypic and genetic variations. A large proportion (38.5%) of QTLs was associated with at least two traits, suggestive of the frequent occurrence of pleiotropic loci or closely linked loci. Key developmental genes, which previously were shown to affect plant architecture in mutant studies, were found to colocalize with many QTLs. Five QTLs were further validated using the segregating populations developed from residual heterozygous lines present in the recombinant inbred line populations. Additionally, one new plant height QTL, qPH3, has been fine-mapped to a 600-kb genomic region where three candidate genes are located. These results provide insights into the genetic mechanisms controlling plant architecture and will benefit the selection of ideal plant architecture in maize breeding. PMID- 28838955 TI - Bosutinib versus Placebo for Autosomal Dominant Polycystic Kidney Disease. AB - Overactivation of Src has been linked to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). This phase 2, multisite study assessed the efficacy and safety of bosutinib, an oral dual Src/Bcr-Abl tyrosine kinase inhibitor, in patients with ADPKD. Patients with ADPKD, eGFR>=60 ml/min per 1.73 m2, and total kidney volume >=750 ml were randomized 1:1:1 to bosutinib 200 mg/d, bosutinib 400 mg/d, or placebo for <=24 months. The primary endpoint was annualized rate of kidney enlargement in patients treated for >=2 weeks who had at least one postbaseline magnetic resonance imaging scan that was preceded by a 30-day washout (modified intent-to-treat population). Of 172 enrolled patients, 169 received at least one study dose. Per protocol amendment, doses for 24 patients who initially received bosutinib at 400 mg/d were later reduced to 200 mg/d. The annual rate of kidney enlargement was reduced by 66% for bosutinib 200 mg/d versus placebo (1.63% versus 4.74%, respectively; P=0.01) and by 82% for pooled bosutinib versus placebo (0.84% versus 4.74%, respectively; P<0.001). Over the treatment period, patients receiving placebo or bosutinib had similar annualized eGFR decline. Gastrointestinal and liver-related adverse events were the most frequent toxicities. In conclusion, compared with placebo, bosutinib at 200 mg/d reduced kidney growth in patients with ADPKD. The overall gastrointestinal and liver toxicity profile was consistent with the profile in prior studies of bosutinib; no new toxicities were identified. (ClinicalTrials.gov: NCT01233869). PMID- 28838956 TI - Adenylyl Cyclase 1 Is Required for Ethanol-Induced Locomotor Sensitization and Associated Increases in NMDA Receptor Phosphorylation and Function in the Dorsal Medial Striatum. AB - Neuroadaptive responses to chronic ethanol, such as behavioral sensitization, are associated with N-methyl-D-aspartate receptor (NMDAR) recruitment. Ethanol enhances GluN2B-containing NMDAR function and phosphorylation (Tyr-1472) of the GluN2B-NMDAR subunit in the dorsal medial striatum (DMS) through a protein kinase A (PKA)-dependent pathway. Ethanol-induced phosphorylation of PKA substrates is partially mediated by calcium-stimulated adenylyl cyclase 1 (AC1), which is enriched in the dorsal striatum. As such, AC1 is poised as an upstream modulator of ethanol-induced DMS neuroadaptations that promote drug responding, and thus represents a therapeutic target. Our hypothesis is that loss of AC1 activity will prevent ethanol-induced locomotor sensitization and associated DMS GluN2B-NMDAR adaptations. We evaluated AC1's contribution to ethanol-evoked locomotor responses and DMS GluN2B-NMDAR phosphorylation and function using AC1 knockout (AC1KO) mice. Results were mechanistically validated with the AC1 inhibitor, NB001. Acute ethanol (2.0 g/kg) locomotor responses in AC1KO and wild-type (WT) mice pretreated with NB001 (10 mg/kg) were comparable to WT ethanol controls. However, repeated ethanol treatment (10 days, 2.5 g/kg) failed to produce sensitization in AC1KO or NB001 pretreated mice, as observed in WT ethanol controls, following challenge exposure (2.0 g/kg). Repeated exposure to ethanol in the sensitization procedure significantly increased pTyr-1472 GluN2B levels and GluN2B-containing NMDAR transmission in the DMS of WT mice. Loss of AC1 signaling impaired ethanol-induced increases in DMS pGluN2B levels and NMDAR mediated transmission. Together, these data support a critical and specific role for AC1 in striatal signaling that mediates ethanol-induced behavioral sensitization, and identify GluN2B-containing NMDARs as an important AC1 target. PMID- 28838959 TI - The professor and the politician. PMID- 28838957 TI - Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation. AB - The vascular endothelium is critical for induction of appropriate lineage differentiation in organogenesis. In this study, we report that dysfunctional pulmonary endothelium, resulting from the loss of matrix Gla protein (MGP), causes ectopic hepatic differentiation in the pulmonary epithelium. We demonstrate uncontrolled induction of the hepatic growth factor (HGF) caused by dysregulated cross talk between pulmonary endothelium and epithelium in Mgp-null lungs. Elevated HGF induced hepatocyte nuclear factor 4 alpha (Hnf4a), which competed with NK2 homeobox 1 (Nkx2.1) for binding to forkhead box A2 (Foxa2) to drive hepatic differentiation in Mgp-null airway progenitor cells. Limiting endothelial HGF reduced Hnf4a, abolished interference of Hnf4a with Foxa2, and reduced hepatic differentiation in Mgp-null lungs. Together, our results suggest that endothelial-epithelial interactions, maintained by MGP, are essential in pulmonary cell differentiation. PMID- 28838958 TI - Evidence for ESCRT- and clathrin-dependent microautophagy. AB - Microautophagy refers to a mode of autophagy in which the lysosomal or vacuolar membrane invaginates and directly engulfs target components. The molecular machinery of membrane dynamics driving microautophagy is still elusive. Using immunochemical monitoring of yeast vacuolar transmembrane proteins, Vph1 and Pho8, fused to fluorescent proteins, we obtained evidence showing an induction of microautophagy after a diauxic shift in the yeast Saccharomyces cerevisiae Components of the endosomal sorting complex required for transport machinery were found to be required for this process, and the gateway protein of the machinery, Vps27, was observed to change its localization onto the vacuolar membrane after a diauxic shift. We revealed the functional importance of Vps27's interaction with clathrin in this microautophagy that also contributed to uptake of lipid droplets into the vacuole. This study sheds light on the molecular mechanism of microautophagy, which does not require the core Atg proteins. PMID- 28838960 TI - Regional Dysfunction After Myocardial Infarction in Rats. AB - BACKGROUND: Detailed understanding of regional function after myocardial infarction (MI) is currently incomplete. We aimed at investigating regional myocardial strain and work in post-MI rats with and without heart failure. METHODS AND RESULTS: Six weeks after induction of MI, 62 male Wistar-Hannover rats with a range of infarct sizes, plus 14 sham-operated rats, were examined by cine and phase-contrast magnetic resonance imaging. After magnetic resonance imaging, the rats were catheterized, and left ventricular pressures were recorded. Regional strain and work were calculated from the magnetic resonance imaging and pressure data. On the basis of end-diastolic left ventricular pressure, 34 MI rats were classified as nonfailing (MINF) and 28 MI rats as failing (MICHF). In the region remote to the infarct, the MINF rats exhibited preserved strain and increased work compared with sham, whereas MICHF had reduced longitudinal strain and no increase in work in this region. In the noninfarcted region adjacent to the infarct, MICHF demonstrated substantially reduced work because of high levels of negative work. CONCLUSIONS: We have demonstrated a distinct difference in regional work between nonfailing and failing hearts after MI and offer novel insight into the relation between regional function and presence of congestion. Work analysis provided significant added value over strain analysis alone. PMID- 28838962 TI - Cardiac Imaging in Patients With Heart Failure and Preserved Ejection Fraction. PMID- 28838963 TI - Regional Myocardial Contractility: The Elusive Phantom of Cardiology. PMID- 28838961 TI - Cardiovascular Magnetic Resonance to Predict Appropriate Implantable Cardioverter Defibrillator Therapy in Ischemic and Nonischemic Cardiomyopathy Patients Using Late Gadolinium Enhancement Border Zone: Comparison of Four Analysis Methods. AB - BACKGROUND: Late gadolinium enhancement (LGE) border zone on cardiac magnetic resonance imaging has been proposed as an independent predictor of ventricular arrhythmias. The purpose was to determine whether size and heterogeneity of LGE predict appropriate implantable cardioverter defibrillator (ICD) therapy in ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM) patients and to evaluate 4 LGE border-zone algorithms. METHODS AND RESULTS: ICM and NICM patients who underwent LGE cardiac magnetic resonance imaging prior to ICD implantation were retrospectively included. Two semiautomatic algorithms, expectation maximization, weighted intensity, a priori information and a weighted border zone algorithm, were compared with a modified full-width half-maximum and a 2-3SD threshold-based algorithm (2-3SD). Hazard ratios were calculated per 1% increase in LGE. A total of 74 ICM and 34 NICM were followed for 63 months (1 140) and 52 months (0-133), respectively. ICM patients had 27 appropriate ICD events, and NICM patients had 7 ICD events. In ICM patients with primary prophylactic ICD, LGE border zone predicted ICD therapy in univariable and multivariable analysis measured by the expectation maximization, weighted intensity, a priori information, weighted border zone, and modified full-width half-maximum algorithms (hazard ratios 1.23, 1.22, and 1.05, respectively; P<0.05; negative predictive value 92%). For NICM, total LGE by all 4 methods was the strongest predictor (hazard ratios, 1.03-1.04; P<0.05), though the number of events was small. CONCLUSIONS: Appropriate ICD therapy can be predicted in ICM patients with primary prevention ICD by quantifying the LGE border zone. In NICM patients, total LGE but not LGE border zone had predictive value for ICD therapy. However, the algorithms used affects the predictive value of these measures. PMID- 28838964 TI - Unraveling the Scar With Cardiac Magnetic Resonance. PMID- 28838965 TI - Blocking autophagy enhances the pro-apoptotic effect of bufalin on human gastric cancer cells through endoplasmic reticulum stress. AB - Bufalin has been used to treat cancer for several years. However, the molecular mechanisms for its anti-tumor function are not fully understood. This work aimed to investigate the effect of bufalin on the proliferation and apoptosis of human gastric cancer (HGC) cells and the roles of endoplasmic reticulum (ER) stress and autophagy in bufalin-induced apoptosis. HGC cell lines, SGC7901 and BGC823, were treated with different concentrations of bufalin or 80 nmol/l bufalin for 1, 2, 3 and 4 days. Cell counting kit-8 (CCK-8) assay and direct cell counting method were used to detect proliferation. Cell cycle arrest and apoptosis was detected using flow cytometry. Protein levels of caspase-3, -8, Bax/Bcl-2, Beclin-1, LC3, inositol-requiring enzyme 1 (IRE1) and C/EBP homologous protein (CHOP) were determined using western blotting. Autophagy was blocked using 3-methyladenine (3MA) or Atg5 siRNA to evaluate the effect of autophagy on bufalin-induced apoptosis. The IRE1 and CHOP were knocked down using specific siRNA to determine the pathway involved in bufalin-induced autophagy. It was found that bufalin significantly suppressed proliferation of SGC7901 and BGC823 cells and induced apoptosis in a time- and dose-dependent manner. The mechanism responsible for bufalin-induced apoptosis was the formation of ER stress via the IRE1-JNK pathway. Moreover, autophagy was activated during ER stress, and blocking autophagy significantly exacerbated bufalin-induced apoptosis. PMID- 28838966 TI - Chlamydomonas IFT25 is dispensable for flagellar assembly but required to export the BBSome from flagella. AB - Intraflagellar transport (IFT) particles are composed of polyprotein complexes IFT-A and IFT-B as well as cargo adaptors such as the BBSome. Two IFT-B subunits, IFT25 and IFT27 were found to form a heterodimer, which is essential in exporting the BBSome out of the cilium but not involved in flagellar assembly and cytokinesis in vertebrates. Controversial results were, however, recorded to show that defects in IFT, flagellar assembly and even cytokinesis were caused by IFT27 knockdown in Chlamydomonas reinhardtii Using C. reinhardtii as a model organism, we report that depletion of IFT25 has no effect on flagellar assembly and does not affect the entry of the BBSome into the flagellum, but IFT25 depletion did impair BBSome movement out of the flagellum, clarifying the evolutionally conserved role of IFT25 in regulating the exit of the BBSome from the flagellum cross species. Interestingly, depletion of IFT25 causes dramatic reduction of IFT27 as expected, which does not cause defects in flagellar assembly and cytokinesis in C. reinhardtii Our data thus support that Chlamydomonas IFT27, like its vertebrate homologues, is not involved in flagellar assembly and cytokinesis. PMID- 28838967 TI - Molecular regulation of high muscle mass in developing Blonde d'Aquitaine cattle foetuses. AB - The Blonde d'Aquitaine (BA) is a French cattle breed with enhanced muscularity, partly attributable to a MSTN mutation. The BA m. Semitendinosus has a faster muscle fibre isoform phenotype comprising a higher proportion of fast type IIX fibres compared to age-matched Charolais (CH). To better understand the molecular network of modifications in BA compared to CH muscle, we assayed the transcriptomes of the m. Semitendinosus at 110, 180, 210 and 260 days postconception (dpc). We used a combination of differential expression (DE) and regulatory impact factors (RIF) to compare and contrast muscle gene expression between the breeds. Prominently developmentally regulated genes in both breeds reflected the replacement of embryonic myosin isoforms (MYL4, MYH3) with adult isoforms (MYH1) and the upregulation of mitochondrial metabolism (CKMT2, AGXT2L1) in preparation for birth. However, the transition to a fast, glycolytic muscle phenotype in the MSTN mutant BA is detectable through downregulation of various slow twitch subunits (TNNC1, MYH7, TPM3, CSRP3) beyond 210 dpc, and a small but consistent genome-wide reduction in mRNA encoding the mitoproteome. Across the breeds, NRIP2 is the regulatory gene possessing a network change most similar to that of MSTN. PMID- 28838968 TI - Tbx1 and Jag1 act in concert to modulate the fate of neurosensory cells of the mouse otic vesicle. AB - The domain within the otic vesicle (OV) known as the neurosensory domain (NSD), contains cells that will give rise to the hair and support cells of the otic sensory organs, as well as the neurons that form the cochleovestibular ganglion (CVG). The molecular dynamics that occur at the NSD boundary relative to adjacent OV cells is not well defined. The Tbx1 transcription factor gene expression pattern is complementary to the NSD, and inactivation results in expansion of the NSD and expression of the Notch ligand, Jag1 mapping, in part of the NSD. To shed light on the role of Jag1 in NSD development, as well as to test whether Tbx1 and Jag1 might genetically interact to regulate this process, we inactivated Jag1 within the Tbx1 expression domain using a knock-in Tbx1Cre allele. We observed an enlarged neurogenic domain marked by a synergistic increase in expression of NeuroD and other proneural transcription factor genes in double Tbx1 and Jag1 conditional loss-of-function embryos. We noted that neuroblasts preferentially expanded across the medial-lateral axis and that an increase in cell proliferation could not account for this expansion, suggesting that there was a change in cell fate. We also found that inactivation of Jag1 with Tbx1Cre resulted in failed development of the cristae and semicircular canals, as well as notably fewer hair cells in the ventral epithelium of the inner ear rudiment when inactivated on a Tbx1 null background, compared to Tbx1Cre/- mutant embryos. We propose that loss of expression of Tbx1 and Jag1 within the Tbx1 expression domain tips the balance of cell fates in the NSD, resulting in an overproduction of neuroblasts at the expense of non-neural cells within the OV. PMID- 28838969 TI - Acquired heart disease in low-income and middle-income countries. AB - The burden of illness associated with acquired cardiac disease in children in low income and middle-income countries (LMIC) is significant and may be equivalent to that of congenital heart disease. Rheumatic heart disease, endomyocardial fibrosis, cardiomyopathy (including HIV cardiomyopathy) and tuberculosis are the most important causes. All are associated with poverty with the neediest children having the least access to care. The associated mortality and morbidity is high. There is an urgent need to improve cardiac care in LMIC, particularly in sub Saharan Africa and parts of Southeast Asia where the burden is highest. PMID- 28838970 TI - Out-of-hospital sudden cardiac arrest in children with congenital heart defects. AB - AIMS: Out-of-hospital sudden cardiac arrest (SCA) is a rare but devastating event in children and adolescents. The risk is assumed to be higher in children with congenital heart defects (CHDs) than in healthy individuals. The aim of the present study was to investigate the rate of and survival after out-of-hospital cardiac arrest in children 2-18 years old with CHDs. METHODS AND RESULTS: Data concerning all live births in Norway between 1994 and 2009 were retrieved from the Medical Birth Registry of Norway, the patient administrative systems at all hospitals in Norway, the Oslo University Hospital's Clinical Registry for Congenital Heart Defects and the Norwegian Cause of Death Registry. Survivors were followed through 2012, and supplementary information for the deceased children was retrieved from medical records at Norwegian hospitals. Among the 943 871 live births in Norway from 1994 to 2009, 11 272 (1.2%) children had a CHD. We identified 11 (0.1%) children 2-18 years old with CHDs who experienced out-of hospital SCA. The estimated rate of out-of-hospital SCA in children 2-18 years old with CHD was 10 per 100 000 person-years. Early cardiopulmonary resuscitation was initiated in all patients. Three children survived. CONCLUSIONS: The incidence of and survival after out-of-hospital SCA in children with CHDs were comparable to the reported rates in the general child population. PMID- 28838972 TI - Acute pancreatitis: recent advances through randomised trials. AB - Acute pancreatitis is one of the most common GI conditions requiring acute hospitalisation and has a rising incidence. In recent years, important insights on the management of acute pancreatitis have been obtained through numerous randomised controlled trials. Based on this evidence, the treatment of acute pancreatitis has gradually developed towards a tailored, multidisciplinary effort, with distinctive roles for gastroenterologists, radiologists and surgeons. This review summarises how to diagnose, classify and manage patients with acute pancreatitis, emphasising the evidence obtained through randomised controlled trials. PMID- 28838973 TI - Can the performance of a quantitative FIT-based colorectal cancer screening programme be enhanced by lowering the threshold and increasing the interval? PMID- 28838971 TI - A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes. AB - Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ~20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction. PMID- 28838975 TI - ERS statement on protracted bacterial bronchitis in children. AB - This European Respiratory Society statement provides a comprehensive overview on protracted bacterial bronchitis (PBB) in children. A task force of experts, consisting of clinicians from Europe and Australia who manage children with PBB determined the overall scope of this statement through consensus. Systematic reviews addressing key questions were undertaken, diagrams in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement constructed and findings of relevant studies summarised. The final content of this statement was agreed upon by all members.The current knowledge regarding PBB is presented, including the definition, microbiology data, known pathobiology, bronchoalveolar lavage findings and treatment strategies to manage these children. Evidence for the definition of PBB was sought specifically and presented. In addition, the task force identified several major clinical areas in PBB requiring further research, including collecting more prospective data to better identify the disease burden within the community, determining its natural history, a better understanding of the underlying disease mechanisms and how to optimise its treatment, with a particular requirement for randomised controlled trials to be conducted in primary care. PMID- 28838978 TI - Changes in magnetic resonance imaging scores and ventilation inhomogeneity in children with cystic fibrosis pulmonary exacerbations. PMID- 28838976 TI - Clinical and biological characteristics of the French COBRA cohort of adult subjects with asthma. AB - The COhort of BRonchial obstruction and Asthma (COBRA) is a longitudinal cohort that involves 12 French academic institutions. DNA, serum samples and clinical data are collected at entry and every 6 months thereafter.Of 1080 patients with asthma recruited between 2007 and 2015, 401 had mild/moderate and 613 had severe asthma. In cross-sectional analyses, compared with patients with milder disease, patients with severe asthma had more symptoms, exacerbations, hospitalisations and visits to the emergency department during the preceding 12 months, higher numbers of blood eosinophils, and more comorbidities. More than 60% of patients with severe asthma were therapy-uncontrolled at entry, and 152 of them were being treated with omalizumab. In addition, patients with asthma who had the highest eosinophilia levels (>300/mm3) had shorter asthma duration, lower lung function, and higher rates of severe exacerbations and unacceptable asthma control than patients with lower eosinophil counts.Longitudinal analyses performed in 427 patients with asthma with at least three differential blood cell counts demonstrated that both eosinophil numbers and eosinophil increase over time were associated with the number of exacerbations occurring until the next visit and with Juniper score.Studies with the COBRA cohort will help to improve knowledge concerning the risk and biological factors associated with asthma severity and to better understand their influence on the disease trajectory. PMID- 28838977 TI - Risk of tuberculosis in patients with solid cancers and haematological malignancies: a systematic review and meta-analysis. AB - There is uncertainty regarding whether patients with cancer should be screened for latent tuberculosis infection (LTBI). We performed a systematic review and meta-analysis to estimate the relative incidence of tuberculosis (TB) in cancer.We searched MEDLINE and Embase for studies published before December 21, 2016. We included studies that evaluated the incidence of TB in patients with solid cancers and haematological malignancies relative to a reference group (study control or general population). A pooled estimate of the incidence rate ratio (IRR) was obtained using standard meta-analysis methods.The search strategy identified 13 unique studies including 921 464 patients with cancer. The IRR of TB for adult patients with cancer was 2.61 (95% CI 2.12-3.22; I2=91%). In haematological cancers, the IRR was 3.53 (95% CI 1.63-7.64; I2=96%); and in solid cancers in adults, it was 2.25 (95% CI 1.96-2.58; I2=91%). The highest IRR was found in children with haematological malignancies or solid cancers (IRR 16.82, 95% CI 8.81-32.12; I2=79%).Considering the limited duration of maximum immunosuppression in cancer and reduced cumulative lifetime risk of TB because of reduced life expectancy, children, but not adults, appear to be at a sufficient level of risk to warrant systematic screening for LTBI. PMID- 28838979 TI - Treatment of limited disease small cell lung cancer: the multidisciplinary team. AB - Small cell lung cancer (SCLC) presents multiple interdisciplinary challenges with several paradigm shifts in its treatment in recent years. SCLC treatment requires multidisciplinary management and timely treatment. The aim of this review is to focus on the team management aspects in the treatment of limited disease SCLC and how this can contribute towards improving outcomes. PMID- 28838980 TI - Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids. AB - Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d) or twice-daily (2, 25, 75 or 150 mg b.i.d) fevipiprant (n=782), montelukast 10 mg q.d (n=139) or placebo (n=137). All patients received inhaled budesonide 200 MUg b.i.dFevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d and 75 mg b.i.d groups, with no clinically meaningful differences between q.d and b.i.d Montelukast also demonstrated a significant improvement in this end point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments.Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted. PMID- 28838981 TI - How prostacyclin therapy improves right ventricular function in pulmonary arterial hypertension. PMID- 28838982 TI - Tuberculosis contact investigation in an intermediate burden setting: implications from a large tuberculosis contact cohort in Taiwan. PMID- 28838983 TI - DLCO: adjust for lung volume, standardised reporting and interpretation. PMID- 28838984 TI - DLCO: adjust for lung volume, standardised reporting and interpretation. PMID- 28838985 TI - Targeting palmitoyl acyltransferase ZDHHC21 improves gut epithelial barrier dysfunction resulting from burn-induced systemic inflammation. AB - Clinical studies in burn patients demonstrate a close association between leaky guts and increased incidence or severity of sepsis and other complications. Severe thermal injury triggers intestinal inflammation that contributes to intestinal epithelial hyperpermeability, which exacerbates systemic response leading to multiple organ failure and sepsis. In this study, we identified a significant function of a particular palmitoyl acyltransferase, zinc finger DHHC domain-containing protein-21 (ZDHHC21), in mediating signaling events required for gut hyperpermeability induced by inflammation. Using quantitative PCR, we show that ZDHHC21 mRNA production was enhanced twofold when intestinal epithelial cells were treated with TNF-alpha-IFN-gamma in vitro. In addition, pharmacological targeting of palmitoyl acyltransferases with 2-bromopalmitate (2 BP) showed significant improvement in TNF-alpha-IFN-gamma-mediated epithelial barrier dysfunction by using electric cell-substrate impedance-sensing assays, as well as FITC-labeled dextran permeability assays. Using acyl-biotin exchange assay and click chemistry, we show that TNF-alpha-IFN-gamma treatment of intestinal epithelial cells results in enhanced detection of total palmitoylated proteins and this response is inhibited by 2-BP. Using ZDHHC21-deficient mice or wild-type mice treated with 2-BP, we showed that mice with impaired ZDHHC21 expression or pharmacological inhibition resulted in attenuated intestinal barrier dysfunction caused by thermal injury. Moreover, hematoxylin and eosin staining of the small intestine, as well as transmission electron microscopy, showed that mice with genetic interruption of ZDHHC21 had attenuated villus structure disorganization associated with thermal injury-induced intestinal barrier damage. Taken together, these results suggest an important role of ZDHHC21 in mediating gut hyperpermeability resulting from thermal injury.NEW & NOTEWORTHY Increased mucosal permeability in the gut is one of the major complications following severe burn. Here we report the novel finding that zinc finger DHHC domain-containing protein-21 (ZDHHC21) mediates gut epithelial hyperpermeability resulting from an experimental model of thermal injury. The hyperpermeability response was significantly attenuated with a pharmacological inhibitor of palmitoyl acyltransferases and in mice with genetic ablation of ZDHHC21. These findings suggest that ZDHHC21 may serve as a novel therapeutic target for treating burn-induced intestinal barrier dysfunction. PMID- 28838986 TI - Ammonia modifies enteric neuromuscular transmission through glial gamma aminobutyric acid signaling. AB - Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated specific mechanisms using novel mutant mice, selective drugs, cellular imaging, and enzyme-linked immunosorbent assays. Exogenous ammonia increased neurogenic contractions and decreased neurogenic relaxations in segments of mouse, pig, and human intestine. Enteric glial cells responded to ammonia with intracellular Ca2+ responses. Inhibition of glutamine synthetase and the deletion of glial connexin-43 channels in hGFAP::CreERT2+/-/connexin43f/f mice potentiated the effects of ammonia on neuromuscular transmission. The effects of ammonia on neuromuscular transmission were blocked by GABAA receptor antagonists, and ammonia drove substantive GABA release as did the selective pharmacological activation of enteric glia in GFAP::hM3Dq transgenic mice. We propose a novel mechanism whereby local ammonia is operational through GABAergic glial signaling to influence enteric neuromuscular circuits that regulate intestinal motility. Therapeutic manipulation of these mechanisms may benefit a number of neurological, hepatic, and renal disorders manifesting hyperammonemia.NEW & NOTEWORTHY We propose that local circuits in the enteric nervous system sense and regulate intestinal ammonia. We show that ammonia modifies enteric neuromuscular transmission to increase motility in human, pig, and mouse intestine model systems. The mechanisms underlying the effects of ammonia on enteric neurotransmission include GABAergic pathways that are regulated by enteric glial cells. Our new data suggest that myenteric glial cells sense local ammonia and directly modify neurotransmission by releasing GABA. PMID- 28838987 TI - Age-related external anal sphincter muscle dysfunction and fibrosis: possible role of Wnt/beta-catenin signaling pathways. AB - Studies show an age-related increase in the prevalence of anal incontinence and sphincter muscle atrophy. The Wnt/beta-catenin signaling pathway has been recently recognized as the major molecular pathway involved in age-related skeletal muscle atrophy and fibrosis. The goals of our study were to 1) evaluate the impact of normal aging on external anal sphincter (EAS) muscle length-tension (L-T) function and morphology and 2) specifically examine the role of Wnt signaling pathways in anal sphincter muscle fibrosis. New Zealand White female rabbits [6 young (6 mo of age) and 6 old (36 mo of age)] were anesthetized, and anal canal pressure was measured to determine the L-T function of EAS. Animals were killed at the end of the study, and the anal canal was harvested and processed for histochemical studies (Masson trichrome stain for muscle/connective tissue) as well as for molecular markers for fibrosis and atrophy [collagen I, beta-catenin, transforming growth factor-beta (TGF-beta), atrogin-1, and muscle specific RING finger protein-1 (MuRF-1)]. The L-T was significantly impaired in older animals compared with young animals. Anal canal sections stained with trichrome showed a significant decrease in the muscle content (52% in old compared with 70% in young) and an increase in the connective tissue/collagen content in the old animals. An increased protein and mRNA expression of all the fibrosis markers was seen in the older animals. Aging EAS muscle exhibits impairment of function and increase in connective tissue. Upregulation of atrophy and profibrogenic proteins with aging may be the reason for the age-related decrease in anal sphincter muscle thickness and function.NEW & NOTEWORTHY Our studies using a female rabbit model show age-related alterations in the structure and function of the external anal sphincter (EAS) muscle. We used endoluminal ultrasound to measure age-related changes in EAS muscle thickness. We employed Western blot and quantitative PCR to demonstrate age-related changes in the levels of important fibrogenic as well as atrophy markers. Our findings may have significant clinical implications, i.e., use of specific antagonists to prevent age-related EAS muscle dysfunction. PMID- 28838988 TI - Impact of prevailing thiamin levels on thiamin pyrophosphate uptake in pancreatic acinar cells: do the shuttle! PMID- 28838989 TI - Resizing Nephrology Training Programs: A Call to Action. PMID- 28838990 TI - Marijuana Use and Estimated Glomerular Filtration Rate in Young Adults. AB - BACKGROUND AND OBJECTIVES: Marijuana use has become more widely accepted in the United States and has been legalized in many areas. Although it is biologically plausible that marijuana could affect kidney function, epidemiologic data are lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a cohort study among young adults with preserved eGFR (i.e., eGFR>=60 ml/min per 1.73 m2) using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. At scheduled examinations occurring every 5 years and starting at study year 10 (calendar years, 1995-1996), cystatin C was collected over a 10-year period, and urine albumin-to-creatinine ratio was collected over a 15-year period. We investigated the cross-sectional association between current and cumulative marijuana use (in marijuana-years; one marijuana-year equals 365 days of marijuana use) and eGFR by cystatin C (eGFRcys) at year 10. In longitudinal analyses, we investigated the association between cumulative marijuana use and eGFRcys change and rapid (>=3%/year) eGFRcys decline over two 5-year intervals and prevalent albuminuria (urine albumin-to-creatinine ratio >=30 mg/g) over a 15 year period. RESULTS: Past or current marijuana use was reported by 83% (3131 of 3765) of the cohort, and the mean eGFRcys was 111 ml/min per 1.73 m2 at year 10. Over the following 10 years, 504 had rapid eGFRcys decline, and over the following 15 years, 426 had prevalent albuminuria. Compared with no use, daily current use and >=5 marijuana-years of cumulative use were associated with lower eGFRcys at year 10: -4.5% (95% confidence interval, -8.1 to -0.7%; P=0.02) and 3.0% (95% confidence interval, -5.6 to -0.4%; P=0.03), respectively. Marijuana use was not significantly associated with eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria. CONCLUSIONS: Although we identified a modest cross sectional association between higher marijuana exposure and lower eGFRcys among young adults with preserved eGFR, our findings were largely null and did not demonstrate a longitudinal association between marijuana use and eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2017_08_24_CJASNPodcast_17_10.mp3. PMID- 28838991 TI - SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia. AB - Although small molecule inhibitors of B-cell receptor-associated kinases have revolutionized therapy in chronic lymphocytic leukemia (CLL), responses are incomplete. Pro-survival signaling emanating from the microenvironment may foster therapeutic resistance of the malignant B cells resident in the protective lymphoid niches. B-cell activating factor (BAFF) is critical to the survival of both healthy and neoplastic B cells. However, the pro-survival pathways triggered by BAFF have not been fully characterized. Here we show that BAFF elicited resistance to spontaneous and drug-induced apoptosis in stromal co-cultures, induced activation of both canonical and non-canonical NFkappaB signaling pathways, and triggered B-cell receptor signaling in CLL cells, independently of IGHV mutational status. SYK, a proximal kinase in the B-cell receptor signaling cascade, acted via STAT3 to bolster transcription of the anti-apoptotic protein Mcl-1, thereby contributing to apoptosis resistance in BAFF-stimulated cells. SYK inhibitor entospletinib downregulated Mcl-1, abrogating BAFF-mediated cell survival. BAFF-B-cell receptor crosstalk in neoplastic B cells was mediated by SYK interaction with TRAF2/TRAF3 complex. Thus, SYK inhibition is a promising therapeutic strategy uniquely poised to antagonize crosstalk between BAFF and B cell receptor, thereby disrupting the pro-survival microenvironment signaling in chronic lymphocytic leukemia. PMID- 28838992 TI - The role of constitutive activation of FMS-related tyrosine kinase-3 and NRas/KRas mutational status in infants with KMT2A-rearranged acute lymphoblastic leukemia. PMID- 28838993 TI - Prognostic discrimination based on the EUTOS long-term survival score within the International Registry for Chronic Myeloid Leukemia in children and adolescents. AB - The EUTOS Long-Term Survival score was tested in 350 children with chronic myeloid leukemia in first chronic phase treated with imatinib and registered in the International Registry for Childhood Chronic Myeloid Leukemia. With a median follow up of 3 years (range, 1 month to 6 years) progression and/or death (whichever came first) occurred in 23 patients. For the entire cohort of patients the 5-year progression-free survival rate was 92% (95% CI: 87%-94%) and the 5 year survival accounting for chronic myeloid leukemia deaths was 97% (95% CI: 94% 99%). Of the 309 patients allocated to low (n=199), intermediate (n=68) and high (n=42) risk groups by the EUTOS Long-Term Survival score, events (progression and/or death) occurred in 6.0%, 8.8% and 26.2%, respectively. Estimates of the 5 year progression-free survival rates according to these three risk groups were 96% (95% CI: 92%-98%), 88% (95% CI: 76%-95%) and 67% (95% CI: 48%-81%), respectively. Differences in progression-free survival according to these risk groups were highly significant (P<0.0001, overall). The EUTOS Long-Term Survival score showed better differentiation of progression-free survival than the Sokal (<45 years), Euro and EUTOS scores in children and adolescents with chronic myeloid leukemia and should be considered in therapeutic algorithms. (Trial registered at: www.clinicaltrials.gov NCT01281735). PMID- 28838994 TI - The Bruton tyrosine kinase inhibitor CC-292 shows activity in mantle cell lymphoma and synergizes with lenalidomide and NIK inhibitors depending on nuclear factor-kappaB mutational status. PMID- 28838995 TI - Mass spectrometry-based identification of a naturally presented receptor tyrosine kinase-like orphan receptor 1-derived epitope recognized by CD8+ cytotoxic T cells. PMID- 28838997 TI - Lack of Constitutively Active DNA Repair Sensitizes Glioblastomas to Akt Inhibition and Induces Synthetic Lethality with Radiation Treatment in a p53 Dependent Manner. AB - Treatment refractory glioblastoma (GBM) remains a major clinical problem globally, and targeted therapies in GBM have not been promising to date. The Cancer Genome Atlas integrative analysis of GBM reported the striking finding of genetic alterations in the p53 and PI3K pathways in more than 80% of GBMs. Given the role of these pathways in making cell-fate decisions and responding to genotoxic stress, we investigated the reliance of these two pathways in mediating radiation resistance. We selected a panel of GBM cell lines and glioma stem cells (GSC) with wild-type TP53 (p53-wt) and mutant TP53, mutations known to interfere with p53 functionality (p53-mt). Cell lines were treated with a brain permeable inhibitor of P-Akt (ser473), phosphatidylinositol ether lipid analogue (PIA), with and without radiation treatment. Sensitivity to treatment was measured using Annexin-V/PI flow cytometry and Western blot analysis for the markers of apoptotic signaling, alkaline COMET assay. All results were verified in p53 isogenic cell lines. p53-mt cell lines were selectively radiosensitized by PIA. This radiosensitization effect corresponded with an increase in DNA damage and a decrease in DNA-PKcs levels. TP53 silencing in p53-wt cells showed a similar response as the p53-mt cells. In addition, the radiosensitization effects of Akt inhibition were not observed in normal human astrocytes, suggesting that this treatment strategy could have limited off-target effects. We demonstrate that the inhibition of the PI3K/Akt pathway by PIA radiosensitizes p53-mt cells by antagonizing DNA repair. In principle, this strategy could provide a large therapeutic window for the treatment of TP53-mutant tumors. Mol Cancer Ther; 17(2); 336-46. (c)2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." PMID- 28838996 TI - The Selective Tie2 Inhibitor Rebastinib Blocks Recruitment and Function of Tie2Hi Macrophages in Breast Cancer and Pancreatic Neuroendocrine Tumors. AB - Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486 501. (c)2017 AACR. PMID- 28838998 TI - The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors. AB - The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments. Mol Cancer Ther; 17(2); 368 80. (c)2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." PMID- 28838999 TI - Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells. AB - Novel approaches for the medical treatment of advanced solid tumors, including testicular germ cell tumors (TGCT), are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual-mode compound animacroxam for TGCT treatment. Animacroxam consists of an HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell-cycle arresting, and apoptosis-inducing effects in TGCT cell lines with different cisplatin sensitivities. The IC50 values of animacroxam ranged from 0.22 to 0.42 MUmol/L and were not correlated to the cisplatin sensitivity of the tumor cells. No unspecific cytotoxicity of animacroxam was observed in either cisplatin sensitive or resistant TGCT cells, even at doses as high as 10 MUmol/L. Furthermore, animacroxam induced the formation of actin stress fibers in cancer cells, thereby confirming the cytoskeleton-disrupting and antimigratory properties of its imidazole moiety. When compared with the clinically established HDAC inhibitor vorinostat, the novel dual-mode compound animacroxam exhibited superior antitumoral efficacy in vitro Animacroxam also reduced the tumor size of TGCT tumors in vivo, as evidenced by performing xenograft experiments on tumor bearing chorioallantoic membranes of fertilizes chicken eggs (CAM assay). The in vivo experiments also revealed a very good tolerability of the compound, and hence, animacroxam may be a promising candidate for innovative treatment of TGCT in general and the more so for platinum-insensitive or refractory TGCT. Mol Cancer Ther; 16(11); 2364-74. (c)2017 AACR. PMID- 28839000 TI - Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity. AB - As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo, using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat on in vivo tumor growth delay were evaluated using subcutaneous xenografts in athymic nude mice. Panobinostat concentration levels in xenografts, plasma, and normal tissues were measured in CD1-nude mice. CD1 nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histologic examination. In vitro effects of panobinostat were assessed by qPCR and of panobinostat, TMP195, and mocetinostat by clonogenic assay, and Western blot analysis. Panobinostat resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitization, but more selective agents may be more useful radiosensitizers clinically, resulting in fewer systemic side effects. Mol Cancer Ther; 17(2); 381-92. (c)2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." PMID- 28839001 TI - T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non-Small Cell Lung Cancer. AB - T790M mutation-selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation-positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with downregulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. Mol Cancer Ther; 16(11); 2563-71. (c)2017 AACR. PMID- 28839002 TI - High-altitude champions: birds that live and migrate at altitude. AB - High altitude is physiologically challenging for vertebrate life for many reasons, including hypoxia (low environmental oxygen); yet, many birds thrive at altitude. Compared with mammals, birds have additional enhancements to their oxygen transport cascade, the conceptual series of steps responsible for acquiring oxygen from the environment and transporting it to the mitochondria. These adaptations have allowed them to inhabit a number of high-altitude regions. Waterfowl are a taxon prolific at altitude. This minireview explores the physiological responses of high-altitude waterfowl (geese and ducks), comparing the strategies of lifelong high-altitude residents to those of transient high altitude performers, providing insight into how birds champion high-altitude life. In particular, this review highlights and contrasts the physiological hypoxia responses of bar-headed geese (Anser indicus), birds that migrate biannually through the Himalayas (4,500-6,500 m), and Andean geese (Chloephaga melanoptera), lifelong residents of the Andes (4,000-5,500 m). These two species exhibit markedly different ventilatory and cardiovascular strategies for coping with hypoxia: bar-headed geese robustly increase convective oxygen transport elements (i.e., heart rate and total ventilation) whereas Andean geese rely predominantly on enhancements that are likely morphological in origin (i.e., increases in lung oxygen diffusion and cardiac stroke volume). The minireview compares the short- and long-term cardiovascular and ventilatory trade-offs of these different physiological strategies and offers hypotheses surrounding their origins. It also draws parallels to high-altitude human physiology and research, and identifies a number of areas of further research. The field of high-altitude avian physiology offers a unique and broadly applicable insight into physiological enhancements in hypoxia. PMID- 28839003 TI - Acute hypoxia in a simulated high-altitude airdrop scenario due to oxygen system failure. AB - High-Altitude High Opening (HAHO) is a military operational procedure in which parachute jumps are performed at high altitude requiring supplemental oxygen, putting personnel at risk of acute hypoxia in the event of oxygen equipment failure. This study was initiated by the Norwegian Army to evaluate potential outcomes during failure of oxygen supply, and to explore physiology during acute severe hypobaric hypoxia. A simulated HAHO without supplemental oxygen was carried out in a hypobaric chamber with decompression to 30,000 ft (9,144 m) and then recompression to ground level with a descent rate of 1,000 ft/min (305 m/min). Nine subjects were studied. Repeated arterial blood gas samples were drawn throughout the entire hypoxic exposure. Additionally, pulse oximetry, cerebral oximetry, and hemodynamic variables were monitored. Desaturation evolved rapidly and the arterial oxygen tensions are among the lowest ever reported in volunteers during acute hypoxia. PaO2 decreased from baseline 18.4 (17.3-19.1) kPa, 138.0 (133.5-143.3) mmHg, to a minimum value of 3.3 (2.9-3.7) kPa, 24.8 (21.6-27.8) mmHg, after 180 (60-210) s, [median (range)], N = 9. Hyperventilation with ensuing hypocapnia was associated with both increased arterial oxygen saturation and cerebral oximetry values, and potentially improved tolerance to severe hypoxia. One subject had a sharp drop in heart rate and cardiac index and lost consciousness 4 min into the hypoxic exposure. A simulated high-altitude airdrop scenario without supplemental oxygen results in extreme hypoxemia and may result in loss of consciousness in some individuals.NEW & NOTEWORTHY This is the first study to investigate physiology and clinical outcome of oxygen system failure in a simulated HAHO scenario. The acquired knowledge is of great value to make valid risk-benefit analyses during HAHO training or operations. The arterial oxygen tensions reported in this hypobaric chamber study are among the lowest ever reported during acute hypoxia. PMID- 28839005 TI - Drowning in a river with an average depth of 3 ft: interpreting athletic performance gains. PMID- 28839004 TI - Ventilation and neurochemical changes during u-opioid receptor activation or blockade of excitatory receptors in the hypoglossal motor nucleus of goats. AB - Neuromodulator interdependence posits that changes in one or more neuromodulators are compensated by changes in other modulators to maintain stability in the respiratory control network. Herein, we studied compensatory neuromodulation in the hypoglossal motor nucleus (HMN) after chronic implantation of microtubules unilaterally ( n = 5) or bilaterally ( n = 5) into the HMN. After recovery, receptor agonists or antagonists in mock cerebrospinal fluid (mCSF) were dialyzed during the awake and non-rapid eye movement (NREM) sleep states. During day studies, dialysis of the u-opioid inhibitory receptor agonist [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO; 100 uM) decreased pulmonary ventilation (Vi), breathing frequency ( f), and genioglossus (GG) muscle activity but did not alter neuromodulators measured in the effluent mCSF. However, neither unilateral dialysis of a broad spectrum muscarinic receptor antagonist (atropine; 50 mM) nor unilateral or bilateral dialysis of a mixture of excitatory receptor antagonists altered Vi or GG activity, but all of these did increase HMN serotonin (5-HT) levels. Finally, during night studies, DAMGO and excitatory receptor antagonist decreased ventilatory variables during NREM sleep but not during wakefulness. These findings contrast with previous dialysis studies in the ventral respiratory column (VRC) where unilateral DAMGO or atropine dialysis had no effects on breathing and bilateral DAMGO or unilateral atropine increased Vi and f and decreased GABA or increased 5-HT, respectively. Thus we conclude that the mechanisms of compensatory neuromodulation are less robust in the HMN than in the VRC under physiological conditions in adult goats, possibly because of site differences in the underlying mechanisms governing neuromodulator release and consequently neuronal activity, and/or responsiveness of receptors to compensatory neuromodulators. NEW & NOTEWORTHY Activation of inhibitory u-opioid receptors in the hypoglossal motor nucleus decreased ventilation under physiological conditions and did not affect neurochemicals in effluent dialyzed mock cerebral spinal fluid. These findings contrast with studies in the ventral respiratory column where unilateral [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) had no effects on ventilation and bilateral DAMGO or unilateral atropine increased ventilation and decreased GABA or increased serotonin, respectively. Our data support the hypothesis that mechanisms that govern local compensatory neuromodulation within the brain stem are site specific under physiological conditions. PMID- 28839006 TI - The physiology of oral whistling: a combined radiographic and MRI analysis. AB - The fluid mechanics of whistling involve the instability of an air jet, resultant vortex rings, and the interaction of these rings with rigid boundaries (see http://www.canal u.tv/video/cerimes/etude_radiocinematographique_d_un_siffleur_turc_de_kuskoy.1305 and Meyer J. Whistled Languages. Berlin, Germany: Springer, 2015, p. 74-774). Experimental models support the hypothesis that the sound in human whistling is generated by a Helmholtz resonator, suggesting that the oral cavity acts as a resonant chamber bounded by two orifices, posteriorly by raising the tongue to the hard palate, and anteriorly by pursed lips (Henrywood RH, Agarwal A. Phys Fluids 25: 107101, 2013). However, the detailed anatomical changes in the vocal tract and their relation to the frequencies generated have not been described in the literature. In this study, videofluoroscopic and simultaneous audio recordings were made of subjects whistling with the bilabial (i.e., "puckered lip") technique. One whistling subject was also recorded, using magnetic resonance imaging. As predicted by theory, the frequency of sound generated decreased as the size of the resonant cavity increased; this relationship was preserved throughout various whistling tasks and was consistent across subjects. Changes in the size of the resonant cavity were primarily modulated by tongue position rather than jaw opening and closing. Additionally, when high-frequency notes were produced, lateral chambers formed in the buccal space. These results provide the first dynamic anatomical evidence concerning the acoustic production of human whistling. NEW & NOTEWORTHY We establish a new and much firmer quantitative and physiological footing to current theoretical models on human whistling. We also document a novel lateral airflow mechanism used by both of our participants to produce high-frequency notes. PMID- 28839007 TI - Curcumin limits weight gain, adipose tissue growth, and glucose intolerance following the cessation of exercise and caloric restriction in rats. AB - Weight regain, adipose tissue growth, and insulin resistance can occur within days after the cessation of regular dieting and exercise. This phenomenon has been attributed, in part, to the actions of stress hormones as well as local and systemic inflammation. We investigated the effect of curcumin, a naturally occurring polyphenol known for its anti-inflammatory properties and inhibitory action on 11beta-HSD1 activity, on preserving metabolic health and limiting adipose tissue growth following the cessation of daily exercise and caloric restriction (CR). Sprague-Dawley rats (6-7 wk old) underwent a "training" protocol of 24-h voluntary running wheel access and CR (15-20 g/day; ~50-65% of ad libitum intake) for 3 wk ("All Trained") or were sedentary and fed ad libitum ("Sed"). After 3 wk, All Trained were randomly divided into one group which was terminated immediately ("Trained"), and two detrained groups which had their wheels locked and were reintroduced to ad libitum feeding for 1 wk. The wheel locked groups received either a daily gavage of a placebo ("Detrained + Placebo") or curcumin (200 mg/kg) ("Detrained + Curcumin"). Cessation of daily CR and exercise caused an increase in body mass, as well as a 9- to 14-fold increase in epididymal, perirenal, and inguinal adipose tissue mass, all of which were attenuated by curcumin ( P < 0.05). Insulin area under the curve (AUC) during an oral glucose tolerance test, HOMA-IR, and C-reactive protein (CRP) were elevated 6-, 9-, and 2-fold, respectively, in the Detrained + Placebo group vs. the Trained group (all P < 0.05). Curcumin reduced insulin AUC, HOMA-IR, and CRP vs. the placebo group (all P < 0.05). Our results indicate that curcumin has a protective effect against weight regain and impaired metabolic control following a successful period of weight loss through diet and exercise, perhaps via inhibition of glucocorticoid action and inflammation. NEW & NOTEWORTHY Weight regain after dieting and exercise is a common phenomenon plaguing many individuals. The biological mechanisms underlying weight regain are incompletely understood and are likely multifactorial. In this paper, we examined the metabolic implications of curcumin, a compound known for its anti-inflammatory properties and inhibitory action on the enzyme 11beta-HSD1, in a rodent model of adiposity rebound after the cessation of diet and exercise. PMID- 28839008 TI - High dislocation density-induced large ductility in deformed and partitioned steels. AB - A wide variety of industrial applications require materials with high strength and ductility. Unfortunately, the strategies for increasing material strength, such as processing to create line defects (dislocations), tend to decrease ductility. We developed a strategy to circumvent this in inexpensive, medium manganese steel. Cold rolling followed by low-temperature tempering developed steel with metastable austenite grains embedded in a highly dislocated martensite matrix. This deformed and partitioned (D and P) process produced dislocation hardening but retained high ductility, both through the glide of intensive mobile dislocations and by allowing us to control martensitic transformation. The D and P strategy should apply to any other alloy with deformation-induced martensitic transformation and provides a pathway for the development of high-strength, high ductility materials. PMID- 28839009 TI - Beneficial effects of a heat wave: higher growth and immune components driven by a higher food intake. AB - While heat waves will become more frequent and intense under global warming, the ability of species to deal with extreme weather events is poorly understood. We investigated how a heat wave influenced growth rate and investment in two immune components (phenoloxidase activity and melanin content) in larvae of two damselfly species, Ischnura elegans and Enallagma cyathigerum Late instar larvae were kept at 18 degrees C (i.e. their average natural water temperature) or under a simulated long heat wave at 30 degrees C. To explain the heat wave effects, we quantified traits related to energy uptake (food intake and growth efficiency), energy expenditure (metabolic rate measured as activity of the electron transport system, ETS) and investment in energy storage (fat content). The two species differed in life strategy, with I. elegans having a higher growth rate, growth efficiency, ETS activity and fat content. In line with its preference for cooler water bodies, the heat wave was only lethal for E. cyathigerum However, both species benefited from the heat wave by increasing growth rate, which can be explained by the higher increase in food intake than metabolic rate. This may also have contributed to the increased investment in energy storage and immune components under the heat wave. This mediatory role of food intake indicates the critical role of food availability and behaviour in shaping the impact of heat waves. Our results highlight the importance of including behavioural and physiological variables to unravel and predict the impact of extreme climate events on organisms. PMID- 28839011 TI - Eye and heart morphogenesis are dependent on melatonin signaling in chick embryos. AB - Calmodulin is vital for chick embryos morphogenesis in the incubation time 48-66 h when the rudimentary C-shaped heart attains an S-shaped pattern and the optic vesicles develop into optic cups. Melatonin is in the extraembryonic yolk sac of the avian egg; melatonin binds calmodulin. The aim of this study was to investigate the function of melatonin in the formation of the chick embryo optic cups and S-shaped heart, by pharmacological methods and immunoassays. Mel1a melatonin receptor immunofluorescence was distributed in the optic cups and rudimentary hearts. We separated embryonated chicken eggs at 48 h of incubation into basal, control and drug-treated groups, with treatment applied in the egg air sac. At 66 h of incubation, embryos were excised from the eggs and analyzed. Embryos from the basal, control (distilled water), melatonin and 6 chloromelatonin (melatonin receptor agonist) groups had regular optic cups and an S-shaped heart, while those from the calmidazolium (calmodulin inhibitor) group did not. Embryos from the luzindole (melatonin receptor antagonist) and prazosin (Mel1c melatonin receptor antagonist) groups did not have regular optic cups. Embryos from the 4-P-PDOT (Mel1b melatonin receptor antagonist) group did not have an S-shaped heart. Previous application of the melatonin, 6-chloromelatonin or forskolin (adenylate cyclase enhancer) prevented the abnormal appearance of chick embryos from the calmidazolium, luzindole, prazosin and 4-P-PDOT groups. However, 6-chloromelatonin and forskolin only partially prevented the development of defective eye cups in embryos from the calmidazolium group. The results suggested that melatonin modulates chick embryo morphogenesis via calmodulin and membrane receptors. PMID- 28839010 TI - Circulatory mechanisms underlying adaptive increases in thermogenic capacity in high-altitude deer mice. AB - We examined the circulatory mechanisms underlying adaptive increases in thermogenic capacity in deer mice (Peromyscus maniculatus) native to the cold hypoxic environment at high altitudes. Deer mice from high- and low-altitude populations were born and raised in captivity to adulthood, and then acclimated to normoxia or hypobaric hypoxia (simulating hypoxia at ~4300 m). Thermogenic capacity [maximal O2 consumption (VO2,max), during cold exposure] was measured in hypoxia, along with arterial O2 saturation (SaO2 ) and heart rate (fH). Hypoxia acclimation increased VO2,max by a greater magnitude in highlanders than in lowlanders. Highlanders also had higher SaO2 and extracted more O2 from the blood per heartbeat (O2 pulse=VO2,max/fH). Hypoxia acclimation increased fH, O2 pulse and capillary density in the left ventricle of the heart. Our results suggest that adaptive increases in thermogenic capacity involve integrated functional changes across the O2 cascade that augment O2 circulation and extraction from the blood. PMID- 28839012 TI - Complete Genome Sequence of Magnetospirillum sp. ME-1, a Novel Magnetotactic Bacterium Isolated from East Lake, Wuhan, China. AB - A novel spiral magnetotactic bacterium, Magnetospirillum sp. ME-1, was isolated from East Lake in China. Here we report the complete genome of ME-1, which contains a 4,551,873-bp circular chromosome and a 5,222-bp circular plasmid. The magnetosome biogenesis-specific genes are located in a 97,664-bp magnetosome genomic island. PMID- 28839013 TI - Genome Sequence of a Novel Reassortant and Very Virulent Strain of Infectious Bursal Disease Virus. AB - Here, we report the complete coding genome sequence of a novel reassortant and very virulent infectious bursal disease virus (IBDV), designated JBN2011. Characterization of the JBN2011 genome suggests that it is a rare recombinant virus having a very virulent IBDV segment A and a Bursine-2-like attenuated IBDV segment B. PMID- 28839014 TI - Complete Genome Sequence of Human Respiratory Syncytial Virus from Lanzhou, China. AB - A complete genome of human respiratory syncytial virus was sequenced and analyzed. Phylogenetic analysis showed that the full-length human respiratory syncytial virus (HRSV) genome sequence belongs to gene type NA1. We sequenced the genome in order to create the full-length cDNA infectious clone and develop vaccines against HRSV. PMID- 28839015 TI - Draft Genome Sequence of Pacificimonas aurantium Type Strain JLT2012, Isolated from the Seawater of the Pacific Ocean. AB - Type strain JLT2012 was isolated from the southeastern Pacific. Here, we report the draft genome sequence and the initial findings from a preliminary analysis of strain JLT2012, which represents a novel species and should be classified in the existing genus Pacificimonas. PMID- 28839016 TI - Genome Sequences of Escherichia coli Strains That Cause Persistent and Transient Mastitis. AB - We report here the genome sequences of two strains of Escherichia coli (ECA-B and ECC-M) that cause bovine mastitis. These strains are known to be associated with persistent and transient mastitis; strain ECA-B causes a transient infection, and ECC-M leads to a persistent infection. PMID- 28839017 TI - Draft Genome Sequence of a Methicillin-Resistant Staphylococcus aureus Isolate (Sequence Type 1) from Seafood. AB - The draft genome sequence of a methicillin-resistant Staphylococcus aureus (MRSA) isolate (sequence type 1 [ST 1]) from the salted dried ribbonfish from Gujarat, India, is reported here. Staphylococcus genus-specific genes were present in this MRSA isolate. The whole-genome sequence of this strain contains 2,797 protein coding genes and 80 RNAs within the 2.85-Mb genome. PMID- 28839018 TI - Complete Genome Characterization of the Porcine Deltacoronavirus HKD/JPN/2016, Isolated in Japan, 2016. AB - In 2016, an outbreak of diarrhea with high mortality in piglets occurred on a swine farm in Hokkaido prefecture, Japan. The causative porcine deltacoronavirus HDK/JPN/2016 was isolated from intestinal samples of the dead piglets on LLC-PK1 cells. The complete genome of HKD/JPN/2016 was sequenced and analyzed by next generation sequencing technology. PMID- 28839020 TI - Genetic Characterization of an Avian Influenza Virus H4N6 Strain Isolated from a Guangxi Pockmark Duck. AB - An H4N6 subtype avian influenza virus was isolated from a pockmark duck in southern China in November 2013 and named A/duck/Guangxi/149D24/2013 (H4N6). All eight gene segments of the strain were sequenced. Sequence analysis indicated that this H4N6 virus was a natural reassortant virus. This H4N6 virus has two basic amino acids in the cleavage site of hemagglutinin 1 (HA1) and HA2, and the amino acid motif of cleavage site was PEKASRGLF, which is the typical characteristic of the low-pathogenic avian influenza virus. This study will help understand the epidemiology and molecular characteristics of avian influenza virus in pockmark ducks. PMID- 28839019 TI - Draft Genome Sequence of the Fungus Associated with Oak Wilt Mortality in South Korea, Raffaelea quercus-mongolicae KACC44405. AB - The fungus Raffaelea quercus-mongolicae is the causal agent of Korean oak wilt, a disease associated with mass mortality of oak trees (e.g., Quercus spp.). The fungus is vectored and dispersed by the ambrosia beetle, Platypus koryoensis Here, we present the 27.0-Mb draft genome sequence of R. quercus-mongolicae strain KACC44405. PMID- 28839021 TI - Draft Genome Sequences of 10 Environmental Pseudomonas aeruginosa Strains Isolated from Soils, Sediments, and Waters. AB - Pseudomonas aeruginosa is an important opportunistic pathogen that has the ability to grow in a range of environmental niches. Here, we report the draft genome sequences of 10 environmental strains of the bacterium isolated from soils, sediments, and waters in various locations in North America and South Africa. PMID- 28839022 TI - Complete Genome Sequence of Streptomyces sp. TN58, a Producer of Acyl Alpha-l Rhamnopyranosides. AB - Streptomyces sp. TN58, isolated from a Tunisian soil sample, produces several natural products, including acyl alpha-l-rhamnopyranosides. It possesses a 7.6-Mb linear chromosome. This is, to our knowledge, the first genome sequence of a microorganism known to produce acyl alpha-l-rhamnopyranosides, and it will be helpful to study the biosynthesis of these specialized metabolites. PMID- 28839023 TI - Whole-Genome Sequence of the Spodoptera frugiperda Sf9 Insect Cell Line. AB - The draft whole-genome sequence of the Spodoptera frugiperda Sf9 insect cell line was obtained using long-read PacBio sequence technology and Canu assembly. The final assembled genome consisted of 451 Mbp in 4,577 contigs, with 12,716* mean coverage and a G+C content of 36.53%. PMID- 28839024 TI - Complete Genome Sequence of Porcine Deltacoronavirus Strain CH/JXJGS01/2016, Isolated in Jiangxi Province, China, 2016. AB - The complete genome sequence of a variant of porcine deltacoronavirus, isolated from a diarrheal piglet and designated CH/JXJGS01/2016, was sequenced and analyzed. Phylogenetic analysis demonstrated that CH/JXJGS01/2016 shares the highest nucleotide and amino acid identities with the Chinese strain NH (GenBank accession number KU981059). PMID- 28839026 TI - Complete Genome Sequence of a Newcastle Disease Genotype XIII Virus Isolated from Indigenous Chickens in Zambia. AB - The first complete genome sequence of an African-origin Newcastle disease virus belonging to genotype XIII is described here. The virulent strain chicken/Zambia/Chiwoko/2015 was isolated from diseased chickens in 2015. PMID- 28839025 TI - Complete Genome Sequence of a Novel Human Gammapapillomavirus Isolated from Skin. AB - A novel human papillomavirus (HPV ICB1) was fully characterized from a skin swab by using a sensitive degenerate PCR protocol combined with next-generation sequencing. The L1 open reading frame of HPV ICB1 shares 70.54% nucleotide homology with its closest relative, HPV164, and thus constitutes a novel human gammapapillomavirus. PMID- 28839027 TI - Complete Genome Sequence of Escherichia coli ABWA45, an rmtB-Encoding Wastewater Isolate. AB - We present the complete genome sequence of Escherichia coli ABWA45, a 16S rRNA methyltransferase-producing wastewater isolate. Assembly and annotation resulted in a 5,094,639-bp circular chromosome and four closed plasmids of 145,220 bp, 113,793 bp, 57,232 bp, and 47,900 bp in size. Furthermore, a small open plasmid (7,537 bp in size) was assembled. PMID- 28839028 TI - Eight Whole-Genome Assemblies of Yersinia pestis subsp. microtus bv. caucasica Isolated from the Common Vole (Microtus arvalis) Plague Focus in Dagestan, Russia. AB - We here report the draft genome sequences of 8 Yersinia pestis subsp. microtus bv. caucasica strains isolated from the East Caucasian (previous name, Dagestan) mountain focus (no. 39), representing the most ancient branch of the 0.PE2 phylogroup circulating in populations of common voles (Microtus arvalis). PMID- 28839029 TI - Genome Sequence of Pantoea ananatis Strain AMG 501, a Plant Growth-Promoting Bacterium Isolated from Rice Leaves Grown in Paddies of Southern Spain. AB - Pantoea ananatis AMG 501 is a plant growth-promoting bacterium isolated from rice leaves. Its genome was estimated at 5,102,640 bp with 4,994 coding sequences, encompassing genes related to the metabolism of carbohydrates, to the synthesis of auxins, siderophores, and homoserine lactones, and to the type I, II, III, IV, and VI secretion systems. PMID- 28839030 TI - Genome Sequences of Seven Foot-and-Mouth Disease Virus Isolates Collected from Serial Samples from One Persistently Infected Carrier Cow in Vietnam. AB - Several foot-and-mouth disease virus (FMDV) carrier cattle were identified in Vietnam by the recovery of infectious virus from oropharyngeal fluid. This report contains the first near-complete genome sequences of seven viruses from sequential samples from one carrier animal collected over the course of 1 year. The characterization of within-host viral evolution has implications for FMDV control strategies. PMID- 28839031 TI - Complete Sequence of a Staphylococcus aureus Clonal Complex 81 Strain, the Dominant Lineage in Food Poisoning Outbreaks in Japan. AB - Staphylococcus aureus No. 10 is an isolate from a staphylococcal food poisoning outbreak in Japan, classified as clonal complex 81 subtype 1. It preferentially produces larger quantities of staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin H (SEH) in foods and media. Here, we report the complete annotated genome sequence of the chromosome and a plasmid. PMID- 28839032 TI - Whole-Genome Sequences of Salmonella enterica subsp. enterica Serovar Typhimurium Strains TT6675 and TT9097 Employed in the Isolation and Characterization of a Giant Phage Mutant Collection. AB - We report here the genome sequences of Salmonella enterica subsp. enterica serovar Typhimurium strains TT6675 and TT9097, which we utilize for genetic analyses of giant bacterial viruses. Our analyses identified several genetic variations between the two strains, most significantly confirming strain TT6675 as a serine suppressor and TT9097 as a nonsuppressor. PMID- 28839033 TI - Draft Genome Sequence of Strain R_RK_3, an Iron-Depositing Isolate of the Genus Rhodomicrobium, Isolated from a Dewatering Well of an Opencast Mine. AB - Rhodomicrobium sp. strain R_RK_3 is an iron-depositing bacterium from which we report the draft genome. This strain was isolated from ochrous depositions of a mining well pump in Germany. The Illumina NextSeq technique was used to sequence the genome of the strain. PMID- 28839034 TI - Complete Genome Sequence of the Yogurt Isolate Lactobacillus delbrueckii subsp. bulgaricus ACA-DC 87. AB - Lactobacillus delbrueckii subsp. bulgaricus is widely used in the production of yogurt and cheese. In this study, we present the complete genome sequence of L. delbrueckii subsp. bulgaricus ACA-DC 87 isolated from traditional Greek yogurt. Whole-genome analysis may reveal desirable technological traits of the strain for dairy fermentations. PMID- 28839035 TI - Complete Genome Sequence of JII-1961, a Bovine Mycobacterium avium subsp. paratuberculosis Field Isolate from Germany. AB - Mycobacterium avium subsp. paratuberculosis causes Johne's disease in ruminants and was also detected in nonruminant species, including human beings, and in milk products. We announce here the 4.829-Mb complete genome sequence of the cattle type strain JII-1961 from Germany, which is very similar to cattle-type strains recovered from different continents. PMID- 28839036 TI - Genome Sequence of Clostridium botulinum Strain Adk2012 Associated with a Foodborne Botulinum Case in Tottori, Japan, in 2012. AB - We report here a draft genome sequence of Clostridium botulinum Adk2012 responsible for a foodborne botulism case that occurred in Tottori, Japan, in 2012. Its genome size was 2,904,173 bp, with 46 rRNAs and 54 tRNAs, at a coverage of 14.5*. PMID- 28839037 TI - Draft Genome Sequences of Two Unclassified Bacteria, Hydrogenophaga sp. Strains IBVHS1 and IBVHS2, Isolated from Environmental Samples. AB - We report here the draft genome sequences of Hydrogenophaga sp. strains IBVHS1 and IBVHS2, two bacteria assembled from the metagenomes of surface samples from freshwater lakes. The genomes are >95% complete and may represent new species within the Hydrogenophaga genus, indicating a larger diversity than currently identified. PMID- 28839038 TI - Draft Genome Sequences of Two Unclassified Bacteria, Sphingomonas sp. Strains IBVSS1 and IBVSS2, Isolated from Environmental Samples. AB - We report here the draft genome sequences of Sphingomonas sp. IBVSS1 and IBVSS2, two bacteria assembled from the metagenomes of surface samples from freshwater lakes. The genomes are >99% complete and may represent new species within the Sphingomonas genus, indicating a larger diversity than currently identified. PMID- 28839039 TI - Draft Genome Sequence of the Anoxygenic Phototrophic Bacterium Phaeospirillum fulvum MGU-K5. AB - Phaeospirillum fulvum MGU-K5 is an anoxygenic, purple, photoheterotrophic, nonsulfur alphaproteobacterium. Unlike most purple nonsulfur bacteria, MGU-K5 is unable to grow aerobically under chemoorganotrophic conditions. Here, we present the draft genome sequence of P. fulvum to provide insights into its physiology. PMID- 28839040 TI - Taxonomic Resolution of the Nematophagous Fungal Isolate ARF18 via Genome Sequencing. AB - The taxonomically uncharacterized nematophagous fungus ARF18, which parasitizes cysts, juveniles, and adults of the soybean cyst nematode (Heterodera glycines), was proposed as a nematode biological control agent in 1991. A 46.3-Mb draft genome sequence of this fungus is presented, and a tentative taxonomic identification as a novel species of Brachyphoris is proposed. PMID- 28839041 TI - Complete Genome Sequence of Vitreoscilla filiformis (ATCC 15551), Used as a Cosmetic Ingredient. AB - We report the first complete genome sequence of a Vitreoscilla filiformis strain (ATCC 15551) that is used in the cosmetic industry as Vitreoscilla ferment. The assembled genome consisted of one chromosome and two plasmids. These data will provide valuable information and important insights into the physiology of this filamentous organism. PMID- 28839044 TI - Response to Comment on "Observation of the Wigner-Huntington transition to metallic hydrogen". AB - Goncharov and Struzhkin present comments on our observation of metallic hydrogen. We show that most of their comments are unfounded and that our observation of a transition to a shiny, high-reflectance phase remains as evidence that hydrogen has transformed to the metallic phase. PMID- 28839043 TI - Incorporating Gene Annotation into Genomic Prediction of Complex Phenotypes. AB - Today, genomic prediction (GP) is an established technology in plant and animal breeding programs. Current standard methods are purely based on statistical considerations but do not make use of the abundant biological knowledge, which is easily available from public databases. Major questions that have to be answered before biological prior information can be used routinely in GP approaches are which types of information can be used, and at which points they can be incorporated into prediction methods. In this study, we propose a novel strategy to incorporate gene annotation into GP of complex phenotypes by defining haploblocks according to gene positions. Haplotype effects are then modeled as categorical or as numerical allele dosage variables. The underlying concept of this approach is to build the statistical model on variables representing the biologically functional units. We evaluate the new methods with data from a heterogeneous stock mouse population, the Drosophila Genetic Reference Panel (DGRP), and a rice breeding population from the Rice Diversity Panel. Our results show that using gene annotation to define haploblocks often leads to a comparable, but for some traits to a higher, predictive ability compared to SNP based models or to haplotype models that do not use gene annotation information. Modeling gene interaction effects can further improve predictive ability. We also illustrate that the additional use of markers that have not been mapped to any gene in a second separate relatedness matrix does in many cases not lead to a relevant additional increase in predictive ability when the first matrix is based on haploblocks defined with gene annotation data, suggesting that intergenic markers only provide redundant information on the considered data sets. Therefore, gene annotation information seems to be appropriate to perceive the importance of DNA segments. Finally, we discuss the effects of gene annotation quality, marker density, and linkage disequilibrium on the performance of the new methods. To our knowledge, this is the first work that incorporates epistatic interaction or gene annotation into haplotype-based prediction approaches. PMID- 28839042 TI - Evolutionarily Conserved Alternative Splicing Across Monocots. AB - One difficulty when identifying alternative splicing (AS) events in plants is distinguishing functional AS from splicing noise. One way to add confidence to the validity of a splice isoform is to observe that it is conserved across evolutionarily related species. We use a high throughput method to identify junction-based conserved AS events from RNA-Seq data across nine plant species, including five grass monocots (maize, sorghum, rice, Brachpodium, and foxtail millet), plus two nongrass monocots (banana and African oil palm), the eudicot Arabidopsis, and the basal angiosperm Amborella In total, 9804 AS events were found to be conserved between two or more species studied. In grasses containing large regions of conserved synteny, the frequency of conserved AS events is twice that observed for genes outside of conserved synteny blocks. In plant-specific RS and RS2Z subfamilies of the serine/arginine (SR) splice-factor proteins, we observe both conservation and divergence of AS events after the whole genome duplication in maize. In addition, plant-specific RS and RS2Z splice-factor subfamilies are highly connected with R2R3-MYB in STRING functional protein association networks built using genes exhibiting conserved AS. Furthermore, we discovered that functional protein association networks constructed around genes harboring conserved AS events are enriched for phosphatases, kinases, and ubiquitylation genes, which suggests that AS may participate in regulating signaling pathways. These data lay the foundation for identifying and studying conserved AS events in the monocots, particularly across grass species, and this conserved AS resource identifies an additional layer between genotype to phenotype that may impact future crop improvement efforts. PMID- 28839046 TI - Comment on "Observation of the Wigner-Huntington transition to metallic hydrogen". AB - Dias and Silvera (Research Article, 17 February 2017, p. 715) claim the observation of the Wigner-Huntington transition to metallic hydrogen at 495 gigapascals. We show that neither the claims of the record pressure nor the phase transition to a metallic state are supported by data and that the data contradict the authors' own unconfirmed previous results. PMID- 28839045 TI - Actin protects mammalian eggs against chromosome segregation errors. AB - Chromosome segregation is driven by a spindle that is made of microtubules but is generally thought to be independent of actin. Here, we report an unexpected actin dependent mechanism that drives the accurate alignment and segregation of chromosomes in mammalian eggs. Prominent actin filaments permeated the microtubule spindle in eggs of several mammalian species, including humans. Disrupting actin in mouse eggs led to significantly increased numbers of misaligned chromosomes as well as lagging chromosomes during meiosis I and II. We found that actin drives accurate chromosome segregation by promoting the formation of functional kinetochore fibers, the microtubule bundles that align and segregate the chromosomes. Thus, actin is essential to prevent chromosome segregation errors in eggs, which are a leading cause of miscarriages, infertility, and Down syndrome. PMID- 28839047 TI - Response to Comment on "Observation of the Wigner-Huntington transition to metallic hydrogen". AB - Liu et al present negative comments on our observation of the Wigner-Huntington transition to metallic hydrogen (MH). Earlier attempts to produce MH were unsuccessful due to diamond failure before the required pressures were achieved. We produced the highest static pressures (495 gigapascals) ever on hydrogen at low temperatures. Here, we respond to their objections. PMID- 28839048 TI - Comment on "Observation of the Wigner-Huntington transition to metallic hydrogen". AB - Dias and Silvera (Research Article, 17 February 2017, p. 715) report on the observation of the Wigner-Huntington transition to metallic hydrogen at 495 gigapascals at 5.5 and 83 kelvin. Here, we show that the claim of metallic behavior is not supported by the presented data, which are scarce, contradictory, and do not prove the presence of hydrogen in the high-pressure cavity. PMID- 28839049 TI - Empowering science advice. PMID- 28839051 TI - Surge in right whale deaths raises alarms. PMID- 28839052 TI - Documents detail gender-related tensions at Salk. PMID- 28839053 TI - The inside story on 20,000 vertebrates. PMID- 28839054 TI - Germany seeks 'big flip' in publishing model. PMID- 28839055 TI - Zebrafish larvae could help to personalize cancer treatments. PMID- 28839056 TI - The organoid architect. PMID- 28839057 TI - The mechanics of positioning skin follicles. PMID- 28839058 TI - The complex that conquered the land. PMID- 28839059 TI - Improving on aquaporins. PMID- 28839060 TI - Seasonal change in the gut. PMID- 28839061 TI - A water window on surface chemistry. PMID- 28839062 TI - Actin divides to conquer. PMID- 28839063 TI - Maryam Mirzakhani (1977-2017). PMID- 28839064 TI - Fostering reproducibility in industry-academia research. PMID- 28839065 TI - China can lead on climate change. PMID- 28839067 TI - Korean physicians' bond defies borders. PMID- 28839066 TI - Confidence in courts: A delicate balance. PMID- 28839068 TI - Harvesting electrical energy from carbon nanotube yarn twist. AB - Mechanical energy harvesters are needed for diverse applications, including self powered wireless sensors, structural and human health monitoring systems, and the extraction of energy from ocean waves. We report carbon nanotube yarn harvesters that electrochemically convert tensile or torsional mechanical energy into electrical energy without requiring an external bias voltage. Stretching coiled yarns generated 250 watts per kilogram of peak electrical power when cycled up to 30 hertz, as well as up to 41.2 joules per kilogram of electrical energy per mechanical cycle, when normalized to harvester yarn weight. These energy harvesters were used in the ocean to harvest wave energy, combined with thermally driven artificial muscles to convert temperature fluctuations to electrical energy, sewn into textiles for use as self-powered respiration sensors, and used to power a light-emitting diode and to charge a storage capacitor. PMID- 28839069 TI - Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C-C bonds: Entry to type II polyketides. AB - Current catalytic processes involving carbon-carbon bond activation rely on pi unsaturated coupling partners. Exploiting the concept of transfer hydrogenative coupling, we report a ruthenium(0)-catalyzed cycloaddition of benzocyclobutenones that functionalizes two adjacent saturated diol carbon-hydrogen bonds. These regio- and diastereoselective processes enable convergent construction of type II polyketide substructures. PMID- 28839070 TI - Enhanced water permeability and tunable ion selectivity in subnanometer carbon nanotube porins. AB - Fast water transport through carbon nanotube pores has raised the possibility to use them in the next generation of water treatment technologies. We report that water permeability in 0.8-nanometer-diameter carbon nanotube porins (CNTPs), which confine water down to a single-file chain, exceeds that of biological water transporters and of wider CNT pores by an order of magnitude. Intermolecular hydrogen-bond rearrangement, required for entry into the nanotube, dominates the energy barrier and can be manipulated to enhance water transport rates. CNTPs block anion transport, even at salinities that exceed seawater levels, and their ion selectivity can be tuned to configure them into switchable ionic diodes. These properties make CNTPs a promising material for developing membrane separation technologies. PMID- 28839071 TI - Intonational speech prosody encoding in the human auditory cortex. AB - Speakers of all human languages regularly use intonational pitch to convey linguistic meaning, such as to emphasize a particular word. Listeners extract pitch movements from speech and evaluate the shape of intonation contours independent of each speaker's pitch range. We used high-density electrocorticography to record neural population activity directly from the brain surface while participants listened to sentences that varied in intonational pitch contour, phonetic content, and speaker. Cortical activity at single electrodes over the human superior temporal gyrus selectively represented intonation contours. These electrodes were intermixed with, yet functionally distinct from, sites that encoded different information about phonetic features or speaker identity. Furthermore, the representation of intonation contours directly reflected the encoding of speaker-normalized relative pitch but not absolute pitch. PMID- 28839072 TI - Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. AB - Although humans have cospeciated with their gut-resident microbes, it is difficult to infer features of our ancestral microbiome. Here, we examine the microbiome profile of 350 stool samples collected longitudinally for more than a year from the Hadza hunter-gatherers of Tanzania. The data reveal annual cyclic reconfiguration of the microbiome, in which some taxa become undetectable only to reappear in a subsequent season. Comparison of the Hadza data set with data collected from 18 populations in 16 countries with varying lifestyles reveals that gut community membership corresponds to modernization: Notably, the taxa within the Hadza that are the most seasonally volatile similarly differentiate industrialized and traditional populations. These data indicate that some dynamic lineages of microbes have decreased in prevalence and abundance in modernized populations. PMID- 28839074 TI - How I found my outreach niche. PMID- 28839073 TI - Structure and assembly mechanism of plant C2S2M2-type PSII-LHCII supercomplex. AB - In plants, the photosynthetic machinery photosystem II (PSII) consists of a core complex associated with variable numbers of light-harvesting complexes II (LHCIIs). The supercomplex, comprising a dimeric core and two strongly bound and two moderately bound LHCIIs (C2S2M2), is the dominant form in plants acclimated to limited light. Here we report cryo-electron microscopy structures of two forms of C2S2M2 (termed stacked and unstacked) from Pisum sativum at 2.7- and 3.2 angstrom resolution, respectively. In each C2S2M2, the moderately bound LHCII assembles specifically with a peripheral antenna complex CP24-CP29 heterodimer and the strongly bound LHCII, to establish a pigment network that facilitates light harvesting at the periphery and energy transfer into the core. The high mobility of peripheral antennae, including the moderately bound LHCII and CP24, provides insights into functional regulation of plant PSII. PMID- 28839076 TI - The Golgi entry core compartment functions as a COPII-independent scaffold for ER to-Golgi transport in plant cells. AB - Many questions remain about how the stacked structure of the Golgi is formed and maintained. In our previous study, we challenged this question using tobacco BY-2 cells and revealed that, upon Brefeldin A (BFA) treatment, previously undescribed small punctate structures containing a particular subset of cis-Golgi proteins are formed adjacent to the ER-exit sites and act as scaffolds for Golgi regeneration after BFA removal. In this study, we analyzed these structures further. The proteins that localize to these punctate structures originate from the cis-most cisternae. 3D time-lapse observations show that the trans-Golgi marker is transported through these structures during Golgi regeneration. These data indicate that the cis-most cisternae have a specialized region that receives cargo from the ER, which becomes obvious upon BFA treatment. Expression of a dominant mutant form of SAR1 does not affect the formation of the punctate structures. We propose to call these punctate structures the 'Golgi entry core compartment' (GECCO). They act as receivers for the rest of the Golgi materials and are formed independently of the COPII machinery.This article has an associated First Person interview with the first author of the paper. PMID- 28839075 TI - A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. AB - The Nrf2 transcription factor is a master regulator of the cellular anti-stress response. A population of the transcription factor associates with the mitochondria through a complex with KEAP1 and the mitochondrial outer membrane histidine phosphatase, PGAM5. To determine the function of this mitochondrial complex, we knocked down each component and assessed mitochondrial morphology and distribution. We discovered that depletion of Nrf2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition. Mechanistically, this disrupted motility results from aberrant degradation of Miro2, a mitochondrial GTPase that links mitochondria to microtubules. Rescue experiments demonstrate that this Miro2 degradation involves the KEAP1-cullin-3 E3 ubiquitin ligase and the proteasome. These data are consistent with a model in which an intact complex of PGAM5-KEAP1-Nrf2 preserves mitochondrial motility by suppressing dominant-negative KEAP1 activity. These data further provide a mechanistic explanation for how age-dependent declines in Nrf2 expression impact mitochondrial motility and induce functional deficits commonly linked to neurodegeneration. PMID- 28839077 TI - Alcohol consumption in a general antenatal population and child neurodevelopment at 2 years. AB - BACKGROUND: Prenatal alcohol exposure (PAE) is a community health problem with up to 50% of pregnant women drinking alcohol. The relationship between low or sporadic binge PAE and adverse child outcomes is not clear. This study examines the association between PAE in the general antenatal population and child neurodevelopment at 2 years, accounting for relevant contributing factors. METHODS: This prospective population-based cohort recruited 1570 pregnant women, providing sociodemographic, psychological and lifestyle information and alcohol use for five time periods. PAE categories were 'low', 'moderate/high', 'binge', in trimester 1 or throughout pregnancy. Measures of cognitive, language and motor development (Bayley Scales of Infant and Toddler Development) were available for 554 children, while measures of sensory processing (Infant/Toddler Sensory Profile) and social-emotional development (Brief Infant Toddler Social Emotional Assessment) were available for 948. RESULTS: A positive association in univariate analysis with low-level PAE throughout pregnancy and cognition (beta=4.1, 95% CI 0.02 to 8.22, p=0.05) was attenuated by adjusting for environmental/social deprivation risk factors (beta=3.06 (-1.19 to 7.30), p=0.16). Early binge drinking, plus continued PAE at lower levels, was associated with the child being more likely to score low in sensation avoidance (adjusted OR 1.88 (1.03 to 3.41), p=0.04). CONCLUSION: Early binge exposure, followed by lower-level PAE, demonstrated an increase in sensation-avoiding behaviour. There were, however, no significant associations between PAE and neurodevelopment following adjustment for important confounders and modifiers. Follow-up is paramount to investigate subtle or later onset problems. PMID- 28839078 TI - Fluoride exposure and indicators of thyroid functioning in the Canadian population: implications for community water fluoridation. AB - BACKGROUND: There are concerns that altered thyroid functioning could be the result of ingesting too much fluoride. Community water fluoridation (CWF) is an important source of fluoride exposure. Our objectives were to examine the association between fluoride exposure and (1) diagnosis of a thyroid condition and (2) indicators of thyroid functioning among a national population-based sample of Canadians. METHODS: We analysed data from Cycles 2 and 3 of the Canadian Health Measures Survey (CHMS). Logistic regression was used to assess associations between fluoride from urine and tap water samples and the diagnosis of a thyroid condition. Multinomial logistic regression was used to examine the relationship between fluoride exposure and thyroid-stimulating hormone (TSH) level (low/normal/high). Other available variables permitted additional exploratory analyses among the subset of participants for whom we could discern some fluoride exposure from drinking water and/or dental products. RESULTS: There was no evidence of a relationship between fluoride exposure (from urine and tap water) and the diagnosis of a thyroid condition. There was no statistically significant association between fluoride exposure and abnormal (low or high) TSH levels relative to normal TSH levels. Rerunning the models with the sample constrained to the subset of participants for whom we could discern some source(s) of fluoride exposure from drinking water and/or dental products revealed no significant associations. CONCLUSION: These analyses suggest that, at the population level, fluoride exposure is not associated with impaired thyroid functioning in a time and place where multiple sources of fluoride exposure, including CWF, exist. PMID- 28839079 TI - pH Conditions under Which Pyrazinamide Works in Humans. PMID- 28839080 TI - Reply to Srivastava et al., "pH Conditions under Which Pyrazinamide Works in Humans". PMID- 28839081 TI - Azithromycin Shows Anti-Zika Virus Activity in Human Glial Cells. PMID- 28839082 TI - Should Piperacillin-Tazobactam Be Used as Definitive Therapy against Enterobacteriaceae Harboring Inducible AmpC beta-Lactamases? PMID- 28839083 TI - Reply to Aitken et al., "Should Piperacillin-Tazobactam Be Used as Definitive Therapy against Enterobacteriaceae Harboring Inducible AmpC beta-Lactamases?" PMID- 28839084 TI - Reply to Iannetta et al., "Azithromycin Shows Anti-Zika Virus Activity in Human Glial Cells". PMID- 28839085 TI - Correction for Arora et al., "Respiratory Flexibility in Response to Inhibition of Cytochrome c Oxidase in Mycobacterium tuberculosis". PMID- 28839086 TI - Erratum for Peloquin et al., "Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis". PMID- 28839087 TI - Murine Roseolovirus, Historically Known as Murine Thymic Lymphotropic Virus. PMID- 28839088 TI - Early Stochastic Dynamics in Human Cytomegalovirus Infection. PMID- 28839089 TI - Reply to "Murine Roseolovirus, Historically Known as Murine Thymic Lymphotropic Virus". PMID- 28839091 TI - Classic Spotlight, 2002 and 2003: Articles of Significant Interest Selected from the Journal of Virology Archives by the Editors. PMID- 28839090 TI - Reply to "Early Stochastic Dynamics in Human Cytomegalovirus Infection". PMID- 28839092 TI - Simple phalanx pattern leads to energy saving in cohesive fish schooling. AB - The question of how individuals in a population organize when living in groups arises for systems as different as a swarm of microorganisms or a flock of seagulls. The different patterns for moving collectively involve a wide spectrum of reasons, such as evading predators or optimizing food prospection. Also, the schooling pattern has often been associated with an advantage in terms of energy consumption. In this study, we use a popular aquarium fish, the red nose tetra fish, Hemigrammus bleheri, which is known to swim in highly cohesive groups, to analyze the schooling dynamics. In our experiments, fish swim in a shallow-water tunnel with controlled velocity, and stereoscopic video recordings are used to track the 3D positions of each individual in a school, as well as their tail beating kinematics. Challenging the widespread idea of fish favoring a diamond pattern to swim more efficiently [Weihs D (1973) Nature 241:290-291], we observe that when fish are forced to swim fast-well above their free-swimming typical velocity, and hence in a situation where efficient swimming would be favored-the most frequent configuration is the "phalanx" or "soldier" formation, with all individuals swimming side by side. We explain this observation by considering the advantages of tail-beating synchronization between neighbors, which we have also characterized. Most importantly, we show that schooling is advantageous as compared with swimming alone from an energy-efficiency perspective. PMID- 28839093 TI - Imaging the emergence and natural progression of spontaneous autoimmune diabetes. AB - Type 1 diabetes in the nonobese diabetic mouse stems from an infiltration of the pancreatic islets by a mixed population of immunocytes, which results in the impairment and eventual destruction of insulin-producing beta-cells. Little is known about the dynamics of lymphocyte movement in the pancreas during disease progression. Using advanced intravital imaging approaches and newly created reporter mice (Flt3-BFP2, Mertk-GFP-DTR, Cd4-tdTomato, Cd8a-tdTomato), we show that the autoimmune process initiates first with a T cell infiltration into the islets, where they have restricted mobility but reside and are activated in apposition to CX3CR1+ macrophages. The main expansion then occurs in the connective tissue outside the islet, which remains more or less intact. CD4+ and CD8+ T cells, Tregs, and dendritic cells (DCs) are highly mobile, going along microvascular tracks, while static macrophages (MF) form a more rigid structure, often encasing the islet cell mass. Transient cell-cell interactions are formed between T cells and both MFs and DCs, but also surprisingly between MFs and DCs themselves, possibly denoting antigen transfer. In later stages, extensive islet destruction coincides with preferential antigen presentation to, and activation of, CD8+ T cells. Throughout the process, Tregs patrol the active compartments, consistent with the notion that they control the activation of many cell types. PMID- 28839095 TI - Heartbeat: Surgical risk scores in infective endocarditis. PMID- 28839096 TI - Takotsubo syndrome: aetiology, presentation and treatment. PMID- 28839097 TI - Expediting the pathway to supraventricular tachycardia ablation. PMID- 28839094 TI - Quantitative tests of a reconstitution model for RNA folding thermodynamics and kinetics. AB - Decades of study of the architecture and function of structured RNAs have led to the perspective that RNA tertiary structure is modular, made of locally stable domains that retain their structure across RNAs. We formalize a hypothesis inspired by this modularity-that RNA folding thermodynamics and kinetics can be quantitatively predicted from separable energetic contributions of the individual components of a complex RNA. This reconstitution hypothesis considers RNA tertiary folding in terms of DeltaGalign, the probability of aligning tertiary contact partners, and DeltaGtert, the favorable energetic contribution from the formation of tertiary contacts in an aligned state. This hypothesis predicts that changes in the alignment of tertiary contacts from different connecting helices and junctions (DeltaGHJH) or from changes in the electrostatic environment (DeltaG+/-) will not affect the energetic perturbation from a mutation in a tertiary contact (DeltaDeltaGtert). Consistent with these predictions, single molecule FRET measurements of folding of model RNAs revealed constant DeltaDeltaGtert values for mutations in a tertiary contact embedded in different structural contexts and under different electrostatic conditions. The kinetic effects of these mutations provide further support for modular behavior of RNA elements and suggest that tertiary mutations may be used to identify rate limiting steps and dissect folding and assembly pathways for complex RNAs. Overall, our model and results are foundational for a predictive understanding of RNA folding that will allow manipulation of RNA folding thermodynamics and kinetics. Conversely, the approaches herein can identify cases where an independent, additive model cannot be applied and so require additional investigation. PMID- 28839098 TI - Sole reliance on I2 may mislead. PMID- 28839099 TI - An unusual cause of tachyarrhythmia in an otherwise healthy young man. AB - CLINICAL INTRODUCTION: A 32-year-old man referred to the cardiology clinic for palpitations was found to have paroxysmal supraventricular tachycardia (SVT) on 24-hour Holter monitoring. His general and cardiac examinations were unremarkable. A transthoracic echocardiographic study to exclude structural heart disease was performed and showed an abnormal structure in relation to the right ventricular (RV) free wall; however, poor echocardiographic windows precluded proper characterisation. Cardiac MR (CMR) was therefore performed. Cine images (figure 1 and online supplementary videos 1 and 2) demonstrated the abnormal structure. Dynamic pass of contrast (rest perfusion module) showed the sequence of intracavitary enhancement across different cardiac chambers in the horizontal long-axis plane (figure 1 and online supplementary video 3).heartjnl;103/18/1472/F1F1F1Figure 1Still frames from balanced steady state free precession images in the horizontal long-axis plane (A,B). Still frames from the dynamic pass of contrast in the horizontal long-axis and the short axis following contrast injection into the right arm (C,D). Images in the horizontal long-axis plane at the basal level using T2-weighted short-tau inversion recovery (E) and half Fourier single-shot turbo spin echo (F).DC1SP110.1136/heartjnl-2017 311485.supp1Supplementary data DC2SP210.1136/heartjnl-2017 311485.supp2Supplementary data DC3SP310.1136/heartjnl-2017 311485.supp3Supplementary data QUESTION: The abnormal structure is most likely which of the following?Pericardial cystRight atrial appendage aneurysmRight ventricular aneurysmJuxtaposed left atrial appendageAccessory right ventricular chamber. PMID- 28839100 TI - Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse. AB - There is no therapeutic intervention proven to prevent acute respiratory distress syndrome (ARDS). Novel mechanistic insights into the pathophysiology of ARDS are therefore required. Platelets are implicated in regulating many of the pathogenic processes that occur during ARDS; however, the mechanisms remain elusive. The platelet receptor CLEC-2 has been shown to regulate vascular integrity at sites of acute inflammation. Therefore the purpose of this study was to establish the role of CLEC-2 and its ligand podoplanin in a mouse model of ARDS. Platelet specific CLEC-2-deficient, as well as alveolar epithelial type I cell (AECI) specific or hematopoietic-specific podoplanin deficient, mice were established using cre-loxP strategies. Combining these with intratracheal (IT) instillations of lipopolysaccharide (LPS), we demonstrate that arterial oxygen saturation decline in response to IT-LPS in platelet-specific CLEC-2-deficient mice is significantly augmented. An increase in bronchoalveolar lavage (BAL) neutrophils and protein was also observed 48 h post-IT-LPS, with significant increases in pro inflammatory chemokines detected in BAL of platelet-specific CLEC-2-deficient animals. Deletion of podoplanin from hematopoietic cells but not AECIs also reduces lung function and increases pro-inflammatory chemokine expression following IT-LPS. Furthermore, we demonstrate that following IT-LPS, platelets are present in BAL in aggregates with neutrophils, which allows for CLEC-2 interaction with podoplanin expressed on BAL inflammatory alveolar macrophages. Taken together, these data suggest that the platelet CLEC-2-podoplanin signaling axis regulates the severity of lung inflammation in mice and is a possible novel target for therapeutic intervention in patients at risk of developing ARDS. PMID- 28839102 TI - The beginnings of cardiac catheterization and the resulting impact on pulmonary medicine. AB - The early history of cardiac catheterization has many interesting features. First, although it would be natural to assume that the procedure was initiated by cardiologists, two of the three people who shared the Nobel Prize for the discovery were pulmonologists, while the third was a urologist. The primary objective of the pulmonologists Andre Cournand and Dickinson Richards was to obtain mixed venous blood from the right heart so that they could use the Fick principle to calculate total pulmonary blood flow. Cournand's initial catheterization studies were prompted by his reading of an account by Werner Forssmann, who catheterized himself 12 years before. His bold experiment was one of the most bizarre in medical history. In the earliest studies that followed, Cournand and colleagues first passed catheters into the right atrium, and then into the right ventricle, and finally, the pulmonary artery. At the time, the investigators did not appreciate the significance of the low vascular pressures, nor that what they had done would revolutionize interventional cardiology. Within a year, William Dock predicted that there would be a very low blood flow at the top of the upright lung, and he proposed that this was the cause of the apical localization of pulmonary tuberculosis. The fact that the pulmonary vascular pressures are very low has many implications in lung disease. Cardiac catheterization changed the face of investigative cardiology, and its instigators were awarded the Nobel Prize in 1956. PMID- 28839103 TI - Levosimendan prevents bronchoconstriction and adverse respiratory tissue mechanical changes in rabbits. AB - Levosimendan has a calcium-sensitizing effect in the myocardium and opens ATP sensitive potassium channels (KATP) in vascular smooth muscle. Because airway smooth muscle also expresses KATP, we characterized the protective potential of levosimendan against increased airway and respiratory tissue resistances. Animals were administered levosimendan alone (group L), levosimendan after pretreatment with a KATP channel blocker (glibenclamide, group LG), glibenclamide only (group G), or solvent alone (dextrose, group C). Airway resistance (Raw), tissue damping, and elastance were determined by forced oscillations under baseline conditions and following provocation tests with intravenous methacholine (MCh). Cardiac output (CO) was assessed by transpulmonary thermodilution. The same sequence of measurements was then repeated during intravenous infusion of levosimendan in groups L and LG or glucose in groups G and C Sham treatments in groups C and G had no effect on lung responsiveness. However, levosimendan treatment in group L elevated CO and inhibited the MCh-induced airway responses [Raw changes of 87.8 +/- 83% (SD) vs. 24.4 +/- 16% at 4 MUg.kg-1.min-1 MCh, P < 0.001], and in G (35.2 +/- 12.7 vs. 25.2 +/- 12.9%, P < 0.05). The preventive affect of levosimendan against lung constriction vanished in the LG group. Levosimendan exerts a KATP-mediated potential to prevent bronchoconstriction and may prohibit adverse lung peripheral changes both in the small bronchi and the pulmonary parenchyma. The identification of a further pleiotropic property of levosimendan that is related to the pulmonary system is of particular importance for patients with decreased cardiorespiratory reserves for which simultaneous circulatory support is complemented with prevention of adverse respiratory events. PMID- 28839101 TI - Hyperoxia treatment of TREK-1/TREK-2/TRAAK-deficient mice is associated with a reduction in surfactant proteins. AB - We previously proposed a role for the two-pore domain potassium (K2P) channel TREK-1 in hyperoxia (HO)-induced lung injury. To determine whether redundancy among the three TREK isoforms (TREK-1, TREK-2, and TRAAK) could protect from HO induced injury, we now examined the effect of deletion of all three TREK isoforms in a clinically relevant scenario of prolonged HO exposure and mechanical ventilation (MV). We exposed WT and TREK-1/TREK-2/TRAAK-deficient [triple knockout (KO)] mice to either room air, 72-h HO, MV [high and low tidal volume (TV)], or a combination of HO + MV and measured quasistatic lung compliance, bronchoalveolar lavage (BAL) protein concentration, histologic lung injury scores (LIS), cellular apoptosis, and cytokine levels. We determined surfactant gene and protein expression and attempted to prevent HO-induced lung injury by prophylactically administering an exogenous surfactant (Curosurf). HO treatment increased lung injury in triple KO but not WT mice, including an elevated LIS, BAL protein concentration, and markers of apoptosis, decreased lung compliance, and a more proinflammatory cytokine phenotype. MV alone had no effect on lung injury markers. Exposure to HO + MV (low TV) further decreased lung compliance in triple KO but not WT mice, and HO + MV (high TV) was lethal for triple KO mice. In triple KO mice, the HO-induced lung injury was associated with decreased surfactant protein (SP) A and SPC but not SPB and SPD expression. However, these changes could not be explained by alterations in the transcription factors nuclear factor-1 (NF-1), NKX2.1/thyroid transcription factor-1 (TTF-1) or c-jun, or lamellar body levels. Prophylactic Curosurf administration did not improve lung injury scores or compliance in triple KO mice. PMID- 28839104 TI - Epigenetic changes by DNA methylation in chronic and intermittent hypoxia. AB - DNA methylation of cytosine residues is a well-studied epigenetic change, which regulates gene transcription by altering accessibility for transcription factors. Hypoxia is a pervasive stimulus that affects many physiological processes. The circulatory and respiratory systems adapt to chronic sustained hypoxia, such as that encountered during a high-altitude sojourn. Many people living at sea level experience chronic intermittent hypoxia (IH) due to sleep apnea, which leads to cardiovascular and respiratory maladaptation. This article presents a brief update on emerging evidence suggesting that changes in DNA methylation contribute to pathologies caused by chronic IH and potentially mediate adaptations to chronic sustained hypoxia by affecting the hypoxia-inducible factor (HIF) signaling pathway. PMID- 28839106 TI - Variation of practice and poor outcomes for extremely low gestation births: ordained before birth? PMID- 28839105 TI - Alcohol abuse is associated with enhanced pulmonary and systemic xanthine oxidoreductase activity. AB - Acute respiratory distress syndrome (ARDS) is a common and devastating disorder. Alcohol use disorders (AUDs) increase ARDS risk and worsen outcomes through mechanisms that may include enhancement of pulmonary oxidative stress. Alcohol consumption increases activity of the enzyme xanthine oxidoreductase (XOR) that contributes to production of both reactive oxygen species (ROS) and uric acid, a damage-associated molecular pattern. These by-products have the potential to modulate proinflammatory pathways, such as those involving cyclooxygenase (COX) 2, and to activate the nucleotide-binding domain, leucine-rich-containing family, pyrin-domain containing-3 (NLRP3) inflammasome. We sought to determine if pulmonary and systemic XOR activity was altered by AUDs. Bronchoscopy with bronchoalveolar lavage (BAL) and blood sampling was performed in otherwise healthy human subjects with AUDs and controls. Uric acid in epithelial-lining fluid, derived from BAL, was substantially higher among individuals with AUDs and did not normalize after 7 days of abstinence; serum uric acid did not differ across groups. XOR enzyme activity in fresh BAL cells and serum was significantly increased in subjects with AUDs. XOR protein in BAL cells from AUD subjects was increased in parallel with COX-2 expression, and furthermore, mRNA expression of NLRP3 inflammasome components was sustained in LPS-stimulated BAL cells from AUD subjects in conjunction with increased IL-1beta. Our data suggest that AUDs augment pulmonary and systemic XOR activity that may contribute to ROS and uric acid generation, promoting inflammation. Further investigations will be necessary to determine if XOR inhibition can mitigate alcohol-associated pulmonary oxidative stress, diminish inflammation, and improve ARDS outcomes. PMID- 28839107 TI - Why or how does the prone sleep position increase the risk of unexpected and unexplained infant death? PMID- 28839108 TI - Antibodies against collagen type II are not a general marker of acute arthritis onset. PMID- 28839109 TI - Ptosis, miosis and cats. AB - Horner's syndrome (HS) is caused by a disruption in the oculosympathetic pathway. Both congenital and acquired HS are unusual in children. Acquired HS can be caused by trauma, surgical intervention, tumours, vascular malformations or infection.We describe the case of a 6-year-old boy who was brought to our emergency department with ptosis, miosis, painful cervical lymphadenopathy and a cat scratch on a hand. The diagnosis of a cat scratch disease was confirmed by serology. A full recovery was observed on antibiotic treatment and cervical lymphadenomegaly reduction 3 weeks later. PMID- 28839110 TI - Validation of Immunohistochemical Assays for Integral Biomarkers in the NCI-MATCH EAY131 Clinical Trial. AB - Biomarkers that guide therapy selection are gaining unprecedented importance as targeted therapy options increase in scope and complexity. In conjunction with high-throughput molecular techniques, therapy-guiding biomarker assays based upon immunohistochemistry (IHC) have a critical role in cancer care in that they inform about the expression status of a protein target. Here, we describe the validation procedures for four clinical IHC biomarker assays-PTEN, RB, MLH1, and MSH2-for use as integral biomarkers in the nationwide NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) EAY131 clinical trial. Validation procedures were developed through an iterative process based on collective experience and adaptation of broad guidelines from the FDA. The steps included primary antibody selection; assay optimization; development of assay interpretation criteria incorporating biological considerations; and expected staining patterns, including indeterminate results, orthogonal validation, and tissue validation. Following assay lockdown, patient samples and cell lines were used for analytic and clinical validation. The assays were then approved as laboratory-developed tests and used for clinical trial decisions for treatment selection. Calculations of sensitivity and specificity were undertaken using various definitions of gold standard references, and external validation was required for the PTEN IHC assay. In conclusion, validation of IHC biomarker assays critical for guiding therapy in clinical trials is feasible using comprehensive preanalytic, analytic, and postanalytic steps. Implementation of standardized guidelines provides a useful framework for validating IHC biomarker assays that allow for reproducibility across institutions for routine clinical use. Clin Cancer Res; 24(3); 521-31. (c)2017 AACR. PMID- 28839111 TI - Super-lncRNAs: identification of lncRNAs that target super-enhancers via RNA:DNA:DNA triplex formation. AB - Super-enhancers are characterized by high levels of Mediator binding and are major contributors to the expression of their associated genes. They exhibit high levels of local chromatin interactions and a higher order of local chromatin organization. On the other hand, lncRNAs can localize to specific DNA sites by forming a RNA:DNA:DNA triplex, which in turn can contribute to local chromatin organization. In this paper, we characterize a new class of lncRNAs called super lncRNAs that target super-enhancers and which can contribute to the local chromatin organization of the super-enhancers. Using a logistic regression model based on the number of RNA:DNA:DNA triplex sites a lncRNA forms within the super enhancer, we identify 442 unique super-lncRNA transcripts in 27 different human cell and tissue types; 70% of these super-lncRNAs were tissue restricted. They primarily harbor a single triplex-forming repeat domain, which forms an RNA:DNA:DNA triplex with multiple anchor DNA sites (originating from transposable elements) within the super-enhancers. Super-lncRNAs can be grouped into 17 different clusters based on the tissue or cell lines they target. Super-lncRNAs in a particular cluster share common short structural motifs and their corresponding super-enhancer targets are associated with gene ontology terms pertaining to the tissue or cell line. Super-lncRNAs may use these structural motifs to recruit and transport necessary regulators (such as transcription factors and Mediator complexes) to super-enhancers, influence chromatin organization, and act as spatial amplifiers for key tissue-specific genes associated with super-enhancers. PMID- 28839112 TI - An Ago2-associated capped transcriptional start site small RNA suppresses adenovirus DNA replication. AB - Here we show that the adenovirus major late promoter produces a 31-nucleotide transcriptional start site small RNA (MLP-TSS-sRNA) that retains the 7 methylguanosine (m7G)-cap and is incorporated onto Ago2-containing RNA-induced silencing complexes (RISC) in human adenovirus-37 infected cells. RNA polymerase II CLIP (UV-cross linking immunoprecipitation) experiments suggest that the MLP TSS-sRNA is produced by promoter proximal stalling/termination of RNA polymerase II transcription at the site of the small RNA 3' end. The MLP-TSS-sRNA is highly stable in cells and functionally active, down-regulating complementary targets in a sequence and dose-dependent manner. The MLP-TSS-sRNA is transcribed from the opposite strand to the adenoviral DNA polymerase and preterminal protein mRNAs, two essential viral replication proteins. We show that the MLP-TSS-sRNA act in trans to reduce DNA polymerase and preterminal protein mRNA expression. As a consequence of this, the MLP-TSS-sRNA has an inhibitory effect on the efficiency of viral DNA replication. Collectively, our results suggest that this novel sRNA may serve a regulatory function controlling viral genome replication during a lytic and/or persistent adenovirus infection in its natural host. PMID- 28839113 TI - Geographic Access Modeling of Emergency Obstetric and Neonatal Care in Kigoma Region, Tanzania: Transportation Schemes and Programmatic Implications. AB - BACKGROUND: Access to transportation is vital to reducing the travel time to emergency obstetric and neonatal care (EmONC) for managing complications and preventing adverse maternal and neonatal outcomes. This study examines the distribution of travel times to EmONC in Kigoma Region, Tanzania, using various transportation schemes, to estimate the proportion of live births (a proxy indicator of women needing delivery care) with poor geographic access to EmONC services. METHODS: The 2014 Reproductive Health Survey of Kigoma Region identified 4 primary means of transportation used to travel to health facilities: walking, cycling, motorcycle, and 4-wheeled motor vehicle. A raster-based travel time model was used to map the 2-hour travel time catchment for each mode of transportation. Live birth density distributions were aggregated by travel time catchments, and by administrative council, to estimate the proportion of births with poor access. RESULTS: Of all live births in Kigoma Region, 13% occurred in areas where women can reach EmONC facilities within 2 hours on foot, 33% in areas that can be reached within 2 hours only by motorized vehicles, and 32% where it is impossible to reach EmONC facilities within 2 hours. Over 50% of births in 3 of the 8 administrative councils had poor estimated access. In half the councils, births with poor access could be reduced to no higher than 12% if all female residents had access to motorized vehicles. CONCLUSION: Significant differences in geographic access to EmONC in Kigoma Region, Tanzania, were observed both by location and by primary transportation type. As most of the population may only have good EmONC access when using mechanized or motorized vehicles, bicycles and motorcycles should be incorporated into the health transportation strategy. Collaboration between private transportation sectors and obstetric service providers could improve access to EmONC services among most populations. In areas where residents may not access EmONC facilities within 2 hours regardless of the type of transportation used, upgrading EmONC capacity among nearby non-EmONC facilities may be required to improve accessibility. PMID- 28839114 TI - Paradoxical effect of IKKbeta inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy. AB - We tested whether NF-kappaB pathway is indispensable for the increase in expression of E3-ligases and unloading-induced muscle atrophy using IKKbeta inhibitor IMD-0354. Three groups of rats were used: nontreated control (C), 3 days of unloading/hindlimb suspension with (HS+IMD) or without (HS) IMD-0354. Levels of IkappaBalpha were higher in HS+IMD (1.16-fold) and lower in HS (0.82 fold) when compared with C group. IMD-0354 treatment during unloading: had no effect on loss of muscle mass; increased mRNA levels of MuRF1 and MAFbx; increased levels of pFoxO3; and had no effect on levels of Bcl-3, p105, and p50 proteins. Our study for the first time showed that inhibiting IKKbeta in vivo during 3-day unloading failed to diminish expression of ubiquitin ligases and prevent muscle atrophy. PMID- 28839115 TI - Genome-Scale Genetic Interactions and Cell Imaging Confirm Cytokinesis as Deleterious to Transient Topoisomerase II Deficiency in Saccharomyces cerevisiae. AB - Topoisomerase II (Top2) is an essential protein that resolves DNA catenations. When Top2 is inactivated, mitotic catastrophe results from massive entanglement of chromosomes. Top2 is also the target of many first-line anticancer drugs, the so-called Top2 poisons. Often, tumors become resistant to these drugs by acquiring hypomorphic mutations in the genes encoding Top2 Here, we have compared the cell cycle and nuclear segregation of two coisogenic Saccharomyces cerevisiae strains carrying top2 thermosensitive alleles that differ in their resistance to Top2 poisons: the broadly-used poison-sensitive top2-4 and the poison-resistant top2-5 Furthermore, we have performed genome-scale synthetic genetic array (SGA) analyses for both alleles under permissive conditions, chronic sublethal Top2 downregulation, and acute, yet transient, Top2 inactivation. We find that slowing down mitotic progression, especially at the time of execution of the mitotic exit network (MEN), protects against Top2 deficiency. In all conditions, genetic protection was stronger in top2-5; this correlated with cell biology experiments in this mutant, whereby we observed destabilization of both chromatin and ultrafine anaphase bridges by execution of MEN and cytokinesis. Interestingly, whereas transient inactivation of the critical MEN driver Cdc15 partly suppressed top2-5 lethality, this was not the case when earlier steps within anaphase were disrupted; i.e., top2-5 cdc14-1 We discuss the basis of this difference and suggest that accelerated progression through mitosis may be a therapeutic strategy to hypersensitize cancer cells carrying hypomorphic mutations in TOP2. PMID- 28839116 TI - Neo-sex Chromosomes in the Monarch Butterfly, Danaus plexippus. AB - We report the discovery of a neo-sex chromosome in the monarch butterfly, Danaus plexippus, and several of its close relatives. Z-linked scaffolds in the D. plexippus genome assembly were identified via sex-specific differences in Illumina sequencing coverage. Additionally, a majority of the D. plexippus genome assembly was assigned to chromosomes based on counts of one-to-one orthologs relative to the butterfly Melitaea cinxia (with replication using two other lepidopteran species), in which genome scaffolds have been mapped to linkage groups. Sequencing coverage-based assessments of Z linkage combined with homology based chromosomal assignments provided strong evidence for a Z-autosome fusion in the Danaus lineage, involving the autosome homologous to chromosome 21 in M. cinxia Coverage analysis also identified three notable assembly errors resulting in chimeric Z-autosome scaffolds. Cytogenetic analysis further revealed a large W chromosome that is partially euchromatic, consistent with being a neo-W chromosome. The discovery of a neo-Z and the provisional assignment of chromosome linkage for >90% of D. plexippus genes lays the foundation for novel insights concerning sex chromosome evolution in this female-heterogametic model species for functional and evolutionary genomics. PMID- 28839117 TI - High-Resolution Maps of Mouse Reference Populations. AB - Genetic reference panels are widely used to map complex, quantitative traits in model organisms. We have generated new high-resolution genetic maps of 259 mouse inbred strains from recombinant inbred strain panels (C57BL/6J * DBA/2J, ILS/IbgTejJ * ISS/IbgTejJ, and C57BL/6J * A/J) and chromosome substitution strain panels (C57BL/6J-Chr#, C57BL/6J-Chr#, and C57BL/6J-Chr#). We genotyped all samples using the Affymetrix Mouse Diversity Array with an average intermarker spacing of 4.3 kb. The new genetic maps provide increased precision in the localization of recombination breakpoints compared to the previous maps. Although the strains were presumed to be fully inbred, we found residual heterozygosity in 40% of individual mice from five of the six panels. We also identified de novo deletions and duplications, in homozygous or heterozygous state, ranging in size from 21 kb to 8.4 Mb. Almost two-thirds (46 out of 76) of these deletions overlap exons of protein coding genes and may have phenotypic consequences. Twenty-nine putative gene conversions were identified in the chromosome substitution strains. We find that gene conversions are more likely to occur in regions where the homologous chromosomes are more similar. The raw genotyping data and genetic maps of these strain panels are available at http://churchill-lab.jax.org/website/MDA. PMID- 28839120 TI - Occupational stress and burnout among Hong Kong dentists. AB - INTRODUCTION: Professional burnout has been described as a gradual erosion of a person and may be one of the possible consequences of chronic occupational stress. Although occupational stress has been surveyed among dentists in Hong Kong, no study has been published about burnout in the profession. This study aimed to evaluate burnout among Hong Kong dentists and its association with occupational stress. METHODS: We surveyed a random sample of 1086 registered dentists in Hong Kong, which formed 50% of the local profession. They were mailed an anonymous questionnaire about burnout and occupational stress in 2015. The questionnaire assessed occupational stress, coping strategies, effects of stress, level of burnout, and socio-demographic characteristics of the respondents. Occupational stress assessment concerned 33 stressors in five groups: patient related, time-related, income-related, job-related, and staff-/technically related. Level of burnout was assessed by the Maslach Burnout Inventory-Human Services Survey (22 items) with three scores: emotional exhaustion, depersonalisation, and personal accomplishment. RESULTS: Completed questionnaires were received from 301 dentists (response rate, 28.3%), of whom 25.4% had a high level of emotional exhaustion, 17.2% had a high level of depersonalisation, and 39.0% had a low level of personal accomplishment. Only 7.0% of respondents, however, had a high level of overall burnout (high emotional exhaustion, high depersonalisation, and low personal accomplishment). A high level of overall burnout was significantly associated with a higher mean score for job-related stressors and lack of postgraduate qualifications (P<0.05). CONCLUSIONS: Patient related stressors are the top occupational stressors experienced by dentists in Hong Kong. In spite of this, a low proportion of dentists have a high level of overall burnout. There was a positive association between occupational stress and level of burnout. PMID- 28839119 TI - Taxonomically Restricted Genes with Essential Functions Frequently Play Roles in Chromosome Segregation in Caenorhabditis elegans and Saccharomyces cerevisiae. AB - Genes encoding essential components of core cellular processes are typically highly conserved across eukaryotes. However, a small proportion of essential genes are highly taxonomically restricted; there appear to be no similar genes outside the genomes of highly related species. What are the functions of these poorly characterized taxonomically restricted genes (TRGs)? Systematic screens in Saccharomyces cerevisiae and Caenorhabditis elegans previously identified yeast or nematode TRGs that are essential for viability and we find that these genes share many molecular features, despite having no significant sequence similarity. Specifically, we find that those TRGs with essential phenotypes have an expression profile more similar to highly conserved genes, they have more protein protein interactions and more protein disorder. Surprisingly, many TRGs play central roles in chromosome segregation; a core eukaryotic process. We thus find that genes that appear to be highly evolutionarily restricted do not necessarily play roles in species-specific biological functions but frequently play essential roles in core eukaryotic processes. PMID- 28839121 TI - Dietary Supplement-Drug Interaction-Induced Serotonin Syndrome Progressing to Acute Compartment Syndrome. AB - BACKGROUND Dietary supplements have been associated with an increase in emergency intervention as a result of unexpected adverse events. Limited resources and information on significant drug-drug interactions with dietary supplements and prescription medications have contributed to associated complications and unexpected events. We present the case of a patient who consumed multiple prescription medications and dietary supplements which resulted in significant complications. CASE REPORT A 28-year-old man presented to the Emergency Department complaining of severe calf pain after exercising. In addition to his prescription medications, which included sertraline, he also consumed dietary supplements prior to his workout. He developed serotonin syndrome with rhabdomyolysis, which rapidly progressed to acute compartment syndrome. An emergency bilateral four-compartment double-incision lower extremity and forearm fasciotomy was performed, with complete recovery. CONCLUSIONS Drug-drug interactions involving dietary supplements are frequently overlooked in most healthcare settings, especially in the Emergency Department. Health care providers should be cognizant of the potential drug- drug interactions resulting in serotonin syndrome to prevent the progression to acute compartment syndrome and associated complications. Pharmacists play a key role in recognizing drug dietary supplement interactions and adverse effects. PMID- 28839118 TI - High-Throughput Genetic Screening of 51 Pediatric Cataract Genes Identifies Causative Mutations in Inherited Pediatric Cataract in South Eastern Australia. AB - Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected individuals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency <1% in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA, and MIP; and three previously reported cataract-causing mutations in GJA8, CRYAA, and CRYBB2 The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for >60% of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified. PMID- 28839122 TI - C1q Test for Identification of Sensitized Liver Recipients at Risk of Early Acute Antibody-Mediated Rejection. AB - BACKGROUND The majority of liver recipients transplanted with positive crossmatch have a post-transplant course free of acute antibody-mediated rejection (AMR). However, 10% of sensitized recipients develop early severe AMR. There is no clear strategy that would allow for predicting the postoperative course in sensitized liver recipients. One of the possible factors contributing to the dichotomous course in sensitized recipients may be the complement-binding characteristics of the donor-specific antibodies (DSA). MATERIAL AND METHODS We tested sera of sensitized recipients with DSA at the time of transplant, diagnosed with severe AMR or 'AMR-free' for C1q reactivity and strength of mean fluorescence intensity (MFI) in single-antigen beads (SAB) assay. RESULTS Both groups tested positive for DSA C1q binding and DSA-SAB. Recipients with early AMR had significantly stronger DSA MFI in the C1q assay (P<.0001). AMR was observed in patients with very high DSA C1q MFI (22681+/-8841 vs. the no-AMR group 7954+/-2061). In SAB assay, DSA MFI strength differences were equivocal (P=0.31). CONCLUSIONS The C1q test is a supportive adjunct in identifying patients at risk of postoperative acute AMR and selects an AMR-free course with 100% negative predictive value despite the presence of DSA. PMID- 28839123 TI - Predictive Value of Clinicopathological Characteristics for Sentinel Lymph Node Metastasis in Early Breast Cancer. AB - BACKGROUND Sentinel lymph node biopsy (SLNB) is one of the preferred treatments for breast cancer including clinically negative lymph node breast cancer. However, for 60-70% of patients this invasive axilla surgery is unnecessary. Our study aimed to identify the predictors for sentinel lymph node (SLN) metastasis in early breast cancer patients and provide evidence for rational decision-making in specified clinical situations. MATERIAL AND METHODS Medical records of 417 breast cancer patients who were treated with a breast surgical procedure and SLNB in Ningbo Medical Center Lihuili Eastern Hospital were retrospectively reviewed. Univariate analysis and multivariate logistic regression analysis were used to analyze the correlation between SLN metastasis and clinicopathological characteristics, including patient age, menstrual status, body mass index (BMI), family history, tumor size, laterality of tumor, histological grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67 index, and molecular subtypes of the tumor. RESULTS In the cohort of 417 cases, the ratio of SLNM was 23.0%. Univariate analysis found that age, tumor size, histological grade, and Ki67 index were associated with SLN metastasis. However, age, tumor size, and histological grade were the only three independent predictors for SLN metastasis by multivariate logistic regression analysis. When these three factors were considered together, three different levels of SLN metastasis groups could be classified: low-risk group with the ratio of 14.3%, moderate-risk group with the ratio of 31.4%, and high-risk group with the ratio of 66.7%. CONCLUSIONS Our study demonstrated that age, tumor size, and histological grade were three independent predictive factors for SLN metastasis in early breast cancer patients. This finding may help surgeons in the decision-making process for early breast cancer patients before considering axilla surgical procedure. PMID- 28839124 TI - Biochemical phosphates observed using hyperpolarized 31P in physiological aqueous solutions. AB - The dissolution-dynamic nuclear polarization technology had previously enabled nuclear magnetic resonance detection of various nuclei in a hyperpolarized state. Here, we show the hyperpolarization of 31P nuclei in important biological phosphates (inorganic phosphate and phosphocreatine) in aqueous solutions. The hyperpolarized inorganic phosphate showed an enhancement factor >11,000 (at 5.8 T, 9.3% polarization) in D2O (T1 29.4 s). Deuteration and the solution composition and pH all affected the lifetime of the hyperpolarized state. This capability opens up avenues for real-time monitoring of phosphate metabolism, distribution, and pH sensing in the live body without ionizing radiation. Immediate changes in the microenvironment pH have been detected here in a cell free system via the chemical shift of hyperpolarized inorganic phosphate. Because the 31P nucleus is 100% naturally abundant, future studies on hyperpolarized phosphates will not require expensive isotope labeling as is usually required for hyperpolarization of other substrates.Real-time monitoring of phosphate metabolism and distribution in the live body without ionizing radiation is highly desirable. Here, the authors show dissolution-dynamic nuclear polarization technology can enable nuclear magnetic resonance detection of hyperpolarized 31P of important biological phosphates in aqueous solutions. PMID- 28839125 TI - Phytochrome-interacting factors directly suppress MIR156 expression to enhance shade-avoidance syndrome in Arabidopsis. AB - Plants have evolved a repertoire of strategies collectively termed the shade avoidance syndrome to avoid shade from canopy and compete for light with their neighbors. However, the signaling mechanism governing the adaptive changes of adult plant architecture to shade is not well understood. Here, we show that in Arabidopsis, compared with the wild type, several PHYTOCHROME-INTERACTING FACTORS (PIFS) overexpressors all display constitutive shade-avoidance syndrome under normal high red to far-red light ratio conditions but are less sensitive to the simulated shade, whereas the MIR156 overexpressors exhibit an opposite phenotype. The simulated shade induces rapid accumulation of PIF proteins, reduced expression of multiple MIR156 genes, and concomitant elevated expression of the SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) family genes. Moreover, in vivo and in vitro assays indicate that PIFs bind to the promoters of several MIR156 genes directly and repress their expression. Our results establish a direct functional link between the phytochrome-PIFs and miR156-SPL regulatory modules in mediating shade-avoidance syndrome.Plants employ developmental strategies to avoid shade and compete with neighbors for light. Here, Xie et al. show that phytochrome interacting factors, which are regulated in a light-dependent manner, directly repress MIR156 genes and promote the expression of SPL genes to enhance shade avoidance responses. PMID- 28839126 TI - Ancestor of land plants acquired the DNA-3-methyladenine glycosylase (MAG) gene from bacteria through horizontal gene transfer. AB - The origin and evolution of land plants was an important event in the history of life and initiated the establishment of modern terrestrial ecosystems. From water to terrestrial environments, plants needed to overcome the enhanced ultraviolet (UV) radiation and many other DNA-damaging agents. Evolving new genes with the function of DNA repair is critical for the origin and radiation of land plants. In bacteria, the DNA-3-methyladenine glycosylase (MAG) recognizes of a variety of base lesions and initiates the process of the base excision repair for damaged DNA. The homologs of MAG gene are present in all major lineages of streptophytes, and both the phylogenic and sequence similarity analyses revealed that green plant MAG gene originated through an ancient horizontal gene transfer (HGT) event from bacteria. Experimental evidence demonstrated that the expression of the maize ZmMAG gene was induced by UV and zeocin, both of which are known as DNA damaging agents. Further investigation revealed that Streptophyta MAG genes had undergone positive selection during the initial evolutionary period in the ancestor of land plants. Our findings demonstrated that the ancient HGT of MAG to the ancestor of land plants probably played an important role in preadaptation to DNA-damaging agents in terrestrial environments. PMID- 28839127 TI - Multi-orbital charge transfer at highly oriented organic/metal interfaces. AB - The molecule-substrate interaction plays a key role in charge injection organic based devices. Charge transfer at molecule-metal interfaces strongly affects the overall physical and magnetic properties of the system, and ultimately the device performance. Here, we report theoretical and experimental evidence of a pronounced charge transfer involving nickel tetraphenyl porphyrin molecules adsorbed on Cu(100). The exceptional charge transfer leads to filling of the higher unoccupied orbitals up to LUMO+3. As a consequence of this strong interaction with the substrate, the porphyrin's macrocycle sits very close to the surface, forcing the phenyl ligands to bend upwards. Due to this adsorption configuration, scanning tunneling microscopy cannot reliably probe the states related to the macrocycle. We demonstrate that photoemission tomography can instead access the Ni-TPP macrocycle electronic states and determine the reordering and filling of the LUMOs upon adsorption, thereby confirming the remarkable charge transfer predicted by density functional theory calculations.Charge transfer at molecule-metal interfaces affects the overall physical and magnetic properties of organic-based devices, and ultimately their performance. Here, the authors report evidence of a pronounced charge transfer involving nickel tetraphenyl porphyrin molecules adsorbed on copper. PMID- 28839128 TI - Reinforcement determines the timing dependence of corticostriatal synaptic plasticity in vivo. AB - Plasticity at synapses between the cortex and striatum is considered critical for learning novel actions. However, investigations of spike-timing-dependent plasticity (STDP) at these synapses have been performed largely in brain slice preparations, without consideration of physiological reinforcement signals. This has led to conflicting findings, and hampered the ability to relate neural plasticity to behavior. Using intracellular striatal recordings in intact rats, we show here that pairing presynaptic and postsynaptic activity induces robust Hebbian bidirectional plasticity, dependent on dopamine and adenosine signaling. Such plasticity, however, requires the arrival of a reward-conditioned sensory reinforcement signal within 2 s of the STDP pairing, thus revealing a timing dependent eligibility trace on which reinforcement operates. These observations are validated with both computational modeling and behavioral testing. Our results indicate that Hebbian corticostriatal plasticity can be induced by classical reinforcement learning mechanisms, and might be central to the acquisition of novel actions.Spike timing dependent plasticity (STDP) has been studied extensively in slices but whether such pairings can induce plasticity in vivo is not known. Here the authors report an experimental paradigm that achieves bidirectional corticostriatal STDP in vivo through modulation by behaviourally relevant reinforcement signals, mediated by dopamine and adenosine signaling. PMID- 28839129 TI - Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a. AB - Complement C3a is an important protein in innate and adaptive immunity, but its specific roles in vivo remain uncertain because C3a degrades rapidly to form the C3a-desArg protein, which does not bind to the C3a receptor and is indistinguishable from C3a using antibodies. Here we develop the most potent, stable and highly selective small molecule modulators of C3a receptor, using a heterocyclic hinge to switch between agonist and antagonist ligand conformations. This enables characterization of C3 areceptor-selective pro- vs. anti inflammatory actions in human mast cells and macrophages, and in rats. A C3a receptor-selective agonist induces acute rat paw inflammation by first degranulating mast cells before activating macrophages and neutrophils. An orally administered C3a receptor-selective antagonist inhibits mast cell degranulation, thereby blocking recruitment and activation of macrophages and neutrophils, expression of inflammatory mediators and inflammation in a rat paw edema model. These novel tools reveal the mechanism of C3a-induced inflammation and provide new insights to complement-based medicines.Complement C3a is an important protein in innate and adaptive immunity, but its roles in vivo are unclear. Here the authors develop novel chemical agonists and antagonists for the C3a receptor, and show that they modulate mast cell degranulation and inflammation in a rat paw edema model. PMID- 28839130 TI - Work stress, anthropometry, lung function, blood pressure, and blood-based biomarkers: a cross-sectional study of 43,593 French men and women. AB - Work stress is a risk factor for cardio-metabolic diseases, but few large-scale studies have examined the clinical profile of individuals with work stress. To address this limitation, we conducted a cross-sectional study including 43,593 working adults from a French population-based sample aged 18-72 years (the CONSTANCES cohort). According to the Effort-Reward Imbalance model, work stress was defined as an imbalance between perceived high efforts and low rewards at work. A standardized health examination included measures of anthropometry, lung function, blood pressure and standard blood-based biomarkers. Linear regression analyses before and after multivariable adjustment for age, socioeconomic status, depressive symptoms, health-related behaviours, and chronic conditions showed that work stress was associated with higher BMI, waist circumference, waist-hip ratio, alanine transaminase, white blood cell count and lower high-density lipoprotein cholesterol in men, and with higher BMI and white blood cell count in women (differences 0.03-0.06 standard deviations, P < 0.05 between individuals with and without work stress). No robust associations were observed with lung function, haemoglobin, creatinine, glucose levels or resting blood pressure measures. This indicates that work stress is associated altered metabolic profile, increased systemic inflammation, and, in men, poorer liver function, which is a marker of high alcohol consumption. PMID- 28839131 TI - Whi7 is an unstable cell-cycle repressor of the Start transcriptional program. AB - Start is the main decision point in eukaryotic cell cycle in which cells commit to a new round of cell division. It involves the irreversible activation of a transcriptional program by G1 CDK-cyclin complexes through the inactivation of Start transcriptional repressors, Whi5 in yeast or Rb in mammals. Here we provide novel keys of how Whi7, a protein related at sequence level to Whi5, represses Start. Whi7 is an unstable protein, degraded by the SCFGrr1 ubiquitin-ligase, whose stability is cell cycle regulated by CDK1 phosphorylation. Importantly, Whi7 associates to G1/S gene promoters in late G1 acting as a repressor of SBF dependent transcription. Our results demonstrate that Whi7 is a genuine paralog of Whi5. In fact, both proteins collaborate in Start repression bringing to light that yeast cells, as occurs in mammalian cells, rely on the combined action of multiple transcriptional repressors to block Start transition.The commitment of cells to a new cycle of division involves inactivation of the Start transcriptional repressor Whi5. Here the authors show that the sequence related protein Whi7 associates to G1/S gene promoters in late G1 and collaborates with Whi5 in Start repression. PMID- 28839132 TI - Neuroimaging of sport concussion: persistent alterations in brain structure and function at medical clearance. AB - The medical decision of return to play (RTP) after a sport concussion is largely based on symptom status following a graded exercise protocol. However, it is currently unknown how objective markers of brain structure and function relate to clinical recovery. The goal of this study was to determine whether differences in brain structure and function at acute injury remain present at RTP. In this longitudinal study, 54 active varsity athletes were scanned using magnetic resonance imaging (MRI), including 27 with recent concussion, imaged at both acute injury and medical clearance, along with 27 matched controls. Diffusion tensor imaging was used to measure fractional anisotropy (FA) and mean diffusivity (MD) of white matter and resting-state functional MRI was used to measure global functional connectivity (Gconn). At acute injury, concussed athletes had reduced FA and increased MD, along with elevated Gconn; these effects remained present at RTP. Athletes who took longer to reach RTP also showed elevated Gconn in dorsal brain regions, but no significant white matter effects. This study presents the first evidence of altered brain structure and function at the time of medical clearance to RTP, with greater changes in brain function for athletes with a longer recovery time. PMID- 28839133 TI - USP26 functions as a negative regulator of cellular reprogramming by stabilising PRC1 complex components. AB - Despite much progress in the comprehension of the complex process of somatic cell reprogramming, many questions regarding the molecular mechanism of regulation remain to be answered. At present, the knowledge on the negative regulation of reprogramming process is indeed poor in contrary to the identification of positive regulators. Here we report for the first time that ubiquitin-specific protease 26 negatively regulates somatic cell-reprogramming process by stabilizing chromobox (CBX)-containing proteins CBX4 and CBX6 of polycomb repressive complex 1 through the removal of K48-linked polyubiquitination. Thus, accumulated CBX4 and CBX6 repress the expression of pluripotency genes, such as Sox2 and Nanog, through PRC1 complexes to ubiquitinate histone H2A at their promoters. In all, our findings have revealed an essential role for ubiquitin specific protease 26 in cellular reprogramming through polycomb-repressive complex 1.The ubiquitin-proteasome system regulates cellular reprogramming by degradation of key pluripotency factors. Here the authors report that the post translational regulation of PRC1 components CBX4 and CBX6 by ubiquitination influences reprogramming. PMID- 28839134 TI - Nanodiamonds suppress the growth of lithium dendrites. AB - Lithium metal has been regarded as the future anode material for high-energy density rechargeable batteries due to its favorable combination of negative electrochemical potential and high theoretical capacity. However, uncontrolled lithium deposition during lithium plating/stripping results in low Coulombic efficiency and severe safety hazards. Herein, we report that nanodiamonds work as an electrolyte additive to co-deposit with lithium ions and produce dendrite-free lithium deposits. First-principles calculations indicate that lithium prefers to adsorb onto nanodiamond surfaces with a low diffusion energy barrier, leading to uniformly deposited lithium arrays. The uniform lithium deposition morphology renders enhanced electrochemical cycling performance. The nanodiamond-modified electrolyte can lead to a stable cycling of lithium | lithium symmetrical cells up to 150 and 200 h at 2.0 and 1.0 mA cm-2, respectively. The nanodiamond co deposition can significantly alter the lithium plating behavior, affording a promising route to suppress lithium dendrite growth in lithium metal-based batteries.Lithium metal is an ideal anode material for rechargeable batteries but suffer from the growth of lithium dendrites and low Coulombic efficiency. Here the authors show that nanodiamonds serve as an electrolyte additive to co-deposit with lithium metal and suppress the formation of dendrites. PMID- 28839135 TI - A versatile platform for precise synthesis of asymmetric molecular brush in one shot. AB - Asymmetric molecular brushes emerge as a unique class of nanostructured polymers, while their versatile synthesis keeps a challenge for chemists. Here we show the synthesis of well-defined asymmetric molecular double-brushes comprising two different side chains linked to the same repeat unit along the backbone by one pot concurrent atom transfer radical polymerization (ATRP) and Cu-catalyzed azide/alkyne cycloaddition (CuAAC) reaction. The double-brushes are based on a poly(Br-acrylate-alkyne) homopolymer possessing an alkynyl for CuAAC reaction and a 2-bromopropionate initiating group for ATRP in each repeat unit. The versatility of this one-shot approach is demonstrated by CuAAC reaction of alkynyl/poly(ethylene oxide)-N3 and ATRP of various monomers. We also show the quantitative conversion of pentafluorophenyl ester groups to amide groups in side chains, allowing for the further fabrication of diverse building blocks. This work provides a versatile platform for facile synthesis of Janus-type double brushes with structural and functional control, in a minimum number of reactions.Producing well-defined polymer compositions and structures facilitates their use in many different applications. Here the authors show the synthesis of well-defined asymmetric double-brushes by a one-pot concurrent atom transfer radical polymerization and Cu-catalyzed Click reaction. PMID- 28839136 TI - Anomalous Dirac point transport due to extended defects in bilayer graphene. AB - Charge transport at the Dirac point in bilayer graphene exhibits two dramatically different transport states, insulating and metallic, that occur in apparently otherwise indistinguishable experimental samples. We demonstrate that the existence of these two transport states has its origin in an interplay between evanescent modes, that dominate charge transport near the Dirac point, and disordered configurations of extended defects in the form of partial dislocations. In a large ensemble of bilayer systems with randomly positioned partial dislocations, the distribution of conductivities is found to be strongly peaked at both the insulating and metallic limits. We argue that this distribution form, that occurs only at the Dirac point, lies at the heart of the observation of both metallic and insulating states in bilayer graphene.In seemingly indistinguishable bilayer graphene samples, two distinct transport regimes, insulating and metallic, have been identified experimentally. Here, the authors demonstrate that these two states originate from the interplay between extended defects and evanescent modes at the Dirac point. PMID- 28839137 TI - The powdery mildew-resistant Arabidopsis mlo2 mlo6 mlo12 triple mutant displays altered infection phenotypes with diverse types of phytopathogens. AB - Arabidopsis thaliana mlo2 mlo6 mlo12 triple mutant plants exhibit complete immunity against infection by otherwise virulent obligate biotrophic powdery mildew fungi such as Golovinomyces orontii. While this phenotype is well documented, the interaction profile of the triple mutant with other microbes is underexplored and incomplete. Here, we thoroughly assessed and quantified the infection phenotypes of two independent powdery mildew-resistant triple mutant lines with a range of microbes. These microorganisms belong to three kingdoms of life, engage in diverse trophic lifestyles, and deploy different infection strategies. We found that interactions with microbes that do not directly enter leaf epidermal cells were seemingly unaltered or showed even enhanced microbial growth or symptom formation in the mlo2 mlo6 mlo12 triple mutants, as shown for Pseudomonas syringae and Fusarium oxysporum. By contrast, the mlo2 mlo6 mlo12 triple mutants exhibited reduced host cell entry rates by Colletotrichum higginsianum, a fungal pathogen showing direct penetration of leaf epidermal cells comparable to G. orontii. Together with previous findings, the results of this study strengthen the notion that mutations in genes MLO2, MLO6 and MLO12 not only restrict powdery mildew colonization, but also affect interactions with a number of other phytopathogens. PMID- 28839138 TI - Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms. AB - Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting anticancer T-cell immunity. We show that Smac-mimetic compound and oncolytic virus therapies synergize in driving CD8+ T-cell responses toward tumors through distinct activities. Smac-mimetic compound treatment with LCL161 reinvigorates exhausted CD8+ T cells within immunosuppressed tumors by targeting tumor-associated macrophages for M1-like polarization. Oncolytic virus treatment with vesicular stomatitis virus (VSVDeltaM51) promotes CD8+ T-cell accumulation within tumors and CD8+ T-cell activation within the tumor-draining lymph node. When combined, LCL161 and VSVDeltaM51 therapy engenders CD8+ T-cell-mediated tumor control in several aggressive mouse models of cancer. Smac-mimetic compound and oncolytic virus therapies are both in clinical development and their combination therapy represents a promising approach for promoting anticancer T-cell immunity.Oncolytic viruses (OV) and second mitochondrial activator of caspase (Smac)-mimetic compounds (SMC) synergistically kill cancer cells directly. Here, the authors show that SMC and OV therapies combination also synergize in vivo by promoting anticancer immunity through an increase in CD8+ T-cell response. PMID- 28839139 TI - Loss of function of Arabidopsis microRNA-machinery genes impairs fertility, and has effects on homologous recombination and meiotic chromatin dynamics. AB - MicroRNAs (miRNAs) are ~22-nt single-stranded noncoding RNAs with regulatory roles in a wide range of cellular functions by repressing eukaryotic gene expression at a post-transcriptional level. Here, we analyzed the effects on meiosis and fertility of hypomorphic or null alleles of the HYL1, HEN1, DCL1, HST and AGO1 genes, which encode miRNA-machinery components in Arabidopsis. Reduced pollen and megaspore mother cell number and fertility were shown by the mutants analyzed. These mutants also exhibited a relaxed chromatin conformation in male meiocytes at the first meiotic division, and increased chiasma frequency, which is likely to be due to increased levels of mRNAs from key genes involved in homologous recombination. The hen1-13 mutant was found to be hypersensitive to gamma irradiation, which mainly causes double-strand breaks susceptible to be repaired by homologous recombination. Our findings uncover a role for miRNA machinery components in Arabidopsis meiosis, as well as in the repression of key genes required for homologous recombination. These genes seem to be indirect miRNA targets. PMID- 28839140 TI - Genomic DNA variation confirmed Seriola lalandi comprises three different populations in the Pacific, but with recent divergence. AB - Captive breeding programs and aquaculture production have commenced worldwide for the globally distributed yellowtail kingfish (Seriola lalandi), and captive bred fingerlings are being shipped from the Southern Hemisphere to be farmed in the Northern Hemisphere. It was recently proposed that Pacific S. lalandi comprise at least three distinct species that diverged more than 2 million years ago. Here, we tested the hypothesis of different "species" in the Pacific using novel genomic data (namely single nucleotide polymorphisms and diversity array technology markers), as well as mtDNA and DNA microsatellite variation. These new data support the hypothesis of population subdivision between the Northeast Pacific, Northwest Pacific and South Pacific, and genetic divergence indicates restriction to the gene flow between hemispheres. However, our estimates of maximum mtDNA and nuclear DNA divergences of 2.43% and 0.67%, respectively, were within the ranges more commonly observed for populations within species than species within genera. Accordingly our data support the more traditional view that S. lalandi in the Pacific comprises three distinct populations rather than the subdivisions into several species. PMID- 28839141 TI - On the performance of pre-microRNA detection algorithms. AB - MicroRNAs are crucial for post-transcriptional gene regulation, and their dysregulation has been associated with diseases like cancer and, therefore, their analysis has become popular. The experimental discovery of miRNAs is cumbersome and, thus, many computational tools have been proposed. Here we assess 13 ab initio pre-miRNA detection approaches using all relevant, published, and novel data sets while judging algorithm performance based on ten intrinsic performance measures. We present an extensible framework, izMiR, which allows for the unbiased comparison of existing algorithms, adding new ones, and combining multiple approaches into ensemble methods. In an exhaustive attempt, we condense the results of millions of computations and show that no method is clearly superior; however, we provide a guideline for biomedical researchers to select a tool. Finally, we demonstrate that combining all of the methods into one ensemble approach, for the first time, allows reliable purely computational pre-miRNA detection in large eukaryotic genomes.As the experimental discovery of microRNAs (miRNAs) is cumbersome, computational tools have been developed for the prediction of pre-miRNAs. Here the authors develop a framework to assess the performance of existing and novel pre-miRNA prediction tools and provide guidelines for selecting an appropriate approach for a given data set. PMID- 28839142 TI - Energetics of Baird aromaticity supported by inversion of photoexcited chiral [4n]annulene derivatives. AB - For the concept of aromaticity, energetic quantification is crucial. However, this has been elusive for excited-state (Baird) aromaticity. Here we report our serendipitous discovery of two nonplanar thiophene-fused chiral [4n]annulenes Th4 COT Saddle and Th6 CDH Screw , which by computational analysis turned out to be a pair of molecules suitable for energetic quantification of Baird aromaticity. Their enantiomers were separable chromatographically but racemized thermally, enabling investigation of the ring inversion kinetics. In contrast to Th6 CDH Screw , which inverts through a nonplanar transition state, the inversion of Th4 COT Saddle , progressing through a planar transition state, was remarkably accelerated upon photoexcitation. As predicted by Baird's theory, the planar conformation of Th4 COT Saddle is stabilized in the photoexcited state, thereby enabling lower activation enthalpy than that in the ground state. The lowering of the activation enthalpy, i.e., the energetic impact of excited-state aromaticity, was quantified experimentally to be as high as 21-22 kcal mol-1.Baird's rule applies to cyclic pi-conjugated molecules in their excited state, yet a quantification of the involved energetics is elusive. Here, the authors show the ring inversion kinetics of two nonplanar and chiral [4n]annulenes to support Baird's rule from an energetic point of view. PMID- 28839143 TI - A novel approach to low-temperature synthesis of cubic HfO2 nanostructures and their cytotoxicity. AB - The development of a strategy to stabilise the cubic phase of HfO2 at lower temperatures is necessary for the emergence of unique properties that are not realised in the thermodynamically stable monoclinic phase. A very high temperature (>2600 degrees C) is required to produce the cubic phase of HfO2, whereas the monoclinic phase is stable at low temperature. Here, a novel rapid synthesis strategy was designed to develop highly crystalline, pure cubic-phase HfO2 nanoparticles (size <10 nm) using microwave irradiation. Furthermore, the as prepared nanoparticles were converted to different morphologies (spherical nanoparticles and nanoplates) without compromising the cubic phase by employing a post-hydrothermal treatment in the presence of surface modifiers. The cytotoxicities and proliferative profiles of the synthesised cubic HfO2 nanostructures were investigated over the MCF-7 breast cancer cell line, along with caspase-3/7 activities. The low-temperature phase stabilisation was significantly attributed to surface imperfections (defects and deformations) induced in the crystal lattice by the desirable presence of Na2S.xH2O and NaOH. Our work provides unprecedented insight into the stabilisation of nanoscale cubic phase HfO2 in ambient environments; the method could be extended to other challenging phases of nanomaterials. PMID- 28839144 TI - The sex ratio of singleton and twin delivery offspring in assisted reproductive technology in China. AB - In order to evaluate the impact of assisted reproductive technology (ART) procedure and individual factors on the sex ratio of singletons and twins at birth after in vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI) treatment in China. We conducted a retrospective cohort study including patients undergoing their first cycle of IVF or ICSI with autologous oocytes from 2001 to 2015. A total of 7410 babies were born from 5832 women with 7410 live birth. The secondary sex ratio (SSR) in singletons was significantly higher than twins (53.97% vs. 50.89%, P = 0.009). The largest disparity was observed in 'thawed blastocyst embryos ICSI' subgroup that SSR was 59.84% in singletons and 42.45% in twins (P = 0.013). Blastocyst transfer was positively associated with elevated SSR when compared to cleavage stage embryos in singletons (Odds Ratio [OR] = 1.17, P < 0.001). In addition, paternal age was significantly associated with SSR (OR = 0.75, P = 0.014). While the decrease of SSR was significantly associated with ICSI when compared to IVF (OR = 0.61, P = 0.046) in twins. Blastocyst transfer increases SSR in comparing with cleavage stage embryos in singletons, while the use of ICSI reduces SSR in twins. Our findings offered important complement for better understanding the underlying determinant of SSR in ART offspring. PMID- 28839145 TI - DACT1 Overexpression in type I ovarian cancer inhibits malignant expansion and cis-platinum resistance by modulating canonical Wnt signalling and autophagy. AB - Type I epithelial ovarian cancer (EOC) is primarily resistant to platinum-based chemotherapies and needs novel therapeutics. Given the aberrant Wnt activation in type I EOC and the involvement of Dapper1 Antagonist of Catenin-1 (DACT1) in Wnt signalling, the role of DACT1 in tumourigenesis of type I EOC was evaluated. Firstly, all tested EOC cell lines and primary EOC tissues, especially type I EOC, were observed to have significantly lower DACT1 expression than normal controls. Next, 3AO cells, which arise from a patient with primary mucinous EOC and express low endogenous levels of DACT1, were transfected with a lentivirus carrying full-length DACT1 (3AO-DACT1), grew slower and formed smaller tumours in nude mice compared to 3AO-NC. Furthermore, 3AO-DACT1 had lower levels of key mediators of canonical Wnt signalling, Dvl2 and beta-catenin, GSK-3beta with phosphorylated Ser9, and the Wnt/beta-catenin target genes, with significantly lower nuclear beta-catenin levels. Additionally, 3AO-DACT which contained higher levels of lipidated LC3 (LC3-II) and Beclin1, but lower levels of p62/SQSTM1, were more sensitive to cis-platinum. And chloroquine partially rescued its cis platinum resistance. We identified DACT1 as a negative regulator in type I EOC, protecting against malignant expansion by inhibiting canonical Wnt signalling and cis-platinum resistance by regulating autophagy. PMID- 28839147 TI - Bone histology sheds new light on the ecology of the dodo (Raphus cucullatus, Aves, Columbiformes). AB - The dodo, Raphus cucullatus, a flightless pigeon endemic to Mauritius, became extinct during the 17th century due to anthropogenic activities. Although it was contemporaneous with humans for almost a century, little was recorded about its ecology. Here we present new aspects of the life history of the dodo based on our analysis of its bone histology. We propose that the dodo bred around August and that the rapid growth of the chicks enabled them to reach a robust size before the austral summer or cyclone season. Histological evidence of molting suggests that after summer had passed, molt began in the adults that had just bred; the timing of molt derived from bone histology is also corroborated by historical descriptions of the dodo by mariners. This research represents the only bone histology analysis of the dodo and provides an unprecedented insight into the life history of this iconic bird. PMID- 28839148 TI - Maximum Power Point Tracking for Cascaded PV-Converter Modules Using Two-Stage Particle Swarm Optimization. AB - The paper presents a novel two-stage particle swarm optimization (PSO) for the maximum power point tracking (MPPT) control of a PV system consisting of cascaded PV-converter modules, under partial shading conditions (PSCs). In this scheme, the grouping method of the shuffled frog leaping algorithm (SFLA) is incorporated with the basic PSO algorithm, ensuring fast and accurate searching of the global extremum. An adaptive speed factor is also introduced to improve its convergence speed. A PWM algorithm enabling permuted switching of the PV sources is applied. The method enables this PV system to achieve the maximum power generation for any number of PV and converter modules. Simulation studies of the proposed MPPT scheme are performed on a system having two chained PV buck-converter modules and a dc-ac H-bridge connected at its terminals for supplying an AC load. The results show that this type of PV system allows each module to achieve the maximum power generation according its illumination level without affecting the others, and the proposed new control method gives significantly higher power output compared with the conventional P&O and PSO methods. PMID- 28839146 TI - Piezo1 channels sense whole body physical activity to reset cardiovascular homeostasis and enhance performance. AB - Mammalian biology adapts to physical activity but the molecular mechanisms sensing the activity remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force to enable vascular development. Here, we address Piezo1 in adult endothelium, the major control site in physical activity. Mice without endothelial Piezo1 lack obvious phenotype but close inspection reveals a specific effect on endothelium-dependent relaxation in mesenteric resistance artery. Strikingly, the Piezo1 is required for elevated blood pressure during whole body physical activity but not blood pressure during inactivity. Piezo1 is responsible for flow-sensitive non-inactivating non-selective cationic channels which depolarize the membrane potential. As fluid flow increases, depolarization increases to activate voltage-gated Ca2+ channels in the adjacent vascular smooth muscle cells, causing vasoconstriction. Physical performance is compromised in mice which lack endothelial Piezo1 and there is weight loss after sustained activity. The data suggest that Piezo1 channels sense physical activity to advantageously reset vascular control.The mechanisms that regulate the body's response to exercise are poorly understood. Here, Rode et al. show that the mechanically activated cation channel Piezo1 is a molecular sensor of physical exercise in the endothelium that triggers endothelial communication to mesenteric vessel muscle cells, leading to vasoconstriction. PMID- 28839149 TI - Microstructure-based constitutive model of coronary artery with active smooth muscle contraction. AB - Currently, there is no full three-dimensional (3D) microstructural mechanical model of coronary artery based on measured microstructure including elastin, collagen and smooth muscle cells. Many structural models employ mean values of vessel microstructure, rather than continuous distributions of microstructure, to predict the mechanical properties of blood vessels. Although some models show good agreements on macroscopic vessel responses, they result in a lower elastin stiffness and earlier collagen recruitment. Hence, a full microstructural constitutive model is required for better understanding vascular biomechanics in health and disease. Here, a 3D microstructural model that accounts for all constituent microstructure is proposed to predict macroscopic and microscopic responses of coronary arteries. Coronary artery microstructural parameters were determined based on previous statistical measurements while mechanical testing of arteries (n = 5) were performed in this study to validate the computational predictions. The proposed model not only provides predictions of active and passive stress distributions of vessel wall, but also enables reliable estimations of material parameters of individual fibers and cells and thus predicts microstructural stresses. The validated microstructural model of coronary artery sheds light on vascular biomechanics and can be extend to diseased vessels for better understanding of initiation, progression and clinical treatment of vascular disease. PMID- 28839150 TI - Lossless Three-Dimensional Parallelization in Digitally Scanned Light-Sheet Fluorescence Microscopy. AB - We introduce a concept that enables parallelized three-dimensional imaging throughout large volumes with isotropic 300-350 nm resolution. By staggering high aspect ratio illumination beams laterally and axially within the depth of focus of a digitally scanned light-sheet fluorescence microscope (LSFM), multiple image planes can be simultaneously imaged with minimal cross-talk and light loss. We present a first demonstration of this concept for parallelized imaging by synthesizing two light-sheets with nonlinear Bessel beams and perform volumetric imaging of fluorescent beads and invasive breast cancer cells. This work demonstrates that in principle any digitally scanned LSFM can be parallelized in a lossless manner, enabling drastically faster volumetric image acquisition rates for a given sample brightness and detector technology. PMID- 28839151 TI - Evaluation of the concentration of point defects in GaN. AB - Photoluminescence (PL) was used to estimate the concentration of point defects in GaN. The results are compared with data from positron annihilation spectroscopy (PAS), secondary ion mass spectrometry (SIMS), and deep level transient spectroscopy (DLTS). Defect-related PL intensity in undoped GaN grown by hydride vapor phase epitaxy increases linearly with the concentration of related defects only up to 1016 cm-3. At higher concentrations, the PL intensity associated with individual defects tends to saturate, and accordingly, does not directly correlate with the concentration of defects. For this reason, SIMS analysis, with relatively high detection limits, may not be helpful for classifying unidentified point defects in GaN. Additionally, we highlight challenges in correlating defects identified by PL with those by PAS and DLTS methods. PMID- 28839152 TI - Nickel-catalyzed synthesis of 1,1-diborylalkanes from terminal alkenes. AB - Organoboron compounds play an irreplaceable role in synthetic chemistry and the related transformations based on the unique reactivity of C-B bond are potentially the most efficient methods for the synthesis of organic molecules. The synthetic importance of multiboron compounds in C-C bond formation and function transformation reactions is growing and the related borations of activated or nonactivated alkenes have been developed recently. However, introducing directly two boron moieties into the terminal sites of alkenes giving 1,1-diborylalkanes in a catalytic fashion has not been explored yet. Here we describe a synthetic strategy of 1,1-diborylalkanes via a Ni-catalyzed 1,1 diboration of readily available terminal alkenes. This methodology shows high level of chemoselectivity and regioselectivity and can be used to convert a large variety of terminal alkenes, such as vinylarenes, aliphatic alkenes and lower alkenes, to 1,1-diborylalkanes.1,1-diborylalkanes are useful building blocks in synthetic chemistry. Here, the authors present a highly chemo- and regioselective Ni-catalyzed reaction for the synthesis of 1,1-diborylalkanes from a wide variety of readily available terminal alkenes. PMID- 28839153 TI - Melittin-induced alterations in morphology and deformability of human red blood cells using quantitative phase imaging techniques. AB - Here, the actions of melittin, the active molecule of apitoxin or bee venom, were investigated on human red blood cells (RBCs) using quantitative phase imaging techniques. High-resolution real-time 3-D refractive index (RI) measurements and dynamic 2-D phase images of individual melittin-bound RBCs enabled in-depth examination of melittin-induced biophysical alterations of the cells. From the measurements, morphological, intracellular, and mechanical alterations of the RBCs were analyzed quantitatively. Furthermore, leakage of haemoglobin (Hb) inside the RBCs at high melittin concentration was also investigated. PMID- 28839154 TI - Genetic determinants restricting the reassortment of heterologous NSP2 genes into the simian rotavirus SA11 genome. AB - Rotaviruses (RVs) can evolve through the process of reassortment, whereby the 11 double-stranded RNA genome segments are exchanged among strains during co infection. However, reassortment is limited in cases where the genes or encoded proteins of co-infecting strains are functionally incompatible. In this study, we employed a helper virus-based reverse genetics system to identify NSP2 gene regions that correlate with restricted reassortment into simian RV strain SA11. We show that SA11 reassortants with NSP2 genes from human RV strains Wa or DS-1 were efficiently rescued and exhibit no detectable replication defects. However, we could not rescue an SA11 reassortant with a human RV strain AU-1 NSP2 gene, which differs from that of SA11 by 186 nucleotides (36 amino acids). To map restriction determinants, we engineered viruses to contain chimeric NSP2 genes in which specific regions of AU-1 sequence were substituted with SA11 sequence. We show that a region spanning AU-1 NSP2 gene nucleotides 784-820 is critical for the observed restriction; yet additional determinants reside in other gene regions. In silico and in vitro analyses were used to predict how the 784-820 region may impact NSP2 gene/protein function, thereby informing an understanding of the reassortment restriction mechanism. PMID- 28839155 TI - Mapping the 'Two-component system' network in rice. AB - Two-component system (TCS) in plants is a histidine to aspartate phosphorelay based signaling system. Rice genome has multifarious TCS signaling machinery comprising of 11 histidine kinases (OsHKs), 5 histidine phosphotransferases (OsHPTs) and 36 response regulators (OsRRs). However, how these TCS members interact with each other and comprehend diverse signaling cascades remains unmapped. Using a highly stringent yeast two-hybrid (Y2H) platform and extensive in planta bimolecular fluorescence complementation (BiFC) assays, distinct arrays of interaction between various TCS proteins have been identified in the present study. Based on these results, an interactome map of TCS proteins has been assembled. This map clearly shows a cross talk in signaling, mediated by different sensory OsHKs. It also highlights OsHPTs as the interaction hubs, which interact with OsRRs, mostly in a redundant fashion. Remarkably, interactions between type-A and type-B OsRRs have also been revealed for the first time. These observations suggest that feedback regulation by type-A OsRRs may also be mediated by interference in signaling at the level of type-B OsRRs, in addition to OsHPTs, as known previously. The interactome map presented here provides a starting point for in-depth molecular investigations for signal(s) transmitted by various TCS modules into diverse biological processes. PMID- 28839156 TI - Diagnostic classification of solitary pulmonary nodules using dual time 18F-FDG PET/CT image texture features in granuloma-endemic regions. AB - Lung cancer, the most commonly diagnosed cancer worldwide, usually presents as solid pulmonary nodules (SPNs) on early diagnostic images. Classification of malignant disease at this early timepoint is critical for improving the success of surgical resection and increasing 5-year survival rates. 18F fluorodeoxyglucose (18F-FDG) PET/CT has demonstrated value for SPNs diagnosis with high sensitivity to detect malignant SPNs, but lower specificity in diagnosing malignant SPNs in populations with endemic infectious lung disease. This study aimed to determine whether quantitative heterogeneity derived from various texture features on dual time FDG PET/CT images (DTPI) can differentiate between malignant and benign SPNs in patients from granuloma-endemic regions. Machine learning methods were employed to find optimal discrimination between malignant and benign nodules. Machine learning models trained by texture features on DTPI images achieved significant improvements over standard clinical metrics and visual interpretation for discriminating benign from malignant SPNs, especially by texture features on delayed FDG PET/CT images. PMID- 28839157 TI - Acute respiratory infections in hospitalized children in Vientiane, Lao PDR - the importance of Respiratory Syncytial Virus. AB - The Human respiratory syncytial virus (RSV) is one of the most important viral pathogens, causing epidemics of acute respiratory infection (ARI), especially bronchiolitis and pneumonia, in children worldwide. To investigate the RSV burden in Laos, we conducted a one-year study in children <5 years old admitted to Mahosot Hospital, Vientiane Capital, to describe clinical and epidemiological characteristics and predictive factors for severity of RSV-associated ARI. Pooled nasal and throat swabs were tested using multiplex real-time PCR for 33 respiratory pathogens (FTD(r) kit). A total of 383 patients were included, 277 (72.3%) of whom presented with pneumonia. 377 (98.4%) patients were positive for at least one microorganism, of which RSV was the most common virus (41.0%), with a peak observed between June and September, corresponding to the rainy season. Most RSV inpatients had pneumonia (84.1%), of whom 35% had severe pneumonia. Children <3-months old were a high-risk group for severe pneumonia, independently of RSV infection. Our study suggests that RSV infection is frequent in Laos and commonly associated with pneumonia in hospitalized young children. Further investigations are required to provide a better overall view of the Lao nationwide epidemiology and public health burden of RSV infection over time. PMID- 28839158 TI - In vivo biodistribution and toxicity of intravesical administration of quantum dots for optical molecular imaging of bladder cancer. AB - Optical molecular imaging holds the potential to improve cancer diagnosis. Fluorescent nanoparticles such as quantum dots (QD) offer superior optical characteristics compared to organic dyes, but their in vivo application is limited by potential toxicity from systemic administration. Topical administration provides an attractive route for targeted nanoparticles with the possibility of minimizing exposure and reduced dose. Previously, we demonstrated successful ex vivo endoscopic imaging of human bladder cancer by topical (i.e. intravesical) administration of QD-conjugated anti-CD47. Herein we investigate in vivo biodistribution and toxicity of intravesically instilled free QD and anti CD47-QD in mice. In vivo biodistribution of anti-CD47-QD was assessed with inductively coupled plasma mass spectrometry. Local and systemic toxicity was assessed using blood tests, organ weights, and histology. On average, there was no significant accumulation of QD outside of the bladder, although in some mice we detected extravesical biodistribution of QD suggesting a route for systemic exposure under some conditions. There were no indications of acute toxicity up to 7 days after instillation. Intravesical administration of targeted nanoparticles can reduce systemic exposure, but for clinical use, nanoparticles with established biosafety profiles should be used to decrease long-term toxicity in cases where systemic exposure occurs. PMID- 28839159 TI - On the use of atomistic simulations to aid bulk metallic glasses structural elucidation with solid-state NMR. AB - Solid-state nuclear magnetic resonance (ssNMR) experimental 27Al metallic shifts reported in the literature for bulk metallic glasses (BMGs) were revisited in the light of state-of-the-art atomistic simulations. In a consistent way, the Gauge Including Projector Augmented-Wave (GIPAW) method was applied in conjunction with classical molecular dynamics (CMD). A series of Zr-Cu-Al alloys with low Al concentrations were selected as case study systems, for which realistic CMD derived structural models were used for a short- and medium-range order mining. That initial procedure allowed the detection of trends describing changes on the microstructure of the material upon Al alloying, which in turn were used to guide GIPAW calculations with a set of abstract systems in the context of ssNMR. With essential precision and accuracy, the ab initio simulations also yielded valuable trends from the electronic structure point of view, which enabled an overview of the bonding nature of Al-centered clusters as well as its influence on the experimental ssNMR outcomes. The approach described in this work might promote the use of ssNMR spectroscopy in research on glassy metals. Moreover, the results presented demonstrate the possibility to expand the applications of this technique, with deeper insight into nuclear interactions and less speculative assignments. PMID- 28839160 TI - Functional characterisation of brassinosteroid receptor MtBRI1 in Medicago truncatula. AB - Brassinosteroids are phytohormones involved in plant development and physiological processes. Brassinosteroids Insensitive 1 (BRI1) is required for BR perception and initiation of subsequent signal transduction in Arabidopsis. In this study, the orthologue of BRI1 in the model legume species Medicago truncatula, MtBRI1, was identified and characterised. Three allelic Tnt1 insertion mutants, mtbri1-1, mtbri1-2, and mtbri1-3, were obtained from the M. truncatula Tnt1 insertion population. mtbri1 mutants displayed characteristic bri1 mutant phenotypes: extreme dwarfness, dark green curled leaves, short primary roots, less lateral roots, and insensitive to exogenous brassinolide (BL). Moreover, mtbri1 mutants show decreased total nodule number and defects in nitrogen fixation. MtBRI1 is able to complement an Arabidopsis BRI1 mutant, bri1 5. Similar to the interaction of BRI1 and BAK1 in Arabidopsis, MtBRI1 interacts with MtSERK1 in vivo. Global gene expression profiling revealed that the expression of BR biosynthesis genes and SAUR genes are significantly altered in mtbri1 mutants. MapMan analysis indicated that genes involved in signaling, hormone, cell wall, and biotic stress responses are over-represented in differentially expressed genes. Taken together, the results indicate that MtBRI1 is the BR receptor in M. truncatula and that BR signaling may play a conserved role in balancing plant growth and defenses. PMID- 28839161 TI - Metagenomic analysis reveals a green sulfur bacterium as a potential coral symbiont. AB - Coral reefs are ecologically significant habitats. Coral-algal symbiosis confers ecological success on coral reefs and coral-microbial symbiosis is also vital to coral reefs. However, current understanding of coral-microbial symbiosis on a genomic scale is largely unknown. Here we report a potential microbial symbiont in corals revealed by metagenomics-based genomic study. Microbial cells in coral were enriched for metagenomic analysis and a high-quality draft genome of "Candidatus Prosthecochloris korallensis" was recovered by metagenome assembly and genome binning. Phylogenetic analysis shows "Ca. P. korallensis" belongs to the Prosthecochloris clade and is clustered with two Prosthecochloris clones derived from Caribbean corals. Genomic analysis reveals "Ca. P. korallensis" has potentially important ecological functions including anoxygenic photosynthesis, carbon fixation via the reductive tricarboxylic acid (rTCA) cycle, nitrogen fixation, and sulfur oxidization. Core metabolic pathway analysis suggests "Ca. P. korallensis" is a green sulfur bacterium capable of photoautotrophy or mixotrophy. Potential host-microbial interaction reveals a symbiotic relationship: "Ca. P. korallensis" might provide organic and nitrogenous nutrients to its host and detoxify sulfide for the host; the host might provide "Ca. P. korallensis" with an anaerobic environment for survival, carbon dioxide and acetate for growth, and hydrogen sulfide as an electron donor for photosynthesis. PMID- 28839162 TI - MicroRNA-204 promotes vascular endoplasmic reticulum stress and endothelial dysfunction by targeting Sirtuin1. AB - Endoplasmic reticulum (ER) stress has been implicated in vascular endothelial dysfunction of obesity, diabetes, and hypertension. MicroRNAs play an important role in regulating ER stress. Here we show that microRNA-204 (miR-204) promotes vascular ER stress and endothelial dysfunction by targeting the Sirtuin1 (Sirt1) lysine deacetylase. Pharmacologic ER stress induced by tunicamycin upregulates miR-204 and downregulates Sirt1 in the vascular wall/endothelium in vivo and in endothelial cells in vitro. Inhibition of miR-204 protects against tunicamycin induced vascular/endothelial ER stress, associated impairment of endothelium dependent vasorelaxation, and preserves endothelial Sirt1. A miR-204 mimic leads to ER stress and downregulates Sirt1 in endothelial cells. Knockdown of Sirt1 in endothelial cells, and conditional deletion of endothelial Sirt1 in mice, promotes ER stress via upregulation of miR-204, whereas overexpression of Sirt1 in endothelial cells suppresses miR-204-induced ER stress. Furthermore, increase in vascular reactive oxygen species induced by ER stress is mitigated by by miR 204 inhibition. Finally, nutritional stress in the form of a Western diet promotes vascular ER stress through miR-204. These findings show that miR-204 is obligatory for vascular ER stress and ER stress-induced vascular endothelial dysfunction, and that miR-204 promotes vascular ER stress via downregulation of Sirt1. PMID- 28839163 TI - Investigation of Copper Cysteamine Nanoparticles as a New Type of Radiosensitiers for Colorectal Carcinoma Treatment. AB - Copper Cysteamine (Cu-Cy) is a new photosensitizer and a novel radiosensitizer that can be activated by light, X-ray and microwave to produce singlet oxygen for cancer treatment. However, the killing mechanism of Cu-Cy nanoparticles on cancer cells is not clear yet and Cu-Cy nanoparticles as novel radiosensitizers have never been tested on colorectal cancers. Here, for the first time, we investigate the treatment efficiency of Cu-Cy nanoparticles on SW620 colorectal cells and elucidate the underlying mechanisms of the effects. The results show that X-ray activated Cu-Cy nanoparticles may kill SW620 cancerscells is in a dose-dependent manner. The JC-1 staining shows the mitochondrial membrane potential is decreased after the treatment. The observations confirm that Cu-Cy nanoparticles may improve X-ray radiotherapy on cancer treatment and X-ray activated Cu-Cy nanoparticles can be efficiently destroy colorectal cancer cells by inducing apoptosis as well as autophagy. As a new type of radiosensitizers and photosensitizers, Cu-Cy nanoparticles have a good potential for colorectal cancer treatment and the discovery of autophagy induced by X-ray irradiated Cu-Cy nanoparticles sheds a good insight to the mechanism of Cu-Cy for cancer treatment as a new radiosensitizers. PMID- 28839164 TI - CUBIC pathology: three-dimensional imaging for pathological diagnosis. AB - The examination of hematoxylin and eosin (H&E)-stained tissues on glass slides by conventional light microscopy is the foundation for histopathological diagnosis. However, this conventional method has some limitations in x-y axes due to its relatively narrow range of observation area and in z-axis due to its two dimensionality. In this study, we applied a CUBIC pipeline, which is the most powerful tissue-clearing and three-dimensional (3D)-imaging technique, to clinical pathology. CUBIC was applicable to 3D imaging of both normal and abnormal patient-derived, human lung and lymph node tissues. Notably, the combination of deparaffinization and CUBIC enabled 3D imaging of specimens derived from paraffin-embedded tissue blocks, allowing quantitative evaluation of nuclear and structural atypia of an archival malignant lymphoma tissue. Furthermore, to examine whether CUBIC can be applied to practical use in pathological diagnosis, we performed a histopathological screening of a lymph node metastasis based on CUBIC, which successfully improved the sensitivity in detecting minor metastatic carcinoma nodules in lymph nodes. Collectively, our results indicate that CUBIC significantly contributes to retrospective and prospective clinicopathological diagnosis, which might lead to the establishment of a novel field of medical science based on 3D histopathology. PMID- 28839165 TI - Gene Expression Profiling of Cutaneous Injured and Non-Injured Nociceptors in SNI Animal Model of Neuropathic Pain. AB - Nociceptors are a particular subtype of dorsal root ganglion (DRG) neurons that detect noxious stimuli and elicit pain. Although recent efforts have been made to reveal the molecular profile of nociceptors in normal conditions, little is known about how this profile changes in pathological conditions. In this study we exploited laser capture microdissection to specifically collect individual injured and non-injured nociceptive DRG neurons and to define their gene profiling in rat spared nerve injury (SNI) model of neuropathic pain. We found minimal transcriptional changes in non-injured neurons at 7 days after SNI. In contrast, several novel transcripts were altered in injured nociceptors, and the global signature of these LCM-captured neurons differed markedly from that the gene expression patterns found previously using whole DRG tissue following SNI. Pathway analysis of the transcriptomic profile of the injured nociceptors revealed oxidative stress as a key biological process. We validated the increase of caspase-6 (CASP6) in small-sized DRG neurons and its functional role in SNI- and paclitaxel-induced neuropathic pain. Our results demonstrate that the identification of gene regulation in a specific population of DRG neurons (e.g., nociceptors) is an effective strategy to reveal new mechanisms and therapeutic targets for neuropathic pain from different origins. PMID- 28839166 TI - The impact of immigration on microbial community composition in full-scale anaerobic digesters. AB - Anaerobic digestion is widely applied to treat organic waste at wastewater treatment plants. Characterisation of the underlying microbiology represents a source of information to develop strategies for improved operation. Hence, we investigated microbial communities of thirty-two full-scale anaerobic digesters over a six-year period using 16S rRNA gene amplicon sequencing. Sampling of the sludge fed into these systems revealed that several of the most abundant populations were likely inactive and immigrating with the influent. This observation indicates that a failure to consider immigration will interfere with correlation analysis and give an inaccurate picture of the growing microbial community. Furthermore, several abundant OTUs could not be classified to genus level with commonly applied taxonomies, making inference of their function unreliable and comparison to other studies problematic. As such, the existing MiDAS taxonomy was updated to include these abundant phylotypes. The communities of individual digesters surveyed were remarkably similar - with only 300 OTUs representing 80% of the total reads across all plants, and 15% of these identified as non-growing and possibly inactive immigrating microbes. By identifying abundant and growing taxa in anaerobic digestion, this study paves the way for targeted characterisation of the process-important organisms towards an in-depth understanding of the microbiology. PMID- 28839167 TI - Analytical performance of reagent for assaying tau protein in human plasma and feasibility study screening neurodegenerative diseases. AB - Immunomagnetic reduction (IMR), which involves the use of antibody-functionalized magnetic nanoparticles to specifically label target biomarkers, was utilized to develop an assay for total tau protein in human plasma. The analytic properties of the IMR assay on tau protein were investigated. The limit of detection was found to be 0.026 pg/ml. Other properties such as Hook effect, assay linearity, dilution recovery range, reagent stability, interference test, and spiked recovery were also characterized. The ultra-sensitive IMR assay was applied to detect the plasma tau protein levels of subjects with prevalent neurodegenerative diseases, such as Alzheimer's disease (AD), mild cognitive impairment (MCI) due to AD, Parkinson's disease (PD), frontotemporal dementia (FTD) and vascular dementia (VD). The concentrations of plasma tau protein in patients with VD, PD, MCI due to AD, FTD, and AD patients were higher than that of healthy controls. Using an ROC curve analysis, the cutoff value for discriminating dementia patients from healthy controls was 17.43 pg/ml, resulting in 0.856 and 0.727 for clinical sensitivity and specificity, respectively. The area under the ROC curve was 0.908. These results imply that the IMR plasma tau assay would be useful to screen for prevalent neurodegenerative diseases. PMID- 28839168 TI - Drug Loaded Gingival Mesenchymal Stromal Cells (GinPa-MSCs) Inhibit In Vitro Proliferation of Oral Squamous Cell Carcinoma. AB - Human mesenchymal stromal cells (MSCs) have been widely investigated both for regenerative medicine and their antinflammatory/immunomodulatory capacity. However, their ability to home pathological tissues suggested the development of strategies for using MSCs as carrier to deliver drug into tumor microenvironment. MSCs obtained from different tissues can be loaded in vitro with anti-cancer drugs by a simple procedures. In this report, we studied MSCs isolated and expanded from gingival papilla (GinPa-MSCs), by testing their ability to uptake and release three important anti-neoplastic drugs: Paclitaxel (PTX), Doxorubicin (DXR) and Gemcitabine (GCB). The efficacy of drugs releasing GinPa-MSCs was studied on a pancreatic cancer cell line and confirmed in vitro against a line of tongue squamous cell carcinoma (SCC154). Our results demonstrated that GinPa-MSCs efficiently incorporate the drugs and then released them in active form and in sufficient amount to produce a dramatic inhibition of squamous cell carcinoma growth in vitro. If compared with other MSCs sources, the collection of GinPa MSCs is poorly invasive and cells can be easily expanded and efficiently loaded with anti cancer drugs. In particular, gemcitabine loaded GinPa-MSCs provide a good "cell-mediated drug delivery system" for a future potential application in the context of the oral oncology. PMID- 28839169 TI - Frequency, moisture content, and temperature dependent dielectric properties of potato starch related to drying with radio-frequency/microwave energy. AB - To develop advanced drying methods using radio-frequency (RF) or microwave (MW) energy, dielectric properties of potato starch were determined using an open ended coaxial-line probe and network analyzer at frequencies between 20 and 4,500 MHz, moisture contents between 15.1% and 43.1% wet basis (w.b.), and temperatures between 25 and 75 degrees C. The results showed that both dielectric constant (epsilon') and loss factor (epsilon") were dependent on frequency, moisture content, and temperature. epsilon' decreased with increasing frequency at a given moisture content or temperature. At low moisture contents (<=25.4% w.b.) or low temperatures (<=45 degrees C), epsilon" increased with increasing frequency. However, epsilon" changed from decrease to increase with increasing frequency at high moisture contents or temperatures. At low temperatures (25-35 degrees C), both epsilon' and epsilon" increased with increasing moisture content. At low moisture contents (15.1-19.5% w.b.), they increased with increasing temperature. The change trends of epsilon' and epsilon" were different and dependent on temperature and moisture content at their high levels. The penetration depth (d p ) decreased with increasing frequency. RF treatments may provide potential large scale industrial drying application for potato starch. This research offers useful information on dielectric properties of potato starch related to drying with electromagnetic energy. PMID- 28839170 TI - CLE peptide-encoding gene families in Medicago truncatula and Lotus japonicus, compared with those of soybean, common bean and Arabidopsis. AB - CLE peptide hormones are critical regulators of many cell proliferation and differentiation mechanisms in plants. These 12-13 amino acid glycosylated peptides play vital roles in a diverse range of plant tissues, including the shoot, root and vasculature. CLE peptides are also involved in controlling legume nodulation. Here, the entire family of CLE peptide-encoding genes was identified in Medicago truncatula (52) and Lotus japonicus (53), including pseudogenes and non-functional sequences that were identified. An array of bioinformatic techniques were used to compare and contrast these complete CLE peptide-encoding gene families with those of fellow legumes, Glycine max and Phaseolus vulgaris, in addition to the model plant Arabidopsis thaliana. This approach provided insight into the evolution of CLE peptide families and enabled us to establish putative M. truncatula and L. japonicus orthologues. This includes orthologues of nodulation-suppressing CLE peptides and AtCLE40 that controls the stem cell population of the root apical meristem. A transcriptional meta-analysis was also conducted to help elucidate the function of the CLE peptide family members. Collectively, our analyses considerably increased the number of annotated CLE peptides in the model legume species, M. truncatula and L. japonicus, and substantially enhanced the knowledgebase of this critical class of peptide hormones. PMID- 28839171 TI - Quantum illumination reveals phase-shift inducing cloaking. AB - In quantum illumination entangled light is employed to enhance the detection accuracy of an object when compared with the best classical protocol. On the other hand, cloaking is a stealth technology based on covering a target with a material deflecting the light around the object to avoid its detection. Here, we propose a quantum illumination protocol especially adapted to quantum microwave technology. This protocol seizes the phase-shift induced by some cloaking techniques, such as scattering reduction, allowing for a 3 dB improvement in the detection of a cloaked target. The method can also be employed for the detection of a phase-shift in bright environments in different frequency regimes. Finally, we study the minimal efficiency required by the photocounter for which the quantum illumination protocol still shows a gain with respect to the classical protocol. PMID- 28839173 TI - Large Thermal Motion in Halide Perovskites. AB - Solar cells based on hybrid perovskites have shown high efficiency while possessing simple processing methods. To gain a fundamental understanding of their properties on an atomic level, we investigate single crystals of CH3NH3PbI3 with a narrow transition (~5 K) near 327 K. Temperature dependent structural measurements reveal a persistent tetragonal structure with smooth changes in the atomic displacement parameters (ADPs) on crossing T*. We show that the ADPs for I ions yield extended flat regions in the potential wells consistent with the measured large thermal expansion parameter. Molecular dynamics simulations reveal that this material exhibits significant asymmetries in the Pb-I pair distribution functions. We also show that the intrinsically enhanced freedom of motion of the iodine atoms enables large deformations. This flexibility (softness) of the atomic structure results in highly localized atomic relaxation about defects and hence accounts for both the high carrier mobility as well as the structural instability. PMID- 28839172 TI - Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene. AB - Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 * 10-6). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 * 10-4) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 * 10-5), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed. PMID- 28839174 TI - Light-patterning of synthetic tissues with single droplet resolution. AB - Synthetic tissues can be generated by forming networks of aqueous droplets in lipid-containing oil. Each droplet contains a cell-free expression system and is connected to its neighbor through a lipid bilayer. In the present work, we have demonstrated precise external control of such networks by activating protein expression within single droplets, by using light-activated DNA to encode either a fluorescent or a pore-forming protein. By controlling the extent of activation, synthetic tissues were generated with graded levels of protein expression in patterns of single droplets. Further, we have demonstrated reversible activation within individual compartments in synthetic tissues by turning a fluorescent protein on-and-off. This is the first example of the high-resolution patterning of droplet networks, following their formation. Single-droplet control will be essential to power subsets of compartments within synthetic tissues or to stimulate subsets of cells when synthetic tissues are interfaced with living tissues. PMID- 28839175 TI - Oxygen nanobubbles revert hypoxia by methylation programming. AB - Targeting the hypoxic tumor microenvironment has a broad impact in cancer epigenetics and therapeutics. Oxygen encapsulated nanosize carboxymethyl cellulosic nanobubbles were developed for mitigating the hypoxic regions of tumors to weaken the hypoxia-driven pathways and inhibit tumor growth. We show that 5-methylcytosine (5mC) hypomethylation in hypoxic regions of a tumor can be reverted to enhance cancer treatment by epigenetic regulation, using oxygen nanobubbles in the sub-100 nm size range, both, in vitro and in vivo. Oxygen nanobubbles were effective in significantly delaying tumor progression and improving survival rates in mice models. Further, significant hypermethylation was observed in promoter DNA region of BRCA1 due to oxygen nanobubble (ONB) treatment. The nanobubbles can also reprogram several hypoxia associated and tumor suppressor genes such as MAT2A and PDK-1, in addition to serving as an ultrasound contrast agent. Our approach to develop nanosized oxygen encapsulated bubbles as an ultrasound contrast agent for methylation reversal is expected to have a significant impact in epigenetic programming and to serve as an adjuvant to cancer treatment. PMID- 28839177 TI - Simple MD-based model for oxidative folding of peptides and proteins. AB - Significant strides have been recently made to fold peptides and small proteins in silico using MD simulations. However, facilities are currently lacking to include disulfide bonding in the MD models of protein folding. To address this problem, we have developed a simple empirical protocol to model formation of disulfides, which is perturbation-free, retains the same speed as conventional MD simulations and allows one to control the reaction rate. The new protocol has been tested on 15-aminoacid peptide guanylin containing four cysteine residues; the net simulation time using Amber ff14SB force field was 61 MUs. The resulting isomer distribution is in qualitative agreement with experiment, suggesting that oxidative folding of guanylin in vitro occurs under kinetic control. The highly stable conformation of the so-called isomer 2(B) has been obtained for full length guanylin, which is significantly different from the poorly ordered structure of the truncated peptide PDB ID 1GNB. In addition, we have simulated oxidative folding of guanylin within the 94-aminoacid prohormone proguanylin. The obtained structure is in good agreement with the NMR coordinates 1O8R. The proposed modeling strategy can help to explore certain fundamental aspects of protein folding and is potentially relevant for manufacturing of synthetic peptides and recombinant proteins. PMID- 28839176 TI - Cerium oxide nanoparticles inhibit differentiation of neural stem cells. AB - Cerium oxide nanoparticles (nanoceria) display antioxidant properties and have shown cytoprotective effects both in vitro and in vivo. Here, we explored the effects of nanoceria on neural progenitor cells using the C17.2 murine cell line as a model. First, we assessed the effects of nanoceria versus samarium (Sm) doped nanoceria on cell viability in the presence of the prooxidant, DMNQ. Both particles were taken up by cells and nanoceria, but not Sm-doped nanoceria, elicited a temporary cytoprotective effect upon exposure to DMNQ. Next, we employed RNA sequencing to explore the transcriptional responses induced by nanoceria or Sm-doped nanoceria during neuronal differentiation. Detailed computational analyses showed that nanoceria altered pathways and networks relevant for neuronal development, leading us to hypothesize that nanoceria inhibits neuronal differentiation, and that nanoceria and Sm-doped nanoceria both interfere with cytoskeletal organization. We confirmed that nanoceria reduced neuron specific beta3-tubulin expression, a marker of neuronal differentiation, and GFAP, a neuroglial marker. Furthermore, using super-resolution microscopy approaches, we could show that both particles interfered with cytoskeletal organization and altered the structure of neural growth cones. Taken together, these results reveal that nanoceria may impact on neuronal differentiation, suggesting that nanoceria could pose a developmental neurotoxicity hazard. PMID- 28839178 TI - Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs. AB - Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to 'ALF', defined as INR >3. In APAP pigs, INR was 1.05 +/- 0.02 at 0 h, 2.15 +/- 0.43 at 16 h and > 3 at 18 +/- 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats-13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 +/- 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability. PMID- 28839179 TI - Evolution of rubisco complex small subunit transit peptides from algae to plants. AB - Chloroplasts evolved from a free-living cyanobacterium acquired by the ancestor of all photosynthetic eukaryotes, including algae and plants, through a single endosymbiotic event. During endosymbiotic conversion, the majority of genes in the endosymbiont were transferred to the host nucleus and many of the proteins encoded by these genes must therefore be transported into the chloroplast after translation in the cytosol. Chloroplast-targeted proteins contain a targeting signal, named the transit peptide (TP), at the N-terminus. However, the evolution of TPs is not well understood. In this study, TPs from RbcS (rubisco small subunit) were compared between lower and higher eukaryotes. Chlamydomonas reinhardtii RbcS (CrRbcS) TP was non-functional in Arabidopsis. However, inclusion of a critical sequence motif, FP-RK, from Arabidopsis thaliana RbcS (AtRbcS) TP allowed CrRbcS TP to deliver proteins into plant chloroplasts. The position of the FP-RK motif in CrRbcS TP was critical for function. The QMMVW sequence motif in CrRbcS TP was crucial for its transport activity in plants. CrRbcS TPs containing additional plant motifs remained functional in C. reinhardtii. These results suggest that TPs evolved by acquiring additional sequence motifs to support protein targeting to chloroplasts during evolution of land plants from algae. PMID- 28839180 TI - Compact flexible multi-pass rotary delay line using spinning micro-machined mirrors. AB - We propose a new method to extend the path length tunability of rotary delay lines. This method was shown to achieve a duty cycle of >80% and repetition rates of over 40 kHz. The new method relies on a new multi-segmented micro-machined mirror and serial injection of a single reflection onto separate segments of this mirror. The tunability is provided by the relative positioning of each reflective point on the mirror segments. There are two distinct modes of operation: synchronous and asynchronous. By simply manipulating the spatial position of the returning paths over the respective mirror segments, we can switch between increasing the repetition rate (asynchronous mode) or the total delay path (synchronous mode). We experimentally demonstrated up to 8 m/s scans with repetition rates of up to 42.7 kHz. Furthermore, we present numerical simulations of 18 reflection points to illustrate possibility of achieving a scan speed of up to 80 m/s. Through intermediate combinations of synchronous and asynchronous operation modes with 4 or more passes, we also show that the system can simultaneously increase both repetition rate and scan depth. PMID- 28839181 TI - DrwH, a novel WHy domain-containing hydrophobic LEA5C protein from Deinococcus radiodurans, protects enzymatic activity under oxidative stress. AB - Water stress and hypersensitive response (WHy) domain is typically found as a component of atypical late embryogenesis abundant (LEA) proteins closely associated with resistance to multiple stresses in numerous organisms. Several putative LEA proteins have been identified in Deinococcus bacteria; however their precise function remains unclear. This work reports the characterization of a Deinococcus-specific gene encoding a novel WHy domain-containing hydrophobic LEA5C protein (named DrwH) in D. radiodurans R1. The expression of the drwH gene was induced by oxidative and salinity stresses. Inactivation of this gene resulted in increased sensitivity to oxidative and salinity stresses as well as reduced activities of antioxidant enzymes. The WHy domain of the DrwH protein differs structurally from that of a previously studied bacterial LEA5C protein, dWHy1, identified as a gene product from an Antarctic desert soil metagenome library. Further analysis indicated that in E. coli, the function of DrwH is related to oxidative stress tolerance, whereas dWHy1 is associated with freezing thawing stress tolerance. Under oxidative stress induced by H2O2, DrwH protected the enzymatic activities of malate dehydrogenase (MDH) and lactate dehydrogenase (LDH). These findings provide new insight into the evolutionary and survival strategies of Deinococcus bacteria under extreme environmental conditions. PMID- 28839182 TI - Combined effects of increased temperature and endocrine disrupting pollutants on sex determination, survival, and development across generations. AB - Understanding the combined effects of anthropogenic impacts such as climate change and pollution on aquatic ecosystems is critical. However, little is known about how predicted temperature increases may affect the activity of endocrine disrupting compounds (EDCs), particularly in species with plasticity in sex determination. We investigated the effects of a concomitant increase in temperature and exposure to estrogenic EDCs on reproduction and development in an estuarine model organism (Menidia beryllina) across multiple generations. Parents (P) were exposed to environmental levels of the estrogenic insecticide bifenthrin or ethinylestradiol (EE2) at 22 degrees C and 28 degrees C for 14 days prior to the initiation of spawning trials. Embryos in the F1 generation were exposed to EDCs until 21 days post hatch (dph), reared to adulthood in clean water at elevated temperatures, and spawned. F1 sex ratios were significantly influenced by elevated temperature and EDCs, potentially altering adaptive development. We also observed fewer viable offspring and increased developmental deformities in the F1 and F2 generations, with a greater impact on F2 juveniles. These findings enhance our understanding of responses to EDCs in the context of climate change and may demonstrate heritable effects. Our study represents the first multigenerational assessment of elevated temperatures in combination with environmentally relevant concentrations of commonly detected endocrine disruptors in a model vertebrate species. PMID- 28839184 TI - Achievability of 3D planned bimaxillary osteotomies: maxilla-first versus mandible-first surgery. AB - The present study was aimed to investigate the effects of sequencing a two component surgical procedure for correcting malpositioned jaws (bimaxillary osteotomies); specifically, surgical repositioning of the upper jaw-maxilla, and the lower jaw-mandible. Within a population of 116 patients requiring bimaxillary osteotomies, the investigators analyzed whether there were statistically significant differences in postoperative outcome as measured by concordance with a preoperative digital 3D virtual treatment plan. In one group of subjects (n = 58), the maxillary surgical procedure preceded the mandibular surgery. In the second group (n = 58), the mandibular procedure preceded the maxillary surgical procedure. A semi-automated analysis tool (OrthoGnathicAnalyser) was applied to assess the concordance of the postoperative maxillary and mandibular position with the cone beam CT-based 3D virtual treatment planning in an effort to minimize observer variability. The results demonstrated that in most instances, the maxilla-first surgical approach yielded closer concordance with the 3D virtual treatment plan than a mandibular-first procedure. In selected circumstances, such as a planned counterclockwise rotation of both jaws, the mandible-first sequence resulted in more predictable displacements of the jaws. PMID- 28839183 TI - Trans-omics approaches used to characterise fish nutritional biorhythms in leopard coral grouper (Plectropomus leopardus). AB - Aquaculture is now a major supplier of fish, and has the potential to be a major source of protein in the future. Leopard coral groupers are traded in Asian markets as superior fish, and production via aquaculture has commenced. As feeding efficiency is of great concern in aquaculture, we sought to examine the metabolism of leopard coral groupers using trans-omics approaches. Metabolic mechanisms were comprehensively analysed using transcriptomic and metabolomic techniques. This study focused on the dynamics of muscular metabolites and gene expression. The omics data were discussed in light of circadian rhythms and fasting/feeding. The obtained data suggest that branched-chain amino acids played a role in energy generation in the fish muscle tissues during fasting. Moreover, glycolysis, TCA cycles, and purine metabolic substances exhibited circadian patterns, and gene expression also varied. This study is the first step to understanding the metabolic mechanisms of the leopard coral grouper. PMID- 28839185 TI - Antisense oligonucleotide and thyroid hormone conjugates for obesity treatment. AB - Using the principle of antibody-drug conjugates that deliver highly potent cytotoxic agents to cancer cells for cancer therapy, we here report the synthesis of antisense-oligonucleotides (ASO) and thyroid hormone T3 conjugates for obesity treatment. ASOs primarily target fat and liver with poor penetrance to other organs. Pharmacological T3 treatment increases energy expenditure and causes weight loss, but is contraindicated for obesity treatment due to systemic effects on multiple organs. We hypothesize that ASO-T3 conjugates may knock down target genes and enrich T3 action in fat and liver. Two established ASOs are tested. Nicotinamide N-methyltransferase (NNMT)-ASO prevents diet-induced obesity in mice. Apolipoprotein B (ApoB)-ASO is an FDA approved drug for treating familial hypercholesterolemia. NNMT-ASO and ApoB-ASO are chemically conjugated with T3 using a non-cleavable sulfo-SMCC linker. Both NNMT-ASO-T3 (NAT3) and ApoB-ASO-T3 (AAT3) enhance thyroid hormone receptor activity. Treating obese mice with NAT3 or AAT3 decreases adiposity and increases lean mass. ASO-T3 enhances white fat browning, decreases genes for fatty acid synthesis in liver, and shows limited effects on T3 target genes in heart and muscle. Furthermore, AAT3 augments LDL cholesterol-lowering effects of ApoB-ASO. Therefore, ASO and hormone/drug conjugation may provide a novel strategy for obesity and hyperlipidemia treatment. PMID- 28839187 TI - Quantitative proteomic characterization of lung-MSC and bone marrow-MSC using DIA mass spectrometry. AB - Mesenchymal stromal cells (MSC) are ideal candidates for cell therapies, due to their immune-regulatory and regenerative properties. We have previously reported that lung-derived MSC are tissue-resident cells with lung-specific properties compared to bone marrow-derived MSC. Assessing relevant molecular differences between lung-MSC and bone marrow-MSC is important, given that such differences may impact their behavior and potential therapeutic use. Here, we present an in depth mass spectrometry (MS) based strategy to investigate the proteomes of lung MSC and bone marrow-MSC. The MS-strategy relies on label free quantitative data independent acquisition (DIA) analysis and targeted data analysis using a MSC specific spectral library. We identified several significantly differentially expressed proteins between lung-MSC and bone marrow-MSC within the cell layer (352 proteins) and in the conditioned medium (49 proteins). Bioinformatics analysis revealed differences in regulation of cell proliferation, which was functionally confirmed by decreasing proliferation rate through Cytochrome P450 stimulation. Our study reveals important differences within proteome and matrisome profiles between lung- and bone marrow-derived MSC that may influence their behavior and affect the clinical outcome when used for cell-therapy. PMID- 28839186 TI - An integrated bioinformatics platform for investigating the human E3 ubiquitin ligase-substrate interaction network. AB - The ubiquitination mediated by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) cascade is crucial to protein degradation, transcription regulation, and cell signaling in eukaryotic cells. The high specificity of ubiquitination is regulated by the interaction between E3 ubiquitin ligases and their target substrates. Unfortunately, the landscape of human E3-substrate network has not been systematically uncovered. Therefore, there is an urgent need to develop a high-throughput and efficient strategy to identify the E3-substrate interaction. To address this challenge, we develop a computational model based on multiple types of heterogeneous biological evidence to investigate the human E3-substrate interactions. Furthermore, we provide UbiBrowser as an integrated bioinformatics platform to predict and present the proteome-wide human E3-substrate interaction network ( http://ubibrowser.ncpsb.org ).Protein stability modulation by E3 ubiquitin ligases is an important layer of functional regulation, but screening for E3 ligase-substrate interactions is time-consuming and costly. Here, the authors take an in silico naive Bayesian classifier approach to integrate multiple lines of evidence for E3-substrate prediction, enabling prediction of the proteome-wide human E3 ligase interaction network. PMID- 28839188 TI - A comparative study of the mechanical and thermal properties of defective ZrC, TiC and SiC. AB - ZrC and TiC have been proposed to be alternatives to SiC as fuel-cladding and structural materials in nuclear reactors due to their strong radiation tolerance and high thermal conductivity at high temperatures. To unravel how the presence of defects affects the thermo-physical properties under irradiation, first principles calculations based on density function theory were carried out to investigate the mechanical and thermal properties of defective ZrC, TiC and SiC. As compared with the defective SiC, the ZrC and TiC always exhibit larger bulk modulus, smaller changes in the Young's and shear moduli, as well as better ductility. The total thermal conductivity of ZrC and TiC are much larger than that of SiC, implying that under radiation environment the ZrC and TiC will exhibit superior heat conduction ability than the SiC. One disadvantage for ZrC and TiC is that their Debye temperatures are generally lower than that of SiC. These results suggest that further improving the Debye temperature of ZrC and TiC will be more beneficial for their applications as fuel-cladding and structural materials in nuclear reactors. PMID- 28839189 TI - A systematic analysis of the RNA-targeting potential of secreted bacterial effector proteins. AB - Many pathogenic bacteria utilize specialized secretion systems to deliver proteins called effectors into eukaryotic cells for manipulation of host pathways. The vast majority of known effector targets are host proteins, whereas a potential targeting of host nucleic acids remains little explored. There is only one family of effectors known to target DNA directly, and effectors binding host RNA are unknown. Here, we take a two-pronged approach to search for RNA binding effectors, combining biocomputational prediction of RNA-binding domains (RBDs) in a newly assembled comprehensive dataset of bacterial secreted proteins, and experimental screening for RNA binding in mammalian cells. Only a small subset of effectors were predicted to carry an RBD, indicating that if RNA targeting was common, it would likely involve new types of RBDs. Our experimental evaluation of effectors with predicted RBDs further argues for a general paucity of RNA binding activities amongst bacterial effectors. We obtained evidence that PipB2 and Lpg2844, effector proteins of Salmonella and Legionella species, respectively, may harbor novel biochemical activities. Our study presenting the first systematic evaluation of the RNA-targeting potential of bacterial effectors offers a basis for discussion of whether or not host RNA is a prominent target of secreted bacterial proteins. PMID- 28839190 TI - Identification and ranking of environmental threats with ecosystem vulnerability distributions. AB - Responses of ecosystems to human-induced stress vary in space and time, because both stressors and ecosystem vulnerabilities vary in space and time. Presently, ecosystem impact assessments mainly take into account variation in stressors, without considering variation in ecosystem vulnerability. We developed a method to address ecosystem vulnerability variation by quantifying ecosystem vulnerability distributions (EVDs) based on monitoring data of local species compositions and environmental conditions. The method incorporates spatial variation of both abiotic and biotic variables to quantify variation in responses among species and ecosystems. We show that EVDs can be derived based on a selection of locations, existing monitoring data and a selected impact boundary, and can be used in stressor identification and ranking for a region. A case study on Ohio's freshwater ecosystems, with freshwater fish as target species group, showed that physical habitat impairment and nutrient loads ranked highest as current stressors, with species losses higher than 5% for at least 6% of the locations. EVDs complement existing approaches of stressor assessment and management, which typically account only for variability in stressors, by accounting for variation in the vulnerability of the responding ecosystems. PMID- 28839191 TI - Loss of Tmem30a leads to photoreceptor degeneration. AB - Phosphatidylserine (PS) is asymmetrically distributed between the outer and inner leaflets of the plasma membrane in eukaryotic cells. PS asymmetry on the plasma membrane depends on the activities of P4-ATPases, and disruption of PS distribution can lead to various disease conditions. Folding and transporting of P4-ATPases to their cellular destination requires the beta subunit TMEM30A proteins. However, the in vivo functions of Tmem30a remain unknown. To this end, we generated retinal-specific Tmem30a-knockout mice to investigate its roles in vivo for the first time. Our data demonstrated that loss of Tmem30a in mouse cone cells leads to mislocalization of cone opsin, loss of photopic electroretinogram (ERG) responses and loss of cone cells. Mechanistically, Tmem30a-mutant mouse embryonic fibroblasts (MEFs) exhibited diminished PS flippase activity and increased exposure of PS on the cell surface. The broad loss of Tmem30a in adult mice led to a reduced scotopic photoresponse, mislocalization of ATP8A2 to the inner segment and cell body, and increased apoptosis in the retina. Our data demonstrated novel essential roles of Tmem30a in the retina. PMID- 28839192 TI - Indole-based perenosins as highly potent HCl transporters and potential anti cancer agents. AB - Prodigiosin is one of the most potent anion transporters in lipid bilayer membranes reported to date. Inspired by the structure of this natural product, we have recently designed and synthesised a new class of H+/Cl- cotransporters named 'perenosins'. Here we report a new library of indole-based perenosins and their anion transport properties. The new transporters demonstrated superior transmembrane transport efficiency when compared to other indole-based transporters, due to favourable encapsulating effects from the substituents on the perenosin backbone. Anion transport assays were used to determine the mechanism of chloride transport revealing that the compounds function as 'strict' HCl cotransporters. Cell viability studies showed that some compounds specifically trigger late-onset cell death after 72 h with a unique correlation to the position of alkyl chains on the perenosins. Further investigations of cell death mechanism showed a mixture of cell cycle arrest and apoptosis was responsible for the observed decrease in cell viability. PMID- 28839193 TI - The epigenetic modifier Fam208a is required to maintain epiblast cell fitness. AB - Gastrulation initiates with the formation of the primitive streak, during which, cells of the epiblast delaminate to form the mesoderm and definitive endoderm. At this stage, the pluripotent cell population of the epiblast undergoes very rapid proliferation and extensive epigenetic programming. Here we show that Fam208a, a new epigenetic modifier, is essential for early post-implantation development. We show that Fam208a mutation leads to impaired primitive streak elongation and delayed epithelial-to-mesenchymal transition. Fam208a mutant epiblasts had increased expression of p53 pathway genes as well as several pluripotency associated long non-coding RNAs. Fam208a mutants exhibited an increase in p53 driven apoptosis and complete removal of p53 could partially rescue their gastrulation block. This data demonstrates a new in vivo function of Fam208a in maintaining epiblast fitness, establishing it as an important factor at the onset of gastrulation when cells are exiting pluripotency. PMID- 28839195 TI - Erratum: Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 28839194 TI - An automated compound screening for anti-aging effects on the function of C. elegans sensory neurons. AB - Discovery of molecular targets or compounds that alter neuronal function can lead to therapeutic advances that ameliorate age-related neurodegenerative pathologies. Currently, there is a lack of in vivo screening technologies for the discovery of compounds that affect the age-dependent neuronal physiology. Here, we present a high-throughput, microfluidic-based assay for automated manipulation and on-chip monitoring and analysis of stimulus-evoked calcium responses of intact C. elegans at various life stages. First, we successfully applied our technology to quantify the effects of aging and age-related genetic and chemical factors in the calcium transients of the ASH sensory neuron. We then performed a large-scale screen of a library of 107 FDA-approved compounds to identify hits that prevented the age-dependent functional deterioration of ASH. The robust performance of our assay makes it a valuable tool for future high-throughput applications based on in vivo functional imaging. PMID- 28839196 TI - Development of novel monoclonal antibodies against starch and ulvan - implications for antibody production against polysaccharides with limited immunogenicity. AB - Monoclonal antibodies (mAbs) are widely used and powerful research tools, but the generation of mAbs against glycan epitopes is generally more problematic than against proteins. This is especially significant for research on polysaccharide rich land plants and algae (Viridiplantae). Most antibody production is based on using single antigens, however, there are significant gaps in the current repertoire of mAbs against some glycan targets with low immunogenicity. We approached mAb production in a different way and immunised with a complex mixture of polysaccharides. The multiplexed screening capability of carbohydrate microarrays was then exploited to deconvolute the specificities of individual mAbs. Using this strategy, we generated a set of novel mAbs, including one against starch (INCh1) and one against ulvan (INCh2). These polysaccharides are important storage and structural polymers respectively, but both are generally considered as having limited immunogenicity. INCh1 and INCh2 therefore represent important new molecular probes for Viridiplantae research. Moreover, since the alpha-(1-4)-glucan epitope recognised by INCh1 is also a component of glycogen, this mAb can also be used in mammalian systems. We describe the detailed characterisation of INCh1 and INCh2, and discuss the potential of a non-directed mass-screening approach for mAb production against some glycan targets. PMID- 28839197 TI - Homophilic binding of the neural cell adhesion molecule CHL1 regulates development of ventral midbrain dopaminergic pathways. AB - Abnormal development of ventral midbrain (VM) dopaminergic (DA) pathways, essential for motor and cognitive function, may underpin a number of neurological disorders and thereby highlight the importance of understanding the birth and connectivity of the associated neurons. While a number of regulators of VM DA neurogenesis are known, processes involved in later developmental events, including terminal differentiation and axon morphogenesis, are less well understood. Recent transcriptional analysis studies of the developing VM identified genes expressed during these stages, including the cell adhesion molecule with homology to L1 (Chl1). Here, we map the temporal and spatial expression of CHL1 and assess functional roles of substrate-bound and soluble forms of the protein during VM DA development. Results showed early CHL1 in the VM, corresponding with roles in DA progenitor migration and differentiation. Subsequently, we demonstrated roles for CHL1 in both axonal extension and repulsion, selectively of DA neurons, suggestive of a role in guidance towards forebrain targets and away from hindbrain nuclei. In part, CHL1 mediates these roles through homophilic CHL1-CHL1 interactions. Collectively, these findings enhance our knowledge of VM DA pathways development, and may provide new insights into understanding DA developmental conditions such as autism spectrum disorders. PMID- 28839198 TI - The effect of the TM6SF2 E167K variant on liver steatosis and fibrosis in patients with chronic hepatitis C: a meta-analysis. AB - The impact of Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant, which causes hepatocellular fat retention by altering lipoprotein secretion, on liver damage and metabolic traits in chronic hepatitis C patients is still debated. We performed a systematic review and meta-analysis to clarify this relationship. Four studies with a total of 4325 patients were included. The risk of histologically-determined advanced steatosis, fibrosis, and cirrhosis (but not of severe inflammation) were increased in carriers of the TM6SF2 variant (P < 0.05). Unlike the inconsistent association with steatosis severity, due to the confounding effect of infection by the genotype-3 hepatitis C virus, the TM6SF2 variant was robustly associated with advanced fibrosis (OR = 1.07; 95% confidence interval [CI] = 1.01-1.14) and in particular with cirrhosis (OR = 2.05; 95% CI = 1.39-3.02). Regarding metabolic features, individuals positive for the TM6SF2 variant exhibited 5.8-12.0% lower levels of circulating triglycerides and non-HDL cholesterol (P < 0.05). Carriers of the variant were leaner, but there was high heterogeneity across studies (I2 = 97.2%). No significant association was observed between the TM6SF2 variant and insulin resistance or hepatitis C viral load (both P > 0.05). In conclusion, the TM6SF2 E167K variant promotes the development of steatosis, fibrosis and cirrhosis in patients with chronic hepatitis C. Conversely, this variant reduces circulating atherogenic lipid fractions. PMID- 28839200 TI - Physical determinants of asymmetric cell divisions in the early development of Caenorhabditis elegans. AB - Asymmetric cell divisions are of fundamental importance for the development of multicellular organisms, e.g. for the generation of founder cells. Prime examples are asymmetric cell divisions in germline precursors during the early embryogenesis of the transparent roundworm Caenorhabditis elegans, one of the major developmental model organisms. However, due to a lack of quantitative data it has remained unclear how frequent unequal daughter cell sizes emerge in the worm's early embryogenesis, and whether these originate from sterical or biochemical cues. Using quantitative light-sheet microscopy, we have found that about 40% of all cell divisions in C. elegans until gastrulation generate daughter cells with significantly different volumes. Removing the embryo's rigid eggshell revealed asymmetric divisions in somatic cells to be primarily induced by steric effects. Division asymmetries in the germline remained unaltered and were correctly reproduced by a model based on a cell-size independent, eccentric displacement of the metaphase plate. Our data suggest that asymmetric cell divisions, imposed by physical determinants, are essential for establishing important cell-cell interactions that eventually fuel a successful embryogenesis. PMID- 28839199 TI - The conserved tyrosine residue 940 plays a key structural role in membrane interaction of Bordetella adenylate cyclase toxin. AB - The adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) translocates its adenylate cyclase (AC) enzyme domain into target cells in a step that depends on membrane cholesterol content. We thus examined what role in toxin activities is played by the five putative cholesterol recognition amino acid consensus (CRAC) motifs predicted in CyaA hemolysin moiety. CRAC-disrupting phenylalanine substitutions had no impact on toxin activities and these were not inhibited by free cholesterol, showing that the putative CRAC motifs are not involved in cholesterol binding. However, helix-breaking proline substitutions in these segments uncovered a structural role of the Y632, Y658, Y725 and Y738 residues in AC domain delivery and pore formation by CyaA. Substitutions of Y940 of the fifth motif, conserved in the acylated domains of related RTX toxins, did not impact on fatty-acylation of CyaA by CyaC and the CyaA-Y940F mutant was intact for toxin activities on erythrocytes and myeloid cells. However, the Y940A or Y940P substitutions disrupted the capacity of CyaA to insert into artificial lipid bilayers or target cell membranes. The aromatic ring of tyrosine 940 side chain thus appears to play a key structural role in molecular interactions that initiate CyaA penetration into target membranes. PMID- 28839201 TI - Development of an ensemble Kalman filter data assimilation system for the Venusian atmosphere. AB - The size and mass of Venus is similar to those of the Earth; however, its atmospheric dynamics are considerably different and they are poorly understood due to limited observations and computational difficulties. Here, we developed a data assimilation system based on the local ensemble transform Kalman filter (LETKF) for a Venusian Atmospheric GCM for the Earth Simulator (VAFES), to make full use of the observational data. To examine the validity of the system, two datasets were assimilated separately into the VAFES forecasts forced with solar heating that excludes the diurnal component Qz; one was created from a VAFES run forced with solar heating that includes the diurnal component Qt, whereas the other was based on observations made by the Venus Monitoring Camera (VMC) onboard the Venus Express. The VAFES-LETKF system rapidly reduced the errors between the analysis and forecasts. In addition, the VAFES-LETKF system successfully reproduced the thermal tide excited by the diurnal component of solar heating, even though the second datasets only included horizontal winds at a single altitude on the dayside with a long interval of approximately one Earth day. This advanced system could be useful in the analysis of future datasets from the Venus Climate Orbiter 'Akatsuki'. PMID- 28839202 TI - Norcantharidin combined with Coix seed oil synergistically induces apoptosis and inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation. AB - The immune system plays a critical role in exerts effects in the growth and progression of hepatocellular carcinoma (HCC), which needs interacting approaches for effective therapy. In this study, we have found that the Norcantharidin (NCTD) + Coix lacryma-jobi seed oil (CLSO) combination exhibited more potent antitumor effects in an terms of cytotoxicity and apoptotic induction in human HepG2 and HepG2/ADM cells than NCTD or CLSO alone. In vivo, administration of NCTD+CLSO combinations significantly suppressed the formation of tumor in Hepal-1 hepatoma-bearing mice. Furthermore, we found that the in vitro co-cultures of HepG2 or HepG2/ADM cells with PBMCs from healthy donors led to an increase in the number of CD4 + CD25 + T cells. This increase was down-regulated by the combination effectively. Down-regulation of FoxP3 mRNA and protein expression occurred during the combination in the co-cultures. The amount of Tregs of Hepal 1 hepatoma-bearing mice was significantly decreased in the combination treated group. The combination down-regulated the expression of FoxP3, CTLA-4 and Tregs related cytokine (TGF-beta and IL-10) in the serum of tumor bearing mice. Taken together, these results suggest that the most valuable aspect of the NCTD+CLSO combined use improves the anti-tumor activity and regulates tumor infiltrating Tregs. PMID- 28839203 TI - Fine particulate matter 2.5 exerted its toxicological effect by regulating a new layer, long non-coding RNA. AB - Fine particulate matter (PM2.5) exposure, especially to its organic components, induces adverse health effects on the respiratory system. However, the molecular mechanisms have still not been fully elucidated. Long non-coding RNA (lncRNA) is involved in various physio-pathological processes. In this study, the roles of lncRNA were investigated to reveal the toxicology of PM2.5. Organic extracts of PM2.5 from Nanjing and Shanghai cities were adopted to treat human bronchial epithelial cell lines (BEAS-2B and A549). RNA sequencing showed that the lncRNA functioned as antisense RNA, intergenic RNA and pre-miRNA. The mRNA profiles were also altered after exposure. PM2.5 from Nanjing showed a more serious impact than that from Shanghai. In detail, higher expression of n405968 was positively related to the elevated mRNA levels of inflammatory factors (IL-6 and IL-8). Increasing levels of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) were positively associated with the induced epithelial-mesenchymal transition (EMT) process. Similar response was observed between both cell lines. The higher content of polycyclic aromatic hydrocarbons (PAHs) is likely to contribute to higher toxicity of PM2.5 from Nanjing than that from Shanghai. Antagonism of aryl hydrocarbon receptor (AHR) or inhibition of CYP1A1 diminished the effects stimulated by PM2.5. Our results indicated that lncRNAs could be involved in the toxicology of PM2.5 through regulating the inflammation and EMT process. PMID- 28839204 TI - Effects of short indels on protein structure and function in human genomes. AB - Insertions and deletions (indels) represent the second most common type of genetic variations in human genomes. Indels can be deleterious and contribute to disease susceptibility as recent genome sequencing projects revealed a large number of indels in various cancer types. In this study, we investigated the possible effects of small coding indels on protein structure and function, and the baseline characteristics of indels in 2504 individuals of 26 populations from the 1000 Genomes Project. We found that each population has a distinct pattern in genes with small indels. Frameshift (FS) indels are enriched in olfactory receptor activity while non-frameshift (NFS) indels are enriched in transcription related proteins. Structural analysis of NFS indels revealed that they predominantly adopt coil or disordered conformations, especially in proteins with transcription-related NFS indels. These results suggest that the annotated coding indels from the 1000 Genomes Project, while contributing to genetic variations and phenotypic diversity, generally do not affect the core protein structures and have no deleterious effect on essential biological processes. In addition, we found that a number of reference genome annotations might need to be updated due to the high prevalence of annotated homozygous indels in the general population. PMID- 28839205 TI - Targeted Genome Replacement via Homology-directed Repair in Non-dividing Cardiomyocytes. AB - Although high-throughput sequencing can elucidate the genetic basis of hereditary cardiomyopathy, direct interventions targeting pathological mutations have not been established. Furthermore, it remains uncertain whether homology-directed repair (HDR) is effective in non-dividing cardiomyocytes. Here, we demonstrate that HDR-mediated genome editing using CRISPR/Cas9 is effective in non-dividing cardiomyocytes. Transduction of adeno-associated virus (AAV) containing sgRNA and repair template into cardiomyocytes constitutively expressing Cas9 efficiently introduced a fluorescent protein to the C-terminus of Myl2. Imaging-based sequential evaluation of endogenously tagged protein revealed that HDR occurs in cardiomyocytes, independently of DNA synthesis. We sought to repair a pathological mutation in Tnnt2 in cardiomyocytes of cardiomyopathy model mice. An sgRNA that avoided the mutated exon minimized deleterious effects on Tnnt2 expression, and AAV-mediated HDR achieved precise genome correction at a frequency of ~12.5%. Thus, targeted genome replacement via HDR is effective in non-dividing cardiomyocytes, and represents a potential therapeutic tool for targeting intractable cardiomyopathy. PMID- 28839206 TI - Grape-seed Polyphenols Play a Protective Role in Elastase-induced Abdominal Aortic Aneurysm in Mice. AB - Abdominal aortic aneurysm (AAA) is a kind of disease characterized by aortic dilation, whose pathogenesis is linked to inflammation. This study aimed to determine whether grape-seed polyphenols (GSP) has anti-AAA effects and what mechanism is involved, thus to find a way to prevent occurrence and inhibit expansion of small AAA. In our study, AAA was induced by incubating the abdominal aorta of the mice with elastase, and GSP was administrated to the mice by gavage at different doses beginning on the day of the AAA inducement. In in vivo experiments, 800 mg/kg GSP could significantly reduce the incidence of AAA, the dilatation of aorta and elastin degradation in media, and dramatically decrease macrophage infiltration and activation and expression of matrix metalloproteinase (MMP) -2 and MMP-9 in the aorta, compared to the AAA model group. Meanwhile, 400 mg/kg GSP could also but not completely inhibit the occurrence and development of AAA. In in vitro experiments, GSP dose-dependently inhibited mRNA expression of interleukin (IL)-1beta, IL-6 and monocyte chemoattractant protein-1 (MCP-1), and significantly inhibited expression and activity of MMP-2 and MMP-9, thus prevented elastin from degradation. In conclusion, GSP showed great anti-AAA effects and its mechanisms were related to inhibition of inflammation. PMID- 28839207 TI - Relationships between serum-induced AhR bioactivity or mitochondrial inhibition and circulating polychlorinated biphenyls (PCBs). AB - Metabolic syndrome and mitochondrial dysfunction have been linked to elevated serum levels of persistent organic pollutants (POPs). However, it is not clear which specific POPs contribute to aryl hydrocarbon receptor (AhR)-dependent bioactivity or inhibit mitochondrial function in human subjects. Here, we measured the cumulative bioactivity of AhR ligand mixture (AhR bioactivity) and the effects on mitochondrial function (ATP concentration) in recombinant Hepa1c1c7 cells incubated with raw serum samples obtained from 911 elderly subjects in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Plasma concentrations of 30 POPs and plastic chemicals have previously been determined in the same PIVUS subjects. Linear regression analysis demonstrated that total toxic equivalence (TEQ) values and polychlorinated biphenyls (PCBs) were significantly correlated with AhR bioactivity (positively) and ATP concentration (negatively). Serum AhR bioactivities were positively associated with some PCBs, regardless of their dioxin-like properties, but only dioxin-like PCBs stimulated AhR bioactivity. By contrast, PCBs mediated a reduction in ATP content independently of their dioxin-like properties. This study suggests that AhR bioactivity and ATP concentrations in serum-treated cells may be valuable surrogate biomarkers of POP exposure and could be useful for the estimation of the effects of POPs on human health. PMID- 28839208 TI - Sensory mutations in Drosophila melanogaster influence associational effects between resources during oviposition. AB - Neighboring resources can affect insect oviposition behavior when the complexity of sensory information obscures information about host resource availability in heterogeneous resource patches. These effects are referred to as associational effects and are hypothesized to occur through constraints in the sensory processing of the insect during host search, resulting into suboptimal resource use. Because the possibilities to study these constraints on naturally occurring animals are limited, we instead used sensory mutants of Drosophila melanogaster to determine the importance of sensory information in the occurrence of associational effects. We found that oviposition was mainly governed by non volatile chemical cues and less by volatile cues. Moreover, the loss of gustatory sensilla resulted in random resource selection and eliminated associational effects. In conclusion, our study shows that associational effects do not necessarily depend on constraints in the sensory evaluation of resource quality, but may instead be a direct consequence of distinctive selection behavior between different resources at small scales. PMID- 28839210 TI - Highly hard yet toughened bcc-W coating by doping unexpectedly low B content. AB - Either hardness or toughness has been the core interest in scientific exploration and technological pursuit for a long time. However, it is still a big challenge to enhance the hardness and toughness at the same time, since the improvement of one side is always at the expense of the other one. Here, we have succeeded in dealing with this pair of conflict based on tungsten (W) coating by doping boron (B) via magnetron co-sputtering. The results reveal that the introduction of low concentrations of B (6.3 at. %), in the doping regime, leads to the formation of W(B) supersaturated solid solution with refined grains. Meanwhile, the doping induced higher compressive stress, higher H/E* and denser microstructure result in a surprising combination of improved hardness (2 * larger than pure W) and superior toughness (higher crack formation threshold compared to pure W). We believe this is an innovative sight to design new generation of transition-metal based multifunctional coatings. Besides, our results are applicable for industrial application because it can be realized by simple manufacturing approaches, e.g. magnetron sputtering technology. PMID- 28839209 TI - Mapping the key residues of SufB and SufD essential for biosynthesis of iron sulfur clusters. AB - Biogenesis of iron-sulfur (Fe-S) clusters is an indispensable process in living cells. In Escherichia coli, the SUF biosynthetic system consists of six proteins among which SufB, SufC and SufD form the SufBCD complex, which serves as a scaffold for the assembly of nascent Fe-S cluster. Despite recent progress in biochemical and structural studies, little is known about the specific regions providing the scaffold. Here we present a systematic mutational analysis of SufB and SufD and map their critical residues in two distinct regions. One region is located on the N-terminal side of the beta-helix core domain of SufB, where biochemical studies revealed that Cys254 of SufB (SufBC254) is essential for sulfur-transfer from SufE. Another functional region resides at an interface between SufB and SufD, where three residues (SufBC405, SufBE434, and SufDH360) appear to comprise the site for de novo cluster formation. Furthermore, we demonstrate a plausible tunnel in the beta-helix core domain of SufB through which the sulfur species may be transferred from SufBC254 to SufBC405. In contrast, a canonical Fe-S cluster binding motif (CxxCxxxC) of SufB is dispensable. These findings provide new insights into the mechanism of Fe-S cluster assembly by the SufBCD complex. PMID- 28839211 TI - A Biomimetic Microfluidic Tumor Microenvironment Platform Mimicking the EPR Effect for Rapid Screening of Drug Delivery Systems. AB - Real-time monitoring of tumor drug delivery in vivo is a daunting challenge due to the heterogeneity and complexity of the tumor microenvironment. In this study, we developed a biomimetic microfluidic tumor microenvironment (bMTM) comprising co-culture of tumor and endothelial cells in a 3D environment. The platform consists of a vascular compartment featuring a network of vessels cultured with endothelial cells forming a complete lumen under shear flow in communication with 3D solid tumors cultured in a tumor compartment. Endothelial cell permeability to both small dye molecules and large liposomal drug carriers were quantified using fluorescence microscopy. Endothelial cell intercellular junction formation was characterized by immunostaining. Endothelial cell permeability significantly increased in the presence of either tumor cell conditioned media (TCM) or tumor cells. The magnitude of this increase in permeability was significantly higher in the presence of metastatic breast tumor cells as compared to non-metastatic ones. Immunostaining revealed impaired endothelial cell-cell junctions in the presence of either metastatic TCM or metastatic tumor cells. Our findings indicate that the bMTM platform mimics the tumor microenvironment including the EPR effect. This platform has a significant potential in applications such as cell-cell/cell drug carrier interaction studies and rapid screening of cancer drug therapeutics/carriers. PMID- 28839212 TI - MiR-34c represses muscle development by forming a regulatory loop with Notch1. AB - Since pork accounts for about 40% of global meat consumption, the pig is an important economic animal for meat production. Pig is also a useful medical model for humans due to its similarity in size and physiology. Understanding the mechanism of muscle development has great implication for animal breeding and human health. Previous studies showed porcine muscle satellite cells (PSCs) are important for postnatal skeletal muscle growth, and Notch1 signaling pathway and miRNAs regulate the skeletal muscle development. Notch1 signal pathway regulates the transcription of certain types of miRNAs which further affects target gene expression. However, the specific relationship between Notch1 and miRNAs during muscle development has not been established. We found miR-34c is decreased in PSCs overexpressed N1ICD. Through the overexpression and inhibition of mi-34c, we demonstrated that miR-34c inhibits PSCs proliferation and promotes PSCs differentiation. Using dual-luciferase reporter assay and Chromatin immunoprecipitation, we demonstrate there is a reciprocal regulatory loop between Notch1 and miR-34c. Furthermore, injection of miR-34c lentivirus into mice caused repression of gastrocnemius muscle development. In summary, our data revealed that miR-34c can form a regulatory loop with Notch1 to repress muscle development, and this result expands our understanding of muscle development mechanism. PMID- 28839213 TI - Metabolomic compounds identified in Piriformospora indica-colonized Chinese cabbage roots delineate symbiotic functions of the interaction. AB - Root colonization by endophytic fungus Piriformospora indica facilitating growth/development and stress tolerance has been demonstrated in various host plants. However, global metabolomic studies are rare. By using high-throughput gas-chromatography-based mass spectrometry, 549 metabolites of 1,126 total compounds observed were identified in colonized and uncolonized Chinese cabbage roots, and hyphae of P. indica. The analyses demonstrate that the host metabolomic compounds and metabolite pathways are globally reprogrammed after symbiosis with P. indica. Especially, gamma-amino butyrate (GABA), oxylipin family compounds, poly-saturated fatty acids, and auxin and its intermediates were highly induced and de novo synthesized in colonized roots. Conversely, nicotinic acid (niacin) and dimethylallylpyrophosphate were strongly decreased. In vivo assays with exogenously applied compounds confirmed that GABA primes plant immunity toward pathogen attack and enhances high salinity and temperature tolerance. Moreover, generation of reactive oxygen/nitrogen species stimulated by nicotinic acid is repressed by P. indica, and causes the feasibility of symbiotic interaction. This global metabolomic analysis and the identification of symbiosis specific metabolites may help to understand how P. indica confers benefits to the host plant. PMID- 28839215 TI - Personalized Monitoring and Advance Warning System for Cardiac Arrhythmias. AB - Each year more than 7 million people die from cardiac arrhythmias. Yet no robust solution exists today to detect such heart anomalies right at the moment they occur. The purpose of this study was to design a personalized health monitoring system that can detect early occurrences of arrhythmias from an individual's electrocardiogram (ECG) signal. We first modelled the common causes of arrhythmias in the signal domain as a degradation of normal ECG beats to abnormal beats. Using the degradation models, we performed abnormal beat synthesis which created potential abnormal beats from the average normal beat of the individual. Finally, a Convolutional Neural Network (CNN) was trained using real normal and synthesized abnormal beats. As a personalized classifier, the trained CNN can monitor ECG beats in real time for arrhythmia detection. Over 34 patients' ECG records with a total of 63,341 ECG beats from the MIT-BIH arrhythmia benchmark database, we have shown that the probability of detecting one or more abnormal ECG beats among the first three occurrences is higher than 99.4% with a very low false-alarm rate. PMID- 28839214 TI - The role of the immunoproteasome in interferon-gamma-mediated microglial activation. AB - Microglia regulate the brain microenvironment by sensing damage and neutralizing potentially harmful insults. Disruption of central nervous system (CNS) homeostasis results in transition of microglia to a reactive state characterized by morphological changes and production of cytokines to prevent further damage to CNS tissue. Immunoproteasome levels are elevated in activated microglia in models of stroke, infection and traumatic brain injury, though the exact role of the immunoproteasome in neuropathology remains poorly defined. Using gene expression analysis and native gel electrophoresis we characterize the expression and assembly of the immunoproteasome in microglia following interferon-gamma exposure. Transcriptome analysis suggests that the immunoproteasome regulates multiple features of microglial activation including nitric oxide production and phagocytosis. We show that inhibiting the immunoproteasome attenuates expression of pro-inflammatory cytokines and suppresses interferon-gamma-dependent priming of microglia. These results imply that targeting immunoproteasome function following CNS injury may attenuate select microglial activity to improve the pathophysiology of neurodegenerative conditions or the progress of inflammation mediated secondary injury following neurotrauma. PMID- 28839216 TI - Habituation/Fatigue behavior of a synapse memristor based on IGZO-HfO2 thin film. AB - A synaptic memristor based on IGZO and oxygen-deficient HfO2 films has been demonstrated. The memristor exhibits a fatigue response to a monotonic stimulus of voltage pulses, which is analogous to the habituation behavior of biological memory. The occurrence of habituation is nearly simultaneous with the transition from short-term memory to long-term memory. The movement and redistribution of oxygen species with the assistance of polarization in HfO2 layer are responsible for the above results. The observation of habituation behavior proves the potential prospect of memristor on the mimic of biological neuron. PMID- 28839218 TI - rs1760944 Polymorphism in the APE1 Region is Associated with Risk and Prognosis of Osteosarcoma in the Chinese Han Population. AB - The effects of single nucleotide polymorphisms (SNPs) at APE1 have been investigated in several types of cancer. However, no reports of the association of APE1 polymorphisms with osteosarcoma (OS) have been published. The present study was designed to determine whether APE1 polymorphisms (rs1130409, rs1760944, rs1760941, rs2275008, rs17111750) are associated with OS. A 2-stage case-control study was performed in a total of 378 OS patients and 616 normal controls. Individuals carrying TG and GG genotypes had significantly lower risk of developing OS than those with the WT genotype TT at rs1760944 (OR = 0.65, 95%CI 0.49-0.86; OR = 0.50, 95%CI 0.34-0.74, respectively). OS patients with allele G at rs1760944 were less susceptible to low differentiation tumor and metastasis (OR = 0.73, 95%CI 0.54-0.98; OR = 0.63, 95%CI 0.43-0.92, respectively). Kaplan Meier curves and log-rank results revealed that OS patients harboring genotype GG and G allele at rs1760944 had better survival (P < 0.001 for both). In addition, the APE1 protein was underexpressed in individuals who carried G allele at rs1760944. This study suggested that APE1 rs1760944 polymorphism is associated with decreased risk of developing OS and better survival of OS patients. PMID- 28839219 TI - Evolutionary divergence of the ABO and GBGT1 genes specifying the ABO and FORS blood group systems through chromosomal rearrangements. AB - Human alleles at the ABO and GBGT1 genetic loci specify glycosylation polymorphism of ABO and FORS blood group systems, respectively, and their allelic basis has been elucidated. These genes are also present in other species, but presence/absence, as well as functionality/non-functionality are species dependent. Molecular mechanisms and forces that created this species divergence were unknown. Utilizing genomic information available from GenBank and Ensembl databases, gene order maps were constructed of a chromosomal region surrounding the ABO and GBGT1 genes from a variety of vertebrate species. Both similarities and differences were observed in their chromosomal organization. Interestingly, the ABO and GBGT1 genes were found located at the boundaries of chromosomal fragments that seem to have been inverted/translocated during species evolution. Genetic alterations, such as deletions and duplications, are prevalent at the ends of rearranged chromosomal fragments, which may partially explain the species dependent divergence of those clinically important glycosyltransferase genes. PMID- 28839217 TI - Re-stepping into the same river: competition problem rather than a reconsolidation failure in an established motor skill. AB - Animal models suggest that consolidated memories return to their labile state when reactivated and need to be restabilized through reconsolidation processes to persist. Consistent with this notion, post-reactivation pharmacological protein synthesis blockage results in mnemonic failure in hippocampus-dependent memories. It has been proposed that, in humans, post-reactivation experience with a competitive task can also interfere with memory restabilization. However, several studies failed to induce performance deficit implementing this approach. Moreover, even upon effective post-reactivation interference, hindered performance may rapidly recover, raising the possibility of a retrieval rather than a storage deficit. Here, to address these issues in procedural memory domain, we used new learning to interfere with restabilization of motor memory acquired through training on a sequence of finger movements. Only immediate post reactivation interference was associated with the loss of post-training delayed gains in performance, a hallmark of motor sequence memory consolidation. We also demonstrate that such performance deficit more likely indicates a genuine memory impairment rather than a retrieval failure. However, the reconsolidation view on a reactivation-induced plasticity is not supported. Instead, our results are in line with the integration model according to which new knowledge acquired during the interfering experience, is integrated through its consolidation creating memory competition. PMID- 28839220 TI - Morphology control of exciton fine structure in polar and nonpolar zinc sulfide nanorods. AB - Electron-hole exchange interaction in semiconductor quantum dots (QDs) splits the band-edge exciton manifold into optically active ("bright") and passive ("dark") states, leading to a complicated exciton fine structure. In the present work, we resolve by atomistic million-atom many-body pseudopotential calculations the exciton fine structure in colloidal polar and nonpolar zinc sulfide (ZnS) nanorods (NRs). We explore that polar NRs with high symmetry exhibit vanishing fine structure splitting (FSS), and are therefore ideal sources of entangled photon pairs. In contrast, nonpolar NRs grown along [Formula: see text] and [Formula: see text] directions with reduced symmetries have significant FSS, which can even reach up to a few mili electron volts. However, such large FSS can be effectively minimized to a few micro electron volts, or even less, by a simple morphology control. PMID- 28839221 TI - Exosomes from high glucose-treated glomerular endothelial cells trigger the epithelial-mesenchymal transition and dysfunction of podocytes. AB - New data indicate that abnormal glomerular endothelial cell (GEC)-podocyte crosstalk plays a critical role in diabetic nephropathy (DN). The aim of our study is to investigate the role of exosomes from high glucose (HG)-treated GECs in the epithelial-mesenchymal transition (EMT) and dysfunction of podocytes. In this study, exosomes were extracted from GEC culture supernatants and podocytes were incubated with the GEC-derived exosomes. Here, we demonstrate that HG induces the endothelial-mesenchymal transition (EndoMT) of GECs and HG-treated cells undergoing the EndoMT secrete more exosomes than normal glucose (NG) treated GECs. We show that GEC-derived exosomes can be internalized by podocytes and exosomes from HG-treated cells undergoing an EndoMT-like process can trigger the podocyte EMT and barrier dysfunction. Our study reveals that TGF-beta1 mRNA is enriched in exosomes from HG-treated GECs and probably mediates the EMT and dysfunction of podocytes. In addition, our experimental results illustrate that canonical Wnt/beta-catenin signaling is involved in the exosome-induced podocyte EMT. Our findings suggest the importance of paracrine communication via exosomes between cells undergoing the EndoMT and podocytes for renal fibrosis in DN. Thus, protecting GECs from the EndoMT and inhibiting TGF-beta1-containing exosomes release from GECs is necessary to manage renal fibrosis in DN. PMID- 28839222 TI - Cesium ion detection by terahertz light. AB - Recent developments in terahertz technologies provide new tools for analysis, inspection, and nondestructive sensing. If a heavy atom is encapsulated in a cage of a porous material, the atom should vibrate slowly and resonate with a low frequency terahertz light. From this perspective, a cyanide-bridged metal framework is a suitable system because it contains many cages that can adsorb Cs ions. Herein we show the vibration mode of a Cs ion in a cage of a cyanide bridged metal framework. First-principles phonon mode calculations and terahertz time-domain spectroscopy (THz-TDS) measurements indicate that the vibration mode of a Cs ion in a cyanide-bridged manganese-iron framework is at 1.5 THz, which is significantly apart from other lattice vibrations. Taking advantage of this feature, we develop a THz-light detection method for Cs ions, which is useful for non-contact sensing of Cs ions in dangerous environments or harmful circumstances. PMID- 28839223 TI - Polymyxin B containing polyion complex (PIC) nanoparticles: Improving the antimicrobial activity by tailoring the degree of polymerisation of the inert component. AB - Here, we describe the preparation and characterisation of polyion complex (PIC) nanoparticles containing last resort antimicrobial polymyxin B (Pol-B). PIC nanoparticles were prepared with poly(styrene sulphonate) (PSS) as an inert component, across a range of degrees of polymerisation to evaluate the effect that multivalency of this electrolyte has on the stability and antimicrobial activity of these nanoparticles. Our results demonstrate that while nanoparticles prepared with longer polyelectrolytes are more stable under simulated physiological conditions, those prepared with shorter polyelectrolytes have a higher antimicrobial activity. Tailoring the degree of polymerisation and the ratio of the components we have been able to identify a formulation that shows a sustained inhibitory effect on the growth of P. aeruginosa and can reduce the number of viable colonies of this pathogen over 10,000 times more effectively than our previously reported formulation. PMID- 28839224 TI - Alien plant invasions of protected areas in Java, Indonesia. AB - Alien plants are invading protected areas worldwide, but there is little information from tropical Asia. Java has the longest record of human occupation in Asia and today supports 145 m people. Remnants of natural ecosystems survive in 12 small National Parks surrounded by dense human populations, making them highly vulnerable to invasions. We surveyed eight of these, along a rainfall gradient from lowland rainforest with >3000 mm annual rainfall to savanna with <1500 mm, and a 0-3158 m altitudinal gradient, using 403 10 * 5 m plots along trails. We found 67 invasive alien plant species, of which 33 occurred in only one park and two (Chromolaena odorata and Lantana camara) in all. Historical factors relating to plant introduction appeared to be as important as environmental factors in determining which species occurred in which park, while within parks canopy cover and altitude were generally most influential. Spread away from trails was only evident in open habitats, including natural savannas in Baluran National Park, threatened by invasion of Acacia nilotica. Existing control attempts for invasive aliens are reactive, localized, and intermittent, and insufficient resources are currently available for the early detection, prompt action, and continued monitoring that are needed. PMID- 28839225 TI - Hypoxia-inducible ERO1alpha promotes cancer progression through modulation of integrin-beta1 modification and signalling in HCT116 colorectal cancer cells. AB - Endoplasmic reticulum disulphide oxidase 1alpha (ERO1alpha) is an oxidase localized in the endoplasmic reticulum that plays a role in the formation of disulphide bonds of secreted and cell-surface proteins. We previously showed that ERO1alpha is overexpressed in various types of cancer and we further identified ERO1alpha expression as a novel factor related to poor prognosis in cancer. However, the biological functions of ERO1alpha in cancer remain unclear. Here, we investigated the cell biological roles of ERO1alpha in the human colon-cancer cell line HCT116. ERO1alpha knockout (KO) by using CRISPR/Cas9 resulted in decreased tumourigenicity in vivo and reduced cell proliferation only under hypoxia in vitro, which suggested that ERO1alpha promotes cancer progression specifically in a low-oxygen environment. Thus, we evaluated the function of ERO1alpha in cell proliferation under hypoxia, and found that under hypoxic conditions, ERO1alpha KO resulted in a contact-inhibited morphology and diminished motility of cells. We further showed that ERO1alpha KO induced a change in integrin-beta1 glycosylation and thus an attenuation of cell-surface integrin-beta1 expression, which resulted in the aforementioned phenotype. Our study has established a previously unrecognized link between ERO1alpha expression and integrin activation, and thus provides new evidence for the effectiveness of ERO1alpha-targeted therapy for colorectal carcinoma. PMID- 28839226 TI - Provision of somatosensory inputs during motor imagery enhances learning-induced plasticity in human motor cortex. AB - Motor learning via physical practice leads to long-term potentiation (LTP)-like plasticity in motor cortex (M1) and temporary occlusion of additional LTP-like plasticity. Motor learning can be achieved through simulation of movement, namely motor imagery (MI). When combined with electrical stimulation, MI influenced M1 excitability to a larger extent than MI itself. We explored whether a training based on the combination of MI and peripheral nerve stimulation (ESMI) modulates M1 LTP-like plasticity inducing retention of a new acquired skill. Twelve subjects mentally performed thumb-index movements, with synchronous electrical nerve stimulation, following an acoustic cue, in order to increase movement speed. Two control groups physically performed or imagined the same number of finger movements following the acoustic cue. After each training session, M1 LTP like plasticity was assessed by using PAS25 (paired associative stimulation) technique. Performance was tested before and after training and 24 hours after training. Results showed that physical practice and ESMI training similarly increased movement speed, prevented the subsequent PAS25-induced LTP-like plasticity, and induced retention of motor skill the following day. Training with MI had significant, but minor effects. These findings suggest that a training combining MI with somatosensory input influences motor performance through M1 plasticity similarly to motor execution. PMID- 28839227 TI - Estrogen receptor alpha/HDAC/NFAT axis for delphinidin effects on proliferation and differentiation of T lymphocytes from patients with cardiovascular risks. AB - Delphinidin, an anthocyanin present in red wine, has been reported to preserve the integrity of endothelium via an estrogen receptor alpha (ERalpha)-dependent mechanism. However, the effect of delphinidin on the immune response in obesity related inflammation remains unknown. Given the important role of T lymphocytes in obesity-related inflammation, we investigated the effect of delphinidin on proliferation and differentiation of T lymphocytes from healthy subjects and metabolic syndrome patients. Delphinidin decreased the proliferation stimulated by different agents acting through different mechanisms. This effect of delphinidin was associated with its ability to inhibit Ca2+ signaling via reduced store-operated Ca2+ entry and release, and subsequent decrease of HDAC and NFAT activations. Delphinidin also inhibited ERK1/2 activation. Pharmacological inhibition of ER with fulvestrant, or deletion of ERalpha, prevented the effect of delphinidin. Further, delphinidin suppressed the differentiation of T cells toward Th1, Th17 and Treg without affecting Th2 subsets. Interestingly, delphinidin inhibited both proliferation and differentiation of T cells taken from patients with cardiovascular risks associated with metabolic syndrome. Together, we propose that delphinidin, by acting on ERalpha via multiple cellular targets, may represent a new approach against chronic inflammation associated with T lymphocyte activation, proliferation and differentiation, in patients with cardiovascular risk factors. PMID- 28839228 TI - Magnetic-Immuno-Loop-Mediated Isothermal Amplification Based on DNA Encapsulating Liposome for the Ultrasensitive Detection of P-glycoprotein. AB - Determination of proteins, especially low-abundance proteins with high sensitivity and specificity, is essential for characterizing proteomes and studying their biochemical functions. Herein, a novel Magnetic-Immuno-Loop Mediated Isothermal Amplification (Im-LAMP) based on DNA-encapsulating liposomes (liposome-Im- LAMP), was developed for trace amounts of proteins. To the best of our knowledge, this is our first report about the magnetic Im-LAMP approach based on liposomes encapsulated template DNA as the detection reagent. The DNA template was released from liposomes and then initiated an Im-LAMP reaction, generating the fluorescence signal with high sensitivity and rapidity. This technique was applied for the determination of P-glycoprotein as a model protein. It was demonstrated that the technique exhibited a dynamic response to P-glycoprotein ranging from 1.6*10-2 to 160 pg/ml with a greatly low detection limit of 5*10-3 pg/ml (5 fg/ml) which is substantially better than conventional enzyme-linked immunosorbent assays (ELISA). This ultra sensitivity was attributed to the LAMP reaction initiated by the enormous DNA targets encapsulated in liposomes. This magnetic liposome-Im-LAMP as an alternative approach is attractive for applications in other low-abundance proteins detection in clinical diagnostics. PMID- 28839229 TI - Metal-induced aggregation of valine capped gold nanoparticles: An efficient and rapid approach for colorimetric detection of Pb2+ ions. AB - In this study, we report a novel application of valine-capped gold nanoparticles for colorimetric and visual detection of lead ions. The -COO- group of the hydrophobic valine molecules present efficient electrostatic repulsion resulting in generation of stable, well-dispersed and size-controlled GNPs. The GNPs were highly selective for Pb2+ ions and showed visible colour change in the assay mixture on addition of solution containing lead ions. Interestingly, a decrease in the intensity of original SPR peak at 530 nm was observed, with concomitant appearance of a new peak at longer wavelength due to agglomerated GNPs. The free COO- groups on GNP surface interacted with Pb2+ and ion-dependent chelation mechanism lead to cross-linking of particles and subsequent agglomeration. Binding of Pb2+ ions and valine-capped GNPs occur in a stochiometric ratio of 1:2. The GNPs displayed colorimetric sensing in the range of 0 to 100 ppm concentration with a very high selectivity towards lead even in the presence of other metal ions. The minimum detection limit (MDL) for Pb2+ was 30.5 uM. We anticipate that these valine-capped GNPs may be employed for lead detection in polluted water/wastewater through a cost-efficient, one-step assay protocol as it does not require additional functionalization with specific ligand molecules. PMID- 28839230 TI - Process performance and methane production optimizing of anaerobic co-digestion of swine manure and corn straw. AB - During anaerobic digestion (AD) process, process parameters e.g., VFA, pH, COD removal ... and kinetic parameters e.g., hydrolysis rate, lag phase and methane production potential... are the important indicator for illustrating AD process performance, however, the AD process performance based on these parameters remains poorly understood. To estimate process performance focusing on initial pH and substrate composition, the effects of initial pH and swine manure to corn straw ratio on biogas production and these parameters and linkages of these parameters were analyzed. Also, the methane production was optimized. The results revealed that the maximum methane yield and methane production rate were obtained with initial pH 7.5 and SM/CS ratio of 70:30. Kinetic parameters are coupled with process parameters, especially for COD removal rate, VS degradation rate, VFA and pH. Hydrolysis constant positively correlated with pH, COD removal rate and VS degradation rate, then impacted methane production and lag phase. Meanwhile, lag phase and the maximum methane production rate were directly determined by VFA and COD removal rate. The optimum initial pH and SM/CS ratio were 7.15 and 0.62, respectively, with a predicted maximum methane content of 55.12%. Thinking these findings together, they provide a scientific theory for estimating AD performance. PMID- 28839231 TI - Genetic deficiency in neuronal peroxisomal fatty acid beta-oxidation causes the interruption of dauer development in Caenorhabditis elegans. AB - Although peroxisomal fatty acid (FA) beta-oxidation is known to be critical for animal development, the cellular mechanisms that control the manner in which its neuronal deficiency causes developmental defects remain unclear. To elucidate the potential cellular consequences of neuronal FA metabolic disorder for dauer development, an alternative developmental process in Caenorhabditis elegans that occurs during stress, we investigated the sequential effects of its corresponding genetic deficiency. Here, we show that the daf-22 gene in peroxisomal FA beta oxidation plays a distinct role in ASK neurons, and its deficiency interrupts dauer development even in the presence of the exogenous ascaroside pheromones that induce such development. Un-metabolized FAs accumulated in ASK neurons of daf-22 mutants stimulate the endoplasmic reticulum (ER) stress response, which may enhance the XBP-1 activity that promotes the transcription of neuronal insulin-like peptides. These sequential cell-autonomous reactions in ASK neurons then activate insulin/IGF-1 signaling, which culminates in the suppression of DAF 16/FOXO activity. This suppression results in the interruption of dauer development, independently of pheromone presence. These findings suggest that neuronal peroxisomal FA beta-oxidation is indispensable for animal development by regulating the ER stress response and neuroendocrine signaling. PMID- 28839232 TI - Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors. AB - The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell membrane receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. Its expression is increased in many human cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and correlates with a poor prognosis and early invasion and metastasis. uPAR is able to control, through a cross-talk with tyrosine kinase receptors, the shift between tumor dormancy and proliferation, that usually precedes metastasis formation. Therefore, we investigated the role of uPAR expression in RAS mutated NSCLC and CRC cells. In this study we provided evidence, for the first time, that RAS mutational condition is functionally correlated to uPAR overexpression in NSCLC and CRC cancer cell lines and patient-derived tissue samples. Moreover, oncogenic features related to uPAR overexpression in RAS mutated NSCLC and CRC, such as adhesion, migration and metastatic process may be targeted, in vitro and in vivo, by new anti-uPAR small molecules, specific inhibitors of uPAR-vitronectin interaction. Therefore, anti-uPAR drugs could represent an effective pharmacological strategy for NSCLC and CRC patients carrying RAS mutations. PMID- 28839233 TI - Optogenetic regulation of insulin secretion in pancreatic beta-cells. AB - Pancreatic beta-cell insulin production is orchestrated by a complex circuitry involving intracellular elements including cyclic AMP (cAMP). Tackling aberrations in glucose-stimulated insulin release such as in diabetes with pharmacological agents, which boost the secretory capacity of beta-cells, is linked to adverse side effects. We hypothesized that a photoactivatable adenylyl cyclase (PAC) can be employed to modulate cAMP in beta-cells with light thereby enhancing insulin secretion. To that end, the PAC gene from Beggiatoa (bPAC) was delivered to beta-cells. A cAMP increase was noted within 5 minutes of photostimulation and a significant drop at 12 minutes post-illumination. The concomitant augmented insulin secretion was comparable to that from beta-cells treated with secretagogues. Greater insulin release was also observed over repeated cycles of photoinduction without adverse effects on viability and proliferation. Furthermore, the expression and activation of bPAC increased cAMP and insulin secretion in murine islets and in beta-cell pseudoislets, which displayed a more pronounced light-triggered hormone secretion compared to that of beta-cell monolayers. Calcium channel blocking curtailed the enhanced insulin response due to bPAC activity. This optogenetic system with modulation of cAMP and insulin release can be employed for the study of beta-cell function and for enabling new therapeutic modalities for diabetes. PMID- 28839235 TI - An investigation into denture loss in hospitals in Kent, Surrey and Sussex. AB - Background The loss of dentures for inpatients can have a detrimental effect on their well-being. Self-respect and dignity become compromised along with their ability to eat meals and communicate clearly, and long-term recovery.Aim This investigation aimed to identify the reported number of dentures lost in hospitals and the financial reimbursements given by trusts to replace them.Method Information on reported denture loss and reimbursement was collected in 12 trusts throughout Kent, Surrey and Sussex.Results Eleven out of 12 trusts returned data about how many dentures were lost in their hospitals, between them 695 dentures were reported lost over five years (2011-16). Seven trusts reported financial reimbursements for dentures losses; results showed L357,672 was reimbursed over six years (2010-16), the highest amount reimbursed for a single denture was L2,200.Conclusion The results indicate that denture loss is a problem in hospitals that contributes to the financial burden for the NHS. Consideration needs to be given by hospitals to find ways to reduce the number of dentures lost every year. PMID- 28839234 TI - Identification of NCAN as a candidate gene for developmental dyslexia. AB - A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure. PMID- 28839236 TI - Association between genetic polymorphisms in the autophagy-related 5 gene promoter and the risk of sepsis. AB - Previous studies demonstrated significant roles of autophagy in the pathogenesis of sepsis, but few studies focused on the effect of autophagy-related SNPs on sepsis susceptibility. In this present study, five polymorphisms of ATG5/ATG16L1 were investigated for the possible risk on sepsis in a Chinese Han population. Our results showed that ATG5 expression levels decreased with the severity of sepsis, and rs506027 T > C and rs510432 G > A were associated with sepsis progression and mortality. Moreover, the rs506027 TT and rs510432 GG carriers also exhibited increased expression levels of ATG5. Functional assays showed that ATG5 knockdown elevated the secretion of pro-inflammatory cytokines in THP-1 cells, and the extracted mononuclear cell of the risk C-A carriers exhibited decreased ATG5 expression levels, leading to enhanced releases of TNF-alpha and IL-1beta under LPS stimulation in vitro. Furthermore, ATG5 T-G haplotype mutation showed higher promoter activities compared to C-A haplotype mutation, suggesting the effect of these SNPs on ATG5 gene transcription. Taken together, these results above indicated that these two ATG5 promoter polymorphisms may be functional and clinically significant for sepsis progression, underscoring its potentially therapeutic implications for sepsis and other inflammatory diseases. PMID- 28839237 TI - A systematic model identification method for chemical transformation pathways - the case of heroin biomarkers in wastewater. AB - This study presents a novel statistical approach for identifying sequenced chemical transformation pathways in combination with reaction kinetics models. The proposed method relies on sound uncertainty propagation by considering parameter ranges and associated probability distribution obtained at any given transformation pathway levels as priors for parameter estimation at any subsequent transformation levels. The method was applied to calibrate a model predicting the transformation in untreated wastewater of six biomarkers, excreted following human metabolism of heroin and codeine. The method developed was compared to parameter estimation methods commonly encountered in literature (i.e., estimation of all parameters at the same time and parameter estimation with fix values for upstream parameters) by assessing the model prediction accuracy, parameter identifiability and uncertainty analysis. Results obtained suggest that the method developed has the potential to outperform conventional approaches in terms of prediction accuracy, transformation pathway identification and parameter identifiability. This method can be used in conjunction with optimal experimental designs to effectively identify model structures and parameters. This method can also offer a platform to promote a closer interaction between analytical chemists and modellers to identify models for biochemical transformation pathways, being a prominent example for the emerging field of wastewater-based epidemiology. PMID- 28839239 TI - Solving the inverse problem for coarse-mode aerosol particle morphology with digital holography. AB - Coarse mode atmospheric aerosol particles are abundant in agricultural, desert, and urban environments. Accurate characterisation of these particles' morphology is an important need in scientific and applied contexts, especially to advance our understanding for how such aerosols influence solar radiative forcing of the atmosphere. Elastic light scattering is a standard method to study aerosol particles in a contact-free manner, wherein measured scattering patterns are interpreted to infer particle morphology. Due in part to the absence of wave phase information in these measurements, the inference is not unique, a difficulty generally known as the inverse problem. An alternative approach is digital holography where wave-phase information is encoded in the measurements. We show that digital holography and spatial filtering can solve the inverse problem for free-flowing aerosol particles in the sense that a measured scattering pattern can be uniquely associated with the particle size, shape, and orientation producing it. PMID- 28839238 TI - In vivo cation exchange in quantum dots for tumor-specific imaging. AB - In vivo tumor imaging with nanoprobes suffers from poor tumor specificity. Here, we introduce a nanosystem, which allows selective background quenching to gain exceptionally tumor-specific signals. The system uses near-infrared quantum dots and a membrane-impermeable etchant, which serves as a cation donor. The etchant rapidly quenches the quantum dots through cation exchange (ionic etching), and facilitates renal clearance of metal ions released from the quantum dots. The quantum dots are intravenously delivered into orthotopic breast and pancreas tumors in mice by using the tumor-penetrating iRGD peptide. Subsequent etching quenches excess quantum dots, leaving a highly tumor-specific signal provided by the intact quantum dots remaining in the extravascular tumor cells and fibroblasts. No toxicity is noted. The system also facilitates the detection of peritoneal tumors with high specificity upon intraperitoneal tumor targeting and selective etching of excess untargeted quantum dots. In vivo cation exchange may be a promising strategy to enhance specificity of tumor imaging.The imaging of tumors in vivo using nanoprobes has been challenging due to the lack of sufficient tumor specificity. Here, the authors develop a tumor-specific quantum dot system that permits in vivo cation exchange to achieve selective background quenching and high tumor-specific imaging. PMID- 28839240 TI - A global analysis of alternative tillage and crop establishment practices for economically and environmentally efficient rice production. AB - Alternative tillage and rice establishment options should aim at less water and labor to produce similar or improved yields compared with traditional puddled transplanted rice cultivation. The relative performance of these practices in terms of yield, water input, and economics varies across rice-growing regions. A global meta and mixed model analysis was performed, using a dataset involving 323 on-station and 9 on-farm studies (a total of 3878 paired data), to evaluate the yield, water input, greenhouse gas emissions, and cost and net return with five major tillage/crop establishment options. Shifting from transplanting to direct seeding was advantageous but the change from conventional to zero or reduced tillage reduced yields. Direct-seeded rice under wet tillage was the best alternative with yield advantages of 1.3-4.7% (p < 0.05) and higher net economic return of 13% (p < 0.05), accompanied by savings of water by 15% (p < 0.05) and a reduction in cost by 2.4-8.8%. Direct-seeding under zero tillage was another potential alternative with high savings in water input and cost of cultivation, with no yield penalty. The alternative practices reduced methane emissions but increased nitrous oxide emissions. Soil texture plays a key role in relative yield advantages, and therefore refinement of the practice to suit a specific agro-ecosystem is needed. PMID- 28839241 TI - Leukocyte TRP channel gene expressions in patients with non-valvular atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a major cause of morbidity and mortality. The upregulation of TRP channels is believed to mediate the progression of electrical remodelling and the arrhythmogenesis of the diseased heart. However, there is limited data about the contribution of the TRP channels to development of AF. The aim of this study was to investigate leukocyte TRP channels gene expressions in non-valvular atrial fibrillation (NVAF) patients. The study included 47 NVAF patients and 47 sex and age matched controls. mRNA was extracted from blood samples, and real-time polymerase chain reaction was performed for gene expressions by using a dynamic array system. Low levels of TRP channel expressions in the controls were markedly potentiated in NVAF group. We observed marked increases in MCOLN1 (TRPML1), MCOLN2 (TRPML2), MCOLN3 (TRPML3), TRPA1, TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, TRPC7, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, TRPV6, and PKD2 (TRPP2) gene expressions in NVAF patients (P < 0.05). However, there was no change in PKD1 (TRPP1) gene expression. This is the first study to provide evidence that elevated gene expressions of TRP channels are associated with the pathogenesis of NVAF. PMID- 28839242 TI - Using Feedback Control to Reduce Limb Impedance during Forceful Contractions. AB - Little is known about the ability to precisely regulate forces or torques during unexpected disturbances, as required during numerous tasks. Effective force regulation implies small changes in force responding to externally imposed displacements, a behavior characterized by low limb impedance. This task can be challenging, since the intrinsic impedance of muscles increases when generating volitional forces. The purpose of this study was to examine the ability to voluntarily reduce limb impedance during force regulation, and the neural mechanisms associated with that ability. Small displacement perturbations were used to quantify elbow impedance during the exertion of volitional elbow torques from 0% to 20% of maximum voluntary contraction. Subjects were instructed either to not intervene with the imposed perturbations or to explicitly intervene so as to minimize the influence of the perturbations on the elbow torque. Our results demonstrated that individuals can reduce the low frequency components of elbow impedance by 35%. Electromyographic analysis suggested that this behavior is mediated by volitional and possibly long-latency reflex pathways with delays of at least 120 ms. These results provide a context for understanding how feedback altered by aging or injuries may influence the ability to regulate forces precisely. PMID- 28839243 TI - Dynamic Image Analysis To Evaluate Subvisible Particles During Continuous Drug Infusion In a Neonatal Intensive Care Unit. AB - Studies have shown that infused particles lead to numerous complications such as inflammation or organ dysfunctions in critically ill children. Nevertheless, there is very little data available to evaluate the amount of particulate matter potentially administered to patients, and none with regard to infants. We have investigated the quantity received by these patients during multidrug IV therapies. Two different protocols commonly used in our neonatal intensive care unit (NICU) to manage excessively preterm infants were reproduced in the laboratory and directly connected to a dynamic particle analyser. The particulate matter of infused therapies was measured over 24 h, so that both overall particulate contamination and particle sizes could be determined. No visible particles were observed during drug infusions. Particulate analyses showed a significant number of particles that can reach 85,000 per day, with peaks during discontinuous drug infusions. Moreover, we showed that very large particles of about 60 um were infused to infants. This study showed that despite very low infusion flow rates, infants may receive a large number of particles during drug infusion, especially in NICUs. Particulate contamination of IV fluids is not without consequences for fragile infants. Preventive solutions could be effective, such as the use of in-line filters. PMID- 28839244 TI - Retinal Vascular Imaging Markers and Incident Chronic Kidney Disease: A Prospective Cohort Study. AB - Retinal microvascular changes indicating microvascular dysfunction have been shown to be associated with chronic kidney disease (CKD) in cross-sectional studies, but findings were mixed in prospective studies. We aimed to evaluate the relationship between retinal microvascular parameters and incident CKD in an Asian population. We examined 1256 Malay adults aged 40-80 years from the Singapore Malay Eye Study, who attended both the baseline (2004-07) and the follow-up (2011-13) examinations and were free of prevalent CKD. We measured quantitative retinal vascular parameters (arteriolar and venular calibre, tortuosity, fractal dimension and branching angle) using a computer-assisted program (Singapore I Vessel Assessment, SIVA) and retinopathy (qualitative parameter) using the modified Airlie house classification system from baseline retinal photographs. Incident CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 + 25% decrease in eGFR during follow up. Over a median follow-up period of 6 years, 78 (6.21%) developed CKD (70.5% had diabetes). In multivariable models, smaller retinal arterioles (hazards ratio [95% confidence interval] = 1.34 [1.00-1.78]), larger retinal venules (2.35 [1.12 5.94] and presence of retinopathy (2.54 [1.48-4.36]) were associated with incident CKD. Our findings suggest that retinal microvascular abnormalities may reflect subclinical renal microvascular abnormalities involved in the development of CKD. PMID- 28839245 TI - Hypermasculinised facial morphology in boys and girls with Autism Spectrum Disorder and its association with symptomatology. AB - Elevated prenatal testosterone exposure has been associated with Autism Spectrum Disorder (ASD) and facial masculinity. By employing three-dimensional (3D) photogrammetry, the current study investigated whether prepubescent boys and girls with ASD present increased facial masculinity compared to typically developing controls. There were two phases to this research. 3D facial images were obtained from a normative sample of 48 boys and 53 girls (3.01-12.44 years old) to determine typical facial masculinity/femininity. The sexually dimorphic features were used to create a continuous 'gender score', indexing degree of facial masculinity. Gender scores based on 3D facial images were then compared for 54 autistic and 54 control boys (3.01-12.52 years old), and also for 20 autistic and 60 control girls (4.24-11.78 years). For each sex, increased facial masculinity was observed in the ASD group relative to control group. Further analyses revealed that increased facial masculinity in the ASD group correlated with more social-communication difficulties based on the Social Affect score derived from the Autism Diagnostic Observation Scale-Generic (ADOS-G). There was no association between facial masculinity and the derived Restricted and Repetitive Behaviours score. This is the first study demonstrating facial hypermasculinisation in ASD and its relationship to social-communication difficulties in prepubescent children. PMID- 28839246 TI - Activation of autophagy attenuates EtOH-LPS-induced hepatic steatosis and injury through MD2 associated TLR4 signaling. AB - Autophagy serves as a protective mechanism to degrade damaged organelles and proteins. Acute alcohol exposure is known to activate the hepatic autophagy response, whereas chronic alcohol exposure slows autophagosome formation along with an elevation of gut-derived endotoxin. In the current study, we examined whether lipopolysaccharide (LPS) administration decreased autophagic response in the liver of mice treated by short-term alcohol and whether activation of autophagy by rapamycin attenuates EtOH-LPS-induced liver steatosis and injury. We demonstrated that ten-day alcohol feeding primed the liver to LPS-induced lipid accumulation and liver injury with significantly increased hepatic steatosis and serum AST level as well as hepatic cellular NF-kappaB activation. LPS increased alcohol-mediated reactive oxygen species (ROS) formation while reducing autophagy activation. These deleterious effects were attenuated by rapamycin administration in mice. The protective effects of rapamycin are associated with decreased cellular MD2/TLR4 expression and interaction in Raw264.7 cells. Taken together, our results demonstrated that enhanced gut-derived LPS decreases the hepatic autophagosome numbers in response to alcohol exposure, and activation of autophagy by rapamycin protects from EtOH-LPS-induced liver injury, probably through reduced macrophage expression and interaction of TLR4/MD2 signaling complex. PMID- 28839247 TI - Spatiotemporal changes in regularity of gamma oscillations contribute to focal ictogenesis. AB - In focal ictogenesis, gamma oscillations (30-70 Hz) recorded by electroencephalography (EEG) are related to the epileptiform synchronization of interneurons that links the seizure onset zone (SOZ) to the surrounding epileptogenic zone. We hypothesized that the synchronization of interneurons could be detected as changes in the regularity of gamma oscillation rhythmicity. We used multiscale entropy (MSE) analysis, which can quantify the regularity of EEG rhythmicity, to investigate how the regularity of gamma oscillations changes over the course of a seizure event. We analyzed intracranial EEG data from 13 pediatric patients with focal cortical dysplasia. The MSE analysis revealed the following characteristic changes of MSE score (gamma oscillations): (1) during the interictal periods, the lowest MSE score (the most regular gamma oscillations) was always found in the SOZ; (2) during the preictal periods, the SOZ became more similar to the epileptogenic zone as the MSE score increased in the SOZ (gamma oscillations became less regular in the SOZ); and (3) during the ictal periods, a decreasing MSE score (highly regular gamma oscillations) propagated over the epileptogenic zone. These spatiotemporal changes in regularity of gamma oscillations constitute an important demonstration that focal ictogenesis is caused by dynamic changes in interneuron synchronization. PMID- 28839248 TI - Sensitization patterns and minimum screening panels for aeroallergens in self reported allergic rhinitis in China. AB - Optimization of skin prick test (SPT) panels, especially in view of significant differences in sensitizations patterns within different geographical areas, is an unmet need within China. Our aim was to assess the patterns and clinical relevance of aeroallergen sensitizations in allergic rhinitis (AR) and define the minimal battery of SPT allergens, classified according to the Koppen-Geiger climate map. Overall, 7148 subjects with self-reported AR completed a standard questionnaire and were assessed for sensitization to relevant allergens by SPT. 6340 (88.7%) patients had at least one positive skin prick reaction, and demonstrated unique sensitization patterns by stratification with age, gender, and geographic region. Sensitization to house dust mites (HDM) was highest in south China, whereas the three most prevalent aeroallergens were mugwort, ragweed and dandelion pollen in north-west China. Higher sensitization rates and multiple sensitizations were associated with AR comorbidities. Eight allergens (Der f, mugwort, Blatella, hazel, goosefoot, Penicillium notatum, animal dander and Der p) allowed identification >96% of sensitized subjects in central China. Differences in optimal panels were observed between regions, with five to six allergens being sufficient for north-east, north-west and south China. These SPT panels may provide a cost-effective tool for screening sensitized patients in China. PMID- 28839249 TI - Deep Western Boundary Current in the South China Sea. AB - Deep western boundary current (DWBC) was observed for the first time by an array of 6 current meter moorings southeast of the Zhongsha Islands in the South China Sea (SCS) deep basin during the period from August 2012 to January 2014. In the mean, the DWBC in the SCS flows southwestward with core velocity of 2.0 cm/s and a volume transport of 1.65 Sv (1 Sv = 1 * 106 m3/s). Its temporal variability is dominated by intraseasonal fluctuations with period around 90 days. The main axis of the DWBC, characterized by a low temperature core, tends not to shift with the 90-day fluctuation. PMID- 28839250 TI - Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating protein and soluble epoxide hydrolase. AB - Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4 dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH. Diflapolin inhibited 5-LOX product formation in intact human monocytes and neutrophils with IC50 = 30 and 170 nM, respectively, and suppressed the activity of isolated sEH (IC50 = 20 nM). Characteristic for FLAP inhibitors, diflapolin (I) failed to inhibit isolated 5-LOX, (II) blocked 5-LOX product formation in HEK cells only when 5-LOX/FLAP was co-expressed, (III) lost potency in intact cells when exogenous AA was supplied, and (IV) prevented 5-LOX/FLAP complex assembly in leukocytes. Diflapolin showed target specificity, as other enzymes related to AA metabolism (i.e., COX1/2, 12/15-LOX, LTA4H, LTC4S, mPGES1, and cPLA2) were not inhibited. In the zymosan-induced mouse peritonitis model, diflapolin impaired vascular permeability, inhibited cysteinyl-LTs and LTB4 formation, and suppressed neutrophil infiltration. Diflapolin is a highly active dual FLAP/sEH inhibitor in vitro and in vivo with target specificity to treat inflammation-related diseases. PMID- 28839252 TI - Macroevolutionary diversification of glands for chemical communication in squamate reptiles. AB - Chemical communication plays a central role in social, sexual and ecological interactions among animals. However, the macroevolutionary diversification of traits responsible for chemical signaling remains fundamentally unknown. Most research investigating evolutionary diversification of glands responsible for the production of chemical signals has focused on arthropods, while its study among vertebrates remains neglected. Using a global-scale dataset covering > 80% (7,904 species) of the living diversity of lizards and snakes (squamates), we investigate rates, trajectories and phylogenetic patterns of diversification of their follicular glands for chemical communication. We observed these glands in 13.66% of species, that their expression has varying phylogenetic signal among lineages, and that the crown squamate ancestor lacked follicular glands, which therefore originated and diversified subsequently during their evolutionary history. Additionally, our findings challenge the longstanding view that within squamates the Iguania are visually oriented while Scleroglossa are chemically oriented, given that Iguania doubles Scleroglossa in the frequency of glands. Our phylogenetic analyses identified stabilizing selection as the best model describing follicular gland diversification, and revealed high rates of disparity. We provide the first global-scale analysis investigating the diversification of one of the main forms of communication among reptiles, presenting a macroevolutionary angle to questions traditionally explored at microevolutionary scale. PMID- 28839251 TI - Odours of Plasmodium falciparum-infected participants influence mosquito-host interactions. AB - Malaria parasites are thought to influence mosquito attraction to human hosts, a phenomenon that may enhance parasite transmission. This is likely mediated by alterations in host odour because of its importance in mosquito host-searching behaviour. Here, we report that the human skin odour profile is affected by malaria infection. We compared the chemical composition and attractiveness to Anopheles coluzzii mosquitoes of skin odours from participants that were infected by Controlled Human Malaria Infection with Plasmodium falciparum. Skin odour composition differed between parasitologically negative and positive samples, with positive samples collected on average two days after parasites emerged from the liver into the blood, being associated with low densities of asexual parasites and the absence of gametocytes. We found a significant reduction in mosquito attraction to skin odour during infection for one experiment, but not in a second experiment, possibly due to differences in parasite strain. However, it does raise the possibility that infection can affect mosquito behaviour. Indeed, several volatile compounds were identified that can influence mosquito behaviour, including 2- and 3-methylbutanal, 3-hydroxy-2-butanone, and 6-methyl-5-hepten-2 one. To better understand the impact of our findings on Plasmodium transmission, controlled studies are needed in participants with gametocytes and higher parasite densities. PMID- 28839253 TI - Complete sequences of two novel bla NDM-1-harbouring plasmids from two Acinetobacter towneri isolates in China associated with the acquisition of Tn125. AB - Two novel New Delhi metallo-beta-lactamase-1 (NDM-1)-positive plasmids containing a complete composite transposon, Tn125, from two respective Acinetobacter towneri isolates were characterized. Plasmid pNDM-GJ01 (30,293 bp) isolated from A. towneri G165 did not show homology to any known plasmid structure, except for the transposon Tn125 containing bla NDM-1. A novel repB gene and two XRE-type transcriptional regulators were found in pNDM-GJ01. Plasmid pNDM-GJ02 (62,011 bp) isolated from A. towneri G295 showed the highest homology to pBJAB0715 (41% coverage, 99% nucleotide identity). In addition to the bla NDM-1-harbouring transposon Tn125, pNDM-GJ02 also had an IS26-composite transposon, which contains ISCR1 and two class 1 integrons carrying different cassette arrays. Both clinical isolates were highly resistant to beta-lactams and susceptible to tigecycline and colistin. Ten other resistance genes were detected in G295, and one other resistance gene was detected in G165. No transconjugant was obtained from any of the donors by broth and filter mating. The emergence of these two novel plasmids carrying NDM-1 in Acinetobacter spp., pNDM-GJ01 and pNDM-GJ02, suggests Tn125 mobile integration. PMID- 28839254 TI - Comparative Transcriptome Analysis Identified Candidate Genes Related to Bailinggu Mushroom Formation and Genetic Markers for Genetic Analyses and Breeding. AB - Bailinggu (Pleurotus tuoliensis) is a major, commercially cultivated mushroom and widely used for nutritional, medicinal, and industrial applications. Yet, the mushroom's genetic architecture and the molecular mechanisms underlying its formation are largely unknown. Here we performed comparative transcriptomic analysis during Bailinggu's mycelia, primordia, and fruiting body stages to identify genes regulating fruiting body development and develop EST-SSR markers assessing the genetic value of breeding materials. The stage-specific and differentially expressed unigenes (DEGs) involved in morphogenesis, primary carbohydrate metabolism, cold stimulation and blue-light response were identified using GO and KEGG databases. These unigenes might help Bailinggu adapt to genetic and environmental factors that influence fructification. The most pronounced change in gene expression occurred during the vegetative-to-reproductive transition, suggesting that is most active and key for Bailinggu development. We then developed 26 polymorphic and informative EST-SSR markers to assess the genetic diversity in 82 strains of Bailinggu breeding materials. These EST-SSRs exhibited high transferability in closely related species P. eryngii var. ferulae and var. eryngii. Genetic population structure analysis indicated that China's Bailinggu has low introgression with these two varieties and likely evolved independently. These findings provide new genes, SSR markers, and germplasm to enhance the breeding of commercially cultivated Bailinggu. PMID- 28839255 TI - Intrinsic Resistance Switching in Amorphous Silicon Suboxides: The Role of Columnar Microstructure. AB - We studied intrinsic resistance switching behaviour in sputter-deposited amorphous silicon suboxide (a-SiO x ) films with varying degrees of roughness at the oxide-electrode interface. By combining electrical probing measurements, atomic force microscopy (AFM), and scanning transmission electron microscopy (STEM), we observe that devices with rougher oxide-electrode interfaces exhibit lower electroforming voltages and more reliable switching behaviour. We show that rougher interfaces are consistent with enhanced columnar microstructure in the oxide layer. Our results suggest that columnar microstructure in the oxide will be a key factor to consider for the optimization of future SiOx-based resistance random access memory. PMID- 28839256 TI - Activation-tagging in indica rice identifies a novel transcription factor subunit, NF-YC13 associated with salt tolerance. AB - Nuclear factor Y (NF-Y) is a heterotrimeric transcription factor with three distinct NF-YA, NF-YB and NF-YC subunits. It plays important roles in plant growth, development and stress responses. We have reported earlier on development of gain-of-function mutants in an indica rice cultivar, BPT-5204. Now, we screened 927 seeds from 70 Ac/Ds plants for salinity tolerance and identified one activation-tagged salt tolerant DS plant (DS-16, T3 generation) that showed enhanced expression of a novel 'histone-like transcription factor' belonging to rice NF-Y subfamily C and was named as OsNF-YC13. Localization studies using GFP fusion showed that the protein is localized to nucleus and cytoplasm. Real time expression analysis confirmed upregulation of transcript levels of OsNF-YC13 during salt treatment in a tissue specific manner. Biochemical and physiological characterization of the DS-16 revealed enhanced K+/Na+ ratio, proline content, chlorophyll content, enzymes with antioxidant activity etc. DS-16 also showed transcriptional up-regulation of genes that are involved in salinity tolerance. In-silico analysis of OsNF-YC13 promoter region evidenced the presence of various key stress-responsive cis-regulatory elements. OsNF-YC13 subunit alone does not appear to have the capacity for direct transcription activation, but appears to interact with the B- subunits in the process of transactivation. PMID- 28839257 TI - Mesohepatectomy Versus Extended Hemihepatectomies for Centrally Located Liver Tumors: A Meta-Analysis. AB - The comparison of Mesohepatectomy (MH) with conventional extended hemihepatectomies (EH) for patients with centrally located liver tumors (CLLTs) were inconsistent. Our aims were to systemically compare MH with EH and to determine whether MH can achieve a similar clinical outcome as EH through this meta-analysis. PubMed/Medline, EMBASE, Web of Knowledge and Cochrane Library were searched updated to June 11, 2016. Blood loss and operation time favored MH in elder patients (mean difference [MD] for blood loss: -692.82 ml, 95% CI: -976.72 to -408.92 ml, P < 0.001; MD for operation time: -78.75 min, 95% CI: -107.66 to 49.81, P < 0.001). Morbidity rate (29.2%, 95% CI: 24.1 to 34.8%), mortality rate (2.0%, 95% CI: 1.2 to 3.3%) and overall survival (median OS 38.2 m, 95% CI: 34.0 to 42.8 m) of MH were comparable with those of EH. The low liver failure rate favored MH (odds ratio [OR]: 0.29, 95% CI: 0.09 to 0.88, P = 0.03). For MH, bile leakage was the most common surgical complication (MH vs. EH: 13.5% vs. 6.7%, P = 0.016), while for EH, it was wound infection (MH vs. EH: 6.9% vs. 15.7%, P < 0.001). Thus MH might be in general safe and feasible for treating CLLTs with a similar clinical outcome as EH. PMID- 28839258 TI - BIRC3 is a biomarker of mesenchymal habitat of glioblastoma, and a mediator of survival adaptation in hypoxia-driven glioblastoma habitats. AB - Tumor hypoxia is an established facilitator of survival adaptation and mesenchymal transformation in glioblastoma (GBM). The underlying mechanisms that direct hypoxia-mediated survival in GBM habitats are unclear. We previously identified BIRC3 as a mediator of therapeutic resistance in GBM to standard temozolomide (TMZ) chemotherapy and radiotherapy (RT). Here we report that BIRC3 is a biomarker of the hypoxia-mediated adaptive mesenchymal phenotype of GBM. Specifically, in the TCGA dataset elevated BIRC3 gene expression was identified as a superior and selective biomarker of mesenchymal GBM versus neural, proneural and classical subtypes. Further, BIRC3 protein was highly expressed in the tumor cell niches compared to the perivascular niche across multiple regions in GBM patient tissue microarrays. Tumor hypoxia was found to mechanistically induce BIRC3 expression through HIF1-alpha signaling in GBM cells. Moreover, in human GBM xenografts robust BIRC3 expression was noted within hypoxic regions of the tumor. Importantly, selective inhibition of BIRC3 reversed therapeutic resistance of GBM cells to RT in hypoxic microenvironments through enhanced activation of caspases. Collectively, we have uncovered a novel role for BIRC3 as a targetable biomarker and mediator of hypoxia-driven habitats in GBM. PMID- 28839260 TI - Tuning Metamaterials by using Amorphous Magnetic Microwires. AB - In this work, we demonstrate theoretically and experimentally the possibility of tuning the electromagnetic properties of metamaterials with magnetic fields by incorporating amorphous magnetic microwires. The large permeability of these wires at microwave frequencies allows tuning the resonance of the metamaterial by using magnetic fields of the order of tens of Oe. We describe here the physical basis of the interaction between a prototypical magnetic metamaterial with magnetic microwires and electromagnetic waves plus providing detailed calculations and experimental results for the case of an array of Split Ring Resonators with Co-based microwires. PMID- 28839259 TI - Resveratrol accumulation and its involvement in stilbene synthetic pathway of Chinese wild grapes during berry development using quantitative proteome analysis. AB - Attention has become focused on resveratrol not only because of its role in grapevine fungal resistance but also because of its benefits in human health. This report describes the Chinese wild grapevine Vitis quinquangularis accession Danfeng-2 in relation to the high resveratrol content of its ripe berries. In this study, we used isobaric tags for relative and absolute quantification (iTRAQ) tandem mass spectrometry strategy to quantify and identify proteome changes, resulting in the detection of a total of 3,751 proteins produced under natural conditions. Among the proteins quantified, a total of 578 differentially expressed proteins were detected between Danfeng-2 and Cabernet Sauvignon during berry development. Differentially expressed proteins are involved in secondary metabolism, biotic stress, abiotic stress and transport activity and indicate novel biological processes in Chinese wild grapevine. Eleven proteins involved in phenylpropanoid metabolism and stilbene synthesis were differently expressed between Danfeng-2 and Cabernet Sauvignon at the veraison stage of berry development. These findings suggest that Chinese wild V. quinquangularis accession Danfeng-2 is an extremely important genetic resource for grape breeding and especially for increasing the resveratrol content of European grape cultivars for disease resistance and for improved human nutritional benefits. PMID- 28839261 TI - Structural basis for therapeutic inhibition of influenza A polymerase PB2 subunit. AB - Influenza virus uses a unique mechanism to initiate viral transcription named cap snatching. The PB2 subunit of the viral heterotrimeric RNA polymerase binds the cap structure of cellular pre-mRNA to promote its cleavage by the PA subunit. The resulting 11-13 capped oligomer is used by the PB1 polymerase subunit to initiate transcription of viral proteins. VX-787 is an inhibitor of the influenza A virus pre-mRNA cap-binding protein PB2. This clinical stage compound was shown to bind the minimal cap-binding domain of PB2 to inhibit the cap-snatching machinery. However, the binding of this molecule in the context of an extended form of the PB2 subunit has remained elusive. Here we generated a collection of PB2 truncations to identify a PB2 protein representative of its structure in the viral heterotrimeric protein. We present the crystal structure of VX-787 bound to a PB2 construct that recapitulates VX-787's biological antiviral activity in vitro. This co-structure reveals more extensive interactions than previously identified and provides insight into the observed resistance profile, affinity, binding kinetics, and conformational rearrangements induced by VX-787. PMID- 28839262 TI - Evolution of risk preference is determined by reproduction dynamics, life history, and population size. AB - Alternative behavioral strategies typically differ in their associated risks, meaning that a different variance in fitness-related outcomes characterizes each behavior. Understanding how selection acts on risk preference is crucial to interpreting and predicting behavior. Despite much research, most theoretical frameworks have been laid out as optimization problems from the individual's perspective, and the influence of population dynamics has been underappreciated. We use agent-based simulations that implement competition between two simple behavioral strategies to illuminate effects of population dynamics on risk taking. We explore the effects of inter-generational reproduction dynamics, population size, the number of decisions throughout an individual's life, and simple alternate distributions of risk. We find that these factors, very often ignored in empirical and theoretical studies of behavior, can have significant and non-intuitive impacts on the selection of alternative behavioral strategies. Our results demonstrate that simple rules regarding predicted risk preference do not hold across the complete range of each of the factors we studied; we propose intuitive interpretations for the dynamics within each regime. We suggest that studies of behavioral strategies should explicitly take into account the species' life history and the ecological context in which selection acted on the risk related behavior of the organism of interest. PMID- 28839263 TI - Ocean dominated expansion and contraction of the late Quaternary tropical rainbelt. AB - The latitude of the tropical rainbelt oscillates seasonally but has also varied on millennial time-scales in response to changes in the seasonal distribution of insolation due to Earth's orbital configuration, as well as climate change initiated at high latitudes. Interpretations of palaeoclimate proxy archives often suggest hemispherically coherent variations, some proposing meridional shifts in global rainbelt position and the 'global monsoon', while others propose interhemispherically symmetric expansion and contraction. Here, we use a unique set of climate model simulations of the last glacial cycle (120 kyr), that compares well against a compilation of precipitation proxy data, to demonstrate that while asymmetric extratropical forcings (icesheets, freshwater hosing) generally produce meridional shifts in the zonal mean rainbelt, orbital variations produce expansion/contractions in terms of the global zonal mean. This is primarily a dynamic response of the rainbelt over the oceans to regional interhemispheric temperature gradients, which is opposite to the largely local thermodynamic terrestrial response to insolation. The mode of rainbelt variation is regionally variable, depending on surface type (land or ocean) and surrounding continental configuration. This makes interpretation of precipitation-proxy records as large-scale rainbelt movement challenging, requiring regional or global data syntheses. PMID- 28839264 TI - Analysis on the Composition/structure and Lacquering Techniques of the Coffin of Emperor Qianlong Excavated from the Eastern Imperial Tombs. AB - This article presents the results of an investigation on the coffin of Emperor Qianlong excavated from the Eastern Imperial Tombs of the Qing Dynasty in Zunhua, China. The composition, structure and lacquering techniques used in the manufacturing process were analyzed in this project. Stereoscopic Microscopy, SEM EDS, XRD, FTIR, Raman, Double-shot Py-GC/MS were used as scientific analytical methods. The results show that the structure of the coffin body consists of a wooden body layer, a lacquer ash layer and a lacquer film pigment layer. The lacquer ash layer consists of nine stucco layers and ten fiber layers on top of each other in an alternating order. The lacquer film pigment layer consists of mineral pigments, lacquer sap, animal gelatin, drying oil, quartz sand and proteinaceous materials. Pigments used in the lacquer film include calcite white, carbon black, cinnabar red and gold. The presence of three distinctive catechols along with the other catechols' and phenols' profiles in the lacquer film matrix clearly indicate the species of the lacquer tree was Rhus. Vernicifera. Several distinctive lacquering techniques that improved the coffin body's stability and mechanical strength were identified in the investigation, including the "wan lacquering", "painting lacquer above the gold" and "Jin Jiao". PMID- 28839265 TI - Combinatorial bioactive botanicals re-sensitize tamoxifen treatment in ER negative breast cancer via epigenetic reactivation of ERalpha expression. AB - Conventional cancer prevention has primarily focused on single chemopreventive compounds that may not be sufficiently efficacious. We sought to investigate potential combinatorial effects of epigenetic bioactive botanicals including epigallocatechin-3-gallate (EGCG) in green tea polyphenols (GTPs) and sulforaphane (SFN) in broccoli sprouts (BSp) on neutralizing epigenetic aberrations in estrogen receptor-alpha (ERalpha) leading to enhanced anti-hormone therapeutic efficacy in ERalpha-negative breast cancer. Our results showed that this combinatorial treatment re-sensitized ERalpha-dependent cellular inhibitory responses to an estrogen antagonist, tamoxifen (TAM), via at least in part, epigenetic reactivation of ERalpha expression in ERalpha-negative breast cancer cells. Further in vivo studies revealed the combinatorial diets of GTPs and BSp significantly inhibited breast tumor growth in ERalpha-negative mouse xenografts, especially when combined with TAM treatment. This novel treatment regimen can lead to remodeling of the chromatin structure by histone modifications and recruitment changes of transcriptional factor complex in the ERalpha promoter thereby contributing to ERalpha reactivation and re-sensitized chemotherapeutic efficacy of anti-hormone therapy. Our studies indicate that combinatorial bioactive botanicals from GTPs and BSp are highly effective in inhibiting ERalpha negative breast cancer due at least in part to epigenetic reactivation of ERalpha, which in turn increases TAM-dependent anti-estrogen chemosensitivity in vitro and in vivo. PMID- 28839267 TI - A Systematic Protein Refolding Screen Method using the DGR Approach Reveals that Time and Secondary TSA are Essential Variables. AB - Refolding of proteins derived from inclusion bodies is very promising as it can provide a reliable source of target proteins of high purity. However, inclusion body-based protein production is often limited by the lack of techniques for the detection of correctly refolded protein. Thus, the selection of the refolding conditions is mostly achieved using trial and error approaches and is thus a time consuming process. In this study, we use the latest developments in the differential scanning fluorimetry guided refolding approach as an analytical method to detect correctly refolded protein. We describe a systematic buffer screen that contains a 96-well primary pH-refolding screen in conjunction with a secondary additive screen. Our research demonstrates that this approach could be applied for determining refolding conditions for several proteins. In addition, it revealed which "helper" molecules, such as arginine and additives are essential. Four different proteins: HA-RBD, MDM2, IL-17A and PD-L1 were used to validate our refolding approach. Our systematic protocol evaluates the impact of the "helper" molecules, the pH, buffer system and time on the protein refolding process in a high-throughput fashion. Finally, we demonstrate that refolding time and a secondary thermal shift assay buffer screen are critical factors for improving refolding efficiency. PMID- 28839266 TI - Neutron crystallography of photoactive yellow protein reveals unusual protonation state of Arg52 in the crystal. AB - Because of its high pKa, arginine (Arg) is believed to be protonated even in the hydrophobic environment of the protein interior. However, our neutron crystallographic structure of photoactive yellow protein, a light sensor, demonstrated that Arg52 adopts an electrically neutral form. We also showed that the hydrogen bond between the chromophore and Glu46 is a so-called low barrier hydrogen bond (LBHB). Because both the neutral Arg and LBHB are unusual in proteins, these observations remain controversial. To validate our findings, we carried out neutron crystallographic analysis of the E46Q mutant of PYP. The resultant structure revealed that the proportion of the cationic form is higher in E46Q than in WT, although the cationic and neutral forms of Arg52 coexist in E46Q. These observations were confirmed by the occupancy of the deuterium atom bound to the N eta1 atom combined with an alternative conformation of the N(eta2)D2 group comprising sp2 hybridisation. Based on these results, we propose that the formation of the LBHB decreases the proton affinity of Arg52, stabilizing the neutral form in the crystal. PMID- 28839268 TI - Analysis and evaluation of the entropy indices of a static network structure. AB - Although degree distribution entropy (DDE), SD structure entropy (SDSE), Wu structure entropy (WSE) and FB structure entropy (FBSE) are four static network structure entropy indices widely used to quantify the heterogeneity of a complex network, previous studies have paid little attention to their differing abilities to describe network structure. We calculate these four structure entropies for four benchmark networks and compare the results by measuring the ability of each index to characterize network heterogeneity. We find that SDSE and FBSE more accurately characterize network heterogeneity than WSE and DDE. We also find that existing benchmark networks fail to distinguish SDSE and FBSE because they cannot discriminate local and global network heterogeneity. We solve this problem by proposing an evolving caveman network that reveals the differences between structure entropy indices by comparing the sensitivities during the network evolutionary process. Mathematical analysis and computational simulation both indicate that FBSE describes the global topology variation in the evolutionary process of a caveman network, and that the other three structure entropy indices reflect only local network heterogeneity. Our study offers an expansive view of the structural complexity of networks and expands our understanding of complex network behavior. PMID- 28839269 TI - Microbiome Dynamics in a Shrimp Grow-out Pond with Possible Outbreak of Acute Hepatopancreatic Necrosis Disease. AB - Acute hepatopancreatic necrosis disease (AHPND) (formerly, early mortality syndrome) is a high-mortality-rate shrimp disease prevalent in shrimp farming areas. Although AHPND is known to be caused by pathogenic Vibrio parahaemolyticus hosting the plasmid-related PirABvp toxin gene, the effects of disturbances in microbiome have not yet been studied. We took 62 samples from a grow-out pond during an AHPND developing period from Days 23 to 37 after stocking white postlarvae shrimp and sequenced the 16S rRNA genes with Illumina sequencing technology. The microbiomes of pond seawater and shrimp stomachs underwent varied dynamic succession during the period. Despite copies of PirABvp, principal co ordinates analysis revealed two distinctive stages of change in stomach microbiomes associated with AHPND. AHPND markedly changed the bacterial diversity in the stomachs; it decreased the Shannon index by 53.6% within approximately 7 days, shifted the microbiome with Vibrio and Candidatus Bacilloplasma as predominant populations, and altered the species-to-species connectivity and complexity of the interaction network. The AHPND-causing Vibrio species were predicted to develop a co-occurrence pattern with several resident and transit members within Candidatus Bacilloplasma and Cyanobacteria. This study's insights into microbiome dynamics during AHPND infection can be valuable for minimising this disease in shrimp farming ponds. PMID- 28839270 TI - A novel mechanism of ERK1/2 regulation in smooth muscle involving acetylation of the ERK1/2 scaffold IQGAP1. AB - Ceramide, a bioactive lipid and signaling molecule associated with cardiovascular disease, is known to activate extracellular signal regulated kinases 1 and 2 (ERK1/2). Here, we determined that the effect of ceramide on ERK1/2 is mediated by ceramide signaling on an ERK scaffold protein, IQ motif containing GTPase activating protein 1 (IQGAP1). Experiments were performed with aortic smooth muscle cells using inhibitor screening, small interfering RNA (siRNA), immunoprecipitation (IP), immunoblots and bioinformatics. We report here that C6 ceramide increases serum-stimulated ERK1/2 activation in a manner dependent on the ERK1/2 scaffold IQGAP1. C6 ceramide increases IQGAP1 protein levels by preventing its cleavage. Bioinformatic analysis of the IQGAP1 amino acid sequence revealed potential cleavage sites for proteases of the proprotein convertase family that match the cleavage products. These potential cleavage sites overlap with known motifs for lysine acetylation. Deacetylase inhibitor treatment increased IQGAP1 acetylation and reduced IQGAP1 cleavage. These data are consistent with a model in which IQGAP1 cleavage is regulated by acetylation of the cleavage sites. Activation of ERK1/2 by ceramide, known to increase lysine acetylation, appears to be mediated by acetylation-dependent stabilization of IQGAP1. This novel mechanism could open new possibilities for therapeutic intervention in cardiovascular diseases. PMID- 28839271 TI - SmartScope2: Simultaneous Imaging and Reconstruction of Neuronal Morphology. AB - Quantitative analysis of neuronal morphology is critical in cell type classification and for deciphering how structure gives rise to function in the brain. Most current approaches to imaging and tracing neuronal 3D morphology are data intensive. We introduce SmartScope2, the first open source, automated neuron reconstruction machine integrating online image analysis with automated multiphoton imaging. SmartScope2 takes advantage of a neuron's sparse morphology to improve imaging speed and reduce image data stored, transferred and analyzed. We show that SmartScope2 is able to produce the complex 3D morphology of human and mouse cortical neurons with six-fold reduction in image data requirements and three times the imaging speed compared to conventional methods. PMID- 28839272 TI - Changes of plasmalogen phospholipid levels during differentiation of induced pluripotent stem cells 409B2 to endothelial phenotype cells. AB - Endothelial cells (EC) are involved in regulating several aspects of lipid metabolism, with recent research revealing the clinicopathological significance of interactions between EC and lipids. Induced pluripotent stem cells (iPSC) have various possible medical uses, so understanding the metabolism of these cells is important. In this study, endothelial phenotype cells generated from human iPSC formed cell networks in co-culture with fibroblasts. Changes of plasmalogen lipids and sphingomyelins in endothelial phenotype cells generated from human iPSC were investigated by reverse-phase ultra-high-pressure liquid chromatography mass spectrometry (UHPLC-MS/MS) analysis. The levels of plasmalogen phosphatidylethanolamines (38:5) and (38:4) increased during differentiation of EC, while sphingomyelin levels decreased transiently. These changes of plasmalogen lipids and sphingomyelins may have physiological significance for EC and could be used as markers of differentiation. PMID- 28839273 TI - Infection increases vulnerability to climate change via effects on host thermal tolerance. AB - Unprecedented global climate change and increasing rates of infectious disease emergence are occurring simultaneously. Infection with emerging pathogens may alter the thermal thresholds of hosts. However, the effects of fungal infection on host thermal limits have not been examined. Moreover, the influence of infections on the heat tolerance of hosts has rarely been investigated within the context of realistic thermal acclimation regimes and potential anthropogenic climate change. We tested for effects of fungal infection on host thermal tolerance in a model system: frogs infected with the chytrid Batrachochytrium dendrobatidis. Infection reduced the critical thermal maxima (CTmax) of hosts by up to ~4 degrees C. Acclimation to realistic daily heat pulses enhanced thermal tolerance among infected individuals, but the magnitude of the parasitism effect usually exceeded the magnitude of the acclimation effect. In ectotherms, behaviors that elevate body temperature may decrease parasite performance or increase immune function, thereby reducing infection risk or the intensity of existing infections. However, increased heat sensitivity from infections may discourage these protective behaviors, even at temperatures below critical maxima, tipping the balance in favor of the parasite. We conclude that infectious disease could lead to increased uncertainty in estimates of species' vulnerability to climate change. PMID- 28839274 TI - Yttrium Copper Titanate as a Highly Efficient Electrocatalyst for Oxygen Reduction Reaction in Fuel Cells, Synthesized via Ultrafast Automatic Flame Technique. AB - Replacing platinum (Pt) metal-based electrocatalysts used in the oxygen reduction reaction (ORR) in fuel cells is an important research topic due to the high cost and scarcity of Pt, which have restricted the commercialization of these clean energy technologies. The ABO3-type perovskite family of an ACu3Ti4O12 (A = Ca, Y, Bi, and La) polycrystalline material can serve as an alternative electrocatalyst for the ORR in terms of low-cost, activity, and stability. These perovskite materials may be considered the next generation electro-catalyst for the ORR because of their photocatalytic activity and physical and chemical properties capable of containing a wide range of A- and B-site metals. This paper reports the ORR activity of a new Y2/3Cu3Ti4O12 perovskite, synthesized via a rapid and facile automatic flame synthesis technique using rotating disk electrode (RDE) measurements. Y2/3Cu3Ti4O12/C has superior ORR activity, stability, and durability compared to commercial Pt/C. The results presented in this article will provide the future perspectives to research based on ACu3Ti4O12 (A = Ca, Y, Bi, Sm, Cd, and La) perovskite as the next generation electro-catalyst for the ORR in various electrochemical devices, such as fuel cells, metal-air batteries, and electrolysis. PMID- 28839276 TI - Corrigendum: Novel missense mutation in DLL4 in a Japanese sporadic case of Adams Oliver syndrome. AB - This corrects the article DOI: 10.1038/jhg.2017.48. PMID- 28839275 TI - Fitness consequences of peak reproductive effort in a resource pulse system. AB - The age trajectory of reproductive performance of many iteroparous species features an early - life increase in performance followed by a late - life senescent decline. The largest contribution of lifetime reproductive success is therefore gained at the age at which reproductive performance peaks. Using long term data on North American red squirrels we show that the environmental conditions individuals encountered could cause variation among individuals in the "height" and timing of this peak, contributing to life history variation and fitness in this population that experiences irregular resource pulses. As expected, high peak effort was positively associated with lifetime reproductive output up to a high level of annual effort. Furthermore, individuals that matched their peak reproductive effort to an anticipated resource pulse gained substantial fitness benefits through recruiting more offspring over their lifetime. Individual variation in peak reproductive effort thus has strong potential to shape life history evolution by facilitating adaptation to fluctuating environments. PMID- 28839278 TI - Electrical performance of lightweight CNT-Cu composite wires impacted by surface and internal Cu spatial distribution. AB - We report ultralong conducting lightweight multiwall carbon nanotube (MWCNT)-Cu composite wires with MWCNTs uniformly distributed in a continuous Cu matrix throughout. With a high MWCNT vol% (40-45%), the MWCNT-Cu wire density was 2/3rd that of Cu. Our composite wires show manufacturing potential because we used industrially compatible Cu electrodeposition protocols on commercial CNT wires. Further, we systematically varied Cu spatial distribution on the composite wire surface and bulk and measured the associated electrical performance, including resistivity (rho), temperature dependence of resistance, and stability to current (measured as current carrying capacity, CCC in vacuum). We find that a continuous Cu matrix with homogeneous MWCNT distribution, i.e., maximum internal Cu filling within MWCNT wires, is critical to high overall electrical performances. Wires with maximum internal Cu filling exhibit (i) low room temperature rho, 1/100th of the starting MWCNT wires, (ii) suppressed resistance-rise with temperature increase and temperature coefficient of resistance (TCR) 1/2 that of Cu, and (iii) vacuum-CCC 28% higher than Cu. Further, the wires showed real-world applicability and were easily soldered into practical circuits. Hence, our MWCNT Cu wires are promising lightweight alternatives to Cu wiring for weight-reducing applications. The low TCR is specifically advantageous for stable high temperature operation, e.g., in motor windings. PMID- 28839277 TI - Quercetin prevents hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing autophagy via the TGF-beta1/Smads and PI3K/Akt pathways. AB - The aim of this study was to investigate the effect of quercetin on hepatic fibrosis, a characteristic response to acute or chronic liver injury. Mice were randomized to bile duct ligation (BDL) or carbon tetrachloride (CCl4) cirrhosis models. Quercetin (100 mg/kg or 200 mg/kg daily) was administered by gavage for 2 or 4 weeks. Liver tissue and blood samples were collected for histological and molecular analysis. The results of our experiments showed that quercetin reduced BDL or CCl4 liver fibrosis, inhibited extracellular matrix formation, and regulated matrix metallopeptidase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1. Quercetin attenuated liver damage by suppressing the TGF-beta1/Smads signaling pathway and activating the PI3K/Akt signaling pathway to inhibit autophagy in BDL- or CCl4- induced liver fibrosis. Quercetin prevented hepatic fibrosis by attenuating hepatic stellate cell activation and reducing autophagy through regulating crosstalk between the TGF-beta1/Smads and PI3K/Akt pathways. PMID- 28839279 TI - Epigallocatechin Gallate-Loaded Gelatin-g-Poly(N-Isopropylacrylamide) as a New Ophthalmic Pharmaceutical Formulation for Topical Use in the Treatment of Dry Eye Syndrome. AB - Given that biodegradable in situ gelling delivery systems may have potential applications in the design of ophthalmic pharmaceutical formulations, this study, for the first time, aims to develop gelatin-g-poly(N-isopropylacrylamide) (GN) carriers for topical epigallocatechin gallate (EGCG) administration in the treatment of dry eye disease (DED). By temperature triggered sol-gel phase transition of copolymers, EGCG-loaded GN was prepared at 32 degrees C and characterized by FTIR, NMR, and HPLC analyses. Results of WST-1 and live/dead assays showed that GN materials have good compatibility with corneal epithelial cells. Gradual biodegradation of delivery carriers allowed sustained release of EGCG without drug toxicity. Anti-inflammatory and antioxidant activity studies also indicated effective therapeutic drug levels at each time point within 3 days of release. In a rabbit dry eye model, corneal epithelial defects was ameliorated by treatment with single-dose administration of EGCG-containing GN. Furthermore, drug molecules released from carrier materials could prevent further tear evaporation and loss of mucin-secreting goblet cells in diseased animals. Our findings suggest that GN carrier is responsible for enhanced pharmacological efficacy of topically instilled EGCG, thereby demonstrating the benefits of using biodegradable in situ gelling delivery system to overcome the drawbacks of limited dry eye relief associated with eye drop dosage form. PMID- 28839280 TI - The adjuvant value of Herba Cistanches when used in combination with statin in murine models. AB - Statins are well known to have muscle toxicity problem. Herba Cistanches (HC) is a Chinese herb traditionally used for pain in the loins and knees. Our previous in vitro study suggested that it could protect against statin-induced muscle toxicity. However, its in vivo protective effect has never been investigated. The objective of this study was to determine if the aqueous extract of HC (HCE) could prevent simvastatin-induced muscle toxicity in rats, and whether HCE could also exert beneficial effects on reducing high-fat diet-induced hypercholesterolemia and elevated liver cholesterol, thereby reducing the dose of simvastatin when used in combined therapy. From our results, HCE significantly restored simvastatin-induced reduction in muscle weights and reduced elevated plasma creatine kinase in rats. HCE also improved simvastatin-induced reduction in muscle glutathione levels, muscle mitochondrial membrane potential, and reduced simvastatin-induced muscle inflammation. Furthermore, HCE could exert reduction on liver weight, total liver lipid levels and plasma lipid levels in high-fat-fed mice. In conclusion, our study provided in vivo evidence that HCE has potential protective effect on simvastatin-induced toxicity in muscles, and also beneficial effects on diet-induced non-alcoholic fatty liver and hyperlipidemia when being used alone or in combination with simvastatin at a reduced dose. PMID- 28839281 TI - Fungal Hybrid B heme peroxidases - unique fusions of a heme peroxidase domain with a carbohydrate-binding domain. AB - Heme peroxidases, essential peroxide converting oxidoreductases are divided into four independently evolved superfamilies. Within the largest one - the peroxidase catalase superfamily - two hybrid lineages were described recently. Whereas Hybrid A heme peroxidases represent intermediate enzymes between ascorbate peroxidases and cytochrome c peroxidases, Hybrid B heme peroxidases are unique fusion proteins comprised of a conserved N-terminal heme peroxidase domain and a C-terminal domain of various sugar binding motifs. So far these peculiar peroxidases are only found in the kingdom of Fungi. Here we present a phylogenetic reconstruction of the whole superfamily with focus on Hybrid B peroxidases. We analyse the domain assembly and putative structure and function of the newly discovered oligosaccharide binding domains. Two distinct carbohydrate binding modules (CBM21 and CBM34) are shown to occur in phytopathogenic ascomycetous orthologs of Hybrid B heme peroxidases only. Based on multiple sequence alignment and homology modeling the structure-function relationships are discussed with respect to physiological function. A concerted action of peroxide cleavage with specific cell-wall carbohydrate binding can support phytopathogens survival within the plant host. PMID- 28839282 TI - Distributed Optical Fiber Sensors with Ultrafast Laser Enhanced Rayleigh Backscattering Profiles for Real-Time Monitoring of Solid Oxide Fuel Cell Operations. AB - This paper reports a technique to enhance the magnitude and high-temperature stability of Rayleigh back-scattering signals in silica fibers for distributed sensing applications. With femtosecond laser radiation, more than 40-dB enhancement of Rayleigh backscattering signal was generated in silica fibers using 300-nJ laser pulses at 250 kHz repetition rate. The laser-induced Rayleigh scattering defects were found to be stable from the room temperature to 800 degrees C in hydrogen gas. The Rayleigh scatter at high temperatures was correlated to the formation and modification of nanogratings in the fiber core. Using optical fibers with enhanced Rayleigh backscattering profiles as distributed temperature sensors, we demonstrated real-time monitoring of solid oxide fuel cell (SOFC) operations with 5-mm spatial resolution at 800 degrees C. Information gathered by these fiber sensor tools can be used to verify simulation results or operated in a process-control system to improve the operational efficiency and longevity of SOFC-based energy generation systems. PMID- 28839283 TI - Formation of a-plane facets in three-dimensional hexagonal GaN structures for photonic devices. AB - Control of the growth front in three-dimensional (3D) hexagonal GaN core structures is crucial for increased performance of light-emitting diodes (LEDs), and other photonic devices. This is due to the fact that InGaN layers formed on different growth facets in 3D structures exhibit various band gaps which originate from differences in the indium-incorporation efficiency, internal polarization, and growth rate. Here, a-plane {[Formula: see text] } facets, which are rarely formed in hexagonal pyramid based growth, are intentionally fabricated using mask patterns and adjustment of the core growth conditions. Moreover, the growth area covered by these facets is modified by changing the growth time. The origin of the formation of a-plane {[Formula: see text]} facets is also discussed. Furthermore, due to a growth condition transition from a 3D core structure to an InGaN multi-quantum well, a growth front transformation (i.e., a transformation of a-plane {[Formula: see text]} facets to semi-polar {[Formula: see text]} facets) is directly observed. Based on our understanding and control of this novel growth mechanism, we can achieve efficient broadband LEDs or photovoltaic cells. PMID- 28839284 TI - A Strategy for Nonmigrating Highly Plasticized PVC. AB - Nonmigrating highly plasticized PVC was prepared based on a new compound that acts as a plasticizer that was derived from di(2-ethylhexyl) 4-hydrophthalate and chlorinated paraffin-52. The as-prepared PVC has a plasticizing efficiency as high as DOP and its migration is totally suppressed. Unlike other reported methods, this approach increases the interaction between phthalate and PVC to suppress its migration, not simply to enlarge its molecular size (or molecular weight). This methodology is highly versatile for producing the desired non leaching PVC with a permanent plasticizer effect. PMID- 28839285 TI - Metastability for discontinuous dynamical systems under Levy noise: Case study on Amazonian Vegetation. AB - For the tipping elements in the Earth's climate system, the most important issue to address is how stable is the desirable state against random perturbations. Extreme biotic and climatic events pose severe hazards to tropical rainforests. Their local effects are extremely stochastic and difficult to measure. Moreover, the direction and intensity of the response of forest trees to such perturbations are unknown, especially given the lack of efficient dynamical vegetation models to evaluate forest tree cover changes over time. In this study, we consider randomness in the mathematical modelling of forest trees by incorporating uncertainty through a stochastic differential equation. According to field-based evidence, the interactions between fires and droughts are a more direct mechanism that may describe sudden forest degradation in the south-eastern Amazon. In modeling the Amazonian vegetation system, we include symmetric alpha-stable Levy perturbations. We report results of stability analysis of the metastable fertile forest state. We conclude that even a very slight threat to the forest state stability represents L'evy noise with large jumps of low intensity, that can be interpreted as a fire occurring in a non-drought year. During years of severe drought, high-intensity fires significantly accelerate the transition between a forest and savanna state. PMID- 28839286 TI - Sensing coral reef connectivity pathways from space. AB - Coral reefs rely on inter-habitat connectivity to maintain gene flow, biodiversity and ecosystem resilience. Coral reef communities of the Red Sea exhibit remarkable genetic homogeneity across most of the Arabian Peninsula coastline, with a genetic break towards the southern part of the basin. While previous studies have attributed these patterns to environmental heterogeneity, we hypothesize that they may also emerge as a result of dynamic circulation flow; yet, such linkages remain undemonstrated. Here, we integrate satellite-derived biophysical observations, particle dispersion model simulations, genetic population data and ship-borne in situ profiles to assess reef connectivity in the Red Sea. We simulated long-term (>20 yrs.) connectivity patterns driven by remotely-sensed sea surface height and evaluated results against estimates of genetic distance among populations of anemonefish, Amphiprion bicinctus, along the eastern Red Sea coastline. Predicted connectivity was remarkably consistent with genetic population data, demonstrating that circulation features (eddies, surface currents) formulate physical pathways for gene flow. The southern basin has lower physical connectivity than elsewhere, agreeing with known genetic structure of coral reef organisms. The central Red Sea provides key source regions, meriting conservation priority. Our analysis demonstrates a cost effective tool to estimate biophysical connectivity remotely, supporting coastal management in data-limited regions. PMID- 28839287 TI - Self-propelled ion gel at air-water interface. AB - We report on a self-propelled gel using ionic liquid as a new type of self propellant that generates a powerful and durable motion at an air-water interface. The gel is composed of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMIM-TFSI) and poly(vinylidene fluoride-co hexafluoropropylene) (P(VDF-co-HFP)). A long rectangular ion gel piece placed on the interface shows rapid rotation motion with maximum frequency close to 10 Hz, corresponding to the velocity over 300 mms-1 at an outmost end of the piece. The rotation continues for ca. 102 s, followed by a reciprocating motion (<~103 s) and a nonlinear motion in long-time observations (>~103 s). The behaviours can be explained by the model considering elution of EMIM-TFSI to the air-water interface, rapid dissolution into water, and slow diffusion in an inhomogeneous polymer gel network. Because the self-propellants are promptly removed from the interface by dissolution, durable self-propelled motions are observed also at limited interface areas close in size to the gel pieces. A variety of motions are induced in such systems where the degree of freedom in motion is limited. As the ion gel possesses formability and processability, it is also advantageous for practical applications. We demonstrate that the gel does work as an engine. PMID- 28839288 TI - Assessing the relationship between surface urban heat islands and landscape patterns across climatic zones in China. AB - The urban heat island (UHI) effect exerts a great influence on the Earth's environment and human health and has been the subject of considerable attention. Landscape patterns are among the most important factors relevant to surface UHIs (SUHIs); however, the relationship between SUHIs and landscape patterns is poorly understood over large areas. In this study, the surface UHI intensity (SUHII) is defined as the temperature difference between urban and suburban areas, and the landscape patterns are quantified by the urban-suburban differences in several typical landscape metrics (DeltaLMs). Temperature and land-cover classification datasets based on satellite observations were applied to analyze the relationship between SUHII and DeltaLMs in 332 cities/city agglomerations distributed in different climatic zones of China. The results indicate that SUHII and its correlations with DeltaLMs are profoundly influenced by seasonal, diurnal, and climatic factors. The impacts of different land-cover types on SUHIs are different, and the landscape patterns of the built-up and vegetation (including forest, grassland, and cultivated land) classes have the most significant effects on SUHIs. The results of this study will help us to gain a deeper understanding of the relationship between the SUHI effect and landscape patterns. PMID- 28839289 TI - Quantitative visualization of pectin distribution maps of peach fruits. AB - Pectin content is an important quality index of fruits, as pectin content undergoes significant changes during the peach ripening process. The commonly used carbazole colorimetry method measures only the total content value of each kind of pectin for each pulp sample and cannot provide distribution maps of the pectin contents for the whole fruit pulp. This work used the hyperspectral imaging technique to quantitatively visualize the distribution maps of pectin contents inside peach pulp at the pixel level. The protopectin contents were well predicted, with the best residual predictive deviation of 2.264, whereas the predictions of the water-soluble pectin and the total pectin contents were not satisfied. On the basis of the best predictive model, the distribution maps of the protopectin contents were quantitatively visualized. A histogram of an example protopectin distribution revealed the existence of a wide range of protopectin contents in peach pulp. Our results show that hyperspectral imaging holds promise as a powerful alternative to the carbazole colorimetry method for measuring the spatial variations in the protopectin distribution inside peach pulp. The distribution maps could be used as a maturity indicator to understand and evaluate the ripening process of peach fruit in depth. PMID- 28839290 TI - Rare occupational cause of nasal septum perforation: Nickel exposure. AB - Many etiologies are held accountable for nasal septum perforations. Topical nasal drug usage, previous surgeries, trauma, nose picking, squamous cell carcinoma, some rheumatological disorders such as granulomatosis with polyangiitis (Wegener granulomatosis), some infectious diseases such as syphilis and leprosy are among the causes of the perforations. Occupational heavy metal exposures by inhalation rarely may also cause nasal septum perforation. Here, we present a 29-year-old patient without any known diseases, who is a worker at a metallic coating and nickel-plating factory, referred for investigation of his nasal cartilage septum perforation from an otorhinolaryngology clinic. The patient questioning, physical examination and laboratory assessment about rheumatic and infectious diseases were negative. There was a metallic smell in the breath during the physical examination. The analysis showed serum nickel level at 31 MUg/l and urine nickel at 18 MUg/l (84.11 MUg/g creatinine). Other possible serum and urine heavy metal levels were within normal ranges. Nickel exposure is usually together with other heavy metals (chromium or cadmium), it is rarely alone. Nickel ingested by inhalation usually leads to respiratory problems such as reduced olfactory acuity, ulcers, septum perforation or tumors of the nasal sinuses. This case demonstrates the importance of occupational anamnesis and awareness of diagnosis. Int J Occup Med Environ Health 2017;30(6):963-967. PMID- 28839291 TI - Experiential learning of professionalism in icu using interprofessionalism. PMID- 28839292 TI - Poor selection criteria for university vice chancellors in Pakistan. PMID- 28839293 TI - Frequency of different blood groups and its association with BMI and blood pressure among the female medical students of Faisalabad. AB - OBJECTIVE: To determine the frequency of different blood groups among female medical students and to find the association of blood groups and body mass index with blood pressure. METHODS: This cross-sectional study was performed at the University Medical and Dental College, Faisalabad, Pakistan, from March to April 2016, and comprised female medical students. Participants were divided into groups on the basis of their ABO blood groups and on body mass index criteria. Blood groups were determined by simple conventional slide method. Blood pressure was estimated by manual auscultatory technique with a mercury sphygmomanometer. Data was analysed usingSPSS20. RESULTS: There were 145 students with an overall mean age of18.4+/-0.75 years (range: 17-23 years). Blood group B was the predominant group 65(44.8%). Besides, 130(89.6%) subjects were rhesus positive and 23(53%) subjects of blood group O were pre-hypertensive. Multiple regression analysis indicated significant positive association of blood group O with both systolic and diastolic blood pressure (p=0.002, 0.001). However, subsequent logistic regression showed significant association only with diastolic blood pressure (p=0.001). Relative risk of pre-hypertension for obese (p=0.001) was greater than non-obese subjects. Body mass index was significantly associated with both systolic and diastolic blood pressure (p=0.004, 0.042). CONCLUSIONS: Blood group B was the most common blood group. Blood group O was associated with diastolic pre-hypertension, while body mass index was associated with both systolic and diastolic pre-hypertension. PMID- 28839294 TI - Ischaemic stroke and peripheral artery disease. AB - OBJECTIVE: To determine the frequency of atherosclerosis by ankle brachial index in patients with an ischaemic stroke and to assess the association of carotid artery stenosis and ankle brachial index in ischaemic stroke. METHODS: This cross sectional study was conducted at Abbasi Shaheed Hospital, Karachi, from July 2011 to May 2014, and comprised patients with ischaemic stroke. The patients were classified according to the Asian stroke criteria for classification of brain infarction. Primary outcome measures included carotid artery stenosis and ankle brachial index. The other independent variables were age, gender, body mass index and waist circumference. SPSS 20 was used for data analysis. RESULTS: A total of 327 patients were enrolled. The overall mean age was 57.6+/-12.8 years. Besides, 168(51.3%) participants were males. Peripheral artery disease was found in 60(18.3%) patients. Mild carotid artery stenosis was found in 182(55.6%) patients, moderate in 140(42.8%), severe in 3(0.9%) and complete occlusion in 2(0.6%) patients. In patients having mild carotid artery stenosis, 32(17.5%) had peripheral artery disease, whereas in patients with moderate carotid artery stenosis, 25(17.8%) had peripheral artery disease. CONCLUSIONS: Abnormally low ankle brachial index suggesting subclinical peripheral artery disease was 18%. PMID- 28839295 TI - Knowledge, attitude and perceptions of Muslim cancer patients regarding cancer treatment during Ramadan: Results from a tertiary care hospital Karachi. AB - OBJECTIVE: To assess the knowledge and attitude of Muslim cancer patients regarding cancer treatment during Ramadan. METHODS: This cross-sectional study was conducted at the Aga Khan University Hospital, Karachi, from July to August 2015, and comprised cancer patients. .Adult Muslim cancer patients receiving active oncological treatment or on surveillance were included. Patients on only supportive treatment were excluded. SPSS 19 was used for data analysis. RESULTS: Of the 265 patients, 87(32.8%) were males and 178(67.2%) were females. The overall mean age was 49+/-13.87 years. Besides, 184(70.9%) patients belonged to the middle class. Breast cancer was the most common cancer 106(40.6%). Overall, 153(57.9%) patients had stage II disease. Further, 201(80%) patients had 0-1 performance status. Moreover, 180(72%) patients were receiving different forms of chemotherapeutic agents. It was found that 113(54.3%) patients sought advice regarding fasting. Most of the patients who observed fast, i.e. 214(81%), had an early stage disease and 19(7.1%) were on hormonal therapy. Patients who did not fast mostly attributed this to fatigue 69(26.3%). Conclusion: Only half of the patients sought advice on fasting and those having early disease more. CONCLUSIONS: Only half of the patients sought advice on fasting and those having early disease more frequently observed fast. PMID- 28839296 TI - Frequency of postpartum depression and its association with breastfeeding: A cross-sectional survey at immunization clinics in Islamabad, Pakistan. AB - OBJECTIVE: To calculate the point frequency of post-partum depression among mothers. METHODS: This cross-sectional, quantitative study was conducted at the immunisation clinics of General Hospital, Islamabad, and Tehsil Headquarters Hospital, Kahuta, Pakistan, in November 2015, and comprised women aged 18-44 years. Primary data collection was done through Edinburgh post-natal depression scale questionnaire. SPSS 20 was used for data analysis. RESULTS: There were 434 participants in the study. Frequency of post-partum depression was 75(17.3%). The odds of post-partum depression was 2.3times more among non-exclusive breastfeeding mothers, 6.6 times more among women with no husband support, 6.1 times more among women with no family support, and 1.92 times more among women with youngest female child. CONCLUSIONS: Exclusive breastfeeding had a strong association with post-partum depression. PMID- 28839297 TI - Use of colistin for the treatment of multi drug resistant isolates in neonates. AB - OBJECTIVE: To determine the impact of using colistin for multidrug-resistant organisms in neonates. METHODS: This retrospective study was conducted at the Shifa International Hospital, Islamabad, Pakistan, and comprised microbiological data of babies from January 2010 to October 2012.The data was reviewed to identify the babies infected with multidrug-resistant organisms and who had received colistin therapy. SPSS 16 was used for data analysis. RESULTS: Of the 30 neonates, 24(80%) were males and 6(20%) were females. Besides, 16(53.3%) neonates were preterm babies (< 37 weeks gestation). Two or more risk factors for multidrug-resistant organisms were present in 13(44%) babies. Mechanical ventilation was found in 26(87%) neonates and prior prolonged use of antibiotics in 7(23%). The commonest pathogen isolated was Acinetobacter, in 22(73%) cases. All isolates were susceptible to colistin but pan-resistant to multiple antibiotics, including cephalosporins, amikacin, meropenem and piperacillin/tazobactam. Colistin therapy was used for bacteraemia in 2(7%) cases, clinical sepsis 18(60%), pneumonia 2(7%) and tracheitis 8(26.7%). Moreover, 15(50%) neonates received both intravenous and aerosolised colistin while 9(30%) received aerosolised therapy alone. CONCLUSIONS: Colistin therapy was well tolerated in neonates for the treatment of multidrug-resistant organisms. PMID- 28839298 TI - Antibiotics susceptibility patterns of uropathogenic E. coli with special reference to fluoroquinolones in different age and gender groups. AB - OBJECTIVE: To identify frequency of uropathogenic Escherichia coli and its antibiotic susceptibility pattern. METHODS: This cross-sectional study was conducted at Khyber Teaching Hospital, Peshawar, Pakistan, from January 2014 to September 2015, and comprised urine specimens. Biochemical techniques were used to identify Escherichia coli and antibiotic susceptibility was determined by Kirby-Bauer disk diffusion and minimum inhibitory concentration methods. SPSS 23 was used for data analysis. RESULTS: Of the 787 urine samples, 458(58.2%) grew significant positive growths. Escherichia coli growths were present in 351(76.6%) positive cultures of which 108(30.8%) came from males and 243(69.2%) from female patients. Resistance to fluoroquinolones tested was almost similar (p>0.05). Escherichia coli was highly sensitive to imipenem (98.6%), meropenem (97.8%), tazobactum (96.2%), cefoperazone+sulbactam (93.9%) and amikacin(92.5%). CONCLUSIONS: Escherichia coli was a common pathogen causing urinary tract infections and was highly sensitive to imipenem, meropenem, tazobactum, cefoperazone+sulbactam and amikacin. PMID- 28839299 TI - Correlates of home and hospital delivery in Pakistan. AB - OBJECTIVE: To identify the socio-economic determinants of home-based and institutional delivery in Pakistan. METHODS: This study has used Pakistan Demographic and Health Survey (PDHS) data collected by the National Institute of Population Studies (NIPS), Islamabad, Pakistan, and Macro International Inc. (now ICF International) Calverton, Maryland, United States. It used three episodes of Pakistan Demographic and Health Survey Data from 1990-91, 2006-07 and 2012-13. Data was analysed using descriptive analysis and odds of delivering at hospital were calculated using logistic regression analysis. RESULTS: Home-based delivery was over 4 times higher in 1990-91 compared with institutional delivery 5,465(85.3%) vs. 852(13.3%), and around 2 times higher in 2006-07 5,900(64.7%) vs. 3,128(34.3%). However, in 2012-13, the share of women delivering at home or health facility was roughly the same, i.e. 6,180(51.6%) at home and 5,773(48.2%) at health facility. CONCLUSIONS: There were wide gaps in the rates of institutional delivery among different subgroups, and they were accentuated by the socio-economic and financial disparities, and high illiteracy rates in the lowest wealth quintiles. PMID- 28839300 TI - Sero-surveillance of dengue in the city Lahore, Pakistan. AB - OBJECTIVE: To conduct sero-surveillance of dengue cases, and to find out the demographic and socio-economic status of dengue patients. METHODS: This community based, cross-sectional, descriptive study was conducted at the Institute of Public Health, Lahore, Pakistan, from July to December each year in 2011, 2012 and 2013, and comprised patients suspected to have dengue. Blood samples of dengue patients in five randomly selected union councils of the 10 towns of the city were subjected to the dengue test. Information about demographic and socio economic characteristics was obtained with the help of pre-tested semi-structured questionnaire. SPSS 16 was used for data analysis. RESULTS: Of the 5,544 dengue patients, 5.263 (94.9%) patients were diagnosed in 2011, followed by 25(0.45%) and 256(4.6%) in 2012 and 2013, respectively. Sero-surveillance of these dengue patients in 2011 showed that on an average 3,094 (58.79%) cases had primary infection, 1,506 (28.61%) had old infection, while only 663 (12.6%) had secondary infection. Similar pattern was observed in 2012 and 2013. It was found that 2,379 (42.9%) participants were aged between 15-30 years and 2,203 (39.7%) between 31 45 years. Besides, 3,618 (65.3%) participants were males and 1,926 (34.7%) females. Also, 2,865 (51.4%) participants were labourers, 2,746 (49.5%) and 2,260 (40.7%) were educated up to primary and secondary levels, respectively. Although sporadic dengue cases were recorded from July to December, most of the cases were observed in late rainy and early post-rainy seasons. CONCLUSIONS: The incidence of dengue was highest in people of 15-45years of age, particularly males, labourers and those with low income. PMID- 28839301 TI - Clinical manifestations of patients with Systemic Lupus Erythematosus (SLE) in Khyber Pakhtunkhwa. AB - OBJECTIVE: To determine major symptoms and signs in patients of systemic lupus erythematosus. METHODS: This cross-sectional study was conducted at the Lady Reading Hospital, Khyber Teaching Hospital and Hayatabad Medical Complex, Peshawar, Pakistan, from January 15, 2014, to August 15, 2016, and comprised patients of systemic lupus erythematosus. Data was collected through an interview based questionnaire containing questions about different symptoms. SPSS 20 was used for data analysis. RESULTS: Of the 663 patients, 606(91.4%) were females and 57(8.6%) males. The overall mean age of patients was 33.09 +/- 12.40 years and the mean age of diagnosis was 31.85 +/- 12.40 years. The most common general symptom in our study was fatigue which was present in 524(79.03%) patients. Other constitutional symptoms were fever 334(50.04%), body aches 443(66.08%) and weakness 411(62%). The most common clinical manifestation in our study was arthritis 518(78.1%). Malar rash was found in 487(73.5%) patients. Dry eye was in 227(34.2%) patients, followed by conjunctivitis 156(23.5%). Anaemia was present in 444(66.96%) patients, followed by leukopenia 166(25.03%) and thrombocytopenia 42(6.33%). CONCLUSIONS: Significant regional differences existed in the clinical manifestations of systemic lupus erythematosus in Khyber Pakhtunkhwa compared to other regions. PMID- 28839302 TI - Maternal health status in terms of utilisation of antenatal, natal and postnatal services in a Periurban setting of Islamabad: A community based survey. AB - OBJECTIVE: To determine the maternal health status in terms of antenatal, natal and postnatal care. METHODS: This cross-sectional study was conducted at Shifa College of Medicine, Islamabad, Pakistan, from August 2015 to February 2016, and comprised married women living in Nurpur Shahan, a peri-urban community..A systemic random sampling method was used to raise the study sample. Only members of the household aged18 to 45 years and permanent residents of that area were selected. SPSS 21 was used to analyse the collected data. RESULTS: There were 1,275 participants in the study with an overall mean age of 31.6+/-8 years. The mean age of marriage was 19+/-3.6 years while the mean age of first childbirth was 20.8+/-3.6 years. Besides, 950(74.5%) participants had undergone an antenatal check-up. Moreover, 685(53.7%) underwent delivery in a hospital, 433(34%) had postnatal check-up, and 432(33.9%) were using contraception. Participants who had undergone hospital delivery were 18.7 times more likely to have taken prenatal care and 6.9 times more likely to utilise postnatal care compared to participants who had not utilised antenatal care (p<0.001). CONCLUSIONS: Most of the participants did not give significant importance to postnatal care. PMID- 28839303 TI - Principled physicians are not born-they are mentored: Medical students perception of the values and need of mentors at the College of Medicine, Saudi Arabia. AB - OBJECTIVE: To discuss the perception of medical students about mentoring at the medical school. METHODS: This cross-sectional descriptive study was conducted at the King Saud University, Riyadh, Saudi Arabia, from April 2015 to April 2016, and comprised medical students. A well-structured, bilingual (English and Arabic) quantitative questionnaire with 21 items was administered online via Google Docs to the students. SPSS 21 was used for data analysis. RESULTS: Of the 311 students who received the questionnaire, 296(95.17%) completed it. Of them, 257(86.8%) expressed an interest in having a mentor during their medical school career and 276(93.2%) selected the role of their mentor as a "guide". Moreover, 107(36.1%) students agreed that it was "not important at all" that their mentor should be of the same gender. CONCLUSIONS: Participants were interested in having a mentor during their medical school career. PMID- 28839304 TI - The malpractices of student nurses in clinical practice in Turkey and their causes. AB - OBJECTIVE: The study was conducted to identify whether or not student nurses made the medical errors as well as the reasons for the errors. METHODS: A study was conducted with 1067 student nurses studying at 12 universities in Turkey. The data were collected by using medical error scale and a questionnaire on demographic characteristics and malpractices. RESULTS: Overall 28% of the student nurses performed malpractice during clinical practice. Medical errors included failure of complying with sterility and asepsis rules (32%), wrong identification of patient identity (19%), and administrating wrong dosage of medications (12%). They obtained a mean score of 4.19+/-0.62 from the overall scale and the lowest score was 3.9+/-0.78 for drug administrations. CONCLUSIONS: Nursing students perform considerable amount of malpractice and they should especially improve concerning administration of drugs. PMID- 28839305 TI - Clinical and histopathological features of breast cancer in Jordan: Experience from a tertiary care hospital. AB - OBJECTIVE: To analyse breast cancer cases with respect to age, menopausal status, hormone receptors and human epidermal growth factor receptor 2 expression, in addition to nodal and distant metastases. METHODS: This retrospective study was conducted at Jordan University Hospital, Amman, Jordan, and comprised cases of breast carcinoma among females between 2006 and 2015. Clinicopathological data was collected from patient files and laboratory reports. Data was analysed using SPSS v 17. RESULTS: Of the 752 cases, 559(74.3%) were invasive ductal carcinomas of non-specific type, followed by 36(4.8%) cases of invasive lobular carcinoma. Upon investigating the clinicopathological data on the breast cancer cases, 466(61.97%) cases had sufficient information for further analysis. Of them, 414(61.97%) patients were aged above 40 years and 190(40.77%) were post menopausal. Moreover, 221(47.42%) cases showed lymph node metastases, but only 32(6.87%) had distant metastases. The expression of oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to be positive in 343(73.6%), 299(66.7%) and 97 (24.6%) cases, respectively. Besides, 42(9.01%) cases were triple negative, which were diagnosed only in females below 40 years age. CONCLUSIONS: These results were in concordance with international reports, except for the association of triple negative breast cancer with age where it was mainly diagnosed among females younger than 40 years age. PMID- 28839306 TI - Role of sociocultural perceptions in malnutrition of children under the age of 5 years in a semi-urban community of Pakistan. AB - OBJECTIVE: To assess the impact of sociocultural perception on the nutritional status of children under five years of age. METHODS: This cross-sectional study using a self-constructed questionnaire was conducted at the Shifa Rotary Clinic, Nurpur Shahan, Pakistan, from February to October 2016, and comprised mothers and children. Mothers age 18-45years having a child less than 5 years old were included. SPSS 21 was used for data analysis. . RESULTS: Of the 564 participants, 526(93.3%) were housewives and 38(6.5%) were working mothers. The overall mean age was 27.49+/-5.197 years. Mother was the decision-maker for child nutrition in 344(61.0%) cases while the father was the decision-maker for child nutrition in 106(18.8%) cases. About 64(11.3%) wasted colostrums, of which 18(28.1%) acted on their own accord 46(71.9%) on others' advice. Mother as the decision-maker for child nutrition was found to be significantly associated with normal child nutritional status (p<0.05).In our study male child was 2.29 times likely to have a normal nutritional status as compared to a female child (p<0.05). CONCLUSIONS: Sociocultural perceptions were found to have a significant impact on nutritional status of children under the age of 5 years. PMID- 28839307 TI - Pulse oximetry as a screening tool for critical congenital heart defects in newborns. AB - OBJECTIVE: To evaluate the effectiveness of pulse oximetry as a screening tool for critical congenital heart defects in newborns. METHODS: This cross-sectional study was conducted at the neonatology department of the Children's Hospital and the Institute of Child Health, Lahore, Pakistan, from January to June 2016, and comprised neonates aged up to 07 days. Babies with a prenatal diagnosis of heart defects and those whose parents refused to give consent were excluded. Oxygen saturation of enrolled patients was measured in right index finger (pre-ductal) and in the left big toe (post-ductal) subsequently. Echocardiography was done on all the enrolled babies to confirm the diagnosis. SPSS 19 was used for data analysis. RESULTS: Of the 145 babies initially enrolled, 138(95.2%) were included. The overall mean age of the babies was 2.17+/-1.62 days (range: <24 hours-07 days) whereas the mean birth weight was 2.95+/-0.47kg (range: <2.5 >4kg). Babies with pre- and post-ductal oxygen saturation measurement difference of >3% showed a detection rate of 16(45.7%) for critical congenital heart defects. Sensitivity and specificity of this screening test was calculated to be 76.19% and 83.76%, respectively, while positive and negative predictive values were 45.71% and 95.15%, respectively. CONCLUSIONS: The measurement of pre- and post-ductal oxygen saturation by pulse oximetry was an effective screening tool for the detection of critical congenital heart defects in newborns. PMID- 28839308 TI - Molecular characterisation of isoniazid resistant clinical isolates of Mycobacterium tuberculosis from Khyber Pakhtunkhwa, Pakistan. AB - OBJECTIVE: To investigate the frequency of mutations in catalase-peroxidase and inhibin alpha genes in clinical isolates of isoniazid resistant Mycobacterium tuberculosis strains. METHODS: The study was conducted at Provincial Tuberculosis Reference Laboratory, Peshawar, Pakistan, from April 2015 to March 2016, and comprised sputum specimens obtained from patients of different ages. All the isolates were analysed for isoniazid resistance. Thirty resistant isolates were randomly selected for mutation analysis of the hotspot regions of catalase peroxidase and inhibin alpha genes. RESULTS: Of the 163 positive isolates, 79(48.46%) were resistant to isoniazid. Among these, 21(70%) had mutation in catalase-peroxidase gene and 2(6.6%) had C15T mutation in inhibin alpha promoter region. Among the 21 catalase-peroxidase mutants, Ser315Thr mutation was detected in 15(71.4%) isolates. Gly316Ser mutation was detected in 3(14.2%) isolates. Ser315Arg mutation was identified in 2(9.5%) isolates. Double mutation of Ser303Trp and Lys274Arg was detected in 1(4.7%) isolate. Among the inhibin alpha promoter region mutations, 2(6.6%) of the thirty isolates had the most common C15T mutation in the promoter region. CONCLUSIONS: One novel mutation at codon 303 in catalase-peroxidase gene was found in the study, and it could contribute to isoniazid resistance. PMID- 28839309 TI - Knowledge around back pain and spinal disorders among Saudi patients: A cross sectional study. AB - OBJECTIVE: To assess the knowledge of patients about low back pain and spinal disorders. METHODS: This cross-sectional study was conducted at King Saud University, Riyadh, Saudi Arabia, from December 2015 to February 2016, and comprised patients presenting with lower back pain. The low back pain knowledge questionnaire was translated to Arabic and distributed, after adding more questions, among patients. The scores were calculated as per the published guidelines. SPSS 21 was used for data analysis. RESULTS: There were 153 patients in the study. The reliability test revealed a Cronbach's alpha score of 0.834 for all items. The overall mean age was 40.2+/-19.3 years (range: 15-76 years). Besides, 61(39.9%) participants were males and 92(60.1%) were females. The overall median score was 9 (interquartile range: 0-19) out of 24 points. Both educational level and monthly income were found to be dependent variables (p<0.001; p=0.007). . CONCLUSIONS: The majority of patients with lower back pain had limited knowledge about their condition and the related complications. PMID- 28839310 TI - Reproductive health issues in Pakistan; do myths take precedence over medical evidence? AB - OBJECTIVE: To analyse the prevalence of myths pertinent to healthcare issues of females of reproductive age. METHODS: This cross-sectional, simple descriptive, knowledge, attitude and practices-education research was conducted at the Combined Military Hospital, Peshawar, Pakistan, from February to August 2016. A 30-item self-designed questionnaire was applied, collecting demographic details and answers to 21 close-ended questions encompassing the prevalence of myths pertinent to reproductive health issues of women in Pakistan.Every question had three options, Yes(myth), No(correct answer) and Don't Know(unsure). SPSS 21 was used for data analysis. RESULTS: There were 594 participants in the study. The overall mean age was 35.11+/-12.711 years and the mean duration of education was 9.41+/-6.353 years. Besides, >50% answers positive for myths and <50% answers positive for myths were given by 326(54.9%) and 268(45.1%) respondents, respectively. The prevalence of myths was directly proportional to age (p=0.004), and inversely proportional to education (p<0.001) and socio-economic class(p<0.001); impact of education was stronger than socio-economic class(Pearson's chi-square being 74.189 and 48.672, respectively). Khyber Pakhtunkhwa-based respondents harboured more myths (p=0.024). There was no significant impact of marital status (p=0.099). CONCLUSIONS: The participants held significant amount of myths regarding health issues in reproductive age. PMID- 28839311 TI - Measuring empathy of medical students studying different curricula; a causal comparative study. AB - OBJECTIVE: To determine the difference in empathy level of undergraduate medical students studying two different curricula. METHODS: This cross-sectional study was conducted at Independent Medical College of Faisalabad and Islamic International Medical Collegeof Islamabad, both in Pakistan, from July to September 2016. The two medical colleges had two different types of curriculum systems; the integrated modular system and the discipline-based curriculum. The Toronto empathy questionnaire was used to calculate empathy scores. The responses were scored between 0 and 64 by taking sum of all the 16 questions. T-test was used to compare the mean scores and empathy levels between the two groups. SPSS 20 was used for data analysis. RESULTS: Of the 160 students, there were 80(50%) belonging to each institute. In the integrated modular system, 44(55%) students were females, whereas in the discipline-based system 45(56%) students were males. Students enrolled in the integrated modular system had a higher mean empathy score than students in the discipline-based system (44.2+/-6.59 versus 39.7+/ 6.54, p<0.001). CONCLUSIONS: Interventions during the educational journey about empathy had positive influence on students' personalities and their future practices. PMID- 28839312 TI - Short-term outcomes after hepatic resection : perspective from a developing country. AB - OBJECTIVE: To review the early outcomes of hepatic resection at our hospital. METHODS: This study was conducted at the Aga Khan University Hospital, Karachi, from January 2008 to December 2015, and comprised patients who underwent hepatic resection. We analysed the pathology, magnitude of hepatic resection and short term outcomes in the patients. Mean and standard deviations were used to describe categorical data whereas frequencies and proportions to describe quantitative data. Univariate analysis was done to look at the factors associated with morbidity, mortality and blood loss during surgery. SPSS 19 was used for data analysis. RESULTS: Of the 75 participants, 43(57.3%) were males and 32(42.7%) were females. The overall mean age was 52+/-14 years. Besides, 37(49.3%) patients underwent hepatic resection for underlying hepatocellular carcinoma, with 30(81%) of them being cirrhotic. Major hepatectomy (>3 segments) was performed in 30(40%) patients. Postoperative complications were observed in 30(40%) patients including postoperative liver failure in 3(4%) patients. The presence of one or more co morbid conditions had a statistically significant association with postoperative morbidity (p=0.018). Mortality rate at 30days and 90days were 3(4%) and 5(6.7%), respectively. DISCUSSION: Morbidity, mortality and blood loss were comparatively higher in cirrhotic patients. PMID- 28839313 TI - Present tendencies of elective caesarean delivery in Romania: Geographic, social and economic factors. AB - The literature review was conducted to identify the causes of the rising incidence of caesarean section (CS) cases in Romania, and to create a database and a measurement plan to quantify the amount of CS on maternal request and the influence of geographical, social and economic factors. The review was conducted at the Department of Obstetrics and Gynaecology Clinical Emergency Hospital Sf Pantelimon, Bucharest, and comprised figures of clinical records of all patients who underwent CS between 2009 and 2014. The results showed an increase in the number of CS on maternal requests. In 2014 it reached a rate of 36.90 cases in every 100 newborn infants, which was 2.62% higher than 2013. Increasing rate of CS seemed to have resulted from a few factors, including the constant preoccupation to improve the obstetrical field in Romania; its services; the prophylactic measures in obstetrics; the trials to prevent the fear of the obstetrical malpraxis and its risks and consequences; and the fact that some obstetricians have done multiple CS deliveries on maternal requests. PMID- 28839314 TI - Reusing dialyzer in low income countries: A good cost saving tactic with complex ethics. AB - Despite almost universal practice of dialyzer reuse from the earliest days of haemodialysis, reusing dialyzer always remains a controversial issue and several ethical concerns have been raised. Some of the important are safety of reuse over single use, informed consent of the patient, conflict of interest on the part of physician or manufacturer, fiscal responsibility and environmental stewardship. Indeed, at the beginning of this century, there was a drastic shift of practice in favour of single use in developed countries due to availability of biocompatible haemodialyzers, at favourable price. Despite this mega shift, dialyzer reuse is still widely practised in low-income countries. Considering cost inflation and limited medical resources in such countries, dialyzer reuse may be justified as a cost-saving strategy for this part of world. However, it poses the same ethical questions to us which were a matter of debate for the western world in the 1980s and 1990s. This review of literature was planned to revisit and highlight these concerns. PMID- 28839315 TI - The need for dietary guidelines in Pakistan. AB - Diet is one of the most important contributors to health and disease. Developing countries such as Pakistan are facing a growing epidemic of under nutrition resulting in stunting, wasting and micronutrient deficiencies in the population. This severe situation of under nutrition in the country is coupled with rising tide of non-communicable diseases (NCD) posing the double burden of disease on the country. These burden of NCD, along with over and under nutrition poses a huge burden on the already over-utilized multi-tiered health care system in Pakistan. In this alarming situation, nutrition education in the form of food based dietary guidelines (FBDGs) naturally becomes the most essential tool for promoting a health culture within the country and eventually changing behaviour. PMID- 28839316 TI - Combating Zika virus through health counseling interventions. AB - Previous research efforts on Zika virus (ZikV) appear to have only focused on biomedical interventions for the patients without realizing that their culture of silence to the psychological aspect is highly reprehensible. The role and importance of health counseling cannot be overemphasized given how it helped in the fight against the Ebola virus disease. It is possible that mental health counselors and clinical psychologists around the world, Nigeria, and Pakistan can provide health counseling intervention that is culturally acceptable, effective and instrumental in tackling ZikV, its spread, and the horrific psychological impacts of the disease. Research is needed to understand the relevance and effectiveness of health counseling interventions in the Zika context. PMID- 28839317 TI - Effect of obesity on academic grades among Saudi female medical students at College of Medicine, King Saud University: Pilot study. AB - The aim was to investigate the effect of obesity on academic grades among Saudi female medical students. This cross sectional study was conducted in the Department of Plastic Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia during the period November 2014 to June 2015. In all 191 second and third year female medical students with an average age of 21.31 years and body mass indices 15-40 were included. An English language questionnaire was established to obtain the information about age, gender, body mass index, level of study and the academic grades [Grade Point Average-GPA]. Female medical students with BMI 21-25 and 26-30 achieved high GPA while female medical students with higher BMI 31-35 and greater than 36 obtained low GPA. High BMI in female medical students impair the academic performance. The academic institutes must establish extra-curricular physical fitness policies to minimize the obesity and achieve better health and academic outcomes. PMID- 28839318 TI - Spatial distribution of health consultations in the past two weeks by provider type and district: Pakistan Social and Living Standards Measurement Survey 2014 15. AB - Place is a nexus between epidemiology and Geographic Information System. In this study, the Pakistan Social and Living Standards Measurement survey 2014-15 data on percent distribution of health consultations, in the past 2-weeks by type of healthcare provider were mapped cumulatively, as well as disaggregated by urban and rural areas, using a GIS programme to visualize spatial distribution in the country by district. Private sector is the main and preferred provider for healthcare services when Pakistanis get sick or injured. Differences between and within provinces - at the district level - exist, but in spite of significant investment by the government in public sector health and nutrition services; most people prefer going to private dispensaries and hospitals. Harnessing the visualization power of GIS for better decision making in health sector is contingent upon easy availability of up-to-date GIS shapefiles to analyze and depict health data on maps. PMID- 28839319 TI - Spinal cord injury without radiographic abnormality (SCIWORA) in adults: A report of two cases. AB - Spinal cord injury without any radiographic abnormality (SCIWORA) is rare in adults. We describe here two case reports of adult patients, who presented to us with quadriplegia, following a road traffic accident. Plain radiography and computed tomography (CT) of cervical spine were normal. Hence the patients were diagnosed as cases of adult SCIWORA. However, subsequent magnetic resonance imaging (MRI) of the two patients revealed cervical cord injury in the form of cord contusion and disc protrusion, respectively. Patient with cord contusion was managed medically, whereas the patient with disc lesion was treated with discectomy. Patient treated with discectomy showed marked improvement. Therefore, patients having no osseous injury on X ray and CT scan should have an MRI study done to look for surgically correctable pathology. As in such rare patients of SCIOWRA an early diagnosis and timely intervention is crucial; with MRI playing a pivotal role. PMID- 28839320 TI - Intramedullary cavernoma with extralesional haemorrhage. AB - Intramedullary cavernomas are rare lesions constituting 5 to 12% of all intramedullary tumours. They are more recognized after introduction of magnetic resonance imaging and detection rates have improved by advance techniques. They may be solitary or multiple or may have associated cranial lesions. They may present with gradual neurological decline or with acute loss of spinal function. In addition neurological deficit depends on the location of the lesion within the spinal cord. We are reporting the case of a 45 year old male who presented with neck pain and progressive right arm weakness with numbness. MRI cervical spine with contrast showed intramedullary lesion with peripheral T2 hypointense rim and extralesional haemorrhage consistent with cavernoma. Patient underwent successful surgery and his symptoms markedly improved with mild residual grip weakness in right hand. PMID- 28839321 TI - Late-onset Hirayama disease presenting with ulnar neuropathy: A case report. AB - Hirayama disease (HD) was first reported by Hirayama et al. in 1959. The disease is considered as a type of benign focal motor neuron disease that primarily affects upper limbs of young males. In this case report, we present a man aged 40 years with rapidly progressive weakness and atrophy in his left hand. The findings of nerve conduction studies were consistent with left ulnar neuropathy at the elbow. Flexion magnetic resonance imaging (MRI) revealed minimal enlargement of the posterior epidural space and anterior displacement of the spinal cord. After exclusion of relevant diseases the patient was diagnosed as having Hirayama disease with ulnar neuropathy. Mild ulnar entrapment at the elbow may be considered as a clinical feature of HD. Therefore, it is recommended that young male patients with wasting in upper extremities with findings of ulnar entrapment should not be judged to have ulnar neuropathy before HD has been carefully excluded. PMID- 28839322 TI - Breast cancer in a patient with Kindlers syndrome. AB - Breast Cancer (BC) has associated risk factors and genetic factors like BRCA1, and BRCA2. Many benign and malignant disease processes are found concurrently with BC and believed to be additional risk factors like gall bladder stones (cholelithiasis), hypertension, diabetes mellitus, cerebrovascular lesions, arthritis, spine and spinal cord degenerative lesions, infertility, depression, sleep disturbances, obesity, autoimmune diseases (SLE), and thyroid diseases. There are some malignant disease associations like synchronous or metachronous ovarian, colonic and endometrial tumours with Breast cancer. Kindler Syndrome (KS) is a rare autosomal recessive genetic disorder manifesting as generalized dermatoses, described in 1954 by Theresa Kindler. KS is associated with acral skin blistering inducible by trauma, mucosal inflammation, photosensitivity, progressive pigmentation, telangiectasia, and skin atrophy (Poikiloderma). Repeated and progressive inflammation and subsequent fibrosis leads to ectropion, esophageal, anal, urethral, and vaginal stenosis and dryness. About 100 cases of Kindler syndrome have been reported in literature so far some from Arab World as well. Pathobiology of Kindler syndrome is not well understood. There are defects in KIND1 gene on chromosome 20. This gene expresses itself in basal keratinocytes, where it encodes a protein, called Kindlin 1. We report the second only case of Kindler's syndrome having breast cancer. These very very rare combinations have diagnostic issues, management restrictions, prognostic and follow up implications. PMID- 28839323 TI - Upper gastrointestinal tract symptoms are predictors of postoperative large pericardial effusion in cardiac surgery. AB - In this prospective observational study we evaluated the clinical symptoms in patients who presented with early or late significant pericardial effusion after cardiac surgery and underwent its open drainage in our institution. It was a series of 35 patients where the clinical symptoms and lab investigations were recorded. There were 21 male and 14 female (3:2). Majority of patients presented with postoperative large pericardial effusion within 2 -3 weeks of cardiac surgery. Eighteen (51.4%) patients presented with predominantly nonspecific upper gastrointestinal tract (GIT) symptoms like nausea, vomiting, loss of appetite and epigastric discomfort, 29 (82.85%) patients with postoperative large pericardial effusion had undergone mechanical valve replacement surgery. Majority of patients were on anticoagulation therapy and had prolonged INR. This study showed that non specific upper gastrointestinal tract (GIT) symptoms like nausea, vomiting, loss of appetite are very frequent in patients with post-operative pericardial effusion. If a patient presents with these non-specific GI symptoms along with raised INR and low haemoglobin in postoperative follow up, significant pericardial effusion should be excluded. PMID- 28839324 TI - Nosocomial spondylodiscitis after intradiscal electrothermal therapy: Case series. AB - Intradiscal electrothermal therapy (IDET) is a method applied for treatment of pain caused by the disc and involves reaching spinal disc through a catheter under fluoroscopy and solidifying disc interior by heating. We retrospectively evaluated ten patients treated and followed up with diagnosis of nosocomial spondylodiscitis after IDET. Ten patients, to whom IDET was applied for low back pain treatment in a tertiary healthcare organization, came with complaints of fever and low back pain during postoperative process. Appropriate antibiotics treatment was commenced after the reproduction of Pseudomonas aeruoginosa in abscess culture.Even though spondylodiscitis developing after IDET is a rare complication, it is also a clinical condition that needs to be thought in the patients whose complaints increase and clinically do not recover after the procedure. Adherence to rules of the asepsis will reduce the frequency of infection as in all nosocomial infections. PMID- 28839325 TI - De-Hearsay (Diabetes e-Hearsay). AB - Hearsay, or reported speech, is an important contributor to diabetes care related behaviour. Modern modes of communication have thrown up a new form of hearsay, termed e-hearsay (electronic hearsay). We describe the concept of diabetes related electronic hearsay or digital hearsay (de-hearsay or dd-hearsay), and suggest pragmatic means of countering negative de-hearsay, so as to benefit diabetes care. PMID- 28839326 TI - Carbohydrate counting-1: South Asian framework. AB - Carbohydrate counting or "carb counting" is a meal planning technique for persons with diabetes for managing blood glucose levels by tracking the grams of carbohydrate consumed at meals. It has shown to improve glycaemic control and glycaemic variability and decreases risk of hypoglycaemia in persons with diabetes especially on insulins. It needs basic education of the patient regarding meal plan, assessment of carbohydrate content of various foods and also exchange lists. It also gives flexibility of food choice, helps to identify patterns in blood glucose levels and adjustment of pre meals short acting insulins as related to food intake. In this short review we have summarised basic principles of carbohydrate counting, its application in clinical practice and also exchange lists primarily pertaining to South Asian population. PMID- 28839327 TI - Role of surgery in brain metastases. AB - Brain metastases remain the commonest type of brain tumour, being four times more common than primary brain tumours. Although surgical intervention may be recommended for one of various reasons in the management of these tumours, including but not limited to conformation of diagnosis, relief of mass effect, improvement of neurological status and prolongation of survival, the guidelines for management of brain metastases remain largely subjective and therefore controversial. Herein the authors have attempted to review some of the existing evidence on role of surgery in the management of brain metastases and have presented their selected guidelines for the readers. PMID- 28839328 TI - Metformin use in renal disease. PMID- 28839329 TI - Adequate social support as the predictor of patient's quality of life. PMID- 28839330 TI - Patient safety practices among nurses - perspectives from Islamabad and Rawalpindi. PMID- 28839332 TI - A dire need for HIV awareness in Pakistan. PMID- 28839331 TI - Comparison of patients satisfaction levels in public and private tertiary care centres. AB - The purpose of our study was to compare patient satisfaction level among tertiary public and private hospitals. We carried out a multi-centre cross-sectional study using Patient SatisfactionQuestionnaire-18 to assess patient satisfaction in a major private and public hospital in Islamabad. Out of 1301 participants, 636 (48.9%) patients were at the public hospital, while 665(51.1%) were at the private hospital. Time spent with doctor, communication, accessibility and convenience component score was significantly higher in patients at the private hospital (p<0.05 each). Interpersonal manner component score was higher at the public hospital (p<0.05). Female patients, patients admitted in medical specialty and patients admitted in private hospitals had higher patient satisfaction score=7% body weight, and 59 (12%) lost >=7% body weight. Overall, there was no clinically meaningful difference between any of these variables and AL dose. CONCLUSION: Long-term treatment with AL in outpatients with schizophrenia was associated with a modest lowering of serum prolactin for both genders and relatively modest changes in average weight, fasting glucose, and HbA1c values. There appeared to be little net change in lipid parameters. This presentation extends a recently published report on the short-term metabolic and endocrine effects of AL over a period of 12 weeks. The present study increased the follow up period to more than a year and was careful to use the first exposure to AL as the baseline. Limitations include lack of a comparison group and difficulty disentangling effects of medication treatment versus factors. Overall, the metabolic, weight, and endocrine effects reported here are consistent with other long-term effects of oral aripiprazole treatment. This study was funded by Alkermes, Inc. PMID- 28839339 TI - Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects. AB - Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI 98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 Cmax and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 Cmax and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%-30% that of VBZ based on molar ratios. In the first study, the maximum-tolerated dose was not achieved; headache (2 events) was the only treatment-emergent adverse event (TEAE) reported by more than one subject. In the second study, fatigue (4 events) was the only TEAE reported by more than one subject following SD VBZ. Following QD VBZ, the TEAEs of fatigue, insomnia, disturbance in attention, and nervousness were dose dependent; the latter three TEAEs were considered dose-limiting. Subject withdrawals due to TEAEs were 1 each for PBO and 50 mg VBZ QD, and 3 for 100 mg VBZ QD. Clinically relevant effects on laboratory parameters, vital signs or ECGs were limited to increased CPK (SD: 1 each for 5 mg VBZ and PBO), ALT (QD: 1 each for 50 and 100 mg VBZ and PBO), and triglycerides (QD: 1 each for 50 mg VBZ and PBO). VBZ has an acceptable safety profile and predictable pharmacokinetics that result in stable concentrations of active compounds with low peak-to-trough fluctuation following once-daily dosing. PMID- 28839340 TI - Efficacy of Valbenazine (NBI-98854) in Treating Subjects with Tardive Dyskinesia and Mood Disorder. AB - BACKGROUND: Valbenazine (VBZ, NBI-98854) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD). The KINECT 3 study (NCT02274558) evaluated the effects of VBZ on TD in subjects with mood disorder or schizophrenia/schizoaffective disorder (SCHZ, presented separately) who received up to 48 weeks of treatment. METHODS: KINECT 3 included: 6-week, double-blind, placebo (PBO)-controlled (DBPC) period (205 completers); 42-week VBZ extension (VE) period (124 completers); 4-week washout period (121 completers). Subjects entering the DBPC were randomized 1:1:1 to once daily VBZ 80 mg, VBZ 40 mg, or PBO; stable concomitant antipsychotic medication regimens were allowed. Subjects completing the DBPC and entering the VE period were re-randomized (blinded) from PBO to VBZ (80 or 40 mg) or continued VBZ treatment at the same dose. Efficacy assessments included: mean changes from baseline in Abnormal Involuntary Movement Scale (AIMS) total score (items 1-7); mean Clinical Global Impression of Change (CGI-TD) scores; AIMS responders (subjects with >=50% score reduction from baseline); and CGI-TD responders (subjects with score <=2 ["much improved" or "very much improved"]). Treatment effect sizes (Cohen's d) and numbers needed to treat (NNTs) were analyzed for DBPC outcomes. RESULTS: Efficacy analyses were conducted in 77 subjects (DBPC) and 73 subjects (VE) with a mood disorder. At Week 6 (end of DBPC), AIMS mean score improvements were greater in the VBZ groups (in a dose-related pattern) than in the PBO group (80 mg, -3.6, d = 0.94; 40 mg, -2.4, d = 0.55; PBO, -0.7). AIMS mean score changes at Week 48 (end of VE) showed continued TD improvement during long-term VBZ treatment (80 mg, -5.8; 40 mg, -4.2). By Week 52 (end of washout), AIMS mean scores in both dose groups were returning toward baseline levels, indicating re-emergence of TD. CGI-TD scores showed a similar pattern: Week 6 (80 mg, 2.7, d = 0.64; 40 mg, 2.9, d = 0.39; PBO, 3.2), Week 48 (80 mg, 2.0; 40 mg, 2.2), Week 52 (80 mg, 3.6; 40 mg, 2.8). AIMS responder rates (>=50% score reduction) were greater with VBZ vs PBO at Week 6 (80 mg, 38.5%, NNT = 4; 40 mg, 19.0%, NNT = 9; PBO, 7.7%), were increased at Week 48 (80 mg, 56.0%; 40 mg, 33.3%), and lower after VBZ washout (Week 52 80 mg, 16.7%; 40 mg, 27.8%). CGI TD responder rates followed a similar pattern: Week 6 (80 mg, 34.6%, NNT = 6; 40 mg, 28.6%, NNT = 8; PBO, 15.4%), Week 48 (80 mg, 80.0%; 40 mg, 61.1%), Week 52 (80 mg, 25.0%; 40 mg, 44.4%). CONCLUSION: Sustained TD improvements were found in subjects with a mood disorder who received up to 48 weeks of VBZ, with TD reverting toward baseline severity when assessed 4 weeks after treatment withdrawal. Together with results from SCHZ subjects and the long-term safety profile (presented separately), these results indicate that long-term VBZ can be beneficial for managing TD regardless of psychiatric diagnosis. PMID- 28839341 TI - Long-Term Safety and Tolerability of Valbenazine (NBI-98854) in Subjects with Tardive Dyskinesia and a Diagnosis of Schizophrenia or Mood Disorder. AB - BACKGROUND: The short-term safety profile of once-daily valbenazine (NBI-98854) has been evaluated in several double-blind, placebo-controlled (DBPC) trials in adults with tardive dyskinesia (TD) who had a diagnosis of schizophrenia/schizoaffective (SCHZ) disorder or mood disorder. Studies with longer treatment duration (up to 48 weeks) were conducted to evaluate the long term safety of this novel drug in subjects with TD. METHODS: The pooled long-term exposure (LTE) population included valbenazine-treated subjects from 3 studies: KINECT (NCT01688037: 6-week DBPC, 6-week open-label); KINECT 3 (NCT02274558: 6 week DBPC, 42-week blinded extension, 4-week drug-free follow-up); KINECT 4 (NCT02405091: 48-week open-label, 4-week drug-free follow-up). Safety assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiograms (ECGs), and extrapyramidal symptom (EPS) scales. Psychiatric stability was monitored using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) (SCHZ subgroup), as well as the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) (mood subgroup). All data were analyzed descriptively. RESULTS: The LTE population included 430 subjects (KINECT, n = 46; KINECT 3, n = 220; KINECT 4, n = 164), 71.7% with SCHZ and 28.3% with a mood disorder; 85.5% were taking an antipsychotic (atypical only, 69.8%; typical only or typical + atypical, 15.7%). In the LTE population, treatment-emergent AEs (TEAEs) and discontinuations due to AEs were reported in 66.5% and 14.7% of subjects, respectively. The TEAE incidence was lower in the SCHZ subgroup (64.4%) than in the mood subgroup (71.9%). The 3 most common TEAEs in the SCHZ subgroup were urinary tract infection (UTI, 6.1%), headache (5.8%), and somnolence (5.2%). The 3 most common TEAEs in the mood subgroup were headache (12.4%), UTI (10.7%), and somnolence (9.1%). Mean score changes from baseline to end of treatment (Week 48) indicated that psychiatric stability was maintained in the SCHZ subgroup (PANSS Total, 3.4; PANSS Positive, -1.1; PANSS Negative, -0.1; PANSS General Psychopathology, 2.2; CDSS total, -0.4) and the mood subgroup (MADRS Total, 0.0; YMRS Total, 1.2). These scores remained generally stable during the 4-week drug-free follow up periods. In the LTE population, mean changes in laboratory parameters, vital signs, ECG, and EPS scales were generally minimal and not clinically significant. CONCLUSION: Valbenazine appeared to be well tolerated in adults with TD who received up to 48 weeks of treatment. In addition to long-term efficacy results (presented separately), these results suggest that valbenazine may be appropriate for the long-term management of TD regardless of underlying psychiatric diagnosis (SCHZ disorder or mood disorder). PMID- 28839342 TI - Efficacy of Valbenazine (NBI-98854) in Treating Subjects with Tardive Dyskinesia and Schizophrenia or Schizoaffective Disorder. AB - BACKGROUND: Valbenazine (VBZ, NBI-98854) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD). The KINECT 3 study (NCT02274558) evaluated the effects of VBZ on TD in subjects with schizophrenia/schizoaffective disorder (SCHZ) or mood disorder (mood disorder presented separately) who received up to 48 weeks of treatment. METHODS: KINECT 3 included: 6-week, double-blind, placebo (PBO)-controlled (DBPC) period (205 completers); 42-week VBZ extension (VE) period (124 completers): 4 week washout period (121 completers). Subjects entering the DBPC were randomized 1:1:1 to once-daily VBZ 80 mg, VBZ 40 mg, or PBO; stable concomitant antipsychotic medication regimens were allowed. Subjects completing the DBPC and entering the VE period were re-randomized (blinded) 1:1 from PBO to VBZ (80 or 40 mg) or continued VBZ treatment at the same dose. Efficacy assessments included: mean changes from baseline in Abnormal Involuntary Movement Scale (AIMS) total score (items 1-7); mean Clinical Global Impression of Change (CGI-TD) scores; AIMS responders (subjects with >=50% score reduction from baseline): and CGI-TD responders (subjects with score <=2 ["much improved" or "very much improved"]). Treatment effect sizes (Cohen's d) and numbers needed to treat (NNTs) were analyzed for DBPC outcomes. RESULTS: Efficacy analyses were conducted in 148 subjects (DBPC) and 125 subjects (VE) with SCHZ. At Week 6 (end of DBPC), AIMS mean score improvements were greater in the VBZ groups (in a dose-related pattern) than in the PBO group (80 mg, -2.9, d = 0.88; 40 mg, -1.6, d = 0.52; PBO, +0.3). AIMS score changes at Week 48 (end of VE) showed continued TD improvement during long-term VBZ treatment (80 mg, -4.2; 40 mg, -2.5). By Week 52 (end of washout), AIMS scores were returning toward baseline levels, indicating re-emergence of TD. CGI-TD mean scores were as follows: Week 6 (80 mg, 3.0, d = 0.11; 40 mg, 2.9, d = 0.23; PBO, 3.2), Week 48 (80 mg, 2.2; 40 mg, 2.4), Week 52 (80 mg, 3.4; 40 mg, 3.3). AIMS responder rates (>=50% score reduction) were greater with VBZ than with PBO at Week 6 (80 mg, 40.9%, NNT = 4; 40 mg, 26.2%, NNT = 6; PBO, 9.3%), were increased at Week 48 (80 mg, 50.0%; 40 mg, 26.2%), and decreased after VBZ washout (80 mg, 21.6%; 40 mg, 9.5%). CGI-TD responder rates followed a similar pattern: Week 6 (80 mg, 29.5%, NNT = 17; 40 mg, 33.3%, NNT = 10; PBO, 23.3%), Week 48 (80 mg, 73.7%; 40 mg, 58.1%), Week 52 (80 mg, 29.7%; 40 mg, 33.3%). CONCLUSION: Sustained TD improvements were found in subjects with SCHZ who received up to 48 weeks of VBZ, with TD reverting toward baseline when assessed 4 weeks after treatment withdrawal. Together with results from mood disorder subjects and the long-term safety profile (presented separately), these results indicate that long-term VBZ can be beneficial for managing TD regardless of psychiatric diagnosis category. PMID- 28839343 TI - Rating Scales and Safety Measurements in Bipolar Disorder and Schizophrenia - A Reference Guide. PMID- 28839344 TI - METHODOLOGICAL PLURALISM AND MIXED METHODOLOGY TO STRENGTHEN COMMUNITY PSYCHOLOGY RESEARCH: AN EXAMPLE FROM OXFORD HOUSE. AB - This article evaluates how a plurality of research methods has served a research program that has functioned in a much-needed area of research: the role of housing and recovery residences in addiction recovery. The review focuses on one mutually supportive recovery residence model, called Oxford House, which represents more than 1,700 democratic, self-governing residences. To date, there has been no comprehensive evaluation of the research methods used with Oxford House or any other recovery residence. In this article, research methods, including study designs and data analyses, are summarized for 114 peer-reviewed empirical studies that included data on Oxford Houses or Oxford House residents. This review of a pluralistic research program can inform community researchers about the value of recovery residences, the many ways in which recovery residences may be assessed, and the benefits of using multiple methods. Implications for future recovery residence research are discussed. PMID- 28839345 TI - Review: Food loss and waste in Sub-Saharan Africa. AB - The research, development practitioner, and donor community has begun to focus on food loss and waste - often referred to as post-harvest losses (PHL) - in Sub Saharan Africa. This article reviews the current state of the literature on PHL mitigation. First, we identify explicitly the varied objectives underlying efforts to reduce PHL levels. Second, we summarize the estimated magnitudes of losses, evaluate the methodologies used to generate those estimates, and explore the dearth of thoughtful assessment around "optimal" PHL levels. Third, we synthesize and critique the impact evaluation literature around on-farm and off farm interventions expected to deliver PHL reduction. Fourth, we suggest a suite of other approaches to advancing these same objectives, some of which may prove more cost-effective. Finally, we conclude with a summary of main points. PMID- 28839346 TI - Relationship Themes Present between Parents and Children in Recovery Homes. AB - Approximately 12.5% of children have a parent with a substance use disorder. These children are likely to experience developmental delays, especially if they are placed into foster care. Oxford House recovery homes provide a useful setting that allows children to live with their parents after treatment for substance use. A sample of parents and their children who lived in Oxford Houses were interviewed, using mixed methods, and the outcomes suggest that Oxford Houses may provide a stable and supportive setting for parents and their children. PMID- 28839347 TI - Estimation of genetic parameters and genetic trends for milk yield traits in Jamunapari goats in semiarid tropics. AB - The Jamunapari goats are reared as dairy animals in semi-arid conditions, therefore it is necessary to evaluate the genetic potential for the genetic improvement of milk production traits. The data comprised of 2217 phenotypic records for milk yield at 90 days (MY90) and 140 days (MY140), total milk yield (TMY) and lactation length (LL) obtained from the progeny of 173 sires and 446 dams during the period 1990-2013. The data were analysed using mixed linear models exploring random effects due to direct additive, maternal and permanent environment variance due to animal. The most appropriate genetic models for milk yield traits were those that included permanent environment effects due to the animal. The direct additive heritability estimates were 0.15 +/- 0.05, 0.26 +/- 0.07, 0.25 +/- 0.08 for MY90, MY140 and TMY, respectively. The additive heritability estimate for LL was low and non-significant at 0.02 +/- 0.03. The repeatability estimates were moderate to high ranging from 0.68 to 0.73 for milk yield traits. The repeatability for lactation length was 0.20 +/- 0.03. Maternal variances were low ranging from 0.03 for MY90 to 0.13 for TMY. There was an increase in mean milk yield of 0.25, 0.70 and 0.72 kg/year respectively at 90 and 140 days, and for TMY. Genetic trends and phenotypic trends for MY90, MY140 and TMY were positive and indicated significant improvement in milk traits due to selective breeding. PMID- 28839350 TI - Does an osteoporotic vertebral fracture treated by balloon kyphoplasty successfully achieve bone union during the follow-up? A retrospective study with a minimum 2-year follow-up. AB - OBJECTIVE: To investigate whether bone union is achieved in osteoporotic vertebral fracture (OVF) patients who undergo balloon kyphoplasty (BKP). METHODS: Thirty-six vertebrae, which were followed-up for more than two years after BKP, were evaluated in the present study. Bone union was assessed by using CT scans and lateral X-ray films obtained in the sitting and supine positions. RESULTS: Twenty-seven vertebrae exhibited bone union at the final follow-up. The VAS scores improved in all cases. CONCLUSIONS: Unstable vertebrae after treatment may develop complications; thus special attention should be paid to the treated vertebrae until bone union has been achieved. PMID- 28839348 TI - Enhanced Expression of IL-18 and IL-18BP in Plasma of Patients with Eczema: Altered Expression of IL-18BP and IL-18 Receptor on Mast Cells. AB - IL-18 has been found to be associated with eczema. However, little is known of the role of IL-18 binding protein (BP) and IL-18 receptor (R) in eczema. We therefore investigated the expression of IL-18, IL-18BP, and IL-18R on mast cells by using flow cytometry analysis and mouse eczema model. The results showed that plasma free IL-18 and free IL-18BP levels in eczema patients were higher than those in healthy controls. IL-18 provoked up to 3.1-fold increase in skin mast cells. IL-18 induced also an increase in IL-18BP+ mast cells, but a reduction of IL-18R+ mast cells in mouse eczema skin. It was found that house dust mite allergen Der p1 and egg allergen OVA induced upregulation of the expression of IL 18, IL-18BP, and IL-18R mRNAs in HMC-1 cells following 2 and 16 h incubation. In conclusion, correlation of IL-18 and IL-18BP in eczema plasma suggests an important balance between IL-18 and IL-18BP in eczema. The decrease in molar concentration ratio of plasma IL-18BP/IL-18 and allergen-induced upregulated expression of IL-18 and IL-18R in skin mast cells of the patients with eczema suggests that anti-IL-18 including IL-18BP therapy may be useful for the treatment of eczema. PMID- 28839351 TI - Relationship between severity of knee osteoarthritis and radiography findings of lower limbs: A cross-sectional study from the TOEI survey. AB - OBJECTIVE: This study aimed to compare radiographic parameters among radiographic severity of the medial knee osteoarthritis and between men and women in a rural Japanese population. METHODS: We measure nine radiographic parameters of the whole lower extremity in participants with neutral or varus alignment. RESULTS: Age and body mass index were related to the knee osteoarthritis severity. The knee osteoarthritis depended on not only varus alignment in the whole leg, but also varus deformity of proximal tibial condyle and the tibial plateau inclination, especially in women. CONCLUSION: We must consider the difference of tibial condyle morphology and tibial plateau inclination before onset of the knee osteoarthritis. PMID- 28839349 TI - The Role of Defensins in HIV Pathogenesis. AB - Profound loss of CD4+ T cells, progressive impairment of the immune system, inflammation, and sustained immune activation are the characteristics of human immunodeficiency virus-1 (HIV-1) infection. Innate immune responses respond immediately from the day of HIV infection, and a thorough understanding of the interaction between several innate immune cells and HIV-1 is essential to determine to what extent those cells play a crucial role in controlling HIV-1 in vivo. Defensins, divided into the three subfamilies alpha-, beta-, and theta defensins based on structure and disulfide linkages, comprise a critical component of the innate immune response and exhibit anti-HIV-1 activities and immunomodulatory capabilities. In humans, only alpha- and beta-defensins are expressed in various tissues and have broad impacts on HIV-1 transmission, replication, and disease progression. theta-defensins have been identified as functional peptides in Old World monkeys, but not in humans. Instead, theta defensins exist only as pseudogenes in humans, chimpanzees, and gorillas. The use of the synthetic theta-defensin peptide "retrocyclin" as an antiviral therapy was shown to be promising, and further research into the development of defensin based HIV-1 therapeutics is needed. This review focuses on the role of defensins in HIV-1 pathogenesis and highlights future research efforts that warrant investigation. PMID- 28839352 TI - Reconstruction of traumatic bone loss using the induced membrane technique: preliminary results about 11 cases. AB - INTRODUCTION: The use of Masquelet technique is a serious option to consider for biologic reconstruction of severe bone loss. Here is exposed a continuous and prospective study on bone loss management using that technique. The aims of this study were to assess epidemiology of bone loss due either to trauma or to non unions and to give preliminary results. PATIENTS AND METHODS: It was a prospective study from April 2015 to december 2016 involving patients treated using the induced membrane technique for a diaphyseal bone defect due either to trauma or non-unions. AO plates or Orthofix external fixators were used for osteosynthesis. Bone healing was radiologically assessed and any complications were listed. RESULTS: During the study period, 11 patients were treated using the induced membrane technique. There were 8 males and 3 females. Their mean age was 40.45 years (21-59). The skeletal segments concerned were 2 humerus, 6 femurs and 3 tibias with a mean bone defect length of 4,45 cm (2.5-8). The delay between reconstruction and trauma was 8 months (20 days - 3 years). After a mean follow up of 6.54 months (3-11) six patients presented a good radiological healing (4 femurs, 2 humerus) whereas in four patients, autograft osteointegration was still ongoing (2 femurs, 2 tibias). A tibia secondary infection was observed in a patient with the graft partial resorption. In another patient, an initial gangrene lead to a leg amputation. CONCLUSION: The induced membrane technique is an excellent option for bone defect reconstruction compared to other usual bone graft techniques. It helped us to manage large bone loss in various skeletal segments. PMID- 28839353 TI - Strain measurements of the tibial insert of a knee prosthesis using a knee motion simulator. AB - OBJECTIVE: The longevity of a knee prosthesis is influenced by the wear of the tibial insert due to its posture and movement. In this study, we assumed that the strain on the tibial insert is one of the main reasons for its wear and investigated the influence of the knee varus-valgus angles on the mechanical stress of the tibial insert. METHODS: Knee prosthesis motion was simulated using a knee motion simulator based on a parallel-link six degrees-of-freedom actuator and the principal strain and pressure distribution of the tibial insert were measured. In particular, the early stance phase obtained from in vivo X-ray images was examined because the knee is applied to the largest load during extension/flexion movement. The knee varus-valgus angles were 0 degrees (neutral alignment), 3 degrees , and 5 degrees malalignment. RESULTS: Under a neutral orientation, the pressure was higher at the middle and posterior condyles. The first and second principal strains were larger at the high and low pressure areas, respectively. Even for a 3 degrees malalignment, the load was concentrated at one condyle and the positive first principal strain increased dramatically at the high pressure area. The negative second principal strain was large at the low pressure area on the other condyle. The maximum equivalent strain was 1.3-2.1 times larger at the high pressure area. For a 5 degrees malalignment, the maximum equivalent strain increased slightly. CONCLUSION: These strain and pressure measurements can provide the mechanical stress of the tibial insert in detail for determining the longevity of an artificial knee joint. PMID- 28839354 TI - Quantification Analysis and In Vitro Anti-Inflammatory Effects of 20 Hydroxyecdysone, Momordin Ic, and Oleanolic Acid from the Fructus of Kochia scoparia. AB - BACKGROUND: The fructus of Kochia scoparia Schrader (Chenopodiaceae) is a traditional herbal medicine that has been used for treating gonorrhea and dermatitis. OBJECTIVE: We investigated the anti-inflammatory activities of three marker compounds, including 20-hydroxyecdysone, momordin Ic, and oleanolic acid, from the fructus of K. scoparia. MATERIALS AND METHODS: The simultaneous analysis of three components was performed using high-performance liquid chromatography and high-performance thin-layer chromatography. We evaluated the anti inflammatory effects of the nine marker compounds by determining their anti inflammatory activities in the murine macrophage cell line RAW 264.7. RESULTS: Among three marker compounds, momordin Ic, but not 20-hydroxyecdysone and oleanolic acid, had inhibitory effects on the production of inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in LPS treated RAW264.7 macrophages. The effects of three marker compounds on prostaglandin E2(PGE2) were also evaluated. All three compounds significantly reduced PGE2 production in LPS-treated cells. CONCLUSIONS: We suggest that momordin Ic is the most potent phytochemical of the fructus of K. scoparia as an anti-inflammatory agent. SUMMARY: Simultaneous analysis of three phenylpropanoids in the Kochia scoparia was established using HPLC-PDA systemThe momordin Ic had inhibitory effects on production of inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in LPS-treated RAW264.7 macrophagesThe momordin Ic, 20-hydroxyecdysone, and oleanolic acid significantly reduced PGE2 production in LPS-treated cells. Abbreviations used: HPLC: High-performance liquid chromatography; TNF-alpha: Tumor necrosis factor alpha; IL-6: Interleukin 6; PGE2: Pro-inflammatory mediator prostaglandin E2; LPS: Lipopolysaccharide. PMID- 28839355 TI - Anticancer Potential of Steviol in MCF-7 Human Breast Cancer Cells. AB - OBJECTIVE: This study aimed to investigate the cytotoxicity, apoptosis induction, and mechanism of action of steviol on human breast cancer cells (Michigan Cancer Foundation-7 [MCF-7]). MATERIALS AND METHODS: Sulforhodamine-B assay was performed to analyze cytotoxic potential of Steviol whereas flow cytometer was used to analyze cell cycle, apoptosis, and reactive oxygen species generation. RESULTS: Studying the viability of cells confirms the IC50 of Steviol in MCF-7 cells which was 185 MUM. The data obtained from fluorescence-activated cell sorter analysis reveal Steviol-mediated G2/M-phase arrest (P < 0.05) in addition to the presence of evident sub-G0/G1 peak (P < 0.05) in the MCF-7 cells, signifying the ongoing apoptosis. CONCLUSION: Thus, results suggest that induction of apoptosis in MCF-7 cells was due to dose-dependent effect of Steviol. Our first in vitro findings indicate Steviol as a promising candidate for the treatment of breast cancer. SUMMARY: Steviol remarkably inhibited the growth MCF-7 HBCCs in a dose dependent mannerIt abolishes cell cycle progression by arresting cells at G2/M phaseSteviol induces the cells to undergo apoptosisSteviol induces the cells to generate reactive oxygen species (ROS). Abbreviations used: MCF-7: Michigan Cancer Foundation-7; SRB: Sulforhodamine-B assay; FACS: Fluorescence-activated cell sorter; ROS: Reactive oxygen species; DNA: Deoxyribonucleic acid. PMID- 28839356 TI - Antitumor Effects and Mechanism of n-butanol Fraction from Aril of Torreya grandis in H22 Mice. AB - BACKGROUND: To determine the antitumor effects and its mechanism of n-butanol fraction from aril of Torreya grandis (BFAT) on H22 mice models of liver cancer. MATERIALS AND METHODS: Sixty ICR male mice were used to establish H22 mice models of liver cancer and then randomly divided into six groups, the normal control group, the model control group, the positive group (cyclophosphamide [CTX]), the BFAT-treated group (high, 4 g/kg, medium, 2 g/kg, and low, 1 g/kg). The animals were sacrificed 15 days after oral administration, and tumors were taken out for the tumor weights and antitumor rates, while thymus and spleen were taken for thymus index and spleen index. Blood in eyeball was collected for the determination of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (Alb), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase enzyme (GSH-Px), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), transforming growth factor-beta1 (TGF-beta1), and IL-10 in serum. Sections of tumor tissue were prepared, and morphological changes in tumor tissue cells were observed using hematoxylin and eosin staining technique. RESULTS: Compared with the model control group, the tumor inhibition rate of the high-dose administered group is 60.15%, which is quite closed to the effect of CTX. Moreover, the tumor weight is decreased, the indexes of spleen, thymus were increased significantly. Furthermore, the administration of BFAT significantly enhanced the activities of TNF-alpha, IL-2, SOD, and GSH-Px and reduced the levels of AST, ALT, MDA, Alb, TGF-beta1, and IL-10 (P < 0.01). CONCLUSIONS: The results demonstrated that n-butanol fraction from aril of T. grandis showed out antitumor activity without obviously liver damage through potentiating immunologic function and antioxidant activity of tumor-bearing mice and which may become one potential as anticancer drug alternatives or supplements. SUMMARY: High and medium groups could significant elevate the thymus and spleen indexes and the interleukin-2 and tumor necrosis factor-alpha level in serum of H22 micen butanol fraction from aril of Torreya grandis (BFAT) could ameliorate the levels of aspartate aminotransferase, alanine aminotransferase and albumin to almost normal, and increase the concentrations of superoxide dismutase and glutathione peroxidase enzyme, decrease the malondialdehyde level in serum of mice significantlyBFAT may indirectly play the role of antitumor activity through improving immunologic functionBFAT had potent antitumor properties without obviously liver damage. Abbreviations used: DDP: Cisplatin; CTX: Cyclophosphamide; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; Alb: Albumin; MDA: Malondialdehyde; SOD: Superoxide dismutase; GSH-Px: Glutathione peroxide enzyme; TNF-alpha: Tumor necrosis factor-alpha; IL-2: Interleukin-2; TGF-beta1: Transforming growth factor-beta1; IL-10: Interleukin 10; HE: Hematoxylin and eosin; PBS: Phosphate-buffered saline; PFAT: Petroleum ether fraction from aril of Torreya grandis; EFAT: Ethyl acetate fraction from aril of Torreya grandis; BFAT: N-butanol fraction from aril of Torreya grandis. PMID- 28839357 TI - Using Molecular Docking Analysis to Discovery Dregea sinensis Hemsl. Potential Mechanism of Anticancer, Antidepression, and Immunoregulation. AB - BACKGROUND: Dregea sinensis Hemsl. plant of the genus Dregea volubilis (Asclepiadaceae), plays a vital role in anticancer, antidepression, and immunoregulation. Steroidal glycosides are the main constituents of this herb, which were significant biological active ingredients. OBJECTIVE: The objective of this study is to recognize the mechanism of anticancer, antidepression, and immunoregulation of D. sinensis Hemsl. MATERIALS AND METHODS: Seventy-two steroidal glycosides of D. sinensis Hemsl. were evaluated on the docking behavior of tumor-associated proteins (PI3K, Akt, mTOR), depression-related proteins (MAO A, MAO-B) and immune-related proteins (tumor necrosis factor-alpha [TNF-alpha], tumor necrosis factor receptor 2 [TNFR2], interleukin-2Ralpha [IL-2Ralpha]) using Discovery Studio version 3.1 (Accelrys, San Diego, USA). RESULTS: The molecular docking analysis revealed that mostly steroidal glycosides of D. sinensis Hemsl. exhibited powerful interaction with the depression-related protein (MAO-A) and the immune-related proteins (TNFR2, IL-2Ralpha). Some ligands exhibited high binding energy for the tumor-associated proteins (PI3K, Akt, mTOR) and the immune related protein (TNF-alpha), but MAO-B showed none interaction with the ligands. CONCLUSION: This study has paved better understanding of steroidal glycosides from D. sinensis Hemsl. as potential constituents to the prevention of associated cancer, depression and disorders of immunoregulation. SUMMARY: The ligand database was consist of 72 steroidal glycosides from Dregea sinensis HemslSteroidal glycosides had the potential to dock with the tumor-associated proteins (PI3K, Akt, mTOR)Steroidal glycosides were bounded with MAO-A rather than MAO-B, accorded with the inhibitor selectivity of MAOs, can be considered as potent candidate inhibitors of MAO-A72 ligands got high interaction with TNFR2 and IL-2Ralpha, regard the steroidal glycoside as powerful candidate inhibitors of TNFR2 and IL-2Ralpha. Abbreviations used: PI3K: Phosphatidyl inositol 3 kinase; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin; MAO-A: Monoamine oxidase A; MAO-B: Monoamine oxidase B; TNF-alpha: Tumor necrosis factor alpha; TNFR2: Tumor necrosis factor receptor 2; IL-2Ralpha: The alpha subunit (CD25) of the interleukin-2 receptor; DS: Discovery Studio; PDB: Protein Database Bank; 3D: three-dimensional. PMID- 28839358 TI - Wound-healing Activity of Zanthoxylum bungeanum Maxim Seed Oil on Experimentally Burned Rats. AB - BACKGROUND: The seed oil of Zanthoxylum bungeanum Maxim (ZBSO) is considered to be rich source of fatty acids, mainly oleic and linoleic acids, and has been used for the treatment of burns in Chinese medicine. OBJECTIVE: We evaluated the healing efficacy of ZBSO and explored its possible mechanism on scalded rats. MATERIALS AND METHODS: Sprague-Dawley rat models with deep second-degree burns were set up, and ZBSO (500 and 1000 MUl/wound) was topically applied twice daily for 7 days and then once daily until wound healing. The therapeutic effects of ZBSO were evaluated by observing wound closure time, decrustation time, wound healing ratio, and pathological changes. Collagen type-III, matrix metalloproteinase-2 (MMP-2), MMP-9, phospho-nuclear factor-kappaB (p-NF-kappaB) p65, inhibitor of NF-kappaB subunit alpha p-IkappaBalpha, and inhibitor of NF kappaB subunit alpha (IkappaBalpha) expression were determined using Western blotting. RESULTS: The ZBSO-treated group showed a higher wound-healing ratio and shorter decrustation and wound closure times than the untreated group. The topical application of ZBSO increased collagen synthesis as evidenced by an increase in hydroxyproline level and upregulated expression of collagen type-III on days 7, 14, and 21 posttreatment. A reduction in MMP-2 and MMP-9 expressions also confirmed the collagen formation efficacy of ZBSO. Furthermore, there was a significant increase in superoxide dismutase levels and a decrease in malondialdehyde levels in ZBSO-treated wounds. ZBSO also decreased tumor necrosis factor alpha, interleukin-1 (IL-1) beta, and IL-6 levels in serum, upregulated IkappaBalpha, and downregulated p-NF-kappaB p65 and p-IkappaBalpha expression in vivo, indicating the anti-inflammatory action of ZBSO. CONCLUSION: ZBSO has significant potential to treat burn wounds by accelerating collagen synthesis and the anti-inflammatory cascade of the healing process. SUMMARY: The seed oil of Zanthoxylum bungeanum Maxim (ZBSO) is rich of fatty acidsThe healing efficacy of ZBSO on experimentally scalded rats was evaluatedZBSO has significant potential to treat deep second-degree burn woundsZBSO could accelerate collagen synthesis and inhibit the inflammatory signaling. Abbreviations used: ECL: Enhanced chemiluminescence; ECM: Extracellular matrix; ELISA: Enzyme-linked immunosorbent assay; GC-MS: Gas chromatography-mass spectrometry; HRP: Horseradish peroxidase; HYP: Hydroxyproline; IkappaBalpha: Inhibitor of NF-kappaB subunit alpha; IL: Interleukin; MDA: Malondialdehyde; MMP: Matrix metalloproteinase-2; NF-kappaB: Nuclear factor-kappaB; SFE: Supercritical fluid extraction; SOD: Superoxide dismutase; SSD: Silver sulfadiazine; TCM: Traditional Chinese medicine; TNF: Tumor necrosis factor. PMID- 28839359 TI - Mechanism of Fructus Aurantii Flavonoids Promoting Gastrointestinal Motility: From Organic and Inorganic Endogenous Substances Combination Point of View. AB - BACKGROUND: Fructus Aurantii (FA) derived from the dried, and unripe fruit of Citrus aurantium L. is one of the commonly used traditional Chinese medicines to treat gastrointestinal motility dysfunction diseases. According to the literature research, FA flavonoids (FAF) are important active ingredients of FA promoting gastrointestinal motility, but the exact material basis and mechanism of action are still not very clear. OBJECTIVE: This experiment was designed to illustrate the material basis of FAF promoting gastrointestinal motility and explore the mechanism of action from an organic and inorganic combination point of view. MATERIALS AND METHODS: In this experiment, high-performance liquid chromatography (HPLC) method was used to analyze the composition and content of FAF. Based on the prominent prokinetic effect of FAF on mice, the mechanism of action was speculated through a combination of HPLC coupled with quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) and inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: With the method of HPLC, ten dominating components of FAF including neoeriocitrin, narirutin, rhoifolin, naringin, hesperidin, neohesperidin, neoponcirin, naringenin, hesperetin, and nobiletin accounting for more than 86% of FAF were identified. Combined HPLC-QTOF-MS with ICP-MS, the endogenous substances with difference in the blood of mice were analyzed, in which 4-dimethylallyltryptophan, corticosterone, phytosphingosine, sphinganine, LysoPC (20:4(5Z, 8Z, 11Z, 14Z)), LysoPC(18:2 (9Z, 12Z)), and Ca2+, Mg2+, Zn2+ metal ions had significant changes, involving tryptophan metabolism, corticosterone metabolism, sphingolipid metabolism, and other pathways. CONCLUSION: The results preliminarily elaborated the mechanism of FAF promoting gastrointestinal motility from an organic and inorganic point of view, which provide valuable information for researching and developing new multi-component Chinese medicine curing gastrointestinal underpower associated diseases. SUMMARY: Fructus Aurantii flavonoids are one of the main components of Fructus Aurantii that possess prominent gastrointestinal motility promoting efficacyThe mainly material basis of Fructus Aurantii flavonoids promoting gastrointestinal motility were neoeriocitrin, narirutin, rhoifolin, naringin, hesperidin, neohesperidin, neoponcirin, naringenin, hesperetin, and nobiletinFructus Aurantii flavonoids can regulate the content of 4-dimethylallyltryptophan, corticosterone, phytosphingosine, sphinganine, LysoPC (20:4(5Z, 8Z, 11Z, 14Z)), LysoPC.(18:2(9Z, 12Z)) and Ca2+, Mg2+, Zn2+-metal ions, through tryptophan metabolism, corticosterone metabolism, sphingolipid metabolism, and other pathways to present its gastrointestinal motility promoting efficacy. Abbreviations used: FA: Fructus Aurantii; FAF: Fructus Aurantii flavonoids; HPLC: High performance liquid chromatography; HPLC-QTOF-MS: High performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry; ICP-MS: Inductively coupled plasma mass spectrometry; PCA: Principal components analysis; CG: Control group; FAFLG: Low-dosage group of Fructus Aurantii flavonoids; FAFMG: Middle-dosage group of Fructus Aurantii flavonoids; FAFHG: High-dosage group of Fructus Aurantii flavonoids; DPG: Domperidone group. PMID- 28839360 TI - Prim-O-glucosylcimifugin Attenuates Lipopolysaccharideinduced Inflammatory Response in RAW 264.7 Macrophages. AB - BACKGROUND: Radix Saposhnikoviae (RS) exerts anti-inflammatory, analgesic, antipyretic, antioxidation effects and has been used in traditional Chinese medicine to treat common colds, headache, and rheumatoid arthritis. Prim-O glucosylcimifugin (POG) is the highest content chromone and one of the major active constituents in RS. OBJECTIVE: The study was aimed to explore the anti inflammation effects of POG in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. MATERIALS AND METHODS: Cell viability was detected by Cell Counting Kit-8 assay. Production of nitric oxide (NO), tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and IL-6 was assessed by enzyme-linked immunosorbent assay. Real-time polymerase chain reaction and Western blot were performed to analyze mRNA and protein levels, respectively. RESULTS: During the whole experiment, 15, 50, and 100 MUg/mL of POG had no cytotoxicity on RAW 264.7 cells. POG dose-dependently inhibited the production of NO, TNF-alpha, IL-1beta, and IL-6 that were induced by LPS. POG treatment downregulated the mRNA and protein expression inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) in LPS-activated RAW 264.7 macrophages in a concentration-dependent manner. Furthermore, LPS-induced JAK2/STAT3 activation was prevented in RAW 264.7 macrophages by POG treatment. STAT3 overexpression significantly reversed the effects of POG on LPS-activated RAW 264.7 macrophages. CONCLUSION: These results demonstrate that POG exerts anti-inflammatory effects through the inhibition of iNOS and COX-2 expression by inhibiting the phosphorylation of JAK2/STAT3. SUMMARY: POG exerts anti-inflammatory effects in RAW 264.7 macrophages through the inhibition of iNOS and COX-2 expression by inhibiting JAK2/STAT3 signaling. Abbreviations used: LPS: Lipopolyssacharide; NO: Nitric oxide; TNF-alpha: Tumor necrosis factor-alpha; IL: Interleukin; RS: Radix Saposhnikoviae; POG: Prim-O glucosylcimifugin; iNOS: Inducible NO synthase; COX2: Cyclooxygenase; FBS: Fetal bovine serum; DMSO: Dimethylsulfoxide; CCK-8: Cell Counting Kit; RIPA: Radio immunoprecipitation assay buffer; ECL: Enhanced chemiluminescence; SD: Standard deviation; ELISA: Enzyme-Linked immunosorbent assay. PMID- 28839361 TI - Ethanolic Fraction of Terminalia tomentosa Attenuates Biochemical and Physiological Derangements in Diet Induced Obese Rat Model by Regulating Key Lipid Metabolizing Enzymes and Adipokines. AB - The prevalence of overweight-obesity and associated comorbidities have reached alarming levels necessitating the need to explore effective therapeutics. In the present work, we demonstrated the promising antiobesity activity of ethanolic fraction of Terminalia tomentosa bark (EFTT) in diet induced obese rat model. High Fat Diet (HFD)-fed obese rats were orally administered with EFTT (50, 100 and 200 mg/kg body weight). Changes in body weight, body composition, bone mineral concentration, bone mineral density, plasma glucose, insulin, leptin, adiponectin, circulatory and tissue lipid profiles, and the activities of liver antioxidant enzymes, key lipid metabolic enzymes and mRNA expressions of fatty acid synthase (FAS), peroxisome proliferator-activated receptor gamma (PPAR gamma), leptin and tumor necrosis factor alpha (TNF-alpha) were assessed in experimental rats in the presence and absence of EFTT. At a dose of 200 mg/kg b.wt, EFTT has substantially attenuated body weight and related patho physiological alterations in HFD-induced obese rats. These findings were correlated with histological observations of adipose tissue. The therapeutic activity of EFTT could be possibly through restoration of antioxidants status, regulation of key lipid metabolizing enzymes, expression of FAS, leptin, PPAR gamma and by synchronized control of energy metabolism in liver and adipose tissue. PMID- 28839362 TI - Effects of Plantago major Extracts and Its Chemical Compounds on Proliferation of Cancer Cells and Cytokines Production of Lipopolysaccharide-activated THP-1 Macrophages. AB - BACKGROUND: Plantago major has been reported to have anticancer and anti inflammatory properties. However, its antiproliferative and anti-inflammatory mechanisms have not been fully elucidated. Moreover, which plant parts are more suitable as starting materials has not been explored. OBJECTIVES: To investigate the antiproliferative activity of P. major extracts against MCF-7, MDA-MB-231, HeLaS3, A549, and KB cancer cell lines as well as their effects on inflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-6, and interferon [IFN]-gamma) production by lipopolysaccharide (LPS)-stimulated THP-1 macrophages. MATERIALS AND METHODS: The methanol and aqueous extracts of P. major from different plant parts and its chemical compounds, i.e., ursolic acid (UA), oleanolic acid (OA), and aucubin were tested in this experiment. RESULTS: Methanol and aqueous extracts of P. major seeds exhibited the greatest antiproliferative activity. The methanol extracts of seeds also demonstrated the highest inhibition of TNF-alpha, IL-1beta, IL-6, and IFN-gamma production. Interestingly, the roots, which were commonly discarded, exhibited comparable activities to those of leaves and petioles. Furthermore, UA exhibited stronger activities than OA and aucubin. CONCLUSIONS: The seeds are being proposed as the main source for further development of anticancer and anti-inflammatory products, whereas the roots could be included in the preparation of P. major derived products with respect to anti-inflammatory. SUMMARY: Amongst the parts of Plantago major, seeds exhibited the greatest antiproliferative activity against MCF-7, MDA-MB-231, HeLaS3, A549, and KB cell lines as well as the highest inhibition on TNF-alpha, IL-1beta, IL-6, and IFN-gamma productionThe roots, which were commonly discarded, exhibited comparable antiproliferative and cytokines inhibition activities to those of leaves and petiolesUrsolic acid, a chemical compound of Plantago major, exhibited stronger activities than oleanolic acid and aucubinThe seeds are being proposed as the main source for further development of anticancer and anti inflammatory products, whereas the roots could be included in the preparation of Plantago major derived products with respect to anti inflammatory. Abbreviations used: TNF: Tumor Necrosis Factor; IL: Interleukin; IFN: Interferon; HPTLC: High Performance Thin Layer Chromatography; UA: Ursolic Acid; OA: Oleanolic Acid; AUC: Aucubin. PMID- 28839363 TI - A Novel Strategy for Bitter Taste Masking of Gankeshuangqing Dispersible Tablets Based on Particle Coating Technology. AB - BACKGROUND: Currently, acute upper respiratory tract infections (AURTIs) are increasingly becoming a significant health burden. Gankeshuangqing dispersible tablets (GKSQDT) which have a good effect on treating AURTIs. GKSQDT is composed of baicalin and andrographolide. However, its severe bitterness limits application of patients. Due to the addition of plentiful accessories, common masking methods are unsuitable for GKSQDT. It is thus necessary to develop a new masking method. MATERIALS AND METHODS: The Previous study showed that baicalin was less bitter than andrographolide. Thus, particle coating technology was adapted to prepare composite particles that baicalin coated on the surface of andrographolide to decrease bitterness. Initially, particle size of baicalin and coating time of composite was investigated to prepare composite. Then, scanning electron microscopy, wettability, and infrared (IR) spectrogram were used to characterize the microstructure of composite. Furthermore, electronic tongue test, animal preference experiment, and human sensory test were applied to evaluate the masking effect. RESULTS: To produce composite, baicalin should be ground in vibromill for 6 min. Then, andrographolide fine powder was added to grind together for 6 min. Contact angle of composite was smaller than mixture, and more similar to baicalin. Other physical characterization including microstructure, wettability, and IR also suggested that andrographolide was successfully coated by baicalin superfine. Furthermore, taste-masking test indicated taste-masked tablets was less bitter than original tablets. CONCLUSION: The study indicated that particle coating technology can be used for taste masking of GKSQDT without adding other substance. Moreover, it provides a new strategy of taste masking for national medicine. SUMMARY: A new strategy to mask bitterness without adding any other substance based on coating technology was providedThe masking effect was confirmed by electronic tongue test, animal preference experiment and human sensory test. Abbreviations used: AURTIs: Acute Upper Respiratory Tract Infections; GSQDT: Gankeshuangqing Dispersible Tablets; IR: Infrared Spectrogram; LHPC: Low-substituted Hydroxypropyl Cellulose; CAs: Contact Angles; FTIR: Fourier Transform Infrared Spectra. PMID- 28839364 TI - Omega-3 Fish Oil Reduces Mortality Due to Severe Sepsis with Acute Gastrointestinal Injury Grade III. AB - BACKGROUND: Sepsis plays an important role in acute gastrointestinal injury (AGI). Our research was designed to determine the effects of omega-3 fish oil (FO) in patients suffering from severe sepsis combined with AGI III, and the ability of FO to modulate immune function. METHODS: Seventy-eight patients diagnosed with severe sepsis with AGI III and a need for mechanical ventilation were randomized to two groups. In the FO group, 50 g of long chain fatty acid soybean oil (n = 6) and 10 g of FO (n = 3) were administered as total parenteral nutrition (TPN). The control group was treated with 50 g of long chain fatty acid soybean oil without addition of FO to TPN. RESULTS: At baseline, there were no significant differences between the two groups. The 60-day mortality was lower in the FO group. Multiple factor logistic regression analysis revealed that intra abdominal pressure (IAP) and abdominal infection were correlated with the FO intervention. The patients with abdominal infection demonstrated a lower mortality rate, fewer CD3 T lymphocytes, and fewer helper/inducer T lymphocytes in the FO group compared with the control group. After 7 days, the Marshall Score was lower in the FO group than in the control group. CONCLUSION: FO has positive effects in terms of improving the long-term prognosis of patients with severe sepsis with AGI III. Patients with a high IAP and abdominal infection might experience greater benefit from FO. This effect might be due, in part, to immunomodulation. SUMMARY: Fish oil (FO) has positive effects in terms of improving the long-term prognosis of patients with severe sepsis with acute gastrointestinal injury Grade IIIPatients with a high intra-abdominal pressure and abdominal infection might experience greater benefit from FOThis effect might be due, in part, to immunomodulation. Abbreviations used: AGI: Acute gastrointestinal injury; FO: Fish oil; TPN: Total parenteral nutrition; IAP: Intra-abdominal pressure; ICU: Intensive Care Unit; MODS: Multiple organ dysfunction syndrome; TLR4: Toll-like receptor 4; DNR: Do Not Resuscitate; WGAP: Working Group of Abdominal Problem; EN: Enteral nutrition; BP: Low blood pressure; CRI: Catheter-related infection; PBS: Phosphate-buffered saline; ELFA: Enzyme-linked fluorescent assay; SD: Standard deviation; PUFAs: Polyunsaturated fatty acids; EPA: Eicosapentenoic acid; DHA: Docosahexaenoic acid. PMID- 28839365 TI - Determination and Tissue Distribution Comparisons of Atractylodin after Oral Administration of Crude and Processed Atractylodes Rhizome. AB - BACKGROUND: Atractylodis rhizoma is one of the most often used drugs in traditional Chinese medicine. Stir frying with wheat bran is the most common processing method. To clarify the principle of processing, an experiment was carried out to compare the tissue distribution of typical constituent after oral administration of raw A. rhizoma and processed ones. OBJECTIVE: To compare the tissues distribution of atractylodin after oral administration of raw and processed A. rhizoma and clarify the processing principle of A. rhizoma. Materials and Methods: High-performance liquid chromatogram with ultraviolet detection was developed and validated for the determination of atractylodin in rat tissues. RESULTS: The atractylodin in raw and processed A. rhizoma was distributed in all tissues involved in this study. CONCLUSIONS: The concentration of atractylodin in it is the highest in the stomach and small intestine. SUMMARY: In this paper, a simple, specific, and rapid reversed phase-high-performance liquid chromatogram method with ultraviolet detection for quantification of atractylodin in rat tissue has been developed for the first time. The result indicates that the concentration of atractylodin in it is the highest in the stomach and small intestine. Abbreviations used: IS: Internal standard substance; A. rhizoma: Atractylodis rhizoma; RSD: Relative standard deviation; HPLC: High performance liquid chromatography. PMID- 28839366 TI - Influence of Boiling Duration of GCSB-5 on Index Compound Content and Antioxidative and Anti-inflammatory Activity. AB - BACKGROUND: GCSB-5, an herbal drug composition with an anti-inflammatory effect, is prepared by boiling, which is the most common herbal extraction method in traditional Korean medicine. Several parameters are involved in the process, i.e., extractant type, herb-to-extractant ratio, extraction temperature and pressure, and total boiling time. OBJECTIVES: The aim of this study was to examine the influence of boiling time on index compound amount and the antioxidative and anti-inflammatory activities of GCSB-5. MATERIALS AND METHODS: Different samples of GCSB-5 were obtained by decocting for 30, 60, 90, 120, 150, and 240 min. Each sample was tested for hydrogen ion concentration (pH), total soluble solid content (TSSC), marker compound profiles, and antioxidative and anti-inflammatory activity. RESULTS: pH was found to decrease while TSSC increased with extended decoction. Marker compound contents for GCSB-5 (acanthoside D for Acanthopanax sessiliflorus Seem, 20-hydroxyecdysone for Achyranthes japonica Nakai, and pinoresinol diglucoside for Eucommia ulmoides Oliver) remained relatively constant regardless of the length of boiling. Total D glucose amount increased with longer boiling. The antioxidative and anti inflammatory potentials of GCSB-5 were not substantially affected by decoction duration. CONCLUSION: Biological characteristics and marker compound content of GCSB-5 were not altered significantly in prolonged boiling. SUMMARY: Longer boiling duration of GCSB-5 did not increase yield in a time-dependent manner, but yields of 210 and 240 min samples were significantly higherHydrogen ion concentration of GCSB-5 samples decreased while total soluble solid content and D glucose concentration levels increased with boiling durationAlthough concentrations of some index compounds increased with extended boiling duration of GCSB-5, increase was small and not in a direct proportional relationshipAntioxidative and anti-inflammatory properties of GCSB-5 were not substantially affected by decoction duration. Abbreviations used: CAM: Complementary and alternative medicine; KIOM: Korea Institute of Oriental Medicine; KMD: Korean medicine doctor; TSSC: Total soluble solid content; pH: Hydrogen ion concentration; HPLC: High-performance liquid chromatography; NO: Nitric oxide; NO2: Nitric dioxide; LPS: Lipopolysaccharide; DMSO: Dimethyl sulfoxide. PMID- 28839367 TI - Simultaneous quantitation of six aconitum alkaloids and three flavonoids in the herb couple of radix aconiti lateralis-radix glycyrrhizae (Fuzi-Gancao) by UHPLC ESI-MS/MS. AB - BACKGROUND: Fuzi-Gancao herb couple is one of the commonly used herb couples involved in the traditional Chinese medicine formulations, with radix aconiti lateralis (Fuzi in Chinese) and radix glycyrrhizae (Gancao in Chinese) as a ratio of 1:1. Alkaloids and flavonoids were considered as the main active ingredients of Fuzi-Gancao herb couple. However, no analytical methods have been reported to quantitatively analyze these activity ingredients in Fuzi-Gancao herb couple simultaneously. OBJECTIVE: To develop a simple, rapid, and sensitive UHPLC-MS/MS method for simultaneous quantitation of six alkaloid and three flavonoid compounds, namely, aconitine (AC), mesaconitine (MA), hypaconitine (HA), benzoylaconitine (BAC), benzoylmesaconitine (BMA), benzoylhypaconitine (BHA), liquiritin, isoliquiritin, and licochalcone A (LCA) in Fuzi-Gancao herb couple. MATERIALS AND METHODS: The chromatographic separation was achieved using a reversed phase C18 column and a mobile phase consisted of water (0.1% formic acid in water, v/v) and acetonitrile. The detection was achieved in multiple reaction monitoring modes. The optimal mass transition ion pairs (m/z) for quantitation were 646.3/586.5 for AC, 632.4/572.5 for MA, 616.3/556.4 for HA, 604.5/572.5 for BAC, 590.4/540.4 for BMA, 574.1/542.5 for BHA, 419.4/257.1 for liquiritin, 419.4/257.1 for isoliquiritin, and 339.2/121.1 for LCA. RESULTS: Good linearity was observed in validated concentration range for each analyte (r > 0.9992), and the intra- and inter-day precisions were <3.12% and 3.65%, respectively. The recovery ranged from 85.36% to 110.14%. CONCLUSIONS: The results demonstrated that the method developed was reliable, rapid, and specific. Moreover, this method was successfully applied to control the quality of Fuzi-Gancao herb couple. SUMMARY: A simple, rapid, and sensitive UHPLC-MS/MS method for simultaneous quantitation of six alkaloid and three flavonoid compounds in Fuzi Gancao herb couple has been developed. Abbreviations used: UHPLC-ESI-MS/MS: Ultra High Performance Liquid Chromatography-electrospray ionization-mass spectrometry; RSD: Relative standard deviations; LOD: Limit of detection; LOQ: Limit of quantification; MRM: Multiple reaction monitor; TCMs: Traditional Chinese medicines. PMID- 28839368 TI - Intervention Effects of Atorvastatin Combined with Panax notoginseng Saponins on Rats with Atherosclerosis Complicated with Hepatic Injury. AB - BACKGROUND: Statins cannot be used for some active liver diseases, which limits its application to some extent. The combined use of statins with other drugs may be one of the ways to solve this dilemma. OBJECTIVE: This research aims to evaluate the effects of atorvastatin combined with Panax notoginseng saponins (PNS) on rats with atherosclerosis (AS) complicated with hepatic injury. MATERIALS AND METHODS: Seventy-two male Wistar rats were randomly categorized into control group (without any intervention, Group A) and AS model groups, which were divided into hepatic injury (Groups B-E) and nonhepatic injury (Groups F-I) groups. Hepatic and nonhepatic injury groups were intragastrically treated with 5.5 mg/kg.d atorvastatin (Group B, F), 200 mg/kg.d PNS (Group C, G), 5.5 mg/kg.d atorvastatin + 200 mg/kg.d PNS (Group D, H), and normal saline (Group E, I). After 8 weeks, total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol, low density lipoprotein-cholesterol (LDL-C), and serum calcium were analyzed to evaluate the hypolipidemic effect. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and r-glutamyltransferase levels were measured to assess liver function. The thoracic aortas were used for hematoxylin-eosin staining. RESULTS: In both hepatic injury and nonhepatic injury groups, TC, TG and LDL-C levels significantly decreased in Groups B, D, F, and H. ALT and AST levels significantly increased in Group B, but significantly decreased in Groups C and D. The aortic intima thickness was significantly lower in Groups B, D, F, and H than that in the normal saline group. CONCLUSION: The combination of atorvastatin and PNS treatment showed a significant hypolipidemic effect and hepatic enzyme stability function. SUMMARY: The single use of Panax notoginseng saponins (PNS) in the rat model for atherosclerosis significantly reduced Ca2+ content in serum, whereas the effect of lowing total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C) is not apparent, especially as compared with atorvastatin treatmentPNS combined with atorvastatin treatment of the rat model for atherosclerosis displayed a noticeable, synergistic effect that allowed for better reduction of TC, TG, LDL-C and Ca2+ in the serum than that with the single use of PNS or atorvastatinIn the rat liver injury combined with atherosclerosis model, the single use of PNS significantly improved liver function, whereas atorvastatin alone only aggravated liver injury in the rat model. The effect of PNS combined with atorvastatin on liver function was significantly better than that of atorvastatin aloneThe combined use of PNS and atorvastatin showed good stability of liver function on the liver injury combined with atherosclerosis model. Abbreviations used: PNS: Panax notoginseng saponins; AS: Atherosclerosis; TC: Total cholesterol; TG: Triglyceride; HDL-C: High density lipoprotein-cholesterol; LDL-C: Low density lipoprotein-cholesterol; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; T BIL: Total bilirubin; r-GT: R-glutamyltransferase; HE: Hematoxylin-eosin. PMID- 28839369 TI - Rapid Detection of Volatile Oil in Mentha haplocalyx by Near-Infrared Spectroscopy and Chemometrics. AB - : Near-infrared spectroscopy combined with partial least squares regression (PLSR) and support vector machine (SVM) was applied for the rapid determination of chemical component of volatile oil content in Mentha haplocalyx. The effects of data pre-processing methods on the accuracy of the PLSR calibration models were investigated. The performance of the final model was evaluated according to the correlation coefficient (R) and root mean square error of prediction (RMSEP). For PLSR model, the best preprocessing method combination was first-order derivative, standard normal variate transformation (SNV), and mean centering, which had of 0.8805, of 0.8719, RMSEC of 0.091, and RMSEP of 0.097, respectively. The wave number variables linking to volatile oil are from 5500 to 4000 cm-1 by analyzing the loading weights and variable importance in projection (VIP) scores. For SVM model, six LVs (less than seven LVs in PLSR model) were adopted in model, and the result was better than PLSR model. The and were 0.9232 and 0.9202, respectively, with RMSEC and RMSEP of 0.084 and 0.082, respectively, which indicated that the predicted values were accurate and reliable. This work demonstrated that near infrared reflectance spectroscopy with chemometrics could be used to rapidly detect the main content volatile oil in M. haplocalyx. SUMMARY: The quality of medicine directly links to clinical efficacy, thus, it is important to control the quality of Mentha haplocalyx. Near-infrared spectroscopy combined with partial least squares regression (PLSR) and support vector machine (SVM) was applied for the rapid determination of chemical component of volatile oil content in Mentha haplocalyx. For SVM model, 6 LVs (less than 7 LVs in PLSR model) were adopted in model, and the result was better than PLSR model. It demonstrated that near infrared reflectance spectroscopy with chemometrics could be used to rapidly detect the main content volatile oil in Mentha haplocalyx. Abbreviations used: 1st der: First-order derivative; 2nd der: Second-order derivative; LOO: Leave-one-out; LVs: Latent variables; MC: Mean centering, NIR: Near-infrared; NIRS: Near infrared spectroscopy; PCR: Principal component regression, PLSR: Partial least squares regression; RBF: Radial basis function; RMSEC: Root mean square error of cross validation, RMSEC: Root mean square error of calibration; RMSEP: Root mean square error of prediction; SNV: Standard normal variate transformation; SVM: Support vector machine; VIP: Variable Importance in projection. PMID- 28839370 TI - Optimization of Surfactant-Mediated, Ultrasonic-assisted Extraction of Antioxidant Polyphenols from Rattan Tea (Ampelopsis grossedentata) Using Response Surface Methodology. AB - BACKGROUND: Rattan tea is a medicinal plant that has been used for many years for the treatment of inflammation, fatty liver, tumor, diabetes, and hyperlipidemia. OBJECTIVE: A green and novel approach based on surfactant-mediated, ultrasonic assisted extraction (SM-UAE) was developed for the extraction of antioxidant polyphenols from Rattan tea. A nonionic surfactant Tween-80 was selected as extraction solvent. The antioxidant activity was measured by total phenolic content (TPC) and ferric-reducing/antioxidant capacity (FRAC) assay. MATERIALS AND METHODS: Optimization of extraction parameters including concentration of solvent, ultrasonic time, and temperature were investigated by response surface methodology. The antioxidant activity was measured by TPC and FRAC assay. RESULTS: The optimal extraction conditions were determined as 6.8% (v/v) of aqueous Tween-80, ultrasonic temperature of 54 degrees C, and ultrasonic time of 28.8 min. Under these conditions, the highest TPC value of 360.4 mg gallic acid equivalent per gram of dry weight material (GAE/g DW) was recorded. Moreover, 6.8% (v/v) of aqueous Tween-80, ultrasonic temperature of 54.5 degrees C, and ultrasonic time of 28.4 min were determined for the highest FRAC value of 478.2 MUmol of Fe2+/g of weight material (MUmol Fe2+/g DW). Compared with other methods, the TPC and FRAC values of 313.5 mg GAE/g DW and 389.6 MUmol Fe2+/g DW were obtained by heat reflux extraction using ethanol as solvent, respectively, and 343.2 mg GAE/g DW and 450.1 MUmol Fe2+/g DW were obtained by UAE using ethanol as solvent, respectively. CONCLUSION: The application of SM-UAE markedly decreased extraction time or extraction cost and improved the extraction efficiency, compared with the other methods. SUMMARY: Surfactant-mediated ultrasonic-assisted extraction of antioxidant polyphenols from Rattan TeaResponse surface methodology used to optimize parameters and study combined effectsOptimized surfactant-mediated ultrasonic-assisted extraction process enhances the antioxidant phenolics extraction in less time. Abbreviations used: SM-UAE: Surfactant-mediated ultrasonic-assisted extraction; TPC: total phenolic content; FRAC: Ferric reducing antioxidant capacity; RSM: Response surface methodology; BBD: Box-Behnken design. PMID- 28839371 TI - Berberine Depresses Contraction of Smooth Muscle via Inhibiting Myosin Light chain Kinase. AB - BACKGROUND: Berberine is a natural isoquinoline alkaloid possessing various pharmacological effects, particularly apparent in the treatment of diarrhea, but the underlying mechanism remains unclear. Smooth muscle myosin light-chain kinase (MLCK) plays a crucial role in the smooth muscle relaxation-contraction events, and it is well known that berberine can effectively depress the contraction of smooth muscle. Hence, whether berberine could inhibit MLCK and then depress the smooth muscle contractility might be researched. OBJECTIVE: The purpose of this study is to investigate the effects of berberine on MLCK. Based on this, the contractility of gastro-intestine, catalysis activity of MLCK, and molecular docking are going to be evaluated. MATERIALS AND METHODS: The experiment of smooth muscle contraction was directly monitored the contractions of the isolated gastrointestine by frequency and amplitude at different concentration of berberine. The effects of berberine on MLCK were measured in the presence of Ca2+ calmodulin, using the activities of 20 kDa myosin light chain (MLC20) phosphorylation, and myosin Mg2+-ATPase induced by MLCK. The docking study was conducted with expert software in the meantime. RESULTS: The phosphorylation of myosin and the Mg2+-ATPase activity is reduced in the presence of berberine. Moreover, berberine could inhibit the contractibility of isolated gastric intestine smooth muscle. Berberine could bind to the ATP binding site of MLCK through hydrophobic effect and hydrogen bonding according to the docking study. CONCLUSION: The present work gives a deep insight into the molecular mechanism for the treatment of diarrhea with berberine, i.e., berberine could suppress the contractility of smooth muscle through binding to MLCK and depressing the catalysis activity of MLCK. SUMMARY: Berberine significantly reduced the amplitude of contraction in isolated duodenum and gastric strips in ratsBerberine inhibited the phosphorylated extents of MLC20 and Mg2+-ATPase activity of phosphorylated myosin induced by MLCKBerberine binds to the ATP binding site of MLCK by hydrophobic effect and hydrogen bondingBerberine may modulate contraction of smooth muscle by inhibiting MLCK. Abbreviations used: MLCK: Myosin light chain kinase; MLC20: 20 KDa regulating myosin light chain; CaM: Calmodulin. PMID- 28839372 TI - Quassinoids from the Root of Eurycoma longifolia and Their Antiproliferative Activity on Human Cancer Cell Lines. AB - BACKGROUND: The roots of Eurycoma longifolia Jack have traditionally been used as an aphrodisiac tonic besides the other remedies for boils, fever, bleeding gums, and wound ulcer. Recently, the antiproliferative activity of E. longifolia has been reported and remained attractive to natural chemists. OBJECTIVE: The objective of this study was to study on antiproliferative compounds from the root of E. longifolia. MATERIALS AND METHODS: Column chromatography was used to separate individual compounds, spectroscopic data including nuclear magnetic resonances and mass spectrometry were analyzed to determine the chemical structure of the isolates and for biological testing, antiproliferative activity of compounds was tested on seven human cancer cell lines (KATO III, HCT-15, Colo205, HepG2, PC-3, Jurkat, HL-60) by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide method. RESULTS: Nine quassinoids including a new C19 longilactone-type quassinoid glycoside were characterized from the roots of the title plant. Among them, the major quassinoid eurycomanone exhibited selectively potential antiproliferative activities on the leukemia cell lines (HL-60 and Jurkat) and had very low toxic effects on normal skin fibroblast cell line (NB1RGB). CONCLUSION: The current study reveals one new quassinoid glycoside and the potential active component (eurycomanone) from E. longifolia for the leukemia treatment. SUMMARY: Nine quassinoids (1-9) including one new quassinoid glycoside (9) and eight known ones were isolated from the roots of Eurycoma longifoliaThe structure of the new quassinoid 9 was determined by extensive chemical and spectroscopic analysesThe major quassinoid, eurycomanone (3), exhibited selectively potential antiproliferative activities on both Jurkat and HL-60 leukemia cells and had very low toxic effects on normal skin fibroblast cell line (NB1RGB). Abbreviations used: COSY: Correlation spectroscopy; HMBC: Heteronuclear multiple-bond correlation; HMQC: Heteronuclear multiple quantum correlation; NMR: Nuclear magnetic resonance; NOESY: Nuclear Overhauser enhancement spectroscopy; TLC: Thin layer chromatography. PMID- 28839373 TI - Comparative Analysis of Transcriptomes of Macrophage Revealing the Mechanism of the Immunoregulatory Activities of a Novel Polysaccharide Isolated from Boletus speciosus Frost. AB - BACKGROUND: The mechanism of the immunoregulatory activities of polysaccharide is still not clear. MATERIALS AND METHODS: Here, we performed the B-cell, T-cell, and macrophage cell proliferation, the cell cycle analysis of macrophage cells, sequenced the transcriptomes of control group macrophages, and Boletus speciosus Frost polysaccharide (BSF-1) group macrophages using Illumina sequencing technology to identify differentially expressed genes (DEGs) to determine the molecular mechanisms of immunomodulatory activity of BSF-1 in macrophages. RESULTS: These results suggested that BSF-1 could promote the proliferation of B cell, T-cell, and macrophages, promote the proliferation of macrophage cells by abolishing cell cycle arrests in the G0/G1 phases, and promote cell cycle progression in S-phase and G2/M phase, which might induce cell division. A total of 12,498,414 and 11,840,624 bp paired-end reads were obtained for the control group and BSF-1 group, respectively, and they corresponded to a total size of 12.5 G bp and 11.8 G bp, respectively, after the low-quality reads and adapter sequences were removed. Approximately 81.83% of the total number of genes (8,257) were expressed reads per kilobase per million mapped reads (RPKM >=1) and more than 1366 genes were highly expressed (RPKM >60) in the BSF-1 group. A gene ontology-enrichment analysis generated 13,042 assignments to cellular components, 13,094 assignments to biological processes, and 13,135 assignments to molecular functions. A Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the mitogen-activated protein kinase (MAPK) signaling pathways are significantly enriched for DEGs between the two cell groups. CONCLUSION: An analysis of transcriptome resources enabled us to examine gene expression profiles, verify differential gene expression, and select candidate signaling pathways as the mechanisms of the immunomodulatory activity of BSF-1. Based on the experimental data, we believe that the significant antitumor activities of BSF-1 in vivo mainly involve the MAPK signaling pathways. SUMMARY: Boletus speciosus Frost-1 (BSF-1) could promote the proliferation of B-cell, T-cell, and macrophages, promote the proliferation of macrophage cells by abolishing cell cycle arrests in the G0/G1 phases, and promote cell cycle progression in S-phase and G2/M phase, which might induce cell divisionApproximately 81.83% of the total number of genes (8257) were expressed (reads per kilobase per million mapped reads [RPKM] =1) and more than 1366 genes were highly expressed (RPKM >60) in the BSF-1 groupA gene ontology-enrichment analysis generated 13,042 assignments to cellular components, 13,094 assignments to biological processes, and 13,135 assignments to molecular functionsA Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the mitogen-activated protein kinase signaling pathways are significantly enriched for DEGs between the two cell groups. Abbreviations used: BSF-1: Boletus speciosus Frost polysaccharide. PMID- 28839374 TI - Hepatoprotective Flavonoids in Opuntia ficus-indica Fruits by Reducing Oxidative Stress in Primary Rat Hepatocytes. AB - BACKGROUND: Liver disorder was associated with alcohol consumption caused by hepatic cellular damages. Opuntia ficus-indica fruit extracts (OFIEs), which contain betalain pigments and polyphenols including flavonoids, have been introduced as reducing hangover symptoms and liver protective activity. OBJECTIVE: To evaluate hepatoprotective activity of OFIEs and isolated compounds by high-speed countercurrent chromatography (HSCCC). MATERIALS AND METHODS: The extract of O. ficus-indica fruits was fractionated into methylene chloride and n butanol. The n-butanol fraction was isolated by HSCCC separation (methylene chloride-methanol-n-butanol-water, 5:4:3:5, v/v/v/v). The hepatoprotective activity of OFIEs and isolated compounds was evaluated on rat primary hepatocytes against ethanol-induced toxicity. Antioxidative parameters such as glutathione reductase and glutathione peroxidase (GSH-Px) enzymes and the GSH content were measured. RESULTS: Two flavonoids, quercetin 3-O-methyl ester (1) and (+) taxifolin, and two flavonoid glycosides, isorhamnetin 3-O-beta-d-glucoside (3) and narcissin (4), were isolated from the n-butanol fraction by HSCCC separation. Among them, compound 2 significantly protected rat primary hepatocytes against ethanol exposure by preserving antioxidative properties of GR and GSH-Px. CONCLUSIONS: OFIEs and (+)-taxifolin were suggested to reduce hepatic damage by alcoholic oxidative stress. SUMMARY: Hepatoprotective Flavonoids were isolated from Opuntia ficus-indica by high -speed countercurrent chromatography (HSCCC). PMID- 28839375 TI - Preparation and Bioactivity of Exopolysaccharide from an Endophytic Fungus Chaetomium sp. of the Medicinal Plant Gynostemma Pentaphylla. AB - BACKGROUND: Many exopolysaccharides from the endophytes in medicinal plants possess various potential bioactivities. MATERIALS AND METHODS: The endophytic fungus JY25 was isolated from the leave of the Chinese medicinal plant Gynostemma pentaphylla and identified as Chaetomium sp. by its phylogenetic and physiological analysis. One exopolysaccharide (EPS) fraction was isolated from the fermentation broth by ethanol precipitation and purified by gel filtration chromatography on Sepharose CL-6B. The molecular characteristics were examined by GC-MS, FT-IR, and multiangle laser light scattering (MALLS). RESULTS: The monosaccharide composition analysis indicated that the purified EPS was mainly composed of glucose, mannose, arabinose, and galactose with the molecular ratio of 78.29: 8.99: 8.64: 4.08. FT-IR spectral analysis of the purified EPS revealed prominent characteristic groups, such as carbonyl bond, pyranose ring, and so on. The weight-average molar mass and the polydispersity ratio of the EPS were revealed to be 1.961*104 g/mol and 1.838, respectively. Furthermore, thermo gravimetric analysis (TGA) indicated that the degradation temperature of the purified EPS was 305 degrees C. The purified EPS from the endophytic fungus Chaetomium sp. displayed antioxidant and antiproliferative activities. CONCLUSION: The results demonstrated that the EPS could be used as a healthful food and material source in pharmaceutical industries. SUMMARY: An exopolysaccharides (EPS) with antioxidant and antiproliferative activities from an endophytic fungus Chaetomium sp. was reported. Abbreviations used: ANOVA: Analysis of variance; DPPH: 2,2-diphenyl-1-picrylhydrazyl; EPS: Exopolysaccharide; FT-IR: Fourier transform infrared spectroscopy; GC-MS: Gas chromatography-mass spectrometry; Mw: Mass weight; MALLS: Multiangle laser light scattering; SEC: Size Exclusion Chomatography; SPSS: Statistical Package of the Social Science; TGA: Thermo gravimetric analysis; TFA: Trifluoroacetic acid. PMID- 28839376 TI - Decoction of Dictamnus Dasycarpus Turcz. Root Bark Ameliorates Skin Lesions and Inhibits Inflammatory Reactions in Mice with Contact Dermatitis. AB - BACKGROUND: The root bark of Dictamnus dasycarpus Turcz. (Dictamni Radicis Cortex) has been widely used to treat skin diseases in Korea, and its anti inflammatory efficacies were recently reported. OBJECTIVE: The paper aims to investigate the inhibitory effects of decoction of Dictamni Radicis Cortex (DDRC) in mice with contact dermatitis (CD). MATERIALS AND METHODS: We investigated the effects of DDRC on skin lesion characteristics such as crust, scales, incrustation and petechiae, the erythema and melanin indexes, skin thickness, histopathologic changes, and cytokine production in 1-fluoro-2,4 dinitrofluorobenzene (DNFB)-induced CD mice. RESULTS: Topical application of DDRC ameliorated crust, scales, incrustation, and induced by DNFB. In addition, DDRC lowered the erythema index significantly (P < 0.05). DDRC effectively inhibited enlargement of skin thickness (P < 0.05). Histopathologic observation showed that DDRC inhibited epidermal hyperplasia, hyperkeratosis, and spongiotic changes. Finally, DDRC decreased production levels of IFN-gamma, TNF-alpha and IL-6 induced by repeated application of DNFB (P < 0.05). CONCLUSION: These data suggest that DDRC can be used in the treatment of inflammatory skin diseases including CD. Moreover, these results are closely related to the decreasing production of TNF-alpha IFN-gamma and IL-6 in inflamed tissues. SUMMARY: DDRC ameliorated skin lesions such as crust, scales, incrustation and petechiae, and lowered erythema index on skin surface in CD miceDDRC inhibited enlargement of dorsal skin and prevented epidermal hyperplasia, hyperkeratosis, and spongiotic changes in inflamed tissuesDDRC reduced the levels of TNF-alpha, IFN-gamma, and IL-6 in inflamed tissues of CD miceDDRC did not affect spleen/body weight ratio in CD mice. Abbreviations used: DDRC: decoction of Dictamni Radicis Cortex, CD: contact dermatitis, DNFB: 1-fluoro-2,4-dinitrofluorobenzene, AOO: acetone and olive oil, DEX: dexamethasone, CBA: cytometric bead array. PMID- 28839377 TI - Flavones and Lignans from the Stems of Wikstroemia scytophylla Diels. AB - BACKGROUND: The genus Wikstroemia has about 70 species, but only a limited number of species have been studied chemically. Wikstroemia indica has long been used as a traditional crude drug in China. However, there is no report about the bioactivity of Wikstroemia scytophylla. OBJECTIVE: This paper reports the chemical investigation and biological evaluation of the W. scytophylla. MATERIALS AND METHODS: The EtOAc extraction of W. scytophylla was isolated using chromatographic methods, and the compounds were analyzed by spectroscopic methods. The in vitro antitumor activities against five human cancer cell lines were performed according to the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide method. RESULTS: The chemical investigation of the stems of W. scytophylla resulted in the isolation of 12 compounds mainly including one biflavone (1), five flavones (2-6) compounds, and six lignans (7 12), in which compound 8 was a new natural product. Compounds 1 and 7-12 were evaluated for their antitumor activities while these compounds showed weak cytotoxicity with the half maximal inhibitory (IC50) values more than 40 MUM. CONCLUSION: All of these compounds were isolated from this plant for the first time, and compounds 2-12 were first reported from genus Wikstroemia, in which compound 8 was a new natural product. Compounds 1 and 7-12 exhibited weak antitumor activities (IC50>40 MUM). The chemotaxonomic significance of all the isolations was summarized. SUMMARY: The chemical investigation of the stems of W. scytophylla resulted in the isolation of 12 compoundsThe 12 compounds including six lignans (7-12), in which compound 8 was a new natural productThe isolated compounds 1 and 7-12 were evaluated for their antitumor activitiesThe chemotaxonomic significance of all the isolations was summarized. Abbreviations used: MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; IC50: Half maximal inhibitory; HL-60: Human leukemia cell line; SMMC-7721: Human hepatocellular carcinoma cell line; A549: Human lung tumor cell line; MCF-7: Human breast cancer cell line; SW480: Human colon cancer cell line; MS: Mass spectrometry; NMR: Nuclear Magnetic Resonance. PMID- 28839378 TI - A Novel Quantitative Prediction Approach for Astringency Level of Herbs Based on an Electronic Tongue. AB - BACKGROUND: The current astringency evaluation for herbs has become dissatisfied with the requirement of pharmaceutical process. It needed a new method to accurately assess astringency. METHODS: First, quinine, sucrose, citric acid, sodium chloride, monosodium glutamate, and tannic acid (TA) were analyzed by electronic tongue (e-tongue) to determine the approximate region of astringency in partial least square (PLS) map. Second, different concentrations of TA were detected to define the standard curve of astringency. Meanwhile, coordinate concentration relationship could be obtained by fitting the PLS abscissa of standard curve and corresponding concentration. Third, Chebulae Fructus (CF), Yuganzi throat tablets (YGZTT), and Sanlejiang oral liquid (SLJOL) were tested to define the region in PLS map. Finally, the astringent intensities of samples were calculated combining with the standard coordinate-concentration relationship and expressed by concentrations of TA. Then, Euclidean distance (Ed) analysis and human sensory test were processed to verify the results. RESULTS: The fitting equation between concentration and abscissa of TA was Y = 0.00498 * e(-X/0.51035) + 0.10905 (r = 0.999). The astringency of 1, 0.1 mg/mL CF was predicted at 0.28, 0.12 mg/mL TA; 2, 0.2 mg/mL YGZTTs was predicted at 0.18, 0.11 mg/mL TA; 0.002, 0.0002 mg/mL SLJOL was predicted at 0.15, 0.10 mg/mL TA. The validation results showed that the predicted astringency of e-tongue was basically consistent to human sensory and was more accuracy than Ed analysis. CONCLUSION: The study indicated the established method was objective and feasible. It provided a new quantitative method for astringency of herbs. SUMMARY: The astringency of Chebulae Fructus, Yuganzi throat tablets, and Sanlejiang oral liquid was predicted by electronic tongueEuclidean distance analysis and human sensory test verified the resultsA new strategy which was objective, simple, and sensitive to compare astringent intensity of herbs and preparations was provided. Abbreviations used: CF: Chebulae Fructus; E-tongue: Electronic tongue; Ed: Euclidean distance; PLS: Partial least square; PCA: Principal component analysis; SLJOL: Sanlejiang oral liquid; TA: Tannic acid; VAS: Visual analog scale; YGZTT: Yuganzi throat tablets. PMID- 28839379 TI - Characterization of Nano Bamboo Charcoal Drug Delivery System for Eucommia ulmoides Extract and Its Anticancer Effect In vitro. AB - BACKGROUND: Nano bamboo charcoal is being widely used as sustained release carrier for chemicals for its high specific surface area, sound biocompatibility, and nontoxicity; however, there have been no reports on nano bamboo charcoal as sustained release carrier for traditional Chinese medicine (TCM). OBJECTIVE: To study the effect of nano bamboo charcoal in absorbing and sustained releasing Eucommia ulmoides extract (EUE) and to verify the in vitro anticancer effect of the sustained release liquid, so as to provide a theoretical basis for the development and utilization of nano bamboo charcoal as TCM sustained-release preparation. MATERIALS AND METHODS: The adsorption capacity for the nano bamboo charcoal on EUE was measured by Langmuir model, and the release experiment was carried out under intestinal fluid condition. Characteristic changes for the nano bamboo charcoal nano-drug delivery system with and without adsorption of E. ulmoides were evaluated by scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and specific surface area. In addition, the anticancer effect from this novel bamboo charcoal E. ulmoides delivery system was evaluated against a human colon cancer cell line (HCT116). RESULTS: It was found that nano bamboo charcoal exhibits good adsorption capacity (up to 462.96 mg/g at 37 degrees C). The cumulative release rate for EUE from this nano bamboo charcoal delivery system was 70.67%, and specific surface area for the nano bamboo charcoal decreased from 820.32 m2/g to 443.80 m2/g after EUE was loaded. An in vitro anticancer study showed that the inhibition rate for E. ulmoides against HCT116 cancer cells was 23.07%, for this novel bamboo charcoal nano-drug delivery system. CONCLUSION: This study provides a novel strategy for the delivery of traditional Chinese medicine using bamboo charcoal nano-drug delivery system. SUMMARY: The adsorption equilibrium was reached after 30 min of ultrasonic treatmentThe saturated adsorption capacity of Eucommia ulmoides extract by nano bamboo charcoal under ultrosonic condition was 462. 96 mg/gThe cumulative release rate of E. ulmoides extract from the nano bamboo charcoal delivery system in artificial intestinal juice was 70.67%The inhibition ratio of HCT116 cancer cells by sustained release liquid was 23.07%. Abbreviation used: EUE: Eucommia ulmoides extract. PMID- 28839380 TI - Optimization of Polysaccharide Ultrasonic Extraction Conditions Using Purple Sweet Potato Tubers Based on Free Radical Scavenging and Glycosylation Inhibitory Bioactivities. AB - BACKGROUND: The purple sweet potato, Ipomoea batatas, belongs to the family Convolvulaceae. It is one of the most widely consumed tubers in Asia and is found in many dishes. Many people with diabetes eat purple sweet potato tubers to help reduce blood glucose in China. OBJECTIVE: To predict the ultrasonic conditions for getting the optimal in vitro antioxidant and antiglycated activity of ultrasonic extracted polysaccharides from purple sweet potato (I. batatas) tubers, the artificial neural network (ANN) regression models was used in this study. MATERIALS AND METHODS: The antioxidant activity of polysaccharides was quantified by evaluating the hydroxyl radical scavenging effect after ultrasonic extraction, and the data were used in conjunction with optimized extraction conditions to train the predictive ANN models. RESULTS: The following conditions were predicted to yield optimal hydroxyl scavenging activity: 200 W, 22 degrees C, and 40 min. In contrast, conditions of 230 W, 22 degrees C, and 50 min yielded the greatest inhibitory effect on albumin nonenzymatic glycosylation. The accuracy and predictive ability of the models ranged from good to excellent, as indicated by R2 values ranging from 0.953 to 0.998. CONCLUSION: The results of the present study showed that ANN predictive models are useful in ultrasonic processing, which can rapidly and accurately predict the optimum extraction conditions for polysaccharides based on their antioxidant and antiglycated activities. In addition, the results of the present study suggest that the consumption of sweet potatoes may help reduce free radicals in the body and prevent or treat diabetes. SUMMARY: Ultrasonic extraction conditions were simulated and optimized using artificial neural networkBioactivities showed nonlinear relationship with ultrasonic conditionsThe optimal extraction conditions were 200 W, 22 degrees C, and 40 min for the highest antioxidant capacityThe optimal extraction conditions were 230 W, 22 degrees C, and 50 min for the highest antiglycated effect. Abbreviations used: IBP: Polysaccharide of Ipomoea batatas; RSM: response surface methodology; ANN: Artificial neural network; BSA: Bovine serum albumin. PMID- 28839381 TI - Anti-epileptic Effects of Valepotriate Isolated from Valeriana jatamansi Jones and Its Possible Mechanisms. AB - OBJECTIVE: This work aimed to investigate the anti-epileptic effects of valepotriate isolated from Valeriana jatamansi Jones and studied its possible mechanisms. METHODS: The anti-epileptic effects of valepotriate were studied using maximal electroshock-induced seizure (MES), pentylenetetrazole (PTZ) induced epilepsy, and pentobarbital sodium-induced sleeping model in mice. The possible anti-epileptic mechanisms of valepotriate were investigated by analyzing the expressions of GABAA, GABAB, glutamic acid decarboxylase (GAD65), Bcl-2, and caspase-3 in the brain using Western blot assay. RESULTS: The results indicated that valepotriate showed significant anti-epileptic activity against MES- and PTZ induced epilepsy at doses of 5, 10, and 20 mg/kg, and ED50 values for MES- and PTZ-induced epilepsy were 7.84 and 7.19 mg/kg, respectively. Furthermore, valepotriate (10 and 20 mg/kg) can significantly prolong sleeping time and shorten the latency time on the pentobarbital sodium-induced sleeping time test. Furthermore, valepotriate (5, 10, and 20 mg/kg) could significantly up-regulate the expression of GABAA, GAD65, and Bcl-2 and down-regulate the expression of caspase-3, but had no significant effect on the expression of GABAB. CONCLUSION: The results indicated that valepotriate had anti-epileptic activity and the mechanisms might be associated with regulation of GABA and inhibition of neuronal apoptosis. SUMMARY: Anti-epileptic effect of valepotriate was investigated for the 1st timeValepotriate showed notable anti-epileptic activityValepotriate can significantly increase the expression of GABAA, glutamic acid decarboxylase 65, and Bcl-2 and reduce the expression of caspase-3. PMID- 28839382 TI - Sugemule-3 Protects against Isoprenaline-induced Cardiotoxicity In vitro. AB - BACKGROUND: Sugemule-3 (SD) is a traditional Chinese medicine with protective effect of myocardium. However, the underlying mechanisms of the effect had not been elucidated. MATERIALS AND METHODS: In the present study, the serum of SD was prepared. A model of beta-adrenergic agonist isoprenaline (ISO)-induced H9c2 cardiomyocytes injury was established in vitro. The changes in cell viability were examined to determine the available concentration of ISO and serum of SD. ELISA, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, and flow cytometry were used to detect the effect of serum of SD on oxidative stress and apoptosis. The expression levels of the mitochondria dependent apoptotic pathway and mitogen-activated protein kinase signalling related proteins were analyzed. RESULTS: Incubation with different dose of ISO (0.015, 0.01, 0.005, and 0.0025 mol/L) for 24 h caused dose-dependent loss of cell viability and 0.01 mol/L of ISO approximately reduced the cell viability to 50%. Pretreatment with 50 MU mol/L serum of SD effectively decreased the levels of ISO-induced cell toxicity. Serum of SD relived ISO-induced oxidative stress and apoptosis in H9c2 cardiomyocytes. A further mechanism study indicated that serum of SD inhibited the mitochondria-dependent apoptotic pathways and regulated the expression levels of Bcl-2 family. ISO activated ERK and P38, whereas serum of SD inhibited their activation. CONCLUSION: Serum of SD inhibits the ISO induced activation of the mitochondria-dependent apoptotic pathway, oxidative stress, and ERK, P38 inactivation. Serum of SD is used for the treatment of ISO induced cardiomyopathy. SUMMARY: The serum of SD pretreatment significantly ameliorated ISO-induced H9c2 cardiomyocytes injuries.The protective effect related with apoptosis and oxidative stressInhibition of MAPK pathway was involed in serum of SD induced cardioprotection.The serum of SD is used for the treatment of ISO-induced cardiomyopathy. Abbreviations used: ELISA: Enzyme-linked Immunosorbent Assay; TUNEL: TdT-mediated dUTP nick end labeling; MTT: 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, DMSO: dimethyl sulfoxide; MDA: Malondialdehyde; SOD: Superoxide Dismutase; GSH-Px: Glutathione peroxidase. PMID- 28839384 TI - Quality Evaluation of Raw Moutan Cortex Using the AHP and Gray Correlation-TOPSIS Method. AB - BACKGROUND: Raw Moutan cortex (RMC) is an important Chinese herbal medicine. Comprehensive and objective quality evaluation of Chinese herbal medicine has been one of the most important issues in the modern herbs development. OBJECTIVE: To evaluate and compare the quality of RMC using the weighted gray correlation- Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) method. MATERIALS AND METHODS: The percentage composition of gallic acid, catechin, oxypaeoniflorin, paeoniflorin, quercetin, benzoylpaeoniflorin, paeonol in different batches of RMC was determined, and then adopting MATLAB programming to construct the gray correlation-TOPSIS assessment model for quality evaluation of RMC. RESULTS: The quality evaluation results of model evaluation and objective evaluation were consistent, reliable, and stable. CONCLUSION: The model of gray correlation-TOPSIS can be well applied to the quality evaluation of traditional Chinese medicine with multiple components and has broad prospect in application. SUMMARY: The experiment tries to construct a model to evaluate the quality of RMC using the weighted gray correlation- Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) method. Results show the model is reliable and provide a feasible way in evaluating quality of traditional Chinese medicine with multiple components. PMID- 28839383 TI - Withaferin-A Induces Apoptosis in Osteosarcoma U2OS Cell Line via Generation of ROS and Disruption of Mitochondrial Membrane Potential. AB - BACKGROUND: Withaferin-A (WF-A) is a well-known dietary compound isolated from Withania sominifera. It has tremendous pharmacological potential and has been shown to exhibit antiproliferative activity against several types of cancerous cells. Currently, the main focus of anti-cancer therapeutic development is to identify apoptosis inducing drug-like molecules. Osteosarcoma is a rare type of osteocancer, affecting human. The present study therefore focused on the evaluation of antitumor potential of WF-A against several osteosarcoma cell lines. MATERIALS AND METHODS: MTT assay was used to evaluate WF-A against osteosarcoma cell lines and to calculate the IC50. DAPI staining was used to confirm the apoptosis inducing potential of WF-A. Mitochondrial membrane potential, reactive oxygen species (ROS) assay, and Western blotting were used to confirm the basis of apoptosis. RESULTS: The results revealed that that WF-A exhibited strong antiproliferative activity against all the cells lines, with IC50 ranging from 0.32 to 7.6 MUM. The lowest IC50 (0.32 MUM) was observed against U2OS cell line and therefore it was selected for further analysis. DAPI staining indicated that WF-A exhibited antiproliferative activity via induction of apoptosis. Moreover, WF-A induced ROS-mediated reduction in mitochondrial membrane potential DeltaPsim) in a dose-dependent manner and activation of caspase-3 in osteosarcoma cells. CONCLUSION: We propose that WF-A may prove a potent therapeutic agent for inducing apoptosis in osteosarcoma cell lines via generation of ROS and disruption of mitochondrial membrane potential. SUMMARY: WF A exhibits strong anticancer activity against osteosarcoma cell linesAntiproliferative activity of WF-A is via induction of apoptosisWF-A induced ROS-mediated reduction in mitochondrial membrane potentialWF-A induced expression of caspase-3 in osteosarcoma cells. Abbreviations used: WA: Withaferin A; ROS: Reactive oxygen species; OS: Osteosarcoma; MMP: Mitochondrial membrane potential. PMID- 28839385 TI - Tinea Capitis in Children and Trichoscopic Criteria. AB - Tinea capitis is the most common pediatric superficial dermatophyte infection. The causative species vary, as for instance, Microsporum canis predominates in Europe, while Trichophyton tonsurans predominates in North America. Tinea capitis does not respond well to topical therapy alone, thus oral therapy is requisite. The drug of choice is griseofulvin; however in some countries, it is no longer available. Fungal culture should be requested in the persistent, scalp lesion and trichoscopy can put forward a speedy diagnosis by its characteristic findings. Scalp dermoscopy or "trichoscopy" represents a valuable, noninvasive technique for the evaluation of patients with hair loss due to tenia capitis. It is simple, quick, and easy to perform. PMID- 28839386 TI - Gastric Trichobezoars in Children: Surgical Overview. AB - BACKGROUND: Development of trichobezoars in children is primarily a psychiatric issue more than a pediatric surgical ailment. A definite history of trichotillomania and trichophagia may or may not be elicited. Surgical removal is required in patients presenting with huge bezoars. Psychiatric follow-up is of utmost importance to avoid recurrence. MATERIALS AND METHODS: Records of children who were diagnosed and managed for the presence of gastric trichobezoars were retrospectively reviewed. RESULTS: Five children presented over past 15 years (2000-2015) with varied presentations ranging from asymptomatic abdominal masses to features of bowel obstruction. There were three adolescent females (aged 10, 12, and 13 years) and two males (aged 2 and 6 years). All had a hugely distended stomach completely filled with the bezoar. After gastrotomy and removal of the bezoar, gastrostomy drainage was provided in three of these five patients whereas the remaining two had nasogastric tube in place. All three with gastrostomy had effective gastric decompression and oral feeds could be established early. On the other hand, remaining two in which gastrostomy was not inserted had prolonged adynamicity of the stomach and delayed establishment of oral feeds. CONCLUSION: A procrastinated history results in a hugely distended stomach which remains adynamic for a long period of time after removal of the bezoar, and decompression by gastrostomy tube drainage in the postoperative period is a feasible option. PMID- 28839387 TI - Scanning Electron Microscopy and X-ray Microanalysis of Reconstructive Hair Fibers. AB - BACKGROUND: Reconstructive hair fibers are an innovative tool in cosmetic dermatology based on electrostatic adherent powder which bonds to the hair shaft and can disguise hair loss in men and women. AIM: This study aims to analyze and compare five different brands of organic hair fibers. MATERIALS AND METHODS: A scanning electron microscope (SEM) was used to obtain amplified images of samples to study their shape and morphological structure. X-ray microanalysis was performed to study the chemical composition of reconstructive hair fibers. The five samples were tested in patients attending a trichology unit of a tertiary hospital. RESULTS: The main component in hair fibers products 1 (Blum SecretTM) and 3 (KeratinTM) was cotton (cellulose of vegetal origin), while product 2 (ViviscalTM) was made of a vegetal keratin. All three samples appeared as parallel-arranged fibres on the scanning electron microscope. The X-ray microanalysis showed an organic polymer mainly composed of C, O, and Si. Hair fibers 4 (ToppikTM) and 5 (NanogenTM) were similar. Sample 4 derived from a keratin organic fiber and sample 5 from pure, positively charged keratin. In both cases, SEM revealed microfibers covered by a fine squamous. The X-ray microanalysis in both cases revealed a high presence of S. CONCLUSION: There was no discrepancy among the cosmetic results of the five samples, providing a successful esthetic effect in all of our patients despite the chemical differences found in the X-ray microanalysis. PMID- 28839388 TI - A Study on Scalp Hair Health and Hair Care Practices among Malaysian Medical Students. AB - INTRODUCTION: Scalp care is essential because it determines the health and condition of the hair and prevents the diseases of scalp and hair. The objectives of our study were to correlate race and hair types, to determine the awareness of hair care among Malaysian medical students, and to distinguish the factors that affect the health of hair and scalp. METHODOLOGY: It was a cross-sectional study wherein validated questionnaires were given to 240 medical undergraduate students who belonged to three ethnic races of Malaysia, i.e., Chinese, Malay, and Malaysian Indians after their informed consent. The results were then analyzed using percentage statistics. RESULTS: Chinese students had comparatively healthier scalp without dandruff. Most Chinese and Indians had silky type of hair while Malay had dry, rough hair. Chinese and Indians colored their hair and used various styling methods; while among the Malays, this percentage was very less. Regarding hair care practices, males used only shampoo and females used shampoo and conditioner for hair wash. Students also faced dietary and examination related stress. CONCLUSION: Results indicate that there exist morphological differences in hair among the studied population. Since most students color their hair and employ various hairstyling methods, they should be educated regarding best hair care practices to improve their scalp hair condition and health. PMID- 28839389 TI - Rare Presentation of Alopecia Universalis Congenita and Twenty-nail Dystrophy in Siblings. AB - Congenital alopecia universalis is one of the rarest anomaly which involves skin and appendages. The inheritance pattern can be autosomal recessive, X-linked recessive, or autosomal dominant. However, the most common is autosomal recessive form and it is the most severe phenotype. Twenty-nail dystrophy refers to the condition in which all the twenty nails are affected in the form of excessive ridging and nail plate roughness leading to unsightly lustureless nails. We report a rare case of two siblings with alopecia universalis congenita with twenty-nail dystrophy. To the best of our knowledge, this case is the first case to be reported with such association in both siblings. This case reports highlights the fact that alopecia areata is an autoimmune disease with a genetic predisposition as in our case both siblings had alopecia universalis and nail dystrophy. There was no evidence of any other ectodermal dyplasia and had normal teeth and seat glands. The skin biopsy ruled out congenital atrichia and was suggestive of alopecia areata. PMID- 28839390 TI - Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome. AB - Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is a rare genetic, oculocutaneous disorder. So far, about forty patients have been reported worldwide. This disorder results from mutations in the membrane-bound transcription factor protease site 2 gene that impairs cholesterol homeostasis and the ability to cope with endoplasmic reticulum stress. We report this rare case of IFAP with atypical presentation and it was interesting to note that alopecia in this child was confined to eyebrows; this unique presentation has not been described earlier. This rare oculocutaneous disorder requires proper documentation so that identification of its variants may be possible in the future. PMID- 28839391 TI - Adult Onset Hair Casts: Nits Which Do Not Itch! AB - Hair casts (HCs) are thin, elongated, firm, whitish cylindrical concretions which ensheath the hair shaft and can be easily dislodge. They are of two different types: peripilar and parakeratotic keratin cast. Due to its clinical resemblance to pediculosis capitis, the entity is also known as pseudonits. Al though not unusual, false diagnoses are common, and thus, it is very important to correctly differentiate it from other similar conditions. We report here a case of HC involving scalp as well as body hair in association with androgenetic alopecia in a 22-year-old male patient. The patient's sister was also affected with pseudonits. PMID- 28839392 TI - Alopecia Areata on Vertex as a Potential Pitfall for Misdiagnosis of Central Centrifugal Cicatricial Alopecia in African-American Women. AB - Trichoscopy is a noninvasive visualization tool used to more accurately diagnose hair and scalp disorders. Alopecia areata (AA) in the patient of African descent can mimic the early signs of central centrifugal cicatricial alopecia (CCCA), especially if the initial presentation of hair loss occurs on the central scalp. Two African-American women presented with singular round-ovoid patches of decreased hair loss on the central scalp. Given the clinical presentation, CCCA was the working diagnosis. However, using dermoscopy, the patients were found to have exclamation hairs and short broken hairs on a background of honeycomb-like pigmented network and regular pinpoint white dots consistent with AA. The diagnosis was confirmed on biopsy. We demonstrate the role of dermoscopy for diagnosing AA in the patient of African descent. PMID- 28839393 TI - Invisible Lichen Planopilaris Unmasked by Dermatoscopy. AB - Lichen planopilaris is a form of lymphocyte-mediated primary cicatricial alopecia characterized by perifollicular scaling progressing to patches of alopecia depending on the clinical variant. The course is relentlessly progressive and chronic. Hence, early diagnosis and institution of therapy are imperative to halt the disease progress. Although definitive diagnosis is made by scalp biopsy, the detection is usually delayed. Dermatoscopy helps in early recognition of this condition which at that stage is clinically invisible. We report a 23-year-old female who presented with hair loss and scalp scaling without clinically obvious patches of alopecia. PMID- 28839394 TI - Eyelash Trichomegaly: A Rare Presenting Feature of Systemic Lupus Erythematosus. AB - An increase in length, curling, pigmentation, or thickness of eyelashes is termed eyelash trichomegaly. It may be inherited as an isolated trait or as a feature of a congenital syndrome such as Oliver-McFarlane syndrome or oculocutaneous albinism. Acquired conditions associated with eyelash trichomegaly include HIV infection, connective tissue disorders, and the administration of drugs such as cyclosporine and topical latanoprost. We hereby report a rare case of acquired eyelash trichomegaly with diffuse hair loss and "lupus hairs" on the scalp in a 16-year-old female diagnosed with systemic lupus erythematosus. PMID- 28839395 TI - Staphylococcus lugdunensis and Trichophyton tonsurans Infection in Synthetic Hair Implants. AB - Synthetic hair implants are considered in alopecia when the patient requests an immediate result with minor surgery and with a poor donor area. However, the procedure has historically been marred by poor quality fiber and performance resulting in serious complications. Nevertheless, companies continue to market the procedure with the claim that previous problems have been sorted out. We report a case of inflammation in synthetic hair implants, in which microbiological studies revealed infection with Staphylococcus lugdunensis and Trichophyton tonsurans. The procedure was performed by a hair stylist. The patient experienced symptoms at the site of the implants. Nevertheless, he had the artificial implants repeated. Despite persistent symptoms of peri implantitis, medical assistance was not sought. It is the view of the International Society of Hair Restoration Surgery that artificial hair fiber implants represent a surgical procedure and as such should be confined to experienced and licensed medical doctors in a reputable medical clinic. As with any surgical procedure, complications may occur which should be handled under a physician's care. Usually, problems result from lack of asepsis during the procedure, lack of patient hygiene, excessive quantity and density of implanted fibers in one session, incorrect choice of implant area, and poor aftercare. In cases, where implant-related problems cannot be resolved within 15 days of antibiotic and anti-inflammatory treatment, an extended microbiological work-up is warranted, and it may be necessary to remove the fibers that may harbor microbial biofilms. PMID- 28839396 TI - Nilotinib-induced Keratosis Pilaris Associated with Alopecia Areata and Eyebrow Thinning. AB - Tyrosine kinase enzymes are an attractive target for anticancer therapies. Tyrosine kinase inhibitors (TKI) are well tolerated; somehow severe systemic side effects are rarely seen during treatment. Toxicities of skin and appendages may lead to poor compliance, psychosocial inconvenience, and drug interruption. Changes of the hair can arise following cures with TKI. Nilotinib, a second generation TKI, has been responsible for various cutaneous side effects including different clinical presentations of alopecia (scarring and nonscarring forms). This paper reports the case of a 45-year-old male diagnosed with chronic myelogenous leukemia (CML) treated with nilotinib, who presented with a keratosis pilaris (KP)-like eruption, autoresolutive alopecia areata plaque of the wrist and diffuse eyebrow thinning. To date, eight cases of nilotinib-induced KP were reported. However, none of them was associated with alopecia areata. Hence, physicians need to be aware of this new cutaneous side effect and investigating the reason of this phenomenon requires additional studies. PMID- 28839397 TI - Discreet Monilethrix: De novo Mutation on the Example of Polish Families. PMID- 28839398 TI - Comment on: Serum Vitamin D3 Levels and Diffuse Hair Fall among the Student Population in South India: A Case-control Study. PMID- 28839399 TI - Linear Morphea Alopecia: New Trichoscopy Findings. PMID- 28839400 TI - Smart Sugar? The Sugar Conspiracy. PMID- 28839401 TI - Digital Imaging in Dentistry: A Review. PMID- 28839402 TI - Comparative Evaluation of Effectiveness of Three Desensitizing Tooth Pastes for Relief in the Dentinal Hypersensitivity. AB - CONTEXT: Dentinal hypersensitivity is a sharp pain occurring on exposure of the exposed dentin to various stimuli such as hot, cold, air, tactile, and chemical. AIM: This study aimed to compare the effectiveness of three desensitizing pastes in the treatment of dentinal hypersensitivity. MATERIALS AND METHODS: A total of 45 individuals (with two teeth per patient) were considered for this study and randomly divided into three groups, Group 1: treated with 5% NovaMin-containing toothpaste, Group 2: treated with 8% arginine-containing toothpaste, and Group 3: herbal desensitizing toothpaste. Using tactile stimulus and air stimulus, the sensitivity scores were recorded on visual analog scale (VAS), immediately after paste application, then at 2 weeks, and then at the end of 4 weeks and compared. RESULTS: There was a significant change in the VAS scores in Group 1 when compared to Group 2 and Group 3. Group 1 showed better reduction in the hypersensitivity in long term. STATISTICAL ANALYSIS: One-way ANOVA test, post hoc Tukey test, and post hoc Bonferroni test were used for statistical analysis. CONCLUSION: Desensitizing pastes can be an effective and economical option in the treatment of the dentinal hypersensitivity. PMID- 28839403 TI - Evaluation of Oral Pentoxifylline in the Management of Oral Submucous Fibrosis - An Ultrasonographic Study. AB - AIM AND OBJECTIVE: To evaluate the therapeutic efficacy of oral pentoxifylline in the treatment of oral submucous fibrosis (OSMF) patients by assessing the clinical symptoms such as burning sensation, mouth opening, and submucosal layer thickness and echogenicity using ultrasonography, both pre- and post-operatively. MATERIALS AND METHODS: Thirty study subjects were included in the study and divided into two groups in single-blind randomized manner, oral pentoxifylline and dexamethasone group. Burning sensation, mouth opening, ultrasonographic submucosal thickness, and echogenicity were recorded both pre- and post operatively. Any adverse effects reported by the patients were also noted. The data collected were statistically analyzed, and response to pentoxifylline and intralesional dexamethasone with hyaluronidase was observed using ultrasonography. RESULTS: A highly significant reduction (P < 0.001) in burning sensation, improvement in mouth opening, and changes in submucosal thickness were noticed in both groups, and significant improvement (P < 0.05) in echogenicity in both the groups was noticed. However, pentoxifylline group showed marginally better improvement than dexamethasone group. CONCLUSION: Pentoxifylline can bring about significant improvement in OSMF, which can be used as better alternative where intralesional steroid was contraindicated or not well tolerated. PMID- 28839404 TI - Comparative Evaluation of the Efficacy of Platelet-rich Fibrin and Calcium Phosphosilicate Putty alone and in Combination in the Treatment of Intrabony Defects: A Randomized Clinical and Radiographic Study. AB - BACKGROUND: Combination of platelet-rich fibrin (PRF) and bone substitutes for the treatment of intrabony pockets is based on sound biologic rationale. The present study aimed to explore the clinical and radiographic effectiveness of autologous PRF and calcium phosphosilicate (CPS) putty alone and in combination in treatment of intrabony defects. MATERIALS AND METHODS: A total of 45 intrabony defects were selected and randomly divided into three groups. In Group I, mucoperiosteal flap elevation followed by placement of PRF was done. In Group II, mucoperiosteal flap elevation followed by placement of CPS putty was done. In Group III, mucoperiosteal flap elevation followed by placement of PRF and CPS putty was done. Clinical parameters such as gingival index (GI), pocket depth (PD), clinical attachment level (CAL), gingival marginal position and radiographic parameters such as bone fill, changes in crestal bone level, and defect depth resolution were recorded at baseline and after 6 months postoperatively. RESULTS: Statistically significant changes in GI, PD reduction, CAL gain, defect fill, and defect depth resolution from baseline to 6 months were seen in all the three groups (P < 0.05). On intergroup comparison, no statistically significant changes were seen in all clinical parameters. However, the difference in defect fill and defect depth resolution between the Groups I and III and Group II and III was significant. CONCLUSION: Within limitations of study, combination of PRF and CPS putty showed a significant improvement in PD reduction, CAL gain, and bone fill. PMID- 28839405 TI - Comparative Alveolar Ridge Preservation Using Allogenous Tooth Graft versus Free dried Bone Allograft: A Randomized, Controlled, Prospective, Clinical Pilot Study. AB - BACKGROUND: For the first time in India, allografts from human extracted teeth were prepared. A randomized, prospective, clinicoradiographical, histological study was conducted to evaluate their efficacy in comparison with freeze-dried bone allograft (FDBA) in alveolar ridge preservation. MATERIALS AND METHODS: Graft preparation: with written consent, teeth were collected from three donors (full mouth extraction cases). Once donors' serums were tested negative for HIV, HBV, HCV, and Venereal disease research laboratory (VDRL), mineralized whole tooth allograft (WTA) and dentin allograft (DA) were prepared using the standard protocol of Tissue Bank at Tata Memorial Hospital, Mumbai, India. STUDY DESIGN: In this randomized controlled trial, 15 patients undergoing extraction of at least four teeth were selected. In each patient after atraumatic extractions, one socket was grafted with WTA, second with DA, third with FDBA, and fourth was left ungrafted (control site). All the sites were covered with chorion membrane. To estimate three-dimensional alveolar crest changes, cone beam computed tomography scans were taken immediately after grafting and 4 months postoperatively. Bone biopsies using 3 mm trephine bur were obtained from four patients at the time of implant placement and evaluated histologically. RESULTS: Clinically uneventful healing was observed at all sites. Compared to other sites, WTA and DA consistently showed superior results demonstrating least reduction in alveolar crest height and width which was statistically significant (P < 0.05). Between WTA and DA sites, there was no statistically significant difference. Histological analysis also confirmed more new bone formation at WTA and DA sites. CONCLUSIONS: Rather than disposing extracted human teeth as a biomedical waste (common practice), they can be collected from suitable systemically healthy donors. With the help of tissue bank, they can be processed into an allograft, serving as an excellent alternative to conventional allografts. PMID- 28839406 TI - An Appraisal of the Prevalence and Attributes of Traumatic Dental Injuries in the Permanent Anterior Teeth among 7-14-Year-Old School Children of North East Delhi. AB - AIMS: The aim of this study was to assess the prevalence, associated risk factors, characteristics, and pattern of traumatic dental injuries (TDIs) in the permanent anterior teeth among school children of North East Delhi area. SETTINGS AND DESIGN: A cross-sectional study was done in 3000 school-going children aged 7 14 years. MATERIALS AND METHODS: A detailed case history and clinical examination were performed on the entire sample population. TDIs were recorded according to Andreasen's epidemiological classification of TDIs including World Health Organization codes. STATISTICAL ANALYSIS USED: For finding the independent association of the significant variables with outcome, multivariable logistic regression analysis was used. RESULTS: A prevalence of 10.7% was observed in the sample being studied. Dental trauma was significantly (P < 0.05) associated with male gender, and high statistical significance (P < 0.001) was noted with age, participation in sports, lip seal, and overjet. Fall of the child while playing by himself/herself was the most common cause; afternoon and schools were the most common time and place of occurrence of TDIs, respectively. Single tooth enamel fractures in the left maxillary central incisors were most commonly seen. Adhesive restorations were the most frequent form of treatment required. CONCLUSIONS: Organizing studies addressing the prevention and treatment needs of TDIs and educational programs aimed toward parents and school teachers are of paramount importance. Furthermore, recognizing the tremendous treatment negligence is extremely critical to adequately analyze indifference of the people toward dental trauma and its consequences. PMID- 28839408 TI - Efficacy of Milk as a Desensitizing Agent for the Treatment of Sensitivity Following Scaling and Root Planing. AB - BACKGROUND: Dentine hypersensitivity (DH) is the most common problem encountered by most of the dentists in their day-to-day clinical practice. It is characterized by a sharp pain or discomfort arising as a response to thermal, chemical, or osmotic stimuli and is caused due to exposure of dentine after the enamel or cementum at the root surface has been lost by the treatment, underlying dental and gingival diseases or physiologic wear and tear of the teeth. This further complicates preventive oral hygiene procedures by the patients, which jeopardize periodontal treatment or may as well aid in periodontal treatment failure. AIM AND OBJECTIVE: To evaluate the efficacy of commercially available milk as a desensitizing agent for the treatment of sensitivity following scaling and root planing. MATERIALS AND METHODS: Patients were selected randomly for scaling and then assessed for sensitivity. Those patients having DH were divided into two groups, wherein the Group A (test) patients were advised to rinse with commercially available milk at room temperature and those in Group B (control) with a commercially available mouthwash (Sentosil-SF). A four-point verbal rating scale was designed to record the numerical value of DH and were recalled for follow-up on 4th, 7th, and 10th day posttreatment. RESULTS: The study demonstrated that there was a considerable reduction in hypersensitivity in both the groups on the 7th and 10th day. In the milk group, eight patients showed a complete reduction in hypersensitivity on 7th day and 13 patients on 10th day, while in the mouthwash group, five patients showed the same on 7th day and ten patients on the 10th day, thus suggesting that more individuals in the milk group were benefited. However, there was no statistically significant difference between the groups in every visit. CONCLUSION: Although there is a vast literature available which suggests the efficacy of commercially available mouthwash in reducing hypersensitivity, this study is the first of its kind which evaluates the efficacy of commercially available milk in reducing sensitivity which is induced postscaling. Considering that milk rinse is cheap and easily available at home, it can be used as a desensitizing agent, and rinsing with milk for few days is effective and stable in quick reduction of hypersensitivity induced by scaling. PMID- 28839407 TI - Smokeless Tobacco: Profiling Sachets and Pattern of Use among Low Socioeconomic Population of Puducherry. AB - BACKGROUND: Tobacco consumption is highest among labor classes and low socioeconomic status (SES), with inclination toward smokeless tobacco (SLT). AIM: The aim of the study was to determine the prevalence and pattern of SLT consumption with secondary objective to profile various sachets of SLT most commonly sold in the study setting. SETTING AND DESIGN: A cross-sectional questionnaire study conducted in rural Puducherry. MATERIALS AND METHODS: A self interviewed structured questionnaire was administered to 150 participants from two villages. Data on education, occupation, and income were collected with details in the form of tobacco consumed, duration of habit, daily consumption, and brand of SLT among other things. Profiling of sachets was done with manufacturing date, date of expiry, presence and absence of warning signs, and name of the manufacturer as parameter. STATISTICAL ANALYSIS: Descriptive analysis was done for frequency distribution and Chi-square test for proportions. RESULTS: The overall prevalence of SLT was 44% with women consuming more than males. 41-50 year-old were highest users of SLT. More than 50% of the participants were unaware of the "pictorial warnings" and 65% did not know about the presence of "contents" on sachets. Pan masala with tobacco was the most preferred form. Only 5 of the 23 commercial brands of sachets had both "pictorial and readable warnings" printed. CONCLUSION: The prevalence of STC was high when compared to the general population. Steps need to be taken to address the adverse effects printed on sachets for low SES populations. The printed warnings need to be inspected regularly. Dual tobacco use is a new addition to the existing list of challenges. PMID- 28839409 TI - Profile Changes and Stability following Distraction Osteogenesis with Rigid External Distraction in Adult Cleft Lip and Palate Deformities. AB - OBJECTIVES: The objective of this study is to analyze the hard and soft-tissue profile changes as well as the upper airway changes after distraction osteogenesis (DO) using rigid external distraction device in adult cleft lip and palate (CLP) patients. The study also evaluates the stability of the surgical result. MATERIALS AND METHODS: Three lateral cephalometric radiographs were taken: Predistraction (T1), postdistraction (T2), and 1 year after distractor removal (T3). The treatment changes (T1 vs. T2) and the stability (T2 vs. T3) were analyzed. The overall treatment changes after 1 year were also evaluated (T1 vs. T3). The lateral cephalograms were digitally analyzed with the help of software named Dolphin. STATISTICAL ANALYSIS USED: Wilcoxon Signed-Ranks test was used, and the probability value (P value) of 0.05 was considered as statistically significant level. RESULTS: Eleven adult patients with CLP were retrospectively analyzed. After distraction, there was a significant mean maxillary advancement of 14 mm (P < 0.01) from a T1 value of 73.54 +/- 10.38 to a T2 value of 88.2 +/- 10.49. The lower facial height and the incisor exposure were significantly increased. The nasolabial angle had a significant improvement of 24.5 degrees (P < 0.01) from a T1 value of 56.6 +/- 21.03 to a T2 value of 81.18 +/- 14.4.The upper airway was significantly improved by 3.7 mm (P < 0.01) with a T1 value of 13.5 +/- 3.8 to a T2 value of 17.2 +/- 3.66. After 1-year follow-up, there was a significant maxillary relapse of 3.20 mm (P < 0.05) from a T2 value of 8.29 +/- 6.84 to a T3 value of 5.09 +/- 5.59. However, the soft-tissue profile and upper airway remained stable. CONCLUSION: The clinician should have an understanding of the related hard and soft tissues as well as airway changes which may assist him when planning for maxillary advancement for CLP patients with DO. There were significant improvements immediately after distraction, but during the 1-year follow-up, some relapse was seen. This stressed on the need for overcorrection of about 35%-40% for adult CLP patients. PMID- 28839410 TI - Effect of Desensitization Using Bioactive Glass, Hydroxyapatite, and Diode Laser on the Shear Bond Strength of Resin Composites Measured at Different Time Intervals: An In vitro Study. AB - BACKGROUND: Dentin desensitizers may change the properties of smear layer and have adverse effects on the bonding performance of adhesive systems. AIM: The aim of this study was to compare the effect of bioactive glass (BG), hydroxyapatite, and diode laser desensitization on shear bond strength of resin composites to dentin at different time intervals. MATERIALS AND METHODS: Seventy-two caries free maxillary premolars were selected. Buccal surfaces were flattened to expose dentin. Teeth were divided into four groups (Groups 1, 2, 3, and 4) according to treatment modality (control with no pretreatment, Sensodyne Repair and Protect, Teethmate Desensitizer, diode laser). Bonding was performed using self-etch adhesive followed by composite buildup. Universal testing machine was used to determine shear bond strengths immediately after bonding, after 3 months, and 5 months storage in artificial saliva. RESULTS: Pretreatment with BG and hydroxyapatite desensitizers increased, whereas diode laser decreased mean shear bond strength of composite to dentin as compared to control group. No statistical significant difference in shear bond strength values was seen in groups after storage. CONCLUSION: Desensitizing toothpastes incorporating remineralizing agents not only occluded open dentinal tubules but also increased shear bond strength of composite to dentin. PMID- 28839411 TI - Long-term Retrospective Study of Implants Placed after Sinus Floor Augmentation with Fresh-frozen homologous block. AB - AIM: The aim of this study was to analyze and follow-up implants placed in the posterior maxillary regions previously grafted with homologous bone. MATERIALS AND METHODS: Forty-one grafts with homologous bone blocks were performed in maxillary sinuses, and 121 implants were placed in premolar and molar regions approximately 6 months after the grafts. Patients were followed up for periods varying from 12 to 124 months after rehabilitation. RESULTS: The results showed two implant failures, for a 98.3% success rate during the follow-up period. DISCUSSION: The implants placed had an average torque of 40 N-cm, regardless of the, design, diameter, and length of the implants used. CONCLUSION: After following up on the implants placed in this study, we concluded that those placed in regions of the maxillary sinuses previously grafted with homologous bone blocks had high long-term success rates and met the functional masticatory requirements. PMID- 28839412 TI - Correlation of ABO Blood Group Phenotype and Rhesus Factor with Periodontal Disease: An Observational Study. AB - BACKGROUND: The knowledge of the ABO blood group phenotype of the patients and their correlation with the periodontal disease maybe important in the development of early treatment strategies, and it would be helpful to target non-responding areas to periodontal therapy of the susceptible individuals. AIMS: The present study was conducted to determine whether there was any correlation between periodontal diseases and ABO blood groups and Rh factor. MATERIAL AND METHOD: This study was carried out on 537 subjects attending Faculty of Dental Sciences OPD in BHU. Subjects were divided into three groups: group I (healthy subjects), group II (subjects with gingivitis), and group III (subjects with periodontitis) based on periodontal examination (Gingival index, Bleeding Index, Probing pocket depth and clinical attachment level). ABO Blood grouping were done and correlated with the periodontal status of study subjects. Statistical Analysis: Data was analyzed using the statistical software namely Statistical Package for the Social Sciences (SPSS, Version 16, IBM Analytics) and Systat 8.0. RESULTS: In this study, there was a greater prevalence of gingivitis in blood group O and periodontitis in blood group B. The blood group AB showed the least prevalence of periodontal diseases. Similarly gingivitis and peridontitis were significantly higher among Rhesus positive groups when compared with Rhesus negative groups. CONCLUSION: Considering the results of this study, it can be concluded that ABO blood groups and Rh factor could be a risk factor for the development of periodontal disease. PMID- 28839413 TI - Evaluation of Salivary Cortisol Changes and Psychological Profiles in Patients with Recurrent Aphthous Stomatitis. AB - BACKGROUND AND OBJECTIVE: Some studies suggest that psychological condition and stress can play role in the development of recurrent aphthous stomatitis (RAS). The purpose of this study was to evaluate salivary cortisol changes and psychological conditions in patients with RAS. MATERIALS AND METHODS: Twenty seven patients (13 males and 14 females, mean age of 32.8 (+/-10.2) years) with minor RAS and 27 age- and sex-matched controls without RAS participated in this study. The concentration of cortisol (nanomole/L) was measured in samples of unstimulated saliva from patients and controls two times; once during the presence of active lesions and once again when the lesions had healed by immunologic assay. The Hospital Anxiety and Depression Scale was employed to determine psychological condition. Visual analog scale for pain severity was recorded for patients with active lesions episode. Data were analyzed by the SPSS software (version 18.0) using paired and unpaired t-tests and Pearson correlation coefficient. RESULTS: Salivary cortisol level was lower in patients during active lesions (12.4 +/- 5.1) and healing (10.5 +/- 3.9) episodes compared to the controls (13.1 +/- 3.6) (P = 0.583, P = 0.015; respectively). There was no significant difference in salivary cortisol between active lesions and healing episodes (P = 0.943). Anxiety and depression represented no significant differences between active lesions and healing episodes (P > 0.05). Anxiety and depression levels in patients were significantly higher than in controls (P < 0.05). Pain severity in active lesions was not significantly correlated to salivary cortisol level, and anxiety or depression scores (P > 0.05). CONCLUSION: The findings showed that occurrence of RAS was associated with anxiety and depression but not with alterations of salivary cortisol level. PMID- 28839414 TI - Effect of Water Storage on the Flexural Strength of Heat-cured Denture Base Resin Reinforced with Stick (s) Glass Fibers. AB - BACKGROUND: Flexural strength (FS) of denture base resins (DBRs) had been improved by reinforcing it with different glass fibers. However, a limited data are available on the effect of glass fiber reinforcement with conventional heat cured resin after prolonged water storage. AIMS AND OBJECTIVES: This study aimed to evaluate the reinforcing effect of novel S-glass and nylon fibers on the FS of acrylic DBRs. It also aimed to evaluate the effect of glass fiber reinforcement on the FS of acrylic DBRs after a prolonged storage in water. MATERIALS AND METHODS: One hundred and sixty identical specimens were fabricated in specially designed molds according to the manufacturer's instructions. The three experimental groups were prepared consisting of conventional (unreinforced) acrylic resin, novel S-glass fiber-reinforced and nylon fiber-reinforced acrylic resin. The specimens were fabricated in a standardized fashion for each experimental group. Each group was further subdivided into two groups on the basis of storage conditions (dry and wet). FS was tested using a three-point universal testing machine at a crosshead speed of 5 mm/min. Glass fiber reinforced group was further tested after prolonged storage in distilled water. Entered data were statistically analyzed with one-way ANOVA and least significant difference post hoc test. RESULTS: In this study, statistically significant differences were noted in the FS of all the groups. S-glass fiber-reinforced group had highest FS compared to the other two groups (P < 0.001). Nylon fiber reinforced group had lowest FS. All the groups stored in distilled water revealed a decrease in strength compared to those stored in dry atmosphere. Among wet specimens, those stored for 3 weeks had a significantly higher FS than those stored at one and 2 weeks (P < 0.01). CONCLUSION: Within the limitations of this investigation, the FS of heat-cured acrylic DBR was improved after reinforcement with glass fibers. It can be recommended to strengthen distal extension partial and complete denture bases. Nylon fibers may not be desirable for strengthening acrylic denture bases. PMID- 28839415 TI - Cervical and Incisal Marginal Discrepancy in Ceramic Laminate Veneering Materials: A SEM Analysis. AB - CONTEXT: Marginal discrepancy influenced by the choice of processing material used for the ceramic laminate veneers needs to be explored further for better clinical application. AIMS: This study aimed to evaluate the amount of cervical and incisal marginal discrepancy associated with different ceramic laminate veneering materials. SETTINGS AND DESIGN: This was an experimental, single blinded, in vitro trial. SUBJECTS AND METHODS: Ten central incisors were prepared for laminate veneers with 2 mm uniform reduction and heavy chamfer finish line. Ceramic laminate veneers fabricated over the prepared teeth using four different processing materials were categorized into four groups as Group I - aluminous porcelain veneers, Group II - lithium disilicate ceramic veneers, Group III - lithium disilicate-leucite-based veneers, Group IV - zirconia-based ceramic veneers. The cervical and incisal marginal discrepancy was measured using a scanning electron microscope. STATISTICAL ANALYSIS USED: ANOVA and post hoc Tukey honest significant difference (HSD) tests were used for statistical analysis. RESULTS: The cervical and incisal marginal discrepancy for four groups was Group I - 114.6 +/- 4.3 MUm, 132.5 +/- 6.5 MUm, Group II - 86.1 +/- 6.3 MUm, 105.4 +/- 5.3 MUm, Group III - 71.4 +/- 4.4 MUm, 91.3 +/- 4.7 MUm, and Group IV - 123.1 +/- 4.1 MUm, 142.0 +/- 5.4 MUm. ANOVA and post hoc Tukey HSD tests observed a statistically significant difference between the four test specimens with regard to cervical marginal discrepancy. The cervical and incisal marginal discrepancy scored F = 243.408, P < 0.001 and F = 180.844, P < 0.001, respectively. CONCLUSION: This study concluded veneers fabricated using leucite reinforced lithium disilicate exhibited the least marginal discrepancy followed by lithium disilicate ceramic, aluminous porcelain, and zirconia-based ceramics. The marginal discrepancy was more in the incisal region than in the cervical region in all the groups. PMID- 28839416 TI - Effect of Nonsurgical Periodontal Therapy on Serum Highly Sensitive Capsule Reactive Protein and Homocysteine Levels in Chronic Periodontitis: A Pilot Study. AB - INTRODUCTION: The aim of the present study was to assess the effect of nonsurgical periodontal therapy on circulating serum high-sensitivity capsule reactive protein (hs-CRP) and homocysteine (Hcy) levels in patients with chronic periodontitis. MATERIALS AND METHODS: The study involved fifty participants. The test group included 25 systemically healthy controls (mean age 38.44 +/- 3.27 years) with severe chronic periodontitis and the control group (n = 25) included age- and sex-matched systemically and periodontally healthy controls. Clinical parameters were recorded, intraoral periapical radiographs were taken, hematological tests and assessment of serum hs-CRP levels and Hcy levels were performed at baseline and 3 months after completion of nonsurgical periodontal therapy. RESULTS: Mean serum hs-CRP and Hcy concentration in patients with chronic periodontitis were 3.37 +/- 0.54 mg/L and 21.47 +/- 7.93 MUmol/L, respectively, and was significantly higher than the controls (1.68 +/- 0.71 mg/L and 13.93 +/- 8.30 MUmol/L, respectively) (P < 0.05). Posttreatment, the mean serum hs-CRP and Hcy concentration reduced significantly in both test and control groups (P < 0.05). CONCLUSION: Chronic periodontitis leads to an increase in circulating levels of hs-CRP and Hcy in plasma and nonsurgical periodontal therapy decreases periodontal inflammation, which in turn reduces systemic inflammation and consequently decreases serum levels of hs-CRP and Hcy. PMID- 28839417 TI - Total Serum Protein Estimation and Its Correlation with Clinical and Histopathological Grading using Masson's Trichrome Stain in Patients of Oral Submucous Fibrosis. AB - OBJECTIVES: Oral submucous fibrosis (OSMF) caused by dense deposition of collagen fibers which is a protein. There is a plethora of research to evaluate degree of collagen deposition using various simple histochemical techniques, but its correlation with total serum protein (TSP) level has not been explored so far. MATERIALS AND METHODS: This case-control study comprised total forty samples with thirty cases of OSMF and ten cases were selected as control group, divided into four groups as per Lai et al. classification. Histological grading was also done according to the Rooban et al.'s classification. Blood sample was collected to evaluate TSP estimation. Findings were tabulated, and comparisons were made between clinical, histological, and TSP estimation. Discrete statistical data were analyzed by Chi-square test, ANOVA, and t-test with a statistical analysis package (SPSS version software 6.0). RESULTS: No significant correlation was obtained between clinical staging and histopathological grading. Definite correlation was obtained in TSP and globulin levels of OSMF patients and their grades of fibrosis histopathologically. CONCLUSION: In the present study, it was observed that biochemical investigations involving assessment of TSP can be used as a diagnostic tool in OSMF, along with histopathological examination. PMID- 28839418 TI - Patient-centered Microsurgical Management of Gingival Recession using Coronally Advanced Flap with Either Platelet-rich Fibrin or Connective Tissue Graft: A Comparative Analysis. AB - PURPOSE: To evaluate autologous platelet-rich fibrin (PRF) and autogenous connective tissue graft (CTG) in gingival recession defects in conjunction with coronally advanced flap (CAF) using a microsurgical technique. MATERIALS AND METHODS: Forty-five Class I and II recession defects were randomly equally (n = 15) divided into three groups: Group I sites treated with CAF with PRF, Group II sites treated with CAF with CTG, and Group III sites treated with CAF alone using microsurgical approach. Parameters recorded were vertical gingival recession (VGR) and horizontal gingival recession (HGR), % complete root coverage (CRC), patient comfort score (PCS), patient esthetic score (PES), and hypersensitivity score (HS) at 10 days, 3 months, and 6 months. RESULTS: CAF surgery alone and in combination with PRF or CTG are effective procedures to cover denuded roots with mean VGR values of 1.26 +/- 0.70 mm (74.4%), 1.26 +/- 0.59 mm (58%), and 1.06 +/- 0.79 mm (53.3%) for Groups I, II, and III, respectively. In terms of CRC achieved at 6 months, results showed that 100% CRC was obtained in 60% sites of Group I, 20% sites of Group II, and 27% sites of Group III. Patient response and acceptance for surgical treatment modality in terms of PCS and PES were highest for Group I (PRF and CAF) followed by Group III and Group II, and there was decrease in HS for Group I (PRF and CAF) while no significant changes in HS were observed for Group II and Group III. At the end of 6 months follow-up, there was a significant increase in gingival thickness measurements using transgingival probing in Group II, whereas nonsignificant changes were observed in Group I and Group III. CONCLUSIONS: A long-term multicenter randomized controlled clinical study may be necessary to evaluate the clinical outcome for autologous PRF in comparison to CTG and CAF alone. PMID- 28839419 TI - Family-Related Factors Associated with Caries Prevalence in the Primary Dentition of 5-6-year-old Children in Urban and Rural Areas of Jabalpur City. AB - AIM: The purpose of this study was to examine the prevalence of dental caries in primary dentition of 5-6-year-old children in urban and rural areas of Jabalpur city. MATERIALS AND METHODS: The present cross-sectional study was conducted in the rural and urban areas of Jabalpur city, India. A power analysis was carried out to select a representative sample of 5-6-year-old children (n = 408), 204 from government schools and 204 from private schools. Parents were interviewed using a self-structured questionnaire to collect data with regard to variables under evaluation. STATISTICAL ANALYSIS: Collected data were subjected to descriptive analysis using the SPSS 12.0 version. Risk factor association with dental caries was investigated using a stepwise logistic regression analysis with P < 0.05 considered significant. RESULTS: This shows significantly higher decayed missing filled teeth among rural children than urban children. It was seen that 46.5% of children whose mothers were illiterate were affected with dental caries. In urban area, 91.5% of children whereas 77% of children in rural area have parental control on sugar consumption. CONCLUSION: It is important to focus on parents' education level when planning preventive programs for young children. Assessing family-related risk factors is essential when instituting preventive/treatment programs for young children. PMID- 28839420 TI - Comparison of Three Different Sealer Placement Techniques: An In vitro Confocal Laser Microscopic Study. AB - INTRODUCTION: Three-dimensional obturation of the root canal system is the final objective of root canal therapy. Greater penetration of sealer in root dentine lesser will be the voids at the dentine-sealer interface. Hence, analysis of the dentin/sealer interface allows the determination of a filling technique which could obturate the root canals with least gaps and voids. Therefore, the aim of this study is to compare the depth and percentage of sealer penetration into root dentin using three different root canal sealer placement techniques under confocal laser scanning microscope. MATERIALS AND METHODS: Thirty single-rooted teeth were selected and prepared. Adseal sealer (Meta Biomed, South Korea) was mixed with Rhodamine B dye and applied using lentulo spiral (Dentsply Maillefer, USA) as Group 1, bidirectional spiral (EZ-Fill- EDS, USA) as Group 2, and ultrasonic endodontic tip (Sonofile- Dentsply Tulsa, USA) as Group 3. Canals were then obturated with gutta-percha. The roots were sectioned at the 3 and 6-mm levels from the apical foramen and examined under confocal laser microscope. RESULTS: Maximum mean depth and percentage of sealer penetration were observed for Group 1 and minimum for Group 3. Furthermore, statistical significant differences among Group 1 and Group 3 were found at 6-mm level and among Group 2 and Group 3 were found at 3-mm level (P < 0.05). CONCLUSION: The depth and percentage of sealer penetration of sealer are influenced by the type of placement technique and by the root canal level, with penetration decreasing apically. Lentulo spiral has shown better penetration of sealer than the bidirectional file and ultrasonics. PMID- 28839421 TI - In vivo Evaluation of 4% Articaine and 2% Lignocaine Intraligamentary Injection Administered with Single Tooth Anesthesia-Wand. AB - BACKGROUND: The available literature confirms the effectiveness of intraligamentary injections equal to nerve blocks and articaine equal to lignocaine with better depth of penetration for single tooth pulpectomy procedures with less postoperative soft tissue trauma. An advancement in the field of local anesthesia delivery is the Single Tooth Anesthesia-Wand (STA-Wand) which is relatively pain-free and offers comfort to the child. AIMS: This study aims to evaluate and compare the anesthetic effectiveness and postoperative complications of 4% articaine and 2% lignocaine intraligamentary injection administered as single tooth anesthesia using a computer-controlled local anesthetic delivery system, the STA-Wand. SETTINGS AND DESIGN: Using a randomized, split-mouth, cross-over study design, twenty children aged 4-10 years who required bilateral mandibular pulpectomies were administered intraligamentary injections with 4% articaine and 2% lidocaine in two appointments using STA-Wand. Pain, anxiety, and cooperation levels were scored by an operator and an observer at four phases of treatment using Wong-Baker Faces Pain Rating Scale and Two-6 point Co-operation Anxiety Rating Scale. Results were tabulated and analyzed. STATISTICAL ANALYSIS: Mann-Whitney U-test, paired t-test, and Student's t-test. RESULTS: Both the local anesthetic agents were equally effective with no significant difference (P > 0.05) throughout rest of the treatment procedure compared to injection phase in minimizing pain, anxiety, and gaining the cooperation levels of children whereas during injection phase, 4% articaine showed superior effectiveness in minimizing pain compared to 2% lignocaine (P = 0.054). CONCLUSION: Both the local anesthetic agents delivered using STA-Wand is clinically acceptable, effective, and safe for usage in children. PMID- 28839422 TI - Clinical and Radiographic Comparative Evaluation of Buccal and Palatal Corticotomy with Buccal Corticotomy in Periodontally Accelerated Osteogenic Orthodontics with Surgical Bur. AB - BACKGROUND: Periodontally accelerated osteogenic orthodontics is a clinical procedure that combines selective corticotomy, particulate grafting, and application of orthodontics. It reduces treatment time, increases stability of teeth, and prevents relapse of orthodontic tooth moment. The present study was aimed to explore the clinical and radiographic comparison of bone density changes, retraction time differences in buccal and palatal corticotomy with buccal corticotomy which was done by surgical bur. MATERIALS AND METHODS: A split mouth was designed in 16 patients and divided into right (buccal and palatal corticotomy) (Group I), left (buccal corticotomy) (Group II) sides. In both groups, decortication was done with surgical bur. Clinical parameters such as gingival bleeding index and probing pocket depth were recorded at baseline, 1 month, 3 months, and 6 months. Bone density changes were measured by computed tomography at baseline and after 6 months after surgery and also used for evaluating differences in bone density changes between two groups. Retraction time differences were also measured in both groups. RESULTS: In both groups, there was significant difference between bone density changes at baseline and 6 months after surgery. However, the difference between two groups was not significant. The difference in clinical parameters between two groups was not significant. The difference in retraction time differences was not significant. CONCLUSION: Within limits of the study, it may be concluded that there was difference between bone density changes before and 6 months after surgery. Difference in total treatment time found to be no significant between two groups. PMID- 28839423 TI - Hemifacial Hyperplasia. AB - Hemifacial hyperplasia is a rare developmental anomaly characterized by marked unilateral facial tissues. It involves orofacial soft tissues, bones of the face, and teeth. The cause remains ambiguous although several predisposing factors have been reported. A case report of a 32-year-old girl with unilateral hemifacial enlargement, pain in temporomandibular joint, and limited mouth opening associated is presented to highlight the clinical and imaging findings and to discuss the differential diagnosis. PMID- 28839424 TI - A 2D Panoramic Surgical Stent Imaging: Complete Arch Mandibular Implant Fixed Prosthesis along with Bar Supported Maxillary over Denture. AB - Successful rehabilitation of a patient should restore function, esthetic, and speech by prosthesis. Treatment modalities vary from patient to patient. Semi precision attachments and implants offer several advantages over the traditional approach. The aim and objective of this report was to assess a case of a 55-year old female patient who had lost all her teeth, except maxillary canines #13 and #23 and with severe bone loss in the mandible. Tooth-supported bar attachment was planned for maxilla, and a total of five dental implants were placed in the mandible using a flapless approach aided by radiographic gutta-percha surgical stents over panoramic two-dimensional imaging. Customized, radiographic stents help for the placement of implant in the view of paralleling and flapless surgery, completely. An immediate loading protocol is adopted as from day of the surgery to 6 weeks along with implant supported full arch fixed dentures after 4 months. The outcome of the treatment was impressive, and the patient gave a positive response with superb esthetics and functions. PMID- 28839425 TI - Ramsay Hunt Syndrome: A Diagnostic Challenge for General Dental Practitioners. AB - Ramsay hunt syndrome is not just a syndrome but it's rather an infectious disease caused by reactivation of latent varicella-zoster virus in geniculate ganglion. This was first explained by J. Ramsay Hunt as a triad of complications like otalgia, mucosal and cutaneous rashes with or without trigeminal facial palsy. The facial palsy can occur with characteristic vesicles along the path of nerve. We present a case of Ramsay Hunt syndrome in a 48-year-old male. The unilateral pattern of facial involvement and presence of vesicles assisted us for early diagnosis, distinguishing the syndrome with diseases mimicking other severe neurological illnesses and prompt treatment. PMID- 28839426 TI - Liver and the defects of cholesterol and bile acids biosynthesis: Rare disorders many diagnostic pitfalls. AB - In recent decades, biotechnology produced a growth of knowledge on the causes and mechanisms of metabolic diseases that have formed the basis for their study, diagnosis and treatment. Unfortunately, it is well known that the clinical features of metabolic diseases can manifest themselves with very different characteristics and escape early detection. Also, it is well known that the prognosis of many metabolic diseases is excellent if diagnosed and treated early. In this editorial we briefly summarized two groups of inherited metabolic diseases, the defects of cholesterol biosynthesis and those of bile acids. Both groups show variable clinical manifestations but some clinical signs and symptoms are common in both the defects of cholesterol and bile acids. The differential diagnosis can be made analyzing sterol profiles in blood and/or bile acids in blood and urine by chromatographic techniques (GC-MS and LC-MS/MS). Several defects of both biosynthetic pathways are treatable so early diagnosis is crucial. Unfortunately their diagnosis is made too late, due either to the clinical heterogeneity of the syndromes (severe, mild and very mild) that to the scarcity of scientific dissemination of these rare diseases. Therefore, the delay in diagnosis leads the patient to the medical observation when the disease has produced irreversible damages to the body. Here, we highlighted simple clinical and laboratory descriptions that can potentially make you to suspect a defect in cholesterol biosynthesis and/or bile acids, as well, we suggest appropriate request of the laboratory tests that along with common clinical features can help to diagnose these defects. PMID- 28839429 TI - Partial external biliary diversion in bile salt export pump deficiency: Association between outcome and mutation. AB - AIM: To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency. METHODS: Mutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatography-tandem mass spectrometry. Wild-type and mutant BSEP transport of [3H]-labeled taurocholate (TC) and taurochenodeoxycholate (TCDC) was assessed by vesicular transport assays. RESULTS: A girl (at 2 mo) presented with pruritus, jaundice and elevated serum bile salts (BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919del and the nonsense mutation p.R1235X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy (age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives (< 5%). The patients' native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919del and p.G1032R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute, respectively. CONCLUSION: In summary, our findings suggest that residual function of BSEP as well as substrate specificity influence the therapeutic effectiveness of PEBD in progressive familial intrahepatic cholestasis type 2 (PFIC-2). PMID- 28839427 TI - Contribution of galectin-1, a glycan-binding protein, to gastrointestinal tumor progression. AB - Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly metastasize, thus identifying effective targets is crucial for treatment. Galectin-1 (Gal-1) belongs to a family of glycan binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies. PMID- 28839430 TI - Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME. AB - AIM: To counteract/reveal celecoxib-induced toxicity and NO system involvement. METHODS: Celecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 MUg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter. RESULTS: This high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME). CONCLUSION: BPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs' post-surgery application and NO system involvement. PMID- 28839428 TI - From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world. AB - Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma. PMID- 28839431 TI - Hwangryunhaedok-tang induces the depolarization of pacemaker potentials through 5 HT3 and 5-HT4 receptors in cultured murine small intestine interstitial cells of Cajal. AB - AIM: To investigate the effects of a water extract of Hwangryunhaedok-tang (HHTE) on the pacemaker potentials of mouse interstitial cells of Cajal (ICCs). METHODS: We dissociated ICCs from small intestines and cultured. ICCs were immunologically identified using an anti-c-kit antibody. We used the whole-cell patch-clamp configuration to record the pacemaker potentials generated by cultured ICCs under the current clamp mode (I = 0). All experiments were performed at 30 degrees C 32 degrees C. RESULTS: HHTE dose-dependently depolarized ICC pacemaker potentials. Pretreatment with a 5-HT3 receptor antagonist (Y25130) or a 5-HT4 receptor antagonist (RS39604) blocked HHTE-induced pacemaker potential depolarizations, whereas pretreatment with a 5-HT7 receptor antagonist (SB269970) did not. Intracellular GDPbetaS inhibited HHTE-induced pacemaker potential depolarization and pretreatment with a Ca2+-free solution or thapsigargin abolished the pacemaker potentials. In the presence of a Ca2+-free solution or thapsigargin, HHTE did not depolarize ICC pacemaker potentials. In addition, HHTE induced pacemaker potential depolarization was unaffected by a PKC inhibitor (calphostin C) or a Rho kinase inhibitor (Y27632). Of the four ingredients of HHT, Coptidis Rhizoma and Gardeniae Fructus more effectively inhibited pacemaker potential depolarization. CONCLUSION: These results suggest that HHTE dose dependently depolarizes ICC pacemaker potentials through 5-HT3 and 5-HT4 receptors via external and internal Ca2+ regulation and via G protein-, PKC- and Rho kinase-independent pathways. PMID- 28839432 TI - MicroRNA exhibit altered expression in the inflamed colonic mucosa of ulcerative colitis patients. AB - AIM: To investigate the miRNA expression in colonic mucosal biopsies from endoscopically inflamed and non inflamed regions of ulcerative colitis (UC) patients. METHODS: Colonic mucosal pinch biopsies were analyzed from the inflamed and non inflamed regions of same UC patient. Total RNA was isolated and differential miRNA profiling was done using microarray platform. Quantitative Real Time PCR was performed in colonic biopsies from inflamed (n = 8) and non inflamed (n = 8) regions of UC and controls (n = 8) to validate the differential expression of miRNA. Potential targets of dysregulated miRNA were identified by using in silico prediction tools and probable role of these miRNA in inflammatory pathways were predicted. RESULTS: The miRNA profile of inflamed colonic mucosa differs significantly from the non-inflamed. Real time PCR analysis showed that some of the miRNA were differentially expressed in the inflamed mucosa as compared to non inflamed mucosa and controls (miR-125b, miR-223, miR-138, and miR 155), while (miR-200a) did not show any significant changes. In contrast to microarray, where miR-378d showed downregulation in the inflamed mucosa, qRT-PCR showed a significant upregulation in the inflamed mucosa as compared to the non inflamed. The in silico prediction analysis revealed that the genes targeted by these miRNAs play role in the major signaling pathways like MAPK pathway, NF kappaB signaling pathway, cell adhesion molecules which are all assciated with UC. CONCLUSION: The present study reports disease specific alteration in the expression of miR-125b, miR-155, miR-223 and miR-138 in UC patients and also predict their biological significance. PMID- 28839433 TI - Salvianolic acid B protects hepatocytes from H2O2 injury by stabilizing the lysosomal membrane. AB - AIM: To investigate the capability of salvianolic acid B (Sal B) to protect hepatocytes from hydrogen peroxide (H2O2)/carbon tetrachloride (CCl4)-induced lysosomal membrane permeabilization. METHODS: Cell Counting Kit-8 assay was used to measure cell viability. Apoptosis and death were assayed through flow cytometry. BrdU incorporation was used to detect cell proliferation. Serum alanine aminotransferase activity and liver malondialdehyde (MDA) content were measured. Liver histopathological changes were evaluated using hematoxylin-eosin staining. Lysosomal membrane permeability was detected with LysoTracker Green labeled probes and acridine orange staining. The levels of protein carbonyl content (PCC), cathepsins (Cat)B/D, and lysosome-associated membrane protein 1 (LAMP1) were evaluated through western blotting. Cytosol CatB activity analysis was performed with chemiluminescence detection. The mRNA level of LAMP1 was evaluated through quantitative real-time polymerase chain reaction. RESULTS: Results indicated that H2O2 induced cell injury/death. Sal B attenuated H2O2 induced cell apoptosis and death, restored the inhibition of proliferation, decreased the amount of PCC, and stabilized the lysosome membrane by increasing the LAMP1 protein level and antagonizing CatB/D leakage into the cytosol. CCl4 also triggered hepatocyte death. Furthermore, Sal B effectively rescued hepatocytes by increasing LAMP1 expression and by reducing lysosomal enzyme translocation to the cytosol. CONCLUSION: Sal B protected mouse embryonic hepatocytes from H2O2/CCl4-induced injury/death by stabilizing the lysosomal membrane. PMID- 28839434 TI - PBX1 attributes as a determinant of connexin 32 downregulation in Helicobacter pylori-related gastric carcinogenesis. AB - AIM: To clarify the mechanisms of connexin 32 (Cx32) downregulation by potential transcriptional factors (TFs) in Helicobacter pylori (H. pylori)-associated gastric carcinogenesis. METHODS: Approximately 25 specimens at each developmental stage of gastric carcinogenesis [non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia and gastric carcinoma (GC)] with H. pylori infection [H. pylori (+)] and 25 normal gastric mucosa (NGM) without H. pylori infection [H. pylori (-)] were collected. After transcriptional factor array analysis, the Cx32 and PBX1 expression levels of H. pylori-infected tissues from the developmental stages of GC and NGM with no H. pylori infection were measured by real-time polymerase chain reaction (RT-PCR) and Western blot analysis. Regarding H. pylori-infected animal models, the Cx32 and PBX1 mRNA expression levels and correlation between the gastric mucosa from 10 Mongolian gerbils with long-term H. pylori colonization and 10 controls were analyzed. PBX1 and Cx32 mRNA and protein levels were further studied under the H. pylori infected condition as well as PBX1 overexpression and knockdown conditions in vitro. RESULTS: Incremental PBX1 was first detected by TF microarray in H. pylori related gastric carcinogenesis. The identical trend of PBX1 and Cx32 expression was confirmed in the developmental stages of H. pylori-related clinical specimens. The negative correlation of PBX1 and Cx32 was confirmed in H. pylori infected Mongolian gerbils. Furthermore, decreased PBX1 expression was detected in the normal gastric epithelial cell line GES-1 with H. pylori infection. Enforced overexpression or RNAi-mediated knockdown of PBX1 contributed to the diminished or restored Cx32 expression in GES-1 and the gastric carcinoma cell line BGC823, respectively. Finally, dual-luciferase reporter assay in HEK293T cells showed that Cx32 promoter activity decreased by 30% after PBX1 vector co transfection, indicating PBX1 as a transcriptional downregulator of Cx32 by directly binding to its promoters. CONCLUSION: PBX1 is one of the determinants in the Cx32 promoter targeting site, preventing further damage of gap junction protein in H. pylori-associated gastric carcinogenesis. PMID- 28839435 TI - Influence of dietary isoflavone intake on gastrointestinal symptoms in ulcerative colitis individuals in remission. AB - AIM: To analyse the association between isoflavone intake and ulcerative colitis motility symptoms in individuals in remission. METHODS: Cross-sectional study was conducted in a group of ulcerative colitis remission individuals, in sub-groups characterised by various intestinal motility and functioning characteristics (abdominal pain, flatulence, constipations, tenesmus). Total of 56 individuals with ulcerative colitis in remission (19 males and 37 females) were recruited for the study. Assessment of diet was based on self-reported data from each patient's dietary records taken over a period of three typical, random days (2 weekdays and 1 d of the weekend). The daily isoflavone intake (daidzein, genistein, glycitein and total isoflavones) and daily isoflavone intake per 1000 kcal of diet were assessed. RESULTS: No correlations between isoflavone intake levels and number of bowel movements per day were observed both in the case of intake and intake per 1000 kcal of diet. In the group of individuals declaring lack of abdominal pain, the higher intakes of daidzein (P = 0.0075), daidzein per 1000 kcal of diet (P = 0.0358) and total isoflavone (P = 0.0358) were stated, than in the group of individuals declaring abdominal pain. In the group of individuals declaring lack of constipations, the lower intakes of glycitein (P = 0.0213) and glycitein per 1000 kcal of diet (P = 0.0213) were stated, than in the group of individuals declaring presence of constipations. No differences were observed in isoflavone intake between groups of ulcerative colitis individuals declaring lack of flatulence and declaring presence of flatulence, as well as between groups declaring lack of tenesmus and declaring presence of tenesmus. CONCLUSION: The moderate dietary isoflavone intake may be beneficial for individuals with ulcerative colitis in remission, however, before including it into recommendations, further prospective studies are needed. PMID- 28839436 TI - Genetic polymorphisms of MAFK, encoding a small Maf protein, are associated with susceptibility to ulcerative colitis in Japan. AB - AIM: To investigate whether single nucleotide polymorphisms in maf protein K (MAFK), which encodes the MAFK, lead to increased susceptibility to ulcerative colitis in the Japanese population. METHODS: This case control study examined the associations between MAFK single nucleotide polymorphisms (rs4268033 G>A, rs3735656 T>C and rs10226620 C>T) and ulcerative colitis susceptibility in 174 patients with ulcerative colitis (UC) cases, and 748 subjects without no lower abdominal symptoms, diarrhea or hematochezia (controls). In addition, as the second controls, we set 360 subjects, who have an irregular bowel movement without abnormal lower endoscopic findings (IBM controls). RESULTS: The genotype frequency of rs4268033 AA and allelic frequency of the rs4268033A allele were significantly higher in the UC cases than in both controls (P = 0.0005 and < 0.0001, P = 0.015 and 0.0027 vs controls and IBM controls, respectively). Logistic regression analysis after adjustment for age and gender showed that the rs4268033 AA and rs3735656 CC genotypes were significantly associated with susceptibility to UC development (OR = 2.63, 95%CI: 1.61-4.30, P = 0.0001 and OR = 1.81; 95%CI: 1.12-2.94, P = 0.015, respectively). Similar findings were observed by the comparison with IBM controls. In addition, the rs4268033 AA genotype was significantly associated with all phenotypes of UC except early onset. There was no significant association between rs10226620 and ulcerative colitis. CONCLUSION: Our results provide the first evidence that MAFK genetic polymorphisms are significantly associated with susceptibility to UC development. In particular, rs4268033 is closely associated with an increased risk for the development of UC. PMID- 28839437 TI - Elaboration and validation of Crohn's disease anoperineal lesions consensual definitions. AB - AIM: To establish consensual definitions of anoperineal lesions of Crohn's (APLOC) disease and assess interobserver agreement on their diagnosis between experts. METHODS: A database of digitally recorded pictures of APLOC was examined by a coordinating group who selected two series of 20 pictures illustrating the various aspects of APLOC. A reading group comprised: eight experts from the Societe Nationale Francaise de Colo Proctologie group of study and research in proctology and one academic dermatologist. All members of the coordinating and reading groups participated in dedicated meetings. The coordinating group initially conducted a literature review to analyse verbatim descriptions used to evaluate APLOC. The study included two phases: establishment of consensual definitions using a formal consensus method and later assessment of interobserver agreement on the diagnosis of APLOC using photos of APLOC, a standardised questionnaire and Fleiss's kappa test or descriptive statistics. RESULTS: Terms used in literature to evaluate visible APLOC did not include precise definitions or reference to definitions. Most of the expert reports on the first set of photos agreed with the main diagnosis but their verbatim reporting contained substantial variation. The definitions of ulceration (entity, depth, extension), anal skin tags (entity, inflammatory activity, ulcerated aspect), fistula (complexity, quality of drainage, inflammatory activity of external openings), perianal skin lesions (abscess, papules, edema, erythema) and anoperineal scars were validated. For fistulae, they decided to follow the American Gastroenterology Association's guidelines definitions. The diagnosis of ulceration (kappa = 0.70), fistulae (kappa = 0.75), inflammatory activity of external fistula openings (86.6% agreement), abscesses (84.6% agreement) and erythema (100% agreement) achieved a substantial degree of interobserver reproducibility. CONCLUSION: This study constructed consensual definitions of APLOC and their characteristics and showed that experts have a fair level of interobserver agreement when using most of the definitions. PMID- 28839438 TI - Efficacy of tolvaptan for the patients with advanced hepatocellular carcinoma. AB - AIM: To investigate the factors influenced the efficacy of tolvaptan (TLV) in liver cirrhosis. METHODS: We retrospectively enrolled 61 consecutive patients with refractory hepatic ascites. All of them had been treated with furosemide and spironolactone before admission, and treated with TLV for 7 d in our hospital. The effect of TLV was defined by the rate of body weight loss, and the factors that influenced TLV efficacy were analyzed using multiple regression. RESULTS: Coexistent hepatocellular carcinoma (HCC) was the only significant predictive variable that attenuated the efficacy of TLV. In stratified analysis, high doses of furosemide decreased the efficacy of TLV in patients with HCC, and increased efficacy in those without HCC. In the latter, a high Child-Pugh-Turcotte score had a positive influence and a high concentration of lactate dehydrogenase had a negative influence on the effectiveness of TLV. CONCLUSION: Development of ascites may differ between patients with liver failure and those with HCC progression. A sufficient preceding dose of furosemide decreases diuretic effect of TLV. PMID- 28839439 TI - Outcomes of preoperative endoscopic nasobiliary drainage and endoscopic retrograde biliary drainage for malignant distal biliary obstruction prior to pancreaticoduodenectomy. AB - AIM: To compare the outcomes of preoperative endoscopic nasobiliary drainage (ENBD) and endoscopic retrograde biliary drainage (ERBD) in patients with malignant distal biliary obstruction prior to pancreaticoduodenectomy (PD). METHODS: Data from 153 consecutive patients who underwent preoperative endoscopic biliary drainage prior to PD between January 2009 and July 2016 were analyzed. We compared the clinical data, procedure-related complications of endoscopic biliary drainage (EBD) and postoperative complications of PD between the ENBD and ERBD groups. Univariate and multivariate analyses with odds ratios (ORs) and 95% confidence intervals (95%CIs) were used to identify the risk factors for deep abdominal infection after PD. RESULTS: One hundred and two (66.7%) patients underwent ENBD, and 51 (33.3%) patients underwent ERBD. Endoscopic sphincterotomy was less frequently performed in the ENBD group than in the ERBD group (P = 0.039); the EBD duration in the ENBD group was shorter than that in the ERBD group (P = 0.036). After EBD, the levels of total bilirubin (TB) and alanine aminotransferase (ALT) were obviously decreased in both groups, and the decreases of TB and ALT in the ERBD group were greater than those in the ENBD group (P = 0.004 and P = 0.000, respectively). However, the rate of EBD procedure-related cholangitis was significantly higher in the ERBD group than in the ENBD group (P = 0.007). The postoperative complications of PD as graded by the Clavien-Dindo classification system were not significantly different between the two groups (P = 0.864). However, the incidence of deep abdominal infection after PD was significantly lower in the ENBD group than in the ERBD group (P = 0.019). Male gender (OR = 3.92; 95%CI: 1.63-9.47; P = 0.002), soft pancreas texture (OR = 3.60; 95%CI: 1.37-9.49; P = 0.009), length of biliary stricture (>= 1.5 cm) (OR = 5.20; 95%CI: 2.23-12.16; P = 0.000) and ERBD method (OR = 4.08; 95%CI: 1.69-9.87; P = 0.002) were independent risk factors for deep abdominal infection after PD. CONCLUSION: ENBD is an optimal method for patients with malignant distal biliary obstruction prior to PD. ERBD is superior to ENBD in terms of patient tolerance and the effect of biliary drainage but is associated with an increased risk of EBD procedure-related cholangitis and deep abdominal infection after PD. PMID- 28839440 TI - Phase I clinical study of personalized peptide vaccination combined with radiotherapy for advanced hepatocellular carcinoma. AB - AIM: To assess the efficacy and safety of a new treatment modality, cellular immune therapy based on personalized peptide vaccination (PPV-DC-CTL) combined with radiotherapy, for treating advanced hepatocellular carcinoma (HCC). METHODS: A total of nine patients with advanced HCC were enrolled. Multidisciplinary consultation confirmed that all the patients definitely had no opportunity of surgery, because four patients had multiple liver metastases (the number of liver lesions > 3), one patient had liver metastases and portal vein tumor thrombosis, one patient had lung and bone metastases, two patients had liver and lung metastases and one patient had liver metastasis and peritoneal metastasis. Patients with metastasis were treated with precise radiotherapy combined with PPV DC-CTL. RESULTS: Following radiotherapy and one to three cycles of PPV-DC-CTL treatment, AFP levels were significantly decreased in six patients and imaging assessment of the lesions showed a partial response (PR) in three patients and stable disease in the other three patients. The response rate was 33% and disease control rate was 66%. This regimen was found to be safe and well tolerated. None of the patients developed liver or kidney side effects. Only one patient developed grade II bone marrow suppression and the remaining patients had no significant hematological side effects. CONCLUSION: Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced HCC, which is well tolerated, safe, feasible and effective. PMID- 28839441 TI - Transition clinic attendance is associated with improved beliefs and attitudes toward medicine in patients with inflammatory bowel disease. AB - AIM: To evaluated the differences in knowledge, adherence, attitudes, and beliefs about medicine in adolescents with inflammatory bowel disease (IBD) attending transition clinics. METHODS: We prospectively enrolled patients from July 2012 to June 2013. All adolescents who attended a tertiary-centre-based dedicated IBD transition clinic were invited to participate. Adolescent controls were recruited from university-affiliated gastroenterology offices. Participants completed questionnaires about their disease and reported adherence to prescribed therapy. Beliefs in Medicine Questionnaire was used to evaluate patients' attitudes and beliefs. Beliefs of medication overuse, harm, necessity and concerns were rated on a Likert scale. Based on necessity and concern ratings, attitudes were then characterized as accepting, ambivalent, skeptical and indifferent. RESULTS: One hundred and twelve adolescents were included and 59 attended transition clinics. Self-reported adherence rates were poor, with only 67.4% and 56.8% of patients on any IBD medication were adherent in the transition and control groups, respectively. Adolescents in the transition cohort held significantly stronger beliefs that medications were necessary (P = 0.0035). Approximately 20% of adolescents in both cohorts had accepting attitudes toward their prescribed medicine. However, compared to the control group, adolescents in the transition cohort were less skeptical of (6.8% vs 20.8%) and more ambivalent (61% vs 34%) (OR = 0.15; 95%CI: 0.03-0.75; P = 0.02) to treatment. CONCLUSION: Attendance at dedicated transition clinics was associated with differences in attitudes in adolescents with IBD. PMID- 28839442 TI - Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis. AB - AIM: To assess the prevalence of a panel of serologic markers that reflect gut barrier dysfunction in a mixed cohort of pediatric and adult primary sclerosing cholangitis (PSC) patients. METHODS: Sera of 67 PSC patients [median age (range): 32 (5-79) years, concomitant IBD: 67% and cirrhosis: 20%] were assayed for the presence of antibodies against to F-actin (AAA IgA/IgG) and gliadin (AGA IgA/IgG)] and for serum level of intestinal fatty acid-binding protein (I-FABP) by ELISA. Markers of lipopolysaccharide (LPS) exposure [LPS binding protein (LBP)] and various anti-microbial antibodies [anti-OMP Plus IgA and endotoxin core IgA antibody (EndoCAb)] were also determined. Poor disease outcome was defined as orthotopic liver transplantation and/or liver-related death during the follow-up [median: 99 (14-106) mo]. One hundred and fifty-three healthy subjects (HCONT) and 172 ulcerative colitis (UC) patients were the controls. RESULTS: A total of 28.4%, 28.0%, 9% and 20.9% of PSC patients were positive for AAA IgA, AAA IgG, AGA IgA and AGA IgG, respectively. Frequencies of AAA IgA and AAA IgG (P < 0.001, for both) and AGA IgG (P = 0.01, for both) but not AGA IgA were significantly higher compared to both of the HCONT and the UC groups. In survival analysis, AAA IgA-positivity was revealed as an independent predictor of poor disease outcome after adjusting either for the presence of cirrhosis [HR = 5.15 (1.27-20.86), P = 0.022 or for the Mayo risk score (HR = 4.24 (0.99-18.21), P = 0.052]. AAA IgA-positivity was significantly associated with higher frequency of anti-microbial antibodies (P < 0.001 for EndoCab IgA and P = 0.012 for anti-OMP Plus IgA) and higher level of the enterocyte damage marker (median I-FABPAAA IgA posvsneg: 365 vs 166 pg/mL, P = 0.011), but not with serum LBP level. CONCLUSION: Presence of IgA type AAA identified PSC patients with progressive disease. Moreover, it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage further highlighting the importance of the gut-liver interaction in PSC. PMID- 28839443 TI - Efficacy of forced coagulation with low high-frequency power setting during endoscopic submucosal dissection. AB - AIM: To investigated the hemostatic ability of the S and F1-10 methods in clinical and ex vivo studies. METHODS: The hemostatic abilities of the two methods were analyzed retrospectively in all six gastric endoscopic submucosal dissection cases. The treated vessel diameter, compressed vessel frequency, and bleeding frequency after cutting the vessels were noted by the recorded videos. The coagulation mechanism of the two power settings was evaluated using the data recording program and histological examination on macro- and microscopic levels in the ex vivo experiments using porcine tissues. RESULTS: F1-10 method showed a significantly better hemostatic ability for vessels >= 2 mm in diameter and a trend of overall better coagulation effect, evaluated by the bleeding rate after cutting the vessels. F1-10 method could sustain electrical current longer and effectively coagulate the tissue wider and deeper than the S method in the porcine model. CONCLUSION: F1-10 method is suggested to achieve a stronger hemostatic effect than the S method in clinical procedures and ex vivo models. PMID- 28839444 TI - Clinical outcomes of isolated renal failure compared to other forms of organ failure in patients with severe acute pancreatitis. AB - AIM: To assess differences in clinical outcomes of isolated renal failure (RF) compared to other forms of organ failure (OF) in patients with severe acute pancreatitis (SAP). METHODS: Using a prospectively maintained database of patients with acute pancreatitis admitted to a tertiary medical center between 2003 and 2016, those with evidence of persistent OF were classified to renal, respiratory, cardiovascular, or multi-organ (2 or more organs). Data regarding demographics, comorbidities, etiology of acute pancreatitis, and clinical outcomes were prospectively recorded. Differences in clinical outcomes after development of isolated RF in comparison to other forms of OF were determined using independent t and Mann-Whitney U tests for continues variables, and chi2 test for discrete variables. RESULTS: Among 500 patients with acute pancreatitis, 111 patients developed persistent OF: mean age was 54 years, and 75 (67.6%) were male. Forty-three patients had isolated OF: 17 (15.3%) renal, 25 (21.6%) respiratory, and 1 (0.9%) patient with cardiovascular failure. No differences in demographics, etiology of acute pancreatitis, systemic inflammatory response syndrome scores, or development of pancreatic necrosis were seen between patients with isolated RF vs isolated respiratory failure. Patients with isolated RF were less likely to require nutritional support (76.5% vs 96%, P = 0.001), ICU admission (58.8% vs 100%, P = 0.001), and had shorter mean ICU stay (2.4 d vs 15.7 d, P < 0.001), compared to isolated respiratory failure. None of the patients with isolated RF or isolated respiratory failure died. CONCLUSION: Among patients with SAP per the Revised Atlanta Classification, approximately 15% develop isolated RF. This subgroup seems to have a less protracted clinical course compared to other forms of OF. Isolated RF might be weighed less than isolated respiratory failure in risk predictive modeling of acute pancreatitis. PMID- 28839446 TI - Socioeconomic Disparities in Smoking Behavior and Early Smoking Initiation Among Men in Malawi. AB - BACKGROUND: Tobacco smoking is a growing concern for health care systems as it is projected to become the leading cause of death in the developing world. Knowledge of how smoking behavior differs across socioeconomic groups is crucial for designing effective preventive policies and alleviating the disparities. The aim of this study was to report the prevalence of (1) smoking status, (2) early smoking initiation, and (3) association with socioeconomic status (SES) of the 2 among Malawian men. METHODS: Cross-sectional data on 1693 men aged between 15 and 49 years were collected from the latest 2013-2014 Multiple Indicator Cluster Survey in Malawi. Educational qualification and wealth index quintile were used as the indicators of SES. Outcome variables were smoking status, first age of smoking being below 18 years, and ever using any form of smokeless tobacco products. Multiple logistic regression models were used to see the contribution of SES to smoking status and early smoking initiation. RESULTS: Mean age of the sample population was 33.23 years (SD: 8.25). Prevalence of smoking, early initiation, and ever using any form of smokeless tobacco were, respectively, 46.6%, 33.7%, and 6%. Compared with men who had higher education, those who had no formal education, primary-level, and secondary-level qualification had, respectively, 21% (adjusted odds ratio [AOR] = 1.209; 95% confidence interval [CI] = 0.498-2.935), 40% (AOR = 1.4; 95% CI = 0.647-3.029), and 26% (AOR = 1.256; 95% CI = 0.593-2.661) higher odds of being a smoker. Those who had no formal education were 2.7 times (AOR = 2.734; 95% CI = 1.123-6.653) as likely to try smoking before reaching 18 years of age. Compared with the richest, those in the lowest wealth quintile had 32% lower odds (AOR = 0.676; 95% CI = 0.455-1.006) of early onset of smoking, 63% lower odds (AOR = 0.372; 95% CI = 0.201-0.690) of trying other tobacco products. CONCLUSIONS: Addressing the socioeconomic disparities could play a vital role in delaying early onset and limiting overall consumption of tobacco. Ongoing health policy talks to reduce the prevalence of smoking should take into consideration improving educational and material well being among men. PMID- 28839447 TI - Hypokalemic Paralysis: A Hidden Card of Several Autoimmune Diseases. AB - Acute hypokalemic paralysis is a rare and potentially fatal condition, with few related causes, one of which highlights distal renal tubular acidosis (dRTA). Distal renal tubular acidosis is a rare complication of several autoimmune diseases such as systemic lupus erythematosus, Sjogren's syndrome, and Hashimoto thyroiditis. We report a case of a lupic patient who presented rapidly progressive quadriparesis in the context of active renal disease. Research revealed severe refractory hypokalemia, metabolic acidosis, and alkaline urine suggestive of dRTA. We diagnosed Sjogren's syndrome based on sicca symptoms, an abnormal salivary glands' nuclear scan and the presence of anti-Ro/SSA and anti La/SSB. In addition, the finding of thyroid peroxidase, thyroglobulin antibodies, and hypothyroidism led us to the diagnosis of Hashimoto thyroiditis. Due to the active renal involvement on the context of systemic lupus erythematosus and Sjogren's syndrome, the patient received immunosuppression with rituximab, resulting in a progressive and complete improvement. PMID- 28839445 TI - Laparoscopic ultrasonography as an alternative to intraoperative cholangiography during laparoscopic cholecystectomy. AB - AIM: To assess the role of laparoscopic ultrasound (LUS) as a substitute for intraoperative cholangiography (IOC) during cholecystectomy. METHODS: We present a MEDLINE and PubMed literature search, having used the key-words "laparoscopic intraoperative ultrasound" and "laparoscopic cholecystectomy". All relevant English language publications from 2000 to 2016 were identified, with data extracted for the role of LUS in the anatomical delineation of the biliary tract, detection of common bile duct stones (CBDS), prevention or early detection of biliary duct injury (BDI), and incidental findings during laparoscopic cholecystectomy. Data for the role of LUS vs IOC in complex situations (i.e., inflammatory disease/fibrosis) were specifically analyzed. RESULTS: We report data from eighteen reports, 13 prospective non-randomized trials, 5 retrospective trials, and two meta-analyses assessing diagnostic accuracy, with one analysis also assessing costs, duration of the examination, and anatomical mapping. Overall, LUS was shown to provide highly sensitive mapping of the extra pancreatic biliary anatomy in 92%-100% of patients, with more difficulty encountered in delineation of the intra-pancreatic segment of the biliary tract (73.8%-98%). Identification of vascular and biliary variations has been documented in two studies. Although inflammatory disease hampered accuracy, LUS was still advantageous vs IOC in patients with obscured anatomy. LUS can be performed before any dissection and repeated at will to guide the surgeon especially when hilar mapping is difficult due to fibrosis and inflammation. In two studies LUS prevented conversion in 91% of patients with difficult scenarios. Considering CBDS detection, LUS sensitivity and specificity were 76%-100% and 96.2%-100%, respectively. LUS allowed the diagnosis/treatment of incidental findings of adjacent organs. No valuable data for BDI prevention or detection could be retrieved, even if no BDI was documented in the reports analyzed. Literature analysis proved LUS as a safe, quick, non-irradiating, cost-effective technique, which is comparatively well known although largely under-utilized, probably due to the perception of a difficult learning curve. CONCLUSION: We highlight the advantages and limitations of laparoscopic ultrasound during cholecystectomy, and underline its value in difficult scenarios when the anatomy is obscured. PMID- 28839449 TI - Comparison of the 3 Different Injection Techniques Used in a Randomized Controlled Study Evaluating a Cross-Linked Sodium Hyaluronate Combined With Triamcinolone Hexacetonide (Cingal) for Osteoarthritis of the Knee: A Subgroup Analysis. AB - A recent trial demonstrated that patients with knee osteoarthritis treated with a sodium hyaluronate and corticosteroid combination (Cingal) experienced greater pain reductions compared with those treated with sodium hyaluronate alone (Monovisc) or saline up to 3 weeks postinjection. In this study, injections were administered by 1 of 3 approaches; however, there is currently no consensus on which, if any, of these techniques produce a more favorable outcome. To provide additional insight on this topic, the results of the previous trial were reanalyzed to determine whether (1) the effect of Cingal was significant within each injection technique and (2) pain reductions were similar between injection techniques across all treatment groups. Greater pain reductions with Cingal up to 3 weeks were only significant in the anteromedial subgroup. Across all therapies, both the anteromedial and anterolateral techniques demonstrated significantly greater pain reductions than the lateral midpatellar approach at 18 and 26 weeks. PMID- 28839448 TI - The Disease-Modifying Effects of Hyaluronan in the Osteoarthritic Disease State. AB - Hyaluronic acid (HA) has been a treatment modality for patients with knee osteoarthritis (OA) for many years now. Since HA was first introduced for the treatment of painful knee OA, much has been elucidated regarding both the etiology of this disease and the mechanisms by which HA may mitigate joint pain and tissue destruction. The objectives of this article are to (1) describe the etiology and pathophysiology of OA including both what is known about the genetics and biochemistry, (2) describe the role of HA on disease progression, (3) detail the antinociceptive and anti-inflammatory actions of HA in OA, and (4) present evidence of disease-modifying effects of HA in the preservation and restoration of the extracellular matrix. These data support that HA is not only just a simple device used for viscosupplementation but also a biologically active molecule that can affect the physiology of articular cartilage. PMID- 28839450 TI - Diffuse Large B-Cell Breast Lymphoma: A Case Series. AB - Primary breast lymphoma (PBL) is a rare disease, and few clinicohistopathologic features of the disease have been discussed in previous studies. It represents 2.2% of extranodal lymphomas and constitutes 0.04% to 0.5% of malignant breast neoplasms, despite the clinical and radiographic similarities between breast lymphoma and carcinoma, the prognosis, as reported in the literature, varies. No consensus exists on the best way to treat PBL. However, radiotherapy and chemotherapy were used alone or in combination to treat various cases of PBL. We retrospectively studied 3 cases of PBL of the breast seen in patients attending a tertiary cancer center in Qatar, between 2012 and 2015, in an attempt to determine the common clinical features, therapy, and prognosis of PBL. PMID- 28839451 TI - Orthographic and Phonological Neighborhood Databases across Multiple Languages. AB - The increased globalization of science and technology and the growing number of bilinguals and multilinguals in the world have made research with multiple languages a mainstay for scholars who study human function and especially those who focus on language, cognition, and the brain. Such research can benefit from large-scale databases and online resources that describe and measure lexical, phonological, orthographic, and semantic information. The present paper discusses currently-available resources and underscores the need for tools that enable measurements both within and across multiple languages. A general review of language databases is followed by a targeted introduction to databases of orthographic and phonological neighborhoods. A specific focus on CLEARPOND illustrates how databases can be used to assess and compare neighborhood information across languages, to develop research materials, and to provide insight into broad questions about language. As an example of how using large scale databases can answer questions about language, a closer look at neighborhood effects on lexical access reveals that not only orthographic, but also phonological neighborhoods can influence visual lexical access both within and across languages. We conclude that capitalizing upon large-scale linguistic databases can advance, refine, and accelerate scientific discoveries about the human linguistic capacity. PMID- 28839452 TI - Corrigendum: A Novel Retinal Oscillation Mechanism in an Autosomal Dominant Photoreceptor Degeneration Mouse Model. AB - [This corrects the article on p. 513 in vol. 9, PMID: 26793064.]. PMID- 28839453 TI - Variants of Interleukin-22 Gene Confer Predisposition to Autoimmune Thyroid Disease. AB - As there are no previous studies on the interleukin-22 (IL-22) variants in autoimmune thyroid disease (AITD), the present study aimed to explore the association between polymorphisms of IL-22 and the predisposition to AITD. The study had 975 AITD patients, including 639 Graves' disease (GD) and 336 Hashimoto's thyroiditis (HT) individuals and 851 healthy cohorts. Ligase detection reaction (LDR) and direct sequencing method were used for genotyping the IL-22 gene polymorphisms at rs2046068, rs2227478, rs2227485, rs11611206, and rs1179251. In comparison to female controls, genotype CC of rs1179251 was increased in the female AITD patients. Alleles C at rs2046068, C at rs2227478, and C at rs1179251 linked to the susceptibility of HT males. Genotype CC in rs1179251 was higher in male HT. Variants at rs2046068, rs2227478, and rs1179251 were associated with the AITD teenagers. Besides, genotype GG in rs11611206 was correlated with thyroid-associated ophthalmopathy (TAO). Moreover, allele G at rs11611206 was associated with decreased risk for TAO by 28.9%. Similarly, genotype CC of rs1179251 and genotype GG of rs11611206 were associated with Graves' ophthalmopathy (GO). Allele G in rs11611206 increased people with HT towards the predisposition of hypothyroidism. In conclusion, genetic variants of IL-22 are associated with the occurrence of AITD. PMID- 28839454 TI - Donor-Cell Origin High-Risk Myelodysplastic Syndrome Synchronous with an Intracranial Meningioma-Like Tumor, 8 Years after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia. AB - Secondary neoplasias are well known consequences of radiotherapy or chemotherapy for a primary cancer. In this report, we describe two rare secondary neoplasias occurring in the same patient: a meningioma-like intracranial tumor and high-risk myelodysplastic syndrome (MDS) of donor-cells origin, both diagnosed simultaneously, 8 years after an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic lymphocytic leukemia (CLL). Due to an engraftment failure during the first allo-HSCT of a matched related donor for CLL treatment, the salvage treatment was a second allo-HSCT. At the moment of meningioma-like tumor diagnosis, the patient was pancytopenic due to high-risk MDS, so it was decided to postpone a surgical intervention until hematological improvement. For the high-risk MDS of donor-cells origin the chosen treatment was induction with intensive chemotherapy. Due to refractory disease, the patient was treated with 5-azacitidine and donor-lymphocytes infusion with no response and, finally, a third allo-HSCT of a matched unrelated donor was performed. The patient died 6 months after the third allo-HSCT, in cytogenetic remission but without hematological recovery, due to an intracranial hemorrhage with origin in the meningioma-like tumor. PMID- 28839455 TI - Detecting and Managing Mental Health Issues within Young Adults. A Systematic Review on College Counselling in Italy. AB - BACKGROUND: College counselling can be considered as a front-line service in detecting and managing mental health issues within young adults. In this sense, it is important to investigate the effectiveness of counselling interventions. OBJECTIVE: To provide a systematic review about college counselling in Italy; to assess which psychological interventions really meet student needs, and their effectiveness; to focus on the level of cohesion between Italian counselling services and the international guidelines about college counselling. METHOD: A systematic review about college counselling through PsycInfo and PubMed was carried out. Because of the scarceness of pertinent available articles, the survey was extended to Google Scholar and Riviste Web. Keywords: counselling, mental health, wellbeing, psychological support, university, students, Italy. RESULTS: Out of thirty-four articles retrieved, 16 are relevant to academic counselling, the other 18 have been considered not pertinent to the aim of the present review. Data show a lack of homogeneity in methodology and organization between each University: different approaches towards students' needs. Furthermore, no follow-up studies or measurement of effectiveness were found. CONCLUSION: This review is a contribution to disseminate the results of counselling experiences in Italy and represents an effort to encourage colleagues working in a web environment to share results and methods for a more organized protocol application. PMID- 28839456 TI - Correlates of Social Functioning in Autism Spectrum Disorder: The Role of Social Cognition. AB - BACKGROUND: Individuals with autism spectrum disorder (ASD) experience marked challenges with social function by definition, but few modifiable predictors of social functioning in ASD have been identified in extant research. This study hypothesized that deficits in social cognition and motor function may help to explain poor social functioning in individuals with ASD. METHOD: Cross-sectional data from 108 individuals with ASD and without intellectual disability ages 9 through 27.5 were used to assess the relationship between social cognition and motor function, and social functioning. RESULTS: Results of hierarchical multiple regression analyses revealed that greater social cognition, but not motor function, was significantly associated with better social functioning when controlling for sex, age, and intelligence quotient. Post-hoc analyses revealed that, better performance on second-order false belief tasks was associated with higher levels of socially adaptive behavior and lower levels of social problems. CONCLUSIONS: Our findings support the development and testing of interventions that target social cognition in order to improve social functioning in individuals with ASD. Interventions that teach generalizable skills to help people with ASD better understand social situations and develop competency in advanced perspective taking have the potential to create more durable change because their effects can be applied to a wide and varied set of situations and not simply a prescribed set of rehearsed situations. PMID- 28839458 TI - Discovery of Aptamer Ligands for Hepatic Stellate Cells Using SELEX. AB - Insulin like growth factor II receptor (IGFIIR) is a transmembrane protein overexpressed in activated hepatic stellate cells (HSCs), which are the major target for the treatment of liver fibrosis. In this study, we aim to discover an IGFIIR-specific aptamer that can be potentially used as a targeting ligand for the treatment and diagnosis of liver fibrosis. Systematic evolution of ligands by exponential enrichment (SELEX) was conducted on recombinant human IGFIIR to identify IGFIIR-specific aptamers. The binding affinity and specificity of the discovered aptamers to IGFIIR and hepatic stellate cells were studied using flow cytometry and Surface Plasmon Resonance (SPR). Aptamer-20 showed the highest affinity to recombinant human IGFIIR protein with a Kd of 35.5 nM, as determined by SPR. Aptamer-20 also has a high affinity (apparent Kd 45.12 nM) to LX-2 human hepatic stellate cells. Binding of aptamer-20 to hepatic stellate cells could be inhibited by knockdown of IGFIIR using siRNA, indicating a high specificity of the aptamer. The aptamer formed a chimera with an anti-fibrotic PCBP2 siRNA and delivered the siRNA to HSC-T6 cells to trigger silencing activity. In Vivo biodistribution study of the siRNA-aptamer chimera also demonstrated a high and specific uptake in the liver of the rats with CCl4-induced liver fibrosis. These data suggest that aptamer-20 is a high-affinity ligand for antifibrotic and diagnostic agents for liver fibrosis. PMID- 28839457 TI - Ambient Ionization and Miniature Mass Spectrometry Systems for Disease Diagnosis and Therapeutic Monitoring. AB - Mass spectrometry has become a powerful tool in the field of biomedicine. The combination of ambient ionization and miniature mass spectrometry systems could most likely fulfill a significant need in medical diagnostics, providing highly specific molecular information in real time for clinical and even point-of-care analysis. In this review, we discuss the recent development of ambient ionization and miniature mass spectrometers as well as their potential in disease diagnosis and therapeutic monitoring, with an emphasis on their capability in analysis of biofluids and tissues. We also speculate the future development of the integrated, miniature MS systems and provide our perspectives on the challenges in technical development as well as possible solutions for path forward. PMID- 28839459 TI - Using Multifunctional Peptide Conjugated Au Nanorods for Monitoring beta-amyloid Aggregation and Chemo-Photothermal Treatment of Alzheimer's Disease. AB - Development of sensitive detectors of Abeta aggregates and effective inhibitors of Abeta aggregation are of diagnostic importance and therapeutic implications for Alzheimer's disease (AD) treatment. Herein, a novel strategy has been presented by self-assembly of peptide conjugated Au nanorods (AuP) as multifunctional Abeta fibrillization detectors and inhibitors. Our design combines the unique high NIR absorption property of AuNRs with two known Abeta inhibitors, Abeta15-20 and polyoxometalates (POMs). The synthesized AuP can effectively inhibit Abeta aggregation and dissociate amyloid deposits with NIR irradiation both in buffer and in mice cerebrospinal fluid (CSF), and protect cells from Abeta-related toxicity upon NIR irradiation. In addition, with the shape and size-dependent optical properties, the nanorods can also act as effective diagnostic probes to sensitively detect the Abeta aggregates. This is the first report to integrate 3 segments, an Abeta-targeting element, a reporter and inhibitors, in one drug delivery system for AD treatment. PMID- 28839460 TI - Degradable Hollow Mesoporous Silicon/Carbon Nanoparticles for Photoacoustic Imaging-Guided Highly Effective Chemo-Thermal Tumor Therapy in Vitro and in Vivo. AB - The development of nanoscaled theranostic agents for cancer combination therapies has received intensive attention in recent years. In this report, a degradable hollow mesoporous PEG-Si/C-DOX NP is designed and fabricated for pH-responsive, photoacoustic imaging-guided highly effective chemo-thermal combination therapy. The intrinsic hollow mesoporous structure endows the as-synthesized nanoparticles (NPs) with a high drug loading capacity (31.1%). Under NIR (808 nm) irradiation, the photothermal conversion efficiency of the Si/C NPs is as high as 40.7%. Preferential accumulation of the PEG-Si/C-DOX NPs around tumor tissue was demonstrated with photoacoustic images. Cellular internalization of the NPs and release of the DOX in nuclei are shown with fluorescent images. With efficient NIR photothermal conversion and high DOX loading capacity, the PEG-Si/C-DOX NPs are demonstrated to have remarkable cancer-cell-killing ability and to achieve complete in vivo tumor elimination via combinational chemo-thermal therapy. Last but not least, the NPs show good biodegradability and biosafety, making them a promising candidate for multifunctional drug delivery and cancer theranostic. PMID- 28839461 TI - Glutamic Pyruvate Transaminase GPT2 Promotes Tumorigenesis of Breast Cancer Cells by Activating Sonic Hedgehog Signaling. AB - Increased glutamine metabolism is a hallmark of cancer. Mitochondrial glutamic pyruvate transaminase (GPT2) catalyzes the reversible transamination between alanine and alpha-ketoglutarate (alpha-KG), also known as 2-oxoglutarate, to generate pyruvate and glutamate during cellular glutamine catabolism. However, the precise role of GPT2 in tumorigenesis remains elusive. Here, we report that in breast cancer tissue samples and breast cancer cell lines, GPT2 expression level was markedly elevated and correlated with the pathological grades of breast cancers. GPT2 overexpression increased the subpopulation of breast cancer stem cells in vitro and promoted tumorigenesis in mice. GPT2 reduced alpha-KG level in cells leading to the inhibition of proline hydroxylase 2 (PHD2) activity involved in the regulation of HIF1alpha stability. Accumulation of HIF1alpha, resulting from GPT2-alpha-KG-PHD2 axial, constitutively activates sonic hedgehog (Shh) signaling pathway. Overall, GPT2 promotes tumorigenesis and stemness of breast cancer cells by activating the Shh signaling, suggesting that GTP2 is a potential target for breast cancer therapy. PMID- 28839462 TI - Albumin-Gold Nanorod Nanoplatform for Cell-Mediated Tumoritropic Delivery with Homogenous ChemoDrug Distribution and Enhanced Retention Ability. AB - Recently, living cells with tumor-homing properties have provided an exciting opportunity to achieve optimal delivery of nanotherapeutic agents. However, premature payload leakage may impair the host cells, often leading to inadequate in vivo investigations or therapeutic efficacy. Therefore, a nanoplatform that provides a high drug-loading capacity and the precise control of drug release is required. In the present study, a robust one-step synthesis of a doxorubicin (DOX)-loaded gold nanorod/albumin core-shell nanoplatform (NR@DOX:SA) was designed for effective macrophage-mediated delivery to demonstrate how nanoparticle-loaded macrophages improve photothermal/chemodrug distribution and retention ability to achieve enhanced antitumor effects. The serum albumin shell of these nanoagents served as a drug reservoir to delay the intracellular DOX release and drug-related toxicity that impairs the host cell carriers. Near infrared laser irradiation enabled on-demand payload release to destroy neighboring tumor cells. A series of in vivo quantitative analyses demonstrated that the nanoengineered macrophages delivered the nanodrugs through tumor-tropic migration to tumor tissues, resulting in the twice homogenous and efficient photothermal activations of drug release to treat prostate cancer. By contrast, localized pristine NR@DOX:SAs exhibit limited photothermal drug delivery that further reduces their retention ability and therapeutic efficacy after second combinational treatment, leading to a failure of cancer therapy. Moreover, the resultant unhealable wounds impair quality of life. Free DOX has rapid clearance and therefore exhibits limited antitumor effects. Our findings suggest that in comparison with pristine nanoparticles or free DOX, the nanoengineered macrophages effectively demonstrate the importance and effect of homogeneous drug distribution and retention ability in cancer therapy. PMID- 28839463 TI - TGFbeta1 Promotes Gemcitabine Resistance through Regulating the LncRNA LET/NF90/miR-145 Signaling Axis in Bladder Cancer. AB - High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFbeta/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFbetaRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFbeta1, combined with decreased levels of lncRNA-LET and miR 145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFbeta1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFbeta1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients. PMID- 28839464 TI - Chelator-Free Radiolabeling of SERRS Nanoparticles for Whole-Body PET and Intraoperative Raman Imaging. AB - A single contrast agent that offers whole-body non-invasive imaging along with the superior sensitivity and spatial resolution of surface-enhanced resonance Raman scattering (SERRS) imaging would allow both pre-operative mapping and intraoperative imaging and thus be highly desirable. We hypothesized that labeling our recently reported ultrabright SERRS nanoparticles with a suitable radiotracer would enable pre-operative identification of regions of interest with whole body imaging that can be rapidly corroborated with a Raman imaging device or handheld Raman scanner in order to provide high precision guidance during surgical procedures. Here we present a straightforward new method that produces radiolabeled SERRS nanoparticles for combined positron emission tomography (PET) SERRS tumor imaging without requiring the attachment of molecular chelators. We demonstrate the utility of these PET-SERRS nanoparticles in several proof-of concept studies including lymph node (LN) tracking, intraoperative guidance for LN resection, and cancer imaging after intravenous injection. We anticipate that the radiolabeling method presented herein can be applied generally to nanoparticle substrates of various materials by first coating them with a silica shell and then applying the chelator-free protocol. PMID- 28839465 TI - FKBP3 Promotes Proliferation of Non-Small Cell Lung Cancer Cells through Regulating Sp1/HDAC2/p27. AB - FKBP3 is a member of FK506-binding proteins (FKBPs). Little is known about the expression and functional role(s) of FKBP3 in non-small cell lung cancer (NSCLC). In the present study, we demonstrated up-regulation of FKBP3 expression, both at mRNA and protein levels, in NSCLC samples which closely correlated with poor survival in NSCLC patients. In vitro and in vivo experiments revealed that FKBP3 could promote NSCLC cell proliferation. Furthermore, knockdown of FKBP3 significantly decreased histone deacetylase 2 (HDAC2) expression and increased p27 (a cell cycle inhibitor) expression. HDAC2 modulated the acetylation of histone H3K4 by directly binding to the p27 promoter. The proliferation-promoting effect of FKBP3 was dependent on HDAC2 and inhibited by p27. Also, FKBP3 induced HDAC2 promoter activity via inhibiting the ubiquitination of transcription factor Sp1. Additionally, we identified miR-145-5p as a regulator of FKBP3. miR-145-5p overexpression suppressed cell proliferation of NSCLC cells which was abrogated by FKBP3 overexpression. Taken together, our data clearly show that FKBP3/Sp1/HDAC2/p27 control cell proliferation during NSCLC development. PMID- 28839466 TI - The gRNA-miRNA-gRNA Ternary Cassette Combining CRISPR/Cas9 with RNAi Approach Strongly Inhibits Hepatitis B Virus Replication. AB - The CRISPR/Cas9 system is a novel genome editing technology which has been successfully used to inhibit HBV replication. Here, we described a novel gRNA microRNA (miRNA)-gRNA ternary cassette driven by a single U6 promoter. With an anti-HBV pri-miR31 mimic integrated between two HBV-specific gRNAs, both gRNAs could be separated from the long transcript of gRNA-miR-HBV-gRNA ternary cassette through Drosha/DGCR8 processing. The results showed that the gRNA-miR-HBV-gRNA ternary cassette could efficiently express two gRNAs and miR-HBV. The optimal length of pri-miRNA flanking sequence in our ternary cassette was determined to be 38 base pairs (bp). Besides, HBV-specific gRNAs and miR-HBV in gRNA-miR-HBV gRNA ternary cassette could exert a synergistic effect in inhibiting HBV replication and destroying HBV genome in vitro and in vivo. Most importantly, together with RNA interference (RNAi) approach, the HBV-specific gRNAs showed the potent activity on the destruction of HBV covalently closed circular DNA (cccDNA). Since HBV cccDNA is an obstacle for the elimination of chronic HBV infection, the gRNA-miR-HBV-gRNA ternary cassette may be a potential tool for the clearance of HBV cccDNA. PMID- 28839467 TI - Circular RNAs: Regulators of Cancer-Related Signaling Pathways and Potential Diagnostic Biomarkers for Human Cancers. AB - Circular RNAs (circRNAs) are newly discovered endogenous non-coding RNAs featuring structural stability, high abundance, and tissue-specific expression. CircRNAs are prevalent and conserved in mammalian cells. They are involved in cellular processes and regulate gene expression at the transcriptional or post transcriptional level by interacting with microRNAs (miRNAs) and other molecules. Recent studies have shown that circRNAs play an important role in the progression of various human diseases including atherosclerosis, nervous system disorders, diabetes, and cancer. In this review, we summarize the advances on endogenous circRNAs in eukaryotic cells and elucidate their diagnostic and prognostic significance in human cancers. Especially, we highlight the involvement of circRNAs in signal transduction pathways as well as their clinical potential to serve as biomarkers. PMID- 28839468 TI - 3D Cell Printed Tissue Analogues: A New Platform for Theranostics. AB - Stem cell theranostics has received much attention for noninvasively monitoring and tracing transplanted therapeutic stem cells through imaging agents and imaging modalities. Despite the excellent regenerative capability of stem cells, their efficacy has been limited due to low cellular retention, low survival rate, and low engraftment after implantation. Three-dimensional (3D) cell printing provides stem cells with the similar architecture and microenvironment of the native tissue and facilitates the generation of a 3D tissue-like construct that exhibits remarkable regenerative capacity and functionality as well as enhanced cell viability. Thus, 3D cell printing can overcome the current concerns of stem cell therapy by delivering the 3D construct to the damaged site. Despite the advantages of 3D cell printing, the in vivo and in vitro tracking and monitoring of the performance of 3D cell printed tissue in a noninvasive and real-time manner have not been thoroughly studied. In this review, we explore the recent progress in 3D cell technology and its applications. Finally, we investigate their potential limitations and suggest future perspectives on 3D cell printing and stem cell theranostics. PMID- 28839469 TI - RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma. AB - Activation of the telomere maintenance mechanism is a key hallmark of cancer. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly expressed in more than 80% of tumors, including hepatocellular carcinoma (HCC). However, the exact mechanisms by which hTERT is up-regulated in HCCs and promotes tumor growth and progression is not fully understood. The aim of this study was to discover the novel molecular targets that modulate hTERT signaling and HCC growth. In this study, we pulled down and identified RBFOX3 (RNA binding protein fox-1 homolog 3) as a novel hTERT promoter binding protein in HCC cells using biotin-streptavidin-agarose pull-down and proteomics approach, and validated it as a regulatory factor for hTERT signaling and tumor growth in HCCs. Knockdown of RBFOX3 suppressed the promoter activity and expression of hTERT and consequently inhibited the growth and progression of HCC cells in vitro and in vivo. The suppression of HCC growth mediated by RBFOX3 knockdown could be rescued by hTERT overexpression. Conversely, exogenous overexpression of RBFOX3 activated the promoter activity and expression of hTERT and promoted the growth and progression of HCC cells. Moreover, we found that RBFOX3 interacted with AP-2beta to regulate the expression of hTERT. Furthermore, we demonstrated that RBFOX3 expression was higher in the tumor tissues of HCC patients compared to the corresponding paracancer tissues, and was positively correlated with hTERT expression. Kaplan-Meier analysis showed that the HCC patients with high levels of RBFOX3 and hTERT had poor prognosis. Collectively, our data indicate that RBFOX3 promotes HCC growth and progression and predicts a poor prognosis by activating the hTERT signaling, and suggest that the RBFOX3/hTERT pathway may be a potential therapeutic target for HCC patients. PMID- 28839470 TI - Decoding Noncoding RNAs: Role of MicroRNAs and Long Noncoding RNAs in Ocular Neovascularization. AB - Ocular neovascularization is a pathological sequel of multiple eye diseases. Based on the anatomical site into which the abnormal neovessels grow, ocular neovascularization can be categorized into corneal neovascularization, choroidal neovascularization, and retinal neovascularization. Each category is intractable, and may lead to blindness if not appropriately treated. However, the current therapeutic modalities, including laser photocoagulation, vitrectomy surgery, and anti-VEGF drugs, raise concerns due to limited efficacy, damage on retinal parenchyma and vasculature, and the patients' unresponsiveness to the treatments. Therefore, the in-depth study on pathogenesis of and the search for novel therapeutic targets to the ocular neovascularization are needed. During the last 10 years or so, a large number of literatures have emerged indicating a critical role of noncoding RNAs, particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), in the pathogenesis and regulation of the ocular neovascularization. This review summarizes the current understanding of the biosynthesis and functions of the miRNAs and lncRNAs, the regulation of the miRNAs and lncRNAs in neovascular eye diseases, as well as the roles of these noncoding RNAs in the disease models of ocular neovascularization, in the hope that it could provide clues for the pathogenesis of and molecular targets to the ocular neovascularization. PMID- 28839471 TI - Spider Toxin Peptide Lycosin-I Functionalized Gold Nanoparticles for in vivo Tumor Targeting and Therapy. AB - Cell penetrating peptides (CPPs) are commonly utilized for intracellular delivery of functional materials to circumvent biomembrane barrier. However, further application of CPPs is hindered by lacking selectivity toward targeted cells. The spider venom peptide, lycosin-I, is a CPP with potent cytotoxicity to cancer cells, which might enable lycosin-I to deliver functional materials into cancer cells selectively. In this study, we demonstrated that the lycosin-I-conjugated spherical gold nanoparticles (LGNPs) not only exhibited efficient cellular internalization efficiency toward cancer cells but also displayed unprecedented selectivity over noncancerous cells. Although LGNPs were removed from the living circulatory system via reticuloendothelial system-dominant clearance modes without noticeable adverse effects to animals, they actually displayed active tumor-targeting effects and efficient accumulation in tumors in vivo. Furthermore, the potential application of this platform for cancer therapy was explored by lycosin-I-conjugated gold nanorods (LGNRs). LGNRs exhibited selective intracellular translocation towards cancer cells and efficient photothermal effect under near infrared (NIR, 808 nm) irradiation, which consequently killed cancer cells in vitro and in vivo effectively. Therefore, the established LGNPs and LGNRs possessed great potential in cancer-targeting delivery and photothermal therapy. PMID- 28839472 TI - Docosahexaenoic Acid Inhibits Vascular Smooth Muscle Cell Proliferation Induced by Glucose Variability. AB - BACKGROUND: Vascular Smooth Muscle cells (VSMC) enact crucial roles in early vasculogenesis and sustenance of vascular integrity. However, aberrant proliferation of VSMC followed by migration into the blood vessel wall leads to the formation of vascular lesions accounting for the degeneration and remodelling of vascular basement membrane. In diabetes, hyperglycaemia accelerates VSMC proliferation and contributes to the initiation and progression of atherosclerotic lesions. Recently, acute glucose fluctuations have been implicated in the abnormal VSMC proliferation and complications of diabetic atherosclerosis. Docosahexaenoic acid (DHA), a omega-3 polyunsaturated fatty acid (PUFA) has been shown to inhibit proliferation of several cell types implicating several different mechanisms. In the present study, we have investigated the effects of DHA on VSMC proliferation induced by stable and intermittent high glucose levels. METHOD: Confluent cultures of rat aortic VSMCs were treated with DHA for 24 hrs and then exposed to stable high glucose (25 mmol/L, SHG) or intermittent high glucose (5 mmol/L and 25 mmol/L alternating every 12 hrs, IHG) for 72 hrs. Cell proliferation was examined by the MTT viability assay, while apoptosis process was evaluated by the Hoechst staining, flow cytometry and caspase-3 activity assays. RESULTS: Our data demonstrated that the hyper proliferation induced by stable and intermittent high glucose levels was significantly inhibited by the DHA pre-treatment. DHA significantly increased caspase-3 activity, resulting in enhanced DNA fragmentation and apoptosis. CONCLUSION: Our results suggest that DHA reduced the high glucose-induced proliferation of VSMC and induced cell apoptosis. PMID- 28839473 TI - Standardization of DNA Residual Quantification Method of Vero Cell Rabies Vaccine for Human Use. AB - OBJECTIVES: Normalize the quantification of residual DNA from Vero cells in the rabies vaccine for use in human VAHV I, by quantitative PCR in real time and the design of primers that amplified, highly repetitive sequences of Cercopithecus aethiops and a constitutive gene according to sequences reported in the GenBank and quantifying the residual DNA in the vaccine VAHV I in three consecutive batches according to the standard set by the World Health Organization. METHODS: A real time quantitative method based on SYBR Green chemistry has been applied for the quantification of residual DNA (resDNA) using highly repetitive DNA (Alu) and a housekeeping gene (B-actin) as target sequences. RESULTS: The sensitivity achieved with this white sequence is within the reported limits and who are between 5 and 50 pg. For real time PCR optimization with Alu-p53, different concentrations of MgCl2 (0.5, 0.75, 1.0, 1.25 and 1.5 mm) in combination with three different concentrations of primers (75, 100 and 150nM) were used. pDNA in concentration of 1x107 copies / ul was used as template. Optimal concentrations were 1.25 mM MgCl2 and 100nM primers. To level of detection of 1.53 ng/ul was found for p53-Alu and Alu-Glob and 0.39 ng/ul for B-actin with gDNA curves. CONCLUSION: Quantification of resDNA of vaccine VAHV I with close-ups of B-actin was normalized. Reached a sensitivity of 30 pg of resDNA/dose VAHV I, with close ups of B-actin. Found, in three consecutive batches, an amount less than 10 ng/dose, these results suggest that the production process ensures vaccine resDNA removal, meeting international requirements for biological products for use in humans that use continuous cell lines for production. PMID- 28839474 TI - Oxidative Stress Evaluation in Patients Treated with Orthodontic Self-ligating Multibracket Appliances: An in Vivo Case-Control Study. AB - OBJECTIVE: Oxidative stress is a pathologic event induced by a prevalence of oxidant agents on the antioxidant ones, with a consequent alteration of oxide reducing balance. INTRODUCTION: Freeradicals produce damages both in cellular and extra-cellular components; phospholipid membranes, proteins, mitochondrial and nuclear DNA, are the target of the oxidative stress, that can finally cause cellular death due to apoptosis. MATERIALS & METHODS: Orthodontic appliances such as brackets, wires, resins and soldering have some components that can be considered as potential allergen, carcinogenic, cytotoxic and gene mutation factors. The primary aim of this research is to evaluate oxidative stress in the saliva of patients treated with multibracket self-ligating vestibular orthodontic appliances; the secondary purpose is to investigate the influence of orthodontic multibracket therapy on oral hygiene and the consequent effect on oxidative stress. Salivary specimens has been collected in a sample of 23 patients were enrolled (12 Female, 11 Male) between 12 and 16 years of age (mean age 14.2). For each patient has been collected a salivary specimen at the following time points; before orthodontic bonding (T1), five weeks (T2) and ten weeks (T3) after orthodontic appliance bonding. RESULTS: Samples has been analysed with a photometer due to SAT Test (Salivary Antioxidant Test). Data obtained show a mean of 2971 mEq/l of anti-oxidant agents before orthodontic treatment, and after five weeks from the bonding the mean was decreased to 2909 mEq/l, instead at ten weeks was increased to 3332 mEq/l. Repeated measures ANOVA did not reveal statistically significant differences between the time points (P = 0.1697). The study did not reveal any correlation between the level of dental hygiene and that of oxidative stress (Pearson Correlation Coefficient R = 0). CONCLUSION: Orthodontic treatment with multibrackets vestibular metallic appliance seems to be not able to affect oxidative stress during the first ten weeks of therapy. PMID- 28839475 TI - The Coronal Tooth Fractures: Preliminary Evaluation of a Three-Year Follow-Up of the Anterior Teeth Direct Fragment Reattachment Technique Without Additional Preparation. AB - OBJECTIVE: The aim of this research is to describe and to analyse the long-term results and the clinical steps of direct fragment reattachment technique with no additional tooth preparation, used to treat crown fracture. This technique achieves the clinical success, combining satisfactory aesthetic and functional results with a minimally invasive approach. METHODS: The 3 years follow-up included 9 patients (5 males, 4 females) with coronal fracture. In all the cases the fragment was available and intact. The authors illustrate the adhesive procedure used. Under local anaesthesia and after positioning the rubber dam, both the tooth and the fragment surface were etched, rinsed and applied by the adhesive system in order to obtain the retention of the fractured part to the tooth without additional tooth preparation or resin cement. RESULTS: The statistical analysis shows the good performances of direct fragment reattachment technique. After 36 months, in 22.2% of the cases, the detachment was observed of the bonded fragment and in 11.1% of patients, complications were recorded. CONCLUSION: Our clinical experience shows how the ultra-conservative procedure used is fast, easy and offers a long term predictability; it also allows good functional and aesthetic outcomes. PMID- 28839476 TI - Bond Capability of Universal Adhesive Systems to Dentin in Self-etch Mode after Short-term Storage and Cyclic Loading. AB - OBJECTIVE: The aim was to evaluate, in vitro, the tensile bond strength to dentin of Scotchbond Universal (SU), All-Bond Universal (AU) and One Coat 7 Universal (OC7) adhesives applied in self-etch mode, after 24 h of storage and after 500,000 loading cycles, using Clearfil SE Bond (SE) as a control. MATERIALS AND METHODS: The adhesives were applied on the dentin of bovine teeth, followed by the application of a composite resin. Thirty specimens were obtained for each adhesive. Half of the specimens were submitted to cyclic loading for 500,000 cycles. All specimens were submitted to a tensile bond strength test in a universal testing machine at a crosshead speed of 0.5 mm/minute. RESULTS: According to two-way ANOVA and Tukey's test (alpha=5%), the interaction between the adhesive and cyclic loading factors was significant (p=0.001). The means followed by the same letter represent no significant difference in the bond strength (MPa) after 24 h: OC7=7.86A (+/-2.90), SU=6.78AB (+/-2.03), AU=5.61BC (+/-2.32), and SE=3.53C (+/-1.89). After cyclic loading, SE, SU and AU maintained bond strength comparable to 24 h period. There was a significant decrease only for OC7. CONCLUSION: SU, AU and OC7 had bond strength to dentin comparable to that of SE. Only OC7 had decreased bond strength to dentin after cyclic loading. PMID- 28839477 TI - Rotational Flap to Enhance Buccal Gingival Thickness and Implant Emergence Profile in the Esthetic Zone: Two Cases Reports. AB - OBJECTIVE: Many techniques have been developed to enhance the gingival thickness, gingival level and emergence profile around the implant in the esthetic zone. INTRODUCTION: In this study, a buccal rotational flap was used to improve the implant site in the esthetic zone and increase gingival tissue thickness. METHODS: Two cases involved the use of a rotational flap during second-stage implant surgery, one case involved the use of a temporary crown with a healing abutment, and another case involved the use of a healing abutment. RESULT: The cases were followed up until the final crown was placed. The implant site was improved in 2 cases; the gingival thickness increased, the gingival level was enhanced and the emergence profile was developed. CONCLUSION: Many factors affect the results of a rotational flap; some factors are surgical, while others are prosthetic, biological and anatomical. PMID- 28839478 TI - Epidemiology of Surgically Managed Mandibular Condylar Fractures at a Tertiary Referral Hospital in Urban Southwest China. AB - BACKGROUND: Mandibular condylar fracture is one of the commonest maxillofacial fractures treated by maxillofacial surgeons. Demography of the patients, causation, and characteristics of the fracture depends on various socio-economic factors. Hence, maxillofacial surgeons should be familiar with epidemiology of mandibular condylar fracture. OBJECTIVE: This study retrospectively describes the demography, etiology, fracture characteristics, and hospital utilization of surgically treated mandibular condylar fractures in a tertiary referral hospital in urban China in past five years. METHODS: Data of all patients who underwent surgical management between 2011 and 2015 were collected. This included aetiology, characteristics of fracture, time, age, sex, associated injuries, and hospital utilization of 166 patients with 208 mandibular condylar fractures. These patients had undergone open reduction and internal fixation with either miniplates or lag screws. Among the fracture of head of mandibular condyle, 21.28% of the patients had the fracture segments removed. These data were statistically analyzed to describe the epidemiology of mandibular condylar fracture. RESULTS: Most of the patients had unilateral mandibular condylar fractures (74.7%). Male patients (76.51%) outnumbered female patients (23.49%) in this cohort. The average age of the patients was 37 years. The fractures were mostly caused by fall from height (60.84%) and were located at the condylar neck (53.61%). Most of the patients had other associated maxillofacial injuries (71.08%) which were mostly located at symphysis and parasymphysis (44.59%). It took 12.58 +/- 0.35 days of hospitalization for the treatment. CONCLUSION: Fall from height was the most prevalent cause of mandibular condylar injury in mountainous urban China. The people at highest risk were middle-aged men. Mandibular condylar fracture was mostly located at the condylar neck and was usually associated with fracture at the symphysis and parasymphysis. PMID- 28839479 TI - Efficacy of Selective Grinding Guided by an Occlusal Splint in Management of Myofascial Pain: A Prospective Clinical Trial. AB - BACKGROUND: For patients whose centric relation (CR) has not been considered at the start and during treatment, the task of achieving an occlusal scheme that works together with the temporomandibular joint, the muscles, and the structures of the stomatognathic apparatus becomes a major concern. OBJECTIVE: This study aims to describe a reproducible, predictable and to date unreported procedure of selective grinding guided by an occlusal splint and to analyze condylar position (CP) based on the skeletal pattern. METHODS: A total of 72 symptomatic patients (38 females and 34 males) were classified into three groups: hyperdivergent, intermediate and hypodivergent. CP was quantified by mounted casts on a measures condyle displacement (MCD) device. Helkimo index was also performed in order to assess the severity of the temporomandibular joint (TMJ) disorders attending to clinical dysfunction, occlusal state and anamnestic dysfunction. Once the stability had been obtained, the splint was progressively reduced until the maximum intercuspation (MIC) was achieved. RESULTS: The vertical displacement was found to be significantly different between the hyperdivergent and other two groups (p<0.01). Comparisons of MCD analysis before and after the selective grinding procedure identified a statistically significant difference in the horizontal and vertical CP (p<0.01) between the different groups whereas the Helkimo Index showed a clear improvement of TMJ disorders. CONCLUSION: All facial types, specially the hyperdivergent face type, showed a reduction in condylar displacement (CD) and less craniomandibular symptoms using this procedure, making it an excellent technique for clinicians. PMID- 28839481 TI - Oro-Maxillofacial Radiology and Imaging: An Update. PMID- 28839482 TI - Comparison of Mesiodistal Root Angulation Measured from Conventional and CBCT Derived Panoramic Radiographs in Orthodontic Patients. AB - INTRODUCTION: Use of cone beam computed tomography (CBCT) in orthodontics is increasing; however, some patients started treatment with conventional images. The objective of this study is to manipulate CBCT panoramic reconstruction to make it comparable to conventional panoramic image and to compare mesiodistal root angulations on both images. MATERIALS AND METHODS: Concurrent conventional panoramics and CBCT volumes were obtained from 40 subjects. CBCT volumes were manipulated to generate pan-like images that mimic the occlusal plane angle of the corresponding panoramic, allowing comparison of mesiodistal root angulations and determination of the head-tilt required to produce the reconstruction. RESULTS: Clinically meaningful differences (p < .05) in the mesiodistal root angulations between standard panoramics and CBCT reconstructions emerged for 13 out of 24 teeth (54%). Greatest variations were seen in the maxillary and mandibular sextants and in first molar regions. Ideal axial head-tilt for image acquisition was determined to be with Frankfort horizontal plane 3.3o nose down. CONCLUSION: CBCT pan images must be used with caution due to variation between methods in specific areas of arches. The images can be useful for the assessment of mesiodistal root angulations if the volume is properly manipulated to create a pan-like image. PMID- 28839480 TI - Insight into Oral Biofilm: Primary, Secondary and Residual Caries and Phyto Challenged Solutions. AB - INTRODUCTION: Dental caries is known to be one of the most widespread, chronic infections affecting all ages and populations worldwide. The plethora of oral microbial population paves way for various endogenous infections and plays a crucial role in polymicrobial interactions contributing to biofilm-mediated diseases like caries and periodontal diseases. METHODS: Extensive literature survey was conducted using the scientific databases like PubMed, Google scholar, Science Direct, etc. using the key words like dental caries, orodental infections, dental microbes, dental biofilm, secondary caries, phytotherapy, etc. The literature was analyzed thoroughly and critical review was performed. RESULTS: The risk of development of secondary caries and residual caries further results in treatment failure. Drug resistance developed by oral microbes and further side effects pose serious hurdles in the current therapeutic strategies. The hyperactivities of various MMPs and the resulting massive ECM degradation are the challenging part in the design of effective therapeutic approaches. Anticariogenic phytotherapy is well appreciated owing to lesser side effects and versatility of their action. But appreciable outcomes regarding the phytochemical bioavailability and bioretention are still challenging. Site-specific delivery of phytoagents at the infected site may enhance the efficiency of these drugs. Accordingly emerging phytodentistry can be promising for the management of secondary and residual caries. CONCLUSION: This article presents major cariogens and their mechanisms in initiating and aggravating dental caries. Effectiveness of phytotherapy and different mode of action of phytochemicals against cariogens are outlined. The article also raises major concerns and possibilities of phytochemical based therapeutics to be applied in the clinical arena of caries management. PMID- 28839483 TI - Efficacy of Panoramic Radiography in the Detection of Osteoporosis in Post Menopausal Women When Compared to Dual Energy X-Ray Absorptiometry. AB - OBJECTIVE: It is a well-known fact that osteoporosis affects the people with old age and remains unnoticeable until the patient presents with fracture. Various studies in the literature reveal that panoramic radiographs may prove to be beneficial in the detection of Osteoporosis in patients. Henceforth this present study was aimed to validate the use of Klemetti Index (KI) on panoramic radiographs so as to detect osteoporosis in the patients at an early stage. METHODS: 60 postmenopausal women were selected. A panoramic radiograph was taken to grade their mandibular cortex on the basis of Klemetti Index. All the panoramic radiographs were evaluated by 5 different Oral Medicine and Radiology specialists. Later all the patients were subjected to dual energy X-ray absorptimetry (DEXA) scan for bone mineral density evaluation. The results were evaluated statistically. RESULTS: The average accuracy of the five observers to demonstrate normal bone, osteopenia and osteoporosis when compared to DEXA scan was 58.08%, 63.3% and 64.74% respectively. The observations of the 5 observers on the basis of KI were not statistically different from the BMD evaluation done with the help of DEXA Scan. CONCLUSION: Panoramic radiographs can be used as a screening tool for the evaluation as well as early detection of osteoporosis with the usage of Klemetti Index. PMID- 28839484 TI - Evaluation of Distolingual Canal/Roots in Mandibular Molars and Mesiobuccal Canals in Maxillary Molars by CBCT. AB - BACKGROUND/PURPOSE: The objectives of this study were to identify the bilateral distolingual (DL) canals / roots of the mandibular first molars and second mesiobuccal (MB2) canals of the maxillary first molars in the same Turkish individuals using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: A total of 150 CBCT images including all mandibular and maxillary first molars were retrospectively investigated in a Turkish subpopulation. The patient age, sex and presence of roots and root canals were assessed. The frequency, of bilateral DL canals, DL roots, and MB2 canals were reviewed. Data were analyzed using Fisher'sexact test and Chi-square test. RESULTS: The prevalences of right DL canals, DL roots and MB2 canals were 31.3, 14.0 and 34.7%, respectively. The prevalences of left DL canals, DL roots and MB2 canals were 31.3, 4 and 27.3%, respectively. There was no statistically difference in the frequency of right and left DL canals, DL roots of mandibular first molars and MB2 canals of maxillary first molars according to gender. CONCLUSION: CBCT is a competent tool for the detection of additional distolingual canals/roots and second mesio buccal canals, and it is a valuable aid for dentists providing root canal treatment. PMID- 28839485 TI - Role of Sinonasal Anatomic Variations in the Development of Maxillary Sinusitis: A Cone Beam CT Analysis. AB - BACKGROUND: Several anatomical variations can lead to the inflammation of the paranasal sinuses; therefore, surgeons should be familiar with these variations and their impacts on the status of the paranasal sinuses. OBJECTIVES: The present study aimed to determine the prevalence of Haller cells and its association with patients' sex and age. Furthermore, the relationships between the presence and size of Haller cells, deviation of the uncinate process and size of the maxillary sinus ostium with the occurrence of maxillary sinusitis were investigated. MATERIALS/ PATIENTS AND METHODS: 120 coronal CBCT images were retrieved and analyzed. Statistical analysis of the data was performed by means of Mann - Whitney, chi2 and T tests. RESULTS: There were statistically significant associations between the presence and surface area of Haller cells and the occurrence of ipsilateral maxillary sinusitis. Neither the angulation of the uncinate process nor the size of the maxillary sinus ostium significantly correlates with the formation of maxillary sinusitis. CONCLUSION: Haller cells can interfere with the normal drainage of the maxillary sinus and result in sinusitis. In contrast, diameter of the sinus ostium and deviation of the uncinate process do not influence the inflammatory status of the maxillary sinus significantly. PMID- 28839486 TI - Facial Soft Tissue Thickness of Midline in an Iranian Sample: MRI Study. AB - BACKGROUND AND AIM: To identify human skeletal remains, different methods can be used and using these techniques, important data can be obtained. However, facial reconstruction is the last method to indentify unknown human faces which requires knowledge about facial soft tissue thickness in the different positions of the face. The present study determined the facial soft tissue thickness in the different landmark points on the MRI images of patients referred to Radiology Department of Shahid Madani Hospital. MATERIALS AND METHODS: In this descriptive cross-sectional trial, MRI images of 179 patients (61 males, 118 females) in the age range of 18-76 years old who did not show any pathologic lesions, were selected. The measurements of the facial soft tissue were done on 12 landmark points on the midline area by two radiologist observers using specific software on the images. The differences in the soft tissue thickness in these landmark points were statistically analyzed by Mann-Whitney U (in term of gender) and Kruskal-Wallis tests (in terms of Body Mass Index [BMI] and age groups). P value less than 0.05 was considered statistically significant. The data were compared with the results of other studies. RESULTS: The results obtained in the present study were higher than Turkish and American studies in most of the landmark points. Facial soft tissue thickness in most of the landmarks was more in males than females. In some of the landmarks, significant differences were found between emaciated, normal and overweight patients while in most cases, soft tissue thickness increased with the increased BMI. In some cases, significant differences were noted between soft tissue thickness values among the different age groups, in which the thickness increased or thinned with the increased age. STATISTICAL ANALYSIS: There were statistically significant associations between the presence and surface area of Haller cells and the occurrence of ipsilateral maxillary sinusitis. Neither the angulation of the uncinate process nor the size of the maxillary sinus ostium significantly correlates with the formation of maxillary sinusitis. CONCLUSION: The data achieved in the present study can be used for the facial reconstruction purposes in the Iranian population; however, the slight differences existing between the studied population and other subgroup races must be considered for accurate reconstructions. PMID- 28839487 TI - Computed Tomography in Craniofacial Fibrous Dysplasia: A Case Series with Review of Literature and Classification Update. AB - INTRODUCTION: Fibrous dysplasia (FD) is a fibroosseous lesion of the osseous structures of the body. It is not a commonly reported lesion yet it is considered as an important lesion which can affect the maxillofacial region as well. As a result, it can cause deformity of the jaw bones which can further lead to severe facial asymmetry. Craniofacial fibrous dysplasia (CFD) is one of the subtypes of FD that can affect the bones of the craniofacial complex, including the mandible and maxilla. It can also present as facial asymmetry and can be investigated with the help of Maxillofacial Radiology and Imaging. The radiographic findings may vary according to the extent and degree of the disease. Although conventional radiographs provide a good clue regarding the lesion, advanced maxillofacial imaging is capable of providing detailed extent of the disease. Furthermore the classification of CFD is not very clear in the literature. CASE REPORT: This particular paper attempts to document and report the CT appearance of CFD with an attempt to propose a better classification system for the same. Four different patients are reported which presented with FD with involvement of bones of craniofacial region. Working diagnosis of CFD was made with the help of clinical features as well as with radiographic assessment. Advanced imaging included CT scan of the lesions. The article highlights the importance of computed tomography in diagnosis as well as assessment of extent of the disease. CONCLUSION: It can be concluded that the Dental professionals must be aware regarding the different radiographic appearances of CFD. Advanced imaging modality like CT can provide with exact diagnosis as well as extent of the lesions like FD. Further collaboration of researchers is required to incorporate this proposed change in classification of CFD. PMID- 28839488 TI - Ultrasonographic Appearances of Cervical Lymph Nodes in Healthy Turkish Adults Subpopulation: Preliminary Study. AB - OBJECTIVES: The aim of the study was to assess whether there was any relation between age, gender and body mass index (BMI) and nodal forms and vascular type in healthy Turkish adults. STUDY DESIGN: Three neck areas in 25 wholesome patients who were aged from 21 to 58 years, were assessed by gray-scale and color doppler ultrasonography. Ultrasonographic examinations were performed using an ALOKA Prosound Alpha 6 (Hitachi Aloka Medical Systems, Tokyo, Japan) and the images were obtained with a 7.2 MHz linear array transducer. Hajek's categorization of cervical lymph nodes for sonographic analysis was used. The ultrasonographic characteristics like size, shape, short axis/long axis ratio (S/L), hilum were evaluated. Ultrasonographic examinations of upper cervical, submandibular and submental lymph nodes were carried out and recorded. RESULTS: The mean age of patients was 31.84+/-12.80 years. The ratios of lymph nodes with avascular pattern were 96% for the upper cervical lymph area, 92% for the submandibular area and 96% for the submental area. The lowest and highest ratios of short to long axis diameter (S/L) were calculated as 0.18 and 0.66 in all areas. Most normal nodes in the study were oval with an S/L ratio of less than 0.5. CONCLUSION: Normal cervical lymph nodes are oval, with an unsharp border and an echogenic hilum but no relation between the age, gender and BMI. Also ultrasonography is an applicable imaging modality for the examination of cervical lymph nodes. However, the deficiency in the number of patients might not allow to generalise our findings to the general populations. PMID- 28839489 TI - Giant Complex Odontoma of Mandible: A Spectacular Case Report. AB - INTRODUCTION: Odontomas are considered as benign tumors of odontogenic tissue origin and are more over non-aggressive. They can also be categorized as hamartomas and are a result of developmental malformation of odontogenic tissues. As the name suggests, they are composed of mature tooth substances. They possess limited and slow growth potential and are well differentiated. They can be ectodermal, mesodermal or mixed in origin. Mixed variety may be further divided into compound or complex depending upon their radio-graphical resemblance to the tooth. Compound odontomes are reported to be twice more common than complex odontomes. Among them, complex odontomes are asymptomatic unless they cause bony expansion of the jaws. CASE REPORT: This paper aims to report and discuss a case of complex odontoma with unusually large size leading to gross facial asymmetry. Further this paper will highlight the important information the general dental practitioner must possess to diagnose such lesions at an early stage. CONCLUSION: Odontomas are benign odontogenic tumors with unusually large size leading to gross facial asymmetry. The general dental practitioners must possess the knowledge and important information to diagnose such lesions at an early stage. PMID- 28839490 TI - Effects of Prenatal Consumption of Caprine Milk Oligosaccharides on Mice Mono associated with Bifidobacterium Bifidum (AGR2166). AB - BACKGROUND: Prenatal consumption of oligosaccharides are associated with changes in the maternal gastrointestinal tract (GIT) microbiota with health consequences for the offspring. It has previously been demonstrated that caprine milk oligosaccharides (CMO) stimulate the growth and fermentation rate of Bifidobacterium bifidum AGR2166. OBJECTIVE: The objective of this study was to examine the effects of B. bifidum AGR2166 and prenatal consumption of CMO, alone or in combination, on the dam's large intestine, foetal development and ability of B. bifidum to translocate from the gastrointestinal lumen to organs and foetal membranes. METHOD: Germ-free BALB/c mice, inoculated with B. bifidum AGR2166 or anaerobic phosphate buffer, were fed either diet supplemented with CMO or with galacto-oligosaccharide. Pregnant mice were euthanised 1 to 3 days before the expected delivery date and samples collected for analysis. RESULTS: Dietary CMO, regardless of bifidobacterial inoculation was shown to increase GIT weight and to reduce foetal weight compared to galacto-oligosaccharide-fed dams. B. bifidum AGR2166 DNA was detected in the mesenteric lymph nodes, liver, plasma and placenta of the dam by amplification of the bifidobacterial 16S rRNA gene. CONCLUSION: B. bifidum AGR2166 DNA was detected in maternal organs, however there is no indication that live bifidobacteria was able to translocate during pregnancy. Further studies using conventionally-raised mouse models will develop a deeper understanding of the interactions between dietary CMOF, the host, and bacteria. PMID- 28839492 TI - Misinterpretation of Gram Stain from the Stationary Growth Phase of Positive Blood Cultures for Brucella and Acinetobacter Species. AB - INTRODUCTION: Acinetobacter baumannii and Brucella species are Gram-negative organisms that are vulnerable to misinterpretation as Gram-positive or Gram variable in blood cultures. OBJECTIVE: We assess the random errors in gram stain interpretation to reduce the likelihood of such errors and therefore patient harm. METHODOLOGY: Aerobic and anaerobic blood cultures from two patients in an acute care facility in Saudi Arabia were subjected to preliminary Gram-staining. In case 1, VITEK-2 Anaerobe Identification, repeat Gram staining from a blood agar plate, Remel BactiDropTM Oxidase test, Urea Agar urease test and real-time PCR were used to confirm presence of Brucella and absence of Coryneform species. In case 2, repeat Gram- staining from the plate and the vials, VITEK-2 Gram Negative Identification, real-time PCR and subculture on to Columbia agar, blood agar, and MacConkey agar were carried out to identify A. baumannii. RESULTS: In case 1, initially pleomorphic Gram-positive bacteria were identified. Coryneform species were suspected. Tiny growth was observed after 24 h on blood agar plates, and good growth by 48 h. Presence of Brucella species was ultimately confirmed. In case 2, preliminary Gram-stain results suggested giant Gram-positive oval cocci. Further testing over 18-24 h identified A. baumannii. CONCLUSIONS: Oxidase test from the plate and urease test from the culture vial is recommended after apparent identification of pleomorphic Gram-positive bacilli from blood culture, once tiny growth is observed, to distinguish Brucella from Corynebacterium species. If giant Gram-positive oval cocci are indicated by preliminary Gram staining, it is recommended that the Gram stain be repeated from the plate after 4-6 h, or culture should be tested in Triple Sugar Iron (TSI) medium and the Gram stain repeated after 2-4 h incubation. PMID- 28839491 TI - Non-Coding RNAs are Differentially Expressed by Nocardia brasiliensis in Vitro and in Experimental Actinomycetoma. AB - INTRODUCTION: Nocardia spp. are common soil-inhabiting bacteria that frequently infect humans through traumatic injuries or inhalation routes and cause infections, such as actinomycetoma and nocardiosis, respectively. Nocardia brasiliensis is the main aetiological agent of actinomycetoma in various countries. Many bacterial non-coding RNAs are regulators of genes associated with virulence factors. OBJECTIVE: The aim of this work was to identify non-coding RNAs (ncRNAs) expressed during infection conditions and in free-living form (in vitro) in Nocardia brasiliensis. METHODS AND RESULT: The N. brasiliensis transcriptome (predominately < 200 nucleotides) was determined by RNA next generation sequencing in both conditions. A total of seventy ncRNAs were identified in both conditions. Among these ncRNAs, 18 were differentially expressed, 12 were located within intergenic regions, and 2 were encoded as antisense of 2 different genes. Finally, 10 of these ncRNAs were studied by rapid amplification of cDNA ends and/or quantitative reverse transcription polymerase chain reaction. Interestingly, 3 transcripts corresponded to tRNA-derived fragments (tRNAsCys, Met, Thr), and one transcript was overlapped between an intergenic region and the 5'end of the 23S rRNA. Expression of these last four transcripts was increased during N. brasiliensis infection compared with the in vitro conditions. CONCLUSION: The results of this work suggest a possible role for these transcripts in the regulation of virulence genes in actinomycetoma pathogenesis. PMID- 28839493 TI - Diversity of Multidrug Efflux Genes and Phenotypic Evaluation of the In vitro Resistance Dynamics of Clinical Staphylococcus Aureus Isolates Using Methicillin; a Model beta-lactam. AB - OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) across the world often leave clinicians with little or no choice of treatment options. The multi drug efflux (MDE) genes are bacterial survival mechanisms responsible for the pumping out of antibiotics and other biocides from the cytoplasm. Whilst effort is being made in the development of antibiotic adjuvants such as efflux pumps inhibitors, information is needed on the diversity of these MDEs in the circulating S. aureus and on the growth dynamics of the clinical isolates in response to antibiotics is not regularly examined. METHODS: Here, we evaluated the diversity of MDEs in cinical S. aureus recovered in a tertiary academic hospital, Pretoria, South African hospital using PCR and also employed visual minimum inhibitory concentration and quantitative analysis of spectrophometric measurements of bacterial growth in the presence of a model beta lactam antibiotic (methicillin), to phenotypically elucidate the resistance pattern of these isolates in response to methicillin. RESULTS: Three major distribution patterns of MDEs were observed in the clinical isolates evaluated. Moreover, norA, nor B and tet38 were present in 98.9% of the isolates while other MDE were present in different proportions ranging from 40 to 98.6% of the isolates. In addition, S. aureus isolates, be it of MRSA or MSSA genotype did not habour the same set of MDEs despite being recovered from the same hospital setting. Finally, we showed that MSSA displayed phenotypic resistance to methicilllin despite the non-detection of the mecA resistance gene. CONCLUSIONS: Our data suggest that the growth of S. aureus may be enhanced by beta lactams (methicillin) and that MSSA may also display resistance to methicillin and perhaps other beta lactam antibiotics. The high prevalence of MDEs suggestive of resistance to a broad spectrum of biocides and fluoroquinolones are particularly disturbing. PMID- 28839495 TI - Survival of Hypercapnic Patients with COPD and Obesity Hypoventilation Syndrome Treated with High Intensity Non Invasive Ventilation in the Daily Routine Care. AB - BACKGROUND: Home ventilation is an effective treatment option for obesity hypoventilation syndrome (OHS). This therapy is still controversial for stable chronic obstructive pulmonary disease (COPD). A recent study showed reduced mortality for COPD patients receiving home ventilation with high inflation pressures and back-up respiratory rates [so called High Intensity non-invasive ventilation (NIV)]. OBJECTIVE: The purpose of this study is whether High Intensity NIV applied in the routine care of COPD and OHS patients can lead to CO2 reduction and survival data comparable to data from controlled studies. METHOD: In this prospective non interventional study fifty-one patients with COPD (FEV1 0.95l, corr. 32.8%) and 34 patients with OHS (VC 1.74l, corr. 50.7%) with chronic hypercapnic respiratory failure, who were treated with NIV were followed up for four years. RESULTS: Elevated CO2 values before NIV in COPD patients (8.6kPa), and in OHS patients (8.3kPa), could be lowered significantly to the upper normal range (COPD: 5.9kPa; OHS: 5.85kPa). The one-, two-, and three-year survival rates for COPD patients were 83%, 73%, and 55%, respectively. The one-, two-, and three-year survival rates for OHS patients were 85%, 72%, and 68%, respectively. CONCLUSION: High intensity NIV within routine care is effective in reducing blood CO2 levels in COPD- and in OHS- related chronic respiratory insufficiency. The survival rates obtained here are comparable to data from controlled clinical trials on COPD. PMID- 28839494 TI - Sub-Inhibitory Concentrations of Rifampicin Strongly Stimulated Biofilm Production in S. aureus. AB - BACKGROUND AND OBJECTIVES: Staphylococcus aureus is an important pathogen and a frequent cause of infections associated with biofilm production in implantable medical devices. Biofilm production can be induced by sub-inhibitory concentrations (sub-MICs) of certain antibiotics, but few studies have researched this occurrence in S. aureus. In this study, we investigated the effect of sub MICs of rifampicin and minocycline on biofilm production by five clinical and five non-clinical S. aureus isolates. METHODS: Microtiter Plate assay and Congo Red Agar Test were used to analyze the biofilm production. The biofilm composition was evaluated by the detachment assay with sodium metaperiodate and proteinase K. RESULTS: Rifampicin sub-MICs induced very high biofilm formation in seven isolates that were non-producers in Tryptic Soy Broth. In one producer isolate, the biofilm formation level was not affected by sub-MICs of this drug. Sub-MICs of minocycline did not induce biofilm production in all isolates tested and in two producer isolates, instead, MIC/2 and MIC/4 inhibited biofilm production. The results of the drugs in combination were similar to those with rifampicin alone. The biofilm matrix was identified as polysaccharide, except for one producer isolate, classified as proteinaceous. Polysaccharide biofilm producer isolates, when grown on Congo Red Agar without sucrose, but with sub MICs of rifampicin, showed results in agreement with those obtained in Microtiter Plate Test. CONCLUSION: The high biofilm production induced by sub-MICs of rifampicin has potential clinical relevance, because this is one of the drugs commonly used in the impregnation of catheters. In addition, it is used adjunctively to treat certain S. aureus infections. PMID- 28839496 TI - Use of Nasal Non-Invasive Ventilation with a RAM Cannula in the Outpatient Home Setting. AB - BACKGROUND: Nasal non-invasive-ventilation (Nasal NIV) is a mode of ventilatory support providing positive pressure to patients via a nasal interface. The RAM Cannula is an oxygen delivery device that can be used as an alternative approach to deliver positive pressure. Together they have been successfully used to provide respiratory support in neonatal in-patient settings. OBJECTIVE: To describe the outpatient use of Nasal NIV/RAM Cannula as a feasible alternative for home respiratory support in children with chronic respiratory failure. METHODS: We performed a retrospective case series of 18 children (4 months to 19 years old) using the Nasal NIV/RAM Cannula in the Pediatric Pulmonary Clinic at the McGovern Medical School, UTHealth (2014-16). Consideration for Nasal NIV/RAM Cannula utilization included: inability to wean-off in-patient respiratory support, comfort for dyspnea, intolerability of conventional mask interfaces and tracheostomy avoidance. RESULTS: Average age was 7 years. 50% were Caucasian, 38% African-American and 11% Hispanics. Pulmonary disorders included: chest wall weakness (38%), central control abnormalities (33%), obstructive lung disease (16%) and restrictive lung disease (11%). Indications for Nasal NIV/RAM Cannula initiation included: CPAP/BPAP masks intolerability (11%), dyspnea secondary to chest wall weakness (38%) and tracheostomy avoidance (50%). Average length of use of Nasal NIV/RAM Cannula was 8.4 months. Successful implementation of Nasal NIV/Ram Cannula was 94%. One patient required a tracheostomy following the use of Nasal NIV/RAM Cannula. Significant decrease in arterial PaCO2 pre and post Nasal NIV/RAM cannula initiation was notable (p=0.001). CONCLUSION: Outpatient use of Nasal NIV/RAM Cannula may prove to be a feasible and save treatment alternative for children with chronic respiratory failure, chest wall weakness, dyspnea and traditional nasal/face mask intolerance to avoid tracheostomy. PMID- 28839497 TI - Bronchodilator Response Assessment of the Small Airways Obstructive Pattern. AB - BACKGROUND: A concomitant decrease in FEV1 and FVC with normal FEV1/FVC ratio and TLC defines small airways obstructive pattern (SAOP) and constitutes a classic pitfall of pulmonary-function-tests interpretation. OBJECTIVE: To evaluate the prevalence of flow- (FEV1 increase>=12% and 200 mL), volume- (FVC or inspiratory capacity [IC] increase>=12% and 200 mL), flow and volume-, and non-response to bronchodilation in patients with SAOP. An additional objective was to assess whether impulse oscillometry (IOS) parameters allow the diagnosis of SAOP and its reversibility. METHODS: Fifty consecutive adult patients with SAOP (FEV1 and FVC < lower limit of normal, FEV1/FVC and TLC > lower limit of normal) diagnosed on spirometry and plethysmography underwent the assessment of reversibility (400 ug salbutamol) on FEV1, FVC, IC and IOS parameters. RESULTS: The diseases most frequently associated with SAOP were COPD and asthma (26 and 15 patients, respectively). Six patients were flow-responders, 20 were volume-responders, 9 were flow and volume-responders and 15 patients were non-responders. Overall, 26 patients had a significant improvement of IC, and 35 / 50 (70%, 95%CI: 57-83) exhibited a significant bronchodilator response. The difference between Rrs5Hz and Rrs20Hz was increased in 28/50 patients (56%, 95%CI: 42-70 with value higher than upper limit of normal) and its decrease after bronchodilator significantly correlated to FEV1 increase only, suggesting proximal airway assessment. CONCLUSION: A significant reversibility, mainly assessed on IC increase, is frequent in Small Airways Obstructive Pattern. Impulse oscillometry is of limited value in this context because of its low sensitivity. PMID- 28839498 TI - Assessment of Range of Movement, Pain and Disability Following a Whiplash Injury. AB - BACKGROUND: Whiplash has been suggested to cause chronic symptoms and long term disability. This study was designed to assess long term function after whiplash injury. MATERIAL & METHODS: A random sample of patients in the outpatient clinic was interviewed, questionnaire completed and clinical examination performed. Assessment was made of passive cervical range of movement and Visual Analogue Scale pain scores. One hundred and sixty-four patients were divided into four different groups including patients with no whiplash injury but long-standing neck pain (Group A), previous symptomatic whiplash injury and long-standing neck pain (Group B), previous symptomatic whiplash injury and no neck symptoms (Group C), and a control group of patients with no history of whiplash injury or neck symptoms (Group D). RESULTS: Data was analyzed by performing an Independent samples t-test and ANOVA, with level of significance taken as p<0.05. Comparing the four groups using a one-way ANOVA showed a significant difference between the groups (p<0.001). There were significant differences when comparing mean ranges of movement between Group A and Group D, and between Group B and Group D. There was no significant difference between Group C and Group D. similar differences were also seen in the pain scores. CONCLUSION: We conclude that osteoarthritis in the cervical spine, and whiplash injury with chronic problems cause a significantly decreased cervical range of movement with a higher pain score. Patients with shorter duration of whiplash symptoms appear to do better in the long-term. PMID- 28839499 TI - Tendon Repair Leads to better Long-Term Clinical Outcome than Debridement in Massive Rotator Cuff Tears. AB - INTRODUCTION: Massive tears in the rotator cuff are debilitating pathologies normally associated with loss of function and pain. Tendon reconstruction is seen as the standard treatment in order to preserve shoulder function and to inhibit cuff associated osteoarthritis. However, the effect on longer-term shoulder function and patient satisfaction is unknown. MATERIAL AND METHODS: 165 consecutive patients with massive tears were included. 57 debridement (mean age 61.9+/-8.7 years (range 43-77)) and 108 reconstruction (mean age 57.5+/-8.9 years (range 45-74)) cases could be followed up 2-4 (short-term), 5-6 (mid-term) and 8 10 (long-term) years after surgery. Evaluation was performed with the Constant, a modified ASES and the DASH score. Statistical analysis was done using Sigma-Stat Version 3.5 with a p-value<0.05 indicating statistical significant differences. RESULTS: All three scoring systems showed no significant differences in the short term follow-up for the two groups (mean values: Constant debridement/repair: 70+/ 11.9/66+/-13.6; ASES debridement/repair: 22.3+/-3.3/ 23.3+/-3.3; DASH debridement/repair: 22.3+/-11.0/ 24.3+/-10.1). In the mid-term (Constant debridement/repair: 51+/-2.9/68.3+/-5.2; ASES debridement/repair: 20.3+/ 1.3/24.3+/-1.7; DASH debridement/repair: 31.0+/-6.5/20.3+/-5.4) and long-term follow-up (Constant debridement/repair: 42.3+/-3.8 /60.7+/-2.6, ASES debridement/repair: 17.3+/-0.5/21.7+/-0.5, DASH debridement/repair: 41.3+/ 6.2/25.0+/-1.4), rotator cuff reconstruction revealed better objective results and better patients' satisfaction. CONCLUSION: Rotator cuff tendon repair leads to better long-term clinical outcome and subjective satisfaction compared to debridement. Tendon reconstruction should be considered as a treatment for patients suffering from massive rotator cuff tears, thus preserving shoulder function and by that means delay indication for reverse arthroplasty. PMID- 28839500 TI - Arthroscopic Acetabular Labral Reconstruction with Fascia Lata Allograft: Clinical Outcomes at Minimum One-Year Follow-Up. AB - BACKGROUND: The integrity of the acetabular labrum is crucial to normal biomechanics of the hip joint. Disruption of the labral seal could be detrimental to the overall nutrition of the cartilage, leading to its premature degeneration. PURPOSE: The aim of this study is to determine the clinical effectiveness of arthroscopic hip labral reconstruction using fascia lata allograft. The hypothesis is that labral reconstruction would provide good clinical outcomes. METHODS: We retrospectively reviewed all 10 patients who underwent labral reconstruction with fascia lata allograft from January 2013 to October 2015. We assessed improvement in pain and function, complications, and subsequent surgery. The minimum follow-up was 12 months (average, 22.9 months; range, 16-36 months). RESULTS: All patients reported subjective improvement in preoperative pain and function. The mean modified Harris hip score improved significantly from 58 (55 60) to 95 (91-98). The mean change of modified Harris hip score was 36 (31-41) and mean post-operative patient satisfaction score was 9.5(8-10). We observed no radiological progression of arthritis as well as no patient had revision procedure including total hip replacement. CONCLUSION: Arthroscopic labral reconstruction using a fascia lata tendon allograft is an effective and safe procedure that not only provides excellent clinical outcomes in short term but also potentially prevent continued cartilage degeneration by restoring acetabular labral seal in patients with deficient or resected labrums. PMID- 28839501 TI - The Effect of Hand Dominance on Functional Outcome Following Single Row Rotator Cuff Repair. AB - INTRODUCTION: Rotator cuff tears are a common cause of shoulder disability and pain. Excellent outcomes can be obtained with surgical treatment although this outcome is affected by several factors. We sought to investigate the effect of hand dominance on subjective functional outcome post rotator cuff repair. METHODS: All patients who had rotator cuff repair over a calendar year were identified and followed up at 3 years post operatively. Patients were consented for inclusion in the study and demographic data, hand dominance and functional outcome data was collected. L'insalata shoulder questionnaire was used for outcome data collection. SPSS version 22 was used for statistical analysis where appropriate. RESULTS: 144 patients were included in this study. Mean age was 63 +/- 10.1 years in the dominant side group and 62 +/- 8.6 years in the non dominant group. 92 patients had dominant side surgery and 52 had non-dominant side surgery. There was a statistically significant correlation between dominant hand and operated side (P=0.005). The mean overall outcome score was marginally higher in the dominant surgery group with a mean of 89.8 +/- 14.2 compared with a mean of 87.4 +/- 17.5 in the non-dominant group. Multi-variate linear regression analysis revealed this difference to be non-significant (p = 0.4). CONCLUSION: No difference was found in the functional outcome of rotator cuff repair between dominant and non-dominant side surgery. This information will help in counselling patients who are concerned about the potential impact of rotator cuff repair on the function of their dominant hand. PMID- 28839502 TI - The Added Value of Postoperative Axial Imaging in Developmental Dysplasia of the Hip. AB - BACKGROUND: Redislocation is a dreaded complication after reduction of developmental dysplasia of the hip (DDH) in young children. While early detection facilitates urgent reoperation, delayed revisions are more complicated. Despite the weak evidence, an axial postoperative imaging tool is recommended. This study's goal is to compare the effectiveness of conventional pelvic radiography alone and axial imaging. METHODS: Data were collected retrospectively between 2012 and 2016. One study group comprised consecutive patients who had operative reduction followed by routine low-dose computed tomography (CT). Hips that had anteroposterior pelvic radiographs as the only confirmatory tool were used as a reference group. RESULTS: We identified 241 patients (339 hips). The mean age and follow up were 19.6 months +/- 9.3, and 15.5 months +/- 11.1, respectively. There were 147 hips in the radiography group and 192 in the CT group. Radiography detected only three out of nine redislocations during the same admission; in contrast, 2/2 redislocations in the routine CT group were addressed before hospital discharge (p<0.01). There was no significant delay in hospital discharge when CT was used (p= 0.28). CONCLUSION: Conventional radiography is not as effective as axial imaging in preventing late detection of redislocation. LEVEL OF EVIDENCE: level III, Diagnostic Study. PMID- 28839503 TI - Emergence and Reemergence of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). PMID- 28839504 TI - Deep Sequencing Details the Cross-over Map of Chimeric Genes in Two Porcine Reproductive and Respiratory Syndrome Virus Infectious Clones. AB - BACKGROUND: Recombination is an important contributor to the genetic diversity of most viruses. A reverse genetics system using green fluorescence protein (GFP)- and enhanced GFP (EGFP)-expressing infectious clones was developed to study the requirements for recombination. However, it is still unclear what types of cross over events occurred to produce the viable offspring. OBJECTIVE: We utilized 454 sequencing to infer recombination events in this system. METHOD: Two porcine reproductive and respiratory syndrome virus (PRRSV) infectious clones, P129-EGFP 97C and P129-GFPm-d (2-6), were co-transfected into HEK-293T cells. P129-EGFP-97C is a fully functional virus that contains a non-fluorescent EGFP. P129-GFPm-d (2 6) is a defective virus but contains a fluorescent GFPm. Successful recombination was evident by the appearance of fully functional progeny virus that expresses fluorescence. Total RNA was extracted from infected cells expressing fluorescence, and the entire fluorescent gene was amplified to prepare an amplicon library for 454 sequencing. RESULTS: Deep sequencing showed that the nucleotide identities changed from ~37% (in the variable region from 21nt to 165nt) to 20% (T289C) to ~38% (456-651nt) then to 100% (672-696nt) when compared to EGFP. The results indicated that cross-over events occurred in three conserved regions (166-288nt, 290-455nt, 652-671nt), which were also supported by sequence alignments. Remarkably, the short conserved region (652-671nt) showed to be a cross-over hotspot. In addition, four cross-over patterns (two single and two double cross-over) might be used to produce viable recombinants. CONCLUSION: The reverse genetics system incorporating the use of high throughput sequencing creates a genetic platform to study the generation of viable recombinant viruses. PMID- 28839505 TI - NADC30-Like Porcine Reproductive and Respiratory Syndrome in China. AB - NADC30-like porcine reproductive and respiratory syndrome virus (PRRSV) has widely spread in China and become locally dominant virus strain in some provinces. Although they are not pathogenic as highly pathogenic PRRSV (HP-RRRSV) that outbreaks since 2006, NADC30-like PRRSVs distinguished themselves by high incidence of recombination with other virus strains which lead to change of virulence. The outbreaks of NADC30-like PRRSV in the vaccinated pig herds suggested that current commercial PRRSV vaccines cannot provide complete protection to the infection. In this review, we have described in detail the current situation of NADC30 PRRSV including epidemiology, genomic characterization, pathogenicity, and efficacy of current commercial vaccines in China. PMID- 28839506 TI - Development and Application of an RT-PCR to Differentiate the Prevalent NA-PRRSV Strains in China. AB - BACKGROUND: PRRSV features with genetic diversity and high mutation which leads to the emergence of a multiple of circulating virus strains with different virulence. North American (genotype 2) PRRSV (NA-PRRSV) can be divided into classical PRRSV (C-PRRSV), highly pathogenic PRRSV (HP-PRRSV), and NADC30-like PRRSV (NL-PRRSV) according to their genomic characteristics and pathogenicity. So far, the above three subtypes of NA-PRRSV are now circulating in China. OBJECTIVE AND METHOD: In this study, a reverse transcript polymerase chain reaction (RT PCR) was established to simultaneously differentiate three subtypes of NA-PRRSV. The established RT-PCR can be applied to PRRSV-infected samples originated from both supernatant of cell culture and pig tissues and showed specificity exclusively to PRRSV. The sensitivity of RT-PCR showed the minimum RNA detection was 0.04ng/ul. RESULT AND CONCLUSION: The established RT-PCR was next used to differentiate the subtypes of 29 NA-PRRSV isolated in 2016 and the results showed that HP-PRRSV is still the dominant circulating virus strain in the presence of NADC30-like PRRSV in Henan province. PMID- 28839507 TI - Comparison of Immune Responses in Pigs Infected with Chinese Highly Pathogenic PRRS Virus Strain HV and North American Strain NADC-20. AB - INTRODUCTION: Chinese HP-PRRSV characterized by high morbidity and mortality of all ages of pigs emerged since 2006 in China. The immune response of HP-PRRSV was never compared with conventional low pathogenic PRRSV strain. OBJECTIVE: In this study, we compared the immune responses elicited by a Chinese HP-PRRSV strain HV and a North American RRSV strain NADC20 infections. RESULT: Pigs infected with NADC-20 showed significantly higher Ab titers than HV-PRRSV infected pigs at 9 DPI. Infection with HV-PRRSV induced a significantly higher levels of TNF-alpha and IL-10 in both sera and lung tissues and higher IFN-alpha and IFN-gamma in the serum. Flow cytometry analysis showed that HV-PRRSV infected pigs generated significantly higher frequencies of NK cells in the peripheral blood and Th/memory, CTLs, and T-reg cells in the lung as compared with NADC-20 infected pigs. CONCLUSION: This study demonstrates that different immunity profiles were elicited by HV-PRRSV and NADC-20, and these differences may contribute to the distinct pathogenesis of HV-PRRSV and NADC-20. PMID- 28839508 TI - Pathogenic Characterization of European Genotype Porcine Reproductive and Respiratory Syndrome Virus Recently Isolated in Mainland China. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen in pig that causes tremendous economic loss in the global swine industry. PRRSV is divided into the European and North American genotypes, with virulence ranging from apathogenic-moderately virulent to highly pathogenic. The emergence of new highly virulent type 1 strains and coexistence of the two genotypes complicate the differential diagnosis, disease prevention, and control of PRRSV. Although the emergence of a novel type 1 PRRSV strain in mainland China was first confirmed in 2011, there is no information available concerning the pathogenesis of this strain. OBJECTIVES: We sought to determine the pathogenesis of a newly emerged Chinese type 1 PRRSV strain HLJB1. METHODS: Pigs were infected with HLJB1 and characterized using serological and histopathological tests. RESULTS: HLJB1 infection induced transient chemosis, reddened conjunctiva, skin cyanosis, mild transient pyrexia, dyspnea, and tachypnea between 7 and 13 days post-infection. Gross pneumonic lesions were characterized by multifocal, tan mottled areas. Lymph nodes and spleen were enlarged. Characteristic microscopic lesions consisted of pulmonary consolidation and alveolar septal thickening with red blood cell infiltration, depletion of splenic lymphocytes, and hyperplasia and activation of macrophage. No pigs infected with HLJB1 died during the experiment. CONCLUSION: Our findings indicate that Chinese type I PRRSV strain HLJB1 caused classic PRRSV-specific lesions. As it caused lower viremia in pigs compared with other classic type 1 isolates, HLJB1 is less virulent than other type I strains. PMID- 28839509 TI - Analysis of Genetic Variation of Two NADC30-like Strains of Porcine Reproductive and Respiratory Syndrome Virus in China. AB - BACKGROUND: NADC30-like strains of porcine reproductive and respiratory syndrome virus first appeared in Chinese swine herds in 2012. OBJECTIVE AND METHOD: To explore the possible genetic diversity of these strains, we sequenced and analyzed the complete genomes of two NADC30-like strains. These isolates shared 95.4% homology with NADC30. RESULT: The two strains displayed a discontinuous deletion of 131 amino acids in NSP2, mutations of amino acids in GP3 and GP5, and a 3-nucleotide deletion in the 3' untranslated region. Phylogenetic analysis showed that the two isolates formed a new branch and clustered in a subgroup with NADC30 isolates from North America. CONCLUSION: We conclude that the above two NADC30-like strains may have been introduced from North America to China, where they acquired new genetic diversity. PMID- 28839510 TI - Combined Intravitreal Dexamethasone Implant And Micropulse Yellow Laser For Treatment Of Anti-VEGF Resistant Diabetic Macular Edema. AB - PURPOSE: To report the efficacy and safety of combined intravitreal dexamethasone implant and micropulse laser for anti-VEGF resistant diabetic macular edema. PATIENTS AND METHODS: Prospective, non-controlled study that was conducted for twenty eyes with center-involved diabetic macular edema not responding to anti VEGF therapy. Ozurdex intravitreal implant was injected to all eyes with subsequent micropulse yellow laser one month after the injection. All eyes were followed up after one, three, four, six, nine and twelve months. The primary outcome measure is the change in best corrected visual acuity (BCVA) after one year and secondary outcome measures are central macular thickness (CMT) change and safety of both dexamethasone implant and micropulse laser. Reinjection was done for those eyes with recurrent edema. RESULTS: The mean age was 58.8 +/-7.94 years. The mean BCVA was 0.6+/- 0.14, 0.57 +/-0.12, 0.51+/-0.15, 0.59+/-0.12, 0.6+/- 0.12 and 0.59+/-0.14 after one, three, four, six, nine and twelve months in comparison to 0.45+/- 0.14 as initial BCVA [SS,P<0.05]. The CMT was 302.5+/ 30.01, 330.6+/-20.24, 357.6+/-32.15, 285.4+/-19.95, 292.9+/-25.07 and 285.2+/ 14.99 after one ,three, four ,six , nine and twelve months um in comparison to initial CMT of 420.7 +/-38.74um [HS, P<0.01]. Cataract occurred in 6 eyes from 14 phakic eyes (42.8%). Transient ocular hypertension occurred in 6 eyes (30%). Reinjection was done for eight eyes (40%). CONCLUSION: Intravitreal dexamethasone implant and micropulse laser are both effective and safe treatment options for anti-VEGF resistant diabetic macular edema. PMID- 28839511 TI - The Core of Sibling Stem Cell Donation - A Grounded Theory Study. AB - BACKGROUND: There is a lack of theoretical framework supporting stem cell transplant nurses in their assessment, judgment and caring interventions of sibling stem cell donors. OBJECTIVE: The purpose of this study was to explore sibling stem cell donors' main concerns and how they deal with them before and after donation. METHOD: Ten healthy sibling donors, 5 men and 5 women, with a median age of 54 years were included in this study when they were due to donate stem cells to a brother or sister. Data were collected prospectively on three occasions (before the donation and three and twelve months after it) through in depth interviews, which were recorded and transcribed verbatim for analysis by the Grounded Theory method according to Charmaz. RESULTS: This study describes the efforts of the ten donors to fulfil their duty as a sibling by doing what they considered necessary in order to help. Their efforts were summarised in a process wherein the grounded theory generated three main categories; Prepare, Promote and Preserve. A clear path of transition leading to fulfilment is evident, starting before the donation and continuing for one year afterwards. CONCLUSIONS: Being a sibling stem cell donor means doing what you have to do to fulfil your duty and if possible, saving the life of a seriously ill brother or sister. The relationship between the siblings is strengthened by the donation process. Sibling stem cell donation appears to be about fulfilment and the theoretical framework may support clinicians in their evaluation and support of donors. PMID- 28839512 TI - Relationship between Capillary Refill Time at Triage and Abnormal Clinical Condition: A Prospective Study. AB - BACKGROUND: Capillary refill time has been studied in literature as a perfusion indicator. Two pilot studies have proposed possible reference values in healthy adults. No data exist regarding capillary refill time as an indicator of abnormal clinical conditions in adults, which might be of help for triage nurses. OBJECTIVE: We wanted to assess if any relationships existed, between altered capillary refill time and abnormal clinical conditions in the emergency department. We investigated relations between capillary refill time and vital signs recorded in triage and blood tests, by analyzing the clinical records. Mortality at 24 hours, 7 days and over 14 days was investigated by calling the patients after discharge. METHOD: Observational, single-center study on a sample of consecutive patients aged >= 18 years in the Emergency Department of a major Milan hospital, from June to October 2014. Multivariate logistic regression was used to investigate the impact of clinical variables on capillary refill time. RESULTS: 1001 patients were enrolled, aged 59 +/- 21 (473 aged 65 or more). Longer refill times were found in patients admitted to hospital units after medical consultations in the emergency department compared to those discharged or sent to outpatients. In elderly patients, statistically significant association was found between increased capillary refill time and sepsis (sensitivity 100%, specificity 83.33%, area under the receiver operating characteristics curve 65.95% CI 47-83), oxygen saturation, mean blood pressure, and lactates. In persons aged 45 to 64, altered refill times were associated with abnormal values of glicemia, platelets, and urea. CONCLUSION: Capillary refill time can be used by nurses at triage as a complementary parameter to normal vital signs. This is one of the few studies investigating refill time in adult patients. PMID- 28839513 TI - Knowledge and Awareness of MTCT and PMTCT Post-Natal Follow-up Services Among HIV Infected Mothers in the Mankweng Region, South Africa. AB - BACKGROUND: The pandemic of Human Immunodeficiency Virus (HIV) is the most severe health challenge affecting children across the world. It is estimated that more than 90% of all HIV infections in children result from Mother-to-Child Transmission (MTCT). Poor knowledge and awareness of MTCT and Prevention of Mother-to-Child Transmission (PMTCT) among HIV positive mothers and their babies is a major setback to the success of the PMTCT programmes. METHODS: A qualitative approach and a cross-sectional design were applied in this study. The sample size of the study was 26 participants. Purposive sampling was used to select HIV infected mothers enrolled for PMTCT follow-up services and health care providers responsible for the implementation of the PMTCT programmes. In-depth interviews were conducted with fifteen HIV infected mothers at two health facilities. Two Focus Group Discussions (FGDs) were conducted with eleven health workers at the two health facilities. Focus groups comprised of six participants from Mankweng Clinic and five participants from Mankweng Gateway Clinic. RESULTS: The findings from the study reveal that the majority of the respondents were aware of MTCT, but lacked knowledge and understanding about how a mother can transmit HIV to her child during pregnancy, labour and breastfeeding. The majority of the participants did not understand the risk of MTCT after birth and failed to mention breastfeeding as a mode of transmission. However, most of the participants were aware that MTCT can be prevented. The respondents were aware of the importance of treatment adherence as a prevention measure to avoid MTCT. CONCLUSION: Based on these findings, a number of recommendations were made. The first is that educational and awareness programmes need to be developed or strengthened on health risks. Mass campaign media should provide information on the importance of PMTCT activities through the use of community radio stations, Television, newsletters, bill boards etc. People need to know more about PMTCT activities, health personnel need continuous training to provide clear information on PMTCT activities. PMID- 28839514 TI - Cholesterol Screening and Statin Prescription is Low Among HIV-Infected Patients on Protease-Inhibitor Regimens in Botswana. AB - BACKGROUND: Little is known about the use of statin for cardiovascular disease (CVD) risk reduction among HIV-infected patients on protease inhibitors (PI's) in sub-Saharan Africa (SSA). OBJECTIVE: Cholesterol screening and statin use were retrospectively assessed among HIV-infected participants on PI's between 2008 and 2012 at a large urban HIV clinic in Botswana. METHODS: Proportion of participants screened per year was calculated and statin indication was assessed using atherosclerosis CVD (ASCVD) and Framingham risk (FRS) scores as of the year 2012 guidelines. RESULTS: Cholesterol screening ranged between 19% and 30% per year (2008-2011) but increased to 80% after study enrollment. The rate of hypercholesterolemia (> 5.0 mmol/L) was 31% in 2012. Fewer than 1% participants were on statin therapy but 14.3% and 9.4% had statins indicated by ASCVD and FRS respectively. CONCLUSION: The high proportion of participants indicated for, but not prescribed statins highlights a substantial gap in the care to reduce CVD risk among these patients. PMID- 28839515 TI - Addictive behaviors in liver transplant recipients: The real problem? AB - Liver transplantation (LT) is the gold standard treatment for end-stage liver disease. Whatever the primary indication of LT, substance abuse after surgery may decrease survival rates and quality of life. Prevalence of severe alcohol relapse is between 11 and 26%, and reduces life expectancy regardless of the primary indication of LT. Many patients on waiting lists for LT are smokers and this is a major risk factor for both malignant tumors and cardiovascular events post surgery. The aim of this review is to describe psychoactive substance consumption after LT, and to assess the impact on liver transplant recipients. This review describes data about alcohol and illicit drug use by transplant recipients and suggests guidelines for behavior management after surgery. The presence of an addiction specialist in a LT team seems to be very important. PMID- 28839516 TI - Low serum albumin predicts early mortality in patients with severe hypoxic hepatitis. AB - AIM: To evaluate the incidence, etiology, and predictors of mortality of severe hypoxic hepatitis. METHODS: We used computerized patient records to identify consecutive cases of severe hypoxic hepatitis admitted to a tertiary hospital in Singapore over a one-year period. We defined severe hypoxic hepatitis as elevation of serum transaminases more than 100 times upper limit of normal in the clinical setting of cardiac, circulatory or respiratory failure after exclusion of other causes of hepatitis. We used multivariable regression analysis to determine predictors for mortality. RESULTS: We identified 75 cases of severe hypoxic hepatitis out of 71380 hospital admissions over one year, providing an incidence of 1.05 cases per 1000 admissions. Median age was 65 years (range 19 88); 57.3% males. The most common etiologies of severe hypoxic hepatitis were acute myocardial infarction and sepsis. Fifty-three patients (71%) died during the hospitalization. The sole independent predictive factor for mortality was serum albumin measured at the onset of severe hypoxic hepatitis. Patients with low serum albumin of less than 28 g/L have more than five-fold increase risk of death (OR = 5.39, 95%CI: 1.85-15.71). CONCLUSION: Severe hypoxic hepatitis is uncommon but has a high mortality rate. Patients with low serum albumin are at highest risk of death. PMID- 28839517 TI - Serum cholinesterase: A predictive biomarker of hepatic reserves in chronic hepatitis D. AB - AIM: To determine the predictive performance of cholinesterase compared to existing prognostic models in evaluating liver function in patients with chronic hepatitis D. METHODS: In an observational, cross-sectional and retrospective study, consecutive patients with hepatitis D cirrhosis were evaluated. Demographic, clinical and laboratory parameters were recorded. Serum cholinesterase levels were correlated with existing scoring models for chronic liver disease and Liver function tests. Receiver operating characteristic (ROC) curves were constructed to find an optimal cholinesterase level predicting ascites, Child Turcotte Pugh (CTP) score >= 10, model for end stage liver disease (MELD) score >= 15, baseline-event-anticipation (BEA) score for hepatitis D >= 5 and the aspartate transaminase to Platelet Ratio Index (APRI) >= 1.5. RESULTS: This study investigated 233 patients with chronic liver disease due to hepatitis D; 192 were male, median age 42 (16-69 years). Fifty patients had ascites and 15 had encephalopathy. One hundred and sixty-seven (71.7%) were in Child class A, 52 (22.3%) in Child class B and 14 (5.0%) in class C. A MELD score of 15 or more was seen in 24 patients. Cholinesterase levels correlated well with the INR, albumin, CTP score, MELD, MELD sodium, BEA and APRI scores (P < 0.001 each). Area under the ROC curve for ascites, CTP >= 10, MELD >= 15, BEA >= 5, APRI >= 1.5 was 0.836, 0.966, 0.913, 0.871 and 0.825 respectively (P < 0.001 each). Cut off values of cholinesterase (IU/L) for predicting ascites, CTP >= 10, MELD >= 15, BEA >= 5 and APRI >= 1.5 were < 3812, < 2853, < 2829, < 4719 and < 3954 with a sensitivity of 80%, 100%, 91.67%, 82.50%, 58.0% and specificity of 81.97%, 84.79%, 87.56%, 77.06% and 55.64% respectively. CONCLUSION: Serum cholinesterase demonstrates promising correlations with serum albumin, INR and CTP, MELD, BEA and APRI scores and is predictive of liver reserves in hepatitis D cirrhosis. PMID- 28839518 TI - Extrahepatic metastasis of hepatocellular carcinoma to the paravertebral muscle: A case report. AB - Identification of extrahepatic metastases (EHM) of hepatocellular carcinoma (HCC) has been paradoxically increasing due to an increase in the survival of HCC patients. However, metastasis of HCC to the skeletal muscle tissue is extremely rare. We describe a unique case of HCC metastasizing to the paravertebral muscle. A 55-year-old man with a history of hepatitis B cirrhosis underwent partial liver resection with complete removal of HCC. Three months later, a computed tomography (CT) scan showed intrahepatic recurrence. The tumors were treated with yttrium-90 microspheres, trans-catheter arterial chemoembolization, and sorafenib. Six months later, a CT scan showed an enhancing lesion of the left paravertebral muscle that on biopsy were consistent with metastatic HCC. The tumor was treated with stereotactic hypo-fractionated image-guided radiation therapy (SHFRT). A follow-up scan 3 mo post-radiotherapy revealed a stable appearance of the paravertebral muscle metastasis. Because of the progression in the intrahepatic tumors, the patient was treated with capecitabine, which was changed to dasatinib 6 mo later. The patient passed away three years after the primary surgical resection. Management of EHM poses an extreme challenge. This is the first case of HCC with EHM to the paravertebral muscle in which stability of disease was achieved using SHFRT. This case highlights the importance of early detection of hepatitis B viral infection and initiation of anti-viral therapy to decrease recurrence of HCC and prevent EHM. PMID- 28839519 TI - Lingual microbiota profiles of patients with geographic tongue. AB - Geographic tongue (GT) is an oral mucosal lesion that affects the tongue. The association between GT and the bacterial colonization profiles of the tongue is not clear. Lingual swabs were collected from lesion sites and healthy sites of 35 patients with GT (19 males and 16 females; Mage = 54.3 +/- 16.1 years) and 22 controls (12 males and 10 females; Mage = 56.3 +/- 15.8 years). Bacterial DNA was extracted and sequenced by next-generation sequencing. At the phylum level, Fusobacteria were significantly less abundant, while Spirochaetes were significantly more abundant in GT patients compared to controls. At the operational taxonomic units level, multivariate analysis revealed distinct clusters for the three groups based on the lingual microbiota composition. Acinetobacter and Delftia were significantly associated with GT lesion and healthy sites. However, Microbacterium, Leptospira, Methylotenera, and Lactococcus were significantly associated with GT lesion sites. Additionally, Mogibacterium and Simonsiella were significantly associated with GT healthy sites and controls. The changes in the lingual microbiota profiles of patients with GT imply a shift in the lingual bacterial ecology. However, it remains unknown if this shift is a consequence of the lesions or of factors associated with the initiation and progression of the disease. PMID- 28839521 TI - Salivary cytokine levels in early gingival inflammation. AB - Salivary protein levels have been studied in periodontitis. However, there is lack of information on salivary cytokine levels in early gingival inflammation. The aim of this study was to determine salivary levels of vascular endothelial growth factor (VEGF), interleukin (IL)-8, monocyte chemoattractant protein (MCP) 1, IL-1beta, and IL-1 receptor antagonist (IL-1Ra) in gingival inflammation. Twenty-eight systemically and orally healthy nonsmokers abstained from oral hygiene protocols for 10 days. After that, self-performed cleaning was resumed for 14 days. Plaque and gingival indexes were measured, and saliva samples were collected at days 1, 4, 7, 10, and 24. Salivary cytokines were detected with Luminex(r)-xMAPTM. Salivary IL-1beta, IL-1Ra, and VEGF levels decreased after 10 days' development of experimental gingivitis and reached baseline levels at the end of the 2-week resolution period. Salivary IL-8 levels decreased and remained low during development and resolution of experimental gingivitis. Initial inflammation in gingival tissues is associated with a decrease in inflammatory cytokines in saliva. Further studies are needed to evaluate if inflammatory cytokines bind to their functional receptors within the gingival tissue during early gingivitis, which may limits their spillover to the gingival crevice and ultimately saliva. PMID- 28839520 TI - Oral microbial profiles of individuals with different levels of sugar intake. AB - The aim was to compare the oral microbial profiles in young adults with an intake of free sugars above or below the current recommendations by the WHO for sugar consumption. Seventy subjects completed a Quantitative Food Frequency Questionnaire to establish the proportion of free sugars in relation to the total energy intake (% E). Subjects with <5% E (n = 30) formed the low-sugar group, while those with >=5% E (n = 40) were regarded as reference group. Saliva and plaque samples were analyzed by qPCR, and 52 of the plaque samples were assayed by HOMINGS. The HOMINGS analysis revealed a comparable core microbiota in plaque samples with Streptococcus, Leptotrichia, Actinobaculum, and Veillonella as predominant. No major differences between groups were revealed by alpha-diversity testing (p = 0.83), principal component analysis, or correspondence analysis. Higher relative abundance of Streptococcus sobrinus and Prevotella melaninogenica was observed in plaque samples in the reference group. By qPCR, Scardovia wiggsiae was associated with elevated sugar intake. The findings suggests that the amount of ingested sugars had a marginal influence on microbial profiles in dental plaque and saliva. However, some caries-associated species were less abundant in the dental plaque of the low sugar group. PMID- 28839522 TI - The thermoregulation of healthy individuals, overweight-obese, and diabetic from the plantar skin thermogram: a clue to predict the diabetic foot. AB - Background: Thermoregulation is a complex autonomic process to keep or to dissipate heat in the human body. Methods: In this work, by means of the thermogram of the plantar skin, the thermoregulation of healthy individuals, overweight-obese, and diabetic is discussed. Results: The thermograms of the plantar skin, for the healthy individuals, are: (1) symmetrical, the temperature distribution of the right foot being a mirror image of that of the left foot ; (2) the thermograms of women, on average, are 3 degrees C colder than those of the men; and (3) the temperature distributions decrease distally from the medial longitudinal arch. The plantar skin thermograms of overweight-obese individuals show: (1) increased average temperature of both feet and for both genders; (2) no symmetry between the left and right feet thermograms; and (3) the temperature distribution is still decreasing from the medial longitudinal arch to the periphery of the foot. However, the standard deviation, for each averaged temperature of the angiosomes, shows greater uncertainty. Most thermograms of diabetic individuals show temperature increase on the plantar skin, and are mostly symmetric between left and right feet. Conclusions: An asymmetric thermogram of the plantar skin of diabetic individuals, where one foot is hotter than the other, may mean that the coldest foot is losing the capacity to communicate properly with the central nervous system and/or that vasoconstriction/vasodilatation is having problems in regulating the passing of blood through the vessels. Thus, the asymmetric thermograms of diabetic patients, and particularly those coldest regions of foot are of interest, because of the reduction of the local autonomic sensing and the lack of achieving properly the passing of the blood. PMID- 28839523 TI - Quantifying the persisting orphan-drug shortage public health crisis in the United States. AB - Background: Orphan drugs (ODs) are pharmaceuticals manufactured for rare conditions that affect less than 200,000 people in the US. ODs are therefore produced in small quantities to meet sparse demand. Since 2010, OD shortages have become frequent, but no comprehensive, quantitative studies exist. Objective: The objective of this study is to assess the rates of OD shortages per therapeutic class and their trends over time in the United States. Study design: OD approvals were collected from publicly available information on the US Food and Drug Administration (FDA) website on 13 June 2016. Data on OD shortages were collected from the FDA and the American Society of Health-System Pharmacists (ASHP) websites. We reviewed the number of shortages per year and per therapeutic area. Multiple indications for the same drug were counted individually. Results: Of 569 ODs approved, 50% were approved in the decade ending in 2015. Oncology was found to be the most represented therapeutic area (34% of all OD approvals), followed by endocrinology (11%). Shortage data were available from 2008. In total, there were 66 (12%) OD shortages, with an average shortage duration of 455.5 days. Shortages were observed mainly for oncology products (19 cases, 13% of oncology ODs) and endocrinology products (14 cases, 22% of endocrinology ODs) Conclusion: Despite the FDA strategic plan for preventing and mitigating drug shortages (October 2013), remaining OD shortages still pose an enduring challenge to patient care, with a median shortage duration of almost 15 months. In many instances, ODs are the only available therapy for rare diseases, and OD shortages can lead to serious health deterioration and death. More research is needed to elucidate the causes of shortages and their impact on patients' health. PMID- 28839525 TI - Annuity payments can increase patient access to innovative cell and gene therapies under England's net budget impact test. AB - Background: Cell and gene therapies have the potential to provide therapeutic breakthroughs, but the high costs of researching, developing, manufacturing and delivering them translate into prices that may challenge healthcare budgets. Various measures exist that aim to address the affordability challenge, including reducing price, limiting patient numbers and/or linking remuneration to product performance. Objective: To explore how the net budget impact test recently introduced in England can affect patient access to high-value, one-off cell and gene therapies, and how managed entry agreements can improve access. Methods: We use a hypothetical example where a new high-value, one-off therapy launches in an indication where it displaces a relatively low cost chronic treatment. We calculate the number of patients that can be treated without exceeding the L20 million net budget impact threshold, and compare results for scenarios where a full upfront payment is used, and where annuity-based payments are used. Results: Charging a full upfront payment at the time of treatment can lead to suboptimal patient access. Conclusion: Annuity-based payments in combination with an outcomes-based remuneration scheme reduce consequences of decision uncertainty and can increase patient access, without exceeding the net budget impact test. PMID- 28839524 TI - A comparative review of Haute Autorite de Sante and National Institute for Health and Care Excellence health technology assessments of Ikervis(r) to treat severe keratitis in adult patients with dry eye disease which has not improved despite treatment with tear substitutes. AB - : Background: In 2015, Ikervis(r) became the only EMA-approved cyclosporine A (CsA) eye-drop for the treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes. Since the 1980s, CsA has been used empirically for ocular conditions in veterinary medicine then in humans. However, its extremely low aqueous solubility led to its administration in vegetable oils, which is characterized by low ocular availability, poor intraocular penetration, poor tolerability and short shelf life. Concentrations from 0.05% to 2% are compounded on an industrial scale and reimbursed throughout Europe. In France, Ikervis(r) has been granted an ASMR score of 5 by HAS, whereas in UK NICE endorsed its use. Objective: To review the dry eye disease environment, its challenges and available treatment options, and compare the NICE and HAS assessments to question HAS' decision to maintain full reimbursement of compounded CsA formulations in the absence of evidence, while reimbursing the EMA-approved drug at 15%. METHOD: extensive search on PubMED. Results: Comparator selection, composite score assessment and use of CE model are key differentiators. Conclusion: In topical formulations, improvements to the vehicle are key innovations that can bring significant benefits. After the USA, a Compounding Act is needed in Europe. PMID- 28839526 TI - Primary Breast Lymphoma: A Case Report and Review of the Literature. AB - Primary breast lymphoma (PBL) represents 0.04-0.5% of all malignant breast tumors, <1% of all patients with non-Hodgkin's lymphomas and 1.7-2.2% of all patients with extra nodal lymphomas. Despite the high prevalence of breast cancer, primary breast lymphoma is very rare. We report a rare case of PBL, successfully treated with surgery, chemotherapy and radiotherapy. This is the first case of PBL to be reported from Sudan to our knowledge. PMID- 28839529 TI - UpFront. PMID- 28839527 TI - A New Imaging Tool for Realtime Measurement of Flow Velocity in Intracranial Aneurysms. AB - With modern imaging modalities of the brain a significant number of unruptured aneurysms are detected. However, not every aneurysm is prone to rupture. Because treatment morbidity is about 10% it is crucial to identify unstable aneurysms for which treatment should be discussed. Recently, new imaging tools allow analysis of flow dynamics and wall stability have become available. It seems that they might provide additional data for better risk profiling. In this study we present a new imaging tool for analysis of flow dynamics, which calculates fluid velocity in an aneurysm (Phillips Electronics, N.V.). It may identify regions with high flow and calculate flow reduction after stenting of aneurysms. Contrast is injected with a stable injection speed of 2 mL/sec for 3 sec. Two clinical cases are illustrated. Velocity in aneurysms and areas of instability can be identified and calculated during angiography in real-time. After stenting and flow diverter deployment flow reduction in the internal carotid aneurysm was reduced by 60% and there was a reduction of about 65% in the posterior cerebral artery in the second case we are reporting. The dynamic flow software calculates the flow profile in the aneurysm immediately after contrast injection. It is a real-time, patient specific tool taking into account systole, diastole and flexibility of the vasculature. These factors are an improvement as compared to current models of computational flow dynamics. We think it is a highly efficient, user friendly tool. Further clinical studies are on their way. PMID- 28839528 TI - Hemochromatosis as Junctional Tachycardia, a Rare Presentation. AB - We present here a 45-year-old male with no past medical problem who presented with palpitations. He was found to have supraventricular tachycardia intractable to medical therapy. Later his rhythm converted to junctional tachycardia. Further workup revealed hemochromatosis to be primary etiology causing the arrhythmia. The low index of suspicion for additional workup is key to diagnosis and successful outcome. PMID- 28839530 TI - A new journal for frontline teams. PMID- 28839531 TI - Welcome to Frontline Gastroenterology. PMID- 28839533 TI - Future content in Frontline Gastroenterology. PMID- 28839532 TI - From conception to delivery. PMID- 28839534 TI - Patient involvement in Frontline Gastroenterology. PMID- 28839535 TI - Ethical issues in nutrition support: a view from the coalface. AB - Artificial nutrition and hydration continue to stimulate debate among physicians and in the wider world. This review aims to give those involved in providing nutrition support the necessary tools to be confident in making decisions in individual cases. It examines basic ethical principles and suggests a structured approach to ensure all the relevant factors are considered in making decisions. The current legal context and in particular the provisions of the Mental Capacity Act 2005 relating to nutrition support are discussed. The review concludes by applying the ethical approach suggested to some clinical examples, demonstrating the decision making process. PMID- 28839536 TI - The characteristics of an excellent endoscopy trainer. AB - A description of the characteristics of an excellent endoscopy trainer is provided. These characteristics are presented in an accessible format for endoscopy trainers to use to develop their endoscopy teaching. Excellent endoscopy teaching is a fundamental part of providing a high quality, motivated endoscopy workforce. PMID- 28839537 TI - Nutritional training in gastroenterology. AB - Despite the clear importance of nutritional knowledge for health professionals, such education has long been notoriously patchy at both undergraduate and postgraduate levels. Gastroenterologists in particular have a special responsibility to provide advice and expertise, not only in general nutrition but also in artificial nutrition support in the setting of extreme risk of malnutrition and intestinal failure. Recently, with the restructuring of undergraduate medical teaching and the advent of modernising medical careers, curricula have been examined in detail and training programmes have become competency based. These changes, together with increasing public expectations regarding both the importance of nutrition and ability of doctors to provide advice and guidance, have provided an opportunity to reassess nutritional training at all levels of medical education. In this review, the authors consider the factors which may have hindered the progression of nutritional education for doctors, and gastroenterologists in particular, as well as the steps which have been taken in recent years to address these issues and move such training forward. There is now a real opportunity to improve the quality of nutrition training in gastroenterology. If this can be achieved, all gastroenterologists of the future, instead of shrinking from difficult nutritional issues, should be able to manage them with confidence and enthusiasm no matter what their subspecialty; indeed, an increasing proportion may become nutrition subspecialists in their own right. PMID- 28839538 TI - Clinical lesson: eosinophilic oesophagitis, a new diagnosis to swallow. AB - Eosinophilic oesophagitis (EoE) is a recently described condition that has gained increasing recognition over the past 5 years. Despite this, many clinicians remain unaware of EoE, often leading to diagnostic delay and therefore significant morbidity. The diagnosis of EoE should be considered in any patient with a history of intermittent or continuous dysphagia, or oesophageal food impaction. It should be strongly suspected in young patients, particularly men, presenting with dysphagia and a history of atopy. Here, three patients are presented that highlight common features of EoE. In addition, a clinical review of the worldwide literature is provided to heighten physician awareness and understanding of the condition. PMID- 28839539 TI - Eosinophilic oesophagitis: from the trenches to the frontline. PMID- 28839540 TI - The importance of the IBD audit for patients who have IBD. PMID- 28839541 TI - Mortality in ulcerative colitis-what should we tell our patients? Three year mortality following admission for the treatment of ulcerative colitis: a 6 year retrospective case review. AB - OBJECTIVES: To determine the 3 year mortality of patients admitted to hospital for the treatment of ulcerative colitis (UC). DESIGN: Retrospective case note review of all patients admitted to hospital for treatment of active UC over a 6 year period from 1 January 2000. SETTING: Teaching hospital with a tertiary referral practice for the management of infiammatory bowel disease. PATIENTS: 106 patients (134 admissions) met the inclusion criteria. INTERVENTIONS: Elective and emergency colectomy was undertaken in 16 and 26 patients, respectively. MAIN OUTCOME MEASURES: Mortality at 3 years. RESULTS: There were six deaths after 3 years. Case fatality at 30 days, 1, 2 and 3 years was 1.0% (95% CI 0.2 to 5.1), 1.9% (95% CI 0.2 to 6.6), 2.9% (95% CI 5.9 to 8.0) and 5.7% (95% CI 2.1 to 11.9), respectively. There were no deaths in either surgical group. One patient (89 years, female) died while awaiting emergency colectomy. Patients who died were significantly older at the time of admission (79 years (95% CI 71 to 88 years) vs 41.2 years (95% CI 38 to 45 years)) and were more likely to have comorbid illness (p<0.001). Severity of disease, prior immunosuppressive use, first presentation and smoking status were not associated with increased mortality. CONCLUSIONS: Three year mortality following admission for treatment of UC was 5.7% (95% CI 2.1 to 11.9), significantly lower than that reported previously. Mortality was significantly associated with increasing age and the presence of comorbid disease. Disease specific factors such as severity, extent and first presentation were associated with emergency colectomy but not mortality. PMID- 28839542 TI - Mortality in ulcerative colitis. PMID- 28839543 TI - Optimising use of thiopurines in inflammatory bowel disease. AB - Azathioprine (AZA) and 6-mercaptopurine (6-MP) are the most widely used immunosuppressive therapies in inflammatory bowel disease. Pretreatment measurement of thiopurine methyltransferase (TPMT) activity is recommended and although conventional practice is to use a dose of 2 mg/kg AZA (1 mg/kg 6-MP), higher doses of 2.5 mg/kg AZA or more may be required in some patients, particularly if TPMT activity is high. Dose raising is limited by toxicity, and a robust monitoring system is mandatory. Patients with side effects to AZA may tolerate 6-MP but pancreatitis is a contraindication to switching. Metabolite monitoring is not widely available but may be useful, particularly if non compliance is possible or where metabolite shunting to 6-methylmercaptopurine is suspected, on the basis of non-response or toxicity. It may allow dose optimisation before switching to alternative immunosuppressants. The drug appears safe in pregnancy and breast feeding. Long term duration of therapy is a balance between benefits in relation to the underlying disease extent, activity and aggressiveness, and the risk of neoplasia, particularly lymphoma. PMID- 28839544 TI - Circumstances in which colonoscopy misses cancer. AB - Colonoscopy is associated with a varying risk of missing colorectal cancer (CRC). The objective of this paper was to review the existing evidence that indicates when colonoscopy may miss cancer in usual clinical practice and to provide information that would be helpful to endoscopists in their daily practice. CRC is diagnosed within 3 years in about 5% of persons with CRC who undergo colonoscopy in whom the cancer is not detected. Future research should be directed at disentangling the relative contributions of tumour biology and colonoscopy quality in explaining this result. When consent is obtained for colonoscopy, patients must be informed of the small risk that a cancer may not be detected. Steps that can be taken to address colonoscopy quality include formal training in colonoscopy and polypectomy technique, coupled with maintenance of skills by performing at least 300 colonoscopies per year. The use of split dose bowel preparation is advised. Colonoscopy should be completed to the caecum with documentation of landmarks (ileocaecal valve; appendiceal orifice). Careful colonoscopy technique includes examining the proximal sides of flexures and folds, washing and suctioning debris and ensuring adequate colonic distension. Caecal intubation and adenoma detection rates should be reported and reviewed. Lesions should be completely removed at polypectomy and attention given to appropriate surveillance. PMID- 28839545 TI - NREG: old banger or new vehicle for research? AB - The Northern Region Endoscopy Group (NREG) is a collaborative endoscopy network. NREG provides the opportunity for clinicians across the entire Northern region to undertake high quality, clinically meaningful, health service based research. NREG research is undertaken across a wide range of endoscopy units with pooling of resources and ideas. NREG has presented a large number of abstracts and is contributing to a number of National Institute for Health Research trials. NREG is collaborating with other research teams in the UK and a number of research grants have been secured. NREG aims to make a significant contribution to the field of endoscopic research over the coming years. PMID- 28839546 TI - UpFront. PMID- 28839547 TI - Improving productivity. PMID- 28839548 TI - Endoscopy Associates Group Symposium 'Research is not just for academics': highlight report from the annual meeting of the BSG, Liverpool 2010. PMID- 28839549 TI - IBD management in 2010: highlight report from the annual meeting of the BSG, Liverpool 2010. PMID- 28839550 TI - Quality in endoscopy: highlight report from the annual meeting of the BSG, Liverpool 2010. PMID- 28839551 TI - Revalidation for gastroenterologists, with or without sedation! AB - From 16 November 2009, all doctors require a license to practise in the UK. Revalidation encompasses relicensing and recertification. This article focuses on recertification for gastroenterologists. Revalidation should not be viewed as a threat, and for the vast majority of doctors it should be straightforward, with the aim of demonstrating safe doctors, while keeping to a minimum time spent on exhaustive data collection. Specialty specific standards for physician medicine are ready to be endorsed by the General Medical Council and the first revalidations will be introduced around 2011. Subspecialty specific standards for gastroenterology are under evaluation and in the early stages of consultation. PMID- 28839552 TI - The emerging role of screen based simulators in the training and assessment of colonoscopists. AB - Incorporation of screen based simulators into medical training has recently gained momentum, as advances in technology have coincided with a government led drive to increase the use of medical simulation training to improve patient safety with progressive reductions in working hours available for junior doctors to train. High fidelity screen based simulators hold great appeal for endoscopy training. Potentially, their incorporation into endoscopy training curricula could enhance speed of acquisition of skills and improve patient comfort and safety during the initial phase of learning. They could also be used to demonstrate competence as part of the future relicensing and revalidation of trained endoscopists. Two screen based simulators are widely available for lower gastrointestinal endoscopy training, with a third recently produced in prototype. The utility of these simulators in lower gastrointestinal endoscopy training has been investigated, and construct and expert validity has been shown. Novices demonstrate a learning curve with simulator training that appears to represent real learning of colonoscopy skills. This learning transfers well to the real patient environment, with improvements in performance and patient discomfort scores in subsequent initial live colonoscopy. The significant limitations of currently available screen based simulators include cost implications, and restrictions on a role in certification and revalidation. Many questions remain to be answered by future research, including how best to incorporate screen based simulators into a colonoscopy training programme, their role in training in therapeutic endoscopy and the impact of simulator training on patient safety. PMID- 28839554 TI - Surveillance of Barrett's oesophagus: do we yet know whether it is worthwhile? AB - In 2004, the Peninsula Technology Assessment Group developed an economic model to assess the effectiveness and cost effectiveness of surveillance of Barrett's oesophagus in preventing morbidity and mortality from oesophageal adenocarcinoma. The conclusion then was that surveillance was dominated (ie, cost more and conferred less health benefit) by non-surveillance in most scenarios and that surveillance was unlikely to be cost effective at usual levels of willingness to pay. The model outputs were highly sensitive, however, to several parameters for which the data were very uncertain. While there are now better estimates of some of the model inputs, such as cancer risk and quality of life, the revised values make it less likely that surveillance could prove cost effective. There remains considerable uncertainty around other key inputs. At present, there seems little reason to change our original conclusion that surveillance of Barrett's oesophagus is unlikely to be cost effective and a definitive answer may only be possible from clinical trials now in progress. As newer endoscopic techniques for treating Barrett's oesophagus and adenocarcinoma become more widely used, however, conventional surveillance programmes may no longer be undertaken, and revised economic models will be needed to assess the cost effectiveness of the new clinical pathways. PMID- 28839553 TI - Capsule endoscopy: 10 years on and in the frontline. AB - Capsule endoscopy is a safe, simple, remote method of visualising the gastrointestinal tract without resorting to conventional endoscopic intubation or radiation exposure. In addition, the ability to visualise the small bowel mucosa directly means that it is considerably more sensitive than existing small bowel imaging modalities in detecting subtle abnormalities. It is a firstline investigative modality for suspected small bowel bleeding and is being increasingly used for detecting evidence of other small bowel diseases. In Crohn's disease, it can confirm evidence of activity without recourse to repeated endoscopic intubation or radiation but does not replace MRI and CT which are better suited to defining stricturing disease and transmural complications. The production of different capsule endoscopes to examine the oesophagus, small bowel and colon now means that almost all of the gut can be examined using this technology. PMID- 28839555 TI - Effective management of acute faecal incontinence in hospital: review of continence management systems. AB - This paper reviews the scientific literature regarding current systems available for the management of acute faecal incontinence (FI) in hospital patients. The review searched Medline from 1950 to October 2009 using the adapted search strategy, as devised by the Cochrane Incontinence Group, in order to identify studies relevant to this review, yielding 197 records. Ten studies fitted the inclusion criteria with none of the studies being randomised control trials. Characteristics identified from the studies included: duration of the management devices, cost implications, length of patient stay, contraindications and patient assessment. The management of acute FI in acute settings is a relatively ignored problem, with little available evidence to support a standardised approach to its management. The review highlights the need for early identification of contraindications when FI management systems are being used, particularly in patients administered antithrombotic drugs such as aspirin. PMID- 28839556 TI - Abnormal liver function tests in the parenteral nutrition fed patient. AB - Liver dysfunction is common in individuals receiving parenteral nutrition (PN) and particularly in neonates and infants. Abnormalities of liver function tests in patients receiving short term PN are usually transient but in individuals receiving long term PN, substantial liver damage and ultimately end stage liver disease may occur. The aetiology is complex, involving a large number of patient related and nutrition related factors. The terminology intestinal failure associated liver disease (IFALD) is therefore more appropriate than PN associated liver disease. Effort should be made to prevent liver dysfunction by managing sepsis, avoiding parenteral overfeeding, employing cyclical parenteral feeding and encouraging enteral nutrition where possible. Intake of soybean based parenteral lipid emulsions should be reduced in individuals with established IFALD, possibly to be replaced by lipid emulsions containing medium chain triacylglycerol, monounsaturated fatty acids or fish oil although larger clinical studies are needed. Similarly, evidence supporting the widespread use of parenteral choline and taurine supplementation in the prevention or treatment of IFALD remains limited. There are more data to support the use of oral antibiotics to treat bacterial overgrowth and oral ursodeoxycholic acid in neonates. Ultimately, severe IFALD may necessitate referral for small intestine and/or liver transplantation. PMID- 28839557 TI - Malnutrition and nutrition support in patients with liver disease. AB - Liver disease, especially alcohol related, is increasingly common and is often accompanied by malnutrition as a result of reduced intake, absorption, processing and storage of nutrients. An increase or alteration in metabolic demands also occurs and some patients have high nutrient losses. Malnutrition in all forms of liver disease is associated with higher rates of mortality and morbidity but it is often under recognised and under treated despite the fact that appropriate treatment can improve outcomes. In this review, the causes, consequences and assessment of nutritional status in patients with liver disease are examined, and an approach to best treatment is proposed. PMID- 28839558 TI - High resolution manometry and multichannel intraluminal impedance oesophageal manometry in clinical practice. AB - The past decade has seen new technological advances in the investigation of oesophageal motility disorders. Multichannel intraluminal impedance monitoring has been used as an adjunct to conventional manometry in the assessment of oesophageal function, independent of radiography. High resolution manometry provides additional information over conventional manometry, and its topographic analysis makes interpretation of studies easier. Both utilities in non obstructive dysphagia have been used ultimately in research; however, more studies are addressing their clinical application. PMID- 28839559 TI - Torrential upper gastrointestinal bleeding from 'downhill' oesophageal varices complicating long term central venous access for total parenteral nutrition. AB - Oesophageal varices usually develop in the setting of portal hypertension secondary to chronic liver disease. However, superior vena cava (SVC) obstruction can result in 'downhill' varices forming in the upper oesophagus. A case of torrential upper gastrointestinal bleeding from SVC obstruction due to chronic central venous access for home total parenteral nutrition is described. It is suggested that in patients presenting with gastrointestinal bleeding in the setting of SVC obstruction, 'downhill' varices should be suspected. The current literature is discussed regarding management of such varices. It is recommended that endoscopic variceal surveillance be carried out in patients with known SVC obstruction. PMID- 28839561 TI - UpFront. PMID- 28839560 TI - Prolonged cholestasis induced by endoscopic retrograde cholangiopancreatography. AB - The case of a 54-year-old woman who presented with choledocholithiasis and underwent successful endoscopic stone extraction to clear the common bile duct is described. However, her jaundice and liver biochemistry continued to deteriorate despite repeat endoscopic retrograde cholangiopancreatography (ERCP), with further imaging confirming a patent biliary tree. The clinical, radiological and pathological features were in keeping with prolonged cholestasis as a complication of ERCP. The pathophysiology of this unusual syndrome and the therapeutic options available are discussed. PMID- 28839562 TI - A practical guide and review of colonoscopic surveillance and chromoendoscopy in patients with colitis. AB - Patients with longstanding extensive colitis have an increased risk of developing colorectal cancer. The British Society of Gastroenterology has recently published revised guidelines for colitis surveillance, taking into account new evidence supporting chromoendoscopy and the endoscopic resection of certain neoplastic lesions. This article reviews some of the evidence behind this paradigm shift and gives a practical guide to chromoendoscopy. PMID- 28839564 TI - Diarrhoea in the enterally fed patient: not just a clinical problem. PMID- 28839563 TI - Cardiac ischaemia and rhythm disturbances during elective colonoscopy. AB - BACKGROUND: The number of colonoscopic procedures continues to rise rapidly. With widespread adoption of colonoscopy based bowel screening programmes, this rising trend is set to continue. AIMS: This study aimed to identify whether elective colonoscopy could provoke cardiac rhythm disturbances and/or myocardial ischaemia, as evidenced by 12 lead Holter ECG recordings and troponin I (cTnI) changes. MATERIALS AND METHODS: Patients were stratified into three groups based on the presence of cardiac disease or cardiovascular risk factors. They underwent real time 12 lead Holter monitoring before, during and after colonoscopy. Bloods were taken for pre- and post-procedure cTnI estimation. RESULTS: Holter ECG recordings of the three groups showed a high incidence of new but silent ischaemic and arrhythmic ECG changes during the colonoscopy in patients with documented but stable heart disease and to a lesser extent in those patients with one or more risk factors for heart disease. Three patients had high cTnI concentrations both before and after colonoscopy. Two patients with known heart disease died within 30 days of colonoscopy. CONCLUSIONS: This study demonstrates for the first time the occurrence of potentially clinically significant ST-T wave changes and rhythm disturbances during elective colonoscopy in patients with known heart disease and to a lesser extent in those patients with a known cardiovascular risk profile. PMID- 28839565 TI - Diarrhoea in the enterally fed patient. AB - Diarrhoea complicating enteral feeding is very common in all clinical settings. The major risk factor is the use of concomitant antibiotics. The underlying mechanisms for the diarrhoea mainly relate to alterations in the colonic flora and physiological responses to the mode of feed delivery although a clear understanding of what is actually happening in vivo remains elusive. Management of diarrhoea includes rationalising medications, excluding relevant comorbidity and using antidiarrhoeal medications. Altering the method and site of feed delivery-for example, continuous to bolus, gastric to postpyloric-can also be tried in the more difficult cases. PMID- 28839566 TI - NICE guidance for anti-tumour necrosis factor therapy in Crohn's disease: what does it mean for the inflammatory bowel disease community? PMID- 28839567 TI - Non-alcoholic fatty liver disease: a non-problem or public health catastrophe? PMID- 28839568 TI - Practical management of the increasing burden of non-alcoholic fatty liver disease. AB - Obesity-induced liver disease (non-alcoholic fatty liver disease (NAFLD)) describes a spectrum from steatosis through steatohepatitis to cirrhosis. Its prevalence is rising in tandem with societal rates of obesity which through consequent insulin resistance and fat deposition in hepatocytes lead to hepatocyte death and attempts at repair, which if persistent, lead to activation of liver fibrogenic cells. NAFLD, which may also progress to primary liver cancer, is now the most common cause of chronic liver disease in affluent countries. There is currently no single accurate diagnostic test besides a liver biopsy. The decision to consider a liver biopsy will be informed by the presence of insulin resistance determined by comparatively easy-to-measure factors together with other putative markers of progression such as hypertension. If a liver biopsy is performed, patients with steatosis with no evidence of inflammation may be less aggressively managed while those with steatohepatitis, since they have a faster trajectory to cirrhosis, should be managed more robustly. Besides lifestyle changes and increased aerobic exercise other strategies include considering referral to centres with ongoing clinical trials. Emerging treatments include alpha1 adrenoceptors antagonists, angiotensin receptor blockers, glitazones and vitamin E. PMID- 28839570 TI - Does constipation predict the quality of bowel preparation during colonoscopy? AB - BACKGROUND: Suboptimal bowel preparation has several consequences, including reduced polyp detection rate and increased cost of colorectal cancer screening. The presence of constipation is thought to be a feature associated with poor bowel preparation. OBJECTIVES: To characterise the relationship between features of constipation and the quality of bowel preparation during colonoscopy. DESIGN: Patients presenting for an outpatient colonoscopy were asked to complete a questionnaire which included demographics, type of bowel purgative and features of bowel movements (BMs)-derived from the ROME III criteria for diagnosis of chronic constipation. PATIENTS: 101 patients from the community undergoing surveillance colonoscopy completed the study. INTERVENTIONS: Patients underwent standard bowel preparation, completed a pre-endoscopy survey, followed by routine surveillance colonoscopy. MAIN OUTCOME MEASUREMENTS: The endoscopist rated the quality of bowel preparation using the previously validated Ottawa scoring scale. Statistical analysis was performed to characterise the relationship between the existence of chronic constipation and quality of bowel preparation. RESULTS: BM frequency of <1/day, 1/day, 2/day, or 3/day was inversely correlated with average total Ottawa score (range 5.93 to 4.00), p=0.028) as well as recto-sigmoid Ottawa score (range 1.8 to 1.0, p=0.006). Among women, there was a statistically significant (p=0.025) association between those who reported hard stools (Ottawa=6.3) and those who denied hard stools (4.5). CONCLUSION: Eliciting features of BMs before colonoscopy may predict those at risk for poor bowel preparations and increase cost effectiveness of colonoscopy. PMID- 28839571 TI - Nutrition support teams: how they work, are set up and maintained. AB - Safe cost effective nutritional support is provided by a multidisciplinary team whose activity is overseen by a Nutrition Steering Group that reports directly to the Hospital Trust Board. When a nutrition support team (NST) is first formed, a nutrition nurse specialist enables parenteral nutrition to be given safely. An NST needs to have a clearly agreed scope of practice and needs to be able to justify its presence in terms of quality and cost savings. PMID- 28839569 TI - The impact of smoking in Crohn's disease: no smoke without fire. AB - Smoking habit is the most widely accepted environmental factor affecting the incidence and disease progression in the inflammatory bowel diseases. The contrasting effects in Crohn's disease (CD) and ulcerative colitis are unexplained. The purpose of this review is to summarise the existing data on the effects of smoking in CD on disease history, recurrence after surgery, effects on drug responses and to review available evidence that carriage of some of the known susceptibility genes may be disproportionate in smokers with CD. The review also highlights potential mechanisms involved and factors that might affect patients' smoking habits. The clinical and scientific implications of the data are discussed. PMID- 28839572 TI - The value of multidisciplinary nutritional gastroenterology clinics for intestinal failure and other gastrointestinal patients. AB - An increasing number of patients have chronic intestinal failure (IF) or other problems needing nutritional support. These patients need regular input from gastroenterologists, nutrition nurse specialists and dietitians, but traditionally these healthcare professionals see them separately. Here the authors describe their experience of a combined regional nutritional gastroenterology clinic and outline strategies that can avoid the need for home parenteral nutrition (HPN) or intravenous fluids in most cases. Over a 1-year period, 73 patients attended their clinic, with the majority (74%) coming from their own catchment area of 500 000. Of the 63 patients with IF, 49 had short bowel syndrome. 38 of the patients with IF (60%) could be managed with dietary and pharmacological modifications alone, while eight (13%) needed enteral tube feeding and 17 (27%) HPN or intravenous fluids. However, only nine (53%) of the 17 patients referred from other centres specifically for HPN instigation actually needed HPN or intravenous fluids. Patient satisfaction with the combined multidisciplinary clinic was high, with 85% of patients preferring to be seen within this model of outpatient care, although questionnaire response rates were low. The authors have therefore shown that a multidisciplinary nutritional gastroenterology clinic can provide effective patient-centred care and can minimise the need for invasive and costly intravenous nutritional support. Clinics of this type should be an integral part of the current plans to implement regional IF services. PMID- 28839573 TI - Why a PhD/MD enhances gastroenterological training. AB - Academic medicine has faced an alarming decline in recent years necessitating the realisation of an integrated academic training pathway. This initiative has enabled many graduates to enter a structured academic training environment potentially leading to the award of a higher degree. A period of out of programme research or experience remains popular with trainees in gastroenterology, with up to 20% of trainees undertaking this at any one time. Most trainees believe that possessing a higher degree leads to improved job aspects. However, it is our belief that undertaking a higher degree leads to a global enhancement of gastroenterological training. Firstly, undertaking a higher degree facilitates the development of a myriad of personal and professional skills ranging from communication, research, scientific, critical thinking, problem solving to time and project management. These multifaceted transferrable skills are as applicable to the bedside as to the bench and in our belief are highly desirable with potential employers. Secondly, the acquisition of a higher degree allows the trainee to develop a subspecialty interest and a network of contacts, both national and international, within one's chosen field. Finally, we argue that the addition of time in research to the training period allows personal and professional maturation hitherto less easily achieved in the standard training period of 5 years. Overall, pursuing a higher degree in gastroenterology is a pursuit of excellence, something we should all strive for. PMID- 28839574 TI - IBD patient panels: a personal reflection on three stages of development of an IBD Patient Involvement Project, initiated and supported by Crohn's and Colitis UK. AB - Crohn's and Colitis UK (formerly The National Association for Colitis and Crohn's Disease) first established a pilot of six inflammatory bowel disease (IBD) patient panels in 2005. There are now 20. Crohn's and Colitis UK offers a framework within which panels can function although there is built in flexibility to suit local circumstances. Patient panels are most effective when they work in partnership with their local NHS professionals. Their uniqueness in the patient and public involvement field lies in their being a disease specific patient group with a focus on their own local IBD services. Panel members are able to speak with the authority of personal experience and with the benefit of assimilated knowledge. A patient panel influences patient care by: (1) providing feedback on current service provision; (2) being a sounding board for departmental developments; (3) initiating suggestions for future developments; and (4) giving support to proposals for departmental developments (perhaps by using the IBD Standards as a benchmark). Most IBD patient panels are self supporting. Some receive assistance from their IBD department. Nationally, Crohn's and Colitis UK provides support through their patient involvement adviser and a patient panel page on their website. Some training and networking is also offered. From the appointment of IBD nurses to changing the way local services are delivered, they have been instrumental in bringing about improvements to IBD services across the country. PMID- 28839575 TI - UpFront. PMID- 28839576 TI - Smoking cessation strategies in Crohn's disease. AB - Although smoking cessation is one of the most effective interventions in patients with Crohn's disease, the prevalence of smoking in these patients is higher than in the general population, and much higher than in patients with other smoking related diseases. There is a lack of awareness of the benefits of cessation among patients and general practitioners, and a lack of engagement in smoking cessation by specialists. This article discusses the strategies that practitioners can use to motivate patients to quit and how the success of a quitting attempt can be maximised. PMID- 28839577 TI - Analysis of risk scoring for the outpatient management of acute upper gastrointestinal bleeding. AB - OBJECTIVE: To determine whether the Glasgow-Blatchford bleeding score (GBS) or pre-endoscopy Rockall score was better at accurately identifying patients with acute upper gastrointestinal bleeding (AUGIB) who were at low risk of the need for clinical intervention and death and therefore suitable for outpatient management. DESIGN: Retrospective database and case note review of all patients admitted to the emergency departments with AUGIB from 1 January 2008 to 31 December 2009. SETTING: Two tertiary centre teaching hospitals. PATIENTS: 432 patients met the inclusion criteria. INTERVENTION: None. MAIN OUTCOME MEASURE: Clinical interventions (blood transfusion, endoscopic therapy and surgery) and death. RESULTS: Of 432 patients, 40 (9.3%) had a GBS of 0 and none required intervention or died. In contrast, 13/104 patients (12.5%) who had a pre endoscopy Rockall score of 0 and 23/125 patients (18.4%) who had a complete Rockall score <3, required clinical intervention. The performance of the scores at these cut-offs were: GBS (sensitivity 100%, specificity 16.1%, positive predictive value (PPV) 37.8%, negative predictive value (NPV) 100%, accuracy 82.3%), pre-endoscopy Rockall (sensitivity 91.2%, specificity 32.0%, PPV 41.2%, NPV 87.5%, accuracy 70.9%) and complete Rockall (sensitivity 84.5%, specificity 50.7%, PPV 55.8%, NPV 81.6%, accuracy 76.2%). For prediction of the need for intervention or death, the accuracy of the GBS (0.82; 95% CI 0.78 to 0.86) was superior to the pre-endoscopy Rockall score (0.71; 95% CI 0.67 to 0.76). CONCLUSION: The GBS but not the pre-endoscopy Rockall score identifies patients with upper gastrointestinal bleeding who may be suitable for outpatient management, therefore potentially allowing for more efficient use of hospital resources. PMID- 28839578 TI - Interferon gamma-release assays for detecting latent tuberculosis infection in patients scheduled for anti-TNFalpha therapy. AB - Screening for, and treatment of, latent tuberculosis infection (LTBI) before anti tumour necrosis factor alpha therapy has been shown to decrease the incidence of active tuberculosis by more than 80% and is recommended before initiation of treatment. In the absence of a 'gold standard' test for LTBI, current screening involves taking a clinical history of risk factors, chest radiograph and tuberculin skin test. Alternative cellular immune-based screening tests have been developed to detect Mycobacterium tuberculosis infection. This paper summarises the current position and advances in the use of newer screening strategies for LTBI. PMID- 28839579 TI - Impact of a care pathway in acute pancreatitis. AB - BACKGROUND: Previous studies have shown that accurate process of care predicts quality of care. Few examples currently exist for process of care for the acute surgical patient. A recent region wide audit had identified good outcomes for patients with acute pancreatitis at our institution but aspects of care that could be improved. METHODS: For this re-audit, a simple written care pathway for the management of those presenting with acute pancreatitis was introduced in our institution from February to July 2009. The audit standards were set against the British Society of Gastroenterology (BSG) guidelines for management of acute pancreatitis and were compared with the previous region wide audit. RESULTS: Marked improvements were noted in the rates of abdominal imaging achieved within 24 h of diagnosis (35.2% vs 47.7%), severity stratification within 48 h of diagnosis (28.7% vs 75%), critical care admission for those classified as severe (39.3% vs 63.6%) and definitive treatment during index admission (22.2% vs 38.5%). Survival rates were 100% for this audit cycle and 95% for all patients within the region wide audit. Despite these improvements, care still does not reach the standards set out by BSG. CONCLUSION: Predefined processes of care may help to recognise those developing or likely to develop severe pancreatitis, ensure accurate documentation of severity, expedite critical care review and/or admission, and help to encourage the timely management of those with a treatable underlying cause of their pancreatitis. PMID- 28839580 TI - Development and roll out of the JETS e-portfolio: a web based electronic portfolio for endoscopists. AB - The JAG Endoscopy Training System (JETS) e-portfolio was designed to provide an electronic log of endoscopic experience, improve the effectiveness of training, streamline the JAG certification process and support the quality assurance of trainers, units and regional training programmes. It was piloted in 2008 with an 82.6% uptake in trainees offered the system. The system was released in the UK in September 2009. Steady adoption across the UK demonstrates the service finds it a valuable tool. In time it will be the only vehicle through which a trainee can achieve certification through JAG to practise independently. PMID- 28839581 TI - Out of programme experience and training: going away to bring something back. PMID- 28839582 TI - Making the most of Out of Programme Experience. PMID- 28839583 TI - Cryptogenic colitis due to occult cytomegalovirus infection. AB - Colitis secondary to cytomegalovirus infection is well recognised and usually straightforward to diagnose. Here two cases are reported in whom all initial investigations failed to demonstrate the presence of virus, with potential adverse consequences for its treatment. A case is made for empirical antiviral therapy despite negative investigations if clinical suspicion is high. PMID- 28839585 TI - UpFront. PMID- 28839584 TI - Identifying small bowel intussusception related to a gastroenteric feeding tube. AB - Enteral feedings through gastroenteric (GE) tubes are commonly utilised in patients with feeding difficulties and intolerance to gastric feeding. A variety of complications related to GE tubes have been described which rarely include small bowel intussusception. The case of a 23-year-old man with proximal small bowel intussusception related to an endoscopically placed low profile GE tube is described. The patient presented with abdominal pain and bilious vomiting. Symptoms resolved with tube shortening. This report includes a short review aimed at raising awareness about this complication with a discussion on diagnosis and management. PMID- 28839586 TI - The development and evolution of a tertiary pancreaticobiliary endoscopic ultrasound service: lessons learned. AB - This article reviews the development of the hepatopancreatobiliary (HPB) endoscopic ultrasound (EUS) service at Freeman Hospital and seeks to identify from our experience learning points for good practice and pitfalls to avoid. The Freeman HPB EUS service has expanded rapidly over the past 10 years in response to the consolidation of cancer care and aligned to the needs of the cancer network. Effective multidisciplinary teamwork and increased subspecialisation by the endosonographers has allowed the efficient use of capacity and development of skills. Mechanisms for monitoring diagnostic performance put in place at the outset of the EUS-fine needle aspiration programme have helped to identify interventions that have led to improved test performance. An excellent working relationship between all stakeholders is critical to the success of such a service as is a preparedness to seek and respond to the views of patients and referrers. PMID- 28839587 TI - Development of an integrated pancreatic disease service. AB - An integrated pancreatic disease unit needs to deliver high-quality care both to patients with malignant and non-malignant pancreatic disease. The regionalisation of pancreatic cancer services which followed the publication of policy frameworks by the Department of Health and NHS executive led to the development of disease site-specialised high-volume multidisciplinary teams. As the majority of patients with pancreatic cancer are not suitable for surgery, partner hospitals within a region need to provide access to a wide range of non-surgical treatment. The implementation of such working may require pooling of local resources to create networks of equivalence to tertiary centres. The provision of care to non malignant pancreatic disease can benefit from this type of working and services can be modelled on, and integrate with, cancer services. One way of achieving this is to establish working groups based upon diseases rather than traditional departments, which can deliver standardised and optimal care with a patient centred approach. However, this poses a number of potential problems. This review examines how an integrated pancreatic unit may be developed in district general and larger hospitals, and also describes our experience in developing such a unit. PMID- 28839588 TI - Collaborative liver and psychiatry care in the Royal Bolton Hospital for people with alcohol-related disease. AB - Since 1990, the Royal Bolton Hospital has been evolving a patient-centred, collaborative, seamless, holistic, gastroenterology, psychiatry, community model of alcohol care, team working, governance, research, training, education and health promotion. The aim is to deliver an accessible, responsive, cost effective, rolled-out service. Consultant gastroenterologists, a specialist liaison psychiatrist, psychiatric alcohol liaison nurse, gastroenterology-based liver nurse practitioner and ward nurses provide joint inpatient and outpatient care for people with alcohol misuse, especially alcohol-related liver disease. A ward based, consultant-led, multidisciplinary team, with a dedicated social worker, meets daily to discuss all inpatients, unify treatment and facilitate discharges. On Monday-Friday, the two alcohol specialist nurses assess, triage and give brief advice to all alcohol-related medical admissions, liaise with consultants about admission or arrange outpatient appointments with the community alcohol team. This has reduced the average length of stay from 8.0 days to 5.7 days, saving the Trust more than 1000 bed days annually. This highlights the need for a 7 day alcohol specialist nurse service, one of 11 key recommendations in a recent position paper by the British Society of Gastroenterology, Alcohol Health Alliance UK and British Association for Study of the Liver on future alcohol care required in British district general hospitals. Other key recommendations include a hospital 'alcohol care team', with a lead clinician, coordinated policies in accident and emergency, with an outreach service, psychiatry input, adequate consultant numbers and integrated alcohol treatment pathways between primary and secondary care. PMID- 28839589 TI - The current status of bariatric surgery. AB - As the incidence of obesity continues to rise, increasing numbers of patients are undergoing bariatric surgery to address morbid obesity and weight related health issues. Bariatric procedures aim to reduce dietary intake and/or interfere with food absorption and are now in widespread use but with a huge capacity shortfall leading to a degree of rationing of the resource. Such treatment should be regarded as palliative in that it does not cure the underlying disorder, and guidelines have been produced to define which patients should be considered for this type of surgery, which must be undertaken in a multidisciplinary setting. Long term results show this to be a cost-effective intervention with a durable positive impact on cardiac risk factors and in particular type 2 diabetes and obstructive sleep apnoea, together with a reduction in all cause mortality and malignancy and an improvement in quality of life. Systematic data collection has now started in the UK and will assist in defining the best application of the resource. PMID- 28839590 TI - CT colonography: what the gastroenterologist needs to know. PMID- 28839591 TI - Colorectal cancer detection: time to abandon barium enema? AB - OBJECTIVES: To assess the sensitivity of double contrast barium enema (DCBE) for diagnosing colorectal cancer (CRC). DESIGN: Retrospective evaluation of DCBE performed in the 2 years prior to diagnosis of CRC. SETTING: Teaching hospital in Cambridge, UK. PATIENTS: 1310 consecutive cases of CRC identified from cancer registry data. INTERVENTIONS: DCBE and colonoscopy. MAIN OUTCOME MEASURES: Sensitivity of DCBE for diagnosing CRC. RESULTS: 215 patients had undergone a DCBE within the 2 years prior to diagnosis with CRC. After excluding those reported as inadequate, 37 of these were reported as normal, giving a sensitivity of 83% (81-85%). CONCLUSIONS: The performance of DCBE is inadequate for the exclusion of CRC. Expansion of colonoscopy and CT colonography capacity is urgently required nationally so that DCBE can finally be abandoned as a firstline test in patients at risk of CRC. PMID- 28839592 TI - Predicting what can go wrong at endoscopic ultrasound: a large series experience. AB - OBJECTIVE: Although prior studies have evaluated complications following endoscopic ultrasound (EUS), data on the incidence of unplanned events at EUS, defined as any deviation from the preprocedure plan, are lacking. The aim of this study was to define the incidence, nature, clinical predictors and implications of unplanned events at EUS. DESIGN: Case control study. SETTING: Tertiary referral centre. PATIENTS: 4624 consecutive patients undergoing EUS during a 6 year period were enrolled. For each patient with an unplanned event, two patients with a successful EUS in the same calendar year were randomly selected as controls. MAIN OUTCOME MEASUREMENTS: Unplanned events occurring prior to, during or after EUS procedures were prospectively recorded in a database. RESULTS: 192/4624 patients had an unplanned event (4.1%). In all, 2.1% had a failed procedure for anatomical reasons, 1.3% because of restlessness despite standard sedation and 0.5% for technical reasons. Adverse events occurred in 0.2%. There was no mortality but 4/6 patients with adverse events had to be admitted to hospital (2/4 operated). Eighty-two per cent of patients with an unplanned event had incomplete examinations, 14% had no procedure performed and 4% had complete procedures. In a multivariate analysis, only Afro-Caribbean patient origin, inpatient procedure and cancer staging procedure were independently related to unplanned events (p<0.05 for all). CONCLUSIONS: Unplanned events at EUS are mainly due to anatomical reasons and restlessness, despite sedation. They commonly result in incomplete examination and are related to Afro-Caribbean origin, inpatient procedure and cancer staging. PMID- 28839593 TI - High oesophageal web formation in association with heterotopic gastric mucosa (the gastric inlet patch): a small case series. AB - BACKGROUND: Upper oesophageal webs or rings have rarely been reported in association with heterotopic gastric mucosa (HGM). OBJECTIVE: To describe the finding of oesophageal webs in association with HGM. DESIGN: Small case series. SETTING: Patients presenting with dysphagia to an open access hospital dysphagia clinic. PATIENTS: Six cases were found. INTERVENTIONS: Symptomatic improvement is demonstrated with oesophageal dilatation in symptomatic patients. MAIN OUTCOME MEASUREMENTS: Symptomatic improvement. RESULTS: The six cases which are described here demonstrate that a web or ring exactly matches the distribution of the heterotopic mucosa, can occur at both proximal and distal squamo-columnar junctions and the inlet patches may be multiple with multiple rings. A radiological double web sign is described. LIMITATIONS: A rare condition with a small number of patients. CONCLUSIONS: Effective treatment can be by oesophageal dilatation and acid suppression. The cause of web formation is thought to be due to heterotopic acid production and is analogous to the Schatzki ring. PMID- 28839594 TI - Helminths: an unrecognised disease burden prevalent among migrants in the gastroenterology clinic. AB - OBJECTIVE: To estimate the prevalence of, and implement a diagnostic strategy for, imported helminth infection in the gastroenterology clinic. DESIGN: A retrospective study of eosinophil count and probable tropical exposure (phase I) followed by a prospective study of parasitological investigation (phase II). SETTING: Gastroenterology service of an inner London hospital. PATIENTS: Adult patients newly attending general gastroenterology and inflammatory bowel disease clinics. INTERVENTIONS: In phase I, evidence of undiagnosed helminth infection was sought by analysing patient records for associations between eosinophil count and ethnicity. In phase II, a UK guideline for investigation of eosinophilia in migrants was implemented and diagnostic yield determined. MAIN OUTCOME MEASURES: In phase I, prevalence of eosinophilia was determined; in phase II, helminth prevalence and degree of eosinophilia before and after treatment were reported. Information on symptomatic response to treatment was recorded. Ethnicity was used as a proxy measure for tropical exposure. RESULTS: 426 new patients attended in a 12 month period. Eosinophilia was present in 27 (6.3%). 10/27 (37.0%) patients with eosinophilia were of African or Asian ethnicity whereas only 20% (85/426) of patients overall were from these ethnic groups (chi2=5.27, p=0.02). Following implementation of the protocol, 25/36 migrants with eosinophilia attended for parasitological investigations. Helminth infection was diagnosed in 10/25 (40%). Strongyloidiasis (six patients) and schistosomiasis (three patients) were the most common diagnoses. Median eosinophil count was 1.06*109/l in those with helminths and 0.58*109/l in those without (p=0.004). Eosinophil counts normalised in, and symptomatic improvement was reported by, most patients after treatment. CONCLUSIONS: Eosinophilia is associated with African or Asian ethnicity in an inner city gastroenterology service. This association is probably explained by imported helminths, which are prevalent in this setting, may be a cause of gastrointestinal symptoms and is easily diagnosed and treated by standard protocols. PMID- 28839596 TI - UpFront. PMID- 28839595 TI - Practical management of the increasing burden of non-alcoholic fatty liver disease. PMID- 28839597 TI - Establishing a biologics service for patients with inflammatory bowel disease. AB - The use of anti-TNF therapy in the management of Crohn's disease and, to a lesser extent ulcerative colitis, is increasing. This article aims to discuss the practicalities of establishing a biologics service for patients with inflammatory bowel disease. Current guidelines on the use of these drugs are reviewed followed by a discussion on the choice of which anti-TNF agent to use based on costs and patient choice. A model for the initiation, administration, monitoring and assessment of patients receiving anti-TNF therapy is proposed. The need for a national biologics registry is highlighted in the summary. PMID- 28839598 TI - Scope for improvement: a toolkit for improving the upper gastrointestinal bleeding service. PMID- 28839599 TI - Evidence-based use of anti-TNFalpha therapy in Crohn's disease; where are we in 2011? AB - The efficacy of anti-tumour necrosis factor (anti-TNFalpha) therapy with infliximab and adalimumab in moderate to severe Crohn's disease has now been proved. This article reviews the evidence supporting best practice with these agents in the light of recent National Institute for Health and Clinical Excellence guidance. Recent studies point to greater efficacy when these drugs are used early in the disease, particularly when mucosal healing can be achieved. For infliximab, the combination with immunomodulator drugs appears to afford greater efficacy, but possibly at the expense of the risk of rare but serious side effects. Patients should be selected carefully for treatment based on prognostic factors predicting aggressive disease, on the one hand, and comorbid factors that might predict side effects, on the other. Multiple drug combinations should be avoided where possible. Finally, a minority of patients in stable remission with complete mucosal healing may be selected for anti-TNFalpha drug withdrawal. PMID- 28839600 TI - Mind the fistula. AB - Thoracic aortic dissection (TAD) with aorto-oesophageal fistula formation is an uncommon but fatal cause of haematemesis. A case is presented of a previously healthy 63-year-old man who presented to the emergency department with syncope and haematemesis. He had no history of heavy alcohol intake and was previously well. Bedside portable chest x ray revealed a widened mediastinum and, while awaiting a CT angiogram, he had a further large haematemesis which led to him undergoing resuscitation and rapid sequence intubation. CT angiography of his thoracic aorta revealed a large thoracic aortic aneurysm with dissection from the arch of the aorta down to the left iliac artery. The dissection had formed an aorto-oesophageal fistula in the proximal oesophagus. He was transferred to a tertiary referral centre for repair of the dissection and aorto-oesophageal fistula. PMID- 28839601 TI - Feasibility of using routinely collected inpatient data to monitor quality and inform choice: a case study using the UK inflammatory bowel disease audit. AB - OBJECTIVE: To assess the utility and cost of using routinely collected inpatient data for large-scale audit. DESIGN: Comparison of audit data items collected nationally in a designed audit of inflammatory bowel disease (UK IBD audit) with routinely collected inpatient data; surveys of audit sites to compare costs. SETTING: National Health Service hospitals across England, Wales and Northern Ireland that participated in the UK IBD audit. PATIENTS: Patients in the UK IBD audit. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Percentage agreement between designed audit data items collected for the UK IBD audit and routine inpatient data items; costs of conducting the designed UK IBD audit and the routine data audit. RESULTS: There were very high matching rates between the designed audit data and routine data for a small subset of basic important information collected in the UK IBD audit, including mortality; major surgery; dates of admission, surgery, discharge and death; principal diagnoses; and sociodemographic patient characteristics. There were lower matching rates for other items, including source of admission, primary reason for admission, most comorbidities, colonoscopy and sigmoidoscopy. Routine data did not cover most detailed information collected in the UK IBD audit. Using routine data was much less costly than collecting designed audit data. CONCLUSION: Although valuable for large population-based studies, and less costly than designed data, routine inpatient data are not suitable for the evaluation of individual patient care within a designed audit. PMID- 28839602 TI - Monitoring clinical activity and performance: how can hospital episode statistics be made fit for purpose? PMID- 28839603 TI - Inter-endoscopist agreement in diagnosis of Barrett's oesophagus. AB - OBJECTIVE: To assess how interpretation of abnormalities at the oesophago-gastric junction (OGJ) when making a diagnosis of Barrett's oesophagus (BO) varies between endoscopists and to examine the impact of the endoscopy experience on these decisions. DESIGN/SETTING: Members of the Irish Society of Gastroenterology who regularly perform gastroscopy were invited to participate in a web based image assessment study. INTERVENTIONS: Questions were posed to ascertain level of endoscopy experience, and participants were asked to indicate the presence or absence of BO in 12 endoscopic images of the OGJ. OUTCOME MEASURES: Primary outcome was overall level of agreement in responses and relationship to endoscopy experience. RESULTS: The responses of 65 clinicians regularly performing gastroscopy were analysed. In 3/12 images, showing typical long segment BO, there was a strong consensus on the endoscopic diagnosis (>95% agreement). However, agreement was fair to poor (kappa for multiple raters, 0.31) on the presence or absence of short BO segments at endoscopy. Minimal differences were observed between experienced endoscopists (individuals with >10 years' endoscopy experience) and less experienced counterparts in the threshold for BO diagnosis. Inter-endoscopist agreement overall was not significantly better within the more experienced group. CONCLUSION: The study demonstrates low interobserver agreement in endoscopic diagnosis of (short segment) BO, even among experienced endoscopists. Given the costs associated with endoscopic surveillance of BO, prompt efforts to promote consensus diagnosis and improve agreement are required as an important quality improvement measure in this area. PMID- 28839604 TI - Understanding Barrett's columnar lined oesophagus from the patients' perspective: qualitative analysis of semistructured interviews with patients. AB - OBJECTIVES: To explore patients' views and perspectives on their experience of living with Barrett's columnar lined oesophagus (CLO) and being part of an endoscopic surveillance programme. DESIGN: Qualitative semistructured interviews. SETTING: District General Hospital. SUBJECTS: 22 men with diagnosis of Barrett's CLO between the ages of 50 and 70 years. RESULTS: All subjects had received some information about Barrett's CLO and had a heightened awareness of the cancer risk. However, many had misinterpreted or poorly assimilated the information and overall health literacy levels were low. From their stories a 'Model of Uncertainty' in Barrett's surveillance was developed as a focus for healthcare professionals to ensure that the service users' perspective is considered in future service development. CONCLUSION: Patients' assimilation of information should not be assumed by healthcare professionals but rather should be verified for individual patients. The model developed highlights the factors found to influence patients' knowledge and understanding of Barrett's CLO. PMID- 28839605 TI - Can shared decision making increase the uptake of evidence in clinical practice? AB - Despite copious research and clear policies in many healthcare systems, evidence based practice has yet to be widely adopted. Part of the problem is insufficient consideration of the patient-clinician consultation, which lies at the heart of clinical practice and is where most decisions are made. Shared decision making (SDM)-the interactive process in which patients and clinicians decide on healthcare together-capitalises on the consultation to better translate the best evidence into clinical decisions while taking the patient's values and preferences into account. This paper takes stock of interventions that seek to embed SDM in clinical practice, such as patient decision aids that target both patients and clinicians. It also presents challenges that remain: among others, the paucity of evidence on effective implementation strategies and the lack of consideration of how SDM works when care is delivered by interprofessional teams. The paper then reviews current initiatives to improve and disseminate SDM across the healthcare continuum, and discusses why SDM should be encouraged as a means to leverage evidence based practice. The evidence suggests that finding ways to overcome the challenges and promote SDM will accelerate the uptake of evidence in gastroenterology and hepatology clinical practice. PMID- 28839606 TI - Utility of screening for hepatocellular carcinoma among cirrhotics. AB - BACKGROUND: Screening known cirrhotics for hepatocellular cancer (HCC) has long been a contentious topic. Studies to date have failed to conclusively prove or disprove the validity of alpha-fetoprotein (AFP) and hepatic ultrasound as screening mechanisms for HCC among cirrhotics, particularly in the American population. It is not clear whether these screening mechanisms provide any benefit in terms of reduced morbidity and mortality. METHODS: The study examined all patients with liver cirrhosis who developed HCC at the Michael E DeBakey VA Medical Center between 1999 and 2005. Those who were screened with AFP and/or imaging (either ultrasound, triphasic liver protocol CT or MRI) were compared with those patients who were not screened at all. The screened and unscreened patients were compared in terms of Barcelona Clinic Liver Cancer (BCLC) stage at the time of diagnosis. RESULTS: Statistical analysis revealed a significant difference between the screened and unscreened groups in terms of BCLC stage at diagnosis, with the unscreened group being diagnosed at later stages than the screened group. Of the 155 patients observed, 26 were appropriately screened, and 129 were not. The BCLC stages at diagnosis for the two groups were as follows: screened patients: 34.6%, 38.5%, 7.7% and 19.2% for BCLC stages A, B, C and D, respectively; unscreened patients: 12.4%, 24.8%, 27.1% and 35.7% for BCLC stages A, B, C and D, respectively. The different trend in the two groups was found to be statistically significant, with a p value of 0.004. Furthermore, among the screened group, no particular method of screening (AFP vs imaging vs combination) was shown to be superior to another. CONCLUSIONS: Screening for HCC among cirrhotics using AFP and/or imaging every 6 months does correlate with HCC diagnosis at an earlier BCLC stage, thus portending better treatment options and improved prognosis. Therefore, screening all known cirrhotics for HCC may lead to decreased mortality. PMID- 28839607 TI - Service provision and training for endoscopic ultrasound in the UK. AB - Endoscopic ultrasound (EUS) is a standard procedure that plays an important role in the management of both malignant and benign disease. The development of EUS services in the UK has been haphazard and training inconsistent. The British Society of Gastroenterology has charged a working group with the task of laying down a national framework for how such services might be commissioned, structured and regulated; with particular attention to defining how endoscopist skills might be acquired, assessed and maintained. This report lays out a map for this process and its future revision. PMID- 28839608 TI - UpFront. PMID- 28839609 TI - Eight top tips for managing patients with medically unexplained symptoms. PMID- 28839610 TI - What you need to know when you prescribe a proton pump inhibitor. AB - Ever since they were launched, proton pump inhibitors (PPIs) have been regarded as profligate prescription interventions and have become a favourite target for pharmacy advisers. Now that they are cheap, with generic omeprazole 20 mg daily costing L1.88 per month (L24.51 per annum) in the UK, it is time to ask whether this status should be reviewed, whether there are areas where the message should be reversed and whether there are any circumstances in which the extra cost of branded PPIs or combined preparations is justified. Equally, with the recognition of an extended toxicity profile, is prescribing profligacy not an economic but a safety issue? PMID- 28839611 TI - A debate on the roles of antireflux surgery and long term acid suppression in the management of gastro-oesophageal reflux disease. PMID- 28839612 TI - Respiratory and laryngeal symptoms secondary to gastro-oesophageal reflux. AB - Gastro-oesophageal reflux may cause a range of laryngeal and respiratory symptoms. Mechanisms responsible include the proximal migration of gastric refluxate beyond the upper oesophageal sphincter causing direct irritation of the larynx and lower airway. Alternatively, refluxate entering the distal oesophagus alone may stimulate oesophageal sensory nerves and indirectly activate airway reflexes such as cough and bronchospasm. Recognising reflux as a cause for these extraoesophageal symptoms can be difficult as many patients do not have typical oesophageal symptoms (eg, heartburn) and clinical findings on laryngoscopy are not very specific. Acid suppression remains an effective treatment in the majority of patients but there is growing appreciation of the need to consider and treat non-acid and volume reflux. New opinions about the role of existing medical and surgical (laparoscopic techniques) treatment are emerging and a number of novel anti-reflux treatments are under development. PMID- 28839613 TI - Mortality following blood transfusion for non-variceal upper gastrointestinal bleeding. AB - OBJECTIVE: Blood transfusion remains an integral step in the management of acute non-variceal upper gastrointestinal bleeding (NV-UGIB), but its safety is being increasingly questioned in less severe cases. The authors aimed to measure 30-day and 2-year mortalities after blood transfusion for NV-UGIB. METHODS: Cox proportional hazards models were used to estimate the association of blood transfusion with mortality while adjusting for age, Charlson comorbidity score, the complete Rockall score for acute UGIB, admission status and medication intake prior to bleeding. MAIN OUTCOME MEASURES: Death from any cause at 30 days and 2 years after NV-UGIB. RESULTS: 1340 patients presented with NV-UGIB< (808 men (60.3%), median age 67 years) of whom 564 (42.1%) were transfused. The overall mortality was 5.3% at 30 days and 26.0% at 2 years in all patients. Comparing subjects with a haemoglobin concentration greater than 10.0 g/dl who were transfused with those who were not, 30-day mortalities (95% CIs) were 11.5% (6.7 to 18.0) versus 3.6% (2.3 to 5.3), respectively, p<0.001, and 2-year mortalities (95% CIs) were 40% (32 to 49) versus 20% (17 to 23), p<0.001. After adjusting for age, Charlson score, Rockall score and haemoglobin, the HRs (95% CIs) for death after transfusion were 1.88 (1.00 to 3.55) (p=0.051) at 30 days and 1.71 (1.28 to 2.28), (p<0.001) at 2 years. CONCLUSION: In patients with moderately severe NV UGIB, mortality is higher following blood transfusion. Whether this reflects selection bias, an effect of comorbidity or an effect of transfusion requires urgent prospective study. PMID- 28839614 TI - Two for the price of one: a dual treatment benefit of long-acting octreotide in occult bleeding and diuretic intractable ascites. AB - Transfusion-dependent anaemia and portal hypertension are recognised complications of hereditary haemorrhagic telangiectasia (HHT). The anaemia is a result of chronic bleeding from gastrointestinal telangiectasias, which are usually multiple and located throughout the gastrointestinal tract. As a result, treatment with argon plasma coagulation via gastroscopy and or colonoscopy is often insufficient to prevent ongoing blood loss. Portal hypertension in HHT occurs as a result of blood shunting between the hepatic artery and the portal vein within the liver. The somatostatin analogue octreotide has been used as a treatment for bleeding angiodysplasia; however, its possible role as a treatment for diuretic intractable ascites secondary to portal hypertension has not been previously established. The authors report a case that apparently illustrates a dual benefit of long-acting octreotide in the management of both occult bleeding and refractory ascites in a patient with HHT. PMID- 28839615 TI - Endoscopic management of postcholecystectomy biliary leaks. AB - OBJECTIVE: To evaluate the nature of bile duct injuries following cholecystectomy and the success of endoscopic retrograde cholangiopancreatography (ERCP) in their identification and management. DESIGN: All patients referred for ERCP with a diagnosis of a postcholecystectomy bile leak were identified prospectively from October 1994 to August 2008. SETTING: The study was carried out in a district general hospital with the endoscopies performed by a single operator. PATIENTS: All patients had undergone imaging with at least two of abdominal ultrasound scanning, CT scanning or MR cholangiopancreatography. INTERVENTIONS: ERCP with treatment of a biliary leak by sphincterotomy and insertion of a temporary 7 Fr plastic biliary stent. MAIN OUTCOME MEASUREMENTS: Clinical healing of the injury was assessed as resolution of symptoms with normalisation of liver function tests, cessation of external drain output and a repeat ERCP with removal of the indwelling stent within 2-8 weeks and no further complications. RESULTS: 46 patients were identified, of whom 42 responded well to endoscopic treatment. Four patients ultimately needed surgery, of whom three had recurrent strictures. One patient had complete transection of the biliary duct and endoscopic treatment was not attempted. CONCLUSION: ERCP, with sphincterotomy and temporary plastic stent placement, is successful in the early management of patients with postcholecystectomy biliary leaks, which most commonly involve the cystic duct stump. ERCP carried out in a district general hospital identifies those patients requiring further specialised hepatobiliary care in a tertiary centre. PMID- 28839616 TI - Epstein-Barr virus infection and central nervous system involvement after orthoptic liver transplant. AB - Epstein-Barr virus (EBV) infection presenting as encephalitis in seronegative adults in the context of solid organ transplantation is rarely reported. EBV seroconversion illnesses in the adult population after organ transplantation are quite uncommon. This report describes a case of encephalitis due to EBV infection after liver transplantation in an adult patient. The patient was seronegative for EBV pretransplant. She showed persistent viral replication indicated by high levels of EBV DNA in the serum, which raised concerns for future development of post-transplant lymphoproliferative disorder. The report discusses the management of such patients, awareness of EBV infection and earlier diagnosis by use of EBV PCR in adult immunocompromised individuals where infection may cause particular problems. PMID- 28839617 TI - Inflammatory bowel disease in transition: challenges and solutions in adolescent care. AB - The prevalence of inflammatory bowel disease (IBD) in childhood is increasing with a phenotype now established as one of complicated and extensive disease. Adolescent patients form a significant proportion of those requiring lifelong care. One of the most important steps in establishing a personal ability to effectively manage chronic disease is appropriate education, communication and a good relationship with healthcare professionals and a successful transition programme and subsequent transfer to adult care underpins this. It is vital to build trust and include parental input while transferring responsibility to the young person Although the literature confirms that the majority of paediatric gastroenterology units now have planned provision for transfer, the quality and appropriateness of these services have not been assessed or audited. This article discusses the drivers for establishing and improving transition services from both the patient's and healthcare provider's perspective. This heterogeneity of provision of healthcare for adolescents needs to be addressed and the experience of young people themselves is good evidence of this need. Barriers to optimal care need to be identified and managed and healthcare providers need to 'buy in' to establishing a flexible, patient focused achievable service for their patient population. PMID- 28839618 TI - A survey of patients' attitudes to upper gastrointestinal endoscopy identifies the value of endoscopist-patient interactive factors. AB - OBJECTIVE: To determine patients' self-reported preferences and expectations for outpatient upper gastrointestinal (UGI) endoscopy, including patients' priorities in obtaining a satisfactory healthcare experience, preprocedure anxiety and its causes, and preferred staff roles. DESIGN: A composite, dedicated endoscopy questionnaire was used. This included demographic information, validated Likert scale anxiety-related questions and a 15-point ranking scale of aspects of care (1=most important to satisfaction; 15=least important). SETTING AND PATIENTS: Unselected patients attending for an elective UGI endoscopy at two separate units were surveyed on randomly identified days. RESULTS: A total of 202 out of 254 patients agreed to participate (79.5%). The values identified as most important to patients included technical skill (2.8) and personal manner of the endoscopist (4.9) and the nurses and support staff (5.8), control of discomfort (5.6) and adequacy of the preprocedure explanation (5.8). The factors considered least important included noise levels (12.5), privacy (10.7) and cleanliness (8.7). Moderate to severe anxiety was recorded in half of the patient cohort, predominantly due to anticipation of pain or the results of the procedure. Most patients preferred the endoscopist to discuss the findings of the endoscopy but expressed no preferences regarding the preprocedure explanation. CONCLUSION: Patients undergoing UGI endoscopy appear to highly prioritise aspects of care relating to interaction with the endoscopist and the procedure itself. Environmental factors are considered to have much less value. These findings may assist in service redesign around patient-centred care and the development of patient satisfaction surveys in endoscopy. PMID- 28839620 TI - Upfront January 2012. PMID- 28839619 TI - Premedications for infliximab infusions do not impact the risk of acute adverse drug reactions. AB - OBJECTIVE: The purpose of this study was to identify the association of premedication with the adverse drug reaction (ADR) rate in infliximab infusions. DESIGN: A retrospective chart review of 684 patients who received 4077 infusions in a network of community clinics over 16.5 months. Data collected included age, weight, sex, diagnosis, dose, premedications and ADR information, which was coded for time of onset, severity and outcome. SETTING: Community infusion clinics located in Ontario, Canada. PATIENTS: Patients aged 12-91 years who receive regular infliximab infusions to treat their autoimmune condition, mainly either Crohn's disease or rheumatoid arthritis. MAIN OUTCOME MEASURES: The number of infusions to the occurrence of an acute ADR by presence of premedication. RESULTS: ADRs are not significantly different (chi2(1, n=644, p=0.651)=0.204) between those who always received premedications and those who never did. When controlling for age, sex, weight and diagnosis, patients receiving premedications were just as likely to experience an ADR as patients who never received any (OR 1.1, 95% CI 0.7 to 1.9, p=0.5). When assessing the number of infusions to the occurrence of an ADR using the Kaplan-Meier method, no significant difference was found between the two groups. CONCLUSIONS: The use of premedications is not associated with a decreased risk of ADR in patients receiving infliximab. This held true for patients who had never had an ADR prior to receiving premedications and while controlling for age, sex, weight and diagnosis. PMID- 28839621 TI - Every new beginning comes from some other beginning's end.... PMID- 28839622 TI - Commentary on small bowel imaging in Crohn's disease. PMID- 28839623 TI - Systemic mastocytosis: a gastroenterological perspective. AB - A 53 year old woman presented with abnormal liver function tests and subsequently developed intermittent abdominal pain, vomiting and diarrhoea. There were no rash or anaphylactoid reactions. Endoscopic biopsies showed excessive density of eosinophils and immunohistochemical staining for tryptase revealed a florid mast cell infiltrate. A diagnosis of systemic mastocytosis was made by bone marrow biopsy. Systemic mastocytosis is a rare myeloid neoplasm often associated with gastrointestinal symptoms due usually to mediator release but may rarely represent organ infiltration. While endoscopic and routine biopsy appearances are non-specific, suggestive features should lead to staining for mast cell tryptase or CD 117. However, diagnose generally requires bone marrow biopsy. The prognosis in the majority of patients is good and supportive management only is required. For patients with aggressive disease, cytoreductive therapy may be needed. PMID- 28839624 TI - Bowel cancer screening is safe, detects earlier stage cancer and adenomas in 50% of cases: experience of the prevalent round of screening from two first wave centres in the North East of England. AB - OBJECTIVE: The NHS Bowel Cancer Screening Programme (BCSP) began roll-out in 2006 aiming to reduce cancer mortality through detection at an earlier stage. We report results from the prevalent round of screening at two first wave centres and compare with the UK pilot study. DESIGN: This is a service evaluation study. Data were collected prospectively for all individuals undergoing faecal occult blood testing (FOBt) and colonoscopy including: uptake and outcomes of FOBt, colonoscopic performance, findings, histological data and complications. Continuous data were compared using a two-tailed test of two proportions. SETTING: The South of Tyne and Tees Bowel Cancer Screening centres. PATIENTS: Participants of the BCSP. MAIN OUTCOME MEASURES: 1) Colonoscopy Quality Assurance and 2) Cancer stage shift. RESULTS: 195,772 individuals were invited to participate. Uptake was 54% and FOBt positivity 1.7%. 1524 underwent colonoscopy with caecal intubation in 1485 (97%). 180 (12%) cancers were detected. Dukes stages were: 76 (42%) A; 47 (26%) B; 47 (26%) C; 8 (4%) D and 2 (1%) unknown. This demonstrates a significantly earlier stage at diagnosis compared with data from 2867 non-screening detected cancers (p<0.001). Adenomas were detected in 758 (50%). One perforation occurred (0.07%) and two intermediate bleeds requiring transfusion only (0.12%). Both caecal intubation and adenoma detection were significantly higher than in the UK pilot study (p<0.001). CONCLUSIONS: The prevalent round of screening demonstrates a high adenoma and cancer detection rate and significantly earlier stage at diagnosis. Complications were few providing reassurance regarding safety. Efforts are required to improve uptake. PMID- 28839625 TI - Improved clinical outcomes and efficacy with a nurse-led colonoscopy surveillance service. AB - BACKGROUND: A nurse practitioner-led colonoscopy surveillance service was introduced to improve appropriateness, validation and compliance with the National Patient Safety Agency safety alert and British Society of Gastroenterology consensus guidance for bowel cleansing agents. OBJECTIVE: To determine the clinical outcomes and efficacy of this new service. DESIGN AND PATIENTS: A 4-month prospective audit of patients due to attend for surveillance colonoscopy. SETTING: Royal Liverpool University Hospital. INTERVENTION: A new nurse practitioner-led surveillance service reviewed all patients before listing. OUTCOMES: Clinical outcomes, service efficiency and cost effectiveness. RESULTS: 224 Patients (median age 68 years, 52% male, and median American Society of Anesthesiologists (ASA) 2) were assessed and 34% had medical factors influencing their colonoscopy. 37% patients were discharged without a colonoscopy, 17% deferred (median >2 years), 6% had died while on the register and the remaining (40%) had their procedure at the agreed interval. The 30-day and 6-month all cause mortality was 0% for those fit for colonoscopy, compared with 5% and 14%, respectively, for those deemed unfit. The did-not-attend (DNA) rate was reduced from 7.6% to <1%. With 95 patients not requiring a colonoscopy a potential L40 000 saving to the primary care trust was made. CONCLUSIONS: The nurse practitioner-led surveillance service has been invaluable for guideline adherence and medical management of patients before colonoscopy. In addition, it potentially avoided procedural all-cause mortality in these patients. It has proved to be efficacious with reduced DNA rates and over one-third of patients assessed did not require a colonoscopy. PMID- 28839626 TI - High negative predictive value of a normal faecal calprotectin in patients with symptomatic intestinal disease. AB - BACKGROUND: Calprotectin is a heat stable intracellular protein shed by neutrophils into the intestinal lumen in response to inflammation. Lack of specificity makes its role in the assessment of inflammatory bowel disease uncertain. However, the strength of faecal calprotectin testing may lie in its negative predictive value (NPV) rather than positive predictive value (PPV) of organic intestinal disease. OBJECTIVES: To determine whether a normal faecal calprotectin in new patients with symptoms safely predicts for functional intestinal disease. METHODS: To determine the predictive values of normal and raised faecal calprotectin by retrospective review of outcomes in consecutive primary care referrals into secondary care. Patients aged 16-60 years (mean age 41 years; 70% female patients) with intestinal symptoms were identified. 500 referrals had a normal faecal calprotectin and 130 had a raised result. 'Fast track' referrals were excluded. Outcome measures were the NPV of a normal faecal calprotectin and PPV of a raised faecal calprotectin. RESULTS: Normal faecal calprotectin had an NPV of 0.964 for excluding symptomatic organic intestinal disease. Significant incidental non-intestinal (3.6%) and intestinal (6.4%) diseases were also identified. Mean follow-up was 4.8 years with no diagnostic revisions. In the raised faecal calprotectin cohort, the PPV for organic intestinal disease was 0.7. CONCLUSIONS: A normal faecal calprotectin safely predicts for functional intestinal disease. It may represent a powerful screening tool for excluding organic intestinal disease in primary care. A prospective primary care based study is needed. PMID- 28839627 TI - Daily consultant gastroenterologist ward rounds: reduced length of stay and improved inpatient mortality. AB - BACKGROUND: For gastroenterology, The Royal College of Physicians reiterates the common practice of two to three consultant ward rounds per week. The Royal Bolton Hospital NHS Foundation Trust operated a 26-bed gastroenterology ward, covered by two consultants at any one time. A traditional system of two ward rounds per consultant per week operated, but as is commonplace, discharges peaked on ward round days. OBJECTIVE: To determine whether daily consultant ward rounds would improve patient care, shorten length of stay and reduce inpatient mortality. METHODS: A new way of working was implemented in December 2009 with a single consultant taking responsibility for all ward inpatients. Freed from all other direct clinical care commitments for their 2 weeks of ward cover, they conducted ward rounds each morning. A multidisciplinary team (MDT) meeting followed immediately. The afternoon was allocated to gastroenterology referrals and reviewing patients on the medical admissions unit. RESULTS: The changes had an immediate and dramatic effect on average length of stay, which was reduced from 11.5 to 8.9 days. The number of patients treated over 12 months increased by 37% from 739 to 1010. Moreover, the number of deaths decreased from 88 to 62, a reduction in percentage mortality from 11.2% to 6%. However, these major quality outcomes involved a reduction in consultant-delivered outpatient and endoscopy activity. CONCLUSION: This new method of working has both advantages and disadvantages. However, it has had a major impact on inpatient care and provides a compelling case for consultant gastroenterology expansion in the UK. PMID- 28839628 TI - A response, and rebuttal, to Roland Valori's 'top tips for managing patients with medically unexplained symptoms'. PMID- 28839629 TI - Parenteral methotrexate for patients with Crohn's disease: how to develop a high quality and safe self-administration service. AB - Parenteral methotrexate is recommended for patients with Crohn's disease who have failed treatment with thiopurines. There is no good evidence for the use of oral methotrexate, yet patients frequently receive this due to the difficulties associated with prescribing and administering an unlicensed, cytotoxic drug. We present our experience of developing a local service to provide our patients with the option to self-administer parenteral methotrexate in a safe and structured manner at home. PMID- 28839630 TI - Small bowel imaging in Crohn's disease. AB - Imaging of Crohn's disease of the small bowel is gradually moving away from barium fluoroscopy and towards cross-sectional modalities. This review explores the strengths and limitations of various techniques, and focuses on several current questions in small bowel imaging, such as the comparison between oral ingestion or nasojejunal intubation and enteroclysis for introduction of contrast, the use of computerised tomography (CT) versus magnetic resonance (MR) and the likely changes over the next decade. PMID- 28839631 TI - Upper gastrointestinal cancer in its early stages is predominantly asymptomatic. AB - BACKGROUND: Current guidelines for urgent endoscopic investigation of dyspepsia are based on alarm features and age criteria. However, there is concern that this type of guideline may delay the diagnosis of upper gastrointestinal (GI) cancer. OBJECTIVE: To evaluate the timescale of symptoms in upper GI cancer, determining whether patients experience dyspepsia before developing alarm features, and hence whether the current guidelines may delay diagnosis. METHOD: A prospective study of patients diagnosed with upper GI cancer between May 2004 and January 2007. A structured interview was performed directly after endoscopic diagnosis regarding the nature and duration of symptoms. RESULTS: Alarm features were present in 56 of the 60 patients interviewed. Only eight patients reported dyspepsia before developing their alarm feature; three of these had complained of dyspepsia for >10 years, one reported dyspepsia preceding the alarm feature by 18 months and in four patients dyspepsia preceded the alarm feature by <=8 weeks. Preceding dyspepsia did not cause significant delay in referral for endoscopy (p=0.670), or affect tumour stage at diagnosis (p=0.436) or length of survival (p=0.325). CONCLUSION: It is rare for patients with upper GI cancer to experience significant dyspepsia before the onset of their alarm symptoms, therefore limiting the prospect of an earlier diagnosis. Early upper GI cancer is largely asymptomatic, and guidelines should limit the availability of open-access gastroscopy in simple dyspepsia. Increased awareness of the need to urgently investigate patients with concurrent anaemia or weight loss is required. PMID- 28839632 TI - Hepatology training in the UK. AB - OBJECTIVES: To establish the perceived adequacy of the hepatology training component of the unified gastroenterology and hepatology training programme in the UK by assessing the attitudes and experiences of trainees in the programme. DESIGN AND INTERVENTION: Online cross-sectional questionnaire survey linked to the annual British Society of Gastroenterology/Trainee in Gastroenterology survey in 2010. SETTING AND PARTICIPANTS: National survey of all specialist gastroenterology trainees in the UK. RESULTS: 283/489 (58%) trainees responded, 68% were male. 54% of all trainees wanted to deliver liver services as consultants. 25% of trainees complete training without exposure to a liver unit providing comprehensive specialist hepatology services. Median time spent in such a unit for the others was 8 months (IQR 6). Significantly fewer trainees lacked confidence in managing liver-related conditions if they had spent time training in a specialist liver unit and with increasing years in training. One in three trainees is dissuaded from a career in hepatology. One in five trainees wished to work part time as consultants-an option preferred significantly more by women. CONCLUSIONS: Hepatology training in the UK is perceived by trainees as being suboptimal. A national strategy aimed at improving and standardising hepatology training and making specialist liver unit experience available for every trainee is required. PMID- 28839633 TI - A drunk and disorderly country: a nationwide cross-sectional survey of alcohol use and misuse in Great Britain. AB - OBJECTIVES: To explore current alcohol drinking patterns, behaviours and attitudes in Great Britain. DESIGN AND SETTING: Independent online cross sectional survey. PATIENTS AND INTERVENTIONS: Survey of 2221 individuals from a representative panel. MAIN OUTCOME MEASURES AND RESULTS: Excessive alcohol consumption is a widespread problem across Great Britain. Binge-drinking is common among 18-24 year olds, with 19% reporting drinking 10+ drinks on the same drinking day. 'Pre-loading' with alcohol at home before going out was reported by 30% of 18-24-year-old drinkers, of whom 36% get drunk twice or more a month, with 27% having injured themselves while drunk. Among older drinkers, 25% regularly drink to excess, 8% drink seven or more drinks on a typical drinking day and 9% self-reported drink-driving. Male gender was an independent risk factor for heavy (>40 units/week) alcohol abuse (odds ratio 3.05 (95% CI 1.82 to 5.10)). Men (19%) were more likely than women (8%, p<0.001) to report binge-drinking, drink-driving (11% vs 3%, p<0.001), or to have missed work owing to alcohol consumption (12% vs 7%, p<0.001). Young drinkers said they were heavily influenced by overall alcohol price and drink promotions. Increasing average weekly alcohol consumption, age <55 years, male gender, never having been married and being in full-time employment were all independently associated with a history of alcohol-related self-harm. Alcohol abuse was not related to socioeconomic status. CONCLUSIONS: Alcohol abuse remains common across all socioeconomic strata and geographical areas of Great Britain. Minimum pricing strategies and interventions that target cheap on-trade alcohol products seem likely to bring major public health benefits. PMID- 28839635 TI - Upfront April 2012. PMID- 28839634 TI - Myocardial ischaemia during endoscopic procedures. PMID- 28839636 TI - Getting involved in clinical trials research in the UK: how can Clinical Research Networks help? AB - The Clinical Research Networks of the National Institute of Health Research have transformed clinical research in the UK, leading to a doubling in the number of patients involved in clinical research studies over the past 3 years. This has been achieved by streamlining the trials approvals process, by providing local infrastructure such as research nurse support for clinical trials recruitment and through recognition of the time and funding necessary for clinicians to contribute to clinical research. Here, we describe the structure and roles of the Comprehensive Clinical Research Networks in gastrointestinal disease and hepatology, particularly in England. We will explain how the networks have already accelerated clinical research in gastrointestinal and liver disease, as well as provide a simple guide about how individual clinicians can contribute to ongoing studies via the networks. PMID- 28839637 TI - Endoscopy and implantable electronic devices. AB - The increasing use of implantable electronic devices such as cardiac pacemakers and neurostimulators means that they are being increasingly encountered in endoscopy departments. The electromagnetic fields generated during electrosurgery and with magnetic imaging systems have the potential to interfere with such devices. The authors present a case that highlights some of the steps necessary for minimising risk, review the evidence and summarise the currently available guidance. PMID- 28839638 TI - Improving outpatient services: the Southampton IBD virtual clinic. AB - The follow-up of inflammatory bowel disease (IBD) patients is challenging due to the relapsing remitting nature of the diseases, the wide spectrum of severity and complexity as well as the need for monitoring of long-term complications and drug treatments. Conventional outpatient follow-up lacks flexibility for patients and there are competing pressures for clinic time. Alternative follow-up pathways include telephone clinics, self-management programmes or discharging patients. The IBD virtual clinic (VC) is a further option. Patients with an established diagnosis for >2 years, who have been stable for >1 year, do not have primary sclerosing cholangitis and who give their consent, are entered into the VC system. Two months before their annual follow-up is due patients are sent blood test forms and a simple questionnaire with an information sheet. If they meet any of the criteria on the questionnaire, they are asked to contact the IBD specialist nursing team to discuss their situation. The blood test results and the patient's database entry are reviewed to ensure that they are not due surveillance investigations. The patients and their GPs then receive a letter informing them of their management plan. We currently follow-up 20% of the Southampton IBD cohort using the VC. The VC system is an innovative, efficient and patient-responsive method for following up mild to moderate IBD. It is well liked by patients but is dependent on a well-maintained database with good integration of IT systems and requires both clerical and IBD nurse specialist support. PMID- 28839639 TI - Positive tissue transglutaminase antibodies with negative endomysial antibodies: coeliac disease or not? PMID- 28839640 TI - The era of modern medicine: implants and all. PMID- 28839641 TI - Effective teamworking in gastroenterology. AB - The majority of healthcare provision within the NHS is delivered by teams, but most attempts at improving team functioning are limited to promoting working relationships within the team. This contrasts with other high risk industries, where formalised team training is recognised to be of paramount importance in reducing error. Some medical specialities have adapted such training methodologies with the aim of improving productivity and clinical outcomes. There are many teams within gastroenterology that could benefit from such attention. Formal analysis of team objectives and identification of essential task sequences can allow redesign of team organisation and enable structured training to strengthen team cohesion, enhance critical team skills and improve clinical outcomes. The challenge is to change teams of experts into expert teams. PMID- 28839642 TI - Aviation: a pilot study for safety in gastroenterology? PMID- 28839643 TI - Safety in the endoscopy suite: lessons from the aviation industry. PMID- 28839644 TI - Improvement of parenteral nutrition-associated cholestasis in an adult using fish oil-based parenteral nutrition. AB - Parenteral nutrition-associated cholestasis (PNAC) is a severe complication of parenteral nutrition. Standard feed preparations contain soybean and olive oil that are rich in omega-6 polyunsaturated fats, and which studies suggest can be hepatotoxic. Preparations containing fish oil, rich in omega-3 polyunsaturated fats, may be hepatoprotective and have been used in the critical care setting as immunotherapy. A case demonstrating dramatic improvement in liver function and overall clinical condition in an adult with PNAC and intestinal failure within 8 weeks of changing to a fish oil-based parenteral feed is reported. As far as is known, this is the first report of an adult patient whose parenteral nutrition associated liver disease resolved after a parenteral nutrition lipid emulsion was changed to the fish oil-containing emulsion, SMOFlipid. PMID- 28839645 TI - Provision of service and training for small bowel endoscopy in the UK. AB - OBJECTIVE: To determine the location and use of small bowel endoscopy services in the UK and to analyse training uptake to assess future demand and shape discussions about training and service delivery. DESIGN: Surveys of British Society of Gastroenterology (BSG) members by web-based and personal contact were conducted to ascertain capsule endoscopy practice and numbers of procedures performed. This was compared with expected numbers of procedures calculated using BSG guidelines, hospital episode statistics and published data of capsule endoscopy in routine practice. Analysis of data from two national training courses provided information about training. RESULTS: 45% of UK gastroenterology services offered in-house capsule endoscopy. 91.3% of survey responders referred patients for capsule endoscopy; 67.7% felt that local availability would increase referrals. Suspected small bowel bleeding and Crohn's disease were considered appropriate indications by the majority. Demand is increasing in spite of restricted use in 21.6% of centres. Only two regions performed more than the minimum estimate of need of 45 procedures per 250 000 population. Eight centres perform regular device-assisted enteroscopy; 14 services are in development. 74% of trainees were interested in training and of those training in image interpretation, 67% are doctors and 28% are nurses. CONCLUSIONS: Capsule endoscopy is used by the majority of UK gastroenterologists but appears to be underused. Current demand for device-assisted enteroscopy seems likely to be matched if new services become established. Future demand is likely to increase, however, suggesting the need to formalise training and accreditation for both doctors and nurses. PMID- 28839646 TI - The endoscopically normal colon: when is mapping biopsy histopathologically justifiable? AB - OBJECTIVE: Mapping biopsy of endoscopically normal colon is a contentious area and generates considerable work for histopathology services. Managing demand for pathological testing is a current healthcare priority. In this retrospective audit, the authors aimed to establish diagnostic yield of mapping biopsy in this specific subgroup and identify situations where practice could be safely streamlined. DESIGN: Cases were retrieved over a 10-month period. Histopathology results were correlated with relevant endoscopy reports. The data were anonymised and analysed. SETTING: Department of Cellular Pathology, Southampton General Hospital, UK. RESULTS: 717 cases were retrieved. 308 (43%) cases were reported as endoscopically normal. 278 (90%) cases with endoscopically normal/near normal mucosa showed normal/near normal histology. 30/308 (9.7%) endoscopically normal cases showed pathological abnormalities. 9/308 (2.9%) cases of microscopic colitis were detected. Of the 30 cases with pathological abnormalities, 20 (66.7%) presented with change in bowel habit and 6 (20%) had a pre-existing diagnosis of inflammatory bowel disease. CONCLUSIONS: Pathological abnormalities in endoscopically normal colon are found most frequently in those who present with change in bowel habit or a known history of inflammatory bowel disease. The authors support biopsy in these individuals and believe that mapping biopsy of endoscopically normal colon in patients referred for other reasons (eg, bright red rectal bleeding or iron deficiency anaemia) should not be performed routinely as diagnostic yields are very low. Guidelines on appropriate use of mapping biopsy in this setting are limited. Streamlining patients based on reason for referral or presenting symptoms may be a useful step towards more effective management of histopathological demand. PMID- 28839647 TI - Efficacy of nasal bridles in avoiding percutaneous endoscopic gastrostomy placement. AB - OBJECTIVE: The aim of the study was to report the use of nasogastric tube bridles to avoid dislodging of percutaneous endoscopic gastrostomy tubes. Specifically it was intended to see if they reduced feeding time, medical input and costs. DESIGN: and setting This was a cohort study in a district hospital setting. PATIENTS: 164 patients admitted with conditions causing acutely impaired swallowing. INTERVENTIONS: 140 of 164 patients referred received a NGT bridle. RESULTS: Of these, 49 (35%) died by 28 days and 68 (48.6%) at 1 year; 73 (52.1%) had regained adequate oral intake at 28 days and 27 (19.2%) had proceeded to PEG. Of those not bridled, nine (37.5%) died by 28 days and 10 (41.7%) at 1 year with the remainder eating. There was no significant difference in mortality between groups. There were no complications attributed to bridles. CONCLUSION: We conclude that nasogastric bridles are safe and represent an appropriate method to maintain nutrition while seeing if the underlying disease process will stabilise in these critically ill patients. They have the benefits of avoiding unnecessary PEG and the associated complications and cost. PMID- 28839650 TI - Upfront July 2012. PMID- 28839648 TI - Teaching and learning on the ward round. AB - Because of the European Working-Time Directive and 'the New Deal', there has been a significant reduction in opportunities for training. To address this deficit, consultants and junior doctors will need to alter their approach, making greater use of the learning opportunities that arise 'on the job'. This paper provides some ideas on how to maximise learning without radically increasing workload. The paper first looks at attitudes and behaviours that influence the learning environment. If the senior doctor encourages discussion and shows enthusiasm during clinical duties, junior doctors will learn more. Second, the paper focuses on key skills that can be adopted to ensure appropriate learning. These attitudes, behaviours and skills can help consultants and senior doctors improve the effectiveness of their teaching in an era when the time available for junior doctors to learn has been reduced. PMID- 28839651 TI - Should patients expect their colonoscopy to reach the standards experienced by bowel cancer screening patients? PMID- 28839649 TI - Quality assurance in the endoscopy unit: the view of endoscopy personnel. AB - INTRODUCTION: Quality of health services depend on the entire medical team. A supportive team culture and effective leadership is required for successful quality assurance (QA). The opinion of endoscopy personnel towards QA is unknown, while they have to collaborate in many quality projects. METHODS: A survey was sent to all endoscopy nurses, assistants and managers. It focused on the implementation of a QA programme. Further, a team assessment was included, focusing on leadership and team functioning, using scores on 5-point Likert scales, with 1 being a very positive opinion, and 5 being a very negative opinion towards the item. RESULTS: 294 persons completed the questionnaire (44%). 87% expressed a positive attitude towards a QA programme, and 54% thought that the implementation of a nationwide QA programme for endoscopy would be feasible. Positive effects of QA were expected on publicity (62%) and overall quality (70%). Most important QA aspects were aftercare (97%) and patient experiences (96%). Concerns were raised about the time investment (18%) and disclosure of results towards media (24%). Team assessment showed good scores on 'team working' with a mean score of 1.97. Lower scores were given to the 'wider organization' (3.00) and 'team process' (2.42). CONCLUSION: Endoscopy personnel have a positive attitude towards a QA programme. Besides, the team culture and its leadership are ready for the implementation of a QA programme. Efforts should be made to improve team processes and the relation with the wider organisation to ensure an optimal team culture, aimed at quality improvement. PMID- 28839652 TI - Scope to improve: a multi-centre audit of 16 064 colonoscopies looking at caecal intubation rates, over a 2-year period. AB - OBJECTIVE: Colonoscopy is the 'gold standard' assessment for large bowel mucosal pathology, but a complete examination is essential. The first national colonoscopy audit carried out in 1999 demonstrated caecal intubation rates (CIRs) of 56.9%. As a result, the Joint Advisory Group (JAG) on gastrointestinal endoscopy launched a programme of continuous quality improvement. JAG recommends that practitioners undertake 100+ procedures per annum with a target CIR of 90%. This current audit provides an assessment of performance against this quality standard. DESIGN: Data were collected from all procedures undertaken in 2008-2009 from six hospitals across three English regions. RESULTS: 16064 colonoscopies performed: CIR = 90.57% (95% CI 90.11% to 91.01%). Operators doing 100+ procedures per annum, CIR=91.76% (91.24% to 92.25%). Operators doing <100 procedures per annum, CIR=87.77% (86.82% to 88.67%). Gastroenterologists, CIR=91.01% (90.32% to 91.70%). Surgeons, CIR=91.03% (90.27% to 91.79%). Other practitioners, CIR=81.51% (78.79% to 84.22%). Bowel cancer screening programme (BCSP) colonoscopies, CIR=97.71% (97.07% to 98.34%). Non-screening colonoscopies, CIR=88.31% (95% CI 87.68% to 88.94%). CONCLUSION: This audit of 16064 colonoscopies across three regions demonstrates aggregated achievement of the CIR quality standard. However, there is a significant performance gap when comparing BCSP colonoscopists with non-screening colonoscopists and the overall CIR of >90% is supported by the volume of BCSP colonoscopy. Endoscopists performing low volume colonoscopy (<100 per annum), have CIR of <90%. Endoscopists with low volume practice who do not meet the quality standards should engage in skills augmentation plus further training and increase volume of colonoscopy with local mentorship, or stop performing colonoscopy. PMID- 28839653 TI - Patient satisfaction with the colonoscopy procedure: endoscopists overestimate the importance of adverse physical symptoms. AB - BACKGROUND: Colonoscopy is a frequently performed procedure associated with a substantial burden for the patient. Most of what is known about patient satisfaction stems from surveys that target issues doctors believe to be important. It has been noticed that patients often focus on different aspects. AIM: To have patients and endoscopists rate the extent to which each of a list of patient-generated issues-of-concern contributes to patient satisfaction with the colonoscopy procedure. SUBJECTS: A sample of consecutive patients undergoing colonoscopy in a Dutch tertiary teaching hospital and a convenience sample of endoscopists. METHODS: Colonoscopy patients and endoscopists were asked to rate on a five-point Likert scale the importance of 55 items concerning the colonoscopy procedure for patient satisfaction. Items were derived from focus group sessions with colonoscopy patients. Endoscopists were invited to rate the importance of the same set of items from a patient perspective. An analysis was carried out of whether patients and endoscopists rated the importance of items differently. RESULTS: 69 patients and 34 endoscopists completed the questionnaire. The ratings of the endoscopists were significantly different from those of patients (p<0.0001). Endoscopists underestimated the importance of involving patients in decisions, discussing risks and complications, providing the opportunity for substantive questions and offering a comfortable temperature in the examination room. Endoscopists overestimated the importance of adverse physical symptoms, such as pain and abdominal cramps, and the role of the treating doctor. CONCLUSIONS: Endoscopists do not have a good perception of the items that contribute most to patient satisfaction with the colonoscopy procedure. Overcoming this gap may be an essential step towards improving patient satisfaction by targeting those concerns most relevant to patients. PMID- 28839654 TI - A dedicated inflammatory bowel disease service quantitatively and qualitatively improves outcomes in less than 18 months: a prospective cohort study in a large metropolitan centre. AB - INTRODUCTION: Maintaining high efficacy and quality of care in inflammatory bowel disease (IBD) management is a priority. The authors examined whether the introduction of a formal IBD Service (IBDS) positively influenced outcomes for their patients. METHODS: In 2007-2008, all IBD patients attending the Royal Adelaide Hospital were surveyed regarding clinical/demographic data, IBD knowledge, quality of life, mental health and satisfaction. Survey responders were re-surveyed >=15 months later. RESULTS: 162 responded to survey 1 and 81 again responded to survey 2. Within the responders, 61% had Crohn's disease and 48% were men. Compared with survey 1, the proportions of patients with improved knowledge, adherence, satisfaction with care, QoL (>=5 points), anxiety and depression scores were 63% (95% CI 51 to 73), 62% (95% CI 50 to 72), 65% (95% CI 54 to 76), 42% (95% CI 31 to 54), 52% (95% CI 40 to 63) and 43% (95% CI 32 to 55), respectively. When comparing survey 2 with survey 1, reductions in hospitalisation (48% vs 30%, p=0.02), courses of corticosteroids and opiates (mean 1.63 vs 0.91 and 1.00 vs 0.61, both p<0.05) and overall medications (5.63 vs 4.65, p<0.05), were seen. Fewer 2009 non-responders required hospitalisation (53% vs 21%, p<0.001), suggesting a 'cohort' rather than 'responder-specific' effect. CONCLUSIONS: The introduction of an IBDS resulted in improved patient outcomes with significant reductions in negative markers for IBD morbidity including: hospitalisations, polypharmacy, steroid and opiate use. Despite increased costs in additional staff, these measures are likely to be cost effective. PMID- 28839656 TI - Abdominal pain and weight loss: an uncommon outcome to a common referral. PMID- 28839655 TI - Colorectal cancer patients: what do they die of? PMID- 28839657 TI - Endoscopic retrograde cholangio-pancreatography services can be accessible and of a high standard in a district general hospital. AB - BACKGROUND: Endoscopic retrograde cholangio-pancreatography (ERCP) is an important tool in the management of pancreato-biliary disease. OBJECTIVE: To compare the current practice of ERCP in a district general hospital with those reported in the 2007 British Society of Gastroenterology (BSG) ERCP audit and assess access to the service. DESIGN: This was a service evaluation study. Data were collected retrospectively for all people who underwent ERCP. Demographic, clinical and procedure related data were collected and analysed. SETTING: Sunderland Hospital. RESULTS: 236 patients (median age 70 years, 56% women) underwent ERCP. The median period from referral to patient review was 1.0 day. The median period from the decision to carry out an ERCP to the actual procedure date was 3 days. All patients had radiological imaging before their first procedure. 96% patients had their bloods checked within 1 week of the procedure. The most common indication was related to choledocholithiasis and its complications. The mean doses of midazolam and diazemul used were 4.4 mg and 11.1 mg, respectively. The selective biliary cannulation rate was 92%. Sphincterotomy, biliary stent insertion and complete stone extraction were achieved in 94%, 85% and 88% of patients before the procedure. Complications that occurred as a result of ERCPs were as follows: bleeding (1.7%), pancreatitis (3.8%), cholangitis (0.4%) and renal failure (0.4%). The 30-day death rate was 4.6%. However, none of these were procedure related. CONCLUSIONS: The structure of the ERCP services at Sunderland Royal Hospital provides patients with a high-quality and accessible service. The technical success rate and sedation rate were better than those reported in the BSG ERCP audit. The complication rate and procedure-related mortality were comparable to the BSG audit and much below the published figures. PMID- 28839658 TI - The ERCP quality network benchmarking project: a preliminary comparison of practice in UK and USA. AB - OBJECTIVE: The Endoscopic retrograde cholangiopancreatography (ERCP) Quality Network is a voluntary system for submission of data to generate individual report cards and benchmarking. The aim of this study was to compare aspects of ERCP practice between USA and UK participants. DESIGN: Analysis was limited to USA and UK based endoscopists who had each entered more than 30 cases. A number of practice and performance measures were studied including, rates of deep biliary cannulation, sedation use and success in bile duct stone removal. SETTING AND PATIENTS: Patients attending for routine and emergency ERCP in participating tertiary and secondary care units in the UK and USA. RESULTS: 61 US endoscopists performed 18 182 procedures and 16 UK endoscopists 3172, respectively. The UK participants performed less complex procedures as judged by the accepted complexity grading system, 8% versus 35% at grade 3, p<0.001. There was a significantly greater use of sedation as opposed to anaesthesia in the UK 97% versus 34%, p<0.001. UK deep biliary cannulation rate was 93% versus 97%, p<0.001. For small bile duct stones (<10 mm) the UK success rate was 96% compared with 99%, p<0.001. CONCLUSION: The present data, while not purporting to be an accurate representation of practice in either country, documents good technical success in both cohorts, albeit significantly better in the USA. The inexorable drive to greater accountability and transparency of outcomes in endoscopic practice is likely to lead to increased participation in subsequent benchmarking projects. PMID- 28839659 TI - Digital dictation and voice transcription software enhances outpatient clinic letter production: a crossover study. AB - BACKGROUND: Digital voice transcription has been introduced widely in the National Health Service (NHS), though primarily in radiology departments. There has been a long-standing problem with recruitment of medical secretaries within the NHS, leading to long delays in the production of correspondence from outpatient clinics. OBJECTIVE: To determine whether use of widely available digital transcription software improves efficiency and the time taken to produce correspondence. METHODS: The project used a prospective, crossover trial design in a 'real-world' environment. Correspondence from clinics was transcribed after dictation by a secretary using conventional analogue audio tape or the dictation software. After a 2-week washout period the same clinics' dictations were transcribed using the other method to produce identical correspondence. The two sets of letters were compared. RESULTS: The mean time for the secretary to produce letters for a complete clinic using digital dictation was 66 min whereas analogue dictation took 121 min (p<0.00002). There was no difference in the number of mistakes per letter (p>0.05). CONCLUSION: Voice transcription software significantly decreased the time taken to transcribe outpatient clinic letters with minimal training of secretarial staff, resulting in improved efficiency. PMID- 28839660 TI - Nutritional management of adults with inflammatory bowel disease: practical lessons from the available evidence. AB - Inflammatory bowel disease (IBD) is associated with impairment of nutritional status both anthropometrically and biochemically, which results from both qualitative and quantitative changes in dietary intake alongside disease activity. Dietary intervention to replace deficiency is essential and may also be used to treat active disease and to reduce symptoms. The evidence for dietary interventions in this area is reviewed and the following recommendations made: ?Assessment of nutritional status is an essential part of the investigation of all patients with IBD and deficiency should be actively sought.?Any patient with macro- or micronutrient deficiency should be referred for dietetic assessment.?Micronutrient deficiency (most frequently iron, vitamin B12, folate and magnesium) should be replaced aggressively, parenterally if necessary.?Significant improvement in gastrointestinal symptoms can be achieved by low-residue diets (for stricturing disease) and (always under dietetic supervision) management of lactose and other intolerances.?Irritable bowel syndrome symptoms in patients with IBD can respond to low fermentable oligo-, di , monosaccharide and polyol (FODMAP) diets, again this must be done under dietetic supervision.?Active Crohn's disease can be treated by exclusive enteral nutrition (elemental/polymeric/altered fat formulations all have equivalent efficacy).?Enteral nutrition can maintain remission in Crohn's disease and in this context can be given alongside normal oral intake.?Nutritional support does not have an established role in the treatment of active ulcerative colitis, other than in the management of malnutrition.?Total parenteral nutrition should not be used unless intestinal failure occurs.?There is insufficient evidence to support the routine use of Omega3 fish oil, prebiotics and glutamine in the treatment of active IBD. PMID- 28839661 TI - Gene-environment interactions in inflammatory bowel disease: microbiota and genes. AB - A recent research workshop gave an update on the genetics of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. This mini-review summarises the updates of the gene-environmental interactions, especially those outlining the contribution of the gut microbiota to the pathogenesis of IBD. PMID- 28839662 TI - Feasibility and experience of nurse-led ultrasound-guided percutaneous liver biopsy. AB - The demand for collaborative and innovative clinical practitioners to act as leaders in healthcare remains strong as many challenges are faced including rising costs, shortage of professionals, the introduction of new technology and difficulties with access to care. Nurses in advanced nursing practice are well positioned to respond to this, playing a key role in building nursing knowledge, advancing the nursing profession and contributing to sustainable and effective healthcare systems. Percutaneous liver biopsy (PLB) is an essential tool used for diagnosis and management in liver disease, being most commonly performed by consultant gastroenterologists, hepatologists and radiologists. While invasive and with complications PLB is a simple, cost-effective procedure that can be undertaken at the bedside. Our study demonstrates that an advanced nurse practitioner (ANP) with a sound working knowledge of hepatology and familiarity with indications, methods and risks of PLB procedure can be trained to perform ultrasound-guided liver biopsy both safely and effectively. PMID- 28839663 TI - Gastroenterology and the provision of care to Panjabi patients in the UK. AB - Panjabi is spoken by 1.3 million people in the UK. It is the second most common language used in the country and is the first choice of 75% of Panjabis. It is becoming more common. For many patients it forms part of the barrier which limits access to gastrointestinal services. The provision of appropriate support services is woeful and yet seldom leads to formal complaints. This review considers the impact of gastrointestinal disorders on the Panjabi community and assesses some of the interventions that could be developed to ensure equity of care. PMID- 28839664 TI - Steroids in villous atrophy: opening a can of worms? AB - A 60 year old man presented to the emergency department with septic shock and respiratory distress. He noted significant weight loss over the last 6 months with associated postprandial bloating. Endoscopy demonstrated partial villous atrophy. He had been on a gluten free diet, received empirical treatment for giardiasis and was receiving treatment with high dose systemic steroids for retroperitoneal fibrosis. This case discusses histology findings, differentials and reason for this acute presentation. PMID- 28839665 TI - Aggressive Helicobacter pylori-negative peptic ulceration as the initial manifestation of Crohn's disease. AB - Peptic ulceration is a recognised feature of Crohn's disease, but the characteristics of this manifestation are rather poorly described. Furthermore, most reports in the literature relate to ulcer disease in cases of established Crohn's disease. The authors report a series of four cases in which the diagnosis of Crohn's disease was preceded by peptic ulceration. Potential confounding factors were as far as possible excluded, implying a true association. Characteristics of the ulcer disease included (1) a multifocal distribution, (2) Helicobacter pylori negativity and (3) an unusually aggressive clinical course despite proton pump inhibitor therapy, necessitating endoscopic or surgical intervention in three cases. Crohn's-related peptic ulceration is a relatively common manifestation which may precede the diagnosis of Crohn's disease itself. Recognition of the underlying diagnosis may be hampered by non-specific histology, but is important in view of the aggressive course of the ulceration, which may respond to medical therapy for Crohn's disease. PMID- 28839666 TI - Definitive therapy for a rare cause of recurrent ascites. AB - Extrahepatic arterioportal fistulas are a rare cause of portal hypertension in infants and adults. Most cases of arterioportal fistulas in adults are due to trauma, liver biopsy, surgery or tumours. The authors present a case of arterioportal fistula diagnosed in adult life without any of the above aetiologies. The patient became acutely symptomatic with diarrhoea and ascites at the age of 66 years and was successfully treated with a single endovascular embolisation procedure after failed medical therapy. PMID- 28839667 TI - Designing and delivering a hypnotherapy service for irritable bowel syndrome in primary care. AB - Evidence-based guidelines recommend hypnotherapy as a treatment option for intractable irritable bowel syndrome (IBS). However, few National Health Service (NHS) hypnotherapy services are in place. We report the experiences and results from the only NHS-funded primary care service for IBS hypnotherapy in England (as identified by a telephone audit of 151 Primary Care Trusts (PCT) in England in February 2011). The service was delivered by a full-time nurse hypnotherapist, commissioned and funded by a PCT. In 18 months, 119 patients have been seen. Validated scoring tools showed improvement in quality of life and symptom severity scores, with improvement in all domains following therapy. This case study illustrates both the clinical effectiveness of hypnotherapy in the treatment of IBS delivered by a nurse hypnotherapist and some of the challenges faced when setting up this service. This paper summarises aspects of a model of care that could act as a template for service providers wishing to deliver hypnotherapy for IBS. PMID- 28839668 TI - The white nipple sign. AB - The white nipple sign is a term used to describe a fresh fibrin clot on a varix that has bled recently. The authors describe a case to highlight the importance of prompt endo-therapy when this sign is recognised as disturbing this clot can cause brisk bleeding. PMID- 28839669 TI - Upfront October 2012. PMID- 28839670 TI - Surveying and understanding colonoscopy technique. PMID- 28839672 TI - Becoming an effective learner. AB - The teaching of medicine and the expectations of trainees has changed enormously over the past two decades in parallel to changes in medical technology, advances in information technology and the provision of healthcare. With a shortened time in medical training efficient learning is ever more crucial and the skills with which to optimise and enhance our learning opportunities are discussed. PMID- 28839671 TI - Fragility fracture risk in cirrhosis: a comparison of the fracture risk assessment tool, British Society of Gastroenterology and National Institute for Health and Clinical Excellence guidelines. AB - OBJECTIVE: Low bone mineral density (BMD) is common in chronic liver disease and predisposes to fracture. We aimed to compare British Society of Gastroenterology (BSG) and National Institute for Health and Clinical Excellence (NICE) osteoporosis guidelines with the fracture risk assessment tool (FRAX). FRAX is a web-based algorithm used to estimate fracture risk with or without dual-emission x-ray absorptiometry (DXA). Pre-BMD FRAX categorises patients to low, intermediate or high risk according to thresholds set by the National Osteoporosis Guidelines Group (NOGG) and recommends lifestyle advice, DXA or anti osteoporosis treatment, respectively. DESIGN: The guidelines were applied to 132 patients with cirrhosis (91% Child-Pugh A). The number that would require DXA and be recommended treatment was determined. Using post-BMD FRAX/NOGG as a reference point, high-risk patients not recommended treatment and low-risk patients treated 'unnecessarily' were identified. RESULTS: BSG guidelines were applicable to 100% of the cohort, 88% required DXA and 30% would be recommended treatment. Equivalent figures for NICE guidelines were 30%, 17% and 12%, and for FRAX/NOGG guidelines were 78%, 27% and 15%, respectively. Using BSG guidance 8% of high risk patients were not recommended treatment and 62% of those treated were low risk, compared with NICE: 3%, 60% and FRAX/NOGG: 13%, 40%, respectively. CONCLUSION: For patients with Child-Pugh A cirrhosis BSG guidelines are the most inclusive, but have high cost implications in terms of DXA scanning and unnecessary treatment. Risk stratification using FRAX requires fewer DXA scans with minimal impact in terms of missing high-risk patients, and yields a modest reduction in unnecessary treatment. PMID- 28839673 TI - Recurrent ascites due to constrictive pericarditis. PMID- 28839674 TI - Administration of hyoscine- n-butylbromide during colonoscopy: a survey of current UK practice. AB - OBJECTIVE: Current British Society of Gastroenterology (BSG) guidelines suggest that hyoscine-n-butylbromide (Buscopan) should be avoided during colonoscopy in patients with a history of angle-closure glaucoma. Angle-closure glaucoma, however, is not very common, is asymptomatic before onset and is treated definitively by a single laser treatment (if spotted early). Open-angle glaucoma is not affected by hyoscine. The aim of this study was to assess the use of hyoscine among colonoscopists, with particular reference to glaucoma. DESIGN AND SETTING: Following BSG endoscopy subcommittee approval, a short questionnaire was electronically administered to members of the BSG and the Association of Coloproctology of Great Britain and Ireland. MAIN OUTCOME MEASURES: Hyoscine use among colonoscopists, and effect of glaucoma history upon prescribing practice. RESULTS: 188 colonoscopists responded to some or all of the questions. 123/183 (67.2%) of respondents claimed they were aware of the BSG guidelines. 160/187 (85.6%) sometimes or always use hyoscine, while 27/187 (14.4%) never do. 137/177 (77.4%) always enquire about glaucoma history prior to administration, although 147/176 (83.0%) make no differentiation between open-angle or angle-closure forms. 126/178 (70.8%) would (incorrectly) withhold hyoscine if the patient declares a history of any form of glaucoma. 140/179 (78.2%) do not substitute glucagon as an antispasmodic. 4/180 (2.2%) had encountered ophthalmic complications post-administration. CONCLUSIONS: Current BSG guidelines pertaining to hyoscine use and glaucoma are inappropriate; the authors recommend revision. Patients undergoing colonoscopy who have received hyoscine should, instead, be advised to seek urgent medical advice if they develop ophthalmic symptoms. PMID- 28839675 TI - Gastrointestinal surgery in adult patients with cystic fibrosis. AB - OBJECTIVE: Gastrointestinal conditions requiring surgical intervention are becoming increasingly frequent in adults with cystic fibrosis (CF) as life expectancy increases. In addition, patients with CF are at risk of specific gastrointestinal complications associated with their disease. This includes distal intestinal obstruction syndrome (DIOS), which may affect up to 15% of patients, and can present diagnostic and therapeutic challenges. The aim of this study was to determine the nature and frequency of general surgical procedures undertaken in a large cohort of adult CF patients so as to guide future care. DESIGN: The medical records of all surviving adult CF patients followed at a large tertiary referral centre in the UK were scrutinised and details retrieved on those who had undergone abdominal surgery after the age of 16 years. RESULTS: A total of 377 patients with CF were identified from the prospectively held database. Thirty-three patients had undergone 43 abdominal operations. The median age at surgery was 22.7 years (range 16-58 years). The three most commonly performed operations were: surgery for DIOS (n=9); cholecystectomy (n=8) and fundoplication (n=6). A past history of surgically treated meconium ileus at birth was a significant risk factor for requiring surgery for DIOS as an adult. CONCLUSIONS: The treatment of DIOS-related complications is one of the main reasons for abdominal surgery in the adult CF population. The general surgical community needs to be increasingly aware of the existence of disease-related gastrointestinal conditions in adult CF patients so that treatment can be optimised. PMID- 28839676 TI - Do we know how to use corticosteroids in acute severe ulcerative colitis? AB - Options for the treatment of acute severe ulcerative colitis have broadened with the use of ciclosporin and infliximab, but corticosteroids remain first-line treatment. However, an optimum regimen for drug, dose and duration has not been established in the 57 years since Truelove and Witts first reported their value. In the absence of evidenced-based guidance this study sought to discover how gastroenterology units in the UK manage patients with acute severe colitis. In January 2010 a questionnaire was sent to all members of the inflammatory bowel disease section of the British Society of Gastroenterology enquiring about their use of corticosteroids in a typical patient with acute severe colitis. One hundred and two responses were obtained, representing more than 50% of the UK gastroenterology units. No consensus, and a wide variation in practice was found between these units. Over 70% of responders initially treat patients with intravenous hydrocortisone (400 mg/day), although some units prefer methylprednisolone and dexamethasone. On transfer to oral treatment, all units use prednisolone, most starting with 40 mg/day. There are no agreed national or international guidelines on the reducing regimen or duration of oral treatment the area of greatest variation in our survey. Most units reduce prednisolone by 5 mg/week, but because of variations in the timing and magnitude of dose reduction, total exposure to prednisolone varies by 2.6-fold. To minimise harm from undertreatment or overtreatment of acute severe colitis a controlled study of prednisolone dose and duration is needed. PMID- 28839678 TI - The provision of paediatric gastrointestinal endoscopy services in the United Kingdom. AB - OBJECTIVE: There are no specific data available regarding paediatric endoscopy provision in the UK and anecdotal experiences suggest that such provision varies widely between the units. The aim of our study was to identify the current provision of paediatric endoscopy services in the UK, the number of endoscopies performed in each unit, the number of operators performing these endoscopies and whether endoscopies were performed under sedation or general anaesthesia. METHODS AND RESULTS: An email questionnaire was sent to all 31 units in the UK performing paediatric endoscopies and responses were received from 25 centres (81%). The median number of total endoscopies (upper and lower) per unit each year was 332 (range 64-2040). The median number of gastrosopy per consultant in each centre was 101 (range 20-288) and median number of colonoscopies performed per consultant per year was 49 (range 10-215). 18 of the 25 centres performed all endoscopies under general anaesthesia with 7 centres using sedation as well as general anaesthesia. Percutaneous endoscopic gastrostomy insertion (PEG) was performed in 24 out of 25 centres with the service undertaken by paediatric surgeons in 11 centres. 11 centres provided formal out of hours endoscopy services. CONCLUSION: There is wide variation in paediatric endoscopy provision and the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) endoscopy working group is collaborating with the Joint Advisory Group (JAG) to provide specific standards for paediatric endoscopy services in the UK. PMID- 28839677 TI - Approach of the patient with a liver mass. AB - The widespread use of imaging techniques has led to an increased diagnosis of incidental liver tumours. The differential diagnosis is extremely broad since it may range from benign asymptomatic lesions to malignant neoplasms. The correct characterisation of a liver mass has become a diagnostic challenge for most clinicians. They can be divided in two major categories; cystic lesions, usually benign with excellent long-term outcome, and solid lesions, in which malignancy should be excluded. A particular population is those patients with cirrhosis, who have high risk for hepatocellular carcinoma development. Dynamic imaging techniques have a pivotal role in the diagnostic work-up of liver tumours, allowing a confident diagnosis in most cases. If imaging is not conclusive, a biopsy should be requested to obtain a definitive diagnosis. PMID- 28839679 TI - Feasibility of small bowel capsule endoscopy in children under the age of 4 years: a single centre experience. AB - Data on the use of wireless capsule endoscopy (WCE) in younger children remain limited. However, this single centre study suggests that it is a relatively complication-free procedure that may be considered in younger children below 4 years of age, when small bowel pathology is suspected. We retrospectively reviewed the King's College Hospital WCE database between August 2009 and August 2011. Patients aged 4 years or younger were included in the study. Six children fulfilled the inclusion criteria. The indications for WCE were unexplained gastrointestinal tract (GIT) bleeding (n=4), chronic diarrhoea with (n=1) and without (n=1) GIT bleeding (n=1). All had an oesophagogastroduodenoscopy and an ileocolonoscopy before WCE. The mean age at the time of WCE was 2 years 6 months (range 1 year 7 months to 3 years 7 months). The mean weight at WCE was 13.3 kg (range 9-17 kg). Four children had a complete study. PMID- 28839680 TI - Attitudes and expectations of gastroenterology outpatients about the importance of diet and possible relationship to their symptoms. AB - OBJECTIVES: To evaluate gastroenterology outpatients' attitudes to the importance of diet and its relationship to their symptoms, as well as their expectations of dietary advice from health professionals. DESIGN: Prospective clinical audit. SETTING: Gastroenterology outpatient department of St George's Healthcare NHS Trust. PATIENTS: Two hundred and twenty-five patients, aged between 18 and 70 years met the inclusion criteria. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Participants' responses to a structured questionnaire. RESULTS: Sixty-nine per cent of participants felt their diet played an important role in their condition. Factors significantly associated with a positive dietary attitude included younger age (40.6 years vs 46.0 years, p<0.01), regularity of dietary pattern (108 vs 35, p<0.01), number of symptoms (4.6 vs 2.5, p<0.01), severity of gastrointestinal symptoms (2.3 vs 1.5, p<0.01), history of weight loss (34% vs 20.3%, p<0.05) and history of dietary advice (71.1% vs 33.3%, p<0.01). Sixty eight per cent (68%) of participants were interested in receiving dietary advice, though only 36% expected to receive it. No differences were found for any comparisons based on average body mass index. CONCLUSION: The majority of gastroenterology outpatients view diet as playing an important role in their condition, particularly those who have more severe symptoms and those who have received dietary advice. Although a large proportion of patients are interested in receiving dietary advice, few expect to receive it in clinics. Further research is required to explore the reasons why, and to assess the confidence of health professionals in providing nutritional advice. PMID- 28839681 TI - Coeliac disease in Asians in a single centre in southern Derbyshire. AB - BACKGROUND: Coeliac disease affects adult Asians from north India, Pakistan and Bangladesh in the UK but how commonly this occurs is unknown. An audit of coeliac disease was therefore conducted in a well-defined area in southern Derbyshire. METHODS: All white and Asian patients with biopsy-confirmed coeliac disease diagnosed between 1958 and 2008 were identified. Population data from the Office of National Statistics allowed the calculation of prevalence. Presenting symptoms, adherence to a gluten-free diet and follow-up record were determined for Asians and compared with matched white patients. RESULTS: Among 1305 coeliac patients diagnosed between 1958 and 2008, 82 were Asian. Coeliac disease occurred significantly more frequently in Asian than white individuals and this could be attributed to the significantly higher prevalence in women 16 years and older and under 60 years of age. No Asian man over the age of 65 years was diagnosed with coeliac disease. Asians are more likely to present with anaemia and less likely to present with diarrhoea than white individuals. Asians are less likely to adhere to a strict gluten-free diet than white patients. CONCLUSIONS: This baseline audit indicates that increased efforts should be directed towards diagnosing coeliac disease in Asian men over the age of 65 years, in whom at present it is unrepresented. Strategies also need to be developed to help more Asian patients adhere strictly to the gluten-free diet. PMID- 28839682 TI - The best way to predict the future is to invent it. PMID- 28839683 TI - The future of gastroenterology: patient choice, patient voice. AB - The policy context for patient choice and public and patient involvement (PPI) in the NHS is set out. Both have become increasingly prominent since 2000. A series of NHS systems and policies have been put in place to enable greater patient choice in the belief that the exercise of choice by patients will influence providers to improve quality. This has had some success in elective surgery. One focus has been the publication of outcome data and this may have led to quality improvement through the inherent competitiveness of professionals and institutions. PPI has suffered from a series of unsuccessful reorganisations of patient involvement organisations but has ensured that most health bodies include patient representatives. Capturing patient experience and providing information to enable patient choice have been constantly developed over this time. A particular framework developed by Angela Coulter is used to review current levels of patient engagement in Inflammatory Bowel Disease (IBD), exploring the extent to which patient choice and patient voice are supported and enhanced within current IBD services locally and in national IBD strategy.1 A 2017 vision of the way in which IBD services might maximise patient choice and patient voice is put forward, based on the adoption of present good practice and current service developments, followed by a few rather more radical thoughts about possibilities for after 2017. PMID- 28839684 TI - The future of gastroenterology nursing. PMID- 28839685 TI - The future of gastroenterology training: the trainee's perspective. PMID- 28839686 TI - The future of gastroenterology training: instruction in technical skills. AB - Endoscopy training has developed extensively over the past decade but despite significant improvements many challenges remain and further development of endoscopy training programmes and content is required. Endoscopy training is struggling with increasing pressure from service provision and competition for limited National Health Service (NHS) resources. There is a rapidly increasing proportion of work shifting from diagnostic to therapeutic practice in the face of limited dedicated therapeutic training provision. In addition, there is a need to align quality assurance outcomes related to endoscopic practice with the key NHS quality indicators of patient experience, clinical effectiveness and safety. A vision for the future of endoscopy training is presented focusing on the need to target training resources most effectively and developing technical skills training in parallel to non-technical skills training (eg, effective decision making, communication and teamwork). Proposals for specialist technical skills training, future information technology systems and quality assurance framework integration are developed. The need to challenge some existing culture and behaviours is explained along with a challenge to embed a life-long learning approach in endoscopy training. Endoscopy training developments aim to ensure a high quality assured endoscopy service for all patients, where a skilled workforce can be provided to meet rising demand and changing technical skills requirements. PMID- 28839687 TI - The future developments in endoscopy. AB - Gastrointestinal endoscopy has seen great changes over recent years, and the future seems bright. Looking forward, some advances in technology can be predicted, but the current financial climate may limit their widespread adoption. Increasing subspecialisation with continuing service development and quality assurance are likely to form the basis of the major changes over the next 5 years. Increasing juxtaposition between laparoscopic and endoscopic procedures presents the most exciting opportunities over the 10-year timeframe. This article extrapolates current trends to try to predict the different possibilities for endoscopy over the next decade. PMID- 28839688 TI - The future developments in upper GI cancer. AB - The ageing population and changes in incidence of upper gastrointestinal cancer will have profound changes for our management of these patients. There is much debate as how to bring forward the diagnosis of early mucosal cancer that may be curable using endoscopy or by surgery. In the older more frail patients, early disease will often be controlled by endoscopic resection and ablation therapy. PMID- 28839690 TI - The future developments in neurogastroenterology: the 'new black'. PMID- 28839689 TI - The future developments in nutrition. AB - Malnutrition is both a cause and consequence of disease. It is imperative that evidence-based approaches to detect and treat malnutrition are embedded into routine practice; these can range from routine malnutrition screening, the safe and appropriate use of enteral feeding and managing more complex patients with intestinal failure. This article outlines service developments over the next 5 years that may enable all hospitals to achieve optimal standards of care for a malnourished patient and examines the role of developments in clinical nutrition over the next 5-10 years. PMID- 28839691 TI - The future developments in gastrointestinal radiology. AB - The last decade has witnessed great advances in abdominal imaging with technological developments and diagnostic improvements in CT, MRI and positron emission tomography-CT. Over the next decade, gastrointestinal imaging is set to rapidly evolve. Fluoroscopic techniques will be left behind and we will develop beyond simply anatomical imaging, embracing increasingly functional and quantitative techniques. Dose reduction and radiation-free modalities will take centre stage as imaging goes mobile, allowing clinicians at the bedside and remote subspecialty radiologists to review radiology from electronic devices. The authors discuss some of the key trends set to define the next decade in gastrointestinal radiology. PMID- 28839692 TI - The future developments in inflammatory bowel disease care. AB - Inflammatory bowel disease (IBD) care has evolved markedly in the last decade and recent innovations in both therapeutics and service development should drive further improvements in the coming years. However, the challenges of the global economic downturn combined with more local issues, such as the reform of the National Health Service, will impact upon IBD service provision in the United Kingdom. Marrying the seemingly conflicting goals of ensuring that IBD care is provided by IBD specialists with the drive towards community-based care will require imaginative solutions. Fortunately, improvements in communication and other technologies should help in this regard. PMID- 28839694 TI - Upfront January 2013. PMID- 28839693 TI - The future developments in hepatology: no need for a jaundiced view. AB - There have been major advances in the diagnosis and management of all forms of liver disease since the British Society of Gastroenterology first came into existence 75 years ago. In this review some of the exciting developments that are likely to enter into routine clinical practice over the next 5 years are highlighted. It is suggested that some critical changes need to take place in UK hepatology over the next decade to ensure that the management of liver disease in this country continues to be among the best in the world. PMID- 28839695 TI - Current concepts in the diagnosis and management of autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is a progressive necroinflammatory liver disease associated with significant morbidity and mortality. Mainly affecting females, AIH has a varied clinical presentation from minor symptomatology to acute liver failure. The diagnosis should be considered in anyone with abnormal liver function tests. Diagnostic features include biochemical evidence of transaminitis, elevated IgG and positive autoantibodies. Liver biopsy may show interface hepatitis with portal-based plasma cell infiltrates. A clinical and pathological spectrum of disease exists with other autoimmune liver disease in rare cases. AIH responds promptly to immunosuppression therapy, including corticosteroids (prednis(ol)one or budesonide) with azathioprine. Treatment failure can be addressed with several second-line immunosuppressive agents. Liver transplantation remains a successful salvage therapy for acute autoimmune liver failure or treatment failure in chronic AIH complicated by synthetic dysfunction, portal hypertension or hepatocellular carcinoma. PMID- 28839697 TI - Surgical endoscopy training: the Joint Advisory Group on gastrointestinal endoscopy national review. AB - BACKGROUND AND AIMS: Endoscopy performance is dependent on the technical ability and experience of the operator. There is anxiety among surgical trainees that certification to perform independent endoscopy to agreed national standards by the date of award of certificate of completion of training is not achievable. The aim of this study was to evaluate the delivery of endoscopy training to UK-based general surgery trainees. MATERIALS AND METHODS: An electronic survey of general surgery trainees holding a national training number or in a locum appointment to training post between July and September 2010 was undertaken. RESULTS: Two hundred and thirty-three trainees responded from all UK training regions. Stated subspeciality interests included coloproctology (47%), oesophagogastric/bariatric (22%) and hepatobiliary/pancreatic (10%) general surgery. 92% of trainees were training or planned to train in endoscopy, 62% of whom had registered with the Joint Advisory Group (JAG). Thirteen trainees had JAG certification in diagnostic upper GI endoscopy and eight in colonoscopy. There were high rates of dissatisfaction with endoscopy training nationally. Two thirds of trainees had no scheduled training lists. Conflicting elective/emergency commitments, competition and absence of training lists were the most common reasons for a failure to access endoscopy training. CONCLUSIONS: Higher surgical trainees are failing to achieve national standards for endoscopy practice. There is an urgent need to address the deficiencies in endoscopy training to ensure a competent cohort of surgical endoscopists. PMID- 28839696 TI - A pregnant patient with a positive hepatitis B surface antigen. AB - Hepatitis B is a major cause of liver disease worldwide. The highest rates of chronic infection occur in subjects who are infected early in life and these patients are also at the greatest risk of developing complications such as hepatocellular carcinoma and cirrhosis from the disease. There has been a concerted worldwide effort to immunise newborns that are at the highest risk of acquiring infection. In 1992, when WHO recommended global vaccination against hepatitis B, only 31 countries elected to participate in the programme. By 2009, 177 countries were part of WHO national infant immunisation programme. Consequently, maternal screening and infant immunoprophylaxis have significantly reduced vertical transmission of hepatitis B. In this paper, we will review the management of hepatitis B in the pregnant population and identify some of the challenges that are encountered in this specialised population. PMID- 28839698 TI - The organisation and structure of inflammatory bowel disease services for children and young people in the UK in 2010: significant progress but still room for improvement. AB - BACKGROUND: Inflammatory bowel disease (IBD) is becoming more common in children. While treatment options remain limited the appropriate organisation and delivery of services are an integral part of good care. METHODS: All eligible UK paediatric sites were invited to submit data for organisation of paediatric IBD services as of 1 September 2010. Comparison, when relevant, was made with the previous paediatric audit (2008) and the concurrently running adult audit. RESULTS: 24/25 (96%) of sites submitted data. The median number of patients managed and the median number of new IBD (ulcerative colitis and Crohn's disease only) cases per annum was 178 (IQR 136-281) and 32 (IQR 23-50), respectively. There was an increase in the IBD workforce including whole-time equivalent (WTE) IBD nurses (1.0 vs 1.5 WTE nurses, p=0.02). 1023 patients 16 years and younger were looked after in the 202 adult sites who submitted data; only 78/202 sites indicated they cared for 16-year-old and younger children; approximately half of these 78 sites had age-appropriate support facilities. Most paediatric sites have access to urgent endoscopy (83%), telephone advice (100%) and urgent clinic appointments (91%). Most sites did not have: shared care pathways with primary care (74%), annual reviews (71%), real time patient management systems (83%) and research network trial participation (78%). CONCLUSIONS: Many aspects of paediatric IBD care in the UK are good and have shown significant improvement over recent years. There are areas in need of further change and specific regional and national action plans should address identified deficiencies before any future audit of paediatric and adult IBD services. PMID- 28839699 TI - Survey of UK and New Zealand gastroenterologists' practice regarding dietary advice and food exclusion in irritable bowel syndrome and inflammatory bowel disease. AB - BACKGROUND: This study aimed to assess the dietary advice practice of UK and New Zealand (NZ) adult gastroenterologists in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). METHODS: A questionnaire regarding dietary advice practice was emailed or mailed to all members of the British Society of Gastroenterology (n=983) and the NZ Society of Gastroenterology (n=54). RESULTS: 363 questionnaires were returned in the UK (response rate 37%) and 51 in NZ (94%). More respondents gave specific dietary advice to more than 25% of their patients on IBS than IBD (84% vs 27% UK, 90% vs 55% NZ; p=0.001 for both) and gave advice about dietary exclusions to more than 25% of patients on IBS than IBD (61% vs 13% UK, 77% vs 14% NZ; p<0.001 for both). They were most likely to provide dietary advice to patients with small bowel Crohn's disease, difficult to control IBD, diarrhoea predominant IBS and difficult to control IBS. The majority of respondents agreed strongly or a little that dietary exclusion was effective in the treatment of IBS, compared to the minority in IBD (71% vs 39% UK, 84% vs 43% p<0.05 for both). CONCLUSIONS: UK and NZ gastroenterologists give dietary advice more commonly to IBS than IBD patients. The majority of gastroenterologists have some confidence in the use of dietary exclusion in IBS, the converse is true in IBD. However, the advice given is largely empiric and mostly comprises the exclusion of fibre, dairy and wheat. PMID- 28839700 TI - Factors associated with vitamin D deficiency in a multicultural inflammatory bowel disease cohort. AB - OBJECTIVE: The aim of this study was to determine the prevalence of vitamin D deficiency in a multicultural inflammatory bowel disease (IBD) cohort and determine predictors of deficiency including ethnicity. DESIGN: Patients with IBD were recruited into a dedicated database over a 6-month period and evaluated retrospectively. SETTING: Department of Gastroenterology, St George's University Hospital, London, UK. OUTCOMES MEASURED: Clinical data including demographics, ethnic group, disease phenotype by the Montreal classification, vitamin D level and season tested were recorded from clinical and electronic medical records. Vitamin D levels were classified as normal (>=50 nmol/l) and deficient (<50 nmol/l). RESULTS: 168 patients had a vitamin D level measured subsequent to diagnosis. There was no significant difference in the median vitamin D level between patients with Crohn's disease (CD) and ulcerative colitis (UC) (39 nmol/l (IQR 23-56) vs 28 nmol/l (IQR 17-51), p=0.35). Overall the median vitamin D level was significantly lower in non-Caucasians (Asian and Black) versus Caucasians (28 nmol/l (IQR 17-41) vs 41 nmol/l (IQR 25-63), p<0.0001). Multiple regression analysis revealed IBD related surgery (OR 2.9) and ethnicity (OR 6.0 non Caucasian vs Caucasian) in CD and ethnicity (OR 5.0 non-Caucasian vs Caucasian) in UC were independently associated with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is common in IBD patients; therefore, we suggest monitoring of vitamin D levels and correction with supplements especially in non-Caucasians and those with a history of IBD related surgery. PMID- 28839701 TI - Managing gastrointestinal symptoms after cancer treatment: a practical approach for gastroenterologists. AB - The percentage of the population living with a diagnosis of cancer is rising. By 2030, there will be 4 million cancer survivors in the UK. One quarter of cancer survivors are left with physical symptoms, which affect their quality of life. Gastrointestinal (GI) symptoms are the most common of all chronic physical side effects of cancer treatment and have the greatest impact on daily activity. Cancer therapies induce long-term changes in bowel function due to alterations to specific GI physiological functions. In addition, the psychological effect of a cancer diagnosis, new GI disease or pre-existing underlying conditions, may also contribute to new symptoms. Twenty-three upper GI symptoms have been identified as occurring after pelvic radiotherapy. After upper GI cancer treatment, the most troublesome symptoms include reflux, abdominal pain, indigestion, diarrhoea and fatigue. Often, several symptoms are present simultaneously and women experience more symptoms than men. The symptoms which patients rate as most difficult are urgency, wind, diarrhoea, incontinence, abdominal pain and rectal bleeding. Recent UK Guidance on managing GI symptoms suggests that these symptoms can be treated especially if gastroenterological advice is combined with dietetic and nursing input to optimise investigations and management. However, as different pathological processes can result in identical symptoms; a systematic, 'algorithmic' approach to assess and treat these symptoms is required. This paper aims to illustrate the value of such an approach to investigate and treat the most common GI symptoms that trouble patients. The algorithm allows clinicians to institute a comprehensive medical management plan. PMID- 28839702 TI - The hidden endoscopic burden of Roux-en-Y gastric bypass surgery. AB - BACKGROUND AND AIMS: Complication rates of Roux-en-Y gastric bypass (RYGB) vary from centre to centre, but anastomotic stricture is the commonest, and is managed in the majority by endoscopic pneumatic dilatation. The aim of this study was to assess the endoscopic burden of RYGB surgery. PATIENTS AND METHODS: All patients undergoing RYGB surgery over a 29-month period were included and were followed-up retrospectively and prospectively for a minimum of 180 days to monitor for endoscopic procedures performed in relation to the RYGB at Walsall Manor Hospital, UK. Five hundred and fifty-three patients underwent RYGB surgery during the study period. RESULTS: One hundred and thirteen patients had 147 endoscopic procedures, including 65 pneumatic dilatations, at a cost to the NHS of L58 077 over a 29-month study period, with an average cost of L2003 a month. or L105 per RYGB operation performed. The anastomotic stricture rate for the group was 11.39%. The complication rate for dilatation of anastomotic strictures was 0%. CONCLUSIONS: RYGB anastomotic strictures can be safely managed by dilatation. If bariatric surgery is performed locally, then endoscopy departments must expect to factor in, not only the burden of dealing with actual complications, but also the burden of investigating for potential complications. PMID- 28839703 TI - Evaluation of a new anaesthetist-led propofol sedation service for endoscopy within a UK day-case setting. AB - INTRODUCTION: The use of propofol in endoscopy is becoming more prevalent both in Europe and North America. Potential advantages over conscious sedation include controlled deep sedation for therapeutic endoscopy and improved patient satisfaction. A new anaesthetist-led propofol-based day-case sedation service was introduced within the endoscopy unit at the Royal Liverpool University Hospital in April 2011. AIMS: To evaluate this new service of anaesthetist-led propofol based sedation for safety, compliance with current guidelines and satisfaction (patient, anaesthetist and endoscopist). DESIGN: A prospective, service evaluation audit of a new, weekly, anaesthetist-led propofol-based sedation service. Administrative records, anaesthetic notes and satisfaction scores (1=very dissatisfied; 5=very satisfied; patients, anaesthetists, endoscopists) and the 'patient journey' were evaluated for 40 consecutive patients treated over 18 weeks. Outcomes were measured against current British Society of Gastroenterology/Royal College of Anaesthetists guidelines. RESULTS: All procedures were completed (100% intention-to-treat rate), all patients were discharged on the day of the procedure and none were readmitted within 7 days. Adverse events were minor (10%) and there were no deaths within 30 days. The median satisfaction score was 5 for patients, anaesthetists and endoscopists. The additional cost for provision of such a service included the services of the anaesthetist (one programmed activity) and operating department personnel and for drugs (propofol). The demand for the service rapidly increased. CONCLUSIONS: Anaesthetist-led propofol-assisted endoscopy is safe in a day-case endoscopy unit and is associated with high satisfaction scores for patients, anaesthetists and endoscopists. There is a high demand for this service in this UK endoscopy day case unit. PMID- 28839704 TI - Double balloon enteroscopy in children: a case series highlighting risks, and a review of the literature. AB - AIM: Double balloon enteroscopy (DBE) is a relatively new endoscopic technique that allows endoscopic access into the small intestine. It has been studied in adults, but the literature remains scarce in the paediatric age group. METHODS: We retrospectively assessed our experience with DBE in children. RESULTS: We describe four procedures performed on three patients. The diagnostic yield was high (100%) with one major complication (perforation) encountered. A review of the benefits and risks in this cohort, and the available literature is included. CONCLUSIONS: DBE is a promising endoscopic modality in children, but some aspects remain unanswered. There is a great need for a prospective study to better assess benefit and risk in this population. PMID- 28839705 TI - Upfront April 2013. PMID- 28839706 TI - Pharmacy-led switches of 5-ASA: impact on secondary care. PMID- 28839707 TI - A hard act to swallow: modern management of eosinophilic oesophagitis. AB - Eosinophilic oesophagitis (EO) is now established as an important cause of oesophageal symptoms. It is presumed to result from eosinophilic activation to dietary antigens, which is limited to the oesophagus. Inflammatory strictures and secondary dysmotility are common and contribute to symptomatology. Current management involves food exclusion diets and swallowed topical steroid. Strictures may require endoscopic dilatation. Relapse is common but strategies for maintaining remission are not well described. Here we describe a patient with severe stricturing EO, whose symptoms were significantly exacerbated by secondary oesophageal spasm. His symptoms were refractory to dietary, endoscopic and medical therapy including parenteral corticosteroid but responded dramatically to diltiazem. Remission was eventually achieved and maintained with azathioprine, and he was able to discontinue the other therapies and relax his dietary restrictions. We discuss the evidence for dietetic, endoscopic and pharmacological interventions for this disease. PMID- 28839708 TI - A pilot study comparing ESO-2 capsule endoscopy with conventional upper endoscopy for the assessment of uncomplicated heartburn and dyspepsia. AB - BACKGROUND: ESO-2 video capsule endoscopy provides images of the oesophageal mucosa and continues to transmit gastric, and often small bowel images, for up to 30 min. This study compares ESO capsule endoscopy capsule oesophago-gastro duodenoscopy (Cap-OGD) with conventional endoscopy (OGD). METHODS: 50 outpatients with uncomplicated dyspepsia underwent Cap-OGD followed by OGD which was recorded on DVD. Cap-OGD and OGD were each reported independently by two gastroenterologists. A benchmark report was also produced by two gastroenterologists viewing both Cap-OGD and OGD on side-by-side monitors. Major findings included large hiatus hernia, Barrett's oesophagus, oesophagitis, erosive gastritis, tumour and ulceration. Minor findings included histologically proven superficial gastritis, pouting gastric folds and fundic gland polyps. A questionnaire assessed the patient experience. RESULTS: 49 patients completed the study. In 61%, Cap-OGD transmitted in the duodenum. In the benchmark study, all the major OGD findings were observed on Cap-OGD. Cap-OGD revealed fewer minor findings. When reported independently, Cap-OGD and OGD reports indicated differences in interpretation most marked between the capsule readers with or without previous ESO-2 experience. Patients expressed a clear preference for Cap OGD. CONCLUSIONS: When compared side-by-side, all the major findings on OGD are seen on Cap-OGD while there is under-reporting of minor findings. Previous experience of ESO-2 capsule reporting improves reading accuracy and indicates the need for training. This pilot study provides a backdrop to explore the possible role of Cap-OGD, especially where patients are reluctant to undergo conventional OGD or where there is risk of prion contamination of the endoscope. PMID- 28839709 TI - Improved clinical outcomes and efficacy with a nurse-led dysphagia hotline service. AB - BACKGROUND: A nurse practitioner-led dysphagia service was introduced to improve appropriateness of investigations. OBJECTIVE: To determine the clinical outcomes and efficacy of this service. DESIGN AND PATIENTS: A 7-year prospective audit of the first 2000 patients referred for investigation of dysphagia. SETTING: Royal Cornwall Hospitals NHS Trust. INTERVENTION: An innovative nurse practitioner-led telephone dysphagia hotline (DHL) assessment service for all patients and consultant review following investigation prior to discharge. OUTCOMES: Clinical outcomes, service efficiency and cost effectiveness. RESULTS: 2000 patients (median age 70 years, 48% male) were referred in less than 7 years, 1775 being managed fully through the DHL. 67% patients had gastroscopy only, 13% barium swallow only and 8.8% both and 11.2% had no investigation. Reflux was the commonest cause (41.3%), 9% had peptic stricture, 10% malignancy 1.9% pharyngeal pouches and 0.8% achalasia. The did not attend rate was reduced from 3.9% to 1.1% and 151 patients either refused or did not require investigation saving a potential L53 040. Although some patients with pharyngeal pouches had gastroscopy as initial investigation, no complications resulted. CONCLUSIONS: The nurse practitioner-led DHL service has improved efficiency and resulted in a safe prompt service to patients. PMID- 28839710 TI - Gastro-protective policy and the incidence of upper gastrointestinal bleeding. AB - OBJECTIVES: In recent years, policies have been proposed in order to guide the safer use of non-steroidal anti-inflammatory drugs (NSAIDs) and antiulcer therapy. We aimed to investigate the incidence of upper gastrointestinal bleeding (UGIB) before and after the introduction of these policies, 2007-2009, in a well defined population in southwest Scotland. METHODS: All patients with non-variceal upper gastrointestinal bleeding (NV-UGIB), diagnosed at a single regional unit, were included. Total drugs prescribed in our population were noted, including antiulcer drugs, antithrombotic drugs and both cyclo-oxygenase-2 enzyme-selective and non-selective inhibiting NSAIDs. RESULTS: The incidence, the number of cases per 100 000 population per annum, of NV-UGIB fell from 134.7 in 2007 to 125.1 in 2008, and to 90.3 cases in 2009 (p<0.001). There was also a significant rise in the use of non-selective NSAIDs, proton pump inhibitors and antithrombotic drugs. CONCLUSIONS: Although a cause-and-effect relationship cannot be fully proven, physician education through drug-use policies is associated with a drop in the incidence of NV-UGIB. This is relevant to the prevention of this common condition. PMID- 28839711 TI - Development and validation of the Bowel Cleansing Impact Review (BOCLIR). AB - OBJECTIVE: Acceptability and tolerability of bowel cleansers influence whether patients are able to complete the prescribed dose and, consequently, the quality of the cleansing achieved. No standardised means of assessing patients' experience of using bowel cleansing is currently available. The aim of the study was to develop the Bowel Cleansing Impact Review (BOCLIR) to assess patient response to bowel cleansing products. DESIGN: Content was derived from qualitative interviews. Face and content validity were assessed via cognitive debriefing interviews. Finally, patients completed the BOCLIR and a demographic questionnaire. Item response theory (Rasch analysis) was employed for item reduction and assessment of unidimensionality. Internal consistency and construct validity were also assessed. RESULTS: Analysis of 40 interviews resulted in the production of three scales; patient satisfaction, symptomatic impact and activity limitations. Scales were designed to be used alone or together. 19 debriefing interviews demonstrated BOCLIR acceptability, relevance and ease of completion. The validation survey involved 166 patients (52% male, mean (SD) age 54.3 (15.2) years). After misfitting and redundant items were removed all scales fit the Rasch model confirming their unidimensionality. Cronbach's alpha-coefficients were high (0.77-0.94) indicating good internal consistency. Scores on the BOCLIR were related to patients' willingness to use the product in future and ease of drinking the full preparation (p<0.01 for each scale). CONCLUSIONS: The BOCLIR is a new measure consisting of three unidimensional scales (satisfaction, symptoms and activity limitations) with good psychometric and scaling properties. The BOCLIR will allow accurate assessment of patients' response to bowel cleansing preparations. PMID- 28839712 TI - Diarrhoeal episodes in travellers suffering from IBD. AB - BACKGROUND AND AIMS: There is limited data on the risk of developing diarrhoea in travelling patients with inflammatory bowel disease (IBD). We analysed the rate of developing diarrhoea among travellers suffering from IBD and their healthy controls. METHODS: We performed a retrospective case-controlled study among 78 patients with IBD and their healthy travelling companion controls, thus matching both groups to the same environmental conditions. Data was retrieved through a structured questionnaire, interview and clinical case notes review. RESULTS: Sixteen (20.5%) patients with IBD developed diarrhoea while abroad (p -0.0001) Statistical analysis using a chi2 test for independence (with Yates Continuity Correction). Prior to travelling, they were in clinical remission. Only one healthy control (1.3%) developed diarrhoea while abroad. In 11 patients (14.1%), the duration of diarrhoea was 3 days or less, and resolved on its own without antibiotics, any increase in their IBD medications and without a medical consultation. The other five patients had a flare-up of their disease and needed medications to put them back into remission. There was no statistically significant difference between patients having immunomodulator medications versus those having aminosalicylates only in developing diarrhoea when abroad. CONCLUSIONS: Patients with IBD have a higher rate of developing diarrhoea compared with controls when travelling. Thus, such patients must always seek a pretravel medical consultation. PMID- 28839713 TI - Improving access to treatment for patients with chronic hepatitis C through outreach. AB - BACKGROUND: Chronic hepatitis C infection (HCV) is common in injecting drug users and is a major cause of liver disease. Antiviral treatment can 'cure' HCV, but is frequently associated with side effects and requires regular monitoring. Non attendance at hospital appointments is frequent. To try and improve attendance and increase the number of current and previous injecting drug users treated we developed three outreach clinics. OBJECTIVE: To review the outcome of patients referred to the outreach clinics. METHODS: Retrospective service review of three clinics at drug treatment centres in Newcastle and Northumberland. Data was collected on attendance rates, patient demographics, treatment rates and outcomes. RESULTS: 141 referrals were received across the three sites with an overall attendance rate of 75% (106 patients, 79% men and median age 36), which compared favourably with that at our hospital (50%). All patients were on methadone/subutex. 45% were infected with Genotype 1 HCV. 10% were cirrhotic. To date, 30% have started treatment and 21% are waiting to start or are still in workup. 13% elected to delay treatment due to early stage disease and 11% were not ready for treatment on psychological or social grounds. Only 12% failed to attend follow up after initial assessment. To date, 24 patients have completed full courses of treatment with sustained viral response in 13 patients. Results are awaited for seven patients. CONCLUSIONS: The development of outreach clinics for HCV in drug treatment centres can substantially improve clinic attendance and increase access to treatment in this marginalised group. PMID- 28839714 TI - Gallbladder perforation following transarterial chemoembolisation; a rare but serious complication. AB - Transarterial chemoembolisation (TACE) is the mainstay of treatment for large or multifocal hepatocellular carcinoma (HCC). However, this procedure is not without potential complications. We report the case of a 72-year-old man with cirrhosis with HCC treated by TACE using drug-eluting beads. He developed persistent fever and severe right upper quadrant pain post-procedure. CT abdomen revealed a large fluid collection closely abutting the gallbladder and tracking inferiorly along the right flank. This fluid collection originated from the gallbladder and contained locules of gas with a contrast-enhancing wall, consistent with an infected biloma. These imaging findings confirmed gallbladder perforation complicating TACE. The development of gallbladder perforation post-TACE from acute ischaemic cholecystitis producing gallbladder wall necrosis is exceedingly rare. The presence of gallbladder perforation must be recognised in patients with persisting symptoms and imaging evidence of a perihepatic fluid collection because specific treatment with intravenous antibiotics and percutaneous drainage of the biloma is necessary. PMID- 28839716 TI - How to teach reflective ethical practice in postgraduate gastroenterology: the SLICE framework. AB - Professionalism and performance are now the focus of assessment in postgraduate medical training and revalidation in the UK. Ethical decision making and clinical reasoning are key elements for practising gastroenterologists to master. The skills required to reflect, teach and appraise ethical decision making are central to the effectiveness of relationships with patients and colleagues. A framework is presented to enable gastroenterologists to reflect and learn from everyday ethical dilemmas in clinical practice. PMID- 28839715 TI - Emergency endoscopic retrograde cholangiopancreatography in critically ill patients is a safe and effective procedure. AB - Emergency ERCP may be required in patients with severe cholangitis who rapidly deteriorate with multi-organ dysfunction and who cannot wait until the next available elective list. A significant proportion of patients require ventilatory and inotropic support. We describe our experience on the outcome of emergency ERCP in this cohort of critically ill patients. Medical records of cases undergoing ERCP between November 2008 and November 2011 were retrospectively reviewed. Patients who were in intensive care unit or required general anaesthesia due to haemodynamic compromise at the time of ERCP were included. Total of 2237 ERCPs were performed during this period, of which 36 (2%) emergency ERCP's were performed in 33 patients. The median age was 79 years. All procedures were performed under general anaesthesia in emergency operating room. In 27/36 procedures (75%), the patients required inotropes. Indications included cholangitis (78%), pancreatitis (14%) and post-operative bile leak (8%). Biliary cannulation was achieved in 100% of cases. Endoscopic findings included CBD stones (64%), CBD stones and an additional pathology (8%), bile leak (8%), CBD stricture (5%), Mirizzi's (3%) and blocked plastic stent (3%). In 23/36 (64%) procedures a stent was inserted. In 11/36 (30%) procedures a balloon trawl was sufficient to clear the bile duct. Thirty-day mortality was 25%. Although the 30 day mortality remains high due to multi-organ failure, ERCP is successful and effective in the majority of patients and results in a good outcome for this cohort of critically ill patients, in whom the prognosis is inevitably poor without emergency biliary drainage. PMID- 28839717 TI - Out of programme experience: going away to bring something back: closing the loop. AB - In the January 2011 edition of Frontline Gastroenterology, I was the lead author of an article: Out of programme experience and training: going away to bring something back. 1 Since then, I have taken time out of my speciality training programme-an out of programme experience. I thought it would be of interest to trainees to read about how I organised my out of programme experience and how this time away has helped me to develop my unique selling point. PMID- 28839718 TI - Out of programme research experience. PMID- 28839720 TI - Dr Falk pharma UK/Core awards. PMID- 28839722 TI - Gastroenterology manpower: what are the future job prospects for gastroenterology trainees? AB - There are over 1100 gastroenterology consultants and approximately 600 higher specialist trainees in the UK in 2012. The speciality has expanded considerably over the past 20 years but will need to expand further over the next 10 years to accommodate those completing training. There is an undoubted need for expansion due to increased demand from an ageing population, cancer screening and an increasing burden of liver disease. However, the UK economy and changes in the way that workforce planning will be made over the next few years will determine whether such expansion occurs. There is accumulating evidence that getting a substantive post in gastroenterology is getting harder and that some trainees are taking up new types of post-training posts. Gastroenterology has historically been a male-dominated speciality but this is changing as more female trainees come through the system. Current trainees have defined expectations about how and where they will want to work as consultants and these expectations are different according to their gender. Trainees are also aware that the way of consultant working is likely to change considerably in the next decade with increased need for acute medicine in hospitals and 7-day working. Medical workforce planning has always been very difficult. There are major changes planned in how training will be controlled in the NHS over the next few years, both locally and nationally. The future for gastroenterology is unclear but almost certainly trainees will have to be more flexible in how and where they work. PMID- 28839719 TI - A multidisciplinary team model of caring for patients with perianal Crohn's disease incorporating a literature review, topical therapy and personal practice. AB - BACKGROUND: Crohn's disease (CD) is characterised by periods of relapse and remission. Over time the disease leads almost inevitably to the complications of stricturing, penetration and fistulisation. Perianal CD involves areas of chronic abscess formation, ulceration, skin tags or fistula formation. This can be a particularly challenging and complex problem to manage, and a range of potential treatment modalities exist. METHODS: This review covers the management of perianal CD and provides recommendations for practice for the multidisciplinary team (MDT), including the use of wound management products and relevant clinical images. RESULTS: Current practice focuses predominantly on the use of antibiotic therapy, immunosuppression, immunomodulation and surgery. These therapies are used individually or in combination. The majority of evidence suggests that a combination of medical and surgical management produces the best disease outcomes. However, this treatment regime can be debilitating for the patient and compliance can be difficult. Published work on the use of topical therapy in the management of perianal CD focuses specifically on topical drug therapy; it does not, however, address the basic guiding principles of chronic wound management-in particular, optimal moisture control and the management of bacterial burden on the wound surface. Honey and silver-containing wound management products act as topical antimicrobial agents and therefore address these principles. CONCLUSIONS: Perianal CD is the archetypal condition that exemplifies the need for an MDT approach in caring for patients with inflammatory bowel disease. A combination of treatment modalities that includes topical wound management is likely to produce the best patient outcomes. PMID- 28839723 TI - The relevance of transient lower oesophageal sphincter relaxations in the pathophysiology and treatment of GORD. AB - Gastro-oesophageal reflux disease (GORD) is associated with the passage of gastric contents into the oesophagus resulting in potential oesophageal damage and impaired quality of life. GORD is a frequently encountered problem in today's population, with 25% of people in western populations reporting such symptoms at least once a month. Proton pump inhibitors (PPI) are the drug of choice, with surgery being employed in refractory cases. Although acid suppression is often effective, some patients remain symptomatic despite maximal PPI therapy. By delving into the mechanisms of the disease, it is clear that transient lower oesophageal sphincter relaxations are a key component of its pathophysiology. Research has demonstrated various therapeutic targets for reducing the frequency of such relaxations through GABA and glutamate modulation, for instance. This review highlights such modulations and hopes to explore these mechanisms and therapeutic targets in an area that will no doubt see a change in its pharmacological management in the near future. PMID- 28839724 TI - The use of biomarkers in neuroendocrine tumours. AB - The incidence and prevalence of neuroendocrine tumours (NETs) arising from the gastrointestinal tract are increasing. At the time of diagnosis, histological grade, based on Ki-67 proliferation index on a tumour biopsy or specimen, offers prognostication but with often lengthy survival, this may not reflect current tumour biology later in the disease course. Biomarkers, including plasma chromogranin A, urinary 5-hydroxyindole acetic acid and pancreatic specific hormones (insulin, gastrin, vasoactive intestinal peptide), have a role in diagnosis but despite being incorporated into routine clinical practice, there is a lack of robust prospectively collected data investigating their prognostic and predictive value. Given the increasing number of treatment options available for NETs and prolonged survival, there is no agreement on the order of treatment for individual NET patients but the emergence of novel biomarkers and validation of existing ones, in addition to better understanding of the molecular biology, may help solve this clinical problem. PMID- 28839725 TI - Trans-jugular intrahepatic porto-systemic shunt placement for refractory ascites: a 'real-world' UK health economic evaluation. AB - OBJECTIVE: To assess the benefit of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement for refractory ascites. DESIGN: A retrospective observational study of all patients undergoing TIPS for refractory ascites in our hospital between 2003 and 2012. SETTING: Secondary care. PATIENTS: Cirrhotic patients with refractory ascites. MAIN OUTCOME MEASURES: We examined direct real world (National Health Service) health related costs in the year before and after the TIPS procedure took place. Data were collected relating to the need for reintervention and hepatic encephalopathy. RESULTS: Data were available for 24 patients who underwent TIPS for refractory ascites (86% of eligible patients). TIPS was technically successful in all cases. Mean number of bed days in the year prior to TIPS was 30.3 and 14.3 in the year following (p=0.005). No patient had ascites at the end of the year after the TIPS with less requirement for paracentesis over the course of the year (p<0.001). Mean reduction in cost was L2759 per patient. TIPS was especially cost-effective in patients requiring between 6 and 12 drains per year with a mean saving of L9204 per patient. CONCLUSIONS: TIPS is both a clinically effective and economically advantageous therapeutic option for selected patients with refractory ascites. PMID- 28839726 TI - Pouchitis: a practical guide. AB - Up to 30% of patients with ulcerative colitis (UC) will require surgical management. The established surgical procedure of choice is colectomy with ileal pouch-anal anastomosis (IPAA) for most patients. Patients with UC who have undergone IPAA are prone to develop inflammatory and non-inflammatory complications. Up to 50% of patients can be expected to experience at least one episode of pouchitis, and most of these patients will experience at least one additional acute episode within 2 years. In other cases, pouchitis might follow a relapsing-remitting course or a chronically active course. The specific aetiology of pouchitis is unknown and the optimal means of diagnosis and classification of pouchitis is not completely agreed upon. Diagnosis of pouchitis based on symptoms alone has been shown to be non-specific due to the fact that symptoms can originate from a myriad of aetiologies, not necessarily inflammatory in nature. As a result, the diagnosis of pouchitis should generally be based on the appropriate constellation of symptoms, combined with endoscopic and histological assessment. Due to the frequently relapsing course of pouchitis, and the fact that the aetiology and pathogenesis are not entirely clear, the long-term management can sometimes be challenging. This review outlines the features suggestive of deviation from 'normal' pouch function and provides an approach to the optimal use of diagnostic modalities and medical therapies to treat pouchitis in its various forms. PMID- 28839727 TI - Azathioprine-associated myelodysplastic syndrome in two patients with ulcerative colitis. AB - Azathioprine is a commonly used immunosuppressive agent in post-transplantation regimens and autoimmune diseases. An increased risk of lymphoma with thiopurine therapy in patients with inflammatory bowel disease has been described previously; however, there are few reported cases of azathioprine therapy-related myelodysplastic syndrome and acute myeloid leukaemia. We report two patients with ulcerative colitis who subsequently developed azathioprine-related myelodysplastic syndrome. It is imperative that gastroenterologists remain vigilant for this rare complication as this subset of patients has a particularly poor prognosis. These cases are also important in considering the risk of open ended thiopurine therapy. PMID- 28839728 TI - Colonic stenting: a practical update. AB - Colonic stenting is part of the UK service provision guidelines for colorectal cancer. However, there are issues about availability and expertise within the UK, and controversies remain regarding various clinical and technical aspects of the technique. Based on the current evidence, this article will provide a practical update on the indications, the clinical and technical considerations and the remaining unanswered questions regarding colonic stenting. PMID- 28839729 TI - The setting up and running of a cross-county out-of-hours gastrointestinal bleed service: a possible blueprint for the future. AB - OBJECTIVE: Acute upper gastrointestinal bleeding (AUGIB) results in 25 000 hospital admissions annually. Patients admitted at weekends with AUGIB have increased mortality, and guidelines advise out-of-hours endoscopy. We present retrospective data from our service involving the interhospital transfer of patients. DESIGN: We pooled resources of two neighbouring general hospitals, just north of London. Emergency endoscopy is performed at the start of the list followed by elective endoscopy in the endoscopy unit on Saturday and Sunday mornings. From Friday evening to Sunday morning, patients admitted to Queen Elizabeth II Hospital (QEII) are medically stabilised and transferred to Lister Hospital by ambulance. RESULTS: 240 endoscopies were performed out of hours from December 2007 to March 2011. Of these, 54 patients were transferred: nine had emergency endoscopy at QEII as they were medically unstable; eight of the patients transferred required therapeutic intervention for active bleeding. The mean pre-endoscopy Rockall score of those transferred was 2.5. We examined the records of 51 of the 54 patients transferred. There were three deaths within 30 days after endoscopy not associated with the transfer process. 19 (37%) patients had reduced hospitalisation after having their endoscopy at the weekend. CONCLUSIONS: The introduction of the out-of-hours endoscopy service in our trust has had multiple benefits, including patients consistently receiving timely emergency endoscopy, significantly reduced disruption to emergency operating theatres, and participation of endoscopy nurses ensures a better and safer experience for patients, and better endoscopy decontamination. We suggest our model is safe and feasible for other small units wishing to set up their own out of-hours endoscopy service to adopt. PMID- 28839730 TI - Managing a patient with rumination. PMID- 28839732 TI - Review of the use of intralesional steroid injections in the management of ileocolonic Crohn's strictures. AB - Most patients with Crohn's disease present with either terminal ileal or colonic disease, with 70% requiring surgery by 10 years after diagnosis. Recurrent stricturing at the anastomotic site is common, often symptomatic and can require re-operation with its inherent risks. Balloon dilation has been shown to provide good symptom relief from such strictures. However, repeat dilations may be required, and further surgical intervention to an anastomotic stricture is needed in up to 30% of cases. Injection of corticosteroids has been suggested as an adjunct to dilation in order to improve outcomes. This paper reviews the current literature on the use of intralesional steroid injections following endoscopic balloon dilation of anastomotic and de novo Crohn's strictures. There have been only two randomised placebo controlled trials and five small non-controlled or retrospective studies. Study numbers vary from 10 to 29 patients. The two randomised trials conflict in their conclusions and numbers are small in these studies. Currently therefore, no firm support can be given to the routine use of intralesional steroid injections. PMID- 28839733 TI - A novel method for determining the difficulty of colonoscopic polypectomy. AB - INTRODUCTION: Endoscopists are now expected to perform polypectomy routinely. Colonic polypectomy varies in difficulty, depending on polyp morphology, size, location and access. The measurement of the degree of difficulty of polypectomy, based on polyp characteristics, has not previously been described. OBJECTIVE: To define the level of difficulty of polypectomy. METHODS: Consensus by nine endoscopists regarding parameters that determine the complexity of a polyp was achieved through the Delphi method. The endoscopists then assigned a polyp complexity level to each possible combination of parameters. A scoring system to measure the difficulty level of a polyp was developed and validated by two different expert endoscopists. RESULTS: Through two Delphi rounds, four factors for determining the complexity of a polypectomy were identified: size (S), morphology (M), site (S) and access (A). A scoring system was established, based on size (1-9 points), morphology (1-3 points), site (1-2 points) and access (1-3 points). Four polyp levels (with increasing level of complexity) were identified based on the range of scores obtained: level I (4-5), level II (6-9), level III (10-12) and level IV (>12). There was a high degree of interrater reliability for the polyp scores (interclass correlation coefficient of 0.93) and levels (kappa=0.888). CONCLUSIONS: The scoring system is feasible and reliable. Defining polyp complexity levels may be useful for planning training, competency assessment and certification in colonoscopic polypectomy. This may allow for more efficient service delivery and referral pathways. PMID- 28839734 TI - Extrahepatic manifestations of hepatitis C virus (HCV). AB - Hepatitis C virus (HCV) is an infectious disease that often remains asymptotic and unrecognised until complications of the virus arise. These often include extrahepatic manifestations of the virus, which first bring patients into contact with the medical profession. First recognised in the 1990s several syndromes and conditions have now been linked to hepatitis C, while others are still emerging. In some patients, extrahepatic manifestations can be the dominant feature, while hepatic disease is mild. Some conditions have an established association with the virus with a proven pathophysiological and epidemiology, such as cryoglobulinaemia. Others have consistently been found to be seen in patients with HCV, but the underlying cause of these conditions is not clearly understood. These include porphyria cutanea tarda. Many other autoimmune conditions are commonly seen in the patients with HCV as well as nephropathies, but the exact interplay between virus and resulting clinical condition is not clear. Clinicians have to have a high index of suspicion and a knowledge of the extrahepatic manifestations of HCV in order to not only treat the manifestation but also in initiated timely therapies for the underlying HCV. PMID- 28839735 TI - Dry blood spot testing for hepatitis C in people who injected drugs: reaching the populations other tests cannot reach. AB - OBJECTIVE: The aim of the study was to evaluate the effectiveness of Dry Blood Spot testing (DBST) for hepatitis C within a geographical area. DESIGN: This is a prospective cohort study of all individuals living in Tayside who had received a hepatitis C virus (HCV) DBST between 2009 and 2011. RESULTS: During the study, 1123 DBSTs were carried out. 946 individuals had one test. 295 (31.2%) of these individuals were HCV antibody positive on their first test. Overall, 94.3% (902/956) individuals returned for the results of their test. During the course of the study 177 individuals were retested and 29 new cases of hepatitis C were detected. 249 individuals attended for further follow-up, and 164 (65.5%) were PCR positive. All 164 PCR-positive individuals were offered referral into specialist HCV services for further assessment. Data showed 62.5% were genotype 3, 65.1% had a low viral load (<600 000 iu/ml) and 77.5% had a Fibroscan score below 7 KPa. To date, 40 have commenced treatment and a further 16 are currently in the assessment period. Overall, we have retained in services or treated 63.6% (105/164) of patients who were initially referred and with effective support mechanisms in place we have achieved sustained viral response rates of 90%. CONCLUSIONS: The study has shown that DBST is a complementary technique to conventional venepuncture for the diagnosis of HCV. The majority of patients have low viral loads and low fibrosis scores, so that while this group of patients may be difficult to reach and may be challenging to maintain in therapy, they are easier to cure. PMID- 28839736 TI - Piloting a multidisciplinary clinic for the management of non-alcoholic fatty liver disease: initial 5-year experience. AB - OBJECTIVE: A multidisciplinary approach is advocated for the management of Non Alcoholic Fatty Liver Disease (NAFLD), but few clinical data exist to support this. The objective of this study was to investigate the effectiveness of a multidisciplinary NAFLD clinic using surrogate markers of liver injury and cardiovascular risk. DESIGN: Retrospective survey of clinical practice. SETTING: The multidisciplinary NAFLD clinic in a secondary/tertiary care setting with hepatology, diabetology, dietetic and exercise therapy input: initial 5-years' experience (2007-2012). PATIENTS: 180 patients with NAFLD but without hepatic comorbidities were followed up for a median of 19.5 (range 3-57) months. 52% had type 2 diabetes mellitus, 48% were Europoid Caucasian, 17% were South Asian. INTERVENTIONS: Multiple clinical interventions were employed including lifestyle (diet and exercise) advice, pharmacological intervention for cardiovascular risk factors, weight loss and exercise therapy. MAIN OUTCOME MEASURES: Change in alanine aminotransferase (ALT), weight, HbA1c, lipid profile and blood pressure. RESULTS: Median ALT fell from 61 (12-270) U/l to 50 (11-221) U/l, -18%, p<0.001, and weight fell from 90.5 (42.7-175.0) kg to 87.3 (45.9-175.3) kg, -3.5%, p<0.001. There were significant improvements in total cholesterol overall, triglycerides (among dyslipidaemic patients), HbA1c (among diabetic patients) and systolic blood pressure (among hypertensive patients). 24% of patients achieved >=7% weight loss during follow-up and 17% maintained this weight loss throughout. CONCLUSIONS: Improvement in liver biochemistry and cardiovascular risk factors was seen in patients attending the multidisciplinary NAFLD clinic. Refinement of this approach is warranted in light of these data, novel therapies and a growing evidence base. PMID- 28839737 TI - Maintaining clinical governance when giving telephone advice. AB - OBJECTIVE: Delivering excellent healthcare depends on accurate communication between professionals who may be in different locations. Frequently, the first point of contact with the liver unit at King's College Hospital (KCH) is through a telephone call to a specialist registrar or liver fellow, for whom no case notes are available in which to record information. The aim of this study was to improve the clinical governance of telephone referrals and to generate contemporaneous records that could be easily retrieved and audited. DESIGN: An electronic database for telephone referrals and advice was designed and made securely available to registrars in our unit. SETTING: Service development in a tertiary liver centre that receives referrals from across the UK and Europe. MAIN OUTCOME MEASURES: Demographic and clinical data were recorded prospectively and analysed retrospectively. RESULTS: Data from 350 calls were entered during 5 months. The information included the nature and origin of the call (200 from 75 different institutions), disease burden and severity of disease among the patients discussed with KCH, and outcome of the call. The majority of cases were discussed with consultants or arrangements were made for formal review at KCH. CONCLUSIONS: A telephone referrals and advice database provides clinical governance, serves as a quality indicator and forms a contemporaneous record at the referral centre. Activity data and knowledge of disease burden help to tailor services to the needs of referrers and commissioners. We recommend implementation of similar models in other centres that give extramural verbal advice. PMID- 28839738 TI - Reversible khat-induced hepatitis: two case reports and review of the literature. AB - Recreational chewing of Catha edulis (khat) leaves is part of the ethnic culture of Somali, Yemeni and other East African societies for its stimulant properties. With increasing emigration, khat use has become common in these ethnic groups once they move to other areas such as Europe and the USA; one-third of the UK Somali population report khat use within the last month. Cathinone, the active component of the khat leaves, is controlled under the UK Misuse of Drugs Act, but the use of the khat plant and its leaves remains not subject to control in the UK. There have been several previous reports of acute hepatitis related to chronic use of khat leading to acute liver failure, and resulting in transplantation or death. We report two cases with severe acute khat-related hepatitis that resolved on cessation of khat use initially, but relapsed with further use, reinforcing the importance of permanent khat cessation to prevent progression to liver failure. With reference to the current literature, we also consider the difficult diagnosis of this disorder, then go on to consider the pathophysiology, mechanisms of liver injury and potential future areas of research. PMID- 28839739 TI - Recurrent ascending cholangitis due to small intestinal bacterial overgrowth, gastrointestinal dysmotility and an afferent loop. AB - We report a complex case involving an extremely rare cause of gastrointestinal dysmotility and an afferent loop, which together predisposed to the development of small intestinal bacterial overgrowth. The bacteria subsequently became multi resistant. As a further consequence of the dysmotility, repeated bile duct reflux occurred despite the afferent loop being unobstructed. This bile duct reflux produced recurrent sepsis through repeated episodes of ascending cholangitis. Ultimately, the patient was referred to a National Small Intestinal Transplant Centre for consideration for enterectomy and subsequent transplantation. We describe the difficulties encountered in managing this unique case and discuss the underlying aetiology. PMID- 28839740 TI - Inflammatory bowel disease in the UK: is quality of care improving? AB - OBJECTIVE: A national audit conducted in 2005/6 showed unacceptable quality of care for inpatients with inflammatory bowel disease (IBD) in the UK. This was re audited in 2007/8 and 2010/11. The aim of this study is to examine the quality of care provided for inpatients with IBD in the UK. DESIGN: A programme of engagement and re-audit in 128 hospitals in the UK providing care for adult patients with IBD admitted to hospital between 1 June 2005 and 31 May 2006, 1 September 2007 and 31 August 2008 and 1 September 2010 and 31August 2011. INTERVENTIONS: Wide dissemination of the results, selected site visits, development of national service standards, and the development of an online document repository. MAIN OUTCOME MEASURES: Mortality, medical and surgical treatment, specialist nursing and dietetic care were audited. RESULTS: Data from 1953, 2016 and 1948 patients with ulcerative colitis (UC) and 2074, 2109 and 1900 patients with Crohn's disease (CD) were audited in 2005/6, 2007/8 and 2010/11, respectively. The mortality rate fell from 1.7% to 0.8% (p=0.034) in UC and from 1.3% to 0.8% (p=0.226) in CD. The proportion of inpatients reviewed by an IBD specialist nurse has risen from 23.7% to 44.9% in UC and from 18.1% to 39.9% (p<0.001) in CD. Anti-tumour necrosis factor therapy has increased in UC and CD (p<0.001) while ciclosporin prescription has slightly fallen in UC. Laparoscopic surgeries have significantly increased in UC and CD (p<0.001). CONCLUSIONS: The results show clear evidence of improvement in most aspects of the quality of care for IBD inpatients. PMID- 28839741 TI - Variations in surgical management from a national bowel cancer screening programme. AB - OBJECTIVE: Population screening for colorectal cancer (CRC) was introduced to Wales in October 2008. The aim of this study was to evaluate the early impact of screening on CRC services. DESIGN: Prospectively collected data from the Bowel Screening Wales (BSW) programme and the Welsh Bowel Cancer Audit (WBCA) were used to identify all screen-detected (SD) CRC diagnoses in Wales between April 2009 and March 2011. Data from the WBCA were used to calculate surgical outcomes. RESULTS: 444 SD cancers were registered during the study period representing 11% of all CRC diagnoses. There was a 9.9% increase in CRC incidence following the introduction of the BSW. SD patients presented with earlier stage disease; SD Dukes' A 35.1% vs 13.9% symptomatic patients (p<0.001) and SD Dukes' D 7.4% vs 21.8% symptomatic, (p<0.001). There were more colonic cancers among the SD population (p<0.001). The resection rate for SD cancers was 89%, significantly higher than symptomatic cancers (67.7%; p<0.0001). There was variability in the use of polypectomy as a definitive procedure to treat CRC between units. Overall laparoscopic resection was used in 52% of cases but with considerable interunit variability (0-92%). CONCLUSIONS: The introduction of screening has increased the workload of the colorectal multidisciplinary teams in Wales. This has occurred through both an increase in case volume and the identification of more patients with early stage disease. There is considerable interunit variability in the use of techniques of local excision and rates of laparoscopic resection that need to be addressed. PMID- 28839743 TI - Highlights from the issue. PMID- 28839742 TI - Pouch dysfunction: don't forget the surgeons! PMID- 28839744 TI - Factors at presentation predictive of a requirement for endoscopic therapy in patients presenting with overt upper gastrointestinal haemorrhage: a retrospective observational study. AB - INTRODUCTION: In patients with upper gastrointestinal haemorrhage (UGIH), endoscopic treatment of high-risk lesions reduces mortality. Performing out of office hours endoscopy places a strain on endoscopy services. This analysis aims to identify factors at presentation associated with lesions requiring endoscopic therapy, allowing triage of those likely to receive benefit from acute out of hours endoscopy. METHODS: Patients presenting between 17 March 2001 and 12 October 2010 with UGIH had clinical and laboratory features on presentation, endoscopic findings and administered treatment recorded. Patients with known cirrhotic liver disease were excluded. Logistic regression was performed, identifying factors at presentation associated with a requirement of endoscopic therapy (RET), which were then used to create a scoring system predictive of RET. RESULTS: In all, 1492 patients were analysed. The presence on presentation of fresh melaena (OR = 3.18, p<0.001), fresh haematemesis (OR=2.13, p<0.001), haemoglobin<130 g/L (OR=2.65, p<0.001), urea >10 mmol/L (OR=2.10, p<0.001), systolic blood pressure <100 mm Hg (OR=1.85, p<0.001), inpatient status (OR=1.43, p=0.04), a history of peptic ulcer disease (OR=1.96, p=0.02), male sex (OR=1.45, p=0.01), presentation within 8 h of symptom onset (OR=1.48, p=0.02), coffee ground vomitus (OR=0.47, p=0.004) and warfarin use (OR=0.57, p=0.005) were associated with RET. Using a simple scoring system (fresh haematemesis=2, fresh melaena=2, haemoglobin <130=2, urea >10=1, BP <100=1, male sex=1, history of peptic ulcer disease=1), a score >=7 was associated with RET in 45% of cases and a score <=4 in 7%. CONCLUSIONS: Application of this scoring system when assessing patients presenting with UGIH out of office hours may help predict the likelihood of RET, and aid in the triage of endoscopy. Prospective validation of this score in an external cohort is required. PMID- 28839745 TI - A candidal oesophageal stricture responsive to fluconazole therapy. AB - We report a case of candidal oesophageal stricture in an 81 year-old man with a 2 year history of gradual onset dysphagia and odynophagia to solids. Although rare, most cases have reported treatment success with oesophageal balloon dilation. We report the first case of candidal oesophageal stricture resolution with a prolonged course of anti-fungal therapy. PMID- 28839746 TI - The role of near-patient coeliac serology testing in the follow-up of patients with coeliac disease. AB - OBJECTIVE: This pilot study was undertaken to assess the validity and effectiveness of near-patient coeliac immunological testing, compared to standard laboratory immunological techniques, used in the context of dietician-led coeliac disease follow-up clinics. DESIGN: The study was designed in two phases, each assessing the near-patient test and standard laboratory immunological techniques. Phase 1 analysed stored serum samples; Phase 2 analysed whole blood from patients attending the dietician-led coeliac disease clinics. SETTING: Patients were recruited from New Cross Hospital, Wolverhampton (n=50), and Imperial College London (n=30), between March 2010 and February 2011. PATIENTS: Those with a diagnosis of coeliac disease for greater than 12 months attending dietician-led coeliac disease clinics. INTERVENTIONS: In addition to whole blood taken for routine analysis, patients required a capillary finger-prick blood sample. MAIN OUTCOME MEASURE: To determine if the whole blood and serum near-patient test results were in correlation with outcomes of standard laboratory evaluation. RESULTS: Phase 1 demonstrated that the near-patient serum test had a sensitivity of 93.5% (95% CI 0.79% to 0.98%), specificity of 94.9% (0.83% to 0.99%), when compared to standard laboratory ELISA. Phase 2, involving patients whole blood, had a sensitivity of 77.8% (0.45% to 0.93%), and specificity of 100% (0.94% to 1%). CONCLUSIONS: This pilot study has demonstrated that there appears to be a role for near-patient testing in coeliac disease, but further studies are recommended. PMID- 28839747 TI - UK colorectal cancer patients are inadequately assessed for Lynch syndrome. AB - OBJECTIVE: To establish whether colorectal cancer patients in two centres in the UK are screened appropriately for Lynch syndrome, in accordance with current international guidance. DESIGN: Patients newly diagnosed with colorectal cancer over an 18-month period were identified from the UK National Bowel Cancer Audit Programme. Their records and management were reviewed retrospectively. SETTING: Two university teaching hospitals, Imperial College Healthcare and Oxford Radcliffe Hospitals NHS Trusts. OUTCOMES MEASURED: Whether patients were screened for Lynch syndrome-and the outcome of that evaluation, if it took place-were assessed from patients' clinical records. The age, tumour location and family history of screened patients were compared to those of unscreened patients. RESULTS: Five hundred and fifty three patients with newly diagnosed colorectal cancer were identified. Of these, 97 (17.5%) satisfied the revised Bethesda criteria, and should have undergone further assessment. There was no evidence that those guidelines had been contemporaneously applied to any patient. In practice, only 22 of the 97 (22.7%) eligible patients underwent evaluation. The results for 14 of those 22 (63.6%) supported a diagnosis of Lynch syndrome, but only nine of the 14 (64.3%) were referred for formal mismatch repair gene testing. No factors reliably predicted whether or not a patient would undergo Lynch syndrome screening. CONCLUSIONS: Colorectal teams in the UK do not follow international guidance identifying the patients who should be screened for Lynch syndrome. Patients and their families are consequently excluded from programmes reducing colorectal cancer incidence and mortality. Multidisciplinary teams should work with their local genetics services to develop reliable algorithms for patient screening and referral. PMID- 28839748 TI - An unusual case of mesenteric ischaemia. AB - We describe an unusual cause of diarrhoea and segmental colitis in a previous well adult man. Mesenteric inflammatory veno-occlusive disease is a rare cause of gastrointestinal tract ischaemia of unknown aetiology. We review the literature of this condition and other mesenteric venous pathologies. PMID- 28839749 TI - Effect of azathioprine intolerance on outcomes of inflammatory bowel disease: a cross-sectional study. AB - BACKGROUND: Azathioprine is well established for the maintenance of remission in patients with inflammatory bowel disease (IBD). However, a significant proportion of patients are intolerant to azathioprine. It is not clear if intolerance of azathioprine is a marker of poor prognosis for patients who will have a more aggressive disease or be more likely to require surgery. OBJECTIVE: To determine if intolerance to azathioprine is a marker of poor prognosis, indicating patients who have a more aggressive disease course, and to analyse the risk factors and causes of intolerance. METHODS: A cross-sectional study using the Milton Keynes Hospital IBD database was performed to compare azathioprine-intolerant and azathioprine-tolerant patients. RESULTS: Two hundred and thirty-nine patients met the inclusion criteria comprising 141 patients with Crohn's disease (CD) and 98 patients with ulcerative colitis (UC). Overall, 28.0% of patients were intolerant to azathioprine. Risk factors for intolerance were female sex and age 50-70 years. Common reasons for intolerance were nausea and vomiting (34.3%), deranged liver function tests (28.4%) and headaches (11.9%). In patients with UC, there was no statistical difference in the disease activity scores between those who were azathioprine intolerant versus tolerant. In patients with CD, azathioprine intolerance was associated with significantly worse disease activity; 25% fewer patients were in clinical remission and 20% more had moderate/severe disease. Rates of surgery were similar between the groups for both UC/CD. CONCLUSIONS: We conclude that azathioprine intolerance acts as a surrogate marker for patients with CD who in future have poorer symptom control. Azathioprine intolerance marks out a group of patients with CD in whom increased vigilance of symptom control and early escalation of treatment is required. PMID- 28839750 TI - Inflammatory bowel disease and exercise: results of a Crohn's and Colitis UK survey. AB - BACKGROUND: Over 250 000 people in the UK are affected with inflammatory bowel disease (IBD) and approximately 10 000 new cases are diagnosed every year. These chronic bowel conditions have been shown to affect both work and recreational activity. In the general population, regular exercise has numerous benefits to health and well-being and there are additional benefits for those with IBD. However, people with IBD face significant challenges in trying to take regular exercise. OBJECTIVE: With the renewed focus on sport brought about by the recent London Olympics, Crohn's and Colitis UK surveyed its members to explore their sport and fitness habits. METHODS: 918 members participated in the survey, which is the largest survey of its kind, investigating the exercise habits of people with IBD. RESULTS: The survey showed widespread uptake of exercise in those with IBD, with a large number feeling better for it. However, it also identified a considerable number of respondents who reported a significant negative impact of IBD on their ability to take up, enjoy and derive benefit from sporting activities. CONCLUSION: Asking questions about sporting leisure activity in clinical consultations may identify those in need of help and support and possibly identify factors to be dealt with, in order to enable them to take part in these beneficial activities. PMID- 28839752 TI - Dr Falk Pharma UK/Core awards. PMID- 28839751 TI - Drug-induced gastrointestinal disorders. AB - Drug-induced gastrointestinal disorders can mimic conditions, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and, hence, recognition can prevent unnecessary investigations and treatment. While the knowledge and awareness relating to the adverse gastrointestinal effects of some medications, such as non-steroidal anti-inflammatory drugs are well established, other commonly prescribed drugs, such as antipsychotics, antidepressants and metformin are less well understood and warrant further study. This review attempts to integrate recent information regarding adverse drug reactions and place this in a useful clinical context. PMID- 28839753 TI - Pyogenic liver abscess. AB - Pyogenic liver abscess has a variable clinical presentation. Its management requires input from several disciplines and is often coordinated by a gastroenterologist. This review examines demographics, clinical presentation, aetiology, diagnosis and prognosis; a suggested management approach, including antibiotic selection, radiological intervention and indications for surgery, is offered from a physician's perspective. PMID- 28839756 TI - Medications and malignancy in inflammatory bowel disease. PMID- 28839754 TI - Gastrointestinal polyposis syndromes for the general gastroenterologist. AB - The occurrence of colonic polyps is a common phenomenon; however, where there are numerous adenomas or other polyps, and/or the patient is at a relatively young age, an inheritable form of gastrointestinal polyposis should be considered. Patients can present via different referral routes, for example, at colonoscopy where multiple polyps are detected, following a personal diagnosis of colorectal cancer, or by family screening. This article outlines the important considerations in the diagnosis of a polyposis syndrome and key diagnostic features to consider. It will also describe the underlying genetic factors associated with the common polyposis syndromes, including classical familial adenomatous polyposis (FAP), attenuated FAP, MUTYH-associated adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome and serrated polyposis, and the subsequent management of each condition. PMID- 28839757 TI - Managing a patient with excessive belching. AB - A 50-year-old man with end-stage renal failure was referred by his general practitioner with dyspeptic symptoms. On further questioning the patient complained of a 10-year history of frequent belching. This was noticeably worse after meals and during times of stress. He did not have nocturnal belching and episodes of belching were less frequent when the patient was talking or distracted. There was no history of gastro-oesophageal reflux, vomiting, dysphagia, loss of appetite or weight loss. He was diagnosed with excessive, probably supragastric, belching. Further investigation was not deemed necessary. His symptoms have since settled with simple reassurance and explanation of their origin provided during the clinic visit. PMID- 28839758 TI - Impact of perioperative enteral synbiotics in hepatic and pancreatic surgery: design and rationale of a single blind placebo controlled prospective randomised control trial. AB - BACKGROUND: Prebiotics and probiotics influence all pathogenic mechanisms of bacterial translocation. Used in combination, they are called synbiotics. Postoperative infective complications in patients undergoing hepatic and pancreatic surgery lead to a significant prolongation of hospital stay and increased costs. While synbiotics are considered to have beneficial effects on human health, their clinical value in surgical patients, especially in South Asia remains unclear given a paucity of applicable clinical studies. In this study we aim to assess their clinical usefulness in patients who undergo hepatic and pancreatic surgery. METHODS: A prospective monocentric randomised single blind controlled trial is being conducted in patients undergoing major pancreatic resections (Whipple procedure, distal pancreatectomy, Frey procedure) and hepatic resections. Group A received a specific synbiotic composition, 5 days prior and 10 days after the surgery. Group B received a placebo. Primary study end point was the occurrence of postoperative infection during the first 30 days. Secondary outcome measures were mortality, first bowel movement, days in intensive care unit, length of hospital stay, and duration of antibiotic therapy. Side effects of probiotics were evaluated. From previous studies we assumed that perioperative synbiotics reduce the proportion of patients with infectious complications from 50% to 12%, with alpha of 0.05 and power 80%, the calculated sample size was 35 patients for each group with a dropout rate of 10%. CONCLUSIONS: This study is intended at determining the impact of perioperative synbiotic therapy on postoperative infectious complications, morbidity and mortality in patients undergoing major pancreatic and hepatic surgery. CLINICAL TRIAL: The Clinical Trials Registry of India (CTRI/2013/06/003737). PMID- 28839759 TI - Diagnosis and treatment of alcoholic hepatitis. AB - Alcoholic liver disease (ALD) is increasing in incidence in the UK. It is the commonest cause of liver-related deaths, predominantly in people below the age of 60. Alcoholic hepatitis (AH) is an acute form of ALD with high mortality when severe. Jaundice and coagulopathy are clinical hallmarks of severe AH. Histology findings are characterised by parenchymal inflammation and hepatocellular damage although biopsy is only required when diagnostic uncertainty exists; clinical findings are usually sufficient for accurate diagnosis. Patients with AH should be stratified as non-severe or severe using non-invasive scoring systems such as the discriminant function or the Glasgow Alcoholic Hepatitis Score. In patients with non-severe AH, abstinence is the mainstay of treatment, and it is important that steps are taken to help patients stop drinking. Severe AH requires specialist treatment. Consensus guidelines recommend the use of prednisolone although this remains subject to clinical trials. Pentoxifylline may have a survival benefit if corticosteroids are contraindicated. Nutritional support and N-acetylcysteine should be considered for use in conjunction with corticosteroids although evidence of benefit is not conclusive. Patients with severe disease who do not respond to therapy within a week have a very poor outcome. Recent data have shown a survival benefit of liver transplantation in this group although this remains experimental at present. Current and future research should focus on targeted therapies for severe AH and those who fail first-line treatment. PMID- 28839760 TI - A national survey of hereditary colorectal cancer services in the UK. AB - OBJECTIVES: The British Society of Gastroenterology (BSG) Cancer Group designed a survey to determine how we might understand and improve the service for patients at elevated risk of hereditary colorectal cancer (CRC). DESIGN AND SETTING: United Kingdom (UK) gastroenterologists, colorectal surgeons, and oncologists were invited by email to complete a 10 point questionnaire. This was cascaded to 1,793 members of the Royal College of Radiologists (RCR), Association of Cancer Physicians (ACP), the Association of Coloproctology of Great Britain and Ireland (ACPGBI), as well as BSG members. RESULTS: Three hundred and eighty-two members responded to the survey, an overall response rate of 21.3%. Although 69% of respondents felt there was an adequate service for these higher risk patients, 64% believed that another clinician was undertaking this work. There was no apparent formal patient pathway in 52% of centres, and only 33% of centres maintain a registry of these patients. Tumour block testing for Lynch Syndrome is not usual practice. Many appeared to be unaware of the BSG/ACPGBI UK guidelines for the management of these patients. CONCLUSIONS: There is wide variability in local management and in subsequent clinical pathways for hereditary CRC patients. There is a perception that they are being managed by 'another', unspecified clinician. National guidelines are not adhered to. We therefore recommend improved education, well defined pathways and cyclical audit in order to improve care of patients with hereditary CRC risk. PMID- 28839763 TI - Endoscopic resection for oesophageal mucosal adenocarcinoma. PMID- 28839764 TI - Correlation of caecal intubation rate to volume: colonoscopists should undertake at least 120 procedures per year. AB - INTRODUCTION: The measurement of the quality of colonoscopy has been in the vanguard of quality improvement. The Joint Advisory Group on Gastrointestinal endoscopy (JAG) has issued guidance for practitioners to achieve caecal intubation rates (CIR) of >=90% and to undertake >=100 colonoscopies per annum. The British Society of Gastroenterology National Colonoscopy Audit published in 2012-2013 demonstrated a combined CIR of 92.3%. In 2012, we published data from 16 064 colonoscopies showing a combined CIR of 90.57%-both meeting JAG's standard. Analysis of our audit looked at the relationship of volume and outcome. CIR of operators performing >=100 procedures per annum was 91.76%; those performing <100 was 87.77%. The 2-year data we collected involved 120+ operators. This provided an opportunity to study the correlation between volume and CIR in detail. METHODS: We analysed 129 operator records who had undertaken 20-399 procedures per annum (total 12 594). Each operator's volume was plotted against CIR as individuals and groups of operators undertaking a similar annual volume. 9859 procedures (78.3%) were performed by operators undertaking 20-199 procedures per annum (120 operators); this subgroup was further analysed. RESULTS: When plotting individuals and groups of individuals who have undertaken a similar annual volume against CIR, the trend-lines cross a 90% CIR at a volume of 120-125 procedures. The subgroup analysis showed the trend-line crossing at 110-120 procedures. CONCLUSIONS: This detailed analysis of 12 594 colonoscopies over 2 years suggests that JAG should advise operators to undertake >=120 procedures per annum to support the quality standard for CIR of >=90%. PMID- 28839761 TI - Investigation and management of pancreatic tumours. AB - Pancreatic cancer is the 10th most commonly diagnosed cancer in the UK and the fifth most common cause of cancer death. It remains one of the most aggressive cancers with over 95% of patients affected dying of their disease. Often presenting at an advanced stage of disease progression, there is currently no simple screening test available. Therefore a high clinical suspicion and prompt appropriate investigation is required from physicians when dealing with patients with symptoms in keeping with pancreatic cancer. The gastroenterology 2010 curriculum states that trainees should learn the presentation and multidisciplinary management of patients with pancreatic tumours. In this article we discuss the typical clinical presentations of common and less common pancreatic tumours followed by the investigation, staging and management required. PMID- 28839765 TI - Biliary boulders. AB - OBJECTIVE: To examine the outcome of endoscopic retrograde cholangiopancreatography (ERCP) in the management of common bile duct (CBD) stones. DESIGN: A retrospective review of 100 consecutive ERCPs performed for CBD stones. RESULTS: 100 ERCPs were performed on 84 patients with a median cohort age of 77. Completion in this cohort, as defined by duct clearance, was achieved in 65% of cases. Completion rates fell rapidly after two ERCPs. 33% of the cohort had small stones <10 mm, and 67% had stones >10 mm. Size, but not number of stones, affected the completion rate and frequency of complications (16%). Presence of periampullary diverticulum did not affect completion or complication rates. MR cholangiopancreatography (MRCP) had a 90% sensitivity for detecting CBD stones compared with 56% for CT. DISCUSSION AND CONCLUSIONS: ERCP remains a high risk procedure with a significant complication rate when performed to deal with CBD stones. MRCP should be the second choice of investigation for CBD stones. This cohort had an unusually high number of larger stones at ERCP of 67% compared with other published UK cohorts of 8%, and this was reflected in the completion and complication rate. PMID- 28839766 TI - Mapping of Crohn's disease outcomes to faecal calprotectin levels in patients maintained on biologic therapy. AB - BACKGROUND: Faecal calprotectin (FC) is a sensitive marker of intestinal mucosal inflammation. The gold standard in Crohn's disease management is mucosal healing. The role of FC to support clinical practice in Crohn's disease is not yet defined. AIMS: To determine, in patients with Crohn's disease established on biologic therapy: (1) the correlation between disease activity and FC levels, (2) whether FC can predict for relapse and (3) the sensitivity and specificity of the C-reactive protein (CRP) when compared with FC. METHODS: In this retrospective, single-site study, Crohn's disease activity, clinical outcomes, FC and CRP of 76 patients established on biologic therapy were reviewed and mapped over time. RESULTS: Patients were mapped for a median of 34 months (IQR 21-57.5). FC levels were determined every 7 (4-13) months on average. Mean FC in quiescent disease was 105 MUg/g (SEM 19); in mild disease, 282 (SEM 71); in moderate disease, 611 (SEM 80) and in severe disease, 1314 (SEM 224) (p<0.001). In asymptomatic patients who relapsed at 6 months, the optimal FC, with an area under the curve of 0.886 (p<0.001), was 357.5. In discriminating quiescent from active disease (FC>100 MUg/g) the sensitivity and specificity of CRP were 0.48 (0.36-0.61) and 0.73 (0.6-0.85), and in mild from moderate or active disease (FC>250 MUg/g), 0.60 (0.43-0.74) and (0.72 (0.60-0.82). CONCLUSIONS: FC is an accurate marker of Crohn's disease activity and predicts for relapse, thus providing the clinician time to optimise therapy. FC is a more sensitive marker of Crohn's disease activity than CRP. PMID- 28839767 TI - Reassessment of Crohn's disease treated with at least 12 months of anti-TNF therapy: how likely is treatment withdrawal? AB - OBJECTIVE: To assess methods of disease reassessment and rates of treatment withdrawal in patients with Crohn's disease (CD) treated with biologics and to report retrospective risk stratification for treatment withdrawal as suggested by the STORI trial in the context of this cohort. DESIGN: A retrospective observational cohort study of all patients with CD treated with antitumour necrosis factor (anti-TNF) therapy for >12 months in 2011. SETTING: Tertiary care. PATIENTS: Patients with CD treated with anti-TNF therapy. MAIN OUTCOME MEASURES: Method and outcome of reassessment and whether patient was withdrawn from therapy; also, whether patients met low-risk criteria for withdrawal as identified by the STORI trial, and outcome of those meeting low-risk criteria. RESULTS: 73 patients (infliximab n=48, adalimumab n=25) underwent disease reassessment. Nine patients were deemed to have achieved remission and were withdrawn from treatment: 6 (67%) maintained remission at 12 months, three patients relapsed and were successfully retreated. 52 patients had sufficient data available for STORI criteria to be applied retrospectively. 37% (19/52) fulfilled low-risk criteria for withdrawal-of these, 26% (5/19) were withdrawn from anti-TNF therapy and three had sustained clinical remission at 1 year. Reasons for non-withdrawal included ongoing endoscopic activity (n=8), radiological activity (n=2) and clinical concern due to previous disease behaviour (n=4). CONCLUSIONS: Relatively few patients were deemed in sufficient depth of remission to warrant a trial of withdrawal of anti-TNF therapy. Many patients were not withdrawn, despite meeting STORI low-risk criteria, due to ongoing disease activity highlighting the limitations of applying such criteria in a 'real world' setting. PMID- 28839768 TI - Disease status, patient quality of life and healthcare resource use for ulcerative colitis in the UK: an observational study. AB - BACKGROUND: Ulcerative colitis is a lifelong, chronic, relapsing-remitting disease. OBJECTIVE: To assess the relationship between ulcerative colitis disease status and patient quality of life, and to determine the impact of ulcerative colitis on healthcare costs and work productivity, in the UK. METHODS: Clinicians assessed 173 adult patients' current disease status at a single study visit using the partial Mayo (pMayo) instrument. Patients completed the Euro Quality of Life 5-dimension, 5-level (EQ-5D-5L) questionnaire, the Work Productivity and Activity Impairment (WPAI) questionnaire. Healthcare resource use was determined from questionnaires and from patients' medical charts. RESULTS: Patients in remission had a significantly higher EQ-5D-5L scores (mean (SD) 0.86 (0.15)) than patients with active disease (0.71 (0.20); p<0.001). Patients with mild disease had significantly higher mean (SD) EQ-5D-5L scores than patients with moderate/severe disease: 0.77 (0.11) and 0.66 (0.24), respectively (p<0.001). The mean percent productivity impairment was greater for patients with active disease than for patients in remission on all items of the WPAI questionnaire: 24.6% vs 1.8% for work time missed, 34.1% vs 12.9% for impairment while working, 40.8% vs 14.4% for overall work impairment and 42.7% vs 13.0% for activity impairment (p<0.001 for all comparisons). The mean (SD) total cost of healthcare for ulcerative colitis in the prior 3 months was L1211 (1588). CONCLUSIONS: When compared with patients in remission, patients with active ulcerative colitis have significantly worse quality of life and significantly more work impairment. The healthcare costs of ulcerative colitis are considerable. PMID- 28839769 TI - Anaemia in inflammatory bowel disease. AB - Anaemia is a common manifestation in inflammatory bowel disease (IBD) and impairs quality of life. Anaemia in IBD is typically caused by iron deficiency or anaemia of chronic disease. Treatment of iron deficiency with oral iron may lead to gastrointestinal intolerance though this may be related to the dose of iron replacement. New intravenous formulations have emerged which allow safe, rapid and effective correction of iron deficiency in IBD. In this article, we provide a review on the topic and cover recent progress in the field for the practicing gastroenterologist. PMID- 28839770 TI - Perspectives and attitudes of young patients with inflammatory bowel disease: symptoms, burden of disease and communication with their healthcare professionals. AB - INTRODUCTION: Inflammatory bowel disease (IBD) affects a significant proportion of young patients in the UK. The role of the healthcare professional, and their relationship with the young patient is particularly important at this difficult stage of their life, when education, social integration and career planning, can be dramatically affected by this consuming condition. OBJECTIVES: To address the attitudes, experiences and erspectives of young patients suffering from IBD, focusing particularly on the relationship between sufferer and healthcare provider. METHODS: Crohn's and Colitis UK invited its young members to respond to a detailed internet based questionnaire addressing various aspects of patients' disease and their relationship with respective healthcare workers. RESULTS: 1081 patients aged 29 years or less responded. Self reported burden of illness was high with only 12% respondents free from a disease flare in the previous 12 months with almost half being hospitalised in the same period. Quality of ommunication with healthcare providers was generally high, with three-quarters of patients feeling appropriately empowered in their healthcare decisions. The IBD nurse specialist was highlighted as a particularly valuable member of the team, scoring the highest of the professional groups in communication comfort scores, as well as being nominated by the patients as the preferred professional group to discuss their disease with. CONCLUSIONS: The results emphasize the considerable impact of the disease that this group is encumbered with, and identifies areas in the patient-professional relationship that can be augmented to improve the overall healthcare of this complex and fragile subgroup of patients. PMID- 28839771 TI - A practical approach to the management of high-output stoma. AB - The development of a high-output stoma (HOS) is associated with water, electrolyte and nutritional complications. Prompt, careful assessment and management is required to avoid rapid clinical deterioration in this patient population. A multidisciplinary approach to management ensures the best possible outcome and quality of life for patients who experience HOS. This article outlines the important considerations in the identification and pathophysiology of HOS. A systematic approach to the management of the condition is outlined, considering fluid and electrolyte requirements, nutrient deficiencies and manipulation of gastrointestinal absorption, motility and secretions using medical and surgical therapies. PMID- 28839772 TI - Ketamine as a possible cause of cirrhosis in a patient with chronic pain. AB - Ketamine has been typically administered in short-term, few doses in the clinical setting of acute pain. Its hallucinogenic side effects have made it popular as a recreational drug. Reports of urological, biliary and liver abnormalities have been reported, mainly in cases of abuse. It is now increasingly used for chronic pain conditions, and here we report liver abnormalities and ultimately cirrhosis in an adult on regular ketamine for chronic facial pain. Abnormal liver function tests were detected incidentally, and with no other cause for liver disease found, liver biopsy was performed. This showed fibrosis with incomplete cirrhosis. PMID- 28839773 TI - The development of a nurse-led iron deficiency anaemia service in a district general hospital. AB - OBJECTIVE: To improve the quality of care provided to patients with iron deficiency anaemia (IDA). DESIGN: Service development. SETTING: District General Hospital. PATIENTS: Adults with IDA. MAIN OUTCOME MEASURES: Descriptive report of the practicalities and benefits of establishing an IDA clinic. CONCLUSIONS: The IDA clinic is a novel service development which enhances the management of patients with this common condition, by facilitating prompt confirmation of the diagnosis, replacement therapy and investigation for serious underlying pathology, in particular gastrointestinal malignancy. PMID- 28839774 TI - Extrahepatic manifestations of hepatitis C. PMID- 28839776 TI - Infliximab and anti-infliximab antibody levels in Crohn's disease. PMID- 28839777 TI - Investigating for GI malignancy in iron-deficiency anaemia-the case for risk stratification. PMID- 28839779 TI - Clinical risk factors for underlying gastrointestinal malignancy in iron deficiency anaemia: the IDIOM study. AB - OBJECTIVE: Ten percent of adults presenting with iron deficiency anaemia (IDA) have underlying cancer. This analysis - the Iron Deficiency as an Indicator Of Malignancy (IDIOM) study - was undertaken to assess whether five simple clinical parameters can usefully predict the likelihood of gastrointestinal (GI) malignancy on subsequent investigation of patients with IDA. DESIGN: Retrospective observational study, with multivariable analysis of the predictive value of sex, age, haemoglobin concentration (Hb), mean red cell volume (MCV) and iron studies for the risk of underlying GI malignancy. SETTING: District General Hospital IDA clinic. PATIENTS: 720 adults with confirmed IDA. RESULTS: Sex, age and Hb were strongly associated with the risk of GI malignancy-the parsimonious model including only these variables yielded ORs of 4.0 (95% CI 2.3 to 7.0) for males compared with females; 3.3 (95% CI 1.7 to 6.4) for age >70 years compared with <=70 years; and 5.3 (95% CI 2.4 to 11.7) for a Hb of <=91.4 g/L compared with >=111.5 g/L. Combining these risk factors identified a subgroup (12% of the study population) at particularly low risk (<2% likelihood), and a second subgroup (16% of the study population) at especially high risk (>20% likelihood) of underlying GI malignancy. CONCLUSIONS: Three simple and objective clinical parameters can be combined to provide a clinically useful cancer risk stratification model for subjects with IDA. This may assist with patient counselling and the prioritisation of investigational resources. PMID- 28839778 TI - Role of faecal occult bloods in the diagnosis of iron deficiency anaemia. AB - OBJECTIVE: To determine whether faecal occult blood (FOB) testing in patients with iron deficiency anaemia (IDA) can predict the presence of gastrointestinal cancer. DESIGN: Cohort study. SETTINGS: Single secondary care hospital UK. PATIENTS: All individuals aged 20 years and older referred for the investigation for IDA. INTERVENTIONS: Data was collected from all the patients regarding haemoglobin (Hb), mean corpuscular volume, age, sex, symptomatology and medication. All patients had FOB tests using laboratory guaiac and haemocell methods, and then underwent gastroscopy and colonoscopy. MAIN OUTCOME MEASURES: Accuracy, sensitivity and specificity of FOBs for identifying cancer in the upper or lower gastrointestinal tract. RESULTS: In total, 292 patients completed the study; 37 patients were diagnosed with carcinoma (colon 34, gastro-oesophageal 3). Using an optimal combination of lab guiaic and haemocell test resulted in just one colorectal cancer being missed, a sensitivity of 97%, specificity of 49% and negative predictive value of 99%. The test was less effective for upper gastrointestinal cancer, with 2/3 tumours missed by the tests. CONCLUSIONS: Patients who have negative FOB tests are very unlikely to have a colorectal cancer, and the benefits to further colonic investigation is limited. This should be carefully considered in patients with significant comorbidities, where the risks of investigation may outweigh the benefits. PMID- 28839780 TI - Falling mortality when adjusted for comorbidity in upper gastrointestinal bleeding: relevance of multi-disciplinary care. AB - OBJECTIVES: The understanding of changes in comorbidity might improve the management of upper gastrointestinal bleeding (UGIB); such changes might not be detectable in short-term studies. We aimed to study UGIB mortality as adjusted for comorbidity and the trends in risk scores over a 14-year period. METHODS: Patients presenting with UGIB to a single institution, 1996-2010, were assessed. Those with multiple comorbidities were managed in a multi-disciplinary care unit since 2000. Trends with time were assessed using logistic regression, including those for Charlson comorbidity score, the complete Rockall score and 30-day mortality. RESULTS: 2669 patients were included. The Charlson comorbidity score increased significantly with time: the odds of a high (3+) score increasing at a relative rate of 4.4% a year (OR 1.044; p<0.001). The overall 30-day mortality was 4.9% and inpatient mortality was 7.1%; these showed no relationship with time. When adjusted for the increasing comorbidity, the odds of death decreased significantly at a relative rate of 4.5% per year (p=0.038). After the introduction of multi-disciplinary care, the raw mortality OR was 0.680 (p=0.08), and adjusted for comorbidity it was 0.566 (p=0.013). CONCLUSIONS: 30-day mortality decreased when adjusted for the rising comorbidity in UGIB; whether this is related to the introduction of multi-disciplinary care needs to be considered. PMID- 28839781 TI - Findings on interval colonoscopies: an auditable performance indicator for colonoscopy quality? AB - OBJECTIVE: An important marker of colonoscopy quality is detection of pathology and incidence of missed pathology. Back-to-back colonoscopies cannot ethically be performed for quality assurance alone yet may be required for clinical reasons. This study aims to investigate the incidence of new findings in colonoscopies repeated within a 12 month period and considers the role of such an analysis in the assessment of colonoscopy quality. DESIGN: All colonoscopies performed over a 3-year period at an endoscopy training unit were studied. Colonoscopies repeated within a 12-month period were analysed. RESULTS: 5747 colonoscopies were performed over the study period. 137 repeat colonoscopies were included with median interval from initial colonoscopy of 174 days. 19 (14%) repeat colonoscopies yielded new findings including one cancer, 234 days following a normal colonoscopy. Additional polyps were identified in 13 colonoscopies indicating a missed polyp rate of 9%. In these, a median number of two polyps per colonoscopy with median size 5.5 mm were found. There was no morbidity associated with repeat colonoscopy in this series. New findings on repeat colonoscopy appeared more likely following initial colonoscopy by non-consultant non-training grade endoscopists (23% vs 11%, p=0.09) yet small numbers involved preclude meaningful comparison. CONCLUSIONS: Analysis of clinically indicated repeat colonoscopies and rate of detection of new pathology may offer utility in colonoscopy quality assurance and would offer a direct assessment of the most important aspect of colonoscopy quality. PMID- 28839782 TI - Nitrous oxide use during colonoscopy: a national survey of English screening colonoscopists. AB - INTRODUCTION: Nitrous oxide can improve patient experience during colonoscopy, and its rapid elimination minimises after effects and inconvenience. Despite its advantages, nitrous oxide is used infrequently in the UK. We sought to understand the reasons for its low use. METHODS: Colonoscopists within the English Bowel Cancer Screening Programme (BCSP) were invited to participate in a web-based survey assessing the availability, current practices and perceptions towards nitrous oxide. Respondents were able to select predefined answers or offer written responses. Free text responses were assessed using thematic analysis. RESULTS: The survey was completed by 68% of the English BCSP colonoscopists. Nitrous oxide was available to 73% of respondents but with considerable regional variation. Most colonoscopists rated the properties of nitrous oxide favourably and would use it if they had a colonoscopy themselves. Despite this, nearly half used it in less than 20% of examinations. 80% instruct patients to use nitrous oxide as required, and differences in how it was used in combination with intravenous sedation and analgesia were reported. Written responses suggest nitrous oxide is often used in the patients who are expected to have the least discomfort. CONCLUSIONS: Most colonoscopists perceive that nitrous oxide is effective and reduces inconvenience and would use it themselves if they required a colonoscopy. Studies to improve patient selection and optimise the use of nitrous oxide would be of value. PMID- 28839783 TI - Prevalence of functional gastrointestinal disorders among consecutive new patient referrals to a gastroenterology clinic. AB - OBJECTIVE: Functional gastrointestinal disorders (FGIDs) are common in the community. Many patients will consult a physician in primary care, but the burden that these diseases represent to secondary care has not been studied for many years. We therefore examined this subject. DESIGN: Unselected consecutive new adult patient referrals were recruited during a 3-year period from January 2010 until December 2012. Medical records were reviewed retrospectively and the following data were recorded: age and sex of the patient, symptoms reported or signs noted at the first consultation, all investigations requested and ultimate diagnosis after investigation to the level deemed appropriate by the consulting physician. SETTING: A luminal gastroenterology clinic at a teaching hospital. RESULTS: There were a total of 613 new patient referrals (mean age 54.2 years, 357 (58.2%) female). In total, 214 (34.9%) patients were diagnosed as having an FGID. Among the 214 patients diagnosed with an FGID, 65.9% were female, compared with 54.1% without an FGID (p=0.005). Mean age of those with an FGID was 47.9 years, compared with 57.5 years among those without (p<0.001). The total number of symptoms reported was significantly higher among patients with an FGID, but the total number of investigations did not differ. CONCLUSIONS: More than one third of new patient referrals to a luminal gastroenterology clinic were diagnosed with an FGID. These conditions form a large part of the workload in secondary care gastroenterology, and primary care commissioning needs to reflect this. PMID- 28839784 TI - Would you have laparoscopic Nissen fundoplication again? A patient satisfaction survey in a UK population. AB - OBJECTIVE: Laparoscopic Nissen fundoplication (LNF) effectively reduces objective gastro-oesophageal reflux. It can however cause side effects which affect quality of life or fail to improve subjective reflux symptoms. This study aims to assess patient satisfaction following LNF by assessing whether patients would have the procedure again. DESIGN: Telephone survey using a structured questionnaire. Participation was voluntary. SETTING: UK Foundation Trust (two university hospitals). PATIENTS: All patients who had LNF performed by a single surgeon between November 2008 and June 2012. MAIN OUTCOME MEASURES: Primarily, current reflux symptoms, antiacid medication requirement and whether participants would choose to have the procedure again (should they still have their initial symptoms). Further measures were conversion to open procedure, need for redo or reversal, and mortality. RESULTS: 99 patients underwent LNF in the quoted period; 71 were contactable and willing to participate. Of the 99, two required redo operations (neither of whom was contactable), and one had a reversal (primary operation included). Median time since the operation was 33 months (range 5-48 months). Compared with preoperatively, 72% rated their current reflux-symptom severity as <=2/10, 23% as 3-6/10 and 4% as 7-10/10. 75% were not taking any antiacid medication. 89% of patients said that they would have the procedure again. CONCLUSIONS: This study provides supporting evidence that LNF improves reflux symptoms and decreases medication use at intermediate-term follow-up. These results will aid counselling and reassurance of patients regarding the risks and benefits of LNF as the majority of postoperative patients were sufficiently satisfied to choose the operation again. PMID- 28839785 TI - Pure white cell aplasia: report of first case associated with autoimmune hepatitis. AB - Pure white cell aplasia (PWCA) is a rare, immune-mediated condition that causes a profound inhibition of myelopoiesis. It has been seen in association with other autoimmune conditions, thymomas, chronic lymphocytic leukaemia and as an adverse drug reaction. We report what we believe to be the first case of PWCA associated with autoimmune hepatitis. An 18-year-old woman presented with jaundice and was found to be suffering from acute hepatitis. Later she became neutropenic and lymphopenic. Liver biopsy was indicative of autoimmune hepatitis. This was later confirmed by autoantibody results. Bone marrow aspirate found an absence of all myeloid progenitor cells, highly suggestive of PWCA. The low white cell count only improved after immunosuppression with corticosteroids. Her condition remains stable 1 year later with azathioprine therapy. PMID- 28839786 TI - Consent in the endoscopy department. AB - The demand for endoscopic procedures continues to increase and is likely to continue to do so for the foreseeable future. Alongside elective diagnostic procedures, the number of complex and therapeutic procedures is increasing. It is therefore vital that the consent process is comprehensive, and high standards in consenting patients are maintained. Consent is defined as a patient's agreement to treatment or an intervention proposed by a health professional. Careful patient selection is required when proposing endoscopic procedures with an appreciation of the risks and complications that are involved. This paper addresses the various components of gaining informed consent and the legal issues surrounding this process. Additionally, this article reviews legislation and focuses upon specific instances where further considerations have to be made; in a patient who lacks capacity, in children, in percutaneous endoscopic gastrostomy and in the patient who is a Jehovah's Witness. PMID- 28839788 TI - Interferon-free treatment for genotypes 2 and 3 patients with hepatitis C. PMID- 28839789 TI - Faecal calprotectin-ready for prime time? PMID- 28839790 TI - Faecal calprotectin for differentiating between irritable bowel syndrome and inflammatory bowel disease: a useful screen in daily gastroenterology practice. AB - OBJECTIVE: To determine the best faecal calprotectin (FCP) cut-off level for differentiating between irritable bowel syndrome (IBS) and organic disease, particularly inflammatory bowel disease (IBD), in patients presenting with chronic diarrhoea. DESIGN: Retrospective analysis of patients who had colonoscopy, histology and FCP completed within 2 months. SETTING: District general hospital. PATIENTS: Consecutive new patients with chronic diarrhoea lasting longer than 4 weeks. INTERVENTIONS: Patients were seen by a single experienced gastroenterologist and listed for colonoscopy with histology. Laboratory investigations included a single faecal specimen for calprotectin assay (lower limit of detection: 8 ug/g), the results used for information only. MAIN OUTCOME MEASURES: Six FCP cut-off levels (range 8-150 ug/g) were compared against the 'gold standard' of histology: inflammation 'present' or 'absent'. RESULTS: Of 119 patients studied, 98 had normal colonoscopy and histology. The sensitivity of FCP to detect IBD at cut-off levels 8, 25 and 50 ug/g was 100% (with corresponding specificity 51%, 51%, 60%). In contrast, the lowest FCP cut off, 8 ug/g, had 100% sensitivity to detect colonic inflammation, irrespective of cause (with negative predictive value (NPV) 100%). Importantly, 50/119 patients (42%) with FCP <8 ug/g had normal colonoscopy and histology. CONCLUSIONS: Our results suggest that using FCP to screen patients newly referred for chronic diarrhoea could exclude all without IBD and, at a lower cut-off, all without colonic inflammation, thus avoiding the need for colonoscopy. Such a major reduction has implications for resource allocation. PMID- 28839791 TI - Do gastroenterologists monitor their patients taking 5-amino-salicylates following initiation of treatment. AB - BACKGROUND: 5-Amino salicylate (5-ASA) medications may rarely be associated with a significant decline in renal function and interstitial nephritis. British Society of Gastroenterology guidelines advise regular renal function monitoring for patients taking these drugs. AIM: To assess whether gastroenterologists in Kent were following best practice guidelines regarding the monitoring of their patients on 5-ASA therapy. METHODS: Using longitudinal community and regional pathology databases for the Kent population, our renal unit regularly screens a total population of 300 000 for evidence of renal disease. The data extracted are analysed using an automated computerised system to identify patients requiring intervention for kidney disease. All patients taking 5-ASA medication were identified from a population of 300 000. The pathology database was studied to identify the patients on 5-ASA treatment and whether they had had renal function tests. RESULTS: 800 adult patients were identified taking 5-ASA therapy. 612 patients received 5-ASAs for 3 months or more, and these were included in the final analysis. 293 patients had no renal function checks while on treatment. 79 patients had renal function tests less than once every 4 years and 36 patients once every 2-4 years. 204 patients had renal function measurements in 50% or more of years of treatment, of whom 116 were checked every year. Some patients were started on treatment with abnormal results at baseline and some with identified kidney disease continued on their 5-ASAs. CONCLUSIONS: The majority of patients receiving 5-ASA compounds do not have regular renal function monitoring. Clinicians are failing to follow best practice guidelines. PMID- 28839792 TI - Experience of propofol sedation in a UK ERCP practice: lessons for service provision. AB - OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) in the UK has been historically performed under conscious sedation. However, given the increasing complexity of cases, the role of propofol-assisted ERCP (propERCP) is increasing. We describe our experience of propERCP and highlight the importance of this service. DESIGN: Our prospective ERCP database was interrogated between January 2013 and January 2014. Data collection included procedural information, patient demographics, American Association of Anaesthesiologists (ASA) status, Cotton grade of endoscopic difficulty and endoscopic and anaesthetic complications. Comparison was made with patients undergoing conscious sedation ERCP (sedERCP). RESULTS: 744 ERCPs were performed in 629 patients (53% male). 161 ERCPs were performed under propofol. PropERCP patients were younger compared with the sedERCP group (54 vs 66 years, p<0.0001) but ASA grade 1-2 status was similar (84% vs 78%, p=0.6). An increased number of Cotton grade 3-4 ERCPs were performed in the propERCP group (64% vs 34%, p<0.0001). Indications for propERCP included sphincter of Oddi manometry (27%), previously poorly tolerated sedERCP (26%), cholangioscopy (21%) and patient request (8%). 77% of cases were elective, 12% were urgent day-case transfers and 11% were urgent inpatients. 59% of cases were tertiary referrals. ERCP was completed successfully in 95% of cases. Anaesthetic and endoscopic complications were comparable between the two groups (5% and 7% vs 3% and 5%). Where sedERCP had been unsuccessful due to patient intolerance, the procedure was completed successfully using propofol. CONCLUSIONS: PropERCP is safe and is associated with high endoscopic success. The need for propERCP is likely to increase given patient preference and the high proportion of complex procedures being undertaken. All endoscopy units should look to incorporate propofol-assisted endoscopy into aspects of their services. PMID- 28839793 TI - IBD: reproductive health, pregnancy and lactation. AB - The peak incidence of inflammatory bowel diseases (IBD) occurs during the child bearing years, and so questions about fertility, pregnancy and breast feeding are often asked by patients. It is known that patients with IBD receive twice as much information about pregnancy-related issues from gastroenterologists as from any other source (including the internet). Therefore, the role of the gastroenterologist in correctly educating patients to avoid misconceptions is paramount, and this should be done proactively prior to planning pregnancy so that the patient's health and medications can be optimised. A clear understanding of medication safety during pregnancy and lactation will improve clinical management. PMID- 28839795 TI - National survey to determine current practices, training and attitudes towards advanced polypectomy in the UK. AB - OBJECTIVE: Developments in advanced polypectomy technique provide an alternative to surgery in the management of large and complex colorectal polyps. These endoscopic techniques require expertise and can potentially incur high complication rates. This survey evaluates current UK practice, attitudes and training in advanced polypectomy. DESIGN: Anonymous online questionnaire. SETTING: Colonoscopists within the UK were asked about their approach to large polyps (>2 cm). RESULTS: Among the 268 respondents (64% of whom were BCSP accredited), 86% were confident in removing lesions >2 cm by endoscopic mucosal resection (EMR). Of these, 27% were classed as low volume operators (<10 lesions resected/annum) and 14% as high volume operators (>50/annum). By comparison, only 3% currently performed endoscopic submucosal dissection (ESD). Referring one or more benign polyps for surgery a year was common among responders of all levels (11-68%). Training deficiencies were common: only 21% of responders had received a period of training dedicated to advanced polypectomy; 58% of responders would welcome a national training scheme and a majority supported the implementation of advanced polypectomy accreditation with national guidelines. However, while 41% wanted nominated regional EMR experts, only 18% would welcome an integrated national referral network for large/complex polyps. CONCLUSIONS: EMR is practised widely while ESD service provision is very limited. Most experienced colonoscopists are confident to perform piecemeal EMR, even if their training is suboptimal and annual numbers low. Practices and attitudes were variable, even among self-defined level 4 operators. Improving training and implementation of accreditation were welcomed, but there was little appetite for mandated referral to subspecialist 'experts' and national networks. PMID- 28839796 TI - Oesophageal stenting for benign and malignant strictures: a systematic approach. AB - Oesophageal stenting is now standard treatment for managing both benign and malignant stenosis of the oesophagus. There is a wide choice in oesophageal stents currently available on the market, with variations in the stent material, size and design. Most oesophageal stents are made from metal alloy compounds for use in malignant strictures, although there are stents made of durable polymers, and now of biodegradable (BD) material, for use in both benign and malignant strictures. With the development of self-expanding plastic stents, self-expanding metal stents and BD stents, stent placement for oesophageal pathologies can be safe and cost-effective. Oesophageal stenting has several challenges for a therapeutic endoscopist which is determined by the location of stricture or tumour, the anatomy of the stenosis and the nature of stent selected. Strictures that have narrow or tortuous lumens can be particularly difficult to stent as the luminal diameter must allow access of at least a 0.035 inch guide wire. This review covers the indications and outcomes of different stents in clinical situations to help rational decision-making. PMID- 28839797 TI - Barrett's oesophagus: how should we manage it? AB - Endoscopic surveillance remains the core management of non-dysplastic Barrett's oesophagus, although questions regarding its efficacy in reducing mortality from oesophageal adenocarcinoma have yet to be definitively answered, and randomised trial data are awaited. One of the main goals of current research is to achieve risk stratification, identifying those at high risk of progression. The recent British Society of Gastroenterology (BSG) guidelines on surveillance have taken a step in this direction with interval stratification on clinicopathological grounds. The majority of Barrett's oesophagus remains undiagnosed, and this has led to investigation of methods of screening for Barrett's oesophagus, ideally non-endoscopic methods capable of reliably identifying dysplasia. Chemoprevention to prevent progression is currently under investigation, and may become a key component of future treatment. The availability of effective endotherapy means that accurate identification of dysplasia is more important than ever. There is now evidence to support intervention with radiofrequency ablation (RFA) for low grade dysplasia (LGD), but recent data have emphasised the need for consensus pathology for LGD. Ablative treatment has become well established for high-grade dysplasia, and should be employed for flat lesions where there is no visible abnormality. Of the ablative modalities, RFA has the strongest evidence base. Endoscopic resection should be performed for all visible lesions, and is now the treatment of choice for T1a tumours. Targeting those with high-risk disease will, hopefully, lead to efficacious and cost-effective surveillance, and the trend towards earlier intervention to halt progression gives cause for optimism that this will ultimately result in fewer deaths from oesophageal adenocarcinoma. PMID- 28839798 TI - Assessment and management of the malignant colorectal polyp. AB - Colorectal cancer is the second most common cancer affecting men and women in England. The introduction of National Bowel Cancer Screening in 2006 has led to a rise in the proportion of colorectal cancers detected at an early stage. Many screen-detected cancers are malignant colorectal polyps and may potentially be cured with endoscopic resection, without recourse to the risk of major surgery or prolonged adjuvant therapies. Endoscopic decision making is crucial to select those early lesions that may be suitable for local endoscopic excision as well as identifying lesions for surgical resection, thus avoiding unnecessary surgical intervention in some and ensuring potentially curative surgery in others. This paper uses the current evidence base to provide a structured approach to the assessment of potentially malignant polyps and their management. http://group.bmj.com/products/journals/instructions-for-authors/licence-forms. PMID- 28839799 TI - Improving quality in endoscopy: are we nearly there yet? PMID- 28839800 TI - Practical aspects of delivering a small bowel endoscopy service in the UK. AB - Capsule endoscopy remains at the forefront of small bowel investigation, offering the only non-invasive means of directly imaging the mucosa of the small bowel. Recommended for the investigation of obscure gastrointestinal bleeding, Crohn's disease, coeliac disease, small bowel tumours and hereditary polyposis syndromes, the uptake of small bowel capsule endoscopy has been widespread in the UK. However, despite a wealth of published literature supporting the utility of capsule endoscopy in clinical practice, there are limited data regarding the actual practical aspects of service delivery, training and quality assurance. In this article, we attempt to address this by considering specific factors that contribute to provision of a high-quality capsule service. The role of formal training, accreditation and quality assurance measures is also discussed. PMID- 28839801 TI - ERCP cannulation success benchmarking: implications for certification and validation. AB - OBJECTIVE: Investigate success rates of cannulating a 'virgin' papilla during endoscopic retrograde cholangiopancreatography (ERCP) at a tertiary referral centre; determine reasons for failure and propose learnings for consideration in future revision of success benchmarking. DESIGN: Review of all ERCPs recorded on Endosoft database from 2006 to 2012 (n=1862). Specifically, 'virgin' papillae, defined as those with no evidence of prior surgical intervention, stents in situ or sphincterotomy (n=947). Virgin papillae present the most challenging target for endoscopists. SETTING: Gastroenterology department, St Thomas' Hospital, London. PATIENTS: All patients who underwent an ERCP recorded on Endosoft from 2006 to 2012 (n=1134). A proportion of these patients underwent repeat procedures, all considered virgin provided the aforementioned criteria were met. INTERVENTIONS: None, retrospective audit and benchmarking exercise. MAIN OUTCOME MEASURES: Determine criteria for successful cannulation of a virgin papilla. RESULTS: Overall success of cannulation of a virgin papilla at ERCP was 79.5%, 753 out of a total of 947 virgin papillae cases. Per patient with a virgin papilla, the success rate was 79.7%, 693 out of 869. Eliminating cases with features complicating cannulation increased success rates to 86% and 87%, respectively. Chronic pancreatitis was the single Indication associated with a failed cannulation (OR=3.9, CI 2.1 to 7.1), while biliary stones were significantly associated with a successful cannulation (OR=0.3, CI 0.2 to 0.4). Reasons for failure included patient agitation (OR=27.1, CI 7.9 to 92.7), duodenal stricturing (OR=12.5, CI 5.5 to 28.5), previous anatomy-changing surgery (OR=12.2, CI 3.3 to 45.4), tumour impingement (OR=9.5, CI 4.1 to 22.3) and equipment failure (OR=7.9, CI 1.4=43.5). CONCLUSIONS: The Joint Advisory Group's 80% success rate for completion of therapeutic intent must be viewed in light of published difficulty rating scales, if fair comparisons and standards are to be met. This highlights the need for standardised success criterion for ERCP training and accreditation. PMID- 28839802 TI - New and emerging endoscopic haemostasis techniques. AB - Endoscopic treatment has been accepted as first-line treatment of upper gastrointestinal bleeding, both for variceal as well as for non-variceal haemorrhage. Dual modality treatment including injection therapy with mechanical or thermal haemostatic techniques has shown superior outcome compared with injection monotherapy in non-variceal bleeding. During recent years, new endoscopic devices have been developed and existing endoscopic techniques have been adapted to facilitate primary control of bleeding or achieve haemostasis in refractory haemorrhage. For mechanical haemostasis, larger, rotatable and repositionable clips have been developed; multiple-preloaded clips are also available now. Over the scope clips allow to ligate larger vessels and can close ulcer defects up to 20 mm. Topical, easily applied substances withdraw fluid from the blood and thereby initiate blood clotting. This can be helpful in diffuse oozing bleeding, for example, from tumour or hypertensive gastropathy and has also shown promising results in variceal and arterial bleeding as bridging before definitive treatment is available. Radiofrequency ablation and multiband ligation have emerged as new tools in the endoscopic management of gastric antral vascular ectasia. In acute refractory variceal bleeding, a covered and removable oesophagus stent can provide tamponade and gain time for transport to an interventional endoscopic centre or for radiological intervention such as TIPS. PMID- 28839805 TI - Are we exposing patients with a mildly elevated faecal calprotectin to unnecessary investigations? AB - OBJECTIVE: Faecal calprotectin (FC) is a non-invasive marker used to differentiate irritable bowel syndrome from inflammatory bowel disease (IBD). However, false positives are common. We sought to determine the diagnostic yield of investigation in patients presenting with new lower gastrointestinal (GI) symptoms and a mildly elevated FC (100-200 ug/g). DESIGN: Retrospective study of electronic patient records. PATIENTS: Patients aged 16-50 years with new lower GI symptoms and an FC 100-200 ug/g were identified from our biochemistry laboratory database between September 2009 and 2011. Patients were excluded if they had a previous FC >200 ug/g, were taking non-steroidal anti-inflammatory drugs (NSAIDs), had IBD, positive stool cultures or 'alarm' symptoms. SETTING: Secondary care gastroenterology clinics. RESULTS: 161 patients (103 female patients) were identified. Mean age was 37.3 years with a mean FC of 147 ug/g. 398 endoscopic, radiological and histological investigations were undertaken in 141 patients (an average of 2.8 investigations per patient). 131 colonoscopies were performed with abnormalities in only 24 (18.3%). In patients with a macroscopically normal upper GI endoscopy and colonoscopy, the diagnostic yield of any further investigation was only 7.3%. The negative predictive value (NPV) of an FC 100-200 ug/g was 86.7% for any pathology and 97.5% for significant luminal pathology (IBD, advanced adenoma or colorectal carcinoma). After a mean follow-up of 172.4 weeks, IBD was the final diagnosis in only 4 (2.5%) of patients. CONCLUSIONS: In adult patients under 50 years old presenting with new lower GI symptoms, the NPV of an FC between 100 and 200 ug/g in excluding significant organic GI disease is high. PMID- 28839806 TI - Development and validation of a new disease severity index: the Inflammatory Bowel Disease Index (IBDEX). AB - OBJECTIVE: To develop, validate and apply a generic clinical severity index applicable to all adult patients with inflammatory bowel disease (IBD). DESIGN: A review of the literature and an expert focus group consultation were carried out in order to draw out relevant items from existing literature. The new index was called the IBD Index (IBDEX). Standard psychometric analysis was carried out. The construct validity was assessed against biochemical markers, clinical and endoscopic indices. The new index was completed again within 6 weeks to check responsiveness and reproducibility. RESULTS: IBDEX was used to assess 255 adult patients with IBD (125 with Crohn's disease and 130 with ulcerative colitis), and 64 patients were re-evaluated within 6 weeks. It had good internal consistency (Cronbach's alpha=0.79) and correlated very well with the Harvey Bradshaw Index (r=0.94), the Simple Clinical Colitis Activity Index (r=0.92), the Mayo Clinic Index (r=0.87) and the Simple Endoscopic Score (r=0.76), all with p values <0.05. IBDEX had a moderate but positive correlation with C reactive protein (r=0.51) and erythrocyte sedimentation rate (r=0.36) p values both <0.05. The test-retest reliability was good (intraclass correlation coefficient 0.97) and responsiveness ratio was 2.27. CONCLUSIONS: IBDEX is the first properly validated Clinical Disease Severity Index in IBD. Our results showed that it is valid, reliable and reproducible and has the potential to be used in clinical practice. PMID- 28839807 TI - A UK cost of care model for inflammatory bowel disease. AB - OBJECTIVES: There are an estimated 620 000 patients with inflammatory bowel disease (IBD) in the UK. The rising incidence of IBD combined with its incurability has significant cost implications. The aim of this cost of care model was to calculate the annual cost per adult patient of treating ulcerative colitis (UC) and Crohn's disease (CD) from a NHS perspective, and to enable areas of potential cost savings to be explored. DESIGN: The cost of IBD was calculated by summing the costs of treatment, treatment side effects and disease-related complications, accounting for the proportions of patients incurring these costs. Default input values for costs, the percentage of patients receiving each treatment, and the percentage of patients experiencing treatment-related side effects or disease-related complications were determined from national sources and published literature. However, the model permitted the user to input local or alternative data. SETTING: The model was designed to be used by NHS trusts in the UK. RESULTS: Using default input values, the annual cost of treating any patient with UC was estimated to be L3084. For a patient with UC in remission, in relapse with mild-to-moderate UC or in relapse with severe UC, annual cost per patient was estimated to be L1693, L2903 and L10 760, respectively. The annual cost for any patient with CD was estimated to be L6156 (L1800 for patients in remission; L10 513 for patients in relapse). CONCLUSIONS: While IBD remains a costly condition with modest potential cost savings, this model facilitates calculation of annual costs per patient with UC and CD, and its customisability will help hospitals identify areas where savings could be made. PMID- 28839808 TI - The Great Pretender: early syphilis mimicking acute sclerosing cholangitis. AB - A 36-year old man with known HIV infection presented to an outpatient genitourinary service with jaundice, rash and sore throat. Investigations revealed marked biochemical abnormalities, including alkaline phosphatase and alanine transaminase >10 times the upper limit of normal. Liver ultrasound was normal, but stricturing and beading of the intrahepatic biliary tree was seen on magnetic resonance cholangiopancreatography (MRCP), similar to changes associated with sclerosing cholangitis. Serological syphilis antibodies were detected with a positive immunoglobulin M (IgM) and rapid plasma reagin of 1:128, in keeping with early infection. Liver biopsy showed large bile duct obstruction with portal oedema, bilirubinostasis and neutrophil polymorph infiltration around proliferating ductules; specific stains for spirochaetes were negative. Symptoms and biochemical markers improved rapidly after treatment for secondary syphilis with oral steroids and intramuscular benzathine penicillin. A repeat MRCP 18 months post syphilis treatment showed resolution. This case illustrates syphilis presenting as acute sclerosing cholangitis. PMID- 28839809 TI - Improving quality in a national intestinal failure unit: greater efficiency, improved access and reduced mortality. AB - PROBLEM: In 2010, there was a significant waiting list for admission to the intestinal failure unit (IFU) at the Salford Royal National Health Service (NHS) Foundation Trust. There had been a steady increase in the number of new patients referred to the IFU (89 patients 2005; 152 patients 2012) and the number of established patients requiring home parenteral nutrition (HPN) (135 patients 2005; 206 patients 2012) over the last decade. The impact of the resulting long waiting list for these complex patients was that patient deaths occurred in those awaiting admission. DESIGN: Continuous improvement methodology using the model for improvement and sequential plan-do-study-act cycles. SETTING: Salford Royal NHS Foundation Trust IFU; a large NHS teaching hospital in Northwest England. KEY MEASURES FOR IMPROVEMENT: The primary outcome measures were inpatient length of stay and time spent on waiting list prior to admission. STRATEGIES FOR CHANGE: A continuous improvement programme, supported by a project manager. RESULTS: There has been a 21% reduction in average length of stay on the IFU from 55.7 to 44.0 days and a reduction of 72% in the average length of time new patients spent on the waiting list for admission from 65.7 to 18.5 days. These changes were associated with concomitant reduction in 30-day readmission rate from 12.1% to 4.5% and early suggestions of reduced inpatient and waiting list mortality. CONCLUSIONS: It is possible to improve the efficiency of a large national service for complex patients using quality improvement methodology, resulting in improved access and reduced waiting list mortality. PMID- 28839810 TI - Observed high incidence of buried bumper syndrome associated with Freka PEG tubes. AB - BACKGROUND: Buried bumper syndrome (BBS) is an uncommon but significant complication of percutaneous endoscopic gastrostomy (PEG), which occurs due to overgrowth of gastric mucosa over the inner bumper of the gastrostomy tube. A high incidence of BBS was observed in patients with Freka PEG tubes. OBJECTIVE: To review case numbers of BBS and confirm the observed association with Freka tubes to determine whether change of practice should be considered. DESIGN: Data was collected on the number of cases of BBS reported to the community nutrition team Birmingham, UK. Data on type of PEG kit and total number of PEGs inserted between 2009 and 2013 were collected. The electronic endoscopy reporting database was used to compare case numbers of BBS in our Trust in years when Corflo and Freka PEG tubes were used, respectively. Data from our Trust were also compared with that from a Trust using Corflo only. RESULTS: Fifty-eight cases of BBS were reported in the area covered by the Birmingham community nutrition team between 2009 and 2013, all of which were associated with Freka PEG tubes. An estimated 1000-1200 PEGs were inserted during this period, representing an incidence of BBS of 4.8-5.8%. No cases of BBS occurred over the same period in the comparison Trust (451 Corflo PEGs inserted). CONCLUSIONS: Our review confirmed our observation of an increased risk of BBS with Freka PEG tubes. Clinicians should be aware of our findings when deciding which brand of PEG tube to insert, particularly in patients with a previous history of BBS. PMID- 28839811 TI - Endoscopic management of peripancreatic fluid collections. AB - Peripancreatic fluid collections are a well-known complication of pancreatitis and can vary from fluid-filled collections to entirely necrotic collections. Although most of the fluid-filled pseudocysts tend to resolve spontaneously with conservative management, intervention is necessary in symptomatic patients. Open surgery has been the traditional treatment modality of choice though endoscopic, laparoscopic and transcutaneous techniques offer alternative drainage approaches. During the last decade, improvement in endoscopic ultrasound technology has enabled real-time access and drainage of fluid collections that were previously not amenable to blind transmural drainage. This has initiated a trend towards use of this modality for treatment of pseudocysts. In this review, we have summarised the existing evidence for endoscopic drainage of peripancreatic fluid collections from published studies. PMID- 28839812 TI - Managing a patient with burning mouth syndrome. AB - A 64-year-old woman presented with an increasing frequency of symptoms of heartburn and retrosternal pain over the last few months, and a constant and intense burning pain affecting her tongue tip, mouth and lips for the past 5 years. She found consuming hot drinks exacerbated the burning oral pain and chewing gum seemed to alleviate some of her symptoms. She thought these oral sensations were caused by frequently licking her finger tips to separate prints in her work in publishing. She had been previously diagnosed with gastro oesophageal reflux disease (GORD), and her heartburn symptoms had been controlled until recently with lansoprazole 15 mg daily. Her past medical history included irritable bowel syndrome and depression, for which she had been treated with mebeverine and paroxetine for a number of years. She was a non-smoker and did not consume alcohol. Clinical examination was unremarkable with no oral lesions on examination. Her routine laboratory tests, including autoimmune serology, haematinics and thyroid function tests were all within normal limits. She underwent a gastroscopy, which revealed moderate reflux oesophagitis, and following commencing omeprazole 20 mg twice daily, her heartburn resolved. However, her oral burning symptoms were not affected and a diagnosis of burning mouth syndrome (BMS) was made. Following explanation and reassurance concerning the cause of her BMS symptoms, she chose not to receive treatment for this but to access cognitive behavioural therapy in the future if her symptoms worsened. PMID- 28839813 TI - Safe sedation practices among gastroenterology registrars: do we need more training? AB - Endoscopy training is a central component of gastroenterology training for the vast majority of UK trainees, and integral to this is the practice of safe sedation. The majority of endoscopic procedures are performed with the patient under conscious sedation with a benzodiazepine, often combined with an opioid. Little data exists on the practice of sedation among gastroenterology trainees, including their degree of knowledge of the common sedation agents used and their actions. Using both an online and paper-based questionnaire, we surveyed current gastroenterology speciality trainees (ST) in the UK and received 78 responses giving a response rate of 10%. Fifty-one per cent of the trainees did not receive structured training in safe sedation, despite national guidelines advising this to be an essential part of the training programme, and 92% felt a structured sedation course would be beneficial. We also identified some gaps in trainees' knowledge of the action of sedation agents. We propose that a formal training session in sedation or an e-learning module could be incorporated as part of a deanery or trust induction for gastroenterology trainees and kept under regular review. PMID- 28839815 TI - Probiotics for secondary prevention of hepatic encephalopathy. PMID- 28839816 TI - Systematic analysis of missed colorectal cancer cases and common pitfalls in diagnosis. AB - BACKGROUND: Missed colorectal cancer on endoscopic or radiological investigations may delay diagnosis and impact outcome. This study audits incidence of previous investigations in patients with colorectal cancer, considers outcome in 'missed' cancer cases and examines the diagnostic pathway in the derived case series to identify common pitfalls in diagnosis. METHODS: Patients diagnosed with colorectal cancer in 2011 at a single National Health Service (NHS) Trust were reviewed. Incidence of endoscopic and radiological investigations in the 3 years preceding diagnosis and outcome data were collected. Cases of prior investigation not leading to diagnosis were considered 'missed' cancers and survival compared with 'detected' cases. The diagnostic pathway in each 'missed' case was reviewed. RESULTS: 395 colorectal cancer cases were studied. Eighteen (4.6%) patients underwent previous investigation including colonoscopy (n=4), flexible sigmoidoscopy (n=5), barium enema (n=5) and diagnostic abdominal CT scan (n=12), median 708 days prior to diagnosis. Previous investigation predicted reduced overall and disease-free survival (HR 2.07, p=0.04 and HR 2.66, p<0.0001), after age and gender adjustment. Ten different categories termed 'pitfalls' were derived from analysis of the diagnostic pathway. These included CT scanning for abdominal pain without further investigation (n=7), rectosigmoid cancer following a previous diagnosis of diverticular disease (n=4) and incomplete diagnostic investigations without adequate follow-up (n=3). CONCLUSIONS: A proportion of patients diagnosed with colorectal cancer have previously been investigated for gastrointestinal symptoms and survival appears reduced in these patients. Regular audit and analysis of previous investigations can identify common pitfalls in diagnosis, which should be used to inform training and improve practice. PMID- 28839817 TI - Managing acute severe ulcerative colitis in the hosptialised setting. AB - Ulcerative colitis affects approximately 146 000 people in the UK and is the most common form of inflammatory bowel disease. The majority of patients will have uncomplicated disease, but around 1 in 10 patients will develop acute severe colitis. Despite modern medical management, colectomy rates of 27% and mortality rates of 1% are still reported. Good supportive care and intravenous corticosteroids remain the mainstay of treatment, but up to one-third of patents will not respond. The Travis criteria allow early recognition of those patients failing to improve by day 3, allowing timely planning of medical rescue therapy or surgery. Rescue therapy with either infliximab or ciclosporin appears equally efficacious. Patients naive to thiopurines seem to have better colectomy-free survival rates following rescue therapy than those previously exposed. We review the published evidence behind the conventional management of acute severe ulcerative colitis. PMID- 28839818 TI - Burden of irritable bowel syndrome in an increasingly cost-aware National Health Service. AB - BACKGROUND: The National Health Service (NHS) is faced with increasing cost pressures that make the efficient use of resources paramount. Irritable bowel syndrome (IBS) places a large burden on the NHS as it has been estimated that at least 12% of the UK population is affected. However, poor clinical coding makes accurate assessment of this burden challenging. OBJECTIVE: To calculate primary care prescribing and both hospital outpatient and admission costs associated with the management of IBS in England. DESIGN AND MAIN OUTCOME MEASURES: Hospital Episode Statistics data for 2012-2013 for all clinical commissioning groups in England were analysed to calculate the tariff cost of IBS. Prescribing analysis and cost tabulation (PACT) data for this period were also analysed. RESULTS: In 2012-2013, there were 1 219 961 outpatient attendances in gastroenterology and colorectal surgery specialties. Despite this, only 1982 patients were recorded with IBS-specific codes, with a total estimated tariff cost of L812 336. In addition, 28 849 patients were recorded with IBS-related symptom codes at a cost of L11 002 874. In 2011-2012, there were 658 698 diagnostic lower gastrointestinal endoscopies at a tariff cost of L16 967 670 4. Of these, 323 752 (49%) had no further follow-up in secondary care over the subsequent 12 months. PACT data indicated that L44 977 959 and L25 582 752, respectively, were spent on selected laxatives and antispasmodics commonly used to treat IBS in primary care. CONCLUSIONS: Better diagnosing, through improved clinical coding and standardisation of diagnostic criteria, is required to more accurately assess the true burden and allow optimal management of IBS. PMID- 28839819 TI - Safety and efficacy of long-term nasobiliary drainage to treat intractable pruritus in cholestatic liver disease. AB - INTRODUCTION: Cholestasis related pruritus, secondary to intrahepatic and/or extrahepatic biliary obstruction is a common manifestation in chronic liver disease. Pruritus is difficult to treat, and results are often suboptimal. A stepwise medical approach is usually employed, followed by a trial molecular adsorbents recirculation system in medication resistant cases. Pruritus resulting in reduced quality of life is a variant syndrome eligible for liver transplantation in the setting of preserved synthetic function. AIM: This case series describes the use of long-term (LT) nasobiliary drainage (NBD) in three patients with intractable pruritus. This case series tests the hypothesis that LT NBD could be successfully used to alleviate cholestasis related pruritus, and prevent or delay the need for liver transplantation. METHOD: LT-NBD was carried out in three female patients (mean age 43 years) with intractable pruritus secondary to primary biliary cirrhosis (PBC) (n=2), and benign recurrent intrahepatic cholestasis (n=1). NBD was carried out through the endoscopic placement of a 6 French Cook Medical nasobiliary catheter into the common bile duct. RESULTS: Symptomatic relief of pruritus was described by all three cases within 24 h of NBD placement. LT-NBD was stopped in the patient with benign recurrent intrahepatic cholestasis after 8 weeks due to complete resolution of pruritus. In one patient with PBC, LT-NBD was undertaken over 12 months, with complete resolution of pruritus. In the second patient with PBC, LT-NBD was carried out over 14 months, with complete resolution of pruritus. DISCUSSION: This case series supports the efficacy of LT-NBD in the treatment of intractable pruritus. We propose that NBD offers an accessible modality for the treatment of intractable pruritus in liver disease, potentially avoiding the need for liver transplantation. PMID- 28839821 TI - Biosimilars: what's around the corner? PMID- 28839820 TI - Statin therapy in patients with cirrhosis. AB - Cardiovascular disease is one of the leading causes of death among patients with cirrhosis and following liver transplantation. Although 3-hydroxy-3-methyl glutaryl-CoA reductase inhibitors ('statins') reduce the risk of cardiovascular events, fears about hepatotoxicity have historically led to underuse in patients with liver disease. In addition, the pharmacokinetics of statins can be significantly altered in cirrhosis, creating challenges with their use in liver disease. However, emerging data from randomised controlled trials and observational studies suggest that statin therapy appears to be safe and effective in patients with chronic liver disease and compensated cirrhosis. The cardiovascular risk benefits as well as the potential pleiotropic benefits of statins warrants strong consideration of use of statin therapy in patients with cirrhosis. PMID- 28839822 TI - A guide to midgut neuroendocrine tumours (NETs) and carcinoid syndrome. AB - Patients with midgut neuroendocrine tumours or carcinoid syndrome often face a delayed diagnosis. This article aims to highlight the different ways in which patients with midgut neuroendocrine tumours (NETs) present, the diagnostic approach to them, the current methods of management available and future considerations. PMID- 28839823 TI - The 2016 Dr Falk pharma UK/core awards are open for applications. PMID- 28839825 TI - Defining the optimal design of the inflammatory bowel disease multidisciplinary team: results from a multicentre qualitative expert-based study. AB - OBJECTIVE: To elicit expert views to define the aims, optimal design, format and function of an inflammatory bowel disease (IBD) multidisciplinary team (MDT) with the overall purpose of enhancing the quality of MDT-driven care within an IBD service provision. DESIGN: This study was a multicentre, prospective, qualitative study using a standard semistructured interview methodology. PARTICIPANTS: A multidisciplinary sample of 28 semistructured interviews of which there are six consultant colorectal surgeons, six IBD nurse specialists, seven consultant gastroenterologists, five consultant radiologists and four consultant histopathologists. SETTING: Participants were recruited from 10 hospitals, which were a mixture of community hospitals and specialist IBD centres between June and October 2013. RESULTS: Experts argued that the main goal of MDT-driven IBD care is to improve patient outcomes via sharing collective expertise in a formalised manner. Themes regarding the necessary requirements for an IBD MDT to occur included good attendance, proactive contribution, a need to define core members and appropriate and functional computer facilities. Emergent themes regarding the logistics of an effective IBD MDT included an eligibility criterion for case selection and discussion and appropriate scheduling. Themes regarding the overall design of the IBD MDT included a 'hub-and-spoke' model versus a 'single-centre' model. CONCLUSIONS: Defining key elements for an optimal design format for the IBD MDT is necessary to ensure quality of care and reduce variation in care standards. This study has produced a set of expert-based standards that can be used to structure the IBD MDT. These standards now require larger scale validation and consensus prior to becoming a practical guideline for the management of IBD care. PMID- 28839824 TI - Low dose thiopurine and allopurinol co-therapy results in significant cost savings at a district general hospital. AB - BACKGROUND: Thiopurines are widely used for maintenance of remission in Crohn's disease (CD). Published data report >50% of patients stop thiopurines due to therapeutic failure, hepatitis or side effects. In this situation, many UK clinicians start biologics in CD patients. This has significant cost implications. An alternative strategy is low dose thiopurine and allopurinol (LDTA) co-therapy. We report the annual cost savings from adopting this strategy at our centre. METHODS: Patients with CD treated with LDTA in preference to biological therapy were identified using a prospective local inflammatory bowel disease database. The annual drug cost of treatment with LDTA compared with biologic therapy was calculated. Cost of attending the day unit for an infusion was not included. RESULTS: 26 patients with CD who failed standard dose thiopurine and were treated with LDTA were identified over a 12-month period and followed up for 1 year. 12 patients failed LDTA and progressed to biological therapy. The remaining 14 patients entered sustained clinical remission on LDTA. The cost savings achieved using the LDTA strategy in this group of patients was L146 413 per year with an average saving of L10 458 per patient per year. CONCLUSIONS: This study has identified a significant annual cost savings with this treatment strategy through the prevention of escalation to biologics. These cost savings are likely to be even more significant in the long term since a significant proportion of patients treated with biological therapy require dose escalation. We believe adopting this strategy more widely could lead to significant healthcare savings. PMID- 28839826 TI - Percutaneous endoscopic gastrostomy (PEG): cui bono? PMID- 28839828 TI - Transoral oesophagogastric fundoplication is effective in treating proton pump inhibitor-resistant regurgitation. PMID- 28839829 TI - Palliative care for cirrhosis: a UK survey of health professionals' perceptions, current practice and future needs. AB - OBJECTIVE: To determine the knowledge and practice patterns of a UK cohort of relevant healthcare professionals (HCPs) about delivering palliative care in cirrhosis, and to inform priorities for future research. DESIGN: An on-line questionnaire survey with closed and open responses. SETTING: HCPs identified from the mailing list of special interest groups in hepatology and gastroenterology (liver), general practice and specialist palliative care (SPC) across the UK. RESULTS: Of the 6181 potential contacts identified, 517 HCPs responded. Most believed a role exists for SPC in caring for people with cirrhosis, but many SPC HCPs felt ill prepared to provide good care to those facing death. Further training was needed in managing liver-related symptoms, symptom control and end of life issues. All HCP groups wished to increase community provision of palliative care support, but many general practitioners felt unable to manage advanced cirrhosis in the community. There were differences in the optimal trigger for SPC referral with liver HCPs less likely to refer at symptom deterioration. Prognostication, symptom management and service configuration were key areas identified for future research. CONCLUSIONS: All who responded acknowledged the role of SPC in caring for those dying with cirrhosis and need for further training to improve confidence and enable joint working between SPC, general practice and liver teams. Low response rates make it difficult to generalise these findings, which require further validation. PMID- 28839830 TI - Do critically ill liver patients experience negative bias? A web-based survey examining doctors opinions to critical care escalation. AB - OBJECTIVE: To test the hypothesis that there is negative bias towards escalating levels of care in decompensated cirrhosis, compared with other patient groups. DESIGN: An electronic survey containing eight acute clinical scenarios with equivalent physiological derangement, in which respondents were asked to score the degree to which they would advocate for intensive care unit admission on a scale of 1-10. Scenarios included respiratory, haematology, vascular, renal, gastrointestinal, postoperative and hepatological conditions. Follow-up questions examined the reasons why the patient should or should not be transferred, and enquired about ceilings of care, end-of-life decisions, degree of organ support and healthcare financial rationing. 273 doctors responded. SETTING: Secondary care hospitals in south of England. PATIENTS: None involved. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Advocacy score (1-10) and subsidiary responses. RESULTS: The hepatology patient ranked 4th of 8 with a mean advocacy score of 7.2. There were no significant differences between intensivists and physicians or between grades of seniority. Of those less likely to escalate (score 1-5, n=42), the reasons given were based on unsurvivability or excessive burden of treatment rather than aetiology. One-fifth cited 'lifestyle decision'. 25 (62.5%) respondents not favouring escalation would make the patient DNACPR, 17 (42.5%) would stipulate ward-based care only and a small minority would instigate active palliation. Of those favouring escalation (advocacy score 6-10), 70% (n=122) would consider unlimited organ support. Fifty-four (29.5% of those who answered) said they 'sometimes' or 'frequently' consider resource allocation when making decisions about escalation of care. CONCLUSIONS: When compared with a variety of acute medical scenarios, doctors did not overly appear to exhibit therapeutic nihilism for patients with decompensated liver disease; however, significant variation in interpretation of the data and management approaches was identified. PMID- 28839831 TI - The new treatment paradigm for Barrett's dysplasia. PMID- 28839832 TI - Upper gastrointestinal haemorrhage: an update. AB - Upper gastrointestinal (GI) haemorrhage is a common cause for admission to hospital and is associated with a mortality of around 10%. Prompt assessment and resuscitation are vital, as are risk stratification of the severity of bleeding, early involvement of the multidisciplinary team and timely access to endoscopy, preferably within 24 h. The majority of bleeds are due to peptic ulcers for which Helicobacter pylori and non-steroidal anti-inflammatory agents are the main risk factors. Although proton pump inhibitors (PPIs) are widely used before endoscopy, this is controversial. Pre-endoscopic risk stratification with the Glasgow Blatchford score is recommended as is the use of the Rockall score postendoscopy. Endoscopic therapy, with at least two haemostatic modalities, remains the mainstay of treating high-risk lesions and reduces rebleeding rates and mortality. High-dose PPI therapy after endoscopic haemostasis also reduces rebleeding rates and mortality. Variceal oesophageal haemorrhage is associated with a higher rebleeding rate and risk of death. Antibiotics and vasopressin analogues are advised in suspected variceal bleeding; however, endoscopic variceal band ligation remains the haemostatic treatment of choice. Balloon tamponade remains useful in the presence of torrential variceal haemorrhage or when endoscopy fails to secure haemostasis, and can be a bridge to further endoscopic attempts or placement of a transjugular intrahepatic portosystemic shunt. This review aims to provide an update on the latest evidence-based recommendations for the management of acute upper GI haemorrhage. PMID- 28839833 TI - How does tolerability of double balloon enteroscopy compare to other forms of endoscopy? AB - BACKGROUND AND AIMS: Gastrointestinal endoscopy can be difficult for patients to tolerate. Studies on endoscopic tolerability mainly focus on gastroscopy or colonoscopy with a paucity of data on double balloon enteroscopy (DBE). We aimed to prospectively evaluate tolerability in patients undergoing several forms of endoscopy including DBE. METHODS: Consecutive patients undergoing colonoscopy, flexible sigmoidoscopy, gastroscopy, endoscopic retrograde pancreatography (ERCP), capsule endoscopy (CE) and DBE were prospectively recruited. A questionnaire recorded demographics, procedural data, patient tolerability (pain, discomfort and distress recorded on numerical rating scales) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: 956 patients were recruited (512 women; median age 57 years). The median pain score for DBE was poor with a score of 5 compared with 1 and 0 for oesophagogastroduodenoscopy and ERCP, respectively (p<0.001). Colonoscopy and retrograde DBE scores were not dissimilar. CE was well tolerated with a median pain score of 0. Patients with DBE required significantly higher doses of sedation and analgesia than other patients. The HADS Anxiety Score was also associated with poorer tolerability. CONCLUSIONS: DBE is poorly tolerated when compared with other forms of endoscopy despite higher doses of sedation. Increasing demand to improve tolerability of DBE in the UK may be addressed with the use of propofol. PMID- 28839834 TI - Laparoscopy-assisted ERCP (LA-ERCP) following bariatric gastric bypass surgery: initial experience of a single UK centre. AB - BACKGROUND: Bariatric gastric bypass surgery is being increasingly performed, but endoscopic retrograde cholangiopancreatography (ERCP) in these patients poses a unique challenge because of a lack of per-oral access to the stomach. Small series suggest a higher technical success rate using laparoscopy-assisted ERCP (LA-ERCP) than with an enteroscopic approach via the Roux-en-Y anastomosis. We present initial experience of LA-ERCP in our unit. DESIGN: Retrospective case series of consecutive patients undergoing LA-ERCP in our unit between September 2011 and July 2014. Data was retrieved from electronic, clinical and endoscopy records. RESULTS: Seven LA-ERCPs were performed. All seven patients were female, with median age 44 years (range 36-71). Indications included symptomatic bile duct stones (5/7), benign papillary fibrosis (1/7) and retained biliary stent (1/7). 5/7 (71%) patients had had a prior cholecystectomy. To facilitate LA-ERCP, laparoscopic gastrostomy ports were created in all patients. Duodenal access, biliary cannulation and completion of therapeutic aim were achieved in all patients. 6/7 (86%) patients required endoscopic sphincterotomy. The median duration of procedures was 94 min (range 70-135). Median postoperative length of stay was 2 days (range 1-9). One patient developed mild postprocedural acute pancreatitis, and another patient developed a mild port-site infection. Otherwise, no procedure-related complications were seen. All patients remained well on follow-up (median 14 months (range 1-35) from date of ERCP), with no evidence of further biliary symptoms. CONCLUSIONS: Our early experience of LA ERCP is that it is safe and effective. The technique may require particular consideration, as bariatric surgery is increasingly performed, in a patient group at significant risk of bile duct stones. PMID- 28839835 TI - Travel health and pretravel preparation in the patient with inflammatory bowel disease. AB - BACKGROUND AND AIMS: Foreign travel for people with inflammatory bowel disease (IBD) carries an increased risk of travel-related morbidity. There is limited research looking specifically at travel-associated health risks and travel preparation in patients with IBD. The aims of this study are to explore the experience of travel, pretravel preparation undertaken by the patient with IBD and examine IBD healthcare professionals' (HCP) confidence at providing travel advice and the content of that advice. METHODS: A survey of patients with IBD attending an outpatient clinic with a separate online survey sent to IBD HCPs recruited using regional and international network databases. RESULTS: A total of 132 patients with IBD, Crohn's disease (67/132, 51%), male (60/132, 45%) and 128 HCPs (IBD nurse specialist 113, 88%; IBD physician 15, 12%) completed the questionnaires. IBD affected travel to some extent in 62% (82/132) of patients, and 64% (84/132) had experienced an IBD flare, of whom 64% still travelled overseas during this time. Only 23% (31/132) travellers sought pretravel medical advice and 40% (53/132) obtained travel insurance. Forty-eight per cent of respondents on immunomodulator therapy were unaware of the need to avoid live vaccines. Twenty-seven per cent (34/128) of IBD HCPs are not confident at providing pretravel advice; vaccination advice (54%), obtaining travel insurance (61%) and healthcare abroad (78%) are the areas of most uncertainty. CONCLUSIONS: Patients do not seek adequate pretravel advice and consultations for those who do are often deficient. The majority of IBD professionals are not confident to provide comprehensive travel advice. Greater IBD-specific travel education and awareness is needed for both patients with IBD and professionals. PMID- 28839836 TI - The 2016 Dr Falk pharma UK/core awards are open for applications. PMID- 28839838 TI - Technology-enhanced learning in gastroenterology. PMID- 28839837 TI - Changing trends in the UK management of upper GI bleeding: is there evidence of reduced UK training experience? AB - OBJECTIVE: The aim of this study was to evaluate UK trainee experience in endoscopy for acute upper gastrointestinal bleeding (AUGIB). METHODS: Data was prospectively collected from all patients presenting to South Yorkshire Hospitals with AUGIB from September 2011 to December 2011 and compared with data from 1996. Concurrently, all gastroenterology trainees registered with the British Society of Gastroenterology were invited to respond to a web-based questionnaire regarding their experience in AUGIB management. RESULTS: 77% (589/766) of the patient cohort underwent endoscopy for AUGIB; 15% (90/589) were performed by trainees. 7.2% (9/125) of the out of hours endoscopy case load was performed by trainees; all were low-risk or medium-risk cases (pre-endoscopy Rockall score <=4). During the study period, dual therapy was delivered by a trainee on only four occasions. Comparison with the 1996 cohort demonstrated a marked reduction in the number of trainee performed endoscopies (76% vs 15%; p<0.001). Questionnaires were returned by 51% (245/478) of British Society of Gastroenterology trainees. 81% (198/245) thought that <10% of the gastroscopies they had performed involved therapeutic intervention. 23% (57/245) felt they would not be competent in AUGIB endoscopy by completion of specialty training. CONCLUSIONS: This study demonstrates the decline over time in trainee experience in AUGIB endoscopy. It also highlights a lack of trainee exposure to more challenging cases, out of hours endoscopy and therapeutic procedures. Furthermore, trainees are concerned that a level of competency may not be attained during specialty training. We advocate reviewing UK endoscopic training provision for AUGIB to ensure that experienced endoscopists are produced to meet future service needs. PMID- 28839840 TI - Pentoxifylline is ineffective in treating severe alcoholic hepatitis. PMID- 28839841 TI - Risk assessment in acute non-variceal upper GI bleeding: the AIMS65 score in comparison with the Glasgow-Blatchford score in a Scottish population. AB - INTRODUCTION: The early use of risk stratification scores is recommended for patients presenting with acute non-variceal upper gastrointestinal (GI) bleeds (ANVGIB). AIMS65 is a novel, recently derived scoring system, which has been proposed as an alternative to the more established Glasgow-Blatchford score (GBS). OBJECTIVE: To validate the AIMS65 scoring system in a predominantly Caucasian population from Scotland and compare it with the GBS. DESIGN: Retrospective study of patients presenting to a district general hospital in Scotland with a suspected diagnosis of ANVGIB who underwent inpatient upper GI endoscopy between March 2008 and March 2013. OUTCOMES: The primary outcome measure was 30-day mortality. Secondary outcome measures were requirement for endoscopic intervention, endoscopy refractory bleeding, blood transfusion, rebleeding and admission to high dependency unit (HDU) and intensive care unit (ICU). The area under the receiver operating characteristic (AUROC) curve was calculated for each score. RESULTS: 328 patients were included. Of these 65.9% (n=216) were men and 34.1% (n=112) women. The mean age was 65.2 years and 30-day mortality 5.2%. AIMS65 was superior to the GBS in predicting mortality, with an AUROC of 0.87 versus 0.70 (p<0.05). The GBS was superior for blood transfusion (AUROC 0.84 vs 0.62, p<0.05) and admission to HDU (AUROC 0.73 vs 0.62, p<0.05). There were no significant differences between the scores with respect to requirement for endoscopic intervention, endoscopy refractory bleeding, rebleeding and admission to ICU. CONCLUSIONS: AIMS65 accurately predicted mortality in a Scottish population of patients with ANVGIB. Large prospective studies are now required to establish the exact role of AIMS65 in triaging patients with ANVGIB. PMID- 28839842 TI - EndoLive UK 2015: introducing the best of UK endoscopy to the world. AB - The inaugural EndoLive UK held in the International Convention Centre (ICC) Birmingham on the 12-13 March 2015 was a watershed moment for UK endoscopy and for the British Society of Gastroenterology (BSG). The event provided the perfect platform to demonstrate how the UK is delivering some of the highest quality endoscopic practice, training and research in the world. Organised by UK endoscopy experts and supported by internationally renowned endoscopists such as Professors Paul Fockens, Douglas Rex and Peter Siersema, EndoLive UK pushed back the boundaries of innovation and interaction during a 'Live Endoscopy' event. Frontline Gastroenterology supported the event with a special edition of this journal dedicated to Endoscopic Practice in April 2015. With over 500 people from around the globe attending this first event, the aim of highlighting the very best of UK endoscopy on a national and international stage was achieved. Furthermore, the educational content of the course was developed to be accessible and appropriate to a variety of clinicians with different levels of experience endoscopy trainees, nurses, General practitioner (GP) endoscopists, gastroenterologists and surgeons. This article reviews this event and its many highlights and successes. PMID- 28839843 TI - Evaluation of patients with abnormalities on intraoperative cholangiogram: time to abandon endoscopic retrograde cholangiopancreatography as the initial follow up study. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is currently the method of choice for the postoperative evaluation of suspected bile duct stones seen on intraoperative cholangiogram (IOC); however, the sensitivity of IOC for identifying biliary pathology is unclear, with studies reporting false positive rates between 30% and 60%. OBJECTIVE: Evaluate the sensitivity of IOC for biliary pathology, using ERCP with sphincterotomy and balloon sweep as gold standard. DESIGN: Retrospective cohort study. SETTING: Tertiary medical centre. PATIENTS: 130 consecutive patients (age 51.3+/-1.7 years, 69.2% women) who underwent ERCP for the evaluation of abnormalities identified on IOC between 2005 and 2013. INTERVENTIONS: Endoscopic retrograde cholangiopancreatography. MAIN OUTCOME MEASUREMENTS: Sensitivity of IOC, identify predictors of positive postoperative ERCP and ERCP-related complications. RESULTS: ERCP was successful in all 130 subjects. ERCP-related adverse events occurred in six (4.3%) patients, including self-limited post-sphincterotomy bleeding in three (2.3%) and mild post ERCP pancreatitis in three (2.3%). Overall, 41 (31.5%) patients had normal cholangiogram at time of ERCP. Finding of a filling defect on IOC was the only predictor for the presence of common bile duct stones on postoperative ERCP (OR 3.3, 95% CI 1.0 to 10.8, p=0.05). LIMITATIONS: Retrospective study design. CONCLUSIONS: Nearly one-third of patients with abnormal IOC had a normal postoperative ERCP. Significant pathology could have been missed in 1/130 patients. Based on these findings, we believe the use of less-invasive diagnostic modalities may be used in place of ERCP in patients with suspected choledocholithiasis on IOC. PMID- 28839844 TI - Disseminated aspergillosis causing intestinal failure following colectomy for perforated colitis. AB - Disseminated aspergillosis is a rare, invasive, opportunistic, fungal infection associated with a high mortality. We report a non-fatal case diagnosed following extensive enterectomy for intestinal infarction in a patient recovering from emergency abdominal colectomy for perforated ulcerative colitis. This resulted in intestinal failure necessitating life-long parenteral nutrition and prolonged antifungal therapy. PMID- 28839845 TI - Meckel's diverticulum: new solutions for an old problem? AB - Meckel's diverticulum (MD) is the most commonly encountered true diverticulum in the small bowel. Although overall a rare cause of gastrointestinal bleeding, it remains an important differential in a child/young adult presenting with lower gastrointestinal bleeding. We present two MD cases, one associated with brisk bleeding resulting in haemodynamic instability and the other in insidious blood loss causing symptoms of chronic iron deficiency. These cases illustrate the heterogeneous nature of the clinical picture associated with Meckel's diverticulae, a condition most gastroenterological and surgical units will encounter. We subsequently discuss the diagnostic and management dilemma Meckel's diverticulae pose and appraise the latest evidence and management strategies in this regard. PMID- 28839846 TI - Anti-TNF drug and antidrug antibody level monitoring in IBD: a practical guide. AB - The antitumour necrosis factor (TNF) medications, adalimumab and infliximab, play an important role in the management of both Crohn's disease and ulcerative colitis. For those in whom anti-TNF is effective, the therapy is associated with fewer symptoms, improved quality of life and disease and surgery-free survival. Unfortunately, up to 30% of patients will fail to respond to anti-TNF drugs while up to 50% of those who do see an initial response will lose response at some point. The introduction of drug monitoring for anti-TNFs, including drug level and antidrug antibody level testing allows a more personalised management of patients and improves patient outcomes. This article reviews the data for the use of anti-TNF monitoring and presents a 'how to' guide for clinicians. PMID- 28839847 TI - Endoscopic submucosal dissection and its potential role in the management of early colorectal neoplasia in UK. AB - In Europe, colorectal cancer is the most common newly diagnosed cancer and the second most common cause of cancer deaths, accounting for approximately 436 000 incident cases and 212 000 deaths in 2008. National screening programmes will increase the number of early (pT1) cancers detected. pT1 cancers are those showing invasion through the muscularis mucosae into the submucosa but not into the muscularis propria. Microstaging of pT1 cancer is crucial in predicting those cases less likely to cause nodal disease and that will be cured with endoscopic resection alone. The submucosal extent and other histological features predict the risk of nodal disease, and for this reason, en bloc resection is highly desirable. Endoscopic submucosal dissection enables en bloc resection of mucosal and submucosal disease and could reduce the need for surgery in some cases by definitive initial resection. PMID- 28839848 TI - An evaluation study of a pilot group education programme for inflammatory bowel disease. AB - BACKGROUND AND AIMS: The emphasis for healthcare clinicians to provide adequate disease-related education is increasing. Yet little is known about the effect of providing disease-related education within inflammatory bowel disease (IBD). Previous studies have demonstrated increased levels of knowledge and satisfaction, but failed to capture any positive effects on the psychosocial elements of living with IBD. The aim of this qualitative study was to evaluate the impact of providing a group patient education programme on the psychosocial elements of living with IBD. METHODS: The data were obtained through eight semistructured qualitative interviews. Participants were recruited at the education programme using purposive sampling. All the interviews were digital recorded and transcribed. Thematic analysis was used by two independent researchers to analyse the transcripts and agreed emerging themes. RESULTS: A global theme of 'mastery' was evident within the transcripts. This was underpinned with two core themes of enablement and cooperative learning. The education programme 'enabled' the participants in a variety of ways: increased confidence, control, courage and power over their disease. An unexpected core theme of cooperative learning was also identified, with participants describing the overwhelming benefit of interaction with other people who also had IBD. CONCLUSIONS: This is the first qualitative study to report on the effects of providing a group patient education within IBD. The results identify new and interesting psychosocial elements that existing quantitative studies have failed to identify. PMID- 28839849 TI - Curriculum based clinical review: small bowel imaging in Crohn's disease. AB - The multidisciplinary management of patients with small bowel Crohn's disease is complex with an increasing reliance on imaging to guide management. The use of barium fluoroscopy is in decline with a shift towards the cross-sectional modalities. This article provides an overview of the various techniques used to image the small bowel, and highlights the clinical scenarios where imaging tests are most useful. PMID- 28839850 TI - Monitoring immunogenicity of protein-based TNF antagonists. PMID- 28839852 TI - Radiofrequency ablation is associated with decreased neoplastic progression in patients with Barrett's oesophagus and confirmed low-grade dysplasia. PMID- 28839854 TI - Endoscopic assessment and management of biliary strictures. PMID- 28839853 TI - A systematic approach to the management of cholestatic pruritus in primary biliary cirrhosis. AB - Pruritus (itch) is an important symptom of primary biliary cirrhosis (PBC), an archetypal cholestatic liver disease. Cholestatic pruritus can be a debilitating symptom causing significant deterioration in patients' quality of life. Effective management of pruritus in PBC involves awareness among clinicians to adequately assess its severity, and treatment with specific drug therapies in line with current practice guidelines. In PBC, antipruritic drugs are not universally effective and/or have significant side effects, and despite best efforts with various combinations of drugs, some patients remain significantly symptomatic, eventually opting for invasive or experimental treatments. Therefore, there is a clear unmet need for better alternative treatments for patients with refractory or intractable cholestatic pruritus. Recent advances in the understanding of pathogenesis of cholestatic pruritus and bile acid physiology have raised hopes for novel therapies, some of which are currently under trial. In this review, we aim to provide a practical guide to the management of this important and complex problem, discussing current knowledge and recent advances in the pathogenesis, summarise the evidence base for available therapeutic approaches and update potential novel future therapies for the management of pruritus in PBC. PMID- 28839855 TI - Endoscopic biliary stenting in irretrievable common bile duct stones: stent exchange or expectant management-tertiary-centre experience and systematic review. AB - INTRODUCTION: Conventional endoscopic duct clearance may not be possible in up to 10%-15% of common bile duct stones (CBDS). Sphincterotomy and biliary drainage by endoprosthesis have for many years been the mainstay of management in irretrievable stones. Recent years have seen the advent of sphincteroplasty or cholangioscopically-guided electrohydraulic lithotripsy (EHL) permitting duct clearance in majority of cases. However, when bile duct clearance is not possible, options include long-term stenting followed by elective stent exchange (ESE) 6-12 monthly or permanent stent insertion (PSI) in selected cases, but it is not clear which management strategy among ESE and PSI is preferable. METHODS AND AIMS: A retrospective review of all patients in Leeds Teaching Hospitals NHS Trust who underwent plastic stent insertion for biliary access for difficult CBDS from January 2006 to December 2011 was undertaken. Adult patients with irretrievable CBDS who had plastic stent insertions throughout the follow-up period were included. Patients who underwent PSI and ESE annually were retrospectively reviewed to determine the long-term outcomes. A detailed systematic review was also performed, examining the outcomes of CBDS managed with stents. RESULTS: During the study period, 674 patients underwent 1769 biliary stent-related procedures; of which, 246 patients met our inclusion criteria. 201 patients had subsequent duct clearance. 45 patients were, therefore, included in the final analysis, 28 of whom underwent annual ESEs and 17 PSIs. Patients in the PSI group had higher American Society of Anesthesiologists (ASA) scores compared with the ESE group. In the PSI group, 9/17 patients presented acutely with blocked stents, 5 of whom presented within 12 months. 2/9 patients were severely ill and died within a fortnight following the repeat endoscopic retrograde cholangiopancreatography (ERCP). In the ESE group, 4/28 patients had duct clearance in subsequent ERCPs, 1/28 patient presented with a blocked stent, and no biliary-related deaths were observed. The mean numbers of ERCPs performed were 0.52 and 1.95 in the PSI and ESE groups, respectively. CONCLUSIONS: Over 50% of patients treated with long-term stenting re-presented acutely with stent blockage, though many of these were before 12 months, meaning planned stent exchange would not have affected the outcome. Duct clearance using all possible modalities is the preferred option, but where not possible, management with biliary stenting either with elective exchange or permanent stenting remains a possibility for carefully selected patients, though maybe best suited to those with limited life expectancy. PMID- 28839856 TI - Variation in preparation for gastroscopy: lessons towards safer and better outcomes. AB - OBJECTIVE: To identify the methods employed within the UK practice prior to diagnostic gastroscopy and compare with published guidelines for patients undergoing general anaesthesia. DESIGN: National Health Service (NHS) endoscopy units were invited to take part in a structured telephone survey to determine the length of time patients are kept nil-by-mouth (NBM) for food and fluids prior to gastroscopy, and whether a preprocedure mucolytic drink was used. METHODS: 212 NHS Trusts providing endoscopy services were identified from the Joint Advisory Group on GI Endoscopy. Trusts were excluded if they were children's hospitals (n=5). RESULTS: 207 NHS Trusts were telephoned. 193 completed the survey (93%), 11 Trusts declined and there was no response from 3 Trusts. 13 separate policies regarding NBM timings were identified. 51 Trusts (21%) used the timings ratified by Surgical and Anaesthetic Societies (6 h NBM for food, 2 h for clear fluid). 135 Trusts (70%) used a policy which starved patients in excess of the standard surgical guidelines. No Trust used a mucolytic drink prior to gastroscopy. CONCLUSIONS: The survey revealed large variation in NHS Trust's policies regarding the times patients were starved prior to gastroscopy. Results of surgical studies demonstrate increased risk of significant pulmonary aspiration with increased fluid-starvation periods, 68% of NHS endoscopy policy would be deemed excessive by surgical practice. There is no routine use of a mucolytic drink to improve mucosal visualisation in the UK practice. PMID- 28839857 TI - Learning from adverse outcomes: guidelines on colonoscopic polypectomy in patients aged 85 years and older. AB - A patient between 80 and 90 years of age died following a polypectomy as part of a colonoscopy surveillance programme for previous polyps. As a consequence of this adverse event, we have amended our local guidelines. While perforation is a recognised complication of polypectomy, it was felt that the decision taken to remove the polyp was incorrect. The decision to remove a polyp should be at the endoscopist's clinical discretion and should depend on polyp size, the patient's age and comorbidities and their performance status. We recommend that polyps <20 mm in size should be regarded as low-risk polyps and that polypectomy of low-risk polyps are not essential in patients aged 85 years and older. Polypectomy of high risk polyps in patients aged 85 years and older should only be undertaken by experienced endoscopists and with appropriate discussion with the patient prior to the procedure. Patients aged >80 years should be dissuaded from having further colonoscopic surveillance and should not be included in polyp detection rate reports to ensure that polypectomy decisions are not influenced by performance monitoring. We recommend other endoscopy units review their local practice and consider introducing these (or similar) guidelines to reduce risk to older patients. We also recommend that the British Society of Gastroenterology should include more specific guidance on surveillance and polypectomy in the older patient when the guidance is next reviewed. PMID- 28839858 TI - The financial impact of a nurse-led telemedicine service for inflammatory bowel disease in a large district general hospital. AB - INTRODUCTION: It has become increasingly recognised that outpatient management is more cost-effective in inflammatory bowel disease (IBD). IBD Standards (Revised 2013) recommend telephone advice for patients with regard to symptoms and medication management. This report attempts to quantify the net financial impact of this service at our hospital since it was introduced in August 2013. METHOD: The Royal Alexandra Hospital in Paisley (National Health Service, Greater Glasgow and Clyde) is a district general hospital with a catchment population of 200 000 with approximately 2500 patients with IBD. Data relating to the use of the IBD telemedicine service were prospectively recorded on a daily basis for a period of 5 months. We documented reasons for calling and the likely action taken by the patient had the telephone advice line not been available. Cost savings based on alternative outcomes were made in accordance with the Department of Health figures (Department of Health reference costs 2011-2012). RESULTS: The mean number of calls per month was 88 (IQR 24)-(the mean number of calls which were deemed non-IBD issues was 30 calls per month (IQR 8.0)) The mean cost of staffing the IBD advice line with an IBD clinical nurse specialist was L482.00 per month (IQR 195.5). The mean time spent on calls per month was 28.5 h (IQR 11.5). Cost savings over 5 months for avoidance of general practitioner (GP) consultation was L3408.00. Savings for avoidance of a consultant appointment made over the 5-month period was L27 454.00. Savings made from patients avoiding either an accident and emergency (A&E) or a hospital admission were L540.00 and L11 488.00, respectively, over the 5-month period. The net saving was L42 890.00. CONCLUSIONS: A nurse-led telephone advice line appears to be a cost-effective intervention. It may prevent patients from unnecessary hospital attendance. Savings can be made to both primary care and secondary care. Overall, it appears that the advice line is providing a highly valuable service not just in terms of accessible treatment decisions and guidance for patients, but cost savings when IBD clinic nurse specialist time is compared with that of GPs, consultants or hospital facilities. PMID- 28839859 TI - Pneumocystis pneumonia complicating immunosuppressive therapy in Crohns disease: A preventable problem? AB - We report the case of a 76-year-old man who presented with moderate active Crohn's colitis that was refractory to high-dose corticosteroids, mesalazine and 6-mercaptopurine. He subsequently received a trial of infliximab with poor response and was diagnosed with cytomegalovirus (CMV) colitis, improving on antiviral therapy. Three weeks into treatment he developed acute respiratory distress with hypoxaemia and diffuse pulmonary interstitial infiltrates. This was confirmed as Pneumocystis jirovecii on bronchoalveolar lavage. He responded well to treatment with trimethoprim-sulfamethoxazole (TMP-SMX) and was subsequently discharged home. Despite the favourable outcome, our case raises the question of whether chemoprophylaxis against opportunistic infections in immunosuppressed patients with inflammatory bowel disease (IBD) is appropriate. There are currently no recommendations on providing chemoprophylaxis against CMV colitis and so we focus on pneumocystis pneumonia (PCP) where wide debate surrounds the use of prophylactic TMP-SMX in HIV-negative patients. Contrasting approaches to chemoprophylaxis against PCP in IBD likely relates to a lack of clear parameters for defining risk of PCP among patient groups. This must be addressed in order to develop universal guidelines that take into account patient-dependent risk factors. Awareness of the severity of PCP among HIV-negative individuals and the current consensus on PCP prophylaxis in IBD must be raised in order to minimise the risk of PCP and drive research in this controversial area. PMID- 28839860 TI - Refractory diversion neovaginitis in a sigmoid-colon-derived neovagina: clinical and histopathological considerations. AB - Colonic segments are being used as pedicled grafts in neovaginoplasty, a surgical procedure to (re)construct a (neo)vagina. A disadvantage of using colonic grafts is the potential occurrence of neovaginal complications due to diversion from the faecal stream. Here, we report a case of severe, refractory diversion colitis of the sigmoid neovagina, so-called 'diversion neovaginitis', in a 42-year-old woman with complete androgen insensitivity syndrome. Neovaginal biopsy specimens showed colonic-type mucosa with strong increase of lymphoplasmacellular infiltrate in the lamina propria, ulceration with fibrinoid deposition and some crypt irregularity. Endoscopy showed erythematous mucosa, superficial ulceration, mucus discharge and multiple pseudopolyp-like lesions. Local application of mesalazine foam enemas and sodium butyrate enemas initially gave symptom relief. However, this was a temporary effect, ultimately necessitating removal of the neovaginal construct. It is important that all patients are informed about neovaginal bowel complications, for example, diversion neovaginitis. Regular medical and endoscopic follow-up appears recommendable. PMID- 28839862 TI - Bowel preparation: defining adequacy and improving metrics. PMID- 28839864 TI - Autoimmune liver disease: evaluating overlapping and cross-over presentations-a case-based discussion. AB - The three classic autoimmune liver diseases are recognised based on identifying varying clinical, laboratory, histological and radiological features that collectively classify patients. In the absence of defined aetiological factors, it is recognised that disease spectrum is broad, and, in this context, it is not infrequent for disease boundaries to be blurred, leading to overlapping features that may be present at the time of diagnosis or may appear later in the course of disease. Given the absence of accepted diagnostic criteria for overlap/cross-over syndromes, alongside weak data for intervention, it is recommended that a multidisciplinary, patient-specific approach be used to establish individual treatment pathways. PMID- 28839863 TI - Short-term changes in liver tests predict long-term mortality. AB - OBJECTIVE: To determine whether short-term changes in liver tests (bilirubin, albumin, gamma glutamyl transferase, alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase) predict 12-month mortality and, if so, which test is most informative. DESIGN: Retrospective review of general medicine inpatients at a tertiary hospital (2005-2012) identified non elective admissions of minimum 7 days' duration. Patients with liver disease, malignancy, admission to the intensive care unit or inpatient mortality were excluded. Linear spline modelled the vector of intra-admission change from admission. The association between 12-month mortality and admission and intra admission changes in liver tests was assessed by logistic regression modelling, adjusted for age, gender, comorbidity index and heart failure. RESULTS: 12-month mortality was 17% in 4160 patients analysed. 12-month mortality for patients with abnormally low albumin at admission was 5% higher per 1 g/L below 34 g/L (OR 0.95, 95% CI 0.93 to 0.98, p<0.001). Albumin and ALT were the only tests for which an intra-admission change significantly predicted mortality; the predictive effects were additive. 12-month mortality was greater by 4% per 1 g/L intra admission decrement in albumin (OR 1.04, 95% CI 1.02 to 1.06, p<0.001) and 6% per 100 IU/L intra-admission increment in ALT (OR 1.06, 95% CI 1.02 to 1.1, p=0.005). Intra-admission changes were superior to admission values in predicting mortality. CONCLUSIONS: Changes in liver tests predict long-term mortality better than a single value and provide prognostic information more quickly than long term monitoring. In the absence of known liver disease, albumin predicts long term mortality better than transaminases. The patient whose albumin decreases in the short term is at high risk of death within 1 year, even from a normal baseline. PMID- 28839865 TI - Transnasal endoscopy: no gagging no panic! AB - BACKGROUND: Transnasal endoscopy (TNE) is performed with an ultrathin scope via the nasal passages and is increasingly used. This review covers the technical characteristics, tolerability, safety and acceptability of TNE and also diagnostic accuracy, use as a screening tool and therapeutic applications. It includes practical advice from an ear, nose, throat (ENT) specialist to optimise TNE practice, identify ENT pathology and manage complications. METHODS: A Medline search was performed using the terms "transnasal", "ultrathin", "small calibre", "endoscopy", "EGD" to identify relevant literature. RESULTS: There is increasing evidence that TNE is better tolerated than standard endoscopy as measured using visual analogue scales, and the main area of discomfort is nasal during insertion of the TN endoscope, which seems remediable with adequate topical anaesthesia. The diagnostic yield has been found to be similar for detection of Barrett's oesophagus, gastric cancer and GORD-associated diseases. There are some potential issues regarding the accuracy of TNE in detecting small early gastric malignant lesions, especially those in the proximal stomach. TNE is feasible and safe in a primary care population and is ideal for screening for upper gastrointestinal pathology. It has an advantage as a diagnostic tool in the elderly and those with multiple comorbidities due to fewer adverse effects on the cardiovascular system. It has significant advantages for therapeutic procedures, especially negotiating upper oesophageal strictures and insertion of nasoenteric feeding tubes. CONCLUSIONS: TNE is well tolerated and a valuable diagnostic tool. Further evidence is required to establish its accuracy for the diagnosis of early and small gastric malignancies. There is an emerging role for TNE in therapeutic endoscopy, which needs further study. PMID- 28839866 TI - Antithrombotic drugs and non-variceal bleeding outcomes and risk scoring systems: comparison of Glasgow Blatchford, Rockall and Charlson scores. AB - OBJECTIVES: Antithrombotic drugs (ATDs) cause non-variceal upper gastrointestinal bleeding (NVUGIB). Risk scoring systems have not been validated in ATD users. We compared Blatchford, Rockall and Charlson scores in predicting outcomes of NVUGIB in ATD users and controls. METHODS: A total of 2071 patients with NVUGIB were grouped into ATD users (n=851) and controls (n=1220) in a single-centre retrospective analysis. Outcomes included duration of hospital admission, the need for blood transfusion, rebleeding requiring surgery and 30-day mortality. RESULTS: Duration of admission correlated with all scores in controls, but correlations were significantly weaker in ATD users. Rank correlation coefficients in control versus ATD: 0.45 vs 0.20 for Blatchford; 0.48 vs 0.32 for Rockall and 0.42 vs 0.26 for Charlson (all p<0.001). The need for transfusion was best predicted by Blatchford (p<0.001 vs Rockall and Charlson in both ATD users and controls), but all scores performed less well in ATD users. Area under the receiver operation characteristic curve (AUC) in control versus ATD: 0.90 vs 0.85 for Blatchford; 0.77 vs 0.61 for Rockall and 0.69 vs 0.56 for Charlson (all p<0.005). In predicting surgery, Rockall performed best; while mortality was best predicted by Charlson with lower AUCs in ATD patients than controls (p<0.05). Stratification showed the scores' performance to be age-dependent. CONCLUSIONS: Blatchford score was the strongest predictor of transfusion, Rockall's had the strongest correlation with duration of admission and with rebleeding requiring surgery and Charlson was best in predicting 30-day mortality. Modifications of these systems should be explored to improve their efficiency in ATD users. PMID- 28839868 TI - Evolving strategies to reduce colectomy rates in primary sclerosing cholangitis inflammatory bowel disease: clinical remission of corticosteroid refractory colitis post-liver transplant with vedolizumab. AB - Primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD) in approximately 70% of patients, with ulcerative colitis (UC) being the most common subtype of IBD identified. There is a paucity of data on the optimum management strategy for IBD flares in the post-liver transplant patient, particularly when refractory to conventional treatments. Vedolizumab is a novel gut-specific monoclonal antibody, which has recently been approved for use by National Institute for Health and Care Excellence for moderate-to-severe UC. We present an exemplar case of successful use of vedolizumab in the management of corticosteroid refractory PSC-IBD after liver transplantation. PMID- 28839867 TI - Transitioning patients with inflammatory bowel disease (IBD) from adolescent to adult services: a systematic review. AB - Approximately a quarter of patients with inflammatory bowel disease (IBD) are diagnosed before 20 years of age, presenting with more extensive distribution and severity of disease than adult onset. The purpose of this review was to determine facilitators of, and barriers to, successful transition of patients with IBD from adolescent to adult services. A systematic review of IBD transition research was conducted in March 2014 searching PubMed, MEDLINE, PsycINFO, Web of Science and the Cochrane Database of Systematic Reviews databases. A hand search of reference lists and narrative reviews was carried out to maximise the potential for retrieving all relevant manuscripts. Primary studies written in English of full length peer-reviewed journal articles that investigated transition of paediatric patients with IBD to adult services were included. Studies were excluded if the primary focus was not IBD. The search produced 283 potentially relevant studies. After removing duplicates and screening for suitability, six met our inclusion criteria. Barriers to transition included system inadequacies and a lack of resources, clinical time and training. Successful transition involved joint medical visits, structured transition services, improved communication between paediatric and adult services and improved education for patients and staff. If the transition process for adolescents suffering with IBD is to improve then it is vital that more research is conducted to better our understanding of ways in which we can ensure that defined protocols are in place for a smooth transition for every adolescent, leading to improved standards and minimal disruption to care. PMID- 28839869 TI - The impact of an inflammatory bowel disease nurse-led biologics service. AB - INTRODUCTION: Southampton General Hospital provides inflammatory bowel disease (IBD) services for a population of 650 000. Biological agents have impacted hugely on IBD but are costly drugs requiring careful supervision. These challenges led us to develop a specialist nurse-led biologics service to improve patient care. METHOD: A 2010 case note audit highlighted areas for improvement in monitoring biologics and follow-up. A business case was developed to establish an IBD nurse to ensure identification and appropriate screening, education and review of biologics patients. A gain share was agreed with the local Care Commissioning Group (CCG) and L60 000 invested. Outcomes were reaudited in 2014. RESULTS: Biologic use has grown rapidly from 90 patients in 2011 to 330 in 2014. All records are now kept in a centralised database. Infection screening improved from 79% to 100%. In 2014, 96% of patients had follow-up <=4 months post induction to assess response, but two patients were seen at 7 months. 80% were followed up again at 9-12 months (100% at 9-14 months), all with treatment decisions. The initial investment was recouped via commissioners funding 368 additional outpatient appointments and 35 colonoscopies. Savings represented 15% total yearly biologic costs. CONCLUSIONS: The introduction of the IBD biologics nurse-led service resulted in significant gains in care quality and costs. The need for improved follow-up of patients on biologics reflects increased pressures on clinic resources across the country. With continued biologics expansion, the introduction of a biologics nurse has provided invaluable support to patients and the IBD team at Southampton General Hospital. PMID- 28839870 TI - Use of anti-TNF drug levels to optimise patient management. AB - Anti-tumour necrosis factor (TNF) therapies, such as infliximab, adalimumab, certolizumab pegol and golimumab, have been proven to be effective for the treatment of patients with Crohn's disease and ulcerative colitis. However, 10% 30% of patients with inflammatory bowel disease (IBD) show no initial clinical benefit to anti-TNF therapy (primary non-response), and over 50% after an initial favourable outcome will lose response over time (secondary loss of response (SLR)). Numerous recent studies in IBD have revealed an exposure-response relationship suggesting a positive correlation between high serum anti-TNF concentrations and favourable therapeutic outcomes including clinical, biomarker and endoscopic remission, whereas antidrug antibodies have been associated with SLR and infusion reactions. Currently, therapeutic drug monitoring (TDM) is typically performed when treatment failure occurs either for SLR, drug intolerance (potential immune-mediated reaction) or infusion reaction (reactive TDM). Nevertheless, recent data demonstrate that proactive TDM and a treat-to target (trough) therapeutic approach may more effectively optimise anti-TNF therapy efficacy, safety and cost. However, implementing TDM in real-life clinical practice is currently limited by the diversity in study design, therapeutic outcomes and assays used, which have hindered the identification of robust clinically relevant concentration thresholds. This review will focus mainly on the pharmacodynamic properties of anti-TNF therapy and the role of TDM in guiding therapeutic decisions in IBD. PMID- 28839871 TI - Monitoring thiopurine metabolites in inflammatory bowel disease. AB - Thiopurines (azathioprine and mercaptopurine) are one of the immunosuppressive mainstays for the treatment of inflammatory bowel disease. In spite of its widespread use, thiopurine metabolism is still not fully understood, and a significant proportion of patients suffer toxicity or lack of efficacy. Different enzymatic pathways with individual variations constitute a pharmacogenetic model that seems to be suitable for monitoring and therapeutic intervention. This review is focused on current concepts and recent research that may help clinicians to rationally optimise thiopurine treatment in patients with inflammatory bowel disease. PMID- 28839873 TI - Low incidence of complications with Freka PEG tubes. PMID- 28839874 TI - Optimal interval times for rescoping after an acute variceal haemorrhage. PMID- 28839872 TI - Advanced imaging in colonoscopy: contemporary approach to dysplasia surveillance in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) (ulcerative colitis (UC) and Crohn's disease (CD)) is a chronic relapsing/remitting condition characterised by intestinal inflammation. One of the main concerns in patients with longstanding ulcerative and Crohn's colitis is development of colonic dysplasia and colorectal cancer (CRC), a risk higher than that of the general population. Colonoscopy surveillance programmes have been developed by major societies worldwide to improve early dysplasia detection and treatment, thus preventing progression to colorectal cancer. Colonoscopy is an imperfect tool as lesions can be missed, an issue even more relevant to colitic patients, where mucosal inspection and lesion recognition may prove challenging. Extensive research has been undertaken on performance improvement in this area while technical advances in optical imaging, such as high-definition, have made their way into modern endoscopy units. Techniques and technologies available to enhance optical diagnosis of dysplasia in inflammatory bowel disease are reviewed in this paper, focusing on those that are realistic, widely available and feasible for everyday practice. PMID- 28839875 TI - Transition of patients with paediatric IBD to adult services. PMID- 28839877 TI - Colonic lesion characterisation skills among UK endoscopists and the impact of a brief training intervention. AB - OBJECTIVE: To assess UK gastroenterology registrars' and consultants' competence in in vivo characterisation of polyps, plus the impact of a dedicated colonic lesion characterisation training intervention. DESIGN: Prospective evaluation of a computer-based colonic lesion training module. SETTING: Three UK general hospitals. PATIENTS: High-quality endoscopic images obtained during colonoscopy in a previous study. INTERVENTIONS: 30 min computer-based training module covering in vivo characterisation of colonic lesions viewed under white light, chromoendoscopy and magnification chromoendoscopy. MAIN OUTCOME MEASURES: Accuracy of characterisation of colonic lesions (hyperplastic vs adenoma vs cancer) before and after training and differences between groups (bowel cancer screening (BCS) nurses vs gastroenterology trainees vs consultant gastroenterologists). RESULTS: Mean accuracy pretraining was 61.1%, 67.6% and 60.0% for the trainee, consultant and nurse groups respectively with no significant difference between the groups. Mean accuracy post-training improved significantly to 71.2%, 72.6% and 67.2% for the trainee, consultant and nurse groups (p<0.001 vs pretraining) with no significant difference between the three groups. Mean sensitivity and specificity improved significantly for the 15 participants overall. CONCLUSIONS: The baseline level of colonic lesion characterisation skills is limited for gastroenterology consultants and trainees and does not differ from that of non-endoscopist BCS nurses. Accuracy of lesion characterisation can be modestly improved with a brief computer-based training intervention. Lesion characterisation should become a standard part of training in colonoscopy, and should be learnt alongside technical skills for endoscope handing and therapeutic procedures. PMID- 28839878 TI - Provision of out-of-hours services for acute upper gastrointestinal bleeding in England: results of the 2014-2015 BSG/NHS England national survey. AB - BACKGROUND: There has been a drive to raise the standard of management of acute upper gastrointestinal bleeding (AUGIB) in the UK, including three previous audits, sponsored by the British Society of Gastroenterology (BSG). OBJECTIVE: To review the results of the latest BSG/National Health Service (NHS) England national survey of endoscopy services in England between 2014 and 2015. METHOD: All NHS hospitals accepting acute admissions in England (168) were invited to respond to the survey. RESULTS: Overall, 142 hospitals (84%) returned data. 85% of hospitals used a validated risk assessment score at the time of patient's admission. While 80% of hospitals provided a 24/7 endoscopy service for unstable patients, and another 10% were in network to provide an acute service, only 60% performed an endoscopy within 24 hours for stable acute admissions or inpatients with AUGIB. 11% of hospitals operated an out-of-hours ad hoc rota. 43% felt that pressure from routine work affected their ability to offer a next-day oesophagogastroduodenoscopy service, while 20% of hospitals struggled to recruit endoscopists. 28% of units reported that the previous national audit performed in 2013 had a positive influence on service development. CONCLUSIONS: This survey has revealed significant deficiencies in provision of services for patients with AUGIB in England, without a significant increase in number of hospitals providing an emergency AUGIB service since the last national audit in 2013. PMID- 28839879 TI - Patients' views on their experience of the delivery of single-sex accommodation within the endoscopy department: is it worth it? AB - INTRODUCTION: Provision of single-sex accommodation (SSA) in hospitals is a key National Health Service objective. Department of Health policy to eliminate mixed sex accommodation (MSA) was implemented in our endoscopy department in 2011. We found no published studies of patients' views on MSA in endoscopy units. AIM: We explored patients' views on MSA and their experience of attending our unit at Royal Albert Edward Infirmary (Wigan, UK) since implementation of the SSA policy. METHODS: Patients attending the endoscopy unit August-October 2012 and February April 2015 were invited to participate. Views were surveyed using a 10-point questionnaire. RESULTS: 155 patients were included. A minority were aware of national (36%) or local (39%) policies regarding MSA provision. Only 20.0% and 22.9% reported that they would feel uncomfortable changing behind a curtain or waiting in a gown in a mixed-sex area, respectively. Most of those that felt uncomfortable (81% and 71%) were female, and women ranked importance of SSA significantly higher than men. However, both sexes ranked importance of SSA significantly lower than that of prompt investigation/treatment. Admissions to an alternative recovery area specifically to maintain SSA compliance reduced from 25% (2012) to 8% (2015), following simple measures to improve list efficiency, with corollary reduction in reports of compromised patient experience. CONCLUSIONS: SSA is an important healthcare priority for some patients, especially women. However, most consider prompt investigation/treatment a much higher priority. Measures to comply with SSA can negatively affect patient experience. However, we demonstrate that simple measures can result in significant improvements in service delivery and patient experience while remaining compliant with SSA guidance. PMID- 28839880 TI - Gastrointestinal stromal tumours (GISTs): an insight into clinical practice with review of literature. AB - BACKGROUND: Gastrointestinal stromal tumours (GISTs) are rare mesenchymal tumours of the gastrointestinal tract. We retrospectively reviewed the clinical management of all patients with GIST presenting to a regional multidisciplinary upper gastrointestinal cancer group in the north of England. METHODS: Clinical, pathological, immunohistochemical treatment strategies, follow-up and outcome data on all patients with GIST between 2007 and 2012 were reviewed. Tumours were categorised by risk according to the National Institutes of Health (NIH) and AFIP models. RESULTS: 36 (85.7%) of 42 tumours were located in the stomach, 5 (11.9%) in the small intestine and 1 (2.4%) in the oesophagus. Median age of patients was 68 (range 43-91) years. 24 patients (57.1%) were female. Tumour size ranged from 1.0 to 12.7 cm with mean size of 5.46 cm. Metastasis was present in 19 (45.2%) patients at diagnosis with distant metastases in 12 patients. Liver was the most common site of metastases. Histology and immunohistochemical analysis was available in 32 (76.2%) patients. Most common histology was spindle cell morphology 17/32 (53.1%) followed by epithelioid 9/32 (28.1%) and mixed morphology 5/32 (15.6%). The positive rate for KIT protein (CD117) was 90.6%, while that for CD34 was 75.0%. 12/25 (48.0%) and 8/23 (34.8%) patients were categorised as high risk as per NIH and AFIP risk scores, respectively. 23/42 (54.8%) patients underwent surgical resection, after which 5/23 (21.7%) had adjuvant imatinib therapy. Imatinib was given as primary therapy in 14/42 (33.3%) patients. CONCLUSIONS: Surgery alone may not be a curative treatment for GISTs. Targeted therapy with imatinib may play an important role in the treatment of GISTs. Further risk categorisation models may be needed to evaluate GIST behaviour and prognosis. PMID- 28839881 TI - A regional EUS service using a collaborative network. AB - Endoscopic ultrasound (EUS) is increasingly used in the management of hepatobiliary lesions, allowing staging and tissue acquisition. It is operator dependent, and fine needle aspiration (FNA) of solid lesions provides an auditable standard; high-volume centres have shown excellent results for solid pancreatic lesion FNA with sensitivities of 92%-97%. The British Society of Gastroenterology guidelines stress that clinical quality should determine service provision, with geographical accessibility a secondary consideration. We set up the Wessex EUS network, working from a single hepatobiliary (HPB) pancreatic multidisciplinary team, with EUS provided in four local centres providing agreed standards and audit. Pancreatic solid lesion FNA results showed a pooled sensitivity of 94%, comparable with high-volume single centres. This demonstrates a network with good clinical governance is a plausible solution to providing a specialist service such as EUS and may be a roadmap that other specialist services under pressure could follow. PMID- 28839882 TI - Primary biliary cholangitis: new treatments for an old disease. AB - Primary biliary cholangitis (PBC) is an immunological condition that causes a significant health disturbance and dramatically reduces the quality of life for those affected with the disease. It is a potentially fatal disease that can lead to multiple hepatic and extrahepatic complications. Having adequate therapeutic interventions that can improve the course of the disease is imperative in reducing the associated morbidity and mortality. Ursodeoxycholic acid (UDCA) is the gold standard therapy. However, it has been associated with suboptimal response rates in a significant proportion of patients. Despite UDCA, approximately 35%-40% of individuals with PBC still experience a progression of the disease, leading to liver failure and requiring liver transplantation. Recent studies of new pharmacological approaches have shown beneficial outcomes. Some of these agents can now be applied to a clinical scenario. In this review article, we will outline the new and emerging treatments for PBC. PMID- 28839883 TI - Virtual touch quantification (VTq) elastography for non-invasive assessment of liver disease and its complications: what the clinician needs to know. AB - Liver stiffness measurement (LSM) is the most widely used non-invasive alternative to biopsy for assessing liver fibrosis in the UK. Virtual touch quantification (VTq, also known as acoustic radiation force impulse) is the principal available alternative to transient elastography (Fibroscan) and is delivered via software enhancements to standard ultrasound (US) machines. It has recently been endorsed by National Institute for Health and Care Excellence in terms of both accuracy and cost-effectiveness for use in viral hepatitis. However, while an increasing proportion of radiologists use VTq, familiarity among gastroenterologists and trainees with LSM techniques is variable and implementation is patchy. This review considers the background, evidence for and practical use of VTq elastography in clinical practice in the UK. Potential future developments in this rapidly evolving field are also highlighted. PMID- 28839884 TI - Integration of palliative and supportive care in the management of advanced liver disease: development and evaluation of a prognostic screening tool and supportive care intervention. AB - BACKGROUND AND OBJECTIVES: Patients with decompensated cirrhosis rarely receive palliative and supportive care interventions, which are routine in other life limiting diseases. We aimed to design and evaluate a prognostic screening tool to routinely identify inpatients with decompensated cirrhosis at high risk of dying over the coming year, alongside the development of a supportive care intervention. DESIGN: Clinical notes from consecutive patients admitted as an emergency to University Hospitals Bristol with a diagnosis of cirrhosis over two distinct 90-day periods were scrutinised retrospectively for the presence or absence of five evidence-based factors associated with poor prognosis. These were analysed against their ability to predict mortality at 1 year. 'Plan-Do-Study Act' (PDSA) methodology was used to incorporate poor-prognosis screening into the routine assessment of patients admitted with cirrhosis, and develop a supportive care intervention. RESULTS: 73 admissions were scrutinised (79.5% male, 63% alcohol-related liver disease, median age 54). The presence of three or more poor prognosis criteria at admission predicted 1-year mortality with sensitivity, specificity and positive predictive value of 72.2%, 83.8% and 81.3%, respectively, and was used as a trigger for implementing the supportive care intervention. Following modification from six PDSA cycles, prognostic screening was integrated into the assessment of all patients admitted with decompensated cirrhosis, with the supportive care intervention (developed simultaneously) instigated for appropriate patients. CONCLUSIONS: We describe a model of care which identifies inpatients with cirrhosis at significant risk of dying over the coming year, and describe development of a supportive care intervention, which can be offered to suitable patients in parallel to ongoing active management. PMID- 28839885 TI - Emergency general surgery 'Hot Clinics' reduce admission rates and duration of inpatient stay. AB - OBJECTIVE: To determine the impact of a 'Hot Clinic' (HC) on emergency general surgery patient flow-through. DESIGN: Prospective service evaluation study. SETTING: HC is a four-bedded area coordinated by a specialist nurse. The HC consultant sees emergency patients referred from the emergency department, general practitioners or those in preceding 24 h considered suitable for interim discharge while awaiting investigations and HC reassessment. PATIENTS: All patients with acute abdominal pain were evaluated in three 4 week groups: before (group 1), 1 month (group 2) and 6 months after the HC was introduced (group 3). Interhospital transfers, intrahospital ward referrals and trauma patients were excluded. INTERVENTION: Introduction of consultant-led surgical HC every weekday afternoon. MAIN OUTCOME MEASURES: Proportion of patients admitted under general surgeons, length of inpatient stay and the proportion of patients referred again within 3 months were investigated. RESULTS: 1409 patients were referred, of which 1061 met the inclusion criteria: 307 in group 1, 326 in group 2 and 428 in group 3. There was no difference in gender distribution (p=0.759). Inpatient admissions were significantly reduced (85.0% vs 78.2% vs 54.4%; p<0.001) and the inpatient duration of stay was significantly shorter after HC introduction (median (IQR) (95% CI) 63.8 (29.0-111.6) (51.8 to 72.8) hours vs 48.8 (21.7-101.2) (42.0 to 55.6) hours vs 47.7 (20.9-92.7) (42.8 to 56.9) hours; p=0.011). CONCLUSIONS: Emergency general surgery HCs are associated with significant reductions in admission rates and inpatient bed occupancy. This service redesign has the potential to dramatically relieve pressure on acute surgical services. PMID- 28839886 TI - A National Biofeedback Practitioners Service Evaluation: Focus on Chronic Idiopathic Constipation. AB - INTRODUCTION: Within the UK, there is anecdotal evidence of disparity in the training, practice, supervision and perception of efficacy among practitioners of biofeedback therapy for chronic constipation. AIMS: To establish the current knowledge, practice and opinions of UK practitioners. METHODS: Between October 2012 and October 2013, a prospective service evaluation was distributed to biofeedback practitioners in the UK through academic conferences or by invitation to complete an on-line assessment form. RESULTS: 76 practitioners responded, consisting of nurses (47%), physiotherapists (35%), physiologists (12%) and others (7%). Only 45% described 'biofeedback' consistent with an accepted definition. 86% use equipment to provide sensory feedback. Methods of biofeedback varied: balloon catheter (54%), brace pump technique (78%), urge resistance (83%), irrigation (16%) and relaxation (12%). Only 65% of practitioners had attended formal training courses, and 52% considered themselves to be self taught. 36% receive formal supervision and only 38% of those by a senior. Regular audit of outcomes is undertaken by 67%. UK-wide perception of treatment response for chronic constipation is markedly variable (mean response=57% (IQR 50-75%, SD 23%)); there were no differences in perception of treatment response between nurses or physiotherapists. Practitioners' free responses demonstrated strong positive themes of a holistic approach and an overall perception of effectiveness. Negative themes included service restrictions. CONCLUSIONS: There is marked variation in practice, training and supervision of biofeedback therapists throughout the UK. Perceptions of efficacy vary greatly. Development of training and supervision standards is a priority as well as a consensus to standardise therapy. PMID- 28839887 TI - A qualitative study of the impact of Crohn's disease from a patient's perspective. AB - OBJECTIVE: To understand how the lives of people with Crohn's disease (CD) are affected. Most research in CD has focused on symptoms and functioning rather than on how these outcomes influence quality of life (QoL). DESIGN: As part of a study to develop a CD-specific patient-reported outcome measure, qualitative interviews were conducted with patients from Manchester Royal Infirmary to determine how CD affects QoL. The needs-based model was adopted for the study. The interviews, which took the form of focused conversations covering all aspects of the impact of CD and its treatment, were audio-recorded. Theoretical thematic analysis of the transcripts identified needs affected by CD. RESULTS: Thirty patients (60% female) aged 25-68 years were interviewed. Participants had experienced CD for between 2 and 40 years. Nearly 1300 statements relating to the impact of CD were identified. Thirteen main need themes were identified: nutrition, hygiene, continence, freedom from infection, security, self-esteem, role, attractiveness, relationships, intimacy, clear-mindedness, pleasure and autonomy. CONCLUSIONS: The findings from the interviews indicate that CD has a major impact on need fulfilment. Such issues should be addressed in CD audit, clinical trials and when evaluating clinical practice. PMID- 28839888 TI - Crohn's disease and sarcoidosis in siblings: follow-up of a published report with a new case and brief review of the literature. AB - Reported in 1971 were the cases of three brothers, two of whom had developed sarcoidosis and the third Crohn's disease. That now presented concerns one brother who, 50 years after the diagnosis and successful treatment of his sarcoidosis, was found incidentally, at colonoscopy performed to exclude malignancy, to have Crohn's colitis in the absence of any symptoms attributable to this. The report concludes with a brief review of the literature. PMID- 28839890 TI - Safe endoscopy. PMID- 28839891 TI - Endoscopy provision: meeting the challenges. AB - BACKGROUND: Endoscopy activity has been increasing in the UK for many years. However, the increasing demand is currently disproportionate to delivered capacity. This, in combination with mandatory efficiency savings, presents an ongoing challenge in the effective continued delivery of diagnostic endoscopy services. RECENT DEVELOPMENTS: New initiatives in the field of endoscopy that may impact on resource include: faecal immunochemical test, straight to test referral systems, nurse endoscopists, home enemas and split dose bowel preparation. FUTURE POTENTIAL: System review and improvement is paramount to ensure the diagnostic pathway is of a high clinical quality, efficient, patient focused and sustainable. PMID- 28839892 TI - Endoscopy for upper gastrointestinal bleeding: where are we in 2017? PMID- 28839893 TI - Endoscopic approach to polyp recognition. AB - Identification and complete resection of colorectal polyps provide a significant mortality benefit from colorectal cancer. With improvements in colonoscopic techniques and advanced endoscopic imaging techniques, polyp detection has taken on greater complexity since the establishment of bowel cancer screening programmes internationally. All endoscopists operating within symptomatic and screening populations should be aware of endoscopic features associated with advanced neoplasia. Chromoendoscopy and advanced imaging techniques, such as narrow spectrum technologies (narrow band imaging, flexible spectral imaging colour enhancement (FICE) and i-Scan digital contrast (iSCAN)), have specific classification systems to support accurate lesion characterisation. This review summarises the evidence in relation to polyp detection, recognition and characterisation as well as the identification of features of invasion. Future areas of interest include optimal management of large polyps, incorporation of a 'detect, resect and discard' strategy for small and diminutive polyps, expected wider use of computer decision support tools (artificial intelligence and deep learning) and the use of fluorescently labelled molecular probes to improve detection and assessment of neoplasia. PMID- 28839894 TI - Polypectomy and advanced endoscopic resection. AB - Most colorectal cancers evolve from colorectal adenomatous polyps in a pathway known as the adenoma to carcinoma sequence. Early detection and removal of colorectal adenomas can prevent the development of colorectal cancer. The vast majority of these polyps can be resected endoscopically. Advances in endoscopic resection techniques have led to expanded indications for endoscopic polypectomy, whereby giant polyps, scarred lesions and early cancers may be cured. We will outline conventional endoscopic mucosal resection techniques as well as more complex resection methods such as endoscopic submucosal dissection, full thickness resection and the use of combined endoscopic and laparoscopic assisted approaches to resection. We will also explore the role of a virtual multidisciplinary team to aid decision-making when managing large and complex colorectal polyps. This review will provide an update on the endoscopic management of colorectal polyps and highlight exciting new developments in this ever-expanding field. PMID- 28839895 TI - Advancing the diagnostic and therapeutic role of EUS in pancreaticobiliary disease: Hopkins Lecture 2016. PMID- 28839896 TI - Training in ERCP and EUS in the UK anno 2017. AB - In the last 20 years, endoscopic retrograde cholangiopancreatography (ERCP) has evolved from being a diagnostic procedure to being almost exclusively therapeutic. Similarly, endoscopic ultrasound (EUS) is developing into ever increasing therapeutic roles. Operator technique is central to diagnostic accuracy in EUS, as is effective and safer therapy for both ERCP and therapeutic EUS. Hence, effective training and robust standards for certification and revalidation are required to ensure ERCP and EUS in the UK are as effective and as safe as possible. PMID- 28839897 TI - Endoscopic management of biliary stone disease. AB - The management of bile duct stone disease is the most common indication for endoscopic retrograde cholangio-pancreatography (ERCP). The majority of cases may be resolved using standard approaches including endoscopic sphincterotomy and balloon stone extraction. Recent advances in the management of large or challenging stones has come from the clear evidence for the role of endoscopic papillary large balloon dilatation (EPLBD)/sphincteroplasty and the development of cholangioscopically directed lithotripsy. Perhaps the greatest improvement in endoscopic stone management will be achieved through the implementation of plans for more formalised training, reflection and audit of ERCP performance indicators and network-wide coordination of ERCP services. PMID- 28839898 TI - Endoscopic management of Barrett's and early oesophageal neoplasia. AB - Barrett's oesophagus (BO) is the only known precursor to oesophageal adenocarcinoma (OAC). Dysplasia and intramucosal cancer arising in BO can safely be treated with endoscopic eradication therapy (EET) due to the low risk of subsequent lymph node metastasis. Treatment at an early stage is paramount due to the ongoing poor prognosis and outcomes of patients with advanced OAC. The mainstay of treatment is endoscopic resection of visible lesions for accurate staging followed by ablation therapy to all remaining columnar-lined epithelium, most commonly with radiofrequency ablation. Successful eradication of dysplasia can be achieved in >95% of patients with this EET combined approach. PMID- 28839899 TI - POEM and the management of achalasia. AB - Achalasia is a rare oesophageal motility disorder predominantly causing dysphagia and regurgitation of food and fluids. Diagnosis is made typically after a combination of tests including endoscopy, barium swallow and oesophageal manometry. The advent of high-resolution manometry has led to the Chicago Classification which divided achalasia into three types. This improved the understanding of presentation, prognosis and might also help tailor therapy. Botulinum toxin has been shown to have good, but short-term efficacy. The predominant treatments include pneumatic balloon dilatation and laparoscopic Heller's myotomy, both of which have similar and durable outcomes, although the success of both reduces with time. Per-oral endoscopic myotomy (POEM) has been shown to be as effective, safe and durable as earlier treatments for achalasia; however, randomised controlled trials are lacking. Indications for POEM are expanding to other hypercontractile motility disorders of the oesophagus. PMID- 28839900 TI - Small bowel endoluminal imaging (capsule and enteroscopy). AB - Over the last 16 years, the disruptive technologies of small bowel capsule endoscopy and device-assisted enteroscopy have revolutionised endoluminal imaging and minimally invasive therapy of the small bowel. Further technological developments continue to expand their indications and use. This brief review highlights the state-of-the-art in this arena and aims to summarise the current and potential future role of these technologies in clinical practice. PMID- 28839901 TI - The 2017 Dr Falk Pharma UK/Core Awards are open for applications. PMID- 28839903 TI - BSPGHAN Motility Working Group position statement: paediatric multichannel intraluminal pH impedance monitoring-indications, methods and interpretation. AB - BACKGROUND: Combined pH-impedance monitoring has been suggested as the investigation of choice for diagnosing gastro-oesophageal reflux in children. Although it is superior to oesophageal pH monitoring in detecting all types of reflux episodes (acid, weakly acidic and alkaline) with the ability to evaluate symptom association with reflux events, it is still limited by the lack of true paediatric normal value and the high cost involved (equipment and personnel). OBJECTIVE: To produce a position statement on behalf of the Motility Working Group of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition on the indications and practical application of combined oesophageal pH impedance monitoring in children. METHODS: Up-to-date review of available evidence. RESULTS: This document provides a practical guide to clinician on indications, methods and results interpretation of paediatric multichannel intraluminal impedance pH (MII-pH). CONCLUSIONS: MII-pH is increasingly used by paediatricians as the diagnostic tool for assessing gastro-oesophageal reflux disease and symptom association. There is wide variation in paediatric practice and a need for standardised practice. PMID- 28839904 TI - UK practice in the prevention of central venous catheter-associated thrombosis in adults on home parenteral nutrition. AB - BACKGROUND: Maintaining central access is imperative for the delivery of home parenteral nutrition (HPN) in those with intestinal failure. Methods to reduce central venous catheter infection are well recognised; however, the prevention of line thrombosis is less well studied. METHODS: This paper reviews the current evidence and reports a survey of current practice within the UK. Using an electronic survey, respondents were asked to detail their use of anticoagulation in different patient groups and the type of anticoagulation used. RESULTS: 41 replies were received from 31 centres. Only one responder used low-dose warfarin routinely; 80% however anticoagulated those with a previous line thrombosis and 65% anticoagulated those that had any deep vein thrombosis or pulmonary embolus. The most commonly used anticoagulant was dose-adjusted warfarin aiming for an international normalised ratio of 2-3. CONCLUSIONS: The evidence from the current literature in both HPN and the wider field is that there is no clear evidence that anticoagulation is either beneficial or harmful in the prevention of line thrombosis. This survey suggested that practice is varied across the UK likely reflecting the lack of evidence within the current literature. PMID- 28839905 TI - Incidence and risk factors for gastrointestinal bleeding among patients admitted to medical intensive care units. AB - OBJECTIVES: To identify incidence and risk factors for new-onset gastrointestinal bleeding (GIB) in a medical intensive care unit (ICU), a topic for which there is a paucity of recent studies. DESIGN: Retrospective cohort study. SETTING: Medical ICUs at our tertiary-care hospital, from 2007 to 2013. PATIENTS: Patients who developed clinically significant GIB after entering the ICU. INTERVENTIONS: Univariable and multivariable analyses. MAIN OUTCOME MEASURES: Incidence and risk factors for development of GIB. RESULTS: 4439 patients entered the medical ICU without a pre-existing GIB and 58 (1.3%) developed GIB while in the ICU. Risk factors included length of ICU stay (OR per additional day 1. 06; 95% CI 1.04 to 1.09) and elevated creatinine on ICU admission (OR 2.35; 95% CI 1.18 to 4.68, p=0.02). Elevated bilirubin on ICU admission (OR 2.08; 95% CI 0.97 to 4.47, p=0.06), and elevated aspartate transaminase (AST) on ICU admission (OR 2.20; 95% CI 0.96 to 5.03, p=0.06) trended towards increased risk of GIB that did not meet statistical significance. Age, gender, admission coagulation studies and mechanical ventilation were not predictive of GIB. Among those patients with new onset GIB in the ICU, 47% died during that hospitalisation, as compared with those 30% of those without a GIB, p<0.01. CONCLUSIONS: Onset of GIB is now an infrequent occurrence in the ICU setting; however those with elevated bilirubin, AST and creatinine upon admission, and with longer length of ICU stay appear at increased risk and may benefit from closer monitoring. PMID- 28839906 TI - An approach to acute lower gastrointestinal bleeding. AB - Lower gastrointestinal bleeding (LGIB) is a common problem that can be treated via a number of endoscopic, radiological and surgical approaches. Although traditionally managed by the colorectal surgeons, surgery should be considered a last resort given the variety of endoscopic and radiological approaches available. This article provides an overview on the common causes of acute LGIB and the various techniques at our disposal to control it. PMID- 28839907 TI - Validation of a care pathway for the use of faecal calprotectin in monitoring patients with Crohn's disease. AB - INTRODUCTION: We have previously published an evidence-based care pathway for the use of faecal calprotectin (FC) to monitor patients with Crohn's disease established on therapy. Patients are treated as low, intermediate or high risk of continuing Crohn's disease activity based on their FC, whatever their phenotype and surgical status are. Low-risk patients (FC <100 ug/g) are offered 12 monthly follow-ups or step down of therapy if asymptomatic or initial expectant symptomatic treatment. Intermediate-risk patients (FC 100-250 ug/g) are reviewed at 6 months with a repeat FC. High-risk patients (two consecutive FCs >250 ug/g) are flagged up to the responsible clinician as likely having an active Crohn's disease. METHODS: To validate this care pathway over a 2-year period, by determining its negative predictive value (NPV) and positive predictive value (PPV). RESULTS: 123 patients were managed by means of the care pathway for a mean of 24.4 months. The NPV and PPV were 0.97 (CI 0.93 to 0.98) and 0.85 (CI 0.80 to 0.94), respectively (sensitivity: 0.92 (0.83 to 0.96) and specificity: 0.95 (0.92 to 0.98)). Importantly 69% of patients with FC >250 ug/g were in clinical remission, the care pathway identifying patients who would benefit from presymptomatic disease modification. CONCLUSIONS: This validation of a pragmatic clinical care pathway demonstrates a safe and effective mechanism by which to use FC to monitor risk of disease activity in patients with Crohn's disease established on therapy. It provides a framework for prioritising follow-up and for identifying patients at risk of continuing disease activity or those in whom therapy could be stepped down. PMID- 28839908 TI - Utilisation of anti-TNF levels in a UK tertiary IBD centre. AB - OBJECTIVE: To ascertain how anti-tumour necrosis factor (TNF) drug and anti-drug antibody levels testing is used in a 'real-world' setting to optimise inflammatory bowel disease (IBD) treatment. DESIGN: Retrospective cohort study of prospectively collected patient data. SETTING: Tertiary IBD centre in London, UK. PATIENTS: All patients at Guy's and St Thomas' Hospitals on anti-TNF who had levels measured between the start of testing in 2012 and October 2014. INTERVENTIONS: Anti-TNF drug and anti-drug antibody levels as part of routine monitoring. MAIN OUTCOME MEASURES: Indication for measuring levels and changes in management made as a result of the levels. RESULTS: 330 infliximab levels were carried out in 199 patients and 143 adalimumab levels were carried out in 103 patients. Levels were primarily done in those with evidence of loss of response; 37% of infliximab levels and 52% of adalimumab levels. Levels resulted in a change in management in 26% of patients in infliximab group and 25% of patients in adalimumab group; however, this was greater in those with loss of response, 62% and 61% respectively. Anti-drug antibodies were detected in 7% of patients. CONCLUSIONS: Our early experience has demonstrated that measuring anti-TNF drug and anti-drug antibody levels can be useful in the optimisation of IBD management. In an increasing number of patients, particularly those with evidence of loss of response, it allows early decisions to be made regarding changing therapy. It also offers the potential for significant cost-saving by preventing pointless dose escalation in the context of therapeutic levels or when high-level anti-drug antibodies are present. PMID- 28839910 TI - Postoperative prophylaxis in Crohn's disease after intestinal resection: a retrospective analysis. AB - INTRODUCTION: Up to 80% of patients with Crohn's disease (CD) may require surgery at some point in their lives, and it is estimated that as many as 40% may require several surgeries. It has been suggested that prophylactic medication decreases the rate of clinical and endoscopic recurrence following intestinal resection. This study aims to describe real-world clinical outcomes observed from a pragmatic, individualised strategy in postoperative CD. METHODS: All patients undergoing intestinal resection for CD between 2009 and 2013 were identified. The endpoint of the study, treatment success, was defined as glucocorticosteroid free, resection-free survival, at the last point of follow-up, without requiring an escalation or change of therapy during this time. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and from prescribing databases. Patients were followed from the date of surgery, and the last point of follow-up was 31 January 2015. RESULTS: 149 patients were analysed. Median duration of follow-up was 32 months (range 1-69 months). 101 patients received postoperative prophylactic therapy, and 48 did not. In 77 (51.7%) patients, thiopurines were used as first-line therapy, with treatment success occurring in 32 (41.6%) with a median follow-up of 25 months. 11 patients (7.4%) received anti-tumour necrosis factor (TNF)-alpha monotherapy, with treatment success occurring in 5 patients (45.5%) with a median follow-up of 35 months. 13 (8.7%) patients received first-line combination therapy, with 11 (84.6%) patients achieving treatment success with a median follow-up of 21 months. CONCLUSIONS: In our study, combination therapy with anti-TNF-alpha and immunomodulator therapy was well tolerated, efficacious (efficacy appeared durable for patients with postoperative CD) and superior to monotherapy with either thiopurines or anti-TNF alpha drugs. Several limitations notwithstanding, our data suggest that there may be merit in the use of combination therapy in carefully selected postoperative patients whose care has been individualised via a multidisciplinary team meeting format. Prospective, controlled studies are therefore required to further assess the efficacy and safety of combination therapy for postoperative prophylaxis in CD. PMID- 28839909 TI - Vedolizumab: early experience and medium-term outcomes from two UK tertiary IBD centres. AB - OBJECTIVE: To gain an understanding of the efficacy of vedolizumab in a 'real world' setting. DESIGN: Retrospective cohort study using prospectively maintained clinical records. SETTING: Two UK tertiary inflammatory bowel disease (IBD) centres. PATIENTS: Patients with IBD commenced on vedolizumab at Guy's & St Thomas' and King's College Hospitals during November 2014-November 2015. INTERVENTION: Vedolizumab, a monoclonal antibody to alpha-4 beta-7 integrins that selectively inhibit leucocyte migration into the gut. MAIN OUTCOME MEASURES: Clinical disease activity was assessed at baseline, weeks 14 and 30 using Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Response was defined as HBI or SCCAI reduction >=3. Remission was defined as HBI <5 or SCCAI <3. Continuous data are summarised as medians, followed by range. RESULTS: Fifty patients were included: 27 CD, 20 UC and 3 IBD-U (included in the UC group for analysis). At baseline visit, the median HBI was 8 (1-16) and SCCAI was 6 (0-15). At week 14, these values had fallen to 5 (0-15) (p=0.117) and 4 (0-10) (p=0.005), respectively. Additionally, week 30 data were available for 19 patients (9 CD, 10 UC). The clinical disease activity scores at that point were HBI 2 (0-7) (p=0.039) and SCCAI 2 (0-10) (p=0.023). At baseline, 37 (74%) of the 50 patients had clinically active disease. Of the patients with active disease, 22 (59%) responded and 14 (38%) achieved remission at week 14. CONCLUSIONS: Our early experience with vedolizumab demonstrates a clear benefit in terms of disease control as well as a steroid-sparing effect in a cohort, which included patients with complex and previously refractory disease. PMID- 28839911 TI - The role of multidisciplinary meetings for benign pancreatobiliary diseases: a tertiary centre experience. AB - Multidisciplinary meetings are central to the management of chronic and complex diseases and they have become widely established across the modern healthcare. Patients with pancreatobiliary diseases can often present with complex clinical dilemmas, which fall out with the scope of current guidelines. Therefore, these patients require a personalised management approach discussed in a multidisciplinary meeting. PMID- 28839912 TI - A quasi-experimental evaluation of dried blood spot testing through community pharmacies in the Tayside region of Scotland. AB - OBJECTIVE: Comparison of uptake of dried blood spot testing (DBST) for hepatitis C virus (HCV) infection between community pharmacies and established services. DESIGN: Quantitative evaluation of a service development with qualitative process evaluation undertaken in parallel. SETTING: Six pharmacies from 36 community pharmacies within Dundee City, a large urban settlement with high levels of socioeconomic deprivation. PARTICIPANTS: Patients in receipt of opioid substitution therapy (OST) not tested for HCV within 12 months. The 6 pharmacies provided OST for approximately 363 patients from a cohort of 1385 patients within Dundee City. INTERVENTION: Provision of DBST by pharmacists. MAIN OUTCOME MEASURE: Receipt of DBST between January and December 2014. RESULTS: 43 of 143 service users with no record of testing from the 6 community pharmacies accepted DBST. Of 561 from the remaining 1022 service users with no record of testing, 75 were tested for HCV (30% vs 13%). The OR for increased uptake of testing within the 6 pharmacies was 2.25 (95% CI 1.48 to 3.41, Z statistic=3.81, p=<0.0001) compared with other services. The DBST taken by the pharmacies provided 12 patients with a reactive test. The process evaluation identified key themes important to staff and recipients of the service. A logic model was constructed. LIMITATIONS: Non-experimental service evaluation performed in community pharmacies records service activity in one location across a single time period. INTERPRETATION: Some evidence that DBST from community pharmacies may be feasible. Service users received the service positively. Staff reported that DBST was straightforward and achievable. PMID- 28839914 TI - Adaptability and evolution. AB - The capacity of organisms to respond in their own lifetimes to new challenges in their environments probably appeared early in biological evolution. At present few studies have shown how such adaptability could influence the inherited characteristics of an organism's descendants. In part, this has been because organisms have been treated as passive in evolution. Nevertheless, their effects on biological evolution are likely to have been important and, when they occurred, accelerated the pace of evolution. Ways in which this might have happened have been suggested many times since the 1870s. I review these proposals and discuss their relevance to modern thought. PMID- 28839913 TI - Biological action in Read-Write genome evolution. AB - Many of the most important evolutionary variations that generated phenotypic adaptations and originated novel taxa resulted from complex cellular activities affecting genome content and expression. These activities included (i) the symbiogenetic cell merger that produced the mitochondrion-bearing ancestor of all extant eukaryotes, (ii) symbiogenetic cell mergers that produced chloroplast bearing ancestors of photosynthetic eukaryotes, and (iii) interspecific hybridizations and genome doublings that generated new species and adaptive radiations of higher plants and animals. Adaptive variations also involved horizontal DNA transfers and natural genetic engineering by mobile DNA elements to rewire regulatory networks, such as those essential to viviparous reproduction in mammals. In the most highly evolved multicellular organisms, biological complexity scales with 'non-coding' DNA content rather than with protein-coding capacity in the genome. Coincidentally, 'non-coding' RNAs rich in repetitive mobile DNA sequences function as key regulators of complex adaptive phenotypes, such as stem cell pluripotency. The intersections of cell fusion activities, horizontal DNA transfers and natural genetic engineering of Read-Write genomes provide a rich molecular and biological foundation for understanding how ecological disruptions can stimulate productive, often abrupt, evolutionary transformations. PMID- 28839915 TI - Domestication as a model system for the extended evolutionary synthesis. AB - One of the challenges in evaluating arguments for extending the conceptual framework of evolutionary biology involves the identification of a tractable model system that allows for an assessment of the core assumptions of the extended evolutionary synthesis (EES). The domestication of plants and animals by humans provides one such case study opportunity. Here, I consider domestication as a model system for exploring major tenets of the EES. First I discuss the novel insights that niche construction theory (NCT, one of the pillars of the EES) provides into the domestication processes, particularly as they relate to five key areas: coevolution, evolvability, ecological inheritance, cooperation and the pace of evolutionary change. This discussion is next used to frame testable predictions about initial domestication of plants and animals that contrast with those grounded in standard evolutionary theory, demonstrating how these predictions might be tested in multiple regions where initial domestication took place. I then turn to a broader consideration of how domestication provides a model case study consideration of the different ways in which the core assumptions of the EES strengthen and expand our understanding of evolution, including reciprocal causation, developmental processes as drivers of evolutionary change, inclusive inheritance, and the tempo and rate of evolutionary change. PMID- 28839916 TI - The evolutionary implications of epigenetic inheritance. AB - The Modern Evolutionary Synthesis (MS) forged in the mid-twentieth century was built on a notion of heredity that excluded soft inheritance, the inheritance of the effects of developmental modifications. However, the discovery of molecular mechanisms that generate random and developmentally induced epigenetic variations is leading to a broadening of the notion of biological heredity that has consequences for ideas about evolution. After presenting some old challenges to the MS that were raised, among others, by Karl Popper, I discuss recent research on epigenetic inheritance, which provides experimental and theoretical support for these challenges. There is now good evidence that epigenetic inheritance is ubiquitous and is involved in adaptive evolution and macroevolution. I argue that the many evolutionary consequences of epigenetic inheritance open up new research areas and require the extension of the evolutionary synthesis beyond the current neo-Darwinian model. PMID- 28839917 TI - Human niche, human behaviour, human nature. AB - The concept of a 'human nature' or 'human natures' retains a central role in theorizing about the human experience. In Homo sapiens it is clear that we have a suite of capacities generated via our evolutionary past, and present, and a flexible capacity to create and sustain particular kinds of cultures and to be shaped by them. Regardless of whether we label these capacities 'human natures' or not, humans occupy a distinctive niche and an evolutionary approach to examining it is critical. At present we are faced with a few different narratives as to exactly what such an evolutionary approach entails. There is a need for a robust and dynamic theoretical toolkit in order to develop a richer, and more nuanced, understanding of the cognitively sophisticated genus Homo and the diverse sorts of niches humans constructed and occupied across the Pleistocene, Holocene, and into the Anthropocene. Here I review current evolutionary approaches to 'human nature', arguing that we benefit from re-framing our investigations via the concept of the human niche and in the context of the extended evolutionary synthesis (EES). While not a replacement of standard evolutionary approaches, this is an expansion and enhancement of our toolkit. I offer brief examples from human evolution in support of these assertions. PMID- 28839918 TI - A second inheritance system: the extension of biology through culture. AB - By the mid-twentieth century (thus following the 'Modern Synthesis' in evolutionary biology), the behavioural sciences offered only the sketchy beginnings of a scientific literature documenting evidence for cultural inheritance in animals-the transmission of traditional behaviours via learning from others (social learning). By contrast, recent decades have seen a massive growth in the documentation of such cultural phenomena, driven by long-term field studies and complementary laboratory experiments. Here, I review the burgeoning scope of discoveries in this field, which increasingly suggest that this 'second inheritance system', built on the shoulders of the primary genetic inheritance system, occurs widely among vertebrates and possibly in invertebrates too. Its novel characteristics suggest significant implications for our understanding of evolutionary biology. I assess the extent to which this second system extends the scope of evolution, both by echoing principal properties of the primary, organic evolutionary system, and going beyond it in significant ways. This is well established in human cultural evolution; here, I address animal cultures more generally. The further major, and related, question concerns the extent to which the consequences of widespread animal cultural transmission interact with the primary, genetically based inheritance systems, shaping organic evolution. PMID- 28839919 TI - Evolutionary biology today and the call for an extended synthesis. AB - Evolutionary theory has been extended almost continually since the evolutionary synthesis (ES), but except for the much greater importance afforded genetic drift, the principal tenets of the ES have been strongly supported. Adaptations are attributable to the sorting of genetic variation by natural selection, which remains the only known cause of increase in fitness. Mutations are not adaptively directed, but as principal authors of the ES recognized, the material (structural) bases of biochemistry and development affect the variety of phenotypic variations that arise by mutation and recombination. Against this historical background, I analyse major propositions in the movement for an 'extended evolutionary synthesis'. 'Niche construction' is a new label for a wide variety of well-known phenomena, many of which have been extensively studied, but (as with every topic in evolutionary biology) some aspects may have been understudied. There is no reason to consider it a neglected 'process' of evolution. The proposition that phenotypic plasticity may engender new adaptive phenotypes that are later genetically assimilated or accommodated is theoretically plausible; it may be most likely when the new phenotype is not truly novel, but is instead a slight extension of a reaction norm already shaped by natural selection in similar environments. However, evolution in new environments often compensates for maladaptive plastic phenotypic responses. The union of population genetic theory with mechanistic understanding of developmental processes enables more complete understanding by joining ultimate and proximate causation; but the latter does not replace or invalidate the former. Newly discovered molecular phenomena have been easily accommodated in the past by elaborating orthodox evolutionary theory, and it appears that the same holds today for phenomena such as epigenetic inheritance. In several of these areas, empirical evidence is needed to evaluate enthusiastic speculation. Evolutionary theory will continue to be extended, but there is no sign that it requires emendation. PMID- 28839920 TI - Niche construction, sources of selection and trait coevolution. AB - Organisms modify and choose components of their local environments. This 'niche construction' can alter ecological processes, modify natural selection and contribute to inheritance through ecological legacies. Here, we propose that niche construction initiates and modifies the selection directly affecting the constructor, and on other species, in an orderly, directed and sustained manner. By dependably generating specific environmental states, niche construction co directs adaptive evolution by imposing a consistent statistical bias on selection. We illustrate how niche construction can generate this evolutionary bias by comparing it with artificial selection. We suggest that it occupies the middle ground between artificial and natural selection. We show how the perspective leads to testable predictions related to: (i) reduced variance in measures of responses to natural selection in the wild; (ii) multiple trait coevolution, including the evolution of sequences of traits and patterns of parallel evolution; and (iii) a positive association between niche construction and biodiversity. More generally, we submit that evolutionary biology would benefit from greater attention to the diverse properties of all sources of selection. PMID- 28839921 TI - The metaphysics of evolution. AB - This paper briefly describes process metaphysics, and argues that it is better suited for describing life than the more standard thing, or substance, metaphysics. It then explores the implications of process metaphysics for conceptualizing evolution. After explaining what it is for an organism to be a process, the paper takes up the Hull/Ghiselin thesis of species as individuals and explores the conditions under which a species or lineage could constitute an individual process. It is argued that only sexual species satisfy these conditions, and that within sexual species the degree of organization varies. This, in turn, has important implications for species' evolvability. One important moral is that evolution will work differently in different biological domains. PMID- 28839922 TI - Genetic, epigenetic and exogenetic information in development and evolution. AB - The idea that development is the expression of information accumulated during evolution and that heredity is the transmission of this information is surprisingly hard to cash out in strict, scientific terms. This paper seeks to do so using the sense of information introduced by Francis Crick in his sequence hypothesis and central dogma of molecular biology. It focuses on Crick's idea of precise determination. This is analysed using an information-theoretic measure of causal specificity. This allows us to reconstruct some of Crick's claims about information in transcription and translation. Crick's approach to information has natural extensions to non-coding regions of DNA, to epigenetic marks, and to the genetic or environmental upstream causes of those epigenetic marks. Epigenetic information cannot be reduced to genetic information. The existence of biological information in epigenetic and exogenetic factors is relevant to evolution as well as to development. PMID- 28839923 TI - Why developmental niche construction is not selective niche construction: and why it matters. AB - In the last decade, niche construction has been heralded as the neglected process in evolution. But niche construction is just one way in which the organism's interaction with and construction of the environment can have potential evolutionary significance. The constructed environment does not just select for, it also produces new variation. Nearly 3 decades ago, and in parallel with Odling Smee's article 'Niche-constructing phenotypes', West and King introduced the 'ontogenetic niche' to give the phenomena of exogenetic inheritance a formal name. Since then, a range of fields in the life sciences and medicine has amassed evidence that parents influence their offspring by means other than DNA (parental effects), and proposed mechanisms for how heritable variation can be environmentally induced and developmentally regulated. The concept of 'developmental niche construction' (DNC) elucidates how a diverse range of mechanisms contributes to the transgenerational transfer of developmental resources. My most central of claims is that whereas the selective niche of niche construction theory is primarily used to explain the active role of the organism in its selective environment, DNC is meant to indicate the active role of the organism in its developmental environment. The paper highlights the differences between the construction of the selective and the developmental niche, and explores the overall significance of DNC for evolutionary theory. PMID- 28839924 TI - Evolution viewed from physics, physiology and medicine. AB - Stochasticity is harnessed by organisms to generate functionality. Randomness does not, therefore, necessarily imply lack of function or 'blind chance' at higher levels. In this respect, biology must resemble physics in generating order from disorder. This fact is contrary to Schrodinger's idea of biology generating phenotypic order from molecular-level order, which inspired the central dogma of molecular biology. The order originates at higher levels, which constrain the components at lower levels. We now know that this includes the genome, which is controlled by patterns of transcription factors and various epigenetic and reorganization mechanisms. These processes can occur in response to environmental stress, so that the genome becomes 'a highly sensitive organ of the cell' (McClintock). Organisms have evolved to be able to cope with many variations at the molecular level. Organisms also make use of physical processes in evolution and development when it is possible to arrive at functional development without the necessity to store all information in DNA sequences. This view of development and evolution differs radically from that of neo-Darwinism with its emphasis on blind chance as the origin of variation. Blind chance is necessary, but the origin of functional variation is not at the molecular level. These observations derive from and reinforce the principle of biological relativity, which holds that there is no privileged level of causation. They also have important implications for medical science. PMID- 28839925 TI - Extended genomes: symbiosis and evolution. AB - Many aspects of an individual's biology derive from its interaction with symbiotic microbes, which further define many aspects of the ecology and evolution of the host species. The centrality of microbes in the function of individual organisms has given rise to the concept of the holobiont-that an individual's biology is best understood as a composite of the 'host organism' and symbionts within. This concept has been further elaborated to posit the holobiont as a unit of selection. In this review, I critically examine whether it is useful to consider holobionts as a unit of selection. I argue that microbial heredity the direct passage of microbes from parent to offspring-is a key factor determining the degree to which the holobiont can usefully be considered a level of selection. Where direct vertical transmission (VT) is common, microbes form part of extended genomes whose dynamics can be modelled with simple population genetics, but that nevertheless have subtle quantitative distinctions from the classic mutation/selection model for nuclear genes. Without direct VT, the correlation between microbial fitness and host individual fitness erodes, and microbe fitness becomes associated with host survival only (rather than reproduction). Furthermore, turnover of microbes within a host may lessen associations between microbial fitness with host survival, and in polymicrobial communities, microbial fitness may derive largely from the ability to outcompete other microbes, to avoid host immune clearance and to minimize mortality through phage infection. These competing selection pressures make holobiont fitness a very minor consideration in determining symbiont evolution. Nevertheless, the importance of non-heritable microbes in organismal function is undoubted-and as such the evolutionary and ecological processes giving rise to variation and evolution of the microbes within and between host individuals represent a key research area in biology. PMID- 28839927 TI - The purpose of adaptation. AB - A central feature of Darwin's theory of natural selection is that it explains the purpose of biological adaptation. Here, I: emphasize the scientific importance of understanding what adaptations are for, in terms of facilitating the derivation of empirically testable predictions; discuss the population genetical basis for Darwin's theory of the purpose of adaptation, with reference to Fisher's 'fundamental theorem of natural selection'; and show that a deeper understanding of the purpose of adaptation is achieved in the context of social evolution, with reference to inclusive fitness and superorganisms. PMID- 28839926 TI - Early Homo, plasticity and the extended evolutionary synthesis. AB - The Modern Synthesis led to fundamental advances in understandings of human evolution. For human palaeontology, a science that works from ancestral phenotypes (i.e. the fossil record), particularly important have been perspectives used to help understand the heritable aspects of phenotypes and how fossil individuals might then be aggregated into species, and relationships among these groups understood. This focus, coupled with the fragmentary nature of the fossil record, however, means that individual phenotypic variation is often treated as unimportant 'noise', rather than as a source of insight into population adaptation and evolutionary process. The emphasis of the extended evolutionary synthesis on plasticity as a source of phenotypic novelty, and the related question of the role of such variation in long-term evolutionary trends, focuses welcome attention on non-genetic means by which novel phenotypes are generated and in so doing provides alternative approaches to interpreting the fossil record. We review evidence from contemporary human populations regarding some of the aspects of adult phenotypes preserved in the fossil record that might be most responsive to non-genetic drivers, and we consider how these perspectives lead to alternate hypotheses for interpreting the fossil record of early genus Homo. We conclude by arguing that paying closer attention to the causes and consequences of intraspecific phenotypic variation in its own right, as opposed to as noise around a species mean, may inspire a new generation of hypotheses regarding species diversity in the Early Pleistocene and the foundations for dispersal and regional diversification in Homo erectus and its descendants. PMID- 28839928 TI - Developmental plasticity: re-conceiving the genotype. AB - In recent decades, the phenotype of an organism (i.e. its traits and behaviour) has been studied as the outcome of a developmental 'programme' coded in its genotype. This deterministic view is implicit in the Modern Synthesis approach to adaptive evolution as a sorting process among genetic variants. Studies of developmental pathways have revealed that genotypes are in fact differently expressed depending on environmental conditions. Accordingly, the genotype can be understood as a repertoire of potential developmental outcomes or norm of reaction. Reconceiving the genotype as an environmental response repertoire rather than a fixed developmental programme leads to three critical evolutionary insights. First, plastic responses to specific conditions often comprise functionally appropriate trait adjustments, resulting in an individual-level, developmental mode of adaptive variation. Second, because genotypes are differently expressed depending on the environment, the genetic diversity available to natural selection is itself environmentally contingent. Finally, environmental influences on development can extend across multiple generations via cytoplasmic and epigenetic factors transmitted to progeny individuals, altering their responses to their own, immediate environmental conditions and, in some cases, leading to inherited but non-genetic adaptations. Together, these insights suggest a more nuanced understanding of the genotype and its evolutionary role, as well as a shift in research focus to investigating the complex developmental interactions among genotypes, environments and previous environments. PMID- 28839929 TI - Why an extended evolutionary synthesis is necessary. AB - Since the last major theoretical integration in evolutionary biology-the modern synthesis (MS) of the 1940s-the biosciences have made significant advances. The rise of molecular biology and evolutionary developmental biology, the recognition of ecological development, niche construction and multiple inheritance systems, the '-omics' revolution and the science of systems biology, among other developments, have provided a wealth of new knowledge about the factors responsible for evolutionary change. Some of these results are in agreement with the standard theory and others reveal different properties of the evolutionary process. A renewed and extended theoretical synthesis, advocated by several authors in this issue, aims to unite pertinent concepts that emerge from the novel fields with elements of the standard theory. The resulting theoretical framework differs from the latter in its core logic and predictive capacities. Whereas the MS theory and its various amendments concentrate on genetic and adaptive variation in populations, the extended framework emphasizes the role of constructive processes, ecological interactions and systems dynamics in the evolution of organismal complexity as well as its social and cultural conditions. Single-level and unilinear causation is replaced by multilevel and reciprocal causation. Among other consequences, the extended framework overcomes many of the limitations of traditional gene-centric explanation and entails a revised understanding of the role of natural selection in the evolutionary process. All these features stimulate research into new areas of evolutionary biology. PMID- 28839930 TI - Human nature, human culture: the case of cultural evolution. AB - In recent years, far from arguing that evolutionary approaches to our own species permit us to describe the fundamental character of human nature, a prominent group of cultural evolutionary theorists has instead argued that the very idea of 'human nature' is one we should reject. It makes no sense, they argue, to speak of human nature in opposition to human culture. The very same sceptical arguments have also led some thinkers-usually from social anthropology-to dismiss the intimately related idea that we can talk of human culture in opposition to human nature. How, then, are we supposed to understand the cultural evolutionary project itself, whose proponents seem to deny the distinction between human nature and human culture, while simultaneously relying on a closely allied distinction between 'genetic' (or sometimes 'organic') evolution and 'cultural' evolution? This paper defends the cultural evolutionary project against the charge that, in refusing to endorse the concept of human nature, it has inadvertently sabotaged itself. PMID- 28839931 TI - The subject as cause and effect of evolution. AB - A family of arguments often presented in opposition to mainstream neo-Darwinian views of evolution assert an 'active' role for organisms in determining the course of their evolution and other kinds of biological change. I assess several of these arguments, beginning with an early treatment by Lewontin and moving to more recent discussions. I then look at a subset of these phenomena, those in which organisms are efficacious in virtue of features and capacities related to subjectivity. In the history of the Earth from the Cambrian onwards, subjectivity has been an increasingly important causal factor. PMID- 28839932 TI - The impact of alteplase on pulmonary graft function in donation after circulatory death - An experimental study. AB - OBJECTIVE: Lung transplantation is hampered by the lack of organs resulting in deaths on the waiting list. The usage of donation after circulatory death (DCD) lungs would dramatically increase donor availability. The most optimal organ preservation method, and the need for antithrombotic and fibrinolytic treatment to prevent thrombosis in the donor lungs is currently on debate. The present study investigated, in a simulated clinical DCD situation, whether the addition of alteplase in the flush-perfusion solution at the time of pulmonary graft harvesting could prevent thrombosis in the donor lung and thereby improve pulmonary graft function. METHODS: Twelve Swedish domestic pigs were randomized into two groups. All animals underwent ventricular fibrillation and were then left untouched for 1 h after declaration of death. None of the animals received heparin. The lungs were then harvested and flush-perfused with Perfadex(r) solution and the organs were then stored at 8 degrees C for 4 h. In one group alteplase was added to the Perfadex(r) solution (donation after cardiac death with alteplase (DCD-A)) and in the other, it was not (DCD). Lung function was evaluated, using ex vivo lung perfusion (EVLP), with blood gases at different oxygen levels, pulmonary vascular resistance (PVR), lung weight, and macroscopic appearance. RESULTS: During EVLP, there were no significant differences between groups in PaO2 at any investigated FiO2 level (1.0, 0.5, or 0.21). At FiO2 1.0, the PaO2 in the DCD and DCD-A was 51.7 +/- 2.05 kPa and 60.3 +/- 3.67 kPa, respectively (p = 0.1320). There were no significant differences between groups PVR levels, in the DCD (372 +/- 31 dyne x s/cm5) and in the DCD-A (297 +/- 37 dyne x s/cm5) groups (p = 0.1720). There was no significant difference between groups in macroscopic appearance. CONCLUSIONS: All the lungs showed excellent blood gases after EVLP, and they all meet the criteria's for clinical lung transplantation. The use of alteplase did not seem to have any obvious benefit to the donor lungs in a DCD situation. The donor lungs treated with alteplas showed slightly better blood gases and slightly lower PVR compared to the group without alteplas, however the difference was not significant. DCD appears to be a safe and effective method to expand the donor pool. PMID- 28839933 TI - Assessment of medication adherence and the costs associated with a calendar blister pack intervention among hypertensive patients in Malaysia: A randomized controlled trial. AB - OBJECTIVES: To assess the efficacy and costs of a calendar blister packaging intervention used to improve medication adherence. METHOD: A parallel randomized controlled trial was conducted with 73 hypertensive patients (intervention group = 35, control group = 38) at Hospital Kulim, Malaysia, for 7 months. RESULTS: The intervention group demonstrated a significant improvement in medication possession ratio (p < 0.05) and percentage of on-time refills (p < 0.01) compared to control group. In addition, there was significantly lower blood pressure (p < 0.05) in intervention group. From the provider perspective, the average annual treatment cost per patient in the intervention group was MYR 2178.66 (~USD 526.95) (95% confidence interval = 1786.39-2570.94) compared to MYR 2693.09 (~USD 651.37) (95% confidence interval = 1903.23-3482.95) in the control group. CONCLUSION: This study provides evidence that calendar blister packaging has a positive impact on medication adherence, blood pressure and also has the potential for considerable cost savings. PMID- 28839934 TI - Impact of organophosphate exposure on farmers' health in Kulon Progo, Yogyakarta: Perspectives of physical, emotional and social health. AB - OBJECTIVE: The exposure of organophosphate could be caused by the absorption in some parts of the body like skin and breath. Toxicity may cause nausea, vomiting and dizziness which are not too specific related with the pesticide toxicity. The purpose of this study is to understand the association between organophosphate exposure and farmers' health in Kulon Progo County from the perspectives of physical, emotional and social health. METHODS: This study was conducted using descriptive observational design. The blood sample was collected during harvesting periods in 2016. The inclusion criterion of farmers was using organophosphate-contained pesticide during the planting period of red onion. The farmers who had renal disease, liver disease and cancer were excluded. The organophosphate exposure parameters were the duration and frequency of pesticide application, width of the area, serum cholinesterase activity and the completeness of personal protective equipment. RESULTS: Among 84 farmers, most of them were male (85.7%), and the mean age was 49.1 (standard deviation: 12.5) years; 71.4% of the subjects experienced tremor, 17.86% experienced dizziness and 8.33% subjects experienced nausea-vomiting after pesticide application. According to the pesticide application, in average, subjects used pesticide 1.4 h/day with the area of 1.285 m2. The frequency of pesticide used is three times per week. Around 97.6% subjects used incomplete personal protective equipment. The average of serum cholinesterase activity in subjects with tremor is higher than subjects without tremor (p > 0.05). There is a significant association between serum cholinesterase activity and creatinine content (p < 0.05). The farmers' quality of-life domain scores are lower than the scores of the normal population in Yogyakarta. CONCLUSION: Organophosphate exposure may affect the farmers' physical health and quality of life. PMID- 28839935 TI - Variables associated with work performance in multidisciplinary mental health teams. AB - OBJECTIVES: This study investigates work performance among 79 mental health teams in Quebec (Canada). We hypothesized that work performance was positively associated with the use of standardized clinical tools and clinical approaches, integration strategies, "clan culture," and mental health funding per capita. METHODS: Work performance was measured using an adapted version of the Work Role Questionnaire. Variables were organized into four key areas: (1) team attributes, (2) organizational culture, (3) inter-organizational interactions, and (4) external environment. RESULTS: Work performance was associated with two types of organizational culture (clan and hierarchy) and with two team attributes (use of standardized clinical tools and approaches). DISCUSSION AND CONCLUSION: This study was innovative in identifying associations between work performance and best practices, justifying their implementation. Recommendations are provided to develop organizational cultures promoting a greater focus on the external environment and integration strategies that strengthen external focus, service effectiveness, and innovation. PMID- 28839936 TI - Pre-surgery evaluations by telephone decrease travel and cost for families of children with cerebral palsy. AB - INTRODUCTION: Children with cerebral palsy need highly specialized care. This can be very burdensome for families, particularly in large rural states, due to the need for long-distance travel to appointments. In this study, children undergoing the selective percutaneous myofascial lengthening surgery utilized a telephone based telemedicine evaluation to assess for surgical eligibility. The goal was to avoid a separate preoperative clinic visit weeks before the surgery. If possible, eligibility was determined by telephone, and then, the patient could be scheduled for a clinic visit and possible surgery the next day, saving the family a trip. The purposes of the study were to calculate estimated reductions in miles traveled, in travel expenses, and in carbon emissions and to determine whether the telephone assessment was accurate and effective in determining eligibility for surgery. METHODS: From 2010 to 2012, 279 patients were retrospectively reviewed, and of those, 161 mailed four-page questionnaire and anteroposterior pelvis X-ray followed by a telephone conference. Geographic information system methods were used to geocode patients by location. Savings in mileage and travel costs were calculated. From 2014 to 2015, 195 patients were additionally studied to determine accuracy and effectiveness. RESULTS: The telephone prescreening method saved 106,070 miles in transportation over 3 years, a 38% reduction with US$55,326 in savings. Each family saved an average of 658 (standard deviation = 340) miles of travel and US$343.64 (standard deviation = US$178) in travel expenses. For each increase of 10 miles in distance from the health center, the odds of a patient utilizing telephone screening increased by 10% (odds ratio: 1.101, 95% confidence interval: 1.073-1.129, p < 0.001). After the telephone prescreening, 86% were determined to be likely candidates for the procedure. For 14%, a clinic visit only was scheduled, and they were not scheduled for surgery. CONCLUSION: Families seeking specialized surgical care for their disabled children particularly benefited from this approach. PMID- 28839937 TI - Proteomic and transcriptomic analyses to explain the pleiotropic effects of Ankaferd blood stopper. AB - Ankaferd blood stopper is a standardized mixture of the plants Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica and has been used as a topical hemostatic agent and with its clinical application established in randomized controlled trials and case reports. Ankaferd has been successfully used in gastrointestinal endobronchial mucosal and cutaneous bleedings and also in abdominal, thoracic, dental and oropharyngeal, and pelvic surgeries. Ankaferd's hemostatic action is thought to form a protein complex with coagulation factors that facilitate adhesion of blood components. Besides its hemostatic action, Ankaferd has demonstrated pleiotropic effects, including anti neoplastic and anti-microbial activities and tissue-healing properties; the underlying mechanisms for these have not been well studied. Ankaferd's individual components were determined by proteomic and chemical analyses. Ankaferd also augments transcription of some transcription factors which is shown with transcriptomic analysis. The independent effects of these ingredients and augmented transcription factors are not known precisely. Here, we review what is known of Ankaferd blood stopper components from chemical, proteomic, and transcriptomic analyses and propose that individual components can explain some pleiotropic effects of Ankaferd. Certainly more research is needed focusing on individual ingredients of Ankaferd to elucidate their precise and effects. PMID- 28839938 TI - Related factors of outcomes of pharyngeal foreign bodies in children. AB - OBJECTIVE: This study aimed to identify factors related to outcomes of the pharyngeal foreign bodies in children and to improve the management protocol of this disease. METHODS: The medical records of 131 children with pharyngeal foreign bodies hospitalized in the hospital were retrospectively reviewed. RESULTS: Significant differences were observed between the two groups (dislodgement and removal group) with respect to location of pharyngeal foreign bodies and age, while sex, time of pharyngeal foreign bodies, and nature of pharyngeal foreign bodies had no significant differences. Moreover, results suggested that location of pharyngeal foreign bodies and nature of pharyngeal foreign bodies were risk factors correlated with complications. CONCLUSION: Pharyngeal foreign body in children has a high rate of dislodgement (>50%). Foreign bodies in the oropharynx were more likely to dislodge compared with the foreign bodies in the laryngopharynx. Younger children were more likely to dislodge compared with older children. Although the risk of complications was very low, attention needs to be paid to the potential risks: local infection, deep abscess, and migration of foreign bodies. Because the possibility of complications caused by bone fragments and foreign bodies in the laryngopharynx increase obviously, hence, it is suggested to remove these kinds of foreign bodies as soon as possible to prevent complications. PMID- 28839939 TI - How mental health service systems are organized may affect the rate of acute admissions to specialized care: Report from a natural experiment involving 5338 admissions. AB - OBJECTIVES: Studies on the dynamics between service organization and acute admissions to psychiatric specialized care have given ambiguous results. We studied the effect of several variables, including service organization, coercion, and patient characteristics on the rate of acute admissions to psychiatric specialist services. In a natural experiment-like study in Norway, we compared a "deinstitutionalized" and a "locally institutionalized" model of mental health services. One had only community outpatient care and used beds at a large Central Mental Hospital; the other also had small bed-units at the local District Psychiatric Centre. METHODS: From the case registries, we identified a total of 5338 admissions, which represented all the admissions to the psychiatric specialist services from 2003 to 2006. The data were analyzed with chi-square tests and Z-tests. In order to control for possible confounders and interaction effects, a multivariate analysis was also performed, with a logistic regression model. RESULTS: The use of coercion emerged as the strongest predictor of acute admissions to specialist care (odds ratio = 7.377, 95% confidence interval = 4.131-13.174) followed by service organization (odds ratio = 3.247, 95% confidence interval = 2.582-4.083). Diagnoses of patients predicted acute admissions to a lesser extent. We found that having psychiatric beds available at small local institutions rather than beds at a Central Mental Hospital appeared to decrease the rate of acute admissions. CONCLUSION: While it is likely that the seriousness of the patients' condition is the most important factor in doctors' decisions to refer psychiatric patients acutely, other variables are likely to be important. This study suggests that the organization of mental health services is of importance to the rate of acute admissions to specialized psychiatric care. Systems with beds at local District Psychiatric Centers may reduce the rate of acute admissions to specialized care, compared to systems with local community outpatient services and beds at Central Mental Hospitals. PMID- 28839940 TI - Effects of combined treatment with fermented soybean (natto) intake and exercise on bone metabolism in ovariectomized rats. AB - OBJECTIVES: Using ovariectomized rats, we examined the influence of combined exercise tolerance and natto intake on the bone loss inhibitory effect. METHODS: We divided female Wistar rats into the following groups: Ovariectomy, Ovariectomy + Exercise, Ovariectomy + Natto Intake, Ovariectomy + Exercise + Natto Intake, and Pseudo-operative (Sham group). After conducting experiments on each group, we collected the tissues and performed morphological and molecular biological analyses. RESULTS: In comparison with the Ovariectomy group, only in the Ovariectomy + Exercise group was there a significant bone loss inhibitory effect in the femoral cancellous bone. Although there was a tendency toward this trend seen in the Natto Intake and Exercise + Natto Intake groups, these differences were not significant. The increase in messenger RNA expression levels of alkaline phosphatase (osteoblast marker) in the bone marrow caused by ovariectomy was suppressed by individual factors, and by those in combination. However, messenger RNA expression levels of estrogen receptor alpha in the bone marrow showed a decreasing tendency with each factor, and decreased significantly with the combination, similar to the Sham group. CONCLUSION: This suggests that natto intake and exercise maintain bone mass by different molecular mechanisms and that these two factors do not simply act synergistically in combination to maintain bone mass. PMID- 28839941 TI - Factors associated with high cardiovascular risk in a primarily African American, urban HIV-infected population. AB - OBJECTIVE: To determine factors associated with increased risk of developing cardiovascular disease in a high-risk patient population. DESIGN: Cross-sectional analysis of a retrospective cohort study. METHODS: One-hundred patients at an inner city HIV clinic in 2008 were reviewed. The atherosclerotic vascular disease risk score was calculated using the Pooled Cohort Equation. Chi-square test was performed to identify associations of potential risk factors with elevated atherosclerotic vascular disease risk. RESULTS: Eighty-one participants were included in the final analysis. In total, 95.1% were African American, and 38.3% were women. The median atherosclerotic vascular disease risk score was 8.8% and 8.1% in 2008 and 2012, respectively. The medical co-morbidities associated with increased atherosclerotic vascular disease risk were hepatitis C infection (X2 = 3.93; p value = 0.048), elevated triglycerides levels (X2 = 4.0; p value = 0.046), and low albumin (X2 = 4.65; p value = 0.031). There were a higher number of women with known atherosclerotic vascular disease despite lower median atherosclerotic vascular disease risk score compared to men. CONCLUSION: An elevated risk of developing cardiovascular disease persists in high-risk demographic groups of the HIV epidemic even in the current HIV era. There is an unexplained gender disparity and some non-traditional risk factors not accounted for in the Pooled Cohort Equation may be contributing to the excess cardiovascular disease risk observed among HIV-infected patients. PMID- 28839942 TI - Early palliative home care: Evaluation of an interprofessional educational intervention for district nurses and general practitioners about nutritional care. AB - BACKGROUND: Teamwork is important in early palliative home care, and interprofessional education is required to achieve teamwork. It is thus crucial to ensure that interprofessional education works well for the members of all participating professions because levels of knowledge and educational needs may vary. AIM: To evaluate, by profession, the effectiveness of an interprofessional educational intervention for district nurses and general practitioners on three areas of nutritional care for patients in a palliative phase. DESIGN: A quasi experimental study that used a computer-based, study-specific questionnaire to evaluate the effectiveness of the intervention. The continuing education in primary health care (ConPrim(r)) model was used to create the intervention. ConPrim includes a web-based program, a practical exercise and a case seminar, all with interprofessional training. SETTING: Primary health care centers in Stockholm County, Sweden. Intervention group (n = 87; 48 district nurses, 39 general practitioners); control group (n = 53; 36 district nurses, 17 general practitioners). RESULTS: The total intervention effect was significant in all three areas, p = 0.000-0.004. The intervention effects were similar and significant for both professions in areas 1 and 2. In area 3, the intervention effects were significant for general practitioners but not for district nurses. CONCLUSIONS: The intervention seems promising, as it may create better prerequisites for teamwork and caring for patients living at home. However, it needs to be optimized to better increase district nurses' level of knowledge (area 3). PMID- 28839943 TI - Involvement of family members in life with type 2 diabetes: Six interconnected problem domains of significance for family health identity and healthcare authenticity. AB - OBJECTIVES: Family involvement plays a key role in diabetes management. Problems and challenges related to type 2-diabetes often affect the whole family, and relatives are at increased risk of developing diabetes themselves. We highlight these issues in our objectives: (1) to uncover specific family problems associated with mutual involvement in life with type 2-diabetes and (2) to analytically look at ways of approaching these problems in healthcare settings. METHODS: Qualitative data were gathered in participatory problem assessment workshops. The data were analysed in three rounds using radical hermeneutics. RESULTS: Problems were categorized in six domains: knowledge, communication, support, everyday life, roles and worries. The final cross-analysis focusing on the link between family identity and healthcare authenticity provided information on how the six domains can be approached in healthcare settings. CONCLUSION: The study generated important knowledge about problems associated with family involvement in life with type 2 diabetes and about how family involvement can be supported in healthcare practice. PMID- 28839944 TI - Novel characteristics identified in two cases of feline cowpox virus infection. AB - CASE SERIES SUMMARY: This case series discusses novel characteristics identified in two cases of cowpox. One presented with upper airway signs, and was identified to have a focal laryngeal lesion. The other had central neurological signs at the terminal stages, with intracytoplasmic inclusion bodies identified within the cerebral hemispheres on histopathology. RELEVANCE AND NOVEL INFORMATION: Currently, cowpox would be an unlikely consideration in patients with neurological signs or upper respiratory noise. These cases both document novel presentations of cowpox infection, which clinicians should be aware of and consider as differential diagnoses in patients with these atypical presentations. PMID- 28839945 TI - Concomitant multiple myeloma and probable phaeochromocytoma in a cat. AB - CASE SUMMARY: Herein a drug-resistant IgG-lambda-type multiple myeloma associated with probable phaeochromocytoma in a cat is described. A 12-year-old cat presented with weakness, weight loss, progressive blindness and open-mouth breathing, in addition to polyuria and polydipsia of 2 months' duration. Abdominal ultrasonography revealed a left adrenal mass. Phaeochromocytoma was suspected on the basis of cytology and was associated with systemic hypertension. Biochemistry showed hyperproteinaemia. Serum protein electrophoresis revealed a narrow spike in the gamma region, identified as IgG lambda type at immunoelectrophoresis. Bone marrow cytology revealed an infiltrate with numerous mature plasma cells. The cat was resistant to two different drugs for multiple myeloma and was euthanased 6 months later because of anorexia and persistent poor general condition. RELEVANCE AND NOVEL INFORMATION: This is the first clinical description of multiple myeloma associated with a suspected phaeochromocytoma in a cat. PMID- 28839946 TI - Serum anti-Mullerian hormone concentrations before and after treatment of an ovarian granulosa cell tumour in a cat. AB - CASE SUMMARY: A 15-year-old female cat was presented for investigation of progressive behavioural changes, polyuria, polydipsia and periuria. An ovarian granulosa cell tumour was identified and the cat underwent therapeutic ovariohysterectomy (OHE). The cat's clinical signs resolved, but 6 months later it was diagnosed as having an anaplastic astrocytoma and was euthanased. Serum anti-Mullerian hormone (AMH) concentration prior to OHE was increased vs a control group of entire and neutered female cats. Following OHE, serum AMH concentration decreased to <1% of the original value. RELEVANCE AND NOVEL INFORMATION: Serum AMH measurement may represent a novel diagnostic and monitoring tool for functional ovarian neoplasms in cats. PMID- 28839947 TI - Dynamic chronic rectal obstruction causing a severe colonic dilatation in a cat. AB - CASE SUMMARY: A 5-year-old male neutered domestic shorthair cat was presented to our referral centre with a 13 month history of chronic tenesmus due to malunion of the right caudal iliac body. Constipation and pelvic canal stenosis were initially addressed by the referring veterinarian with a right femoral head and neck excision and a right acetabulectomy without observable clinical improvement. At admission, abdominal radiographs revealed severe colonic distension and a narrowed pelvic canal caused by the right proximal femur. Rectal examination and colonography revealed a dynamic compression of the rectum, which worsened with femoral abduction and improved with femoral adduction. A right hindlimb amputation was performed to relieve the obstruction. The cat defaecated 2 days postoperatively and was discharged uneventfully. Neither faecal tenesmus nor dyschaezia were observed over the following 10 months. RELEVANCE AND NOVEL INFORMATION: The dynamic nature of the rectal obstruction most likely prevented the development of an irreversible colonic dilatation leading to a megacolon. This is the first report describing a chronic dynamic rectal compression, which was successfully managed with a right hindlimb amputation without the need for subtotal colectomy. PMID- 28839948 TI - Uterine torsion in a full-term pregnant cat. AB - CASE SUMMARY: A 5-year-old intact female Maine Coon cat presented with a 2 day history of lethargy, anorexia and anaemia. The cat had bred 60 days previously and jumped from a height 3 days earlier, which was followed by a worsening of its condition. Ultrasonography revealed that two fetuses had died and one remained alive. Urgent surgical intervention was deemed necessary, and the cat underwent a blood transfusion and laparotomy. The right uterine horn was dark red in appearance and had rotated 360 degrees in the clockwise direction at its base. Subsequently, an ovariohysterectomy and caesarean section were performed, and the fetus in the left uterine horn initially survived. Although the cat appeared to recover from anaemia and physical injury, the kitten died on postoperative day 1. RELEVANCE AND NOVEL INFORMATION: In cases involving only one twisted uterine horn, the fetuses located in the contralateral horn could potentially survive; however, many such fetuses do not survive, and only a few reports have described fetal survival in a pregnant cat with uterine torsion. In the present case, early surgical intervention and blood transfusion allowed us to save the cat. Our findings demonstrate the life-saving abilities of initial support treatment and early surgical intervention for both the pregnant cat and fetuses in cases of acute abdomen caused by uterine torsion. PMID- 28839949 TI - Comparison of fingolimod and dimethyl fumarate in the treatment of multiple sclerosis: Two-year experience. AB - BACKGROUND: Fingolimod (FTY) and dimethyl fumarate (DMF) are multiple sclerosis (MS) oral therapies that became available in 2010 and 2013, respectively. OBJECTIVE: The objective of this article is to compare discontinuation rates, efficacy, and adverse events (AEs) of FTY and DMF over two years. METHODS: Patients prescribed FTY or DMF at the Rocky Mountain MS Center at University of Colorado prior to October 2013 were identified. Clinician-reported data were retrospectively collected. Primary outcome was discontinuation of drug by the end of year two. Reasons for discontinuation were evaluated. RESULTS: A total of 271 FTY and 342 DMF patients were evaluated. Patients had a mean age of 42.5 (FTY) and 45.8 (DMF) years and were predominantly female (72.0% FTY; 69.6% DMF) and white (86.3% FTY; 82.2% DMF). At <=24 months, 93 (34.3%) and 161 (47.1%) discontinued FTY and DMF, respectively, with an unadjusted odds ratio (OR) of 1.70 (1.23-2.37, p = 0.002), or 1.69 (1.16-2.46, p = 0.006) for the doubly robust propensity score weighted estimator. Primary reason for discontinuation was AEs, which were less likely for FTY 46 (17.0%) compared to DMF 82 (24.0%) (OR 1.54, 1.03-2.31, p = 0.035). Discontinuation due to disease activity (FTY (10%) DMF (11.1%); OR 1.13, 0.67-1.90, p = 0.647) and breakthrough disease activity, regardless of discontinuation (FTY (34.7%) DMF (33.6%); OR 0.95, 0.68-1.34, p = 0.783), were similar. CONCLUSIONS: The odds of discontinuation were less for FTY than DMF, and were driven by AEs for both drugs. PMID- 28839950 TI - Application of the Betty Neuman systems model in the nursing care of patients/clients with multiple sclerosis. AB - OBJECTIVE: This study aimed to assess the application of the Betty Neuman systems model to the care of patient/clients with multiple sclerosis. METHODS: This clinical study resulted from the application of the nursing process to a patient/client admitted with multiple sclerosis in the neurological ward of a hospital in an urban area of Iran. RESULTS: A patient/client was evaluated according to the Neuman model. Intrapersonal stressors (physiological, psychological, socio-cultural, and spiritual), interpersonal stressors (being away from family and children) and extra-personal stressors (aggression and psychological pressure from the spouse) were found. Based on the examination, 12 nursing diagnoses based on the taxonomy of the North American Nursing Diagnosis Association International, and nursing care based on three levels of prevention that are important in the view of Neuman, are presented. The results were used in the classification of nursing interventions and the classification and nursing outcomes respectively. CONCLUSIONS: The results suggest the desirability of care and patient/client satisfaction in the evaluation of nursing care based on the Neuman model. The model can be used as a framework to help nurses care for patients/clients. Thus, the application of this model and other models is recommended in the nursing care of patients/clients. PMID- 28839951 TI - Spindle cell/sclerosing rhabdomyosarcoma with intracranial invasion without destroying the bone of the skull base: a case report and literature review. AB - Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a new subtype of rhabdomyosarcoma included in the World Health Organization soft tissue and bone tumor classification in 2013. Despite the increasing number of reported cases of ssRMS, the imaging characteristics of ssRMS are not established. Herein, we present the case of an elderly Japanese woman with ssRMS of the masticator space with intracranial invasion without destruction of the adjacent bone. Attention should be paid to the presence of intracranial infiltration that may indicate a worse prognosis. Tumor growth without bone destruction could be a key finding to differentiate ssRMSs from conventional subtypes of rhabdomyosarcoma. PMID- 28839952 TI - A case of real spinal cord injury without radiologic abnormality in a pediatric patient with spinal cord concussion. AB - INTRODUCTION: Real spinal cord injury without radiologic abnormality (SCIWORA) is a rare clinical entity. CASE PRESENTATION: The patient was a 13-year-old girl whose body was overturned anteriorly after crashing her bicycle into a curb. Following the accident, in which her neck and upper back hit the ground, she could not move due to paralysis. On arrival, she had paresis of the bilateral upper extremities and experienced a painful sensation when her upper extremities were touched. Cervical roentgenography and whole-body computed tomography revealed no traumatic lesions in either the intracranium or the cervical bone. Urgent spinal magnetic resonance imaging (MRI) showed no significant spinal cord lesions or spinal canal stenosis. She was put on complete bed rest with a cervical collar. On the 2nd hospital day (24 h after the accident), her motor weakness had almost completely subsided, and she felt only mild dysesthesia in both forearms. Roentgenography revealed no instability. Her motor weakness completely recovered on the third day after accident and she was diagnosed with spinal cord concussion. DISCUSSION: The present case study, in which MRI was performed, showed that an immediate improvement was obtained in a patient who experienced real SCIWORA. The importance of not only spinal cord lesions, but also perispinal soft tissue injury on MRI has been emphasized for predicting patient outcomes. Accordingly, immediate MRI is essential for evaluating patients with signs and symptoms of spinal cord injury, even when plain neck roentgenography and cervical CT are negative. PMID- 28839953 TI - Re-visiting D-dimers and fibrin degradation products for the diagnosis of acute aortic dissection. PMID- 28839954 TI - The large tumor suppressor family: friend or foe? PMID- 28839955 TI - Allosterically targeting EGFR drug-resistance gatekeeper mutations. PMID- 28839956 TI - CRISPR-barcoding in non small cell lung cancer: from intratumor genetic heterogeneity modeling to cancer therapy application. PMID- 28839957 TI - High flow nasal cannulae for acute viral bronchiolitis in young infants: evidence based medicine is underway to define target populations and optimal flows. PMID- 28839958 TI - Esophageal cancer developed in a radiated field: can we reduce the risk of a poor prognosis cancer? PMID- 28839959 TI - Risk markers for excess mortality in adults with congenital heart disease: does one size fit all? PMID- 28839960 TI - Do we have enough evidence for adjuvant postoperative chemoradiation in esophageal cancer? PMID- 28839961 TI - The pathogenetic role of CMV in intensive care unit patients: the uncertainity remains. PMID- 28839962 TI - Optimized local therapy for locally advanced non-small cell lung cancer. PMID- 28839963 TI - Walking the right path: the story of bioresorbable stents. PMID- 28839964 TI - Prognosis is better, still not good, and variable, for adults with congenital heart disease. PMID- 28839965 TI - Spread through air spaces (STAS): prognostic impact of a semi-quantitative assessment. PMID- 28839966 TI - Neurological complications during veno-venous extracorporeal membrane oxygenation. PMID- 28839967 TI - Yes-associated protein and immunosuppressive microenvironment in pancreatic cancer development: a new strategy to improve immunotherapy efficacy? PMID- 28839968 TI - A critical appraisal of the morphine in the acute pulmonary edema: real or real uncertain? PMID- 28839969 TI - Could tumor location-specific lymph node dissection be a tailored approach? PMID- 28839970 TI - Closing, opening and reopening: the difficult coexistence. PMID- 28839971 TI - Life-style modification at the edge. PMID- 28839972 TI - Oligometastatic non-small cell lung cancer: is there a role for locoregional therapy? PMID- 28839973 TI - Deciding on the neoadjuvant approach for esophageal adenocarcinomas. PMID- 28839974 TI - Effect of evacetrapib on cardiovascular outcomes in patients with high-risk cardiovascular disease. PMID- 28839975 TI - Editorial on: multidisciplinary therapy of marginally operable stage IIIA non small cell lung cancer. PMID- 28839976 TI - Extending the survival advantage of ground glass. PMID- 28839977 TI - Harmful impact of morphine use in acute heart failure. PMID- 28839978 TI - Target blood pressure and cardiovascular risk. PMID- 28839979 TI - Nodal downstaging in esophageal and esophagogastric junction cancer: more important than ever. PMID- 28839980 TI - Vasopressor hormones in shock-noradrenaline, vasopressin or angiotensin II: which one will make the race? PMID- 28839981 TI - Mediastinal lymph node dissection: the debate is not resolved. PMID- 28839982 TI - Morphine in acute heart failure. PMID- 28839983 TI - A female patient with recurrent lung lesion and hilar lymphadenopathy. PMID- 28839984 TI - Theobromine for the treatment of persistent cough: a randomised, multicentre, double-blind, placebo-controlled clinical trial. AB - BACKGROUND: To investigate the effect of BC1036 on health-related quality of life (QOL) in subjects with persistent cough. The secondary objective was to investigate the effect of BC1036 on subjective cough severity. METHODS: This was a randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 289 subjects with persistent cough. Subjects received BC1036 or placebo twice daily for 14 days. The primary endpoint comprised cough-related QOL assessed using the validated Leicester Cough Questionnaire (LCQ) at Day 14. Secondary endpoints comprised the LCQ scores at Day 7 and Day 28, cough severity VAS scores at each visit and pulmonary function tests. RESULTS: At baseline, mean total LCQ score in the BC1036 group was lower (i.e., worse QOL) than placebo (P<0.001), indicating significant between-group heterogeneity. Mean baseline-adjusted change in LCQ score at Day 14 was greater for BC1036 [mean (SD) 2.4+/-3.5] compared to placebo [mean (SD) score 2.2+/-3.0], but did not reach statistical significance (P=0.60). Mean cough severity VAS score decreased to a greater extent in the BC1036 group compared to placebo, but again the results were not statistically significant (-12.2+/-23.28 in BC1036 group and -11.0+/-21.34 in placebo group at Day 14, P=0.688). There was no significant change in pulmonary function measurements. The adverse event (AE) profile was similar in both groups. CONCLUSIONS: This study showed that BC1036 was well tolerated and, although the primary endpoint did not achieve statistical significance, the magnitude of improvement was greater with BC1036 compared to placebo with respect to improving QOL and reducing cough severity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01656668. PMID- 28839985 TI - Sputum mucin 1 is increased during the acute phase of chronic obstructive pulmonary disease exacerbation. AB - BACKGROUND: Mucin 1 (MUC1) is a membrane tethered protein on airway epithelial cells. This protein is upregulated and plays an important anti-inflammatory role during acute lung inflammation. However, the relationship between sputum MUC1 level and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is unknown. METHODS: The levels of MUC1, IL-8, and TNF-alpha in induced sputum from 78 COPD patients were assessed by ELISA. The association between COPD exacerbation and MUC1 fragment levels was analyzed. An acute airway inflammation mouse model was established by intranasal LPS inhalation. The expression of Muc1 in lung and the levels of Muc1, TNF-alpha and KC in BAL fluid from mice were determined with western blotting and ELISA, respectively. RESULTS: Higher levels of MUC1 membrane-tethered (CT) and extracellular (EC) fragments, cytokines TNF alpha and IL-8, more leucocyte and neutrophil counts were found in sputum from COPD patients in acute than in remission phase. Linear regression analysis confirmed that the level of sputum MUC1 CT fragment is positively correlated with sputum neutrophil number and patients' age; whereas the sputum EC fragment level is correlated inversely with FEV1/FVC value and positively with patients' age. Inhalation of lipopolysaccharide (LPS) induced acute lung inflammation in mice which exhibited increased levels of Muc1 CT fragment in lung and only Muc1 EC fragment increase in BAL fluid. CONCLUSIONS: Unlike pure bacterial induced lung inflammation, both sputum MUC1 CT and EC fragments are increased during acute exacerbation of COPD. The clinical benefits from measuring the changes of various sputum MUC1 fragments in AECOPD need to be elucidated in future studies. PMID- 28839986 TI - Comparison of right- and left-approach esophagectomy for elderly patients with operable thoracic esophageal squamous cell carcinoma: a propensity matched study. AB - BACKGROUND: the right- and left-approach open esophagectomies remain the general procedures among patients with operable thoracic esophageal squamous cell carcinoma (ESCC). The choice between the two approaches for elderly patients is controversial. METHODS: we performed a 1:1 propensity score matching (PSM) analysis to compare the impact of right- and left-approach esophagectomies on survival and perioperative complications of elderly ESCC patients. Patients aged over 70 receiving esophagectomy to treat the thoracic ESCC were retrospectively retrieved. RESULTS: a total of 276 patients were included in the study. Among them, 75 (27.2%) patients received right-approach esophagectomy. After match, 114 patients (57 pairs) undertook right or left-approach esophagectomy displayed no difference among clinicopathological characteristics. Both the overall survival (54.6% vs. 32.6%, P=0.036) and disease-free survival (52.7% vs. 20.2%, P=0.021) were significant better in right-approach group, along with better lymph node resection, and lower incidence of recurrence. However, increased incidences of postoperative pneumonia (P=0.040), respiratory failure (P=0.028), and sub clinical anastomotic leak (P=0.032) were found in right-approach group as well, although the perioperative mortality was similar between groups. CONCLUSIONS: Right-approach esophagectomy should be accepted as a preferential surgical approach for elderly patients with ESCC. PMID- 28839987 TI - Effect of Huisheng oral solution on coagulation function in perioperative period in patients with primary lung cancer. AB - BACKGROUND: The incidence of venous thromboembolism (VTE) is about 4-10% in lung cancer patients. Huisheng oral solution (HSOS) has been previously demonstrated to inhibit carageenan induced acute thrombosis in rats, reduce the incidence of thrombosis in the lungs and mesentery of tumor-bearing mice and inhibit tumor cell metastasis. The purpose of this study was to assess the anticoagulant effect of HSOS in lung cancer patients in the perioperative period. METHODS: This study was a multicenter, randomized, single-blind, blank-controlled clinical trial. A total of patients at five hospitals in Hebei Province, China were included. The patients were randomly divided into study group or control group according to random number table. The primary outcome was the blood test indices in both groups. The study group was given oral HSOS (20 mL, bid) from admission until 24 h before surgery. If no active bleeding was observed, the patients were given oral HSOS (20 mL, tid) from 24 h to 24 d postoperatively. The patients in the study group did not receive any other anticoagulation therapy during the study period and the control group only underwent surgery. The study protocol was approved by the local ethics committee of principal investigator hospital. Blood samples were taken at admission (before therapy), 24 h, 72 h, 10 d (before discharge) and 24 d (first visit after discharge) after surgery. Routine blood tests [red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin (HGB), and platelet (PLT) count] and coagulation function test [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), and plasma D-dimer] were performed. The changes in outcome measures over time were analyzed by repeated measures analysis of variance to compare the differences between groups and between different time points and assess the impact of tumor stage and mode of surgery on them. All tests were two tailed, and P values <0.05 were considered statistically significant. RESULTS: The results differed between different tumor stage groups. In stage III-IV group, there was no significant difference in various indices between the study group and control group. In stage I-II group, there was significant difference in hemoglobin (P=0.004), platelet count (P=0.007), fibrinogen (P=0.046), and plasma D-dimer (24 d: P=0.032) between two groups. Fibrinogen reach the peak 72 h after surgery, and other indices reach the peak 7-10 d postoperatively and declined one month after surgery, and the decline tendency was different between two groups. In addition, no adverse drug reaction was observed in both the study group and control group. CONCLUSIONS: HSOS (20 mL, tid) is of good safety profile and does not increase the risk of bleeding. With its unique characteristic of convenience for being taken, HSOS (20 mL, tid) could be a proper treatment for lung cancer patients in the perioperative period. PMID- 28839988 TI - Prognostic significance of sites of extrathoracic metastasis in patients with non small cell lung cancer. AB - BACKGROUND: Metastatic non-small cell lung cancer (NSCLC) continues to have a poor prognosis despite recent advances in both targeted radiotherapy methodologies such as stereotactic body radiotherapy (SBRT) and immunotherapies. The impact of location of metastatic disease in patients with NSCLC has not been investigated; we aimed to investigate this using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: We included 39,910 patients from the SEER database treated for M1b NSCLC from 2010-2013. We identified patients with metastatic disease in the brain, lung, liver, and bone. We used Kaplan-Meier analyses and Cox proportional hazards models to assess the impact of varying sites of metastatic disease on overall survival (OS). RESULTS: Patients with disease coded as in the brain without other disease in the lung, liver, or bone had improved OS relative to all other comers with M1b disease (HR =0.84, 95% CI, 0.84-0.90, P<0.001). Likewise, patients with disease coded as in the bone without other disease in the lung, liver, or brain had improved OS relative to all other comers with M1b disease (HR =0.89, 95% CI, 0.86-0.92, P<0.001). CONCLUSIONS: This hypothesis-generating analysis suggests that patients with limited metastatic NSCLC to the bone or brain may particularly benefit from aggressive upfront therapies. PMID- 28839989 TI - Factors affecting satisfaction with education program for chronic airway disease in primary care settings. AB - BACKGROUND: A well-organized education program improved the patients' knowledge about their disease, inhaler technique and quality of life in asthma and chronic obstructive pulmonary disease (COPD) patients. The effectiveness of the education program can be evaluated by assessing patients' satisfaction with the education program as well. In this study, we compared the patients' satisfaction with education program between COPD and asthma patients. METHODS: A total of 284 asthma and COPD patients were enrolled. Three educational visits were conducted at 2-week intervals. On the first visit, we taught the patients about their diseases and the proper inhaler technique. On the second visit, non-pharmacologic treatments and action plans for acute exacerbation were introduced. On the final appointment, we summarized the educational concepts covered in the two prior visits. After the education program, the patients were assessed for their quality of life, knowledge of chronic airways disease, and satisfaction with the education program, using a structured questionnaire. RESULTS: After the education program, 99.3% of the asthma patients knew much more about their disease and 96.8% agreed that education from the hospital is needed. For COPD patients, 94.8% felt more informed about their disease and 95.7% agreed that education from the hospital is needed. However, 17.1% of asthma patients and 13.5% of COPD patients disagreed to paying an additional fee for the education program. Finally, the knowledge improvement was linked to patient satisfaction with the education program. CONCLUSIONS: The improvement in self-knowledge about their disease was linked to their satisfaction with the education program. However, costs associated with the program could limit its accessibility to the patients. The patient education program is a self-management intervention to improve the lives of patients with asthma and COPD. Thus, a policy to reduce the economic burden of the patients should be considered to disseminate the education program in primary care clinics. PMID- 28839990 TI - Short-term high-intensity rehabilitation in radically treated lung cancer: a three-armed randomized controlled trial. AB - BACKGROUND: The feasibility and practicality of preoperative rehabilitation (PR) programs remains quite controversial in the treatment of lung cancer (LC). This study explored whether a short-term high-intensity rehabilitation program could improve postoperative outcomes compared to those achieved with conventional inspiratory muscle training (IMT). METHODS: A three-armed randomized controlled trial comparing the two training modalities and routine care was conducted in surgical LC patients. Patient groups received one of three treatment regimens: (I) high-intensity pulmonary rehabilitation (PR) that combined IMT with conventional resistance training (CRT) (combined PR group); (II) conventional PR (single IMT group); or (III) routine preoperative preparation (control group). The primary endpoint was a change in the occurrence of post-operative pulmonary complications (PPCs) that occurred within 30 days after surgery, while secondary endpoints included changes in length of hospital stay, quality of life (QoL) scores, 6-min walk distance (6-MWD) and peak expiratory flow (PEF). RESULTS: A total of 90 enrolled patients were randomized into three groups with a computer based 1:1:1 ratio. The intention-to-treat analysis of the study revealed that, compared with the Control Group, the Combined PR Group had a significant increase in ?6-MWD (by 32.67 m, P=0.002), ?PEF (by 14.3 L/min, P=0.001), ?global scores (by 3.7, P=0.035); and a reduced ?average total hospital stay (by 3.2 d, P=0.001) and ?postoperative stay (by 3.6 d, P=0.001). With regard to PPC rate, the Combined PR Group had a somewhat lower PPC severity (grade II-V) compared to the Control Group. CONCLUSIONS: This hospital-based short-term program of PR combining high-intensity IMT with CRT was significantly superior to the conventional IMT program, indicating that this approach would be a feasible strategy for treating LC patients, especially those waiting operations with surgery-related risk factors. PMID- 28839991 TI - Combination of virtual bronchoscopic navigation, endobronchial ultrasound, and rapid on-site evaluation for diagnosing small peripheral pulmonary lesions: a prospective phase II study. AB - BACKGROUND: The diagnostic yield of peripheral pulmonary lesions (PPLs) by flexible bronchoscopy (FB) is still insufficient. To improve the diagnostic yield of bronchoscopy, several techniques such as endobronchial ultrasound (EBUS), virtual bronchoscopic navigation (VBN), and rapid on-site evaluation (ROSE) have been examined. The primary purpose of the present study was to evaluate the usefulness of combining EBUS, VBN, and ROSE for diagnosing small PPLs. METHODS: Patients with PPLs 30 mm or less on chest computed tomography (CT) were prospectively enrolled. We determined the responsible bronchus for the target lesions using VBN before bronchoscopy was performed. EBUS and ROSE were performed during the examination to determine whether the bronchus and specimen were adequate. On the basis of previous studies, we assumed that the diagnostic yield of 85% among eligible patients would indicate potential usefulness, whereas, the diagnostic yield of 75% would indicate the lower limit of interest. The required number of patients was estimated as 45 for a one-sided alpha value of 0.2 and a beta value of 0.8. The primary study endpoint was the diagnostic yield. RESULTS: Between June 2014 and July 2015, we enrolled 50 patients in the present study, and we excluded 5 patients. The total diagnostic yield of 45 PPLs was 77.7%. In cases of lung cancer, the diagnostic yield was 84.2%. The sensitivity, specificity, positive predictive value, and negative predictive value of ROSE were 90.6%, 92.3%, 96.7%, and 80.0%, respectively. The diagnostic yield of PPLs from 20 to 30 mm was 87.5%, and the diagnostic yield of PPLs less than 20 mm was 66.7%. PPLs for which the probe was located within the lesion had the highest diagnostic yield. CONCLUSIONS: We could not demonstrate usefulness for diagnosing small PPLs by combining EBUS, VBN, and ROSE. However, combining these techniques may be useful for diagnosing lung cancer. PMID- 28839992 TI - Optical coherence tomography in imaging of peripheral pulmonary arteries. AB - BACKGROUND: To establish an optical coherence tomography (OCT)-based method for imaging peripheral pulmonary arteries. METHODS: We recruited eight patients (five men; average age, 48+/-12 years; peripheral pulmonary artery thrombosis, three patients; idiopathic pulmonary hypertension, three patients; interstitial lung disease, two patients) who underwent OCT of the peripheral pulmonary arteries in the First Affiliated Hospital of Guangzhou Medical University and Guangzhou Institute of Respiratory Diseases, between September 2009 and September 2010. OCT was performed using both the conventional OCT imaging method (COI) and the improved pulmonary artery imaging method (IPI). In the IPI, contrast agent was used as an indicator of balloon inflation meanwhile increases in flushing speed of the replacement fluid. The percentage of optimal images, inflation pressure, flushing speeds and complications were compared between the two methods. RESULTS: We performed OCT of 33 vessel segments by both methods. IPI produced more optimal images than COI (88% vs. 24%). Mean inflation pressure and flushing speed were higher during IPI than COI (0.62+/-0.15 vs. 0.43+/-0.08 atm; 1 atm =101.3 kPa; 0.82+/-0.10 vs. 0.42+/-0.06 mL/s; both P<0.01). Decreased blood oxygen saturation (SaO2) was associated with 9% and 30% segments (P<0.01) in the COI (mean decrease, 8.4%+/-3.6%) and IPI groups (mean decrease, 12.1%+/-5.3%; P<0.05) respectively. SaO2 recovered to pre-imaging levels after oxygen inhalation. CONCLUSIONS: IPI is safe and effective for OCT of peripheral pulmonary arteries. PMID- 28839993 TI - Screening for obstructive sleep apnea syndrome in asthma patients: a prospective study based on Berlin and STOP-Bang questionnaires. AB - BACKGROUND: The bidirectional relationship of asthma and obstructive sleep apnea (OSA) has been confirmed in recent years. However, in the clinical practice, majority of asthma patients did not pay adequate attention to their sleep apnea condition. Berlin questionnaire (BQ) and STOP-Bang questionnaire (SBQ) are two most common OSA screening questionnaires to screen high-risk patients for OSA. This study aimed at evaluating the predictive performance of BQ and SBQ for OSA in asthma patients. METHODS: Asthma outpatients of Zhongshan Hospital were enrolled into the study. All patients were asked to fill in the BQ and SBQ and clinical characteristics and asthma characteristics were recorded. Univariate and multivariate logistic regression analyses were applied to identify risk factors of OSA in asthma patients. With the gold standard of laboratory-based overnight polysomnography (PSG), the predictive performance of SBQ and BQ was evaluated and compared. The probability of OSA severity was predicted by various SBQ scores in asthma patients. RESULTS: A total of 123 asthma patients (average age 47.56+/ 12.12 years; 57.72% males) were enrolled and underwent PSG diagnosis overnight at Sleep Center. Logistic regression analyses showed that rhinitis (adjusted OR =4.30; 95% CI: 1.50-12.37, P=0.007) and dyslipidemia (adjusted OR =2.75; 95% CI: 1.16-6.51, P=0.021) were associated with OSA in asthma patients after adjusting for known OSA risk factors. No asthma functional characteristic differences were found to be associated with OSA severity in the study. The prevalence of moderate to-severe OSA (AHI >=15) in the asthmatic population sample was 36.59% (45/123). Questionnaires predictive results showed that compared with BQ, SBQ has higher diagnostic sensitivity (84.4% vs. 60%), lower specificity (79.5% vs. 91%) lower positive predictive value (PPV): (70.4% vs. 79.4%) and higher negative predictive value (NPV) (90% vs. 80%) to detect moderate-to-severe OSA at the cut-off as AHI of 15/h. OSA probability results showed that with the increasing of the questionnaire scores, the moderate and severe OSA probability of SBQ rose significantly. CONCLUSIONS: SBQ is a preferable sleep questionnaire better than BQ for detecting moderate and severe OSA in asthma patients which should be validated in larger population sample. PMID- 28839994 TI - Transcutaneous electrical acupoint stimulation (TEAS) relieved cancer-related fatigue in non-small cell lung cancer (NSCLC) patients after chemotherapy. AB - BACKGROUND: To explore the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) approach on cancer-related fatigue (CRF) in non-small cell lung cancer (NSCLC) chemotherapy patients. METHODS: A total of 162 participants who treated with gemcitabine combined with platinum-based drugs (GP chemotherapy) were randomly assigned to three groups: Control (Group A, n=56), Sham TEAS (Group B, n=49), and TEAS (Group C, n=57). The following acupoints were used in this study: Qihai (CV6), Keshu (UB17), and Zusanli (ST36). The Revised Piper Fatigue Scale (RPFS) were used to measure CRF on the day before chemotherapy (P1), days 8 (P2) and 28 (P3) separately. The Differences among three groups were analyzed. RESULTS: At the 28th day, the outcomes of the fatigue scores for Group C, Group B and Group A were 2.06+/-0.90, 2.80+/-1.34, 3.00+/-1.29 respectively. There were significantly different among three groups (F=9.784, P<0.01). At the 28th day, the outcomes of the affective fatigue (F=8.161, P<0.01), sensory fatigue (F=3.06, P=0.05) and cognitive fatigue (F=8.06, P<0.01) for Group C, Group B and Group A were significantly different among three groups. CONCLUSIONS: Chemotherapy may increase the fatigue from P1 to P2 and P3 in NSCLC patients. And TEAS could help to relived CRF, especially at P3. PMID- 28839995 TI - Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax. AB - BACKGROUND: Familial spontaneous pneumothorax (FSP) is an inherited disease, and Birt-Hogg-Dube (BHD) syndrome is its leading cause. BHD syndrome is an autosomal dominant disorder characterized by pulmonary cysts, spontaneous pneumothorax, renal cancer, and skin fibrofolliculomas. It is caused by germline mutations in the FLCN gene. Thus far a variety of mutations have been reported; however, the unique characteristics of BHD syndrome-related FSP are still unclear. METHOD: We reviewed the family history of a large Chinese family that presented with FSP. Genetic testing of the FLCN gene was performed and the special clinical characteristics of BHD syndrome-related FSP were discussed. RESULTS: This family comprised 5 generations and 76 members. Six of these had experienced pneumothorax episodes and 35 members had undergone genetic analysis of the FLCN gene, except for one member who had pneumothorax. Among the 35 members, 17 had the mutation in the FLCN gene. All five members with pneumothorax had the mutation. Frequency of pneumothorax in the mutation members was 29.4% (5/17). Clinical characteristics of the BHD syndrome-related pneumothorax differed from those of primary spontaneous pneumothorax, which typically affects tall, thin young men, and the recurrence rate of BHD syndrome-related pneumothorax after observation, needle aspiration or tube drainage was higher than that of primary spontaneous pneumothorax, and higher than that observed after VATS bullectomy and mechanical pleurodesis. CONCLUSIONS: We reported the largest single family that presented with FSP from China. The clinical and genetic characteristics of the BHD syndrome related pneumothorax differ from those of primary spontaneous pneumothorax. PMID- 28839996 TI - Clinical profiles and trend analysis of newly diagnosed lung cancer in a tertiary care hospital of East China during 2011-2015. AB - BACKGROUND: More than one-third of lung cancer worldwide occurring in China. However, the clinical profiles of lung cancer patients in the mainland of China are rarely reported and largely unknown. The objective of this study is to analyze the characteristics and time trends of newly diagnosed lung cancer cases during the past 5 years in East China. METHODS: The data came from an academic tertiary care hospital of East China. Patients who were newly diagnosed as lung cancer from 2011 to 2015 were enrolled. All new cases got pathological supports by lung biopsy or surgery. Tumor staging was performed according to the seventh edition of the tumor node metastasis (TNM) classification of malignant tumors. The patients' disease information was collected from the database of the hospital information system (HIS). RESULTS: From 2011 to 2015, aggregately 5,779 patients, including 3,719 males and 2,060 females, were diagnosed as lung cancer. The major histologic subtypes of lung cancer were adenocarcinoma (ADC, 60.0%), squamous cell carcinoma (SCC, 25.6%), small cell lung cancer (SCLC, 8.5%), large cell carcinoma (0.6%), adenosquamous carcinoma (1%), other non-small cell carcinoma (1.6%) and unclassified or rare carcinoma (2.8%). ADC proportion of female was much higher than that of male. A higher proportion of advanced stage (stage IIIB, IV) of lung cancer existed in patients who were admitted to hospital due to respiratory or cancer related symptoms (RCRS) than those without RCRS. Smoking rate in male patients reached 80.2%, while it was only 2.7% in females. EGFR mutation existed in 66% of female and 37% of male patients with ADC. CONCLUSIONS: This study demonstrates the clinicopathologic characteristics of lung cancer patients from East China, including histologic composition, staging proportion, smoking prevalence and gene mutation status. During the past 5 years, the proportion of ADC has increased gradually whereas SCC decreased. PMID- 28839998 TI - High rate of arterial complications in patients supported with extracorporeal life support for drug intoxication-induced refractory cardiogenic shock or cardiac arrest. AB - BACKGROUND: Cardiac failure is still a leading cause of death in drug intoxication. Extracorporeal life support (ECLS) could be used as a rescue therapeutic option in patients developing refractory cardiogenic shock or cardiac arrest. The aim of this report is to present our results of ECLS in the setting of poisoning from cardiotoxic drugs. METHODS: We included in this analysis consecutive patients who received an ECLS for refractory cardiogenic shock or in hospital cardiac arrest due to drug intoxication. The primary endpoint of our study was survival to hospital discharge with good neurological recovery after ECLS support. RESULTS: Between January 2010 and December 2015, we performed 12 ECLS. Mean age was 44.2+/-17.8 years and there was a predominance of females (66.7%). Drug intoxication was mainly due to beta-blockers and/or calcium channel inhibitors (83.3%) and 5 (41.7%) patients had multiple drugs overdose. Weaning rate and survival to hospital discharge with good neurological recovery were 75% (9 patients). Among patients weaned from ECLS, mean duration of support was 2.4+/ 1.1 days. Three (25%) patients underwent ECLS implantation during cardiopulmonary resuscitation, 2 (66.6%) of them died while on mechanical circulatory support (MCS). Six (50%) patients developed lower limb ischemia. Each patient was managed with ECLS decannulation: 2 (16.7%) patients underwent a concomitant iliofemoral thrombectomy, 3 (25%) needed further fasciotomy and the remaining patient (8.3%) required an amputation. CONCLUSIONS: Refractory cardiogenic shock due to drug intoxication is still one of the best indications for ECLS owing to the satisfactory survival with good neurological outcome in such a critically ill population. Further data are however necessary in order to best understand the possible relation between drug intoxication and lower limb ischemia, which was quite superior to the reported rates. PMID- 28839997 TI - The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis. AB - BACKGROUND: The first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, have become the standard first line treatment for non-small-cell lung cancer (NSCLC) patients with EGFR mutation. However, there was no pooled analysis focused on the usage of the second-generation TKI, afatinib, in advanced EGFR-positive NSCLC patients after failure of first generation TKIs. Therefore, a meta-analysis was conducted to solve the above question. METHODS: Electronic databases were searched for eligible literatures. ORR (objective response rate), DCR (disease controlled rate), PFS (progression-free survival), OS (overall survival) and primary grade 3/4 adverse events were pooled with the corresponding 95% confidence interval using R software. Sensitivity analyses and heterogeneity were quantitatively evaluated. RESULTS: A total of 545 EGFR-positive patients were available for analysis from five studies after detailed screening from 909 relevant studies. The pooled ORR and DCR of afatinib in EGFR-positive patients after failure of the first generation EGFR-TKIs were 0.12 (0.08-0.19) and 0.60 (0.53-0.68), respectively. Besides, the 6 m-PFS rate, 1 y-PFS rate and 6 m-OS rate were 0.26 (0.22-0.30), 0.08 (0.06-0.10) and 0.74 (0.56-0.86). The grade 3/4 rate of diarrhea and that of skin deformity were 0.23 (0.10-0.46) and 0.14 (0.05-0.33), respectively. Sensitivity analyses revealed similar results with lower heterogeneity. CONCLUSIONS: Considering the efficacy, toxicity and current availability, afatinib could be a therapeutic option for advanced EGFR mutated NSCLC patients after the failure of 1st-generation TKIs. PMID- 28839999 TI - A comparison of three approaches for the treatment of early-stage thymomas: robot assisted thoracic surgery, video-assisted thoracic surgery, and median sternotomy. AB - BACKGROUND: This aim of this study was to compare three approaches of extended thymectomy for the treatment of early-stage thymomas, which included robot assisted thoracic surgery (RATS), video-assisted thoracic surgery (VATS), and median sternotomy (MS) perioperative parameters. METHODS: A retrospective study was conducted on 123 patients with early stage thymomas at Shanghai Chest Hospital who underwent extended thymectomy between February 2009 and August 2014. Among them, MS was performed on 37 patients, VATS was performed on 35 patients, and RATS was performed on 51 patients. A series of outcome measures were compared between these three approaches, including operative time, intra-operative blood loss volume, occurrence of intra-operative complications, post-operative pleural drainage duration, post-operative pleural drainage volume, duration of hospital stay, and the incidence of post-operative complications. RESULTS: A series of intra- and post-operative parameters showed significant differences in intra operative blood loss volume, mean post-operative pleural drainage duration, pleural drainage volume and mean duration of hospital stay. For these parameters, during further analysis, significant differences were also demonstrated for comparisons between any two groups. RATS reduces the post-operative drainage duration and volume (2.88 vs. 3.77 and 4.41 days, P<0.05; 352.2 vs. 613.9 and 980 mL, P<0.05) and the hospital stay versus the MS and VATS groups (4.3 vs. 5.5 and 6.6 days). Three patients experienced post-operative complications in the MS group, and no post-operative complications occurred in the RATS or VATS group. CONCLUSIONS: RATS and VATS both appear feasible and safe for the resection of early-stage thymomas as compared to MS. RATS is less invasive than VATS with a shorter post-operative pleural drainage duration time, a reduced drainage volume, and a shorter hospital stay. PMID- 28840000 TI - A meta-analysis of video-assisted thoracoscopic decortication versus open thoracotomy decortication for patients with empyema. AB - BACKGROUND: Thoracic pleural empyema is a collection of pus within a thoracic cavity. In stage 2 (fibrinopurulent) and stage 3 (organizational), decortication is the only choice. But there is no consensus on whether to choose video-assisted thoracoscopic decortication (VATD) or open thoracotomy decortication (OTD). We sought to answer this question by performing a meta-analysis. METHOD: Six electronic databases were searched. Primary outcomes were operative time, postoperative hospital stay, prolonged air leak, chest tube duration, relapse rate, morbidity and mortality. Review Manager (RevMan) [Computer program]. Version 5.2, 2014 was used to pool the data. Subgroup analysis and publication bias analysis were also conducted. RESULT: The operative time [mean difference 36.89; 95% confidence interval (CI), -60.96 to -12.82; P=0.003], postoperative hospital stay (mean difference -2.41; 95% CI, -3.74 to -1.09; P=0.0004), prolonged air leak (9.7% vs. 17.1%; RR 0.56; 95% CI, 0.33 to 0.94; P=0.03), chest tube duration (mean difference -1.52; 95% CI, -2.55 to -0.48; P=0.004), morbidity (16.4% vs. 24.5%; RR 0.62; 95% CI, 0.44 to 0.88; P=0.007) and mortality (4.1% vs. 6.2%; RR 0.47; 95% CI, 0.26 to 0.86; P=0.01) of VATD were statistically less than the OTD. In terms of relapse rate, there was no statistical significance between two surgical approaches (7.2% vs. 4.2%; RRN1.28; 95% CI, 0.39 to 4.15; P=0.68). CONCLUSIONS: The present study summarized and compared the clinical outcomes of VATD versus OTD for the empyema patients. The current data showed that VATD might be comparable or even better than OTD in terms of operative time, postoperative hospital stay, chest tube duration, prolonged air leak rate, morbidity and mortality. But referring to the relapse rate, there was no statistical significance. The results from analysis was subject bias because of prospective randomized studies were not selected. However, VATD could be implemented safely as first-line management for most of empyema. PMID- 28840001 TI - Bronchial hyperreactivity in perimenstrual asthma is associated with increased Th 2 response in lower airways. AB - BACKGROUND: Perimenstrual asthma (PMA) is a commonly observed, usually difficult to-treat asthma phenotype. The mechanisms underlying this phenomenon remain unexplained. The aim of the study was to assess the degree of airway hyperresponsiveness and its relationship to proinflammatory cytokines concentration in lower airways of PMA compared to non-PMA patients. METHODS: Premenopausal women with regular menstrual cycles diagnosed as: PMA (n=12), non PMA asthmatics (n=9), and healthy controls (n=10) were prospectively followed for 10 weeks over two consecutive menstrual cycles. The bronchial responsiveness (BR) test to methacholine was performed in each subject prior to the study. The serum for total immunoglobulin E (IgE) concentrations was taken and sputum was induced in the 26th day of each of the two cycles. Sputum concentration of eotaxin, IL-4 and IL-10 were measured by ELISA. RESULTS: Levels of BR to metacholine as well, as total blood IgE concentrations in PMA subjects were significantly higher than in non-PMA asthmatics and healthy controls (P=0.001, P=0.022 respectively) and correlated with each other (P=0.030; r =-0.65). Sputum eotaxin and IL-4 concentrations in luteal phase were increased in PMA patients when compared with non-PMA asthmatics (P=0.016; P=0.041, respectively) and healthy subjects (P<0.001 both cytokines). No differences for the sputum levels of IL-10 among studied groups were seen. CONCLUSIONS: BR level in perimenstrual asthma is higher than in non-PMA asthmatics and correlates with increased total IgE serum concentration. The increased level of BR in PMA patients is associated with a shift in the type 1/type-2 cytokine balance toward a type-2 response. PMID- 28840002 TI - Video-assisted thoracoscopic surgery for intrathoracic first rib resection in thoracic outlet syndrome. AB - BACKGROUND: First rib resection is a surgical treatment for decompressing the neurovascular structures in thoracic outlet syndrome (TOS). Historically, extrathoracic approaches have used a posterior, supraclavicular, or transaxillary incision to remove the first rib. In this report, we demonstrate video-assisted thoracoscopic surgery for intrathoracic first rib resection (VATS-IFRR). METHODS: Between 2009 and 2014, eight patients underwent VATS-IFRR for TOS. Surgery was performed through two 5-mm ports and one 10-mm port. Endoscopic graspers, a hook type electrocautery probe, a long peapod intervertebral disc rongeur, and Kerrison punches were used. The types of disease, operative times, chest tube indwelling days, lengths of hospital stay after operation, perioperative complications, postoperative pain scale ratings, and postoperative symptom recurrence rates at provocation tests were reviewed. The surgical outcomes were compared to published outcomes of extrathoracic approaches and other VATS approaches. RESULTS: The eight patients (3 right ribs, 5 left ribs) exhibited neurogenic (1 patient), combined type (2 patients), arterial (4 patients), and venous type (1 patient) TOS. The mean operative time was 190 (range 155-310) minutes. No mortalities or major complications occurred. The mean chest tube indwelling duration was 6 (range 3-10) days, and the mean postoperative hospital stay was 9 (range 4-21) days. The mean immediate postoperative pain numeric rating scale (NRS) score was 2.7/10 (range 2-4). No recurrence was observed during follow-up (median 25.5 months, range 10-64 months) in any patient. CONCLUSIONS: VATS-IFRR was safe and had several advantages. Thus, VATS-IFRR is a minimally invasive surgical option suitable for treating selective cases of TOS. PMID- 28840003 TI - Expedite recovery from esophagectomy and reconstruction for esophageal squamous cell carcinoma after perioperative management protocol reinvention. AB - BACKGROUND: Surgery for esophageal cancer is invasive and challenging, and always to be followed with arduous post-operative care and recovery. This study, maybe one of the first in Asian populations, is to determine whether a reinvented protocol for perioperative management for esophageal cancer surgery which is being implemented in our department, will lead to a faster convalescence and also significantly decrease financial burdens garnered by patients during hospitalization. METHODS: Operated on by the same surgeon and team in the same hospital, consecutive patients who had received esophagectomy and reconstruction for esophageal squamous cell carcinoma were retrospectively reviewed. On the basis of two different treatment periods, patients were divided into two groups: A and B. Group A was patients who had received the new reinvented protocol between 2012 and 2016, while group B patients were those having received the previous protocol between 2008 and 2011. Their demographics, post-operative outcome, and hospital charges were collected and compared. RESULTS: There were 64 patients in group A, and 69 in group B. Ventilator days (P<0.001), ICU stay (P<0.001), and post-operative stay (P<0.001) were significantly shorter in group A patients. Complication rates were similar between the two groups. No hospital mortality was noted in either group. Hospital charges in group A were found to be perceptively lower, although not statistically significant (P value =0.078). CONCLUSIONS: The current protocol of perioperative care effectively ameliorated convalescence after esophagectomy and reconstruction for esophageal squamous cell carcinoma without increasing complication rate or mortality. It is also potentially more practical in future health care policies during this era of financial shortage. PMID- 28840004 TI - Effects of cryopreservation on tracheal allograft antigenicity in dogs. AB - BACKGROUND: Prolonged cryopreservation (~8-10 months) has been shown to reduce the antigenicity of tracheal allografts due to subsequent denuding of epithelium. In the present study, tracheal epithelium was assessed after variable periods of cryopreservation. Immunosuppressant-free allotransplantation was then undertaken to evaluate the impact of cryopreservation on tracheal antigenicity in dogs. METHODS: Tracheal rings [7-8] were removed from mongrel adult dogs for cryopreservation (1-10 months, -85 degrees C) and grafting. Before transplantation, one ring was sectioned from each end for histologic examination. The residual five-ring segments of mediastinal trachea were then transplanted into recipient dogs after 1-7 months (group 1, n=9) or 8-10 months (group 2, n=6) of cryopreservation. Anastomotic sites and allografts were covered by omental pedicles. No immunosuppressants whatsoever were administered. RESULTS: In microscopic views, the ciliated tracheal epithelium of most grafts showed variable loss but was generally intact after cryopreservation, still demonstrating major histocompatibility complex (MHC)-II positivity. By postoperative bronchoscopy, allografts in both groups had largely developed lethal strictures. In group 1, eight dogs were sacrificed or died within 50 days post-transplantation, whereas survival times in group 2 were somewhat longer, with three dogs surviving for >60 days. Upon sacrifice, histologic preparations of grafted tissue in both groups were typically denuded of epithelium, with marked lymphocytic/monocytic submucosal infiltrates. Tracheal cartilage had been absorbed or destroyed. CONCLUSIONS: After cryopreservation, some degree of tracheal epithelium loss maybe expected, but complete denudation is not obligatory. Retained epithelial antigenicity is thus capable of triggering rejection, resulting in transplant failures. Although prolonging transplant survival to an extent, fatal rejection of tracheal allografts was not preventable by prior cryopreservation. PMID- 28840005 TI - Outcomes after implementing the enhanced recovery after surgery protocol for patients undergoing tuberculous empyema operations. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols provide recommendations for care in various surgical fields. However, there is scarce information on the application of these protocols in tuberculous empyema surgery. The purpose of this research is to evaluate the outcomes of ERAS recommendations for patients who received tuberculous empyema surgery. METHODS: A retrospective analysis was performed on patients who underwent tuberculous empyema surgery in our hospital from March 2011 to March 2016. The patients were divided into an ERAS group and a conventional control group. The main outcome measure was the postoperative median length of stay (including readmissions). Principles related to ERAS were documented, and the postoperative median hospital stay was analyzed statistically between the two groups. RESULTS: A total of 92 patients underwent 93 consecutive tuberculous empyema surgical treatments. The postoperative fasting time, chest tube duration, and length of stay were shorter in the ERAS group compared with the control group. The volume of chest tube drainage in the ERAS group was significantly smaller than that of the control group. No statistical differences were observed in the postoperative complications and reasons for readmission between the two groups. CONCLUSIONS: Application of ERAS recommendations in patients receiving tuberculous empyema operations decreased the length of stay and chest tube drainage compared to the control group. PMID- 28840006 TI - Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients. AB - BACKGROUND: Protein regulator of cytokinesis-1 (PRC1) has been shown to participate in the completion of cytokinesis, and it is dysregulated in cancer processes. However, its relevance in lung squamous cell carcinoma (SCC) remained largely unknown. We aimed to study the expression pattern of PRC1 and assess its clinical significance in lung SCC. METHODS: PRC1 protein expression in human lung SCC and adjacent normal lung tissues was detected by immunohistochemistry. PRC1 expression was assessed in association with clinicopathological features and clinical outcomes of lung SCC patients. RESULTS: In lung SCC tissues, PRC1 protein expression was significantly higher than those in paired normal lung tissues. The lung SCC patients with PRC1 overexpression had an advanced pathological stage (TNM stage), positive lymph node metastasis, and a shorter overall survival (OS) time more frequently than patients with low PRC1 expression. Additional, PRC1 expression was also shown to be poor as a prognostic factor for OS in patients with lung SCC. CONCLUSIONS: Our study indicated that aberrant expression of PRC1 may point to biochemical recurrence in lung SCC. This highlights its potential as a valuable prognostic marker for lung SCC. PMID- 28840007 TI - Nodal management and upstaging of disease: initial results from the Italian VATS Lobectomy Registry. AB - BACKGROUND: VATS lobectomy is an established option for the treatment of early stage NSCLC. Complete lymph node dissection (CD), systematic sampling (SS) or resecting a specific number of lymph nodes (LNs) and stations are possible intra operative LN management strategies. METHODS: All VATS lobectomies from the "Italian VATS Group" prospective database were retrospectively reviewed. The type of surgical approach (CD or SS), number of LN resected (RN), the positive/resected LN ratio (LNR) and the number and types of positive LN stations were recorded. The rates of nodal upstaging were assessed based on different LN management strategies. RESULTS: CD was the most frequent approach (72.3%). Nodal upstaging rates were 6.03% (N0-to-N1), 5.45% (N0-to-N2), and 0.58% (N1-to-N2). There was no difference in N1 or N2 upstaging rates between CD and SS. The number of resected nodes was correlated with both N1 (OR =1.02; CI, 1.01-1.04; P=0.03) and N2 (OR =1.02; CI, 1.01-1.05; P=0.001) upstaging. Resecting 12 nodes had the best ability to predict upstaging (6 N1 LN or 7 N2 LN). The finding of two positive LN stations best predicted N2 upstaging [area under the curve (AUC) of receiver operating characteristic (ROC) =0.98]. CONCLUSIONS: Nodal upstaging (and, indirectly, the effectiveness of intra-operative nodal management) cannot be predicted based on the surgical technique (CD or SS). A quantitative assessment of intra-operative LN management may be a more appropriate and measurable approach to justify the extension of LN resection during VATS lobectomy. PMID- 28840008 TI - Differences between low and high grade fetal adenocarcinoma of the lung: a clinicopathological and molecular study. AB - BACKGROUND: Fetal adenocarcinoma of the lung (FLAC) is a rare entity of lung cancer. It is classified into low-grade fetal adenocarcinoma (L-FLAC) and high grade fetal adenocarcinoma (H-FLAC). We aim to report the clinicopathological and molecular features of FLAC in Chinese patients. METHODS: FLACs were screened from a consecutive lung adenocarcinoma series comprising 920 cases. The clinicopathological features L-FLAC and H-FLAC were retrospectively reviewed via immunohistochemical study and mutation analysis. RESULTS: Three L-FLAC and five H FLAC cases were identified. L-FLAC mainly occurred in young patients and was predominantly in stage I upon diagnosis and conferred favorable outcomes. L-FLAC tumors were characterized by the glycogen-rich columnar cells lining the complex glandular structures, with low nuclear atypia, morule formation, and mainly nuclear- and cytoplasmic-localized beta-catenin expression. In contrast, H-FLAC predominantly occurred in elderly men with a history of smoking. The stage of H FLAC was often advanced at presentation and had a poor prognosis. H-FLAC tumors exhibited more prominent atypia of the nucleus, the absence of morule formation, and largely membrane-localized beta-catenin. All 5 H-FLACs were immunohistochemically characterized by overexpression of the p53 protein; the L FLAC tumors were negative for p53. Two cases of H-FLAC were positive for AFP. No Her-2 or ALK-D5F3 overexpression was observed in any of the tumors. EGFR L858R point mutation was identified in one of the H-FLAC cases. EGFR T790M mutation was detected in one of the L-FLAC cases. No mutations in KRAS, PIK3CA or BRAF were detected. CONCLUSIONS: L-FLAC and H-FLAC exhibited distinctive clinicopathological, immunophenotypic and molecular features with potential prognostic value. PMID- 28840009 TI - Role of cannabis in cardiovascular disorders. AB - The growing popularity of medical and recreational consumption of cannabis, especially among the youth, raises immediate concerns regarding its safety and long-terms effects. The cardiovascular effects of cannabis are not well known. Cannabis consumption has been shown to cause arrhythmia including ventricular tachycardia, and potentially sudden death, and to increase the risk of myocardial infarction (MI). These effects appear to be compounded by cigarette smoking and precipitated by excessive physical activity, especially during the first few hours of consumption. Cannabinoids, or the active compounds of cannabis, have been shown to have heterogeneous effects on central and peripheral circulation. Acute cannabis consumption has been shown to cause an increase in blood pressure, specifically systolic blood pressure (SBP), and orthostatic hypotension. Cannabis use has been reported to increase risk of ischemic stroke, particularly in the healthy young patients. The endocannabinoid system (ECS) is currently considered as a promising therapeutic target in the management of several disease conditions. Synthetic cannabinoids (SCs) are being increasingly investigated for their therapeutic effects; however, the value of their benefits over possible complications remains controversial. Despite the considerable research in this field, the benefits of cannabis and its synthetic derivatives remains questionable even in the face of an increasingly tolerating attitude towards recreational consumption and promotion of the therapeutic complications. More efforts are needed to increase awareness among the public, especially youth, about the cardiovascular risks associated with cannabis use and to disseminate the accumulated knowledge regarding its ill effects. PMID- 28840010 TI - Delamanid and bedaquiline to treat multidrug-resistant and extensively drug resistant tuberculosis in children: a systematic review. AB - The new drugs delamanid and bedaquiline are increasingly used to treat multidrug resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). As evidence is lacking, the World Health Organization recommends their use under specific conditions in adults, delamanid only being recommended in children >=6 years of age. No systematic review has yet evaluated the efficacy, safety and tolerability of the new drugs in children. A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with confirmed M/XDR-TB. We used PubMed and Embase to identify any relevant manuscripts in English until 31 December 2016, excluding editorials and reviews. Three out of 96 manuscripts retrieved satisfied the inclusion criteria, while 93 were excluded because dealing exclusively with adults (12: 4 on delamanid and 8 on bedaquiline), being recommendations or guidelines (8 manuscripts), reviews (17 papers) or other studies (56 papers). One of the studies retrieved reported evidence on 19 M/XDR-TB children, 16 of them treated under compassionate use with delamanid (13 achieving consistent bacteriological conversion) and 3 candidates for the drug. Two studies reported details on the first paediatric case treated (and cured) with a delamanid-containing regimen. Eight trials including children were also retrieved (clinicaltrials.gov). Although the methodology used in the study was rigorous, the results are limited by the paucity of the studies available in the literature on the use of new anti-TB drugs in children. In conclusion, more evidence is needed on the use of delamanid and bedaquiline in paediatric patients. PMID- 28840011 TI - Selective lymph node dissection in early-stage non-small cell lung cancer. AB - Lymph node dissection is a vital part of surgical treatment in early-stage non small cell lung cancer (NSCLC). Removal of metastatic lymph nodes while preservation of intact lymph nodes are equally important. For hospitalized early stage patients with limited lymph node metastasis, the operation treatment should be made according to some rules such as lobe-specific lymph node drainage pattern. In order to prevent unnecessary surgical trauma in early-stage patients, a minimally invasive approach with selective lymph node excision is preferred for more clinical benefits. This review summarizes the existing findings on lobe specific lymph node drainage pattern and we hope to provide guidance for selective lymph node dissection (SLND). Furthermore, we include information on histologic views, a tumor marker and protocols of SLND, with hope to inspire creative research and clinical trials in this field. PMID- 28840012 TI - Extracorporeal support in airway surgery. AB - Extracorporeal life support (ECLS) is increasingly used for major airway surgery. It facilitates complex reconstructions and maintains gas exchange during endoscopic procedures in patients with critical airway obstruction. ECLS offers the advantage of an uncluttered surgical field and eliminates the need for crossing ventilation tubes, thus, making precise surgical dissection easier. ECLS is currently used for hemodynamic and respiratory support in lung transplantation as well as extended tumor resections with an acceptable risk profile. This work reviews the published experience of ECLS in airway surgery both in adults and in pediatric patients. It highlights currently available devices and their indications. PMID- 28840013 TI - Training and certification in endobronchial ultrasound-guided transbronchial needle aspiration. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) plays a key role in the staging of lung cancer, which is crucial for allocation to surgical treatment. EBUS-TBNA is a complicated procedure and simulation-based training is helpful in the first part of the long learning curve prior to performing the procedure on actual patients. New trainees should follow a structured training programme consisting of training on simulators to proficiency as assessed with a validated test followed by supervised practice on patients. The simulation-based training is superior to the traditional apprenticeship model and is recommended in the newest guidelines. EBUS-TBNA and oesophageal ultrasound guided fine needle aspiration (EUS-FNA or EUS-B-FNA) are complementary to each other and the combined techniques are superior to either technique alone. It is logical to learn and to perform the two techniques in combination, however, for lung cancer staging solely EBUS-TBNA simulators exist, but hopefully in the future simulation-based training in EUS will be possible. PMID- 28840014 TI - Cardiovascular benefits of the newer medications for treating type 2 diabetes mellitus. AB - Diabetes mellitus is growing in pandemic proportions and is associated with significant morbidity, mortality, and health care expenditure. Type 2 diabetes mellitus (T2DM) is the most common, accounting for about 90-95% of diagnosed diabetes in United States adults. Individuals with T2DM have a 2- to 3-fold increased risk of cardiovascular (CV) events compared with their non-diabetic counterparts, and CV mortality is responsible for around 80% of the mortality in T2DM. Emerging evidence suggest that in T2DM patients, hyperglycemia plays a little role in the progression of CV disease, and metabolic risk factors like insulin resistance, hypertension, obesity, and dyslipidemia are the major culprits in the initiation and progression of CV disease. This calls for development of drugs which control hyperglycemia as well as the various metabolic risk factors in T2DM patients to improve CV outcomes. Recent clinical trials of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and sodium glucose cotransporter-2 (SGLT-2) inhibitors showed encouraging CV outcomes in T2DM patients, which are attributed to the diverse extra-pancreatic effects of these medications. This review article will discuss the CV benefits of the newer incretin based therapies and SGLT-2 inhibitors as observed in their CV safety trials. As T2DM or insulin resistance syndrome, CV disease, and HF and frequently coexistent, it would be interesting to design studies evaluating the combinations of GLP-1 RAs, SGLT-2 inhibitors, and pioglitazone in T2DM patient at an elevated CV risk, and in non-diabetic patients with insulin resistance to study the possible CV protective role of these combinations. PMID- 28840015 TI - A review of the management of complex para-pneumonic effusion in adults. AB - A complex para-pneumonic effusion is a descriptive term for exudative effusions, which complicate or are likely to complicate the anatomy of the pleural space after pneumonia. We performed an online search was performed using the resources PubMed and Google Scholar to provide an update on the management of such effusions based on review of published literature. Search terms including pleural effusion (PE), parapneumonic effusion, and empyema were used. Relevant studies were identified and original articles were studied, compared and summarized. References in these articles were examined for relevance and included where appropriate. Studies involving pediatric patients were excluded. Management of para-pneumonic PE has changed tremendously over the last decade. As we accumulate more evidence in this area, approach to pleural fluid drainage is becoming more specific and guideline based. An example of a practice changing study in this aspect is the Multi-center Intrapleural Streptokinase Trial (MIST) 2 trial which demonstrated that a combination of intra-pleural tPA and DNAse improved outcomes in pleural infections compared to DNase or t-PA alone. More randomized control trials are needed to describe the role of surgical techniques like VATS (video assisted thoracoscopic surgery) when MIST 2 protocol fails; this combination has revolutionized the management of empyema in recently. PMID- 28840017 TI - Complete versus culprit only revascularization in ST-elevation myocardial infarction-a perspective on recent trials and recommendations. AB - The presence of multivessel coronary artery disease (CAD) is strongly associated with higher 30-day mortality, reduced myocardial reperfusion success, reinfarction, and occurrence of major adverse cardiac events (MACE) at 1 year compared with single-vessel CAD. Despite higher morbidity and mortality in patients with ST-elevation myocardial infarction (STEMI) and coexistent multivessel CAD, major guidelines recommended against percutaneous coronary intervention (PCI) on non-culprit lesions at the time of primary PCI in patients with STEMI who are hemodynamically stable. The presence of multivessel CAD often poses a therapeutic dilemma for interventional cardiologists. A few larger scale randomized controlled trials (RCTs) and meta-analyses have been conducted. The conclusions regarding multivessel PCI generally trend towards lower risk of MACE, repeat revascularization, with similar risks of recurrent myocardial infarction (MI) and mortality. However, none of the RCTs were adequately powered for hard outcomes of death and MI. PMID- 28840016 TI - Lung adenocarcinoma: from molecular basis to genome-guided therapy and immunotherapy. AB - Although adenocarcinoma (ADC) is the most frequent lung cancer, its diagnosis is often late, when the local invasion is important and/or the metastases have already appeared. Therefore, the mortality at 5 years is still very high, ranging from 51% to 99%, depending on the stage. The implementation of different molecular techniques has allowed genomic studies even in relatively small histological samples such as obtained with non-invasive or minimally invasive techniques, facilitating a better phenotyping of lung ADC. Thus, current classification differentiates between preinvasive lesions (atypical adenomatous hyperplasia and in situ ADC), minimally invasive ADC (MIA) and invasive ADC. 'Field cancerization' is a concept that refers to progressive loco-regional changes occurring in tissues exposed to carcinogens, due to the interaction of the latter with a predisposing genetic background and an appropriate tissue microenvironment. Somatic genetic alterations, including mutations but also other changes, are necessary for oncogenesis, being especially frequent in lung ADC. Changes in the epidermal growth factor receptor (EGFR) gene, Kirsten rat sarcoma viral oncogene (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), gene encoding neurofibromin (NF1), anaplastic lymphoma kinase (ALK) and ROS1 are the main genes that suffer alterations in the tumors of patients with ADC. Molecular profiling of these tumors allows more targeted treatments through two distinct strategies, genome-guided therapy and immunotherapy. The former, targets the aberrant pathways secondary to the genomic alteration, whereas the latter may be based on the administration of antibodies [such as those against cytotoxic T lymphocyte antigen 4 (CTLA-4) or the programmed cell death ligand 1/protein 1 pathway (PD-L1/PD-1)] or the stimulation of the patient's own immune system to produce a specific response. These strategies are obtaining better results in selected ADC patients. PMID- 28840018 TI - The role of bone marrow-derived endothelial progenitor cells and angiogenic responses in chronic obstructive pulmonary disease. AB - Increased vascularity of the bronchial sub-mucosa is a cardinal feature of chronic obstructive pulmonary disease (COPD) and is associated with disease severity. Capillary engorgement, leakage, and vasodilatation can directly increase airway wall thickness resulting in airway luminal narrowing and facilitate inflammatory cell trafficking, thereby contributing to irreversible airflow obstruction, a characteristic of COPD. Airway wall neovascularisation, seen as increases in both the size and number of bronchial blood vessels is a prominent feature of COPD that correlates with reticular basement membrane thickening and airway obstruction. Sub-epithelial vascularization may be an important remodelling event for airway narrowing and airflow obstruction in COPD. Post-natal angiogenesis is a complex process, whereby new blood vessels sprouting from extant microvasculature, can arise from the proliferation of resident mature vascular endothelial cells (ECs). In addition, this may arise from increased turnover and lung-homing of circulating endothelial progenitor cells (EPCs) from the bone marrow (BM). Following lung-homing, EPCs can differentiate locally within the tissue into ECs, further contributing to vascular repair, maintenance, and expansion under pathological conditions, governed by a locally elaborated milieu of growth factors (GFs). In this article, we will review evidence for the role of BM-derived EPCs in the development of angiogenesis in the lug and discuss how this may relate to the pathogenesis of COPD. PMID- 28840019 TI - Bronchoscopy with endobronchial ultrasound guided transbronchial needle aspiration vs. transthoracic needle aspiration in lung cancer diagnosis and staging. AB - BACKGROUND: In evaluating patients with suspected lung cancer, it is important to not only obtain a tissue diagnosis, but also to obtain enough tissue for both histologic and molecular analysis in order to appropriately stage the patient with a safe and efficient strategy. The diagnostic approach may often be dependent on local resources and practice patterns rather than current guidelines. We Describe lung cancer staging at two large academic medical centers to identify the impact different procedural approaches have on patient outcomes. METHODS: We conducted a retrospective cohort study of all patients undergoing a lung cancer diagnostic evaluation at two multidisciplinary centers during a 1 year period. Identifying complication rates and the need for multiple biopsies as our primary outcomes, we developed a multivariate regression model to determine features associated with complications and need for multiple biopsies. RESULTS: Of 830 patients, 285 patients were diagnosed with lung cancers during the study period. Those staged at the institution without an endobronchial ultrasound (EBUS) program were more likely to require multiple biopsies (OR 3.62, 95% CI: 1.71-7.67, P=0.001) and suffer complications associated with the diagnostic procedure (OR 10.2, 95% CI: 3.08-33.58, P<0.001). Initial staging with transthoracic needle aspiration (TTNA) and conventional bronchoscopy were associated with greater need for subsequent biopsies (OR 8.05 and 14.00, 95% CI: 3.43-18.87 and 5.17-37.86, respectively) and higher complication rates (OR 37.75 and 7.20, 95% CI: 10.33-137.96 and 1.36-37.98, respectively). CONCLUSIONS: Lung cancer evaluation at centers with a dedicated EBUS program results in fewer biopsies and complications than at multidisciplinary counterparts without an EBUS program. PMID- 28840021 TI - Early pleural fluid dynamics following video-assisted thoracoscopic lobectomy has limited clinical value. AB - The objective of this study was to evaluate the potential of predicting the pleural fluid output in patients after video-assisted thoracoscopic lobectomy of the lung. Detailed measurements of continuous fluid output were obtained prospectively using an electronic thoracic drainage device (Thopaz+TM, Medela AG, Switzerland). Patients were divided into high (>=500 mL) and low (<500 mL) 24 hour fluid output, and detailed flow curves were plotted graphically to identify arithmetic patterns predicting fluid output in the early (<=24 hours) and later (24-48 hours) post-operative phase. Furthermore, multiple logistic regression analysis was used to predict high 24-hour fluid output using baseline data. Data were obtained from 50 patients, where 52% had a fluid output of <500 mL/24 hours. From visual assessment of flow curves, patients were grouped according to fluid output 6 hours postoperatively. An output >=200 mL/6 hours was predictive of 'high 24-hour fluid output' (P<0.0001). However, 33% of patients with <200 mL/6 hours ended with a 'high 24-hour fluid output'. Baseline data showed no predictive value of fluid production, and 24-hour fluid output had no predictive value of fluid output between 24 and 48 hours. Assessment of initial fluid production may predict high 24-hour fluid output (>=500 mL) but seems to lack clinical value in drain removal criteria. PMID- 28840020 TI - Transbronchial cryobiopsy for diffuse parenchymal lung disease: a state-of-the art review of procedural techniques, current evidence, and future challenges. AB - Transbronchial lung biopsy with a cryoprobe, or cryobiopsy, is a promising new bronchoscopic biopsy technique capable of obtaining larger and better-preserved samples than previously possible using traditional biopsy forceps. Over two dozen case series and several small randomized trials are now available describing experiences with this technique, largely for the diagnosis of diffuse parenchymal lung disease (DPLD), in which the reported diagnostic yield is typically 70% to 80%. Cryobiopsy technique varies widely between centers and this predominantly single center-based retrospective literature heterogeneously defines diagnostic yield and complications, limiting the degree to which this technique can be compared between centers or to surgical lung biopsy (SLB). This review explores the broad range of cryobiopsy techniques currently in use, their rationale, the current state of the literature, and suggestions for the direction of future study into this promising but unproven procedure. PMID- 28840022 TI - Common data manipulations with R in biological researches. AB - R is a computer language and has been widely used in science community due to the powerful capability in data analysis and visualization; and these functions are mainly provided by the developed packages. Because every package has strict format definitions on the inputted data, it is always required to appropriately manipulate the original data in advance. Unfortunately, users, especially for the beginners, are always confused by the extreme flexibility with R in data manipulation. In the present paper, we roughly categorize the common manipulations with R for biological data into four classes, including overview of data, transformation, summarization, and reshaping. Subsequently, these manipulations are exemplified in a sample data of clinical records of diabetic patients. Our main purpose is to provide a better landscape on the data manipulation with R and hence facilitate the practical applications in biological researches. PMID- 28840023 TI - Dr. Hui Li-thoracic surgeon in Beijing Chao-Yang Hospital: a good doctor is a master of his scalpel and his thoughts. PMID- 28840024 TI - Elucidation of radiation-resistant clones by a serial study of intratumor heterogeneity before and after stereotactic radiotherapy in lung cancer. AB - Stereotactic radiotherapy (SRT) for inoperable stage I non-small cell lung cancer has shown promising results and is now an alternative therapy for this disease. Several reports have detailed changes in mutation profiles after treatment with chemotherapy; however, such changes after SRT for lung cancer have not been reported. A patient who received SRT for lung cancer developed local recurrence 9 months after treatment and underwent surgery in our department. Using bronchoscopically biopsied and surgically resected specimens, we performed targeted sequencing of 53 lung cancer-related genes and compared the tumor mutation profiles before and after SRT. Identical mutations were detected from tumor specimens collected before and after SRT, and the specimens were confirmed to be clonal. However, the number of mutations decreased after SRT, suggesting that it induced mutation selection. Analyses of the statistical inference of clonal population structure showed that this evolving heterogeneous genomic landscape may be caused by heterogeneous responsiveness to SRT. PMID- 28840025 TI - Development of acute parotitis after non-invasive ventilation. AB - A 90-year-old woman underwent laparoscopic exploratory laparotomy for evaluation of suspected mesenteric ischemia. She was promptly extubated postoperatively and transferred to the intensive care unit, where on the first postoperative day she developed hypoxemia necessitating initiation of noninvasive ventilation (NIV) with bilevel positive airway pressure (BiPAP). After 8 hours of BiPAP, she was noted to have swelling, erythema and tenderness in the right preauricular area. Ultrasound evaluation demonstrated an enlarged right parotid gland. With discontinuation of BiPAP and supportive measures, parotitis resolved within 6 days. The mechanism of NIV-induced acute parotitis likely involves transmission of positive pressure to the oral cavity, causing obstruction to salivary flow within the parotid (Stensen) duct. Conditions that increase salivary viscosity and promote salivary stasis, such as advanced age, dehydration, and absence of salivary gland stimulation due to restriction of oral intake, may render patients more susceptible to this complication. As NIV will continue to be a commonly-used modality for the treatment of acute respiratory failure, clinicians should be aware of this phenomenon. PMID- 28840026 TI - Ectopic right parietal pleural thymic carcinoma: a rare case and review of the literature. AB - Ectopic thymic carcinoma is extremely rare. We present a case of a 73-year-old male patient with ectopic right parietal pleural thymic carcinoma and performed a literature review. Computed tomography (CT) of the chest demonstrated a sharp edged soft tissue mass with intense enhancement measuring 47 mm * 29 mm with a broader base adjacent to the right axillary chest wall at the level of the 5th rib. There was no hilar or mediastinal lymphadenopathy or evidence of a mediastinal tumor or pleural nodules. A totally extra-pleural tumor resection and partial right lung resection was performed. Histological examination demonstrated infiltrative growth typical of carcinoma cells with a nest-like distribution locally invading the surface of the lung tissue. Immunohistochemical examination confirmed the diagnosis of thymic squamous carcinoma positive for CD5. Mediastinal radical radiotherapy (60 Gy) was performed postoperatively. The patient was followed for 17 months without any evidence of recurrence or metastasis. PMID- 28840027 TI - Temporary bypass for superior vena cava reconstruction with Anthron bypass tubeTM. AB - Total superior vena cava (SVC) clamping for SVC replacement or repair can be used in thoracic surgery. A bypass technique is an option to avoid hemodynamic instability and cerebral venous hypertension and hypoperfusion. The present report describes a venous bypass technique using Anthron bypass tubeTM for total SVC clamping. Indications for this procedure include the need for a temporary bypass between the brachiocephalic vein and atrium for complete tumor resection. This procedure allows the surgeons sufficient time to complete replacement of SVC or partial resection of SVC without adverse effects. Further, it is a relatively simple procedure requiring minimal time. PMID- 28840028 TI - Video-assisted thoracoscopic right anterior, lateral, and medial segmentectomy for primary lung cancer of the middle lobe with incomplete interlobar fissures. AB - A 63-year-old woman was referred to our hospital due to an abnormal shadow in the right middle lung field on chest X-ray. Chest computed tomography revealed a 2.0 cm nodule in the right lateral segment of the middle lobe. The nodule was confirmed to be lung adenocarcinoma by transbronchial lung biopsy. Because the tumor was located near the incomplete interlobar fissures, resection might traditionally be performed by right upper and middle lobectomy. However, we chose a minimally invasive intervention and performed anterior, lateral, and medial segmentectomy under video-assisted thoracic surgery. This technique resulted in complete tumor resection with minimal adverse effects. PMID- 28840029 TI - Profuse and acute hemorrhagic gastroesophageal injury after cryotherapy in a cardiac surgery patient. AB - Upper gastrointestinal injury associated with cryoablation and under placement of transesophageal echocardiography (TEE) during cardiac surgery is a rare complication but potentially fatal. During the cryoablation for the treatment of atrial fibrillation, delivered cryoenergy can adversely affect the esophagus, resulting in gastroesophageal ulceration. The TEE probe itself also can induce adverse effects like esophageal ulceration or perforation. In this case report, we describe a case of emergent gastroesophageal injury with massive bleeding that occurred after manipulation of a TEE probe during cryoablation therapy in a cardiac surgery patient. PMID- 28840030 TI - Veno-arterial extracorporeal membrane oxygenation without therapeutic anticoagulation for intra-operative cardiopulmonary support during lung transplantation. AB - Cardiopulmonary support is frequently required during lung transplantation. Veno arterial extracorporeal membrane oxygenation (VA-ECMO) has been recently shown to be an acceptable and, perhaps, safer alternative to cardiopulmonary bypass machine (CBM) for lung transplantation. However, therapeutic anticoagulation used during both these techniques can cause significant bleeding diathesis, especially in the setting of re-transplantation or when severe adhesions are encountered. Technological advances have reduced the thrombogenic potential of VA-ECMO circuits and unlike CBM, VA-ECMO does not include a reservoir containing a stagnant column of blood. Here, we demonstrate that VA-ECMO can be used without therapeutic anticoagulation for short-term intraoperative support. PMID- 28840031 TI - Bronchopulmonary foregut malformation presenting as extralobar pulmonary sequestration associated with a bronchogenic cyst: an unusual clinical and radiological feature in an adolescent patient. AB - We present a case of symptomatic complex bronchopulmonary foregut malformation (BPFM), including extralobar pulmonary sequestration and a bronchogenic cyst, in the left anterior mediastinum of a 15-year-old boy. Preoperative computed tomography showed a cystic mass with heterogeneous enhancement of adjacent soft tissue components and pleural effusion. We suggested the infected bronchogenic cyst as the first impression. However, pathological examination after surgical resection revealed extralobar pulmonary sequestration and a bronchogenic cyst with unusual manifestation, which was located in the left upper hemithorax and supplied by the pulmonary artery. In patients presenting with a cystic mass with features of inflammation or infection and collateral vasculature, the possibility of a complex bronchopulmonary foregut malformation should be considered in the differential diagnosis. PMID- 28840032 TI - The missed diagnosis of aortic dissection in patients with acute myocardial infarction: a disastrous event. AB - We present a case of aortic dissection (AD) accompanied by acute myocardial infarction (AMI). For patients with AMI, the missed diagnosis of AD could be catastrophic. Therefore, we strongly recommend that portable echocardiography should be routinely available in the ambulance. Moreover, multicenter studies concerning the cost-benefit ratio of portable echocardiography routinely available in the ambulance should urgently be considered. PMID- 28840033 TI - Successful anticoagulation therapy for a giant left atrial thrombus following mitral valve repair. AB - A 72-year-old male with atrial fibrillation (AF) underwent mitral valve (MV) repair and concomitant procedures. He was discharged with therapeutic Warfarin dosing but was readmitted 3 weeks later with a right caudate nucleus infarct and subtherapeutic anticoagulation. Echocardiography showed a giant left atrial (LA) thrombus. Low-molecular-weight heparin was promptly initiated. Unfortunately, the patient suffered an intracranial hemorrhage (ICH) 2 days later. He declined surgical thrombectomy and was managed conservatively, remaining stable without neurological deficits. Serial brain imaging showed interval stability, allowing Warfarin to be resumed. Follow-up echocardiography demonstrated partial and complete resolution of the thrombus at 1 and 3 months, respectively. PMID- 28840034 TI - Long non-coding RNA TUG1: a novel therapeutic target in small cell lung cancer. PMID- 28840035 TI - Perspectives on the effect of nodal downstaging and its implication of the role of surgery in stage IIIA (N2) non-small cell lung cancer. PMID- 28840036 TI - Forward "MOMENTUM" in left ventricular assist systems: advanced engineering meets biology. PMID- 28840037 TI - Intravenous hydration according to current guidelines in the prevention of contrast induced nephropathy-the AMACING trial. PMID- 28840038 TI - Erratum to the prevalence of pulmonary hypertension in patients with obesity hypoventilation syndrome: a prospective observational study. AB - [This corrects the article DOI: 10.21037/jtd.2017.03.21.]. PMID- 28840039 TI - Outcomes of Vitrectomy in Pediatric Retinal Detachment with Proliferative Vitreoretinopathy. AB - AIM: To report outcomes of pars plana vitrectomy (PPV) in pediatric retinal detachment (RD) with proliferative vitreoretinopathy (PVR), complications, factors influencing the final anatomical and functional results. METHODS: Retrospective consecutive case series of 14 eyes. Average postoperative follow-up period was 34 months. RESULTS: Mean age of patients was 10 years; eleven patients (79%) were males. The most common etiology was trauma (57%), the second-myopia (36%) and one case of uveitis (7%). At the day of presentation, the best corrected visual acuity (BCVA) was worse than hand motion (50%); macula was detached in 86% of cases. Simultaneous PPV and phacoemulsification with intraocular lens (IOL) implantation were performed in 12 cases (86%). The most common endotamponade during PPV was silicone oil (93%). Anatomic reattachment was accomplished in 86% of cases. Final BCVA was equal or better than 0.1 in 50% of patients. The postoperative complications were found in 5 eyes (36%). CONCLUSION: Complete PPV was allowed for anatomically reattached retina and preserved vision in pediatric complex RD with PVR. However, visual outcomes were not satisfactory. Preserving vision in children with RD is of great importance for their future motor and intellectual development. This trial is registered with ClinicalTrials.gov Identifier: NCT03208205. PMID- 28840040 TI - Predictors of Hypertension in a Population of Undergraduate Students in Sierra Leone. AB - We report on the first survey of hypertension in undergraduates in Sierra Leone. Levels of hypertension (12%) and obesity (4%) appear low compared to the general population but given the rapid increase of both and the expectation that many graduates will enter the formal employment sector and a sedentary lifestyle, there is still cause for concern. We measured their BMI (body mass index) and used a questionnaire to investigate demographic and lifestyle choices. In agreement with most authorities, we found that BMI and age were statistically significant predictors of systolic and diastolic blood pressure but that the explanatory power was low (r = 0.21 to 0.27). Men may be more sensitive than women to an increase in BMI on blood pressure (p < 0.1). We failed to find statistically significant relationships with ethnicity, religion, stress, course of study, levels of physical activity, diet, smoking, or consumption of caffeine and alcohol. Family history of hypertension, consumption of red palm oil, and self-diagnosed attacks of typhoid fever were close to conventional levels of significance (p < 0.1). We intend to use this as a baseline for longitudinal studies to assess risks and suggest appropriate public health action. PMID- 28840041 TI - A comparison between different finite elements for elastic and aero-elastic analyses. AB - In the present paper, a comparison between five different shell finite elements, including the Linear Triangular Element, Linear Quadrilateral Element, Linear Quadrilateral Element based on deformation modes, 8-node Quadrilateral Element, and 9-Node Quadrilateral Element was presented. The shape functions and the element equations related to each element were presented through a detailed mathematical formulation. Additionally, the Jacobian matrix for the second order derivatives was simplified and used to derive each element's strain-displacement matrix in bending. The elements were compared using carefully selected elastic and aero-elastic bench mark problems, regarding the number of elements needed to reach convergence, the resulting accuracy, and the needed computation time. The best suitable element for elastic free vibration analysis was found to be the Linear Quadrilateral Element with deformation-based shape functions, whereas the most suitable element for stress analysis was the 8-Node Quadrilateral Element, and the most suitable element for aero-elastic analysis was the 9-Node Quadrilateral Element. Although the linear triangular element was the last choice for modal and stress analyses, it establishes more accurate results in aero elastic analyses, however, with much longer computation time. Additionally, the nine-node quadrilateral element was found to be the best choice for laminated composite plates analysis. PMID- 28840043 TI - Revascularization in Immature Permanent Teeth with Necrotic Pulp and Apical Pathology: Case Series. AB - INTRODUCTION: To present and discuss the results of five clinical cases treated using the revascularization protocol, showing clinical and radiographic monitoring. Necrotic immature teeth with periapical pathology present a challenge to dentists because the techniques used in apexification leave the tooth susceptible to fracture, since the root does not continue to grow in length and the canal walls are thin. Revascularization has emerged as an alternative to resolve these deficiencies, enabling apical closure, continued development of the roots, and thickening of the dentinal walls. CASE SERIES: Five clinically and radiographically diagnosed necrotic immature permanent teeth were treated using revascularization treatment. The therapeutic protocol involved accessing the pulp chamber; irrigating copiously with NaOCl; applying a triple antibiotic paste as intracanal dressing; then provisionally sealing it. After 3 weeks, the canal was cleaned and the apex irritated with a size 15 K-file to induce blood that would serve as a scaffold for pulp revascularization. MTA was used to seal the chamber before final obturation (composite or metallic crown). CONCLUSION: The discussion of the results leads to debate about different restorative materials and other published protocols. PMID- 28840042 TI - A Review of the Conceptualisation and Risk Factors Associated with Treatment Resistant Depression. AB - Major depression does not always remit. Difficult-to-treat depression is thought to contribute to the large disease burden posed by depression. Treatment resistant depression (TRD) is the conventional term for nonresponse to treatment in individuals with major depression. Indicators of the phenomenon are the poor response rates to antidepressants in clinical practice and the overestimation of the efficacy of antidepressants in medical scientific literature. Current TRD staging models are based on anecdotal evidence without an empirical rationale to rank one treatment strategy above another. Many factors have been associated with TRD such as inflammatory system activation, abnormal neural activity, neurotransmitter dysfunction, melancholic clinical features, bipolarity, and a higher traumatic load. This narrative review provides an overview of this complex clinical problem and discusses the reconceptualization of depression using an illness staging model in line with other medical fields such as oncology. PMID- 28840044 TI - Cosmetic Remodeling of the Smile: Combining Composite Resin and Ceramics over Teeth and Implants. AB - The aim of this paper is to describe a restorative approach to the cosmetic remodeling of the teeth of a young adult patient with right maxillary lateral hypodontia and left lateral microdontia. A conservative restorative management was proposed to improve smile esthetics by combining direct composite resins and ceramics. Initially, periodontal therapy and dental bleaching were performed. Subsequently, direct composite resins were applied to the central incisors and canines to reestablish the sizes and shapes of these teeth. Finally, ceramics were placed on the implant and the microdontia to unite with the new alignment and color of the anterior teeth. Thus, conservative remodeling to improve the harmony of the smile was provided. PMID- 28840045 TI - Hemoperitoneum Secondary to Spontaneous Rupture of a Retroperitoneal Varix. AB - Hemoperitoneum due to a ruptured retroperitoneal varix is an exceedingly rare condition and a poor prognostic sign with catastrophic and life-threatening complication of portal hypertension. We present a unique case of a 56-year-old female with cirrhosis secondary to primary sclerosing cholangitis who presented with acute abdominal pain and hypovolemic shock prior to a cardiac arrest following a ruptured retroperitoneal varix without prior esophageal varices and a newly identified intrahepatic cholangiocarcinoma. The clinical presentation with abdominal pain and hemorrhagic shock is consistently reported in the relevant literature. Early recognition affords appropriate management and urgent surgical intervention leading to survival. PMID- 28840046 TI - Uterine Rupture at 21 Weeks in Twin Pregnancy with TTTS and Previous C-Section. AB - Uterine rupture is a health problem in every country. The diagnosis is not always obvious and fetal and maternal morbidity and mortality can be high. PMID- 28840047 TI - Complete Laparoscopic Extirpation of a Giant Ovarian Cyst in an Adolescent. AB - The giant ovarian serous cystadenoma is a rare finding and often benign. The use of the laparoscopic approach versus open approach for the management of huge ovarian cysts is controversial. We report a case of a 27-year-old woman with a history of increasing abdominal girth over a period of two years along with radiological investigations revealed a large tumor arising from the right ovary treated by complete laparoscopic extirpation of a giant ovarian cyst. The complete laparoscopic approach for huge cyst is a feasible treatment when having a normal tumor marker profile and benign imaging appearance. In addition to the advantages of laparoscopic surgery, it is less invasive, with perfect cosmetic outcome and shorter hospital stay, which are particularly important for young women. PMID- 28840048 TI - Recurrence of Chronic Myeloid Leukemia during Pregnancy Subsequently Achieving Complete Medical Remission. AB - The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) in reproductive-aged women poses major dilemmas concerning its associated teratogenicity as observed in many animal studies. Much controversy exists regarding continuation versus discontinuation of its use in pregnancy with some studies suggesting safety of TKIs before and during pregnancy and others reporting toxicity and adverse outcomes. TKIs have become a well-established treatment option for CML, significantly improving prognosis, and yet have been reported to be fetotoxic. We present a case of a 25-year-old woman who achieved successful pregnancy and delivery after withholding treatment, meanwhile relapsing, eventually achieving complete molecular remission after reinitiation of high dose dasatinib. PMID- 28840049 TI - Recalcitrant Lateral Premalleolar Bursitis of the Ankle Associated with Lateral Ankle Instability. AB - Lateral premalleolar bursitis of the ankle is a rarely reported disorder in the English literature although it is not uncommon in Asian countries where people commonly sit on their feet. Here, we present the case of a 66-year-old woman with recalcitrant lateral premalleolar bursitis associated with lateral ankle instability which was successfully treated with surgical resection of the bursa and repair of the anterior talofibular ligament. Operative findings revealed a communication between the bursa and articular cavity of the ankle joint via the sheath of the extensor digitorum longus tendon, which was considered to act as a check valve leading to a large and recalcitrant bursitis. This report provides a novel concept about the etiology of recalcitrant lateral premalleolar bursitis of the ankle. PMID- 28840050 TI - Gastric Medullary Carcinoma with Sporadic Mismatch Repair Deficiency and a TP53 R273C Mutation: An Unusual Case with Wild-Type BRAF. AB - Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin. Overall, the histopathologic findings were consistent with gastric medullary carcinoma. A mismatch repair panel revealed a mismatch repair protein deficient tumor with loss of MLH1 and PMS2 expression. BRAF V600E immunostain (VE1) and BRAF molecular testing were negative, indicating a wild-type gene. Tumor sequencing of MLH1 demonstrated a wild-type gene, while our molecular panel identified TP53 c.817C>T (p.R273C) mutation. These findings were compatible with a sporadic tumor. Given that morphologically identical medullary tumors often occur in Lynch syndrome, it is possible that mismatch repair loss is an early event in sporadic tumors with p53 mutation being a late event. Despite having wild-type BRAF, this tumor is sporadic and unrelated to Lynch syndrome. This case report demonstrates that coordinate ancillary studies are needed to resolve sporadic versus hereditary rare tumors. PMID- 28840051 TI - Split-Hand Malformation in a 4-Year-Old Child. AB - Split-hand deformity is one of the milder manifestations of a congenital disorder called split-hand/split-foot malformation. We present a case of a 4-year-old child with split-hand malformation in his left hand since birth. A median cleft was present in the affected hand with absence of the 3rd and 4th digits, giving rise to a characteristic lobster-claw appearance. Functionality of the affected hand was modestly impaired. As none of the close family members of the patient had similar limb malformations, the deformity was postulated to arise most likely from a de novo mutation. The patient was discharged after the parents were provided with genetic counseling. PMID- 28840052 TI - Predictors of Memory in Healthy Aging: Polyunsaturated Fatty Acid Balance and Fornix White Matter Integrity. AB - Recent evidence demonstrates that age and disease-related decline in cognition depends not only upon degeneration in brain structure and function, but also on dietary intake and nutritional status. Memory, a potential preclinical marker of Alzheimer's disease, is supported by white matter integrity in the brain and dietary patterns high in omega-3 and omega-6 polyunsaturated fatty acids. However, the extent to which memory is supported by specific omega-3 and omega-6 polyunsaturated fatty acids, and the degree to which this relationship is reliant upon microstructure of particular white matter regions is not known. This study therefore examined the cross-sectional relationship between empirically-derived patterns of omega-3 and omega-6 polyunsaturated fatty acids (represented by nutrient biomarker patterns), memory, and regional white matter microstructure in healthy, older adults. We measured thirteen plasma phospholipid omega-3 and omega 6 polyunsaturated fatty acids, memory, and regional white matter microstructure in 94 cognitively intact older adults (65 to 75 years old). A three-step mediation analysis was implemented using multivariate linear regressions, adjusted for age, gender, education, income, depression status, and body mass index. The mediation analysis revealed that a mixture of plasma phospholipid omega-3 and omega-6 polyunsaturated fatty acids is linked to memory and that white matter microstructure of the fornix fully mediates the relationship between this pattern of plasma phospholipid polyunsaturated fatty acids and memory. These results suggest that memory may be optimally supported by a balance of plasma phospholipid omega-3 and omega-6 polyunsaturated fatty acids through the preservation of fornix white matter microstructure in cognitively intact older adults. This report provides novel evidence for the benefits of plasma phospholipid omega-3 and omega-6 polyunsaturated fatty acid balance on memory and underlying white matter microstructure. PMID- 28840053 TI - Effect of Adventitial Dissection of Superficial Temporal Artery on the Outcome of Superficial Temporal Artery-Middle Cerebral Artery Bypass in Moyamoya Disease. AB - Superficial temporal artery-middle cerebral artery (STA-MCA) has been used for the treatment of occlusive cerebrovascular disease including moyamoya disease. The effect of STA-MCA bypass depends not only on the patency of anastomosis, but also on integrity and functional capacity of the donor artery. In the present prospective study, we investigated the effect of extensive stripping STA adventitia and fasciae on hemodynamic function in STA-MCA bypass of moyamoya disease patients. Twenty patients (n=8 in control group, n=12 in stripping group) of moyamoya disease were subjected to STA-MCA end-to-side direct anastomosis. Perfusion unit (PU) values of the cortex were measured and recorded using a Laser Doppler flowmetry (LDF) for 5 days. Computed tomography perfusion was performed to determine blood flow before and after bypass. No patient experienced significant neurologic deficits associated with neurosurgical complications. LDF demonstrated that adventitial stripping group had higher cerebral blood flow increase than control group. The adventitia stripping group tends to have higher rate of increased cerebral perfusion after bypass than non-stripping group. Furthermore, the ultrasound examination at 3 days after bypass demonstrated that the adventitial stripping group has a tendency of bigger STA and higher peak systolic velocity than control group. Our result suggests that stripping adventitia of STA improves hemodynamics of STA-MCA bypass in moyamoya disease. PMID- 28840055 TI - One-Year Readmission Risk and Mortality after Hip Fracture Surgery: A National Population-Based Study in Taiwan. AB - Early readmission following hip fracture (HFx) is associated with high morbidity and mortality. We conducted a survival analysis of patients with readmission within 1 year after HFx to elucidate the trend and predictors for readmission. We used Taiwan National Health Insurance Database to recruit HFx patients who underwent operations between 2000 and 2009. Patients < 60 years; with pathological fractures; involved in major traffic accidents; with previous pelvis, femur, and hip operations; or who died during the index admission were excluded. We used the Chi-square test, logistic regression, Kaplan-Meier method, and Cox proportional hazards model to analyze variables, including age, gender, hospital stay duration, index admission time, and comorbidity on readmission. 5,442 subjects (61.2% female) met the criteria with mean age of 78.8 years. Approximately 15% and 43% HFx patients were readmitted within 30 days (early) and between 30 days and 1 year (late) after discharge, respectively. Highest readmission incidence was observed within the first 30 days. Most common causes of readmission in early and late groups were respiratory system diseases and injuries, respectively. Cox model showed male, old age, hospital stay > 9 days, Charlson Comorbidity Index >= 1, index admission during 2000-2003, and internal fixation of HFx were independent predictors of readmission. One-year mortality of the early and the late readmission groups was 44.9% and 32.3%, much higher than overall mortality which was 16.8%. Predictive factors for readmission within 1 year included male, old age, comorbidities, and longer hospital stay. One-year mortality in readmitted patients was significantly higher. HFx patients with these factors need careful follow-up, especially within 30 days after discharge. PMID- 28840054 TI - Limb Remote Ischemic Conditioning Promotes Myelination by Upregulating PTEN/Akt/mTOR Signaling Activities after Chronic Cerebral Hypoperfusion. AB - Limb Remote ischemic conditioning (LRIC) has been proved to be a promising neuroprotective method in white matter lesions after ischemia; however, its mechanism underlying protection after chronic cerebral hypoperfusion remains largely unknown. Here, we investigated whether LRIC promoted myelin growth by activating PI3K/Akt/mTOR signal pathway in a rat chronic hypoperfusion model. Thirty adult male Sprague Dawley underwent permanent double carotid artery (2VO), and limb remote ischemic conditioning was applied for 3 days after the 2VO surgery. Cognitive function, oligodendrocyte counts, myelin density, apoptosis and proliferation activity, as well as PTEN/Akt/mTOR signaling activity were determined 4 weeks after treatment. We found that LRIC significantly inhibited oligodendrocytes apoptosis (p<0.05), promoted myelination (p<0.01) in the corpus callosum and improved spatial learning impairment (p<0.05) at 4 weeks after chronic cerebral hypoperfusion. Oligodendrocytes proliferation, along with demyelination, in corpus callosum were not obviously affected by LRIC (p>0.05). Western blot analysis indicated that LRIC upregulated PTEN/Akt/mTOR signaling activities in corpus callosum (p<0.05). Our results suggest that LRIC exerts neuroprotective effect on white matter injuries through activating PTEN/Akt/mTOR signaling pathway after chronic cerebral hypoperfusion. PMID- 28840056 TI - Effects of Erythropoietin on Gliogenesis during Cerebral Ischemic/Reperfusion Recovery in Adult Mice. AB - Erythropoietin (EPO) promotes oligodendrogenesis and attenuates white matter injury in neonatal rats. However, it is unknown whether this effect extends to adult mice and whether EPO regulate microglia polarization after ischemic stroke. Male adult C57BL/6 mice (25-30g) were subjected to 45 min of middle cerebral artery occlusion (MCAO). EPO (5000 IU/kg) or saline was injected intraperitoneally every other day after reperfusion. Neurological function was evaluated using the rotarod test at 1, 3, 7 and 14 days after MCAO. Brain tissue loss volume was determined by hematoxylin-eosin staining. Immunofluorescence staining and Western blot were also used to assess the severity of white matter injury and phenotypic changes in microglia/macrophages. Bromodeoxyuridine (BrdU) was injected intraperitoneally daily for 1 week to analyze the number of newly proliferating glia cells (oligodendrocytes, microglia, and astrocytes). We found that EPO significantly reduced Brain tissue loss volume, ameliorated white matter injury, and improved neurobehavioral outcomes at 14 days after MCAO (P<0.05). In addition, EPO also increased the number of newly generated oligodendrocytes and attenuated the rapid hypertrophy and hyperplasia of microglia and astrocytes after ischemic stroke (P<0.05). Furthermore, EPO reduced M1 microglia and increased M2 microglia (P<0.05). Taken together, our results suggest that EPO treatment improves white matter integrity after cerebral ischemia, which could be attributed to EPO attenuating gliosis and facilitating the microglial polarization toward the beneficial M2 phenotype to promote oligodendrogenesis. PMID- 28840057 TI - Evaluation of the Mann Assessment of Swallowing Ability in Elderly Patients with Pneumonia. AB - Elderly pneumonia patients have various underlying diseases and social backgrounds, and it is difficult to predict their mortality using the current severity assessment tools. However, aspiration is a risk factor for mortality in pneumonia patients. In the evaluation of aspiration, endoscopic and video fluoroscopic methods are reliable but cannot be performed in all pneumonia patients. We evaluated the significance of the Mann Assessment of Swallowing Ability (MASA) in these patients. This study was prospectively performed between December 2014 and June 2015, and all adult hospitalized patients with pneumonia were consecutively enrolled. The MASA score was evaluated soon after admission. The outcome measures were in-hospital mortality, a recurrence of pneumonia within 30 days, 6-month mortality, and the detection of antibiotic-resistant bacteria. A total of 153 patients were ultimately included. The proportion of in-hospital mortality was greater among the severe MASA score patients than normal score patients (p < 0.01), as was the proportion of recurrence of pneumonia (p < 0.01) and 6-month mortality (p < 0.01). In addition, patients with a moderate MASA score more often experienced recurrence of pneumonia than normal score patients (p < 0.05). Furthermore, patients with a mild MASA score more often experienced recurrence of pneumonia (p < 0.01) and 6-month mortality (p < 0.05) than normal score patients. The areas under the curve were 0.74 (95% confidence interval [CI], 0.67-0.82) for in-hospital mortality, 0.75 (95% CI, 0.68-0.82) for recurrence of pneumonia, 0.72 (95% Cl, 0.64-0.81) for 6-month mortality, and 0.60 (95% CI, 0.46-0.73) for detection of antibiotic-resistant bacteria. A multivariate analysis showed an abnormal MASA score to be an independent risk factor for the recurrence of pneumonia (p = 0.001) and 6-month mortality (p = 0.005). The MASA is useful for predicting the mortality and recurrence of pneumonia in elderly patients. PMID- 28840058 TI - P2X7 Receptor and APOE Polymorphisms and Survival from Heart Failure: A Prospective Study in Frail Patients in a Geriatric Unit. AB - Heart failure (HF) is one of the most frequent cause of hospitalization in elderly and often coexists with concurrent geriatric syndromes, like cognitive disturbances; various pathophysiological mechanisms are shared by HF and cognitive decline, notably a substrate of low-grade inflammation. We investigated whether SNPs in the purinergic receptor (P2X7R) and apolipoprotein (APO) E genes, both involved in a series of inflammatory responses, are associated to HF or cognitive impairment and are able to predict post-discharge mortality in the elderly. We prospectively analyzed 198 patients (age 85 +/- 8 years, predominantly females) admitted to a Geriatric unit for acute HF, whose diagnosis was based on clinical signs, brain natriuretic peptide (BNP) values and ecocardiography in uncertain diagnosis (BNP values between 100 and 400 pg/mL); cognitive performance was assesed by Short Portable Mental Status Questionnaire (SPMSQ). In all the participants, SNPs rs208294 and rs3751143 for P2X7R gene and rs429558 and rs7412 for APOE gene were assessed. Information on all-cause mortality was adjudicated by medical records review 36 months after discharge. We found no relationship between P2X7R and APOE polymorphisms and 36-month post discharge mortality; a better outcome for overall survival was observed in patients with BNP values below the median (281 pg/mL) (p=0.002) persisting after adjustment for renal function and age, and in those with cognitive impairment (p<0.001). Patients harboring APOE-epsilon4 genotype showed higher BNP concentrations than noncarriers (1289.9 +/- 226.9 vs 580.5 +/- 90.2 pg/mL respectively,p=0.004), whereas none of the studied SNPs were associated to impairment in cognitive performance. In conclusion, neither P2X7R or APOE genotype seem to predict long-term mortality in elderly patients. Interestingly, APOE-epsilon4 genotype was associated to higher BNP values, suggesting a putative interaction between genetic and biochemical markers in identifying people at risk for HF. PMID- 28840059 TI - Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy. AB - Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). The relationship of the Shh pathway with memory loss in MHE, however, is elusive. In the current study, rats with MHE induced with DA displayed downregulation of the Shh pathway. Additionally, injection of Shh into MHE/DA treated rats reversed downregulation of BDNF/NT3, whereas administration of cyclopamine (Cyc) enhanced the inhibition of expression of BDNF/NT3. Furthermore, naringin (Nrg) substantially prevented cognitive impairment in MHE/DA-treated rats and upregulated the Shh pathway, paralleling the elevated expression of BDNF/NT3. Overall, our results indicate that the Shh pathway can induce the expression of BDNF/NT3, and DA causes memory loss by inactivation of Shh pathway signaling to BDNF/NT3 in MHE rats, which is reversed by Nrg. Our study may provide new theory basis of pathogenesis and therapeutic target of MHE. PMID- 28840060 TI - Mitochondrial Ferritin Protects Hydrogen Peroxide-Induced Neuronal Cell Damage. AB - Oxidative stress and iron accumulation are tightly associated with neurodegenerative diseases. Mitochondrial ferritin (FtMt) is identified as an iron-storage protein located in the mitochondria, and its role in regulation of iron hemeostasis in neurodegenerative diseases has been reported. However, the role of FtMt in hydrogen peroxide (H2O2)-induced oxidative stress and iron accumulation in neuronal cells has not been studied. Here, we overexpressed FtMt in neuroblastoma SH-SY5Y cells and induced oxidative stress by treating with extracellular H2O2. We found that overexpression of FtMt significantly prevented cell death induced by H2O2, particularly the apoptosis-dependent cell death. The protective effects involved inhibiting the generation of cellular reactive oxygen species, sustaining mitochondrial membrane potential, maintaining the level of anti-apoptotic protein Bcl-2, and inhibiting the activation of pro-apoptotic protein caspase 3. We further explored the mechanism of these protective effects and found that FtMt expression markedly altered iron homeostasis of the H2O2 treated cells as compared to that of controls. The FtMt overexpression significantly reduced cellular labile iron pool (LIP) and protected H2O2-induced elevation on LIP. While in H2O2 treated SH-SY5Y cells, the increased iron uptake and reduced iron release, in correlation with levels of DMT1(-IRE) and ferroportin 1, resulted in heavy iron accumulation, the FtMt overexpressing cells didn't show any significant changes in levels of iron transport proteins and in the level of LIP. These results implicate a neuroprotective role of FtMt on H2O2 induced oxidative stress, which may provide insights into the treatment of iron accumulation associated neurodegenerative diseases. PMID- 28840061 TI - Aging Airways: between Normal and Disease. A Multidimensional Diagnostic Approach by Combining Clinical, Functional, and Imaging Data. AB - The lack of data on lung function decline in the aging process as well as the lack of gold standards to define obstructive and restrictive respiratory disease in older people point out the need for a multidimensional assessment and interpretation of the aging airways. By integrating clinical data together with morphologic and morphometric findings clinicians can assess the airways with a more comprehensive perspective, helpful in the interpretation of the "grey zone" between normal aging and disease. This review focuses on the value of a multidimensional approach in the study of the aging airways, including clinical findings, respiratory function tests, and imaging as parts of a whole. Nowadays this multidimensional diagnostic approach can be used in daily clinical practice. In next future, it can be implemented by the analysis of exhaled gases, post processing imaging techniques, and genetic analysis, that will hopefully reduce the gaps in knowledge of normal aging and airway disease in older people. PMID- 28840064 TI - Polyostotic craniofacial fibrous dysplasia with bizarre radiologic finding: Mandible, anterior skull base, frontal, temporal, parietal, and occipital bones involvement. PMID- 28840065 TI - Management of acute subdural hematoma in a patient with portopulmonary hypertension on prostanoid therapy. AB - BACKGROUND: Treprostinil is a prostacyclin analog used to treat portopulmonary hypertension (PPHTN) and is one of several drugs shown to increase survival, but results in platelet dysfunction. Little is known about the management of patients on treprostinil who present with an acute subdural hematoma (aSDH). We describe such a case and offer our recommendations on management based on our experience and review of the literature. CASE DESCRIPTION: A 63-year-old, right-handed female with a history of PPHTN presented with severe headache and was found to have a large left aSDH with midline shift on imaging. She was admitted to the neurosurgical intensive care unit (ICU) where she developed hemiparesis and subsequently underwent emergent decompression. Postoperatively she improved, but several hours after became obtunded and imaging showed reaccumulation of the aSDH, which required reoperation. At 6 months postoperatively she had only a mild hemiparesis and was being reconsidered for treprostinil therapy as a bridge to liver transplant. Only one paper in the literature thus far has reported a patient with an aSDH managed with treprostinil. The authors achieved adequate intraoperative hemostasis without the use of platelet transfusion and lack of complications intraoperatively. CONCLUSION: While concerns related to the risk of bleeding in surgery are valid, intraoperative hemostasis does not appear to be profoundly affected. Surgical intervention should not be delayed and prostanoid therapy discontinued, if possible, postoperatively. Patients should be placed in an intensive care setting with assistance from pulmonary specialists and close monitoring of neurological status and blood pressure. PMID- 28840066 TI - Pituitary carcinoma: A case report and discussion of potential value of combined use of Ga-68 DOTATATE and F-18 FDG PET/CT scan to better choose therapy. AB - BACKGROUND: Pituitary carcinoma is extremely rare and carries a very poor prognosis. In most cases, apparently indolent tumors become malignant; however, there are no satisfactory biomarkers for predicting tumor behavior. Thus, scientific advances in the search for new biological markers, diagnostic methods, and therapies are needed to improve the prognosis of these patients. CASE DESCRIPTION: We report the case of a woman with initial diagnosis of nonfunctioning pituitary adenoma which evolved to carcinoma after 4 years. Diagnosis was confirmed after biopsy of metastatic pulmonary nodules, in which neoplastic cells were immunohistochemically positive for chromogranin, synaptotophysin, prolactin, and growth hormone. Investigation with conventional somatostatin receptor scintigraphy, positron emission tomography-computed tomography (PET-CT) with Ga-68 DOTATATE and F-18 fluorodeoxyglucose (FDG) are showed. During temozolomide therapy, our patient had severe pancytopenia resulting in death from generalized infection despite 10 days of intensive care. CONCLUSION: The present case of an aggressive pituitary carcinoma rising from a typical adenoma illustrates the importance of developing new prognostic biomarkers in these cases. In addition to demonstrating a serious side effect with the use of temozolomide, our case report suggests that the combined use of Ga-68 DOTATATE and F-18 FDG PET-CT scan may scale somatostatin receptors vs. tumor aggressiveness, therefore, helping to better choose the therapy for aggressive pituitary tumors. PMID- 28840063 TI - P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes? AB - Neurodegenerative diseases are a heterogeneous, mostly age-associated group of disorders characterized by progressive neuronal loss, the most prevalent being Alzheimer disease. It is anticipated that, with continuously increasing life expectancy, these diseases will pose a serious social and health problem in the near feature. Meanwhile, however, their etiology remains largely obscure even though all possible novel clues are being thoroughly examined. In this regard, a concept has been proposed that p53, as a transcription factor controlling many vital cellular pathways including apoptosis, may contribute to neuronal death common to all neurodegenerative disorders. In this work, we review the research devoted to the possible role of p53 in the pathogenesis of these diseases. We not only describe aberrant changes in p53 level/activity observed in CNS regions affected by particular diseases but, most importantly, put special attention to the complicated reciprocal regulatory ties existing between p53 and proteins commonly regarded as pathological hallmarks of these diseases, with the ultimate goal to identify the primary element of their pathogenesis. PMID- 28840067 TI - Surgical treatment of cerebellar hemangioblastomas. AB - BACKGROUND: Hemangioblastomas (HBL) are uncommon tumors of the central nervous system (CNS), corresponding to 1-2.5% of all intracranial tumors. They can present sporadically or in patients with von Hippel-Lindau (VHL) disease and are most often located in the cerebellum, brainstem, and spinal cord. VHL disease is a multiple neoplasia syndrome inherited in an autosomal dominant fashion and caused by a VHL suppressor gene deletion. We present our experience in the management of patients with cerebellar HBL. METHODS: Thirty consecutive patients with cerebellar HBL were included in this study. Hospital charts, radiological images, and operative records were reviewed. Modified Rankin scores were used to evaluate the clinical course. RESULTS: Thirty patients diagnosed with cerebellar HBL were operated. Complete total resection was achieved in 93% of the cases. Postoperatively, 83% of the patients showed good functional recovery. CONCLUSIONS: HBL of the cerebellum should be resected when symptomatic or when the tumor (or a tumor-associated cyst) shows signs of enlargement. Surgical intent should seek en bloc resection to minimize intraoperative bleeding. Patients with HBLs must be tested for VHL gene mutations, and in confirmed cases, relatives should be offered genetic counseling. PMID- 28840062 TI - Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases. AB - As with many age-related diseases including vascular dysfunction, age is considered an independent and crucial risk factor. Complicated alterations of structure and function in the vasculature are linked with aging hence, understanding the underlying mechanisms of age-induced vascular pathophysiological changes holds possibilities for developing clinical diagnostic methods and new therapeutic strategies. Here, we discuss the underlying molecular mediators that could be involved in vascular aging, e.g., the renin-angiotensin system and pro-inflammatory factors, metalloproteinases, calpain-1, monocyte chemoattractant protein-1 (MCP-1) and TGFbeta-1 as well as the potential roles of testosterone and estrogen. We then relate all of these to clinical manifestations such as vascular dementia and stroke in addition to reviewing the existing clinical measurements and potential interventions for age-related vascular dysfunction. PMID- 28840068 TI - A case of symptomatic spinal dural arteriovenous fistula after high-volume lumbar puncture. AB - BACKGROUND: Spinal dural arteriovenous fistulas (DAVFs) are rare lesions that lead to venous congestion and ischemic injury resulting in neurologic deterioration. Here we present a patient diagnosed with glioblastoma multiforme (GBM) who became symptomatic from a spinal DAVF after a diagnostic high-volume lumbar puncture (LP). CASE DESCRIPTION: When a 72-year-old female developed partial seizures in her left upper extremity without other focal neurological deficits, she underwent a magnetic resonance imaging (MRI) scan of the brain. The MRI revealed a right frontal/posterior corpus callosal lesion. She next had a MR guided high-volume LP. A GBM was diagnosed following a biopsy. Postoperatively, after the LP, she was noted to have bilateral deltoid and bilateral 4/5 lower extremity weakness, with diffuse hyperreflexia. The MRI and magnetic resonance angiogram (MRA) of the cervical spine demonstrated a large venous varix at the C5 C6 level within the left neural foramen. She underwent successful complete embolization of two thyrocervical branches with direct communication to an enlarged anterior spinal artery. One month later, her neurological examination returned to baseline; she was walking independently with only 4+/5 residual weakness in her left lower extremity. CONCLUSIONS: Here we report a patient with a cranial GBM and an incidental cervical spinal C5-C6 DAVF that became symptomatic after a high-volume LP. It is possible that the high-volume LP increased vascular congestion, thus precipitating the onset of cervical myelopathy. PMID- 28840069 TI - Hydrocephalus as the sole presentation of primary diffuse large B-cell lymphoma of the brain: Report of a case and review of literature. AB - BACKGROUND: The most common lymphoid malignancy in adults is diffuse large B-cell lymphoma (DLBCL). The median age of occurrence of DLBCL is between 6th and 7th decade of life, although some other types of aggressive non-Hodgkin's lymphomas (NHL) are present in younger age. Primary central nervous system lymphoma (PCNSL) is an uncommon type of extranodal NHL, which is either more prevalent or is diagnosed more often than before. CASE DESCRIPTION: A 22-year-old man with ventriculoperitoneal shunt (VPS) performed at another center was referred with manifestations of shunt malfunction, unusual behavior, dysphasia, and hallucination. The shunt malfunction was handled appropriately several times and exploration of the enhancing cystic temporal lesion confirmed the diagnosis of DLBCL. CONCLUSION: In this communication, we intend to highlight the issue that hydrocephalus refractory to several interventions can be the sole manifestation of PCNSL and needs special clinical considerations. PMID- 28840070 TI - Embolization of a spinal dural arteriovenous fistula with ethylene-vinyl alcohol copolymer (Onyx) using a dual-lumen microballoon catheter and buddy wire technique. AB - BACKGROUND: N-butyl 2-cyanoacrylate (NBCA) remains the standard embolic agent for spinal dural arteriovenous fistula (SDAVF) treatment. Treatment of SDAVF with ethylene-vinyl alcohol copolymer (Onyx, ev3-Covidien, Irvine CA, USA) is currently not well established. Although several cases have reported the use of Onyx to embolize an intracranial dural arteriovenous fistula using a dual-lumen microballoon catheter, Onyx embolization of an SDAVF using a dual-lumen microballoon catheter has not been reported. CASE DESCRIPTION: We treated a 57 year-old man with an SDAVF using a dual-lumen microballoon catheter and buddy wire technique to perform transarterial Onyx embolization via the left sixth intercostal artery. CONCLUSIONS: Onyx embolization using a dual-lumen microballoon catheter was effective. Furthermore, the buddy wire technique was useful for providing rigid support of the microcatheter in a narrow and tortuous intercostal artery. PMID- 28840071 TI - Chronic thoracolumbar subdural empyema: Case report and surgical management. AB - BACKGROUND: Spinal cord abscesses and spinal subdural empyemas are rare and difficult to treat. CASE DESCRIPTION: A 35-year-old male presented to an outside institution with 2 months of progressive low back pain, weakness, and bowel incontinence; he was diagnosed with an L4 epidural abscess that was poorly managed. When the patient presented to our institution, magnetic resonance imaging (MRI) revealed a well-organized chronic subdural abscess at the thoracolumbar junction. Following resection, his back pain resolved but he was left with a residual paraparesis. CONCLUSION: Subdural abscesses are rare and should be considered among the differential diagnoses for intraspinal mass lesions. Treatment should include prompt surgical exploration and decompression combined with appropriate prolonged antibiotic treatment. PMID- 28840072 TI - Treatment of racemose neurocysticercosis. AB - BACKGROUND: Neurocysticercosis (NCC) is a common parasitic infection of the central nervous system, caused by the tapeworm Taenia solium. It is endemic to certain parts of the world, including Central America, South America, Asia, and Africa. The racemose form, characterized by extraparenchymal location, increased morbidity and mortality, and large loculated cystic lesions, is rarely seen in industrialized countries, such as the United States. The management of racemose neurocysticercosis (RNCC) differs from that of the typical parenchymal variant. The ideal course of treatment is debated by experts, but typically includes either surgical intervention with subsequent medical therapy or medical therapy alone. CASE DESCRIPTION: We present the case of a 34-year-old male diagnosed with RNCC and treated successfully with surgical cyst drainage, resection, and subsequent medical therapy. CONCLUSION: Currently, no standardized evidence-based protocol exists that dictate appropriate treatment for extraparenchymal or racemose NCC. We present a case of RNCC treated successfully with surgical and medical intervention. Further research encompassing well-designed clinical trials is necessary to delineate appropriate and standardized protocols for treatment of this disease. PMID- 28840073 TI - Epidural scarring after lumbar disc surgery: Equivalent scarring with/without free autologous fat grafts. AB - BACKGROUND: To limit epidural fibrosis and prevent scar formation/nerve tethering that may contribute to chronic postoperative pain; some surgeons have utilized epidural autologous fat grafts following lumbar microdiscectomy. METHODS: We investigated the correlation between post-microdiscectomy epidural scarring [including select magnetic resonance imaging (MRI) studies] and clinical outcomes in 36 patients operated for symptomatic. MRI documented L4-L5 and L5-S1 disk herniations with (18 patients) and without (18 patient) the application of free fat grafts. In addition, histological evaluation of the original fat grafts was performed in 4 patients requiring additional surgery. RESULTS: We found no clear association between the use of autologous graft fats and the clinical outcomes in this study. CONCLUSION: In this preliminary study involving only 36 patients, the prospective randomized use of free autologous fat grafts did not appear to influence outcomes following microdiscectomy. PMID- 28840074 TI - Introducing "computational neurosurgery". PMID- 28840075 TI - Vestibular schwannoma appears to be very rare in a region of Sub-Saharan Africa. AB - BACKGROUND: Vestibular schwannoma (VS) is a significant neurosurgical problem hence it enjoys a special attention at conferences and workshops. It accounts for about 8-10% of all intracranial tumors with an annual incidence of about 11-14 per million per year. Most VS are sporadic with 5-10% attributed to neurofibromatosis type 2 (NF2). However, VS is alleged to be rare in Africans and uncommon in African Americans, connoting a racial bias. To our knowledge, no study from sub-Saharan Africa has addressed this subject. The aim of this study is to determine the frequency of VS in a tertiary neurosurgical hospital in sub Saharan Africa. METHODS: This is a retrospective study of all intracranial neoplasms and VS managed in a major tertiary hospital in sub-Saharan Africa from January 2003 to December 2015. Patients' records and neuroimaging studies were reviewed retrospectively. Additionally, database of all cranial computed tomography (CT) and magnetic resonance imaging (MRI) done for various indications within the same period was searched retrospectively for "incidental" VS cases. RESULTS: Over the study period of 13 years, out of 612 cases of intracranial neoplasms, only three (0.49%) were VSs (two sporadic, one bilateral VS in NF2). A search for "incidental" cases of VS from a pool of 7475 cranial scans (CT: 5290; MRI: 2185), yielded none. CONCLUSIONS: The findings strongly suggest that VS is very rare in the study population. It is hoped that other centers in Africa and beyond would perform similar studies. PMID- 28840076 TI - Middle meningeal artery aneurysm: Case report. AB - BACKGROUND: Aneurysms of meningeal middle artery (MMA) are extremely rare. These aneurysms are of two types: true aneurysm and pseudoaneurysm. The true type is usually seen with pathologic conditions. Pseudoaneurysms, on the other hand, are associated with a skull fracture. Epilepsy caused by MMA aneurysm has never been described to our knowledge. We report a case of true aneurysm isolated from MMA revealed by epilepsy. CASE DESCRIPTION: A 57-year-old patient with a history of high blood pressure developed epilepsy which was treated by valproic acid. Initial scalp electroencephalography (EEG) showed seizure activity arising from the right temporal area. Epilepsy had become drug-resistant. Cerebral angiography revealed an aneurysm of the right middle meningeal artery without any other intraparenchymal anomaly. The interrogation did not reveal any history of family aneurysm. The patient underwent surgery with coagulation of the aneurysm and the MMA. The aneurysm was intradural in contact with the temporal cortex, and the surrounding brain tissues were preserved. The operative follow-up was favorable with amelioration of convulsions with a single antiepileptic. We planned to stop antiepileptic treatment according to electroencephalograms. CONCLUSIONS: Aneurysms of the MMA are rare. Their mode of revelation by seizures is unusual. The factors of rupture are not known. When isolated, their physiopathology is identical to that of the aneurysms of the Willis polygon. Their management uses the same techniques as for other cerebral aneurysms. PMID- 28840077 TI - Engineering CRISPR-Cpf1 crRNAs and mRNAs to maximize genome editing efficiency. AB - Cpf1, a type-V CRISPR-Cas effector endonuclease, exhibits gene-editing activity in human cells through a single RNA-guided approach. Here, we report the design and assessment of an array of 42 types of engineered Acidaminococcus sp. Cpf1 (AsCpf1) CRISPR RNAs (crRNAs) and 5 types of AsCpf1 mRNAs, and show that the top performing modified crRNA (cr3'5F, containing five 2'-fluoro ribose at the 3' termini) and AsCpf1 mRNA (full psi-modification) improved gene-cutting efficiency by, respectively, 127% and 177%, with respect to unmodified crRNA and plasmid encoding AsCpf1. We also show that the combination of cr3'5F and psi-modified AsCpf1 or Lachnospiraceae bacterium Cpf1 (LbCpf1) mRNAs augmented gene-cutting efficiency by over 300% with respect to the same control, and discovered that 11 out of 16 crRNAs from Cpf1 orthologs enabled genome editing in the presence of AsCpf1. Engineered CRISPR-Cpf1 systems should facilitate a broad range of genome editing applications. PMID- 28840078 TI - Social Media Participation in an Activist Movement for Racial Equality. AB - From the Arab Spring to the Occupy Movement, social media has been instrumental in driving and supporting socio-political movements throughout the world. In this paper, we present one of the first social media investigations of an activist movement around racial discrimination and police violence, known as "Black Lives Matter". Considering Twitter as a sensor for the broader community's perception of the events related to the movement, we study participation over time, the geographical differences in this participation, and its relationship to protests that unfolded on the ground. We find evidence for continued participation across four temporally separated events related to the movement, with notable changes in engagement and language over time. We also find that participants from regions of historically high rates of black victimization due to police violence tend to express greater negativity and make more references to loss of life. Finally, we observe that social media attributes of affect, behavior and language can predict future protest participation on the ground. We discuss the role of social media in enabling collective action around this unique movement and how social media platforms may help understand perceptions on a socially contested and sensitive issue like race. PMID- 28840079 TI - The Language of Social Support in Social Media and its Effect on Suicidal Ideation Risk. AB - Online social support is known to play a significant role in mental well-being. However, current research is limited in its ability to quantify this link. Challenges exist due to the paucity of longitudinal, pre- and post mental illness risk data, and reliable methods that can examine causality between past availability of support and future risk. In this paper, we propose a method to measure how the language of comments in Reddit mental health communities influences risk to suicidal ideation in the future. Incorporating human assessments in a stratified propensity score analysis based framework, we identify comparable subpopulations of individuals and measure the effect of online social support language. We interpret these linguistic cues with an established theoretical model of social support, and find that esteem and network support play a more prominent role in reducing forthcoming risk. We discuss the implications of our work for designing tools that can improve support provisions in online communities. PMID- 28840080 TI - Adult Case of Atlantoaxial Rotatory Fixation Treated with In Situ Fixation Using an Unusual Posterior Instrumentation Construct. AB - Atlantoaxial rotatory fixation (AARF) occurs commonly in children who have undergone trauma. It is usually corrected with conservative therapy. In this report, however, the patient was an adult with AARF who was treated surgically. A 64-year-old woman presented with a 1-year history of spastic gait and hand clumsiness. Imaging studies revealed the presence of AARF, os odontoideum, and severe spinal cord compression at that spinal level. As the AARF had not been responded to head traction with a halo device, we decided to treat the patient with in situ posterior fixation. Because the rigid dislocation was present between the atlas and the axis, we were forced to make an unusual instrumentation construct. Neurological symptoms other than hand numbness diminished after the surgery, and arthrodesis was obtained between the occiput and the axis. It should be noted that surgical planning for posterior instrumentation construct is required when rigid AARF is treated surgically. PMID- 28840081 TI - Segmental Aplasia of Bilateral Internal Carotid Arteries Accompanied by Intracranial Aneurysms: A Case Report. AB - A 68-year-old woman presented with segmental aplasia of bilateral internal carotid arteries accompanied by unruptured intracranial aneurysms. The abnormality was discovered incidentally at the age of 44 years. Cerebral angiography showed occlusion of bilateral internal carotid arteries, and the carotid territory was supplied by each posterior communicating artery with small intracranial aneurysms. Endovascular treatment for the intracranial aneurysms was planned. However, the patient did not want to undergo the endovascular procedure because of the increased risk due to the associated bilateral carotid abnormalities. Cerebral angiography was performed again at the age of 66 years, and the size of the aneurysms had not changed. Based on their segmental identity, aplasia of segment 6 of the internal carotid artery (ICA) including the first portion of the ophthalmic artery was observed bilaterally. PMID- 28840082 TI - The Potentiality for Development of Multiple Dural Arteriovenous Fistulas after Ligation of the Internal Jugular Vein: A Case Report. AB - A 74-year-old male presented with an intracranial hemorrhage caused by multiple dural arteriovenous fistulas (DAVFs) in the left transverse sinus and right sigmoid sinus. Four months previously, the patient underwent tongue cancer removal with lymph node dissection and ligation of the right internal jugular vein. Endovascular embolization (transvenous and transarterial embolization) resulted in the complete disappearance of the fistulas. Follow-up angiography revealed new arteriovenous shunts at the superior sagittal sinus and right transverse sinus, and we treated the patient with staged transarterial embolization. Finally, venous congestion almost completely resolved and the DAVFs disappeared without any sign of recurrence. This case speculates the concept of DAVF as an acquired lesion caused by intravenous hypertension and alerts clinicians to take precautions against ligation of the internal jugular vein during a cervical operation. PMID- 28840083 TI - Nervus Intermedius Neuralgia Treated with Microvascular Decompression: A Case Report and Review of the Literature. AB - Nervus intermedius neuralgia is one of the craniofacial neuralgias, which is extremely rare compared with trigeminal or glossopharyngeal neuralgia. Despite its unique symptom, the aetiology remains unclear. We present a case of a surgically treated 36-year-old woman who suffered from paroxysmal stabbing deep ear pain for over 10 years. Preoperative magnetic resonance imaging demonstrated a vascular loop compressing the root entry zone of the vestibulocochlear nerve between the seventh and eighth cranial nerves, suggesting nervus intermedius neuralgia as a cause of her pain. Surgical exploration revealed that the nervus intermedius was displaced upward by the anterior inferior cerebellar artery. Transposition of the artery from the brainstem relieved the patient's neurological symptom immediately after the surgery, supporting the hypothesis that nervus intermedius neuralgia could be caused by neurovascular compression. PMID- 28840084 TI - Right Aortic Arch Associated with Left Internal Carotid Artery Agenesis. AB - We report the rare case of a right aortic arch associated with agenesis of the left internal carotid artery. A 75-year-old woman with a medical history of tetralogy of Fallot presented with dizziness. Magnetic resonance angiography revealed agenesis of the left internal carotid artery in addition to a previously diagnosed right aortic arch. The left common carotid artery was present, but it was thin. Computed tomography showed the absence of the left carotid canal. The left anterior cerebral artery was fed via the anterior communicating artery. The left middle cerebral artery was fed via a thickened posterior communicating artery originating from the left posterior cerebral artery. Although a right aortic arch and agenesis of the internal carotid artery are both very rare, association of the two conditions may occur. Both anomalies depend on the abnormal regression of the dorsal aorta during embryonic development. In such a situation, the presence of other anomalies in the cardiac or central nervous system should be taken into consideration. PMID- 28840085 TI - "Pure" Suprasellar Schwannoma Presented with Communicating Hydrocephalus: A Case Report. AB - Schwannoma is a benign peripheral nerve sheath tumor originating from Schwann cells. Most intracranial schwannomas arise from vestibular nerve and schwannoma in the suprasellar region is extremely rare. A 64-year-old man presented with walking disturbance and blurred vision for three months. Lateral hemianopsia in the left eye and brachybasia were observed. Magnetic resonance imaging revealed a suprasellar tumor with strong contrast enhancement associated with communicating hydrocephalus. The cerebrospinal fluid tap test improved gait disturbance. Hypothalamic stimulation test revealed hypo-reaction of GH, FSH and LH. After ventriculo-peritoneal shunting, the tumor was totally removed via a bilateral front-basal approach with a clinical diagnosis of craniopharyngioma. No adhesion was observed between the tumor and surrounding structures such as meninges and brain. The histopathological diagnosis was schwannoma. Here we report a case of suprasellar schwannoma associated with communicating hydrocephalus that has not ever been previously reported, with special reference to its pathogenesis. PMID- 28840086 TI - De Novo Arteriovenous Malformation after Aneurysm Clipping. AB - We report a 73-year-old woman with de novo arteriovenous malformations (AVMs) that developed in the ipsilateral parietal lobe after craniotomy and aneurysm clipping. While intracerebral AVMs are considered to be congenital lesions, there have been several reported cases of acquired AVM arising after ischemic or traumatic episodes. We summarize previously reported cases of such acquired 'de novo' AVMs with a discussion of some pathophysiological responses or factors suggested to promote their development. PMID- 28840087 TI - Posterior Inferior Cerebellar Artery Thrombosed Aneurysm Associated with Persistent Primitive Hypoglossal Artery Successfully Treated with Condylar Fossa Approach. AB - A 68-year-old woman presented with generalized seizure due to the left internal carotid artery (ICA) aneurysmal compression of the ipsilateral medial temporal lobe. Computed tomography angiography (CTA) revealed multiple aneurysms of the right persistent primitive hypoglossal artery (PPHA), the right ICA, and the right anterior cerebral artery (ACA). The right PPHA originated from the ICA at the level of the C1 and C2 vertebral bodies and passed through the hypoglossal canal (HC). The PPHA aneurysm was large and thrombosed, which was located at the bifurcation of the right PPHA and the right posterior inferior cerebellar artery (PICA), projecting medially to compress the medulla oblongata. Since this patient had no neurological deficits, sequential imaging studies were performed to follow this lesion, which showed gradual growth of the PPHA aneurysm with further compression of the brain stem. Although the patient remained neurologically intact, considering the growing tendency clipping of the aneurysm was performed. Drilling of the condylar fossa was necessary to expose the proximal portion of the PPHA inside the HC. The key of this surgery was the preoperative imaging studies to fully understand the anatomical structures. The PPHA was fully exposed from the dura to the corner its turning inferiorly without damaging the occipital condylar facet. Utilizing this technique, the neck ligation of the aneurysm was safely achieved without any surgical complications. PMID- 28840089 TI - Disinfection effect of microwave radiation on Bacillus subtilis as indicator organism on contaminated dental stone casts under dry and wet conditions. AB - Objective: The disinfection of dental stone casts using microwave radiation has been shown, but doubts remain regarding its efficacy under various conditions. The aim of the present study was to evaluate the efficacy of microwave disinfection on wet and dry dental stone casts contaminated by a resistant microorganism. Material and methods: In this in vitro study, 34 stone half-casts were prepared, contaminated with Bacillus subtilis and divided into two groups. After drying the specimens of one group for 15 minutes using 450 W microwave energy, all the wet and dry specimens were exposed to 900 W microwave energy for 5 minutes. Specimens were then individually transferred to nutrient broth culture medium and after 10 minutes, one milliliter from each tube was cultured in nutrient agar media for 24 hours, and the colonies were counted in CFU/mL. Data were analyzed using multifactorial ANOVA and Bonferroni tests. Results: Casts in both wet and dry groups were disinfected to a high level (6 log), with no statistically significant differences between them (P<0.05). Conclusion: According to the results, microwave irradiation can disinfect dental stone casts to a high degree, irrespective of moisture level. However, the result should be confirmed by exploring with other species of resistant microorganisms. PMID- 28840088 TI - Mechanisms of Cognitive Aging in the HIV-Positive Adult. AB - PURPOSE OF REVIEW: As of the year 2016, an estimated 50% of the United States' HIV-Positive population is aged 50 years or older. Due to a combination of increased rates of infection in older adults, and successful anti-retroviral (ART) regimens allowing HIV-positive adults to survive for decades with the disease, we are now faced with a steadily graying HIV-positive population, with only limited knowledge of how the cognitive and physiological effects of aging intersect with those of chronic HIV-infection. RECENT FINDINGS: Age-related changes to mood, cognition, and neurological health may be experienced differently in those living with HIV, and research concerning quality of life, mental health, and cognitive aging needs to account for and explore these factors more carefully in the coming years. SUMMARY: This review will explore the topic of cognitive aging with HIV: 1. Central nervous system (CNS) infection of HIV and how the virus affects brain integrity and function; 2. Cognitive and behavioral symptoms of HIV-Associated Neurocognitive Disorders (HAND); 3. Neurobiological theories of Cognitive Aging and how these processes may be exacerbated by HIV infection; 4: Clinical implications and complications of aging with HIV and factors that may result in poorer cognitive outcomes. PMID- 28840090 TI - Cold atmospheric plasma in orthopaedic and urologic tumor therapy. AB - Cold atmospheric plasma (CAP) is a highly reactive ionized physical state thereby provoking divers biological effects. In medical applications, CAP treatment promotes wound healing, provokes immunostimulation, and is antiseptically active. Moreover, CAP interacts with antiproliferative mechanisms suggesting CAP treatment as a promising anticancer strategy. Here we review the current state of science concerning the so far investigated CAP effects on different cancer entities in orthopaedic and urologic oncology. PMID- 28840091 TI - The relationship between subjective perception and the psychological effects of patients in spatial isolation. AB - Background: Spatial isolation is a common infection control measure, but negative psychological effects are often neglected. We investigated which factors influence the perception of single room isolated patients. Methods: In the present correlative cross-sectional study, 32 isolated patients have been interviewed within three departments of the Heidelberg University Hospital, one of Germany's largest hospitals. The following questionnaires were used: 10-Item Big Five Inventory (BFI-10), Positive and Negative Affect Schedule (PANAS), Hospital Anxiety and Depression Scale (HADS) and a self-developed questionnaire to evaluate the individual experience of isolation. Data were analysed using correlation and regression analysis. Results: A significant positive correlation was found between the isolation period and anxiety (r=.42, p<.05). Interestingly, a significant positive correlation was demonstrated between the duration of contact to nursing staff and negative daydreaming (r=.89, p<.01). The activity watching television was associated with higher levels of anxiety (r=.38, p<.05). Surfing the internet had a positive relationship with thinking about beautiful things (r=.41, p<.05). Conclusions: Our study results have implications how to improve the psychological situation of patients during spatial isolation. Contact between nursing staff and patients is crucial, since this contact significantly associated with negative daydreaming, probably due to increased neediness of emotional and physical care in some patients. The duration of the isolation has an influence on the experience of anxiety. Activities to cope with the isolation, however, not always have positive effects on the well-being of the patient. PMID- 28840092 TI - Smear grading and the Mantoux skin test can be used to predict sputum smear conversion in patients suffering from tuberculosis. AB - Purpose: Smear scores and induration sizes resulting from the PPD (tuberculin purified protein derivative) test can serve as indicators of whether a patient suffering from tuberculosis shows smear conversion or not. Methods: Using microbiological methods smear and sputum tests, patients diagnosed as infected with Mycobacterium tuberculosis between 2002 and 2015 were included in this study. All of the assumed factors that may have a role in smear conversion were studied, in addition to the prolongation of tuberculosis. Results: 398 of 512 patients fulfilled all the inclusion criteria and formed the basis of this study. 215 patients (54%) were females and 183 (46%) were males. The median age for both men and women was 36 years. We found a statistically significant difference between the size of induration resulting from the PPD skin test and the rate of non-conversion (P=0.002). Further univariate analysis also showed that smear grading and an induration size of >=10 mm were independently associated with delayed smear conversion. Patients with cavitary lesions showed a higher rate of non-conversion after two months, which was not significant. We could not find any association between some of the variables, such as age, sex, weight, smoking, alcoholism, addictions, respiratory diseases, diabetes mellitus, alternative anti TB treatment, and smear conversion. Conclusion: Intensified treatment and precautions against transmission should be especially considered for TB patients with high smear grading and an induration size of more than 10 mm. PMID- 28840093 TI - nim gene-independent metronidazole-resistant Bacteroides fragilis in surgical site infections. AB - Background:Bacteroides fragilis is the most common anaerobic pathogen isolated from surgical site infections (SSIs). Metronidazole resistance is increasing and the mechanisms of resistance are not clear in some isolates. The aim of the present study was to investigate the metronidazole susceptibility prevalence, and detect nim genes in B. fragilis isolates from SSIs. Methods: This study included 100 surgery patients with signs and symptoms indicative of SSIs. Syringe aspiration of the infected site was used to collect specimens. All specimens were cultured on BBA (Brucella blood agar), KVLB (kanamycin-vancomycin laked blood), and BBE (Bacteroides bile esculin) agar. The MIC (minimum inhibitory concentration) of metronidazole was determined by the agar dilution method according to the Clinical and Laboratory Standard Institute (CLSI). Then the PCR method was used to determine the presence of the nim gene. Results: In the present study, 26 B. fragilis were isolated from 100 SSIs specimens. Eight isolates were metronidazole resistant; the metronidazole MIC was 32 ug/mL for 7 isolates and 64 ug/mL for one isolate. All isolates were nim gene negative. Conclusion: The emergence of metronidazole-resistant B. fragilis limits the application of this drug for treatment and prophylaxis of SSIs. Thus, rapid identification of metronidazole-resistant B. fragilis is essential to restrict inappropriate, superfluous administration. In spite of various metronidazole resistance mechanisms other than that depending on the nim gene, detection of nim by PCR is unsuitable for identifying resistant isolates. Therefore, phenotypic methods are better to screen for and identify metronidazole-resistant B. fragilis. PMID- 28840094 TI - The risk benefit ratio of glucocorticoids in SLE: have things changed over the past 40 years? AB - PURPOSE OF REVIEW: Glucocorticoids have been the mainstay of treatment in systemic lupus erythematosus for more than half a century. Despite advancements in knowledge concerning the pathophysiology of systemic lupus, the genomic/non genomic actions of glucocorticoids, and the use of novel therapeutic agents in SLE, the burden of toxicity from glucocorticoid use remains unchanged. RECENT FINDINGS: SLE patients receiving long-term prednisone therapy are at significant risk of morbidity due to permanent organ damage and prednisone daily dosages above 6 mg have been shown to increase the risk of future organ damage by 50%. Glucocorticoid use carries a higher risk of opportunistic infections, iatrogenic osteoporosis and avascular necrosis, an increase in risk of cardiovascular events, cataracts and glaucoma, as well as psychiatric adverse effects like psychosis and manic episodes. There are limited data regarding the relative efficacy of the different glucocorticoid formulations or dosing regimens. SUMMARY: The use and dosing of glucocorticoids in SLE remains more art than science, although our knowledge regarding their complex genomic and non-genomic effects, as well as the resultant adverse effects, has greatly expanded over the past half a century. PMID- 28840095 TI - Food insecurity and physical activity insecurity among rural Oregon families. AB - Among rural families, rates of both child obesity and household food insecurity (FI) are higher compared to non-rural families. These disparities result from a complex interplay of social and environmental conditions that influence behavior. The Transtheoretical Model suggests individual readiness to change underlies success in modifying obesity-preventing behaviors; however, whether an association between readiness to change obesity-related behaviors and FI status among rural families exists is unknown. We examined the association between readiness to change family-level nutrition and physical activity (PA) behaviors that predict child obesity and family FI status within a sample of rural families to better understand these relationships. Families (n = 144) were recruited from six rural Oregon communities in 2013. Families completed a FI screener and the Family Stage of Change Survey (FSOC), a measure of readiness to change family level nutrition and PA behaviors associated with obesity. Demographic differences by FI status were explored, and regression was applied to examine relationships between FI and FSOC scores, adjusting for relevant covariates. Among FI families (40.2%), more were non-white (77.8% vs. 22.2%; p = 0.036) and had lower adult education (30.4% vs. 11.8% with > high school degree; p = 0.015) compared to non FI families. After adjusting for education, race, ethnicity, and eligibility for federal meal programs, readiness to provide opportunities for PA was lower among FI families (p = 0.002). These data highlight a need to further investigate how food insecurity and low readiness to provide PA opportunities, i.e. "physical activity insecurity" may be contributing to the higher obesity rates observed among rural children and families. PMID- 28840096 TI - Profiles of sociodemographic, behavioral, clinical and psychosocial characteristics among primary care patients with comorbid obesity and depression. AB - The objective of this study is to characterize profiles of obese depressed participants using baseline data collected from October 2014 through December 2016 for an ongoing randomized controlled trial (n = 409) in Bay Area, California, USA. Four comorbidity severity categories were defined by interaction of the binary levels of body mass index (BMI) and depression Symptom Checklist 20 (SCL20) scores. Sociodemographic, behavioral, clinical and psychosocial characteristics were measured. Mean (SD) age was 51 (12.1) years, BMI 36.7 (6.4) kg/m2, and SCL20 1.5 (0.5). Participants in the 4 comorbidity severity categories had similar sociodemographic characteristics, but differed significantly in the other characteristics. Two statistically significant canonical dimensions were identified. Participants with BMI >= 35 and SCL20 >= 1.5 differed significantly from those with BMI < 35 and SCL20 < 1.5 on dimension 1, which primarily featured high physical health (e.g., central obesity, high blood pressure and impaired sleep) and mental health comorbidities (e.g., post-traumatic stress and anxiety), poor health-related quality of life (in general and problems specifically with obesity, anxiety, depression, and usual daily activities), and an avoidance problem-solving style. Participants with BMI < 35 and SCL20 >= 1.5 differed significantly from those with BMI >= 35 and SCL20 < 1.5 on dimension 2, which primarily included fewer Hispanics, less central obesity, and more leisure-time physical activity, but greater anxiety and post-traumatic stress and poorer obesity- or mental health-related quality of life. In conclusion, patients with comorbid obesity and depression of varying severity have different profiles of behavioral, clinical and psychosocial characteristics. This insight may inform analysis of treatment heterogeneity and development of targeted intervention strategies. Trial registration:ClinicalTrials.gov #NCT02246413. PMID- 28840097 TI - A case of delayed exacerbation of interstitial lung disease after discontinuation of temsirolimus. AB - Temsirolimus is an inhibitor of mammalian target of rapamycin and interstitial lung disease (ILD) is known to be one of the adverse events associated with temsirolimus, which usually improves rapidly after discontinuation of the drug and rarely worsens thereafter. Herein, we report a case of delayed exacerbation of ILD after discontinuation of temsirolimus for metastatic renal cell carcinoma in an 86-year-old male with chronic ILD. The patient developed gradually worsening dyspnea five weeks after an initiation of temsirolimus and was admitted to our facility. On his admission, although a pulmonary function test revealed a decreased diffusion capacity, there was no obvious progression of ILD on HRCT scan. His dyspnea once improved after discontinuation of temsirolimus, but it recurred and acute exacerbation of ILD was diagnosed 40 days after his last administration of temsirolimus. He received high-dose steroid therapy, however, he deteriorated and died. Histopathological examination of the lungs at autopsy revealed overlapping diffuse alveolar damage with chronic interstitial changes. In the present case, since there were no specific factors that could have caused acute exacerbation of ILD except for temsirolimus, it was considered to contribute to the exacerbation of underlying ILD. In conclusion, physicians should be aware of the possibility of temsirolimus-induced ILD not only while the medication is administered, but also even after it is discontinued. It is important to carefully interview the patient and to recognize the value of physiological tests, such as respiratory function tests and blood gas analysis, as well as imaging findings on HRCT. PMID- 28840098 TI - White matter microstructure of 6-year old children born preterm and full term. AB - AIM: We previously observed a complex pattern of differences in white matter (WM) microstructure between preterm-born (PT) and full-term-born (FT) children and adolescents age 9-17 years. The aim of this study was to determine if the same differences exist as early as age 6 years. METHOD: We obtained diffusion MRI (dMRI) scans in children born PT at age 6 years (n = 20; 11 males) and FT (n = 38; 14 males), using two scanning protocols: 30 diffusion directions (b = 1000 s/mm2) and 96 diffusion directions (b = 2500 s/mm2). We used deterministic tractography and analyzed fractional anisotropy (FA) along bilateral cerebral WM pathways that demonstrated differences in the older sample. RESULTS: Compared to the FT group, the PT group showed (1) significantly decreased FA in the uncinate fasciculi and forceps major and (2) significantly increased FA in the right anterior thalamic radiation, inferior fronto-occipital fasciculi, and inferior longitudinal fasciculi. This pattern of group differences resembles findings in the previous study of older PT and FT participants. Group differences were similar across dMRI acquisition protocols. INTERPRETATION: The underlying neurobiology driving the pattern of PT-FT differences in FA is present as early as age 6 years. Generalization across dMRI acquisition protocols demonstrates the robustness of group differences in FA. Future studies will use quantitative neuroimaging techniques to understand the tissue properties that give rise to this consistent pattern of WM differences after PT birth. PMID- 28840100 TI - Genome-wide identification and tissue-specific expression analysis of nucleotide binding site-leucine rich repeat gene family in Cicer arietinum (kabuli chickpea). AB - The nucleotide binding site-leucine rich repeat (NBS-LRR) proteins play an important role in the defense mechanisms against pathogens. Using bioinformatics approach, we identified and annotated 104 NBS-LRR genes in chickpea. Phylogenetic analysis points to their diversification into two families namely TIR-NBS-LRR and non-TIR-NBS-LRR. Gene architecture revealed intron gain/loss events in this resistance gene family during their independent evolution into two families. Comparative genomics analysis elucidated its evolutionary relationship with other fabaceae species. Around 50% NBS-LRRs reside in macro-syntenic blocks underlining positional conservation along with sequence conservation of NBS-LRR genes in chickpea. Transcriptome sequencing data provided evidence for their transcription and tissue-specific expression. Four cis-regulatory elements namely WBOX, DRE, CBF, and GCC boxes, that commonly occur in resistance genes, were present in the promoter regions of these genes. Further, the findings will provide a strong background to use candidate disease resistance NBS-encoding genes and identify their specific roles in chickpea. PMID- 28840101 TI - Radiofrequency ablation of ventricular tachycardia originating from a lipomatous hamartoma localized in the right ventricle cavity. PMID- 28840102 TI - Management of device-related malignant sarcoma. PMID- 28840099 TI - Specific DTI seeding and diffusivity-analysis improve the quality and prognostic value of TMS-based deterministic DTI of the pyramidal tract. AB - OBJECT: Navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI) is used preoperatively in patients with eloquent located brain lesions and allows analyzing non-invasively the spatial relationship between the tumor and functional areas (e.g. the motor cortex and the corticospinal tract [CST]). In this study, we examined the diffusion parameters FA (fractional anisotropy) and ADC (apparent diffusion coefficient) within the CST in different locations and analyzed their interrater reliability and usefulness for predicting the patients' motor outcome with a precise approach of specific region of interest (ROI) seeding based on the color-coded FA-map. METHODS: Prospectively collected data of 30 patients undergoing bihemispheric nTMS mapping followed by nTMS-based DTI fiber tracking prior to surgery of motor eloquent high-grade gliomas were analyzed by 2 experienced and 1 unexperienced examiner. The following data were scrutinized for both hemispheres after tractography based on nTMS-motor positive cortical seeds and a 2nd region of interest in one layer of the caudal pons defined by the color-coded FA-map: the pre- and postoperative motor status (day of discharge und 3 months), the closest distance between the tracts and the tumor (TTD), the fractional anisotropy (FA) and the apparent diffusion coefficient (ADC). The latter as an average within the CST as well as specific values in different locations (peritumoral, mesencephal, pontine). RESULTS: Lower average FA-values within the affected CST as well as higher average ADC-values are significantly associated with deteriorated postoperative motor function (p = 0.006 and p = 0.026 respectively). Segmental analysis within the CST revealed that the diffusion parameters are especially disturbed on a peritumoral level and that the degree of their impairment correlates with motor deficits (FA p = 0.065, ADC p = 0.007). No significant segmental variation was seen in the healthy hemisphere. The interrater reliability showed perfect agreement for almost all analyzed parameters. CONCLUSIONS: Adding diffusion weighted imaging derived information on the structural integrity of the nTMS-based tractography results improves the predictive power for postoperative motor outcome. Utilizing a second subcortical ROI which is specifically seeded based on the color-coded FA map increases the tracking quality of the CST independently of the examiner's experience. Further prospective studies are needed to validate the nTMS-based prediction of the patient's outcome. PMID- 28840103 TI - "Closing the loop" on palpitations. A report of unexpected communication between a loop recorder symptom marker and pacemaker. PMID- 28840104 TI - T-wave oversensing from postural changes: A rare cause of inappropriate shock from a subcutaneous defibrillator. PMID- 28840105 TI - Brugada syndrome-Malignant phenotype associated with acute cardiac inflammation? PMID- 28840106 TI - Bronchogenic cyst of the atrioventricular septum presenting with ventricular fibrillation. PMID- 28840107 TI - Cardiac inflammation and ventricular tachycardia in Chagas disease. PMID- 28840108 TI - Iatrogenic type A aortic dissection during idiopathic ventricular tachycardia ablation. PMID- 28840109 TI - Emergency left arial appendage clipping after percutaneous pulmonary vein isolation in a patient with a partial anomalous pulmonary venous connection. PMID- 28840110 TI - A case of an incision-related single-loop intra-atrial reentrant tachycardia showing an eccentric atrial activation sequence and widely separate potentials resembling a double-loop reentry; its mechanism and analysis. PMID- 28840111 TI - Ocular involvement with secondary syphilis in a non-HIV infected man. PMID- 28840112 TI - Kinetics of petroleum oil biodegradation by a consortium of three protozoan isolates (Aspidisca sp., Trachelophyllum sp. and Peranema sp.). AB - Petroleum oil is a complex mixture of substances, the majority of which are hydrocarbons; the latter represent an extremely important and heterogeneous group of compounds that find their way into water resources by anthropogenic or natural ways. The majority of toxic hydrocarbon components of petroleum are biodegradable, where bioremediation using microbial species has become an integral process for the restoration of oil-polluted areas. In this study, three bioremediation processes, namely natural attenuation, nutrient supplementation by adding glucose and biostimulation by adding Tween(r) 80, were carried out in various petroleum hydrocarbon concentrations in polluted water media using a consortium of three protozoan isolates (Aspidisca sp., Trachelophyllum sp. and Peranema sp.). A first-order kinetics model was fitted to the biodegradation data to evaluate the biodegradation rate and to determine the corresponding half-life time. First-order kinetics satisfactorily described the biodegradation of the petroleum-based contaminants under abiotic conditions. The results showed an increase in the percentage removal of petroleum oil at the lower petroleum concentrations and a gradual percentage decrease in removing petroleum oil residues occurred when there was an increase in the initial concentrations of the petroleum oil: 39%, 27%, 22%, 12%, 10% for various petroleum oil concentrations of 50, 100, 150, 200, 250 mg/L, respectively. A similar trend was also observed in the glucose-supplemented culture media where the reduction was 45% and 78% for petroleum concentrations of 250 mg/L and 50 mg/L, respectively. Biodegradation of between 33 and 90% was achieved at a Tween(r) 80 concentration of between 50 mg/L and 250 mg/L. The degradation rate constants for the natural attenuation process ranged between >=0 to <=0.50, >=0 to <=0.35, >=0 to <=0.25, >=0 to <= 0.14 and >= 0 to <=0.11 for petroleum oil concentrations varying from 50, 100, 150, 200 and 250 mg/L, respectively, during the study after 30 days. In the presence of glucose as a nutrient supplement, the degradation rate constants increased from 0 day-1 to 0.8 day-1 when exposed to the lowest oil concentration of 50 mg/L, while the lowest rate constants (from 0 day-1 to 0.25 day-1) were observed at the highest petroleum oil concentration of 250 mg/L for the same period. Overall enhancement of the degradation rates was achieved when adding the Tween(r) 80 surfactant compared to the first two biodegradation processes. The longest half life was achieved after 217 days during the natural attenuation process for samples with an oil concentration of 250 mg/L and this was reduced to 85 days using the glucose-supplemented process. There was a further decrease to 45 days when Tween(r) 80 surfactant was added during the biostimulation process. The highest efficiency of >=20% of Tween(r) 80 was observed between 6 and 18 days and thereafter it decreased slightly to <=20%. PMID- 28840113 TI - Quantitative EEG Signatures through Amplitude and Phase Modulation Patterns. AB - Cortical spatiotemporal signal patterns based on object recognition can be discerned from visual stimulation. These are in the form of amplitude modulation (AM) and phase modulation (PM) patterns, which contain perceptual information gathered from sensory input. A high-density Electroencephalograph (EEG) device consisting of 48 electrodes with a spacing of 5 mm was utilized to measure frontal lobe activity in order to capture event-related potentials from visual stimuli. Four randomized stimuli representing different levels of salient responsiveness were measured to determine if mild stimuli can be discerned from more extreme stimuli. AM/PM response patterns were detected between mild and more salient stimuli across participants. AM patterns presented distinct signatures for each stimulus. AM patterns had the highest number of incidents detected in the middle of the frontal lobe. Through this work, we can expand our encyclopedia of neural signatures to object recognition, and provide a broader understanding of quantitative neural responses to external stimuli. The results provide a quantitative approach utilizing spatiotemporal patterns to analyze where distinct AM patterns can be linked to object perception. PMID- 28840114 TI - ICA-Based Imagined Conceptual Words Classification on EEG Signals. AB - Independent component analysis (ICA) has been used for detecting and removing the eye artifacts conventionally. However, in this research, it was used not only for detecting the eye artifacts, but also for detecting the brain-produced signals of two conceptual danger and information category words. In this cross-sectional research, electroencephalography (EEG) signals were recorded using Micromed and 19-channel helmet devices in unipolar mode, wherein Cz electrode was selected as the reference electrode. In the first part of this research, the statistical community test case included four men and four women, who were 25-30 years old. In the designed task, three groups of traffic signs were considered, in which two groups referred to the concept of danger, and the third one referred to the concept of information. In the second part, the three volunteers, two men and one woman, who had the best results, were chosen from among eight participants. In the second designed task, direction arrows (up, down, left, and right) were used. For the 2/8 volunteers in the rest times, very high-power alpha waves were observed from the back of the head; however, in the thinking times, they were different. According to this result, alpha waves for changing the task from thinking to rest condition took at least 3 s for the two volunteers, and it was at most 5 s until they went to the absolute rest condition. For the 7/8 volunteers, the danger and information signals were well classified; these differences for the 5/8 volunteers were observed in the right hemisphere, and, for the other three volunteers, the differences were observed in the left hemisphere. For the second task, simulations showed that the best classification accuracies resulted when the time window was 2.5 s. In addition, it also showed that the features of the autoregressive (AR)-15 model coefficients were the best choices for extracting the features. For all the states of neural network except hardlim discriminator function, the classification accuracies were almost the same and not very different. Linear discriminant analysis (LDA) in comparison with the neural network yielded higher classification accuracies. ICA is a suitable algorithm for recognizing of the word's concept and its place in the brain. Achieved results from this experiment were the same compared with the results from other methods such as functional magnetic resonance imaging and methods based on the brain signals (EEG) in the vowel imagination and covert speech. Herein, the highest classification accuracy was obtained by extracting the target signal from the output of the ICA and extracting the features of coefficients AR model with time interval of 2.5 s. Finally, LDA resulted in the highest classification accuracy more than 60%. PMID- 28840115 TI - Metal Artifact Reduction in Dental Computed Tomography Images Based on Sinogram Segmentation Using Curvelet Transform Followed by Hough Transform. AB - In X-ray computed tomography (CT), the presence of metal objects in a patient's body produces streak artifacts in the reconstructed images. During the past decades, many different methods were proposed for the reduction or elimination of the streaking artifacts. When scanning a patient, the projection data affected by metal objects (missing projections) appear as regions with high intensities in the sinogram. In spiral fan beam CT, these regions are sinusoid-like curves on sinogram. During the first time, if the metal curves are detected carefully, then, they can be replaced by corresponding unaffected projections using other slices or opposite views; therefore, the CT slices regenerated by the modified sonogram will be imaged with high quality. In this paper, a new method of the segmentation of metal traces in spiral fan-beam CT sinogram is proposed. This method is based on a sinogram curve detection using a curvelet transform followed by 2D Hough transform. The initial enhancement of the sinogram using modified curvelet transform coefficients is performed by suppressing all the coefficients of one band and applying 2D Hough transform to detect more precisely metal curves. To evaluate the performance of the proposed method for the detection of metal curves in a sinogram, precision and recall metrics are calculated. Compared with other methods, the results show that the proposed method is capable of detecting metal curves, with better precision and good recovery. PMID- 28840116 TI - A Non-Parametric Approach for the Activation Detection of Block Design fMRI Simulated Data Using Self-Organizing Maps and Support Vector Machine. AB - Functional magnetic resonance imaging (fMRI) is a popular method to probe the functional organization of the brain using hemodynamic responses. In this method, volume images of the entire brain are obtained with a very good spatial resolution and low temporal resolution. However, they always suffer from high dimensionality in the face of classification algorithms. In this work, we combine a support vector machine (SVM) with a self-organizing map (SOM) for having a feature-based classification by using SVM. Then, a linear kernel SVM is used for detecting the active areas. Here, we use SOM for feature extracting and labeling the datasets. SOM has two major advances: (i) it reduces dimension of data sets for having less computational complexity and (ii) it is useful for identifying brain regions with small onset differences in hemodynamic responses. Our non parametric model is compared with parametric and non-parametric methods. We use simulated fMRI data sets and block design inputs in this paper and consider the contrast to noise ratio (CNR) value equal to 0.6 for simulated datasets. fMRI simulated dataset has contrast 1-4% in active areas. The accuracy of our proposed method is 93.63% and the error rate is 6.37%. PMID- 28840117 TI - A New Energy-Efficient Topology for Wireless Body Area Networks. AB - Wireless body area networks consist of several devices placed on the human body, sensing vital signs and providing remote recognition of health disorders. Low power consumption is crucial in these networks. A new energy-efficient topology is provided in this paper, considering relay and sensor nodes' energy consumption and network maintenance costs. In this topology design, relay nodes, placed on the cloth, are used to help the sensor nodes forwarding data to the sink. Relay nodes' situation is determined such that the relay nodes' energy consumption merges the uniform distribution. Simulation results show that the proposed method increases the lifetime of the network with nearly uniform distribution of the relay nodes' energy consumption. Furthermore, this technique simultaneously reduces network maintenance costs and continuous replacements of the designer clothing. The proposed method also determines the way by which the network traffic is split and multipath routed to the sink. PMID- 28840118 TI - Designing an Optimized Novel Femoral Stem. AB - BACKGROUND: After total hip arthroplasty, there would be some problems for the patients. Implant loosening is one of the significant problems which results in thigh pain and even revision surgery. Difference between Young's modulus of bone metal is the cause of stress shielding, atrophy, and subsequent implant loosening. MATERIALS AND METHODS: In this paper, femoral stem stiffness is reduced by novel biomechanical and biomaterial design which includes using proper design parameters, coating it with porous surface, and modeling the sketch by the software. Parametric design of femoral stem is done on the basis of clinical reports. RESULTS: Optimized model for femoral stem is proposed. Curved tapered stem with trapezoidal cross-section and particular neck and offset is designed. Fully porous surface is suggested. Moreover, Designed femoral stem analysis showed the Ti6Al4V stem which is covered with layer of 1.5 mm in thickness and 50% of porosity is as stiff as 77 GPa that is 30% less than the stem without any porosity. Porous surface of designed stem makes it fix biologically; thus, prosthesis loosening probability decreases. CONCLUSION: By optimizing femoral stem geometry (size and shape) and also making a porous surface, which had an intermediate stiffness of bone and implant, a more efficient hip joint prosthesis with more durability fixation was achieved due to better stress transmission from implant to the bone. PMID- 28840119 TI - The Correction of Focal Point Displacement Caused by the Refraction of the Beams in High-Intensity Focused Ultrasound. AB - Nowadays, high-intensity focused ultrasound (HIFU) as nonionizing radiation is used for cancer treatment. Basically, the function of HIFU is similar to conventional ultrasound. Ultrasound beams are perverted when crossing the border of different environments. This decreases the beam's focus within the tumor and may induce damage to the normal tissues. In this study, we aim to develop appropriate algorithms for correcting the focal point displacement duced by the beam's refraction. First, the level of displacement due to difference in two specific tissues was calculated for one element of the transducer and, then, it extended to all of the elements. Finally, a new focal point was calculated, which is considered as a desired focal point of the transducer in which the maximum temperature occurs. Designed algorithms were implemented in MATLAB software. A HIFU simulator (by the Food and Drug Administration of US) was used to simulate HIFU therapy. The proposed algorithm was tested on four models with two layers of tissue. Results illustrated the use of proposed algorithm results for 78% correction in the focal point displacement. In addition, it was noted that a part of this displacement was caused by the absorption of the beam in the tissues. The proposed algorithm can significantly correct the focal point displacement in HIFU therapy and consequently prevent damage to the normal tissues. PMID- 28840120 TI - Optical Ring Resonators: A Platform for Biological Sensing Applications. AB - Rapid advances in biochemistry and genetics lead to expansion of the various medical instruments for detection and prevention tasks. On the other hand, food safety is an important concern which relates to the public health. One of the most reliable tools to detect bioparticles (i.e., DNA molecules and proteins) and determining the authenticity of food products is the optical ring resonators. By depositing a recipient polymeric layer of target particle on the periphery of an optical ring resonator, it is possible to identify the existence of molecules by calculating the shift in the spectral response of the ring resonators. The main purpose of this paper is to investigate the performance of two structures of optical ring resonators, (i) all-pass and (ii) add-drop resonators for sensing applications. We propose a new configuration for sensing applications by introducing a nanogap in the all-pass ring resonator. The performance of these resonators is studied from sensing point of view. Simulation results, using finite difference time domain paradigm, revealed that the existence of a nanogap in the ring configuration achieves higher amount of sensitivity; thus, this structure is more suitable for biosensing applications. PMID- 28840121 TI - A Pilot Genome-Wide Association Study in Postmenopausal Mexican-Mestizo Women Implicates the RMND1/CCDC170 Locus Is Associated with Bone Mineral Density. AB - To identify genetic variants influencing bone mineral density (BMD) in the Mexican-Mestizo population, we performed a GWAS for femoral neck (FN) and lumbar spine (LS) in Mexican-Mestizo postmenopausal women. In the discovery sample, 300,000 SNPs were genotyped in a cohort of 411 postmenopausal women and seven SNPs were analyzed in the replication cohort (n = 420). The combined results of a meta-analysis from the discovery and replication samples identified two loci, RMND1 (rs6904364, P = 2.77 * 10-4) and CCDC170 (rs17081341, P = 1.62 * 10-5), associated with FN BMD. We also compared our results with those of the Genetic Factors for Osteoporosis (GEFOS) Consortium meta-analysis. The comparison revealed two loci previously reported in the GEFOS meta-analysis: SOX6 (rs7128738) and PKDCC (rs11887431) associated with FN and LS BMD, respectively, in our study population. Interestingly, rs17081341 rare in Caucasians (minor allele frequency < 0.03) was found in high frequency in our population, which suggests that this association could be specific to non-Caucasian populations. In conclusion, the first pilot Mexican GWA study of BMD confirmed previously identified loci and also demonstrated the importance of studying variability in diverse populations and/or specific populations. PMID- 28840122 TI - Retina Image Vessel Segmentation Using a Hybrid CGLI Level Set Method. AB - As a nonintrusive method, the retina imaging provides us with a better way for the diagnosis of ophthalmologic diseases. Extracting the vessel profile automatically from the retina image is an important step in analyzing retina images. A novel hybrid active contour model is proposed to segment the fundus image automatically in this paper. It combines the signed pressure force function introduced by the Selective Binary and Gaussian Filtering Regularized Level Set (SBGFRLS) model with the local intensity property introduced by the Local Binary fitting (LBF) model to overcome the difficulty of the low contrast in segmentation process. It is more robust to the initial condition than the traditional methods and is easily implemented compared to the supervised vessel extraction methods. Proposed segmentation method was evaluated on two public datasets, DRIVE (Digital Retinal Images for Vessel Extraction) and STARE (Structured Analysis of the Retina) (the average accuracy of 0.9390 with 0.7358 sensitivity and 0.9680 specificity on DRIVE datasets and average accuracy of 0.9409 with 0.7449 sensitivity and 0.9690 specificity on STARE datasets). The experimental results show that our method is effective and our method is also robust to some kinds of pathology images compared with the traditional level set methods. PMID- 28840123 TI - Serum Butyrylcholinesterase Activity: A Biomarker for Parkinson's Disease and Related Dementia. AB - OBJECTIVE: This study aim to determine changes of serum butyrylcholinesterase (BChE) activity in PD patients and related dementia. PATIENTS AND METHODS: Consecutive PD patients and healthy controls were included and clinical data were collected. Fast serum BChE activity was determined and compared between healthy controls and PD patients. Independent risk factors were performed for BChE activity, PD, and related dementia. The relationship between BChE activity and disease severity was also evaluated. Receiver operating characteristic (ROC) curves were obtained to explore serum BChE activity in distinguishing PD patients and related dementia. RESULTS: Serum BChE activity mainly independently correlated with gender, albumin, triglyceride, body mass index, and PD. Serum BChE activity decreased in PD patients compared with healthy controls. Based on the ROC curve, the optimal cut-off point was 6864.08 IU/L for distinguishing PD patients, and the sensitivity and specificity values were 61.8% and 72.1%. It inversely correlated with Unified Parkinson's Disease Rating Scale score. BChE activity decreased in PD-related dementia compared with those without dementia. The sensitivity and specificity values were 70.6% and 76.3%, respectively, with an optimal cut-off point of 6550.00 IU/L. CONCLUSIONS: Serum BChE activity can be regarded as a biomarker for PD and related dementia. PMID- 28840124 TI - The Effect of Patient-Specific Instrumentation Incorporating an Extramedullary Tibial Guide on Operative Efficiency for Total Knee Arthroplasty. AB - This retrospective study was to determine if patient-specific instrumentation (PSI) for total knee arthroplasty (TKA) leads to shortened surgical time through increased operating room efficiency according to different tibial PSI designs. 166 patients underwent primary TKA and were categorized into three groups as follows: PSI without extramedullary (EM) tibial guide (group 1, n = 48), PSI with EM tibial guide (group 2, n = 68), and conventional instrumentation (CI) group (group 3, n = 50). Four factors were compared between groups, namely, operative room time, thickness of bone resection, tibial slope, and rotation of the component. The mean surgical time was significantly shorter in the PSI with EM tibial guide group (group 2, 63.9 +/- 13.6 min) compared to the CI group (group 3, 82.8 +/- 24.9 min) (P < 0.001). However, there was no significant difference in the PSI without EM tibial guide group (group 1, 75.3 +/- 18.8 min). This study suggests that PSI incorporating an EM tibial guide may lead to high operative efficiency in TKA compared to CI. This trial is registered with KCT0002384. PMID- 28840125 TI - Enhanced Energy Localization in Hyperthermia Treatment Based on Hybrid Electromagnetic and Ultrasonic System: Proof of Concept with Numerical Simulations. AB - This paper proposes a hybrid hyperthermia treatment system, utilizing two noninvasive modalities for treating brain tumors. The proposed system depends on focusing electromagnetic (EM) and ultrasound (US) energies. The EM hyperthermia subsystem enhances energy localization by incorporating a multichannel wideband setting and coherent-phased-array technique. A genetic algorithm based optimization tool is developed to enhance the specific absorption rate (SAR) distribution by reducing hotspots and maximizing energy deposition at tumor regions. The treatment performance is also enhanced by augmenting an ultrasonic subsystem to allow focused energy deposition into deep tumors. The therapeutic faculty of ultrasonic energy is assessed by examining the control of mechanical alignment of transducer array elements. A time reversal (TR) approach is then investigated to address challenges in energy focus in both subsystems. Simulation results of the synergetic effect of both modalities assuming a simplified model of human head phantom demonstrate the feasibility of the proposed hybrid technique as a noninvasive tool for thermal treatment of brain tumors. PMID- 28840126 TI - Autologous Stem Cells Combined Core Decompression for Treatment of Avascular Necrosis of the Femoral Head: A Systematic Meta-Analysis. AB - OBJECTIVE: This study aims to systematically evaluate the efficacy and safety of core decompression combined transplantation of autologous bone marrow stem cells (CDBMSCs) for treatment of avascular necrosis of the femoral head (ANFH). METHODS: Randomized controlled trials (RCTs) regarding effectiveness of core decompression combined transplantation of autologous bone marrow stem cells for treating ANFH were searched in 8 comprehensive databases prior to September 2016. The data analysis was performed by using the RevMan version 5.3. RESULTS: A total of 11 studies with 507 participants were included. Results showed that CDBMSCs group was more effective than CD group in increasing Harris hip score, decreasing necrotic area of femoral head, collapse of femoral head, and conversion to total hip replacement incidence. In the subgroup analysis, the results did not change in different intervention measure substantially. In addition, the safety of CDBMSCs for ANFH is reliable. CONCLUSION: Based on the systematic review, our findings suggest that core decompression combined transplantation of autologous bone marrow stem cells appeared to be more efficacious in the treatment at early stages of ANFH. PMID- 28840127 TI - Leaf Senescence, Root Morphology, and Seed Yield of Winter Oilseed Rape (Brassica napus L.) at Varying Plant Densities. AB - In this study, the yield and yield components were studied using a conventional variety Zhongshuang 11 (ZS 11) and a hybrid variety Zhongyouza 12 (ZYZ 12) at varying plant densities. The increase in plant density led to an initial increase in seed yield and pod numbers per unit area, followed by a decrease. The optimal plant density was 58.5 * 104 plants ha-1 in both ZS 11 and ZYZ 12. The further researches on physiological traits showed a rapid decrease in the green leaf area index (GLAI) and chlorophyll content and a remarkable increase in malondialdehyde content in high plant density (HPD) population than did the low plant density (LPD) population, which indicated the rapid leaf senescence. However, HPD had higher values in terms of pod area index (PAI), pod photosynthesis, and radiation use efficiency (RUE) after peak anthesis. A significantly higher level of dry matter accumulation and nitrogen utilization efficiency were observed, which resulted in higher yield. HPD resulted in a rapid decrease in root morphological parameters (root length, root tips, root surface area, and root volume). These results suggested that increasing the plant density within a certain range was a promising option for high seed yield in winter rapeseed in China. PMID- 28840128 TI - Calcium Phosphate Product Is Associated with Subclinical Carotid Atherosclerosis in Type 2 Diabetes. AB - AIMS: To assess whether circulating 25-hydroxyvitamin D3 (25OHD) and mineral metabolism-related factors (serum phosphate, calcium, and parathormone) are associated with subclinical carotid atherosclerosis (SCA), defined as the presence of carotid atherosclerotic plaques (main study outcome), in patients with type 2 diabetes mellitus (T2DM) without kidney disease or previous cardiovascular disease. METHODS: We undertook a post hoc analysis of a cross sectional study in adults with T2DM in whom we evaluated SCA. A total of 303 subjects with T2DM were included. Clinical variables and carotid ultrasound imaging were obtained. RESULTS: We found no association of 25OHD with the presence of SCA. However, calcium phosphate (CaP; mg2/dL2) product was positively associated with the presence of carotid plaques (ORadj = 1.078; 95% CI: 1.017 1.142). An inverse association was observed between higher levels of 25OHD (>=30 ng/mL versus <20 ng/mL concentrations) and common carotid intima-media thickness (cIMT; mm) (betaadj +/- SE = -0.055 +/- 0.024). We conclude that the CaP product is independently associated with the presence of established subclinical carotid atherosclerosis in patients with T2DM. PMID- 28840129 TI - Rs46522 in the Ubiquitin-Conjugating Enzyme E2Z Gene Is Associated with the Risk of Coronary Artery Disease in Individuals of Chinese Han Population with Type 2 Diabetes. AB - AIMS: We investigated the association between ubiquitin-conjugating enzyme E2Z (UBE2Z) gene SNP rs46522 and the risk of CAD in a Chinese Han population with type 2 diabetes and explored a possible interactive effect with environmental risk factors of CAD. METHODS: 665 patients with T2D were enrolled; 390 were CAD patients and 275 were non-CAD patients. Genotype analysis of rs46522 (T>C) was performed using PCR-RFLP. RESULTS: The SNP rs47522 was associated with the risk of CAD supposing recessive inheritance model (TT versus CC+CT, OR' = 1.277, 95%CI' 1.039-1.570, p' = 0.020) and codominant model (TT versus CT, OR' = 1.673, 95%CI' 1.088-2.570, p' = 0.019) after adjustment for confounders of CAD. A synergistic effect of rs46522 and BMI was discovered (beta = 0.012, p for interreaction = 0.028). In subgroup analysis, minor allele T was significantly associated with CAD in overweight and obesity subgroup (p = 0.034), and the association was also proved in recessive model (OR = 1.537, 95%CI 1.075-2.196, p = 0.018). Smokers with genotype TT had threefold risk of CAD in comparison to nonsmokers with genotype TC or CC (p < 0.001). CONCLUSIONS: The SNP rs46522 in UBE2Z gene is associated with the risk of CAD in the individuals of Chinese Han descent with type 2 diabetes and is of synergistic effect with BMI. PMID- 28840130 TI - Development of a Plantar Load Estimation Algorithm for Evaluation of Forefoot Load of Diabetic Patients during Daily Walks Using a Foot Motion Sensor. AB - Forefoot load (FL) contributes to callus formation, which is one of the pathways to diabetic foot ulcers (DFU). In this study, we hypothesized that excessive FL, which cannot be detected by plantar load measurements within laboratory settings, occurs in daily walks. To demonstrate this, we created a FL estimation algorithm using foot motion data. Acceleration and angular velocity data were obtained from a motion sensor attached to each shoe of the subjects. The accuracy of the estimated FL was validated by correlation with the FL measured by force sensors on the metatarsal heads, which was assessed using the Pearson correlation coefficient. The mean of correlation coefficients of all the subjects was 0.63 at a level corridor, while it showed an intersubject difference at a slope and stairs. We conducted daily walk measurements in two diabetic patients, and additionally, we verified the safety of daily walk measurement using a wearable motion sensor attached to each shoe. We found that excessive FL occurred during their daily walks for approximately three hours in total, when any adverse event was not observed. This study indicated that FL evaluation method using wearable motion sensors was one of the promising ways to prevent DFUs. PMID- 28840132 TI - AOJNMB is Indexed in PubMed Central from the First Issue. PMID- 28840131 TI - Characterization of Metabolically Healthy Obese People and Metabolically Unhealthy Normal-Weight People in a General Population Cohort of the ABCD Study. AB - There is actually no consensus about the possibility that in some instances, obesity may be a benign metabolically healthy (MH) condition as opposed to a normal-weight but metabolically unhealthy (MUH) state. The aim of this study was to characterize MH condition and to investigate possible associations with metabolic and cardiovascular complications. One thousand nineteen people (range of age 18-90 years) of the cohort of the ABCD_2 study were investigated. Participants were classified as normal weight (BMI < 24.9 kg/m2) or overweight obese (BMI >=25 kg/m2); they were also classified as MH in the presence of 0-1 among the following conditions: (a) prediabetes/type 2 diabetes, (b) hypertension, (c) hypertriglyceridemia or low HDL cholesterolemia, and (d) hypercholesterolemia. MUH condition was diagnosed if >=2 of the conditions listed were found. The prevalence of overweight/obese people was 71.1%, of whom 27.4% were found to be MH. In addition, 36.7% of the normal-weight participants were MUH. HOMA-IR, high sensitivity C-reactive protein, and the carotid intima-media thickness were significantly different in the 4 subgroups (P < 0.001), with higher values observed in the MUH normal-weight and obese groups. In conclusion, this study highlights the importance of identifying a MH condition in normal weight and in obese people in order to offer better treatment. PMID- 28840133 TI - Whole-Body Distribution of Donepezil as an Acetylcholinesterase Inhibitor after Oral Administration in Normal Human Subjects: A 11C-donepezil PET Study. AB - OBJECTIVES: It is difficult to investigate the whole-body distribution of an orally administered drug by means of positron emission tomography (PET), owing to the short physical half-life of radionuclides, especially when 11C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11C-DNP PET imaging, combined with the oral administration of pharmacological doses of DNP. METHODS: We studied 14 healthy volunteers, divided into group A (n=4) and group B (n=10). At first, we studied four females (mean age: 57.3+/-4.5 y), three of whom underwent 11C-DNP PET scan at 2.5 h after the oral administration of 1 mg and 30 ug of DNP, respectively, while one patient was scanned following the oral administration of 30 ug of DNP (group A). Then, we studied five females and five males (48.3+/-6.1 y), who underwent 11C-DNP PET scan, without the oral administration of DNP (group B). Plasma DNP concentration upon scanning was measured by tandem mass spectrometry. Arterialized venous blood samples were collected periodically to measure plasma radioactivity and metabolites. In group A, 11C-DNP PET scan of the brain and whole body continued for 60 and 20 min, respectively. Subjects in group B underwent sequential whole-body scan for 60 min. The regional uptake of 11C-DNP was analyzed by measuring the standard uptake value (SUV) through setting regions of interest on major organs with reference CT. RESULTS: In group A, plasma DNP concentration was significantly correlated with the orally administered dose of DNP. The mean plasma concentration was 2.00 nM (n=3) after 1 mg oral administration and 0.06 nM (n=4) after 30 ug oral administration. No significant difference in plasma radioactivity or fraction of metabolites was found between groups A and B. High 11C-DNP accumulation was found in the liver, stomach, pancreas, brain, salivary glands, bone marrow, and myocardium in groups A and B, in this order. No significant difference in SUV value was found among 11C-DNP PET studies after the oral administration of 1 mg of DNP, 30 ug of DNP, or no DNP. CONCLUSION: The present study demonstrated that the whole-body distribution of DNP after the oral administration of pharmacological doses could be evaluated by 11C-DNP PET studies, combined with the oral administration of DNP. PMID- 28840134 TI - Diagnostic Performance and Safety of Positron Emission Tomography Using 18F Fluciclovine in Patients with Clinically Suspected High- or Low-grade Gliomas: A Multicenter Phase IIb Trial. AB - OBJECTIVES: The study objective was to assess the diagnostic performance of positron emission tomography (PET) for gliomas using the novel tracer 18F fluciclovine (anti-[18F]FACBC) and to evaluate the safety of this tracer in patients with clinically suspected gliomas. METHODS: Anti-[18F]FACBC was administered to 40 patients with clinically suspected high- or low-grade gliomas, followed by PET imaging. T1-weighted, contrast-enhanced T1-weighted, and fluid attenuated inversion recovery (or T2-weighted) magnetic resonance imaging (MRI) scans were obtained to plan for the tissue collection. Tissues were collected from either "areas visualized using anti-[18F]FACBC PET imaging but not using contrast-enhanced T1-weighted imaging" or "areas visualized using both anti [18F]FACBC-PET imaging and contrast-enhanced T1-weighted imaging" and were histopathologically examined to assess the diagnostic accuracy of anti-[18F]FACBC PET for gliomas. RESULTS: The positive predictive value of anti-[18F]FACBC-PET imaging for glioma in areas visualized using anti-[18F]FACBC-PET imaging, but not visualized using contrast-enhanced T1-weighted images, was 100.0% (26/26), and the value in areas visualized using both contrast-enhanced T1-weighted imaging and anti-[18F]FACBC-PET imaging was 87.5% (7/8). Twelve adverse events occurred in 7 (17.5%) of the 40 patients who received anti-[18F]FACBC. Five events in five patients were considered to be adverse drug reactions; however, none of the events were serious, and all except one resolved spontaneously without treatment. CONCLUSION: This Phase IIb trial showed that anti-[18F]FACBC-PET imaging was effective for the detection of gliomas in areas not visualized using contrast enhanced T1-weighted MRI and the tracer was well tolerated. PMID- 28840135 TI - Assessment of Mediastinal Tumors Using SUVmax and Volumetric Parameters on FDG PET/CT. AB - OBJECTIVES: This study aimed to evaluate the role of pretreatment SUVmax and volumetric FDG positron emission tomography (PET) parameters in the differentiation between benign and malignant mediastinal tumors. In addition, we investigated whether pretreatment SUVmax and volumetric FDG-PET parameters could distinguish thymomas from thymic carcinomas, and low-risk from high-risk thymomas. METHODS: This study was conducted on 52 patients with mediastinal tumors undergoing FDG-PET/CT. Histological examination indicated that 29 mediastinal tumors were benign, and 23 cases were malignant. To obtain quantitative PET/CT parameters, we determined the maximum standardized uptake value (SUVmax), volumetric parameters, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for primary tumors using SUVmax cut-off value of 2.5. SUVmax, MTV and TLG of benign and malignant tumors were compared using the Mann Whitney U test. Moreover, receiver-operating curve (ROC) analysis was applied to identify the cut-off values of SUVmax, MTV and TLG for the accurate differentiation of benign and malignant tumors. SUVmax, MTV and TLG were compared between thymomas and thymic carcinomas, as well as low-risk and high-risk thymomas. RESULTS: Mean SUVmax, MTV and TLG of malignant mediastinal tumors were significantly higher compared to benign tumors (P<0.001). Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of SUVmax were 78.2%, 86.2%, 82.6%, 81.8%, and 83.3%, respectively. These values were estimated at 82.6%, 96.6%, 90.4%, 95%, and 87.5% for MTV and TLG, respectively. Additionally, optimal cut-off values for the differentiation of benign and malignant mediastinal tumors were determined at 4.2 and 22.3 mL and 79.7 g for SUVmax, MTV and TLG, respectively. Mean SUVmax, MTV and TLG of thymic carcinomas were significantly higher compared to thymomas (P<0.01), while no significant differences were observed in the mean quantitative parameters between low-risk and high-risk thymomas. CONCLUSION: Although SUVmax, MTV and TLG could not distinguish between low-risk and high-risk thymomas, these parameters might be able to differentiate benign tumors from malignant mediastinal tumors noninvasively. These parameters could be used to distinguish between thymomas and thymic carcinomas as well. Therefore, FDG-PET/CT parameters seem to be accurate indices for the detection of malignant mediastinal tumors. PMID- 28840136 TI - The Efficiency of Respiratory-gated 18F-FDG PET/CT in Lung Adenocarcinoma: Amplitude-gating Versus Phase-gating Methods. AB - OBJECTIVES: In positron emission tomography (PET) studies, thoracic movement under free-breathing conditions is a cause of image degradation. Respiratory gating (RG) is commonly used to solve this problem. Two different methods, i.e., phase-gating (PG) and amplitude-gating (AG) PET, are available for respiratory gating. It is important to know the strengths and weaknesses of both methods when selecting an RG method for a given patient. We conducted this study to clarify whether AG or PG is preferable for measuring fluorodeoxyglucose (FDG) accumulation in lung adenocarcinoma and to investigate patient conditions which are most suitable for AG and PG methods. METHODS: A total of 31 patients (11 males, 20 females; average age: 70.1+/-11.6 yrs) with 44 lung lesions, diagnosed as lung adenocarcinoma between April 2012 and March 2013, were investigated. Whole-body FDG-PET/CT scan was performed with both PG and AG methods in all patients. The maximum standardized uptake value (SUVmax) of PG, AG, and the control data of these two methods were measured, and the increase ratio (IR), calculated as IR(%)= (Post - Pre)/Pre * 100, was calculated. The diameter and position of lung lesions were also analyzed. We defined an 'effective lesion' of PG (or AG) as a lesion which showed a higher IR compared to AG (or PG). 8 (25.8%). RESULTS: The average SUVmax and average IR were 8.99+/-7.94 and %21.4+/ 25.6 in PG and 7.60+/-6.70 and %4.0+/-14.4 in AG, respectively. Although there was no significant difference between the average SUVmax of PG and AG (P=0.09), the average IR of PG was significantly higher than that of AG (P<0.01). The number of PG- and AG-effective lesions was 32 (72.7%) and 12 (28.3%), respectively. There was no significant difference in the average diameter or position of the lesions between the PG- and AG-effective lesions. There were 23 (74.2%) PG-effective and 8 (25.8%) AG-effective patients. No significant difference was observed in sex or age between PG- and AG-effective patients. CONCLUSION: The PG method was more effective for measuring FDG accumulation of lung lesions under free-breathing conditions in comparison with the AG method. PMID- 28840137 TI - Uptake Index of 123I-metaiodobenzylguanidine Myocardial Scintigraphy for Diagnosing Lewy Body Disease. AB - OBJECTIVES: Iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy has been used to evaluate cardiac sympathetic denervation in Lewy body disease (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The heart-to-mediastinum ratio (H/M) in PD and DLB is significantly lower than that in Parkinson's plus syndromes and Alzheimer's disease. Although this ratio is useful for distinguishing LBD from non-LBD, it fluctuates depending on the system performance of the gamma cameras. Therefore, a new, simple quantification method using 123I-MIBG uptake analysis is required for clinical study. The purpose of this study was to develop a new uptake index with a simple protocol to determine 123I-MIBG uptake on planar images. METHODS: The 123I-MIBG input function was obtained from the input counts of the pulmonary artery (PA), which were assessed by analyzing the PA time-activity curves. The heart region of interest used for determining the H/M was used for calculating the uptake index, which was obtained by dividing the heart count by the input count. RESULTS: Forty eight patients underwent 123I-MIBG chest angiography and planar imaging, after clinical feature assessment and tracer injection. The H/M and 123I-MIBG uptake index were calculated and correlated with clinical features. Values for LBD were significantly lower than those for non-LBD in all analyses (P<0.001). The overlapping ranges between non-LBD and LBD were 2.15 to 2.49 in the H/M method, and 1.04 to 1.22% in the uptake index method. The diagnostic accuracy of the uptake index (area under the curve (AUC), 0.98; sensitivity, 96%; specificity, 91%; positive predictive value (PPV), 90%; negative predictive value (NPV), 93%; and accuracy, 92%) was approximately equal to that of the H/M (AUC, 0.95; sensitivity, 93%; specificity, 91%; PPV, 90%; NPV, 93%; and accuracy, 92%) for discriminating patients with LBD and non-LBD. CONCLUSION: A simple uptake index method was developed using 123I-MIBG planar imaging and the input counts determined by analyzing chest radioisotope angiography images of the PA. The diagnostic accuracy of the uptake index was approximately equal to that of the H/M for discriminating patients with LBD and non-LBD. PMID- 28840138 TI - Evaluation of the Efficacy of Standardized Uptake Value (SUV)-shape Scheme for Thyroid Volume Determination in Graves' Disease: A Comparison with Ultrasonography. AB - OBJECTIVES: In this study, we aimed to evaluate the efficacy of thyroid volume measurement using 99mTc pertechnetate single-photon emission computed tomography (SPECT) images, acquired by the standardized uptake value (SUV)-shape scheme designed by our expert team. METHODS: A total of 18 consecutive patients with Graves' disease (GD) were subjected to both ultrasonographic and 99mTc pertechnetate SPECT examinations of thyroid within a five-day interval. The volume of thyroid lobes and isthmus was measured by ultrasonography (US) according to the ellipsoid volume equation. The total thyroid volume, determined as the sum of the volume of both lobes and isthmus, was recorded as TV-US (i.e., thyroid volume measured by US) and set as the reference. The thyroid volume was defined according to our SUV-shape scheme and was recorded as TV-SS (i.e., thyroid volume determined by the SUV-shape scheme). The data were analyzed using the Bland-Altman plot, linear regression analysis, Spearman's rank correlation, and paired t-test, if necessary. RESULTS: The values of TV-SS (40.2+/-29.4 mL) and TV-US (43.0+/-34.7 mL) were not significantly different (t=0.813; P=0.43). The linear regression equation of the two values was determined as TV-US= 1.072 * TV-SS - 0.29 (r=0.906; P<0.01). CONCLUSION: The new scheme, i.e., SUV-shape scheme, exhibited potential for the measurement of thyroid volume in patients with GD. PMID- 28840139 TI - Influence of the Different Primary Cancers and Different Types of Bone Metastasis on the Lesion-based Artificial Neural Network Value Calculated by a Computer aided Diagnostic System, BONENAVI, on Bone Scintigraphy Images. AB - OBJECTIVES: BONENAVI, a computer-aided diagnostic system, is used in bone scintigraphy. This system provides the artificial neural network (ANN) and bone scan index (BSI) values. ANN is associated with the possibility of bone metastasis, while BSI is related to the amount of bone metastasis. The degree of uptake on bone scintigraphy can be affected by the type of bone metastasis. Therefore, the ANN value provided by BONENAVI may be influenced by the characteristics of bone metastasis. In this study, we aimed to assess the relationship between ANN value and characteristics of bone metastasis. METHODS: We analyzed 50 patients (36 males,14 females; age range: 87-42 yrs median age:72.5 yrs) with prostate, breast, or lung cancer who had undergone bone scintigraphy and were diagnosed with bone metastasis (32 cases of prostate cancer, nine cases of breast cancer, and nine cases of lung cancer). Those who had received systematic therapy over the past years were excluded. Bone metastases were diagnosed clinically, and the type of bone metastasis (osteoblastic, mildly osteoblastic, osteolytic, and mixed components) was decided visually by the agreement of two radiologists. We compared the ANN values (case based and lesion-based) among the three primary cancers and four types of bone metastasis. RESULTS: There was no significant difference in case-based ANN values among prostate, breast, and lung cancers. However, the lesion-based ANN values were the highest in cases with prostate cancer and the lowest in cases of lung cancer (median values: prostate cancer, 0.980; breast cancer 0.909; and lung cancer, 0.864). Mildly osteoblastic lesions showed significantly lower ANN values than the other three types of bone metastasis (median values: osteoblastic,; 0.939 mildly osteoblastic; 0.788, mixed type; 0.991, and osteolytic. 0.969) The possibility of a lesion-based ANN value below 0.5 was %10.9 for bone metastasis in prostate cancer, %12.9 for breast cancer, and %37.2 for lung cancer. The corresponding possibility were %14.7 for osteoblastic metastases, %23.9 for mildly osteoblastic metastases, %7.14 for mixed-type metastases, and %16.0 for osteolytic metastases. CONCLUSION: The lesion-based ANN values calculated by BONENAVI can be influenced by the type of primary cancer and bone metastasis. PMID- 28840140 TI - Salivary Gland Scintigraphy in Patients with Sjogren's Syndrome: A local Experience with Dual-tracer. AB - OBJECTIVES: To review the findings of the patients with Sjogren's syndrome (SS) having technetium99-m-pertechnetate (99mTc-pertechnetate) and gallium67- citrate (Ga-67) salivary gland scintigraphy in the past eight years. METHODS: The patients with SS, who were referred to our department for salivary gland scintigraphy during January -2008December 2015 were studied using both 99mTc pertechnetate and Ga-67 citrate scintigraphy. RESULTS: Eighteen patients were included in the study, 17 of whom had positive findings on 99mTc-pertechnetate salivary gland scintigraphy. One patient had negative parotid glands findings on 99mTc-pertechnetate, but positive findings in Ga-67 study. Four patients had asymmetric involvement of the parotid glands, and one patient had asymmetric involvement of the submandibular glands in 99mTc-pertechnetate salivary gland scintigraphy. On the other hand, one patient had only submandibular gland involvement in the 99mTc-pertechnetate scan. Nine patients (18/9) had positive parotid gland findings on Ga-67 study. The involvements of the parotid glands were all symmetrical, except for one patient. No abnormal gallium uptake in the submandibular glands in our patients was noted. CONCLUSION: 99mTc-pertechnetate salivary gland scintigraphy is sufficient for the assessment in the majority of patients with SS. Ga-67 scintigraphy may be a useful supplementary test, especially if the result of 99mTc-pertechnetate scintigraphy is not conclusive. PMID- 28840141 TI - Changing Therapeutic Paradigms: Predicting mCRC Lesion Response to Selective Internal Radionuclide Therapy (SIRT) based on Critical Absorbed Dose Thresholds: A Case Study. AB - A 65 year old male with metastatic colorectal cancer (mCRC) in the liver was referred for selective internal radionuclide therapy (SIRT) following a history of extensive systemic chemotherapy. 90Y PET imaging was performed immediately after treatment and used to confirm lesion targeting and measure individual lesion absorbed doses. Lesion dosimetry was highly predictive of eventual response in the follow-up FDG PET performed 8 weeks after therapy. The derived radiation dose map was used to plan a second SIRT procedure aiming to protect healthy liver by keeping absorbed dose below the critical dose threshold, whilst targeting the remaining lesions that had received sub-critical dosing. Again, 90Y PET was performed immediately post-treatment and used to derive absorbed dose measures to both lesions and healthy parenchyma. Additional follow-up FDG PET imaging again confirmed the role of the 90Y PET dose map as an early predictor of response, and a tool for safe repeat treatment planning. PMID- 28840142 TI - 18F-FDG PET/CT in Pleural Epithelioid Hemangioendothelioma. AB - Pleural epithelioid hemangioendothelioma (EHE) is a rare malignancy of vascular endothelial origin with non-specific symptoms and an unpredictable outcome. Diagnosis of this condition by imaging modalities is challenging, and no standard therapeutic approaches have been established in this regard. In this paper, we described the case of a patient with a low-grade fever, coughing and chest pain who underwent 18F-FDG PET/CT after a positive thorax CT showing multiple bilateral calcified pulmonary nodules and extensive right-sided pleural effusion. Moreover, PET/CT revealed increased tracer uptake on the nodular pleural thickening and one nodule in the upper lobe of the right lung. A diagnostic thoracentesis was performed to obtain the pleural fluid. However, cytology was not diagnostic, and the subsequent thoracotomy with pleural fluid drainage and pleural biopsy was positive for pleural EHE. The study showed also an abundant non-FDG-avid pleural effusion in the collapsed right lung. Despite chest tube insertion and partial drainage of the volume, patient's condition deteriorated, and patient passed away six months after the PET scan. PMID- 28840143 TI - Allograft Maturation After Reconstruction of the Anterior Cruciate Ligament Is Dependent on Graft Parameters in the Sagittal Plane. AB - BACKGROUND: Allograft healing (ligamentization) after reconstruction of the anterior cruciate ligament (ACL) is dependent on multiple factors, including tissue processing, host biologic environment, and biomechanical stressors. Magnetic resonance imaging (MRI) can be used to assess graft maturation after ACL reconstruction. HYPOTHESIS: A significant difference will exist in the MRI analysis between 2 distinct allograft constructs. Specifically, the MRI signal-to noise quotient (SNQ) value will be smaller in quadrupled hamstring tendon (HT) allografts compared with doubled tibialis anterior (TA) allografts due to the difference in graft geometry (surface area-to-volume ratio). STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Prospectively collected data from a subset of patients who participated in a randomized controlled trial at a single center from July 2010 to April 2012 were reviewed. Patients underwent ACL reconstruction using either HT or TA allografts. Six months postoperatively, 32 patients underwent noncontrast MRI to assess ligamentization. The SNQ was calculated for the allograft using sagittal noncontrast T2-weighted MRI as follows: SNQ = (Sgraft - Sqaudriceps )/Sbackgroud . Graft properties including sagittal and coronal angle as well as tibial and femoral tunnel location were measured. All participants completed validated patient-reported outcome measures preoperatively and at 2 years postoperatively. RESULTS: The mean MRI SNQ for the HT and TA allografts was 2.56 +/- 2.41 and 3.15 +/- 3.38, respectively (P = .57). For the entire group, there was a significant correlation between MRI SNQ and both sagittal graft angle (P = .02) and sagittal tibial tunnel position (P < .001). We did not find a significant correlation between the tibial tunnel location in the coronal plane, coronal graft angle, or location of the femoral tunnel and the MRI SNQ. CONCLUSION: Allograft ligamentization 6 months postoperatively, as assessed by MRI, is dependent on position of the tibial tunnel in the sagittal plane as well as sagittal graft orientation. We did not detect a difference in graft maturation at 6 months between the tibialis anterior and hamstring tendon allografts. This is the only study to our knowledge that directly compares quadrupled HT allografts and doubled TA allografts using postoperative MRI. PMID- 28840144 TI - Transtibial Versus Anteromedial Portal ACL Reconstruction: Is a Hybrid Approach the Best? AB - BACKGROUND: Improved biomechanical and clinical outcomes are seen when the femoral tunnels of the anterior cruciate ligament (ACL) are placed in the center of the femoral insertion. The transtibial (TT) technique has been shown to be less capable of this than an anteromedial (AM) portal approach but is more familiar to surgeons and less technically challenging. A hybrid transtibial (HTT) technique using medial portal guidance of a transtibial guide wire without knee hyperflexion may offer anatomic tunnel placement while maintaining the relative ease of a TT technique. PURPOSE: To evaluate the anatomic and biomechanical performance of the HTT technique compared with TT and AM approaches. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty-six paired, fresh-frozen human knees were used. Twenty-four knees (12 pairs) underwent all 3 techniques (TT, AM, HTT) for femoral tunnel placement, with direct measurement of femoral insertional overlap and femoral tunnel length. The remaining 12 knees (6 pairs) underwent completed reconstructions to evaluate graft anisometry and tunnel orientation, with each technique performed in 4 specimens and tested using motion sensors with a quad-load induced model. Graft length changes and graft/femoral tunnel angle were measured at varying degrees of flexion. RESULTS: Percentage overlap of the femoral insertion averaged 37.0% +/- 28.6% for TT, 93.9% +/- 5.6% for HTT, and 79.7% +/- 7.7% for AM, with HTT significantly greater than both TT (P = .007) and AM (P = .001) approaches. Graft length change during knee flexion (anisometry) was 30.1% for HTT, 12.8% for AM, and 8.5% for TT. When compared with the TT approach, HTT constructs exhibited comparable graft-femoral tunnel angulation (TT, 150 degrees +/- 3 degrees vs HTT, 142 degrees +/- 2.3 degrees ; P < .001) and length (TT, 42.6 +/- 2.8 mm vs HTT, 38.5 +/- 2.0 mm; P = .12), while AM portal tunnels were significantly shorter (31.6 +/- 1.6 mm; P = .001) and more angulated (121 degrees +/- 6.5 degrees ; P < .001). CONCLUSION: The HTT technique avoids hyperflexion and maintains femoral tunnel orientation and length, similar to the TT technique, but simultaneously achieves anatomic graft positioning. CLINICAL RELEVANCE: The HTT technique offers an anatomic alternative to an AM portal approach while maintaining the technical advantages of a traditional TT reconstruction. PMID- 28840145 TI - Athletic Pubalgia in Females: Predictive Value of MRI in Outcomes of Endoscopic Surgery. AB - BACKGROUND: Athletic pubalgia is typically associated with male athletes participating in contact sports and less frequently with females. Endoscopic surgery may fully treat the patient with athletic pubalgia. PURPOSE: To perform an outcomes analysis of magnetic resonance imaging (MRI) and endoscopic surgery in female patients with athletic pubalgia. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Fifteen physically active female patients (mean age, 37 years) with athletic pubalgia were treated surgically via placement of total extraperitoneal endoscopic polypropylene mesh behind the injured groin area. The presence of preoperative bone marrow edema (BME) at the pubic symphysis seen on MRI was graded from 0 to 3 and correlated with pain scores after surgery. The outcome measures were pre- and postoperative pain scores and recovery to daily activity between 1 and 12 months after surgery. Results were compared with previously published scores from male athletes (n = 30). RESULTS: With the exception of lower body mass index, the females with (n = 8) and without (n = 7) pubic BME had similar patient characteristics to the corresponding males. Mean inguinal pain scores (0-10) before surgical treatment were greater in females than males (during exercise, 7.8 +/- 1.1 vs 6.9 +/- 1.1; P = .0131). One month after surgery, mean pain scores for females were still greater compared with males (2.9 +/- 1.7 vs 1.3 +/- 1.6; P = .0034). Compared with female athletes with normal MRI, pubic BME was related to increased mean preoperative pain scores (8.13 +/- 0.99 vs 6.43 +/- 1.2; P = .0122). After 1 year, surgical outcomes were excellent or good in 47% of women. CONCLUSION: Endoscopic surgery was helpful in half of the females with athletic pubalgia in this study. The presence of pubic BME may predict slightly prolonged recovery from surgery. PMID- 28840146 TI - Performance and Return to Sport After Clavicle Open Reduction and Internal Fixation in National Football League Players. AB - BACKGROUND: Clavicle fractures are common injuries in professional football. Surgical fixation of these injuries may lead to decreased nonunion rates, improved shoulder strength, and decreased residual functional impairment. PURPOSE: To determine (1) return-to-sport (RTS) rate in National Football League (NFL) players after clavicle fracture open reduction and internal fixation (ORIF), (2) postoperative career length and games per season, (3) pre- and postoperative performance, and (4) postoperative performance compared with control players matched by position, age, years of experience, and performance. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Publicly available records were used to identify players who underwent surgical treatment of a clavicle fracture while playing in the NFL. Demographic and performance data were collected for each player, and matched controls were identified. Control and case performance scores were calculated using a standardized scoring system. RTS was defined as playing in 1 NFL game after surgery. Comparisons between case and control groups at preoperative and postoperative time points were made using paired-samples Student t tests. RESULTS: Seventeen surgeries (16 players) were analyzed. Fifteen players (94.1%) were able to RTS in the NFL at a mean 211.3 +/- 144.7 days postsurgery; 7 (44%) returned within the same season as their injury and subsequent fixation. The overall rate of a player's remaining in the NFL 1 year after surgery was 88.2%. Players who underwent surgery played in a similar number of games per season and had similar career lengths in the NFL as controls (P > .05). There were no significant (P > .05) differences between cases and matched controls presurgery and preindex. There was no difference (P > .05) in postoperative performance scores or games per season compared with preoperative scores or games per season for any position. Quarterbacks (n = 3, P = .049) and running backs (n = 5, P = .039) had significantly worse postoperative performance scores when compared with postindex matched controls. CONCLUSION: There is a high rate of RTS in the NFL after clavicle fracture ORIF. Players who underwent clavicle fracture ORIF played in a similar number of games per season and had similar career lengths in the NFL as controls. Quarterbacks and running backs had significantly worse postoperative performance scores when compared with postindex matched controls. PMID- 28840147 TI - Perioperative Testosterone Supplementation Increases Lean Mass in Healthy Men Undergoing Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Trial. AB - BACKGROUND: Rehabilitation after repair of the anterior cruciate ligament (ACL) is complicated by the loss of leg muscle mass and strength. Prior studies have shown that preoperative rehabilitation may improve muscle strength and postoperative outcomes. Testosterone supplementation may likewise counteract this muscle loss and potentially improve clinical outcomes. PURPOSE: The purpose was to investigate the effect of perioperative testosterone administration on lean mass after ACL reconstruction in men and to examine the effects of testosterone on leg strength and clinical outcome scores. It was hypothesized that testosterone would increase lean mass and leg strength and improve clinical outcome scores relative to placebo. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Male patients (N = 13) scheduled for ACL reconstruction were randomized into 2 groups: testosterone and placebo. Participants in the testosterone group received 200 mg of intramuscular testosterone weekly for 8 weeks beginning 2 weeks before surgery. Participants in the placebo group received saline following the same schedule. Both groups participated in a standard rehabilitation protocol. The primary outcome was the change in total lean body mass at 6 and 12 weeks. Secondary outcomes were extensor muscle strength, Tegner activity score, and Knee injury and Osteoarthritis Outcome Score. RESULTS: There was an increase in lean mass of a mean 2.7 +/- 1.7 kg at 6 weeks postoperatively in the testosterone group compared with a decrease of a mean 0.1 +/- 1.5 kg in the placebo group (P = .01). Extensor muscle strength of the uninjured leg also increased more from baseline in the testosterone group (+20.8 +/- 25.6 Nm) compared with the placebo group (-21.4 +/- 36.7 Nm) at 12 weeks (P = .04). There were no significant between-group differences in injured leg strength or clinical outcome scores. There were no negative side effects of testosterone noted. CONCLUSION: Perioperative testosterone supplementation increased lean mass 6 weeks after ACL reconstruction, suggesting that this treatment may help minimize the effects of muscle atrophy associated with ACL injuries and repair. This study was not powered to detect differences in strength or clinical outcome scores to assess the incidence of testosterone-related adverse events. CLINICAL RELEVANCE: Supraphysiological testosterone supplementation may be a useful adjunct therapy for counteracting muscle atrophy after ACL reconstruction. Further investigation is necessary to determine the safety profile and effects of perioperative testosterone administration on leg strength and clinical outcomes after surgery. REGISTRATION: NCT01595581 (ClinicalTrials.gov). PMID- 28840148 TI - Prevalence and Impact of Glenoid Augmentation in American Football Athletes Participating in the National Football League Scouting Combine. AB - BACKGROUND: Bony augmentation of the anterior glenoid is used in athletes with recurrent shoulder instability and bone loss; however, the prevalence and impact of repair in elite American football athletes are unknown. PURPOSE: To evaluate the prevalence and impact of glenoid augmentation in athletes invited to the National Football League (NFL) Scouting Combine from 2012 to 2015. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 1311 athletes invited to the NFL Combine from 2012 to 2015 were evaluated for history of either Bristow or Latarjet surgery for recurrent anterior shoulder instability. Athlete demographics, surgical history, imaging, and physical examination results were recorded using the NFL Combine database. Prospective participation data with regard to draft status, games played, games started, and status after the athletes' first season in the NFL were gathered using publicly available databases. RESULTS: Surgical repair was performed on 10 shoulders in 10 athletes (0.76%), with the highest prevalence in defensive backs (30%; n = 3). Deficits in shoulder motion were exhibited in 70% (n = 7) of athletes, while 40% (n = 4) had evidence of mild glenohumeral arthritis and 80% demonstrated imaging findings consistent with a prior instability episode (8 labral tears, 2 Hill-Sachs lesions). Prospectively, 40% (n = 4) of athletes were drafted into the NFL. In the first season after the combine, athletes with a history of glenoid augmentation were not found to be at significant risk for diminished participation with regard to games played or started when compared with athletes with no history of glenoid augmentation or athletes undergoing isolated shoulder soft tissue repair. After the conclusion of the first NFL season, 60% (n = 6 athletes) were on an active NFL roster. CONCLUSION: Despite being drafted at a lower rate than their peers, there were no significant limitations in NFL participation for athletes with a history of glenoid augmentation when compared with athletes without a history of shoulder surgery or those with isolated soft tissue shoulder repair. Glenohumeral arthritis and advanced imaging findings of labral tearing and Hill-Sachs lesions in elite American football players with a history of glenoid augmentation did not significantly affect NFL participation 1 year after the combine. PMID- 28840149 TI - Bony Morphology of Femoroacetabular Impingement in Young Female Dancers and Single-Sport Athletes. AB - BACKGROUND: Femoroacetabular impingement (FAI) is a painful and limiting condition of the hip that is often seen in young athletes. Previous studies have reported a higher prevalence of this disorder in male athletes, but data on the structural morphology of adolescent and young adult female athletes, specifically those involved in dance, are lacking. PURPOSE: (1) To investigate the radiographic morphology of FAI deformities in adolescent and young adult female single-sport dance and nondance athletes and (2) to examine the differences in the radiographic findings between these 2 groups. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A retrospective chart review of 56 female single-sport athletes 10 to 21 years of age with a diagnosis of FAI within a single-sports medicine division of a pediatric academic medical center was performed. Acetabular index (AI), lateral center-edge angle (LCEA), crossover sign, and ischial spine sign were measured bilaterally on anteroposterior radiographs; alpha angle (AA) was measured on lateral films, and anterior center edge angle (ACEA) was measured on false-profile films. Independent t tests and Mann-Whitney U tests were used to compare mean angle measurements between dance and nondance athletes. Dichotomized categorical variables and crossover and ischial spine signs were analyzed between dance and nondance athletes by applying a chi-square test. Statistical significance was set as P < .05 a priori. RESULTS: Significant differences in angle measurements were noted. AA was significantly lower in the dancers compared with the nondance athlete group (49.5 degrees +/- 6.0 degrees vs 53.9 degrees +/- 7.3 degrees , P = .001). The LCEA and ACEA of dance athletes were significantly greater compared with nondance athletes (33.8 degrees +/- 6.7 degrees vs 30.9 degrees +/- 5.8 degrees [P = .016] and 36.0 degrees +/- 8.1 degrees vs 32.3 degrees +/- 7.0 degrees [P = .035], respectively). No significant difference in AI was seen between the 2 cohorts (5.0 degrees +/- 4.0 degrees for dancers vs 5.9 degrees +/- 3.4 degrees for nondancers, P = .195). CONCLUSION: Significant differences existed in the radiographic bony morphology of young female single-sport dance athletes compared with nondance athletes with FAI. In dance athletes, symptoms were seen in the setting of normal bony morphology. PMID- 28840150 TI - Outcomes for Arthroscopic Treatment of Anterior Inferior Iliac Spine (Subspine) Hip Impingement. AB - BACKGROUND: Femoroacetabular hip impingement (FAI) is now well recognized; however, anterior inferior iliac spine (AIIS; or subspine) impingement is a form of hip impingement that is underrecognized and can be an important source of hip disability and functional limitation. PURPOSE: To investigate the outcomes after arthroscopic treatment of AIIS/subspine-related hip impingement in the absence of FAI surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A prospective institutional hip preservation registry was reviewed to identify patients who underwent arthroscopic AIIS decompression without concurrent treatment of FAI. Primary outcome tools captured in the registry included the modified Harris Hip Score (mHHS), the Hip Outcome Score (HOS), and the International Hip Outcome Tool-33 (iHOT-33). Patients with minimum 1-year follow up were included. Meaningful outcome improvement was determined per minimal clinically important difference (MCID). Statistical analyses were primarily descriptive. RESULTS: Thirty-three patients with a mean follow-up of 19.1 months (range, 12-44 months) were identified. All patients were female, with a mean +/- SD age of 26.1 +/- 10.3 years. All patients were found to have an associated labral tear, and the mean acetabular version was increased at 2 and 3 o'clock (14.5 degrees and 19.8 degrees , respectively). Mean preoperative outcome scores on the mHHS, HOS ADL (activities of daily living), HOS sport, and iHOT-33 were 57.2 +/- 15.3, 66.9 +/- 18.8, 43.9 +/- 23.6, and 33.5 +/- 18.3, respectively. At final available follow-up, mean scores on these outcome measures were 79.5 +/- 19.0, 86.8 +/- 15.8, 70.4 +/- 32.8, and 65.0 +/- 31.0, respectively. By the 1 year follow-up, MCID had been achieved in the majority of patients across all 4 tools. CONCLUSION: There is a paucity of outcomes evidence on AIIS/subspine related hip impingement. This study demonstrates that isolated subspine impingement can be a cause of hip disability, even in the absence of FAI. Patients with isolated subspine impingement are more likely to be women and to present with low patient-reported outcome scores. However, meaningful outcome improvement can be achieved with arthroscopic AIIS decompression. PMID- 28840151 TI - Epidemiology of Navicular Injury at the NFL Combine and Their Impact on an Athlete's Prospective NFL Career. AB - BACKGROUND: Navicular injuries can result in persistent pain, posttraumatic osteoarthritis, and diminished performance and function. PURPOSE: To determine the epidemiology of navicular fracture in players participating in the National Football League (NFL) Scouting Combine and evaluate the impact of a navicular injury on the NFL draft position and NFL game play compared with matched controls. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were collected on players who previously sustained a navicular injury and participated in the NFL Combine between 2009 and 2015. The epidemiology of navicular injury was determined through an evaluation of the number of injuries, surgeries, and collegiate games missed as well as the position played, a physical examination, the surgical technique, and imaging findings. Players with a previous navicular injury (2009-2013) were compared with a set of matched controls. NFL performance outcomes included the draft position, career length >=2 years, and number of games played and started within the first 2 years. RESULTS: Between 2009 and 2015, 14 of 2285 (0.6%) players were identified as having sustained a navicular injury. A total of 11 of 14 (79%) athletes had sustained an overt navicular fracture, while 3 of 14 (21%) were diagnosed with stress reactions on magnetic resonance imaging. Eight patients who sustained a navicular fracture underwent surgery. There was evidence of ipsilateral talonavicular arthritis in 75% of players with a navicular fracture versus only 60% in the uninjured foot (odds ratio, 1.3; P = .04). Fifty-seven percent of players with navicular injury (72.7% of fractures) were undrafted versus 30.9% in the control group (P = .001). Overall, 28.6% of players with navicular fracture played >=2 years in the NFL compared with 69.6% in the control group (P = .02). CONCLUSION: A previous navicular fracture results in a greater risk of developing posttraumatic osteoarthritis. Although only a low prevalence of navicular injury in prospective NFL players was noted, players with these injuries had a greater probability of not being drafted and not competing in at least 2 NFL seasons when compared with matched controls without an injury history to the NFL Combine. PMID- 28840152 TI - Humeral Avulsion of the Glenohumeral Ligament: Indications for Surgical Treatment and Outcomes-A Systematic Review. AB - BACKGROUND: The inferior glenohumeral ligament, the most important static anterior stabilizer of the shoulder, becomes disrupted in humeral avulsion of the glenohumeral ligament (HAGL) lesions. Unfortunately, HAGL lesions commonly go unrecognized. A missed HAGL during an index operation to treat anterior shoulder instability may lead to persistent instability. Currently, there are no large studies describing the indications for surgical repair or the outcomes of patients with HAGL lesions. PURPOSE: To search the literature to identify surgical indications for the treatment of HAGL lesions and discuss reported outcomes. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: Two reviewers completed a comprehensive literature search of 3 online databases (MEDLINE, EMBASE, and Cochrane Library) from inception until May 25, 2016, using the keywords "humeral avulsion of the glenohumeral ligament" or "HAGL" to generate a broad search. Systematic screening of eligible studies was undertaken in duplicate. Abstracted data were organized in table format, with descriptive statistics presented. RESULTS: After screening, 18 studies comprising 118 patients were found that described surgical intervention and outcomes for HAGL lesions. The mean patient was 22 years (range, 12-50 years), and 82% were male. Sports injuries represented 72% of all HAGL injuries. The main surgical indication was primary anterior instability, followed by pain and failed nonoperative management. Commonly associated injuries in patients with identified HAGL lesions included a Bankart lesion (15%), Hill-Sachs lesions (13%), and glenoid bone loss (7%). Reporting of outcome scores varied among the included studies. Meta-analysis was not possible, but all included studies reported significantly improved postoperative stability and function. There were no demonstrated differences in outcomes for patients treated with open versus arthroscopic surgical techniques. All but 2 patients undergoing operative management for HAGL lesions were able to return to sport at their previous levels; these included Olympians and professional athletes. CONCLUSION: HAGL lesions typically occur in younger male patients and are often associated with Bankart lesions and bone loss. Open and arthroscopic management techniques are both effective in preventing recurrent instability. PMID- 28840153 TI - Lower Quarter Y-Balance Test Scores and Lower Extremity Injury in NCAA Division I Athletes. AB - BACKGROUND: Functional movement tests that are predictive of injury risk in National Collegiate Athletic Association (NCAA) athletes are useful tools for sports medicine professionals. The Lower Quarter Y-Balance Test (YBT-LQ) measures single-leg balance and reach distances in 3 directions. PURPOSE: To assess whether the YBT-LQ predicts the laterality and risk of sports-related lower extremity (LE) injury in NCAA athletes. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The YBT-LQ was administered to 294 NCAA Division I athletes from 21 sports during preparticipation physical examinations at a single institution. Athletes were followed prospectively over the course of the corresponding season. Correlation analysis was performed between the laterality of reach asymmetry and composite scores (CS) versus the laterality of injury. Receiver operating characteristic (ROC) analysis was used to determine the optimal asymmetry cutoff score for YBT-LQ. A multivariate regression analysis adjusting for sex, sport type, body mass index, and history of prior LE surgery was performed to assess predictors of earlier and higher rates of injury. RESULTS: Neither the laterality of reach asymmetry nor the CS correlated with the laterality of injury. ROC analysis found optimal cutoff scores of 2, 9, and 3 cm for anterior, posteromedial, and posterolateral reach, respectively. All of these potential cutoff scores, along with a cutoff score of 4 cm used in the majority of prior studies, were associated with poor sensitivity and specificity. Furthermore, none of the asymmetric cutoff scores were associated with earlier or increased rate of injury in the multivariate analyses. CONCLUSION: YBT-LQ scores alone do not predict LE injury in this collegiate athlete population. Sports medicine professionals should be cautioned against using the YBT-LQ alone to screen for injury risk in collegiate athletes. PMID- 28840154 TI - Do Tibial Plateau Fractures Worsen Outcomes of Knee Ligament Injuries? A Matched Cohort Analysis. AB - BACKGROUND: Tibial plateau fractures account for a small portion of all fractures; however, these fractures can pose a surgical challenge when occurring concomitantly with ligament injuries. PURPOSE/HYPOTHESIS: The purpose of this study was to compare 2-year outcomes of soft tissue reconstruction with or without a concomitant tibial plateau fracture and open reduction internal fixation. We hypothesized that patients with a concomitant tibial plateau fracture at the time of soft tissue surgery would have inferior outcomes compared with patients without an associated tibial plateau fracture. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Forty patients were included in this study: 8 in the fracture group and 32 in the matched control group. Inclusion criteria for the fracture group included patients who were at least 18 years old at the time of surgery and sustained a tibial plateau fracture and a concomitant injury of the anterior cruciate ligament, posterior cruciate ligament, medial collateral ligament, or fibular collateral ligament in isolation or any combination of cruciate or collateral ligaments and who subsequently underwent isolated or combined ligament reconstruction. Patients were excluded if they underwent prior ipsilateral knee surgery, sustained additional bony injuries, or sustained an isolated extra-articular ligament injury at the time of injury. Each patient with a fracture was matched with 4 patients from a control group who had no evidence of a tibial plateau fracture but underwent the same soft tissue reconstruction procedure. RESULTS: Patients in the fracture group improved significantly from preoperatively to postoperatively with respect to Short Form-12 (P < .05) and Western Ontario and McMaster Universities Osteoarthritis Index total scores (P < .05). The Lysholm (P = .075) and Tegner scores (P = .086) also improved, although this was not statistically significant. Patients in the control group improved significantly from preoperatively to postoperatively across all measured scores. A comparison of the postoperative results between the 2 groups showed no statistically significant difference. CONCLUSION: The presence of a tibial plateau fracture in conjunction with a ligamentous knee injury did not have a negative effect on postoperative patient-reported outcomes. Patient-reported outcome scores after surgery in both the fracture and control groups improved beyond the minimally clinically important difference, indicating that the presence of a fracture did not detract from the outcomes observed in patients without fractures undergoing concomitant ligament reconstruction. PMID- 28840155 TI - Incidence of Second Anterior Cruciate Ligament Tears and Identification of Associated Risk Factors From 2001 to 2010 Using a Geographic Database. AB - BACKGROUND: The reported rate of second anterior cruciate ligament (ACL) injuries (20%-30%), including graft failure and contralateral ACL tears, after ACL reconstruction (ACLR) or nonoperative therapy indicates that multiple factors may predispose patients to subsequent ACL injuries. PURPOSE: To determine the incidence of second ACL injuries in a population-based cohort over a 10-year observation period (2001-2010) and to identify factors that contribute to the risk of second injuries. STUDY DESIGN: Descriptive epidemiological study. METHODS: International Classification of Diseases, 9th Revision (ICD-9) codes relevant to the diagnosis of an ACL tear and the procedure code for ACLR were utilized to search the Rochester Epidemiology Project, a multidisciplinary county database, between the years of 2001 and 2010. The complete medical records for all cases were reviewed to confirm diagnosis and treatment details. A total of 914 unique patients with 1019 acute, isolated ACL tears were identified. These patients were stratified by primary and secondary tears, sex, age, activity level, side of injury, sex * side of injury, and graft type of reconstruction. RESULTS: Second ACL tears were recorded in 141 (13.8%) of the 914 patients diagnosed with an ACL tear in Olmsted County, Minnesota, USA, from 2001 to 2010; 50.4% of these occurred in the contralateral knee. A noncontact mechanism was responsible for 76.4% of all ACL injuries. A second ACL injury was influenced by factors of sex * age group, treatment type * age group, and treatment type * activity level. Nonparametric analysis of graft disruption * graft type demonstrated that a higher prevalence of second ACL tears occurred with allografts compared with hamstring autografts (P = .0054) and patellar tendon autografts (P = .0001). CONCLUSION: The incidence of second ACL tears in this population-based cohort was 13.8%, and half occurred to the ACL of the contralateral knee. Statistically, second ACL injuries differed by sex, occurring in female patients younger than 25 years and male patients aged 26 to 45 years. Allografts continued to be associated with a greater risk of second ACL injuries compared with hamstring and patellar tendon autografts. Nonoperative treatment carried more risk of contralateral tears than ACLR. PMID- 28840156 TI - Clinical Outcome Reporting in Youth ACL Literature Is Widely Variable. AB - BACKGROUND: Advances in anterior cruciate ligament (ACL) reconstruction procedures in pediatric and adolescent patients have resulted in an increase in recent clinical studies on this topic. However, the consistency with which outcome measures are reported in this demographic is unknown. PURPOSE: To document outcome reporting patterns of youth ACL reconstruction studies in high impact journals. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: All articles published in 5 high-impact orthopaedic journals from 2010 to 2016 were reviewed to identify those reporting clinical outcomes of young patients who underwent ACL reconstruction. Studies that were nonclinical, reported on patients older than 18 years, or included fewer than 10 patients were excluded. Outcome measures used in all included studies were recorded. RESULTS: Seventeen studies encompassing 772 subjects (mean age, 14.3 years; range, 6.3-18.0 years) were analyzed. Eight studies (47%) reported on Tanner stage of subjects, while 1 study reported skeletal age. Ten studies (59%) clearly documented the presence or absence of surgical complications. Range of motion was reported in 65% of studies. Leg-length discrepancy and angular deformity were each reported in 76% of studies, with 12% quantifying results through radiographic measurements. Ligament testing was variably defined by inclusion of instrumented testing (65%), Lachman test (53%), and pivot-shift test (53%). Fourteen studies (82%) explicitly reported on the rate of ACL rerupture, while 71% reported on the rate of revision surgery. Rate of return to preinjury activity was reported in 8 studies (47%), of which 2 defined criteria for return to sport and 3 defined the level of competitive sport. Patient-reported outcome measures (PROMs) were used variably. For the 3 most commonly reported PROMs (Lysholm, International Knee Documentation Committee, and Tegner), 24% of studies reported all 3 PROMs, 35% of studies reported 2 PROMs, and 6% of studies reported 1 PROM in isolation. A pediatric specific PROM was reported in 1 of the 17 studies. CONCLUSION: Studies on pediatric ACL reconstruction published in high-impact journals unreliably defined subjects' skeletal maturity, inconsistently reported on objective outcome measures, and used disparate adult-validated PROMs to assess subjective outcomes. These findings highlight the need for standardized, pediatric-specific outcome measures to be applied in future studies evaluating ACL reconstruction in children and adolescents. PMID- 28840157 TI - Evaluation of evoked responses to pulse-matched high frequency and intermittent theta burst transcranial magnetic stimulation using simultaneous functional near infrared spectroscopy. AB - Transcranial magnetic stimulation (TMS) is a noninvasive method used to excite or inhibit cortical activity for experimental, diagnostic, and therapeutic interventions. However, nonmotor regions of the brain targeted in TMS therapies, such as the dorsolateral prefrontal cortex (DLPFC), offer no extrinsic response to stimulation, resulting in a need for a practical method for the evaluation of treatment. We sought to determine the capability of a continuous-wave light emitting diodes (LED)-based functional near-infrared spectroscopy (fNIRS) system to measure evoked cortical hemoglobin changes in the DLPFC during the simultaneous application of TMS to the left-DLPFC under brief stimulation paradigms used in the clinic. Seventeen healthy participants received short TMS trains at F3 in four different stimulation conditions (single pulse, high frequency, intermittent theta burst, and sham) while adjacent fNIRS measurements were recorded. Ten 2-s trains of each stimulation type were delivered with an intertrial interval of 40 s. Results indicated that high-frequency stimulation produces a larger and more evident response than other measured conditions. These findings show that a continuous-wave LED-based fNIRS system can be used to measure TMS-evoked responses and that future TMS applications can benefit from concurrent assessment of localized cortical activation changes. PMID- 28840158 TI - Utilizing functional near-infrared spectroscopy for prediction of cognitive workload in noisy work environments. AB - Occupational noise frequently occurs in the work environment in military intelligence, surveillance, and reconnaissance operations. This impacts cognitive performance by acting as a stressor, potentially interfering with the analysts' decision-making process. We investigated the effects of different noise stimuli on analysts' performance and workload in anomaly detection by simulating a noisy work environment. We utilized functional near-infrared spectroscopy (fNIRS) to quantify oxy-hemoglobin (HbO) and deoxy-hemoglobin concentration changes in the prefrontal cortex (PFC), as well as behavioral measures, which include eye tracking, reaction time, and accuracy rate. We hypothesized that noisy environments would have a negative effect on the participant in terms of anomaly detection performance due to the increase in workload, which would be reflected by an increase in PFC activity. We found that HbO for some of the channels analyzed were significantly different across noise types ([Formula: see text]). Our results also indicated that HbO activation for short-intermittent noise stimuli was greater in the PFC compared to long-intermittent noises. These approaches using fNIRS in conjunction with an understanding of the impact on human analysts in anomaly detection could potentially lead to better performance by optimizing work environments. PMID- 28840159 TI - Graph theoretical approach to functional connectivity in prefrontal cortex via fNIRS. AB - Functional near-infrared spectroscopy (fNIRS) has been proposed as an affordable, fast, and robust alternative to many neuroimaging modalities yet it still has long way to go to be adapted in the clinic. One request from the clinicians has been the delivery of a simple and straightforward metric (a so-called biomarker) from the vast amount of data a multichannel fNIRS system provides. We propose a simple-straightforward signal processing algorithm derived from [Formula: see text] data collected during a modified version of the color-word matching Stroop task that consists of three different conditions. The algorithm starts with a wavelet-transform-based preprocessing, then uses partial correlation analysis to compute the functional connectivity matrices at each condition and then computes the global efficiency values. To this end, a continuous wave 16 channels fNIRS device (ARGES Cerebro, Hemosoft Inc., Turkey) was used to measure the changes in [Formula: see text] concentrations from 12 healthy volunteers. We have considered 10% of strongest connections in each network. A strong Stroop interference effect was found between the incongruent against neutral condition ([Formula: see text]) while a similar significance was observed for the global efficiency values decreased from neutral to congruent to incongruent conditions [[Formula: see text], [Formula: see text]]. The findings bring us closer to delivering a biomarker derived from fNIRS data that can be reliably and easily adopted by the clinicians. PMID- 28840160 TI - Investigation of data-driven optical neuromonitoring approach during general anesthesia with sevoflurane. AB - Anesthesia monitoring currently needs a reliable method to evaluate the effects of the anesthetics on its primary target, the brain. This study focuses on investigating the clinical usability of a functional near-infrared spectroscopy (fNIRS)-derived machine learning classifier to perform automated and real-time classification of maintenance and emergence states during sevoflurane anesthesia. For 19 surgical procedures, we examine the entire continuum of the maintenance transition-emergence phases and evaluate the predictive capability of a support vector machine (SVM) classifier during these phases. We demonstrate the robustness of the predictions made by the SVM classifier and compare its performance with that of minimum alveolar concentration (MAC) and bispectral (BIS) index-based predictions. The fNIRS-SVM investigated in this study provides evidence to the usability of the fNIRS signal for anesthesia monitoring. The method presented enables classification of the signal as maintenance or emergence automatically as well as in real-time with high accuracy, sensitivity, and specificity. The features local mean HbTotal, std [Formula: see text], local min Hb and [Formula: see text], and range Hb and [Formula: see text] were found to be robust biomarkers of this binary classification task. Furthermore, fNIRS-SVM was capable of identifying emergence before movement in a larger number of patients than BIS and MAC. PMID- 28840161 TI - Impairment of cerebral autoregulation in pediatric extracorporeal membrane oxygenation associated with neuroimaging abnormalities. AB - Extracorporeal membrane oxygenation (ECMO) is a life-supporting therapy for critically ill patients with severe respiratory and/or cardiovascular failure. Cerebrovascular impairment can result in hemorrhagic and ischemic complications commonly seen in the patients supported on ECMO. We investigated the degree of cerebral autoregulation impairment during ECMO as well as whether it is predictive of neuroimaging abnormalities. Spontaneous fluctuations of mean arterial pressure (MAP) and cerebral tissue oxygen saturation ([Formula: see text]) were continuously measured during the ECMO run. The dynamic relationship between the MAP and [Formula: see text] fluctuations was assessed based on wavelet transform coherence (WTC). Neuroimaging was conducted during and/or after ECMO as standard of care, and the abnormalities were evaluated based on a scoring system that had been previously validated among ECMO patients. Of the 25 patients, 8 (32%) had normal neuroimaging, 7 (28%) had mild to moderate neuroimaging abnormalities, and the other 10 (40%) had severe neuroimaging abnormalities. The degrees of cerebral autoregulation impairment quantified based on WTC showed significant correlations with the neuroimaging scores ([Formula: see text]; [Formula: see text]). Evidence that cerebral autoregulation impairment during ECMO was related to the patients' neurological outcomes was provided. PMID- 28840163 TI - Restoring vision in mice with retinal degeneration using multicharacteristic opsin. AB - Retinal degenerative diseases, such as retinitis pigmentosa (RP) and dry age related macular degeneration, have led to loss of vision in millions of individuals. Currently, no surgical or medical treatment is available, although optogenetic therapies are in clinical development. We demonstrate vision restoration using multicharacteristics opsin (MCO1) in animal models with degenerated retina. MCO1 is reliably delivered to specific retinal cells via intravitreal injection of adeno-associated virus (vMCO1), leading to significant improvement in visually guided behavior conducted using a radial arm water maze. The time to reach the platform and the number of error arms decreased significantly after delivery of MCO1. Notably, the improvement in visually guided behavior was observed even at light intensity levels orders of magnitude lower than that required for channelrhodopsin-2 opsin. Viability of vMCO1-treated retina is not compromised by chronic light exposure. Safe virus-mediated MCO1 delivery has potential for effective gene therapy of diverse retinal degenerations in patients. PMID- 28840164 TI - Wearable and modular functional near-infrared spectroscopy instrument with multidistance measurements at four wavelengths. AB - With the aim of transitioning functional near-infrared spectroscopy (fNIRS) technology from the laboratory environment to everyday applications, the field has seen a recent push toward the development of wearable/miniaturized, multiwavelength, multidistance, and modular instruments. However, it is challenging to unite all these requirements in a precision instrument with low noise, low drift, and fast sampling characteristics. We present the concept and development of a wearable fNIRS instrument that combines all these key features with the goal of reliably and accurately capturing brain hemodynamics. The proposed instrument consists of a modular network of miniaturized optode modules that include a four-wavelength light source and a highly sensitive silicon photomultiplier detector. Simultaneous measurements with short-separation (7.5 mm; containing predominantly extracerebral signals) and long-separation (20 mm or more; containing both extracerebral and cerebral information) channels are used with short-channel regression filtering methods to increase robustness of fNIRS measurements. Performance of the instrument was characterized with phantom measurements and further validated in human in vivo measurements, demonstrating the good raw signal quality (signal-to-noise ratio of 64 dB for short channels; robust measurements up to 50 mm; dynamic optical range larger than 160 dB), the valid estimation of concentration changes (oxy- and deoxyhemoglobin, and cytochrome-c-oxidase) in muscle and brain, and the detection of task-evoked brain activity. The results of our preliminary tests suggest that the presented fNIRS instrument outperforms existing instruments in many aspects and bears high potential for real-time single-trial fNIRS applications as required for wearable brain-computer interfaces. PMID- 28840162 TI - Simultaneous functional near-infrared spectroscopy and electroencephalography for monitoring of human brain activity and oxygenation: a review. AB - Multimodal monitoring has become particularly common in the study of human brain function. In this context, combined, synchronous measurements of functional near infrared spectroscopy (fNIRS) and electroencephalography (EEG) are getting increased interest. Because of the absence of electro-optical interference, it is quite simple to integrate these two noninvasive recording procedures of brain activity. fNIRS and EEG are both scalp-located procedures. fNIRS estimates brain hemodynamic fluctuations relying on spectroscopic measurements, whereas EEG captures the macroscopic temporal dynamics of brain electrical activity through passive voltages evaluations. The "orthogonal" neurophysiological information provided by the two technologies and the increasing interest in the neurovascular coupling phenomenon further encourage their integration. This review provides, together with an introduction regarding the principles and future directions of the two technologies, an evaluation of major clinical and nonclinical applications of this flexible, low-cost combination of neuroimaging modalities. fNIRS-EEG systems exploit the ability of the two technologies to be conducted in an environment or experimental setting and/or on subjects that are generally not suited for other neuroimaging modalities, such as functional magnetic resonance imaging, positron emission tomography, and magnetoencephalography. fNIRS-EEG brain monitoring settles itself as a useful multimodal tool for brain electrical and hemodynamic activity investigation. PMID- 28840165 TI - In vivo measure of neonate brain optical properties and hemodynamic parameters by time-domain near-infrared spectroscopy. AB - By exploiting a multichannel portable instrument for time-domain near-infrared spectroscopy (TD-NIRS), we characterized healthy neonates' brains in term of optical properties and hemodynamic parameters. In particular, we assessed the absolute values of the absorption and reduced scattering coefficients at two wavelengths, together with oxy-, deoxy- and total hemoglobin concentrations, and the blood oxygen saturation of the neonates' brains. In this study, 33 healthy full-term neonates were tested, obtaining the following median values: 0.28 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; 5.8 and [Formula: see text] for [Formula: see text] at 690 and 820 nm, respectively; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; [Formula: see text] for [Formula: see text]; 72% for [Formula: see text]. In general, the agreement of these values with the sparse existing literature appears not always consistent. These findings demonstrate the first measurements of optical properties of the healthy neonate brain using TD-NIRS and show the need for clarification of optical properties across methods and populations. PMID- 28840166 TI - Non-neuronal evoked and spontaneous hemodynamic changes in the anterior temporal region of the human head may lead to misinterpretations of functional near infrared spectroscopy signals. AB - Several functional near-infrared spectroscopy (fNIRS) studies report their findings based on changes of a single chromophore, usually concentration changes of oxygenated hemoglobin ([[Formula: see text]]) or deoxygenated hemoglobin (HHb). However, influence of physiological actions may differ depending on which element is considered and the assumption that the chosen measure correlates with the neural response of interest might not hold. By assessing the correlation between [[Formula: see text]] and [HHb] in task-evoked activity as well as resting-state data, we identified a spatial dependency of non-neuronal hemodynamic changes in the anterior temporal region of the human head. Our findings support the importance of reporting and discussing fNIRS outcomes obtained with both chromophores ([[Formula: see text]] and [HHb]), in particular, for studies concerning the anterior temporal region of the human head. This practice should help to achieve a physiologically correct interpretation of the results when no measurements with short-distance channels are available while employing continuous-wave fNIRS systems. PMID- 28840167 TI - Decoding semantic representations from functional near-infrared spectroscopy signals. AB - This study uses representational similarity-based neural decoding to test whether semantic information elicited by words and pictures is encoded in functional near infrared spectroscopy (fNIRS) data. In experiment 1, subjects passively viewed eight audiovisual word and picture stimuli for 15 min. Blood oxygen levels were measured using the Hitachi ETG-4000 fNIRS system with a posterior array over the occipital lobe and a left lateral array over the temporal lobe. Each participant's response patterns were abstracted to representational similarity space and compared to the group average (excluding that subject, i.e., leave-one out cross-validation) and to a distributional model of semantic representation. Mean accuracy for both decoding tasks significantly exceeded chance. In experiment 2, we compared three group-level models by averaging the similarity structures from sets of eight participants in each group. In these models, the posterior array was accurately decoded by the semantic model, while the lateral array was accurately decoded in the between-groups comparison. Our findings indicate that semantic representations are encoded in the fNIRS data, preserved across subjects, and decodable by an extrinsic representational model. These results are the first attempt to link the functional response pattern measured by fNIRS to higher-level representations of how words are related to each other. PMID- 28840168 TI - Size-based quality-informed framework for quantitative optimization of pediatric CT. AB - The purpose of this study was to formulate a systematic, evidence-based method to relate quantitative diagnostic performance to radiation dose, enabling a multidimensional system to optimize computed tomography imaging across pediatric populations. Based on two prior foundational studies, radiation dose was assessed in terms of organ doses, effective dose ([Formula: see text]), and risk index for 30 patients within nine color-coded pediatric age-size groups as a function of imaging parameters. The cases, supplemented with added noise and simulated lesions, were assessed in terms of nodule detection accuracy in an observer receiving operating characteristic study. The resulting continuous accuracy-dose relationships were used to optimize individual scan parameters. Before optimization, the nine protocols had a similar [Formula: see text] of [Formula: see text] with accuracy decreasing from 0.89 for the youngest patients to 0.67 for the oldest. After optimization, a consistent target accuracy of 0.83 was established for all patient categories with [Formula: see text] ranging from 1 to 10 mSv. Alternatively, isogradient operating points targeted a consistent ratio of accuracy-per-unit-dose across the patient categories. The developed model can be used to optimize individual scan parameters and provide for consistent diagnostic performance across the broad range of body sizes in children. PMID- 28840169 TI - Assessment of organ and effective dose when using region-of-interest attenuators in cone-beam CT and interventional fluoroscopy. AB - In some medical-imaging procedures using cone-beam CT (CBCT) and fluoroscopy, only the center of the field of view (FOV) may be needed to be visualized with optimal image quality. To reduce the dose to the patient while maintaining visualization of the entire FOV, a Cu attenuator with a circular aperture for the region of interest (ROI) is used. The potential organ and effective dose reductions of ROI imaging when applied to CBCT and interventional fluoroscopic procedures were determined using EGSnrc Monte Carlo code. The Monte Carlo model was first validated by comparing the surface dose distribution in a solid-water block phantom with measurement by Gafchromic film. The dependence of dose reduction on the ROI attenuator thickness, the opening size of the ROI, the axial beam position, and the location of the different organs for both neuro and thoracic imaging was evaluated. The results showed a reduction in most organ doses of 45% to 70% and in effective dose of 46% to 66% compared to the dose in a CBCT scan and in an interventional procedure without the ROI attenuator. This work provides evidence of a substantial reduction of organ and effective doses when using an ROI attenuator during CBCT and fluoroscopic procedures. PMID- 28840170 TI - Effective user interaction in online interactive semantic segmentation of glioblastoma magnetic resonance imaging. AB - Interactive segmentation is a promising approach to solving the pervasive shortage of reference annotations for automated medical image processing. We focus on the challenging task of glioblastoma segmentation in magnetic resonance imaging using a random forest pixel classifier trained iteratively on scribble annotations. Our experiments use data from the MICCAI Multimodal Brain Tumor Segmentation Challenge 2013 and simulate expert interactions using different approaches: corrective annotations, class-balanced corrections, annotations where classifier uncertainty is high, and corrections where classifier uncertainty is high/low. We find that it is better to correct the classifier than to provide annotations where the classifier is uncertain, resulting in significantly better Dice scores in the edema (0.662 to 0.686) and necrosis (0.550 to 0.676) regions after 20 interactions. It is also advantageous to balance inputs among classes, with significantly better Dice in the necrotic (0.501 to 0.676) and nonenhancing (0.151 to 0.235) regions compared to fully random corrections. Corrective annotations in regions of high classifier uncertainty provide no additional benefit, low uncertainty corrections perform worst. Preliminary experiments with real users indicate that those with intermediate proficiency make a considerable number of annotation errors. The performance of corrective approaches suffers most strongly from this, leading to a less profound difference to uncertainty based annotations. PMID- 28840171 TI - Estimation of subject coregistration errors during multimodal preclinical imaging using separate instruments: origins and avoidance of artifacts. AB - We use high-resolution [Formula: see text] data in multiple experiments to estimate the sources of error during coregistration of images acquired on separate preclinical instruments. In combination with experiments with phantoms, we completed in vivo imaging on mice, aimed at identifying the possible sources of registration errors, caused either by transport of the animal, movement of the animal itself, or methods of coregistration. The same imaging cell was used as a holder for phantoms and animals. For all procedures, rigid coregistration was carried out using a common landmark coregistration system, placed inside the imaging cell. We used the fiducial registration error and the target registration error to analyze the coregistration accuracy. We found that moving an imaging cell between two preclinical devices during a multimodal procedure gives an error of about [Formula: see text] at most. Therefore, it could not be considered a source of coregistration errors. Errors linked to spontaneous movements of the animal increased with time, to nearly 1 mm at most, excepted for body parts that were properly restrained. This work highlights the importance of animal intrinsic movements during a multiacquisition procedure and demonstrates a simple method to identify and quantify the sources of error during coregistration. PMID- 28840172 TI - Multimodality registration of two-dimensional echocardiography and cardiac CT for mitral valve diagnosis and surgical planning. AB - A registration method to fuse two-dimensional (2-D) echocardiography images with cardiac computed tomography (CT) volume is presented. The method consists of two major procedures: temporal and spatial registrations. In temporal registration, the echocardiography frames at similar cardiac phases as the CT volume were interpolated based on electrocardiogram signal information, and the noise of the echocardiography image was reduced using the speckle reducing anisotropic diffusion technique. For spatial registration, an intensity-based normalized mutual information method was applied with a pattern search optimization algorithm to produce an interpolated cardiac CT image. The proposed registration framework does not require optical tracking information. Dice coefficient and Hausdorff distance for the left atrium assessments were [Formula: see text] and [Formula: see text], respectively; for left ventricle, they were [Formula: see text] and [Formula: see text], respectively. There was no significant difference in the mitral valve annulus diameter measurement between the manually and automatically registered CT images. The transformation parameters showed small deviations ([Formula: see text] deviation in translation and [Formula: see text] for rotation) between manual and automatic registrations. The proposed method aids the physician in diagnosing mitral valve disease as well as provides surgical guidance during the treatment procedure. PMID- 28840173 TI - Automatic magnetic resonance prostate segmentation by deep learning with holistically nested networks. AB - Accurate automatic segmentation of the prostate in magnetic resonance images (MRI) is a challenging task due to the high variability of prostate anatomic structure. Artifacts such as noise and similar signal intensity of tissues around the prostate boundary inhibit traditional segmentation methods from achieving high accuracy. We investigate both patch-based and holistic (image-to-image) deep learning methods for segmentation of the prostate. First, we introduce a patch based convolutional network that aims to refine the prostate contour which provides an initialization. Second, we propose a method for end-to-end prostate segmentation by integrating holistically nested edge detection with fully convolutional networks. Holistically nested networks (HNN) automatically learn a hierarchical representation that can improve prostate boundary detection. Quantitative evaluation is performed on the MRI scans of 250 patients in fivefold cross-validation. The proposed enhanced HNN model achieves a mean +/- standard deviation. A Dice similarity coefficient (DSC) of [Formula: see text] and a mean Jaccard similarity coefficient (IoU) of [Formula: see text] are used to calculate without trimming any end slices. The proposed holistic model significantly ([Formula: see text]) outperforms a patch-based AlexNet model by 9% in DSC and 13% in IoU. Overall, the method achieves state-of-the-art performance as compared with other MRI prostate segmentation methods in the literature. PMID- 28840175 TI - RNA Capping by Transcription Initiation with Non-canonical Initiating Nucleotides (NCINs): Determination of Relative Efficiencies of Transcription Initiation with NCINs and NTPs. AB - It recently has been established that adenine-containing cofactors, including nicotinamide adenine dinucleotide (NAD+), reduced nicotinamide adenine dinucleotide (NADH), and 3'-desphospho-coenzyme A (dpCoA), can serve as 'non canonical initiating nucleotides' (NCINs) for transcription initiation by bacterial and eukaryotic cellular RNA polymerases (RNAPs) and that the efficiency of the reaction is determined by promoter sequence (Bird et al., 2016). Here we describe a protocol to quantify the relative efficiencies of transcription initiation using an NCIN vs. transcription initiation using a nucleoside triphosphate (NTP) for a given promoter sequence. PMID- 28840174 TI - Noninvasive radiomics signature based on quantitative analysis of computed tomography images as a surrogate for microvascular invasion in hepatocellular carcinoma: a pilot study. AB - We explore noninvasive biomarkers of microvascular invasion (mVI) in patients with hepatocellular carcinoma (HCC) using quantitative and semantic image features extracted from contrast-enhanced, triphasic computed tomography (CT). Under institutional review board approval, we selected 28 treatment-naive HCC patients who underwent surgical resection. Four radiologists independently selected and delineated tumor margins on three axial CT images and extracted computational features capturing tumor shape, image intensities, and texture. We also computed two types of "delta features," defined as the absolute difference and the ratio computed from all pairs of imaging phases for each feature. 717 arterial, portal-venous, delayed single-phase, and delta-phase features were robust against interreader variability ([Formula: see text]). An enhanced cross validation analysis showed that combining robust single-phase and delta features in the arterial and venous phases identified mVI (AUC [Formula: see text]). Compared to a previously reported semantic feature signature (AUC 0.47 to 0.58), these features in our cohort showed only slight to moderate agreement (Cohen's kappa range: 0.03 to 0.59). Though preliminary, quantitative analysis of image features in arterial and venous phases may be potential surrogate biomarkers for mVI in HCC. Further study in a larger cohort is warranted. PMID- 28840176 TI - IgLON5 disease responsive to immunotherapy. PMID- 28840177 TI - Long-term improvement after combined immunomodulation in early post-H1N1 vaccination narcolepsy. PMID- 28840178 TI - Postmalaria neurologic syndrome associated with neurexin-3alpha antibodies. PMID- 28840179 TI - Feldenkrais Movement Lessons Improve Older Adults' Awareness, Comfort, and Function. AB - This prospective controlled intervention study assessed Feldenkrais Moving Forward movement lessons for older adults. Participants (N = 87 returning from original sample of 124; median age = 76 years) were assigned to movement (n = 51) or waitlist control (n = 36) groups. The movement groups took twelve 60-min lessons across either 6 or 12 weeks, to compare lesson density. Pretests and posttests included Base of Support, Timed Up and Go, Tandem Stance, Functional Reach, modified OPTIMAL, and questions about individual priorities and outcomes. Results included significant correlations between lessons attended and both improved Functional Reach and improved OPTIMAL score. A significantly higher proportion of the movement (vs. control) group reported positive changes at the posttest in both prioritized and newly identified activities. These results show that Feldenkrais lessons are helpful to older adults for promoting balance, mobility, and confidence. PMID- 28840180 TI - Time (and space) in the hippocampus. AB - There is considerable recent evidence that, in addition to its representation of space, the hippocampus also represents the temporal organization of memories. Time plays a central role in episodic memory, and studies have identified the hippocampus as playing an essential role in the temporal organization of memories in humans and animals. Temporal organization is supported by a gradually changing temporal context signal in the hippocampus, and this changing context signal involves "time cells" in the hippocampus that code sequential moments in temporally organized experiences. Finally, hippocampal temporal context representations mechanisms in intrinsic circuitry and oscillatory patterns throughout hippocampal subfields and likely depend on inputs from parahippocampal cortical areas and a widespread temporal processing system in the neocortex. PMID- 28840181 TI - Measles virus nucleocapsid protein modulates the Signal Regulatory Protein-beta1 (SIRPbeta1) to enhance osteoclast differentiation in Paget's disease of bone. AB - Paget's disease of bone (PDB) is a chronic localized bone disorder in an elderly population. Environmental factors such as paramyxovirus are implicated in PDB and measles virus nucleocapsid protein (MVNP) has been shown to induce pagetic osteoclasts (OCLs). However, the molecular mechanisms underlying MVNP stimulation of OCL differentiation in the PDB are unclear. We therefore determined the MVNP regulated gene expression profiling during OCL differentiation. Agilent microarray analysis of gene expression identified high levels of SIRPbeta1 (353 fold) expression in MVNP transduced human bone marrow mononuclear cells stimulated with RANKL. Real-time PCR analysis further confirmed that MVNP alone upregulates SIRPbeta1 mRNA expression in these cells. Also, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPbeta1 mRNA expression compared to normal subjects. We further show that MVNP increases SIRPbeta1 interaction with DAP12 adaptor protein in the presence and absence of RANKL stimulation. shRNA knockdown of SIRPbeta1 expression in normal human bone marrow monocytes decreased the levels of MVNP enhanced p-Syk and c-Fos expression. In addition, SIRPbeta1 knockdown significantly decreased MVNP stimulated dendritic cell-specific transmembrane protein (DC-STAMP) and connective tissue growth factor (CTGF) mRNA expression during OCL differentiation. Furthermore, we demonstrated the contribution of SIRPbeta1 in MVNP induced OCL formation and bone resorption. Thus, our results suggest that MVNP modulation of SIRPbeta1 provides new insights into the molecular mechanisms which control high bone turnover in PDB. PMID- 28840182 TI - Data on a Laves phase intermetallic matrix composite in situ toughened by ductile precipitates. AB - The data presented in this article are related to the research article entitled "Laves phase intermetallic matrix composite in situ toughened by ductile precipitates" (Knowles et al.) [1]. The composite comprised a Fe2(Mo, Ti) matrix with bcc (Mo, Ti) precipitated laths produced in situ by an aging heat treatment, which was shown to confer a toughening effect (Knowles et al.) [1]. Here, details are given on a focused ion beam (FIB) slice and view experiment performed on the composite so as to determine that the 3D morphology of the bcc (Mo, Ti) precipitates were laths rather than needles. Scanning transmission electron microscopy (S(TEM)) micrographs of the microstructure as well as energy dispersive X-ray spectroscopy (EDX) maps are presented that identify the elemental partitioning between the C14 Laves matrix and the bcc laths, with Mo rejected from the matrix into laths. A TEM selected area diffraction pattern (SADP) and key is provided that was used to validate the orientation relation between the matrix and laths identified in (Knowles et al.) [1] along with details of the transformation matrix determined. PMID- 28840183 TI - Data for the elaboration of the CIPROS checklist with items for a patient registry software system: Examples and explanations. AB - The data presented relates to the publication "Enhancing Requirements Engineering for Patient Registry Software Systems with Evidence-based Components" (Lindoerfer and Mansmann, 2017) [1], which describes the strategy behind the development of the CIPROS checklist. This manuscript also compares CIPROS with general requirements specification templates, and standards. The data is shortly described in Section 2.4 and presented in . The examples represent the material extracted from the literature used in qualitative analysis. The explanations summarize the example contents from which the CIPROS checklist was created. Patient registries are a crucial part of medical research. High quality registries use efficient information systems software selected from a wide variety of existing software solutions. An efficient selection process requires focused selection criteria. The evidence-based CIPROS checklist [2] accelerates this requirements engineering process. CIPROS was developed in a multistep procedure: (1) A systematic literature review provided an exhaustive collection of relevant publications (64 articles), (2) a catalogue of relevant criteria was derived by a qualitative content analysis, and (3) the checklist containing 72 items was composed which provides a minimal appraisal standard. The data presented per checklist item provide the relevant textual information (examples) and a first qualitative summary (explanation). The examples and explanations provide the background information on CIPROS. They elucidate how to implement the checklist items in other projects. The literature list and the selected texts serve as a reference for scientists and system developers. PMID- 28840184 TI - Maintaining a Vibrant and Productive Laboratory as a Senior Investigator. PMID- 28840185 TI - In NAFLD, You Are What You Eat, Not Simply How Much You Eat. PMID- 28840187 TI - Bacterial Encroachment in Metabolic Syndrome: Too Much Togetherness? PMID- 28840186 TI - Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: Cancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolic gene alterations that repeatedly occur in liver cancer are largely unknown. We aimed to identify metabolic genes that are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC). METHODS: We studied the expression of 2,761 metabolic genes in 8 microarray datasets comprising 521 human HCC tissues. Genes exclusively up-regulated or down-regulated in 6 or more datasets were defined as consistently deregulated. The consistent genes that correlated with tumor progression markers (ECM2 and MMP9) (Pearson correlation P < .05) were used for Kaplan-Meier overall survival analysis in a patient cohort. We further compared proteomic expression of metabolic genes in 19 tumors vs adjacent normal liver tissues. RESULTS: We identified 634 consistent metabolic genes, ~60% of which are not yet described in HCC. The down-regulated genes (n = 350) are mostly involved in physiologic hepatocyte metabolic functions (eg, xenobiotic, fatty acid, and amino acid metabolism). In contrast, among consistently up-regulated metabolic genes (n = 284) are those involved in glycolysis, pentose phosphate pathway, nucleotide biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, proton transport, membrane lipid, and glycan metabolism. Several metabolic genes (n = 434) correlated with progression markers, and of these, 201 predicted overall survival outcome in the patient cohort analyzed. Over 90% of the metabolic targets significantly altered at the protein level were similarly up- or down-regulated as in genomic profile. CONCLUSIONS: We provide the first exposition of the consistently altered metabolic genes in HCC and show that these genes are potentially relevant targets for onward studies in preclinical and clinical contexts. PMID- 28840188 TI - All Hands on Deck: Commensals, Th17 Cells, and Neutrophils Provide Short-term Compensation of Constitutive Permeability Defects Against Acute Infection. PMID- 28840189 TI - Refractoriness Accounts for Variable Spike Burst Responses in Somatosensory Cortex. AB - Neurons in the primary somatosensory cortex (S1) respond to peripheral stimulation with synchronized bursts of spikes, which lock to the macroscopic 600 Hz EEG waves. The mechanism of burst generation and synchronization in S1 is not yet understood. Using models of single-neuron responses fitted to unit recordings from macaque monkeys, we show that these synchronized bursts are the consequence of correlated synaptic inputs combined with a refractory mechanism. In the presence of noise these models reproduce also the observed trial-to-trial response variability, where individual bursts represent one of many stereotypical temporal spike patterns. When additional slower and global excitability fluctuations are introduced the single-neuron spike patterns are correlated with the population activity, as demonstrated in experimental data. The underlying biophysical mechanism of S1 responses involves thalamic inputs arriving through depressing synapses to cortical neurons in a high-conductance state. Our findings show that a simple feedforward processing of peripheral inputs could give rise to neuronal responses with nontrivial temporal and population statistics. We conclude that neural systems could use refractoriness to encode variable cortical states into stereotypical short-term spike patterns amenable to processing at neuronal time scales (tens of milliseconds). PMID- 28840190 TI - Activity Dynamics and Signal Representation in a Striatal Network Model with Distance-Dependent Connectivity. AB - The striatum is the main input nucleus of the basal ganglia. Characterizing striatal activity dynamics is crucial to understanding mechanisms underlying action selection, initiation, and execution. Here, we studied the effects of spatial network connectivity on the spatiotemporal structure of striatal activity. We show that a striatal network with nonmonotonically changing distance dependent connectivity (according to a gamma distribution) can exhibit a wide repertoire of spatiotemporal dynamics, ranging from spatially homogeneous, asynchronous-irregular (AI) activity to a state with stable, spatially localized activity bumps, as in "winner-take-all" (WTA) dynamics. Among these regimes, the unstable activity bumps [transition activity (TA)] regime closely resembles the experimentally observed spatiotemporal activity dynamics and neuronal assemblies in the striatum. In contrast, striatal networks with monotonically decreasing distance-dependent connectivity (in a Gaussian fashion) can exhibit only an AI state. Thus, given the observation of spatially compact neuronal clusters in the striatum, our model suggests that recurrent connectivity among striatal projection neurons should vary nonmonotonically. In brain disorders such as Parkinson's disease, increased cortical inputs and high striatal firing rates are associated with a reduction in stimulus sensitivity. Consistent with this, our model suggests that strong cortical inputs drive the striatum to a WTA state, leading to low stimulus sensitivity and high variability. In contrast, the AI and TA states show high stimulus sensitivity and reliability. Thus, based on these results, we propose that in a healthy state the striatum operates in a AI/TA state and that lack of dopamine pushes it into a WTA state. PMID- 28840191 TI - Wrong Blood in Tube. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28840193 TI - What does phenotype have to do with it? PMID- 28840194 TI - Rectus Muscle Reapproximation at Cesarean Delivery and Postoperative Pain: A Randomized Controlled Trial. AB - Objective Rectus muscle reapproximation at cesarean delivery (CD) is performed frequently by some obstetricians; however, the effect on postoperative pain is unclear. To this end, we investigated whether rectus muscle reapproximation increases postoperative pain. Materials and Methods This is a prospective, double-blind, randomized controlled trial of women undergoing primary CD with singleton or twin pregnancy at >35 weeks' gestation. Women were randomized to rectus muscle reapproximation with three interrupted sutures or no reapproximation. Exclusion criteria were prior cesarean, prior laparotomy, vertical skin incision, active labor, chronic analgesia use, allergy to opioid or nonsteroidal anti-inflammatory drugs, and body mass index >= 40. Intra- and postoperative pain management was standardized within the study protocol. The primary outcome was a combined movement pain and opioid use score averaged over the 72-hour study period, called the Silverman integrated assessment. Movement pain scores were assessed at 24, 48, and 72 postoperative hours. Results In total, 63 women were randomized, of whom 35 underwent rectus muscle reapproximation and 28 did not. Demographic and obstetric variables were similar between groups. Silverman integrated assessment scores during the 72-hour postoperative period were higher in the rectus muscle reapproximation group (15 +/- 100% vs. -31 +/- 78% difference from the mean; p = 0.04). Operative times were similar between groups (63 +/- 15 vs. 65 +/- 15 minutes; p = 0.61), and there were no surgical complications in either group. Maternal satisfaction with analgesia at 72 hours was high in both groups (85% [73-90] rectus muscle reapproximation vs. 90% [75-100]; p = 0.16). Conclusion Rectus muscle reapproximation increased immediate postoperative pain without differences in operative time, surgical complications, or maternal satisfaction. Benefits of rectus muscle reapproximation should be weighed against increased postoperative pain, and analgesia should be planned accordingly. PMID- 28840192 TI - Androgen receptor as a mediator and biomarker of radioresistance in triple negative breast cancer. AB - Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R2 = 0.72, p < 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors. PMID- 28840195 TI - Pediatric Posterior Cruciate Ligament Avulsion Fracture of the Tibial Insertion: Case Report and Review of the Literature. AB - Background Posterior cruciate ligament (PCL) avulsion fracture of the tibial insertion is a very rare injury in children. In addition to performing an attentive clinical examination, radiologic studies are fundamental for its correct diagnosis and treatment. Its management may be either conservative or operative. So far, only a few cases treated conservatively have been reported in the pediatric population, with controversial results. Methods We prospectively collected and reviewed clinical and radiographic data of an 11-year-old boy with avulsion fracture of the tibial insertion of the PCL. In addition, we performed a systematic review of the literature available to date. Results We decided to treat the avulsion fracture in a conservative way. The patient has been followed with accurate clinical and radiological follow-up controls until complete recovery. Conclusion Posterior cruciate avulsion fracture is a very rare finding in children, and no definitive indications for its appropriate management exist. With this report, we demonstrate that these fractures can be treated conservatively in selected cases with good results, avoiding potential surgical related complications. Study Design This is a case report (level of evidence V). PMID- 28840196 TI - Trapping and proliferation of target cells on C60 fullerene nano fibres. AB - The ratio of the surface area to the volume of materials increases in inverse proportion to their size and therefore the surface area of nanostructures and nanomaterials is extremely large compared to that of macroscopic materials of the same volume, thanks to which it is supposed that chemical and biochemical reactions may be greatly enhanced and target molecules and cells may be efficiently trapped on the surface of nanomaterials. It is well known that C60 molecules are stable both physically and chemically and the affinity of C60 molecules with biomolecules is rather high. Here, we synthesise fibres composed of C60 and sulphur and immobilise the surface of the fibres with the primary antibody; i.e., epithelial cell adhesion molecules (anti-EpCAM), to trap target cells. The primary antibody is evenly immobilised on the fibres confirmed by a fluorescent secondary antibody attached to the primary one and then TE2 esophageal and DLD-1 colon cancer cells are successfully trapped by the primary antibody immobilised on the fibres thanks to its high affinity with TE2 and DLD-1 cells, whereas few IM9 B lymphoblast cells are captured on the fibres since the affinity of the primary antibody with IM9 cells is extremely low. Furthermore, those cells trapped by the primary antibody immobilised on the fibres proliferate faster than native cells thanks to the primary antibody acting as a growth factor. The present result suggests that different types of cells can be trapped and grown on nano fibres by immobilising appropriate antibody molecules on the surface of the fibres. Even an extremely small number of cells in sample fluids may be analysed and characterised for the detection of diseases such as cancer in the early stage by trapping and proliferating target cells on the fibres. PMID- 28840197 TI - Associations of Protein-Energy Wasting Syndrome Criteria With Body Composition and Mortality in the General and Moderate Chronic Kidney Disease Populations in the United States. AB - INTRODUCTION: It is unknown whether the criteria used to define Protein-energy wasting (PEW) syndrome in dialysis patients reflect protein or energy wasting in the general and moderate CKD populations. METHODS: In 11,834 participants in the 1999-2004 National Health and Nutrition Examination Survey, individual PEW syndrome criteria and the number of PEW syndrome categories were related to lean body and fat masses (measured by dual-energy absorptiometry) using linear regression in the entire cohort and CKD sub-population. RESULTS: Serum chemistry, body mass and muscle mass PEW criteria tended to be associated with lower lean body and fat masses, but the low dietary protein and energy intake criteria were associated with significantly higher protein and energy stores. When the number of PEW syndrome categories was defined by non-dietary categories alone, there was a monotonic inverse relationship with lean body and fat masses and strong positive relationship with mortality. In contrast, when dietary category alone was present, mean BMI was in the obesity range; additional presence of two non dietary categories was associated with lower BMI and lower lean body and fat masses. Thus, the association of dietary category plus two additional non-dietary categories with lower protein or energy stores was driven by the presence of the two non-dietary categories. Results were similar in CKD subgroup. CONCLUSION: Hence, a definition of PEW syndrome without dietary variables has face validity and reflects protein or energy wasting. PMID- 28840199 TI - Computational Approaches Toward Integrating Quantified Self Sensing and Social Media. AB - The growing amount of data collected by quantified self tools and social media hold great potential for applications in personalized medicine. Whereas the first includes health-related physiological signals, the latter provides insights into a user's behavior. However, the two sources of data have largely been studied in isolation. We analyze public data from users who have chosen to connect their MyFitnessPal and Twitter accounts. We show that a user's diet compliance success, measured via their self-logged food diaries, can be predicted using features derived from social media: linguistic, activity, and social capital. We find that users with more positive affect and a larger social network are more successful in succeeding in their dietary goals. Using a Granger causality methodology, we also show that social media can help predict daily changes in diet compliance success or failure with an accuracy of 77%, that improves over baseline techniques by 17%. We discuss the implications of our work in the design of improved health interventions for behavior change. PMID- 28840200 TI - Ethnic Differences in Abstinence Self-Efficacy among Recovering Individuals. AB - The purpose of the current study was to explore ethnic differences in drug abstinence self-efficacy among recovering individuals. Levels of abstinence self efficacy among African Americans and European Americans increased, decreased, and then increased again over the year. Drug abstinence self-efficacy remained stable over time among Latinos in this study. It is possible that, although they have reported positive experiences in Oxford House, Latinos may not receive the same benefits other groups gain from participation in Oxford House. Another possible explanation for the lack of change in abstinence selfefficacy among Latinos in Oxford House may be that factors outside the house and support networks may lower expectations for recovery. These factors may include inability to find work, experiences of discrimination, or lack of access to care. Future research needs to explore the social networks of Latinos in Oxford House as well as the experiences of this ethnic group in this program and in the community. PMID- 28840198 TI - Biobehavioral Mechanisms of Mindfulness as a Treatment for Chronic Stress: An RDoC Perspective. AB - Mindfulness-based interventions have been heralded as promising means of alleviating chronic stress. While meta-analyses indicate that mindfulness-based interventions significantly reduce global measures of stress, how mindfulness based interventions modulate the specific mechanisms underpinning chronic stress as operationalized by the National Institute of Mental Health research domain criteria (RDoC) of sustained threat has not yet been detailed in the literature. To address this knowledge gap, this article aims to (1) review evidence that mindfulness-based interventions ameliorate each of the 10 elements of behavioral dysregulation characterizing sustained threat via an array of mindful counter regulatory strategies; (2) review evidence that mindfulness-based interventions modify biological domains implicated in sustained threat, such as the hypothalamic-pituitary-adrenal axis, as well as brain circuits involved in attentional function, limbic reactivity, habit behavior, and the default mode network; and (3) integrate these findings into a novel conceptual framework of mindful self-regulation in the face of stress-the Mindfulness-to-Meaning Theory. Taken together, the extant body of scientific evidence suggests that the practice of mindfulness enhances a range biobehavioral factors implicated in adaptive stress coping and induces self-referential plasticity, leading to the ability to find meaning in adversity. These mechanistic findings can inform the treatment development process to optimize the next generation of mindfulness-based interventions for greater therapeutic efficacy. PMID- 28840201 TI - Recovery Amid Pro-Anorexia: Analysis of Recovery in Social Media. AB - Online communities can promote illness recovery and improve well-being in the cases of many kinds of illnesses. However, for challenging mental health condition like anorexia, social media harbor both recovery communities as well as those that encourage dangerous behaviors. The effectiveness of such platforms in promoting recovery despite housing both communities is underexplored. Our work begins to fill this gap by developing a statistical framework using survival analysis and situating our results within the cognitive behavioral theory of anorexia. This model identifies content and participation measures that predict the likelihood of recovery. From our dataset of over 68M posts and 10K users that self-identify with anorexia, we find that recovery on Tumblr is protracted - only half of the population is estimated to exhibit signs of recovery after four years. We discuss the effectiveness of social media in improving well-being around anorexia, a unique health challenge, and emergent questions from this line of work. PMID- 28840202 TI - A Social Media Based Index of Mental Well-Being in College Campuses. AB - Psychological distress in the form of depression, anxiety and other mental health challenges among college students is a growing health concern. Dearth of accurate, continuous, and multi-campus data on mental well-being presents significant challenges to intervention and mitigation efforts in college campuses. We examine the potential of social media as a new "barometer" for quantifying the mental well-being of college populations. Utilizing student contributed data in Reddit communities of over 100 universities, we first build and evaluate a transfer learning based classification approach that can detect mental health expressions with 97% accuracy. Thereafter, we propose a robust campus-specific Mental Well-being Index: MWI. We find that MWI is able to reveal meaningful temporal patterns of mental well-being in campuses, and to assess how their expressions relate to university attributes like size, academic prestige, and student demographics. We discuss the implications of our work for improving counselor efforts, and in the design of tools that can enable better assessment of the mental health climate of college campuses. PMID- 28840204 TI - Influence of co-non-solvency on hydrophobic molecules driven by excluded volume effect. AB - We demonstrate by molecular dynamics simulation that co-non-solvency manifests itself in the solvent-induced interaction between three hydrophobes, methane, propane and neopentane, in methanol-water mixtures. Decomposition of the potential of mean force, based on the potential distribution theorem, clearly shows that the solute-solvent entropic change is responsible for stabilizing the aggregation of these hydrophobic molecules. Furthermore, we show that the entropic change pertains to the excluded volume effect. PMID- 28840203 TI - Determining rotational dynamics of the guanidino group of arginine side chains in proteins by carbon-detected NMR. AB - Arginine residues are imperative for many active sites and protein-interaction interfaces. A new NMR-based method is presented to determine the rotational dynamics around the Nepsilon-Czeta bond of arginine side chains. An application to a 19 kDa protein shows that the strengths of interactions involving arginine side chains can be characterised. PMID- 28840205 TI - Kinetics in directional drying of water that contains deformable non-volatile oil droplets. AB - Herein, we report assessments of the kinetics in directional drying of water that contains non-volatile oil droplets, based on direct observations using a confocal microscope. The water was found to evaporate at a constant rate during the initial stage of drying, after which the evaporation rate decreased. The dispersed oil droplets were compressed and distorted as the surrounding water was lost. Further evaporation of water resulted in coalescence of the oil droplets, with the eventual formation of an oil layer at the drying interface. However, it was apparent that the drying rate decreased even before the formation of this oil layer. We propose that the restricted transport of water via the narrow paths between the distorted oil droplets was responsible for the decreased drying rate. A mathematical model based on foam drainage theory is proposed and describes the experimental data very well. This work also determined that the critical disjoining pressure for the oil droplets is affected by the drying rate, such that higher pressure values are associated with slow drying conditions. The drying kinetics and stability of the dispersed oil droplets are discussed. PMID- 28840206 TI - Trapping and patterning of large particles and cells in a 1D ultrasonic standing wave. AB - The use of ultrasound for trapping and patterning particles or cells in microfluidic systems is usually confined to particles which are considerably smaller than the acoustic wavelength. In this regime, the primary forces result in particle clustering at certain locations in the sound field, whilst secondary forces, those arising due to particle-particle interaction forces, assist this clustering process. Using a wavelength closer to the size of the particles allows one particle to be held at each primary force minimum. However, to achieve this, the influence of secondary forces needs to be carefully studied, as inter particle attraction is highly undesirable. Here, we study the effect of particle size and material properties on both the primary and secondary acoustic forces as the particle diameter is increased towards the wavelength of the 1-dimensional axisymmetric ultrasonic field. We show that the resonance frequencies of the solid sphere have an important role in the resulting secondary forces which leads to a narrow band of frequencies that allow the patterning of large particles in a 1-D array. Knowledge regarding the naturally existent secondary forces would allow for system designs enabling single cell studies to be conducted in a biologically safe manner. PMID- 28840207 TI - Minor methane emissions from an Alpine hydropower reservoir based on monitoring of diel and seasonal variability. AB - We monitored CH4 emissions during the ice-free period of an Alpine hydropower reservoir in the Swiss Alps, Lake Klontal, to investigate mechanisms responsible for CH4 variability and to estimate overall emissions to the atmosphere. A floating eddy-covariance platform yielded total CH4 and CO2 emission rates at high temporal resolution, while hydroacoustic surveys provided no indication of CH4 ebullition. Higher CH4 fluxes (2.9 +/- 0.1 mg CH4 per m2 per day) occurred during the day when surface water temperatures were warmer and wind speeds higher than at night. Piston velocity estimates (k600) showed an upper limit at high wind speeds that may be more generally valid also for other lakes and reservoirs with limited CH4 dissolved in the water body: above 2.0 m s-1 a further increase in wind speed did not lead to higher CH4 fluxes, because under such conditions it is not the turbulent mixing and transport that limits effluxes, but the resupply of CH4 to the lake surface. Increasing CH4 fluxes during the warm season showed a clear spatial gradient once the reservoir started to fill up and flood additional surface area. The warm period contributed 27% of the total CH4 emissions (2.6 t CH4 per year) estimated for the full year and CH4 accounted for 63% of carbonic greenhouse gas emissions. Overall, the average CH4 emissions (1.7 to 2.2 mg CH4 per m2 per day determined independently from surface water samplings and eddy covariance, respectively) were small compared to most tropical and some temperate reservoirs. The resulting greenhouse gas (GHG) emissions in CO2-equivalents revealed that electricity produced in the Lake Klontal power plant was relatively climate-friendly with a low GHG-to-power output ratio of 1.24 kg CO2,eq per MW h compared to 6.5 and 8.1 kg CO2,eq per MW h associated with the operation of solar photovoltaics and wind energy, respectively, or about 980 kg CO2,eq per MW h for coal-fired power plants. PMID- 28840208 TI - The nature of selenium hydrogen bonding: gas phase spectroscopy and quantum chemistry calculations. AB - Subsequent to the recent re-definition of hydrogen bonding by the IUPAC committee, there has been a growing search for finding the presence of this ever interesting non-covalent interaction between a hydrogen atom in an X-H group and any other atom in the periodic table. In recent gas phase experiments, it has been observed that hydrogen bonding interactions involving S and Se are of similar strength to those with an O atom. However, there is no clear explanation for the unusual strength of this interaction in the case of hydrogen bond acceptors which are not conventional electronegative atoms. In this work, we have explored the nature of Se hydrogen bonding by studying indoledimethyl selenide (indmse) and phenoldimethyl selenide (phdmse) complexes using gas phase IR spectroscopy and quantum chemistry calculations. We have found through various energy decomposition analysis (EDA) methods and natural bond orbital (NBO) calculations that, along with electrostatics and polarization, charge transfer interactions are important to understand Se/S hydrogen bonding and there is a delicate balance between the various interactions that plays the crucial role rather than a single component of the interaction energy. An in-depth understanding of this type of non-covalent interaction has immense significance in biology as amino acids containing S and Se are widely present in proteins and hence hydrogen bonding interactions involving S and Se atoms contribute to the folding of proteins. PMID- 28840209 TI - Complexation induced aggregation and deaggregation of acridine orange with sulfobutylether-beta-cyclodextrin. AB - The present study reports a contrasting interaction behaviour of a biologically important dye, acridine orange (AOH+), with a highly water soluble anionic host, based on a beta-cyclodextrin (betaCD) scaffold, i.e. sulfobutylether-beta cyclodextrin (SBEbetaCD), in comparison to native betaCD. AOH+ shows striking modulation in its photophysical properties, representing sequential changes in the modes of interaction with increasing SBEbetaCD concentration. At lower SBEbetaCD concentrations, AOH+ preferentially binds in dimeric forms at the negatively charged SBEbetaCD portals, leading to strong fluorescence quenching. At higher SBEbetaCD concentrations, the dimeric dyes convert to monomeric forms and subsequently undergo both inclusion and exo complex formation with 1 : 1 stoichiometry, resulting in a large fluorescence enhancement. The intriguing observation of sequential fluorescence switch off and switch on for an AOH+ SBEbetaCD system is clearly facilitated by the presence of butylether chains with SO3- end groups at the portals of SBEbetaCD, providing an additional ion-ion interaction and much enhanced hydrophobic interaction for cationic AOH+ compared to the native betaCD host. To the best of our knowledge, such fluorescence off/on switching through multistep host-guest binding has not been reported so far in the literature. The present study not only provides a detailed insight into the unique binding interactions of AOH+ with the SBEbetaCD host, but the findings of this study are also expected to be useful in designing supramolecular based drug formulations, drug delivery systems, sensors, and so on. PMID- 28840210 TI - Optimized FTO seeding enables the growth of highlyefficient Ta-doped TiO2 nanorod photoanodes. AB - Tantalum doped rutile nanorods were hydrothermally grown on FTO substrates using a new seeding approach. This approach allows the incorporation of high concentrations of up to 4.8 at% tantalum as active doping and results in a significant enhancement of the photoelectrochemical water splitting rate (1.8 mA cm-2 at a potential of +1.5 V vs. RHE) which corresponds to ~1% photocurrent conversion efficiency under AM 1.5, 100 mW cm-2 simulated sunlight irradiation. PMID- 28840211 TI - A highly stable polyoxometalate-based metal-organic framework with an ABW zeolite like structure. AB - A novel polyoxometalate-based metal-organic framework (POMOF) with an ABW network, NENU-601, was synthesized in situ. To the best of our knowledge, this is the first POMOF with a zeolite-like structure, which was designed by regulating the length and angle of mixed ligands and rationally choosing suitable Polyoxometalates (POMs) as nodes. PMID- 28840212 TI - Transfer matrix theory of polymer complex coacervation. AB - Oppositely charged polyelectrolytes can undergo a macroscopic, associative phase separation in solution, via a process known as complex coacervation. Significant recent effort has gone into providing a clear, physical picture of coacervation; most work has focused on improving the field theory picture that emerged from the classical Voorn-Overbeek theory. These methods have persistent issues, however, resolving the molecular features that have been shown to play a major role in coacervate thermodynamics. In this paper, we outline a theoretical approach to coacervation based on a transfer matrix formalism that is an alternative to traditional field-based approaches. We develop theoretical arguments informed by experimental observation and simulation, which serve to establish an analytical expression for polymeric complex coacervation that is consistent with the molecular features of coacervate phases. The analytical expression provided by this theory is in a form that can be incorporated into more complicated theoretical or simulation formalisms, and thus provides a starting point for understanding coacervate-driven self-assembly or biophysics. PMID- 28840213 TI - Heuristics for precise supramolecular control of soft matter structure and properties - 2,3,4-tris(dodecyloxy)benzenesulfonates with alkaline and organic cations. AB - Comprehensive analysis of the structure and phase behavior for a number of 2,3,4 tris(dodecyloxy)benzenesulfonates with alkali metal and organic focal groups revealed that the shape of the mesogenic group plays a decisive role in phase behavior of the material. Cubic and layered types of packing prevail when the size of the cation is small and, thus, the shape of the mesogenic molecule is close to conic one. With increasing cation size, the shape becomes more tapered, and columnar mesophases appear to be more stable. Interactions of the focal groups however determine the stability of mesophases. Comparatively strong interactions may, morever, provide substantial deviations from a phase diagram plotting the transition temperatures versus the radius of focal group, as in the case of pyridinium 2,3,4-tris(dodecyloxy)benzenesulfonate. PMID- 28840214 TI - Correction: Metal-free oxidative ring contraction of benzodiazepinones: an entry to quinoxalinones. AB - Correction for 'Metal-free oxidative ring contraction of benzodiazepinones: an entry to quinoxalinones' by Hasan Mtiraoui, et al., Org. Biomol. Chem., 2017, 15, 3060-3068. PMID- 28840215 TI - Multiplexed photoluminescent sensors: towards improved disease diagnostics. AB - The ability to simultaneously monitor multiple analytes in, for example, a single microplate well, is important for both basic research and clinical applications. In particular, for disease diagnosis there is a growing awareness that determination of a single disease biomarker is insufficient to pathologically confirm a disease state. Consequently, much recent literature has been directed towards the development of multiplexed photoluminescent sensors which can simultaneously detect multiple and diverse biomarkers that exist in a homogenous solution or a single cell, accelerating the progress towards precise disease diagnosis. This tutorial review highlights a selection of recent contributions towards this emerging interdisciplinary field that incorporates chemistry, chemical biology, materials sciences and medical sciences. PMID- 28840216 TI - A simple route to complex materials: the synthesis of alkaline earth - transition metal sulfides. AB - A simple, low-temperature synthesis of a family of alkaline earth metal chalcogenide thin films is reported. These materials have previously only been produced from demanding, high temperature, high pressure reactions. The decomposition of calcium, barium and copper xanthates leads to the clean formation of CaS, BaS, CaCu2S2, beta-BaCu2S2 and beta-BaCu4S3. PMID- 28840217 TI - Transfer of chiral information from a chiral solvent to a two-dimensional network. AB - Chiral induction in self-assembled monolayers has garnered considerable attention in the recent past, not only due to its importance in chiral resolution and enantioselective heterogeneous catalysis but also because of its relevance to the origin of homochirality in life. Here, we demonstrate the emergence of homochirality in a supramolecular low-density network formed by achiral molecules at the interface of a chiral solvent and an atomically-flat achiral substrate. We focus on the impact of structure and functionality of the adsorbate and the chiral solvent on the chiral induction efficiency in self-assembled physisorbed monolayers, as revealed by scanning tunneling microscopy. Different induction mechanisms are proposed and evaluated, with the assistance of advanced molecular modeling simulations. PMID- 28840218 TI - Counter electrodes in dye-sensitized solar cells. AB - Dye-sensitized solar cells (DSSCs) are regarded as prospective solar cells for the next generation of photovoltaic technologies and have become research hotspots in the PV field. The counter electrode, as a crucial component of DSSCs, collects electrons from the external circuit and catalyzes the redox reduction in the electrolyte, which has a significant influence on the photovoltaic performance, long-term stability and cost of the devices. Solar cells, dye sensitized solar cells, as well as the structure, principle, preparation and characterization of counter electrodes are mentioned in the introduction section. The next six sections discuss the counter electrodes based on transparency and flexibility, metals and alloys, carbon materials, conductive polymers, transition metal compounds, and hybrids, respectively. The special features and performance, advantages and disadvantages, preparation, characterization, mechanisms, important events and development histories of various counter electrodes are presented. In the eighth section, the development of counter electrodes is summarized with an outlook. This article panoramically reviews the counter electrodes in DSSCs, which is of great significance for enhancing the development levels of DSSCs and other photoelectrochemical devices. PMID- 28840219 TI - Isolation, structure elucidation and racemization of (+)- and (-)-pratensilins A C: unprecedented spiro indolinone-naphthofuran alkaloids from a marine Streptomyces sp. AB - Three pairs of new enantiomeric alkaloids with an unprecedented spiro indolinone naphthofuran skeleton were isolated from a marine Streptomyces sp. The pure enantiomers had a marked difference in the enantiomerization processes for the three compounds. DFT calculations in combination with chemical derivatization were performed to corroborate the racemization process via a keto-enol-type tautomerism. PMID- 28840220 TI - Microfluidic systems for high-throughput and high-content screening using the nematode Caenorhabditis elegans. AB - In a typical high-throughput drug screening (HTS) process, up to millions of chemical compounds are applied to cells cultured in well plates, aiming to find molecules that exhibit a robust dose-response, as evidenced for example by a fluorescence signal. In high-content screening (HCS), one goes a step further by linking the tested compounds to phenotypic information, obtained, for instance, from microscopic cell images, thereby creating richer data sets that also require more advanced analysis methods. The nematode Caenorhabditis elegans came into the screening picture due to the wide availability of its mutants and human disease models, its relatively easy culture and short life cycle. Being a whole-organism model, it allows drug testing under physiological conditions at multi-tissue levels and provides additional observable phenotypes with respect to cell models, related, for instance, to development, aging, behavior or motility. Worm-based HTS studies in liquid environments on microwell plates have been demonstrated, while microfluidic devices allowed surpassing the performance of plates by enabling more versatile and accurate assays, precise and dynamic dosing of compounds, and readouts down to single-animal resolution. In this review, we discuss microfluidic devices for C. elegans analysis and related studies, published in the period from 2012 to 2017. After an introduction to the different screening approaches, we first focus on microfluidic systems with potential for screening applications. Various enabling technologies, e.g. electrophysiological on-chip recordings or laser axotomy, have been implemented, as well as techniques for reversible worm immobilization and high-resolution imaging, combined with algorithms for automated experimentation and analysis. Several devices for developmental or behavioral assays, and worm sorting based on different phenotypes, have been proposed too. In a subsequent section, we review the application of microfluidic-based systems for medium- and high-throughput screens, including neurobiology and neurodegeneration studies, aging and developmental assays, toxicity and pathogenesis screens, as well as behavioral and motility assays. A thorough analysis of this work reveals a trend towards microfluidic systems more and more capable of offering high-quality analyses of large worm populations, based on multi-phenotypic and/or longitudinal readouts, with clear potential for their application in larger HTS/HCS contexts. PMID- 28840221 TI - Erratum to: hypospadias, all there is to know. PMID- 28840222 TI - Erratum to: Activation of liver X receptor inhibits OCT2-mediated organic cation transport in renal proximal tubular cells. PMID- 28840224 TI - ? PMID- 28840223 TI - Erratum to: investigation of metabolites for estimating blood deposition time. PMID- 28840230 TI - Mitteilungen der DGKFO. PMID- 28840231 TI - Use of Mass Spectrometry to Study the Centromere and Kinetochore. AB - A number of paths have led to the present list of centromere proteins, which is essentially complete for constitutive structural proteins, but still may be only partial if we consider the many other proteins that briefly visit the centromere and kinetochore to fine-tune the chromatin and adjust other functions. Elegant genetics led to the description of the budding yeast point centromere in 1980. In the same year was published the serendipitous discovery of antibodies that stained centromeres of human mitotic chromosomes in antisera from CREST patients. Painstaking biochemical analyses led to the identification of the human centromere antigens several years later, with the first yeast proteins being described 6 years after that. Since those early days, the discovery and cloning of centromere and kinetochore proteins has largely been driven by improvements in technology. These began with expression cloning methods, which allowed antibodies to lead to cDNA clones. Next, functional screens for kinetochore proteins were made possible by the isolation of yeast centromeric DNAs. Ultimately, the completion of genome sequences for humans and model organisms permitted the coupling of biochemical fractionation with protein identification by mass spectrometry. Subsequent improvements in mass spectrometry have led to the current state where virtually all structural components of the kinetochore are known and where a high-resolution map of the entire structure will likely emerge within the next several years. PMID- 28840232 TI - Critical Foundation of the Kinetochore: The Constitutive Centromere-Associated Network (CCAN). AB - The kinetochore is a large protein complex, which is assembled at the centromere of a chromosome to ensure faithful chromosome segregation during M-phase. The centromere in most eukaryotes is epigenetically specified by DNA sequence independent mechanisms. The constitutive centromere-associated network (CCAN) is a subcomplex in the kinetochore that localizes to the centromere throughout the cell cycle. The CCAN has interfaces bound to the centromeric chromatin and the spindle microtubule-binding complex; therefore, it functions as a foundation of kinetochore formation. Here, we summarize recent progress in our understanding of the structure and organization of the CCAN. We also discuss an additional role of the CCAN in the maintenance of centromere position and dynamic reorganization of the CCAN. PMID- 28840234 TI - Centrochromatin of Fungi. AB - The centromere is an essential chromosomal locus that dictates the nucleation point for assembly of the kinetochore and subsequent attachment of spindle microtubules during chromosome segregation. Research over the last decades demonstrated that centromeres are defined by a combination of genetic and epigenetic factors. Recent work showed that centromeres are quite diverse and flexible and that many types of centromere sequences and centromeric chromatin ("centrochromatin") have evolved. The kingdom of the fungi serves as an outstanding example of centromere plasticity, including organisms with centromeres as diverse as 0.15-300 kb in length, and with different types of chromatin states for most species examined thus far. Some of the species in the less familiar taxa provide excellent opportunities to help us better understand centromere biology in all eukaryotes, which may improve treatment options against fungal infection, and biotechnologies based on fungi. This review summarizes the current knowledge of fungal centromeres and centrochromatin, including an outlook for future research. PMID- 28840235 TI - Evolutionary Lessons from Species with Unique Kinetochores. AB - The kinetochore is the multi-protein complex that drives chromosome segregation in eukaryotes. It assembles onto centromeric DNA and mediates attachment to spindle microtubules. Kinetochore research over the last several decades has been focused on a few animal and fungal model organisms, which revealed a detailed understanding of the composition and organization of their kinetochores. Yet, these traditional model organisms represent only a small fraction of all eukaryotes. To gain insights into the actual degree of kinetochore diversity, it is critical to extend these studies to nontraditional model organisms from evolutionarily distant lineages. In this chapter, we review the current knowledge of kinetochores across diverse eukaryotes with an emphasis on variations that arose in nontraditional model organisms. In addition, we also review the literature on species, in which the subcellular localization of kinetochores has changed from the nucleoplasm to the nuclear membrane. Finally, we speculate on the organization of the chromosome segregation machinery in an early eukaryotic ancestor to gain insights into fundamental principles of the chromosome segregation machinery, which are common to all eukaryotes. PMID- 28840233 TI - The Power of Xenopus Egg Extract for Reconstitution of Centromere and Kinetochore Function. AB - Faithful transmission of genetic information during cell division requires attachment of chromosomes to the mitotic spindle via the kinetochore. In vitro reconstitution studies are beginning to uncover how the kinetochore is assembled upon the underlying centromere, how the kinetochore couples chromosome movement to microtubule dynamics, and how cells ensure the site of kinetochore assembly is maintained from one generation to the next. Here we give special emphasis to advances made in Xenopus egg extract, which provides a unique, biochemically tractable in vitro system that affords the complexity of cytoplasm and nucleoplasm to permit reconstitution of the dynamic, cell cycle-regulated functions of the centromere and kinetochore. PMID- 28840236 TI - Quantitative Microscopy Reveals Centromeric Chromatin Stability, Size, and Cell Cycle Mechanisms to Maintain Centromere Homeostasis. AB - Centromeres are chromatin domains specified by nucleosomes containing the histone H3 variant, CENP-A. This unique centromeric structure is at the heart of a strong self-templating epigenetic mechanism that renders centromeres heritable. We review how specific quantitative microscopy approaches have contributed to the determination of the copy number, architecture, size, and dynamics of centromeric chromatin and its associated centromere complex and kinetochore. These efforts revealed that the key to long-term centromere maintenance is the slow turnover of CENP-A nucleosomes, a critical size of the chromatin domain and its cell cycle coupled replication. These features come together to maintain homeostasis of a chromatin locus that directs its own epigenetic inheritance and facilitates the assembly of the mitotic kinetochore. PMID- 28840238 TI - Artificial Chromosomes and Strategies to Initiate Epigenetic Centromere Establishment. AB - In recent years, various synthetic approaches have been developed to address the question of what directs centromere establishment and maintenance. In this chapter, we will discuss how approaches aimed at constructing synthetic centromeres have co-evolved with and contributed to shape the theory describing the determinants of centromere identity. We will first review lessons learned from artificial chromosomes created from "naked" centromeric sequences to investigate the role of the underlying DNA for centromere formation. We will then discuss how several studies, which applied removal of endogenous centromeres or over-expression of the centromere-specific histone CENP-A, helped to investigate the contribution of chromatin context to centromere establishment. Finally, we will examine various biosynthetic approaches taking advantage of targeting specific proteins to ectopic sites in the genome to dissect the role of many centromere-associated proteins and chromatin modifiers for centromere inheritance and function. Together, these studies showed that chromatin context matters, particularly proximity to heterochromatin or repetitive DNA sequences. Moreover, despite the important contribution of centromeric DNA, the centromere-specific histone H3-variant CENP-A emerges as a key epigenetic mark to establish and maintain functional centromeres on artificial chromosomes or at ectopic sites of the genome. PMID- 28840239 TI - Post-translational Modifications of Centromeric Chromatin. AB - Regulation of chromatin structures is important for the control of DNA processes such as gene expression, and misregulation of chromatin is implicated in diverse diseases. Covalent post-translational modifications of histones are a prominent way to regulate chromatin structure and different chromatin regions bear their specific signature of histone modifications. The composition of centromeric chromatin is significantly different from other chromatin structures and mainly defined by the presence of the histone H3-variant CENP-A. Here we summarize the composition of centromeric chromatin and what we know about its differential regulation by post-translational modifications. PMID- 28840240 TI - Centromere Silencing Mechanisms. AB - Centromere function is essential for genome stability and chromosome inheritance. Typically, each chromosome has a single locus that consistently serves as the site of centromere formation and kinetochore assembly. Decades of research have defined the DNA sequence and protein components of functional centromeres, and the interdependencies of specific protein complexes for proper centromere assembly. Less is known about how centromeres are disassembled or functionally silenced. Centromere silencing, or inactivation, is particularly relevant in the cases of dicentric chromosomes that occur via genome rearrangements that place two centromeres on the same chromosome. Dicentrics are usually unstable unless one centromere is inactivated, thereby allowing the structurally dicentric chromosome to behave like one of the monocentric, endogenous chromosomes. The molecular basis for centromere inactivation is not well understood, although studies in model organisms and in humans suggest that both genomic and epigenetic mechanisms are involved. In this chapter, we review recent studies using synthetic chromosomes and engineered or induced dicentrics from various organisms to define the molecular processes that are involved in the complex process of centromere inactivation. PMID- 28840241 TI - Centromere Transcription: Means and Motive. AB - The chromosome biology field at large has benefited from studies of the cell cycle components, protein cascades and genomic landscape that are required for centromere identity, assembly and stable transgenerational inheritance. Research over the past 20 years has challenged the classical descriptions of a centromere as a stable, unmutable, and transcriptionally silent chromosome component. Instead, based on studies from a broad range of eukaryotic species, including yeast, fungi, plants, and animals, the centromere has been redefined as one of the more dynamic areas of the eukaryotic genome, requiring coordination of protein complex assembly, chromatin assembly, and transcriptional activity in a cell cycle specific manner. What has emerged from more recent studies is the realization that the transcription of specific types of nucleic acids is a key process in defining centromere integrity and function. To illustrate the transcriptional landscape of centromeres across eukaryotes, we focus this review on how transcripts interact with centromere proteins, when in the cell cycle centromeric transcription occurs, and what types of sequences are being transcribed. Utilizing data from broadly different organisms, a picture emerges that places centromeric transcription as an integral component of centromere function. PMID- 28840242 TI - The Promises and Challenges of Genomic Studies of Human Centromeres. AB - Human centromeres are genomic regions that act as sites of kinetochore assembly to ensure proper chromosome segregation during mitosis and meiosis. Although the biological importance of centromeres in genome stability, and ultimately, cell viability are well understood, the complete sequence content and organization in these multi-megabase-sized regions remains unknown. The lack of a high-resolution reference assembly inhibits standard bioinformatics protocols, and as a result, sequence-based studies involving human centromeres lag far behind the advances made for the non-repetitive sequences in the human genome. In this chapter, I introduce what is known about the genomic organization in the highly repetitive regions spanning human centromeres, and discuss the challenges these sequences pose for assembly, alignment, and data interpretation. Overcoming these obstacles is expected to issue a new era for centromere genomics, which will offer new discoveries in basic cell biology and human biomedical research. PMID- 28840243 TI - DNA Sequences in Centromere Formation and Function. AB - Faithful chromosome segregation during cell division depends on the centromere, a complex DNA/protein structure that links chromosomes to spindle microtubules. This chromosomal domain has to be marked throughout cell division and its chromosomal localization preserved across cell generations. From fission yeast to human, centromeres are established on a series of repetitive DNA sequences and on specialized centromeric chromatin. This chromatin is enriched with the histone H3 variant, named CENP-A, that was demonstrated to be the epigenetic mark that maintains centromere identity and function indefinitely. Although centromere identity is thought to be exclusively epigenetic, the presence of specific DNA sequences in the majority of eukaryotes and of the centromeric protein CENP-B that binds to these sequences, suggests the existence of a genetic component as well. In this review, we will highlight the importance of centromeric sequences for centromere formation and function, and discuss the centromere DNA sequence/CENP-B paradox. PMID- 28840244 TI - The Unique DNA Sequences Underlying Equine Centromeres. AB - Centromeres are highly distinctive genetic loci whose function is specified largely by epigenetic mechanisms. Understanding the role of DNA sequences in centromere function has been a daunting task due to the highly repetitive nature of centromeres in animal chromosomes. The discovery of a centromere devoid of satellite DNA in the domestic horse consolidated observations on the epigenetic nature of centromere identity, showing that entirely natural chromosomes could function without satellite DNA cues. Horses belong to the genus Equus which exhibits a very high degree of evolutionary plasticity in centromere position and DNA sequence composition. Examination of horses has revealed that the position of the satellite-free centromere is variable among individuals. Analysis of centromere location and composition in other Equus species, including domestic donkey and zebras, confirms that the satellite-less configuration of centromeres is common in this group which has undergone particularly rapid karyotype evolution. These features have established the equids as a new mammalian system in which to investigate the molecular organization, dynamics and evolutionary behaviour of centromeres. PMID- 28840237 TI - Orchestrating the Specific Assembly of Centromeric Nucleosomes. AB - Centromeres are chromosomal loci that are defined epigenetically in most eukaryotes by incorporation of a centromere-specific nucleosome in which the canonical histone H3 variant is replaced by Centromere Protein A (CENP-A). Therefore, the assembly and propagation of centromeric nucleosomes are critical for maintaining centromere identify and ensuring genomic stability. Centromeres direct chromosome segregation (during mitosis and meiosis) by recruiting the constitutive centromere-associated network of proteins throughout the cell cycle that in turn recruits the kinetochore during mitosis. Assembly of centromere specific nucleosomes in humans requires the dedicated CENP-A chaperone HJURP, and the Mis18 complex to couple the deposition of new CENP-A to the site of the pre existing centromere, which is essential for maintaining centromere identity. Human CENP-A deposition occurs specifically in early G1, into pre-existing chromatin, and several additional chromatin-associated complexes regulate CENP-A nucleosome deposition and stability. Here we review the current knowledge on how new CENP-A nucleosomes are assembled selectively at the existing centromere in different species and how this process is controlled to ensure stable epigenetic inheritance of the centromere. PMID- 28840245 TI - Centromere Dynamics in Male and Female Germ Cells. AB - In sexually reproducing organisms the germ line is the cellular lineage that gives rise to gametes. All germ cells originate from germline stem cells that divide asymmetrically to generate gonial pre-cursors, which are amplified in number by mitotic divisions, undergo meiosis and eventually differentiate into mature gametes (haploid eggs and sperm). Information transmitted with gametes is inherited by offspring, and potentially by subsequent generations, instructing in organismal development and beyond. Meiosis comprises one round of DNA replication, followed by two rounds of chromosome segregation; homologous chromosomes segregate in the first division (meiosis I) and sister chromatids segregate in the second division (meiosis II). Important mechanistic features of meiosis occur in substages of prophase I and are critical for genetic recombination, including pairing and synapsis of homologous chromosomes (at leptotene and zygotene), crossing-over (at pachytene), and the appearance of chiasmata (at diplotene/diakinesis). Another unique feature of meiosis is the altered centromere/kinetochore geometry at metaphase I, such that sister kinetochores face the same spindle pole (mono-orientation) and stay together at anaphase I. This chapter reviews centromere dynamics in germ cells, focusing on centromere function and assembly in meiotic cell cycles, as well as centromere inheritance in zygotes. Centromeres are functionally defined by the presence of the histone H3 variant CENP-A, the epigenetic determinant of centromere identity. In most eukaryotes, it is well established that CENP-A function is essential for chromosome segregation in mitosis. CENP-A function in meiosis is less well understood and emerging insights into the differential regulation of meiotic and mitotic CENP-A are discussed. PMID- 28840246 TI - Cell Biology of Cheating-Transmission of Centromeres and Other Selfish Elements Through Asymmetric Meiosis. AB - Mendel's First Law of Genetics states that a pair of alleles segregates randomly during meiosis so that one copy of each is represented equally in gametes. Whereas male meiosis produces four equal sperm, in female meiosis only one cell, the egg, survives, and the others degenerate. Meiotic drive is a process in which a selfish DNA element exploits female meiotic asymmetry and segregates preferentially to the egg in violation of Mendel's First Law, thereby increasing its transmission to the offspring and frequency in a population. In principle, the selfish element can consist either of a centromere that increases its transmission via an altered kinetochore connection to the meiotic spindle or a centromere-like element that somehow bypasses the kinetochore altogether in doing so. There are now examples from eukaryotic model systems for both types of meiotic drive. Although meiotic drive has profound evolutionary consequences across many species, relatively little is known about the underlying mechanisms. We discuss examples in various systems and open questions about the underlying cell biology, and propose a mechanism to explain biased segregation in mammalian female meiosis. PMID- 28840247 TI - Biophysics of Microtubule End Coupling at the Kinetochore. AB - The main physiological function of mitotic kinetochores is to provide durable attachment to spindle microtubules, which segregate chromosomes in order to partition them equally between the two daughter cells. Numerous kinetochore components that can bind directly to microtubules have been identified, including ATP-dependent motors and various microtubule-associated proteins with no motor activity. A major challenge facing the field is to explain chromosome motions based on the biochemical and structural properties of these individual kinetochore components and their assemblies. This chapter reviews the molecular mechanisms responsible for the motions associated with dynamic microtubule tips at the single-molecule level, as well as the activities of multimolecular ensembles called couplers. These couplers enable persistent kinetochore motion even under load, but their exact composition and structure remain unknown. Because no natural or artificial macro-machines function in an analogous manner to these molecular nano-devices, understanding their underlying biophysical mechanisms will require conceptual advances. PMID- 28840248 TI - Molecular Mechanisms of Spindle Assembly Checkpoint Activation and Silencing. AB - In eukaryotic cell division, the Spindle Assembly Checkpoint (SAC) plays a key regulatory role by monitoring the status of chromosome-microtubule attachments and allowing chromosome segregation only after all chromosomes are properly attached to spindle microtubules. While the identities of SAC components have been known, in some cases, for over two decades, the molecular mechanisms of the SAC have remained mostly mysterious until very recently. In the past few years, advances in biochemical reconstitution, structural biology, and bioinformatics have fueled an explosion in the molecular understanding of the SAC. This chapter seeks to synthesize these recent advances and place them in a biological context, in order to explain the mechanisms of SAC activation and silencing at a molecular level. PMID- 28840249 TI - A Kinase-Phosphatase Network that Regulates Kinetochore-Microtubule Attachments and the SAC. AB - The KMN network (for KNL1, MIS12 and NDC80 complexes) is a hub for signalling at the outer kinetochore. It integrates the activities of two kinases (MPS1 and Aurora B) and two phosphatases (PP1 and PP2A-B56) to regulate kinetochore microtubule attachments and the spindle assembly checkpoint (SAC). We will first discuss each of these enzymes separately, to describe how they are regulated at kinetochores and why this is important for their primary function in controlling either microtubule attachments or the SAC. We will then discuss why inhibiting any one of them individually produces secondary effects on all the others. This cross-talk may help to explain why all enzymes have been linked to both processes, even though the direct evidence suggests they each control only one. This chapter therefore describes how a network of kinases and phosphatases work together to regulate two key mitotic processes. PMID- 28840250 TI - Centromeric Cohesin: Molecular Glue and Much More. AB - Sister chromatid cohesion, mediated by the cohesin complex, is a prerequisite for faithful chromosome segregation during mitosis. Premature release of sister chromatid cohesion leads to random segregation of the genetic material and consequent aneuploidy. Multiple regulatory mechanisms ensure proper timing for cohesion establishment, concomitant with DNA replication, and cohesion release during the subsequent mitosis. Here we summarize the most important phases of the cohesin cycle and the coordination of cohesion release with the progression through mitosis. We further discuss recent evidence that has revealed additional functions for centromeric localization of cohesin in the fidelity of mitosis in metazoans. Beyond its well-established role as "molecular glue", centromeric cohesin complexes are now emerging as a scaffold for multiple fundamental processes during mitosis, including the formation of correct chromosome and kinetochore architecture, force balance with the mitotic spindle, and the association with key molecules that regulate mitotic fidelity, particularly at the chromosomal inner centromere. Centromeric chromatin may be thus seen as a dynamic place where cohesin ensures mitotic fidelity by multiple means. PMID- 28840251 TI - Centromere Structure and Function. AB - The centromere is the genetic locus that specifies the site of kinetochore assembly, where the chromosome will attach to the kinetochore microtubule. The pericentromere is the physical region responsible for the geometry of bi-oriented sister kinetochores in metaphase. In budding yeast the 125 bp point centromere is sufficient to specify kinetochore assembly. The flanking region is enriched (3X) in cohesin and condensin relative to the remaining chromosome arms. The enrichment spans about 30-50 kb around each centromere. We refer to the flanking chromatin as the pericentromere in yeast. In mammals, a 5-10 Mb region dictates where the kinetochore is built. The kinetochore interacts with a very small fraction of DNA on the surface of the centromeric region. The remainder of the centromere lies between the sister kinetochores. This is typically called centromere chromatin. The chromatin sites that directly interface to microtubules cannot be identified due to the repeated sequence within the mammalian centromere. However in both yeast and mammals, the total amount of DNA between the sites of microtubule attachment in metaphase is highly conserved. In yeast the 16 chromosomes are clustered into a 250 nm diameter region, and 800 kb (16 * 50 kb) or ~1 Mb of DNA lies between sister kinetochores. In mammals, 5-10 Mb lies between sister kinetochores. In both organisms the sister kinetochores are separated by about 1 MUm. Thus, centromeres of different organisms differ in how they specify kinetochore assembly, but there may be important centromere chromatin functions that are conserved throughout phylogeny. Recently, centromeric chromatin has been reconstituted in vitro using alpha satellite DNA revealing unexpected features of centromeric DNA organization, replication, and response to stress. We will focus on the conserved features of centromere in this review. PMID- 28840252 TI - The Role of Centromere Defects in Cancer. AB - The accurate segregation of chromosomes to daughter cells is essential for healthy development to occur. Imbalances in chromosome number have long been associated with cancers amongst other medical disorders. Little is known whether abnormal chromosome numbers are an early contributor to the cancer progression pathway. Centromere DNA and protein defects are known to impact on the fidelity of chromosome segregation in cell and model systems. In this chapter we discuss recent developments in understanding the contribution of centromere abnormalities at the protein and DNA level and their role in cancer in human and mouse systems. PMID- 28840254 TI - Abstracts of the 50th Anniversary ESPN Meeting, Glasgow, September 2017. PMID- 28840255 TI - [Appropriate treatment of acute stroke at all times and in all places : Organizational concepts and new approaches]. AB - Stroke is one of the most common neurological diseases in acute care. The introduction of new organizational concepts in the rescue chain and in acute inpatient services can significantly reduce time to treatment and patients can receive specific therapeutic options that have been shown to improve acute stroke prognosis. This review provides an overview of organizational structures that lead to improved medical care and outlines the evidence-based therapeutic options. This is intended to give the reader a decision support on provision of specific treatment in acute ischemic stroke. The almost simultaneous proof of effectiveness of mechanical thrombectomy for targeted patient populations in five randomized trials has challenged the organization of stroke care. This provides a good example of how an optimized interplay within the rescue chain from emergency services via community hospitals to referral centers with intervention facilities can ensure access to this novel treatment for as many patients as possible. For the limited time span between onset of symptoms and start of treatment, creative but nevertheless well-standardized concepts have emerged that lead to measurable therapeutic success. It has become an urgent challenge to create sustainable regional infrastructures that allow access to appropriate treatment for all patients. PMID- 28840256 TI - [Neurophysiological monitoring during surgical procedures]. AB - The application of intraoperative neurophysiological monitoring (IONM) is gaining more and more importance in daily clinical practice. The use of IONM allows the localization of neural structures and to control functioning of the peripheral and central nervous systems in anesthetized patients. This enables surgeons to identify and to protect neural structures and cerebral areas. The use of IONM also enables anesthesiologists to adjust anesthesia and cardiopulmonary therapy to the individual needs of the patient. Thereby, it may be possible to reduce the incidence of postoperative delirium and the incidence of postoperative cognitive deficits. To exploit the full potential anesthesiologists and surgeons must be able to use the methods of IONM safely and understand the results; therefore, basic knowledge of the technology, options and limitations of IONM is necessary. It is also important to be aware of the influence of anesthetics on the methods of IONM. Total intravenous anesthesia (TIVA) is the anesthetic method of choice, because it has only minimal influence on IONM methods. It is important to avoid bolus injections of hypnotics to achieve stable blood concentrations. Long- acting neuromuscular blocking agents should be avoided, because they disturb the signals of electromyography and motor-evoked potentials. By using IONM anesthesiologists and surgeons can identify changes in the function of the peripheral and central nervous system prior to irreversible damage. PMID- 28840253 TI - Interaction and cross-talk between non-coding RNAs. AB - Non-coding RNA (ncRNA) has been shown to regulate diverse cellular processes and functions through controlling gene expression. Long non-coding RNAs (lncRNAs) act as a competing endogenous RNAs (ceRNAs) where microRNAs (miRNAs) and lncRNAs regulate each other through their biding sites. Interactions of miRNAs and lncRNAs have been reported to trigger decay of the targeted lncRNAs and have important roles in target gene regulation. These interactions form complicated and intertwined networks. Certain lncRNAs encode miRNAs and small nucleolar RNAs (snoRNAs), and may regulate expression of these small RNAs as precursors. SnoRNAs have also been reported to be precursors for PIWI-interacting RNAs (piRNAs) and thus may regulate the piRNAs as a precursor. These miRNAs and piRNAs target messenger RNAs (mRNAs) and regulate gene expression. In this review, we will present and discuss these interactions, cross-talk, and co-regulation of ncRNAs and gene regulation due to these interactions. PMID- 28840257 TI - Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: results from the TULIP study. AB - AIMS/HYPOTHESIS: Lifestyle intervention is effective to prevent type 2 diabetes. However, a considerable long-term non-response occurs to a standard lifestyle intervention. We investigated which risk phenotypes at baseline and their changes during the lifestyle intervention predict long-term glycaemic non-response to the intervention. METHODS: Of 300 participants at high risk for type 2 diabetes who participated in a 24 month lifestyle intervention with diet modification and increased physical activity, 190 participants could be re-examined after 8.7 +/- 1.6 years. All individuals underwent a five-point 75 g OGTT and measurements of body fat compartments and liver fat content with MRI and spectroscopy at baseline, 9 and 24 months during the lifestyle intervention, and at long-term follow-up. Fasting proinsulin to insulin conversion (PI/I ratio) and insulin sensitivity and secretion were calculated from the OGTT. Non-response to lifestyle intervention was defined as no decrease in glycaemia, i.e. no decrease in AUC for glucose at 0-120 min during OGTT (AUCglucose0-120 min). RESULTS: Before the lifestyle intervention, 56% of participants had normal glucose regulation and 44% individuals had impaired fasting glucose and/or impaired glucose tolerance. At long-term follow-up, 11% had developed diabetes. Multivariable regression analysis with adjustment for age, sex, BMI and change in BMI during the lifestyle intervention revealed that baseline insulin secretion and insulin sensitivity, as well as change in insulin sensitivity during the lifestyle intervention, predicted long-term glycaemic control after 9 years. In addition, increased hepatic lipid content as well as impaired fasting proinsulin conversion at baseline were newly detected phenotypes that independently predicted long-term glycaemic control. CONCLUSIONS/INTERPRETATION: Increased hepatic lipid content and impaired proinsulin conversion are new predictors, independent of change in body weight, for non-response to lifestyle intervention in addition to the confirmed factors, impaired insulin secretion and insulin sensitivity. PMID- 28840258 TI - Individualised variable-interval risk-based screening for sight-threatening diabetic retinopathy: the Liverpool Risk Calculation Engine. AB - AIMS/HYPOTHESIS: Individualised variable-interval risk-based screening offers better targeting and improved cost-effectiveness in screening for diabetic retinopathy. We developed a generalisable risk calculation engine (RCE) to assign personalised intervals linked to local population characteristics, and explored differences in assignment compared with current practice. METHODS: Data from 5 years of photographic screening and primary care for people with diabetes, screen negative at the first of > 1 episode, were combined in a purpose-built near-real time warehouse. Covariates were selected from a dataset created using mixed qualitative/quantitative methods. Markov modelling predicted progression to screen-positive (referable diabetic retinopathy) against the local cohort history. Retinopathy grade informed baseline risk and multiple imputation dealt with missing data. Acceptable intervals (6, 12, 24 months) and risk threshold (2.5%) were established with patients and professional end users. RESULTS: Data were from 11,806 people with diabetes (46,525 episodes, 388 screen-positive). Covariates with sufficient predictive value were: duration of known disease, HbA1c, age, systolic BP and total cholesterol. Corrected AUC (95% CIs) were: 6 months 0.88 (0.83, 0.93), 12 months 0.90 (0.87, 0.93) and 24 months 0.91 (0.87, 0.94). Sensitivities/specificities for a 2.5% risk were: 6 months 0.61, 0.93, 12 months 0.67, 0.90 and 24 months 0.82, 0.81. Implementing individualised RCE-based intervals would reduce the proportion of people becoming screen-positive before the allocated screening date by > 50% and the number of episodes by 30%. CONCLUSIONS/INTERPRETATION: The Liverpool RCE shows sufficient performance for a local introduction into practice before wider implementation, subject to external validation. This approach offers potential enhancements of screening in improved local applicability, targeting and cost-effectiveness. PMID- 28840259 TI - Treatment outcomes of recurrent respiratory papillomatosis : Retrospective analysis of juvenile and adult cases. AB - BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease of viral etiology which is characterized by multiple, recurrent growth of papillomas in the aerodigestive tract. MATERIALS AND METHODS: The surgical outcomes and the recurrence rates of 106 patients with RRP of the larynx were analyzed. The patients were treated at the University of Magdeburg between 1983 and 2014. The surgical outcomes of conventional and laser surgery regarding time to relapse and complications were compared. In addition, the influence of the quadrivalent vaccine Gardasil(r) on the disease was analyzed in 10 patients. RESULTS: Children with RRP had a statistically significant greater number of surgeries throughout their lifetimes compared to adult patients. There were no differences between the adult (n = 79) and juvenile (n = 27) groups in the time to relapse and the number of surgeries/year. The time to relapse and number of procedures/year were not influenced by the various surgical methods. Complications after conventional and laser surgery were not statistically different between the two groups. Serious complications and the need for a tracheotomy were only reported after conventional surgery. In the 10 patients who were immunized with Gardasil(r), a statistically significant lower number of surgeries/year after vaccination was achieved. CONCLUSION: RRP is a rare disease. Treatment requires experience and may be very difficult. The analysis of the course of the disease has shown that the treatment of choice is surgical excision with the CO2 laser combined with the quadrivalent or polyvalent vaccine. Consequent vaccination of both boys and girls has the potential to reduce the occurrence of RRP. PMID- 28840261 TI - Effect of Environmental Pollutant Mixtures on Acid DNase Activity in Mussel Mytilus galloprovincialis: Ex Situ and In Situ Study. AB - Acid DNase activity in marine organisms displays a sensitive response to pollutants. In the present study, ex situ effect of toxic seawater organic extracts (Rijeka, Vranjic, Ploce) and in situ impact of environmental factors at referent (St. Andrew) and a polluted site (ACI Rovinj) on acid DNase in the digestive gland and gills of mussels was investigated. In the digestive gland, enzyme activity was related to potential toxicity of seawater organic extracts. Seawater organic extracts showed an increase of the enzyme activity in digestive gland following exposure. In in situ study, polluted environment affected mussel's acid DNase activity in digestive gland, when compared to gills. Acid DNase activity in the digestive gland expressed significant difference between the referent and polluted site, particularly from early spring through summer. Both ex situ and in situ studies displayed more sensitive acid DNase response to the presence of toxic mixtures in the digestive gland. PMID- 28840260 TI - miR-217-casein kinase-2 cross talk regulates ERK activation in ganglioglioma. AB - : Gangliogliomas (GGs) are the most commonly diagnosed long-term epilepsy associated tumors (LEATs). Although molecular characterizations of brain tumors have identified few novel biomarkers among the LEATs, mechanisms of pathogenesis remain poorly understood. In this study, global microarray-based microRNA (miRNA) expression profile on a set of 9 GGs indicated 66 miRNAs to be differentially expressed in GG as compared to normal brain. The differences validated by qRT-PCR indicated microRNA-217 to be the most downregulated. Through insilico analysis, ERK1/2 and casein kinase (CK-2alpha) were predicted to be miR-217 regulated. As decreased miR-217 expression was concomitant with upregulated ERK1/2 and CK 2alpha levels in GG; the interplay between these molecules was investigated in primary human neural precursor cells to mimic the glioneuronal characteristics of these tumors. miR-217 over-expression-mediated decrease in pERK, CK-2alpha, and mGluR1 levels was accompanied with increase in glycogen accumulation. Importantly, increase in miR-217 levels upon CK-2alpha inhibition indicated inverse correlation between the two. Inhibition of CK-2alpha also decreased ERK and mGluR1 levels. By demonstrating, for the first time, the existence of miR-217 CK-2 cross talk and its effects on known epileptogenic factors, these findings provide a unique insight into the pathogenesis of ganglioglioma. By highlighting the role of CK-2 in affecting miR-217/ERK/mGluR1 interplay, this study suggests that targeting CK-2 may afford a novel strategy aimed at LEATs. KEY MESSAGES: Global microarray of ganglioglioma indicates downregulation of miR-217. Decreased miR-217 expression is concomitant with elevated CK-2alpha and Erk levels. Inverse correlation between miR-217 and CK-2alpha in primary human neural precursors. miR 217 agomir or CK-2alpha inhibition decreases pERK and mGluR1 levels. CK-2alpha affects miR-217/ERK/mGluR1 interplay in long-term epilepsy-associated tumors. PMID- 28840262 TI - Effect of Abiotic Factors on Degradation of Imidacloprid. AB - The role of soil moisture, light and pH on imidacloprid dissipation was investigated. A high performance liquid chromatography (HPLC) based method was developed to quantify imidacloprid present in soil with a recovery of more than 82%. Rate of dissipation of imidacloprid from soil was faster in submerged condition compared to field capacity and air dried condition. Imidacloprid dissipated non-significantly between sterile and non-sterile soils, but at field capacity, the dissipation was faster in non-sterile soil compared to sterile soil after 60 days of incubation. Similarly, under submergence, the dissipation of imidacloprid was 66.2% and 79.8% of the initial in sterile and non-sterile soils, respectively. Imidacloprid was rather stable in acidic and neutral water but was prone to photo-degradation. Therefore, imidacloprid degradation will be faster under direct sunlight and at higher soil moisture. PMID- 28840263 TI - Closed-loop glucose control in young people with type 1 diabetes during and after unannounced physical activity: a randomised controlled crossover trial. AB - AIMS/HYPOTHESIS: Hypoglycaemia during and after exercise remains a challenge. The present study evaluated the safety and efficacy of closed-loop insulin delivery during unannounced (to the closed-loop algorithm) afternoon physical activity and during the following night in young people with type 1 diabetes. METHODS: A randomised, two-arm, open-label, in-hospital, crossover clinical trial was performed at a single site in Slovenia. The order was randomly determined using an automated web-based programme with randomly permuted blocks of four. Allocation assignment was not masked. Children and adolescents with type 1 diabetes who were experienced insulin pump users were eligible for the trial. During four separate in-hospital visits, the participants performed two unannounced exercise protocols: moderate intensity (55% of [Formula: see text]) and moderate intensity with integrated high-intensity sprints (55/80% of [Formula: see text]), using the same study device either for closed-loop or open loop insulin delivery. We investigated glycaemic control during the exercise period and the following night. The closed-loop insulin delivery was applied from 15:00 h on the day of the exercise to 13:00 h on the following day. RESULTS: Between 20 January and 16 June 2016, 20 eligible participants (9 female, mean age 14.2 +/- 2.0 years, HbA1c 7.7 +/- 0.6% [60.0 +/- 6.6 mmol/mol]) were included in the trial and performed all trial-mandated activities. The median proportion of time spent in hypoglycaemia below 3.3 mmol/l was 0.00% for both treatment modalities (p = 0.7910). Use of the closed-loop insulin delivery system increased the proportion of time spent within the target glucose range of 3.9-10 mmol/l when compared with open-loop delivery: 84.1% (interquartile range 70.0-85.5) vs 68.7% (59.0-77.7), respectively (p = 0.0057), over the entire study period. This was achieved with significantly less insulin delivered via the closed-loop (p = 0.0123). CONCLUSIONS/INTERPRETATION: Closed-loop insulin delivery was safe both during and after unannounced exercise protocols in the in-hospital environment, maintaining glucose values mostly within the target range without an increased risk of hypoglycaemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT02657083 FUNDING: University Medical Centre Ljubljana, Slovenian National Research Agency, and ISPAD Research Fellowship. PMID- 28840264 TI - Reply to the letter to the editor: shortening osteotomy of the proximal radius. PMID- 28840265 TI - Benefits and harms of early rehabilitation. PMID- 28840267 TI - Erratum to: Prospective Clinical and Pharmacological Evaluation of the Delcath System's Second-Generation (GEN2) Hemofiltration System in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan. PMID- 28840266 TI - Accelerating wheat breeding for end-use quality with multi-trait genomic predictions incorporating near infrared and nuclear magnetic resonance-derived phenotypes. AB - KEY MESSAGE: Using NIR and NMR predictions of quality traits overcomes a major barrier for the application of genomic selection to accelerate improvement in grain end-use quality traits of wheat. Grain end-use quality traits are among the most important in wheat breeding. These traits are difficult to breed for, as their assays require flour quantities only obtainable late in the breeding cycle, and are expensive. These traits are therefore an ideal target for genomic selection. However, large reference populations are required for accurate genomic predictions, which are challenging to assemble for these traits for the same reasons they are challenging to breed for. Here, we use predictions of end-use quality derived from near infrared (NIR) or nuclear magnetic resonance (NMR), that require very small amounts of flour, as well as end-use quality measured by industry standard assay in a subset of accessions, in a multi-trait approach for genomic prediction. The NIR and NMR predictions were derived for 19 end-use quality traits in 398 accessions, and were then assayed in 2420 diverse wheat accessions. The accessions were grown out in multiple locations and multiple years, and were genotyped for 51208 SNP. Incorporating NIR and NMR phenotypes in the multi-trait approach increased the accuracy of genomic prediction for most quality traits. The accuracy ranged from 0 to 0.47 before the addition of the NIR/NMR data, while after these data were added, it ranged from 0 to 0.69. Genomic predictions were reasonably robust across locations and years for most traits. Using NIR and NMR predictions of quality traits overcomes a major barrier for the application of genomic selection for grain end-use quality traits in wheat breeding. PMID- 28840268 TI - No bias for developer publications and no difference between first-generation trochlear-resurfacing versus trochlear-cutting implants in 15,306 cases of patellofemoral joint arthroplasty. AB - PURPOSE AND HYPOTHESIS: The study aim was to assess the outcome of patellofemoral arthroplasty (PFA), paying particular interest to 'revisions for any reason'. The hypothesis was that there is a superior outcome of PFA reported in dependent clinical studies in contrast to independent clinical literature and that there is a superior outcome of 'trochlear-cutting' PFA in comparison with 'first generation trochlear-resurfacing' implants. METHODS: Studies on PFA from its market introduction in 1955 onwards were systematically reviewed. The revision rate, which was calculated as 'revisions per 100 component years (CY)', was evaluated in 45 studies published in indexed, peer-reviewed international scientific journals. In addition, 'first-generation trochlear-resurfacing' and 'trochlear-cutting' implants as well as dependent and independent clinical literature were analysed. Furthermore, the data of three arthroplasty registers were analysed. RESULTS: A total of 15,306 PFA were included consisting of 2266 cases in worldwide literature data and of 13,040 cases in register data. 2.22 revisions per 100 CY were observed in worldwide literature data, which corresponds to a revision rate of 22.2% after 10 years. Revision rates between 18.9 and 27% after 10 years were shown by the included three national joint registers. In the group analyses no significant differences were detected. CONCLUSIONS: This meta-analysis did not reveal significant differences in the comparison between developer over independent publications and between 'first generation-resurfacing' over 'trochlear-cutting' implants. In conclusion the data of developer publications do not seem to be biased. 'Trochlear-cutting' devices of PFA had slightly superior outcomes, but that benefit was not statistically significant. Nevertheless, we would recommend 'trochlear-cutting' devices for further use in PFA. LEVEL OF EVIDENCE: Meta-analysis of Level IV case series. PMID- 28840269 TI - Impact of task difficulty on gaze behavior in a sequential object manipulation task. AB - Task difficulty affects both gaze behavior and hand movements. Therefore, the present study aimed to investigate how task difficulty modulates gaze behaviour with respect to the balance between visually monitoring the ongoing action and prospectively collecting visual information about the future course of the ongoing action. For this, we examined sequences of reach and transport movements of water glasses that differed in task difficulty using glasses filled to different levels. Participants had to grasp water glasses with different filling levels (100, 94, 88, 82, and 76%) and transport them to a target. Subsequently, they had to grasp the next water glass and transport it to a target on the opposite side. Results showed significant differences in both gaze and movement kinematics for higher filling levels. However, there were no relevant differences between the 88, 82, and 76% filling levels. Results revealed a significant influence of task difficulty on the interaction between gaze and kinematics during transport and a strong influence of task difficulty on gaze during the release phase between different grasp-to-place movements. In summary, we found a movement and gaze pattern revealing an influence of task difficulty that was especially evident for the later phases of transport and release. PMID- 28840271 TI - Observing painful events in others leads to a temporally extended general response facilitation in the self. AB - Excitability in the motor cortex is modulated when we observe other people receiving a painful stimulus (Avenanti et al., Nat Neurosci 8(7):955-960, 2005). However, the task dependency of this modulation is not well understood, as different paradigms have yielded seemingly different results. Previous neurophysiological work employing transcranial magnetic stimulation (TMS) suggests that watching another person's hand being pierced by a needle leads to a muscle specific inhibition, assessed via motor evoked potentials. Results from previous behavioural studies suggest that overt behavioural responses are facilitated due to pain observation (Morrison et al., Cereb Cortex 17:2214-2222, 2007b; Morrison et al., Cognition 104:407-416, 2007a). There are several paradigmatic differences both between typical TMS studies and behavioural studies, and within behavioural studies themselves, that limit our overall understanding of how pain observation affects the motor system. In the current study, we combine elements of typical TMS experimental designs in a behavioural assessment of how pain observation affects overt behavioural responding. Specifically, we examined the muscle specificity, timing, and direction of modulation of motor responses due to pain observation. To assess muscle specificity, we employed pain and non-pain videos from previous TMS studies in a Go/No-Go task in which participants responded by either pressing a key with their index finger or with their foot. To assess timing, we examined response times for Go signals presented at 0 or 500 ms after the video. Results indicate that observation of another individual receiving a painful stimulus leads to a non effector specific, temporally extended response facilitation (e.g., finger and foot facilitation present at 0 and 500 ms delays), compared to observation of non pain videos. This behavioural facilitation effect differs from the typical motor inhibition seen in TMS studies, and we argue that the effects of pain observation on the motor system are state-dependent, with different states induced via task instructions. We discuss our results in light of previous work on motor responses to pain observation. PMID- 28840270 TI - Natural history of pelvic organ prolapse in symptomatic patients actively seeking treatment. AB - INTRODUCTION AND HYPOTHESIS: At our institution many symptomatic patients must wait months or years for surgery. Our aim was to determine the rates of clinically significant pelvic organ prolapse (POP) progression and identify risk factors associated with POP progression. METHODS: Data from a prospectively maintained database of POP patients evaluated between 2008 and 2013 were analyzed. Women with symptomatic POP and two or more POP-Q examinations prior to surgery were included. POP progression was defined as having any of the POP-Q points Aa, Ba, C, D, Ap or Bp above the hymen at the baseline examination and at or below the hymen at the follow-up examination. Multivariable logistic analysis was preformed and the results are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Of consecutive patients evaluated between July 2008 and June 2013, 388 met the inclusion criteria and were included. The median time between the POP-Q examinations was 9.9 months (IQR 7.8 to 13.8 months). The POP progression rate was 29.1% (95% CI 24.6-33.6%). Predictors of progression included age (OR 1.7, 95% CI 1.01-2.87) and the baseline status of points Ba, C, Bp and gH (OR 1.91, 95% CI 1.01-3.62; OR 0.53, 95% CI 0.3-0.94; OR 0.54, 95% CI 0.32-0.93; OR 2.15, 95% CI 1.13-4.1; respectively). POP-Q point correlations showed that anterior and posterior compartment points evolve with apical compartment points and gH evolves with both the anterior compartment and the apex. CONCLUSIONS: Up to 29.1% of symptomatic patients with POP showed clinically significant progression over a median follow-up of 9.9 months. The likelihood of progression was not significantly associated with time. Those >=60 years of age as well as those with point Ba >=4 cm or gH >=5 cm at baseline were at increased risk of POP progression. PMID- 28840272 TI - The utility of hepatic artery velocity in diagnosing patients with acute cholecystitis. AB - PURPOSE: To test the diagnostic performance of elevated peak systolic hepatic arterial velocity (HAv) in the diagnosis of acute cholecystitis. METHODS: 229 patients with an ultrasound (US) performed for right upper quadrant (RUQ) pain were retrospectively reviewed. 35 had cholecystectomy within 10 days of ultrasound and were included as test subjects. 47 had normal US and serology and were included as controls. Each test patient US was reviewed for the presence of gallstones, gallbladder distention, sludge, echogenic pericholecystic fat, pericholecystic fluid, gallbladder wall thickening, gallbladder wall hyperemia, and reported sonographic Murphy sign. Demographic, clinical, and hepatic artery parameters at time of original imaging were recorded. Acute cholecystitis at pathology was the primary outcome variable. RESULTS: 21 patients had acute cholecystitis and 14 had chronic cholecystitis by pathology. For patients who went to cholecystectomy, HAv >=100 cm/s to diagnose acute cholecystitis was more accurate (69%) than the original radiology report (63%), the presence of gallstones (51%), and sonographic Murphy sign (50%). Statistically significant predictors of acute cholecystitis included HAv >=100 cm/s (p = 0.008), older age (p = 0.012), and elevated WBC (p = 0.002), while gallstones (p = 0.077), hepatic artery resistive index (HARI) (p = 0.199), gallbladder distension (p = 0.252), sludge (p = 0.147), echogenic fat (p = 0.184), pericholecystic fluid (p = 0.357), wall thickening (p = 0.434), hyperemia (p = 0.999), and sonographic Murphy sign (p = 0.765) were not significantly correlated with acute cholecystitis compared to chronic cholecystitis. CONCLUSION: HAv >=100 cm/s is a useful objective parameter that may improve the performance of US in the diagnosis of acute cholecystitis. PMID- 28840274 TI - Prevalence of levator ani muscle avulsion and effect on quality of life in women with pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Levator ani muscle (LAM) avulsion is associated with pelvic organ prolapse (POP). There is limited information on the prevalence of LAM avulsion in Chinese women with POP. This study evaluated the prevalence of LAM avulsion in women presenting with POP and the effects on their quality of life (QoL). METHODS: This prospective study was conducted in a tertiary urogynecology center. Chinese women presenting with POP were recruited and completed standardized questionnaires exploring their symptoms and QoL and underwent gynecological examination to assess the stage of POP and involved compartments. Four-dimensional translabial ultrasound (US) was performed on all women, and evaluation of LAM avulsion was done offline. RESULTS: Three hundred and ninety-eight women completed the study. The prevalence of LAM avulsion was 38.9% [95% confidence interval (CI) 34.1-43.7%]; 31 (7.8%), 26 (6.5%), and 98 (24.6%) had left, right, and bilateral LAM avulsion, respectively. LAM avulsion was associated with a more advanced stage of prolapse (P < 0.005) and prolapse of stage >=II of all three compartments. Bilateral LAM avulsion was associated with a more severe stage of prolapse. More women with LAM avulsion reported bothersome symptoms of prolapse and had higher Pelvic Organ Prolapse Distress Inventory (POPDI) and Urinary Incontinence Questionnaire (UIQ) scores, implying more impairment in QoL. However, after multivariate linear regression analysis, POP stage remained a significant predictor of POPDI and UDI scores (P <= 0.006); LAM avulsion was not a predictor (P = 0.2 and 0.27, respectively). CONCLUSIONS: LAM avulsion was detected in 39% of Chinese women with POP. It was associated with a more advanced POP stage, and these women had more impairment of QoL. However, LAM avulsion was not an independent factor influencing the QoL of these women. PMID- 28840273 TI - A Kinetic Characterization of the Gill (Na+, K+)-ATPase from the Semi-terrestrial Mangrove Crab Cardisoma guanhumi Latreille, 1825 (Decapoda, Brachyura). AB - We provide a kinetic characterization of (Na+, K+)-ATPase activity in a posterior gill microsomal fraction from the semi-terrestrial mangrove crab Cardisoma guanhumi. Sucrose density gradient centrifugation reveals two distinct membrane fractions showing considerable (Na+, K+)-ATPase activity, but also containing other microsomal ATPases. The (Na+, K+)-ATPase, notably immuno-localized to the apical region of the epithelial pillar cells, and throughout the pillar cell bodies, has an M r of around 110 kDa and hydrolyzes ATP with V M = 146.8 +/- 6.3 nmol Pi min-1 mg protein-1 and K M = 0.05 +/- 0.003 mmol L-1 obeying Michaelis Menten kinetics. While stimulation by Na+ (V M = 139.4 +/- 6.9 nmol Pi min-1 mg protein-1, K M = 4.50 +/- 0.22 mmol L-1) also follows Michaelis-Menten kinetics, modulation of (Na+, K+)-ATPase activity by MgATP (V M = 136.8 +/- 6.5 nmol Pi min 1 mg protein-1, K 0.5 = 0.27 +/- 0.04 mmol L-1), K+ (V M = 140.2 +/- 7.0 nmol Pi min-1 mg protein-1, K 0.5 = 0.17 +/- 0.008 mmol L-1), and NH4+ (V M = 149.1 +/- 7.4 nmol Pi min-1 mg protein-1, K 0.5 = 0.60 +/- 0.03 mmol L-1) shows cooperative kinetics. Ouabain (K I = 52.0 +/- 2.6 umol L-1) and orthovanadate (K I = 1.0 +/- 0.05 umol L-1) inhibit total ATPase activity by around 75%. At low Mg2+ concentrations, ATP is an allosteric modulator of the enzyme. This is the first study to provide a kinetic characterization of the gill (Na+, K+)-ATPase in C. guanhumi, and will be useful in better comprehending the biochemical underpinnings of osmoregulatory ability in a semi-terrestrial mangrove crab. PMID- 28840275 TI - The effects of a two-step transfer on a visuomotor adaptation task. AB - The literature has shown robust effects of transfer-of-learning to the contralateral side and more recently transfer-of-learning effects to a new effector type on the ipsilateral side. Few studies have investigated the effects of transfer-of-learning when skills transfer to both a new effector type and the contralateral side (two-step transfer). The purpose of the current study was to investigate the effects of two-step transfer and to examine which aspects of the movement transfer and which aspects do not. Individuals practiced a 30 degrees visual rotation task with either the dominant or non-dominant limb and with either the use of the fingers and wrist or elbow and shoulder. Following practice, participants performed the task with the untrained effector type on the contralateral side. Results showed that initial direction error and trajectory length transferred from the dominant to the non-dominant side and movement time transferred from the elbow and shoulder condition to the wrist and finger conditions irrespective of which limb was used during practice. The results offer a unique perspective on the current theoretical and practical implications for transfer-of-learning and are further discussed in this paper. PMID- 28840276 TI - Two-dimensional motion analysis of dynamic knee valgus identifies female high school athletes at risk of non-contact anterior cruciate ligament injury. AB - PURPOSE: Female athletes are at greater risk of non-contact ACL injury. Three dimensional kinematic analyses have shown that at-risk female athletes have a greater knee valgus angle during drop jumping. The purpose of this study was to evaluate the relationship between knee valgus angle and non-contact ACL injury in young female athletes using coronal-plane two-dimensional (2D) kinematic analyses of single-leg landing. METHODS: Two hundred ninety-one female high school athletes newly enrolled in basketball and handball clubs were assessed. Dynamic knee valgus was analysed during single-leg drop jumps using 2D coronal images at hallux-ground contact and at maximal knee valgus. All subjects were followed up for 3 years for ACL injury. Twenty-eight (9.6%) of 291 athletes had ACL rupture, including 27 non-contact ACL injuries. The injured group of 27 knees with non contact ACL injury was compared with a control group of 27 randomly selected uninjured knees. The relationship between initial 2D movement analysis results and subsequent ACL injury was investigated. RESULTS: Dynamic knee valgus was significantly greater in the injured group compared to the control group at hallux-ground contact (2.1 +/- 2.4 vs. 0.4 +/- 2.2 cm, P = 0.006) and at maximal knee valgus (8.3 +/- 4.3 vs. 5.1 +/- 4.1 cm, P = 0.007). CONCLUSION: The results of this study confirm that dynamic knee valgus is a potential risk factor for non contact ACL injury in female high school athletes. Fully understanding the risk factors that increase dynamic knee valgus will help in designing more appropriate training and interventional strategies to prevent injuries in at-risk athletes. LEVEL OF EVIDENCE: Prognostic studies, Level II. PMID- 28840277 TI - Head and neck angiography at 70 kVp with a third-generation dual-source CT system in patients: comparison with 100 kVp. AB - PURPOSE: This study was conducted in order to evaluate the image quality of 70 kVp and 25 mL contrast medium (CM) volume for head and neck computed tomographic angiography (CTA) and assess the diagnostic accuracy for arterial stenosis. METHODS: Fifty patients were prospectively divided into two groups randomly: group A (n = 25), 70 kVp with 25 mL CM, and group B (n = 25), 100 kVp with 40 mL CM. CT attenuation values, noise, signal-to-noise ratio (SNR), and contrast-to noise ratio (CNR) of the shoulder, neck, and cerebral arteries were measured for objective image quality. Subjective image quality of the shoulder and cerebral arteries was also evaluated. For patients undergoing digital subtracted angiography (DSA), diagnostic accuracy of CTA was assessed with DSA as reference standard. RESULTS: The SNRs of the shoulder, neck, and cerebral arteries in group A were higher than those in group B (P < 0.05). The CNRs of the shoulder and neck arteries in group A were higher than those in group B (P < 0.05). There was no significant difference in subjective image quality of arteries between group A and group B (P > 0.05). The accuracy was noted as 94.0% (156/166) in group A and 97.1% (134/138) in group B for >= 50% stenosis. The accuracy of intracranial arterial stenosis was lower than that of extracranial arterial stenosis in group A. The radiation dose of group A was significantly decreased by 56% than that of group B. CONCLUSION: Head and neck CTA at 70 kVp using 25 mL CM can obtain diagnostic image quality with lower radiation dose while maintaining high accuracy in detecting the arterial stenosis compared with the 100-kVp and 40-mL CM. PMID- 28840278 TI - Determination of pesticides in sewage sludge from an agro-food industry using QuEChERS extraction followed by analysis with liquid chromatography-tandem mass spectrometry. AB - An analytical method was developed and validated for the determination of ten pesticides in sewage sludge coming from an agro-food industry. The method was based on the application of Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) extraction for solid sewage sludge and SPE extraction for sludge aqueous phase, followed by liquid chromatography (LC) coupled to hybrid quadrupole/linear ion trap mass spectrometry (QqLIT-MS). The QuEChERS method was reported 14 years ago and nowadays is mainly applied to the analysis of pesticides in food. More recent applications have been reported in other matrices as sewage sludge, but the complexity of the matrix makes necessary the optimization of the cleanup step to improve the efficiency of the analysis. With this aim, several dispersive solid-phase extraction cleanup sorbents were tested, choosing C18 + PSA as a d-SPE sorbent. The proposed method was satisfactorily validated for most compounds investigated, showing recoveries higher than 80% in most cases, with the only exception of prochloraz (71%) at low concentration level. Limits of quantification were lower than 40 ng l-1 in the aqueous phase and below 40 ng g-1 in the solid phase for the majority of the analytes. The method was applied to solid sludge and the sludge aqueous phase coming from an agro-food industry which processes fruits and vegetables. Graphical abstract Application of LC/MS/MS advanced analytical techniques for determination of pesticides contained in sewage sludge. PMID- 28840279 TI - Bufalin attenuates cancer-induced pain and bone destruction in a model of bone cancer. AB - Bufalin is a natural anti-inflammatory small molecule. Given the close relationship between inflammation and cancer, many scholars have studied the effect of bufalin on cancer in vitro, but in vivo research is still lacking. A murine bone cancer model was used in this study. We conducted pain sensitive test on mice with bone cancer, by nocifensive behavior, mechanical allodynia, and thermal hyperalgesia. Serum levels of bone loss markers with bufalin treatment were measured by ELISA. Expressions of osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) were analyzed in bufalin-treated mice by real-time PCR and Western blot. Cannabinoid 2 receptor (CB2) inverse agonist AM630 was administrated to mice with bone cancer together with bufalin. Bufalin relieved cancer-induced pain and bone destruction in the murine bone cancer model. Serum levels of bone loss markers after bufalin treatment were reduced. Bufalin upregulated OPG and downregulated RANKL. The CB2 receptor inverse agonist, AM630, reduced the pain relief of bufalin treatment in the mouse bone cancer model. This study demonstrates that bufalin relieves cancer-induced pain and bone destruction, which is mediated through the CB2 receptor. PMID- 28840281 TI - Gastroenteropancreatic neuroendocrine tumors: impact of consistent contrast agent selection on radiologists' confidence in hepatic lesion assessment on restaging MRIs. AB - PURPOSE: To evaluate the impact of contrast agent selection on radiologists' confidence in assessing liver lesions on follow-up magnetic resonance imaging (MRI) studies in patients with neuroendocrine tumors. METHODS: This Institutional Review Board-approved, retrospective study performed at a tertiary cancer center and a quaternary care urban academic hospital included all 694 follow-up abdominal MRI studies from 179 patients with gastroenteropancreatic neuroendocrine tumor performed from 01/01/2010 to 05/31/2015. Primary outcome measure was radiologists' confidence in assessing liver lesions on follow-up MRI. MRI reports were reviewed to abstract radiologists' confidence, classified as "equivocal" if any equivocal connotation (mention of limitation due to differences in contrast agent or follow-up recommendation with specific contrast agent) was present; or "unequivocal" if a precise, confident comparison to prior was documented without the use of ambiguous terms. A fellowship-trained radiologist separately evaluated 100 randomly selected reports and images to calculate interobserver agreement with the report classification (equivocal vs. unequivocal) and with the original MRI report, respectively. Chi-square test was used to compare the proportion of equivocal reports when "same" or "different" contrast agent was used for successive examinations. RESULTS: Rates of equivocal reports were higher when different contrast agents were used for successive examinations compared to examinations with same contrast agent (13.2% [21/159] vs. 1.8% [10/535]; p < 0.0001). There was very good interobserver agreement for assessment of radiologist confidence (kappa = 0.92 for report review, kappa = 0.82 for image review). CONCLUSIONS: Consistent use of contrast agent for follow up MRIs allows more confident assessment of liver lesions in patients with neuroendocrine tumors. PMID- 28840280 TI - Comparison of quantitative apparent diffusion coefficient parameters with prostate imaging reporting and data system V2 assessment for detection of clinically significant peripheral zone prostate cancer. AB - PURPOSE: To compare diagnostic performance of PI-RADSv2 with ADC parameters to identify clinically significant prostate cancer (csPC) and to determine the impact of csPC definitions on diagnostic performance of ADC and PI-RADSv2. METHODS: We retrospectively identified treatment-naive pathology-proven peripheral zone PC patients who underwent 3T prostate MRI, using high b-value diffusion-weighted imaging from 2011 to 2015. Using 3D slicer, areas of suspected tumor (T) and normal tissue (N) on ADC (b = 0, 1400) were outlined volumetrically. Mean ADCT, mean ADCN, ADCratio (ADCT/ADCN) were calculated. PI RADSv2 was assigned. Three csPC definitions were used: (A) Gleason score (GS) >= 4 + 3; (B) GS >= 3 + 4; (C) MRI-based tumor volume >0.5 cc. Performances of ADC parameters and PI-RADSv2 in identifying csPC were measured using nonparametric comparison of receiver operating characteristic curves using the area under the curve (AUC). RESULTS: Eighty five cases met eligibility requirements. Diagnostic performances (AUC) in identifying csPC using three definitions were: (A) ADCT (0.83) was higher than PI-RADSv2 (0.65, p = 0.006); (B) ADCT (0.86) was higher than ADCratio (0.68, p < 0.001), and PI-RADSv2 (0.70, p = 0.04); (C) PI-RADSv2 (0.73) performed better than ADCratio (0.56, p = 0.02). ADCT performance was higher when csPC was defined by A or B versus C (p = 0.038 and p = 0.01, respectively). ADCratio performed better when csPC was defined by A versus C (p = 0.01). PI-RADSv2 performance was not affected by csPC definition. CONCLUSIONS: When csPC was defined by GS, ADC parameters provided better csPC discrimination than PI-RADSv2, with ADCT providing best result. When csPC was defined by MRI calculated volume, PI-RADSv2 provided better discrimination than ADCratio. csPC definition did not affect PI-RADSv2 diagnostic performance. PMID- 28840282 TI - Evaluation of A Well-Known Technique with Ultrasound: Dorsal Grafting in Rhinoplasty. AB - OBJECTIVE: We aimed to evaluate the survival of a well-known camouflage technique using ultrasound imaging of the graft through the nasal dorsum and supratip. MATERIAL AND METHOD: Twenty-two patients (8 women and 14 men) who underwent primary rhinoplasty performed by the same surgeon in Isparta, Turkey, between December 2013 and February 2015, were evaluated in this retrospective study. We used the remaining pieces of harvested septal cartilage during rhinoplasty as autologous graft material and venous blood mixture as a scaffold in a Turkish Delight fashion. We used a 10- to 14-MHz broadband linear ultrasound probe (Toshiba Aplio MX ultrasound system, Toshiba Medical Systems, Tustin, California). The mean total skin thickness values through bone (nasal dorsum) and cartilage (upper lateral cartilage) were calculated for each patient. Data were recorded for statistical analysis. We evaluated the patients pre- and postoperatively on the seventh day, first month, sixth month, and just before the end of the first year using ultrasonography. We made detailed ultrasonographic images of the skin and the underskin through the bone sculpture and compared the measurements. All patients were scanned at the same time of day to exclude diurnal variation of dermal edema. Patients who presented for primary functional rhinoplasty were included in the study. RESULTS: Nasal dorsum cartilage was significantly thicker on the seventh postoperative day, but the difference was not statistically significant in the sixth month after surgery compared with baseline values. There was no statistically significant difference between preoperative measures and measures in the sixth month. The difference in supratip thickness was significantly greater on the seventh postoperative day, and there was a large difference at the first month compared with preoperative values, but this did not reach significance. There was no significant difference in supratip thickness between pre- and postoperative values at the sixth month. CONCLUSION: This method can be easily performed to reduce visual and tactual irregularities on the dorsum of the nose and can promote perfection on the dorsal esthetic line, but it is not sufficient for augmentation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28840284 TI - Nutmeg liver. AB - Nutmeg liver refers to the mottled appearance of the liver as a result of hepatic venous congestion. Radiologically, it is most appreciable on portovenous phase imaging on cross-sectional imaging. It is named after the cut appearance of the nutmeg seed. PMID- 28840283 TI - Role of point of application of perturbation in control of vertical posture. AB - The role of point of application of perturbation in the anticipatory (APAs) and compensatory (CPAs) postural control was studied. Twelve healthy participants stood on a sliding board (that was either locked and as such motionless or unlocked and as such free to move in the anterior-posterior direction). The body perturbations were applied either to the shoulders (by a pendulum impact) or the feet (by the movement of the sliding board). Electromyographic activity (EMG) of the trunk and lower extremity muscles was recorded. Latencies, integrals of EMG and muscle co-contraction (C) and reciprocal (R) activation indices were calculated and analyzed within the intervals typical for the APAs and CPAs. Higher EMG integrals were seen in the APAs phase when perturbation was applied to the shoulders. Reciprocal activation of muscles was seen in the APAs phase in the shoulders perturbation condition, while co-contraction was seen in the feet perturbation condition. Co-contraction was observed within the CPA phase in both experimental conditions. Higher C values were found in the feet perturbation condition in the CPA phase. The results suggest that different motor control strategies are employed by the central nervous system when encounter perturbations of similar magnitude but applied to different parts of the body. The outcome highlights the importance of investigation of the role of the point of application of the perturbation. PMID- 28840285 TI - Osseous spurs at the fovea capitis femoris-a frequent finding in asymptomatic volunteers. AB - OBJECTIVE: To investigate the different morphologic types of the fovea capitis femoris and the spectrum of osseous spurs/osteophytes of the fovea in asymptomatic volunteers and patients with hip osteoarthritis. MATERIAL AND METHODS: Sixty-five patients (mean age 63.6 years) with radiographically confirmed osteoarthritis of the hip and 59 asymptomatic healthy volunteers (mean age 33.9 years) underwent non-contrast MRI of the hip joint. Two radiologists independently evaluated all images. Fovea morphology (standard type, diamond type, flat type, triangular type) as well as the frequency, size and location of spurs/osteophytes of the fovea were assessed. Descriptive and inferential statistics were applied. RESULTS: The most frequent morphologic type of the fovea capitis femoris was the standard type for both asymptomatic volunteers (average 45%) and patients (average 49%). Osseous spurs were detected in 70% of the asymptomatic volunteers, and 97% of the patients had osteophytes. Spur size at all locations was significantly smaller in asymptomatic volunteers (range 1-2 mm) than osteophyte size in patients (range 1-4 mm) (p <= 0.035). In volunteers and patients, the spurs/osteophytes were most frequently located at the anterior border of the fovea capitis femoris. CONCLUSION: Smaller osseous spurs (<2 mm) at the border of the fovea capitis femoris are very common in asymptomatic volunteers and do not seem to be pathologic. PMID- 28840287 TI - Gender- and Age-Specific Relationships Between Phthalate Exposures and Obesity in Shanghai Adults. AB - Phthalate exposure has been reported to be associated with obesity (measured by body mass index [BMI]) and central obesity (measured by waist circumference [WC]). Yet, reported associations and the potential gender and age differences are inconsistent. We conducted a cross-sectional study involving 2330 participants in the fall of 2012. Urinary metabolites of ten phthalates were measured. Height, body weight, and waist circumference (WC) were measured using standardized methods. We performed logistic regression analyses to estimate the association between each urine phthalate metabolite (categorized into quartiles) and obesity and central obesity and conducted an additional, stratified analysis to explore the gender and age differences. In the overall study population, higher urinary levels of MMP, MEHHP, and MECPP were associated with increased ratios of central obesity. When stratifying by gender and central obesity, higher urinary levels of MMP, MEHHP, and MEOHP were associated with increased odds of central obesity in females, whereas MBzP was significantly associated inversely with central obesity in females. In males, it showed no significant P value for trend (P trend). When stratifying by age in females, higher urinary levels of MEHP, MEOHP, MEHHP, and MECPP were associated with increased odds of central obesity in women aged <=45 years. In females aged >45 years, it showed no significant P trend. In conclusion, we found that association between phthalates and central obesity was stronger than between phthalates and obesity; association between phthalates and central obesity was stronger in females than in males and was stronger in younger females (aged <=45 years) than in older females (aged >45 years). PMID- 28840286 TI - Adrenal Chromaffin Cells Exposed to 5-ns Pulses Require Higher Electric Fields to Porate Intracellular Membranes than the Plasma Membrane: An Experimental and Modeling Study. AB - Nanosecond-duration electric pulses (NEPs) can permeabilize the endoplasmic reticulum (ER), causing release of Ca2+ into the cytoplasm. This study used experimentation coupled with numerical modeling to understand the lack of Ca2+ mobilization from Ca2+-storing organelles in catecholamine-secreting adrenal chromaffin cells exposed to 5-ns pulses. Fluorescence imaging determined a threshold electric (E) field of 8 MV/m for mobilizing intracellular Ca2+ whereas whole-cell recordings of membrane conductance determined a threshold E-field of 3 MV/m for causing plasma membrane permeabilization. In contrast, a 2D numerical model of a chromaffin cell, which was constructed with internal structures representing a nucleus, mitochondrion, ER, and secretory granule, predicted that exposing the cell to the same 5-ns pulse electroporated the plasma and ER membranes at the same E-field amplitude, 3-4 MV/m. Agreement of the numerical simulations with the experimental results was obtained only when the ER interior conductivity was 30-fold lower than that of the cytoplasm and the ER membrane permittivity was twice that of the plasma membrane. A more realistic intracellular geometry for chromaffin cells in which structures representing multiple secretory granules and an ER showed slight differences in the thresholds necessary to porate the membranes of the secretory granules. We conclude that more sophisticated cell models together with knowledge of accurate dielectric properties are needed to understand the effects of NEPs on intracellular membranes in chromaffin cells, information that will be important for elucidating how NEPs porate organelle membranes in other cell types having a similarly complex cytoplasmic ultrastructure. PMID- 28840288 TI - Comparison of Sensory Changes Following Superomedial and Inferior Pedicle Breast Reduction. AB - BACKGROUND: More attention is focused on sensory outcomes following breast reduction operations. We conducted this prospective, non-randomized study to compare two commonly used breast reduction techniques, superomedial pedicle and inferior pedicle, regarding sensation of the nipple-areolar complex. METHODS: We prospectively assigned 60 patients with macromastia into the superomedial pedicle group (SMP group, n = 30) or the inferior pedicle (IP group, n = 30) group. Six patients who withdrew from the study and another six patients who did not attend return visits were excluded. Algometry was used to measure the sensation of breast skin, cardinal points of the areola and the nipple. Two-point discrimination was also measured on the areola. Measurements were performed before surgery, at 3 weeks, and 6 months postoperatively. RESULTS: There were 20 patients in the SMP group and 28 patients in the IP group. The mean ages of the patients were 43.2 +/- 12.7 and 45.9 +/- 10.8 years, respectively (p = 0.438). The mean BMI of the patients were 32.4 +/- 6.7 and 30.4 +/- 5.3 kg/m2, respectively (p = 0.257). The mean weights of resected tissues were 802.5 (280 2180) versus 773.7 (349.5-1425.0) g, respectively (p = 0.900). Although breast sensation did not change in the SMP group, sensation in the upper medial and lower lateral portions of breast skin was reduced in the IP group. Two-point discrimination test results did not change in either group. The amount of changes in algometry and two-point discrimination tests were similar in both groups. CONCLUSION: Both superomedial and inferior pedicle breast reduction techniques are safe and reliable in terms of sensory changes. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28840289 TI - Lead pipe sign in ulcerative colitis. PMID- 28840290 TI - Functionalization of MgZnO nanorod films and characterization by FTIR microscopic imaging. AB - Metal organic chemical vapor deposition grown films consisting of MgxZn1-xO (4% < x < 5%) nanorod arrays (MgZnOnano) were functionalized with 11-azidoundecanoic acid (1). The MgZnOnano was used instead of pure ZnO to take advantage of the etching resistance of the MgZnOnano during the binding and subsequent sensing device fabrication processes of sensor devices, while the low Mg composition level ensures that selected ZnO properties useful for sensors development, such as piezoelectricity, are retained. Compound 1 was bound to the MgZnOnano surface through the carboxylic acid group, leaving the azido group available for click chemistry and as a convenient infrared spectroscopy (IR) probe. The progress of the functionalization with 1 was characterized by FTIR microscopic imaging as a function of binding time, solvents employed, and MgZnOnano morphology. Binding of 1 was most stable in solutions of 3-methoxypropionitrile (MPN), a non-protic polar solvent. This occurred first in MUm-scale islands, then expanded to form a rather uniform layer after 22 h. Binding in alcohols resulted in less homogenous coverage, but the 1/MgZnOnano films prepared from MPN were stable upon treatment with alcohols at room temperature. The binding behavior was significantly dependent on the surface morphology of MgZnOnano. Graphical abstract The functionalization of MgZnO nanorod films with a click-ready linker and its dependence on bidning conditions and morphology has been studied by FTIR microscopic imaging using the azido group as the IR tag. PMID- 28840291 TI - Augmented-pressure distal colostogram: the most important diagnostic tool for planning definitive surgical repair of anorectal malformations in boys. AB - There is little current literature on the augmented-pressure distal colostogram, the single most important diagnostic study performed in boys with imperforate anus prior to definitive repair. Accurate understanding of the anatomy of the anorectal malformation including an associated fistulous communication between the rectum and the urogenital tract is essential for optimal surgical management. Specifically, the position of the rectal pouch and recto-urinary fistula relative to posterior sagittal structures of the perineum, especially the sacral spine, dictates the operative approach. This pictorial essay is a guide for those who encounter such children with relative infrequency to become more comfortable with the technique. We report how to perform this radiologic exam and the potential pitfalls from our experience of performing the technique in our large pediatric colorectal practice. PMID- 28840292 TI - A novel heterozygous ALAS2 mutation in a female with macrocytic sideroblastic anemia resembling myelodysplastic syndrome with ring sideroblasts: a case report and literature review. PMID- 28840293 TI - Hepatocellular carcinoma imaging systems: why they exist, how they have evolved, and how they differ. AB - Over the past 16 years, several scientific organizations have proposed systems that incorporate imaging for surveillance, diagnosis, staging, treatment, and monitoring of treatment response of hepatocellular carcinoma (HCC). These systems are needed to standardize the acquisition, interpretation, and reporting of liver imaging examinations; help differentiate benign from malignant observations; improve consistency between radiologists; and provide guidance for management of HCC. This review article discusses the historical evolution of HCC imaging systems. We indicate the features differentiating these systems, including target population, screening and surveillance algorithm, diagnostic imaging modalities, diagnostic scope, expertise and technical requirements, terminology, major and ancillary imaging features, staging and transplant eligibility, and assessment of treatment response. We highlight the potential benefits of unifying the systems, which we anticipate will enable sharing, pooling, and meta-analysis of data; facilitate multi-center trials; and accelerate dissemination of knowledge. PMID- 28840294 TI - Prediction of successful shock wave lithotripsy with CT: a phantom study using texture analysis. AB - OBJECTIVE: To apply texture analysis (TA) in computed tomography (CT) of urinary stones and to correlate TA findings with the number of required shockwaves for successful shock wave lithotripsy (SWL). MATERIALS AND METHODS: CT was performed on thirty-four urinary stones in an in vitro setting. Urinary stones underwent SWL and the number of required shockwaves for disintegration was recorded. TA was performed after post-processing for pixel spacing and image normalization. Feature selection and dimension reduction were performed according to inter- and intrareader reproducibility and by evaluating the predictive ability of the number of shock waves with the degree of redundancy between TA features. Three regression models were tested: (1) linear regression with elimination of colinear attributes (2), sequential minimal optimization regression (SMOreg) employing machine learning, and (3) simple linear regression model of a single TA feature with lowest squared error. RESULTS: Highest correlations with the absolute number of required SWL shockwaves were found for the linear regression model (r = 0.55, p = 0.005) using two weighted TA features: Histogram 10th Percentile, and Gray Level Co-Occurrence Matrix (GLCM) S(3, 3) SumAverg. Using the median number of required shockwaves (n = 72) as a threshold, receiver-operating characteristic analysis showed largest area-under-the-curve values for the SMOreg model (AUC = 0.84, r = 0.51, p < 0.001) using four weighted TA features: Histogram 10th Percentile, and GLCM S(1, 1) InvDfMom, S(3, 3) SumAverg, and S(4, -4) SumVarnc. CONCLUSION: Our in vitro study illustrates the proof-of-principle of TA of urinary stone CT images for predicting the success of stone disintegration with SWL. PMID- 28840295 TI - Liver Function, Quantified by LiMAx Test, After Major Abdominal Surgery. Comparison Between Open and Laparoscopic Approach. AB - INTRODUCTION: Major abdominal surgery may lead to a systemic inflammatory response (SIRS) with a risk of organ failure. One possible trigger for a postoperative hepatic dysfunction is an altered hepatic blood flow during SIRS, resulting in a decreased oxygen delivery. This pilot study investigated the role of liver dysfunction measured by the LiMAx test after major abdominal surgery, focussing on open and laparoscopic surgical approaches. METHODS: We prospectively investigated 25 patients (7 females and 18 males, age range 55-72 years) scheduled for upper abdominal surgery. The LiMAx test, ICG-PDR and duplex sonography were carried out preoperatively, followed by postoperative days (PODs) 1, 3, 5 and 10. Laboratory parameters and clinical parameters were measured daily. Clinical outcome parameters were examined at the end of treatment. The population was divided into group A (laparotomy) versus group B (laparoscopy). RESULTS: LiMAx values decreased significantly on POD 1 (290 ug/kg/h, P < 0.001), followed by a significant increase at POD 3 (348 ug/kg/h, P = 0.013). Only INR showed a significant increase on POD 1 (1.26, P < 0.001). Duplex sonography and ICG-PDR revealed a hyper-dynamic liver blood flow. No differences between group A and B were found. CONCLUSIONS: Hepatic dysfunction after major abdominal surgery is evident and underestimated. The LiMAx test provides an adequate tool to determine liver dysfunction. Open and laparoscopic approaches appeared similar in terms of liver dysfunction and postoperative SIRS. PMID- 28840296 TI - Stability of two versus three peripheral pegs of the glenoid component in modern total shoulder arthroplasty. AB - PURPOSE: In total shoulder arthroplasty (TSA), the optimum number of peripheral pegs required for stability in the glenoid component is unknown. This study compared the stability of two versus three peripheral pegs in cemented glenoid components possessing a central press-fit peg. METHODS: Six unmodified glenoid components with three peripheral pegs, a large, central press-fit peg and six modified glenoid components with one inferior peripheral peg sharply removed were cemented into bone substitute polyurethane blocks. A modified rocking-horse test was completed by comparing superior- and inferior-edge displacement before and after 100,000 vertical motion cycles. Then, a torsional failure test applied 2 N axial load, followed by a rotational force to the glenoid component at 0.5 degrees /s until failure. RESULTS: Modified rocking-horse testing showed no statistically significant edge displacement at the superior or inferior aspect of the glenoid component before or after testing. During torsional testing, peak torque and degrees of rotation at failure also showed no significant difference. CONCLUSION: Two peripheral pegs offer equivalent stability as three peripheral pegs, as assessed by cyclic rocking and rotational failure testing. Fewer peripheral pegs during glenoid component implantation may lead to less dissection, less strain on soft tissues and decreased operative time. PMID- 28840297 TI - Therapeutic antibodies against cancer stem cells: a promising approach. AB - Monoclonal antibodies have been extensively used to treat malignancy along with routine chemotherapeutic drugs. Chemotherapy for metastatic cancer has not been successful in securing long-term remission of disease. This is in part due to the resistance of cancer cells to drugs. One aspect of the drug resistance is the inability of conventional drugs to eliminate cancer stem cells (CSCs) which often constitute less than 1-2% of the whole tumor. In some tumor types, it is possible to identify these cells using surface markers. Monoclonal antibodies targeting these CSCs are an attractive option for a new therapeutic approach. Although administering antibodies has not been effective, when combined with chemotherapy they have proved synergistic. This review highlights the potential of improving treatment efficacy using functional antibodies against CSCs, which could be combined with chemotherapy in the future. PMID- 28840298 TI - Therapy-related acute myeloid leukemia with inv(16) after successful therapy for de novo acute myeloid leukemia with t(8;21). PMID- 28840299 TI - Antimicrobial and Antioxidant Activities of the Extract and Fractions of Tetradenia riparia (Hochst.) Codd (Lamiaceae) Leaves from Brazil. AB - Tetradenia riparia (Lamiaceae) is native to Central Africa popularly known as myrrh, used in folk medicine to treat various diseases like malaria, gastroenteritis, and tropical skin disease. This research was to evaluate the antioxidant and antibacterial activities of the crude extract (CE) and fractions (FR) of the T. riparia by classical chromatography. The CE of T. riparia leaves was submitted to column chromatographic fractionation to obtain four fractions of the interest, which were identified by nuclear magnetic resonance and gas chromatograph coupled to mass spectrum: FR-I (abieta-7,9(11)-dien-13-beta-ol), FR II (Ibozol), FR-III (8 (14), 15-sandaracopimaradiene-2alpha, 18-diol and 8 (14), 15-sandaracopimaradiene-7alpha, 18-diol), and FR-IV (Astragalin, Boronolide and Luteolin). Total phenol content of CE and FR were measured, and antioxidant action by methods of DPPH (2,2-diphenyl-1-picrylhydrazyl), beta-carotene/linoleic acid system, and ferric reducing/antioxidant power (FRAP) and the antibacterial activity was evaluated by the broth microdilution method with the determination of the minimum inhibitory concentration (MIC). The FR-IV presented antioxidant potential with 181.67 MUg gallic acid/mg, IC50 of 0.61 MUg/mL by DPPH method, 55.61% oxidation protection by beta-carotene/linoleic acid system and 4.59 uM ferrous sulfate/mg of sample by FRAP, and the FR-I showed higher antibacterial potential on the strain Staphylococcus aureus with MIC 0.98 MUg/mL, Enterococcus faecalis and Bacillus cereus with MIC 31.2 MUg/mL. Thus, the fractionation of CE was extremely important to detect fractions with potential activities, and investigations are necessary regarding the mechanism of action and action in vivo. PMID- 28840300 TI - Optimal Positioning of the Nipple-Areola Complex in Men Using the Mohrenheim Estimated-Tangential-Tracking-Line (METT-Line): An Intuitive Approach. PMID- 28840301 TI - Does Kinesiotaping improve pain and functionality in patients with newly diagnosed lateral epicondylitis? AB - PURPOSE: This study aimed to compare the short-term effects of kinesiotaping and extracorporeal shock wave therapy (ESWT) along with physiotherapy on pain, functionality, and grip strength in patients with newly diagnosed lateral epicondylitis undergoing rehabilitation. METHODS: Forty-five voluntary patients (mean age 48 years) were randomly assigned to three groups. Patients in all groups received physiotherapy consisting of a cold pack and transcutaneous electrical nerve stimulation five times per week for a total of 15 sessions and a home exercise programme including stretching and eccentric strength exercises. In the second group, patients received kinesiotaping 5 days a week for 3 weeks. In the third group, ESWT was applied three times for 3 weeks. Patients were assessed by visual analogue scale for pain intensity, pain-free grip strength using a hand dynamometer, Cyriax Resisted Muscle Test, and Patient-Rated Tennis Elbow Evaluation Scale. All measurements were collected at baseline and after treatment. RESULTS: There were no significant differences in the demographic characteristics of the patients in all groups at baseline. Intra-group analysis revealed that pain intensity decreased, whereas maximum grip strength and functionality increased in all groups at the end of the treatment (p < 0.05). Inter-group analysis revealed that the kinesiotaping group yielded better results in decreasing pain intensity than the other groups (p < 0.05). The kinesiotaping group (p < 0.001) and ESWT group (p = 0.002) yielded better results in improving functionality than the physiotherapy group. There were significant differences in recovering pain-free grip strength in the kinesiotaping group (p < 0.05). CONCLUSION: Kinesiotaping was found to be effective for decreasing pain intensity, recovering grip strength, and improving functionality in patients with lateral epicondylitis undergoing rehabilitation. LEVEL OF EVIDENCE: Therapeutic study, Level II. PMID- 28840303 TI - Pancreatic cancer screening. AB - PURPOSE: This article reviews the current evidence surrounding pancreatic cancer screening. The current targets of screening include identification of early pancreatic cancer, as well as the two most important precursor lesions; intraductal papillary mucinous neoplasm and high grade pancreatic intraepithelial neoplasia. Given the relatively low incidence of pancreatic adenocarcinoma in the general population, patients with elevated risk based on family history or an underlying genetic syndrome are felt to be the most appropriate patients to undergo screening. METHODS: An extensive review of the literature was performed and the major findings of the available literature regarding pancreatic screening are reviewed in detail. RESULTS: Several prospective trials have evaluated pancreatic cancer screening in high-risk groups. The results of those trials are summarized in this article. Current consensus guidelines and recommendations from the International Cancer of the Pancreas Screening Consortium Summit are also discussed. CONCLUSIONS: The exact benefit of pancreatic cancer screening remains unclear at this time, but emerging evidence suggests that there is a window of opportunity to detect precursor lesions and early pancreatic adenocarcinomas in high-risk patient populations. Better understanding of the pathway of carcinogenesis will hopefully improve our ability to detect early, resectable pancreatic carcinomas, and provide a mortality benefit to patients at significantly elevated risk of pancreatic adenocarcinoma. PMID- 28840302 TI - Comparison of 18F-FDG PET/MRI and MRI for pre-therapeutic tumor staging of patients with primary cancer of the uterine cervix. AB - PURPOSE: The aim of the present study was to assess and compare the diagnostic performance of integrated PET/MRI and MRI alone for local tumor evaluation and whole-body tumor staging of primary cervical cancers. In addition, the corresponding impact on further patient management of the two imaging modalities was assessed. METHODS: A total of 53 consecutive patients with histopathological verification of a primary cervical cancer were prospectively enrolled for a whole body 18F-FDG PET/MRI examination. Two experienced physicians analyzed the MRI data, in consensus, followed by a second reading session of the PET/MRI datasets. The readers were asked to perform a dedicated TNM staging in accordance with the 7th edition of the AJCC staging manual. Subsequently, the results of MRI and PET/MRI were discussed in a simulated interdisciplinary tumor board and therapeutic decisions based on both imaging modalities were recorded. Results from histopathology and cross-sectional imaging follow-up served as the reference standard. RESULTS: PET/MRI allowed for a correct determination of the T stage in 45/53 (85%) cases, while MRI alone enabled a correct identification of the tumor stage in 46/53 (87%) cases. In 24 of the 53 patients, lymph node metastases were present. For the detection of nodal-positive patients, sensitivity, specificity and accuracy of PET/MRI were 83%, 90% and 87%, respectively. The respective values for MRI alone were 71%, 83% and 77%. In addition, PET/MRI showed higher values for the detection of distant metastases than MRI alone (sensitivity: 87% vs. 67%, specificity: 92% vs. 90%, diagnostic accuracy: 91% vs. 83%). Among the patients with discrepant staging results in the two imaging modalities, PET/MRI enabled correct treatment recommendations for a higher number (n = 9) of patients than MRI alone (n = 3). CONCLUSION: The present results demonstrate the successful application of integrated PET/MRI imaging for whole-body tumor staging of cervical cancer patients, enabling improved treatment planning when compared to MRI alone. PMID- 28840304 TI - MybA, a new player driving survival of the conidium of the human pathogen Aspergillus fumigatus. AB - Aspergillus fumigatus is an opportunistic human pathogen that causes various complications in patients with a weakened immune system functions. Asexual spores of A. fumigatus are responsible for initiation of aspergillosis. Long-term viability and proper germination of dormant conidia depend on trehalose accumulation, which protect the spores against thermal and oxidative stress. A putative Myb transcription factor, MybA has been recently found to be responsible for a variety of physiological and molecular roles ranging from conidiation, spore viability, trehalose accumulation, cell wall integrity and protection against reactive oxygen species. In this perspective review, we discuss the recent findings of MybA and its overlapping functions with the other regulators of conidia viability and trehalose accumulation. Therefore, the aim of this perspective is to raise interesting and stimulating questions on the molecular functions of MybA in conidiation and trehalose biogenesis and to question its genetic and physical interactions with the other regulators of conidial viability. PMID- 28840305 TI - Subtypes of endothelial progenitor cells affect healing of segmental bone defects differently. AB - PURPOSE: Treating fracture nonunion with endothelial progenitor cells (EPCs) is a promising approach. Nevertheless, the effect of different EPC-related cell populations remains unclear. In this study, we compared the therapeutic potential of early (E-EPCs) and late EPCs (L-EPCs). METHODS: Male Fischer 344 rats were used for cell isolation and in vivo experiments. Bone marrow-derived E-EPCs and L EPCs were kept in culture for seven to ten days and four weeks, respectively. For each treatment group, we seeded one million cells on a gelatin scaffold before implantation in a segmental defect created in a rat femur; control animals received a cell-free scaffold. Bone healing was monitored via radiographs for up to ten weeks after surgery. In vitro, secretion of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2 was quantified by ELISA for both cell populations. Tube formation assays were also performed. RESULTS: Final radiographs showed complete (four out of five rats) or partial (one out of five rats) union with E-EPC treatment. In contrast, complete healing was achieved in only one of five animals after L-EPC implantation, while control treatment resulted in nonunion in all animals. In vitro, E-EPCs released more VEGF, but less BMP-2 than L-EPCs. In addition, L-EPCs formed longer and more mature tubules on basement membrane matrix than E-EPCs. However, co-culture with primary osteoblasts stimulated tubulogenesis of E-EPCs while inhibiting that of L-EPCs. CONCLUSIONS: We demonstrated that bone marrow-derived E-EPCs are a better alternative than L-EPCs for treatment of nonunion. We hypothesize that the expression profile of E-EPCs and their adaptation to the local environment contribute to superior bone healing. PMID- 28840306 TI - Role of magnetic resonance urography in pediatric renal fusion anomalies. AB - Renal fusion is on a spectrum of congenital abnormalities that occur due to disruption of the migration process of the embryonic kidneys from the pelvis to the retroperitoneal renal fossae. Clinically, renal fusion anomalies are often found incidentally and associated with increased risk for complications, such as urinary tract obstruction, infection and urolithiasis. These anomalies are most commonly imaged using ultrasound for anatomical definition and less frequently using renal scintigraphy to quantify differential renal function and assess urinary tract drainage. Functional magnetic resonance urography (fMRU) is an advanced imaging technique that combines the excellent soft-tissue contrast of conventional magnetic resonance (MR) images with the quantitative assessment based on contrast medium uptake and excretion kinetics to provide information on renal function and drainage. fMRU has been shown to be clinically useful in evaluating a number of urological conditions. A highly sensitive and radiation free imaging modality, fMRU can provide detailed morphological and functional information that can facilitate conservative and/or surgical management of children with renal fusion anomalies. This paper reviews the embryological basis of the different types of renal fusion anomalies, their imaging appearances at fMRU, complications associated with fusion anomalies, and the important role of fMRU in diagnosing and managing children with these anomalies. PMID- 28840307 TI - Quantification of perfusion reduction by using 2D-perfusion angiography following transarterial chemoembolization with drug-eluting beads. AB - PURPOSE: To analyze the feasibility of 2D-perfusion angiography (2D-PA) for the quantification of perfusion reduction following transarterial chemoembolization with drug-eluting beads (DEB-TACE). METHODS: Overall, 24 DEB-TACE procedures in 19 patients were included. To quantify changes in tumor perfusion following DEB TACE using 2D-PA, the acquired digital subtraction angiography (DSA) series were post-processed. A reference region-of-interest (ROI) in a main hepatic artery and two, distal target ROIs in embolized tumor tissue and in non-target liver parenchyma were placed in corresponding areas on DSA pre- and post-DEB-TACE. The time to peak (TTP), peak density (PD), and the area under the curve (AUC) were assessed and the ratios reference ROI/target ROIs were calculated. RESULTS: In the embolized tumor, the 2D-PA ratios changed significantly (p < 0.05) after DEB TACE, whereas no significant change was observed for non-target liver parenchyma (p > 0.05). PDtumor/PDinflow differed significantly to PDparenchyma/PDinflow pre DEB-TACE (p < 0.0001), likewise AUCtumor/AUCinflow to AUCparenchyma/AUCinflow (p < 0.0001) with higher values in tumor tissue. The post-DEB-TACE ratios of AUC decreased significantly in the tumor tissue compared to the non-target liver parenchyma (p < 0.05). CONCLUSION: 2D-PA offers an objective approach to quantify the immediate perfusion reduction of embolized tumor tissue following DEB-TACE and may therefore be used to monitor peri-interventional stasis and to quantify technical success. PMID- 28840308 TI - Frequency of bilateral cervical metastases in hypopharyngeal squamous cell carcinoma: a retrospective analysis of 203 cases after bilateral neck dissection. AB - The decision whether to perform an elective neck dissection in patients with head and neck squamous cell carcinoma and clinically negative lymph nodes (cN0) is made based on the probability of micrometastases in the neck for the given subsite and size of the primary. A retrospective chart review was performed of 203 patients with hypopharyngeal SCC who received a bilateral neck dissection. The frequency of histologically unveiled bilateral neck metastases was determined. A high frequency of contralateral metastases above 20% was detected for all carcinomas affecting the midline and those involving the medial wall of the pyriform sinus except of T1-stages (13%) and a low frequency for laterally located primaries (3%). Ipsilateral nodal status predicted contralateral neck metastases. Bilateral neck dissection should be recommended for primaries affecting the midline and T2-4 tumors involving the medial wall of the pyriform sinus. PMID- 28840309 TI - Impact of hybrid molecular imaging in retroperitoneal fibrosis: a systematic review. AB - The aim of this article was to critically assess the usefulness of hybrid molecular imaging (FDG PET/CT and FDG PET/MR) procedures in the evaluation of inflammatory activity in retroperitoneal fibrosis (RPF). A systematic review of the literature was performed using PubMed without timeline restriction and using the following keywords: retroperitoneal fibrosis, disease activity, diagnostic techniques, PET/CT, PET/MR. We evaluated full text articles written in the English language. Case reports, review articles or editorials and articles not in the field of interest of this review were excluded. Nine articles comprising a total of 186 patients met the inclusion criteria and were included and described in this systematic review. The new hybrid molecular imaging methods give promising results in the evaluation of the activity of the disease, quantification and prediction of therapeutic response and in tailoring medical therapy in RPF. FDG PET/CT can be a valuable tool in detecting disease activity, particularly in asymptomatic patients with RPF with acute phase reactant increase. Hybrid imaging can predict therapy response outcome and the best time for stent removal. Although PET/MR has potential advantage in small lesions and has reduced radiation exposure in comparison to PET/CT, PET quantification parameters have potentially higher diagnostic value over MR parameters in the evaluation of RPF. Acute phase reactants alone may not be reliable for the management and follow-up assessment of the disease. Hybrid imaging in RFP could be more comfortable, more accurate, with less radiation burden than different separate imaging studies acquired at different points in time. PMID- 28840310 TI - Topical cis-urocanic acid prevents ocular surface irritation in both IgE independent and -mediated rat model. AB - PURPOSE: Our purpose was to investigate the effect of locally administered cis urocanic (cis-UCA) in two experimental models of allergic conjunctivitis. METHODS: The compound 48/80 (C48/80)-induced ocular irritation model (IgE independent) and the ovalbumin (OA)-induced ocular allergy model (IgE-mediated) were used to test and compare the effect of cis-UCA on dexamethasone, ketotifen and olopatadine. In the C48/80 model, clinical severity scoring from photographs, immunohistochemical analysis of nuclear Ki-67 antigen to quantify actively proliferating epithelial cells and of caspase-3 enzyme to identify apoptotic activity in the conjunctival tissue were used. In the OA model, an Evans Blue stain concentration of conjunctival tissue was used to evaluate vascular leakage due to allergic reaction. RESULTS: The cis-UCA was well tolerated and effective in both the IgE-independent and -mediated rat models. Treatment with C48/80 caused conjunctival hyperaemia, which was significantly inhibited by ketotifen at the 6 h time point (p = 0.014) and by dexamethasone and cis-UCA 0.5% at 12 (p = 0.004) and 24 (p = 0.004) hour time points. In a comparison between the active drug treatments, only ketotifen showed a significant difference (p = 0.023) to cis-UCA treatment at the 1 h time point, otherwise there were no statistically significant differences between the active drugs. Ketotifen, dexamethasone and cis-UCA 0.5% significantly inhibited the C48/80-induced nuclear accumulation of Ki-67, without differences between the active treatment groups. In the OA model, cis-UCA 0.5% did not inhibit the vascular leakage of conjunctiva, whereas cis-UCA 2.5% of was at least equally effective compared to olopatadine, abolishing the allergic vascular leakage response almost completely. CONCLUSIONS: The present findings in the two AC models suggest that cis-UCA might have anti-allergic potency both in immediate and delayed-type allergic reactions in the eye. PMID- 28840311 TI - Molecular interaction study of flavonoids with human serum albumin using native mass spectrometry and molecular modeling. AB - Noncovalent interactions between proteins and small-molecule ligands widely exist in biological bodies and play significant roles in many physiological and pathological processes. Native mass spectrometry (MS) has emerged as a new powerful tool to study noncovalent interactions by directly analyzing the ligand protein complexes. In this work, an ultrahigh-resolution native MS method based on a 15-T SolariX XR Fourier transform ion cyclotron resonance mass spectrometer was firstly used to investigate the interaction between human serum albumin (HSA) and flavonoids. Various flavonoids with similar structure were selected to unravel the relationship between the structure of flavonoids and their binding affinity for HSA. It was found that the position of the hydroxyl groups and double bond of flavonoids could influence the noncovalent interaction. Through a competitive experiment between HSA binding site markers and apigenin, the subdomain IIA (site 1) of HSA was determined as the binding site for flavonoids. Moreover, a cooperative allosteric interaction between apigenin and ibuprofen was found from their different HSA binding sites, which was further verified by circular dichroism spectroscopy and molecular docking studies. These results show that native MS is a useful tool to investigate the molecular interaction between a protein and its ligands. Graphical abstract Unravel the relationship between the structure of flavonoids and their binding affinity to HSA by native MS. PMID- 28840312 TI - [The telemedical service centre as an essential element of the conceptual approach for telemonitoring of cardiac patients : Requirements on the service, quality, and technical realization of telemonitoring]. AB - Telemonitoring as part of a treatment strategy supports and facilitates the monitoring, disease management and education of patients with heart failure and cardiac arrhythmias. Therefore, telemonitoring affects quality and success of the therapy. Thus, meeting the needs of the patients and of the involved health care professionals is important for the success of the telemonitoring service. Moreover, a high quality of the service has to be ensured. The following article describes several configuration options for telemonitoring services considering technical as well as quality- and service-related aspects. PMID- 28840314 TI - What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG-IgG positive? A cross sectional study of 132 patients. AB - Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been described in patients with neuromyelitis optica spectrum disorders (NMOSD) without aquaporin-4 antibodies (AQP4-IgG). We aimed to identify the proportion of AQP4 IgG-negative NMOSD patients who are seropositive for MOG-IgG. In a cross sectional study, we reviewed all patients seen in the National NMO clinic over the last 4 years (after the availability of MOG-IgG testing), including clinical information, MRI, and antibody tests. 261 unique patients were identified. 132 cases satisfied the 2015 NMOSD diagnostic criteria. Of these, 96 (73%) were AQP4 IgG positive and 36 (27%) were AQP4-IgG negative. These 36 patients were tested for MOG-IgG and 15/36 (42%) tested positive. 20% (25/125) of the patients who did not satisfy NMOSD criteria had MOG-IgG. Approximately half of seronegative NMOSD is MOG-Ig seropositive and one in five of non-NMOSD/non-MS demyelination is MOG IgG positive. Since MOG-associated demyelinating disease is likely different from AQP4-IgG disease in terms of underlying disease mechanisms, relapse risk and possibly treatment, testing for MOG-IgG in patients with AQP4-IgG-negative NMOSD and other non-MS demyelination may have significant implications to management and clinical trials. PMID- 28840315 TI - Right bundle branch block and anterior wall ST elevation myocardial infarction. AB - We report the case of an acute anterior wall ST elevation myocardial infarction with new left anterior fascicular block and pre-existing right bundle branch block. Due to a wide right bundle branch block, no ST segment elevation was visible in lead V1. The left anterior fascicular block was caused by proximal occlusion of the left artery descending and disappeared after acute revascularization. However, also the R' of the right bundle branch block became significantly shorter after revascularization, dismanteling a minor ST segment elevation. The ST elevation in lead V1 in anterior wall infarction and right bundle branch block may merge with the R' and cause a further QRS widening as an "equivalent" to the ST elevation. PMID- 28840313 TI - Reliability and Validity of the MD Anderson Dysphagia Inventory Among Japanese Patients. AB - This study aimed to validate the Japanese version of a dysphagia-specific quality of life questionnaire, the MD Anderson Dysphagia Inventory (MDADI-J), and to verify trends between MDADI-J and Functional Oral Intake Scale (FOIS) scores. The original 20 MDADI items were translated using a forward-backward method following accepted cultural adaptation guidelines. Seventy-two patients with a history of head and neck cancer treatment completed the MDADI-J between October 2015 and August 2016. Concurrent validity was determined by correlations with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35 (EORTC QLQ-H&N35) instruments. Discriminant validity was examined using cancer stage grouping between stages I-II and III-IV. Additionally, trends between the FOIS and the MDADI-J total scores were analyzed using a trend test. The Cronbach's alpha coefficient of the MDADI-J total score was 0.92, indicating high internal consistency. The average inter-item correlation coefficients ranged from 0.39 to 0.49. ICC, an indicator of test-retest reliability, was 0.84 for the total score, and 0.58 to 0.81 for individual subscales. The total score and all subscales were significantly associated with the scores for each factor of the EORTC QLQ-C30 and EORTC QLQ-H&N35. The total score and all subscales were significantly different between clinical tumor stages I-II and III-IV. The total scores all increased with the progress of the FOIS. In conclusion, this study validated the Japanese version of the MDADI and showed that as FOIS scores deteriorate, MDADI-J scores tend to constantly decrease. PMID- 28840317 TI - Impact of visual-spatial ability on laparoscopic camera navigation training. AB - BACKGROUND: Technical limitations of minimally invasive surgery challenge both surgeons and camera assistants. Current research indicates that visual-spatial ability (VSA) has impact on learning of laparoscopic camera navigation (LCN). However, it remains unclear if complexity of LCN tasks influences the impact of VSA. The aim of this study was to examine the influence of VSA on LCN training within tasks of different complexity levels. METHODS: The present study was conducted as a monocentric prospective trial. VSA was assessed with a cube comparison test before participants underwent LCN training. LCN training consisted of three tasks with increasing complexity. Each task was performed four times and performance was assessed each time. Correlations and multivariate regression analysis were used to assess the influence of VSA on LCN skills. RESULTS: Seventy-one participants were included (35 males). Significant performance improvement and faster completion times were observed from the first to fourth trial of all three LCN training tasks. Significant positive correlations between VSA and performance on LCN task 3 were found (performance: r s = 0.47; p < 0.001, time: r s = -0.43; p < 0.001). Multivariate regression revealed that higher VSA resulted in greater reduction of time between the first trials of LCN training task 3 (B = -1.67, p = 0.031). CONCLUSION: In the present study, all trainees improved LCN performance during the training. VSA seems to have impact on LCN performance and training progress particularly for complex LCN tasks. The relation of VSA and LCN performance was stronger for less experienced participants and in the beginning of the learning phase. PMID- 28840316 TI - Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, which goes along with increased risk for sudden cardiac death (SCD). Despite the knowledge about the different causal genes, the relationship between individual genotypes and phenotypes is incomplete. METHODS AND RESULTS: We retrieved PubMed/Medline literatures on genotype-phenotype associations in patients with HCM and mutations in MYBPC3, MYH7, TNNT2, and TNNI3. Altogether, 51 studies with 7675 HCM patients were included in our meta analysis. The average frequency of mutations in MYBPC3 (20%) and MYH7 (14%) was higher than TNNT2 and TNNI3 (2% each). The mean age of HCM onset for MYH7 mutation positive patients was the beginning of the fourth decade, significantly earlier than patients without sarcomeric mutations. A high male proportion was observed in TNNT2 (69%), MYBPC3 (62%) and mutation negative group (64%). Cardiac conduction disease, ventricular arrhythmia and heart transplantation (HTx) rate were higher in HCM patients with MYH7 mutations in comparison to MYBPC3 (p < 0.05). Furthermore, SCD was significantly higher in patients with sarcomeric mutations (p < 0.01). CONCLUSION: A pooled dataset and a comprehensive genotype phenotype analysis show that the age at disease onset of HCM patients with MYH7 is earlier and leads to a more severe phenotype than in patient without such mutations. Furthermore, patients with sarcomeric mutations are more susceptible to SCD. The present study further supports the clinical interpretation of sarcomeric mutations in HCM patients. PMID- 28840318 TI - How innate immunity proteins kill bacteria and why they are not prone to resistance. AB - Recent advances on antibacterial activity of peptidoglycan recognition proteins (PGRPs) offer some insight into how innate immunity has retained its antimicrobial effectiveness for millions of years with no frequent emergence of resistant strains. First, PGRP can bind to multiple components of bacterial envelope (peptidoglycan, lipoteichoic acid, and lipopolysaccharide). Second, PGRP simultaneously induces oxidative, thiol, and metal stress responses in bacteria, which individually are bacteriostatic, but in combination are bactericidal. Third, PGRP induces oxidative, thiol, and metal stress responses in bacteria through three independent pathways. Fourth, antibacterial effects of PGRP are enhanced by other innate immune responses. Thus, emergence of PGRP resistance is prevented by bacteriostatic effect and independence of each PGRP-induced stress response, as PGRP resistance would require simultaneous acquisition of three separate mechanisms disabling the induction of all three stress responses. By contrast, each antibiotic has one primary target and one primary antibacterial mechanism, and for this reason resistance to antibiotics can be generated by inhibition of this primary mechanism. Manipulating bacterial metabolic responses can enhance bacterial killing by antibiotics and elimination of antibiotic tolerant bacteria, but such manipulations do not overcome genetically encoded antibiotic resistance. Pathogens cause infections by evading, inhibiting, or subverting host immune responses. PMID- 28840319 TI - Southwick angle measurements and SCFE slip severity classifications are affected by frog-lateral positioning. AB - OBJECTIVE: Slipped capital femoral epiphysis (SCFE) is a hip disorder where the femoral head slips relative to the neck at the physis. Appropriate treatment of SCFE depends on the severity of the slip, commonly categorised using the Southwick (SW) angle. The SW angle is measured in the frog-lateral leg position, which can be painful and potentially unattainable for patients. The purpose of this study is to determine how errors in frog-lateral radiograph positioning affect measured SW angles and slip classifications. METHODS: Models of SCFE hips were produced from one CT scan of a normal hip; 360 deformities were created. SW angles were measured from a simulated frog-lateral position. Femoral lateral head neck angles (LHNA; equivalent to SW in incorrect frog-lateral plane) were measured over a range of 837 incorrect frog-lateral leg positions with positioning errors in flexion and/or internal/external rotation. RESULTS: Seventy six per cent of all imaging position-deformity combinations had error in the reported angle (>1 degrees difference between LHNA and SW). Of those, 70% had <5 degrees , 24% had 5 degrees to 10 degrees , and 6% had >10 degrees of error from the actual SW angle. Three per cent of LHNAs that had >10 degrees error resulted from <10 degrees of positioning error. CONCLUSIONS: If the patient is limited in flexion or external rotation, more diagnostic testing should be considered if error in the reported slip measurement would affect treatment decisions or if accurate severity classification is needed for research. Small positioning errors in moderate and severe slips can cause a > 10 degrees LHNA error; additional three-dimensional imaging should be considered. PMID- 28840320 TI - Cre/lox-based multiple markerless gene disruption in the genome of the extreme thermophile Thermus thermophilus. AB - Markerless gene-disruption technology is particularly useful for effective genetic analyses of Thermus thermophilus (T. thermophilus), which have a limited number of selectable markers. In an attempt to develop a novel system for the markerless disruption of genes in T. thermophilus, we applied a Cre/lox system to construct a triple gene disruptant. To achieve this, we constructed two genetic tools, a loxP-htk-loxP cassette and cre-expressing plasmid, pSH-Cre, for gene disruption and removal of the selectable marker by Cre-mediated recombination. We found that the Cre/lox system was compatible with the proliferation of the T. thermophilus HB27 strain at the lowest growth temperature (50 degrees C), and thus succeeded in establishing a triple gene disruptant, the (?TTC1454::loxP, ?TTC1535KpnI::loxP, ?TTC1576::loxP) strain, without leaving behind a selectable marker. During the process of the sequential disruption of multiple genes, we observed the undesired deletion and inversion of the chromosomal region between multiple loxP sites that were induced by Cre-mediated recombination. Therefore, we examined the effects of a lox66-htk-lox71 cassette by exploiting the mutant lox sites, lox66 and lox71, instead of native loxP sites. We successfully constructed a (?TTC1535::lox72, ?TTC1537::lox72) double gene disruptant without inducing the undesired deletion of the 0.7-kbp region between the two directly oriented lox72 sites created by the Cre-mediated recombination of the lox66-htk lox71 cassette. This is the first demonstration of a Cre/lox system being applicable to extreme thermophiles in a genetic manipulation. Our results indicate that this system is a powerful tool for multiple markerless gene disruption in T. thermophilus. PMID- 28840321 TI - Review of the implementation of plasma ctDNA testing on behalf of IQN Path ASBL: a perspective from an EQA providers' survey. PMID- 28840322 TI - Functional significance of extent and timing of muscle activation during double poling on-snow with increasing speed. AB - PURPOSE: To evaluate the level of activation and timing of upper- and lower-body muscles during double poling at different speeds on snow. METHODS: Nineteen well trained cross-country skiers volunteered to double pole on a flat snowy track at different speeds (15, 18, 21 km h-1). The target speeds could be maintained by the skiers thanks to the use of an audio-pace system in combination with cones spaced equally alongside the track. Only 11 subjects were finally included in the analysis, since their actual speeds, calculated through a photocell system, were within +/-0.5 km h-1 from those requested. Cycle and poling durations were measured from the recordings of an accelerometer attached to a wrist, while the pattern and the level of muscle activation were evaluated from electromyographyc signals. RESULTS: Double poling speed did not alter the sequence of muscle activation that started with hip flexors, continued with trunk flexors, shoulder, elbow and trunk extensors and ended with ankle plantar-flexors. However, higher speeds required an increasing involvement of thigh, trunk and shoulder muscles (P < 0.05) as well as an anticipation of their activation before pole plant (P < 0.05). CONCLUSIONS: A progressively earlier activation of trunk and lower limb muscles is a coordinative strategy that allows rapid achievement of optimal body posture prior to the exertion of poling phase. Moreover, earlier activation of these muscles as the speed increases provides adequate muscle stiffness in the shoulder and core regions for the acceptance of the poling load. PMID- 28840323 TI - Improved immediate postoperative pain following laparoscopic inguinal herniorrhaphy using self-adhering mesh. AB - BACKGROUND: Several synthetic meshes are available to reinforce the inguinal region following laparoscopic hernia reduction. We sought to compare postoperative pain of patients who underwent laparoscopic inguinal herniorrhaphy using self-adhering polyester mesh to those who had non-adhering, synthetic mesh implanted using absorbable tacks. MATERIALS AND METHODS: This study is a retrospective review of patients who underwent primary laparoscopic inguinal herniorrhaphy at the Medical College of Wisconsin between October 2012 and July 2014. Clinical information and perioperative pain scores using the visual analog scale (VAS) were obtained to evaluate immediate pre and postoperative pain. RESULTS: A total of 98 patients (88 male) underwent laparoscopic inguinal herniorrhaphy during the study interval. Forty-two patients received self adhering mesh and 56 patients received mesh secured with tacks. Patient demographics and comorbidities did not differ significantly between the two groups. There was no difference in preoperative VAS scores between groups. The self-adhering mesh patients had a lower mean VAS change score (less pain). Postoperative complications did not differ between groups apart from a higher observed incidence of seroma in the self-adhering mesh group (p = 0.04). No hernias recurred in either group during the study interval. CONCLUSIONS: Self adhering mesh in laparoscopic inguinal herniorrhaphy resulted in less immediate postoperative pain than tacked mesh as demonstrated by VAS score. Postoperative complications were similar between the two groups. The results of this study demonstrate that laparoscopic inguinal herniorrhaphy using self-adhering mesh is comparable to tacked mesh in regards to short-term complication rates, but show a favorable advantage in regards to immediate postoperative pain. PMID- 28840325 TI - Tunnel widening after single- versus double-bundle anterior cruciate ligament reconstruction: a randomized 8-year follow-up study. AB - OBJECTIVE: The purpose of this study was to compare the single-bundle (SB) and double-bundle (DB) surgical techniques for anterior cruciate ligament (ACL) reconstruction with regard to tunnel widening, isokinetic muscle strength, and clinical outcomes over an 8-year follow-up period. METHODS: This study included 31 patients with ACL injury who underwent ACL reconstruction via the SB (n = 16) or the DB (n = 15) technique. Isokinetic and concentric strength measurements of the quadriceps and hamstring muscles were conducted at postoperative 6 months and postoperative 8 years, and 3D-CT scans of the knee joints were performed on the 2nd, 3rd and 6th month, and the 8th year postoperatively. Clinical evaluations were performed at 8 years postoperatively with the International Knee Documentation Committee (IKDC), Tegner, and Lysholm knee scoring systems. RESULTS: There was marked widening of the parts of the femoral tunnel close to the knee joint in both the SD and the DB groups. There was no difference between the two groups in terms of clinical results and isometric muscle strength at postoperative 8 years; however, there was a significant difference between the preoperative and 6 months postoperative clinical and strength results in both group (P < 0.05). There was no difference between the groups in IKDC score, Lysholm score, Tegner activity scale, and anterior drawer test at postoperative 8 years. On evaluation of the anteromedial bundles alone, the DB group had greater widening than the SB group. CONCLUSION: In this study, we have found that the tunnels continue to enlarge after 6 months. However, that has no impact in patients comfort and that did not made any change in our daily routine. On the other hand, we found that the reconstruction of the double-band ligament technique is useless for non-professional athletes. PMID- 28840324 TI - Patient-specific mental rehearsal with interactive visual aids: a path worth exploring? AB - BACKGROUND: Surgeons of today are faced with unprecedented challenges; necessitating a novel approach to pre-operative preparation which takes into account the specific tests each case poses. In this study, we examine patient specific mental rehearsal for pre-surgical practice and assess whether this method has an additional effect when compared to generic mental rehearsal. METHODS: Sixteen medical students were trained how to perform a simulated laparoscopic cholecystectomy (SLC). After baseline assessments, they were randomised to two equal groups and asked to complete three SLCs involving different anatomical variants. Prior to each procedure, Group A practiced mental rehearsal with the use of a pre-prepared checklist and Group B mental rehearsal with the checklist combined with virtual models matching the anatomical variations of the SLCs. The performance of the two groups was compared using simulator provided metrics and competency assessment tool (CAT) scoring by two blinded assessors. RESULTS: The participants performed equally well when presented with a "straight-forward" anatomy [Group A vs. Group B-time sec: 445.5 vs. 496 p = 0.64-NOM: 437 vs. 413 p = 0.88-PL cm: 1317 vs. 1059 p = 0.32-per: 0.5 vs. 0 p = 0.22-NCB: 0 vs. 0 p = 0.71-DVS: 0 vs. 0 p = 0.2]; however, Group B performed significantly better [Group A vs. B Total CAT score-Short Cystic Duct (SCD): 20.5 vs. 26.31 p = 0.02 eta 2 = 0.32-Double cystic Artery (DA): 24.75 vs. 30.5 p = 0.03 eta 2 = 0.28] and committed less errors (Damage to Vital Structures DVS, SCD: 4 vs. 0 p = 0.03 eta 2=0.34, DA: 0 vs. 1 p = 0.02 eta 2 = 0.22). in the cases with more challenging anatomies. CONCLUSION: These results suggest that patient-specific preparation with the combination of anatomical models and mental rehearsal may increase operative quality of complex procedures. PMID- 28840326 TI - Prophylactic pelvic drainage after rectal resection with extraperitoneal anastomosis: is it worthwhile? A meta-analysis of randomized controlled trials. AB - BACKGROUND: The role of prophylactic pelvic drainage in reducing the postoperative complication rate after rectal surgery remains unclear and controversial. OBJECTIVE: This review and meta-analysis of prospective randomized controlled trials was performed to determine whether drainage of the extraperitoneal anastomosis after rectal surgery impacts the postoperative complication rate. STUDY ELIGIBILITY CRITERIA: Study eligibility criteria included randomized controlled trials comparing prophylactic pelvic drainage after rectal surgery. METHODS: The Medline and Cochrane Trials Register databases were searched for prospective randomized controlled trials comparing drainage versus no drainage after rectal surgery. Studies published until December 2016 were included. The meta-analysis was performed using Review Manager 5.0 (Cochrane Collaboration, Oxford, UK). RESULTS: Three randomized controlled trials involving 660 patients with extraperitoneal anastomosis after rectal surgery (330 with and 330 without prophylactic pelvic drains) were included. The overall mortality rate was 0.7% (2/267) in the drain group and 1.9% (5/261) in the no-drain group (P = 0.900). The anastomotic leakage rate was 14.8% (49/330) in the drain group and 16.7% (55/330) in the no-drain group (P = 0.370). The postoperative small bowel obstruction rate was significantly higher in the drain than no-drain group (50/267, 18.7% vs. 33/261, 12.6%; odds ratio, 1.61; 95% confidence interval, 1.00 2.60; P = 0.050). CONCLUSIONS: Prophylactic use of pelvic drainage after extraperitoneal colorectal anastomosis has no impact on the incidence of anastomotic leakage or postoperative death. However, it significantly increases the rate of postoperative small bowel obstruction. PMID- 28840327 TI - The Safety and Effectiveness of Flecainide in Children in the Current Era. AB - This retrospective study sought to determine the safety and effectiveness of flecainide in children with normal hearts and those with congenital heart disease (CHD) or cardiomyopathy (CMO). Baseline and follow-up data at two pediatric cardiology sites were queried (2000-2015); a total of 175 patients (20 with CHD and two with CMO) receiving flecainide were assessed. When comparing patients with CHD to those with normal hearts, patients with CHD were younger at diagnosis (median age 19 days; IQR 3-157.5 days vs normal heart patients median age 21 days; IQR 7-172 days, p = 0.4) and severe cardiac dysfunction was more prevalent (30% in CHD patients vs 8% in normal heart patients, p = 0.009). Treatment duration did not differ between the two groups (CHD patients median duration 52 weeks; IQR 27-91.5 weeks vs normal heart patients median duration 55 weeks; IQR 32-156 weeks, p = 0.5). Cardiac dysfunction resulting in flecainide discontinuation occurred in two patients (1%), one with CHD and one without. Three patients experienced proarrhythmia (2%) and there were no cardiac arrests during follow-up. There was one death in this cohort in a patient with severe CHD and an RSV infection (<1%). Arrhythmia control did not differ between the groups (90% in CHD patients vs 77% in normal heart patients, p = 0.2). Flecainide was well tolerated in this cohort, with fewer than 3% discontinuing medication due to flecainide-associated adverse events. Contrary to adult studies, there was no difference in the incidence of adverse events between patients with normal hearts and patients with CHD. Flecainide is a safe and effective antiarrhythmic medication, even for children with underlying CHD. PMID- 28840328 TI - Comparison of 8 and 5 mm robotic instruments in small cavities : 5 or 8 mm robotic instruments for small cavities? AB - INTRODUCTION: Robotic surgery has seen increasing use in the field of pediatric surgery. Our clinical experience suggested instrument size can impact on the surgical ability. This study aimed to compare the performance of robot-assisted laparoscopic skills in confined spaces using either 5 or 8 mm instruments. METHODS: A preclinical randomized crossover study design was implemented. 24 assessors performed three different reproducible drill procedures (M1: peg transfer, M2: circle cutting, M3: intracorporeal suturing). To assess surgical proficiency in confined working spaces, these exercises were performed with 5 and 8 mm instruments of the da Vinci(r) Surgical Systems Si in a cubic box with 60 mm sized edges. Each performance was recorded and evaluated by two reviewers using both objective structured assessment of technical skills (OSATS) and global evaluative assessment of robotic skills (GEARS) scores. Parietal iatrogenic impacts and instrument collisions were specifically analyzed using a dedicated scoring system. RESULTS: Regardless of their experience, trainees performed significantly better when using 8 mm instruments in terms of OSATS scores (20.5 vs. 18.4; p < 0.01) and GEARS scores (23.4 vs. 21.9; p < 0.01) for most items, except for "depth perception" and "autonomy." The 8 mm performances involved significantly less parietal box damage (4.1 vs. 3.4; p < 0.01), and tool collisions (4.1 vs. 3.2; p < 0.01). CONCLUSIONS: In light of the better performances with 8 mm tools for specific tasks and parietal sparing constraints in restricted spaces, this study indicates that 5 mm instruments can be deemed to be less effective for reconstructive procedures in small children. PMID- 28840329 TI - Organ and effective dose rate coefficients for submersion exposure in occupational settings. AB - External dose coefficients for environmental exposure scenarios are often computed using assumption on infinite or semi-infinite radiation sources. For example, in the case of a person standing on contaminated ground, the source is assumed to be distributed at a given depth (or between various depths) and extending outwards to an essentially infinite distance. In the case of exposure to contaminated air, the person is modeled as standing within a cloud of infinite, or semi-infinite, source distribution. However, these scenarios do not mimic common workplace environments where scatter off walls and ceilings may significantly alter the energy spectrum and dose coefficients. In this paper, dose rate coefficients were calculated using the International Commission on Radiological Protection (ICRP) reference voxel phantoms positioned in rooms of three sizes representing an office, laboratory, and warehouse. For each room size calculations using the reference phantoms were performed for photons, electrons, and positrons as the source particles to derive mono-energetic dose rate coefficients. Since the voxel phantoms lack the resolution to perform dose calculations at the sensitive depth for the skin, a mathematical phantom was developed and calculations were performed in each room size with the three source particle types. Coefficients for the noble gas radionuclides of ICRP Publication 107 (e.g., Ne, Ar, Kr, Xe, and Rn) were generated by folding the corresponding photon, electron, and positron emissions over the mono-energetic dose rate coefficients. Results indicate that the smaller room sizes have a significant impact on the dose rate per unit air concentration compared to the semi-infinite cloud case. For example, for Kr-85 the warehouse dose rate coefficient is 7% higher than the office dose rate coefficient while it is 71% higher for Xe-133. PMID- 28840330 TI - Do Endophytes Promote Growth of Host Plants Under Stress? A Meta-Analysis on Plant Stress Mitigation by Endophytes. AB - Endophytes are microbial symbionts living inside plants and have been extensively researched in recent decades for their functions associated with plant responses to environmental stress. We conducted a meta-analysis of endophyte effects on host plants' growth and fitness in response to three abiotic stress factors: drought, nitrogen deficiency, and excessive salinity. Ninety-four endophyte strains and 42 host plant species from the literature were evaluated in the analysis. Endophytes increased biomass accumulation of host plants under all three stress conditions. The stress mitigation effects by endophytes were similar among different plant taxa or functional groups with few exceptions; eudicots and C4 species gained more biomass than monocots and C3 species with endophytes, respectively, under drought conditions. Our analysis supports the effectiveness of endophytes in mitigating drought, nitrogen deficiency, and salinity stress in a wide range of host species with little evidence of plant-endophyte specificity. PMID- 28840331 TI - Influential factors and clinical significance of fluid-attenuated inversion recovery vascular hyperintensities in transient ischemic attacks of carotid arterial system. AB - PURPOSE: Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is often observed in conjunction with acute ischemic stroke (AIS) of the carotid system. Despite its bearing on patient care outcomes, factors influencing FVH and its clinical significance in patients with transient ischemic attacks (TIAs) of the carotid arterial system have yet to be evaluated. METHODS: Consecutive inpatients (N = 154) diagnosed with TIAs of the carotid system in a 2-year period (2012-2014) were enrolled in our study. Each had undergone magnetic resonance imaging (MRI) within 72 h of symptom onset, followed by intracranial and extracranial vascular imaging. We investigated the frequency and nature of factors associated with FVH, also examining its clinical significance in the 30 day prognosis of TIA. RESULTS: Of the 154 patients enrolled (male, 92; mean age 63.0 +/- 11.9), FVH was confirmed in 61 patients (39.6%). In logistic regression analysis, intracranial large-artery disease (LAD) (OR = 2.39, 95% CI 1.16-4.92; p = 0.018) and prior stroke (OR = 3.33, 95% CI 1.48-7.51; p = 0.004) emerged as factors independently associated with FVH positivity. Ultimately, 25 patients (16.2%) progressed to AIS within a 30-day follow-up period. Logistic regression analysis indicated that contralateral FVH positivity (OR = 5.98, 95% CI 1.81 19.76; p = 0.003), atrial fibrillation (OR = 7.05, 95% CI 1.33-37.40; p = 0.022), and extracranial LAD (OR = 4.12, 95% CI 1.26-13.41; p = 0.019) were independently associated with AIS during the 30-day follow-up of TIAs in these patients. CONCLUSION: Intracranial LAD and previous stroke are independently associated with FVH in patients experiencing carotid system TIAs. If present, FVH may predict an oncoming AIS in the 30 days following a TIA. PMID- 28840332 TI - Can fatigue affect acquisition of new surgical skills? A prospective trial of pre and post-call general surgery residents using the da Vinci surgical skills simulator. AB - OBJECTIVE: To study the effects of fatigue on general surgery residents' performance on the da Vinci Skills Simulator (dVSS). METHODS: 15 General Surgery residents from various postgraduate training years (PGY2, PGY3, PGY4, and PGY5) performed 5 simulation tasks on the dVSS as recommended by the Robotic Training Network (RTN). The General Surgery residents had no prior experience with the dVSS. Participants were assigned to either the Pre-call group or Post-call group based on call schedule. As a measure of subjective fatigue, residents were given the Epworth Sleepiness Scale (ESS) prior to their dVSS testing. The dVSS MScoreTM software recorded various metrics (Objective Structured Assessment of Technical Skills, OSATS) that were used to evaluate the performance of each resident to compare the robotic simulation proficiency between the Pre-call and Post-call groups. RESULTS: Six general surgery residents were stratified into the Pre-call group and nine into the Post-call group. These residents were also stratified into Fatigued (10) or Nonfatigued (5) groups, as determined by their reported ESS scores. A statistically significant difference was found between the Pre-call and Post-call reported sleep hours (p = 0.036). There was no statistically significant difference between the Pre-call and Post-call groups or between the Fatigued and Nonfatigued groups in time to complete exercise, number of attempts, and high MScoreTM score. CONCLUSION: Despite variation in fatigue levels, there was no effect on the acquisition of robotic simulator skills. PMID- 28840333 TI - Comment on Kortram et al.: risk factors for infectious complications after open fractures; a systematic review and meta-analysis. PMID- 28840334 TI - Patient preference and timing for exercise in breast cancer care. AB - Exercise is recommended following cancer diagnosis and may be particularly valuable for women receiving cardiotoxic chemotherapy treatments. We investigated breast cancer patient preference on exercise programming in a prospective manner and retrospectively assessed length of time between diagnosis and chemotherapy initiation. Sixty-seven newly diagnosed breast cancer patients responded to questions regarding exercise programming related to cancer treatment and surveys on current activity level. Additionally, a retrospective chart review was conducted on 500 random breast cancer patients. Age, cancer stage, treatment, and treatment dates were extracted. Women were interested in, or, absolutely wanted to, participate in an exercise program before treatment (76.2%). There was uncertainty regarding willingness to delay treatment; 49.2% were willing to delay their treatment if the program was recommended by their doctors, 41.8% would not, and 9.0% were too unsure to respond. However, women would like to hear information about an exercise program for cancer patients when they are first diagnosed (61.9%). We observed that 64.6% of women were below recommended levels of physical activity; yet, current activity was not associated with an interest in an exercise program or willingness to delay treatment. Retrospectively, we observed an average interval of 72.6 +/- 34.6 days between cancer diagnosis and initiation of anthracycline-based chemotherapy treatment, with younger women with more advanced cancer receiving anthracycline-based chemotherapy. Based on patient preference and length of time to chemotherapy initiation, a reasonable next step to promote the current recommendations for exercise could be to integrate exercise into breast cancer care earlier in treatment. PMID- 28840335 TI - Developmental landmarks during floral ontogeny of jalapeno chili pepper (Capsicum annuum L.) and the effect of gibberellin on ovary growth. AB - Pepper (Capsicum annuum L.) is an important horticultural crop in many regions of the world. The final shape and size of the fruit are known to be determined at a very early step of flower development. During flower development hormonal treatments using gibberellins seem to promote growth resulting in higher yield and fruit quality. However, the morphological changes that occur in the pepper flowers after these treatments are largely unknown. In the present study, we provide a description of floral development landmarks of jalapeno chili pepper (cultivar Huichol), divided in nine representative stages from its initiation until the opening of the bud. We established a correlation among external flower development and the time and pattern of reproductive organogenesis. Male and female gametogenesis progression was used to define specific landmarks during flower maturation. The pattern of expression of key genes involved in gibberellin metabolism and response was also evaluated in the nine flower stages. The proposed development framework was used to analyze the effect of gibberellin treatments in the development of the flower. We observed both an effect of the treatment in the histology of the ovary tissue and an increase in the level of expression of CaGA2ox1 and CaGID1b genes. The developmental stages we defined for this species are very useful to analyze the molecular and morphological changes after hormonal treatments. PMID- 28840336 TI - Implications of climate and outdoor thermal comfort on tourism: the case of Italy. AB - Whether a journey is pleasant or not usually depends on the climatic conditions which permit to perform outdoor activities. The perception of climatic conditions, determined by physiological and psychological factors, can vary according to different adaptation phenomena related to the person involved and the weather conditions of the place where they live. Studying the bioclimatology of a country characterized by a high flux of tourism, as e.g. Italy, can provide some important information about where and when is it better to visit a place. Some differences have to be specified though, like the local tourism, which is used to that type of climate, and international tourism, which is formed by people coming from countries with different types of climates. Therefore this paper examined the climatic conditions and outdoor thermal comfort through the Mediterranean Outdoor Comfort Index (MOCI) for local tourism and through the predicted mean vote (PMV) for international tourism. The cities examined were three (Venice, Rome and Palermo located in the North, Centre and South of Italy, respectively), where average information were collected every week for an entire year. Finally, a map of the entire Italian territory reporting the seasonal average values of these indexes was also reported. PMID- 28840337 TI - Long-term outcomes of patients with early gastric cancer found to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after endoscopic submucosal dissection. AB - BACKGROUND: Gastric cancer treatment guidelines recommend additional surgery as the standard treatment for lesions for which endoscopic submucosal dissection (ESD) is not indicated. However, the incidence of lymph-node metastasis is low in most patients. METHODS AND MATERIALS: The study comprised 231 patients (231 lesions) who underwent ESD for early gastric cancer (EGC) in our hospital from September 2002 through March 2015 and were found to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD. The patients were divided into the additional operation group and the follow-up group, and long-term outcomes were studied retrospectively. Risk factors for metastasis and recurrence were also studied (capture rate, 98.7%). RESULTS: The median follow-up was 48 months. There were 174 men and 57 women with a median age of 72 years. The additional operation group comprised 118 patients, and the follow-up group comprised 113 patients. The rates of 5-year cause-specific survival and 5-year overall survival were significantly higher in the additional operation group (100 and 96.0%, respectively) than in the follow-up group (92.6 and 73.3%, respectively; p = 0.010, p < 0.001). In the follow-up group, 5 patients (4.4%) died of gastric cancer (p = 0.021). Among elderly patients 75 years or older, long-term outcomes did not differ significantly between the groups. Sixteen patients had metastasis or recurrence, and the presence of lymphatic involvement was an independent risk factor for metastasis, recurrence, or both (p = 0.003; odds ratio 10.594; 95% confidence interval 2.294-48.927). CONCLUSIONS: In patients with EGC who are confirmed to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD, additional surgery should be aggressively performed if the patient can tolerate such treatment. In elderly patients aged 75 years or older and patients with serious underlying diseases, follow-up observation was suggested to be one option in patients who give informed consent after receiving an explanation of the risk of recurrence. PMID- 28840338 TI - Physiologic and psychological gender differences in bariatric surgery. AB - BACKGROUND: Bariatric surgery is a safe and effective treatment for clinically severe obesity, but inequity in male and female utilization is well recognized. Approximately 20% of patients undergoing bariatric surgery are male. This paper aims to describe differences in outcomes by gender and to understand the physiologic and psychological differences that may explain this gender gap. METHODS: We examined 61,708 patients from the Michigan Bariatric Surgery Collaborative (MBSC) undergoing primary bariatric surgery between 2006 and 2016. Clinical data regarding demographics, comorbidities, and outcomes were compared by gender. Preoperative and 1-year postoperative surveys gathered psychological outcomes. RESULTS: This cohort was consistent with the national population with approximately 22% male patients. There were several significant differences between males and females at the time of surgery. Males tended to be older, have a higher BMI, be married, have lower self-reported depression scores, and have more comorbidities (all p < 0.05). Postoperatively, males suffered more serious complications than women (2.67 vs. 2.12, respectively, p < 0.05). At 1 year postoperatively, males were significantly more satisfied with their operation despite increased complications, decreased weight loss, and decreased rates of comorbidity resolution as compared to females (all p < 0.05). CONCLUSIONS: Despite significantly lower weight loss and increased complication rates, males tend to have markedly higher satisfaction and psychological well-being scores than females. To improve outcomes in males, earlier referral to surgery may help to significantly reduce their risk. Conversely, increased attention to psychological support in the perioperative period for females may lead to improved psychological outcomes (i.e., body image, depression, psychological well being). PMID- 28840339 TI - Occurrence of Infected Free-Living Amoebae in Cooling Towers of Southern Brazil. AB - This study determined the occurrence of potentially pathogenic free-living amoebae (FLA) and bacteria associated with amoebae in air-conditioning cooling towers in southern Brazil. Water samples were collected from 36 cooling systems from air-conditioning in the state of Rio Grande do Sul, Brazil. The organisms were identified using polymerase chain reaction (PCR) and sequencing automated. The results showed that these aquatic environments, with variable temperature, are potential "hot spots" for emerging human pathogens like free-living amoebae and bacteria associated. In total, 92% of the cooling-tower samples analyzed were positive for FLA, and Acanthamoeba was the dominant genus by culture and PCR. Amoebal isolates revealed intracellular bacteria in 39.3% of them and all were confirmed as members of the genus Pseudomonas. The results obtained show the important role of cooling towers as a source of amoebae-associated pathogens. PMID- 28840340 TI - Trait shifts associated with the subshrub life-history strategy in a tropical savanna. AB - Over the past 10 million years, tropical savanna environments have selected for small growth forms within woody plant lineages. The result has been the evolution of subshrubs (geoxyles), presumably as an adaptation to frequent fire. To evaluate the traits associated with the shift from tree to subshrub growth forms, we compared seed biomass, germination, survival, resprouting, biomass allocation, and photosynthesis between congeneric trees and subshrubs, and quantified phylogenetic conservatism. Despite large differences in adult morphology between trees and subshrub species, the differences are modest in seedlings, and most of the variation in traits was explained by genus, indicating considerable phylogenic conservatism. Regardless, tree seedlings invested more heavily in aboveground growth, compared to subshrubs, which is consistent with the adult strategy of savanna trees, which depend on a large resistant-fire stem. Subshrub seedlings also invest in greater non-structural carbohydrate reserves, likely as an adaptation to the high fire frequencies typical of tropical savannas. The modest differences as seedlings suggest that selective pressures during early development may not have contributed substantially to the evolution of the subshrub growth form and that the distinct allocation and life history must arise later in life. This is consistent with the interpretation that the subshrub growth form arose as a life-history strategy in which maturity is reached at a small stem size, allowing them to reproduce despite repeated fire-induced topkill. The convergent evolution of subshrubs within multiple tree lineages reaffirms the importance of fire in the origin and diversification of the flora of mesic savannas. PMID- 28840341 TI - Usefulness of neutrophil-to-lymphocyte ratio as a biomarker for diagnosing infections in patients with systemic lupus erythematosus. AB - Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have been investigated as disease activity markers for systemic lupus erythematosus (SLE). Hence, we investigated the clinical significance of these parameters in diagnosing infection in patients with SLE. In total, 120 patients with SLE, who were admitted to hospital due to disease flares or infection, were recruited for the study. Of the 120 patients, 60 had a concurrent infection (SLE with infection), while the remaining 60 patients were admitted with a flare without any evidence of infection (SLE with flare). NLR was higher in the patients with SLE with infection, compared to patients with SLE with flare (14.2 +/- 15.4 versus 3.3 +/- 2.2, p < 0.001). Additionally, PLR was higher in the SLE with infection group than in the SLE with flare group (357.7 +/- 350.1 versus 231.7 +/- 152.9, p = 0.012), but not MLR. In the SLE with infection group, C-reactive protein (CRP) levels positively correlated with NLR and PLR. NLR with a cut-off value of 5.70 and an area under the curve (AUC) of 0.872 indicated good sensitivity (75%) and specificity (90%), for the diagnosis of SLE with infection. CRP with a cut-off value of 1.28 mg/dL (AUC 0.942) showed the sensitivity (93.3%) and specificity (91.7%). NLR with a cut-off value of 5.70 and CRP with a cut-off value of 1.28 mg/dL showed the increased specificity (98.3%) than only CRP, but not significant. NLR could be a good additive marker for diagnosing infection in patients with SLE. PMID- 28840342 TI - Vertebral subluxation during three-column osteotomy in surgical correction of adult spine deformity: incidence, risk factors, and complications. AB - PURPOSE: To investigate incidence, risk factors, and complications of vertebral subluxation (VS) during three-column osteotomy in surgical correction of adult spine deformity. METHODS: Adult spine deformity patients who underwent three column osteotomies including VCR, PSO, and other modified types from March 2000 to December 2014 in our center were retrospectively reviewed. The following parameters were measured pre- and postoperatively: Cobb angle of main curve, global kyphosis, sagittal vertical axis, and kyphosis flexibility. Radiographic parameters between groups (VCR vs. PSO and subluxation vs. non-subluxation) were compared. RESULTS: 171 ASD patients were recruited, 18 of which (10.5%) developed sagittal vertebral subluxation at the osteotomy site. 5 of 18 patients (27.8%) developed neurological complications after surgery. For these five patients, two patients got partial recovery, and three got complete recovery at 2-year follow up. 116 patients underwent PSO, 12 of which (10.3%) developed sagittal vertebral subluxation. In 55 patients receiving VCR, 6 (10.9%) developed sagittal vertebral subluxation. No significant difference was noted between the two groups (P > 0.05). The mean age of VS group was larger than that of non-VS group (46.2 vs. 34.2, P < 0.05). VS group had less kyphosis flexibility (11 vs. 23%, P < 0.05). More patients in VS group had preoperative sagittal VS as compared to non-VS group (77.8 vs. 20.9%, P < 0.05). VS group had more neurological complications than non-VS group (25 vs. 5.4%, P < 0.05). CONCLUSION: VS occurred in one-tenth of patients receiving three-column osteotomies, one-fourth of which would develop neurological deficits. Older age, rigid kyphosis, and the pre-existence of VS were risk factors for developing VS. PMID- 28840343 TI - Sleeve Gastrectomy: the first 3 Years: evaluation of emergency department visits, readmissions, and reoperations for 14,080 patients in New York State. AB - INTRODUCTION: The purpose of our study was to evaluate the indications for and incidence of both emergency department (ED) visits and hospital readmissions within the first postoperative year. We also sought to identify the rate of reoperation within the first 3 years following a SG operation in New York State (NYS). METHODS: The SPARCS database was examined for all SGs performed between 2011 and 2013. Using a unique identifier, patients were followed for at least 1 year. Patients were followed for reoperation and/or conversion to Roux-en-Y Gastric Bypass (RYGB), as well as for any other hospital-based encounter. Using primary diagnosis codes, the top five reasons for ED visits and readmission were identified. RESULTS: There were 14,080 SG between 2011 and 2013. Among all patients, just over one-third of patients visited the ED (33.9%). One in every ten of these visits resulted in readmission (9.5%), with 12.5% of the total postoperative patient population undergoing readmission within their first year after SG surgery. ED visits were unrelated to surgery in just over half of the patients (n = 4977; 53.88%). However, ED visits for abdominal pain (n = 1029; 11.14%), vomiting (n = 237; 2.57%), dehydration (n = 224; 2.43%), and syncope (n = 206; 2.23%) were attributed to surgery. The top five causes for readmission within the first year after SG were unrelated to surgery (n = 1101; 41.74%), complication related to bariatric surgery (n = 211; 8%), dehydration (n = 171; 6.48%), postoperative wound complication (n = 89; 3.37%), abdominal pain (n = 78; 2.96%). Overall, there was a low reoperation rate (0.32%); specifically, rates of sleeve revision and conversion to RYBG were 0.11 and 0.21%, respectively. CONCLUSION: SG has increasing popularity in NYS. Although postoperative ED visits are high, SG has a low overall reoperation rate (0.32%), and of these patients, most undergo conversion to RYGB compared to sleeve revision. Overall 1-year readmission rates after SG are 12.5%. PMID- 28840344 TI - Sit4-Associated Protein is Required for Pathogenicity of Leptosphaeria maculans on Brassica napus. AB - An insertional mutant with reduced pathogenicity on Brassica napus was identified in the plant pathogenic fungus Leptosphaeria maculans. The transfer-DNA molecule from Agrobacterium tumefaciens inserted into a gene encoding a protein with similarity to Sit4-associated proteins (SAPs). In contrast to Saccharomyces cerevisiae which has four members of the SAP family, there is a single copy of the gene in L. maculans. The mutant had normal spore production and spore germination, but altered hyphal branching, suggesting that nutrient signaling is impaired in the strain. This is the first time that a SAP gene has been mutated in a filamentous fungus and links the function of SAP proteins to plant pathogenesis and hyphal branching. PMID- 28840345 TI - Platelet reactivity in sepsis syndrome: results from the PRESS study. AB - Platelet activation mediates systemic inflammatory response during infection. However, data on platelet reactivity (PR) varies among different settings. We assessed PR along different stages of sepsis and tried to predict for determinants of its variance. In parallel, we evaluated it as an early bedside diagnostic biomarker. This was an observational prospective cohort study. Incoming patients were assorted to distinct groups of uncomplicated infection, sepsis, and severe sepsis/septic shock. A control group of healthy volunteers was used as comparison. PR was assessed using the bedside point-of-care VerifyNow assay, in P2Y12 reaction units (PRU) alongside with levels of major inflammatory markers and whole blood parameters. A total of 101 patients and 27 healthy volunteers were enrolled. PR significantly and reversibly increases during sepsis compared to uncomplicated infection and healthy controls (244 +/- 66.7 vs 187.33 +/- 60.98, p < 0.001 and 192.17 +/- 47.51, p < 0.001, respectively). In severe sepsis, PR did not significantly differ compared to other groups. Sepsis stage uniquely accounts for 15.5% of PR in a linear regression prediction model accounting for 30% of the variance of PR (F = 8.836, p < 0.001). PRU >253 had specificity of 91.2% and sensitivity of 40.8% in discriminating septic from non septic patients. The addition of PRU to SOFA and qSOFA scores significantly increased their c-statistic (AUC SOFA + PRU, 0.867 vs SOFA, 0.824, p < 0.003 and AUC qSOFA + PRU, 0.842 vs qSOFA, 0.739, p < 0.001), making them comparable (AUC SOFA + PRU vs qSOFA + PRU, p = 0.4). PR significantly and reversibly increases early in sepsis, but seems to exhaust while disease progresses. Bedside assessment of PR can provide robust discriminative accuracy in the early diagnosis of septic patients. PMID- 28840346 TI - Disease stage-dependent relationship between diffusion tensor imaging and electrophysiology of the visual system in a murine model of multiple sclerosis. AB - PURPOSE: Diffusion tensor imaging (DTI) is commonly used to evaluate white matter integrity in multiple sclerosis (MS), but the relationship between DTI measures and functional changes during disease remains ambiguous. Using a mouse model of MS, we tested the hypothesis that DTI measures would correlate to the visual evoked potential (VEPs) dynamically at different disease stages. METHODS: In vivo DTI, gadolinium-enhanced T1WI (Gd-T1WI) and VEPs were performed in 5 control and 25 mice after 2-12 weeks of experimental autoimmune encephalomyelitis (EAE). DTI indices, including fractional anisotropy (FA), axial and radial diffusivities (AD and RD), and Gd-T1WI enhancement, were measured in the optic nerve and tract (ON and OT), which were compared with measured VEPs. RESULTS: Gd-T1WI showed a 3- to 4-fold enhancement over controls beginning after 2 weeks of EAE. Across the time course, we found progressive reductions in FA and increases in RD with increases in VEP latency and reductions in amplitude. Significant correlations between DTI (FA and RD) and VEP evolved; in control/early asymptomatic EAE mice, both FA and RD were highly correlated with VEP latency (but not amplitude), while in late EAE, both DTI indices were highly correlated with VEP amplitude (but not latency). CONCLUSION: DTI measures FA and RD are associated to VEP latency in early stages of EAE but associated to VEP amplitude in later stages, suggesting that the patterns of DTI related to the functional decline may depend on the stage of disease progression. PMID- 28840347 TI - Ultrastructural and cytochemical aspects of female gametophyte development in Sedum hispanicum L. (Crassulaceae). AB - Until now, development of the female gametophyte has been investigated only in some species of Crassulaceae using a light microscope. To the best of our knowledge, this is the first report that describes the process of megasporogenesis and megagametogenesis in Crassulaceae in detail. To achieve this, we performed embryological studies on Sedum hispanicum L. (Crassulaceae). Cytochemical analysis detected the presence of proteins, lipids, and insoluble polysaccharides in individual cells of the gametophyte. The development of the embryo sac conforms to the monosporic or Polygonum-type in anatropous, crassinucellate, and bitegmic ovules. One megaspore mother cell initiates the process of megasporogenesis. Prior to the first meiotic division, the nucleus is centrally located within the meiocyte. Other organelles seem to be distributed evenly over the micropylar and chalazal parts during the development. Most storage reserves detected during megasporogenesis were observed in the megaspore mother cell. Three mitotic divisions within the chalazal functional megaspore resulted in the enlargement of the eight-nucleated embryo sac. In the seven celled gametophyte, three chalazally located antipodes degenerated. A mature embryo sac was formed by the egg apparatus and central cell. When the antipodes degenerated, both synergids became organelle-rich and more active. The concentration of lipid droplets, starch grains, and proteins increased during megagametogenesis in the growing gametophyte. In the cellular embryo sac, the central cell can be distinguished by its largest accumulation. Our data confirm the hypothesis that plasmodesmata with electron-dense dome are formed during development of the female gametophyte in S. hispanicum and not just during the stages of embryogenesis. We observed these structures in megaspores and coenocytic embryo sac walls. Functions of observed plasmodesmata are discussed. PMID- 28840348 TI - Posttraumatic stress disorder and correlates of disease activity among veterans with ankylosing spondylitis. AB - The objective of this retrospective study was to evaluate the prevalence of comorbid Posttraumatic stress disorder (PTSD) and the association of PTSD with pain, disease activity, and medication use in ankylosing spondylitis (AS). Veterans with one or more visit to an outpatient rheumatology clinic at a single Veterans Affairs site during a 2-year study period were identified by ICD codes for AS and included if there was documentation of AS diagnosis by a rheumatologist. Data were collected on PTSD diagnosis, demographics, pain scores, disease activity by the Bath AS Disease Activity Index (BASDAI), and medication use. Characteristics were compared by PTSD status using t tests for continuous variables and Chi-square or Fischer's exact test for categorical variables. Of 113 Veterans with AS, 20 (18%) had a diagnosis of PTSD. Those with PTSD were significantly younger, 52 +/- 17 years, as compared to those without PTSD, 59 +/- 14 years (p = 0.04). BASDAI was recorded for 30% with a mean score of 4.3 +/- 2.0. Those with PTSD had higher mean pain and BASDAI scores as compared to those without PTSD (p = 0.06 for both comparisons). Prescribed medications were similar for both groups in regards to synthetic disease modifying antirheumatic drugs (DMARDs), biologics, and opioids, although those with PTSD were significantly more likely to receive NSAIDs (p = 0.03). Veterans with AS and comorbid PTSD were younger and had higher reported pain and disease activity scores compared to those without PTSD in this single site study. These findings underscore the importance of identifying PTSD in patients with AS. PMID- 28840349 TI - Sagittal spino-pelvic alignment in rapidly destructive coxarthrosis. AB - PURPOSE: To investigate the sagittal spino-pelvic alignment (SSPA) in patients with rapidly destructive coxarthrosis (RDC). METHODS: SSPA was investigated in 44 patients with RDC and 70 patients with hip osteoarthritis (HOA). The study included only female patients over the age of 70 years because epidemiological reports indicate that RDC most commonly occurs in this group of patients. The SSPA parameters that were analyzed included lumbar lordosis (LL), lumbar range of motion (DeltaLL), sacral slope (SS), pelvic incidence (PI), and pelvic tilt (PT). The pelvic inclination angle (PIA) in the supine position and the change in the PIA from the supine to the standing position (DeltaPIA) were measured using anteroposterior pelvic radiographs. The values of these parameters were compared between the two groups. The levels of the SRS-Schwab classification modifiers were used to investigate the degree of sagittal malalignment. RESULTS: The RDC group showed significant lower LL, DeltaLL and SS values, and significantly higher PT and DeltaPIA values than the HOA group (P < 0.01). With regard to the sagittal modifiers in the SRS-Schwab classifications of the patients, the PI-LL and PT levels of the RDC group were significantly worse than those in the HOA group (P < 0.01). CONCLUSIONS: The present study suggests that the static factors of a reduction in the lumbar lordotic angle and greater posterior pelvic tilt, the dynamic factors of small DeltaLL values and large DeltaPIA values and the complex interaction of these two types of factors, may play important roles in the development of RDC. PMID- 28840350 TI - Regulatory T cells and IL-10 as modulators of chikungunya disease outcome: a preliminary study. AB - Regulatory T (Treg) cells hold centre stage in regulating the immune responses in most viral infections. However, their involvement in chikungunya infection is unexplored. In the current study, the frequencies and functionality of peripheral Treg and T effector (Teff) cells were assessed during different phases of chikungunya by flow cytometry and in-vitro cytokine assays. Treg cells were also studied in rheumatoid arthritis (RA) patients, whose symptoms closely mimic chronic chikungunya arthritis patients. Frequency of Treg cells was lower in acute and chronic chikungunya arthritis patients than in recovered individuals and controls, and comparable among recovered individuals and controls. Treg/Teff ratio was lower in acute than in chronic chikungunya arthritis patients, recovered individuals and controls. Higher secretion of CHIKV specific IL-10 was observed in recovered individuals than in acute, chronic chikungunya arthritis patients and controls. Frequencies of Treg and Teff cells were higher and Treg/Teff ratio was lower in RA patients than in chronic chikungunya arthritis patients. The results indicate that reduction of Treg cells was associated with ongoing CHIKV infection and normalization of Treg cells with resolution of disease. Contrasting phenotypic data in RA and chronic chikungunya arthritis suggest an altogether different mechanism of Treg-mediated pathology in both arthritis conditions. Overall, our preliminary study, suggesting an association of peripheral Treg cells and IL-10 with recovery from chikungunya, may provide insight into chikungunya disease prognosis and warrants further study. PMID- 28840352 TI - Barriers to laparoscopic colon resection for cancer: a national analysis. AB - BACKGROUND: Level one evidence has shown that minimally invasive surgery (MIS) for colon cancer improves short-term outcomes with equivalent long-term oncologic results when compared to open surgery. However, the adoption of MIS for patients with colon cancer has not been universal. The goal of this study is to identify barriers to the use of MIS surgery in colon cancer resection across the United States. METHODS: The National Cancer Database was queried for all cases of colonic adenocarcinoma resection from 2010 to 2012. Patients undergoing an MIS approach were compared with those undergoing open surgery (OS). MIS was defined as either robotic or laparoscopic surgery. Patients with metastatic disease, surgery for palliation, or tumors >8 cm were excluded. Multivariable modeling was used to identify variables associated with the use of open surgery. RESULTS: After applying exclusion criteria, 124,205 cases were identified. An MIS approach was used in only 54,621 (44%) patients. In a multivariable model adjusting for stage and tumor size, a number of important factors were associated with decreased odds of a MIS approach including black race (OR .91; p < .0001), lack of insurance (OR .51; p < .0001), lower education (OR .88; p < .0001), lower income (OR .83; p < .0001), treatment at a community program (OR .86; p < .0001), and treatment at a low-volume center (OR .79; p < .0001). Utilization of MIS increased over the study period (2010: 38.7%, 2011: 44.0%, 2012: 49.1%; p < .0001). CONCLUSIONS: MIS approach is utilized in less than half of all colon resections in this national database, which accounts for over 70% of all diagnosed cancers in the US. Significant variability exists among age, race, insurance status, socioeconomic status, region, and facility type. In light of the recognized benefits of the MIS approach, local and national policy should focus on narrowing these disparities and continuing the upward trend of MIS utilization. PMID- 28840351 TI - Activity of temocillin and 15 other agents, including fosfomycin and colistin, against Enterobacteriaceae in Hong Kong. AB - Limited data are available on temocillin susceptibilities in Enterobacteriaceae from Asian countries where antimicrobial resistance is prevalent. The in vitro activities of temocillin and 15 commonly used antimicrobials against 613 non duplicate blood (n = 310) and urine (with clinically significant bacteriuria; n = 303) isolates of Enterobacteriaceae from patients who attended 3 out of 7 clusters of public hospitals of the Hospital Authority, Hong Kong, during 2015/2016 were tested. Minimum inhibitory concentrations (MICs) were determined by Clinical and Laboratory Standards Institute (CLSI) microbroth dilution (agar dilution with fosfomycin). For temocillin, MICs were also obtained using the British Society of Antimicrobial Chemotherapy (BSAC) microbroth dilution method and interpreted using the BSAC breakpoints. Overall, 93.0% (570) isolates were susceptible to temocillin using BSAC systemic breakpoint (<=8 mg/L) and all except 2 isolates were susceptible using the urinary breakpoint (<=32 mg/L). The extended spectrum beta-lactamase (ESBL) positivity rate was 23.2% (118 out of 508 E. coli, Klebsiella spp., Proteus spp.). Temocillin resistance rate to ESBL positive isolates was 16.1% using the systemic breakpoint of <=8 mg/L (MIC50 and MIC90 were 8 mg/L and 16 mg/L respectively). Two isolates (1 E. coli, temocillin MIC 64 mg/L, 1 Klebsiella sp., MIC 32 mg/mL) were resistant to meropenem and possessed the NDM-5 and KPC-2 genes respectively. Other susceptibility rates were: amoxicillin/clavulanate (59.1%), trimethoprim/sulfamethoxazole (62.5%), ciprofloxacin (71.5%), ceftriaxone (75.4%), nitrofurantoin (76.4%), gentamicin (78.3%), cefepime (81.1%), ceftazidime (83.5%), piperacillin/tazobactam (86%), colistin (88.8%), tigecycline (89.4%), fosfomycin (92.8%), ertapenem (99.0%), amikacin (99.2%) and meropenem (99.7%). Temocillin may be a useful alternative for the treatment of infections caused by ESBL and multi-drug-resistant Enterobacteriaceae in Hong Kong, particularly as resistance rates to ciprofloxacin, nitrofurantoin and piperacillin/tazobactam are high. PMID- 28840353 TI - Recurrence of ossification of ligamentum flavum at the same intervertebral level in the thoracic spine: a report of two cases and review of the literature. AB - PURPOSE: Ossification of the ligamentum flavum (OLF) is a possible cause of thoracic myelopathy. We report two rare cases with recurrent thoracic myelopathy caused by OLF markedly re-extended at the same intervertebral level after the primary surgery. METHODS: Both patients had thoracic myelopathy caused by OLF and underwent decompressive laminectomy and resection of the OLF in the primary surgery. However, the neurological conditions gradually deteriorated following recovery after the primary surgery due to the recurrent OLF at the same intervertebral level. RESULTS: These patients were successfully treated by revision surgery via resection of the recurrent OLF and posterior spinal fusion with instrumentation. Two years after the second surgery, the neurological disturbance was resolved satisfactorily, and re-growth of the resected ossified lesion was not observed. CONCLUSIONS: The recurrence of OLF following resection of the ossified lesions is exceedingly rare but should be noted in patients treated surgically for thoracic myelopathy due to OLF. PMID- 28840354 TI - Single center experience with the modified retromuscular Sugarbaker technique for parastomal hernia repair. AB - PURPOSE: Parastomal hernias are challenging to manage, and an optimal repair has yet to be defined. An open, modified, retromuscular Sugarbaker technique has recently been described in the literature as a technically feasible approach to parastomal hernia repair. This study evaluates our initial institutional experience with parastomal hernia repair with the aforementioned technique with respect to safety and durability. METHODS: All patients who underwent an open, modified retromuscular Sugarbaker parastomal hernia repair from 2014 through 2016 at our institution were identified. Patient characteristics, hernia variables, operative details, and 30-day and medium-term outcomes were abstracted from the Americas Hernia Society Quality Collaborative database. Outcomes of interest included 30-day wound morbidity, mesh-related complications, and hernia recurrence. RESULTS: Thirty-eight patients met inclusion criteria. 20 (53%) patients presented to our institution for management of a recurrent parastomal hernia. 35 (92%) patients had a concurrent midline incisional hernia with a mean total hernia width of 15.1 cm and mean defect size of 353 cm2. Thirty-day wound morbidity rate was 13%. At a mean of follow-up of 13 months (range 4-30), the hernia recurrence rate was 11%. Three patients (8%) experienced mesh erosion into the stoma bowel, leading to stoma necrosis, bowel obstruction, and/or perforation which required reoperation at day 8, 12, and 120 days, respectively. CONCLUSIONS: The outcomes of the retromuscular Sugarbaker technique for the management of parastomal hernias have been disappointing at our institution, with a concerning rate of serious mesh-related complications. This operation, as originally described, needs further study before widespread adoption with a particular focus on the technique of mesh placement, the most appropriate mesh selection, and the long-term rate of mesh erosion. PMID- 28840355 TI - Methanogenic community compositions in surface sediment of freshwater aquaculture ponds and the influencing factors. AB - Aquaculture ponds represent ecologically relevant environments to study the community composition and diversity of methanogenic assemblages, as well as their interactions with cultivated species and chemical indicators. In this study, aquaculture ponds with crab (Eriocheir sinensis), oriental river prawn (Macrobrachium nipponense), perch (Micropterus salmonides) and Wuchang fish (Parabramis pekinensis) were sampled, and Illumina high-throughput sequencing was used to investigate the methanogenic communities. The results revealed that the abundant methanogenic orders in surface sediment were Methanomicrobiales, Methanosarcinales and Methanocellales. The relative abundance of Methanocellales was higher in crab and prawn ponds as compared to other ponds. Methanogenic 16S rRNA gene abundance and beta diversity of the community was affected by the cultivated species. Methanogenic communities in aquaculture ponds with higher contents of total nitrogen and organic matter had decreased species richness, while those with higher contents of ammonia and nitrite had an overall decreased abundance of methanogens and their respective diversities. Overall, in addition to the differences in cultivated species, the consequent differences in farming practices including the types and amounts of feeds used, the contents of total nitrogen, organic matter, ammonia and nitrite could all influence the methanogenic community in surface sediment of aquaculture ponds. PMID- 28840356 TI - Physical activity and change in fasting glucose and HbA1c: a quantitative meta analysis of randomized trials. AB - AIMS: A systematic review was conducted of randomized trials which evaluated the impact of physical activity on the change in fasting glucose and HbA1c. METHODS: A literature search was conducted in PubMed until December 2015. Studies reporting glucose or HbA1c at baseline and at the end of study were included, and the change and its variance were estimated from studies with complete data. Mixed effect random models were used to estimate the change of fasting glucose (mg/dl) and HbA1c (%) per additional minutes of physical activity per week. RESULTS: A total of 125 studies were included in the meta-analysis. Based on 105 studies, an increase of 100 min in physical activity per week was associated with an average change of -2.75 mg/dl of fasting glucose (95% CI -3.96; -1.55), although there was a high degree of heterogeneity (83.5%). When restricting the analysis on type 2 diabetes and prediabetes subjects (56 studies), the average change in fasting glucose was -4.71 mg/dl (95% CI -7.42; -2.01). For HbA1c, among 76 studies included, an increase of 100 min in physical activity per week was associated with an average change of -0.14% of HbA1c (95% CI -0.18; -0.09) with heterogeneity (73%). A large degree of publication bias was identified (Egger test p < 0.001). When restricting the analysis on type 2 diabetes and prediabetes subjects (60 studies), the average change in HbA1c was -0.16% (95% CI -0.21; 0.11). CONCLUSIONS: This analysis demonstrates that moderate increases in physical activity are associated with significant reductions in both fasting glucose and HbA1c. PMID- 28840357 TI - Hereditary breast cancer: molecular biology and management update. PMID- 28840358 TI - Ectomycorrhizal fungi reduce the light compensation point and promote carbon fixation of Pinus thunbergii seedlings to adapt to shade environments. AB - We examined the effects of three ectomycorrhizal (ECM) symbionts on the growth and photosynthesis capacity of Japanese black pine (Pinus thunbergii) seedlings and estimated physiological and photosynthetic parameters such as the light compensation point (LCP), biomass, and phosphorus (Pi) concentration of P. thunbergii seedlings. Through this investigation, we documented a new role of ectomycorrhizal (ECM) fungi: enhancement of the survival and competitiveness of P. thunbergii seedlings under low-light condition by reducing the LCP of seedlings. At a CO2 concentration of 400 ppm, the LCP of seedlings with ECM inoculations was 40-70 MUmol photons m-2 s-1, significantly lower than that of non-mycorrhizal (NM) seedlings (200 MUmol photons m-2 s-1). In addition, photosynthetic carbon fixation (Pn) increased with light intensity and CO2 level, and the Pn of ECM seedlings was significantly higher than that of NM seedlings; Pisolithus sp. (Pt)- and Laccaria amethystea (La)-mycorrhizal seedlings had significantly lower Pn than Cenococcum geophilum (Cg)-mycorrhizal seedlings. However, La-mycorrhizal seedlings exhibited the highest fresh weight, relative water content (RWC), and the lowest LCP in the mycorrhizal group. Concomitantly, ECM seedlings showed significantly increased chlorophyll content of needles and higher Pi concentrations compared to NM seedlings. Overall, ECM symbionts promoted growth and photosynthesis while reducing the LCP of P. thunbergii seedlings. These findings indicate that ECM fungi can enhance the survival and competitiveness of host seedlings under low light. PMID- 28840359 TI - Lysobacter zhanggongensis sp. nov. Isolated from a Pit Mud. AB - The Gram-stain-negative, rod-shaped and non-motile bacterial strain, designated ZGLJ7-1T, was isolated from a pit mud. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain ZGLJ7-1T was related to the genus Lysobacter and had the highest 16S rRNA gene sequence similarity with the type strain of Lysobacter arseniciresistens ZS79T (97.4%). The predominant cellular fatty acids were iso-C15:0, iso-C17:1omega9c, iso-C11:0 and iso-C11:03-OH. Strain ZGLJ7-1T had Q-8 as the predominant ubiquinone. The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid, two unidentified aminolipids and two unidentified lipids. The genomic DNA G+C content of strain ZGLJ7-1T was 69.5 mol%. Strain ZGLJ7-1T shared DNA relatedness with 35% Lysobacter arseniciresistens CGMCC 1.10752T. Combined data from phenotypic, phylogenetic and DNA-DNA relatedness studies demonstrated that the strain ZGLJ7-1T is a representative of a novel species of the genus Lysobacter, for which we propose the name Lysobacter zhanggongensis sp. nov. (type strain ZGLJ7-1T = KACC 18547T = CGMCC 1.15404T). PMID- 28840360 TI - Minimizing Barriers in Learning for On-Call Radiology Residents-End-to-End Web Based Resident Feedback System. AB - Feedback is an essential part of medical training, where trainees are provided with information regarding their performance and further directions for improvement. In diagnostic radiology, feedback entails a detailed review of the differences between the residents' preliminary interpretation and the attendings' final interpretation of imaging studies. While the on-call experience of independently interpreting complex cases is important to resident education, the more traditional synchronous "read-out" or joint review is impossible due to multiple constraints. Without an efficient method to compare reports, grade discrepancies, convey salient teaching points, and view images, valuable lessons in image interpretation and report construction are lost. We developed a streamlined web-based system, including report comparison and image viewing, to minimize barriers in asynchronous communication between attending radiologists and on-call residents. Our system provides real-time, end-to-end delivery of case specific and user-specific feedback in a streamlined, easy-to-view format. We assessed quality improvement subjectively through surveys and objectively through participation metrics. Our web-based feedback system improved user satisfaction for both attending and resident radiologists, and increased attending participation, particularly with regards to cases where substantive discrepancies were identified. PMID- 28840361 TI - Visual word recognition and vowelization in Arabic: new evidence from lexical decision task performances. AB - The effect of vowelization signs on the process of visual word recognition in Arabic was investigated among 41 native Arab skilled readers with age average of 30.66 +/- 9.09. The participants performed a lexical decision task using three types of words and pseudowords; full, partial and non-vowelized. The results showed that for both words and pseudowords, response times were shorter and accuracy levels were higher for the non-vowelized condition compared to the other conditions of vowelization. The results reinforce the argument that automatic lexical processes during word recognition in Arabic orthography might be disturbed by supplementary information such as vowelization. PMID- 28840362 TI - Effect of endoplasmic reticulum stress inhibition on hyperoxaluria-induced oxidative stress: influence on cellular ROS sources. AB - PURPOSE: Hyperoxaluria-induced calcium oxalate crystallisation is associated with the generation of reactive oxygen species (ROS) via mitochondria and NADPH oxidase. Endoplasmic reticulum (ER) has emerged as an organelle which could influence mitochondrial functioning and ROS generation. Plugging an upstream pathway of mitochondrial and NADPH oxidase-induced ROS generation may have better prophylaxis. Therefore, we propose to investigate the linkage of hyperoxaluria induced ROS generation with ER stress by inhibiting the later with 4 Phenylbutyric acid (4-PBA). METHODS: Male wistar rats were divided into three groups: a normal control group, an ethylene glycol with ammonium chloride-induced hyperoxaluric group (EA) and a third group which has hyperoxaluric animals given 4-PBA at a dose of 300 mg/kg. After 9 days of treatment, animals were sacrificed and renal tissues were analysed for histopathological examination, ROS, mitochondrial dysfunction, ER stress markers, inflammatory markers and NADPH oxidase subunits expression. RESULTS: Hyperoxaluric rats exhibited a significant increase in the levels of ROS, subsequently up-regulated levels of ER stress markers, inflammatory indicators, NADPH oxidase subunits and compromised mitochondrial functioning. However, ER stress amelioration appreciably curtailed the alterations caused by hyperoxaluric abuse. CONCLUSIONS: Therefore, suggesting the major role of ER in hyperoxaluric manifestations thereby providing an opportunity to target ER stress for future therapeutic interventions. PMID- 28840363 TI - Long-Term Effectiveness of the Question, Persuade, Refer (QPR) Suicide Prevention Gatekeeper Training Program: Lessons from Missouri. AB - Suicide in Missouri is a significant public health issue that has taken the lives of 8351 individuals over the last decade. The recognition of suicide as an imminent concern has led to the development of evidence-based prevention programs to decrease suicide-related mortality. One program, question, persuade, refer (QPR), has become the most widely-distributed gatekeeper training program in the world. This article presents both immediate and 2-year follow-up analyses of QPR trainees who work with youth, specifically examining changes in knowledge, self efficacy, and help-giving behaviors. Results indicate both short- and long-term positive outcomes in knowledge and self-efficacy, supporting use of QPR. PMID- 28840364 TI - Perservative paroxysmal atrioventricular block : Cardiac syncope misdiagnosed as anxiety for more than 20 years. AB - A 42-year-old woman was referred for cardiac diagnostic work-up of loss of recurrent consciousness over the past 25 years. She received medication with an anxiolytic, an antidepressant, and a neuroleptic drug. After a normal resting ECG, there were 112 episodes of paroxysmal atrioventricular block III degrees in her 24 h Holter recording with asystole for up to 27 s. The patient was symptomatic only once with dizziness due to an asystole of 8.8 s while she was awake in the early morning. After DDDR pacemaker implantation, the patient was asymptomatic during the following 2 years. This case illustrates the complex and not fully understood problem of paroxysmal AV block, in this instance neither intrinsic, nor phase 4 or vagally induced. It further reminds us to carefully clarify the cause of loss of consciousness consistently which may render prolonged ECG monitoring necessary also in patients without heart disease. PMID- 28840365 TI - Radiology and Enterprise Medical Imaging Extensions (REMIX). AB - Radiology and Enterprise Medical Imaging Extensions (REMIX) is a platform originally designed to both support the medical imaging-driven clinical and clinical research operational needs of Department of Radiology of The Ohio State University Wexner Medical Center. REMIX accommodates the storage and handling of "big imaging data," as needed for large multi-disciplinary cancer-focused programs. The evolving REMIX platform contains an array of integrated tools/software packages for the following: (1) server and storage management; (2) image reconstruction; (3) digital pathology; (4) de-identification; (5) business intelligence; (6) texture analysis; and (7) artificial intelligence. These capabilities, along with documentation and guidance, explaining how to interact with a commercial system (e.g., PACS, EHR, commercial database) that currently exists in clinical environments, are to be made freely available. PMID- 28840366 TI - In vitro feeding of Hyalomma lusitanicum ticks on artificial membranes. AB - In vitro feeding of ticks (Acari: Ixodidae) is an important means to study the biology of ticks and their vectorial capacity. Here, we have adapted the tick Hyalomma lusitanicum Koch to previously published silicone-based membranes for in vitro feeding. For comparison purposes data on pre-oviposition, oviposition and hatching from females engorged on animals were used. A total of 68 engorged females out of 169 were obtained; feeding duration and feeding behaviour were similar to that of ticks on live host animals, although the final weight achieved for membrane-fed ticks was lower than that of their animal-fed counterparts. Comparison of the time taken for egg production and hatching showed that pre oviposition was faster for membrane-fed ticks (16 days) than for animal-fed ticks (36 days), whereas the duration of oviposition-hatching was the same for the two feeding methods (34 days). We also observed that seasonality has an influence on tick feeding success: the conditions in Spring/Summer accelerated the tick life cycle. It is concluded that relatively large numbers of homogeneous laboratory raised Hyalomma ticks can be produced without feeding them on experimental animals. PMID- 28840367 TI - Assessment of using recombinant Ixodes ricinus AV422 saliva protein for confirmation of tick bites in hunting dogs as naturally infested hosts. AB - Due to the recorded spreading of ticks in past years, a higher incidence of tick borne diseases (TBDs) can be expected in the future in endemic areas, but can also pose an emerging public health concern in areas where they have not yet been recognized. Assessment of the exposure of vulnerable hosts to ticks would be a very helpful tool for TBD epidemiological studies, as well as for their proper managing. To confirm previous tick bites, the method of choice is detection of antibodies in host serum as markers developed against injected tick saliva proteins during feeding. We recently showed that the recombinant form of Ixodes ricinus AV422 saliva protein (rIrAV422) can serve for detection of markers in experimentally infested rats. Here we examine whether it can be used in the same manner in naturally exposed hosts. We chose hunting dogs as good sentinel animals. The study group consisted of 15 dogs that varied in breed, age, sex, previous tick infestation history and repellent treatment. Western blot analysis with rIrAV422 as an antigen confirmed the presence of tick bite markers in all analysed dogs. For some of the dogs, their previous tick infestation history was unclear, which emphasizes the usefulness of rIrAV422 for revealing it. Since hunting dogs are naturally infested with different ticks, the potential of rIrAV422 in assessment of general exposure to ticks is highlighted. Use of rIrAV422 can also be helpful in veterinary practice and research as a tool for validation of the efficiency of tick repellent products. PMID- 28840368 TI - MRI of anal canal: normal anatomy, imaging protocol, and perianal fistulas: Part 1. AB - Anal complaints are very common in the general population and are caused by a variety of disorders mostly benign in nature. The aim of this article is to provide the radiologist with a detailed description of the MRI anatomy and technique, and an overview of the various diseases most commonly presenting with anal pain, by descriptions and illustrative examples of MRI features of each entity. PMID- 28840369 TI - Novel histone deacetylase 8-selective inhibitor 1,3,4-oxadiazole-alanine hybrid induces apoptosis in breast cancer cells. AB - Identification of isoform-specific histone deacetylase inhibitors (HDACi) is a significant advantage to overcome the adverse side effects of pan-HDACi for the treatment of various diseases, including cancer. We have designed, and synthesized novel 1,3,4 oxadiazole with glycine/alanine hybrids as HDAC8-specific inhibitors and preliminary evaluation has indicated that 1,3,4 oxadiazole with alanine hybrid [(R)-2-amino-N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)propanamide (10b)] to be a potent HDAC8 inhibitor. In the present study, the in vitro efficacy of the molecule in inhibiting the cancer cell proliferation and the underlying molecular mechanism was studied. 10b inhibited the growth of MDA-MB 231 and MCF7 breast cancer cells, with a lower IC50 of 230 and 1000 nM, respectively, compared to K562, COLO-205 and HepG2 cells and was not cytotoxic to normal breast epithelial cells, MCF10A. 10b was specific to HDAC8 and did not affect the expression of other class I HDACs. Further, a dose-dependent increase in H3K9 acetylation levels demonstrated the HDAC-inhibitory activity of 10b in MDA-MB-231 cells. Flow cytometric analysis indicated a dose-dependent increase and decrease in the percent apoptotic cells and mitochondrial membrane potential, respectively, when treated with 10b. Immunoblot analysis showed a modulation of Bax/Bcl2 ratio with a decrease in Bcl2 expression and no change in Bax expression. 10b treatment resulted in induction of p21 and inhibition of CDK1 proteins along with cytochrome c release from mitochondria, activation of caspases-3 and -9 and cleavage of poly ADP-ribose polymerase leading to apoptotic death of MDA-MB-231 and MCF7 cells. In conclusion, our results clearly demonstrated the efficacy of 10b as an anticancer agent against breast cancer. PMID- 28840370 TI - Clinical and microbiological profile of chronic Burkholderia cepacia complex infections in a cystic fibrosis reference hospital in Brazil. AB - Burkholderia sp. infections are extremely complex in cystic fibrosis (CF) patients, especially considering the lack of knowledge regarding its behavior, its relationship with prognosis, as well as its transmissibility and multidrug resistance features. This study evaluated the frequency of chronic infection by Burkholderia, using microbiological and clinical data. Ninety-eight patients with CF attended from July 2011 to April 2014 in a Brazilian reference hospital were included. Antimicrobial activity, molecular epidemiology, Shwachman score, body mass index, exacerbations, and lung function were analyzed. Nine patients had chronic colonization, and all of them showed preserved pulmonary function levels, body mass index, and Shwachman score. Meropenem was the most effective antibiotic; however, divergent results were shown by other studies. Cross contamination may have occurred in only two unrelated patients of different ages, who were colonized by B. vietnamiensis, which does not occur frequently. Twelve new sequence types (STs) were identified and three STs have presented intercontinental distribution. None of the patients presented known epidemic strains. In conclusion, a relatively low number of patients with chronic colonization and suspected cross-infection were identified. Different from other studies that have found CF patients chronically colonized with Burkholderia sp. having a greater deterioration of lung function, more frequent antibiotic therapy, and increased mortality, in the current study, the patients showed good clinical outcomes and favorable options for antibiotics therapy. This study also updated the epidemiological database, which facilitates the multicentric collaborative analysis and assists in the control of global infection by these pathogens. PMID- 28840371 TI - Pathogenesis of peri-tumoral edema in intracranial meningiomas. AB - Peri-tumoral edema in intracranial meningiomas occurs frequently and obviously impacts the morbidity and mortality of these predominantly benign neoplasms. Several causative factors (age, gender, volume, location...) have been unsuccessfully investigated. Despite recent progresses in metabolic imaging and molecular biology, the pathogenesis of peri-tumoral edema remains debated. Hypotheses include vascular endothelial growth factor, metalloproteinases and interleukins among many others. It is probable that this pathogenesis encompasses all these factors with different levels. The current review aims to shed the light on the investigated factors involved in the pathogenesis of peri-tumoral edema in meningiomas and identify the potential therapeutic targets. PMID- 28840374 TI - [Choosing wisely together in pain medicine]. PMID- 28840372 TI - Persistent perineal sinus after abdominoperineal resection. AB - BACKGROUND AND AIMS: Persistent perineal sinus (PPS) defined as a perineal wound remaining unhealed more than 6 months after abdominoperineal resection (APR) is a well-known complication. The aim of our study was (1) to evaluate the incidence of PPS after APR for Crohn's disease (CD) in the era of biotherapy, (2) to determine long-term outcome of PPS, (3) to study risk factors associated with delayed perineal healing, and (4) to compare the results in this CD patient group with patients without CD. METHODS: From 1997 to 2013, the records of patients who underwent APR for CD and for non-CD rectal cancer with or without radiochemotherapy at two French university hospitals were studied retrospectively. Perineal healing was evaluated by clinical examination at 1, 6, and 12 months after surgery. RESULTS: The cumulative probability of perineal wound unhealed at 6 and 12 months after surgery was 85 and 48%, respectively, for 81 patients who underwent APR for CD patients in contrast to 21 and 13%, respectively, for 25 non-CD patients with rectal cancer. Eight patients with CD (10%) remained with PPS after a median follow up of 4 years and spontaneous perineal healing occurred with time for all non-CD patients. Factors associated with delayed perineal healing in CD included age at surgery < 49 years (p = 0.001) and colonic-only Crohn's disease location (p = 0.045). Medical treatments had no significant impact on perineal healing. CONCLUSIONS: PPS beyond 6 months post-APR remains a frequent complication but mostly resolves over time. CD is a risk factor for developing PPS and factors associated with higher incidence of PPS were age at surgery < 49 years and colonic-only Crohn's disease location. Prevention of PPS in this population with muscle flap during APR deserves to be evaluated. PMID- 28840373 TI - Implementing ultrasound-guided hydrostatic reduction of intussusception in a low resource country in Sub-Saharan Africa: our initial experience in Ethiopia. AB - BACKGROUND: Despite advances in non-invasive radiological techniques for the treatment of intussusception, management of the entity still remains exclusively surgical in many developing countries, including Ethiopia. Fluoroscopic units are rare or mostly dysfunctional. Ultrasound scanners are more commonly available. Ultrasound-guided hydrostatic reduction (USGHR) was recently introduced to the main referral hospital in Ethiopia, and subsequently has been adopted as the initial management option for intussusception. PURPOSE: The aim of this study was to evaluate our experience with USGHR in Ethiopia and measure the impact on patient care. METHODS: A prospective study was conducted between July 2014 and August 2015 on all pediatric patients, with US-confirmed intussusception, at the Tikur Anbessa Specialized Teaching Hospital in Addis Ababa, Ethiopia. All patients, excluding those with signs of peritonitis, bowel ischemia, or symptoms lasting longer than 4 days, were selected to undergo USGHR. RESULTS: A total of 53 children were diagnosed with intussusception, confirmed via ultrasound. Following exclusion criteria, USGHR was attempted in 47 of the patients. Forty one of the 47 patients (87.2%) had successful reduction, resulting in a 77% overall rate of successful non-operative management in all patients with intussusception. CONCLUSION: The rate of operative reduction of intussusception decreased by 77% following the introduction of USGHR as the initial non-surgical intervention. Therefore, we believe USGHR should be fully implemented in our hospital, and recommend that this study serves as an example to other institutions in our country as well as in other developing countries facing similar challenges. PMID- 28840375 TI - Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis. AB - Secreted frizzled-related protein 2 (SFRP2) is a pro-angiogenic factor expressed in the vasculature of a wide variety of human tumors, and modulates angiogenesis via the calcineurin-dependent nuclear factor of activated T-cells cytoplasmic 3 (NFATc3) pathway in endothelial cells. However, until now, SFRP2 receptor for this pathway was unknown. In the present study, we first used amino acid alignments and molecular modeling to demonstrate that SFRP2 interaction with frizzled-5 (FZD5) is typical of Wnt/FZD family members. To confirm this interaction, we performed co-immunofluorescence, co-immunoprecipitation, and ELISA binding assays, which demonstrated SFRP2/FZD5 binding. Functional knock down studies further revealed that FZD5 is necessary for SFRP2-induced tube formation and intracellular calcium flux in endothelial cells. Using protein analysis on endothelial cell nuclear extracts, we also discovered that FZD5 is required for SFRP2-induced activation of NFATc3. Our novel findings reveal that FZD5 is a receptor for SFRP2 and mediates SFRP2-induced angiogenesis via calcineurin/NFATc3 pathway in endothelial cells. PMID- 28840376 TI - Molecular characterization of transport lectin vesicular integral membrane protein 36 kDa (VIP36) in the life cycle of Schistosoma mansoni. AB - VIP36 is a protein described as an L-type lectin in animals, responsible for the intracellular transport of glycoproteins within the secretory pathway, and also localized on the plasma membrane. Schistosoma mansoni has a complex system of vesicles and protein transport machinery to the cell surface. The excreted/secreted products of the larvae and eggs are known to be exposed to the host immune system. Hence, characterizing the role and action of SmVIP36 in the S. mansoni life cycle is important for a better understanding of the parasite host relationship. To this purpose, we firstly performed in silico analysis. Analysis of SmVIP36 in silico revealed that it contains a lectin leg-like domain with a jellyroll fold as seen by its putative 3D tertiary structure. Additionally, it was also observed that its CRD contains calcium ion-binding amino acids, suggesting that the binding of SmVIP36 to glycoproteins is calcium dependent. Finally, we observed that the SmVIP36 predicted amino acid sequence relative to its orthologs was conserved. However, phylogenetic analysis revealed that SmVIP36 follows species evolution, forming a further cluster with its definitive host Homo sapiens. Moreover, q-PCR analysis in the S. mansoni life cycle points to a significant increase in gene expression in the eggs, schistosomulae, and female adult stages. Similarly, protein expression increased in eggs, cercariae, schistosomulae, and adult worm stages. These results suggest that SmVIP36 might participate in the complex secretory activity within the egg envelope and tegument proteins, both important for the stages of the parasite that interact with the host. PMID- 28840377 TI - A simplified sampling procedure for the estimation of methane emission in rice fields. AB - Manual closed chamber methods are widely used for CH4 measurement from rice paddies. Despite diurnal and seasonal variations in CH4 emissions, fixed sampling times, usually during the day, are used. Here, we monitored CH4 emission from rice paddies for one complete rice-growing season. Daytime CH4 emission increased from 0800 h, and maximal emission was observed at 1200 h. Daily averaged CH4 flux increased during plant growth or fertilizer application and decreased upon drainage of plants. CH4 measurement results were linearly interpolated and matched with the daily averaged CH4 emission calculated from the measured results. The time when daily averaged emission and the interpolated CH4 curve coincided during the daytime was largely invariant within each of the five distinctive periods. One-hourly sampling during each of these five periods was utilized to estimate the emission during each period, and we found that five one hourly samples during the season accurately reflected the CH4 emission calculated based on all 136 hourly samples. This new sampling scheme is simple and more efficient than current sampling practices. Previously reported sampling schemes yielded estimates 9 to 32% higher than the measured CH4 emission, while our suggested scheme yielded an estimate that was only 5% different from that based on all 136-h samples. The sampling scheme proposed in this study can be used in rice paddy fields in Korea and extended worldwide to countries that use similar farming practices. This sampling scheme will help in producing more accurate global methane budget from rice paddy fields. PMID- 28840379 TI - A comparison of the effects of exercises plus connective tissue massage to exercises alone in women with fibromyalgia syndrome: a randomized controlled trial. AB - This study aimed to compare the effectiveness of a 6-week combined exercise program with and without connective tissue massage (CTM) on pain, fatigue, sleep problem, health status, and quality of life in patients with fibromyalgia syndrome (FMS). Patients were randomly allocated into Exercise (n = 20) and Exercise + CTM (n = 20) groups. The exercise program with and without CTM was carried out 2 days a week for 6 weeks. Pain, fatigue, sleep problem with Visual Analog Scales, health status with Fibromyalgia Impact Questionnaire (FIQ), and quality of life with Short Form-36 were evaluated. After the program, pain, fatigue and sleep problem reduced, health status (except of the scores of FIQ-1 and FIQ-10), physical functioning, role limitations due to physical health, bodily pain, role limitations due to emotional health, vitality, and general health perceptions parameters related to quality of life improved in the Exercise group, (P < 0.05). In the Exercise + CTM group, pain, fatigue and sleep problem decreased, health status and quality of life improved (P < 0.05). Pain, fatigue, sleep problem, and role limitations due to physical health improved in the Exercise + CTM group in comparison to the Exercise group (P < 0.05). The study suggested that exercises with and without CTM might be effective for decreasing pain, fatigue and sleep problem whereas increasing health status and quality of life in patients with FMS. However, exercises with CTM might be superior in improving pain, fatigue, sleep problem, and role limitations due to physical health compared to exercise alone. PMID- 28840378 TI - Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families. AB - PURPOSE: The main aim of this study was to screen epigenetic modifier genes and known breast cancer driver genes for germline mutations in non-BRCA1/2 (BRCAx) breast cancer families in order to identify novel susceptibility genes of moderate-high penetrance. METHODS: We screened 264 candidate susceptibility genes in 656 index cases from non-BRCA1/2 families. Potentially pathogenic candidate mutations were then genotyped in all available family members for the assessment of co-segregation of the variant with disease in the family in order to estimate the breast cancer risks associated with these mutations. For 11 of the candidate susceptibility genes, we screened an additional 800 non-BRCA1/2 breast cancer cases and 787 controls. RESULTS: Only two genes, CHD8 and USH2A showed any evidence of an increased risk of breast cancer (RR = 2.40 (95% CI 1.0-7.32) and 2.48 (95% CI 1.11-6.67), respectively). CONCLUSIONS: We found no convincing evidence that epigenetic modifier and known breast cancer driver genes carry germline mutations that increase breast cancer risk. USH2A is no longer regarded as a breast cancer driver gene and seems an implausible candidate given its association with Usher syndrome. However, somatic mutations in CHD8 have been recently reported, making it an even more promising candidate, but further analysis of CHD8 in very large cohorts of families or case-control studies would be required to determine if it is a moderate-risk breast cancer susceptibility gene. PMID- 28840380 TI - Implementation of a novel efficacy score to compare sealing and cutting devices in a porcine model. AB - BACKGROUND: In general surgery, minimally invasive laparoscopic procedures have been steadily increasing over the last decade. The application of advanced bipolar and ultrasonic energy devices for sealing and cutting of blood vessels plays a vital role in routine clinical procedures. The advantages of energy-based instruments are enhanced sealing capability combined with both fast sealing time and minimal thermal injury. The purpose of this study was to compare the safety and efficacy profiles of nine laparoscopic sealing and cutting devices in a porcine model, with a new scoring system. METHODS: Comparative studies in a porcine model were performed to assess vessel sealing, burst pressure, thermal spread, maximum heat, sealing/cooling time, and compression strength over the full jaw. Nine different devices from five manufacturers were tested in this study. The sealing and cutting devices (SCD) score has been developed to enable standardized comparisons of various devices. For this purpose, the most important parameters were identified through a consensus approach. RESULTS: All sealed vessels with different devices could withstand a median pressure of more than 300 mmHg (range 112-2046 mmHg). The time for the sealing procedure was 7.705 s (range 5.305-18.38 s) for the ultrasonic and 7.860 s (range 5.08-10.17 s) for the bipolar devices. The ultrasonic instruments reached a median temperature of 218.1 degrees C (range 81.3-349.75 degrees C) and the bipolar devices a temperature of 125.5 degrees C (range 94.1-133.35 degrees C). The tissue reached a median temperature of 61.9 (range 47.1-80.6 degrees C) after ultrasonic sealing and 76.7 degrees C (range 63.1-94.2 degrees C) after bipolar sealing. The median SCD score was 10.47 (range 7.16-13.72). CONCLUSION: All the instruments used seemed safe for use on the patient. The SCD score allows an indirect comparability of the instruments. PMID- 28840381 TI - Early Abdominal Imaging Remains Over-Utilized in Acute Pancreatitis. AB - BACKGROUND: Early abdominal computed tomography (CT) or magnetic resonance (MR) imaging is common in acute pancreatitis (AP). Guidelines (2007-2013) indicate routine use is unwarranted. AIMS: To compare the frequency and evaluate the predictors of early CT/MR utilization for AP between September 2006-2007 (period A) and September 2014-2015 (period B). METHODS: AP patients presenting directly to a large academic emergency department were prospectively enrolled during each period. Cases requiring imaging to fulfill diagnostic criteria were excluded. Early CT/MR (within 24 h of presentation) utilization rates were compared using Fisher's exact test. Predictors of early imaging usage were assessed with multivariate logistic regression. RESULTS: The cohort included 96 AP cases in period A and 97 in period B. There were no significant differences in patient demographics, comorbidity scores, or AP severity. Period B cases manifested decreased rates of the systemic inflammatory response syndrome (SIRS) during the first 24 h of hospitalization (67% period A vs. 43% period B, p = 0.001). Independent predictors of early imaging included age >60 and SIRS or organ failure on day 1. No significant decrease in early CT/MR usage was observed from period A to B on both univariate (49% period A vs. 40% period B, p = 0.25) and multivariate (OR 1.0 for period B vs. A, 95% CI 0.5-1.9) analysis. CONCLUSIONS: In a comparison of imaging practices for AP, there was no significant decrease in early abdominal CT/MR utilization from 2007 to 2015. Quality improvement initiatives specifically targeting early imaging overuse are needed. PMID- 28840382 TI - New photobiomodulation protocol prevents oral mucositis in hematopoietic stem cell transplantation recipients-a retrospective study. AB - Oral mucositis (OM) is an adverse side effect among hematopoietic stem cell transplantation (HSCT) recipients. The objective of this retrospective study was to evaluate the preventive effect of photobiomodulation (PBM) applied three times per week versus seven times per week in patients undergoing HSCT. The risk factors related to the incidence and severity of OM were also assessed. This was a retrospective study that evaluated 99 HSCT recipients who received different PBM protocols. Group I received three sessions per week, and group II received daily treatment. PBM was applied using a continuous-wave diode laser (InGaAlP; MM Optics, Sao Carlos, SP, Brazil) at a wavelength of 660 nm (visible-red) and a total radiant energy of 0.24 J per point. The baseline disease, type of transplant, type of conditioning, prophylaxis against graft-versus-host disease, OM grade, absolute leukocyte and platelet counts, and levels of liver and renal function markers were collected from medical records. The patients' age ranged from 13 to 71 years (mean/SD, 40.54 +/- 16.45). No significant difference was observed between groups I and II regarding sex, age, ethnic, diagnosis, donor type, and conditioning treatment. Both PBM protocols were equally efficient in preventing OM (p = 0.34, ANOVA). Independent of the PBM protocol used, patients who received allogeneic transplant (p < 0.01-Fischer's exact test), total body irradiation (TBI-12Gy) (p = 0.01-chi-square test), busulfan + cyclophosphamide (p < 0.01-chi-square test), or methotrexate-containing regimens (p < 0.01-Fischer's exact test) demonstrated higher OM incidence and severity. Myelosuppression (p < 0.01-Mann-Whitney test) and impaired renal function (p = 0.02-Mann-Whitney test) were also considered risk factors for OM. Based on this retrospective data, PBM was effective in preventing OM in patients undergoing HSCT even when it was applied three times a week. A prospective study might be necessary to confirm these findings. PMID- 28840383 TI - Comprehensive echocardiographic assessment of biventricular function in the rabbit, animal model in cardiovascular research: feasibility and normal values. AB - Quantification of cardiac structure and function is central in cardiovascular research. Rabbits are valuable research models of cardiovascular human disease; however, there is little normal data available. The aim of this study was to investigate feasibility and provide normal values for comprehensive echocardiographic assessment of biventricular function in rabbits. New Zealand white rabbits underwent trans-thoracic echocardiography using a general electric (GE) Vivid 7/E9 system with a 10 MHz transducer, under light sedation, to evaluate biventricular function and dimensions. Images for two-dimensional, M mode, tissue Doppler imaging (TDI) and speckle-tracking strain echocardiography were acquired and analysed. 55 male rabbits (sized matched with a newborn human baby) were studied, mean weight was 2.9 +/- 0.23 kg. Adequate images were obtained in 90% for the left ventricle (LV) and 80% for the right ventricle (RV). Two-dimensional speckle-tracking strain was feasible in 60%. Average heart rate was 248 +/- 36 beats per minute; LV ejection faction 72 +/- 8.0; RV fractional area change 45.9 +/- 9.0%; RV myocardial performance index 0.39 +/- 0.35; tricuspid annular planar systolic excursion 0.60 +/- 0.24 cm. LV TDI parameters were S' 8.6 +/- 3.1 cm/s; E' 12.0 +/- 4.46 cm/s. RV TDI parameters were S' 10.49 +/- 3.18; E' 14.95 +/- 4.64 cm/s. LV and RV global peak systolic longitudinal strain were -17 +/- 5 and -22 +/- 8%, respectively. Comprehensive investigation of biventricular dimensions and function by echocardiography is feasible in the rabbit. Apical views and strain imaging have lower feasibility. Normal values of LV and RV functional parameters are with comparable values to human children. Animal cardiovascular research is key to develop new goals in clinical practice. PMID- 28840385 TI - Nonalcoholic Steatohepatitis: The Second Leading Indication for Liver Transplantation in the USA. PMID- 28840384 TI - Survival benefit of pelvic and paraaortic lymphadenectomy in high-grade endometrial carcinoma: a retrospective population-based cohort analysis. AB - OBJECTIVE: The standard therapy for high-grade endometrial cancer is surgery but the therapeutic effects of pelvic and paraaortic lymph node dissection (LND) are poorly investigated. In this study, we retrospectively evaluated overall survival, recurrence rates and recurrence-free survival among patients with high grade type I and II endometrial carcinoma who underwent LND. METHODS: This study included 284 patients who are recorded in the German Tumor Centre Regensburg form 1998 to 2015 and were selected by cancer grading, the absence of secondary tumors, primary surgery including hysterectomy and available follow-up. 244 of the 284 patients in this cohort were unequivocally classified as R0 after resection. RESULTS: A significantly increased overall survival was observed for systematic LND of 25 or more paraaortic and pelvic lymph nodes versus patients who did not undergo such intervention (p < 0.001) or had elective LND of 1-24 lymph nodes both in univariable (p = 0.016) and multivariable (p = 0.014) analysis. A similar observation was made for recurrence-free survival of patients in the cohort who underwent complete tumor resection (R0). In addition, a reduced cumulative recurrence rate was observed for patients with systematic LND. CONCLUSIONS: Our study provides evidence that the systematic removal of 25 or more pelvic and paraaortic lymph nodes reduces the recurrence rate and that it is beneficial for the long-term overall and recurrence-free survival of patients with high-grade endometrial cancer. PMID- 28840386 TI - Medical Image Retrieval Using Multi-Texton Assignment. AB - In this paper, we present a multi-texton representation method for medical image retrieval, which utilizes the locality constraint to encode each filter bank response within its local-coordinate system consisting of the k nearest neighbors in texton dictionary and subsequently employs spatial pyramid matching technique to implement feature vector representation. Comparison with the traditional nearest neighbor assignment followed by texton histogram statistics method, our strategies reduce the quantization errors in mapping process and add information about the spatial layout of texton distributions and, thus, increase the descriptive power of the image representation. We investigate the effects of different parameters on system performance in order to choose the appropriate ones for our datasets and carry out experiments on the IRMA-2009 medical collection and the mammographic patch dataset. The extensive experimental results demonstrate that the proposed method has superior performance. PMID- 28840387 TI - Systematic and progressive implementation of the centers of excellence for rheumatoid arthritis: a methodological proposal. AB - The implementation of excellence centers in specific diseases has been gaining recognition in the field of health; specifically in rheumatoid arthritis, where the prognosis of the disease is related to an early diagnosis and a timely intervention, it is necessary that the provision of health services is developed in an environment of quality, opportunity, and safety with the highest standards of care. A methodology that allows this implementation in such a way that is achievable by the most of the care centers is a priority to achieve a better attention to populations with this disease. In this paper, we propose a systematic and progressive methodology that will help all the institutions to develop successful models without faltering in the process. The expected impact on public health is defined by a better effective coverage of high-quality treatments, obtaining better health outcomes with safety and accessibility that reduces the budgetary impact for the health systems of our countries. PMID- 28840388 TI - Molecular screening of multidrug-resistance tuberculosis by a designated public health laboratory in Taiwan. AB - This manuscript describes our experience in early identifying MDR-TB cases in high-risk populations by setting up a single-referral molecular diagnosis laboratory in Taiwan. Taiwan Centers for Disease Control designated a single referral laboratory to provide the GenoType MTBDRplus test for screening high risk MDR-TB populations nationwide in 2012-2015. A total of 5,838 sputum specimens from 3,308 patients were tested within 3 days turnaround time. Compared with the conventional culture and drug susceptibility testing, the overall performance of the GenoType MTBDRplus test for detecting TB infection showed accuracy of 70.7%, sensitivity of 85.9%, specificity of 65.7%, positive predictive value of 45.5%, and negative predictive value of 93.3%. And the accuracy of detecting rifampin (RIF) resistance, isoniazid (INH) resistance, and MDR-TB (resistant to at least RIF and INH) were 96.5%, 95.2%, and 97.7%, respectively. MDR-TB contacts presented a higher rate of mutated codons 513-519, GenoType MTBDRplus banding pattern: rpoB WT3(-), and rpoB WT4(-) than the treatment failure group. The MDR-TB contact group also had a higher rate of inhA C15T mutation, banding pattern: inhA WT1(-), and inhA MUT1(+) than the recurrent group. Resistance profiles of MDR-TB isolates also varied geographically. The referral molecular diagnosis system contributed to rapid detection and initiation of appropriate therapy. PMID- 28840389 TI - Maternal use of household pesticides during pregnancy and risk of neuroblastoma in offspring. A pooled analysis of the ESTELLE and ESCALE French studies (SFCE). AB - PURPOSE: Neuroblastoma (NB) is an embryonic tumor that occurs almost exclusively in infancy and early childhood. While considerable evidence suggests that it may be initiated during embryonic development, the etiology of NB is still unknown. The aim of this study was to explore whether there is an association between maternal use of household pesticides during pregnancy and the risk of NB in the offspring. METHODS: We conducted a pooled analysis of two French national-based case-control studies. The mothers of 357 NB cases and 1,783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on sociodemographic and perinatal characteristics, childhood environment, and life-style. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. RESULTS: After controlling for matching variables, study of origin, and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with NB (OR 1.5 [95% CI 1.2-1.9]). The most commonly used type of pesticides were insecticides and there was a positive association with their use alone (OR 1.4 [95% CI 1.1-1.9]) or with other pesticides (OR 2.0 [95% CI 1.1-3.4]). CONCLUSIONS: Although there is the potential for recall bias due to the study design, our findings add to the evidence of an association between the household use of pesticides and NB. Until a better study design can be found, our findings add yet another reason why to advise pregnant women to limit pesticide exposure during the periconceptional period. PMID- 28840390 TI - Laparoscopic mesh removal for otherwise intractable inguinal pain following endoscopic hernia repair is feasible, safe and may be effective in selected patients. AB - BACKGROUND: Laparoscopic inguinal hernia repair is preferred over an open technique because of reduced recovery time, favorable cost effectiveness, and less chronic postoperative inguinal pain. Nevertheless, some patients develop a nociceptive inguinal pain syndrome possibly related to the presence of the mesh. This is the first study describing feasibility, safety, and effectiveness of laparoscopic mesh removal in patients with chronic pain after endoscopic hernia repair. METHODS: Pre- and intraoperative data of chronic pain patients scheduled for endoscopic mesh removal were prospectively collected by a standard evaluation form. Long-term efficacy was determined using pain scores, patient satisfaction, and quality of life questionnaire. A Wilcoxon signed-rank test was used to determine significant differences between pre- and postoperative pain scores. RESULTS: Fourteen patients were studied (11 males, median 52 years). Median operating time was 103 min. Conversion to open surgery was not required. One intraoperatively recognized bladder laceration was laparoscopically closed. Otherwise, no intraoperative or postoperative complications occurred. Eight months postoperatively (median), pain scores had dropped from eight to four (p < 0.01). Satisfaction was good or excellent in ten patients. A recurrent hernia developed in two patients requiring an open mesh repair in one. CONCLUSIONS: Laparoscopic mesh removal is a feasible, safe, and effective option in selected patients with chronic groin pain after endoscopic hernia repair in the hands of an experienced surgeon. PMID- 28840391 TI - Respiratory Sinus Arrhythmia in Cognitive Behavioral Therapy for Posttraumatic Stress Symptoms in Children: Preliminary Treatment and Gender Effects. AB - Cognitive behavioral therapy (CBT) is an efficacious treatment for posttraumatic stress disorder (PTSD) symptoms, but the effect of CBT on physiological indicators is largely unknown. Respiratory sinus arrhythmia (RSA) is an established parasympathetic marker of self-regulatory capacity and stress responsivity. The present study tested if and how resting RSA and RSA reactivity changed following treatment among a sample of children (n = 48) who experienced at least one traumatic event and presented with PTSD symptoms. RSA reactivity was measured in response to personalized trauma-related scripts. Results indicated that changes in RSA after treatment were dependent on pretreatment resting levels of RSA, with individuals with high and low pretreatment resting RSA levels appearing to converge over time in both resting RSA and RSA reactivity by the 3 month follow up. Specific to RSA reactivity, a sex difference was evident, as following treatment, females showed less RSA withdrawal whereas males showed more RSA withdrawal. PTSD symptoms were significantly reduced after CBT but symptom change was not associated with pretreatment resting RSA levels. Overall, these results suggest that there may be multiple physiological patterns within children with PTSD and the direction of the physiological changes after CBT may depend on initial differences in resting RSA levels. PMID- 28840393 TI - A matter of you versus me? Experiences of control in a joint go/no-go task. AB - When interacting with others, people represent their own as well as their interaction partners' actions. Such joint action representation is essential for action coordination, but may also interfere with action control. We investigated how joint action representations affect experienced control over people's own actions and their interaction partners' actions. Participants performed a joint go/no-go task, which is commonly used to measure to what extent people represent their own actions in spatial reference to their interaction partner (e.g., as 'left' vs. 'right'). After each second trial, participants indicated experienced control over their own action, their interaction partner's action, or over action inhibition. Despite this frequent interruption of the go/no-go task, we found strong evidence for the spatial representation of joint actions. However, this joint action representation did not affect experiences of control. Possible explanations and implications of these findings are discussed. PMID- 28840392 TI - Advances in metabolome information retrieval: turning chemistry into biology. Part I: analytical chemistry of the metabolome. AB - Metabolites are small molecules produced by enzymatic reactions in a given organism. Metabolomics or metabolic phenotyping is a well-established omics aimed at comprehensively assessing metabolites in biological systems. These comprehensive analyses use analytical platforms, mainly nuclear magnetic resonance spectroscopy and mass spectrometry, along with associated separation methods to gather qualitative and quantitative data. Metabolomics holistically evaluates biological systems in an unbiased, data-driven approach that may ultimately support generation of hypotheses. The approach inherently allows the molecular characterization of a biological sample with regard to both internal (genetics) and environmental (exosome, microbiome) influences. Metabolomics workflows are based on whether the investigator knows a priori what kind of metabolites to assess. Thus, a targeted metabolomics approach is defined as a quantitative analysis (absolute concentrations are determined) or a semiquantitative analysis (relative intensities are determined) of a set of metabolites that are possibly linked to common chemical classes or a selected metabolic pathway. An untargeted metabolomics approach is a semiquantitative analysis of the largest possible number of metabolites contained in a biological sample. This is part I of a review intending to give an overview of the state of the art of major metabolic phenotyping technologies. Furthermore, their inherent analytical advantages and limits regarding experimental design, sample handling, standardization and workflow challenges are discussed. PMID- 28840394 TI - Lipophilic gold(I) complexes with 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2 thione moieties: synthesis and their cytotoxic and antimicrobial activities. AB - Novel lipophilic gold(I) complexes containing 1,3,4-oxadiazol-2-thione or 1,3 thiazolidine-2-thione derivatives were synthesized and characterized by IR, high resolution mass spectrometry, and 1H, 13C 31P NMR. The cytotoxicity of the compounds was evaluated considering cisplatin and/or auranofin as reference in different tumor cell lines: colon cancer (CT26WT), metastatic skin melanoma (B16F10), breast adenocarcinoma (MCF-7), cervical carcinoma (HeLa), glioblastoma (M059 J). Normal human lung fibroblasts (GM07492-A) and kidney normal cell (BHK 21) were also evaluated. The gold(I) complexes were more active than their respective free ligands and cisplatin. Furthermore, antibacterial activity was evaluated against Gram-positive bacteria Staphylococcus aureus ATCC 25213, Staphylococcus epidermidis ATCC 12228 and Gram-negative bacteria Escherichia coli ATCC 11229 and Pseudomonas aeruginosa ATCC 27853 and expressed as the minimum inhibitory concentration (MIC). The complexes exhibited lower MIC values when compared to the ligands and chloramphenicol against Gram-positive bacteria and Gram-negative bacteria. Escherichia coli was sensitive one to the action of gold(I) complexes. PMID- 28840395 TI - Clopidogrel IBS Patients Have Higher Incidence of Gastrointestinal Symptoms Influenced by Age and Gender. AB - BACKGROUND: Clopidogrel is an irreversible antagonist of P2Y12 receptors (P2Y12Rs) used as an antiplatelet drug to reduce risk of thrombosis. P2Y12Rs are expressed in gastrointestinal (GI) tract where they might regulate GI function. AIM: To evaluate if blockade of P2Y12Rs by clopidogrel is associated with higher incidence of GI symptoms in patients with irritable bowel syndrome (IBS). METHODS: A retrospective analysis of our institutional database was conducted for a 13-year period. IBS patients were identified, and their demographics, GI symptoms and clopidogrel therapy were collected. Logistic regression models were used to characterize symptoms in clopidogrel versus no-clopidogrel IBS-groups, adjusting for Age and Sex differences. An additional study characterized the P2Y12R distribution in human gut. RESULTS: The search identified 7217 IBS patients (6761 no-clopidogrel/456 clopidogrel). There were a higher proportion of patients with GI symptoms on clopidogrel (68%) compared to controls (60%, p = 0.0011) that were Females (70 vs. 60%, p = 0.0003) not Males (61 vs. 60%; p = 0.8312). In Females, clopidogrel was associated with higher incidence of GI symptoms (Age adjusted; p < 0.0001) for pain, constipation, gastroparesis (p <= 0.0001) and psychogenic pain (p = 0.0006). Age or Sex (adjusted models) influenced one or more GI symptoms (i.e., pain, p < 0.0001; constipation, p < 0.0001/p = 0.008; diarrhea, flatulence, p = 0.01). P2Y12R immunoreactivity was abundant in human ENS; glial-to-neuron ratio of P2Y12Rs expressed in Females ? Males. CONCLUSIONS: Irreversible blockade of P2Y12R by clopidogrel is associated with higher incidence of GI symptoms in Female IBS patients, although Age or Sex alone contributes to symptomatology. Prospective studies can determine clinical implications of P2Y12Rs in IBS. PMID- 28840396 TI - Impact of a Structural Intervention to Address Alcohol Use Among Gay Bar Patrons in San Francisco: The PACE Study. AB - We evaluated the impact on alcohol intake and blood alcohol concentration (BAC) of a multi-level structural intervention to increase the availability of free water, coupled with messaging on pacing alcohol intake and normative feedback of blood alcohol concentration in a convenience sample of gay bars in San Francisco. Participants (n = 1,293) were recruited among exiting patrons of four gay bars (two intervention bars and two control bars). Participants were surveyed on alcohol intake and BAC was measured by breathalyzer. Prior to the intervention there were no significant differences in baseline alcohol measures between intervention and control bars. Post-intervention there were significant differences on objective and subjective measures of alcohol consumption: 30% of intervention bar participants had BAC% levels over the legal driving limit (0.08%) compared to 43% of control bar participants, p < 0.0001 and 78% of intervention bar participants were above the AUDIT-C cut-off for hazardous drinking compared to 87% in control bars, p < 0.001. PMID- 28840397 TI - Right ventricular involvement evaluated by cardiac magnetic resonance imaging predicts mortality in patients with light chain amyloidosis. AB - Few studies have focused on right ventricular (RV) involvement in cardiac amyloidosis (CA). We investigated the prognostic value of RV assessment by cardiovascular magnetic resonance (CMR) in CA. In 2011-2014, consecutive patients with suspected CA referred for CMR were retrospectively evaluated. Demographic and baseline clinical characteristics were collected. Healthy volunteers were matched for sex and age and served as controls. All subjects underwent a contrast enhanced CMR examination. RV size, function, and late gadolinium enhancement (LGE) were analyzed. All deaths during follow-up were recorded. Sixty-one patients [37 males (60.7%), age 60 +/- 11 years] were included; CA was diagnosed in 47 (77.0%) patients. CA patients displayed decreased biventricular ejection fraction, elevated left ventricular mass index, and increased biventricular end systolic volume index (ESVi) compared with controls. A total of 27 deaths (57.4%) occurred in the CA group at 21-month median follow-up. Multivariable analysis demonstrated that RVESVi (HR 1.033, 95% CI 1.004-1.063, P = 0.026) and RV-LGE (HR 2.814, 95% CI 1.063-7.450, P = 0.037) were independent predictors of mortality in CA. For all amyloid patients, log NT-proBNP (HR 3.412; 95% CI 1.484-7.845; P = 0.004) and RV-LGE (HR 4.149; 95% CI 1.623-10.607; P = 0.003) were identified as independent predictors. RVESVi and RV-LGE are independent predictors of survival and evaluation of RV by CMR enables risk stratification in patients with CA. PMID- 28840398 TI - Delayed sciatic nerve compression following hamstring injury. AB - A 47-year-old man presented three months post-hamstring injury with posterior thigh and buttock pain, paraesthesia over the lateral part of the leg and dorsum of the foot and a foot drop. MRI identified a hamstring muscle injury with a lesion surrounding 20 cm of the proximal sciatic nerve consistent with an extensive haematoma. Surgical debridement and release was planned; however, his signs spontaneously resolved with rest, physiotherapy and splintage prior to surgery. There have been no other reports of a sciatic nerve lesion with neurological signs resolving without surgical exploration. PMID- 28840399 TI - Transition Metal (II) Complexes with a Novel Azo-azomethine Schiff Base Ligand: Synthesis, Structural and Spectroscopic Characterization, Thermal Properties and Biological Applications. AB - The pyrimidine based azo-linked Schiff base ligand, 5-benzoyl-1-((E)-(2-hydroxy-3 methoxy-5-((E)phenyldiazenyl)benzylidene)amino)-4-phenylpyrimidin-2(1H)-one (HL), and its transition metal (II) complexes were synthesized and defined by using 1H NMR, 13C-NMR, Elemental analysis, FT-IR, MS, UV-vis, molar conductance, magnetic susceptibility and thermal analysis techniques. According to the conductance data obtained indicate all of the metal complexes have non-electrolytic nature. Square pyramidal geometry for Pd(II) and octahedral geometry for all the other complexes synthesized was concluded from the electronic absorption spectra and magnetic susceptibility measurements of the complexes. Investigation of the significant infrared bands of the active groups in the ligand and the solid complexes alludes that HL is coordinated to the metal ions ONO tridentate manner. Moreover, the absorption and emission properties of the azo-azomethine based ligand and its complexes were investigated. The results obtained show that fluorescence emissions of the ligand and its metal (II) complexes depend on the type of transition metal ions and the derivatives displayed moderate Stokes' shift values between 44 and 107 nm. All the compounds exhibited superb photostability. Further, antioxidant, antimicrobial and pBR322 plasmid DNA cleavage activities were investigated. All compounds showed good DPPH* (1,1-diphenyl-2 picrylhydrazyl) radical scavenging activity and complexes of [MnL2]*H2O and [NiL2]*H2O exhibited excellent metal chelating activity. All the compounds tested demonstrated two strand DNA cleavage activities. PMID- 28840401 TI - Rural and Urban Differences in Sexual Behaviors Among Adolescents in Florida. AB - The national teen birth rate is higher in rural compared to urban areas. While national data suggest rural areas may present higher risk for adverse sexual health outcomes among adolescents, it is unknown whether there are differences within the state of Florida. Overall, Florida has poorer sexual health indicators for adolescents compared to national rates. The purpose of this study was to assess differences in sexual behaviors among Florida adolescents by rural-urban community location. This study includes baseline data from a randomized controlled trial conducted in Florida high schools. Of the 6316 participants, 74% were urban and 26% were rural. Participants responded to questions on sexual behaviors, sexual behavior intentions, and demographics. We estimated the effect of rural-urban status on risk outcomes after controlling for demographic variables using generalized linear mixed models. More teens from rural areas reported ever having sex (24.0%) compared to urban teens (19.7%). No significant differences were observed for most of sexual behaviors assessed. Nonetheless, urban participants were less likely to intend to have sex without a condom in the next year compared to rural participants (aOR = 0.76, 95% CI 0.63-0.92). Overall, there were no major differences in sexual behaviors between rural and urban adolescents in Florida. However, sexual intentions differed between rural and urban adolescents; specifically, rural adolescents were more likely to intend to have sex without a condom in the next year compared to urban adolescents. Understanding the specific disparities can inform contraception and sexual health interventions among rural youth. PMID- 28840400 TI - Therapeutic effects of the combination of inhaled beta2-agonists and beta blockers in COPD patients with cardiovascular disease. AB - Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide, with co-morbidities contributing to the overall severity and mortality of the disease. The incidence and prevalence of cardiovascular disease among COPD patients are high. Both disorders often co-exist, mainly due to smoking, but they also share common underlying risk factors, such as aging and low-grade systemic inflammation. The therapeutic approach is based on agents, whose pharmacological properties are completely opposed. Beta2-agonists remain the cornerstone of COPD treatment due to their limited cardiac adverse effects. On the other hand, beta blockers are administered in COPD patients with cardiovascular disease, but despite their proven cardiac benefits, they remain underused. There is still a trend among physicians over underprescription of these drugs in patients with heart failure and COPD due to bronchoconstriction. Therefore, cardioselective beta-blockers are preferred, and recent meta-analyses have shown reduced rates in mortality and exacerbations in COPD patients treated with beta-blockers. PMID- 28840402 TI - Optimization of the purine operon and energy generation in Bacillus amyloliquefaciens for guanosine production. AB - OBJECTIVES: To deregulate the purine operon of the purine biosynthetic pathway and optimize energy generation of the respiratory chain to improve the yield of guanosine in Bacillus amyloliquefaciens XH7. RESULTS: The 5'-untranslated region of the purine operon, which contains the guanine-sensing riboswitch, was disrupted. The native promoter Pw in B. amyloliquefaciens XH7 was replaced by different strong promoters. Among the promoter replacement mutants, XH7purE::P41 gave the highest guanosine yield (16.3 g/l), with an increase of 23% compared with B. amyloliquefaciens XH7. The relative expression levels of the purine operon genes (purE, purF, and purD) in the XH7purE::P41 mutant were upregulated. The concentration of inosine monophosphate (IMP), the primary intermediate in the purine pathway, was also significantly increased in the XH7purE::P41 mutant. Combined modification of the low-coupling branched respiratory chains (cytochrome bd oxidase) improved guanosine production synergistically. The final guanosine yield in the XH7purE::P41?cyd mutant increased by 41% to 19 g/l compared with B. amyloliquefaciens XH7. CONCLUSION: The combined modification strategy used in this study is a novel approach to improve the production of guanosine in industrial bacterial strains. PMID- 28840403 TI - Updated 2016 WHO classification of tumors of the CNS: turning the corner where molecule meets pathology. PMID- 28840404 TI - The effect of excluding ungulates on the abundance of ixodid ticks on wild rabbit (Oryctolagus cuniculus). AB - Tick abundance depends heavily on host density, so reducing access to the host should reduce tick populations in a determined area. In this study we compared the Parasitic Index (PI = average number of ticks per rabbit) of two wild rabbit populations separated 16 years ago by a fence keeping ungulates from moving freely. Two areas were selected (closed and open) wherein 50 wild rabbits per area were sampled for ticks. The PI in the open area (PI = 989.62) was significantly higher than in the closed area (PI = 515.40). Hyalomma lusitanicum Koch was globally the most abundant species, followed by Rhipicephalus pusillus Gil Collado, Rhipicephalus bursa Canestrini and Fanzago, Haemaphysalis hispanica Gil Collado, Rhipicephalus sanguineus s.l. Latreille and Ixodes ventalloi Gil Collado. Differences between areas varied depending on the species. The number of H. hispanica, R. bursa and R. pusillus were significantly more abundant on rabbits in the closed area, whereas H. lusitanicum predominated in the open area. Ungulates in the open area may have played an important role as the main or alternative host for ticks and/or drawing some tick species away from rabbits. In the closed area other reasons such as inter-specific competition could have influenced the tick abundance. These results show a clear reduction in tick abundance for at least 16 years as well as influenced species distribution. PMID- 28840405 TI - Cooperative problem solving in giant otters (Pteronura brasiliensis) and Asian small-clawed otters (Aonyx cinerea). AB - Cooperative problem solving has gained a lot of attention over the past two decades, but the range of species studied is still small. This limits the possibility of understanding the evolution of the socio-cognitive underpinnings of cooperation. Lutrinae show significant variations in socio-ecology, but their cognitive abilities are not well studied. In the first experimental study of otter social cognition, we presented two species-giant otters and Asian small clawed otters-with a cooperative problem-solving task. The loose string task requires two individuals to simultaneously pull on either end of a rope in order to access food. This task has been used with a larger number of species (for the most part primates and birds) and thus allows for wider cross-species comparison. We found no differences in performance between species. Both giant otters and Asian small-clawed otters were able to solve the task successfully when the coordination requirements were minimal. However, when the temporal coordination demands were increased, performance decreased either due to a lack of understanding of the role of a partner or due to difficulty inhibiting action. In conclusion, two species of otters show some ability to cooperate, quite similar to most other species presented with the same task. However, to draw further conclusions and more nuanced comparisons between the two otter species, further studies with varied methodologies will be necessary. PMID- 28840406 TI - Religiousness and health in Europe. AB - Recent research suggests that epidemiological forces in religion and health can have opposed effects. Using longitudinal data of people aged 50+ included in wave 1 (2004-2005) of the Survey of Health, Ageing and Retirement in Europe (SHARE), and followed up through waves 2 (2006-2007), 4 (2011) and 5 (2013), we examined two forms of religious internalization and their association with health. Multivariate logistic regressions were used to examine all associations. Taking part in a religious organization was associated with lower odds of GALI (global activity limitation index) (OR = 0.86, 95% CI 0.75, 0.98) and depressive symptoms 0.80 (95% CI 0.69, 0.93), whereas being religiously educated lowered odds of poor self-rated health (SRH) 0.81 (95% CI 0.70, 0.93) and long-term health problems 0.84 (95% CI 0.74, 0.95). The more religious had lower odds of limitations with activities of daily living 0.76 (95% CI 0.58, 0.99) and depressive symptoms 0.77 (95% CI 0.64, 0.92) than other respondents, and compared to people who only prayed and did not have organizational involvement, they had lower odds of poor SRH 0.71 (95% CI 0.52, 0.97) and depressive symptoms 0.66 (95% CI 0.50, 0.87). Conversely, people who only prayed had higher odds of depressive symptoms than non-religious people 1.46 (95% CI 1.15, 1.86). Our findings suggest two types of religiousness: 1. Restful religiousness (praying, taking part in a religious organization and being religiously educated), which is associated with good health, and 2. Crisis religiousness (praying without other religious activities), which is associated with poor health. PMID- 28840407 TI - Clinical characteristics and risk factors for retinal diabetic neurodegeneration in type 2 diabetes. AB - AIMS: To identify clinical characteristics and risk factors of retinal neurodegeneration represented by macular ganglion cell/inner plexiform layer (mGCIPL) thinning in patients with long-standing type 2 diabetes mellitus (T2DM). METHODS: Patients who had T2DM for >15 years were prospectively recruited from September 2014 to July 2015. Clinical data and samples were collected according to the Common Data Element and Standards of Procedure developed by the Korean Diabetes Association research council. Baseline characteristics included age, gender, family history, medical record of comorbidity, and microvascular complications. All patients underwent optical coherence tomography with automatic segmentation of the mGCIPL in six parafoveal regions. Multivariable regression analysis identified factors associated with mGCIPL thinning. RESULTS: Of 220 registered patients, 162 were included after ophthalmologic examination. The mean (SD) age was 65.0 (9.3) years, the mean duration of T2DM was 20.5 (4.0) years; mGCIPL thickness was 76.2 (8.5) um. Hypertension, diabetic retinopathy, statin medication, estimated glomerular filtration rate, conduction velocity of the posterior tibial, peroneal, and sural nerves, and cardiac autonomic neuropathy (CAN) score were significantly correlated with mGCIPL thickness. Multivariate regression analysis showed that the CAN score (coefficient = -1.78, p = 0.001) and sural nerve velocity (coefficient = 0.458, p = 0.035) yielded a significant high regression correlation with mGCIPL thickness (overall R 2 = 0.46). CONCLUSIONS: This study demonstrated that various clinical features were associated with retinal neurodegeneration in T2DM. In particular, peripheral nerve conduction and autonomic nerve function were confirmed to be strong risk factors for mGCIPL thinning in patients with T2DM. PMID- 28840408 TI - Synthesis and Spectroscopic Properties of Carbazole-Oxadiazoles. AB - Four new carbazole-oxadiazole derivatives (3a-b, 6a-b) were prepared from the reaction of aromatic aldehydes and carbohydrazides which were synthesized from carbazole aldehydes namely 9-hexyl-9H-carbazole-3-carbaldehyde 1 and 4-(9H carbazole-9-yl)benzaldehyde 4 and acid hydrazides. The structures of the new derivatives were confirmed by 1H-NMR and FT-IR. The optical properties such as maximum absorption and emission wavelengths (lambda; nm), molar extinction coefficients (epsilon; cm-1 M-1), Stoke's shifts (DeltalambdaST; nm) and quantum yields (phiF), of the carbazole-oxadiazole derivatives were declared in dichloromethane, toluene and tetrahydrofuran solutions. PMID- 28840409 TI - Physician Experiences and Understanding of Genomic Sequencing in Oncology. AB - The amount of information produced by genomic sequencing is vast, technically complicated, and can be difficult to interpret. Appropriately tailoring genomic information for non-geneticists is an essential next step in the clinical use of genomic sequencing. To initiate development of a framework for genomic results communication, we conducted eighteen qualitative interviews with oncologists who had referred adult cancer patients to a matched tumor-normal tissue genomic sequencing study. In our qualitative analysis, we found varied levels of clinician knowledge relating to sequencing technology, the scope of the tumor genomic sequencing study, and incidental germline findings. Clinicians expressed a perceived need for more genetics education. Additionally, they had a variety of suggestions for improving results reports and possible resources to aid in results interpretation. Most clinicians felt genetic counselors were needed when incidental germline findings were identified. Our research suggests that more consistent genetics education is imperative in ensuring the proper utilization of genomic sequencing in cancer care. Clinician suggestions for results interpretation resources and results report modifications could be used to improve communication. Clinicians' perceived need to involve genetic counselors when incidental germline findings were found suggests genetic specialists could play a critical role in ensuring patients receive appropriate follow-up. PMID- 28840410 TI - Characterization of common bile duct injury after laparoscopic cholecystectomy in a high-volume hospital system. AB - BACKGROUND: Despite the popularity of laparoscopic cholecystectomy, rates of common bile duct injury remain higher than previously observed in open cholecystectomy. This retrospective chart review sought to determine the prevalence of, and risk factors for, biliary injury during laparoscopic cholecystectomy within a high-volume healthcare system. METHODS: 800 of approximately 3000 cases between 2009 and 2015 were randomly selected and retrospectively reviewed. A single reviewer examined all operative notes, thereby including all cases of BDI regardless of ICD code or need for a second procedure. Biliary injuries were classified per Strasberg et al. (J Am Coll Surg 180:101 125, 1995). Logistic regression models were utilized to identify univariable and multivariable predictors of biliary injuries. RESULTS: 31.0% of charts stated that the Critical View of Safety was obtained, and 12.4% of charts correctly described the critical view in detail. Three patients (0.4%) had a cystic duct leak, and 4 (0.5%) had a common bile duct injury. Of the four CBDI, three patients had a partial transection of the CBD and one had a partial stricture. Patients who suffered BDI were more likely to have had lower hemoglobin, urgent surgery, choledocholithiasis, or acutely inflamed gallbladder. Multivariable analysis of BDI risk factors showed higher preoperative hemoglobin to be independently protective against CBDI. Acutely inflamed gallbladder and choledocholithiasis were independently predictive of CBDI. CONCLUSIONS: The rate of CBDI in this study was 0.5%. Acutely inflamed conditions were risk factors for biliary injury. Multivariable analysis suggests a protective effect of higher preoperative hemoglobin. There was no correlation of CVS with prevention of biliary injury, although only 12.4% of charts could be verified as following the technique correctly. Better implementation of CVS, and increased caution in patients with perioperative inflammatory signs, may be important for preventing bile duct injury. Additionally, counseling patients with acute inflammation on increased risk is important. PMID- 28840411 TI - Long-term durability of orthodontic mini-implants. AB - The current study aimed at examining surface and chemical composition changes of retrieved mini-implants after different periods of service as aids of anchorage for orthodontic patients. This study examined 72 retrieved orthodontic self tapping and self-drilling mini-implants, 1.7 mm in diameter and 8 mm in length (OrthoEasy system, Forestadent, Pforzheim, Germany) from 36 adult orthodontic patients (18 men and 18 women, mean age = 23 years). The retrieved mini-implants were divided into 3 groups according to service period: 3-6 months (3M-6M) group, 6-12 months (6M-12M) group, and 12-24 months (12M-24M) group, with 24 mini implants in each group. The control group (As Received) comprised of 24 unused mini-implants of the same type (AR group). All mini-implant heads and threaded bodies were examined for chemical characterization and topographical features by SEM-EDS. The average weight percentages for the following elements Ti, Al, and O2 were obtained and compared among the 4 groups. There was significant decrease in titanium content and deterioration for the surface properties for all parts of the mini-implants after being used inside patients' oral cavities for more than 6 months p < 0.05. The period of mini-implant service inside patients' oral cavities should not exceed 6 months. PMID- 28840412 TI - Gambling Participation, Expenditure and Risk of Harm in Australia, 1997-1998 and 2010-2011. AB - Gambling-related harm results primarily from financial losses. Internationally Australia continues to rank as the largest spending nation per capita on gambling products. This would suggest that Australian gamblers are at disproportionately high risk of harm despite almost two decades of industry scrutiny and regulation, and investment in research, treatment and education programs. However, declines in participation rates, per capita expenditure, household expenditure, national disposable income spent on gambling and problem gambling rates have been cited as evidence that fewer people are gambling, that gamblers are spending less, and that gambling safety in Australia has improved. The current study investigated these propositions using national population and accounts data, and statistics from Australia's two population-representative gambling surveys conducted in 1997 1998 and 2010-2011. Despite a falling participation rate the study found no real change in the number of people gambling overall, and increasing numbers consuming casino table games, race wagering and sports betting. Further found were increases rather than decreases in average gambler expenditure, overall, and across most products, particularly electronic gaming machines (EGMs). Potentially risky levels of average expenditure were observed in both periods, overall and for race wagering, casino table gaming, and EGMs. Changes in the proportion of income spent on gambling suggest risks declined overall and for race wagering and casino table gaming, but increased for EGMs. Finally, while problem gambling statistics were not comparable between periods, the study found double the number of moderate risk gamblers previously estimated for 2010-2011 amongst the 2 million Australians found to have experienced one or more gambling-related problems. The findings have implications for public health policy and resourcing, and the way in which prevalence and expenditure statistics have been interpreted by researchers, government and industry in Australia and elsewhere. PMID- 28840413 TI - The relationship between fat and progesterone, estradiol, and chorionic gonadotropin levels in Quebec cow's milk. AB - PURPOSE: The majority of milk in industrialized countries is obtained from pregnant cows, which contains increased levels of estrogen and progesterone compared to non-pregnant cows. The aim of this study was to quantify the amount of hormones present in milk with different fat content because previous studies on humans have shown potential effects of increased milk consumption on serum and urine hormone levels as well as on sperm parameters. However, it is unclear whether consumption of milk at the currently recommended levels would lead to systemic effects. METHODS: Samples of cow's milk of varying fat concentrations (0, 1, 2, 3.25, 10, and 35%) were analyzed via competitive ELISA assays. RESULTS: Progesterone concentrations were significantly correlated to increasing fat content of milk (r = 0.8251, p = 0.04). CONCLUSIONS: Research on conditions in which additional progesterone may have an effect on human health should consider inclusion of limitation of milk intake and its effects. Further studies are needed to determine the concentration of progesterone in milk of different fat content in other regions and countries and to quantify the potential pathophysiologic role. PMID- 28840414 TI - Bis-spirochromanones as potent inhibitors of Mycobacterium tuberculosis: synthesis and biological evaluation. AB - On the basis of reported antimycobacterial property of chroman-4-one pharmacophore, a series of chemically modified bis-spirochromanones were synthesized starting from 2-hydroxyacetophenone and 1,4-dioxaspiro[4.5] decan-8 one using a Kabbe condensation approach. The synthesized bis-spirochromanones were established based on their spectral data and X-ray crystal structure of 6e. All synthesized compounds were evaluated against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain, finding that some products exhibited good antimycobacterial activity with minimum inhibitory concentration as low as [Formula: see text]. Docking studies were carried out to identify the binding interactions of compounds II, 6a and 6n with FtsZ. Compounds exhibiting good in vitro potency in the MTB MIC assay were further evaluated for toxicity using the HEK cell line. PMID- 28840415 TI - Endothelial progenitor cells in multiple myeloma neovascularization: a brick to the wall. AB - Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow that leads to events such as bone destruction, anaemia and renal failure. Despite the several therapeutic options available, there is still no effective cure, and the standard survival is up to 4 years. The evolution from the asymptomatic stage of monoclonal gammopathy of undetermined significance to MM and the progression of the disease itself are related to cellular and molecular alterations in the bone marrow microenvironment, including the development of the vasculature. Post-natal vasculogenesis is characterized by the recruitment to the tumour vasculature of bone marrow progenitors, known as endothelial progenitor cells (EPCs), which incorporate newly forming blood vessels and differentiate into endothelial cells. Several processes related to EPCs, such as recruitment, mobilization, adhesion and differentiation, are tightly controlled by cells and molecules in the bone marrow microenvironment. In this review, the bone marrow microenvironment and the mechanisms associated to the development of the neovasculature promoted by EPCs are discussed in detail in both a non-pathological scenario and in MM. The latest developments in therapy targeting the vasculature and EPCs in MM are also highlighted. The identification and characterization of the pathways relevant to the complex setting of MM are of utter importance to identify not only biomarkers for an early diagnosis and disease progression monitoring, but also to reveal intervention targets for more effective therapy directed to cancer cells and the endothelial mediators relevant to neovasculature development. PMID- 28840416 TI - Modified spreader for facilitating controlled osteotomy in orthognathic surgery: RAI and JAIN Modification. PMID- 28840417 TI - Biomechanical Stretch Induces Inflammation, Proliferation, and Migration by Activating NFAT5 in Arterial Smooth Muscle Cells. AB - The increasing wall stress as is elicited by arterial hypertension promotes their reorganization in the vessel wall which may lead to arterial stiffening and contractile dysfunction. The nuclear factor of activated T cells 5 (NFAT5) pathway plays a role in regulating growth and differentiation in various cell types. We investigated whether the NFAT5 pathway was involved in the regulation of biomechanical stretch-induced human arterial smooth muscle cell (HUASMC) proliferation, inflammation, and migration. Herein, we showed that stretch promoted the expression of NFAT5 in human arterial smooth muscle cells and regulated through activation of c-Jun N-terminal kinase under these conditions. This may contribute to an improved activity of HUASMCs and thus promote reorganization in vascular remodeling processes such as hypertension-induced arterial stiffening and contractile dysfunction. PMID- 28840418 TI - Combining self- and cross-docking as benchmark tools: the performance of DockBench in the D3R Grand Challenge 2. AB - Molecular docking is a powerful tool in the field of computer-aided molecular design. In particular, it is the technique of choice for the prediction of a ligand pose within its target binding site. A multitude of docking methods is available nowadays, whose performance may vary depending on the data set. Therefore, some non-trivial choices should be made before starting a docking simulation. In the same framework, the selection of the target structure to use could be challenging, since the number of available experimental structures is increasing. Both issues have been explored within this work. The pose prediction of a pool of 36 compounds provided by D3R Grand Challenge 2 organizers was preceded by a pipeline to choose the best protein/docking-method couple for each blind ligand. An integrated benchmark approach including ligand shape comparison and cross-docking evaluations was implemented inside our DockBench software. The results are encouraging and show that bringing attention to the choice of the docking simulation fundamental components improves the results of the binding mode predictions. PMID- 28840419 TI - Both Intrinsic and Extrinsic Religious Orientation are Positively Associated with Attitudes Toward Cleanliness: Exploring Multiple Routes from Godliness to Cleanliness. AB - In the present study, we explore how intrinsic and extrinsic religious orientations are associated with cleanliness attitudes. We find that reported importance of religion is associated with increased cleanliness concerns and interest in cleanliness. Attitudes toward cleanliness were also associated with both intrinsic religious orientation and extrinsic religious orientation. Together, religiosity and religious orientation account for 14.7% of cleanliness attitudes and remained significant in the presence of personality, socioeconomic status, age, education, obsessive-compulsive attitudes toward cleanliness, and other covariates. These results show that religiosity is associated with cleanliness via multiple routes. We suggest that intrinsic religious orientation leads to increased interest in cleanliness due to the link between physical and spiritual purity. Extrinsic religious orientation may be linked with cleanliness because of the secondary benefits, including health and the facilitation in communal cohesiveness, that cleanliness rituals offer. The implications of these findings for the relationship between religion and health are discussed. PMID- 28840420 TI - Special Issue: the 3rd meeting of the Bergey's International Society for Microbial Systematics (BISMIS). PMID- 28840421 TI - Enablers and Barriers to Community Engagement in Public Health Emergency Preparedness: A Literature Review. AB - Public health emergency preparedness (PHEP) all too often focusses only on institutional capabilities, including their technical expertise and political influence, while overlooking community capabilities. However, the success of institutional emergency preparedness plans depends upon communities and institutions working together to ensure successful anticipation, response and recovery. Broader community engagement is therefore recommended worldwide. This literature review was carried out to identify enablers and barriers to community and institutional synergies in emergency preparedness. Searches were undertaken across bibliographic databases and grey literature sources. The literature identified was qualitative in nature. A qualitative, 'best fit' framework approach using a pre-existing framework was used to analyse the literature, whereby themes were added and changed as analysis progressed. A working definition of community was identified, based on a 'whole community' approach, inclusive of the whole multitude of stakeholders including community residents and emergency management staff. Given the diversity in community make-up, the types of emergencies that could be faced, the socio-economic, environmental and political range of communities, there are no set practices that will be effective for all communities. The most effective way of engaging communities in emergency preparedness is context-dependent and the review did draw out some important key messages for institutions to consider. PMID- 28840422 TI - Determining an optimal clinical dose of elobixibat, a novel inhibitor of the ileal bile acid transporter, in Japanese patients with chronic constipation: a phase II, multicenter, double-blind, placebo-controlled randomized clinical trial. AB - BACKGROUND: Elobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat. METHODS: Japanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined. RESULTS: Among 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (+/-standard deviation) were significantly higher than baseline (5.7 +/- 4.2 and 5.6 +/- 3.5 times per week, respectively, compared with 2.6 +/- 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once daily oral doses up to 15 mg for 2 weeks. CONCLUSIONS: Our study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-142608. PMID- 28840423 TI - HDlive Flow silhouette mode for the diagnosis of uterine enhanced myometrial vascularity/arteriovenous malformations. AB - We present our initial experience of using the HDlive Flow silhouette mode to construct images of two cases of uterine enhanced myometrial vascularity/arteriovenous malformations (EMV/AVMs). In the first case, the HDlive Flow silhouette mode clearly depicted a fused vascular tumor with irregular contour in the posterior myometrium. In the second case, a large hypervascular mass occupying the entire fundal lesion of the uterus was clearly identified using the HDlive Flow silhouette mode. Moreover, spatial relationships among the hypervascular mass, intrauterine blood collection, and dilated, spiral-shaped right uterine artery enabled the clear localization of the mass. The HDlive Flow silhouette mode provides a novel, unique sonographic image of uterine EMV/AVMs, and might facilitate their diagnosis and localization in the myometrium. PMID- 28840424 TI - Economic evaluation of sequencing strategies in HER2-positive metastatic breast cancer in Mexico: a contrast between public and private payer perspectives. AB - PURPOSE: Breast cancer is the most common malignancy among women in Mexico. A large proportion of Mexican patients present with advanced disease, and 25% have HER2-positive tumors. We performed a cost-effectiveness analysis of different sequencing strategies of HER2-targeted agents in Mexico according to various payer perspectives. METHODS: A Markov model was constructed to evaluate the cost effectiveness of four different HER2-targeted treatment sequences among patients with HER2-positive metastatic breast cancer treated in Mexico according to three public and one private payer perspectives. Patients were followed weekly over their remaining life expectancies within the model. Health states considered were progression-free survival (PFS) 1st-3rd lines, and death. Transition probabilities between states were based on published trials. Cost data were obtained from official publications from Mexican healthcare institutions. The evaluated outcomes were PFS, OS, costs, QALYs, and incremental cost effectiveness ratio (ICER). RESULTS: In the public payer perspective, sequences containing pertuzumab or T-DM1 were not cost-effective when compared with a sequence including the combination of trastuzumab/docetaxel as first line without subsequent T-DM1 or pertuzumab, even when utilizing alternate definitions for willingness to pay thresholds. In the private payer perspective, a sequence containing T-DM1 but not pertuzumab proved cost-effective at a lower clinical effectiveness. CONCLUSIONS: In Mexico, the use of at least three lines of trastuzumab in combination with other therapies, but not with pertuzumab or TDM 1, represents the most cost-effective option for patients covered by the public healthcare system, and this sequence should be made available for all patients. PMID- 28840425 TI - HFE mRNA expression is responsive to intracellular and extracellular iron loading: short communication. AB - In liver hepatocytes, the HFE gene regulates cellular and systemic iron homeostasis by modulating cellular iron-uptake and producing the iron-hormone hepcidin in response to systemic iron elevation. However, the mechanism of iron sensing in hepatocytes remain enigmatic. Therefore, to study the effect of iron on HFE and hepcidin (HAMP) expressions under distinct extracellular and intracellular iron-loading, we examined the effect of holotransferrin treatment (1, 2, 5 and 8 g/L for 6 h) on intracellular iron levels, and mRNA expressions of HFE and HAMP in wild-type HepG2 and previously characterized iron-loaded recombinant-TfR1 HepG2 cells. Gene expression was analyzed by real-time PCR and intracellular iron was measured by ferrozine assay. Data showed that in the wild type cells, where intracellular iron content remained unchanged, HFE expression remained unaltered at low holotransferrin treatments but was upregulated upon 5 g/L (p < 0.04) and 8 g/L (p = 0.05) treatments. HAMP expression showed alternating elevations and increased upon 1 g/L (p < 0.05) and 5 g/L (p < 0.05). However, in the recombinant cells that showed higher intracellular iron levels than wild-type cells, HFE and HAMP expressions were elevated only at low 1 g/L treatment (p < 0.03) and were repressed at 2 g/L treatment (p < 0.03). Under holotransferrin-untreated conditions, the iron-loaded recombinant cells showed higher expressions of HFE (p < 0.03) and HAMP (p = 0.05) than wild-type cells. HFE mRNA was independently elevated by extracellular and intracellular iron excess. Thus, it may be involved in sensing both, extracellular and intracellular iron. Repression of HAMP expression under simultaneous intracellular and extracellular iron-loading resembles non-hereditary iron-excess pathologies. PMID- 28840426 TI - Human Infections with Microsporum gypseum Complex (Nannizzia gypsea) in Slovenia. AB - Microsporum gypseum complex is a group of geophillic dermatophytes with a worldwide distribution and is a rare cause of dermatomycoses in humans. The infection most commonly presents as tinea corporis, with some geographical and occupational variations. We studied M. gypseum complex infections in patients examined in the Mycological Laboratory of the Department of Dermatovenereology, University Medical Centre Ljubljana, during the period 2000-2015. Diagnosis was confirmed by mycological examination. Skin scales were examined by direct microscopy and cultivated on Sabouraud glucose agar. A total of 226 patients were identified, representing 1.5% of all dermatophyte infections during the study period. Tinea corporis was diagnosed in majority of patients, followed by tinea manus, tinea faciei, tinea inguinalis and tinea pedis. Tinea capitis was observed in three and onychomycosis in two patients only. Infection was disseminated on different parts of the body in nine patients. In 39% of patients, infection was diagnosed in children younger than 9 years. Face and scalp infection was more often observed in children. The incidence was the highest during July and October. Contacts with soil and domestic animals were often reported. Data on the prevalence and clinical characteristics of M. gypseum complex infection in other countries are reviewed. PMID- 28840428 TI - Long-term monitoring of streambed sedimentation and scour in a dynamic stream based on streambed temperature time series. AB - This study presented the monitoring and quantification of streambed sedimentation and scour in a stream with dynamically changing streambed based on measured phase and amplitude of the diurnal signal of sediment temperature time series. With the applied method, changes in streambed elevation were estimated on a sub-daily scale with 2-h intervals without continuous maintenance of the measurement system, thus making both high temporal resolution and long-term monitoring of streambed elevations possible. Estimates of streambed elevation showed that during base flow conditions streambed elevation fluctuates by 2-3 cm. Following high stream stages, scouring of 2-5 cm can be observed even at areas with low stream flow and weak currents. Our results demonstrate that weather variability can induce significant changes in the stream water and consequently sediment temperatures influencing the diurnal temperature signal in such an extent that the sediment thickness between paired temperature sensors were overestimated by up to 8 cm. These observations have significant consequences on the design of vertical sensor spacing in high-flux environments and in climates with reduced diurnal variations in air temperature. PMID- 28840427 TI - Musculoskeletal system in children and adolescents with inflammatory bowel disease: normal muscle force, decreased trabecular bone mineral density and low prevalence of vertebral fractures. AB - : Low bone mineral density (BMD) and an increased fracture incidence are two extraintestinal complications associated with inflammatory bowel disease (IBD). We aimed to evaluate musculoskeletal traits and assess vertebral fracture (VF) rate in children and adolescents with IBD. Seventy patients with IBD with a median age of 13.8 years were included. The BMD and geometric parameters of the non-dominant tibia were assessed using pQCT. Dynamic muscle functions were evaluated using jumping mechanography. VFs were assessed according to the semiquantitative standardized method by Genant. The muscle functions adjusted for the patients' weight did not differ from the reference population. A low trabecular BMD (Z-score - 1.6; p < 0.001) and cortical thickness (Z-score - 0.7; p < 0.001) were found in children and adolescents with IBD. Conversely, an increased cortical BMD (Z-score 1.1; p < 0.001) was noted. No significant association was found between the 25-OHD serum levels and the bone or muscle measurements. One patient with asymptomatic VF was identified. CONCLUSION: IBD in childhood or adolescents affects bones but not muscles. Bone changes are independent of the 25-OHD serum level. A thoracolumbar spine X-ray should not be routinely recommended in children with IBD. What is Known: * Low bone mineral density and an increased fracture rate are the complications associated with IBD. * Bone strength and structural development is strongly dependent on skeletal muscle stimulation. What is New: * Children with IBD have altered bone density and geometry but normal dynamic muscle functions. * Thoracolumbar spine X-ray should be indicated on an individual basis in children with IBD. PMID- 28840430 TI - Mevastatin promotes neuronal survival against Abeta-induced neurotoxicity through AMPK activation. AB - Statins or HMG-CoA reductase inhibitors have been shown to be effective at lowering cholesterol levels, and the application of these molecules has gradually emerged as an attractive therapeutic strategy for neurodegenerative diseases. Epidemiological studies suggest that statin use is associated with a decreased incidence of Alzheimer's disease (AD). Thus, statins may play a beneficial role in reducing amyloid beta (Abeta) toxicity, the most relevant pathological feature and pathogenesis of AD. However, the precise mechanisms involved in statin inhibited Abeta toxicity remain unclear. In the present study, we report that mevastatin significantly protects against Abeta-induced neurotoxicity in SK-N-MC neuronal cells by restoring impaired insulin signaling. This protection appears to be associated with the activation of AMP-activated protein kinase (AMPK), which has long been known to increase insulin sensitivity. Our results also indicate that high levels of cholesterol likely underlie Abeta-induced neurotoxicity and that activation of AMPK by mevastatin alleviates insulin resistance. Signaling through the insulin receptor substrate-1/Akt pathway appears to lead to cell survival. These findings demonstrate that mevastatin plays a potential therapeutic role in targeting Abeta-mediated neurotoxicity. The molecule presents a novel therapeutic strategy for further studies in AD prevention and therapeutics. PMID- 28840431 TI - cDNA microarray analysis of human keratinocytes cells of patients submitted to chemoradiotherapy and oral photobiomodulation therapy: pilot study. AB - Oral mucositis is an acute toxicity that occurs in patients submitted to chemoradiotherapy to treat head and neck squamous cell carcinoma. In this study, we evaluated differences in gene expression in the keratinocytes of the oral mucosa of patients treated with photobiomodulation therapy and tried to associate the molecular mechanisms with clinical findings. From June 2009 to December 2010, 27 patients were included in a randomized double-blind pilot study. Buccal smears from 13 patients were obtained at days 1 and 10 of chemoradiotherapy, and overall gene expression of samples from both dates were analyzed by complementary DNA (cDNA) microarray. In addition, samples from other 14 patients were also collected at D1 and D10 of chemoradiotherapy for subsequent validation of cDNA microarray findings by qPCR. The expression array analysis identified 105 upregulated and 60 downregulated genes in our post-treatment samples when compared with controls. Among the upregulated genes with the highest fold change, it was interesting to observe the presence of genes related to keratinocyte differentiation. Among downregulated genes were observed genes related to cytotoxicity and immune response. The results indicate that genes known to be induced during differentiation of human epidermal keratinocytes were upregulated while genes associated with cytotoxicity and immune response were downregulated in the laser group. These results support previous clinical findings indicating that the lower incidence of oral mucositis associated with photobiomodulation therapy might be correlated to the activation of genes involved in keratinocyte differentiation. PMID- 28840432 TI - Development of Halofluorochromic Polymer Nanoassemblies for the Potential Detection of Liver Metastatic Colorectal Cancer Tumors Using Experimental and Computational Approaches. AB - PURPOSE: To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes. METHODS: We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter < 30 nm. RESULTS: Dye-conjugated PNAs showed no aggregation under opsonizing conditions for 24 h and displayed low tissue diffusion and cellular uptake. Both hfPNAs and n-hfPNAs accumulated in primary and liver metastatic CRC tumors within 12 h post intravenous injection. In comparison to n-hfPNAs, hfPNAs fluoresced strongly only in the acidic tumor microenvironment (pH < 7.0) and distinguished small metastatic CRC tumors from healthy liver stroma. Computational simulations revealed that PNAs would steadily accumulate mainly in acidic (hypoxic) interstitium of metastatic tumors, independently of the vascularization degree of the tissue surrounding the lesions. CONCLUSION: The combined experimental and computational data confirms that hfPNAs detecting acidic tumor tissue can be used to identify small liver metastatic CRC tumors with improved accuracy. PMID- 28840433 TI - The AMT1 family genes from Malus robusta display differential transcription features and ammonium transport abilities. AB - Ammonium is an important nitrogen sources for plant growth. In this study, we report on the gene characterization of the ammonium transporter AMT1 subfamily in the apple rootstock Malus robusta Rehd. Thirteen AMT genes were comprehensively evaluated from the apple genome (version 1.0). Then the gene features and expression patterns of five AMT1 members from M. robusta were analyzed. These genes fell into four clusters in the AMT phylogenetic tree: clade I (MrAMT1;1 and MrAMT1;3), clade II (MrAMT1;4), clade III (MrAMT1;2), and clade IV (MrAMT1;5). All the AMT1s, apart from MrAMT1;4, were expressed in vegetative organs and strongly responded to nitrogen concentration changes. For example, MrAMT1;2 and MrAMT1;3 had high transcript accumulation levels in the leaves and roots, respectively. Finally, the functions of these AMT1s were studied in detail by heterologous expression in yeast. These genes allowed strain 31019b to assimilate nitrogen, but their 15NH4+ uptake kinetics varied. These results revealed the functional roles of AMT1 during ammonium absorption in the AMT-defective mutant yeast system. PMID- 28840435 TI - Psychosocial Syndemic Correlates of Sexual Compulsivity Among Men Who Have Sex with Men: A Meta-Analysis. AB - Efforts have been made to better understand sexual compulsivity by examining salient psychosocial syndemic correlates, though examination of such factors has yielded inconclusive results. Given that research on sexual compulsivity has predominately involved men who have sex with men (MSM), the aims of the current study were to establish the mean effect sizes of seven psychosocial syndemic indicators with sexual compulsivity, to determine if the effect varied as a function of the type of psychosocial syndemic, and investigate the potential moderating effects using MSM samples. A total of 95 studies were included for analyses among the psychosocial syndemic indicators of interest (i.e., depression, anxiety, alcohol use, drug use, intimate partner violence, childhood sexual abuse, and sexual risk behavior). Results revealed a medium mean effect size of sexual compulsivity, the strength of which was significantly moderated by type of psychosocial syndemic indicator. Significant mean effect sizes for all syndemic indicators on sexual compulsivity were found, with depression and anxiety having the strongest relationships; significant moderating effects were found and are discussed. Findings highlight clinical considerations regarding sexual compulsivity and its role within the HIV syndemic framework among MSM. PMID- 28840434 TI - Robust RNAi-mediated resistance to infection of seven potyvirids in soybean expressing an intron hairpin NIb RNA. AB - Viral pathogens, such as soybean mosaic virus (SMV), are a major constraint in soybean production and often cause significant yield loss and quality deterioration. Engineering resistance by RNAi-mediated gene silencing is a powerful strategy for controlling viral diseases. In this study, a 248-bp inverted repeat of the replicase (nuclear inclusion b, NIb) gene was isolated from the SMV SC3 strain, driven by the leaf-specific rbcS2 promoter from Phaseolus vulgaris, and introduced into soybean. The transgenic lines had significantly lower average disease indices (ranging from 2.14 to 12.35) than did the non-transformed (NT) control plants in three consecutive generations, exhibiting a stable and significantly enhanced resistance to the SMV SC3 strain under field conditions. Furthermore, seed mottling did not occur in transgenic seeds, whereas the NT plants produced ~90% mottled seeds. Virus resistance spectrum screening showed that the greenhouse-grown transgenic lines exhibited robust resistance to five SMV strains (SC3, SC7, SC15, SC18, and a recombinant SMV), bean common mosaic virus, and watermelon mosaic virus. Nevertheless, no significantly enhanced resistance to bean pod mottle virus (BPMV, Comovirus) was observed in the transgenic lines relative to their NT counterparts. Consistent with the results of resistance evaluation, the accumulation of each potyvirid (but not of BPMV) was significantly inhibited in the transgenic plants relative to the NT controls as confirmed by quantitative real-time (qRT-PCR) and double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA). These results demonstrate that robust RNAi-mediated resistance to multiple potyvirids in soybean was conferred by expressing an intron hairpin SMV NIb RNA. PMID- 28840436 TI - Optimising patient safety using pharmaceutical intervention in domiciliary hospitalization. AB - Introduction The domiciliary hospitalization unit (DHU) is an innovative model of care provision, where hospital care is transferred to the patients' home. However, this shift adds a care transition layer to the process, which may increase the probability of medication errors to occur. Method A pharmacist has been integrated into the DHU team to improve medication use. We developed an observational study documenting his intervention for 6 months. Information about the patient's drug therapy before admission, during hospitalization and after hospital discharge were gathered, enabling comparison of possible discrepancies that may happen during care transitions. The pharmacist evaluated the appropriateness, necessity, effectiveness, and safety of medication and intervened when deemed appropriate. Conclusions Data suggests that a pharmacist involved in the DHU may have a positive impact on medication use. Medication review and reconciliation are examples of pharmaceutical interventions that may lead to increased effectiveness and patient safety. PMID- 28840437 TI - Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Colorectal Cancer: Potential use of Perioperative Desmopressin to Reduce Allogenic Blood Transfusion Rates. PMID- 28840438 TI - A Dual-Signaling Ferrocene-Pyrene Dyad: Triple-Mode Recognition of the Cu(II) Ions in Aqueous Medium. AB - We report a structure of ferrocene-pyrene conjugate (1) comprising electro and photo-active dual-signaling units. In particular, 1 upon interaction with Cu(II), displays selectively one-photon fluorescence quenching, but it shows two-photon absorption (TPA) cross-section 1230 GM (at 780 nm). Further, 1 displayed two irreversible oxidative waves at 0.39 V and 0.80 V (vs Ag/AgCl), in the electrochemical analysis which upon addition of Cu2+, led to the negative potential shift in both the oxidative waves to appear at 0.25 V and 0.68 V. The triple mode changes in presence of Cu(II) suggesting the possible application of 1 for the detection of Cu(II) in aqueous media. Graphical Abstract. PMID- 28840439 TI - Identification of a novel reassortant A (H9N6) virus in live poultry markets in Poyang Lake region, China. AB - Live poultry markets (LPM) are one of the most important sources of human infection with avian influenza virus (AIV). During our routine surveillance of AIV, we identified an H9N6 virus (JX-H9N6) in a LPM in Nanchang city, Jiangxi Province, China. Using Bayesian coalescent analysis, it was predicted that JX H9N6 had originated from a reassortment event between H9N2 and H6N6 AIVs in early 2014, instead of being derived from an H9N6 virus reported previously. Mutations in HA, PB1, PA, M, and NS protein, which could increase mammalian transmission and virulence, were also detected. Currently, both H9N2 and H6N6 AIVs are widely distributed in poultry and contribute to the generation of novel reassortant viruses causing human infection. Our findings highlight the importance of enhanced surveillance in birds for early prediction of human infections. PMID- 28840440 TI - Pathological fractures in a patient with severe osteomalacia and hyperparathyroidism: a multidisciplinary challenge. PMID- 28840441 TI - Performance, emission, and combustion characteristics of twin-cylinder common rail diesel engine fuelled with butanol-diesel blends. AB - Nitrogen oxides and smoke are the substantial emissions for the diesel engines. Fuels comprising high-level oxygen content can have low smoke emission due to better oxidation of soot. The objective of the paper is to assess the potential to employ oxygenated fuel, i.e., n-butanol and its blends with the neat diesel from 0 to 30% by volume. The experimental and computational fluid dynamic (CFD) simulation is carried out to estimate the performance, combustion, and exhaust emission characteristics of n-butanol-diesel blends for various injection timings (9 degrees , 12 degrees , 15 degrees , and 18 degrees ) using modern twin cylinder, four-stroke, common rail direct injection (CRDI) engine. Experimental results reveal the increase in brake thermal efficiency (BTE) by ~ 4.5, 6, and 8% for butanol-diesel blends of 10% (Bu10), 20% (Bu20), and 30% (Bu30), respectively, compared to neat diesel (Bu0). Maximum BTE for Bu0 is 38.4%, which is obtained at 12 degrees BTDC; however, for Bu10, Bu20 and Bu30 are 40.19, 40.9, and 41.7%, which are obtained at 15 degrees BTDC, respectively. Higher flame speed of n-butanol-diesel blends burn a large amount of fuel in the premixed phase, which improves the combustion as well as emission characteristics. CFD and experimental results are compared and validated for all fuel blends for in-cylinder pressure and nitrogen oxides (NOx), and found to be in good agreement. Both experimental and simulation results witnessed in reduction of smoke opacity, NOx, and carbon monoxide emissions with the increasing n-butanol percentage in diesel fuel. PMID- 28840442 TI - Reply to Li et al. "Can Preoperative Frailty Accurately Predict Morbidity and Mortality Following Liver Surgery?" PMID- 28840443 TI - Preoperative Carbohydrate Antigen 19-9: Its Neglected Role in Alpha-Fetoprotein Negative Hepatocellular Carcinoma Patients. AB - PURPOSE: The study aimed to investigate the prognostic role of the preoperative carbohydrate antigen 19-9 (CA19-9) level in alpha-fetoprotein (AFP)-negative (AFP < 25 ng/ml) hepatocellular carcinoma (HCC) patients. METHODS: From December 2004 to December 2013, 750 patients diagnosed with AFP-negative HCC following curative resection were enrolled. Both univariate and multivariate analyses were performed to clarify the prognostic factors for overall survival (OS) and disease-free survival (DFS). RESULTS: The optimal cutoff point for preoperative CA19-9 was 32.6 U/ml, and the value of the area under the curve was 0.640. The 1-, 3-, and 5 year OS rates were 88.4, 72.2, and 57.0%, respectively, for the CA19-9 > 32.6 U/ml group and 97.0, 83.3, and 79.9%, respectively, for the CA19-9 <= 32.6 U/ml group (P < 0.001). The 1-, 3-, and 5-year DFS rates were 71.8, 47.7, and 34.8%, respectively, for the CA19-9 > 32.6 U/ml group and 80.8, 63.6, and 55.5%, respectively, for the CA19-9 <= 32.6 U/ml group (P < 0.001). The multivariate analysis showed that CA19-9 > 32.6 U/ml was one of the most significant unfavorable predictors of OS and DFS (P < 0.001 for both). CONCLUSIONS: Preoperative CA19-9 > 32.6 U/ml is a predictor of dismal prognosis and can be employed as a prognostic marker for patient selection in AFP-negative HCC management. PMID- 28840445 TI - MR image reconstruction via guided filter. AB - Magnetic resonance imaging (MRI) reconstruction from the smallest possible set of Fourier samples has been a difficult problem in medical imaging field. In our paper, we present a new approach based on a guided filter for efficient MRI recovery algorithm. The guided filter is an edge-preserving smoothing operator and has better behaviors near edges than the bilateral filter. Our reconstruction method is consist of two steps. First, we propose two cost functions which could be computed efficiently and thus obtain two different images. Second, the guided filter is used with these two obtained images for efficient edge-preserving filtering, and one image is used as the guidance image, the other one is used as a filtered image in the guided filter. In our reconstruction algorithm, we can obtain more details by introducing guided filter. We compare our reconstruction algorithm with some competitive MRI reconstruction techniques in terms of PSNR and visual quality. Simulation results are given to show the performance of our new method. PMID- 28840444 TI - Effects of Excessive Dietary Phosphorus Intake on Bone Health. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an overview of dietary phosphorus, its sources, recommended intakes, and its absorption and metabolism in health and in chronic kidney disease and to discuss recent findings in this area with a focus on the effects of inorganic phosphate additives in bone health. RECENT FINDINGS: Recent findings show that increasing dietary phosphorus through inorganic phosphate additives has detrimental effects on bone and mineral metabolism in humans and animals. There is new data supporting an educational intervention to limit phosphate additives in patients with chronic kidney disease to control serum phosphate. The average intake of phosphorus in the USA is well above the recommended dietary allowance. Inorganic phosphate additives, which are absorbed at a high rate, account for a substantial and likely underestimated portion of this excessive intake. These additives have negative effects on bone metabolism and present a prime opportunity to lower total phosphorus intake in the USA. Further evidence is needed to confirm whether lowering dietary phosphorus intake would have beneficial effects to improve fracture risk. PMID- 28840446 TI - Giant Esophageal Liposarcoma. PMID- 28840447 TI - Genome-wide analysis of GDSL-type esterases/lipases in Arabidopsis. AB - KEY MESSAGE: In this present study, we introduce a fundamental framework and provide information regarding the possible roles of GDSL-type esterase/lipase gene family in Arabidopsis. GDSL-type esterases/lipases are hydrolytic enzymes with multifunctional properties such as broad substrate specificity, regiospecificity, and stereoselectivity. In this study, we identified 105 GDSL type esterase/lipase genes in Arabidopsis thaliana by conducting a comprehensive computational analysis. Expression studies indicated that GDSL-type lipase proteins showed varied expression patterns. Phylogenetic tree analysis indicated that AtGELP (Arabidopsis thaliana GDSL-type esterase/lipase protein) gene family was divided into four clades. The phylogenetic analysis, combined with protein motif architectures, and expression profiling were used to predict the roles AtGELP genes. To investigate the physical roles of the AtGELP gene family, we successfully screened 88 AtGELP T-DNA knockout lines for 54 AtGELP genes from 199 putative SALK T-DNA mutants. Transgenic plants of AtGELP genes were used to elucidate the phenotypic characteristics in various developmental stages or stress conditions. Our results suggest that the AtGELP genes have diverse physical functions such as affecting the germination rate and early growth of seedlings subjected to high concentrations of glucose, or being involved in biotic stress responses. PMID- 28840448 TI - Answer to the Letter to the Editor Concerning "Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism". PMID- 28840450 TI - Does Bariatric Surgery Affect the Incidence of Breast Cancer Development? A Systematic Review. AB - We reviewed the evidence for bariatric surgery reducing the risk of breast cancer. Data was extracted from multiple libraries, including PubMed, EMBASE, and Medline, to perform a systematic review. Abstracts were reviewed by two independent reviewers. Thirty-eight full-text articles were identified from 1171 abstracts. Four studies were included for meta-analysis; 114 of 10,533 (1.1%) patients receiving bariatric surgery versus 516 of 20,130 (2.6%) controls developed breast cancer, odds ratio 0.564 (95% CI 0.453 to 0.702) using a fixed effects model (P < 0.001) and odds ratio 0.585 (95% CI 0.247 to 1.386) using a random effects model (P 0.223). Bariatric surgery may reduce the risk of breast cancer. More research is required due to heterogeneity of studies, difficulty in identifying accurate controls, and limited follow-up. PMID- 28840449 TI - From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue. AB - Methylene blue (MB) is a well-established drug with a long history of use, owing to its diverse range of use and its minimal side effect profile. MB has been used classically for the treatment of malaria, methemoglobinemia, and carbon monoxide poisoning, as well as a histological dye. Its role in the mitochondria, however, has elicited much of its renewed interest in recent years. MB can reroute electrons in the mitochondrial electron transfer chain directly from NADH to cytochrome c, increasing the activity of complex IV and effectively promoting mitochondrial activity while mitigating oxidative stress. In addition to its beneficial effect on mitochondrial protection, MB is also known to have robust effects in mitigating neuroinflammation. Mitochondrial dysfunction has been identified as a seemingly unifying pathological phenomenon across a wide range of neurodegenerative disorders, which thus positions methylene blue as a promising therapeutic. In both in vitro and in vivo studies, MB has shown impressive efficacy in mitigating neurodegeneration and the accompanying behavioral phenotypes in animal models for such conditions as stroke, global cerebral ischemia, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. This review summarizes recent work establishing MB as a promising candidate for neuroprotection, with particular emphasis on the contribution of mitochondrial function to neural health. Furthermore, this review will briefly examine the link between MB, neurogenesis, and improved cognition in respect to age-related cognitive decline. PMID- 28840451 TI - Early prediction of cardiac resynchronization therapy response by non-invasive electrocardiogram markers. AB - Cardiac resynchronization therapy (CRT) is an effective treatment for those patients with severe heart failure. Regrettably, there are about one third of CRT "non-responders", i.e. patients who have undergone this form of device therapy but do not respond to it, which adversely affects the utility and cost effectiveness of CRT. In this paper, we assess the ability of a novel surface ECG marker to predict CRT response. We performed a retrospective exploratory study of the ECG previous to CRT implantation in 43 consecutive patients with ischemic (17) or non-ischemic (26) cardiomyopathy. We extracted the QRST complexes (consisting of the QRS complex, the S-T segment, and the T wave) and obtained a measure of their energy by means of spectral analysis. This ECG marker showed statistically significant lower values for non-responder patients and, joint with the duration of QRS complexes (the current gold-standard to predict CRT response), the following performances: 86% accuracy, 88% sensitivity, and 80% specificity. In this manner, the proposed ECG marker may help clinicians to predict positive response to CRT in a non-invasive way, in order to minimize unsuccessful procedures. PMID- 28840452 TI - Transthyretin Cardiac Amyloidosis. AB - PURPOSE OF REVIEW: Transthyretin (TTR)-related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive, hypertrophic heart disease and may go undiagnosed. Transthyretin-derived amyloidosis accounts for 18% of all cases of cardiac amyloidosis. Thus, the study's purpose is to provide a comprehensive review of transthyretin cardiac amyloidosis. RECENT FINDINGS: Wild-type transthyretin (ATTRwt) protein causes cardiac amyloidosis sporadically, with 25 to 36% of the population older than 80 years of age are at risk to develop a slowly progressive, infiltrative amyloid cardiomyopathy secondary to ATTRwt. In contrast, hereditary amyloidosis (ATTRm) is an autosomal dominant inherited disease associated with more than 100 point mutations in the transthyretin gene and has a tendency to affect the heart and nervous system. Up to 4% of African-Americans carry the Val122Ile mutation in the transthyretin gene, the most prevalent cause of hereditary cardiac amyloidosis in the USA. Identifying transthyretin cardiac amyloidosis requires increased awareness of the prevalence, signs and symptoms, and diagnostic tools available for discrimination of this progressive form of cardiomyopathy associated with left ventricular hypertrophy. While there are no FDA-approved medical treatments, investigation is underway on agents to reduce circulating mutated transthyretin. PMID- 28840453 TI - Immunotherapy in Gynecologic Cancers: Are We There Yet? AB - OPINION STATEMENT: Immune-targeted therapies have demonstrated durable responses in many tumor types with limited treatment options and poor overall prognosis. This has led to enthusiasm for expanding such therapies to other tumor types including gynecologic malignancies. The use of immunotherapy in gynecologic malignancies is in the early stages and is an active area of ongoing clinical research. Both cancer vaccines and immune checkpoint inhibitor therapy continue to be extensively studied in gynecologic malignancies. Immune checkpoint inhibitors, in particular, hold promising potential in specific subsets of endometrial cancer that express microsatellite instability. The key to successful treatment with immunotherapy involves identification of the subgroup of patients that will derive benefit. The number of ongoing trials in cervical, ovarian, and endometrial cancer will help to recognize these patients and make treatment more directed. Additionally, a number of studies are combining immunotherapy with standard treatment options and will help to determine combinations that will enhance responses to standard therapy. Overall, there is much enthusiasm for immunotherapy approaches in gynecologic malignancies. However, the emerging data shows that with the exception of microsatellite unstable tumors, the use of single-agent immune checkpoint inhibitors is associated with response rates of 10 15%. More effective and likely combinatorial approaches are needed and will be informed by the findings of ongoing trials. PMID- 28840454 TI - Clinical Reasoning Education at US Medical Schools: Results from a National Survey of Internal Medicine Clerkship Directors. AB - BACKGROUND: Recent reports, including the Institute of Medicine's Improving Diagnosis in Health Care, highlight the pervasiveness and underappreciated harm of diagnostic error, and recommend enhancing health care professional education in diagnostic reasoning. However, little is known about clinical reasoning curricula at US medical schools. OBJECTIVE: To describe clinical reasoning curricula at US medical schools and to determine the attitudes of internal medicine clerkship directors toward teaching of clinical reasoning. DESIGN: Cross sectional multicenter study. PARTICIPANTS: US institutional members of the Clerkship Directors in Internal Medicine (CDIM). MAIN MEASURES: Examined responses to a survey that was emailed in May 2015 to CDIM institutional representatives, who reported on their medical school's clinical reasoning curriculum. KEY RESULTS: The response rate was 74% (91/123). Most respondents reported that a structured curriculum in clinical reasoning should be taught in all phases of medical education, including the preclinical years (64/85; 75%), clinical clerkships (76/87; 87%), and the fourth year (75/88; 85%), and that more curricular time should be devoted to the topic. Respondents indicated that most students enter the clerkship with only poor (25/85; 29%) to fair (47/85; 55%) knowledge of key clinical reasoning concepts. Most institutions (52/91; 57%) surveyed lacked sessions dedicated to these topics. Lack of curricular time (59/67, 88%) and faculty expertise in teaching these concepts (53/76, 69%) were identified as barriers. CONCLUSIONS: Internal medicine clerkship directors believe that clinical reasoning should be taught throughout the 4 years of medical school, with the greatest emphasis in the clinical years. However, only a minority reported having teaching sessions devoted to clinical reasoning, citing a lack of curricular time and faculty expertise as the largest barriers. Our findings suggest that additional institutional and national resources should be dedicated to developing clinical reasoning curricula to improve diagnostic accuracy and reduce diagnostic error. PMID- 28840455 TI - Effects of Laparoscopic Roux-en-Y Gastric Bypass on Chinese Type 2 Diabetes Mellitus Patients with Different Levels of Obesity: Outcomes After 3 Years' Follow-Up. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has been proven to be effective on treating type 2 diabetes mellitus (T2DM) in severely obese patients, but whether LRYGB surgery should be performed in obese class I patients is controversial. MATERIALS AND METHODS: A retrospective study of 3-year bariatric and metabolic outcomes in different obese class T2DM patients who underwent LRYGB was conducted to compare the effectiveness of LRYGB in obese class I patients with that in obese class II/III patients in a Chinese T2DM population. RESULTS: Totally, 58 patients with class I obesity and 45 patients with class II/III obesity were enrolled in this study. Major complications included two cases of incomplete intestinal obstructions and one anastomotic leak. The remission rates of T2DM were 70.6% in obese class I group and 77.8% in obese class II/III group at 1 year after surgery and 55.6 versus 64.3% at 3 years (all P > 0.05). Logistic regression analysis showed that higher waist circumference, lower fasting plasma glucose, and higher FCP at 2 h of OGTT were independently associated with diabetes remission at 1 year after surgery. At 1 year and thereafter, the percentage of excess weight loss was significantly greater in obese class II/III patients. At 3 years, body mass index was not significantly different between the two groups, and the obese class I patients had high recurrence rates of hypertension and hyperuricemia. CONCLUSIONS: LRYGB surgery is feasible, safe, and effective in Chinese obese class I patients with T2DM. PMID- 28840456 TI - Effects of statin therapy on platelet reactivity after percutaneous coronary revascularization in patients with acute coronary syndrome. AB - Statin use is associated with enhanced pharmacodynamic response to clopidogrel in patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI). However, the impact of statin therapy on clopidogrel response profiles in patients with acute coronary syndrome (ACS) undergoing PCI has not been established and represents the objective of this investigation. On-treatment P2Y12 platelet reactivity was measured using the vasodilator stimulated phosphoprotein (VASP) phosphorylation assay before PCI, at hospital discharge, and at 1 month after PCI in ACS patients enrolled in the multicenter, prospective GEne polymorphisms, Platelet Reactivity, and Syntax Score (GEPRESS) study (n = 962). High platelet reactivity (HPR) was defined as platelet reactivity index >=50%. Statins were prescribed at hospital discharge in 87% (n = 835) of patients. All patients were followed for 1 year. The 1-month HPR rate was lower in statin than in non-statin treated patients (39.6 vs 52%, respectively, p = 0.009). This finding was confirmed also among statin-treated patients with high Syntax score (>=15). After adjustment for differences in baseline characteristics, statin use at discharge was independently associated with 1 month HPR rate (odds ratio, 0.58, 95% confidence interval, 0.38-0.89; p = 0.015). In ACS patients undergoing PCI treated with clopidogrel the use of statins at discharge was associated with significantly lower 1-month HPR rates compared with patients not treated with statins. PMID- 28840457 TI - VA's National PTSD Brain Bank: a National Resource for Research. AB - The National PTSD Brain Bank (NPBB) is a brain tissue biorepository established to support research on the causes, progression, and treatment of PTSD. It is a six-part consortium led by VA's National Center for PTSD with participating sites at VA medical centers in Boston, MA; Durham, NC; Miami, FL; West Haven, CT; and White River Junction, VT along with the Uniformed Services University of Health Sciences. It is also well integrated with VA's Boston-based brain banks that focus on Alzheimer's disease, ALS, chronic traumatic encephalopathy, and other neurological disorders. This article describes the organization and operations of NPBB with specific attention to: tissue acquisition, tissue processing, diagnostic assessment, maintenance of a confidential data biorepository, adherence to ethical standards, governance, accomplishments to date, and future challenges. Established in 2014, NPBB has already acquired and distributed brain tissue to support research on how PTSD affects brain structure and function. PMID- 28840458 TI - Biogas Production from Distilled Grain Waste by Thermophilic Dry Anaerobic Digestion: Pretreatment of Feedstock and Dynamics of Microbial Community. AB - Distilled grain waste (DGW) eluted from the Chinese liquor making process poses potential serious environmental problems. The objective of this study is to evaluate the feasibility of converting DGW to biogas by thermophilic dry anaerobic digestion. To improve biogas production, the effects of dilute H2SO4 and thermal pretreatment on DGW were evaluated by biochemical methane potential (BMP) tests. The results indicate that 90 degrees C thermal pretreatment provided the highest methane production at 212.7 mL/g-VTSadd. The long-term thermophilic dry anaerobic digestion process was conducted in a 5-L separable flask for more than 3 years at a volatile total solid (VTS) loading rate of 1 g/kg-sludge/d, using synthetic waste, untreated and 90 degrees C thermal pretreated DGW as the feedstock, respectively. A higher methane production, 451.6 mL/g-VTSadd, was obtained when synthetic waste was used; the methane production decreased to 139.4 mL/g-VTSadd when the untreated DGW was used. The 90 degrees C thermal pretreated DGW increased the methane production to 190.5 mL/g-VTSadd, showing an increase of 36.7% in methane production compared with that using untreated DGW. The microbial community structure analysis indicates that the microbial community in the thermophilic dry anaerobic digestion system maintained a similar structure when untreated or pretreated DGW was used, whereas the structure differed significantly when synthetic waste was used as the feedstock. PMID- 28840460 TI - Synthesis of Chitin Oligosaccharides Using Dried Stenotrophomonas maltophilia Cells Containing a Transglycosylation Reaction-Catalyzing beta-N Acetylhexosaminidase as a Whole-Cell Catalyst. AB - Bacterial strain NYT501, which we previously isolated from soil, was identified as Stenotrophomonas maltophilia, and it was confirmed that this strain produces an intracellular beta-N-acetylhexosaminidase exhibiting transglycosylation activity. Several properties of this enzyme were characterized using a partially purified enzyme preparation. Using N,N'-diacetylchitobiose (GlcNAc)2 and N,N',N" triacetylchitotriose (GlcNAc)3 as substrates and dried cells of this bacterium as a whole-cell catalyst, chitin oligosaccharides of higher degrees of polymerization were synthesized. (GlcNAc)3 was generated from (GlcNAc)2 as the major transglycosylation product, and a certain amount of purified sample of the trisaccharide was obtained. By contrast, in the case of the reaction using (GlcNAc)3 as a substrate, the yield of higher-degree polymerization oligosaccharides was comparatively low. PMID- 28840459 TI - Pancreatogastrostomy Vs. Pancreatojejunostomy: a Risk-Stratified Analysis of 5316 Pancreatoduodenectomies. PMID- 28840461 TI - Simultaneous BOLD detection and incomplete fMRI data reconstruction. AB - The problem of simultaneous blood oxygenation level dependent (BOLD) detection and data completion is addressed in this paper. It is assumed that a set of fMRI data with significant number of missing samples is available and the aim is to recover those samples with least possible quality degradation. At the same time, BOLD should be detected. We propose a new cost function comprising both BOLD detection and data reconstruction terms. A solution based on singular value thresholding and sparsity-inducing approach is proposed. Due to the low-rank nature of the fMRI data, it is expected that the related techniques to be very effective for reconstruction. Extensive experiments are conducted on different datasets in noisy conditions. The achieved results, both in terms of data quality and data analysis accuracy, are promising and confirm that the proposed method can be effective for recovery of compressed/incomplete fMRI data. Several state of-the art image reconstruction techniques are compared with the proposed method. In addition, the results of applying general linear model (GLM) using statistical parameter mapping (SPM) toolbox are compared with those of the proposed method. PMID- 28840462 TI - A Heart-Healthy Diet: Recent Insights and Practical Recommendations. AB - PURPOSE OF REVIEW: The purpose of this study is to review the current evidence on the relationship between diet and heart, giving practical recommendations for cardiovascular prevention. RECENT FINDINGS: A heart-healthy diet should maximize the consumption of whole grains, vegetables, fruit, and legumes and discourage the consumption of meat and meat products as well as refined and processed foods. Plant-based diets fully meet these criteria, and the evidence supporting the protective effect of these dietary patterns evolved rapidly in recent years. Among plant-based diets, the Mediterranean and vegetarian diets gained the greater interest, having been associated with numerous health benefits such as reduced levels of traditional and novel risk factors and lower risk of cardiovascular disease. These positive effects may be explained by their high content of dietary fiber, complex carbohydrate, vitamins, minerals, polyunsaturated fatty acids, and phytochemicals. Current evidence suggests that both Mediterranean and vegetarian diets are consistently beneficial with respect to cardiovascular disease. PMID- 28840463 TI - Renal Dysfunction: How to Think About That in Acute Coronary Syndromes. AB - PURPOSE OF REVIEW: Reduction of kidney function and heart disease frequently coexisted in the seam patient. The relation between renal and heart function is quite complex and bring out some unresolved questions about diagnosis (mostly related to the biomarkers levels interpretation), pharmacological therapy (mostly related to drugs kinetics and efficacy), and non-pharmacological therapy. RECENT FINDINGS: Patients with kidney dysfunction (KD) are frequently excluded and underrepresented in the large trials. It is well-known that coronary revascularization reduces mortality also in KD patients presenting with acute coronary syndrome. However, acute kidney injury (AKI), primarily related at contrast medium administration, is worse prognosis. For this reason, prevention, early diagnosis, and effective therapy of ACK are key elements in assistance of these patients. In this context, recently, some new biomarkers of renal function have been proposed. Frequently, patients with acute coronary syndromes and kidney disease are undertreated, worsening their prognosis. Undertreatment and comorbidities associated with renal dysfunction explain the higher mortality of these patients. PMID- 28840465 TI - Gold and Female Reproductive Organs: an Ultrastructural Study. AB - Gold, a heavy yellow-colored metal, is usually found in nature as a metallic element or as salts. This noble metal historically had a reputation as an anti inflammatory medicine for rheumatoid arthritis, a nervine, and a remedy for nervous disorders, as well as a potential anticancer agent. It has also been used as component in dental restorations and in implant materials. The present study was undertaken to point out histological and ultrastructural effects of gold, administered by intraperitoneal route, in pregnant female reproductive organs (ovary and uterus), in order to clarify its side effects on the reproductive function. Using the transmission electron microscopy (TEM), the ultrastructural investigations of both ultrathin ovarian and uterine sections of treated pregnant rats revealed the existence of numerous heterogeneous clusters with very electron dense inclusions characterized by various aspects in the lysosomes of granulosa, theca interna cells, and theca externa cells. Degeneration of these tissues, like cell vacuolization, marked expansion of the endoplasmic reticulum, mitochondrial alterations, and necrotic foci, were also highlighted. Moreover, huge phagolysosomes and high numbers of eosinophils as signs of inflammation were also identified especially in endometrial and myometrial cells of gold-treated rats. The ultrastructural investigations of reproductive organ sections of control pregnant rats showed a normal ultrastructural aspect and no loaded lysosomes. These results speculated the toxicity of gold at the used dose. The observed signs of toxicity allowed concluding that the important role of lysosome in the sequestration of this element under an insoluble form in all categories of cells in the studied tissues does not seem to be efficient. PMID- 28840464 TI - Different Arabidopsis thaliana photosynthetic and defense responses to hemibiotrophic pathogen induced by local or distal inoculation of Burkholderia phytofirmans. AB - Pathogen infection of plant results in modification of photosynthesis and defense mechanisms. Beneficial microorganisms are known to improve plant tolerance to stresses. Burkholderia phytofirmans PsJN (Bp), a beneficial endophytic bacterium, promotes growth of a wide range of plants and induces plant resistance against abiotic and biotic stresses such as coldness and infection by a necrotrophic pathogen. However, mechanisms underlying its role in plant tolerance towards (hemi)biotrophic invaders is still lacking. We thus decipher photosynthetic and defense responses during the interaction between Arabidopsis, Bp and the hemibiotrophic bacterium Pseudomonas syringae pv. tomato DC3000 (Pst). Different Bp inoculations allowed analyzes at both systemic and local levels. Despite no direct antibacterial action, our results showed that only local presence of Bp alleviates Pst growth in planta during the early stage of infection. Molecular investigations showed that seed inoculation of Bp, leading to a restricted presence in the root system, transiently primed PR1 expression after challenge with Pst but continuously primed PDF1.2 expression. Bacterization with Bp reduced Y(ND) but had no impact on PSII activity or RuBisCO accumulation. Pst infection caused an increase of Y(NA) and a decrease in PhiPSI, ETRI and in PSII activity, showed by a decrease in Fv/Fm, Y(NPQ), PhiPSII, and ETRII values. Inoculation with both bacteria did not display any variation in photosynthetic activity compared to plants inoculated with only Pst. Our findings indicated that the role of Bp here is not multifaceted, and relies only on priming of defense mechanisms but not on improving photosynthetic activity. PMID- 28840466 TI - Advances in Percutaneous Therapies for Peripheral Artery Disease: Drug-Coated Balloons. AB - PURPOSE OF REVIEW: This review paper provides a summary on the use of drug-coated balloons in peripheral artery disease. It covers the main drug-coated balloon (DCB) trials. It is divided into categories of lesions: superficial femoral artery and popliteal lesions, infra-popliteal lesions and in-stent restenosis. It also includes an overview of the future of DCBs, highlighting the main ongoing trials. RECENT FINDINGS: The latest research on DCB focuses on newer types of DCBs, mainly paclitaxel-coated but with lower doses. Another area of latest DCB research is its use in superficial femoral artery and popliteal artery in-stent restenosis, with superior outcomes. Drug-coated balloons produce better outcomes than percutaneous transluminal angioplasty alone in de novo and in-stent restenosis lesions of superficial femoral artery and popliteal arteries. More data are needed to demonstrate efficacy and safety of DCBs in infrapopliteal disease. Newer DCBs and adjunctive therapy may provide improved outcomes for peripheral artery disease interventions. PMID- 28840467 TI - Value-based Healthcare: A Novel Transitional Care Service Strives to Improve Patient Experience and Outcomes. PMID- 28840469 TI - Early Exposure to Ketamine Impairs Axonal Pruning in Developing Mouse Hippocampus. AB - Mounting evidence suggests that prolonged exposure to general anesthesia (GA) during brain synaptogenesis damages the immature neurons and results in long-term neurocognitive impairments. Importantly, synaptogenesis relies on timely axon pruning to select axons that participate in active neural circuit formation. This process is in part dependent on proper homeostasis of neurotrophic factors, in particular brain-derived neurotrophic factor (BDNF). We set out to examine how GA may modulate axon maintenance and pruning and focused on the role of BDNF. We exposed post-natal day (PND)7 mice to ketamine using a well-established dosing regimen known to induce significant developmental neurotoxicity. We performed morphometric analyses of the infrapyramidal bundle (IPB) since IPB is known to undergo intense developmental modeling and as such is commonly used as a well established model of in vivo pruning in rodents. When IPB remodeling was followed from PND10 until PND65, we noted a delay in axonal pruning in ketamine-treated animals when compared to controls; this impairment coincided with ketamine induced downregulation in BDNF protein expression and maturation suggesting two conclusions: a surge in BDNF protein expression "signals" intense IPB pruning in control animals and ketamine-induced downregulation of BDNF synthesis and maturation could contribute to impaired IPB pruning. We conclude that the combined effects on BDNF homeostasis and impaired axon pruning may in part explain ketamine-induced impairment of neuronal circuitry formation. PMID- 28840468 TI - The Kinase Fyn As a Novel Intermediate in L-DOPA-Induced Dyskinesia in Parkinson's Disease. AB - Dopamine replacement therapy with L-DOPA is the treatment of choice for Parkinson's disease; however, its long-term use is frequently associated with L DOPA-induced dyskinesia (LID). Many molecules have been implicated in the development of LID, and several of these have been proposed as potential therapeutic targets. However, to date, none of these molecules have demonstrated full clinical efficacy, either because they lie downstream of dopaminergic signaling, or due to adverse side effects. Therefore, discovering new strategies to reduce LID in Parkinson's disease remains a major challenge. Here, we have explored the tyrosine kinase Fyn, as a novel intermediate molecule in the development of LID. Fyn, a member of the Src kinase family, is located in the postsynaptic density, where it regulates phosphorylation of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor in response to dopamine D1 receptor stimulation. We have used Fyn knockout and wild-type mice, lesioned with 6 hydroxydopamine and chronically treated with L-DOPA, to investigate the role of Fyn in the induction of LID. We found that mice lacking Fyn displayed reduced LID, DeltaFosB accumulation and NR2B phosphorylation compared to wild-type control mice. Pre-administration of saracatinib (AZD0530), an inhibitor of Fyn activity, also significantly reduced LID in dyskinetic wild-type mice. These results support that Fyn has a critical role in the molecular pathways affected during the development of LID and identify Fyn as a novel potential therapeutic target for the management of dyskinesia in Parkinson's disease. PMID- 28840470 TI - Congenital and Acquired Valvular Heart Disease in Pregnancy. AB - PURPOSE OF REVIEW: The number of pregnancies complicated by valvular heart disease is increasing. This review describes the hemodynamic effects of clinically important valvular abnormalities during pregnancy and reviews current guideline-driven management strategies. RECENT FINDINGS: Valvular heart disease in women of childbearing age is most commonly caused by congenital abnormalities and rheumatic heart disease. Regurgitant lesions are well tolerated, while stenotic lesions are associated with a higher risk of pregnancy-related complications. Management of symptomatic disease during pregnancy is primarily medical, with percutaneous interventions considered for refractory symptoms. Most guidelines addressing the management of valvular heart disease during pregnancy are based on case reports and observational studies. Additional investigation is required to further advance the care of this growing patient population. PMID- 28840471 TI - The Effects of Duodenojejunal Omega Switch in Combination with High-Fat Diet and Control Diet on Incretins, Body Weight, and Glucose Tolerance in Sprague-Dawley Rats. AB - BACKGROUND: Despite excellent results of bariatric surgery in the treatment of type 2 diabetes and weight loss in human subjects, some patients do not obtain desired results. One of the reasons for this is that not all patients follow caloric intake recommendations. AIM: The aim of this study was to investigate the effect of duodenojejunal omega switch (DJOS) surgery on body weight, glucose tolerance, and incretins in rats. METHODS: DJOS and SHAM surgery were performed on rats maintained for 8 weeks on high-fat diet (HF) and control diet (CD), respectively. After surgery, four groups were kept on the same diet as before the surgery, and four groups had a changed diet (CD vs. HF and HF vs. CD) for the next 8 weeks. Glucose tolerance, insulin tolerance, glucose-stimulated insulin, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide/glucose dependent insulinotropic polypeptide (GIP) secretion, food intake, and body weight were measured. RESULTS: A change of diet after surgery resulted in reduced glucose tolerance. Plasma insulin levels were lowered between DJOS and SHAM surgeries for the HF/HF and CD/HF groups. DJOS surgery did not reduce body weight in the studied groups, irrespective of diet. In the HF/HF group, DeltaGLP-1 was lower for DJOS surgery in comparison with other groups. Differences of weight changes were observed for groups HF/HF and HF/CD. After DJOS surgery, DeltaGIP was lower in the CD/HF group compared with HF/HF. CONCLUSIONS: Our results show that applications of different types of diets, before and after surgery, is a sensitive method for studies of mechanism of glucose intolerance after DJOS surgery. PMID- 28840472 TI - Thirty-Day Hospital Readmission After Restorative Proctocolectomy and Ileal Pouch Anal Anastomosis for Chronic Ulcerative Colitis at a High-Volume Center. AB - BACKGROUND: Ileal pouch anal anastomosis (IPAA) is associated with a high 30-day hospital readmission rate. Risk factors and etiology of readmission remain poorly defined. We sought to determine the 30-day hospital readmission rate following IPAA at a high-volume center and identify any modifiable perioperative factors. METHODS: A retrospective review of all patients undergoing two- or three-stage IPAA for chronic ulcerative colitis at our institution between 2002 and 2013 was performed. Analysis was performed on rate of readmission, readmission diagnosis, intervention performed upon readmission, and risk factors for readmission. RESULTS: Thirty-day primary and secondary readmission rates after IPAA were 20.3% (n = 185) and 2.1% (n = 19), respectively. The leading etiologies for readmission included partial small bowel obstruction/ileus (n = 52, 21.9%), pelvic sepsis (n = 43, 18.1%), dehydration (n = 42, 17.7%), and venous thromboembolism (n = 31, 13.1%). While the majority of readmissions were managed medically (n = 119, 65.4%), 19.2% (n = 35) required radiologic intervention and 15.3% (n = 28) required a return to the operating room. On univariate analysis, younger age (p = 0.03) and female sex (p = 0.04) had a significantly increased risk of readmission. On multivariable analysis, BMI >= 30 (OR 0.51; 95% CI, 0.25-0.97, p = 0.04) was protective of readmission. CONCLUSIONS: Thirty-day hospital readmission following IPAA remains a common problem. Preventable etiologies of readmission include dehydration and venous thromboembolism (VTE). Future quality improvement efforts should focus on education regarding stoma output and extended VTE prophylaxis to decrease hospital readmission rates following IPAA. PMID- 28840473 TI - DREAM-Dependent Activation of Astrocytes in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown origin and characterized by a relentless loss of motor neurons that causes a progressive muscle weakness until death. Among the several pathogenic mechanisms that have been related to ALS, a dysregulation of calcium-buffering proteins in motor neurons of the brain and spinal cord can make these neurons more vulnerable to disease progression. Downstream regulatory element antagonist modulator (DREAM) is a neuronal calcium-binding protein that plays multiple roles in the nucleus and cytosol. The main aim of this study was focused on the characterization of DREAM and glial fibrillary acid protein (GFAP) in the brain and spinal cord tissues from transgenic SOD1G93A mice and ALS patients to unravel its potential role under neurodegenerative conditions. The DREAM and GFAP levels in the spinal cord and different brain areas from transgenic SOD1G93A mice and ALS patients were analyzed by Western blot and immunohistochemistry. Our findings suggest that the calcium-dependent excitotoxicity progressively enhanced in the CNS in ALS could modulate the multifunctional nature of DREAM, strengthening its apoptotic way of action in both motor neurons and astrocytes, which could act as an additional factor to increase neuronal damage. The direct crosstalk between astrocytes and motor neurons can become vulnerable under neurodegenerative conditions, and DREAM could act as an additional switch to enhance motor neuron loss. Together, these findings could pave the way to further study the molecular targets of DREAM to find novel therapeutic strategies to fight ALS. PMID- 28840474 TI - Natural or Natural-Synthetic Hybrid Polymer-Based Fluorescent Polymeric Materials for Bio-imaging-Related Applications. AB - Fluorescent polymeric materials such as hydrogels and particles have been attracting attention in many biomedical applications including bio-imaging, optical sensing, tissue engineering, due to their good biocompatibility, biodegradability, and advanced optical property. This review article aims at summarizing recent progress in fluorescent hydrogels and particles based on natural polymers or natural-synthetic hybrid polymers as the building blocks with a concentration on their bio-imaging-related applications. The challenges and future perspectives for the development of natural or natural-synthetic hybrid polymer-based fluorescent hydrogels and particles are also presented. PMID- 28840475 TI - Histone Deacetylase Inhibitor Entinostat (MS-275) Restores Anesthesia-induced Alteration of Inhibitory Synaptic Transmission in the Developing Rat Hippocampus. AB - Recent evidence strongly supports the idea that common general anesthetics (GAs) such as isoflurane (Iso) and nitrous oxide (N2O; laughing gas), as well as sedative drugs such as midazolam are neurotoxic for the developing mammalian brain having deleterious effects on neural circuits involved in cognition, learning and memory. However, to date, very little is known about epigenetic mechanisms involved in GA-induced plasticity of synaptic transmission in the hippocampus, the main memory-processing region in the brain. Here, we used patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) from hippocampal neurons in slice cultures exposed to the clinically relevant GA combination. We found that in vitro exposure to a combination of midazolam, 0.75% Iso, and 70% N2O for 6 h leads to lasting increase in frequency of mIPSCs, while amplitudes and kinetics of the events were spared. Importantly, co-application of entinostat (MS-275), a selective inhibitor of class I histone deacetylases (HDAC), completely reversed GA-induced synaptic plasticity. Furthermore, when given in vivo to P7 pups exposed to GA with midazolam, Iso and N2O for 6 h, MS 275 reversed GA-induced histone-3 hypoacetylation as shown by an increase in Ac H3 protein expression in the hippocampus. We conclude that exposure to a combination of Iso with N2O and midazolam causes plasticity of mIPSCs in hippocampal neurons by epigenetic mechanisms that target presynaptic sites. We hypothesize that GA-induced epigenetic alterations in inhibitory synaptic transmission in the hippocampus may contribute to altered neuronal excitability and consequently abnormal learning and memory later in life. PMID- 28840476 TI - Making Sense of Cerebellar Contributions to Perceptual and Motor Adaptation. AB - The cerebellum is thought to adapt movements to changes in the environment in order to update an implicit understanding of the association between our motor commands and their sensory consequences. This trial-by-trial motor recalibration in response to external perturbations is frequently impaired in people with cerebellar damage. In healthy people, adaptation to motor perturbations is also known to induce a form of sensory perceptual recalibration. For instance, hand reaching adaptation tasks produce transient changes in the sense of hand position, and walking adaptation tasks can lead to changes in perceived leg speed. Though such motor adaptation tasks are heavily dependent on the cerebellum, it is not yet understood how the cerebellum is associated with these accompanying sensory recalibration processes. Here we asked if the cerebellum is required for the recalibration of leg-speed perception that normally occurs alongside locomotor adaptation, as well as how ataxia severity is related to sensorimotor recalibration deficits in patients with cerebellar damage. Cerebellar patients performed a speed-matching task to assess perception of leg speed before and after walking on a split-belt treadmill, which has two belts driving each leg at a different speed. Healthy participants update their perception of leg speed following split-belt walking such that the "fast" leg during adaptation feels slower afterwards, whereas cerebellar patients have significant deficits in this sensory perceptual recalibration. Furthermore, our analysis demonstrates that ataxia severity is a crucial factor for both the sensory and motor adaptation impairments that affect patients with cerebellar damage. PMID- 28840477 TI - A Working Module for the Neurovascular Unit in the Sexually Dimorphic Nucleus of the Preoptic Area. AB - The neurovascular unit (NVU) can be conceptualized as a functional entity consisting of neurons, astrocytes, pericytes, and endothelial and smooth muscle cells that operate in concert to affect blood flow to a very circumscribed area. Although we are currently in a "golden era" of bioengineering, there are, as yet, no living NVUs-on-a-chip modules available and the development of a neural chip that would mimic NVUs is a seemingly lofty goal. The sexually dimorphic nucleus of the preoptic area (SDN-POA) is a tiny brain structure (between 0.001~0.007 mm3 in rats) with an assessable biological function (i.e., male sexual behavior). The present effort was undertaken to determine whether there are identifiable NVUs in the SDN-POA by assessing its vasculature relative to its known neural components. First, a thorough and systematic review of thousands of histologic and immunofluorescent images from 201 weanling and adult rats was undertaken to define the characteristics of the vessels supplying the SDN-POA: its primary supply artery/arteriole and capillaries are physically inseparable from their neural elements. A subsequent immunofluorescent study targeting alpha-smooth muscle actin confirmed the identity of an artery/arteriole supplying the SDN-POA. In reality, the predominant components of the SDN-POA are calbindin D28k-positive neurons that are comingled with tyrosine hydroxylase-positive projections. Finally, a schematic of an SDN-POA NVU is proposed as a working model of the basic building block of the CNS. Such modules could serve the study of neurovascular mechanisms and potentially inform the development of next generation bioengineered neural transplants, i.e., the construct of an NVU neural chip. PMID- 28840478 TI - The Focal-Focal Preconditioning Effect of Photothrombotic Impact on the Signaling Protein Profile in the Penumbra Surrounding the Ischemic Core Induced by Another Photothrombotic Impact. AB - Ischemic tolerance is the establishment of brain resistance to severe ischemic damage by a mild preconditioning stimulus, insufficient to irreversible tissue damage, but capable of initiating a defense response. We developed the model of focal-focal ischemic tolerance, in which the first local photothrombotic infarct (PTI) in the rat brain cortex reduced the infarct caused by second PTI applied to the contralateral cortex of the same rat 7 days later. Using antibody microarrays, we compared protein profiles in the penumbra surrounding the PTI core after single and double PTI. We observed up- or downregulation of several dozens of proteins that are aimed at neurodegeneration or neuroprotection. Both single and double PTI induced damaging processes in the rat cerebral cortex that included over-expression of various pro-apoptotic and signaling proteins and downregulation of other signaling proteins and regulators of proliferation, some components of actin, intermediate fiber and microtubular cytoskeletons, and proteins involved in vesicle transport and synaptic transmission. The simultaneous protective processes included the upregulation of different signaling and anti-apoptotic proteins, stimulators of proliferation, and proteins involved in remodeling of actin cytoskeleton. The elevated expression of some signaling proteins, such as calcium-dependent PLCgamma1, PKValpha1, CaMKIIalpha, calnexin, and calreticulin was preserved after double PTI. Less pro-survival proteins were downregulated in the penumbra after double than single impact. PMID- 28840479 TI - Population Survey of Knowledge about Oral Cancer and Related Factors in the Capital of Iran. AB - Knowledge about oral cancer risk factors and signs is thought to improve prevention and early diagnosis, and in turn, increases survival. In this population-based survey, knowledge about oral cancer was assessed in Iran. A total of 1800 self-administered questionnaires (collecting sociodemographic data and questions regarding oral cancer risk factors and signs) were distributed through random sampling. Final scores ranged between 0 and 15 for the risk factors and 0-11 for the signs. Scores below the median indicated a low level of knowledge, scores representing the third quartile of correct answers indicated a moderate level of knowledge, and scores representing the upper quartile indicated a high level of knowledge. Statistical tests were used for analysis of knowledge level in different sociodemographic categories. A total of 1312 participants completed the questionnaires. The average of knowledge scores for risk factors was 5.3 +/- 3.0 and for signs was 4.5 +/- 2.9. Overall, 75 and 56% respectively were able to identify major risk factors (smoking and alcohol); 23.5% could not define any related signs and symptoms. Dividing scores into quartiles indicated that three out of four people had "low" knowledge about risk factors and 58% had "low" knowledge about signs and symptoms. Females and highly educated people had more knowledge of oral cancer. Significant difference was found between job and level of knowledge (P = 0.001). This survey revealed that public knowledge of oral cancer was not satisfactory in Iran. Efforts should be done to inform and educate people with risk factors, initial clinical presentation, and symptoms, in order to improve prevention and promote early diagnosis. PMID- 28840480 TI - Hepcidin and Thalassemia. PMID- 28840481 TI - Self-Interest and the Design of Rules. AB - Rules regulating social behavior raise challenging questions about cultural evolution in part because they frequently confer group-level benefits. Current multilevel selection theories contend that between-group processes interact with within-group processes to produce norms and institutions, but within-group processes have remained underspecified, leading to a recent emphasis on cultural group selection as the primary driver of cultural design. Here we present the self-interested enforcement (SIE) hypothesis, which proposes that the design of rules importantly reflects the relative enforcement capacities of competing parties. We show that, in addition to explaining patterns in cultural change and stability, SIE can account for the emergence of much group-functional culture. We outline how this process can stifle or accelerate cultural group selection, depending on various social conditions. Self-interested enforcement has important bearings on the emergence, stability, and change of rules. PMID- 28840482 TI - Nanodelivery of Cerebrolysin and Rearing in Enriched Environment Induce Neuroprotective Effects in a Preclinical Rat Model of Parkinson's Disease. AB - Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO2-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL + EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL + EE group showed more significant number of laps in the wheel than EE group. In SN, CBL + EE group also presented the highest neuronal density. Moreover, p Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL + EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD. PMID- 28840483 TI - Endoscopic Management of Benign Esophageal Strictures. AB - PURPOSE OF REVIEW: This paper presents the author's approach to esophageal dilation. It offers a tailored approach to the application of dilation to specific types of esophageal stenotic lesions. RECENT FINDINGS: In patients with inflammatory stricture, recent studies confirm the importance of treating the underlying inflammatory condition in order to decrease the rate of recurrence. The paper reviews some of the novel techniques that have been suggested for the treatment of refractory benign esophageal strictures, including incisional therapy, stenting, or the injection steroids or antifibrotic agents. The endoscopist who treats esophageal strictures must be familiar with the tools of the dilation and how they are best applied to specific types of stenotic lesions. If inflammation is present, effective management requires treatment of the inflammatory process in addition to mechanical dilation of the stenotic lesion. Controlled trials of novel approaches to treatment of refractory benign esophageal strictures are limited and will be necessary to determine efficacy. PMID- 28840484 TI - Pulmonary fluorosis: a review. AB - The increased industrialization and improvised human lifestyle lead to a surge in environmental pollution nowadays. Even the chemicals which are known as prophylactic agents were currently liable to be toxic. One among them is inorganic fluoride whose wider application in numerous processes makes it as an inevitable environmental contaminant and industrial pollutant. Although the systemic toxicity of fluoride has been extensively studied, still there is lacuna in the field of pulmonary fluoride toxicity. Hence, we have focused on the molecular mechanism of action of fluoride compounds on pulmonary system. A study of literatures that focused on the potential physiological and toxicological consequences of fluoride on pulmonary system was carried out. The goal of this review is to present an overview of the research carried out till date on the molecular aspects of fluoride exposure with emphasis on pulmonary system and their possible mechanisms. PMID- 28840486 TI - Editor's Spotlight/Take 5: Increased Mortality After Prosthetic Joint Infection in Primary THA. PMID- 28840485 TI - How Surrogates Decide: A Secondary Data Analysis of Decision-Making Principles Used by the Surrogates of Hospitalized Older Adults. AB - BACKGROUND: Many hospitalized adults do not have the capacity to make their own health care decisions and thus require a surrogate decision-maker. While the ethical standard suggests that decisions should focus on a patient's preferences, our study explores the principles that surrogates consider most important when making decisions for older hospitalized patients. OBJECTIVES: We sought to determine how frequently surrogate decision-makers prioritized patient preferences in decision-making and what factors may predict their doing so. DESIGN AND PARTICIPANTS: We performed a secondary data analysis of a study conducted at three local hospitals that surveyed surrogate decision-makers for hospitalized patients 65 years of age and older. MAIN MEASURES: Surrogates rated the importance of 16 decision-making principles and selected the one that was most important. We divided the surrogates into two groups: those who prioritized patient preferences and those who prioritized patient well-being. We analyzed the two groups for differences in knowledge of patient preferences, presence of advance directives, and psychological outcomes. KEY RESULTS: A total of 362 surrogates rated an average of six principles as being extremely important in decision-making; 77.8% of surrogates selected a patient well-being principle as the most important, whereas only 21.1% selected a patient preferences principle. Advance directives were more common to the patient preferences group than the patient well-being group (61.3% vs. 44.9%; 95% CI: 1.01-3.18; p = 0.04), whereas having conversations with the patient about their health care preferences was not a significant predictor of surrogate group identity (81.3% vs. 67.4%; 95% CI: 0.39-1.14; p = 0.14). We found no differences between the two groups regarding surrogate anxiety, depression, or decisional conflict. CONCLUSIONS: While surrogates considered many factors, they focused more often on patient well-being than on patient preferences, in contravention of our current ethical framework. Surrogates more commonly prioritized patient preferences if they had advance directives available to them. PMID- 28840487 TI - Revascularization Strategies in STEMI with Multivessel Disease: Deciding on Culprit Versus Complete-Ad Hoc or Staged. AB - PURPOSE OF REVIEW: This review will address the clinical conundrum of those who may derive clinical benefit from complete revascularization of coronary stenosis that are discovered at the time of ST segment elevation myocardial infarction (STEMI). The decision to revascularize additional vessels with angiographic stenosis beyond the culprit lesion remains controversial, as does the timing of revascularization. RECENT FINDINGS: STEMI patients represent a high-risk patient population that have up to a 50% prevalence of multivessel disease. Multivessel disease represents an important risk factor for short- and long-term morbidity and mortality. Potential benefits of multivessel PCI for STEMI might include reduced short- and long-term mortality, revascularization, reduced resource utilization, and costs. Which population will benefit and what the optimal timing of revascularization in the peri-MI period remains controversial. Consideration of multivessel revascularization in the setting of STEMI may occur in up to one half of STEMI patients. Evaluation of the comorbidities including diabetes, extent of myocardium at risk, lesion complexity, ventricular function, and risk factors for complications such as contrast induced nephropathy which is important in determining the appropriate care pathway. PMID- 28840488 TI - Towards a Complete In Silico Assessment of the Outcome of Cochlear Implantation Surgery. AB - Cochlear implantation (CI) surgery is a very successful technique, performed on more than 300,000 people worldwide. However, since the challenge resides in obtaining an accurate surgical planning, computational models are considered to provide such accurate tools. They allow us to plan and simulate beforehand surgical procedures in order to maximally optimize surgery outcomes, and consequently provide valuable information to guide pre-operative decisions. The aim of this work is to develop and validate computational tools to completely assess the patient-specific functional outcome of the CI surgery. A complete automatic framework was developed to create and assess computationally CI models, focusing on the neural response of the auditory nerve fibers (ANF) induced by the electrical stimulation of the implant. The framework was applied to evaluate the effects of ANF degeneration and electrode intra-cochlear position on nerve activation. Results indicate that the intra-cochlear positioning of the electrode has a strong effect on the global performance of the CI. Lateral insertion provides better neural responses in case of peripheral process degeneration, and it is recommended, together with optimized intensity levels, in order to preserve the internal structures. Overall, the developed automatic framework provides an insight into the global performance of the implant in a patient-specific way. This enables to further optimize the functional performance and helps to select the best CI configuration and treatment strategy for a given patient. PMID- 28840489 TI - Plain radiography in patients treated with intrathecal drug delivery using an implantable pump device. AB - OBJECTIVES: Intrathecal drug administration using an implanted pump system is well established in intractable spasticity and pain. However, despite continuous advancements in manufacturing technology, adverse events related to the pump and catheter still occur. Most of them, such as migration, damage, disconnection and occlusion, are related to the spinal catheter. The aim of this overview is to update radiologists on how plain radiography of the implanted delivery system for intrathecal drug administration should be interpreted and to increase awareness for the need of urgent and timely multidisciplinary troubleshooting. METHODS: Plain radiographic images of patients treated with intrathecal drug administration using an implantable drug delivery system were analysed in a multidisciplinary setting at our (university) referral centre for complications in intrathecal drug administration. RESULTS: Examples of catheter-related adverse events are described and a proposal is made for stepwise interpretation of standard plain radiographic images. CONCLUSIONS: Plain radiological images are the mainstay for the diagnosis of catheter-related adverse events in intrathecal drug delivery. Radiologists play an important role in an early diagnosis. An awareness of abnormal radiological findings seems important to avoid a life threatening withdrawal syndrome. TEACHING POINTS: * Untimely cessation of intrathecal drug delivery can lead to a life-threatening withdrawal syndrome. * Initially mild symptoms can lead to an exacerbation of a withdrawal syndrome. * Most intrathecal catheter-related problems are visible on plain radiography. * Common causes of catheter problems are migration, lacerations, occlusion and disconnection. * Knowledge on implanted intrathecal catheters is crucial for interpretation of plain radiography. PMID- 28840491 TI - Longitudinal qualitative research in medical education. PMID- 28840490 TI - Usability of Computerized Lung Auscultation-Sound Software (CLASS) for learning pulmonary auscultation. AB - The mastering of pulmonary auscultation requires complex acoustic skills. Computer-assisted learning tools (CALTs) have potential to enhance the learning of these skills; however, few have been developed for this purpose and do not integrate all the required features. Thus, this study aimed to assess the usability of a new CALT for learning pulmonary auscultation. Computerized Lung Auscultation-Sound Software (CLASS) usability was assessed by eight physiotherapy students using computer screen recordings, think-aloud reports, and facial expressions. Time spent in each task, frequency of messages and facial expressions, number of clicks and problems reported were counted. The timelines of the three methods used were matched/synchronized and analyzed. The tasks exercises and annotation of respiratory sounds were the ones requiring more clicks (median 132, interquartile range [23-157]; 93 [53-155]; 91 [65-104], respectively) and where most errors (19; 37; 15%, respectively) and problems (n = 7; 6; 3, respectively) were reported. Each participant reported a median of 6 problems, with a total of 14 different problems found, mainly related with CLASS functionalities (50%). Smile was the only facial expression presented in all tasks (n = 54). CLASS is the only CALT available that meets all the required features for learning pulmonary auscultation. The combination of the three usability methods identified advantages/disadvantages of CLASS and offered guidance for future developments, namely in annotations and exercises. This will allow the improvement of CLASS and enhance students' activities for learning pulmonary auscultation skills. PMID- 28840492 TI - Proximal Leakage After Laparoscopic Sleeve Gastrectomy: an Analysis of Preoperative and Operative Predictors on 1738 Consecutive Procedures. AB - BACKGROUND: The purpose of this paper was to search for predictive factors for proximal leakage after laparoscopic sleeve gastrectomy (LSG) in a large cohort from a single referral center. MATERIALS AND METHODS: One thousand seven hundred and thirty-eight patients, collected in a prospectively held database from 2008 to 2016, were retrospectively analyzed. The correlation between postoperative leakage and both preoperative (age, gender, height, weight, BMI, and obesity related morbidities) and operative variables (the distance from pylorus at which the gastric section was started, operative time, experience of surgeons who performed the LSG, and the surgical materials used) was analyzed. The experience of the surgeons was calculated in the number of LSGs performed. The surgical materials considered were stapler, cartridges, and reinforcement of the suture. RESULTS: Proximal leakage was observed in 45 patients out of 1738 (2.6%). No correlation was found between leakage and the preoperative variables analyzed. The operative variables that were found to be associated with lower incidence of leakage at the multivariate analysis (p < 0.05) were the reinforcement of the staple line (or overriding suture or buttressing materials) and the experience of the surgeons. A distance of less than 2 cm from the pylorus resulted to be significantly related to a higher incidence of fistula at the univariate analysis. CONCLUSIONS: In this large consecutive cohort study of LSG, proximal staple line reinforcement (buttress material or suture) reduced the risk of a leak. The risk of a proximal leak was much higher in the surgeons first 100 cases, which has implications for training and supervision during this "learning curve" period. PMID- 28840493 TI - Orthorexia nervosa: relationship with obsessive-compulsive symptoms, disordered eating patterns and body uneasiness among Italian university students. AB - INTRODUCTION: The present study aimed to investigate the relationship between ORTO-15 score and obsessive-compulsive symptoms, disordered eating patterns and body uneasiness among female and male university students and to examine the predictive model of ORTO-15 in both groups. METHODS: One hundred and twenty students participated in the present study (mean age 22.74 years, SD 7.31). The ORTO-15 test, the Maudsley Obsessive-Compulsive Questionnaire, the Eating Attitudes Test-26 and the Body Uneasiness Test were used for the present study. RESULTS: Our results revealed no gender differences in ORTO-15 score. Our results show, rather unexpectedly, that in female students lower scores, corresponding to greater severity, were related to less pathological body image discomfort and obsessive-compulsive signs, while in male students, lower ORTO-15 scores were related to less pathological eating patterns, as behaviors and symptoms. CONCLUSION: Further studies regarding the relationship between ON and anorexia nervosa, as well as obsessive-compulsive symptoms, are needed to better understand the causality. Level of Evidence Level V, descriptive study. PMID- 28840494 TI - Ultrapure dialysis water obtained with additional ultrafilter may reduce inflammation in patients on hemodialysis. AB - BACKGROUND: Patients on standard dialysis, in particular those on high-flux and high-efficiency dialysis, are exposed to hundreds of liters of dialysis-water per week. The quality of dialysis-water is a factor responsible for inflammation in dialysis patients. Inflammation is a potent trigger of atherosclerosis and a pathogenetic factor in anemia, increasing mortality and morbidity in dialysis patients. Current systems for water treatment do not completely eliminate bacteria and endotoxins. This prospective study tested whether improved dialysis water purity by an additional ultrafilter can reduce inflammation and ameliorate hemoglobin levels, with a consequent reduction in erythropoietin-stimulating agents (ESA). METHODS: An ultrafilter, composed of two serially positioned devices with polysulfone membranes of 2.0 and 1.0 m2, respectively, was positioned within the fluid pathway before the dialysis machine. Prevalent dialysis patients were assigned either to continue dialysis with conventional dialysis-water (control phase) or to initiate dialysis sessions with improved dialysis-water purity (study phase). After 6 months, patients were crossed over. Total study duration was 1 year. Routine chemistry, bacterial count, endotoxin levels in dialysis-water as well as blood levels of pro- and anti-inflammatory cytokines, human serum amyloid A, C-reactive protein and fraction 5 of complement were measured. RESULTS: Thirty-two patients completed the study. Mean bacterial count was lower and endotoxin levels were absent in dialysis-water obtained with the ultrafilter. At the end of the study-phase, C-reactive protein and pro inflammatory cytokines decreased while anti-inflammatory ones increased. Hemoglobin levels were improved with lower ESA doses. CONCLUSIONS: An additional ultrafilter improved dialysis-water purity, reduced levels of inflammation markers, ameliorated hemoglobin concentration with reduced ESA doses. These results remain speculative but they may generate studies to assess whether improved dialysis-water quality with an ultrafilter can reduce inflammation and improve survival of dialysis patients. PMID- 28840495 TI - Comparison of conventional and bio-treated methods as dust suppressants. AB - Dust is an environmental, geotechnical, health, and economical hazard. Fugitive dust emanating along transportation systems such as roads, railways, and airports especially can have significant impacts on health, safety, material loss, cost of maintenance, and interfere with the facilities. Quantitative studies on the effectiveness of the proper dust palliatives and their environmental impact have been studied with a number of biological and chemical methods. The objective of this study was to establish a method for using the microbial Induced calcium carbonate precipitation (MICP) approach to reduce the percent of mass loss against erosive force of wind regarding to the concentration and characteristics of aggregate used, climate, and traffic amounts. The results of this study showed that the required precipitation for dust control of sand by 70% is less than 15 g CaCO3/m2 between sand grains in bio-treated sand. The wind tunnel test results of this study also indicate that the effectiveness of the bio-treatment method for dust control depends on many variables, such as the percent of precipitated calcium carbonate and tensile strength. PMID- 28840496 TI - Membrane-active peptides, IUPAB/EBSA symposium, Edinburgh. PMID- 28840497 TI - Defining Long-Term Survivors Following Resection of Intrahepatic Cholangiocarcinoma. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary tumor of the liver. While surgery remains the cornerstone of therapy, long-term survival following curative-intent resection is generally poor. The aim of the current study was to define the incidence of actual long-term survivors, as well as identify clinicopathological factors associated with long-term survival. METHODS: Patients who underwent a curative-intent liver resection for ICC between 1990 and 2015 were identified using a multi-institutional database. Overall, 679 patients were alive with >= 5 years of follow-up or had died during follow-up. Prognostic factors among patients who were long-term survivors (LT) (overall survival (OS) >= 5) were compared with patients who were not non-long-term survivors (non-LT) (OS < 5). RESULTS: Among the 1154 patients who underwent liver resection for ICC, 5- and 10-year OS were 39.6 and 20.3% while the actual LT survival rate was 13.3%. After excluding 475 patients who survived < 5 years, as well as patients were alive yet had < 5 years of follow-up, 153 patients (22.5%) who survived >= 5 years were included in the LT group, while 526 patients (77.5%) who died < 5 years from the date of surgery were included in the non-LT group. Factors associated with not surviving to 5 years included perineural invasion (OR 4.78, 95% CI, 1.92-11.8; p = 0.001), intrahepatic metastasis (OR 3.75, 95% CI, 0.85-16.6, p = 0.082), satellite lesions (OR 2.12, 95% CI, 1.15-3.90, p = 0.016), N1 status (OR 4.64, 95% CI, 1.77-12.2; p = 0.002), ICC > 5 cm (OR 2.40, 95% CI, 1.54-3.74, p < 0.001), and direct invasion of an adjacent organ (OR 3.98, 95% CI, 1.18-13.4, p = 0.026). However, a subset of patients (< 10%) who had these pathological characteristics were LT. CONCLUSION: While ICC is generally associated with a poor prognosis, some patients will be LT. In fact, even a subset of patients with traditional adverse prognostic factors survived long term. PMID- 28840498 TI - Downregulation of 14-3-3 Proteins in a Kainic Acid-Induced Neurotoxicity Model. AB - The 14-3-3 proteins are among the most abundant proteins expressed in the brain, comprising about 1% of the total amount of soluble brain proteins. Through phosphoserine- and phosphothreonine-binding motifs, 14-3-3 proteins regulate many signaling proteins and cellular processes including cell death. In the present study, we utilized a well-known kainic acid (KA)-induced excitotoxicity rat model and examined the expression of 14-3-3 and its isoforms in the frontal cortex of KA-treated and control animals. Among the different 14-3-3 isoforms, abundant levels of eta and tau were detected in the frontal cortex, followed by sigma, epsilon, and gamma, while the expression levels of alpha/beta and zeta/delta isoforms were low. Compared to the control animals, KA treatment induced a significant downregulation of the overall 14-3-3 protein level as well as the levels of the abundant isoforms eta, tau, epsilon, and gamma. We also investigated two 14-3-3-interacting proteins that are involved in the cell death process: Bcl-2-associated X (BAX) and extracellular signal-regulated kinase (ERK). Both BAX and phosphorylated ERK showed increased levels following KA treatment. Together, these findings demonstrate an abundance of several 14-3-3 isoforms in the frontal cortex and that KA treatment can cause a downregulation of 14-3-3 expression and an upregulation of 14-3-3-interacting proteins BAX and phospho-ERK. Thus, downregulation of 14-3-3 proteins could be one of the early molecular events associated with excitotoxicity. This could lead to subsequent upregulation of 14-3-3-binding proteins such as BAX and phospho-ERK that contribute to further downstream apoptosis processes, eventually leading to cell death. Maintaining sufficient levels of 14-3-3 expression and function may become a target of therapeutic intervention for excitotoxicity-induced neurodegeneration. PMID- 28840499 TI - Enrollment and Retention in 34 United States Pregnancy Registries Contrasted with the Manufacturer's Capture of Spontaneous Reports for Exposed Pregnancies. AB - INTRODUCTION: Pregnancy registries and spontaneous reports are essential pharmacovigilance tools to evaluate drug safety during pregnancy. OBJECTIVES: The aim of this study was to evaluate postmarket capture of exposed pregnancies. METHODS: Pregnancy registries for drugs and biologics were identified in a systematic review. Through a standardized questionnaire, manufacturers provided information on (1) pregnancy registry enrollment and retention, and (2) worldwide receipt of spontaneous reports for exposed pregnancies. A validated algorithm for live-birth pregnancies allowed calculation of exposure rates per 100,000 live births using claims data. RESULTS: Among 34 products with a pregnancy registry, median (interquartile range) registry enrollment was 36 pregnancies (5-258) and median spontaneous report capture was 450 pregnancies (89-1192). Products used in >20/100,000 live births had a median registry enrollment of 490 pregnancies and median capture of 1061 spontaneously reported exposed pregnancies. Lower median registry enrollment and spontaneous report capture was observed for products used in 0.5-20/100,000 live births (36 from registries, 541 spontaneous reports) and <0.5/100,000 live births (3 from registries, 41 spontaneous reports). Among 24 registries enrolling >=10 pregnancies, median capture of pregnancy outcomes (e.g. live birth, spontaneous abortion) was 83.9%. For 19 registries enrolling >=10 infants, the median proportion of infants achieving protocol-specified follow-up was 89.9% for up to 4 weeks post-birth, 75.0% for 1-5 months, and 57.1% for >=6 months. CONCLUSIONS: Relatively higher product utilization among pregnant women predicted greater pregnancy registry enrollment. For products rarely used during pregnancy, registry enrollment was low and differences in registry enrollment compared with worldwide spontaneous report receipt were most pronounced. Products with very low utilization levels during pregnancy may require a combination of worldwide pharmacovigilance, pregnancy registries, and additional study methods to achieve adequate surveillance. PMID- 28840501 TI - Notes on the Occurrence of Oligonychus milleri (McGregor) and Oligonychus ununguis (Jacobi) (Acari: Tetranychidae) in Brazil. AB - We verified infestation of Oligonychus milleri (McGregor) on plantations of Pinus caribaea (Pinaceae) and of Oligonychus ununguis (Jacobi) on plantations of Eucalyptus urophylla x Eucalyptus grandis (Myrtaceae) in State of Rondonia, Northern region of Brazil. This represents the first record of O. milleri in Brazil. Oligonychus ununguis was recorded previously, on cypress. The damage caused by these two spider mites in the plantations is described herein. PMID- 28840500 TI - Hypertension in Obesity and the Impact of Weight Loss. AB - PURPOSE OF REVIEW: Several interrelated mechanisms promote the development of hypertension in obesity, often contributing to end organ damage including cardiovascular disease and chronic kidney disease. RECENT FINDINGS: The treatment of hypertension in obesity is complicated by a high prevalence of resistant hypertension, as well as unpredictable hemodynamic effects of many medications. Weight loss stabilizes neurohormonal activity and causes clinically significant reductions in blood pressure. While lifestyle interventions can improve blood pressure, they fail to consistently yield sustained weight loss and have not demonstrated long-term benefits. Bariatric surgery provides more permanent weight reduction, corresponding with dramatic declines in blood pressure and attenuation of long-term cardiovascular risk. Hypertension is closely linked to the prevalence, pathophysiology, and morbidity of obesity. There are multiple barriers to managing hypertension in obesity. Surgical weight loss offers the most promise in reducing blood pressure and decreasing end organ damage in this patient population. PMID- 28840502 TI - Case report: Coxiella burnetii vascular infection and lymphoma in the Netherlands. AB - OBJECTIVES AND DESIGN: Non-Hodgkin lymphoma has been linked to infection with Coxiella burnetii, potentially through overproduction of IL-10 during infection with C. burnetii. MATERIALS AND METHODS: Description of a case report. RESULTS: We describe a patient with retroperitoneal non-Hodgkin lymphoma and vascular infection with C. burnetii. Immunofluorescence staining and fluorescence in situ hybridization targeting specific C. burnetii 16S rRNA were performed on the retroperitoneal lymphoma tissue sample obtained at diagnosis of NHL. Both were strongly positive for the presence of C. burnetii. CONCLUSIONS: This case provokes questions regarding a potential association between C. burnetii and NHL, and underlines the importance of further exploration of this association. PMID- 28840503 TI - Metabolic Engineering of Escherichia coli K12 for Homofermentative Production of L-Lactate from Xylose. AB - The efficient utilization of xylose is regarded as a technical barrier to the commercial production of bulk chemicals from biomass. Due to the desirable mechanical properties of polylactic acid (PLA) depending on the isomeric composition of lactate, biotechnological production of lactate with high optical pure has been increasingly focused in recent years. The main objective of this work was to construct an engineered Escherichia coli for the optically pure L lactate production from xylose. Six chromosomal deletions (pflB, ldhA, ackA, pta, frdA, adhE) and a chromosomal integration of L-lactate dehydrogenase-encoding gene (ldhL) from Bacillus coagulans was involved in construction of E. coli KSJ316. The recombinant strain could produce L-lactate from xylose resulting in a yield of 0.91 g/g xylose. The chemical purity of L-lactate was 95.52%, and the optical purity was greater than 99%. Moreover, three strategies, including overexpression of L-lactate dehydrogenase, intensification of xylose catabolism, and addition of additives to medium, were designed to enhance the production. The results showed that they could increase the concentration of L-lactate by 32.90, 20.13, and 233.88% relative to the control, respectively. This was the first report that adding formate not only could increase the xylose utilization but also led to the fewer by-product levels. PMID- 28840504 TI - From Big Data to Smart Data for Pharmacovigilance: The Role of Healthcare Databases and Other Emerging Sources. AB - In the last decade 'big data' has become a buzzword used in several industrial sectors, including but not limited to telephony, finance and healthcare. Despite its popularity, it is not always clear what big data refers to exactly. Big data has become a very popular topic in healthcare, where the term primarily refers to the vast and growing volumes of computerized medical information available in the form of electronic health records, administrative or health claims data, disease and drug monitoring registries and so on. This kind of data is generally collected routinely during administrative processes and clinical practice by different healthcare professionals: from doctors recording their patients' medical history, drug prescriptions or medical claims to pharmacists registering dispensed prescriptions. For a long time, this data accumulated without its value being fully recognized and leveraged. Today big data has an important place in healthcare, including in pharmacovigilance. The expanding role of big data in pharmacovigilance includes signal detection, substantiation and validation of drug or vaccine safety signals, and increasingly new sources of information such as social media are also being considered. The aim of the present paper is to discuss the uses of big data for drug safety post-marketing assessment. PMID- 28840505 TI - Anesthesia in per-oral endoscopic myotomy: A large tertiary care centre experience. AB - BACKGROUND AND OBJECTIVES: Per-oral endoscopic myotomy (POEM) is safe and efficacious for the management of achalasia cardia (AC). POEM is usually performed under general anesthesia in an endoscopy suite or operating theatre. The current study was conducted with the aim to analyse anesthetic management of patients with AC who underwent POEM at our institution. METHODS: We retrospectively analysed the data of patients with AC who underwent POEM at our institution from January 2013 to September 2016. All cases were performed in an endoscopy suite under supervision of an anesthesia management team. Pre-procedure endoscopic evacuation of esophagogastric contents was done in all cases. Management strategies used for gas-related adverse events and outcomes were assessed. RESULTS: Four hundred and eighty patients (median age 40 years, range 4 77 years) underwent POEM during the study period. The sub-types of AC were type I (163), type II (297), and type III (20). POEM was successfully completed in 97.5% patients. Gas-related events were noted in 30.6% cases including-capno-thorax in 1%, capno-peritoneum in 12.3%, retroperitoneal air in 16.5%, capno-mediastinum in 0.2%, and capno-pericardium in 0.4% patients. Significant rise in end tidal CO2 (> 45) and peak airway pressure were observed in 8.1% and 5.4% cases, respectively. Drainage was required in 12.3% patients. There was no occurrence of aspiration during or after POEM. CONCLUSIONS: POEM could be safely performed in an endoscopy suite under supervision of an expert anesthesia management team. Gas related adverse events were common during POEM and could be managed with a standardized approach. PMID- 28840506 TI - Perception of the length of an object through dynamic touch is invariant across changes in the medium. AB - Rotational inertia-a mechanical quantity that describes the differential resistance of an object to angular acceleration in different directions-has been shown to support perception of the properties of that object through dynamic touch (wielding). The goal of the present study was to examine if perception of the length of an object through dynamic touch depends on its rotational inertia, independent of the medium in which it is wielded. The participants (n = 14) wielded 12 different objects held in air or completely immersed in water and reported perceived lengths of those objects. Each object consisted of a rod of a particular density with a particular number of stacked steel rings attached at a particular location along its length. Perceived length was invariant across medium. In addition, a single-valued function of the major eigenvalue, I 1, and the minor eigenvalue, I 3, of the rotational inertia, I, of the 12 objects predicted the perceived lengths of those objects in both air and water, and the perceived lengths were invariant across the two media. These results support the hypothesis that the informational support for perception of the length of an object through dynamic touch is invariant across changes in the medium. PMID- 28840507 TI - Racial and Socioeconomic Disparities in Hysterectomy Route for Benign Conditions. AB - BACKGROUND: The aim of this paper was to explore disparities associated with the route of hysterectomy in the University of Pittsburgh Medical Center (UPMC) health system and to evaluate whether the hysterectomy clinical pathway implementation impacted disparities in the utilization of minimally invasive hysterectomy (MIH). METHODS: We performed a retrospective medical record review of all the patients who have undergone hysterectomy for benign indications at UPMC-affiliated hospitals between fiscal years (FY) 2012 and 2014. RESULTS: A total number of 6373 hysterectomy patient cases were included in this study: 88.7% (5653) were European American (EA), 11.02% (702) were African American (AA), and the remaining 0.28% (18) were of other ethnicities. We found that non EA, women aged 45-60, traditional Medicaid, and traditional Medicare enrollees were more likely to have a total abdominal hysterectomy (TAH). Residence in higher median income zip code (> $61,000) was associated with 60% lower odds of undergoing TAH. Both FY 2013 and 2014 were associated with significantly lower odds of TAH. Logistic regression results from the model for non-EA patients for FY 2012 and FY 2014 demonstrated that FY and zip code income group were not significant predictors of surgery type in this subgroup. Pathway implementation did not reduce racial disparity in MIH utilization. CONCLUSION: This study demonstrated that there is a significant disparity in MIH utilization, where non EA and Medicaid/Medicare recipients had higher odds of undergoing TAH. Further research is needed to investigate how care standardization may alleviate healthcare disparities. PMID- 28840508 TI - The roles of microRNA-34b-5p in angiogenesis of thyroid carcinoma. AB - PURPOSE: This study aims to determine the expression of miR-34b-5p in thyroid carcinomas and to investigate the role of miR34b-5p in the modulation of proteins involved in angiogenesis of thyroid carcinoma cells. METHODS: The expressions of miR-34b-5p levels in five cell lines and 65 tissue samples from thyroid carcinomas were examined by real-time polymerase chain reaction. An exogenous miR 34b-5p (mimic) transiently overexpress miR-34b-5p in theses thyroid carcinoma cells. The effects of miR-34b-5p overexpression on the proteins involved in angiogenesis and cell cycle regulations (VEGF-A, Bcl-2 and Notch1) were investigated by Western blot, immunofluorescence, enzyme-linked immunosorbent assay followed by cell cycle analysis and apoptosis assays. RESULTS: miR-34b-5p is markedly downregulated in all thyroid carcinoma cell lines and tissues samples when compared with non-neoplastic immortalised thyroid cell line and non neoplastic thyroid tissues, respectively. The expression levels of miR-34b were significantly associated with T-stages of thyroid carcinomas (p = 0.042). Downregulation of VEGF-A, Bcl-2 and Notch1 proteins in thyroid carcinoma cells were noted in cells that transiently transfected with miR-34b-5p mimic. In addition, enzyme-linked immunosorbent assay confirmed the decreased expression of VEGF in thyroid carcinoma cells after transfection with miR-34b-5p mimic. Furthermore, miR-34b-5p mimic transfection induces significant accumulation of cells in G0-G1 of the cell cycle by blocking of their entry into the S transitional phase as well as increasing the total apoptosis. CONCLUSIONS: miR 34b-5p functions as a potent regulator of angiogenesis, apoptosis and cell proliferation via modulation of VEGF-A, Bcl-2 and Notch1 proteins. It could be a target for developing treatment strategies of thyroid carcinoma with aggressive clinical behaviour. PMID- 28840509 TI - Kynurenic Acid Prevents Cytoskeletal Disorganization Induced by Quinolinic Acid in Mixed Cultures of Rat Striatum. AB - Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan known to modulate a number of mechanisms involved in neural dysfunction. Although its activity in the brain has been widely studied, the effect of KYNA counteracting the actions of quinolinic acid (QUIN) remains unknown. The present study aims at describing the ability of 100 MUM KYNA preventing cytoskeletal disruption provoked by QUIN in astrocyte/neuron/microglia mixed culture. KYNA totally preserved cytoskeletal organization, cell morphology, and redox imbalance in mixed cultures exposed to QUIN. However, KYNA partially prevented morphological alteration in isolated primary astrocytes and failed to protect the morphological alterations of neurons caused by QUIN exposure. Moreover, KYNA prevented QUIN-induced microglial activation and upregulation of ionized calcium-binding adapter molecule 1 (Iba-1) and partially preserved tumor necrosis factor-alpha (TNF-alpha) level in mixed cultures. TNF-alpha level was also partially preserved in astrocytes. In addition to the mechanisms dependent on redox imbalance and microglial activation, KYNA prevented downregulation of connexin-43 and the loss of functionality of gap junctions (GJs), preserving cell-cell contact, cytoskeletal organization, and cell morphology in QUIN-treated cells. Furthermore, the toxicity of QUIN targeting the cytoskeleton of mixed cultures was not prevented by the N-methyl-D aspartate (NMDA) antagonist MK-801. We suggest that KYNA protects the integrity of the cytoskeleton of mixed cultures by complex mechanisms including modulating microglial activation preventing oxidative imbalance and misregulated GJs leading to disrupted cytoskeleton in QUIN-treated cells. This study contributed to elucidate the molecular basis of KYNA protection against QUIN toxicity. PMID- 28840510 TI - Cypermethrin Activates Autophagosome Formation Albeit Inhibits Autophagy Owing to Poor Lysosome Quality: Relevance to Parkinson's Disease. AB - Parkinson's disease (PD) is the second most familiar, progressive and movement related neurodegenerative disorder after Alzheimer disease. This study aimed to decipher the role of autophagy in cypermethrin-induced Parkinsonism, an animal model of PD. Indicators of autophagy [expression of beclin 1, autophagy-related protein 12 (Atg 12), unc-51 like autophagy activating kinase 1 (Ulk 1), p62 and lysosome-associated membrane protein 2 (LAMP 2) and conversion of microtubule associated protein 1A/1B-light chain 3 (LC3) I to II], signalling cascade [phosphorylated (p) 5' adenosine monophosphate-activated protein kinase (p-AMPK), sirtuin 1 (Sirt 1), phosphorylated-mammalian target of rapamycin (p-mTOR), tuberous sclerosis complex 2 (TSC 2), p317Ulk 1 and p757Ulk 1 levels] and lysosome morphology were assessed in control and cypermethrin-treated rat model of PD. Autophagy markers were also measured in cypermethrin-treated neuroblastoma cells in the presence of 3-methyl adenine, a phosphatidylinositol-4,5 bisphosphate 3-kinase (PI3K) class III inhibitor; vinblastine, an autophagosome elongation inhibitor; bafilomycin A1, an autophagolysosome and lysosome fusion/abnormal acidification inhibitor or torin 1, a mechanistic target of rapamycin inhibitor. Cypermethrin reduced LAMP 2 and increased p-AMPK and Sirt 1 without causing any change in other signalling proteins. 3-Methyl adenine did not change LC3 conversion; vinblastine and bafilomycin A1 decreased LAMP 2 expression in controls. While cypermethrin increased LC3 conversion in the presence of 3 methyl adenine, LAMP 2 reduction was more pronounced in vinblastine and bafilomycin A1-treated cells. Torin 1 normalized the expression of LAMP 2 without any change in other autophagy markers. Results demonstrate that albeit cypermethrin activates autophagosome formation, it reduces LAMP 2 expression and lysosome quality leading to autophagy inhibition. PMID- 28840511 TI - Nanoparticle-encapsulated emodin decreases diabetic neuropathic pain probably via a mechanism involving P2X3 receptor in the dorsal root ganglia. AB - Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). More than 90% of all cases of DM belong to type 2 diabetes mellitus (T2DM). Emodin is the main active component of Radix et rhizoma rhei and has anti-bacterial, anti-viral, anti-ulcerogenic, anti-inflammatory, and anti cancer effects. Nanoparticle encapsulation of drugs is beneficial for drug targeting and bioavailability as well as for lowering drug toxicity side effects. The aim of this study was to investigate the effects of nanoparticle-encapsulated emodin (nano emodin) on diabetic neuropathic pain (DNP) mediated by the Purin 2X3 (P2X3) receptor in the dorsal root ganglia (DRG). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values in T2DM rats were lower than those of control rats. MWT and TWL in T2DM rats treated with nano emodin were higher compared with those in T2DM rats. Expression levels of P2X3 protein and messenger RNA (mRNA) in the DRG of T2DM rats were higher than those of controls, while levels in T2DM rats treated with nano emodin were significantly lower than those of the T2DM rats. Phosphorylation and activation of ERK1/2 in the T2DM DRG were decreased by nano emodin treatment. Nano emodin significantly inhibited currents activated by the P2X3 agonist alpha,beta-meATP in HEK293 cells transfected with the P2X3 receptor. Therefore, nano emodin treatment may relieve DNP by decreasing excitatory transmission mediated by the DRG P2X3 receptor in T2DM rats. PMID- 28840512 TI - Sub-micromolar concentrations of retinoic acid induce morphological and functional neuronal phenotypes in SK-N-SH neuroblastoma cells. AB - Neuroblastoma cells are neural crest derivatives that can differentiate into neuron-like cells in response to exogenous agents, and are known to be particularly sensitive to retinoic acid. The spectrum of neuroblastoma responses, ranging from proliferation, migration, differentiation, or apoptosis, is difficult to predict due to the heterogeneity of these tumors and to the broad effective range of retinoic acid. Our study focused on the effects of nanomolar concentrations of retinoic acid on neuroblastoma differentiation in two cell lines cells: SK-N-SH (HTB-11) and IMR-32. Each cell line was treated with retinoic acid from 1 to 100 nM for up to 6 d. Morphological changes were quantified; immunocytochemistry was used to observe changes in neuronal protein expression and localization, while live-cell calcium imaging utilizing pharmacological agents was conducted to identify neuron-like activity. Retinoic acid-treated HTB-11 but not IMR-32 cells developed specific neuronal phenotypes: acquisition of long neurite-like processes, expression of neurofilament-200, increased responsiveness to acetylcholine, and decreased responsiveness to nicotine and epinephrine. In addition, nanomolar levels of retinoic acid elicited increased nuclear trafficking of the CRABP2, which is traditionally associated with gene expression of cellular pathways related to neuronal differentiation. Collectively, these results show that nanomolar concentrations of retinoic acid are capable of inducing both structural and functional neuron-like features in HTB-11 cells using CRABP2, suggesting differentiation in neuroblastoma cells into neuronal phenotypes. These have important implications for both chemotherapeutic design and for the use of neuroblastomas as in vitro models for neuron differentiation. PMID- 28840513 TI - Fertility Sparing Strategies in Patients Affected by Placental Site Trophoblastic Tumor. AB - OPINION STATEMENT: Placental site trophoblastic tumor (PSTT) is the least common and the most ambiguous gestational trophoblastic tumor. Presentation of PSTT may occur in the course of gestation or from 1 week to 14 years after a normal or an abnormal pregnancy (mole, ectopic pregnancy, abortion). The indicators of aggressive behavior for this tumor are not well established. Due to the rarity of this disease that usually affects women of childbearing potential, we aimed to review the current literature, to identify risk factors and the best conservative therapeutic choices among the cases described. We performed a systematic literature search of articles in English language, published from 1996 to 2017 and indexed in PubMed and Scopus. Based on selective inclusion/exclusion criteria, we considered eight papers eligible for the review. Five were case reports and three were retrospective studies. We extracted and organized data into three different categories depending on the main treatment used. A total of 12 cases were treated with laparotomy; in 5 cases, the treatment was not curative. Therefore, a total abdominal hysterectomy was needed. Five cases were treated successfully with a minimally invasive approach, 2 with uterine evacuation, 2 with hysteroscopic resection, and 1 with a combined hysteroscopic/laparoscopic resection. Only 1 case treated with exclusive chemotherapy proved curative for the patient. Preservation of fertility in PSTT patients of childbearing age should be considered and as showed by the abovementioned studies, is a possible and safe therapeutic choice. Laparotomy for local uterine resection with the modified Strassman approach could be offered in patients at clinical stage 1 that are very motivated to retain fertility, extensively informing the patient of the risks and benefits related to this choice. PMID- 28840514 TI - Galphaq/p63RhoGEF interaction in RhoA/Rho kinase signaling: investigation in Gitelman's syndrome and implications with hypertension. AB - PURPOSE: Gitelman's syndrome (GS) presents normo-hypotension and absence of cardiovascular-renal remodeling despite high angiotensin II (Ang II), activation of renin-angiotensin-aldosterone system and is a human model of endogenous antagonism of Ang II signaling, opposite to hypertension. GS's clinical presentation leads to questions regarding what features might be responsible. One area of investigation involves Ang II signaling. In hypertensive patients, RhoA/Rho kinase (RhoA/ROCK) pathway activation by Ang II is involved in hypertension development/maintenance and induction of long-term consequences (cardiovascular-renal remodeling), while GS has reduced p63RhoGEF gene and protein levels and ROCK activity. Ang II signaling is mediated by Galphaq, which interacts with p63RhoGEF via the alpha6-alphaN linker connecting p63RhoGEF's DH and PH domains acting as a conformational switch to activate RhoA/ROCK signaling. METHODS: We have investigated in GS patients, the presence of mutations in either p63RhoGEF's alpha6-alphaN linker domain and in Galphaq's Ala253, Trp263, and Tyr356 residues, crucial for p63RhoGEF-Galphaq interplay. RESULTS: No mutations have been found in specific aminoacids of p63RhoGEF alpha6-alphaN linker and Galphaq, key for p63RhoGEF/Galphaq interplay. CONCLUSIONS: Gitelman's syndrome normo/hypotension and lack of cardiovascular-renal remodeling are not due to mutations of p63RhoGEF alpha6-alphaN linker and Galphaq interactions. This opens the way for investigations on different coding and no-coding regions (p63RhoGEF and Galphaq promoters) and on altered transcriptional/post-transcriptional regulation. Clarification of how these biochemical/molecular mechanisms work/interact would provide insights into mechanisms involved in the GS's Ang II signaling fine tuning, in human physiology/pathophysiology in general and could also identify significant targets for intervention in the treatments of hypertension. PMID- 28840515 TI - High-Sensitivity Cardiac Troponin for the Diagnosis of Patients with Acute Coronary Syndromes. AB - PURPOSE OF REVIEW: High-sensitivity cardiac troponin (hscTn) assays are replacing the older-generation assays used to detect myocardial injury because they have improved analytical sensitivity and lead to a more rapid diagnosis of acute myocardial infarction (AMI) and enhanced risk stratification in patients with non ST elevation acute coronary syndromes (NSTE-ACS). This review focuses on advantages and difficulties of using hscTn as diagnostic and prognostic tools in acute coronary syndromes (ACS). RECENT FINDINGS: The newer assays have a lower specificity for AMI as compared to conventional assays, potentially leading to an increased number of unwarranted hospitalizations and amplified cost unless how to use these assays appropriately is appreciated. Several approaches can increase the specificity of the high sensitivity assays. This review will present the current literature data regarding the use of hscTn assays and will focus on modalities used to increase the specificity, as well as the advantages and pitfalls of using the high sensitivity approach in clinical practice. PMID- 28840516 TI - Deleterious Effects of VEGFR2 and RET Inhibition in a Preclinical Model of Parkinson's Disease. AB - Neurotrophic factors (NTFs) are a promising therapeutic option for Parkinson's disease (PD). They exert their function through tyrosine kinase receptors. Our goal was to assess the effects of administering a selective tyrosine kinase inhibitor (vandetanib) that blocks VEGFR2 and RET receptors in a preclinical model of PD. Rats underwent intrastriatal injections of 6-hydroxydopamine (6 OHDA). Two weeks later, the rats received 30 mg/kg vandetanib or saline orally. The effects were assessed using the rotational behavioral test, tyrosine hydroxylase (TH) immunohistochemistry, and western blot. In 6-OHDA-lesioned rats, motor symptoms were almost undetectable, but morphological and biochemical changes were significant. Vandetanib treatment, combined with the presence of 6 OHDA lesions, significantly increased behavioral impairment and morphological and biochemical changes. Therefore, after vandetanib treatment, the TH-immunopositive striatal volume, the percentage of TH+ neurons, and the extent of the axodendritic network in the substantia nigra decreased. Glial fibrillary acidic protein-positivity significantly decreased in the striatum and substantia nigra in the vandetanib-treated group. In addition, p-Akt and p-ERK 1/2 levels were significantly lower and caspase-3 expression significantly increased after vandetanib administration. In conclusion, we demonstrate for the first time the deleterious effect of a tyrosine kinase inhibitor on the dopaminergic system, supporting the beneficial and synergistic effect of NTFs reported in previous papers. PMID- 28840517 TI - Ultimate and proximate explanations of strong reciprocity. AB - Strong reciprocity (SR) has recently been subject to heated debate. In this debate, the "West camp" (West et al. in Evol Hum Behav 32(4):231-262, 2011), which is critical of the case for SR, and the "Laland camp" (Laland et al. in Science, 334(6062):1512-1516, 2011, Biol Philos 28(5):719-745, 2013), which is sympathetic to the case of SR, seem to take diametrically opposed positions. The West camp criticizes advocates of SR for conflating proximate and ultimate causation. SR is said to be a proximate mechanism that is put forward by its advocates as an ultimate explanation of human cooperation. The West camp thus accuses advocates of SR for not heeding Mayr's original distinction between ultimate and proximate causation. The Laland camp praises advocates of SR for revising Mayr's distinction. Advocates of SR are said to replace Mayr's uni directional view on the relation between ultimate and proximate causes by the bi directional one of reciprocal causation. The paper argues that both the West camp and the Laland camp misrepresent what advocates of SR are up to. The West camp is right that SR is a proximate cause of human cooperation. But rather than putting forward SR as an ultimate explanation, as the West camp argues, advocates of SR believe that SR itself is in need of ultimate explanation. Advocates of SR tend to take gene-culture co-evolutionary theory as the correct meta-theoretical framework for advancing ultimate explanations of SR. Appearances notwithstanding, gene-culture coevolutionary theory does not imply Laland et al.'s notion of reciprocal causation. "Reciprocal causation" suggests that proximate and ultimate causes interact simultaneously, while advocates of SR assume that they interact sequentially. I end by arguing that the best way to understand the debate is by disambiguating Mayr's ultimate-proximate distinction. I propose to reserve "ultimate" and "proximate" for different sorts of explanations, and to use other terms for distinguishing different kinds of causes and different parts of the total causal chain producing behavior. PMID- 28840518 TI - Does Acculturative Stress Influence Immigrant Sexual HIV Risk and HIV Testing Behavior? Evidence from a Survey of Male Mexican Migrants. AB - OBJECTIVE: Migration is a structural factor that increases HIV vulnerability. Acculturative stress represents a possible mechanism through which migration may negatively impact HIV risk. This study investigated socio-ecological factors associated with acculturative stress levels and examined the association between acculturative stress and HIV-related behavior among Mexican im/migrants. METHODOLOGY: We used data from a probability survey of Mexican im/migrants (N = 1383) conducted in Tijuana, Mexico, in 2009-2010. The sample included migrants returning to Mexico via deportation or voluntarily after a recent stay in the USA. Linear regression models were estimated to identify individual, migration, and contextual factors independently associated with overall acculturative stress levels. Logistic regression models were used to test for associations between acculturative stress, sexual HIV risk, and HIV testing history behavior. RESULTS: We found that levels of acculturative stress were significantly and independently related to socio-economic markers, acculturation level, legal residence status, and sexual minority status. The analyses also showed that acculturative stress was positively related to sexual HIV risk behavior and negatively related to recent HIV testing. CONCLUSIONS: The results underscore that both individual and environmental factors contribute to levels of acculturative stress among Mexican im/migrants. In turn, acculturative stress may exacerbate sexual HIV risk and impede testing among this im/migrant population. Targeted interventions to prevent and decrease acculturative stress represent a potential strategy to reduce sexual HIV risk behavior and promote HIV testing among this vulnerable population of im/migrants in the USA. PMID- 28840519 TI - Neighborhood Disadvantage is Associated with High Cytomegalovirus Seroprevalence in Pregnancy. AB - BACKGROUND: Cytomegalovirus (CMV) is the most common infectious cause of fetal malformations and childhood hearing loss. CMV is more common among socially disadvantaged groups, and geographically clusters in poor communities. The Area Deprivation Index (ADI) is a neighborhood-level index derived from census data that reflects material disadvantage. METHODS: We performed a geospatial analysis to determine if ADI predicts the local odds of CMV seropositivity. We analyzed a dataset of 3527 women who had been tested for CMV antibodies during pregnancy. We used generalized additive models to analyze the spatial distribution of CMV seropositivity. Adjusted models included individual-level age and race and neighborhood-level ADI. RESULTS: Our dataset included 1955 CMV seropositive women, 1549 who were seronegative, and 23 with recent CMV infection based on low avidity CMV antibodies. High ADI percentiles, representing greater neighborhood poverty, were significantly associated with the nonwhite race (48 vs. 22, p < 0.001) and CMV seropositivity (39 vs. 28, p < 0.001). Our unadjusted spatial models identified clustering of high CMV odds in poor, urban neighborhoods and clustering of low CMV odds in more affluent suburbs (local odds ratio 0.41 to 1.90). Adjustment for both individual race and neighborhood ADI largely eliminated this spatial variability. ADI remained a significant predictor of local CMV seroprevalence even after adjusting for individual race. CONCLUSIONS: Neighborhood-level poverty as measured by the ADI is a race-independent predictor of local CMV seroprevalence among pregnant women. PMID- 28840521 TI - Utility of Serum Inflammatory Markers for Predicting Microvascular Invasion and Survival for Patients with Hepatocellular Carcinoma. AB - BACKGROUND: Preoperative serum inflammatory markers have been correlated with outcome after resection of hepatocellular carcinoma (HCC), but studies have had conflicting results. This study aimed to evaluate the association of six inflammatory markers with recurrence-free survival (RFS), overall survival (OS), and microvascular invasion (MVI), a well-known prognostic factor. METHODS: This study investigated 370 patients who underwent resection of HCC from 1992 to 2016, retrospectively evaluating their inflammatory indices and individual components including their neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), aspartate aminotransferase-to-platelet ratio index (APRI), and aspartate aminotransferase-to-neutrophil ratio index (ANRI). Uni- and multivariate analyses were performed to evaluate these markers for RFS, OS, and MVI. RESULTS: The median RFS was 23 months, and the median OS was 60 months. Factors independently associated with worse RFS were higher PLR and alpha-fetoprotein level, male gender, and the presence of MVI as well as multiple nodules. Factors independently associated with worse OS were higher PLR and international normalized ratio, male gender, older age, presence of MVI and multiple nodules, larger tumor, presence of cirrhosis, and absence of steatosis. The study identified MVI in 47% of the patients. Lower level of albumin, higher level of alpha-fetoprotein, and larger tumor on preoperative imaging were independently associated with MVI. CONCLUSIONS: This largest Western series to evaluate the utility of preoperative inflammatory markers in patients with HCC found that only PLR was associated with RFS and OS and that albumin was associated with MVI. PMID- 28840520 TI - Five mechanisms of sound symbolic association. AB - Sound symbolism refers to an association between phonemes and stimuli containing particular perceptual and/or semantic elements (e.g., objects of a certain size or shape). Some of the best-known examples include the mil/mal effect (Sapir, Journal of Experimental Psychology, 12, 225-239, 1929) and the maluma/takete effect (Kohler, 1929). Interest in this topic has been on the rise within psychology, and studies have demonstrated that sound symbolic effects are relevant for many facets of cognition, including language, action, memory, and categorization. Sound symbolism also provides a mechanism by which words' forms can have nonarbitrary, iconic relationships with their meanings. Although various proposals have been put forth for how phonetic features (both acoustic and articulatory) come to be associated with stimuli, there is as yet no generally agreed-upon explanation. We review five proposals: statistical co-occurrence between phonetic features and associated stimuli in the environment, a shared property among phonetic features and stimuli; neural factors; species-general, evolved associations; and patterns extracted from language. We identify a number of outstanding questions that need to be addressed on this topic and suggest next steps for the field. PMID- 28840522 TI - Endoscopic Evaluation of Post-Fundoplication Anatomy. AB - PURPOSE OF REVIEW: We aim to review the endoscopic evaluation of post fundoplication anatomy and its role in assessment of fundoplication outcomes and in pre-operative planning for reoperation in failed procedures. RECENT FINDINGS: There is no universally accepted system for evaluating post-fundoplication anatomy endoscopically. However, multiple reports described the usefulness of post-operative endoscopy as a quality control measure and in the evaluation of complex cases such as repeat procedures and paraesophageal hernias (PEH). Endoscopic evaluation of post-fundoplication anatomy has an important role in assessing the outcomes of operative repair and pre-operative planning for failed fundoplications. Attempts have been made to characterize the appearance of the newly formed gastroesophageal valve after successful repairs and to standardize endoscopic reporting and classification of anatomic descriptions of failed fundoplications. However, there is no consensus. More studies are needed to evaluate the applicability and reproducibility of proposed endoscopic evaluation systems in order for such tools to become widely accepted. PMID- 28840523 TI - A Case Report of Solitary Sclerosis: This is Really Multiple Sclerosis. AB - Progressive solitary sclerosis is characterized by an isolated central nervous system demyelinating lesion arising in the spinal cord and brainstem, responsible for progressive motor impairment. We describe the case of a 40-year-old patient treated for more than 2 years with high doses of biotin (CERENDAY(r)) for progressive symptoms of solitary sclerosis, who presented asymptomatic new T2 white matter lesions on brain magnetic resonance imaging (MRI). As there is no treatment option for solitary sclerosis, high doses of biotin were proposed, but had no impact on the progression of motor deficit. As the brain MRI showed no evidence of T2 lesions during the 10 years before the introduction of biotin, the demonstration of dissemination over time with this treatment raises questions. High doses of biotin have shown efficacy in some patients with spinal progressive MS, but could reveal a latent inflammatory condition. PMID- 28840524 TI - Prevalence of Anal Human Papillomavirus Infection in Hungarian Men Who Have Sex with Men. AB - Anal cancer is one of the leading causes of death in non-AIDS defining cancers. Most of these cancers are associated with high risk HPV infection. So far, the prevalence and the significance of anal HPV infection have not been studied in the Hungarian MSM population. The main objective of our study was to determine the prevalence and associated risk factors of HPV-infection in the Hungarian MSM community, particularly in HIV-infected MSM. Out of 109 examinations 92 samples (80 HIV-infected and 12 HIV-negative MSM) were evaluated for both cytological abnormalities and HPV genotyping PCR. Using a questionnaire all enrolled individuals were interviewed about their sexual behavior, socioeconomic factors, drug use and other known or suspected risk factors. In the HIV-infected cohort 97.5% of the examined individuals were positive for any HPV type. In this group we detected high risk (HR) HPV in 88.8%, low risk (LR) HPV in 75.0% and probably high risk (PHR) HPV in 47.5% and multiple HPV infection was absolutely common (82.5%). In the HIV-negative MSM group the incidence of HPV-infection was 58.3%. The respective rate of HR-HPV, LR-HPV and PHR-HPV genotypes were 33.3%, 58.4%, and 16.7%. In the HIV-negative group both HPV infection frequency and the prevalence of the pertinent genotypes were much lower. The Hungarian MSM population is severely infected with HPV and HR-HPV. High-risk sexual behaviors are strong predictors for acquiring HR-HPV co-infections. Our results underline the necessity of anal cancer screening and the introduction of the vaccination program in the high-risk population. PMID- 28840525 TI - Laparoscopic Sleeve Gastrectomy Versus Banded Roux-en-Y Gastric Bypass for Diabetes and Obesity: a Prospective Randomised Double-Blind Trial. AB - BACKGROUND: There are very few randomised, blinded trials comparing laparoscopic sleeve gastrectomy (LSG) versus laparoscopic Roux-en-Y gastric bypass (LRYGB) in achieving remission of type 2 diabetes (T2D), particularly silastic ring (SR) LRYGB. We compared the effectiveness of (LSG) versus SR-LRYGB among patients with T2D and morbid obesity. METHODS: Prospective, randomised, parallel, 2-arm, blinded clinical trial conducted in a single Auckland (New Zealand) centre. Eligible patients aged 20-55 years, T2D of at least 6 months duration and BMI 35 65 kg/m2 were randomised 1:1 to LSG (n = 58) or SR-LRYGB (n = 56) using random number codes disclosed after anaesthesia induction. Primary outcome was T2D remission defined by different HbA1c thresholds at 1 year. Secondary outcomes included weight loss, quality of life, anxiety and depressive symptoms, post operative complications and mortality. RESULTS: Mean +/- standard deviation (SD) pre-operative BMI was 42.5 +/- 6.2 kg/m2, HbA1c 63 +/- 16 mmol/mol (30% insulin treated, 28% had diabetes duration over 10 years). Proportions achieving HbA1c <= 38 mmol/mol, < 42 mmol/mol, < 48 mmol/mol and < 53 mmol/mol without diabetes medication at 1 year in SR-LRYGB vs LSG were 38 vs 43% (p = 0.56), 52 vs 49% (p = 0.85), 75 vs 72% (p = 0.83) and 80 vs 77% (p = 0.82), respectively. Mean +/- SD % total weight loss at 1 year was greater after SR-LRYGB than LSG: 32.2 +/- 7.7 vs 27.1 +/- 7.5%, respectively (p < 0.001). Gastrointestinal complications were more frequent after SR-LRYGB (including 3 ulcers, 1 anastomotic leak, 1 abdominal bleeding). Quality of life and depression symptoms improved significantly in both groups. CONCLUSION: Despite significantly greater weight loss after SR-LRYGB, there was similar T2D remission and psychosocial improvement after LSG and SR LRYGB at 1 year. TRIAL REGISTRATION: Prospectively registered at Australia and New Zealand Clinical Trials Register (ACTRN 12611000751976) and retrospectively registered at Clinical Trials (NCT1486680). PMID- 28840526 TI - Impact of stimulus format and reward value on quantity discrimination in capuchin and squirrel monkeys. AB - Quantity discrimination abilities are seen in a diverse range of species with similarities in performance patterns, suggesting common underlying cognitive mechanisms. However, methodological factors that impact performance make it difficult to draw broad phylogenetic comparisons of numerical cognition across studies. For example, some Old World monkeys selected a higher quantity stimulus more frequently when choosing between inedible (pebbles) than edible (food) stimuli. In Experiment 1 we presented brown capuchin (Cebus [Sapajus] paella) and squirrel monkeys (Saimiri sciureus) with the same two-choice quantity discrimination task in three different stimulus conditions: edible, inedible, and edible replaced (in which choice stimuli were food items that stood in for the same quantity of food items that were given as a reward). Unlike Old World monkeys, capuchins selected the higher quantity stimulus more in the edible condition and squirrel monkeys showed generally poor performance across all stimulus types. Performance patterns suggested that differences in subjective reward value might motivate differences in choice behavior between and within species. In Experiment 2 we manipulated the subjective reinforcement value of the reward by varying reward type and delay to reinforcement and found that delay to reinforcement had no impact on choice behavior, while increasing the value of the reward significantly improved performance by both species. The results of this study indicate that species presented with identical tasks may respond differently to methodological factors such as stimulus and reward types, resulting in significant differences in choice behavior that may lead to spurious suggestions of species differences in cognitive abilities. PMID- 28840527 TI - Erratum to: Establishment of immortalized murine mesothelial cells and a novel mesothelioma cell line. PMID- 28840528 TI - Erratum to: Abstract P-1003--An Approach Towards Generating Selectable Marker Free, Transgenic, Insecticidal Chickpea by Means of Plumular Meristem Transformation. PMID- 28840529 TI - Co-Spray Dried Mannitol/Poly(amidoamine)-Doxorubicin Dry-Powder Inhaler Formulations for Lung Adenocarcinoma: Morphology, In Vitro Evaluation, and Aerodynamic Performance. AB - nhaled chemotherapeutics have emerged as a promising regimen to combat lung cancer as they maximize local drug concentration while significantly reduce systemic exposure. However, the poor lung/systemic safety profiles and lack of clinically efficient formulations restrict the applicability of inhaled chemotherapeutics. This work developed a dry-powder inhaler (DPI) formulation that dispersed a pH-responsive poly(amidoamine) dendrimer-doxorubicin conjugate (G4-12DOX) into mannitol microparticles. The dendrimer conjugate only releases cytotoxic agents in response to intracellular pH drop, leading to reduced systemic and local toxicity. This work investigated the effect of G4-12DOX content on the microparticle size and morphology, redispersibility, in vitro cytotoxicity, and aerosol properties of the formulations. The spray-dried G4 12DOX/mannitol microparticles showed smooth and spherical morphology with 1-4 MUm in diameter. As the content of the G4-12DOX conjugate in the microparticles increased, the size, and degree of aggregation of microparticles increased dramatically. The G4-12DOX/mannitol microparticles were readily redispersed in the aqueous environment, reverting to nanoscale dendrimer conjugates to escape alveolar phagocytosis. All DPI formulations demonstrated the similar cytotoxicity as the original conjugate against a lung adenocarcinoma cell line. The emitted dose (ED) and fine particle fraction (FPF) of the DPI formulations decreased as the content of G4-12DOX increased, but EDs and FPFs of all formulations fell within the range of 85-60% and 60-40%, which were higher than those of commercial products (EDs = 40-60%; FPFs = 12-40%). Therefore, the spray-dried dendrimer/mannitol microparticle is an efficient and practical DPI formulation for direct delivery of large dose of chemotherapeutics to lung tumors. PMID- 28840530 TI - Erratum to: Omeprazole Absorption and Fasting Gastrinemia After Roux-en-Y Gastric Bypass. PMID- 28840531 TI - Long-Term Effectiveness of Adalimumab in Patients with Rheumatoid Arthritis: An Observational Analysis from the Corrona Rheumatoid Arthritis Registry. AB - INTRODUCTION: Current recommendations for the management of rheumatoid arthritis (RA) focus on a treat-to-target approach with the objective of maximizing long term health-related quality-of-life in patients with RA. Published studies from randomized clinical trials have reported limited data regarding the long-term efficacy and safety of adalimumab in patients with RA. This study aims to evaluate the long-term (10+ years) persistency and effectiveness of adalimumab in patients with RA in a real-world setting. METHODS: Included in this study were biologic-naive adults with RA initiating adalimumab during follow-up enrolled in the Corrona RA registry. More than 10 years of data on persistency of adalimumab and rheumatologist-supplied reasons for discontinuation were examined. Among patients who persisted on adalimumab over the years, clinical [e.g., clinical disease activity index scores (CDAI), physician global assessment, tender joint count, and swollen joint count] and patient-reported outcomes (PRO), such as physical function, pain, fatigue, and morning stiffness, were examined. RESULTS: Of 1791 biologic-naive patients treated with adalimumab who had >=1 follow-up registry visit, 64.1% were still on therapy at 1 year and 10.2% were still on therapy by the end of year 12. Among patients who persisted on adalimumab for at least 1 year (77.1% female, mean age 53.9 years), 67.0% were in low disease activity (LDA)/remission (CDAI <=10) and had clinically meaningful improvements from baseline in all clinical assessments and PROs. Initial improvements in LDA/remission and in clinical and PRO assessments observed at year 1 were sustained in those patients who remained on adalimumab over 10 years of follow up. Among patients who discontinued adalimumab, 61.6% were not in LDA/remission and 41.9% switched to another biologic within 12 months after discontinuing adalimumab. CONCLUSIONS: Real-world data demonstrate a sustained effectiveness of adalimumab in the treatment of RA for patients who remained on therapy for 10 years. FUNDING: Corrona, LLC and AbbVie. PMID- 28840532 TI - Reconstruction of a hybrid nucleoside antibiotic gene cluster based on scarless modification of large DNA fragments. AB - Genetic modification of large DNA fragments (gene clusters) is of great importance in synthetic biology and combinatorial biosynthesis as it facilitates rational design and modification of natural products to increase their value and productivity. In this study, we developed a method for scarless and precise modification of large gene clusters by using RecET/RED-mediated polymerase chain reaction (PCR) targeting combined with Gibson assembly. In this strategy, the biosynthetic genes for peptidyl moieties (HPHT) in the nikkomycin biosynthetic gene cluster were replaced with those for carbamoylpolyoxamic acid (CPOAA) from the polyoxin biosynthetic gene cluster to generate a ~40 kb hybrid gene cluster in Escherichia coli with a reusable targeting cassette. The reconstructed cluster was introduced into Streptomyces lividans TK23 for heterologous expression and the expected hybrid antibiotic, polynik A, was obtained and verified. This study provides an efficient strategy for gene cluster reconstruction and modification that could be applied in synthetic biology and combinatory biosynthesis to synthesize novel bioactive metabolites or to improve antibiotic production. PMID- 28840533 TI - Statistical characteristics of forest litterfall in China. PMID- 28840534 TI - Gut-liver axis: gut microbiota in shaping hepatic innate immunity. AB - Gut microbiota play an essential role in shaping immune cell responses. The liver was continuously exposed to metabolic products of intestinal commensal bacterial through portal vein and alteration of gut commensal bateria was always associated with increased risk of liver inflammation and autoimmune disease. Considered as a unique immunological organ, the liver is enriched with a large number of innate immune cells. Herein, we summarize the available literature of gut microbiota in shaping the response of hepatic innate immune cells including NKT cells, NK cells, gammadelta T cells and Kupffer cells during health and disease. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of innate immune cell-related liver disease. PMID- 28840535 TI - Chronic Exposure to beta-Alanine Generates Oxidative Stress and Alters Energy Metabolism in Cerebral Cortex and Cerebellum of Wistar Rats. AB - beta-Alanine occurs naturally in the human central nervous system and performs different functions. It can act as either a neurotransmitter or a neuromodulator, depletion of taurine levels and competitive antagonist of gamma-aminobutyric acid (GABA). The beta-amino acid accumulation exerts an important biological function as delay in brain development, oxidative stress and disturbances in energy metabolism, characterized as an inborn error of metabolism classified as beta alaninemia. We evaluated the effects of the chronic administration of beta alanine on some parameters of oxidative stress and enzymes of energy metabolism in cerebral cortex and cerebellum of 21-day-old Wistar rats. The animals received peritoneal injections of beta-alanine (300 mg/kg of body weight), and the controls received the same volume (10 MUl/g of body weight) of saline solution (NaCl 0.9%), twice a day at 12-h interval, from the 7th to the 21st postpartum day. We observed that beta-amino acid was able to increase the levels of reactive oxygen species (ROS) in the two tissues; however, only in cerebral cortex total content of sulfhydryl was increased. ROS are possibly acting on antioxidant enzymes glutathione peroxidase (GPx) (cerebral cortex and cerebellum) and superoxide dismutase (SOD) (cerebellum) inhibiting their activities. We also evaluated the activities of enzymes of the phosphoryl transfer network, where we observed an increase in hexokinase and cytosolic creatine kinase (Cy-CK) activities; however, it decreased glyceraldehyde 3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK) and lactate dehydrogenase (LDH) activities, in both tissues. Besides, the beta-alanine administration increased the activities of complex II, complex IV and succinate dehydrogenase (SDH). Those results suggest that the chronic administration of beta-alanine causes cellular oxidative damage, significantly changing the energy metabolism. PMID- 28840536 TI - Astilbin alleviates sepsis-induced acute lung injury by inhibiting the expression of macrophage inhibitory factor in rats. AB - Sepsis is a systemic inflammatory response syndrome caused by severe infections. Astilbin is a dihydroflavonol derivative found in many medicinal and food plants with multiple pharmacological functions. To investigate the effects of astilbin on sepsis-induced acute lung injury (ALI), cecal ligation and puncture was performed on rats to establish a sepsis-induced ALI model; these rats were then treated with astilbin at different concentrations. Lung injury scores, including lung wet/dry ratio, protein leakage, myeloperoxidase activity, and inflammatory cell infiltration were determined to evaluate the effects of astilbin on sepsis induced ALI. We found that astilbin treatment significantly attenuates sepsis induced lung injury and improves survival rate, lung injury scores, lung wet/dry ratio, protein leakage, myeloperoxidase activity, and inflammatory cell infiltration. Astilbin treatment also dramatically decreased the production of inflammatory cytokines and chemokines in bronchoalveolar lavage fluid. Further, astilbin treatment inhibited the expression and production of macrophage inhibitory factor (MIF), which inhibits the inflammatory response. Collectively, these data suggest that astilbin has a protective effect against sepsis-induced ALI by inhibiting MIF-mediated inflammatory responses. This study provides a molecular basis for astilbin as a new medical treatment for sepsis-induced ALI. PMID- 28840537 TI - Environmental Surveillance of Enteroviruses in Central Argentina: First Detection and Evolutionary Analyses of E14. AB - Environmental surveillance is an effective approach to investigate the circulation of human enteroviruses in the population. Enteroviruses E14, CVA9, E 6, E16, E20, E25, E13, and CVA24 were detected in sewage and a watercourse in central Argentina. E14 was the most frequent serotype and was found for the first time in environmental samples in our region. Phylogenetic and coalescence analyses showed at least two recent introduction events. PMID- 28840538 TI - Erratum to: Provider and Staff Perceptions and Experiences Implementing Behavioral Health Integration in Six Low-Income Health Care Organizations. PMID- 28840539 TI - Recent advances in pharmacological research on Ecklonia species: a review. AB - The genus Ecklonia (Lessoniaceae, Phaeophyceae), commonly called kelp (brown algae), is abundant on the coasts of Japan and Korea. During the past few decades, Ecklonia species have received tremendous attention for their wide range of therapeutic properties and multiple health benefits, such as great nutritional value and being rich in vitamins, minerals, dietary fiber, proteins, and polysaccharides. Several novel functional ingredients with diversified biological activities have been isolated and possess antimicrobial, antiviral, hepatoprotective, cardioprotective, anti-inflammatory, neuroprotective, anticarcinogenic, immunomodulatory, hypolipidemic, anti-diabetic, and antioxidant therapeutic properties. The present review discusses the phytochemical, pharmacological, therapeutic, nutritional, and health benefits of different species of genus Ecklonia, as well as their use in the prevention of disease and maintenance of good health. PMID- 28840540 TI - A more tubulocentric view of diabetic kidney disease. AB - Diabetic nephropathy (DN) is a common complication of Diabetes Mellitus (DM) Types 1 and 2, and prevention of end stage renal disease (ESRD) remains a major challenge. Despite its high prevalence, the pathogenesis of DN is still controversial. Initial glomerular disease manifested by hyperfiltration and loss of glomerular size and charge permselectivity may initiate a cascade of injuries, including tubulo-interstitial disease. Clinically, 'microalbuminuria' is still accepted as an early biomarker of glomerular damage, despite mounting evidence that its predictive value for DN is questionable, and findings that suggest the proximal tubule is an important link in the development of DN. The concept of 'diabetic tubulopathy' has emerged from recent studies, and its causative role in DN is supported by clinical and experimental evidence, as well as plausible pathogenetic mechanisms. This review explores the 'tubulocentric' view of DN. The recent finding that inhibition of proximal tubule (PT) glucose transport (via SGLT2) is nephro-protective in diabetic patients is discussed in relation to the tubule's potential role in DN. Studies with a tubulocentric view of DN have stimulated alternative clinical approaches to the early detection of diabetic kidney disease. There are tubular biomarkers considered as direct indicators of injury of the proximal tubule (PT), such as N-acetyl-beta-D-glucosaminidase, Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1, and other functional PT biomarkers, such as Urine free Retinol-Binding Protein 4 and Cystatin C, which reflect impaired reabsorption of filtered proteins. The clinical application of these measurements to diabetic patients will be reviewed in the context of the need for better biomarkers for early DN. PMID- 28840541 TI - Drugs in Clinical Development for Fungal Infections. AB - Despite increasing rates of invasive fungal infections being reported globally, only a single antifungal drug has been approved during the last decade. Resistance, toxicity, drug interactions and restricted routes of administration remain unresolved issues. This review focuses on new antifungal compounds which are currently in various clinical phases of development. We discuss two azoles with a tetrazole moiety that allows selective activity against the fungal CYP: VT 1161 for Candida infections and VT-1129 for cryptococcal meningoencephalitis. We also discuss two glucan synthesis inhibitors: CD101, an echinocandin with an increased half-life, and SCY-078 with oral bioavailability and increased activity against echinocandin-resistant isolates. Among the polyenes, we discuss MAT023, an encochleated amphotericin B formulation that allows oral administration. Two novel classes of antifungal drugs are also described: glycosylphosphatidylinositol inhibitors, and the leading drug APX001, which disrupt the integrity of the fungal wall; and the orotomides, inhibitors of pyrimidine synthesis with the leading drug F901318. Finally, a chitin synthesis inhibitor and progress on human monoclonal antifungal antibodies are discussed. PMID- 28840542 TI - Baseline motives for eating palatable food: racial differences and preliminary utility in predicting weight loss. AB - PURPOSE: Behavioral predictors of weight-loss program (WLP) outcomes are needed and important because they can be modified. Eating calorie-dense palatable foods (PFs) outside of hunger contributes to obesity. This study assessed if habitual motives to consume PFs could predict weight-loss outcomes. METHODS: N = 171 Black and N = 141 White adults in a reduced-calorie program completed the Palatable Eating Motives Scale (PEMS). Body weight and body mass index (BMI) lost after 3 and 6 months were analyzed controlling for initial BMI and demographics. Greater PEMS motive scores meant more frequent habitual intake of PFs for that motive. RESULTS: Whites vs. Blacks had higher scores on most of the PEMS motives: Social, Coping, and Reward Enhancement. In Whites at 3 months, greater Reward Enhancement scores and initial BMI predicted more BMI loss (p < 0.05). At 6 months, greater Reward Enhancement and lower Conformity scores predicted more weight (p < 0.05) and BMI loss (Conformity: p < 0.05; Reward Enhancement: p = 0.05). PEMS motives did not predict outcomes for Blacks. CONCLUSION: The results provide preliminary evidence for the PEMS to predict WLP outcomes. White patients who eat PFs primarily for their rewarding properties and less to conform should fare better in Lifestyle programs while group or family-based interventions may be more efficacious when conformity is the main motive. Lower motive scores among Blacks suggest that eating PFs outside of hunger may go unrecognized or underreported and warrants further investigation. The findings highlight the motive-based heterogeneity of obesity and how it may be used to predict outcomes and customize interventions to improve WLP outcomes. LEVEL OF EVIDENCE: Level IV, multiple time series. PMID- 28840543 TI - Memory accessibility shapes explanation: Testing key claims of the inherence heuristic account. AB - People understand the world by constructing explanations for what they observe. It is thus important to identify the cognitive processes underlying these judgments. According to a recent proposal, everyday explanations are often constructed heuristically: Because people need to generate explanations on a moment-by-moment basis, they cannot perform an exhaustive search through the space of possible reasons, but may instead use the information that is most easily accessible in memory (Cimpian & Salomon 2014a, b). In the present research, we tested two key claims of this proposal that have so far not been investigated. First, we tested whether-as previously hypothesized-the information about an entity that is most accessible in memory tends to consist of inherent or intrinsic facts about that entity, rather than extrinsic (contextual, historical, etc.) facts about it (Studies 1 and 2). Second, we tested the implications of this difference in the memory accessibility of inherent versus extrinsic facts for the process of generating explanations: Does the fact that inherent facts are more accessible than relevant extrinsic facts give rise to an inherence bias in the content of the explanations generated (Studies 3 and 4)? The findings supported the proposal that everyday explanations are generated in part via a heuristic process that relies on easily accessible-and often inherent-information from memory. PMID- 28840544 TI - Transferring an Analytical Technique from Ecology to the Sport Sciences. AB - BACKGROUND: Learning transfer is defined as an individual's capability to apply prior learnt perceptual, motor, or conceptual skills to a novel task or performance environment. In the sport sciences, learning transfers have been investigated from an athlete-specific perspective. However, sport scientists should also consider the benefits of cross-disciplinary learning to aid critical thinking and metacognitive skill gained through the interaction with similar quantitative scientific disciplines. OBJECTIVE: Using team sports performance analysis as an example, this study aimed to demonstrate the utility of a common analytical technique in ecology in the sports sciences, namely, nonmetric multidimensional scaling. METHODS: To achieve this aim, three novel research examples using this technique are presented, each of which enables the analysis and visualization of athlete (organism), team (aggregation of organisms), and competition (ecosystem) behaviors. RESULTS: The first example reveals the technical behaviors of Australian Football League Brownlow medalists from the 2001 to 2016 seasons. The second example delineates dissimilarity in higher and lower ranked National Rugby League teams within the 2016 season. Lastly, the third example shows the evolution of game play in the basketball tournaments between the 2004 and 2016 Olympic Games. CONCLUSIONS: In addition to the novel findings of each example, the collective results demonstrate that, by embracing cross-disciplinary learning and drawing upon an analytical technique common to ecology, novel solutions to pertinent research questions within sports performance analysis could be addressed in a practically meaningful way. Cross disciplinary learning may subsequently assist sport scientists in the analysis and visualization of multivariate datasets. PMID- 28840546 TI - Obstructive sleep apnea does not impair cardiorespiratory responses to progressive exercise performed until exhaustion in hypertensive elderly. AB - BACKGROUND: Elderly people have a high prevalence to systemic arterial hypertension (SAH) and obstructive sleep apnea (OSA). Both comorbidities are closely associated and inflict damage on cardiorespiratory capacity. METHODS: In order to assess cardiorespiratory responses to the cardiopulmonary exercise test (CPET) among hypertensive elderly with OSA, we enrolled 28 subjects into two different groups: without OSA (No-OSA: apnea/hypopnea index (AHI) < 5 events/h; n = 15) and with OSA (OSA: AHI >= 15 events/h; n = 13). All subjects underwent CPET and polysomnographic assessments. After normality and homogeneity evaluations, independent t test and Pearson's correlation were performed. The significance level employed was p <= 0.05. RESULTS: Hypertensive elderly with OSA presented lower heart rate recovery (HRR) in the second minute (HRR2) in relation to the No OSA group. A negative correlation between AHI and ventilation (VE) (r = -0.63, p = 0.02) was found in polysomnography and CPET data comparisons, and oxygen saturation (O2S) levels significantly correlated with VE/VCO2slope (r = 0.66, p = 0.01); in addition, OSA group presented a positive correlation between oxygen consumption and O2S (r = 0.60, p = 0.02), unlike the no-OSA group. CONCLUSIONS: OSA does not affect the CPET variables in hypertensive elderly, but it attenuates the HRR2. The association between O2S during sleep with ventilatory responses probably occurs due to the adaptations in the oxygen transport system unleashed via mechanical respiratory feedback; thus, it has been identified that OSA compromises the oxygen supply in hypertensive elderly. PMID- 28840545 TI - Depressive Symptoms During Adolescence Predict Adulthood Obesity Among Black Females. AB - AIM: This study aimed to investigate gender differences in the association between baseline depressive symptoms and subsequent changes in obesity in a sample of urban Black youth in the USA. METHODS: The current study followed 681 Black youth (335 male and 346 female) for up to 18 years from 1994 to 2012. All youth were selected from an economically disadvantaged urban area in MI, USA. The main independent variable was baseline depressive symptoms measured in 1994. The main outcome was change in body mass index (BMI) from 1999 to 2012, calculated based on self-reported height and weight. Scio-demographics (age, number of parents in the household, and parental employment) were covariates. Gender was the focal moderator. We used linear regressions to test the predictive role of baseline depressive symptoms on change in BMI (from 1999 to 2012) in the pooled sample, and also based on gender. RESULTS: Among Black females, but not Black males, baseline depressive symptoms predicted the BMI change from 1999 to 2012. The association remained significant for Black females after controlling for covariates. CONCLUSION: High depressive symptoms at baseline better predict BMI change over the next decade for female than male Black youth. As a result, detection and reduction of depressive symptoms may be a vital element of obesity prevention programs for Black females. Policies and programs that address determinants of psychological distress as a strategy to prevent obesity among female Black youth in disadvantaged neighborhoods may be especially useful. PMID- 28840547 TI - Cognitive control in media multitaskers: Two replication studies and a meta Analysis. AB - Ophir, Nass, and Wagner (2009, Proceedings of the National Academy of Sciences of the United States of America, 106(37), 15583-15587) found that people with high scores on the media-use questionnaire-a questionnaire that measures the proportion of media-usage time during which one uses more than one medium at the same time-show impaired performance on various tests of distractor filtering. Subsequent studies, however, did not all show this association between media multitasking and distractibility, thus casting doubt on the reliability of the initial findings. Here, we report the results of two replication studies and a meta-analysis that included the results from all published studies into the relationship between distractor filtering and media multitasking. Our replication studies included a total of 14 tests that had an average replication power of 0.81. Of these 14 tests, only five yielded a statistically significant effect in the direction of increased distractibility for people with higher scores on the media-use questionnaire, and only two of these effects held in a more conservative Bayesian analysis. Supplementing these outcomes, our meta-analysis on a total of 39 effect sizes yielded a weak but significant association between media multitasking and distractibility that turned nonsignificant after correction for small-study effects. Taken together, these findings lead us to question the existence of an association between media multitasking and distractibility in laboratory tasks of information processing. PMID- 28840548 TI - (La0.97RE0.01Yb0.02)2O2S Nanophosphors Converted from Layered Hydroxyl Sulfate and Investigation of Upconversion Photoluminescence (RE=Ho, Er). AB - Phase-pure (La0.97RE0.01Yb0.02)2O2S upconversion (UC) nanophosphors (average crystallite size ~ 45 nm; RE=Ho, Er) were annealed from their hydrothermally crystallized layered hydroxyl sulfate precursors in flowing hydrogen at 1200 degrees C for 1 h, with water vapor as the only exhaust. Under 978-nm laser excitation (up to 2.0 W), the Ho3+-doped phosphor exhibited green (medium), red (weak), and near-infrared (strong) emissions at ~ 546 (5F4 -> 5I8), 658 (5F7 -> 5I8), and 763 nm (5F4 -> 5I7), respectively, and has the stable chromaticity coordinates of about (0.30, 0.66) in the visible-light region (400-700 nm). The Er3+-doped UC phosphor, on the other hand, showed weak green (~ 527/549 nm, 2H11/2,4S3/2 -> 4I15/2), weak red (~668/672 nm, 4F9/2 -> 4I15/2), and strong near infrared (~ 807/58 nm, 4I9/2 -> 4I15/2) luminescence, whose emission color in the visible region drifted from yellowish-green [(0.36, 0.61)] to green [(0.32, 0.64)] with increasing excitation power. Analysis of the power-dependent UC luminescence found three- and two-photon processes for RE=Ho and Er, respectively, and the possible UC mechanisms were proposed. PMID- 28840549 TI - Approaches for Identifying Novel Targets in Precision Medicine: Lessons from DNA Repair. AB - Genome stability is maintained by a number of elegant mechanisms, which sense and repair damaged DNA. Germline defects that compromise genomic integrity result in cancer predisposition, exemplified by rare syndromes caused by mutations in certain DNA repair genes. These individuals often exhibit other symptoms including progeria and neurodegeneration. Paradoxically, some of these deleterious genetic alterations provide novel therapeutic opportunities to target cancer cells; an excellent example of such an approach being the recent development of poly (ADP-ribose) polymerase inhibitors as the first 'synthetic lethal' medicine for patients with BRCA-mutant cancers. The therapeutic exploitation of synthetic lethal interactions has enabled a novel approach to personalised medicine based on continued molecular profiling of patient and tumour material. This profiling may also aid clinicians in the identification of specific drug resistance mechanisms following relapse, and enable appropriate modification of the therapeutic regimen. This chapter focuses on therapeutic strategies designed to target aspects of the DNA damage response, and examines emerging themes demonstrating mechanistic overlap between DNA repair and neurodegeneration. PMID- 28840550 TI - Nucleotide Excision Repair: From Neurodegeneration to Cancer. AB - DNA damage poses a constant threat to genome integrity taking a variety of shapes and arising by normal cellular metabolism or environmental insults. Human syndromes, characterized by increased cancer pre-disposition or early onset of age-related pathology and developmental abnormalities, often result from defective DNA damage responses and compromised genome integrity. Over the last decades intensive research worldwide has made important contributions to our understanding of the molecular mechanisms underlying genomic instability and has substantiated the importance of DNA repair in cancer prevention in the general population. In this chapter, we discuss Nucleotide Excision Repair pathway, the causative role of its components in disease-related pathology and recent technological achievements that decipher mutational landscapes and may facilitate pathological classification and personalized therapy. PMID- 28840551 TI - Role of Protein Linked DNA Breaks in Cancer. AB - Topoisomerases are a group of specialized enzymes that function to maintain DNA topology by introducing transient DNA breaks during transcription and replication. As a result of abortive topoisomerases activity, topoisomerases catalytic intermediates may be trapped on the DNA forming topoisomerase cleavage complexes (Topcc). Topoisomerases trapping on the DNA is the mode of action of several anticancer drugs, it lead to formation of protein linked DAN breaks (PDBs). PDBs are now considered as one of the most dangerous forms of endogenous DNA damage and a major threat to genomic stability. The repair of PDBs involves both the sensing and repair pathways. Unsuccessful repair of PDBs leads to different signs of genomic instabilities such as chromosomal rearrangements and cancer predisposition. In this chapter we will summarize the role of topoisomerases induced PDBs, identification and signaling, repair, role in transcription. We will also discuss the role of PDBs in cancer with a special focus on prostate cancer. PMID- 28840552 TI - The Emerging Role of Proteomics in Precision Medicine: Applications in Neurodegenerative Diseases and Neurotrauma. AB - Inter-individual variability in response to pharmacotherapy has provoked a higher demand to personalize medical decisions. As the field of pharmacogenomics has served to translate personalized medicine from concept to practice, the contribution of the "omics" disciplines to the era of precision medicine seems to be vital in improving therapeutic outcomes. Although we have observed significant advances in the field of genomics towards personalized medicine , the field of proteomics-with all its capabilities- is still in its infancy towards the area of personalized precision medicine. Neurodegenerative diseases and neurotrauma are among the areas where the implementation of neuroproteomics approaches has enabled neuroscientists to broaden their understanding of neural disease mechanisms and characteristics. It has been shown that the influence of epigenetics, genetics and environmental factors were among the recognized factors contributing to the diverse presentation of a single disease as well as its treatment establishing the factor-disease interaction. Thus, management of these variable single disease presentation/outcome necessitated the need for factoring the influence of epigenetics, genetics, epigenetics, and other factors on disease progression to create a custom treatment plan unique to each individual. In fact, neuroproteomics with its high ability to decipher protein alterations along with their post translational modifications (PTMs) can be an ideal tool for personalized medicine goals including: discovery of molecular mechanisms underlying disease pathobiology, development of novel diagnostics, enhancement of pharmacological neurotherapeutic approaches and finally, providing a "proteome identity" for patients with certain disorders and diseases. So far, neuroproteomics approaches have excelled in the areas of biomarker discovery arena where several diagnostic, prognostic and injury markers have been identified with a direct impact on the neurodegenerative diseases and neurotrauma. However, other applications in proteomics such as "individual" proteome sequencing with its signature PTMs, have not been fully investigated as compared to the achievements in the genomics discipline This infers that proteomics research work has promising potential, yet to be discovered, in the precision medicine and comprises a major component of the personalized medicine infrastructure as it allows individual characterization of disease at the protein level. To conclude, the field of proteomics-based personalized medicine is still in its infancy compared to genomics field due to several technical and instrumentation-based obstacles; however, we anticipate to have this initiative leading in the coming future. This chapter will discuss briefly how neuroproteomics can impact personalized medicine in the fields of neurodegenerative disorders particularly in Alzheimer's disease and brain injury . PMID- 28840553 TI - The Role of Nitric Oxide from Neurological Disease to Cancer. AB - Until the beginning of the 1980s, nitric oxide (NO) was just a toxic molecule of a lengthy list of environmental pollutants such as cigarette smoke and smog. In fact, NO had a very bad reputation of being destroyer of ozone, suspected carcinogen and precursor of acid rain. However, by the early 1990s it was well recognized by the medical research community. Over the last two decades, the picture has been totally changed. Diverse lines of evidence have converged to show that this sometime poison is a fundamental player in the everyday business of the human body. NO activity was probed in the brain, arteries, immune system, liver, pancreas, uterus, peripheral nerves, lungs, and almost every system in the human body. NO is a major player in the cardiovascular system as it is involved in regulating blood pressure. In the CNS, it is involved in memory formation and the regulation of cerebral blood flow to ensure adequate supply of blood to the brain. Because NO is involved in many pathways, it has a role in several diseases related to modern life as hypertension, coronary heart diseases, Alzheimer's Disease, stroke and cancer. This chapter focuses on the discussion of the role of NO in neurological diseases and cancer and how can this Janus-faced molecule play a role in the pathology and personalized treatment of these diseases. PMID- 28840554 TI - RNA Nuclear Export: From Neurological Disorders to Cancer. AB - The presence of a nuclear envelope, also known as nuclear membrane, defines the structural framework of all eukaryotic cells by separating the nucleus, which contains the genetic material, from the cytoplasm where the synthesis of proteins takes place. Translation of proteins in Eukaryotes is thus dependent on the active transport of DNA-encoded RNA molecules through pores embedded within the nuclear membrane. Several mechanisms are involved in this process generally referred to as RNA nuclear export or nucleocytoplasmic transport of RNA. The regulated expression of genes requires the nuclear export of protein-coding messenger RNA molecules (mRNAs) as well as non-coding RNAs (ncRNAs) together with proteins and pre-assembled ribosomal subunits. The nuclear export of mRNAs is intrinsically linked to the co-transcriptional processing of nascent transcripts synthesized by the RNA polymerase II. This functional coupling is essential for the survival of cells allowing for timely nuclear export of fully processed transcripts, which could otherwise cause the translation of abnormal proteins such as the polymeric repeat proteins produced in some neurodegenerative diseases. Alterations of the mRNA nuclear export pathways can also lead to genome instability and to various forms of cancer. This chapter will describe the molecular mechanisms driving the nuclear export of RNAs with a particular emphasis on mRNAs. It will also review their known alterations in neurological disorders and cancer, and the recent opportunities they offer for the potential development of novel therapeutic strategies. PMID- 28840555 TI - Can Astrocytes Be a Target for Precision Medicine? AB - Astrocytes are the most abundant non-neural cell type residing within the central nervous system (CNS) displaying tremendous heterogeneity depending on their location. Once believed to be 'passive support cells for electrically active neurons', astrocytes are now recognised to play an active role in brain homeostasis by forming connections with the surrounding neurons, microglia and endothelial cells. Most importantly, they provide an optimum microenvironment for functional neurons through regulation of the blood brain barrier, energy supply and removal of debris and toxic waste.Their dysfunction has been identified as a potential contributing factor for several neurodegenerative disorders, from Alzheimer's Disease to Amyotrophic Lateral Sclerosis.In this chapter, we will explore the implications of astrocyte dysfunction in neurodegenerative diseases and how these cells can be used as therapeutic targets in precision medicine. PMID- 28840556 TI - Mitochondrial Diseases as Model of Neurodegeneration. AB - "Mitochondria" partially autonomous sophisticated cellular organelle involved in a wide range of crucial cellular functions, well known as the power house of the cell where ATP (adenosine triphosphate) production takes place, that is the cellular source of energy.Mitochondria has its own genome, however proper functioning of the mitochondria is dependent upon the coordinated expression of both nuclear and mitochondrial encoded gene products. Peculiar maternal inheritance of mitochondrial DNA has led the scientists to think about mitochondrial donation as a solution to maternally inherited mitochondriopathy "Three parent baby", raising many ethical and scientific issues, concerns about safety of the procedure, long term outcome and effect of genetic modification are still questionable.Mitochondrial DNA has a higher mutation rate compared to nuclear DNA. Mitochondrial research has revealed a lot about methods of its DNA repair emphasizing the role of nuclear encoded products in this process.Mitochondrial diseases are clinically and genetically diverse, fortunately next generation sequencing (NGS) technologies have made a breakthrough in mitochondrial disorders, the whole mitochondrial genome has been sequenced with more than 250 nuclear encoded genes associated with mitochondrial syndromes identified to date, It unraveled the role of mitochondrial disorders in neurodegenerative disorders. However many pathogenic candidate genes remain uncharacterized even with whole exome sequencing (WES).In this chapter here we handle cases with various neurodegenerative diseases that have been genetically diagnosed thanks to NGS, revealing the role of mitochondrial dysfunction in neurodegeneration, offering a therapeutic target for these handicapping disorders. PMID- 28840557 TI - Personalised Medicine: Genome Maintenance Lessons Learned from Studies in Yeast as a Model Organism. AB - Yeast research has been tremendously contributing to the understanding of a variety of molecular pathways due to the ease of its genetic manipulation, fast doubling time as well as being cost-effective. The understanding of these pathways did not only help scientists learn more about the cellular functions but also assisted in deciphering the genetic and cellular defects behind multiple diseases. Hence, yeast research not only opened the doors for transforming basic research into applied research, but also paved the roads for improving diagnosis and innovating personalized therapy of different diseases. In this chapter, we discuss how yeast research has contributed to understanding major genome maintenance pathways such as the S-phase checkpoint activation pathways, repair via homologous recombination and non-homologous end joining as well as topoisomerases-induced protein linked DNA breaks repair. Defects in these pathways lead to neurodegenerative diseases and cancer. Thus, the understanding of the exact genetic defects underlying these diseases allowed the development of personalized medicine, improving the diagnosis and treatment and overcoming the detriments of current conventional therapies such as the side effects, toxicity as well as drug resistance. PMID- 28840558 TI - The Power of Zebrafish in Personalised Medicine. AB - The goal of personalised medicine is to develop tailor-made therapies for patients in whom currently available therapeutics fail. This approach requires correlating individual patient genotype data to specific disease phenotype data and using these stratified data sets to identify bespoke therapeutics. Applications for personalised medicine include common complex diseases which may have multiple targets, as well as rare monogenic disorders, for which the target may be unknown. In both cases, whole genome sequence analysis (WGS) is discovering large numbers of disease associated mutations in new candidate genes and potential modifier genes. Currently, the main limiting factor is the determination of which mutated genes are important for disease progression and therefore represent potential targets for drug discovery. Zebrafish have gained popularity as a model organism for understanding developmental processes, disease mechanisms and more recently for drug discovery and toxicity testing. In this chapter, we will examine the diverse roles that zebrafish can make in the expanding field of personalised medicine, from generating humanised disease models to xenograft screening of different cancer cell lines, through to finding new drugs via in vivo phenotypic screens. We will discuss the tools available for zebrafish research and recent advances in techniques, highlighting the advantages and potential of using zebrafish for high throughput disease modeling and precision drug discovery. PMID- 28840559 TI - Personalized Medicine and Resurrected Hopes for the Management of Alzheimer's Disease: A Modular Approach Based on GSK-3beta Inhibitors. AB - Alzheimer's disease (AD) is one of the most common neurological disorders with vast reaching worldwide prevalence. Research attempts to decipher what's happening to the human mind have shown that pathogenesis of AD is associated with misfolded protein intermediates displaying tertiary structure conformational changes eventually leading to forming large polymers of unwanted aggregates. The two hallmarks of AD pathological protein aggregates are extraneuronal beta amyloid (Abeta) based senile plaques and intraneuronal neurofibrillary tangles (NFTs). As such, AD is categorized as a protein misfolding neurodegenerative disease (PMND) . Therapeutic interventions interfering with the formation of these protein aggregates have been widely explored as potential pathways for thwarting AD progression. One such tactic is modulating the function of enzymes involved in the metabolic pathways leading to formation of these misfolded protein aggregates. Much evidence has shown that glycogen synthase kinase-3beta (GSK-3beta) plays a key role in hyperphosphorylation of tau protein leading eventually to its aggregation to form NFTs. Data presented hereby will display a plethora of information as to how to interfere with progression of AD through the route of GSK-3beta activity control. PMID- 28840560 TI - Regenerative Medicine: Advances from Developmental to Degenerative Diseases. AB - Chronic tissue and organ failure caused by an injury, disease, ageing or congenital defects represents some of the most complex therapeutic challenges and poses a significant financial healthcare burden. Regenerative medicine strategies aim to fulfil the unmet clinical need by restoring the normal tissue function either through stimulating the endogenous tissue repair or by using transplantation strategies to replace the missing or defective cells. Stem cells represent an essential pillar of regenerative medicine efforts as they provide a source of progenitors or differentiated cells for use in cell replacement therapies. Whilst significant leaps have been made in controlling the stem cell fates and differentiating them to cell types of interest, transitioning bespoke cellular products from an academic environment to off-the-shelf clinical treatments brings about a whole new set of challenges which encompass manufacturing, regulatory and funding issues. Notwithstanding the need to resolve such issues before cell replacement therapies can benefit global healthcare, mounting progress in the field has highlighted regenerative medicine as a realistic prospect for treating some of the previously incurable conditions. PMID- 28840561 TI - Gene Therapy in the Nervous System: Failures and Successes. AB - Genetic disorders, caused by deleterious changes in the DNA sequence away from the normal genomic sequence, affect millions of people worldwide. Gene therapy as a treatment option for patients is an attractive proposition due to its conceptual simplicity. In principle, gene therapy involves correcting the genetic disorder by either restoring a normal functioning copy of a gene or reducing the toxicity arising from a mutated gene. In this way specific genetic function can be restored without altering the expression of other genes and the proteins they encode. The reality however is much more complex, and as a result the vector systems used to deliver gene therapies have by necessity continued to evolve and improve over time with respect to safety profile, efficiency, and long-term expression. In this chapter we examine the current approaches to gene therapy, assess the different gene delivery systems utilized, and highlight the failures and successes of relevant clinical trials. We do not intend for this chapter to be a comprehensive and exhaustive assessment of all clinical trials that have been conducted in the CNS, but instead will focus on specific diseases that have seen successes and failures with different gene therapy vehicles to gauge how preclinical models have informed the design of clinical trials. PMID- 28840562 TI - Biases in multilevel analyses caused by cluster-specific fixed-effects imputation. AB - When datasets are affected by nonresponse, imputation of the missing values is a viable solution. However, most imputation routines implemented in commonly used statistical software packages do not accommodate multilevel models that are popular in education research and other settings involving clustering of units. A common strategy to take the hierarchical structure of the data into account is to include cluster-specific fixed effects in the imputation model. Still, this ad hoc approach has never been compared analytically to the congenial multilevel imputation in a random slopes setting. In this paper, we evaluate the impact of the cluster-specific fixed-effects imputation model on multilevel inference. We show analytically that the cluster-specific fixed-effects imputation strategy will generally bias inferences obtained from random coefficient models. The bias of random-effects variances and global fixed-effects confidence intervals depends on the cluster size, the relation of within- and between-cluster variance, and the missing data mechanism. We illustrate the negative implications of cluster specific fixed-effects imputation using simulation studies and an application based on data from the National Educational Panel Study (NEPS) in Germany. PMID- 28840563 TI - Influence of Amaranth dye concentration on the efficiency of hybrid system of photocatalytic fuel cell and Fenton process. AB - A novel sustainable hybrid system of photocatalytic fuel cell (PFC) and Fenton process is an alternative wastewater treatment technology for energy-saving and efficient treatment of organic pollutants. The electrons generated from PFC photoanode are used to produce H2O2 in the Fenton reactor and react with the in situ generation of Fe2+ from sacrificial iron for hydroxyl radical formation. In this study, the effect of different initial Amaranth dye concentrations on degradation and electricity generation were investigated. ZnO/Zn photoanode was prepared by anodizing method and characterized by X-ray diffraction (XRD) and scanning electron microscope (SEM). Results revealed that the maximum power density (9.53 mW/m2) and current density (0.0178 mA/m2) were achieved at 10 mg/L of Amaranth. The correlation between dye degradation, voltage output, and kinetic photocatalytic degradation were also investigated and discussed. PMID- 28840564 TI - Human leukemia antigen-A*0201-restricted epitopes of human endogenous retrovirus W family envelope (HERV-W env) induce strong cytotoxic T lymphocyte responses. AB - Human endogenous retrovirus W family (HERV-W) envelope (env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity. However, there are no reports investigating whether human leukemia antigen (HLA)-A*0201+ restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLA-A*0201 binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A*0201+ donors with each of these peptides induced peptide-specific CD8+ T cells. High numbers of IFN-gamma secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides (W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases. PMID- 28840565 TI - Interplay between hepatitis C virus and ARF4. AB - In summary, we show here that HCV infection is associated with an upregulation of ARF4, which promotes HCV replication. Upon HCV infection, CREB3 was redistributed to nucleus and activated ARF4 transcription. Our studies demonstrate a host factor ARF4 upregulated in HCV replication, which may provide new therapeutic targets for antiviral therapy. PMID- 28840566 TI - Photo-Induced Oxidative Stress Impairs Mitochondrial Metabolism in Neurons and Astrocytes. AB - Photodynamic therapy is selective destruction of cells stained with a photosensitizer upon irradiation with light at a specific wavelength in the presence of oxygen. Cell death upon photodynamic treatment is known to occur mainly due to free radical production and subsequent development of oxidative stress. During photodynamic therapy of brain tumors, healthy cells are also damaged; considering this, it is important to investigate the effect of the treatment on normal neurons and glia. We employed live-cell imaging technique to investigate the cellular mechanism of photodynamic action of radachlorin (200 nM) on neurons and astrocytes in primary rat cell culture. We found that the photodynamic effect of radachlorin increases production of reactive oxygen species measured by dihydroethidium and significantly decrease mitochondrial membrane potential. Mitochondrial depolarization was independent of opening of mitochondrial permeability transition pore and was insensitive to blocker of this pore cyclosporine A. However, irradiation of cells with radachlorin dramatically decreased NADH autofluorescence and also reduced mitochondrial NADH pool suggesting inhibition of mitochondrial respiration by limitation of substrate. This effect could be prevented by inhibition of poly (ADP-ribose) polymerase (PARP) with DPQ. Thus, irradiation of neurons and astrocytes in the presence of radachlorin leads to activation of PARP and decrease in NADH that leads to mitochondrial dysfunction. PMID- 28840567 TI - What Does 3D Echocardiography Add to 2D Echocardiography in the Assessment of Mitral Regurgitation? AB - PURPOSE OF REVIEW: The purpose of this review was to elucidate the additional value of 3D echocardiography for the assessment of mitral regurgitation (MR) compared to standard 2D echocardiography. RECENT FINDINGS: 3D echocardiography provides key information, aetiology, degenerative mitral valve disease vs. secondary MR, causes and mechanism, severity by measurements of effective regurgitant orifice area and regurgitant volume; likelihood of reparability and assessment of pre- and intra-mitral valve transcatheter procedures. 3D echocardiography as a promising method for assessment of MR is useful and crucial for research, clinical practice and patient management in all heart valve team members. PMID- 28840568 TI - Fitts' Law is modulated by movement history. AB - Fitts' Law is one of the most robust and well-studied principles in psychology. It holds that movement time (MT) for target-directed aiming movements increases as a function of target distance and decreases as a function of target width. The purpose of this study was to determine whether Fitts' Law is affected not only by the demands of the target on the current trial but also by the requirements for performance on the previous trial. Experiments 1 and 2 examined trial-to-trial effects of varying target width; Experiment 3 examined trial-to-trial effects of varying target distance. The findings from Experiments 1 and 2 showed that moving a finger or cursor towards a large object on a previous trial shortened the movement time on the current trial, whereas the opposite occurred with a small object. In contrast, target distance on the previous trial had no effect on movement time on the current trial. These findings suggest that performance on trial n has a clear and predictable effect on trial n+1 (at least for target width) and that Fitts' Law as it is normally expressed does not accurately predict performance when the width of the target varies from trial to trial. PMID- 28840569 TI - PCDD/F formation during thermal desorption of chlorobenzene contaminated soil. AB - Unintentional formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) is observed and investigated during the thermal desorption in an airflow of a sandy soil, doped artificially with either 1,2-dichlorobenzene (1,2-DiCBz) or hexachlorobenzene (HCBz) using a lab-scale experimental set-up. At all temperatures investigated (200, 250, 300, 350 and 400 degrees C), this thermal treatment creates significant amounts of PCDD, PCDF and polychlorinated biphenyls (PCB), starting from 1,2-DiCBz. The highest yield of PCDD/F formed from 1,2-DiCBz occurs at 250 degrees C, with a total (gas + residual soil) output of 117 and 166 pg/g PCDD and PCDF, respectively. Most output reports to the gas phase and the PCDD/F signature is significantly different for residue and gas phase. Also PCB are formed, at a scale of 224 ng/g (300 degrees C). Compared with 1,2-DiCBz, HCBz converts into PCDD/F even more actively at 350 and 400 degrees C: the total PCDD/F output created attains 967 pg/g PCDD and 465 pg/g PCDF at 350 degrees C. As a precursor, 1,2-DiCBz favours formation of PCDF, while PCDD predominates, when the HCBz contaminated soil is treated. PMID- 28840570 TI - 3Rs and biophysics. PMID- 28840571 TI - Drunkorexia: an emerging trend in young adults. AB - OBJECTIVE: Several studies demonstrated an association between alcohol consumption and unhealthy food habits. Particularly, in young adults it has been observed the tendency to use extreme forms of weight control as a way to compensate planned binge drinking. METHOD: A questionnaire was administered to a sample of 4275 healthy subjects (43.9% males; 56.1% females), aged between 18 and 26 (mean age 22.04). The survey investigated socio-economic characteristics, drinking habits with a specific focus on binge consumption, abnormal eating behaviours and psychoactive substance use. RESULTS: 34.1% of the overall sample reported to limit their calorie intake before drinking, with no significant gender difference. A significant correlation was found between drunkorexic attitudes and, respectively, binge drinking behaviours (p < .01), use of cocaine (p < .01), and use of Novel Psychoactive Substances (p < .01). DISCUSSION: Our data identified drunkorexia as a common behaviour among Italian young adults. Raising awareness on drunkorexia may help health care providers to timely address and approach its possible short- and long-term consequences. LEVEL OF EVIDENCE: Level V (descriptive study). PMID- 28840572 TI - Pharmacologic Management for Heart Failure and Emerging Therapies. AB - PURPOSE OF REVIEW: This review aims to summarize the growing body of literature of HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) with a focus on recent pharmacologics. RECENT FINDINGS: HFrEF continues to be more widely investigated than HFpEF. Ivabradine and combinatorial treatment with sacubitril and valsartan are promising newly approved therapies. Other experimental therapies have emerged, which include Serelaxin, Empagliflozin, Neuregulin, and Omecamtive mecarbil, among others. These drugs need to continue to be investigated for safety and efficacy. We predict ivabradine and combinatorial treatment with sacubitril-valsartan to develop as a widespread therapy. New therapies should be aimed at treating HFpEF or target the cardiomyocyte itself. PMID- 28840573 TI - Response time modeling reveals multiple contextual cuing mechanisms. AB - Contextual cuing refers to a response time (RT) benefit that occurs when observers search through displays that have been repeated over the course of an experiment. Although it is generally agreed that contextual cuing arises via an associative learning mechanism, there is uncertainty about the type(s) of process(es) that allow learning to influence RT. We contrast two leading accounts of the contextual cuing effect that differ in terms of the general process that is credited with producing the effect. The first, the expedited search account, attributes the cuing effect to an increase in the speed with which the target is acquired. The second, the decision threshold account, attributes the cuing effect to a reduction in the response threshold used by observers when making a subsequent decision about the target (e.g., judging its orientation). We use the diffusion model to contrast the quantitative predictions of these two accounts at the level of individual observers. Our use of the diffusion model allows us to also explore a novel decision-level locus of the cuing effect based on perceptual learning. This novel account attributes the RT benefit to a perceptual learning process that increases the quality of information used to drive the decision process. Our results reveal both individual differences in the process(es) involved in contextual cuing but also identify several striking regularities across observers. We find strong support for both the decision threshold account as well as the novel perceptual learning account. We find relatively weak support for the expedited search account. PMID- 28840574 TI - Cardioprotection by minocycline in a rabbit model of ischemia/reperfusion injury: Detection of cell death by in vivo 111In-GSAO SPECT. AB - BACKGROUND: Preclinical studies indicate that minocycline protects against myocardial ischemia/reperfusion injury. In these studies, minocycline was administered before ischemia, which can rarely occur in clinical practice. The current study aimed to evaluate cardioprotection by minocycline treatment upon reperfusion. METHODS: Rabbits were subjected to myocardial ischemia/reperfusion injury and received either intravenous minocycline (n = 8) or saline (n = 8) upon reperfusion. Cardiac cell death was assessed by in vivo micro-SPECT/CT after injection of Indium-111-labeled 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (111In-GSAO). Thereafter, hearts were explanted for ex vivo imaging, gamma counting, and histopathological characterization. RESULTS: Myocardial damage was visualized by micro-SPECT/CT imaging. Quantitative GSAO uptake (expressed as percent injected dose per gram, %ID/g) in the area at risk was lower in minocycline-treated animals than that in saline-treated control animals (0.32 +/- 0.13% vs 0.48 +/- 0.15%, P = 0.04). TUNEL staining confirmed the reduction of cell death in minocycline-treated animals. CONCLUSIONS: This study demonstrates cardioprotection by minocycline in a clinically translatable protocol. PMID- 28840576 TI - Demographic and Psychosocial Influences on Treatment Adherence for Children and Adolescents with PKU: A Systematic Review. AB - Phenylketonuria (PKU) is a rare genetic disorder in which the amino acid phenylalanine cannot be sufficiently metabolised. Although a build-up of phenylalanine causes irreversible cognitive impairment, this can be prevented through a strict, lifelong diet restricted in natural protein. Despite the severe consequences of poor metabolic control, many children and adolescents have phenylalanine levels above their recommended limits. This systematic review was the first to examine studies reporting demographic and/or psychosocial influences on blood phenylalanine levels, with the aim to identify factors that were robustly linked with metabolic control. Four electronic databases were searched, yielding 1,808 articles. Articles were included if they reported a statistical examination of the association between one or more demographic or psychosocial factor(s) and metabolic control (as measured by blood phenylalanine concentration) for children and adolescents with PKU. Twenty-nine studies were selected for inclusion, which examined a range of child, parent and family factors related to blood phenylalanine levels. The most reproducible association was with child age, with metabolic control worsening with increasing age. This suggests that interventions promoting treatment adherence would be particularly beneficial for adolescents. There was a paucity of studies in some areas, and the quality of included studies varied; therefore, the conclusions of this review are preliminary. Research recommendations focus on promoting the growth of the evidence-base to support clinical practice. PMID- 28840575 TI - Key factors involved in obesity development. AB - Obesity has been considered to be a chronic disease that requires medical prevention and treatment. Intriguingly, many factors, including adipose tissue dysfunction, mitochondrial dysfunction, alterations in the muscle fiber phenotype and in the gut microbiota composition, have been identified to be involved in the development of obesity and its associated metabolic disorders (in particular type 2 diabetes mellitus). In this narrative review, we will discuss our current understanding of the relationships of these factors and obesity development, and provide a summary of potential treatments to manage obesity. Level of Evidence Level V, narrative review. PMID- 28840577 TI - Mercury Concentrations in the Fish Community from Indrawati River, Nepal. AB - This study quantified concentrations of mercury (Hg) and its trophic transfer along the fish community in the Indrawati River, Nepal. Stable isotope ratios of nitrogen (delta15N) and carbon (delta13C), complemented by stomach contents data were used to assess the food web structure and trophic transfer of Hg in 54 fishes; 43 Shizothorax richardsonii and 11 Barilius spp. [B. bendelisis (1), B. vagra (3) and B. barila (7)]. Sixty-one muscle samples (including six replicates) were used for the analysis of total mercury (THg) and stable isotopes. Mean THg concentrations in B. spp. and the more common species S. richardsonii was observed to be 218.23 (ng/g, ww) and 90.82 (ng/g, ww), respectively. THg versus total length in both S. richardsonii and B. spp. showed a decreasing tendency with an increase in age. Regression of logTHg versus delta15N among the fish species showed a significant positive correlation only in S. richardsonii indicating biomagnification along the trophic level in this species. PMID- 28840578 TI - Bone Mineral Density is Lower in Patients with Severe Knee Osteoarthritis and Attrition. AB - Bone quality is probably important for the survival of knee arthroplasty (KA), but little is known about systemic bone mineral density and bone turnover in patients prior to KA surgery. The aim of this study was to explore the prevalence of osteoporosis and bone turnover in relation to knee osteoarthritis (OA) grade in patients scheduled for KA surgery. Prospective preoperative evaluation of 450 patients (259 females) prior to KA between 2014 and 2016 with standing knee radiography, Dual-energy X-ray absorptiometry (DXA), biomarkers for bone turnover (CTX, P1NP), and vitamin D. Grading of knee OA was done with the Altman Atlas and Kellgren Lawrence (KL). Adjustments for age and BMI were made. The mean age was 67.9 years (range 39-94), and mean BMI was 28.8 (SD 4.8). The prevalence of osteoporosis was 9.6% (CI 95% 7.2; 12.7), while the proportion of patients with osteopenia was 36.0%. T score was similar between KL OA grade 3 and 4 (p = 0.06); however, T score was lower (p = 0.02) with the worst knee OA grade (attrition). The median serum Vitamin D level was 78.5 nmol/L (range 10-196), and there was no association between serum vitamin D and the grade of OA (p > 0.88). P1NP was significantly higher in KL grade 4 compared to KL grade 3 (p = 0.03), but there was no association between KL grade and CTX (p = 0.21). 10% had osteoporosis, which is similar to the age-matched background population. Bone mineral density was lower with severe knee osteoarthritis (attrition), and P1NP was higher with worse osteoarthritis grading. PMID- 28840579 TI - The role of N-terminal pro-brain natriuretic peptide in evaluating the prognosis of patients with intracerebral hemorrhage. AB - A prognostic biomarker that can provide a good prediction of prognosis in patients with intracerebral hemorrhage (ICH) would be beneficial in guiding the initial management decisions in the setting of ICH. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker of prognosis in patients with cardiovascular disease and ischemic stroke. However, the prognostic role of NT proBNP in patients with spontaneous ICH is still a controversial issue. This study aimed to determine the prognostic value of NT-proBNP in patients with spontaneous ICH. A total of 132 patients from 571 ICH cases in inpatient settings were enrolled in this study. Blood samples from each subject were obtained and analyzed for NT-proBNP on admission and on days 4 and 7. The first end point was functional outcome at discharge, which was dichotomized into favorable or unfavorable; the secondary end point was mortality within 6 months after ICH. Compared with the baseline levels on admission after ICH, the NT-proBNP levels increased markedly on day 4 (P < 0.05). Multivariate logistic regression analysis indicated that the NT-proBNP level on day 4, the ICH score, and the APACHE II score were independent prognostic factors of functional outcome and 6-month mortality in ICH patients. A cutoff NT-proBNP level of 999.85 pg/ml predicted an unfavorable functional outcome (with 66.1% sensitivity and 98.7% specificity) and 6-month mortality (with 93.8% sensitivity and 92.0% specificity) in ICH patients. Thus, the NT-proBNP level on day 4 was found to be a powerful prognostic predictor of functional outcome and 6-month mortality in ICH patients, which would be beneficial to guiding the initial management decisions in the setting of ICH. PMID- 28840580 TI - FMT in IBD: What Have We Learned? PMID- 28840581 TI - Dishevelled proteins and CYLD reciprocally regulate each other in CML cell lines. AB - Dishevelled (Dvl) proteins are activated by Wnt pathway stimulation and have crucial roles in the regulation of beta-catenin destruction complex. CYLD is a tumor suppressor and a deubiquitination enzyme. CYLD negatively regulates the Wnt/beta-catenin signaling pathway by deubiquitinating Dvl proteins. Loss of function and mutations of CYLD were linked to different types of solid tumors. Loss of function in CYLD is associated with Dvl hyper ubiquitination, resulting in the transmission of Wnt signaling to downstream effectors. beta-catenin upregulation is observed during disease progression in chronic myeloid leukemia (CML). Deregulated Dvl signaling may be a reason for beta-catenin activation in CML; and CYLD may contribute to Dvl deregulation. First, we evaluated mRNA expression in three CML cell lines and mRNA expression of the CYLD gene was found to be present in all (K562, MEG01, KU812). Unlike solid tumors sequencing revealed no mutations in the coding sequences of the CYLD gene. DVL genes were silenced by using a pool of siRNA oligonucleotides and gene expression differences in CYLD was determined by RT-PCR and western blot. CYLD protein expression decreased after Dvl silencing. An opposite approach of overexpressing Dvl proteins resulted in upregulated CYLD expression. While previous reports have described CYLD as a regulator of DVL proteins; our data suggests the presence of a more complicated reciprocal regulatory mechanism in CML cell lines. PMID- 28840582 TI - N-Acetylcysteine Prevents the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells. AB - The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease proposes that the deaminated dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is toxic to nigrostriatal dopaminergic neurons. Inhibiting monoamine oxidase (MAO) should therefore slow the disease progression; however, MAO inhibition increases spontaneous oxidation of dopamine, as indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels, and the oxidation products may also be toxic. This study examined whether N-acetylcysteine (NAC), a precursor of the anti-oxidant glutathione, attenuates the increase in Cys-DA production during MAO inhibition. Rat pheochromocytoma PC12 cells were incubated with NAC, the MAO-B inhibitor selegiline, or both. Selegiline decreased DOPAL and increased Cys-DA levels (p < 0.0001 each). Co-incubation of NAC at pharmacologically relevant concentrations (1-10 uM) with selegiline (1 uM) attenuated or prevented the Cys DA response to selegiline, without interfering with the selegiline-induced decrease in DOPAL production or inhibiting tyrosine hydroxylation. NAC therefore mitigates the increase in spontaneous oxidation of dopamine during MAO inhibition. PMID- 28840584 TI - Metabolic Enzymes in Sarcomagenesis: Progress Toward Biology and Therapy. AB - Cellular metabolism reprogramming is an emerging hallmark of cancer, which provides tumor cells with not only necessary energy but also crucial materials to support growth. Exploiting the unique features of cancer metabolism is promising in cancer therapies. The growing interest in this field has led to numerous inhibitors being developed against key molecules in metabolic pathways, though most of them are still in preclinical development. Potential targeted cancer cell metabolic pathways under investigation include glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), glutaminolysis, pentose phosphate pathway (PPP), lipid synthesis, amino acid and nucleotide metabolism. Sarcoma is a type of cancer that arises from transformed cells of mesenchymal origin, in contrast to carcinoma which originates from epithelial cells. Compared with carcinoma, progress towards harnessing the therapeutic potential of targeting sarcoma cell metabolism has been relatively slow. Recently however, with the discovery of cancer-specific mutations in metabolic enzymes such as isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH) in certain sarcoma types, cancer cellular metabolism has been considered more as a source of new targets for treating sarcoma. In this article, we review metabolic enzymes currently tested for cancer therapies and describe the therapeutic potential of targeting IDH mutations and SDH deficiency in sarcomas. PMID- 28840583 TI - Therapeutic implications of granulocyte colony stimulating factor in patients with acute-on-chronic liver failure: increased survival and containment of liver damage. AB - BACKGROUND AND PURPOSE: Mobilization of bone marrow-derived stem cells by granulocyte colony stimulating factor (G-CSF) supports hepatic regeneration and may augment clinical improvement in patients with acute-on-chronic liver failure (ACLF). The aim of this study is to assess the impact of G-CSF on complications and transplant-free survival in patients with ACLF. METHODS: Thirty-two patients with ACLF defined by Asian Pacific Association for the Study of the Liver (APASL) criteria were openly randomized to control (group A) or intervention (group B) receiving G-CSF (5 MUg/kg/day, for 6 consecutive days) in addition to standard medical therapy with antiviral drugs. The patients were followed for 90 days. RESULTS: Simultaneous use of G-CSF and antiviral drugs in hepatitis B virus (HBV) ACLF significantly improved survival over antiviral drugs alone. Incidence of hepatorenal syndrome and hyponatremia were reduced due to use of G-CSF. Baseline parameters of the two groups of patients were comparable. Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD), disease severity scores improved in patients treated with G-CSF, with significant difference only for the CTP score at 90 days follow-up. In addition, mean white blood cell (WBC) count at day 15 was significantly higher in G-CSF group in absence of infection compared with control group. CONCLUSIONS: G-CSF therapy improved survival and clinical recovery in HBV-ACLF. G-CSF therapy also prevented renal failure and hyponatremia. We strongly recommend use of G-CSF therapy in addition to standard medical therapy. PMID- 28840585 TI - Efficacy and Safety of Quxie Capsule () in Metastatic Colorectal Cancer: A Double Blind Randomized Placebo Controlled Trial. AB - OBJECTIVE: To verify the efficacy and safety of Quxie Capsule () in patients with metastatic colorectal cancer (mCRC). METHODS: The present study was a randomized, double-blind, placebo-controlled trial. Sixty patients with mCRC were randomized into two groups at a 1:1 ratio by sealed envelope. The treatment group received conventional therapy combined with Quxie Capsule for 3 months. The control group was treated with conventional therapy combined with placebo for 3 months. Main outcome measures were overall survival (OS) and progression-free survival (PFS). Subgroup analysis was performed according to age, right or left-sided disease, and second-line therapy to determine the differences in PFS and OS between the two groups. Patients were followed up every 3 months until Dec 31st 2016. RESULTS: The median OS was 23 months in the treatment group [95% confidence interval (CI): 15-not calculated] vs. 14 months in the control group (95% CI: 11 22, P=0.060). The OS of the treatment group tended to be longer than that of the control group (P>0.05). In the subgroups of patients <65 years old, left-sided colon, and 2nd-line therapy, the treatment group showed a significant survival benefit compared with the control group (P=0.006, 0.038, 0.013, respectively). There were no significant differences between the two groups in PFS (P>0.05). Safety analysis showed no severe hematological toxicity or liver and renal function injury in the treatment group. CONCLUSIONS: Quxie Capsule showed good safety and efficacy, and could prolong the OS of patients with mCRC. (Registration No. ChiCTR-IOR-16009733). PMID- 28840586 TI - Analysis on composition rules of Chinese patent drugs treating pain-related diseases based on data mining method. AB - OBJECTIVE: To analyze the composition rules of oral prescriptions in the treatment of headache, stomachache and dysmenorrhea recorded in National Standard for Chinese Patent Drugs (NSCPD) enacted by Ministry of Public Health of China and then make comparison between them to better understand pain treatment in different regions of human body. METHODS: Constructed NSCPD database had been constructed in 2014. Prescriptions treating the three pain-related diseases were searched and screened from the database. Then data mining method such as association rules analysis and complex system entropy method integrated in the data mining software Traditional Chinese Medicine Inheritance Support System (TCMISS) were applied to process the data. RESULTS: Top 25 drugs with high frequency in the treatment of each disease were selected, and 51, 33 and 22 core combinations treating headache, stomachache and dysmenorrhea respectively were mined out as well. CONCLUSIONS: The composition rules of the oral prescriptions for treating headache, stomachache and dysmenorrhea recorded in NSCPD has been summarized. Although there were similarities between them, formula varied according to different locations of pain. It can serve as an evidence and reference for clinical treatment and new drug development. PMID- 28840588 TI - Outcome of implantable loop recorder evaluation. AB - BACKGROUND: The aim of this study was to evaluate implantable loop recorders (ILRs) in an unselected cohort in order to determine diagnostic yield, time to pacemaker/implantable cardioverter-defibrillator (ICD) implantation, predictors thereof, safety issues, and syncope management including usage of preceding diagnostic tools. METHODS: Patients who underwent ILR evaluation in any of three centers in Region Gavleborg, Swe-den, between April 2007 and April 2013 were included and their medical records retrieved. Logistic regression was used to evaluate predictors of pacemaker/ICD outcome expressed as odds ratios (ORs) and Kaplan-Meier estimates for time-dependent analysis. RESULTS: A total of 173 patients (52.6% females) with a mean age of 56.2 years received an ILR dur-ing a mean follow-up of 605 days. In the 146 patients evaluated for syncope/presyncope, 28.1% received a pacemaker (n = 39) or ICD (n = 2). The cumulative incidence at 6, 12, and 18 months were 8.8%, 21.3%, and 26.7%, respectively. Age > 75 years was the only significant predictor for outcome (p = 0.010) and the following variables showed a tendency toward significance: abnormal elevation of the biomarker B-type natriuretic peptide (OR 2.05, p = 0.100), a history of trauma (OR 1.71, p = 0.179), and patho-logic electrocardiogram (OR 1.68, p = 0.231). A computerized tomography of the skull was performed in 52.1% of the syncope cases. CONCLUSIONS: In syncope evaluation in an unselected cohort, 28.1% were diagnosed with an arrhyth-mia necessitating a pacemaker/ICD. The only significant predictor was advanced age. Time to diag-nosis is unpredictable and prolonged ILR monitoring is warranted in addition to optimal use of other diagnostic tools. PMID- 28840587 TI - Study design and rationale for biomedical shirt-based electrocardiography monitoring in relevant clinical situations: ECG-shirt study. AB - BACKGROUND: Today, the main challenge for researchers is to develop new technologies which may help to improve the diagnoses of cardiovascular disease (CVD), thereby reducing healthcare costs and improving the quality of life for patients. This study aims to show the utility of biomedical shirt-based electrocardiography (ECG) monitoring of patients with CVD in different clinical situations using the Nuubo(r) ECG (nECG) system. METHODS: An investigator initiated, multicenter, prospective observational study was carried out in a cardiology (adult and pediatric) and cardiac rehabilitation wards. ECG monitoring was used with the biomedical shirt in the following four independent groups of patients: 1) 30 patients after pulmonary vein isolation (PVI), 2) 30 cardiac resynchronization therapy (CRT) recipients, 3) 120 patients during cardiac rehabilitation after myocardial infarction, and 4) 40 pediatric patients with supraventricular tachycardia (SVT) before electrophysiology study. Approval for all study groups was obtained from the institutional review board. The biomedical shirt captures the electrocardiographic signal via textile electrodes integrated into a garment. The software allows the visualization and analysis of data such as ECG, heart rate, arrhythmia detecting algorithm and relative position of the body is captured by an electronic device. DISCUSSION: The major advantages of the nECG system are continuous ECG monitoring during daily activities, high quality of ECG recordings, as well as assurance of a proper adherence due to adequate comfort while wearing the shirt. There are only a few studies that have examined wearable systems, especially in pediatric populations. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov: Identifier NCT03068169. (Cardiol J 2018; 25, 1: 52-59). PMID- 28840589 TI - Occurrence and extraction of implantable cardioverter-defibrillator leads with conductor externalization. AB - BACKGROUND: The increasing number of patients with implantable cardioverter defibrillators (ICD) contributes to the rising number of patients qualifying for a transvenous lead extraction (TLE) due to infection, vascular or lead failure related indications. The purpose of this study was to perform a retrospective analysis of the occurrence of conductor externalization in TLE patients and to assess the success rate in the extraction of these leads. METHODS: TLE procedure was performed between 2012 and 2014 of 428 electrodes in 259 patients. Out of these, 143 (33.4%) leads in 138 (52.9%) patients were ICD leads. The indications for the TLE in ICD patients were: infection in 37 patients, lead failure in 84 patients, and others in 17 patients. Conductor externalization was observed in 8 ICD leads (5.6%) in 8 (5.8%) patients. The mean dwell-ing time for externalized leads was 87.9 (55 to 132) months compared to 60.1 (3 to 246) months of the remaining 135 ICD leads (p = 0.0329). All externalized leads were successfully and completely extracted using device traction, mechanical telescopic sheaths and/or autorotational cutting sheaths. No complica-tions of lead extraction procedures were observed in 8 patients with externalization. RESULTS: Patients with lead externalization were often in a better New York Heart Association func tional class (I or II) compared to those in the rest of the study group (p = 0.0212). CONCLUSIONS: Conductor externalization is a rare finding in patients undergoing TLE. This occurs with different manufacturers and lead types. In this complication transvenous lead extraction with the mechanical extraction tools can be safely performed. PMID- 28840590 TI - Right ventricular morphology and function is not related with microRNAs and fibrosis markers in dilated cardiomyopathy. AB - BACKGROUND: The relationship between right ventricle (RV), extracellular matrix (ECM) fibrosis and fibrosis-linked, circulating microRNAs in dilated cardiomyopathy (DCM) is unknown. AIMS: To uncover the associations between serum markers of ECM metabolism and circulating microRNAs with RV morphological and functional parameters. METHODS: The study population consisted of 70 consecutive DCM patients (ejection fraction 24.4 +/- 7.4%). Based on detailed echocardiographic assessment - 15 patients had normal RV, whereas 55 patients had RV dilatation (RVD) and/or systolic dysfunction (RVSD). Procollagens type I and III carboxy- and amino-terminal peptides, osteopontin (OPN), TGF1-beta1, connective tissue growth factor (CTGF), MMP-2, MMP-9 and TIMP-1 were measured in serum as well as expression of miR-21, miR-26, miR-29, miR-30 and miR-133a. All patients underwent endomyocardial biopsy. RESULTS: Biopsy-proven fibrosis was evenly distributed in two groups. Serum levels of fibrosis markers did not differ between groups. OPN, CTGF, MMP-2, and TIMP-1 correlated with RV parameters. Only miR-133 a was differently expressed in both groups. MiR-21, -26, -30, and -133a correlated with RV morphological but without functional parameters. Not a single marker of fibrosis was independently associated with RV. Mir-30 was associated with RV impairment in the logistic regression model adjusted for age, sex, body mass index, and disease duration; however, lost its significance in the more comprehensive model. CONCLUSIONS: Right ventricle structural and functional abnormalities are common in DCM. ECM fibrosis and serum markers are not associated with RV impairment. The prognostic value of studied microRNAs on RV is limited in DCM. PMID- 28840591 TI - Comparison of dedicated BIOSS bifurcation stents with regular drug-eluting stents for coronary artery bifurcated lesions: Pooled analysis from two randomized studies. AB - BACKGROUND: Coronary bifurcation treatment poses a therapeutic challenge. The aim of this study was to analyze pooled data of two randomized clinical trials, POLBOS I and POLBOS II, to compare 1-year follow-up results and identify possible prognostic factors. METHODS: In POLBOS trials dedicated bifurcation BiOSS(r) stents were compared with regular drug eluting stents (rDES) in patients with stable coronary artery disease or non ST-segment elevation acute coronary syndrome (POLBOS I: paclitaxel eluting BiOSS(r) Expert vs. rDES; POLBOS II: sirolimus eluting BiOSS(r) LIM vs. rDES). Provisional T-stenting was the default strategy. Angiographic control was performed at 12 months. The primary endpoint was major adverse cardiovascular events (MACE) rate defined as the rate of cardiac death, myocardial infarction (MI) or target lesion revascularization (TLR). RESULTS: 445 patients, with 222 patients in the BiOSS group and 223 patients in the rDES group, were analyzed. In 26.7% cases procedures were performed within distal left main, and true bifurca-tions which accounted for 81.6% of treated lesions. At 12 months the whole population exhibited no statistical differences in terms of MACE, TLR, MI or cardiac death between rDES and BiOSS groups. In multivariate analysis odds for MACE decreased with female sex (OR 0.433, 95% CI 0.178-0.942, p = 0.047) and with proximal optimization technique use (OR 0.208, 95% CI 0.097-0.419, p < 0.001), whereas the odds for MACE increased with main vessel predilatation (OR 2.191, 95% CI 1.042-5.066, p = 0.049) and diabetes mellitus treated with insulin (OR 2.779, 95% CI 1.1-6.593, p = 0.024). CONCLUSIONS: Pooled data showed no significant difference between MACE and TLR rates for BiOSS(r) group vs. rDES group. PMID- 28840592 TI - Left atrial appendage closure for "primary primary" prevention during percutaneous closure of septal defects in patients with large atria but no atrial fibrillation. AB - BACKGROUND: Percutaneous atrial septal defect (ASD) closure is a routine procedure to prevent right ventricular failure, pulmonary hypertension, or paradoxical embolism. The latter is the typical reason for percutaneous patent foramen ovale (PFO) closure. Atrial enlargement represents a risk for develop-ing atrial fibrillation (AF). Percutaneous left atrial appendage (LAA) closure is emerging as a preven-tive therapy for patients in AF who suffered from a previous stroke or bleeding (secondary prevention) or patients without previous stroke or bleeding (primary prevention). Percutaneous septal closure, particularly that of large ASDs, may inhibit future percutaneous left atrial access when required for LAA closure. Reported herein is the feasibility and safety of concomitant percutaneous closure of the LAA and a septal shunt, mostly large ASDs, in patients without AF, in the sense of "primary primary" preventive LAA closure. The first "primary" relates to "in anticipation of AF" and potentially also for "for prevention of AF". The second "primary" relates to "prevention of stroke or bleeding". METHODS: Thirteen consecutive patients, older than 40 years without any clinical or electrocardio-graphic evidence of AF, underwent percutaneous closure of large ASDs or PFOs in the presence of enlarged atria at the university hospitals of Bern and Zurich between April 2013 and June 2015. They concomitantly received "primary primary" preventive LAA closure after informed consent. RESULTS: Mean patient age was 58 +/- 9 years (46% male). Procedural success was achieved in all pa-tients and no major adverse events occurred acutely or during the following 2.0 +/- 0.8 years. No patient developed AF. CONCLUSIONS: Concomitant closure of ASD or PFO in the presence of enlarged atria and LAA for "primary primary" prevention appears feasible and safe but has yet to prove its justification. PMID- 28840593 TI - A pilot study with flow mediated skin fluorescence: A novel device to assess microvascular endothelial function in coronary artery disease. AB - BACKGROUND: Endothelial dysfunction is one of the earliest vascular manifestations in the pathogen-esis of cardiovascular disease. Noninvasive, simple, and inexpensive methods of endothelial function assessment are therefore needed. METHODS: Microvascular endothelial function was assessed in coronary artery disease (CAD) patients by flow mediated skin fluorescence (FMSF), based on measurements of reduced form of nicotinamide adenine dinucleotide (NADH) fluorescence intensity during brachial artery occlusion (ischemic re-sponse [IRmax]) and immediately after occlusion (hyperemic response [HRmax]). Additionally, plasma levels of asymmetric dimethylarginine (ADMA) and endothelin 1 (ET-1) were measured to assess the association between biochemical markers and microvascular function evaluated in vivo by FMSF. RESULTS: A significant inverse correlation was found between ADMA levels and hyperemic response (r = -0.534, p = 0.003), while ET-1 levels were inversely related to the ischemic response (r= 0.575, p = 0.001). Both IR and HR were found lowest in patients with advanced CAD and diabetes. When the repeatability of the method was tested, the intraclass correlation coefficient for IRmax and HRmax were 0.985 (p < 0.001) and 0.914 (p < 0.001), respectively. Moreover, in Bland and Altman analysis, both variables IRmax and HRmax showed good agreement in repeated measurements. CONCLUSIONS: In this pilot study, it was demonstrated that NADH fluorescence measured by FMSF device in CAD patients was associated with established plasma endothelial markers, and that both ischemic and hyperemic response were blunted in patients with advanced disease and diabetes. Fur-thermore, FMSF device showed excellent repeatability and good agreement for repeated measurements. However, further study is warranted to confirm these results in a larger patient cohort. (Cardiol J 2018; 25, 1: 120-127). PMID- 28840594 TI - Occupational exposure to wood dust and risk of nasal and nasopharyngeal cancer: A case-control study among men in four nordic countries-With an emphasis on nasal adenocarcinoma. AB - The current study aims to provide stronger evidence to aid in our understanding of the role of cumulative occupational exposure to (softwood-dominated) mixed wood dust in aetiology of nasal cancer. We included broad exposure occurred in a range of wood-processing occupation across varied industries in four Nordic countries. A population-based case-control study was conducted on all male cases with nasal adenocarcinoma (393 cases), other types of nasal cancer (2,446) and nasopharyngeal cancer (1,747) diagnosed in Finland, Sweden, Norway and Iceland between 1961 and 2005. For each case, five male controls, who were alive at the time of diagnosis of the case (index date), were randomly selected, matched by birth-year and country. Cumulative exposures (CE)s to wood dust and formaldehyde before the index date were quantified based on a job-exposure matrix linked to occupational titles derived from population censuses. Hazard ratios (HRs) for the CE of wood dust were estimated by conditional logistic regression, adjusted for CE to formaldehyde and 95% confidence intervals (CIs) were calculated. There was an increasing risk of nasal adenocarcinoma related to wood dust exposure. The HR in the highest CE category of wood dust (>= 28.82 mg/m3 -years) was 16.5 (95% CI 5.05-54.1). Neither nonadenocarcinoma of the nose nor nasopharyngeal cancer could be linked to wood dust exposure. CE to softwood-dominated mixed wood dusts is strongly linked with elevated risk in nasal adenocarcinoma but not with other types of nasal or nasopharyngeal cancer. PMID- 28840595 TI - Tissue distribution following 28 day repeated oral administration of aluminum based nanoparticles with different properties and the in vitro toxicity. AB - The tissue distribution and toxicity of nanoparticles (NPs) depend on their physical and chemical properties both in the manufactured condition and within the biological system. We characterized three types of commercially available aluminum-based NPs (Al-NPs), two rod-type aluminum oxide NPs (Al2 O3 , AlONPs), with different aspect ratios (short [S]- and long [L]-AlONPs), and spherical aluminum cerium oxide NPs (AlCeO3 , AlCeONPs). The surface area was in order of the S-AlONPs > L-AlONPs > AlCeONPs. Very importantly, we found that AlCeONPs is Al2 O3 -coated CeO2 NPs, but not AlCeO3 NPs, and that the Al level in AlCeONPs is approximately 20% of those in S- and L-AlONPs. All three types of Al-NPs were slightly ionized in gastric fluid and rapidly particlized in the intestinal fluid. There were no significant differences in the body weight gain following 28 days of repeated oral administration of the three different types of Al-NPs. All Al-NPs elevated Al level in the heart, spleen, kidney and blood at 24 hours after the final dose, accompanied by the altered tissue level of redox reaction-related trace elements. Subsequently, in four types of cells derived from the organs which Al-NPs are accumulated, H9C2 (heart), HEK-293 (kidney), splenocytes and RAW264.7 (blood), S-AlONPs showed a very low uptake level and did not exert significant cytotoxicity. Meanwhile, cytotoxicity and uptake level were the most remarkable in cells treated with AlCeONPs. In conclusion, we suggest that the physicochemical properties of NPs should be examined in detail before the release into the market to prevent unexpected adverse health effects. PMID- 28840596 TI - Risk of Cause-Specific Death in Individuals with Cancer-Modifying Role Diabetes, Statins and Metformin. AB - Both diabetes mellitus (DM) and cancer are common diseases and they frequently occur in the same patients. We investigated the all-cause and cause-specific mortality dynamics in relation to baseline DM, statin use and metformin use. The study population consisted of 39,900 incident cancer cases from Finland, 19,822 patients were free of DM at the start of follow-up and 20,078 had DM. Mortality from all causes, and cancer, cardiovascular (CVD) and other causes was analysed using Poisson regression model with the following variables: sex, age, DM, statin and metformin usage in baseline, cancer type and stage and calendar period. Statin usage was associated with a reduced cancer-specific mortality with incidence rate ratio (IRR) 0.72 (95% confidence interval 0.69-0.74), IRR for CVD mortality was 0.95 (0.88-1.02) and for other causes 0.64 (0.56-0.74). In a sub population of DM patients, IRR for metformin in all-cause mortality was 0.74 (0.71-0.78), in cancer mortality 0.75 (0.72-0.79), in CVD mortality 0.75 (0.68 0.83) and other causes 0.68 (0.60-0.78). In conclusion, our register-based study of survival after cancer diagnosis showed that patients with diabetes had substantially poorer outcome in all measures. An association between baseline statin usage and lower all-cause, cancer and cardiovascular mortality was modified by cancer type. The effect of statin use was largest for breast and colorectal cancer. Metformin usage in a subpopulation of oral antidiabetic users was in general associated with lower mortality, but this association was modified by cancer type. The association was strongest for liver, colorectal and breast cancer. PMID- 28840597 TI - Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation. AB - BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. OBJECTIVES: To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: The update search did not identify any additional studies. We identified one RCT that included people with high-risk neuroblastoma who received HDCT followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a second random allocation. These 98 participants had no progressive disease after HDCT followed by autologous HSCT. There was no clear evidence of difference between the treatment groups either in overall survival (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.46 to 1.63; one trial; P = 0.66) or in event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59). We calculated the HR values using the complete follow up period of the trial. The study also reported overall survival estimates at a fixed point in time. At the time point of five years, the survival estimate was reported to be 59% for the retinoic acid group and 41% for the no-further-therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. We could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. We judged the evidence to be of low quality for overall survival and event-free survival, downgraded because of study limitations and imprecision. AUTHORS' CONCLUSIONS: We identified one RCT that evaluated additional retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT versus no further therapy in people with high-risk neuroblastoma. There was no clear evidence of a difference in overall survival and event-free survival between the treatment alternatives. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since when many changes in treatment and risk classification have occurred. Based on the currently available evidence, we are therefore uncertain about the effects of retinoic acid in people with high-risk neuroblastoma. More research is needed for a definitive conclusion. PMID- 28840598 TI - Therapeutic monoclonal antibodies in combination with pomalidomide can overcome refractoriness to both agents in multiple myeloma: A case-based approach. AB - In multiple myeloma (MM), the synergy between immunomodulatory drugs (IMiDs) and monoclonal antibodies (MABs) has been demonstrated in several pivotal trials. However, disease refractory to either class of compounds remains a major therapeutic challenge. We here report on 3 heavily pretreated MM patients who were refractory to pomalidomide as well as to MABs against CD38 (daratumumab) or CD20 (rituximab), respectively, but who responded to retreatment with the same agents in combination. Responses were durable with PFS of 7, 10 (ongoing), and 30 months from initiation of combination treatment. The combination of IMiDs with MABs directed against MM cell surface antigens can overcome refractoriness to both agents. PMID- 28840599 TI - Butyltin compounds alter secretion of interleukin 6 from human immune cells. AB - Butyltins (BTs), tributyltin (TBT) and dibutyltin (DBT) are organotin compounds that have been used in a variety of industrial applications; as a result, these compounds have been found in human blood. Interleukin (IL)-6 is a proinflammatory mediator that is produced by T lymphocytes and monocytes. It is responsible for immune response regulation as well as tissue repair and cellular growth. Both BTs decrease the ability of human natural killer cells to destroy tumor cells and alter the secretion of proinflammatory cytokines tumor necrosis factor alpha, interferon gamma and IL-1 beta (beta) from human lymphocytes ex vivo. Here, we show that BTs alter the secretion of IL-6 from increasingly reconstituted preparations of human immune cells. IL-6 secretion was examined after 24 hour, 48 hour or 6 day exposures to TBT and DBT in highly enriched human natural killer cells, monocyte-depleted peripheral blood mononuclear cells (PBMCs), PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes (PBMCs + granulocytes). The results indicated that both BTs altered IL-6 secretion from all cell preparations. Significant decreases of IL-6 secretion were seen at the highest concentration of TBT (200 nm) and DBT (5-2.5 MUm) while the lower concentrations of DBT (0.05 and 0.1 MUm) caused elevation of IL-6 secretion. The data indicate that BT-induced alterations of IL-6 secretion from immune cells may be a significant consequence of BT exposures that may potentially affect immune competence. PMID- 28840601 TI - Digest: Premating barriers drive reproductive isolation between two damselfly species. PMID- 28840600 TI - Red blood cell minor antigen mismatches during chronic transfusion therapy for sickle cell anemia. AB - BACKGROUND: Red blood cell (RBC) alloimmunization occurs at a high frequency in sickle cell anemia (SCA) despite serologic matching for Rh (C/c, E/e) and K antigens. RBC minor antigen genotyping allows for prediction of antigens and RH variants that may lead to alloimmunization. STUDY DESIGN AND METHODS: RBC antigen genotyping was performed on chronically transfused pediatric SCA patients, using PreciseType human erythrocyte antigen (HEA), RHCE, and RHD BeadChip arrays. All patients received C/c, E/e, and K serologically matched units (Category 1); patients with prior RBC antibodies were also matched for Fya , Jkb , and any antibodies (Category 2). The RBC genotypes of all leukoreduced (LR) units transfused over a 12-month period were determined by the prototype HEA-LR BeadChip assay. RESULTS: There were 2320 RBC units transfused to 90 patients in 1135 transfusion episodes. Thirty-five (38.9%) patients had homozygous or compound heterozygous RH variants. Seven new alloantibodies were detected, with alloantibody incidence of 0.706 in 100 units for Category 2 transfusions and 0.068 in 100 units for Category 1 (p = 0.02). Three patients on Category 2 transfusions formed new anti-Jsa and had a higher rate of exposure to Jsa than those who did not form anti-Jsa (20.4 vs. 8.33 exposures/100 units, p = 0.02). The most frequent mismatches were S (43.9%), Doa (43.9%), Fya (29.2%), M (28.4%), and Jkb (28.1%). CONCLUSIONS: Alloimmunization incidence was higher in those with prior RBC antibodies, suggesting that past immunologic responders are at higher risk for future alloimmunization and therefore may benefit from more extensive antigen matching beyond C/c, E/e, K, Fya , and Jkb . PMID- 28840602 TI - Longing for homeliness: exploring mealtime experiences of patients suffering from a neurological disease. AB - BACKGROUND: Many patients suffering from a neurological disease experience eating difficulties during mealtimes in the hospital. Consequently, they often refrain from eating in public places to avoid potentially awkward situations. Eating is an essential part of life, providing patients with comfort during their hospitalisation. Therefore, attention should be paid to these patients, who encounter eating difficulties to foster a positive mealtime experience. AIM: To study what patients afflicted with a neurological disease experience and assign meaning when participating in mealtimes during hospitalisation. METHOD: Ten semi structured interviews with patients were conducted and recorded. After transcription the text was analysed, and interpreted compromising three methodological steps inspired by the French philosopher, Paul Ricouer. FINDINGS: Three themes were identified through data analysis and interpretation: i) The missing feeling of homeliness, ii) The battle between socialisation vs. isolation, and iii) The sense of time, rhythm, and presence. CONCLUSIONS: To patients suffering from a neurological disease, mealtimes are not only a manageable task, but also a part of existential care that leads to positive experience. Aesthetic elements were shown to have the potential of making the patients feel comfortable and homely when hospitalised. This was important, as our study also identified that patients were longing for homeliness when participating in mealtimes during hospitalisation. RELEVANCE TO CLINICAL PRACTICE: Our findings emphasised the need of proceeding to interventions that includes mealtime assistance and protects the mealtime activity. Hence, it informs hospital organisations of the importance of restructuring mealtime environment, so that existential care can take place. PMID- 28840603 TI - Hemovigilance monitoring of platelet septic reactions with effective bacterial protection systems. AB - BACKGROUND: Delayed, large-volume bacterial culture and amotosalen/ultraviolet-A light pathogen reduction are effective at reducing the risk of bacterial proliferation in platelet concentrates (PCs). Hemovigilance programs continue to receive reports of suspected septic transfusion reactions, most with low imputability. Here, we compile national hemovigilance data to determine the relative efficacy of these interventions. STUDY DESIGN AND METHODS: Annual reports from the United Kingdom, France, Switzerland, and Belgium were reviewed between 2005 and 2016 to assess the risk of bacterial contamination and septic reactions. RESULTS: Approximately 1.65 million delayed, large-volume bacterial culture-screened PCs in the United Kingdom and 2.3 million amotosalen/ultraviolet A-treated PCs worldwide were issued with no reported septic fatalities. One definite, one possible, and 12 undetermined/indeterminate septic reactions and eight contaminated "near misses" were reported with delayed, large-volume bacterial cultures between 2011 and 2016, for a lower false-negative culture rate than that in the previous 5 years (5.4 vs. 16.3 per million: odds ratio, 3.0; 95% confidence interval, 1.4-6.5). Together, the Belgian, Swiss, and French hemovigilance programs documented zero probable or definite/certain septic reactions with 609,290 amotosalen/ultraviolet-A-treated PCs (<1.6 per million). The rates were significantly lower than those reported with concurrently transfused, nonpathogen-reduced PCs in Belgium (<4.4 vs. 35.6 per million: odds ratio, 8.1; 95% confidence interval,1.1-353.3) and with historic septic reaction rates in Switzerland (<6.0 vs. 82.9 per million: odds ratio, 13.9; 95% confidence interval, 2.1-589.2), and the rates tended to be lower than those from concurrently transfused, nonpathogen-reduced PCs in France (<4.7 vs. 19.0 per million: odds ratio, 4.1; 95% confidence interval, 0.7-164.3). CONCLUSION: Pathogen reduction and bacterial culture both reduced the incidence of septic reactions, although under-reporting and strict imputability criteria resulted in an underestimation of risk. PMID- 28840604 TI - Environmental complexity and the purging of deleterious alleles. AB - Sexual interactions among adults can generate selection on both males and females with genome-wide consequences. Sexual selection through males is one component of this selection that has been argued to play an important role in purging deleterious alleles. A common technique to assess the influence of sexual selection is by a comparison of experimental evolution under enforced monogamy versus polygamy. Mixed results from past studies may be due to the use of highly simplified laboratory conditions that alter the nature of sexual interactions. Here, we examine the rate of purging of 22 gene disruption mutations in experimental polygamous populations of Drosophila melanogaster in each of two mating environments: a simple, high-density environment (i.e., typical fly vials), and a lower density, more spatially complex environment. Based on past work, we expect sexual interactions in the latter environment to result in stronger selection in both sexes. Consistent with this, we find that mutations tend to be purged more quickly in populations evolving in complex environments. We discuss possible mechanisms by which environmental complexity might modulate the rate at which deleterious alleles are purged and putatively ascribe a role for sexual interactions in explaining the treatment differences in our experiment. PMID- 28840605 TI - Digest: Ancient codispersals and host shifts in passerine bird-feather mite symbiosis. PMID- 28840606 TI - High estimated prevalence of asymptomatic dengue viremia in blood donors during a dengue epidemic in southern Taiwan, 2015. AB - BACKGROUND: Southern Taiwan experienced a severe dengue epidemic in 2015. Adult asymptomatic cases would raise concerns on transfusion-transmitted dengue virus (DENV) infection. The aim of this study was to evaluate the magnitude of such a risk in Tainan City during this epidemic. STUDY DESIGN AND METHODS: The daily prevalence of asymptomatic dengue viremia in blood donors in Tainan City and in selected high-incidence districts during the 2015 dengue epidemic was estimated by an established mathematical model. Duration of viremia, duration of viremia before symptom onset, apparent-to-inapparent infection ratio, and reporting-to underreporting ratio were four main parameters used in the model. RESULTS: The estimated maximal and mean daily prevalence of asymptomatic dengue viremia in blood donors in Tainan during this dengue epidemic was 74.4 (95% confidence interval [CI], 60.8-88.0) and 15.0 (95% CI, 12.3-17.7) per 10,000, respectively. In the district with the highest incidence, the maximal and mean daily prevalence of asymptomatic viremia was 328.8 (95% CI, 271.1-386.2) and 55.3 (95% CI, 43.4 63.3) per 10,000, respectively. Approximately 234 (95% CI, 191-276) blood components containing DENV were produced during the epidemic. CONCLUSION: Although dengue is currently not endemic in Taiwan, physicians need to be aware of the risk of transfusion-transmitted DENV infection. Our results suggest that screening measures to ensure blood safety should be evaluated and implemented during dengue epidemics even in nonendemic areas. Timely estimation of daily asymptomatic viremia prevalence by districts can help to select high-risk areas for such measures and to evaluate cost-effectiveness. PMID- 28840607 TI - Andrology on the Internet: Most wanted, controversial and often primary source of information for patients. AB - The Internet is an important source of health information with relevant impact on the physician-patient relationship. The German urological associations host one of the most comprehensive platforms for patient information on urological diseases. The aim of the study was to characterise its users and their specific needs. We invited users of the website www.urologenportal.de via pop-up to complete a 26-item online survey to evaluate health-related behaviour, distress and decision-making preferences. We received n = 551 complete responses. The most frequently requested topics were from the field of andrology (45.4%, n = 250). Of these, the most popular topics were circumcision (28.9%, n = 159) and erectile dysfunction (18.1%; n = 100). Overall, 216 users (39.2%) searched for information prior to their first doctor's appointment, and 89.3% (n = 492) preferred autonomous or shared decision-making. Users seeking information on circumcision were less frequently under urological treatment (p < .001), and more self determined regarding healthcare decisions (p = .01). Circumcision was the only information on the website, which received relevant critical comments. Andrology was the most frequently requested urological topic. The vast majority of patients wanted to take self-determined healthcare decisions and searched for information prior to a doctor's appointment. This might have an impact on the physician patient relationship and causes a high demand for good-quality health information websites. PMID- 28840608 TI - A practice model for rural district nursing success in end-of-life advocacy care. AB - AIM: The development of a practice model for rural district nursing successful end-of-life advocacy care. BACKGROUND: Resources to help people live well in the end stages of life in rural areas can be limited and difficult to access. District nurse advocacy may promote end-of-life choice for people living at home in rural Australia. The lack of evidence available internationally to inform practice in this context was addressed by exploratory study. METHOD: A pragmatic mixed method study approved by the University Faculty Ethics Committee and conducted from March 2014 to August 2015 was used to explore the successful end of-life advocacy of 98 rural Australian district nurses. The findings and results were integrated then compared with theory in this article to develop concepts for a practice model. RESULTS: The model illustrates rural district nurse advocacy success based on respect for the rights and values of people. Advocacy action is motivated by the emotional responses of nurses to the end-of-life vulnerability people experience. The combination of willing investment in relationships, knowing the rural people and resources, and feeling supported, together enables district nurses to develop therapeutic emotional intelligence. This skill promotes moral agency in reflection and advocacy action to overcome emotional and ethical care challenges of access and choice using holistic assessment, communication, organisation of resources and empowering support for the self determination of person-centred end-of-life goals. Recommendations are proposed from the theoretical concepts in the model. LIMITATIONS: Testing the model in practice is recommended to gain the perceptions of a broader range of rural people both giving and receiving end-of-life-care. CONCLUSION: A model developed by gathering and comparing district nursing experiences and understanding using mixed methods and existing theory offers evidence for practice of a philosophy of successful person-centred advocacy care in a field of nursing that lacks specific guidance. PMID- 28840609 TI - Red blood cell alloimmunization in pregnancy during the years 1996-2015 in Iceland: a nation-wide population study. AB - BACKGROUND: Red blood cell (RBC) alloimmunization during pregnancy is still a major problem. Historically, anti-D antibodies are most likely to cause severe hemolysis, but other antibodies are also important. In Iceland, postnatal RhIg prophylaxis was implemented in 1969, universal RBC antibody screening was implemented in 1978, but antenatal RhIg prophylaxis is not yet routine. STUDY DESIGN AND METHODS: This nation-wide population study gathered data on alloimmunized pregnancies in Iceland between 1996 and 2015. Blood bank alloimmunization data were linked to Icelandic Medical Birth Registry data. RBC antibodies were classified as either clinically significant or clinically nonsignificant. RESULTS: In total, 912 positive antibody screens from 87,437 births were identified (1.04% prevalence). The most frequent antibodies were anti M (19.4%), anti-E (19.0%), and anti-D (12.5%). Anti-D prevalence among D-negative mothers was 1.1%. Icelandic Medical Birth Registry data were available for 881 (96.6%) pregnancies. In the clinically significant group (n = 474), anti-E (27%) and anti-D (20%) were most common, whereas anti-M was most frequent (53%) in the clinically nonsignificant group (n = 407). Mothers in the clinically significant group were older, more often multigravidae, had more abortions and stillbirths, and had shorter gestational length. Newborns in the clinically significant group were less healthy, had lower weight and Apgar scores, and required more treatment. Among specificities in the clinically significant group, anti-D antibodies were most strongly associated with severe hemolysis. CONCLUSION: In this study, the prevalence of alloimmunization was similar to that in previous reports. Of all clinically significant antibodies, anti-D was most strongly associated with severe hemolysis, requiring phototherapy or exchange transfusions. Our data emphasize the importance of implementing an antenatal prophylactic RhIg program in Iceland in the near future. PMID- 28840610 TI - Soils and fire jointly determine vegetation structure in an African savanna. AB - Savanna vegetation is variable, and predicting how water, nutrients, and chronic disturbances interact to determine vegetation structure in savannas represents a challenge. Here, we examined in situ interactions among rainfall, soils, grasses, fire, and elephants that determine tree layer responses to resource gradients in Kruger National Park in South Africa, using 363 long-term monitoring sites throughout the park. Grass biomass increased with rainfall and on nutrient-rich clay soils. Fire frequency, too, increased with rainfall. Conversely, tree density was greater on sandier soils, where water infiltrates more readily, and in areas where the maximum interval between fires was longer, irrespective of average fire frequency. Elephant density responded positively to tree density, but did not contribute significantly to decreasing tree density. Savanna vegetation structure was reasonably predictable, via a combination of rainfall (favoring grasses), soil (sandy soils favoring trees), and fire (limiting trees until a longer interval between fires allows them to establish). Explicit consideration of bottom-up and top-down interactions may thus contribute to a predictive understanding of savanna vegetation heterogeneity. PMID- 28840611 TI - Prospective motion correction with NMR markers using only native sequence elements. AB - PURPOSE: To develop a method of tracking active NMR markers that requires no alterations of common imaging sequences and can be used for prospective motion correction (PMC) in brain MRI. METHODS: Localization of NMR markers is achieved by acquiring short signal snippets in rapid succession and evaluating them jointly. To spatially encode the markers, snippets are timed such that signal phase is accrued during sequence intervals with suitably diverse gradient actuation. For motion tracking and PMC in brain imaging, the markers are mounted on a lightweight headset. PMC is then demonstrated with high-resolution T2 *- and T1 -weighted imaging sequences in the presence of instructed as well as residual unintentional head motion. RESULTS: With both unaltered sequences, motion tracking was achieved with precisions on the order of 10 um and 0.01 degrees and temporal resolution of 48 and 39 ms, respectively. On this basis, PMC improved image quality significantly throughout. CONCLUSION: The proposed approach permits high-precision motion tracking and PMC with standard imaging sequences. It does so without altering sequence design and thus overcomes a key hindrance to routine motion tracking with NMR markers. Magn Reson Med 79:2046-2057, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28840612 TI - Simultaneous multi-slice MRI using cartesian and radial FLASH and regularized nonlinear inversion: SMS-NLINV. AB - PURPOSE: The development of a calibrationless parallel imaging method for accelerated simultaneous multi-slice (SMS) MRI based on Regularized Nonlinear Inversion (NLINV), evaluated using Cartesian and radial fast low-angle shot (FLASH). THEORY AND METHODS: NLINV is a parallel imaging method that jointly estimates image content and coil sensitivities using a Newton-type method with regularization. Here, NLINV is extended to SMS-NLINV for reconstruction and separation of all simultaneously acquired slices. The performance of the extended method is evaluated for different sampling schemes using phantom and in vivo experiments based on Cartesian and radial SMS-FLASH sequences. RESULTS: The basic algorithm was validated in Cartesian experiments by comparison with ESPIRiT. For Cartesian and radial sampling, improved results are demonstrated compared to single-slice experiments, and it is further shown that sampling schemes using complementary samples outperform schemes with the same samples in each partition. CONCLUSION: The extension of the NLINV algorithm for SMS data was implemented and successfully demonstrated in combination with a Cartesian and radial SMS-FLASH sequence. Magn Reson Med 79:2057-2066, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28840613 TI - Characterizing and eliminating errors in enhancement and subtraction artifacts in dynamic contrast-enhanced breast MRI: Chemical shift artifact of the third kind. AB - PURPOSE: To characterize errors in enhancement in breast dynamic contrast enhanced (DCE) MRI studies as a function of echo time and determine the source of dark band artifacts in clinical subtraction images. METHODS: Computer simulations, oil and water substitute (methylene chloride), as well as an American College of Radiology quality control phantom were tested. Routine clinical DCE breast MRI study was bracketed with (accelerated) in-phase DCE acquisitions in five patients. RESULTS: Simulation results demonstrated up to 160% suppression of the expected enhancement caused by differential enhancement of fat and water. Two-dimensional gradient-recalled echo and fat-suppressed 3D GRE phantom imaging confirmed the simulation results and showed that fat suppression does not eliminate the artifact. In vivo in-phase DCE images showed increased enhancement consistent with predictions and also confirmed increased spatial blurring on in-phase 3D gradient-recalled echo images. Combined multi dimensional partial Fourier and parallel imaging provided a time-equivalent in phase DCE MRI acquisition. CONCLUSION: Errors in expected enhancement occur in DCE breast MRI subtraction images because of differential enhancement of fat and water and incomplete fat signal suppression. These errors can lead to artificial suppression of enhancement as well as dark band artifacts on subtraction images. These artifacts can be eliminated with a time-equivalent in-phase fat-suppressed 3D gradient-recalled echo sequence. Understanding chemical shift artifact of the third kind, a unique artifact of artificial enhancement suppression in the presence of intravoxel fat and water signal, will aid DCE breast MRI image interpretation. In-phase acquisitions (combined with simultaneous minimum echo time or opposed-phase echoes) may facilitate qualitative, quantitative and longitudinal analysis of contrast enhancement. Magn Reson Med 79:2277-2289, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28840614 TI - Pharmacological Evaluation of Gut Modulatory and Bronchodilator Activities of Achyranthes aspera Linn. AB - Achyranthes aspera L. is traditionally used to relieve constipation, diarrhea, and asthma. Its crude extract (Aa.Cr) was evaluated through in vivo and ex vivo experiments to rationalize these medicinal uses of A. aspera and to provide their scientific basis. Aa.Cr, at 3 and 10 mg/kg, increased fecal output, similar to castor oil, whereas at 30, 100, 300, and 700 mg/kg, it protected against castor oil-induced diarrhea in mice when administered orally. Aa.Cr caused spasmogenic effect on rabbit jejunum and guinea pig ileum preparations, which was partially inhibited by atropine while completely blocked by cyproheptadine preincubation. Aa.Cr also relaxed high K+ (80 mM)-induced contraction in rabbit jejunum. Aa.Cr inhibited CCh (100 MUg/kg)-induced bronchospasm in rats, similar to aminophylline. Like dicyclomine, Aa.Cr relaxed high K+ and CCh (1 MUM)-induced contractions in guinea pig trachea and caused rightwards parallel shift of CCh concentration-response curves at the lower concentrations followed by non parallel shift at the higher concentrations. On activity-directed fractionation, spasmogenic and spasmolytic activities of Aa.Cr were concentrated in aqueous and organic fraction, respectively. This study suggests the presence of dose-specific laxative and antidiarrheal effects in A. aspera, possibly mediated through cyproheptadine-sensitive receptors and dual cholinergic and calcium channel blockade, respectively. The latter combination is also a suggested mechanism underlying its bronchodilator effect. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28840615 TI - The Effects of Curcumin and Curcumin-Phospholipid Complex on the Serum Pro oxidant-Antioxidant Balance in Subjects with Metabolic Syndrome. AB - Metabolic syndrome (MetS) is defined by a clustering of metabolic and anthropometric abnormalities and is associated by an increased risk of cardiovascular disease. We have investigated the effect of curcumin supplementation on the serum pro-oxidant-antioxidant balance (PAB) in patients with MetS. This double-blind, randomized, placebo-controlled trial was conducted over 6 weeks. Subjects (n = 120) were randomly allocated to one of three groups (curcumin, phospholipidated curcumin, and placebo). The curcumin group received 1 g/day of simple curcumin, the phospholipidated curcumin group received 1 g/day of phospholipidated curcumin (containing 200 mg of pure curcumin), and the control group received 1 g/day of placebo. Serum PAB was measured before and after the intervention (at baseline and at 6 weeks). Data analyses were performed using spss software (version 16.0). Serum PAB increased significantly in the curcumin group (p < 0.001), but in the phospholipidated curcumin group, elevation of PAB level was not significant (p = 0.053). The results of our study did not suggest any improvement of PAB following supplementation with curcumin in MetS subjects. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28840616 TI - Murraya paniculata (L.) (Orange Jasmine): Potential Nutraceuticals with Ameliorative Effect in Alloxan-Induced Diabetic Rats. AB - Orange jasmine, Murraya paniculata (Rutaceae), is a plant from India widely used in folk medicine as antinociceptive, antiinflammatory, and antioxidant. Although oral hypoglycemic agents and insulin are the mainstays of treatment of diabetes mellitus (DM), there is a significant demand for new natural products to reduce the development of diabetic complications. Alloxan-induced diabetic rats were treated for 60 days with a hydroalcoholic extract of M. paniculata (MPE), at doses of 100, 200, and 400 mg/kg. MPE decreased glycemia and also cholesterol and triglyceride levels, starting 1 week after treatments, as compared with the same group before treatments. Glucose values were reduced toward normality after 1 week of treatment. MPE hypoglycemic effects were potentiated by glibenclamide and metformin. MPE also decreased fructosamine and glycated hemoglobin values. MPE reduced diabetes-induced morphological alterations of the kidney, pancreas, and liver. MPE acts similarly to glibenclamide and metformin, and its glucose lowering action is partly a consequence of ATP-sensitive K+ channel inhibition. MPE may be a potential therapeutic alternative for the treatment of diabetes and its complications. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28840617 TI - Immunomodulatory Activity of the Glycoprotein Isolated from the Chinese Yam (Dioscorea opposita Thunb). AB - The yam (Dioscorea opposita Thunb) is a well-known edible food and widely used as the traditional Chinese medicine. The present investigation was designed to evaluate the immunomodulatory activity of glycoprotein (DOT) from yam and explore its possible molecular mechanisms. Results showed that the DOT could improve the cell immunity, humoral immunity and phagocytic system function of the normal mice. The DOT could also increase the production of TNF-alpha, interleukin-6 and nitric oxide and enhance the pinocytosis function of macrophages. Furthermore, the DOT increased phosphor-p38, JNK, ERK1/2 and nuclear factor kappa B (NF kappaB) p65 protein expression in peritoneal macrophages. Taken together, our data suggest that DOT could be used as a potential immunostimulant and exert its immunomodulatory activity via mitogen-activated protein kinases and NF-kappaB signal pathways. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28840618 TI - The Beneficial Effect of Anthocyanidin-Rich Vitis vinifera L. Grape Skin Extract on Metabolic Changes Induced by High-Fat Diet in Mice Involves Antiinflammatory and Antioxidant Actions. AB - We hypothesized that a polyphenol-rich extract from Vitis vinifera L. grape skin (GSE) may exert beneficial effects on obesity and related metabolic disorders induced by a high-fat diet (HFD). C57/BL6 mice were fed a standard diet (10% fat, control, and GSE groups) or an HFD (60% fat, high fat (HF), and HF + GSE) with or without GSE (200 mg/kg/day) for 12 weeks. GSE prevented weight gain; dyslipidemia; insulin resistance; the alterations in plasma levels of leptin, adiponectin, and resistin; and the deregulation of leptin and adiponectin expression in adipose tissue. These beneficial effects of GSE may be related to a positive modulation of insulin signaling proteins (IR, pIRS, PI3K, pAKT), pAMPK/AMPK ratio, and GLUT4 expression in muscle and adipose tissue. In addition, GSE prevented the oxidative damage, evidenced by the restoration of antioxidant activity and decrease of malondialdehyde and carbonyl levels in muscle and adipose tissue. Finally, GSE showed an anti-inflammatory action, evidenced by the reduced plasma and adipose tissue inflammatory markers (TNF-alpha, IL-6). Our results suggest that GSE prevented the obesity and related metabolic disorders in HF-fed mice by regulating insulin sensitivity and GLUT4 expression as well as by preventing the oxidative stress and inflammation in skeletal muscle and adipose tissue. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28840619 TI - Adding C-reactive protein and procalcitonin to the model of end-stage liver disease score improves mortality prediction in patients with complications of cirrhosis. AB - BACKGROUND AND AIM: This study aims to determine the performance of models adding C-reactive protein (CRP) and procalcitonin (PCT) to the model of end-stage liver disease (MELD) score for mortality prediction in patients hospitalized with complications of cirrhosis. METHODS: A prospective cohort study was carried out in consecutive cirrhotic patients admitted with complications of cirrhosis between September 2012 and December 2013 at Phramongkutklao Hospital, Bangkok, Thailand. All patients had venous CRP, PCT, and laboratory values for MELD score calculation measured at emergency room or admission. Cox regression analysis and the c-statistic were used to predict mortality. The MELD-CRP score was externally validated in 818 eligible patients from Mayo Clinic, Rochester, using data from 1288 cirrhotic patients diagnosed between 2010 and 2014. RESULTS: A cohort of 177 patients with cirrhosis was admitted during the study period. Seventy-one patients were eligible for analysis. The MELD score was predictive of 90-day mortality odds ratio (OR) 1.19 (95% confidence interval [CI] 1.09-1.32). Adding CRP and/or PCT to the MELD score improved the predictive of 90-day mortality: MELD-CRP OR 2.71 (95% CI 1.66-4.99); MELD-PCT OR 2.72 (95% CI 1.66-4.99); MELD CRP-PCT OR 2.71 (95% CI 1.67-4.92). The c-statistics for MELD, MELD-CRP, MELD PCT, and MELD-CRP-PCT were 0.81, 0.83, 0.84, and 0.85, respectively. Adding CRP and/or PCT to the MELD score also improved 30-day mortality prediction. Similar results for the MELD-CRP score were obtained from the Mayo Clinic external validation cohort. CONCLUSION: The MELD-CRP, MELD-PCT, and MELD-CRP-PCT scores may be superior to the MELD score alone in predicting mortality in patients hospitalized with complications of cirrhosis. PMID- 28840620 TI - Changing current practice in urological cancer care: Providing better information, advice and related support on work engagement. AB - There is a growing body of evidence on the importance of work following a diagnosis of cancer and the need to provide better information, advice and related support to patients on work engagement. The aim of this study was to better understand the nature of those needs and to identify better ways to meet these for those with a urological cancer. The focus was on the issues that were common to three key stakeholder groups. Semi-structured interviews were conducted with stakeholders in North East Scotland: 12 individuals with kidney, bladder or prostate cancer, 10 healthcare providers and 10 managers from large organisations. Five key themes emerged from the Framework Analysis: perceived importance of work engagement; decision-making: treatment, work and cancer; roles and responsibilities; education and training; information, advice and support resources. The data confirmed that work engagement is important to those with urological cancer. It also made clear that the current provision of information and advice could be improved. Any such interventions should involve all three key stakeholder groups with greater clarity on their respective roles and responsibilities. Finally, any new system would be best integrated with existing care provision and supported by adequate education and training of those involved. PMID- 28840621 TI - Controlling confounding by frailty when estimating influenza vaccine effectiveness using predictors of dependency in activities of daily living. AB - PURPOSE: To improve control of confounding by frailty when estimating the effect of influenza vaccination on all-cause mortality by controlling for a published set of claims-based predictors of dependency in activities of daily living (ADL). METHODS: Using Medicare claims data, a cohort of beneficiaries >65 years of age was followed from September 1, 2007, to April 12, 2008, with covariates assessed in the 6 months before follow-up. We estimated Cox proportional hazards models of all-cause mortality, with influenza vaccination as a time-varying exposure. We controlled for common demographics, comorbidities, and health care utilization variables and then added 20 ADL dependency predictors. To gauge residual confounding, we estimated pre-influenza season hazard ratios (HRs) between September 1, 2007 and January 5, 2008, which should be 1.0 in the absence of bias. RESULTS: A cohort of 2 235 140 beneficiaries was created, with a median follow-up of 224 days. Overall, 52% were vaccinated and 4% died during follow-up. During the pre-influenza season period, controlling for demographics, comorbidities, and health care use resulted in a HR of 0.66 (0.64, 0.67). Adding the ADL dependency predictors moved the HR to 0.68 (0.67, 0.70). Controlling for demographics and ADL dependency predictors alone resulted in a HR of 0.68 (0.66, 0.70). CONCLUSIONS: Results were consistent with those in the literature, with significant uncontrolled confounding after adjustment for demographics, comorbidities, and health care use. Adding ADL dependency predictors moved HRs slightly closer to the null. Of the comorbidities, health care use variables, and ADL dependency predictors, the last set reduced confounding most. However, substantial uncontrolled confounding remained. PMID- 28840622 TI - Propolis in the prevention of oral mucositis in breast cancer patients receiving adjuvant chemotherapy: A pilot randomised controlled trial. AB - Chemo-induced oral mucositis (OM) is associated with significant symptoms, treatment delays and increased costs. This pilot randomised controlled trial aimed at evaluating the safety, tolerability and compliance with propolis in breast cancer patients receiving doxorubicin and cyclophosphamide, testing preliminary clinical efficacy of propolis in the prevention of OM, and prospectively evaluating the incidence of OM. Sixty patients were randomised to receive either a dry extract of propolis with 8%-12% of galangin plus mouth rinsing with sodium bicarbonate (experimental arm), or mouth rinsing with sodium bicarbonate (control arm). OM was evaluated with the NCI-CTCAE v4.0 after 5, 10, 15 and 21 days of treatment. Compliance with, tolerability of propolis and adverse events were recorded. The incidence of OM was also prospectively evaluated for 6 months. Two patients (6.7%) manifested a suspected skin reaction to propolis. No patient in the experimental arm developed OM > G1, while in the control arm OM > G1 was 16.7% (p = .02). The incidence of OM >= G1 at the end of cycles 2-8 was higher at the second (25%) and fifth cycles (45.8%). Propolis plus bicarbonate was safe, well tolerated and promisingly effective in the prevention of OM in patients with breast cancer. PMID- 28840623 TI - Chemoselective Reduction of Phosphine Oxides by 1,3-Diphenyl-Disiloxane. AB - Reduction of phosphine oxides to the corresponding phosphines represents the most straightforward method to prepare these valuable reagents. However, existing methods to reduce phosphine oxides suffer from inadequate chemoselectivity due to the strength of the P=O bond and/or poor atom economy. Herein, we report the discovery of the most powerful chemoselective reductant for this transformation to date, 1,3-diphenyl-disiloxane (DPDS). Additive-free DPDS selectively reduces both secondary and tertiary phosphine oxides with retention of configuration even in the presence of aldehyde, nitro, ester, alpha,beta-unsaturated carbonyls, azocarboxylates, and cyano functional groups. Arrhenius analysis indicates that the activation barrier for reduction by DPDS is significantly lower than any previously calculated silane reduction system. Inclusion of a catalytic Bronsted acid further reduced the activation barrier and led to the first silane-mediated reduction of acyclic phosphine oxides at room temperature. PMID- 28840627 TI - Editorial. PMID- 28840624 TI - Chemical Composition and Antioxidant, Antinociceptive, and Anti-inflammatory Activities of Four Amazonian Byrsonima Species. AB - Species of the Byrsonima genus are widely used in Brazil, especially for the treatment of gastrointestinal disorders. However, species from the Amazonian region are still poorly studied. Thus, we studied the antioxidant, antinociceptive, and anti-inflammatory activities of for Amazonian species, Byrsonima crispa, Byrsonima duckeana, Byrsonima garcibarrigae, and Byrsonima incarnata. Phenolic composition was determined by chemical and chromatographic methods. The aqueous extracts were evaluated in DPPH* , ABTS+* , and superoxide (O2*- ) tests, LPS-activated macrophage assay, and formalin test. All species contained a high phenolic and flavonoid content. We identified 15 phenolic compounds, including phenolic acids, hydroxycinnamic acids, flavonoids, and catechins. The extracts showed high antioxidant activity and were more active than quercetin at inhibiting nitric oxide release in the LPS-activated macrophage assay. B. duckeana and B. garcibarrigae showed higher in vivo antinociceptive and anti-inflammatory activities. B. garcibarrigae presented significant effect on the early phase of the formalin test, pointing to an antinociceptive mechanism distinct from traditional anti-inflammatory medicines. In conclusion, the pharmacological potential of these species is closely related to their flavonoid rich chemical composition, which seems to act through antioxidant mechanisms. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28840628 TI - Survey shows that Swedish healthcare professionals have a positive attitude towards surrogacy but the health of the child is a concern. AB - AIM: In February 2016, Sweden upheld its ban on surrogacy following a Government enquiry. This survey investigated attitudes towards surrogacy among primary health professionals working with children and their experiences of working with families following surrogacy abroad. METHODS: From April to November 2016, nurses, physicians and psychologist working in primary child health care in four counties in Sweden were invited to participate in a cross-sectional online survey about surrogacy. RESULTS: The mean age of the 208 participants was 49.2 years (range 27-68) and nearly 91% were women. Approximately 60% supported legalised surrogacy. Wanting a conscience clause to be introduced in Sweden was associated with not supporting surrogacy for any groups, while personal experiences of infertility and clinical experiences with families following surrogacy were associated with positive attitudes towards surrogacy for heterosexual couples. The majority (64%) disagreed that surrogate children were as healthy as other children, and many believed that they risked worse mental health (21%) and social stigmatisation (21%). CONCLUSION: We found that 60% supported legalised surrogacy, but many expressed concerns about the children's health and greater knowledge about the medical and psychosocial consequences of surrogacy is needed. PMID- 28840629 TI - Extent and risks of antidepressant off-label use in children and adolescents in Germany between 2004 and 2011. AB - PURPOSE: So far, only little is known about antidepressant off-label use in pediatric patients. This is the first study examining the prevalence and the risks of off-label antidepressant prescriptions in minors over time in Germany and analyzing patterns regarding age, sex, drug class, and type of off-label use. METHODS: We used claims data of about two million individuals (<18 y) to calculate the share of off-label antidepressant prescriptions for the years 2004 to 2011, stratified by age, sex, and drug class. Off-label prescriptions were analyzed regarding underlying diagnoses, the prescribing doctor's specialty, and the type of off-label use. Incidence rates of adverse events were calculated for off- and on-label use, and the risk of suicidal events associated with off- or on label use was examined in a nested case-control study. RESULTS: The prevalence of off-label prescriptions decreased from 58.0% to 40.9%. Selective serotonin reuptake inhibitors were more frequently prescribed off-label than tricyclic antidepressants (37.7% vs 17.5% in 2011). The most common type of off-label use was off-label use by age, followed by off-label use by indication, and off-label use by contraindication. Adverse events were rare with no significant differences between on- and off-label use. CONCLUSIONS: Although off-label antidepressant use in minors decreased over time, it is still common. However, this rather indicates a lack of approved drugs for the treatment of depression in this population than inappropriate medical treatment. This is supported by the fact that off-label use was not associated with a higher risk of adverse events than on-label use. PMID- 28840630 TI - The Music Therapy Session Assessment Scale (MT-SAS): Validation of a new tool for music therapy process evaluation. AB - BACKGROUND: Music therapy (MT) interventions are aimed at creating and developing a relationship between patient and therapist. However, there is a lack of validated observational instruments to consistently evaluate the MT process. AIM: The purpose of this study was the validation of Music Therapy Session Assessment Scale (MT-SAS), designed to assess the relationship between therapist and patient during active MT sessions. METHODS: Videotapes of a single 30-min session per patient were considered. A pilot study on the videotapes of 10 patients was carried out to help refine the items, define the scoring system and improve inter rater reliability among the five raters. Then, a validation study on 100 patients with different clinical conditions was carried out. The Italian MT-SAS was used throughout the process, although we also provide an English translation. RESULTS: The final scale consisted of 7 binary items accounting for eye contact, countenance, and nonverbal and sound-music communication. In the pilot study, raters were found to share an acceptable level of agreement in their assessments. Explorative factorial analysis disclosed a single homogeneous factor including 6 items (thus supporting an ordinal total score), with only the item about eye contact being unrelated to the others. Moreover, the existence of 2 different archetypal profiles of attuned and disattuned behaviours was highlighted through multiple correspondence analysis. CONCLUSIONS: As suggested by the consistent results of 2 different analyses, MT-SAS is a reliable tool that globally evaluates sonorous-musical and nonverbal behaviours related to emotional attunement and empathetic relationship between patient and therapist during active MT sessions. PMID- 28840631 TI - Domiciliary non-invasive ventilation post lung transplantation. AB - BACKGROUND AND OBJECTIVE: The benefits of domiciliary non-invasive ventilation (NIV) post lung transplantation (LTx) have not previously been described. This was a single-centre retrospective audit of patients requiring domiciliary NIV post-LTx. Our aim was to describe indications for NIV and outcomes in chronic lung allograft dysfunction (CLAD) and diaphragmatic palsy. METHODS: All patients requiring domiciliary NIV post-LTx between 2010 and June 2016 were assessed. NIV indications, respiratory function and patient outcomes were collected. RESULTS: Out of 488 LTx recipients, 20 patients were identified as requiring NIV over the 6.5-year study period. The most common indications for NIV were CLAD and diaphragmatic palsy. Hypercapnia improved significantly with NIV. Patient outcomes were poor with nine (45%) patients dying, four (20%) undergoing redo LTx, four (20%) continuing domiciliary NIV and only three (15%) patients weaned off NIV. CONCLUSION: This is the first case series to describe the use of domiciliary NIV post-LTx. Patients commenced on NIV post-LTx had severely impaired lung function and severe hypercapnia. Patients with diaphragmatic palsy often recovered. The mortality rate was high in chronic allograft dysfunction. PMID- 28840632 TI - Energetic Barriers to Interfacial Charge Transfer and Ion Movement in Perovskite Solar Cells. AB - Highly efficient perovskite solar cells have been characterized by current density/voltage measurements in the dark at varied scan rates. The results were compared to the solar cells without a hole-transporting layer to investigate the role of ultrathin hole-transporting layers in solar-cell function. The parameters of internal voltage, diode ideality factor, capacitive current, and capacitance were calculated from the current-density/voltage response of the cells in the dark. The results show that the absence of the hole-transporting layer can cause a large recombination current within the depletion region at the gold contact/perovskite interface, and thus affects the cell performance. PMID- 28840633 TI - Platelet-rich plasma intra-articular injections for haemophilic synovitis: Scientific knowledge does not support its use. PMID- 28840634 TI - Influence of luteinizing hormone support on granulosa cells transcriptome in cattle. AB - In cows, the use of follicle-stimulating hormone (FSH) to stimulate follicular growth followed by a short period of FSH withdrawal has been shown to be beneficial for oocyte developmental competence. Although this treatment represents a useful optimization to generate highly competent oocytes, the underlying physiological process is not completely understood. The goal of this study was to investigate the role of luteinizing hormone (LH) action during FSH withdrawal before ovulation. To accomplish this, LH release was pharmacologically inhibited during the coasting period with gonadotropin-releasing hormone (GnRH) antagonists. Granulosa cells samples were obtained from cows stimulated with FSH during 3 days followed by a coasting period of 68 h and treated with a GnRH antagonist (cetrorelix group) or not (control). A significant reduction in the number of follicles at >10 mm diameter was observed with the cetrorelix group and gene expression of granulosa cells reveals that 747 transcripts are potentially regulated by LH. Further analysis indicates how the absence of LH may trigger early atresia, the upregulation of atretic agent as tumor protein P53 and transforming growth factor beta1 and the inhibition of growth support. This work allows identification of genes that are associated with maintained follicular growth and conversely the ones leading to atresia in dominant pre-ovulatory follicles. PMID- 28840635 TI - Adaptive phase I/II clinical trials for drug combination assessment in oncology using the outcomes of each cycle. AB - Many new anticancer agents can be combined with existing drugs, as combining a number of drugs may be expected to have a better therapeutic effect than monotherapy owing to synergistic effects. Furthermore, to drive drug development and to reduce the associated cost, there has been a growing tendency to combine these as phase I/II trials. With respect to phase I/II oncology trials for the assessment of dose combinations, in the existing methodologies in which efficacy based on tumor response and safety based on toxicity are modeled as binary outcomes, it is not possible to enroll and treat the next cohort of patients unless the best overall response has been determined in the current cohort. Thus, the trial duration might be potentially extended to an unacceptable degree. In this study, we proposed a method that randomizes the next cohort of patients in the phase II part to the dose combination based on the estimated response rate using all the available observed data upon determination of the overall response in the current cohort. We compared the proposed method to the existing method using simulation studies. These demonstrated that the percentage of optimal dose combinations selected in the proposed method is not less than that in the existing method and that the trial duration in the proposed method is shortened compared to that in the existing method. The proposed method meets both ethical and financial requirements, and we believe it has the potential to contribute to expedite drug development. PMID- 28840636 TI - An evaluation of a school-based dental sealant programme. AB - OBJECTIVES: To evaluate the effectiveness of Bengal Smiles, a school-based dental sealant programme and assess outcomes related to the U.S. Healthy People 2020 oral health objectives. METHODS: A needs assessment identified high caries prevalence in Idaho children and supported the need for a school-based dental sealant programme at a local Title 1 school. Children (n=54) ages 6-12 were screened by dental hygiene students for suspected dental caries, sealant placement and need for referral for dental treatment. Sealant retention and sealant caries rates were computed at 12 months (n=32) using descriptive statistics. Caries rates were analysed with a t test for paired samples, while a chi-square test was used to determine a difference in referral treatment rates before and after the intervention of administrative staff who contacted parents of children in need of dental treatment. RESULTS: Bengal Smiles participants had a 16% decrease in suspected dental caries; however, there was no statistically significant difference in caries rates (P=.21) at baseline and 12 months. Sealant prevalence increased 370%. Sealant retention outcomes were 74% fully retained with 0% caries, 13% partially retained with 25% caries and 13% no retention with 25% caries. At 12 months, 50% of participants referred for dental treatment accessed care. The intervention of contacting parents had no statistically significant effect on increasing dental treatments (P=.75). CONCLUSIONS: School based sealant programmes eliminate disparities in accessing oral health care and contribute to attaining U.S. Healthy People 2020 oral health objectives. PMID- 28840637 TI - Reduction in microalbuminuria by calcium channel blockers in patients with type 2 diabetes mellitus and hypertension-A randomized, open-label, active-controlled, superiority, parallel-group clinical trial. AB - BACKGROUND: It has been suggested that renoprotection with calcium channel blockers (CCBs) may differ. This study aimed to compare the anti-proteinuric effect of different CCBs in patients with type 2 diabetes (T2D). METHODS: A multicentre, randomized, open-label, active-controlled study was performed in seven centres in Korea. A total of 74 patients with T2D and microalbuminuria treated with renin-angiotensin system (RAS) blockers were randomized to a cilnidipine 10 mg treatment (n=38) or amlodipine 5 mg treatment (n=36). RESULTS: Urine albumin to creatinine ratio (ACR) reduction was similar between the two groups at 12 weeks (-53.0+/-123.2 mg/g in cilnidipine group and -35.7+/-83.6 mg/g in amlodipine group, P=.29) or 24 weeks (-57.3+/-106.9 mg/g in cilnidipine group and -20.0+/-110.4 mg/g in amlodipine group, P=.24). In a subgroup analysis, cilnidipine treatment showed a larger ACR reduction than amlodipine treatment at 12 weeks (-84.7+/-106.8 mg/g in cilnidipine group and -9.5+/-79.2 mg/g in amlodipine group, P=.01) and 24 weeks (-84.0+/-111.7 mg/g in cilnidipine group and 14.6+/-119.4 mg/g in amlodipine group, P=.008), particularly in patients with a longer duration of diabetes more than 10 years. CONCLUSIONS: Cilnidipine did not show any additional anti-albuminuric effect compared with amlodipine in patients with T2D and microalbuminuria treated with an RAS blocker. However, the anti-albuminuric effect of cilnidipine might differ according to the duration of diabetes. PMID- 28840638 TI - Combining walking and relaxation for stress reduction-A randomized cross-over trial in healthy adults. AB - Both physical activity and relaxation have stress-relieving potential. This study investigates their combined impact on the relaxation response while considering participants' initial stress level. In a randomized cross-over trial, 81 healthy adults completed 4 types of short-term interventions for stress reduction, each lasting for 1 hr: (1) physical activity (walking) combined with resting, (2) walking combined with balneotherapy, (3) combined resting and balneotherapy, and (4) resting only. Saliva cortisol, blood pressure, state of mood, and relaxation were measured preintervention and postintervention. Stress levels were determined by validated questionnaires. All interventions were associated with relaxation responses in the variables saliva cortisol, blood pressure, state of mood, and subjective relaxation. No significant differences were found regarding the reduction of salivary cortisol (F = 1.30; p = .281). The systolic blood pressure was reduced best when walking was combined with balneotherapy or resting (F = 7.34; p < .001). Participants with high stress levels (n = 25) felt more alert after interventions including balneotherapy, whereas they reported an increase of tiredness when walking was combined with resting (F = 3.20; p = .044). Results suggest that combining physical activity and relaxation (resting or balneotherapy) is an advantageous short-term strategy for stress reduction as systolic blood pressure is reduced best while similar levels of relaxation can be obtained. PMID- 28840639 TI - Use of oral antidiabetic drugs in the treatment of maturity-onset diabetes of the young: A mini review. AB - MODY (maturity-onset diabetes of the young) is a genetically linked group of clinically heterogeneous subtypes of diabetes. Roughly 5% of people with diabetes mellitus diagnosed prior to age 45 have MODY diabetes. Most of them have been erroneously diagnosed as patients with either type 1 or type 2 diabetes and, as a result, have been improperly treated. Genetic identification of MODY diabetes and its subtypes allows proper treatment and enables clinicians to switch many patients to oral antidiabetic agents, mainly sulphonylureas. However, some new classes of oral antidiabetic drugs have also been tested and found to be effective in MODY patients. We have searched for research articles and case reports written in full-text English or with an English abstract, using the following keywords: MODY and oral antidiabetic* in the databases Cochrane Library, PubMed, and Science Direct. Therapeutic options using currently standardized oral antidiabetic drugs (mainly sulphonylureas), as well as more experimental treatment with other classes of oral antidiabetic drugs in different types of MODY, are discussed, with special focus on the therapy of the most common MODY subtypes, including specific conditions such as pregnancy. This review article summarizes the currently available information about oral antidiabetic treatment of patients with MODY diabetes. PMID- 28840640 TI - De novo pathogenic variant in TUBB2A presenting with arthrogryposis multiplex congenita, brain abnormalities, and severe developmental delay. AB - Disorders of brain formation can occur from pathogenic variants in various alpha and beta tubulin genes. Heterozygous pathogenic variants in the beta tubulin isotype A gene, TUBB2A, have been recently implicated in brain malformations, seizures, and developmental delay. Limited information is known regarding the phenotypic spectrum associated with pathogenic variants in this gene given the rarity of the condition. We report the sixth individual with a de novo heterozygous TUBB2A pathogenic variant, who presented with a severe neurological phenotype along with unique features of arthrogryposis multiplex congenita, optic nerve hypoplasia, dysmorphic facial features, and vocal cord paralysis, thereby expanding the gene-related phenotype. PMID- 28840641 TI - Bacterial community analysis in upflow multilayer anaerobic reactor treating high solids organic wastes. AB - A novel anaerobic digestion configuration, the upflow multi-layer anaerobic reactor (UMAR), was developed to treat high-solids organic wastes. The UMAR was hypothesized to form multi-layer along depth due to the upflow plug flow; use of a recirculation system and a rotating distributor and baffles aimed to assist treating high-solids influent. The chemical oxygen demand (COD) removal efficiency and methane (CH4 ) production rate were 89% and 2.10 L CH4 /L/d, respectively, at the peak influent COD concentration (110.4 g/L) and organic loading rate (7.5 g COD/L/d). The 454 pyrosequencing results clearly indicated heterogeneous distribution of bacterial communities at different vertical locations (upper, middle, and bottom) of the UMAR. Firmicutes was the dominant (>70%) phylum at the middle and bottom parts, while Deltaproteobacteria and Chloroflexi were only found in the upper part. Potential functions of the bacteria were discussed to speculate on their roles in the anaerobic performance of the UMAR system. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1226-1234, 2017. PMID- 28840642 TI - The predictive value of early maladaptive schemas in paranoid responses to social stress. AB - BACKGROUND: Social stress and negatively valenced cognitive representations of the self (self-schemas) play an important role in the formation of delusions. However, it has not been investigated whether and which self-schemas explain paranoid responses to social stress. Building on the framework of schema theory, the aim of this study was thus to investigate whether more pronounced early maladaptive schemas (EMSs) were associated with increased paranoid ideation after a social stress induction in patients with persecutory delusions (PD). METHOD: Patients with PD (n = 20) and healthy controls (n = 40) were assessed for EMSs with the Young Schema Questionnaire. They were then exposed to a social stress situation in which they were socially excluded in a Cyberball paradigm. Prior to and after the social stress induction, paranoid symptoms were assessed. RESULTS: Patients with PD responded with a stronger increase in paranoia and revealed a significantly higher EMS total score compared to the healthy controls. As expected, higher increases in paranoia following the social stress were accounted for by higher EMS total scores. Exploratory analyses showed that particularly the specific EMSs Defectiveness/Shame and Enmeshment/Undeveloped Self were associated with the increase in paranoia. CONCLUSIONS: EMSs are associated with stress related symptom increases in patients with PD. It thus seems worthwhile to further investigate the relevance of specific schemas for paranoia. The findings also suggest that addressing EMSs in psychological treatment of patients with PD holds potential. PMID- 28840643 TI - Benzoate Anion-Intercalated Layered Cobalt Hydroxide Nanoarray: An Efficient Electrocatalyst for the Oxygen Evolution Reaction. AB - Efficient oxygen evolution reaction (OER) catalysts are highly desired to improve the overall efficiency of electrochemical water splitting. We develop a benzoate anion-intercalated layered cobalt hydroxide nanobelt array on nickel foam (benzoate-Co(OH)2 /NF) through a one-pot hydrothermal process. As a 3 D electrode, benzoate-Co(OH)2 /NF with an expanded interlayer spacing (14.72 A) drives a high OER catalytic current density of 50 mA cm-2 at an overpotential of 291 mV, outperforming its carbonate anion-intercalated counterpart with a lower interlayer spacing of 8.81 A (337 mV overpotential at 50 mA cm-2 ). Moreover, this benzoate-Co(OH)2 /NF can maintain its catalytic activity for 21 h. PMID- 28840645 TI - Temporally and spatially shaped meanings of at-homeness among people 85 years and over with severe illness. AB - AIMS AND OBJECTIVES: The aim of the study was to illuminate how meanings of at homeness are temporally and spatially shaped by older people with severe illness. BACKGROUND: At-homeness can be understood as a feeling of being metaphorically at home while experiencing well-being. The research field of at-homeness among older people with severe illness is under researched and knowledge about how at homeness is shaped by time and place is limited. METHOD: Narrative interviews were conducted in Sweden with a total of twenty men and women who were aged 85 years or over and affected by severe illness. The narrative interviews were analysed based on a phenomenological hermeneutical method. RESULTS: Meanings of at-homeness that were shaped temporally and spatially were interpreted, where time and place were shaped individually by other aspects and also interwoven. Two main inter-related themes were constructed: shaping at-homeness through relying on a familiar place and shaping at-homeness through continuous balancing between the past, present and future. CONCLUSION AND IMPLICATIONS: At-homeness is temporally and spatially shaped in two ways: through a process over time, or momentarily, where older people's earlier experiences and expectations are interwoven with their experiences of place and the people around them. The results of this study would be applicable to similar societal contexts. For future research, it is important to continue to study how at-homeness can be promoted for severely ill older people, in specific situations and over time. PMID- 28840644 TI - Telocytes play a key role in prostate tissue organisation during the gland morphogenesis. AB - Telocytes are CD34-positive interstitial cells, known to exert several functions, one of which is a role in tissue organisation, previously demonstrated by telocytes in the myocardium. The existence of telocytes in the prostate has recently been reported, however, there is a lack of information regarding the function of these cells in prostate tissue, and information regarding the possible role of these cells in prostatic development. This study used immunofluorescence techniques in prostate tissue and prostatic telocytes in culture to determine the relationship between telocytes and prostate morphogenesis. Furthermore, immunofluorescent labelling of telocytes was performed on prostate tissue at different stages of early postnatal development. Initially, CD34-positive cells are found at the periphery of the developing alveoli, later in the same region, c-kit-positive cells and cells positive for both factors are verified and CD34-positive cells were predominantly observed in the interalveolar stroma and the region surrounding the periductal smooth muscle. Fluorescence assays also demonstrated that telocytes secrete TGF-beta1 and are ER Beta (ERbeta) positive. The results suggest that telocytes play a changing role during development, initially supporting the differentiation of periductal and perialveolar smooth muscle, and later, producing dense networks that separate alveoli groups and form a barrier between the interalveolar region and periurethral smooth muscle. We conclude that telocytes play a relevant role in prostate tissue organisation during postnatal development. PMID- 28840646 TI - Performance of an allele-level multi-locus HLA genotype imputation tool in hematopoietic stem cell donors from Quebec. AB - INTRODUCTION: Donor-recipient HLA compatibility is an important determinant of transplant outcomes. Allele-group to allele-level imputations help assign HLA genotypes when allele-level genotypes are not available during donor selection. METHODS: We evaluated the performance of HaploStats, an allele-level multi-locus HLA genotype imputation tool from the National Marrow Donor Program, in a cross sectional study including hematopoietic stem cell donors (HSCD) from Quebec, Canada. A total of 144 self-identified Caucasian HSCD genotyped at the allele group and allele-level for HLA-A, -B, -C, -DRB1, and -DQB1 loci were studied. We compared allele-level genotypes imputed by HaploStats to those obtained by the reference standard, sequenced-based typing (SBT). RESULTS: Imputation performance, determined by allele-level genotype recall (fraction of matching imputed and sequenced genotypes) was 97%, 96%, 95%, 84%, and 81% for HLA-A, -B, C, -DRB1, and -DQB1 loci, respectively. Our sample deviated from Hardy-Weinberg equilibrium only at the HLA-DRB1 locus. Residual ambiguity, determined by typing resolution scores (TRS), was greatest for HLA class II loci (average TRS 0.65 and 0.80 for DRB1 and DQB1, respectively). In contrast, average TRS of 0.88, 0.84, and 0.92 was observed for HLA-A, -B, and -C, respectively. CONCLUSIONS: HLA allele imputation from ambiguous genotypes demonstrate satisfactory prediction accuracy for HLA class I but modest prediction accuracy for HLA class II loci in self-identified Caucasian HSCD from Quebec. While consideration of high resolution allele and haplotype frequencies in the Quebec population may improve the performance of available allele-level multi-locus genotype imputation tools in Quebec, this study suggests that genotyping at the first two field level should be conducted whenever possible. PMID- 28840647 TI - Incorporating Refractory Period in Mechanical Stimulation Mitigates Obesity Induced Adipose Tissue Dysfunction in Adult Mice. AB - OBJECTIVE: The aim of this study was to determine whether inclusion of a refractory period between bouts of low-magnitude mechanical stimulation (LMMS) can curb obesity-induced adipose tissue dysfunction and sequelae in adult mice. METHODS: A diet-induced obesity model that included a diet with 45% of kilocalories from fat was employed with intention to treat. C57BL/6J mice were weight matched into four groups: low-fat diet (LFD, n = 8), high-fat diet (HFD, n = 8), HFD with one bout of 30-minute LMMS (HFDv, n = 9), and HFD with two bouts of 15-minute LMMS with a 5-hour separation (refractory period, RHFDv, n = 9). Two weeks of diet was followed by 6 weeks of diet plus LMMS. RESULTS: HFD and HFDv mice continued gaining body weight and visceral adiposity throughout the experiment, which was mitigated in RHFDv mice. Compared with LFD mice, HFD and HFDv mice had increased rates of adipocyte hypertrophy, increased immune cell infiltration (B cells, T cells, and macrophages) into adipose tissue, increased adipose tissue inflammation (tumor necrosis factor alpha gene expression), and a decreased proportion of mesenchymal stem cells in adipose tissue, all of which were rescued in RHFDv mice. Glucose intolerance and insulin resistance were elevated in HFD and HFDv mice, but not in RHFDv mice, as compared with LFD mice. CONCLUSIONS: Incorporating a 5-hour refractory period between bouts of LMMS attenuates obesity-induced adipose tissue dysfunction and improves glucose metabolism. PMID- 28840648 TI - Iron-Catalyzed C-O Bond Activation: Opportunity for Sustainable Catalysis. AB - Oxygen-based electrophiles have emerged as some of the most valuable cross coupling partners in organic synthesis due to several major strategic and environmental benefits, such as abundance and potential to avoid toxic halide waste. In this context, iron-catalyzed C-O activation/cross-coupling holds particular promise to achieve sustainable catalytic protocols due to its natural abundance, inherent low toxicity, and excellent economic and ecological profile. Recently, tremendous progress has been achieved in the development of new methods for functional-group-tolerant iron-catalyzed cross-coupling reactions by selective C-O cleavage. These methods establish highly attractive alternatives to traditional cross-coupling reactions by using halides as electrophilic partners. In particular, new easily accessible oxygen-based electrophiles have emerged as substrates in iron-catalyzed cross-coupling reactions, which significantly broaden the scope of this catalysis platform. New mechanistic manifolds involving iron catalysis have been established; thus opening up vistas for the development of a wide range of unprecedented reactions. The synthetic potential of this sustainable mode of reactivity has been highlighted by the development of new strategies in the construction of complex motifs, including in target synthesis. The most recent advances in sustainable iron-catalyzed cross-coupling of C-O based electrophiles are reviewed, with a focus on both mechanistic aspects and synthetic utility. It should be noted that this catalytic manifold provides access to motifs that are often not easily available by other methods, such as the assembly of stereodefined dienes or C(sp2 )-C(sp3 ) cross-couplings, thus emphasizing the synthetic importance of this mode of reactivity. PMID- 28840649 TI - Yersiniabactin metal binding characterization and removal of nickel from industrial wastewater. AB - Yersiniabactin (Ybt) is a metal-binding natural product that has been re-purposed for water treatment. The early focus of this study was the characterization of metal binding breadth attributed to Ybt. Using LC-MS analysis of water samples exposed to aqueous and surface-localized Ybt, quantitative assessment of binding was completed with metals that included Pd2+ , Mg2+ , and Zn2+ . In total, Ybt showed affinity for 10 metals. Next, Ybt-modified XAD-16N resin (Ybt-XAD) was utilized to quantify the affinity for metal removal, showing a rank order of Fe3+ > Ga3+ > Ni2+ > Cu2+ > Cr2+ ~Zn2+ > Co2+ > Pd2+ > Mg2+ > Al3+ , and in the applied treatment of wastewater from a local precious metal plating company, showing selective removal of nickel from the aqueous effluent. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1548-1554, 2017. PMID- 28840650 TI - pH variations during diafiltration due to buffer nonidealities. AB - Diafiltration is used for final formulation of essentially all biotherapeutics. Several studies have demonstrated that buffer/excipient concentrations in the final diafiltered product can be different than that in the diafiltration buffer due to interactions between buffer species and the protein product. However, recent work in our lab has shown variations in solution pH that are largely independent of the protein concentration during the first few diavolumes. Our hypothesis is that these pH variations are due to nonidealities in the acid-base equilibrium coefficient. A model was developed for the diafiltration process accounting for the ionic strength dependence of the pKa . Experimental results obtained using phosphate and histidine buffers were in excellent agreement with model predictions. A decrease in ionic strength leads to an increase in the pKa for the phosphate buffer, causing a shift in the solution pH, even under conditions where the initial feed and the diafiltration buffer are at the same pH. This effect could be eliminated by matching the ionic strength of the feed and diafiltration buffer. The experimental data and model provide new insights into the factors controlling the pH profile during diafiltration processes. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1555-1560, 2017. PMID- 28840651 TI - Two Series of Homodinuclear Lanthanide Complexes: Greatly Enhancing Energy Barriers through Tuning Terminal Solvent Ligands in Dy2 Single-Molecule Magnets. AB - The utilization of 2-ethoxy-6-{[(2-hydroxy-3-methoxybenzyl)imino]methyl}phenol (H2 L) as a chelating ligand, in combination with the employment of alcohols (EtOH and MeOH) as auxiliary ligands, in 4 f-metal chemistry afforded two series of dinuclear lanthanide complexes of compositions [Ln2 L2 (NO3 )2 (EtOH)2 ] (Ln=Sm (1), Eu (2), Gd (3), Tb (4), Dy (5), Ho (6), Er (7)) and [Ln2 L2 (NO3 )2 (MeOH)2 ] (Ln=Sm (8), Eu (9), Gd (10), Tb (11), Dy (12), Ho (13), Er (14)). The structures of 1-14 were determined by single-crystal X-ray crystallography. Complexes 1-7 are isomorphous. The two lanthanide(III) ions in 1-7 are doubly bridged by two deprotonated aminophenoxide oxygen atoms of two MU2 :eta0 :eta1 :eta2 :eta1 :eta1 :eta0 -L2- ligands. One nitrogen atom, two oxygen atoms of the NO3- anion, two methoxide oxygen atoms of two ligand sets, and one oxygen atom of the terminally coordinated EtOH molecule complete the distorted dodecahedron geometry of each lanthanide(III) ion. Compounds 8-14 are isomorphous and their structures are similar to those of 1-7. The slight difference between 1-7 and 8 14 stems from purposefully replacing the EtOH ligands in 1-7 with MeOH in 8-14. Direct-current magnetic susceptibility studies in the 2-300 K range reveal weak antiferromagnetic interactions for 3, 4, 7, 10, 11, and 14, and ferromagnetic interactions at low temperature for 5, 6, 12, and 13. Complexes 5 and 12 exhibit single-molecule magnet (SMM) behavior with energy barriers of 131.3 K for 5 and 198.8 K for 12. The energy barrier is significantly enhanced by dexterously regulating the terminal ligands. To rationalize the observed difference in the magnetic behavior, complete-active-space self-consistent field (CASSCF) calculations were performed on two Dy2 complexes. Subtle variation in the angle between the magnetic axes and the vector connecting two dysprosium(III) ions results in a weaker influence on the tunneling gap of individual dysprosium(III) ions by the dipolar field in 12. This work proposes an efficient strategy for synthesizing Dy2 SMMs with high energy barriers. PMID- 28840652 TI - Computer-Assisted Design of Imidazolate-Based Ionic Liquids for Improving Sulfur Dioxide Capture, Carbon Dioxide Capture, and Sulfur Dioxide/Carbon Dioxide Selectivity. AB - A new strategy involving the computer-assisted design of substituted imidazolate based ionic liquids (ILs) through tuning the absorption enthalpy as well as the basicity of the ILs to improve SO2 capture, CO2 capture, and SO2 /CO2 selectivity was explored. The best substituted imidazolate-based ILs as absorbents for different applications were first predicted. During absorption, high SO2 capacities up to ~5.3 and 2.4 molSO2 molIL-1 could be achieved by ILs with the methylimidazolate anions under 1.0 and 0.1 bar (1 bar=0.1 MPa), respectively, through tuning multiple N???S interactions between SO2 and the N atoms in the imidazolate anion with different substituents. In addition, CO2 capture by the imidazolate-based ILs could also be easily tuned through changing the substituents of the ILs, and 4-bromoimidazolate IL showed a high CO2 capacity but a low absorption enthalpy. Furthermore, a high selectivity for SO2 /CO2 could be reached by IL with 4,5-dicyanoimidazolate anion owing to its high SO2 capacity but low CO2 capacity. The results put forward in this work are in good agreement with the predictions. Quantum-chemical calculations and FTIR and NMR spectroscopy analysis methods were used to discuss the SO2 and CO2 absorption mechanisms. PMID- 28840653 TI - Relationships Among Obesity, Type 2 Diabetes, and Plasma Cytokines in African American Women. AB - OBJECTIVE: The principal objective of this investigation was to identify novel cytokine associations with BMI and type 2 diabetes (T2D). METHODS: Cytokines were profiled from African American women with obesity who donated plasma to the Komen Tissue Bank. Multiplex bead arrays of analytes were used to quantify 88 cytokines and chemokines in association with clinical diagnoses of metabolic health. Regression models were generated after elimination of outliers. RESULTS: Among women with obesity, T2D was associated with breast adipocyte hypertrophy and with six plasma analytes, including four chemokines (chemokine [C-C motif] ligand 2, chemokine [C-C motif] ligand 16, chemokine [C-X-C motif] ligand 1, and chemokine [C-X-C motif] ligand 16) and two growth factors (interleukin 2 and epidermal growth factor). In addition, three analytes were associated with obesity independently of diabetes: interleukin 4, soluble CD40 ligand, and chemokine (C-C motif) ligand 3. CONCLUSIONS: Profiling of inflammatory cytokines combined with measures of BMI may produce a more personalized risk assessment for obesity associated disease in African American women. PMID- 28840654 TI - Isotope labeling to determine the dynamics of metabolic response in CHO cell perfusion bioreactors using MALDI-TOF-MS. AB - The steady-state operation of Chinese hamster ovary (CHO) cells in perfusion bioreactors requires the equilibration of reactor dynamics and cell metabolism. Accordingly, in this work we investigate the transient cellular response to changes in its environment and their interactions with the bioreactor hydrodynamics. This is done in a benchtop perfusion bioreactor using MALDI-TOF MS through isotope labeling of complex intracellular nucleotides (ATP, UTP) and nucleotide sugars (UDP-Hex, UDP-HexNAc). By switching to a 13 C6 glucose containing feed media during constant operation at 20 * 106 cells and a perfusion rate of 1 reactor volume per day, isotopic steady state was studied. A step change to the 13 C6 glucose medium in spin tubes allowed the determination of characteristic times for the intracellular turnover of unlabeled metabolites pools, tauST (<=0.56 days), which were confirmed in the bioreactor. On the other hand, it is shown that the reactor residence time tauR (1 day) and characteristic time for glucose uptake tauGlc (0.33 days), representative of the bioreactor dynamics, delayed the consumption of 13 C6 glucose in the bioreactor and thus the intracellular 13 C enrichment. The proposed experimental approach allowed the decoupling of bioreactor hydrodynamics and intrinsic dynamics of cell metabolism in response to a change in the cell culture environment. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1630-1639, 2017. PMID- 28840656 TI - Effect of zinc chloride and PEG concentrations on the critical flux during tangential flow microfiltration of BSA precipitates. AB - There is renewed interest in the possibility of using precipitation for initial capture of high value therapeutic proteins as part of an integrated continuous downstream process. These precipitates can be continuously washed using tangential flow filtration, with long term operation achieved by operating the membrane modules below the critical filtrate flux for fouling. Our hypothesis was that the critical flux for the precipitated protein would be a function of the properties of the precipitate as determined by the precipitation conditions. We evaluated the critical flux using a flux-stepping procedure for model protein precipitates (bovine serum albumin) generated using a combination of a crosslinking agent (zinc chloride) and an excluded volume precipitant (polyethylene glycol [PEG]). The critical flux varied with shear rate to approximately the 1/3 power, consistent with predictions of the classical polarization model. The critical flux increased significantly with increasing zinc chloride concentration, going from 60 L/m2 /h for a 2 mM ZnCl2 solution to 200 L/m2 /h for an 8 mM ZnCl2 solution. In contrast, the critical flux achieved a maximum value at an intermediate PEG concentration. Independent measurements of the effective size and viscosity of the protein precipitates were used to obtain additional understanding of the effects of ZnCl2 and PEG on the precipitation and the critical flux. These results provide important insights into the development of effective tangential flow filtration systems for processing large quantities of precipitated protein as would be required for large scale continuous protein purification by precipitation. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1561-1567, 2017. PMID- 28840655 TI - Low-birthweight infants born to short-stature mothers are at additional risk of stunting and poor growth velocity: Evidence from secondary data analyses. AB - Low-birthweight (LBW) infants are at an increased risk of stunting and poor linear growth. The risk might be additionally higher in these infants when born to short mothers. However, this hypothesis has been less explored. The objective of this secondary data analysis was to determine the risk of linear growth faltering and difference in linear growth velocity in LBW infants born to short mothers (<150 cm) compared to those born to mothers with height >=150 cm during the first year of life. This analysis uses data from a community-based randomized controlled trial of 2,052 hospital-born term infants with birthweight <=2,500g from urban low-middle socioeconomic neighbourhoods in Delhi, India. Data on maternal height and infant birth length were available from 1,858 (90.5%) of the infants. Infant anthropometry outcomes were measured at birth, 3, 6, 9, and 12 months of age. We found that infants born to short mothers had around twofold higher odds of stunting and lower attained length-for-age Z scores compared to infants of mothers with height >=150 cm, at all ages of assessment. Linear growth velocity was significantly lower in infants of short mothers particularly in the first 6 months of life. We conclude that LBW infants born to short mothers are at a higher risk of stunting and have slower postnatal growth velocity resulting in lower attained length-for-age Z scores in infancy. Evidence-based strategies need to be tested to optimize growth velocity in LBW infants especially those born to short mothers. PMID- 28840657 TI - A new type of gene-disruption cassette with a rescue gene for Pichia pastoris. AB - Pichia pastoris has been used for the production of many recombinant proteins, and many useful mutant strains have been created. However, the efficiency of mutant isolation by gene-targeting is usually low and the procedure is difficult for those inexperienced in yeast genetics. In order to overcome these issues, we developed a new gene-disruption system with a rescue gene using an inducible Cre/mutant-loxP system. With only short homology regions, the gene-disruption cassette of the system replaces its target-gene locus containing a mutation with a compensatory rescue gene. As the cassette contains the AOX1 promoter-driven Cre gene, when targeted strains are grown on media containing methanol, the DNA fragment, i.e., the marker, rescue and Cre genes, between the mutant-loxP sequences in the cassette is excised, leaving only the remaining mutant-loxP sequence in the genome, and consequently a target gene-disrupted mutant can be isolated. The system was initially validated on ADE2 gene disruption, where the disruption can easily be detected by color-change of the colonies. Then, the system was applied for knocking-out URA3 and OCH1 genes, reported to be difficult to accomplish by conventional gene-targeting methods. All three gene-disruption cassettes with their rescue genes replaced their target genes, and the Cre/mutant loxP system worked well to successfully isolate their knock-out mutants. This study identified a new gene-disruption system that could be used to effectively and strategically knock out genes of interest, especially whose deletion is detrimental to growth, without using special strains, e.g., deficient in nonhomologous end-joining, in P. pastoris. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1201-1208, 2017. PMID- 28840658 TI - Experimental design and metabolic flux analysis tools to optimize industrially relevant Haemophilus influenzae type b growth medium. AB - Haemophilus influenzae type b (Hib), a Gram-negative capsulated bacterium, is a causative agent of meningitis worldwide. The capsular polysaccharide, a high molecular mass polymer consisting of the repeated units of the polyribosyl ribitol-phosphate, is considered the main virulence factor and it is used as an antigen to vaccines, conjugated to a carrier protein. The industrial production of the polysaccharide requires the cultivation of Hib in rich medium, which impacts process costs and product recovery. In this study, a central composite rotational experimental design strategy was used to access the influence of key components of culture medium (soy peptone, yeast extract and glucose) on biomass formation and polysaccharide production in shake-flasks. The optimized medium formulation, containing half of the usual yeast extract and soytone concentrations, was further validated in batch bioreactor cultivations. High polysaccharide production (~500 mg/L) was obtained in a cheaper and more competitive production process for use in Hib vaccine production. In addition, simulations of a metabolic model describing Hib central metabolism were used to assess the role of key amino acids on growth. A chemically defined medium supplemented only with amino acids from alpha-ketoglutarate and oxaloacetate families as well as phenylalanine was suggested as a promising alternative for reduced acetate accumulation and enhanced polysaccharide production in Hib cultures. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1508-1519, 2017. PMID- 28840659 TI - Violence exposure and resulting psychological effects suffered by psychiatric visiting nurses in Japan. AB - : WHAT IS KNOWN ON THE SUBJECT?: There is a developing body of research on violence in healthcare workplaces. Although psychiatric visiting nurses (PVNs) are an important group of professionals who provide medical services for people with mental disorders live in the community, little is known about the experiences and characteristics of violence exposure among PVNs, or the characteristics and work situations of PVNs related to violence exposure. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE?: Approximately 40% of participants were exposed to violence during the previous 12 months; approximately 50% had been exposed during their PVN careers in PVN settings. The most frequent violence was verbal abuse. Longer career length as a PVN and greater number of visits per month were both positively associated with verbal abuse during the previous 12 months. Twenty-eight of the 34 participants (83%) who completed the IES-R-J survey had some residual psychological distress, and two (6%) had a potentially high risk of posttraumatic stress disorder. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: In devising policies and strategies against violence, PVN organizations and administrators should consider the characteristics of the violence, especially verbal abuse, as well as the characteristics and work situations of PVNs that are related to verbal abuse. Furthermore, they might provide relevant information on violence in PVN settings within their violence prevention manuals or education. It would be important to provide support and to construct a safe workplace environment for PVNs who are experiencing residual psychological distress. ABSTRACT: Introduction Psychiatric visiting nurses (PVNs) play a crucial role by providing medical services for community-living individuals with mental disorders in Japan. However, little is known about violence towards PVNs. Aim This cross-sectional study investigated violence during visits and the resulting psychological effects for PVNs. Methods PVNs were assessed using a violence exposure questionnaire and the Impact of Event Scale Revised (IES-R-J); a measure of posttraumatic distress. Result Thirty-eight (41%) of 94 participants had experienced violence during the previous 12 months and 49 (53%) over their entire career. The most frequent violence was verbal abuse. Career length as a PVN and number of visits per month were significantly positively associated with verbal abuse during the previous 12 months. The IES-R J scores indicated 28 of the 34 participants who completed the questionnaire exhibited psychological distress for the most traumatic violence during their career and two had a potentially high risk of posttraumatic stress disorder. Discussion and Implications Policies and strategies aimed at reducing violence in PVN settings should be developed according to characteristics of the violence, as well as the characteristics and work situation of PVNs. Furthermore, the provision of support and a safe workplace environment would be important for PVNs with residual psychological distress. PMID- 28840660 TI - Corrigendum. PMID- 28840662 TI - Competing risk analysis in a large cardiovascular clinical trial: An APEX substudy. AB - Competing risk methods are time-to-event analyses that account for fatal and/or nonfatal events that may potentially alter or prevent a subject from experiencing the primary endpoint. Competing risk methods may provide a more accurate and less biased estimate of the incidence of an outcome but are rarely applied in cardiology trials. APEX investigated the efficacy of extended-duration betrixaban versus standard-duration enoxaparin to prevent a composite of symptomatic deep vein thrombosis (proximal or distal), nonfatal pulmonary embolism, or venous thromboembolism (VTE)-related death in acute medically ill patients (n = 7513). The aim of the current analysis was to determine the efficacy of betrixaban vs standard-duration enoxaparin accounting for non-VTE-related deaths using the Fine and Gray method for competing risks. The proportion of non-VTE-related death was similar in both the betrixaban (133, 3.6%) and enoxaparin (136, 3.7%) arms, P = .85. Both the traditional Kaplan-Meier method and the Fine and Gray method accounting for non-VTE-related death as a competing risk showed equal reduction of VTE events when comparing betrixaban to enoxaparin (HR/SHR = 0.65, 95% 0.42 0.99, P = 0.046). Due to the similar proportion of non-VTE-related deaths in both treatment arms and the use of a univariate model, the Fine and Gray method provided identical results to the traditional Cox model. Using the Fine and Gray method in addition to the traditional Cox proportional hazards method can indicate whether the presence of a competing risk, which is dependent of the outcome, altered the risk estimate. PMID- 28840663 TI - Chromatin-associated noncoding RNAs in development and inheritance. AB - Noncoding RNAs (ncRNAs) have emerged as crucial players in chromatin regulation. Their diversity allows them to partake in the regulation of numerous cellular processes across species. During development, long and short ncRNAs act in conjunction with each other where long ncRNAs (lncRNAs) are best understood in establishing appropriate gene expression patterns, while short ncRNAs (sRNAs) are known to establish constitutive heterochromatin and suppress mobile elements. Additionally, increasing evidence demonstrates roles of sRNAs in several typically lncRNA-mediated processes such as dosage compensation, indicating a complex regulatory network of noncoding RNAs. Together, various ncRNAs establish many mitotically heritable epigenetic marks during development. Additionally, they participate in mechanisms that regulate maintenance of these epigenetic marks during the lifespan of the organism. Interestingly, some epigenetic traits are transmitted to the next generation(s) via paramutations or transgenerational inheritance mediated by sRNAs. In this review, we give an overview of the various functions and regulations of ncRNAs and the mechanisms they employ in the establishment and maintenance of epigenetic marks and multi-generational transmission of epigenetic traits. WIREs RNA 2017, 8:e1435. doi: 10.1002/wrna.1435 For further resources related to this article, please visit the WIREs website. PMID- 28840665 TI - Continuing Professional Development. PMID- 28840664 TI - Day one 'patch-off' visual loss due to retinal ischaemic injury: can we blame sub Tenon's or peribulbar anaesthesia? PMID- 28840666 TI - High yield process for the production of active human alpha-galactosidase a in CHO-K1 cells through lentivirus transgenesis. AB - Fabry disease is an X-linked recessive disorder caused by a deficiency in lysosomal alpha-Galactosidase A. Currently, two enzyme replacement therapies (ERT) are available. However, access to orphan drugs continues to be limited by their high price. Selection of adequate high-expression systems still constitutes a challenge for alleviating the cost of treatments. Several strategies have been implemented, with varying success, trying to optimize the production process of recombinant human alpha-Galactosidase A (rhalphaGAL) in Chinese hamster ovary (CHO-K1) cells. Herein, we describe for the first time the application of a strategy based on third-generation lentiviral particles (LP) transduction of suspension CHO-K1 cells to obtain high-producing rhalphaGAL clones (3.5 to 59.4 pg cell-1 d-1 ). After two purification steps, the active enzyme was recovered (2.4 * 106 U mg-1 ) with 98% purity and 60% overall yield. Michaelis-Menten analysis demonstrated that rhalphaGAL was capable of hydrolyzing the synthetic substrate 4MU-alpha-Gal at a comparable rate to Fabrazyme(r), the current CHO derived ERT available for Fabry disease. In addition, rhalphaGAL presented the same mannose-6-phosphate (M6P) content, about 40% higher acid sialic amount and 33% reduced content of the immunogenic type of sialic acid (Neu5Gc) than the corresponding ones for Fabrazyme(r). In comparison with other rhalphaGAL production processes reported to date, our approach achieves the highest rhalphaGAL productivity preserving adequate activity and glycosylation pattern. Even more, considering the improved glycosylation characteristics of rhalphaGAL, which might provide advantages regarding pharmacokinetics, our enzyme could be postulated as a promising alternative for therapeutic use in Fabry disease. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1334-1345, 2017. PMID- 28840667 TI - Corrigendum. PMID- 28840668 TI - Characterization of a low expression haplotype in canine glutathione S transferase (GSTT1) and its prevalence in golden retrievers. AB - Glutathione S-transferase-theta (GSTT1) is a carcinogen detoxification enzyme, and low activity variants are associated with lymphoma in humans. We recently found a variant in the 3' untranslated region (UTR) of canine GSTT1, *101_102insT, which was predicted to change miRNA binding and was found in 5 of 17 golden retriever (GR) dogs with lymphoma but none of 14 healthy GRs. The aim of this study was to determine whether this variant led to decreased GSTT1 expression and was a discernible risk factor for lymphoma within the GR breed. On resequencing, *101_102insT appeared to be in complete linkage disequilibrium with 3 additional 3'UTR variants, leading to the inferred haplotype *3T>C; *101_102insT; *190C>A; *203T>C. In canine livers that were heterozygous for this variant haplotype, GSTT1 protein expression was significantly lower compared to the reference haplotype (densitometry .40 vs .64, P = .022), and GSTT1 transcript levels by qPCR were also significantly lower (fold difference .52, P = .012), without evidence of substantial allelic expression imbalance. The variant haplotype led to >50% decrease in expression in vitro (.31 +/- .07 vs .64 +/- .19; P = .019). We found no significant difference in minor allele frequencies between 71 GR dogs with lymphoma (MAF .162) and 33 healthy age-matched controls (MAF .136, P = .69). Our results indicate that the variant GSTT1 3'UTR haplotype containing *101_102insT reduces gene expression, which could lead to impaired carcinogen detoxification, but was not a detectable risk factor for lymphoma in GR dogs. PMID- 28840669 TI - Role of Poor Urethral Sphincter Relaxation in Men with Voiding Dysfunction Refractory to alpha-blocker Therapy: Clinical Characteristics and Predictive Factors. AB - OBJECTIVES: This study evaluates the diagnostic value of poorly relaxed external sphincter (PRES) in men with voiding dysfunction. We analyzed clinical and video urodynamic characteristics to identify predictive factors of PRES in patients with lower urinary tract symptoms (LUTS) refractory to alpha-1 adrenoceptor blocker (alpha-blocker) therapy. METHODS: This retrospective study included 3379 men with LUTS in whom the initial 1-month alpha-blocker therapy failed. Clinical parameters and video-urodynamic results were analyzed. Patients with bladder outlet disorders including bladder neck obstruction (BNO), benign prostatic obstruction (BPO), urethral stricture (US), or PRES were categorized according to video-urodynamic findings. Predictive factors for PRES were analyzed. RESULTS: A total of 3379 men were included in this study. Among the patients with voiding dysfunction, 905 (43.6%) had BPO, 624 (30.0%) had BNO, 487 (23.4%) had PRES, and 62 (3.0%) had US. Patients with PRES were younger and had a higher maximum flow rate, larger bladder capacity, smaller total prostate volume (TPV) and transition zone index, and a lower rate of LUTS of urgency or urge urinary incontinence (UUI) than other groups. On multivariate analysis, only small TPV and lower urgency/UUI rate were predictive factors of PRES. A scale composed of voided volume, TPV, and urgency/UUI predicted PRES with high specificity. CONCLUSIONS: PRES was the etiology of voiding dysfunction in 23.4% of the men with LUTS refractory to alpha-blocker therapy. A simple scale composed of voiding volume, TPV, and urgency/UUI was useful in predicting the presence of PRES before video urodynamic studies. PMID- 28840670 TI - [Adult experience with the tibialis posterior transposition to the center of the foot in neuromuscular disease]. AB - : The transfer of the posterior tibial tendon to the center of the dorsum of the foot is a method used to achieve dorsiflexion in flaccid paralysis of the anterolateral leg muscles or muscular imbalance of clubfoot. OBJECTIVE: To describe functional results back to the surgical procedure for transposition of posterior tibial the center of the foot. MATERIAL AND METHODS: The study design was observational, descriptive, transversal, ambispective with a description of the world of work patients with impaired dorsiflexora foot muscles and impaired gait in the period January 2008 to December 2014. RESULTS: A total of 18 patients who were candidates for what this type of treatment was obtained. DISCUSSION: We believe that this study can be estimated as generating hypotheses about whether it is a superior alternative to arthrodesis. For this plan to continue studies in this field, with an increased number of assessments both before and after surgery to have more objective results and a greater number of individuals. PMID- 28840671 TI - [Treatment for Charcot arthropathy. Five-year follow-up]. AB - INTRODUCTION: Charcot arthropathy is a deformity which alters foot biomechanics and generate bichemical reactions that affect articular joints and bone. The natural history shown us a prevalence on 1% and is classified by Eichenholtz and Simmons modification in four stages; Sanders describe its location in 5 specific areas. MATERIAL AND METHODS: Our goal was to evaluate the specific method of treatment depending in the different stages of the deformity according to the literature review and to our proposed algoritm. RESULTS: A succesful treatment were based on alignment, bone healing and independent gait with regular shoes occurred in 85 % of our population. 15% were considered failures because of lack of consolidation, malalignment or use of gait aids and reactivation of the disease. CONCLUSIONS: There were no differences in the treatment regardless of the phase of the disease; it is more important the individualized treatment. PMID- 28840672 TI - [Minimal invasive osteosynthesis with cannulated screws in metacarpal fractures]. AB - : Metacarpal fractures comprise 18 to 44% of hand fractures. Fractures from the second to the fifth metacarpals are 88% of the metacarpal fractures and fractures of the fifth metacarpals are the most common. Fractures of the neck of the fifth metacarpal are about 20% of all the hand fractures. Most of these fractures can be treated conservatively with good functional results. However, for those neck and shaft unstable fractures that need surgical treatment, there is no gold standard for osteosynthesis. Recently, there have been reports of minimally invasive osteosynthesis using headless retrograde intramedullary cannulated screws with good functional results. MATERIAL AND METHODS: We report our short term experience treating nine fifth metacarpal neck fractures, one fourth metacarpal neck fracture and a transverse fifth metacarpal shaft fracture that did not fulfill criteria for conservative treatment. We treated them with minimally invasive osteosynthesis using retrograde intramedullary headless cannulated screws. RESULTS: All patients showed radiographic healing and had full range of motion of the metacarpophalangeal joint at one month follow up except for one patient who suffered a dorsal mutilating hand injury along with a fifth metacarpal neck fracture. One patient had osteoporotic bone and we could not control height loss with screws, so we had to use k-wires. CONCLUSION: Minimally invasive osteosynthesis with cannulated headless retrograde screws is a good option to treat neck and transverse diaphyseal fractures of the metacarpals. It confers a stable construct that allows early range of motion and return to activities. PMID- 28840673 TI - [Posterior corpectomy, transpedicular fixation and expandable cage placement in thoracolumbar fractures]. AB - OBJECTIVE: The objective is to evaluate the outcome of vertebral corpectomy and placement of an expandable cage in patients with thoracolumbar fractures, using a posterior-only approach. MATERIAL AND METHODS: A retrospective, case series study in the period from May 2011 to May 2014, in which eight patients with thoracolumbar burst fractures were treated surgically with corpectomy of fractured spinal body, placement of expandable box and fixation with transpedicular system, via posterior-only approach. Neurologic examination was done pre- and postoperatively with the ASIA score in a one year span. The angular deformity correction was also measured. RESULTS: The mean age was 38 years (24 to 58 years); five male and three female patients. All the patients had burst fracture, one of them with aggregate rotational component. Only one vertebral level was worked with corpectomy in all patients. Mean surgical time was 236 minutes (195-330 min). Mean surgical bleeding was 1,731 ml. CONCLUSION /DISCUSSION: Patients who underwent posterior approach corpectomy showed favorable clinical results. None presented neurological damage or surgical related injury. This technique can be a useful option to avoid complications related to anterior vertebral approach or double approach. PMID- 28840674 TI - [Case report: comprehensive treatment of forefoot with double brachymetatarsia in one surgical stage]. AB - Brachymetatarsia (shortening of the metatarsal) directly affects the transversal arch of the foot causing severe deformities, such as hallux valgus, divergent toes, overlapping toes, metatarsalgia, all of these alter the biomechanics of the foot and gait. Treatment consists of two main techniques, one-stage lengthening with bone graft or elongation through callotaxis with external fixator; there are variants of both techniques used to minimize the disadvantages of each. The objective of treatment must be to return the structural harmony to the forefoot, improving the biomechanics, resulting in a satisfactory outcome for the patients. This article presents a surgical treatment for feet with closed physis to obtain the appropriate metatarsal formula and to reestablish aesthetics and function. This case was treated by means of one-stage lengthening with bone graft to the affected metatarsal; shortening of the adjacent metatarsals; hallux valgus alignment through the necessary osteotomies and the treatment of deformities of the lesser toes as needed. This surgical technique has as one of its advantages the correction of the entire forefoot at one time, without the need of an external fixator and its required postoperative care. Its main disadvantages are its dependence on structural bone graft and the need of postoperative dressing until healing of the bone has taken place. Satisfactory clinical and radiographical outcomes were obtained in treated patient. PMID- 28840675 TI - Spontaneous rupture of the digital extensor tendons of the hand in unrecognized carpal lunatefracture. AB - Spontaneous rupture of the digital extensor tendons of the hand has been reported after Kienbocks disease, rheumatoid arthritis, Vaughan-Jackson syndrome, distal radial fracture. Rupture may also occur as a consequence of unrecognized carpal lunate fracture. We present a case report of a man affected with spontaneous rupture of the digital extensor tendons secondary to unrecognized carpal lunate fracture with partial dorsal dislocation. The edges of the tendon were debrided and sutured using a locked modified Kessler suture. A dynamic splinting cast was applied in moderate extension of the wrist. The aim of this case report is to highlight that in absence of a clear etiology for rupture of the extensor tendons of the hand, carpal lunate fracture, though rare, is an important cause of spontaneous extensor tendons rupture. PMID- 28840676 TI - [Lower glenohumeral recurrent luxation (luxatio erecta) arthroscopic treatment, literature review and case report]. AB - It is extremely important to take into account the complications of inferior gelnohumeral dislocation, which, although infrequent, may become incapacitating in the medium and long term, even in some cases reported, endangering the life of the same. Material and methods: We present the case of a young adult patient diagnosed with inferior rectal glenohumeral dislocation (luxatio erecta), with Bankart lesion and Hill Sachs lesion, treated by arthroscopy with repair of the Bankart lesion, plication of the lower capsular recess and remplissage. Results: We evaluated the functionality of the patient at 18 months with the UCLA scale, obtaining a final score of 30 points with good functional results. PMID- 28840677 TI - Microsurgical reconstruction in limb salvage due to a giant cell tumor of the distal radius. Case report. AB - The giant cell tumor of bone is one of the most controversial neoplasms due to growth patterns that may present. The case reported shows a very aggressive tumor in a classic location, but key to hand function. Rather than treat with radical surgery, was planned and performed a wide resection with an ulnar-carpus arthrodesis and microsurgical reconstruction of the defect throught an anterolateral thigh flap. The multidisciplinary approach of bone neoplasms produce a positive impact on patients. PMID- 28840678 TI - [Pathomechanism and treatment of gut microbiota dysbiosis in chronic kidney disease and interventional effects of Chinese herbal medicine]. AB - The gut microbiota dysbiosis is one of the risk factors in the progression from the advanced chronic kidney disease(CKD)to uremia, characterized by the reduction of probiotics and the increase of opportunistic pathogens including urease related microbes, endotoxin-related microbes and toxin-related microbes, which can produce uremic toxins. According to the core point of "the gut-kidney axis" theory and "the chronic kidney disease-colonic axis" concept, the gut microbiota dysbiosis aggravates renal damage by accumulating uremic toxins and inducing the systemic micro-inflammation. The preliminary clinical trials and animal experiments show that the probiotics biologicals from Lactobacillus acidophilus or Bifidobacterium, and the prebiotics including inulin and galactooligosaccharides, as well as lubiprostone and activated carbon adsorbents can be used for improving dysfunction of CKD patients with the gut microbiota dysbiosis via reducing uremic toxins and inhibiting the systemic micro inflammation. But not only that, it is reported that, to some extent, a number of the single Chinese herbal medicine(CHM), the CHM prescriptions and the CHM extracts(emodin, etc.)with oral or enema administration can also regulate the gut microbiota dysbiosis, protect the intestinal epithelial barrier, reduce uremic toxins accumulation and delay CKD progression. Thereinto, Dahuang Gancao Decoction(the concentrated granule TJ-84), a classical CHM prescription of rhubarb, can ameliorate uremic toxins accumulation in the animal models with renal failure probably through targeting the gut-kidney axis triggered from gut microbiota, but not targeting the kidney. Based on these results, the interventional studies targeting the gut microbiota-related pathological factors such as tight junction proteins, helper T cells and regulatory T cells in the intestinal tract of the advanced CKD patients will become one of the key development directions in the future. PMID- 28840679 TI - [Application of natural plant pigments in enlarged health industry]. AB - Natural plant pigment is rich in resources, with the features of natural color and environment friendly, which has a broad space for development and market prospects. In order to further develop and utilize of natural plant pigment, this paper mainly introduces the natural plant dyes in the domains of food, cosmetics and health care products on the historical development process and their application. In addition,this paper summarizes the application of representative natural plant pigment, dyes, and prospects the market of natural plant pigment, so as to provide reference for the development of natural plant pigment in the enlarged health industry of China. PMID- 28840680 TI - [Pharmacological effect and toxicology of Sophorae Tonkinensis Radix et Rhizoma]. AB - Sophorae Tonkinensis Radix et Rhizoma, which has been commonly used in clinic, shows activities in antitumor, antivirus, antibacteria, analgesia, anti inflammation, anti-liver injury, anti-oxidation and immune enhancement, but can cause liver toxicity, neurotoxicity, gastrointestinal toxicity and respiratory toxicity. Its pharmacological effect and toxicity are related to extraction process, dosage and administration time. Therefore, exploration of appropriate extraction process, toxicity-effect dosage range, toxic substance basis provides guarantee for attenuation and safe clinical medication. PMID- 28840681 TI - [Studies on effects of water temperature, stocking density and feeding cycle on growth and feeding in Hirudo nipponica]. AB - Effects of different water temperature, stocking density and feeding cycle on growth, feeding and survival of Hirudo nipponica have been studied, six temperature gradients were set: 18, 22, 26, 30, 34 and 38 C, five stocking density gradients were set: 30, 60, 120, 180 and 240 leech/L, four feeding cycle gradients were set: 2, 5, 10 and 20 d, respectively. The results showed that there exists a significant regression relationship between water temperature and specific growth rate: y=-0.016 5x2+0.836 9x-6.847 5(R2=0.990 8)(P<0.05), a regression analysis indicated that specific growth rate reached the maximum (3.76) at 25.36 C. When water temperature was beyond 30 C, the survival rate significantly decreased as water temperature increased (P<0.05). The specific growth rate and survival rate decreased as stocking density increased. A linear relationship exists between the feeding cycle and the SGR: y=-0.094 1x+3.832 9(R2=0.992 7). From this study, it can be concluded that the optimal water temperature and stocking density for the growth of H. nipponica is 22-26 C and 30 120 leech/L, respectively. PMID- 28840682 TI - [Effects of different substrates on low temperature fresh ginseng]. AB - The SOD and POD enzyme activities were detected, ginseng saponin content and protein concentration at 4 C preservation on fresh ginseng by different substrates were determined. The results showed that the appearance of the ginseng and the survival ability were good after six months by perlite preservation. It has lower SOD, POD enzyme activity and higher saponins and protein contention. It is the best fresh storing conditions for ginseng by using perlite at 4 C preservation. PMID- 28840683 TI - [Characterization of tissue expression of ginsenoside biosynthetic gene expression in Panax ginseng]. AB - The study is aimed to characterize the tissue expression of 10 key ginsenoside biosynthetic genes using bioinformatics method and real-time quantitative PCR. Heatmap and cluster analysis of 10 ginsenoside biosynthetic genes were performed in four-year-old Jilin ginseng. Using real-time quantitative PCR, the expression correlation of 10 key genes involved in ginsenoside biosynthesis was analyzed in different organs of four-year-old Jilin ginseng including, tissue culture seedling and adventitious root. Pearson correlation was used to analyze the relation between those 10 key genes involved in ginsenoside biosynthesis. The results showed that beta-AS and CYP716A52v2 were expressed highly in root of Jilin ginseng and ginseng culture seedling, which was consistent with Ro distribution. In addition, CYP716A53v2 and CYP716A47 which involved in dammarane type ginsenoside biosynthesis were positively correlated, which revealed that the difference of ginsenoside distribution was caused by transport system. PMID- 28840684 TI - [Transcriptome characterization for Scrophularia ningpoensis based on high throughput sequencing technology and related genes for synthesis of terpenoid compounds]. AB - To investigate the profile of gene function and search for SSR, a new technology of high-throughput Solexa/Illumina sequencing was used to generate the root transcriptome of Scrophularia ningpoensis, and 65 602 036 raw reads were obtained. Based on the bioinformatics analysis and Trinity, 73 983 unigenes were obtained with an average length of 823 bp. The comparison of sequence homology in database showed that 56 389 unigenes had different degrees of homology. A total of 520 metabolic pathways related genes and 191 relDODO transcription factors were identified by the Swiss-Prot, GO, KEGG and COG.The 11 659 SSRs were found by MISA and the highest frequency was AG/CT. In this study, we obtained numerous SSRs to provide references for the study of functional gene cloning and genetic diversity of S. ningpoensis. The key genes involved in the secondary metabolism are the basis for the study of biosynthesis and regulatory mechanism of the secondary metabolites. PMID- 28840685 TI - [Application of rapid PCR to authenticate Ranae Oviductus]. AB - Rapid allele-specific PCR primer was designed base on Cytb 155 A/T single nucleotide polymorphism, DNA was extracted by alkaline lysis and the PCR reaction systems including denatured and annealing temperature and cycle numbers were optimized. The results were performed to authenticate Ranae Oviductus and its 4 adulterants. When 100*SYBR Green I was added in the PCR product at 90 C denatured 3 s, 62 C annealing 20 s and 32 cycle. Ranae Oviductus visualized strong green fluorescence under 365 nm UV lamp whereas adulterants appeared negative. The whole process can be completed in 40 minutes.The established method provides the technical support for authentication of the Ranae Oviductus. PMID- 28840686 TI - [Preparation of isopsoralen loaded nanostructured carrier and its in vitro transdermal permeation characteristics]. AB - To increase the permeation and retention of isopsoralen in skin, and improve its bioavailability.Isopsoralen loaded nanostructure liquid carrier (IPRN-NLC) was prepared by high pressure homogenization andoptimized by orthogonal experiment with the encapsulation efficiency, drug loading and average particle size as the evaluation indexes. The in vitro transdermal permeation of IPRN-NLC was evaluated by Franze diffusion cells.The results showed that solid-liquid lipid ratio of optimum IPRN-NLC formulation was 7?3,drug-lipid ratio of 1?30, 1% surfactant. Under these conditions, IPRN-NLC had an average encapsulation of (90.25+/ 0.73)%,drug loading of (1.56+/-0.27)% and an average particle size of (305+/ 1.57) nm.The in vitro transdermal permeation results showed that IPRN-NLC could increase the amount of IPRN permeated though skin, with 3 times of the epidermal retention as compared with IPRN solution. From the results we can know that the IPRN-NLC prepared by high pressure homogenization can improve the permeation andaccumulation of IPRN in the skin, with wide application prospects in the field of transdermal administration. PMID- 28840687 TI - [Optimize dropping process of Ginkgo biloba dropping pills by using design space approach]. AB - In this paper, a design space approach was applied to optimize the dropping process of Ginkgo biloba dropping pills. Firstly, potential critical process parameters and potential process critical quality attributes were determined through literature research and pre-experiments. Secondly, experiments were carried out according to Box-Behnken design. Then the critical process parameters and critical quality attributes were determined based on the experimental results. Thirdly, second-order polynomial models were used to describe the quantitative relationships between critical process parameters and critical quality attributes. Finally, a probability-based design space was calculated and verified. The verification results showed that efficient production of Ginkgo biloba dropping pills can be guaranteed by operating within the design space parameters. The recommended operation ranges for the critical dropping process parameters of Ginkgo biloba dropping pills were as follows: dropping distance of 5.5-6.7 cm, and dropping speed of 59-60 drops per minute, providing a reference for industrial production of Ginkgo biloba dropping pills. PMID- 28840688 TI - [Molecular authentication of Jinyinhua formula granule by using allele-specific PCR]. AB - Traditional authentication method is hard to identify herb's authenticity of traditional Chinese medicine(TCM) formula granules because they have lost all their morphological characteristics. In this study, a new allele-specific PCR method was established for identifying the authentication of Jinyinhua formula granule (made from Lonicerae Japonicae Flos) based on an SNP site in trnL-trnF fragment. Genomic DNA was successfully extracted from Lonicerae Japonicae Flos and its formula granules by using an improved spin column method and then PCR was performed with the designed primer. Approximately 110 bp specific bands was obtained only in the authentic Lonicerae Japonicae Flos and its formula granules, while no bands were found in fake mixed products. In addition, the PCR product sequence was proved from Lonicerae Japonicae Flos trnL-trnF sequence by using BLAST method. Therefore, DNA molecular authentication method could make up the limitations of character identification method and microscopic identification, and quickly identify herb's authenticity of TCM formula granules, with enormous potential for market supervision and quality control. PMID- 28840689 TI - [Application of relative quality constant in grades evaluation of Glycyrrizae Radix et Rhizome pieces]. AB - Quality constant evaluation is a comprehensive method for grades evaluation of traditional Chinese medicine pieces, but when it comes to Glycyrrizae Radix et Rhizome pieces, grades evaluation is diverged due to significant difference in contents of liquiritin and glycyrrhizic acid and unreasonable weight of index. To solve this problem, we have established a relative quality constant method in this paper to evaluate grades of Glycyrrizae Radix et Rhizome pieces. Twenty-nine batches of different quality samples were collected and tested, and finally, 17 batches of them were chosen as researcher objects. The results revealed that the range of the relative quality constant of these samples was from 1.78 to 11.49. When Glycyrrizae Radix et Rhizome pieces are divided into three grades: the relative quality constant of first grade is greater than or equal to 9.19; the second grade is greater than or equal to 5.75 but less than 9.19; while the third grade is less than 5.75. This research indicates that relative quality constant can divide the grades of herbal pieces in a scientific, reasonable, objective and specific way and remedy the shortage of quality constant perfectly. It provides a novel mode for grading pieces of Chinese medicine that contains multi-target ingredients. PMID- 28840690 TI - [Pro-inflammatory mechanism of lectin from Pinellia pedatisecta on macrophage]. AB - To investigate the mechanism of lectin from Pinellia pedatisecta(PPL) on macrophage-induced inflammation and its association with inflammatory corpuscles NLRP3. Lectin from P. pedatisecta was isolated and purified by gel chromatography, and its purity was analyzed by using SDS-PAGE gel electrophoresis. ELISA was used to investigate the effect of PPL on inflammatory cytokines released by macrophages, with IL-1beta as indicators;and fluorescence probe DCFH-DA fluorometer was used to determine changes in active oxygen ROS of macrophages after application of lectin from P. pedatisecta.RAW264.7 cells were pre-treated with ROS inhibitor N-acetylcysteine (NAC) to investigate the effect on ROS and the release of inflammatory factor IL-1beta from macrophages to research the relationship between them. The protein levels of NLRP3, Caspase-1 p20, ASC and TXNIP were determined by Western blot.The results showed that isolated and purified PPL could reach electrophoretic purity; PPL stimulated macrophages and induced the excessive release of ROS, leading to strong oxidative stress reaction, and the levels of intracellular inflammatory factorsIL-1beta were significantly increased. NAC could inhibit PPL-induced ROS excessive production and significantly reduce the release of IL-1beta. In addition, PPL could induce the increase in protein expression levels of Caspase-1 p20, NLRP3 and ASC, and significantly reduce TXNIP expression. The results showed that PPL could cause a strong oxidative stress response by stimulating macrophages, activate inflammatory corpuscles NLRP3, and result in large amount of IL-1beta release. That is, PPL could lead to inflammatory cascade reaction by promoting the maturation and secretion of IL-1beta through ROS-TXNIP-NLRP3-IL-1beta signaling pathway. PMID- 28840691 TI - [A new oleanane-type triterpenoid glycoside from roots of Ilex asprella]. AB - A new delta-oleanane-type triterpenoid glycoside, 3-O-(3-O-sulfo)-beta-D glucopyranosiduronic acid 3beta-hydroxy-13(18)-oleanen- 28-oic acid 28-beta-D glucopyranosyl ester (1), along with ten known triterpenoid glycosides, rotundinoside A (2), oblonganoside M (3), 3-O-beta-D-glucopyranosyl-(1->2)-alpha L-arabinopyranosyl 3beta,19alpha-dihydroxy-20alpha- urs-12-en-28-oic acid 28-O beta-D- glucopyranosyl ester (4), ilexsaponin B2 (5), ilexside II (6), rotundinoside B (7), ilekudinoside B (8), ilexpublesnin E (9), ilekudinoside D (10) and ilexpernoside D (11), was isolated from the 75% ethanol extract of the roots of Ilex asprella by various chromatographic separation. Their structures were identified on the basis of MS, NMR spectroscopic analysis and chemical methods. In addition, 2-11 were isolated from I. asprella for the first time. PMID- 28840692 TI - [Studies on chemical constituents of Clinopodium chinense]. AB - Twenty-eight compounds were isolated and purified from Clinopodium chinense by Sephedax LH-20, ODS, MCI and preparative HPLC. Their structures were identified as apigenin (1), apigenin-7-O-beta-D-glucopyranoside (2), apigenin-7-O-beta-D glucuronopyranoside (3), thellungianol (4), apigenin-7-O-beta-D-rutinoside (5), luteolin (6), luteolin-4'-O-beta-D-glucopyranoside (7), apigenin-7-O-beta-D pyranglycuronate butyl ester (8), luteolin-7-O-beta-D-rutinoside (9), luteolin-7 O-beta-D-noehesperidoside (10), acacetin (11), acacetin-7-O-beta-D glucuronopyranoside (12), buddleoside (13), naringenin (14), pruning (15), nairutin (16), isosakuranetin (17), isosakuranin (18), didymin (19), hesperidin (20), kaempferol (21), quercetin (22), kaempferol-3-O-alpha-L-rahmnoside (23), p hydroxycinnamic acid (24), caffeic acid (25), cis-3-[2-[1-(3,4-dihydroxy-phenyl) 1 -hydroxymethyl]-1,3-ben-zodioxol-5-yl]-(E)-2-propenoic acid (26), mesaconic acid (27), gentisic acid 5-O-beta-D-(6'-salicylyl)-glucopyranoside (28). Among them, compounds 7, 9-10, 12, 23, 26-28 were isolated from the Clinopodium for the first time. The protective effects of compounds 1-6, 8-17 and 19 against H2O2 induced H9c2 cardiomyocyte injury were tested, compounds 15 exhibited significantly protective effects. Compared with the cell viability of (62.12+/ 6.18)% in the model, pruning exhibited viabilities of (84.25+/-7.36)% at 25.0 mg*L-1, respectively, using quercetin as a positive control [cell viability of (84.55+/-8.26)%, 20 mg*L-1]. PMID- 28840693 TI - [Structure-activity relationship of annonaceous acetogenins against multidrug resistant human hepatic carcinoma cell line SMMC-7721/ADR]. AB - The present research was launched to investigate the effects of 12 annonaceous acetogenins (ACGs) on human hepatic carcinoma cell line SMMC-7721/ADR, and to find out their structure-activity relationship. SMMC-7721/ADR cells were treated with 12 ACGs including annosquamin A(1),annosquamin B(2),annotemoyin 1(3),uvariamicin II(4),annosquacin D(5),annosquacin B(6),isodesacetyluvaricin(7),uvarigrandin A(8),squamostatin D(9),squamostatin E(10),squamostatin A(11),and 12,15-cis-squamostatin A(12) for 24 h, and the different expression of the target gene NDUFV2 were detected by quantitative real time PCR. All the tested compounds made the expression of the target gene NDUFV2 decreased on human hepatic carcinoma cell line SMMC-7721/ADR, of which the bistetrahydrofuran ACGs showed the best activity,which the non-adjacent bistetrahydrofuran ACGs displayed the worst activity.The ACGs with the reducing number of carbons between gamma-unsaturated lactone and the close tetrahydrofuran (THF) ring are more potent. For bistetrahydrofuran ACGs with the same nucleus skeleton,they would be more active as more hydroxyls on aliphatic chain, which for the non-adjacent bistetrahydrofuran ACGs with less hydroxyls on aliphatic chain that would be more active. ACGs with 3 hydroxyls on aliphatic chain would be more active. ACGs with threo configuration are more active than erythro configurotion, and the compounds with cis THF ring seem to be superior to those of trans THF ring. Furthermore, the ACGs with the reducing number of carbons between terminal methyl and the close tetrahydrofuran (THF) ring are more potent. PMID- 28840694 TI - [Development of Tianma HPLC fingerprint and discriminant analysis]. AB - Tianma(the tuber of Gastrodia eleta) is a widely used and pricy Chinese herb. Its counterfeits are often found in herbal markets, which are the plant materials with similar macroscopic characteristics of Tianma. Moreover, the prices of Winter Tianma(cultivated Tianma) and Spring Tianma(mostly wild Tianma) have significant difference. However, it is difficult to identify the true or false, good or bad quality of Tianma samples. Thus, a total of 48 Tianma samples with different characteristics(including Winter Tianma, Spring Tianma, slice, powder, etc.) and 9 plant species 10 samples of Tianma counterfeits were collected and analyzed by HPLC-DAD-MS techniques. After optimizing the procedure of sample preparation, chromatographic and mass-spectral conditions, the HPLC chromatograms of all those samples were collected and compared. The similarities and Fisher discriminant analysis were further conducted between the HPLC chromatograms of Tianma and counterfeit, Winter Tianma and Spring Tianma. The results showed the HPLC chromatograms of 48 Tianma samples were similar at the correlation coefficient more than 0.848(n=48). Their mean chromatogram was simulated and used as Tianma HPLC fingerprint. There were 11 common peaks on the HPLC chromatograms of Tianma, in which 6 main peaks were chosen as characteristic peaks and identified as gastrodin, p-hydroxybenzyl alcohol, parishin A, parishin B, parishin C, parishin E, respectively by comparison of the retention time, UV and MS data with those of standard chemical compounds. All the six chemical compounds are bioactive in Tianma. However, the HPLC chromatograms of the 10 counterfeit samples were significantly different from Tianma fingerprint. The correlation coefficients between HPLC fingerprints of Tianma with the HPLC chromatograms of counterfeits were less than 0.042 and the characteristic peaks were not observed on the HPLC chromatograms of these counterfeit samples. It indicated the true or false Tianma can be identified by either the similarity or characteristic peaks on HPLC fingerprint. Comparing the Winter Tianma with Spring Tianma showed that the HPLC chromatograms of 15 winter Tianma samples and 11 spring Tianma samples were similar at the mean correlation coefficient of 0.908. But the intensity of the characteristic peaks were different between the two groups of Tianma samples, i.e. the intensity of gastrodin, paishin A and C in winter Tianma was lower than those in spring Tianma. The Winter Tianma and Spring Tianma could be discriminated by either the Fisher unstandardized discrimination function or Linear discriminant function, based on the peak areas of 11 common peaks on HPLC chromatograms as variate. PMID- 28840695 TI - [Simultaneous determination of eight hydroxyl naphthoquinones in different parts of Arnebiae euchroma by HPLC]. AB - This present study is to develop an HPLC method for simultaneous determination of eight hydroxyl naphthoquinones, shikonin, beta-hydroxy-isovalerylshikonin, acetylshikonin, beta-acetoxy-isovalerylshikonin, deoxyshikonin, isobutyrylshikonin, beta,beta'-dimethylacrylshikonin and isovalerylshikonin. The eight constituents were measured on a Waters Xbridge C18 column (4.6 mm*250 mm,5 MUm) with isocratic elution of acetonitrile-0.05% formic acid solution (70?30) at a flow rate of 1.0 mL*min-1. The detection wavelength was 275 nm and the column temperature was 30 C. The results of content determination indicated that significant differences of the eight compounds exist in every part of Arnebia euchroma,in which the highest part was the root bark, followed with the root, then the stem residues. The content of the xylem of root and aerial part was lower than the above parts. The results provided scientific basis for the medicinal parts of A. euchroma. PMID- 28840696 TI - [Effects of Curcumae Rhizoma/vinegar-processed Curcumae Rhizoma on immune hepatic fibrosis, proliferation of HSC-T6 and expression of alpha-SMA and Procollagen I]. AB - To compare the effects of Curcumae Rhizoma/vinegar-processed Curcumae Rhizomaon immune hepatic fibrosis, proliferation of HSC-T6, and expressions of alpha-SMA and Procollagen I. The immunological liver fibrosis model was prepared through intraperitoneal injection with porcine serum 0.5 mL in each rat, twice a week, for 14 weeks. Expressions of serum ALT, AST, PC-III, IV-C, LN, HA and HYP, MDA in liver tissues were observed after administration of Curcumae Rhizoma/vinegar processed Curcumae Rhizoma (0.95, 1.90 g*kg-1). The pathological changes in liver tissues were observed by HE staining. Masson staining and Sirius red staining were used to observe the expression of collagen in rat liver. HSC-T6 was cultured, and the proliferation of HSC-T6 was determined by MTT assay at different concentrations in 12, 24, 36, 48 h. The expressions of alpha-SMA and Procollagen I were detected by Real-time PCR. The results showed that expressions of serum ALT, AST, PC-III, IV-C, LN and HA in Curcumae Rhizoma/vinegar-processed Curcumae Rhizoma groups (0.95, 1.90 g*kg-1) were significantly lower than model group; in terms of effect, vinegar-processed Curcumae Rhizoma group was superior to Curcumae Rhizoma group. Curcumae Rhizoma/vinegar-processed Curcumae Rhizoma containing serum could inhibit the proliferation of HSC-T6 in a dose-effect and time-effect manner. Expressions of alpha-SMA and Procollagen I in HSC-T6 were decreased after 24 h, especially in 20% vinegar-processed Curcumae Rhizoma containing serum group (P<0.01). Both Curcumae Rhizoma/vinegar-processed Curcumae Rhizoma could reduce immune hepatic fibrosis to varying extent. Their anti hepatic fibrosis mechanism may be correlated with inhibition of the proliferation of HSC-T6, and reduction of the formation of extracellular matrix and promotion of its degradation. PMID- 28840697 TI - [Effect of Psoralea corylifolia in treating fatty liver disease in juvenal mouse by inhibiting hepatic NF-kappaB activation]. AB - To investigate the mechanism and effect of Psoralea corylifolia(PC) in the treatment of NAFLD in juvenal mice. The NAFLD model in juvenal mice was established by feeding high-fat diet. Then PC herbal granules (at low and high dose) were administered for 5 weeks. Blood glucose (FBG, PG-1 h/2 h), blood lipid (TC, TG, HDL-C, LDL-C), fasting insulin, liver function (ALT, AST) were examined. HOMA-IR was calculated. Hepatic histological changes were observed. The content of TG, inflammatory factor (TNF-alpha, IL-8) and protein expressions of CD44, NF kappaB p65, p-NF-kappaB p65 in hepatic tissues were determined. The ratio of p-NF kappaB p65 to NF-kappaB p65 (p-p65/p65) was calculated. The result showed that compared with the model group, both PC treatment groups showed reduction in hepatic steatosis, inflammatory cell infiltration and fibroplasia in portal area. HOMA-IR, ALT, AST, FBG, PG-2 h, TC, TG, LDL-C concentrations and hepatic TG content were also significantly decreased, with the reduction of TNF-alpha, IL-8 contents, CD44 expression and p-p65/p65 ratio in hepatic tissues (P<0.01). High dose PC group had a better effect than low-dose group (P<0.01, P<0.05). In conclusion, PC is effective in treating hepatic injury, glucolipid metabolism disturbances and fibrosis in juvenal NAFLD mice. The mechanism may be related to inhibition of inflammation and down-regulation of the activation of hepatic NF kappaB. PMID- 28840698 TI - [Effect of ACai (Euterpe oleracea) on lipid metabolism, immune substances and endocrine hormone in rats with deficiency-heat and deficiency-cold syndrome]. AB - To study the effects of ACai(Euterpe oleracea) on lipid metabolism, immune substances and endocrine hormone level in rats with deficiency-heat and deficiency-cold syndrome. SD rats were divided into blank control group, deficiency-heat model group, deficiency-heat & Phellodendri Cortex group, deficiency-heat & ACai high dose and low dose groups, deficiency-cold model group, deficiency-cold & Cinnamomi Cortex group, deficiency-cold & ACai high dose and low dose groups. The rats received intramuscular injection of dexamethasone sodium phosphate (0.35 mg) or hydrocortisone sodium succinate (20 mg) for 21 days to set up deficiency-heat models and deficiency-cold models. Then the changes in fatmetabolism levels (FFA, LPL, HL) and immune indexes (IgG, IgM, C3 and C4) were detected by colorimeter; and the levels of endocrine hormone indexes (CORT, E2 and T) were detected by radioimmunoassay. The levels of FFA, LPL and HL in serum were reduced (P<0.01 or P<0.001); levels of IgG, IgM and C3 in serum were increased (P<0.05 or P<0.001); level of CORT in serum was increased (P<0.05) and the level of E2, E2/T in serum were reduced in the ACai high dose group (P<0.05). The effect of high dose ACai on fat metabolism was not obvious in deficiency-cold models, but the levels of IgG, IgM, C3 and CORT in serum were increased (P<0.05 or P<0.001). ACai was showed the same effect trend with Phellodendri Cortex in adjusting the levels of deficiency-heat rats; but unlike Cinnamomi Cortex, ACai was showed no obvious effect in adjusting the levels of deficiency-cold rats. In this experiment, homogeneous comparison and heterogeneous disproof were used to verify the cold nature of Cai. PMID- 28840699 TI - [Effect of Er-xian decoction on femur proteomics in ovariectomized osteoporosis rats]. AB - This experiment was mainly aimed to investigate the effect of Er-xian decoction on osteoporosis and the femur proteomics in ovariectomized rats with osteoporosis. The female SD rats were randomly divided into sham operation group, model group, Alendronate group (1 mg*kg-1), Er-xian decoction group (in dose of 8 g*kg-1) according to their weight. The rats in sham operation group and model group were gavaged with normal saline; the rats in Alendronate group were gavaged with the Alendronate at the dose of 1 mg*kg-1 and the rats in Er-xian decoction group were gavaged with Er-xian decoction at the dose of 8 g*kg-1, once a day for continuous 90 days. Then the femoral bone mineral density (BMD) was detected. The femoral bone proteins were detected by NanoLC-LTQ-Orbitrap system, identified by Protein Discovery software, and the intensity of differentially expressed proteins were quantitated by SIEVE software. The results showed that Er-xian decoction could significantly improve femoral BMD in ovariectomized rats. As compared with model group, 41 differentially expressed proteins whose variation trend was consistent with the sham operation group, were found in Er-xian decoction group, mainly including biological oxidation related protein, signal transduction pathway related protein, proteins involved in aliphatic acid metabolism, cytoskeleton related protein, proteins involved in energy metabolism, and proteins involved in glucose metabolism etc. The osteoporosis could be prevented and cured by Er-xian decoction. The differentially expressed proteins such as carbonic anhydrase 2 and integrin beta1 may be the action targets for Er xian decoction. PMID- 28840700 TI - [Pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia]. AB - To study the pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia. In this study, the hyperlipidemia model was established by intravenous injection of protocatechuic aldehyde (20 mg*kg-1) and hydroxysafflor yellow A (12 mg*kg-1). The HPLC-DAD method was applied to determine the plasma concentration of protocatechuic aldehyde and hydroxysafflor yellow A at different time points and draw the drug effect-time curve. Meanwhile, the platelet activating factors (PAF) and plasma a granule membrane protein (GMP-140) contents were determined at different time points to draw the time-effect curve. Then DAS 3.2.6 software was used to process the data, analyze their correlation, and compare the difference of pharmacokinetics and pharmacodynamics of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combined application, so as to evaluate the effect of protocatechuic aldehyde and hydroxysafflor yellow A on hyperlipidemia rats. According to the result, the pharmacokinetics and pharmacodynamics process of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combination were consistent to the three-compartment model. In model group, the plasma PAF and GMP-140 were significantly increased, and the PAF and GMP-140 in vivo contents were decreased in a certain time after treatment. The effects of protocatechuic aldehyde and hydroxysafflor yellow A against the pharmacodynamic action may be related with their level in vivo, and their plasma concentration was positively related to the PAF and GMP-140 contents. The pharmacodynamic indexes were better after the combined use of protocatechuic aldehyde and hydroxysafflor yellow A, with certain influence on each other in hyperlipidemia rats; at the same time, it also reflected the rationality of protocatechuic aldehyde and hydroxysafflor yellow A combined application. PMID- 28840701 TI - [Intestinal absorptive characteristics of ingredients from ethanol extracts of Gandou decoction by rat everted intestinal sac models]. AB - To study the intestinal absorptive characteristics of the ethanol extracts from Gandou decoction(GDD), everted intestinal sac models were used. The six representative ingredients (berberine hydrochloride, quercetin, kaempferide, rhein, chrysophanol, and aloe emodin) of GDD, were selected as the experimental targets to investigate the absorptive characteristics of various ingredients in different intestinal sections. The results showed that all six ingredients from GDD were detected in the intestinal sac, three active ingredients (berberine hydrochloride, quercetin, kaempferide) in high, medium and low doses had linear absorption properties in the small intestine segment, consistent with zero-order absorption rate; in addition, the absorption rate constant (Ka) of three components in jejunum and ileum were increased with the increase of the concentration of GDD (P<0.05), consistent with passive absorption. However, the Ka of rhein in jejunum and ileum showed little difference with the increase of dosage, suggesting a possibility of active transport mechanism. Chrysophanol and aloe-emodin were poorly absorbed in the two segments, which had not been detected in the previous time. The results suggested that the components of GDD were selectively absorbed in the intestinal sac, and the absorption characteristic of the ingredients were not exactly similar. PMID- 28840702 TI - [Effect of combination of gastrodia and uncaria on pharmacokinetics of gastrodin and rhynchophylline]. AB - To investigate the effect of the combination of gastrodia and uncaria on the pharmacokinetics of gastrodin and rhynchophylline, and determine their pharmacokinetic parameters after administration of the combination of gastrodia and uncaria at the ratio of 12?9. Compared with uncaria group or gastrodia group, Cmax and AUC of both gastrodin and rhynchophylline were significantly increased, and tmax was retroceded by 1.5 h for rhynchophylline and 0.25 h for gastrodin. The change of tmax resulted in a 1.25 h difference in the peak time between gastrodin and rhynchophylline , which was the same between them. Uncaria shows a more effect in suppressing hyperactive Yang, while gastrodia has a balancing effect by nourishing Yin and suppressing hyperactive Yang. As a result, gastrodia could exert the effect in nourishing Yin and suppressing effect of uncaria, which could avoid the deficiency of Yang affecting Yin due to mono-treatment of uncaria. On one hand, the enhanced AUC and Cmax of gastrodin could increase the average plasma drug concentration of gastrodin, and remedy the losing effect of uncaria at the early stage; On the other hand, the increased AUC and Cmax of rhynchophylline could make up the quick elimination of gastrodia in vivo at the late stage. Their combination could lead to an increased anti-hypertensive effect with the balance of Yin and Yang. They showed unique advantages compared with simple dosage increase of western medicines. The results were consistent with the principle of TCM treatment for the hypertension due to hyperactivity of the liver Yang. In short, this study gives a good pharmacokinetic explanation of the balance of Yin and Yang and TCM treatment for both symptoms and root cause. PMID- 28840703 TI - [Adjuvant effects of Zhenyuan capsule on chronic heart failure: Meta-analysis]. AB - To systematically review the adjuvant effects of Zhenyuan capsule on improving the cardiac function of patients with chronic heart failure. Databases including PubMed, EMbase, the Cochrane Library, CBM, CNKI, VIP and Wanfang Data were searched electronically from inception to October 2016 to collect randomized controlled trials (RCTs) about Zhenyuan capsule for adjuvant treatment of chronic heart failure. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, Meta-analysis was performed by using RevMan 5.3 software. A total of 14 RCTs involving 1 204 patients were included. The results of Meta-analysis showed that the Zhenyuan capsule group had significantly better effectiveness in cardiac function (RR=1.27, 95%CI 1.20 to 1.35, P < 0.000 01), stroke volume (WMD=7.62, 95%CI 6.39 to 8.84,P < 0.000 01), scores of HAMA (WMD=-4.16, 95%CI -5.59 to -2.72, P < 0.000 01), psychological effect of HAMA (RR=1.47, 95%CI 1.15 to 1.89, P=0.002), and traditional Chinese medical syndrome (RR=1.46, 95%CI 1.25 to 1.72, P < 0.000 01) than those of the control group, with statistically significant differences. Current evidence showed that Zhenyuan capsule combined with routine treatment could improve the cardiac function and quality of life of patients with chronic heart failure, and with high safety. Due to the limited quantity and quality of the included studies, the above conclusion still needs to be verified by carrying out more high-quality RCTs. PMID- 28840704 TI - [Meta-analysis on effectiveness and safety of traditional Chinese medicine combined with first-generation EGFR-TKI in treating advanced non-small cell lung cancer]. AB - To evaluate the efficacy and safety of traditional Chinese medicine combined with first-generation EGFR-TKI in treating advanced non-small cell lung cancer (NSCLC). China biomedical literature database (CBM), China Journal Full-text Database (CNKI), VIP, PubMed, CochraneLibrary, EMbase and other Chinese and English databases were searched for randomized and clinical controlled trials of traditional Chinese medicine combined with first-generation EGFR-TKI in treating advanced NSCLC. The statistical effect was measured by Revman 5.3.5 based on the outcome indexes of total response rate, disease control rate, quality of life, one-year survival rate, and adverse reactions/events. Meanwhile, a bias risk assessment was conducted by Stata12.0. A total of 17 studies were included, involving 1 391 cases, with 706 cases in the treatment group and 685 cases in the control group. The studies featured a low methodological quality, high homogeneity and low publication bias risk. The meta-analysis showed that total response rate [RR=1.33, 95%CI (1.17, 1.51)], disease control rate [RR=1.21, 95%CI (1.13, 1.29)], quality of life improvement rate [RR=1.28, 95%CI (1.17, 1.41)], one-year survival rate [RR=1.27, 95%CI (1.01, 1.61)], and other indexes of effectiveness of Chinese medicine combined with first-generation EGFR-TKI were all superior to those of first-generation EGFR-TKI alone, with significant differences (P<0.05). Meanwhile, the incidence of adverse reaction/events, such as the skin toxic response [RR=0.74,95%CI (0.63, 0.86)], gastrointestinal reaction [RR=0.54,95%CI (0.41, 0.71)], damage to hepatic function [RR=0.41, 95%CI (0.26, 0.67)] in Chinese medicine combined with first-generation EGFR-TKI group were lower than those in first-generation EGFR-TKI group, with significant differences (P<0.01). There was no publication bias according to Begg Rank correlation test. In short, traditional Chinese medicine combined with first generation EGFR-TKI had a better efficacy and safety in treating advanced NSCLC than EGFR-TKI alone. However, due to the small sample size and the low methodological quality of included papers, the conclusion still needs to be further proved by high-quality, large-sample randomized controlled trials. PMID- 28840705 TI - [Analysis of traditional Chinese medicine syndromes in 159 German migraine patients]. AB - Data mining method was adopted to collect 159 cases of German migraine patients who live in the TCM-Klinik Bad Kotzting Hospital from January 2013 to March 2015. The general case information was divided into age, gender, profession, characteristics of headache, degree of headache, accompanied symptoms and tongue pulse, and included in corresponding databases. Initial data was standardized and cleaned to get a data form suitable for analysis. SPSS system software was adopted to make a frequency statistics analysis for such variables as gender, age, profession, headache characteristic and accompanied symptoms. The results showed that German migraine cases feature a universality of age, long disease cycle and easy recurrence; And most of the patients were mental workers. There were two common clinical TCM symptoms, namely hyperactivity of liver Yang type and Qi deficiency & phlegm dampness. The common symptoms are forehead tingling, recurrent headache, vomiting and nausea, dark tongue, thin and white fur tongue, wiry pulse and slippery pulse. The disease is related to the pathology of stagnation of Qi, phlegm and blood stasis in liver, spleen, kidney and stomach. PMID- 28840706 TI - [Evolution and transition of source of Patrinia Herba and Patrinia Radix]. AB - Both Patrinia Herba and Patrinia Radix are traditional Chinese herbal medicines. The herbal source and medicinal part of them are confusing in the herbal medicine market of China. To explore the evolution and transition of the herbal source and medicinal part of Patrinia Herba and Patrinia Radix, this paper systematically summarizes the record of the herbal source and medicinal part of them in ancient classics of herbal medicine in China. According to the findings, before Ming Dynasty, Patrinia Herba originated from the radix of the plants with yellow flowers of Patrinia. In Ming and Qing Dynasty, Patrinia Herba originates from the whole plant (including the radix)of the plant with white flowers of Patrinia. In Ming Dynasty, Patrinia Radix, stemming from the radix of the plants with yellow flowers of Patrinia, started to be used as a traditional Chinese herbal medicine, which had the same herbal source with that of Patrinia Herba before Ming Dynasty. Therefore, Patrinia Herba and Patrinia Radix can be seen as the same traditional Chinese herbal medicine, and the genuine of Patrinia Herba should be the radix and the whole herba of P. scabiosaefolia and P. heterophylla. PMID- 28840707 TI - [Exploration and research on comprehensive evaluation model of Chinese patent medicines supply in national essential drugs]. AB - Chinese medicine prices often have sharp rise or fall, and even the impact of short-term price rise on the quality of feed can't be ignored.On the other hand, the production of traditional Chinese medicine is strictly subject to resource constraints, so much of the industrial production due to lack of or prohibited use of resources must bestopped. Based on 203 Chinese patent medicines in the National Essential Drugs (2012 Edition), the factors that influence the supply of essential drugs of traditional Chinese medicine were analyzed and seven indicators for the supply of essential medicines were designed in this paper. According to the Chinese herbal medicine resources survey and dynamic monitoring service system data, a multi-index comprehensive evaluation model based on radar chart analysis was proposed, providing a holistic and overall evaluation of the supply situation of essential drugs of traditional Chinese medicine. The evaluation results were concise, clear and intuitive. In this paper, Jiuwei Qianghuo Wan and Ganmao Qingre Keli were taken as the examples to prove that the proposed comprehensive evaluation method is concise, clear, intuitive, credible and practical. PMID- 28840708 TI - [Suggestions on improving administration of local crude drug quality standards]. AB - To improve the administration of local crude drug quality standard, the administration history, and current administration situation of local crude drugs were reviewed, the legal orientation and positive effect of local crude drugs were analyzed, and the existing problems were summarized. It was found that many problems existed in the administration of local crude drug quality standards, especially the phenomenon of homonym and synonym on their names. The suggestions on improving the administration of local crude drug quality standards were proposed. First of all, the construction of legal system should be strengthened to improve the administration methods. Secondly, the coordination mechanism should be developed to solve the outstanding problems. Thirdly, the basic research should be enhanced to resolve the general technical problems. Lastly, the channels to transfer the local crude drugs into pharmacopeia standards should be developed to achieve dynamic administration. PMID- 28840709 TI - [Research strategies and application of reference Dao-di herbs]. AB - Establishing evaluation system of Dao-di herbs has been a problem to be solved in the field of traditional Chinese medicine (TCM), and is also a difficult problem in restricting the realization of TCM quality. On the basis of national drug standard substance requirements, this paper puts forward to set up reference Dao di herbs in the first step of the evaluation system of Dao-di herbs, and discusses the properties, evaluation index system and its development requirements of reference Dao-di herbs, aiming at supporting the modern research and characteristics identification of Dao-di herbs in the future. PMID- 28840710 TI - Constructing Three-Dimensional Honeycombed Graphene/Silicon Skeletons for High Performance Li-Ion Batteries. AB - Silicon has been considered to be an attractive high-capacity anode material for next-generation lithium-ion batteries (LIBs). Currently, the commercial application of Si-based anodes is still restricted by its limited cycle life and rate capacity, which could be ascribed to the colossal volumetric change during the cycling process and poor electronic conductivity. We report the design of a unique Si-based nanocomposite of three-dimensional (3D) honeycombed graphene aerogel and the reduced graphene oxide sheets preprotected silicon secondary particles (SiNPs@rGO1). Through simple electrostatic self-assembly and hydrothermal processes, SiNPs are able to be wrapped with rGO1 to form reunited SiNPs@rGO1, and embedded into the backbone of 3D graphene honeycomb (rGO2). Such an intriguing design (namely, SiNPs@rGO1/rGO2) not only provides a conductive skeleton to improve the electrical conductivity, but also possesses abundant void spaces to accommodate the dramatic volume changes of SiNPs. Meanwhile, the outer rGO1 coats protect the inner SiNPs away from the electrolyte and prevent the destruction of the solid electrolyte interphase (SEI) film. As a result, the 3D honeycombed architecture achieves a high cyclability and excellent rate capability. PMID- 28840711 TI - Porous Stimuli-Responsive Self-Folding Electrospun Mats for 4D Biofabrication. AB - We report fabrication and characterization of electrospun, porous multi-layer scaffolds based-on thermo-responsive polymers polycaprolactone (PCL) and poly(N isopropylacrylamide). We found that the electrospun mats fold into various 3D structures in an aqueous environment at different temperatures. We could determine the mechanism behind different folding behaviors under different conditions by consideration of the properties of the individual polymers. At 37 degrees C in an aqueous environment, the scaffolds spontaneously rolled into tubular structures with PCL as the inner layer, making them suitable for cell encapsulation. We also demonstrated that the cell adhesion and viability could be improved by coating the polymers with collagen, showing the suitability of this scaffold for several tissue engineering applications. PMID- 28840712 TI - Organic-Inorganic Hybrid Interfacial Layer for High-Performance Planar Perovskite Solar Cells. AB - 4,7-Diphenyl-1,10-phenanthroline (Bphen) is an efficient electron transport and hole blocking material in organic photoelectric devices. Here, we report cesium carbonate (Cs2CO3) doped Bphen as cathode interfacial layer in CH3NH3PbI3-xClx based planar perovskite solar cells (PSCs). Investigation finds that introducing Cs2CO3 suppresses the crystallization of Bphen and benefits a smooth interface contact between the perovskite and electrode, resulting in the decrease in carrier recombination and the perovskite degradation. In addition, the matching energy level of Bphen film in the PSCs effectively blocks the holes diffusion to cathode. The resultant power conversion efficiency (PCE) achieves as high as 17.03% in comparison with 12.67% of reference device without doping. Besides, experiments also demonstrate the stability of PSCs have large improvement because the suppressed crystallization of Bphen by doping Cs2CO3 as a superior barrier layer blocks the Ag atom and surrounding moisture access to the vulnerable perovskite layer. PMID- 28840713 TI - Ultrasensitive Detection of Antiseptic Antibiotics in Aqueous Media and Human Urine Using Deep UV Resonance Raman Spectroscopy. AB - Deep UV resonance Raman spectroscopy is introduced as an analytical tool for ultrasensitive analysis of antibiotics used for empirical treatment of patients with sepsis and septic shock, that is, moxifloxacin, meropenem, and piperacillin in aqueous solution and human urine. By employing the resonant excitation wavelengths lambdaexc = 244 nm and lambdaexc = 257 nm, only a small sample volume and short acquisition times are needed. For a better characterization of the matrix urine, the main ingredients were investigated. The capability of detecting the antibiotics in clinically relevant concentrations in aqueous media (LODs: 13.0 +/- 1.4 MUM for moxifloxacin, 43.6 +/- 10.7 MUM for meropenem, and 7.1 +/- 0.6 MUM for piperacillin) and in urine (LODs: 36.6 +/- 11.0 MUM for moxifloxacin, and 114.8 +/- 3.1 MUM for piperacillin) points toward the potential of UV Raman spectroscopy as point-of-care method for therapeutic drug monitoring (TDM). This procedure enables physicians to achieve fast adequate dosing of antibiotics to improve the outcome of patients with sepsis. PMID- 28840714 TI - Thalassosamide, a Siderophore Discovered from the Marine-Derived Bacterium Thalassospira profundimaris. AB - Here we describe the rapid identification and prioritization of novel active marine natural products using an improved dereplication strategy. During the course of our screening of marine natural product libraries, a new cyclic trihydroxamate compound, thalassosamide, was discovered from the alpha proteobacterium Thalassospira profundimaris. Its structure was determined by 2D NMR and MS/MS experiments, and the absolute configuration of the lysine-derived units was established by Marfey's analysis, whereas that of C-9, 9', and 9" was determined via the circular dichroism data of the [Rh2(OCOCF3)4] complex and DFT NMR calculations. Thalassosamide showed moderate in vivo efficacy against Pseudomonas aeruginosa. PMID- 28840715 TI - Supramolecular Peptide Nanofiber Morphology Affects Mechanotransduction of Stem Cells. AB - Chirality and morphology are essential factors for protein function and interactions with other biomacromolecules. Extracellular matrix (ECM) proteins are also similar to other proteins in this sense; however, the complexity of the natural ECM makes it difficult to study these factors at the cellular level. The synthetic peptide nanomaterials harbor great promise in mimicking specific ECM molecules as model systems. In this work, we demonstrate that mechanosensory responses of stem cells are directly regulated by the chirality and morphology of ECM-mimetic peptide nanofibers with strictly controlled characteristics. Structural signals presented on l-amino acid containing cylindrical nanofibers (l VV) favored the formation of integrin beta1-based focal adhesion complexes, which increased the osteogenic potential of stem cells through the activation of nuclear YAP. On the other hand, twisted ribbon-like nanofibers (l-FF and d-FF) guided the cells into round shapes and decreased the formation of focal adhesion complexes, which resulted in the confinement of YAP proteins in the cytosol and a corresponding decrease in osteogenic potential. Interestingly, the d-form of twisted-ribbon like nanofibers (d-FF) increased the chondrogenic potential of stem cells more than their l-form (l-FF). Our results provide new insights into the importance and relevance of morphology and chirality of nanomaterials in their interactions with cells and reveal that precise control over the chemical and physical properties of nanostructures can affect stem cell fate even without the incorporation of specific epitopes. PMID- 28840716 TI - Supramolecular Self-Assembly in a Sub-micrometer Electrodic Cavity: Fabrication of Heat-Reversible pi-Gel Memristor. AB - The use of biomimetic approaches toward the production of nonsolid yet functional architectures holds potential for the emergence of novel device concepts. Gels, in particular those obtained via self-assembly of pi-conjugated molecules, are dynamic materials possessing unique (opto)electronic properties. Their adaptive nature imparts unprecedented responsivity to various stimuli. Hitherto, a viable device platform to electrically probe in situ a sol-gel transition is still lacking. Here we describe the fabrication of a sub-micrometer electrodic cavity, which enables low-voltage electrical operation of pi-gels. Thanks to the in situ supramolecular self-assembly of the pi-gelator occurring within the cavity, we conceived a novel gel-based memristor whose sol-gel transition is reversible and can be controlled via heating and dc bias. This work opens perspectives toward the fabrication of a novel generation of nonsolid multiresponsive devices. PMID- 28840717 TI - Photonic Shape Memory Polymer with Stable Multiple Colors. AB - A photonic shape memory polymer film that shows large color response (~155 nm) in a wide temperature range has been fabricated from a semi-interpenetrating network of a cholesteric polymer and poly(benzyl acrylate). The large color response is achieved by mechanical embossing of the photonic film above its broad glass transition temperature. The embossed film, as it recovers to its original shape on heating through the broad thermal transition, exhibits multiple structural colors ranging from blue to orange. The relaxation behavior of the embossed film can be fully described using a Kelvin-Voigt model, which reveals that the influence of temperature on the generation of colors is much stronger than that of time, thereby producing stable multiple colors. PMID- 28840718 TI - Detection and Quantification of Biologically Active Botulinum Neurotoxin Serotypes A and B Using a Forster Resonance Energy Transfer-Based Quantum Dot Nanobiosensor. AB - Botulinum neurotoxin (BoNT) is the most potent toxin known. The ingestion of food contaminated with biologically active BoNT causes foodborne botulism, which can lead to respiratory paralysis, coma, and death after ingestion of as little as 70 MUg for a 70 kg human. Because of its lethality and challenges associated with current detection methods, there is an urgent need for highly sensitive rapid screening techniques capable of detecting biologically active BoNT. Here, we describe a Forster resonance energy transfer-based nanobiosensor that uses quantum dots (QDs) and two specific quencher-labeled peptide probes to detect and differentiate two biologically active forms of BoNT, serotypes A and B, which were responsible for 80% of human foodborne botulism cases in the U.S. from 2012 to 2015. Each peptide probe contains an enzymatic cleavage site specific to only one serotype. QDs were selected based on the spectral overlap with the quenchers. In the presence of the target BoNT serotype, the peptide probe is cleaved and the quenching of QD photoluminescence (PL) is reduced, giving a signal that is easily detected by a PL spectrophotometer. This sensor performance was evaluated with light chains of BoNT/A and BoNT/B (LcA and LcB), catalytic domains of the respective serotypes. LcA and LcB were detected in 3 h with limits of detection of 0.2 and 2 ng/mL, respectively. The specificity of the sensor was evaluated, and no cross-reactivity from nontarget serotypes was observed with 2 h of incubation. Because each serotype-specific peptide is conjugated to a QD with a unique emission wavelength, multiple biologically active BoNT serotypes could be detected in one PL spectrum. The sensor was also shown to be responsive to BoNT/A and BoNT/B holotoxins. Good performance of this sensor implies its potential application as a rapid screening method for biologically active BoNT/A and BoNT/B in the laboratory and in the field. PMID- 28840719 TI - Iso-Oriented NaTi2(PO4)3 Mesocrystals as Anode Material for High-Energy and Long Durability Sodium-Ion Capacitor. AB - Sodium-ion capacitors (SIC) combine the merits of both high-energy batteries and high-power electrochemical capacitors as well as the low cost and high safety. However, they are also known to suffer from the severe deficiency of suitable electrode materials with high initial Coulombic efficiency (ICE) and kinetic balance between both electrodes. Herein, we report a facile solvothermal synthesis of NaTi2(PO4)3 nanocages constructed by iso-oriented tiny nanocrystals with a mesoporous architecture. It is notable that the NaTi2(PO4)3 mesocrystals exhibit a large ICE of 94%, outstanding rate capability (98 mA h g-1 at 10 C), and long cycling life (over 77% capacity retention after 10 000 cycles) in half cells, all of which are in favor to be utilized into a full cell. When assembled with commercial activated carbon to an SIC, the system delivers an energy density of 56 Wh kg-1 at a power density of 39 W kg-1. Even at a high current rate of 5 A g-1 (corresponds to finish a full charge/discharge process in 2 min), the SIC still works well after 20 000 cycles without obvious capacity degradation. With the merits of impressive energy/power densities and longevity, the obtained hybrid capacitor should be a promising device for highly efficient energy storage systems. PMID- 28840720 TI - Ultralight, Thermally Insulating, Compressible Polyimide Fiber Assembled Sponges. AB - Tunable density, thermally and mechanically stable, elastic, and thermally insulating sponges are required for demanding applications. Hierarchically structured sponges with bimodal interconnected pores, porosity more than 99%, and tunable densities (between 7.6 and 10.1 mg/cm3) are reported using polyimide (PI) as high temperature stable polymer. The sponges are made by freeze-drying a dispersion of short PI fibers and precursor polymer, poly(amic acid) (PAA). The concept of "self-gluing" the fibrous network skeleton of PI during sponge formation was applied to achieve mechanical stability without sacrificing the thermal properties. The sponges showed initial degradation above 400 and 500 degrees C in air and nitrogen, respectively. They have low thermal conductivity of 0.026 W/mK and thermal diffusivity of 1.009 mm2/s for a density of 10.1 mg/cm3. The sponges are compressible for at least 10 000 cycles and good thermal insulators even at high compressions. These fibrous PI sponges are promising candidates for potential applications in thermal insulation, lightweight construction, high-temperature filtration, sensors, and catalyst carrier for high temperature reactions. PMID- 28840721 TI - Individual Au-Nanocube Based Plasmonic Nanoprobe for Cancer Relevant MicroRNA Biomarker Detection. AB - MicroRNA205 (miR-205), as a significant tumor biomarker, is of vital importance for diagnosis of lung cancer and its overexpression patterns have been extensively studied. Here, we report a novel and label-free nanoprobe with high sensitivity and selectivity for miRNA biomarker detection using localized surface plasmon resonance (LSPR) technology on a single DNA modified gold nanocube (AuNC). This method allowed real-time monitoring of the subtle LSPR scattering peak position's change which was aroused by the variation of dielectric constant in the hybridization process of target miRNA with ssDNA modified on the surface of AuNCs. Notably, the limit of detection of the AuNC-ssDNA probe is up to 5 pM in serum sample, and these results showed that the square structure has more superior sensitivity for design and development of nanoprobe for trace lung cancer relevant miRNAs detection. The better sensing ability and stability of LSPR probe on a AuNC provide potential application to developing a high flux biochip in the future. PMID- 28840722 TI - Multivariate Curve Resolution for Signal Isolation from Fast-Scan Cyclic Voltammetric Data. AB - The use of multivariate analysis techniques, such as principal component analysis inverse least-squares (PCA-ILS), has become standard for signal isolation from in vivo fast-scan cyclic voltammetric (FSCV) data due to its superior noise removal and interferent-detection capabilities. However, the requirement of collecting separate training data for PCA-ILS model construction increases experimental complexity and, as such, has been the source of recent controversy. Here, we explore an alternative method, multivariate curve resolution-alternating least squares (MCR-ALS), to circumvent this issue while retaining the advantages of multivariate analysis. As compared to PCA-ILS, which relies on explicit user definition of component number and profiles, MCR-ALS relies on the unique temporal signatures of individual chemical components for analyte-profile determination. However, due to increased model freedom, proper deployment of MCR ALS requires careful consideration of the model parameters and the imposition of constraints on possible model solutions. As such, approaches to achieve meaningful MCR-ALS models are characterized. It is shown, through use of previously reported techniques, that MCR-ALS can produce similar results to PCA ILS and may serve as a useful supplement or replacement to PCA-ILS for signal isolation from FSCV data. PMID- 28840723 TI - Fluorenyl Based Macrocyclic Polyradicaloids. AB - Synthesis of stable open-shell polyradicaloids including control of intramolecular spin-spin interactions is a challenging topic in organic chemistry and materials science. Herein, we report the synthesis and physical characterization of two series of fluorenyl based macrocyclic polyradicaloids. In one series (FR-MCn, n = 4-6), the fluorenyl radicals are directly linked at 3,6 positions; whereas in the other series (MC-FnAn, n = 3-5), an additional ethynylene moiety is inserted between the neighboring fluorenyl units. To access stable macrocyclic polyradicaloids, three synthetic methods were developed. All of these stable macrocycles can be purified by normal silica gel column chromatography under ambient conditions. In all cases, moderate polyradical characters were calculated by restricted active space spin-flip method due to the moderate intramolecular antiferromagnetic spin-spin interactions. The excitation energies from the low-spin ground state to the lowest high-spin excited state were evaluated by superconducting quantum interference device measurements. Their physical properties were also compared with the respective linear fluorenyl radical oligomers (FR-n, n = 3-6). It is found that the geometry, i.e., the distortional angle and spacer (w or w/o ethynylene) between the neighboring fluorenyl units, has significant effect on their polyradical character, excitation energy, one-photon absorption, two-photon absorption and electrochemical properties. In addition, the macrocyclic tetramers FR-MC4 and MC F4A4 showed global antiaromatic character due to cyclic pi-conjugation with 36 and 44 pi-electrons, respectively. PMID- 28840724 TI - Strategy for Fabricating Multiple-Shape-Memory Polymeric Materials via the Multilayer Assembly of Co-Continuous Blends. AB - Shape-memory polymeric materials containing alternating layers of thermoplastic polyurethane (TPU) and co-continuous poly(butylene succinate) (PBS)/polycaprolactone (PCL) blends (denoted SLBs) were fabricated through layer multiplying coextrusion. Because there were two well-separated phase transitions caused by the melt of PCL and PBS, both the dual- and triple-shape-memory effects were discussed. Compared with the blending specimen with the same components, the TPU/SLB multilayer system with a multicontinuous structure and a plenty of layer interfaces was demonstrated to have higher shape fixity and recovery ability. When the number of layers reached 128, both the shape fixity and recovery ratios were beyond 95 and 85% in dual- and triple-shape-memory processes, respectively, which were difficult to be achieved through conventional melt-processing methods. On the basis of the classic viscoelastic theory, the parallel-assembled TPU and SLB layers capable of maintaining the same strain along the deforming direction were regarded to possess the maximum ability to fix temporary shapes and trigger them to recover back to original ones through the interfacial shearing effect. Accordingly, the present approach provided an efficient strategy for fabricating outstanding multiple-shape-memory polymers, which may exhibit a promising application in the fields of biomedical devices, sensors and actuators, and so forth. PMID- 28840725 TI - Antiprotozoal Linear Furanosesterterpenoids from the Marine Sponge Ircinia oros. AB - Chemical investigation of the marine sponge Ircinia oros yielded four linear furanosesterterpenoids, including the known metabolites ircinin-1 (1) and ircinin 2 (2) and two new compounds, ircinialactam E (3) and ircinialactam F (4). Their chemical structures were elucidated by using a combination of [alpha]D, NMR, HRMS, and FT-IR spectroscopy. The absolute configuration of C-18 in compounds 1-3 was identified as R by electronic circular dichroism (ECD) spectroscopy coupled with time-dependent density functional theory calculations. Compounds 1-4 showed moderate leishmanicidal, trypanocidal, and antiplasmodial activities (IC50 values 28-130 MUM). This is the second report of rare glycinyl lactam derivatives 3 and 4 from the genus Ircinia. PMID- 28840726 TI - Electrophilic Triflyl-arylation and Triflyl-pyridylation by Unsymmetrical Aryl/Pyridyl-lambda3-iodonium Salts: Synthesis of Aryl and Pyridyl Triflones. AB - Unsymmetrical diaryl-lambda3-iodonium salts containing aryl triflone (Ar-SO2CF3) were designed and synthesized. X-ray crystal structure analysis of the salt indicated a T-shaped geometry at the iodine atom. The salts were found to be powerful electrophilic reagents for triflyl-arylation of C-, N-, and O-centered nucleophiles under mild conditions. Electrophilic transfer of pyridine triflone (Py-SO2CF3) to nucleophiles was also realized by the use of corresponding triflylpyridyl-aryl-lambda3-iodonium salts. Selection of auxiliaries (dummy ligands) of unsymmetrical diaryl-lambda3-iodonium salts is crucial for this transformation. PMID- 28840727 TI - High-Quality (CH3NH3)3Bi2I9 Film-Based Solar Cells: Pushing Efficiency up to 1.64. AB - Bismuth-based solar cells have exhibited some advantages over lead perovskite solar cells for nontoxicity and superior stability, which are currently two main concerns in the photovoltaic community. As for the perovskite-related compound (CH3NH3)3Bi2I9 applied for solar cells, the conversion efficiency is severely restricted by the unsatisfactory photoactive film quality. Herein we report a novel two-step approach- high-vacuum BiI3 deposition and low-vacuum homogeneous transformation of BiI3 to (CH3NH3)3Bi2I9-for highly compact, pinhole-free, large grained films, which are characterized with absorption coefficient, trap density of states, and charge diffusion length comparable to those of some lead perovskite analogues. Accordingly, the solar cells have realized a record power conversion of efficiency of 1.64% and also a high external quantum efficiency approaching 60%. Our work demonstrates the potential of (CH3NH3)3Bi2I9 for highly efficient and long-term stable solar cells. PMID- 28840728 TI - Site-Specific Fluorescence Depolarization Kinetics Distinguishes the Amyloid Folds Responsible for Distinct Yeast Prion Strains. AB - The prion determinant of a yeast prion protein, Sup35NM, assembles into beta-rich amyloid fibrils that switch the nonprion [psi-] state to the prion [PSI+] state of yeast. Previous studies showed that two distinct forms of amyloids (Sc4 and Sc37), generated in vitro at two different temperatures (4 and 37 degrees C), recapitulate the strain phenomenon in Saccharomyces cerevisiae. Sc4 demonstrates a strong [PSI+] phenotype, whereas Sc37 shows a weak phenotype. To discern the residue-specific structural and dynamical attributes associated with the amyloids that display strain diversity, we took advantage of the nonoccurrence of tryptophan (Trp) in the NM-domain and created 18 single-Trp variants spanning the entire polypeptide length. The fluorescence readouts from these locations reported the site-specific structural details in Sc4 and Sc37 fibrils. Highly sensitive picosecond fluorescence depolarization measurements at these positions allowed a conformational mobility map to be constructed. Nearly all of the residue positions demonstrated higher local flexibility in Sc4 amyloid, which exhibits a strong phenotype. The differences in the amplitude of local mobility were more pronounced at the two end segments of the N-domain than in the central region. The M-domain is partially exposed and exhibits a higher amplitude of local mobility, indicating a lower degree of chain packing in the amyloid state, as well as a higher mobility in the Sc4 state compared to the Sc37 state. The altered local conformational dynamics in these two distinct amyloid states provide molecular insights into the varied fragility and severing efficiency that govern the inheritance patterns of strong and weak prion strains. PMID- 28840729 TI - DIPEA-Promoted Reaction of 2-Nitrochalcones with Elemental Sulfur: An Unusual Approach to 2-Benzoylbenzothiophenes. AB - DIPEA was found to be an excellent sulfur activator to promote the reaction of 2 nitrochalcones with elemental sulfur. A wide range of 2-benzoylbenzothiophenes was obtained as a result of a cascade of alkene C?C bond thiolation, aromatic sulfur-denitration. PMID- 28840730 TI - Facet-Dependent Deposition of Highly Strained Alloyed Shells on Intermetallic Nanoparticles for Enhanced Electrocatalysis. AB - Surface strains can enhance the performance of platinum-based core@shell electrocatalysts for the oxygen reduction reaction (ORR). Bimetallic core@shell nanoparticles (NPs) are widely studied nanocatalysts but often have limited lattice mismatch and surface compositions; investigations of core@shell NPs with greater compositional complexity and lattice misfit are in their infancy. Here, a new class of multimetallic NPs composed of intermetallic cores and random alloy shells is reported. Specifically, face-centered cubic Pt-Cu random alloy shells were deposited on PdCu B2 intermetallic seeds in a facet-dependent manner, giving rise to faceted core@shell NPs with highly strained surfaces. High-resolution transmission electron microscopy revealed orientation-dependent surface strains, where the compressive strains were greater on Pt-Cu {200} than {111} facets. These core@shell NPs provide higher specific area and mass activities for the ORR when compared to conventional Pt-Cu NPs. Moreover, these intermetallic@random alloy NPs displayed high endurance, undergoing 10,000 cycles with only a slight decay in activity and no apparent structural changes. PMID- 28840731 TI - Syntheses and Biological Activities of the LMNO, ent-LMNO, and NOPQR(S) Ring Systems of Maitotoxin. AB - Structure-activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki Hiyama-Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca2+ influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 MUM, whereas the NOPQR(S) ring system elicited no inhibitory activity. PMID- 28840732 TI - Deuteration as a Means to Tune Crystallinity of Conducting Polymers. AB - The effects of deuterium isotope substitution on conjugated polymer chain stacking of poly(3-hexylthiophene) is studied experimentally by X-ray diffraction (XRD) in combination with gel permeation chromatography and theoretically using density functional theory and quantum molecular dynamics. For four P3HT materials with different levels of deuteration (pristine, main-chain deuterated, side-chain deuterated, and fully deuterated), the XRD measurements show that main-chain thiophene deuteration significantly reduces crystallinity, regardless of the side chain deuteration. The reduction of crystallinity due to the main-chain deuteration is a quantum nuclear effect resulting from a static zero-point vibrational energy combined with a dynamic correlation of the dipole fluctuations. The quantum molecular dynamics simulations confirm the interchain correlation of the proton-proton and deuteron-deuteron motions but not of the proton-deuteron motion. Thus, isotopic purity is an important factor affecting stability and properties of conjugated polymer crystals, which should be considered in the design of electronic and spintronic devices. PMID- 28840733 TI - Utilization of MeOH as a C1 Building Block in Tandem Three-Component Coupling Reaction. AB - Ru(II) catalyzed tandem synthesis of alpha-branched methylated ketones via multicomponent reactions following the hydrogen borrowing process is described. This nonphosphine-based air and moisture stable catalyst efficiently produced various methylated ketones using methanol as a methylating agent. This system was found to be highly effective in three-component coupling between methanol, primary alcohols, and methyl ketones. A proposed catalytic cycle for the alpha methylation is supported by DFT calculations as well as kinetic experiments. PMID- 28840734 TI - Predictors of quality of life in Czech female breast cancer survivors following treatment with special interest to coping strategies. AB - OBJECTIVES: This study examined the prognostic significance of breast cancer patients characteristics (coping strategies, BMI, age) and disease characteristics (stage of disease, relapse) with respect to quality of life (QoL) following treatment.Sample and settings: 120 breast cancer patients following treatment were recruited. Health-related QoL was assessed using the Czech version of FACT-B and SF-36; additionally, we used a life satisfaction questionnaire. Coping strategies were assessed using the SVF-78 method. In our sample of women, the average time from diagnosis to start of the study was 5.3 years. STATISTICAL ANALYSIS: Factors influencing QoL after treatment were analysed with univariate and multivariate linear regression. RESULTS: Overall negative strategy defined in SVF-78 (Flight tendency, Resignation and Self-accusation) was found to be associated with lower scores of most components of used QoL methods, while Resignation was found as the most negatively influencing strategy. Active problem confrontation (Situation control and Positive self-instruction) was associated with better QoL. More advanced stages and recurrence were related to a significant decrease in QoL for certain components only. CONCLUSION: Our findings suggest a significant predictive power of disease-related factors and of patients characteristics including coping strategies for QoL following treatment in Czech breast cancer survivors.Key words: breast cancer survivors - coping strategy - linear regression model - quality of life prediction - resignation. PMID- 28840735 TI - [Risk factors for cardiovascular diseases in the descendants of patients after early myocardial infarction]. AB - GOAL: The cardiovascular diseases (CVDs) developing as the result of atherosclerosis are among the most frequent causes of morbidity and mortality within the Czech Republic and elsewhere. Genetic predisposition for cardiovascular diseases is amplified in the presence of routine risk factors which can be influenced. Our aim was to establish whether the level of the risk factors for ICHS already differs in the population of healthy descendants of the patients after early myocardial infarction, as opposed to the control group of examined individuals. METHODOLOGY: We approached adult children (n = 127; age 28.7 +/- 6.5 years) of the patients with early manifestation of ICHS, who were examined within the study EUROASPIRE IV. The examination of both the descendants and the control group (n = 199; age 28.9 +/- 5.3 years) focused on identifying the risk factors for ICHS. RESULTS: Descendants presented arterial hypertension more often (18.9 vs 8.0 %, p = 0.003) and there were more smokers among them compared to the control group (37 vs 24.1 %, p = 0.01). The levels of triglycerides (1.13 vs 0.99 mmol/l, p = 0.05) and LDL-cholesterol (2.7 vs 2.45 mmol/l, p = 0.01) were higher in the descendant group, HDL-cholesterol was similar in both groups (1.6 vs 1.67 mmol/l, p = 0.17). Increased fasting glycemia occurred more frequent in the descendant group (5.5 vs 1.5 %, p = 0.05). None of the examined participants met the criteria for the diagnosis of diabetes mellitus. Aortic stiffness was higher in the descendant group as opposed to the control group (6.2 vs 5.8 m/s, p = 0.001). The total calculated cardiovascular risk based on the SCORE system was also higher in the descendant group as compared to the control group - the current risk related to the age of 40 years: 0.35 (0.19-0.64) vs 0.20 (0.13-0.47), p < 0.0001 and the risk related to the age of 60 years: 3.35 (2.23-5.36) vs 2.40 (1.58-4.11), p < 0.0001. CONCLUSION: The population of the descendants includes, based on our results, a greater number of smokers and hypertensive patients. They also have higher levels of LDL cholesterol, triglycerides and impaired fasting glycemia more frequently. Unfavourable genetic predisposition along with unfitting lifestyle contributes to a higher likelihood of accumulation of risk factors, and therefore to a higher risk of a cardiovascular disease manifestation. In practice we should try, with regard to these predisposed individuals, to lower their cardiovascular risk and implement a healthy lifestyle.Key words: atherosclerosis - cardiovascular disease - lifestyle - myocardial infarction - primary prevention - risk factors for CVD. PMID- 28840736 TI - ["Snags" connected with establishing the vitamin D]. AB - OBJECTIVE: The aim of proposed paper was to compare a three total 25-hydroxy vitamin D immunoassays to that of HPLC with UV detection. MATERIAL AND METHODS: Serum 25-(OH) D levels were measured from blood samples of 109 patients with different immunoassays (ABBOTT, ROCHE, SIEMENS) and method of HPLC which was chosen as the reference. In the first step immunoassays were compared to HPLC. In the second step immunoassays were compared to each other. Further purpose of methods comparison the Passing-Bablok regression and Bland-Altman analysis were used. The limits of maximum acceptable differences were set at 21.5 %, according to Vitamin D Standardization-Certification Program (VDSCP). In the last step, the concordance in the interpretation of measured results was evaluated. RESULTS: None of the examined 25-(OH) D immunoassays was comparable to HPLC and to each other. Bland-Altman analysis revealed, in comparison to HPLC, that ROCHE showed positive bias +28.0 %, ABBOTT +0.2 % and SIEMENS -23.4 %. Although average bias of ABBOTT immunoassay is insignificant, particular results do deviate significantly (-89.4 % to 89.0 %). The concordance in the interpretation of measured results, in comparison to HPLC, was highest with ABBOTT (65.21 %), then with ROCHE (59.63 %) and lowest with SIEMENS (47.79 %). CONCLUSION: The results of the proposed papers suggest low levels of 25-(OH) D immunoassays standardization and an alternative to use assay-specific decision limits. PMID- 28840737 TI - [Clinical study FOURIER]. AB - A new group of hypolipidemic substances, i.e. PCSK9 protein inhibitors, is now coming into use in clinical practice, to what extent a high residual cardiovascular risk remains also in patients treated with statins. The FOURIER study (Further cardiovascular OUtcomes Research with PCSK9 Inhibition subjects with Elevated Risk) is the first "event" study which has shown that evolocumab (PCSK9 antibody) further significantly reduces serum LDL cholesterol and subsequently also cardiovascular morbidity and mortality: (a) composite primary goal (cardiovascular mortality, incidence of heart attacks, strokes, hospitalizations for unstable angina, coronary revascularization) by 15 % (p < 0.001), (b) secondary goal (cardiovascular mortality, incidence of heart attacks, strokes) by 20 % (p < 0.001), (c) the treatment effect increased with length of treatment, and (d) the treatment was safe. The study has therefore confirmed that further reduction of serum LDL cholesterol by means of evolocumab significantly reduces incidence of cardiovascular events in patients with elevated risk. This treatment is primarily needed for individuals with elevated cardiovascular risk.Key words: atherosclerosis - evolocumab - cardiovascular diseases - LDL cholesterol - PCSK9 inhibitors. PMID- 28840738 TI - [Primary testicular lymphoma]. AB - Primary testicular lymphoma (PTL) is a rare form of extranodal lymphoma and accounts for approximately 1 to 2 % of all non-Hodgkins lymphoma and 5 % of testicular malignancies. PTL typically affects patients older than 60 years. The most common clinical symptom is painless scrotal swelling. The ultrasound of testicles followed by orchiectomy and histological and imunohistochemical examinations are the most important tools for diagnostic assessment. Diffuse large B cell lymphoma (DLBCL) is the most common histological type of PTL. Orchiectomy is an important part of the treatment, which includes the combination of systemic imunochemotherapy and prophylactic modalities such as radiotherapy of contralateral testis and central nervous system (CNS) prophylaxis. This combined treatment approach improved the outcome of patients with PTL, however, the high frequency of extranodal relapses including CNS involvement represents a significant problem. The prognosis of PTL still remains less favorable in comparison to the some subtypes of non-Hodgkins lymphomas.Key words: central nervous system lymphoma involvement prophylaxis - primary testicular lymphoma - prognosis - radiotherapy - relapse. PMID- 28840739 TI - [Rivaroxaban in high-risk patients]. AB - Blockade of factor Xa becomes a routine part of clinical practice instead of vitamin K blockade with warfarin, providing a more beneficial and safer effect. The main indications are prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation, deep vein thrombosis and pulmonary embolism. Rivaroxaban has the largest number of data across high risk patients. Rivaroxaban is an oral selective anti Xa inhibitor with well predictive pharmacokinetics and pharmacodynamics. It inhibits thrombin formation for 24 hours, is well absorbed and biological availability is 80-100 %. The excretion is mainly renal and the mean elimination time is 5-9 hours in younger and 11-13 hours in elderly. The pharmacokinetics is minimally influenced by sex and age. The ROCKET AF trial has shown in 14 246 high-risk patients a trend to lowering stroke and systemic embolization by rivaroxaban compared to warfarin without a bleeding increase. The number of events per 100 patient-years was 1.71 in group treated with rivaroxaban compared to 2.16 treated with warfarin (p < 0.001 for non inferiority). A sub-analysis of the ROCKET AF trial has shown numerically trend to higher efficacy and safety of rivaroxaban in patients with moderate renal insufficiency compared to warfarin. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. The effects by age and concomitant diseases are discussed. The X-VeRT trial shows a new indication for rivaroxaban - electric cardioversion.Key words: age - anticoagulation - heart failure - high risk patients - renal insufficiency - thromboembolic disease. PMID- 28840740 TI - [Two perspectives on venous thromboembolism in oncology]. AB - An increased risk of venous thromboembolism (VTE) in patients with malignancy compared with the current population is determined by risk factors including the use of anticancer treatments, in particular some hormonal drugs, cytostatics, vascular endothelial growth factor (VEGF) inhibitors and epidermal receptor growth factor (EGFR) inhibitors, immunomodulators, and erythropoietins. The population of cancer patients is divided into a group of individuals with a history of malignant disease in complete remission and patients with active (locally advanced or metastatic) malignant disease in terms of approach to VTE. Venous thromboembolism negatively influences the prognosis of a patient with malignancy. Cancer associated VTE is associated with higher risk of recurrence as well as higher risk of bleeding during anticoagulation. For initial and long-term treatment, low molecular weight heparin should be preferred, for a minimum of 3-6 months. Some subgroups deserve a special approach - patients with thrombocytopenia, renal insufficiency, and patients with recurrent VTE despite anticoagulation. The treatment of an incidental pulmonary embolism is another controversial issue. The approach to a patient with cancer associated VTE should be individualized and should take into account patient's overall prognosis and risk/benefit ratio of treatment.Key words: anticoagulation treatment - cancer - risk factors - venous thromboembolism. PMID- 28840741 TI - [Insulin pump in type 2 diabetes: B-cell focused treatment]. AB - Type 2 diabetes is a disorder characterized by insulin resistance and progressive deterioration of B-cell insulin secretion. B-cell protective strategies for lowering glucolipotoxicity by rapid achievement of normoglycemia using exogenous insulin improve their function and prolong diabetes remission. Insulin pump is an effective treatment method in newly diagnosed diabetes, where even short-term pump therapy is B-cell protective. Combination therapy with insulin pump and antidiabetics targeting the incretin system acts in synergy to protect the B cell. While the positive effect of insulin pump is apparent even a year after stopping the therapy, the effect of incretins lasts only while on the medication. Short-term insulin treatment, especially delivered by insulin pump, is an effective method of B-cell protection in recent type 2 diabetes.Key words: B-cell function - diabetes mellitus - insulin pump - insulin resistance - type 2 diabetes. PMID- 28840742 TI - International Ballroom Dancing Against Neurodegeneration: A Randomized Controlled Trial in Greek Community-Dwelling Elders With Mild Cognitive impairment. AB - BACKGROUND: Many studies have highlighted the positive effects of dance in people with neurodegenerative diseases. OBJECTIVES: To explore the effects of International Ballroom Dancing on cognitive function in elders with amnestic mild cognitive impairment (aMCI). METHODS: One-hundred twenty-nine elderly patients with aMCI diagnosis (mean age 66.8 +/- 10.1 years) were randomly assigned into 2 groups: intervention group (IG, n = 66) and control group (CG, n = 63). The IG exercised systematically for 10 months, and both groups were submitted to extensive neuropsychological assessment prior and after the 10-month period. RESULTS: According to the independent sample t test at the follow-up, significant differences between groups were found in benefit of the IG while the CG showed worse performance in the majority of neuropsychological tests. According to the Student t test, better performance is detected in IG in contrast with CG, which had worse performance almost in all scales. CONCLUSION: Dance may be an important nonpharmacological approach that can benefit cognitive functions. PMID- 28840743 TI - Self-Awareness for Memory Impairment in Amnestic Mild Cognitive Impairment: A Longitudinal Study. AB - AIM: To assess memory impairment insight as a predictor of dementia and Alzheimer's disease (AD) in amnestic mild cognitive impairment (MCI). METHODS: To verify whether the awareness of memory impairment assessed by Geriatric Depression Scale (GDS) was associated with the risk of progression to dementia and AD in a cohort of MCI, we used a Cox regression model adjusted for age, sex, education, subtypes of amnestic MCI, Mini-Mental State Examination, Cumulative Illness Rating Scale severity index, and apolipoprotein E genotype. RESULTS: During a follow-up of 27.7 (20.8) months, 205 (63.3%) of 324 patients with amnestic MCI progressed to dementia, including 141 to AD. No association was found in the unadjusted, partially adjusted (for sociodemographic variables), and fully adjusted multivariate Cox analysis between the awareness of memory impairment and the progression to dementia and AD. DISCUSSION: Awareness or anosognosia of memory deficits, identified by GDS, is not useful to predict progression to dementia of patients with amnestic MCI. PMID- 28840744 TI - The evolution of chicken stem cell culture methods. AB - 1. The avian embryo is an excellent model for studying embryology and the production of pharmaceutical proteins in transgenic chickens. Furthermore, chicken stem cells have the potential for proliferation and differentiation and emerged as an attractive tool for various cell-based technologies. 2. The objective of these studies is the derivation and culture of these stem cells is the production of transgenic birds for recombinant biomaterials and vaccine manufacture, drug and cytotoxicity testing, as well as to gain insight into basic science, including cell tracking. 3. Despite similarities among the established chicken stem cell lines, fundamental differences have been reported between their culture conditions and applications. Recent conventional protocols used for expansion and culture of chicken stem cells mostly depend on feeder cells, serum containing media and static culture. 4. Utilising chicken stem cells for generation of cell-based transgenic birds and a variety of vaccines requires large-scale cell production. However, scaling up the conventional adherent chicken stem cells is challenging and labour intensive. Development of a suspension cell culture process for chicken embryonic stem cells (cESCs), chicken primordial germ cells (PGCs) and chicken induced pluripotent stem cells (ciPSCs) will be an important advance for increasing the growth kinetics of these cells. 6. This review describes various approaches and suggestions to achieve optimal cell growth for defined chicken stem cells cultures and use in future manufacturing applications. PMID- 28840745 TI - Delayed diagnosis of bronchial transection following blunt chest trauma. AB - Diagnosis of blunt tracheobronchial injuries can be challenging. These injuries may appear within months or years following the initial trauma. In general, diagnosis and treatment of delayed presentation of tracheobronchial injuries are uncommon. Herein, we present the case of a 48-year-old woman with complete transection of the right bronchus that was diagnosed 50 days after the initial trauma. Reconstructive surgery of the bronchus was performed successfully without any need for pulmonary resection. PMID- 28840746 TI - Evaluation of vascular invasion in patients with musculoskeletal tumors of lower extremities: use of time-resolved 3D MR angiography at 3-T. AB - Background Time-resolved angiography with stochastic trajectories (TWIST) sequence makes considerable progress in temporal and spatial resolution, which presents high potential in evaluation of vascular diseases. Purpose To assess magnetic resonance imaging (MRI) using TWIST MR angiography (MRA) sequence in the assessment of vascular invasion for bone and soft-tissue tumors in comparison to computed tomography angiography (CTA) as the reference standard. Material and Methods Thirty-three patients with lower extremity musculoskeletal tumors were imaged with conventional MR and TWIST MRA. CTA was performed 48 h later. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the femoral artery were calculated. Vascular invasion as determined by MRA and CTA was separately analyzed. Vascular invasion by MRA and CTA were analyzed with kappa coefficients to determine agreement between the imaging methods. Results Seven cases of bone and 26 cases of soft tissue tumors were examined. SNR and CNR of the femoral artery were excellent for TWIST MRA (mean +/- SD values of 317 +/- 80 and 276 +/- 76, respectively). Based on the TWIST sequence, the vessels were free of tumor in 16 cases. Vascular displacement was found in 11 cases and vascular stenosis in six cases. The MRA findings conflicted with CTA findings in only one case. The kappa value was 0.953 ( P < 0.01). In five cases, vascular malformations were found with TWIST MRA but not CTA. Conclusion TWIST MRA enables accurate delineation of anatomical structures and tumor arterial involvement, providing reliable preoperative imaging information with respect to lower extremity musculoskeletal tumors. PMID- 28840747 TI - Pediatric Somatic Symptom and Related Disorders: Primary Care Provider Perspectives. AB - Somatization, or physical symptoms that are inconsistent with a physiological cause that may or may not involve an identified stressor, is common in outpatient pediatrics. When these symptoms persist, they can impair function and progress to a somatic symptom and related disorder (SSRD), resulting in increased health care use and increased demands on primary care providers (PCPs). We performed a needs assessment among PCPs to better understand how best to support providers caring for children with SSRDs. Pediatric PCPs (n = 77) were surveyed to better understand their training, experience, perceptions, and practices of SSRD care. Findings indicate that PCPs have limited training in SSRD care but express interest in learning more. Many barriers to effective care were reported. We hope to use these findings to develop training materials and support services for pediatric PCPs managing SSRDs. PMID- 28840748 TI - Inactivation of Vibrio parahaemolyticus in shucked raw oyster ( Grassostrea gigas) and clam ( Venerupis phillippinarum) by using a combination of NaClO and gamma irradiation. AB - This study investigated the synergistic effects of sodium hypochlorite (NaClO) and gamma irradiation combination against Vibrio parahaemolyticus in shucked oysters and clams. V. parahaemolyticus decreased to 1.1-5.6 log10 CFU/g in oysters and 1.1-5.7 log10CFU/g in clams by NaClO (20-80 ppm) + gamma irradiation (0.1-2.0 kGy) combinations. V. parahaemolyticus was not detected by 60 or 80 ppm NaClO + 2.0 kGy. Synergistic reduction of >1 log was observed by 60 ppm NaClO + 0.3-2 kGy and 80 ppm NaClO + 0.5 or 2 kGy. Specifically, >2 log of the synergistic reduction was obtained by 60 or 80 ppm NaClO + 2 kGy. Furthermore, using the Weibull model, 5D values (5-log reductions) were calculated for 60 or 80 ppm NaClO + 0.5-0.9 kGy. No significant differences were observed for all sensory parameters between samples of 2.0 kGy + 0-80 ppm NaClO. This study suggests that 60 ppm NaClO + 2.0 kGy in reducing 7-log V. parahaemolyticus without any deteriorative changes of sensory qualities could be a potential strategy for post-harvest process in seafood processing and distribution to enhance the microbial safety of molluscan shellfish. PMID- 28840749 TI - Evaluation of the quality of life in patients with arsenic keratosis. AB - BACKGROUND: Chronic exposure to inorganic arsenic is an important public health problem and leads to hyperpigmentation, hyperkeratosis, Bowen's disease and non melanoma skin cancers in humans. Arsenic keratosis is the most common skin change that is associated with arsenic exposure. It may be an indicator of arsenic induced health hazards. OBJECTIVE: To determine the needs of patients with arsenic keratosis by evaluating the impact of disease on the quality of life with respect to treatment and provide rehabilitation services. METHODS: A total of 47 subjects with arsenic hyperkeratosis, were enrolled in this crossover study. The demographics, smoking status and the presence of chronic diseases diagnosed by the physician were recorded. Weight and height of the subjects were measured and BMI was calculated. The patients were asked to respond the visual analogue scale and EuroQoL-5D scales for assessing the pain and quality of life impairment associated with arsenic hyperkeratosis. RESULTS: In the study group, moderate to severe problems were reported in 78.7% of patients for pain/uncomfortable condition domains and in 91.5% in anxiety/depression domains. Lower quality of life was reported in those with associated chronic disorders, at an advanced age, in thin patients and in those with severe lesions. CONCLUSION: According to our knowledge, our study is the first one measuring the quality of life in patients with arsenic keratosis in the literature. By this study, we tried to underline the guidance of health services to be developed towards the needs of patients and the need for the development of new health policies by determining the requirements of these patients. PMID- 28840750 TI - Efficacy and safety of adalimumab by intra-articular injection for moderate to severe knee osteoarthritis: An open-label randomized controlled trial. AB - Objective To evaluate the efficacy and safety of adalimumab (ADA) versus hyaluronic acid (HA) by intra-articular injection for moderate to severe knee osteoarthritis. Methods Fifty-six consecutive patients with moderate to severe knee osteoarthritis were randomly allocated to either the ADA group or HA group. On day 0, patients in the ADA group received 10 mg of ADA by intra-articular injection, while those in the HA group received 25 mg of HA. All patients received celecoxib at 200 mg/day for 4 weeks. The pain visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Patient Global Assessment (PGA), and Physician Global Assessment (PhGA) scores were assessed. Results At baseline, the pain VAS, WOMAC, PGA, and PhGA scores were similar between the two groups. The decrease in the pain VAS score, WOMAC pain score, WOMAC physical function score, and WOMAC total score from baseline to week 4 were greater in the ADA than HA group. A greater decrease in the PGA and PhGA scores from baseline to week 4 was noted in the ADA than HA group. No difference in adverse events was observed between the two groups. Conclusion ADA by intra articular injection was effective and tolerated for moderate to severe knee osteoarthritis. PMID- 28840751 TI - Gastrodin causes vasodilation by activating KATP channels in vascular smooth muscles via PKA-dependent signaling pathway. AB - Gastrodin, one of the major components extracted from the Chinese herb Gastrodia elata Bl., has been widely used as an anticonvulsant, sedative, analgesic and hypotensive. In our study, we aimed to investigate the effects and possible mechanisms of gastrodin on vascular KATP channels. Tension experiments were used on rat mesenteric artery rings without an endothelium. Patch clamp experiments were executed to investigate the influences of gastrodin on the membrane current in mesenteric artery smooth muscle cells. Gastrodin induced vasorelaxation in a concentration dependent manner when rat mesenteric artery rings were pre contracted with Phenylephrine. The vasorelaxation effect was partially diminished by pre-treating with a KATP channel inhibitor, or a PKA inhibitor. With whole cell patch-clamp recording techniques, we found that gastrodin is a activator of KATP in rat mesenteric artery smooth muscle cells, and this effect was eliminate by pre-treating with H89or PKI, PKA inhibitor. In addition, when rat vascular smooth muscle cells were treated with 100 MUM gastrodin for 24 h, maximum KATP current density increased by 28.1%. The results indicate that gastrodin exerts vasorelaxation effect through activation of PKA and subsequent opening of smooth muscle KATP channels. PMID- 28840753 TI - Comparative effectiveness of indacaterol/glycopyrronium in the treatment of chronic obstructive pulmonary disease. AB - Indacaterol/glycopyrronium has been the first long-acting beta2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combination to be approved as a maintenance treatment in chronic obstructive pulmonary disease patients. Comparative effectiveness studies indicate that it is constantly superior to a LAMA or a LABA alone or even a LABA/inhaled corticosteroid combination, regardless of the drugs used. However, definitive data documenting the benefit of indacaterol/glycopyrronium fixed-dose combination over these consolidated therapies are still absent in a real-world setting, although the results of pivotal randomized controlled trials show that this is the case. Therefore, in addition to the large body of evidence already available supporting the use of indacaterol/glycopyrronium, pragmatic observational studies or ad hoc designed trials should be planned to collect data that could confirm the high effectiveness of indacaterol/glycopyrronium even in the real-life clinical practice. PMID- 28840752 TI - Pneumatic retinopexy combined with scleral buckling in the management of relatively complicated cases of rhegmatogenous retinal detachment: A multicenter, retrospective, observational consecutive case series. AB - Objective To evaluate the efficacy of maximal pneumatic retinopexy (PR) and subretinal fluid (SRF) drainage combined with scleral buckling (SB) in the treatment of complicated rhegmatogenous retinal detachment (RRD). Methods Patients with RRD who underwent maximal PR and SRF drainage combined with SB from June 2007 to June 2012 were included in this multicenter retrospective study. The outcome measures were the primary and final operation success rates and best corrected visual acuity (BCVA). Results In total, 159 consecutive patients were included. The mean follow-up period was 13.76 +/- 1.97 months. Primary operation success was achieved in 146/159 (91.82%) eyes. After salvage management, the final reattachment rate increased to 98.11%. All eyes had improved BCVA, with 62/159 (38.99%) attaining BCVA of >=20/40. Conclusions Maximal PR and SRF drainage combined with SB achieved satisfactory anatomical and visual recovery in relatively complicated cases of RRD. The decreased need for vitrectomy makes this surgical approach more widely available. PMID- 28840754 TI - Standard of care in high-dose radiotherapy for localized non-small cell lung cancer. PMID- 28840755 TI - An Alternative Cuprizone-Induced Demyelination and Remyelination Mouse Model. AB - The cuprizone model is a well-established and investigated paradigm to study demyelination and remyelination in rodents. Cuprizone is usually administrated by mixing in the powdered or pelleted rodent chow. However, since cuprizone is sensitive to the environment and the consumption of it varies between different animals, the major issue is the discrepancy in demyelination of the animals. This study reports the development of the cuprizone model by gavage administrations in mice. Following testing a series of doses of cuprizone, 400 mg/kg/day was found to be the best dosage to induce dramatic and consistent demyelination after 5 weeks of administration; while remyelination quickly occurred after 9 days of cuprizone withdrawal. The advantage of this alternative model is that the consumption of cuprizone could be well controlled, and the mice were exposed to the same dose of cuprizone. Thus, the variation in demyelination was minimized. This alternative cuprizone dosing regime minimizes the interanimal variability on demyelination and hence provides a consistent model for pharmacological evaluations, in addition to reducing the number of animals used in the experiments. PMID- 28840756 TI - The Nun Study and Alzheimer's disease: Quality of vocation as a potential protective factor? AB - Data from the Nun Study, the most famous longitudinal epidemiology of Alzheimer's disease to date, are analyzed and reformulated in terms of Max Weber's discussion of the centrality of beruf - "calling" - fulfilling a life task in pursuit of a vocation. Qualitative differences in the Nuns' vocations are uncovered, which are correlated to their resilience to dementia. Extrapolating, we argue that Alzheimer's disease and the dementia reputed to it should be understood as a social pathology of contemporary civilization related to the loss of moral foundations from which coherent, meaningful life-projects can be conducted. PMID- 28840757 TI - A Visual Arts Education pedagogical approach for enhancing quality of life for persons with dementia (innovative practice). AB - A new and innovative pedagogical approach that administers hands-on visual arts activities to persons with dementia based on the field of Visual Arts Education is reported in this paper. The aims of this approach are to enhance cognition and improve quality of life. These aims were explored in a small qualitative study with eight individuals with moderate dementia, and the results are published as a thesis. In this paper, we summarize and report the results of this small qualitative study and expand upon the rationale for the Visual Arts Education pedagogical approach that has shown promise for enhancing cognitive processes and improving quality of life for persons with dementia. PMID- 28840758 TI - Trust at stake: Is the "dual mission" of the U.S. Alzheimer's Association out of balance? AB - The official vision of the U.S. Alzheimer's Association is "A world without Alzheimer's disease." The "dual mission" of the organization is "to eliminate Alzheimer's disease through the advancement of research and to enhance care and support for individuals, their families and caregivers." Using numerous reports from leading researchers and practitioners, a case is made by which the "dual mission" is grossly unbalanced with predominant focus on biomedical research aimed at curing the disease compared to research and practices focused on the psycho-social impacts of and adaptations to living with it. These experts discuss the likelihood of curing the disease, the complexity of realizing this goal, and the urgent need to "bring back the social and psychological aspects" of living with dementia to center stage. The moral responsibility to balancing the "dual mission" in accordance with the original motivation of the grassroots organizations who formed the association in 1980 is discussed. PMID- 28840759 TI - The potential of hyperpolarized 13C magnetic resonance spectroscopy to monitor the effect of combretastatin based vascular disrupting agents. AB - BACKGROUND: Targeting tumor vasculature with vascular disrupting agents (VDAs) results in substantial cell death that precede tumor shrinkage. Here, we investigate the potential of hyperpolarized magnetic resonance spectroscopy (HPMRS) to monitor early metabolic changes associated with VDA treatment. METHODS: Mice bearing C3H mammary carcinomas were treated with the VDAs combretastatin-A4-phosphate (CA4P) or the analog OXi4503, and HPMRS was performed following [1-13C]pyruvate administration. Similarly, treated mice were positron emission tomography (PET) scanned following administration of the glucose analog FDG. Finally, metabolic imaging parameters were compared to tumor regrowth delay and measures of vascular damage, derived from dynamic contrast-agent enhanced magnetic resonance imaging (DCE-MRI) and histology. RESULTS: VDA-treatment impaired tumor perfusion (histology and DCE-MRI), reduced FDG uptake, increased necrosis, and slowed tumor growth. HPMRS, revealed that the [1-13C]pyruvate-to-[1 13C]lactate conversion remained unaltered, whereas [1-13C]lactate-to [13C]bicarbonate (originating from respiratory CO2) ratios increased significantly following treatment. CONCLUSIONS: DCE-MRI and FDG-PET revealed loss of vessel functionality, impaired glucose delivery and reduced metabolic activity prior to cell death. [1-13C]lactate-to-[13C]bicarbonate ratios increased significantly during treatment, indicating a decline in respiratory activity driven by the onset of hypoxia. HPMRS is promising for early detection of metabolic stress inflicted by VDAs, which cannot easily be inferred based on blood flow measurements. PMID- 28840760 TI - Validation of the English and Mandarin versions of the Fear of Cancer Recurrence Inventory in an Asian population. AB - The Fear of Cancer Recurrence Inventory has shown adequate psychometric properties to assess for fear of cancer recurrence among cancer survivors. However, the use of the Fear of Cancer Recurrence Inventory in Asia is limited due to the paucity of validation studies. Participants include 331 cancer survivors who completed the English and newly developed Mandarin versions of the Fear of Cancer Recurrence Inventory. The results revealed that both versions of the Fear of Cancer Recurrence Inventory demonstrated satisfactory internal reliability, test-retest reliability, convergent validity, and concurrent validity. A confirmatory factor analysis provided support for the original seven factor structure. The validated Fear of Cancer Recurrence Inventory is applicable to cancer survivors in Singapore. PMID- 28840761 TI - Induction of reactive oxygen species by diphenyl diselenide is preceded by changes in cell morphology and permeability in Saccharomyces cerevisiae. AB - Organoselenium compounds, such as diphenyl diselenide (PhSe)2 and phenylselenium zinc chloride (PhSeZnCl), show protective activities related to their thiol peroxidase activity. However, depending on experimental conditions, organoselenium compounds can cause toxicity by oxidising thiol groups of proteins and induce the production of reactive oxygen species (ROS). Here, we analysed the toxicity of (PhSe)2 and PhSeZnCl in yeast Saccharomyces cerevisiae. Cell growth of S. cerevisiae after 1, 2, 3, 4, 6, and 16 h of treatment with 2, 4, 6, and 10 MUM of (PhSe)2 was evaluated. For comparative purpose, PhSeZnCl was analysed only at 16 h of incubation at equivalent concentrations of selenium (i.e. 4, 8, 12, and 20 MUM). ROS production (DCFH-DA), size, granularity, and cell membrane permeability (propidium iodide) were determined by flow cytometry. (PhSe)2 inhibited cell growth at 2 h (10 MUM) of incubation, followed by increase in cell size. The increase of cell membrane permeability and granularity (10 MUM) was observed after 3 h of incubation, however, ROS production occurs only at 16 h of incubation (10 MUM) with (PhSe)2, indicating that ROS overproduction is a more likely consequence of (PhSe)2 toxicity and not its determinant. All tested parameters showed that only concentration of 20 MUM induced toxicity in samples incubated with PhSeZnCl. In summary, the results suggest that (PhSe)2 toxicity in S. cerevisiae is time and concentration dependent, presenting more toxicity when compared with PhSeZnCl. PMID- 28840762 TI - Impact of stressful death or divorce in people with HIV: A prospective examination and the buffering effects of religious coping and social support. AB - This study examined the impact of a stressful death/divorce on psychological and immune outcomes in people with HIV. People with HIV with stressful death/divorce were examined from before the event to up to 12 months later ( n = 45); controls were assessed at similar intervals ( n = 112). Stressful deaths/divorces were associated with increased viral load and anxiety over time ( ps <= .014), but not CD4+ or depression. Increased use of religious coping after the stressful death/divorce was associated with slower increases in viral load ( p = .010). These data suggest people with HIV should consider the potentially elevated risk of transmission after such events and seek appropriate monitoring and care. PMID- 28840763 TI - alpha+-Thalassemia Caused by an 811 bp Deletion in Individuals from Nanning, Guangxi: A Report of Two Cases. AB - A novel 811 bp deletion was first identified in two families of Nanning City, Guangxi Zhuang Autonomous Region, People's Republic of China (PRC). The molecular basis of this anomaly is a deletion from NG_000006.1: g.32945_33755, and is 20 bp upstream of the translation initiation codon of HBA2. From analyses of the blood indices of the two probands, the 811 bp deletion is an alpha+-thalassemia (alpha+ thal). This is the first report of this deletional thalassemia anywhere in the world. PMID- 28840764 TI - Genetic characterization of the Turkish gray hamster (Cricetulus migratorius) based on mitochondrial cytochrome b and 12S rRNA sequences. AB - Although genetic diversity and phylogenetic status of the gray hamster (Cricetulus migratorius) have been investigated from different regions in previous studies, genetic data on this species from Turkey are still lacking, since previous data have been based on a limited number of gray hamsters sampled across the Anatolian part of Turkey. The aim of this study was to determine the genetic diversity of the Anatolian population and to reveal the phylogenetic relationships among the Anatolian population and conspecific populations of the gray hamster. The complete and partial fragments of mitochondrial Cyt b and 12S rRNA from the 20 Turkish samples were amplified and sequenced. Ten 12S rRNA (901 bp) and 15 Cyt b (1140 bp) haplotypes found in this work were not previously reported. Based on Bayesian, Maximum Likelihood, Neighbour-Joining and Median Joining network analyses by using mitochondrial data under the name Cricetulus, the results of phylogenetic and network analyses indicated that there was a deep separation among the distinct lineages within the genus Cricetulus. When considering the position of the Turkish haplotypes in median joining network, the Anatolian part of Turkey may have hosted a source population of the gray hamster for expansion to adjacent regions in the past period. Additionally, the Anatolian population of gray hamster had relatively high haplotype diversity and the present study propounded the importance of data obtained from the Anatolian population of gray hamster to reveal the phylogenetic relationships among conspecific populations of the gray hamster. PMID- 28840765 TI - Hypoxia positron emission tomography imaging: combining information on perfusion and tracer retention to improve hypoxia specificity. AB - BACKGROUND: Static positron emission tomography (PET) allows mapping of tumor hypoxia, but low resolution and slow tracer retention/clearance results in poor image contrast and the risk of missing areas where hypoxic cells and necrosis are intermixed. Fully dynamic PET may improve accuracy but scan protocols suitable for routine clinical use are warranted. A modeling study proposed that hypoxia specificity can be improved by a clinically feasible blood-flow normalization procedure that only requires a 10- to 15-min dynamic scan (perfusion), followed by a short late static scan, but experimental validation is desired. METHODS: Tumor-bearing mice were administered pimonidazole (hypoxia marker) and the PET hypoxia-tracer 18F-azomycin arabinoside (FAZA) and scanned for 3h. Subsequently, the distributions of FAZA (autoradiography) and hypoxic cells (pimonidazole) were compared on tissue sections. PET images collected in 10-min time intervals between 60 and 90 min post-injection (PETearly), which mimics the image contrast seen in patients, were compared voxel-by-voxel to 3-h PET (PETlate). For comparison, PETearly was normalized to the perfusion peak area, deduced from the first 10 min of the scan (PETperf), and the resulting parameter PETearly/PETperf was compared with PETlate. RESULTS: Tissue analysis revealed a near-perfect spatial match between FAZA signal and hypoxic cell density (pimonidazole) 3 h post-injection, regardless of the tumor type. Only a weak inverse or no correlation between PETperf and PETlate was seen, and the correlation between PETearly/PETperf and PETlate proved inferior to the correlation between PETearly and PETlate. CONCLUSIONS: Late PET scans in rodents, unlike patients, provide an accurate map of hypoxia against which earlier time-point scans can be compared. PETearly and PETlate correlated to a variable extent but the correlation was lowered by normalization to perfusion (PETearly/PETperf). Our study challenges the validity/robustness of a perfusion normalization approach. This may reflect that the chaotic tumor vasculature uncouples microregional blood flow and oxygen extraction. PMID- 28840766 TI - Immunohistochemical and molecular imaging biomarker signature for the prediction of failure site after chemoradiation for head and neck squamous cell carcinoma. AB - OBJECTIVE: To identify a failure site-specific prognostic model by combining immunohistochemistry (IHC) and molecular imaging information to predict long-term failure type in squamous cell carcinoma of the head and neck. PATIENT AND METHODS: Tissue microarray blocks of 196 head and neck squamous cell carcinoma cases were stained for a panel of biomarkers using IHC. Gross tumor volume (GTV) from the PET/CT radiation treatment planning CT scan, maximal Standard Uptake Value (SUVmax) of fludeoxyglucose (FDG) and clinical information were included in the model building using Cox proportional hazards models, stratified for p16 status in oropharyngeal carcinomas. Separate models were built for time to locoregional failure and time to distant metastasis. RESULTS: Higher than median p53 expression on IHC tended toward a risk factor for locoregional failure but was protective for distant metastasis, chi2 for difference p = .003. The final model for locoregional failure included p53 (HR: 1.9; p: .055), concomitant cisplatin (HR: 0.41; p: .008), beta-tubulin-1 (HR: 1.8; p: .08), beta-tubulin-2 (HR: 0.49; p: .057) and SUVmax (HR: 2.1; p: .046). The final model for distant metastasis included p53 (HR: 0.23; p: .025), Bcl-2 (HR: 2.6; p: .08), SUVmax (HR: 3.5; p: .095) and GTV (HR: 1.7; p: .063). CONCLUSIONS: The models successfully distinguished between risk of locoregional failure and risk of distant metastasis, which is important information for clinical decision-making. High p53 expression has opposite prognostic effects for the two endpoints; increasing risk of locoregional failure, but decreasing the risk of metastatic failure, but external validation of this finding is needed. PMID- 28840767 TI - Automatic treatment planning facilitates fast generation of high-quality treatment plans for esophageal cancer. AB - BACKGROUND: The quality of radiotherapy planning has improved substantially in the last decade with the introduction of intensity modulated radiotherapy. The purpose of this study was to analyze the plan quality and efficacy of automatically (AU) generated VMAT plans for inoperable esophageal cancer patients. MATERIAL AND METHODS: Thirty-two consecutive inoperable patients with esophageal cancer originally treated with manually (MA) generated volumetric modulated arc therapy (VMAT) plans were retrospectively replanned using an auto planning engine. All plans were optimized with one full 6MV VMAT arc giving 60 Gy to the primary target and 50 Gy to the elective target. The planning techniques were blinded before clinical evaluation by three specialized oncologists. To supplement the clinical evaluation, the optimization time for the AU plan was recorded along with DVH parameters for all plans. RESULTS: Upon clinical evaluation, the AU plan was preferred for 31/32 patients, and for one patient, there was no difference in the plans. In terms of DVH parameters, similar target coverage was obtained between the two planning methods. The mean dose for the spinal cord increased by 1.8 Gy using AU (p = .002), whereas the mean lung dose decreased by 1.9 Gy (p < .001). The AU plans were more modulated as seen by the increase of 12% in mean MUs (p = .001). The median optimization time for AU plans was 117 min. CONCLUSIONS: The AU plans were in general preferred and showed a lower mean dose to the lungs. The automation of the planning process generated esophageal cancer treatment plans quickly and with high quality. PMID- 28840768 TI - Phenotypic Evaluation of a Novel Nucleotide Substitution (HBD: c.442T>C) on the delta-Globin Gene. AB - HBD: c.442T>C is a new mutation at the stop codon (TGA>CGA) of the delta-globin gene, which produces a new codon for arginine. This substitution causes a 51 nucleotides longer open reading frame determining the synthesis of a potential larger delta subunit, which is a probable target of mechanisms for the degradation of aberrant proteins as well as the defective synthesized mRNA molecules, and may also be rapidly degraded by a variety of RNA surveillance pathways. We identified this molecular defect in four patients: three women with a reduced HbA2 level and a 37-year-old male showing the typical phenotype of an alpha-thalassemia (alpha-thal) carrier with reduced values of red cell indices and normal HbA2 level (2.5%). The mutation on the delta-globin gene was found to have been coinherited with a beta-globin gene defect leading to a normalized HbA2 level. These data support the necessity of investigating these cases at a molecular level, particularly if the partner is also a beta-thalassemia (beta thal) carrier. The present data emphasizes the importance of a careful evaluation of correlation between genotypes resulting from DNA analysis and phenotypes, especially in cases of atypical hematological parameters, in order to carry out an adequate diagnostic process finalized to appropriate genetic counseling. PMID- 28840769 TI - A Rare Case of Isolated Congenital Asplenia Presenting in Septic Shock: Howell Jolly Bodies a Clue to Early Diagnosis. PMID- 28840770 TI - Predicting tumor hypoxia in non-small cell lung cancer by combining CT, FDG PET and dynamic contrast-enhanced CT. AB - BACKGROUND: Most solid tumors contain inadequately oxygenated (i.e., hypoxic) regions, which tend to be more aggressive and treatment resistant. Hypoxia PET allows visualization of hypoxia and may enable treatment adaptation. However, hypoxia PET imaging is expensive, time-consuming and not widely available. We aimed to predict hypoxia levels in non-small cell lung cancer (NSCLC) using more easily available imaging modalities: FDG-PET/CT and dynamic contrast-enhanced CT (DCE-CT). MATERIAL AND METHODS: For 34 NSCLC patients, included in two clinical trials, hypoxia HX4-PET/CT, planning FDG-PET/CT and DCE-CT scans were acquired before radiotherapy. Scans were non-rigidly registered to the planning CT. Tumor blood flow (BF) and blood volume (BV) were calculated by kinetic analysis of DCE CT images. Within the gross tumor volume, independent clusters, i.e., supervoxels, were created based on FDG-PET/CT. For each supervoxel, tumor-to background ratios (TBR) were calculated (median SUV/aorta SUVmean) for HX4-PET/CT and supervoxel features (median, SD, entropy) for the other modalities. Two random forest models (cross-validated: 10 folds, five repeats) were trained to predict the hypoxia TBR; one based on CT, FDG, BF and BV, and one with only CT and FDG features. Patients were split in a training (trial NCT01024829) and independent test set (trial NCT01210378). For each patient, predicted, and observed hypoxic volumes (HV) (TBR > 1.2) were compared. RESULTS: Fifteen patients (3291 supervoxels) were used for training and 19 patients (1502 supervoxels) for testing. The model with all features (RMSE training: 0.19 +/- 0.01, test: 0.27) outperformed the model with only CT and FDG-PET features (RMSE training: 0.20 +/- 0.01, test: 0.29). All tumors of the test set were correctly classified as normoxic or hypoxic (HV > 1 cm3) by the best performing model. CONCLUSIONS: We created a data-driven methodology to predict hypoxia levels and hypoxia spatial patterns using CT, FDG-PET and DCE-CT features in NSCLC. The model correctly classifies all tumors, and could therefore, aid tumor hypoxia classification and patient stratification. PMID- 28840771 TI - Clinical outcome in prostate cancer treated with magnetic resonance imaging guided high-dose-rate brachytherapy combined with external beam radiotherapy. PMID- 28840772 TI - A health economic lifetime treatment pathway model for low back pain in Sweden. AB - AIMS: To develop a health economic model to evaluate the long-term costs and outcomes over the healthcare treatment pathway for patients with low back pain (LBP). MATERIALS AND METHODS: A health economic model, consisting of a decision tree structure with a Markov microsimulation model at the end of each branch, was created. Patients were followed from first observed clinical presentation with LBP until the age of 100 years or death. The underlying data to populate the model were based on Swedish national and regional registry data on healthcare resource use and sickness insurance in patients presenting with LBP in the Swedish region Vastra Gotaland during 2008-2012. Costs (outpatient healthcare visits, inpatient bed days, pharmaceuticals, productivity loss), EUR 2016, and quality-of-life based on EQ-5D data from the registries and published estimates were summarized over the lifetime of the patients with 3% annual discount. A lost quality-adjusted life year (QALY) was valued at ?70,000. RESULTS: Mean lifetime total cost was estimated at ?47,452/patient, of which indirect costs were 57%. Total lifetime economic burden for all patients coming to clinical presentation in Sweden per year was ?8.8bn. The average LBP patient was estimated to face a loss of 2.7 QALYs over their lifetime compared with the general population. For all patients in Sweden coming to clinical presentation in 1 year this gives 505,407 QALYs lost, valued at ?35.3bn. Adding the economic burden, the total societal burden amounts to ?44.1bn. CONCLUSION: This pathway model shows that most patients with LBP receive conservative care, and a minority consume high cost healthcare interventions like surgery. The model could be used to see broad economic effects of different patterns of healthcare provision in sub-groups with LBP and to estimate where it is possible to influence these pathways to increase utility for patients and for society. PMID- 28840774 TI - Electroencephalography Pattern Variations During Motor Skill Acquisition. AB - The present study examined how motor skill acquisition affects electroencephalography patterns and compared short- and long-term electroencephalography variations. For this purpose, 17 volunteers with no history of disease, aged 18 to 22 years, attended seven training sessions every other day to practice a pursuit tracking motor skill. Electroencephalography brainwaves were recorded and analyzed on the first and last days within pre- and post-training intervals. The results showed a significant decrease in performance error and variability with practice over time. This progress slowed at the end of training, and there was no significant improvement in individual performance at the last session. In accordance with performance variations, some changes occurred in brainwaves. Specifically, theta power at Fz and alpha power at Cz increased on the last test day, compared with the first, while the coherence of alpha at Fz-T3 and Fz-Cz decreased. beta Coherence between Fz-Cz was significantly reduced from pre- to posttest. Based on these results, power changes seem to be more affected by long-term training, whereas coherence changes are sensitive to both short- and long-term training. Specifically, beta coherence at Fz-Cz was more influenced by short-term effects of training, whereas theta power at Fz, alpha power at Cz, and alpha coherence at Fz-T3 and Fz-Cz were affected by longer training. PMID- 28840775 TI - Untargeted metabolomic analysis and pathway discovery in perinatal asphyxia and hypoxic-ischaemic encephalopathy. AB - Elucidating metabolic effects of hypoxic-ischaemic encephalopathy (HIE) may reveal early biomarkers of injury and new treatment targets. This study uses untargeted metabolomics to examine early metabolic alterations in a carefully defined neonatal population. Infants with perinatal asphyxia who were resuscitated at birth and recovered (PA group), those who developed HIE (HIE group) and healthy controls were all recruited at birth. Metabolomic analysis of cord blood was performed using direct infusion FT-ICR mass spectrometry. For each reproducibly detected metabolic feature, mean fold differences were calculated HIE vs. controls (DeltaHIE) and PA vs. controls (DeltaPA). Putative metabolite annotations were assigned and pathway analysis was performed. Twenty-nine putatively annotated metabolic features were significantly different in DeltaPA after false discovery correction ( q < 0.05), with eight of these also significantly altered in DeltaHIE. Altered putative metabolites included; melatonin, leucine, kynurenine and 3-hydroxydodecanoic acid which differentiated between infant groups (DeltaPA and DeltaHIE); and D-erythrose-phosphate, acetone, 3-oxotetradecanoic acid and methylglutarylcarnitine which differentiated across severity grades of HIE. Pathway analysis revealed DeltaHIE was associated with a 50% and 75% perturbation of tryptophan and pyrimidine metabolism, respectively. We have identified perturbed metabolic pathways and potential biomarkers specific to PA and HIE, which measured at birth, may help direct treatment. PMID- 28840776 TI - Naturally occurring antibodies in cats against dog erythrocyte antigens and vice versa. AB - Objectives The aim of this study was to investigate the presence of naturally occurring antibodies against canine erythrocyte antigens in cats and vice versa. The influence of canine and feline blood type on cross-match results was also studied. Methods Blood samples from 34 cats and 42 dogs were used to perform test tube major and minor cross-match tests and blood typing. Blood from each cat was cross-matched with blood from 2-6 dogs, for a total of 111 cross-match tests. Haemolysis, macro- and microagglutination were considered markers of a positive cross-match. Results Eighty-three overall major cross-match tests were positive at 37 degrees C, 86 at room temperature and 90 at 4 degrees C. The minor cross match tests were positive in all but two cross-matches performed at 37 degrees C, all tests performed at room temperature and all but one test performed at 4 degrees C. No cats tested totally negative at both major and minor cross-matches performed with samples from any single dog. Prevalence of warm natural antibodies against canine erythrocyte antigens was lower in type B cats than in type A cats, regardless of the blood type of donor dogs. Conclusions and relevance This study reveals a high prevalence of naturally occurring antibodies in cats against dog erythrocyte antigens and vice versa, and suggests that transfusion of cats with canine blood is not recommended as a routine procedure owing to the potential high risk of either acute severe or milder transfusion reactions. PMID- 28840773 TI - Prorenin receptor (PRR)-mediated NADPH oxidase (Nox) signaling regulates VEGF synthesis under hyperglycemic condition in ARPE-19 cells. AB - The stimulation of angiotensin II (Ang II), the effector peptide of renin angiotensin system, has been reported to increase the expression of vascular endothelial growth factor (VEGF) through the activation of the Ang II type 1 receptor (AT1R). In this study, we investigated whether hyperglycemia (HG, 33 mM glucose) in ARPE-19 cells could promote the expression of VEGF independently of Ang II through prorenin receptor (PRR), via an NADPH oxidase (Nox)-dependent mechanism. ARPE-19 cells were treated with the angiotensin converting enzyme (ACE) inhibitor perindopril to block the synthesis of Ang II. Treatment with HG induced VEGF expression in ARPE-19 cells, which was attenuated by pretreatment with the inhibitors of Nox, but not those of nitric oxide synthase, xanthine oxidase and mitochondrial O2 synthesis. In addition, Nox-derived [Formula: see text] and H2O2 signaling in the regulation of VEGF was determined by using both polyethylene glycol (PEG)-catalase (CAT) and PEG-superoxide dismutase (SOD). We demonstrated that small interfering RNA (siRNA)-mediated knockdown of PRR, Nox2 and Nox4 significantly reduced the HG-induced stimulation of VEGF. On the other hand, Nox4 overexpression significantly potentiated PRR-induced stimulation of VEGF under hyperglycemia in ARPE-19 cells. Furthermore, Nox4 was shown to be associated with enhanced activities of ERK1/2 and NF-kappaB (p65), indicating their involvement in PRR-induced activation of VEGF under HG in ARPE-19 cells. Our results support the hypothesis that Nox4-derived reactive oxygen species (ROS) signaling is implicated in the hyperglycemia-induced increase of VEGF expression through PRR in ARPE-19 cells. However, further work is needed to evaluate the role of PRR and Nox-s in HG-induced stimulation of VEGF in vivo. PMID- 28840777 TI - In utero exposure to alcohol alters reactivity of cerebral arterioles. AB - Our goal was to examine whether in utero exposure to alcohol impaired reactivity of cerebral arterioles during development. We fed Sprague-Dawley dams a liquid diet with or without alcohol (3% ethanol) for the duration of pregnancy (21-23 days). Around 4-6 weeks after birth, we examined reactivity of cerebral arterioles to eNOS- (ADP) and nNOS-dependent (NMDA) agonists in the offspring. We found that in utero exposure to alcohol attenuated responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in rats exposed to alcohol in utero. L-NMMA reduced responses to agonists in control rats, but not in rats exposed to alcohol in utero. Treatment of dams with apocynin for the duration of pregnancy rescued the impairment in reactivity to ADP and NMDA in the offspring. Protein expression of NOX-2 and NOX-4 was increased in alcohol rats compared to control rats. We also found an increase in superoxide levels in the cortex of rats exposed to alcohol in utero. Our findings suggest that in utero exposure to alcohol impairs eNOS and nNOS reactivity of cerebral arterioles via a chronic increase in oxidative stress. PMID- 28840778 TI - Structure, function, and regulation of enzymes involved in amino acid metabolism of bacteria and archaea. AB - Amino acids are essential components in all organisms because they are building blocks of proteins. They are also produced industrially and used for various purposes. For example, L-glutamate is used as the component of "umami" taste and lysine has been used as livestock feed. Recently, many kinds of amino acids have attracted attention as biological regulators and are used for a healthy life. Thus, to clarify the mechanism of how amino acids are biosynthesized and how they work as biological regulators will lead to further effective utilization of them. Here, I review the leucine-induced-allosteric activation of glutamate dehydrogenase (GDH) from Thermus thermophilus and the relationship with the allosteric regulation of GDH from mammals. Next, I describe structural insights into the efficient production of L-glutamate by GDH from an excellent L-glutamate producer, Corynebacterium glutamicum. Finally, I review the structural biology of lysine biosynthesis of thermophilic bacterium and archaea. PMID- 28840779 TI - Continuum of Care for Inmates Taking Psychiatric Medications While Incarcerated in Minnesota County Jails. AB - Mental illness is more prevalent among adult inmates in Minnesota county jails than nationally. All 78 Minnesota county jails were surveyed about their continuum-of-care procedures to help ensure that inmates who have mental illness continue to receive psychiatric medications after release. Of the 28 county jails responding to the survey (36%), most estimated that greater than 40% of their inmates receive medication for mental illness during incarceration. But while 89% of respondents reported that inmates are frequently taking medication(s) to treat mental illness at release, prerelease planning for these inmates was rarely undertaken. Few Minnesota jails reported having continuum-of-care procedures in place for inmates who have mental illness when these inmates are released back into the community. Jail staff desire greater collaboration between jails, human services agencies, and community mental health providers to help support discharge planning and enhance the continuum of care for inmates who have mental illness. PMID- 28840780 TI - A novel multi-walled carbon nanotube-based antibody conjugate for quantitative and semi-quantitative lateral flow assays. AB - In this study, the multi-walled carbon nanotubes (MWCNTs) were applied in lateral flow strips (LFS) for semi-quantitative and quantitative assays. Firstly, the solubility of MWCNTs was improved using various surfactants to enhance their biocompatibility for practical application. The dispersed MWCNTs were conjugated with the methamphetamine (MET) antibody in a non-covalent manner and then manufactured into the LFS for the quantitative detection of MET. The MWCNTs-based lateral flow assay (MWCNTs-LFA) exhibited an excellent linear relationship between the values of test line and MET when its concentration ranges from 62.5 to 1500 ng/mL. The sensitivity of the LFS was evaluated by conjugating MWCNTs with HCG antibody and the MWCNTs conjugated method is 10 times more sensitive than the one conjugated with classical colloidal gold nanoparticles. Taken together, our data demonstrate that MWCNTs-LFA is a more sensitive and reliable assay for semi-quantitative and quantitative detection which can be used in forensic analysis. PMID- 28840781 TI - The role of ethnicity and socioeconomic status in Southeast Asian mothers' parenting sensitivity. AB - Past research indicates that socioeconomic status (SES) accounts for differences in sensitivity across ethnic groups. However, comparatively little work has been conducted in Asia, with none examining whether ethnicity moderates the relation between SES and sensitivity. We assessed parenting behavior in 293 Singaporean citizen mothers of 6-month olds (153 Chinese, 108 Malay, 32 Indian) via the Maternal Behavioral Q-Sort for video interactions. When entered into the same model, SES (F(1,288) = 17.777, p < .001), but not ethnicity, predicted maternal sensitivity (F(2,288) = .542, p = .582). However, this positive relation between SES and sensitivity was marginally moderated by ethnicity. SES significantly positively predicted sensitivity in Chinese, but not Malay dyads. Within Indian dyads, SES marginally positively predicted sensitivity only when permanent residents were included in analyses. We discuss the importance of culture on perceived SES-associated stress. However, because few university-educated Malays participated, we also consider whether university education, specifically, positively influences sensitivity. PMID- 28840782 TI - Comparison of three blood transfusion guidelines applied to 31 feline donors to minimise the risk of transfusion-transmissible infections. AB - Objectives The increased demand for animal blood transfusions creates the need for an adequate number of donors. At the same time, a high level of blood safety must be guaranteed and different guidelines (GLs) deal with this topic. The aim of this study was to evaluate the appropriateness of different GLs in preventing transfusion-transmissible infections (TTI) in Italian feline blood donors. Methods Blood samples were collected from 31 cats enrolled as blood donors by the owners' voluntary choice over a period of approximately 1 year. Possible risk factors for TTI were recorded. Based on Italian, European and American GLs, specific TTI, including haemoplasmas, feline leukaemia virus (FeLV), feline immunodeficiency virus (FIV), Anaplasma phagocytophilum, Ehrlichia species, Bartonella species, Babesia species, Theileria species, Cytauxzoon species, Leishmania donovani sensu lato and feline coronavirus (FCoV), were screened. Rapid antigen and serological tests and biomolecular investigations (PCR) were used. Several PCR protocols for haemoplasma and FeLV DNA were compared. Results The presence of at least one recognised risk factor for TTI was reported in all cats. Results for FIV and FeLV infections were negative using rapid tests, whereas five (16.1%) cats were positive for FCoV antibodies. Four (12.9%) cats were PCR positive for haemoplasma DNA and one (3.2%) for FeLV provirus, the latter being positive only using the most sensitive PCR protocol applied. Other TTI were not detected using PCR. Conclusions and relevance Blood safety increases by combining the recommendations of different GLs. To reduce the risk of TTI, sensitive tests are needed and the choice of the best protocol is a critical step in improving blood safety. The cost and time of the screening procedures may be reduced if appropriate tests are selected. To this end, the GLs should include appropriate recruitment protocols and questionnaire-based risk profiles to identify suitable donors. PMID- 28840783 TI - The Challenges of Mobilizing Workers on Gender Issues: Lessons from Two Studies on the Occupational Health of Teachers in Quebec: Les defis de mobiliser les travailleur.ses sur la question du genre: Constats issus de deux recherches portant sur la sante au travail d'enseignant.es du Quebec. AB - In partnership with the largest teachers' union confederation in Quebec ( Centrale des syndicats du Quebec), two qualitative research studies that integrate gender were conducted in the teaching community. These ergonomic studies advocated a participatory approach involving interviews and observations with high school teachers (thirty-five) and female teachers responsible for vocational training in trades with predominantly male clientele (twelve). The results revealed that gender influences work success by reducing the operational leeway available for female teachers to carry out their work and protect their health. In both studies, it was difficult to discuss these results with the teachers, especially with female teachers. Resistance, even denial, was present among high school teachers, while, in vocational training, resignation and a feeling of helplessness were observed. These reactions demonstrate that taking gender into account in prevention poses particular challenges that need to be addressed in order to promote equality between women and men in workplaces. PMID- 28840784 TI - Indirect regulation of CYP2C19 gene expression via DNA methylation. AB - 1. Despite speculation that the CYP2C19 gene may contain CpG islands, there has been little direct assessment of the role for epigenetics in the regulation of this pharmacogene. The effect of 5-aza-2'-deoxycytidine (5azaDC), a DNA methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylases, on the expression of CYP2C19 and five of its known transcription factors (TF) has been assessed in cell lines derived from neoplastic liver and intestine. 2. CYP2C19 mRNA was substantially up-regulated (>18-fold) after treatment with 5azaDC despite the fact that the two intronic CpG islands in this gene remained substantially methylated (>50%). The TF NR1I3 was also consistently up-regulated after treatment with 5azaDC. NR1I3 lacks CpG islands in the proximal promoter region and is therefore not likely to be directly regulated by DNA methylation. Therefore, it appears that 5azaDC treatment affects an unidentified upstream regulator of both CYP2C19 and/or NR1I3. This is supported by the fact that the relationships between TF for CYP2C19 and the expression of this target gene in human liver samples only accounted for ~70% of the variability of CYP2C19 mRNA levels. These data suggest that an yet un-identified 'master regulator' of CYP2C19 transcription could itself be a target of epigenetic control. PMID- 28840785 TI - Wheat streak mosaic virus Coat Protein Deletion Mutants Elicit More Severe Symptoms Than Wild-Type Virus in Multiple Cereal Hosts. AB - Previously, we reported that coat protein (CP) of Wheat streak mosaic virus (WSMV) (genus Tritimovirus, family Potyviridae) tolerates deletion of amino acids 36 to 84 for efficient systemic infection of wheat. In this study, we demonstrated that WSMV mutants with deletion of CP amino acids 58 to 84 but not of 36 to 57 induced severe chlorotic streaks and spots, followed by acute chlorosis in wheat, maize, barley, and rye compared with mild to moderate chlorotic streaks and mosaic symptoms by wild-type virus. Deletion of CP amino acids 58 to 84 from the WSMV genome accelerated cell-to-cell movement, with increased accumulation of genomic RNAs and CP, compared with the wild-type virus. Microscopic examination of wheat tissues infected by green fluorescent protein tagged mutants revealed that infection by mutants lacking CP amino acids 58 to 84 caused degradation of chloroplasts, resulting in acute macroscopic chlorosis. The profile of CP-specific proteins was altered in wheat infected by mutants causing acute chlorosis, compared with mutants eliciting wild-type symptoms. All deletion mutants accumulated CP-specific major protein similarly to that in wild-type virus; however, mutants that elicit acute chlorosis failed to accumulate a 31-kDa minor protein compared with wild-type virus or mutants lacking amino acids 36 to 57. Taken together, these data suggest that deletion of CP amino acids 58 to 84 from the WSMV genome enhanced accumulation of CP and genomic RNA, altered CP specific protein profiles, and caused severe symptom phenotypes in multiple cereal hosts. PMID- 28840786 TI - Type III Secretion-Dependent and -Independent Phenotypes Caused by Ralstonia solanacearum in Arabidopsis Roots. AB - The causal agent of bacterial wilt, Ralstonia solanacearum, is a soilborne pathogen that invades plants through their roots, traversing many tissue layers until it reaches the xylem, where it multiplies and causes plant collapse. The effects of R. solanacearum infection are devastating, and no effective approach to fight the disease is so far available. The early steps of infection, essential for colonization, as well as the early plant defense responses remain mostly unknown. Here, we have set up a simple, in vitro Arabidopsis thaliana-R. solanacearum pathosystem that has allowed us to identify three clear root phenotypes specifically associated to the early stages of infection: root-growth inhibition, root-hair formation, and root-tip cell death. Using this method, we have been able to differentiate, on Arabidopsis plants, the phenotypes caused by mutants in the key bacterial virulence regulators hrpB and hrpG, which remained indistinguishable using the classical soil-drench inoculation pathogenicity assays. In addition, we have revealed the previously unknown involvement of auxins in the root rearrangements caused by R. solanacearum infection. Our system provides an easy-to-use, high-throughput tool to study R. solanacearum aggressiveness. Furthermore, the observed phenotypes may allow the identification of bacterial virulence determinants and could even be used to screen for novel forms of early plant resistance to bacterial wilt. PMID- 28840787 TI - Altering Plant Defenses: Herbivore-Associated Molecular Patterns and Effector Arsenal of Chewing Herbivores. AB - Chewing herbivores, such as caterpillars and beetles, while feeding on the host plant, cause extensive tissue damage and release a wide array of cues to alter plant defenses. Consequently, the cues can have both beneficial and detrimental impacts on the chewing herbivores. Herbivore-associated molecular patterns (HAMPs) are molecules produced by herbivorous insects that aid them to elicit plant defenses leading to impairment of insect growth, while effectors suppress plant defenses and contribute to increased susceptibility to subsequent feeding by chewing herbivores. Besides secretions that originate from glands (e.g., saliva) and fore- and midgut regions (e.g., oral secretions) of chewing herbivores, recent studies have shown that insect frass and herbivore-associated endosymbionts also play a critical role in modulating plant defenses. In this review, we provide an update on a growing body of literature that discusses the chewing insect HAMPs and effectors and the mechanisms by which they modulate host defenses. Novel "omic" approaches and availability of new tools will help researchers to move forward this discipline by identifying and characterizing novel insect HAMPs and effectors and how these herbivore-associated cues are perceived by host plant receptors. PMID- 28840788 TI - CaHDZ27, a Homeodomain-Leucine Zipper I Protein, Positively Regulates the Resistance to Ralstonia solanacearum Infection in Pepper. AB - Homeodomain-leucine zipper class I (HD-Zip I) transcription factors have been functionally characterized in plant responses to abiotic stresses, but their roles in plant immunity are poorly understood. Here, a HD-Zip I gene, CaHZ27, was isolated from pepper (Capsicum annum) and characterized for its role in pepper immunity. Quantitative real-time polymerase chain reaction showed that CaHDZ27 was transcriptionally induced by Ralstonia solanacearum inoculation and exogenous application of methyl jasmonate, salicylic acid, or ethephon. The CaHDZ27-green fluorescent protein fused protein was targeted exclusively to the nucleus. Chromatin immunoprecipitation demonstrated that CaHDZ27 bound to the 9-bp pseudopalindromic element (CAATAATTG) and triggered beta-glucuronidase expression in a CAATAATTG-dependent manner. Virus-induced gene silencing of CaHDZ27 significantly attenuated the resistance of pepper plants against R. solanacearum and downregulated defense-related marker genes, including CaHIR1, CaACO1, CaPR1, CaPR4, CaPO2, and CaBPR1. By contrast, transient overexpression of CaHDZ27 triggered strong cell death mediated by the hypersensitive response and upregulated the tested immunity-associated marker genes. Ectopic CaHDZ27 expression in tobacco enhances its resistance against R. solanacearum. These results collectively suggest that CaHDZ27 functions as a positive regulator in pepper resistance against R. solanacearum. Bimolecular fluorescence complementation and coimmunoprecipitation assays indicate that CaHDZ27 monomers bind with each other, and this binding is enhanced significantly by R. solanacearum inoculation. We speculate that homodimerization of CaHZ27 might play a role in pepper response to R. solanacearum, further direct evidence is required to confirm it. PMID- 28840789 TI - Ultradian Rhythmicity in Sleep-Wakefulness Is Related to Color in Nestling Barn Owls. AB - The possession of a rhythm is usually described as an important adaptation to regular changing environmental conditions such as the light-dark cycle. However, recent studies have suggested plasticity in the expression of a rhythm depending on life history and environmental factors. Barn owl ( Tyto alba) nestlings show variations in behavior and physiology in relation to the size of black feather spots, a trait associated with many behavioral and physiological phenotypes including the circadian expression of corticosterone and the regulation of body mass. This raises the possibility that individual spottiness could be associated with rhythmicity in sleep-wakefulness. Owlets showed ultradian rhythms in sleep wakefulness, with a period length of 4.5 to 4.9 h. The period length of wakefulness and non-REM sleep was shorter in heavily compared to lightly spotted female nestlings, whereas in males, the opposite result was found. Furthermore, male and female nestlings displaying small black spots showed strong rhythmicity levels in wakefulness and REM sleep. This might be an advantage in a stable environment with predictable periodic changes in light, temperature, or social interactions. Heavily spotted nestlings displayed weak rhythms in wakefulness and REM sleep, which might enable them to be more flexible in reactions to unexpected events such as predation or might be a mechanism to save energy. These findings are consistent with previous findings showing that large-spotted nestlings switch more frequently between wakefulness and sleep, resulting in higher levels of vigilance compared to small-spotted conspecifics. Thus, nestlings with larger black feather spots might differently handle the trade-off between wakefulness and sleep, attention, and social interactions compared to nestlings with smaller black spots. PMID- 28840790 TI - A New Rhodopsin Influences Light-dependent Daily Activity Patterns of Fruit Flies. AB - Rhodopsin 7 ( Rh7), a new invertebrate Rhodopsin gene, was discovered in the genome of Drosophila melanogaster in 2000, but its function has remained elusive. We generated an Rh7 null mutant ( Rh70) by P element-mediated mutagenesis and found that an absence of Rh7 had significant effects on fly activity patterns during light-dark (LD) cycles: Rh70 mutants exhibited less morning activity and a longer siesta than wild-type controls. Consistent with these results, we found that Rh7 appears to be expressed in a few dorsal clock neurons that have been previously implicated in the control of the siesta. We also found putative Rh7 expression in R8 photoreceptor cells of the compound eyes and in the Hofbauer Buchner eyelets, which have been shown to control the precise timing of locomotor activity. The absence of Rh7 alone impaired neither the flies' responses to constant white light nor the ability to follow phase shifts of white LD cycles. However, in blue light (470 nm), Rh70 mutants needed significantly longer to synchronize than wild-type controls, suggesting that Rh7 is a blue light sensitive photopigment with a minor contribution to circadian clock synchronization. In combination with mutants that lacked additionally cryptochrome-based and/or eye-based light input to the circadian clock, the absence of Rh7 provoked slightly stronger effects. PMID- 28840791 TI - Pediatric Pathology Fellowship Recruitment-Report of a Survey Conducted by the Fellowship Committee of the Society for Pediatric Pathology. AB - Pediatric pathology (PP) is a subspecialty of pathology encompassing disease states during human development from the fetus to the young adult. Despite the existence of ACGME-accredited fellowship programs and opportunity for pediatric pathology subspecialty board certification, many pediatric pathology fellowship positions remain unfilled in North America. We sought to understand the difficulties in recruitment to the PP training programs by conducting a survey. A 3-pronged survey targeting pathology residents (PR), PP fellows and recent fellowship graduates (F&G), and PP training programs was conducted. Three separate questionnaires were prepared, one for each group; and administered online via SurveyMonkey. There were 175 responses to PR survey, 29 to F&G and 19 to programs survey. The results of the PR and F&G survey revealed that trainees select a subspecialty early in their residency training, primarily based on their interest, followed by prospects of employment. Nearly half of resident respondents had discounted pediatric pathology subspecialty training without prior exposure to the specialty. Senior residents and faculty members were reported as the main source for fellowship information for residents choosing subspecialty training and the choice of the training program was mostly dictated by geographic location. Most fellow recruits are racially diverse, female, and American medical graduates. Pathology residents decide on subspecialty training based on their interest; however, many are not exposed to pediatric pathology early on in training. The survey results suggest that existing PP fellowship positions likely will continue to exceed demand for subspecialty training. The results of the study could aid in developing strategies to boost recruitment to PP. PMID- 28840792 TI - Epidemiology of Adaptive and Intrinsic Polymyxin Resistance Mechanisms by Comparing Polymyxin-Resistant Pathogen Prevalence in a One-Year Follow-Up Survey. PMID- 28840793 TI - Role of Ethanol Locks in Reducing Bloodstream Infections in Adults on Parenteral Nutrition. PMID- 28840794 TI - Moving to a More Level Playing Field: The Need for Risk Adjustment of Publicly Reported Hospital CLABSI Performance. PMID- 28840795 TI - Psychrobacter pasteurii and Psychrobacter piechaudii sp. nov., two novel species within the genus Psychrobacter. AB - Six Gram-negative, non-motile, non-spore-forming, non-pigmented, oxidase- and catalase-positive bacterial strains were deposited in 1972, in the Collection of the Institut Pasteur (CIP), Paris, France. The strains, previously identified as members of the genus Moraxella on the basis of their phenotypic and biochemical characteristics, were placed within the genus Psychrobacter based on the results from comparative 16S rRNA gene sequence studies. Their closest phylogenetic relatives were Psychrobacter sanguinis CIP 110993T, Psychrobacter phenylpyruvicus CIP 82.27T and Psychrobacter lutiphocae CIP 110018T. The DNA G+C contents were between 42.1 and 42.7 mol%. The predominant fatty acids were C18 : 1omega9c, C16 : 0, C12 : 0 3-OH, and C18 : 0. Average nucleotide identity between the six strains and their closest phylogenetic relatives, as well as their phenotypic characteristics, supported the assignment of these strains to two novel species within the genus Psychrobacter. The proposed names for these strains are Psychrobacter pasteurii sp. nov., for which the type strain is A1019T (=CIP 110853T=CECT 9184T), and Psychrobacter piechaudii sp. nov., for which the type strain is 1232T (=CIP110854T=CECT 9185T). PMID- 28840796 TI - Monaibacterium marinum, gen. nov, sp. nov, a new member of the Alphaproteobacteria isolated from seawater of Menai Straits, Wales, UK. AB - The novel Gram-negative, aerobic, non-motile, non-spore-forming, short-rod bacterium, strain C7T, was isolated from a seawater sample from Menai Straits (Wales, UK) and characterized. Phylogenetic analysis of 16S rRNA gene sequences showed that this strain represented a distinct lineage within the Roseobacterclade of family Rhodobacteracea within Alphaproteobacteria. The members of the genera Pontivivens (Pontivivensinsulae GYSW-23T), Celeribacter (Celeribactermanganoxidans DY2-5T), Donghicola (Donghicola eburneus SW-277T), Roseovarius (Roseovariushalotolerans HJ50T and Roseovariuspacificus 81-2T), Cribrihabitans (Cribrihabitansmarinus CZ-AM5T) and Aestuariihabitans (Aestuariihabitansbeolgyonensis BB-MW15T) were the closest relatives with 16S rRNA gene sequence identities between 93.4 and 95.6 %. Strain C7T could utilize a restricted number of complex substrates with a preference for yeast extract and tryptone, which is consistent with earlier observations that peptides may serve as an important energy and carbon source for bacteria from the Roseobacterclade. Growth occurred in the absence of sodium ions. The isolate C7T is a mesophilic bacterium that optimally grows at 20 degrees C. The strain can grow under microaerophilic conditions. The major fatty acid was C18 : 1cis d11. The only detected ubiquinone was Q10. The polar lipids of strain C7T were phosphatidylglycerol, two unknown aminolipids and three unknown lipids. The DNA G+C content of the strain was 60.0 mol%. Based on the results of the morphological, physiological and phylogenetic analyses, the new genus, Monaibacterium gen. nov., to include the new species Monaibacterium marinum sp. nov., is proposed. Strain C7T (=DSM 100241T, =LMG 28800T) is the type and only strain of M. marinum. PMID- 28840797 TI - Flavobacterium gossypii sp. nov. isolated from the root tissue of field-grown cotton. AB - A yellow-pigmented bacterial strain, JM-222T, isolated from the root tissue of field-grown cotton (Gossypium hirsutum) in Auburn, Alabama, USA, was studied for its taxonomic allocation. Cells of the isolate were rod-shaped and Gram-stain negative. A blast analysis using the EzTaxon database showed that strain JM-222T shared highest 16S rRNA gene sequence similarity with the type strain of Flavobacterium endophyticum (98.9 %) followed by Flavobacterium qiangtangense (96.7 %). 16S rRNA gene sequence similarities to all other Flavobacterium species were below 95 %. The fatty acid profile of strain JM-222T consisted of the major fatty acids C15 : 0, iso-C15 : 0, iso-C15 : 0 2-OH/C16 : 1omega7c and iso-C17 : 0 3-OH. Major compounds in the polar lipid profile were phosphatidylethanolamine and several unidentified lipids. The quinone system consisted predominantly of menaquinone MK-6. The polyamine pattern consisted of the major compound sym homospermidine and only minor amounts of other polyamines. These data and the differential biochemical and chemotaxonomic properties showed that the isolate JM 222T represents a novel species of the genus Flavobacterium, for which the name Flavobacterium gossypii sp. nov. is proposed. The type strain is JM-222T (LMG 28821T=CCM 8610T). PMID- 28840798 TI - Dyella caseinilytica sp. nov., Dyella flava sp. nov. and Dyella mobilis sp. nov., isolated from forest soil. AB - Three strains, DHOB09T, DHOC52T and DHON07T, were isolated from the forest soil of Dinghushan Biosphere Reserve, Guangdong Province, PR China. They were all Gram stain-negative, aerobic, rod-shaped cells. The ranges (optimum) for the temperature, pH and NaCl concentration for growth of DHOB09T, DHOC52T and DHON07T were 10-42 (25-28) degrees C, pH 5.5-9.0 (7.0-7.5) and 0-4.0 (0-0.5) % (w/v); 10 42 (28) degrees C, pH 4.0-7.0 (4.5-6.5) and 0-2.0 (0) % (w/v) and 10-37 (25-28) degrees C, pH 4.0-7.5 (5.5-6.0) and 0-2.5 (0) % (w/v), respectively. Phylogenetic analysis based on 16S rRNA gene sequences showed that DHOB09T, DHOC52T and DHON07T formed a phyletic cluster with seven species of the genus Dyella within the major clade of Dyella with sequence similarities ranged from 96.9 to 98.6 %. This indicated that the three strains may represent three novel species of the genus Dyella. This result was also strongly supported by the concatenated analysis of partial gyrB, lepA and recA gene sequences. DNA-DNA hybridization between strains DHON07T and DHOB09T, as well as DHON07T and Dyella koreensis BB4T was much lower than 70 %. The G+C content of strains DHOB09T, DHOC52T and DHON07T were 59.4, 60.7 and 59.5 %, respectively. The major fatty acids of the three strains were iso-C15 : 0, iso-C16 : 0 and iso-C17 : 0 and the predominant respiratory lipoquinone was ubiquinone-8. All of the physiological, phylogenetic and chemotaxonomic data showed that strains DHOB09T, DHOC52T and DHON07T are distinctive from each other and from all species of the genus Dyellawith validly published names. Therefore, we suggest that they represent three novel species of the genus, for which the names Dyella caseinilytica sp. nov. (type strain DHOB09T=CGMCC 1.15434T=LMG 29202T), Dyella flava sp. nov. (type strain DHOC52T=NBRC 111979T=KCTC 52128T) and Dyella mobilis sp. nov. (type strain DHON07T=CGMCC 1.15400T=NBRC 111475T) are proposed. PMID- 28840799 TI - Pigmentiphaga aceris sp. nov., isolated from tree sap. AB - Two Gram-stain-negative bacterial strains, SAP-32T and SAP-36, were isolated from sap drawn from the Acer pictum from Mount Halla in Jeju, Republic of Korea. The organisms were strictly aerobic, non-sporulating, motile rods and showed growth at 10-30 degrees C, pH 7-8 and with 0-2 % NaCl. The major isoprenoid quinone was Q-8. The predominant fatty acids were C16 : 0, cyclo-C17 : 0, summed feature 3 and C18 : 0. The polar lipids contained phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, an unknown aminophosphoglycolipid, an unknown glycolipid, an unknown phospholipid and two unknown lipids. The DNA G+C content was 64.4 mol%. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that SAP-32T and SAP-36 formed a distinct cluster with members of the genus Pigmentiphaga within the family Alcaligenaceae. Both strains showed 16S rRNA gene sequence similarity of 100 % to each other. The closest relatives of the isolates were Pigmentiphaga daeguensis (97.08 % sequence similarity), Pigmentiphaga kullae (97.01 %) and Pigmentiphaga litoralis (96.73 %). On the basis of data from phenotypic, chemotaxonomic and phylogenetic analyses, SAP-32T (=KCTC 52619T=DSM 104039T) and SAP-36 (=KCTC 52620=DSM 104072) represent members of a novel species of the genus Pigmentiphaga, for which the name Pigmentiphaga aceris sp. nov. is proposed. PMID- 28840800 TI - Altererythrobacter aquaemixtae sp. nov., isolated from the junction between the ocean and a freshwater spring. AB - A Gram-stain-negative, aerobic, non-motile and ovoid or rod-shaped bacterial strain, designated JSSK-8T, was isolated from the place where the ocean and a freshwater spring meet at Jeju Island, South Korea. Strain JSSK-8T grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2.0 % (w/v) NaCl. In a neighbour-joining phylogenetic tree based on 16S rRNA gene sequences, strain JSSK 8T fell within the clade comprising the type strains of species of the genus Altererythrobacter. Strain JSSK-8T exhibited 16S rRNA gene sequence similarity values of 97.7 and 97.2 % to the type strains of Altererythrobacteraestiaquae and Altererythrobacterluteolus, respectively, and of 93.5-96.2 % to the type strains of the other species of the genus Altererythrobacter. Strain JSSK-8T contained Q 10 as the predominant ubiquinone and C18 : 1omega7c, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c), C17 : 1omega6c, C16 : 0 and 11-methyl C18 : 1omega7c as the major fatty acids. The major polar lipids detected in strain JSSK 8T were phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and sphingoglycolipid. The DNA G+C content of strain JSSK-8T was 59.0 mol%, and its mean DNA-DNA relatedness values with the type strains of A. aestiaquae and A. luteolus were 13 and 16 %, respectively. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain JSSK-8T is separated from recognized species of the genus Altererythrobacter. On the basis of the data presented, strain JSSK-8T is considered to represent a novel species of the genus Altererythrobacter, for which the name Altererythrobacter aquaemixtae sp. nov. is proposed. The type strain is JSSK-8T (=KCTC 52763T=NBRC 112764T). PMID- 28840801 TI - Pelagibacterium lentulum sp. nov., a marine bacterium from the culture broth of Picochlorum sp. 122. AB - A Gram-stain-negative, motile, non-spore-forming, rod-shaped bacterium, designated strain B2T, was isolated from the culture broth of a marine microalga, Picochlorum sp. 122. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain B2T forms a robust cluster with members of the genus Pelagibacterium, and shares the highest sequence similarity of 96.80 % with Pelagibacterium halotolerans CGMCC 1.7692T. Optimal growth of strain B2T was observed at 33 degrees C, at pH 8 and in the presence of 1 % (w/v) NaCl. The predominant ubiquinone of strain B2T was Q-10, and the G+C content of the genomic DNA was 58.6 mol%. The major fatty acid profile comprised C18 : 1omega7c/omega6c, C19 : 0 cyclo omega8c and C16 : 0. The major polar lipids of strain B2T were diphosphatidylglycerol, phosphatidylglycerol, two unidentified glycolipids and seven unidentified lipids. Comprehensive analyses based on a polyphasic characterization of strain B2T indicated that it represents a novel species of the genus Pelagibacterium, for which the name Pelagibacterium lentulum sp. nov. is proposed. The type strain is B2T (=MCCC 1K03218T=CGMCC 1.15896T=KCTC 52551T). PMID- 28840802 TI - Mabikibacter ruber gen. nov., sp. nov., a bacterium isolated from marine sediment, and proposal of Mabikibacteraceae fam. nov. in the class Alphaproteobacteria. AB - Bacterial strain YP382-1-AT was isolated from marine sediment at Gimnyeong Beach, Jeju Island, Republic of Korea. This strain was found to be aerobic and Gram stain-negative, with red to purple pigmentation. Cells of strain YP382-1-AT were motile, had a single polar flagellum and were short rod-shaped. The predominant quinone in strain YP382-1-AT was Q-10. The major fatty acid was C18 : 1omega7c and the DNA G+C content was 60.3 mol%. Phylogenetic analysis based on comparisons of 16S rRNA gene sequences showed that strain YP382-1-AT belonged to the order Rhizobiales in the class Alphaproteobacteria. This strain exhibited very low 16S rRNA gene sequence similarity (no higher than 94.5 %) to the type strains of recognized bacterial species of the order Rhizobiales. Strain YP382-1-AT appeared as a distinct branch within Rhizobiales in the phylogenetic tree generated. On the basis of the data presented, strain YP382-1-AT is considered to represent a novel species of a new genus, classified within a new family. The name Mabikibacter ruber gen. nov., sp. nov., of the new family Mabikibacteraceae fam. nov. is proposed. The type strain of Mabikibacter ruber is YP382-1-AT (=JCM 31727T=KCCM 90265T). PMID- 28840803 TI - Isolation and full-genome sequences of Japanese encephalitis virus genotype I strains from Cambodian human patients, mosquitoes and pigs. AB - Japanese encephalitis remains the most important cause of viral encephalitis in humans in several southeast Asian countries, including Cambodia, causing at least 65 000 cases of encephalitis per year. This vector-borne viral zoonosis - caused by Japanese encephalitis virus (JEV) - is considered to be a rural disease and is transmitted by mosquitoes, with birds and pigs being the natural reservoirs, while humans are accidental hosts. In this study we report the first two JEV isolations in Cambodia from human encephalitis cases from two studies on the aetiology of central nervous system disease, conducted at the two major paediatric hospitals in the country. We also report JEV isolation from Culextritaeniorhynchus mosquitoes and from pig samples collected in two farms, located in peri-urban and rural areas. Out of 11 reverse-transcription polymerase chain reaction-positive original samples, we generated full-genome sequences from 5 JEV isolates. Five additional partial sequences of the JEV NS3 gene from viruses detected in five pigs and one complete coding sequence of the envelope gene of a strain identified in a pig were generated. Phylogenetic analyses revealed that JEV detected in Cambodia belonged to genotype I and clustered in two clades: genotype I-a, mainly comprising strains from Thailand, and genotype I b, comprising strains from Vietnam that dispersed northwards to China. Finally, in this study, we provide proof that the sequenced JEV strains circulate between pigs, Culex tritaeniorhynchus and humans in the Phnom Penh vicinity. PMID- 28840804 TI - Kodamaea neixiangensis f.a., sp. nov. and Kodamaea jinghongensis f.a., sp. nov., two yeast species isolated from rotting wood. AB - Seven strains representing two novel yeast species were isolated from rotting wood in Henan and Yunnan Provinces, PR China. The results of phylogenetic analysis based on the D1/D2 domains of the large subunit (LSU) rRNA gene revealed that these two species are members of the genus Kodamaea, although the formation of ascospores was not observed. Kodamaea neixiangensis f.a., sp. nov. (type strain NYNU 167139T=CICC 33170T=CBS 14699T) formed a clade with Candida kaohsiungensis and Candida hsintzibuensis, from which it differed by 10-16 substitutions in the D1/D2 domain. The ITS sequences of K. neixiangensis sp. nov. differed by 27 substitutions from those of the type strain of C. kaohsiungensis. The most closely related species with a validly published name to Kodamaea jinghongensis f.a., sp. nov. (type strain NYNU 167162T=CICC 33171T=CBS 14700T) was Candida fukazawae, but this differed by 14 substitutions in the D1/D2 domain and by 15 substitutions in the ITS region. PMID- 28840805 TI - Pathogenic, phenotypic and molecular characterisation of Xanthomonas nasturtii sp. nov. and Xanthomonas floridensis sp. nov., new species of Xanthomonas associated with watercress production in Florida. AB - We describe two new species of the genus Xanthomonas, represented by yellow mucoid bacterial strains isolated from diseased leaves of watercress (Nasturtium officinale) produced in Florida, USA. One strain was pathogenic on watercress, but not in other species including a range of brassicas; other strains were not pathogenic in any of the tested plants. Data from Biolog carbon source utilization tests and nucleotide sequence data from 16S and gyrB loci suggested that both pathogenic and non-pathogenic strains were related to, yet distinct from, previously described Xanthomonas species. Multilocus sequence analysis and whole genome-wide comparisons of the average nucleotide identity (ANI) of genomes of two strains from watercress showed that these are distinct and share less than 95 % ANI with all other known species; the non-pathogenic strain WHRI 8848 is close to Xanthomonascassavae (ANI of 93.72 %) whilst the pathogenic strain WHRI 8853 is close to a large clade of species that includes Xanthomonasvesicatoria (ANI <=90.25 %). Based on these results, we propose that both strains represent new Xanthomonas species named Xanthomonas floridensis sp. nov. (type strain WHRI 8848=ATCC TSD-60=ICMP 21312=LMG 29665=NCPPB 4601) and Xanthomonas nasturtii sp. nov. (type strain WHRI 8853=ATCC TSD-61=ICMP 21313=LMG 29666=NCPPB 4600), respectively. The presence of non-pathogenic Xanthomonas strains in watercress and their interaction with pathogenic strains needs to be further investigated. Although the importance of the new pathogenic species is yet to be determined, the bacterial disease that it causes constitutes a threat to watercress production and its distribution should be monitored. PMID- 28840806 TI - Microbiota, Liver Diseases, and Alcohol. AB - Being overweight and obesity are the leading causes of liver disease in Western countries. Liver damage induced by being overweight can range from steatosis, harmless in its simple form, to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol consumption is an additional major cause of liver disease. Not all individuals who are overweight or excessively consume alcohol develop nonalcoholic fatty liver diseases (NAFLD) or alcoholic liver disease (ALD) and advanced liver disease. The role of the intestinal microbiota (IM) in the susceptibility to liver disease in this context has been the subject of recent studies. ALD and NAFLD appear to be influenced by the composition of the IM, and dysbiosis is associated with ALD and NAFLD in rodent models and human patient cohorts. Several microbial metabolites, such as short-chain fatty acids and bile acids, are specifically associated with dysbiosis. Recent studies have highlighted the causal role of the IM in the development of liver diseases, and the use of probiotics or prebiotics improves some parameters associated with liver disease. Several studies have made progress in deciphering the mechanisms associated with the modulation of the IM. These data have demonstrated the intimate relationship between the IM and metabolic liver disease, suggesting that targeting the gut microbiota could be a new preventive or therapeutic strategy for these diseases. PMID- 28840807 TI - Defining the taxonomic status of Streptococcus suis serotype 33: the proposal for Streptococcus ruminantium sp. nov. AB - To clarify the taxonomic classification of Streptococcus suis serotype 33, we performed biochemical and molecular genetic analyses using isolates (GUT-183, GUT 184, GUT-185, GUT-186, GUT-187T, GUT-188, GUT-189, GUT-190, GUT-191, GUT-192 and GUT-193) from bovine endocarditis. A comparative sequence analysis showed 99.2 100 % sequence similarity among the reference strain of S. suis serotype 33 and our isolates for the 16S rRNA gene. These similarities were higher than those between the isolate GUT-187T and S. suis and other streptococci. Comparison of sodA genes also showed high degrees of similarities among the reference strain of S. suis serotype 33 and our isolates (99.7-100 %), which were higher than those between the GUT-187T and S. suis and other streptococci. DNA-DNA relatedness among three isolates (GUT-186, GUT-187T, the reference strain of S. suis serotype 33) was over 76.7 %. In contrast, the relatedness between GUT-187T and the other streptococcal species (S. suis, Streptococcus parasuis, Streptococcus acidominimus and Streptococcus porci) was 8.4-24.9 %. Phylogenetic analyses showed that the isolates did not affiliate closely to any known species of the genus Streptococcus. Moreover, GUT-187T could be distinguished from S. suis and other closely related species of genus Streptococcus using biochemical tests. On the basis of the phenotypic and molecular genetic data, we propose that the isolates of S. suis serotype 33 should be classified into the genus Streptococcus, Streptococcus ruminantium sp. nov. with the type strain GUT-187T (=DSM 104980T=JCM 31869T). PMID- 28840808 TI - Puniceibacterium confluentis sp. nov., isolated from the junction between the ocean and a freshwater spring, and emended description of the genus Puniceibacterium. AB - A Gram-stain-negative, non-motile, aerobic and ovoid or rod-shaped bacterium, designated JSSK-17T, was isolated from the place where the ocean and a freshwater spring meet at Jeju island, South Korea. Strain JSSK-17T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 1.0-2.0 % (w/v) NaCl. Phylogenetic trees, based on 16S rRNA gene sequences, showed that strain JSSK-17T clustered with the type strains of Puniceibacterium antarcticum and Puniceibacterium sediminis, exhibiting sequence similarities of 98.1-98.2 %. Strain JSSK-17T and the type strains of P. antarcticum and P. sediminis contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The predominant polar lipids detected in strain JSSK-17T and the type strains of P. antarcticum and P. sediminis were phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminolipid, one unidentified glycolipid and one unidentified phospholipid. The DNA G+C content of strain JSSK-17T was 64.4 mol% and its DNA DNA relatedness values with the type strains of P. antarcticum and P. sediminis were 24 and 15 %, respectively. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain JSSK-17T is separated from the two reference species of the genus Puniceibacteriumwith validly published names. On the basis of the data presented, strain JSSK-17T is considered to represent a novel species of the genus Puniceibacterium, for which the name Puniceibacterium confluentis sp. nov. is proposed. The type strain is JSSK-17T (=KCTC 52765T=NBRC 112766T). PMID- 28840809 TI - Fecal Microbiota Transplantation: Therapeutic Potential for a Multitude of Diseases beyond Clostridium difficile. AB - The human intestinal tract contains trillions of bacteria, collectively called the gut microbiota. Recent insights have linked the gut microbiota to a plethora of diseases, including Clostridium difficile infection (CDI), inflammatory bowel disease (IBD), and metabolic diseases such as obesity, type 2 diabetes (T2D), and nonalcoholic steatohepatitis (NASH). Fecal microbiota transplantation (FMT) is currently tested as a therapeutic option in various diseases and can also help to dissect association from causality with respect to gut microbiota and disease. In CDI, FMT has been shown to be superior to antibiotic treatment. For IBD, T2D, and NASH, several placebo-controlled randomized controlled trials are under way. Moreover, techniques and standardization are developing. With the extension of FMT as a treatment modality in diseases other than CDI, a whole new treatment option may be emerging. Moreover, correlating alterations in specific strains to disease outcome may prove pivotal in finding new bacterial targets. Thus, although causality of the gut microbiota in various diseases still needs to be proven, FMT may prove to be a powerful tool providing us with diagnostic and therapeutic leads. PMID- 28840810 TI - Proposal to modify Rule 10a and to delete Recommendation 10a(3) from the International Code of Nomenclature of Prokaryotes. AB - Principle 2 of the Prokaryotic Code, as modified by the ICSP in 1999, reads: 'The nomenclature of prokaryotes is not independent of botanical and zoological nomenclature. When naming new taxa in the rank of genus or higher, due consideration is to be given to avoiding names which are regulated by the International Code of Zoological Nomenclature and the International Code of Nomenclature for algae, fungi and plants'. But in the current version of the Prokaryotic Code no Rule implements this version of Principle 2. I therefore propose adding the following sentence to Rule 10a: 'As from January 2001, newly proposed generic names must not be later homonyms of names in use in botany or zoology'. Recommendation 10a(3) of the Code states: 'Avoid introducing into bacteriology as generic names such names as are in use in botany or zoology, in particular well-known names'. This Recommendation contravenes the current version of Principle 2 and the proposed new version of Rule 10a. Therefore I propose to delete Recommendation 10a(3) from the Prokaryotic Code. PMID- 28840811 TI - Bacteriophage Clinical Use as Antibacterial "Drugs": Utility and Precedent. AB - For phage therapy-the treatment of bacterial infections using bacterial viruses-a key issue is the conflict between apparent ease of clinical application, on the one hand, and on the other hand, numerous difficulties that can be associated with undertaking preclinical development. These conflicts between achieving efficacy in the real world versus rigorously understanding that efficacy should not be surprising because equivalent conflicts have been observed in applied biology for millennia: exploiting the inherent, holistic tendencies of useful systems, e.g., of dairy cows, inevitably is easier than modeling those systems or maintaining effectiveness while reducing such systems to isolated parts. Trial and error alone, in other words, can be a powerful means toward technological development. Undertaking trial and error-based programs, especially in the clinic, nonetheless is highly dependent on those technologies possessing both inherent safety and intrinsic tendencies toward effectiveness, but in this modern era we tend to forget that ideally there would exist antibacterials which could be thus developed, that is, with tendencies toward both safety and effectiveness, and which are even relatively inexpensive. Consequently, we tend to demand rigor as well as expense of development even to the point of potentially squandering such utility, were it to exist. In this review I lay out evidence that in phage therapy such potential, in fact, does exist. Advancement of phage therapy unquestionably requires effective regulation as well as rigorous demonstration of efficacy, but after nearly 100 years of clinical practice, perhaps not as much emphasis on strictly laboratory-based proof of principle. PMID- 28840812 TI - Proposal to designate the order Actinomycetales Buchanan 1917, 162 (Approved Lists 1980) as the nomenclatural type of the class Actinobacteria. Request for an Opinion. AB - The name of the class Actinobacteria is illegitimate according to Rules 15, 22 and 27(3) because it was proposed without the designation of a nomenclatural type. I therefore propose to designate the order Actinomycetales Buchanan 1917, 162 (Approved Lists 1980) as its nomenclatural type, based on Rule 22 of the International Code of Nomenclature of Prokaryotes. PMID- 28840813 TI - Novosphingobium clariflavum sp. nov., isolated from a household product plant. AB - A Gram-stain-negative, rod-shaped, bright-yellow-pigmented bacterium, designated 164T, was isolated from a used sponge for equipment cleaning at a household product plant in China. The 16S rRNA gene sequence comparisons indicated that strain 164T was most closely related to Novosphingobium panipatense DSM 22890T (98.28 % similarity) and shared sequence similarities of 97.73-98.27 % with other members of the genus Novosphingobium. In DNA-DNA hybridization studies the relatedness between strain 164T and its closest phylogenetic neighbours was <70 %, which indicated that strain 164T represented a novel species of the genus Novosphingobium. The DNA G+C content of strain 164T was 65.9 mol%. The major respiratory quinone was ubiquinone Q-10 (83.5 %) with minor amounts of Q-9 (16.5 %). The polar lipid profile included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidyldimethylethanolamine, sphingoglycolipid, phosphatidylcholine, unidentified aminolipids and unidentified aminophospholipids. Spermidine was the major polyamine. The major fatty acids were summed feature 8 (consisting of C18 : 1omega7c and/or C18 : 1omega6c) and C14 : 0 2-OH. The results obtained from phylogenetic analysis, DNA-DNA hybridization, and chemotaxonomic and phenotypic analysis support the conclusion that strain 164T represents a novel species of the genus Novosphingobium, for which the name Novosphingobium clariflavum sp. nov. is proposed. The type strain is 164T (=CICC 11035sT=DSM 103351T). PMID- 28840814 TI - Molecular characterization and phylogeny of four new species of the genus Trichonympha (Parabasalia, Trichonymphea) from lower termite hindguts. AB - Members of the genus Trichonympha are among the most well-known, recognizable and widely distributed parabasalian symbionts of lower termites and the wood-eating cockroach species of the genus Cryptocercus. Nevertheless, the species diversity of this genus is largely unknown. Molecular data have shown that the superficial morphological similarities traditionally used to identify species are inadequate, and have challenged the view that the same species of the genus Trichonympha can occur in many different host species. Ambiguities in the literature, uncertainty in identification of both symbiont and host, and incomplete samplings are limiting our understanding of the systematics, ecology and evolution of this taxon. Here we describe four closely related novel species of the genus Trichonympha collected from South American and Australian lower termites: Trichonympha hueyi sp. nov. from Rugitermes laticollis, Trichonympha deweyi sp. nov. from Glyptotermes brevicornis, Trichonympha louiei sp. nov. from Calcaritermes temnocephalus and Trichonympha webbyae sp. nov. from Rugitermes bicolor. We provide molecular barcodes to identify both the symbionts and their hosts, and infer the phylogeny of the genus Trichonympha based on small subunit rRNA gene sequences. The analysis confirms the considerable divergence of symbionts of members of the genus Cryptocercus, and shows that the two clades of the genus Trichonympha harboured by termites reflect only in part the phylogeny of their hosts. PMID- 28840815 TI - Natronoarchaeum persicum sp. nov., a haloarchaeon isolated from a hypersaline lake. AB - A novel halophilic archaeon, designated strain WIIAL99T, was isolated from Lake Meyghan, a hypersaline lake in Iran. Cells of strain WIIAL99T were non-motile, catalase-positive and oxidase-negative. Strain WIIAL99T required at least 2.5 M NaCl and 0.05 M MgCl2 for growth. Optimal growth was achieved at 3.5 M NaCl and 0.1 M MgCl2. The optimum pH and temperature for growth were pH 7.0 and 37-40 degrees C; it was able to grow at pH 6.0-8.5 and 20-55 degrees C. Cells lysed in distilled water and the minimal NaCl concentration to prevent cell lysis was 8 % (w/v). The major polar lipids of strain WIIAL99T were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, disulfated diglycosyl diether and one unidentified glycolipid. The DNA G+C content of strain WIIAL99T was 66.7 mol%. The closest relative was Natronoarchaeum rubrum JCM 17119T with 98.2 % similarity in the orthologous 16S rRNA gene sequence. Analysis of 16S rRNA and rpoB' gene sequences indicated that strain WIIAL99T is a member of the genus Natronoarchaeum in the family Halobacteriaceae and forms a distinct cluster. It was concluded that strain WIIAL99T (=IBRC-M 11062T=LMG 29814T) represents a novel species of the genus Natronoarchaeum, for which the name Natronoarchaeum persicum sp. nov. is proposed. PMID- 28840816 TI - A persistently infecting coronavirus in hibernating Myotis lucifugus, the North American little brown bat. AB - Bats are important reservoir hosts for emerging viruses, including coronaviruses that cause diseases in people. Although there have been several studies on the pathogenesis of coronaviruses in humans and surrogate animals, there is little information on the interactions of these viruses with their natural bat hosts. We detected a coronavirus in the intestines of 53/174 hibernating little brown bats (Myotis lucifugus), as well as in the lungs of some of these individuals. Interestingly, the presence of the virus was not accompanied by overt inflammation. Viral RNA amplified from little brown bats in this study appeared to be from two distinct clades. The sequences in clade 1 were very similar to the archived sequence derived from little brown bats and the sequences from clade 2 were more closely related to the archived sequence from big brown bats. This suggests that two closely related coronaviruses may circulate in little brown bats. Sequence variation among coronavirus detected from individual bats suggested that infection occurred prior to hibernation, and that the virus persisted for up to 4 months of hibernation in the laboratory. Based on the sequence of its genome, the coronavirus was placed in the Alphacoronavirus genus, along with some human coronaviruses, bat viruses and the porcine epidemic diarrhoea virus. The detection and identification of an apparently persistent coronavirus in a local bat species creates opportunities to understand the dynamics of coronavirus circulation in bat populations. PMID- 28840817 TI - Planktotalea arctica sp. nov., isolated from Arctic seawater. AB - A Gram-staining-negative, non-motile, non-pigmented, rod-shaped bacterium was isolated from an Arctic coastal seawater sample and was designated strain IMCC9565T. Analysis of the 16S rRNA gene sequence of strain IMCC9565T revealed that the closest phylogenetic neighbours of the strain were members of the genus Planktotalea. Furthermore, the strain formed a robust clade with Planktotalea frisia SH6-1T, with which it shared 97.9 % 16S rRNA gene sequence similarity. Determination of genomic relatedness based on average nucleotide identity and genome-to-genome distance showed that strain IMCC9565T was distantly related to P. frisia, meaning the Arctic strain represents a novel species. Optimum growth of strain IMCC9565T was observed at 20 degrees C, pH 7.0 and in the presence of 2 % (w/v) NaCl. The major respiratory isoprenoid quinone was ubiquinone-10 (Q-10) and the major polar lipids consisted of phosphatidylglycerol, phosphatidylcholine, one unidentified aminolipid and two unidentified lipids. The principal fatty acids were C18 : 1omega7c and/or C18 : 1omega6c, C18 : 1omega7c 11-methyl and C16 : 0, and the DNA G+C content was 57.1 mol%. Based on these data, Planktotalea arctica sp. nov. is proposed to accommodate the bacterial isolate and the type strain is IMCC9565T (=KACC 18009T=NBRC 110393T). PMID- 28840818 TI - Polycladomyces subterraneus sp. nov., isolated from soil in Thailand. AB - A thermophilic poly(L-lactide)-degrading Gram-stain-positive filamentous bacterial strain that develops single spores on the aerial mycelium was isolated from forest soil at Srinagarind Dam, Kanchanaburi Province, Thailand. The results of a polyphasic taxonomic study showed that our isolate had characteristics typical of members of the genus Polycladomyces. The isolate grew aerobically at an optimum temperature of 50-55 degrees C and optimal pH 6-7. Meso diaminopimelic acid was present as the diagnostic diamino acid in the peptidoglycan but no characteristic sugars are detected. The predominant menaquinone was MK-7. The diagnostic phospholipids were phosphatidylethanolamine, phosphatidylmethylethanolamine diphosphatidylglycerol, phosphatidylglycerol and phosphatidylserine. The predominant cellular fatty acid was iso-C15 : 0. The DNA G+C content of strain KSR 13T was 53.4 mol%. The 16S rRNA gene sequence analysis also indicated that strain KSR 13T belonged to the genus Polycladomyces, being most closely related to Polycladomyces abyssicola JIR-001T (99.2 %). The DNA-DNA relatedness values that distinguished KSR 13T from P. abyssicola JIR-001T were 17.8-32.1 %, which were significantly below the 70 % cutoff value recommended for species delineation. Following an evaluation of phenotypic, chemotaxonomic and genotypic studies, the new isolate is proposed as a novel species and named Polycladomyces subterraneus sp. nov. The type strain is KSR 13T (=BCC 50740T=NBRC 109332T). PMID- 28840819 TI - The Potential of Probiotics as a Therapy for Osteoporosis. AB - Osteoporosis, characterized by low bone mass and micro-architectural deterioration of bone tissue with increased risk of fracture, can be categorized into two forms: primary and secondary, depending on whether it occurs as part of the natural aging process (estrogen deficiency) or as part of disease pathology. In both forms bone loss is due to an imbalance in the bone remodeling process, with resorption/formation skewed more toward bone loss. Recent studies and emerging evidence consistently demonstrate the potential of the intestinal microbiota to modulate bone health. This review discusses the process of bone remodeling and the pathology of osteoporosis and introduces the intestinal microbiota and its potential to influence bone health. In particular, we highlight recent murine studies that examine how probiotic supplementation can both increase bone density in healthy individuals and protect against primary (estrogen deficiency) as well as secondary osteoporosis. Potential mechanisms are described to account for how probiotic treatments could be exerting their beneficial effect on bone health. PMID- 28840821 TI - Dengue Virus Type 2 in Travelers Returning to Japan from Sri Lanka, 2017. AB - In June 2017, dengue virus type 2 infection was diagnosed in 2 travelers returned to Japan from Sri Lanka, where the country's largest dengue fever outbreak is ongoing. Travelers, especially those previously affected by dengue fever, should take measures to avoid mosquito bites. PMID- 28840822 TI - Association Between Food Distress and Smoking Among Racially and Ethnically Diverse Adults, Schenectady, New York, 2013-2014. AB - INTRODUCTION: Smoking and poor nutrition are 2 leading preventable causes of death. This study investigated associations between smoking and indicators of individual- and neighborhood-level food distress among racially and ethnically diverse urban adults. METHODS: We analyzed data from a health interview survey and a food environment assessment collected in 2013 and 2014 in Schenectady, New York. We constructed logistic regression models for current smoking with 6 indicators of food distress as exposure variables and sociodemographic characteristics, depression, anxiety, perceived stress, alcohol binge drinking, and disability as covariates. RESULTS: The analytic sample consisted of 1,917 adults; 59.4% were female, more than half were racial/ethnic minorities (26.2% non-Hispanic black, 10.3% Hispanic, 10.9% Guyanese, 4.0% multiracial and other), and 37.1% were current smokers. All indicators of food distress remained in the parsimonious final model: consuming 0 or 1 serving of fruits and vegetables daily more than doubled the odds of smoking, compared with consuming 5 or more servings (odds ratio [OR], 2.05). Food insecurity (OR, 1.77), receiving Supplemental Nutrition Assistance Program benefits (OR, 1.79), using a food pantry (OR, 1.41), living in a neighborhood with low access to healthy food (OR, 1.40), and shopping for food often at a store with limited healthy food choices (OR, 1.38) were also associated with significantly higher odds of smoking. CONCLUSION: Recognizing that smoking and food distress are independently associated would lead to innovative public health intervention strategies. We suggest stronger collaboration between tobacco and nutrition public health professionals to synergistically reduce tobacco use and improve nutrition behavior and food environments in communities. PMID- 28840823 TI - Availability of Low-Fat Milk and Produce in Small and Mid-Sized Grocery Stores After 2014 WIC Final Rule Changes, Tennessee. AB - INTRODUCTION: The 2007 Interim Rule mandated changes to food packages in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) for implementation by 2009. The 2014 Final Rule required additional changes, including increasing the cash value voucher for fruits and vegetables from $6 to $8 for children by June 2014, and allowing only low-fat (1%) or nonfat milk for mothers and children aged 2 to 4 years by October 2014. This study evaluated the effect of the 2014 Final Rule changes on the food environment of small and mid sized WIC-authorized grocery stores. METHODS: We analyzed secondary data using a natural experimental design to compare the percentage of shelf space for low-fat and nonfat milk and the number of fresh fruit and vegetable varieties in stock before and after the changes. We collected observational data on 18 small and mid sized WIC-authorized grocery stores in Nashville, Tennessee, using the Nutrition Environment Measures in Store tool in March 2014 and February 2016. RESULTS: The mean percentage of shelf space occupied by low-fat and nonfat milk increased from 2.5% to 14.4% (P = .003), primarily because of an increase in the proportion of low-fat milk (P = .001). The mean number of fresh fruit and vegetable varieties increased from 24.3 to 27.7 (P = .01), with a significant increase for vegetables (P = .008) but not fruit. CONCLUSION: Availability of low-fat milk and variety of fresh vegetables increased after the Final Rule changes in the observed stores. Future research should examine outcomes in other cities. PMID- 28840824 TI - A Framework for Implementing the National Diabetes Prevention Program in Los Angeles County. AB - INTRODUCTION: Preventing type 2 diabetes is a public health priority in the United States. An estimated 86 million Americans aged 20 years or older have prediabetes, 90% of whom are unaware they have it. The National Diabetes Prevention Program (NDPP) has the potential to reduce the incidence of type 2 diabetes; however, little is known about the best way to institutionalize such a program in a jurisdiction with a racially/ethnically diverse population. The objective of this study was to develop a practice-grounded framework for implementing the NDPP in Los Angeles County. METHODS: In 2015, the Los Angeles County Department of Public Health (LACDPH) partnered with Ad Lucem Consulting to conduct a 3-stage formative assessment that consisted of 1) in-depth interviews with key informants representing community-based organizations to learn about their experiences implementing the NDPP and similar lifestyle-change programs and 2) 2 strategic planning sessions to obtain input and feedback from the Los Angeles County Diabetes Prevention Coalition. LACDPH identified core activities to increase identification of people with type 2 diabetes and referral and enrollment of eligible populations in the NDPP. RESULTS: We worked with LACDPH and key informants to develop a 3-pronged framework of core activities to implement NDPP: expanding outreach and education, improving health care referral systems and protocols, and increasing access to and insurance coverage for NDPP. The framework will use a diverse partner network to advance these strategies. CONCLUSION: The framework has the potential to identify people with prediabetes and to expand NDPP among priority populations in Los Angeles County and other large jurisdictions by using a diverse partner network. PMID- 28840820 TI - Ecological Therapeutic Opportunities for Oral Diseases. AB - The three main oral diseases of humans, that is, caries, periodontal diseases, and oral candidiasis, are associated with microbiome shifts initiated by changes in the oral environment and/or decreased effectiveness of mucosal immune surveillance. In this review, we discuss the role that microbial-based therapies may have in the control of these conditions. Most investigations on the use of microorganisms for management of oral disease have been conducted with probiotic strains with some positive but very discrete clinical outcomes. Other strategies such as whole oral microbiome transplantation or modification of community function by enrichment with health-promoting indigenous oral strains may offer more promise, but research in this field is still in its infancy. Any microbial based therapeutics for oral conditions, however, are likely to be only one component within a holistic preventive strategy that should also aim at modification of the environmental influences responsible for the initiation and perpetuation of microbiome shifts associated with oral dysbiosis. PMID- 28840825 TI - Ongoing large measles outbreak with nosocomial transmission in Milan, northern Italy, March-August 2017. AB - A large measles outbreak has been ongoing in Milan and surrounding areas. From 1 March to 30 June 2017, 203 measles cases were laboratory-confirmed (108 sporadic cases and 95 related to 47 clusters). Phylogenetic analysis revealed the co circulation of two different genotypes, D8 and B3. Both genotypes caused nosocomial clusters in two hospitals. The rapid analysis of epidemiological and phylogenetic data allowed effective surveillance and tracking of transmission pathways. PMID- 28840826 TI - A cluster of measles linked to an imported case, Finland, 2017. AB - One imported and five secondary cases of measles were detected in Finland between June and August 2017. The measles sequences available for five laboratory confirmed cases were identical and belonged to serotype D8. The large number of potentially exposed Finnish and foreign individuals called for close cooperation of national and international public health authorities and other stakeholders. Raising awareness among healthcare providers and ensuring universally high vaccination coverage is crucial to prevent future clusters and outbreaks. PMID- 28840827 TI - A nosocomial measles outbreak in Italy, February-April 2017. AB - We describe a nosocomial outbreak of measles that occurred in an Italian hospital during the first months of 2017, involving 35 persons and including healthcare workers, support personnel working in the hospital, visitors and community contacts. Late diagnosis of the first case, support personnel not being promptly recognised as hospital workers and diffusion of the infection in the emergency department had a major role in sustaining this outbreak. PMID- 28840828 TI - Imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection from Oman to Thailand, June 2015. AB - Thailand reported the first Middle East respiratory syndrome (MERS) case on 18 June 2015 (day 4) in an Omani patient with heart condition who was diagnosed with pneumonia on hospital admission on 15 June 2015 (day 1). Two false negative RT PCR on upper respiratory tract samples on days 2 and 3 led to a 48-hour diagnosis delay and a decision to transfer the patient out of the negative pressure unit (NPU). Subsequent examination of sputum later on day 3 confirmed MERS coronavirus (MERS-CoV) infection. The patient was immediately moved back into the NPU and then transferred to Bamrasnaradura Infectious Disease Institute. Over 170 contacts were traced; 48 were quarantined and 122 self-monitored for symptoms. High-risk close contacts exhibiting no symptoms, and whose laboratory testing on the 12th day after exposure was negative, were released on the 14th day. The Omani Ministry of Health (MOH) was immediately notified using the International Health Regulation (IHR) mechanism. Outbreak investigation was conducted in Oman, and was both published on the World Health Organization (WHO) intranet and shared with Thailand's IHR focal point. The key to successful infection control, with no secondary transmission, were the collaborative efforts among hospitals, laboratories and MOHs of both countries. PMID- 28840830 TI - Mesh materials and hernia repair. AB - Hernia incidence has been observed since ancient time. Advancement in the medical textile industry came up with the variety of mesh materials to repair hernia, but none of them are without complications including recurrence of hernia. Therefore individuals once developed with the hernia could not lead a healthy and comfortable life. This drawn attention of surgeons, patients, researchers and industry to know the exact mechanism behind its development, complications and recurrence. Recent investigations highlighted the role of genetic factors and connective tissue disorders being the reason for the development of hernia apart from the abnormal pressure that is known to develop during other disease conditions. This review discusses different mesh materials, their advantages and disadvantages and their biological response after its implantation. PMID- 28840831 TI - Fluvastatin use and risk of acute pancreatitis: a population-based case-control study in Taiwan. AB - OBJECTIVES: This study aimed to examine the association between fluvastatin use and acute pancreatitis in Taiwan. METHODS: Using the database from the Taiwan National Health Insurance (NHI) Program, we designed a case-control study which consisted of 3501 individuals aged 20-84 with new at-the-time diagnoses acute pancreatitis as the case group and 8373 randomly selected individuals without acute pancreatitis as the control group during the period of 1998-2011. Both groups were matched for sex, age, and index year of being diagnosed with acute pancreatitis. "Current use" of fluvastatin was defined as individuals whose last remaining tablet of fluvastatin was noted <= 7 days before the date of their being diagnosed with acute pancreatitis. "Late use" of fluvastatin was defined as individuals whose last remaining tablet of fluvastatin was noted within 8-30 days before the date of their being diagnosed with acute pancreatitis. "No use" of fluvastatin was defined as individuals who had never had a fluvastatin prescription. The odds ratio (OR) and 95% confidence interval (CI) for acute pancreatitis associated with fluvastatin use was examined using a multivariable unconditional logistic regression analysis. RESULTS: After adjustment for potential confounders, the multivariable analysis showed that the adjusted ORs of acute pancreatitis were 1.17 for individuals with "current use" of fluvastatin (95% CI 0.69, 1.97) and 1.82 for individuals with "late use" of fluvastatin (95% CI 0.41, 8.19), but there was no statistical significance when compared with individuals with "no use" of fluvastatin. CONCLUSIONS: In this this study, no association was detected between fluvastatin use and acute pancreatitis. PMID- 28840829 TI - Transglutaminase 2 in human diseases. AB - Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that catalyzes Ca(2+)-dependent protein modifications. In addition to being an enzyme, TG2 also serves as a G protein for several seven transmembrane receptors and acts as a co-receptor for integrin beta1 and beta3 integrins distinguishing it from other members of the transglutaminase family. TG2 is ubiquitously expressed in almost all cell types and all cell compartments, and is also present on the cell surface and gets secreted to the extracellular matrix via non-classical mechanisms. TG2 has been associated with various human diseases including inflammation, cancer, fibrosis, cardiovascular disease, neurodegenerative diseases, celiac disease in which it plays either a protective role, or contributes to the pathogenesis. Thus modulating the biological activities of TG2 in these diseases will have a therapeutic value. PMID- 28840832 TI - Torenia concolor Lindley var. formosana Yamazaki extracts improve inflammatory response and lipid accumulation via PPARs activation. AB - : Background/Introduction: At present, human diet is replete with sugar and fat. Abnormal metabolism and hyperglycemia or hyperlipidemia in the body induces the development of an overactive and continuous inflammatory response, resulting in obesity and metabolic syndromes, including hypertension, hyperlipidemia, and insulin resistance. Torenia concolor Lindley var. formosana Yamazaki (TC), a perennial creeping herbaceous plant, is a traditional Chinese medicinal herb widely used for the treatment of heat stroke, aching muscles and bones, cold, dysentery, and ambustion. PURPOSE: This study evaluated the influence of TC on inflammation responses and lipid metabolism. METHODS: In this study, ground TC powder was extracted with 95% ethanol. The ethanol was removed by vacuum concentration, and the resulting extract was further extracted with a number of solvents of different polarity to produce four final extracts: an ethanol extract (TCEE), an ethyl acetate extract (TCEAE), an n-butanol extract (TCBUE), and a water extract (TCWE). The anti-inflammatory efficacy of the extracts and their capability for lipid metabolism regulation was then explored. RESULTS: TCEE, TCEAE, and TCBUE exhibited good anti-inflammatory efficacy; TCEAE also simultaneously regulated lipid metabolism. In RAW264.7 cells, these three extracts suppressed the expression of iNOS and IL-6 via the signaling pathway activation of the transcription factor peroxisome proliferator activated receptor gamma (PPARgamma) and thereby showed anti-inflammatory efficacy. In 3T3-L1 cells, these three extracts promoted lipid metabolism and reduced lipid accumulation through the activation of PPARalpha and the increased expression of adiponectin, thus demonstrating regulation of lipid metabolism. CONCLUSION: These results indicate that TC possesses anti-inflammatory efficacy and can regulate lipid metabolism through the activation of transcription factor PPARs. We speculate that these nutraceutical effects are attributable to betulin, an active ingredient in this herbal medicine. PMID- 28840833 TI - The anti-inflammatory and anti-glycative effects of rosmarinic acid in the livers of type 1 diabetic mice. AB - BACKGROUND: Rosmarinic acid (RA) is a polyphenol present in members of the Lamiaceae family. In this study, yhe anti-inflammatory and anti-glycative effects of RA in the livers of type 1 diabetic mice were examined. METHODS: The diabetic mice were divided into three groups: diabetic mice with 0, low dose RA (25 mg/ml), and high dose RA (50 mg/ml). One group of non-diabetic mice was used as a control for comparison. RA was supplied via daily 200 MUL oral injections for 9 weeks. The level of interleukin (IL)-6, the tumor necrosis factor (TNF)-alpha, the prostaglandin E2 (PGE2), and the activity of cyclooxygenase (COX)-2 in the livers were measured. The hepatic receptor of advanced glycative endproduct (RAGE), the sorbitol levels, and the glyoxalase 1 (GLO-1) activity were also determined. RESULTS: Compared with diabetic group that received no RA, the groups with RA supplements at both levels of dosages had increased body weight and had both decreased water intake and feed intake (p < 0.05). RA intake was found to reduce plasma glucose level and elevate plasma insulin level when compared with the diabetic group that received no RA (p < 0.05). RA treatments lowered the hepatic level of IL-6, TNF-alpha, and PGE2, as well as the activity of COX-2 (p < 0.05). RA administration also decreased hepatic RAGE and sorbitol levels, and GLO 1 activity when compared with the diabetic group that received no RA (P < 0.05). CONCLUSION: These findings support the conclusion that rosmarinic acid (RA) could be a potent protective agent for the liver against diabetic injury. PMID- 28840834 TI - Risk of contracting pneumonia among patients with predialysis chronic kidney disease: a population-based cohort study in Taiwan. AB - OBJECTIVES: The objective of the study was to investigate the association between predialysis chronic kidney disease and contracting pneumonia in Taiwan. METHODS: We employed a population-based, retrospective cohort design using the database of the Taiwan National Health Insurance (NHI) Program. There were 18807 subjects aged 20-84 years who were newly diagnosed with predialysis chronic kidney disease between 2000 to 2012 as the predialysis chronic kidney disease group and 18807 randomly selected subjects without chronic kidney disease as the non-chronic kidney disease group. The predialysis chronic kidney disease and non-chronic kidney disease groups were matched according to sex, age, comorbidities, and the year of index date. The incidence of contracting pneumonia among both groups at the end of 2013 was calculated. The multivariable Cox proportional hazards regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for contracting pneumonia being associated with predialysis chronic kidney disease. RESULTS: The overall incidence of contracting pneumonia was 1.47 fold higher in the predialysis chronic kidney disease group than that in the non chronic kidney disease group (24.6 vs. 16.7 per 1, 000 person-years, 95% CI 1.40, 1.55). After adjusting for co-variables, the HR of contracting pneumonia became 1.52 for subjects with predialysis chronic kidney disease (95% CI 1.43, 1.60) compared to subjects without chronic kidney disease. With even further analysis, in the absence of any comorbidity, the adjusted HR of contracting pneumonia was 1.53 for subjects with predialysis chronic kidney disease alone (95% CI 1.32, 1.76). CONCLUSIONS: Patients with predialysis chronic kidney disease have a 1.52 fold increased risk of contracting pneumonia as compared to those with non chronic kidney disease. Even in the absence of any comorbidity, a greater than average risk of contracting pneumonia remains present. PMID- 28840835 TI - Skin innate immune response to flaviviral infection. AB - Skin is a complex organ and the largest interface of the human body exposed to numerous stress and pathogens. Skin is composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity, at once providing the first line of defense against microbial infections and ensuring skin homeostasis. Being inoculated directly through the epidermis and the dermis during a vector blood meal, emerging Dengue, Zika and West Nile mosquito-borne viruses lead to the initiation of the innate immune response in resident skin cells and to the activation of dendritic cells, which migrate to the draining lymph node to elicit an adaptive response. This literature review aims to describe the inflammatory response and the innate immune signalization pathways involved in human skin cells during Dengue, Zika and West Nile virus infections. PMID- 28840836 TI - Predictive ability of circulating osteoprotegerin as a novel biomarker for early detection of acute kidney injury induced by sepsis. AB - Though significant progress has been made towards new diagnostic approaches for early detection of acute kidney injury (AKI) induced by different factors, there is still an urgent demand for a more specific and predictive biomarker for each type. The aim of this study is to unravel the potential diagnostic utility of circulating osteoprotegerin (OPG) in septic patients who developed AKI in the ICU, compared to cystatin C (a renal function maker) and KIM-1 (a kidney damage marker). Eighty patients (male = 43, female = 37) with ages ranging from 42 to 46 years and with sepsis, 40 of whom developed AKI, and 30 healthy controls were enrolled in this prospective study. Results revealed significant progressive elevation of OPG, along with cystatin C and KIM-1, among sepsis, severe sepsis, and sepsis-AKI patients. The progression of OPG levels paralleled the deterioration of kidney and endothelial functions from sepsis to sepsis-AKI, revealed as progressively increased levels of serum E-selectin (15.3%), endothelin-1 (ET-1) (19.6%), and decreased nitric oxide (NO) (29.7%), associated with elevations of TNF-alpha (25.5%) and TGF-beta (18%). Their comparative prognostic validity of sepsis-AKI was assessed using ROC analysis, which revealed that OPG, KIM-1, and cystatin C showed similar AUCs (0.827-0.83) but with different sensitivities, viz., 84%, 88%, and 92%, respectively. Although cystatin showed 82% specificity, OPG showed a higher, similar specificity to KIM-1 of 85%, indicating its potential function as a marker of renal damage such as KIM-1. This study revealed a significant elevation of circulating OPG in septic patients with different levels of severity and those who progressed to AKI. Moreover, OPG showed a significant correlation to KIM-1 and cystatin, as well as conventional renal, inflammatory, and endothelial markers. Having a similar specificity to KIM 1, as evidenced by the ROC analysis, OPG has the potential to serve as a reliable biomarker of kidney damage in cases of sepsis-AKI. PMID- 28840837 TI - Characterization of a long isoform of IL-1R8 (TIR8/SIGIRR). AB - IL-1R8, also known as SIGIRR or TIR8, is a trans-membrane protein belonging to the IL-1 receptor family. The human gene includes ten exons, and alternative splicing can result in different isoforms. We, herein, characterized a longer isoform of IL-1R8 containing an in-frame additional sequence between the TIR domain and the C-terminal portion of the protein. IL-1R8 Long (IL-1R8L1) mRNA was specifically expressed and regulated in distinct cell lines, in a manner similar to the classic isoform. Overexpression of IL-1R8L1 resulted in the production of a corresponding protein that showed a pattern of cell localization similar to the classic isoform. An antibody directed against an IL-1R8L1 specific peptide, detected this novel isoform in different cell lines and tissues where this protein may complement the anti-inflammatory functions of classic IL-1R8. PMID- 28840838 TI - The role of host immune cells and Borrelia burgdorferi antigens in the etiology of Lyme disease. AB - Lyme disease is a zoonosis caused by infection with bacteria belonging to the Borrelia burgdorferi species after the bite of an infected tick. Even though an infection by this bacterium can be effectively treated with antibiotics, when the infection stays unnoticed B. burgdorferi can persist and chronic post-treatment Lyme disease syndrome is able to develop. Although a cellular and humoral response is observed after an infection with the Borrelia bacteria, these pathogens are still capable to stay alive. Several immune evasive mechanisms have been revealed and explained and much work has been put into the understanding of the contribution of the innate and adaptive immune response. This review provides an overview with the latest findings regarding the cells of the innate and adaptive immune systems, how they recognize contribute and mediate in the killing of the B. burgdorferi spirochete. Moreover, this review also elaborates on the antigens that are expressed by on the spirochete. Since antigens drive the adaptive and, indirectly, the innate response, this review will discuss briefly the most important antigens that are described to date. Finally, there will be a brief elaboration on the escape mechanisms of B. burgdorferi with a focus on tick salivary proteins and spirochete antigens. PMID- 28840839 TI - Buprenorphine differentially affects M1- and M2-polarized macrophages from human umbilical cord blood. AB - As a partial MU-opioid receptor agonist with long half-life time, buprenorphine has been widely used to relieve chronic cancer and nonmalignant pain. The maintenance of chronic pain involves inflammation; however whether buprenorphine has anti-inflammation property remains unclear. Macrophages, the immune cells that initiate and maintain inflammation, were isolated from human umbilical cord blood, and were polarized into M1 or M2 macrophages with IFN-gamma in the presence of lipopolysaccharide (LPS) or IL-4, respectively. Quantitative PCR, ELISA, Western blotting analysis, and chromatin immunoprecipitation assays were employed to characterize M1 and M2 macrophages. 1) Buprenorphine did not change not only the apoptosis, survival, and morphology of resting macrophages, but also the antigen-presenting function of macrophages. 2) Buprenorphine inhibited the levels of mRNA and protein of several cytokines in M1 macrophages, and enhanced the expression of Ym1 and Fizz1 in M2 macrophages. 3) Buprenorphine did not affect the modulation of NF-kappaB and MAPK cascades by LPS in M1 macrophages. 4) Buprenorphine inhibited the expression of IRF5 and reduced binding of DNA to IRF5. Buprenorphine may downregulate IRF5 pathway and limit M1 macrophage phenotype. These effects may contribute to its therapeutic benefit for chronic neuropathic pain. PMID- 28840840 TI - Pulmonary artery hypertension: pertinent vasomotorial cytokines. AB - Pulmonary artery hypertension is a syndrome that shows similar clinical and pathophysiological features characterized by elevated pulmonary arterial pressure and resistance. There have been a series of hypotheses trying to describe the development of pulmonary artery hypertension; however, none of them perfectly explains its pathogenesis. To highlight the pathogenesis, novel vasomotorial cytokines including hypoxia-inducible factor-1alpha, endothelin-1, urotensin II, Kruppel-like factor 4, calcitonin gene-related peptide, angiopoietins, and serotonin closely related to pulmonary artery hypertension are discussed. The development of the new agents relating to these cytokines may improve the relevant treatment strategies. PMID- 28840841 TI - Upregulation of cytokine mRNA in circulating leukocytes during human endotoxemia. AB - Endotoxemia induces pronounced changes in leukocyte count and enhances the release of many cytokines. However, the molecular regulation of this cytokine release is poorly characterized in humans. The time course of mRNA expression of 24 cytokines in circulating leukocytes was studied in a well-standardized model of human endotoxemia (2 ng/kg). Real-time polymerase chain reaction (RT-PCR) was used to quantify the lipopolysaccharide (LPS)-inducible mRNA levels of leukocytes from 16 healthy volunteers in a randomized, placebo-controlled trial. Baseline mRNA levels of interleukins including IL-1alpha, IL-3, IL-5, IL-6, IL-12p40, IL 13, IL-15, IL-17, granulocyte colony-stimulating factor (G-CSF) and granulocyte monocyte CSF (GM-CSF) were below detectable levels in normal blood of the healthy participants. After 2 h, LPS infusion increased median mRNA levels of IL-1alpha by >1100-fold and IL-1beta and IL-8 by 33-fold and 46-fold, respectively. In contrast, levels of tumor necrosis factor (TNF-alpha) and IL-10 mRNA increased by only 7-fold, whereas changes in mRNA expression of other cytokines showed either a more than two fold increase or were undetectable. In vitro incubation of whole blood with 50 pg/mL LPS for 2 h enhanced transcription levels of IL-1alpha mRNA by >10,000-fold, IL-6 and IL-12p40 by >1000-fold, IL-1beta by 400-fold, TNF-alpha by 100-fold, IL-8, IL-18, interferon gamma (IFN-gamma) and G-CSF by >10-25-fold, and IL-10, IL-12p35, TNF-beta, and IL-13 by 10-25-fold. Only half of the 24 evaluated cytokines were expressed at the mRNA level in circulating leukocytes under basal conditions and after an LPS challenge. Only IL-1alpha, IL-1beta, IL 10, IL-8, and TNF-alpha were upregulated in the circulating leukocytes, whereas several other cytokines (including IL-6 and G-CSF), were expressed on the mRNA level following in vitro incubation of blood with LPS. In addition, IL-1alpha and IL-1beta might be potential diagnostic targets in inflammatory diseases. PMID- 28840842 TI - Chemokine and chemokine receptor patterns in patients with benign and malignant salivary gland tumors: a distinct role for CCR7. AB - To explore the molecular mechanisms involved in pathophysiology of malignant and benign salivary gland tumors (SGTs), we investigated main tumor-inducing chemokines and chemokine receptors, CXCL12/CXCR4/ACKR3 (CXCR7), CXCR3/CXCL10, CCR5/CCL5, CCL21/CCR7, CCL2, CCR4, CXCR5, CCR6, and CXCL8 in tumor tissues. Parotid tissues were obtained from 30 patients with malignant and benign SGTs. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the mRNA expression pattern of the mentioned chemokines/chemokine receptors and immunohistochemistry (IHC) was performed to verify the expression of CCR7. Expression levels of CCR7 and CCR4 transcripts were higher in the tumor tissues of malignant cases in comparison to benign ones (p = 0.03 and 0.02). Immunohistochemistry analysis confirmed that the protein level of CCR7 concurred with the mRNA expression. CCL2 gene transcripts were observed with a higher expression in patients with tumor-free lymph nodes (LN-) and early stages, whereas CCR7 transcript was higher in LN+ and late stages of the disease. A significant inverse correlation was found between CXCL10 transcript and tumor size in benign cases. The mRNA expression of CCR7, CCR4, CXCR3, CCL21, CCL5, and CXCL12 was significantly higher in mucoepidermoid carcinoma in comparison to pleomorphic adenoma subtypes (p < 0.05). On the basis of the present study, it was determined that malignant and benign SGTs exhibit a distinct pattern of chemokines and chemokine receptors, which are probably associated with known biological and clinical behaviors of these tumors. Significant increased CCR4 and CCR7 expression in malignant SGTs might play a central role in malignant transformation that introduces them as new targets for cancer immunotherapy. PMID- 28840843 TI - Interferon Gamma Release Assay in response to PE35/PPE68 proteins: a promising diagnostic method for diagnosis of latent tuberculosis. AB - Tuberculosis control relies on the identification and preventive treatment of people who are latently infected with Mycobacterium tuberculosis (Mtb). PE/PPE proteins have been reported to elicit CD4 and/or CD8 responses either in the form of whole recombinant proteins or as individual peptides. Very few of the PE and PPE proteins have been previously tested for responses in patients with TB and healthy donors. This is the first study to evaluate the Interferon Gamma Release Assay (IGRA) after stimulation with PE35 and PPE68. The antigen-specific levels of IFN-gamma following stimulation with QuantiFERON-TB gold in-tube (QFT-G-IT) antigens, and PE35 and PPE68 recombinant proteins were evaluated in 79 children and 102 adults, respectively. Using QFT-G-IT kit, latent tuberculosis infection (LTBI) was detected in 26 children (33%) and 41 adults (40%); IGRA following stimulation with PE35 and PPE68 recombinant proteins, was positive, respectively, in 36 (46%) and 32 (40.5%) children, respectively. In addition, 53 adults (52%) had positive results following stimulation with these two proteins. The sensitivity and specificity of IGRA following stimulation with recombinant PE35 in children were 76% and 80%, and following stimulation with recombinant PPE68 in this group, it was 73% and 75%, respectively. Meanwhile, there is no gold standard test for LTBI. Our designed tests using PE35 and PPE68 PE/PPE proteins, two PE/PPE proteins not present in BCG vaccins, which elicit CD4 and/or CD8 responses, might be helpful for rapid diagnosis of TB and improve the detection of LTBI. However, further validation studies to determine the advantage of IGRAs using these proteins, alone or combined, are highly recommended. PMID- 28840844 TI - Increased serum IL-17A and Th2 cytokine levels in patients with severe uncontrolled asthma. AB - Asthma is a syndrome of chronic bronchial inflammation and airway remodelling. Initially, asthma has been categorized into atopic and nonatopic types, based on antigen-specific IgE levels. Moreover, recently, asthma has been classified into different endotypes based on its pathophysiology, leading to the selection of the most optimal and effective therapies. Although T helper cell type 2 (Th2) cytokines were proven to play critical roles in atopic asthma, IL-17A has been reported to be involved in severe refractory asthma. In this study, we measured the levels of 24 cytokines/chemokines in the sera of healthy controls (HCs) (n = 34) and patients with asthma (n = 77), that were compared among patient groups with different disease activities and characteristics. The serum levels of nine cytokines were significantly higher in patients with asthma than in HCs, and the levels of IL-17A and SCF were significantly different between uncontrolled and well-controlled patient groups (p = 0.003). The IL-17A levels were significantly correlated with those of IL-4, IL-25, IL-10, and IFN-gamma in patients with uncontrolled asthma, and the patients with the highest levels of all the above cytokines were refractory to high-dose of inhaled corticosteroid therapy and have a history of acute exacerbation within 1 year, requiring systemic steroid therapy. This study examines the profiles of upregulation and downregulation of various cytokines and chemokines in relation to asthmatic control status. IL-17A was significantly upregulated in patients with the uncontrolled and refractory status. Therefore, IL-17A may play important roles in asthmatic exacerbation, and its high level, in combination with upregulated Th2 and other cytokines, may indicate the refractory endotype of asthma. PMID- 28840845 TI - The Value of Preoperative Volumetric Analysis by Computerised Tomography of Retrosternal Goiter to Predict the Need for an Extra-Cervical Approach. AB - BACKGROUND: A thyroidectomy can be performed via a cervical incision in most patients with retrosternal goiter. AIMS: To investigate the correlation between the volume of the mediastinal portion of the thyroid gland and the need for an extra-cervical approach for retrosternal goiter. STUDY DESIGN: Diagnostic accuracy study. METHODS: The measurement of craniocaudal length and the volume of the mediastinal component of the thyroid gland on computerised tomography images was performed in 47 patients with retrosternal goiter. Of these 47 patients, 8 (17%) required an extra-cervical approach and were classified as group 1, and 39 (83%) patients that required a cervical incision were classified as group 2. Receiver operating characteristic analysis was performed to determine the cut-off value for the craniocaudal length and the volume of the mediastinal thyroid mass, which significantly correlated with an extra-cervical approach for retrosternal goiter. RESULTS: Reoperative surgery was significantly more frequent in group 1 than in group 2 (50% vs 13%; p=0.03). The craniocaudal length of the mediastinal thyroid gland was significantly longer in group 1 than in group 2 (77+/-11 mm vs 31+/-21 mm, respectively; p=0.0001). The volume of the mediastinal component was significantly larger in group 1 compared to group 2 (264+/-106 cm3 vs 40+/-41 cm3, respectively; p=0.0001). The receiver operating characteristic curve of craniocaudal length and the volume of the mediastinal component identified >=66 mm and >=162 cm3 as the cut-off values with the maximum accuracy, respectively. The craniocaudal length of the thyroid mass below the thoracic inlet >=66 mm or a volume of the mediastinal portion >=162 cm3 were significantly associated with an extra-cervical approach (p=0.0001). For predicting an extra-cervical approach, the sensitivity, positive predictive value and negative predictive value of the cut-off value for craniocaudal length was 87.5%, 64% and 97%, respectively. For predicting an extra-cervical approach, the sensitivity, positive predictive value and negative predictive value of the cut-off values for the mediastinal volume were 100%, 89% and 100%, respectively. CONCLUSION: A thyroid volume of >=162 cm3 extending below the thoracic inlet was a significant determining factor for an extra-cervical approach, with a negative predictive value for the extra-cervical approach of 100% for retrosternal goiter with smaller volumes. Further studies with an increased number of patients are needed to determine the value of volumetric analysis of retrosternal goiter to predict the need for an extra cervical approach in retrosternal goiter. PMID- 28840846 TI - Tumour Necrosis Factor-alpha and Nuclear Factor-kappa B Gene Variants in Sepsis. AB - BACKGROUND: The humoral system is activated and various cytokines are released due to infections in tissues and traumatic damage. Nuclear factor-kappa B dimers are encoded by nuclear factor-kappa B genes and regulate transcription of several crucial proteins of inflammation such as tumour necrosis factor-alpha. AIMS: To investigate the possible effect of polymorphisms on tumour necrosis factor-alpha serum levels with clinical and prognostic parameters of sepsis by determining the nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A) gene polymorphisms and tumour necrosis factor-alpha serum levels. STUDY DESIGN: Case-control study. METHODS: Seventy-two patients with sepsis and 104 healthy controls were included in the study. In order to determine the polymorphisms of nuclear factor-kappa B-1-94 ins/del ATTG and tumour necrosis factor-alpha (-308 G/A), polymerase chain reaction-restriction fragment length polymorphism analysis was performed and serum tumour necrosis factor-alpha levels were determined using an enzyme-linked immunosorbent assay. RESULTS: We observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p>0.05). CONCLUSION: Our results showed the AA genotype and the A allele of the tumour necrosis factor alpha (-308 G/A) polymorphism may be used as a predictor of elevated tumour necrosis factor-alpha levels in patients with sepsis. PMID- 28840847 TI - Myxoma of the Ovary. PMID- 28840848 TI - Time to Cure Hairy Cell Leukemia. PMID- 28840849 TI - Circulating Tumor Cells in Neuroblastoma. PMID- 28840850 TI - Classification and Current Management of Inner Ear Malformations. AB - Morphologically congenital sensorineural hearing loss can be investigated under two categories. The majority of congenital hearing loss causes (80%) are membranous malformations. Here, the pathology involves inner ear hair cells. There is no gross bony abnormality and, therefore, in these cases high-resolution computerized tomography and magnetic resonance imaging of the temporal bone reveal normal findings. The remaining 20% have various malformations involving the bony labyrinth and, therefore, can be radiologically demonstrated by computerized tomography and magnetic resonance imaging. The latter group involves surgical challenges as well as problems in decision-making. Some cases may be managed by a hearing aid, others need cochlear implantation, and some cases are candidates for an auditory brainstem implantation (ABI). During cochlear implantation, there may be facial nerve abnormalities, cerebrospinal fluid leakage, electrode misplacement or difficulty in finding the cochlea itself. During surgery for inner ear malformations, the surgeon must be ready to modify the surgical approach or choose special electrodes for surgery. In the present review article, inner ear malformations are classified according to the differences observed in the cochlea. Hearing and language outcomes after various implantation methods are closely related to the status of the cochlear nerve, and a practical classification of the cochlear nerve deficiency is also provided. PMID- 28840851 TI - Anisotropic phase coherence in GaAs/InAs core/shell nanowires. AB - Low-temperature transport in nanowires is accompanied by phase-coherent effects, which are observed as modulation of the conductance in an external magnetic field. In the GaAs/InAs core/shell nanowires investigated here, these are h/e flux periodic oscillations in a magnetic field aligned parallel to the nanowire axis and aperiodic universal conductance fluctuations in a field aligned perpendicularly to the nanowire axis. Both electron interference effects are used to analyse the phase coherence of the system. Temperature-dependent measurements are carried out, in order to derive the phase coherence lengths in the cross sectional plane as well as along the nanowire sidewalls. It is found that these values show a strong anisotropy, which can be explained by the crystal structure of the GaAs/InAs core/shell nanowire. For nanowires with a radius as low as 45 nm, flux periodic oscillations were observed up to a temperature of 55 K. PMID- 28840852 TI - Stacking fault-mediated ultrastrong nanocrystalline Ti thin films. AB - In this work, we prepared nanocrystalline (NC) Ti thin films with abundant stacking faults (SFs), which were created via partial dislocations emitted from grain boundaries and which were insensitive to grain sizes. By employing the nanoindentation test, we investigated the effects of SFs and grain sizes on the strength of NC Ti films at room temperature. The high density of SFs significantly strengthens NC Ti films, via dislocation-SF interactions associated with the reported highest Hall-Petch slope of ~20 GPa nm1/2, to an ultrahigh strength of ~4.4 GPa, approaching ~50% of its ideal strength. PMID- 28840853 TI - Characterization of seal whisker morphology: implications for whisker-inspired flow control applications. AB - Seals with beaded whiskers-the majority of true seals (Phocids)-are able to trace even minute disturbance caused by prey fish in the ambient flow using only sensory input from their whiskers. The unique three-dimensional undulating morphology of seal whiskers has been associated with their capability of suppressing vortex-induced vibration and reducing drag. The exceptional hydrodynamic traits of seal whiskers are of great interest in renovating the design of aero-propulsion flow components and high-sensitivity flow sensors. It is essential to have well-documented data of seal whisker morphology with statistically meaningful generalization, as the solid foundation for whisker inspired flow control applications. However, the available whisker morphology data is either incomplete, with measurements of only a few key parameters, or based on a very limited sample size in case studies. This work characterizes the morphology of 27 beaded seal whiskers (harbor seal and elephant seal), using high resolution computer-tomography scanning at NASA's Glenn Research Center in Cleveland, OH. Over two thousand cross-sectional slices for every individual whisker sample are reconstructed, to generate three-dimensional morphology. This is followed by detailed statistical analysis of a set of key parameters, under an established framework (Hanke et al 2010 J. Exp. Biol. 213 2665-72). While the length parameters are generally consistent with previous studies, we note that the angle of incidence of elliptical cross-sections varies in a wide range, with a majority falling between [Formula: see text] and [Formula: see text]. Angles of incidence at both peaks and troughs appear to roughly follow a Gaussian distribution, but no clear preference of orientation is identified. We discuss the current knowledge of whisker-inspired flow studies, focusing on choices of morphology parameters. The new understanding of whisker morphology can better inform future design of high-sensitivity flow sensors and aero-propulsion flow structures. PMID- 28840854 TI - Comment on 'Licence to save: a UK survey of anti-VEGF use for the eye in 2015'. PMID- 28840855 TI - Comments on 'Treatment patterns of ranibizumab intravitreal injection and dexamethasone intravitreal implant for retinal vein occlusion in the USA'. PMID- 28840856 TI - Response to 'The importance of immunosuppression as risk and prognostic factor for periorbital non-melanoma skin cancers'. PMID- 28840857 TI - Detection of 6 TFEB-amplified renal cell carcinomas and 25 renal cell carcinomas with MITF translocations: systematic morphologic analysis of 85 cases evaluated by clinical TFE3 and TFEB FISH assays. AB - Renal cell carcinomas with MITF aberrations demonstrate a wide morphologic spectrum, highlighting the need to consider these entities within the differential diagnosis of renal tumors encountered in clinical practice. Herein, we describe our experience with application of clinical fluorescence in situ hybridization (FISH) assays for detection of TFE3 and TFEB gene aberrations from 85 consecutive renal cell carcinoma cases submitted to our genitourinary FISH service. Results from 170 FISH assays performed on these tumors were correlated with available clinicopathologic findings. Ninety-eight percent of renal tumors submitted for FISH evaluation were from adult patients. Thirty-one (37%) tumors were confirmed to demonstrate MITF aberrations (21 TFE3 translocation, 4 TFEB translocation, and 6 TFEB amplification cases). Overall, renal cell carcinomas with MITF aberrations demonstrated morphologic features overlapping with clear cell, papillary, or clear cell papillary renal cell carcinomas. Renal cell carcinomas with MITF aberrations were significantly more likely to demonstrate dual (eosinophilic and clear) cytoplasmic tones (P=0.030), biphasic TFEB translocation renal cell carcinoma-like morphology (P=0.002), psammomatous calcifications (P=0.002), and nuclear pseudoinclusions (P=0.001) than renal cell carcinomas without MITF aberrations. Notably, 7/9 (78%) renal cell carcinomas exhibiting subnuclear clearing and linear nuclear array (6 of which showed high World Health Organization/International Society of Urological Pathology nucleolar grade) demonstrated TFE3 translocation, an association that was statistically significant when compared with renal cell carcinomas without MITF aberrations (P=0.009). In this cohort comprising consecutive cases, TFEB-amplified renal cell carcinomas were more commonly identified than renal cell carcinomas with TFEB translocations, and four (67%) of these previously unreported TFEB-amplified renal cell carcinomas demonstrated oncocytic and papillary features with a high World Health Organization/International Society of Urological Pathology nucleolar grade. In summary, TFE3 and TFEB FISH evaluation aids in identification and accurate classification of renal cell carcinomas with MITF aberrations, including TFEB-amplified renal cell carcinoma, which may demonstrate aggressive behavior. PMID- 28840858 TI - Parvalbumin Interneurons of the Mouse Nucleus Accumbens are Required For Amphetamine-Induced Locomotor Sensitization and Conditioned Place Preference. AB - To determine the requirement for parvalbumin (PV) expressing GABAergic interneurons of the nucleus accumbens (NAc) in the behavioral adaptations induced by amphetamine (AMPH), we blocked synaptic vesicle release from these neurons using Cre-inducible viral expression of the tetanus toxin light chain in male and female PV-Cre mice. Silencing PV+ interneurons of the NAc selectively inhibited the expression of locomotor sensitization following repeated injections of AMPH and blocked AMPH-induced conditioned place preference (CPP). AMPH induced significantly more expression of the activity-dependent gene Fos in both D1 and D2 dopamine receptor-expressing medium spiny neurons (MSNs) of the NAc of PV+ interneuron silenced mice, suggesting a function for PV+ interneuron-mediated MSN inhibition in the expression of AMPH-induced locomotor sensitization and CPP. These data show a requirement for PV+ interneurons of the NAc in behavioral responses to AMPH, and they raise the possibility that modulation of PV+ interneuron function may alter the development or expression of psychostimulant induced behavioral adaptations. PMID- 28840860 TI - tsRNAs: new players in mammalian retrotransposon control. AB - A recent study led by Professor Rob Martienssen in Cell showed that 3'-tRNA derived small RNAs can suppress long terminal repeat retrotransposon activity in mammalian cells by mechanisms independent of DNA-associated epigenetic marks, suggesting how the genome may defend itself from retrotransposon invasion during epigenetic reprogramming. PMID- 28840859 TI - Cryo-EM structure of human DNA-PK holoenzyme. AB - DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 A resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal alpha-solenoid (~2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA. DNA-PKcs and KU70/80 together form a DNA binding tunnel, which cradles ~30-bp DNA and prevents sliding inward of DNA-PKcs along with DNA duplex, suggesting a mechanism by which the broken DNA end is protected from unnecessary processing. Structural and biochemical analyses indicate that KU70/80 and DNA coordinately induce conformational changes of DNA PKcs and allosterically stimulate its kinase activity. We propose a model for activation of DNA-PKcs in which allosteric signals are generated upon DNA-PK holoenzyme formation and transmitted to the kinase domain through N-terminal HEAT repeats and FAT domain of DNA-PKcs. Our studies suggest a mechanism for recognition and protection of broken DNA ends and provide a structural basis for understanding the activation of DNA-PKcs and DNA-PK-mediated NHEJ pathway. PMID- 28840863 TI - Conference report: Mouth Care Matters conference: 'Making it sustainable - can you afford not to?' PMID- 28840862 TI - Alternative sugars: Agave nectar. PMID- 28840865 TI - DIY whitening. PMID- 28840866 TI - Jamie Newlands. PMID- 28840867 TI - My experience in an oral and maxillofacial post as a profoundly deaf dental core trainee. AB - This article reviews my experience as a profoundly deaf dental core trainee (DCT) in oral and maxillofacial surgery at Wythenshawe Hospital - working on call, carrying out daily clinics and assisting in theatre. A novel set of challenges presented, such as understanding conversations on the phone and minimising interference from background noise. Support was sought from Occupational Health, Access to Work and FM Hearing Systems, who provided practical advice and technological solutions. This year has improved my confidence and who I am as a person, and as a dentist. Plus, due to my newfound technical support I am able to hear a lot better on the phone now. It is hoped this article this will provide a useful insight for employers on how to support employees with hearing difficulties, and inspire future candidates. PMID- 28840869 TI - Identity change and informed consent. AB - Is there a distinction between gaining informed consent for identity change and other interventions? PMID- 28840870 TI - Dental education: Difficulties in comparing standards. PMID- 28840871 TI - An evaluation of a two-site pilot model for dental foundation training. AB - Objectives To evaluate the feasibility, strengths, weaknesses, and challenges of a two-site model of dental foundation training.Methods A mixed methods approach was used to evaluate the two-site pilot. Qualitative interviews and focus groups were employed to gain an in-depth understanding of the expectations, experiences and concerns of the stakeholders. Additionally, purposefully designed questionnaires were used to rate different elements of the training.Results Participants included 12 foundation dentists, 15 educational supervisors and seven assistant educational supervisors. An increased breadth of clinical experience, a more variable case-mix, feedback from two teams of supervisors, and the experience of working within two different practices with two different teams and cultures were perceived to be the main strengths. The key challenges reported by the trainers were increased workload, a perceived disruption to the continuity of patient-care and perceived difficulties in establishing professional relationships.Conclusions This paper reports on the evaluation of a new model of dental foundation training in London. It highlights potential advantages and drawbacks of providing dental foundation training in two dental practices. Given the limitations of the of evaluation reported in this paper, additional work is required to establish the feasibility and effectiveness of the two-site training model. PMID- 28840872 TI - Oral health: Dental neglect on wards. PMID- 28840873 TI - Survey of consultants in restorative dentistry in the UK regarding ongoing care of patients provided with dental implants. AB - Background Funding for implant-based treatment within secondary care is limited, and acceptance criteria are determined locally according to funding agreements with NHS England. Indefinite review of all patients in secondary care is unlikely to be feasible due to limitations on departmental capacity. The increasing number of patients provided with implant-based treatment in secondary care has resulted in a growing maintenance burden, raising the question of who should provide this care. Management of some complications within primary care would facilitate patients' access to treatment, although no specific provision for maintenance of implant-retained prostheses is made within the NHS Dental Charges Regulations.Materials and methods An online survey was carried out to review services provided within restorative dentistry departments across the UK, investigating departmental protocols for review and maintenance of patients provided with dental implants.Results There was no consensus view on review protocols, discharge or provision of maintenance following implant placement. Fifty-seven percent would indefinitely carry out remake of implant-retained overdentures when clinically indicated, replace worn inserts, housings or abutments. Sixty-one percent would manage loose/lost screw- or cement-retained restorations and 68% would manage fractured restorations. Re-referral for peri implant disease would be accepted by 64% of respondents. The lack of clear NHS funding for the management of complications was of concern to respondents in this survey. PMID- 28840879 TI - Restorative dentistry: Heads in the sand. PMID- 28840880 TI - Erratum. PMID- 28840875 TI - An evaluation of the influence of teeth and the labial soft tissues on the perceived aesthetics of a smile. AB - Objective The aim of this study was to investigate how the lips and teeth may affect the perceived aesthetics of a given smile. Lips and teeth were collectively assessed in different fields of view to see how they may contribute to smile aesthetics. The perception of 'beauty' was assessed to determine whether differences existed between; dentists, non-dentists, males and females.Methods Five subjects were photographed to produce the following views: 1) retracted anterior teeth; 2) lips at rest; 3) zoomed smile; and 4) smile showing the lower face. Images were compiled in a survey questionnaire and shown to respondents who ranked the subjects in order of aesthetic appeal. Kendall's coefficient of concordance (W) and median rank scores were used to determine the statistical significance.Results All groups demonstrated statistically significant agreement in the perception of beauty. Both the teeth and lips seemed to contribute similarly to the attractiveness of a smile. Dentists seemed to be more influenced by teeth in a zoomed smile view, however, this was negated when viewing a broader field of view. All other groups showed no difference in perception of aesthetics with changing field of view.Conclusion Both lips and teeth seem to contribute to the aesthetic appeal of a smile. Dentists may have a tendency to place a disproportionate weight to teeth when assessing a smile close up. PMID- 28840883 TI - Systematic review of literature: functional outcomes of implant-prosthetic treatment in patients with surgical resection for oral cavity tumors. AB - No improvement in quality of life after implant prosthetic reconstruction following resective surgery for cancer. PMID- 28840885 TI - 'Non-standard' panoramic programmes and the unusual artefacts they produce. AB - Dental panoramic radiographs (DPTs) are commonly taken in dental practice in the UK with the number estimated to be 2.7 million per annum. They are used to diagnose caries, periodontal disease, trauma, pathology in the jaws, supernumerary teeth and for orthodontic assessment. Panoramic radiographs are not simple projections but involve a moving X-ray source and detector plate. Ideally only the objects in the focal trough are displayed. This is achieved with a tomographic movement and one or more centre(s) of rotation. One advantage of digital radiography is hardware and software changes to optimise the image. This has led to increasingly complex manufacturer specific digital panoramic programmes. Panoramic radiographs suffer from ghost artefacts which can limit the effectiveness and make interpretation difficult. Conversely 'conventional dental imaging' such as intraoral bitewings do not suffer the same problems. There are also now several 'non-standard' panoramic programmes which aim to optimise the image for different clinical scenarios. These include 'improved interproximality', 'improved orthogonality' and 'panoramic bitewing mode'.This technical report shows that these 'non-standard' panoramic programmes can produce potentially confusing ghost artefacts, of which the practitioner may not be aware. PMID- 28840886 TI - Self-help package successful in combating dentist stress. PMID- 28840887 TI - Light at the end of the tunnel? PMID- 28840892 TI - The rise of dentine hypersensitivity and tooth wear in an ageing population. AB - Our understanding of the aetiology of dentine hypersensitivity (DH) has changed dramatically over the past few decades. It is no longer an enigma, but other problems exist. The prevalence of DH in the world and in particular in the UK is increasing, predominately due to increases in tooth wear and the erosive dietary intake in the younger population. DH is increasingly reported in all age groups and is shown to provide clinical indication of an active erosive tooth wear. As the population ages and possibly retain teeth for longer, the likelihood of tooth wear and DH could increase. This paper describes the prevalence, aetiology, diagnosis and management of DH in relation to tooth wear, which work together through a surface phenomenon. The aim is to raise awareness of the conditions and to help inform a prevention strategy in an ageing population, which starts from younger age groups to reduce disease into older age. PMID- 28840893 TI - Endodontic treatment in single and multiple visits: an overview of systematic reviews. AB - Regardless of pulpal or periradicular status, there was no difference in 'repair or success rates' between single or multiple visits for root canal therapy. PMID- 28840894 TI - Medical emergencies: Quick-release mechanism. PMID- 28840899 TI - OMFS: Tangled upper lip. PMID- 28840900 TI - [Dimensions of work ethic as predictors of strategies to cope with stress]. AB - BACKGROUND: The article presents the mutual relations between the components of work ethic and the strategies of coping with stress used by employees of different branches. MATERIAL AND METHODS: Work ethic was presented as a syndrome of the following attitudes: perceiving work as a moral value, treating work as a central value in life, and the belief in the importance of hard work that leads to success. This ethic also consists of the following components: unwillingness to waste time, disapproval of spare time (anti-leisure), willingness to delay gratification, willingness to act honestly at work (morality/ethic), and being independent (self-reliance). Coping strategies were presented as 3 dimensions (obtained by application of factor analysis of the questionnaire scales COPE (Coping Orientations to Problems Experienced)): proactive cognitive operations, avoidance of action and seeking support. RESULTS: The study conducted on 360 employees of different branches shows that the dimensions of the work ethic are moderately related to strategies emphasizing proactive cognitive operations and poorly related to seeking support and avoidance of action. At the same time, the relations between work ethic and avoidance of action are negative (higher work ethic is linked with lower tendency to avoid action). CONCLUSIONS: Predictors of proactive cognitive operations are unwillingness to waste time, treating work as a central value in life, willingness to act honestly at work (morality/ethic) and being independent (self-reliance). Med Pr 2017;68(6):711-724. PMID- 28840895 TI - The evaluation of a continuing professional development package for primary care dentists designed to reduce stress, build resilience and improve clinical decision-making. AB - Introduction Stress and burnout are widely accepted as a problem for primary care dental practitioners. Previous programmes to address this issue have met with some success. Burnout is associated with poor coping skills and emotion regulation, and increased rates of clinical errors. Anxiety is associated with poor decision-making and is thought to be associated with poor clinical decision making. Attempts to improve decision-making use increasing meta-awareness and review of thinking processes. Bibliotherapy is an effective method of delivering cognitive behavioural therapy as self-help or guided self-help (with some therapist input) formats.Objective To evaluate the efficacy of a specially designed CPD package which was designed to improve coping skills, build resilience and reduce the impact of anxiety on dentists' clinical decision making.Design A multi-centred quasi-experiment.Setting Lincolnshire and Nottinghamshire (England) 2014.Materials and methods Thirty-five volunteer primary care dentists used two versions (self-help [SH] and guided self-help [GSH], which included a 3 hour workshop) of a specially written cognitive behavioural therapy bibliotherapy programme designed to improve well-being and decision-making.Main Outcome Measures The main outcome measures were dentists' burnout, depression, anxiety, stress and decision-making style. Data were also collected on use and evaluation of the programme.Results At 6 weeks there was a clinically and statistically significant reduction in depression, anxiety and stress levels, a statistically significant reduction in burnout (emotional exhaustion) and hypervigilant decision-making, and an increase in personal achievement. The improvements in depression, stress, emotional exhaustion and hypervigilant decision-making were maintained at 6 months. Dentists were overwhelmingly positive in their evaluation of the project and used most of its contents.Conclusion With the caveat of small numbers and the lack of a no treatment control, this project demonstrated that a self-help package can be highly acceptable to dentists and, in the short-to-medium term, improve dentists' well-being and decision-making with implications for patient safety. PMID- 28840901 TI - Cloning of intronic sequence within DsRed2 increased the number of cells expressing red fluorescent protein. AB - AIM: Cloning of artificial intronic sequence within the open reading frame (ORF) of DsRed2 gene. METHOD: Splice prediction software was used to analyze DsRed2 sequence to find an ideal site for cloning artificial intronic sequence. Intron was cloned within DsRed2 using cyclic ligation assembly. Flow cytometry was used to quantify the number of cells expressing red fluorescence. RESULT: Sequencing data confirmed precise cloning of intron at the desired position using cyclic ligation assembly. Successful expression of red fluorescence after cloning of intron confirmed successful intron recognition and splicing by host cell line. Cloning of intron increased the number of cells expressing red fluorescent protein. CONCLUSION: Cloning of intronic sequence within DsRed2 has helped to increase the number of cells expressing red fluorescence by approximately four percent. PMID- 28840902 TI - Reply. PMID- 28840903 TI - New Barrett's oesophagus surveillance guidelines: significant cost savings over the next 10 years on implementation. AB - OBJECTIVE: We aimed to estimate the cost saving (over the next 10 years) by our trust implementing the new British Society of Gastroenterology (BSG) surveillance guidelines for Barrett's oesophagus (BO). DESIGN: Retrospective endoscopy database analysis. SETTING: Two endoscopy units of St George's Hospital NHS Trust, London. PATIENTS: Gastroscopy records between 2009 and 2012 were retrieved and patients with an endoscopic diagnosis of BO were identified. BO segment length was recorded and the presence (or absence) of intestinal metaplasia in the oesophageal biopsy samples was reviewed from pathology databases. Patients were then stratified into risk groups in accordance with the new BSG guidelines. INTERVENTIONS: Nil. MAIN OUTCOME MEASURES: The projected surveillance costs using the new and the old guidelines were calculated over the next 10 years and the cost saving by the implementation of the new guidelines thus determined. RESULTS: The 10 year projected cost saving for our trust by implementing the new BO surveillance guidelines was L720 330 (or L72 033 per annum). Projected across the NHS, implementation of the new guidance may save L100 million over the next 10 years. CONCLUSIONS: All trusts should review their Barrett's surveillance population and implement these new recommendations expeditiously. PMID- 28840904 TI - Adult-onset dystonia with marfanoid features. PMID- 28840906 TI - Risk and reward: rethinking the paradigm for adenoma surveillance. PMID- 28840905 TI - Guidance on the effective use of upper gastrointestinal histopathology. AB - Given the ever-increasing demand for upper gastrointestinal endoscopy, for diagnosis and surveillance, there is a need to consider when it is appropriate, and when it is not appropriate, to take an endoscopic biopsy for histological evaluation. In this article, we consider this in relation to each of the anatomical compartments encountered during oesophagogastroduodenoscopy, and in relation to the common clinical scenarios and endoscopic abnormalities encountered. There are clear indications to biopsy suspicious ulceration or mass lesions and for investigation of some inflammatory conditions, such as eosinophilic oesophagitis and coeliac disease. Increasing guidance is available on optimal biopsy sites and biopsy numbers to maximise yield from histology. Outside these areas, the endoscopist should consider whether biopsy of normal or abnormal appearing mucosa is likely to contribute to patient management, to ensure effective use of limited healthcare resources. PMID- 28840907 TI - The new oral anticoagulants: practical management for patients attending for endoscopic procedures. AB - Guidelines published by the British Society of Gastroenterology have standardised the care of patients attending for endoscopy procedures, taking aspirin, clopidogrel and warfarin. Two new oral anticoagulant drugs, Rivaroxaban and Dabigatran, are licensed and National Institute of Clinical Excellence (NICE) approved for use in the UK. Unlike warfarin, these drugs do not require regular monitoring, and are at least as effective in preventing stroke in non-valvular atrial fibrillation. As such, they are likely to become popular among patients and clinicians alike. This paper summarises the practical management of patients taking these drugs attending for endoscopic procedures. PMID- 28840908 TI - What we can learn from Medicare data on early deaths after emergency department discharge. PMID- 28840909 TI - Surveillance colonoscopy in low-risk postpolypectomy patients: Is it necessary? AB - AIM: Patients who have had colorectal adenomas removed are at increased risk of developing colorectal cancer in the future. We sought to determine whether surveillance colonoscopy at 5 years in low-risk postpolypectomy patients is necessary and effective. METHOD: UK multicentre retrospective study. Patients diagnosed with 'low-risk' colorectal adenomas between April 2004 and April 2007 were identified and results of all subsequent lower gastrointestinal (GI) endoscopies were noted. Where no colonoscopy had been done at or after 5 years from the index investigation, patient details were cross-checked against hospital colorectal multidisciplinary team databases to ensure no colorectal cancer had been detected in the meantime. RESULTS: 641 patients were included. 131 patients (20.4%) had a 'per protocol' surveillance colonoscopy at 5 years. Of these, no patients were found to have colorectal cancer, 10 patients (7.6%) had advanced adenomas, 26 patients (19.8%) had non-advanced adenomas and 95 patients (72.5%) had no further adenomas. 510 patients (79.6%) did not have a surveillance colonoscopy at 5 years. Of these, 110 patients (17.2%) developed lower GI symptoms within 5 years of their index endoscopy and underwent a further lower GI endoscopy to investigate these symptoms. 3 colorectal cancers in 3 patients were found during these endoscopies and two further colorectal cancers were found at symptomatic colonoscopies at or after 5 years from index. CONCLUSIONS: Patients with low-risk adenomas should be risk profiled. Those with risk factors, such as two adenomas, male sex and advanced adenomas at index procedure should be offered 5-year surveillance colonoscopy. PMID- 28840910 TI - Opportunities to improve surveillance for hepatocellular carcinoma in the UK. PMID- 28840912 TI - Improving acute upper GI bleeding services in a district general hospital. PMID- 28840911 TI - A national survey of the provision of ultrasound surveillance for the detection of hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular carcinoma (HCC), the sixth most common cancer worldwide and third most common cause of cancer related death, is closely associated with the presence of cirrhosis. Survival is determined by the stage of the cancer, with asymptomatic small tumours being more amenable to treatment. Early diagnosis is dependent on regular surveillance and the primary objective of this survey was to gain a better understanding of the baseline attitudes towards and provision of ultrasound surveillance (USS) HCC surveillance in the UK. In addition, information was obtained on the stages of cancer of the patients being referred to and discussed at regional multidisciplinary team meetings. DESIGN: UK hepatologists, gastroenterologists and nurse specialists were sent a questionnaire survey regarding the provision of USS for detection of HCC in their respective hospitals. RESULTS: Provision of surveillance was poor overall, with many hospitals lacking the necessary mechanisms to make abnormal results, if detected, known to referring clinicians. There was also a lack of standard data collection and in many hospitals basic information on the number of patients with cirrhosis and how many were developing HCC was not known. For the majority of new HCC cases was currently being made only at an incurable late stage (60%). CONCLUSIONS: In the UK, the current provision of USS based HCC surveillance is poor and needs to be upgraded urgently. PMID- 28840913 TI - Effect of integrated community neurology on utilization, diagnostic testing, and access. AB - BACKGROUND: The primary care medical home (PCMH) aims to promote delivery of high value health care. However, growing demand for specialists due to increasingly older adults with complicated and chronic disease necessitates development of novel care models that efficiently incorporate specialty expertise while maintaining coordination and continuity with the PCMH. We describe the effect of a model of integrated community neurology (ICN) on health care utilization, diagnostic testing, and access. METHODS: This is a retrospective, matched case control comparison of patients referred to ICN for a face-to-face consultation over a 12-month period. The control group consisted of propensity score-matched patients referred to a non-colocated neurology practice during the study period. Administrative data were used to assess for diagnostic testing, visit utilization, and patient time to appointment. RESULTS: From October 1, 2014, to September 30, 2015, we identified 459 patients evaluated by ICN for a face-to face visit and 459 matched controls evaluated by the non-colocated neurology practice. The majority of patients were Caucasian and female. ICN patients had lower odds of EMGs ordered (adjusted odds ratio [OR] 0.64; 95% confidence interval [CI] 0.46-0.89; p = 0.009), MRI brain (adjusted OR 0.60; 95% CI 0.45 0.79; p = 0.0004), or subsequent referral to outpatient neurology (adjusted OR 0.62; 95% CI 0.47-0.83; p = 0.001). ICN was not associated with an increase in emergency department visits, hospitalizations, or appointment wait time. CONCLUSIONS: The ICN model in a PCMH has the potential to reduce diagnostic testing and utilization. PMID- 28840914 TI - Robotic-assisted thoracoscopic surgery: state of the art and future perspectives. PMID- 28840915 TI - Lower gastrointestinal endoscopy: guidance on indications for biopsy. AB - Lower gastrointestinal endoscopy is a commonly undertaken procedure and has assumed even greater prominence with the inception of the NHS Bowel Cancer Screening Programme (BCSP). Workloads are also constantly increasing within histopathology departments and this has led to a need for workload management by laboratories. Advanced endoscopic techniques now allow for targeted biopsies within settings such as inflammatory bowel disease surveillance and the BCSP. In this article, we provide guidance to the endoscopist for optimal biopsy protocols that are designed to maximise the chance of a subsequent histopathological examination providing definitive results and to reduce the number of unnecessary biopsies, in which histopathology is unlikely to deliver clinically useful information. The majority of the article focuses on biopsy taking within a defined range of clinical situations that are commonly encountered by endoscopists. PMID- 28840916 TI - The new oral anticoagulants: new uncertainties for endoscopists. PMID- 28840917 TI - Combined pH-impedance testing for reflux: current state of play and future challenges. PMID- 28840918 TI - New Barrett's guidelines: an opportunity to improve patient experience and save resources. PMID- 28840920 TI - The effective use of gastrointestinal histopathology: guidance for endoscopic biopsy in the gastrointestinal tract. AB - This is the first of three articles, published in Frontline Gastroenterology, that provides practical guidance of what to, and what not to, biopsy in the gastrointestinal (GI) tract. This initiative was established by the Endoscopy and Pathology Sections of the British Society of Gastroenterology, and the guidance is published with an initial general review (this manuscript), followed by practical guidance on upper GI and lower GI endoscopic biopsy practice. The three articles are written by experienced operatives, each one by a pathologist and an endoscopist, working in the same hospital/group of hospitals. PMID- 28840919 TI - Virtual visits for Parkinson disease: A multicenter noncontrolled cohort. AB - BACKGROUND: Previous small-scale studies have demonstrated the feasibility of providing remote specialty care via virtual visits. We assessed the feasibility and benefits of a one-time consultation between a remote Parkinson Disease (PD) specialist and an individual with PD at home on a larger scale. METHODS: We conducted a multicenter noncontrolled cohort of virtual visits administered over videoconferencing between remote PD specialists and individuals with PD in their home. Specialists performed a patient history and a PD-specific physical examination and provided recommendations to patients and their local physicians. The primary outcome measures were feasibility, as measured by the proportion of visits completed as scheduled, and the 6-month change in quality of life, as measured by the Parkinson's Disease Questionnaire 39. Additional outcomes included satisfaction with visits and interest in future virtual visits. RESULTS: A total of 277 participants from 5 states enrolled, 258 participants completed virtual visits with 14 different physicians, and 91% of visits were completed as scheduled. No improvement in quality of life was observed at 6 months (0.4-point improvement; 95% confidence interval -1.5 to 0.6; p = 0.39). Overall satisfaction with virtual visits was high among physicians (94% satisfied or very satisfied) and patients (94% satisfied or very satisfied), and 74% of participants were interested in receiving future care via virtual visits. CONCLUSIONS: Providing specialty care remotely into the homes of individuals with PD is feasible, but a one-time visit did not improve quality of life. Satisfaction with the visits was high among physicians and patients, who were interested in receiving such care in the future. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with PD, remote specialty care is feasible but does not improve quality of life. CLINICALTRIALSGOV IDENTIFIER: NCT02144220. PMID- 28840921 TI - Provision of an out-of-hours emergency endoscopy service: the Leicester experience. AB - INTRODUCTION: The British Society of Gastroenterology (BSG) Strategy document 'Care of patients with Gastrointestinal (GI) disorders' recommends that all acute hospitals should have arrangements for out-of-hours (OOH) endoscopy staffed with appropriately trained endoscopists. The UK national audit published in 2010 found that only 52% of hospitals across the UK had a formal consultant-led OOH endoscopy on-call rota. The University Hospitals of Leicester (UHL) established a consultant-led rota in 2006, which now provides 24/7 endoscopy cover. To define the workload of a newly established OOH service, we examined procedures performed since the introduction of an OOH service in 2006. METHODS: The audit period covered August-January (6 months) for each of five consecutive years. Data were gathered from formal endoscopy reports on Unisoft reporting tool and OOH record books. We examined indication for endoscopy, timing of procedure, findings at index endoscopy, intervention and immediate outcome. RESULTS: Across the three UHL sites, data on 982 patients were analysed. Eighty-one percent of procedures performed were gastroscopies. 63% of the procedures were performed for GI bleed indications. Over the five years, there was an overall increase in the number of procedures performed where no pathology was found. Immediate outcomes postendoscopy were good, with over 90% being returned to their base ward. CONCLUSIONS: The experience at UHL appears to show a trend towards an increasing number of procedures performed OOH, with fewer positive findings and less need for therapy. A likely contributing factor is the ongoing shortage of medical beds, requiring more routine work to be done OOH in order to expedite discharges. However, early specialist endoscopic input is likely to improve patient management. The impact of an OOH service on other services, however, needs to be carefully considered. PMID- 28840923 TI - On the critical Casimir interaction between anisotropic inclusions on a membrane. AB - Using a lattice model and a versatile thermodynamic integration scheme, we study the critical Casimir interactions between inclusions embedded in a two dimensional critical binary mixtures. For single-domain inclusions we demonstrate that the interactions are very long range, and their magnitudes strongly depend on the affinity of the inclusions with the species in the binary mixtures, ranging from repulsive when two inclusions have opposing affinities to attractive when they have the same affinities. When one of the inclusions has no preference for either of the species, we find negligible critical Casimir interactions. For multiple-domain inclusions, mimicking the observations that membrane proteins often have several domains with varying affinities to the surrounding lipid species, the presence of domains with opposing affinities does not cancel the interactions altogether. Instead we can observe both attractive and repulsive interactions depending on their relative orientations. With increasing number of domains per inclusion, the range and magnitude of the effective interactions decrease in a similar fashion to those of electrostatic multipoles. Finally, clusters formed by multiple-domain inclusions can result in an effective affinity patterning due to the anisotropic character of the Casimir interactions between the building blocks. PMID- 28840922 TI - A microfluidic oxygen gradient demonstrates differential activation of the hypoxia-regulated transcription factors HIF-1alpha and HIF-2alpha. AB - Gas-perfused microchannels generated a linear oxygen gradient via diffusion across a 100 MUm polydimethylsiloxane (PDMS) membrane. The device enabled exposure of a single monolayer of cells sharing culture media to a heterogeneous oxygen landscape, thus reflecting the oxygen gradients found at the microscale in the physiological setting and allowing for the real-time exchange of paracrine factors and metabolites between cells exposed to varying oxygen levels. By tuning the distance between two gas supply channels, the slope of the oxygen gradient was controlled. We studied the hypoxic activation of the transcription factors HIF-1alpha and HIF-2alpha in human endothelial cells within a spatial linear gradient of oxygen. Quantification of the nuclear to cytosolic ratio of HIF immunofluorescent staining demonstrated that the threshold for HIF-1alpha activation was below 2.5% O2 while HIF-2alpha was activated throughout the entire linear gradient. We show for the first time HIF-2alpha is subject to hyproxya, hypoxia by proxy, wherein hypoxic cells activate HIF in close-proximity normoxic cells. These results underscore the differences between HIF-1alpha and HIF-2alpha regulation and suggest that a microfluidic oxygen gradient is a novel tool for identifying distinct hypoxic signaling activation and interactions between differentially oxygenated cells. PMID- 28840924 TI - Esterase-sensitive sulfur dioxide prodrugs inspired by modified Julia olefination. AB - Sulfur dioxide (SO2) is an endogenously produced gaseous molecule, and is emerging as a potential gasotransmitter. Herein, we describe the first series of esterase-sensitive prodrugs inspired by modified Julia olefination as SO2 donors. PMID- 28840925 TI - Electron ionization of helium droplets containing C60 and alcohol clusters. AB - We report a mass spectrometric investigation of (C60)n clusters mixed with either methanol or ethanol clusters inside helium nanodroplets. The abundance of ion products produced by electron ionization shows marked differences compared with pure methanol/ethanol clusters without C60 [M. Goulart, P. Bartl, A. Mauracher, F. Zappa, A. M. Ellis and P. Scheier, Phys. Chem. Chem. Phys., 2013, 15, 3577], where clusters containing in excess of a hundred alcohol monomers were observed. In contrast, under identical conditions concerning He droplet size and alcohol pickup pressure, only a small number of alcohol molecules become attached to the fullerene ions. Our results suggest that each fullerene cluster acts as a charge sink, which hampers alcohol cluster formation, as well as intra-cluster ion molecule reactions. The appearance of specific 'magic number' peaks suggests an enhanced probability for the attachment of small alcohol rings to (C60)n+ clusters. PMID- 28840926 TI - Structure-dependent reactivity of Criegee intermediates studied with spectroscopic methods. AB - Criegee intermediates are very reactive carbonyl oxides that are formed in reactions of unsaturated hydrocarbons with ozone (ozonolysis). Recently, Criegee intermediates have gained significant attention since a new preparation method has been reported in 2012, which employs the reaction of iodoalkyl radical with molecular oxygen: for instance, CH2I + O2 -> CH2OO + I. This new synthesis route can produce Criegee intermediates with a high number density, which allows direct detection of the Criegee intermediate via various spectroscopic tools, including vacuum UV photoionization mass spectrometry, absorption and action spectroscopy in the UV and IR regions, and microwave spectroscopy. Criegee intermediates have been thought to play important roles in atmospheric chemistry, such as in OH radical formation as well as oxidation of atmospheric gases such as SO2, NO2, volatile organic compounds, organic and inorganic acids, and even water. These reactions are relevant to acid rain and aerosol formation. Kinetics data including rate coefficients, product yields and their temperature and pressure dependences are important for understanding and modeling relevant atmospheric chemistry. In fundamental physical chemistry, Criegee intermediates have unique and interesting features, which have been partially revealed through spectroscopic, kinetic, and dynamic investigations. Although previous review articles have discussed Criegee intermediates, new data and knowledge on Criegee intermediates are still being accumulated. In this tutorial review, we have focused on structure-dependent reactivity of Criegee intermediates and various spectroscopic tools that have been utilized to probe the kinetics of Criegee intermediates. PMID- 28840927 TI - Magnetic particles assisted capture and release of rare circulating tumor cells using wavy-herringbone structured microfluidic devices. AB - A wavy-herringbone (wavy-HB) structured microfluidic device was used to effectively and selectively capture and release circulating tumor cells (CTCs) by using immunoaffinity and magnetic force. This device was designed to create passive turbulence and increase the possibility of tumor cells colliding with the device wall. Under an external magnetic field, magnetic particles (MPs) coated with anti-EpCAM against a tumor cell surface protein (EpCAM) were immobilized over the wavy-HB surface to capture tumor cells. After removing the magnetic field, the captured cells with surplus MPs were released from the device and collected; thus, these cells could be re-cultured for further analysis. Under optimized conditions, the capture efficiency of the tumor cells can be as high as 92% +/- 2.8%. Capture experiments were also performed on whole blood samples, and the capture efficiency was in a high range of 81-95%, at different tumor cell concentrations. Such a method can potentially be used for CTC sorting from patient blood samples, CTC concentration monitoring, therapeutic guidance and drug dosage choice, and further study of tumors, such as drug screening and tumor mutations. PMID- 28840928 TI - What [plasma used for growing] diamond can shine like flame? AB - Diamond synthesis by chemical vapour deposition (CVD) from carbon-containing gas mixtures has by now long been an industrial reality, but commercial interest and investment into the technology has grown dramatically in the last several years. This Feature Article surveys recent advances in our understanding of the gas phase chemistry of microwave-activated methane/hydrogen plasmas used for diamond CVD, including that of added boron-, nitrogen- and oxygen-containing dopant species. We conclude by considering some of the remaining challenges in this important area of contemporary materials science. PMID- 28840929 TI - Diversity and controllability of particle distribution under coupling vibration and airflow. AB - The vertical, horizontal, and three-dimensional (3D) distribution of binary particles with different diameters are investigated simultaneously in a cylindrical container under coupling vibration and airflow. Airflow is blown into the vertically vibrating granular bed from its bottom with vibration frequency of f = 15, 30, and 45 Hz; vibration acceleration Gamma = 2-7; and air velocity u = 0 1.82 m s-1 (fluidization number u/umf = 0-1.49). In our experiments, several distribution states have been observed, such as the mixing state, where particles are uniformly mixed; Brazil nut separation (BN), where large particles rise to the top; reverse Brazil nut separation (RBN), where large particles sink to the bottom; horizontal separation (HS), where binary particles separate horizontally; and combined distribution of BN/RBN and HS, in which one type of particles is above the other and close to one side of the container wall. Briefly, the vertical distribution forms five pattern types, and the horizontal distribution has four pattern types. The resultant pattern of 3D distribution exhibits 15 pattern types. These patterns can be always obtained under the conditions of certain control parameters, but the condition differs with the diameter ratio of binary particles. Phase diagrams of vertical, horizontal, and 3D distributions are drawn to provide the excitation condition of various patterns. These experimental results contribute to the further understanding of the entire distribution of particles and the control of particle distribution for different industry requirements. PMID- 28840930 TI - Trauma-Informed Care and Practice: Practice Improvement Strategies in an Inpatient Mental Health Ward. AB - A growing body of evidence highlights that trauma is the single most significant predictor that an individual will need support from mental health services. Yet despite this association, mental health services have been slow to provide approaches to care and treatment that deal directly with trauma. Embedding the principles of trauma-informed care and practice (TICP) in acute inpatient ward practice can lead to practice improvement and cultural change over a number of areas. The current service evaluation highlights how these principles can inform practice and the positive affect this has on areas such as seclusion and restraint, therapeutic engagement, and ward routines. TICP complements recovery focused models of care and promotes collaborative and empowering relationships in the inpatient setting. Embedding this approach in inpatient mental health units can lead to changes in professional practice and service provision that benefit service users. [Journal of Psychosocial Nursing and Mental Health Services, 55(10), 34-38.]. PMID- 28840931 TI - Parent-Child Relationships: Implementation of a Screening and Referral Program for Adolescents With Mood Disorders. AB - Parent-child relational problems (PCRP) have been increasingly recognized as a risk factor in the development and/or progression of childhood mental illnesses. Despite many young individuals being at risk, health care providers do not specifically screen for PCRP in children diagnosed with mental illnesses. The objective of the current project was to implement a PCRP screening program in a metropolitan children's hospital and refer those with PCRP for treatment. Adolescents ages 10 to 17 presenting for admission in an inpatient pediatric psychiatric unit were screened with the PCRP semi-structured questionnaire and diagnostic criteria developed by the American Psychiatric Association's Relational Processes Workgroup. Eleven (73%) of 15 patients screened were found to have PCRP. Patients may be screened with a PCRP screening tool during biopsychosocial assessment without undue time burden on the provider. It is recommended that PCRP be added to electronic health records so providers can select PCRP in problem lists as well as formulate PCRP-sensitive care plans. [Journal of Psychosocial Nursing and Mental Health Services, 55(11), 23-29.]. PMID- 28840932 TI - Existing But Not Living: Experiences of Long-Term Caregivers of Individuals With Unipolar Depression. AB - The shift in care from long-term hospitalization of individuals with mental illness to the community places a greater onus of responsibility on informal caregivers. The purpose of the current study was to explore the lived experiences of long-term caregivers of individuals with unipolar depression. A qualitative phenomenological methodology was used and two sets of semi-structured interviews were conducted with nine informal caregivers. Data were transcribed following Giorgi's phenomenological method. The following three themes were identified: Flooded by Emotions, Personal Growth and Satisfaction, and Psychosocial Effects and Challenges. Caregivers described adapting by adjusting their behavior to avoid conflict with care recipients. These adjustments had a detrimental effect on their well-being, where they described that they were "existing but not living." These findings highlight the need for ongoing support, which should be tailored to the unique needs and concerns of individuals who are providing long term care to individuals with depression. [Journal of Psychosocial Nursing and Mental Health Services, 55(12), 16-21.]. PMID- 28840933 TI - Implementing a Workplace Violence Simulation for Undergraduate Nursing Students: A Pilot Study. AB - Workplace violence (WPV) is an undesired phenomenon affecting nurses and nursing students. Nursing simulations allow students to learn and practice skills in a controlled setting. The development of the pilot study, "Mental Health Nursing Simulation on Workplace Violence," is presented. A simulated scenario using a standardized patient (SP) behaving as an agitated psychiatric patient was developed for undergraduate nursing students enrolled in a psychiatric nursing course. The simulation aimed to enhance students' knowledge about WPV, increase their confidence and ability to recognize signs of aggression, practice evidence based interventions to de-escalate agitated patients, and evaluate the simulation. Surveys and the Mental Health Nursing Clinical Confidence Scale were used to measure the aims yielding qualitative and quantitative data. An increase in students' confidence and knowledge was obtained post-simulation. Students rated the simulation as useful. The use of a SP created an experiential learning environment for participants. [Journal of Psychosocial Nursing and Mental Health Services, 55(10), 39-44.]. PMID- 28840934 TI - Measurement-Based Care in Psychiatry. AB - Measurement-based care (MBC) uses patient-reported rating scales in conjunction with evidence-based clinical practice guidelines to provide an objective assessment of patient progress over time to guide a more precise plan of care. Use of MBC is routine in medical disease management. Unfortunately, MBC is not standard practice in psychiatric care. The current nonsystematic approach to the delivery of mental health care has created considerable variability in practice and may stall recovery. Although MBC has proven benefits, there are perceived barriers to its implementation. Greater research is needed to standardize psychiatric measures and clinical practice guidelines and determine the most effective implementation strategies. A review of the literature was conducted to (a) provide an overview of MBC and relevant screening tools; (b) examine the clinical use of MBC, including its relevance to evidence-based clinical guidelines and empirical support; and (c) detail the benefits and challenges of MBC implementation. As mental health care moves in the direction of value-driven incentives, it will be important for providers and organizations to consider MBC as an evidence-based framework to reduce variability in psychiatric treatment and improve patient outcomes. [Journal of Psychosocial Nursing and Mental Health Services, 55(11), 30-35.]. PMID- 28840935 TI - Effects of Physical Limitations on Daily Activities Among Adults With Mental Health Disorders: Opportunities for Nursing and Occupational Therapy Interventions. AB - Individuals living with mental health disorders served by the public mental health system often face comorbid medical conditions that affect their quality of life and lifespan. The effect of physical limitations on the engagement in daily activities among individuals living with mental health disorders has not been extensively researched. Adults attending community wellness centers (N = 53) in a northeastern United State were included in a descriptive study exploring the impact of physical limitations on daily activities. The activities most frequently affected were: walking or moving around, sleeping, and finding a job. The physical limitations affecting these three activities were lack of energy and pain. Health care professionals, including mental health nurses and occupational therapy practitioners, are in an ideal position to collaborate by evaluating and offering treatment interventions that address physical limitations to positively affect occupational functioning and recovery. [Journal of Psychosocial Nursing and Mental Health Services, 55(10), 45-51.]. PMID- 28840936 TI - Effects of static magnetic fields on the enteropathogenic Escherichia coli. AB - This study reports the effects of exposing cells of the prototypical enteropathogenic Escherichia coli (EPEC) strain E2348/69 to static magnetic fields (SMF) of varying intensities to observe their capacity to autoaggregate and the effect on cell adherence. The results showed that bacteria exposure over the course of 5 min to an intensity of 53 mT reduced autoaggregation by 28%. However, with intensities of up to 100 mT with the same exposure time, bacteria autoaggregation was reduced by approximately 50%; and after 30 min at the same intensity, it was indistinguishable from that observed in a non-autoaggregative strain. Furthermore, it was observed that SMF treatment also modified the typical localized adherence pattern of EPEC E2348/69. The observed effects are not related to bacteria damage. The above was confirmed because, after a 107 mT SMF treatment over the course of 30 min, cell viability and membrane permeability were the same to that observed in untreated controls. The obtained results suggest that the SMF effect on the E2348/69 EPEC strain alters the expression of the bundle-forming pilus (BFP), due to the fact that the same strain without the EPEC adherence factor plasmid that encodes the BFP operon was unable to autoaggregate. Electron microscopic analyses revealed structural differences between cells exposed to SMF with respect to untreated controls. In conclusion, the SMF treatment of 107 mT for 30 min reduced EPEC E2348/69 autoaggregation and modified its adherence pattern, with both events likely being associated with changes in BFP expression. Bioelectromagnetics. 38:570-578, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28840937 TI - Impact of growth mode, phase, and rate on the metabolic state of the extremely thermophilic archaeon Pyrococcus furiosus. AB - The archaeon Pyrococcus furiosus is emerging as a metabolic engineering platform for production of fuels and chemicals, such that more must be known about this organism's characteristics in bioprocessing contexts. Its ability to grow at temperatures from 70 to greater than 100 degrees C and thereby avoid contamination, offers the opportunity for long duration, continuous bioprocesses as an alternative to batch systems. Toward that end, we analyzed the transcriptome of P. furiosus to reveal its metabolic state during different growth modes that are relevant to bioprocessing. As cells progressed from exponential to stationary phase in batch cultures, genes involved in biosynthetic pathways important to replacing diminishing supplies of key nutrients and genes responsible for the onset of stress responses were up-regulated. In contrast, during continuous culture, the progression to higher dilution rates down regulated many biosynthetic processes as nutrient supplies were increased. Most interesting was the contrast between batch exponential phase and continuous culture at comparable growth rates (~0.4 hr-1 ), where over 200 genes were differentially transcribed, indicating among other things, N-limitation in the chemostat and the onset of oxidative stress. The results here suggest that cellular processes involved in carbon and electron flux in P. furiosus were significantly impacted by growth mode, phase and rate, factors that need to be taken into account when developing successful metabolic engineering strategies. PMID- 28840938 TI - Loss of Hdac3 in osteoprogenitors increases bone expression of osteoprotegerin, improving systemic insulin sensitivity. AB - Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone derived factors that reduce RANKL (receptor activator of NF-kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1-expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3-deficient mice on a high fat diet. Thus, Hdac3-depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity. PMID- 28840939 TI - Viruses in cancers among the immunosuppressed. AB - Most cancer forms known to be caused by viruses are increased among the immunosuppressed, but several cancer forms without established viral etiology are also increased, notably nonmelanoma skin carcinoma (NMSC). We followed all 13,429 solid organ transplantation patients in Sweden for cancer occurrence after transplantation. We requested these tumor specimens and sequenced the first 89 specimens received (62 NMSCs, 27 other cancers). The sequences were analyzed for viruses based on two bioinformatics algorithms (paracel-blast (sensitive for detection of known viruses) and hidden Markov model (HMM; sensitive for distantly related viruses)). Among the 62 NMSCs, the virus family detected in the largest proportion of specimens was Mimiviridae (9/62 NMSCs). The majority of the virus related reads belonged to Papillomaviridae. The HMM analysis identified 86 additional previously not described viral contigs related to 11 virus families, with reads related to Mimiviridae being the most common (detected in 28/62 NMSCs) with the most prevalent contig (Mimivirus SE906, 1937 bp) detected in 17/62 NMSCs. Among the 27 other cancers, viral sequences were detected in only 5 specimens by blast analysis, compared to in all 27 specimens by HMM (Mimiviridae, Poxviridae, Phycodnaviridae and virus-related sequences yet unclassified to any family). 99% of the virus reads belonged to a single previously not described sequence (Mimivirus SE996, 911 bp). A multitude of viruses is readily detectable in specimens with cancers occurring among the immunosuppressed, with sequences related to Mimiviridae being the most prevalent. Further research would be needed to elucidate the biological significance of the viruses. PMID- 28840940 TI - Research priorities for specialized nursing practice in the United Arab Emirates. AB - BACKGROUND: Globally, nurses are undertaking expanded and more specialized roles in healthcare planning and service delivery in response to changing patterns and levels of health service demand. This means the nursing profession is increasingly considered as leaders in health service policy, research and practice. The United Arab Emirates has strengthened nursing governance and practice by establishing a Nursing and Midwifery Council and increasing the activity of nursing specialization, service leadership and research. This study aimed to identify clinically relevant research priorities to facilitate nursing contributions to evidence-based care and strengthening health services in the country. METHODS: A two-stage Delphi study design was used. RESULTS: The first round involved 783 participants. The second round involved 1116 participants, as more clinical settings were accessed. In total, 58 research priorities across a variety of nursing specialties (paediatrics, emergency care, intensive care, labour and maternity care, operating theatre and long-term care) were identified as highly important. CONCLUSION: These identified priorities will guide a more informed programme of research in each nursing specialty, with the aim of strengthening the evidence base to improving outcomes for patients and their families in the United Arab Emirates. IMPLICATIONS FOR NURSING PRACTICE, RESEARCH AND POLICY: The findings provide guidance on key areas for nurses to focus research contributions to enhance evidence-based care and strengthen health systems. The identified priorities may also guide researchers in academic institutions to conduct research informed by current, clinically relevant issues. The findings may help inform funders and policymakers to support allocation of funding to research that has potential to contribute to enhancing nursing care in specialist areas. PMID- 28840941 TI - Acute fall and long-term rise in oxygen saturation in response to meditation. AB - The effects of meditation on arterial and tissue oxygenation are unknown and difficult to assess because respiration is often altered, directly or indirectly, during meditation practice. Thus, changes in respiration may affect cardiovascular responses independently from meditation. In this study, we aim to isolate the specific effect of meditation on arterial and tissue oxygenation and other cardiorespiratory indexes while systematically controlling for the role of respiration. Furthermore, we aim to clarify to what extent prior expertise in meditation practice is needed to observe reliable changes. Eighty participants, half with and half without prior meditation experience, were tested while pacing breathing at predetermined rates, in the presence or absence of mantra meditation instructions, and in a body scan meditation that did not involve controlled breathing. Continuous recordings were acquired for arterial and brain oxygenation, respiratory excursion, electrocardiogram, skin vasomotion, and blood pressure. In both groups, meditation acutely decreased arterial and cerebral oxygen saturation, reduced chemoreflex sensitivity, and prolonged the RR interval, independently of respiration. Conversely, slow breathing improved heart rate variability, independently of concurrent meditation. In addition to the immediate effects of meditation, the individuals with long-term practice of meditation had overall higher arterial and cerebral oxygen saturation, overall lower blood pressure, and slower baseline respiration. Meditation acutely lowers arterial and tissue oxygenation. A repeated exposure to this condition may lead to long-term adaptation and, through increased ventilatory efficiency and improved gas exchanges, to an increase in baseline oxygenation. Meditation induces favorable changes in cardiovascular and respiratory end points of clinical interest. PMID- 28840942 TI - Hemolysis related to intravenous immunoglobulins is dependent on the presence of anti-blood group A and B antibodies and individual susceptibility. AB - BACKGROUND: Patients treated with intravenous immunoglobulins (IVIG) rarely experience symptomatic hemolysis. Although anti-A and anti-B isoagglutinins from the product are involved in most cases, the actual mechanisms triggering hemolysis are unclear. STUDY DESIGN AND METHODS: A prospective, open-label, multicenter, single-arm clinical trial in 57 patients with immune thrombocytopenia treated with IVIG (Privigen, CSL Behring) was conducted. RESULTS: Twenty-one patients received one infusion (1 g/kg) and 36 received two infusions (2 * 1 g/kg) of IVIG. After a study duration of more than 2 years, no cases of clinically significant hemolysis as defined in the protocol were identified. Data of patients with mild hematologic and biochemical changes were analyzed in more detail. Twelve cases (10/23 patients with blood group A1 and 2/11 patients with blood group B, all having received 2 g/kg IVIG) were adjudicated as mild hemolysis (median hemoglobin [Hb] decrease, -3.0 g/dL); Hb decreases were transient, with partial or full recovery achieved by last visit. Eighteen patients (31.6%), all with non-O blood group, of whom 16 (88.9%) received 2 g/kg IVIG, fulfilled post hoc criteria for hemolytic laboratory reactions. Red blood cell (RBC) eluates of all direct antiglobulin test-positive samples were negative for non-ABO blood group antibodies. Blood groups A and B antigen density on RBCs appeared to be a risk factor for hemolytic laboratory reactions. Platelet response to treatment was observed in 42 patients (74%); eight of 12 patients with complete response had blood group A1. CONCLUSION: Isoagglutinins are involved in clinically nonsignificant hemolysis after treatment with IVIG, but individual susceptibility varies greatly. PMID- 28840944 TI - Who donates? Cross-country and periodical variation in blood donor demographics in Europe between 1994 and 2014. AB - BACKGROUND: Ageing European populations put pressure on national blood supplies, increasing the need for blood and donor base rejuvenation. Therefore, we investigate how European countries' blood donor populations differ and how they have evolved over the last 2 decades. Previous comparative research, based on 1994 Eurobarometer data, indicate that the typical donor is an educated, middle aged, white, married male. Other sociodemographic and socioeconomic correlates, such as employment status and type of community, are less clear. STUDY DESIGN AND METHODS: Multilevel analyses are performed on repeated cross-level data from the Eurobarometer (waves 1994, 2002, 2009, and 2014) to compare information on "ever having donated" across sociodemographic categories, countries, and periods. RESULTS: There are consistent but moderate country and period differences. The donor population rose to become largest in most countries by 2009, and stabilized thereafter. Over the studied period, donors were more likely to be higher educated, married men. Nevertheless, changes across time in donor profiles within countries did occur. Women were less likely to donate blood, especially in Southern and Eastern Europe, but this gender gap has declined. Furthermore, educational attainment seems more relevant for women, although, more recently, to a lesser extent. CONCLUSION: Although there is a promising trend in which women, young people, and students are increasingly likely to donate, more attention is needed to reach the unemployed and the low to medium educated. Because the unemployed may lack structural opportunities to donate, and the low to medium educated may lack relevant knowledge on blood donation necessity, we recommend providing practical opportunities and information on the necessity of blood donation. PMID- 28840943 TI - An international investigation into O red blood cell unit administration in hospitals: the GRoup O Utilization Patterns (GROUP) study. AB - BACKGROUND: Transfusion of group O blood to non-O recipients, or transfusion of D blood to D+ recipients, can result in shortages of group O or D- blood, respectively. This study investigated RBC utilization patterns at hospitals around the world and explored the context and policies that guide ABO blood group and D type selection practices. STUDY DESIGN AND METHODS: This was a retrospective study on transfusion data from the 2013 calendar year. This study included a survey component that asked about hospital RBC selection and transfusion practices and a data collection component where participants submitted information on RBC unit disposition including blood group and D type of unit and recipient. Units administered to recipients of unknown ABO or D group were excluded. RESULTS: Thirty-eight hospitals in 11 countries responded to the survey, 30 of which provided specific RBC unit disposition data. Overall, 11.1% (21,235/191,397) of group O units were transfused to non-O recipients; 22.6% (8777/38,911) of group O D- RBC units were transfused to O D+ recipients, and 43.2% (16,800/38,911) of group O D- RBC units were transfused to recipients that were not group O D-. Disposition of units and hospital transfusion policy varied within and across hospitals of different sizes, with transfusion of group O D- units to non-group O D- patients ranging from 0% to 33%. CONCLUSION: A significant proportion of group O and D- RBC units were transfused to compatible, nonidentical recipients, although the frequency of this practice varied across sites. PMID- 28840945 TI - The fabrication and the use of immobilized cells as test organisms in a ferricyanide-based toxicity biosensor. AB - Cell immobilization is an effective method to prolong the lifetime of a microorganism and has proven feasibility in some other biosensors. Thus, we studied the use of Escherichia coli immobilized by agar, gelatin, an agar/gelatin mixture, chitosan, and polyvinyl alcohol (PVA) to screen toxicity electrochemically. The E. coli immobilized by PVA gel showed the highest apparent bioactivity and the longest storage time in pH 7.0 phosphate-buffered saline solution. Furthermore, the E. coli immobilized by different gels was applied in the toxicity determination via a reported ferricyanide-mediated electrochemical method, where 3,5-dichlorophenol (DCP) was used as a model toxin. The E. coli immobilized by PVA showed the highest sensitivity to DCP, and the corresponding value of 50% inhibition concentration was 9.62 mg L-1 . Inhibition concentrations were in the range of 6.32 to 13.75% when the E. coli immobilized by PVA was challenged by wastewater, which were comparable with values obtained with the standard luminescent bacteria method (effective inhibition were in the range 7.96 25.42% for the same samples). Given the apparent bioactivity, storage ability, and sensitivity to toxin, PVA was the best polymer to confine cells among the polymers used in the present study. Environ Toxicol Chem 2018;37:329-335. (c) 2017 SETAC. PMID- 28840946 TI - High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas. AB - Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent beta-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia. PMID- 28840947 TI - The conceptualization of childhood in North American pediatric dentistry texts: a discursive case study analysis. AB - BACKGROUND: In recent years, conceptions of childhood have been evolving towards an increased recognition of children as active agents, capable of participating in the determination of their wellbeing. In pediatric dentistry, the extent to which these conceptions are being discursively endorsed is not well known. AIM: The aim of this investigation was to examine the discursive construction of childhood in seminal North American pedagogical dentistry materials. DESIGN: We conducted a qualitative discourse analysis of a sample of prominent texts using a sociological discourse analysis approach. RESULTS: We analyzed the latest edition of Macdonald and Avery's textbook (Chapter: Non pharmacologic management of children's behaviors) and the clinical practice guidelines published by the American Academy of Pediatric Dentistry, AAPD (Behavior guidance for the pediatric dental patient). The analysis produced five salient discursive categories: socialization through behavior modification; development and behavior; paternalism; the utility of child-centered communication; and consequentialism. While there were instances of a child-centered focus in the texts, the main discourses were rooted in developmentalism and behaviorism. There was scant acknowledgment of the importance of children's agency or voice, which runs contrary to child-centered discourses and practices in related disciplines (e.g., pediatric medicine, nursing). CONCLUSION: Predominant discourses in pediatric dentistry suggest a paternalistic, behaviorist approach to the 'management' of children in the dental office, focused primarily on completing interventions. Priorities for the future development of pediatric dentistry are discussed, integrating more child-centered approaches. PMID- 28840948 TI - Reduced Bone Mineral Density in m.3243A>G Carriers May Be Multifactorial. PMID- 28840949 TI - Hidden in the heart: A peculiar type of left ventricular remodeling after acute myocardial infarction. AB - We reported an unusual case of left ventricular pouch, in a 72-year-old man who had an acute coronary syndrome treated with percutaneous revascularization. The echocardiogram showed a sort of pouch, delimited by epicardium and endocardium, confirmed by 3D echo. This finding appeared as an echo free area, with a really slight color flow inside. We consequently supposed it would be a dissecting hematoma, a rare complication of the ischemic disease, due to the rupture of the intramyocardial vessels among the spiral myocardial fibers. This would produce a hemorrhagic pouch contained by epicardial and endocardial layers, which could evolve into mural thrombi. PMID- 28840950 TI - 3D transesophageal echocardiography and radiography of mitral valve prostheses and repairs. AB - This paper provides a comprehensive overview of 3D transesophageal echocardiography still images and movies of mechanical mitral valves, mitral bioprostheses, and mitral valve repairs. Alongside these visual descriptions, the historical overview of surgical and percutaneous mitral valve intervention is described with the special emphasis on the incremental value of 3D transesophageal echocardiography (3DTEE). For each mitral valve intervention, 2D echocardiography, chest x-ray, and fluoroscopy images corresponding to 3DTEE are given. In addition, key references on echocardiographic imaging of individual valves and procedures are enumerated in accompanying figures and tables. PMID- 28840951 TI - Young alcohol binge drinkers have elevated blood endotoxin, peripheral inflammation and low cortisol levels: neuropsychological correlations in women. AB - Alcohol binge drinking is a pattern of heavy alcohol consumption that is increasingly practiced by adolescents and young adults. Evidence indicates that alcohol binges induce peripheral inflammation and an exacerbated neuroimmune response that may participate in alcohol-induced cognitive/behavioral dysfunctions. Here, we recruited 20-year-old male and female university students who were identified as binge drinkers for at least 2 years. Compared with controls, young alcohol binge drinkers had elevated levels of blood endotoxin and upregulated markers of the toll-like receptor 4/NF-kappaB inflammatory pathway in peripheral blood mononuclear cells, together with pro-inflammatory cytokine/chemokine release, oxidative stress and lipid peroxidation. These changes positively correlate with the estimated blood alcohol levels achieved during alcohol binge intoxication and negatively correlate with the time elapsed from the last alcohol consumption. The immune/inflammatory changes were more prominent in female drinkers, who showed elevated levels of alcohol danger associated molecules, such as high mobility group box 1, indicating that there are sex-related differences in the peripheral inflammatory response to alcohol. In contrast, cortisol levels were decreased in alcohol binge drinkers. Finally, higher levels of inflammatory markers, mainly monocyte chemoattractant protein-1, as well as LPS, high mobility group box 1, toll-like receptor 4, IL-6 and ciclooxygenase-2, correlated with worse scores on episodic memory and executive functioning tasks in female binge drinkers but not in male binge drinkers. These results emphasize possible risky consequences of alcohol use in binge episodes during young adulthood and call attention to sex-related differences in the alcohol-induced immune/inflammatory and neurocognitive responses. PMID- 28840952 TI - Metabolic dysregulation accelerates injury-induced joint degeneration, driven by local inflammation; an in vivo rat study. AB - Evidence is growing for the existence of an obesity-related phenotype of osteoarthritis in which low-grade inflammation and a disturbed metabolic profile play a role. The contribution of an obesity-induced metabolic dysbalance to the progression of the features of osteoarthritis upon mechanically induced cartilage damage was studied in a rat in vivo model. Forty Wistar rats were randomly allocated 1:1 to a standard diet or a high-fat diet. After 12 weeks, in 14 out of 20 rats in each group, cartilage was mechanically damaged in the right knee joint. The remaining six animals in each group served as controls. After a subsequent 12 weeks, serum was collected for metabolic state, subchondral bone changes assessed by MUCT imaging, osteoarthritis severity determined by histology, and macrophage presence assessed by CD68 staining. The high-fat diet increased statistically all relevant metabolic parameters, resulting in a dysmetabolic state and subsequent synovial inflammation, whereas cartilage degeneration was hardly influenced. The high-fat condition in combination with mechanical cartilage damage resulted in a clear statistically significant progression of the osteoarthritic features, with increased synovitis and multiple large osteophytes. Both the synovium and osteophytes contained numerous CD68 positive cells. It is concluded that a metabolic dysbalance due to a high-fat diet increases joint inflammation without cartilage degeneration. The dysmetabolic state clearly accelerates progression of osteoarthritis upon surgically induced cartilage damage supported by inflammatory responses as demonstrated by histology and increased CD68 expressing cells localized on the synovial membrane and osteophytes. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:881-890, 2018. PMID- 28840953 TI - Recognition-then-Reaction Enables Site-Selective Bioconjugation to Proteins on Live-Cell Surfaces. AB - Site-selective protein modification is a key step in facilitating protein functionalization and manipulation. To accomplish this, genetically engineered proteins were previously required, but the procedure was laborious, complex, and technically challenging. Herein we report the development of aptamer-based recognition-then-reaction to guide site-selective protein/DNA conjugation in a single step with outstanding selectivity and efficiency. As models, several proteins, including human thrombin, PDGF-BB, Avidin, and His-tagged recombinant protein, were studied, and the results showed excellent selectivity under mild reaction conditions. Taking advantage of aptamers as recognition elements with extraordinary selectivity and affinity, this simple preparation method can tag a protein in a complex milieu. Thus, with the aptamer obtained from cell-SELEX, real-time modification of live-cell membrane proteins can be achieved in one step without any pre-treatment. PMID- 28840954 TI - Assessing the kinetics of microbubble appearance in cirrhotic patients using transthoracic saline contrast-enhanced echocardiography. AB - BACKGROUND: The number of cardiac cycles that need to be reviewed by echocardiography before a significant intrapulmonary shunt can be excluded remains unclear. METHODS: We retrospectively identified patients with cirrhosis who underwent technetium-99 m-labeled macroaggregated albumin scanning. The kinetics of bubble appearance after the injection of agitated saline during transthoracic echocardiograms were assessed in these patients. RESULTS: For the 64 eligible patients, the mean +/- SD age was 56 +/- 9 years. The median (IQR) shunt fraction by radionuclide scanning was 7.7% (2.8%-19.9%). Microbubbles were seen in the left atrium (LA) and left ventricle (LV) at a median (IQR) of 4 (2-5) and 4 (2-5) beats, respectively. The number of heart cycles before microbubbles appeared in the LA or LV was inversely associated with the nuclear scanning shunt fraction (R = -0.42, P = .001, R = -0.46, P < .001, respectively). If no microbubbles were detected by heart cycle 7, the shunt fraction was uniformly less than 3%. Patients with arterial oxygen <60 mm Hg, compared to >=60 mm Hg, had earlier appearance of microbubbles in the left heart chambers (2.6 +/- 1.9 vs 4.0 +/- 2.3 beats, P = .046). CONCLUSIONS: In patients with advanced cirrhosis suspected of having hepatopulmonary syndrome, a greater shunt fraction during nuclear scanning was associated with more pronounced hypoxemia and a prompt and more intense appearance of microbubbles in the left-sided heart chambers. Patients with a shunt fraction above 3% have microbubbles in the LA or LV at some point during the first seven heart cycles. PMID- 28840955 TI - Effects of moist- and dry-heat cooking on the meat quality, microstructure and sensory characteristics of native chicken meat. AB - This study investigates the effects of moist- (water-cooking; WC) and dry-heat (oven-cooking; OC) on the quality, microstructure and sensory characteristics of native chicken breast meat. The results revealed that OC meat had a significantly higher cooking time, cooking loss, and shear force values and lower L* values. Protein solubility decreased after cooking in both cooking methods; however, no statistical difference was observed between WC and OC meats, whereas collagen solubility and myofibrillar fragmentation index (MFI) increased after cooking and WC meat exhibited higher collagen solubility and MFI (P < 0.05). The fiber diameter and sarcomere length decreased substantially after cooking, and fibril shrinkage was noticeable in OC meat (P < 0.05). Descriptive sensory analysis revealed that WC meat exhibited a significantly higher moisture release and lower initial hardness, chewdown hardness and residual loose particles. A darker color and enhanced chickeny flavor were observed for OC meat. Based on the unique sensory and physicochemical characteristics in demand, producers should employ appropriate cooking methods to optimize native chicken meat quality. PMID- 28840956 TI - Characterization of the RhI /dppe-Catalyzed Ring Expansion of 2-Alkyl Benzocyclobutenones by DFT Calculations. AB - The [(dppe)RhCl]-catalysed ring expansion of 2-methylbenzocyclobutenone has been proposed to occur by C-C oxidative addition to rhodaindanone, beta-hydride elimination, hydrorhodation and C-C reductive elimination. DFT calculations [IEFPCM(1,4-dioxane, 383.15 K)/PBE0/DGDZVP level of theory] here confirm this mechanism. As proposed, oxidative addition into CHMe-CO bond is preferred over the alternative CHMe-aryl insertion. The barriers of oxidative addition, beta hydride elimination hydrorhodation, and reductive elimination are 23.6 (rate determining), 8.9, 10.4, and 13.1 kcal mol-1 , respectively. Therefore, the beta hydride elimination/hydrorhodation steps to/from an octahedral RhIII -hydride serve as a fast equilibrating hydrogen shuffle flanking the two slower C-C bond breaking/making steps. This is consistent with the weak kinetic isotope effect observed experimentally when 2-CH3 and 2-CD3 benzocyclobutenone react competitively in a 1:1 ratio. The reaction barriers calculated with more modern, dispersion interaction-corrected methods (SMD/M06 and IEFPCM/omegaB97xD) follow identical trends. PMID- 28840958 TI - The caudolaterally inserted transposition flap and its variations for reconstruction of defects of the nasal ala. AB - Closure of non-full-thickness defects of the nasal ala can be a surgical challenge. While there is a plethora of various reconstructive techniques, not all of them are easy to learn and carry out. Recently, the dermatosurgeon Andreas Losler from the Department of Dermatology at the Hornheide Medical Center, Germany, developed and published the caudolaterally inserted transposition flap for the reconstruction of alar defects. Given its relative novelty, this technique, which is characterized by a very low complication rate, is still unknown to most dermatosurgeons and has not yet found its way into standard dermatosurgery textbooks. The present review describes the caudolaterally inserted transposition flap and two modifications thereof, which allow for the closure of large alar defects as well as defects of the alar crease. Comparisons are made to the two flaps most commonly employed for alar reconstruction, the bilobed flap and the cranially inserted nasolabial transposition flap (melolabial flap). PMID- 28840957 TI - Progression rate of severity of aortic stenosis in patients with rheumatoid arthritis. AB - OBJECTIVE: Valvular heart disease is common in patients with rheumatoid arthritis (RA). However, there is uncertainty about how often to perform echocardiographic surveillance in this population. The objective of this study was to assess the progression rate of mild and moderate aortic stenosis (AS) in patients with RA. METHODS: A population-based cohort of patients with RA and either mild (2.0-2.9 m/second) or moderate (3.0-3.9 m/second) AS was identified. Demographic, clinical, and echocardiographic data were collected. Annual progression rate of AS was then calculated for the study cohort and the impact of pertinent RA variables on progression rate determined. RESULTS: Sixty-eight patients with RA and mild or moderate AS met the inclusion requirements. Peak aortic valve (AV) velocity and mean AV gradient increased during the study period, whereas AV area decreased, consistent with progression of AS (P<.001). Mean (SD) annual increase in peak AV jet velocity was 0.05 m/second (0.01) and in mean AV gradient was 1.0 mm Hg (0.18). Mean annual decrease in AV area was 0.04 (0.01) cm2 . The progression rate of AS was higher in patients with increased erythrocyte sedimentation rates (ESR) (P=.001). CONCLUSIONS: The rate of AS progression in the RA population was higher in patients with increased ESR but less than that of the reported rate of AS progression in the general population. Although the cause for this finding is uncertain, these results suggest that patients with RA who have mild or moderate AS should undergo echocardiographic surveillance for disease progression similar to that of the general population. PMID- 28840959 TI - Tiny Microbes, Big Yields: enhancing food crop production with biological solutions. AB - Plant-associated microbiomes have tremendous potential to improve plant resilience and yields in farming systems. There is increasing evidence that biological technologies that use microbes or their metabolites can enhance nutrient uptake and yield, control pests and mitigate plant stress responses. However, to fully realize the potential of microbial technology, their efficacy and consistency under the broad range of real-world conditions need to be improved. While the optimization of microbial biofertilizers and biopesticides is advancing rapidly to enable use in various soils, crop varieties and environments, crop breeding programmes have yet to incorporate the selection of beneficial plant-microbe interactions to breed 'microbe-optimized plants'. Emerging efforts exploring microbiome engineering could lead to microbial consortia that are better suited to support plants. The combination of all three approaches could be integrated to achieve maximum benefits and significantly improved crop yields to address food security. PMID- 28840960 TI - Parental hospital-treated somatic illnesses and psychosis of the offspring-The Northern Finland Birth Cohort 1986 study. AB - AIM: The aim of this study was to investigate whether parental somatic illnesses during childhood increase the risk for later psychosis in the offspring. In addition, we examined which parental illnesses in particular are associated with increased risk of psychosis in the offspring. METHOD: The data of the Northern Finland Birth Cohort 1986 (NFBC 1986), included 9137 children born alive in northern Finland between the July 1, 1985, and the June 30, 1986. Information regarding the parents' somatic morbidity was collected through various healthcare registers up to age 28 of the cohort members. RESULTS: Psychosis was diagnosed in 169 (1.8%) of the cohort members between the ages of 16 and 28. Accumulation of parental somatic diseases was related to later psychosis in the offspring. In addition, some specific somatic diagnostic groups of parents were emphasized in relation to psychosis in the offspring. CONCLUSIONS: Our study findings indicated that parental somatic illness should be taken into account in the prevention of serious mental health problems in their offspring. PMID- 28840962 TI - Biomarkers and therapeutic advances in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is a malignant tumor within the brain. Generally classified as primary and secondary with several different subtypes, ample molecular biomarkers have risen throughout the years which have garnered the attention of researchers. The advancements in genomics and proteomics have allowed researchers to gather prominent molecular biomarkers. All these biomarkers are gathered by means of biopsy or bodily fluid sample collection and are quantitatively analyzed by polymerase chain reaction coupled with other computational technologies. This review highlights the significance, regulation and prevalence of molecular biomarkers such as O6 -methylguanine-DNA methyltransferase, epidermal growth factor receptor vIII, isocitrate dehydrogenase mutation and several others which expressed differently in different types and molecular subtypes of GBM. The discoveries and roles of GBM specific microRNAs including miR-21 and miR-10b as biomarkers with promising prognostic values were also delineated. The role and mechanism of biomarkers in GBM tumorigenesis are essential in the development of therapy for patients suffering from the disease itself. Thus, this review also discusses the mechanisms, effects and limitations of therapy such as temozolomide, viral gene transfer, biomarker-based vaccines or even engineered T cells for more specific responses. Biomarkers have displayed a high value and could eventually be utilized as drug targets. It is hoped that by combining different aspects of the disease which present with different biomarkers could lead to the development of a robust, effective and innovative take on GBM therapy. PMID- 28840961 TI - A technology for the investigation of biofilm transmission under shearing pressures. AB - Biofilm formation is a multifactorial and dynamic process. Stages of biofilm formation are highly regulated and include bacterial attachment to a target surface, formation of microcolonies, biofilm maturation and dispersion. This article highlights recent research by Gusnaniar et al., () in which the authors develop a device to investigate bacterial biofilm transmission between surfaces under shearing pressures. The instrument can potentially be used to investigate the role of different genetic determinants and environmental cues on biofilm stability and transmission. PMID- 28840963 TI - The enhancement of combination of berberine and metformin in inhibition of DNMT1 gene expression through interplay of SP1 and PDPK1. AB - Berberine (BBR), one of active alkaloid found in the rhizome, exhibited anti cancer properties. We have showed that BBR inhibited growth of non-small cell lung cancer (NSCLC) cells through mitogen-activated protein kinase (MAPK) mediated increase in forkhead box O3a (FOXO3a). However, the in-depth mechanism underlying the anti-tumor effects still remained to be elucidated. Herein, we further confirmed that BBR not only induced cell cycle arrest, but also reduced migration and invasion of NSCLC cells. Mechanistically, we observed that BBR reduced 3-phosphoinositide-dependent protein kinase-1 (PDPK1) and transcription factor SP1 protein expressions. Exogenously expressed SP1 overcame BBR-inhibited PDPK1 expression. Moreover, BBR inhibited DNA methyltransferase 1 (DNMT1) gene expression and overexpressed DNMT1 resisted BBR-inhibited cell growth. Intriguingly, overexpressed PDPK1 antagonized BBR-inhibited SP1 and DNMT1 expressions. Finally, metformin enhanced the effects of BBR both in vitro and in vivo. Collectively, we observe that BBR inhibits proliferation of NSCLC cells through inhibition of SP1 and PDPK1; this results in a reduction of DNMT1 expression. The interplay of PDPK1 and SP1 contributes to the inhibition of DNMT1 in response to BBR. In addition, there is a synergy of BBR and metformin. This study uncovers a new mechanism of BBR in combination with metformin for NSCLC associated therapy. PMID- 28840965 TI - A vitamin D protocol post-liver transplantation. AB - BACKGROUND AND PURPOSE: Adults with compromised liver function are inherently deficient and especially vulnerable to the consequences of vitamin D deficiency. Consequences of vitamin D deficiency include liver disease progression, infection, and graft failure. A vitamin D supplementation protocol is proposed to systematically optimize serum vitamin D levels according to guidelines in both pre- and post-liver transplanted patients. METHODS: This quasiexperimental study included a sample of N = 45 post-liver transplanted patients taking daily cholecalciferol (vitamin D3) 2500 units for 12 weeks, with a pre- and post-lab measure of serum 25-hydroxyvitamin D levels at a large academic facility. CONCLUSIONS: Seventy-eight percent of patients reached minimum guideline levels using the protocol with an average increase of serum vitamin D of 13.8 ng/mL. Long-term outcomes of clinical significance may include decreased incidence of acute T-cell-mediated graft rejection and infections in the immunocompromised patient. IMPLICATIONS FOR PRACTICE: Optimizing vitamin D in vulnerable patient populations such as chronic liver disease and the immunosuppressed posttransplanted patient has the potential to curtail complications of vitamin D deficiency. As a result, nurse practitioners employing a vitamin D protocol can create a favorable impact on patient quality of life, safety, and healthcare spending. PMID- 28840964 TI - Modelling of microbial polyhydroxyalkanoate surface binding protein PhaP for rational mutagenesis. AB - Phasins are unusual amphiphilic proteins that bind to microbial polyhydroxyalkanoate (PHA) granules in nature and show great potential for various applications in biotechnology and medicine. Despite their remarkable diversity, only the crystal structure of PhaPAh from Aeromonas hydrophila has been solved to date. Based on the structure of PhaPAh , homology models of PhaPAz from Azotobacter sp. FA-8 and PhaPTD from Halomonas bluephagenesis TD were successfully established, allowing rational mutagenesis to be conducted to enhance the stability and surfactant properties of these proteins. PhaPAz mutants, including PhaPAz Q38L and PhaPAz Q78L, as well as PhaPTD mutants, including PhaPTD Q38M and PhaPTD Q72M, showed better emulsification properties and improved thermostability (6-10 degrees C higher melting temperatures) compared with their wild-type homologues under the same conditions. Importantly, the established PhaP homology-modelling approach, based on the high-resolution structure of PhaPAh , can be generalized to facilitate the study of other PhaP members. PMID- 28840966 TI - The DIY Digital Medical Centre. AB - Healthcare systems worldwide are confronted with major economic, organizational and logistical challenges. Historic evolution of health care has led to significant healthcare sector fragmentation, resulting in systemic inefficiencies and suboptimal resource exploitation. To attain a sustainable healthcare model, fundamental, system-wide improvements that effectively network, and ensure fulfilment of potential synergies between sectors, and include and facilitate coherent strategic planning and organisation of healthcare infrastructure are needed. Critically, they must be specifically designed to sustainably achieve peak performance within the current policy environment for cost-control, and efficiency and quality improvement for service delivery. We propose creation of a new healthcare cluster, to be embedded in existing healthcare systems. It consists of (i) local 24/7 walk-in virtually autonomous do-it-yourself Digital Medical Centres performing routine diagnosis, monitoring, prevention, treatment and standardized documentation and health outcome assessment/reporting, which are online interfaced with (ii) regional 24/7 eClinician Centres providing on-demand clinical supervision/assistance to Digital Medical Centre patients. Both of these are, in turn, online interfaced with (iii) the National Clinical Informatics Centre, which houses the national patient data centre (cloud) and data analysis units that conduct patient- and population-level, personalized and predictive( medicine) intervention optimization analyses. The National Clinical Informatics Centre also interfaces with biomedical research and prioritizes and accelerates the translation of new discoveries into clinical practice. The associated Health Policy Innovation and Evaluation Centre rapidly integrates new findings with health policy/regulatory discussions. This new cluster would synergistically link all health system components in a circular format, enable not only access by all arms of the health service to latest patient data, but also automatic algorithm analysis and prediction of clinical development of individual patients, reduce bureaucratic burden on medical professionals by enabling a greater level of focus of their expertise on non-routine medical tasks, lead to automatic translation of aggregate patient data/new knowledge into medical practice, and orient future evolution of health systems towards greater cohesion/integration and hence efficiency. A central plank of the proposed concept is increased emphasis on reduction of disease incidence and severity, to diminish both patient suffering and treatment costs. This will be achieved at the individual and population levels, through (i) significantly improved access to medical services, (ii) stronger focus on primary and secondary prevention and early treatment measures, and disease susceptibility prediction via personalized medicine, involving inter alia genome analysis at birth and periodic analysis of microbiomes and biomarkers, and integration with other patient health and epidemiology parameters, (iii) improved surveillance and (iv) intervention outcome benchmarking. The dMCs will become drivers of innovation and integrative evolution in health systems, of disease reduction and efficiency gains, and thus major contributors to development of sustainability of health care. PMID- 28840967 TI - Photocatalytic Conversion of CO2 to CO by a Copper(II) Quaterpyridine Complex. AB - The invention of efficient systems for the photocatalytic reduction of CO2 comprising earth-abundant metal catalysts is a promising approach for the production of solar fuels. One bottleneck is to design highly selective and robust molecular complexes that are able to transform the CO2 gas. The CuII quaterpyridine complex [Cu(qpy)]2+ (1) is found to be a highly efficient and selective catalyst for visible-light driven CO2 reduction in CH3 CN using [Ru(bpy)3 ]2+ (bpy: bipyridine) as photosensitizer and BIH/TEOA (1,3-dimethyl-2 phenyl-2,3-dihydro-1H-benzo[d]imidazole/triethanolamine) as sacrificial reductant. The photocatalytic reaction is greatly enhanced by the presence of H2 O (1-4 % v/v), and a turnover number of >12 400 for CO production can be achieved with 97 % selectivity, which is among the highest of molecular 3d CO2 reduction catalysts. Results from Hg poisoning and dynamic light scattering experiments suggest that this photocatalyst is homogenous. To the best of our knowledge, 1 is the first example of molecular Cu-based catalyst for the photoreduction of CO2 . PMID- 28840969 TI - Intraprostatic botulinum toxin type "A" injection in patients with benign prostatic hyperplasia and unsatisfactory response to medical therapy: A randomized, double-blind, controlled trial using urodynamic evaluation. AB - AIMS: The injection of botulinum neurotoxin A (BTA) into the prostate represents a minimally invasive treatment in patients with lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia (BPH). We evaluated the effectiveness of BTA in treating patients with BPH unresponsive to combined medical therapy (CMT), using urodynamic investigations. METHODS: This is a randomized, placebo-controlled, double blind trial. Twenty consecutive patients were randomly assigned to receive intraprostatic BTA injection (n = 10) or saline solution (SS) (n = 10). Patients in the intervention group (IG) received 200-300 UI of BTA diluted in 6-8 mL of SS and injected into the transitional zone. Patients in the control group (CG) were treated with SS alone. Primary endpoint was International Prostate Symptom Score (IPSS). Secondary endpoints were: maximum flow rate (Qmax), postvoid residual volume (PVR), maximum cystometric capacity (MCC), bladder outlet obstruction index (BOOI), safety, quality of life (QoL) score, and Patient Reported Outcome (PROs). RESULTS: All patients in the IG reported subjective improvement starting after 1 month. At 3 months of follow-up IPSS, QoL, PVR were reduced by 55,3% (P < 0.01), and 50% (P < 0.01), 80,6%, (P < 0.01), respectively. Qmax was increased by 68% (P < 0.01). MCC increased by 27% (P < 0.01) and BOOI decreased by 54% (P < 0.01). PROs analysis revealed that 90% of patients in the IG reported a subjective symptomatic relief and treatment satisfaction. No local or systemic side effects were observed in any group. CONCLUSIONS: These results indicated that intraprostatic BTA is safe and can improve LUTS and QoL in patients with BPH and unsatisfactory response to CMT. PMID- 28840968 TI - Naphthalene biodegradation under oxygen-limiting conditions: community dynamics and the relevance of biofilm-forming capacity. AB - Toxic polycyclic aromatic hydrocarbons (PAHs) are frequently released into the environment from anthropogenic sources. PAH remediation strategies focus on biological processes mediated by bacteria. The availability of oxygen in polluted environments is often limited or absent, and only bacteria able to thrive in these conditions can be considered for bioremediation strategies. To identify bacterial strains able to degrade PAHs under oxygen-limiting conditions, we set up enrichment cultures from samples of an oil-polluted aquifer, using either anoxic or microaerophilic condition and with PAHs as the sole carbon source. Despite the presence of a significant community of nitrate-reducing bacteria, the initial community, which was dominated by Betaproteobacteria, was incapable of PAH degradation under strict anoxic conditions, although a clear shift in the structure of the community towards an increase in the Alphaproteobacteria (Sphingomonadaceae), Actinobacteria and an uncultured group of Acidobacteria was observed in the enrichments. In contrast, growth under microaerophilic conditions with naphthalene as the carbon source evidenced the development of a biofilm structure around the naphthalene crystal. The enrichment process selected two co dominant groups which finally reached 97% of the bacterial communities: Variovorax spp. (54%, Betaproteobacteria) and Starkeya spp. (43%, Xanthobacteraceae). The two dominant populations were able to grow with naphthalene, although only Starkeya was able to reproduce the biofilm structure around the naphthalene crystal. The pathway for naphthalene degradation was identified, which included as essential steps dioxygenases with high affinity for oxygen, showing 99% identity with Xanthobacter polyaromaticivorans dbd cluster for PAH degradation. Our results suggest that the biofilm formation capacity of Starkeya provided a structure to allocate its cells at an appropriate distance from the toxic carbon source. PMID- 28840970 TI - Evaluating Efficacy and Safety of Combination Medication of Atorvastatin and a Herbal Formula Containing Salvia miltiorrhiza and Pueraria lobata on Hyperlipidemia. AB - Despite being a potent hypolipidemic drug, atorvastatin (AS) possesses certain adverse effects. Using AS and an herbal formula (Danshen and Gegen, DG) in combination may achieve potentiated hypolipidemic effects and also reduce its adverse effects. Hence, this study aimed to investigate the efficacy and safety of an AS and DG combination on high-fat diet-induced hyperlipidemia. Treatment outcomes were assessed by measuring parameters including body weight, adipose tissue, liver, total cholesterol, triglyceride, and low-density and high-density lipoprotein cholesterol. Measurements of adverse effects were achieved by determining aspartate aminotransferase (AST), alanine transaminase (ALT), and creatine kinase (CK). Danshen and Gegen, as well as AS alone, reduced body weight, adipose tissue, liver weight, liver fat vacuoles, total liver lipids, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high density lipoprotein cholesterol in high-fat diet-fed mice but increased AST, ALT, and CK. A combination of AS and DG was able to enhance reduced effects on the aforementioned parameters in relation to hyperlipidemia over AS or DG alone. It also reduced the elevation of AST, ALT, and CK induced than by AS or DG alone. Results demonstrated that an AS and DG combination resulted in stronger hypolipidemic effects than with AS or DG alone. Additionally, DG might attenuate adverse effects of AS on the liver and skeletal muscle. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28840971 TI - Specific mutations of penicillin-binding protein 1A in 77 clinically acquired amoxicillin-resistant Helicobacter pylori strains in comparison with 77 amoxicillin-susceptible strains. AB - BACKGROUND: Amoxicillin (Amx) is one of the most important antibiotics for eradication of Helicobacter pylori (H. pylori). Main determinants of genetically stable Amx resistance are mutations in the C-terminus of penicillin-binding protein 1A (pbp1A). However, contribution of individual mutation remains unclear. METHODS: 77 Amx-resistant (AmxR ) and 77 Amx-susceptible (AmxS ) H. pylori strains were isolated from gastric tissues, and DNA sequencing was performed to compare C-terminus sequences of pbp1A gene between AmxR and AmxS strains. Natural transformation of these mutated genes into amoxicillin-susceptible strains was performed. RESULTS: Among many mutations in pbp1A, D479E (OR: 37.4, 95% CI: 5.53 252.49, P < .001), and T593 mutation (OR: 32.0, 95% CI: 4.04-252.86, P < .001) independently contributed to Amx resistance in H. pylori strains. In the transformation experiment, T593 mutations were identified in their transformants showing Amx resistance. However, PCR product of D479E was not inserted into recipient (ATCC 43504) resulting in transformation failure. CONCLUSION: Amx resistance is associated with various substitutions in pbp1A and T593 mutation contributes to Amx resistance of H. pylori. PMID- 28840972 TI - Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. AB - Chronic ethanol consumption stimulates neuroimmune signaling in the brain, and Toll-like receptor (TLR) activation plays a key role in ethanol-induced inflammation. However, it is unknown which of the TLR signaling pathways, the myeloid differentiation primary response gene 88 (MyD88) dependent or the TIR domain-containing adapter-inducing interferon-beta (TRIF) dependent, is activated in response to chronic ethanol. We used voluntary (every-other-day) chronic ethanol consumption in adult C57BL/6J mice and measured expression of TLRs and their signaling molecules immediately following consumption and 24 hours after removing alcohol. We focused on the prefrontal cortex where neuroimmune changes are the most robust and also investigated the nucleus accumbens and amygdala. Tlr mRNA and components of the TRIF-dependent pathway (mRNA and protein) were increased in the prefrontal cortex 24 hours after ethanol and Cxcl10 expression increased 0 hour after ethanol. Expression of Tlr3 and TRIF-related components increased in the nucleus accumbens, but slightly decreased in the amygdala. In addition, we demonstrate that the IKKepsilon/TBK1 inhibitor Amlexanox decreases immune activation of TRIF-dependent pathway in the brain and reduces ethanol consumption, suggesting the TRIF-dependent pathway regulates drinking. Our results support the importance of TLR3 and the TRIF-dependent pathway in ethanol induced neuroimmune signaling and suggest that this pathway could be a target in the treatment of alcohol use disorders. PMID- 28840973 TI - Absolute configuration of the ocimene monoterpenoids from Artemisia absinthium. AB - The absolute configuration (AC) of the naturally occurring ocimenes (-)-(3S,5Z) 2,6-dimethyl-2,3-epoxyocta-5,7-diene (1) and (-)-(3S,5Z)-2,6-dimethylocta-5,7 dien-2,3-diol (2), isolated from the essential oils of domesticated specimens of Artemisia absinthium, followed by vibrational circular dichroism (VCD) studies of 1, as well as from the acetonide 3 and the monoacetate 4, both derived from 2, since secondary alcohols are not the best functional groups to be present during VCD studies in solution due to intermolecular associations. The AC follows from comparison of experimental and calculated VCD spectra that were obtained by Density Functional Theory computation at the B3LYP/DGDZVP level of theory. Careful nuclear magnetic resonance (NMR) measurements were compared with literature values, providing for the first time systematic 1 H and 13 C chemical shift data. Regarding homonuclear 1 H coupling constants, after performing a few irradiation experiments that showed the presence of several small long-range interactions, the complete set of coupling constants for 3, which is representative of the four studied molecules, was determined by iterations using the PERCH software. This procedure even allowed assigning the pro-R and pro-S methyl group signals of the two gem-dimethyl groups present in 3. PMID- 28840974 TI - The contribution of microbial biotechnology to sustainable development goals. AB - The signature and almost unique characteristic of microbial technology is the exceptional diversity of applications it can address, and the exceptional range of human activities and needs to which it is and can be applied. Precisely because sustainability goals have very diverse and complex components and requirements, microbial technology has the ability to contribute substantively on many levels in many arenas to global efforts to achieve sustainability. Indeed, microbial technology could be viewed as a unifying element in our progress towards sustainability. PMID- 28840975 TI - Cardioprotection mediated by exosomes is impaired in the setting of type II diabetes but can be rescued by the use of non-diabetic exosomes in vitro. AB - Many patients with ischaemic heart disease also have diabetes. As myocardial infarction is a major cause of mortality and morbidity in these patients, treatments that increase cell survival in response to ischaemia and reperfusion are needed. Exosomes-nano-sized, lipid vesicles released from cells-can protect the hearts of non-diabetic rats. We previously showed that exosomal HSP70 activates a cardioprotective signalling pathway in cardiomyocytes culminating in ERK1/2 and HSP27 phosphorylation. Here, we investigated whether the exosomal cardioprotective pathway remains intact in the setting of type II diabetes. Exosomes were isolated by differential centrifugation from non-diabetic and type II diabetic patients, from non-diabetic and Goto Kakizaki type II diabetic rats, and from normoglycaemic and hyperglycaemic endothelial cells. Exosome size and number were not significantly altered by diabetes. CD81 and HSP70 exosome markers were increased in diabetic rat exosomes. However, exosomes from diabetic rats no longer activated the ERK1/2 and HSP27 cardioprotective pathway and were no longer protective in a primary rat cardiomyocytes model of hypoxia and reoxygenation injury. Hyperglycaemic culture conditions were sufficient to impair protection by endothelial exosomes. Importantly, however, exosomes from non-diabetic rats retained the ability to protect cardiomyocytes from diabetic rats. Exosomes from diabetic plasma have lost the ability to protect cardiomyocytes, but protection can be restored with exosomes from non-diabetic plasma. These results support the concept that exosomes may be used to protect cardiomyocytes against ischaemia and reperfusion injury, even in the setting of type II diabetes. PMID- 28840976 TI - Beneficial microbial signals from alternative feed ingredients: a way to improve sustainability of broiler production? AB - More sustainable broiler meat production can be facilitated by the increased use of cheap by-products and local crops as feed ingredients, while not affecting animal performance and intestinal health, or even improving intestinal health, so that antibiotic usage is further reduced. To achieve this, knowledge of the relationship between the taxonomic and functional microbiota composition and intestinal health is required. In addition, the relationship between the novel feed sources, the substrates present in these feed sources, and the breakdown by enzymes and microbial networks can be crucial, because this can form the basis for development of tailored feed-type specific solutions for optimal digestion and animal performance. PMID- 28840977 TI - Sensory characteristics of youth at clinical high risk for psychosis. AB - AIM: To identify and compare the sensory characteristics of young people at clinical high risk (CHR) for psychosis to those of peers at clinical low risk (CLR), and to national normative data. CHR and CLR participants were recruited from 6 US regions. METHOD: A descriptive cohort design was used to analyse baseline data collected as part of the Early Detection and Intervention for the Prevention of Psychosis Program (EDIPPP). Raw scores on the Adolescent/Adult Sensory Profile (AASP) were analysed for 205 young people with CHR and 87 with CLR in 2 age groups: 12 to 17 years (N = 203) and 18 to 25 years (N = 89). ANOVA procedures were used to determine whether differences in AASP scores existed across CLR, CHR, and normative groups by age group. RESULTS: CHR participants differed significantly from the normative group for all 4 AASP quadrant scores (Low Registration, Sensory Seeking, Sensory Sensitivity and Sensory Avoiding) in both age groups. CLR participants were similar to norms, except for Sensory Seeking scores that were significantly lower than norms in both age ranges. CONCLUSION: Young people with CHR demonstrate active avoidance, heightened sensitivity, reduced seeking, and reduced registration of sensations in everyday life compared to typical peers. This pattern of differences may be a valuable marker for identifying individuals who are at high risk for developing a psychotic illness, and may also inform interventions designed to prevent or minimize the illness process and accompanying dysfunction. PMID- 28840978 TI - Phase II study of celecoxib with docetaxel chemoradiotherapy followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer. AB - TITLE: Phase II study of celecoxib with docetaxel chemoradiotherapy (CRT) followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer. INTRODUCTION: Concurrent CRT has been associated with improvement in absolute 5-year survival by 10% and is the standard of care for inoperable stage III nonsmall cell lung cancer. Preclinical evidence suggests that cyclooxygenase-2 inhibition may increase the efficacy of CRT. METHODS: Patients were treated with CRT (weekly docetaxel at 30 mg/m2 over 6 weeks with concurrent external beam radiotherapy with 60 Gy in 30 fractions) followed by consolidation chemotherapy with docetaxel and cisplatin, each at 75 mg/m2 given 3 weekly for four cycles. Patients were to receive celecoxib 400 mg twice daily during treatment. Prophylactic cranial irradiation (30 Gy in 15 fractions) was offered if there was disease response. RESULTS: Twenty-four patients commenced CRT. Nineteen patients commenced consolidation therapy with 14 patients completing treatment. Twelve patients had treatment with celecoxib. In the total cohort, the median overall survival (mOS) was 21 months and progression-free survival (PFS) was 16 months. Overall response rate was 59% and disease control rate was 82%. Three patient deaths occurred. Significant grade 3/4 toxicity included radiation pneumonitis (17%), febrile neutropenia (17%), infection/sepsis with or with neutropenia (25%) and esophagitis (12.5%). Retrospective analysis of celecoxib versus no celecoxib treatment showed favorable mOS 26.5 versus 17.5 months and PFS 22 versus 16 months, but this did not reach statistical significance. CONCLUSIONS: The activity of this regimen has been demonstrated. Treatment-related toxicity was substantial. The role of celecoxib in addition to CRT could not be demonstrated in this study because of the small number of patients. PMID- 28840979 TI - Design of a tailor-made platform for syngas bioconversion into polyhydroxybutyrate. AB - Biodegradable polymers such as polyhydroxybutyrate (PHB) are part of the emerging portfolio of renewable materials, which are addressing the issue of plastic waste. Syngas, as a cheap, renewable and sustainable resource that can be obtained from biomass or waste, is viewed as an excellent feedstock for different bioprocesses, including syngas to PHB bioconversion. However, due to the hazardous nature of syngas, it is of utmost importance to consider safety aspects of the process. This recently developed tailor-made platform for safe syngas fermentation and PHB production addresses safety aspects and demonstrates the importance of robust online and in-line analytical tools allowing for monitoring and controlling of this bioprocess. PMID- 28840980 TI - Is definitive concurrent chemoradiotherapy effective for locally advanced head and neck cancer in the elderly aged >= 75 years: A single-institute, retrospective, cohort study. AB - BACKGROUND: Definitive chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck cancer (HNC). However, for very elderly patients, the comparison of benefit/risk between definitive radiotherapy (RT) with and without systemic chemotherapy was equivocal. PATIENTS AND METHODS: The study was a single-institute, retrospective, cohort study. Seventy patients aged >=75 years who had a locally advanced HNC were enrolled. The patients were divided into those with CRT and those with RT alone. Survival, compliance/adverse events and independent prognostic factors were analyzed. RESULTS: For baseline characteristics, the patients who received RT alone had worse performance status, comorbidity score and neutrophil-to-lymphocyte ratio. However, during definitive therapy, the CRT group had more adverse events such as neutropenia, febrile neutropenia and thrombocytopenia. There were no significant differences in disease-specific survival (DSS) and overall survival (OS) (P = 0.864 and 0.788, respectively). As to OS, several independent prognostic factors were identified. Performance status (hazard ratio [HR], 2.312; confidence interval [CI], 1.176 4.546; P = 0.015), clinical T staging (HR, 2.240; 95% CI, 1.021-4.913; P = 0.004) and total RT dose (HR, 2.555; 95% CI, 1.246-5.238; P = 0.010) were independent prognostic factors of OS. CONCLUSIONS: Definitive RT with or without systemic chemotherapy did not significantly influence DSS and OS for very elderly patients. Therefore, for elderly patients aged >= 75 years who have HNC, conservative RT might be sufficient for treatment purposes. PMID- 28840982 TI - So you want to be a Fellow in the American Association of Nurse Practitioners: Navigating the Fellowship process to ensure your success. AB - The professional designation as Fellow of the American Association of Nurse Practitioners (FAANP) is the highest professional designation for any nurse practitioner (NP). The Fellows of the American Association of Nurse Practitioners (AANP) operate the FAANP program and annually invite colleagues that have made a significant impact on the NP profession for consideration of this prestigious designation. Since its inception in 2000, nearly 700 NPs, or less than 1% of the membership, have been inducted as FAANPs. The number of candidates for consideration has continued to rise given that there are more than 75,000 members, many of whom have made significant contributions to health care. This article provides updates regarding the Fellows application process and provides guidance for both the candidate and the sponsors on how to prepare a competitive application. PMID- 28840981 TI - Bioengineering Solutions for Manufacturing Challenges in CAR T Cells. AB - The next generation of therapeutic products to be approved for the clinic is anticipated to be cell therapies, termed "living drugs" for their capacity to dynamically and temporally respond to changes during their production ex vivo and after their administration in vivo. Genetically engineered chimeric antigen receptor (CAR) T cells have rapidly developed into powerful tools to harness the power of immune system manipulation against cancer. Regulatory agencies are beginning to approve CAR T cell therapies due to their striking efficacy in treating some hematological malignancies. However, the engineering and manufacturing of such cells remains a challenge for widespread adoption of this technology. Bioengineering approaches including biomaterials, synthetic biology, metabolic engineering, process control and automation, and in vitro disease modeling could offer promising methods to overcome some of these challenges. Here, we describe the manufacturing process of CAR T cells, highlighting potential roles for bioengineers to partner with biologists and clinicians to advance the manufacture of these complex cellular products under rigorous regulatory and quality control. PMID- 28840983 TI - Diagnostics and Prognostication of Myelodysplastic Syndromes. AB - MDS are a heterogeneous and complex group of clonal hematological neoplasms arising from a hematopoietic stem cell, and characterized by ineffective hematopoiesis, resulting in increased apoptosis in the bone marrow and peripheral cytopenia, which involves one or more lineages. Epigenetic changes are reported as 'founder' mutations in the case of MDS. Its incidence in the general population has been reported as five new MDS diagnoses per 100,000 people. It affects men more frequently than it does women, and its incidence increases with age. The diagnostic classification, now in use, is the one of the World Health Organization, revised in August 2016. It recognizes six distinct entities in addition to a provisional entity of childhood. In most of the cases, diagnosis is based on the morphologic quantitative and qualitative evaluation of the peripheral blood and bone marrow using basic hematological techniques. Bone marrow biopsy and flow cytometric immunophenotyping also offer support for further diagnostic elucidation, while cytogenetics and molecular genetics are presently fully integrated into prognostication, treatment processes, and decision-making. PMID- 28840984 TI - Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry in Clinical Microbiology: What Are the Current Issues? AB - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has revolutionized the identification of microbial species in clinical microbiology laboratories. MALDI-TOF-MS has swiftly become the new gold standard method owing to its key advantages of simplicity and robustness. However, as with all new methods, adoption of the MALDI-TOF MS approach is still not widespread. Optimal sample preparation has not yet been achieved for several applications, and there are continuing discussions on the need for improved database quality and the inclusion of additional microbial species. New applications such as in the field of antimicrobial susceptibility testing have been proposed but not yet translated to the level of ease and reproducibility that one should expect in routine diagnostic systems. Finally, during routine identification testing, unexpected results are regularly obtained, and the best methods for transmitting these results into clinical care are still evolving. We here discuss the success of MALDI-TOF MS in clinical microbiology and highlight fields of application that are still amenable to improvement. PMID- 28840985 TI - Benefits of Thromboelastography and Thrombin Generation Assay for Bleeding Prediction in Patients With Thrombocytopenia or Hematologic Malignancies. AB - BACKGROUND: Thromboelastography (TEG) provides comprehensive information on the whole blood clot formation phases, whereas thrombin generation assay (TGA) reveals the endogenous thrombin levels in plasma. We investigated the potential significance of TEG and TGA parameters for prediction of clinical bleeding in hematologic patients on the basis of the patient's platelet levels. METHODS: TEG and TGA were performed in 126 patients with thrombocytopenia or hematologic malignancies. The bleeding tendencies were stratified on the basis of the World Health Organization bleeding grade. RESULTS: Maximum amplitude (MA) and clot formation in TEG and endogenous thrombin potential (ETP) in TGA showed significant associations with high bleeding grades (P=0.001 and P=0.011, respectively). In patients with platelet counts <=10*109/L, low MA values were strongly associated with a high bleeding risk. For bleeding prediction, the area under the curve (AUC) of MA (0.857) and ETP (0.809) in patients with severe thrombocytopenia tended to be higher than that of platelets (0.740) in all patients. Patients with platelet counts <=10*109/L displayed the highest AUC of the combined MA and ETP (0.929). CONCLUSIONS: Both TEG and TGA were considered to be good predictors of clinical bleeding in patients with severe thrombocytopenia. Combination of the ETP and MA values resulted in a more sensitive bleeding risk prediction in those with severe thrombocytopenia. PMID- 28840986 TI - Performance Evaluation of the PowerChek MERS (upE & ORF1a) Real-Time PCR Kit for the Detection of Middle East Respiratory Syndrome Coronavirus RNA. AB - BACKGROUND: Molecular detection of Middle East respiratory syndrome coronavirus (MERS-CoV) using real-time reverse transcription (rRT)-PCR assays is the method of choice for diagnosis of MERS. We evaluated the performance of the PowerChek MERS (upE & ORF1a) real-time PCR Kit (PowerChek MERS assay; Kogene Biotech, Korea) a one-step rRT-PCR assay for the qualitative detection of MERS-CoV. METHODS: We evaluated PowerChek MERS assay performance in comparison with nested RT-PCR and sequencing of the RNA-dependent RNA polymerase (RdRp) and N genes. To evaluate diagnostic sensitivity and specificity, 100 clinical specimens (50 positive and 50 negative for MERS-CoV) were simultaneously tested by using the PowerChek MERS and sequencing assays. Assay performance, including limit of detection and precision, was evaluated in vitro by using MERS-CoV RNA transcripts. Analytical specificity was evaluated with a diverse collection of 16 respiratory virus-positive clinical specimens and 14 respiratory bacterial isolates. RESULTS: The 95% limits of detection of the PowerChek MERS assay for the upE and the open rading frame (ORF)1a were 16.2 copies/MUL and 8.2 copies/MUL, respectively. No cross-reactivity was observed. The diagnostic sensitivity and specificity of the PowerChek MERS assay were both 100% (95% confidence interval, 91.1-100%). CONCLUSIONS: The PowerChek MERS assay is a straightforward and accurate assay for detecting MERS-CoV RNA. The assay will be a useful tool for the rapid diagnosis of MERS and could prove especially important for MERS outbreak control. PMID- 28840987 TI - Multicenter Evaluation of an Image Analysis Device (APAS): Comparison Between Digital Image and Traditional Plate Reading Using Urine Cultures. AB - BACKGROUND: The application of image analysis technologies for the interpretation of microbiological cultures is evolving rapidly. The primary aim of this study was to establish whether the image analysis system named Automated Plate Assessment System (APAS; LBT Innovations Ltd., Australia) could be applied to screen urine cultures. A secondary aim was to evaluate differences between traditional plate reading (TPR) and the reading of cultures from images, or digital plate reading (DPR). METHODS: A total of 9,224 urine samples submitted for culture to three clinical laboratories, two in Australia and one in the USA, were included in the study. Cultures were prepared on sheep blood and MacConkey agar plates and read by panels of three microbiologists. The plates were then presented to APAS for image capture and analysis, and the images and results were stored for later review. RESULTS: Image analysis of cultures using APAS produced a diagnostic sensitivity and specificity of 99.0% and 84.5%, respectively. Colonies were detected by APAS on 99.0% of blood agar plates with growth and on 99.5% of MacConkey agar plates. DPR agreed with TPR for colony enumeration on 92.1% of the plates, with a sensitivity of 90.8% and specificity of 92.8% for case designation. However, several differences in the classification of colony morphologies using DPR were identified. CONCLUSIONS: APAS was shown to be a reliable screening system for urine cultures. The study also showed acceptable concordance between DPR and TPR for colony detection, enumeration, and case designation. PMID- 28840988 TI - Utility of a Direct 16S rDNA PCR and Sequencing for Etiological Diagnosis of Infective Endocarditis. AB - BACKGROUND: Cases of infective endocarditis (IE) require prompt etiological diagnosis for effective treatment. Molecular methods can aid in rapid and reliable diagnosis of culture-negative IE cases. We evaluated the utility of 16S rDNA PCR and sequencing in determining the causative agents of IE in valve tissues, especially when specimens were obtained after initiation of antimicrobial therapy. METHODS: We performed 16S rDNA PCR and sequencing in heart valve specimens and medical records review of 80 patients who underwent protocol based cardiac surgery from 2013 to 2015. One patient did not meet the criteria for IE. Sixty-five (81.3%) and 14 pa-tients (17.5%) were diagnosed as having definite IE and possible IE, respectively. Blood and heart valve biopsy tissue were examined by using routine microbiological methods. RESULTS: Blood cultures in our hospital were IE-positive for 33 patients (41.8%), whereas 49 patients (62.0%) showed positive blood cultures when initial blood cultures performed at the referring hospital were included. Eighteen (22.8%) and 40 patients (50.6%) were IE-positive in valve tissue cultures and 16S rDNA PCR, respectively. Bacteria in the Streptococcus mitis group (n=26) were the most common etiological agents of IE. Eight (10.1%) culture-negative specimens tested positive by 16S rDNA PCR. In five of eight PCR-positive and culture-negative cases, fastidious or anaerobic organisms were the cause of IE. CONCLUSIONS: Direct 16S rDNA PCR and sequencing can be used as a supplementary method to conventional blood and biopsy culture testing, especially in culture-negative IE cases that are negative for IE by culture. PMID- 28840989 TI - Comparison of Traditional and Reverse Syphilis Screening Algorithms in Medical Health Checkups. AB - BACKGROUND: The syphilis diagnostic algorithms applied in different countries vary significantly depending on the local syphilis epidemiology and other considerations, including the expected workload, the need for automation in the laboratory and budget factors. This study was performed to investigate the efficacy of traditional and reverse syphilis diagnostic algorithms during general health checkups. METHODS: In total, 1,000 blood specimens were obtained from 908 men and 92 women during their regular health checkups. Traditional screening and reverse screening were applied to the same specimens using automatic rapid plasma regain (RPR) and Treponema pallidum latex agglutination (TPLA) tests, respectively. Specimens that were reverse algorithm (TPLA) reactive, were subjected to a second treponemal test performed by using the chemiluminescent microparticle immunoassay (CMIA). RESULTS: Of the 1,000 specimens tested, 68 (6.8%) were reactive by reverse screening (TPLA) compared with 11 (1.1%) by traditional screening (RPR). The traditional algorithm failed to detect 48 specimens [TPLA(+)/RPR(-)/CMIA(+)]. The median TPLA cutoff index (COI) was higher in CMIA-reactive cases than in CMIA-nonreactive cases (90.5 vs 12.5 U). CONCLUSIONS: The reverse screening algorithm could detect the subjects with possible latent syphilis who were not detected by the traditional algorithm. Those individuals could be provided with opportunities for evaluating syphilis during their health checkups. The COI values of the initial TPLA test may be helpful in excluding false-positive TPLA test results in the reverse algorithm. PMID- 28840990 TI - A Unique Mutational Spectrum of MLC1 in Korean Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts: p.Ala275Asp Founder Mutation and Maternal Uniparental Disomy of Chromosome 22. AB - BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder characterized by infantile-onset macrocephaly, slow neurologic deterioration, and seizures. Mutations in the causative gene, MLC1, are found in approximately 75% of patients and are inherited in an autosomal recessive manner. We analyzed MLC1 mutations in five unrelated Korean patients with MLC. METHODS: Direct Sanger sequencing was used to identify MLC1 mutations. A founder effect of the p.Ala275Asp variant was demonstrated by haplotype analysis using single-nucleotide polymorphic (SNP) markers. Multiple ligation dependent probe amplification (MLPA) and comparative genomic hybridization plus SNP array were used to detect exonic deletions or uniparental disomy (UPD). RESULTS: The most prevalent pathogenic variant was c.824C>A (p.Ala275Asp) found in 7/10 (70%) alleles. Two pathogenic frameshift variants were found: c.135delC (p.Cys46Alafs*12) and c.337_353delinsG (p.Ile113Glyfs*4). Haplotype analysis suggested that the Korean patients with MLC harbored a founder mutation in p.Ala275Asp. The p.(Ile113Glyfs*4) was identified in a homozygous state, and a family study revealed that only the mother was heterozygous for this variant. Further analysis of MLPA and SNP arrays for this patient demonstrated loss of heterozygosity of chromosome 22 without any deletion, indicating UPD. The maternal origin of both chromosomes 22 was demonstrated by haplotype analysis. CONCLUSIONS: This study is the first to describe the mutational spectrum of Korean patients with MLC, demonstrating a founder effect of the p.Ala275Asp variant. This study also broadens our understanding of the mutational spectrum of MLC1 by demonstrating a homozygous p.(Ile113Glyfs*4) variant resulting from UPD of chromosome 22. PMID- 28840991 TI - Evaluation of the Triage TOX Drug Screen Assay for Detection of 11 Drugs of Abuse and Therapeutic Drugs. AB - The demand for rapid and broad clinical toxicology screens is on the rise. Recently, a new rapid toxicology screening test, the Triage TOX Drug Screen (Alere Inc., USA), which can simultaneously detect 11 drugs of abuse and therapeutic drugs with an instrument-read cartridge, was developed. In the present study, we evaluated the efficacy of this new on-site immunoassay using 105 urine specimens; the results were compared with those obtained by using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-TMS). Precision was evaluated according to the CLSI EP12-A2 for analyte concentrations near the cutoff, including C50 and+/-30% of C50, for each drug using standard materials. The C50 specimens yielded 35-65% positive results and the+/-30% concentration range of all evaluated drugs encompassed the C5-C95 interval. The overall percent agreement of the Triage TOX Drug Screen was 92.4-100% compared with UPLC-TMS; however, the Triage TOX Drug Screen results showed some discordant cases including acetaminophen, amphetamine, benzodiazepine, opiates, and tricyclic antidepressants. The overall performance of the Triage TOX Drug Screen assay was comparable to that of UPLC-TMS for screening of drug intoxication in hospitals. This assay could constitute a useful screening method for drugs of abuse and therapeutic drugs in urine. PMID- 28840992 TI - Clinical Usefulness of Human Epididymis Protein 4 in Lung Cancer. AB - Human epididymis protein 4 (HE4) has been suggested as a useful new biomarker of lung cancer; however, few relevant large-scale studies have been published. In this study, we evaluated the utility of serum HE4 for lung cancer detection. HE4 levels were measured in serum samples from 100 lung cancer patients, 57 patients with benign lung diseases, and 274 healthy controls by using a chemiluminescent immunoassay, and variations in HE4 levels were analyzed by clinical status such as lung cancer, benign lung disease, and healthy condition, Tumor, Lymph Nodes, Metastasis (TNM) stage, tumor score, and histological cancer type. Lung cancer patients had significantly higher serum HE4 levels than patients with benign lung diseases and healthy controls (P<0.0001). The area under the ROC curve for HE4 was 0.84 (95% confidence interval, 0.78-0.89; P<0.0001) between lung cancer patients and healthy controls. Serum HE4 levels were significantly higher in patients with advanced disease (according to TNM stage) than in healthy controls (P<0.0001). HE4 levels were significantly elevated in patients with tumors of all types, those of different histological subgroups, and those with the smallest tumors (P=0.002). This report supports the potential of serum HE4 as an ancillary diagnostic marker for lung cancer detection. PMID- 28840993 TI - Comparison of a New Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Platform, ASTA MicroIDSys, With Bruker Biotyper for Species Identification. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, with its accuracy and speed, is widely used for bacterial identification. The ASTA MicroIDSys system (ASTA, Korea) was recently developed for species identification. We compared its performance with that of Bruker Biotyper (Bruker Daltonics, Germany). Microbes were recovered from sputum, urine, and pus samples from patients admitted to a tertiary care hospital in Korea from January to April 2016. Matrix solution (alpha-cyano-4-hydroxycinnamic acid) was used, and the peptide profiles acquired from the Microflex LT (Bruker Daltonics) and Tinkerbell LT (ASTA) were analyzed by using their respective software. From 5,322 isolates, Bruker Biotyper identified 163 species; fifty species from 4,919 isolates were identified more than 10 times, including Klebsiella pneumoniae (n=571), Acinetobacter baumannii (n=436), Pseudomonas aeruginosa (n=358), Escherichia coli (n=372), Staphylococcus aureus (n=511), S. epidermidis (n=444), Enterococcus faecium (n=262), E. faecalis (n=220), and Candida albicans (n=248). Identical results, confidence scores (>= 2.0 for Bruker Biotyper), and acceptable scores (>=140 for ASTA MicroIDSys) were obtained for 86.1% of isolates. Of 4,267 isolates, 99.2% showed acceptable scores in both systems. Results from the ASTA MicroIDSys showed good agreement with those from the Bruker Biotyper. The ASTA MicroIDSys could reliably identify clinically important microorganisms. PMID- 28840994 TI - Identification of the PROM1 Mutation p.R373C in a Korean Patient With Autosomal Dominant Stargardt-like Macular Dystrophy. AB - Stargardt-like macular dystrophy 4 (STGD4) is a rare macular dystrophy characterized by bull's eye atrophy of the macula and the underlying retinal pigment epithelium. Patients with STGD4 show decreased central vision, which often progresses to severe vision loss. The PROM1 gene encodes prominin-1, which is a 5-transmembrane glycoprotein also known as CD133 and is involved in photoreceptor disk morphogenesis. PROM1 mutations have been identified as genetic causes for STGD4 and other retinal degenerations such as retinitis pigmentosa. We report a case of STGD4 with a PROM1 p.R373C mutation in a Korean patient. Ophthalmic examinations of a 38-yr old man complaining of decreased visual acuity revealed bilateral atrophic macular lesions consistent with STGD4. Targeted exome sequencing of known inherited retinal degeneration genes revealed a heterozygous missense mutation c.1117C>T (p.R373C) of PROM1, which was confirmed by Sanger sequencing. To the best of our knowledge, this is the first case of a PROM1 mutation causing STGD4 in Koreans. PMID- 28840995 TI - Novel 4-bp Intronic Deletion (c.1560+3_1560+6del) in LEMD3 in a Korean Patient With Osteopoikilosis. AB - Osteopoikilosis is an autosomal dominant bone disorder characterized by symmetric multiple osteosclerotic lesions throughout the axial and appendicular skeleton. Pathogenic variants in the LEMD3 have been identified as the cause of osteopoikilosis. LEMD3 encodes an inner nuclear membrane protein that interacts with bone morphogenetic protein (BMP) and transforming growth factor (TGF)-beta pathways. We report the case of a 19-year-old man presenting with lower back pain and sciatica. His radiograph revealed bilateral and symmetrical multiple osteosclerotic bone lesions in both scapular areas. Sanger sequencing of LEMD3 revealed a four-base-pair deletion in intron 2 (c.1560+3_1560+6del), which was inherited from his father. We found that this four-base-pair deletion in intron 2 causes aberrant splicing and consequent deletion of exon 2. To the best of our knowledge, this is the first report of genetically confirmed osteopoikilosis in Korea. PMID- 28840996 TI - A Case of Primary Bone Marrow Diffuse Large B-cell Lymphoma Presenting With Fibrillar Projections and Hemophagocytic Lymphohistiocytosis. PMID- 28840997 TI - Highly Aggressive de novo Aleukemic Variant of Mast Cell Leukemia Without KIT D816V Mutation. PMID- 28840998 TI - Lipoprotein X Detected in a Case of Hypercholesterolemia Associated With Chronic Cholangiohepatitis. PMID- 28840999 TI - Performance of Matrix-Assisted Laser Desorption Ionization Time-of-Fight Mass Spectrometry for Rapid Discrimination of Methicillin-Resistant Staphylococcus aureus (MRSA): First Report of a Relation Between Protein Peaks and MRSA spa Type. PMID- 28841000 TI - First Case of Echinocandin-Resistant Candida albicans in Korea. PMID- 28841001 TI - A Case of Antley-Bixler Syndrome With a Novel Likely Pathogenic Variant (c.529G>C) in the POR Gene. PMID- 28841002 TI - Phenotype of a Patient With a 1p36.11-p35.3 Interstitial Deletion Encompassing the AHDC1. PMID- 28841003 TI - Superficial Chiral Etching on Achiral Metal-Organic Framework for Enantioselective Sorption. AB - Chiral recognition and separation is of general research interests in natural product separation and the pharmacy industry. In this work, we develop a novel strategy to modify achiral porous metal-organic framework (MOF) surfaces via a superficial chiral etching process (SCEP), in which reacting a presynthesized achiral MOF with a chiral ligand produces an achiral@chiral MOF core-shell hybrid composition. SCEP creates chiral species on an achiral porous MOF surface but does not change the porosity and pore structure, enabling core-shell composition enantioselective sorption. Reacting (+)-camphoric acid, (+)-Cam, and 1,4 diazabicyclo[2.2.2]octane (Dabco) with [Cu3(Btc)2] microcrystals leads to a chiral MOF of [Cu2((+)-Cam)2Dabco] crystallites attached on the surface of [Cu3(Btc)2] (Btc = 1,3,5-benzenetricarboxylate). The resulting [Cu3(Btc)2]@[Cu2((+)-Cam)2Dabco] core-shell composition displays preferred sorption kinetics toward (S)-limonene against (R)-limonene, with a similar discrimination effect with pure chiral [Cu2((+)-Cam)2Dabco]. Superficial chiral etching of the porous achiral MOF represents an economic and efficient strategy for enantioselective separation. PMID- 28841004 TI - Nanoporous PtFe Nanoparticles Supported on N-Doped Porous Carbon Sheets Derived from Metal-Organic Frameworks as Highly Efficient and Durable Oxygen Reduction Reaction Catalysts. AB - Designing and exploring catalysts with high activity and stability for oxygen reduction reaction (ORR) at the cathode in acidic environments is imperative for the industrialization of proton exchange membrane fuel cells (PEMFCs). Theoretical calculations and experiments have demonstrated that alloying Pt with a transition metal can not only cut down the usage of scarce Pt metal but also improve performance of mass activity compared with pure Pt. Herein, we exhibit the preparation of nanoporous PtFe nanoparticles (np-PtFe NPs) supported on N doped porous carbon sheets (NPCS) via facile in situ thermolysis of a Pt-modified Fe-based metal-organic framework (MOF). The np-PtFe/NPCS exhibit a more positive half-wave potential (0.92 V) compared with commercial Pt/C catalyst (0.883 V). The nanoporous structure allows our catalyst to possess high mass activity, which is found to be 0.533 A.mgPt-1 and 3.04 times better than that of Pt/C (0.175 A.mgPt-1). Moreover, the conversion of PtFe NPs from porous to hollow structure can maintain the activity of electrocatalyst. Our strategy provides a facile design and synthesis process of noble-transition metal alloy electrocatalysts via noble metal modified MOFs as precursors. PMID- 28841005 TI - Confined Nucleation and Growth of PdO Nanocrystals in a Seed-Free Solution inside Hollow Nanoreactor. AB - This paper reports a novel and adaptable hollow nanoreactor system containing a solution of cucurbituril (CB) inside a silica nanoparticle (CB@h-SiO2) which enables the nucleation and formation of nanocrystals (NCs) to be confined at the seed-free interior solution inside the cavity. The above nanospace confinement strategy restricted the volume of medium available for NC formation to the solution inside the cavity to a few tens of nanometers in size and allowed homogeneous NC nucleation to be examined. Harboring of CB@h-SiO2 in a Pd2+ complex solution confined the nucleation and formation of PdO NCs to the well isolated nanosized cavity protected by the silica nanoshell, allowing the convoluted formation of clustered PdO NCs to be thoroughly examined. The corresponding temporal investigation indicated that PdO NC clusters evolved via a distinct pathway combining dendritic growth on early nucleated seed NCs and attachment of small intermediate clusters. In addition, the explored strategy was used to fabricate a recyclable nanocatalyst system for selective catalytic oxidation of cinammyl alcohols, featuring a cavity-included Fe3O4/PdO nanocomposite. PMID- 28841006 TI - ESI-IM-MS and Collision-Induced Unfolding That Provide Insight into the Linkage Dependent Interfacial Interactions of Covalently Linked Diubiquitin. AB - Understanding protein higher order structure and interfacial interactions is crucial to understanding protein binding motifs and cellular function, that is, an interactome. Polyubiquitylation is a post-translational modification that functions as a tag for a diverse array of cellular processes, wherein differences in chain length, branching, and linkage site encode different cellular functions. Investigation of covalently linked diubiquitin (diUbq) molecules specifically selects for the effect of covalent linkage site on the conformational preference of the molecule and the interfacial interactions between the subunits. Here, we report results for electrospray ionization ion mobility-mass spectrometry (ESI-IM MS) and collision-induced unfolding (CIU) analysis of four diUbq ions to provide new understanding of the differences in subunit interfacial interactions and conformational preferences induced by the four most common covalent linkage sites. The specific hydrophobic patch interface adopted by K48-linked diUbq results in unique CIU fingerprints dominated by conformational broadening and primarily gradual unfolding, as opposed to the distinct transitions through gas phase unfolding intermediates observed of K6-, K11-, and K63-linked diUbq. Comparison of the intermediate conformational families of K6-, K11-, and K63 linked diUbq suggests that K6- and K11-linked diUbq adopt a mixture of conformers stabilized by either electrostatic interactions or hydrophobic interactions involving the I36 hydrophobic patch. Furthermore, conditions favoring the partially folded A-state of monoubiquitin, that is, methanolic solution, induce conformational collapse and distinct unfolding intermediates for all four linkage types, providing an end-point at which all solution-phase conformational "memory" has been lost. PMID- 28841007 TI - DNA-Compatible Nitro Reduction and Synthesis of Benzimidazoles. AB - DNA-encoded chemical libraries have emerged as a cost-effective alternative to high-throughput screening (HTS) for hit identification in drug discovery. A key factor for productive DNA-encoded libraries is the chemical diversity of the small molecule moiety attached to an encoding DNA oligomer. The library structure diversity is often limited to DNA-compatible chemical reactions in aqueous media. Herein, we describe a facile process for reducing aryl nitro groups to aryl amines. The new protocol offers simple operation and circumvents the pyrophoric potential of the conventional method (Raney nickel). The reaction is performed in aqueous solution and does not compromise DNA structural integrity. The utility of this method is demonstrated by the versatile synthesis of benzimidazoles on DNA. PMID- 28841008 TI - Size Fractionation of Graphene Oxide Nanosheets via Controlled Directional Freezing. AB - The properties and functions of graphene oxide (GO)-based materials strongly depend on the lateral size and size distribution of GO nanosheets; therefore, GO and its derivatives with narrow size distributions are highly desired. Here we report the size fractionation of GO nanosheets by controlled directional freezing of GO aqueous dispersions. GO nanosheets with a narrow size distribution can be obtained by controlling the growth rate of the freezing front. This interesting phenomenon can be explained by the adsorption of GO nanosheets on the ice crystal surface in combination with the stratification of GO nanosheets at the ice growth front. Such a convenient size fractionation approach will be essential for practical applications of chemically modified graphene, including GO, reduced GO, and their assemblies or composites. PMID- 28841009 TI - Projecting the Water Footprint Associated with Shale Resource Production: Eagle Ford Shale Case Study. AB - Production of oil from shale and tight reservoirs accounted for almost 50% of 2016 total U.S. production and is projected to continue growing. The objective of our analysis was to quantify the water outlook for future shale oil development using the Eagle Ford Shale as a case study. We developed a water outlook model that projects water use for hydraulic fracturing (HF) and flowback and produced water (FP) volumes based on expected energy prices; historical oil, natural gas, and water-production decline data per well; projected well spacing; and well economics. The number of wells projected to be drilled in the Eagle Ford through 2045 is almost linearly related to oil price, ranging from 20 000 wells at $30/barrel (bbl) oil to 97 000 wells at $100/bbl oil. Projected FP water volumes range from 20% to 40% of HF across the play. Our base reference oil price of $50/bbl would result in 40 000 additional wells and related HF of 265 * 109 gal and FP of 85 * 109 gal. The presented water outlooks for HF and FP water volumes can be used to assess future water sourcing and wastewater disposal or reuse, and to inform policy discussions. PMID- 28841011 TI - Coordination-Driven Self-Assembly of Ionic Irregular Hexagonal Metallamacrocycles via an Organometallic Clip and Their Cytotoxicity Potency. AB - Two new irregular hexagons (6 and 7) were synthesized from a pyrazine motif containing an organometallic acceptor clip [bearing platinum(II) centers] and different neutral donor ligands (4,4'-bipyridine or pyrazine) using a coordination-driven self-assembly protocol. The two-dimensional supramolecules were characterized by multinuclear NMR, mass spectrometry, and elemental analyses. Additionally, one of the macrocycles (6) was characterized by single crystal X-ray analyses. Macrocycles are unique examples of [2 + 2] self-assembled ensembles that are hexagonal but irregular in shape. These hexagon frameworks require the assembly of only four tectons/subunits. The cytotoxicity of platinum(II)-based macrocycles was studied using various cell lines such as A549 (human lung carcinoma), KB (human oral cancer), MCF7 (human breast cancer), and HaCaT (human skin keratinocyte) cell lines, and the results were compared with those of cisplatin. The smaller macrocycle (7) exhibited a higher cytotoxic effect against all cell types, and its sensitivity was found to be comparable with that of cisplatin for A549 and MCF7 cells. Cell cycle analysis and live propidium iodide staining suggest that the macrocycles 6 and 7 induced a loss of membrane integrity that ultimately might lead to necrotic cell death. PMID- 28841010 TI - Luminescent Carbon Dot Mimics Assembled on DNA. AB - Nanometer-sized fragments of carbon in the form of multilayer graphene ("carbon dots") have been under highly active study for applications in imaging. While offering advantages of low toxicity and photostability, such nanomaterials are inhomogeneous and have limited wavelengths of emission. Here we address these issues by assembling luminescent aromatic C16-C38 hydrocarbons together on a DNA scaffold in homogeneous, soluble molecular compounds. Monomer deoxyribosides of five different aromatic hydrocarbons were synthesized and assembled into a library of 1296 different tetramer compounds on PEG-polystyrene beads. These were screened for photostability and a range of emission colors using 365 nm excitation, observing visible light (>400 nm) emission. We identified a set of six oligomers (DNA-carbon assemblies, DNA-CAs) with exceptional photostability that emit from 400 to 680 nm in water, with Stokes shifts of up to 110 nm, quantum yields ranging from 0.01 to 0.29, and fluorescence lifetimes from 3 to 42 ns. In addition, several of these DNA-CAs exhibited white emission in aqueous solution. The molecules were used in multispectral cell imaging experiments and were taken up into cells passively. The results expand the range of emission properties that can be achieved in water with all-hydrocarbon chromophores and establish the use of the DNA scaffold to arrange carbon layers in homogeneous, rapidly synthesized assemblies. PMID- 28841013 TI - Stereoselective Postassembly CH Oxidation of Self-Assembled Metal-Ligand Cage Complexes. AB - Self-assembled Fe-iminopyridine cage complexes containing doubly benzylic methylene units such as fluorene and xanthene can be selectively oxidized at the ligand backbone with tBuOOH, with no competitive oxidation observed at the metal centers. The self-assembled cage structure controls the reaction outcome, yielding oxidation products that are favored by the assembly, not by the reactants or functional groups. Whereas uncomplexed xanthene and fluorene control ligands are solely oxidized to the ketone equivalents with tBuOOH, the unfavorability of the self-assembled ketone cages forces the reaction to form the tbutyl peroxide and alcohol-containing oxidation products, respectively. In addition, the oxidation is diastereoselective, with only single isomers of the cage assemblies formed, despite the presence of as many as 10 stereocenters in the final product. The self-assembled structures exploit self-complementary hydrogen bonding and geometrical constraints to direct the postassembly reactions to outcomes not observed in free solution. This selectivity is reminiscent of the fine control of post-translational modification seen in biomacromolecules. PMID- 28841014 TI - Synthesis and Photophysical Properties of Porphyrin Macrorings Composed of Free Base Porphyrins and Slipped-Cofacial Zinc Porphyrin Dimers. AB - The self-assembled macroring N-(Zn-Fb-Zn)3 has been constructed by intermolecular complementary coordination among three trisporphyrin Zn-Fb-Zn molecules, each of which consists of a central free-base porphyrin and two imidazolyl-zinc-porphyrin ends. Thus, N-(Zn-Fb-Zn)3 has three slipped-cofacial zinc porphyrin dimers ("special pair model") and three free-base porphyrins, alternately. The zinc porphyrin dimers in N-(Zn-Fb-Zn)3 are covalently connected by a ring-closing olefin metathesis reaction between the allyl ether groups substituted on the zinc porphyrin dimers, giving a covalently linked macroring C-(Zn-Fb-Zn)3. The fluorescence spectra of C-(Zn-Fb-Zn)3 in several solvents show that the photoinduced energy transfer from one of the zinc porphyrin dimers to a free-base porphyrin occurs intramolecularly in toluene, whereas the photoinduced electron transfer predominantly occurs intramolecularly in N,N-dimethylformamide. Treatment of C-(Zn-Fb-Zn)3 with copper(II) acetate gives a Cu-containing heteromultinuclear porphyrin macroring C-(Zn-Cu-Zn)3, demonstrating that C-(Zn-Fb Zn)3 could be a good precursor to construct various heteromultinuclear porphyrin macrorings. PMID- 28841015 TI - Calorimetrically Determined U(VI) Toxicity in Brassica napus Correlates with Oxidoreductase Activity and U(VI) Speciation. AB - Radioecological studies depend on the quantitative toxicity assessment of environmental radionuclides. At low dose exposure, the life span of affected organisms is barely shortened, enabling the transfer of radionuclides through an almost-intact food chain. Lethality-based toxicity estimates are not adequate in this regime because they require higher concentrations. However, increased radionuclide concentration alters its speciation, rendering the extrapolation to the low dose exposure chemically inconsistent. Here, we demonstrate that microcalorimetry provides a sensitive real-time monitor of toxicity of uranium (in the U(VI) oxidation state) in a plant cell model of Brassica napus. We introduce the calorimetric descriptor "metabolic capacity" and show that it correlates with enzymatically determined cell viability. It is independent of physiological models and robust against the naturally occurring fluctuations in the metabolic response to U(VI) of plant cell cultures. In combination with time resolved laser-induced fluorescence spectroscopy and thermodynamic modeling, we show that the plant cell metabolism is affected predominantly by hydroxo-species of U(VI) with an IC50 threshold of ~90 MUM. The data emphasize the yet-little exploited potential of microcalorimetry for the speciation-sensitive ecotoxicology of radionuclides. PMID- 28841016 TI - Selective C-H Bond Oxidation Catalyzed by the Fe-bTAML Complex: Mechanistic Implications. AB - Nonheme iron complexes bearing tetradentate N-atom-donor ligands with cis labile sites show great promise for chemoselective aliphatic C-H hydroxylation. However, several challenges still limit their widespread application. We report a mechanism-guided development of a peroxidase mimicking iron complex based on the bTAML macrocyclic ligand framework (Fe-bTAML: biuret-modified tetraamido macrocyclic ligand) as a catalyst to perform selective oxidation of unactivated 3 degrees bonds with unprecedented regioselectivity (3 degrees :2 degrees of 110:1 for adamantane oxidation), high stereoretention (99%), and turnover numbers (TONs) up to 300 using mCPBA as the oxidant. Ligand decomposition pathways involving acid-induced demetalation were identified, and this led to the development of more robust and efficient Fe-bTAML complexes that catalyzed chemoselective C-H oxidation. Mechanistic studies, which include correlation of the product formed with the FeV(O) reactive intermediates generated during the reaction, indicate that the major pathway involves the cleavage of C-H bonds by FeV(O). When these oxidations were performed in the presence of air, the yield of the oxidized product doubled, but the stereoretention remained unchanged. On the basis of 18O labeling and other mechanistic studies, we propose a mechanism that involves the dual activation of mCPBA and O2 by Fe-bTAML, leading to formation of the FeV(O) intermediate. This high-valent iron oxo remains the active intermediate for most of the reaction, resulting in high regio- and stereoselectivity during product formation. PMID- 28841017 TI - Hydrogeological Controls on Regional-Scale Indirect Nitrous Oxide Emission Factors for Rivers. AB - Indirect nitrous oxide (N2O) emissions from rivers are currently derived using poorly constrained default IPCC emission factors (EF5r) which yield unreliable flux estimates. Here, we demonstrate how hydrogeological conditions can be used to develop more refined regional-scale EF5r estimates required for compiling accurate national greenhouse gas inventories. Focusing on three UK river catchments with contrasting bedrock and superficial geologies, N2O and nitrate (NO3-) concentrations were analyzed in 651 river water samples collected from 2011 to 2013. Unconfined Cretaceous Chalk bedrock regions yielded the highest median N2O-N concentration (3.0 MUg L-1), EF5r (0.00036), and N2O-N flux (10.8 kg ha-1 a-1). Conversely, regions of bedrock confined by glacial deposits yielded significantly lower median N2O-N concentration (0.8 MUg L-1), EF5r (0.00016), and N2O-N flux (2.6 kg ha-1 a-1), regardless of bedrock type. Bedrock permeability is an important control in regions where groundwater is unconfined, with a high N2O yield from high permeability chalk contrasting with significantly lower median N2O-N concentration (0.7 MUg L-1), EF5r (0.00020), and N2O-N flux (2.0 kg ha-1 a 1) on lower permeability unconfined Jurassic mudstone. The evidence presented here demonstrates EF5r can be differentiated by hydrogeological conditions and thus provide a valuable proxy for generating improved regional-scale N2O emission estimates. PMID- 28841018 TI - Photoinduced, Copper-Catalyzed Decarboxylative C-N Coupling to Generate Protected Amines: An Alternative to the Curtius Rearrangement. AB - The Curtius rearrangement is a classic, powerful method for converting carboxylic acids into protected amines, but its widespread use is impeded by safety issues (the need to handle azides). We have developed an alternative to the Curtius rearrangement that employs a copper catalyst in combination with blue-LED irradiation to achieve the decarboxylative coupling of aliphatic carboxylic acid derivatives (specifically, readily available N-hydroxyphthalimide esters) to afford protected amines under mild conditions. This C-N bond-forming process is compatible with a wide array of functional groups, including an alcohol, aldehyde, epoxide, indole, nitroalkane, and sulfide. Control reactions and mechanistic studies are consistent with the hypothesis that copper species are engaged in both the photochemistry and the key bond-forming step, which occurs through out-of-cage coupling of an alkyl radical. PMID- 28841020 TI - Ab Initio Studies on Spectroscopic Constants for the HAsO Molecule. AB - The anharmonic force fields and spectroscopic constants of the electronic ground state (X1A') for the HAsO molecule are reported employing the MP2, B3LYP, B3P86, and B3PW91 methods with cc-pVQZ and cc-pV5Z basis sets. The calculated molecular geometries, rotational constants, vibrational frequencies, and anharmonic constants of the HAsO molecule are compared with the experimental data. It is found that the best agreement between the calculated results and experiment data is at the B3LYP/cc-pV5Z theoretical level. The predicted cubic and quartic force fields, vibration-rotation interaction constants, quartic and sextic centrifugal distortion constants, and Coriolis coupling constants of the HAsO molecule at the B3LYP/cc-pV5Z theoretical level are expected to be reliable. PMID- 28841021 TI - Excited-State Aromaticity Improves Molecular Motors: A Computational Analysis. AB - A new approach to the design of more efficient light-driven rotary molecular motors is presented and evaluated computationally based on molecular dynamics simulations. The approach involves enabling part of the motor to become aromatic in the photoactive excited state, and is found to sharply increase the rotary quantum yields of the photoisomerizations that underlie the motor function. Excited-state aromaticity thus holds promise as a guiding principle toward better performing molecular motors. PMID- 28841023 TI - Thermal Expansion of Carbamazepine: Systematic Crystallographic Measurements Challenge Quantum Chemical Calculations. AB - We report systematic temperature-dependent X-ray measurements on the most stable carbamazepine polymorph. This active pharmaceutical ingredient is used to demonstrate how the thermal expansion can probe certain intermolecular interactions resulting in anisotropic expansion behavior. We show that most structural features can be captured by electronic structure calculations at the quasi-harmonic approximation (QHA) provided a dispersion-corrected density functional based method is employed. The impact of thermal expansion on the phonon modes and hence free energy contributions is large enough to impact the relative stability of different polymorphs. PMID- 28841022 TI - Combination Treatment of Citral Potentiates the Efficacy of Hyperthermic Intraperitoneal Chemoperfusion with Pirarubicin for Colorectal Cancer. AB - Citral is a widely used penetration enhancer that has been used to assist the delivery of drugs through the skin. In this study we aimed to investigate the effectiveness of combination treatments of citral with hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer and to unravel the underlying mechanism by which citral increased the efficacy of HIPEC. In vitro experiments indicated that citral increased cytoplasmic absorption of pirarubicin and potentiated the effects of pirarubicin on colorectal cancer cells to induce apoptosis. Intracellular reactive oxygen species (ROS) activity was elevated after single or combo treatments with pirarubicin, leading to compromised NF kappaB signaling. Therefore, the results suggested that the effects of citral were mediated by increasing cell permeability and ROS productions. Furthermore, the colorectal xenograft model was used to evaluate the efficacy of the combo treatment at the histological and molecular levels, which showed that the cotreatment with citral for colorectal cancer increased the efficacy of HIPEC with pirarubicin with respect to both ascite control and tumor load. The results indicated that citral was an effective additive for HIPEC with pirarubicin for colorectal cancer, which warrant further effort to explore the translational application of this new treatment regimen. PMID- 28841024 TI - Pharmacometabolomics in Endogenous Drugs: A New Approach for Predicting the Individualized Pharmacokinetics of Cholic Acid. AB - The evaluation of individual variability in endogenous drugs' metabolism and disposition is a very challenging task. We developed and validated a metabotype to pharmacokinetics (PK) matching approach by taking cholic acid as an example to predict the individualized PK of endogenous drugs. The stable isotope-labeled cholic acid was selected as the substitute analyte of cholic acid to ensure the accurate measurement of blood concentration. First, large-scale metabolite profiling studies were performed on the predose urine samples of 28 rats. Then, to examine the individualized PK of deuterium 4-cholic acid (d4-cholic acid) in these rats, we determined its plasma concentrations and calculated the differential AUC values. Subsequently, we conducted a two-stage partial least squares analysis in which 31 baseline metabolites were screened initially for predicting the individualized AUC values of d4-cholic acid using the data of predose urine metabolites. Finally, network biology analysis was applied to give the biological interpretation of the individual variances in cholic acid metabolism and disposition, and the result further narrowed the selection of baseline metabolites from 31 to 2 (sarcosine and S-adenosyl-l-homocysteine) for such prediction. Collectively, this pharmacometabolomics research provided a new strategy for predicting individualized PK of endogenous drugs. PMID- 28841025 TI - Comparative Study of REDOR and CPPI Derived Order Parameters by 1H-Detected MAS NMR and MD Simulations. AB - The measurement of dipolar couplings among directly bonded nuclei yields direct information on the amplitude of dynamic processes in the solid-state. For a reliable motional analysis using, e.g., the model-free approach, a correct quantification of the absolute values of these order parameters is absolutely essential. In the absence of a reference value for the rigid limit, too low dipolar coupling values might be misinterpreted as motion. Therefore, a detailed understanding of the effects that influence the quantification of the experimental order parameters is necessary. We compare here REDOR and CPPI derived order parameters assessed in 1H-detected experiments, and discuss the influence of remote protons and rf inhomogeneity on the extracted dipolar coupling constant for MAS rotation frequencies in the range 20-100 kHz. Experimental results are furthermore compared with the order parameter obtained from a molecular dynamics simulation. We find that fast magic-angle spinning up to 100 kHz can yield artifact-free REDOR based 1H,15N order parameters for perdeuterated and 100% amide back-exchanged proteins, and potentially even in uniformly protonated samples. We believe that awareness of systematic errors introduced by the measurement and in the analysis of order parameters will yield a better understanding of the dynamic properties of a protein derived from solid state NMR observables. PMID- 28841026 TI - Seebeck Coefficient of a Single van der Waals Junction in Twisted Bilayer Graphene. AB - When two planar atomic membranes are placed within the van der Waals distance, the charge and heat transport across the interface are coupled by the rules of momentum conservation and structural commensurability, leading to outstanding thermoelectric properties. Here we show that an effective "interlayer phonon drag" determines the Seebeck coecient (S) across the van der Waals gap formed in twisted bilayer graphene (tBLG). The cross-plane thermovoltage, which is nonmonotonic in both temperature and density, is generated through scattering of electrons by the out-of-plane layer breathing (ZO'/ZA2) phonon modes and differs dramatically from the expected Landauer-Buttiker formalism in conventional tunnel junctions. The tunability of the cross-plane Seebeck effect in van der Waals junctions may be valuable in creating a new genre of versatile thermoelectric systems with layered solids. PMID- 28841027 TI - Biomimetic-Inspired Syntheses of Myrtucommuacetalone and Myrtucommulone J. AB - Driven by bioinspiration and appreciation of their structures, the first biomimetic total syntheses with structural revision of the acylphloroglucinols myrtucommulone J and myrtucommuacetalone, two biologically meaningful natural products, were achieved through a biosynthetic hemiacetalization/dehydration/[3 + 3]-type cycloaddition domino sequence with high step efficiency. These syntheses result in a corrected structure for myrtucommulone J. PMID- 28841028 TI - Clinical impact and predictors of complete ST segment resolution after primary percutaneous coronary intervention: A subanalysis of the ATLANTIC Trial. AB - BACKGROUND: In the ATLANTIC (Administration of Ticagrelor in the catheterization laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery) trial the early use of aspirin, anticoagulation, and ticagrelor coupled with very short medical contact-to-balloon times represent good indicators of optimal treatment of ST-elevation myocardial infarction and an ideal setting to explore which factors may influence coronary reperfusion beyond a well-established pre-hospital system. METHODS: This study sought to evaluate predictors of complete ST-segment resolution after percutaneous coronary intervention in ST-elevation myocardial infarction patients enrolled in the ATLANTIC trial. ST-segment analysis was performed on electrocardiograms recorded at the time of inclusion (pre-hospital electrocardiogram), and one hour after percutaneous coronary intervention (post-percutaneous coronary intervention electrocardiogram) by an independent core laboratory. Complete ST-segment resolution was defined as >=70% ST-segment resolution. RESULTS: Complete ST segment resolution occurred post-percutaneous coronary intervention in 54.9% ( n=800/1456) of patients and predicted lower 30-day composite major adverse cardiovascular and cerebrovascular events (odds ratio 0.35, 95% confidence interval 0.19-0.65; p<0.01), definite stent thrombosis (odds ratio 0.18, 95% confidence interval 0.02-0.88; p=0.03), and total mortality (odds ratio 0.43, 95% confidence interval 0.19-0.97; p=0.04). In multivariate analysis, independent negative predictors of complete ST-segment resolution were the time from symptoms to pre-hospital electrocardiogram (odds ratio 0.91, 95% confidence interval 0.85 0.98; p<0.01) and diabetes mellitus (odds ratio 0.6, 95% confidence interval 0.44 0.83; p<0.01); pre-hospital ticagrelor treatment showed a favorable trend for complete ST-segment resolution (odds ratio 1.22, 95% confidence interval 0.99 1.51; p=0.06). CONCLUSIONS: This study confirmed that post-percutaneous coronary intervention complete ST-segment resolution is a valid surrogate marker for cardiovascular clinical outcomes. In the current era of ST-elevation myocardial infarction reperfusion, patients' delay and diabetes mellitus are independent predictors of poor reperfusion and need specific attention in the future. PMID- 28841019 TI - Structural and Chemical Biology of Terpenoid Cyclases. AB - The year 2017 marks the twentieth anniversary of terpenoid cyclase structural biology: a trio of terpenoid cyclase structures reported together in 1997 were the first to set the foundation for understanding the enzymes largely responsible for the exquisite chemodiversity of more than 80000 terpenoid natural products. Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that more than half of the substrate carbon atoms undergo changes in bonding and hybridization during a single enzyme-catalyzed cyclization reaction. The past two decades have witnessed structural, functional, and computational studies illuminating the modes of substrate activation that initiate the cyclization cascade, the management and manipulation of high-energy carbocation intermediates that propagate the cyclization cascade, and the chemical strategies that terminate the cyclization cascade. The role of the terpenoid cyclase as a template for catalysis is paramount to its function, and protein engineering can be used to reprogram the cyclization cascade to generate alternative and commercially important products. Here, I review key advances in terpenoid cyclase structural and chemical biology, focusing mainly on terpenoid cyclases and related prenyltransferases for which X-ray crystal structures have informed and advanced our understanding of enzyme structure and function. PMID- 28841029 TI - An Expanding Role for Environmental Microbes in Shaping the Immune Response to Infection with Mycobacterium tuberculosis. PMID- 28841031 TI - Moving Nontuberculous Mycobacteria Infections into the 21st Century. PMID- 28841030 TI - Effective positioning of the fingers for intraoperative x-rays. PMID- 28841032 TI - Pre-caecal digestible phosphorus in maize and wheat for broiler chickens. AB - 1. The objective of this study was to determine the coefficient of pre-caecal digestion of P in maize (3.9 g/kg of total P, 0.83 g/kg of phytate P, 138 FTU [phytase units]/kg) and wheat (3.17 g/kg of total P, 1.94 g/kg of phytate P, 666 FTU/kg) in broilers according to the WPSA protocol. 2. For the diets, monosodium phosphate was used as an additional P supplement. Two sets of diets containing 200, 460 and 740 g/kg of wheat or 200, 500 and 740 g/kg of maize were formulated. A total of 288 21-d-old male broilers (Ross 308) were assigned to 24 cages (8 birds per cage) and the 6 test diets were assigned to cages. The coefficient of pre-caecal digestion of P was determined by the indicator method and linear regression. 3. In both ingredients, pre-caecal digestible P increased linearly with increasing inclusion levels of maize or wheat (P < 0.05). The coefficients of digestion of pre-caecal P were estimated to be 0.18 for wheat and 0.33 for maize. PMID- 28841033 TI - Exploring the impact of malocclusion and dentofacial anomalies on the occurrence of traumatic dental injuries in adolescents. AB - OBJECTIVE: To investigate the association between malocclusion/dentofacial anomalies and traumatic dental injuries (TDI) in adolescents. MATERIALS AND METHODS: The sample of this cross-sectional study comprised 509 adolescents aged 11 to 14 years enrolled at public schools in the city of Osorio, southern Brazil. Parents answered a structured questionnaire addressing demographic and socioeconomic characteristics. An examiner who had undergone a training and calibration exercise recorded malocclusion/dentofacial anomalies (Dental Aesthetic Index, DAI), TDI (Andreasen), and dental caries (World Health Organisation). Statistical analyses (SPSS software) involved Poisson regression with robust variance. RESULTS: The prevalence of TDI was 11.6%, and the prevalence of defined, severe, and handicapping malocclusion was 24.0%, 21.6%, and 22.0%, respectively. The multivariate analysis demonstrated that the probability of TDI was approximately twofold higher among adolescents with severe malocclusion (prevalence ratio [PR] 2.22; 95% confidence interval [CI] 1.14-4.31) and handicapping malocclusion (PR 1.95; 95% CI 1.01-3.85) in comparison to those with normal occlusion or minor malocclusion. Defined malocclusion was not significantly associated with the outcome. Among the dentofacial anomalies evaluated, the probability of TDI was nearly twofold higher among adolescents with overjet greater than 3 mm (PR 1.96; 95% CI 1.14-3.37) and 2.2-fold higher among those with an abnormal molar relationship (PR 2.24; 95% CI 1.17-4.32), after controlling for confounding variables. CONCLUSIONS: Severe and handicapping malocclusion, accentuated overjet, and abnormal molar relationship were strongly associated with the occurrence of TDI. Future studies should investigate whether the treatment of these conditions can help reduce the occurrence of TDI in adolescents. PMID- 28841034 TI - Effectiveness of high irradiance for short-time exposures on polymerization of composite under metal brackets. AB - OBJECTIVE: To evaluate the effect of different curing modes available in a dental light-curing unit on degree of conversion (DC) of a composite photoactivated under a metal orthodontic bracket. MATERIALS AND METHODS: The average irradiance and total energy delivered by three curing modes (standard, high, and extra power) of a multiwave LED unit (Valo Cordless, Ultradent Products, South Jordan, Utah) were measured using the longest time available for each mode (20, 4, and 3 seconds, respectively). Brackets (n = 3/group) were bonded to molar epoxy resin replicas using each curing mode. Mesiodistal sections, 0.5 mm thick, were assessed using an infrared spectrometer microscope. Spectra of composite beneath the brackets were sequentially collected using the mapping tool in near-infrared (NIR)-transmittance mode. Composite conversion was mapped between the mesial and distal edges of the bracket base using 400-MUm steps for a total of 10 measurements per specimen. Data from irradiance and total energy were analyzed by one-way ANOVA, while data of DC were analyzed with two-way repeated measures ANOVA (alpha = 0.05). RESULTS: The highest DC values were observed for standard power (mean 56%, P < .05), while no difference was observed between high (50%) and extra power (49%) modes. Regarding the site of measurement, higher DC was observed close to the bracket edges (52%, P < .05). CONCLUSIONS: The use of high irradiance for a short time slightly reduced the DC. The small magnitude of reduction suggests that use of a high irradiance protocol is a clinically valid approach when bonding metal brackets. PMID- 28841035 TI - Evaluation of ground grain versus pre- and post-pellet whole grain additions to poultry diets via a response surface design. AB - 1. The objective of this study was to compare the effects of pre- and post-pellet whole grain wheat additions to diets on growth performance, gizzard and pancreas development, nutrient utilisation and starch and protein (N) digestibility coefficients in broiler chickens via an equilateral triangle response surface design. 2. The three apical treatments of the equilateral triangle comprised (1A) a standard diet containing 600 g/kg ground wheat, (2B) the same diet containing 600 g/kg pre-pellet whole wheat and (3C) the same diet containing 300 g/kg ground wheat and 300 g/kg post-pellet whole wheat. Seven blends of the three apical diets were located within the triangle to complete the design and a total of 360 male Ross 308 chicks were offered the ten experimental diets from 7 to 28 d post hatch. Model prediction and response surface plots were generated with R 3.0.3 software. 3. The most efficient FCR of 1.466 was observed in birds offered an almost equal mixture of the pre- and post-pellet whole grain apical dietary treatments, which corresponded to 172 g/kg ground grain, 256 g/kg pre-pellet whole grain, 172 g/kg post-pellet whole grain in a diet containing 600 g/kg wheat. 4. The most efficient energy utilisation (ME:GE ratio of 0.766) was observed in birds offered a blend of the ground grain and pre-pellet whole grain apical dietary treatments which corresponded to a mixture of 384 g/kg pre-pellet whole grain and 216 g/kg ground grain. 5. Pre-pellet whole grain feeding generated the most pronounced responses in increased relative gizzard contents, reduced gizzard pH and increased relative pancreas weights. Consideration is given to the likely differences between pre- and post-pellet whole grain feeding. PMID- 28841036 TI - Do Randomized Clinical Trials Always Provide Certain Results? The Case of Tralokinumab in Idiopathic Pulmonary Fibrosis. PMID- 28841037 TI - Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers. AB - Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules. PMID- 28841038 TI - Statistical versus Clinical Significance in Nursing Research. PMID- 28841039 TI - Promoting Clinical Reasoning Among Nursing Students: Why Aren't Clinical Decision Support Systems a Popular Option? PMID- 28841040 TI - Migrant Nurses and Federal Caregiver Programs in Canada: Migration and Health Human Resources Paradox. AB - Despite the links between health human resources policy, immigration policy, and education policy, silos persist in the policy-making process that complicate the professional integration of internationally educated nurses in Canada. Drawing on the literature on nurse migration to Canada through the Live-in Caregiver Program, this paper sheds light on the contradictions between immigration and health human resources policy and their effect on the integration of internationally educated nurses in Canada. The analysis reveals a series of paradoxes within and across immigration and health human resources policy that affect the process of professional integration of this group of health professionals into the nursing workforce in Canada. I will further link the discussion to the recently implemented Caregiver Program, which provides a unique pathway for healthcare workers, including nurses, to migrate to Canada. Given recent introduction of the Canadian Caregiver Program, major policy implications include the need to bridge the gap between health human resources policy and immigration policy to ensure the maximum integration of migrant nurses in Canada. PMID- 28841041 TI - Perspectives on Patient Safety Among Practical Nursing Students. AB - Background Practical nursing students are students enrolled in a two-year college practical nursing diploma program. They are responsible for providing safe patient care to the patients they care for. Assessing students' perceptions of their own patient safety competencies can help educators identify gaps in their knowledge and skills and identify, at a curricula level, the concepts and information required to improve the quality of their care. Purpose To explore practical nursing students' confidence in what they are learning about patient safety within their nursing education. Methods This cross-sectional descriptive study used a modified version of the Health Professional Education in Patient Safety Survey. Results Overall, students expressed the greatest confidence in their abilities to provide care in Clinical Safety topics. More than 75% of the students' feared punishment when making an error and 88% have difficulty questioning other healthcare providers. Less than 30% of students stated that a system-level focus on errors was taught to them in their education programs. Conclusions More investigation is needed to understand what practical nursing students' fear about the provision of safe care. Additional focus on systems aspects of hazard identification and the prevention of errors needs to be present in nursing education programs. PMID- 28841042 TI - Effectiveness of Nurse-Driven Inhaler Education on Inhaler Proficiency and Compliance Among Obstructive Lung Disease Patients: A Quasi-Experimental Study. AB - Background Health education on proper inhaler usage is the most feasible and accessible strategy to increase inhaler effectiveness. Purpose To assess the impact of nurse-driven inhaler education on the compliance and proficiency of using inhalers among inhaler users. Methods This single-center, quasi experimental study included the implementation of an individualized 60-min educational session on inhalers use. Health education and pretest and posttest outcomes were assessed by the Inhaler Proficiency Schedule and Patient Reported Behaviour tools. Results One hundred and twenty-one participants joined the study. At pretest, participants showed inadequate knowledge of general inhaler use. No previous training had been received by participants and difficulty with use and complications from using the inhalers were reported. At posttest, participants reported improvement in inhaler proficiency scores from 5.72 to 8.60 ( t = 17.99, df = 220, p < 0.001). Likewise, they showed a significant reduction towards the noncompliant behaviors from 15.21 to 11.19 ( t = 16.388, df = 238, p < 0.001). Conclusions Nurse-driven inhaler education yielded positive outcomes in both inhaler proficiency and compliance. The patients' assessment of using inhalers is crucial to determine the patients' educational deficits. PMID- 28841043 TI - Prognostic value of miRNA-181a/b in colorectal cancer: a meta-analysis. AB - AIMS: miR-181a and miR-181b have been investigated as prognostic biomarkers of colorectal cancer (CRC). However, there is controversy about the role of miR-181a and miR-181b in predicting CRC prognosis. Therefore, we performed this meta analysis to evaluate prognostic values of miR-181a and miR-181b in CRC patients. MATERIALS & METHODS: Studies were systemically searched from publications and analyzed, and 999 CRC cases in nine studies were examined in this meta-analysis. RESULTS: Hazard ratio for overall survival of high miR-181a and miR-181b expression in CRC was 1.65. More prominent predictive effects were observed in black people, miR-181b group and small-sample-size group. CONCLUSION: High levels of miR-181a and miR-181b predict poor overall survival in CRC patients. miR-181a and miR-181b are promising biomarkers for CRC prognosis. PMID- 28841044 TI - A multicomponent microemulsion using rational combination strategy improves lung cancer treatment through synergistic effects and deep tumor penetration. AB - Previously, we have developed a multicomponent-based microemulsion composed of etoposide, coix seed oil, and ginsenoside Rh2 (ECG-MEs). In this study, our goal was to validate the feasibility of ECG-MEs in lung cancer treatment and explore the mechanism underling the enhanced antitumor efficacy. The optimal weight ratio of ginsenoside Rh2 (G-Rh2) in ECG-MEs was determined as 3% (wt%), that was capable of forming the microemulsion readily with small particle size and high drug encapsulation efficiency. In cellular studies, the intracellular fluorescence of human non-small cell lung cancer (A549) cells treated with fluorescein isothiocyanate-labeled ECG-MEs (FITC/ECG-MEs) was significantly higher than that of various controls, leading to the obviously synergistic anticancer activities in cytotoxicity and in vitro cell apoptosis induction. The anticancer efficacy in vivo results showed that ECG-MEs markedly inhibited the growth of A549 tumor xenografts, potently induced tumor cells apoptosis, and obviously prolonged the survival time of mice. Of note, the mechanisms of enhanced anticancer efficiency were connected with the small size-mediated deep tumor penetration and increase in serum concentration of T helper 1 (Th1) cytokines. In summary, ECG-MEs exerting the rational drug combination strategy offers a solid evidence for lung cancer treatment, and has a promising potential for clinical application. PMID- 28841045 TI - Guns, Culture or Mental Health? Framing Mass Shootings as a Public Health Crisis. AB - In recent years, public health scholars and policymakers have been calling for increased research on the public health implications of gun violence. However, scientific research on this issue has been stifled by a 1996 budget rider that eliminated Centers for Disease Control and Prevention's (CDC) funding for gun research. In this study, we examined newspaper coverage of three mass shootings that took place over a 20-year period before and after the passage of this budget rider. We found that sources and frames provided by news media to contextualize gun violence shifted markedly over time, progressing from episodic and individual level frames to broader thematic societal-level concerns, with increased discussion of mental health but limited discourse explicitly related to public health. PMID- 28841046 TI - Electroretinographic Assessment of Inner Retinal Signaling in the Isolated and Superfused Murine Retina. AB - PURPOSE: Longer-lasting electroretinographic recordings of the isolated murine retina were initially achieved by modification of a phosphate-buffered nutrient solution originally developed for the bovine retina. During experiments with a more sensitive mouse retina, apparent model-specific limitations were addressed and improvements were analyzed for their contribution to an optimized full electroretinogram (ERG). MATERIAL AND METHODS: Retinas were isolated from dark adapted mice, transferred to a recording chamber and superfused with different solutions. Scotopic and photopic ERGs were recorded with white flashes every 3 minutes. The phosphate buffer (Sickel-medium) originally used was replaced by a carbonate-based system (Ames-medium), the pH of which was adjusted to 7.7-7.8. Moreover, addition of 0.1 mM BaCl2 was investigated to reduce b-wave contamination by the slow PIII component typically present in the murine ERG. RESULTS: B-wave amplitudes were increased by the pH-shift (pH 7.4 to pH 7.7) from 22.9 +/- 1.9 uV to 37.5 +/- 2.5 uV. Improved b-wave responses were also achieved by adding small amounts of Ba2+ (100 uM), which selectively suppressed slow PIII components, thereby unmasking more of the true b-wave amplitude (100.0% with vs. 22.2 +/- 10.7% without Ba2+). Ames medium lacking amino acids and vitamins was unable to maintain retinal signaling, as evident in a reversible decrease of the b-wave to 31.8 +/- 3.9% of its amplitude in complete Ames medium. CONCLUSIONS: Our findings provide optimized conditions for ex vivo ERGs from the murine retina and suggest that careful application of Ba2+ supports reliable isolation of b wave responses in mice. Under our recording conditions, murine retinas show reproducible ERGs for up to six hours. PMID- 28841048 TI - The potential role of in silico approaches to identify novel bioactive molecules from natural resources. AB - In recent years, integration of in silico approaches to natural product (NP) research reawakened the declined interest in NP-based drug discovery efforts. In particular, advancements in cheminformatics enabled comparison of NP databases with contemporary small-molecule libraries in terms of molecular properties and chemical space localizations. Virtual screening and target fishing approaches were successful in recognizing the untold macromolecular targets for NPs to exploit the unmet therapeutic needs. Developments in molecular docking and scoring methods along with molecular dynamics enabled to predict the target ligand interactions more accurately taking into consideration the remarkable structural complexity of NPs. Hence, innovative in silico strategies have contributed valuably to the NP research in drug discovery processes as reviewed herein. [Formula: see text]. PMID- 28841047 TI - Synthesis and biological evaluation of curcumin analogs as beta-amyloid imaging agents. AB - AIM: Detection of beta-amyloid (Abeta) plaques in the brain is a very promising biomarker approach for early diagnosis of Alzheimer's disease (AD). MATERIALS & METHODS: A series of curcumin analogs (1,5-diphenyl-1,4-pentadien-3-one derivatives) were synthesized and evaluated. Specific binding to Abeta plaques was demonstrated in vitro using postmortem AD homogenates, and the fluorescent staining and autoradiography in vitro of postmortem AD brain sections were performed. RESULTS: Some compounds showed high binding affinities with Abeta plaques. Fluorescent staining indicated that compound 4e clearly stained Abeta plaques within AD brain sections. In biodistribution, radioiodinated ligand [125I]4e exhibited high brain uptake and favorable clearance from the brain. Autoradiography in vitro further confirmed the high affinities of [125I]4e. CONCLUSION: The results strongly suggested that [125I]4e might be developed into potential amyloid imaging agent for the detection of senile plaques in AD. [Formula: see text]. PMID- 28841049 TI - The protein oxidation of soybean meal induced by heating decreases its protein digestion in vitro and impairs growth performance and digestive function in broilers. AB - 1. The soybean meal (SBM) was heated at 100 degrees C for 1, 2, 4 and 8 h, respectively, and their resultant oxidative status was evaluated. 2. A total of 400 one-day-old Arbor Acres broilers were randomly divided into 5 treatments with 8 replicates of 10 birds each, and fed with diets containing non-heated SBM (NHSBM) or 1 of 4 heated SBMs (HSBMs, SBMs heated at 100 degrees C for 1, 2, 4 and 8 h, respectively) for 42 d. 3. The contents of carbonyl in the SBMs were both linearly and quadratically increased, whereas the nitrogen solubility index, and in vitro digestibility of crude protein (CP) and dry matter (DM) in the SBMs were both linearly and quadratically decreased as heating time increased (P < 0.05). The concentrations of sulfhydryl and total sulfhydryl in the SBMs were linearly decreased as heating time increased (P < 0.05). 4. The average daily gain was linearly decreased while the feed conversion ratio (FCR) was linearly increased in broilers as heating time of dietary HSBMs increased during both d 22 42 and d 1-42 of study (P < 0.05), though FCR of broilers during d 22-42 study were unaffected when the heating time of dietary HSBMs was 1 h (P > 0.05). The serum glucose concentration and the activity of trypsin at d 42, and the apparent total digestibility of CP and DM were all linearly reduced in broilers when heating time of dietary HSBMs increased (P < 0.05). However, 1 h HSBM has a numerical higher CP and DM digestibility than NHSBM. The serum urea nitrogen contents were both linearly and quadratically increased at both d 21 and 42 (P < 0.05), and relative pancreas weight was linearly increased at d 42 in broilers as heating time of dietary HSBMs increased (P < 0.05). PMID- 28841051 TI - Confidence in confidence intervals! PMID- 28841050 TI - Bacillus subtilis and yeast cell wall improve the intestinal health of broilers challenged by Clostridium perfringens. AB - 1. The objective was to investigate the effects of Bacillus subtilis, yeast cell wall (YCW) and their combination on intestinal health of broilers challenged by Clostridium perfringens over a 21-d period. 2. Using a 5 * 2 factorial arrangement of treatments, 800 1-d-old male Cobb 500 broilers were used to study the effects of feed additives (without additive or with zinc bacitracin, B. subtilis, YCW, and the combination of B. subtilis and YCW), pathogen challenge (without or with Clostridium perfringens challenge), and their interactive effects. 3. C. perfringens infection increased intestinal lesions scores, damaged intestinal histomorphology, increased serum endotoxin concentration, cytokine mRNA expression and intestinal population of C. perfringens and Escherichia coli and decreased ileal bifidobacteria numbers. The 4 additives decreased serum endotoxin. Zinc bacitracin tended to decrease cytokine mRNA expression and the intestinal number of C. perfringens and E. coli. B. subtilis, YCW and their combination increased cytokine mRNA expression. B. subtilis and YCW decreased the number of C. perfringens and E. coli in the ileum, and their combination decreased pathogens numbers in the ileum and caecum. 4. In conclusion, B. subtilis, YCW and their combination improved the intestinal health of NE-infected broilers, and could be potential alternatives to antibiotics. PMID- 28841052 TI - A Qualitative Study of Challenges and Opportunities in Mobilizing Research Knowledge on Violence Against Women. AB - Background Effective delivery of interventions by health and social services requires research-based knowledge which identifies the causes and consequences of violence against women. Methods to effectively share new knowledge with violence against women decision-makers remain under studied. Purpose This paper examines how new research-based knowledge-namely, the lack of efficacy of health-care screening for exposure to intimate partner violence against women-is received by stakeholders in the violence against women field. Methods Data from 10 stakeholder group discussions ( N = 86) conducted during a knowledge-sharing forum were analyzed to assess how stakeholders responded to the new knowledge. Results Participant reactions ranged from full acceptance to significant resistance to the research findings. We suggest themes that help explain these reactions, including the context and content of our findings and their epistemological match to participants' experiences and beliefs, and the perceived value of research evidence, compared to other forms of knowledge. Conclusions Violence against women is a complex psycho-social phenomenon, and people with an interest in this field bring diverse and even conflicting perspectives regarding its causes, consequences, and potential solutions. PMID- 28841053 TI - The Productive Ward ProgramTM: A Two-Year Implementation Impact Review Using a Longitudinal Multilevel Study. AB - Aim To investigate the impact of the quality improvement program "Productive Ward - Releasing Time to CareTM" using nurses' and midwives' reports of practice environment, burnout, quality of care, job outcomes, as well as workload, decision latitude, social capital, and engagement. Background Despite the requirement for health systems to improve quality and the proliferation of quality improvement programs designed for healthcare, the empirical evidence supporting large-scale quality improvement programs impacting patient satisfaction, staff engagement, and quality care remains sparse. Method A longitudinal study was performed in a large 600-bed acute care university hospital at two measurement intervals for nurse practice environment, burnout, and quality of care and job outcomes and three measurement intervals for workload, decision latitude, social capital, and engagement between June 2011 and November 2014. Results Positive results were identified in practice environment, decision latitude, and social capital. Less favorable results were identified in relation to perceived workload, emotional exhaustion. and vigor. Moreover, measures of quality of care and job satisfaction were reported less favorably. Conclusion This study highlights the need to further understand how to implement large-scale quality improvement programs so that they integrate with daily practices and promote "quality improvement" as "business as usual." PMID- 28841054 TI - Reorienting Public Health Nurses' Practice With a Professional Practice Model. AB - Purpose Documents articulating public health nurses' (PHNs') roles, including Canadian standards and competencies, depict a broad focus working at multiple levels to improve population outcomes through the promotion of health equity. Conversely, Canadian experts depict a looming crisis, based on the rising disconnect between daily activities and ideal practice. While perfectly positioned, PHNs' skills and abilities are under-utilized and largely invisible. The intention of this study was to develop a model to support the full scope of equity-focused PHN practice. Method A participatory action research approach was used. Qualitative data were gathered using semistructured interview guides during audio-recorded meetings. The data were coded into central themes using content analysis and constant comparison. A researcher reflexive journal and field notes were kept. A significant feature was full participant involvement. Results The outcome was a professional practice model to reframe the PHN role to focus on population health and equity. The model was imperative in promoting full scope of practice, dealing with workload pressures, and describing PHNs' value within the organization and broader health system. Conclusion Professional practice models hold promise as frameworks to depict autonomous practice activities, situated within organizations and healthcare systems, and underpinned by nursing knowledge. PMID- 28841055 TI - Take Care and Care Well. AB - Evidence-based practice supports the patient care process by integrating patient values and preferences with clinician expertise and the best available evidence. This approach to patient care focuses on quality and safety with the aim of improving patient outcomes. Despite its obvious value, healthcare professionals struggle to integrate evidence-based best practices into their clinical practice. PMID- 28841056 TI - Nurses' Perspectives on the Geriatric Nursing Practice Environment and the Quality of Older People's Care in Ontario Acute Care Hospitals. AB - Background Cultivating hospital environments that support older people's care is a national priority. Evidence on geriatric nursing practice environments, obtained from studies of registered nurses (RNs) in American teaching hospitals, may have limited applicability to Canada, where RNs and registered practical nurses (RPNs) care for older people in predominantly nonteaching hospitals. Purpose This study describes nurses' perceptions of the overall quality of care for older people and the geriatric nursing practice environment (geriatric resources, interprofessional collaboration, and organizational value of older people's care) and examines if these perceptions differ by professional designation and hospital teaching status. Methods A cross-sectional survey, using Dillman's tailored design, that included Geriatric Institutional Assessment Profile subscales, was completed by 2005 Ontario RNs and registered practical nurses to assess their perceptions of the quality of care and geriatric nursing practice environment. Results Scores on the Geriatric Institutional Assessment Profile subscales averaged slightly above the midpoint except for geriatric resources which was slightly below. Registered practical nurses rated the quality of care and geriatric nursing practice environment higher than RNs; no significant differences were found by hospital teaching status. Conclusions Nurses' perceptions of older people's care and the geriatric nursing practice environment differ by professional designation but not hospital teaching status. Teaching and nonteaching hospitals should both be targeted for geriatric nursing practice environment improvement initiatives. PMID- 28841057 TI - Guidelines for the Institutional Implementation of Developmental Neuroprotective Care in the NICU. Part B: Recommendations and Justification. A Joint Position Statement From the CANN, CAPWHN, NANN, and COINN. AB - The use of age-appropriate care as an organized framework for care delivery in the NICU is founded on the work of Heidelise Als, PhD, and her synactive theory of development. This theoretical construct has recently been advanced by the work of Gibbins and colleagues with the "universe of developmental care" conceptual model and developmental care core measures which were endorsed by the National Association of Neonatal Nurses in their age-appropriate care of premature infant guidelines as best-practice standards for the provision of high-quality care in the NICU. These guidelines were recently revised and expanded. In alignment with the Joint Commission's requirement for healthcare professionals to provide age specific care across the lifespan, the core measures for developmental care suggest the necessary competencies for those caring for the premature and critically ill hospitalized infant. Further supported by the Primer Standards of Accreditation and Health Canada, the institutional implementation of these core measures require a strong framework for institutional operationalization presented in these guidelines. Part B will present the recommendations and justification of each steps behind the present guidelines to facilitate their implementation. PMID- 28841058 TI - Guidelines for the Institutional Implementation of Developmental Neuroprotective Care in the Neonatal Intensive Care Unit. Part A: Background and Rationale. A Joint Position Statement From the CANN, CAPWHN, NANN, and COINN. AB - The use of age-appropriate care as an organized framework for care delivery in the neonatal intensive care unit is founded on the work of Heidelise Als, PhD, and her synactive theory of development. This theoretical construct has recently been advanced by the work of Gibbins and colleagues with the "universe of developmental care" conceptual model and developmental care core measures which were endorsed by the National Association of Neonatal Nurses in their age appropriate care of premature infant guidelines as best-practice standards for the provision of high-quality care in the neonatal intensive care unit. These guidelines were recently revised and expanded. In alignment with the Joint Commission's requirement for health-care professionals to provide age-specific care across the lifespan, the core measures for developmental care suggest the necessary competencies for those caring for the premature and critically ill hospitalized infant. Further supported by the Primer Standards of Accreditation and Health Canada, the institutional implementation of theses core measures requires a strong framework for institutional operationalization, presented in these guidelines. Part A of this article will present the background and rationale behind the present guidelines and their condensed table of recommendations. PMID- 28841059 TI - The Role of Interpersonal Relations in Healthcare Team Communication and Patient Safety: A Proposed Model of Interpersonal Process in Teamwork. AB - Patient safety is compromised by medical errors and adverse events related to miscommunications among healthcare providers. Communication among healthcare providers is affected by human factors, such as interpersonal relations. Yet, discussions of interpersonal relations and communication are lacking in healthcare team literature. This paper proposes a theoretical framework that explains how interpersonal relations among healthcare team members affect communication and team performance, such as patient safety. We synthesized studies from health and social science disciplines to construct a theoretical framework that explicates the links among these constructs. From our synthesis, we identified two relevant theories: framework on interpersonal processes based on social relation model and the theory of relational coordination. The former involves three steps: perception, evaluation, and feedback; and the latter captures relational communicative behavior. We propose that manifestations of provider relations are embedded in the third step of the framework on interpersonal processes: feedback. Thus, varying team-member relationships lead to varying collaborative behavior, which affects patient-safety outcomes via a change in team communication. The proposed framework offers new perspectives for understanding how workplace relations affect healthcare team performance. The framework can be used by nurses, administrators, and educators to improve patient safety, team communication, or to resolve conflicts. PMID- 28841060 TI - Acute fish liver intoxication induced blisters formation and generalized skin peeling. AB - INTRODUCTION: Acute fish liver intoxication, including hypervitaminosis A and hypervitaminosis D, may result from the ingestion of certain fish livers. The typical symptoms of hypervitaminosis A include nausea, headache, blurred vision, and cutaneous manifestations, such as flushing, vesicles formation, and desquamation. Hypervitaminosis D may result in hypercalcemia. We report a case of acute fish liver intoxication with systemic and cutaneous manifestations. CASE: A 63-year-old male presented to the clinic with generalized desquamation and multiple clear-fluid filled flaccid vesicles after eating approximately two fist sized portions (about 300-400 g) of cooked seerfish (Scomberomorus spp.) liver. Laboratory examination showed a high serum level of vitamin A and D, and hypercalcemia. CONCLUSIONS: Fish liver consumption from particular fish may result in acute hypervitaminosis A and D. In patients with skin detachment or blister formation, headache, drowsiness, and other symptoms and signs consistent with hypervitaminosis A and/or hypercalcemia, a history of fish intake should be sought, and a serum level of vitamin A and D should be measured. PMID- 28841061 TI - The Clinical Placement Challenges of Quebec's Nurse Practitioner Students: A Call for a New Research Focus. PMID- 28841062 TI - Direct Oral Anticoagulants in the Real World: Insights Into Appropriate Prescribing and Medication Use. AB - Background Direct oral anticoagulants are convenient because of their fixed dosing and without laboratory monitoring. There are instructions on avoidance of moisture, no crushing of capsules, and administration with food for some direct oral anticoagulants. Whether patients adhere to this and are prescribed appropriate doses are unknown. Aims To assess direct oral anticoagulant dosing and medication use. Methods Patients >=18 years old, receiving a direct oral anticoagulant for any diagnosis, were prospectively included. Nurses at our perioperative anticoagulation clinic helped patients complete a 12-item questionnaire. Results Ninety-three consecutive patients were recruited. Forty nine were on dabigatran, 18 on apixaban, and 26 were on rivaroxaban. Sixty-two patients (67%) received appropriate direct oral anticoagulant dosing and administered the medication correctly. Eighteen patients (19%) administered the direct oral anticoagulant properly but at an inappropriate dose. Thirteen patients (14%) received an appropriate dose but administered the direct oral anticoagulant inappropriately: 10 (11%) removed dabigatran from its packaging before administration (exposing it to moisture); 2 (2%) did not take rivaroxaban with food; and 1 (1%) crushed the dabigatran capsule. Conclusion Our study demonstrates a large variability in how direct oral anticoagulants are dosed, and how patients take them. Improved medication literacy around direct oral anticoagulants is needed. Our study highlights opportunities that nurses have to improve patients' medication literacy. PMID- 28841063 TI - The Hope Research Community of Practice: Building Advanced Practice Nurses' Research Capacity. AB - Background Clinical nurses have multiple challenges in conducting high-quality nursing research to inform practice. Theoretically, the development of a community of practice on nursing research centered on the concept of hope is an approach that may address some of the challenges. Purpose This article describes the delivery and evaluation of a hope research community of practice (HRCoP) approach to facilitate research expertise in a group of advanced practice nurses in one hospital. It addressed the question: Does the establishment of a HRCoP for master's prepared nurses increase their confidence and competence in leading nursing research? Method Using interpretive descriptive qualitative research methodology, five participants were interviewed about their experiences within the HRCoP and facilitators engaged in participant observation. Results At 13 months, only four of the original seven participants remained in the HRCoP. While all participants discussed positive impacts of participation, they identified challenges of having protected time to complete their individual research projects, despite having administrative support to do so. Progress on individual research projects varied. Conclusion Nurse-led research remains a challenge for practicing nurses despite participating in an evidence-based HRCoP. Lessons learned from this project can be useful to other academic clinical partnerships. PMID- 28841064 TI - A Pain Education Intervention for Patients Undergoing Ambulatory Inguinal Hernia Repair: A Randomized Controlled Trial. AB - Background Inguinal hernia repair is a common ambulatory surgery after which many patients experience moderate to severe post-operative pain. Limited research has examined the effect of education interventions to reduce pain after ambulatory surgery. Purpose This trial evaluated the effectiveness of an individualized Hernia Repair Education Intervention (HREI) for patients following inguinal hernia repair. Method Pre-operatively, participants (N = 82) were randomized to either the intervention (HREI) or the usual care group. The HREI included written and verbal information regarding managing pain and two telephone support calls (before and after surgery). The primary outcome was WORST 24-h pain intensity on movement on post-operative day 2. Secondary outcomes included pain intensity at rest and movement, pain-related interference with activities, pain quality, analgesics consumed, and adverse effects at post-operative days 2 and 7. Results At day 2, the intervention group reported significantly lower scores across pain intensity outcomes, including WORST 24-h pain on movement and at rest (p < 0.001), and pain NOW on movement and at rest (p = 0.001). Conclusion These findings suggest that the HREI may improve patients' pain and function following ambulatory inguinal hernia repair. Further research should examine the effectiveness of an education intervention over a longer period of time. PMID- 28841066 TI - A New Dawn for CJNR: Embracing the Future While Celebrating the Past. PMID- 28841065 TI - Psychiatric Hospital Workers' Exposure to Disturbing Patient Behavior and Its Relation to Post-Traumatic Stress Disorder Symptoms. AB - Background About 10% of health-care workers experience post-traumatic stress disorder (PTSD); the rate is higher among workers exposed to aggression. Objective We extended this research by examining PTSD and exposure to violence and other disturbing patient behaviors, among nursing and other staff on inpatient psychiatric units (forensic and nonforensic). Method Surveys were completed online or in person by 219 respondents (30% response rate). Participants indicated which disturbing behaviors they had been exposed to and ranked the worst three behaviors in each of three categories: most unpleasant to work with, most disruptive to patient care, and most upsetting. Most ( n = 192) also completed the PTSD Checklist (PCL). Results All but two participants reported exposure to at least one disturbing behavior and ranked violence, feces smearing, and screaming constantly as the worst experiences overall. On the PCL, 24% scored above the cut off for probable PTSD. Nursing staff had the highest scores, with no difference between nursing staff on forensic versus nonforensic units. PCL score showed a small positive correlation with the number of disturbing behaviors experienced. Conclusion PTSD symptoms are common among psychiatric hospital workers, not only nursing staff. Future research using clinical assessment, longitudinal designs, and measurement of nonviolent disturbing behaviors is recommended. PMID- 28841067 TI - Nurse-Led Interventions to Promote Optimal Aging at Home for Older Adults With Multimorbidity and Their Caregivers: Moving the Nursing Research Agenda Forward. PMID- 28841068 TI - Narrative Inquiry: Experience matters. AB - Narrative Inquiry is a research methodology that we adapted over the past two decades from Canadian higher education and curriculum studies to nursing research, education, and health-care practice. The Narrative Inquiry we use originated from Connelly and Clandinin in the 1990s, and rests on John Dewey's philosophy that experience is relational, temporal, and situational, and as such, if intentionally explored, has the potential to be educational. More specifically, it is only when experience is reflected upon and reconstructed that it has the potential to reveal the construction of identity, knowledge, and the humanness of care. Congruent with the expectation that nurses are reflective practitioners and knowledge-makers, Narrative Inquiry provides a means to enhance, not only quality of care, but quality of experience of those in our care: in education, our students, and in practice, our patients. In this article, we explicate how Narrative Inquiry may be lived in health-care education and practice, with a primary focus on nursing. We illuminate how we support our graduate students, the next generation of narrative inquirers, through a Narrative Inquiry Works-in-Progress group. PMID- 28841069 TI - Has the Experience of Hepatitis C Diagnosis Improved Over the Last Decade? An Analysis of Canadian Women's Experiences. AB - Background In Canada, incidents of new hepatitis C virus infections are rising among women aged 15-29 years and now comprise 60% of new infections among this age group. A negative diagnosis experience continues to be a problem affecting women living with hepatitis C virus. With new effective treatments, nurses will have more involvement in hepatitis C virus care and diagnosis, which is a critical time to facilitate appropriate education and management. Purpose This study explored Canadian women's experience of hepatitis C virus diagnosis in order to develop recommendations to improve care at the point of diagnosis. Methods Purposive sampling was used to recruit and interview 25 women. Using narrative inquiry, we examined Canadian women's experience of hepatitis C virus diagnosis. Results Women's diagnosis experiences were shaped by the context of diagnosis, factors prompting the testing, the testing provider, and information/education received. The context of diagnosis foreshadowed how prepared women were for their results, and the absence of accurate information magnified the psychological distress that can follow an hepatitis C virus diagnosis. Conclusion Our findings provide a compelling case for a proactive nursing response, which will improve women's experiences of hepatitis C virus diagnosis and, in turn, enhance women's access to hepatitis C virus care and other healthcare services. PMID- 28841070 TI - Challenges in Using the Randomized Trial Design to Examine the Influence of Treatment Preferences. AB - The overall purpose of this methodological study was to investigate the strengths and limitations of the randomized clinical trial design in examining the influence of treatment preferences on outcomes. The study was a secondary analysis of data obtained in two randomized clinical trials that evaluated behavioral therapies for insomnia. In both trials, the same design and methods were used to assess participants' treatment preferences and outcomes, however, the treatments differed. The results illustrated the challenges encountered in using the randomized clinical trial design. The challenges were related to the unbalanced distribution of participants with preferences for the study treatments, non-comparability of the subgroups with treatments matched or mismatched to their preferences, differential attrition, which compromised the sample size and composition of the subgroups and limited the use of the planned statistical analyses. Whether these challenges occur in trials of other types of treatments and target populations should be explored in future research. Some strategies were proposed and should be evaluated for their utility in addressing these challenges. PMID- 28841071 TI - Editorial. PMID- 28841072 TI - Pain: Something for Everyone. PMID- 28841073 TI - Shall Research Ethics Boards be Reviewing Research Methodology! PMID- 28841074 TI - Moving From Field Text to Research Text in Narrative Inquiry: A Study Exemplar. AB - Narrative Inquiry is a research methodology that enables a researcher to explore experience through a metaphorical analytic three-dimensional space where time, interaction of personal and social conditions, and place make up the dimensions for working with co-participant stories. This inquiry process, analysis, and interpretation involve a series of reflective cognitive movements that make possible the reformulations that take place in the research journey. In this article, I retell the process of my inquiry in moving from field texts (data sources) to research text (interpretation of experience) in Narrative Inquiry. I draw from an inquiry on how nurses experience living their values amidst organizational change to share how I as an inquirer/researcher, moved from field texts to narrative accounts; narrative resonant threads; composite letter as the narrative of experience; personal, practical, and social justifications to construct the research text and represent it another form as a poem. These phases in the inquiry involve considerations in the analytic and interpretive process that are essential in understanding how to conduct Narrative Inquiry. Lastly and unique to my inquiry, I share how a letter can be used as an analytic device in Narrative Inquiry. PMID- 28841075 TI - Ontario's Poverty Reduction Strategy: A Critical Discourse Analysis. AB - This article overviews the second phase of a two-phase study which examined experiences of health and social exclusion among mothers experiencing homelessness in Ontario, Canada. A critical discourse analysis was employed to analyze the policy document, Realizing Our Potential: Ontario's Poverty Reduction Strategy, 2014-2019. In nursing, analysis of policy is an emerging form of scholarship, one that draws attention to the macro levels influencing health and health promotion, such as the social determinants of health, and the policies that impact them. The clear neo-liberal underpinnings, within the strategy, with a focus on productivity and labor market participation leave little room for an understanding of poverty reduction from a human rights perspective. Further, gender-neutrality rendered the poverty experienced by women, and mothers, invisible. Notably, there were a lack of deadlines, target dates, and thorough action and evaluation plans. Such absence troubles whether poverty reduction is truly a priority for the government, and society as a whole. PMID- 28841076 TI - Strategic Workforce Planning for Health Human Resources: A Nursing Case Analysis. AB - Background Health-care organizations provide services in a challenging environment, making the introduction of health human resources initiatives especially critical for safe patient care. Purpose To demonstrate how one specialty hospital in Ontario, Canada, leveraged an employment policy to stabilize its nursing workforce over a six-year period (2007 to 2012). Methods An observational cross-sectional study was conducted in which administrative data were analyzed to compare full-time status and retention of new nurses prepolicy and during the policy. The Professionalism and Environmental Factors in the Workplace Questionnaire(r) was used to compare new nurses hired into the study hospital with new nurses hired in other health-care settings. Results There was a significant increase in full-time employment and a decrease in part-time employment in the study hospital nursing workforce. On average, 26% of prepolicy new hires left the study hospital within one year of employment compared to 5% of new hires during policy implementation. The hospital nurses scored significantly higher than nurses employed in other health-care settings on 5 out of 13 subscales of professionalism. Conclusions Decision makers can use these findings to develop comprehensive health human resources guidelines and mechanisms that support strategic workforce planning to sustain and strengthen the health-care system. PMID- 28841077 TI - Insights Into Roles for Health-Care Professionals in Meeting the Needs of Older Adults and Unpaid Caregivers During Health-Care Transitions. AB - We provided insights from older adults, their unpaid caregivers, and health-care professionals into specific roles for professionals within the health system to better meet the needs of community-dwelling older adults and their unpaid caregivers experiencing transitions between health services. We used a qualitative approach to collect data within one Canadian province from older adults and unpaid caregivers of older adults who participated in focus groups ( n = 98) and professionals working in the health system who participated in an online survey ( n = 52). Questions included experiences with health service transitions, strengths, challenges, and suggestions to improve transitions. Thematic analysis resulted in identifying seven specific roles for professionals in supporting health-care transitions: information and education, planning for future health needs, supporting the acceptance of necessary care, facilitating access to the right services at the right time, facilitating communication between services, facilitating the discharge planning process and advocacy for older adults and unpaid caregivers. Our results based on evidence from older adults, unpaid caregivers, and health-care professionals will inform future research and further development of the instrumental and relational roles for professionals supporting older adults and their caregivers experiencing health care transitions. PMID- 28841078 TI - Semantic Examination of a Japanese Center for Epidemiologic Studies Depression: A Cautionary Analysis Using Mixed Methods. AB - Background Cross-cultural research relies on the linguistic, conceptual, and semantic equivalence of instruments. Widely used translations of the Center for Epidemiologic Studies Depression (CESD) for cross-cultural samples should be analyzed to reaffirm conceptual and semantic equivalence. Purpose This methodological study aimed to discover and resolve problematic translations of a Japanese version of the CESD. Design Sequential explanatory mixed method design using spiraling integration. Methods Sample includes 34 first-generation Japanese women living in the US and 72 community-based women in Japan. Ethnographic analysis of the semantic meanings of items was followed by t tests to compare original and retranslated item means, as well as Cronbach's reliability and corrected item-total correlations analyses. Results Six problematic items were retranslated: bothered, failure, hope, restless sleep, happiness, and "getting going." Reliabilities for the CESD that included the new CESD item translations were the same; however, most item-scale correlations were higher for the revised translations across the two groups. Conclusions We conclude that both failure and "getting going" may be culturally bound items. Implications for cross-cultural and ethnographic nursing research include planning mini-ethnographic analysis when using translations to discover and reconcile cultural differences in connotations, motivations, and goals. PMID- 28841079 TI - Lifitegrast for the treatment of dry eye disease in adults. AB - INTRODUCTION: Dry eye disease (DED) is a common ocular disorder that can have a substantial burden on quality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved in the US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize the preclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatment landscape for DED. Areas covered: A literature search of published preclinical and clinical data was conducted to review the chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. The impact that lifitegrast may have on DED treatment practices is also discussed. Expert opinion: The introduction of lifitegrast provides a potentially important additional option for eye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmic solution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptom improvements were observed as early as 2 weeks, which may be explained by lifitegrast's unique mechanism of action of blocking a specific signaling pathway in inflammation. Future research should include evaluation of whether lifitegrast can be used in combination with other DED treatments. PMID- 28841080 TI - Gains of Continuing Resuscitation in Refractory Out-of-hospital Cardiac Arrest: A Model-based Analysis to Identify Deaths Due to Intra-arrest Prognostication. AB - OBJECTIVE: Prognostication bias, in which a clinician predicts a negative outcome and terminates resuscitation (TR) thereby ensuring a poor outcome, is a rarely identified limitation of out-of-hospital cardiac arrest (OHCA) research. We sought to estimate the number of deaths due to intra-arrest prognostication in a cohort of OHCA's, and use this data to estimate the incremental benefit of continuing resuscitation. METHODS: This study examined a cohort of consecutive non-traumatic EMS-treated OHCAs from a provincial ambulance service, between 2007 and 2011 inclusive. We used Cox and logistic regression modeling, adjusting for Utstein covariates, to estimate the probability of ROSC, survival, and favorable neurological outcomes as a function of resuscitation time, and applied these models to estimate the number of missed survivors in those who had TR (prior to 20, 30, or 40 minutes). We determined the time juncture at which (1) the likelihood of survival fell below 1%, and (2) the proportion of survivors who had achieved ROSC exceeded 99%. RESULTS: Of 5674 adult EMS-treated cases, 46% achieved ROSC, and 12% survived. The median time of TR was 27.0 minutes (IQR 19.0 35.0). Continuing resuscitation until 40 minutes yielded an estimated 17 additional survivors (95% CI 13-21), 10 (95% CI 7-13) with favorable neurological outcomes. The probability of survival of those in refractory arrest decreased below 1% at 28 minutes (95% CI 24-30 minutes). At 36 minutes (95% CI 34-38 minutes) >99% of survivors had achieved ROSC. CONCLUSION: We identified possible deaths due to intra-arrest prognostication. Resuscitation should be continued for a minimum of 30 minutes in all patients, however for those with initial shockable rhythms 40 minutes appears to be warranted. Interventional trials and observational studies should standardize or adjust for duration of resuscitation prior to TR. PMID- 28841081 TI - On the Nature of Objectification: Implications of Considering People as Means to Goals. AB - People are objectified when they are treated as a means to a goal. The most common example is when women are sexually objectified and reduced to their physical appearance, sexuality, or individual body parts. In such instances, people are used in the same way as objects and are evaluated according to their instrumentality to the others' goals. The aim of this paper is to gain a better understanding of objectification. We will (a) outline basic principles of means goal relations during goal pursuit, (b) review research in which people are means to goals, (c) explain objectification according to a means-goal psychology in which people serve as means to goals, and (d) explain the implications of our account for the consequences of objectification. Specifically, we argue objectification is inevitable and that the consequences of objectification, including its morality, depend on the goal to which a person serves and whether the objectified person wants to serve that goal. PMID- 28841082 TI - A shorter period of therapy is associated with higher mortality in bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae in a Brazilian centre. PMID- 28841083 TI - Hypokalaemia periodic paralysis. AB - Hypokalaemic periodic paralysis is a rare skeletal muscle channelopathy causing flaccid paralysis, which predominantly presents in adolescents and young adults. I report a case of a 33-year-old Caucasian man who presented with sudden onset paralysis, following previous similar presentations without investigation. Blood tests revealed undetectable serum potassium levels in the context of paralysis. Other causes of hypokalaemia were excluded, and the patient was treated with planned lifelong prophylactic potassium replacement for a diagnosis of primary hypokalaemic periodic paralysis. This case demonstrates that, although rare, hypokalaemic periodic paralysis should be considered as a differential diagnosis in young patients who present with sudden flaccid paralysis and can easily be excluded by checking serum potassium levels at presentation. PMID- 28841085 TI - Observational Multicenter Study of a Direct-to-CT Protocol for EMS-transported Patients with Suspected Stroke. AB - OBJECTIVE: In an effort to decrease door-to-needle times for patients with acute ischemic stroke, some hospitals have begun taking stable EMS patients with suspected stroke directly from the ambulance to the CT scanner, then to an emergency department (ED) bed for evaluation. Minimal data exist regarding the potential for time savings with such a protocol. The study hypothesis was that a direct-to-CT protocol would be associated with decreases in both door-to-CT ordered and door-to-needle times. METHODS: An observational, multicenter before/after study was conducted of time/process measures at hospitals that have implemented direct-to-CT protocols for patients transported by EMS with suspected stroke. Participating hospitals submitted data on at least the last 50 "EMS stroke alert" patients before the launch of the direct-to-CT protocol, and at least the first 50 patients after. Time elements studied were arrival at the ED, time the head CT was ordered, and time tPA was started. Data were submitted in blinded fashion (patient and hospital identifiers removed); at the time of data analysis, the lead investigator was unaware of which data came from which hospital. Simple descriptive statistics were used, along with the Mann-Whitney test to compare time medians. RESULTS: Seven hospitals contributed data on 1040 patients (529 "before" and 511 "after"); 512 were male, and 627 had final diagnoses of ischemic stroke, of whom 275 received tPA. The median door-to-CT ordered time for all patients was 7 minutes in the before phase, and 4 minutes after (difference 3 minutes, p = < 0.0001); similarly, the median door-to-CT started time was 6 minutes "before" and 10 minutes after (p < 0.0001). The median door-to-needle time for all patients given tPA was 42 minutes before, and 44 minutes after (p = 0.78). Four hospitals had modest decreases in door-to-CT ordered time (of 2, 4, 2, and 5 minutes), and only one hospital had a decrease in door-to-needle time (32 min vs 26 min, p = 0.012). CONCLUSIONS: In this sample from seven hospitals, a minimal reduction in door-to-CT-ordered and door-to-CT started time, but no change in door-to-needle time, was found for EMS patients with suspected stroke taken directly to the CT scanner, compared to those evaluated in the ED prior to CT. PMID- 28841084 TI - Human Papillomavirus Vaccination and Pap Smear Uptake Among Young Women in the United States: Role of Provider and Patient. AB - BACKGROUND: It has been reported that Pap smear use is higher among U.S. women who received the human papillomavirus (HPV) vaccine than unvaccinated women. This study assessed the role of provider and patient in the difference of Pap smear use by vaccination status. METHODS: We conducted a cross-sectional study of 5416 young women (21-30 years of age) with detailed information on Pap smear use and HPV vaccination status from the National Health Interview Survey (NHIS) 2013 2015. Vaccinated women received at least one dose of HPV vaccine. Main outcomes included Pap smear in the past year, provider's recommendation for Pap smear, and patient-initiated Pap smear. RESULTS: The prevalence of Pap smear in the past year was much higher among vaccinated women than unvaccinated women (67.5% vs. 52.8%, p < 0.001). Compared with unvaccinated women, vaccinated women were more likely to receive a provider's recommendation for Pap testing (60.8% vs. 50.8%, p < 0.001), to obtain Pap testing after receiving a provider's recommendation (75.1% vs. 67.9%, p = 0.004), and to initiate Pap testing themselves (57.7% vs. 38.2%, p < 0.001). However, among women who visited an obstetrician/gynecologist (OB/GYN) in the past year, the positive association between HPV vaccination and Pap smear recommendation and uptake vanished. CONCLUSIONS: Unvaccinated women who have not visited an OB/GYN in the past year are less likely to receive a recommendation for Pap testing from their providers or to initiate Pap testing themselves without a provider's recommendation. They should be encouraged to visit an OB/GYN provider for cervical cancer screening. PMID- 28841086 TI - Choosing Prediction Over Explanation in Psychology: Lessons From Machine Learning. AB - Psychology has historically been concerned, first and foremost, with explaining the causal mechanisms that give rise to behavior. Randomized, tightly controlled experiments are enshrined as the gold standard of psychological research, and there are endless investigations of the various mediating and moderating variables that govern various behaviors. We argue that psychology's near-total focus on explaining the causes of behavior has led much of the field to be populated by research programs that provide intricate theories of psychological mechanism but that have little (or unknown) ability to predict future behaviors with any appreciable accuracy. We propose that principles and techniques from the field of machine learning can help psychology become a more predictive science. We review some of the fundamental concepts and tools of machine learning and point out examples where these concepts have been used to conduct interesting and important psychological research that focuses on predictive research questions. We suggest that an increased focus on prediction, rather than explanation, can ultimately lead us to greater understanding of behavior. PMID- 28841088 TI - Knowledge of Constituent Ingredients in Enteral Nutrition Formulas Can Make a Difference in Patient Response to Enteral Feeding. AB - Enteral feeding is considered the preferred method for providing a complete or supplemental source of nutrition to patients. Enteral formulas (EFs) are traditionally assessed from general information provided by the manufacturer such as caloric density, percentage of macronutrients, and micronutrients to meet the Recommended Dietary Allowance. Sometimes labeling information highlights particular ingredients to indicate specific properties at a metabolic or nutrition level. However, it is necessary to review the quality and composition of any enteral formula, since the basic components are responsible for tolerance and nutrition efficacy, and this should not be overshadowed by the benefit of a single constituent. Intolerance to EF is commonly attributed to individual patient response or to the means of administration. The objective of this review is to highlight the importance of appraising EFs with regard to composition and effect on the gastrointestinal tract. PMID- 28841087 TI - Single cell cloning generates lung endothelial colonies with conserved growth, angiogenic, and bioenergetic characteristics. AB - Pulmonary artery, capillary, and vein endothelial cells possess distinctive structures and functions, which represent a form of vascular segment specific macroheterogeneity. However, within each of these segmental populations, individual cell functional variability represents a poorly characterized microheterogeneity. Here, we hypothesized that single cell clonogenic assays would reveal microheterogeneity among the parent cell population and enable isolation of highly representative cells with committed parental characteristics. To test this hypothesis, pulmonary microvascular endothelial cells (PMVECs) and pulmonary arterial endothelial cells (PAECs) were isolated from different Sprague Dawley rats. Serum stimulated proliferation of endothelial populations and single cell clonogenic potential were evaluated. In vitro Matrigel assays were utilized to analyze angiogenic potential and the Seahorse assay was used to evaluate bioenergetic profiles. PMVEC populations grew faster and had a higher proliferative potential than PAEC populations. Fewer PMVECs were needed to form networks on Matrigel when compared with PAECs. PMVECs primarily utilized aerobic glycolysis, while PAECs relied more heavily on oxidative phosphorylation, to support bioenergetic demands. Repeated single cell cloning and expansion of PAEC colonies generated homogeneous first-generation clones that were highly reflective of the parental population in terms of growth, angiogenic potential, and bioenergetic profiles. Repeated single cell cloning of the first-generation clones generated second-generation clones with increased proliferative potential while maintaining other parental characteristics. Second-generation clones were highly homogeneous populations. Thus, single cell cloning reveals microheterogeneity among the parent cell population and enables isolation of highly representative cells with parental characteristics. PMID- 28841089 TI - Intimate Partner Violence, Small for Gestational Age Birth and Cigarette Smoking in the Pregnancy Risk Assessment Monitoring System. AB - BACKGROUND: Exposure to intimate partner violence (IPV) in the perinatal period is associated with obstetric complications, poor maternal mental health, neonatal complications, and increased risk of infant mortality and morbidity. Less is known about how IPV may influence small for gestational age (SGA) birth. MATERIALS AND METHODS: Data were obtained for 231,081 United States mothers who delivered neonates from 2004 to 2011 and completed the Pregnancy Risk Assessment Monitoring System survey 2-9 months after delivery. Weighted descriptive statistics and multivariate logistic regression models were used. RESULTS: IPV in the year before or during pregnancy was related to SGA bivariately (odds ratio 1.39, 95% confidence interval [CI] 1.28, 1.51), and after adjustment for demographic and obstetric factors, this association attenuated after further adjustment for perinatal smoking patterns, (adjusted odds ratio [aOR] 1.06, 95% CI 0.97, 1.15). Compared with nonabused women, women experiencing perinatal IPV were more than twice as likely to smoke before pregnancy (aOR 2.34, 95% CI 2.19, 2.49), and nearly 1.5 times as likely to report sustained smoking into the last 3 months of pregnancy (aOR 1.45, 95% CI 1.32, 1.59). In turn, among prepregnancy smokers, sustained smoking was associated with delivery of a SGA neonate (aOR 1.87, 95% CI 1.72, 2.03), fully attenuating the association of perinatal IPV with SGA. CONCLUSION: Women who experienced perinatal IPV were significantly more likely to smoke prepregnancy and sustain smoking into the last 3 months of pregnancy. Through behavioral and physiological pathways, smoking cessation may be uniquely challenging for women experiencing IPV, yet critical to address clinically to mitigate risk for SGA. PMID- 28841090 TI - Risk of venous thromboembolism following surgical treatment of superficial venous incompetence. AB - BACKGROUND: The invasive management of varicose veins has a known risk of post operative deep venous thrombosis and subsequent pulmonary embolism. The aim of this study was to evaluate absolute and relative risk of venous thromboembolism (VTE) following commonly used varicose vein procedures. PATIENTS AND METHODS: A retrospective analysis of secondary data using Hospital Episode Statistics database was performed for all varicose vein procedures performed between 2003 and 2013 and all readmissions for VTE in the same patients within 30 days, 90 days, and one year. Comparison of the incidence of VTEs between procedures was performed using a Pearson's Chi-squared test. RESULTS: In total, 261,169 varicose vein procedures were performed during the period studied. There were 686 VTEs recorded at 30 days (0.26 % incidence), 884 at 90 days (0.34 % incidence), and 1,246 at one year (0.48 % incidence). The VTE incidence for different procedures was between 0.15-0.35 % at 30 days, 0.26-0.50 % at 90 days, and 0.46-0.58 % at one year. At 30 days there was a significantly lower incidence of VTEs for foam sclerotherapy compared to other procedures (p = 0.01). There was no difference in VTE incidence between procedures at 90 days (p = 0.13) or one year (p = 0.16). CONCLUSIONS: Patients undergoing varicose vein procedures have a small but appreciable increased risk of VTE compared to the general population, with the effect persisting at one year. Foam sclerotherapy had a lower incidence of VTE compared to other procedures at 30 days, but this effect did not persist at 90 days or at one year. There was no other significant difference in the incidence of VTE between open, endovenous, and foam sclerotherapy treatments. PMID- 28841091 TI - Persistent inequity in maternal health care utilization in Nepal despite impressive overall gains. AB - BACKGROUND: Maternal health care utilization is at the core of global public health provision and an area of focus in the now-concluded Millennium Development Goal agenda. OBJECTIVE: This study aims to examine trends in maternal health care utilization over the last 15 years in Nepal, focusing on coverage and equity. METHODS: This paper used data from the Demographic Health Survey (DHS) 2001, 2006 and 2011 and Multiple Indicator Cluster Survey (MICS), 2014. Coverage rates were calculated and logistic regression models used to examine inequity. RESULTS: Impressive gains were found in antenatal care (ANC) attendance, which increased from nearly half of women attending (49%) in 2001 to 88% in 2014, and the rate of facility delivery increased from just 7-44%. This development did not, however, influence the equity gap in ANC and skilled attendance at birth, as women from low socioeconomic backgrounds were six times more likely to deliver without skilled assistance than those from high socioeconomic backgrounds (AdjOR 6.38 CI 95% 4.57-8.90) in 2014. CONCLUSION: These persistent equity gaps call for targeted interventions focusing on the most disadvantaged and vulnerable women in order to achieve the new Sustainable Development Goal of universal health coverage. PMID- 28841092 TI - It's Complicated: Sociocultural factors and the Disclosure Decision of Transgender Individuals in Pakistan. AB - The literature on the disclosure decision of transsexual individuals is sparse, and that which does exist either uses empirical quantitative methods or aggregates transsexuals with other non-heterosexual individuals. The current study focuses this underresearched group and examines the disclosure decision of transsexual people in Pakistan, a developing Muslim country with a unique amalgam of social, cultural, and religious ground realities. Drawing on thematic analysis technique using in-depth interviews with 16 transsexuals, we show how sociocultural factors that are inherently embedded in the environment influence the disclosure decision in work and non-work settings. In particular, our respondents illustrate that their disclosure decision, which ranges from total disclosure on one end to nondisclosure on the other end, is influenced by the complexities of family honor, tightly integrated family network, social obligation to get married, and prevalent religious beliefs in the society. This study advances understanding of identity and disclosure decision of transsexual individuals by explicating the ways in which sociocultural factors are intricate part of their decision of coming out. PMID- 28841093 TI - Stereotypical Disease Inferences From Gay/Lesbian Versus Heterosexual Voices. AB - Voice is a cue used to categorize speakers as members of social groups, including sexual orientation. We investigate the consequences of such voice-based categorization, showing that people infer stereotype-congruent disease likelihood on the basis of vocal information and without explicit information about the speaker's sexual orientation. Study 1 and Study 2 reveal that participants attribute diseases to gay/lesbian and heterosexual men and women in line with stereotypes. Gay speakers were more likely to be associated with gay and female diseases, and lesbian speakers with male diseases. These findings demonstrate that likelihood to suffer from diseases is erroneously, but stereotypically, inferred from targets' vocal information. PMID- 28841094 TI - Do Perceptual Instructions Lead to Enhanced Performance Relative to Behavioral Instructions? AB - As people we commonly instruct people in terms of physical actions to carry out to perform any task. However, according to perceptual control theory (Powers, 1973 ), human action serves to control perception. Using a drawing task, it was hypothesized that instructions describing the perceivable effects of the movement would result in greater accuracy of image drawing than those describing the movement. Participants were asked to draw images using different instructions; describing the expected perceptions and describing the movements. As predicted, it was found that describing the perceptual outcome of the task led to significantly more accurate drawings than describing the movements did. This highlights the importance of instructions based on desired perceptions when precise execution of a skill is necessary. PMID- 28841095 TI - Hiring a Gay Man, Taking a Risk?: A Lab Experiment on Employment Discrimination and Risk Aversion. AB - We investigate risk aversion as a driver of labor market discrimination against homosexual men. We show that more hiring discrimination by more risk-averse employers is consistent with taste-based and statistical discrimination. To test this hypothesis we conduct a scenario experiment in which experimental employers take a fictitious hiring decision concerning a heterosexual or homosexual male job candidate. In addition, participants are surveyed on their risk aversion and other characteristics that might correlate with this risk aversion. Analysis of the (post-)experimental data confirms our hypothesis. The likelihood of a beneficial hiring decision for homosexual male candidates decreases by 31.7% when employers are a standard deviation more risk-averse. PMID- 28841097 TI - Immature, but Not Mature, Dendritic Cells Are More Often Present in Aggressive Periodontitis Than Chronic Periodontitis: An Immunohistochemical Study. PMID- 28841096 TI - Unmet needs in the management of intra-abdominal infections. AB - INTRODUCTION: Intra-abdominal infections remain a leading cause of death, morbidity and resource use in surgical wards and intensive care units. The growing complexity of their management has led to new paradigms and unresolved issues in anti-infective therapy described in the current review. Areas covered: We analyzed the literature, recent guidelines, and expert opinions published over the last decade. Expert commentary: Prospective randomized trials are difficult to perform and observational studies or database analyses should be encouraged. Epidemiologic and microbiologic reports should be promoted, especially in developing/resource-limited countries and in specific subpopulations such as children, older people and patients with underlying diseases. The diagnostic process, including imaging procedures, could be improved. The value of biomarkers for diagnosis, monitoring and discontinuation of therapy should be clarified and improved. New microbiologic techniques are needed to speed up the diagnostic process and to improve the adequacy of anti-infective therapy. Very little progress has been made in the detection of clinical failures. Many aspects of anti-infective management, both for bacteria and fungi, remain unresolved, such as the high inoculum, the type of microorganisms to be treated, the timing of therapy, the value of de-escalation, drug monitoring and duration of therapy. New antibiotics are expected. PMID- 28841098 TI - Letter to the Editor: Re: Is There Clinical Benefit From Using a Diode or Neodymium:Yttrium-Aluminum-Garnet Laser in the Treatment of Periodontitis? PMID- 28841099 TI - Survey of guidelines and current practices for safe handling of antineoplastic and other hazardous drugs used in 24 countries. AB - PURPOSE: A survey of guidelines and current practices was conducted to examine the safe handling procedures for antineoplastic and other hazardous drugs that are used in 24 countries including the Americas, Europe, the Mideast, Far East, and Australia. METHODS: Subject experts were asked to complete a brief survey regarding safe handling guidelines and practices for hazardous drugs in their countries. Questions addressed practices for handling monoclonal antibodies, the use of closed-system transfer devices, medical surveillance practices, and measurements of compliance with existing guidelines. RESULTS: Responses from 37 subject experts representing 24 countries revealed considerable variation in the content and scope of safe handling guidelines and pharmacy practices among the participating countries. Guidelines in the majority of countries used the term "cytotoxics," while others referred to "hazardous" or "antineoplastic" drugs. The International Society of Oncology Pharmacy Practice standard was cited by six countries, and five cited the National Institute for Occupational Safety and Health Alert. Others cited international guidelines other than International Society of Oncology Pharmacy Practice, or they have created their own guidelines. Approximately half reported that their guidelines were mandatory under federal, state, or provincial legislation. Only 11 countries reported that monoclonal antibodies were covered in their guidelines. Closed-system drug-transfer devices are widely used, but were not specifically recommended in four countries, while one country required their use. Medical surveillance programs are in place in 20 countries, but only in The Netherlands is surveillance mandatory. Nine countries reported that they have completed recent updates or revisions of guidelines, and the measures for their adoption have been initiated. CONCLUSIONS: Although the overall goals in the participating countries were similar, the approaches taken to assure safe handling of hazardous drugs varied considerably in some cases. PMID- 28841100 TI - The oral education clinic: A pharmacist- and nurse-led clinic to support patients starting oral systemic anti-cancer treatments. AB - With the increased number of oral systemic anti-cancer treatments available, patients need to be managed safely and effectively in line with national guidance. In response to guidance in 2011, Oxford University Hospitals NHS Foundation Trust implemented an 'Oral Education Clinic'. This nurse- and pharmacist-led clinic facilitates the delivery of patient education, highlighting key safety aspects of drug administration and management, and ensures follow-up is arranged as per protocol. Patients have found this service to be effective and it has had a positive impact on the running of outpatient units, the volume of triage calls, emergency admissions and workload associated with consenting patients to an oral systemic anti-cancer treatments. PMID- 28841101 TI - Implementation and evaluation of medicine and therapeutic information service by clinical pharmacists in oncology care setting. AB - BACKGROUND: This study was conducted to explore the role of clinical pharmacists in providing medicine and therapeutic information service in oncology care setting. METHODS: It was a prospective study conducted for a period of three years after implementation of medicine and therapeutic information service as an integral part of oncology pharmacy services. The medicine and therapeutic information queries were received during ward rounds, at ambulatory care and via telephone by clinical pharmacists. All the medicine and therapeutic information requests were reviewed and answered to the concerned requester(s). Answered medicine and therapeutic information requests were electronically documented in the hospital drug information database and analyzed further. RESULTS: A total of 484 medicine and therapeutic information requests were received by clinical pharmacists during period of August 2013 to June 2016. Majority of medicine and therapeutic information queries were requested by radiation oncologists (27.2%) followed by medical oncologists (26.4%), general physicians (14.04%), resident medical officers (11.7%), ambulatory care nurses (8.6%), in-patient nurses (5.1%) and patients and care takers (6.6%). Majority of the medicine and therapeutic information queries were asked for the purpose of improving patient care (48.3%) followed by to update knowledge (30.9%) and training sessions to nurses (6.6%). The most common categories of medicine and therapeutic information were adverse drug reactions and its management (21.4%) followed by dosage adjustments of chemotherapy and biologicals (15.5%), supportive care related (14.6%), contraindications (14%), drug-drug interactions (11.9%), management of co morbidities (7.8%), chemotherapy selection in special populations (4.5%). CONCLUSION: The provision of medicine and therapeutic information was found to be useful in providing medicine information to improve patient care and to update knowledge of health care professionals at the study hospital. PMID- 28841102 TI - Association of Burnout with Workforce-Reducing Factors among EMS Professionals. AB - OBJECTIVES: Emergency medical services (EMS) professionals often work long hours at multiple jobs and endure frequent exposure to traumatic events. The stressors inherent to the prehospital setting may increase the likelihood of experiencing burnout and lead providers to exit the profession, representing a serious workforce and public health concern. Our objectives were to estimate the prevalence of burnout, identify characteristics associated with experiencing burnout, and quantify its relationship with factors that negatively impact EMS workforce stability, namely sickness absence and turnover intentions. METHODS: A random sample of 10,620 emergency medical technicians (EMTs) and 10,540 paramedics was selected from the National EMS Certification database to receive an electronic questionnaire between October, 2015 and November, 2015. Using the validated Copenhagen Burnout Inventory (CBI), we assessed burnout across three dimensions: personal, work-related, and patient-related. We used multivariable logistic regression modeling to identify burnout predictors and quantify the association between burnout and our workforce-related outcomes: reporting ten or more days of work absence due to personal illness in the past 12 months, and intending to leave an EMS job or the profession within the next 12 months. RESULTS: Burnout was more prevalent among paramedics than EMTs (personal: 38.3% vs. 24.9%, work-related: 30.1% vs. 19.1%, and patient-related: 14.4% vs. 5.5%). Variables associated with increased burnout in all dimensions included certification at the paramedic level, having between five and 15 years of EMS experience, and increased weekly call volume. After adjustment, burnout was associated with over a two-fold increase in odds of reporting ten or more days of sickness absence in the past year. Burnout was associated with greater odds of intending to leave an EMS job (personal OR:2.45, 95% CI:1.95-3.06, work-related OR:3.37, 95% CI:2.67-4.26, patient-related OR: 2.38, 95% CI:1.74-3.26) or the EMS profession (personal OR:2.70, 95% CI:1.94-3.74, work-related OR:3.43, 95% CI:2.47 4.75, patient-related OR:3.69, 95% CI:2.42-5.63). CONCLUSIONS: The high estimated prevalence of burnout among EMS professionals represents a significant concern for the physical and mental well-being of this critical healthcare workforce. Further, the strong association between burnout and variables that negatively impact the number of available EMS professionals signals an important workforce concern that warrants further prospective investigation. PMID- 28841103 TI - Impact of patient-reported flares on radiographic progression and functional impairment in patients with rheumatoid arthritis: a cohort study based on the AMBRA trial. AB - OBJECTIVE: To investigate the impact of patient-reported flares on radiographic damage and disability in rheumatoid arthritis (RA). METHOD: Patients with low active (Disease Activity Score based on 28-joint count with C-reactive protein < 3.2) RA were followed for 2 years. Based on annual questionnaires about incidence of flares, three 'flare phenotypes' were distinguished: no flares (NF), transient flares (TF), and a mixed category reporting persistent joint complaints (PJC) in at least one year. Baseline and 2 year radiographs of hands and feet were evaluated according to the Sharp/van der Heijde method. Major outcomes were change from baseline in Total Sharp Score (DeltaTSS) and functional impairment, expressed by the Health Assessment Questionnaire (DeltaHAQ). Their association with flare phenotype was analysed by logistic regression. RESULTS: The study included 268 RA patients (70% female; 73% immunoglobulin M rheumatoid factor positive), with a median age (interquartile range) of 63 (55-70) years, and 7 (4 13) years' disease duration. Flares were recalled as NF (n = 77), TF (n = 141), and PJC (n = 50). DeltaTSS > 0 was observed in 35%, 37%, and 46%, respectively (p = 0.42), but statistically significantly (p = 0.01) more patients progressed in the TF (10%) and PJC (14%) compared to NF (0%), based on the smallest detectable change (> 4.4 DeltaTSS unit). DeltaHAQ above the minimal clinically important difference (> 0.22) was seen in 13% (NF), 21% (TF), and 40% (PJC) (p = 0.0015), with PJC being associated with statistically significant impairment in function (odds ratio 4.47, 95% confidence interval 1.87-10.69) compared to NF. CONCLUSION: In RA patients with low disease activity, the incidence of radiographic progression and functional impairment was higher in patients with flares and persistent complaints, compared to those without flares. PMID- 28841104 TI - Letter to the Editor. Utility of intravenous tranexamic acid in single-level posterior lumbar interbody fusions. PMID- 28841105 TI - T-1 pedicle subtraction osteotomy for the treatment of rigid cervical kyphotic deformity: report of 4 cases. AB - Cervical kyphotic deformity represents a difficult to treat pathology often arising from multiple factors including, but not limited to, traumatic injuries, degenerative changes, and ankylosing spondylitis. Furthermore, treatment of these deformities becomes increasingly difficult with any preexisting instrumentation. Currently, several options exist to treat these severe deformities, with the Smith-Petersen osteotomy and C-7 pedicle subtraction osteotomy being the most frequently used approaches. However, these techniques come with significant risk to the patient including nerve root injury as well as compression of the vertebral arteries. The authors here report on a series of 4 patients with rigid cervical deformity who underwent T-1 pedicle subtraction osteotomy. The authors review the relevant literature and provide a novel, less risky, and potentially more corrective approach for treating cervical deformities. PMID- 28841106 TI - A novel index for quantifying the risk of early complications for patients undergoing cervical spine surgeries. AB - OBJECTIVE It is becoming increasingly necessary for surgeons to provide evidence supporting cost-effectiveness of surgical treatment for cervical spine pathology. Anticipating surgical risk is critical in accurately evaluating the risk/benefit balance of such treatment. Determining the risk and cost-effectiveness of surgery, complications, revision procedures, and mortality rates are the most significant limitations. The purpose of this study was to determine independent risk factors for medical complications (MCs), surgical complications (SCs), revisions, and mortality rates following surgery for patients with cervical spine pathology. The most relevant risk factors were used to structure an index that will help quantify risk and anticipate failure for such procedures. METHODS The authors of this study performed a retrospective review of the National Inpatient Sample (NIS) database for patients treated surgically for cervical spine pathology between 2001 and 2010. Multivariate models were performed to calculate the odds ratio (OR) of the independent risk factors that led to MCs and repeated for SCs, revisions, and mortality. The models controlled for age (< and > 65 years old), sex, race, revision status (except for revision analysis), surgical approach, number of levels fused/re-fused (2-3, 4-8, >= 9), and osteotomy utilization. ORs were weighted based on their predictive category: 2 times for revision surgery predictors and 4 times for mortality predictors. Fifty points were distributed among the predictors based on their cumulative OR to establish a risk index. RESULTS Discharges for 362,989 patients with cervical spine pathology were identified. The mean age was 52.65 years, and 49.47% of patients were women. Independent risk factors included medical comorbidities, surgical parameters, and demographic factors. Medical comorbidities included the following: pulmonary circulation disorder, coagulopathy, metastatic cancer, renal failure, congestive heart failure, alcohol abuse, neurological disorder, nonmetastatic cancer, liver disease, rheumatoid arthritis/collagen vascular diseases, and chronic blood loss/anemia. Surgical parameters included posterior approach to fusion/re-fusion, >= 9 levels fused/re-fused, corpectomy, 4-8 levels fused/re-fused, and osteotomy; demographic variables included age >= 65 years. These factors increased the risk of at least 1 of MC, SC, revision, or mortality (risk of death). A total of 50 points were distributed among the factors based on the cumulative risk ratio of every factor in proportion to the total risk ratios. CONCLUSIONS This study proposed an index to quantify the potential risk of morbidity and mortality prior to surgical intervention for patients with cervical spine pathology. This index may be useful for surgeons in patient counseling efforts as well as for health insurance companies and future socioeconomics studies in assessing surgical risks and benefits for patients undergoing surgical treatment of the cervical spine. PMID- 28841107 TI - Editorial. Cervical kyphotic deformity. PMID- 28841108 TI - Editorial. "Horses for courses". PMID- 28841109 TI - One hundred consecutive endoscopic repairs of sagittal craniosynostosis: an evolution in care. AB - OBJECTIVE Endoscope-assisted repair of sagittal craniosynostosis was adopted at St. Louis Children's Hospital in 2006. This study examines the first 100 cases and reviews the outcomes and evolution of patient care protocols at our institution. METHODS The authors performed a retrospective chart review of the first 100 consecutive endoscopic repairs of sagittal craniosynostosis between 2006 and 2014. The data associated with length of hospital stay, blood loss, transfusion rates, operative times, cephalic indices (CIs), complications, and cranial remolding orthosis were reviewed. Measurements were taken from available preoperative and 1-year postoperative 3D reconstructed CT scans. RESULTS The patients' mean age at surgery was 3.3 +/- 1.1 months. Of the 100 patients, 30 were female and 70 were male. The following perioperative data were noted. The mean operative time (+/- SD) was 77.1 +/- 22.2 minutes, the mean estimated blood loss was 34.0 +/- 34.8 ml, and the mean length of stay was 1.1 +/- 0.4 days; 9% of patients required transfusions; and the mean pre- and postoperative CI values were 69.1 +/- 3.8 and 77.7 +/- 4.2, respectively. Conversion to open technique was required in 1 case due to presence of a large emissary vein that was difficult to control endoscopically. The mean duration of helmet therapy was 8.0 +/- 2.9 months. Parietal osteotomies were eventually excluded from the procedure. CONCLUSIONS The clinical outcomes and improvements in CI seen in our population are similar to those seen at other high-volume centers. Since the inception of endoscope-assisted repair at our institution, the patient care protocol has undergone several significant changes. We have been able to remove less cranium using our "narrow-vertex" suturectomy technique without affecting patient safety or outcome. Patient compliance with helmet therapy and collaborative care with the orthotists remain the most essential aspects of a successful outcome. PMID- 28841110 TI - Assessment of spring cranioplasty biomechanics in sagittal craniosynostosis patients. AB - OBJECTIVE Scaphocephaly secondary to sagittal craniosynostosis has been treated in recent years with spring-assisted cranioplasty, an innovative approach that leverages the use of metallic spring distractors to reshape the patient skull. In this study, a population of patients who had undergone spring cranioplasty for the correction of scaphocephaly at the Great Ormond Street Hospital for Children was retrospectively analyzed to systematically assess spring biomechanical performance and kinematics in relation to spring model, patient age, and outcomes over time. METHODS Data from 60 patients (49 males, mean age at surgery 5.2 +/- 0.9 months) who had received 2 springs for the treatment of isolated sagittal craniosynostosis were analyzed. The opening distance of the springs at the time of insertion and removal was retrieved from the surgical notes and, during the implantation period, from planar radiographs obtained at 1 day postoperatively and at the 3-week follow-up. The force exerted by the spring to the patient skull at each time point was derived after mechanical testing of each spring model-3 devices with the same geometry but different wire thicknesses. Changes in the cephalic index between preoperatively and the 3-week follow-up were recorded. RESULTS Stiffer springs were implanted in older patients (p < 0.05) to achieve the same opening on-table as in younger patients, but this entailed significantly different-higher-forces exerted on the skull when combinations of stiffer springs were used (p < 0.001). After initial force differences between spring models, however, the devices all plateaued. Indeed, regardless of patient age or spring model, after 10 days from insertion, all the devices were open. CONCLUSIONS Results in this study provide biomechanical insights into spring-assisted cranioplasty and could help to improve spring design and follow-up strategy in the future. PMID- 28841111 TI - Spinal drop metastasis from a benign fourth ventricular choroid plexus papilloma in a pediatric patient: case report. AB - Choroid plexus papillomas (CPPs) are typically benign tumors that can occur in any age group but are more commonly found in pediatric patients. Although these tumors are benign, there are several reports in adult patients of distant metastases present either at the time of diagnosis or occurring months to years after initial resection. Here, the authors report the case of a 14-year-old boy who presented with symptoms of elevated intracranial pressure due to obstructive hydrocephalus that was caused by a large fourth ventricular mass. Preoperative imaging included a full MRI of the spine, which revealed an intradural lesion that encased the distal sacral nerve roots at the tip of the thecal sac and was concerning for a drop metastasis. The patient underwent gross-total resection of both the fourth ventricular and sacral tumors with histology of both lesions consistent with benign CPP (WHO Grade I). In addition, the authors review prior reports of both pediatric and adult patients in whom benign CPPs have metastasized with either benign or atypical pathology found at a distant site. Taking into account this unusual case and reports in the literature, patients with even benign CPPs may warrant initial and routine follow-up imaging of the total neural axis in search of the rare, but possible, occurrence of drop metastasis. PMID- 28841113 TI - Pharmacoepigenomics of opiates and methadone maintenance treatment: current data and perspectives. AB - Current treatments of opioid addiction include primarily maintenance medications such as methadone. Chronic exposure to opiate and/or long-lasting maintenance treatment induce modulations of gene expression in brain and peripheral tissues. There is increasing evidence that epigenetic modifications underlie these modulations. This review summarizes published results on opioid-induced epigenetic changes in animal models and in patients. The epigenetic modifications observed with other drugs of abuse often used by opiate abusers are also outlined. Specific methadone maintenance treatment induced epigenetic modifications at different treatment stages may be combined with the ones resulting from patients' substance use history. Therefore, research comparing groups of addicts with similar history and substances use disorders but contrasting for well-characterized treatment phenotypes should be encouraged. PMID- 28841112 TI - Development and Validation of the ADAS Scale and Prediction of Attitudes Toward Affective-Sexual Diversity Among Spanish Secondary Students. AB - Violence against non-heterosexual adolescents in educational contexts remains a worrying reality, but no adequate attitudes toward affective-sexual diversity (AtASD) measure exists for Spanish adolescent students. We developed a 27-item scale including cognitive, affective, and behavioral aspects, which was completed by 696 secondary school students from the Madrid area. Factor analyses suggested a unidimensional model, Cronbach's alpha indicated excellent scale scores reliability, and item calibration under the item response theory framework showed that the scale is especially informative for homophobic attitudes. A hierarchical multiple regression analysis showed that variables traditionally related to AtASD (gender, age, religion, nationality, perceived parental/peer attitudes, direct contact with LGB people) also were so in our sample. Moreover, interest in sexuality topics and perceived center's efforts to provide AtASD education were related to better AtASD. Our scale was reliable and valid, and it may also prove useful in efforts to detect those students with homophobic attitudes and to guide interventions. PMID- 28841114 TI - Alterations in Grapevine Leaf Metabolism Occur Prior to Esca Apoplexy Appearance. AB - Esca disease is one of the major grapevine trunk diseases in Europe and the etiology is complex, since several inhabiting fungi are identified to be associated with this disease. Among the foliar symptom expressions, the apoplectic form may be distinguished and characterized by sudden dieback of shoots, leaf drop, and shriveling of grape clusters in a few days that can ultimately induce the plant death. To further understand this drastic event, we conducted transcriptomic and metabolomic analyses to characterize responses of leaves during the period preceding symptom appearance (20 and 7 days before foliar symptom expression) and at the day of apoplexy expression. Transcriptomic and metabolomic analyses provide signatures for the apoplectic leaves and most changes concerning the metabolism of carbohydrates, amino acids, and phenylpropanoids. In deciphering glutathione-S-transferase (GST), its preferential location in phloem, correlated with the upregulation of GST genes and a decrease of the glutathione level, offers further support to the putative role of glutathione during apoplexy expression. PMID- 28841115 TI - Cost of coils for intracranial aneurysms: clinical decision analysis for implementation of a capitation model. AB - OBJECTIVE The price of coils used for intracranial aneurysm embolization has continued to rise despite an increase in competition in the marketplace. Coils on the US market range in list price from $500 to $3000. The purpose of this study was to investigate potential cost savings with the use of a price capitation model. METHODS The authors built a clinical decision analytical tree and compared their institution's current expenditure on endovascular coils to the costs if a capped-price model were implemented. They retrospectively reviewed coil and cost data for 148 patients who underwent coil embolization from January 2015 through September 2016. Data on the length and number of coils used in all patients were collected and analyzed. The probabilities of a treated aneurysm being <=/> 10 mm in maximum dimension, the total number of coils used for a case being <=/> 5, and the total length of coils used for a case being <=/> 50 cm were calculated, as was the mean cost of the currently used coils for all possible combinations of events with these probabilities. Using the same probabilities, the authors calculated the expected value of the capped-price strategy in comparison with the current one. They also conducted multiple 1-way sensitivity analyses by applying plausible ranges to the probabilities and cost variables. The robustness of the results was confirmed by applying individual distributions to all studied variables and conducting probabilistic sensitivity analysis. RESULTS Ninety-five (64%) of 148 patients presented with a rupture, and 53 (36%) were treated on an elective basis. The mean aneurysm size was 6.7 mm. A total of 1061 coils were used from a total of 4 different providers. Companies A (72%) and B (16%) accounted for the major share of coil consumption. The mean number of coils per case was 7.3. The mean cost per case (for all coils) was $10,434. The median total length of coils used, for all coils, was 42 cm. The calculated probability of treating an aneurysm less than 10 mm in maximum dimension was 0.83, for using 5 coils or fewer per case it was 0.42, and for coil length of 50 cm or less it was 0.89. The expected cost per case with the capped policy was calculated to be $4000, a cost savings of $6564 in comparison with using the price of Company A. Multiple 1-way sensitivity analyses revealed that the capped policy was cost saving if its cost was less than $10,500. In probabilistic sensitivity analyses, the lowest cost difference between current and capped policies was $2750. CONCLUSIONS In comparison with the cost of coils from the authors' current provider, their decision model and probabilistic sensitivity analysis predicted a minimum $407,000 to a maximum $1,799,976 cost savings in 148 cases by adapting the capped-price policy for coils. PMID- 28841116 TI - Early imaging radioresponsiveness of melanoma brain metastases as a predictor of patient prognosis. AB - OBJECTIVE The aim of this study was to analyze the early radiological response of melanoma brain metastases to single high-dose irradiation and to reveal possible correlations between tumor radioresponsiveness and patient clinical outcomes. METHODS The authors performed a retrospective analysis of the medical data for all patients with melanoma brain metastases who had undergone Gamma Knife radiosurgery (GKRS) and follow-up MRI examinations with standard protocols at regular 2- to 3-month intervals. Volumetric measurements of the metastases on pretreatment and initial posttreatment images were performed to assess the rate of early radiological response. Patients were divided into 2 groups according to the rate of response, and overall survival, local control, and the appearance of new metastases in the brain were compared in these groups using the long-rank test. Univariate and multivariate analyses were performed to identify predictors of clinical outcomes. RESULTS After retrospective analysis of 298 melanoma brain metastases in 78 patients, the authors determined that early radiological responses of these metastases to GKRS differ considerably and can be divided into 2 distinct groups. One group of tumors underwent rapid shrinkage after radiosurgery, whereas the other showed minor fluctuations in size (rapid- and slow-response groups, respectively). Median survival for patients with a slow response was 15.2 months compared with 6.3 months for those with a rapid response (p < 0.0001). In the multivariate analysis, improved overall survival was associated with a slow response to radiosurgery (p < 0.0001), stable systemic disease (p = 0.001), and a higher Karnofsky Performance Scale score (p = 0.001). Stratification by Recursive Partitioning Analysis, score index for radiosurgery, and diagnosis-specific Graded Prognostic Assessment classes further confirmed the difference in overall survival for patients with a slow versus rapid radiation response. Local recurrence was observed in 11% of patients with a rapid response and in 6% of patients with a slow response, at a median of more than 8 months after radiosurgery. New brain metastases were diagnosed in 67% of patients with a slow response at a median of 8.6 months after radiosurgery and in 82% of patients with a rapid response at a considerably earlier median time of 2.7 months. In the multivariate analysis, a longer time to the development of new brain metastases was associated with a slow response (p = 0.012), stable systemic disease (p = 0.034), and a single brain metastasis (p = 0.030). CONCLUSIONS Melanoma brain metastases show different early radioresponsiveness to radiosurgery. Rapid shrinkage of brain metastases is associated with poor patient prognosis, which may indicate more aggressive biological behavior of this tumor phenotype. PMID- 28841117 TI - Transient resolution of venous sinus stenosis after high-volume lumbar puncture in a patient with idiopathic intracranial hypertension. AB - Stenosis of the transverse sinus (TS) and sigmoid sinus (SS), with a trans stenosis pressure gradient, has been implicated in the pathophysiology of idiopathic intracranial hypertension (IIH). MRI has shown improvement in TS and SS stenosis after high-volume lumbar puncture (HVLP) in a subset of patients with IIH. The authors present the first report of an IIH patient with immediate post HVLP TS and SS trans-stenosis pressure gradient reduction and an attendant increase in TS and SS cross-sectional area confirmed using intravascular ultrasonography (IVUS). Recurrence of the patient's TS-SS stenosis coincided with elevated HVLP opening pressure, and venous sinus stent placement resulted in clinical improvement. This report suggests that TS and SS stenosis may be a downstream effect of elevated intracranial pressure in IIH, rather than its principal etiological mechanism. However, the authors hypothesize that endovascular stenting may obliterate a positive feedback loop involving trans stenosis pressure gradients, and still benefit appropriately selected patients. PMID- 28841118 TI - Treatment of aneurysms in patients with moyamoya disease: a 10-year single-center experience. AB - OBJECTIVE Moyamoya disease (MMD) is occasionally accompanied by intracranial aneurysms. The purpose of this study was to delineate the efficacy of the authors' current surgical strategy in the management of MMD-associated aneurysms of different types. METHODS Between January 2007 and March 2016, a consecutive cohort of 34 patients with 36 MMD-associated aneurysms was enrolled in this prospective single-center cohort study. The lesions were classified as peripheral (17 aneurysms) or main trunk aneurysms (13 in the anterior circulation and 6 in the posterior circulation). For the peripheral aneurysms, revascularization with or without endovascular treatment was suggested. For the main trunk aneurysms, revascularization alone, revascularization with aneurysm clipping, or revascularization with aneurysm embolization were used, depending on the location of the aneurysms. RESULTS Of the peripheral aneurysms, 4 were treated endovascularly with staged revascularization, and 13 were treated solely with cerebral revascularization. Of the 13 main trunk aneurysms in the anterior circulation, 10 were clipped followed by revascularization, and 3 were coiled followed by staged cerebral revascularization. Of the 6 main trunk aneurysms in the posterior circulation, 4 underwent endovascular coiling and 2 were treated solely with revascularization. One patient died of contralateral intracerebral hemorrhage 6 months after the operation. No other patients suffered recurrent intracranial hemorrhage, cerebral ischemia, or aneurysm rupture. An angiographic follow-up study showed that all the bypass grafts were patent. Complete occlusion was achieved in all 21 aneurysms that were clipped or embolized. Of the remaining 15 aneurysms that were not directly treated, 12 of 13 peripheral aneurysms were obliterated during the follow-up, whereas 1 remained stable; 1 of 2 posterior main trunk aneurysms remained stable, and the other became smaller. CONCLUSIONS The authors' current treatment strategy may benefit patients with MMD-associated aneurysms. PMID- 28841119 TI - Predictive anatomical factors for rupture in middle cerebral artery mirror bifurcation aneurysms. AB - OBJECTIVE The aim of this study was to define predictive factors for rupture of middle cerebral artery (MCA) mirror bifurcation aneurysms. METHODS The authors retrospectively analyzed the data in patients with ruptured MCA bifurcation aneurysms with simultaneous presence of an unruptured MCA bifurcation mirror aneurysm treated in two neurosurgical centers. The following parameters were measured and analyzed with the statistical software R: neck, dome, and width of both MCA aneurysms-including neck/dome and width/neck ratios, shape of the aneurysms (regular vs irregular), inflow angle of both MCA aneurysms, and the diameters of the bilateral A1 and M1 segments and the frontal and temporal M2 trunks, as well as the bilateral diameter of the internal carotid artery (ICA). RESULTS The authors analyzed the data of 44 patients (15 male and 29 female, mean age 50.1 years). Starting from the usual significance level of 0.05, the Sidak corrected significance level is 0.0039. The diameter of the measured vessels was statistically not significant, nor was the inflow angle. The size of the dome was highly significant (p = 0.0000069). The size of the neck (p = 0.0047940) and the width of the aneurysms (p = 0.0056902) were slightly nonsignificant at the stated significance level of 0.0039. The shape of the aneurysms was bilaterally identical in 22 cases (50%). In cases of asymmetrical presentation of the aneurysm shape, 19 (86.4%) ruptured aneurysms were irregular and 3 (13.6%) had a regular shape (p = 0.001). CONCLUSIONS In this study the authors show that the extraaneurysmal flow dynamics in mirror aneurysms are nonsignificant, and the aneurysmal geometry also does not seem to play a role as a predictor for rupture. The only predictors for rupture were size and shape of the aneurysms. It seems as though under the same conditions, one of the two aneurysms suffers changes in its wall and starts growing in a more or less stochastic manner. Newer imaging methods should enable practitioners to see which aneurysm has an unstable wall, to predict the rupture risk. At the moment one can only conclude that in cases of MCA mirror aneurysms the larger one, with or without shape irregularities, is the unstable aneurysm and that this is the one that needs to be treated. PMID- 28841120 TI - Endoscopic extradural supraorbital approach to the temporal pole and adjacent area: technical note. AB - The authors' initial experience with the endoscopic extradural supraorbital approach to the temporal pole and adjacent area is reported. Fully endoscopic surgery using the extradural space via a supraorbital keyhole was performed for tumors in or around the temporal pole, including temporal pole cavernous angioma, sphenoid ridge meningioma, and cavernous sinus pituitary adenoma, mainly using 4 mm, 0 degrees and 30 degrees endoscopes and single-shaft instruments. After making a supraorbital keyhole, a 4-mm, 30 degrees endoscope was advanced into the extradural space of the anterior cranial fossa during lifting of the dura mater. Following identification of the sphenoid ridge, orbital roof, and anterior clinoid process, the bone lateral to the orbital roof was drilled off until the dura mater of the anterior aspect of the temporal lobe was exposed. The dura mater of the temporal lobe was incised and opened, exposing the temporal pole under a 4-mm, 0 degrees endoscope. Tumors in or around the temporal pole were safely removed under a superb view through the extradural corridor. The endoscopic extradural supraorbital approach was technically feasible and safe. The anterior trajectory to the temporal pole using the extradural space under endoscopy provided excellent visibility, allowing minimally invasive surgery. Further surgical experience and development of specialized instruments would promote this approach as an alternative surgical option. PMID- 28841121 TI - Elaborate mapping of the posterior visual pathway in awake craniotomy. AB - OBJECTIVE Resection of intraaxial tumors adjacent to the optic radiation (OR) may be associated with postoperative visual field (VF) deficits. Intraoperative navigation using MRI-based tractography and electrophysiological monitoring of the visual pathways may allow maximal resection while preserving visual function. In this study, the authors evaluated the value of visual pathway mapping in a series of patients undergoing awake craniotomy for tumor resection. METHODS A retrospective analysis of prospectively collected data was conducted in 18 patients who underwent an awake craniotomy for resection of intraaxial tumors involving or adjacent to the OR. Preoperative MRI-based tractography was used for intraoperative navigation, and intraoperative acquisition of 3D ultrasonography images was performed for real-time imaging and correction of brain shift. Goggles with light-emitting diodes were used as a standard visual stimulus. Direct cortical visual evoked potential (VEP) recording, subcortical recordings from the OR, and subcortical stimulation of the OR were used intraoperatively to assess visual function and proximity of the lesion to the OR. VFs were assessed pre- and postoperatively. RESULTS Baseline cortical VEP recordings were available for 14 patients (77.7%). No association was found between preoperative VF status and baseline presence of cortical VEPs (p = 0.27). Five of the 14 patients (35.7%) who underwent subcortical stimulation of the OR reported seeing phosphenes in the corresponding contralateral VF. There was a positive correlation (r = 0.899, p = 0.04) between the subcortical threshold stimulation intensity (3-11.5 mA) and the distance from the OR. Subcortical recordings from the OR demonstrated a typical VEP waveform in 10 of the 13 evaluated patients (76.9%). These waveforms were present only when recordings were obtained within 10 mm of the OR (p = 0.04). Seven patients (38.9%) had postoperative VF deterioration, and it was associated with a length of < 8 mm between the tumor and the OR (p = 0.05). CONCLUSIONS Intraoperative electrophysiological monitoring of the visual pathways is feasible but may be of limited value in preserving the functional integrity of the posterior visual pathways. Subcortical stimulation of the OR may identify the location of the OR when done in proximity to the pathways, but such proximity may be associated with increased risk of postoperative worsening of the VF deficit. PMID- 28841122 TI - Folate receptor overexpression can be visualized in real time during pituitary adenoma endoscopic transsphenoidal surgery with near-infrared imaging. AB - OBJECTIVE Pituitary adenomas account for approximately 10% of intracranial tumors and have an estimated prevalence of 15%-20% in the general US population. Resection is the primary treatment for pituitary adenomas, and the transsphenoidal approach remains the most common. The greatest challenge with pituitary adenomas is that 20% of patients develop tumor recurrence. Current approaches to reduce recurrence, such as intraoperative MRI, are costly, associated with high false-positive rates, and not recommended. Pituitary adenomas are known to overexpress folate receptor alpha (FRalpha), and it was hypothesized that OTL38, a folate analog conjugated to a near-infrared (NIR) fluorescent dye, could provide real-time intraoperative visual contrast of the tumor versus the surrounding nonneoplastic tissues. The preliminary results of this novel clinical trial are presented. METHODS Nineteen adult patients who presented with pituitary adenoma were enrolled. Patients were infused with OTL38 2-4 hours prior to surgery. A 4-mm endoscope with both visible and NIR light capabilities was used to visualize the pituitary adenoma and its margins in real time during surgery. The signal-to-background ratio (SBR) was recorded for each tumor and surrounding tissues at various endoscope-to-sella distances. Immunohistochemical analysis was performed to assess the FRalpha expression levels in all specimens and classify patients as having either high or low FRalpha expression. RESULTS Data from 15 patients (4 with null cell adenomas, 1 clinically silent gonadotroph, 1 totally silent somatotroph, 5 with a corticotroph, 3 with somatotrophs, and 1 somatocorticotroph) were analyzed in this preliminary analysis. Four patients were excluded for technical considerations. Intraoperative NIR imaging delineated the main tumors in all 15 patients with an average SBR of 1.9 +/- 0.70. The FRalpha expression level of the adenomas and endoscope-to-sella distance had statistically significant impacts on the fluorescent SBRs. Additional considerations included adenoma functional status and time from OTL38 injection. SBRs were 3.0 +/- 0.29 for tumors with high FRalpha expression (n = 3) and 1.6 +/- 0.43 for tumors with low FRalpha expression (n = 12; p < 0.05). In 3 patients with immunohistochemistry-confirmed FRalpha overexpression (2 patients with null cell adenoma and 1 patient with clinically silent gonadotroph), intraoperative NIR imaging demonstrated perfect classification of the tumor margins with 100% sensitivity and 100% specificity. In addition, for these 3 patients, intraoperative residual fluorescence predicted postoperative MRI results with perfect concordance. CONCLUSIONS Pituitary adenomas and their margins can be intraoperatively visualized with the preoperative injection of OTL38, a folate analog conjugated to NIR dye. Tumor-to background contrast is most pronounced in adenomas that overexpress FRalpha. Intraoperative SBR at the appropriate endoscope-to-sella distance can predict adenoma FRalpha expression status in real time. This work suggests that for adenomas with high FRalpha expression, it may be possible to identify margins and to predict postoperative MRI findings. PMID- 28841123 TI - Optic neuropathy after anterior communicating artery aneurysm clipping: 3 cases and techniques to address a correctable pitfall. AB - Brain shifts following microsurgical clip ligation of anterior communicating artery (ACoA) aneurysms can lead to mechanical compression of the optic nerve by the clip. Recognition of this condition and early repositioning of clips can lead to reversal of vision loss. The authors identified 3 patients with an afferent pupillary defect following microsurgical clipping of ACoA aneurysms. Different treatment options were used for each patient. All patients underwent reexploration, and the aneurysm clips were repositioned to prevent clip-related compression of the optic nerve. Near-complete restoration of vision was achieved at the last clinic follow-up visit in all 3 patients. Clip ligation of ACoA aneurysms has the potential to cause clip-related compression of the optic nerve. Postoperative visual examination is of utmost importance, and if any changes are discovered, reexploration should be considered as repositioning of the clips may lead to resolution of visual deterioration. PMID- 28841124 TI - The epitrigeminal approach to the brainstem. AB - OBJECTIVE Surgical approaches to the ventrolateral pons pose a significant challenge. In this report, the authors describe a safe entry zone to the brainstem located just above the trigeminal entry zone which they refer to as the "epitrigeminal entry zone." METHODS The approach is presented in the context of an illustrative case of a cavernous malformation and is compared with the other commonly described approaches to the ventrolateral pons. The anatomical nuances were analyzed in detail with the aid of surgical images and video, anatomical dissections, and high-definition fiber tractography (HDFT). In addition, using the HDFT maps obtained in 77 normal subjects (154 sides), the authors performed a detailed anatomical study of the surgically relevant distances between the trigeminal entry zone and the corticospinal tracts. RESULTS The patient treated with this approach had a complete resection of his cavernous malformation, and improvement of his symptoms. With regard to the HDFT anatomical study, the average direct distance of the corticospinal tracts from the trigeminal entry zone was 12.6 mm (range 8.7-17 mm). The average vertical distance was 3.6 mm (range -2.3 to 8.7 mm). The mean distances did not differ significantly from side to side, or across any of the groups studied (right-handed, left-handed, and ambidextrous). CONCLUSIONS The epitrigeminal entry zone to the brainstem appears to be safe and effective for treating intrinsic ventrolateral pontine pathological entities. A possible advantage of this approach is increased versatility in the rostrocaudal axis, providing access both above and below the trigeminal nerve. Familiarity with the subtemporal transtentorial approach, and the reliable surgical landmark of the trigeminal entry zone, should make this a straightforward approach. PMID- 28841125 TI - Spectroscopy applied to feed additives of the European Union Reference Laboratory: a valuable tool for traceability. AB - Feed additives need to be authorised to be placed on the market according to Regulation (EU) No. 1831/2003. Next to laying down the procedural requirements, the regulation creates the European Union Reference Laboratory for Feed Additives (EURL-FA) and requires that applicants send samples to the EURL-FA. Once authorised, the characteristics of the marketed feed additives should correspond to those deposited in the sample bank of the EURL-FA. For this purpose, the submitted samples were subjected to near-infrared (NIR) and Raman spectroscopy for spectral characterisation. These techniques have the valuable potential of characterising the feed additives in a non-destructive manner without any complicated sample preparation. This paper describes the capability of spectroscopy for a rapid characterisation of products to establish whether specific authorisation criteria are met. This study is based on the analysis of feed additive samples from different categories and functional groups, namely products containing (1) selenium, (2) zinc and manganese, (3) vitamins and (4) essential oils such as oregano and thyme oil. The use of chemometrics turned out to be crucial, especially in cases where the differentiation of spectra by visual inspection was very difficult. PMID- 28841126 TI - Percutaneous sclerotherapy for spongiform venous malformations - analysis of patient-evaluated outcome and satisfaction. AB - BACKGROUND: Congenital venous malformations are frequently treated with sclerotherapy. Primary treatment goal is to control the often size-related symptoms. Functional impairment and aesthetical aspects as well as satisfaction have rarely been evaluated. PATIENTS AND METHODS: Medical records of patients who underwent sclerotherapy of spongiform venous malformations were reviewed and included in this retrospective study. The outcome of sclerotherapy as self reported by patients was assessed in a 21 item questionnaire. RESULTS: Questionnaires were sent to 166 patients with a total of 327 procedures. Seventy seven patients (48 %) with a total of 159 procedures (50 %) responded to the survey. Fifty-seven percent of patients were male. The age ranged from 1 to 38.1 years with a median age of 16.4 years. The lower extremities were the most common treated area. Limitations caused by the venous malformation improved in the majority of patients (e.g. pain improvement 87 %, improvement of swelling 83 %) but also worsening of symptoms occurred in a minority of cases. Seventy-seven per cent would undergo sclerotherapy again. CONCLUSIONS: Sclerotherapy for treatment of venous malformations results in significant reduction of symptoms. Multiple treatments are often needed, but patients are willing to undergo them. PMID- 28841127 TI - New ways of seeing: Health social work leadership and research capacity building. AB - Building research capacity amongst social work practitioners is critically important for leaders in the social work profession. To reverse an apparent reluctance to use evidence and engage in research, strong social work leadership in practice organisations is needed. The literature on leadership in health social work is relatively silent regarding research capacity building as a leadership attribute but it is argued in this paper that leadership is crucial. A programme of research capacity building and its outcomes in a health social work department is described, identifying key principles guiding its establishment and tasks undertaken. A transformational leadership style characterised this approach to research capacity building which delivered benefits to the staff and the service. PMID- 28841128 TI - Discrete Effects of Religiosity and Spirituality on Gay Identity and Self-Esteem. AB - Previous research has indicated that although spirituality may bolster development of a positive gay identity, religiosity may prove detrimental. Because the majority of this research confounds these constructs, there is little evidence as to the discrete roles religiosity and spirituality may play in LGB identity development. The present study endeavored to tease apart the unique effects of religion and spirituality on positive and negative gay identity and self-esteem. A sample of 376 self-identified sexual minority adults were given measures of religiosity, spirituality, LGB identity, and self-esteem. Models were built to evaluate the effects of religiosity (independent of spirituality) and spirituality (independent of religiosity), understanding that the constructs are greatly overlapped, on identity and self-esteem. Results included a positive association between spirituality and identity affirmation, identity superiority, and self-esteem. Religiosity was negatively associated with identity affirmation and self-esteem and positively associated with internalized homonegativity and heteronormativity. Limitations and implications are discussed. PMID- 28841129 TI - Stem Cell Smart Technology, where are we now and how far we have to go? AB - Approximately eight million people in the United States have peripheral arterial disease, which increases exponentially with age. There have been a plethora of available treatments including surgery, angioplasty, atherectomy, laser technology, and cell-based therapies. Cell-based therapies were developed in the hope of translating laboratory-based technology into clinical successes. However, clinical results have been disappointing. Infusion or injection for stem cell therapy is still considered experimental and investigational, and major questions on safety and durability have arisen. In no option patients, how can they be treated safely and successfully? In this article, we review contemporary practice for cell therapy, its pitfalls and breakthroughs, and look at the future ahead. We introduce a novel smart system for minimally invasive delivery of cell therapies, which exemplifies the next generation of endovascular solutions to stem cell technology and promises safety, efficacy, and reliability. PMID- 28841130 TI - Outcomes of open and endovascular repair of inflammatory abdominal aortic aneurysms. AB - Objective Reports on inflammatory aortic abdominal aneurysm treatment are scarce. Traditionally, open surgery has been validated as the gold standard of treatment; however, high technical skills are required. Endovascular aortic repair has been suggested as a less invasive treatment by some authors offering good results. The purpose of our study was to report our experience and outcomes in the treatment of inflammatory aortic abdominal aneurysm using both approaches. Material and methods A retrospective review and data collection of all patients treated for inflammatory aortic abdominal aneurysm between 2000 and 2015 was done in one academic center. Diagnosis of inflammatory aortic abdominal aneurysm was based on preoperative CT-scan imaging. Type of treatment, postoperative and long-term morbidity and mortality are described. Abdominal compressive symptoms (hydronephrosis) severity and relief after treatment are described. Results Thirty-four patients with intact inflammatory aortic abdominal aneurysm were included. Twenty-nine (85.3%) patients were treated by open means and the remaining five (14.7%) with endovascular aortic repair. Nearly 90% were considered high-risk patients. Median follow-up was 46 months (range 24-112). The two groups were comparable, except for the age and preoperative hydronephrosis. There was no statistical significance in blood transfusion requirements, intensive care hospitalization, 30-day and long-term mortality between the two groups. Preoperative hydronephrosis was diagnosed in four (13.8%) patients in the open surgery group and three (60%) patients in the endovascular aortic repair group. Improvement of hydronephrosis was recognized in three out of the four patients in the open repair group and two out of the three in the endovascular aortic repair group. Renal function remained stable in both groups during follow up. Conclusions Open surgery remains a safe and valid option for the treatment of inflammatory aortic abdominal aneurysm. Although our study included a small number of patients with endovascular aortic repair treatment, results are promising. Further randomized controlled studies may be necessary to assess long term effectiveness of endovascular aortic repair treatment in this disease. PMID- 28841132 TI - Adenoids in paediatric chronic rhinosinusitis, deep neck space infections and optimising otowicks in otitis externa. PMID- 28841131 TI - A seven-year retrospective analysis of the clinicopathological and mycological manifestations of fungal rhinosinusitis in a single-centre tropical climate hospital. AB - OBJECTIVE: To evaluate the clinicopathological and mycological manifestations of fungal rhinosinusitis occurring in the Tengku Ampuan Rahimah Hospital, in Klang, Malaysia, which has a tropical climate. METHODS: Records of patients treated from 2009 to 2016 were analysed retrospectively. Data from the records were indexed based on age, gender, clinical presentations, symptom duration, clinical signs and mycological growth. RESULTS: Of 80 samples, 27 (33.75 per cent) had fungal growth. Sixteen patients were classified as having non-invasive fungal rhinosinusitis and 11 as having invasive fungal rhinosinusitis. The commonest clinical presentation was nasal polyposis in non-invasive fungal rhinosinusitis patients (p < 0.05) and ocular symptoms in invasive fungal rhinosinusitis patients (p < 0.05). The commonest organism was aspergillus sp. (p < 0.05) in non invasive fungal rhinosinusitis and mucorales in invasive fungal rhinosinusitis. CONCLUSION: There is an almost equal distribution of both invasive and non invasive fungal rhinosinusitis, as seen in some Asian countries. Invasive fungal rhinosinusitis, while slightly uncommon when compared to non-invasive fungal rhinosinusitis, is potentially life threatening, and may require early and extensive surgical debridement. The clinical presentation of nasal polyposis was often associated with non-invasive fungal rhinosinusitis, whereas ocular symptoms were more likely to be associated with invasive fungal rhinosinusitis. PMID- 28841133 TI - Transcription factor clusters regulate genes in eukaryotic cells. AB - Transcription is regulated through binding factors to gene promoters to activate or repress expression, however, the mechanisms by which factors find targets remain unclear. Using single-molecule fluorescence microscopy, we determined in vivo stoichiometry and spatiotemporal dynamics of a GFP tagged repressor, Mig1, from a paradigm signaling pathway of Saccharomyces cerevisiae. We find the repressor operates in clusters, which upon extracellular signal detection, translocate from the cytoplasm, bind to nuclear targets and turnover. Simulations of Mig1 configuration within a 3D yeast genome model combined with a promoter specific, fluorescent translation reporter confirmed clusters are the functional unit of gene regulation. In vitro and structural analysis on reconstituted Mig1 suggests that clusters are stabilized by depletion forces between intrinsically disordered sequences. We observed similar clusters of a co-regulatory activator from a different pathway, supporting a generalized cluster model for transcription factors that reduces promoter search times through intersegment transfer while stabilizing gene expression. PMID- 28841134 TI - Astrin-SKAP complex reconstitution reveals its kinetochore interaction with microtubule-bound Ndc80. AB - Chromosome segregation requires robust interactions between the macromolecular kinetochore structure and dynamic microtubule polymers. A key outstanding question is how kinetochore-microtubule attachments are modulated to ensure that bi-oriented attachments are selectively stabilized and maintained. The Astrin SKAP complex localizes preferentially to properly bi-oriented sister kinetochores, representing the final outer kinetochore component recruited prior to anaphase onset. Here, we reconstitute the 4-subunit Astrin-SKAP complex, including a novel MYCBP subunit. Our work demonstrates that the Astrin-SKAP complex contains separable kinetochore localization and microtubule binding domains. In addition, through cross-linking analysis in human cells and biochemical reconstitution, we show that the Astrin-SKAP complex binds synergistically to microtubules with the Ndc80 complex to form an integrated interface. We propose a model in which the Astrin-SKAP complex acts together with the Ndc80 complex to stabilize correctly formed kinetochore-microtubule interactions. PMID- 28841135 TI - Ubiquitination-dependent control of sexual differentiation in fission yeast. AB - In fission yeast, meiosis-specific transcripts are selectively eliminated during vegetative growth by the combined action of the YTH-family RNA-binding protein Mmi1 and the nuclear exosome. Upon nutritional starvation, the master regulator of meiosis Mei2 inactivates Mmi1, thereby allowing expression of the meiotic program. Here, we show that the E3 ubiquitin ligase subunit Not4/Mot2 of the evolutionarily conserved Ccr4-Not complex, which associates with Mmi1, promotes suppression of meiotic transcripts expression in mitotic cells. Our analyses suggest that Mot2 directs ubiquitination of Mei2 to preserve the activity of Mmi1 during vegetative growth. Importantly, Mot2 is not involved in the constitutive pathway of Mei2 turnover, but rather plays a regulatory role to limit its accumulation or inhibit its function. We propose that Mmi1 recruits the Ccr4-Not complex to counteract its own inhibitor Mei2, thereby locking the system in a stable state that ensures the repression of the meiotic program by Mmi1. PMID- 28841136 TI - Modulation of occluding junctions alters the hematopoietic niche to trigger immune activation. AB - Stem cells are regulated by signals from their microenvironment, or niche. During Drosophila hematopoiesis, a niche regulates prohemocytes to control hemocyte production. Immune challenges activate cell-signalling to initiate the cellular and innate immune response. Specifically, certain immune challenges stimulate the niche to produce signals that induce prohemocyte differentiation. However, the mechanisms that promote prohemocyte differentiation subsequent to immune challenges are poorly understood. Here we show that bacterial infection induces the cellular immune response by modulating occluding-junctions at the hematopoietic niche. Occluding-junctions form a permeability barrier that regulates the accessibility of prohemocytes to niche derived signals. The immune response triggered by infection causes barrier breakdown, altering the prohemocyte microenvironment to induce immune cell production. Moreover, genetically induced barrier ablation provides protection against infection by activating the immune response. Our results reveal a novel role for occluding junctions in regulating niche-hematopoietic progenitor signalling and link this mechanism to immune cell production following infection. PMID- 28841137 TI - Autoinhibition of ankyrin-B/G membrane target bindings by intrinsically disordered segments from the tail regions. AB - Ankyrins together with their spectrin partners are the master organizers of micron-scale membrane domains in diverse tissues. The 24 ankyrin (ANK) repeats of ankyrins bind to numerous membrane proteins, linking them to spectrin-based cytoskeletons at specific membrane microdomains. The accessibility of the target binding groove of ANK repeats must be regulated to achieve spatially defined functions of ankyrins/target complexes in different tissues, though little is known in this regard. Here we systemically investigated the autoinhibition mechanism of ankyrin-B/G by combined biochemical, biophysical and structural biology approaches. We discovered that the entire ANK repeats are inhibited by combinatorial and quasi-independent bindings of multiple disordered segments located in the ankyrin-B/G linkers and tails, suggesting a mechanistic basis for differential regulations of membrane target bindings by ankyrins. In addition to elucidating the autoinhibition mechanisms of ankyrins, our study may also shed light on regulations on target bindings by other long repeat-containing proteins. PMID- 28841139 TI - Sensitive optical bio-sensing of p-type WSe2 hybridized with fluorescent dye attached DNA by doping and de-doping effects. AB - Layered transition metal dichalcogenides, such as MoS2, WSe2 and WS2, are exciting two-dimensional (2D) materials because they possess tunable optical and electrical properties that depend on the number of layers. In this study, the nanoscale photoluminescence (PL) characteristics of the p-type WSe2 monolayer, and WSe2 layers hybridized with the fluorescent dye Cy3 attached to probe-DNA (Cy3/p-DNA), have been investigated as a function of the concentration of Cy3/DNA by using high-resolution laser confocal microscopy. With increasing concentration of Cy3/p-DNA, the measured PL intensity decreases and its peak is red-shifted, suggesting that the WSe2 layer has been p-type doped with Cy3/p-DNA. Then, the PL intensity of the WSe2/Cy3/p-DNA hybrid system increases and the peak is blue shifted through hybridization with relatively small amounts of target-DNA (t-DNA) (50-100 nM). This effect originates from charge and energy transfer from the Cy3/DNA to the WSe2. For t-DNA detection, our systems using p-type WSe2 have the merit in terms of the increase of PL intensity. The p-type WSe2 monolayers can be a promising nanoscale 2D material for sensitive optical bio-sensing based on the doping and de-doping responses to biomaterials. PMID- 28841140 TI - Chemical states of surface oxygen during CO oxidation on Pt(110) surface revealed by ambient pressure XPS. AB - The study of CO oxidation on Pt(110) surface is revisited using ambient pressure x-ray photoemission spectroscopy. When the surface temperature reaches the activation temperature for CO oxidation under elevated pressure condition, both the -phase of PtO2 oxide and chemisorbed oxygen are formed simultaneously on the surface. Due to exothermic nature of CO oxidation, the temperature of Pt surface increases as CO oxidation takes places. As the CO/O2 ratio increases, the production of CO2 increases continuously and the surface temperature also increases. Interestingly, during the mass transfer limiting regions, the amount of surface oxide changes little while the chemisorbed oxygen is being reduced. . PMID- 28841138 TI - Aneuploidy as a cause of impaired chromatin silencing and mating-type specification in budding yeast. AB - Aneuploidy and epigenetic alterations have long been associated with carcinogenesis, but it was unknown whether aneuploidy could disrupt the epigenetic states required for cellular differentiation. In this study, we found that ~3% of random aneuploid karyotypes in yeast disrupt the stable inheritance of silenced chromatin during cell proliferation. Karyotype analysis revealed that this phenotype was significantly correlated with gains of chromosomes III and X. Chromosome X disomy alone was sufficient to disrupt chromatin silencing and yeast mating-type identity as indicated by a lack of growth response to pheromone. The silencing defect was not limited to cryptic mating type loci and was associated with broad changes in histone modifications and chromatin localization of Sir2 histone deacetylase. The chromatin-silencing defect of disome X can be partially recapitulated by an extra copy of several genes on chromosome X. These results suggest that aneuploidy can directly cause epigenetic instability and disrupt cellular differentiation. PMID- 28841141 TI - Outcome of Cochlear Implantation in Prelingually Deafened Children According to Molecular Genetic Etiology. AB - OBJECTIVES: About 60% of Korean pediatric cochlear implantees could be genetically diagnosed (GD) and we previously reported that a substantial portion of undiagnosed cases by deafness gene panel sequencing were predicted to have a nongenetic or complex etiology. We aimed to compare the outcomes of cochlear implantation (CI) in GD and genetically undiagnosed (GUD) patients and attempted to determine CI outcomes according to etiology. DESIGN: Ninety-three pediatric cochlear implantees underwent molecular genetic testing. Fifty-seven patients carried pathogenic variants and 36 patients remained GUD after panel sequencing of 204 known or potential deafness genes (TRS-204). Among them, 55 cochlear implantees with reliable speech evaluation results with a follow-up of longer than 24 months were recruited. Longitudinal changes in the audiologic performance were compared between the GD (n = 31) and GUD (n = 24) groups. The GD group was subdivided into cochlear implantee with SLC26A4 mutations (group 1) and cochlear implantee with other genetic etiology (group 2), and the GUD group was subdivided into groups 3 and 4, that is, patients with or without inner ear anomaly, respectively. RESULTS: Group 1 related to SLC26A4 mutations had the highest categories of auditory perception scores among all groups pre- and postoperatively. Group 4 with inner ear anomaly had the lowest categories of auditory perception scores. At 24 months post-CI, the group 2 with another genetic etiology had significantly better outcomes than molecularly undiagnosed group 3, which had with the same condition as group 2 except that the candidate gene was not detected. This finding was recapitulated when we limited cases to those that underwent CI before 24 months of age to minimize age-related bias at implantation. Furthermore, on extending the follow-up to 36 months postoperatively, this tendency became more prominent. Additionally, our preliminary clinical data suggest a narrower sensitive window period for good CI outcomes for implantees with OTOF mutation rather than the GJB2 and other genes. CONCLUSIONS: Current molecular genetic testing including deafness panel sequencing helps to predict the 2-year follow-up outcomes after CI in prelingually deafened children. GD cochlear implantees show better functional outcomes after CI than undiagnosed cochlear implantees as determined by deafness panel sequencing, suggesting a genotype-functional outcome correlation. The genetic testing may provide a customized optimal window period in terms of CI timing for favorable outcome according to genetic etiology. PMID- 28841142 TI - Validation of a High Sampling Rate Inertial Measurement Unit for Acceleration During Running. AB - The musculo-skeletal response of athletes to various activities during training exercises has become a critical issue in order to optimize their performance and minimize injuries. However, dynamic and kinematic measures of an athlete's activity are generally limited by constraints in data collection and technology. Thus, the choice of reliable and accurate sensors is crucial for gathering data in indoor and outdoor conditions. The aim of this study is to validate the use of the accelerometer of a high sampling rate ( 1344 Hz ) Inertial Measurement Unit (IMU) in the frame of running activities. To this end, two validation protocols are imposed: a classical one on a shaker, followed by another one during running, the IMU being attached to a test subject. For each protocol, the response of the IMU Accelerometer (IMUA) is compared to a calibrated industrial accelerometer, considered as the gold standard for dynamic and kinematic data collection. The repeatability, impact of signal frequency and amplitude (on shaker) as well as the influence of speed (while running) are investigated. Results reveal that the IMUA exhibits good repeatability. Coefficient of Variation CV is 1 % 8.58 +/- 0.06 m / s 2 on the shaker and 3 % 26.65 +/- 0.69 m / s 2 while running. However, the shaker test shows that the IMUA is affected by the signal frequency (error exceeds 10 % beyond 80 Hz ), an observation confirmed by the running test. Nevertheless, the IMUA provides a reliable measure in the range 0-100 Hz, i.e., the most relevant part in the energy spectrum over the range 0-150 Hz during running. In our view, these findings emphasize the validity of IMUs for the measurement of acceleration during running. PMID- 28841144 TI - Radiation-Induced Attenuation of Perfluorinated Polymer Optical Fibers for Radiation Monitoring. AB - Due to some of their unique properties, optical fiber dosimeters are attractive and extensively researched devices in several radiation-related areas. This work evaluates the performance and potential of commercial perfluorinated polymer optical fibers (PF-POFs) for radiation monitoring applications. Gamma radiation induced attenuation (RIA) of two commercial PF-POFs is evaluated in the VIS spectral region. Influence of a dose rate and temperature on RIA measurement is investigated, along with defect stability and measurement repeatability. Co extruded PF-POFs are identified as more suitable for radiation monitoring applications due to lower dose-rate dependence. With co-extruded PF-POF, RIA measurement holds potential for highly-sensitive radiation monitoring with good reproducibility. The results show that operation in the blue part of the spectrum provides most favorable performance in terms of the largest nominal radiation sensitivity, lower temperature, and dose-rate dependence as well as higher defect stability. We demonstrate for the first time to our knowledge, that PF-POFs can be used for distributed detection of radiation with doses down to tens of Grays. The off-the-shelf, user-friendly PF-POF could be of interest as a cheap, disposable sensor for various applications, especially of a more qualitative nature. PMID- 28841143 TI - Extract of Sheng-Mai-San Ameliorates Myocardial Ischemia-Induced Heart Failure by Modulating Ca2+-Calcineurin-Mediated Drp1 Signaling Pathways. AB - Sheng-Mai-San (SMS) is a well-known traditional Chinese medicine (TCM) complex prescription used to treat heart failure (HF) and angina in clinic. However, its potential therapeutic mechanisms remain unclear. The present study evaluated the cardioprotection of extract of SMS (ESMS) on myocardial ischemia (MI)-induced HF, and explored the underlying molecular mechanisms. The results demonstrated that ESMS (728.0 mg/kg) significantly attenuated MI injury-induced HF by improving cardiac function and pathological changes, decreasing lactate dehydrogenase (LDH), creatine kinase (CK) activities, and brain natriuretic peptide (BNP) levels; increasing ATPase activity; and reducing intracellular Ca2+ levels in MI induced HF mice model. It also significantly decreased the apoptotic index. In vitro, ESMS (400 MUg/mL) inhibited mitochondrial-dependent myocardial apoptosis by modulating the expression of caspase-3 and the Bcl-2/Bax ratio, and improved mitochondrial function through increasing mitochondrial membrane potential and cellular ATP content. ESMS restored intracellular Ca2+ and downregulated the expression of Calcineurin A (CnA), thus inhibiting phosphorylation of dynamin related protein 1 (Drp1) at Ser616 and increasing phosphorylation of Drp1 at Ser637 to prevent cardiomyocyte mitochondrial fission. Above-mentioned results demonstrated ESMS suppressed mitochondrial-mediated apoptosis in oxygen glucose deprivation (OGD) injured H9c2 cardiomyocytes. These findings suggested that ESMS attenuated MI-induced HF by regulating Ca2+ homeostasis and suppressing mitochondrial mediated apoptosis through the modulation of Ca2+-calcineurin mediated Drp1 signaling pathways. Our results provide insight into the mechanism and clinical applications of SMS and suggest a potential therapeutic strategy for HF. PMID- 28841145 TI - Acceptor Side-Chain Effects on the Excited State Dynamics of Two-Dimensional-Like Conjugated Copolymers in Solution. AB - Excited state dynamics of two-dimensional-like conjugated copolymers PFDCN and PFSDCN based on alternating fluorene and triphenylamine main chains and malononitrile pendant acceptor groups with thiophene as pi-bridge, have been investigated by using transient absorption spectroscopy. There is an additional conjugated -C=C- bond in PFDCN, which distinguishes it from PFSDCN. The lowest energy absorption band of each copolymer absorption spectrum is attributed to the pi-pi* transition with intramolecular charge-transfer, which has a lower fluorescence contribution than those of higher energy absorption bands. The optical excitation of either PFDCN or PFSDCN solution generates polaron pairs that then self-localize and evolve to a bound singlet exciton within a few picoseconds. Due to the additional conjugated -C=C- bond in the acceptor side chain, PFDCN has a stronger intramolecular charge-transfer characteristic compared with PFSDCN, therefore exhibiting a longer self-localization time (7 ps vs. 3 ps for PFSDCN) and a shorter fluorescence lifetime (1.48 ns vs. 1.60 ns for PFSDCN). PMID- 28841146 TI - Differential Phononic Crystal Sensor: Towards a Temperature Compensation Mechanism for Field Applications Development. AB - Phononic crystals are resonant structures with great potential to be implemented in applications as liquid sensors. The use of the symmetry reduction technique allows introducing relevant transmission features inside bandgaps by creating defect modes in a periodic regular structure. These features can be used as measures to quantify changes in the speed of sound of liquid samples that could be related to the concentration of analytes or the presence of pathogens among other interesting applications. In order to be able to implement this new technology in more challenging applications, such as biomedical applications, it is necessary to have a very precise and accurate measurement. Changes in temperature greatly affect the speed of sound of the liquid samples, causing errors in the measurements. This article presents a phononic crystal sensor that, by introducing additional defect modes, can carry out differential measurements as a temperature compensation mechanism. Theoretical studies using the transmission line model and analytes at various temperatures show that the proposed temperature compensation mechanism enhances the performance of the sensor in a significant way. This temperature compensation strategy could also be implemented in crystals with different topologies. PMID- 28841147 TI - Importance of Endogenous Fibrinolysis in Platelet Thrombus Formation. AB - The processes of thrombosis and coagulation are finely regulated by endogenous fibrinolysis maintaining healthy equilibrium. When the balance is altered in favour of platelet activation and/or coagulation, or if endogenous fibrinolysis becomes less efficient, pathological thrombosis can occur. Arterial thrombosis remains a major cause of morbidity and mortality in the world despite advances in medical therapies. The role endogenous fibrinolysis in the pathogenesis of arterial thrombosis has gained increasing attention in recent years as it presents novel ways to prevent and treat existing diseases. In this review article, we discuss the role of endogenous fibrinolysis in platelet thrombus formation, methods of measurement of fibrinolytic activity, its role in predicting cardiovascular diseases and clinical outcomes and future directions. PMID- 28841148 TI - Targeting Tumor Adaption to Chronic Hypoxia: Implications for Drug Resistance, and How It Can Be Overcome. AB - The rapid and uncontrolled proliferation of tumors limits the availability of oxygen and nutrients supplied from the tumor vasculature, thus exposing them to low oxygen environments. Thus, diminished oxygen availability, or hypoxia, is the most common microenvironment feature of nearly all solid tumors. All living cells have the ability to sense changes in oxygen tension and adapt to this stress to preserve survival. Likewise, cancer cells adapt to chronic hypoxic stress via several mechanisms, including promotion of angiogenic factor production, metabolic shift to consume less oxygen, and reduction of apoptotic potential. Adaptation of tumor cells to hypoxia is believed to be the main driver for selection of more invasive and therapy-resistant cancer phenotypes. In this review, we discuss molecular mechanisms by which tumor cells adapt to hypoxia, with a specific focus on hypoxia-inducible factor (HIF) transcription factor. We further discuss the current understandings on hypoxia-mediated drug resistance and strategies to overcome it. PMID- 28841149 TI - Self-Nanoemulsifying Drug Delivery System for Resveratrol: Enhanced Oral Bioavailability and Reduced Physical Fatigue in Rats. AB - Resveratrol (RES), a natural polyphenolic compound, exerts anti-fatigue activity, but its administration is complicated by its low water solubility. To improve RES bioavailability, this study developed a self-nanoemulsifying drug delivery system (SNEDDS) for RES and evaluated its anti-fatigue activity and rat exercise performance by measuring fatigue-related parameters, namely lactate, ammonia, plasma creatinine phosphokinase, and glucose levels and the swimming time to exhaustion. Through solubility and emulsification testing, the optimized SNEDDS composed of Capryol 90, Cremophor EL, and Tween 20 was developed; the average particle size in this formulation, which had favorable self-emulsification ability, was approximately 41.3 +/- 4.1 nm. Pharmacokinetic studies revealed that the oral bioavailability of the optimized RES-SNEDDS increased by 3.2-fold compared with that of the unformulated RES-solution. Pretreatment using the RES SNEDDS before exercise accelerated the recovery of lactate after exercise; compared with the vehicle group, the plasma ammonia level in the RES-SNEDDS group significantly decreased by 65.4%, whereas the glucose level significantly increased by approximately 1.8-fold. Moreover, the swimming time to exhaustion increased by 2.1- and 1.8-fold, respectively, compared with the vehicle and RES solution pretreatment groups. Therefore, the developed RES-SNEDDS not only enhances the oral bioavailability of RES but may also exert anti-fatigue pharmacological effect. PMID- 28841150 TI - Negative Correlation between the Diffusion Coefficient and Transcriptional Activity of the Glucocorticoid Receptor. AB - The glucocorticoid receptor (GR) is a transcription factor, which interacts with DNA and other cofactors to regulate gene transcription. Binding to other partners in the cell nucleus alters the diffusion properties of GR. Raster image correlation spectroscopy (RICS) was applied to quantitatively characterize the diffusion properties of EGFP labeled human GR (EGFP-hGR) and its mutants in the cell nucleus. RICS is an image correlation technique that evaluates the spatial distribution of the diffusion coefficient as a diffusion map. Interestingly, we observed that the averaged diffusion coefficient of EGFP-hGR strongly and negatively correlated with its transcriptional activities in comparison to that of EGFP-hGR wild type and mutants with various transcriptional activities. This result suggests that the decreasing of the diffusion coefficient of hGR was reflected in the high-affinity binding to DNA. Moreover, the hyper phosphorylation of hGR can enhance the transcriptional activity by reduction of the interaction between the hGR and the nuclear corepressors. PMID- 28841152 TI - The Candida albicans Inhibitory Activity of the Extract from Papaya (Carica papaya L.) Seed Relates to Mitochondria Dysfunction. AB - The inhibitory activity of the papaya seed extract (PSE) on Candida albicans (C. albicans) was determined by turbidimetry method. The inhibitory mechanisms were also evaluated from the prospective of reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) decrease, and the activities of four complex enzymes in mitochondria respiratory chain. Results obtained from this study indicated that the PSE exhibited an effective inhibitory activity on C. albicans and induced significant accumulation of ROS and collapse of MMP. The Complex I and Complex III exhibited continues significant decrease in mitochondrial enzyme activity assays, but the Complex II and Complex IV activities were not positively correlated. Furthermore, the GC-MS analysis demonstrated that the PSE represents a rich and high-purity source of benzyl isothiocyanate (BITC), which indicated the BITC may be responsible for the mitochondrial dysfunction. PMID- 28841151 TI - CCR7 Sulfotyrosine Enhances CCL21 Binding. AB - Chemokines are secreted proteins that direct the migration of immune cells and are involved in numerous disease states. For example, CCL21 (CC chemokine ligand 21) and CCL19 (CC chemokine ligand 19) recruit antigen-presenting dendritic cells and naive T-cells to the lymph nodes and are thought to play a role in lymph node metastasis of CCR7 (CC chemokine receptor 7)-expressing cancer cells. For many chemokine receptors, N-terminal posttranslational modifications, particularly the sulfation of tyrosine residues, increases the affinity for chemokine ligands and may contribute to receptor ligand bias. Chemokine sulfotyrosine (sY) binding sites are also potential targets for drug development. In light of the structural similarity between sulfotyrosine and phosphotyrosine (pY), the interactions of CCL21 with peptide fragments of CCR7 containing tyrosine, pY, or sY were compared using protein NMR (nuclear magnetic resonance) spectroscopy in this study. Various N-terminal CCR7 peptides maintain binding site specificity with Y8-, pY8 , or sY8-containing peptides binding near the alpha-helix, while Y17-, pY17-, and sY17-containing peptides bind near the N-loop and beta3-stand of CCL21. All modified CCR7 peptides showed enhanced binding affinity to CCL21, with sY having the largest effect. PMID- 28841153 TI - Fabrication of Monodisperse Flower-Like Coordination Polymers (CP) Microparticles by Spray Technique. AB - In this manuscript, we have developed an efficient spraying method to successfully fabricate a series of flower-like coordination polymers (CP) microparticles, including Co/BDC (1,4-benzenedicarboxylate) metal organic frameworks (MOF) and infinite coordination polymers (ICP) microparticles, as well as Ni-Co/BDC MOF and Zn/DOBDC (2,5-dioxido-1,4-benzenedicarboxylate) MOF. The spraying method has shown high efficiency and universality in synthesizing the flower-like CP. The crystalline structure can be adjusted by varying the solvent composition in the spraying process. SEM observation demonstrated the MOF and ICP microparticles possess the similar flower-like structure, which is composed of nanoflakes with smooth surface, and the flower-like microparticles could be monodisperse with as low as 5% polydispersity. Moreover, the fabrication of the flower-like CP microparticles by spraying has a wide operation window, because there is no need to precisely control the experiment conditions, like solvents, concentration, and spray order. Due to the practicality of spray technique, this work would pave the way for the manufacture of the flower-like materials and have great potential in applications of catalysis, sensor, energy storage, and so on. PMID- 28841154 TI - Review of CMOS Integrated Circuit Technologies for High-Speed Photo-Detection. AB - The bandwidth requirement of wireline communications has increased exponentially because of the ever-increasing demand for data centers and high-performance computing systems. However, it becomes difficult to satisfy the requirement with legacy electrical links which suffer from frequency-dependent losses due to skin effects, dielectric losses, channel reflections, and crosstalk, resulting in a severe bandwidth limitation. In order to overcome this challenge, it is necessary to introduce optical communication technology, which has been mainly used for long-reach communications, such as long-haul networks and metropolitan area networks, to the medium- and short-reach communication systems. However, there still remain important issues to be resolved to facilitate the adoption of the optical technologies. The most critical challenges are the energy efficiency and the cost competitiveness as compared to the legacy copper-based electrical communications. One possible solution is silicon photonics which has long been investigated by a number of research groups. Despite inherent incompatibility of silicon with the photonic world, silicon photonics is promising and is the only solution that can leverage the mature complementary metal-oxide-semiconductor (CMOS) technologies. Silicon photonics can be utilized in not only wireline communications but also countless sensor applications. This paper introduces a brief review of silicon photonics first and subsequently describes the history, overview, and categorization of the CMOS IC technology for high-speed photo detection without enumerating the complex circuital expressions and terminologies. PMID- 28841155 TI - Wake-Up Receiver with Equal-Gain Antenna Diversity ?. AB - Small scale fading signals resulting from multipath propagation can cause signal strength variations in the range of several dB. Resulting from the fluctuating signal strengths, the wake-up packet reception rate can decrease significantly. Using antenna diversity can greatly mitigate these effects. This article presents a novel wireless sensor node with wake-up receiver that uses an equal-gain diversity method with two antennas in the wake-up path. Summation of the two diversity branch signals is done after the passive demodulation of the incoming signals. As a result, the wireless sensor node requires almost no additional active parts that would increase power consumption. Furthermore, we demonstrate experimentally the improved wake-up robustness and reliability achieved by this diversity technique in a multipath environment. PMID- 28841156 TI - Bacterial Contaminants of Poultry Meat: Sources, Species, and Dynamics. AB - With the constant increase in poultry meat consumption worldwide and the large variety of poultry meat products and consumer demand, ensuring the microbial safety of poultry carcasses and cuts is essential. In the present review, we address the bacterial contamination of poultry meat from the slaughtering steps to the use-by-date of the products. The different contamination sources are identified. The contaminants occurring in poultry meat cuts and their behavior toward sanitizing treatments or various storage conditions are discussed. A list of the main pathogenic bacteria of concern for the consumer and those responsible for spoilage and waste of poultry meat is established. PMID- 28841157 TI - Development and Properties of Valine-Alanine based Antibody-Drug Conjugates with Monomethyl Auristatin E as the Potent Payload. AB - Antibody-drug conjugates (ADCs), designed to selectively deliver cytotoxic agents to antigen-bearing cells, are poised to become an important class of cancer therapeutics. Human epithelial growth factor receptor (HER2) is considered an effective target for cancer treatment, and a HER2-targeting ADC has shown promising results. Most ADCs undergoing clinical evaluation contain linkers that have a lysosomal protease-cleavable dipeptide, of which the most common is valine citrulline (VC). However, valine-alanine (VA), another dipeptide comprising two human essential amino acids, has been used in next generation ADCs loading new toxins, but the druggable properties of ADCs loaded the most popular monomethyl auristatin E (MMAE) remain to be further explored. In this study, we generated VA based ADCs that connected MMAE to an anti-HER2 antibody. We studied the differences in the preparation process, in vitro stability, cathepsin B activity and in vitro cytotoxicity of VA-based ADC compared to the ADC of VC. VA had comparable performance to VC, which preliminarily displays its practicability. Additional efficacy and safety studies in a xenograft model indicate this novel ADC exerted potent anti-tumor activity and negligible toxicity. The results of this study show the application potential of VA-based ADC with MMAE as the payload. PMID- 28841160 TI - Experimental Study on Fatigue Behaviour of Shot-Peened Open-Hole Steel Plates. AB - This paper presents an experimental study on the fatigue behaviour of shot-peened open-hole plates with Q345 steel. The beneficial effects induced by shot peening on the fatigue life improvement are highlighted. The characteristic fatigue crack initiation and propagation modes of open-hole details under fatigue loading are revealed. The surface hardening effect brought by the shot peening is analyzed from the aspects of in-depth micro-hardness and compressive residual stress. The fatigue life results are evaluated and related design suggestions are made as a comparison with codified detail categories. In particular, a fracture mechanics theory-based method is proposed and demonstrated its validity in predicting the fatigue life of studied shot-peened open-hole details. PMID- 28841159 TI - Bisphenol A and Metabolic Diseases: Challenges for Occupational Medicine. AB - The prevalence of metabolic diseases has markedly increased worldwide during the last few decades. Lifestyle factors (physical activity, energy-dense diets), together with a genetic predisposition, are well known factors in the pathophysiology of health problems. Bisphenol A (BPA) is a chemical compound used for polycarbonate plastics, food containers, epoxy resins coating metallic cans for food and beverage conservation. The ability of BPA to act as an endocrine disruptor-xenoestrogen in particular-is largely documented in literature, with numerous publications of in vivo and in vitro studies as well as epidemiological data on humans. Recently, different researchers studied the involvement of BPA in the development of insulin resistance; evidences in this way showed a potential role in etiology of metabolic disease, both for children and for adults. We review the epidemiological literature in the relation between BPA exposure and the risk of metabolic diseases in adults, with a focus on occupational exposure. Considering published data and the role of occupational physicians in promoting Workers' Health, specific situations of exposure to BPA in workplace are described, and proposals for action to be taken are suggested. The comparison of the studies showed that exposure levels were higher in workers than in the general population, even if, sometimes, the measurement units used did not permit rapid comprehension. Nevertheless, occupational medicine focus on reproductive effects and not metabolic ones. PMID- 28841158 TI - Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. AB - Earlier research primarily attributed the effects of mesenchymal stem cell (MSC) therapies to their capacity for local engrafting and differentiating into multiple tissue types. However, recent studies have revealed that implanted cells do not survive for long, and that the benefits of MSC therapy could be due to the vast array of bioactive factors they produce, which play an important role in the regulation of key biologic processes. Secretome derivatives, such as conditioned media or exosomes, may present considerable advantages over cells for manufacturing, storage, handling, product shelf life and their potential as a ready-to-go biologic product. Nevertheless, regulatory requirements for manufacturing and quality control will be necessary to establish the safety and efficacy profile of these products. Among MSCs, human uterine cervical stem cells (hUCESCs) may be a good candidate for obtaining secretome-derived products. hUCESCs are obtained by Pap cervical smear, which is a less invasive and painful method than those used for obtaining other MSCs (for example, from bone marrow or adipose tissue). Moreover, due to easy isolation and a high proliferative rate, it is possible to obtain large amounts of hUCESCs or secretome-derived products for research and clinical use. PMID- 28841161 TI - Disease Modifying Effects of the Spider Toxin Parawixin2 in the Experimental Epilepsy Model. AB - (1) Background: Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. It is also the one with the highest percentage of drug-resistance to the current available anti-epileptic drugs (AED). Additionaly, most antiepileptic drugs are only able to control seizures in epileptogenesis, but do not decrease the hippocampal neurodegenerative process. TLE patients have a reduced population of interneuronal cells, which express Parvalbumin (PV) proteins. This reduction is directly linked to seizure frequency and severity in the chronic period of epilepsy. There is therefore a need to seek new therapies with a disease modifying profile, and with efficient antiepileptic and neuroprotective properties. Parawixin2, a compound isolated from the venom of the spider Parawixia bistriata, has been shown to inhibit GABA transporters (GAT) and to have acute anticonvulsant effects in rats. (2) Methods: In this work, we studied the effects of Parawixin2 and Tiagabine (an FDA- approved GAT inhibitor), and compared these effects in a TLE model. Rats were subjected to lithium-pilocarpine TLE model and the main features were evaluated over a chronic period including: (a) spontaneous recurrent seizures (SRS), (b) neuronal loss, and (c) PV cell density in different regions of the hippocampus (CA1, CA3, DG and Hilus). (3) Results: Parawixin2 treatment reduced SRS frequency whereas Tiagabine did not. We also found a significant reduction in neuronal loss in CA3 and in the hilus regions of the hippocampus, in animals treated with Parawixin2. Noteworthy, Parawixin2 significantly reversed PV cell loss observed particularly in DG layers. (4) Conclusions: Parawixin2 exerts a promising neuroprotective and anti epileptic effect and has potential as a novel agent in drug design. PMID- 28841162 TI - Dihydrochalcones and Diterpenoids from Pteris ensiformis and Their Bioactivities. AB - Two new dihydrochalcone enantiomers (+)-1 and (-)-1, along with eight known compounds 3-10, were obtained from Pteris ensiformis. The planar structures were determined on the basis of extensive 1D and 2DNMR and HRESIMS. The resolution of (+)-1 and (-)-1 was achieved by chiral HPLC analysis. The absolute configurations of (+)-1 and (-)-1 were established by the bulkiness rule using Rh2(O2CCF3)4 induced circular dichroism (ICD) method. Compounds (+)-1, (-)-1, 8, 9 and 10 exhibited the inhibitory assay of NO production in mouse macrophages stimulated by LPS, with IC50 values of 2.0, 2.5, 8.0, 9.5 and 5.6 MUM, respectively. Otherwise, compound 10 showed moderate cytotoxic activity against HCT-116, HepG-2 and BGC-823 cell lines with IC50 values of 3.0, 10.5 and 6.3 MUM, respectively. PMID- 28841164 TI - Dietary Cholesterol in the Elderly Chinese Population: An Analysis of CNHS 2010 2012. AB - Dietary cholesterol intake increased dramatically over the past two decades in the elderly Chinese population. However, the nationwide dietary cholesterol intake and its related factors seldom been investigated. Based on data from 16,594 participants aged 60 years or older (49.0% male, 54.8% urban residents) from the China National Nutrition and Health Survey (CNHS) 2010-2012, we aimed to describe the intake of cholesterol and major food contributions, as well as its association with serum cholesterol level and relationship with protein intake. Mean daily cholesterol intake for all participants was 217.4 mg, the mean cholesterol intakes in urban and rural areas were 264.0 mg and 168.8 mg, respectively. Cholesterol intake levels varied by age, gender, BMI and region (p < 0.001). In addition, the proportion of all participants who consumed greater than 300 mg of cholesterol per day was 26.6%. Eggs, red meats, and seafood were the top three food sources and their contributions to total daily cholesterol intake were 57.7%, 24.0% and 10.9% respectively. Serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) were related to dietary cholesterol intake, with each 100 mg increase in dietary cholesterol intake apparently leading to a 0.035 mmol/L (p = 0.001) increase in serum TC and a 0.038 mmol/L (p < 0.001) increase in LDL-C. The partial correlation coefficients between dietary cholesterol and total protein, high-quality protein, intake of protein per kilogram body weight (BW), and high-quality protein percentage were 0.538, 0.580, 0.426, and 0.548, respectively, after adjusting for age, gender, and energy, fat and carbohydrate intakes (p < 0.001). In conclusion, there was a substantial urban-rural difference in cholesterol intake. Eggs and red meat were the main sources of dietary cholesterol intake. Serum TC and LDL-C were associated with dietary cholesterol and the response was linear. Dietary cholesterol intake was closely related to the intake of high-quality protein. PMID- 28841165 TI - A Research Communication Brief: Gluten Analysis in Beef Samples Collected Using a Rigorous, Nationally Representative Sampling Protocol Confirms That Grain Finished Beef Is Naturally Gluten-Free. AB - Knowing whether or not a food contains gluten is vital for the growing number of individuals with celiac disease and non-celiac gluten sensitivity. Questions have recently been raised about whether beef from conventionally-raised, grain finished cattle may contain gluten. To date, basic principles of ruminant digestion have been cited in support of the prevailing expert opinion that beef is inherently gluten-free. For this study, gluten analysis was conducted in beef samples collected using a rigorous nationally representative sampling protocol to determine whether gluten was present. The findings of our research uphold the understanding of the principles of gluten digestion in beef cattle and corroborate recommendations that recognize beef as a naturally gluten-free food. PMID- 28841163 TI - Potential Diagnostic and Therapeutic Applications of Oligonucleotide Aptamers in Breast Cancer. AB - Breast cancer is one of the most common causes of cancer related deaths in women. Currently, with the development of early detection, increased social awareness and kinds of treatment options, survival rate has improved in nearly every type of breast cancer patients. However, about one third patients still have increased chances of recurrence within five years and the five-year relative survival rate in patients with metastasis is less than 30%. Breast cancer contains multiple subtypes. Each subtype could cause distinct clinical outcomes and systemic interventions. Thereby, new targeted therapies are of particular importance to solve this major clinical problem. Aptamers, often termed "chemical antibodies", are functionally similar to antibodies and have demonstrated their superiority of recognizing target with high selectivity, affinity and stability. With these intrinsic properties, aptamers have been widely studied in cancer biology and some are in clinical trials. In this review, we will firstly discuss about the global impacts and mechanisms of breast cancer, then briefly highlight applications of aptamers that have been developed for breast cancer and finally summarize various challenges in clinical translation of aptamers. PMID- 28841166 TI - Life's Late Digital Revolution and Why It Matters for the Study of the Origins of Life. AB - The information contained in life exists in two forms, analog and digital. Analog information is manifest mainly in the differing concentrations of chemicals that get passed from generation to generation and can vary from cell to cell. Digital information is encoded in linear polymers such as DNA and RNA, whose side chains come in discrete chemical forms. Here, we argue that the analog form of information preceded the digital. Acceptance of this dichotomy, and this progression, can help direct future studies on how life originated and initially complexified on the primordial Earth, as well as expected trajectories for other, independent origins of complex life. PMID- 28841167 TI - 18F-FDG PET/CT Findings in a Patient with Chikungunya Virus Infection. AB - We present a case demonstrating the diagnostic work-up and follow-up of a patient with Chikungunya infection. An 18F-FDG PET/CT performed four weeks after debut of symptoms revealed pathological 18F-FDG uptake in enlarged lymph nodes on both side of the diaphragm, and inflammation of both shoulder and hip joints. Lymphoma and infection were the main differential diagnoses. Follow-up 18F-FDG PET/CT scan in the patient performed 14 weeks after the abnormal scan, revealed almost complete resolution of the metabolically active disease. This case is to our knowledge the first to demonstrate sequential 18F-FDG PET/CT scan results in a patient with Chikungunya virus infection. PMID- 28841168 TI - Slot Antenna Integrated Re-Entrant Resonator Based Wireless Pressure Sensor for High-Temperature Applications. AB - The highly sensitive pressure sensor presented in this paper aims at wireless passive sensing in a high temperature environment by using microwave backscattering technology. The structure of the re-entrant resonator was analyzed and optimized using theoretical calculation, software simulation, and its equivalent lump circuit model was first modified by us. Micro-machining and high temperature co-fired ceramic (HTCC) process technologies were applied to fabricate the sensor, solving the common problem of cavity sealing during the air pressure loading test. In addition, to prevent the response signal from being immersed in the strong background clutter of the hermetic metal chamber, which makes its detection difficult, we proposed two key techniques to improve the signal to noise ratio: the suppression of strong background clutter and the detection of the weak backscattered signal of the sensor. The pressure sensor demonstrated in this paper works well for gas pressure loading between 40 and 120 kPa in a temperature range of 24 degrees C to 800 degrees C. The experimental results show that the sensor resonant frequency lies at 2.1065 GHz, with a maximum pressure sensitivity of 73.125 kHz/kPa. PMID- 28841169 TI - Phytostabilization-Management Strategy for Stabilizing Trace Elements in Contaminated Soils. AB - Contamination of soil by copper (Cu) has become a serious problem throughout the world, causing the reduction of agricultural yield and harmful effects on human health by entering the food chain. A glasshouse pot experiment was designed to evaluate the potential use of halloysite as an immobilizing agent in the aided phytostabilization of Cu-contaminated soil, using Festuca rubra L. The content of Cu in plants, i.e., total and extracted by 0.01 M CaCl2, was determined using the method of spectrophotometry. Cu content in the tested parts of F. rubra differed significantly when halloysite was applied to the soil, as well as with increasing concentrations of Cu. The addition of halloysite significantly increased plant biomass. Cu accumulated in the roots, thereby reducing its toxicity to the aerial parts of the plant. The obtained values of bioconcentration and translocation factors observed for halloysite treatment indicate the effectiveness of using F. rubra in phytostabilization techniques. PMID- 28841170 TI - Contaminations, Sources, and Health Risks of Trace Metal(loid)s in Street Dust of a Small City Impacted by Artisanal Zn Smelting Activities. AB - To investigate the impact of artisanal zinc smelting activities (AZSA) on the distribution and enrichment of trace metal(loid)s in street dust of a small city in Guizhou province, SW China, street dust samples were collected and analyzed for 10 trace metal(loid)s (Cr, Co, Ni, Cu, Zn, As, Cd, Sb, Pb, and Hg). Meanwhile, the health risks of local resident exposed to street dust were assessed. The result showed that the average concentrations of 10 elements were Zn (1039 mg kg-1), Pb (423 mg kg-1), Cr (119 mg kg-1), Cu (99 mg kg-1), As (55 mg kg-1), Ni (39 mg kg-1), Co (18 mg kg-1), Sb (7.6 mg kg-1), Cd (2.6 mg kg-1), and Hg (0.22 mg kg-1). Except Ni, Co, and Cr, other elements in street dust were obviously elevated compared to the provincial soil background. Pb, Zn, Cd, Sb, and Cu were at heavy to moderate contamination status, especially Pb and Zn, with maximums of 1723 and 708 mg kg-1, respectively; As and Hg were slightly contaminated; while Cr, Ni, and Co were at un-contaminated levels. Multivariate statistical analysis revealed AZSA contributed to the increase of Pb, Zn, Cd, Sb, As, and Hg, while, natural sources introduced Ni, Co, Cr, and Cu. The health risk assessment disclosed that children had higher non-carcinogenic risk than those found in adults, and As has hazardous index (HI) higher than 1 both for children and adults, while Pb and Cr only had HIs higher than 1 for children, other elements were relatively safe. For carcinogenic risks, the major concern was As, then a lesser concern for Cr. The study showed that although the scale of AZSA was small, the contamination of heavy metal(loid)s in street dust and associated health risks were severe. PMID- 28841171 TI - The Red Algae Compound 3-Bromo-4,5-dihydroxybenzaldehyde Protects Human Keratinocytes on Oxidative Stress-Related Molecules and Pathways Activated by UVB Irradiation. AB - Skin exposure to ultraviolet B (UVB) irradiation leads to the generation of reactive oxygen species (ROS). Excessive ROS cause aging of the skin via basement membrane/extracellular matrix degradation by matrix metalloproteinases (MMPs). We recently demonstrated that 3-bromo-4,5-dihydroxybenzaldehyde (BDB), a natural compound of red algae, had a photo-protective effect against UVB-induced oxidative stress in human keratinocytes. The present study focused on the effect of BDB on UVB-irradiated photo-aging in HaCaT keratinocytes and the underlying mechanism. BDB significantly impeded MMP-1 activation and expression, and abrogated the activation of mitogen-activated protein kinases and intracellular Ca2+ level in UVB-irradiated HaCaT cells. Moreover, BDB decreased the expression levels of c-Fos and phospho-c-Jun and the binding of activator protein-1 to the MMP-1 promoter induced by UVB irradiation. These results offer evidence that BDB is potentially useful for the prevention of UVB-irradiated skin damage. PMID- 28841172 TI - Zytoprotektion mit Amifostin (Ethyol(r)) in der Chemotherapie: Meta-Analyse zum pharmakokinetischen Interaktionspotential mit Zytostatika. AB - The cytoprotective agent amifostine (AMI) is capable to protect healthy cells (contrary to tumor cells) due to higher activity of alkaline phosphatase at the membrane site of normal cells. In seven clinical trials the influence of AMI on the pharmacokinetics of different cytostatics was investigated. Preadministration of AMI increased Cmax of doxorubicin (+ 44 %, p < 0.06), epirubicin (+ 31 %, P < 0.08), mitomycin C (+ 41 %, p < 0.01) and docetaxel (+ 31 % and + 17 %, not significant). In contrary, the peak concentration of pirarubicin , the tetrahydropyranyl-prodrug of doxorubicin was decreased (- 50 %, P < 0.03), leading to an equal higher concentrationof doxorubicin in the blood . In accordance to the peak concentrations, the AUC'ast was increased by chemoprotection: doxorubicin + 53 % (p < 0.01) and epirubicin + 23 % (not significant), docetaxel + 25 % and + 31 % (not significant). AUC'ast of mitomycin C and paclitaxel seemed to be unaffected by preadministered AMI. A particular inhibition of the protein binding by AMI has been identified as one reason for higher serum concentrations of anthracycline drugs. After cytoprotection, a possible increase of the cytostatic's Serum concentrations should be taken into account for optimal dosage schedules. PMID- 28841175 TI - UV-Writing of a Superstructure Waveguide Bragg Grating in a Planar Polymer Substrate. AB - We report on the fabrication of a superstructure Bragg grating in a planar polymer substrate. Based on a twofold illumination process an integrated waveguide and a superstructure Bragg grating are subsequently written into bulk polymethylmethacrylate by UV-induced refractive index modification. The measured reflected spectrum of the superstructure Bragg grating exhibits multiple reflection peaks and is in good agreement with performed standard simulations based on the beam propagation method and coupled mode theory algorithms. By applying a varying tensile load we determine the strain sensitivity to be about 1.10 pm/uepsilon and demonstrate the applicability of the superstructure Bragg grating for strain measurements with redundant sensing signals. PMID- 28841174 TI - Purification, Preliminary Characterization and Hepatoprotective Effects of Polysaccharides from Dandelion Root. AB - In this study, purification, preliminary characterization and hepatoprotective effects of water-soluble polysaccharides from dandelion root (DRP) were investigated. Two polysaccharides, DRP1 and DRP2, were isolated from DRP. The two polysaccharides were alpha-type polysaccharides and didn't contain protein. DRP1, with a molecular weight of 5695 Da, was composed of glucose, galactose and arabinose, whereas DRP2, with molecular weight of 8882 Da, was composed of rhamnose, galacturonic acid, glucose, galactose and arabinose. The backbone of DRP1 was mainly composed of (1->6)-linked-alpha-d-Glc and (1->3,4)-linked-alpha-d Glc. DRP2 was mainly composed of (1->)-linked-alpha-d-Ara and (1->)-linked-alpha d-Glc. A proof-of-concept study was performed to assess the therapeutic potential of DRP1 and DRP2 in a mouse model that mimics acetaminophen (APAP) -induced liver injury (AILI) in humans. The present study shows DRP1 and DRP2 could protect the liver from APAP-induced hepatic injury by activating the Nrf2-Keap1 pathway. These conclusions demonstrate that the DRP1 and DRP2 might be suitable as functional foods and natural drugs in preventing APAP-induced liver injury. PMID- 28841173 TI - Sigma Receptor (sigmaR) Ligands with Antiproliferative and Anticancer Activity. AB - Sigma receptor (sigmaR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various sigmaR ligands generate cancer cell death in vitro and in vivo. These sigmaR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy. PMID- 28841176 TI - Relationships between Safe Pesticide Practice and Perceived Benefits and Subjective Norm, and the Moderation Role of Information Acquisition: Evidence from 971 Farmers in China. AB - Improper use of pesticides among farmers has caused food safety issues which are serious threats to public health in China. A central question concerns how to motivate farmers to self-regulate their pesticide usage. The paper aims to identify the influence of an internal driving factor, i.e., perceived benefits, and an external driving factor, i.e., subjective norm, on farmers' safe pesticide behaviors, and whether the two factors are moderated by the exposure to information on government policies and the market, based on a sample of 971 farmers selected from 5 Chinese provinces. The results revealed that farmers' safe pesticide usage was predominately driven by perceived benefits whereas external pressure or subjective norm did not play much of a role. Interaction effects were found between the exposure to market information and perceived benefits, and also between subjective norm and exposure to government policy. Extensions agencies are recommended to effectively convey to farmers the benefits to follow safe pesticide practices. Meanwhile, surveillance and monitoring systems should be established so that the prices of their agricultural products are reflected by the quality of the products. PMID- 28841177 TI - Enantiomeric-Enriched Ferrocenes: Synthesis, Chiral Resolution, and Mathematic Evaluation of CD-chiral Selector Energies with Ferrocene-Conjugates. AB - Enantiomeric-enriched ferrocene-modified pyrazoles were synthesized via the reaction of the ferrocene alcohol, (S)-FcCH(OH)CH3 (Fc = ferrocenyl), with various pyrazoles in acidic conditions at room temperature within several minutes. X-ray structural data for racemic (R,S)-1N-(3,5-dimethyl pyrazolyl)ethyl ferrocene (1) and its (S)-enantiomer (S)-1 were determined. A series of racemic pyrazolylalkyl ferrocenes was separated into enantiomers by analytical HPLC on beta- and gamma-cyclodextrins (CD) chiral stationary phases. The quantum chemical calculations of interaction energies of beta-CD were carried out for both (R)- and (S)-enantiomers. A high correlation between experimental HPLC data and calculated interaction energies values was obtained. PMID- 28841178 TI - Biosynthesis of Silver Nanoparticles on Orthodontic Elastomeric Modules: Evaluation of Mechanical and Antibacterial Properties. AB - In the present study, silver nanoparticles (AgNPs) were synthesized in situ on orthodontic elastomeric modules (OEM) using silver nitrate salts as metal-ion precursors and extract of the plant Hetheroteca inuloides (H. inuloides) as bioreductant via a simple and eco-friendly method. The synthesized AgNPs were characterized by UV-visible spectroscopy; scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and transmission electron microscopy (TEM). The surface plasmon resonance peak found at 472 nm confirmed the formation of AgNPs. SEM and TEM images reveal that the particles are quasi-spherical. The EDS analysis of the AgNPs confirmed the presence of elemental silver. The antibacterial properties of OEM with AgNPs were evaluated against the clinical isolates Streptococcus mutans, Lactobacillus casei, Staphylococcus aureus and Escherichia coli using agar diffusion tests. The physical properties were evaluated by a universal testing machine. OEM with AgNPs had shown inhibition halos for all microorganisms in comparison with OEM control. Physical properties increased with respect to the control group. The results suggest the potential of the material to combat dental biofilm and in turn decrease the incidence of demineralization in dental enamel, ensuring their performance in patients with orthodontic treatment. PMID- 28841179 TI - Investigations of Pro- and Anti-Apoptotic Factors Affecting African Swine Fever Virus Replication and Pathogenesis. AB - African swine fever virus (ASFV) is a large DNA virus that replicates predominantly in the cell cytoplasm and is the only member of the Asfarviridae family. The virus causes an acute haemorrhagic fever, African swine fever (ASF), in domestic pigs and wild boar resulting in the death of most infected animals. Apoptosis is induced at an early stage during virus entry or uncoating. However, ASFV encodes anti-apoptotic proteins which facilitate production of progeny virions. These anti-apoptotic proteins include A179L, a Bcl-2 family member; A224L, an inhibitor of apoptosis proteins (IAP) family member; EP153R a C-type lectin; and DP71L. The latter acts by inhibiting activation of the stress activated pro-apoptotic pathways pro-apoptotic pathways. The mechanisms by which these proteins act is summarised. ASF disease is characterised by massive apoptosis of uninfected lymphocytes which reduces the effectiveness of the immune response, contributing to virus pathogenesis. Mechanisms by which this apoptosis is induced are discussed. PMID- 28841180 TI - Radiolabeled Dendrimers for Nuclear Medicine Applications. AB - Recent advances in nuclear medicine have explored nanoscale carriers for targeted delivery of various radionuclides in specific manners to improve the effect of diagnosis and therapy of diseases. Due to the unique molecular architecture allowing facile attachment of targeting ligands and radionuclides, dendrimers provide versatile platforms in this filed to build abundant multifunctional radiolabeled nanoparticles for nuclear medicine applications. This review gives special focus to recent advances in dendrimer-based nuclear medicine agents for the imaging and treatment of cancer, cardiovascular and other diseases. Radiolabeling strategies for different radionuclides and several challenges involved in clinical translation of radiolabeled dendrimers are extensively discussed. PMID- 28841182 TI - Reduced Enterotoxin D Formation on Boiled Ham in Staphylococcus Aureus Deltaagr Mutant. AB - Staphylococcal food poisoning (SFP) is a common cause of foodborne illness worldwide, and enterotoxin D (SED) is one of the most frequent Staphylococcus aureus enterotoxins associated with it. It has been reported that the expression and formation of SED in S. aureus is regulated by the quorum sensing Agr system. In this study, the effect of agr deletion on sed expression in S. aureus grown on boiled ham was investigated. Growth, sed mRNA and SED protein levels in an S. aureus wild type strain and its isogenic Deltaagr mutant were monitored for 14 days at 22 degrees C. The results showed that although deletion of the agr gene did not affect the growth rate or maximum cell density of S. aureus on boiled ham, it had a pronounced effect on SED formation during the first 5 days of incubation. The SED concentration was not reflected in the amount of preceding sed transcripts, suggesting that sed transcription levels may not always reflect SED formation. The expression of RNAIII transcript, the regulatory signal of the Agr system, was also monitored. Similar transcription patterns were observed for RNAIII and sed. Surprisingly, in the Deltaagr mutant, sed expression was comparable to that in the wild type strain, and was thus unaffected by deletion of the Agr system. These results demonstrate that the Agr system appears to only partially affect SED formation, even in a real food environment. PMID- 28841181 TI - The Role of Kinase Modulators in Cellular Senescence for Use in Cancer Treatment. AB - Recently, more than 30 small molecules and eight monoclonal antibodies that modulate kinase signaling have been approved for the treatment of several pathological conditions, including cancer, idiopathic pulmonary fibrosis, and rheumatoid arthritis. Among them, kinase modulators have been a primary focus for use in cancer treatment. Cellular senescence is believed to protect cells from tumorigenesis by irreversibly halting cell cycle progression and avoiding the growth of damaged cells and tissues. Senescence can also contribute to tumor suppression and be utilized as a mechanism by anti-cancer agents. Although the role of kinase modulators in cancer treatment and their effects on senescence in tumor development have been extensively studied, the relationship between kinase modulators for cancer treatment and senescence has not been fully discussed. In this review, we discuss the pro- and anti-tumorigenesis functions of senescence and summarize the key roles of kinase modulators in the regulation of senescence against tumors. PMID- 28841183 TI - Preparation of Luminescent Metal-Organic Framework Films by Soft-Imprinting for 2,4-Dinitrotoluene Sensing. AB - A novel technique for the creation of metal-organic framework (MOF) films based on soft-imprinting and their use as gas sensors was developed. The microporous MOF material [Zn2(bpdc)2(bpee)] (bpdc = 4,4'-biphenyldicarboxylate; bpee = 1,2 bipyridylethene) was synthesized solvothermally and activated by removing the occluded solvent molecules from its inner channels. MOF particles were characterized by powder X-ray diffraction and fluorescence spectroscopy, showing high crystallinity and intense photoluminescence. Scanning electron microscope images revealed that MOF crystals were mainly in the form of microneedles with a high surface-to-volume ratio, which together with the high porosity of the material enhances its interaction with gas molecules. MOF crystals were soft imprinted into cellulose acetate (CA) films on quartz at different pressures. Atomic force microscope images of soft-imprinted films showed that MOF crystals were partially embedded into the CA. With this procedure, mechanically stable films were created, with crystals protruding from the CA surface and therefore available for incoming gas molecules. The sensing properties of the films were assessed by exposing them to saturated atmospheres of 2,4-dinitrotoluene, which resulted in a substantial quenching of the fluorescence after few seconds. The soft-imprinted MOF films on CA/quartz exhibit good sensing capabilities for the detection of nitroaromatics, which was attributed to the MOF sensitivity and to the novel and more efficient film processing method based on soft-imprinting. PMID- 28841184 TI - Experimental Investigation on Surface Quality Processed by Self-Excited Oscillation Pulsed Waterjet Peening. AB - High-speed waterjet peening technology has attracted a lot of interest and is now being widely studied due to its great ability to strengthen metal surfaces. In order to further improve the mechanical properties of metals, self-excited oscillation pulsed waterjets (SOPWs) were used for surface peening with an experimental investigation focused on the surface topography and properties. By impinging the aluminum alloy (5052) specimens with SOPWs issuing from an organ pipe oscillation nozzle, the hardness and roughness at various inlet pressures and stand-off distances were measured and analyzed, as well as the residual stress. Under the condition of optimum stand-off distances, the microscopic appearances of peened specimens obtained by SEM were displayed and analyzed. Results show that self-excited oscillation pulsed waterjet peening (SOPWP) is capable of improving the surface quality. More specifically, compared with an untreated surface, the hardness and residual stress of the peened surfaces were increased by 61.69% and 148%, respectively. There exists an optimal stand-off distance and operating pressure for creating the highest surface quality. SOPWP can produce almost the same enhancement effect as shot peening and lead to a lower surface roughness. Although such an approach is empirical and qualitative in nature, this procedure also generated information of value in guiding future theoretical and experimental work on the application of SOPWP in the industry practice. PMID- 28841185 TI - Heat-Assisted Multiferroic Solid-State Memory. AB - A heat-assisted multiferroic solid-state memory design is proposed and analysed, based on a PbNbZrSnTiO3 antiferroelectric layer and Ni81Fe19 magnetic free layer. Information is stored as magnetisation direction in the free layer of a magnetic tunnel junction element. The bit writing process is contactless and relies on triggering thermally activated magnetisation switching of the free layer towards a strain-induced anisotropy easy axis. A stress is generated using the antiferroelectric layer by voltage-induced antiferroelectric to ferroelectric phase change, and this is transmitted to the magnetic free layer by strain mediated coupling. The thermally activated strain-induced magnetisation switching is analysed here using a three-dimensional, temperature-dependent magnetisation dynamics model, based on simultaneous evaluation of the stochastic Landau Lifshitz-Bloch equation and heat flow equation, together with stochastic thermal fields and magnetoelastic contributions. The magnetisation switching probability is calculated as a function of stress magnitude and maximum heat pulse temperature. An operating region is identified, where magnetisation switching always occurs, with stress values ranging from 80 to 180 MPa, and maximum temperatures normalised to the Curie temperature ranging from 0.65 to 0.99. PMID- 28841186 TI - Fatigue Performance of Ti-6Al-4V Additively Manufactured Specimens with Integrated Capillaries of an Embedded Structural Health Monitoring System. AB - Additive manufacturing (AM) of metals offers new possibilities for the production of complex structures. Up to now, investigations on the mechanical response of AM metallic parts show a significant spread and unexpected failures cannot be excluded. In this work, we focus on the detection of fatigue cracks through the integration of a Structural Health Monitoring (SHM) system in Ti-6Al-4V specimens. The working principle of the presented system is based on the integration of small capillaries that are capable of detecting fatigue cracks. Four-point bending fatigue tests have been performed on Ti-6Al-4V specimens with integrated capillaries and compared to the reference specimenswithout capillaries. Specimens were produced by conventional subtractive manufacturing of wrought material and AM, using the laser based Directed Energy Deposition (DED) process. In this study, we investigated the effect of the presence of the capillary on the fatigue strength and fatigue initiation location. Finite element (FEM) simulations were performed to validate the experimental test results. The presence of a drilled capillary in the specimens did not alter the fatigue initiation location. However, the laser based DED production process introduced roughness on the capillary surface that altered the fatigue initiation location to the capillary surface. The fatigue performance was greatly reduced when considering a printed capillary. It is concluded that the surface quality of the integrated capillary is of primary importance in order not to influence the structural integrity of the component to be monitored. PMID- 28841187 TI - Improvement of Interaction in a Composite Structure by Using a Sol-Gel Functional Coating on Carbon Fibers. AB - The modification of carbon fibers for improving adhesion between fibers and an epoxy resin in composite materials has become the focus of attention. In this work the carbon fiber coating process has been devised in a way preventing the stiffening and clumping of fibers. To improve interactions between coated fibers and a resin in composites, four types of silica coatings with different organic functional groups (3-aminopropyl-coating 1, 3-mercaptopropyl-coating 2, 2-(3,4 epoxycyclohexyl) ethyl-coating 3, methyl-coating 4) were obtained. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to distinguish the changes of a carbon fibers surface after coating deposition. The thickness of the obtained coatings, including the diversity of thickness, was determined by transmission electron microscopy (TEM). The increase in surface free energy (SFE) of modified fibers, including the distinction between the polar and dispersive parts, was examined by wettability measurements using a tensometric test. The developed coating preparation process allowed to cover fibers separately with nanoscale silica layers, which changed their morphology. The introduction of organic functional groups resulted in surface free energy changes, especially an increase in specific polar surface energy components. PMID- 28841188 TI - Synthesis of Hollow Sphere and 1D Structural Materials by Sol-Gel Process. AB - The sol-gel method is a simple and facile wet chemical process for fabricating advanced materials with high homogeneity, high purity, and excellent chemical reactivity at a relatively low temperature. By adjusting the processing parameters, the sol-gel technique can be used to prepare hollow sphere and 1D structural materials that exhibit a wide application in the fields of catalyst, drug or gene carriers, photoactive, sensors and Li-ion batteries. This feature article reviewed the development of the preparation of hollow sphere and 1D structural materials using the sol-gel method. The effects of calcination temperature, soaking time, pH value, surfactant, etc., on the preparation of hollow sphere and 1D structural materials were summarized, and their formation mechanisms were generalized. Finally, possible future research directions of the sol-gel technique were outlined. PMID- 28841189 TI - Enhancing the Ignition, Hardness and Compressive Response of Magnesium by Reinforcing with Hollow Glass Microballoons. AB - Magnesium (Mg)/glass microballoons (GMB) metal matrix syntactic foams (1.47-1.67 g/cc) were synthesized using a disintegrated melt deposition (DMD) processing route. Such syntactic foams are of great interest to the scientific community as potential candidate materials for the ever-changing demands in automotive, aerospace, and marine sectors. The synthesized composites were evaluated for their microstructural, thermal, and compressive properties. Results showed that microhardness and the dimensional stability of pure Mg increased with increasing GMB content. The ignition response of these foams was enhanced by ~22 degrees C with a 25 wt % GMB addition to the Mg matrix. The authors of this work propose a new parameter, ignition factor, to quantify the superior ignition performance that the developed Mg foams exhibit. The room temperature compressive strengths of pure Mg increased with the addition of GMB particles, with Mg-25 wt % GMB exhibiting the maximum compressive yield strength (CYS) of 161 MPa and an ultimate compressive strength (UCS) of 232 MPa for a GMB addition of 5 wt % in Mg. A maximum failure strain of 37.7% was realized in Mg-25 wt % GMB foam. The addition of GMB particles significantly enhanced the energy absorption by ~200% prior to compressive failure for highest filler loading, as compared to pure Mg. Finally, microstructural changes in Mg owing to the presence of hollow GMB particles were elaborately discussed. PMID- 28841190 TI - ALKALOIDS FROM OXYTROPIS MYRIOPHYLLA (PALL) DC. AB - Five alkaloids were isolated from the epigeal part of Oxytropis myriophylla. Three alkaloids were identified as N-benzoyl-beta-phenylethylamine, N-trans cinnamoyl-beta-phenylethylamine, N-cis-cinnamoyl-beta-phenylethylamine and the structures of two new alkaloids were elucidated to be N-benzoyl-beta hydroxyphenylethylarnine(2), N-trans-cinnamoyl-beta-hydroxy-phenylethylamine(5). The absolu.te structures were established by modified Mosher method. PMID- 28841191 TI - Structure Identification and In Vitro Anticancer Activity of Lathyrol-3 phenylacetate-5,15-diacetate. AB - Natural products from the genus Euphorbia show attention-attracting activities, such as anticancer activity. In this article, classical isolation and structure identification were used in a study on Caper Euphorbia Seed. Subsequently, MTT and wound healing assays, flow cytometry, western blotting, Hoechst 33258 staining and fluorescence microscopy examination were applied to investigate the anticancer activity of the obtained compounds. In a result, lathyrol-3-phenyl- acetate-5,15-diacetate (deoxy Euphorbia factor L1, DEFL1) was isolated from Caper Euphorbia Seed. Moreover, the NMR signals were totally assigned. DEFL1 showed potent inhibition against lung cancer A549 cells, with an IC50 value of 17.51 +/- 0.85 MUM. Furthermore, DEFL1 suppressed wound healing of A549 cells in a concentration-dependent manner. Mechanically, DEFL1 induced apoptosis, with involvement of an increase of reactive oxygen species (ROS), decrease of mitochondrial membrane potential (DeltaPsim), release of cytochrome c, activity raise of caspase-9 and 3. Characteristic features of apoptosis were observed by fluorescence microscopy. In summary, DEFL1 inhibited growth and induced apoptosis in lung cancer A549 cells via a mitochondrial pathway. PMID- 28841192 TI - Eicosapentaenoic Acid (EPA) Induced Macrophages Activation through GPR120 Mediated Raf-ERK1/2-IKKbeta-NF-kappaB p65 Signaling Pathways. AB - Objectives: To investigate the immunomodulatory effect and molecular mechanisms of Eicosapentaenoic acid (EPA, a typical kind of n-3PUFAs) on RAW264.7 cells. Methods: A variety of research methods, including the RAW264.7 cells culture, cell proliferation assays, morphologic observations, measurements of NO production, cytokine assays, nuclear protein extractions, western blot analyses and NF-kappaB p65 immunofluorescence assays were used in this study. Results: The results showed that EPA could increase the proliferation index and enhance the release of nitric oxide (NO) and cytokines in RAW264.7 cells. Western blotting results revealed that the protein level of GPR120 increased significantly in RAW264.7 cells after EPA treatment. Meanwhile, EPA elevated the phosphorylation status of Raf, which may act as an upstream regulator of EPA-induced phosphorylated ERK1/2. In addition, the phosphorylated ERK1/2 may then promote IKKbeta in endochylema and translocate the NF-kappaB p65 subunit into the nucleus, thus regulating the production of inducible nitric oxide synthase (iNOS) and cytokines. Conclusions: EPA (0.6-3.0 MUmol) activates RAW264.7 cells through GPR120-mediated Raf-ERK1/2-IKKbeta-NF-kappaB p65 signaling pathways. PMID- 28841193 TI - Bis(1-pyrenylmethyl)-2-benzyl-2-methyl-malonate as a Cu2+ Ion-Selective Fluoroionophore. AB - A new malonate possessing two pyrene moieties was synthesized as a fluoroionophore, and its structure and fluorescence spectroscopic properties were investigated. When excited at 344 nm in acetonitrile/chloroform (9:1, v/v), the synthesized bispyrenyl malonate has the fluorescence of intramolecular excimer (lambdaem = 467 nm) emissions and not a pyrene monomer emission (lambdaem = 394 nm). A large absolute fluorescence quantum yield was obtained in the solid state (PhiPL = 0.65) rather than in solution (PhiPL = 0.13). X-ray crystallography analysis clarified the molecular structure and alignment of the bispyrenyl malonate in the crystal phase, elucidating its fluorescence spectroscopic properties. Such analysis also suggests there are intramolecular C-H...pi interactions and intermolecular pi...pi interactions between the pyrenyl rings. Interestingly, the synthesized bispyrenyl malonate exhibits excellent fluorescence sensing for the Cu2+ ion. Remarkable fluorescence intensity enhancement was only observed with the addition of the Cu2+ ion. PMID- 28841194 TI - PSFM-DBT: Identifying DNA-Binding Proteins by Combing Position Specific Frequency Matrix and Distance-Bigram Transformation. AB - DNA-binding proteins play crucial roles in various biological processes, such as DNA replication and repair, transcriptional regulation and many other biological activities associated with DNA. Experimental recognition techniques for DNA binding proteins identification are both time consuming and expensive. Effective methods for identifying these proteins only based on protein sequences are highly required. The key for sequence-based methods is to effectively represent protein sequences. It has been reported by various previous studies that evolutionary information is crucial for DNA-binding protein identification. In this study, we employed four methods to extract the evolutionary information from Position Specific Frequency Matrix (PSFM), including Residue Probing Transformation (RPT), Evolutionary Difference Transformation (EDT), Distance-Bigram Transformation (DBT), and Trigram Transformation (TT). The PSFMs were converted into fixed length feature vectors by these four methods, and then respectively combined with Support Vector Machines (SVMs); four predictors for identifying these proteins were constructed, including PSFM-RPT, PSFM-EDT, PSFM-DBT, and PSFM-TT. Experimental results on a widely used benchmark dataset PDB1075 and an independent dataset PDB186 showed that these four methods achieved state-of-the art-performance, and PSFM-DBT outperformed other existing methods in this field. For practical applications, a user-friendly webserver of PSFM-DBT was established, which is available at http://bioinformatics.hitsz.edu.cn/PSFM-DBT/. PMID- 28841195 TI - Recommendations for Improving Identification and Quantification in Non-Targeted, GC-MS-Based Metabolomic Profiling of Human Plasma. AB - The field of metabolomics as applied to human disease and health is rapidly expanding. In recent efforts of metabolomics research, greater emphasis has been placed on quality control and method validation. In this study, we report an experience with quality control and a practical application of method validation. Specifically, we sought to identify and modify steps in gas chromatography-mass spectrometry (GC-MS)-based, non-targeted metabolomic profiling of human plasma that could influence metabolite identification and quantification. Our experimental design included two studies: (1) a limiting-dilution study, which investigated the effects of dilution on analyte identification and quantification; and (2) a concentration-specific study, which compared the optimal plasma extract volume established in the first study with the volume used in the current institutional protocol. We confirmed that contaminants, concentration, repeatability and intermediate precision are major factors influencing metabolite identification and quantification. In addition, we established methods for improved metabolite identification and quantification, which were summarized to provide recommendations for experimental design of GC-MS based non-targeted profiling of human plasma. PMID- 28841196 TI - Growth Description for Vessel Wall Adaptation: A Thick-Walled Mixture Model of Abdominal Aortic Aneurysm Evolution. AB - (1) Background: Vascular tissue seems to adapt towards stable homeostatic mechanical conditions, however, failure of reaching homeostasis may result in pathologies. Current vascular tissue adaptation models use many ad hoc assumptions, the implications of which are far from being fully understood; (2) Methods: The present study investigates the plausibility of different growth kinematics in modeling Abdominal Aortic Aneurysm (AAA) evolution in time. A structurally motivated constitutive description for the vessel wall is coupled to multi-constituent tissue growth descriptions; Constituent deposition preserved either the constituent's density or its volume, and Isotropic Volume Growth (IVG), in-Plane Volume Growth (PVG), in-Thickness Volume Growth (TVG) and No Volume Growth (NVG) describe the kinematics of the growing vessel wall. The sensitivity of key modeling parameters is explored, and predictions are assessed for their plausibility; (3) Results: AAA development based on TVG and NVG kinematics provided not only quantitatively, but also qualitatively different results compared to IVG and PVG kinematics. Specifically, for IVG and PVG kinematics, increasing collagen mass production accelerated AAA expansion which seems counterintuitive. In addition, TVG and NVG kinematics showed less sensitivity to the initial constituent volume fractions, than predictions based on IVG and PVG; (4) Conclusions: The choice of tissue growth kinematics is of crucial importance when modeling AAA growth. Much more interdisciplinary experimental work is required to develop and validate vascular tissue adaption models, before such models can be of any practical use. PMID- 28841197 TI - Auxin Response Factor Genes Repertoire in Mulberry: Identification, and Structural, Functional and Evolutionary Analyses. AB - Auxin Response Factors (ARFs) are at the core of the regulation mechanism for auxin-mediated responses, along with AUX/IAA proteins.They are critical in the auxin-mediated control of various biological responses including development and stress. A wild mulberry species genome has been sequenced and offers an opportunity to investigate this important gene family. A total of 17 ARFs have been identified from mulberry (Morus notabilis) which show a wide range of expression patterns. Of these 17 ARFs, 15 have strong acidic isoelectric point (pI) values and a molecular mass ranging from 52 kDa to 101 kDa. The putative promoters of these ARFs harbour cis motifs related to light-dependent responses, various stress responses and hormone regulations suggestive of their multifactorial regulation. The gene ontology terms for ARFs indicate their role in flower development, stress, root morphology and other such development and stress mitigation related activities. Conserved motif analysis showed the presence of all typical domains in all but four members that lack the PB1 domain and thus represent truncated ARFs. Expression analysis of these ARFs suggests their preferential expression in tissues ranging from leaf, root, winter bud, bark and male flowers. These ARFs showed differential expression in the leaf tissue of M. notabilis, Morus laevigata and Morus serrata. Insights gained from this analysis have implications in mulberry improvement programs. PMID- 28841198 TI - Social Environment of Older People during the First Year in Senior Housing and Its Association with Physical Performance. AB - Increasing numbers of older people relocate into senior housing when their physical performance declines. The change in social environment is known to affect their wellbeing, providing both challenges and opportunities, but more information on the relations between social and physical parameters is required. Thus, we elicited perceptions of the social environment of 81 older people (aged 59-93 years, living in northern Finland) and changes in it 3 and 12 months after relocation to senior housing. We also measured their physical performance, then analysed associations between the social and physical variables. Participants reported that they had freedom to do whatever they liked and generally had enough contact with close people (which have recognized importance for older people's wellbeing), but changes in their physical condition limited their social activity. Moreover, their usual walking speed, dominant hand's grip strength and instrumental activities of daily living (IADL) significantly decreased. The pleasantness of the residential community, peer support, constraints on social activity imposed by changes in physical condition, meaningful activity at home and meeting close people all affected these physical performance parameters. Clearly, in addition to assessing physical performance and encouraging regular exercise, the complex interactions among social factors, physical performance and wellbeing should be considered when addressing individuals' needs. PMID- 28841200 TI - Mind-Body Medicine in Pediatrics. AB - The primary goals of this Special Issue are to encourage readers to become more familiar with the range of mind-body therapies and to explore their application in the pediatric clinical setting. The Special Issue includes a deliberate mix of case studies and practical clinical guidance, with the dual goals of piquing curiosity and providing resources for clinicians interested in pursuing further training. PMID- 28841199 TI - The Role of Red Meat and Flavonoid Consumption on Cancer Prevention: The Korean Cancer Screening Examination Cohort. AB - Markedly increased red meat consumption is a cancer risk factor, while dietary flavonoids may help prevent the disease. The purpose of this study was to investigate the associations of red meat and flavonoid consumption with cancer risk, based on data from 8024 subjects, drawn from the 2004-2008 Cancer Screening Examination Cohort of the Korean National Cancer Center. Hazard ratios (HRs) were obtained by using a Cox proportional hazard model. During the mean follow-up period of 10.1 years, 443 cases were newly diagnosed with cancer. After adjusting for age, there was a significant correlation between cancer risk and the daily intake of >=43 g of red meat per day (HR 1.31; 95% CI 1.01, 1.71; p = 0.045), and total flavonoid intake tended to decrease cancer risk (HR 0.70; 95% CI 0.49, 0.99; highest vs. lowest quartile; p-trend = 0.073) in men. Following multivariable adjustment, there were no statistically significant associations between flavonoid intake and overall cancer risk in individuals with high levels of red meat intake. Men with low daily red meat intake exhibited an inverse association between flavonoid consumption and cancer incidence (HR 0.41; 95% CI 0.21, 0.80; highest vs. lowest; p-trend = 0.017). Additional research is necessary to clarify the effects of flavonoid consumption on specific cancer incidence, relative to daily red meat intake. PMID- 28841201 TI - Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2017-18 Influenza Season. AB - This report updates the 2016-17 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines (MMWR Recomm Rep 2016;65[No. RR-5]). Routine annual influenza vaccination is recommended for all persons aged >=6 months who do not have contraindications. A licensed, recommended, and age-appropriate vaccine should be used.For the 2017-18 season, quadrivalent and trivalent influenza vaccines will be available. Inactivated influenza vaccines (IIVs) will be available in trivalent (IIV3) and quadrivalent (IIV4) formulations. Recombinant influenza vaccine (RIV) will be available in trivalent (RIV3) and quadrivalent (RIV4) formulations. Live attenuated influenza vaccine (LAIV4) is not recommended for use during the 2017 18 season due to concerns about its effectiveness against (H1N1)pdm09 viruses during the 2013-14 and 2015-16 seasons. Recommendations for different vaccine types and specific populations are discussed. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended product is available.Updates to the recommendations described in this report reflect discussions during public meetings of ACIP held on October 20, 2016; February 22, 2017; and June 21, 2017. New and updated information in this report includes the following:*Vaccine viruses included in the 2017-18 U.S. trivalent influenza vaccines will be an A/Michigan/45/2015 (H1N1)pdm09-like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008-like virus (Victoria lineage). Quadrivalent influenza vaccines will contain these three viruses and an additional influenza B vaccine virus, a B/Phuket/3073/2013-like virus (Yamagata lineage).* Information on recent licensures and labelling changes is discussed, including licensure of Afluria Quadrivalent (IIV4; Seqirus, Parkville, Victoria, Australia); Flublok Quadrivalent (RIV4; Protein Sciences, Meriden, Connecticut); and expansion of the age indication for FluLaval Quadrivalent (IIV4; ID Biomedical Corporation of Quebec, Quebec City, Quebec, Canada), previously licensed for >=3 years, to >=6 months.* Pregnant women may receive any licensed, recommended, age-appropriate influenza vaccine.* Afluria (IIV3; Seqirus, Parkville, Victoria, Australia) may be used for persons aged >=5 years, consistent with Food and Drug Administration approved labeling.* FluMist Quadrivalent (LAIV4; MedImmune, Gaithersburg, Maryland) should not be used during the 2017-18 season due to concerns about its effectiveness against influenza A(H1N1)pdm09 viruses in the United States during the 2013-14 and 2015-16 influenza seasons.This report focuses on the recommendations for use of vaccines for the prevention and control of influenza during the 2017-18 season in the United States. A Background Document containing further information and a summary of these recommendations are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to licensed influenza vaccines used within Food and Drug Administration-licensed indications, including those licensed after the publication date of this report. Updates and other information are available at CDC's influenza website (https://www.cdc.gov/flu). Vaccination and health care providers should check CDC's influenza website periodically for additional information. PMID- 28841202 TI - Microbial functional trait of rRNA operon copy numbers increases with organic levels in anaerobic digesters. AB - The ecological concept of the r-K life history strategy is widely applied in macro-ecology to characterize functional traits of taxa. However, its adoption in microbial communities is limited, owing to the lack of a measureable, convenient functional trait for classification. In this study, we performed an experiment of stepwise organic amendments in triplicate anaerobic digesters. We found that high resource availability significantly favored microbial r-strategists such as Bacillus spp. Incremental resource availability heightened average rRNA operon copy number of microbial community, resulting in a strong, positive correlation (r>0.74, P<0.008). This study quantifies how resource availability manipulations influence microbial community composition and supports the idea that rRNA operon copy number is an ecologically meaningful trait which reflects resource availability. PMID- 28841203 TI - High sensitivity blood-based M-protein detection in sCR patients with multiple myeloma. AB - We assessed the ability of a mass spectrometry-based technique, called monoclonal immunoglobulin rapid accurate mass measurement (miRAMM), to extend the analytical range of M-protein detection in serum samples obtained from myeloma patients in stringent complete response (sCR) post-autologous stem cell transplant (ASCT). To aid the M-protein detection post ASCT, the accurate molecular mass of the M protein light chain at diagnosis was determined in all patients (N=30) and used to positively identify clones in the sCR serum. Day 100 post-ASCT, sCR samples had miRAMM identifiable M-proteins in 81% of patients. Patients who had achieved only a partial remission (PR) pre-ASCT and those with IgG isotypes serum samples had the highest rate of M-protein detection by miRAMM. miRAMM positivity at single time points (day 100, 6 months or 12 months) did not correlate with progression-free survival (PFS). In contrast, sCR patients who did not decrease their miRAMM M-protein intensities in serial measurements had shorter PFS than those whose miRAMM intensities decreased (median 17.9 months vs 51.6 months; P<0.0017). miRAMM M-protein is a more sensitive blood-based test than traditional M-protein tests and could cost effectively aid in serially monitoring complete remission for continue response or biochemical relapse. PMID- 28841205 TI - Revisiting gene mutations and prognosis of ex-M6a-acute erythroid leukemia with regard to the new WHO classification. PMID- 28841204 TI - From Waldenstrom's macroglobulinemia to aggressive diffuse large B-cell lymphoma: a whole-exome analysis of abnormalities leading to transformation. AB - Transformation of Waldenstrom's macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) occurs in up to 10% of patients and is associated with an adverse outcome. Here we performed the first whole-exome sequencing study of WM patients who evolved to DLBCL and report the genetic alterations that may drive this process. Our results demonstrate that transformation depends on the frequency and specificity of acquired variants, rather than on the duration of its evolution. We did not find a common pattern of mutations at diagnosis or transformation; however, there were certain abnormalities that were present in a high proportion of clonal tumor cells and conserved during this transition, suggesting that they have a key role as early drivers. In addition, recurrent mutations gained in some genes at transformation (for example, PIM1, FRYL and HNF1B) represent cooperating events in the selection of the clones responsible for disease progression. Detailed comparison reveals the gene abnormalities at diagnosis and transformation to be consistent with a branching model of evolution. Finally, the frequent mutation observed in the CD79B gene in this specific subset of patients implies that it is a potential biomarker predicting transformation in WM. PMID- 28841206 TI - Overexpression of SOX4 correlates with poor prognosis of acute myeloid leukemia and is leukemogenic in zebrafish. AB - The SOX4 transcription factor is a key regulator of embryonic development, cell fate decision, cellular differentiation and oncogenesis. Abnormal expression of SOX4 is related to malignant tumor transformation and cancer metastasis. However, no reports are available regarding the clinical significance of SOX4 in acute myeloid leukemia (AML) and the role of SOX4 in leukemogenesis. In the current study, we found that AML patients with low bone marrow (BM) SOX4 expression had higher remission rates and longer overall survival than those with high SOX4 expression, regardless of age, white blood cell count at diagnosis, karyotype profile and NPM1/FLT3-ITD status. To elucidate the role of SOX4 in leukemogenesis, we generated a transgenic zebrafish model that overexpressed human SOX4 in the myeloid lineage Tg(spi1-SOX4-EGFP). These transgenic zebrafish showed, at 5 months of age, increased myelopoiesis with dedifferentiation in kidney marrow. At 9 months of age, their kidney structure was significantly effaced and distorted by increased infiltration of myeloid progenitor cells. These results suggest that SOX4 is not only an independent prognostic factor of AML, but also an important molecular factor in leukemogenesis. PMID- 28841208 TI - Clinical features and outcomes of extramedullary myeloid sarcoma in the United States: analysis using a national data set. PMID- 28841207 TI - Vitamin D insufficiency is associated with an increased risk of early clinical failure in follicular lymphoma. AB - We evaluated whether vitamin D insufficiency (VDI; 25(OH)D <20 ng/ml) was associated with adverse outcomes among follicular lymphoma (FL) patients using an observational prospective cohort study of 642 FL patients enrolled from 2002 2012. The median age at diagnosis was 60 years. At a median follow-up of 59 months, 297 patients (46%) had an event (progression, treatment failure), 78 had died and 42 (6.5%) had a lymphoma-related death. VDI was associated with inferior event-free survival (EFS) at 12 months (EFS12, odds ratio (OR)=2.05; 95% confidence interval (CI) 1.18-3.54), overall survival (OS, hazards ratio (HR)=2.35; 95%CI 1.37-4.02), and lymphoma-specific survival (LSS, HR=2.97; 95% CI 1.52-5.80) for the full cohort. Among patients treated with immunochemotherapy (IC), VDI was associated with inferior EFS12 (OR=3.00; 95% CI 1.26-7.13), OS (HR=2.86; 95% CI 1.39-5.85), and LSS (HR=2.96; 95% CI 1.29-6.79). For observed patients, VDI was associated with inferior OS (HR=2.85; 95% CI 1.20-6.76). For other therapies, VDI was associated with inferior OS (HR=3.06; 95% CI 1.01-9.24). Our work is the first to reveal an association of VDI with early clinical failure, and to demonstrate an association of VDI with adverse outcomes among patients who are observed or treated with therapies other than IC. Our findings suggest a potentially modifiable prognostic factor to address in patients with FL. PMID- 28841209 TI - Clonal evolution is a prognostic factor for the clinical progression of monoclonal B-cell lymphocytosis. PMID- 28841210 TI - Alternative splicing discriminates molecular subtypes and has prognostic impact in diffuse large B-cell lymphoma. AB - Effect of alternative splicing (AS) on diffuse large B-cell lymphoma (DLBCL) pathogenesis and survival has not been systematically addressed. Here, we compared differentially expressed genes and exons in association with survival after chemoimmunotherapy, and between germinal center B-cell like (GCB) and activated B-cell like (ABC) DLBCLs. Genome-wide exon array-based screen was performed from samples of 38 clinically high-risk patients who were treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis. The exon expression profile separated the patients according to molecular subgroups and survival better than the gene expression profile. Pathway analyses revealed enrichment of AS genes in inflammation and adhesion related processes, and in signal transduction, such as phosphatidylinositol signaling system and adenosine triphosphate binding cassette transporters. Altogether, 49% of AS-related exons were protein coding, and domain prediction showed 28% of such exons to include a functional domain, such as transmembrane helix domain or phosphorylation sites. Validation in an independent cohort of 92 DLBCL samples subjected to RNA-sequencing confirmed differential exon usage of selected genes and association of AS with molecular subtypes and survival. The results indicate that AS events are able to discriminate GCB and ABC DLBCLs and have prognostic impact in DLBCL. PMID- 28841212 TI - Impact of Notch disruption on myeloid development. PMID- 28841211 TI - Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group. AB - For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic significance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P<0.0001). Of 66 patients with SMM based on CSS, 12 (22.2%) had osteolytic lesions on WBCT. In comparison, WBCT failed to detect some bone destructions in the appendicular skeleton possibly due to limitations of the field of view. Presence of lytic bone lesions in WBCT was of borderline prognostic significance (P=0.051) for SMM patients, with a median time to progression of 38 versus 82 months for those without bone destructions. In conclusion, WBCT identifies significantly more sites of bone destruction than CSS. More than 20% of patients with SMM according to CSS have in fact active MM detectable with WBCT. On the basis of this and other studies, WBCT (either computed tomography (CT) alone or as part of a positron emission tomography-CT protocol) should be considered the current standard for the detection of osteolytic lesions in MM. PMID- 28841213 TI - Complete in vitro oogenesis: retrospects and prospects. AB - Precise control of mammalian oogenesis has been a traditional focus of reproductive and developmental biology research. Recently, new reports have introduced the possibility of obtaining functional gametes derived in vitro from stem cells. The potential to produce functional gametes from stem cells has exciting applications for regenerative medicine though still remains challenging. In mammalian females ovulation and fertilization is a privilege reserved for a small number of oocytes. In reality the vast majority of oocytes formed from primordial germ cells (PGCs) will undergo apoptosis, or other forms of cell death. Removal occurs during germ cell cyst breakdown and the establishment of the primordial follicle (PF) pool, during the long dormancy at the PF stage, or through follicular atresia prior to reaching the ovulatory stage. A way to solve this limitation could be to produce large numbers of oocytes, in vitro, from stem cells. However, to recapitulate mammalian oogenesis and produce fertilizable oocytes in vitro is a complex process involving several different cell types, precise follicular cell-oocyte reciprocal interactions, a variety of nutrients and combinations of cytokines, and precise growth factors and hormones depending on the developmental stage. In 2016, two papers published by Morohaku et al. and Hikabe et al. reported in vitro procedures that appear to reproduce efficiently these conditions allowing for the production, completely in a dish, of a relatively large number of oocytes that are fertilizable and capable of giving rise to viable offspring in the mouse. The present article offers a critical overview of these results as well as other previous work performed mainly in mouse attempting to reproduce oogenesis completely in vitro and considers some perspectives for the potential to adapt the methods to produce functional human oocytes. PMID- 28841214 TI - Tudor-domain protein PHF20L1 reads lysine methylated retinoblastoma tumour suppressor protein. AB - The retinoblastoma tumour suppressor protein (pRb) classically functions to regulate early cell cycle progression where it acts to enforce a number of checkpoints in response to cellular stress and DNA damage. Methylation at lysine (K) 810, which occurs within a critical CDK phosphorylation site and antagonises a CDK-dependent phosphorylation event at the neighbouring S807 residue, acts to hold pRb in the hypo-phosphorylated growth-suppressing state. This is mediated in part by the recruitment of the reader protein 53BP1 to di-methylated K810, which allows pRb activity to be effectively integrated with the DNA damage response. Here, we report the surprising observation that an additional methylation dependent interaction occurs at K810, but rather than the di-methyl mark, it is selective for the mono-methyl K810 mark. Binding of the mono-methyl PHF20L1 reader to methylated pRb occurs on E2F target genes, where it acts to mediate an additional level of control by recruiting the MOF acetyltransferase complex to E2F target genes. Significantly, we find that the interplay between PHF20L1 and mono-methyl pRb is important for maintaining the integrity of a pRb-dependent G1 S-phase checkpoint. Our results highlight the distinct roles that methyl-lysine readers have in regulating the biological activity of pRb. PMID- 28841216 TI - Modelling charge transport of discotic liquid-crystalline triindoles: the role of peripheral substitution. AB - We have performed a multiscale approach to study the influence of peripheral substitution in the semiconducting properties of discotic liquid-crystalline triindoles. Charge carrier mobility as high as 1.4 cm2 V-1 s-1 was experimentally reported for triindoles substituted with alkynyl chains on the periphery (Gomez Lor et al. Angew. Chem., Int. Ed., 2011, 50, 7399-7402). In this work, our goal is to get a deeper understanding of both the molecular electronic structure and microscopic factors affecting the charge transport properties in triindoles as a function of the spacer group connecting the central cores with the external alkyl chains (i.e., alkyne or phenyl spacers groups). To this end, we first perform Quantum Mechanical (QM) calculations to assess how the peripheral substitution affects the electronic structure and the internal reorganization energy. Secondly, boxes of stacked molecules were built and relaxed through molecular dynamics to obtain realistic structures. Conformational analysis and calculations of transfer integrals for closed neighbours were performed. Our results show that the insertion of ethynyl spacers between the central aromatic core and the flexible peripheral chains results in lower reorganization energies and enhanced intermolecular order within the stacks with a preferred cofacial 60 degrees staggered conformation, which would result in high charge-carrier mobilities in good agreement with the experimental data. This work allows a deeper understanding of charge carrier mobility in columnar phases, linking the structural order at the molecular level to the property of interest, i.e. the charge carrier mobility. We hope that this understanding will improve the design of systems at the supramolecular level aiming at obtaining a more defined conducting channel, higher mobility and smaller fluctuations within the column. PMID- 28841215 TI - Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells. AB - Chimeric antigen receptor (CAR) T-cell immunotherapies have shown unprecedented success in treating leukemia but limited clinical efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed improved expansion, persistency and effector function against CD19+ leukemia or mesothelin+ solid tumors respectively in vitro and in vivo. In a patient with relapsed B-cell acute lymphoblastic leukemia, a single dose of 5 * 104/kg 1928zT2 T cells resulted in robust expansion and leukemia eradication and led to complete remission. Hence, our results demonstrate that TLR2 signaling can contribute to the efficacy of CAR T cells. Further clinical trials are warranted to establish the safety and efficacy of this approach. PMID- 28841217 TI - Sunlight assisted direct amide formation via a charge-transfer complex. AB - We report on the use of charge-transfer complexes between amines and carbon tetrachloride, as a novel way to activate the amine for photochemical reactions. This principle is demonstrated in a mild, transition metal free, visible light assisted, dealkylative amide formation from feedstock carboxylic acids and amines. The low absorption coefficient of the complex allows deep light penetration and thus scale up to a gram scale. PMID- 28841218 TI - When It Comes to Older Adults, Language Matters. PMID- 28841221 TI - Feasibility of Providing Safe Mouth Care and Collecting Oral and Fecal Microbiome Samples from Nursing Home Residents with Dysphagia: Proof of Concept Study. AB - Individuals with dysphagia who reside in nursing homes often receive inadequate mouth care and experience poor oral health. From a policy perspective, the combination of absent evidence-based mouth care protocols coupled with insufficient dental coverage create a pool of individuals at great risk for preventable infectious illnesses that contribute to high health care costs. The purpose of the current study was to determine (a) the safety of a mouth care protocol tailored for individuals with dysphagia residing in nursing homes without access to suction equipment, and (b) the feasibility of collecting oral and fecal samples for microbiota analyses. The mouth care protocol resulted in improved oral hygiene without aspiration, and oral and fecal samples were safely collected from participants. Policies supporting ongoing testing of evidence based mouth care protocols for individuals with dysphagia are important to improve quality, demonstrate efficacy, and save health care costs. [Journal of Gerontological Nursing, 43(9), 9-15.]. PMID- 28841222 TI - Looking at Our Words as if Seeing Them for the First Time. PMID- 28841223 TI - The role of surgery and adjuvant therapy in lymph node-positive cancers of the gallbladder and intrahepatic bile ducts. AB - BACKGROUND: Lymph node metastasis is a poor prognostic factor for biliary tract cancers (BTCs). The optimal management of patients who have BTC with positive regional lymph nodes, including the impact of surgery and adjuvant therapy (AT), is unclear. METHODS: This was a retrospective cohort study of patients who had T1 T3N1M0 gallbladder cancer (GBC) and intrahepatic cholangiocarcinoma (IHC) in the National Cancer Database (2004-2012). Patients were classified by treatment approach (nonoperative, surgery, surgery plus AT). Associations between the overall risk of death and treatment strategy were evaluated with multivariable Cox regression. RESULTS: Rates of surgical resection were 84.1% for patients with GBC (n = 1335) and 36.6% for those with IHC (n = 1009). The median overall survival of patients in the nonoperative, surgery, and surgery plus AT group was 11.6, 13.3, and 19.6 months, respectively, for those with GBC (log-rank P < .001), and 12.7, 16.2, and 22.6 months, respectively, for those with IHC (log rank P < .001), respectively. Compared with nonoperative therapy, surgery with or without AT was associated with a lower risk of death from GBC (surgery with AT: hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.48-0.73; surgery without AT: HR, 0.71; 95% CI, 0.56-0.89) and from IHC (surgery with AT: HR, 0.52; 95% CI, 0.42-0.63; surgery without AT: HR, 0.70; 95% CI, 0.56-0.87). AT that included radiation was associated with a lower risk of death relative to surgery alone for patients with GBC regardless of margin status (margin-negative resection: HR, 0.66; 95% CI, 0.52-0.84; margin-positive resection: HR, 0.54; 95% CI, 0.39-0.75), but adjuvant chemotherapy alone was not. For patients with IHC, no survival benefit was detected with adjuvant chemotherapy or radiation for those who underwent either margin-positive or margin-negative resection. CONCLUSIONS: The best outcomes for patients who have lymph node-positive BTCs are associated with margin-negative resection and, in those who have GBC, the inclusion of adjuvant chemotherapy with radiation regardless of margin status. Cancer 2018;124:74-83. (c) 2017 American Cancer Society. PMID- 28841224 TI - Parasitoid gene expression changes after adaptation to symbiont-protected hosts. AB - Reciprocal selection between aphids, their protective endosymbionts, and the parasitoid wasps that prey upon them offers an opportunity to study the basis of their coevolution. We investigated adaptation to symbiont-conferred defense by rearing the parasitoid wasp Lysiphlebus fabarum on aphids (Aphis fabae) possessing different defensive symbiont strains (Hamiltonella defensa). After ten generations of experimental evolution, wasps showed increased abilities to parasitize aphids possessing the H. defensa strain they evolved with, but not aphids possessing the other strain. We show that the two symbiont strains encode different toxins, potentially creating different targets for counter-adaptation. Phenotypic and behavioral comparisons suggest that neither life-history traits nor oviposition behavior differed among evolved parasitoid lineages. In contrast, comparative transcriptomics of adult female wasps identified a suite of differentially expressed genes among lineages, even when reared in a common, symbiont-free, aphid host. In concurrence with the specificity of each parasitoid lineages' infectivity, most differentially expressed parasitoid transcripts were also lineage-specific. These transcripts are enriched with putative venom toxins and contain highly expressed, potentially defensive viral particles. Together, these results suggest that wild populations of L. fabarum employ a complicated offensive arsenal with sufficient genetic variation for wasps to adapt rapidly and specifically to their hosts' microbial defenses. PMID- 28841226 TI - Selection on an extreme weapon in the frog-legged leaf beetle (Sagra femorata). AB - Biologists have been fascinated with the extreme products of sexual selection for decades. However, relatively few studies have characterized patterns of selection acting on ornaments and weapons in the wild. Here, we measure selection on a wild population of weapon-bearing beetles (frog-legged leaf beetles: Sagra femorata) for two consecutive breeding seasons. We consider variation in both weapon size (hind leg length) and in relative weapon size (deviations from the population average scaling relationship between hind leg length and body size), and provide evidence for directional selection on weapon size per se and stabilizing selection on a particular scaling relationship in this population. We suggest that whenever growth in body size is sensitive to external circumstance such as nutrition, then considering deviations from population-level scaling relationships will better reflect patterns of selection relevant to evolution of the ornament or weapon than will variation in trait size per se. This is because trait-size versus body-size scaling relationships approximate underlying developmental reaction norms relating trait growth with body condition in these species. Heightened condition-sensitive expression is a hallmark of the exaggerated ornaments and weapons favored by sexual selection, yet this plasticity is rarely reflected in the way we think about-and measure-selection acting on these structures in the wild. PMID- 28841227 TI - A Darwinian view of cancer and the environment. PMID- 28841225 TI - Long-term weight loss after colorectal cancer diagnosis is associated with lower survival: The Colon Cancer Family Registry. AB - BACKGROUND: Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. METHODS: CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. RESULTS: At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs <=5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). CONCLUSIONS: Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. (c) 2017 American Cancer Society. PMID- 28841228 TI - The shifting paradigm in the treatment of type 2 diabetes mellitus-A cardiologist's perspective. AB - In patients with diabetes mellitus, cardiovascular (CV) disease is the leading cause of morbidity and mortality. A multitude of contemporary antidiabetic agents presents different CV safety profiles. Metformin forms the cornerstone agent to reduce CV events. Newer agents, such as glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors, have appealing CV benefits. Insulin, dipeptidyl peptidase-4 inhibitors, and sulfonylureas have neutral CV effects. Cardiologists should familiarize themselves with these agents to promote comprehensive CV care in patients with diabetes mellitus. PMID- 28841229 TI - Effect of Vitamin D in the Prevention of Myocardial Injury Following Elective Percutaneous Coronary Intervention: A Pilot Randomized Clinical Trial. AB - Myocardial injury following elective percutaneous coronary intervention (PCI) occurs in about one-third of patients and is associated with mortality. Platelet aggregation, thrombosis formation, and inflammation are the main causes of cardiac injury during PCI. Vitamin D plays a key role in the cardiovascular system by exerting antiplatelet, anticoagulant, and anti-inflammatory properties. There is no published study that investigated the effect of vitamin D in the prevention of cardiac injury following elective PCI. In a randomized clinical trial, 99 patients admitted for elective PCI were randomized into vitamin D (n = 52) and control (n = 47) groups. The intervention group received 300 000 IU vitamin D orally 12 hours before PCI. The cardiac biomarkers were checked at baseline, 8 and 24 hours after PCI. hs-CRP was also measured at baseline and after 24 hours. The increase in CK-MB was documented in 20 patients (42%) in the control group and 18 patients (34.6%) in the intervention group (P = .417). Furthermore, the increase in cTnI occurred in 4 patients (8%) and 2 patients (3.3%) in the control and intervention groups, respectively (P = .419). No significant changes were noted in the level of cardiac biomarkers. In the vitamin D group, the mean difference in CK-MB between 8 and 24 hours was significantly lower (P = .048). The mean difference in hs-CRP was significantly lower in the vitamin D group (P = .045). This study could not show a clear effect of vitamin D in the prevention of cardiac injury during elective PCI. Further outcome-based studies are needed to describe the role of vitamin D in the prevention of periprocedural myocardial injury. PMID- 28841230 TI - Rationale and design of the Drug-Eluting Stents vs Bare-Metal Stents in Saphenous Vein Graft Angioplasty (DIVA) Trial. AB - VA Cooperative Studies Program #571 (DIVA) was designed to evaluate the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure when compared with bare-metal stents (BMS) in participants undergoing stenting of de novo SVG lesions. Participants undergoing clinically indicated stenting of de novo SVG lesions were randomized in a 1:1 ratio to DES or BMS. Randomization was stratified by presence/absence of diabetes mellitus and the number of target SVG lesions (1 vs >=2) within each participating site. At sites that did not routinely administer 12-months of dual antiplatelet therapy after SVG stenting participants without acute coronary syndromes received 1 month of open-label clopidogrel, followed by 11 months of clopidogrel for those assigned to DES and 11 months of placebo for those assigned to BMS. The primary endpoint was the 12-month incidence of target-vessel failure (defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization). Secondary endpoints included the incidence of other clinical endpoints and the incremental cost-effectiveness of DES relative to BMS. Due to lower-than-anticipated target-vessel failure rates, target enrollment was increased from 519 to 762. The study had randomized 599 participants when recruitment ended in December 2015. The DIVA trial will provide clarity on the appropriate stent type for de novo SVG lesions. PMID- 28841231 TI - Noncholestatic acute hepatocellular injury following candesartan administration. AB - Arterial hypertension is a highly manageable disorder due to a variety of drugs available for its treatment. Since the late 1990s, angiotensin II receptor blockers have been widely prescribed, achieving appropriate control in patients' blood pressure. Few cases of serious adverse effects have been reported to date. Here, we present a case of acute hepatocellular injury secondary to candesartan administration. Further studies should be performed in patients who present with this adverse effect, in order to prevent more serious outcomes. PMID- 28841232 TI - Inhibiting heat shock protein 90 and the ubiquitin-proteasome pathway impairs metabolic homeostasis and leads to cell death in human pancreatic cancer cells. AB - BACKGROUND: Heat shock protein 90 (HSP90) and the ubiquitin-proteasome pathway play crucial roles in the homeostasis of pancreatic cancer cells. This study combined for the first time the HSP90 inhibitor ganetespib (Gan) and the proteasome inhibitor carfilzomib (Carf) to target key mechanisms of homeostasis in pancreatic cancer. It was hypothesized that Gan plus Carf would elicit potent antitumor activity by modulating complementary homeostatic processes. METHODS: In vitro and in vivo effects of this combination on mechanisms of cell growth and viability were evaluated with human pancreatic cancer cell lines (MIA PaCa-2 and HPAC). RESULTS: Combined treatment with Gan and Carf significantly decreased cell viability. The mechanism varied by cell line and involved G2 -M cell-cycle arrest accompanied by a consistent reduction in key cell-cycle regulatory proteins and concomitant upregulation of p27. Further studies revealed increased autophagy markers, including the upregulation of autophagy related 7 and light chain 3 cleavage, and evidence of apoptosis (increased Bax expression and processing of caspase 3). Immunoblot analyses confirmed the modulation of other pathways that influence cell viability, including phosphoinositide 3-kinase/Akt and nuclear factor kappaB. Finally, the treatment of athymic mice bearing HPAC tumors with Gan and Carf significantly reduced tumor growth in vivo. An immunoblot analysis of freshly isolated tumors from animals at the end of the study confirmed in vivo modulation of key signaling pathways. CONCLUSIONS: The results reveal Gan plus Carf to be a promising combination with synergistic antiproliferative, apoptotic, and pro-autophagy effects in preclinical studies of pancreatic cancer and will further the exploration of the utility of this treatment combination in clinical trials. Cancer 2017;123:4924-33. (c) 2017 American Cancer Society. PMID- 28841233 TI - Patients without comorbidities at the time of diagnosis of atrial fibrillation: causes of death during long-term follow-up compared to matched controls. AB - BACKGROUND: Little is known about the long-term, cause-specific mortality risk in patients without comorbidities at the time of diagnosis of atrial fibrillation (AF). METHODS: From a nation-wide registry of patients hospitalized with incident AF between 1995 and 2008 we identified 9 519 patients with a first diagnosed AF and no comorbidities at the time of AF diagnosis. They were matched with 12 468 controls. The follow-up continued until December 2008. Causes of death were classified according to the ICD-10 codes. RESULTS: During follow-up, 11.1% of patients with AF and 8.3% of controls died. Cardiovascular diseases were the most common causes of death and the only diagnoses which showed significantly higher relative risk in patients with AF than controls (HR 2.0, 95% CI 1.8-2.3), and the relative risk was significantly higher in women than in men. Stroke was a more common cause among patients with AF, 13.1% versus 9.7% (HR 2.7, 95% CI 1.8-4.0), while cerebral hemorrhage was more common among controls, 4.7% versus 10.2% (HR 0.9, 95% CI 0.6-1.5). The time from AF diagnosis to death was 6.0 +/- 3.1 years. CONCLUSIONS: In patients with incident AF and no known comorbidities at the time of AF diagnosis, only cardiovascular diseases were more often causes of death as compared to controls. Women carried a significantly higher relative risk than men. PMID- 28841235 TI - Harms of off-label erythropoiesis-stimulating agents for critically ill people. AB - BACKGROUND: Anaemia is a common problem experienced by critically-ill people. Treatment with erythropoiesis-stimulating agents (ESAs) has been used as a pharmacologic strategy when the blunted response of endogenous erythropoietin has been reported in critically-ill people. The use of ESAs becomes more important where adverse clinical outcomes of transfusing blood products is a limitation. However, this indication for ESAs is not licensed by regulatory authorities and is called off-label use. Recent studies concern the harm of ESAs in a critical care setting. OBJECTIVES: To focus on harms in assessing the effects of erythropoiesis-stimulating agents (ESAs), alone or in combination, compared with placebo, no treatment or a different active treatment regimen when administered off-label to critically-ill people. SEARCH METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO via OvidSP, CINAHL, all evidence-based medicine (EBM) reviews including IPA and SCI-Expanded, Conference Proceedings Citation Index- Science, BIOSIS Previews and TOXLINE up to February 2017. We also searched trials registries, checked reference lists of relevant studies and tracked their citations by using SciVerse Scopus. SELECTION CRITERIA: We considered randomized controlled trials (RCTs) and controlled observational studies, which compared scheduled systemic administration of ESAs versus other effective interventions, placebo or no treatment in critically-ill people. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and evaluated the eligibility of retrieved records, extracted data and assessed the risks of bias and quality of the included studies. We resolved differences in opinion by consensus or by involving a third review author. We assessed the evidence using GRADE and created a 'Summary of findings' table. We used fixed-effect or random-effects models, depending on the heterogeneity between studies. We fitted three-level hierarchical Bayesian models to calculate overall treatment effect estimates. MAIN RESULTS: Of the 27,865 records identified, 39 clinical trials and 14 observational studies, including a total of 945,240 participants, were eligible for inclusion. Five studies are awaiting classification. Overall, we found 114 adverse events in 33 studies (30 RCTs and three observational studies), and mortality was reported in 41 studies (32 RCTs and nine observational studies). Most studies were at low to moderate risk of bias for harms outcomes. However, overall harm assessment and reporting were of moderate to low quality in the RCTs, and of low quality in the observational studies. We downgraded the GRADE quality of evidence for venous thromboembolism and mortality to very low and low, respectively, because of risk of bias, high inconsistency, imprecision and limitations of study design.It is unclear whether there is an increase in the risk of any adverse events (Bayesian risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.21; 3099 participants; 9 studies; low-quality evidence) or venous thromboembolism (Bayesian RR 1.04, 95% CI 0.70 to 1.41; 18,917 participants; 18 studies; very low-quality evidence).There was a decreased risk of mortality with off-label use of ESAs in critically-ill people (Bayesian RR 0.76, 95% CI 0.61 to 0.92; 930,470 participants; 34 studies; low-quality evidence). AUTHORS' CONCLUSIONS: Low quality of evidence suggests that off-label use of ESAs may reduce mortality in a critical care setting. There was a lack of high-quality evidence about the harm of ESAs in critically-ill people. The information for biosimilar ESAs is less conclusive. Most studies neither evaluated ESAs' harm as a primary outcome nor predefined adverse events. Any further studies of ESA should address the quality of evaluating, recording and reporting of adverse events. PMID- 28841234 TI - Effect of time to initiation of postoperative radiation therapy on survival in surgically managed head and neck cancer. AB - BACKGROUND: The objective of this study was to determine the effects of National Comprehensive Cancer Network (NCCN) guideline-adherent initiation of postoperative radiation therapy (PORT) and different time-to-PORT intervals on the overall survival (OS) of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: The National Cancer Data Base was reviewed for the period of 2006-2014, and patients with HNSCC undergoing surgery and PORT were identified. Kaplan-Meier survival estimates, Cox regression analysis, and propensity score matching were used to determine the effects of initiating PORT within 6 weeks of surgery and different time-to-PORT intervals on survival. RESULTS: This study included 41,291 patients. After adjustments for covariates, starting PORT >6 weeks postoperatively was associated with decreased OS (adjusted hazard ratio [aHR], 1.13; 99% confidence interval [CI], 1.08-1.19). This finding remained in the propensity score-matched subset (hazard ratio, 1.21; 99% CI, 1.15-1.28). In comparison with starting PORT 5 to 6 weeks postoperatively, initiating PORT earlier was not associated with improved survival (aHR for <= 4 weeks, 0.93; 99% CI, 0.85-1.02; aHR for 4-5 weeks, 0.92; 99% CI, 0.84-1.01). Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements (aHR, 1.09, 1.10, and 1.12 for 7-8, 8-10, and >10 weeks, respectively). CONCLUSIONS: Nonadherence to NCCN guidelines for initiating PORT within 6 weeks of surgery was associated with decreased survival. There was no survival benefit to initiating PORT earlier within the recommended 6-week timeframe. Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements. Cancer 2017;123:4841-50. (c) 2017 American Cancer Society. PMID- 28841237 TI - Singlet Oxygen Detection Using Red Wine Extracts as Photosensitizers. AB - Moderate consumption of red wine provides beneficial effects to health. This is attributed to polyphenol compounds present in wine such as resveratrol, quercetin, gallic acid, rutin, and vanillic acid. The amount of these antioxidants is variable; nevertheless, the main beneficial effects of red wine are attributed to resveratrol. However, it has been found that resveratrol and quercetin are able to photosensitize singlet oxygen generation and conversely, gallic acid acts as quencher. Therefore, and since resveratrol and quercetin are some of the most important antioxidants reported in red wines, the aim of this research was to evaluate the photosensitizing ability of 12 red wine extracts through photo-oxidation of ergosterol. The presence of 1 O2 was detected by ergosterol conversion into peroxide of ergosterol through 1 H NMR analysis. Our results showed that 10 wine extracts were able to act as photosensitizers in the generation of singlet oxygen. The presence of 1 O2 can damage other compounds of red wine and cause possible organoleptic alterations. Finally, although the reaction conditions employed in this research do not resemble the inherent conditions in wine making processing or storing, or even during its consumption, this knowledge could be useful to prevent possible pro-oxidant effects and avoid detrimental effects in red wines. PMID- 28841236 TI - Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies. AB - BACKGROUND: Pracinostat is a potent histone deacetylase inhibitor with antitumor activity in both solid tumor and acute myeloid leukemia (AML) cell lines. Pracinostat is reported to have modest clinical activity in patients with advanced solid tumors. Given the higher preclinical sensitivity of hematologic malignancies to pracinostat, the authors conducted a phase 1 study to assess the safety, maximum tolerated dose, recommended phase 2 dose, efficacy, pharmacokinetics, and pharmacodynamics of pracinostat in patients with advanced hematological malignancies. METHODS: Pracinostat was administered orally 3 times a week for 3 weeks on a 28-day cycle. Patients were assigned to 7 dose levels using a 3 + 3 dose escalation design. RESULTS: A total of 44 patients were enrolled, 25 of whom had AML and 14 of whom had myelodysplastic syndrome. The maximum tolerated dose was 120 mg and the recommended phase 2 dose was 60 mg. Two patients with AML achieved a response: 1 complete remission (CR) and 1 complete cytogenetic response. Despite a dose-dependent increase in the plasma concentration of pracinostat, a similar increase in histone acetylation was not observed. As an extension, 10 additional patients with myelodysplastic syndrome were enrolled to assess the safety and efficacy of pracinostat in combination with azacitidine. Six patients achieved a CR and 3 achieved a CR without platelet recovery with no added toxicity. CONCLUSIONS: The results of the current study demonstrate that pracinostat is safe, with modest single-agent activity in patients with hematological malignancies. Cancer 2017;123:4851-9. (c) 2017 American Cancer Society. PMID- 28841238 TI - Behavioral protective factors of increased depressive symptoms in community dwelling older adults: A prospective cohort study. AB - BACKGROUND: It remains unclear what kinds of behavior prevent the development of geriatric depression. This study aimed to elucidate behavioral predictors of increased depressive symptoms in older adults focusing on gender differences. METHODS: A total of 3106 community-dwelling older people aged older than or equal to 65 years without depressive symptoms at baseline participated. The 15-item Geriatric Depression Scale was used to assess depressive symptoms with a score of 6 or more at baseline and 15 month follow-up. Behavioral status was investigated by using dichotomous questions about the aspects of physical, cognitive, and social activities. Each category included 3 specific items. Demographic data and other potential confounding factors were also assessed. RESULTS: In the 15 month follow-up survey, 239 participants (7.7%) reported increased depressive symptoms. Multiple logistic regression analysis indicated that engagement in light physical exercise (odds ratio = 0.74, 95%, CI = 0.56-0.98), taking enrichment lessons (0.62, 0.46-0.85), using a personal computer (0.68, 0.48-0.97), participation in events at the community center (0.54, 0.40-0.72), and attending a community meeting (0.69, 0.52-0.92) were independently associated with lower risk of increased depressive symptoms. In a separate analysis for each gender, significant odds ratios of using a personal computer were observed in men, whereas significant odds ratios of light physical exercise, participation in events at the community center, and attending a community meeting were observed in women. CONCLUSIONS: Light physical exercise, taking lessons, usage of a computer, and participation in community events showed protective effects against depressive symptoms. However, the significance of each behavioral factor may vary according to gender. PMID- 28841239 TI - Efficacy of independence sampling in replica exchange simulations of ordered and disordered proteins. AB - Recasting temperature replica exchange (T-RE) as a special case of Gibbs sampling has led to a simple and efficient scheme for enhanced mixing (Chodera and Shirts, J. Chem. Phys., 2011, 135, 194110). To critically examine if T-RE with independence sampling (T-REis) improves conformational sampling, we performed T RE and T-REis simulations of ordered and disordered proteins using coarse-grained and atomistic models. The results demonstrate that T-REis effectively increase the replica mobility in temperatures space with minimal computational overhead, especially for folded proteins. However, enhanced mixing does not translate well into improved conformational sampling. The convergences of thermodynamic properties interested are similar, with slight improvements for T-REis of ordered systems. The study re-affirms the efficiency of T-RE does not appear to be limited by temperature diffusion, but by the inherent rates of spontaneous large scale conformational re-arrangements. Due to its simplicity and efficacy of enhanced mixing, T-REis is expected to be more effective when incorporated with various Hamiltonian-RE protocols. (c) 2017 Wiley Periodicals, Inc. PMID- 28841240 TI - Preanalytic processing of rat plasma influences thrombin generation and fibrinolysis assays. AB - BACKGROUND: Thrombin generation assays (TGA) have potential applications as measures of hemostatic balance in animal models. However, variations in plasma processing greatly influence human TGA, and may also impact on the translational value of TGA in animal studies. OBJECTIVES: The purpose of the study was to compare the performance characteristics of Sprague-Dawley rat plasma prepared by single vs double centrifugation protocols in TGA and fibrinolysis assays. METHODS: Platelet-poor plasma (PPP) from adult rats (n = 20 males; 20 females) was prepared by centrifugation at 1200g * 12 min, or 2 sequential centrifugations of 2500g * 15 min. Plasma aliquots were assayed fresh and after freeze-thaw in a commercial fluorogenic TGA (Technothrombin TGA, Technoclone) using 2 different trigger reagents containing approximately 7 pM human tissue factor. In addition to TGA variables (lag time, peak thrombin, endogenous thrombin potential), we compared clotting time test and fibrinogen concentration, residual platelet and platelet-derived microparticle (PMP) counts measured by flow cytometry, and variables of fibrin clot formation and lysis measured in turbidimetric assays. RESULTS: Single-centrifugation PPP demonstrated significantly greater thrombin generating potential regardless of trigger reagent, yielded higher residual platelet and procoagulant PMP counts, and more stable fibrin clot profiles. The influence of a freeze-thaw cycle on TGA varied depending on trigger reagent, and male sex was associated with an overall "procoagulant" phenotype. CONCLUSIONS: Preanalytic processing and sex have significant effects on many functional measures of hemostasis in rats. A standardized double centrifugation protocol to prepare PPP is recommended for future studies. PMID- 28841242 TI - Under-recognized immunoexpression of "neuroendocrine markers" and "myoepithelial markers" in basal cell carcinomas: Does it indicate true neuroendocrine and myoepithelial differentiation? PMID- 28841241 TI - Unfavorable regions in the ramachandran plot: Is it really steric hindrance? The interacting quantum atoms perspective. AB - Accurate description of the intrinsic preferences of amino acids is important to consider when developing a biomolecular force field. In this study, we use a modern energy partitioning approach called Interacting Quantum Atoms to inspect the cause of the phi and psi torsional preferences of three dipeptides (Gly, Val, and Ile). Repeating energy trends at each of the molecular, functional group, and atomic levels are observed across both (1) the three amino acids and (2) the phi/psi scans in Ramachandran plots. At the molecular level, it is surprisingly electrostatic destabilization that causes the high-energy regions in the Ramachandran plot, not molecular steric hindrance (related to the intra-atomic energy). At the functional group and atomic levels, the importance of key peptide atoms (Oi-1 , Ci , Ni , Ni+1 ) and some sidechain hydrogen atoms (Hgamma ) are identified as responsible for the destabilization seen in the energetically disfavored Ramachandran regions. Consistently, the Oi-1 atoms are particularly important for the explanation of dipeptide intrinsic behavior, where electrostatic and steric destabilization unusually complement one another. The findings suggest that, at least for these dipeptides, it is the peptide group atoms that dominate the intrinsic behavior, more so than the sidechain atoms. (c) 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 28841243 TI - Untangling outcomes of de jure and de facto community-based management of natural resources. AB - We systematically reviewed the literature on the tragedy of the commons and common-property resources. We segregated studies by legal management regimes (de jure regimes) and management that develops in practice (de facto regimes) to understand how the structure of regime formation affects the outcome of community management on sustainability of resource use. De facto regimes, developed within the community, are more likely to have positive impacts on the resource. However, de facto regimes are fragile and not resilient in the face of increased population pressure and unregulated markets, and de facto management regimes are less successful where physical exclusion of external agents from resources is more difficult. Yet, formalization or imposition of de jure management regimes can have complicated impacts on sustainability. The imposition of de jure regimes usually has a negative outcome when existing de facto regimes operate at larger scales than the imposed de jure regime. In contrast, de jure regimes have largely positive impacts when the de facto regimes operate at scales smaller than the overlying de jure regimes. Formalization may also be counterproductive because of elite capture and the resulting de facto privatization (that allows elites to effectively exclude others) or de facto open access (where the disenfranchised may resort to theft and elites cannot effectively exclude them). This underscores that although the global movement to formalize community-management regimes may address some forms of inequity and may produce better outcomes, it does not ensure resource sustainability and may lead to greater marginalization of users. Comparison of governance systems that differentiate between initiatives that legitimize existing de facto regimes and systems that create new de facto regimes, investigations of new top-down de jure regimes, and studies that further examine different approaches to changing de jure regimes to de facto regimes are avenues for further inquiry. PMID- 28841244 TI - Right coronary ostial extra anatomical bypass following an aortic root false aneurysm after a composite graft procedure. PMID- 28841245 TI - Marked accumulation of oligodendroglia-like cells in temporal lobe epilepsy with amygdala enlargement and hippocampal sclerosis. AB - Although an increasing number of cases of temporal lobe epilepsy (TLE) with ipsilateral amygdala enlargement (AE) have been reported, there are few pathological reports, and no clear consensus has been established. Oligodendroglia or oligodendroglia-like cells (OLCs) have recently attracted attention in epilepsy studies. Here, we report the clinical and pathological findings of a 40-year-old male TLE patient with AE and hippocampal sclerosis, in whom histopathological study demonstrated remarkable clustering of OLCs around the uncus. The patient began to have refractory seizures at the age of 14, and preoperative MRI revealed left amygdala enlargement and left hippocampal atrophy. Other examinations were consistent with left mesial temporal epileptogenicity. He underwent surgical resection and achieved seizure freedom. Histopathological study of the amygdala showed swollen neurons with relatively large bodies and thick neurites, accompanied by vacuolar degeneration in the background. Additionally, there were marked clusters of OLCs with round nuclei and densely stained chromatin around the uncus. The OLCs were Olig2-positive. In the hippocampus, severe cell loss in CA1 and granule cell dispersion in the dentate gyrus were found. These findings may provide some insights for further pathological investigations of TLE with non-neoplastic AE. PMID- 28841246 TI - Facility-level variation in diabetes and blood pressure control in patients with diabetes: Findings from the Veterans Affairs national database. AB - BACKGROUND: Intensive glycemic and blood pressure (BP) control in diabetic patients is associated with improved cardiovascular outcomes. HYPOTHESIS: We hypothesized that there is suboptimal glycemic and BP control with significant facility-level variation in patients with diabetes. METHODS: We identified patients with diabetes receiving care in 130 facilities in the Veterans Affairs Health Care System. We assessed facility-level rates of glycemic (hemoglobin [Hb]A1c <7%), BP (BP <140/90 mmHg), and combined glycemic and BP control (HbA1c <7% and BP <140/90 mmHg), and their facility-level variation in using median rate ratios (MRR). RESULTS: Among 1 103 302 patients with diabetes, 50.2% participants had an HbA1c <7%, 77.5% had a BP <140/90 mmHg, and 39.8% had both, HbA1c <7% and BP <140/90 mmHg. Median facility-level rates were 50.3% (interquartile range [IQR], 47.9%-52.4%) for glycemic control, 78.4% (IQR, 75.2%-80.0%) for BP control, and 39.9% (IQR, 38.14%-42.34%) for combined glycemic and BP control. Unadjusted MRR for glycemic control was 1.61 (95% confidence interval [CI]: 1.51 1.70) which decreased to 1.16 (95% CI: 1.14-1.19) after adjusting for patient and facility-level variables, indicating a 16% variation in glycemic control between 2 identical patients receiving care at 2 random facilities. Unadjusted MRR for BP control was 1.49 (95% CI: 1.41-1.56), which decreased to 1.25 (95% CI: 1.21 1.28), whereas unadjusted MRR for combined glycemic and BP control was 1.59 (95% CI: 1.50-1.68), which decreased to 1.15 (95% CI: 1.13-1.17) after adjustment. CONCLUSIONS: Facility-level rates for BP control and glycemic control remain low with significant facility-level variation. Much of this is explained by patient and facility-level variables although 16%, 25%, and 15% variation in glycemic, BP, and combined glycemic and BP control remains unexplained. PMID- 28841247 TI - Heart-bound adiponectin, not serum adiponectin, inversely correlates with cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. AB - NEW FINDINGS: What is the central question of this study? An inverse correlation between circulating adiponectin and many diseases has been reported, but some studies have found no correlation. To evaluate this controversy, we investigated the relationship between heart-bound adiponectin and hypertension or cardiac hypertrophy, compared with serum adiponectin. What is the main finding and its importance? Using hypertensive and normotensive rats, we found that heart-bound adiponectin was inversely correlated with cardiac hypertrophy, suggesting that heart-bound adiponectin has a more important function in preventing cardiac hypertrophy than circulating adiponectin. Our study provides new insights regarding the role of adiponectin in diseases. The inverse correlation between circulating adiponectin concentration and hypertension or cardiac hypertrophy is still controversial. In addition to circulating adiponectin, adiponectin is also bound to tissues such as the heart and skeletal muscle. In this study, we investigated the relationship of serum adiponectin and heart-bound adiponectin with hypertension and cardiac hypertrophy. Four types of hypertensive rats presenting different blood pressure levels were used at different ages, as follows: normotensive Wistar-Kyoto rats (WKYs); two sub-strains (strains C and B2, having low and high blood pressure, respectively) of spontaneously hypertensive rats (SHRs); and stroke-prone SHRs (SHRSPs). Blood pressure, heart to-body weight ratio, serum adiponectin and heart-bound adiponectin were determined. Histopathological analysis of the heart was carried out to evaluate the relationship with heart-bound adiponectin. Serum adiponectin concentration was not inversely correlated with blood pressure or heart-to-body weight ratio. In contrast, heart-bound adiponectin levels were significantly lower in SHRSPs than in other strains at respective ages. This resulted from a decrease in T cadherin expression, which induced adiponectin binding to tissues. No significant difference in heart-bound adiponectin among WKYs and SHRs (C and B2) was detected, indicating that heart-bound adiponectin is not related to hypertension. In addition, differences in heart-bound adiponectin did not affect AMP-activated protein kinase in the traditional adiponectin activation cascade. Histopathological analysis revealed that heart-bound adiponectin was inversely correlated with cardiomyocyte hypertrophy and left ventricular wall thickness and, in part, with cardiac fibrosis. These results suggest that the decreased level of heart-bound adiponectin in SHRSPs is more related to their cardiac hypertrophy than circulating adiponectin. PMID- 28841248 TI - Radical Hydrodehalogenation of Aryl Bromides and Chlorides with Sodium Hydride and 1,4-Dioxane. AB - A practical method for radical chain reduction of various aryl bromides and chlorides is introduced. The thermal process uses NaH and 1,4-dioxane as reagents and 1,10-phenanthroline as an initiator. Hydrodehalogenation can be combined with typical cyclization reactions, proving the nature of the radical mechanism. These chain reactions proceed by electron catalysis. DFT calculations and mechanistic studies support the suggested mechanism. PMID- 28841249 TI - Assessing physician knowledge regarding indications for a primary prevention implantable defibrillator and potential barriers for referral. AB - BACKGROUND: Although there is clear evidence to demonstrate that primary prevention implantable defibrillators (ICDs) reduce mortality in high-risk patients, ICDs are underutilized. Limited data exist assessing referring physicians' knowledge about guideline indications and attitudes towards ICDs, which may influence decision for referral. METHODS AND RESULTS: The Arrhythmia Working Group from the Alberta Cardiovascular and Stroke Strategic Clinical Network developed a web-based survey consisting of case scenarios regarding primary prevention ICD indications and a list of barriers for referral to aid in the design of a complex device care pathway. We invited referring physicians to participate in the survey including internists and cardiologists and cardiology residents. The survey was completed by 109 of 799 (response rate = 14%) of physicians. Of those, 55% were internists, 32% cardiologists, and 13% cardiology residents. The majority of physicians were male (62%), practicing in a university hospital (66%). Overall, complete guideline-concordant answers were provided by 34% of physicians. In multivariable analysis, predictors of complete guideline concordance were being a cardiologist (odd ratio [OR] 5.9, confidence interval [CI] 2.1-16.4, P = 0.001) and cardiology resident (OR 6.7, CI 1.7-27.3, P = 0.007). The most common barrier for referral for internists was lack of confidence in knowledge of guideline recommendations; while cardiologists reported concerns about cost-effectiveness and cardiology residents were most concerned with inappropriate shocks. CONCLUSION: Knowledge regarding indications for primary prevention ICD is limited and varies significantly among referring physicians. The barriers for referral differ among physician groups and addressing these identified barriers may help to improve appropriate ICD utilization. PMID- 28841250 TI - Narrow QRS tachycardia in a patient with old infarction. What Is the mechanism? PMID- 28841251 TI - Procedural findings and ablation outcome in patients with atrial fibrillation referred after two or more failed catheter ablations. AB - INTRODUCTION: This study reports the procedural findings and ablation outcome in AF patients referred after >=2 failed PV isolation (PVI). METHODS: Three hundred and five consecutive AF patients referred after >=2 PVI were included in the analysis. High-dose isoproterenol challenge was used to identify PV reconnection and non-PV triggers; the latter were ablated based on the operator's discretion during the index procedure. At the repeat procedure, non-PV triggers were ablated in all. Empirical isolation of LA appendage (LAA) and coronary sinus (CS) was performed if the PVs were silent and no non-PV triggers were detected. RESULTS: PV reconnection was detected in 226 and non-PV triggers were identified or empirically isolated in 285 patients during the index procedure. At follow-up, 182 (60%) patients were recurrence-free off-AAD; the success rate with and without non-PV ablation was 81% vs. 8% (P < 0.0001). 104 patients underwent repeat procedure with non-PV trigger ablation in all. At 1 year, 90% were arrhythmia free off-AAD in non-PV ablation group, and 72% who did not receive non PV triggers ablation at the index procedure (P = 0.035). The success rate of empirical LAA and CS isolation was 78.5% and 82% after the index and repeat procedure, respectively. CONCLUSION: In patients experiencing AF recurrence after multiple failed PVI, despite PV reconnection, non-PV triggers were found to be responsible for AF maintenance in the majority and ablating those triggers increased ablation success. Additionally, in the presence of permanent PVI and no non-PV triggers on isoproterenol, empirical isolation of LAA and CS provided high rate of arrhythmia-free survival. PMID- 28841252 TI - Prioritizing novel and existing ambulance performance measures through expert and lay consensus: A three-stage multimethod consensus study. AB - BACKGROUND: Current ambulance quality and performance measures, such as response times, do not reflect the wider scope of care that services now provide. Using a three-stage consensus process, we aimed to identify new ways of measuring ambulance service quality and performance that represent service provider and public perspectives. DESIGN: A multistakeholder consensus event, modified Delphi study, and patient and public consensus workshop. SETTING AND PARTICIPANTS: Representatives from ambulance services, patient and public involvement (PPI) groups, emergency care clinical academics, commissioners and policymakers. RESULTS: Nine measures/principles were highly prioritized by >75% of consensus event participants, including measures relating to pain, patient experience, accuracy of dispatch decisions and patient safety. Twenty experts participated in two Delphi rounds to further refine and prioritize measures; 20 measures in three domains scored >=8/9, indicating good consensus, including proportion of calls correctly prioritized, time to definitive care and measures related to pain. Eighteen patient/public representatives attended a consensus workshop, and six measures were identified as important. These include time to definitive care, response time, reduction in pain scores, calls correctly prioritized to appropriate levels of response and survival to hospital discharge for treatable emergency conditions. CONCLUSIONS: Using consensus methods, we identified a shortlist of ambulance outcome and performance measures that are important to ambulance clinicians and service providers, service users, commissioners, and clinical academics, reflecting current pre-hospital ambulance care and services. The measures can potentially be used to assess pre-hospital quality or performance over time, with most calculated using routinely available data. PMID- 28841253 TI - Identification of Highly Expressed Plasmodium Vivax Proteins from Clinical Isolates Using Proteomics. AB - Plasmodium vivax is the most geographically widespread species responsible for malaria in humans. Our study focused on identifying highly expressed parasite proteins using a shotgun proteomics approach. Parasites (P. vivax) are isolated from seven patient samples using saponin lysis. Protein extracts from these parasites are processed and subjected to LC-MS/MS analysis. An overall proteome coverage of 605 P. vivax proteins along with 1670 human host proteins are obtained upon combining the data from LC-MS/MS runs. While a major proportion of the P. vivax proteins are either hypothetical or involved in basic cellular activities, few proteins such as tryptophan-rich antigen (Pv-fam-a; PVX_090265), Pv-fam-d protein (PVX_101520), Plasmodium exported protein (PVX_003545), Pvstp1 (PVX_094303) and hypothetical protein (PVX_083555) are detected in more than 80% of the clinical isolates and found to be unique to P. vivax without orthologs in P. falciparum. Our proteomics study on individual parasite isolates reveals highly expressed P. vivax proteins, few of which may be good candidates for vivax malaria diagnosis due to their abundance and absence in P. falciparum. This study represents the first step towards the identification of biomarkers for P. vivax malaria. In future, their clinical diagnostic values must be explored and validated on large patient cohorts. PMID- 28841254 TI - Functional capacity in a rat model of heart failure: impact of myocardial infarct size. AB - NEW FINDINGS: What is the central question of this study? To the best of our knowledge, no studies have evaluated oxygen uptake, carbon dioxide production and exercise tolerance in rats that have undergone myocardial infarction classified by myocardial infarct (MI) size. What is the main finding and its importance? Oxygen uptake and exercise intolerance are MI size dependent, and classification based on MI size can distinguish rats with functional capacity impairment. Rats with a large MI (>40% of the left ventricle) might provide a good model for the testing of new therapies that have the potential to modify the variables of functional capacity. Oxygen uptake (VO2) and exercise tolerance in rats classified by myocardial infarct (MI) size are underexplored. The aim of this study was to evaluate VO2, carbon dioxide production (VCO2) and exercise tolerance in rats that had undergone myocardial infarction. Fourteen weeks after myocardial infarction or sham surgery, rats underwent an integrated approach to evaluation of left ventricular function and VO2/VO2VCO2VCO2, exercise tolerance and skeletal muscle weight. Based on determination of MI size, rats were assigned to sham-operated controls (Sham, n = 12), small myocardial infarction (SMI, n = 8) and large myocardial infarction (LMI, n = 5) groups. The LMI rats showed lower systolic (ejection fraction and fractional shortening) and diastolic (E/A ratio) left ventricular function compared with SMI. Maximal VO2 (~24%, P < 0.05), VO2 reserve (~30%, P < 0.05), time to exhaustion (~36%, P < 0.05) and maximal velocity (~30%, P < 0.05) were lower in LMI compared with sham-operated control animals, with no difference between SMI rats and sham-operated controls. Maximal VCO2 and respiratory exchange ratio showed no significant difference between MI rats and sham-operated control rats. The LMI rats demonstrated lower gastrocnemius weight (~12%, P < 0.05) and soleus weight (~19%, P = 0.07) compared with sham-operated control rats. Significant correlations between MI size, left ventricular end-diastolic pressure, right ventricle hypertrophy, pulmonary congestion, ejection fraction and fractional shortening with maximal VO2 and distance run were observed. Oxygen uptake and exercise intolerance are MI size dependent. PMID- 28841255 TI - Alkynyl Thioethers in Gold-Catalyzed Annulations To Form Oxazoles. AB - Non-oxidative, regioselective, and convergent access to densely functionalized oxazoles is realized in a functional-group tolerant manner using alkynyl thioethers. Sulfur-terminated alkynes provide access to reactivity previously requiring strong donor-substituted alkynes such as ynamides. Sulfur does not act in an analogous donor fashion in this gold-catalyzed reaction, thus leading to complementary regioselective outcomes and addressing the limitations of using ynamides. PMID- 28841256 TI - Stimuli-Responsive Dipeptide-Protein Hydrogels through Schiff Base Coassembly. AB - Different from the conventional irreversible covalent conjugations, a simple and efficient dynamic Schiff base covalent assembly is developed to construct the stable and smart dipeptide-protein hydrogels under mild conditions. Diphenylalanine-hemoglobin hydrogel is chosen to investigate the gelation formation process and mechanism. It is found that such assembled dipeptide protein hydrogels are sensitive to pH variation, and simultaneously the proteins can be released without changing the native secondary structures from the gels. Furthermore, these adaptive hydrogels can encapsulate a series of small molecules, multicomponent proteins, and functional nanoparticles. These versatile hydrogels may find a great potential in bioapplications. PMID- 28841257 TI - Magnetic ionic liquid assisted single-drop microextraction of ascorbic acid before its voltammetric determination. AB - For the first time, we coupled a microextraction technique using a magnetic ionic liquid with voltammetric determination. A hydrophobic magnetic ionic liquid that contains the tetrachloromanganate(II) anion, namely, aliquat tetrachloromanganate(II), was synthesized and used for the extraction of ascorbic acid from aqueous solutions followed by voltammetric determination. The extraction procedure was carried out using a single drop microextraction technique in which the ascorbic acid containing magnetic ionic liquid was separated with a magnet and then cast onto the surface of a carbon paste electrode modified with TiO2 nanoparticles for the voltammetric quantification of the extracted ascorbic acid. Electrochemical quantification was carried out in a blank phosphate buffer solution. After optimizing different experimental conditions, a linear concentration range of 1.50-40.0 nM with a detection limit of 0.43 nM was obtained for the determination of ascorbic acid. The presented approach was successfully applied to the determination of ascorbic acid in samples of vitamin C effervescent tablets and orange juice. PMID- 28841258 TI - Cesium Lead Halide Perovskite Nanostructures: Tunable Morphology and Halide Composition. AB - Inorganic halide perovskite (CsPbX3 ) nanostructures have gained considerable interest in recent years owing to their enhanced stability and optoelectronic applications. Recent developments in the synthesis of nanostructures are reviewed. The impact of the precursor and ligand nature, temperature and growth time on the morphology and shape tuning of CsPbX3 nanostructures is described in relation to their optical properties. The presynthetic and postsynthetic anion exchange strategies to retain pre-existing crystal phase and shape are discussed in this minireview. PMID- 28841259 TI - Use of Ionic liquids as additives in ion exchange chromatography for the analysis of cations. AB - The behavior of acids (citric acid, nitric acid, oxalic acid, tartaric acid) as a mobile phase and imidazolium ionic liquids (the bromides, tetrafluoroborates and hexafluorophosphates of 1-ethyl, 1-butyl, and 1-hexyl-3-methylimidazolium) as additives in ion exchange chromatography for cations (Na+ , K+ , Mg2+ , Ca2+ ) separation were studied. The results showed that nitric acid and 1-hexyl-3-methyl imidazolium hexafluorophosphate offered the most interesting features in the separation of cations, such as lower retention time and better resolution. The selected optimal conditions were achieved by adding 0.10 mM 1-hexyl-3-methyl imidazolium hexafluorophosphate in 4.0 mM HNO3 mobile phase for the separation of four cations with the flow rate of 0.9 mL/min at room temperature (25 degrees C). The linear regression equations of Na+ , K+ , Mg2+ , Ca2+ were S = 4.4763c + 0.0209, S = 3.8903c - 0.0087, S = 6.3974c - 0.0173, and S = 7.601c - 0.0339 and the limits of detection of Na+ , K+ , Mg2+ , Ca2+ were 0.296, 4.98, 0.0970, and 1.22 MUg/L, respectively. In this work, four cations in samples were successfully detected. PMID- 28841260 TI - Carers' involvement in decision making about antipsychotic medication: A qualitative study. AB - BACKGROUND: Current Australian mental health policy recommends that carers should be involved in the provision of mental health services. Carers often provide intensive support to mental health consumers and gain detailed insight into their lives. As such, carers could make valuable contributions to well-informed decisions about mental health consumers' use of antipsychotic medication. OBJECTIVES: The aim of this study was to explore carers' participation in antipsychotic medication decision making. METHODS: Snowball sampling was used to enrol 29 carers in this study. Of these carers, 19 participated in semi structured interviews, and ten participated in a focus group. Data were analysed thematically. RESULTS: Four main themes emerged from the analysis. The findings highlighted that carers typically received little or no information about antipsychotic medication. Carers commonly addressed the shortfall in information by obtaining additional information through online sources or distributing among carer networks material that they had developed themselves. Almost all carers emphasized that they should be involved in decisions about antipsychotic medication, but noted that they were typically excluded. The lack of involvement in medication decisions was a source of frustration, as carers could contribute saliently through sharing detailed knowledge about mental health consumers' lives, address communication gaps that resulted from disjointed care and improve communication between health professionals and mental health consumers. CONCLUSION: Health professionals could consider improving the extent to which they collaborate with carers in medication decisions. PMID- 28841261 TI - High-throughput LC-MS method for the rapid characterization of multiple chemical constituents and metabolites of Da-Bu-Yin-Wan. AB - Traditional Chinese medicine is the clinical experience accumulated by Chinese people against diseases. Da-Bu-Yin-Wan is a famous traditional Chinese medicine formula consisting of Phellodendri amurensis Rupr., Anemarrhenae asphodeloides Bge., Radix Rehmanniae Preparata and Chinemys reevesii. In this study, ultra high performance liquid chromatography with electrospray ionization quadrupole time-of flight high-definition mass spectrometry with the control software of Masslynx (V4.1) was established for comprehensive screening and identification of the chemical constituents and serum metabolites of Da-Bu-Yin-Wan in vivo and in vitro. Consequently, 70 peaks in the methanol extract from Da-Bu-Yin-Wan and 38 peaks absorbed into rat blood were characterized. The 70 constituents in vitro included alkaloids, flavonoids, polysaccharide, limonoids, flavonoid, etc. And the 38 constituents consist of 22 absorbed prototypes and 16 metabolites of Da-Bu Yin-Wan absorbed in vivo. We fully clarified the chemical constituents of Da-Bu Yin-Wan and provided a scientific strategy for the screening and characterization of the chemical constituents and metabolites of traditional Chinese medicine in vitro and in vivo. PMID- 28841262 TI - Measuring 13 C-enriched CO2 in air with a cavity ring-down spectroscopy gas analyser: Evaluation and calibration. AB - RATIONALE: Cavity ring-down spectroscopy (CRDS) is becoming increasingly popular for delta13 C-CO2 analysis of air. However, little is known about the effect of high 13 C abundances on the performance of CRDS. Overlap between 12 CO2 and 13 CO2 spectral lines may adversely affect isotopic-CO2 CRDS measurements of 13 C enriched samples. Resolving this issue is important so that CRDS analysers can be used in CO2 flux studies involving 13 C-labelled tracers. METHODS: We tested a Picarro G2131-i CRDS isotopic-CO2 gas analyser with specialty gravimetric standards of widely varying 13 C abundance (from natural to 20.1 atom%) and CO2 mole fraction (xCO2 : <0.1 to 2116 ppm) in synthetic air. The presence of spectroscopic interference between 12 CO2 and 13 CO2 bands was assessed by analysing errors in measurements of the standards. A multi-component calibration strategy was adopted, incorporating isotope ratio and mole fraction data to ensure accuracy and consistency in corrected values of delta13 C-CO2 , x12 CO2 , and x13 CO2 . RESULTS: CRDS measurements of x13 CO2 were found to be accurate throughout the tested range (<0.005 to 100 ppm). On the other hand, spectral cross-talk in x12 CO2 measurements of standards containing elevated levels of 13 CO2 led to inaccuracy in x12 CO2 , total-xCO2 (x12 CO2 + x13 CO2 ), and delta13 C-CO2 data. An empirical relationship for x12 CO2 measurements that incorporated the 13 C/12 C isotope ratio (i.e. 13 CO2 /12 CO2 , RCO2) as a secondary (non linear) variable was found to compensate for the perturbations, and enabled accurate instrument calibration for all CO2 compositions covered by our standard gases. CONCLUSIONS: 13 C-enrichement in CO2 leads to minor errors in CRDS measurements of x12 CO2 . We propose an empirical correction for measurements of 13 C-enriched CO2 in air by CRDS instruments such as the Picarro G2131-i. PMID- 28841263 TI - Improved Glass Transition Temperature towards Thermal Stability via Thiols Solvent Additive versus DIO in Polymer Solar Cells. AB - The halogen-free solvent additive, 1,4-butanedithiol (BT) has been incorporated into PTB7-Th:PC71 BM, leading to higher power conversion efficiency (PCE) value as well as substantially enhanced thermal stability, as compared with the traditional 1,8-diiodooctane (DIO) additive. More importantly, the improved thermal stability after processing with BT contributes to a higher glass transition temperature (Tg ) of PTB7-Th, as determined by dynamic mechanical analysis. After thermal annealing at 130 degrees C in nitrogen atmosphere for 30 min, the PCE of the specimen processed with BT reduces from 9.3% to 7.1%, approaching to 80% of its original value. In contrast, the PCE of specimens processed with DIO seriously depresses from 8.3% to 3.8%. These findings demonstrate that smart utilization of low-boiling-point solvent additive is an effective and practical strategy to overcome thermal instability of organic solar cells via enhancing the Tg of donor polymer. PMID- 28841264 TI - Patient-centred care is a way of doing things: How healthcare employees conceptualize patient-centred care. AB - BACKGROUND: Patient-centred care is now ubiquitous in health services research, and healthcare systems are moving ahead with patient-centred care implementation. Yet, little is known about how healthcare employees, charged with implementing patient-centred care, conceptualize what they are implementing. OBJECTIVE: To examine how hospital employees conceptualize patient-centred care. RESEARCH DESIGN: We conducted qualitative interviews about patient-centred care during site four visits, from January to April 2013. SUBJECTS: We interviewed 107 employees, including leadership, middle managers, front line providers and staff at four US Veteran Health Administration (VHA) medical centres leading VHA's patient-centred care transformation. MEASURES: Data were analysed using grounded thematic analysis. Findings were then mapped to established patient-centred care constructs identified in the literature: taking a biopsychosocial perspective; viewing the patient-as-person; sharing power and responsibility; establishing a therapeutic alliance; and viewing the doctor-as-person. RESULTS: We identified three distinct conceptualizations: (i) those that were well aligned with established patient-centred care constructs surrounding the clinical encounter; (ii) others that extended conceptualizations of patient-centred care into the organizational culture, encompassing the entire patient-experience; and (iii) still others that were poorly aligned with patient-centred care constructs, reflecting more traditional patient care practices. CONCLUSIONS: Patient-centred care ideals have permeated into healthcare systems. Additionally, patient-centred care has been expanded to encompass a cultural shift in care delivery, beginning with patients' experiences entering a facility. However, some healthcare employees, namely leadership, see patient-centred care so broadly, it encompasses on-going hospital initiatives, while others consider patient-centred care as inherent to specific positions. These latter conceptualizations risk undermining patient-centred care implementation by limiting transformational initiatives to specific providers or simply repackaging existing programmes. PMID- 28841265 TI - Release of Enzymatically Active Deubiquitinating Enzymes upon Reversible Capture by Disulfide Ubiquitin Reagents. AB - Deubiquitinating enzymes (DUBs) catalyze the cleavage of ubiquitin from target proteins. Ubiquitin is post-translationally attached to proteins and serves as an important regulatory signal for key cellular processes. In this study, novel activity-based probes to study DUBs were synthesized that comprise a ubiquitin moiety and a novel disulfide warhead at the C-terminus. These reagents can bind DUBs covalently by forming a disulfide bridge between the active-site cysteine residue and the ubiquitin-based probe. As disulfide bridges can be broken by the addition of a reducing agent, these novel ubiquitin reagents can be used to capture and subsequently release catalytically active DUBs, whereas existing capturing agents bind irreversibly. These novel reagents allow for the study of these enzymes in their active state under various conditions. PMID- 28841266 TI - Functional and molecular studies in primary carnitine deficiency. AB - Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or cardiomyopathy in children, and sudden death in children and adults. Fibroblasts from affected patients have reduced carnitine transport. We evaluated carnitine transport in fibroblasts from 358 subjects referred for possible carnitine deficiency. Carnitine transport was reduced to 20% or less of normal in fibroblasts of 140 out of 358 subjects. Sequencing of the 10 exons and flanking regions of the SLC22A5 gene in 95 out of 140 subjects identified causative variants in 84% of the alleles. The missense variants identified in our patients and others previously reported (n = 92) were expressed in CHO cells. Carnitine transport was impaired by 73 out of 92 variants expressed. Prediction algorithms (Polyphen-2, SIFT) correctly predicted the functional effects of expressed variants in about 80% of cases. These results indicate that mutations in the coding region of the SLC22A5 gene cannot be identified in about 16% of the alleles causing primary carnitine deficiency. Prediction algorithms failed to determine the functional effects of amino acid substitutions in this transmembrane protein in about 20% of cases. Therefore, functional studies in fibroblasts remain the best strategy to confirm or exclude a diagnosis of primary carnitine deficiency. PMID- 28841269 TI - Calculated Nanocube Vacancy Formation Energy and Cohesion Energy at 0 K. AB - Nanoparticles of face-centered cubic Cu are modeled using the Sutton-Chen potential. Shapes ranging from perfect cubes through to octahedrons are modeled and characterized. Bulk properties, surface energies, vacancy formation energy, Ev , and cohesive energies, Ecoh , are investigated for particles simulated to up to 5 nm in diameter. Below the subsurface layers, particles larger than 1 nm diameter are compared well to bulk. Of the different shapes, rhombicuboctahedrons are both more stable and have more reactive surfaces. As Ev is dependent on surface orientation, there is a little correlation with size and Ev is mostly dependent on nanoparticle shape. Ecoh is not as dependent on surface orientation and shows both size and shape dependency. PMID- 28841268 TI - Simultaneous determination of ferulic acid and gastrodin of Tianshu Capsule in rat plasma by ultra-fast liquid chromatography with tandem mass spectrometry and its application to a comparative pharmacokinetic study in normal and migraine rats. AB - Tianshu Capsule, consisting of Ligusticum chuanxiong Hort and Gastrodia elata Blume, is a widely used Traditional Chinese Medicine preparation for the treatment of migraine. Ferulic acid and gastrodin are main active constituents in Ligusticum chuanxiong Hort and Gastrodia elata Blume, and have been used as marker components for quality control of Tianshu Capsule. In this study, a selective, sensitive, and reliable ultra-fast liquid chromatography with tandem mass spectrometry method was developed for simultaneous determination of ferulic acid and gastrodin in rat plasma using geniposide as internal standard. The plasma samples were extracted by protein precipitation with methanol after acidification and separated on a Shim-Pack XR-ODS C18 column (75 * 3.0 mm, 2.2 MUm) using gradient elution with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile at a flow rate of 0.6 mL/min. Detection was performed on 3200 QTRAP mass spectrometry equipped with turbo ion spray source in negative ionization mode. Validation parameters were within acceptable ranges. The validated method was applied to compare the pharmacokinetic profiles of ferulic acid and gastrodin in normal and migraine rats. Our results showed that there were remarkable differences in the pharmacokinetic properties of the analytes between the normal and migraine groups. PMID- 28841267 TI - Effects of respiratory muscle work on respiratory and locomotor blood flow during exercise. AB - NEW FINDINGS: What is the central question of this study? Does manipulation of the work of breathing during high-intensity exercise alter respiratory and locomotor muscle blood flow? What is the main finding and its importance? We found that when the work of breathing was reduced during exercise, respiratory muscle blood flow decreased, while locomotor muscle blood flow increased. Conversely, when the work of breathing was increased, respiratory muscle blood flow increased, while locomotor muscle blood flow decreased. Our findings support the theory of a competitive relationship between locomotor and respiratory muscles during intense exercise. Manipulation of the work of breathing (WOB) during near-maximal exercise influences leg blood flow, but the effects on respiratory muscle blood flow are equivocal. We sought to assess leg and respiratory muscle blood flow simultaneously during intense exercise while manipulating WOB. Our hypotheses were as follows: (i) increasing the WOB would increase respiratory muscle blood flow and decrease leg blood flow; and (ii) decreasing the WOB would decrease respiratory muscle blood flow and increase leg blood flow. Eight healthy subjects (n = 5 men, n = 3 women) performed a maximal cycle test (day 1) and a series of constant-load exercise trials at 90% of peak work rate (day 2). On day 2, WOB was assessed with oesophageal balloon catheters and was increased (via resistors), decreased (via proportional assist ventilation) or unchanged (control) during the trials. Blood flow was assessed using near-infrared spectroscopy optodes placed over quadriceps and the sternocleidomastoid muscles, coupled with a venous Indocyanine Green dye injection. Changes in WOB were significantly and positively related to changes in respiratory muscle blood flow (r = 0.73), whereby increasing the WOB increased blood flow. Conversely, changes in WOB were significantly and inversely related to changes in locomotor blood flow (r = 0.57), whereby decreasing the WOB increased locomotor blood flow. Oxygen uptake was not different during the control and resistor trials (3.8 +/- 0.9 versus 3.7 +/- 0.8 l min-1 , P > 0.05), but was lower on the proportional assist ventilator trial (3.4 +/- 0.7 l min-1 , P < 0.05) compared with control. Our findings support the concept that respiratory muscle work significantly influences the distribution of blood flow to both respiratory and locomotor muscles. PMID- 28841270 TI - Tuning Crystallization Pathways through the Mesoscale Assembly of Biomacromolecular Nanocrystals. AB - Macromolecular crystallization has many implications in biological and materials science. Similar to the crystallization of other molecules, macromolecular crystallization conventionally considers a critical nucleus, followed by crystallographic packing of macromolecules to drive further crystal growth. Herein, we discover a distinctive macromolecular crystallization pathway by developing the concept of a macromolecular mesocrystal. This nonclassical polymer crystallization occurs through the mesoscale self-assembly of (bio)macromolecular nanocrystals. The new concept for macromolecular crystallization presented herein is fundamental and relevant to many fields, including materials science, chemistry, biomimetics, nanoscience, and structural biology. PMID- 28841271 TI - Who seeks bariatric surgery? Psychosocial functioning among adolescent candidates, other treatment-seeking adolescents with obesity and healthy controls. AB - Limited data are available on the characteristics of adolescents with obesity who seek bariatric surgery. Existing data suggest that adolescent surgery candidates have a higher body mass index (BMI) than comparison adolescents with obesity, but the limited findings regarding psychosocial functioning are mixed. This study aimed to compare BMI and psychosocial functioning among adolescent bariatric surgery candidates, outpatient medical-treatment-seeking adolescents with obesity (receiving lifestyle modification), and adolescents in the normal-weight range. All adolescents completed self-report measures of impulsivity, delay discounting, depression, anxiety, stress, eating pathology, family functioning and quality of life, and had their height and weight measured. Adolescent surgical candidates had higher BMIs than both comparison groups. Surgical candidates did not differ from medical-treatment-seeking adolescents with obesity on any measure of psychosocial functioning, but both groups of adolescents with obesity reported greater anxiety and eating pathology and poorer quality of life than normal weight adolescents. Quality of life no longer differed across groups after controlling for BMI, suggesting that it is highly related to weight status. Adolescents with obesity may experience greater anxiety, eating pathology, and quality of life impairments than their peers in the normal-weight range regardless of whether they are seeking surgery or outpatient medical treatment. Clinical implications and directions for future research are discussed. PMID- 28841272 TI - A coproduced patient and public event: An approach to developing and prioritizing ambulance performance measures. AB - BACKGROUND: Patient and public involvement (PPI) is recognized as an important component of high-quality health services research. PPI is integral to the Pre hospital Outcomes for Evidence Based Evaluation (PhOEBE) programme. The PPI event described in detail in this article focusses on the process of involving patients and public representatives in identifying, prioritizing and refining a set of outcome measures that can be used to support ambulance service performance measurement. OBJECTIVE: To obtain public feedback on little known, complex aspects of ambulance service performance measurement. DESIGN: The event was codesigned and coproduced with the PhOEBE PPI reference group and PhOEBE research team. The event consisted of brief researcher-led presentations, group discussions facilitated by the PPI reference group members and electronic voting. SETTING AND PARTICIPANTS: Data were collected from eighteen patient and public representatives who attended an event venue in Yorkshire. RESULTS: The results of the PPI event showed that this interactive format and mode of delivery was an effective method to obtain public feedback and produced a clear indication of which ambulance performance measures were most highly favoured by event participants. DISCUSSION AND CONCLUSIONS: The event highlighted valuable contributions the PPI reference group made to the design process, supporting participant recruitment and facilitation of group discussions. In addition, the positive team working experience of the event proved a catalyst for further improvements in PPI within the PhOEBE project. PMID- 28841273 TI - Psychosis Induced by Varenicline in a Patient With No Psychiatric History. PMID- 28841274 TI - Short Sleep in Patients With Chronic Paranoid Schizophrenia. PMID- 28841275 TI - Neuropsychiatric Manifestations of Pediatric NMDA Receptor Autoimmune Encephalitis: A Case Series From a Tertiary Care Center in India. AB - Objective: Although psychiatric manifestations are one of the most common presentations of pediatric N-methyl-D-aspartate receptor (NMDAR) encephalitis, there is a lack of studies that characterize psychiatric aspects of this disorder. This study was designed to address this gap. Methods: Initial clinical presentations including psychiatric symptoms, treatment details, and outcome with respect to psychiatric symptoms were collected from medical case records of children aged less than 18 years with seropositive NMDAR encephalitis from a single tertiary care center (May 2010-November 2016). The Brief Psychiatric Rating Scale for Children (BPRS-C) was administered at the time of presentation and at follow-up. Results: Clinical records from 16 girls and 5 boys of whom 12 were prepubertal (< 12 years) and 9 were postpubertal (>= 12 years) were analyzed. All 21 children presented with psychiatric symptoms at initial presentation. In 10 children (47.6%), psychiatric symptom was the first symptom. Major psychiatric symptoms included inappropriate crying (most common, 66.7%, n = 14), social withdrawal (57.1%, n = 12), unprovoked anger outburst (47.6%, n = 10), unprovoked screaming behavior (38.1%, n = 8), and talking to self irrelevantly (42.9%, n = 9). In addition to psychiatric symptoms, at least 1 of the following was also seen in all children: speech disturbance (85.7%, n = 18), seizure (85.7%, n = 18), or movement disorder (76.2%, n = 16). Mood symptoms (85.7%, n = 18) were the most common psychopathology. A comorbid psychiatric diagnosis (ICD-10 criteria) was made in 11 children (52.4%); the most common was organic mood disorder (n = 6). The mean BPRS-C score at presentation in prepubertal children was higher than that of postpubertal children (21 vs 17). After immune modulation, clinical improvement was noted after a mean +/- SD of 7.4 +/- 4.8 months in all 20 children followed up. Three of the 4 children with residual psychiatric symptoms and persistent academic difficulties were prepubertal. Conclusions: Psychiatric manifestations that are usually mood related are quite common in pediatric NMDAR encephalitis. Prepubertal presentation of this disorder appears to be more severe and may lead to persistent psychiatric and cognitive symptoms. PMID- 28841276 TI - Tuning Surface and Topographical Features to Investigate Competitive Guidance of Spiral Ganglion Neurons. AB - Cochlear Implants (CIs) suffer from limited tonal resolution due, in large part, to spatial separation between stimulating electrode arrays and primary neural receptors. In this work, a combination of physical and chemical micropatterns, formed on acrylate polymers, are used to direct the growth of primary spiral ganglion neurons (SGNs), the inner ear neurons. Utilizing the inherent temporal and spatial control of photopolymerization, physical microgrooves are fabricated using a photomask in a single step process. Biochemical patterns are generated by adsorbing laminin, a cell adhesion protein, to acrylate polymer surfaces followed by irradiation through a photomask with UV light to deactivate protein in exposed areas and generate parallel biochemical patterns. Laminin deactivation was shown increase as a function of UV light exposure while remaining adsorbed to the polymer surface. SGN neurites show alignment to both biochemical and physical patterns when evaluated individually. Competing biochemical and physical patterns were also examined. The relative guiding strength of physical cues was varied by independently changing both the amplitude and the band spacing of the microgrooves, with higher amplitudes and shorter band spacing providing cues that more effective guide neurite growth. SGN neurites aligned to laminin patterns with lower physical pattern amplitude and thus weaker physical cues. Alignment of SGNs shifted toward the physical pattern with higher amplitude and lower periodicity patterns which represent stronger cues. These results demonstrate the ability of photopolymerized microfeatures to modulate alignment of inner ear neurites even in the presence of conflicting physical and biochemical cues laying the groundwork for next generation cochlear implants and neural prosthetic devices. PMID- 28841277 TI - Large-Area Fabrication of Droplet Pancake Bouncing Surface and Control of Bouncing State. AB - Superhydrophobic pillar arrays, which can generate the droplet pancake bouncing phenomenon with reduced liquid-solid contact time, have huge application prospects in anti-icing of aircraft wings from freezing rain. However, the previously reported pillar arrays, suitable for obtaining pancake bouncing, have a diameter <=100 MUm and height-diameter ratio >10, which are difficult to fabricate over a large area. Here, we have systematically studied the influence of the dimension of the superhydrophobic pillar arrays on the bouncing dynamics of water droplets. We show that the typical pancake bouncing with 57.8% reduction in contact time with the surface was observed on the superhydrophobic pillar arrays with 1.05 mm diameter, 0.8 mm height, and 0.25 mm space. Such pillar arrays with millimeter diameter and <1 height-diameter ratio can be easily fabricated over large areas. Further, a simple replication-spraying method was developed for the large-area fabrication of the superhydrophobic pillar arrays to induce pancake bouncing. No sacrificial layer was needed to reduce the adhesion in the replication processes. Since the bouncing dynamics were rather sensitive to the space between the pillars, a method to control the contact time, bouncing shape, horizontal bouncing direction, and reversible switch between pancake bouncing and conventional bouncing was realized by adjusting the inclination angle of the shape memory polymer pillars. PMID- 28841279 TI - Regulating Near-Infrared Photodynamic Properties of Semiconducting Polymer Nanotheranostics for Optimized Cancer Therapy. AB - Development of optical nanotheranostics for the capability of photodynamic therapy (PDT) provides opportunities for advanced cancer therapy. However, most nanotheranostic systems fail to regulate their generation levels of reactive oxygen species (ROS) according to the disease microenvironment, which can potentially limit their therapeutic selectivity and increase the risk of damage to normal tissues. We herein report the development of hybrid semiconducting polymer nanoparticles (SPNs) with self-regulated near-infrared (NIR) photodynamic properties for optimized cancer therapy. The SPNs comprise a binary component nanostructure: a NIR-absorbing semiconducting polymer acts as the NIR fluorescent PDT agent, while nanoceria serves as the smart intraparticle regular to decrease and increase ROS generation at physiologically neutral and pathologically acidic environments, respectively. As compared with nondoped SPNs, the NIR fluorescence imaging ability of nanoceria-doped SPNs is similar due to the optically inactive nature of nanoceria; however, the self-regulated photodynamic properties of nanoceria-doped SPN not only result in dramatically reduced nonspecific damage to normal tissue under NIR laser irradiation but also lead to significantly enhanced photodynamic efficacy for cancer therapy in a murine mouse model. This study thus provides a simple yet effective hybrid approach to modulate the phototherapeutic performance of organic photosensitizers. PMID- 28841278 TI - Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist. AB - Adamantanyl benzamide 1 was identified as a potent P2X7R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X7R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X7R polymorphisms. PMID- 28841280 TI - Highly Conducting and Highly Transparent Oxide/Metal/Oxide Structures for Ultraviolet-C Light Sources Utilizing a Thin Cu Wetting Interlayer. AB - The Zn0.8-xMg0.2BexO/Cu/Ag/Zn0.8-xMg0.2BexO multilayer structures were designed, sputter-deposited at room temperature, and characterized in detail. Results indicated that the multilayer structures with high transmission (higher than 90% at the visual wavelength range) can be readily obtained by simply inserting a thin (~5 nm) Cu wetting layer, which renders the thin Ag layers (~5 nm thick) continuous and smooth. It was also observed that the optical absorption edges of the multilayer structures increase as the energy band-gaps of the top/bottom oxide layers increase and the multilayer structures with the energy band gap of ~6.0 eV can be obtained by employing the ZnMgBeO layers, with an excellent resistivity of ~1.7 * 10-4 Omega cm. These results represent a significant improvement over the previous reports and the first report on the design and fabrication of the highly conducting transparent materials for the UV-C application. PMID- 28841281 TI - Formation and Characterization of Dendritic Interfacial Electrodes inside an Ionomer. AB - Formation of dendritic interfacial electrodes (DIEs) between metal/polymer interfaces has high demands in a variety of areas. By combining impregnation electroplating (IEP) step with impregnation-reduction (IR) step under straightforward conditions, we report a novel method of preparation of dendritic interfacial metal electrodes of palladium, platinum, silver and copper inside an ionomer for ionic polymer-metal composites (IPMC) application. The depth of palladium DIEs can be controlled by adjusting the reaction time, and the maximum depth can almost reach up to contact from the both sides of ionomer with a total thickness of 200 MUm. The capacitance and actuation performance of IPMC was dramatically enhanced because of the presence of DIEs. PMID- 28841282 TI - Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors. AB - In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways. PMID- 28841283 TI - Evaluation of the Photothermal Properties of a Reduced Graphene Oxide/Arginine Nanostructure for Near-Infrared Absorption. AB - Strong near-infrared (NIR) absorption of reduced graphene oxide (rGO) make this material a candidate for photothermal therapy. The use of rGO has been limited by low stability in aqueous media due to the lack of surface hydrophilic groups. We report synthesis of a novel form of reduced graphene-arginine (rGO-Arg) as a nanoprobe. Introduction of Arg to the surface of rGO not only increases the stability in aqueous solutions but also increases cancer cell uptake. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) images are recorded to characterize the morphology of rGO-Arg. Fourier transform infrared (FTIR), X-ray photoelectron spectra (XPS), Raman, and UV-vis spectroscopy are utilized to analyze the physiochemical properties of rGO-Arg. Interaction of rGO Arg with 808 nm laser light has been evaluated by measuring the absorption cross section in response to periodically modulated intensity to minimize artifacts arising from lateral thermal diffusion with a material scattering matched to a low scattering optical standard. Cell toxicity and cellular uptake by MD-MB-231 cell lines provide supporting data for the potential application of rGO-Arg for photothermal therapy. Absorption cross-section results suggest rGO-Arg is an excellent NIR absorber that is 3.2 times stronger in comparison to GO. PMID- 28841284 TI - Metallosupramolecular Architectures Obtained from Poly-N-heterocyclic Carbene Ligands. AB - Over the past two decades, self-assembly of supramolecular architectures has become a field of intensive research due to the wide range of applications for the resulting assemblies in various fields such as molecular encapsulation, supramolecular catalysis, drug delivery, metallopharmaceuticals, chemical and photochemical sensing, and light-emitting materials. For these purposes, a large number of coordination-driven metallacycles and metallacages featuring different sizes and shapes have been prepared and investigated. Almost all of these are Werner-type coordination compounds where metal centers are coordinated by nitrogen and/or oxygen donors of polydentate ligands. With the evolving interest in the coordination chemistry of N-heterocyclic carbenes (NHCs), discrete supramolecular complexes held together by M-CNHC bonds have recently become of interest. The construction of such metallosupramolecular assemblies requires the synthesis of suitable poly-NHC ligands where the NHC donors form labile bonds with metal centers thus enabling the formation of the thermodynamically most stable reaction product. In organometallic chemistry, these conditions are uniquely met by the combination of poly-NHCs and silver(I) ions where the resulting assemblies also offer the possibility to generate new structures by transmetalation of the poly-NHC ligands to additional metal centers forming more stable CNHC-M bonds. Stable metallosupramolecular assemblies obtained from poly NHC ligands feature special properties such as good solubility in many less polar organic solvents and the presence of the often catalyticlly active {M(NHC)n} moiety as building block. In this Account, we review recent developments in organometallic supramolecular architectures derived from poly-NHC ligands. We describe dinuclear (M = AgI, AuI, CuI) tetracarbene complexes obtained from bis NHC ligands with an internal olefin or two external coumarin pendants and their postsynthetic modification via a photochemically induced single or double [2 + 2] cycloaddition to form dinuclear tetracarbene complexes featuring cyclobutane units. Even three-dimensional cage-like structures can be prepared by this postsynthetic strategy. Cylinder-like trinuclear, tetranuclear, and hexanuclear (M = AgI, AuI, CuI, HgII, PdII) complexes have been obtained from benzene-bridged tris-, tetrakis-, or hexakis-NHC ligands. These complexes resemble polynuclear assemblies obtained from related polydentate Werner-type ligands. Contrary to the Werner-type complexes, cylinder-like assemblies with three, four, or six silver(I) ions sandwiched in between two tris-, tetrakis-, or hexakis-NHC ligands undergo a facile transmetalation reaction to give the complexes featuring more stable M-CNHC bonds, normally with retention of the metallosupramolecular structure. This unique behavior of NHC-Ag+ complexes allows the prepration of assemblies containing various metals from the poly-NHC silver(I) assemblies. Narcissistic self-sorting phenomena have also been observed for mixtures of selected poly-NHC ligands and silver(I) ions. Even a very early type of metallosupramolecular assembly, the tetranuclear molecular square, can be prepared from four bridging dicarbene ligands and four transition metal ions either by a stepwise assembly or by a single-step protocol. At this point, it appears that procedures for the synthesis of metallosupramolecular assemblies using polydentate Werner-type ligands and metal ions can be transferred to organometallic chemistry by using suitable poly-NHC ligands. The resulting structures feature stable M-CNHC bonds (with the exception of the labile CNHC-Ag+ bond) when compared to M-N/M-O bonds in classical Werner-type complexes. The generally good solubility of the compounds and the presence of the often catalytically active {M(NHC)n} moiety make organometallic supramolecular complexes a promising new class of molecular hosts for catalytic transformations and encapsulation of selected substrates. PMID- 28841285 TI - Quantum Dot Light-Emitting Devices: Beyond Alignment of Energy Levels. AB - Multinary semiconductor nanoparticles such as CuInS2, AgInS2, and the corresponding alloys with ZnS hold promise for designing future quantum dot light emitting devices (QLED). The QLED architectures require matching of energy levels between the different electron and hole transport layers. In addition to energy level alignment, conductivity and charge transfer interactions within these layers determine the overall efficiency of QLED. By employing CuInS2-ZnS QDs we succeeded in fabricating red-emitting QLED using two different hole-transporting materials, polyvinylcarbazole and poly(4-butylphenyldiphenylamine). Despite the similarity of the HOMO-LUMO energy levels of these two hole transport materials, the QLED devices exhibit distinctly different voltage dependence. The difference in onset voltage and excited state interactions shows the complexity involved in selecting the hole transport materials for display devices. PMID- 28841286 TI - High-Rate Long-Life Pored Nanoribbon VNb9O25 Built by Interconnected Ultrafine Nanoparticles as Anode for Lithium-Ion Batteries. AB - VNb9O25 is a novel lithium storage material, which has not been systematically investigated so far. Via electrospinning technology, VNb9O25 samples with two different morphologies, pored nanoribbon and rodlike nanoparticles, are prepared in relatively low temperature and time-saving calcination conditions. It is found that the formation process of different morphologies depends on the control of self-aggregation of the precursor by using different sample collectors. Compared with rodlike VNb9O25 (RL-VNb9O25), pored nanoribbon VNb9O25 (PR-VNb9O25) can deliver a higher specific capacity, lower capacity loss, and better cyclability. Even cycled at 1000 mA g-1, the reversible capacity of 132.3 mAh g-1 is maintained by PR-VNb9O25 after 500 cycles, whereas RL-VNb9O25 only exhibits a capacity of 102.7 mAh g-1. The enhancement should be attributed to the pored nanoribbon structure with large specific surface area and shorter pathway for lithium ions transport. Furthermore, the lithium ions insertion/extraction process is verified from refinement results of in situ X-ray diffraction data, which is associated with a lithium occupation process in type III and VI cavities through tunnels I, II, and III. In addition, high structural stability and electrochemical reversibility are also demonstrated. All of these advantages suggest that PR-VNb9O25 is a promising anode material for lithium-ion batteries. PMID- 28841288 TI - Antiorganic Fouling and Low-Protein Adhesion on Reverse-Osmosis Membranes Made of Carbon Nanotubes and Polyamide Nanocomposite. AB - We demonstrate efficient antifouling and low protein adhesion of multiwalled carbon nanotubes-polyamide nanocomposite (MWCNT-PA) reverse-osmosis (RO) membranes by combining experimental and theoretical studies using molecular dynamics (MD) simulations. Fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (FITC-BSA) was used for the fouling studies. The fouling was observed in real time by using a crossflow system coupled to a fluorescence microscope. Notably, it was observed that BSA anchoring on the smooth MWCNT-PA membrane was considerably weaker than that of other commercial/laboratory-made plain PA membranes. The permeate flux reduction of the MWCNT-PA nanocomposite membranes by the addition of FITC-BSA was 15% of its original value, whereas those of laboratory-made plain PA and commercial membranes were much larger at 34%-50%. Computational MD simulations indicated that the presence of MWCNT in PA results in weaker interactions between the membrane surface and BSA molecule due to the formation of (i) a stiffer PA structure resulting in lower conformity of the molecular structure against BSA, (ii) a smoother surface morphology, and (iii) an increased hydrophilicity involving the formation of an interfacial water layer. These results are important for the design and development of promising antiorganic fouling RO membranes for water treatment. PMID- 28841287 TI - Picomolar Fingerprinting of Nucleic Acid Nanoparticles Using Solid-State Nanopores. AB - Nucleic acid nanoparticles (NANPs) are an emerging class of programmable structures with tunable shape and function. Their promise as tools for fundamental biophysics studies, molecular sensing, and therapeutic applications necessitates methods for their detection and characterization at the single particle level. In this work, we study electrophoretic transport of individual ring-shaped and cube-shaped NANPs through solid-state nanopores. In the optimal nanopore size range, the particles must deform to pass through, which considerably increases their residence time within the pore. Such anomalously long residence times permit detection of picomolar amounts of NANPs when nanopore measurements are carried out at a high transmembrane bias. In the case of a NANP mixture, the type of individual particle passing through nanopores can be efficiently determined from analysis of a single electrical pulse. Molecular dynamics simulations provide insight into the mechanical barrier to transport of the NANPs and corroborate the difference in the signal amplitudes observed for the two types of particles. Our study serves as a basis for label-free analysis of soft programmable-shape nanoparticles. PMID- 28841289 TI - Nanoscale Zeolitic Imidazolate Framework-8 as Efficient Vehicles for Enhanced Delivery of CpG Oligodeoxynucleotides. AB - CpG oligodeoxynucleotides (ODNs) activate the immune system and induce Th 1 responses by stimulation of Toll-like receptor 9 (TLR9). Thus, CpG ODNs have become immunotherapeutics against various diseases including cancers, allergies, and infection. However, applications of CpG ODNs are largely limited because of their easy degradation by DNase as well as inefficient cellular uptake. Development of efficient delivery systems capable of transferring CpG ODNs into immune cells is important to enhance their therapeutic efficacy. Herein, for the first time, we demonstrated the construction of a novel CpG ODNs delivery system by encapsulating CpG ODNs into zeolitic imidazolate framework-8 (ZIF-8) nanoparticles. ZIF-8 possessed high CpG ODNs loading capacity due to its porous structure. ZIF-8/CpG ODNs complexes exhibited good stability in a physiological environment but effectively released CpG ODNs in acid conditions corresponding to the TLR 9-localized endolysosomes. ZIF-8/CpG ODNs complexes had no cytotoxicity in contrast to ZIF-8. ZIF-8 significantly increased the intracellular uptake of CpG ODNs in RAW264.7 cells, which further enhanced the secretion of immune cytokines both in vitro and in vivo. Our results suggest that nanoscale metal organic frameworks (MOFs) can serve as ideal vehicles for the delivery of CpG ODNs. PMID- 28841290 TI - Hydrothermal Preparation, Crystal Chemistry, and Redox Properties of Iron Muscovite Clay. AB - The development of functional materials based on Earth-abundant, environmentally benign compositions is critical for ensuring their commercial viability and sustainable production. Here we present an investigation into the crystal chemistry and electrochemical properties of the muscovite clay KFe2.75Si3.25O10(OH)2. We first report a low-temperature hydrothermal reaction that allows for a significant degree of control over sample crystallinity, particle morphology, and cation distribution through the lattice. A complex sequence of stacking faults is identified and characterized using a combination of Mossbauer spectroscopy and total scattering neutron experiments. We then show the existence of a reversible electrochemical process using galvanostatic cycling with complementary cyclic voltammetry suggesting that the redox activity occurs primarily on the surface of the particles. We conclude by determining that the ability to (de)intercalate Li ions from the material is hindered by the strong negative charge on the transition metal silicate layers, which prevents the displacement of the interlayer K ions. This work calls attention to a hugely Earth-abundant family of minerals that possesses useful electrochemical properties that warrant further exploration. PMID- 28841291 TI - Tribological Behavior of NiAl-Layered Double Hydroxide Nanoplatelets as Oil-Based Lubricant Additives. AB - Layered double hydroxides (LDHs) are a class of naturally occurring inorganic minerals that are composed of divalent and trivalent metal cations. In this study, three different sized NiAl-LDH nanoplatelets were synthesized by varying crystallization time during the microemulsification process. The layered structure and three-dimensional size of nanoplatelets were confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM). As lubricant additives, their tribological properties in base oil were evaluated by use of a ball-on-disk reciprocating tribometer under three different loads: 50, 100, and 150 N (which created peak Hertz pressures of 1.74, 2.16, and 2.47 GPa). Under contact pressures of up 2.16 GPa, not only did the coefficient of friction (COF) decrease by about 10% after nano-LDHs were added but also the wear performance improved substantially. These improvements resulted from a protective tribolayer formation on the contact interface, as revealed by detailed surface and structure analytical studies. In particular, cross-sectional TEM images revealed that the larger size nanoplatelets (NiAl-24h), rather than the smaller ones (NiAl-6h) showed the best and most stable tribological performance. This was mainly because of their higher degree of crystallinity, which in turn resulted in the formation of a tribofilm with far superior mechanical properties during sliding. Owing to the simple synthetic method and superior tribological properties as oil-based additives, nano-LDHs hold great potential for use in demanding industrial applications in the future. PMID- 28841292 TI - Remote Control of Multimodal Nanoscale Ligand Oscillations Regulates Stem Cell Adhesion and Differentiation. AB - Cellular adhesion is regulated by the dynamic ligation process of surface receptors, such as integrin, to adhesive motifs, such as Arg-Gly-Asp (RGD). Remote control of adhesive ligand presentation using external stimuli is an appealing strategy for the temporal regulation of cell-implant interactions in vivo and was recently demonstrated using photochemical reaction. However, the limited tissue penetration of light potentially hampers the widespread applications of this method in vivo. Here, we present a strategy for modulating the nanoscale oscillations of an integrin ligand simply and solely by adjusting the frequency of an oscillating magnetic field to regulate the adhesion and differentiation of stem cells. A superparamagnetic iron oxide nanoparticle (SPION) was conjugated with the RGD ligand and anchored to a glass substrate by a long flexible poly(ethylene glycol) linker to allow the oscillatory motion of the ligand to be magnetically tuned. In situ magnetic scanning transmission electron microscopy and atomic force microscopy imaging confirmed the nanoscale motion of the substrate-tethered RGD-grafted SPION. Our findings show that ligand oscillations under a low oscillation frequency (0.1 Hz) of the magnetic field promoted integrin-ligand binding and the formation and maturation of focal adhesions and therefore the substrate adhesion of stem cells, while ligands oscillating under high frequency (2 Hz) inhibited integrin ligation and stem cell adhesion, both in vitro and in vivo. Temporal switching of the multimodal ligand oscillations between low- and high-frequency modes reversibly regulated stem cell adhesion. The ligand oscillations further induced the stem cell differentiation and mechanosensing in the same frequency-dependent manner. Our study demonstrates a noninvasive, penetrative, and tunable approach to regulate cellular responses to biomaterials in vivo. Our work not only provides additional insight into the design considerations of biomaterials to control cellular adhesion in vivo but also offers a platform to elucidate the fundamental understanding of the dynamic integrin-ligand binding that regulates the adhesion, differentiation, and mechanotransduction of stem cells. PMID- 28841293 TI - Heading toward Macromolecular and Nanosized Bioresponsive MRI Probes for Successful Functional Imaging. AB - The quest for bioresponsive or smart contrast agents (SCAs) in molecular imaging, in particular magnetic resonance imaging (MRI), is progressively increasing since they allow for the monitoring of essential biological processes on molecular and cellular levels in a dynamic fashion. These are offshoot molecules of common contrast agents that are sensitive to biochemical changes in their environment, capable of reporting on such changes by inducing MRI signal alteration. Various mechanistic approaches and different types of SCAs have been developed in order to visualize desired processes, using diverse imaging protocols and methods. To date, the most frequently exploited probes are paramagnetic molecules that change longitudinal or transverse relaxation at proton frequency, or so-called T1- and T2-weighted probes, respectively. Moreover, SCAs operating by the chemical exchange saturation transfer mechanism, suitable for 19F MRI or possessing hyperpolarized nuclei have also appeared in the past decade, slowly finding their role in functional imaging studies. Following these mechanistic principles, a large number of SCAs suitable for diverse targets have been reported to date. This Account condenses this exciting progress, particularly focusing on probes designed for abundant targets that are suitable for practical, in vivo utilization. To date, the greatest advancements have been certainly made in the preparation of pH sensitive probes, which usually contain protonable groups that interact with paramagnetic centers, or take advantage of supramolecular (dis)assembling to induce the MRI signal change, thereupon enabling pH mapping in vivo. In a complementary approach, a combination of metal chelating ligands for Ca2+ or Zn2+ with MR reporting units results in a wide variety of SCAs that operate with different contrast mechanisms and can be used for initial functional experiments. Finally, the first examples of molecular sensing by creating host guest complexes to track neurotransmitter flux have also been recently reported, allowing the study of brain function in an unprecedented manner. Nevertheless, wider SCA utilization in vivo has not yet been achieved. There are a few reasons for this disparity between their nominal potential and practical usage, with one of the major reasons being the low sensitivity of the MRI technique. Subsequently, the production of detectable signal change can be achieved using higher concentrations of the bioresponsive probe; however, the biocompatibility of these probes then starts to play an important role. An elegant solution to these practical challenges has been found with the integration of multiple small sized SCAs into macromolecular and nanosized probes. In such case, the multivalent SCAs are able to circumvent the sensitivity issue, thus enhancing the MR signal and desired contrast changes. Moreover, they prolong the probe tissue retention time, while often reducing their toxicity. Finally, with altered size and properties, they allow for exploitation of mechanisms that induce the contrast change which is not possible with small-sized SCAs. To this end, this Account also discusses the current approaches that aim to develop macromolecular and nanosized SCAs suitable for practical MRI applications. With these, further progress of this exciting field is affirmed, with remarkable results expected in the near future on both the probe preparation and their utilization in functional molecular imaging. PMID- 28841294 TI - Transparent Large-Area MoS2 Phototransistors with Inkjet-Printed Components on Flexible Platforms. AB - Two-dimensional (2D) transition-metal dichalcogenides (TMDCs) have gained considerable attention as an emerging semiconductor due to their promising atomically thin film characteristics with good field-effect mobility and a tunable band gap energy. However, their electronic applications have been generally realized with conventional inorganic electrodes and dielectrics implemented using conventional photolithography or transferring processes that are not compatible with large-area and flexible device applications. To facilitate the advantages of 2D TMDCs in practical applications, strategies for realizing flexible and transparent 2D electronics using low-temperature, large area, and low-cost processes should be developed. Motivated by this challenge, we report fully printed transparent chemical vapor deposition (CVD)-synthesized monolayer molybdenum disulfide (MoS2) phototransistor arrays on flexible polymer substrates. All the electronic components, including dielectric and electrodes, were directly deposited with mechanically tolerable organic materials by inkjet printing technology onto transferred monolayer MoS2, and their annealing temperature of <180 degrees C allows the direct fabrication on commercial flexible substrates without additional assisted-structures. By integrating the soft organic components with ultrathin MoS2, the fully printed MoS2 phototransistors exhibit excellent transparency and mechanically stable operation. PMID- 28841295 TI - Switching between Plasmonic and Fluorescent Copper Sulfide Nanocrystals. AB - Control over the doping density in copper sulfide nanocrystals is of great importance and determines its use in optoelectronic applications such as NIR optical switches and photovoltaic devices. Here, we demonstrate that we can reversibly control the hole carrier density (varying from >1022 cm-3 to intrinsic) in copper sulfide nanocrystals by electrochemical methods. We can control the type of charge injection, i.e., capacitive charging or ion intercalation, via the choice of the charge compensating cation (e.g., ammonium salts vs Li+). Further, the type of intercalating ion determines whether the charge injection is fully reversible (for Li+) or leads to permanent changes in doping density (for Cu+). Using fully reversible lithium intercalation allows us to switch between thin films of covellite CuS NCs (Eg = 2.0 eV, hole density 1022 cm-3, strong localized surface plasmon resonance) and low-chalcocite CuLiS NCs (Eg = 1.2 eV, intrinsic, no localized surface plasmon resonance), and back. Electrochemical Cu+ ion intercalation leads to a permanent phase transition to intrinsic low-chalcocite Cu2S nanocrystals that display air stable fluorescence, centered around 1050 nm (fwhm ~145 meV, PLQY ca. 1.8%), which is the first observation of narrow near-infrared fluorescence for copper sulfide nanocrystals. The dynamic control over the hole doping density and fluorescence of copper sulfide nanocrystals presented in this work and the ability to switch between plasmonic and fluorescent semiconductor nanocrystals might lead to their successful implementation into photovoltaic devices, NIR optical switches and smart windows. PMID- 28841296 TI - Maltose Utilization as a Novel Selection Strategy for Continuous Evolution of Microbes with Enhanced Metabolite Production. AB - We have developed a novel selection circuit based on carbon source utilization that establishes and sustains growth-production coupling over several generations in a medium with maltose as the sole carbon source. In contrast to traditional antibiotic resistance-based circuits, we first proved that coupling of cell fitness to metabolite production by our circuit was more robust with a much lower escape risk even after many rounds of selection. We then applied the selection circuit to the optimization of L-tryptophan (l-Trp) production. We demonstrated that it enriched for specific mutants with increased l-Trp productivity regardless of whether it was applied to a small and defined mutational library or a relatively large and undefined one. From the latter, we identified four novel mutations with enhanced l-Trp output. Finally, we used it to select for several high l-Trp producers with randomly generated genome-wide mutations and obtained strains with up to 65% increased l-Trp production. This selection circuit provides new perspectives for the optimization of microbial cell factories for diverse metabolite production and the discovery of novel genotype-phenotype associations at the single-gene and whole-genome levels. PMID- 28841297 TI - Molecular Face-Rotating Cube with Emergent Chiral and Fluorescence Properties. AB - Chiral cage compounds are mainly constructed from chiral precursors or based on the symmetry breaking during coordination-driven self-assembly. Herein, we present a strategy to construct chiral organic cages by restricting the P or M rotational configuration of tetraphenylethylene (TPE) faces through dynamic covalent chemistry. The combination of graph theory, experimental characterizations and theoretical calculations suggests emergent chirality of cages is originated from complex arrangements of TPE faces with different orientational and rotational configurations. Accompanied by the generation of chirality, strong fluorescence also emerged during cage formation, even in dilute solutions with various solvents. In addition, the circularly polarized luminescence of the cages is realized as a synergy of their dual chiral and fluorescence properties. Chirality and fluorescence of cages are remarkably stable, because intramolecular flipping of phenyl rings in TPE faces is restricted, as indicated by calculations. This study provides insight into construct chiral cages by the rational design through graph theory, and might facilitate further design of cages and other supramolecular assemblies from aggregation-induced emission active building blocks. PMID- 28841298 TI - YScSi4N6C:Ce3+-A Broad Cyan-Emitting Phosphor To Weaken the Cyan Cavity in Full Spectrum White Light-Emitting Diodes. AB - On the basis of a rough rule of thumb that the difference in ionic radius for the interstitial cationic pair may affect the structure of some nitride and carbonitride compounds, a novel carbonitride phosphor, YScSi4N6C:Ce3+, was successfully designed. The crystal structure (space group P63mc (No. 186), a = b = 5.9109(8) A, c = 9.67701(9) A, alpha = beta = 90 degrees , gamma = 120 degrees ) was characterized by single-crystal synchrotron X-ray diffraction and further confirmed by powder X-ray diffraction and refined with Rietveld methods. Ce3+ doped YScSi4N6C shows a broad excitation band ranging from 280 to 425 nm and a broad cyan emission band peaking at about 469 nm upon excitation by near-UV light (400 nm). The mechanism of thermal quenching for this phosphor was also investigated. In addition, a white light-emitting diode (w-LED) was prepared by coating a near-UV chip (lambdaem = 405 nm) with YScSi4N6C:Ce3+, beta-sialon:Eu2+ (green), and CaAlSiN3:Eu2+ (red) phosphors. It emitted a well-distributed warm white light with high color rendering index (CRI) of 94.7 and a correlated color temperature (CCT) of 4159 K. The special color rendering index R12 of the obtained white light was as high as 88. All of the results indicate that this novel phosphor can compensate for the cyan cavity and has potential applications in the full-spectrum lighting field. PMID- 28841299 TI - Cellulose-Organic Montmorillonite Nanocomposites as Biomacromolecular Quorum Sensing Inhibitor. AB - The aim of this study was to develop simple cellulose nanocomposites that can interfere with the quorum-sensing (QS)-regulated physiological process of bacteria, which will provide a sustainable and inexpensive solution to the serious challenges caused by bacterial infections in various products like food packaging or biomedical materials. Three cellulose nanocomposites with 1-5 w% octadecylamine-modified montmorillonite (ODA-MMT) were prepared by regeneration of cellulose from ionic liquid solutions in the presence of ODA-MMT suspension. Structural characterization of the nanocomposites showed that the ODA-MMT can be exfoliated or intercalated, depending on the load level of the nanofiller. Thermal gravimetric analysis showed that the incorporation of ODA-MMT nanofiller can improve the thermal stability of the nanocomposites compared with regenerated cellulose. Evaluation of the anti-QS effect against a pigment-producing bacteria C. violaceum CV026 by disc diffusion assay and flask incubation assay revealed that the QS-regulated violacein pigment production was significantly inhibited by the cellulose nanocomposites without interfering the bacterial vitality. Interestingly, the nanocomposite with the lowest load of ODA-MMT exhibited the most significant anti-QS effect, which may be correlated to the exfoliation of nanofillers. To our knowledge, this is the first report on the anti-QS effect of cellulose nanocomposites without the addition of any small molecular agents. Such inexpensive and nontoxic biomaterials will thus have great potential in the development of new cellulosic materials that can effectively prevent the formation of harmful biofilms. PMID- 28841300 TI - Corona Discharge Suppression in Negative Ion Mode Nanoelectrospray Ionization via Trifluoroethanol Addition. AB - Negative ion mode nanoelectrospray ionization (nESI) is often utilized to analyze acidic compounds, from small molecules to proteins, with mass spectrometry (MS). Under high aqueous solvent conditions, corona discharge is commonly observed at emitter tips, resulting in low ion abundances and reduced nESI needle lifetimes. We have successfully reduced corona discharge in negative ion mode by trace addition of trifluoroethanol (TFE) to aqueous samples. The addition of as little as 0.2% TFE increases aqueous spray stability not only in nESI direct infusion, but also in nanoflow liquid chromatography (nLC)/MS experiments. Negative ion mode spray stability with 0.2% TFE is approximately 6* higher than for strictly aqueous samples. Upon addition of 0.2% TFE to the mobile phase of nLC/MS experiments, tryptic peptide identifications increased from 93 to 111 peptides, resulting in an average protein sequence coverage increase of 18%. PMID- 28841301 TI - Cytotoxicity and Efflux Pump Inhibition Induced by Molybdenum Disulfide and Boron Nitride Nanomaterials with Sheetlike Structure. AB - Sheetlike molybdenum disulfide (MoS2) and boron nitride (BN) nanomaterials have attracted attention in the past few years due to their unique material properties. However, information on adverse effects and their underlying mechanisms for sheetlike MoS2 and BN nanomaterials is rare. In this study, cytotoxicities of sheetlike MoS2 and BN nanomaterials on human hepatoma HepG2 cells were systematically investigated at different toxic end points. Results showed that MoS2 and BN nanomaterials decreased cell viability at 30 MUg/mL and induced adverse effects on intracellular ROS generation (>=2 MUg/mL), mitochondrial depolarization (>=4 MUg/mL), and membrane integrity (>=8 MUg/mL for MoS2 and >=2 MUg/mL for BN). Furthermore, this study first found that low exposure concentrations (0.2-2 MUg/mL) of MoS2 and BN nanomaterials could increase plasma membrane fluidity and inhibit transmembrane ATP binding cassette (ABC) efflux transporter activity, which make both nanomaterials act as a chemosensitizer (increasing arsenic toxicity). Damage to plasma membrane and release of soluble Mo or B species might be two reasons that both nanomaterials inhibit efflux pump activities. This study provides a systematic understanding of the cytotoxicity of sheetlike MoS2 and BN nanomaterials at different exposure levels, which is important for their safe use. PMID- 28841302 TI - Molecular Mechanism for the (-)-Epigallocatechin Gallate-Induced Toxic to Nontoxic Remodeling of Abeta Oligomers. AB - (-)-Epigallocatechin gallate (EGCG) effectively reduces the cytotoxicity of the Alzheimer's disease beta-amyloid peptide (Abeta) by remodeling seeding-competent Abeta oligomers into off-pathway seeding-incompetent Abeta assemblies. However, the mechanism of EGCG-induced remodeling is not fully understood. Here we combine 15N and 1H dark-state exchange saturation transfer (DEST), relaxation, and chemical shift projection NMR analyses with fluorescence, dynamic light scattering, and electron microscopy to elucidate how EGCG remodels Abeta oligomers. We show that the remodeling adheres to a Hill-Scatchard model whereby the Abeta(1-40) self-association occurs cooperatively and generates Abeta(1-40) oligomers with multiple independent binding sites for EGCG with a Kd ~10-fold lower than that for the Abeta(1-40) monomers. Upon binding to EGCG, the Abeta(1 40) oligomers become less solvent exposed, and the beta-regions, which are involved in direct monomer-protofibril contacts in the absence of EGCG, undergo a direct-to-tethered contact shift. This switch toward less engaged monomer protofibril contacts explains the seeding incompetency observed upon EGCG remodeling and suggests that EGCG interferes with secondary nucleation events known to generate toxic Abeta assemblies. Unexpectedly, the N-terminal residues experience an opposite EGCG-induced shift from tethered to direct contacts, explaining why EGCG remodeling occurs without release of Abeta(1-40) monomers. We also show that upon binding Abeta(1-40) oligomers the relative positions of the EGCG B and D rings change with respect to that of ring A. These distinct structural changes occurring in both Abeta(1-40) oligomers and EGCG during remodeling offer a foundation for understanding the molecular mechanism of EGCG as a neurotoxicity inhibitor. Furthermore, the results reported here illustrate the effectiveness of DEST-based NMR approaches in investigating the mechanism of low-molecular-weight amyloid inhibitors. PMID- 28841303 TI - Sieved Transport and Redistribution of Bioavailable Phosphorus from Watershed with Complex River Networks to Lake. AB - An innovative approach was developed to reveal phosphorus (P) transport and redistribution in large and complex river networks in the Lake Taihu basin by establishing the relations between sediment P spatial distribution and P sorption behavior on particles with different grain size, sorted by hydrodynamics. The sediment P fractionation composition changed greatly across the basin, where 69% consisted of acid-soluble fractions (HCl-P) in upstream rivers while 70% was in fractions associated with reducible metal hydroxides (BD-P) and amorphous hydroxides (NaOH25-P) in downstream rivers. Fine particles enriched in BD-P and NaOH25-P fractions tended to sorb liberated P during the resuspension process, and fine particles were more easily delivered downstream toward the lake, forming a sieved transport of P in the river networks. This will lead to a great potential for sediment P release when environmental anoxia develops in the sediments or high pH occurs in the sediment surface during intensive algal blooms in the shallow lake. Reduction of external P from point sources from urbanized areas is an important requirement at the basin scale; however, long-term efforts are needed to restore aquatic macrophytes in the lake, which would decrease P recycling rates at the water-sediment interface. PMID- 28841304 TI - Silver-Catalyzed Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids. AB - The silver-catalyzed decarboxylative trifluoromethylation of aliphatic carboxylic acids is described. With AgNO3 as the catalyst and K2S2O8 as the oxidant, the reactions of aliphatic carboxylic acids with (bpy)Cu(CF3)3 (bpy = 2,2' bipyridine) and ZnMe2 in aqueous acetonitrile at 40 degrees C afford the corresponding decarboxylative trifluoromethylation products in good yield. The protocol is applicable to various primary and secondary alkyl carboxylic acids and exhibits wide functional group compatibility. Mechanistic studies reveal the intermediacy of -Cu(CF3)3Me, which undergoes reductive elimination and subsequent oxidation to give Cu(CF3)2 as the active species responsible for the trifluoromethylation of alkyl radicals. PMID- 28841305 TI - Living on the Edge: DNA Polymerase Lambda between Genome Stability and Mutagenesis. AB - In human cells, only four DNA polymerases (pols) are necessary and sufficient for the duplication of the genetic information. However, more than a dozen DNA pols are required to maintain its integrity. Such a high degree of specialization makes DNA repair pols able to cope with specific lesions or repair pathways. On the other hand, the same DNA pols can have partially overlapping roles, which could result in possible conflicts of functions, if the DNA pols are not properly regulated. DNA pol lambda is a typical example of such an enzyme. It is a multifunctional enzyme, endowed with special structural and biochemical properties, which make it capable of participating in different DNA repair pathways such as base excision repair, nonhomologous end joining, and translesion synthesis. However, when mutated or deregulated, DNA pol lambda can also be a source of genetic instability. Its multiple roles in DNA damage tolerance and its ability in promoting tumor progression make it also a possible target for novel anticancer approaches. PMID- 28841306 TI - Fluorescence Polarization Assay for Small Molecule Screening of FK506 Biosynthesized in 96-Well Microtiter Plates. AB - The fluorescence polarization (FP) assay has been widely used to study enzyme kinetics, antibody-antigen interactions, and other biological interactions. We propose that the FP assay can be adapted as a high-throughput and potentially widely applicable screen for small molecules. This is useful in metabolic engineering, which is a promising approach to synthesizing compounds of pharmaceutical, agricultural, and industrial importance using bioengineered strains. There, the development of high-yield strains is often a costly and time consuming process. This problem can be addressed by generating and testing large mutant strain libraries. However, a current key bottleneck is the lack of high throughput screens to detect the small molecule products. The FP assay is quantitative, sensitive, fast, and cheap. As a proof of principle, we established the FP assay to screen for FK506 (tacrolimus) produced by Streptomyces tsukubaensis, which was cultivated in 96-well plates. An ultraviolet mutagenized library of 160 colonies was screened to identify strains showing higher FK506 productivities. The FP assay has the potential to be generalized to detect a wide range of other small molecules. PMID- 28841308 TI - Palladium(II) Chloride Complexes of N,N'-Disubstituted Imidazole-2-thiones: Syntheses, Structures, and Catalytic Performances in Suzuki-Miyaura and Sonogashira Coupling Reactions. AB - Reactions of PdCl2 with 2 equiv of N,N'-disubstituted-imidazole-2-thiones R1R2C3N2S (R1 = R2 = Me (1a), iPr (1b), Cy (1c), C6Me3H2 (1d); R1 = Me, R2 = Ph (1e)) under the different conditions afford five mononuclear complexes trans [(R1R2C3N2S)2PdCl2] (R1 = R2 = Me (2a), iPr (2b), Cy (2c), C6Me3H2 (2d); R1 = Me, R2 = Ph (2e)) and five binuclear Pd(II) complexes [(PdCl2){MU-(R1R2C3N2S)}]2 (R1 = R2 = Me (3a), iPr (3b), Cy (3c), C6Me3H2 (3d); R1 = Me, R2 = Ph (3e)), respectively. Complexes 2a-2e are easily converted into the corresponding 3a-3e by adding equimolar PdCl2 in refluxing MeOH, while the reverse reaction is achieved at room temperature by addition of 2 equiv of 1a-1e. In 2b, 2d, and 2e, each Pd(II) holds a distorted square planar geometry completed by two trans Cl atoms and two trans S atoms. Complexes 3a-3e have a dimeric [Pd2S2] structure in which two {PdCl2} units are interlinked by two N,N'-disubstituted-imidazole-2 thiones. Each Pd(II) adopts a distorted square planar geometry accomplished by two cis Cl atoms and two cis bridging S atoms. Among them, complex 3d has the two largest C6Me3H2 groups on the 2 and 5 positions of imidazole-2-thione, the longest Pd-MU-S bond, the largest S-Pd-S angle, and displays the highest catalytic activity toward Suzuki-Miyaura and copper-free Sonogashira cross coupling reactions, which are confirmed by density functional theory calculations. The results provide an interesting insight into the introduction of various substituent groups into the periphery ligands of coordination complex based catalysts, which could tune their geometric structures to acquire the best catalytic activity toward organic reactions. PMID- 28841307 TI - The Timing of Transcriptional Regulation in Synthetic Gene Circuits. AB - Transcription factors and their target promoters are central to synthetic biology. By arranging these components into novel gene regulatory circuits, synthetic biologists have been able to create a wide variety of phenotypes, including bistable switches, oscillators, and logic gates. However, transcription factors (TFs) do not instantaneously regulate downstream targets. After the gene encoding a TF is turned on, the gene must first be transcribed, the transcripts must be translated, and sufficient TF must accumulate in order to bind operator sites of the target promoter. The time to complete this process, here called the "signaling time," is a critical aspect in the design of dynamic regulatory networks, yet it remains poorly characterized. In this work, we measured the signaling time of two TFs in Escherichia coli commonly used in synthetic biology: the activator AraC and the repressor LacI. We found that signaling times can range from a few to tens of minutes, and are affected by the expression rate of the TF. Our single-cell data also show that the variability of the signaling time increases with its mean. To validate these signaling time measurements, we constructed a two-step genetic cascade, and showed that the signaling time of the full cascade can be predicted from those of its constituent steps. These results provide concrete estimates for the time scales of transcriptional regulation in living cells, which are important for understanding the dynamics of synthetic transcriptional gene circuits. PMID- 28841309 TI - Synthetic, Structural, and Spectroscopic Characterization of a Novel Family of High-Spin Iron(II) [(beta-Diketiminate)(phosphanylphosphido)] Complexes. AB - This work describes a series of iron(II) phosphanylphosphido complexes. These compounds were obtained by reacting lithiated diphosphanes R2PP(SiMe3)Li (R = t Bu, i-Pr) with an iron(II) beta-diketiminate complex, [LFe(MU2-Cl)2Li(DME)2] (1), where DME = 1,2-dimethoxyethane and L = Dippnacnac (beta-diketiminate). While the reaction of 1 with t-Bu2PP(SiMe3)Li yields [LFe(eta1-Me3SiPP-t-Bu2)] (2), that of 1 with equimolar amounts of i-Pr2PP(SiMe3)Li, in DME, leads to [LFe(eta2-i Pr2PPSiMe3)] (3). In contrast, the reaction of 1 with (i-Pr2N)2PP(SiMe3)Li provides not an iron-containing complex but 1-[(diisopropylamino)phosphine]-2,4 bis(diisopropylamino)-3-(trimethylsilyl)tetraphosphetane (4). The structures of 2 4 were determined using diffractometry. Thus, 2 exhibits a three-coordinate iron site and 3 a four-coordinate iron site. The increase in the coordination number is induced by the change from an anticlinal to a synclinal conformation of the phoshpanylphosphido ligands. The electronic structures of 2 and 3 were assessed through a combined field-dependent 57Fe Mossbauer and high-frequency and -field electron paramagnetic resonance spectroscopic investigation in conjunction with analysis of their magnetic susceptibility and magnetization data. These studies revealed two high-spin iron(II) sites with S = 2 ground states that have different properties. While 2 exhibits a zero-field splitting described by a positive D parameter (D = +17.4 cm-1; E/D = 0.11) for 3, this parameter is negative [D = -25(5) cm-1; E/D = 0.15(5)]. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations provide insights into the origin of these differences and allow us to rationalize the fine and hyperfine structure parameters of 2 and 3. Thus, for 2, the spin-orbit coupling mixes a z2-type ground state with two low-lying {xz/yz} orbital states. These interactions lead to an easy plane of magnetization, which is essentially parallel to the plane defined by the N-Fe-N atoms. For 3, we find a yz-type ground state that is strongly mixed with a low-lying z2-type orbital state. In this case, the spin orbit interaction leads to a partial unquenching of the orbital momentum along the x axis, that is, to an easy axis of magnetization oriented roughly along the Fe-P bond of the phosphido moiety. PMID- 28841310 TI - Hydroisomerization of n-Hexane Using Acidified Metal-Organic Framework and Platinum Nanoparticles. AB - Exceptionally high surface area and ordered nanopores of a metal-organic framework (MOF) are exploited to encapsulate and homogeneously disperse a considerable amount of phosphotungstic acid (PTA). When combined with platinum nanoparticles positioned on the external surface of the MOF, the construct shows a high catalytic activity for hydroisomerization of n-hexane, a reaction requiring hydrogenation/dehydrogenation and moderate to strong Bronsted acid sites. Characterization of the catalytic activity and acidic sites as a function of PTA loading demonstrates that both the concentration and strength of acidic sites are highest for the catalyst with the largest amount of PTA. The MOF construct containing 60% PTA by weight produces isoalkanes with 100% selectivity and 9-fold increased mass activity as compared to a more traditional aluminosilicate catalyst, further demonstrating the capacity of the MOF to contain a high concentration of active sites necessary for the isomerization reaction. PMID- 28841312 TI - Hypervalent Iodonium Alkynyl Triflate Generated Phenylcyanocarbene and Its Reactivity with Aromatic Systems. AB - Phenylcyanocarbene was generated by the reaction of azide with a hypervalent iodonium alkynyl triflate and reacted in situ with 21 different carbocyclic and heterocyclic aromatic compounds. These reactions led to more complex products that frequently underwent subsequent rearrangements. The reactivity was further explored in a mechanistic study to ascertain the chemoselectivity and stereospecificity. PMID- 28841311 TI - Peptidomimetics That Inhibit and Partially Reverse the Aggregation of Abeta1-42. AB - The peptide sequence KLVFF resembles the hydrophobic core of the Abeta peptide known to form amyloid plaques in Alzheimer's disease. Starting from its retro inverso peptide, we have synthesized three generations of peptidomimetics. Step by step natural amino acids have been replaced by aromatic building blocks accessible from the Pd-catalyzed Catellani reaction. The final compound 18 is stable against proteolytic decay and largely prevents the aggregation of Abeta1 42 over extended periods of time. The activity of the new inhibitors was tested first by fluorescence correlation spectroscopy. For closer examination of compound 18, additional techniques were also applied: laser-induced liquid bead ion desorption mass spectrometry, confocal laser scanning microscopy, thioflavin T fluorescence, and gel electrophoresis. Compound 18 not only retards the aggregation of chemically synthesized Abeta but also can partially dissolve the oligomeric structures. Thioflavin binding mature fibrils, however, seem to resist the inhibitor. PMID- 28841313 TI - Decoupling between the Temperature-Dependent Structural Relaxation and Shear Viscosity of Concentrated Lithium Electrolyte. AB - The intermediate scattering functions of concentrated solutions of LiPF6 in propylene carbonate (PC) were measured at various temperatures, two different wavenumbers, and three different concentrations using neutron spin echo (NSE) spectroscopy. The temperature dependence of the relaxation time was larger than that of the steady-state shear viscosity in all cases. The shear relaxation spectra were also determined at different temperatures. The normalized spectra reduced to a master curve when the frequency was multiplied by the steady-state shear viscosity, indicating that the temperature dependence of the steady-state shear viscosity can be explained by that of the relaxation time of the shear stress. It is thus suggested that the dynamics of the shear stress is decoupled from the structural dynamics on the molecular scale. PMID- 28841314 TI - Optimal Alignment of Structures for Finite and Periodic Systems. AB - Finding the optimal alignment between two structures is important for identifying the minimum root-mean-square distance (RMSD) between them and as a starting point for calculating pathways. Most current algorithms for aligning structures are stochastic, scale exponentially with the size of structure, and the performance can be unreliable. We present two complementary methods for aligning structures corresponding to isolated clusters of atoms and to condensed matter described by a periodic cubic supercell. The first method (Go-PERMDIST), a branch and bound algorithm, locates the global minimum RMSD deterministically in polynomial time. The run time increases for larger RMSDs. The second method (FASTOVERLAP) is a heuristic algorithm that aligns structures by finding the global maximum kernel correlation between them using fast Fourier transforms (FFTs) and fast SO(3) transforms (SOFTs). For periodic systems, FASTOVERLAP scales with the square of the number of identical atoms in the system, reliably finds the best alignment between structures that are not too distant, and shows significantly better performance than existing algorithms. The expected run time for Go-PERMDIST is longer than FASTOVERLAP for periodic systems. For finite clusters, the FASTOVERLAP algorithm is competitive with existing algorithms. The expected run time for Go-PERMDIST to find the global RMSD between two structures deterministically is generally longer than for existing stochastic algorithms. However, with an earlier exit condition, Go-PERMDIST exhibits similar or better performance. PMID- 28841315 TI - Thermoactinoamide A, an Antibiotic Lipophilic Cyclopeptide from the Icelandic Thermophilic Bacterium Thermoactinomyces vulgaris. AB - The thermophilic bacterium Thermoactinomyces vulgaris strain ISCAR 2354, isolated from a coastal hydrothermal vent in Iceland, was shown to contain thermoactinoamide A (1), a new cyclic hexapeptide composed of mixed d and l amino acids, along with five minor analogues (2-6). The structure of 1 was determined by one- and two-dimensional NMR spectroscopy, high-resolution tandem mass spectrometry, and advanced Marfey's analysis of 1 and of the products of its partial hydrolysis. Thermoactinoamide A inhibited the growth of Staphylococcus aureus ATCC 6538 with an MIC value of 35 MUM. On the basis of literature data and this work, cyclic hexapeptides with mixed d/l configurations, one aromatic amino acid residue, and a prevalence of lipophilic residues can be seen as a starting point to define a new, easily accessible scaffold in the search for new antibiotic agents. PMID- 28841316 TI - Lamellodysidines A and B, Sesquiterpenes Isolated from the Marine Sponge Lamellodysidea herbacea. AB - Four new sesquiterpenes, lamellodysidines A and B, O,O-dimethyllingshuiolide A, and 11-epi-O,O-dimethyllingshuiolide A (1-4), were obtained from the marine sponge, Lamellodysidea herbacea, collected in Indonesia. Their planar structures were elucidated by analysis of spectroscopic data. The absolute configurations of the new compounds were determined by the calculated ECD spectra. Compound 1 has a unique carbon framework, and 2 is a new nitrogenous sesquiterpene. PMID- 28841317 TI - Palladium-Catalyzed One-Pot Conversion of Aldehydes and Ketones into 4 Substituted Homopropargyl Alcohols and 5-En-3-yn-1-ols ?. AB - Sequential treatment of 2,3-dichloropropene with magnesium and n-BuLi generated the equivalent of 1,3-dilithiopropyne, which adds regiospecifically to aldehydes and ketones to produce homopropargyl alcohols. The lithium acetylide intermediate formed in this protocol can be further reacted with aromatic and vinyl halides, under palladium catalysis, to produce 4-substituted homopropargyl alcohols and 5 en-3-yn-1-ols, respectively, in one-pot with good overall yields. PMID- 28841318 TI - TD-DFT Study on Thiacalix[4]arene, the Receptor of a Fluorescent Chemosensor for Cu2. AB - The electronic and spectral properties of p-tert-butylthiacalix[4]arene (TCA) and its Cu2+ complexes (CuTCA and Cu2TCA) were characterized by time-dependent density functional theory (TD-DFT). Geometries of TCA, CuTCA, and Cu2TCA were optimized at the CAM-B3LYP/6-31+G(d,p) level of theory in water using the conductor-like polarizable continuum model. The absorption spectra of TCA, CuTCA, and Cu2TCA were demonstrated by TD-DFT method. The quenching mechanism of perylene as the fluorophore of a chemosensor based on thiacalix[4]arene was discussed. The addition of Cu2+ to TCA introduced a series of low-lying excited states involving copper d orbitals. The overlap between absorption of TCA complexes and emission of perylene indicated that the quenching of perylene fluorescence is due to fluorescence resonance energy transfer. PMID- 28841319 TI - Origins of the Stereoretentive Mechanism of Olefin Metathesis with Ru-Dithiolate Catalysts. AB - A comprehensive computational study of stereoretentive olefin metathesis with Ru dithiolate catalysts has been performed. We have determined how the dithiolate ligand enforces a side-bound mechanism and how the side-bound mechanism allows for stereochemical control over the forming olefin. We have used density functional theory (DFT) and ligand steric contour maps to elucidate the origins of stereoretentive metathesis with the goal of understanding how to design a new class of E-selective metathesis catalysts. PMID- 28841320 TI - Iridoid Glycosides from the Twigs of Sambucus williamsii var. coreana and Their Biological Activities. AB - Six new iridoid glycosides, sambucusides A-F (1-6), and two known derivatives (7 and 8) were isolated from a methanol extract of the twigs of Sambucus williamsii var. coreana. Their chemical structures were elucidated by spectroscopic methods, including NMR (1H and 13C NMR, 1H-1H COSY, HMQC, HMBC, and NOESY) and HRMS. All isolated compounds (1-8) were evaluated for their antiproliferative activities against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and Bt549). Their effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated BV 2 cells and their neuroprotective effects through induction of nerve growth factor (NGF) in C6 glioma cells were also examined. Compounds 2, 3, and 5 showed cytotoxic effects (IC50 1.3-8.7 MUM) against the SK-MEL-2 and Bt549 cell lines and inhibitory effects on NO production (IC50 of 0.9, 1.3, and 1.2 MUM, respectively). Compounds 2, 4, and 8 exhibited NGF-releasing effects (147.0 +/- 5.8%, 158.7 +/- 5.2%, and 152.6 +/- 7.3%, respectively). PMID- 28841321 TI - Base-Mediated Synthesis of Unsymmetrical 1,3,5-Triazin-2-amines via Three Component Reaction of Imidates, Guanidines, and Amides or Aldehydes. AB - A simple and efficient method for the base-mediated synthesis of unsymmetrical 1,3,5-triazin-2-amines has been developed. The protocol uses readily available imidates, guanidines, and amides or aldehydes as the starting materials, cesium carbonate as the base, no catalyst or additive is required, and the three component reaction provides diverse 1,3,5-triazin-2-amines in moderate to good yields with tolerance of wide functional groups. PMID- 28841322 TI - Dissolution Kinetics of Cubic Tricalcium Aluminate Measured by Digital Holographic Microscopy. AB - In situ digital holographic microscopy is used to characterize the dissolution flux of polycrystalline cubic tricalcium aluminate (C3A-c). The surface dissolves at rates that vary considerably with time and spatial location. This implies a statistical distribution of fluxes, but an approximately steady-state median rate was obtained by using flowing solutions and by reducing the water activity in the solution. The dissolution flux from highly crystalline C3A-c depends on the water activity raised to an empirically derived exponent of 5.2 and extrapolates to a median flux of - 2.1 MUmol m-2 s-1 in pure water with an interquartile range of 3.2 MUmol m-2 s-1. The flux from a less crystalline source of C3A-c has an empirical water activity exponent of 4.6 and an extrapolated median flux of only 1.4 MUmol m-2 s-1 in pure water with an interquartile range of 1.9 MUmol m-2 s-1. These data suggest that the bulk dissolution rate of C3A-c can vary by at least 30% from one source to another and that variability in the local rate within a single material is even greater because of the heterogeneous spatial distribution of structural characteristics (i.e., degree of crystallinity, chemical impurities, and defects). PMID- 28841323 TI - Organocatalytic, Dioxirane-Mediated C-H Hydroxylation under Mild Conditions Using Oxone. AB - Dioxiranes are among the most selective and useful reagents for C(sp3)-H hydroxylation, but the development of a general dioxirane-mediated catalytic method has been an elusive goal. A trifluoromethyl ketone catalyst in combination with Oxone is shown to enable the first dioxirane-mediated catalytic hydroxylations that approximate the reactivity and selectivity of isolated dioxiranes. The mild reaction conditions allow for selective 3 degrees hydroxylation and 2 degrees oxidation and are tolerant of acid-sensitive functionality and electron-neutral arenes. PMID- 28841324 TI - Silver Nitrate-Catalyzed Isocyanide Insertion/Lactamization Sequence to Imidazolones and Quinazolin-4-ones: Development and Application in Natural Product Synthesis. AB - Silver nitrate-catalyzed reaction of methyl alpha,alpha-disubstituted alpha isocyanoacetates with primary amines afforded 3,5,5-trisubstituted imidazolones in good to excellent yields. A silver salt-catalyzed insertion of the isocyano group into the N-H bond of the amine followed by in situ lactamization accounted for the reaction outcome. The same transformation between methyl 2 isocyanobenzoate and amines afforded quinazolin-4-ones in excellent yields. The utility of this chemistry was illustrated by the development of concise syntheses of (+/-)-evodiamine and rutaecarpine. PMID- 28841325 TI - Ab Initio Confirmation of a Harpoon-Type Electron Transfer in a Helium Droplet. AB - An ab initio study of a long-range electron transfer or "harpoon"-type process from Cs and Cs2 to C60 in a superfluid helium droplet is presented. The heliophobic Cs or Cs2 species are initially located at the droplet surface, while the heliophilic C60 molecule is fully immersed in the droplet. First, probabilities for the electron transfer in the gas phase are calculated for reactants with velocities below the critical Landau velocity of 57 m/s to account for the superfluid helium environment. Next, reaction pathways are derived that also include the repulsive contribution from the extrusion of helium upon the approach of the two reactants. Our results are in perfect agreement with recent experimental measurements of electron ionization mass spectroscopy [ Renzler , M. ; et al., J. Chem. Phys. 2016 , 145 , 181101 ], showing a high possibility for the formation of a Cs2-C60 complex inside of the droplet through a direct harpoon type electron transfer involving the rotation of the molecule but a negligibly low reactivity for atomic Cs. PMID- 28841326 TI - Spheroidal Microparticle Monolayers Characterized by Streaming Potential Measurements. AB - An efficient method was developed enabling the synthesis of spheroidal polymer microparticles. Thorough physicochemical characteristics of the particles were acquired comprising the size, shape, electrophoretic mobility, and the diffusion coefficient. The particles were monodisperse, and their shape was well-fitted by prolate spheroids having the axis ratio equal to 4.17. Knowing the diffusion coefficient, their hydrodynamic diameter of 449 nm was calculated, which matched the value derived from Brenner's analytical expression. Particle deposition kinetics on mica and silicon/silica substrates, modified by poly(allylamine hydrochloride) (PAH) adsorption, was studied by optical microscopy and AFM imaging. The validity of the random sequential adsorption model was confirmed. Additionally, monolayers of the particles on these substrates were thoroughly characterized in situ by the streaming potential measurements for different ionic strengths. These measurements confirmed that the zeta potential change with the spheroidal particle coverage is less abrupt than for spheres and agrees with theoretical predictions. Exploiting these results, a useful analytical expression was derived that allows one to calculate the spheroidal particle coverage in situ via the streaming potential measurements. This expression, especially accurate for low coverage range, can be used for a quantitative interpretation of adsorption and desorption kinetics of anisotropic macromolecules, e.g., proteins on solid substrates. PMID- 28841327 TI - Direct Evidence of Relaxation Anisotropy Resolved by High Pressure in a Rigid and Planar Glass Former. AB - Rigid molecular glass-formers with no internal degrees of freedom nonetheless have a single secondary beta-relaxation. For a rigid and planar molecule, 1 methylindole (1MID), although a secondary relaxation is resolved at ambient pressure, its properties do not conform to the rules established for rigid molecules reported in early studies. By applying pressure to the dielectric spectra of 1MID, we find the single secondary relaxation splits into two. The slower one is pressure sensitive showing connections to the alpha-relaxation as observed in other rigid molecules, while the faster one is almost pressure insensitive and dominate the loss at ambient pressure. The two secondary relaxations, identified to associate with the out-of-plane and in-plane rotations of the rigid and planar 1MID, are resolved and observed for the first time by increasing density via elevating pressure. PMID- 28841328 TI - Out-of-Plane Piezoelectricity and Ferroelectricity in Layered alpha-In2Se3 Nanoflakes. AB - Piezoelectric and ferroelectric properties in the two-dimensional (2D) limit are highly desired for nanoelectronic, electromechanical, and optoelectronic applications. Here we report the first experimental evidence of out-of-plane piezoelectricity and ferroelectricity in van der Waals layered alpha-In2Se3 nanoflakes. The noncentrosymmetric R3m symmetry of the alpha-In2Se3 samples is confirmed by scanning transmission electron microscopy, second-harmonic generation, and Raman spectroscopy measurements. Domains with opposite polarizations are visualized by piezo-response force microscopy. Single-point poling experiments suggest that the polarization is potentially switchable for alpha-In2Se3 nanoflakes with thicknesses down to ~10 nm. The piezotronic effect is demonstrated in two-terminal devices, where the Schottky barrier can be modulated by the strain-induced piezopotential. Our work on polar alpha-In2Se3, one of the model 2D piezoelectrics and ferroelectrics with simple crystal structures, shows its great potential in electronic and photonic applications. PMID- 28841331 TI - Additional Abstracts for the 21st Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28841330 TI - Recovery from Critical Illness: Physical Rehabilitation in the Intensive Care Unit, Timing of Persistent Critical Illness, and Caregiver Outcomes. PMID- 28841332 TI - Beijing Declaration of International Association of Neurorestoratology (IANR). PMID- 28841333 TI - Abstracts for the 19th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28841334 TI - Eyelid Merkel cell carcinoma in a patient treated with golimumab. AB - PURPOSE: To describe a clinical case of biopsy-proven Merkel cell carcinoma of the eyelid following golimumab therapy for rheumatoid arthritis (RA). METHODS: Interventional case report. RESULTS: A 73-year-old woman with a history of chronic RA presented with a right upper eyelid mass. She had been treated with golimumab (tumor necrosis factor (TNF) inhibitors) injection therapy for the past 6 months. A biopsy showed findings suggestive of a Merkel cell carcinoma of the eyelid. CONCLUSIONS: Merkel cell carcinoma may be associated with anti-TNF treatment and should be included in the differential diagnosis of an eyelid tumor in patients treated with TNF inhibitors. PMID- 28841336 TI - Additional Abstracts for the 15th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28841339 TI - The influence of semen quality on male pronucleus demethylation process during ICSI cycle. AB - There is growing evidence that the spermatozoon's epigenetic structure is of the utmost importance in the health of the future embryo. Following fertilization, sperm chromatin undergoes epigenetic reprogramming including DNA demethylation and remethylation, which resets gene expression. In some infertile patients, it is inevitable that sperm cells that are not within the range of normal human sperm parameters will be used for intracytoplasmic sperm injection. Understanding the relationship between the human sperm parameters and male pronucleus DNA demethylation seems necessary. We hypothesized that demethylation of the male pronucleus might be altered in zygotes conceived from a spermatozoa obtained from a sample exhibiting an abnormal semen analysis profile. To test the hypothesis, sperm cells from normal and abnormal human semen samples were injected into mouse oocytes. A group of cultured zygotes was fixed before the onset of DNA demethylation and the other group was fixed after DNA demethylation. Both groups were then labeled with a 5 methylcytosine antibody and the level of pronuclei methylation was detected as a function of fluorescent intensity. The level of demethylation was then determined as the difference between 5 methylcytosine fluorescent intensity before and after DNA demethylation. A negative correlation (p<0.05) was observed between sperm motility, morphology, percentage of head defects, protamine deficiency, and DNA demethylation level. However, no correlation was found between the demethylation level and sperm count. In conclusion, these observations suggest that demethylation is altered in the male pronucleus when low quality sperm samples are used. PMID- 28841335 TI - Future Directions for the Examination of Mediators of Treatment Outcomes in Youth. AB - How do psychological therapies work? How can we enhance treatment to improve outcomes? Questions of mediation lie at the heart of these inquiries. However, within the child and adolescent treatment literature, studies of mediation often rely on methodological and statistical approaches that limit the inferences that can be drawn from study findings. This future directions review delineates some of these issues and suggests improvements through two interrelated paths. We propose that mediation studies in the youth treatment literature will be enhanced (a) by adopting best practices in nomothetic (group-based) methodologies for assessing putative mediating variables and conducting appropriate statistical analyses and (b) by increasing the use of idiographic (individual-focused) approaches to youth outcome research through mediation studies that use innovative designs, data collection techniques, and analytic methods. We discuss the applicability of findings using these approaches to the treatment of youth in particular. PMID- 28841340 TI - Surgical technique: Lateral canthal tendon relieving incisions in lower lid reconstruction. PMID- 28841341 TI - Systemic vascular resistance and endogenous inhibitors of nitric oxide synthesis in early- compared to late-onset preeclampsia: preliminary findings. AB - OBJECTIVE: To examine systemic vascular resistance index (SVRI), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) levels in preeclampsia at different gestations. METHODS: Twenty-four preeclamptic patients (14 at >= 34 weeks') and 72 matched healthy controls were included. SVRI was calculated from impedance cardiography measurements. ADMA and SDMA levels were determined using enzyme linked immunosorbent assay. RESULTS: SVRI and SDMA were higher in preeclampsia overall, in early onset and late onset compared to controls. SVRI was correlated with ADMA and SDMA, respectively. CONCLUSIONS: Early-onset and late-onset preeclampsia are both characterized by increased systemic vascular resistance and elevated levels of nitric oxide synthesis inhibitors. PMID- 28841342 TI - Children's Rumination to Sadness and Anger: Implications for the Development of Depression and Aggression. AB - The current study examined the transdiagnostic nature of rumination in the development of childhood depression and aggression by examining the relation between two forms of rumination, sadness and anger, in a single study and assessing their unique and shared behavioral correlates. A community sample of 254 children (ages 7-14, 50.4% female, 66.5% Caucasian) completed self-report measures of rumination and depressive symptoms, and peer nominations of aggressive behaviors. Hierarchical regression analyses were conducted to assess unique and shared behavioral correlates. Anger rumination uniquely predicted aggression (beta = .40, p < .001) and depressive symptoms (beta = .62, p < .001), controlling for sadness rumination. Sadness rumination, controlling for anger rumination, did not predict depressive symptoms (beta = -.10, p = .10) and negatively predicted aggressive symptoms (beta = -.21, p = .003). In addition, a significant interaction between sadness rumination and anger rumination on aggressive behaviors was observed (beta = -.24, p < .001), such that children who reported high anger and low sadness rumination tendencies were perceived as more aggressive by their peers than other children, including those with high levels of anger and sadness rumination. These results offer support for anger rumination as a transdiagnostic factor for children's depressive symptoms and aggression. Sadness rumination did not uniquely predict depressive symptoms, although it did moderate the association between anger rumination and aggression. These findings underscore the importance of assessing both anger and sadness rumination for increasing our understanding of children's risk for depression and aggression. PMID- 28841343 TI - Effect of Methyl Palmitate on the Formation of Epidural Fibrosis in an Experimental Epidural Fibrosis Model. AB - AIM: To investigate the effects of local and systemic administration of methyl palmitate on the formation of epidural fibrosis. MATERIAL AND METHODS: Twenty eight rats were randomly divided into four equal groups (control, Spongostan, local methyl palmitate and orally methyl palmitate) and laminectomy was performed between T11 and L1 in all rats. Local methyl palmitate (300 mg/kg) was applied with Spongostan; methyl palmitate (300 mg/kg) was given orally three times per week on different days for a total period of 4 weeks. Four weeks later, the vertebral column from T9 to L3, including the paraspinal muscles and epidural scar tissue, was removed en bloc and epidural fibrosis and arachnoidal involvement was graded and evaluated histopathologically. Kruskal-Wallis and Pearson Chi-Square test were used for statistical analysis. A statistically significant p-value was determined as p < 0.05. RESULTS: The grading of epidural fibrosis was lower at a statistically significant level in orally-administrated methyl palmitate groups compared to the control and spongostan groups (p < 0.05). CONCLUSION: The findings of this study show that oral methyl palmitate decreases the formation of epidural fibrosis and that this effect of methyl palmitate could be mediated by reducing the functions of inflammatory cells such as macrophages, neutrophils and fibroblasts, including anti-inflammatory and antioxidant effects. PMID- 28841347 TI - Noninvasive Imaging of Liver Repopulation following Hepatocyte Transplantation. AB - Near infrared fluorescence (NIRF) optical imaging is a technique particularly powerful when studying in vivo processes at the molecular level in preclinical animal models. We recently demonstrated liver irradiation under the additional stimulus of partial hepatectomy as being an effective primer in the rat liver repopulation model based on hepatocyte transplantation. The purpose of this study was to assess optical imaging and the feasibility of donor cell expansion tracking in vivo using a fluorescent probe. Livers of dipeptidylpeptidase IV (DPPIV)-deficient rats were preconditioned with irradiation. Four days later, a partial hepatectomy was performed and wild-type (DPPIV+) hepatocytes were transplanted into recipient livers via the spleen. Repopulation by transplanted DPPIV+ hepatocytes was detected in vivo with Cy5.5-conjugated DPPIV antibody using the eXplore OptixTM System (GE HealthCare). Results were compared with nontransplanted control animals and transplanted animals receiving nonspecific antibody. Optical imaging detected Cy5.5-specific fluorescence in the liver region of the transplanted animals, increasing in intensity with time, representing extensive host liver repopulation within 16 weeks following transplantation. A general pattern of donor cell multiplication emerged, with an initially accelerating growth curve and later plateau phase. In contrast, no specific fluorescence was detected in the control groups. Comparison with ex vivo immunofluorescence staining of liver sections confirmed the optical imaging results. Optical imaging constitutes a potent method of assessing the longitudinal kinetics of liver repopulation in the rat transplantation model. Our results provide a basis for the future development of clinical protocols for suitable fluorescent dyes and imaging technologies. PMID- 28841344 TI - Retrospective on Cholesterol Homeostasis: The Central Role of Scap. AB - Scap is a polytopic membrane protein that functions as a molecular machine to control the cholesterol content of membranes in mammalian cells. In the 21 years since our laboratory discovered Scap, we have learned how it binds sterol regulatory element-binding proteins (SREBPs) and transports them from the endoplasmic reticulum (ER) to the Golgi for proteolytic processing. Proteolysis releases the SREBP transcription factor domains, which enter the nucleus to promote cholesterol synthesis and uptake. When cholesterol in ER membranes exceeds a threshold, the sterol binds to Scap, triggering several conformational changes that prevent the Scap-SREBP complex from leaving the ER. As a result, SREBPs are no longer processed, cholesterol synthesis and uptake are repressed, and cholesterol homeostasis is restored. This review focuses on the four domains of Scap that undergo concerted conformational changes in response to cholesterol binding. The data provide a molecular mechanism for the control of lipids in cell membranes. PMID- 28841348 TI - Cotransplantation of Mouse Embryonic Stem Cells and Bone Marrow Stromal Cells following Spinal Cord Injury Suppresses Tumor Development. AB - Embryonic stem (ES) cells are a potential source for treatment of spinal cord injury (SCI). Although one of the main problems of ES cell-based cell therapy is tumor formation, there is no ideal method to suppress tumor development. In this study, we examined whether transplantation with bone marrow stromal cells (BMSCs) prevented tumor formation in SCI model mice that received ES cell-derived grafts containing both undifferentiated ES cells and neural stem cells. Embryoid bodies (EBs) formed in 4-day hanging drop cultures were treated with retinoic acid (RA) at a low concentration of 5 * 10-9 M for 4 days, in order to allow some of the ES cells to remain in an undifferentiated state. RA-treated EBs were enzymatically digested into single cells and used as ES cell-derived graft cells. Mice transplanted with ES cell-derived graft cells alone developed tumors at the grafted site and behavioral improvement ceased after day 21. In contrast, no tumor development was observed in mice cotransplanted with BMSCs, which also showed sustained behavioral improvement. In vitro results demonstrated the disappearance of SSEA-1 expression in cytochemical examinations, as well as attenuated mRNA expressions of the undifferentiated markers Oct3/4, Utf1, Nanog, Sox2, and ERas by RT-PCR in RA-treated EBs cocultured with BMSCs. In addition, MAP2-immunopositive cells appeared in the EBs cocultured with BMSCs. Furthermore, the synthesis of NGF, GDNF, and BDNF was confirmed in cultured BMSCs, while immunohistochemical examinations demonstrated the survival of BMSCs and their maintained ability of neurotrophic factor production at the grafted site for up to 5 weeks after transplantation. These results suggest that BMSCs induce undifferentiated ES cells to differentiate into a neuronal lineage by neurotrophic factor production, resulting in suppression of tumor formation. Cotransplantation of BMSCs with ES cell-derived graft cells may be useful for preventing the development of ES cell-derived tumors. PMID- 28841353 TI - ESRRA (estrogen-related receptor alpha) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense. AB - The orphan nuclear receptor ESRRA (estrogen-related receptor alpha) is a key regulator of energy homeostasis and mitochondrial function. Macroautophagy/autophagy, an intracellular degradation process, is a critical innate effector against intracellular microbes. Here, we demonstrate that ESRRA is required for the activation of autophagy to promote innate antimicrobial defense against mycobacterial infection. AMP-activated protein kinase pathway and SIRT1 (sirtuin 1) activation led to induction of ESRRA, which is essential for autophagosome formation, in bone marrow-derived macrophages. ESRRA enhanced the transcriptional activation of numerous autophagy-related (Atg) genes containing ERR response elements in their promoter regions. Furthermore, ESRRA, operating in a feed-forward loop with SIRT1, was required for autophagy activation through deacetylation of ATG5, BECN1, and ATG7. Importantly, ESRRA deficiency resulted in a decrease of phagosomal maturation and antimicrobial responses against mycobacterial infection. Thus, we identify ESRRA as a critical activator of autophagy via both transcriptional and post-translational control to promote antimicrobial host responses. PMID- 28841352 TI - Toward understanding of the mechanisms of Mediator function in vivo: Focus on the preinitiation complex assembly. AB - Mediator is a multisubunit complex conserved in eukaryotes that plays an essential coregulator role in RNA polymerase (Pol) II transcription. Despite intensive studies of the Mediator complex, the molecular mechanisms of its function in vivo remain to be fully defined. In this review, we will discuss the different aspects of Mediator function starting with its interactions with specific transcription factors, its recruitment to chromatin and how, as a coregulator, it contributes to the assembly of transcription machinery components within the preinitiation complex (PIC) in vivo and beyond the PIC formation. PMID- 28841354 TI - Speciation of As in environmental samples using the nano-TiO2/PCHG-FAAS online system. AB - This work presents an alternative method for arsenic speciation using the nano TiO2 hydride generation photocatalytic hydride generation (PCHG) system, which is easily separated from the medium. Nano-TiO2 was studied as photocatalyst to reduction of arsenic species by UV-induced with formic acid and atomic absorption detection of different forms of arsenic [As (III), As (V), dimethylarsinic acid (DMA)] in environmental samples (water, sediment and plant). The effect of the average pH, the organic acid concentration, the ultraviolet irradiation time and their amount were investigated. With the presence of formic acid, the process was more effective in the reduction of arsenic when compared to other organic acids, mainly acetic acid. In addition, the photocatalytic hydride generation and flame atomic absorption spectrometry (nano-TiO2/PCHG-FAAS) increased the identification and quantification of different arsenic species. The ultrasound extraction procedure was used as a method to prepare samples with solutions of 1.0 mol L-1 phosphoric acid. The accuracy of the measurements (n = 12), calculated as relative standard deviation, was less than 8.6%. The detection limits for As (III) and As (total) in samples were 0.418 and 0.574 MUg g-1, respectively. PMID- 28841355 TI - Topological requirements of the mitochondrial heavy-strand promoters. AB - In vitro studies of mitochondrial transcription often use linear templates that fail to replicate key features of transcription on a circular genome. We developed a plasmid-based system for the analysis of heavy-strand promoters that recapitulates key features of native mtDNA to study topological and protein requirements of promoter activation. The heavy-strand promoters (HSP1 and HSP2) are simultaneously active on a circular template. HSP2 requires supercoiling for maximal activation. Increasing TFAM concentrations suppress HSP2 at levels that result in HSP1 stimulation. This study shows distinct modes of promoter activation, providing opportunities for the regulation of mitochondrial gene expression by promoter selection. PMID- 28841356 TI - Removal of phosphate from electrocoagulation post-treatment phosphate reduction using Octolig(r). AB - The present study examined the removal of phosphorus following electrocoagulation post-treatment using a sample from a commercial firm. Samples were subjected to column chromatography using Octolig(r) a polyethylenediimine covalently attached to high-surface-area silica. Two commercial samples with significantly different phosphorus concentrations were evaluated: 10.2 ppm from polyphosphates and raw sample of 983 ppm P. After passing over Octolig(r), the sample phosphate concentration was reduced to values of <0.05 ppm P. PMID- 28841357 TI - Abscisic acid (ABA) and key proteins in its perception and signaling pathways are ancient, but their roles have changed through time. AB - Homologs of the Arabidopsis core abscisic acid (ABA) signaling component OPEN STOMATA1 (OST1) are best known for their role in closing stomata in angiosperm species. We recently characterized a fern OST1 homolog, GAMETOPHYTES ABA INSENSITIVE ON ANTHERDIOGEN 1 (GAIA1), which is not required for stomatal closure in ferns, consistent with physiologic evidence that shows the stomata of these plants respond passively to changes in leaf water status. Instead, gaia1 mutants reveal a critical role in ABA signaling for spore dormancy and sex determination, in a system regulated by antagonism between ABA and the gibberellin (GA)-derived fern hormone antheridiogen (ACE). ABA and key proteins, including ABA receptors from the PYR/PYL/RCAR family and negative regulators of ABA-signaling from Group A of the type-2C protein phosphatases (PP2Cs), in addition to OST1 homologs, can be found in all terrestrial land plant lineages, ranging from liverworts that lack stomata, to angiosperms. As land plants have evolved and diversified over the past 450 million years, so too have the roles of this important plant hormone and the genes involved in its signaling and perception. PMID- 28841358 TI - The dual defensive strategy of Amorphophallus throughout its ontogeny. AB - Amorphophallus bufo is a rarely studied plant in Malaysian tropical rainforests. We measured the spectral reflectance of different developmental stages of A. bufo (seedlings, juveniles and adults), background soil/ debris and leaves from other neighboring plant species. Results show that the leaves of A. bufo seedling have a similar reflectance curve as the background soil and debris. Adults and juveniles of A. bufo are similar to other neighboring plants' leaf colors. We hypothesize that the cryptic coloration of A. bufo seedlings plays an important role in camouflage and that the numerous black spots on the surface of the petioles and rachises, may serve as a defensive mimicry against herbivores. PMID- 28841359 TI - Comparison of the effects and distribution of zinc oxide nanoparticles and zinc ions in activated sludge reactors. AB - Zinc Oxide nanoparticles (ZnO NPs) are being increasingly applied in the industry, which results inevitably in the release of these materials into the hydrosphere. In this study, simulated waste-activated sludge experiments were conducted to investigate the effects of Zinc Oxide NPs and to compare it with its ionic counterpart (as ZnSO4). It was found that even 1 mg/L of ZnO NPs could have a small impact on COD and ammonia removal. Under 1, 10 and 50 mg/L of ZnO NP exposure, the Chemical Oxygen Demand (COD) removal efficiencies decreased from 79.8% to 78.9%, 72.7% and 65.7%, respectively. The corresponding ammonium (NH4+ N) concentration in the effluent significantly (P < 0.05) increased from 11.9 mg/L (control) to 15.3, 20.9 and 28.5 mg/L, respectively. Under equal Zn concentration, zinc ions were more toxic towards microorganisms compared to ZnO NPs. Under 50 mg/L exposure, the effluent Zn level was 5.69 mg/L, implying that ZnO NPs have a strong affinity for activated sludge. The capacity for adsorption of ZnO NPs onto activated sludge was found to be 2.3, 6.3, and 13.9 mg/g MLSS at influent ZnO NP concentrations of 1.0, 10 and 50 mg/L respectively, which were 1.74-, 2.13- and 2.05-fold more than under Zn ion exposure. PMID- 28841360 TI - Prehospital End-tidal Carbon Dioxide Predicts Mortality in Trauma Patients. AB - BACKGROUND: End-tidal carbon dioxide (EtCO2) measurement has been shown to have prognostic value in acute trauma. OBJECTIVE: Evaluate the association of prehospital EtCO2 and in-hospital mortality in trauma patients and to assess its prognostic value when compared to traditional vital signs. METHODS: Retrospective, cross-sectional study of patients transported by a single EMS agency to a level one trauma center. We evaluated initial out-of-hospital vital signs documented by EMS personnel including EtCO2, respiratory rate (RR), systolic BP (SBP), diastolic BP (DBP), pulse (P), and oxygen saturation (O2) and hospital data. The main outcome measure was mortality. RESULTS: 135 trauma patients were included; 9 (7%) did not survive. The mean age of patients was 40 (SD17) [Range 16-89], 97 (72%) were male, 76 (56%) were admitted to the hospital and 15 (11%) went to the ICU. The mean EtCO2 level was 18 mmHg (95%CI 9-28) [Range 5-41] in non-survivors compared to 34 mmHg (95%CI 32-35) [Range 11-51] in survivors. The area under the ROC curve (AUC) for EtCO2 in predicting mortality was 0.84 (0.67-1.00) (p = 0.001), RR was 0.82 (0.63-1.00), SBP was 0.72 (0.49 0.96), DBP was 0.72 (0.47-0.97), pulse was 0.51 (0.26-0.76), and O2 was 0.64 (0.37-0.91). Cut-off values at 30 mmHg yielded sensitivity = 89% (51-99), specificity = 68% (59-76), PPV = 13% (6-24) and NPV = 99% (93-100) for predicting mortality. There was no correlation between RR and EtCO2 (correlation 0.16; p = 0.06). CONCLUSION: We found an inverse association between prehospital EtCO2 and mortality. This has implications for improving triage and assisting EMS in directing patients to an appropriate trauma center. PMID- 28841361 TI - p53R2 overexpression in cervical cancer promotes AKT signaling and EMT, and is correlated with tumor progression, metastasis and poor prognosis. AB - p53R2 is a p53-inducible ribonucleotide reductase subunit involved in deoxyribonucleotide biosynthesis and DNA repair. Although p53R2 has been linked to human cancer, its role in cervical cancer remains unknown. In this study, we investigated the expression and clinical significance of p53R2 in early-stage cervical cancer. p53R2 expression is significantly upregulated at both mRNA and protein levels in cervical cancer cells and tissues, compared with that in matched normal cervical cells and tissues, respectively. p53R2 overexpression is associated with increased risk of pelvic lymph node metastasis (PLNM, p = 0.001) and cancer relapse (p = 0.009). Patients with high p53R2 expression have a shorter overall survival (OS) and disease-free survival (DFS). p53R2 is an independent factor for predicting OS and DFS of cervical cancer patients. We further show that p53R2 is important for oncogenic growth, migration and invasion in cervical cancer cells. Mechanistically, p53R2 promotes Akt signaling and epithelial-mesenchymal transition (EMT). In conclusion, our study demonstrates for the first time that p53R2 protein is overexpressed in early-stage cervical cancer and unravels some unconventional oncogenic functions of p53R2. p53R2 may be a useful prognostic biomarker and therapeutic target for cervical cancer. PMID- 28841362 TI - Use of the live attenuated Japanese Encephalitis vaccine SA 14-14-2 in children: A review of safety and tolerability studies. AB - Japanese encephalitis (JE) is the leading cause of viral neurological disease and disability in Asia. Some 50-80% of children with clinical JE die or have long term neurologic sequelae. Since there is no cure, human vaccination is the only effective long-term control measure, and the World Health Organization recommends that at-risk populations receive a safe and effective vaccine. Four different types of JE vaccines are currently available: inactivated mouse brain-derived vaccines, inactivated Vero cell vaccines, live attenuated SA 14-14-2 vaccines and a live recombinant (chimeric) vaccine. With the rapidly increasing demand for and availability and use of JE vaccines, countries face an important decision in the selection of a JE vaccine. This article provides a comprehensive review of the available safety literature for the live attenuated SA 14-14-2 JE vaccine (LAJEV), the most widely used new generation JE vaccine. With well-established effectiveness data, a single dose of LAJEV protects against clinical JE disease for at least 5 years, providing a long duration of protection compared with inactivated mouse brain-derived vaccines. Since 1988, about 700 million doses of the LAJEV have been distributed globally. Our review found that LAJEV is well tolerated across a wide age range and can safely be given to children as young as 8 months of age. While serious adverse events attributable to LAJEV have been reported, independent experts have not found sufficient evidence for causality based on the available data. PMID- 28841364 TI - Quality Improvement Initiatives to Optimize the Management of Chronic Obstructive Pulmonary Disease in Patients With Lung Cancer. AB - PURPOSE: Patients with lung cancer (LC) frequently have chronic obstructive pulmonary disease (COPD), the optimization of which improves outcomes. A 2014 Queen's University Hospitals audit demonstrated that COPD was underdiagnosed and undertreated in outpatients with LC. We sought to improve the diagnosis and management of COPD in this population. METHODS: We implemented change using a Define/Measure/Analyze/Improve/Control (DMAIC) improvement cycle. Data were obtained by chart review from the Cancer Care Ontario database and e-Patient System for patients with newly diagnosed LC, including patient characteristics, pulmonary function test (PFT) data, and bronchodilator therapies. Improvement cycle 1 included engaging stakeholders and prioritizing COPD management by respirologists in the Lung Diagnostic Assessment Program. Improvement cycle 2 included physician restructuring and developing a standard work protocol. Data were analyzed monthly and presented on statistical process control P-charts, which assessed differences over time. The chi2 and McNemar tests assessed for significance between independent and dependent groups, respectively. RESULTS: A total of 477 patients were studied (165 patients at baseline, 166 patients in cycle 1, and 127 patients in cycle 2). There was no change in PFT completion over time, although respirology-managed patients were significantly more likely to undergo a PFT than patients who were not managed by respirology (56.7% v 96.1%; P < .00001). The proportion of respirology-managed patients with LC with airflow obstruction receiving inhaled bronchodilator significantly increased (baseline, 46.3%; cycle 1, 51.0%; and cycle 2, 74.3%). By cycle 2, patients with airflow obstruction were more likely to receive a long-acting bronchodilator if managed by respirology (74.3% v 44.8%; P = .0009). CONCLUSION: COPD is underdiagnosed and undertreated in outpatients with LC. A DMAIC quality improvement strategy emphasizing COPD treatment during LC evaluation in the Lung Diagnostic Assessment Program significantly improved COPD management. PMID- 28841363 TI - Tocilizumab (Actemra). AB - Tocilizumab (TCZ), is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody which has a main use in the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis (sJIA) and polyarticular juvenile idiopathic arthritis (pJIA). This article provides an overview of TCZ including looking into the past at the discovery of interleukin-6 (IL-6) as a pro inflammatory cytokine. It also looks at how tocilizumab was developed, manufactured and tested to ensure both safety and efficacy in a human population. The article then explores the advantages and disadvantages of using TCZ when compared to other biologics approved in RA, sJIA and pJIA and finally looks ahead to the future and the emerging role of IL-6 and its blockade by TCZ as a treatment for giant cell arteritis (GCA), polymyalgia rheumatica (PMR) and large vessel vasculitis (LVV). PMID- 28841365 TI - TAF10 and TAF10b partially redundant roles during Drosophila melanogaster morphogenesis. AB - Transcription of eukaryotic genes requires the cooperative action of the RNA polymerase complex, the general transcription factors (TFIIB, TFIID, TFIIE, TFIIF and TFIIH) and chromatin modifiers. The TFIID complex contributes to transcriptional activation by several mechanisms and has a subunit with associated histone acetyltransferase (HAT) activity. The histone modifier SAGA complex has both HAT and deubiquitylase (DUB) activities. TFIID and SAGA share several TBP-associated factors (TAFs), but not their HAT subunit. Recently, several duplicated TAF proteins have been identified in higher eukaryotes, but their functional diversity has been so far poorly characterized. Here, we report the functional similarities and differences of TAF10 and TAF10b, the two TAF10 orthologs of Drosophila melanogaster. Results from in silico modeling suggest that dTAF10 and dTAF10b have similar secondary structures characterized by the presence of a histone-fold domain. Additionally, dTAF10 and dTAF10b share interaction partners and show similar expression patterns in neuronal tissues. Nonetheless, dTAF10 and dTAF10b seem to have partly distinct functions. To investigate their roles, we generated dTaf10-dTaf10b double-mutants and rescued the mutant flies with transgenes, which allowed the translation of either dTAF10 or dTAF10b protein. We found that the loss of dTAF10b resulted in pupal lethality, while animals lacking dTAF10 were able to form puparium. dTaf10 mutant adults showed distorted eye morphology. During DNA repair, dTAF10 and dTAF10b act redundantly, suggesting that these proteins have distinct but partially overlapping functions. PMID- 28841366 TI - Mortality and transcriptional effects of inorganic mercury in the marine copepod Calanus finmarchicus. AB - Inorganic mercury (Hg) is highly toxic to organisms including crustaceans and displays multiple toxic modes of action (MoA). The main aim of this investigation was to assess the acute and sublethal toxicity mediated by mercury chloride (HgCl2) in the marine copepod Calanus finmarchicus. A combination of short-term static studies to determine acute toxicity and a transcriptional investigation to characterize the sublethal MoA of HgCl2 were conducted with an in-house continuous culture of C. finmarchicus. Transcriptional changes were determined by a custom 6.6 k C. finmarchicus Agilent oligonucleotide microarray and quantitative RT-PCR analysis. Data demonstrate that HgCl2 produced a concentration- and time-dependent reduction in survival (NOEC48 h = 6.9 MUg/L [Hg2+] and LC50 of 279, 73, 48, and 34 ug/L [Hg2+] after 24, 48, 72, and 96 h, respectively) and that exposure to sublethal concentrations of HgCl2 (5 MUg/L [Hg2+]) induced differential expression of 98 features (probes) on the microarray. Gene ontology (GO) and toxicological pathway analyses suggested that the main MOA were (1) uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) and ATP production, (2) oxidative stress and macromolecular damage, (3) inactivation of cellular enzymes, (4) induction of cellular apoptosis and autophagocytosis, (5) over-excitation of glutamate receptors (neurotoxicity), (6) disruption of calcium homeostasis and signaling, and (7) modulation of nuclear receptor activity involved in vitamin D receptor signaling. Quantitative RT-PCR analysis verified that oligoarray performed reliably in terms of specificity and response, thus demonstrating that Hg2+ exerts multiple potential MoA in C. finmarchicus. PMID- 28841367 TI - Knowledge, attitude, and experience of health professionals of female genital mutilation (FGM): A qualitative study in Iraqi Kurdistan Region. AB - We aimed to assess the knowledge, attitude, and experience of health professionals of female genital mutilation (FGM). The study involved content analysis of semistructured interviews with 21 health professionals. The participants had poor knowledge regarding different aspects of FGM including its types, prevalence, and complications as well as the existing legislation that prohibits FGM. They believed that FGM is mainly practiced for religious reasons and to reduce sexual desire/arousal. Health professionals are apparently not involved in performing FGM, and they do not support its continuation. Health professionals can take a leading role in raising the awareness of women and combating FGM. PMID- 28841368 TI - Polychlorinated biphenyls (PCBs) modulate both phagocytosis and NK cell activity in vitro in juvenile loggerhead sea turtles (Caretta caretta). AB - Threatened loggerhead sea turtles (Caretta caretta) face numerous environmental challenges, including exposure to anthropogenic chemicals such as polychlorinated biphenyls (PCBs). Despite being banned by the USA in the 1970s, PCBs persist in the environment and produce immunotoxic effects in a wide range of marine vertebrate species. This is of particular concern, as the modulation of the immune system may enhance the susceptibility to a variety of pathogens. Blood samples were collected from 19 immature, captive-reared loggerhead sea turtles. Functional immune assays phagocytosis and natural killer (NK) cell activity were used to quantify the direct effects of PCB congeners 105, 138, and 169 on innate immune functions upon in vitro exposure of sea turtle cells to increasing concentrations (control (0), 0.5, 1, 2.5, 5, 10, 15, or 20 ppm) of each PCB. PCB 105 significantly elevated eosinophil phagocytosis at 10 and 15 ppm and PCB 138 at 15 ppm compared to unexposed (0 ppm). The effects of PCB 169 on phagocytosis were not evaluated. PCB 138 and 105 significantly decreased NK cell activity at 15 and 20 ppm, compared to unexposed (0 ppm) controls. PCB 169 did not markedly modulate NK activity. This constitutes the first study to investigate the in vitro effects of these three PCBs on sea turtle innate immune functions. These results add to our understanding of PCB-induced immunotoxicity in sea turtles and may provide a framework for establishing the relationships between chemical levels and turtle immunity. PMID- 28841369 TI - Richard Paul Korf (1925-2016). AB - "With poetry, the tune is in the words themselves-and once you begin to hear it, it will stay with you." Richard P. Korf, notes to his narration of John Brown's Body. PMID- 28841370 TI - Reversed-Phase High-Performance Liquid Chromatography for the Quantification and Optimization for Extracting 10 Kinds of Carotenoids in Pepper (Capsicum annuum L.) Leaves. AB - Carotenoids are considered to be crucial elements in many fields and, furthermore, the significant factor in pepper leaves under low light and chilling temperature. However, little literature focused on the method to determinate and extract the contents of carotenoid compositions in pepper leaves. Therefore, a time-saving and highly sensitive reversed-phase high-performance liquid chromatography method for separation and quantification of 10 carotenoids was developed, and an optimized technological process for carotenoid composition extraction in pepper leaves was established for the first time. Our final method concluded that six xanthophylls eluted after about 9-26 min. In contrast, four carotenes showed higher retention times after nearly 28-40 min, which significantly shortened time and improved efficiency. Meanwhile, we suggested that 8 mL of 20% KOH-methanol solution should be added to perform saponification at 60 degrees C for 30 min. The ratio of solid-liquid was 1:8, and the ultrasound-assisted extraction time was 40 min. PMID- 28841371 TI - Membrane Dynamics of gamma-Secretase Provides a Molecular Basis for beta-Amyloid Binding and Processing. AB - gamma-Secretase produces beta-amyloid (Abeta) within its presenilin (PS1) subunit, mutations in which cause Alzheimer's disease, and current therapies thus seek to modulate its activity. While the general structure is known from recent electron microscopy studies, direct loop and membrane interactions and explicit dynamics relevant to substrate processing remain unknown. We report a modeled structure utilizing the optimal multitemplate information available, including loops and missing side chains, account of maturation cleavage, and explicit all atom molecular dynamics in the membrane. We observe three distinct conformations of gamma-secretase (open, semiopen, and closed) that remarkably differ by tilting of helices 2 and 3 of PS1, directly controlling active site availability. The large hydrophilic loop of PS1 where maturation occurs reveals a new helix segment that parallels the likely helix character of other substrates. The semiopen conformation consistently shows the best fit of Abeta peptides, that is, longer residence before release and by inference more trimming. In contrast, the closed, hydrophobic conformation is largely inactive and the open conformation is active but provides fewer optimal interactions and induces shorter residence time and by inference releases Abeta peptides of longer lengths. Our simulations thus provide a molecular basis for substrate processing and changes in the Abeta42/Abeta40 ratio. Accordingly, selective binding to protect the semiopen "innocent" conformation provides a molecular recipe for effective gamma-secretase modulators; we provide the full atomic structures for these states that may play a key role in developing selective gamma-secretase modulators for treatment of Alzheimer's disease. PMID- 28841372 TI - Vitamin B12 Inhibits Tau Fibrillization via Binding to Cysteine Residues of Tau. AB - Two mechanisms underlie the inhibitory/acceleratory action of chemical compounds on tau aggregation including the regulation of cellular kinases and phosphatases activity and direct binding to tau protein. Vitamin B12 is one of the tau polymerization inhibitors, and its deficiency is linked to inactivation of protein phosphatase 2A and subsequently hyperphosphorylation and aggregation of tau protein. Regarding the structure and function of vitamin B12 and tau protein, we assumed that vitamin B12 is also able to directly bind to tau protein. Hence, we investigated the interaction of vitamin B12 with tau protein in vitro using fluorometry and circular dichrosim. Interaction studies was followed by investigation into the effect of vitamin B12 on tau aggregation using ThT fluorescence, circular dichroism, transmission electron microscopy, and SDS-PAGE. The results indicated that vitamin B12 interacts with tau protein and prevents fibrillization of tau protein. Blocking the cysteine residues of tau confirmed the cysteine-mediated binding of vitamin B12 to tau and showed that binding to cysteine is essential for inhibitory effect of vitamin B12 on tau aggregation. SDS-PAGE analysis indicated that vitamin B12 inhibits tau aggregation and that tau oligomers formed in the presence of vitamin B12 are mostly SDS-soluble. We propose that direct binding of vitamin B12 is another mechanism underlying the inhibitory role of vitamin B12 on tau aggregation and neurodegeneration. PMID- 28841373 TI - Facile Assembly/Disassembly of DNA Nanostructures Anchored on Cell-Mimicking Giant Vesicles. AB - DNA nanostructures assembled on living cell membranes have become powerful research tools. Synthetic lipid membranes have been used as a membrane model to study the dynamic behavior of DNA nanostructures on fluid soft lipid bilayers, but without the inherent complexity of natural membranes. Herein, we report the assembly and disassembly of DNA nanoprisms on cell-mimicking micrometer-scale giant membrane vesicles derived from living mammalian cells. Three-dimensional DNA nanoprisms with a DNA arm and a cholesterol anchor were efficiently localized on the membrane surface. The assembly and disassembly of DNA nanoprisms were dynamically manipulated by DNA strand hybridization and toehold-mediated strand displacement. Furthermore, the heterogeneity of reversible assembly/disassembly of DNA nanoprisms was monitored by Forster resonance energy transfer. This study suggests the feasibility of DNA-mediated functional biomolecular assembly on cell membranes for biomimetics studies and delivery systems. PMID- 28841374 TI - Translesion DNA Synthesis in Cancer: Molecular Mechanisms and Therapeutic Opportunities. AB - The genomic landscape of cancer is one marred by instability, but the mechanisms that underlie these alterations are multifaceted and remain a topic of intense research. Cellular responses to DNA damage and/or replication stress can affect genome stability in tumors and influence the response of patients to therapy. In addition to direct repair, DNA damage tolerance (DDT) is an element of genomic maintenance programs that contributes to the etiology of several types of cancer. DDT mechanisms primarily act to resolve replication stress, and this can influence the effectiveness of genotoxic drugs. Translesion DNA synthesis (TLS) is an important component of DDT that facilitates direct bypass of DNA adducts and other barriers to replication. The central role of TLS in the bypass of drug induced DNA lesions, the promotion of tumor heterogeneity, and the involvement of these enzymes in the maintenance of the cancer stem cell niche presents an opportunity to leverage inhibition of TLS as a way of improving existing therapies. In the review that follows, we summarize mechanisms of DDT, misregulation of TLS in cancer, and discuss the potential for targeting these pathways as a means of improving cancer therapies. PMID- 28841375 TI - Two-Dimensional Stoichiometric Boron Oxides as a Versatile Platform for Electronic Structure Engineering. AB - Oxides of two-dimensional (2D) atomic crystals have been widely studied due to their unique properties. In most 2D oxides, oxygen acts as a functional group, which makes it difficult to control the degree of oxidation. Because borophene is an electron-deficient system, it is expected that oxygen will be intrinsically incorporated into the basal plane of borophene, forming stoichiometric 2D boron oxide (BO) structures. By using first-principles global optimization, we systematically explore structures and properties of 2D BO systems with well defined degrees of oxidation. Stable B-O-B and OB3 tetrahedron structure motifs are identified in these structures. Interesting properties, such as strong linear dichroism, Dirac node-line (DNL) semimetallicity, and negative differential resistance, have been predicted for these systems. Our results demonstrate that 2D BO represents a versatile platform for electronic structure engineering via tuning the stoichiometric degree of oxidation, which leads to various technological applications. PMID- 28841376 TI - Triblock-Copolymer-Assisted Mixed-Micelle Formation Results in the Refolding of Unfolded Protein. AB - The present work reports a new strategy for triblock-copolymer-assisted refolding of sodium dodecyl sulfate (SDS)-induced unfolded serum protein human serum albumin (HSA) by mixed-micelle formation of SDS with poly(ethylene oxide) poly(propylene oxide)-poly(ethylene oxide) triblock copolymer EO20PO68EO20 (P123) under physiological conditions. The steady-state and time-resolve fluorescence results show that the unfolding of HSA induced by SDS occurs in a stepwise manner through three different phases of binding of SDS, which is followed by a saturation of interaction. Interestingly, the addition of polymeric surfactant P123 to the unfolded protein results in the recovery of ~87% of its alpha-helical structure, which was lost during SDS-induced unfolding. This is further corroborated by the return of the steady-state and time-resolved fluorescence decay parameters of the intrinsic tryptophan (Trp214) residue of HSA to the initial nativelike condition. The isothermal titration calorimetry (ITC) data also substantiates that there is almost no interaction between P123 and the native state of the protein. However, the mixed-micelle formation, accompanied by substantial binding affinities, removes the bound SDS molecules from the scaffolds of the unfolded state of the protein. On the basis of our experiments, we conclude that the formation of mixed micelles between SDS and P123 plays a pivotal role in refolding the protein back to its nativelike state. PMID- 28841377 TI - Role of Sporadic Parkinson Disease Associated Mutations A18T and A29S in Enhanced alpha-Synuclein Fibrillation and Cytotoxicity. AB - Deposition of presynaptic protein alpha-synuclein in Lewy bodies and Lewy neurites in the substantia nigra region of brain has been linked with the clinical symptoms of the Parkinson's disease (PD). Proteotoxic stress conditions and mutations that cause abnormal aggregation of alpha-synuclein have close association with onset of PD and its progression. Therefore, studies pertaining to alpha-synuclein mutations play important roles in mechanistic understanding of aggregation behavior of the protein and subsequent pathology. Herein, guided by this fact, we have studied the aggregation kinetics, morphology, and neurotoxic effects of the two newly discovered sporadic PD associated mutants A18T and A29S of alpha-synuclein. Our studies demonstrate that both of the mutants are aggregation prone and undergo rapid aggregation compared to wild-type alpha synuclein. Further, it was found that A18T mutant followed faster aggregation kinetics compared to A29S substitution. Additionally, we have designed three point mutations of alpha-synuclein for better understanding of the effects of substitutions on protein aggregation and demonstrated that substitution of alanine at the 18th position is highly sensitive compared to adjacent positions. Our results provide better understanding of the effects of alpha-synuclein mutations on its aggregation behavior that may be important in development of PD pathology. PMID- 28841378 TI - Insights into the Dynamics and Dissociation Mechanism of a Protein Redox Complex Using Molecular Dynamics. AB - Leishmania major peroxidase (LmP) is structurally and functionally similar to the well-studied yeast Cytochrome c peroxidase (CCP). A recent Brownian dynamics study showed that L. major Cytochrome c (LmCytc) associates with LmP by forming an initial complex with the N-terminal helix A of LmP, followed by a movement toward the electron transfer (ET) site observed in the LmP-LmCytc crystal structure. Critical to forming the active electron transfer complex is an intermolecular Arg-Asp ion pair at the center of the interface. If the dissociation reaction is effectively the reverse of the association reaction, then rupture of the Asp-Arg ion pair should be followed by movement of LmCytc back toward LmP helix A. To test this possibility, we have performed multiple molecular dynamics (MD) simulations of the LmP-LmCytc complex. In five separate simulations, LmCytc is observed to indeed move toward helix A, and in two of the simulations, the Asp-Arg ion pair breaks, which frees LmCytc to fully associate with the LmP helix A secondary binding site. These results support the "bind and crawl" or "velcro" mechanism of association, wherein LmCytc forms a nonspecific electrostatic complex with LmP helix A, followed by a "crawl" toward the ET active site, where the Asp-Arg ion pair holds the LmCytc in position for rapid ET. These simulations also point to Tyr134LmP as being important in the association/dissociation reactions. Experimentally mutating Tyr134 to Phe was found to decrease Km by 3.6-fold, which is consistent with its predicted role in complex formation by MD simulations. PMID- 28841380 TI - Roads and motorized transport as major sources of priority substances? A data register study. AB - A data register study was performed in order to identify the amounts of hazardous substances in products related to motorized transport in Norway during 2012. The hazardous substances were selected from legislative investigations performed by the European Chemicals Agency (ECHA), European Union (EU), and Norwegian Environment Agency (NEA). Information regarding hazardous substances in 52 selected product categories associated with traffic-related activities was obtained from the Norwegian Product Register administrated by the NEA. Substances present on ECHA list of substances of very high concern (SVHC), NEA national priority list, and priority substances under the EU Water Framework Directive (WFD) were given most attention, with substances from ECHA community rolling action plan (CoRAP) also included. Results showed that selected products contained a diverse range of substances that were classified as hazardous to either human or environmental health. The quantities of hazardous substances in the selected products were 120 tons (SVHC), 280 tons (Norway priority list), and 2,400 tons (WFD). It proved difficult to pinpoint these quantities only to traffic-related operations since product categories included compounds used for other activities. However, data illustrate that large quantities of hazardous substances are employed concurrent with being prioritized for reduction/elimination by national and international authorities. A list of substances with annual use in 2012 >1 ton was prepared to aid a prioritization for further actions such as substitution, phasing out, or environmental monitoring. The list contains substances that are toxic to humans, especially as adverse reproductive/carcinogenic agents, and/or pose a threat to the environment. PMID- 28841379 TI - New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors. AB - Mandelalides A-D (1-4) are macrocyclic polyketides known to have an unusual bioactivity profile influenced by compound glycosylation and growth phase of cultured cells. The isolation and characterization of additional natural congeners, mandelalides E-L (5-12), and the supply of synthetic compounds 1 and 12, as well as seco-mandelalide A methyl ester (13), have now facilitated mechanism of action and structure-activity relationship studies. Glycosylated mandelalides are effective inhibitors of aerobic respiration in living cells. Macrolides 1 and 2 inhibit mitochondrial function similar to oligomycin A and apoptolidin A, selective inhibitors of the mammalian ATP synthase (complex V). 1 inhibits ATP synthase activity from isolated mitochondria and triggers caspase dependent apoptosis in HeLa cells, which are more sensitive to inhibition by 1 in the presence of the glycolysis inhibitor 2-deoxyglucose. Thus, mandelalide cytotoxicity depends on basal metabolic phenotype; cells with an oxidative phenotype are most likely to be inhibited by the mandelalides. PMID- 28841381 TI - Rethinking monogamy's nature: From the truth of non/monogamy to a dyke ethics of "antimonogamy". AB - Following Lynne Huffer's work on queer feminism, this abridged essay centers the figure of the lesbian in order to develop a dyke ethics that engenders nuanced thinking about both monogamy and embodiment. The essay reads Alison Bechdel's comic strip, Dykes to Watch Out For, to elaborate a "dyke ethics of anti monogamy." Grounded in notions of friendship, community, and social justice, this ethics decenters the sexual dyad in a way that polyamory does not. It also insists upon a theoretical and ethical disposition of respect for the simultaneously political and embodied nature of desire. In so doing, it offers first a way of re-thinking the story of monogamy's nature as a naturecultural tale about mononormative desire and further places that desire in a field of relationality that renders its significance as a feature of humanness and an object of scientific inquiry strange. PMID- 28841382 TI - Maternal polycyclic aromatic hydrocarbon (PAH) transfer and effects on offspring of copepods exposed to dispersed oil with and without oil droplets. AB - Copepods of the genus Calanus have the potential for accumulating lipophilic oil components due to their high lipid content and found to filter and ingest oil droplets during exposure. As female copepods produce eggs at the expense of lipid storage, there is a concern for transfer of lipophilic contaminants to offspring. To assess the potential for maternal transfer of oil components, ovigerous female copepods (Calanus finmarchicus) were exposed to filtered and unfiltered oil dispersions for 4 days, collected and eggs maintained in clean seawater and hatching and gene expression examined in hatched nauplii. Oil droplet exposure contributed to polycyclic aromatic hydrocarbon (PAH) uptake in dispersion-treated adult copepods, as displayed through PAH body residue analyses and fluorescence microscopy. Applying the latter methodology, transfer of heavy PAH from copepod mothers to offspring were detected Subtle effects were observed in offspring as evidenced by a temporal reduction in hatching success appear to be occurring only when mothers were exposed to the unfiltered oil dispersions. Offspring reared in clean water through to late naupliar stages were collected for RNA extraction and preparation of libraries for high-throughput transcriptome sequencing. Differentially expressed genes were identified through pairwise comparisons between treatments. Among these, several expressed genes have known roles in responses to chemical stress including xenobiotic metabolism enzymes, antioxidants, chaperones, and components of the inflammatory response. While gene expression results suggest a transgenerational activation of stress responses, the increase in relatively small number of differentially expressed genes suggests a minor long-term effect on offspring following maternal exposure. PMID- 28841383 TI - Refinement of the Affordable Care Act. AB - Regardless of what legislation the federal government adopts to address health insurance coverage for nonelderly Americans, private insurance will likely play a major role. This article begins by listing some of the major reasons critics dislike the Affordable Care Act (ACA), then discusses the validity of these concerns from an economics perspective. Criticisms of the ACA include the increased role of government in health care, the ACA's implicit income redistribution, and concern about high and rising insurance premiums. Suggestions for refining the ACA and its market-based insurance system are then offered, with the goals of lowering insurance premiums, improving coverage rates, and/or addressing the concerns of ACA critics. Americans favor the increase in insurance coverage that has occurred under the ACA. In order to sustain this level of coverage, steps to lower Marketplace premiums through a variety of strategies affecting potential enrollees, insurers, and healthcare providers are offered. PMID- 28841384 TI - Rehabilitation With an Implant-Supported Metal-Acrylic Fixed Prosthesis After Ameloblastoma Resection in Mandible: Clinical Case Letter. PMID- 28841386 TI - Androgen Deprivation Therapy and Dementia: New Opportunities and Challenges in the Big-Data Era. PMID- 28841385 TI - Characterization of wood dust emission from hand-held woodworking machines. AB - This article focuses on the prevention of exposure to wood dust when operating electrical hand-held sawing and sanding machines. A laboratory methodology was developed to measure the dust concentration around machines during operating processes. The main objective was to characterize circular saws and sanders, with the aim of classifying the different power tools tested in terms of dust emission (high dust emitter vs. low dust emitter). A test set-up was developed and is described and a measurement methodology was determined for each of the two operations studied. The robustness of the experimental results is discussed and shows good tendencies. The impact of air-flow extraction rate was assessed and the pressure loss of the system for each machine established. For the circular saws, three machines over the nine tested could be classified in the low dust emitter group. Their mean concentration values measured are between 0.64 and 0.98 mg/m3 for the low dust emitter group and from 2.55 and 4.37 mg/m3 for the high dust emitter group. From concentration measurements, a machine classification is possible-one for sanding machines and one for sawing machines-and a ratio from 1 7 is obtained when comparing the results. This classification will be helpful when a choice of high performance power tools, in terms of dust emission, must be made by professionals. PMID- 28841387 TI - Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials. AB - Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy. PMID- 28841388 TI - Risk of Alzheimer's Disease Among Senior Medicare Beneficiaries Treated With Androgen Deprivation Therapy for Prostate Cancer. AB - Purpose To assess the relative risk of Alzheimer's disease (AD) among patients with prostate cancer who received androgen deprivation therapy (ADT), after adjustment for other cancer therapies. Methods Data from demographics, survival, diagnoses codes, procedure codes, and other information about beneficiaries age 67 years or older in the Medicare claims database was assessed to determine the unadjusted and adjusted risks of AD and of dementia from ADT. The prespecified survival analysis method was competing risk regression. Results Of the 1.2 million fee-for-service Medicare beneficiaries who developed prostate cancer in 2001 to 2014, 35% received ADT. Of these, 109,815 (8.9%) and 223,765 (18.8%) developed AD and dementia, respectively, and 26% to 33% died without either outcome. Unadjusted rates of AD and all-cause mortality per 1,000 patient-years were higher among ADT recipients; the unadjusted rates of AD were 17.0 and 15.5 per 1,000 person-years in recipients and nonrecipients, respectively, and the unadjusted rates of all-cause mortality were 73.0 and 51.6 per 1,000 person years, respectively. The unadjusted rates for dementia in ADT recipients versus nonrecipients were 38.5 and 32.9, respectively, and the unadjusted rates of mortality were 60.2 versus 40.4, respectively. However, after analysis was adjusted for other cancer therapies and other covariates, patients with ADT treatment had no increased risk of AD (subdistribution hazard ratio [SHR], 0.98; 95% CI, 0.97 to 0.99) and had only a miniscule (1%) risk of dementia (SHR, 1.01; 95% CI, 1.01 to 1.02); patients treated with ADT were more likely to die before progression to AD (SHR, 1.24; 95% CI, 1.23 to 1.24) or dementia (SHR, 1.26; 95% CI, 1.25 to 1.26). The risks of AD and dementia were not associated with duration of ADT (ie, no dose effect). Other secondary analyses confirmed these results. Conclusion These data suggest that ADT treatment has no hazard for AD and no meaningful hazard for dementia among men age 67 years or older who are enrolled in Medicare. PMID- 28841389 TI - Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer. AB - Purpose The AURA study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naive patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naive patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma samples were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. Results At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median PFS time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected. Conclusion Osimertinib demonstrated a robust ORR and prolonged PFS in treatment-naive patients with EGFRm advanced NSCLC. There was no evidence of acquired EGFR T790M mutation in postprogression plasma samples. PMID- 28841390 TI - Attitudes and Attitude Change. AB - This review covers research on attitudes and attitude change published between 2010 and 2017. We characterize this period as one of significant progress toward an understanding of how attitudes form and change in three critical contexts. The first context is the person, as attitudes change in connection to values, general goals, language, emotions, and human development. The second context is social relationships, which link attitude change to the communicator of persuasive messages, social media, and culture. The third context is sociohistorical and highlights the influence of unique events, including sociopolitical, economic, and climatic occurrences. In conclusion, many important recent findings reflect the fact that holism, with a focus on situating attitudes within their personal, social, and historical contexts, has become the zeitgeist of attitude research during this period. PMID- 28841391 TI - Atmospheric Cosmic-Ray Variation and Ambient Dose Equivalent Assessments Considering Ground Level Enhancement Thanks to Coupled Anisotropic Solar Cosmic Ray and Extensive Air Shower Modeling. AB - This work investigates the impact of Forbush decrease (FD) and ground-level enhancement (GLE) in the atmosphere, based on solar and galactic cosmic-ray models and the extensive air shower simulations. This approach gives the possibility to investigate both the dynamic behavior of neutron monitors (NM) (using response function) and the flight dose. The ambient dose equivalent during quiet solar activity and solar events (i.e., FDs and GLEs) were investigated for realistic flight plans issued from the Eurocontrol Demand Data Repository. The calculated ambient dose equivalents were compared with flight measurements in quiet solar conditions; comparisons are relevant and demonstrate the ability to estimate the dose level. The GLE model was validated for the GLEs 5 and 69 using the cosmic-ray variation recorded by NMs. The GLE model was applied to flight dose calculations. All of these results show that dose values vary drastically with the route path (latitude, longitude and altitude) and with the delay between the flight departure and the solar event occurrence. Doses induced by extreme GLE events were investigated specifically for London to New York flights, and resulting additional doses are a few hundred or 1,000 MUSv, impacting significantly the annual effective dose. This highlights the importance of monitoring extreme solar events and using realistic semi-empirical and particle transport methods for reliable calculation of dose levels. PMID- 28841392 TI - Nutrition Care in Patients With Head and Neck or Esophageal Cancer: The Patient Perspective. AB - BACKGROUND: Patients with head/neck or esophageal (HNE) cancer are likely to develop malnutrition throughout the course of their disease and its treatment. Although nutrition care is considered a cornerstone of disease management, clinical practices to treat malnutrition vary. The objective of this qualitative study is to understand the patients' experiences with nutrition care in the context of their treatment and recovery. METHODS: A descriptive qualitative study design was used to explore patients' experiences. Ten patients with head and neck (HN) cancer and 10 patients with esophageal cancer were interviewed near the completion of their cancer treatment using a semistructured interview guide. The data sets were analyzed separately using qualitative content analysis. The preliminary findings from each data set were compared and contrasted; 3 themes that crossed both data sets were identified. RESULTS: Three themes were identified: (1) coping with physical and psychosocial aspects of illness and nutrition; (2) understanding the nature of the illness, treatment, and nutrition pathway; and (3) being supported during the trajectory of care. The major differences between HN and esophageal groups were identified in the context of understanding and being supported: the lack of coordination throughout the trajectory of care and conflicting messages from healthcare providers were a source of uncertainty, confusion, and isolation in the HN group. The need for timely and ongoing patient-focused nutrition care, with formal and informal support, was identified in both groups. CONCLUSION: Models for nutrition care should support provision of consistent information across health professionals and throughout the treatment trajectory. PMID- 28841393 TI - Evaluation of Fracture Resistance of Varying Thicknesses of Zirconia Around Implant Abutment Cylinders. AB - Zirconia is becoming increasingly used as a restorative material for implant supported restorations; however, information is lacking with respect to the minimum thickness of zirconia surrounding the implant components. The purpose of this study is to evaluate the resistance to fracture of different thicknesses of zirconia luted to implant components. Thirty cylinders of zirconia (Prettau, Zirkonzahn) with 13-mm height, designed with indented occlusal surface for loading, and varying wall thicknesses (0.5 mm, 1 mm, 1.5 mm; n = 10/group) were milled using a computer-aided design/computer-aided manufacturing system (Modellier, Zirkonzahn), after which they were sintered. Titanium temporary cylinders (ITCS41, Biomet3i) were attached to 30 implant analogs (ILA20, Biomet3i) that were embedded into polymethylmethacrylate blocks (Palapress Vario, Heraeus Kulzer) with dimensions of 4.5 * 1.8 * 2 cm. Zirconia specimens were cemented to the titanium cylinders using a self-adhesive, dual-cure resin cement (Panavia SA, Kuraray). Load to failure test was performed under compression until fracture using a universal testing machine (Instron5965, Instron) at a crosshead speed of 0.5 mm/min and measured in N (Newton). Statistical analysis was performed using 1-way analysis of variance and Tukey B test at alpha = .05 (SPSS19, IBM). Mean load to failure was 1059.94 N, 2019.46 N, and 4074.79 N for groups 0.5 mm, 1 mm, and 1.5 mm, respectively. Values were significantly different between the groups (P < .05). Study limitations are that it is in vitro, specimens do not replicate tooth dimensions, and forces are static and directed toward the occlusal portion of each specimen. Within these limitations and considering the average human bite force, a thickness of 0.5 mm to 1 mm of this particular type of zirconia around this type of implant component can avoid fracture with these dimensions. PMID- 28841394 TI - Surgical Ciliated Cyst Following Maxillary Sinus Floor Augmentation: A Case Report. AB - Maxillary sinus floor augmentation is considered to play a critical role in dental implant treatment. Although many complications, such as maxillary sinusitis and infection, are well known, few reports are available on the risk of surgical ciliated cyst following the procedure. Here, we report a case of surgical ciliated cyst following maxillary sinus floor augmentation. A 55-year old Japanese woman was referred to our hospital because of alveolar bone atrophy in the bilateral maxilla. We performed bilateral maxillary sinus floor augmentation by the lateral window technique without covering the window. The Schneiderian membrane did not perforate during the operation. She returned to our hospital after 9 years due to swelling of the left buccal region. Computerized tomography revealed a well-defined radiolucent area with radiodense border intraosseously localized in the left maxilla. We performed enucleation of the cyst with the patient under general anesthesia. Histological examination of the specimen showed a surgical ciliated cyst. In conclusion, the course of this patient has 2 important implications. First, the sinus membrane entrapped in the grafted bone without visible perforation and or tearing can develop into a surgical ciliated cyst. Second, there is a possibility that covering the lateral window tightly might prevent the development of a surgical ciliated cyst. PMID- 28841395 TI - Kolaviron attenuates ischemia/reperfusion injury in the stomach of rats. AB - Kolaviron (KV), an active complex of at least 3 compounds in Garcinia kola seed, which is known for its antioxidant and anti-inflammatory activity, was investigated for its gastro-protective effect in the stomach of rats subjected to ischemia/reperfusion-induced gastric ulceration. Male adult Wistar rats (180-210 g) were randomized into 6 groups (n = 15) as follows: (i) control, (ii) ulcerated untreated (UU), (iii) KV alone (KVA), (iv) KV + ulcer (KVU), (v) ulcer + KV (UKV), and (vi) ulcer + omeprazole (20 mg/kg). Ulcer was induced through ischemia/reperfusion method after 2 weeks of daily oral KV (100 mg/kg). Rats were weighed daily, and gastric acid secretion, ulcer scores, hematological, biochemical, and histological variables were assessed 1 h after induction at 3 and 7 days post-ulceration. Body weight decreased in KVA (179.1 +/- 1.6 g), and KVU (170.1 +/- 2.2 g) compared with UU (199.0 +/- 1.4 g). Gastric acid secretion decreased significantly in KVU after 1 h and 3 days post-ulceration (0.27 +/- 0.03 mEq/L; 0.49 +/- 0.02 mEq/L) compared with UU (0.60 +/- 0.06 mEq/L; 0.85 +/- 0.29 mEq/L), respectively. There was significant reduction in neutrophil/lymphocyte ratio of KVA (0.29 +/- 0.06) and KVU (0.35 +/- 0.02) compared with UU (0.54 +/- 0.04). Malondialdehyde level decreased significantly with concomitant increase in anti-oxidative activities and nitric oxide level in the KV treated groups (KVA, KVU, UKV) compared with UU. In conclusion, treatment with KV protects the stomach by reducing gastric acid secretion, promoting antioxidant activity and suppressing action of reactive oxygen species. PMID- 28841396 TI - Rhizosphere effect is stronger than PAH concentration on shaping spatial bacterial assemblages along centimetre-scale depth gradients. AB - At centimetre scale, soil bacterial assemblages are shaped by both abiotic (edaphic characteristics and pollutants) and biotic parameters. In a rhizobox experiment carried out on planted industrial soil contaminated with polycyclic aromatic hydrocarbons (PAHs), we previously showed that pollution was distributed randomly with hot and cold spots. Therefore, in the present study, we investigated the effect of this patchy PAH distribution on the bacterial community assemblage and compared it with that of root depth gradients found in the rhizosphere of either alfalfa or ryegrass. Sequencing of 16S rRNA amplicons revealed a higher bacterial diversity in ryegrass rhizosphere and enrichment in specific taxa by the 2 plant species. Indeed, Bacteroidetes, Firmicutes, and Gammaproteobacteria were globally favored in alfalfa, whereas Acidimicrobiia, Chloroflexi, Alpha-, and Betaproteobacteria were globally favored in ryegrass rhizosphere. The presence of alfalfa created depth gradients of root biomass, carbohydrate, and pH, and actually shaped the bacterial assemblage, favoring Actinobacteria near the surface and Gemmatimonadetes and Proteobacteria at greater depths. Contrarily, the bacterial assemblage was homogeneous all along depths of the ryegrass root system. With both plant species, the PAH content and random distribution had no significant effect on bacterial assemblage. Globally, at centimeter scale, bacterial community assemblages were mostly shaped by soil physical and chemical depth gradients induced by root growth but not by patchy PAH content. PMID- 28841397 TI - Changes in HDL-c concentrations after 16 weeks of combined training in postmenopausal women: characteristics of positive and negative responders. AB - This study aimed to investigate the individual characteristics of body composition and metabolic profile that could explain interindividual variation in high-density lipoprotein cholesterol (HDL-c) concentrations in response to 16 weeks of combined strength plus aerobic (combined) training in postmenopausal women. The participants were divided into tertiles based on percentage of changes in HDL-c concentrations after combined training. Only women in the upper tertile (positive responders: Delta > 10.4%; n = 19) and lower tertile (negative responders: Delta < -1.4%; n = 19) were considered for analyses. The total body fat (BF), trunk fat (TF), android fat (AF), gynoid fat, and lean body mass were estimated by dual-energy X-ray absorptiometry. The metabolic profile - glucose, triacylglycerol, total cholesterol, HDL-c, low-density lipoprotein cholesterol, and very-low-density lipoprotein (VLDL) - were assessed. After 16 weeks, both positive and negative responders presented similar improvement in body composition, such as a decrease in percentage and kilograms of BF, TF, and AF, and increase in lean body mass (p value for time < 0.05). As expected, there was an effect of time and also a significant interaction (time vs. group) (p value < 0.001) in the improvement of HDL-c, with higher values for positive responders. Regarding metabolic profile, there were significant interactions (time vs. group) for triacylglycerol (p value = 0.032) and VLDL (p value = 0.027) concentrations, with lower values for positive responders. Our results suggests there is heterogeneity in combined training-induced HDL-c changes in postmenopausal women, and the positive responders were those who presented more pronounced decreases in triacylglycerol and VLDL concentrations. PMID- 28841398 TI - The complete microbiologist, Dr. Terry Beveridge. PMID- 28841399 TI - Infant and Young Child Feeding Decision Making and Practices: Malawian Mothers' and Fathers' Roles in the Context of HIV. AB - BACKGROUND: Few studies in low- and middle-income countries have examined the roles of couples in infant and young child feeding decision making and practices, and there is no corresponding data in the context of human immunodeficiency virus (HIV). Research aim: This study aimed to explore mothers' and fathers' perceptions of their roles in feeding decision making and practices. METHODS: The authors conducted in-depth interviews with 15 mothers and their male partners, recruited from the catchment areas of two urban and two rural government clinics in Lilongwe District, Malawi. The mothers were >= 18 years of age, were HIV positive, and had a child < 24 months of age. Twelve of the 15 fathers were also HIV positive. The interviews were analyzed using content analysis. RESULTS: Mothers were responsible for child care, including breastfeeding and complementary feeding. Fathers provided monetary support for purchasing food and offered verbal support to encourage mothers to implement recommended feeding practices. Many fathers found it difficult to support adequate complementary feeding because of household food insecurity. Mothers were advised on child feeding during prevention of mother-to-child transmission clinic visits. No fathers in this study accompanied women to clinic appointments, so they were less well-informed about feeding than mothers. Fathers usually deferred to mothers in feeding decision making. One-third of mothers wanted fathers to be more involved in child feeding. CONCLUSION: Malawian mothers' and fathers' roles in feeding decision making in the context of HIV align with local gender norms. Strategies are needed to improve fathers' knowledge of and involvement in child feeding, as desired by mothers. PMID- 28841400 TI - Reference transcriptome assembly and annotation for perennial ryegrass. AB - RNA-Seq methodology has been used to generate a comprehensive transcriptome sequence resource for perennial ryegrass, an important temperate pasture grass species. A total of 931 547 255 reads were obtained from libraries corresponding to 19 distinct tissue samples, including both vegetative and reproductive stages of development. Assembly of data generated a final filtered reference set of 48 713 contigs and scaffolds. The transcriptome resource will support whole genome sequence assembly, comparative genomics, implementation of genotyping-by sequencing (GBS) methods based on transcript sampling, and identification of candidate genes for multiple biological functions. PMID- 28841401 TI - Pacifiers and Exclusive Breastfeeding: Does Risk for Postpartum Depression Modify the Association? AB - BACKGROUND: Postpartum depression is associated with lower rates of breastfeeding. Evidence describing the effect of pacifiers on breastfeeding is inconsistent, and previous research suggests that pacifiers may help vulnerable mothers breastfeed. Research aim: This study aimed to determine (a) how receiving a pacifier in the hospital affects exclusive breastfeeding (EBF) at 1 week and 3 months postpartum and (b) whether this association is modified by risk for postpartum depression (PPD). METHODS: Data were derived from Listening to Mothers III. We included participants ( n = 1,349) who intended to breastfeed and delivered at term. Mothers were considered at high risk for PPD if they reported feeling the need to receive treatment for depression during pregnancy. We used weighted multivariable logistic regression models to adjust for covariates. RESULTS: Receiving a pacifier in the hospital was not significantly associated with EBF at 1 week (odds ratio [ OR] = 0.84, 95% confidence interval [CI] [0.62, 1.12]) but was significantly associated with lower odds of EBF at 3 months postpartum ( OR = 0.72, 95% CI [0.54, 0.95]). Risk for PPD modified this association. Among mothers at high risk for PPD, receiving a pacifier was significantly associated with increased odds of EBF ( OR = 3.31, 95% CI [1.23, 8.97] at 1 week and OR = 5.27, 95% CI [1.97, 14.12] at 3 months); however, among mothers who were at lower risk for PPD, receiving a pacifier was associated with decreased odds of EBF ( OR = 0.75, 95% CI [0.56, 1.02] at 1 week and OR = 0.62, 95% CI [0.46, 0.82] at 3 months). CONCLUSION: Pacifiers may help protect against early cessation of EBF among mothers at high risk for depression. Additional research is needed to better understand this association. PMID- 28841402 TI - Genome-wide identification and analysis of the basic leucine zipper (bZIP) transcription factor gene family in Ustilaginoidea virens. AB - The basic leucine zipper (bZIP) transcription factor (TF) family is one of the largest and most diverse TF families widely distributed across the eukaryotes. The bZIP TF family plays an important role in growth, development, and response to abiotic or biotic stresses, which have been well characterized in plants, but not in plant pathogenic fungi. In this study, we performed genome-wide and systematic bioinformatics analysis of bZIP genes in the fungus Ustilaginoidea virens, the causal agent of rice false smut disease. We identified 28 bZIP family members in the U. virens genome by searching for the bZIP domain in predicted genes. The gene structures, motifs, and phylogenetic relationships were analyzed for bZIP genes in U. virens (UvbZIP). Together with bZIP proteins from two other fungi, the bZIP genes can be divided into eight groups according to their phylogenetic relationships. Based on RNA-Seq data, the expression profiles of UvbZIP genes at different infection stages were evaluated. Results showed that 17 UvbZIP genes were up-regulated during the infection period. Furthermore, 11 infection-related UvbZIP genes were investigated under H2O2 stress and the expression level of eight genes were changed, which confirmed their role in stress tolerance and pathogenicity. In summary, our genome-wide systematic characterization and expression analysis of UvbZIP genes provided insight into the molecular function of these genes in U. virens and provides a reference for other pathogens. PMID- 28841403 TI - Identification of quantitative trait loci for seedling root traits from Tibetan semi-wild wheat (Triticum aestivum subsp. tibetanum). AB - As a primitive hexaploid wheat resource distributed only in Tibet, Tibetan semi wild wheat (Triticum aestivum subsp. tibetanum Shao) possesses unique characteristics that could be exploited in wheat breeding programs. Its good root system could offer a stable platform for above-ground components. To detect possible excellent locus for root traits from Tibetan semi-wild wheat, we identified QTLs for root traits using a recombinant inbred line population derived from a cross between Tibetan semi-wild wheat Q1028 and Zhengmai 9023. A total of 15 QTLs on eight chromosomes were detected, including four major QTLs, QMrl.sau-7B, QTrl.sau-4B, QAd.sau-7A, and QSa.sau-4B. The phenotypic variation explained by each of these QTLs ranges from 5.67% to 16.68%. Positive alleles of six QTLs were derived from Q1028. Several novel QTLs for root traits were identified. In addition, significant correlations were detected amongst root traits and agronomic traits. Taken together, these results suggest that Tibetan semi-wild wheat and the newly identified novel QTLs could be useful in future breeding programs. PMID- 28841404 TI - The North Carolina Lactation Educator Training Program: A Report at 20 Years. PMID- 28841405 TI - Experimental Infection of Common Eider Ducklings with Wellfleet Bay Virus, a Newly Characterized Orthomyxovirus. AB - Wellfleet Bay virus (WFBV), a novel orthomyxovirus in the genus Quaranjavirus, was first isolated in 2006 from carcasses of common eider (Somateria mollissima) during a mortality event in Wellfleet Bay (Barnstable County, Massachusetts, USA) and has since been repeatedly isolated during recurrent mortality events in this location. Hepatic, pancreatic, splenic, and intestinal necrosis was observed in dead eiders. We inoculated 6-week-old common eider ducklings with WFBV in an attempt to recreate the naturally occurring disease. Approximately 25% of inoculated eiders had onset of clinical disease and required euthanasia; an additional 18.75% were adversely affected based on net weight loss during the trial. Control ducklings did not become infected and did not have clinical disease. Infected ducklings with clinical disease had pathologic lesions consistent with those observed during natural mortality events. WFBV was reisolated from 37.5% of the inoculated ducklings. Ducklings surviving to 5 days postinoculation developed serum antibody titers to WFBV. PMID- 28841406 TI - G-quadruplex and calf thymus DNA interaction of quaternized tetra and octa pyridyloxy substituted indium (III) phthalocyanines. AB - The interactions of small molecules with G-quadruplex and double stranded DNA are important due to their potential biological and medical usages. In the present paper, the interactions of indium (III) phthalocyanines (quaternized 2,3,9,10,16,17,23,24-octakis-[(3-pyridyloxy) phthalocyaninato] chloroindium(III): OInPc and quaternized 2(3),9(10),16(17),23(24)-tetrakis-[(3-pyridyloxy) phthalocyaninato] chloroindium(III): TInPc) with hybrid G-quadruplex (Tel 21) and parallel G-quadruplexes (nucleolin, KRAS, c-MYC, vegf) were studied. The interactions of these phthalocyanines with ctDNA were also investigated. These interactions were measured by different spectroscopic techniques such as UV-Vis, fluorescence and circular dichroism. The UV-Vis spectroscopic data treated with Benesi-Hildebrand equation and Benesi-Hildebrand constants (KBH) were calculated. These constants were found higher for octa peripheral pyridyloxy substituted phthalocyanine, OInPc. Besides, UV-Vis analysis showed that the interaction of G quadruplexes with tetra peripheral pyridyloxy substituted phthalocyanine derivative (TInPc) resulted in removal of central indium (III) atom from the cavity of phthalocyanine macrocycle. The UV-Vis melting studies as well as fluorescence replacement techniques were also employed for clarification of mechanism. The binding mode of molecules with ct DNA was also supported with viscosity measurements. From the results, the stabilization and destabilization of G-quadruplex depending on the concentration of the OInPc and TInPc showed that these two indium (III) phthalocyanines have the potential of both the elucidation role of G-quadruplexes in gene expression and the usage in cancer therapy. PMID- 28841407 TI - Quantitative analysis of pedestrian safety at uncontrolled multi-lane mid-block crosswalks in China. AB - A lot of pedestrian-vehicle crashes at mid-block crosswalks severely threaten pedestrian's safety around the world. The situations are even worse in China due to low yielding rate of vehicles at crosswalks. In order to quantitatively analyze pedestrian's safety at multi-lane mid-block crosswalks, the number of pedestrian-vehicle conflicts was utilized to evaluate pedestrian's accident risk. Five mid-block crosswalks (Wuhan, China) were videoed to collect data of traffic situation and pedestrian-vehicle conflicts, and the quantity and spatial distribution of pedestrian-vehicle conflicts at multi-lane mid-block crosswalk were analyzed according to lane-based post-encroachment time(LPET). Statistical results indicate that conflicts are mainly concentrated in lane3 and lane6. Percentage of conflict of each lane numbered from 1 to 6 respectively are 4.1%, 13.1%, 19.8%, 8.4%, 19.0%, 28.1%. Conflict rate under different crossing strategies are also counted. Moreover, an order probit (OP) model of pedestrian vehicle conflict analysis (PVCA) was built to find out the contributions corresponding to those factors (such as traffic volume, vehicle speed, pedestrian crossing behavior, pedestrian refuge, etc.) to pedestrian-vehicle conflicts. The results show that: pedestrian refuge have positive effects on pedestrian safety; on the other hand, high vehicle speed, high traffic volume, rolling gap crossing pattern, and larger pedestrian platoon have negative effects on pedestrian safety. Based on our field observation and PVCA model, the number of conflicts will rise by 2% while the traffic volume increases 200 pcu/h; similarly, if the vehicle speed increases 5km/h, the number of conflicts will rise by 12% accordingly. The research results could be used to evaluate pedestrian safety at multi-lane mid-block crosswalks, and useful to improve pedestrian safety by means of pedestrian safety education, pedestrian refuge setting, vehicle speed limiting, and so on. PMID- 28841408 TI - Comparison of four statistical and machine learning methods for crash severity prediction. AB - Crash severity prediction models enable different agencies to predict the severity of a reported crash with unknown severity or the severity of crashes that may be expected to occur sometime in the future. This paper had three main objectives: comparison of the performance of four statistical and machine learning methods including Multinomial Logit (MNL), Nearest Neighbor Classification (NNC), Support Vector Machines (SVM) and Random Forests (RF), in predicting traffic crash severity; developing a crash costs-based approach for comparison of crash severity prediction methods; and investigating the effects of data clustering methods comprising K-means Clustering (KC) and Latent Class Clustering (LCC), on the performance of crash severity prediction models. The 2012-2015 reported crash data from Nebraska, United States was obtained and two vehicle crashes were extracted as the analysis data. The dataset was split into training/estimation (2012-2014) and validation (2015) subsets. The four prediction methods were trained/estimated using the training/estimation dataset and the correct prediction rates for each crash severity level, overall correct prediction rate and a proposed crash costs-based accuracy measure were obtained for the validation dataset. The correct prediction rates and the proposed approach showed NNC had the best prediction performance in overall and in more severe crashes. RF and SVM had the next two sufficient performances and MNL was the weakest method. Data clustering did not affect the prediction results of SVM, but KC improved the prediction performance of MNL, NNC and RF, while LCC caused improvement in MNL and RF but weakened the performance of NNC. Overall correct prediction rate had almost the exact opposite results compared to the proposed approach, showing that neglecting the crash costs can lead to misjudgment in choosing the right prediction method. PMID- 28841409 TI - Cannabis and crash responsibility while driving below the alcohol per se legal limit. AB - There is a growing interest in how extensively the use of marijuana by drivers relates to crash involvement. While cognitive, lab-based studies are consistent in showing that the use of cannabis impairs driving tasks, epidemiological, field based studies have been inconclusive regarding whether cannabis use causes an increased risk of accidents. There is ample evidence that the presence of cannabis among drivers with a BAC>=0.08g/dL highly increases the likelihood of a motor vehicle crash. Less clear, however, is the contribution of cannabis to crash risk when drivers have consumed very little or no alcohol. This effort addresses this gap in knowledge. We took advantage of a unique database that merged fatal crashes in the California Statewide Integrated Traffic Records System (SWITRS) and the Fatality Analysis Reporting System (FARS), which allows for a precise identification of crash responsibility. To account for recent increase in lab testing, we restricted our sample to cover only the years 1993 2009. A total of 4294 drivers were included in the analyses. Descriptive analyses and logistic regressions were run to model the contribution of alcohol and drugs to the likelihood of being responsible in a fatal crash. We found evidence that compared with drivers negative for alcohol and cannabis, the presence of cannabis elevates crash responsibility in fatal crashes among drivers at zero BACs (OR=1.89) and with 091%) for each of the eight cannabinoids. The optimized method was validated for specificity, linearity, sensitivity, precision, accuracy, and stability. The combined relative standard deviation (%RSD) for intra-day and inter-day precision for all eight analytes varied from 2.5% to 5.2% and 0.28% to 5.5%, respectively. The %RSD for the repeatability study varied from 1.1% to 5.5%. The recoveries from spiked cannabis matrix samples were greater than 90% for all analytes, except delta-8 tetrahydrocannabinol (Delta8-THC), which was 80%. The recoveries varied from 81% to 107% with a precision of 0.7-8.1%RSD. Delta-9-tetrahydrocannabinol (Delta9 THC) in all of the cannabis samples (n=635) was less than 10%, which is in compliance with the NJ Medicinal Marijuana regulation. Analysis of samples from two cultivars, which included ten individual samples, four composite samples, seven calibration standards, and four quality control standards, can be performed within 24hours by this high throughput method. PMID- 28841428 TI - A new polymorph of ciprofloxacin saccharinate: Structural characterization and pharmaceutical profile. AB - In this study, a new polymorph of ciprofloxacin saccharinate has been thoroughly evaluated with respect to structural as well as biopharmaceutical properties. Preliminary characterization of the new polymorph was performed by differential scanning calorimetry and thermogravimetric analysis, later confirmed by Fourier transform infra-red spectroscopy. The crystal structure was determined from the powder X-ray diffraction pattern using the direct-space algorithm. It lies in the triclinic P-1 space group. It is having lattice parameters different from previously reported forms. The solid-state 13C NMR data calculated from the crystal structure by exploiting density functional theory were found to be in excellent agreement with corresponding experimental 13C NMR data, thus providing a robust validation of the authenticity of the structure. The prepared polymorph shows enhanced aqueous solubility and dissolution rate in contrast to previously reported polymorph. The new form demonstrated improved oral bioavailability and inhibition of bacterial species. The enhanced biopharmaceutical properties are attributed to the higher extent of its absorption and distribution with respect to the individual components. The new form is a potential candidate for the pharmaceutical industry. PMID- 28841429 TI - Mother- and father-infant interactions at 3 months of corrected age: The effect of severity of preterm birth. AB - Early interactions of 92 preterm infants with their mothers (n=54) and fathers (n=38) were explored at 3 months using CARE-Index. Results showed differences in interactions based on parent's gender, with higher control in mothers and unresponsiveness in fathers, while no effect of severity of birth weight emerged. PMID- 28841430 TI - Evolution of protein specificity: insights from ancestral protein reconstruction. AB - Specific interactions between proteins and their molecular partners drive most biological processes, so understanding how these interactions evolve is an important question for biochemists and evolutionary biologists alike. It is often thought that ancestral proteins were systematically more promiscuous than modern proteins and that specificity usually evolves after gene duplication by partitioning and refining the activities of multifunctional ancestors. However, recent studies using ancestral protein reconstruction (APR) have found that ligand-specific functions in some modern protein families evolved de novo from ancestors that did not already have those functions. Further, the new specific interactions evolved by simple mechanisms, with just a few mutations changing classically recognized biochemical determinants of specificity, such as steric and electrostatic complementarity. Acquiring new specific interactions during evolution therefore appears to be neither difficult nor rare. Rather, it is likely that proteins continually gain and lose new activities over evolutionary time as mutations cause subtle but consequential changes in the shape and electrostatics of interaction interfaces. Only a few of these activities, however, are incorporated into the biological processes that contribute to fitness before they are lost to the ravages of further mutation. PMID- 28841431 TI - Diastolic hypotension due to intensive blood pressure therapy: Is it harmful? AB - BACKGROUND AND AIMS: Reducing the diastolic blood pressure (DBP) below a certain threshold may lead to inadequate organ perfusion. This raises some concerns, because pharmacotherapy reduces both systolic and diastolic pressure. We aimed to investigate whether a pathway from intensive systolic blood pressure (SBP) treatment influences cardiovascular outcomes by inducing too low DBP. METHODS: We had access to data from the Systolic Blood Pressure Intervention Trial (SPRINT) including 9361 patients with a SBP of 130 mmHg or higher and an increased cardiovascular risk. In a formal mediation analysis, we investigated whether the effect of intense (target SBP: 120 mm Hg) vs. standard (target SBP: 140 mmHg) intervention on a composite endpoint would be mediated through an indirect, potentially harmful, effect through low DBP (< 60 mmHg). RESULTS: Adjusting for treatment, we find that low DBP per se is associated with poor cardiovascular outcomes (HR 1.90 (95% CI [1.46, 2.47]). However, in a formal mediation analyses, we observed that the unadjusted indirect effect of intensive blood pressure treatment going through low DBP of HR 1.12 (95% CI [1.06, 1.18]) attenuates to a statistically non-significant effect of HR 1.04 (95% CI [0.98, 1.10]) after adjustment for important covariates, suggesting that the mere association is considerably confounded. CONCLUSIONS: The increased risk in subjects with diastolic pressure below 60 cannot fully be explained by the intensive treatment itself, but may be due to other measured factors. More generally, this analysis shows that adjusting for mediator-outcome confounding is essential, even in RCTs. PMID- 28841432 TI - Reduction pathway and mechanism of chloronitrobenzenes synergistically catalyzed by bioPd and Shewanella oneidensis MR-1 assisted by calculation. AB - Although microbial synthesized palladium nanoparticles (bioPd) have been demonstrated to exhibit a great activity toward dechlorination of several chlorinated pollutants, there is no systematic investigation into the substituent effect on dechlorination. Chloronitrobenzenes are widely used for manufacturing and known as persistent pollutants with recalcitrance of biodegradation for nitro groups. In this work, bioPd was synthesized by Shewanella oneidensis MR-1. The dechlorination of 2-chloronitrobenzene, 4-chloronitrobenzene and 2,4 dichloronitrobenzene catalyzed by bioPd were investigated. Simultaneous dechlorination and nitro reduction were observed by synergistic catalysis of bioPd and S. oneidensis MR-1. Pd concentration was optimized for the reduction. Producing profiles of intermediates changed with the ratio of Pd to cell, supporting a size- or shape-controlled catalytic activity of bioPd. The removal of chloro atoms at para-position was easier than that at ortho-position in 2,4 DCNB, suggesting a position effect on the reduction, which was further supported by the frontier molecular orbital and frontier electron density of 2,4-DCNB according to density functional theory. PMID- 28841433 TI - Lead-induced oxidative stress and antioxidant response provide insight into the tolerance of Phanerochaete chrysosporium to lead exposure. AB - The present work investigated the effect of lead (Pb) on the growth, metal accumulation, oxidative stress, and antioxidant response in Phanerochaete chrysosporium, which is a well-known hyperaccumulating species for heavy metal with appreciable bioaccumulation capacity. Results revealed that P. chrysosporium exhibited a good ability in Pb accumulation and tolerance over a concentration range of 50-100 mg L-1 Pb. The removal rate of Pb decreased with the increasing levels of Pb and reached a maximum of 91.3% at 50 mg L-1. Both extracellular adsorption and intracellular bioaccumulation contributed to the removal of Pb, with the maximum of 123.8 mg g-1 and 162.5 mg g-1 dry weight, respectively. Pb may exert its toxicity to P. chrysosporium by impairing oxidative metabolism, as evidenced by the enhanced accumulation of hydrogen peroxide (H2O2) and lipid peroxidation product malonaldehyde (MDA). P. chrysosporium evolved an antioxidant system by elevating the activity of superoxide dismutase (SOD) and the level of reduced glutathione (GSH) in response to Pb stress, whereas decreasing the activities of catalase (CAT) and peroxidase (POD). Moreover, Pearson correlation analysis demonstrated a good correlation between oxidative stress biomarkers and enzymatic antioxidants. The preset work suggested that P. chrysosporium exhibited an outstanding accumulation of Pb and tolerance of Pb-induced oxidative stress by the effective antioxidant defense mechanism. PMID- 28841434 TI - Atmospheric deposition of polycyclic aromatic compounds and associated sources in an urban and a rural area of Chongqing, China. AB - Monthly bulk (dry + wet) deposition samples were collected at an urban and a rural site in Chongqing, southwestern China during May 2014 to April 2015 for analyzing the contents of parent polycyclic aromatic hydrocarbons (PPAHs) and three types of substituted PAHs (SPAHs) including oxygenated PAHs (OPAHs), nitrated PAHs (NPAHs) and methyl PAHs (MPAHs). Annual average (+/-standard deviation) deposition fluxes of SigmaPPAHs, SigmaOPAHs, and SigmaMPAHs were 536 +/- 216; 221 +/- 118, and 131 +/- 41.9 ng/m2/d, respectively, in the urban area, and 347 +/- 185, 160 +/- 112, and 85.2 +/- 32.0 ng/m2/d, respectively in the rural area. Deposition of SigmaNPAHs (6.01 +/- 3.93 and 3.91 +/- 4.84 ng/m2/d) were about two orders of magnitude lower than those of SigmaPPAHs. In the urban area, temporal variations of PPAHs and MPAHs fluxes were positively correlated with particle deposition, while the trends of OPAHs and NPAHs were probably controlled by secondary formation. In the rural area, SPAHs and PPAHs deposition fluxes had similar temporal trends but differed from particle deposition. High relative humidity in Chongqing likely played an important role in facilitating the partitioning of OPAHs to atmospheric aerosols and resulting in the relatively high OPAHs level in winter. Principle component analysis identified secondary formation (21.7%) and combustion emission (52.7%) as two important contributors to polycyclic aromatic compounds (PACs) deposition fluxes in urban area. PMID- 28841435 TI - Toxicological effects of tris(2-chloropropyl) phosphate in human hepatic cells. AB - Organophosphate flame retardants (OPFRs) are widely used as flame retardants which are ubiquitous in various environment media. As many of OPFRs are toxic and persistent, concerns have been raised in regards to their environmental impact. In this study, the toxicological effects of tris(2-chloropropyl) phosphate (TCPP) in human L02 cells was investigated by cell proliferation and apoptosis, oxidative stress, metabolomic and proteomic responses as well as gene expressions related to apoptosis. Results showed that TCPP did not significantly affect the L02 cell apoptosis, however, a significant increase of ROS production was observed in L02 cells with TCPP treatment compared with that in control group (p < 0.05). The expression levels of Bcl-2 family-encoding genes (Bax, Hrk and Bax/Bcl-2) were up-regulated significantly in 10-4 M group (p < 0.05). Metabolomic and proteomic responses indicated that TCPP mainly caused disturbance in cell growth/division and gene expression, energy and material metabolism, signal transduction, defense and cytoskeleton, which was further confirmed by the western blot analysis. PMID- 28841436 TI - Biomarker responses of rice plants growing in a potentially toxic element polluted region: A case study in the Le'An Region. AB - Rice plants, planted and grown in the field, were chosen in this study to evaluate the potentially toxic element pollution by combining pollutant analysis and a molecular biomarker response evaluation together in the Le'An Region, a highly polluted area due to anthropogenic activities. Soils and crops at 18 sites classified into four areas based on hydrological, geological and pollutant survey results were collected during the whole growth cycle for chemical and biological analysis. Sediment quality values and pollution indexes were combined with statistical analyses to assess the hazard of potentially toxic elements and evaluate ecological risks. As effective stress-related signals, chlorophyll (Chl), superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), glutathione content (GSH) and lipoperoxidation (as TBARS) were also determined during the rice plant growth period. The results revealed that heavy metal concentrations were significantly higher than corresponding background values and significantly related to those of the soils. The maximum concentration of potentially toxic elements was observed at the tillering stage, followed by the grain filling stage and heading stage. As biomarkers in field monitoring, a significant increase or decrease in Chl, SOD, POD, CAT, GSH and TBARS in crops means a potential relationship between the indexes and pollutants. This study also demonstrates that the integrated biomarker response (IBR) calculated by combining different biomarkers could be used effectively to evaluate the pollutant-induced stress levels in different areas. PMID- 28841437 TI - New insights into olivo-cerebellar circuits for learning from a small training sample. AB - Artificial intelligence such as deep neural networks exhibited remarkable performance in simulated video games and 'Go'. In contrast, most humanoid robots in the DARPA Robotics Challenge fell down to ground. The dramatic contrast in performance is mainly due to differences in the amount of training data, which is huge and small, respectively. Animals are not allowed with millions of the failed trials, which lead to injury and death. Humans fall only several thousand times before they balance and walk. We hypothesize that a unique closed-loop neural circuit formed by the Purkinje cells, the cerebellar deep nucleus and the inferior olive in and around the cerebellum and the highest density of gap junctions, which regulate synchronous activities of the inferior olive nucleus, are computational machinery for learning from a small sample. We discuss recent experimental and computational advances associated with this hypothesis. PMID- 28841438 TI - Modeling the mammalian sleep cycle. AB - During sleep, the mammalian brain transitions through repeated cycles of non rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. The physiological implementation of this slow ultradian brain rhythm is largely unknown. Two differing dynamical mechanisms have been proposed to underlie the NREM-REM cycle. The first model type relies on reciprocal interactions between inhibitory and excitatory neural populations resulting in stable limit cycle oscillations. Recent experimental findings instead favor a model, in which mutually inhibitory interactions between REM sleep-promoting (REM-on) and REM sleep-suppressing (REM off) neural populations stabilize the brain state. Slow modulations in the neural excitability, that are hypothesized to reflect the homeostatic need for REM sleep, abruptly switch the brain in and out of REM sleep. PMID- 28841439 TI - Characterizing and interpreting the influence of internal variables on sensory activity. AB - The concept of a tuning curve has been central for our understanding of how the responses of cortical neurons depend on external stimuli. Here, we describe how the influence of unobserved internal variables on sensory responses, in particular correlated neural variability, can be understood in a similar framework. We suggest that this will lead to deeper insights into the relationship between stimulus, sensory responses, and behavior. We review related recent work and discuss its implication for distinguishing feedforward from feedback influences on sensory responses, and for the information contained in those responses. PMID- 28841440 TI - Long non-coding RNAs: The novel diagnostic biomarkers for leukemia. AB - Long non-coding RNAs (LncRNAs) are a category of non-coding RNAs (ncRNAs) with a length of 200nt-100kb lacking a significant open reading frame. The study of lncRNAs is a newly established field, due in part to their capability to act as the novel biomarkers in disease. A growing body of research shows that lncRNAs may not only useful as biomarkers for the diagnosis and clinical typing and prognosis of cancers, but also as potential targets for novel therapies. Differential expression of lncRNAs has been found in leukemia in the last two years, however, the majority of the lncRNAs described here are transcripts of unknown function and their role in leukemogenesis is still unclear. Here, we summarize the lncRNAs associated with leukemia in order to find a potential classification tool for leukemia, and a new field of research is being explored. PMID- 28841441 TI - HLA-G molecules and clinical outcome in Chronic Myeloid Leukemia. AB - The human leukocyte antigen-G (HLA-G) gene encodes a tolerogenic protein known to promote tumor immune-escape. We investigated HLA-G polymorphisms and soluble molecules (sHLA-G) in 68 chronic myeloid leukemia (CML) patients. Patients with G*01:01:01 or G*01:01:02 allele had higher value of sHLA-G compared to G*01:01:03 (109.2+/-39.5 vs 39.9+/-8.8 units/ml; p=0.03), and showed lower event free survival (EFS) (62.3% vs 90.0%; p=0.02). The G*01:01:03 allele was associated with higher rates and earlier achievement of deep molecular response (MR)4.5 (100% vs 65%, median of 8 vs 58 months, p=0.001). HLA-G alleles with higher secretion of sHLA-G seem associated with lower EFS, possibly because of an inhibitory effect on the immune system. Conversely, lower levels of sHLA-G promoted achievement of MR4.5, suggesting increased cooperation with immune system. PMID- 28841442 TI - Externalizing and internalizing behaviours in adolescence, and the importance of parental behavioural and psychological control practices. AB - The aims of the present study were to explore the impact of parental characteristics (behavioural control and psychological control) on adolescents' expression of externalizing and internalizing behaviours. To address the aim of the study, participants completed quantitative measures; the study included 538 adolescents and their mothers and fathers. Overall, 513 mothers and 464 fathers participated in the study. Adolescents completed the Children's Report on Parent Behaviour Inventory (CRPBI), while parents completed the Child Behaviour Checklist - Parent Report (Short Form; CBCL). Results of the study showed that only maternal and paternal psychological control predicted externalizing and internalizing behaviours. The conclusions have practical applications, as they can provide novel approaches in parent training programmes. Furthermore, results are discussed in relation to the connection with earlier studies and the theoretical contribution. PMID- 28841443 TI - Detection and characterization of an H4N6 avian-lineage influenza A virus in pigs in the Midwestern United States. AB - H4Nx viruses were reported in swine in Canada and China, but had not been recognized in swine in the USA. In late 2015, an avian-origin H4N6 influenza A virus was isolated from pigs in the United States during a routine diagnostic investigation of clinical respiratory disease in the herd. Serological analysis from additional pigs at the farm and other pigs within the swine production system indicated that the virus did not efficiently transmit from pig-to-pig and the mode of transmission to swine could not be determined. The isolate was characterized at the molecular level and the pathogenesis and transmission was experimentally evaluated in pigs. Although the virus replicated in the lungs of pigs and caused mild pulmonary lesions, there was no evidence of replication in the upper respiratory tract or transmission to indirect contacts, supporting the findings on the farm. PMID- 28841444 TI - Herpes simplex virus 1 infection of T cells causes VP11/12-dependent phosphorylation and degradation of the cellular protein Dok-2. AB - Previous studies have shown that HSV-1 infection of lymphocytes induces the tyrosine phosphorylation of several proteins that might correspond to viral or host proteins. VP11/12, a viral tegument protein, is the major HSV-induced tyrosine phosphorylated protein identified thus far. In this report, we demonstrated that the cellular adaptor proteins Dok-2 and Dok-1 are tyrosine phosphorylated upon HSV-1 infection. In addition, HSV-1 induced the selective degradation of Dok-2. Finally, we provide evidence that Dok-2 interacts with VP11/12, and that HSV-induced tyrosine phosphorylation and degradation of Dok-2 require VP11/12. Inactivation of either the Src Family Kinases binding motifs or the SHC binding motif of VP11/12 eliminated the interaction of Dok-2 with VP11/12. Elimination of the binding of Dok-2 to VP11/12 prevented Dok-2 phosphorylation and degradation. We propose that HSV-induced Dok phosphorylation and Dok-2 degradation is an immune evasion mechanism to inactivate T cells that might play an important role in HSV pathogenesis. PMID- 28841446 TI - The phenotype of the RABV glycoprotein determines cellular and global virus load in the brain and is decisive for the pace of the disease. AB - The Rabies lyssavirus glycoprotein (RABV-G) is largely responsible for the neuroinvasiveness of the virus and the induction of antiviral immune responses. To study the effects of RABV-G we compared the G of the attenuated RABV variant SPBN with that of the pathogenic DOG4 strain. Infection via the olfactory route caused 100% mortality in mice with both virus variants. Of note, with the attenuated SPBN, progression of the disease was accelerated, microglia response less pronounced and IL-6 expression higher than in the presence of RABV-G from the pathogenic DOG4. However, while virus spread was less extensive, viral gene expression in individual neurons was actually higher in SPBN-infected brains without causing apoptosis of infected neurons. These differences between the two variants were not observed in infected neuronal cultures indicating that the effects of RABV-G on virus spread and viral gene expression depend on factors only present in the intact brain. PMID- 28841445 TI - APOBEC3B lysine residues are dispensable for DNA cytosine deamination, HIV-1 restriction, and nuclear localization. AB - The APOBEC3 DNA cytosine deaminase family comprises a fundamental arm of the innate immune response and is best known for retrovirus restriction. Several APOBEC3 enzymes restrict HIV-1 and related retroviruses by deaminating viral cDNA cytosines to uracils compromising viral genomes. Human APOBEC3B (A3B) shows strong virus restriction activities in a variety of experimental systems, and is subjected to tight post-translational regulation evidenced by cell-specific HIV-1 restriction activity and active nuclear import. Here we ask whether lysines and/or lysine post-translational modifications are required for these A3B activities. A lysine-free derivative of human A3B was constructed and shown to be indistinguishable from the wild-type enzyme in DNA cytosine deamination, HIV-1 restriction, and nuclear localization activities. However, lysine loss did render the protein resistant to degradation by SIV Vif. Taken together, we conclude that lysine side chains and modifications thereof are unlikely to be central to A3B function or regulation in human cells. PMID- 28841447 TI - Variation of genomic islands and flanking fragments in Vibrio parahaemolyticus isolates from environmental and clinical sources in Taiwan. AB - Vibrio parahaemolyticus is a halophilic foodborne pathogenic bacterium that causes gastroenteritis; it has become an issue of global concern since the emergence and spread of pandemic O3:K6 strains. This study evaluated the role of Vibrio pathogenicity island (VPaI)-associated fragments in the genetic variation and grouping of this pathogen. Distribution of some VPaI fragments and flanking fragments (VPaI-1, VPaI-4, VPaI-5, VPaI-6 and VPaI-7) was determined in a total of 53 V. parahaemolyticus isolates from environmental and clinical sources in Taiwan, and supported by the sequences of seven fragments of VPaI-4 and its flanking fragment VP2145. As determined from the distribution of these VPaI associated fragments, the clinical pandemic isolates were closely related in a single cluster; the clinical nonpandemic isolates were grouped into several clusters, while the environmental isolates were comparatively highly diversified. The profiles of virulence-associated genes of environmental pathogenic isolates varied, and were closer to those of clinical nonpandemic isolates than those of pandemic isolates. Isolates with atypical profiles of the VPaI-associated fragments and virulence-associated genes were identified. Sequences of VP2145 exhibited a close phylogenetic relationship among these local isolates, which were distinct from most V. parahaemolyticus strains from other geographic regions. This investigation demonstrated the application of VPaI-associated fragments in studying the genetic variation and clustering of V. parahaemolyticus isolates from different sources. PMID- 28841448 TI - Pre-crash scenarios at road junctions: A clustering method for car crash data. AB - Given the recent advancements in autonomous driving functions, one of the main challenges is safe and efficient operation in complex traffic situations such as road junctions. There is a need for comprehensive testing, either in virtual simulation environments or on real-world test tracks. This paper presents a novel data analysis method including the preparation, analysis and visualization of car crash data, to identify the critical pre-crash scenarios at T- and four-legged junctions as a basis for testing the safety of automated driving systems. The presented method employs k-medoids to cluster historical junction crash data into distinct partitions and then applies the association rules algorithm to each cluster to specify the driving scenarios in more detail. The dataset used consists of 1056 junction crashes in the UK, which were exported from the in depth "On-the-Spot" database. The study resulted in thirteen crash clusters for T junctions, and six crash clusters for crossroads. Association rules revealed common crash characteristics, which were the basis for the scenario descriptions. The results support existing findings on road junction accidents and provide benchmark situations for safety performance tests in order to reduce the possible number parameter combinations. PMID- 28841449 TI - Contribution to 'Predatory Journals' from India-Taking a closer look. PMID- 28841450 TI - Seizure secondary to Bupropion extended release preparation: A report. PMID- 28841451 TI - A pragmatic trial to improve adherence with scheduled appointments in an inner city pain clinic by human phone calls in the patient's preferred language. AB - STUDY OBJECTIVE: We investigated if human reminder phone calls in the patient's preferred language increase adherence with scheduled appointments in an inner city chronic pain clinic. We hypothesized that language and cultural incongruence is the underlying mechanism to explain poor attendance at clinic appointments in underserved Hispanic populations. DESIGN: Pragmatic randomized controlled clinical trial SETTING: Innercity academic chronic pain clinic with a diverse, predominantly African-American and Hispanic population PATIENTS: All (n=963) adult patients with a scheduled first appointment between October 2014 and October 2015 at the Montefiore Pain Center in the Bronx, New York were enrolled. INTERVENTIONS: Patients were randomized to receive a human reminder call in their preferred language before their appointment, or no contact. MEASUREMENTS: We recorded patients' demographic characteristics and as primary outcome attendance as scheduled, failure to attend and/or cancellation calls. We fit Bayesian and classical multinomial logistic regression models to test if the intervention improved adherence with scheduled appointments. MAIN RESULTS: Among the 953 predominantly African American and Hispanic/Latino patients, 475 patients were randomly selected to receive a language-congruent, human reminder call, while 478 were assigned to receive no prior contact, (after we excluded 10 patients, scheduled for repeat appointments). In the experimental group, 275 patients adhered to their scheduled appointment, while 84 cancelled and 116 failed to attend. In the control group, 249 patients adhered to their scheduled appointment, 31 cancelled and 198 failed to attend. Human phone reminders in the preferred language increased adherence (RR 1.89, CI95% [1.42, 1.42], (p<0.01). The intervention seemed particularly effective in Hispanic patients, supporting our hypothesis of cultural congruence as possible underlying mechanism. CONCLUSIONS: Human reminder phone calls prior in the patient's preferred language increased adherence with scheduled appointments. The intervention facilitated access to much needed care in an ethnically diverse, resource poor population, presumably by overcoming language barriers. PMID- 28841452 TI - Epidural labor analgesia: Whence come our patients' misconceptions? PMID- 28841453 TI - Argon embolus from argon beam coagulator. PMID- 28841454 TI - FGF-2-mediated FGFR1 signaling in human microvascular endothelial cells is activated by vaccarin to promote angiogenesis. AB - Angiogenesis is a complex physiological process involving the growth of new capillaries. The impaired angiogenesis plays important roles in chronic wounds and ischaemic heart disease. Fibroblast growth factor 2 (FGF-2) exerts pro angiogenic actions via activation of fibroblast growth factor receptor 1 (FGFR 1). We have identified that vaccarin increased the angiogenic activity of endothelial cells. In this study, we investigated whether FGF-2-mediated FGFR1 signaling pathway participated in vaccarin-mediated neovascularization formation. Human microvascular endothelial cells (HMEC)-1 were incubated with various doses of vaccarin. Our results showed that vaccarin dose-dependently up-regulated FGF-2 levels and phosphorylation of FGFR-1. Neutralization of FGF-2 with anti-FGF-2 antibody also abolished the proliferation, migration and tube formation of HMEC-1 cells induced by vaccarin. Both FGFR-1 inhibitor SU5402 and FGFR-1 siRNA blocked vaccarin-induced cell cycle progression and angiogenesis. The mouse Matrigel model study further unveiled that vaccarin stimulated the neovascularization and microvessel density in vivo, which was prevented by FGFR-1 inhibitor SU5402. Taken together, our results demonstrated for the first time that vaccarin was a novel inducer for FGF-2 expression, followed by phosphorylation of FGFR-1 and subsequent angiogenic behaviors in endothelial cells. Vaccarin may be a promising candidate of angiogenesis activator for neurovascular repair or therapy. PMID- 28841455 TI - Cardiovascular dysfunction in sepsis at the dawn of emerging mediators. AB - Subcellular dysfunction and impaired metabolism derived from the complex interaction of cytokines and mediators with cellular involvement are on the basis of the cardiovascular response to sepsis. The lethal consequences of an infection are intimately related to its ability to spread to other organ sites and the immune system of the host. About one century ago, William Osler (1849-1919), a Canadian physician, remarkably defined the sequelae of the host response in sepsis: "except on few occasions, the patient appears to die from the body's response to infection rather than from it." Cardiac dysfunction has received considerable attention to explain the heart failure in patients progressing from infection to sepsis, but our understanding of the processes remains limited. In fact, most concepts are linked to a mechanical concept of the sarcomeric structure, and physiological data seems to be often disconnected. Cytokines, prostanoids, and nitric oxide release are high direct impact factors, but coronary circulation and cardiomyocyte physiology also play a prominent role in modulating the effects of monocyte adhesion and infiltration. Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are involved in the host response. The identification of microRNAs, as well as the cyclic activation of the inflammatory cascade, has further added complexity to the scene. In this review, we delineate the current concepts of cellular dysfunction of the cardiomyocyte in the setting of sepsis and consider potential therapeutic strategies. PMID- 28841456 TI - Resveratrol improves smooth muscle carcinogenesis in the progression of chronic prostatitis via the downregulation of c-kit/SCF by activating Sirt1. AB - PURPOSE: Bladder smooth muscle cell death accompanied by hyperplasia and hypertrophy, as induced by inflammation, is the primary cause for poor bladder function. There are emerging evidences on the role of chronic inflammation as a factor involved in carcinogenesis and progression. We aim to determine the bladder smooth muscle pathological changes and dysfunction in chronic prostatitis (CP), to investigate whether resveratrol can improve the urinary dysfunction and the role of c-kit/SCF pathway, that has been associated with the smooth muscle carcinogenesis. METHOD: Rat model of CP was established via subcutaneous injections of DPT vaccine and subsequently treated with resveratrol. H&E staining was performed to identify the histopathological changes in prostates and bladders. Western blotting and immunohistochemical staining examined the expression level of C-kit, stem cell factor (SCF), Sirt1, apoptosis associated proteins. RESULTS: the model group exhibited severe diffuse chronic inflammation, characterized by leukocyte infiltration and papillary frond protrusion into the gland cavities, and a notable increase in prostatic epithelial height. Meanwhile, bladder muscle arranged in disorder with fracture, and cells appeared atypia. The activity of C-kit/SCF was up-regulated, the carcinogenesis associated proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. CONCLUSIONS: activated c-kit/SCF and bladder muscle carcinogenesis were involved in the pathological processes of CP, which was improved after resveratrol treatment via the downregulation of c kit/SCF by activating Sirt1. PMID- 28841457 TI - Associations between rejection sensitivity and mental health outcomes: A meta analytic review. AB - Rejection sensitivity is a personality disposition characterized by oversensitivity to social rejection. Using a three-level meta-analytic model, 75 studies were reviewed that examined associations between rejection sensitivity and five mental health outcomes: depression, anxiety, loneliness, borderline personality disorder, and body dysmorphic disorder. The results showed significant and moderate associations between rejection sensitivity and depression (pooled r=0.332; p<0.001), anxiety (pooled r=0.407; p<0.001), loneliness (pooled r=0.386; p<0.001), borderline personality disorder (pooled r=0.413; p<0.001), and body dysmorphic disorder (pooled r=0.428; p<0.001). The associations between rejection sensitivity and depression, anxiety, and borderline personality disorder varied by type of sample, but the associations were similar for clinical and non-clinical (i.e., community) samples. The association between rejection sensitivity and anxiety was negatively moderated by percentage of females in samples. The association between rejection sensitivity and depression was negatively moderated by length of follow-up. The longitudinal associations between rejection sensitivity and depression, anxiety, and loneliness were stable over time. Implications of the findings for both risk assessment and prevention and intervention strategies in mental health practice are discussed. PMID- 28841458 TI - Improving microstructural quantification in FIB/SEM nanotomography. AB - FIB/SEM nanotomography (FIB-nt) is a powerful technique for the determination and quantification of the three-dimensional microstructure in subsurface features. Often times, the microstructure of a sample is the ultimate determiner of the overall performance of a system, and a detailed understanding of its properties is crucial in advancing the materials engineering of a resulting device. While the FIB-nt technique has developed significantly in the 15 years since its introduction, advanced nanotomographic analysis is still far from routine, and a number of challenges remain in data acquisition and post-processing. In this work, we present a number of techniques to improve the quality of the acquired data, together with easy-to-implement methods to obtain "advanced" microstructural quantifications. The techniques are applied to a solid oxide fuel cell cathode of interest to the electrochemistry community, but the methodologies are easily adaptable to a wide range of material systems. Finally, results from an analyzed sample are presented as a practical example of how these techniques can be implemented. PMID- 28841459 TI - Performance comparison between wrist and chest actigraphy in combination with heart rate variability for sleep classification. AB - The concurrent usage of actigraphy and heart rate variability (HRV) for sleep efficiency quantification is still matter of investigation. This study compared chest (CACT) and wrist (WACT) actigraphy (actigraphs positioned on chest and wrist, respectively) in combination with HRV for automatic sleep vs wake classification. Accelerometer and ECG signals were collected during polysomnographic studies (PSGs) including 18 individuals (25-53 years old) with no previous history of sleep disorders. Then, an experienced neurologist performed sleep staging on PSG data. Eleven features from HRV and accelerometry were extracted from series of different lengths. A support vector machine (SVM) was used to automatically distinguish sleep and wake. We found 7 min as the optimal signal length for classification, while maximizing specificity (wake detection). CACT and WACT provided similar accuracies (78% chest vs 77% wrist), larger than what yielded by HRV alone (66%). The addition of HRV to CACT reduced slightly the accuracy, while improving specificity (from 33% to 51%, p < 0.05). On the contrary, the concurrent usage of HRV and WACT did not provide statistically significant improvements over WACT. Then, a subset of features (3 from HRV + 1 from actigraphy) was selected by reducing redundancy using a strategy based on Spearman's correlation and area under the ROC curve. The usage of the reduced set of features and SVM classifier gave only slightly reduced classification performances, which did not differ from the full sets of features. The study opens interesting possibilities in the design of wearable devices for long-term monitoring of sleep at home. PMID- 28841460 TI - Automatic counting of trypanosomatid amastigotes in infected human cells. AB - This article presents an automatic approach to counting amastigotes in human cells infected with Chagas. The approach is divided into four steps: first, morphological pretreatment removes the complex image background; sets are then segmented by unsupervised classification; the infected cells are then preserved using a thresholding process; and, finally, they undergo morphological granulometric processing and are filtered by the average. An experimental protocol was employed to compare the amastigotes nuclei labeled by a professional biochemist with the results obtained by the proposed approach. We observed that using the granulometric sieving conducted with square SE plus average size filtering is the best option to obtain the minor error and the best precision and using the granulometric sieving conducted with rhombus SE without average size filtering represents the best combination for obtaining the best F-measure and recall rates. PMID- 28841461 TI - Associations between urban upbringing and cortical thickness and gyrification. AB - Urbanicity has been linked to several psychiatric disorders, especially schizophrenia. Recent studies suggest effects of urban upbringing and stress on brain structure and function. Here, we used surface-based and voxel-based morphometry to study the effects of urban upbringing in different environments on variation in brain structure in a non-clinical sample. We recruited 85 young and healthy individuals from the community and recorded urban vs. rural background in their first 15 years of live. All participants underwent T1-weighted 3T MRI, which were then processed via CAT12 toolbox (in SPM12) to analyse cortical volume, thickness and gyrification. These parameters were correlated with an established measure of cumulative childhood and adolescence exposure to urban environments. We found significant (p < 0.05, FWE-corrected) negative correlations of cortical thickness with higher index of urban upbringing in the left dorsolateral prefrontal cortex, bilateral medial prefrontal cortices, as well as temporal cortices including the left superior temporal and left parahippocampal cortex. In contrast, results for volume and gyrification (incl. left posterior cingulate cortex) did not survive correction for multiple comparisons. We show a strong association of early-life urbanicity with cortical thickness in several areas, which are also impaired in schizophrenia patients. Along with other findings, these results converge on the dorsolateral prefrontal cortex as an area mediating this environmental risk. PMID- 28841462 TI - A theoretical survey of substituent effects on the properties of pnicogen and hydrogen bonds in cationic complexes of PH4+ with substituted benzonitrile. AB - In this paper, we analyze the substituent effects on the nature and characteristics of P?N and H?N interactions in X-PhCN:PH4+ complexes (X=H, F, Cl, Br, CN, NH2, NO2, CH3 and N(CH3)2) as a working model at MP2(FC)/6-311++G(d,p) level of theory. The natural bond orbital (NBO) method as well as the quantum theory of atoms in molecules (AIM) is applied to characterize interactions in the studied complexes. In general, the pnicogen bonded systems are more stable than the corresponding hydrogen bonded cases. The strength of the interactions generally correlates well with the magnitudes of the negative electrostatic potentials of the nitrogen atom of isolated substituted benzonitrile (Vs,min(N)). The results indicate that increase in the electron withdrawing power of substituents is accompanied by decrease in the absolute value of Vs,min(N). Also, there are meaningful relationships between Vs,min(N) values and the results of AIM and NBO analyses in studied systems. Moreover, it is found that substituent effects on characteristics of P?N pnicogen and H?N hydrogen bonds can be expressed by Hammett constants. PMID- 28841464 TI - The role of insulin growth factor-1 on the vascular regenerative effect of MAA coated disks and macrophage-endothelial cell crosstalk. AB - The IGF-1 signaling pathway and IGF-1-dependent macrophage/endothelial cell crosstalk was found to be critical features of the vascular regenerative effect displayed by implanted methacrylic acid -co-isodecyl acrylate (MAA-co-IDA; 40% MAA) coated disks in CD1 mice. Inhibition of IGF-1 signaling using AG1024 an IGF1 R tyrosine kinase inhibitor abrogated vessel formation 14 days after disk implantation in a subcutaneous pocket. Explanted tissue had increased arginase 1 expression and reduced iNOS expression consistent with the greater shift from "M1" ("pro-inflammatory") macrophages to "M2" ("pro-angiogenic") macrophages for MAA coated disks relative to control MM (methyl methacrylate-co-IDA) disks; the latter did not generate a vascular response and the polarization shift was muted with AG1024. In vitro, medium conditioned by macrophages (both human dTHP1 cells and mouse bone marrow derived macrophages) had elevated IGF-1 mRNA and protein levels, while the cells had reduced IGF1-R but elevated IGFBP-3 mRNA levels. These cells also had reduced iNOS and elevated Arg1 expression, consistent with the in vivo polarization results, including the inhibitory effects of AG1024. On the other hand, HUVEC exposed to dTHP1 conditioned medium migrated and proliferated faster suggesting that the primary target of the macrophage released IGF-1 was endothelial cells. Although further investigation is warranted, IGF-1 appears to be a key feature underpinning the observed vascularization. Why MAA based materials have this effect remains to be defined, however. PMID- 28841463 TI - Vascular scaffolds with enhanced antioxidant activity inhibit graft calcification. AB - There is a need for off-the-shelf, small-diameter vascular grafts that are safe and exhibit high long-term patency. Decellularized tissues can potentially be used as vascular grafts; however, thrombogenic and unpredictable remodeling properties such as intimal hyperplasia and calcification are concerns that hinder their clinical use. The objective of this study was to investigate the long-term function and remodeling of extracellular matrix (ECM)-based vascular grafts composited with antioxidant poly(1, 8-octamethylene-citrate-co-cysteine) (POCC) with or without immobilized heparin. Rat aortas were decellularized to create the following vascular grafts: 1) ECM hybridized with POCC (Poly-ECM), 2) Poly-ECM subsequently functionalized with heparin (Poly-ECM-Hep), and 3) non-modified vascular ECM. Grafts were evaluated as interposition grafts in the abdominal aorta of adult rats at three months. All grafts displayed antioxidant activity, were patent, and exhibited minimal intramural cell infiltration with varying degrees of calcification. Areas of calcification co-localized with osteochondrogenic differentiation of vascular smooth muscle cells, lipid peroxidation, oxidized DNA damage, and cell apoptosis, suggesting an important role for oxidative stress in the calcification of grafts. The extent of calcification within grafts was inversely proportional to their antioxidant activity: Poly-ECM-Hep > ECM > Poly-ECM. The incorporation of antioxidants into vascular grafts may be a viable strategy to inhibit degenerative changes. PMID- 28841465 TI - Design of a nanocomposite substrate inducing adult stem cell assembly and progression toward an Epiblast-like or Primitive Endoderm-like phenotype via mechanotransduction. AB - This work shows that the active interaction between human umbilical cord matrix stem cells and Poly (l-lactide)acid (PLLA) and PLLA/Multi Walled Carbon Nanotubes (MWCNTs) nanocomposite films results in the stem cell assembly as a spheroid conformation and affects the stem cell fate transition. We demonstrated that spheroids directly respond to a tunable surface and the bulk properties (electric, dielectric and thermal) of plain and nanocomposite PLLA films by triggering a mechanotransduction axis. This stepwise process starts from tethering of the cells' focal adhesion proteins to the surface, together with the adherens junctions between cells. Both complexes transmit traction forces to F Actin stress fibres that link Filamin-A and Myosin-IIA proteins, generating a biological scaffold, with increased stiffening conformation from PLLA to PLLA/MWCNTs, and enable the nucleoskeleton proteins to boost chromatin reprogramming processes. Herein, the opposite expression of NANOG and GATA6 transcription factors, together with other lineage specification related proteins, steer spheroids toward an Epiblast-like or Primitive Endoderm-like lineage commitment, depending on the absence or presence of 1 wt% MWCNTs, respectively. This work represents a pioneering effort to create a stem cell/material interface that can model the stem cell fate transition under growth culture conditions. PMID- 28841466 TI - Antioxidant potential and hypolipidemic effect of whey protein against gamma irradiation induced damages in rats. AB - PURPOSE: Evaluation of the efficacy of whey protein as antioxidant against gamma irradiation induced oxidative stress and dyslipidemia in male rats. METHOD: Rats were divided into groups; group 1 (control), rats in group 2 & 3 were exposed to gamma-irradiation 5 & 10Gy respectively and rats in group 4 & 5 were orally administrated with whey protein after gamma-irradiation. The antioxidant status (glutathione (GSH), Superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC) and malondialdehyde (MDA), lipid profile (total cholesterol (TC), triglyceride (TG) and high-density lipoprotein (HDL) as well as the hematological parameters were determined. RESULTS: gamma-irradiation had depletion in GSH, SOD, CAT and TAC levels and elevation in MDA. Moreover, an increase in TC & TG coupled with decrease in HDL after gamma-irradiation. The hematological parameters decreased after gamma-irradiation. Treated rats with whey protein improved the antioxidant status and minimized the alterations of lipid and blood cells induced by gamma-irradiation. CONCLUSION: whey protein has a positive effect on lipid and antioxidant status to minimize the oxidative stress due to exposure to gamma irradiation. PMID- 28841467 TI - Chronological age prediction based on DNA methylation: Massive parallel sequencing and random forest regression. AB - The use of DNA methylation (DNAm) to obtain additional information in forensic investigations showed to be a promising and increasing field of interest. Prediction of the chronological age based on age-dependent changes in the DNAm of specific CpG sites within the genome is one such potential application. Here we present an age-prediction tool for whole blood based on massive parallel sequencing (MPS) and a random forest machine learning algorithm. MPS allows accurate DNAm determination of pre-selected markers and neighboring CpG-sites to identify the best age-predictive markers for the age-prediction tool. 15 age dependent markers of different loci were initially chosen based on publicly available 450K microarray data, and 13 finally selected for the age tool based on MPS (DDO, ELOVL2, F5, GRM2, HOXC4, KLF14, LDB2, MEIS1-AS3, NKIRAS2, RPA2, SAMD10, TRIM59, ZYG11A). Whole blood samples of 208 individuals were used for training of the algorithm and a further 104 individuals were used for model evaluation (age 18-69). In the case of KLF14, LDB2, SAMD10, and GRM2, neighboring CpG sites and not the initial 450K sites were chosen for the final model. Cross-validation of the training set leads to a mean absolute deviation (MAD) of 3.21 years and a root-mean square error (RMSE) of 3.97 years. Evaluation of model performance using the test set showed a comparable result (MAD 3.16 years, RMSE 3.93 years). A reduced model based on only the top 4 markers (ELOVL2, F5, KLF14, and TRIM59) resulted in a RMSE of 4.19 years and MAD of 3.24 years for the test set (cross validation training set: RMSE 4.63 years, MAD 3.64 years). The amplified region was additionally investigated for occurrence of SNPs in case of an aberrant DNAm result, which in some cases can be an indication for a deviation in DNAm. Our approach uncovered well-known DNAm age-dependent markers, as well as additional new age-dependent sites for improvement of the model, and allowed the creation of a reliable and accurate epigenetic tool for age-prediction without restriction to a linear change in DNAm with age. PMID- 28841468 TI - Performance of a sequencing-batch membrane bioreactor (SMBR) with an automatic control strategy treating high-strength swine wastewater. AB - Due to high-strength of organic matters, nutrients and pathogen, swine wastewater is a major source of pollution to rural environment and surface water. A sequencing-batch membrane bioreactor (SMBR) system with an automatic control strategy was developed for high-strength swine wastewater treatment. Short-cut nitrification and denitrification (SND) was achieved at nitrite accumulation rate of 83.6%, with removal rates of COD, NH4+-N and TN at 95%, 99% and 93%, respectively, at reduced HRT of 6.0 d and TN loading rate of 0.02kgN/(kgVSS d). With effective membrane separation, the reduction of total bacteria (TB) and putative pathogen were 2.77 logs and 1%, respectively. The shift of microbial community was well responded to controlling parameters. During the SND process, ammonia oxidizing bacteria (AOB) (Nitrosomonas, Nitrosospira) and nitrite oxidizing bacteria (NOB) (Nitrospira) were enriched by 52 times and reduced by 2 times, respectively. The denitrifiers (Thauera) were well enriched and the diversity was enhanced. PMID- 28841469 TI - Catalytic oxidation of PCDD/F on a V2O5-WO3/TiO2 catalyst: Effect of chlorinated benzenes and chlorinated phenols. AB - Catalytic oxidation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) is a well-proven technique, applied in a rising number of Municipal Solid Waste Incineration plants, yet the simultaneous and possibly competitive co oxidation of other compounds, such as chlorinated benzenes (CBz) or phenols (CP), is still poorly documented. In this study, a grinded commercial catalyst (vanadium-tungsten supported on titanium dioxide) was submitted to exploratory testing: the PCDD/F present in a gas test flow were catalytically oxidised (200 degrees C, 10,000h-1), either as such or in the presence of benzene (Bz), monochlorobenzene (MCBz), and 1,2-dichlorobenzene (DCBz) and the effect of these additions on the catalytic destruction of PCDD/F was verified experimentally. Both removal efficiency (RE) and destruction efficiency (DE) declined during the exploratory testing and, importantly, some DCBz even converted into supplemental PCDD/F. Also, the occurrence of carbon deposition negatively influenced catalytic oxidation activity. Regeneration with oxygen or air allowed to remove the deposited carbon and the original catalytic activity was largely restored after calcination. In a second part of this study, the PCDD/F-formation from DCBz, hexachlorobenzene (HCBz), o-monochlorophenol (o-MCP) and pentachlorophenol (PeCP) was demonstrated and tentatively explored. To prepare for further elucidation of the reaction mechanism, a complete isomer-specific analysis was prepared. PMID- 28841470 TI - Experimental study on fire smoke control using water mist curtain in channel. AB - The hazards of the spread of fire smoke in a channel have been recognized. This paper relates to the potential use of a water mist curtain (WMC) for preventing the spread of fire smoke, focusing particularly on smoke control at the early stage of a fire, with the aim of reducing the harm of fire smoke and allowing time for people to escape. Fatal factors for occupant evacuation in a fire, such as carbon monoxide concentration, smoke temperature, and visibility, were measured in the section controlled by the WMC. The results indicate that the WMC can be effective in preventing fire smoke from spreading at the early stage, and may provide a useful reference for developing a novel method of smoke control. Furthermore, the effects of nozzles with different spray characteristics were investigated and an optimal working pressure was suggested. In addition, a mathematical model was simplified and used to analyze the interaction between the fire-induced smoke layer and WMC spray. PMID- 28841471 TI - Teaching caring and competence: Student transformation during an older adult focused service-learning course. AB - Innovative teaching strategies develop nurses' knowledge, skills, and attitudes while simultaneously integrating the art of caring and transforming attitudes toward adults over age 65. The study's purpose was to explore students' experiences and attitudes toward older adults with cognitive and/or physical limitations as well as the effects on students' knowledge and skills during a baccalaureate nursing, course which included a service-learning experience. Service-learning synthesizes meaningful community service, academic instruction, and reflection. Participants included baccalaureate students enrolled in a service-learning nursing course focused on older adults. This retrospective, qualitative, phenomenological study used reflective journals and an online survey to explore baccalaureate nursing students' experiences toward older adults with cognitive and/or physical limitations. Themes included initial attitudes of anticipation, apprehension, anxiety, and ageist stereotypes. Final attitudes included a "completely changed perspective" of caring, compassion, and respect indicative of a rewarding, "life-changing" experience. Participants cited enhanced learning, especially in the areas of patient-centered care, collaboration, communication, advocacy, empathy, assessment skills, and evidence based practice. This innovative teaching strategy led to transformed attitudes toward older adults, reduced fear of older adult populations, an increased desire to work with older adults, and the ability to form a transpersonal, caring relationship while enhancing nursing knowledge and skills. PMID- 28841472 TI - Neuropsychological outcomes following stereotactic laser amygdalohippocampectomy. AB - OBJECTIVE: The objective was to analyze neuropsychological testing data from 15 patients before and after stereotactic laser ablation surgery for temporal lobe epilepsy and to describe the seizure outcomes after stereotactic laser ablation surgery. METHODS: A retrospective review of 15 patients who underwent stereotactic laser ablation and who also underwent neuropsychological testing before and after surgery was performed. Verbal and visual memory was assessed in all 15 patients using California Verbal Learning Test and Wechsler Memory Scale IV. Naming was assessed in 9 of 15 patients using the Boston Naming Test. Statistical analysis was performed to determine clinically significant changes using previously validated reliable change indices and proprietary Advanced Clinical Solutions software. Seizure outcome data were evaluated using Engel classification. RESULTS: Postsurgery neuropsychological evaluation demonstrated that all 15 patients experienced at least 1 clinically significant decline in either verbal or visual memory. Ten patients in this series, including five with dominant-hemisphere surgery, demonstrated decline in delayed memory for narrative information (Logical Memory II). By contrast, the Boston Naming Test demonstrated more favorable results after surgery. Two of nine patients demonstrated a clinically significant increase in naming ability, and only one of nine patients demonstrated a clinically significant decline in naming ability. With at least 6months of follow-up after surgery, 33% reported seizure freedom. CONCLUSION: Stereotactic laser ablation can result in clinically significant and meaningful decline in verbal and visual memory when comparing patients to their own presurgical baseline. Naming ability, conversely, is much less likely to be impacted by stereotactic laser ablation and may improve after the procedure. PMID- 28841473 TI - "Metabolism of Odontoblast-like cells submitted to transdentinal irradiation with blue and red LED". AB - OBJECTIVES: The present study evaluated the trans-dentinal effect of light emitting diodes (LEDs) irradiation on the metabolism of odontoblast-like cells. METHODS: Seventy-two dentin discs (0.2mm thick) were obtained from human molar teeth. MDPC-23 cells (20,000 cells/disc) were seeded on the pulpal side of the discs using DMEM, supplemented with 10% fetal bovine serum (FBS). After 12h, the culture medium was replaced with DMEM containing 0.5% FBS. After additional 12h, blue (455+/-10nm) or red (630+/-10nm) LEDs were used at irradiances of 80 and 40mW/cm2, respectively, to irradiate the occlusal side of the discs. The energy doses were fixed at 2 or 4J/cm2. Cell viability, alkaline phosphatase activity (ALP), total protein production and collagen synthesis were evaluated 72h after irradiation. Data were submitted to Kruskal-Wallis and Mann-Whitney tests (alpha=0.05). RESULTS: Red light promoted proliferative effects at the energy dose of 4J/cm2. Conversely, cell cultures irradiated with 2J/cm2 emitted by the blue light showed reduced viability. ALP production was stimulated by red light in comparison with blue light at 4J/cm2. Total protein production was reduced after exposure to blue light at 4J/cm2, while no effect was observed on collagen production. CONCLUSIONS: Irradiation with red LED at 4J/cm2 bio-stimulated the viability of odontoblast-like cells, whilst blue light had unfavorable effects on the cellular metabolism. PMID- 28841474 TI - Relatively low invasive capacity of Porphyromonas gingivalis strains into human gingival fibroblasts in vitro. AB - OBJECTIVE: Bacterial invasion into host cells is a common strategy to escape the host immune system. Gingival fibroblasts (GFs) are the most predominant non phagocytic cell type in gingival connective tissue. Therefore, invasion into GFs was thought to be the first strategy for the survival of Porphyromonas gingivalis. The present study compared the invasive ability of P. gingivalis into GFs with those of other red-complex and relatively less pathogenic bacterial strains, especially Fusobacterium nucleatum. MATERIALS AND METHODS: Invasive ability of bacterial strains into GFs was measured using a flow cytometric invasion assay at a multiplicity of infection of 1000. The effect of dual infection with F. nucleatum CCUG 37843T on P. gingivalis ATCC 49417 invasion was investigated. The invasive ability of F. nucleatum and P. gingivalis was confirmed using confocal microscopy. RESULTS: The invasive ability of red-complex bacteria was markedly lower than that of F. nucleatum or Campylobacter gracilis. The invasive ability of 4 types and 10 clinical strains of P. gingivalis was less than 6%, and that of F. nucleatum strains was greater than 45%. Confocal analysis revealed that the percentage of bacteria invading GFs in the cell-treated P. gingivalis and F. nucleatum were 0.0068% and 1.22%, respectively. Dual infection with F. nucleatum increased the invasive ability of P. gingivalis. CONCLUSION: The invasive capacities of P. gingivalis into GFs were comparatively lower than those of relatively less pathogenic bacteria. Invasion into GFs cannot be the first strategy for survival of P. gingivalis in gingival connective tissue. PMID- 28841475 TI - Reflective function mediates the relationship between emotional maltreatment and borderline pathology in adolescents: A preliminary investigation. AB - Deficits in mentalizing, particularly within the context of attachment relationships i.e., reflective function (RF), are posited to result from childhood maltreatment and to influence the development of borderline personality disorder (BPD). Whilst a mentalization-based model of BPD provides a theoretical explanation, direct empirical support for this model, in linking childhood maltreatment to borderline pathology remains limited. This study examined the interrrelationships between childhood maltreatment, RF, and borderline pathology in a mixed adolescent sample, consisting of adolescents with BPD (n=26) and a group of non-clinical adolescents (n=25). With the aim of directly testing the mentalization-based model of BPD, we additionally investigated the influence of each form of childhood maltreatment within this developmental pathway. Self report data supported the hypothesized indirect effect of childhood maltreatment on elevated borderline pathology through lowered RF in adolescents. Both emotional abuse and emotional neglect were found to indirectly influence borderline pathology through adolescent RF, however, only emotional abuse indirectly influenced borderline pathology through RF, after all other maltreatment types were controlled for. Findings support the promotion of mentalization, within attachment-related contexts, as an intervention target for adolescents with borderline pathology and as a potential target of prevention for at-risk children and adolescents with histories of childhood maltreatment, especially emotional abuse. Future research should delineate other underlying mechanisms, independent of RF, which may also link the influence of childhood maltreatment, and in particular, emotional abuse, to BPD. PMID- 28841477 TI - pH-insusceptible cobalt-manganese immobilizing mesoporous siliceous MCM-41 catalyst for ozonation of dimethyl phthalate. AB - Mesoporous siliceous MCM-41 immobilized with Co and Mn metal ions (Co-Mn-MCM-41) was synthesized using a hydrothermal method. The structural regularity and the valence states of the metal species were measured by X-ray diffractometer and X ray photoelectron spectrometer. The resultant bimetallic Co-Mn-MCM-41 catalyst was tested for the degradation of dimethyl phthalate (DMP) via a catalytic ozonation mechanism, demonstrating that the catalytic properties of Co-Mn-MCM-41 catalyst significantly accelerated the ozonation process. Total organic carbon (TOC) and DMP removal efficiency reached 94% and 99.7% at 15min under the optimal conditions. The oxidation pathways were proposed after identifying the intermediate products from ozonation using a gas chromatography-mass spectrometer. The enhanced catalytic reactivity was attributed to the highly dispersive cobalt and manganese species in MCM-41 scaffolds, which promoted the ozone decomposition and hydroxyl radicals' generation in catalytic ozonation and accelerated the degradation of DMP. Bimetallic Co-Mn-MCM-41 catalyst remained stable in mild acidic conditions and continued to show high activity after repeated runs. PMID- 28841476 TI - Novel functional mesoporous silica nanoparticles loaded with Vitamin E acetate as smart platforms for pH responsive delivery with high bioactivity. AB - Vitamin E (VE) exerts promising antioxidant activities against free radicals. However, its therapeutic efficacy and practical application are greatly restricted as a result of poor solubility, instability and low bioavailability. In this work, novel amino functionalized mesoporous silica nanoparticles (MSNs) were employed as the smart carriers to encapsulate Vitamin E acetate by the combination of soft-template method and recrystallization approach. Typically, two different surfactants were used as organic templates to fabricate different MSNs with various pore size distributions (~4nm and ~25nm). According to the characterization results such as Brunauer-Emmet-Teller (BET), fourier transform infrared spectroscopy (FTIR), transmission electron microscope (TEM), thermal gravity analysis (TGA), differential thermal analysis (DTA), X-ray diffraction (XRD), dynamic light scattering (DLS) and UV-vis diffuse reflectance spectroscopy, the drug delivery systems were successfully fabricated and the loading capacity (LC%) and entrapment efficiency (EE%) were also assessed. In addition, the results revealed that the VE loaded nanoparticles dispersed very well in PBS (pH = 7.4) and released VE in a pH-responsive manner. Importantly, the antioxidant effects of the VE loaded nanoparticles were also investigated by DPPH assays after exposure to air for 48h, showing that VE molecules encapsulated inside the mesoporous channels suffered from less degradation, compared to the pure VE. In vitro cell tests and hemolytic experiments revealed the outstanding biocompatibility and low cytotoxicity. In conclusion, the functionalized mesoporous silica combined with VE might act as potential antioxidant drug formations in clinical application. PMID- 28841478 TI - Effects of chemical and processing variables on paclitaxel-loaded polymer nanoparticles prepared using microfluidics. AB - For paclitaxel (PAX)-loaded polymeric nanoparticles PNPs prepared in a two-phase gas-liquid microfluidic reactor, the effects of microfluidic flow rate on the multiscale structure, loading efficiency and release rate are determined for three different copolymer compositions and two orders of magnitude variation in the PAX loading ratio. All experiments are carried out in the limit of low drug to-polymer loading ratios (r<=0.01, w/w). In this range of r, PCL crystallinity, loading efficiency and release rate are not significantly affected by the amount of PAX dissolved in the core. These results are in sharp contrast to microfluidic PNPs prepared in a range of high loading ratios (r>=0.1), where the amount of added PAX has a strong influence on the multiscale structure and properties of drug delivery PNPs. For the case of r=0.01, we show that flow rate strongly affects PNP morphologies for all three block copolymer compositions. For the shortest and longest PCL block lengths, the relative number of cylindrical morphologies increases and then decreases with increasing flow rate, whereas for the intermediate PCL block length, the number of cylinders steadily increases as the flow rate increases. Internal PCL crystallinities and PAX loading efficiencies show similar trends, both parameters increasing and decreasing with increasing flow rate for the extreme PCL block lengths and steadily increasing for the intermediate PCL block length. PAX release profiles indicate a marked slowing of PAX release as either the PCL block length or the microfluidic flow rate increase. Working in the limit of low loading ratio, this work provides clarity on separating the relative effects of copolymer composition and processing along with perturbations caused by the molecular cargo on the structure and function of drug delivery PNPs. These critical insights thus inform controlled microfluidic preparation of more medically-relevant PNPs at higher therapeutic loading levels. PMID- 28841479 TI - Enhancing the colloidal stability and surface functionality of molybdenum disulfide (MoS2) nanosheets with hyperbranched polyglycerol for photothermal therapy. AB - Molybdenum disulfide (MoS2) nanosheets are gaining increasing attention due to their attractive properties and myriads of potential applications. However, challenges in the enhancement of their colloidal stability and surface functionality still remain and significantly restrict their practical applications. Herein, we present a viable approach to functionalize MoS2 nanosheets with multihydroxy hyperbranched polyglycerol (HPG) shell by surface initiated ring-opening polymerization technique. The grafting of HPG from the surface of MoS2 nanosheet yielded MoS2-g-HPG nanohybrid with excellent water dispersibility, good biocompatibility, and greatly enhanced colloidal stability against pH change, ionic strength variation and long-term storage. The MoS2-g-HPG also exhibited excellent light-to-heat conversion capability for in vitro photothermal therapy application. Meanwhile, the MoS2-g-HPG showed favorable surface functionality owing to its numerous surface hydroxyl groups, as demonstrated by the conjugation of functional molecules such as fluorescent dye rhodamine B. As such, this paper opens up new opportunities to empower MoS2 nanosheets and other two-dimensional inorganic nanosheets with desired properties for various applications. PMID- 28841480 TI - Stabilising nanofluids in saline environments. AB - Nanofluids (i.e. nanoparticles dispersed in a fluid) have tremendous potential in a broad range of applications, including pharmacy, medicine, water treatment, soil decontamination, or oil recovery and CO2 geo-sequestration. In these applications nanofluid stability plays a key role, and typically robust stability is required. However, the fluids in these applications are saline, and no stability data is available for such salt-containing fluids. We thus measured and quantified nanofluid stability for a wide range of nanofluid formulations, as a function of salinity, nanoparticle content and various additives, and we investigated how this stability can be improved. Zeta sizer and dynamic light scattering (DLS) principles were used to investigate zeta potential and particle size distribution of nanoparticle-surfactant formulations. Also scanning electron microscopy was used to examine the physicochemical aspects of the suspension. We found that the salt drastically reduced nanofluid stability (because of the screening effect on the repulsive forces between the nanoparticles), while addition of anionic surfactant improved stability. Cationic surfactants again deteriorated stability. Mechanisms for the different behaviour of the different formulations were identified and are discussed here. We thus conclude that for achieving maximum nanofluid stability, anionic surfactant should be added. PMID- 28841481 TI - A novel array of interface-confined molecules: Assembling natural segments for delivery of multi-functionalities. AB - HYPOTHESIS: Anionic surfactants can form stable monolayers around oil droplets via interactions with macromolecules thereby physically stabilizing high fish oil enriched emulsions (50-70% fish oil) while phenolic acids have antioxidant properties to prevent lipid oxidation. COSMO-RS (Conductor-like Screening Model for Real Solvents) is a powerful tool for the rational design of molecules with multi-functionalities. Therefore, it should be possible to assemble segments of natural molecules into a single multifunctional molecule using COSMO-RS to confer both physical and oxidative stability to fish oil enriched systems. EXPERIMENTS: COSMO-RS was used to predict the thermodynamic properties of series phenoleoyl malic acid esters of monoglycerides in comparison with commercial emulsifiers. A novel series of amphiphilic lipids, equipped with multi-functional groups from natural building blocks (fatty-acyl, glycerol, malic & phenolic acids), were then synthesized in a facile approach and characterized by various spectroscopy techniques. Oil-in-water emulsions stabilized by the amphiphilic lipids were formulated and characterized by dynamic light scattering measurements and fluorescence imaging. FINDINGS: An elaborate integration of multi-functions into a single molecule was achieved, displaying superior or comparable emulsion stability and antioxidant property, compared to a commercial emulsifier, phenolic acids and their combinations. This is the first report to holistically integrate the rational design, synthesis and functional characterization of natural-based multifunctional molecules for high capacity fish oil delivery systems. PMID- 28841482 TI - Oxygen vacancies induced by zirconium doping in bismuth ferrite nanoparticles for enhanced photocatalytic performance. AB - Doping with certain foreign metal ions in a photocatalyst might introduce surface defects (such as extrinsic oxygen vacancies), which can probably play an important role in the photocatalytic performance. In this work, oxygen vacancies were for the first time introduced into bismuth ferrite (BiFeO3, denoted as BFO) nanoparticles by zirconium (Zr) doping, and the relationship between oxygen vacancies and the photocatalytic activity of Zr-doped BFO was investigated. It was found that the optical properties and the photocatalytic activities of Zr doped BFO photocatalysts were significantly affected by the Zr doping amount. The Zr-doped BFO photocatalysts showed much higher photocatalytic activities for methyl orange degradation or Cr(VI) reduction than the pristine BFO. When the Zr doping content was 2mol%, the highest photocatalytic efficiency was achieved, which was more than two times that of the pristine BFO. The boosted photocatalytic performance of Zr-doped BFO was mainly attributed to the presence of surface oxygen vacancies induced by Zr doping, which could act as electron traps and active sites to promote the efficient separation and migration of photogenerated charge carriers, as verified by the trapping experiments and the photoelectrochemical measurements. Thus, the present work provides a simple approach to introduce oxygen vacancies in semiconductor photocatalysts through metal ion doping with a great potential for development of efficient visible light photocatalysts, and also enlarges the understanding of surface-defect dependence of photocatalytic performance for environmental remediation. PMID- 28841483 TI - Major depressive disorder discrimination using vocal acoustic features. AB - BACKGROUND: The voice carries various information produced by vibrations of the vocal cords and the vocal tract. Though many studies have reported a relationship between vocal acoustic features and depression, including mel-frequency cepstrum coefficients (MFCCs) which applied to speech recognition, there have been few studies in which acoustic features allowed discrimination of patients with depressive disorder. Vocal acoustic features as biomarker of depression could make differential diagnosis of patients with depressive state. In order to achieve differential diagnosis of depression, in this preliminary study, we examined whether vocal acoustic features could allow discrimination between depressive patients and healthy controls. METHODS: Subjects were 36 patients who met the criteria for major depressive disorder and 36 healthy controls with no current or past psychiatric disorders. Voices of reading out digits before and after verbal fluency task were recorded. Voices were analyzed using OpenSMILE. The extracted acoustic features, including MFCCs, were used for group comparison and discriminant analysis between patients and controls. RESULTS: The second dimension of MFCC (MFCC 2) was significantly different between groups and allowed the discrimination between patients and controls with a sensitivity of 77.8% and a specificity of 86.1%. The difference in MFCC 2 between the two groups reflected an energy difference of frequency around 2000-3000Hz. CONCLUSIONS: The MFCC 2 was significantly different between depressive patients and controls. This feature could be a useful biomarker to detect major depressive disorder. LIMITATIONS: Sample size was relatively small. Psychotropics could have a confounding effect on voice. PMID- 28841484 TI - Can we recommend mirtazapine and bupropion for patients at risk for bleeding?: A systematic review and meta-analysis. AB - BACKGROUND: Many studies have reported that selective serotonin reuptake inhibitors (SSRI) are associated with an increased risk of bleeding. Mirtazapine and bupropion, which commonly lack serotonin reuptake inhibition, have been recommended as alternatives for patients who are at risk for bleeding. However, the evidence for these recommendations is insufficient. METHODS: We conducted a systematic search, systematic review, and meta-analysis to investigate an evidence-based approach for the bleeding risks of mirtazapine and bupropion. From 1946 to May 2017, a total of 3981 studies were searched from PubMed, Embase, and the Cochrane Library. Among the studies, two independent reviewers selected studies per predefined eligibility criteria. RESULTS: A total of five meta analyses were conducted. Patients taking mirtazapine were at a greater risk of gastrointestinal bleeding (OR = 1.17, 95% CI = 1.01-1.38) than those who did not take antidepressants. No differences were observed in the bleeding risk between mirtazapine and SSRI or between bupropion and SSRI. LIMITATIONS: The number of studies included in the meta-analysis was small. CONCLUSION: Our results suggest that it is premature to recommend mirtazapine and bupropion for patients who have a bleeding risk. More studies with larger sample sizes and longitudinal follow ups are warranted. PMID- 28841485 TI - Exploration of comorbid obsessive-compulsive disorder in patients with bipolar disorder: The clinic-based prevalence rate, symptoms nature and clinical correlates. AB - BACKGROUND: Comorbidity of bipolar disorder (BD) and obsessive-compulsive disorder (OCD) has received clinical attention. However, the detailed nature and nolosogic validity of the comorbidity have not been fully explored. This study investigated the comorbidity rate, clinical nature, and correlates of OCD in patients with BD. METHODS: Patients (n = 314) with BD were recruited and lifetime clinical characteristics were evaluated comprehensively. The comorbid OCD ('OCD BD') group and the 'non-OC BD' group were compared in terms of the clinical variables of BD. RESULTS: OCD was found in 15.9% of patients. Earlier age at onset, more frequent pharmacological (hypo)manic switch and a higher rate of comorbid panic disorder were associated with comorbid OCD. In two-thirds (65.4%) of the OCD-BD subjects, obsessive-compulsive symptoms worsened or were confined to depressive episodes. Contamination obsession and checking compulsion were the most common types of obsessive-compulsive symptoms. Drug-induced (hypo)manic switch was observed in more than 60% of the OCD-BD subjects who were previously exposed to antidepressants. None of the OCD-BD subjects were taking antidepressants for OCD in the current specialty clinics. LIMITATIONS: Subject recruitment from specialty clinics, retrospective and cross-sectional evaluation, and difficulties in clarifying the causal relationships. CONCLUSIONS: The comorbidity rate of OCD in Korean BD patients was comparable to that of Caucasian patients. Even though OCD seems to be more often linked to depressive episodes, a heterogeneous nosologic relationship including a possibility of drug-mediated induction is suggested. PMID- 28841486 TI - The effectiveness of adjunct mindfulness-based intervention in treatment of bipolar disorder: A systematic review and meta-analysis. AB - BACKGROUND: Mindfulness-based interventions (MBIs) have been increasingly used as an adjunctive treatment to pharmacotherapy for a few psychiatric disorders. However, few studies have investigated the efficacy of MBIs in bipolar disorder (BD). METHODS: We performed a systematic review and meta-analysis to evaluate the efficacy of MBIs as an adjunctive treatment in BD. Major electronic databases were independently searched by two authors for controlled and uncontrolled studies which examined the effects of MBIs on psychiatric symptoms in subjects with BD. Data from original studies were synthesized by using a random effects model. RESULTS: Twelve trials were eligible for inclusion into current meta analysis, including three controlled studies (n=132) and nine uncontrolled studies (n=142). In within-group analysis, MBIs significantly reduced depressive (7 studies, n=100, Hedges' g=0.58, p<0.001) and anxiety (4 studies, n=68, Hedges' g=0.34, p=0.043) symptoms, but not manic symptoms (6 studies, n=89, Hedges' g=0.09, p=0.488) and cognition (3 studies, n=43, Hedges' g=0.35, p=0.171), compared to baseline. In between-group analysis (intervention group versus waiting list group, all patients with BD), MBIs did not reduce depressive (3 studies, n=132, Hedges' g=0.46, p=0.315) or anxiety (3 studies, n=132, Hedges' g=0.33, p=0.578) symptoms. LIMITATIONS: Only three controlled trials compared MBIs to control conditions. CONCLUSIONS: Our meta-analysis showed significantly beneficial effects on depressive and anxiety symptoms of BD patients in within group analysis. However, this significance was not observed in comparison with the control groups. Further clinical trials are warranted to investigate the differences in the benefits of MBIs between treatment and control subjects. PMID- 28841487 TI - CSF Apolipoprotein E in attempted suicide. AB - BACKGROUND: Cholesterol and cholesterol metabolism, involved in continued neural plasticity, has been associated to suicide and suicidal behavior. Apolipoprotein E (ApoE) plays an important role in the cholesterol metabolism. The purpose of this study was to investigate whether ApoE in cerebrospinal fluid was related to severity of suicidal behavior as measured by number of earlier suicide attempts, reversibility/interruptabilty and violent method of suicide attempt. METHODS: CSF ApoE and 5-hydroxyindolacetic acid (5-HIAA) were measured in 42 medication free suicide attempters. Earlier suicide attempts and the reversibility of suicide attempt method were assessed with the Suicide Intent Scale (SIS) and the Freeman Scale. Suicide attempts were classified according to violence of method. RESULTS: CSF ApoE levels significantly negatively correlated to the scores on Freeman Reversibility and there was a trend for lower CSF ApoE levels in suicide attempters using a violent method. Patients with at least one earlier suicide attempt (repeaters) showed a trend for higher CSF ApoE levels compared to suicide attempters debuting with suicidal behavior at inclusion in the study. The correlation between CSF ApoE and 5-HIAA was not significant. LIMITATIONS: The main limitations to this study were a relatively small sample size and lack of a healthy control group. CONCLUSION: Irreversible suicide attempts, representing a high risk for completed suicide, may be associated with lower level of ApoE in CSF. PMID- 28841488 TI - Longitudinal relationship between clinical course and neurocognitive impairments in bipolar disorder. AB - BACKGROUND: The aim of this study was to estimate the relationship between clinical course and trajectory of neurocognitive functioning during a follow-up period in a sample of euthymic bipolar patients. METHODS: Fifty-one patients with BD performed two-neurocognitive assessment separated by a period of at least 48 months. The clinical course during the follow-up period was documented by: three measures 1) number of affective episodes, 2) time spent ill, and 3) mood instability. RESULTS: Patients were followed-up for a mean period of 73.21 months. Neurocognitive performance tended to be stable throughout the follow-up. Performance in verbal memory and executive functions at the end of study were related with the number of hypo/manic episodes and time spent with hypo/manic symptoms during the follow-up. None of the clinical measures considered were related to changes in neurocognitive performance over the follow-up period. LIMITATIONS: The relatively small sample size limits the value of subgroup analysis. The study design does not rule out some risk of selection bias. CONCLUSIONS: Although there may be a positive relationship between number of episodes and neurocognitive deficits in patients with bipolar disorder, successive episodes do not seem to modify the trajectory of neurocognitive functioning over time. Theoretical implications of these findings are discussed. PMID- 28841489 TI - The illusion of handy wins: Problem gambling, chasing, and affective decision making. AB - BACKGROUND: Chasing losses is a behavioral marker and a diagnostic criterion for gambling disorder. It consists in continuing gambling to recoup previous losses. Although chasing has been recognized playing a central role in gambling disorder, research on this topic is relatively scarce, and it remains unclear whether chasing affects decision-making in behavioral tasks in which participants gain or loss some money. Even if several studies found that the more the gambling involvement, the poorer the decision-making, to date no research investigated the role of chasing in decision-making. METHODS: The study aimed to first investigate the relation between chasing and decision-making in adult gamblers. One hundred and four VLT players were administered the South Oaks Gambling Screen (SOGS), a computerized task measuring chasing, and the Iowa Gambling Task (IGT). RESULTS: Correlation analysis showed that the higher the SOGS scores, the higher the propensity to chase, and the poorer the decision-making performance. Regression analysis revealed that chasing propensity and gambling severity predicted IGT performance. Mediation analysis indicated that the association between gambling severity and poor decision-making is mediated by chasing. LIMITATIONS: Gambling severity was assessed by means of a self-report measure. The generalizability of findings is limited, since the study focused only on VLT players. CONCLUSIONS: This study provides the first evidence that chasing, along with gambling severity, affects decision-making, at least in behavioral tasks involving money. Since chasers and non-chasers could be two different sub-types of gamblers, treatment protocols should take into account the additive role of chasing in gambling disorder. PMID- 28841490 TI - Major depression and secondhand smoke exposure. AB - BACKGROUND: Epidemiological studies have consistently linked smoking to poor mental health. Among non-smokers, some studies have also reported associations between secondhand smoke exposure and psychological symptoms. However, an association between secondhand smoke exposure and depressive disorders has not been well established. METHODS: This analysis used cross-sectional data from a series of 10 population surveys conducted in Canada between 2003 and 2013. The surveys targeted the Canadian household population, included a brief structured interview for past year major depressive episode (MDE) and included items assessing secondhand smoke exposure. We used two-stage individual-level random effects meta-regression to synthesize results from these surveys. RESULTS: Over the study interval, about 20% of non-smokers reported substantial exposure to secondhand smoke. In this group, the pooled annual prevalence of MDE was 6.1% (95% CI 5.3-6.9) compared to 4.0% (95% CI 3.7-4.3) in non-smokers without secondhand smoke exposure. The crude odds ratio was 1.5 (95% CI 1.4-1.7). With adjustment for a set of potential confounding variables the odds ratio was unchanged, 1.4 (95% CI 1.2 - 1.6). CONCLUSIONS: These results provide additional support for public health measures aimed at reducing secondhand smoke exposure. A causal connection between secondhand smoke exposure and MDEs cannot be confirmed due to the cross-sectional nature of the data. Longitudinal studies are needed to establish temporal sequencing. PMID- 28841491 TI - Video game addiction in emerging adulthood: Cross-sectional evidence of pathology in video game addicts as compared to matched healthy controls. AB - BACKGROUND: The Internet Gaming Disorder Scale (IGDS) is a widely used measure of video game addiction, a pathology affecting a small percentage of all people who play video games. Emerging adult males are significantly more likely to be video game addicts. Few researchers have examined how people who qualify as video game addicts based on the IGDS compared to matched controls based on age, gender, race, and marital status. METHOD: The current study compared IGDS video game addicts to matched non-addicts in terms of their mental, physical, social emotional health using self-report, survey methods. RESULTS: Addicts had poorer mental health and cognitive functioning including poorer impulse control and ADHD symptoms compared to controls. Additionally, addicts displayed increased emotional difficulties including increased depression and anxiety, felt more socially isolated, and were more likely to display internet pornography pathological use symptoms. Female video game addicts were at unique risk for negative outcomes. LIMITATIONS: The sample for this study was undergraduate college students and self-report measures were used. CONCLUSIONS: Participants who met the IGDS criteria for video game addiction displayed poorer emotional, physical, mental, and social health, adding to the growing evidence that video game addictions are a valid phenomenon. PMID- 28841492 TI - Neurocognitive impairment and suicide risk among prison inmates. AB - BACKGROUND: Worldwide, prisoners are at high risk of suicide. Reducing the number of suicides in jails and prisons is an international priority. Several risk factors for suicide attempts, such as historical, prison-related, psychosocial and clinical factors, have been found in prisoners. We assessed whether demographic, conviction-related and neuro-behavioral variables might be associated with current suicide risk and lifetime suicide attempts in two large central Italy prisons. METHODS: On a preliminary sample of 254 detainees within an ongoing project, we assessed whether demographic, conviction-related, psychiatric, cognitive variables and illness comorbidity might be associated with current suicide risk and lifetime suicide attempts in two large central Italy prisons. Psychiatric disorders and suicide risk was evaluated using the Mini International Neuropsychiatric Interview. We also have identified the detainees with clear-cut previous suicide attempts. The cognitive function was assessed with a brief neuropsychological battery including trail making A, trail making B, Digit Span, and Symbol Digit test. Impulsivity was assessed with the Barratt Impulsiveness Scale. Cumulative illness was evaluated with Charlson Comorbidity Index. RESULTS: Impairment in global cognitive function was the strongest predictor of both high suicide risk and lifetime suicide attempts (both p < 0.001), independently of psychiatric disorders, psychopharmacological treatment, detention status, conviction time, substance use disorder, impulsivity, and illness comorbidity. Limitation LIMITATION: Cross-sectional study design and relatively small sample size. CONCLUSION: Cognitive deficits may improve our understanding of the suicidal vulnerability and should be systematically included in the assessment of suicide risk, as potential predictors of suicidal acts and targets of preventive interventions. PMID- 28841493 TI - Transcranial magnetic stimulation for treating older patients with treatment resistant depression. PMID- 28841494 TI - Zebrafish sex differentiation and gonad development: A review on the impact of environmental factors. AB - Zebrafish (Danio rerio) is extensively used in research; however the mechanisms that control this species sex determination are still poorly understood. In the latest decades, it has been established that zebrafish sex is determined by genetic factors on a polygenic basis, as various candidate genes with sex dimorphic expression, as well sex-linked loci have been identified in different zebrafish strains. However, it has been evidenced that sex determination in this species is also influenced by environmental factors. For instance, temperature can have a crucial role in zebrafish sex determination. Likewise, the exposure to endocrine disrupting chemicals (EDCs), the most studied zebrafish sex changing factor, can strongly influence the course of sex differentiation and unbalance the sex ratio of zebrafish populations. Despite this, so far the influence of environmental factors is still less understood and only few studies have addressed this topic. Therefore, this review intends to gather current knowledge on the environmental factors involved in sex determination of zebrafish and identify important gaps in this research area. Briefly, the current understanding on zebrafish sex related genetics is also addressed. PMID- 28841496 TI - Needles in the haystack: Using open-text fields to identify persons with intellectual and developmental disabilities in administrative home care data. AB - BACKGROUND: Use of administrative health data to study populations of interest is becoming more common. Identifying individuals with intellectual and developmental disabilities (IDD) in existing databases can be challenging due to inconsistent definitions and terminologies of IDD over time and across sectors, and the inability to rely on etiologies of IDD as they are frequently unknown. AIMS: To identify diagnoses related to IDD in an administrative database and create a cohort of persons with IDD. METHODS: Open-text diagnostic entries related to IDD were identified in an Ontario home care database (2003-2015) and coded as being either acceptable (e.g. Down syndrome) or ambiguous (e.g. intellectually challenged). The cognitive and functional skills of the resulting groups were compared using logistic regressions and standardized differences, and their age distributions were compared to that of the general home care population. RESULTS: Just under 1% of the home care population had a diagnostic entry related to IDD. Ambiguous terms were most commonly used (61%), and this group tended to be older and less impaired than the group with more acceptable terms used to describe their IDD. CONCLUSIONS: Open-text diagnostic variables in administrative health records can be used to identify and study individuals with IDD. IMPLICATIONS: Future work is needed to educate assessors on the importance of using standard, accepted terminology when recording diagnoses related to IDD. PMID- 28841495 TI - Adverse childhood experience effects on opioid use initiation, injection drug use, and overdose among persons with opioid use disorder. AB - INTRODUCTION: Adverse childhood experiences are associated with the development of substance use disorders. With opioid use disorder, a growing concern in the United States, we were interested in examining the relationship between adverse experiences and three landmarks of opioid use: age of opioid initiation, injection drug use, and lifetime overdose. METHODS: Between May and December 2015, we interviewed consecutive persons seeking inpatient opioid detoxification. Participants were asked about age of opioid initiation, last month injection drug use, and lifetime history of overdose, and completed the ten-item Adverse Childhood Experience (ACE) questionnaire. RESULTS: Participants (n=457) averaged 32.2 (+/-8.64) years of age, 71.3% were male, and 82.5% were non-Hispanic White. The mean score on the ACE scale was 3.64 (+/-2.75). Mean age at time of initiating opioid use was 21.7 (+/-7.1) years, 68.7% had injected drugs within the past month, and 39.0% had overdosed. After adjusting for age, gender, and ethnicity, the ACE score was inversely associated with age of initiating opioid use (b=-0.50, 95% CI -0.70; -0.29, p<.001), and positively associated with recent injection drug use (OR=1.11, 95% CI 1.02; 1.20, p=0.014) and the likelihood of experiencing an overdose (OR=1.10, 95% CI 1.02; 1.20, p=0.015) in a graded dose response manner. CONCLUSION: Greater adverse childhood experiences are associated with three landmarks of opioid use risk. ACE screening may be useful in identifying high-risk subsets of opioid-using populations. PMID- 28841497 TI - Injectable hydrogels for treatment of osteoarthritis - A rheological study. AB - Osteoarthritis (OA) is a disabling condition especially in the elderly population. The current therapeutic approaches do not halt the OA progression or reverse joint damage. In order to overcome the problem of rapid clearance of hyaluronic acid (HA), a standard viscosupplement for OA, we investigated the rheological properties of a relatively non-degradable dendritic polyglycerol sulfate (dPGS) hydrogel to determine a suitable concentration for intra articular injections that mimics HA in terms of its viscoelastic and mechanical properties. To do so, the concentration range from 3.6 to 4.8wt% of dPGS and, as a reference, blends of commercially available HAs (Ostenil(r), GO-ON(r), Synocrom(r) Forte and Synvisc(r)), were investigated by means of oscillating and flow rheology, thereby yielding storage (G') and loss modulus (G"), as well as yield stress and shear viscosity. In our rheological experiments we observe a pronounced coupling of the molecular weight and the rheological properties for the HAs. Furthermore, we find the dPGS hydrogel to form more compact networks with increasing concentration. From a broader comparison the current findings suggest that an overall polymer concentration of 4.0wt% dPGS has viscoelastic properties that are comparable to hyaluronic acid in the medically relevant frequency range, where for medical application the dPGS hydrogel has the advantage of being much less easily displaced from its injection place than HA. PMID- 28841498 TI - Highly cell-penetrating and ultra-pH-responsive nanoplatform for controlled drug release and enhanced tumor therapy. AB - A stimuli-triggered drug release strategy could considerably reduce side effects while improving the bioavailability of chemotherapeutics. Here, we report that a series of ultra-pH-responsive copolymers are highly efficient drug delivery systems for near-infrared (NIR) imaging and controlled drug release. These polymers self-assemble into nano-sized micelles due to their amphipathic structure and deliver hydrophobic drugs (maximum drug loading rate ~10wt%) into tumor cells via a controlled and pH-triggered modality. By altering the proportion of hydrophilic and hydrophobic chains, the drug loading rate and the in vitro drug release efficiency can be regulated. Moreover, the drug-loaded micelles with optimized compositions exhibited excellent antitumor efficacy in HeLa and MCF-7 cells, while the blank micelles had minimal cytotoxicity. Cellular uptake experiments further indicated that the ultra-pH-responsive micelles could be rapidly internalized in the tumor cells. This study demonstrated the strong potential of the ultra-pH-responsive platform as a universal carrier for the delivery of anticancer drugs to maximize their therapeutic effect. PMID- 28841499 TI - Si-doped porous TiO2 coatings enhanced in vitro angiogenic behavior of human umbilical vein endothelial cells. AB - Recent evidence demonstrates that vessel involvement is crucial in various bone remodeling situations, indicating that blood vessel formation within or surrounding the implant is essential for establishment of rigid implant fixation. In this work, the ability of the silicon-doped porous TiO2 coatings fabricated via plasma electrolyte oxidation method (PEO) to enhance the angiogenic potential of human umbilical vein endothelial cells (HUVECs) were investigated. The cellular responses of HUVECs on the silicon-doped porous TiO2 coatings were studied through cell proliferation, vascular endothelial growth factor (VEGF) secretion, and angiogenic-associated gene (VEGF, HIF-1alpha and HGF) expression analysis. The results show that small amount of silicon significantly enhanced angiogenic activity of HUVECs, while larger amount of silicon appears excessive. Hence, the silicon-doped TiO2 coating offers a potential solution to improve bone vascularization to achieve efficient osseointegration and restoration of function after implantation. PMID- 28841500 TI - Reduced arsenic accumulation in indica rice (Oryza sativa L.) cultivar with ferromanganese oxide impregnated biochar composites amendments. AB - The effects of biochar (BC) and ferromanganese oxide biochar composites (FMBC1 and FMBC2) on As (Arsenic) accumulation in rice were determined using a pot experiment. Treatments with BC or FMBC improved the dry weights of rice roots, stems, leaves, and grains in soils containing different As contamination levels. Compared to BC treatment, FMBC treatments significantly reduced As accumulation in different parts of the rice plants (P < 0.05), and FMBC2 performed better than FMBC1 did. Furthermore, exposure to 2% FMBC2 decreased the total As concentration in the grain by 68.9-78.3%. The addition of FMBC increased the ratio of essential amino acids in the grain, decreased As availability in the soil, and significantly increased the Fe and Mn plaque contents. The reduced As accumulation in rice can be attributed to As(III) to As(V) oxidation by ferro - manganese binary oxide, which increased the As adsorbed by FMBC. Furthermore, Fe and Mn plaques on the rice root surface decreased the transport of As in rice. Taken together, our results demonstrated the applicability of FMBC as a potential measure for reducing As accumulation in rice, improving the amino acid content of rice grains, and effectively remediating As-polluted soil. PMID- 28841501 TI - Analysis of polycyclic aromatic hydrocarbons (PAHs) in air using passive sampling calibrated with active measurements. AB - There are limited ambient air measurements of extended (beyond EPA Priority 16) lists of polycyclic aromatic hydrocarbons (PAHs). We measured air concentrations of 45 PAHs using passive and active air sampling at 15 sites in a central urban community and one rural site for two years. Passive sampling was conducted with cylindrical XAD-based samplers deployed to capture spatial variability. High volume active samplers with quartz fiber filters for particles and XAD-4 absorbent for gases were deployed at two urban sites and the rural site to calibrate the passive measurements directly. Estimated passive sampling rates (PSRs) were evaluated as functions of meteorological data, seasons, locations, study year, and compared with other studies. Possible particle collection by the passive samplers was evaluated using a variety of particle measurements (TSP, PM10, PM2.5 and ultrafines <100 nm). Total PAHs were statistically associated with ultrafine particle concentrations and to a lesser extent PM2.5 and PM10, but not TSP. PSRs were more variable when PAH mass loadings were lower and near method detection limits; this occurred more often at the rural site. The PSRs were not statistically associated with meteorological conditions in this study, but wind speed had the highest potential to impact PSR results. The resulting passive PAH measurements are reported with respect to proximity to major roadways and other known air emissions types. PSRs were quantifiable for some PAHs that were found predominantly in the particulate phase in active sampling. This information, together with particle fraction calculations from active sampling, were used to estimate the particulate PAH capture of the passive sampler. Summed PAH (?PAH) passive concentrations were measured within the range of 10-265 ng/m3, with the highest concentrations from naphthalene and the lowest detected concentrations from anthracene. These results indicated a stronger seasonal signal within 200 m of a major roadway. PMID- 28841502 TI - Wintertime pollution level, size distribution and personal daily exposure to particulate matters in the northern and southern rural Chinese homes and variation in different household fuels. AB - This study investigated and compared wintertime air pollution and personal exposure in the rural northern and southern Chinese homes. Daily indoor and outdoor particle samples were simultaneously collected by using stationary samplers, and personal exposure was directly measured using portable carried samplers. The daily average concentrations of indoor and outdoor PM2.5 were 521 +/- 234 and 365 +/- 185 MUg/m3 in the northern village, that were about 2.3-2.7 times of 188 +/- 104 and 150 +/- 29 MUg/m3 in indoor and outdoor air in the southern villages. Particle size distribution was similar between indoor and outdoor air, and had relatively smaller difference between the two sites, relative to the particle mass concentration difference. PM2.5 contributed to ~80% of the TSP mass, and in PM2.5, near 90% were PM1.0. In homes using electricity in the southern villages, outdoor air pollution could explain 70-80% of the variation in indoor air pollution. The daily exposure to PM2.5 measured using personal carried samplers were 451 +/- 301 MUg/m3 in the northern villages with traditional solid fuels used for daily cooking and heating, and in the southern villages without heating, the exposure to PM2.5 were 184 +/- 83 and 166 +/- 45 MUg/m3, respectively, for the population using wood and electricity for daily cooking. Time-weighted daily average exposure estimated from area concentration and time spent indoor and outdoor was generally correlated the directly measured exposure. PMID- 28841503 TI - Biodegradation of polycyclic aromatic hydrocarbons: Using microbial bioelectrochemical systems to overcome an impasse. AB - Polycyclic aromatic hydrocarbons (PAHs) are hardly biodegradable carcinogenic organic compounds. Bioremediation is a commonly used method for treating PAH contaminated environments such as soils, sediment, water bodies and wastewater. However, bioremediation has various drawbacks including the low abundance, diversity and activity of indigenous hydrocarbon degrading bacteria, their slow growth rates and especially a limited bioavailability of PAHs in the aqueous phase. Addition of nutrients, electron acceptors or co-substrates to enhance indigenous microbial activity is costly and added chemicals often diffuse away from the target compound, thus pointing out an impasse for the bioremediation of PAHs. A promising solution is the adoption of bioelectrochemical systems. They guarantee a permanent electron supply and withdrawal for microorganisms, thereby circumventing the traditional shortcomings of bioremediation. These systems combine biological treatment with electrochemical oxidation/reduction by supplying an anode and a cathode that serve as an electron exchange facility for the biocatalyst. Here, recent achievements in polycyclic aromatic hydrocarbon removal using bioelectrochemical systems have been reviewed. This also concerns PAH precursors: total petroleum hydrocarbons and diesel. Removal performances of PAH biodegradation in bioelectrochemical systems are discussed, focussing on configurational parameters such as anode and cathode designs as well as environmental parameters like porosity, salinity, adsorption and conductivity of soil and sediment that affect PAH biodegradation in BESs. The still scarcely available information on microbiological aspects of bioelectrochemical PAH removal is summarised here. This comprehensive review offers a better understanding of the parameters that affect the removal of PAHs within bioelectrochemical systems. In addition, future experimental setups are proposed in order to study syntrophic relationships between PAH degraders and exoelectrogens. This synopsis can help as guide for researchers in their choices for future experimental designs aiming at increasing the power densities and PAH biodegradation rates using microbial bioelectrochemistry. PMID- 28841504 TI - Combined acid rain and lanthanum pollution and its potential ecological risk for nitrogen assimilation in soybean seedling roots. AB - Rare earth elements (REEs) are used in various fields, resulting in their accumulation in the environment. This accumulation has affected the survival and distribution of crops in various ways. Acid rain is a serious global environmental problem. The combined effects on crops from these two types of pollution have been reported, but the effects on crop root nitrogen assimilation are rarely known. To explore the impact of combined contamination from these two pollutants on crop nitrogen assimilation, the soybean seedlings were treated with simulated environmental pollution from acid rain and a representative rare earth ion, lanthanum ion (La3+), then the indexes related to plant nitrogen assimilation process in roots were determined. The results showed that combined treatment with pH 4.5 acid rain and 0.08 mM La3+ promoted nitrogen assimilation synergistically, while the other combined treatments all showed inhibitory effects. Moreover, acid rain aggravated the inhibitory effect of 1.20 or 0.40 mM La3+ on nitrogen assimilation in soybean seedling roots. Thus, the effects of acid rain and La3+ on crops depended on the combination levels of acid rain intensity and La3+ concentration. Acid rain increases the bioavailability of La3+, and the combined effects of these two pollutants were more serious than that of either pollutant alone. These results provide new evidence in favor of limiting overuse of REEs in agriculture. This work also provides a new framework for ecological risk assessment of combined acid rain and REEs pollution on soybean crops. PMID- 28841505 TI - Emergency department visits of young children and long-term exposure to neighbourhood smoke from household heating - The Growing Up in New Zealand child cohort study. AB - In developed countries, exposure to wood or coal smoke occurs predominantly from neighbourhood emissions arising from household heating. The effect of this exposure on child health is not well characterized. Within a birth cohort study in New Zealand we assessed healthcare events associated with exposure to neighbourhood smoke from household heating. Our outcome measure was non accidental presentations to hospital emergency departments (ED) before age three years. We matched small area-level census information with the geocoded home locations to measure the density of household heating with wood or coal in the neighbourhood and applied a time-weighted average exposure method to account for residential mobility. We then used hierarchical multiple logistic regression to assess the independence of associations of this exposure with ED presentations adjusted for gender, ethnicity, birth weight, breastfeeding, immunizations, number of co-habiting smokers, wood or coal heating at home, bedroom mold, household- and area-level deprivation and rurality. The adjusted odds ratio of having a non-accidental ED visit was 1.07 [95%CI: 1.03-1.12] per wood or coal heating household per hectare. We found a linear dose-response relationship (p value for trend = 0.024) between the quartiles of exposure (1st as reference) and the same outcome (odds ratio in 2nd to 4th quartiles: 1.14 [0.95-1.37], 1.28 [1.06-1.54], 1.32 [1.09-1.60]). Exposure to neighbourhoods with higher density of wood or coal smoke-producing households is associated with an increased odds of ED visits during early childhood. Policies that reduce smoke pollution from domestic heating by as little as one household per hectare using solid fuel burners could improve child health. PMID- 28841506 TI - Parkinsonian rest tremor can be detected accurately based on neuronal oscillations recorded from the subthalamic nucleus. AB - OBJECTIVE: To investigate the possibility of tremor detection based on deep brain activity. METHODS: We re-analyzed recordings of local field potentials (LFPs) from the subthalamic nucleus in 10 PD patients (12 body sides) with spontaneously fluctuating rest tremor. Power in several frequency bands was estimated and used as input to Hidden Markov Models (HMMs) which classified short data segments as either tremor-free rest or rest tremor. HMMs were compared to direct threshold application to individual power features. RESULTS: Applying a threshold directly to band-limited power was insufficient for tremor detection (mean area under the curve [AUC] of receiver operating characteristic: 0.64, STD: 0.19). Multi-feature HMMs, in contrast, allowed for accurate detection (mean AUC: 0.82, STD: 0.15), using four power features obtained from a single contact pair. Within-patient training yielded better accuracy than across-patient training (0.84vs. 0.78, p=0.03), yet tremor could often be detected accurately with either approach. High frequency oscillations (>200Hz) were the best performing individual feature. CONCLUSIONS: LFP-based markers of tremor are robust enough to allow for accurate tremor detection in short data segments, provided that appropriate statistical models are used. SIGNIFICANCE: LFP-based markers of tremor could be useful control signals for closed-loop deep brain stimulation. PMID- 28841507 TI - Copy-move forgery detection through stationary wavelets and local binary pattern variance for forensic analysis in digital images. AB - The most common image tampering often for malicious purposes is to copy a region of the same image and paste to hide some other region. As both regions usually have same texture properties, therefore, this artifact is invisible for the viewers, and credibility of the image becomes questionable in proof centered applications. Hence, means are required to validate the integrity of the image and identify the tampered regions. Therefore, this study presents an efficient way of copy-move forgery detection (CMFD) through local binary pattern variance (LBPV) over the low approximation components of the stationary wavelets. CMFD technique presented in this paper is applied over the circular regions to address the possible post processing operations in a better way. The proposed technique is evaluated on CoMoFoD and Kodak lossless true color image (KLTCI) datasets in the presence of translation, flipping, blurring, rotation, scaling, color reduction, brightness change and multiple forged regions in an image. The evaluation reveals the prominence of the proposed technique compared to state of the arts. Consequently, the proposed technique can reliably be applied to detect the modified regions and the benefits can be obtained in journalism, law enforcement, judiciary, and other proof critical domains. PMID- 28841508 TI - Adding motor control training to muscle strengthening did not substantially improve the effects on clinical or kinematic outcomes in women with patellofemoral pain: A randomised controlled trial. AB - DESIGN: Randomized controlled trial. BACKGROUND: Patients with Patellofemoral pain (PFP) usually present muscular weakness, pain and impaired motor control. Muscle strengthening is an effective treatment strategy for PFP, but the additional benefits of movement control training remain unknown. Therefore, the aim of this study was to compare the effects of movement control training associated with muscle strengthening, with a conventional program of strengthening alone in women with PFP. METHODS: Thirty-four women were randomly assigned to two groups. The Strengthening group (S group) performed 12 sessions to strengthen the knee and hip muscles. The Movement Control & Strengthening group (MC&S group) performed the same exercises and movement control training of the trunk and lower limbs. Effects of the treatment (i.e., between-group differences) were calculated using linear mixed models. Primary outcomes were function and pain intensity after completion of the treatment protocol. Secondary outcomes were; muscle strength and kinematic outcomes during the step down task after 4 weeks of treatment; and function and pain intensity 3 and 6 months after randomization. RESULTS: The MC&S group did not present significantly better function (MD -2.5 points, 95% CI;-10.7-5.5) or pain (MD -0.3 points, 95% CI;-1.7 1.0) at 4 weeks. There was a small difference in favour of the MC&S group for AKPS scores at 3 months (MD -8.5 points; 95% CI;-16.8 to -0.3). No significant between-group differences were observed for the other outcomes. CONCLUSION: Movement control training was no more effective than the isolated strengthening protocol, in terms of pain, function, muscle strength, or kinematics. PMID- 28841510 TI - The psychometric properties of the Life History of Aggression evaluated in patients from a psychiatric emergency setting. AB - Aggression is a major concern in psychiatric units even more so in emergency settings and is prevalent across many mental disorders. Since a prior history of aggression remains a crucial predictor of violence in hospitalized patients, appropriate tools assessing the history of violence are essential to implement management plans. The Life History of Aggression (LHA) is a widely-utilized instrument. Yet, its psychometric properties have not been thoroughly evaluated and it has neither been validated in a variety of psychiatric illnesses nor in psychiatric emergency settings. To fill this gap, the properties of a French version of the LHA administered to 1097 psychiatric patients in this setting were examined. The internal consistency, construct validity, test-retest reliability and convergent validity were analysed. Regarding the internal consistency, the Cronbach's alpha varied between 0.83 and 0.89. The confirmatory factor analysis showed that it had one underlying factor, though gender invariance was not observed. Amid 148 patients reassessed within 30 days, the test-retest reliability produced a strong correlation coefficient above 0.80. Lastly, as for convergent validity, the scale was significantly correlated with a validated drug misuse scale. Hence, the LHA retains very good psychometric properties even when evaluated in a psychiatric emergency setting, justifying its clinical pertinence. PMID- 28841511 TI - Psychometric properties of three measures assessing advanced theory of mind: Evidence from people with schizophrenia. AB - Patients with schizophrenia tend to have deficits in advanced Theory of Mind (ToM). The "Reading the mind in the eyes" test (RMET), the Faux Pas Task, and the Strange Stories are commonly used for assessing advanced ToM. However, most of the psychometric properties of these 3 measures in patients with schizophrenia are unknown. The aims of this study were to validate the psychometric properties of the 3 advanced ToM measures in patients with schizophrenia, including: (1) test-retest reliability; (2) random measurement error; (3) practice effect; (4) concurrent validity; and (5) ecological validity. We recruited 53 patients with schizophrenia, who completed the 3 measures twice, 4 weeks apart. The Revised Social Functioning Scale-Taiwan short version (R-SFST) was completed within 3 days of first session of assessments. We found that the intraclass correlation coefficients of the RMET, Strange Stories, and Faux Pas Task were 0.24, 0.5, and 0.76. All 3 advanced ToM measures had large random measurement error, trivial to small practice effects, poor concurrent validity, and low ecological validity. We recommend that the scores of the 3 advanced ToM measures be interpreted with caution because these measures may not provide reliable and valid results on patients' advanced ToM abilities. PMID- 28841509 TI - Exploring online communication about cigarette smoking among Twitter users who self-identify as having schizophrenia. AB - Novel approaches are needed to address elevated tobacco use among people with schizophrenia. This exploratory study examined the frequency, timing, and type of communication about tobacco-related content on Twitter among users who self identify as having schizophrenia compared with users from the general population. Over a 200-day period from January to July 2016, Twitter users who self-identify as having a schizophrenia spectrum disorder (n = 203) and a randomly selected group of general population control users (n = 173) posted 1,544,122 tweets. Communication frequency did not differ between groups. Tweets containing tobacco related keywords were extracted. Twitter users with schizophrenia posted significantly more tweets containing any tobacco-related terms (mean = 3.74; SD = 16.3) compared with control users (mean = 0.82; SD = 1.8). A significantly greater proportion of Twitter users with schizophrenia (45%; n = 92) posted tweets containing any tobacco terms compared with control users (30%; n = 52). Schizophrenia users showed significantly greater odds of tweeting about tobacco compared with control users (OR = 1.99; 95% CI 1.29-3.07). These findings suggest that online communication about tobacco may parallel real world trends of elevated tobacco use observed among people with schizophrenia. By showing that Twitter users who self-identify as having schizophrenia discuss tobacco-related content online, popular social media could inform smoking cessation efforts targeting this at-risk group. PMID- 28841512 TI - Variation in global DNA hydroxymethylation with age associated with schizophrenia. AB - To improve understanding of DNA hydroxymethylation (5hmC) and methylation (5mC) in the development of schizophrenia, this study examined global 5hmC and 5mC levels in peripheral blood DNA of 264 patients with schizophrenia and 221 controls and observed increased 5mC levels in the patients and increased 5hmC levels in male patients but decreased levels in female patients as compared with the controls. The 5mC level displayed a gender-dependent positive correlation with age and the 5hmC level displayed a correlation with age positively in controls but negatively in patients, and their role in the pathogenesis of schizophrenia remains to be elucidated. PMID- 28841513 TI - Synthesis and biological investigation of 2,4-substituted quinazolines as highly potent inhibitors of breast cancer resistance protein (ABCG2). AB - Expression of ABCG2, a member of the ABC transporter superfamily, has been correlated to the clinical outcome of multiple cancers and is often associated with the occurrence of multidrug resistance (MDR) in chemotherapy. Inhibition of the transport protein by potent and selective inhibitors might be a way to treat cancer more efficiently and improve the therapy of cancer patients. Recently we reported the synthesis of new inhibitors based on a quinazoline scaffold. In the present study more structural variations were explored. Compounds with 3,4 dimethoxy groups and meta or para nitro substituents were found to be highly potent inhibitors of ABCG2. The most potent compound was more than five-fold more potent than Ko143, one of the best inhibitors of ABCG2. To determine the new compounds selectivity toward ABCG2 their inhibitory effects on ABCB1 and ABCC1 were also investigated identifying selective as well as broadspectrum inhibitors. Furthermore, intrinsic cytotoxicity and efficacy regarding the reversal of multidrug resistance toward SN-38 and mitoxantrone were explored. The most potent compounds were able to reverse the resistance toward the cytostatic agents with EC50 values below 20 nM. Additionally, the type of interaction between inhibitors and the ABCG2 substrate Hoechst 33342 was investigated yielding competitive and non-competitive interactions suggesting different modes of binding. Finally the effect of the derivatives on vanadate-sensitive ATPase activity of ABCG2 was determined. According to the different effects on ATPase activity we conclude the existence of different binding sites. This study provides the structural requirements for high potency inhibition and elucidates the interaction with ABCG2 setting the basis for further studies. PMID- 28841515 TI - Comparison of phthalic acid removal from aqueous solution by electrochemical methods: Optimization, kinetic and sludge study. AB - In this work, comparative study between electrochemical processes such as electrocoagulation (EC), peroxi-coagulation (PC) and peroxi-electrocoagulation (PEC) was performed for the removal of phthalic acid (PA) and chemical oxygen demand (COD) from aqueous medium. Initially, acid treatment was studied at various pH (1-3) and temperature (10-55 degrees C). Subsequently, the supernatant was re-treated by electrochemical processes such as EC, PC and PEC separately. Independent parameters viz. pH, current density (CD), electrolyte concentration (m), electrode gap (g), H2O2 concentration and electrolysis time (t) were optimized by Central Composite Design (CCD) for these electrochemical processes. All three processes were compared based on removal, energy consumption, kinetic analysis, operating cost and sludge characteristics. In this study, PEC process was found more efficient among EC, PC and PEC processes in order to get maximum removal, minimum energy consumption and minimum operating cost. Maximum removal of PA- 68.21%, 74.36%, 82.25% & COD- 64.79%, 68.15%, 75.21% with energy consumption - 120.95, 97.51, 65.68 (kWh/kg COD removed) were attained through EC, PC and PEC processes respectively at their corresponding optimum conditions. Results indicated that PA and COD removals are in order of PEC > PC > EC under optimum conditions. First order kinetic model was found able to describe the degradation kinetics and provided best correlation for the removal rate within the acceptable error range. PMID- 28841514 TI - A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer's disease. AB - Over 44 million people live with Alzheimer's disease (AD) worldwide. Currently, only symptomatic treatments are available for AD and no cure exists. Considering the lack of effective treatments for AD due to its multi-factorial pathology, development of novel multi-target-directed drugs are desirable. Herein, we report the development of a novel series of thiosemicarbazones derived from 1 benzylpiperidine, a pharmacophore within the acetylcholinesterase inhibitor, Donepezil. These thiosemicarbazones were designed to target five major AD hallmarks, including: low acetylcholine levels, dysfunctional autophagy, metal dys-homeostasis, protein aggregation and oxidative stress. Of these thiosemicarbazones, pyridoxal 4-N-(1-benzylpiperidin-4-yl)thiosemicarbazone (PBPT) emerged as the lead compound. This agent demonstrated the most promising multi-functional activity by exhibiting very low anti-proliferative activity, substantial iron chelation efficacy, inhibition of copper-mediated amyloid-beta aggregation, inhibition of oxidative stress, moderate acetylcholinesterase inhibitory activity and autophagic induction. These diverse properties highlight the potential of the lead ligand, PBPT, as a promising multi-functional agent for AD treatment. PMID- 28841516 TI - From which soil metal fractions Fe, Mn, Zn and Cu are taken up by olive trees (Olea europaea L., cv. 'Chondrolia Chalkidikis') in organic groves? AB - Organic farming has been proposed as an alternative agricultural system to help solve environmental problems, like the sustainable management of soil micronutrients, without inputs of chemical fertilizers. The purposes of this study were: i) to assess Fe, Mn, Zn and Cu bioavailability through the determination of sequentially extracted chemical forms (fractions) and their correlation with foliar micronutrient concentrations in mature organic olive (cv. 'Chondrolia Chalkidikis') groves; ii) to determine the soil depth and the available forms (fractions) by which the 4 metals are taken up by olive trees. DTPA extractable (from the soil layers 0-20, 20-40 and 40-60 cm) and foliar micronutrient concentrations were determined in two organic olive groves. Using the Tessier fractionation, five fractions, for all the metals, were found: exchangeable, bound to carbonates (acid-soluble), bound to Fe-Mn oxides (reducible), organic (oxidizable), as well as residual form. Our results indicated that Fe was taken up by the olive trees as organic complex, mainly from the soil layer 40-60 cm. Manganese was taken up from the exchangeable fraction (0 20 cm); Zinc was taken up as organic complex from the layers 0-20 and 40-60 cm, as well as in the exchangeable form from the upper 20 cm. Copper was taken up from the soil layers 0-20 and 40-60 cm as soluble organic complex, and as exchangeable ion from the upper 20 cm. Our data reveal the crucial role of organic matter to sustain metal (Fe, Zn and Cu) uptake -as soluble complexes-by olive trees, in mature organic groves grown on calcareous soils; it is also expected that these data will constitute a thorough insight and useful tool towards a successful nutrient and organic C management for organic olive groves, since no serious nutritional deficiencies were found. PMID- 28841517 TI - Surface water retention systems for cattail production as a biofuel. AB - Surface water retention systems act to reduce nutrient pollution by collecting excess nutrients within a watershed via runoff. Harvesting aquatic biomass, such as the invasive cattail, from retention systems removes nutrients absorbed by the plant from the ecosystem permanently. Harvested biomass can be used as a renewable energy source in place of fossil fuels, offsetting carbon emissions. The purpose of this research was to simulate cattail harvest from surface water retention systems to determine their ability to provide suitable growing conditions with annual fluctuations in water availability. The economic and environmental benefits associated with nutrient removal and carbon offsets were also calculated and monetized. A proposed upstream and existing downstream water retention system in southern Manitoba were modelled using a system dynamics model with streamflow inputs provided by a physical hydrologic model, Modelisation Environmentale Communautaire - Surface and Hydrology (MESH). Harvesting cattail and other unconventional feedstocks, such as reeds, sedges, and grasses, from retention systems provided a viable revenue stream for landowners over a ten-year period. This practice generates income for landowners via biomass and carbon credit production on otherwise underutilized marginal cropland invaded with cattail. The economic benefits promote wetland habitat restoration while managing cattail growth to maintain biodiversity. Excess nitrogen and phosphorus are also removed from the ecosystem, reducing downstream nutrient loading. Utilizing surface water retention systems for cattail harvest is a best management strategy for nutrient retention on the landscape and improving agricultural resilience. PMID- 28841518 TI - Effectiveness of community-based mangrove management for sustainable resource use and livelihood support: A case study of four villages in Central Java, Indonesia. AB - Community-Based Mangrove Management (CBMM) is implemented with different approaches and outcomes. This study examined the effectiveness of various CBMM practices to achieve sustainable management of mangrove resources. We analyzed local mangrove resource management strategies in four coastal villages (e.g. Sriwulan, Bedono, Timbulsloko, and Surodadi) on Central Java, Indonesia. Local data on institutions, socio-economic conditions and mangrove resources utilization was collected through participatory resource mapping and interviews with 16 key actors and 500 households. The main differences in CBMM-practices that affect the outcomes in each village were the type of community participation, the level of organizational and economic assistance from external institutions, the magnitude of the rehabilitation project, the time selected for rehabilitation and the maintenance strategies applied in each village. Surodadi achieved most in terms of both efficient resource utilization and local livelihood improvement. Bedono's management strategy was most effective in extending and maintaining the rehabilitated mangrove areas but less in terms of livelihood support while the strategy applied in Timbulsloko resulted in higher resource utilization compared to Surodadi. Sriwulan failed on most criteria. This study suggests that combining the management strategies practiced in Bedono and Surodadi and adding external scientific and technological assistance, income diversification, institutional reinforcement and continuous monitoring of the functioning of local institutions can improve the CBMM performance to sustainably manage mangrove resources and improve livelihoods. PMID- 28841519 TI - Reduction of soil erosion and mercury losses in agroforestry systems compared to forests and cultivated fields in the Brazilian Amazon. AB - In addition to causing physical degradation and nutrient depletion, erosion of cultivated soils in the Amazon affects aquatic ecosystems through the release of natural soil mercury (Hg) towards lakes and rivers. While traditional agriculture is generally cited as being among the main causes of soil erosion, agroforestry practices are increasingly appreciated for soil conservation. This study was carried out in family farms of the rural Tapajos region (Brazil) and aimed at evaluating soil erosion and associated Hg release for three land uses. Soils, runoff water and eroded sediments were collected at three sites representing a land cover gradient: a recently burnt short-cycle cropping system (SCC), a 2-year old agroforestry system (AFS) and a mature forest (F). At each site, two PVC soil erosion plots (each composed of three 2 * 5 m isolated subplots) were implemented on steep and moderate slopes respectively. Sampling was done after each of the 20 rain events that occurred during a 1-month study period, in the peak of the 2011 rain season. Runoff volume and rate, as well as eroded soil particles with their Hg and cation concentrations were determined. Total Hg and cation losses were then calculated for each subplot. Erosion processes were dominated by land use type over rainfall or soil slope. Eroded soil particles, as well as the amount of Hg and cations (CaMgK) mobilized at the AFS site were similar to those at the F site, but significantly lower than those at the SCC site (p < 0.0001). Erosion reduction at the AFS site was mainly attributed to the ground cover plants characterizing the recently established system. Moreover, edaphic change throughout AFS and F soil profiles differed from the SCC site. At the latter site, losses of fine particles and Hg were enhanced towards soil surface, while they were less pronounced at the other sites. This study shows that agroforestry systems, even in their early stages of implementation, are characterized by low erosion levels resembling those of local forest environments, thus contributing to the maintenance of soil integrity and to the reduction of Hg and nutrient mobility. PMID- 28841520 TI - In utero exposure to DDT and incidence of diarrhea among boys from tropical Mexico. AB - BACKGROUND: A higher incidence rate (IR) of acute gastrointestinal (GI) infections associated with prenatal exposure to p,p'-DDE was suggested by the results in two studies. Given the high mortality rate due to childhood diarrhea in some countries with ongoing use of DDT, additional data on this association is relevant for those making decisions about vector-borne disease control. OBJECTIVE: To evaluate whether higher levels of prenatal exposure to p,p'-DDE and p,p'-DDT increase the risk of having diarrhea in a birth cohort of boys from tropical Mexico. METHODS: Our analysis was based on 747 boys whose exposure was measured in maternal serum collected at delivery (2002-2003). Mothers reported the number of diarrhea episodes of their children during in-person interviews. The median age of the children at their last interview was 21.4 months. Poisson regression models were fitted to estimate adjusted incidence rate ratios (aIRR) of diarrhea by levels of p,p'-DDE and p,p'-DDT. RESULTS: Overall, there were 1.7 episodes of diarrhea per child-year. Among those in the highest category of exposure (> 9ug DDE/g serum lipid), the aIRR for diarrhea was 1.14 (95% CI: 0.94, 1.30) compared to those in the lowest category of exposure (<= 3ug/g). Among boys living in the urban area, the corresponding aIRR was 1.39 (95% CI: 1.07-1.80). Among rural boys, no associations emerged. CONCLUSION: Although the results were consistent with a small positive association, the overall estimate was not precise. While urban boys in this study appeared to be more susceptible to DDE associated diarrhea, a ready explanation for such increased susceptibility was not apparent. PMID- 28841522 TI - Human biomonitoring data analysis for metals in an Italian adolescents cohort: An exposome approach. AB - The first Italian human biomonitoring survey (PROBE - PROgramme for Biomonitoring general population Exposure) considered a reference population of adolescents, aged 13-15 years, living in urban and rural areas and investigated their exposure to metals. The study was expanded up to 453 adolescents living in the same areas of Latium Region (Italy) and blood samples were analyzed for 19 metals (As, Be, Cd, Co, Cr, Hg, Ir, Mn, Mo, Ni, Pb, Pd, Pt, Rh, Sb, Sn, Tl, V, and W) by sector field inductively coupled plasma mass spectrometry. The exposure assessment was contextualized following an exposome approach that considered several determinants related to the subjects, available environmental parameters and geo coding of residence address. To assess the influence of exposure determinants and modifiers on children biomarkers levels we used two independent methodologies. The first makes use of the so-called Environment-Wide Association Study (EWAS) methodology while the second was based on the application of a Generalized Liner Model (GLM) capturing co-exposures to pairs of key determinants. Based on our analysis, Hg and As were positively associated with dietary pathways (primarily linked to fish and to a lesser extent to milk consumption) while Cr showed a more complex interaction between co-exposure to different dietary pathways (milk and fish) coupled to proximity of residence to industrial activities. In addition to diet, socio-economic status of the mother revealed robust statistical associations with Cd, Ni and W biomonitoring levels in the respective children. PMID- 28841521 TI - Low-level arsenic exposure from drinking water is associated with prostate cancer in Iowa. AB - Inorganic arsenic is a toxic naturally occurring element in soil and water in many regions of the US including the Midwest. Prostate cancer is the second most common type of cancer in men in Iowa, surpassed only by non-melanotic skin cancer. Epidemiology studies have evaluated arsenic exposure from drinking water and prostate cancer, but most have focused on high-level exposures outside the US. As drinking water from groundwater sources is a major source of arsenic exposure, we conducted an ecologic study to evaluate prostate cancer and arsenic in drinking water from public water sources and private wells in Iowa, where exposure levels are low, but duration of exposure can be long. Arsenic data from public water systems were obtained from the Iowa Safe Drinking Water Information System for the years 1994-2003 and for private wells from two Iowa Well Water Studies, the Iowa Community Private Well Study (ICPWS, 2002-2003) and Iowa Statewide Rural Well Water Survey Phase 2 (SWIRL2, 2006-2008) that provided data for 87 Iowa counties. Prostate cancer incidence data from 2009 to 2013 for Iowa were obtained from Surveillance, Epidemiology and End Results' SEER*Stat software. County averages of water arsenic levels varied from 1.08 to 18.6 ppb, with three counties above the current 10 ppb limit. Based on the tertiles of arsenic levels, counties were divided into three groups: low (1.08-2.06 ppb), medium (2.07-2.98 ppb), and high (2.99-18.6 ppb). Spatial Poisson regression modeling was conducted to estimate the risk ratios (RR) of prostate cancer by tertiles of arsenic level at a county level, adjusted for demographic and risk factors. The RR of prostate cancer were 1.23 (95% CI, 1.16-1.30) and 1.28 (95% CI, 1.21-1.35) in the medium and high groups, respectively, compared to the low group after adjusting for risk factors. The RR increased to 1.36 (95% CI, 1.28 1.45) in the high group when analyses were restricted to aggressive prostate cancers (Gleason score >= 7). This study shows a significant dose-dependent association between low-level arsenic exposure and prostate cancer, and if this result is replicated in future individual-level studies, may suggest that 10 ppb is not protective for human health. PMID- 28841523 TI - Normalizing shoulder EMG: An optimal set of maximum isometric voluntary contraction tests considering reproducibility. AB - Normalization of the electromyography (EMG) signal is often performed relatively to maximal voluntary activations (MVA) obtained during maximum isometric voluntary contraction (MVIC). The first aim was to provide an inter-session reproducible protocol to normalize the signal of eight shoulder muscles. The protocol should also lead to a level of activation >90% of MVA for >90% of the volunteers. The second aim was to evaluate the influence of the method used to extract the MVA from the EMG envelope on the normalized EMG signal. Thirteen volunteers performed 12 MVICs twice (one week interval). Several time constants (100ms to 2s) were compared when extracting the MVA from the EMG envelope. The EMG activity was also acquired during an arm elevation. Our results show that a combination of nine MVIC tests was required to meet our requirements including reproducibility. Both the number of MVIC tests and the size of the time constant influence the normalized EMG signal during the dynamic activity (variations up to 15%). A time constant of 1s was a good compromise to extract the MVA. These findings are valuable to improve the reproducibility of EMG signal normalization. PMID- 28841524 TI - Hexavalent chromium reduction potential of Cellulosimicrobium sp. isolated from common effluent treatment plant of tannery industries. AB - Present study deals with the isolation and characterization of a bacterium capable for the effective reduction of Cr(VI) from tannery wastewater. Based on the 16S rRNA gene sequence analysis, this bacterium was identified as Cellulosimicrobium sp. (KX710177). During the Cr(VI) reduction experiment performed at 50, 100, 200,and 300mg/L of Cr(VI) concentrations, the bacterium showed 99.33% and 96.98% reduction at 50 and 100mg/L at 24 and 96h, respectively. However, at 200 and 300mg/L concentration of Cr(VI), only 84.62% and 62.28% reduction was achieved after 96h, respectively. The SEM analysis revealed that bacterial cells exposed to Cr(VI) showed increased cell size in comparison to unexposed cells, which might be due to either the precipitation or adsorption of reduced Cr(III) on bacterial cells. Further, the Energy Dispersive X-ray (EDX) analysis showed some chromium peaks for cells exposed to Cr(VI), which might be either due to the presence of precipitated reduced Cr(III) on cells or complexation of Cr(III) with cell surface molecules. The bacterium also showed resistance and sensitivity against the tested antibiotics with a wide range of MIC values ranging from 250 to 800mg/L for different heavy metals. Thus, this multi-drug and multi-metal resistant bacterium can be used as a potential agent for the effective bioremediation of metal contaminated sites. PMID- 28841525 TI - Chronic dietary toxicity of zinc oxide nanoparticles in common carp (Cyprinus carpio L.): Tissue accumulation and physiological responses. AB - Concerns regarding the potential toxic effects of zinc oxide nanoparticles (ZnO NPs) on aquatic organisms are growing due to the fact that NPs may be released into aquatic ecosystems. This study aimed to investigate the effects of dietary exposure to ZnO NPs on juvenile common carp (Cyprinus carpio). Fish were fed a spiked diets at doses 50 and 500mg of ZnO NPs per kg of feed for 6 weeks followed by a 2-week recovery period. Fish were sampled every 2 weeks for haematology trends, blood biochemistry measures, histology analyses, and determination of the accumulation of zinc in tissues. At the end of the exposure and post-exposure periods, fish were sampled for an assessment of lipid peroxidation levels. Dietborne ZnO NPs had no effects on haematology, blood biochemistry, and lipid peroxidation levels during the exposure period. After the recovery period, aspartate aminotransferase activity significantly (p < 0.05) increased and alanine transferase activity significantly (p < 0.05) decreased in the higher exposure group. The level of lipid peroxidation significantly (p < 0.05) decreased in liver of treated fish after 2 weeks post-exposure period. A histological examination revealed mild histopathological changes in kidneys during exposure. Our results did not show a significant increase of zinc content at the end of experiment in any of tested organs. However, chronic dietary exposure to ZnO NPs might affect kidney and liver function. PMID- 28841526 TI - A comprehensive adsorption study and modeling of antibiotics as a pharmaceutical waste by graphene oxide nanosheets. AB - The adsorption behavior of tetracycline (TCN), doxycycline (DCN) as the most common antibiotics in veterinary and ciprofloxacin (CPN) onto graphene oxide nanosheets (GOS) in aqueous solution was evaluated. The four factors influencing the adsorption of antibiotics (initial concentration, pH, temperature and contact time) were studied. The results showed that initial pH ~ 6 to 7 and contact time ~ 100 - 200min are optimum for each drug. The monolayer adsorption capacity was reduced with the increasing temperature from 25 degrees C to 45 degrees C. Non linear regressions were carried out in order to define the best fit model for every system. To do this, eight error functions were applied to predict the optimum model. Among various models, Hill and Toth isotherm models represented the equilibrium adsorption data of antibiotics while the kinetic data were well fitted by pseudo second-order (PSO) kinetic model (DCN and TCN) and Elovich (CPN) models. The maximum adsorption capacity (qmax) is found to be in the following order: CPN >> DCN > TCN, obtained from sips equation at the same temperature. The GOS shows highest adsorption capacity towards CPN up to 173.4mgg-1. The study showed that GOS can be removed more efficiently from water solution. PMID- 28841527 TI - Estimating the potential effects of pesticide seed treatments on the reproductive success of arable birds. AB - In temperate zones, seeds of spring-sown crops may be an attractive food source for breeding farmland birds. We modelled the effects of pesticide seed treatments on the reproductive success of 4 UK arable bird species (Rook, Linnet, Skylark, Yellowhammer) exposed to treated seeds of 3 spring-sown crops (beans, barley and linseed). We ran three types of model, 1) a "broods-at-risk" model looking at the temporal overlap between nesting and seed-sowing dates, and estimating the proportion of those nests that suffered toxicity-exposure ratios < 5; 2) a "seasonal success" Markov chain model estimating the number of chicks successfully raised in the course of a breeding season.; and 3) the potential effects of pesticides on population growth rates. Based on physiology, Rooks, should be less at risk from treated seeds than smaller species because bigger birds eat less as a proportion of their bodyweights. However, in nearly all our scenarios, Rooks were more vulnerable, followed by Skylark and Linnet, with Yellowhammer being least affected. A principal cause is that Rooks are more likely to be breeding at a time when treated seeds are being sown. Furthermore, whereas the other species may make several breeding attempts and early failures from pesticide exposure may be compensated by later successes, Rooks breed only once in a season. The results are also supported by historical evidence of Rook population declines following pesticide seed treatments. PMID- 28841528 TI - The influence of seawater properties on toxicity of copper pyrithione and its degradation product to brine shrimp Artemia salina. AB - Copper pyrithione (CuPT) is a biocide, used worldwide to prevent biofouling on submerged surfaces. In aquatic environments it rapidly degrades, however, one of the degradation products (HPT) is known to react with cupric ion back to its parent compound. Not much is known about the behavior and toxicity of CuPT and its degradation product HPT in different water systems. Hence, our aim was to investigate the ecotoxicity of CuPT, HPT as well as Cu2+ to the brine shrimp Artemia salina in natural seawater and organic matter-free artificial seawater. Moreover, in order to elucidate the influence of ionic strength of water on CuPT toxicity, tests were performed in water media with modified salinity. The results showed that CuPT was the most toxic to the exposed crustaceans in a seawater media with the highest salinity and with no organic matter content. HPT in a presence of cupric ion converted to CuPT, but the measured CuPT concentrations and the mortality of A. salina in natural water were lower than in artificial water. The toxicity of CuPT to A. salina was significantly influenced by the organic matter content, salinity, and proportions of constituent salts in water. In a combination with cupric ion, non-hazardous degradation product HPT exhibits increased toxicity due to its rapid transformation to its parent compound. PMID- 28841529 TI - Modification of saltwater stress response in Cyprinus carpio (Linnaeus, 1758) pre exposed to pesticide indoxacarb. AB - To evaluate the effects of indoxacarb on saltwater stress response in Cyprinus carpio, the fish were pre-exposed to indoxacarb (0, 0.75, 1.5 and 3mg/L denoted as CP, 0.75IT, 1.5IT and 3IT, respectively) for 21 days and then released to saltwater. A negative control (CN) group was included (the fish were held in indoxacarb-free water for the entire experiment). The fish were sampled immediately (0h) and 24, 48 and 72h after the salinity exposure for the analysis of plasma cortisol, glucose and sodium, chloride, potassium and calcium levels. All fish pre-exposed to 3mg/L indoxacarb, died after the first day of salinity challenge. CP showed typical cortisol response after the salinity challenge, but, cortisol response of the fish pre-exposed to indoxacarb (0.75IT and 1.5IT) was blocked. Plasma glucose increased significantly in all groups compared to the CN; however, this elevation had no consistent trend in 0.75IT and 1.5IT which indicated interference in glucose response due to indoxacarb exposure. Plasma sodium increased (compared to CN) in all groups after the salinity challenge. However, elevation in plasma chloride and potassium was significantly different among the groups and the indoxacarb-treated fish showed slightly sooner ionic disturbance. The results clearly indicate that indoxacarb impairs stress response of C. carpio and the fish may not be able to respond normally to additional stressors, which threatens their survival. PMID- 28841530 TI - Biodegradation of atrazine by the novel Citricoccus sp. strain TT3. AB - A previously undescribed atrazine-degrading bacterial strain TT3 capable of growing with atrazine as its sole nitrogen source was isolated from soil at the wastewater outfall of a pesticide factory in China. Phenotypic characterization and 16S rRNA gene sequencing indicated that the isolate belonged to the genus Citricoccus. Polymerase chain reaction (PCR) analysis revealed that TT3 contained the atrazine-degrading genes trzN, atzB, and atzC. The range for growth and atrazine degradation of TT3 was found to be pH 6.0-11.0, with a preference for alkaline conditions. At 30 degrees C and pH 7.0, the strain removed 50mg/L atrazine in 66h with 1% inoculum. These results demonstrate that Citricoccus sp. TT3 has great potential for bioremediation of atrazine-contaminated sites, particularly in alkaline environments. To the best of our knowledge, there are no previous reports of Citricoccus strains that degrade atrazine, and therefore this work provides a novel candidate for atrazine bioremediation. PMID- 28841531 TI - DDTs-induced antioxidant responses in plants and their influence on phytoremediation process. AB - Phytoremediation is a low cost technology based on the use of plants to remove a wide range of pollutants from the environment, including the insecticide DDT. However, some pollutants are known to enhance generation of reactive oxygen species (ROS), which can generate toxic effects on plants affecting the phytoremediation efficiency. This study aims to analyze the potential use of antioxidant responses as a measure of tolerance to select plants for phytoremediation purposes. Tomato and zucchini plants were grown for 15 days in soils contaminated with DDTs (DDT + DDE + DDD). Protein content, glutathione-S transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) and catalase (CAT) activities were measured in plant tissues. Exposure to DDTs did not affect protein content or CAT activity in any of the species. GST, GR and GPx activity showed different responses in exposed and control tomato plants. After DDTs exposure, tomato showed increased GR and GPX activity in stems and leaves, respectively, and a decrease in the GST activity in roots. As no effects were observed in zucchini, results suggest different susceptibility and/or defense mechanisms involved after pesticide exposure. Finally, both species differed also in terms of DDTs uptake and translocation. The knowledge about antioxidant responses induced by pesticides exposure could be helpful for planning phytoremediation strategies and for the selection of tolerant species according to particular scenarios. PMID- 28841532 TI - Enantiomeric separation of five acidic drugs via capillary electrophoresis using streptomycin as chiral selector. AB - A simple capillary zone electrophoresis (CZE) method was developed to achieve the rapid enantiomeric separation of a set of acidic drugs using streptomycin as chiral selector. The enantiomers of 5 chiral phenyl-containing acidic pharmaceutical compounds were separated excellently by CE using an uncoated silica capillary. Several experimental parameters such as the concentration of streptomycin, buffer concentration and pH, running voltage, and capillary temperature were all investigated systematically in order to optimize the chiral separation. All analytes were got baseline separation within 10min. And the results showed that streptomycin can be used as a chiral selector to the enantioseparation of five acidic drugs by CZE method. PMID- 28841533 TI - Gene detection: An essential process to precision medicine. AB - Gene detection plays an important role in public health and consumer finances cause its prominent functions in precision medicine, pathogens detection and species identification. What's more, the announcement of Precision Medicine Initiative would strengthen its status further in many aspects. Therefore, rapid and simplified gene detection techniques are in urgent demand to meet the practical use. During the last decades, gene detection techniques have advanced considerably by integrating various strategies such as microassay, nanotechnologies and electrochemical methods. Herein, we summerized the recent innovations of gene detection methods based on the signal read-out modalities, and highlight those techniques with the potentials to realize Point-of-care (POC) tests. Additionally, gene detection principle, amplification strategies and their applications are also discussed. PMID- 28841534 TI - Xanthine oxidase functionalized Ta2O5 nanostructures as a novel scaffold for highly sensitive SPR based fiber optic xanthine sensor. AB - Fabrication and characterization of a surface plasmon resonance based fiber optic xanthine sensor using entrapment of xanthine oxidase (XO) enzyme in several nanostructures of tantalum (v) oxide (Ta2O5) have been reported. Chemical route was adopted for synthesizing Ta2O5 nanoparticles, nanorods, nanotubes and nanowires while Ta2O5 nanofibers were prepared by electrospinning technique. The synthesized Ta2O5 nanostructures were characterized by photoluminescence, scanning electron microscopy, UV-Visible spectra and X-ray diffraction pattern. The probes were fabricated by coating an unclad core of the fiber with silver layer followed by the deposition of XO entrapped Ta2O5 nanostructures. The crux of sensing mechanism relies on the modification of dielectric function of sensing layer upon exposure to xanthine solution of diverse concentrations, reflected in terms of shift in resonance wavelength. The sensing probe coated with XO entrapped Ta2O5 nanofibers has been turned out to possess maximum sensitivity amongst the synthesized nanostructures. The probe was optimized in terms of pH of the sample and the concentration of XO entrapped in Ta2O5 nanofibers. The optimized sensing probe possesses a remarkably good sensitivity of 26.2nm/uM in addition to linear range from 0 to 3uM with an invincible LOD value of 0.0127uM together with a response time of 1min. Furthermore, probe selectivity with real sample analysis ensure the usage of the sensor for practical scenario. The results reported open a novel perspective towards a sensitive, rapid, reliable and selective detection of xanthine. PMID- 28841535 TI - Female reproductive traits of a commercially exploited skate: Atlantoraja platana (Gunther, 1880) (Chondrichthyes, Rajidae). Ovarian morphology, gametogenesis and microscopic verification of maturity criteria. AB - Atlantoraja platana is an endemic species of the Southwest Atlantic Ocean, and is one of the most captured by the local bottom trawl industrial fisheries. In this work, the microscopic architecture of mature female's gonads and the dynamics of follicle development are studied as a contribution to raise awareness of reproductive biology of the species. Folliculogenesis depicts the same histologic pattern as in other Elasmobranchs. Follicles in different degrees of maturation coexist in mature animals. The oogonia were only found in immature individuals. Likewise, atretic follicles were recorded in ovaries of all sexual maturity stages. The microscopic size recorded from the beginning of yolk input is smallest than the detected with the necked eye. This study provides valuable information about female's gametogenesis that could be taken into account in the development of fisheries management. PMID- 28841536 TI - Effect of instructions on EMG during the bench press in trained and untrained males. AB - Strength and rehabilitation professionals strive to emphasize certain muscles used during an exercise and it may be possible to alter muscle recruitment strategies with varying instructions. This study aimed to determine whether resistance trained and untrained males could selectively activate the pectoralis major or triceps brachii during the bench press according to various instructions. This study included 13 trained males (21.5+/-2.9years old, 178.7+/ 7.0cm, 85.7+/-10.7kg) and 12 untrained males (20.3+/-1.6years old, 178.8+/-9.4cm, 74.6+/-17.3kg). Participants performed a bench press one-repetition maximum (1 RM) test, 3 uninstructed repetitions at 80% 1-RM and two more sets of three repetitions with instructions to isolate the chest or arm muscles. Electromyography (EMG) was obtained from the pectoralis major, anterior deltoid, and the long head and short head of the triceps brachii. Maximum EMG activity normalized to 1-RM for each muscle was averaged over the three repetitions for each set and compared between the uninstructed, chest-instructed and arm instructed conditions among the groups. The trained participants had a greater 1 RM (126.2+/-30.6kg) than the untrained participants (61.6+/-14.8kg) (P<0.01). EMG activity was not different between the groups for any of the instructions (P>0.05). When the group data was combined, short head of the triceps activity was significantly lower in the chest instruction (80.1+/-19.3%) when compared to the uninstructed (85.6+/-23.3%; P=0.01) and arm-instructed (86.0+/-23.2; P=0.01) conditions. It can be concluded that instructions can affect muscle activation during the bench press, and this is not dependent on training status. PMID- 28841537 TI - Effect of static and dynamic muscle stretching as part of warm up procedures on knee joint proprioception and strength. AB - BACKGROUND: The importance of warm up procedures prior to athletic performance is well established. A common component of such procedures is muscle stretching. There is conflicting evidence regarding the effect of static stretching (SS) as part of warm up procedures on knee joint position sense (KJPS) and the effect of dynamic stretching (DS) on KJPS is currently unknown. The aim of this study was to determine the effect of dynamic and static stretching as part warm up procedures on KJPS and knee extension and flexion strength. METHODS: This study had a randomised cross-over design and ten healthy adults (20+/-1years) attended 3 visits during which baseline KJPS, at target angles of 20 degrees and 45 degrees , and knee extension and flexion strength tests were followed by 15min of cycling and either a rest period (CON), SS, or DS and repeat KJPS and strength tests. All participants performed all conditions, one condition per visit. RESULTS: There were warm up*stretching type interactions for KJPS at 20 degrees (p=0.024) and 45 degrees (p=0.018), and knee flexion (p=0.002) and extension (p<0.001) strength. The SS and DS improved KJPS but CON condition did not and SS decreased strength. No change in strength was present for DS or CON. CONCLUSIONS: Both SS and DS improve KJPS as part of pre-exercise warm up procedures. However, the negative impact of SS on muscle strength limits the utility of SS before athletic performance. If stretching is to be performed as part of a warm up, DS should be favoured over SS. PMID- 28841538 TI - Effects of practice schedule and task specificity on the adaptive process of motor learning. AB - This study investigated the effects of practice schedule and task specificity based on the perspective of adaptive process of motor learning. For this purpose, tasks with temporal and force control learning requirements were manipulated in experiments 1 and 2, respectively. Specifically, the task consisted of touching with the dominant hand the three sequential targets with specific movement time or force for each touch. Participants were children (N=120), both boys and girls, with an average age of 11.2years (SD=1.0). The design in both experiments involved four practice groups (constant, random, constant-random, and random constant) and two phases (stabilisation and adaptation). The dependent variables included measures related to the task goal (accuracy and variability of error of the overall movement and force patterns) and movement pattern (macro- and microstructures). Results revealed a similar error of the overall patterns for all groups in both experiments and that they adapted themselves differently in terms of the macro- and microstructures of movement patterns. The study concludes that the effects of practice schedules on the adaptive process of motor learning were both general and specific to the task. That is, they were general to the task goal performance and specific regarding the movement pattern. PMID- 28841539 TI - Salvage transhepatic arterial embolization after failed stage I ALPPS in a patient with a huge HCC with chronic liver disease: A case report. AB - INTRODUCTION: The degree of hypertrophy of the future liver remnant (FLR) induced by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in patients with HCC and chronic liver disease is often limited as compared with patients with a healthy liver. PRESENTATION OF CASE: We reported a 53-year-old male who had a huge HCC (14.8*12*9.4cm) arising from a background of hepatitis B liver fibrosis (METAVIR score F3). The ratio of the FLR/standard liver volume (SLV) was 23.8%. After stage I ALPPS, volumetric assessment on postoperative day (POD) 7 and 13 showed insufficient FLR hypertrophy (FLR/SLV: 28.7% and 30.7%, respectively). A postoperative computed tomographic 3D reconstruction and hepatic angiography showed steal of arterial blood from the FLR to the huge tumour in the right liver. Salvage transhepatic arterial embolization (TAE) was performed to block the major arterial blood supply to the tumour on POD 13. The FLR/SLV increased to 42.5% in 7days. Stage II ALPPS consisting of right trisectionectomy was successfully performed. DISCUSSION: Salvage TAE which blocked the main arterial blood supply to the huge HCC improved the arterial supply with subsequent adequate and fast hypertrophy of the FLR to allow trisectionectomy in stage II ALPPS to be carried out. CONCLUSION: Salvage TAE after failed stage I ALPPS with inadequate hypertrophy of the FLR allowed trisectionectomy in stage II ALPPS to be carried out in a patient with a huge HCC with chronic liver disease. PMID- 28841540 TI - Laparoscopically assisted treatment of entero-atmospheric fistula following abdominal wall repair of complex incisional hernia: Case report. AB - INTRODUCTION: Entero-atmospheric fistula (EAF) is an uncommon complication. Its timing and surgical management could be extremely challenging because extensive adhesions may heavily affect the approach to the abdominal cavity. PRESENTATION OF CASE: We hereby report a case of EAF in a 70 year-old man. In order to control the fistula output and the surrounding tissue damage from enteric content, the patient was managed conservatively using different technical solutions. Finally, the patient underwent surgery that started with a laparoscopic approach in order to avoid the hostile abdomen. DISCUSSION: Due to the lack of guidelines, treatment of EAF requires a multidisciplinary approach and different technical options based on the experience and inventiveness of the surgeon. Among others, the vacuum assisted wound management proved to be a useful support andlaparoscopy demonstrated to be valuable in approaching the abdominal cavity. CONCLUSION: According to our experience the success of the treatment of EAF may be improved adopting a multidisciplinary approach and well-planned surgery in referral centers. PMID- 28841541 TI - Use of the liver maximum function capacity test (LiMAx) for the management of liver resection in cirrhosis - A case of hypopharyngeal cancer liver metastasis. AB - INTRODUCTION: The presence of liver cirrhosis goes along with a higher chance for the need of liver resection. As established laboratory parameters often underestimate the degree of cirrhosis this is associated with an increased risk for postoperative liver failure due to the preoperatively impaired liver function. Known liver function tests are unlikely to be performed in daily use because of high cost or expenditure of time. Liver maximum function capacity test (LiMAx) provides a novel tool for measurement of liver function and references for the safety of liver resection. PRESENTATION OF CASE: A 63-year old patient presented at our hospital with a large, solitary liver metastasis from hypopharyngeal cancer in segments VII/VIII with infiltration of the diaphragm. Liver resection was unsuccessful in a peripheral hospital 10 months before due to considerable macroscopic liver cirrhosis (CHILD B). Upon presentation conventional laboratory parameters revealed sufficient liver function. LiMAx was performed and showed regular liver function (354MUg/kg/h; at norm >315MUg/kg/h). Consequently, atypical liver resection (R0) was performed resulting in a postoperative LiMAx value of 281MUg/h/kg (>150MUg/kg/h). The patient was discharged from hospital 37days after surgery without any signs of postoperative liver failure. CONCLUSION: The LiMAx-test enables determination of liver function at a so far unavailable level (metabolism via cytochrome P450 1A2) and hence might provide crucial additional diagnostic information to allow for safe liver resection even in cirrhotic patients. PMID- 28841542 TI - High-depth sequencing of paired primary and metastatic tumours: Implications for personalised medicine. AB - BACKGROUND: Next-generation sequencing of large panel of genes had been associated with clinical benefit in a significant proportion of patients with advanced cancer. However, the molecular profile of the primary tumour from the initial surgical specimen might significantly differ from the molecular profile in a tumour sample obtained from a biopsy of a metastatic site. PATIENTS AND METHODS: We compare the genetic profile of primary tumours and paired metastases by using a large panel of cancer genes. Training and validation set including a total of 152 primary and metastatic tumour pairs were sequenced (up to 429 genes) focussing on variants described in the Catalogue of Somatic Mutations in Cancer (COSMIC). RESULTS: Training and validation set including a total of 152 primary and metastatic tumour pairs were sequenced focussing on variants described in COSMIC. Agreement rate between the couples of primary and metastasis on COSMIC variants was 65% (24/37) and 43% (49/115) in the training and validation cohort, respectively. That rose to 74% (20/27) and 58% (42/73) when focussing on targetable mutations. In five cases, the discordance was related to appearance of secondary resistance mutation, giving a targetable refined agreement rate of 67% (67/100). CONCLUSION: Up to 40% of paired primary tumour/metastases have discordant molecular profile. Liquid biopsies may overcome, in the near future, the limits of tumour tissue genotyping. PMID- 28841543 TI - The fate of new fosfamides in phase III studies in advanced soft tissue sarcoma. AB - For decades, doxorubicin alone or in combination with ifosfamide has been used in advanced soft tissue sarcoma (STS). In 2014, a comparison of doxorubicin alone versus the combination with ifosfamide (in the randomised phase III EORTC 62012) showed no difference in overall survival (OS), but a difference in response and progression-free survival (PFS) were observed in favour of the combination but at the expense of increased toxicity. Newer fosfamides, with slightly different modes of action, and potentially less toxicity, namely evofosfamide and palifosfamide have recently been tested in randomised phase III clinical trials in STS. The TH CR-406/SARC021 (June 2017) and the PICASSO III (September 2016) studies compared doxorubicin, as the standard arm, to doxorubicin in combination with evofosfamide and palifosfamide, respectively. In both studies, the combination arm produced increased response rates but at the expense of higher toxicity. However, there was no difference in OS or PFS in favour of the combination. Importantly, the median OS of patients receiving standard of care, doxorubicin, in both studies appeared improved from 12.8 months (95.5% CI 10.5 14.III) in the EORTC 62012 to 16.9 months (95% CI 14.8 to 22.9) in PICASSO III and 19.0 months (95% CI 16.2-22.4) in TH CR-406/SARC021. The results of these three randomised phase III studies highlight several critical issues related to the design and conduct of such trials in STS. We discuss these issues aiming to contribute to the ongoing debate about the optimal approach to perform clinical research in STS. PMID- 28841544 TI - GsSNAP33, a novel Glycine soja SNAP25-type protein gene: Improvement of plant salt and drought tolerances in transgenic Arabidopsis thaliana. AB - The N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) superfamily, specifically the SNAP25-type proteins and t-SNAREs, have been proposed to regulate cellular processes and plant resistance mechanisms. However, little is known about the role of SNAP25-type proteins in combating abiotic stresses, specifically in wild soybean. In the current study, the isolation and functional characterization of the putative synaptosomal-associated SNAP25-type protein gene GsSNAP33 from wild soybean (Glycine soja) were performed. GsSNAP33 has a molecular weight of 33,311 Da and comprises 300 amino acid residues along with Qb-Qc SNARE domains. Multiple sequence alignment revealed the highest similarity of the GsSNAP33 protein to GmSNAP33 (91%), VrSNAP33 (89%), PvSNAP33 (86%) and AtSNAP33 (63%). Phylogenetic studies revealed the abundance of SNAP33 proteins mostly in dicotyledons. Quantitative real-time PCR assays confirmed that GsSNAP33 expression can be induced by salt, alkali, ABA and PEG treatments and that GsSNAP33 is highly expressed in the pods, seeds and roots of Glycine soja. Furthermore, the overexpression of the GsSNAP33 gene in WT Arabidopsis thaliana resulted in increased germination rates, greater root lengths, improved photosynthesis, lower electrolyte leakage, higher biomass production and up regulated expression levels of various stress-responsive marker genes, including KINI, COR15A, P5Cs, RAB18, RD29A and COR47 in transgenic lines compared with those in WT lines. Subcellular localization studies revealed that the GsSNAP33 eGFP fusion protein was localized to the plasma membrane, while eGFP was distributed throughout whole cytoplasm of onion epidermal cells. Collectively, our findings suggest that GsSNAP33, a novel plasma membrane protein gene of Glycine soja, might be involved in improving plant responses to salt and drought stresses in Arabidopsis. PMID- 28841545 TI - A novel strategy to enhance interfacial adhesion in fiber-reinforced calcium phosphate cement. AB - Calcium phosphate cements (CPCs) are extensively used as synthetic bone grafts, but their poor toughness limits their use to non-load-bearing applications. Reinforcement through introduction of fibers and yarns has been evaluated in various studies but always resulted in a decrease in elastic modulus or bending strength when compared to the CPC matrix. The aim of the present work was to improve the interfacial adhesion between fibers and matrix to obtain tougher biocompatible fiber-reinforced calcium phosphate cements (FRCPCs). This was done by adding a polymer solution to the matrix, with chemical affinity to the reinforcing chitosan fibers, namely trimethyl chitosan (TMC). The improved wettability and chemical affinity of the chitosan fibers with the TMC in the liquid phase led to an enhancement of the interfacial adhesion. This resulted in an increase of the work of fracture (several hundred-fold increase), while the elastic modulus and bending strength were maintained similar to the materials without additives. Additionally the TMC-modified CPCs showed suitable biocompatibility with an osteoblastic cell line. PMID- 28841546 TI - Transfer Learning: A Riemannian Geometry Framework With Applications to Brain Computer Interfaces. AB - OBJECTIVE: This paper tackles the problem of transfer learning in the context of electroencephalogram (EEG)-based brain-computer interface (BCI) classification. In particular, the problems of cross-session and cross-subject classification are considered. These problems concern the ability to use data from previous sessions or from a database of past users to calibrate and initialize the classifier, allowing a calibration-less BCI mode of operation. METHODS: Data are represented using spatial covariance matrices of the EEG signals, exploiting the recent successful techniques based on the Riemannian geometry of the manifold of symmetric positive definite (SPD) matrices. Cross-session and cross-subject classification can be difficult, due to the many changes intervening between sessions and between subjects, including physiological, environmental, as well as instrumental changes. Here, we propose to affine transform the covariance matrices of every session/subject in order to center them with respect to a reference covariance matrix, making data from different sessions/subjects comparable. Then, classification is performed both using a standard minimum distance to mean classifier, and through a probabilistic classifier recently developed in the literature, based on a density function (mixture of Riemannian Gaussian distributions) defined on the SPD manifold. RESULTS: The improvements in terms of classification performances achieved by introducing the affine transformation are documented with the analysis of two BCI datasets. CONCLUSION AND SIGNIFICANCE: Hence, we make, through the affine transformation proposed, data from different sessions and subject comparable, providing a significant improvement in the BCI transfer learning problem. PMID- 28841547 TI - A 750-MHz Electronically Tunable Resonator Using Microstrip Line Couplers for Electron Paramagnetic Resonance Imaging of a Mouse Tumor-Bearing Leg. AB - OBJECTIVE: The purpose of this work was to develop an electronically tunable resonator operating at 750 MHz for continuous-wave electron paramagnetic resonance (CW-EPR) imaging of a mouse tumor-bearing leg. METHODS: The resonator had a multi-coil parallel-gap structure with a sample space of 16 mm in diameter and 20 mm in length. Microstrip line couplers were used in conjunction with varactor diodes to enable resonance frequency adjustment and to reduce the nonlinear effects of the varactor diodes. The resonator was modeled by the finite element method and a microwave circuit simulation was performed to clarify its radiofrequency characteristics. RESULTS: A tunable resonator was evaluated in terms of its resonance frequency, tunable frequency band, and conversion efficiency of the RF magnetic field. The developed resonator provided a tunable frequency band of 4 MHz at a central frequency of 747 MHz and a conversion efficiency of 34 MUT/W1/2. To demonstrate the application of this tunable resonator to EPR imaging, three-dimensional EPR images of a sample solution and a mouse tumor-bearing leg were obtained. CONCLUSION: The developed tunable resonator satisfied our initial requirements for in vivo EPR imaging and may be able to be further improved using the present finite-element and circuit models if any problems arise during future practical applications. SIGNIFICANCE: This work may help to promote EPR imaging of tumor-bearing mice in cancer-related studies. PMID- 28841548 TI - Multi-Atlas Segmentation Using Partially Annotated Data: Methods and Annotation Strategies. AB - Multi-atlas segmentation is a widely used tool in medical image analysis, providing robust and accurate results by learning from annotated atlas datasets. However, the availability of fully annotated atlas images for training is limited due to the time required for the labelling task. Segmentation methods requiring only a proportion of each atlas image to be labelled could therefore reduce the workload on expert raters tasked with annotating atlas images. To address this issue, we first re-examine the labelling problem common in many existing approaches and formulate its solution in terms of a Markov Random Field energy minimisation problem on a graph connecting atlases and the target image. This provides a unifying framework for multi-atlas segmentation. We then show how modifications in the graph configuration of the proposed framework enable the use of partially annotated atlas images and investigate different partial annotation strategies. The proposed method was evaluated on two Magnetic Resonance Imaging (MRI) datasets for hippocampal and cardiac segmentation. Experiments were performed aimed at (1) recreating existing segmentation techniques with the proposed framework and (2) demonstrating the potential of employing sparsely annotated atlas data for multi-atlas segmentation. PMID- 28841549 TI - Discriminatively Trained Latent Ordinal Model for Video Classification. AB - We address the problem of video classification for facial analysis and human action recognition. We propose a novel weakly supervised learning method that models the video as a sequence of automatically mined, discriminative sub-events (e.g., onset and offset phase for "smile", running and jumping for "highjump"). The proposed model is inspired by the recent works on Multiple Instance Learning and latent SVM/HCRF - it extends such frameworks to model the ordinal aspect in the videos, approximately. We obtain consistent improvements over relevant competitive baselines on four challenging and publicly available video based facial analysis datasets for prediction of expression, clinical pain and intent in dyadic conversations, and on three challenging human action datasets. We also validate the method with qualitative results and show that they largely support the intuitions behind the method. PMID- 28841550 TI - Scalable Joint Models for Reliable Uncertainty-Aware Event Prediction. AB - Missing data and noisy observations pose significant challenges for reliably predicting events from irregularly sampled multivariate time series (longitudinal) data. Imputation methods, which are typically used for completing the data prior to event prediction, lack a principled mechanism to account for the uncertainty due to missingness. Alternatively, state-of-the-art joint modeling techniques can be used for jointly modeling the longitudinal and event data and compute event probabilities conditioned on the longitudinal observations. These approaches, however, make strong parametric assumptions and do not easily scale to multivariate signals with many observations. Our proposed approach consists of several key innovations. First, we develop a flexible and scalable joint model based upon sparse multiple-output Gaussian processes. Unlike state-of-the-art joint models, the proposed model can explain highly challenging structure including non-Gaussian noise while scaling to large data. Second, we derive an optimal policy for predicting events using the distribution of the event occurrence estimated by the joint model. The derived policy trades-off the cost of a delayed detection versus incorrect assessments and abstains from making decisions when the estimated event probability does not satisfy the derived confidence criteria. Experiments on a large dataset show that the proposed framework significantly outperforms state-of-the-art techniques in event prediction. PMID- 28841551 TI - Self-Expressive Dictionary Learning for Dynamic 3D Reconstruction. AB - We target the problem of sparse 3D reconstruction of dynamic objects observed by multiple unsynchronized video cameras with unknown temporal overlap. To this end, we develop a framework to recover the unknown structure without sequencing information across video sequences. Our proposed compressed sensing framework poses the estimation of 3D structure as the problem of dictionary learning, where the dictionary is defined as an aggregation of the temporally varying 3D structures. Given the smooth motion of dynamic objects, we observe any element in the dictionary can be well approximated by a sparse linear combination of other elements in the same dictionary (i.e., self-expression). Our formulation optimizes a biconvex cost function that leverages a compressed sensing formulation and enforces both structural dependency coherence across video streams, as well as motion smoothness across estimates from common video sources. We further analyze the reconstructability of our approach under different capture scenarios, and its comparison and relation to existing methods. Experimental results on large amounts of synthetic data as well as real imagery demonstrate the effectiveness of our approach. PMID- 28841552 TI - Reflectance and Natural Illumination from Single-Material Specular Objects Using Deep Learning. AB - In this paper, we present a method that estimates reflectance and illumination information from a single image depicting a single-material specular object from a given class under natural illumination. We follow a data-driven, learning-based approach trained on a very large dataset, but in contrast to earlier work we do not assume one or more components (shape, reflectance, or illumination) to be known. We propose a two-step approach, where we first estimate the object's reflectance map, and then further decompose it into reflectance and illumination. For the first step, we introduce a Convolutional Neural Network (CNN) that directly predicts a reflectance map from the input image itself, as well as an indirect scheme that uses additional supervision, first estimating surface orientation and afterwards inferring the reflectance map using a learning-based sparse data interpolation technique. For the second step, we suggest a CNN architecture to reconstruct both Phong reflectance parameters and high-resolution spherical illumination maps from the reflectance map. We also propose new datasets to train these CNNs. We demonstrate the effectiveness of our approach for both steps by extensive quantitative and qualitative evaluation in both synthetic and real data as well as through numerous applications, that show improvements over the state-of-the-art. PMID- 28841553 TI - Reduced-Dose Imageless Needle and Patient Tracking in Interventional CT Procedures. AB - This paper describes a new method for imageless needle and patient tracking in interventional CT procedures based on fractional CT scanning. Our method accurately locates a needle with a spherical marker attached to it at a known distance from the tip with respect to the patient in the CT scanner coordinate frame with online sparse scan sampling and without reconstructing the CT image. The key principle of our method is to detect the needle and attached spherical marker in projection (sinogram) space based on the strongly attenuated X-ray signal due to the metallic composition of the needle and the needle's thin cylindrical geometry, and based on the marker's spherical geometry. A transformation from projection space to physical space uniquely determines the location and orientation of the needle and the needle tip position. Our method works directly in projection space and simultaneously performs patient registration and needle localization for every fractional CT scanning acquisition using the same sparse set of views. We performed registration and needle tip localization in five abdomen phantom scans using a rigid needle, and obtained a voxel-size tip localization error. Our experimental results indicate a voxel sized deviation of the localization from a comparable method in 3-D image space, with the benefit of allowing X-ray dose reduction via fractional scanning at each localization. This benefit enables more frequent tip localizations during needle insertion for a similar total dose, or a reduced total dose for the same frequency of tip localization. PMID- 28841554 TI - Optimization of Coil Element Configurations for a Matrix Gradient Coil. AB - Recently, matrix gradient coils (also termed multi-coils or multi-coil arrays) were introduced for imaging and B0 shimming with 24, 48, and even 84 coil elements. However, in imaging applications, providing one amplifier per coil element is not always feasible due to high cost and technical complexity. In this simulation study, we show that an 84-channel matrix gradient coil (head insert for brain imaging) is able to create a wide variety of field shapes even if the number of amplifiers is reduced. An optimization algorithm was implemented that obtains groups of coil elements, such that a desired target field can be created by driving each group with an amplifier. This limits the number of amplifiers to the number of coil element groups. Simulated annealing is used due to the NP-hard combinatorial nature of the given problem. A spherical harmonic basis set up to the full third order within a sphere of 20-cm diameter in the center of the coil was investigated as target fields. We show that the median normalized least squares error for all target fields is below approximately 5% for 12 or more amplifiers. At the same time, the dissipated power stays within reasonable limits. With a relatively small set of amplifiers, switches can be used to sequentially generate spherical harmonics up to third order. The costs associated with a matrix gradient coil can be lowered, which increases the practical utility of matrix gradient coils. PMID- 28841555 TI - A Vector Flow Imaging Method for Portable Ultrasound Using Synthetic Aperture Sequential Beamforming. AB - This paper presents a vector flow imaging method for the integration of quantitative blood flow imaging in portable ultrasound systems. The method combines directional transverse oscillation (TO) and synthetic aperture sequential beamforming to yield continuous velocity estimation in the whole imaging region. Six focused emissions are used to create a high-resolution image (HRI), and a dual-stage beamforming approach is used to lower the data throughput between the probe and the processing unit. The transmit/receive focal points are laterally separated to obtain a TO in the HRI that allows for the velocity estimation along the lateral and axial directions using a phase-shift estimator. The performance of the method was investigated with constant flow measurements in a flow rig system using the SARUS scanner and a 4.1-MHz linear array. A sequence was designed with interleaved B-mode and flow emissions to obtain continuous data acquisition. A parametric study was carried out to evaluate the effect of critical parameters. The vessel was placed at depths from 20 to 40 mm, with beam to-flow angles of 65 degrees , 75 degrees , and 90 degrees . For the lateral velocities at 20 mm, a bias between -5% and -6.2% was obtained, and the standard deviation (SD) was between 6% and 9.6%. The axial bias was lower than 1% with an SD around 2%. The mean estimated angles were 66.70 degrees +/- 2.86 degrees , 72.65 degrees +/- 2.48 degrees , and 89.13 degrees +/- 0.79 degrees for the three cases. A proof-of-concept demonstration of the real-time processing and wireless transmission was tested in a commercial tablet obtaining a frame rate of 27 frames/s and a data rate of 14 MB/s. An in vivo measurement of a common carotid artery of a healthy volunteer was finally performed to show the potential of the method in a realistic setting. The relative SD averaged over a cardiac cycle was 4.33%. PMID- 28841556 TI - Viscoelasticity Mapping by Identification of Local Shear Wave Dynamics. AB - Estimation of soft tissue elasticity is of interest in several clinical applications. For instance, tumors and fibrotic lesions are notoriously stiff compared with benign tissue. A fully quantitative measure of lesion stiffness can be obtained by shear wave (SW) elastography. This method uses an acoustic radiation force to produce laterally propagating SWs that can be tracked to obtain the velocity, which in turn is related to Young's modulus. However, not only elasticity, but also viscosity plays an important role in the propagation process of SWs. In fact, viscosity itself is a parameter of diagnostic value for the detection and characterization of malignant lesions. In this paper, we describe a new method that enables imaging viscosity from SW elastography by local model-based system identification. By testing the method on simulated data sets and performing in vitro experiments, we show that the ability of the proposed technique to generate parametric maps of the viscoelastic material properties from SW measurements, opening up new possibilities for noninvasive tissue characterization. PMID- 28841557 TI - Localization Performance of Multiple Vibrotactile Cues on Both Arms. AB - To present information using vibrotactile stimuli in wearable devices, it is fundamental to understand human performance of localizing vibrotactile cues across the skin surface. In this paper, we studied human ability to identify locations of multiple vibrotactile cues activated simultaneously on both arms. Two haptic bands were mounted in proximity to the elbow and shoulder joints on each arm, and two vibrotactile motors were mounted on each band to provide vibration cues to the dorsal and palmar side of the arm. The localization performance under four conditions were compared, with the number of the simultaneously activated cues varying from one to four in each condition. Experimental results illustrate that the rate of correct localization decreases linearly with the increase in the number of activated cues. It was 27.8 percent for three activated cues, and became even lower for four activated cues. An analysis of the correct rate and error patterns show that the layout of vibrotactile cues can have significant effects on the localization performance of multiple vibrotactile cues. These findings might provide guidelines for using vibrotactile cues to guide the simultaneous motion of multiple joints on both arms. PMID- 28841558 TI - Effect of Electrostatic Tactile Feedback on Accuracy and Efficiency of Pan Gestures on Touch Screens. AB - Recently, many studies examined electrostatic tactile feedback on touch screens to enrich interaction experience. However, it is unclear as to whether added tactile feedback during a sliding process increases the accuracy of pan gestures with velocity constraints. In this study, a custom-designed electrostatic tactile display was considered. Initially, the accuracy and efficiency of pan gestures were compared under two conditions, namely with and without electrostatic tactile feedback. This was followed by exploring the evolution of completion time (CT) with different indices of difficulties (ID). Experimental results with 12 participants indicated that the accuracy and completion time of pan gestures with added tactile feedback significantly exceeded those without tactile feedback. Furthermore, the relationship between CT and ID satisfied Fitts' Law with a correlation coefficient exceeding 0.9. Based on the findings, a "Tactile Fruit Sorting" game was designed, and subjective and objective evaluations were conducted. The results confirmed that the added tactile feedback enhanced both user performance and interest with respect to the game. PMID- 28841559 TI - On Selecting Effective Patterns for Fast Support Vector Regression Training. AB - It is time consuming to train support vector regression (SVR) for large-scale problems even with efficient quadratic programming solvers. This issue is particularly serious when tuning the model's parameters. One way to address the issue is to reduce the problem's scale by selecting a subset of the training set. This paper presents a fast pattern selection method by scanning the training data set to reduce a problem's scale. In particular, we find the k-nearest neighbors (kNNs) in a local region around each pattern's target value, and then determine to retain the pattern according to the distribution of its nearest neighbors. There is a high probability that the pattern locates outside the -tube. Since the kNNs of a pattern are found in a very small region, it is fast to scan the whole training data set. The proposed method deals with the year prediction Million Song Data set, which contains 463 715 patterns, within 10 s on a personal computer with an Intel Core i5-4690 CPU at 3.50 GHz and 8GB DRAM. An additional advantage of the proposed method is that it can predefine the size of the selected subset according to the training set. Comprehensive empirical evaluations demonstrate that the proposed method can significantly eliminate redundant patterns for SVR training with only a slight decrease in performance. PMID- 28841560 TI - Segmentation and Measurement of Chronic Wounds for Bioprinting. AB - OBJECTIVE: to provide a proof-of-concept tool for segmenting chronic wounds and transmitting the results as instructions and coordinates to a bioprinter robot and thus facilitate the treatment of chronic wounds. METHODS: several segmentation methods used for measuring wound geometry, including edge-detection and morphological operations, region-growing, Livewire, active contours, and texture segmentation, were compared on 26 images from 15 subjects. Ground-truth wound delineations were generated by a dermatologist. The wound coordinates were converted into G-code understandable by the bioprinting robot. Due to its desirable properties, alginate hydrogel was synthesized by dissolving 16% (w/v) sodium-alginate and 4% (w/v) gelatin in deionized water and used for cell encapsulation. RESULTS: Livewire achieved the best performance, with minimal user interaction: 97.08%, 99.68% 96.67%, 96.22, 98.15, and 32.26, mean values, respectively, for accuracy, sensitivity, specificity, Jaccard index, Dice similarity coefficient, and Hausdorff distance. The bioprinter robot was able to print skin cells on the surface of skin with a 95.56% similarity between the bioprinted patch's dimensions and the desired wound geometry. CONCLUSION: we have designed a novel approach for the healing of chronic wounds, based on semiautomatic segmentation of wound images, improving clinicians' control of the bioprinting process through more accurate coordinates. SIGNIFICANCE: this study is the first to perform wound bioprinting based on image segmentation. It also compares several segmentation methods used for this purpose to determine the best. PMID- 28841561 TI - Stochastic Configuration Networks: Fundamentals and Algorithms. AB - This paper contributes to the development of randomized methods for neural networks. The proposed learner model is generated incrementally by stochastic configuration (SC) algorithms, termed SC networks (SCNs). In contrast to the existing randomized learning algorithms for single layer feed-forward networks, we randomly assign the input weights and biases of the hidden nodes in the light of a supervisory mechanism, and the output weights are analytically evaluated in either a constructive or selective manner. As fundamentals of SCN-based data modeling techniques, we establish some theoretical results on the universal approximation property. Three versions of SC algorithms are presented for data regression and classification problems in this paper. Simulation results concerning both data regression and classification indicate some remarkable merits of our proposed SCNs in terms of less human intervention on the network size setting, the scope adaptation of random parameters, fast learning, and sound generalization. PMID- 28841562 TI - A Study on the Security Levels of Spread-Spectrum Embedding Schemes in the WOA Framework. AB - Security analysis is a very important issue for digital watermarking. Several years ago, according to Kerckhoffs' principle, the famous four security levels, namely insecurity, key security, subspace security, and stego-security, were defined for spread-spectrum (SS) embedding schemes in the framework of watermarked-only attack. However, up to now there has been little application of the definition of these security levels to the theoretical analysis of the security of SS embedding schemes, due to the difficulty of the theoretical analysis. In this paper, based on the security definition, we present a theoretical analysis to evaluate the security levels of five typical SS embedding schemes, which are the classical SS, the improved SS (ISS), the circular extension of ISS, the nonrobust and robust natural watermarking, respectively. The theoretical analysis of these typical SS schemes are successfully performed by taking advantage of the convolution of probability distributions to derive the probabilistic models of watermarked signals. Moreover, simulations are conducted to illustrate and validate our theoretical analysis. We believe that the theoretical and practical analysis presented in this paper can bridge the gap between the definition of the four security levels and its application to the theoretical analysis of SS embedding schemes. PMID- 28841563 TI - Simultaneous Observation of Hybrid States for Cyber-Physical Systems: A Case Study of Electric Vehicle Powertrain. AB - As a typical cyber-physical system (CPS), electrified vehicle becomes a hot research topic due to its high efficiency and low emissions. In order to develop advanced electric powertrains, accurate estimations of the unmeasurable hybrid states, including discrete backlash nonlinearity and continuous half-shaft torque, are of great importance. In this paper, a novel estimation algorithm for simultaneously identifying the backlash position and half-shaft torque of an electric powertrain is proposed using a hybrid system approach. System models, including the electric powertrain and vehicle dynamics models, are established considering the drivetrain backlash and flexibility, and also calibrated and validated using vehicle road testing data. Based on the developed system models, the powertrain behavior is represented using hybrid automata according to the piecewise affine property of the backlash dynamics. A hybrid-state observer, which is comprised of a discrete-state observer and a continuous-state observer, is designed for the simultaneous estimation of the backlash position and half shaft torque. In order to guarantee the stability and reachability, the convergence property of the proposed observer is investigated. The proposed observer are validated under highly dynamical transitions of vehicle states. The validation results demonstrates the feasibility and effectiveness of the proposed hybrid-state observer. PMID- 28841564 TI - Fuzzy Finite-Time Command Filtered Control of Nonlinear Systems With Input Saturation. AB - This paper considers the fuzzy finite-time tracking control problem for a class of nonlinear systems with input saturation. A novel fuzzy finite-time command filtered backstepping approach is proposed by introducing the fuzzy finite-time command filter, designing the new virtual control signals and the modified error compensation signals. The proposed approach not only holds the advantages of the conventional command-filtered backstepping control, but also guarantees the finite-time convergence. A practical example is included to show the effectiveness of the proposed method. PMID- 28841565 TI - A Multiview Learning Framework With a Linear Computational Cost. AB - Learning features from multiple views has attracted much research attention in different machine learning tasks, such as multiclass and multilabel classification problems. In this paper, we propose a multiclass multilabel multiview learning framework with a linear computational cost where an example is associated with at least one label and represented by multiple information sources. We simultaneously analyze all features by learning an integrated projection matrix. We can also automatically select more important views for subsequent classifier to predict each class. As the proposed objective function is nonsmooth and difficult to solve, we apply a novel optimization method that converts the multiview learning problem to a set of linear single-view learning problems by bridging our problem to an easily solvable approach. Compared to the conventional methods which learn the entire projection matrix, our algorithm independently optimizes each column of the projection matrix for each class, which can be easily parallelized. In each column optimization, the most computationally intensive step is pure and simple matrix-by-vector multiplication. As a result, our algorithm is much more applicable to large-scale problems than the multiview learning methods with a nonlinear computational cost. Moreover, rigorous convergence proof of the proposed algorithm is also provided. To evaluate the effectiveness of the proposed approach, experimental comparisons are made with state-of-the-art algorithms in multiclass and multilabel classification tasks on many multiview benchmarks. We also report the efficiency comparison results on different numbers of data samples. The experimental results demonstrate that our algorithm can achieve superior performance to all the compared algorithms. PMID- 28841566 TI - Protein kinase C-alpha and the regulation of diverse cell responses. AB - Protein kinase C (PKC) comprises a family of lipid-sensitive enzymes that have been involved in a broad range of cellular functions. PKC-alpha is a member of classical PKC with ubiquitous expression and different cellular localization. This unique PKC isoform is activated by various signals which evoke lipid hydrolysis, after activation it interacts with various adapter proteins and is localized to specific cellular compartments where it is devised to work. The universal expression and activation by various stimuli make it a perfect player in uncountable cellular functions including differentiation, proliferation, apoptosis, cellular transformation, motility, adhesion and so on. However, these functions are not intrinsic properties of PKC-alpha, but depend on cell types and conditions. The activities of PKC-alpha are managed by the various pharmacological activators/inhibitors and antisense oligonucleotides. The aim of this review is to elaborate the structural feature, and provide an insight into the mechanism of PKC-alpha activation and regulation of its key biological functions in different cellular compartments to develop an effective pharmacological approach to regulate the PKC-alpha signal array. PMID- 28841568 TI - Extended device profiles and testing procedures for the approval process of integrated medical devices using the IEEE 11073 communication standard. AB - Nowadays, only closed and proprietary integrated operating room systems (IORS) from big manufacturers are available on the market. Hence, the interconnection of components from third-party vendors is only possible with increased time and costs. In the context of the German Federal Ministry of Education and Research (BMBF)-funded project OR.NET (2012-2016), the open integration of medical devices from different manufacturers was addressed. An integrated operating theater based on the open communication standard IEEE 11073 shall give clinical operators the opportunity to choose medical devices independently of the manufacturer. This approach would be advantageous especially for hospital operators and small- and medium-sized enterprises (SME) of medical devices. Actual standards and concepts regarding technical feasibility and the approval process do not cope with the requirements for a modular integration of medical devices in the operating room (OR), based on an open communication standard. Therefore, innovative approval strategies and corresponding certification and test procedures, which cover actual legal and normative standards, have to be developed in order to support the future risk management and the usability engineering process of open integrated medical devices in the OR. The use of standardized device and service profiles and a three-step testing procedure, including conformity, interoperability and integration tests are described in this paper and shall support the manufacturers to integrate their medical devices without disclosing the medical devices' risk analysis and related confidential expertise or proprietary information. PMID- 28841567 TI - Breaking in and busting out: cell-penetrating peptides and the endosomal escape problem. AB - Cell-penetrating peptides (CPPs) have long held great promise for the manipulation of living cells for therapeutic and research purposes. They allow a wide array of biomolecules from large, oligomeric proteins to nucleic acids and small molecules to rapidly and efficiently traverse cytoplasmic membranes. With few exceptions, if a molecule can be associated with a CPP, it can be delivered into a cell. However, a growing realization in the field is that CPP-cargo fusions largely remain trapped in endosomes and are eventually targeted for degradation or recycling rather than released into the cytoplasm or trafficked to a desired subcellular destination. This 'endosomal escape problem' has confounded efforts to develop CPP-based delivery methods for drugs, enzymes, plasmids, etc. This review provides a brief history of CPP research and discusses current issues in the field with a primary focus on the endosomal escape problem, for which several promising potential solutions have been developed. Are we on the verge of developing technologies to deliver therapeutics such as siRNA, CRISPR/Cas complexes and others that are currently failing because of an inability to get into cells, or are we just chasing after another promising but unworkable technology? We make the case for optimism. PMID- 28841569 TI - Results of the first external quality assessment scheme (EQA) for isolation and analysis of circulating tumour DNA (ctDNA). AB - BACKGROUND: Circulating tumour DNA (ctDNA) is considered to have a high potential for future management of malignancies. This pilot external quality assessment (EQA) scheme aimed to address issues of analytical quality in this new area of laboratory diagnostics. METHODS: The EQA scheme consisted of three 2-mL EDTA plasma samples spiked with fragmented genomic DNA with a mutant allele frequency ranging from 0% to 10% dedicated to the analysis of nine known sequence variations in KRAS codon 12/13 and of BRAF V600E. Laboratories reported: (1) time elapsed for processing, (2) storage temperatures, (3) methods for extraction and quantification, (4) genotyping methodologies and (5) results. RESULTS: Specimens were sent to 42 laboratories from 10 European countries; 72.3% reported to isolate cell-free DNA (cfDNA) manually, 62.5% used the entire plasma volume for cfDNA isolation and 38.5% used >10% of cfDNA extracted for downstream genotyping. Of the methods used for quantification, PicoGreen demonstrated the lowest coefficient of variation (33.7%). For genotyping, 11 different methods were reported with the highest error rate observed for Sanger sequencing and the lowest for highly sensitive approaches like digital PCR. In total, 197 genotypes were determined with an overall error rate of 6.09%. CONCLUSIONS: This pilot EQA scheme illustrates the current variability in multiple phases of cfDNA processing and analysis of ctDNA resulting in an overall error rate of 6.09%. The areas with the greatest variance and clinical impact included specimen volume, cfDNA quantification method, and preference of genotyping platform. Regarding quality assurance, there is an urgent need for harmonisation of procedures and workflows. PMID- 28841570 TI - Diagnosis biomarkers in acute intestinal ischemic injury: so close, yet so far. AB - Acute intestinal ischemic injury (i3) is a life-threatening condition with disastrous prognosis, which is currently difficult to diagnose at the early stages of the disease; a rapid diagnosis is mandatory to avoid irreversible ischemia, extensive bowel resection, sepsis and death. The overlapping protein expression of liver and gut related to the complex physiopathology of the disease, the heterogeneity of the disease and its relative rarity could explain the lack of a useful early biochemical marker of i3. Apart from non-specific biological markers of thrombosis, hypoxia inflammation, and infection, several more specific biomarkers in relation with the gut barrier dysfunction, the villi injury and the enterocyte mass have been used in the diagnosis of acute i3. It includes particularly D-lactate, intestinal fatty acid-binding protein (FABP) and citrulline. Herein, we will discuss leading publications concerning these historical markers that point out the main limitations reagrding their use in routine clinical practice. We will also introduce the first and limited results arising from omic studies, underlying the remaining effort that needs to be done in the field of acute i3 biological diagnosis, which remains a challenge. PMID- 28841571 TI - BD Vacutainer(r) Barricor tube in the emergency department: reduced hemolysis rates using partial draw tubes with reduced vacuum. PMID- 28841572 TI - Use of the sFlt-1/PlGF ratio to rule out preeclampsia requiring delivery in women with suspected disease. Is the evidence reproducible? AB - BACKGROUND: Soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio has been proven to predict preeclampsia occurrence. METHODS: Blood samples from 195 pregnant women with suspected preeclampsia were obtained at obstetric triage admission or from the high-risk pregnancy outpatient office. Serum PlGF and sFlt-1 were measured by an electrochemiluminescence immunoassay (ECLIA) on the immunoanalyser Cobas e601 (Roche Diagnostics) and the corresponding ratio was calculated. Final outcomes were reviewed by an independent obstetrician. Only the first determination was considered. RESULTS: A sFlt-1/PlGF ratio of 38 or lower ruled out the need for pregnancy termination due to preeclampsia in the subsequent week with a negative predictive value (NPV) of 99.1% (sensitivity 97.1% and specificity 67.5%). None of the 76 pregnancies with first determination of an sFlt-1/PlGF ratio of 38 or lower between 24 and 34 weeks of gestation delivered due to early-onset preeclampsia. Positive likelihood ratio (PLR) of an sFlt-1/PlGF ratio above 38 for prediction of pregnancy termination due to preeclampsia within 4 weeks is analogous to published evidence. CONCLUSIONS: Between 24 and 34 weeks of gestation, no subsequent determination was needed to completely rule out early-onset preeclampsia when the first sFlt-1/PlGF ratio determination was 38 or lower in singleton pregnancies with signs or symptoms of this syndrome. These findings, if confirmed, will reduce costs and facilitate the implementation of the sFlt-1/PlGF ratio in women with clinical suspicion of preeclampsia in the third trimester. PMID- 28841573 TI - Pediatric providers' attitudes and practices regarding concussion diagnosis and management. AB - Background Concussions, a form of mild traumatic brain injury, are a current "hot topic" in sports and medicine, with current research focusing on diagnosis, treatment, and the long-term effects of repeated concussions on development of chronic traumatic encephalopathy. Concussions represent 8.9% of all high school athletic injuries, and pediatricians see many of these patients in their practices, however evolving guidelines and recommendations have resulted in varying practices among providers. Objective To assess how local pediatricians in New York Chapter 2 of the American Academy of Pediatrics (AAP) diagnose and treat concussion patients, and to evaluate the need for continuing education in this area. Design and methods Survey MonkeyTM was used to query providers regarding their diagnosis and treatment of concussion patients. A total of three emails containing a link to the 22 question multiple-choice survey were sent to AAP Chapter 2 members between January 2015 and June 2015. The survey was adapted and modified with permission from one previously used by "Zonfrillo MR, Master CL, Grady MF, Winston FK, Callahan JM, Arbogast KB. Pediatric providers' self reported knowledge, practices, and attitudes about concussion. Pediatrics. 2012;130:1120-5". Results We received 115 responses from 1436 potential participants to whom the survey link was sent, resulting in an 8% response rate. We excluded subspecialists from our data analysis, resulting in data from 95 primary care pediatricians. Of the PCPs 98.7% reported seeing at least one child or adolescent with a concussion in the previous 12 months and 76.6% reported referring some or all of their concussion patients for ongoing management. The most common reason for referral was "I am not always comfortable with management" and the most common subspecialist referral was to a neurologist. Most providers reported that they did not use any guidelines for management (58.3%) and only 57.4% were familiar with the New York State Education Department concussion guidelines. Almost half reported inadequate training in performing neurocognitive assessments (48.6%). Most were comfortable educating families about the diagnosis of concussion (81.7%), as well as recommending the appropriate time to resume school (70.4%) and prescribing and monitoring a return to play protocol (62%). A total of 84.3% also responded, however, that they would be interested in a webinar for a continuing medical education(CME) credit focused on concussion diagnosis and management. Conclusions Most pediatric providers care for patients who have suffered a concussion, however many identify barriers to diagnosis and treatment, which results in patients being referred to subspecialists for further management. Many providers are also unfamiliar with, or do not use, published concussion guidelines and report varying practices in treatment of concussion patients due to evolving recommendations. This study demonstrates that there is a need for further education for pediatric providers who see patients with concussion. PMID- 28841574 TI - Subjective social status and its relationship to health and health behavior: comparing two different scales in university students. AB - Background Little is known about the relationship between socioeconomic status (SES) and health in late adolescence. As it is difficult to measure SES in this age group directly, we used two subjective social status (SSS) scales with different reference groups for social comparison in the relatively homogeneous group of university students and analyzed the relationship with health and health behaviors. Methods We used two 10-rung ladders, a societal and a university one, to measure SSS in students (n = 689, 16-29 years). We compared the scales' ratings and analyzed relationships with sociodemographic factors, health outcomes and behaviors. Results On average, students rated their individual SSS higher on the university scale (6.87) than on the societal one (6.41). Regarding health outcomes and behaviors, we found similar results for both scales, while sociodemographic variables were more likely to be associated with the societal scale. Conclusion SSS seems to be a useful measure besides the objective SES. Our data suggest that both SSS scales are helpful in the framework of health inequality but differ slightly in what they measure. More detailed research may help to determine which scale is appropriate for individual study context. PMID- 28841575 TI - Relation of insulin resistance to neurocognitive function and electroencephalography in obese children. AB - BACKGROUND: Childhood obesity may lead to neuronal impairment in both the peripheral and the central nervous system. This study aimed to investigate the impact of obesity and insulin resistance (IR) on the central nervous system and neurocognitive functions in children. METHODS: Seventy-three obese children (38 male and 35 female) and 42 healthy children (21 male and 21 female) were recruited. Standard biochemical indices and IR were evaluated. The Wechsler Intelligence Scale for Children-Revised (WISC-R) and electroencephalography (EEG) were administered to all participants. The obese participants were divided into two groups based on the presence or absence of IR, and the data were compared between the subgroups. RESULTS: Only verbal scores on the WISC-R in the IR+ group were significantly lower than those of the control and IR- groups. There were no differences between the groups with respect to other parameters of the WISC-R or the EEG. Verbal scores of the WISC-R were negatively correlated with obesity duration and homeostatic model assessment-insulin resistance (HOMA-IR) values. EEGs showed significantly more frequent 'slowing during hyperventilation' (SDHs) in obese children than non-obese children. CONCLUSIONS: Neurocognitive functions, particularly verbal abilities, were impaired in obese children with IR. An early examination of cognitive functions may help identify and correct such abnormalities in obese children. PMID- 28841576 TI - Diagnostic value of perinatal autopsies: analysis of 486 cases. AB - AIM: Autopsy is a beneficial procedure to determine the cause of death and the frequency of anomalies in perinatal losses. Even in the event of an autopsy not providing any additional information, completion of the procedure confirming the clinical diagnoses gives reassurance to both clinicians and parents. Here we present a 15-year archival study based on findings of perinatal autopsies. DESIGN AND METHODS: Four hundred and eighty-six cases from our archive were reviewed and according to the findings they were divided into three subcategories; (1) miscarriages (MCF); (2) fetuses terminated (FTA) for vital anomalies detected by prenatal ultrasonography; (3) premature or term newborns died within first month of life (neonates: NN). Autopsies were documented and classified according to week/age of cases, anomalies and causes of abortion or death. RESULTS: Two hundred and twenty-six of 486 cases (46.5%) were in MCF group while 227 (46.7%) and 33 (6.8%) were of them in FTA and NN groups, respectively. In FTA group, the most frequent anomaly detected was neural tube defects. In NN group, prematurity related complications were the most common cause of death. The autopsy process was found valuable in 39.7% of all cases. CONCLUSIONS: We suggest that autopsy procedure is diagnostically valuable even in situations when there is USG findings that are confirming FTAs or there is no important major fetal or placental anomaly detected in MCFs. PMID- 28841577 TI - Experimental neonatal hypoxia ischemia causes long lasting changes of oxidative stress parameters in the hippocampus and the spleen. AB - Neonatal hypoxia ischemia (HI) is the main cause of mortality and morbidity in newborns. The mechanisms involved in its progression start immediately and persist for several days. Oxidative stress and inflammation are determinant factors of the severity of the final lesion. The spleen plays a major part in the inflammatory response to HI. This study assessed the temporal progression of HI induced alterations in oxidative stress parameters in the hippocampus, the most affected brain structure, and in the spleen. HI was induced in Wistar rat pups in post-natal day 7. Production of reactive oxygen species (ROS), and the activity of the anti oxidant enzyme superoxide dismutase and catalase were assessed 24 h, 96 h and 38 days post-HI. Interestingly, both structures showed a similar pattern, with few alterations in the production of ROS species up to 96 h often combined with an increased activity of the anti oxidant enzymes. However, 38 days after the injury, ROS were at the highest in both structures, coupled with a decrease in the activity of the enzymes. Altogether, present results suggest that HI causes long lasting alterations in the hippocampus as well as in the spleen, suggesting a possible target for delayed treatments for HI. PMID- 28841578 TI - Psychiatric Presentations During All 4 Phases of the Lunar Cycle. AB - Context * Anecdotal evidence concerning a relationship between human illnesses and a full moon is frequently claimed by as many as 81% of mental health workers. Previous scientific investigations have studied only the full-moon phase and its possible effect on psychiatric presentations. However, information is limited about all 4 phases of the lunar cycle and their effects on different types of psychiatric disorders. Objective * This study primarily intended to evaluate the number of psychiatric presentations to a hospital's emergency department across all 4 phases of the lunar cycle. The secondary objective was to investigate the statistical differences among 5 categories of common mental disorders in relation to the 4 lunar phases. Design * This study was an observational analytic cohort study. Setting * The study took place in the emergency department of a 140-bed, community-teaching hospital. Participants * Participants were 1857 patients who were aged >17 y and who had had a psychiatric component to a visit to the emergency department. Outcome Measures * Data from electronic medical records were collected for 41 consecutive months. The participants were divided into 5 diagnostic groups based on the Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5). The study measured the number of psychiatric presentations for each group during the 4 National Aeronautics and Space Administration (NASA)-defined phases of the lunar cycle, and the study was statistically powered to detect small effects. Results * The following psychiatric presentations occurred: (1) 464 during the new moon; (2) 483 during the first quarter; (3) 449 during the full moon; and (4) 461 during the third quarter (4-group overall chi2, P = .89). Differences between the 5 diagnostic categories across the 4 lunar phases were not statistically significant (4-group overall chi2, P = .85 for the 5 diagnostic categories). Conclusions * Although many traditional and nontraditional providers believe in effects caused by the full moon based on casual observation or anecdotal evidence, this perception was not supported in the current study. Furthermore, no evidence demonstrated increased psychiatric presentations during the other 3 phases of the lunar cycle. The study found that the lunar cycle did not have an effect on the incidence of psychiatric presentations or on the DSM-5 categories. If lunar effects exist, they are probably small or infrequent, making them difficult to validate statistically. The current study's results, in concert with those of most other studies on the subject, provide evidence that should help dismiss misconceptions about the magnitude or frequency of lunar effects on psychiatric illnesses. PMID- 28841579 TI - Oxygen beams for therapy: advanced biological treatment planning and experimental verification. AB - Nowadays there is a rising interest towards exploiting new therapeutical beams beyond carbon ions and protons. In particular, [Formula: see text]O ions are being widely discussed due to their increased LET distribution. In this contribution, we report on the first experimental verification of biologically optimized treatment plans, accounting for different biological effects, generated with the TRiP98 planning system with [Formula: see text]O beams, performed at HIT and GSI. This implies the measurements of 3D profiles of absorbed dose as well as several biological measurements. The latter includes the measurements of relative biological effectiveness along the range of linear energy transfer values from ~20 up to ~750 keV MU [Formula: see text], oxygen enhancement ratio values and the verification of the kill-painting approach, to overcome hypoxia, with a phantom imitating an unevenly oxygenated target. With the present implementation, our treatment planning system is able to perform a comparative analysis of different ions, according to any given condition of the target. For the particular cases of low target oxygenation, [Formula: see text]O ions demonstrate a higher peak-to-entrance dose ratio for the same cell killing in the target region compared to [Formula: see text]C ions. Based on this phenomenon, we performed a short computational analysis to reveal the potential range of treatment plans, where [Formula: see text]O can benefit over lighter modalities. It emerges that for more hypoxic target regions (partial oxygen pressure of ~0.15% or lower) and relatively low doses (~4 Gy or lower) the choice of [Formula: see text]O over [Formula: see text]C or [Formula: see text]He may be justified. PMID- 28841580 TI - Durable Biventricular Support Using Right Atrial Placement of the HeartWare HVAD. AB - Patients with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) levels 1-2 who either have or are at risk for right ventricular failure face significant morbidity and mortality after continuous flow left ventricular assist device (CF-LVAD) implantation. Currently, the options for biventricular support are limited the Total Artificial Heart (TAH; CardioWest, Syncardia, Tuscon, AZ) or biventricular assist device (BiVAD), which uses bulky extracorporeal or implantable displacement pumps. We describe a successful series based on an innovative approach for biventricular support in consecutive INTERMACS levels 1-2 patients utilizing a HeartWare Ventricular Assist Device (HVAD; HeartWare, Framingham, MA) in a left ventricular (LV-HVAD) and a right atrial (RA-HVAD) configuration. From June 2014 through May 2016, 11 consecutive INTERMACS levels 1-2 patients with evidence of biventricular failure underwent implantation of a CF LVAD (10 LV-HVAD and 1 HeartMate II LVAD, Thoratec, Pleasanton, CA) and RA-HVAD pumps. A total of 4,314 BiVAD support days were accumulated in our case series. Seven patients have undergone orthotopic heart transplant, whereas 3 are ambulatory and are either waiting transplant or reconsideration for transplantation. There is one mortality in this case series, which was due to an intracranial bleed from supratherapeutic anticoagulation. Two other patients experienced hemorrhagic strokes, but without neurologic sequelae, whereas no patients have experienced ischemic strokes. There were two episodes of gastrointestinal bleeding. This is the largest series to date involving this approach with outcomes superior to those previously described in patients receiving biventricular support. We conclude this novel therapy is a viable alternative to current practices in the management of biventricular failure. PMID- 28841581 TI - Predictors of Survival for Nonhighly Selected Patients Undergoing Resuscitation With Extracorporeal Membrane Oxygenation After Cardiac Arrest. AB - In several case reports and case series, extracorporeal membrane oxygenation during chest compression (CPR) has been shown to be a reasonable tool to improve outcome of patients under resuscitation. Although recommendations for extracorporeal cardiopulmonary resuscitation (ECPR) include younger patients with shockable rhythm and short previous CPR-time, it remains unclear if nonhighly selected patients have a similar outcome. Aim of this study was to determine outcome in our nonhighly selected patient population treated with ECPR and investigate possible predictors of survival. We made a retrospective single center study of adults who underwent ECPR for in-hospital cardiac arrest between June 2008 and September 2016. Outcome and predictors of survival were identified. In this period of time, 59 patients underwent ECPR due to cardiac arrest. Fifteen patients (25.4%) survived discharge of which all had a good neurological outcome (cerebral performance category <= 2). Survival to discharge of patients with shockable rhythm (ventricular fibrillation or ventricular tachycardia) was 40.7%. Serum lactate >= 8, pulseless electrical activity (PEA) or asystole and male gender could be identified as predictors for low survival rate. Age, body mass index, renal replacement-dependent kidney injury had no significant influence on survival outcome. Mean CPR-time was 41.1 minutes (interquartile range, +/-29.25 minutes). Extracorporeal membrane oxygenation seems to be a useful tool to improve the outcome of CPR also in nonhighly selected patients when compared with CPR alone and could be considered in patients with refractory cardiac arrest also after longer previous CPR-time. Serum lactate and heart rhythm should be taken into account for patient selection. PMID- 28841582 TI - Virologic Response to Early Antiretroviral Therapy in HIV-infected Infants: Evaluation After 2 Years of Treatment in the Pediacam Study, Cameroon. AB - INTRODUCTION: Little is known about virologic responses to early antiretroviral therapy (ART) in HIV-infected infants in resource-limited settings. We estimated the probability of achieving viral suppression within 2 years of ART initiation and investigated the factors associated with success. METHODS: We analyzed all 190 infants from the Cameroon Pediacam who initiated ART by 12 months of age. The main outcome measure was viral suppression (<1000 copies/mL) on at least 1 occasion; the other outcome measures considered were viral suppression (<400 copies/mL) on at least 1 occasion and confirmed viral suppression (both thresholds) on 2 consecutive occasions. We used competing-risks regression for a time-to-event analysis to estimate the cumulative incidence of outcomes and univariate and multivariate models to identify risk factors. RESULTS: During the first 24 months of ART, 20.0% (38) of the infants died, giving a mortality rate of 11.9 deaths per 100 infant-years (95% confidence interval: 8.1-15.7). The probability of achieving a viral load below 1000 or 400 copies/mL was 80.0% (69.0 81.0) and 78.0% (66.0-79.0), respectively. The probability of virologic suppression (with these 2 thresholds) on 2 consecutive occasions was 67.0% (56.0 70.0) and 60.0% (49.0-64.0), respectively. Virologic success was associated with not having missed any doses of treatment before the visit, but not with socioeconomic and living conditions. CONCLUSION: Many early treated children failed to achieve virologic suppression, likely due to a combination of adherence difficulties, drug dosing and viral resistance, which highlights the need for routine viral load monitoring. The high infant mortality despite early ART initiation needs to be addressed in sub-Saharan countries. PMID- 28841583 TI - Persistent Gram-negative Neurosurgical Meningitis in a Neonate, Successfully Treated With Intraventricular Colistin: Case Report and Review of the Literature. AB - We present a case of Gram-negative neurosurgical meningitis in a neonate, refractory to optimal intravenous therapy and removal of ventriculoperitoneal shunt. Cerebrospinal fluid was sterilized within 24 hours using intraventricular colistin. This is the first report of intraventricular colistin use in neonatal meningitis caused by Enterobacter cloacae. PMID- 28841584 TI - CONTAMINATION OF ANTI-VEGF DRUGS FOR INTRAVITREAL INJECTION: How Do Repackaging and Newly Developed Syringes Affect the Amount of Silicone Oil Droplets and Protein Aggregates? AB - PURPOSE: The particle counts and the nature of particles of three different antivascular endothelial growth factor agents (VEGF) in different containers in a laboratory setting were compared. METHODS: Original prefilled ranibizumab glass syringes, original vials with aflibercept, and repacked ready-to-use plastic syringes with bevacizumab from a compounding pharmacy and a compounding company (CC) were analyzed. Particle counts and size distributions were quantified by different particle characterization methods (nephelometry, light obscuration, Micro-Flow Imaging, nanotracking analysis, resonant mass measurement). Using high performance size-exclusion chromatography (HP-SEC), levels of protein drug monomer and soluble aggregates were determined. RESULTS: Nearly all samples showed similar product quality. Light obscuration and Micro-Flow Imaging showed a 4-fold to 9-fold higher total particle count in compounding company bevacizumab (other samples up to 42,000 particles/mL). Nanotracking analysis revealed highest values for compounding company bevacizumab (6,375 million particles/mL). All containers showed similar amounts of silicone oil microdroplets. Ranibizumab showed lowest particle count of all tested agents with only one monomer peak in HP-SEC. Repackaged bevacizumab from different suppliers showed varying product quality. CONCLUSION: All three tested agents are available in similar quality regarding particulate purity and silicone oil microdroplet count. Repackaging can have a major impact on the quality. PMID- 28841585 TI - Optic Disc Drusen in Children: The Copenhagen Child Cohort 2000 Eye Study. AB - BACKGROUND: Optic disc drusen (ODD) are seen in up to 2.4% of the general population, but the etiology and pathophysiology of the condition is still unknown. The purpose of this study was to determine the prevalence of ODD in a population-based child cohort and to determine if scleral canal diameter and fetal birth and pubertal parameters are associated with the presence of ODD. METHODS: This observational, longitudinal population-based birth cohort study, with a nested case-control, included 1,406 children. Eye examinations were performed when the children were between 11 and 12 years of age. Assessment was performed of optical coherence tomography (OCT) scans from 1,304 children with gradable enhanced depth imaging scans of the optic disc. RESULTS: ODD in one or both eyes were found in 13 (1.0%) of all children. All but one of the cases were found in children with scleral canal diameter in the lowest quartile (1,182-1,399 MUm) in the nested case-control study. Children with ODD had a mean disc diameter of 1,339 MUm (interquartile range, 30 MUm), whereas it was 1,508 MUm (interquartile range, 196 MUm) in the 130 controls without ODD (P < 0.001). No differences in sex, birth weight, refractive error, and Tanner stages (of puberty) were found between children with and without ODD. CONCLUSIONS: The prevalence of ODD was 1% in a large child cohort examined by OCT. ODD was found only in eyes with a narrow scleral canal, which is consistent with the hypothesis that ODD might arise as a consequence of retinal nerve fiber congestion in the scleral canal. PMID- 28841586 TI - Jaw Claudication and Temporal Artery Abnormalities in Giant Cell Arteritis: Take Advantage of Clinical Clues. PMID- 28841587 TI - Jaw Claudication and Temporal Artery Abnormalities in Giant Cell Arteritis: Take Advantage of Clinical Clues: Response. PMID- 28841588 TI - Thrombosis in adult patients with acute leukemia. AB - PURPOSE OF REVIEW: Recent studies indicate that the risk of thrombosis in hematologic patients may be similar or even higher than that found in patients with solid tumors. However, available information about pathogenesis and incidence of thrombosis in acute leukemia is limited. This review focuses on mechanisms underlying thrombosis in acute leukemia and discusses recent literature data. RECENT FINDINGS: In the last few years, proofs have been provided that leukemic cells release free prothrombotic products, such as micro vesicles, tissue factors, circulating free DNA and RNA. Furthermore, leukemic blasts can activate the procoagulant population of platelets, which initiate and amplify coagulation, causing thrombosis. In addition to factors produced by acute leukemia itself, others concur to trigger thrombosis. Some drugs, infections and insertion of central venous catheter have been described to increase risk of thrombosis in patients with acute leukemia. SUMMARY: Thrombosis represents a serious complication in patients affected by myeloid and lymphoid acute leukemia. A proper knowledge of its pathophysiology and of the predisposing risk factors may allow to implement strategies of prevention. Improving prevention of thrombosis appears a major goal in patients whose frequent conditions of thrombocytopenia impede an adequate delivery of anticoagulant therapy. PMID- 28841589 TI - Role of stem cell transplant in lymphoma in the era of new drugs. AB - PURPOSE OF REVIEW: Better understanding of the lymphoma pathogenesis and molecular biology has introduced a new era in the lymphoma therapy with the advent of targeted drugs. In this new era, the role of hematopoietic stem cell transplantation (HSCT) is evolving, and the purpose of this review is to demonstrate how the introduction of novel agents has affected the current treatment strategy of different subtypes of lymphoma. RECENT FINDINGS: Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed Hodgkin Lymphoma and high-grade non-Hodgkin lymphoma (NHL). In the group of the indolent lymphomas, ASCT maintains its role in the relapsed setting. Novel targeted agents like idelalisib and ibrutinib have shown to induce prolonged remissions with a very good safety profile. However, the follow-up is still relatively short and none of these drugs have demonstrated a curative potential, as opposed to HSCT. SUMMARY: For many authors, the advent of new targeted drugs is challenging the role of HSCT in different subsets of lymphoma. The actual challenge is how to make the best use of these drugs, in certain circumstances in combination with HSCT, to further improve the outcome of patients with lymphoma. PMID- 28841590 TI - Cardiovascular involvement in myositis. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update on cardiovascular involvement in idiopathic inflammatory myopathy (IIM). Studies from the past 18 months are identified and reviewed. Finally, the clinical impact of these findings is discussed. RECENT FINDINGS: Epidemiological studies have revealed an increased risk of myocardial infraction and venous thromboembolism (VTE) - including deep venous thrombosis and pulmonary embolism - in adults with polymyositis or dermatomyositis compared to the general population, even after adjustment for potential confounders. This increased risk applies particularly within the initial year of diagnosis. In addition, cross-sectional studies have shown subclinical cardiac involvement in IIM effecting both heart function and rhythm, and conduction abnormalities, which in part might be because of myocarditis. The International Consensus Group on cardiac magnetic resonance (CMR) imaging suggests that CMR should be considered as a potentially viable diagnostic tool to evaluate the possibility of silent myocardial inflammation in IIM with normal routine noninvasive evaluation. SUMMARY: Updated literature on cardiovascular involvement in IIM has identified an increased risk for subclinical and clinical cardiovascular disease in these rare inflammatory muscle diseases. PMID- 28841591 TI - Further developments. PMID- 28841592 TI - Intracranial Enterogenous Cysts Close to the Brainstem Treated Through the Nerve Endoscope. AB - Enterogenous cysts (ECs) are rare, inborn lesions of central nervous system, which mostly occurred in the ventral side of the spinal cord as well as common in children; adult intracranial cysts are rare. Although the morbidity of intracranial ECs is quite low, we also can make a preliminary diagnosis of those patients with the help of imaging examination. In this article, we introduced 1 case of ECs ventral to the brainstem, which present images on magnetic resonance imaging as hypointense lesions on T1-weighted and high-intensity mass on T2 weighted image. In consideration of the difficulty of the surgical approach and the surgical visual field exposure, we use microscope and nerve endoscope to design personalized surgical approach to minimize the surgical injury. Pathologic examination showed that it was typical EC. Not only is the location extremely rare, but also the surgical method is uncommon in this disease. We not only study the intracranial ECs' manifestations, but also discuss the surgical approach and the application of nerve endoscope of our choice,which aims to provides a new surgical therapeutic approach for these lesions. PMID- 28841593 TI - Repair of Craniomaxillofacial Traumatic Soft Tissue Defects With Tissue Expansion in the Early Stage. AB - BACKGROUND: Craniomaxillofacial traumatic soft tissue defects severely affect the function and appearance of the patients. The traditional skin grafting or free flap transplantation can only close the defects in the early stage of operation but cannot ensure similar color, texture, and relative aesthetic contour. In the present study, the authors have explored a novel strategy to repair craniomaxillofacial traumatic soft tissue defects by tissue expansion in the early stage and have obtained satisfactory results. METHODS: Eighteen patients suffering large craniomaxillofacial traumatic soft tissue defects were treated by thorough debridement leaving the wounds unclosed or simply closed with thin split thickness scalp grafts, adjacent expander implantation in the first stage, and expanded flap transposition in the second stage. RESULTS: There were 11 male patients and 7 female patients ranging in age from 3.5 to 40 years (mean, 19.4 +/ 12.2 years), with average 15 months follow-up (range, 3-67 months). The average expansion time was 74.3 days (range, 53-96 days). The 18 patients with a total of 22 expanders were treated with satisfactory results. All the flaps survived and the skin color, texture, and contour well matched those of the peripheral tissue. Only 1 complication of infection happened in the 18 cases (5.56%) and the 22 expanders (4.55%), which was similar to the rate reported in the literature. No other complications related to the expanders occurred. CONCLUSION: Debridement and tissue expansion in the early stage has been proved to be a more effective strategy to repair craniomaxillofacial traumatic soft tissue defects. This strategy can not only achieve satisfactory color, unbulky and well-matched texture similar to normal, but also avoid unnecessary donor site injuries. PMID- 28841594 TI - Comprehensive Treatment of Primary Orbital Arteriovenous Malformation. AB - Primary orbital arteriovenous malformations are a rare kind of vascular malformation lesions. The authors present a 17-year-old man presented with swelling and pulsation in the left upper eyelid. The angiogram of the left internal carotid artery showed that arteriovenous malformations at the left upper eyelid area were supplied with one of the branches of ophthalmic artery. In this report, the authors elaborated the comprehensive treatments of primary arteriovenous malformation. PMID- 28841595 TI - Evaluation of Palatal Bone Thickness for Insertion of Orthodontic Mini-Implants in Adults and Adolescents. AB - OBJECTIVE: The aim of this study was to measure palatal bone thickness and select relatively safe regions for mini-implant insertion, and to determine the effect of age and sex on palatal bone thickness and whether there is any difference between right and left sides. MATERIALS AND METHODS: Cone beam computed tomographic (CBCT) evaluation was used on 107 healthy orthodontic patients, including 51 adolescents (12.90 +/- 1.71 years) and 56 adults (26.09 +/- 4.35 years), who were selected from the Zhongshan Hospital, Fudan University (Shanghai, China). Seventy-two sites of bone thickness were measured in the palate. Intragroup, intergroup, and sex differences were analyzed by repeated measures analysis of variance. RESULTS: Palatal bone thickness exhibited significant differences in 3 anteroposterior areas of the 2 groups. From anterior to posterior region, palatal bone thickness gradually decreased. Meanwhile, on the sagittal plane, palatal bone thickness decreased gradually from reference line 0 to 9 mm among adults, and from reference line 0 to 12 mm among adolescents posterior to the level of the posterior rim of the incisive foramen. However, on the coronal plane, no significant differences were found in the palatal bone thickness among reference lines 2, 4, 6, and 8 mm lateral to the midpalatal suture. Nor were there differences between right and left sides, between adults and adolescents or between males and females. CONCLUSIONS: In terms of bone thickness, the anterior region is relatively safe for orthodontic mini-implant insertion. However, since subjects vary greatly, CBCT scans are needed before undertaking mini-implant insertion. PMID- 28841596 TI - Global Medical Cooperation With the East and West: Achieve Excellence in Craniofacial Surgery. PMID- 28841597 TI - Macrotextured Breast Implants with Defined Steps to Minimize Bacterial Contamination around the Device: Experience in 42,000 Implants. AB - BACKGROUND: Bacteria/biofilm on breast implant surfaces has been implicated in capsular contracture and breast implant-associated anaplastic large-cell lymphoma (ALCL). Macrotextured breast implants have been shown to harbor more bacteria than smooth or microtextured implants. Recent reports also suggest that macrotextured implants are associated with a significantly higher incidence of breast implant-associated ALCL. Using techniques to reduce the number of bacteria around implants, specifically, the 14-point plan, has successfully minimized the occurrence of capsular contracture. The authors hypothesize that a similar effect may be seen in reducing the risk of breast implant-associated ALCL. METHODS: Pooled data from eight plastic surgeons assessed the use of macrotextured breast implants (Biocell and polyurethane) and known cases of breast implant-associated ALCL. Surgeon adherence to the 14-point plan was also analyzed. RESULTS: A total of 42,035 Biocell implants were placed in 21,650 patients; mean follow-up was 11.7 years (range, 1 to 14 years). A total of 704 polyurethane implants were used, with a mean follow-up of 8.0 years (range, 1 to 20 years). The overall capsular contracture rate was 2.2 percent. There were no cases of implant associated ALCL. All surgeons routinely performed all 13 perioperative components of the 14-point plan; two surgeons do not routinely prescribe prophylaxis for subsequent unrelated procedures. CONCLUSIONS: Mounting evidence implicates the role of a sustained T-cell response to implant bacteria/biofilm in the development of breast implant-associated ALCL. Using the principles of the 14 point plan to minimize bacterial load at the time of surgery, the development and subsequent sequelae of capsular contracture and breast implant-associated ALCL may be reduced, especially with higher-risk macrotextured implants. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28841598 TI - Discussion: Prepectoral Breast Reconstruction: A Safe Alternative to Submuscular Prosthetic Reconstruction following Nipple-Sparing Mastectomy. PMID- 28841599 TI - Treating Breast Conservation Therapy Defects with Brava and Fat Grafting: Technique, Outcomes, and Safety Profile. AB - BACKGROUND: Fat grafting has been demonstrated as a means of reconstructing breast conservation therapy defects. However, there is continued uncertainty regarding its clinical efficacy and oncologic safety. Furthermore, the role of external preexpansion (i.e., with the Brava device) remains unclear in this setting. The purpose of this study was to examine the safety and clinical outcomes of Brava/fat grafting following breast conservation therapy. METHODS: A retrospective chart review was performed on all patients undergoing fat grafting following breast conservation therapy. Complications were defined as either a clinically palpable oil cyst/area of fat necrosis or infection. The mean time of follow-up was 2.3 years. RESULTS: A total of 27 fat grafting sessions were performed on 20 patients, with an overall complication rate of 25 percent. The mean interval from completion of radiation therapy to fat grafting was 7 years and was not a significant predictor for complications (p = 0.46). Among those who underwent repeated grafting, there was no difference in the complication rates between their first and second encounters (p = 0.56). There was no difference in complication rates between patients with Brava preexpansion and those without preexpansion. Patients undergoing Brava preexpansion had a significantly higher initial fill volume in comparison with those who did not (219 cc versus 51 cc; p = 0.0017). There were no cases of locoregional cancer recurrence following fat grafting. CONCLUSION: Brava preexpansion was associated with higher initial fill volume in the setting of breast conservation therapy defects. PMID- 28841600 TI - Determining the Oncologic Safety of Autologous Fat Grafting as a Reconstructive Modality: An Institutional Review of Breast Cancer Recurrence Rates and Surgical Outcomes. AB - BACKGROUND: The increasing use of autologous fat grafting in breast cancer patients has raised concerns regarding its oncologic safety. This study evaluated patient outcomes and tumor recurrence following mastectomy reconstruction and autologous fat grafting. METHODS: Retrospective chart review identified patients who underwent mastectomy followed by breast reconstruction from 2010 to 2015. Eight hundred twenty-nine breasts met inclusion criteria: 248 (30.0 percent) underwent autologous fat grafting, whereas 581 (70.0 percent) breasts did not. Patient demographics, cancer characteristics, oncologic treatment, surgical treatment, surgical complications, local recurrence, and distant metastases were analyzed. RESULTS: Autologous fat grafting patients and control patients were of similar body mass index, smoking status, and BRCA status. Patients who underwent fat grafting were significantly younger than control patients and were less likely to have diabetes, hypertension, or hyperlipidemia. The two groups represented similar distributions of BRCA status, Oncotype scores, and hormone receptor status. Patients underwent one to four grafting procedures: one procedure in 83.1 percent, two procedures in 13.7 percent, three in 2.8 percent, and four in 0.4 percent. Mean follow-up time from initial surgery was 45.6 months in the fat grafting group and 38.8 months in controls. The overall complication rate following fat grafting was 9.4 percent. Among breasts undergoing surgery for therapeutic indications, there were similar rates of local recurrence (fat grafting group, 2.5 percent; controls, 1.9 percent; p = 0.747). Interestingly, mean time to recurrence was significantly longer in the fat grafting group (52.3 months versus 22.8 months from initial surgery; p = 0.016). CONCLUSIONS: Autologous fat grafting is a powerful tool in breast reconstruction. This large, single-institution study provides valuable evidence-based support for its oncologic safety. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28841601 TI - Prophylactic Nipple-Sparing Mastectomy and Direct-to-Implant Reconstruction of the Large and Ptotic Breast: Is Preshaping of the Challenging Breast a Key to Success? AB - BACKGROUND: Nipple-sparing mastectomy with simultaneous hammock technique direct to-implant reconstruction is increasingly offered to patients opting for risk reducing mastectomy. Despite this promising method, patients with macromastia and ptotic breasts remain a challenging group to treat satisfactorily and more often end up undergoing a difficult corrective procedure and experience an unacceptably high rate of failed reconstruction. The authors examined whether targeted preshaping mastopexy/reduction could prepare these patients for a successful nipple-sparing mastectomy/direct-to-implant reconstruction. METHODS: Patients seeking risk-reducing nipple-sparing mastectomy/direct-to-implant reconstruction at the authors' institutions deemed unfit for a one-stage procedure based on their previous experience were offered a targeted two-stage, risk-reducing mastopexy/reduction followed by a delayed secondary nipple-sparing mastectomy and direct-to-implant reconstruction. Patients were followed up at 3 weeks and 6 or 12 months. RESULTS: Forty-four reconstructions were performed in 22 patients aged 43 years (range, 26 to 57 years). All 44 procedures were completed successfully without any failure or nipple-areola complex losses. Patients' median body mass index was 30 kg/m (range, 22 to 44 kg/m). Six patients were smokers and one had hypertension. Two patients underwent reoperation because of hematoma and fat necrosis. CONCLUSIONS: The authors' results demonstrate that a targeted preshaping mastopexy/reduction followed by nipple-sparing mastectomy/direct-to implant reconstruction can be safely planned in women who opt for a risk-reducing mastectomy and can be performed successfully with a 3- to 4-month time span between operations. On the basis of these results and the superior cosmetic outcome, the two-stage approach has become the authors' standard of care in all such settings. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28841602 TI - Breast Cancer Genetics for Plastic Surgeons. AB - Multidisciplinary genetic clinics offer counseling and testing to those who meet criteria for familial breast cancer, and plastic surgeons become integral to this process when risk-reducing surgery and postmastectomy reconstruction are deemed appropriate. As reconstructive surgeons, it is important that plastic surgeons are aware of the risks and issues associated with the genetic variants that cause patients to present for prophylactic or therapeutic surgery. PMID- 28841603 TI - Discussion: Free Diced Cartilage: A New Application of Diced Cartilage Grafts in Primary and Secondary Rhinoplasty. PMID- 28841604 TI - Facial Assessment and Injection Guide for Botulinum Toxin and Injectable Hyaluronic Acid Fillers: Focus on the Lower Face. AB - This third article of a three-part series addresses techniques and recommendations for aesthetic treatment of the lower face. The lower face is considered an advanced area for facial aesthetic treatment. In this region, soft tissue fillers play a more important role than neuromodulators and should be used first to provide structure and support before neuromodulators are considered for treatment of dynamic lines. Treatment of the lip, perioral region, and chin, in addition to maintaining balance of the lower face with the face overall, is challenging. Procedures on the lip should avoid overcorrection while respecting the projection of the lips on the profile view and the ratio of lip size to chin. The chin is often neglected, but reshaping the jawline can provide dramatic improvement in facial aesthetics. Both profile and anterior views are critical in assessment and treatment of the lower face. Finally, rejuvenation of the neck region requires fillers for structural support of the chin and jawline and neuromodulators for treatment of the masseter and platysma. PMID- 28841605 TI - Anatomical and Clinical Implications of the Deep and Superficial Fat Compartments of the Neck. AB - Anatomical study has proven vital to the understanding and improvement of rejuvenation techniques of the face and neck. The microscopic septa responsible for individual facial fat compartments are also present in the neck. The authors' anatomical studies of the neck, including supraplatysmal and subplatysmal elements, have influenced their surgical and nonsurgical techniques. Careful muscular resuspension and modification of both deep and superficial fat compartments can lead to impressive and lasting aesthetic outcomes. The authors present their algorithm and approach to both surgical and noninvasive methods for aesthetic neck contouring. The discussion contained here is augmented by video footage of injected, fresh cadaver dissection that highlights the anatomical relationships of neck fat compartments discussed in this article. PMID- 28841606 TI - Transabdominal Breast Augmentation: A Review of 114 Cases Performed over 14 Years. AB - BACKGROUND: Abdominoplasty patients are frequently candidates for breast rejuvenation as well. Transabdominal breast augmentation permits insertion of breast implants through the abdominoplasty incision. This combined procedure is preferentially performed in an outpatient setting under monitored anesthesia care and nerve blocks. METHODS: This study was a 14-year retrospective review of a single surgeon's technique and outcomes using transabdominal breast augmentation through a low transverse abdominoplasty incision in select patients requesting simultaneous abdominoplasty and bilateral breast augmentation. Patients had minimal ptosis, smoking cessation a minimum of 4 weeks before surgery and indefinitely thereafter, and a lack of superior abdominal or significant breast surgery. RESULTS: The study's 114 patients had a mean follow-up of 19.2 months. The procedure was performed under monitored anesthesia care with intercostal nerve blocks for most patients [n = 107 (93.9 percent)] and general anesthesia [n = 7 (6.1 percent)] for a few. Seventy-nine patients [n = 74 (64.9 percent)] underwent additional procedures, with most (n = 48) undergoing suction-assisted lipectomy. Many patients underwent multiple procedures. Most complications occurred predictably along the central distal abdominoplasty flap and were minor (small wound breakdown, seroma, and mild skin infection). Major complications [n = 8 (7.0 percent)] included two patients with implant malposition requiring revision and one patient with a Baker grade III capsule; notably, this patient was a half-pack-per-day smoker with a body mass index of 27 kg/m. CONCLUSIONS: Transabdominal breast augmentation is a safe, reliable procedure in the appropriately selected, healthy patient and may be used in minimally to moderately ptotic patients who request concurrent breast augmentation and abdominoplasty. Morbidity compares favorably to reported abdominoplasty series in the appropriately selected patient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28841607 TI - Discussion: Transabdominal Breast Augmentation: A Review of 114 Cases Performed over 14 Years. PMID- 28841608 TI - Surgical Indications and Outcomes of Mastectomy in Transmen: A Prospective Study of Technical and Self-Reported Measures. AB - BACKGROUND: Although transgender surgery constitutes a growing field within plastic surgery, prospective studies on masculinizing mastectomies are lacking. The objectives of the present study were to prospectively follow a cohort of transmen undergoing mastectomy to assess technical and self-reported outcomes and to evaluate surgical decision-making. METHODS: Fifty-four transmen were recruited during a 10-month period at the Department of Plastic Surgery of the Centre of Expertise on Gender Dysphoria. Preoperative assessment included standardized chest examination. Six months postoperatively, participants rated their satisfaction with surgery, and 12-month postoperative surgical outcomes were reviewed independently. Surgical decision-making was evaluated by comparing indications and outcomes per technique, and assessing the clinical validity of the most-used decision aid (using the Cohen's kappa statistic). RESULTS: One periareolar mastectomy, 26 concentric circular mastectomies, and 22 inframammary skin resections with free nipple graft were performed in the authors' cohort. Five participants were still to be operated on. Concentric circular mastectomy was performed in smaller or medium-size breasts with low ptosis grade and good elasticity, whereas the inframammary skin resection group showed a wider range of physical characteristics. Despite being performed in better quality breasts, concentric circular mastectomy was associated with more secondary corrections (38.5 percent), dehiscence, seroma, and lower postoperative satisfaction compared with inframammary skin resections. Clinical decision-making was generally in line with the published decision aid. CONCLUSIONS: Compared with inframammary skin resections, concentric circular mastectomy-despite being performed in favorable breast types-appears to produce poorer technical and self-reported outcomes. Surgical indications and preoperative counseling regarding secondary corrections may therefore be subject to improvement. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28841609 TI - Patient-Reported Outcomes in Weight Loss and Body Contouring Surgery: A Cross Sectional Analysis Using the BODY-Q. AB - BACKGROUND: Health-related quality of life and satisfaction with appearance are important outcomes in bariatric and body contouring surgery. To investigate these outcomes, scientifically sound and clinically meaningful patient-reported outcome instruments are needed. The authors measured health-related quality of life and appearance in a cohort of Danish patients at different phases in the weight loss journey: before bariatric surgery, after bariatric surgery, before body contouring surgery, and after body contouring surgery. METHODS: From June of 2015 to June of 2016, a cross-sectional sample of 493 bariatric and body contouring patients were recruited from four different hospital departments. Patients were asked to fill out the BODY-Q, a new patient-reported outcomes instrument designed specifically to measure health-related quality of life and appearance over the entire patient journey, from obesity to the post-body contouring surgery period. Data were collected using REDCap, and analyzed using SPSS software. RESULTS: For all appearance and health-related quality-of-life scales, the mean score was significantly lower in the pre-bariatric surgery group compared with the post body contouring group. Furthermore, the correlation between body mass index and mean scores was significant for all appearance and health-related quality-of-life scales, with higher scores associated with lower body mass index. The mean score for the group reporting no excess skin compared with the group reporting a lot of excess skin was significantly higher for five of seven appearance scales and four of five health-related quality-of-life scales. CONCLUSION: This study provides evidence to suggest that body contouring plays an important role in the weight loss patient's journey and that patients need access to treatments. PMID- 28841610 TI - Discussion: Patient-Reported Outcomes in Weight Loss and Body Contouring Surgery: A Cross-Sectional Analysis Using the BODY-Q. PMID- 28841611 TI - Perioperative and Long-Term Smoking Behaviors in Cosmetic Surgery Patients. AB - BACKGROUND: Many plastic surgeons advocate smoking cessation before patients undergo cosmetic surgery with extensive soft-tissue dissection. Smoking cessation rates after cosmetic surgery are unknown. The preoperative consultation may be an opportunity to promote long-term smoking cessation. METHODS: This is a retrospective, cross-sectional cohort study. All patients over an 8-year study period who smoked before their preoperative consultation; who quit 2 weeks before surgery; and who subsequently underwent rhytidectomy, abdominoplasty, or mastopexy were included. Patients were asked to complete a Web-based survey at long-term follow-up. RESULTS: Eighty-five smokers were included, and 47 patients completed the survey, for a response rate of 55.3 percent. Average follow-up was 63.3 months. Five respondents were social smokers and thus excluded. Of the 42 daily smokers, 17 patients (40.5 percent) were no longer smoking cigarettes on a daily basis at long-term follow-up. Of these 17 patients, 10 (23.8 percent) had not smoked since their operation. A total of 24 patients (57.1 percent) had reduced their cigarette consumption by any amount, and 70.8 percent (17 of 24) of these patients agreed that discussing adverse surgical outcomes related to smoking influenced their ability to quit/reduce. Twenty-one of 42 patients (50.0 percent) admitted that they were not compliant with the preoperative smoking cessation instructions. CONCLUSIONS: This is the first report to investigate long term smoking cessation from a cosmetic surgery practice. The authors have shown a positive association between smoking cessation and cosmetic surgery. Requesting a period of cessation before cosmetic surgery may promote long-lasting smoking cessation. PMID- 28841612 TI - Implications of Facial Asymmetry in Rhinoplasty. AB - : Many rhinoplasty patients present with a chief complaint of nasal deviation and are unaware of any inherent facial asymmetries; however, recognizing and discussing the interrelation between the deviated nose and facial asymmetry is an important consideration in surgical planning. The objective of this study was to evaluate whether a surgeon's subjective assessment of facial analysis in the setting of nasal deviation correlates with objective anthropometric measurements. In addition, this study sought to further quantify the frequency of facial asymmetry associated with nasal deviation to highlight important anatomical trends for the rhinoplasty surgeon. Finally, this study presents the senior author's (R.J.R.) method of addressing a deviated nose on an asymmetric face. In this study, the authors demonstrated that nasal deviation is closely related to facial asymmetry. Furthermore, the authors demonstrated that objective facial analysis closely correlates to anthropometric facial measurements. In addition, the wide side of the face correlates to the short side of the face and the nose tends to deviate away from the wide side of the face. During surgical correction of the deviated nose in the setting of facial asymmetry, the surgeon's goal should be to obtain nasal symmetry and center the nose on a line between the mid glabella and the mid Cupid's bow. This may reduce the perception of a facial asymmetry, leading to increased patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 28841613 TI - Dedifferentiated Adipocytes Promote Adipose Tissue Generation within an External Suspension Device. AB - BACKGROUND: Mature adipocytes can dedifferentiate into fibroblast-like cells in vitro and acquire proliferation and redifferentiation/transdifferentiation abilities. A soft-tissue expander can induce adipocyte dedifferentiation in vivo. This study combined a tissue expander and an external suspension device to generate a large volume of adipose tissue. METHODS: A soft-tissue expander was implanted beneath the dorsal adipose flaps of rabbits. After 7 days of expansion, the expander was removed and an external suspension device was applied. Samples were collected at various time points, and morphologic, histologic, immunohistochemical, and gene expression analyses were conducted. A silicone sheet was implanted as a control. RESULTS: After 7 days of expansion, the adipose flap was much thinner. Hematoxylin and eosin and whole-mount staining revealed that adipocytes became smaller (p < 0.05) and some contained multilocular lipid droplets. The number of Ki67 cells increased (p < 0.01), adipokine expression decreased (p < 0.01), and octamer-binding transcription factor 4 expression increased (p < 0.01). After the external suspension device was applied, the normalized volume of adipose flaps was much larger in the expanded group than in the control group (p < 0.05). The expanded group also exhibited more proliferating cells, a larger vascularized area, and higher adipokine expression (p < 0.05). CONCLUSION: Dedifferentiated adipocytes in adipose flaps can participate in adipose tissue generation as seed cells and increase the volume of adipose tissue. PMID- 28841614 TI - Autologous Fat Grafting as a Novel Antiestrogen Vehicle for the Treatment of Breast Cancer. AB - BACKGROUND: Adipose fat transfer is increasingly used for contour corrections of the tumor bed after lumpectomy and breast reconstructions after mastectomy. The lipophilic nature of the fat tissue may render adipocytes an ideal vehicle with which to deliver a high boost of an antiestrogen to the tumor bed to serve as an adjunct systemic hormonal therapy. The authors therefore tested whether adipocytes could safely be loaded with an antiestrogen and allow for release at therapeutic concentrations to treat breast cancer. METHODS: Adipose tissue was collected from patients undergoing autologous fat grafting. The influence of adipose tissue on tumorigenesis was determined both in vitro and in vivo using breast cancer cell lines. Ex vivo, adipose tissue was assessed for its ability to depot fulvestrant and inhibit the growth of breast cancer cell lines. RESULTS: Adipose tissue harvested from patients did not promote breast cancer cell growth in vitro or in an in vivo mouse model. Adipose tissue was successfully loaded with fulvestrant and released at levels sufficient to inhibit estrogen receptor signaling and growth of breast cancer cells. CONCLUSIONS: This work supports the hypothesis that adipose tissue used for autologous fat grafting can serve as a novel method for local drug delivery. As this technique is used to reconstruct a variety of postsurgical defects following cancer resection, this approach for local drug delivery may be an effective alternative in therapeutic settings beyond breast cancer. PMID- 28841615 TI - Normative Values of the Michigan Hand Outcomes Questionnaire for Patients with and without Hand Conditions. AB - BACKGROUND: The Michigan Hand Outcomes Questionnaire has been widely used for nearly 20 years to assess patients with a variety of hand and upper extremity conditions. However, normative data have not previously been collected, limiting interpretation. METHODS: The Michigan Hand Outcomes Questionnaire was administered to 579 participants recruited from the general population. In addition, participants were asked to identify any problem affecting their hand(s), including trauma, hand disease/condition, systemic illness, or nonspecific symptoms. Comorbidities and demographic data were also collected. RESULTS: Total Michigan Hand Outcomes Questionnaire score for healthy individuals was indicative of generally good hand function (95.2; 95 percent CI, 94.3 to 96.1). Individuals with unilateral trauma scored for their affected hand (90.3; 95 percent CI, 87.9 to 92.6) lower than their healthy hand (mean difference, 5.7; 95 percent CI, 3.2 to 8.3). For individuals with and without hand trauma, total Michigan Hand Outcomes Questionnaire score decreased with increasing number of comorbidities. Many of the differences in Michigan Hand Outcomes Questionnaire score between the problem hand and unaffected hand were smaller than the minimal clinically important difference of 3.0 to 23.0 for known abnormalities of the hand and upper extremity. CONCLUSIONS: These normative data provide appropriate baseline information for individuals with and without underlying hand conditions. Most notably, these findings suggest that individuals with a unilateral problem establish new subnormative values for both their affected and unaffected hands. These data will encourage an appropriate understanding of the results of future studies using the Michigan Hand Outcomes Questionnaire. PMID- 28841616 TI - Superficial Radial Nerve Transection Improves Sensory Outcomes in First Dorsal Metacarpal Artery Flaps. AB - BACKGROUND: This article reports the operative technique and clinical effect of repairing thumb pulp defects using a modified first dorsal metacarpal artery flap method. In this method, the dorsal branches of the radial and ulnar proper digital nerves of the index finger were preserved but the superficial branches of the radial nerve were transected. METHODS: Data obtained from 121 patients with thumb pulp defects who were admitted to the authors' hospital from June of 2011 to December of 2014 were retrospectively analyzed. Patients were divided into two groups based on whether the superficial branches of the radial nerve were transected. The dorsal branches of the radial and ulnar proper digital nerves of the index finger and the proper digital nerves in the wound were coapted using the end-to-end style. Static two-point discrimination, Semmes-Weinstein monofilament scores, pain, cold intolerance of the reconstructed finger, allachesthesia, and patient satisfaction were compared between the two groups. RESULTS: The authors observed significant differences in static two-point discrimination, Semmes-Weinstein monofilament flap score, pain of finger pulp, allachesthesia duration, and patient satisfaction (p < 0.05). The transection group presented slightly better discriminatory sensation in the flap and higher patient satisfaction. In addition, the duration of allachesthesia in the transection group was significantly shorter than that in the preservation group. CONCLUSION: In the repair of thumb pulp defects using a modified first dorsal metacarpal artery flap carrying the dorsal branches of the radial and ulnar proper digital nerves of the index finger, transecting the superficial branches of the radial nerve achieved better clinical outcome compared with preserving them. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28841617 TI - Benefit of Local Anesthesia in Reducing Pain during Collagenase Injection for Dupuytren's Contracture. AB - : Collagenase injection for Dupuytren's contracture is commonly administered without anesthesia. The authors studied the benefit of injecting local anesthesia before collagenase in reducing treatment-related pain. This prospective cohort study included 187 patients (mean age, 69 years; 80 percent men) at two orthopedic departments in Sweden. At one center, 161 consecutive patients scheduled for collagenase injection were assigned to two groups by alternating outpatient clinics; 78 received collagenase without local anesthesia using a modified method (injecting 0.80 mg in multiple spots in the cord) and 83 received local anesthesia injected in the proximal palm before collagenase. At the other center, 26 consecutive patients received collagenase using the standard method (0.58 mg injected in one spot) without local anesthesia. Immediately after the first injection (collagenase or local anesthesia), the patients rated the severity of injection-related pain on a visual analogue scale from 0 (no pain) to 10 (worst pain). Before finger manipulation 1 or 2 days after injection, the patients rated the pain experienced since injection. Mean score +/- SD for pain experienced during modified collagenase injection was 4.3 +/- 2.5 without local anesthesia and 2.3 +/- 1.7 during injection of local anesthesia (before collagenase) (age- and sex-adjusted mean difference, 2.1; 95 percent CI, 1.5 to 2.7; p < 0.001). Mean pain score +/- SD during standard collagenase injection without local anesthesia was 4.8 +/- 1.8. Mean pain score +/- SD during the injection-manipulation interval was 2.9 +/- 1.9 in the group without local anesthesia and 2.9 +/- 2.3 in the local anesthesia group (p = 0.79). This study shows that local anesthesia significantly reduces the patient's overall pain experience during collagenase treatment for Dupuytren's contracture. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 28841619 TI - Discussion: Minor Suture Fusion in Syndromic Craniosynostosis. PMID- 28841618 TI - Intelligence and Academic Achievement of Adolescents with Craniofacial Microsomia. AB - BACKGROUND: The authors compared the IQ and academic achievement of adolescents with craniofacial microsomia (cases) and unaffected children (controls). Among cases, the authors analyzed cognitive functioning by facial phenotype. METHODS: The authors administered standardized tests of intelligence, reading, spelling, writing, and mathematics to 142 cases and 316 controls recruited from 26 cities across the United States and Canada. Phenotypic classification was based on integrated data from photographic images, health history, and medical chart reviews. Hearing screens were conducted for all participants. RESULTS: After adjustment for demographics, cases' average scores were lower than those of controls on all measures, but the magnitude of differences was small (standardized effect sizes, -0.01 to -0.3). There was little evidence that hearing status modified case-control group differences (Wald p > 0.05 for all measures). Twenty-five percent of controls and 38 percent of cases were classified as having learning problems (adjusted OR, 1.5; 95 percent CI, 0.9 to 2.4). Comparison of cases with and without learning problems indicated that those with learning problems were more likely to be male, Hispanic, and to come from lower income, bilingual families. Analyses by facial phenotype showed that case control group differences were largest for cases with both microtia and mandibular hypoplasia (effect sizes, -0.02 to -0.6). CONCLUSIONS: The highest risk of cognitive-academic problems was observed in patients with combined microtia and mandibular hypoplasia. Developmental surveillance of this subgroup is recommended, especially in the context of high socioeconomic risk and bilingual families. Given the early stage of research on craniofacial microsomia and neurodevelopment, replication of these findings is needed. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 28841620 TI - A Treatment Algorithm for Patients Presenting with Sagittal Craniosynostosis after the Age of 1 Year. AB - BACKGROUND: Sagittal craniosynostosis typically presents shortly after birth, with a scaphocephalic head shape, and is addressed surgically for functional and aesthetic concerns. This study highlights the authors' experience with a challenging patient population: those with phenotypically mild, missed, and late developing sagittal craniosynostosis. METHODS: A prospective cohort study was conducted for all cases of sagittal craniosynostosis presenting to the authors' institution between July of 2013 and December of 2015. Patients older than 1 year with isolated sagittal craniosynostosis were included. All children were evaluated by craniofacial surgery, neurosurgery, and ophthalmology departments. All patients had dilated fundus examinations and visual evoked potentials. RESULTS: Fifty-two patients met inclusion criteria. Only nine patients have been treated surgically (17.3 percent). Two patients underwent operative correction for obvious scaphocephaly. Four patients who presented with concerning ophthalmologic evaluations and another patient with classic intracranial hypertension-related headaches underwent cranial vault expansion. Eight patients presented with inconclusive ophthalmologic evaluations. These patients were admitted for intracranial pressure monitoring, of which two were found to have elevated levels (25 percent) and underwent operative intervention. Thirty-seven other patients presented with isolated sagittal craniosynostosis in the setting of overall normocephaly without any signs concerning for intracranial hypertension. These patients continue to undergo serial evaluation. CONCLUSIONS: The authors describe their treatment protocol for a large series of patients presenting with the delayed diagnosis of sagittal craniosynostosis. Based on the early experience of the authors' center with this protocol, the risk of intracranial hypertension appears to be low in this population. The majority of patients to date have been managed nonsurgically without invasive monitoring. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28841621 TI - Analysis of Craniofacial Remodeling in the Aging Midface Using Reconstructed Three-Dimensional Models in Paired Individuals. AB - BACKGROUND: Aging leads to a panoply of changes of facial morphology. The present study was conducted to analyze modifications of the facial skeleton with aging, using high-resolution imaging and comparing the same individuals at two time points. METHODS: The electronic medical record system was reviewed since its inception in 2001 for patients for whom two computed tomographic scans of the midface were obtained at least 9 years apart. The computed tomographic scans were converted into three-dimensional craniofacial models for each patient, using the initial and the follow-up computed tomographic scan data. The models were used to highlight areas of bone growth and bone resorption using a color scale and to perform a cephalometric analysis. RESULTS: Seven patients with a mean age of 61 years and computed tomographic scans on average 10.3 years apart were included. Bone resorption was consistently present (100 percent) at the pyriform aperture and the anterior wall of the maxilla. Resorption was noted at the superocentral (71 percent), inferolateral (57 percent), and superomedial (57 percent) aspects of the orbital rim. Resorption occurred earlier at the inferolateral orbital rim followed by the superomedial orbital rim in later decades of life. Paired analysis of change in the orbital rim height and width demonstrated a mean decrease over time but was not significant. CONCLUSION: Bone remodeling in the same individual, over a period of 10 years, was characterized by resorption at the pyriform aperture; anterior wall of the maxilla; and superocentral, superomedial, and inferolateral aspects of the orbital rims. PMID- 28841622 TI - Adipose Tissue-Preserved Skin Graft: Applicability and Long-Term Results. AB - BACKGROUND: Composite grafts consisting of adipose tissue and skin have been reported in the literature but have been restricted to areas smaller than 4 to 5 cm. The senior author (D.T.W.C.) has developed a technique of adipose tissue preserved full-thickness skin grafts for larger areas with success similar to that achieved with conventional full-thickness skin grafts. METHODS: All cases of the senior author involving a full-thickness skin graft were identified and reviewed to identify cases in which adipose tissue-preserved full-thickness skin grafts were used. Indication for skin grafting, anatomical location of recipient and donor sites, size of graft, total number of grafts received by each patient, and percentage take were extracted from patient charts. Graft take was measured between days 5 and 14. RESULTS: A total of 72 adipose tissue-preserved skin grafts on 47 patients were identified from 1994 to 2009, with a median follow-up of 8 years. The size of defect ranged from 0.7 to 210 cm, with a median area of 6 cm (interquartile range, 2.5 to 15 cm). Only six of 72 grafts were found to have less than 100 percent take. The lowest take percentage was 85 percent in a graft with an area of 2.6 cm. There were no graft failures. CONCLUSIONS: This study confirms the proof-of-concept that both larger and distant donor- site adipose tissue-preserved skin grafts are a viable alternative to conventional defatted full-thickness skin grafting. It appears that there is a low complication rate with respect to graft failure or incomplete graft take. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28841624 TI - Predictors, Quality Markers, and Economics of Volunteering Internationally: Results from a Comprehensive Survey of American Society of Plastic Surgeons Members. AB - BACKGROUND: Plastic surgeons have a long history of international volunteer work. To date, there have been no outcome-based studies among surgeons who volunteer internationally. The purpose of this study was to describe predictors of volunteering, clinical quality markers, and economics of international volunteering among American plastic surgeons. METHODS: A cross-sectional validated e-mail survey tool was sent to all board-certified plastic surgeons by the American Society of Plastic Surgeons. The survey response rate was 15 percent (745 total individuals), of which 283 respondents traveled within the past 5 years. Analysis was performed in R. Stepwise multivariate logistic regression was performed to determine the predictors of death/complication. RESULTS: Respondents reported high use of medical records, follow-up care, and host affiliation. Fewer than half of all respondents reported use of international safety surgery guidelines, and the majority of respondents reported volunteering abroad outside of their scope of practice. The majority of children younger than 5 years were not cared for by a pediatric anesthesiologist. The majority of participants reported personally spending more than $1000 on their last trip and performing surgery estimated to be worth on average $28,000 each. CONCLUSIONS: International surgical volunteer trips attempt to ease the global burden of surgical disease. The authors' study reports variation in quality of care provided on these trips. Most significantly, the majority of children younger than 5 years were not cared for by a pediatric anesthesiologist, and many plastic surgeons operated outside of their scope of practice. PMID- 28841623 TI - Associations of Surgeon and Hospital Volumes with Outcome for Free Tissue Transfer by Using the National Taiwan Population Health Care Data from 2001 to 2012. AB - BACKGROUND: Greater hospital case volumes are associated with improved outcomes for high-risk procedures. The hospital-outcome association for complex but low mortality procedures and the association between surgeon versus hospital case volume and surgical outcomes have been less explored. The authors examined the association between surgeon and hospital volume and the success for free tissue transfer (free flap) surgery. The authors hypothesized that there would be positive associations between hospital and surgeon volume and the success of free flap surgery. METHODS: The study design was a cross-sectional analysis of adults aged 18 to 64 years who underwent free flap surgery. The authors used 100 percent of all free flap operations between 2001 and 2012 using Taiwan's national data that cover the entire population of 23 million in the country. The authors applied hierarchical regression modeling to analyze volume-outcome associations. RESULTS: The association between hospital volume and free flap success was small but positive (OR, 1.007; 95 percent CI, 1.00 to 1.01). For surgeons, their years of experience had a positive association with success of the operation (OR, 1.04; 95 percent CI, 1.02 to 1.06) rather than their annual case volume. Compared with low-volume surgeons (<11 annual cases) working in low-volume hospitals (<95 annual cases), high-volume surgeons (>25 annual cases) working in high-volume hospitals (>156 annual cases) showed greater odds of operation success (OR, 2.97; 95 percent CI, 1.21 to 7.29). CONCLUSIONS: Higher volume hospitals and more experienced surgeons, regardless of their annual volume, showed better outcomes. Increasing demand for high-quality care and Taiwan's national policies toward centralization of complex surgical procedures have increased competition among hospitals. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28841625 TI - American Society of Maxillofacial Surgeons 2006 to 2016: Another Decade of Excellence in Education and Research. AB - Over the past 10 years, the American Society of Maxillofacial Surgeons (ASMS) has continued to advance to meet its mission of being the premier organization to represent maxillofacial and pediatric plastic surgery in the United States. These advances are focused on education of its members, to include the American Society of Maxillofacial Surgeons basic course, the preconference symposium, the annual meeting, two basic maxillofacial courses per year, advanced maxillofacial courses, a boot camp for craniofacial fellows, a cleft course, quarterly webinars, sponsored fellowships, a visiting professorship, and the ASMS journal. In addition, the ASMS has continued to advance as the premier national organization representing maxillofacial and pediatric plastic surgery in the United States, thereby positioning the organization as a primary advocate for these surgical specialties. Outreach of the ASMS has grown over the past decade and now includes representatives to the American Society of Plastic Surgeons/Plastic Surgery Foundation, the American Board of Plastic Surgeons, the American Medical Association, and most recently a seat as a governor with the American College of Surgeons. The ASMS has also initiated an annual Summer Leadership Seminar to explore topics of relevance in a changing health care environment. The present report outlines the major initiatives of the ASMS over the past 10 years. PMID- 28841626 TI - Disclosure of Financial Conflicts of Interest in Plastic and Reconstructive Surgery. AB - BACKGROUND: Recent articles in the scientific literature have expressed concerns about financial conflicts of interest in the profession of medicine in general and the specialty of plastic surgery in particular. Disclosure of financial ties to industry has been regarded as an address of a possible bias. The policies of medical journals places responsibility on authors for self-reporting of financial conflicts of interest, yet underreporting of conflicts of interest has occurred. The investigative hypothesis was that authors in the plastic surgery literature, in particular, Plastic and Reconstructive Surgery, underreported financial conflicts of interest. METHODS: A review of articles published in Plastic and Reconstructive Surgery from July of 2015 through April of 2016 for author disclosures was accomplished. The disclosure statements were compared to the information available in the Open Payments database for 2015. The lack of disclosure on the part of an author, when present, was individually examined for relevance of the corporate conflicts of interest to the subject matter of the involved article. RESULTS: A total of 302 articles authored by 1262 individuals were reviewed. One hundred thirty-nine (45.5 percent) had neither a disclosed nor an actual conflict of interest. In 61 articles (20.2 percent), one or more authors disclosed; 105 articles (34.8 percent) did not provide disclosure of a financial conflict of interest. In assessment of relevance, 10 undisclosed conflicts of interest (9.5 percent) were determined relevant, and one-third of that total were non-plastic surgeons. CONCLUSION: Nondisclosure of financial conflicts of interest is common, but only a small minority pose a potential for harm from bias. PMID- 28841627 TI - How Has Dr. Marko Godina Influenced Us? PMID- 28841630 TI - Reply: Revision Buttock Implantation: Indications, Procedures, and Recommendations. PMID- 28841631 TI - Very Low Prevalence of Intracranial Hypertension in Trigonocephaly. PMID- 28841633 TI - Extracorporeal Circulatory Support in Acute Coronary Syndromes: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Extracorporeal circulatory support is a life-saving technique, and its use is increasing in acute coronary syndromes. A meta-analysis on pooled event rate of short-term mortality and complications of acute coronary syndrome patients treated with extracorporeal circulatory support was performed. DATA SOURCES: Articles were searched in MEDLINE, Cochrane Library, Google Scholar, and Biomed Central. STUDY SELECTION: Inclusion criteria were observational studies on acute coronary syndrome patients treated with extracorporeal circulatory support. Primary outcome was short-term mortality. Secondary outcomes were extracorporeal circulatory support-related complications, causes of death, long-term mortality, and bridge therapy. DATA EXTRACTION: Sixteen articles were selected. Data about clinical characteristics, acute coronary syndrome diagnosis and treatment, extracorporeal circulatory support setting, outcome definitions, and event rate were retrieved from the articles. Random effect meta-analytic pooling was performed reporting results as a summary point estimate and 95% CI. DATA SYNTHESIS: A total of 739 patients were included (mean age, 59.8 +/- 2.9). The event rate of short-term mortality was 58% (95% CI, 51-64%), 6-month mortality was affecting 24% (95% CI, 5-63%) of 1-month survivors, and 1-year mortality 17% (95% CI, 6-40%) of 6-month survivors. The event rates of extracorporeal circulatory support-related complications were acute renal failure 41%, bleeding 25%, neurologic damage in survivors 21%, sepsis/infections 21%, and leg ischemia 12%. Between causes of death, multiple organ failure and brain death affected respectively 40% and 27% of patients. Bridge to ventricular assistance device was offered to 14% of patients, and 7% received a transplant. CONCLUSIONS: There is still a high rate of short-term mortality and complications in acute coronary syndrome patients treated with extracorporeal circulatory support. New studies are needed to optimize and standardize extracorporeal circulatory support. PMID- 28841632 TI - Delirium and Catatonia in Critically Ill Patients: The Delirium and Catatonia Prospective Cohort Investigation. AB - OBJECTIVES: Catatonia, a condition characterized by motor, behavioral, and emotional changes, can occur during critical illness and appear as clinically similar to delirium, yet its management differs from delirium. Traditional criteria for medical catatonia preclude its diagnosis in delirium. Our objective in this investigation was to understand the overlap and relationship between delirium and catatonia in ICU patients and determine diagnostic thresholds for catatonia. DESIGN: Convenience cohort, nested within two ongoing randomized trials. SETTING: Single academic medical center in Nashville, TN. PATIENTS: We enrolled 136 critically ill patients on mechanical ventilation and/or vasopressors, randomized to two usual care sedation regimens. MEASUREMENTS AND MAIN RESULTS: Patients were assessed for delirium and catatonia by independent and masked personnel using Confusion Assessment Method for the ICU and the Bush Francis Catatonia Rating Scale mapped to Diagnostic Statistical Manual 5 criterion A for catatonia. Of 136 patients, 58 patients (43%) had only delirium, four (3%) had only catatonia, 42 (31%) had both, and 32 (24%) had neither. In a logistic regression model, more catatonia signs were associated with greater odds of having delirium. For example, patient assessments with greater than or equal to three Diagnostic Statistical Manual 5 symptoms (75th percentile) had, on average, 27.8 times the odds (interquartile range, 12.7-60.6) of having delirium compared with patient assessments with zero Diagnostic Statistical Manual 5 criteria (25th percentile) present (p < 0.001). A cut-off of greater than or equal to 4 Bush Francis Catatonia Screening Instrument items was both sensitive (91%; 95% CI, 82.9-95.3) and specific (91%; 95% CI, 87.6-92.9) for Diagnostic Statistical Manual 5 catatonia. CONCLUSIONS: Given that about one in three patients had both catatonia and delirium, these data prompt reconsideration of Diagnostic Statistical Manual 5 criteria for "Catatonic Disorder Due to Another Medical Condition" that preclude diagnosing catatonia in the presence of delirium. PMID- 28841634 TI - Mammalian target of rapamycin complex 1 and FoxO1 in the transcriptional control of lipolysis and de novo lipogenesis. AB - PURPOSE OF REVIEW: Postprandial suppression of lipolysis in adipose tissue and stimulation of de novo lipogenesis (DNL) in the liver by insulin are essential for the metabolic homeostasis in the mammalian organism. The mechanism of coregulation of lipolysis and DNL is not clear. RECENT FINDINGS: Insulin controls both lipolysis and DNL at the level of transcription via the same mammalian target of rapamycin complex 1 (mTORC1) and FoxO1-mediated signaling pathways. SUMMARY: mTORC1 suppresses lipolysis in adipose tissue and activates DNL in the liver, whereas FoxO1 has the opposite effect. Individual inputs of either mTORC1 or FoxO1 in the regulation of lipid metabolism may be difficult to evaluate because of the cross talk between these pathways. PMID- 28841635 TI - Perspectives on the global obesity epidemic. PMID- 28841636 TI - Research ethics committee approval as reported for abstracts submitted to the annual Euroanaesthesia meeting. AB - BACKGROUND: The annual congress of the European Society of Anaesthesiology (ESA) is one of the largest anaesthesia congresses in the world and exhibits more than 1200 abstracts annually. OBJECTIVES: The aims of this study were to quantify the frequency of inadequate evidence of ethical approval for abstracts submitted to the ESA congress and to examine whether abstracts without appropriate ethical approval were subsequently accepted. DESIGN AND SETTING: All abstracts submitted in 2015 were adjudicated according to European ethical criteria. MAIN OUTCOME MEASURE: The proportion of submitted abstracts that lacked evidence of appropriate ethics committee approval. Secondary outcomes included the proportion of accepted abstract that lacked evidence of appropriate ethical approval; the proportion of correctly identified case reports; the proportion of accepted abstracts that lacked evidence of appropriate ethics committee approvals corresponding to location (within/outside Europe); and the proportion of accepted abstracts that lacked evidence of appropriate ethics committee approvals corresponding to a specific area of research. RESULTS: In total, 1792 abstracts were reviewed and 1572 (87.7%) involved humans. In 527 (29.4%), the authors failed to demonstrate adequate ethical approval with higher rates in abstracts submitted from Europe (32.1%) than the rest of the world (23.5%), P < 0.001. Appropriate approvals were reported in 80% of animal studies, 74.6% of case reports and 57.6% of human research studies. The proportion with evidence of adequate ethical approvals was lowest in obstetric anaesthesia and emergency medicine. Case reports were identified correctly 98.6% (347/352) of the time, but 14 research abstracts were assigned wrongly to this category. Most abstracts (68.5%, 361/527) lacking evidence of ethical approval were still accepted for presentation. CONCLUSION: Research abstracts lacking evidence of appropriate ethical approval are common worldwide. Societies shoulder the responsibility for ensuring that only ethically sound abstracts are presented at meetings. Abstract submission systems must include mechanisms to ensure that publications are accepted and judged not just on scientific merit but also on adherence to best ethical practice. PMID- 28841637 TI - Evolving understanding of the heterogeneous natural history of individual coronary artery plaques and the role of local endothelial shear stress. AB - PURPOSE OF REVIEW: Anatomic and morphologic features of high-risk coronary plaque have been identified by novel imaging modalities, but it has been less clear which ostensibly high-risk plaques will actually destabilize and cause a new cardiac event. Different plaques with different morphologies coexist within the same artery, but the impact of this heterogeneity on the natural history of coronary artery disease has not been extensively investigated. RECENT FINDINGS: Coronary plaques exhibit remarkable heterogeneity of local morphological and blood-flow patterns, including endothelial shear stress (ESS), along their longitudinal axis, with important implications for the heterogeneous natural history of coronary disease. The natural history of individual plaques is considerably divergent, with most plaques, even ostensibly high-risk plaques, becoming quiescent and only a minority progressing to destabilize and precipitate a new clinical event. Local areas of proinflammatory low ESS appear to be an important condition for plaque destabilization. SUMMARY: Characterization of an individual atherosclerotic plaque based on a snapshot of morphological features at a specific location, such as the minimal lumen diameter, may not be sufficiently comprehensive to accurately reflect the risk associated with that plaque. A detailed assessment of both anatomical and functional pathobiologic characteristics in the longitudinal plaque dimension may enhance our understanding of atherosclerosis progression and improve the management of individual patients with coronary artery disease. PMID- 28841639 TI - Neurodevelopment of the newborn hospitalized in the Neonatal Intensive Care Unit. PMID- 28841638 TI - Cerebrovascular Protective Effect of Boldine Against Neural Apoptosis via Inhibition of Mitochondrial Bax Translocation and Cytochrome C Release. AB - BACKGROUND In the present study, we explored the protective effect and mechanism of action of boldine (BOL) against neural apoptosis, which is a mediator of TBI. MATERIAL AND METHODS The effect of BOL on mitochondrial and cytosol proteins of extracted from cerebral cortical tissue of mice was evaluated. The grip test was used to assess the neurological deficit and brain water content of the subjects after administration of BOL to assess its effect on SOD, GSH, and MDA activity in brain ischemic tissues. To further confirm the effect of the BOL, the histopathological analysis and morphology of neurons were studied by Nissl staining. The effect of BOL against TBI-induced neural apoptosis by immuno histochemistry and Western blotting assay were also studied. RESULTS BOL showed significant improvement against TBI in a dose-dependent manner. In the BOL treated group, the apoptotic index was significantly reduced, but the level of caspase-3 was greatly diminished. Additionally, the level of the Bax in mitochondria (mit) and cytosol was elevated in the TBI-treated group as compared to the sham group. Further BOL at the test dose causes significant reduction in the level of mitochondrial MDA together with increase in SOD activity as compared to the TBI alone group. CONCLUSIONS BOL showed a cerebroprotective effect against TBI by attenuating the oxidative stress and the mitochondrial apoptotic pathway. It also inhibited mitochondrial Bax translocation and cytochrome c release. PMID- 28841640 TI - Multidisciplinary university research and service camps: what is the role of Peruvian universities? PMID- 28841641 TI - Noise correlations in the human brain and their impact on pattern classification. AB - Multivariate decoding methods, such as multivoxel pattern analysis (MVPA), are highly effective at extracting information from brain imaging data. Yet, the precise nature of the information that MVPA draws upon remains controversial. Most current theories emphasize the enhanced sensitivity imparted by aggregating across voxels that have mixed and weak selectivity. However, beyond the selectivity of individual voxels, neural variability is correlated across voxels, and such noise correlations may contribute importantly to accurate decoding. Indeed, a recent computational theory proposed that noise correlations enhance multivariate decoding from heterogeneous neural populations. Here we extend this theory from the scale of neurons to functional magnetic resonance imaging (fMRI) and show that noise correlations between heterogeneous populations of voxels (i.e., voxels selective for different stimulus variables) contribute to the success of MVPA. Specifically, decoding performance is enhanced when voxels with high vs. low noise correlations (measured during rest or in the background of the task) are selected during classifier training. Conversely, voxels that are strongly selective for one class in a GLM or that receive high classification weights in MVPA tend to exhibit high noise correlations with voxels selective for the other class being discriminated against. Furthermore, we use simulations to show that this is a general property of fMRI data and that selectivity and noise correlations can have distinguishable influences on decoding. Taken together, our findings demonstrate that if there is signal in the data, the resulting above chance classification accuracy is modulated by the magnitude of noise correlations. PMID- 28841642 TI - Modeling zoonotic cutaneous leishmaniasis incidence in central Tunisia from 2009 2015: Forecasting models using climate variables as predictors. AB - Transmission of zoonotic cutaneous leishmaniasis (ZCL) depends on the presence, density and distribution of Leishmania major rodent reservoir and the development of these rodents is known to have a significant dependence on environmental and climate factors. ZCL in Tunisia is one of the most common forms of leishmaniasis. The aim of this paper was to build a regression model of ZCL cases to identify the relationship between ZCL occurrence and possible risk factors, and to develop a predicting model for ZCL's control and prevention purposes. Monthly reported ZCL cases, environmental and bioclimatic data were collected over 6 years (2009 2015). Three rural areas in the governorate of Sidi Bouzid were selected as the study area. Cross-correlation analysis was used to identify the relevant lagged effects of possible risk factors, associated with ZCL cases. Non-parametric modeling techniques known as generalized additive model (GAM) and generalized additive mixed models (GAMM) were applied in this work. These techniques have the ability to approximate the relationship between the predictors (inputs) and the response variable (output), and express the relationship mathematically. The goodness-of-fit of the constructed model was determined by Generalized cross validation (GCV) score and residual test. There were a total of 1019 notified ZCL cases from July 2009 to June 2015. The results showed seasonal distribution of reported ZCL cases from August to January. The model highlighted that rodent density, average temperature, cumulative rainfall and average relative humidity, with different time lags, all play role in sustaining and increasing the ZCL incidence. The GAMM model could be applied to predict the occurrence of ZCL in central Tunisia and could help for the establishment of an early warning system to control and prevent ZCL in central Tunisia. PMID- 28841643 TI - Towards a category theory approach to analogy: Analyzing re-representation and acquisition of numerical knowledge. AB - Category Theory, a branch of mathematics, has shown promise as a modeling framework for higher-level cognition. We introduce an algebraic model for analogy that uses the language of category theory to explore analogy-related cognitive phenomena. To illustrate the potential of this approach, we use this model to explore three objects of study in cognitive literature. First, (a) we use commutative diagrams to analyze an effect of playing particular educational board games on the learning of numbers. Second, (b) we employ a notion called coequalizer as a formal model of re-representation that explains a property of computational models of analogy called "flexibility" whereby non-similar representational elements are considered matches and placed in structural correspondence. Finally, (c) we build a formal learning model which shows that re representation, language processing and analogy making can explain the acquisition of knowledge of rational numbers. These objects of study provide a picture of acquisition of numerical knowledge that is compatible with empirical evidence and offers insights on possible connections between notions such as relational knowledge, analogy, learning, conceptual knowledge, re-representation and procedural knowledge. This suggests that the approach presented here facilitates mathematical modeling of cognition and provides novel ways to think about analogy-related cognitive phenomena. PMID- 28841644 TI - Robust averaging protects decisions from noise in neural computations. AB - An ideal observer will give equivalent weight to sources of information that are equally reliable. However, when averaging visual information, human observers tend to downweight or discount features that are relatively outlying or deviant ('robust averaging'). Why humans adopt an integration policy that discards important decision information remains unknown. Here, observers were asked to judge the average tilt in a circular array of high-contrast gratings, relative to an orientation boundary defined by a central reference grating. Observers showed robust averaging of orientation, but the extent to which they did so was a positive predictor of their overall performance. Using computational simulations, we show that although robust averaging is suboptimal for a perfect integrator, it paradoxically enhances performance in the presence of "late" noise, i.e. which corrupts decisions during integration. In other words, robust decision strategies increase the brain's resilience to noise arising in neural computations during decision-making. PMID- 28841645 TI - The dominant role of climate change in determining changes in evapotranspiration in Xinjiang, China from 2001 to 2012. AB - The Xinjiang Uyghur Autonomous Region of China has experienced significant land cover and climate change since the beginning of the 21st century. However, a reasonable simulation of evapotranspiration (ET) and its response to environmental factors are still unclear. For this study, to simulate ET and its response to climate and land cover change in Xinjiang, China from 2001 to 2012, we used the Common Land Model (CoLM) by adding irrigation effects for cropland and modifying root distributions and the root water uptake process for shrubland. Our results indicate that mean annual ET from 2001 to 2012 was 131.22 (+/-21.78) mm/year and demonstrated no significant trend (p = 0.12). The model simulation also indicates that climate change was capable of explaining 99% of inter-annual ET variability; land cover change only explained 1%. Land cover change caused by the expansion of croplands increased annual ET by 1.11 mm while climate change, mainly resulting from both decreased temperature and precipitation, reduced ET by 21.90 mm. Our results imply that climate change plays a dominant role in determining changes in ET, and also highlight the need for appropriate land-use strategies for managing water sources in dryland ecosystems within Xinjiang. PMID- 28841646 TI - Prediction of coreceptor usage by five bioinformatics tools in a large Ethiopian HIV-1 subtype C cohort. AB - BACKGROUND: Genotypic tropism testing (GTT) has been developed largely on HIV-1 subtype B. Although a few reports have analysed the utility of GTT in other subtypes, more studies using HIV-1 subtype C (HIV-1C) are needed, considering the huge contribution of HIV-1C to the global epidemic. METHODS: Plasma was obtained from 420 treatment-naive HIV-1C infected Ethiopians recruited 2009-2011. The V3 region was sequenced and the coreceptor usage was predicted by five tools: Geno2Pheno clinical-and clonal-models, PhenoSeq-C, C-PSSM and Raymond's algorithm. The impact of baseline tropism on antiretroviral treatment (ART) outcome was evaluated. RESULTS: Of 352 patients with successful baseline V3 sequences, the proportion of predicted R5 virus varied between the methods by 12.5% (78.1%-90.6%). However, only 58.2% of the predictions were concordant and only 1.7% were predicted to be X4-tropic across the five methods. Compared pairwise, the highest concordance was between C-PSSM and Geno2Pheno clonal (86.4%). In bivariate intention to treat (ITT) analysis, R5 infected patients achieved treatment success more frequently than X4 infected at month six as predicted by Geno2Pheno clinical (77.8% vs 58.7%, P = 0.004) and at month 12 by C PSSM (61.9% vs 46.6%, P = 0.038). However, in the multivariable analysis adjusted for age, gender, baseline CD4 and viral load, only tropism as predicted by C-PSSM showed an impact on month 12 (P = 0.04, OR 2.47, 95% CI 1.06-5.79). CONCLUSION: Each of the bioinformatics models predicted R5 tropism with comparable frequency but there was a large discordance between the methods. Baseline tropism had an impact on outcome of first line ART at month 12 in multivariable ITT analysis but only based on prediction by C-PSSM which thus possibly could be used for predicting outcome of ART in HIV-1C infected Ethiopians. PMID- 28841647 TI - Probing the compartmentalization of HIV-1 in the central nervous system through its neutralization properties. AB - Compartmentalization of HIV-1 has been observed in the cerebrospinal fluid (CSF) of patients at different clinical stages. Considering the low permeability of the blood-brain barrier, we wondered if a reduced selective pressure by neutralizing antibodies (NAb) in the central nervous system (CNS) could favor the evolution of NAb-sensitive viruses in this compartment. Single genome amplification (SGA) was used to sequence full-length HIV-1 envelope variants (453 sequences) from paired CSF and blood plasma samples in 9 subjects infected by HIV variants of various clades and suffering from diverse neurologic disorders. Dynamics of viral evolution were evaluated with a bayesian coalescent approach for individuals with longitudinal samples. Pseudotyped viruses expressing envelope glycoproteins variants representative of the quasi-species present in each compartment were generated, and their sensitivity to autologous neutralization, broadly neutralizing antibodies (bNAbs) and entry inhibitors was assessed. Significant compartmentalization of HIV populations between blood and CSF were detected in 5 out of 9 subjects. Some of the previously described genetic determinants for compartmentalization in the CNS were observed regardless of the HIV-1 clade. There was no difference of sensitivity to autologous neutralization between blood and CSF-variants, even for subjects with compartmentalization, suggesting that selective pressure by autologous NAb is not the main driver of HIV evolution in the CNS. However, we observed major differences of sensitivity to sCD4 or to at least one bNAb targeting either the N160-V1V2 site, the N332-V3 site or the CD4bs, between blood- and CSF-variants in all cases. In particular, HIV-1 variants present in the CSF were more resistant to bNAbs than their blood counterpart in some cases. Considering the possible migration from CSF to blood, the CNS could be a reservoir of bNAb resistant viruses, an observation that should be considered for immunotherapeutic approaches. PMID- 28841648 TI - Network analysis of surgical innovation: Measuring value and the virality of diffusion in robotic surgery. AB - BACKGROUND: Existing surgical innovation frameworks suffer from a unifying limitation, their qualitative nature. A rigorous approach to measuring surgical innovation is needed that extends beyond detecting simply publication, citation, and patent counts and instead uncovers an implementation-based value from the structure of the entire adoption cascades produced over time by diffusion processes. Based on the principles of evidence-based medicine and existing surgical regulatory frameworks, the surgical innovation funnel is described. This illustrates the different stages through which innovation in surgery typically progresses. The aim is to propose a novel and quantitative network-based framework that will permit modeling and visualizing innovation diffusion cascades in surgery and measuring virality and value of innovations. MATERIALS AND METHODS: Network analysis of constructed citation networks of all articles concerned with robotic surgery (n = 13,240, Scopus(r)) was performed (1974-2014). The virality of each cascade was measured as was innovation value (measured by the innovation index) derived from the evidence-based stage occupied by the corresponding seed article in the surgical innovation funnel. The network-based surgical innovation metrics were also validated against real world big data (National Inpatient Sample-NIS(r)). RESULTS: Rankings of surgical innovation across specialties by cascade size and structural virality (structural depth and width) were found to correlate closely with the ranking by innovation value (Spearman's rank correlation coefficient = 0.758 (p = 0.01), 0.782 (p = 0.008), 0.624 (p = 0.05), respectively) which in turn matches the ranking based on real world big data from the NIS(r) (Spearman's coefficient = 0.673;p = 0.033). CONCLUSION: Network analysis offers unique new opportunities for understanding, modeling and measuring surgical innovation, and ultimately for assessing and comparing generative value between different specialties. The novel surgical innovation metrics developed may prove valuable especially in guiding policy makers, funding bodies, surgeons, and healthcare providers in the current climate of competing national priorities for investment. PMID- 28841649 TI - Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab. Evidence from the randomised controlled NEO-RACo trial. AB - OBJECTIVE: YKL-40, a chitinase-like glycoprotein associated with inflammation and tissue remodeling, is produced by joint tissues and recognized as a candidate auto-antigen in rheumatoid arthritis (RA). In the present study, we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aiming for early remission. METHODS: Ninety-nine patients with early DMARD-naive RA participated in the NEO-RACo study. For the first four weeks, the patients were treated with the combination of sulphasalazine, methotrexate, hydroxychloroquine and low dose prednisolone (FIN-RACo DMARD combination), and subsequently randomized to receive placebo or infliximab added on the treatment for further 22 weeks. Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay. RESULTS: At the baseline, plasma YKL 40 concentration was 57 +/- 37 (mean +/- SD) ng/ml. YKL-40 was significantly associated with the disease activity score, interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks' treatment. The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment, and there was no further reduction when the tumour necrosis factor alpha antagonist infliximab was added on the combination treatment. CONCLUSIONS: High YKL-40 levels were found to be associated with disease activity in early DMARD-naive RA and during intensive treat-to-target therapy. The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission. PMID- 28841650 TI - Transparency ethics in practice: Revisiting financial conflicts of interest disclosure forms in clinical practice guidelines. AB - BACKGROUND: Authors of clinical practice guidelines (CPGs) disclose financial conflicts of interest (FCOIs) to promote transparency ethics. Typically, they do so on standard declaration forms containing generic open-ended questions on FCOIs. Yet, the literature is scant on the format and effect of alternative disclosure forms. Does supplementing a standard form with subsequent detailed disclosure forms tailored to the context of the CPG improve the yield or accuracy of FCOIs declarations? METHODS: For an international CPG in gastroenterology on the endoscopic surveillance for colorectal neoplasia in inflammatory bowel disease, we compared the use of a standard FCOIs disclosure form with a contextual FCOIs disclosure form that detailed commercial relations related to the CPG topic. This included manufacturers of endoscopes, endoscopy equipment and accessories. Participants completed the generic form early, and the supplementary contextual form six months later. We then compared the FCOI disclosures obtained. FINDINGS: 26 participants provided FCOIs disclosures using both disclosure forms. We found discrepancies regarding (1) the disclosure of FCOIs (presence/absence), and (2) the listing of financial entities. While the number of participants who disclosed a FCOI remained the same (30.8%) using the two forms, disclosures were not from the same individuals: two additional participants disclosed a FCOI, whereas two participants withdrew previous disclosures. Among those who reported a FCOI in either form, we noted inconsistencies in disclosures for 70% of the participants. This included changes in FCOIs disclosure status or modifications of "their commercial relations". DISCUSSION: Accurate reporting of FCOIs advances the transparency and ethical integrity of CPGs. Our experience suggests that a contextual FCOIs disclosure form tailored to content of the CPG with narrow, detailed questions provides supplementary, more complete FCOIs declarations than generic forms alone. The finding raises challenges on how forms are best written and formatted, optimally timed, and more effectively processed with sensitivity to professional behaviour, so as to heighten transparency. PMID- 28841651 TI - Functional significance of rare neuroligin 1 variants found in autism. AB - Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders. PMID- 28841652 TI - Fresh frozen cortical strut allograft in two-level anterior cervical corpectomy and fusion. AB - Anterior cervical corpectomy and fusion (ACCF) is one of the main surgical strategies for the management of multilevel cervical spondylotic myelopathy (MCSM). High complication rates of graft bone fracture, resorption, displacement, and fusion collapse or pseudarthrosis have been previously reported. The strategies to prevent the aforementioned complications include using fresh frozen cortical strut allograft (FFCSA) to keep most of the original bone quality and using additional anterior plate fixation to improve the fusion stability and union rate. In this study, we evaluated 4-year follow-ups for surgical outcomes and analyzed the risk factors of MCSM patients who received 2-level ACCF with FFCSA and titanium dynamic plate fixation. We retrospectively collected preoperative and postoperative radiographic and clinical data of patients from 2005 to 2009; the inclusion criteria were having been diagnosed as MCSM and having received 2-level ACCF with an FFCSA fibular shaft and an anterior dynamic plate. The cervical curvature lordosis improved and the neurogenic function recovered well postoperatively. Visual analog scale for neck pain and neck disability index scores both decreased after 12 and 48 months following surgery. The Japanese Orthopaedic Association score recovery rate at postoperative 4 years was 87.5%. Fusion rates achieved 100% at 12 months. The preoperative Nurick score seemed to be the only significant risk factor correlated with the functional recovery rate at 4 years after the surgery. In conclusion, based on a minimum 4 year follow-up of 2-level ACCF with FFCSA and dynamic titanium plates for patients with MCSM, the surgical results were satisfying and the complication rates were low. PMID- 28841653 TI - Treatment of Schistosoma mansoni with miltefosine in vitro enhances serological recognition of defined worm surface antigens. AB - BACKGROUND: Miltefosine, an anti-cancer drug that has been successfully repositioned for treatment of Leishmania infections, has recently also shown promising effects against Schistosoma spp targeting all life cycle stages of the parasite. The current study examined the effect of treating Schistosoma mansoni adult worms with miltefosine on exposure of worm surface antigens in vitro. METHODOLOGY/PRINCIPAL FINDINGS: In an indirect immunofluorescence assay, rabbit anti-S.mansoni adult worm homogenate and anti-S. mansoni infection antisera gave strong immunofluorescence of the S. mansoni adult worm surface after treatment with miltefosine, the latter antiserum having previously been shown to synergistically enhance the schistosomicidal activity of praziquantel. Rabbit antibodies that recognised surface antigens exposed on miltefosine-treated worms were recovered by elution off the worm surface in low pH buffer and were used in a western immunoblotting assay to identify antigenic targets in a homogenate extract of adult worms (SmWH). Four proteins reacting with the antibodies in immunoblots were purified and proteomic analysis (MS/MS) combined with specific immunoblotting indicated they were the S. mansoni proteins: fructose-1,6 bisphosphate aldolase (SmFBPA), Sm22.6, alkaline phosphatase and malate dehydrogenase. These antibodies were also found to bind to the surface of 3-hour schistosomula and induce immune agglutination of the parasites, suggesting they may have a role in immune protection. CONCLUSION/SIGNIFICANCE: This study reveals a novel mode of action of miltefosine as an anti-schistosome agent. The immune dependent hypothesis we investigated has previously been lent credence with praziquantel (PZQ), whereby treatment unmasks parasite surface antigens not normally exposed to the host during infection. Antigens involved in this molecular mechanism could have potential as intervention targets and antibodies against these antigens may act to increase the drug's anti-parasite efficacy and be involved in the development of resistance to re-infection. PMID- 28841654 TI - Inter-laboratory agreement on embryo classification and clinical decision: Conventional morphological assessment vs. time lapse. AB - The aim of this study is to determine inter-laboratory variability on embryo assessment using time-lapse platform and conventional morphological assessment. This study compares the data obtained from a pilot study of external quality control (EQC) of time lapse, performed in 2014, with the classical EQC of the Spanish Society for the Study of Reproductive Biology (ASEBIR) performed in 2013 and 2014. In total, 24 laboratories (8 using EmbryoScopeTM, 15 using Primo VisionTM and one with both platforms) took part in the pilot study. The clinics that used EmbryoScopeTM analysed 31 embryos and those using Primo VisionTM analysed 35. The classical EQC was implemented by 39 clinics, based on an analysis of 25 embryos per year. Both groups were required to evaluate various qualitative morphological variables (cell fragmentation, the presence of vacuoles, blastomere asymmetry and multinucleation), to classify the embryos in accordance with ASEBIR criteria and to stipulate the clinical decision taken. In the EQC time-lapse pilot study, the groups were asked to determine, as well as the above characteristics, the embryo development times, the number, opposition and size of pronuclei, the direct division of 1 into 3 cells and/or of 3 into 5 cells and false divisions. The degree of agreement was determined by calculating the intra-class correlation coefficients and the coefficient of variation for the quantitative variables and the Gwet index for the qualitative variables. For both EmbryoScopeTM and Primo VisionTM, two periods of greater inter-laboratory variability were observed in the times of embryo development events. One peak of variability was recorded among the laboratories addressing the first embryo events (extrusion of the second polar body and the appearance of pronuclei); the second peak took place between the times corresponding to the 8-cell and morula stages. In most of the qualitative variables analysed regarding embryo development, there was almost-perfect inter-laboratory agreement among conventional morphological assessment (CMA), EmbryoScopeTM and Primo VisionTM, except for false divisions, vacuoles and asymmetry (users of all methods) and multinucleation (users of Primo VisionTM), where the degree of agreement was lower. The inter-laboratory agreement on embryo classification according to the ASEBIR criteria was moderate-substantial (Gwet 0.41-0.80) for the laboratories using CMA and EmbryoScopeTM, and fair-moderate (Gwet 0.21-0.60) for those using Primo VisionTM. The inter-laboratory agreement for clinical decision was moderate (Gwet 0.41-0.60) on day 5 for CMA users and almost perfect (Gwet 0.81-1) for time lapse users. In conclusion, time-lapse technology does not improve inter laboratory agreement on embryo classification or the analysis of each morphological variable. Moreover, depending on the time-lapse platform used, inter-laboratory agreement may be lower than that obtained by CMA. However, inter laboratory agreement on clinical decisions is improved with the use of time lapse, regardless of the platform used. PMID- 28841655 TI - Lower frequency routine surveillance endomyocardial biopsies after heart transplantation. AB - In heart transplantation (HTx) patients, routine surveillance endomyocardial biopsies (rsEMB) are recommended for the detection of early cardiac allograft rejection. However, there is no consensus on the optimal frequency of rsEMB. Frequent rsEMB have shown a low diagnostic yield in the new era of potent immunosuppressive regimen. Efficacy and safety of lower frequency rsEMB have not been investigated so far. In this retrospective, single centre, observational study we evaluated 282 patients transplanted between 2004 and 2014. 218 of these patients were investigated by rsEMB and symptom-triggered EMB (stEMB). We evaluated EMB results, complications, risk factors for rejection, survival 1 and 5 years as well as incidence of cardiac allograft vasculopathy (CAV) 3 years after HTx. A mean of 7.1 +/- 2.5 rsEMB were conducted per patient within the first year after HTx identifying 7 patients with asymptomatic and 9 patients with symptomatic acute rejection requiring glucocorticoide pulse therapy. Despite this relatively low frequency of rsEMB, only 6 unscheduled stEMB were required in the first year after HTx leading to 2 additional treatments. In 6 deaths among all 282 patients (2.1%), acute rejection could not be ruled out as a potential underlying cause. Overall survival at 1 year was 78.7% and 5-year survival was 74%. Incidence of CAV was 17% at 3-year follow-up. Morbidity and mortality of lower frequency rsEMB are comparable with data from the International Society for Heart and Lung Transplantation (ISHLT) registry. Consensus is needed on the optimal frequency of EMB. PMID- 28841656 TI - Clinical characteristics of patients with tinnitus evaluated with the Tinnitus Sample Case History Questionnaire in Japan: A case series. AB - BACKGROUND: The Tinnitus Sample Case History Questionnaire was determined as a standardized questionnaire for obtaining patient case histories and for characterizing patients into subgroups at the Tinnitus Research Initiative in 2006. In this study, we developed a Japanese version of this questionnaire for evaluating the clinical characteristics of patients with tinnitus. The Japanese version of the questionnaire will be available for evaluating treatments for tinnitus and for comparing data on tinnitus in research centers. AIMS/OBJECTIVES: To evaluate the clinical characteristics of patients with tinnitus in Japan using a newly developed Japanese version of Tinnitus Sample Case History Questionnaire. STUDY DESIGN: This was a prospective study based on patient records. SETTING: University hospitals, general hospitals, and clinics. SUBJECTS AND METHODS: We collected patient data using a Japanese translated version of the Tinnitus Sample Case History Questionnaire. In total, 584 patients who visited our institutions in Japan between August 2012 and March 2014 were included (280 males and 304 females; age 13-92 years; mean age, 60.8). We examined patients after dividing them into two groups according to the presence or absence of hyperacusis. The collected results were compared with those from the Tinnitus Research Initiative database. RESULTS: Compared with the TRI database, there were significantly more elderly female patients and fewer patients with trauma-associated tinnitus. There was a statistically lower ratio of patients with hyperacusis. We found that patients with tinnitus in addition to hyperacusis had greater tinnitus severity and exhibited higher rates of various complications. CONCLUSION: The Japanese version of the Tinnitus Sample Case History Questionnaire developed in this study can be a useful tool for evaluating patients with tinnitus in Japan. The results of this multicenter study reflect the characteristics of patients with tinnitus who require medical care in Japan. Our data provides a preliminary basis for an international comparison of tinnitus epidemiology. PMID- 28841657 TI - A prediction model for advanced colorectal neoplasia in an asymptomatic screening population. AB - BACKGROUND: An electronic medical record (EMR) database of a large unselected population who received screening colonoscopies may minimize sampling error and represent real-world estimates of risk for screening target lesions of advanced colorectal neoplasia (CRN). Our aim was to develop and validate a prediction model for assessing the probability of advanced CRN using a clinical data warehouse. METHODS: A total of 49,450 screenees underwent their first colonoscopy as part of a health check-up from 2002 to 2012 at Samsung Medical Center, and the dataset was constructed by means of natural language processing from the computerized EMR system. The screenees were randomized into training and validation sets. The prediction model was developed using logistic regression. The model performance was validated and compared with existing models using area under receiver operating curve (AUC) analysis. RESULTS: In the training set, age, gender, smoking duration, drinking frequency, and aspirin use were identified as independent predictors for advanced CRN (adjusted P < .01). The developed model had good discrimination (AUC = 0.726) and was internally validated (AUC = 0.713). The high-risk group had a 3.7-fold increased risk of advanced CRN compared to the low-risk group (1.1% vs. 4.0%, P < .001). The discrimination performance of the present model for high-risk patients with advanced CRN was better than that of the Asia-Pacific Colorectal Screening score (AUC = 0.678, P < .001) and Schroy's CAN index (AUC = 0.672, P < .001). CONCLUSION: The present 5-item risk model can be calculated readily using a simple questionnaire and can identify the low- and high-risk groups of advanced CRN at the first screening colonoscopy. This model may increase colorectal cancer risk awareness and assist healthcare providers in encouraging the high-risk group to undergo a colonoscopy. PMID- 28841658 TI - Convective and diffusive effects on particle transport in asymmetric periodic capillaries. AB - We present here results of a theoretical investigation of particle transport in longitudinally asymmetric but axially symmetric capillaries, allowing for the influence of both diffusion and convection. In this study we have focused attention primarily on characterizing the influence of tube geometry and applied hydraulic pressure on the magnitude, direction and rate of transport of particles in axi-symmetric, saw-tooth shaped tubes. Three initial value problems are considered. The first involves the evolution of a fixed number of particles initially confined to a central wave-section. The second involves the evolution of the same initial state but including an ongoing production of particles in the central wave-section. The third involves the evolution of particles a fully laden tube. Based on a physical model of convective-diffusive transport, assuming an underlying oscillatory fluid velocity field that is unaffected by the presence of the particles, we find that transport rates and even net transport directions depend critically on the design specifics, such as tube geometry, flow rate, initial particle configuration and whether or not particles are continuously introduced. The second transient scenario is qualitatively independent of the details of how particles are generated. In the third scenario there is no net transport. As the study is fundamental in nature, our findings could engender greater understanding of practical systems. PMID- 28841659 TI - Pre-treatment with Lactobacillus plantarum prevents severe pathogenesis in mice infected with Leptospira interrogans and may be associated with recruitment of myeloid cells. AB - Recent estimates on global morbidity and mortality caused by Leptospirosis point to one million cases and almost 60,000 deaths a year worldwide, especially in resource poor countries. We analyzed how a commensal probiotic immunomodulator, Lactobacillus plantarum, affects Leptospira interrogans pathogenesis in a murine model of sub-lethal leptospirosis. We found that repeated oral pre-treatment of mice with live L. plantarum restored body weight to normal levels in mice infected with L. interrogans. Pre-treatment did not prevent L. interrogans access to the kidney but it affected the inflammatory response and it reduced histopathological signs of disease. Analysis of the immune cell profiles in lymphoid tissues of mice pre-treated with L. plantarum showed increased numbers of B cells as well as naive and memory CD4+ helper T cell populations in uninfected mice that shifted towards increased numbers of effector CD4+ helper T in infected mice. CD8+ cytotoxic T cell profiles in pre-treated uninfected and infected mice mirrored the switch observed for CD4+ except that CD8+ memory T cells were not affected. In addition, pre-treatment led to increased populations of monocytes in lymphoid tissues of uninfected mice and to increased populations of macrophages in the same tissues of infected mice. Immunohistochemistry of kidney sections of pre-treated infected mice showed an enrichment of neutrophils and macrophages and a reduction of total leucocytes and T cells. Our results suggest that complex myeloid and T cell responses orchestrate the deployment of monocytes and other cells from lymphoid tissue and the recruitment of neutrophils and macrophages to the kidney, and that, the presence of these cells in the target organ may be associated with reductions in pathogenesis observed in infected mice treated with L. plantarum. PMID- 28841660 TI - Threshold-activated transport stabilizes chaotic populations to steady states. AB - We explore Random Scale-Free networks of populations, modelled by chaotic Ricker maps, connected by transport that is triggered when population density in a patch is in excess of a critical threshold level. Our central result is that threshold activated dispersal leads to stable fixed populations, for a wide range of threshold levels. Further, suppression of chaos is facilitated when the threshold activated migration is more rapid than the intrinsic population dynamics of a patch. Additionally, networks with large number of nodes open to the environment, readily yield stable steady states. Lastly we demonstrate that in networks with very few open nodes, the degree and betweeness centrality of the node open to the environment has a pronounced influence on control. All qualitative trends are corroborated by quantitative measures, reflecting the efficiency of control, and the width of the steady state window. PMID- 28841661 TI - Association between self-reported vegetarian diet and the irritable bowel syndrome in the French NutriNet cohort. AB - BACKGROUND: There is growing interest in using diet counselling in the management of patients with irritable bowel syndrome (IBS). Among new emerging diets, vegetarian diets (VD) seem to be experiencing an important popularity, partly because of their alleged health benefits. A recent study performed among a rural Indian population showed that predominant VD could be associated with IBS. OBJECTIVE: This cross-sectional study aimed at assessing the association between the VD and IBS, among a large French cohort, the NutriNet-sante study. METHODS: Subjects participating in the NutriNet-Sante cohort study completed a questionnaire based on Rome III criteria (N = 41,682). Anthropometrics, socio demographical and lifestyle data, including VD, were collected prior to the completion of Rome III questionnaire via self-administered questionnaires. Association between VD and IBS and its subtypes was investigated through multivariate logistic regression. RESULTS: The included subjects were mainly women (78.0%) and the mean age was 49.8+/-14.3 years. Among these individuals, 2,264 (5.4%) presented an IBS, and 805 (1.9%) reported a VD. Overall, VD was not associated with IBS or subtypes. A stable VD (i.e. self-declared at least three times) was associated with IBS (aOR 2.60 95%CI [1.37-4.91]), IBS mixed (aOR 2.97 95%CI [1.20-7.36]) and IBS diarrhoea (aOR 2.77 95%CI [1.01-7.59]). CONCLUSIONS: This study suggests that a long term VD could be associated with IBS. Nevertheless, further studies are needed to confirm these results, and investigate the multiple aspects of the vegetarian diet, possibly related to the IBS. PMID- 28841662 TI - The need for strong clinical leaders - Transformational and transactional leadership as a framework for resident leadership training. AB - BACKGROUND: For the purpose of providing excellent patient care, residents need to be strong, effective leaders. The lack of clinical leadership is alarming given the detrimental effects on patient safety. The objective of the study was to assess whether a leadership training addressing transactional and transformational leadership enhances leadership skills in residents. METHODS: A volunteer sample of 57 residents from postgraduate year one to four was recruited across a range of medical specialties. The residents took part in an interventional controlled trial. The four-week IMPACT leadership training provided specific strategies for leadership in the clinical environment, addressing transactional (e.g. active control, contingent reward) and transformational leadership skills (e.g. appreciation, inspirational motivation). Transactional and transformational leadership skill performance was rated (1) on the Performance Scale by an external evaluator blinded to the study design and (2) self-assessed transformational and transactional leadership skills. Both measures contained items of the Multifactor Leadership Questionnaire, with higher scores indicating greater leadership skills. RESULTS: Both scores were significantly different between the IMPACT group and the control group. In the IMPACT group, the Performance Scale increased 15% in transactional leadership skill performance (2.10 to 2.86) (intervention effect, 0.76; 95% CI, 0.40 to 1.13; p < .001, eta2 = 0.31) and 14% in transformational leadership skill performance (2.26 to 2.94) (intervention effect, 0.68; 95% CI, 0.27 to 1.09; p < .001, eta2 = 0.22). The self-assessed transactional skills revealed a 4% increase (3.83 to 4.03) (intervention effect, 0.20; 95% CI, 0.08 to 0.33; p < .001, eta2 = 0.18) and a 6% increase in transformational leadership skills (3.54 to 3.86) (intervention effect, 0.31; 95% CI, 0.02 to 0.40; p< .001, eta2 = 0.53). DISCUSSION AND CONCLUSIONS: These findings support the use of the transactional and transformational leadership framework for graduate leadership training. Future studies should incorporate time-latent post-tests, evaluating the stability of the behavioral performance increase. PMID- 28841663 TI - Valuation of opportunity costs by rats working for rewarding electrical brain stimulation. AB - Pursuit of one goal typically precludes simultaneous pursuit of another. Thus, each exclusive activity entails an "opportunity cost:" the forgone benefits from the next-best activity eschewed. The present experiment estimates, in laboratory rats, the function that maps objective opportunity costs into subjective ones. In an operant chamber, rewarding electrical brain stimulation was delivered when the cumulative time a lever had been depressed reached a criterion duration. The value of the activities forgone during this duration is the opportunity cost of the electrical reward. We determined which of four functions best describes how objective opportunity costs, expressed as the required duration of lever depression, are translated into their subjective equivalents. The simplest account is the identity function, which equates subjective and objective opportunity costs. A variant of this function called the "sigmoidal-slope function," converges on the identity function at longer durations but deviates from it at shorter durations. The sigmoidal-slope function has the form of a hockey stick. The flat "blade" denotes a range over which opportunity costs are subjectively equivalent; these durations are too short to allow substitution of more beneficial activities. The blade extends into an upward-curving portion over which costs become discriminable and finally into the straight "handle," over which objective and subjective costs match. The two remaining functions are based on hyperbolic and exponential temporal discounting, respectively. The results are best described by the sigmoidal-slope function. That this is so suggests that different principles of intertemporal choice are involved in the evaluation of time spent working for a reward or waiting for its delivery. The subjective opportunity-cost function plays a key role in the evaluation and selection of goals. An accurate description of its form and parameters is essential to successful modeling and prediction of instrumental performance and reward-related decision making. PMID- 28841664 TI - Frequent gene flow blurred taxonomic boundaries of sections in Lilium L. (Liliaceae). AB - Gene flow between species may last a long time in plants. Reticulation inevitably causes difficulties in phylogenetic reconstruction. In this study, we looked into the genetic divergence and phylogeny of 20 Lilium species based on multilocus analyses of 8 genes of chloroplast DNA (cpDNA), the internally transcribed nuclear ribosomal DNA (nrITS) spacer and 20 loci extracted from the expressed sequence tag (EST) libraries of L. longiflorum Thunb. and L. formosanum Wallace. The phylogeny based on the combined data of the maternally inherited cpDNA and nrITS was largely consistent with the taxonomy of Lilium sections. This phylogeny was deemed the hypothetical species tree and uncovered three groups, i.e., Cluster A consisting of 4 taxa from the sections Pseudolirium and Liriotypus, Cluster B consisting of the 4 taxa from the sections Leucolirion, Archelirion and Daurolirion, and Cluster C comprising 10 taxa mostly from the sections Martagon and Sinomartagon. In contrast, systematic inconsistency occurred across the EST loci, with up to 19 genes (95%) displaying tree topologies deviating from the hypothetical species tree. The phylogenetic incongruence was likely attributable to the frequent genetic exchanges between species/sections, as indicated by the high levels of genetic recombination and the IMa analyses with the EST loci. Nevertheless, multilocus analysis could provide complementary information among the loci on the species split and the extent of gene flow between the species. In conclusion, this study not only detected frequent gene flow among Lilium sections that resulted in phylogenetic incongruence but also reconstructed a hypothetical species tree that gave insights into the nature of the complex relationships among Lilium species. PMID- 28841665 TI - Prevalence and pattern of co morbidity among type2 diabetics attending urban primary healthcare centers at Bhubaneswar (India). AB - OBJECTIVE: India has the second largest diabetic population in the world. The chronic nature of the disease and high prevalence of co-existing chronic medical conditions or "co morbidities" makes diabetes management complex for the patient and for health care providers. Hence a strong need was felt to explore the problem of co morbidity among diabetics and its dimensions in primary health care practices. METHOD: This cross sectional survey was carried out on 912 type 2 diabetes patients attending different urban primary health care facilities at Bhubaneswar. Data regarding existence of co morbidity and demographical details were elicited by a predesigned, pretested questionnaire"Diabetes Co morbidity Evaluation Tool in Primary Care (DCET- PC)". Statistical analyses were done using STATA. RESULTS: Overall 84% had one ormore than one comorbid condition. The most frequent co morbid conditions were hypertension [62%], acid peptic disease [28%], chronic back ache [22%] and osteoarthritis [21%]. The median number of co morbid conditions among both males and females is 2[IQR = 2]. The range of the number of co morbid conditions was wider among males [0-14] than females [0-6]. The number of co morbidities was highest in the age group > = 60 across both sexes. Most of the male patients below 40 years of age had either single [53%] or three co morbidities [11%] whereas among female patients of the same age group single [40%] or two co morbidities [22%] were more predominantly present. Age was found to be a strong independent predictor for diabetes co morbidity. The odds of having co morbidity among people above poverty line and schedule caste were found to be[OR = 3.50; 95%CI 1.85-6.62]and [OR = 2.46; CI 95%1.16-5.25] respectively. Odds were increased for retired status [OR = 1.21; 95% CI 1.01-3.91] and obesity [OR = 3.96; 95%CI 1.01-15.76]. CONCLUSION: The results show a high prevalence of co morbidities in patients with type 2 diabetes attending urban primary health care facilities. Hypertension, acid peptic disease, chronic back ache and arthritis being the most common, strategies need to be designed taking into account the multiple demands of co morbidities. PMID- 28841666 TI - Vicious circles of gender bias, lower positions, and lower performance: Gender differences in scholarly productivity and impact. AB - It is often argued that female researchers publish on average less than male researchers do, but male and female authored papers have an equal impact. In this paper we try to better understand this phenomenon by (i) comparing the share of male and female researchers within different productivity classes, and (ii) by comparing productivity whereas controlling for a series of relevant covariates. The study is based on a disambiguated Swedish author dataset, consisting of 47,000 researchers and their WoS-publications during the period of 2008-2011 with citations until 2015. As the analysis shows, in order to have impact quantity does make a difference for male and female researchers alike-but women are vastly underrepresented in the group of most productive researchers. We discuss and test several possible explanations of this finding, using a data on personal characteristics from several Swedish universities. Gender differences in age, authorship position, and academic rank do explain quite a part of the productivity differences. PMID- 28841667 TI - The effects of d-aspartic acid supplementation in resistance-trained men over a three month training period: A randomised controlled trial. AB - CONTEXT: Research on d-aspartic acid (DAA) has demonstrated increases in total testosterone levels in untrained men, however research in resistance-trained men demonstrated no changes, and reductions in testosterone levels. The long-term consequences of DAA in a resistance trained population are currently unknown. OBJECTIVE: To evaluate the effectiveness of DAA to alter basal testosterone levels over 3 months of resistance training in resistance-trained men. DESIGN: Randomised, double-blind, placebo controlled trial in healthy resistance-trained men, aged 18-36, had been performing regular resistance training exercise for at least 3 d.w-1 for the previous 2 years. Randomised participants were 22 men (d aspartic acid n = 11; placebo n = 11) (age, 23.8+/-4.9 y, training age, 3.2+/-1.5 y). INTERVENTION: D-aspartic acid (6 g.d-1, DAA) versus equal-weight, visually matched placebo (PLA). All participants performed 12 weeks of supervised, periodised resistance training (4 d.w-1), with a program focusing on all muscle groups. MEASURES: Basal hormones, total testosterone (TT), free testosterone (FT), estradiol (E2), sex-hormone-binding globulin (SHBG) and albumin (ALB); isometric strength; calf muscle cross-sectional area (CSA); calf muscle thickness; quadriceps muscle CSA; quadriceps muscle thickness; evoked V-wave and H-reflexes, were assessed at weeks zero (T1), after six weeks (T2) and after 12 weeks (T3). RESULTS: No change in basal TT or FT were observed after the intervention. DAA supplementation (n = 10) led to a 16%, 95% CI [-27%, -5%] reduction in E2 from T1-T3 (p<0.01). The placebo group (n = 9) demonstrated improvements in spinal responsiveness (gastrocnemius) at the level of the alpha motoneuron. Both groups exhibited increases in isometric strength of the plantar flexors by 17%, 95% CI [7%, 28%] (p<0.05) as well as similar increases in hypertrophy in the quadriceps and calf muscles. CONCLUSIONS: The results of this paper indicate that DAA supplementation is ineffective at changing testosterone levels, or positively affecting training outcomes. Reductions in estradiol and the blunting of peripheral excitability appear unrelated to improvements from resistance training. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000041358. PMID- 28841668 TI - Differential gene expression in leaf tissues between mutant and wild-type genotypes response to late leaf spot in peanut (Arachis hypogaea L.). AB - Late leaf spot (LLS) is a major foliar disease in peanut (A. hypogaea L.) worldwide, causing significant losses of potential yield in the absence of fungicide applications. Mutants are important materials to study the function of disease-related genes. In this study, the mutant line M14 was derived from cultivar Yuanza 9102 treated with EMS. Yuanza 9102 was selected from an interspecific cross of cultivar Baisha 1016 with A. diogoi, and is resistant to several fungal diseases. By contrast, the M14 was highly susceptible to late leaf spot. RNA-Seq analysis in the leaf tissues of the M14 and its wild type Yuanza 9102 under pathogen challenge showed 2219 differentially expressed genes including1317 up-regulated genes and 902 down-regulated genes. Of these genes, 1541, 1988, 1344, 643 and 533 unigenes were obtained and annotated by public protein databases of SwissPort, TrEMBL, gene ontology (GO), KEGG and clusters of orthologous groups (COG), respectively. Differentially expressed genes (DEGs) showed that expression of inducible pathogenesis-related (PR) proteins was significantly up-regulated; in the meantime DEGs related to photosynthesis were down-regulated in the susceptible M14 in comparison to the resistant WT. Moreover, the up-regulated WRKY transcription factors and down-regulated plant hormones related to plant growth were detected in the M14. The results suggest that down-regulated chloroplast genes, up-regulated WRKY transcription factors, and depressed plant hormones related to plant growth in the M14 might coordinately render the susceptibility though there was a significant high level of PRs. Those negative effectors might be triggered in the susceptible plant by fungal infection and resulted in reduction of photosynthesis and phytohormones and led to symptom formation. PMID- 28841669 TI - The nature of the Syntaxin4 C-terminus affects Munc18c-supported SNARE assembly. AB - Vesicular transport of cellular cargo requires targeted membrane fusion and formation of a SNARE protein complex that draws the two apposing fusing membranes together. Insulin-regulated delivery and fusion of glucose transporter-4 storage vesicles at the cell surface is dependent on two key proteins: the SNARE integral membrane protein Syntaxin4 (Sx4) and the soluble regulatory protein Munc18c. Many reported in vitro studies of Munc18c:Sx4 interactions and of SNARE complex formation have used soluble Sx4 constructs lacking the native transmembrane domain. As a consequence, the importance of the Sx4 C-terminal anchor remains poorly understood. Here we show that soluble C-terminally truncated Sx4 dissociates more rapidly from Munc18c than Sx4 where the C-terminal transmembrane domain is replaced with a T4-lysozyme fusion. We also show that Munc18c appears to inhibit SNARE complex formation when soluble C-terminally truncated Sx4 is used but does not inhibit SNARE complex formation when Sx4 is C-terminally anchored (by a C-terminal His-tag bound to resin, by a C-terminal T4L fusion or by the native C-terminal transmembrane domain in detergent micelles). We conclude that the C-terminus of Sx4 is critical for its interaction with Munc18c, and that the reported inhibitory role of Munc18c may be an artifact of experimental design. These results support the notion that a primary role of Munc18c is to support SNARE complex formation and membrane fusion. PMID- 28841670 TI - A biomechanical analysis of the roundhouse kicking technique of expert practitioners: A comparison between the martial arts disciplines of Muay Thai, Karate, and Taekwondo. AB - The purpose of this study was first, to determine whether there were differences in the roundhouse kicking leg kinematics performed by highly skilled Muay Thai, Karate and Taekwondo practitioners (n = 8 per group). Next, analysis aimed to identify the kinematic determinants of effective roundhouse kicking performance. Three-dimensional (3D) lower limb kinematics were recorded using a nine camera infra-red motion capture system (500 Hz) during three maximal roundhouse kicks. Impact forces were recorded using a strain gauge (1000 Hz) attached to a kicking pad positioned at the height of each participant's mastoid process. Results showed that linear foot velocity at impact was moderately correlated with relative impact force (r = 0.66, P = 0.001). Discipline specific analyses of the temporal data indicated that the Muay Thai group had a shorter execution time (1.02 +/- 0.15 s) than Taekwondo (1.54 +/- 0.52 s, P = 0.028). Analysis of lower limb kinematic data indicated that both Karate (-947 +/- 94 deg/s, P = 0.010) and Taekwondo (-943 +/- 106 deg/s, P = 0.011) practitioners had faster knee extension velocities than the Muay Thai group (-706 +/- 200 deg/s). Conversely, the Muay Thai practitioners (1.24 +/- 0.15 m/s) had greater vertical centre of mass movement than both Karate (0.78 +/- 0.24 m/s, P = 0.001) and Taekwondo groups (0.93 +/- 0.19 m/s, P = 0.02). Our findings show that several fundamental movement patterns were common to the roundhouse kicking techniques across the Muay Thai, Karate, and Taekwondo disciplines. Effective roundhouse kicking performance was characterized by rapid pelvic axial rotation, hip abduction, hip flexion and knee extension velocities, combined with rapid movements of the COM towards the target. PMID- 28841671 TI - Microbiome balance in sputum determined by PCR stratifies COPD exacerbations and shows potential for selective use of antibiotics. AB - BACKGROUND: While a subgroup of patients with exacerbations of chronic obstructive pulmonary disease (COPD) clearly benefit from antibiotics, their identification remains challenging. We hypothesised that selective assessment of the balance between the two dominant bacterial groups (Gammaproteobacteria (G) and Firmicutes (F)) in COPD sputum samples might reveal a subgroup with a bacterial community structure change at exacerbation that was restored to baseline on recovery and potentially reflects effective antibiotic treatment. METHODS: Phylogenetically specific 16S rRNA genes were determined by quantitative real time PCR to derive a G:F ratio in serial sputum samples from 66 extensively phenotyped COPD exacerbation episodes. RESULTS: Cluster analysis based on Euclidean distance measures, generated across the 4 visit times (stable and exacerbation day: 0,14 and 42) for the 66 exacerbation episodes, revealed three subgroups designated HG, HF, and GF reflecting predominance or equivalence of the two target bacterial groups. While the other subgroups showed no change at exacerbation, the HG cluster (n = 20) was characterized by G:F ratios that increased significantly at exacerbation and returned to baseline on recovery (p<0.00001); ratios in the HG group also correlated positively with inflammatory markers and negatively with FEV1. At exacerbation G:F showed a significant receiver-operator-characteristic curve to identify the HG subgroup (AUC 0.90, p<0.0001). CONCLUSIONS: The G:F ratio at exacerbation can be determined on a timescale compatible with decisions regarding clinical management. We propose that the G:F ratio has potential for use as a biomarker enabling selective use of antibiotics in COPD exacerbations and hence warrants further clinical evaluation. PMID- 28841672 TI - Integrated analysis of long non-coding RNAs in human gastric cancer: An in silico study. AB - Accumulating evidence highlights the important role of long non-coding RNAs (lncRNAs) in a large number of biological processes. However, the knowledge of genome scale expression of lncRNAs and their potential biological function in gastric cancer is still lacking. Using RNA-seq data from 420 gastric cancer patients in The Cancer Genome Atlas (TCGA), we identified 1,294 lncRNAs differentially expressed in gastric cancer compared with adjacent normal tissues. We also found 247 lncRNAs differentially expressed between intestinal subtype and diffuse subtype. Survival analysis revealed 33 lncRNAs independently associated with patient overall survival, of which 6 lncRNAs were validated in the internal validation set. There were 181 differentially expressed lncRNAs located in the recurrent somatic copy number alterations (SCNAs) regions and their correlations between copy number and RNA expression level were also analyzed. In addition, we inferred the function of lncRNAs by construction of a co-expression network for mRNAs and lncRNAs. Together, this study presented an integrative analysis of lncRNAs in gastric cancer and provided a valuable resource for further functional research of lncRNAs in gastric cancer. PMID- 28841673 TI - CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy. AB - C/EBP-homologous protein (CHOP) is an important component of the endoplasmic reticulum (ER) stress response. We demonstrated the induction of ER stress in response to tunicamycin stimulation, as evidenced by increased expression of chaperone proteins Grp78, Grp94, and enhanced eukaryotic initiation factor 2 subunit 1 (eIF2alpha) phosphorylation in hepatocellular carcinoma cells. Tunicamycin-induced ER stress resulted in apoptosis and autophagy simultaneously. While inhibition of autophagy mediated by 3-methyladenine pretreatment or direct knockdown of LC3B promoted cell apoptosis, activation of autophagy with rapamycin decreased tunicamycin- induced apoptosis in HCC cells. Furthermore, CHOP was shown to be significantly upregulated upon treatment with tunicamycin in HCC cells. Specific knockdown of CHOP not only enhanced tunicamycin-induced autophagy, but also significantly attenuated ER stress-induced apoptosis in HCC cells. Accordingly, simultaneous inhibition of autophagy in HCC cells with CHOP knockdown could partially resensitize ER stress-induced apoptosis. Taken together, our data indicate that CHOP may favor ER stress-induced apoptosis in HCC cells via inhibition of autophagy in vitro. PMID- 28841674 TI - Cryopreservation and re-culture of a 2.3 litre biomass for use in a bioartificial liver device. AB - For large and complex tissue engineered constructs to be available on demand, long term storage using methods, such as cryopreservation, are essential. This study optimised parameters such as excess media concentration and warming rates and used the findings to enable the successful cryopreservation of 2.3 litres of alginate encapsulated liver cell spheroids. This volume of biomass is typical of those required for successful treatment of Acute Liver Failure using our Bioartificial Liver Device. Adding a buffer of medium above the biomass, as well as slow (0.6 degrees C/min) warming rates was found to give the best results, so long as the warming through the equilibrium melting temperature was rapid. After 72 h post thaw-culture, viable cell number, glucose consumption, lactate production, and alpha-fetoprotein production had recovered to pre-freeze values in the 2.3 litre biomass (1.00 +/- 0.05, 1.19 +/- 0.10, 1.23 +/- 0.18, 2.03 +/- 0.04 per ml biomass of the pre-cryopreservation values respectively). It was also shown that further improvements in warming rates of the biomass could reduce recovery time to < 48 h. This is the first example of a biomass of this volume being successfully cryopreserved in a single cassette and re-cultured. It demonstrates that a bioartificial liver device can be cryopreserved, and has wider applications to scale-up large volume cryopreservation. PMID- 28841675 TI - Neural encoding of saltatory pneumotactile velocity in human glabrous hand. AB - Neurons in the somatosensory cortex are exquisitely sensitive to mechanical stimulation of the skin surface. The location, velocity, direction, and adaptation of tactile stimuli on the skin's surface are discriminable features of somatosensory processing, however the representation and processing of dynamic tactile arrays in the human somatosensory cortex are poorly understood. The principal aim of this study was to map the relation between dynamic saltatory pneumatic stimuli at discrete traverse velocities on the glabrous hand and the resultant pattern of evoked BOLD response in the human brain. Moreover, we hypothesized that the hand representation in contralateral Brodmann Area (BA) 3b would show a significant dependence on stimulus velocity. Saltatory pneumatic pulses (60 ms duration, 9.5 ms rise/fall) were repetitively sequenced through a 7 channel TAC-Cell array at traverse velocities of 5, 25, and 65 cm/s on the glabrous hand initiated at the tips of D2 (index finger) and D3 (middle finger) and sequenced towards the D1 (thumb). The resulting hemodynamic response was sampled during 3 functional MRI scans (BOLD) in 20 neurotypical right-handed adults at 3T. Results from each subject were inserted to the one-way ANOVA within subjects and one sample t-test to evaluate the group main effect of all three velocities stimuli and each of three different velocities, respectively. The stimulus evoked BOLD response revealed a dynamic representation of saltatory pneumotactile stimulus velocity in a network consisting of the contralateral primary hand somatosensory cortex (BA3b), associated primary motor cortex (BA4), posterior insula, and ipsilateral deep cerebellum. The spatial extent of this network was greatest at the 5 and 25 cm/s pneumotactile stimulus velocities. PMID- 28841676 TI - Can quartet analyses combining maximum likelihood estimation and Hennigian logic overcome long branch attraction in phylogenomic sequence data? AB - Systematic biases such as long branch attraction can mislead commonly relied upon model-based (i.e. maximum likelihood and Bayesian) phylogenetic methods when, as is usually the case with empirical data, there is model misspecification. We present PhyQuart, a new method for evaluating the three possible binary trees for any quartet of taxa. PhyQuart was developed through a process of reciprocal illumination between a priori considerations and the results of extensive simulations. It is based on identification of site-patterns that can be considered to support a particular quartet tree taking into account the Hennigian distinction between apomorphic and plesiomorphic similarity, and employing corrections to the raw observed frequencies of site-patterns that exploit expectations from maximum likelihood estimation. We demonstrate through extensive simulation experiments that, whereas maximum likeilihood estimation performs well in many cases, it can be outperformed by PhyQuart in cases where it fails due to extreme branch length asymmetries producing long-branch attraction artefacts where there is only very minor model misspecification. PMID- 28841677 TI - Development and evaluation of a training workshop for lay health promoters to implement a community-based intervention program in a public low rent housing estate: The Learning Families Project in Hong Kong. AB - : This paper presents the development and evaluation of the train-the-trainer (TTT) workshop for lay resident leaders to be lay health promoters. The TTT workshop aimed to prepare the trainees to implement and/or assist in conducting a series of community-based family well-being activities for the residents in a public low rent housing estate, entitled "Learning Families Project", under the FAMILY project. The four-hour TTT workshop was conducted for 32 trainees (72% women, 43% aged >= 60, 41% <= elementary school education). The workshop aimed to promote trainees' knowledge, self-efficacy, attitude and practice of incorporating the positive psychology themes into their community activities and engaging the residents to join these activities and learn with their family members. Post-training support was provided. The effectiveness of the TTT was examined by self-administered questionnaires about trainees' reactions to training content, changes in learning and practice at three time points (baseline, and immediately and one year after training), and the difference in residents' survey results before and after participating in the community activities delivered by the trainees. The trainees' learning about the general concepts of family well-being, learning family, leadership skills and planning skills increased significantly with medium to large effect sizes (Cohen's d: 0.5 1.4) immediately after the training. The effects of perceived knowledge and attitude towards practice were sustained to one year (Cohen's d: 0.4-0.6). The application of planning skills to implement community activities was higher at one year (Cohen's d: 0.4), compared with baseline. At one year, the residents' survey results showed significant increases in the practice of positive communication behaviours and better neighbour cohesions after joining the family well-being activities of LFP. Qualitative feedback supported the quantitative results. Our TTT workshop could serve as a practical example of development and evaluation of training programs for lay personnel to be lay health promoters. TRIAL REGISTRATION: ClinicalTrials.gov NCT02844244. PMID- 28841678 TI - The relationship between dietary quality and the local food environment differs according to level of educational attainment: A cross-sectional study. AB - There is evidence that food outlet access differs according to level of neighbourhood deprivation but little is known about how individual circumstances affect associations between food outlet access and diet. This study explored the relationship between dietary quality and a measure of overall food environment, representing the balance between healthy and unhealthy food outlet access in individualised activity spaces. Furthermore, this study is the first to assess effect modification of level of educational attainment on this relationship. A total of 839 mothers with young children from Hampshire, United Kingdom (UK) completed a cross-sectional survey including a 20-item food frequency questionnaire to measure diet and questions about demographic characteristics and frequently visited locations including home, children's centre, general practitioner, work, main food shop and physical activity location. Dietary information was used to calculate a standardised dietary quality score for each mother. Individualised activity spaces were produced by creating a 1000m buffer around frequently visited locations using ArcGIS. Cross-sectional observational food outlet data were overlaid onto activity spaces to derive an overall food environment score for each mother. These scores represented the balance between healthy and unhealthy food outlets using weightings to characterise the proportion of healthy or unhealthy foods sold in each outlet type. Food outlet access was dominated by the presence of unhealthy food outlets; only 1% of mothers were exposed to a healthy overall food environment in their daily activities. Level of educational attainment moderated the relationship between overall food environment and diet (mid vs low, p = 0.06; high vs low, p = 0.04). Adjusted stratified linear regression analyses showed poorer food environments were associated with better dietary quality among mothers with degrees (beta = 0.02; 95%CI: -0.03, -0.001) and a tendency toward poorer dietary quality among mothers with low educational attainment, however this relationship was not statistically significant (beta = 0.01; 95%CI: -0.01, 0.02). This study showed that unhealthy food outlets, like takeaways and convenience stores, dominated mothers' food outlet access, and provides some empirical evidence to support the concept that individual characteristics, particularly educational attainment, are protective against exposure to unhealthy food environments. Improvements to the imbalance of healthy and unhealthy food outlets through planning restrictions could be important to reduce dietary inequalities. PMID- 28841679 TI - Survival inequalities in patients with lung cancer in France: A nationwide cohort study (the TERRITOIRE Study). AB - The French healthcare system is a universal healthcare system with no financial barrier to access to health services and cancer drugs. The objective of the study is to investigate associations between, on the one hand, incidence and survival of patients diagnosed with lung cancer in France and, on the other, the socioeconomic deprivation and population density of their municipality of residence. A national, longitudinal analysis using data from the French National Hospital database crossed with the population density of the municipality and a social deprivation index based on census data aggregated at the municipality level. For lung cancer diagnosed at the metastatic stage, one-year and two-year survival was not associated with the population density of the municipality of residence. In contrast, mortality was higher for people living in very deprived, deprived and privileged areas compared to very privileged areas (hazard ratios at two years: 1.19 [1.13-1.25], 1.14 [1.08-1.20] and 1.10 [1.04-1.16] respectively). Similar associations are also observed in patients diagnosed with non-metastatic disease (hazard ratios at two years: 1.21 [1.13-1.30], 1.15 [1.08-1.23] and 1.10 [1.03-1.18] for people living in very deprived, deprived and privileged areas compared to very privileged areas). Despite a universal healthcare coverage, survival inequalities in patients with lung cancer can be observed in France with respect to certain socioeconomic indicators. PMID- 28841680 TI - Usefulness of multiecho fast field echo MRI in the evaluation of ossification of the posterior longitudinal ligament and dural ossification of the cervical spine. AB - OBJECTIVES: The diagnosis of ossification of the posterior longitudinal ligament (OPLL) on magnetic resonance imaging (MRI) is challenging. The purpose of this study is to evaluate the usefulness of the multiecho fast field echo (mFFE) MRI in the detection of ossification of the posterior longitudinal ligament and dural ossification (DO) of the cervical spine. METHODS: Sixty-three patients who underwent MRI with mFFE and CT for cervical spine were retrospectively evaluated. The presence of OPLL and DO on MR images was assessed by two independent readers. The sensitivity, specificity, and accuracy of MRI for detecting OPLL and DO were determined using CT as a reference standard. Image contrast ratios were obtained between the OPLL and perilesional structures on each sequence. RESULTS: There were 31 patients with OPLL and 13 DO lesions. The mean sensitivity, specificity, and accuracy of both readers were 94%, 81%, 88% for OPLL and 92%, 81%, 86% for DO, respectively. The contrast ratios for OPLL and intervertebral disc, spinal cord and cerebrospinal fluid were significantly superior on mFFE images, whereas those for OPLL and bone marrow were significantly inferior on mFFE images than those of T1-and T2-weighted images (p <= 0.016). CONCLUSIONS: MRI with mFFE may be sufficient for the assessment of OPLL and DO, with good contrasts between OPLL and intervertebral disc, spinal cord, and cerebrospinal fluid. PMID- 28841681 TI - Religion and HPV vaccine-related awareness, knowledge, and receipt among insured women aged 18-26 in Utah. AB - INTRODUCTION: We investigate the associations between religious practice and human papillomavirus (HPV) vaccine-related awareness, knowledge, and receipt among young women in Utah. METHODS: We surveyed 326 insured women aged 18-26 by mail. Fisher's Exact Tests and multivariable logistic regression models were used to evaluate the relations between religious practice and HPV vaccine-related outcomes. Data collection occurred January-December 2013; analyses were conducted June-September 2015. RESULTS: Multivariable analyses reveal that when controlling for age, educational attainment, and marital status, participants who practiced an organized religion were significantly less likely to have heard of HPV (aOR = 0.25, p = 0.0123), to have heard of the HPV vaccine (aOR = 0.41, p = 0.0368), to know how HPV is spread (aOR = 0.45, p = 0.0074), to have received a provider recommendation for the HPV vaccine (aOR = 0.36, p = 0.0332), and to have received at least one (aOR = 0.50, p = 0.0073) or all three (aOR = 0.47, p = 0.0026) doses of the HPV vaccine. Bivariate analyses produce parallel results. CONCLUSIONS: Results indicate that religious young women in Utah are not only under vaccinated, but are also under-informed about HPV and the HPV vaccine. These results suggest that suboptimal vaccine coverage among religious young women may present a serious health risk for the community. Strategies for educational interventions targeted to this population are discussed. PMID- 28841683 TI - Quantification of the evolution of firm size distributions due to mergers and acquisitions. AB - The distribution of firm sizes is known to be heavy tailed. In order to account for this stylized fact, previous economic models have focused mainly on growth through investments in a company's own operations (internal growth). Thereby, the impact of mergers and acquisitions (M&A) on the firm size (external growth) is often not taken into consideration, notwithstanding its potential large impact. In this article, we make a first step into accounting for M&A. Specifically, we describe the effect of mergers and acquisitions on the firm size distribution in terms of an integro-differential equation. This equation is subsequently solved both analytically and numerically for various initial conditions, which allows us to account for different observations of previous empirical studies. In particular, it rationalises shortcomings of past work by quantifying that mergers and acquisitions develop a significant influence on the firm size distribution only over time scales much longer than a few decades. This explains why M&A has apparently little impact on the firm size distributions in existing data sets. Our approach is very flexible and can be extended to account for other sources of external growth, thus contributing towards a holistic understanding of the distribution of firm sizes. PMID- 28841682 TI - Downregulation of endometrial mesenchymal marker SUSD2 causes cell senescence and cell death in endometrial carcinoma cells. AB - The cause of death among the majority of endometrial cancer patients involves migration of cancer cells within the peritoneal cavity and subsequent implantation of cancer spheroids into neighbouring organs. It is, thereby, important to identify factors that mediate metastasis. Cell adhesion and migration are modified by the mesenchymal stem cell (MSC) marker Sushi domain containing 2 (SUSD2), a type I transmembrane protein that participates in the orchestration of cell adhesion and migration through interaction with its partner Galactosidase-binding soluble-1 (LGALS1). MSCs have emerged as attractive targets in cancer therapy. Human endometrial adenocarcinoma (Ishikawa) cells were treated with TGFbeta (10 ng/ml) for 72h. SUSD2, LGALS1 and MKI67 transcript levels were quantified using qRT-PCR. The proportion of SUSD2 positive (SUSD2+) cells and SMAD2/3 abundance were quantified by FACS and Western blotting, respectively. Senescent cells were identified with beta-galactosidase staining; cell cycle and cell death were quantified using Propidium Iodide staining. Treatment of endometrial cancer cells (Ishikawa cells) with TGFbeta (10 ng/ml) significantly decreased SUSD2 transcript levels and the proportion of SUSD2 positive cells. Silencing of SUSD2 using siRNA resulted in senescence and cell death of Ishikawa cells via activation of SMAD2/3. These findings suggest that SUSD2 counteracts senescence and cell death and is thus a potential chemotherapeutic target in human endometrial cancer. PMID- 28841685 TI - Antibiotic drug usage in pigs in Germany-Are the class profiles changing? AB - The development of antimicrobial resistance is triggered by the use of antibiotic drugs. Therefore, the consumption of antibiotics in livestock is monitored, and different measures may be applied if the usage of antibiotic drugs seems inappropriate. Unfortunately, the surveillance of antibiotic consumption is not standardised, and surveillance systems differ. In Germany, the food quality assurance system QS Qualitat und Sicherheit GmbH (QS) began the documentation of antibiotic drug usage in pigs in 2012 in a private economic based database, and for its members, documentation has been mandatory in all pig age groups since 2014. In this investigation, we calculated the distribution of the antibiotics use per pig age group and half-year, and the percentage of the active substances used from overall treatments within German pig holdings from 1 July, 2013 to 30 June, 2015. In fattening pigs, the median of the treatment frequency is 4.3 in 2013-2 and exhibits a decreasing trend in this time period up to 2.1 in 2015-1. In weaners the median ranged between 11.3 in 2014-2 and 5.8 in 2013-2. The median of sucklers varies between 21.6 and 25.0. In sucklers and weaners, a clear temporal trend is not seen to date. The share of the active substances differs between the age groups. In fattening pigs, mostly tetracyclines and penicillines were used, occurring in approximately 60% of the total treatments. In weaners, amoxicillin and colistin have the highest shares of the treatment frequency, at approximately 60%. The treatment frequencies of macrolides and penicillines have the highest share in sucklers. PMID- 28841684 TI - Infection with purified Piscine orthoreovirus demonstrates a causal relationship with heart and skeletal muscle inflammation in Atlantic salmon. AB - Viral diseases pose a significant threat to the productivity in aquaculture. Heart- and skeletal muscle inflammation (HSMI) is an emerging disease in Atlantic salmon (Salmo salar) farming. HSMI is associated with Piscine orthoreovirus (PRV) infection, but PRV is ubiquitous in farmed Atlantic salmon and thus present also in apparently healthy individuals. This has brought speculations if additional etiological factors are required, and experiments focusing on the causal relationship between PRV and HSMI are highly warranted. A major bottleneck in PRV research has been the lack of cell lines that allow propagation of the virus. To bypass this, we propagated PRV in salmon, bled the fish at the peak of the infection, and purified virus particles from blood cells. Electron microscopy, western blot and high-throughput sequencing all verified the purity of the viral particles. Purified PRV particles were inoculated into naive Atlantic salmon. The purified virus replicated in inoculated fish, spread to naive cohabitants, and induced histopathological changes consistent with HSMI. PRV specific staining was demonstrated in the pathological lesions. A dose-dependent response was observed; a high dose of virus gave earlier peak of the viral load and development of histopathological changes compared to a lower dose, but no difference in the severity of the disease. The experiment demonstrated that PRV can be purified from blood cells, and that PRV is the etiological agent of HSMI in Atlantic salmon. PMID- 28841686 TI - Functional properties of an alternative, tissue-specific promoter for rice NADPH dependent dihydroflavonol reductase. AB - NADPH-dependent dihydroflavonol reductase (DFR) plays an important role in both anthocyanin biosynthesis and proanthocyanidin synthesis in plants. A specific and quantitative RT-PCR assay for transcription from the DFR promoter detected high expression with limited variability in rice tissues. A 440 bp minimal promoter region was identified by transfection of beta-glucuronidase (GUS) reporter constructs into Jeokjinju variety. Alignment of the region with orthologous promoters revealed three conserved segments containing both bHLH (-386 to -381) and Myb (-368 to -362) binding sites. Transfection of beta-glucuronidase constructs with targeted point mutations in the minimal promoter defined two sites important for promoter function to the transcription factor binding consensus sequences. The expression study showed that the bHLH binding domain ( 386 to -381) is essential for DFR expression, and that a Myb binding domain (-368 to -362) is also required for full expression of the DFR gene, while the two bHLH binding domains (-104 to -99 and -27 to -22) nearest to the transcriptional start site are not necessary for DFR expression. PMID- 28841687 TI - A Trp53fl/flPtenfl/fl mouse model of undifferentiated pleomorphic sarcoma mediated by adeno-Cre injection and in vivo bioluminescence imaging. AB - Genetic mouse models of soft tissue sarcoma provide critical insights into disease pathophysiology, which are oftentimes unable to be extracted from human tumor samples or xenograft models. In this study we describe a mouse model of soft tissue sarcoma mediated by adenoviral-Cre recombinase injection into Trp53fl/fl/Ptenfl/fl lox-stop-lox luciferase mice. Injection of adenovirus expressing Cre recombinase, either subcutaneously or intramuscularly in two experimental groups, results in viral infection and gene recombination with 100% penetrance within the first 24 hours following injection. Luciferase expression measured by real-time bioluminescence imaging increases over time, with an initial robust increase following viral injection, followed by a steady rise over the next several weeks as primary tumors develop and grow. Intramuscular injections were more commonly associated with evidence of systemic viral distribution than subcutaneous injections. All mice developed soft tissue sarcomas at the primary injection site, with histological examination identifying 93% of tumors as invasive pleomorphic sarcomas based on microscopic morphology and immunohistochemical expression of sarcoma markers. A lymphocytic infiltrate was present in 64% of the sarcomas in this immunocompetent model and 71% of tumors expressed PD-L1. This is the first report of a viral-Cre mediated Trp53/Pten mouse model of undifferentiated pleomorphic sarcoma. The bioluminescence imaging feature, along with high penetrance of the model and its immunological characteristics, makes it suited for pre-clinical studies of soft tissue sarcoma. PMID- 28841688 TI - Correlation between ICDAS and histology: Differences between stereomicroscopy and microradiography with contrast solution as histological techniques. AB - Detection of occlusal caries with visual examination using ICDAS correlates strongly with histology under stereomicroscopy (SM), but dentin aspects under SM are ambiguous regarding mineral content. Thus, our aim was to test two null hypotheses: SM and microradiography result in similar correlations between ICDAS and histology; SM and microradiography result in similar positive (PPV) and negative predictive values (NPV) of ICDAS cut-off 1-2 (scores 0-2 as sound) with histological threshold D3 (demineralization in the inner third of dentin). Occlusal surfaces of extracted permanent teeth (n = 115) were scored using ICDAS. Undemineralized ground sections were histologically scored using both SM without contrast solution and microradiography after immersion in Thoulet's solution 1.47 for 24 h (MRC). Correlation between ICDAS and histology differed from SM (0.782) to MRC (0.511) (p = 0.0002), with a large effect size "q" of 0.49 (95% CI: 0.638/0.338). For ICDAS cut-off 1-2 and D3, PPV from MRC (0.56) was higher than that from SM (0.28) (p< 0.00001; effect size h = 0.81), and NPV from MRC (0.72) was lower than that from SM (1,00) (p < 0.00001; effect size h = 1.58). In conclusion, SM overestimated the correlation between ICDAS and lesion depth, and underestimated the number of occlusal surfaces with ICDAS cut-off 1-2 and deep dentin demineralization. PMID- 28841689 TI - Mixed methods research in tobacco control with youth and young adults: A methodological review of current strategies. AB - INTRODUCTION: Tobacco use among young people is a complex and serious global dilemma that demands innovative and diverse research approaches. The purpose of this methodological review was to examine the current use of mixed methods research in tobacco control with youth and young adult populations and to develop practical recommendations for tobacco control researchers interested in this methodology. METHODS: Using PubMed, we searched five peer-reviewed journals that publish tobacco control empirical literature for the use of mixed methods research to study young populations, age 12-25 years. Our team analyzed the features of each article in terms of tobacco control topic, population, youth engagement strategies, and several essential elements of mixed methods research. RESULTS: We identified 23 mixed methods studies published by authors from five different countries reported between 2004 and 2015. These 23 articles examined various topics that included tobacco use behavior, tobacco marketing and branding, and cessation among youth and young adults. The most common mixed methods approach was variations of the concurrent design in which the qualitative and quantitative strands were administered at the same time and given equal priority. This review documented several innovative applications of mixed methods research as well as challenges in the reporting of the complex research designs. CONCLUSIONS: The use of mixed methods research in tobacco control has great potential for advancing the understanding of complex behavioral and sociocultural issues for all groups, especially youth and young adults. PMID- 28841690 TI - Different methods for volatile sampling in mammals. AB - Previous studies showed that olfactory cues are important for mammalian communication. However, many specific compounds that convey information between conspecifics are still unknown. To understand mechanisms and functions of olfactory cues, olfactory signals such as volatile compounds emitted from individuals need to be assessed. Sampling of animals with and without scent glands was typically conducted using cotton swabs rubbed over the skin or fur and analysed by gas chromatography-mass spectrometry (GC-MS). However, this method has various drawbacks, including a high level of contaminations. Thus, we adapted two methods of volatile sampling from other research fields and compared them to sampling with cotton swabs. To do so we assessed the body odor of common marmosets (Callithrix jacchus) using cotton swabs, thermal desorption (TD) tubes and, alternatively, a mobile GC-MS device containing a thermal desorption trap. Overall, TD tubes comprised most compounds (N = 113), with half of those compounds being volatile (N = 52). The mobile GC-MS captured the fewest compounds (N = 35), of which all were volatile. Cotton swabs contained an intermediate number of compounds (N = 55), but very few volatiles (N = 10). Almost all compounds found with the mobile GC-MS were also captured with TD tubes (94%). Hence, we recommend TD tubes for state of the art sampling of body odor of mammals or other vertebrates, particularly for field studies, as they can be easily transported, stored and analysed with high performance instruments in the lab. Nevertheless, cotton swabs capture compounds which still may contribute to the body odor, e.g. after bacterial fermentation, while profiles from mobile GC MS include only the most abundant volatiles of the body odor. PMID- 28841691 TI - Nipple sparing mastectomy in breast cancer patients and long-term survival outcomes: An analysis of the SEER database. AB - PURPOSE: To determine the prevalence of nipple-sparing mastectomy (NSM) and its long-term survival outcomes in breast cancer patients. METHOD: We used the Surveillance, Epidemiology, and End Results database and identified 2,440 breast cancer patients who received NSM during 1998-2013. We used chi-square and binary logistic regression to identify factors associated with the use of radiotherapy after NSM. We used Kaplan-Meier analysis to estimate cancer-specific survival (CSS) and overall survival (OS). We used the log-rank test and Cox regression to identify factors associated with CSS and OS. RESULTS: The median age of the population was 50 years. There were 725 (29.7%), 1064 (43.6%) and 651 (26.7%) patients who had Tis, T1 and T2-3 disease and 1943 (79.6%), 401 (16.4%) and 96 (3.9%) patients who had N0, N1 and N2-3 disease, respectively. The rates of RT use were 61.4%, 39.6% and 10.9% in patients with N2-3 disease, N1 or T3/N0 disease and Tis/T1-2N0 disease, respectively. Elderly age, African American race, and higher T-stage and N-stage were associated with receiving radiotherapy. For patients diagnosed between 1998-2010 (N = 763), the median follow-up was 69 months. The 5- and 10-yr CSS were 96.9% and 94.9%, respectively. The 5- and 10-yr OS were 94.1% and 88.0%, respectively. Ethnicity, T-stage and N-stage were factors independently associated with CSS, and age and T-stage were factors independently associated with OS. CONCLUSIONS: The use of NSM has increased, and it is oncologically safe for breast cancer patients. PMID- 28841692 TI - Using niche-modelling and species-specific cost analyses to determine a multispecies corridor in a fragmented landscape. AB - Misiones, Argentina, contains the largest remaining tract of Upper Parana Atlantic Forest ecoregion; however, ~50% of native forest is unprotected and located in a mosaic of plantations, agriculture, and pastures. Existing protected areas are becoming increasingly isolated due to ongoing habitat modification. These factors, combined with lower than expected regional carnivore densities, emphasize the need to understand the effect of fragmentation on animal movement and connectivity between protected areas. Using detection dogs and genetic analyses of scat, we collected data on jaguars (Panthera onca), pumas (Puma concolor), ocelots (Leopardus pardalis), oncillas (Leopardus tigrinus), and bush dogs (Speothos venaticus) across habitats that varied in vegetation, disturbance, human proximity, and protective status. With MaxEnt we evaluated habitat use, habitat suitability, and potential species richness for the five carnivores across northern-central Misiones, Argentina. Through a multifaceted cost analysis that included unique requirements of each carnivore and varying degrees of overlap among them, we determined the optimal location for primary/secondary corridors that would link the northern-central zones of the Green Corridor in Misiones and identified areas within these corridors needing priority management. A secondary analysis, comparing these multispecies corridors with the jaguar's unique requirements, demonstrated that this multispecies approach balanced the preferences of all five species and effectively captured areas required by this highly restricted and endangered carnivore. We emphasize the potential importance of expanding beyond a single umbrella or focal species when developing biological corridors that aim to capture the varied ecological requirements of coexisting species and ecological processes across the landscape. Detection dogs and genetic analyses of scat allow data on multiple species to be collected efficiently across multiple habitat types independent of the degree of legal protection. These data used with multifocal GIS analyses balance the varying degree of overlap and unique properties among them allowing for comprehensive conservation strategies to be developed relatively rapidly. Our comprehensive approach serves as a model to other regions faced with habitat loss and lack of data. The five carnivores focused on in our study have wide ranges, so the results from this study can be expanded and combined with surrounding countries, with analyses at the species or community level. PMID- 28841693 TI - The effect of aqueous extract of Xinjiang Artemisia rupestris L. (an influenza virus vaccine adjuvant) on enhancing immune responses and reducing antigen dose required for immunity. AB - Potent adjuvant can improve the effectiveness of vaccines and reduce the antigen doses required for initiating the protective immunity. In this study, we identified that aqueous extract of Artemisia rupestris L. (AEAR) could be employed as an efficient adjuvant for influenza virus vaccine (V) to enhance immune responses and reduce the antigen doses required for initiating immunity, without compromising the immune response. ICR mice were subcutaneously co administrated with V combined with different concentrations of AEAR demonstrated that 300 MUg AEAR could significantly improve hemagglutination inhibition (HI) and increase IgG antibody titers in serum (P<0.05) and the population of CD4+CD44+ and CD8+CD44+ (P<0.05). Next, 300 MUg AEAR combined with different doses of V in vivo markedly increased HI and specific IgG antibody level(P<0.05). It also significantly increased the amount of CD4+ and CD8+ T cells, CD4+CD44+ and CD8+CD44+ T cells (P<0.05), improved lymphocyte proliferation, the secretion of CD4+IL-4, CD4+IFN-gamma and CD8+IFN-gamma (P<0.05), and the killing efficacy of cytotoxic T lymphocyte (CTL) (P<0.05). Furthermore, the combination increased the expression of major histocompatibility complex-II (MHC-II) and co-stimulatory molecules including CD40, CD80, and CD86 on dendritic cells (DCs), and downregulated the expression of CD25+Foxp3+Treg cells (P<0.05). No significant difference was observed between high-dose V and low-dose AEAR-V (10-fold lower) vaccination group (P>0.05), indicating a 10-fold reduction of antigen required for V vaccine administration. In conclusion, this study demonstrated that AEAR, as an adjuvant for influenza vaccine, could stimulate potent humoral and cellular immune responses and reduce the antigen dose required for effective vaccination, which were mediated by promoting DCs activation and repressing Treg expression. PMID- 28841694 TI - Differential diagnosis between Parkinson's disease and essential tremor using the smartphone's accelerometer. AB - BACKGROUND: The differential diagnosis between patients with essential tremor (ET) and those with Parkinson's disease (PD) whose main manifestation is tremor may be difficult unless using complex neuroimaging techniques such as 123I-FP-CIT SPECT. We considered that using smartphone's accelerometer to stablish a diagnostic test based on time-frequency differences between PD an ET could support the clinical diagnosis. METHODS: The study was carried out in 17 patients with PD, 16 patients with ET, 12 healthy volunteers and 7 patients with tremor of undecided diagnosis (TUD), who were re-evaluated one year after the first visit to reach the definite diagnosis. The smartphone was placed over the hand dorsum to record epochs of 30 s at rest and 30 s during arm stretching. We generated frequency power spectra and calculated receiver operating characteristics curves (ROC) curves of total spectral power, to establish a threshold to separate subjects with and without tremor. In patients with PD and ET, we found that the ROC curve of relative energy was the feature discriminating better between the two groups. This threshold was then used to classify the TUD patients. RESULTS: We could correctly classify 49 out of 52 subjects in the category with/without tremor (97.96% sensitivity and 83.3% specificity) and 27 out of 32 patients in the category PD/ET (84.38% discrimination accuracy). Among TUD patients, 2 of 2 PD and 2 of 4 ET were correctly classified, and one patient having PD plus ET was classified as PD. CONCLUSIONS: Based on the analysis of smartphone accelerometer recordings, we found several kinematic features in the analysis of tremor that distinguished first between healthy subjects and patients and, ultimately, between PD and ET patients. The proposed method can give immediate results for the clinician to gain valuable information for the diagnosis of tremor. This can be useful in environments where more sophisticated diagnostic techniques are unavailable. PMID- 28841695 TI - Earwax metabolomics: An innovative pilot metabolic profiling study for assessing metabolic changes in ewes during periparturition period. AB - Important metabolic changes occur during transition period of late pregnancy and early lactation to meet increasing energy demands of the growing fetus and for milk production. The aim of this investigation is to present an innovative and non-invasive tool using ewe earwax sample analysis to assess the metabolic profile in ewes during late pregnancy and early lactation. In this work, earwax samples were collected from 28 healthy Brazilian Santa Ines ewes divided into 3 sub-groups: 9 non-pregnant ewes, 6 pregnant ewes in the last 30 days of gestation, and 13 lactating ewes <= 30 days postpartum. Then, a range of metabolites including volatile organic compounds (VOC), amino acids (AA), and minerals were profiled and quantified in the samples by applying headspace gas chromatography/mass spectrometry, high performance liquid chromatography/tandem mass spectrometry, and inductively coupled plasma-optical emission spectrometry, respectively. As evident in our results, significant changes were observed in the metabolite profile of earwax between the studied groups where a remarkable elevation was detected in the levels of non-esterified fatty acids, alcohols, ketones, and hydroxy urea in the VOC profile of samples obtained from pregnant and lactating ewes. Meanwhile, a significant decrease was detected in the levels of 9 minerals and 14 AA including essential AA (leucine, phenyl alanine, lysine, isoleucine, threonine, valine), conditionally essential AA (arginine, glycine, tyrosine, proline, serine), and a non-essential AA (alanine). Multivariate analysis using robust principal component analysis and hierarchical cluster analysis was successfully applied to discriminate the three study groups using the variations of metabolites in the two stress states (pregnancy and lactation) from the healthy non-stress condition. The innovative developed method was successful in evaluating pre- and post-parturient metabolic changes using earwax and can in the future be applied to recognize markers for diagnosis, prevention, and intervention of pregnancy complications in ewes. PMID- 28841696 TI - Trans-regional migration of the beet armyworm, Spodoptera exigua (Lepidoptera: Noctuidae), in North-East Asia. AB - The beet armyworm, Spodoptera exigua (Hubner) (Lepidoptera: Noctuidae), is a serious polyphagous insect pest worldwide. This species is known as a long distance migrant, and previous studies on its migration have been mostly carried out in regions where it can overwinter. However, what pattern of seasonal migration this species exhibits in regions where it cannot overwinter (i.e., the 'summer breeding region') remains unknown. Here, we present data from 14-years of monitoring on a small remote island located in the center of the Bohai Strait, in northern China, by means of searchlight trapping and ovarian dissection. We found that the population size of this overseas migration varied significantly among years, with very large migrations in 2005, 2007, 2009, and 2014 that resulted in annual total catches of more than ten thousand individuals. In addition, nightly catches exhibited a significant inter-month variability, with the vast majority of S. exigua moths being trapped in August and September, (81.1 +/- 3.6%), making S. exigua one of the most frequently encountered species in that period. The mean time from the earliest trap capture to the latest capture within a given year was 113 +/- 22 d (range 57 d [2003] to 138 d [2008]). The sex ratio (females: males) was significantly less than 1:1 in each month, but the proportion of females showed an upward trend from June to October. The majority of trapped females in summer were mated (94.4 +/- 10.7% in June, 80.0 +/- 6.4% in July) and sexually mature (88.9 +/- 11.1% in June, 61.8 +/- 12.3% in July), suggesting the onset of mating and/or sexual maturation does not terminate the migration behavior in this species. These findings provide a good starting point for study of the trans regional migration of S. exigua across different climate zones. PMID- 28841697 TI - Dynamic thoracohumeral kinematics are dependent upon the etiology of the shoulder injury. AB - Obtaining kinematic patterns that depend on the shoulder injury may be important when planning rehabilitation. The main goal of this study is to explore whether the kinematic patterns of continuous and repetitive shoulder elevation motions are different according to the type of shoulder injury in question, specifically tendinopathy or rotator cuff tear, and to analyze the influence of the load handled during its assessment. For this purpose, 19 individuals with tendinopathy and 9 with rotator cuff tear performed a repetitive scaption movement that was assessed with stereophotogrammetry. Furthermore, static range of motion (ROM) and isometric strength were evaluated with a goniometer and a dynamometer, respectively. Dynamic measurements of maximum elevation (Emax), variablility of the maximum angle (VMA), maximum angular velocity (Velmax), and time to maximum velocity (tmaxvel) were found to be significantly different between the tendinopathy group (TG) and the rotator cuff tear group (RTCG). No differences were found in the ROM assessed with goniometry and the isometric strength. The effect of increasing the load placed in the hand during the scaption movement led to significant differences in Emax, VMA, tmaxvel and repeatability. Therefore, only the dynamic variables showed sufficient capability of detecting differences in functional performance associated with structural shoulder injury. The differences observed in the kinematic variables between patients with tendinopathy and rotator cuff tear seem to be related to alterations in thoracohumeral rhythm and neuromuscular control. Kinematic analysis may contribute to a better understanding of the functional impact of shoulder injuries, which would help in the assessment and treatment of shoulder pain. PMID- 28841698 TI - Long-term follow-up of MRI changes in thigh muscles of patients with Facioscapulohumeral dystrophy: A quantitative study. AB - Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary muscular disorders. Currently FSHD has no known effective treatment and detailed data on the natural history are lacking. Determination of the efficacy of a given therapeutic approach might be difficult in FSHD given the slow and highly variable disease progression. Magnetic resonance imaging (MRI) has been widely used to qualitatively and quantitatively evaluate in vivo the muscle alterations in various neuromuscular disorders. The main aim of the present study was to investigate longitudinally the time-dependent changes occurring in thigh muscles of FSHD patients using quantitative MRI and to assess the potential relationships with the clinical findings. Thirty-five FSHD1 patients (17 females) were enrolled. Clinical assessment tools including manual muscle testing using medical research council score (MRC), and motor function measure (MFM) were recorded each year for a period ranging from 1 to 2 years. For the MRI measurements, we used a new quantitative index, i.e., the mean pixel intensity (MPI) calculated from the pixel-intensity distribution in T1 weighted images. The corresponding MPI scores were calculated for each thigh, for each compartment and for both thighs totally (MPItotal). The total mean pixel intensity (MPItotal) refers to the sum of each pixel signal intensity divided by the corresponding number of pixels. An increased MPItotal indicates both a raised fat infiltration together with a reduced muscle volume thereby illustrating disease progression. Clinical scores did not change significantly over time whereas MPItotal increased significantly from an initial averaged value of 39.6 to 41.1 with a corresponding rate of 0.62/year. While clinical scores and MPItotal measured at the start of the study were significantly related, no correlation was found between the rate of MPItotal and MRC sum score changes, MFMtotal and MFM subscores. The relative rate of MPItotal change was 2.3% (0.5 4.3)/year and was significantly higher than the corresponding rates measured for MRCS 0% (0-1.7) /year and MFMtotal 0% (0-2.0) /year (p = 0.000). On the basis of these results, we suggested that muscle MRI and more particularly the MPItotal index could be used as a reliable biomarker and outcome measure of disease progression. In slowly progressive myopathies such as FSHD, the MPItotal index might reveal subclinical changes, which could not be evidenced using clinical scales over a short period of time. PMID- 28841699 TI - Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma. AB - BACKGROUND: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients. METHODS: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses. RESULTS: The majority of PVC patients (72%) had >50% LRIG1- and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival. CONCLUSION: LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified. PMID- 28841700 TI - An empirical comparison of different implicit measures to predict consumer choice. AB - While past research has found that implicit measures are good predictors of affectively driven, but not cognitively driven, behavior it has not yet been tested which implicit measures best predict behavior. By implementing a consumer context, in the present experiment, we assessed two explicit measures (i.e. self reported habit and tastiness) and three implicit measures (i.e. manikin task, affective priming, ID-EAST) in order to test the predictive validity of affectively versus cognitively driven choices. The results indicate that irrespective of whether participants chose affectively or cognitively, both explicit measures, but not the implicit measures, predicted consumer choice very strongly. Likewise, when comparing the predictive validity among all measures, the explicit measures were the best predictors of consumer choice. Theoretical implications and limitations of the study are discussed. PMID- 28841701 TI - Pregnancy outcomes in perinatally HIV-infected young women in Madrid, Spain: 2000 2015. AB - BACKGROUND: An increasing number of perinatally HIV-infected women (PHIV) are reaching adulthood and becoming pregnant. Most PHIV women have been exposed to a high number of antiretroviral regimens, and they may have difficulties to achieve viral suppression. Psychosocial problems are not uncommon and could be an important barrier for treatment adherence. The effects of chronic HIV infection and long-term exposure to antiretroviral treatment of PHIV women cause concerns on the developing fetus. The aims of this study were to describe the prevention of mother-to-child transmission strategies in PHIV women and the infant outcomes in the Madrid Cohort of HIV-infected mother-infant pairs. METHODS: All PHIV pregnant women registered in the Cohort that gave birth from 2000 to 2015 were included in the study. RESULTS: Twenty-eight pregnancies in twenty-two perinatally infected women were registered. Most women were Caucasian and heavily treatment-experienced. Nine cases (32.1%) were at high risk of HIV mother-to child transmission. Maternal HIV-1 viral load was detectable close to delivery in four women (14.3%). The management of these cases was described, and the treatment strategies were discussed. None of the newborns acquired HIV infection. Eight infants (28.6%) were small for gestational age. CONCLUSIONS: This study included a large series of pregnancies among PHIV women attended according to a youth-centered care model. The challenges in the management of this population by health-care providers were described. Specific strategies to minimize perinatal transmission risks should be addressed in future collaborative studies. PMID- 28841702 TI - Prognostic value of FDG-PET indices for the assessment of histological response to neoadjuvant chemotherapy and outcome in pediatric patients with Ewing sarcoma and osteosarcoma. AB - PURPOSE: The objective of this retrospective work was to evaluate the prognostic value on histological response and survival of quantitative indices derived from FDG-PET performed before and after chemotherapy (CHT), in a homogeneous pediatric Ewing sarcoma (EWS) and Osteosarcoma (OST) population. METHODS: Thirty-one patients with EWS and 31 with OST were included. All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had FDG PET at diagnosis and after CHT, prior to surgery. Several parameters were evaluated: SUVmax, SUVpeak, SUVmean, metabolic tumor volume, total lesion glycolysis, 7 textural features and 3 shape features (SF). The segmentation was performed using an adaptive approach. Results were compared to histopathological regression of the resected tumor and to clinical follow-up for survival evaluation. RESULTS: For EWS, univariate analysis did not highlight any prognostic value on histological response, or survival regardless of all the considered metrics. For OST, only one of the SF, namely elongation, was significantly associated with PFS and OS on both univariate and multivariate analysis (PFS: p = 0.019, HR = 5.583; OS: p = 0.0062, HR = 7.113). CONCLUSION: Only elongation determined on initial FDG-PET has a potential interest as a prognostic factor of PFS and OS in pediatric OST patients. Unlike recent studies of the literature realized in adult population, all the metrics reveal limited additional prognostic value in pediatric EWS patients. This seems to reinforce the question of whether children experience different subtypes of the same pathologies than older patients, with different outcomes. PMID- 28841703 TI - The geometric model of the human mitral valve. AB - The mitral valve, which lies between the left atrium and the left ventricle, plays an important role in controlling the uniflux of blood from the left atrium to the left ventricle as one of the four human heart valves. A precise description of the shape of human mitral valve has vital significance in studying its physiological structure and periodic movement. Unsatisfyingly, there is almost no unified mathematical description of the same shape of human mitral valve in literature. In this paper, we present a geometric model for human mitral valve, as an elastic shell with a special shape. Parametric equations for the shape of human mitral valve are provided, including the anterior and the posterior parts, which can be thought as portions of two interfacing semi elliptic cylindrical shells. The minor axis of one ellipse is equal to the major axis of the other. All the parameters are determined from the statistical data. Comparison of fitting results with existing examples validates the accuracy of our geometric model. Based on the fitting shape, one can further simulate the physiological function of the mitral valve using a suitable dynamic physical equation. PMID- 28841704 TI - Different cadences and resistances in sub-maximal synchronous handcycling in able bodied men: Effects on efficiency and force application. AB - BACKGROUND: With the introduction of an add-on handcycle, a crank system that can be placed in front of a wheelchair, handcycling was made widely available for daily life. With it, people go into town more easily, e.g. to do groceries; meet up with friends, etc. They have more independency and can be socially active. Our aim is to explore some settings of the handcycle, so that it can be optimally used as a transportation device. Therefore, the effects of cadence and added resistance on gross mechanical efficiency and force application during sub maximal synchronous handcycling were investigated. We hypothesized that a cadence of 52 rpm with a higher resistance (35 W) would lead to a higher gross mechanical efficiency and a more tangential force application than a higher cadence of 70 rpm and no extra resistance (15 W). METHODS: Twelve able-bodied men rode in an instrumented add-on handcycle on a motorized level treadmill at 1.94 m/s. They performed three sessions of three four-minute blocks of steady state exercise. Gear (70, 60 and 52 rpm) was changed in-between the blocks and resistance (rolling resistance +0 W, +10 W, +20 W) was changed across sessions, both in a counterbalanced order. 3D force production, oxygen uptake and heart rate were measured continuously. Gross mechanical efficiency (ME) and fraction of effective force (FEF) were calculated as main outcomes. The effects of cadence and resistance were analyzed using a repeated measures ANOVA (P<0.05) with Bonferroni corrected post-hoc pairwise comparisons. RESULTS: With a decrease in cadence a slight increase in ME (70 rpm: 5.5 (0.2)%, 60 rpm: 5.7 (0.2)%, 52 rpm: 5.8 (0.2)%, P = 0.008, eta2p = 0.38), while an increase in FEF (70 rpm: 58.0 (3.2)%, 60 rpm: 66.0 (2.8)%, 52 rpm: 71.3 (2.3)%, P<0.001, eta2p = 0.79) is seen simultaneously. Also with an increase in resistance an increase in ME (+0 W: 4.0 (0.2)%, +10 W: 6.0 (0.3)%, +20 W: 7.0 (0.2)%, P<0.001, eta2p = 0.92) and FEF (+0 W: 59.0 (2.9)%, +10 W: 66.1 (3.4)%, +20 W: 70.2 (2.4)%, P<0.001, eta2p = 0.56) was found. INTERPRETATION: A cadence of 52 rpm against a higher resistance of about 35 W leads to a more optimal direction of forces and is more mechanically efficient than propelling at a higher cadence or lower resistance. Therefore, changing gears on a handcycle is important, and it is advised to keep the linear hand velocity relatively low for locomotion purposes. PMID- 28841705 TI - Single nucleotide polymorphisms at miR-146a/196a2 and their primary ovarian insufficiency-related target gene regulation in granulosa cells. AB - MicroRNAs post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to identify new target genes for microRNA polymorphisms (miR-146aC>G and miR-196a2T>C) in primary ovarian insufficiency (POI). We cloned and transfected miR-146aC>G and miR-196a2T>C into human granulosa cells and used microarrays and qPCR-arrays to examine the changes in the messenger RNA expression profile. We show miR-146aC>G and miR-196a2T>C change the mRNA expression patterns in granulosa cell. In each case, mRNAs were up or down regulated after treatments with miR-146a C or G and miR-196a2 T or C. We found that miR-146a led to a significantly altered regulation of the mRNA levels of FOXO3, FOXL2 and CCND2 compared to controls. We also found that the polymorphisms of miR-146a led to a significantly altered regulation of CCND2 and FOXO3. Our results suggest that miR-146aC>G and miR-196a2T>C can regulate the levels of many of their target transcripts. In addition, specific target genes of miR-146aC>G polymorphisms may be involved in granulosa cell regulation. PMID- 28841706 TI - Effects of manipulating the duration and intensity of aerobic training sessions on the physical performance of rats. AB - This study investigated the effects of manipulating the load components of aerobic training sessions on the physical performance of rats. To achieve this purpose, adult male Wistar rats were divided into four groups: an untrained control (CON) group and training groups with a predominant overload in intensity (INT) or duration (DUR) or alternating and similar overloads in intensity and duration (ID). Prior to, during, and after 8 weeks of the control or training protocols, the performance of the rats (evaluated by their workload) was determined during fatiguing, incremental-speed treadmill running. Two additional incremental running tests were performed prior to and at the end of the protocols to measure the peak rate of oxygen consumption (VO2peak). As expected, the rats in the trained groups exhibited increased performance, whereas the untrained rats showed stable performance throughout the 8 weeks. Notably, the performance gain exhibited by the DUR rats reached a plateau after the 4th week. This plateau was not present in the INT or ID rats, which exhibited increased performance at the end of training protocol compared with the DUR rats. None of the training protocols changed the VO2peak values; however, these values were attained at faster speeds, which indicated increased running economy. In conclusion, our findings demonstrate that the training protocols improved the physical performance of rats, likely resulting from enhanced running economy. Furthermore, compared with overload in duration, overload in the intensity of training sessions was more effective at inducing performance improvements across the 8 weeks of the study. PMID- 28841707 TI - A qualitative study of the knowledge, attitudes, and behaviors of people exposed to diesel exhaust at the workplace in British Columbia, Canada. AB - PURPOSE: To identify exposure-related knowledge, attitudes and behaviors of individuals occupationally exposed to diesel exhaust (DE); to reveal strengths, knowledge gaps and misperceptions therein. METHODS: A Mental Models approach was used to gather information about current scientific understanding of DE exposure hazards and the ways in which exposure can be reduced. Thirty individuals in British Columbia who were regularly exposed to occupational DE were interviewed. The audio was recorded and transcribed. Data was grouped together and examined to draw out themes around DE awareness, hazard assessment and risk reduction behaviors. These themes were then compared and contrasted with existing grey and research literature in order to reveal strengths, gaps and misperceptions regarding DE exposure. RESULTS: Study participants were aware and concerned about their exposure to DE but had incomplete and sometimes incorrect understanding of exposure pathways, health effects, and effective strategies to reduce their exposures. The perceived likelihood of exposure to DE was significantly greater compared to that of other work hazards (p<0.01), whereas the difference for their perceived severity of consequences was not significant. There was no universally perceived main source of information regarding DE, and participants generally distrusted sources of information based on their past experience with the source. Most of the actions that were taken to address DE exposure fell into the area of administrative controls such as being aware of sources of DE and avoiding these sources. CONCLUSIONS: This study of the knowledge, attitude, and behavior of those occupationally exposed to DE found, most notably, that more education and training and the creation of a health effects inventory regarding DE exposure were desired. PMID- 28841708 TI - Using transrectal ultrasound to examine the effect of exogenous progesterone on early embryonic loss in sheep. AB - The financial impact of early embryonic loss in Australia may be as high as $137 million AUD/year. Embryos may be lost due to environmental conditions, or maternal factors such as nutrition or progesterone (P4) profiles. However, studies on the supplementation of P4 during early pregnancy have returned contradictory results, partly as a reliable method of detecting embryos in the early stages of gestation (=65 years) patients. Aim of this study was therefore to describe demographic, physical, psychological and social characteristics of working TKA patients and to subsequently compare these characteristics with retired TKA patients and the general population. METHODS: A cross-sectional analysis. Preoperative data of 152 working TKA patients was used. These data were compared with existing data of retired TKA patients in hospital registers and with normative values from literature on the general population. Demographic, physical, psychological and social (including work) characteristics were analyzed. RESULTS: The majority (83.8%) of working TKA patients was overweight (42.6%) or obese (41.2%), a majority (72.4%) was dealing with two or more comorbidities, and most (90%) had few depressive symptoms. Mean physical activity level was 2950 minutes per week. Compared to the retired TKA population, working TKA patients perceived significantly more stiffness and better physical functioning and vitality, were more physically active, and perceived better mental health. Compared to the general population working TKA patients perceived worse physical functioning, worse physical health and better mental health, and worked fewer hours. CONCLUSION: This study shows that a majority of working TKA patients are overweight/obese, have multiple comorbidities, but are highly active in light-intensity activities and have few depressive symptoms. Working patients scored overall better on preoperative characteristics than retired patients, and except for physical activity scored overall worse than the general population. PMID- 28841710 TI - Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer. AB - ROCK, or Rho-associated coiled coil-containing protein kinase, is a member of the AGC kinase family and has been shown to play a role in cell migration, ECM synthesis, stress-fiber assembly, and cell contraction. Increased ROCK expression has been reported in multiple pathological conditions, including cancer. Here, we report increased expression of ROCK 1 in pancreatic tumor epithelial cells as well as in cancer associated fibroblasts (CAF). In our analysis, 62% of tumor samples exhibited >=2+ in staining intensity by IHC analysis, versus 40% of adjacent normal tissue samples (P<0.0001). Thus, we hypothesized that ROCKs may play a significant role in pancreatic cancer progression, and may serve as a suitable target for treatment. We report a low frequency (4/34) amplification of the ROCK1 gene locus at chromosome 18q11.1 in pancreatic ductal adenocarcinoma (PDAC) patient tissue samples by aCGH analysis. Inhibition of ROCK kinase activity by a small molecule inhibitor (fasudil) resulted in moderate (IC50s of 6 71 MUM) inhibition of PDAC cell proliferation, migration, and activation of co cultured stellate cells. In the KPC mouse model for pancreatic cancer, fasudil decreased tumor collagen deposition. This translated to an enhanced overall survival of the mice and an increase in gemcitabine uptake. Though fasudil may target both the tumor epithelial cells and the CAFs, our findings are consistent with the hypothesis that inhibition of tumor stroma enhances drug penetration and efficacy in PDAC. Overall, our data suggests that ROCK1 may serve as a potential therapeutic target to enhance current treatment regimens for pancreatic cancer. PMID- 28841711 TI - Evidence for a cytoplasmic pool of ribosome-free mRNAs encoding inner membrane proteins in Escherichia coli. AB - Translation-independent mRNA localization represents an emerging concept in cell biology. In Escherichia coli, mRNAs encoding integral membrane proteins (MPRs) are targeted to the membrane where they are translated by membrane associated ribosomes and the produced proteins are inserted into the membrane co translationally. In order to better understand aspects of the biogenesis and localization of MPRs, we investigated their subcellular distribution using cell fractionation, RNA-seq and qPCR. The results show that MPRs are overrepresented in the membrane fraction, as expected, and depletion of the signal recognition particle-receptor, FtsY reduced the amounts of all mRNAs on the membrane. Surprisingly, however, MPRs were also found relatively abundant in the soluble ribosome-free fraction and their amount in this fraction is increased upon overexpression of CspE, which was recently shown to interact with MPRs. CspE also conferred a positive effect on the membrane-expression of integral membrane proteins. We discuss the possibility that the effects of CspE overexpression may link the intriguing subcellular localization of MPRs to the cytosolic ribosome free fraction with their translation into membrane proteins and that the ribosome free pool of MPRs may represent a stage during their targeting to the membrane, which precedes translation. PMID- 28841712 TI - Characterization of the pollen beetle, Brassicogethes aeneus, dispersal from woodlands to winter oilseed rape fields. AB - Many crop pests rely on resources out of crop fields; understanding how they colonize the fields is an important factor to develop integrated pest management. In particular, the time of crop colonization and damage severity might be determined by pest movements between fields and non-crop areas. Notably, the pollen beetle, Brassicogethes aeneus, previously named Meligethes aeneus, one of the most important pests of winter oilseed rape, overwinters in woodlands. As a result, its abundance increases in oilseed rape fields near wooded areas. Here, we assessed the spatio-temporal patterns of the dispersal from woodlands to oilseed rape fields in diversified landscapes of a same region. We observed on four dates the abundance of pollen beetles in 24 fields spread in the Eure department, France. We modeled the abundance as a result of the dispersal from the neighboring woodlands. We compared the modalities of dispersal corresponding to different hypotheses on the dispersal origin, kernel shape and sources of variability. Within oilseed rape the distance to the edges of woodlands is not the main determinant of pollen beetle abundance. On the contrary, the variability of the abundance between fields is largely explained by the dispersal from neighboring woodlands but there is considerable variability between dates, sites and, to a lesser extent, between fields. The two dispersal kernels received similar support from the data and lead to similar conclusions. The mean dispersal distance is 1.2 km but seems to increase from a few hundred meters the first week to more than two kilometers the fourth, allowing the pollen beetles to reach more distant OSR fields. These results suggest that early varieties away from woodlands and late varieties close to the woodlands may limit attacks at the time when oilseed rape is the most sensitive. PMID- 28841713 TI - Processing of OPA1 with a novel N-terminal mutation in patients with autosomal dominant optic atrophy: Escape from nonsense-mediated decay. AB - Autosomal Dominant Optic Atrophy (ADOA) is the most common dominantly inherited optic neuropathy. In the majority of patients it is caused by OPA1 mutations and those predicted to introduce a premature termination codon (PTC) are frequently detected. Transcripts containing PTC may be degraded by nonsense-mediated mRNA decay (NMD), however very little is known about an effect of OPA1 mutations on NMD activation. Here, using a combination of linkage analysis and DNA sequencing, we have identified a novel c.91C>T OPA1 mutation with a putative premature stop codon (Q31*), which segregated with ADOA in two Polish families. At the mRNA level we found no changes in the amount of OPA1 transcript among mutation carriers vs. non-carriers. Specific allele quantification revealed a considerable level of the OPA1 mutant transcript. Our study identifies a novel pathogenic OPA1 mutation and shows that it is located in the transcript region not prone for NMD activation. The data emphasizes the importance of analyzing how mutated genes are being processed in the cell. This gives an insight into the molecular mechanism of a genetic disease and promotes development of innovative therapeutic approaches. PMID- 28841714 TI - DNA barcoding-based sexual association of Sovia lucasii and S. lii (Lepidoptera: Hesperiidae), with description of a new subspecies. AB - Both sexes of two sympatric and sexually dimorphic species, Sovia lucasii (Mabille, 1876) and S. lii Xue, 2015, are associated based on DNA barcoding using the COI (mitochondrial cytochrome coxidase I) gene. The females are thus identified for the first time, and their wing patterns and genitalia are described and illustrated for the convenience of morphological identification hereafter. A new subspecies, S. lucasii minor ssp. nov., from the northeastern and eastern parts of the Sichuan Basin of China, is reported. External and genital differences between the new taxon and the nominate subspecies, which is distributed in western Sichuan and newly discovered in northwestern Guangxi, are illustrated and discussed. PMID- 28841715 TI - Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases. AB - During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, the viral endonu- clease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs, including the transcript encoding interleukin-6 (IL-6), escape SOX-induced cleavage. IL-6 escape is mediated through a 3' UTR RNA regulatory element that overrides the SOX targeting mechanism. Here, we reveal that this protective RNA element functions to broadly restrict cleavage by a range of homologous and non-homologous viral endonucleases. However, it does not impede cleavage by cellular endonucleases. The IL-6 protective sequence may be representative of a larger class of nuclease escape elements, as we identified a similar protective element in the GADD45B mRNA. The IL-6 and GADD45B-derived elements display similarities in their sequence, putative structure, and several associated RNA binding proteins. However, the overall composition of their ribonucleoprotein complexes appears distinct, leading to differences in the breadth of nucleases restricted. These findings highlight how RNA elements can selectively control transcript abundance in the background of widespread virus induced mRNA degradation. PMID- 28841716 TI - Self-esteem and subjective well-being revisited: The roles of personal, relational, and collective self-esteem. AB - Previous studies have shown that self-esteem is an important predictor of subjective well-being. However, the majority of research has focused on self esteem at the individual and the collective level, but has mostly ignored self esteem at the relational level. According to social identity theory, individuals can maintain and enhance self-esteem through personal traits (personal self esteem, PSE), relationships with significant others (relational self-esteem, RSE), and relationships with larger groups (collective self-esteem, CSE). The current research investigated whether RSE and CSE can predict subjective well being beyond PSE among Chinese college students. With four cross-sectional studies and one longitudinal study (N = 847), we found that, when controlling for PSE, RSE was associated with greater life satisfaction, positive affect, meaning in life, happiness, and subjective vitality (Studies 1-5), but CSE was not (Studies 2-5). Implications are discussed. PMID- 28841717 TI - Streptococcus pneumoniae in the heart subvert the host response through biofilm mediated resident macrophage killing. AB - For over 130 years, invasive pneumococcal disease has been associated with the presence of extracellular planktonic pneumococci, i.e. diplococci or short chains in affected tissues. Herein, we show that Streptococcus pneumoniae that invade the myocardium instead replicate within cellular vesicles and transition into non purulent biofilms. Pneumococci within mature cardiac microlesions exhibited salient biofilm features including intrinsic resistance to antibiotic killing and the presence of an extracellular matrix. Dual RNA-seq and subsequent principal component analyses of heart- and blood-isolated pneumococci confirmed the biofilm phenotype in vivo and revealed stark anatomical site-specific differences in virulence gene expression; the latter having major implications on future vaccine antigen selection. Our RNA-seq approach also identified three genomic islands as exclusively expressed in vivo. Deletion of one such island, Region of Diversity 12, resulted in a biofilm-deficient and highly inflammogenic phenotype within the heart; indicating a possible link between the biofilm phenotype and a dampened host-response. We subsequently determined that biofilm pneumococci released greater amounts of the toxin pneumolysin than did planktonic or RD12 deficient pneumococci. This allowed heart-invaded wildtype pneumococci to kill resident cardiac macrophages and subsequently subvert cytokine/chemokine production and neutrophil infiltration into the myocardium. This is the first report for pneumococcal biofilm formation in an invasive disease setting. We show that biofilm pneumococci actively suppress the host response through pneumolysin mediated immune cell killing. As such, our findings contradict the emerging notion that biofilm pneumococci are passively immunoquiescent. PMID- 28841718 TI - Inverted recruitment of autophagy proteins to the Plasmodium berghei parasitophorous vacuole membrane. AB - Selective autophagy and related mechanisms can act as variable defense mechanisms against pathogens and can therefore be considered as intracellular immune responses. When in hepatocytes, Plasmodium parasites reside in a parasitophorous vacuole (PV) and the PV membrane (PVM) is the main contact site between host cell and parasite. Early in infection, the PVM is directly labeled with host cell autophagy proteins LC3B and p62 (nucleoporin 62). We investigated the recruitment of different selective autophagy receptors and could show that mainly p62 and NBR1 (neighbour of BRCA1 gene 1) and to a lesser extent NDP52 (nuclear dot protein 52) associate with the PVM. To investigate the recruitment of these receptors to the PVM in Plasmodium-infected cells, we generated LC3B knock out HeLa cells. In these cell lines, autophagosome formation and autophagic flux are not different to those in WT cells. Unexpectedly, p62 and NBR1 recruitment to the PVM was strongly impaired in LC3B-negative host cells, suggesting that LC3B recruits both receptors to the PVM of Plasmodium parasites. We also noticed that LC3B recruited ubiquitin to the PVM. This indicates that, in comparison to classical selective autophagy, in P. berghei-infected cells the order of membrane labeling with autophagy proteins appears to be inverted from canonical ubiquitin receptor-LC3B recruitment to LC3B-receptor and possibly ubiquitin. PMID- 28841719 TI - Tensor decomposition-based unsupervised feature extraction applied to matrix products for multi-view data processing. AB - In the current era of big data, the amount of data available is continuously increasing. Both the number and types of samples, or features, are on the rise. The mixing of distinct features often makes interpretation more difficult. However, separate analysis of individual types requires subsequent integration. A tensor is a useful framework to deal with distinct types of features in an integrated manner without mixing them. On the other hand, tensor data is not easy to obtain since it requires the measurements of huge numbers of combinations of distinct features; if there are m kinds of features, each of which has N dimensions, the number of measurements needed are as many as Nm, which is often too large to measure. In this paper, I propose a new method where a tensor is generated from individual features without combinatorial measurements, and the generated tensor was decomposed back to matrices, by which unsupervised feature extraction was performed. In order to demonstrate the usefulness of the proposed strategy, it was applied to synthetic data, as well as three omics datasets. It outperformed other matrix-based methodologies. PMID- 28841720 TI - Whole-genome sequencing reveals mutational landscape underlying phenotypic differences between two widespread Chinese cattle breeds. AB - Whole-genome sequencing provides a powerful tool to obtain more genetic variability that could produce a range of benefits for cattle breeding industry. Nanyang (Bos indicus) and Qinchuan (Bos taurus) are two important Chinese indigenous cattle breeds with distinct phenotypes. To identify the genetic characteristics responsible for variation in phenotypes between the two breeds, in the present study, we for the first time sequenced the genomes of four Nanyang and four Qinchuan cattle with 10 to 12 fold on average of 97.86% and 98.98% coverage of genomes, respectively. Comparison with the Bos_taurus_UMD_3.1 reference assembly yielded 9,010,096 SNPs for Nanyang, and 6,965,062 for Qinchuan cattle, 51% and 29% of which were novel SNPs, respectively. A total of 154,934 and 115,032 small indels (1 to 3 bp) were found in the Nanyang and Qinchuan genomes, respectively. The SNP and indel distribution revealed that Nanyang showed a genetically high diversity as compared to Qinchuan cattle. Furthermore, a total of 2,907 putative cases of copy number variation (CNV) were identified by aligning Nanyang to Qinchuan genome, 783 of which (27%) encompassed the coding regions of 495 functional genes. The gene ontology (GO) analysis revealed that many CNV genes were enriched in the immune system and environment adaptability. Among several CNV genes related to lipid transport and fat metabolism, Lepin receptor gene (LEPR) overlapping with CNV_1815 showed remarkably higher copy number in Qinchuan than Nanyang (log2 (ratio) = -2.34988; P value = 1.53E-102). Further qPCR and association analysis investigated that the copy number of the LEPR gene presented positive correlations with transcriptional expression and phenotypic traits, suggesting the LEPR CNV may contribute to the higher fat deposition in muscles of Qinchuan cattle. Our findings provide evidence that the distinct phenotypes of Nanyang and Qinchuan breeds may be due to the different genetic variations including SNPs, indels and CNV. PMID- 28841721 TI - Docking-based modeling of protein-protein interfaces for extensive structural and functional characterization of missense mutations. AB - Next-generation sequencing (NGS) technologies are providing genomic information for an increasing number of healthy individuals and patient populations. In the context of the large amount of generated genomic data that is being generated, understanding the effect of disease-related mutations at molecular level can contribute to close the gap between genotype and phenotype and thus improve prevention, diagnosis or treatment of a pathological condition. In order to fully characterize the effect of a pathological mutation and have useful information for prediction purposes, it is important first to identify whether the mutation is located at a protein-binding interface, and second to understand the effect on the binding affinity of the affected interaction/s. Computational methods, such as protein docking are currently used to complement experimental efforts and could help to build the human structural interactome. Here we have extended the original pyDockNIP method to predict the location of disease-associated nsSNPs at protein-protein interfaces, when there is no available structure for the protein protein complex. We have applied this approach to the pathological interaction networks of six diseases with low structural data on PPIs. This approach can almost double the number of nsSNPs that can be characterized and identify edgetic effects in many nsSNPs that were previously unknown. This can help to annotate and interpret genomic data from large-scale population studies, and to achieve a better understanding of disease at molecular level. PMID- 28841722 TI - Development of tailored indigenous marine consortia for the degradation of naturally weathered polyethylene films. AB - This study investigated the potential of bacterial-mediated polyethylene (PE) degradation in a two-phase microcosm experiment. During phase I, naturally weathered PE films were incubated for 6 months with the indigenous marine community alone as well as bioaugmented with strains able to grow in minimal medium with linear low-density polyethylene (LLDPE) as the sole carbon source. At the end of phase I the developed biofilm was harvested and re-inoculated with naturally weathered PE films. Bacteria from both treatments were able to establish an active population on the PE surfaces as the biofilm community developed in a time dependent way. Moreover, a convergence in the composition of these communities was observed towards an efficient PE degrading microbial network, comprising of indigenous species. In acclimated communities, genera affiliated with synthetic (PE) and natural (cellulose) polymer degraders as well as hydrocarbon degrading bacteria were enriched. The acclimated consortia (indigenous and bioaugmented) reduced more efficiently the weight of PE films in comparison to non-acclimated bacteria. The SEM images revealed a dense and compact biofilm layer and signs of bio-erosion on the surface of the films. Rheological results suggest that the polymers after microbial treatment had wider molecular mass distribution and a marginally smaller average molar mass suggesting biodegradation as opposed to abiotic degradation. Modifications on the surface chemistry were observed throughout phase II while the FTIR profiles of microbially treated films at month 6 were similar to the profiles of virgin PE. Taking into account the results, we can suggest that the tailored indigenous marine community represents an efficient consortium for degrading weathered PE plastics. PMID- 28841723 TI - Relation of the protein glycation, oxidation and nitration to the osteocalcin level in obese subjects. AB - Carboxylated osteocalcin (Gla-OC) contributes to the bone formation, whereas its undercarboxylated form (Glu-OC) takes part in the energy metabolism. In vitro studies had shown that treatment of osteoblast-like cells with advanced glycation end product-modified bovine serum resulted in reduced synthesis of collagen 1 and osteocalcin. The aim of this study was to find association between Gla-OC and markers of protein glycation, oxidation and nitration, as well as pro inflammatory and antioxidant defense markers in obese subjects. Non-obese [(body mass index (BMI)<30 kg/m; n=34)] and obese subjects (3079. Preoperative scores were compared among age categories including age category, gender, body mass index (BMI), and length of stay (LOS) in the model as fixed effects. Scores collected postoperatively (~10, 30, 90, and 180 days postoperation) were analyzed as repeated measures including age category, day and their interaction, gender, BMI, LOS, and preoperative score in the model. Preoperative OXFORD scores significantly differed among age categories (p < 0.05) and were numerically higher for the older (>=60 years old) compared with younger patients (<60 years old). After adjusting for preoperative scores, postoperative WOMAC and overall, pain, and function OXFORD scores significantly differed among the age groups (p < 0.05), with patients younger than 60 years reporting the worst scores in the postoperative time period. Older patients reported better preoperative overall, pain, and function scores and greater post-TKA outcomes than younger patients. A better understanding of factors that influence patient reported outcomes can help providers to better manage patient expectations. PMID- 28841730 TI - Corrective Osteotomies for Complex Intra-Articular Tibial Plateau Malunions using Three-Dimensional Virtual Planning and Novel Patient-Specific Guides. AB - Corrective osteotomy of intra-articular tibial plateau malunions is technically demanding for orthopaedic surgeons. The aim of our study was to evaluate the feasibility of the combination of three-dimensional (3D) virtual planning and novel patient-specific guides for assisting correction of complex intra-articular tibial plateau malunions. Six patients with posttraumatic intra-articular tibial plateau malunions were included. Preoperatively 3D models of the tibias were reconstructed using the computed tomography scan data. Virtual surgical planning was performed, and patient-specific guides for osteotomy and reduction were designed, which were then 3D printed. Intraoperatively they were applied to guide the osteotomy and reduction. After surgery, radiographs were taken to evaluate the knee joint surface. The operating surgeons were asked to complete the Likert scale questionnaire to assess their attitude to the novel technology. The guides were successfully used for guiding osteotomy correction of malunion in all patients. Postoperative radiographs showed the articular step-off was considerably reduced and the articular congruency was satisfactory in all patients. The results of the questionnaire demonstrated a high level of surgeon satisfaction and acceptance to the technology. For selective patients with complex intra-articular tibial plateau malunions, the novel technique could serve as a valuable option for guiding precise malunion correction. PMID- 28841731 TI - Influence of Bone Marrow Edema on Medial Unicompartmental Knee Arthroplasty among Patients with Patellofemoral Osteoarthritis. PMID- 28841732 TI - Indication for Unicompartmental Knee Replacement versus Osteotomy around the Knee. PMID- 28841733 TI - Comparison of Outcomes of Tricuspid Valve Surgery in Patients with Reduced and Normal Right Ventricular Function. AB - Background: To study the effect of tricuspid valve repair/replacement on outcomes ofpatients with reduced systolic right ventricular function. Methods: Between January 2012 and July 2016, 191 patients with isolated tricuspidvalve regurgitation and/or in combination with other valve diseases were enrolled intothis retrospective study. We compared early postoperative outcomes (i.e., 30 days aftersurgery) between patients' cohort with a preoperative reduced (i.e., at least moderately)versus normal (or mildly reduced) right ventricular function as defined by meansof preoperative echocardiography. Results: A total of 82 (43%) patients had preoperatively reduced right ventricle function with tricuspid annular plane systolic excursion (TAPSE) of 13.3 +/- 3.3 versus 20.2 +/- 4.9 mm (p < 0.001). Ring annuloplasty was the most common surgical technique (i.e., 91% in both groups). Time of procedure (317 +/- 123 vs. 262 +/- 88 minutes, p < 0.01) and time on cardiopulmonary bypass (163 +/- 77 vs. 143 +/- 57 minutes, p = 0.036) were significantly longer in patients with impaired right ventricular function. Postoperative lactate (3.5 +/- 3 vs. 2 +/- 1 mmol/L, p = 0.001) and dose of catecholamines (epinephrine, 0.07 +/- 0.15 vs. 0.013 +/- 0.02 ug/kg/min, p = 0.001; norepinephrine, 0.18 +/- 0.23 vs. 0.07 +/- 0.09 ug/kg/min, p = 0.007) were also higher in this group. Postoperative rate of low cardiac output syndrome (10 vs. 27%, p = 0.005) and early mortality (n = 2 vs. n = 9, p = 0.018) were significantly increased in patients with reduced right ventricular function. Previous cardiac operation (p = 0.045), preoperative higher number of acute decompensations of heart failure (p < 0.001), reduced right ventricular function (p = 0.018), postoperative low cardiac output syndrome (p < 0.001), and renal replacement therapy (p < 0.001) were identified as risk factors for early mortality. Echocardiography at discharge revealed tricuspid valve regurgitation grade of 0.9 +/- 0.7 versus 0.7 +/- 0.6 (p = 0.052) and TAPSE of 12 +/- 3 versus 15 +/- 5 mm (p = 0.026) in patients with reduced right ventricular function. The New York Heart Association (NYHA) class improved to 1.7 +/- 0.7 versus 1.3 +/- 1 (p < 0.001) in this group of patients. Conclusion: Tricuspid valve repair/replacement effectively eliminated severe tricuspid regurgitation and improved clinical signs of heart failure. Although mortality and morbidity were increased in the group with reduced right ventricular function, even these patients benefitted from improved functional status and right ventricular systolic function early postoperatively. PMID- 28841734 TI - The Propeller Concept Applied to Free Flaps and the Proposal of a "Clock Flap" Nomenclature. PMID- 28841735 TI - Agreement between Perometry and Sequential Arm Circumference Measurements in Objective Determination of Arm Volume. AB - BACKGROUND: Limb circumference measurements (CM) and perometry are the preferred methods for objectively measuring arm volume in lymphedema surgery research. Understanding the measurement bias involved in these measuring systems is important to properly interpret and compare studies and their results. METHODS: Arm volumes from 91 patients were measured using sequential girths and the truncated cone formula (CM) and with the use of an automated perometer (perometry). The absolute volume of the largest arm (V), the volume difference between the arms (VD), and the relative difference between them (percentage of excess volume [PEV]) were calculated with both methods. The agreement between methods was assessed by the Pearson's correlation test and the Bland-Altman's method. RESULTS: Correlations were strong for V (r = 0.99), VD (r = 88), and PEV (r = 0.86). Volumes measured by perometry were, on average, 10.6 mL smaller than volumes calculated from CM, while their limits of agreement (LOA) ranged from 202 to 181 mL. The LOA represents the range we could expect the arm volumes measured with the two methods to differ by chance alone, 95% of the times. For VD, LOA was -101 to 141 mL, with a mean difference of 19.9 mL, while PEV had a mean difference of 0.9%, with LOA ranging from -5 to 6.8%. CONCLUSION: There is considerable measurement error between arm volume estimated by perometry and by CM. Volumes calculated with these methods should be compared with caution. Furthermore, we observed an increasingly relevant measurement bias in outcomes that are mathematically derived from arm volumes. PMID- 28841736 TI - Myocutaneous Gracilis Free Flaps in Microsurgical Breast Reconstruction: A Systematic Review Comparing Variations of the Upper Gracilis Flap. PMID- 28841737 TI - Neurotization of the Superficial Sensory Branch of Ulnar Nerve by the Distal Posterior Interosseous Nerve: Cadaveric Feasibility Study. PMID- 28841739 TI - Sources and Management of Knee Pain. PMID- 28841738 TI - Aucubin Protects against TGFbeta1-Induced Cardiac Fibroblasts Activation by Mediating the AMPKalpha/mTOR Signaling Pathway. AB - Fibrosis is a key feature of various cardiovascular diseases and compromises cardiac systolic and diastolic performance. The lack of effective anti-fibrosis drugs is a major contributor to the increasing prevalence of heart failure. The present study was performed to investigate whether the iridoid aucubin alleviates cardiac fibroblast activation and its underlying mechanisms. Neonatal rat cardiac fibroblasts were incubated with aucubin (1, 10, 20, 50 uM) followed by transforming growth factor beta1 (TGFbeta1, 10 ng/mL) stimulation for 24 h. Fibrosis proliferation was measured by cell counting kit-8 assay. The differentiation of fibroblasts into myofibroblasts was determined by measuring the expression of alpha-smooth muscle actin. Then, the expressions levels of cardiac fibrosis-related proteins in myofibroblasts were analyzed by western blot and real-time PCR to confirm the anti-fibrosis effect of aucubin. As a result, aucubin suppressed TGFbeta1-induced proliferation in fibroblasts and inhibited the TGFbeta1-induced activation of fibroblasts to myofibroblasts. In addition, aucubin further attenuated fibrosis-related protein expression in myofibroblasts. Furthermore, this protective effect was related to increased adenosine 5' monophosphate-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, which was confirmed by an mTOR inhibitor (rapamycin), an AMPK agonist (AICAR) and an AMPKalpha inhibitor compound C. Collectively, our findings suggest that aucubin protects against TGFbeta1-induced fibroblast proliferation, activation and function by regulating the AMPKalpha/mTOR signal axis. PMID- 28841740 TI - [Massive Morgagni Hernia as a Reason for Lung Function Impairment]. AB - Hernia of Morgagni is the most rare of the four types of congenital diaphragmatic hernia (2 % - 3 % of all cases). In adults, it commonly presents with non specific symptoms. In severe cases patients complain about shortness of breath and in lung function analysis a restrictive pattern can be observed. This paper presents a rare case of a massive diaphragmatic hernia of the right thorax which remained undiagnosed over many years and gives an up-to-date overview of the literature. The transabdominal approach using laparoscopic repair is favored in adults especially in non-acute cases. In our patient, the lung expanded postoperatively in most parts resulting in improvement of lung function and blood gas analysis. PMID- 28841741 TI - [Obstructive Sleep Apnea Syndrome and Pregnancy]. PMID- 28841742 TI - [Welcome to the DGN Congress]. PMID- 28841743 TI - [Treatment of laryngeal dystonia with botulinum toxin]. AB - The treatment of laryngeal dystonias with botulinum toxin is successful. Every patient suffering from a laryngeal dystonia should be assured of high quality therapeutic intervention. Therefore it is important to establish general standards by experts in this field. In this connection, we want to focus here on different relevant aspects of laryngeal dystonias. This includes new aspects in etiology, anatomical landmarks for the injection, standards in diagnostics and therapy and finally open issues needing discussion. PMID- 28841744 TI - [Hope for Huntington's disease patients: first clinical gene silencing study in progress]. AB - Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder, characterized by motor, psychiatric and cognitive symptoms for which as yet no causal treatment is available. It has a prevalence of 1 : 10 000 in Germany. Its cause is a mutation in the Huntington gene (CAG-repeat). The mutation induces a polyglutamine expansion in the huntingtin protein (HTT). Mutant HTT (mHTT) has cytotoxic properties, aggregates in the cell and leads to complex pathophysiological disturbances ending in cell death. This review explains the principles of gene silencing which suppresses transcription and translation of huntingtin. One way to achieve gene silencing is the use of antisense oligonucleotides (ASO) that bind to pre-mRNA. Since August 2015, a first clinical trial with ASO (study drug: IONIS-HTTRx) in early manifest HD patients is in progress (NCT02519036). Results from this study could lead to a first causal treatment option in HD. PMID- 28841745 TI - [Sharp increase in newly diagnosed patients with dementia in German primary care practices 2013. Better diagnostic process or monetary incentives?] AB - : Background In 2013, the incidence of patients with dementia (PwD) in primary care practices (PCP) drastically increased. RESEARCH QUESTIONS: (1) Is the increase also detectable in a subsample, (2) was there a comparable increase in specialist practices (SP), and (3) did the increase affect diagnostics and therapy? Methods We analyzed billing data from 874 PCP and 141 SP (2011 to 2015) pertaining to more than 14,000 PwD/year with regard to the incidence of dementia diagnoses (ICD-10: G30, F01, F03) and antidementia prescriptions. Results The incidence abruptly increased by 47 % (2013) and 73 % (2014) compared to 2012. Proportions of nonspecific and vascular dementia diagnoses increased. Proportions of Alzheimer's and antidementia prescriptions decreased. No comparable developments were observed in SP. Conclusion The drastic incidence increase in 2013 was closely linked to physician- and patient-related economic incentives. Whether a causal relationship existed and what consequences monetary incentives may have for PwD should be further investigated. PMID- 28841746 TI - [The power plants of the cell: Treatment of psychiatric symptoms in patients with mitochondriopathy]. AB - Introduction Mitochondriopathies are pathologies of cell organelles, which are essential for the formation of adenosine triphosphate (ATP), which is responsible for cellular energy stock. When mitochondrial mutations occur, symptoms arise frequently in those organs that rely on a continuous energy supply, such as the nervous system. Although psychiatric illness is increasingly prevalent in patients with mitochondrial disease, less attention has been paid to its psychiatric presentations. Case Report We describe a case of a 21-year-old woman who presented in our outpatient department with panic attacks and depression. The patient experienced major side effects after low-dose sertraline therapy. Conclusion Mitochondriopathies belong to the class of rare illnesses in psychiatry; nevertheless, they require adaptations of psychopharmacological therapy. Psychotropic drugs are potential respiratory chain inhibitors and could lead to distinct side effects. PMID- 28841747 TI - [Psychotherapy: Quo vadis?] AB - Background: The science and practice of psychotherapy is continuously developing. The goal of this article is to describe new impulses, guiding current advancements in the field. Methods: This paper provides a selective narrative review, synthesizing and condensing relevant literature identified through various sources, including MEDLINE, EMBASE, PsycINFO, and "Web of Science", as well as citation tracking, to elaborate key developments in the field of psychotherapy Results: We describe several dynamics: 1) Following up the so called "third wave of cognitive behavioral therapy", new interventions arise that have at their core fostering interpersonal virtues, such as compassion, forgiveness, and gratitude; 2) Based on technological quantum leaps, new interventions arise that exploit current developments in the field of new media, information, and communication technologies, as well as brain imaging, such as digital interventions for mental disorders and new forms of neurofeedback; 3) Inspired by the field of positive psychology, there is a revival of the promotion of strength and resilience in therapeutic contexts; 4) In light of the new paradigm "precision medicine", the issue of differential and adaptive indication of psychotherapy, addressed with new methods, regains relevance and drives a new field of "precision psychotherapy". 5) Last but not least, the "embodied turn" opens the door for body psychotherapy to gain relevance in academic psychotherapy. Conclusion: These and further developments, such as the use of systemic and network approaches as well as machine learning techniques, outline the vivid activities in the field of psychotherapy. PMID- 28841748 TI - Intraspecific adaptive radiation: Competition, ecological opportunity, and phenotypic diversification within species. AB - Intraspecific variation in resource-use traits can have profound ecological and evolutionary implications. Among the most striking examples are resource polymorphisms, where alternative morphs that utilize different resources evolve within a population. An underappreciated aspect of their evolution is that the same conditions that favor resource polymorphism-competition and ecological opportunity-might foster additional rounds of diversification within already existing morphs. We examined these issues in spadefoot toad tadpoles that develop into either a generalist "omnivore" or a specialist "carnivore" morph. Specifically, we assessed the morphological diversity of tadpoles from natural ponds and experimentally induced carnivores reared on alternative diets. We also surveyed natural ponds to determine if the strength of intramorph competition and the diversity and abundance of dietary resources (measures of ecological opportunity) influenced the diversity of within-morph variation. We found that five omnivore and four carnivore types were present in natural ponds; alternative diets led to shape differences, some of which mirrored variation in the wild; and both competition and ecological opportunity were associated with enhanced morphological diversity in natural ponds. Such fine-scale intraspecific variation might represent an underappreciated form of biodiversity and might constitute a crucible of evolutionary innovation and diversification. PMID- 28841749 TI - Society for Paediatric and Perinatal Epidemiology 30th Annual Meeting: Present and Future. PMID- 28841750 TI - WHO Growth Standards - Suitable for Everyone? Yes. PMID- 28841751 TI - Air Pollution - Who Is at Risk? PMID- 28841752 TI - Superior Photocatalytic H2 Production with Cocatalytic Co/Ni Species Anchored on Sulfide Semiconductor. AB - Downsizing transition metal-based cocatalysts on semiconductors to promote photocatalytic efficiency is important for research and industrial applications. This study presents a novel and facile strategy for anchoring well-dispersed metal species on CdS surface through controlled decarboxylation of the ethylenediaminetetraacetate (EDTA) ligand in the metal-EDTA (M-EDTA) complex and CdS mixture precursor to function as a cocatalyst in the photocatalytic H2 evolution. Microstructure characterization and performance evaluation reveal that under visible light the resulting pentacoordinated Co(II) and hexacoordinated Ni(II) on CdS exhibits a high activity of 3.1 mmol h-1 (with turnover frequency (TOF) of 626 h-1 and apparent quantum efficiency (AQE) of 56.2% at 420 nm) and 4.3 mmol h-1 (with TOF of 864 h-1 and AQE of 67.5% at 420 nm), respectively, toward cocatalytic hydrogen evolution, and the cocatalytic activity of such a hexacoordinated Ni(II) even exceeds that of platinum. Further mechanistic study and theoretical modeling indicate that the fully utilized Co(II)/Ni(II) active sites, efficient charge transfer, and favorable kinetics guarantee the efficient activities. This work introduces a promising precursor, i.e., M-EDTA for planting well-dispersed transition metal species on the sulfide supports by a facile wet chemistry approach, providing new opportunities for photocatalytic H2 production at the atomic/molecular scale. PMID- 28841753 TI - Material practices for meaningful engagement: An analysis of participatory learning and action research techniques for data generation and analysis in a health research partnership. AB - BACKGROUND: The material practices which researchers use in research partnerships may enable or constrain the nature of engagement with stakeholder groups. Participatory learning and action (PLA) research approaches show promise, but there has been no detailed analysis of stakeholders' and researchers' experiences of PLA techniques for data generation and co-analysis. OBJECTIVES: To explore stakeholders' and researchers' experiences of PLA techniques for data generation and co-analysis. DESIGN: The EU RESTORE implementation science project employed a participatory approach to investigate and support the implementation of guidelines and training initiatives (GTIs) to enhance communication in cross cultural primary care consultations. We developed a purposeful sample of 78 stakeholders (migrants, general practice staff, community interpreters, service providers, service planners) from primary care settings in Austria, England, Greece, Ireland and The Netherlands. We used speed evaluations and participatory evaluations to explore their experiences of two PLA techniques-Commentary Charts and Direct Ranking-which were intended to generate data for co-analysis by stakeholders about the GTIs under analysis. We evaluated 16 RESTORE researchers' experiences using interviews. We conducted thematic and content analysis of all evaluation data. RESULTS: PLA Commentary Charts and Direct Ranking techniques, with their visual, verbal and tangible nature and inherent analytical capabilities, were found to be powerful tools for involving stakeholders in a collaborative analysis of GTIs. Stakeholders had few negative experiences and numerous multifaceted positive experiences of meaningful engagement, which resonated with researchers' accounts. CONCLUSION: PLA techniques and approaches are valuable as material practices in health research partnerships. PMID- 28841754 TI - Synthetic Control of Kinetic Reaction Pathway and Cationic Ordering in High-Ni Layered Oxide Cathodes. AB - Nickel-rich layered transition metal oxides, LiNi1-x (MnCo)x O2 (1-x >= 0.5), are appealing candidates for cathodes in next-generation lithium-ion batteries (LIBs) for electric vehicles and other large-scale applications, due to their high capacity and low cost. However, synthetic control of the structural ordering in such a complex quaternary system has been a great challenge, especially in the presence of high Ni content. Herein, synthesis reactions for preparing layered LiNi0.7 Mn0.15 Co0.15 O2 (NMC71515) by solid-state methods are investigated through a combination of time-resolved in situ high-energy X-ray diffraction and absorption spectroscopy measurements. The real-time observation reveals a strong temperature dependence of the kinetics of cationic ordering in NMC71515 as a result of thermal-driven oxidation of transition metals and lithium/oxygen loss that concomitantly occur during heat treatment. Through synthetic control of the kinetic reaction pathway, a layered NMC71515 with low cationic disordering and a high reversible capacity is prepared in air. The findings may help to pave the way for designing high-Ni layered oxide cathodes for LIBs. PMID- 28841755 TI - Motion Manipulation of Micro- and Nanomotors. AB - Inspired by the self-migration of microorganisms in nature, artificial micro- and nanomotors can mimic this fantastic behavior by converting chemical fuel or external energy into mechanical motion. These self-propelled micro- and nanomotors, designed either by top-down or bottom-up approaches, are able to achieve different applications, such as environmental remediation, sensing, cargo/sperm transportation, drug delivery, and even precision micro-/nanosurgery. For these various applications, especially biomedical applications, regulating on demand the motion of micro- and nanomotors is quite essential. However, it remains a continuing challenge to increase the controllability over motors themselves. Here, we will discuss the recent advancements regarding the motion manipulation of micro- and nanomotors by different approaches. PMID- 28841756 TI - Gastroschisis in Europe - A Case-malformed-Control Study of Medication and Maternal Illness during Pregnancy as Risk Factors. AB - BACKGROUND: Gastroschisis, a congenital anomaly of the abdomen, is associated with young maternal age and has increased in prevalence in many countries. Maternal illness and medication exposure are among environmental risk factors implicated in its aetiology. METHODS: A population-based case-malformed control study was conducted using data from 18 European congenital anomaly registries, with information on first trimester medication use, covering 8 million births 1995-2012. 1577 gastroschisis cases (of which 4% stillbirths, 11% terminations of pregnancy) were compared to 153 357 non-chromosomal/monogenic controls. Literature review identified previous associations concerning maternal illness and medication exposure to be tested as signals. Logistic regression adjusted for maternal age group, registry, and time period was used to evaluate associations. RESULTS: Comparing gastroschisis to other congenital anomalies, the data supported signals concerning maternal depression (aOR 2.52, 95% CI 1.45, 4.39), antidepressant use (aOR 2.03, 95% CI 1.22, 3.38), postnatal depression/psychosis following a previous pregnancy (aOR 8.32, 95% CI 2.56, 27.01), sexually transmitted infections (aOR 2.85, 95% CI 1.13, 7.24), topical antivirals (aOR 5.31, 95% CI 1.63, 17.33), and continuation of oral contraceptives in early pregnancy (aOR 2.17, 95% CI 1.13, 4.18). Exploratory analyses suggested associations with a wider range of maternal infections and medications, including tonsillitis and the expectorant bromhexine. CONCLUSIONS: While it is difficult to disentangle the effects of the medication and underlying indication, our results add to the evidence base on preventable risk factors for gastroschisis. These risk factors may contribute to the higher risk among young mothers, and geographical and temporal variation in prevalence. PMID- 28841757 TI - The Influence of Nurses' Demographics on Patient Participation in Hospitals: A Cross-Sectional Study. AB - BACKGROUND: Patient participation is an important issue in contemporary healthcare as it improves quality of care and enhances positive health outcomes. The participation of patients is mainly initiated by the nurses' willingness to share their power and responsibility, but knowledge on nurses' demographic characteristics influencing this behavior is nonexistent. This knowledge is essential to understand and improve patient participation. AIM: To determine if nurses' demographic characteristics influence their willingness to engage in patient participation. METHODS: A cross-sectional multicenter study in 22 general and three university hospitals with 997 nurses was performed. The Patient Participation Culture Tool for healthcare workers, which measures patient participation behavior, was used. Multilevel analysis, taking into account the difference in wards and hospitals, was used to identify the influence of demographic characteristics. RESULTS: A position as supervisor (range: p < .001 .028) and a higher level of education (range: p = <.001-.012) show significant higher scores. Younger nurses seem to be more reluctant in accepting a collaborative patient role (p = .002) and coping with more active patient behavior (p < .001). This new role was less accepted by nurses on geriatric wards (p = .013), who also showed less sharing of information with their patients (p < .001). LINKING EVIDENCE TO ACTION: Age and level of education influence nurses' willingness to share power and responsibility with their patients, perhaps indicating that patient participation behavior is an advanced nursing skill and multifaceted interventions, are needed for optimal implementation. Moreover, supervising nurses have different perceptions on patient participation and possibly regard patient participation as an easier task than their team members. This could lead to misunderstandings about the expectations toward patient participation in daily practice, leading to struggles with their nursing staff. Both findings implicate that implementing patient participation on a wide scale is more difficult than expected, which is conflicting with the widespread societal demand for more participation. PMID- 28841758 TI - Precision and accuracy of diffusion kurtosis estimation and the influence of b value selection. AB - Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging that accounts for leading non-Gaussian diffusion effects. In DKI studies, a wide range of different gradient strengths (b-values) is used, which is known to affect the estimated diffusivity and kurtosis parameters. Hence there is a need to assess the accuracy and precision of the estimated parameters as a function of b-value. This work examines the error in the estimation of mean of the kurtosis tensor (MKT) with respect to the ground truth, using simulations based on a biophysical model for both gray (GM) and white (WM) matter. Model parameters are derived from densely sampled experimental data acquired in ex vivo rat brain and in vivo human brain. Additionally, the variability of MKT is studied using the experimental data. Prevalent fitting protocols are implemented and investigated. The results show strong dependence on the maximum b-value of both net relative error and standard deviation of error for all of the employed fitting protocols. The choice of b-values with minimum MKT estimation error and standard deviation of error was found to depend on the protocol type and the tissue. Protocols that utilize two terms of the cumulant expansion (DKI) were found to achieve minimum error in GM at b-values less than 1 ms/MUm2 , whereas maximal b-values of about 2.5 ms/MUm2 were found to be optimal in WM. Protocols including additional higher order terms of the cumulant expansion were found to provide higher accuracy for the more commonly used b-value regime in GM, but were associated with higher error in WM. Averaged over multiple voxels, a net average error of around 15% for both WM and GM was observed for the optimal b-value choice. These results suggest caution when using DKI generated metrics for microstructural modeling and when comparing results obtained using different fitting techniques and b-values. PMID- 28841759 TI - Quantification of six potential unspecific human biomarkers of 1-vinyl-2 pyrrolidone exposure in Sprague-Dawley rat urine using gas chromatography coupled with triple mass spectrometry. AB - RATIONALE: The monomer 1-vinyl-2-pyrrolidone (VP) is a substance with excellent solvent features. It is used in a wide variety of pharmaceutical, cosmetic, food industrial or technical applications and produced on an industrial scale. Since VP has caused adenocarcinoma of the nasal cavity and liver cell carcinoma in long term experiments with rats, a human biomarker would be appreciated for risk assessment. METHODS: A sensitive analytical electron ionization gas chromatography/tandem mass spectrometry (GC/MS/MS) method for the determination of six possible biomarkers for VP in urine was established and validated. Two isotope-labeled internal standards (ISTD) were used for quantification. A simple and easy to use freeze-drying step was performed prior to derivatization with N tert-butyldimethylsilyl-N-methyltrifluoracetamide (MTBSTFA) and following sample extraction for cleanup purposes. RESULTS: A calibration curve with six calibration standards ranging from 50 MUg/L to 2000 MUg/L (10-fold higher for H OPAA) in urine was prepared. Validation results were satisfactory with recoveries ranging from 88.2 to 110.2 % with two exceptions for the lowest quality control for two substances without ISTD (126.4 % and 139.3 %). Three of the substances could be identified as VP metabolites in an exposure study with Sprague-Dawley (SD) rats. CONCLUSIONS: A quick and easy to use method has been established for six target molecules investigated for a better understanding of the metabolism of VP. Two of three substances identified as metabolites of VP could serve as a nonspecific human biomarker for VP exposure as shown with an excerpt of an exposure study performed in SD rats. PMID- 28841760 TI - Direct screening of enzyme activity using infrared matrix-assisted laser desorption electrospray ionization. AB - RATIONALE: High-throughput screening (HTS) is a critical step in the drug discovery process. However, most mass spectrometry (MS)-based HTS methods require sample cleanup steps prior to analysis. In this work we present the utility of infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) for monitoring an enzymatic reaction directly from a biological buffer system with no sample cleanup and at high throughput. METHODS: IR-MALDESI was used to directly analyze reaction mixtures from a well plate at different time points after reaction initiation. The percent conversion of precursors to products was used to screen the enzyme activity. The reaction was performed with two different concentrations of precursors and enzyme in order to assess the dynamic range of the assay. Eventually, a pseudo-HTS study was designed to investigate the utility of IR-MALDESI screening enzyme activity in a high-throughput manner. RESULTS: IR MALDESI was able to readily monitor the activity of IDH1 over time at two different concentrations of precursors and enzyme. The calculated Z-factors of 0.65 and 0.41 confirmed the suitability of the developed method for screening enzyme activity in HTS manner. Finally, in a single-blind pseudo-HTS analysis IR MALDESI was able to correctly predict the identity of all samples, where 8/10 samples were identified with high confidence and the other two samples with lower confidence. CONCLUSIONS: The enzymatic activity of IDH1 was screened by directly analyzing the reaction content from the buffer in well plates with no sample cleanup steps. This proof-of-concept study demonstrates the robustness of IR MALDESI for direct analysis of enzymatic reactions from biological buffers with no sample cleanup and its immense potential for HTS applications. PMID- 28841761 TI - User-independent diffusion tensor imaging analysis pipelines in a rat model presenting ventriculomegalia: A comparison study. AB - Automated analysis of diffusion tensor imaging (DTI) data is an appealing way to process large datasets in an unbiased manner. However, automation can sometimes be linked to a lack of interpretability. Two whole-brain, automated and voxelwise methods exist: voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). In VBA, the amount of smoothing has been shown to influence the results. TBSS is free of this step, but a projection procedure is introduced to correct for residual misalignments. This projection assigns the local highest fractional anisotropy (FA) value to the mean FA skeleton, which represents white matter tract centers. For both methods, the normalization procedure has a major impact. These issues are well documented in humans but, to our knowledge, not in rodents. In this study, we assessed the quality of three different registration algorithms (ANTs SyN, DTI-TK and FNIRT) using study-specific templates and their impact on automated analysis methods (VBA and TBSS) in a rat pup model of diffuse white matter injury presenting large unilateral deformations. VBA and TBSS results were stable and anatomically coherent across the three pipelines. For VBA, in regions around the large deformations, interpretability was limited because of the increased partial volume effect. With TBSS, two of the three pipelines found a significant decrease in axial diffusivity (AD) at the known injury site. These results demonstrate that automated voxelwise analyses can be used in an animal model with large deformations. PMID- 28841762 TI - Comparison of different compressed sensing algorithms for low SNR 19 F MRI applications-Imaging of transplanted pancreatic islets and cells labeled with perfluorocarbons. AB - Transplantation of pancreatic islets is a possible treatment option for patients suffering from Type I diabetes. In vivo imaging of transplanted islets is important for assessment of the transplantation site and islet distribution. Thanks to its high specificity, the absence of intrinsic background signal in tissue and its potential for quantification, 19 F MRI is a promising technique for monitoring the fate of transplanted islets in vivo. In order to overcome the inherent low sensitivity of 19 F MRI, leading to long acquisition times with low signal-to-noise ratio (SNR), compressed sensing (CS) techniques are a valuable option. We have validated and compared different CS algorithms for acceleration of 19 F MRI acquisition in a low SNR regime using pancreatic islets labeled with perfluorocarbons both in vitro and in vivo. Using offline simulation on both in vitro and in vivo low SNR fully sampled 19 F MRI datasets of labeled islets, we have shown that CS is effective in reducing the image acquisition time by a factor of three to four without seriously affecting SNR, regardless of the particular algorithms used in this study, with the exception of CoSaMP. Using CS, signals can be detected that might have been missed by conventional 19 F MRI. Among different algorithms (SPARSEMRI, OMMP, IRWL1, Two-level and CoSAMP), the two-level l1 method has shown the best performance if computational time is taken into account. We have demonstrated in this study that different existing CS algorithms can be used effectively for low SNR 19 F MRI. An up to fourfold gain in SNR/scan time could be used either to reduce the scan time, which is beneficial for clinical and translational applications, or to increase the number of averages, to potentially detect otherwise undetected signal when compared with conventional 19 F MRI acquisitions. Potential applications in the field of cell therapy have been demonstrated. PMID- 28841763 TI - The influence of different skin types on GSR sampling by tape lifting for SEM analysis. AB - In this study, the change in the amounts the gunshot residues (GSR) collected by the "swab" method from shooter's right hand was analyzed using Scanning Electron Microscope-Energy Dispersive Spectroscopy (SEM-EDS) to test dependency on various conditions (such as skin color of the shooter, various physical properties, hair density of hands, size of the hands, sweaty or creamy (oiliness) hands). As a result of the analysis, there was no significant difference in the amount of GSR according to skin color, however, there was a change in the amount of GSR depending on the physical characteristics of the shooter. These results thought to have practical benefits for the experts performing GSR analysis using the swab technique to assess the incidence. PMID- 28841764 TI - How do people become plasma and platelet donors in a VNR context? AB - BACKGROUND: The demand for therapeutic plasma-derived products poses a challenge to blood collection agencies (BCAs). In 2014-2015, the volume of plasma sent for fractionation met 17.7% of Quebec's needs for immunoglobulins. This article aims to offer an exploration of the paths blood donors follow in order to become plasma and platelet donors (PPDs). STUDY DESIGN AND METHOD: This analysis is based on semi-structured interviews with 50 PPDs in Quebec, Canada. Our analysis focused on the occurrence of events and the presence of contextual elements identified through: (1) factual data on PPDs; and (2) what PPDs identified as being an influence on their donation experience. This information was synthesized using a typology of trajectories. RESULTS: Six typical trajectories have been distinguished, first by the presence (19/50 respondents) or absence (31/50) of blood donation as a family tradition. Of the latter 31 donors, some pointed instead to inherited family values as having a significant influence on their commitment (11/31). Donors' careers were then distinguished as having started early (34) or late (16). Sub-types then appeared with the addition of other contextual elements, motivation profiles, and circumstances under which the conversion to apheresis donation occurred. CONCLUSION: Our findings suggest the existence of diversified donor trajectories, and confirm the importance of conducting more in-depth analyses of the sequence of events occurring along PPDs career. BCAs should develop strategies carefully tailored to different potential clienteles if they wish to convert whole blood donors to apheresis donation, and also focus on recruiting and retaining young PPDs. PMID- 28841765 TI - Enabling a Disaster-Resilient Workforce: Attending to Individual Stress and Collective Trauma. AB - PURPOSE: Superstorm Sandy forced the evacuation and extended shutdown of New York University Langone Medical Center. This investigation explored how nurses were impacted by the disasters and how they can best be supported in their nursing responsibilities. DESIGN: Sequential mixed methods were used to explore the psychosocial issues nurses experienced throughout the course of this natural disaster and its lingering aftermath. METHODS: In-depth interviews were conducted from April to June 2013 with a subsample of nurses who participated in the evacuation deployment (n = 16). An anonymous, Internet-based cross-sectional survey sent to all registered nurses employed at the hospital at the time of the storm explored storm impact and recovery. Between July and September 2013, 528 surveys were completed. FINDINGS: The qualitative data revealed challenges in balancing professional obligations and personal concerns. Accounts described dealing in the immediate recovery period with unexpected job changes and resultant work uncertainty. The storm's lingering aftermath did not signify restoration of their predisaster lifestyle for some, but necessitated coping with this massive storm's long-lasting impact on their personal lives and communal loss. CONCLUSIONS: Nurses working under the rapidly changing, uncontrolled, and potentially dangerous circumstances of a weather-related disaster are also experiencing concerns about their families' welfare and worries about personal loss. These multiple issues increase the psychosocial toll on nurses during a disaster response and impending recovery. CLINICAL RELEVANCE: Awareness of concerns and competing demands nurses experience in a disaster and aftermath can inform education and services to enable nurses to perform their critical functions while minimizing risk to patients and themselves. PMID- 28841766 TI - Subunit-dependent oxidative stress sensitivity of LRRC8 volume-regulated anion channels. AB - KEY POINTS: Swelling-activated anion currents are modulated by oxidative conditions, but it is unknown if oxidation acts directly on the LRRC8 channel forming proteins or on regulatory factors. We found that LRRC8A-LRRC8E heteromeric channels are dramatically activated by oxidation of intracellular cysteines, whereas LRRC8A-LRRC8C and LRRC8A-LRRC8D heteromers are inhibited by oxidation. Volume-regulated anion currents in Jurkat T lymphocytes were inhibited by oxidation, in agreement with a low expression of the LRRC8E subunit in these cells. Our results show that LRRC8 channel proteins are directly modulated by oxidation in a subunit-specific manner. ABSTRACT: The volume-regulated anion channel (VRAC) is formed by heteromers of LRRC8 proteins containing the essential LRRC8A subunit and at least one among the LRRC8B-E subunits. Reactive oxygen species (ROS) play physiological and pathophysiological roles and VRAC channels are highly ROS sensitive. However, it is unclear if ROS act directly on the channels or on molecules involved in the activation pathway. We used fluorescently tagged LRRC8 proteins that yield large constitutive currents to test direct effects of oxidation. We found that 8A/8E heteromers are dramatically potentiated (more than 10-fold) by oxidation of intracellular cysteine residues by chloramine-T or tert-butyl hydroperoxide. Oxidation was, however, not necessary for hypotonicity-induced activation. In contrast, 8A/8C and 8A/8D heteromers were strongly inhibited by oxidation. Endogenous VRAC currents in Jurkat T lymphocytes were similarly inhibited by oxidation, in agreement with the finding that LRRC8C and LRRC8D subunits were more abundantly expressed than LRRC8E in Jurkat cells. Our results show that LRRC8 channels are directly modulated by oxidation in a subunit-dependent manner. PMID- 28841767 TI - Enzyme Activity by Design: An Artificial Rhodium Hydroformylase for Linear Aldehydes. AB - Artificial metalloenzymes (ArMs) are hybrid catalysts that offer a unique opportunity to combine the superior performance of natural protein structures with the unnatural reactivity of transition-metal catalytic centers. Therefore, they provide the prospect of highly selective and active catalytic chemical conversions for which natural enzymes are unavailable. Herein, we show how by rationally combining robust site-specific phosphine bioconjugation methods and a lipid-binding protein (SCP-2L), an artificial rhodium hydroformylase was developed that displays remarkable activities and selectivities for the biphasic production of long-chain linear aldehydes under benign aqueous conditions. Overall, this study demonstrates that judiciously chosen protein-binding scaffolds can be adapted to obtain metalloenzymes that provide the reactivity of the introduced metal center combined with specifically intended product selectivity. PMID- 28841768 TI - Honeysuckle flowers extract loaded Bombyx mori silk fibroin films for inducing apoptosis of HeLa cells. AB - This study aimed to prepare silk fibroin (SF) films loaded with honeysuckle flowers extract (HFE) for inducing apoptosis of HeLa cells. We mixed solution of SF and HFE by air-drying for preparing the honeysuckle flowers extract loaded silk fibroin (SFH) films. The physical properties including morphologies, contact angle, roughness, and Z range were characterized. MTS assay and fluorescence micrographs proved that SFH films inhibited the proliferation rate of HeLa cells due to induction of HFE into SF films. Furthermore, cell apoptosis assay and cell cycle analysis confirmed that the apoptosis of HeLa cells resulted from SFH films. Therefore, SFH films designed in our study might be a promising candidate material for cancer therapy. PMID- 28841769 TI - Reprogrammable Phononic Metasurfaces. AB - Phononic metamaterials rely on the presence of resonances in a structured medium to control the propagation of elastic waves. Their response depends on the geometry of their fundamental building blocks. A major challenge in metamaterials design is the realization of basic building blocks that can be tuned dynamically. Here, a metamaterial plate is realized that can be dynamically tuned by harnessing geometric and magnetic nonlinearities in the individual unit cells. The proposed tuning mechanism allows a stiffness variability of the individual unit cells and can control the amplitude of transmitted excitation through the plate over three orders of magnitude. The concepts can be extended to metamaterials at different scales, and they can be applied in a broad range of engineering applications, from seismic shielding at low frequency to ultrasonic cloaking at higher frequency ranges. PMID- 28841770 TI - Synthetic Biomaterials to Rival Nature's Complexity-a Path Forward with Combinatorics, High-Throughput Discovery, and High-Content Analysis. AB - Cells in tissue receive a host of soluble and insoluble signals in a context dependent fashion, where integration of these cues through a complex network of signal transduction cascades will define a particular outcome. Biomaterials scientists and engineers are tasked with designing materials that can at least partially recreate this complex signaling milieu towards new materials for biomedical applications. In this progress report, recent advances in high throughput techniques and high content imaging approaches that are facilitating the discovery of efficacious biomaterials are described. From microarrays of synthetic polymers, peptides and full-length proteins, to designer cell culture systems that present multiple biophysical and biochemical cues in tandem, it is discussed how the integration of combinatorics with high content imaging and analysis is essential to extracting biologically meaningful information from large scale cellular screens to inform the design of next generation biomaterials. PMID- 28841771 TI - Introduction of Nature's Complexity in Engineered Blood-compatible Biomaterials. AB - Biomaterials with excellent blood-compatibility are needed for applications in vascular replacement therapies, such as vascular grafts, heart valves and stents, and in extracorporeal devices such as hemodialysis machines and blood-storage bags. The modification of materials that are being used for blood-contacting devices has advanced from passive surface modifications to the design of more complex, smart biomaterials that respond to relevant stimuli from blood to counteract coagulation. Logically, the main source of inspiration for the design of new biomaterials has been the endogenous endothelium. Endothelial regulation of hemostasis is complex and involves a delicate interplay of structural components and feedback mechanisms. Thus, challenges to develop new strategies for blood-compatible biomaterials now lie in incorporating true feedback controlled mechanisms that can regulate blood compatibility in a dynamic way. Here, supramolecular material systems are highlighted as they provide a promising platform to introduce dynamic reciprocity, due to their inherent dynamic nature. PMID- 28841772 TI - PROP Nontaster Women Lose More Weight Following a Low-Carbohydrate Versus a Low Fat Diet in a Randomized Controlled Trial. AB - OBJECTIVE: Taste blindness to 6-n-propylthiouracil (PROP) associates with increased fat preference and intake. No studies have matched a diet to a woman's PROP phenotype to improve weight loss. This study investigated (1) whether PROP nontaster (NT) women would lose more weight following a low-carbohydrate (LC) diet than a low-fat (LF) diet, and (2) whether PROP supertaster (ST) women would lose more weight following a LF diet than a LC diet. METHODS: One hundred seven women (BMI = 34.8 +/- 0.5 kg/m2 ), classified as PROP NTs (n = 47) and STs (n = 60), were randomized to a LC or LF diet within a 6-month lifestyle intervention. Assessments included 4-day dietary recalls and biobehavioral and psychosocial questionnaires. RESULTS: At 6 months, NTs lost more weight following the LC than the LF diet (-8.5 +/- 0.5 kg vs. -6.6 +/- 0.5 kg, P = 0.008); there was no difference between STs following either diet (-8.8 +/- 0.4 vs. -8.9 +/- 0.5, P = 0.35). Dietary self-reports were unrelated to weight loss, and prescription of a LC diet associated with greater self-efficacy. CONCLUSIONS: NT women lost more weight following the LC diet compared to the LF diet. Screening for PROP phenotype may help personalize diet therapy for NT women to optimize their short term weight loss. PMID- 28841773 TI - Adverse effects of subcutaneous, drug-releasing implants for the treatment of opioid drug addiction. PMID- 28841774 TI - Light-Induced Contraction/Expansion of 1D Photoswitchable Metallopolymer Monitored at the Solid-Liquid Interface. AB - The use of a bottom-up approach to the fabrication of nanopatterned functional surfaces, which are capable to respond to external stimuli, is of great current interest. Herein, the preparation of light-responsive, linear supramolecular metallopolymers constituted by the ideally infinite repetition of a ditopic ligand bearing an azoaryl moiety and Co(II) coordination nodes is described. The supramolecular polymerization process is followed by optical spectroscopy in dimethylformamide solution. Noteworthy, a submolecularly resolved scanning tunneling microscopy (STM) study of the in situ reversible trans-to-cis photoisomerization of a photoswitchable metallopolymer that self-assembles into 2D crystalline patterns onto a highly oriented pyrolytic graphite surface is achieved for the first time. The STM analysis of the nanopatterned surfaces is corroborated by modeling the physisorbed species onto a graphene slab before and after irradiation by means of density functional theory calculation. Significantly, switching of the monolayers consisting of supramolecular Co(II) metallopolymer bearing trans-azoaryl units to a novel pattern based on cis isomers can be triggered by UV light and reversed back to the trans conformer by using visible light, thereby restoring the trans-based supramolecular 2D packing. These findings represent a step forward toward the design and preparation of photoresponsive "smart" surfaces organized with an atomic precision. PMID- 28841775 TI - Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling. AB - A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. PMID- 28841777 TI - Free-Blockage Mesoporous Anticancer Nanoparticles Based on ROS-Responsive Wetting Behavior of Nanopores. AB - To achieve an excellent delivery effect of drug, stimuli-responsive nano "gate" with physical blockage units is usually constructed on the surface of the mesoporous silica nanocarriers (MSNs). In nature, the aquaporins in cell membrane can control the transport of water molecules by regulating the channel wettability, which is resulted from the conformational change of amino acids in the channel. Inspired by this phonomenon, herein a new concept of free-blockage controlled release system is proposed, which is achieved by controlling the wettability of the internal surface of nanopores on MSNs. Such a new system is different from the physical-blockage controlled release system, which bypasses the use of nano "gate" and overcomes the limitations of traditional physical blockage system. Moreover, further studies have shown that the system can selectively release the entrapped doxorubicin in human breast adenocarcinoma (MCF 7) cells triggered by intracellular reactive oxygen species (ROS) but not in normalhuman umbilical vein endothelial cells (HUVECs) containing ROS with low levels. The wettability-determined free-blockage controlled release system is simple and effective, and it can also be triggered by intracellular biological stimuli, which provides a new approach for the future practical application of drug delivery and cancer therapy. PMID- 28841776 TI - Cholera Toxin Subunit B Enabled Multifunctional Glioma-Targeted Drug Delivery. AB - Glioma is among the most formidable brain cancers due to location in the brain. Cholera toxin subunit B (CTB) is investigated to facilitate multifunctional glioma-targeted drug delivery by targeting the glycosphingolipid GM1 expressed in the blood-brain barrier (BBB), neovasulature, and glioma cells. When modified on the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CTB-NPs), CTB fully retains its bioactivity after 24 h incubation in the fresh mouse plasma. The formed protein corona (PC) of CTB-NP and plain PLGA nanoparticles (NP) after incubation in plasma is analyzed using liquid chromatography tandem massspectrometry (nano-LC-MS/MS). CTB modification does not alter the protein components of the formed PC, macrophage phagocytosis, or pharmacokinetic profiles. CTB-NP can efficiently penetrate the in vitro BBB model and target glioma cells and human umbilical vascular endothelial cells. Paclitaxel is loaded in NP (NP/PTX) and CTB-NP (CTB-NP/PTX), and their antiglioma effects are assessed in nude mice bearing intracranial glioma. CTB-NP/PTX can efficiently induce apoptosis of intracranial glioma cells and ablate neovasulature in vivo, resulting in significant prolongation of survival of nude mice bearing intracranial glioma (34 d) in comparison to those treated with NP/PTX (29 d), Taxol (24 d), and saline (21 d). The present study suggests a potential multifunctional glioma-targeted drug delivery system enabled by cholera toxin subunit B. PMID- 28841778 TI - Dermatopathology 101. Part 2 - Skin tumors. AB - The present CME article highlights fundamental aspects with respect to the histopathology of the most common skin tumors (epidermal, adnexal, melanocytic, and mesenchymal), their laboratory workup, as well as the importance of supplementary immunohistochemical and molecular studies. The information provided is meant to assist experienced clinicians in choosing the correct biopsy technique and in interpreting dermatopathology reports, and to provide dermatology residents with a better understanding of dermatopathology. Similar to inflammatory dermatoses, the diagnosis of skin tumors, too, requires the close cooperation between clinicians and dermatopathologists. The diagnostic quality and the resultant therapeutic approach can be significantly improved if this collaboration is based on the same dermatological understanding. PMID- 28841779 TI - Review: Metabolic Control of Immune System Activation in Rheumatic Diseases. AB - Metabolic pathways mediate lineage specification within the immune system through the regulation of glucose utilization, a process that generates energy in the form of ATP and synthesis of amino acids, nucleotides, and lipids to enable cell growth, proliferation, and survival. CD4+ T cells, a proinflammatory cell subset, preferentially produce ATP through glycolysis, whereas cells with an antiinflammatory lineage, such as memory and regulatory T cells, favor mitochondrial ATP generation. In conditions of metabolic stress or a shortage of nutrients, cells rely on autophagy to secure amino acids and other substrates, while survival depends on the sparing of mitochondria and maintenance of a reducing environment. The pentose phosphate pathway acts as a key gatekeeper of inflammation by supplying ribose-5-phosphate for cell proliferation and NADPH for antioxidant defenses. Increased lysosomal catabolism, accumulation of branched amino acids, glutamine, kynurenine, and histidine, and depletion of glutathione and cysteine activate the mechanistic target of rapamycin (mTOR), an arbiter of lineage development within the innate and adaptive immune systems. Mapping the impact of susceptibility genes to metabolic pathways allows for better understanding and therapeutic targeting of disease-specific expansion of proinflammatory cells. Therapeutic approaches aimed at glutathione depletion and mTOR pathway activation appear to be safe and effective for treating lupus, while an opposing intervention may be of benefit in rheumatoid arthritis. Environmental sources of origin for metabolites within immune cells may include microbiota and plants. Thus, a better understanding of the pathways of immunometabolism could provide new insights into the pathogenesis and treatment of the rheumatic diseases. PMID- 28841780 TI - Evaluating the mutual pathways among electronic cigarette use, conventional smoking and nicotine dependence. AB - BACKGROUND AND AIMS: The implications of the rapid rise in electronic cigarette (e-cigarette) use remain unknown. We examined mutual associations between e cigarette use, conventional cigarette use and nicotine dependence over time to (1) test the association between e-cigarette use and later conventional smoking (both direct and via nicotine dependence), (2) test the converse associations and (3) determine the strongest pathways predicting each product's use. DESIGN: Data from four annual waves of a prospective cohort study were analyzed. Path analysis modeled the bidirectional, longitudinal relationships between past-month smoking frequency, past-month e-cigarette frequency and nicotine dependence. SETTING: Chicago area, Illinois, USA. PARTICIPANTS: A total of 1007 young adult smokers and non-smokers (ages 19-23 years). MEASUREMENTS: Frequency of (1) cigarettes and (2) e-cigarettes was the number of days in the past 30 on which the product was used. The Nicotine Dependence Syndrome Scale measured nicotine dependence to cigarettes. FINDINGS: E-cigarette use was not associated significantly with later conventional smoking, either directly (beta = 0.021, P = 0.081) or through nicotine dependence (beta = 0.005, P = 0.693). Conventional smoking was associated positively with later e-cigarette use, both directly (beta = 0.118, P < 0.001) and through nicotine dependence (beta = 0.139, P < 0.001). The strongest predictors of each product's use was prior use of the same product; this pathway was strong for conventional cigarettes (beta = 0.604, P < 0.001) but weak for e cigarettes (beta = 0.120, P < 0.001). Nicotine dependence moderately strongly predicted later conventional smoking (beta = 0.169, P < 0.001), but was a weak predictor of later e-cigarette use (beta = 0.069, P = 0.039). CONCLUSIONS: Nicotine dependence is not a significant mechanism for e-cigarettes' purported effect on heavier future conventional smoking among young adults. Nicotine dependence may be a mechanism for increases in e-cigarette use among heavier conventional smokers, consistent with e-cigarettes as a smoking reduction tool. Overall, conventional smoking and, to a lesser extent, its resulting nicotine dependence, are the strongest drivers or signals of later cigarette and e cigarette use. PMID- 28841781 TI - Non-medical use of psychoactive prescription drugs is associated with fatal poisoning. AB - AIMS: The aims of this study were to estimate the prevalence and predictors of non-medical substance use, and to assess the association between non-medical substance use and fatal poisoning or history of drug abuse in Finland. DESIGN AND SETTING: Retrospective cohort study of all medico-legally investigated death cases in Finland. The postmortem toxicology database was linked together with the register on reimbursed prescription medicines. PARTICIPANTS AND CASES: All postmortem cases between 2011 and 2013 positive for one or more of the following drugs: oxycodone, fentanyl, tramadol, clonazepam, gabapentin, pregabalin, tizanidine, olanzapine, quetiapine, risperidone, alprazolam, zolpidem, mirtazapine and bupropion, n = 2974. MEASUREMENTS: Non-medical use of substance was the outcome variable. Predictors were the following: gender, residence at the time of death, place of death, blood alcohol concentration, age, drug abuse, number of prescriptions of any psychoactive drugs in last year and proportion of prescriptions issued by psychiatrist in last year. FINDINGS: In 50.4% of the studied cases, at least one drug was detected without a prescription. Clonazepam, alprazolam and tramadol were the most prevalent non-medical findings in these cases (6.6, 6.1 and 5.6%, respectively). The risk of non-medical use of prescription drugs was especially high in cases with history of drug abuse (88.5%) and in fatal poisonings (71.0%). The proportion of non-medical use of the studied substances varied between 5.9% [95% confidence interval (CI) = 3.1 10.1%)] for risperidone and 55.7% for fentanyl (95% CI = 44.1-66.9%). Valid prescription for one or more of any psychoactive drug was associated with lower odds for non-medical use of the studied substances. Additionally, the higher the proportion of psychoactive drugs prescribed by a psychiatrist, the lower the probability of non-medical use. CONCLUSIONS: Non-prescribed psychoactive drugs are found commonly at postmortem in drug poisoning deaths in Finland, with history of drug abuse being a major contributing factor. PMID- 28841782 TI - Risk of malignancies in autoimmune hepatitis type 1 patients with a long-term follow-up in Japan. AB - AIM: The risk of malignancies in autoimmune diseases is high and is regarded to be due to immunological abnormalities, the use of immunosuppressive agents, and/or chronic inflammation. The aim of this study was to investigate the incidence and risk of malignancies in patients with autoimmune hepatitis (AIH) type 1 in Japan. METHODS: Two hundred and fifty-six patients diagnosed with AIH were enrolled. A person-year calculation was carried out for AIH patients, and the numbers of expected events were clarified using data from "The Monitoring of Cancer Incidence in Japan Project" in order to examine the standard incident rate (SIR) of each type of malignancy. Biochemical data regarding carcinogenesis and its background factors were also examined. RESULTS: Twenty-seven patients (10.5%) developed malignancies; 11 (4.3%) with hepatobiliary cancer and 16 (6.3%) with extrahepatic malignancies. The overall SIR for malignancies in AIH was significantly high at 2.04 (95% confidence interval [CI], 1.34-2.96), and was high among female patients at 2.49 (95% CI, 1.60-3.71). The SIR for hepatobiliary cancer was 14.14 (95% CI, 7.05-25.30), and was markedly high for female patients at 21.83 (95% CI, 10.45-40.16). The SIR for oral/pharyngeal cancer was significantly high for female patients at 14.61 (95% CI, 1.64-52.77). The risk factors for hepatobiliary cancer at the diagnosis of AIH were low levels of alanine aminotransferase (P = 0.0226), low platelet counts (P < 0.0001), and cirrhosis (P = 0.0004). The risk factor for extrahepatic malignancy was relapse of AIH (P = 0.0485). CONCLUSION: The risk of malignancies was generally high among AIH patients. Those with the risk factors of malignancies should be carefully followed up. PMID- 28841783 TI - Zinc oxide nanoparticle toxicity in embryonic zebrafish: Mitigation with different natural organic matter. AB - Exposure experiments were conducted to evaluate the influence of dissolved organic matter (DOM) on the toxicity of ZnO-NPs (10-30 nm) and dissolved Zn at sub-lethal doses (50 and 5 ppm, respectively) to zebrafish (Danio rerio). Humic acid, alginic acid, bovine serum albumin and various natural DOM isolated from rivers as the Milwaukee River-WI (NOMW), Yukon River-AK (NOMA) and Suwannee River GA DOM (NOMS) were used to represent humic substances (HA), carbohydrates (CHO), proteins (PTN), and natural organic matter (NOM), respectively. Initial experiments were carried out to confirm the toxic effect of ZnO-NPs at 50 ppm, followed by mitigation experiments with different types and concentrations of DOM (0.4-40 mg-C/L). Compared to 0% hatch of 50 ppm ZnO-NPs exposed embryos at 72 h post fertilization (hpf), NOMS, NOMW and HA had the best mitigative effects on hatching (53-65%), followed by NOMA, CHO and PTN (19-35%); demonstrating that the mitigation effects on ZnO-NPs toxicity were related to DOM's quantity and composition. At 96 hpf, 20% of embryos exposed to 50 ppm ZnO-NPs hatched, 100% of embryos reared in embryo medium hatched, and close to 100% of the embryos hatched upon mitigation, except for those mitigated with PTN which had less effect. Dissolved Zn (5 ppm) also exhibited the same toxicity on embryos as ZnO-NPs (50 ppm). However, in the presence of HA, NOM and CHO, the hatching rates at 72 and 96 hpf increased significantly compared to 5% hatch without DOM. The overall mitigation effects produced by DOM followed the order of HA >= NOMS > NOM (A&W) > CHO >> PTN, although specific mitigation effects varied with DOM concentration and functionalities. Our results also indicate that the toxicity of ZnO-NPs to embryos was mostly derived from NPs although dissolved Zn released from ZnO-NPs also interacted with embryos, affecting hatching, but to a less extent. PMID- 28841784 TI - Regulation of microRNA using promising dietary phytochemicals: Possible preventive and treatment option of malignant mesothelioma. AB - Malignant mesothelioma (MM) is a very aggressive, lethal cancer, and its incidence is increasing worldwide. Development of multi-drug resistance, therapy related side-effects, and disease recurrence after therapy are the major problems for the successful treatment of MM. Emerging evidence indicates that dietary phytochemicals can exert anti-cancer activities by regulating microRNA expression. Until now, only one dietary phytochemical (ursolic acid) has been reported to have MM microRNA regulatory ability. A large number of dietary phytochemicals still remain to be tested. In this paper, we have introduced some dietary phytochemicals (curcumin, epigallocatechin gallate, quercetin, genistein, pterostilbene, resveratrol, capsaicin, ellagic acid, benzyl isothiocyanate, phenethyl isothiocyanate, sulforaphane, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid) which have shown microRNA regulatory activities in various cancers and could regulate MM microRNAs. In addition to microRNA regulatory activities, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, phenethyl isothiocyanate, and sulforaphane have anti-mesothelioma potentials, and pterostilbene, capsaicin, ellagic acid, benzyl isothiocyanate, indole-3-carbinol, 3,3'-diindolylmethane, diallyl disulphide, betulinic acid, and oleanolic acid have potentials to inhibit cancer by regulating the expression of various genes which are also known to be aberrant in MM. PMID- 28841785 TI - Biodiesel synthesis using chicken manure biochar and waste cooking oil. AB - This study laid an emphasis on the possible employment of biochar generated from pyrolysis of chicken manure to establish a green platform for producing biodiesel. To this end, the pseudo-catalytic transesterification reaction using chicken manure biochar and waste cooking oil was investigated. Compared with a commercial porous material (SiO2), chicken manure biochar generated from 350 degrees C showed better performance, resulting in 95.6% of the FAME yield at 350 degrees C. The Ca species in chicken manure biochar imparted strong catalytic capability by providing the basicity for transesterification. The identified catalytic effect also led to the thermal cracking of unsaturated FAMEs, which decreased the overall FAME yield. For example, 40-60% of converted FAMEs were thermally degraded. To avoid undesirable thermal cracking arising from the high content of the Ca species in chicken manure biochar, the fabrication of chicken manure biochar at temperatures >=350 degrees C was highly recommended. PMID- 28841786 TI - Dry anaerobic digestion of chicken manure coupled with membrane separation of ammonia. AB - In this study, the anaerobic digestion of egg-laying hen manure combined with membrane-based ammonia separation was investigated. Long-term continuous experiments with and without ammonia separation were performed by increasing the organic loading rate (OLR). Although the control digester was completely inhibited at an OLR and influent total Kjeldahl nitrogen (TKN) concentration of 3.85kgVS/m3.d and 8.2g/l, respectively, an average methane yield of 0.30+/ 0.02m3/kgVS was achieved with a membrane-integrated digester at an OLR and influent TKN concentration of 6.0kgVS/m3.d and 15g/l, respectively. When the ammonia concentration increased above 4000mg/l, hydrogenotrophic methanogens Methanoculleus bourgensis and Methanobrevibacter sp. performed methane production via syntrophic acetate oxidation. PMID- 28841787 TI - Depth-resolved microbial community analyses in the anaerobic co-digester of dewatered sewage sludge with food waste. AB - This study evaluated the impacts of FW addition on co-digestion in terms of microbial community. Anaerobic co-digestion (AcoD) reactors were conducted at gradually increased addition of food waste (FW) from 0 to 4kg-VSm-3d-1 for 220days. Although no markable acidification was found at an OLR of 4kg-VSm-3d-1, the unhealthy operation was observed in aspect of an inhibited methane yield (185mLg-1VSadded), which was restricted by 40% when compared with its peak value. Deterioration of digestion process was timely indicated by the dramatic decrease of archaeal population and microbial biodiversity. Furthermore, the cooperation network showed a considerable number of rare species (<1%) were strongly correlated with methane production, which were frequently overlooked due to the limits of detecting resolution or analysis methods before. Advances in the analysis of sensitive microbial community enable us to detect the early disturbances in AcoD reactors. PMID- 28841788 TI - Influence of thermal hydrolysis pretreatment on organic transformation characteristics of high solid anaerobic digestion. AB - The study evaluated the influence of thermal hydrolysis pretreatment (THP) on anaerobic digestion (AD) ability of high solid sludge. The transformation characteristics of organics during the THP+AD process of dewatering sludge from wastewater treatment plant was investigated using a lab-scale THP reactor and four anaerobic digesters. The reduction efficiency of volatile suspended solids using THP+AD exceeded 49%. The acceleration of biogas production during AD was due to the enhancement of protein hydrolysis and acidogenesis by THP. THP had only minimal influence on the improvement of carbohydrate acidogenesis. The hydrolysis of poly phosphates was likely the main reaction of phosphorus transformation. Biochemical generation of sulfide and ammonia nitrogen occurred during the acidogenesis. PMID- 28841789 TI - Polyethyleneimine-bacterial cellulose bioadsorbent for effective removal of copper and lead ions from aqueous solution. AB - Bacterial cellulose (BC) is a green biopolymer suitable for heavy metal ion removal from aqueous solution due to its nano-porous microstructure. Polyethyleneimine-bacterial cellulose (PEI-BC) was prepared by reductive amination of dialdehyde BC with polyethyleneimine. The capacity of PEI-BC in Cu(II) and Pb(II) adsorption from aqueous solution was investigated. The adsorption kinetics could be well expressed by pseudo-second-order model and the adsorption isotherm data were well fitted with Freundlich model. Adsorption processes of Cu(II) and Pb(II) by PEI-BC reached equilibrium very rapid in 30 and 60min, respectively. The maximum adsorption capacity of PEI-BC on Cu(II) and Pb(II) was found to be 148 and 141mg/g, respectively, which was higher than that of unmodified BC and other modified BC reported. PEI-BC also showed good reusability in the adsorption of Cu(II) and Pb(II). This study demonstrates that polyethyleneimine modification makes BC a potential bioadsorbent for heavy metal ion removal in waste water. PMID- 28841790 TI - Seasonal variation and ex-situ nitrification activity of ammonia oxidizing archaea in biofilm based wastewater treatment processes. AB - The abundance of ammonia oxidizing archaea (AOA) and ammonia oxidizing bacteria (AOB) was investigated in full-scale two-stage trickling filters (TF) and moving bed bioreactor (MBBR) treating municipal wastewater. Biofilm samples were collected for 17months from nitrifying TF (NTF), biochemical oxygen demand TF (BTF), and MBBR media. The abundance of AOA and AOB was determined using a quantitative PCR approach targeting the ammonia monooxygenase subunit A gene of archaea and bacteria. AOA were dominant in the NTF and MBBR, while AOB dominated in the BTF. AOA and AOB were more abundant during warmer months, and AOA were detected in the BTF only during warmer months. In laboratory nitrification activity experiments, ammonia oxidation to nitrite decreased when AOA populations from the NTF and MBBR were inhibited, demonstrating that AOA contributed to nitrification. This study has shown that AOA outnumber AOB and contribute to ammonia oxidation in full-scale nitrifying biofilm processes. PMID- 28841791 TI - Fatty acids from high rate algal pond's microalgal biomass and osmotic stress effects. AB - The extraction of oil from a wild microalgae biomass collected from a domestic wastewater treatment facility's high rate algal pond (HRAP) was investigated. An experiment plan was used to determine the most efficient extraction method, the optimal temperature, time and solvent system based on total lipids yield. Microwave-assisted extraction was the most efficient method whether in n-hexane or in a mixture of chloroform/methanol compared to Soxhlet, homogenization, and ultrasounds assisted extractions. This same wild biomass was cultivated in a photobioreactor (PBR) and the effect of osmotic stress was studied. The lipids extraction yield after 3days of stress increased by more than four folds without any significant loss of biomass, however, the quality of extracted total lipids in terms of saturated, monounsaturated and polyunsaturated fatty acids was not affected by salinity change in the culture medium. PMID- 28841792 TI - [Importance of the forensic autopsy in the diagnosis of septic shock: a case report]. AB - Septic shock sometimes starts with unspecific symptoms that hamper the clinical diagnosis and, therefore an appropriate treatment. When the septic shock follows a fulminating course with a fatal outcome, the etiological diagnosis has to be conducted post-mortem. Sudden unexpected deaths in children and young adults are frequently the object of medico-legal autopsies. Some sudden unexpected deaths have an infectious origin, which requires further analyses, including microbiology, to establish the cause of death. Here, the case of a fatal septic shock in a 19-month old male infant is presented. After a mild foot injury, an infection by Streptococcus pyogenes progressed to septic shock with a fatal outcome as post-mortem studies demonstrated. PMID- 28841793 TI - Highly Efficient and Robust Oil/Water Separation Materials Based on Wire Mesh Coated by Reduced Graphene Oxide. AB - We develop a simple approach for the preparation of oil/water separation material based on the reduced graphene oxide. First, the graphene oxide (GO) is coated on the commercially available wire mesh. The treatment of O2 plasma is exploited to open the pores from the back side using the wire mesh as a ready-made mask, and the GO-coated mesh is subjected to the thermal annealing at 200 degrees C for 2 h to form stable superhydrophobic reduced graphene oxide (RGO) coating. The as prepared mesh has excellent stability and reusability and the separation selectivity is above 98% for a variety of mixtures of oil and water. Meanwhile, the as-prepared RGO@mesh-300 shows stable and robust superhydrophobic properties including the stability of long-term storage, the resistance to high temperatures, high humidities, and mechanical abrasion. It is expected that this method of fabricating superhydrophobic materials can find more practical applications, especially in the oil/water separation. PMID- 28841794 TI - Enzymatic Cross-Linking of Side Chains Generates a Modified Peptide with Four Hairpin-like Bicyclic Repeats. AB - Macrocyclization of peptides is often employed to generate novel structures and biological activities in the biosynthesis of natural products and drug discovery. The enzymatic cross-linking of two side chains in a peptide via an ester or amide has a high potential for making topologically diverse cyclic peptides but is found with only a single consensus sequence in the microviridin class of natural products. Here, we report that a peptide with a new sequence pattern can be enzymatically cross-linked to make a novel microviridin-like peptide, plesiocin, which contains four repeats of a distinct hairpin-like bicyclic structure and shows strong inhibition of proteases. A single ATP-grasp enzyme binds to a leader peptide, of which only 13 residues are required for binding, and performs eight esterification reactions on the core peptide. We also demonstrate that the combination of tandem mass spectrometry and an ester-specific reaction greatly facilitates the determination of connectivity. We suggest that the enzymatic cross-linking of peptide side chains can generate more diverse structures in nature or by engineering. PMID- 28841795 TI - Drug Loading and Release Behavior Depending on the Induced Porosity of Chitosan/Cellulose Multilayer Nanofilms. AB - The ability to control drug loading and release is the most important feature in the development of medical devices. In this research, we prepared a functional nanocoating technology to incorporate a drug-release layer onto a desired substrate. The multilayer films were prepared using chitosan (CHI) and carboxymethyl cellulose (CMC) polysaccharides by the layer-by-layer (LbL) method. By using chemical cross-linking to change the inner structure of the assembled multilayer, we could control the extent of drug loading and release. The cross linked multilayer film had a porous structure and enhanced water wettability. Interestingly, more of the small-molecule drug was loaded into and released from the non-cross-linked multilayer film, whereas more of the macromolecular drug was loaded into and released from the cross-linked multilayer film. These results indicate that drug loading and release can be easily controlled according to the molecular weight of the desired drug by changing the structure of the film. PMID- 28841796 TI - Preface. PMID- 28841797 TI - An update on radiation therapy for brain metastases. AB - Radiation therapy (RT) is an important treatment modality for brain metastases. Recent clinical trials have established the role of stereotactic radiosurgery (SRS) in the improvement of local control of brain metastases. Prospective trial data confirmed the feasibility and efficacy of using SRS alone to treat 5 or more brain metastatic tumors. Besides tumor control, there is increased emphasis on quality of life and neurocognitive function preservation. The new approach of hippocampi-sparing whole brain RT has been tested in an attempt to minimize the neurocognitive toxicity of whole brain RT. There is now level 1 evidence to support the multidisciplinary approach of surgical resection of brain metastases followed by cavity SRS which has been shown to preserve neurocognitive function without compromising survival. The current review summarizes the recent advances in RT for brain metastases. PMID- 28841798 TI - Re-irradiation for recurrent glioblastoma multiforme. AB - As our understanding of normal brain tissue tolerance and radiation technology have improved, central nervous system (CNS) re-irradiation has garnered more attention; whereas, in the past there had been hesitancy due to late toxicity concerns, particularly radionecrosis (RN). There is minimal prospective data evaluating repeat radiation in recurrent gliomas. In this review, the rationale for and different approaches to re-irradiation will be discussed, and the biology and clinical impact of late CNS toxicity will be reviewed. PMID- 28841799 TI - Updated response assessment criteria for high-grade glioma: beyond the MacDonald criteria. AB - High-grade glioma continues to be a challenging disease with few effective treatment options and a poor prognosis, necessitating intensive research into alternate therapies. The Response Assessment in Neuro-Oncology (RANO) committee was formed to create a robust endpoint assessment criteria in Neuro-Oncology in order to streamline the assessment of new therapies in a uniform fashion. The aim of this committee is to create standardized guidelines to assess clinical and imaging response in the treatment of brain tumors, which can then be applied in clinical trials. Since the first RANO report was published in 2010, its criteria have been widely adopted and utilized in clinical trials worldwide. Standardized application of the RANO response assessment criteria in clinical trials will result in the generation of strong clinical data, which can subsequently be pooled and analyzed to attain a more accurate assessment of treatment efficacy. In this review, we summarize the current RANO guidelines in patients with high grade glioma, highlighting the key clinical and imaging criteria used for RANO evaluation and introducing the role of newer imaging and biomarkers. PMID- 28841800 TI - Current management of primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) is a rare but treatable disease. The hallmark therapy is based on the use of high-dose intravenous methotrexate (HDMTX), with clinical trial data suggesting that a more aggressive and targeted chemoimmunotherapeutic approach, to include the use of targeted therapy with rituximab (RTX) and the addition of other chemotherapeutic agents, may improve prognosis and reduce or defer the need for radiation therapy. Understanding of the molecular basis of tumor growth and proliferation may allow for the use of new targeted agents. PMID- 28841801 TI - Glioblastoma in the elderly: initial management. AB - Glioblastoma is the most common primary CNS malignancy and it is becoming more frequently diagnosed in the elderly population. Glioblastoma is associated with a dismal prognosis and remains a huge challenge for the neuro-oncology community. Surgical resection/biopsy is well defined as an important first approach in the care of this disease, for tumor diagnosis, molecular analysis and maximum resection. MGMT promoter methylation status has proved to be a useful indicator of whether single modality (RT or TMZ alone) or combined modality treatment may achieve better outcomes. Post-operative treatment options include: (I) hypofractionated radiotherapy (HRT) with concurrent and adjuvant temozolomide (TMZ) or (II) HRT alone (MGMT unmethylated patients); (III) TMZ alone (MGMT methylated patients) when combined modality is not feasible due to patient poor performance status or multiple comorbidities. Following the positive survival outcomes of the CCTG CE.6/EORTC 26062-22061 phase III trial which randomized newly diagnosed glioblastoma patients aged 65 or older to HRT (40 Gy/15 fractions) with concurrent and adjuvant temozolomide to HRT alone, combined modality therapy (CMT) with HRT with concurrent temozolomide as the initial post surgical approach should be considered in patients well enough to have treatment. In meantime, future trials addressing new approaches are needed to improve outcomes in this fatal disease. PMID- 28841802 TI - Advanced magnetic resonance imaging in glioblastoma: a review. AB - Glioblastoma, the most common and most rapidly progressing primary malignant tumor of the central nervous system, continues to portend a dismal prognosis, despite improvements in diagnostic and therapeutic strategies over the last 20 years. The standard of care radiographic characterization of glioblastoma is magnetic resonance imaging (MRI), which is a widely utilized examination in the diagnosis and post-treatment management of patients with glioblastoma. Basic MRI modalities available from any clinical scanner, including native T1-weighted (T1w) and contrast-enhanced (T1CE), T2-weighted (T2w), and T2-fluid-attenuated inversion recovery (T2-FLAIR) sequences, provide critical clinical information about various processes in the tumor environment. In the last decade, advanced MRI modalities are increasingly utilized to further characterize glioblastomas more comprehensively. These include multi-parametric MRI sequences, such as dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE), higher order diffusion techniques such as diffusion tensor imaging (DTI), and MR spectroscopy (MRS). Significant efforts are ongoing to implement these advanced imaging modalities into improved clinical workflows and personalized therapy approaches. Functional MRI (fMRI) and tractography are increasingly being used to identify eloquent cortices and important tracts to minimize postsurgical neuro deficits. A contemporary review of the application of standard and advanced MRI in clinical neuro-oncologic practice is presented here. PMID- 28841803 TI - Tumor treating fields: a novel and effective therapy for glioblastoma: mechanism, efficacy, safety and future perspectives. AB - BACKGROUND: Tumor treating fields (TTF, Optune(r)), one of the low-intensity alternating electric fields, have been demonstrated to disrupt mitosis and inhibit tumor growth with antimitotic properties in a variety of tumor types. The Food and Drug Administration (FDA) of the United States approved TTF for recurrent GBM and newly diagnosed GBM in 2011 and 2015, respectively. METHODS: A systematic review was conducted regarding the relevant studies published between January 1, 2000, and May 31, 2017 in PubMed database. The search term included "Tumor Treating Fields", "Optune", "TTF", "Novocure", and "GBM". This review summarizes the mechanism of action, efficacy, and adverse events based on pre clinical studies and clinical trials for TTF in GBM. RESULTS: Pre-clinical studies showed that TTF could inhibit tumor growth in vitro and in vivo by disrupting mitosis, inducing cell cycle arrest and apoptosis. Two randomized phase III trials evaluated the efficacy and safety of TTF in GBM patients. It was revealed that the combination of TTF and standard chemotherapy (temozolomide) prolonged the progression-free survival (PFS) and overall survival (OS) without systemic safety issues in newly diagnosed GBM (EF-14 trial). For recurrent GBM, the efficacy of TTF monotherapy was shown to be equivalent in PFS and OS without systemic adverse events when compared to the control group that received best physicians-chosen chemotherapies (EF-11 trial). CONCLUSIONS: The advantages of TTF in GBM treatment, including non-invasive antitumor effect, superior therapeutic benefit in combination with chemotherapy, and minimal systematic toxicity, have been demonstrated in pre-clinical data and randomized phased III clinical trials. Future investigations will be needed to explore combinations of chemotherapy, radiation therapy, targeted therapy, as well as immunotherapy with this novel anti-tumor treatment modality to achieve additive or synergistic therapeutic benefit for GBM and other solid tumors. PMID- 28841804 TI - Advances in surgical approaches in glioblastoma (GBM). PMID- 28841805 TI - Low grade glioma: a journey towards a cure. PMID- 28841806 TI - Endothelin B receptor promotes the proliferation and immune escape of malignant gliomas. AB - PURPOSE: As a kind of difficult to cure tumour, malignant gliomas have attracted widespread attention. The proliferation and immune escape of tumour cells were closely related to the development of malignant gliomas. The aim of this study was to investigate the role of endothelin B receptor (NTBR) in gliomas. METHODS: RT-PCR was used to detect the expression of NTBR mRNA in glioma tissue and glioma cell lines. The expression of NTBR in glioma tissues was detected by immunohistochemistry. MTT assay was used to detect the viability of U87 cells after adding NTBR. Cell cloning assay was used to detect the cell proliferation ability. Western blot was used to detect the expression of TGF-beta and the expression of Treg after adding NTBR to U87. RESULT: The expression of NTBR in glioma tissues and cells was significantly higher than that in the control group by RT-PCR. After adding NTBR, cell proliferation of U87 was significantly enhanced and TGF-beta and Treg were significantly expressed. It was suggested that NTBR could contribute to tumour immune escape in glioma, and it was found that there was a positive correlation between NTBR expression and different stages in malignant gliomas. CONCLUSION: Endothelin B receptor can increase the proliferation of glioma cells and tumour immune escape. The expression of endothelin B is closely related to the clinical stage of glioma. PMID- 28841807 TI - Development of a novel nano-sized anti-VEGFA nanobody with enhanced physicochemical and pharmacokinetic properties. AB - Since physiological and pathological processes occur at nano-environments, nanotechnology has considered as an efficient tool for designing of next generation specific biomolecules with enhanced pharmacodynamic and pharmacodynamic properties. In the current investigation, by control of the size and hydrodynamic volume at the nanoscale, for the first time, physicochemical and pharmacokinetic properties of an anti-VEGFA nanobody was remarkably improved by attachment of a Proline-Alanine-Serine (PAS) rich sequence. The results elucidated unexpected impressive effects of PAS sequence on physicochemical properties especially on size, hydrodynamics radius, and even solubility of nanobody. CD analysis revealed an increment in random coil structure of the PASylated protein in comparison to native one without any change in charge state or binding kinetic parameters of nanobody assessed by isoelectric focusing and surface plasmon resonance measurements, respectively. In vitro biological activities of nanobody were not affected by coupling of the PAS sequence. In contrast, the terminal half-life was significantly increased by a factor of 14 for the nanobody-PAS after single dose IV injection to the mice. Our study demonstrated that the control of size in the design of small therapeutic proteins has a promising effect on the stability and solubility, in addition to their physiochemical and pharmacokinetic properties. The designed new anti-VEGFA nanobody could promise a better therapeutic agent with a long administration intervals and lower dose, which in turn leads to a better patient compliance. Size adjustment of an anti-VEGF nanobody at the nanoscale by the attachment of a natural PAS polymer remarkably improves physicochemical properties, as well as a pharmacokinetic profile without any change in biological activity of the miniaturized antibody. PMID- 28841808 TI - Don't forget the hidden curriculum. PMID- 28841809 TI - Twelve tips for teaching brief motivational interviewing to medical students. AB - BACKGROUND: Shifting from paternalistic to patient-centred doctor-patient relationships has seen a growing number of medical programs incorporate brief motivational interviewing training in their curriculum. Some medical educators, however, are unsure of precisely what, when, and how to incorporate such training. AIMS: This article provides educators with 12 tips for teaching brief motivational interviewing to medical students, premised on evidence-based pedagogy. METHODS: Tips were drawn from the literature and authors' own experiences. RESULTS: The 12 tips are: (1) Set clear learning objectives, (2) Select experienced educators, (3) Provide theoretical perspectives, (4) Share the evidence base, (5) Outline the "spirit", principles, and sequence, (6) Show students what it looks like, (7) Give students a scaffold to follow, (8) Provide opportunities for skill practice, (9) Involve clinical students in teaching, (10) Use varied formative and summative assessments, (11) Integrate and maintain, and (12) Reflect and evaluate. CONCLUSIONS: We describe what to include and why, and outline when and how to teach the essential components of brief motivational interviewing knowledge and skills in a medical curriculum. PMID- 28841810 TI - PROMsBase: Web-based repository portal for patient-reported outcome measures in orthopaedics. AB - Patient-reported outcome measures lead to better communication and decision making between clinicians and patients. Applying a web-based repository system for data collection was previously suggested, but such system is not available. This article introduces the development and implementation of a new web-based application, PROMsBase, in orthopaedics clinical practice. PROMsBase was developed using a web interface, allows access using both desktop and mobile devices. Between 2013 and 2016, a total of 3192 pre-surgery questionnaires were collected. In total, 238 patients completed their post-surgery questionnaire online from home. PROMsBase was well embedded into routine practice without disrupting clinical workflow and overloading clinicians' and researchers' workload. Tablets were not more useful and only 37 per cent of the patients completed the questionnaire online. PROMsBase provided a platform to easily collect and store data in clinical practice. If properly integrated, this could promote better care and communication between providers and patients. PMID- 28841811 TI - Assessing work disability for social security benefits: international models for the direct assessment of work capacity. AB - PURPOSE: It has been argued that social security disability assessments should directly assess claimants' work capacity, rather than relying on proxies such as on functioning. However, there is little academic discussion of how such assessments could be conducted. METHOD: The article presents an account of different models of direct disability assessments based on case studies of the Netherlands, Germany, Denmark, Norway, the United States of America, Canada, Australia, and New Zealand, utilising over 150 documents and 40 expert interviews. RESULTS: Three models of direct work disability assessments can be observed: (i) structured assessment, which measures the functional demands of jobs across the national economy and compares these to claimants' functional capacities; (ii) demonstrated assessment, which looks at claimants' actual experiences in the labour market and infers a lack of work capacity from the failure of a concerned rehabilitation attempt; and (iii) expert assessment, based on the judgement of skilled professionals. CONCLUSIONS: Direct disability assessment within social security is not just theoretically desirable, but can be implemented in practice. We have shown that there are three distinct ways that this can be done, each with different strengths and weaknesses. Further research is needed to clarify the costs, validity/legitimacy, and consequences of these different models. Implications for rehabilitation It has recently been argued that social security disability assessments should directly assess work capacity rather than simply assessing functioning - but we have no understanding about how this can be done in practice. Based on case studies of nine countries, we show that direct disability assessment can be implemented, and argue that there are three different ways of doing it. These are "demonstrated assessment" (using claimants' experiences in the labour market), "structured assessment" (matching functional requirements to workplace demands), and "expert assessment" (the judgement of skilled professionals). While it is possible to implement a direct assessment of work capacity for social security benefits, further research is necessary to understand how best to maximise validity, legitimacy, and cost effectiveness. PMID- 28841812 TI - Response to: E-lectures and online learning: Not a replacement for live teaching. PMID- 28841813 TI - "You need to do your research": Vaccines, contestable science, and maternal epistemology. AB - Individuals who refuse vaccines are often painted as anti-science or ill informed. However, drawing from interviews with 50 mothers who refused one or more vaccines ( n = 50), results from this study suggest that such depictions lack nuance and may detract from the ability of communication efforts to effectively address concerns. In particular, participants' explanations for vaccine refusal relied on paradoxical arguments about science and expertise. On one hand, participants defended the ideal of science but criticized existing research for failing to meet requisite standards. On the other hand, they suggested that maternal experience could supplant the ways of knowing that give rise to such claims. Collectively, these explanations reflected critical, postmodern, and feminist perspectives on science and knowledge production and can help explain the persistence of the controversy surrounding childhood vaccines in the United States. PMID- 28841814 TI - The impact of commercial rapid respiratory virus diagnostic tests on patient outcomes and health system utilization. AB - INTRODUCTION: Acute respiratory tract infections due to influenza A/B and respiratory syncytial virus (RSV) are major causes of morbidity and mortality globally. Rapid tests for detection of these pathogens include antigen detection point of care tests (POC) and newer easy to use molecular tests. From experience, these assays improve both laboratory workflow and assay interpretation issues. However, the question of the benefits of using rapid test technology compared to routine laboratory testing for respiratory viral pathogens is still often asked. Areas covered: Specifically, this review aims to; 1) identify clinical/patient indicators that can be measured prior to and following the implementation of rapid diagnostic test for influenza and RSV, 2) provide multiple perspectives on the extent of impact of a rapid diagnostic test, including direct and indirect outcomes, and 3) identify the technological advancements in the development of rapid testing, demonstrating a timeline that transitions from antigen-based assays to molecular assays. Expert commentary: Key benefits to the use of either antigen-based or molecular rapid tests for patient care, patient flow within institutions, as well as laboratory utilization are identified. Due to improved test characteristics, the authors feel that rapid molecular tests have greater benefits than antigen-based detection methods. PMID- 28841815 TI - A cardio-abdominal dilemma. PMID- 28841816 TI - Medical migration: A qualitative exploration of the atypical path of Japanese international medical graduates. AB - BACKGROUND: International Medical Graduates (IMGs) are commonly understood to move from low to high resource countries with motivations including improved financial situations and cultures of emigration. A presumable exception to the above themes would be the Japanese IMG population. The aim of this study was to develop an understanding of the Japanese IMG experience. METHODS: Using a grounded theory approach, we interviewed 19 Japanese IMGs working in the US and 16 Japanese IMGs working in Japan who had completed US clinical training. Questions addressed decision-making to pursue US clinical training, goals for the training, and career decision-making upon completing the training. Data collection and constant comparative analysis were conducted iteratively to identify emerging themes. RESULTS: The emerging model of the Japanese IMG experience is focused around pivotal experiences that often include dissatisfaction with the quality of Japanese clinical training and personal exposures to US clinical education. Further decision-making in the pursuit of US residency is influenced by educator training quality, and clinical training and career opportunities. The desire to improve Japanese clinical training commonly influences career decision-making after US training. CONCLUSIONS: The Japanese IMG experience contrasts numerous perceptions of international physician migration and, in turn, enhances understanding of this paradigm. PMID- 28841817 TI - Plasma osteopontin concentration is elevated in patients with coronary bare metal stent restenosis. AB - OBJECTIVE: Osteopontin is a component of atherosclerotic lesions, secreted by monocytes, macrophages and endothelial and vascular smooth muscle cells, which together are responsible for neointimal proliferation. We examined whether elevated plasma osteopontin concentration was associated with in-stent restenosis in patients with coronary artery disease. SUBJECTS AND METHODS: We enrolled 91 patients who underwent coronary artery stenting, and 60 control patients with normal findings on coronary angiography, between June 2012 and September 2013. For patients with stents, we measured plasma osteopontin concentration at the first follow-up coronary angiogram. For controls, plasma osteopontin concentration was measured at the time of angiography. RESULTS: Of the 91 patients who had undergone coronary artery stenting, 31 (34.1%) had developed in stent restenosis and the mean time passed to control coronary angiography was 36.7 months (+/-SD 35.1 months). Mean plasma osteopontin concentration in this group was 2721.4 +/- 1787.8 pg/ml, significantly higher than the 60 patients (65.9%) with no in-stent restenosis (1770.4 +/- 1208.2 pg/ml, p = .011) and the 60 patients with a normal coronary angiogram (1572.4 +/- 904.8 pg/ml, p = .002). There was no significant difference in mean osteopontin concentration between the patients with no in-stent restenosis and the control group (p = .312). CONCLUSIONS: Elevated plasma osteopontin concentration is associated with in stent stenosis in patients with coronary artery disease. Further studies will be needed to establish whether osteopontin can predict in-stent restenosis and guide clinical management strategies. PMID- 28841818 TI - Scientists' views about communication objectives. AB - This study looks at how United States-based academic scientists from five professional scientific societies think about eight different communication objectives. The degree to which scientists say they would prioritize these objectives in the context of face-to-face public engagement is statistically predicted using the scientists' attitudes, normative beliefs, and efficacy beliefs, as well as demographics and past communication activity, training, and past thinking about the objectives. The data allow for questions about the degree to which such variables consistently predict views about objectives. The research is placed in the context of assessing factors that communication trainers might seek to reshape if they wanted get scientists to consider choosing specific communication objectives. PMID- 28841819 TI - Redefining the extinct orders Miomoptera and Hypoperlida as stem acercarian insects. AB - BACKGROUND: The systematic positions of the extinct insect orders Hypoperlida, Miomoptera and Permopsocida were enigmatic and unstable for nearly a century. The recent studies based on new material, especially from the Cenomanian Burmese amber, shed light on evolutionary history of Acercaria resolving Permopsocida as the stem group of Condylognatha. However, the knowledge of the remaining two orders differs significantly. RESULTS: In this study, we describe new specimens and evaluate morphology of various structures with emphasis on the mouthparts and wing venation. Our results are primary based on revisions of the type specimens with a proper delimitation of taxa Hypoperlida and Miomoptera followed by their significance for the evolutionary history of Acercaria. Three new genera as Belmomantis gen. nov., Elmomantis gen. nov., and Mazonopsocus gen. nov. are designated as members of Palaeomanteidae. The Pennsylvanian Mazonopsocus provides a minimum age for calibration, in accordance to the presence of crown acercarians during the late Carboniferous. CONCLUSIONS: This contribution demonstrates that Hypoperlida and Miomoptera are stem groups of Acercaria. The putative clade (Hypoperlida + Miomoptera) is appearing as potential sister group of (Psocodea + (Permopsocida + (Thripida + Hemiptera))). PMID- 28841820 TI - A weighted string kernel for protein fold recognition. AB - BACKGROUND: Alignment-free methods for comparing protein sequences have proved to be viable alternatives to approaches that first rely on an alignment of the sequences to be compared. Much work however need to be done before those methods provide reliable fold recognition for proteins whose sequences share little similarity. We have recently proposed an alignment-free method based on the concept of string kernels, SeqKernel (Nojoomi and Koehl, BMC Bioinformatics, 2017, 18:137). In this previous study, we have shown that while Seqkernel performs better than standard alignment-based methods, its applications are potentially limited, because of biases due mostly to sequence length effects. METHODS: In this study, we propose improvements to SeqKernel that follows two directions. First, we developed a weighted version of the kernel, WSeqKernel. Second, we expand the concept of string kernels into a novel framework for deriving information on amino acids from protein sequences. RESULTS: Using a dataset that only contains remote homologs, we have shown that WSeqKernel performs remarkably well in fold recognition experiments. We have shown that with the appropriate weighting scheme, we can remove the length effects on the kernel values. WSeqKernel, just like any alignment-based sequence comparison method, depends on a substitution matrix. We have shown that this matrix can be optimized so that sequence similarity scores correlate well with structure similarity scores. Starting from no information on amino acid similarity, we have shown that we can derive a scoring matrix that echoes the physico-chemical properties of amino acids. CONCLUSION: We have made progress in characterizing and parametrizing string kernels as alignment-based methods for comparing protein sequences, and we have shown that they provide a framework for extracting sequence information from structure. PMID- 28841821 TI - Influence of epistasis on response to genomic selection using complete sequence data. AB - BACKGROUND: The effect of epistasis on response to selection is a highly debated topic. Here, we investigated the impact of epistasis on response to sequence based selection via genomic best linear prediction (GBLUP) in a regime of strong non-symmetrical epistasis under divergent selection, using real Drosophila sequence data. We also explored the possible advantage of including epistasis in the evaluation model and/or of knowing the causal mutations. RESULTS: Response to selection was almost exclusively due to changes in allele frequency at a few loci with a large effect. Response was highly asymmetric (about four phenotypic standard deviations higher for upward than downward selection) due to the highly skewed site frequency spectrum. Epistasis accentuated this asymmetry and affected response to selection by modulating the additive genetic variance, which was sustained for longer under upward selection whereas it eroded rapidly under downward selection. Response to selection was quite insensitive to the evaluation model, especially under an additive scenario. Nevertheless, including epistasis in the model when there was none eventually led to lower accuracies as selection proceeded. Accounting for epistasis in the model, if it existed, was beneficial but only in the medium term. There was not much gain in response if causal mutations were known, compared to using sequence data, which is likely due to strong linkage disequilibrium, high heritability and availability of phenotypes on candidates. CONCLUSIONS: Epistatic interactions affect the response to genomic selection by modulating the additive genetic variance used for selection. Epistasis releases additive variance that may increase response to selection compared to a pure additive genetic action. Furthermore, genomic evaluation models and, in particular, GBLUP are robust, i.e. adding complexity to the model did not modify substantially the response (for a given architecture). PMID- 28841822 TI - Diminished accuracy of biomarkers of fibrosis in low replicative chronic hepatitis B. AB - BACKGROUND: We evaluated the diagnostic accuracy of aspartate aminotransferase (AST)-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), AST/alanine aminotransferase (ALT) ratio (AAR), and age-platelet index (API) for significant fibrosis (Metavir F2-4) in low-replicative (HBV DNA <20,000 IU/mL) chronic hepatitis B virus (HBV) patients. METHODS: The sensitivity, specificity, and area under the receiver-operating characteristic curve (AUROC) of HBeAg-negative, low replicative (n = 213) and high-replicative (HBV DNA >=20,000 IU/mL, n = 153) patients was assessed. RESULTS: Overall, 113 patients (30.9%) had F2-4 fibrosis. Of the low and high-replicative patients, 40 (18.8%) and 73 (47.7%) had F2-4, respectively (P < 0.0001). APRI >=0.5 less frequently identified F2-4 fibrosis in low vs. high-replicative patients (48.7% vs. 69.6%, P = 0.032) and AAR identified it more frequently in low-replicative patients (37.5% vs. 19.4%, P = 0.037). FIB 4 and API were not different (P > 0.05) for identifying F2-4 fibrosis in low and high-replicative patients. Higher specificities were seen at the lowest cut-offs in low vs. high-replicative states for APRI (>=0.5, 98% vs. 68.9%), AAR (84.3% vs. 76.6%), FIB-4 (>=1.45, 97.5% vs. 87.8%) and API (>4, 94.8% vs. 93.8%). At ROC defined thresholds, APRI (>=0.33), AAR (>=0.93), FIB-4 (>=0.70) and API (>2) showed greater AUROCs for F2-4 diagnosis in low replicative (0.80, 0.62, 0.81 and 0.71, respectively) vs. high-replicative patients (0.73, 0.52, 0.67 and 0.69, respectively). CONCLUSION: All 4 biomarkers in both, low and high-replicative HBV demonstrate modest accuracy for fibrosis diagnosis at conventional cut-offs. Lowering the cut-offs may increase the diagnostic relevance of these biomarkers, particularly for APRI and FIB-4 in low-replicative disease. PMID- 28841823 TI - 'My child did not like using sun protection': practices and perceptions of child sun protection among rural black African mothers. AB - BACKGROUND: Photodamage is partially mitigated by darker skin pigmentation, but immune suppression, photoaging and cataracts occur among individuals with all skin types. METHODS: To assess practices and acceptability to Black African mothers of sun protection equipment for their children living in a rural area, participants were recruited at the time of their child's 18-month vaccinations. Mothers completed a baseline questionnaire on usual sun behaviours and sun protection practices. They were then provided with sun protection equipment and advice. A follow-up questionnaire was administered two weeks later. RESULTS: Mothers reported that during the week prior to the baseline questionnaire, children spent on average less than 1 hour of time outdoors (most often spent in the shade). Most mothers (97%) liked the sun protection equipment. However, many (78 of 86) reported that their child did not like any of the sun protection equipment and two-thirds stated that the sun protection equipment was not easy to use. CONCLUSIONS: Among Black Africans in rural northern South Africa, we found a mismatch between parental preferences and child acceptance for using sun protection when outdoors. A better understanding of the health risks of incidental excess sun exposure and potential benefits of sun protection is required among Black Africans. PMID- 28841824 TI - Factors related to the improvement in quality of life for depressed inpatients treated with fluoxetine. AB - BACKGROUND: The aim of this study was to explore the relationships between depressive symptoms and health-related quality of life (HRQOL) measurements for inpatients with major depressive disorder (MDD) before and after 6-week fluoxetine treatment, and to elucidate the factors related to the HRQOL changes. METHODS: A total of 131 inpatients with MDD were enrolled to receive 20 mg of fluoxetine for 6 weeks. Symptom severity and adverse events were assessed at weeks 0, 1, 2, 3, 4, and 6 using the 17-item Hamilton Depression Rating Scale (HAMD-17) and UKU Side Effect Rating Scale, respectively. HRQOL was measured using the Short Form 36 (SF-36), including 8 subscales, physical component summary (PCS) and mental component summary (MCS), at baseline and week 6. Spearman's coefficient, Cohen's d, and multiple linear regression model were used for statistical analysis. RESULTS: One hundred and six patients completing all measures at weeks 0 and 6 entered the analysis. HAMD-17 negatively correlated with SF-36 at baseline and week 6. The HAMD-17 had a larger effect size than SF 36. MCS, rather than PCS, showed statistically significant improvement. After using multiple linear regression analysis, age at onset, HAMD-17 score change, and number of adverse events reported during the trial period were related to MCS change after adjusting for confounding variables. CONCLUSIONS: Fluoxetine treatment was associated with an improvement in depressive symptomology and HRQOL. Depressive symptoms had a greater extent of change than HRQOL. Clinicians must consider the negative effects of adverse events caused by antidepressants on the improvement of HRQOL. TRIAL REGISTRATION: http://clinicaltrials.gov , NCT01075529 , retrospectively registered 24/2/2010. PMID- 28841825 TI - The transverse abdominal muscle is excessively active during active straight leg raising in pregnancy-related posterior pelvic girdle pain: an observational study. AB - BACKGROUND: Many studies suggest that impairment of motor control is the mechanical component of the pathogenesis of painful disorders in the lumbo-sacral region; however, this theory is still unproven and the results and recommendations for intervention remain questionable. The need for a force to compress both innominate bones against the sacrum is the basis for treatment of pregnancy-related pelvic girdle pain (PGP). Therefore, it is advised to use a pelvic belt and do exercises to enhance contraction of the muscles which provide this compression. However, our clinical experience is that contraction of those muscles appears to be excessive in PGP. Therefore, in patients with long-lasting pregnancy-related posterior PGP, there is a need to investigate the contraction pattern of an important muscle that provides a compressive force, i.e. the transverse abdominal muscle (TrA), during a load transfer test, such as active straight leg raising (ASLR). METHODS: TrA thickness was measured by means of ultrasound imaging at rest and during ASLR in 43 non-pregnant women with ongoing posterior PGP that started during a pregnancy or delivery, and in 39 women of the same age group who had delivered at least once and had no current PGP (healthy controls). RESULTS: In participants with PGP, the median TrA thickness increase with respect to rest during ipsilateral and contralateral ASLR was 31% (SD 46%) and 31% (SD 57%), respectively. In healthy controls, these values were 11% (SD 25%) and 13% (SD 22%), respectively. CONCLUSIONS: Significant excessive contraction of the TrA is present during ASLR in patients with long-lasting pregnancy-related posterior PGP. The present findings do not support the idea that contraction of the TrA is decreased in long-lasting pregnancy-related PGP. This implies that there is no rationale for the prescription of exercises to enhance contraction of TrA in patients with long-lasting pregnancy-related PGP. PMID- 28841826 TI - Only a small proportion of patients with first episode psychosis come via prodromal services: a retrospective survey of a large UK mental health programme. AB - BACKGROUND: Little is known about patients with a first episode of psychosis (FEP) who had first presented to prodromal services with an "at risk mental state" (ARMS) before making the transition to psychosis. We set out to identify the proportion of patients with a FEP who had first presented to prodromal services in the ARMS state, and to compare these FEP patients with FEP patients who did not have prior contact with prodromal services. METHODS: In this study information on 338 patients aged <=37 years who presented to mental health services between 2010 and 2012 with a FEP was examined. The data on pathways to care, clinical and socio-demographic characteristics were extracted from the Biomedical Research Council Case Register for the South London and Maudsley NHS Trust. RESULTS: Over 2 years, 14 (4.1% of n = 338) young adults presented with FEP and had been seen previously by the prodromal services. These ARMS patients were more likely to enter their pathway to psychiatric care via referral from General Practice, be born in the UK and to have had an insidious mode of illness onset than FEP patients without prior contact with the prodromal services. CONCLUSIONS: In the current pathways to care configuration, prodromal services are likely to prevent only a few at-risk individuals from transitioning to psychosis even if effective preventative treatments become available. PMID- 28841827 TI - Comparison of 12-month therapeutic effect of conbercept and ranibizumab for diabetic macular edema: a real-life clinical practice study. AB - BACKGROUND: To compare the efficacy of intravitreal conbercept and ranibizumab in the treatment of diabetic macular edema (DME) in a real-life clinical practice. METHODS: This was a retrospective study. Among 62 Chinese patients with DME, 32 patients (36 eyes) received intravitreal conbercept (IVC) injections and 30 patients (32 eyes) received intravitreal ranibizumab (IVR) injections, once a month for 3 months followed by as needed therapy. All participants had at least 12 months of follow-up. We compared the changes in best-corrected visual acuity (BCVA) letter score and central retinal thickness (CRT) between groups, as well as the number of intravitreal injections delivered. Safety was assessed with the incidence of adverse events (AEs). RESULTS: At month 12, the mean BCVA letter score improved by 9.3 +/- 5.2 with conbercept, and by 8.9 +/- 4.4 with ranibizumab, the mean CRT reduction was 138.4 +/- 97.7 MUm and 145.2 +/- 72.5 MUm, respectively. There was no statistically significant difference of improvement in BCVA (P = 0.756) and decrease in CRT (P = 0.748) between the two groups. The number of intravitreal injections delivered was significantly higher (P = 0.027) in the IVR group (7.2 +/- 1.0 per eye) than in the IVC group (6.6 +/- 0.9 per eye). There were no severe ocular adverse reactions or systemic adverse events. CONCLUSIONS: Both conbercept and ranibizumab are effective in the treatment of DME, achieving the similar clinical efficacy. In comparison to ranibizumab, conbercept shows a longer treatment interval and fewer intravitreal conbercept injections are needed. PMID- 28841828 TI - Blink rate is associated with drug-induced parkinsonism in patients with severe mental illness, but does not meet requirements to serve as a clinical test: the Curacao extrapyramidal syndromes study XIII. AB - BACKGROUND: Drug-induced parkinsonism (DIP) has a high prevalence and is associated with poorer quality of life. To find a practical clinical tool to assess DIP in patients with severe mental illness (SMI), the association between blink rate and drug-induced parkinsonism (DIP) was assessed. METHODS: In a cohort of 204 SMI patients receiving care from the only mental health service of the previous Dutch Antilles, blink rate per minute during conversation was assessed by an additional trained movement disorder specialist. DIP was rated on the Unified Parkinson's Disease Rating Scale (UPDRS) in 878 assessments over a period of 18 years. Diagnostic values of blink rate were calculated. RESULTS: DIP prevalence was 36%, average blink rate was 14 (standard deviation (SD) 11) for patients with DIP, and 19 (SD 14) for patients without. There was a significant association between blink rate and DIP (p < 0.001). With a blink rate cut-off of 20 blinks per minute, sensitivity was 77% and specificity was 38%. A 10% percentile cut-off model resulted in an area under the ROC curve of 0.61. A logistic prediction model between dichotomous DIP and continuous blink rate per minute an area under the ROC curve of 0.70. CONCLUSIONS: There is a significant association between blink rate and DIP as diagnosed on the UPDRS. However, blink rate sensitivity and specificity with regard to DIP are too low to replace clinical rating scales in routine psychiatric practice. TRIAL REGISTRATION: The study was started over 20 years ago in 1992, at the time registering a trial was not common practice, therefore the study was never registered. PMID- 28841829 TI - Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. AB - BACKGROUND: To overcome the hostile hypoxic microenvironment of solid tumors, tumor cells secrete a large number of non-coding RNA-containing exosomes that facilitate tumor development and metastasis. However, the precise mechanisms of tumor cell-derived exosomes during hypoxia are unknown. Here, we aim to clarify whether hypoxia affects tumor growth and progression by transferring long non coding RNA-urothelial cancer-associated 1 (lncRNA-UCA1) enriched exosomes secreted from bladder cancer cells. METHODS: We used bladder cancer 5637 cells with high expression of lncRNA-UCA1 as exosome-generating cells and bladder cancer UMUC2 cells with low expression of lncRNA-UCA1 as recipient cells. Exosomes derived from 5637 cells cultured under normoxic or hypoxic conditions were isolated and identified by transmission electron microscopy, nanoparticle tracking analysis and western blotting analysis. These exosomes were co-cultured with UMUC2 cells to evaluate cell proliferation, migration and invasion. We further investigated the roles of exosomal lncRNA-UCA1 derived from hypoxic 5637 cells by xenograft models. The availability of lncRNA-UCA1 in serum-derived exosomes as a biomarker for bladder cancer was also assessed. RESULTS: We found that hypoxic exosomes derived from 5637 cells promoted cell proliferation, migration and invasion, and hypoxic exosomal RNAs could be internalized by three bladder cancer cell lines. Importantly, lncRNA-UCA1 was secreted in hypoxic 5637 cell-derived exosomes. Compared with normoxic exosomes, hypoxic exosomes derived from 5637 cells showed the higher expression levels of lncRNA-UCA1. Moreover, Hypoxic exosomal lncRNA-UCA1 could promote tumor growth and progression though epithelial-mesenchymal transition, in vitro and in vivo. In addition, the expression levels of lncRNA-UCA1 in the human serum-derived exosomes of bladder cancer patients were higher than that in the healthy controls. CONCLUSION: Together, our results demonstrate that hypoxic bladder cancer cells remodel tumor microenvironment to facilitate tumor growth and development though secreting the oncogenic lncRNA-UCA1-enriched exosomes and exosomal lncRNA-UCA1 in human serum has the possibility as a diagnostic biomarker for bladder cancer. PMID- 28841831 TI - Two promoters in the esx-3 gene cluster of Mycobacterium smegmatis respond inversely to different iron concentrations in vitro. AB - BACKGROUND: The ESX secretion system, also known as the Type VII secretion system, is mostly found in mycobacteria and plays important roles in nutrient acquisition and host pathogenicity. One of the five ESXs, ESX-3, is associated with mycobactin-mediated iron acquisition. Although the functions of some of the membrane-associated components of the ESX systems have been described, the role of by mycosin-3 remains elusive. The esx-3 gene cluster encoding ESX-3 in both Mycobacterium tuberculosis and Mycobacterium smegmatis has two promoters, suggesting the presence of two transcriptional units. Previous studies indicated that the two promoters only showed a difference in response under acid stress (pH 4.2). This study aimed to study the effect of a mycosin-3 deletion on the physiology of M. smegmatis and to assess the promoter activities in wildtype, mycosin-3 mutant and complementation strains. RESULTS: The gene mycP 3 was deleted from wildtype M. smegmatis via homologous recombination. The mycP 3 gene was complemented in the deletion mutant using each of the two intrinsic promoters from the M. smegmatis esx-3 gene cluster. The four strains were compared in term of bacterial growth and intracellular iron content. The two promoter activities were assessed under iron-rich, iron-deprived and iron-rescued conditions by assessing the mycP 3 expression level. Although the mycP 3 gene deletion did not significantly impact bacterial growth or intracellular iron levels in comparison to the wild-type and complemented strains, the two esx-3 promoters were shown to respond inversely to iron deprivation and iron rescue. CONCLUSION: This finding correlates with the previously published data that the first promoter upstream of msmeg0615, is upregulated under low iron levels but downregulated under high iron levels. In addition, the second promoter, upstream of msmeg0620, behaves in an inverse fashion to the first promoter implying that the genes downstream may have additional roles when the iron levels are high. PMID- 28841830 TI - Alcohol consumption and its interaction with adiposity-associated genetic variants in relation to subsequent changes in waist circumference and body weight. AB - BACKGROUND: Studies have suggested a link between alcohol intake and adiposity. However, results from longitudinal studies have been inconsistent, and a possible interaction with genetic predisposition to adiposity measures has often not been taken into account. OBJECTIVE: To examine the association between alcohol intake recorded at baseline and subsequent annual changes in body weight (?BW), waist circumference (DeltaWC) and WC adjusted for BMI (DeltaWCBMI), and to test for interaction with genetic predisposition scores based on single nucleotide polymorphisms (SNPs) associated with various forms of adiposity. METHOD: This study included a total of 7028 adult men and women from MONICA, the Diet, Cancer and Health cohort (DCH), and the Inter99 studies. We combined 50 adiposity associated SNPs into four scores indicating genetic predisposition to BMI, WC, WHRBMI and all three traits combined. Linear regression was used to examine the association of alcohol intake (drinks of 12 g (g) alcohol/day) with DeltaBW, DeltaWC, and DeltaWCBMI, and to examine possible interactions with SNP-scores. Results from the analyses of the individual cohorts were combined in meta analyses. RESULTS: Each additional drink/day was associated with a DeltaBW/year of -18.0 g (95% confidence interval (CI): -33.4, -2.6, P = 0.02) and a DeltaWC of -0.3 mm/year (-0.5, -0.0, P = 0.03). In analyses of women only, alcohol intake was associated with a higher DeltaWCBMI of 0.5 mm/year (0.2, 0.9, P = 0.002) per drink/day. Overall, we found no statistically significant interactions between the four SNP-scores and alcohol intake in relation to changes in adiposity measures. However in analyses of women separately, we found interaction between the complete score of all 50 SNPs and alcohol intake in relation to DeltaBW (P for interaction = 0.03). No significant interaction was observed among the men. CONCLUSION: Alcohol intake was associated with a decrease in BW and WC among men and women, and an increase in WCBMI among women only. We found no strong indication that these associations depend on a genetic predisposition to adiposity. TRIAL REGISTRATION: Registry: ClinicalTrials.gov Trial number: CT00289237 , Registered: 19 September 2005 retrospectively registered. PMID- 28841832 TI - Repeat cesarean section in subsequent gestation of women from a birth cohort in Brazil. AB - BACKGROUND: The current literature indicates increasing concern regarding the number of safe cesarean sections which a woman can undergo, mainly in face of the high cesarean section rates, which are growing in Brazil and worldwide. Aimed to describe the prevalence and associated factors of repeat cesarean section in a cohort of Brazilian women who had a cesarean section in the first birth. METHODS: This is a prospective cohort study using data from the 2004 Pelotas Birth Cohort. The sample included 480 women who had their first delivery in 2004, regardless of the form of delivery, and who had a second delivery identified in the cohort's follow-ups (in 2005, 2006, 2008, and 2010). Descriptive, bivariate and multivariate analyses using Poisson regression with robust error variance were carried out. RESULTS: Among the women who underwent a cesarean section in their first delivery (49.47%), 87.44% had a second surgical delivery. The risk factors for repeat cesarean section included ages 21-34 (PR 1.67, CI 95% 1.07-2.60), not being seen by SUS (Public Healthcare System) in 2004 (PR 2.27, CI 95% 1.44-3.60), and the number of prenatal medical visits, i.e., women with ten or more visits were at 2.33 times higher risk (CI 95% 1.10-4.96) compared to those who had five or fewer visits. CONCLUSIONS: The proportion of cesarean sections both in the first and in the subsequent delivery is quite high. This high rate may compromise the reproductive future of the women who undergo consecutive cesarean sections with possible consequent complications and changes in care policies for pregnant women should be implemented. PMID- 28841834 TI - Cutaneous leishmaniasis in a severely immunocompromised HIV patient in Kumbo, Northwest region of Cameroon: case report. AB - BACKGROUND: Leishmaniasis is a rising opportunistic infection in individuals with human immunodeficiency virus (HIV). Cases of leishmania and HIV co-infection have been documented in several countries in the world with most reporting on the association between visceral leishmaniasis (VL) and HIV. We herein report the case of cutaneous leishmaniasis (CL) occurring in an HIV seropositive patient. CASE PRESENTATION: A 28 year old Cameroonian female diagnosed with HIV for 6 months earlier, presented to our facility with a 3 months history of non-painful rash. Clinical examination revealed non prurigeneous papulo-nodular lesions on the face and thighs which later became crusty ulcerative lesions. Giemsa staining with examination under oil objective immersion identified amastigotes and a diagnosis of CL was made which was managed with amphotericine B (1 mg/kg of body weight) for 14 days with mild improvement of lesions. Patient developed hypokalemia due to the amphotericine B during admission which was corrected and died 1 month after discharge. CONCLUSIONS: Current evidence suggest higher incidence of VL in HIV, however we report the occurrence of CL in HIV. A high index of suspicion for CL is warranted among clinicians in Africa when faced with HIV patients with inconsistent cutaneous rash. PMID- 28841833 TI - Lifetime occupational exposure to metals and welding fumes, and risk of glioma: a 7-country population-based case-control study. AB - BACKGROUND: Brain tumor etiology is poorly understood. Based on their ability to pass through the blood-brain barrier, it has been hypothesized that exposure to metals may increase the risk of brain cancer. Results from the few epidemiological studies on this issue are limited and inconsistent. METHODS: We investigated the relationship between glioma risk and occupational exposure to five metals - lead, cadmium, nickel, chromium and iron- as well as to welding fumes, using data from the seven-country INTEROCC study. A total of 1800 incident glioma cases and 5160 controls aged 30-69 years were included in the analysis. Lifetime occupational exposure to the agents was assessed using the INTEROCC JEM, a modified version of the Finnish job exposure matrix FINJEM. RESULTS: In general, cases had a slightly higher prevalence of exposure to the various metals and welding fumes than did controls, with the prevalence among ever exposed ranging between 1.7 and 2.2% for cadmium to 10.2 and 13.6% for iron among controls and cases, respectively. However, in multivariable logistic regression analyses, there was no association between ever exposure to any of the agents and risk of glioma with odds ratios (95% confidence intervals) ranging from 0.8 (0.7 1.0) for lead to 1.1 (0.7-1.6) for cadmium. Results were consistent across models considering cumulative exposure or duration, as well as in all sensitivity analyses conducted. CONCLUSIONS: Findings from this large-scale international study provide no evidence for an association between occupational exposure to any of the metals under scrutiny or welding fumes, and risk of glioma. PMID- 28841835 TI - Differential analysis between somatic mutation and germline variation profiles reveals cancer-related genes. AB - A major aim of cancer genomics is to pinpoint which somatically mutated genes are involved in tumor initiation and progression. We introduce a new framework for uncovering cancer genes, differential mutation analysis, which compares the mutational profiles of genes across cancer genomes with their natural germline variation across healthy individuals. We present DiffMut, a fast and simple approach for differential mutational analysis, and demonstrate that it is more effective in discovering cancer genes than considerably more sophisticated approaches. We conclude that germline variation across healthy human genomes provides a powerful means for characterizing somatic mutation frequency and identifying cancer driver genes. DiffMut is available at https://github.com/Singh Lab/Differential-Mutation-Analysis . PMID- 28841836 TI - Oxalobacter formigenes-associated host features and microbial community structures examined using the American Gut Project. AB - BACKGROUND: Increasing evidence shows the importance of the commensal microbe Oxalobacter formigenes in regulating host oxalate homeostasis, with effects against calcium oxalate kidney stone formation, and other oxalate-associated pathological conditions. However, limited understanding of O. formigenes in humans poses difficulties for designing targeted experiments to assess its definitive effects and sustainable interventions in clinical settings. We exploited the large-scale dataset from the American Gut Project (AGP) to study O. formigenes colonization in the human gastrointestinal (GI) tract and to explore O. formigenes-associated ecology and the underlying host-microbe relationships. RESULTS: In >8000 AGP samples, we detected two dominant, co-colonizing O. formigenes operational taxonomic units (OTUs) in fecal specimens. Multivariate analysis suggested that O. formigenes abundance was associated with particular host demographic and clinical features, including age, sex, race, geographical location, BMI, and antibiotic history. Furthermore, we found that O. formigenes presence was an indicator of altered host gut microbiota structure, including higher community diversity, global network connectivity, and stronger resilience to simulated disturbances. CONCLUSIONS: Through this study, we identified O. formigenes colonizing patterns in the human GI tract, potential underlying host microbe relationships, and associated microbial community structures. These insights suggest hypotheses to be tested in future experiments. Additionally, we proposed a systematic framework to study any bacterial taxa of interest to computational biologists, using large-scale public data to yield novel biological insights. PMID- 28841837 TI - Decreased ex vivo production of interferon-gamma is associated with severity and poor prognosis in patients with lupus. AB - BACKGROUND: Lupus pathogenesis is closely associated with interferon gamma (IFN gamma), which plays a central role in innate and adaptive immunity. The aim of this study was to evaluate the ex vivo production of IFN-gamma after stimulation of peripheral blood mononuclear cells with phytohemagglutinin (PHA) in patients with lupus, according to disease activity. METHODS: This study included 118 patients with lupus who had undergone IFN-gamma-releasing assays (IGRAs) to screen for tuberculosis. Data on IFN-gamma production in negative (nil) and positive (mitogen with PHA) controls were collected and analysed. The difference (mitogen minus nil) was used to calculate ex vivo IFN-gamma production. Disease activity was evaluated using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Poor hospitalisation outcome was defined as in-hospital mortality or intensive care unit admission. Associations among disease activity, poor hospitalisation outcome, and ex vivo IFN-gamma production were assessed. RESULTS: The level of ex vivo IFN-gamma production was significantly lower in patients with active systemic lupus erythematosus (SLE) (n = 64) than in those with inactive SLE (n = 54) (median 0.92 vs. 11.06 IU/mL, p < 0.001). Ex vivo IFN gamma production was correlated with the SLEDAI-2 K (r = - 0.587, p < 0.001). Results of multivariate logistic regression analysis showed that ex vivo IFN gamma production <= 7.19 IU/mL was an independent predictor for discriminating active and inactive lupus. In addition, patients with ex vivo IFN-gamma production <= 0.40 IU/mL had more frequent poor hospitalisation outcomes than those with ex vivo IFN-gamma production > 0.40 (40.0% vs. 9.3%, p = 0.001). The proportion of indeterminate IGRA results was higher in patients with active lupus than in those with inactive lupus (45.3% vs. 0.0%, p < 0.001) because of decreased ex vivo IFN-gamma production. CONCLUSIONS: Ex vivo IFN-gamma production is a useful biomarker for assessing disease activity and predicting poor clinical outcomes of SLE. PMID- 28841838 TI - Maternal and perinatal outcome after previous caesarean section in rural Rwanda. AB - BACKGROUND: Offering a trial of labor (ToL) after previous caesarean section (CS) is an important strategy to reduce short- and long-term morbidity associated with repeated CS. We compared maternal and perinatal outcomes between ToL and elective repeat caesarean section (ERCS) at a district hospital in rural Rwanda. METHODS: Audit of women's records with one prior CS who delivered at Ruhengeri district hospital in Rwanda between June 2013 and December 2014. RESULTS: Out of 4131 women who came for delivery, 435 (11%) had scarred uteri. ToL, which often started at home or at health centers without appropriate counseling, occurred in 297/435 women (68.3%), while 138 women (31.7%) delivered by ERCS. ToL was successful in 134/297 (45.1%) women. There were no maternal deaths. Twenty-eight out of all 435 women with a scarred uterus (6.4%) sustained severe acute maternal morbidity (puerperal sepsis, postpartum hemorrhage, uterine rupture), which was higher in women with ToL (n = 23, 7.7%) compared with women who had an ERCS (n = 5, 3.6%): adjusted odds ration (aOR) 1.4 (95% CI 1.2-5.4). There was no difference in neonatal admissions between women who underwent ToL (n = 64/297; 21.5%) and those who delivered by ERCS (n = 35/138; 25.4%: aOR 0.8; CI 0.5-1.6). The majority of admissions were due to perinatal asphyxia that occurred more often in infants whose mothers underwent ToL (n = 40, 13.4%) compared to those who delivered by ERCS (n = 15, 10.9%: aOR 1.9; CI 1.6-3.6). Perinatal mortality was similar among infants whose mothers had ToL (n = 8; 27/1000 ToLs) and infants whose mothers underwent ERCS (n = 4; 29/1000 ERCSs). CONCLUSIONS: A considerable proportion of women delivering at a rural Rwandan hospital had scarred uteri. Severe acute maternal morbidity was higher in the ToL group, perinatal mortality did not differ. ToL took place under suboptimal conditions: access for women with scarred uteri into a facility with 24-h surgery should be guaranteed to increase the safety of ToL. PMID- 28841839 TI - Urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and epidermal growth factor receptor (EGFR): tumor expression patterns and prognostic value in oral cancer. AB - BACKGROUND: Tumor-specific biomarkers are a prerequisite for the development of targeted imaging and therapy in oral squamous cell carcinoma (OSCC). urokinase type Plasminogen Activator Receptor (uPAR), Tissue Factor (TF) and Epidermal Growth Factor Receptor (EGFR) are three biomarkers that exhibit enhanced expression in many types of cancers, and have been investigated as potential biomarkers for targeted strategies and prognostication. The aim of the study was to investigate the expression patterns of uPAR, TF and EGFR and their potential prognostic value in OSCC. METHODS: Immunohistochemical expression of uPAR, TF and EGFR in tumor resection specimens from 191 patients with primary OSCC was analyzed. Overall (OS) and disease-free survival (DFS) was calculated. Associations between biomarker expression, clinicopathological factors and patient survival was analyzed using the Cox proportional hazards model for univariate and multivariate analysis, log rank and Kaplan-Meier statistics. RESULTS: uPAR and TF exhibited a highly tumor-specific expression pattern while EGFR also showed expression in normal tissues outside the tumor compartment. The overall positive expression rate of uPAR, TF and EGFR was 95%, 58% and 98%, respectively. High uPAR expression across the entire cohort was negatively associated with OS (p = 0.031, HR = 1.595 (95%CI 1.044-2.439)) in univariate analysis. The 5-year OS for high and low uPAR expression was 39% and 56%, respectively. The expression of TF and EGFR was not associated with survival outcome. CONCLUSIONS: This study may suggest that uPAR and TF could potentially be attractive targets for molecular imaging and therapy in OSCC due to high positive expression rates and tumor-specific expression patterns. High uPAR expression was significantly associated with a reduced survival. uPAR seems to be a prognostic biomarker in oral cancer. PMID- 28841841 TI - Isolated non-traumatic, non-aneurysmal convexal subarachnoid hemorrhage in a patient with Evans syndrome. AB - BACKGROUND: Non-traumatic, spontaneous subarachnoid hemorrhage occurs in approximately 85% of cases where there is a ruptured saccular aneurysm. An additional 10% of cases arise from non-aneurysmal peri-mesencephalic hemorrhages. CASE PRESENTATION: We report a rare case of a young female, with underlying Evans syndrome, who was initially thought to have non-hemorrhagic stroke, eventually diagnosed having isolated non-traumatic, non-aneurysmal convexal subarachnoid haemorrhage. CONCLUSIONS: Spontaneous non-traumatic, non-aneurysmal convexal subarachnoid hemorrhage is a rare entity - of which there are multiple possible etiologies. PMID- 28841842 TI - Erratum to: Phylogenomic analyses of Crassiclitellata support major Northern and Southern hemisphere clades and a Pangaean origin for earthworms. PMID- 28841840 TI - Can brain impermeable BACE1 inhibitors serve as anti-CAA medicine? AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of beta-amyloid peptides (Abeta) in and surrounding the wall of microvasculature in the central nervous system, together with parenchymal amyloid plaques collectively referred to as cerebral amyloidosis, which occurs in the brain commonly among the elderly and more frequently in patients with Alzheimer's disease (AD). CAA is associated with vascular injury and may cause devastating neurological outcomes. No therapeutic approach is available for this lesion to date. MAIN BODY: beta-Secretase 1 (BACE1) is the enzyme initiating Abeta production. Brain permeable BACE1 inhibitors targeting primarily at the parenchymal plaque pathology are currently evaluated in clinical trials. This article presents findings in support of a role of BACE1 elevation in the development of CAA, in addition to plaque pathogenesis. The rationale, feasibility, benefit and strategic issues for developing BACE1 inhibitors against CAA are discussed. Brain impermeable compounds are considered preferable as they might exhibit sufficient anti-CAA efficacy without causing significant neuronal/synaptic side effects. CONCLUSION: Early pharmacological intervention to the pathogenesis of CAA is expected to provide significant protection for cerebral vascular health and hence brain health. Brain impermeable BACE1 inhibitors should be optimized and tested as potential anti-CAA therapeutics. PMID- 28841843 TI - The contribution of respiratory pathogens to fatal and non-fatal respiratory hospitalizations: a pilot study of Taqman Array Cards (TAC) in Kenya. AB - BACKGROUND: Respiratory diseases cause substantial morbidity and mortality worldwide, with sub-Saharan Africa bearing the greatest burden. Identifying etiologies of respiratory disease is important to inform cost effective treatment, prevention and control strategies. Testing for all of the different pathogens that are potentially associated with respiratory illnesses is challenging. We piloted the use of a multi-pathogen respiratory Taqman Array Cards (TAC) to identify pathogens in respiratory samples collected from non-fatal and fatal cases and their matched asymptomatic controls. METHODS: This is a case control study comparing viral and bacterial pathogens detected among non-fatal and fatal cases to those detected among age and time matched asymptomatic controls. We used McNemar's test to compare proportions of pathogens detected among cases (non-fatal and fatal) to their matched asymptomatic controls. We used Mann-Whitney test to compare the distribution of median Cycle threshold (Ct) values among non-fatal and fatal cases to their corresponding asymptomatic controls. RESULTS: There were 72 fatal and 72 non-fatal cases matched to 72 controls. We identified at least one pathogen in 109/144 (76%) cases and 59/72 (82%) controls. For most pathogens, the median Ct values were lower among cases (fatal and non-fatal) compared to asymptomatic controls. CONCLUSIONS: Similar rates of pathogen detection among cases and controls make interpretation of results challenging. Ct-values might be helpful in interpreting clinical relevance of detected pathogens using multi-pathogen diagnostic tools. PMID- 28841844 TI - Acute autonomic neuropathy with severe gastrointestinal symptoms in children: a case series. AB - BACKGROUND: Acute autonomic neuropathy (AAN) is rare disorder with anecdotal report, especially for childhood onset patients. Misdiagnosis or delays in treatment can always be found in clinical practice. We conducted this study to give a description of the manifestations and treatment of AAN in children and therefore help clinicians to make the accurate diagnosis early so that the prognosis of the patients can be improved. METHODS: A systematic record from 3 clinical centers was used to identify 11 subject, 3 males and 8 females, with clinical diagnosed AAN. RESULT: The age ranged from 2 years and 4 months to 14 years and 6 months (mean, 9 +/- 3.6 years old) and the course from onset to diagnosis ranged from 7 days to 8 months. All children shared prominent initial symptoms, 7 with frequent vomiting and 4 with motor dysfunctions. The condition of 9 patients improved after treatment of IVIg and intravenous glucocorticoid. CONCLUSION: The clinical manifestations of AAN are diverse, generalized, and non specific. Gastrointestinal disorders were the most common initial symptoms. Symptoms of gastrointestinal system and abnormal secretion of glands were severe and more common than other symptoms. The mechanism of AAN remains unknown. Although IVIg and intravenous glucocorticoid can be used in clinical practice, there is still no treatment recommendation and further study is needed. PMID- 28841846 TI - Validity and reliability of a performance evaluation tool based on the modified Barthel Index for stroke patients. AB - BACKGROUND: The Barthel Index (BI) is a measure of independence in activities of daily living (ADL). In the modified Barthel Index (MBI), a five-point system replaced the original two or three or four point rating system. Based on this modified measure, the performance evaluation tool MBI (PET-MBI) was developed in Japan. Although the reliability and validity of PET-MBI have been verified for older people, the use of this tool in stroke patients has not been evaluated. This study investigated the validity and reliability of PET-MBI for stroke patients. METHODS: Ten raters independently determined the BI and PET-MBI scores of stroke patients by direct observation. These patients' ADL were videotaped, and 10 other raters then evaluated the videos privately and assigned PET-MBI scores twice, one month apart. The criterion-related validity of the PET-MBI against the BI was evaluated using the correlation coefficients for their total scores. Furthermore, to assess inter- and intra-rater reliabilities from the results of the first and second sessions, Fleiss' intraclass correlation coefficients (ICCs) were calculated for the total scores, with the lower limits of the 95% confidence interval (95%CI), along with weighted kappa (kappaw) coefficients for agreement in individual tasks of this evaluation tool. ICC and kappaw coefficients of 0.81-1.00 were considered to be "almost perfect" agreement. RESULTS: The mean age of the 30 patients (23 men, 7 women) was 71.9 (standard deviation 10.5) years. One patient had diplegia, 14 had right hemiplegia, and 15 had left hemiplegia. For the total scores obtained by direct evaluation, Pearson's and Spearman's correlation coefficients of the BI versus the PET-MBI were both 0.95 (lower limit of the 95%CI, 0.90). The ICC representing inter-rater reliability for the first session was 0.99 (lower limit of the 95%CI, 0.98]. For intra-rater reliability, the mean value of the ICCs was 0.99 (range, 0.99-1.00). For individual tasks of the PET-MBI, inter-rater kappaw coefficients for the first session ranged from 0.77 to 0.94, with intra-rater kappaw coefficients from 0.85 to 0.96. CONCLUSIONS: PET-MBI showed strong criterion related validity against the BI, with high reliabilities. This scoring system may become a convenient tool allowing anyone to assess ADL. PMID- 28841845 TI - Sociodemographic factors and pregnancy outcomes associated with prepregnancy obesity: effect modification of parity in the nationwide Epifane birth-cohort. AB - BACKGROUND: In light of the adverse outcomes for mothers and offspring related to maternal obesity, identification of subgroups of women at risk of prepregnancy obesity and its related-adverse issues is crucial for optimizing antenatal care. We aimed to identify sociodemographic factors and maternal and neonatal outcomes associated with prepregnancy obesity, and we tested the effect modification of parity on these associations. METHODS: In 2012, 3368 mothers who had delivered in 136 randomly selected maternity wards were included just after birth in the French birth cohort, Epifane. Maternal height and weight before and at the last month of pregnancy were self-reported. Maternal and neonatal outcomes were collected in medical records. Prepregnancy Body Mass Index (pBMI) was classified into underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9) and obesity (>=30.0). Since we found statistically significant interactions with parity, the multinomial logistic regression model estimating associations of pBMI class with sociodemographic characteristics and pregnancy outcomes was stratified on parity (1335 primiparous and 1814 multiparous). RESULTS: Before pregnancy, 7.6% of women were underweight, 64.2% were of normal weight, 18.0% were overweight and 10.2% were obese. Among the primiparous, maternal age of 25-29 years (OR = 2.09 [1.13 3.87]; vs. 30-34 years), high school level (OR = 2.22 [1.33-3.73]; vs. university level), gestational diabetes (OR = 2.80 [1.56-5.01]) and hypertensive complications (OR = 3.80 [1.83-7.89]) were independently associated with prepregnancy obesity. Among the multiparous, primary (OR = 6.30 [2.40-16.57]), junior high (OR = 2.89 [1.81-4.64]) and high school (OR = 1.86 [1.18-2.93]) education levels (vs. university level), no attendance at antenatal classes (OR = 1.77 [1.16-2.72]), excess gestational weight gain (OR = 1.82 [1.20-2.76]), gestational diabetes (OR =5.16 [3.15-8.46]), hypertensive complications (OR = 8.13 [3.97-16.64]), caesarean delivery (OR = 1.80 [1.18-2.77]) and infant birth weight >= 4 kg (OR = 1.70 [1.03-2.80]; vs. birth weight between 2.5 kg and 4 kg) were independently associated with prepregnancy obesity. CONCLUSION: Obesity before pregnancy is associated with a set of sociodemographic characteristics and adverse pregnancy outcomes that differ across parity groups. Such findings are useful for targeted health policies aimed at attaining healthy prepregnancy weight and organizing perinatal care. PMID- 28841847 TI - The social and behavioral influences (SBI) study: study design and rationale for studying the effects of race and activation on cancer pain management. AB - BACKGROUND: Racial disparities exist in the care provided to advanced cancer patients. This article describes an investigation designed to advance the science of healthcare disparities by isolating the effects of patient race and patient activation on physician behavior using novel standardized patient (SP) methodology. METHODS/DESIGN: The Social and Behavioral Influences (SBI) Study is a National Cancer Institute sponsored trial conducted in Western New York State, Northern/Central Indiana, and lower Michigan. The trial uses an incomplete randomized block design, randomizing physicians to see patients who are either black or white and who are "typical" or "activated" (e.g., ask questions, express opinions, ask for clarification, etc.). The study will enroll 91 physicians. DISCUSSION: The SBI study addresses important gaps in our knowledge about racial disparities and methods to reduce them in patients with advanced cancer by using standardized patient methodology. This study is innovative in aims, design, and methodology and will point the way to interventions that can reduce racial disparities and discrimination and draw links between implicit attitudes and physician behaviors. TRIAL REGISTRATION: https://clinicaltrials.gov/ , #NCT01501006, November 30, 2011. PMID- 28841848 TI - Comparative efficacy and safety of paricalcitol versus vitamin D receptor activators for dialysis patients with secondary hyperparathyroidism: a meta analysis of randomized controlled trials. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT) is a severe complication for dialysis patients. Vitamin D receptor activators (VDRAs) are used to treat SHPT, but the comparative efficacy and safety between paricalcitol and other vitamin D receptor activators for management of SHPT in dialysis patients has been unproven. METHODS: We searched PubMed, Embase, and the Cochrane Library for the time period through June 2017 to identify randomized controlled trials that evaluated paricalcitol compared with other VDRAs for treatment of SHPT. The primary outcome was the percentage of patients with target reduction of intact parathyroid hormone (iPTH) from baseline. Secondary outcomes included incidences of hypercalcemia and hyperphosphatemia. The random-effects model was used to estimate relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: Eight studies (N = 759) were eligible for final inclusion. Compared with other VDRAs, no significant differences were found in the percentage of patients with target reduction of intact parathyroid hormone (iPTH) from baseline for paricalcitol treatment of SHPT in dialysis patients (RR, 1.01; 95% CI, 0. 87-1.18; p = 0.85). There were no differences in the incidence of hypercalcemia (RR, 0.95; 95% CI, 0.74-1.21; p = 0. 65) and hyperphosphatemia (RR, 0.94; 95% CI, 0.77-1.16; p = 0.58). CONCLUSIONS: The presently available evidence is insufficient to draw a conclusion regarding whether paricalcitol therapy has a comparative efficacy and safety over other VDRAs for treating dialysis patients with SHPT. Large-sample, well-conducted, high-quality RCTs with patient-level outcomes (i.e., mortality) are urgently needed. PMID- 28841849 TI - The diagnostic pathway of Parkinson's disease: a cross-sectional survey study of factors influencing patient dissatisfaction. AB - BACKGROUND: The diagnostic pathway of Parkinson's disease (PD) is often complicated. Experiences during this pathway can affect patients' satisfaction and their confidence and trust in healthcare providers. Although healthcare providers cannot influence the impact of the diagnosis, they can influence how patients experience the pathway. This study, therefore, aims to provide insight into PD patients' dissatisfaction with the diagnostic pathway and to describe the factors that influence it. METHODS: We carried out a cross-sectional survey study among 902 patient members of the Dutch Parkinson's Disease Association, who were each asked to write an essay about their diagnostic pathway. A coding format was developed to examine the content of these essays. Inter-observer agreement on coding patient dissatisfaction was calculated using Cohen's kappa. The chi2 test and a multivariable logistic regression analysis were performed to assess the relation between dissatisfaction and sex, level of education, duration of the pathway, communication with the general practitioner (GP) and the neurologist, the number of healthcare providers involved, whether or not a second opinion had taken place (including the person who initiated it) and diagnostic delay (taking into consideration who caused the delay according to the patient). A subgroup analysis was performed to gain insight into sex-related differences. RESULTS: Of all patients, 16.4% explicitly described they were dissatisfied with the diagnostic pathway, whereas 4.8% were very satisfied. The inter-observer agreement on coding dissatisfaction was kappa = 0.82. The chance of dissatisfaction increased with a lower level of education, the involvement of more than one additional healthcare provider, a second opinion initiated by the patient and delay caused by a healthcare provider. When only the GP and the neurologist were involved, women were more likely to be dissatisfied than men. CONCLUSIONS: PD patients' dissatisfaction with the diagnostic pathway is related to a lower level of education, a second opinion initiated by the patient and experienced diagnostic delay. GPs can positively influence patients' experiences if they are aware of these risk factors for dissatisfaction and pay extra attention to communication and shared decision making. This will contribute to a trusting therapeutic relationship that is indispensable with progression of the disease. PMID- 28841850 TI - Implementing the WHO integrated tool to assess quality of care for mothers, newborns and children: results and lessons learnt from five districts in Malawi. AB - BACKGROUND: In 2014 the World Health Organization (WHO) developed a new tool to be used to assess the quality of care for mothers, newborns and children provided at healthcare facility level. This paper reports on the feasibility of using the tool, its limitations and strengths. METHODS: Across 5 districts in Malawi, 35 healthcare facilities were assessed. The WHO tool includes checklists, interviews and observation of case management by which care is assessed against agreed standards using a Likert scale (1 lowest: not meeting standard, 5 highest: compliant with standard). Descriptive statistics were used to provide summary scores for each standard. A 'dashboard' system was developed to display the results. RESULTS: For maternal care three areas met standards; 1) supportive care for admitted patients (71% of healthcare facilities scored 4 or 5); 2) prevention and management of infections during pregnancy (71% scored 4 or 5); and 3) management of unsatisfactory progress of labour (84% scored 4 or 5). Availability of essential equipment and supplies was noted to be a critical barrier to achieving satisfactory standards of paediatric care (mean score; standard deviation: 2.9; SD 0.95) and child care (2.7; SD 1.1). Infection control is inadequate across all districts for maternal, newborn and paediatric care. Quality of care varies across districts with a mean (SD) score for all standards combined of 3 (SD 0.19) for the worst performing district and 4 (SD 0.27) for the best. The best performing district has an average score of 4 (SD 0.27). Hospitals had good scores for overall infrastructure, essential drugs, organisation of care and management of preterm labour. However, health centres were better at case management of HIV/AIDS patients and follow-up of sick children. CONCLUSIONS: There is a need to develop an expanded framework of standards which is inclusive of all areas of care. In addition, it is important to ensure structure, process and outcomes of health care are reflected. PMID- 28841851 TI - Combined Brown syndrome and superior oblique palsy without a trochlear nerve: case report. AB - BACKGROUND: Congenital Brown syndrome is characterized by limited elevation particularly during adduction. The pathogenesis of congenital Brown syndrome is still controversial. CASE PRESENTATION: A 6-year-old boy had been tilting his head to the left since infancy. He showed right hypertropia (RHT) of 2 prism diopters (Delta) in the primary position. He showed RHT 6Delta in right gaze, RHT 2Delta in left gaze, RHT 12Delta in right head tilt, and orthotropia in left head tilt. The right eye showed limitation of elevation and depression on adduction, and the left eye showed overdepression on adduction. MR images showed an absent right trochlear nerve with a hypoplastic ipsilateral superior oblique muscle. CONCLUSIONS: Congenital Brown syndrome may be associated with an absent trochlear nerve and hypoplastic superior oblique muscle suggesting an etiologic mechanism of congenital cranial dysinnervation disorder. PMID- 28841852 TI - Prevalence and risk factors for Staphylococcus aureus nasopharyngeal carriage during a PCV trial. AB - BACKGROUND: We conducted an ancillary study among individuals who had participated in a cluster-randomized PCV-7 trial in rural Gambia (some clusters were wholly-vaccinated while in others only young children had been vaccinated), to determine the prevalence and risk factors for Staphylococcus aureus nasopharyngeal carriage. METHODS: Two hundred thirty-two children aged 5-10 years were recruited and followed from 4 to 20 months after vaccination started. We collected 1264 nasopharyngeal swabs (NPS). S. aureus was isolated following conventional microbiological methods. Risk factors for carriage were assessed by logistic regression. RESULTS: Prevalence of S. aureus carriage was 25.9%. In the univariable analysis, prevalence of S. aureus carriage was higher among children living in villages wholly-vaccinated with PCV-7 [OR = 1.57 95%CI (1.14 to 2.15)] and children with least 1 year of education [OR = 1.44 95%CI (1.07 to 1.92)]. S. aureus carriage was also higher during the rainy season [OR = 1.59 95%CI (1.20 to 2.11)]. Carriage of S. pneumoniae did not have any effect on S. aureus carriage for any pneumococcal, vaccine-type (VT) or non-vaccine-type (NVT) carriage. Multivariate analysis showed that the higher prevalence of S. aureus observed among children living in villages wholly-vaccinated with PCV-7 occurred only during the rainy season OR 2.72 95%CI (1.61-4.60) and not in the dry season OR 1.28 95%CI (0.78-2.09). CONCLUSIONS: Prevalence of nasopharyngeal carriage of S. aureus among Gambian children increased during the rainy season among those children living in PCV-7 wholly vaccinated communities. However, carriage of S. aureus is not associated with carriage of S. pneumoniae. TRIAL REGISTRATION: ISRCTN51695599 . Registered August 04th 2006. PMID- 28841853 TI - Childhood cancer incidence by ethnic group in England, 2001-2007: a descriptive epidemiological study. AB - BACKGROUND: After the first year of life, cancers are the commonest cause of death in children. Incidence rates vary between ethnic groups, and recent advances in data linkage allow for a more accurate estimation of these variations. Identifying such differences may help identify potential risk or protective factors for certain childhood cancers. This study thus aims to ascertain whether such differences do indeed exist using nationwide data across seven years, as have previously been described in adult cancers. METHODS: We obtained data for all cancer registrations for children (aged 0-14) in England from January 2001 to December 2007. Ethnicity (self-assigned) was established through record linkage to the Hospital Episodes Statistics database or cancer registry data. Cancers were classified morphologically according to the International Classification of Childhood Cancer into four groups - leukaemias; lymphomas; central nervous system; and other solid tumours. Age standardised incidence rates were estimated for each ethnic group, as well as incidence rate ratios comparing each individual ethnic group (Indian, Pakistani, Bangladeshi, Black African, Black Carribean, Chinese) to Whites, adjusting for sex, age and deprivation. RESULTS: The majority of children in the study are UK born. Black children (RR = 1.18, 99% CI: 1.01-1.39), and amongst South Asians, Pakistani children (RR = 1.19, 99% CI: 1.02-1.39) appear to have an increased risk of all cancers. There is an increased risk of leukaemia in South Asians (RR = 1.31, 99% CI: 1.08-1.58), and of lymphoma in Black (RR = 1.72, 99% CI: 1.13-2.63) and South Asian children (RR = 1.51, 99% CI: 1.10-2.06). South Asians appear to have a decreased risk of CNS cancers (RR = 0.71, 99% CI: 0.54-0.95). CONCLUSIONS: In the tradition of past migrant studies, such descriptive studies within ethnic minority groups permit a better understanding of disease incidence within the population, but also allow for the generation of hypotheses to begin to understand why such differences might exist. Though a major cause of mortality in this age group, childhood cancer remains a relatively rare disease; however, the methods used here have permitted the first nationwide estimation of childhood cancer by individual ethnic group. PMID- 28841854 TI - Distribution of Streptococcus pneumoniae serotypes in the northeast macro-region of Sao Paulo state/Brazil after the introduction of conjugate vaccine. AB - BACKGROUND: Infections caused by Streptococcus pneumoniae (Spn) still challenge health systems around the world, even with advances in vaccination programs. The present study evaluated the frequency of various Spn serotypes isolated in Regional Health Care Network 13 (RRAS 13), which includes the regional health departments (RHDs) of Araraquara, Barretos, Franca and Ribeirao Preto, especially after the introduction of 10-valent pneumococcal conjugate vaccine (PCV10) in 2010. METHODS: The analyzed Spn strains were isolated from patients with invasive pneumococcal diseases (IPDs) and then sent to Adolfo Lutz Institute (ALI) for further confirmative identification tests during the period from 1998 to 2013. The samples were from the cities in RRAS13, which is located in the Northeast region of Sao Paulo State, and totals 90 municipalities. RESULTS: We analyzed strains isolated from 796 patients. They were predominantly: men (58.9%); 20 to 60 years old (32.2%); evaluated from 2003 to 2010 (60.2%); and diagnosed with meningitis (45.7%) and pneumonia (45.0%), the most common invasive pneumococcal diseases. In 2010, serotypes 3, 19F, 1, 23F, 6A and 6B were among the most frequent, while serotypes 3, 12F, 14, 6A, 18C, 8 and 6B were more common after the introduction of PCV10. Serotypes 14, 19F and 3 were more frequent in meningitis, while serotypes 14, 3 and 1 prevailed in pneumonia. After 2010, there was a decrease in serotypes 14, 1, 23F and 5 and an increase in serotypes 3, 12F, 11A and 8, which were not present in the vaccine. CONCLUSIONS: The present study noted the increase in serotypes 3, 12F, 11A and 8 after vaccination. None of those serotypes are included in the available conjugate vaccines, which highlights the importance of continued monitoring of IPDs in order to measure the disease burden in the population in the long term and provide new epidemiological information to determine the impact of PCV10 in Brazil. PMID- 28841855 TI - Comparison of PSA value at last follow-up of patients who underwent low-dose rate brachytherapy and intensity-modulated radiation therapy for prostate cancer. AB - BACKGROUND: To compare the PSA value at the last follow-up of patients who underwent prostate low-dose rate brachytherapy (LDR-BT) with that of patients who underwent intensity-modulated radiation therapy (IMRT). METHODS: A total of 610 prostate cancer patients (cT1c-3bN0M0) were enrolled, and 445 of them underwent LDR-BT, while 165 received IMRT (74-76 Gy). The median follow-up period of these two groups was 75 months (LDR-BT) and 78 months (IMRT), respectively. We also evaluated the biochemical recurrence (BCR)-free rate using two definitions (Phoenix definition and PSA >= 0.2 ng/mL). RESULTS: The percentage of patients who achieved PSA < 0.2 ng/mL at the last follow-up was 77.5% in the LDR-BT group and 49.7% in the IMRT group (p < 0.001). Among patients with a normal testosterone level at the last follow-up, the percentage of those who achieved PSA < 0.2 ng/mL at the last follow-up was 79.2% in the LDR-BT group and 32.1% in the IMRT group (p < 0.001). The 5-year BCR-free rate by the Phoenix definition in the IMRT and LDR-BT groups was 89.5 and 95.0% (p < 0.001), respectively. On the other hand, the 5-year BCR-free rate using the definition of PSA >= 0.2 ng/mL was 59.1 and 80.1% in the IMRT and LDR-BT groups, respectively (p < 0.001). CONCLUSIONS: The PSA value at the last follow-up of LDR-BT was significantly lower than that of IMRT, and this result was particularly marked in patients with a normal testosterone level at the last follow-up. PMID- 28841856 TI - Neuropathy-specific alterations in a Mexican population of diabetic patients. AB - BACKGROUND: Neuropathy is one of the major complications of type 2 diabetes mellitus. Our first aim was to determine the clinical characteristics of a population of diabetic patients with different types of neuropathy. Our next goal was to characterize the cytokine profile (IL-6 and IL-10), nerve growth factor (NGF) and circulating cell-adhesion molecules in these patients. Finally, we aimed to compare the renal function among the groups of neuropathic patients. METHODS: In a cross-sectional study, we included 217 diabetic patients classified in three groups: sensory polyneuropathy with hypoesthesia (DShP) or hyperesthesia (DSHP), and motor neuropathy (DMN). Two control groups were included: one of 26 diabetic non-neuropathic patients (DNN), and the other of 375 non-diabetic (ND) healthy subjects. The participants were attending to the Mexican Institute of Social Security. RESULTS: The circulating levels of NGF were significantly lower in diabetic patients, compared to healthy subjects. The range of IL-6 and IL-10 levels in neuropathic patients was higher than the control groups; however, several samples yielded null measurements. Neuropathic patients also showed increased circulating levels of the adhesion molecules ICAM, VCAM, and E Selectin, compared to the ND group. Moreover, neuropathic patients showed reduced glomerular filtration rates compared to healthy subjects (82-103 ml/min per 1.73 m2, data as range from 25th-75th percentiles), especially in the group with DMN (45-76 ml/min per 1.73 m2). CONCLUSIONS: Some particular alterations in neuropathic patients included -but were not limited to- changes in circulating NGF, cell adhesion molecules, inflammation, and the worsening of the renal function. This study supports the need for further clinical surveillance and interventions considering a neuropathy-related basis. PMID- 28841857 TI - Regional association analysis-based fine mapping of three clustered QTL for verticillium wilt resistance in cotton (G. hirsutum. L). AB - BACKGROUND: Verticillium wilt is one of the most destructive diseases affecting global cotton production. The most effective way to control wilt disease has been the development of new cotton varieties that are resistant to VW. VW-resistant Upland cotton cultivars have been created in both the USA and China by Gossypium barbadense introgression. More than 100 VW resistance quantitative trait loci have been detected. RESULTS: Three clustered VW resistance-related QTL were detected in a 120-line association population and assigned to a genome region of 14,653,469-55,190,112 bp in Dt_chr9. A regional association analysis-based fine mapping strategy was developed to narrow down the confidence intervals of the above QTL. The estimated LD decay of the genome region of interest was much faster than those of the Dt_chr9 chromosome and the whole genome, suggesting the existence of a recombination hotspot. Thirty-seven haplotype blocks were detected. The confidence intervals of the three clustered QTL were narrowed down to a region of 937,906 bp involving QTL-i23734Gh and a region of 1,389,417 bp involving QTL- i10740Gh, respectively. Each region contained the strongest association signal. Comparative analysis redefined the confidence intervals of the other three QTLs, qDL52T2-c19, QTL-BNL4069, and QTL-JESPR0001. The broad spectrum VW resistance QTL qVW-D9-1 was demonstrated to be closely linked with the three redefined QTL, QTL-i23734Gh, QTL- i10740Gh and QTL-JESPR0001. Twelve functional genes were detected to be located within the redefined confidence intervals of VW resistance QTL. The mRNA CotAD_60243, encoding E3 ubiquitin protein ligase UPL2-like, responsible for plant innate immunity and broad spectrum disease resistance, was found to be overlapped with the strongest association signal i10740Gh. Six mRNAs encoding putative disease-resistance proteins were within the redefined confidence interval of QTL-JESPR0001, suggesting a tandem arrangement of R genes. CONCLUSIONS: Our results proved that the VW resistance effect related to three clustered VW resistance-related QTL was actually controled by two redefined major QTL and severlal minor loci. The broad spectrum VW resistance QTL qVW-D9-1 may be closely linked with the two redefined major QTLs. The tandem arrangement of R genes were detected in the redefined confidence interval of QTL-JESPR0001. The candidate genes obtained should be helpful in identifying and characterizing defense genes related to VW resistance QTL. PMID- 28841858 TI - Skeletal muscle depletion during chemotherapy has a large impact on physical function in elderly Japanese patients with advanced non-small-cell lung cancer. AB - BACKGROUND: Elderly patient with advanced cancer is one of the most vulnerable populations. Skeletal muscle depletion during chemotherapy may have substantial impact on their physical function. However, there is little information about a direct relationship between quantity of muscle and physical function. We sought to explore the quantitative association between skeletal muscle depletion, and muscle strength and walking capacity in elderly patients with advanced non-small cell lung cancer (NSCLC). METHODS: Thirty patients aged >=70 years with advanced NSCLC (stage III-IV) scheduled to initiate first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. Lumbar skeletal muscle index (LSMI, cm2/m2), incremental shuttle walking distance (ISWD, m), and hand-grip strength (HGS, kg) were assessed at baseline, and 6 +/- 2 weeks (T2) and 12 +/- 4 weeks (T3) after study enrollment. Associations were analyzed using linear regression. RESULTS: Altogether, 11 women and 19 men with a median age of 74 (range, 70-82) years were included in the study; 24 received cytotoxic chemotherapy and 6, gefitinib. Mean +/- standard deviation of LSMI, ISWD and HGS were 41.2 +/- 7.8 cm2/m2, 326.0 +/- 127.9 m, and 29.3 +/- 8.5 kg, respectively. LSMI and ISWD significantly declined from baseline to T2 and T3. HGS significantly declined from baseline to T2 and T3 only in men. Change in LSMI was significantly associated with change in HGS (beta = 0.3 +/- 0.1, p = 0.0127) and ISWD (beta = 8.8 +/- 2.4, p = 0.0005). CONCLUSIONS: Skeletal muscle depletion accompanied with physical functional decline started in the early phase of the chemotherapy in elderly patients with advanced NSCLC. Our results suggest that there may be a need for early supportive care in these patients to prevent functional decline during chemotherapy. TRIAL REGISTRATION: Trial registration number: UMIN000009768 Name of registry: UMIN (University hospital Medical Information Network). URL of registry: Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013. PMID- 28841859 TI - A GJA9 frameshift variant is associated with polyneuropathy in Leonberger dogs. AB - BACKGROUND: Many inherited polyneuropathies (PN) observed in dogs have clinical similarities to the genetically heterogeneous group of Charcot-Marie-Tooth (CMT) peripheral neuropathies in humans. The canine disorders collectively show a variable expression of progressive clinical signs and ages of onset, and different breed prevalences. Previously in the Leonberger breed, a variant highly associated with a juvenile-onset PN was identified in the canine orthologue of a CMT-associated gene. As this deletion in ARHGEF10 (termed LPN1) does not explain all cases, PN in this breed may encompass variants in several genes with similar clinical and histopathological features. RESULTS: A genome-wide comparison of 173 k SNP genotypes of 176 cases, excluding dogs homozygous for the ARHGEF10 variant, and 138 controls, was carried out to detect further PN-associated variants. A single suggestive significant association signal on CFA15 was found. The genome of a PN-affected Leonberger homozygous for the associated haplotype was sequenced and variants in the 7.7 Mb sized critical interval were identified. These variants were filtered against a database of variants observed in 202 genomes of various dog breeds and 3 wolves, and 6 private variants in protein-coding genes, all in complete linkage disequilibrium, plus 92 non-coding variants were revealed. Five of the coding variants were predicted to have low or moderate effect on the encoded protein, whereas a 2 bp deletion in GJA9 results in a frameshift of high impact. GJA9 encodes connexin 59, a connexin gap junction family protein, and belongs to a group of CMT-associated genes that have emerged as important components of peripheral myelinated nerve fibers. The association between the GJA9 variant and PN was confirmed in an independent cohort of 296 cases and 312 controls. Population studies showed a dominant mode of inheritance, an average age of onset of approximately 6 years, and incomplete penetrance. CONCLUSIONS: This GJA9 variant represents a highly probable candidate variant for another form of PN in Leonberger dogs, which we have designated LPN2, and a new candidate gene for CMT disease. To date, approximately every third PN-diagnosed Leonberger dog can be explained by the ARHGEF10 or GJA9 variants, and we assume that additional genetic heterogeneity in this condition exists in the breed. PMID- 28841860 TI - Usefulness of intraoperative insular electrocorticography in modified functional hemispherectomy. AB - BACKGROUND: The insular cortex is not routinely removed in modified functional hemispherectomy due to the risk of injury to the main arteries and to deep structures. Our study evaluates the safety and usefulness of applying intraoperative electrocorticography (ECoG) on the insular during the hemispherectomy. METHODS: We included all patients who underwent insular ECoG during a modified functional hemispherectomy from 2012 to 2015. After the surgery, the decision for further resection of the insular cortex was made based on the presence of electrographic seizures on ECoG. RESULTS: The study included 19 patients (age, 6.4 +/- 4.7 years, mean +/- standard deviation). Electrographic seizures were identified in 5 patients (26.3%). Sixteen of the 19 patients (84.2%) became seizure-free with a follow-up duration of 3.1 +/- 0.6 years and no vascular complication occurred. CONCLUSIONS: Intraoperative insular ECoG monitoring can be performed safely while providing a tailored approach for insular resection during modified hemispherectomy. PMID- 28841861 TI - Reflections on two years after establishing an orthogeriatric unit: a focus group study of healthcare professionals' expectations and experiences. AB - BACKGROUND: For decades hospitals have been "vertically" organized, with the risk that specialization leads to fragmented and one-sided views of patient care and treatment that may cause poor communication and coordination of care and treatment. Two years after the introduction of an orthogeriatric unit for elderly patients admitted with fragility fractures, we studied the involved healthcare professionals' perspectives and experiences with working in an interprofessional organization. METHODS: We performed four focus groups interviews with 19 healthcare workers representing different professions. The interviews were analysed using systematic text condensation (STC). RESULTS: Three themes were identified: 1) A patient-centred approach, 2) An opportunity for professional growth and 3) The benefits of interprofessional collaboration. The interviewees emphasized in particular the systematic and frequent face-to-face communication enabled by the interprofessional team meetings as essential to their feeling of enhanced collegial solidarity. All groups expressed their respect for other groups' competences and their vital contributions to good orthogeriatric care. However, collaboration was challenged by the groups' divergent views of the patients and of the relevance of the information given in the weekly meetings. Heavy workloads were also mentioned. The opportunity for professional growth was also felt to be imperilled by some professionals. CONCLUSIONS: All participants indicated their view that the orthogeriatric organization had improved the quality of care and treatment. Furthermore, good communication, mutual respect for other professional competences and shared goals were found to have enhanced interprofessional collaboration and improved the sense of having a shared mission. However, differences in approaches and expectations continued to challenge the orthogeriatric model after 2 years. Neither did all professionals find orthogeriatric care professionally challenging. PMID- 28841862 TI - Erratum to: The Liverpool Care Pathway: discarded in cancer patients but good enough for dying nursing home patients? A systematic review. PMID- 28841863 TI - Erratum to: Expression and function of phosphodiesterases (PDEs) in the rat urinary bladder. PMID- 28841864 TI - Comparison of statistical models to estimate parasite growth rate in the induced blood stage malaria model. AB - BACKGROUND: The efficacy of vaccines aimed at inhibiting the growth of malaria parasites in the blood can be assessed by comparing the growth rate of parasitaemia in the blood of subjects treated with a test vaccine compared to controls. In studies using induced blood stage malaria (IBSM), a type of controlled human malaria infection, parasite growth rate has been measured using models with the intercept on the y-axis fixed to the inoculum size. A set of statistical models was evaluated to determine an optimal methodology to estimate parasite growth rate in IBSM studies. METHODS: Parasite growth rates were estimated using data from 40 subjects published in three IBSM studies. Data was fitted using 12 statistical models: log-linear, sine-wave with the period either fixed to 48 h or not fixed; these models were fitted with the intercept either fixed to the inoculum size or not fixed. All models were fitted by individual, and overall by study using a mixed effects model with a random effect for the individual. RESULTS: Log-linear models and sine-wave models, with the period fixed or not fixed, resulted in similar parasite growth rate estimates (within 0.05 log10 parasites per mL/day). Average parasite growth rate estimates for models fitted by individual with the intercept fixed to the inoculum size were substantially lower by an average of 0.17 log10 parasites per mL/day (range 0.06 0.24) compared with non-fixed intercept models. Variability of parasite growth rate estimates across the three studies analysed was substantially higher (3.5 times) for fixed-intercept models compared with non-fixed intercept models. The same tendency was observed in models fitted overall by study. Modelling data by individual or overall by study had minimal effect on parasite growth estimates. CONCLUSIONS: The analyses presented in this report confirm that fixing the intercept to the inoculum size influences parasite growth estimates. The most appropriate statistical model to estimate the growth rate of blood-stage parasites in IBSM studies appears to be a log-linear model fitted by individual and with the intercept estimated in the log-linear regression. Future studies should use this model to estimate parasite growth rates. PMID- 28841865 TI - Comparison of outcomes according to fixation technique following the modified Ludloff osteotomy for hallux valgus in patients with rheumatoid arthritis. AB - BACKGROUND: Clinical and radiological outcomes including fixation stability of osteotomy site were compared in rheumatoid arthritis (RA) patients who underwent modified Ludloff osteotomy to correct hallux valgus with osteotomy site fixation using two screws versus those who underwent additional fixation using a plate. METHODS: The fixation technique performed with two screws was used to fix the osteotomy sites following modified Ludloff osteotomy in 15 patients (15 feet, Group S), while the augmented plate fixation technique was used in 14 patients (16 feet, Group P). Surgical outcomes were analysed using the American Orthopedic Foot and Ankle Society (AOFAS) scores, and radiologic parameters measured before surgery and during follow-up examinations. To evaluate the stability of each osteotomy site fixation technique, the 1-2 inter-metatarsal angle (IMA) and angle of the altered margin of the lateral cortex (AMLC) were measured immediately and 6 weeks after surgery, and variations in the angles were compared. In addition, bone mineral density (BMD) values were compared between patients with correction loss at the osteotomy site and those with no loss of correction. RESULTS: No significant differences between groups were found for total AOFAS scores before surgery and at the final follow-up. However, significant differences were observed in the 1-2 IMA, beginning at 6 weeks postoperatively and continuing through the final follow-up. The 1-2 IMA and angle of AMLC measured immediately after and 6 weeks after surgery showed significantly greater variation in Group S than in Group P. In Group S, patients with correction loss (5 feet) at osteotomy site showed significantly lower BMD values than those with no loss of correction (10 feet). Despite the lower BMD values of patients in Group P than in Group S, a loss of correction did not occur in these patients. CONCLUSIONS: Correction loss occurred at the osteotomy site within 6 weeks postoperatively in patients who underwent fixation using only the two-screw fixation technique following modified Ludloff osteotomy; such loss could be reduced using the augmented plate fixation technique even in patients with osteoporosis. PMID- 28841867 TI - Yang-warming method in the treatment of diabetic peripheral neuropathy: an updated systematic review and meta-analysis. AB - BACKGROUND: Various studies have suggested the effectiveness of Chinese medicine in the treatment of diabetic peripheral neuropathy (DPN). There are several principles and methods in Chinese medicine for the treatment of DPN and yang warming method is one of them. The purpose of this meta-analysis was to review the effectiveness and safety of yang-warming method using yang-warming Chinese medicine (YCM) in the treatment of DPN. METHODS: A computer-based search of the articles from January 2001 to April 2016 with Chinese and English databases such as CNKI, CBM, Wanfang, VIP, Medline, Embase and Cochrane central register of controlled trials as well as manual search of the related articles was conducted. Randomized Controlled Trials (RCTs) comparing yang-warming Chinese medicines with western medicines in the treatment of DPN were considered for the study. The outcome measures were change in the sensory or motor nerve conduction velocity, total efficacy rate evaluated by clinical symptoms improvement, and adverse events. Two authors independently assessed the methodological quality of the included articles using Jadad scale and the twelve criteria recommended by Cochrane Back Review Group. Data were analyzed using RevMan 5.3 software provided by Cochrane collaboration. RESULTS: A total of 25 articles were taken for the study. Meta-analysis results showed that yang-warming Chinese medicines used in the formula alone or in combination with western medicines improved the nerve conduction velocity (NCV) in comparison to western medicines alone (p < 0.001). There was also a significant difference in the total efficacy rate between the two groups (p < 0.001). Most of the included studies did not clearly report the adverse events. CONCLUSIONS: Yang-warming Chinese medicines alone or in combination with western medicines were apparently better than conventional western medicines in the treatment of DPN. Because of the poor quality of the reported works that were available for the present meta-analysis, it is earlier to claim the superiority of yang-warming method using YCM to western medicines for the treatment of DPN. To support these early findings, further standardized and rigorous RCTs are required. PMID- 28841866 TI - Differences in lumbar spine and lower extremity kinematics in people with and without low back pain during a step-up task: a cross-sectional study. AB - BACKGROUND: Low back pain (LBP) affects more than one third of the population at any given time, and chronic LBP is responsible for increased medical costs, functional limitations and decreased quality of life. A clear etiology is often difficult to identify, but aberrant posture and movement are considered contributing factors to chronic LBP that are addressed during physiotherapy intervention. Information about aberrant movement during functional activities in people with LBP can help inform more effective interventions. The purpose of this study was to determine if there are differences in lumbar spine and lower extremity kinematics in people with and without LBP during a step-up task. METHODS: A convenience sample of 37 participants included 19 with LBP and 18 without a history of LBP. All participants were between the ages of 18 and 65, and controls were matched to participants with LBP based on age, gender and BMI. A motion capture system was used to record spine and lower extremity kinematics during the step-up task. ANOVA tests were used to determine differences in three dimensional kinematics between groups. RESULTS: Participants with LBP displayed less lower lumbar motion in the sagittal plane (P = 0.001), more knee motion in the coronal plane (P = 0.001), and more lower extremity motion in the axial plane (P = 0.002) than controls. CONCLUSIONS: People with LBP display less lower lumbar spine motion in the sagittal plane and more out-of-plane lower extremity motion. Clinically, the step-up task can be used to identify these aberrant movements to develop more focused functional interventions for patients with LBP. TRIAL REGISTRATION: Not applicable. PMID- 28841868 TI - A systematic review of the effectiveness of policies restricting access to pregabalin. AB - BACKGROUND: Formularies often employ restriction policies to reduce pharmacy costs. Pregabalin, an alpha-2-delta ligand, is approved for treatment of fibromyalgia (FM); neuropathic pain (NeP) due to postherpetic neuralgia (PHN), diabetic peripheral neuropathy (pDPN), spinal cord injury; and as adjunct therapy for partial onset seizures. Pregabalin is endorsed as first-line therapy for these indications by several US and EU medical professional societies. However, restriction policies such as prior authorization (PA) and step therapy (ST) often favor less costly generic pain medications over pregabalin. METHODS: A structured literature search (PubMed, past 11 years) was conducted to evaluate whether restriction policies against pregabalin support real-world economic and healthcare utilization benefits. RESULTS: Search criteria identified three claims analyses and a modeling study that evaluated patients with NeP and/or FM with and without PA restrictions; three other studies included patients with FM and NeP in plans with ST requirements, and one evaluated a mail order requirement program. All studies evaluated outcomes during follow-up periods of 6 months or longer. Overall, PA, ST, and mail order restriction policies effectively reduced pregabalin usage, but the effects were inconsistent with reducing pharmacy costs and were non-significant for total disease-related medical costs. Two studies (one PA; one ST) reported significantly higher disease-related costs in restricted plans. The modeling study failed to demonstrate cost savings with PA. Opioid usage was higher in PA-restricted plans (two studies). The US Centers for Disease Control and Prevention and several professional NeP guidelines recommend opioid use only in cases when other non-opioid pain therapies have proven ineffective. New US Government taskforce guidelines now seek to reduce opioid exposure. Additionally, in both ST studies, gabapentin utilization (a common ST edit) was significantly increased. Both studies had substantial proportions of FM and pDPN patients and the only pain condition gabapentin is approved to treat in the United States is PHN. CONCLUSION: PA and ST restriction policies significantly decrease utilization of pregabalin, but do not consistently demonstrate cost savings for US health plans. More research is needed to evaluate whether these policies may lead to increased opioid usage as found in some studies. TRIAL REGISTRATION: N/A. PMID- 28841869 TI - Measurements of the trapezius and erector spinae muscles using virtual touch imaging quantification ultrasound-Elastography: a cross section study. AB - BACKGROUND: This study uses virtual touch imaging quantification (VTIQ) technology for the first time to conduct measurements of the trapezius and erector spinae muscles in a large study population. The significance of various influencing factors, such as age and sex, are also examined. METHOD: The study population comprised 278 subjects. The Siemens Acuson S3000 and VTIQ technology were used for measurements of the trapezius and erector spinae muscles (Siemens Healthcare, Erlangen, Germany). RESULTS: The following mean values +/- standard deviation were calculated: left trapezius: males 2.89 +/- 0.38 m/s, females 2.71 +/- 0.37 m/s; right trapezius: males 2.84 +/- 0.41 m/s, females 2.70 +/- 0.38 m/s; left erector spinae: males 2.97 +/- 0.50 m/s, females 2.81 +/- 0.57 m/s; right erector spinae: males 3.00 +/- 0.52 m/s, females 2.77 +/- 0.59 m/s. A significant difference between male and female subjects was demonstrated both for the shear wave velocities of the trapezius and erector spinae as well as for the thickness of the trapezius muscle (p < 0.05). There was also a significant difference in muscle elasticity between subjects over 60 years of age and those under 60 (p < 0.05). Furthermore, the results indicate that regular physical activity has an effect on muscle elasticity. CONCLUSIONS: Our results demonstrate significantly different results between male and female subjects and between under- and over-sixty-year-old subjects. This means that sex-related and age adapted considerations are obviously needed for further studies. PMID- 28841870 TI - Molecular characterization of bovine tuberculosis strains in two slaughterhouses in Morocco. AB - BACKGROUND: Bovine tuberculosis (BTB) is caused by Mycobacterium bovis, which belongs to the Mycobacterium tuberculosis complex. Mycobacterium bovis have been described to be responsible of most cases of bovine tuberculosis. Although M. tuberculosis, M. africanum and non-complex mycobacteria were isolated from cattle. In Morocco, so far, no molecular studies were conducted to characterize the strains responsible of BTB. The present study aims to characterize M. bovis in Morocco. The present study was conducted in slaughterhouses in Rabat and El Jadida. Samples were collected from 327 slaughtered animals with visible lesions suggesting BTB. RESULTS: A total of 225 isolates yielded cultures, 95% (n = 215) of them were acid-fast (AF). Sixty eight per cent of the AF positive samples were confirmed as tuberculous mycobacteria (n = 147), 99% of these (n = 146) having RD9 and among the latter, 98% (n = 143) positive while 2% (n = 3) negative for RD4 A total of 134 samples were analyzed by spoligotyping of which 14 were in cluster and with 41 different spoligotypes, ten of them were new patterns (23%). The most prevalent spoligotypes were SB0121, SB0265, and SB0120, and were already identified in many other countries, such as Algeria, Spain, Tunisia, the United States and Argentina. CONCLUSION: The shared borders between Algeria and Morocco, in addition to the previous importation of cattle from Europe and the US could explain the similarities found in M. bovis spoligotypes. On the other hand, the desert of Morocco could be considered as an efficient barrier preventing the introduction of BTB to Morocco from West Central and East Africa. Our findings suggest a low level endemic transmission of BTB similar to other African countries. However, more research is needed for further knowledge about the transmission patterns of BTB in Morocco. PMID- 28841871 TI - Insulin treatment corrects hepcidin but not YKL-40 levels in persons with type 2 diabetes mellitus matched by body mass index, waist-to-height ratio, C-reactive protein and Creatinine. AB - BACKGROUND: It has been shown that hepcidin and YKL-40 levels change in persons with insulin resistance in different circumstances. However, variations of the levels of these parameters through the stages of prediabetes and type 2 diabetes mellitus are unclear. We hypothesized that hepcidin levels will decrease in persons with prediabetes, while these levels will tend to correct when persons with diabetes are treated with insulin. Finally we sought to determine the levels of YKL-40 in all groups of participants included in the study. METHODS: Serum hepcidin levels and YKL-40 levels were measured in control group (n = 20), persons with prediabetes (n = 30) and persons with diabetes on insulin therapy (n = 30) using ELISA method. Patients in all three groups were matched by Body Mass Index, Waist-to-Height Ratio, C-Reactive Protein and creatinine levels. RESULTS: Hepcidin levels were lower in persons with prediabetes compared to control, while persons with diabetes on insulin therapy had higher values than those with prediabetes (p = 0,00001). YKL-40 levels showed no significant changes. CONCLUSIONS: Serum hepcidin levels in matched persons with prediabetes are a stronger marker of early changes in glucose metabolism compared to YKL-40 levels. Also, treatment with insulin corrects hepcidin levels, but not YKL-40 levels. Correcting levels of hepcidin is important for reducing iron-overload, which is a risk factor for diabetes. PMID- 28841873 TI - Responding to health and social needs of aging Latinos in new-growth communities: a qualitative study. AB - BACKGROUND: The development of new-growth communities of Latino immigrants in southern states has challenged the traditional health and social service infrastructure. An interprofessional team of service providers, Latino leaders, and university faculty partnered to establish linkages with the Latino community and providers serving aging adults and to explore the health and social needs of aging Latinos residing in a rural region. METHODS: A qualitative descriptive study was conducted through a community-university partnership, the Aging Latino Research Team (ALRT). Data were generated from nine focus groups and 15 key informant interviews with Latino and non-Latino community members and service providers in rural, eastern North Carolina (ENC). RESULTS: Thematic analysis was used to identify common patterns and form recommendations for future research and programs. Themes common to Latino participants were: "We are put off to one side"; "If I can't work, I can't survive"; and "Without documents, you are no one." Themes common to non-Latino participants were: "Older Latinos are not well served"; "Older Latinos are invisible"; "Older Latinos are undocumented and afraid"; and "Older Latinos are wandering the highway". CONCLUSION: A major finding of this research was the extent to which discrepancies in perceptions between Latino participants and non-Latino participants exist. These discrepancies revealed ethnic stereotyping and cultural insensitivity as major barriers in access to care. PMID- 28841872 TI - From habits of attrition to modes of inclusion: enhancing the role of private practitioners in routine disease surveillance. AB - BACKGROUND: Private practitioners are the preferred first point of care in a majority of low and middle-income countries and in this position, best placed for the surveillance of diseases. However their contribution to routine surveillance data is marginal. This systematic review aims to explore evidence with regards to the role, contribution, and involvement of private practitioners in routine disease data notification. We examined the factors that determine the inclusion of, and the participation thereof of private practitioners in disease surveillance activities. METHODS: Literature search was conducted using the PubMed, Web of Knowledge, WHOLIS, and WHO-IRIS databases to identify peer reviewed and gray full-text documents in English with no limits for year of publication or study design. Forty manuscripts were reviewed. RESULTS: The current participation of private practitioners in disease surveillance efforts is appalling. The main barriers to their participation are inadequate knowledge leading to unsatisfactory attitudes and misperceptions that influence their practices. Complicated reporting mechanisms with unclear guidelines, along with unsatisfactory attitudes on behalf of the government and surveillance program managers also contribute to the underreporting of cases. Infrastructural barriers especially the availability of computers and skilled human resources are critical to improving private sector participation in routine disease surveillance. CONCLUSION: The issues identified are similar to those for underreporting within the Integrated infectious Disease Surveillance and Response systems (IDSR) which collects data mainly from public healthcare facilities. We recommend that surveillance program officers should provide periodic training, supportive supervision and offer regular feedback to the practitioners from both public as well as private sectors in order to improve case notification. Governments need to take leadership and foster collaborative partnerships between the public and private sectors and most importantly exercise regulatory authority where needed. PMID- 28841874 TI - Science of health care delivery milestones for undergraduate medical education. AB - BACKGROUND: The changing healthcare landscape requires physicians to develop new knowledge and skills such as high-value care, systems improvement, population health, and team-based care, which together may be referred to as the Science of Health Care Delivery (SHCD). To engender public trust and confidence, educators must be able to meaningfully assess physicians' abilities in SHCD. We aimed to develop a novel set of SHCD milestones based on published Accreditation Council for Graduate Medical Education (ACGME) milestones that can be used by medical schools to assess medical students' competence in SHCD. METHODS: We reviewed all ACGME milestones for 25 specialties available in September 2013. We used an iterative, qualitative process to group the ACGME milestones into SHCD content domains, from which SHCD milestones were derived. The SHCD milestones were categorized within the current ACGME core competencies and were also mapped to Association of American Medical Colleges' Entrustable Professional Activities (AAMC EPAs). RESULTS: Fifteen SHCD sub-competencies and corresponding milestones are provided, grouped within ACGME core competencies and mapped to multiple AAMC EPAs. CONCLUSIONS: This novel set of milestones, grounded within the existing ACGME competencies, defines fundamental expectations within SHCD that can be used and adapted by medical schools in the assessment of medical students in this emerging curricular area. These milestones provide a blueprint for SHCD content and assessment as ongoing revisions to milestones and curricula occur. PMID- 28841875 TI - Prevalence and change of central obesity among US Asian adults: NHANES 2011-2014. AB - BACKGROUND: Central obesity is a major risk factor for cardiometabolic diseases. The prevalence of central obesity has not been reported fully among Asian adults in the United States (US). METHODS: Cross-sectional data of 1288 Asian adults aged 20 years or over was selected from the US National Health and Nutrition Examination Survey with a stratified multi-stage sampling design. The prevalence of central obesity was calculated with 95% confidence intervals (CIs) and Chi square tests were conducted to test the significance of the prevalence differences across characteristic groups. RESULTS: The overall prevalence of central obesity among US Asian adults was 58.1% in 2011-2014. The prevalence of central obesity was higher in older adults (73.5%) than in young adults (45.4%) (p < 0.0001). Women had 13.4% higher prevalence than men (64.4% vs 51.0%, p < 0.0001). The prevalence increased over time (2011-2012 vs 2013-2014) in young adults (39.2% vs 51.5%), men (45.4% vs 56.6%), adults with college education or above (54.2% vs 61.7%) and non-poor adults (55.4% vs 62.4%). Compared with men, women had higher prevalence in each subgroup of age, education, poverty, and length of time (except for the subgroup of "born in the US") (all p < 0.05) and in the subgroup of "married or living with partner" for marital status (p < 0.0001). CONCLUSION: Central obesity is prevalent in Asian adults, particularly in older adults and women. More efforts are needed to prevent and treat obesity in Asian adults as Asians are incurring the greatest increase in type 2 diabetes in parallel with the rising rate of central adiposity. PMID- 28841876 TI - Specific entrustable professional activities for undergraduate medical internships: a method compatible with the academic curriculum. AB - BACKGROUND: Competency-based education has been considered the most important pedagogical trend in Medicine in the last two decades. In clinical contexts, competencies are implemented through Entrustable Professional Activities (EPAs) which are observable and measurable. The aim of this paper is to describe the methodology used in the design of educational tools to assess students' competencies in clinical practice during their undergraduate internship (UI). In this paper, we present the construction of specific APROCs (Actividades Profesionales Confiables) in Surgery (S), Gynecology and Obstetrics (GO) and Family Medicine (FM) rotations with three levels of performance. METHODS: The study considered a mixed method exploratory type design, a qualitative phase followed by a quantitative validation exercise. In the first stage data was obtained from three rotations (FM, GO and S) through focus groups about real and expected activities of medical interns. Triangulation with other sources was made to construct benchmarks. In the second stage, narrative descriptions with the three levels were validated by professors who teach the different subjects using the Delphi technique. RESULTS: The results may be described both curricular and methodological wise. From the curricular point of view, APROCs were identified in three UI rotations within clinical contexts in Mexico City, benchmarks were developed by levels and validated by experts' consensus. In regard to methodological issues, this research contributed to the development of a strategy, following six steps, to build APROCs using mixed methods. CONCLUSIONS: Developing benchmarks provides a regular and standardized language that helps to evaluate student's performance and define educational strategies efficiently and accurately. The university academic program was aligned with APROCs in clinical contexts to assure the acquisition of competencies by students. PMID- 28841877 TI - Influence of resting lung diffusion on exercise capacity in patients with COPD. AB - BACKGROUND: Lung diffusing capacity for carbon monoxide (DLCO) gives an overall assessment of functional lung surface area for gas exchange and can be assessed using various methods. DLCO is an important factor in exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). We investigated if the intra-breath (IBDLCO) method may give a more sensitive measure of available gas exchange surface area than the more typical single breath (SBDLCO) method and if COPD subjects with the largest resting DLCO relative to pulmonary blood flow (Qc) would have a more preserved exercise capacity. METHODS: Informed consent, hemoglobin, spirometry, SBDLCO, IBDLCO, and Qc during IBDLCO were performed in moderate to severe COPD patients, followed by progressive cycle ergometry to exhaustion with measures of oxygen saturation (SaO2) and expired gases. RESULTS: Thirty two subjects (47% female, age 66 +/- 9 yrs., BMI 30.4 +/- 6.3 kg/m2, smoking hx 35 +/- 29 pkyrs, 2.3 +/- 0.8 on the 0-4 GOLD classification scale) participated. The majority used multiple inhaled medications and 20% were on oral steroids. Averages were: FEV1/FVC 58 +/- 10%Pred, peak VO2 11.4 +/- 3.1 ml/kg/min, and IBDLCO 72% of the SBDLCO (r = 0.88, SB vs IB methods). Using univariate regression, both the SB and IBDLCO (% predicted but not absolute) were predictive of VO2peak in ml/kg/min; SBDLCO/Qc (r = 0.63, p < 0.001) was the best predictor of VO2peak; maximal expiratory flows over the mid to lower lung volumes were the most significantly predictive spirometric measure (r = 0.49, p < 0.01). However, in multivariate models only BMI added additional predictive value to the SBDLCO/Qc for predicting aerobic capacity (r = 0.73). Adjusting for current smoking status and gender did not significantly change the primary results. CONCLUSION: In patients with moderate to severe COPD, preservation of lung gas exchange surface area as assessed using the resting SBDLCO/Qc appears to be a better predictor of exercise capacity than more classic measures of lung mechanics. PMID- 28841878 TI - The role of Lutheran/basal cell adhesion molecule in human bladder carcinogenesis. AB - BACKGROUND: Lutheran/basal cell adhesion molecule (Lu/BCAM) is a membrane bound glycoprotein. This study was performed to investigate the role and downstream signaling pathway of Lu/BCAM in human bladder tumorigenesis. METHODS: Five human bladder cancer (E6, RT4, TSGH8301, TCCSUP and J82), one stable mouse fibroblast cell line (NIH-Lu) expressing Lu/BCAM transgene and sixty human uroepithelial carcinoma specimens were analyzed by real-time PCR, immunohistochemistry (IHC), immunofluorescence (IFA) staining, Western blotting and promoter luciferase assay for Lu/BCAM, respectively. The tumorigenicity of Lu/BCAM was demonstrated by focus formation, colony-forming ability, tumour formation, cell adhesion and migration. RESULTS: H-ras V12 was revealed to up-regulate Lu/BCAM at both transcriptional and translation levels. Lu/BCAM expression was detected on the membrane of primary human bladder cancer cells. Over-expression of Lu/BCAM in NIH Lu stable cells increased focus number, colony formation and cell adhesion accompanied with F-actin rearrangement and decreased cell migration compared with parental NIH3T3 fibroblasts. In the presence of laminin ligand, Lu/BCAM overexpression further suppressed cell migration accompanied with increased cell adhesion. We further revealed that laminin-Lu/BCAM-induced cell adhesion and F actin rearrangement were through increased Erk phosphorylation with an increase of RhoA and a decrease of Rac1 activity. Similarly, high Lu/BCAM expression was detected in the tumors of human renal pelvis, ureter and bladder, and was significantly associated with advanced tumor stage (p = 0.02). Patients with high Lu/BCAM expression showed a trend toward larger tumor size (p = 0.07) and lower disease-specific survival (p = 0.08), although not reaching statistical significance. CONCLUSION: This is the first report showing that Lu/BCAM, in the presence of its ligand laminin, is oncogenic in human urothelial cancers and may have potential as a novel therapeutic target. PMID- 28841879 TI - An Integrative multi-lineage model of variation in leukopoiesis and acute myelogenous leukemia. AB - BACKGROUND: Acute myelogenous leukemia (AML) progresses uniquely in each patient. However, patients are typically treated with the same types of chemotherapy, despite biological differences that lead to differential responses to treatment. RESULTS: Here we present a multi-lineage multi-compartment model of the hematopoietic system that captures patient-to-patient variation in both the concentration and rates of change of hematopoietic cell populations. By constraining the model against clinical hematopoietic cell recovery data derived from patients who have received induction chemotherapy, we identified trends for parameters that must be met by the model; for example, the mitosis rates and the probability of self-renewal of progenitor cells are inversely related. Within the data-consistent models, we found 22,796 parameter sets that meet chemotherapy response criteria. Simulations of these parameter sets display diverse dynamics in the cell populations. To identify large trends in these model outputs, we clustered the simulated cell population dynamics using k-means clustering and identified thirteen 'representative patient' dynamics. In each of these patient clusters, we simulated AML and found that clusters with the greatest mitotic capacity experience clinical cancer outcomes more likely to lead to shorter survival times. Conversely, other parameters, including lower death rates or mobilization rates, did not correlate with survival times. CONCLUSIONS: Using the multi-lineage model of hematopoiesis, we have identified several key features that determine leukocyte homeostasis, including self-renewal probabilities and mitosis rates, but not mobilization rates. Other influential parameters that regulate AML model behavior are responses to cytokines/growth factors produced in peripheral blood that target the probability of self-renewal of neutrophil progenitors. Finally, our model predicts that the mitosis rate of cancer is the most predictive parameter for survival time, followed closely by parameters that affect the self-renewal of cancer stem cells; most current therapies target mitosis rate, but based on our results, we propose that additional therapeutic targeting of self-renewal of cancer stem cells will lead to even higher survival rates. PMID- 28841880 TI - Introducing voluntary private health insurance in a mixed medical economy: are Hong Kong citizens willing to subscribe? AB - BACKGROUND: Struggling to correct the public-private imbalance in its health care system, the Hong Kong SAR Government seeks to introduce a government-regulated voluntary health insurance scheme, or VHIS, a distinctive financing instrument that combines the characteristics of private insurance with strong government regulation. This study examines citizens' responses to the new scheme and their willingness to subscribe. METHODS: First-hand data were collected from a telephone survey that randomly sampled 1793 Hong Kong adults from September 2014 to February 2015. Univariate and multivariate methods were employed in data analysis. RESULTS: More than one third of the respondents explicitly stated intention of subscribing to the VHIS, a fairly high figure considering the scheme's voluntary nature. Multivariate analysis revealed moderate evidence of adverse selection, defined as individuals' opportunistic behaviors when making insurance purchasing decision based on their own assessment of risks or likelihood of making a claim. CONCLUSION: The excellent performance of Hong Kong's public medical system has had two parallel impacts. On the one hand, high risk residents, particularly the uninsured, do not face a pressing need to switch out of the overloaded public system despite its inadequacies; this, in turn, may reduce the impact of adverse selection that may lead to detrimental effects to the insurance market. On the other hand, high satisfaction reinforces the interests of those who have both the need for better services and the ability to pay for supplementary insurance. Furthermore, the high-risk population demonstrates a moderate interest in the insurance despite the availability of government subsidies. This may offset the intended effect of the reform to some extent. PMID- 28841881 TI - Reference values of fractional excretion of exhaled nitric oxide among non smokers and current smokers. AB - BACKGROUND: Fractional exhaled nitric oxide (FENO) is used to assess of airway inflammation; diagnose asthma and monitor adherence to advised therapy. Reliable and accurate reference values for FENO are needed for both non-smoking and current smoking adults in the clinical setting. The present study was performed to establish reference adult FENO values among never-smokers, former smokers and current smokers. METHODS: FENO was measured in 5265 subjects aged 25-75 years in a general-population study, using a chemiluminescence (Niox TM) analyser according to the guidelines of the American Thoracic Society and the European Respiratory Society. Atopy was based on the presence of immunoglobulin E (IgE) antibodies to common inhalant allergens (measured using Phadiatop(r) test). Spirometry without bronchodilation was performed and forced vital capacity (FVC), forced expired volume in 1 s (FEV1) and the ratio of FEV1 to FVC values were obtained. After excluding subjects with asthma, chronic bronchitis, spirometric airway obstruction and current cold, 3378 subjects remained. Equations for predictions of FENO values were modelled using nonparametric regression models. RESULTS: FENO levels were similar in never-smokers and former smokers, and these two groups were therefore merged into a group termed "non-smokers". Reference equations, including the 5th and 95th percentiles, were generated for female and male non-smokers, based on age, height and atopy. Regression models for current smokers were unstable. Hence, the proposed reference values for current smokers are based on the univariate distribution of FENO and fixed cut-off limits. CONCLUSIONS: Reference values for FENO among respiratory healthy non-smokers should be outlined stratified for gender using individual reference values. For current smokers separate cut-off limits are proposed. PMID- 28841882 TI - Improving completion rates of students in biomedical PhD programs: an interventional study. AB - BACKGROUND: Analysis of graduation success at the University of Split School of Medicine PhD programs conducted in 2011 revealed that only 11% of students who enrolled and completed their graduate coursework between 1999 and 2011 earned a doctoral degree. In this prospective cohort study we evaluated and compared three PhD programs within the same medical school, where the newest program, called Translational Research in Biomedicine (TRIBE), established in the academic year 2010/11, aimed to increase the graduation rate through an innovative approach. METHODS: The intervention in the new program was related to three domains: redefined recruitment strategy, strict study regulations, and changes to the curriculum. We compared performance of PhD students between the new and existing programs and analyzed their current status, time to obtain a degree (from enrolment to doctorate), age at doctorate, number of publications on which the thesis was based and the impact factor of journals in which these were published. RESULTS: These improvement strategies were associated with higher thesis completion rate and reduced time to degree for students enrolled in the TRIBE program. There was no change in the impact factor or number of publications that were the basis for the doctoral theses. CONCLUSION: Our study describes good practices which proved useful in the design or reform of the PhD training program. PMID- 28841883 TI - Are women adequately informed before gynaecological surgery? AB - BACKGROUND: Surgery for pelvic organ prolapse, urinary incontinence, and hysterectomy are the most common gynaecological surgeries that can affect the function of the bladder and bowel as well as one's sexual life. There is evidence that adequate patient information given preoperatively regarding expected outcomes of surgery is important because well-informed patients are more satisfied with the results of surgery and recover faster. However, there is little known about the amount and quality of information given to women before surgery. This study investigates whether women received information before gynaecological surgery on the effect of surgery with respect to the functioning of the bladder (micturition, ability to stay continent) and the bowel (empty bowel) as well as the surgery's effect on sexual functioning. METHODS: A prospective, cross-sectional study was conducted. Women undergoing hysterectomy, surgery for vaginal prolapse, or surgery for urinary incontinence (n = 972) and included in the Swedish National Register for Gynaecological Surgery participated in the study. A questionnaire was developed and distributed to the women along with the preoperative questionnaire from the register. RESULTS: About 50% of the women undergoing prolapse surgery were supplied with information regarding the effect of the surgery with respect to remaining continent, to emptying bowels, micturitaion, and sexual life. One out of four women undergoing hysterectomy received information about the effect of the surgery on the sexual life and bladder function. In the incontinence group, the given information about the surgery's effect on bladder function and sexual function was 80 and 30%, respectively. CONCLUSION: Surgery in the vagina and the genital organs may affect function of the organs close to the surgical area (i.e., bladder and bowel) and may affect sexual function. According to this study, women are inadequately informed before surgery. Access to information via oral and written counselling needs to be improved. PMID- 28841884 TI - Early post-traumatic seizures are associated with valproic acid plasma concentrations and UGT1A6/CYP2C9 genetic polymorphisms in patients with severe traumatic brain injury. AB - BACKGROUND: Seizure is a common complication for severe traumatic brain injury (TBI). Valproic acid (VPA) is a first-line antiepileptic drug, though its metabolism is affected by genetic polymorphisms and varies between individuals. The aim of this study was to investigate such association and to explore its influence on the occurrence of early post-traumatic seizure. METHODS: A prospective case control study was conducted from 2012 to 2016 recruiting adult patients with severe TBI. Electroencephalograph (EEG) monitoring was performed approximately 4 h for each patient from day 1 to day 7 after injury. If seizures were detected, EEG monitoring was extended until 12 h after seizures being controlled. Genetic polymorphisms in UGT1A6, UGT2B7, CYP2C9, and CYP2C19 were analyzed in association with daily VPA plasma concentrations, adjusted dosages, and occurrence of seizures. RESULTS: Among the 395 recruited patients, eighty three (21%) had early post-traumatic seizure, of which 30 (36.14%) were non convulsive. Most seizures were first detected on day 1 (34.94%) and day 2 (46.99%) after injury. Patients with seizure had longer ICU length of stay and relatively lower VPA plasma concentrations. Patients with UGT1A6_19T > G/541A > G/552A > C double heterozygosities or CYP2C9 extensive metabolizers (EMs) initially had lower adjusted VPA plasma concentrations (power >0.99) and accordingly require higher VPA dosages during later time of treatment (power >0.99). The odds ratio indicated a higher risk of early post-traumatic seizure occurrence in male patients (OR 1.96, 95% CI 1.01-3.81, p = 0.043), age over 65 (OR 2.13, 95% CI 1.01-4.48), and with UGT1A6_19T > G/541A > G/552A > C double heterozygosities (OR 2.38, 95% CI 1.11-5.10, p = 0.02), though the power of the difference was between 0.54 to 0.61. DISCUSSION: Due to limited facility, the actual frequency of non-convulsive seizures is suspected to be higher than identified. There has been discrepancy regarding to genetic polymorphisms and VPA metab olism between this study and some previous reports. This could be related to confounders such as sample size, race, and patient age. Another limitation is that the case numbers of certain genotypes are limited in this study. CONCLUSIONS: Continuous EEG monitoring is necessary to detect both convulsive and non-convulsive early post-traumatic seizures in severe TBI patients. UGT1A6/CYP2C9 polymorphisms have influence on VPA metabolism. UGT1A6_19T > G/541A > G/552A > C double heterozygositie is associated with occurrence of early post traumatic seizures in addition to patients' age and gender. Further investigations with larger sample size are required to confirm the difference. TRIAL REGISTRATION: Retrospectively registered with Chinese Clinical Trail Registry on 1st Jan 2016 ( ChiCTR-OPC-16007687 ). PMID- 28841885 TI - Current clinical nutrition practices in critically ill patients in Latin America: a multinational observational study. AB - BACKGROUND: Malnutrition in critically ill adults in the intensive care unit (ICU) is associated with a significantly elevated risk of mortality. Adequate nutrition therapy is crucial to optimise outcomes. Currently, there is a paucity of such data in Latin America. Our aims were to characterise current clinical nutrition practices in the ICU setting in Latin America and evaluate whether current practices meet caloric and protein requirements in critically ill patients receiving nutrition therapy. METHODS: We conducted a cross-sectional, retrospective, observational study in eight Latin American countries (Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Panama, and Peru). Eligible patients were critically ill adults hospitalised in the ICU and receiving enteral nutrition (EN) and/or parenteral nutrition (PN) on the Screening Day and the previous day (day -1). Caloric and protein balance on day -1, nutritional status, and prescribed nutrition therapy were recorded. Multivariable logistic regression analysis was performed to identify independent predictors of reaching daily caloric and protein targets. RESULTS: The analysis included 1053 patients from 116 hospitals. Evaluation of nutritional status showed that 74.1% of patients had suspected/moderate or severe malnutrition according to the Subjective Global Assessment. Prescribed nutrition therapy included EN alone (79.9%), PN alone (9.4%), and EN + PN (10.7%). Caloric intake met >90% of the daily target in 59.7% of patients on day -1; a caloric deficit was present in 40.3%, with a mean (+/ SD) daily caloric deficit of -688.8 +/- 455.2 kcal. Multivariable logistic regression analysis showed that combined administration of EN + PN was associated with a statistically significant increase in the probability of meeting >90% of daily caloric and protein targets compared with EN alone (odds ratio, 1.56; 95% confidence interval, 1.02-2.39; p = 0.038). CONCLUSIONS: In the ICU setting in Latin America, malnutrition was highly prevalent and caloric intake failed to meet targeted energy delivery in 40% of critically ill adults receiving nutrition therapy. Supplemental administration of PN was associated with improved energy and protein delivery; however, PN use was low. Collectively, these findings suggest an opportunity for more effective utilisation of supplemental PN in critically ill adults who fail to receive adequate nutrition from EN alone. PMID- 28841886 TI - Plasmodium berghei Cap93, a novel oocyst capsule-associated protein, plays a role in sporozoite development. PMID- 28841887 TI - A case of intravascular large B cell lymphoma presenting as nodular goiter. AB - BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that is rare and highly aggressive and that may progressively involve many organs. CNS (central nervous system), BM (bone marrow) and skin are the most common systems involved. To date, only 2 cases of IVLBCL involving the thyroid have been reported. CASE PRESENTATION: Here, we report a case of IVLBCL involving the thyroid and accompanied by bilateral nodular goiter. In this case, a thyroid mass was identified in a physical examination of a 68 year-old male who initially presented with dyspnea accompanied by intermittent headache for approximately 1 month. Computed tomography scans revealed that the left lobar thyroid was occupied by a large, slightly lower density mass (5.8 * 4.7 * 8.4 cm). However, the patient had no hyperthyroidism or hoarseness. Levels of thyroid hormones and anti-thyroid autoantibodies in the serum were normal preoperatively. Thyroid mass resection was performed to establish a diagnosis and to relieve symptoms. CONCLUSIONS: Pathological results of the surgical specimen revealed that large atypical lymphoma cells filled the capillaries in the lesion area. Immunohistochemical staining revealed that the large-sized tumor cells were positive for CD20, PAX-5, MUM-1 and BCL-2, and were negative for CD3, CD5, CD43, CD10, CD23, CyclinD1, CD138, CD30, ALK, CD56, MPO, S-100, TTF-1, TG (thyroglobulin) and CT (calcitonin). The Ki-67 index was estimated to be approximately 85%. The patient was subsequently diagnosed as "Classical" IVLBCL non-germinal center B-cell type. The patient declined chemotherapy and died in the fifth month after operation. PMID- 28841888 TI - Immunosuppression and herpes viral reactivation in intensive care unit patients: one size does not fit all. PMID- 28841889 TI - Variability of response to the fluid bolus is again demonstrated. PMID- 28841890 TI - Effect of classroom-based physical activity interventions on academic and physical activity outcomes: a systematic review and meta-analysis. AB - BACKGROUND: Physical activity is associated with many physical and mental health benefits, however many children do not meet the national physical activity guidelines. While schools provide an ideal setting to promote children's physical activity, adding physical activity to the school day can be difficult given time constraints often imposed by competing key learning areas. Classroom-based physical activity may provide an opportunity to increase school-based physical activity while concurrently improving academic-related outcomes. The primary aim of this systematic review and meta-analysis was to evaluate the impact of classroom-based physical activity interventions on academic-related outcomes. A secondary aim was to evaluate the impact of these lessons on physical activity levels over the study duration. METHODS: A systematic search of electronic databases (PubMed, ERIC, SPORTDiscus, PsycINFO) was performed in January 2016 and updated in January 2017. Studies that investigated the association between classroom-based physical activity interventions and academic-related outcomes in primary (elementary) school-aged children were included. Meta-analyses were conducted in Review Manager, with effect sizes calculated separately for each outcome assessed. RESULTS: Thirty-nine articles met the inclusion criteria for the review, and 16 provided sufficient data and appropriate design for inclusion in the meta-analyses. Studies investigated a range of academic-related outcomes including classroom behaviour (e.g. on-task behaviour), cognitive functions (e.g. executive function), and academic achievement (e.g. standardised test scores). Results of the meta-analyses showed classroom-based physical activity had a positive effect on improving on-task and reducing off-task classroom behaviour (standardised mean difference = 0.60 (95% CI: 0.20,1.00)), and led to improvements in academic achievement when a progress monitoring tool was used (standardised mean difference = 1.03 (95% CI: 0.22,1.84)). However, no effect was found for cognitive functions (standardised mean difference = 0.33 (95% CI: 0.11,0.77)) or physical activity (standardised mean difference = 0.40 (95% CI: 1.15,0.95)). CONCLUSIONS: Results suggest classroom-based physical activity may have a positive impact on academic-related outcomes. However, it is not possible to draw definitive conclusions due to the level of heterogeneity in intervention components and academic-related outcomes assessed. Future studies should consider the intervention period when selecting academic-related outcome measures, and use an objective measure of physical activity to determine intervention fidelity and effects on overall physical activity levels. PMID- 28841891 TI - Peculiarities of situational and personal anxiety degree in the schoolchildren with ENT chronic diseases. AB - BACKGROUND: A number of the QL researches in case of different pathologies are being increased during the last decade. The existing traditional research methods provide mostly arbitrary data on the disease and its treatment, which are not sufficient for the schoolchildren overall psychological and social adaptation and wellness evaluation. METHODS: The research object became schoolchildren of 3 randomly selected schools in Yerevan. 443 monitoring units formed the selection population. The degree of situational and personal anxiety was evaluated with the help of Spielberger's and Gerbachevski's tests. RESULTS: According to our research data the anxiety degree was 29,2 +/- 2,3 points among the girls and 12,5 +/- 1,6 points among the boys, respectively. The individual anxiety level was especially high: it made up 44,5 +/- 0,8 points, and that of the situational anxiety made up 37,2 +/- 0,5 points (p < 0,05). According to Gerbachovski's test in the group of schoolchildren with ENT pathology those with a high level of demands made up 53,5 +/- 3,2%, with a medium level of demands - 32,4 +/- 3,0% and with a low level of demands -14,1 +/- 2,2%. A number of the practically healthy schoolchildren with a low level of demands made up 50,3%, and with a high level - 30,7%. CONCLUSION: According to the investigation data those children who suffer from the ENT chronic diseases usually avoided communication, were sluggish and shy. According to the results of the research, the socio-psychological and adaptation abilities of children with the ENT chronic diseases were lower than those of the practically healthy (without ENT pathologies) coevals. This fact urges to improve the prophylactic measures provision in the mentioned pathologies aspect. PMID- 28841892 TI - The impact of financial incentives on participants' food purchasing patterns in a supermarket-based randomized controlled trial. AB - BACKGROUND: The impacts of supermarket-based nutrition promotion interventions might be overestimated if participants shift their proportionate food purchasing away from their usual stores. This study quantified whether participants who received price discounts on fruits and vegetables (FV) in the Supermarket Healthy Eating for Life (SHELf) randomized controlled trial (RCT) shifted their FV purchasing into study supermarkets during the intervention period. METHODS: Participants were 642 females randomly assigned to a 1) skill-building (n = 160), 2) price reduction (n = 161), 3) combined skill-building and price reduction (n = 160), or 4) control (n = 161) group. Participants self-reported the proportion of FV purchased in study supermarkets at baseline, 3- and 6-months post intervention. Fisher's exact and chi2 tests assessed differences among groups in the proportion of FV purchased in study supermarkets at each time point. Multinomial logistic regression assessed differences among groups in the change in proportionate FV purchasing over time. RESULTS: Post-intervention, 49% of participants purchased >=50% of their FV in study supermarkets. Compared to all other groups, the price reduction group was approximately twice as likely (RRR: 1.8-2.2) to have increased proportionate purchasing of FV in study supermarkets from baseline to post-intervention (p< 0.05). CONCLUSIONS: Participants who received price reductions on FV were approximately twice as likely to shift their FV purchasing from other stores into study supermarkets during the intervention period. Unless food purchasing data are available for all sources, differential changes in purchasing patterns can make it difficult to discern the true impacts of nutrition interventions. TRIAL REGISTRATION: The SHELf trial is registered with Current Controlled Trials Registration ISRCTN39432901, Registered 30 June 2010, Retrospectively registered ( http://www.isrctn.com/ISRCTN39432901 ). PMID- 28841893 TI - The role of nutritional support in the physical and functional recovery of critically ill patients: a narrative review. AB - The lack of benefit from randomised controlled trials has resulted in significant controversy regarding the role of nutrition during critical illness in terms of long-term recovery and outcome. Although methodological caveats with a failure to adequately appreciate biological mechanisms may explain these disappointing results, it must be acknowledged that nutritional support during early critical illness, when considered alone, may have limited long-term functional impact.This narrative review focuses specifically on recent clinical trials and evaluates the impact of nutrition during critical illness on long-term physical and functional recovery.Specific focus on the trial design and methodological limitations has been considered in detail. Limitations include delivery of caloric and protein targets, patient heterogeneity, short duration of intervention, inappropriate clinical outcomes and a disregard for baseline nutritional status and nutritional intake in the post-ICU period.With survivorship at the forefront of critical care research, it is imperative that nutrition studies carefully consider biological mechanisms and trial design because these factors can strongly influence outcomes, in particular long-term physical and functional outcome. Failure to do so may lead to inconclusive clinical trials and consequent rejection of the potentially beneficial effects of nutrition interventions during critical illness. PMID- 28841894 TI - An exploration of group-based HIV/AIDS treatment and care models in Sub-Saharan Africa using a realist evaluation (Intervention-Context-Actor-Mechanism-Outcome) heuristic tool: a systematic review. AB - INTRODUCTION: It is increasingly acknowledged that differentiated care models hold potential to manage large volumes of patients on antiretroviral therapy (ART). Various group-based models of ART service delivery aimed at decongesting local health facilities, encouraging patient retention in care, and enhancing adherence to medication have been implemented across sub-Saharan Africa. Evidence from the literature suggests that these models of ART service delivery are more effective than corresponding facility-based care and superior to individual-based models. Nevertheless, there is little understanding of how these care models work to achieve their intended outcomes. The aim of this study was to review the theories explicating how and why group-based ART models work using a realist evaluation framework. METHODS: A systematic review of the literature on group based ART support models in sub-Saharan Africa was conducted. We searched the Google Scholar and PubMed databases and supplemented these with a reference chase of the identified articles. We applied a theory-driven approach-narrative synthesis-to synthesise the data. Data were analysed using the thematic content analysis method and synthesised according to aspects of the Intervention-Context Actor-Mechanism-Outcome heuristic-analytic tool-a realist evaluation theory building tool. RESULTS: Twelve articles reporting primary studies on group-based models of ART service delivery were included in the review. The six studies that employed a quantitative study design failed to identify aspects of the context and mechanisms that work to trigger the outcomes of group-based models. While the other four studies that applied a qualitative and the two using a mixed methods design identified some of the aspects of the context and mechanisms that could trigger the outcomes of group-based ART models, these studies did not explain the relationship(s) between the theory elements and how they interact to produce the outcome(s). CONCLUSION: Although we could distill various components of the Intervention-Context-Actor-Mechanism-Outcome analytic tool from different studies exploring group-based programmes, we could not, however, identify a salient programme theory based on the Intervention-Context-Actor-Mechanism-Outcome heuristic analysis. The scientific community, policy makers and programme implementers would benefit more if explanatory findings of how, why, for whom and in what circumstances programmes work are presented rather than just reporting on the outcomes of the interventions. PMID- 28841895 TI - The relationships of school-based sexuality education, sexual knowledge and sexual behaviors-a study of 18,000 Chinese college students. AB - BACKGROUND: A growing prevalence of unexpected pregnancies and younger age of sexual debut is observed among Chinese young people, while they lack formal sexuality education from schools and parents. It is necessary to measure their knowledge level of sexual and reproductive health, and how such knowledge associates with their sexual behaviors and reproductive health outcomes, which would shed light on the effectiveness of sexuality education in China. METHODS: An Internet-based questionnaire survey was conducted from January to August, 2015. 130 colleges were selected from eastern, central, and western parts China with a good balance of geographic distributions. The survey link was subsequently delivered to the focal points in each college for voluntary participation, targeting on undergraduates aged 18 ~ 25. Information on demographics, experience of school-based sexuality education (defined as any course introducing information on sexual and reproductive health) and SRH knowledge quiz was collected. Multivariate linear regression and logistic regression were applied to explore the relationship between students' SRH knowledge, sexual behaviors and reproductive health outcomes, such as sexual intercourse (penetrative sex by vaginal or anal), unprotected sex, pregnancy and abortion, etc. RESULTS: A total sample of 17,966 Chinese college students (mean age = 20.2, 60.4% female) eventually entered the analysis. Only 55.6% of the respondents self-reported having received sexuality education before, and they scored significantly higher (2.33/4.00) in the SRH knowledge quiz than those who had not (1.75/4.00). Among the sexually experienced students (n = 3639, 20.2%), both males and females with higher SRH knowledge were less likely to report having experience of (partner's) pregnancy or abortion (OR < 1, p < 0.05). In the group of sexually experienced males, those with higher SRH knowledge had a slightly later age of sexual debut (coefficient = 0.28, p < 0.001), and were less likely to have unprotected sex during the last or in most sexual intercourses (OR = 0.82, 95%C.I.: 0.69 ~ 0.96). CONCLUSION: Students' experience of school-based sexuality education may be positively associated with their SRH knowledge level as well as with their sexual behaviors and reproductive health outcomes, but such associations were stronger among males than females. A more effective implementation of school-based sexuality education needs to be scaled up, and a gender-sensitive education strategy to different needs is desirable for SRH promotion among Chinese young people. PMID- 28841896 TI - A systematic review of diagnostic methods to differentiate acute lung injury/acute respiratory distress syndrome from cardiogenic pulmonary edema. AB - BACKGROUND: Discriminating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema (CPE) is often challenging. This systematic review examines studies using biomarkers or images to distinguish ALI/ARDS from CPE. METHODS: Three investigators independently identified studies designed to distinguish ALI/ARDS from CPE in adults. Studies were identified from PubMed, and the Cochrane Central Register of Controlled Trials database until July 3, 2017. RESULTS: Of 475 titles and abstracts screened, 38 full texts were selected for review, and we finally included 24 studies in this systematic review: 21 prospective observational studies, two retrospective observational studies, and one retrospective combined with prospective study. These studies compared various biomarkers to differentiate subjects with ALI/ARDS and in those with CPE, and 13 calculated the area under the receiver operator characteristic curve (AUC). The most commonly studied biomarker (four studies) was brain natriuretic peptide (BNP) and the discriminatory ability ranged from AUC 0.67 0.87 but the timing of measurement varied. Other potential biomarkers or tools have been reported, but only as single studies. CONCLUSIONS: There were no identified biomarkers or tools with high-quality evidence for differentiating ALI/ARDS from CPE. Combining clinical criteria with validated biomarkers may improve the predictive accuracy. PMID- 28841897 TI - Developing an informational tool for ethical engagement in medical tourism. AB - BACKGROUND: Medical tourism, the practice of persons intentionally travelling across international boundaries to access medical care, has drawn increasing attention from researchers, particularly in relation to potential ethical concerns of this practice. Researchers have expressed concern for potential negative impacts to individual safety, public health within both countries of origin for medical tourists and destination countries, and global health equity. However, these ethical concerns are not discussed within the sources of information commonly provided to medical tourists, and as such, medical tourists may not be aware of these concerns when engaging in medical tourism. This paper describes the methodology utilized to develop an information sheet intended to be disseminated to Canadian medical tourists to encourage contemplation and further public discussion of the ethical concerns in medical tourism. METHODS: The methodology for developing the information sheet drew on an iterative process to consider stakeholder feedback on the content and use of the information sheet as it might inform prospective medical tourists' decision making. This methodology includes a literature review as well as formative research with Canadian public health professionals and former medical tourists. RESULTS: The final information sheet underwent numerous revisions throughout the formative research process according to feedback from medical tourism stakeholders. These revisions focused primarily on making the information sheet concise with points that encourage individuals considering travelling for medical tourism to do further research regarding their safety both within the destination country, while travelling, and once returning to Canada, and the potential impacts of their trip on third parties. This methodology may be replicated for the development of information sheets intending to communicate ethical concerns of other practices to providers or consumers of a certain service. PMID- 28841898 TI - Heavy alcohol drinking downregulates ALDH2 gene expression but heavy smoking up regulates SOD2 gene expression in head and neck squamous cell carcinoma. AB - BACKGROUND: This study aims to determine the relationship between expression levels of ALDH2 and SOD2 genes and clinical parameters such as alcohol drinking, tobacco smoking, primary site of HNSCC, and human papilloma virus (HPV) state. METHODS: Gene expression data were obtained from gene expression omnibus (GEO accession number: GSE65858). Clinical data (N = 270) including survival result, gender, age, TNM stage, primary site of HNSCC, HPV status, alcohol drinking, and tobacco smoking habit were analyzed according to gene expression pattern. RESULTS: ALDH2 gene was expressed in low levels in patients with heavy alcohol consumption. It was expressed in high (p = 0.01) levels in patients with no or light alcohol consumption. ALDH2 gene was also expressed in low levels in patients with oral cavity cancers or hypopharynx cancers. However, ALDH2 gene was expressed in high (p = 0.03) levels in patients with oropharyngeal cancers or laryngeal cancers. HPV-positive patients were found to have high (p = 0.02) expression levels of ALDH2. SOD2 gene was expressed in high (p = 0.005) levels in patients who had greater mean pack-year of tobacco smoking. Based on log rank test, the group of patients with high expression of ALDH2 showed better (p = 0.002) clinical results than those with low expression of ALDH2. Difference of survival results between ALDH2 high-expressed group and ALDH2 low-expressed group was validated in another cohort (GSE39368, N = 138). CONCLUSIONS: Heavy alcohol drinking downregulates ALDH2 gene expression level. Heavy smoking up-regulates SOD2 gene expression level in patients with head and neck squamous cell carcinoma. The group of patients with low expression levels of ALDH2 showed significantly poorer survival results compared to those with high expression levels of ALDH2. PMID- 28841899 TI - Ethical, legal and societal considerations on Zika virus epidemics complications in scaling-up prevention and control strategies. AB - Much of the fear and uncertainty around Zika epidemics stem from potential association between Zika virus (ZIKV) complications on infected pregnant women and risk of their babies being born with microcephaly and other neurological abnormalities. However, much remains unknown about its mode of transmission, diagnosis and long-term pathogenesis. Worries of these unknowns necessitate the need for effective and efficient psychosocial programs and medical-legal strategies to alleviate and mitigate ZIKV related burdens. In this light, local and global efforts in maintaining fundamental health principles of moral, medical and legal decision-making policies, and interventions to preserve and promote individual and collectiveHuman Rights, autonomy, protection of the most vulnerable, equity, dignity, integrity and beneficence that should not be confused and relegated by compassionate humanitarian assistance and support. This paper explores the potential medical and ethical-legal implications of ZIKV epidemics emergency response packages and strategies alongside optimizing reproductive and mental health policies, programs and best practice measures. Further long-term cross-borders operational research is required in elucidating Zika-related population-based epidemiology, ethical-medical and societal implications in guiding evidence-based local and global ZIKV maternal-child health complications related approaches and interventions. Core programs and interventions including future Zika safe and effective vaccines for global Zika immunization program in most vulnerable and affected countries and worldwide should be prioritized. PMID- 28841900 TI - Activation of PKC triggers rescue of NPC1 patient specific iPSC derived glial cells from gliosis. AB - BACKGROUND: Niemann-Pick disease Type C1 (NPC1) is a rare progressive neurodegenerative disorder caused by mutations in the NPC1 gene. The pathological mechanisms, underlying NPC1 are not yet completely understood. Especially the contribution of glial cells and gliosis to the progression of NPC1, are controversially discussed. As an analysis of affected cells is unfeasible in NPC1 patients, we recently developed an in vitro model system, based on cells derived from NPC1-patient specific iPSCs. Here, we asked if this model system recapitulates gliosis, observed in non-human model systems and NPC1 patient post mortem biopsies. We determined the amount of reactive astrocytes and the regulation of the intermediate filaments GFAP and vimentin, all indicating gliosis. Furthermore, we were interested in the assembly and phosphorylation of these intermediate filaments and finally the impact of the activation of protein kinase C (PKC), which is described to ameliorate the pathogenic phenotype of NPC1 deficient fibroblasts, including hypo-phosphorylation of vimentin and cholesterol accumulation. METHODS: We analysed glial cells derived from NPC1 patient specific induced pluripotent stem cells, carrying different NPC1 mutations. The amount of reactive astrocytes was determined by means of immuncytochemical stainings and FACS-analysis. Semi-quantitative western blot was used to determine the amount of phosphorylated GFAP and vimentin. Cholesterol accumulation was analysed by Filipin staining and quantified by Amplex Red Assay. U18666A was used to induce NPC1 phenotype in unaffected cells of the control cell line. Phorbol 12-myristate 13-acetate (PMA) was used to activate PKC. RESULTS: Immunocytochemical detection of GFAP, vimentin and Ki67 revealed that NPC1 mutant glial cells undergo gliosis. We found hypo-phosphorylation of the intermediate filaments GFAP and vimentin and alterations in the assembly of these intermediate filaments in NPC1 mutant cells. The application of U18666A induced not only NPC1 phenotypical accumulation of cholesterol, but characteristics of gliosis in glial cells derived from unaffected control cells. The application of phorbol 12-myristate 13-acetate, an activator of protein kinase C resulted in a significantly reduced number of reactive astrocytes and further characteristics of gliosis in NPC1-deficient cells. Furthermore, it triggered a restoration of cholesterol amounts to level of control cells. CONCLUSION: Our data demonstrate that glial cells derived from NPC1-patient specific iPSCs undergo gliosis. The application of U18666A induced comparable characteristics in un-affected control cells, suggesting that gliosis is triggered by hampered function of NPC1 protein. The activation of protein kinase C induced an amelioration of gliosis, as well as a reduction of cholesterol amount. These results provide further support for the line of evidence that gliosis might not be only a secondary reaction to the loss of neurons, but might be a direct consequence of a reduced PKC activity due to the phenotypical cholesterol accumulation observed in NPC1. In addition, our data support the involvement of PKCs in NPC1 disease pathogenesis and suggest that PKCs may be targeted in future efforts to develop therapeutics for NPC1 disease. PMID- 28841901 TI - Outcome of colon cancer initially presenting as colon perforation and obstruction. AB - BACKGROUND: Emergency complications of colon cancer include perforation and obstruction which were recognized as poor prognostic factors. Few studies have directly compared the outcomes of these two groups. In this study, we evaluated mortality and morbidity in patients with colon cancer initially presenting as perforation and obstruction. METHODS: Newly diagnosed colon cancer cases initially presenting with perforation or obstruction at Tzu Chi General Hospital, Hualien, Taiwan, between 2009 and 2015 were included. Cases of iatrogenic perforation or perforation sites far away from the tumor sites and rectal (< 15 cm from the anal verge) cancer were excluded. Progression-free survival, local recurrence rate, distant metastasis rate, and overall survival were the evaluated outcomes. RESULTS: Eighty-one patients met the selection criteria; 23 and 58 patients had perforation and obstruction, respectively, as the initial symptom. The median age was 72 years. The median tumor stage was stage IIIB. The 1-year and 3-year survival rates were 83.7 and 59.7%, respectively. The perforation group (PRG) and obstruction group (OBG) did not differ significantly in intensive care unit (ICU) stay rate (p = 0.147), sex (p = 0.45), comorbidities (heart, liver, and renal diseases and diabetes mellitus), median stage (p = 0.198), and overall survival (p = 0.328). However, PRG had a higher age at diagnosis (74 vs. 64 years, p = 0.037), a higher APACHE II score (12 vs. 7, p = 0.002), lower disease-free survival (p = 0.001), a higher recurrence rate (56.5 vs. 19%, p = 0.002), a higher distant metastasis rate (39.1 vs. 13.8%, p = 0.015), and a higher local recurrence rate (43.5 vs. 5.2%, p < 0.001) than did OBG. OBG had a higher two-stage operation rate (46.6 vs. 17.4%, p = 0.022). After adjustment for the tumor stage, comorbidity (chronic renal disease), body mass index (BMI), and adjuvant chemotherapy or radiotherapy in multivariate statistics, PRG had lower disease-free survival (p = 0.005) than OBG but overall survival was identical. CONCLUSION: For colon cancer initially presenting as perforation or obstruction, the PRG had poorer progression-free survival, a higher local recurrence rate, and a higher distant metastasis rate than did OBG. Overall survival did not differ between these two groups. PMID- 28841902 TI - Markers of acute kidney injury in patients with sepsis: the role of soluble thrombomodulin. AB - BACKGROUND: Endothelial activation and damage occur early during sepsis, with activated coagulopathy and playing a major role in the pathophysiology of sepsis induced acute kidney injury (AKI). The aim of this study was to compare the various biomarkers of endothelial injury with the biomarkers of coagulation and inflammation and to determine a significant predictor of AKI in patients with sepsis. METHODS: We conducted a single-center, retrospective, observational study on patients with sepsis fulfilling the Third International Consensus Definitions for Sepsis and Septic Shock criteria admitted to an adult intensive care unit (ICU) at a university hospital from June 2011 to December 2016. Levels of 13 biomarkers were measured on ICU admission, including markers of endothelial injury (soluble thrombomodulin [sTM], E-selectin, protein C, and plasminogen activator inhibitor-1 [PAI-1]) and markers of coagulation derangement (platelet count, fibrin degradation product [FDP], prothrombin time [PT], fibrinogen, alpha2-plasminogen inhibitor [alpha2-PI], antithrombin III [AT III], plasminogen, thrombin-antithrombin complex, and plasmin-alpha2-plasmin inhibitor complex). All patients with sepsis were reviewed, and the development of AKI was evaluated. Multivariate logistic regression analysis was performed to identify significant independent predictive factors for AKI. RESULTS: Of the 514 patients admitted with sepsis, 351 (68.3%) developed AKI. Compared with the non-AKI group, all the endothelial biomarkers were significantly different in the AKI group (sTM [23.6 vs. 15.6 U/ml, P < 0.0001], E-selectin [65.5 vs. 46.2 ng/ml, P = 0.0497], PAI-1 [180.4 vs. 75.3 ng/ml, P = 0.018], and protein C [45.9 vs. 58.7 ng/ml, P < 0.0001]). Biomarkers of coagulopathy and inflammation, platelet counts, FDP, PT, alpha2-PI, AT III, plasminogen, and C-reactive protein were significantly different between the two groups. Multivariable logistic regression analysis showed that sTM was an independent predictive factor of AKI, with an AUROC of 0.758 (P < 0.0001). CONCLUSIONS: Endothelial biomarkers were significantly changed in the sepsis patients with AKI. Particularly, sTM was an independent predictive biomarker for the development of AKI that outperformed other coagulation and inflammation biomarkers as well as organ function in patients with sepsis. PMID- 28841903 TI - A feasibility study investigating the acceptability and design of a multicentre randomised controlled trial of needle fasciotomy versus limited fasciectomy for the treatment of Dupuytren's contractures of the fingers (HAND-1): study protocol for a randomised controlled trial. AB - BACKGROUND: Dupuytren's contractures are fibrous cords under the skin of the palm of the hand. The contractures are painless but cause one or more fingers to curl into the palm, resulting in loss of function. Standard treatment within the NHS is surgery to remove (fasciectomy) or divide (fasciotomy) the contractures, and the treatment offered is frequently determined by surgeon preference. This study aims to determine the feasibility of conducting a large, multicentre randomised controlled trial to assess the clinical and cost-effectiveness of needle fasciotomy versus limited fasciectomy for the treatment of Dupuytren's contracture. METHODS/DESIGN: HAND-1 is a parallel, two-arm, multicentre, randomised feasibility trial. Eligible patients aged 18 years or over who have one or more fingers with a Dupuytren's contracture of more than 30 degrees in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints, well defined cord(s) causing contracture, and have not undergone previous surgery for Dupuytren's on the same hand will be randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy. Participants will be followed-up for up to 6 months post surgery. Feasibility outcomes include number of patients screened, consented and randomised, adherence with treatment, completion of follow-up and identification of an appropriate patient-reported outcome measure (PROM) to use as primary outcome for a main trial. Embedded qualitative research, incorporating a QuinteT Recruitment Intervention, will focus on understanding and optimising the recruitment process, and exploring patients' experiences of trial participation and the interventions. DISCUSSION: This study will assess whether a large multicentre trial comparing the clinical and cost-effectiveness of needle fasciotomy and limited fasciectomy for the treatment of Dupuytren's contractures is feasible, and if so will provide data to inform its design and successful conduct. TRIAL REGISTRATION: International Standard Registered Clinical/soCial sTudy Number: ISRCTN11164292 . Registered on 28 August 2015. PMID- 28841904 TI - A comparison of radiographic and clinical outcomes of anterior lumbar interbody fusion performed with either a cellular bone allograft containing multipotent adult progenitor cells or recombinant human bone morphogenetic protein-2. AB - BACKGROUND: Both the map3 Cellular Allogeneic Bone Graft(r) and recombinant human bone morphogenetic protein 2 (rhBMP-2, Infuse(r)) were developed to provide an alternative to iliac crest autograft, thus eliminating the morbidity associated with its harvest. The recent literature concerning adverse events associated with the use of rhBMP-2, however, highlights the need for a safe and effective alternative. The multipotent adult progenitor cells (MAPC) found in map3 allograft may provide this alternative. The purpose of this study is to report 1 year outcomes of patients treated via anterior lumbar interbody fusion (ALIF) using either map3 Cellular Allogeneic Bone Graft or rhBMP-2 for bony fusion. METHODS: This was a retrospective evaluation of 41 patients treated via ALIF with either map3 or rhBMP-2 in a polyetheretherketone cage with posterior stabilization at 1, 2, or 3 consecutive levels (L3-S1). Patients were equally divided between treatment groups. The Oswestry Disability Index (ODI) and visual analog scores (VAS) for pain were documented as part of the standard of care. An independent radiologist assessed bridging of bone, disc height, and lordosis. Primary outcome measures included radiographic analysis of fusion by plain film and CTs. Secondary clinical outcomes included visual analogue scale for neck and arm pain and low back disability index scores. RESULTS: The overall fusion rate was 91%, with no significant difference between groups. Improvements in ODI and VAS were observed among all patients (p < 0.001), with no significant difference between groups for ODI (p = 0.966) or VAS (p = 0.251). There was no significant difference in terms of changes to disc height and lordosis between groups (p < 0.05). The rhBMP-2 group had increased post-operative complications when compared to the map3 group, but the low numbers precluded statistical analysis. CONCLUSION: Improvements in radiographic and clinical findings were observed in both treatment groups one-year postoperatively. Map3 allograft demonstrated equivalent fusion rates to rhBMP-2. A review of surgical supply costs at the treatment facility favored map3 allograft for the treatment of patients with DDD undergoing an ALIF in 1-3 levels compared to rhBMP-2. Further studies to evaluate long-term outcomes and post-operative complications are required. PMID- 28841905 TI - The widespread biting midge Culicoides impunctatus (Ceratopogonidae) is susceptible to infection with numerous Haemoproteus (Haemoproteidae) species. AB - BACKGROUND: Haemoproteus parasites are widespread, and some species cause disease in wild and domestic birds. However, the insect vectors remain unknown for the majority of species and genetic lineages of avian Haemoproteus. This information is crucial for better understanding the biology of haemoproteids, the epidemiology of haemoproteosis, and the development of morphological characters of sporogonic stages in wildlife haemosporidian parasites. It remains unclear whether the specificity of Haemoproteus parasites for vectors is broad or the transmission of a given parasite can be restricted to a single or few species of vectors. The aim of this study was to examine the sporogonic development of four species of common European avian haemoproteids in the common biting midge Culicoides impunctatus. METHODS: Wild-caught females of C. impunctatus were infected experimentally by allowing them to take blood meals on naturally infected Muscicapa striata, Cyanistes caeruleus, Ficedula hypoleuca and Motacilla flava harbouring mature gametocytes of Haemoproteus balmorali (genetic lineage hSFC9), H. majoris (hPARUS1), H. motacillae (hYWT1) and H. pallidus (hPFC1), respectively. Infected insects were collected, maintained under laboratory conditions and dissected daily in order to detect the development of ookinetes, oocysts and sporozoites. Microscopic examination and polymerase chain reaction based methods were used to detect the parasites. Bayesian analysis was applied to identify phylogenetic relationships among Haemoproteus lineages. RESULTS: All investigated parasites completed sporogony in C. impunctatus, indicating broad susceptibility of this biting midge for numerous Haemoproteus parasites. Ookinetes, oocysts and sporozoites were reported, described and compared morphologically. The investigated parasite species can be distinguished at the sporogony stage, particularly with regards to the morphology and rate of development of mature ookinetes. Analysis of data from the literature, and this study, shows that 12 genetically distantly related Haemoproteus parasites complete sporogony in C. impunctatus. CONCLUSIONS: Susceptibility of C. impunctatus is broad for Haemoproteus parasites, indicating that this biting midge is an important natural vector of numerous species of avian haemoproteids in Europe. Some Haemoproteus species can be readily distinguished using morphological characters of ookinetes and sporozoites, as well as the rate of ookinete development. These characters can be used for the identification of Haemoproteus species during sporogony in vectors, and are worth more attention in these parasite taxonomy studies at the species levels. PMID- 28841906 TI - Term amniotic fluid: an unexploited reserve of mesenchymal stromal cells for reprogramming and potential cell therapy applications. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are currently being evaluated in numerous pre-clinical and clinical cell-based therapy studies. Furthermore, there is an increasing interest in exploring alternative uses of these cells in disease modelling, pharmaceutical screening, and regenerative medicine by applying reprogramming technologies. However, the limited availability of MSCs from various sources restricts their use. Term amniotic fluid has been proposed as an alternative source of MSCs. Previously, only low volumes of term fluid and its cellular constituents have been collected, and current knowledge of the MSCs derived from this fluid is limited. In this study, we collected amniotic fluid at term using a novel collection system and evaluated amniotic fluid MSC content and their characteristics, including their feasibility to undergo cellular reprogramming. METHODS: Amniotic fluid was collected at term caesarean section deliveries using a closed catheter-based system. Following fluid processing, amniotic fluid was assessed for cellularity, MSC frequency, in-vitro proliferation, surface phenotype, differentiation, and gene expression characteristics. Cells were also reprogrammed to the pluripotent stem cell state and differentiated towards neural and haematopoietic lineages. RESULTS: The average volume of term amniotic fluid collected was approximately 0.4 litres per donor, containing an average of 7 million viable mononuclear cells per litre, and a CFU-F content of 15 per 100,000 MNCs. Expanded CFU-F cultures showed similar surface phenotype, differentiation potential, and gene expression characteristics to MSCs isolated from traditional sources, and showed extensive expansion potential and rapid doubling times. Given the high proliferation rates of these neonatal source cells, we assessed them in a reprogramming application, where the derived induced pluripotent stem cells showed multigerm layer lineage differentiation potential. CONCLUSIONS: The potentially large donor base from caesarean section deliveries, the high yield of term amniotic fluid MSCs obtainable, the properties of the MSCs identified, and the suitability of the cells to be reprogrammed into the pluripotent state demonstrated these cells to be a promising and plentiful resource for further evaluation in bio-banking, cell therapy, disease modelling, and regenerative medicine applications. PMID- 28841907 TI - A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature. AB - BACKGROUND: Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome. CASE PRESENTATION: A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard deviation). His past medical history was significant for soft cleft palate and bilateral cataracts. He had a flat midface, micrognathia, and limitations in bilateral elbow flexion. Radiographs showed mild spondyloepiphyseal dysplasia. Initially, we suspected Marshall syndrome, but no mutation was identified in COL11A1. At 8 years old, his height was 116.2 cm ( 1.89 standard deviation), and his orofacial characteristics appeared unremarkable. We analyzed the COL2A1 gene and found a novel heterozygous mutation (c.1142 G > A, p.Gly381Asp). CONCLUSIONS: In this case report, we identify a novel missense mutation in the COL2A1 gene in a patient with Stickler syndrome type 1, and we describe age-related changes in the clinical phenotype with regard to orofacial characteristics and height. Genetic analysis is helpful for the diagnosis of this clinically variable and genetically heterogeneous disorder. PMID- 28841908 TI - Barriers and facilitators to the integration of mental health services into primary health care: a systematic review protocol. AB - BACKGROUND: Mental health is an integral part of health and well-being and yet health systems have not adequately responded to the burden of mental disorders. Integrating mental health services into primary health care (PHC) is the most viable way of closing the treatment gap and ensuring that people get the mental health care they need. PHC was formally adapted by the World Health Organization (WHO), and they have since invested enormous amounts of resources across the globe to ensure that integration of mental health services into PHC works. METHODS: This review will use the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) framework approach to identify experiences of mental health integration into PHC; the findings will be reported using the "Best fit" framework synthesis. PubMed, EMBASE, PsycINFO, and Cochrane Central Register of Controlled trials (CENTRAL) will be searched including other sources like the WHO website and OpenGrey database. Assessment of bias and quality will be done at study level using two separate tools to check for the quality of evidence presented. Data synthesis will take on two synergistic approaches (qualitative and quantitative studies). Synthesizing evidence from countries across the globe will provide useful insights into the experiences of integrating mental health services into PHC and how the barriers and challenges have been handled. The findings will be useful to a wide array of stakeholders involved in the implementation of the mental health integration into PHC. DISCUSSION: The SPIDER framework has been chosen for this review because of its suitable application to qualitative and mixed methods research and will be used as a guide when selecting articles for inclusion. Data extracted will be synthesized using the "Best fit" framework because it has been used before and proved its suitability in producing new conceptual models for explaining decision-making and possible behaviors. Synthesizing evidence from countries across the globe will provide useful insights into the experiences of integrating mental health services into PHC and how the barriers and challenges have been handled. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016052000. PMID- 28841910 TI - The HIV Care Cascade from HIV diagnosis to viral suppression in sub-Saharan Africa: a systematic review and meta-regression analysis protocol. AB - BACKGROUND: In 2014, UNAIDS announced the 90-90-90 treatment targets to curb the HIV epidemic by 2020: 90% of people living with HIV know their HIV status, 90% of people who know their HIV status access treatment and 90% of people on treatment have suppressed viral loads. Monitoring and evaluation are needed to track linkage and retention throughout the continuum of care. We propose a systematic review and meta-regression to identify the different methodological approaches used to define the steps in the HIV care cascade in sub-Saharan Africa (SSA), where most people with HIV live, and to assess the proportion of participants retained at each step. METHODS: We will include cohort and cross-sectional studies published between 2004 and 2016 that report on the HIV care cascade among adults in SSA. The PubMed, Embase and CINAHL databases will be searched. Two reviewers will independently screen titles and abstracts, assess the full texts for eligibility and extract data. Disagreements will be resolved by consensus or consultation with a third reviewer. We will assess the number and proportion of individuals retained in the HIV care cascade from HIV diagnosis to linkage to care, engagement in pre-ART care, initiation of ART, retention on ART, and viral suppression. The data will be analysed using random effects meta-regression analysis. Publication bias will be assessed by funnel plots. DISCUSSION: This review will contribute to a better understanding of the HIV care cascade in SSA. It will help programs identify gaps and approaches to improve care and treatment for people living with HIV and reduce HIV transmission. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055863. PMID- 28841909 TI - Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD groups (Epitopes-HPV02 study). AB - BACKGROUND: The squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5 fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months. We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses. Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients. METHODS: This multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) <2, and being eligible for DCF. Patients receive either 6 cycles of standard DCF or 8 cycles of modified DCF depending on age (> vs. <= 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon's optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy. DISCUSSION: Since the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA. TRIAL REGISTRATION: NCT02402842 , EudraCT: 2014-001789-81. PMID- 28841911 TI - Blood as a route of transmission of uterine pathogens from the gut to the uterus in cows. AB - BACKGROUND: Metritis is an inflammatory disease of the uterus caused by bacterial infection, particularly Bacteroides, Porphyromonas, and Fusobacterium. Bacteria from the environment, feces, or vagina are believed to be the only sources of uterine contamination. Blood seeps into the uterus after calving; therefore, we hypothesized that blood could also be a seeding source of uterine bacteria. Herein, we compared bacterial communities from blood, feces, and uterine samples from the same cows at 0 and 2 days postpartum using deep sequencing and qPCR. The vaginal microbiome 7 days before calving was also compared. RESULTS: There was a unique structure of bacterial communities by sample type. Principal coordinate analysis revealed two distinct clusters for blood and feces, whereas vaginal and uterine bacterial communities were more scattered, indicating greater variability. Cluster analysis indicated that uterine bacterial communities were more similar to fecal bacterial communities than vaginal and blood bacterial communities. Nonetheless, there were core genera shared by all blood, feces, vaginal, and uterine samples. Major uterine pathogens such as Bacteroides, Porphyromonas, and Fusobacterium were part of the core genera in blood, feces, and vagina. Other uterine pathogens such as Prevotella and Helcococcus were not part of the core genera in vaginal samples. In addition, uterine pathogens showed a strong and significant interaction with each other in the network of blood microbiota, but not in feces or vagina. These microbial interactions in blood may be an important component of disease etiology. The copy number of total bacteria in blood and uterus was correlated; the same did not occur in other sites. Bacteroides heparinolyticus was more abundant in the uterus on day 0, and both B. heparinolyticus and Fusobacterium necrophorum were more abundant in the uterus than in the blood and feces on day 2. This indicates that B. heparinolyticus has a tropism for the uterus, whereas both pathogens thrive in the uterine environment early postpartum. CONCLUSIONS: Blood harbored a unique microbiome that contained the main uterine pathogens such as Bacteroides, Porphyromonas, and Fusobacterium. The presence of these pathogens in blood shortly after calving shows the feasibility of hematogenous spread of uterine pathogens in cows. PMID- 28841912 TI - Choice of initial antiretroviral drugs and treatment outcomes among HIV-infected patients in sub-Saharan Africa: systematic review and meta-analysis of observational studies. AB - BACKGROUND: The effectiveness of antiretroviral therapy (ART) depends on the choice of regimens during initiation. Most evidences from developed countries indicated that there is difference between efavirenz (EFV) and nevirapine (NVP). However, the evidences are limited in resource poor countries particularly in Africa. Thus, this systematic review and meta-analysis was carried out to summarize reported long-term treatment outcomes among people on first line therapy in sub-Saharan Africa. METHODS: Observational studies that reported odds ratio, relative risk, hazard ratio, or standardized incidence ratio to compare risk of treatment failure among HIV/AIDS patients who initiated ART with EFV versus NVP were systematically searched. Searches were conducted using the MEDLINE database within PubMed, Google Scholar, HINARI, and Research Gates between 2007 and 2016. Information was extracted using standardized form. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using random effect, generic inverse variance method. RESULT: A total of 6394 articles were identified, of which, 29 were eligible for review and abstraction in sub-Saharan Africa. Seventeen articles were used for the meta-analysis. Of a total of 121,092 independent study participants, 76,719 (63.36%) were females. Of these, 40,480 (33.43%) initiated with NVP containing regimen. Two studies did not report the median CD4 cell counts at initiation. Patients who have low CD4 cell counts initiated with EFV containing regimen. The pooled effect size indicated that treatment failure was reduced by 15%, 0.85 (95%CI: 0.75-0.98), and non-nucleoside reverse transcriptase inhibitor (NNRTI) switch was reduced by 43%, 0.57 (95%CI: 0.37-0.89). CONCLUSION: The risk of treatment failure and NNRTI switch were lower in patients who initiated with EFV than NVP-containing regimen. The review suggests that initiation of patients with EFV-containing regimen will reduce treatment failure and NNRTI switch. PMID- 28841913 TI - Accuracy of different diagnostic tests for early, delayed and late prosthetic joint infection. AB - BACKGROUND: A combination of laboratory, histopathological and microbiological tests for diagnosis of prosthetic joint infection (PJI) have been strongly recommended. This study aims to characterize the accuracy of individual or group tests, such as culture of sonicate fluid, synovial fluid and peri-implant tissue, C-reactive protein (CRP) and histopathology for detection of early, delayed and late PJI. METHODS: A prospective study of patients undergoing hip or knee arthroplasty from February 2009 to February 2014 was performed in a Spanish tertiary health care hospital. The diagnostic accuracy of the different methods was evaluated constructing receiver-operating-characteristic (ROC) curve areas. RESULTS: One hundred thirty consecutive patients were included: 18 (13.8%) early PJI, 35 (27%) delayed PJI and 77 (59.2%) late PJI. For individual parameters, the area under the ROC curve for peri-implant tissue culture was larger for early (0.917) than for delayed (0.829) and late PJI (0.778), p = 0.033. There was a significantly larger difference for ROC area in the synovial fluid culture for delayed (0.803) than for early (0.781) and late infections (0.679), p = 0.039. The comparison of the areas under the ROC curves for the two microbiological tests showed that sonicate fluid was significantly different from peri-implant tissue in delayed (0.951 vs 0.829, p = 0.005) and late PJI (0.901 vs 0.778, p = 0.000). The conjunction of preoperative parameters, synovial fluid culture and CRP, improved the accuracy for late PJI (p = 0.01). The conjunction of histopathology and sonicate fluid culture increased the area under ROC curve of sonication in early (0.917 vs 1.000); p = 0.06 and late cases (0.901 vs 0.999); p < 0.001. CONCLUSION: For early PJI, sonicate fluid and peri-implant tissue cultures achieve the same best sensitivity. For delayed and late PJI, sonicate fluid culture is the most sensitive individual diagnostic method. By combining histopathology and peri-implant tissue, all early, 97% of delayed and 94.8% of late cases are diagnosed. The conjunction of histopathology and sonicate fluid culture yields a sensitivity of 100% for all types of infection. PMID- 28841914 TI - The associations between socioeconomic status and risk of Staphylococcus aureus bacteremia and subsequent endocarditis - a Danish nationwide cohort study. AB - BACKGROUND: Staphylococcus aureus bacteremia (SAB) is the leading cause of infective endocarditis in several countries. Since socioeconomic status (SES) is known to influence the risk of infectious diseases in general, we aimed to investigate the association between SES and SAB, and risk of subsequent endocarditis in a nationwide adult population. METHODS: All Danish residents were consecutively included at age >= 30 years during 1996-2010. We obtained information on SES (highest attained educational level), comorbidities, and microbiologically verified SAB by cross-linking nationwide registries. The incidence rate ratios (IRRs) of SAB and later endocarditis were investigated using Poisson regression models adjusted for sex, age and year (reference = highest SES). RESULTS: Our study population comprised 3,394,936 individuals (median age = 43.2 years). Over a median follow-up of 15.9 years, 13,181 individuals acquired SAB. SES was inversely associated with SAB acquisition, which declined with increasing age, e.g. in individuals with lowest SES, IRRs were 3.78 (95% confidence interval [CI] = 2.89-4.95) in age 30-50 years, 1.87 (CI = 1.60-2.18) in age > 50-70 years and 1.31 (CI = 1.11-1.54) in age > 70 years (interaction-p < 0.0001). Adjustment for comorbidities attenuated the IRRs, but the pattern persisted. No association between SES and endocarditis risk among patients with SAB was observed. CONCLUSIONS: Decreasing SES was associated with an increased risk of SAB, particularly in younger adults. SES was not associated with risk of subsequent endocarditis. PMID- 28841915 TI - Expiratory central airway collapse in stable COPD and during exacerbations. AB - BACKGROUND: Tracheal obstruction resulting from expiratory tracheal deformation has been associated with respiratory symptoms and severe airway exacerbations. In chronic obstructive pulmonary disease (COPD), acute exacerbations (AECOPD) create large intrathoracic pressure swings which may increase tracheal deformation. Excessive central airway collapse (ECAC) may be diagnosed when the tracheal area on expiration is less than 50% of that on inspiration. The prevalence of ECAC in AECOPD and its temporal course have not been systematically studied. METHODS: We prospectively recruited healthy volunteers (n = 53), stable outpatients with COPD (n = 40) and patients with hospitalised acute exacerbations of COPD (AECOPD, n = 64). 17 of the AECOPD group returned for repeat evaluation when clinically well at 6-12 weeks. All subjects underwent dynamic 320-slice computed tomography of the larynx and trachea during tidal breathing, enabling quantitation of tracheal area and dimensions (mean +/- SD). RESULTS: No healthy individuals had ECAC. The prevalence of ECAC in stable COPD and AECOPD was 35% and 39% respectively. Mean tracheal collapse did not differ between stable COPD (57.5 +/- 19.8%), AECOPD (53.8 +/- 19.3%) and in the subset who returned when convalescent (54.9 +/- 17.2%). AECOPD patients with and without ECAC had similar clinical characteristics. CONCLUSIONS: Tracheal collapse in both stable and AECOPD is considerably more prevalent than in healthy individuals. ECAC warrants assessment as part of comprehensive COPD evaluation and management. Further studies should evaluate the aetiology of ECAC and whether it predisposes to exacerbations. PMID- 28841916 TI - Neoadjuvant chemotherapy versus surgery first for resectable pancreatic cancer (Norwegian Pancreatic Cancer Trial - 1 (NorPACT-1)) - study protocol for a national multicentre randomized controlled trial. AB - BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer-related death. While surgical resection remains the foundation for potentially curative treatment, survival benefit is achieved with adjuvant oncological treatment. Thus, completion of multimodality treatment (surgical resection and (neo)adjuvant chemotherapy) to all patients and early treatment of micrometastatic disease is the ideal goal. NorPACT-1 aims to test the hypothesis that overall mortality at one year after allocation of treatment can be reduced with neoadjuvant chemotherapy in surgically treated patients with resectable pancreatic cancer. METHODS/DESIGN: The NorPACT- 1 is a multicentre, randomized controlled phase III trial organized by the Norwegian Gastrointestinal Cancer Group for Hepato Pancreato-Biliary cancer. Patients with resectable adenocarcinoma of the pancreatic head are randomized to receive either surgery first (Group 1: SF/control) or neoadjuvant chemotherapy (Group 2: NT/intervention) with four cycles FOLFIRINOX followed by resection. Both groups receive adjuvant chemotherapy with gemicitabine and capecitabine (six cycles in Group 1, four cycles in Group 2). In total 90 patients will be randomized in all the five Norwegian university hospitals performing pancreatic surgery. Primary endpoint is overall mortality at one year following commencement of treatment for those who ultimately undergo resection. Secondary endpoints are overall survival after date of randomization (intention to treat), overall survival after resection, disease free survival, histopathological response, complication rates after surgery, feasibility of neoadjuvant and adjuvant chemotherapy, completion rates of all parts of multimodal treatment, and quality-of-life. Bolt-on to the study is a translational research program that aims at identifying factors that are predictive of response to NT, the risk of distant cancer spread, and patient outcome. DISCUSSION: NorPACT- 1 is designed to investigate the additional benefit of NT compared to standard treatment only (surgery + adjuvant chemotherapy) for resectable cancer of the pancreatic head to decrease early mortality (within one year) in resected patients. TRIAL REGISTRATION: Trial open for accrual 01.02.2017. ClinicalTrials.gov Identifier: NCT02919787 . Date of registration: September 14, 2016. PMID- 28841917 TI - Effects of Wolbachia on ovarian apoptosis in Culex quinquefasciatus (Say, 1823) during the previtellogenic and vitellogenic periods. AB - BACKGROUND: Apoptosis is programmed cell death that ordinarily occurs in ovarian follicular cells in various organisms. In the best-studied holometabolous insect, Drosophila, this kind of cell death occurs in all three cell types found in the follicles, sometimes leading to follicular atresia and egg degeneration. On the other hand, egg development, quantity and viability in the mosquito Culex quinquefasciatus are disturbed by the infection with the endosymbiont Wolbachia. Considering that Wolbachia alters reproductive traits, we hypothesised that such infection would also alter the apoptosis in the ovarian cells of this mosquito. The goal of this study was to comparatively describe the occurrence of apoptosis in Wolbachia-infected and uninfected ovaries of Cx. quinquefasciatus during oogenesis and vitellogenesis. For this, we recorded under confocal microscopy the occurrence of apoptosis in all three cell types of the ovarian follicle. In the first five days of adult life we observed oogenesis and, after a blood meal, the initiation step of vitellogenesis. RESULTS: Apoptoses in follicular cells were found at all observation times during both oogenesis and vitellogenesis, and less commonly in nurse cells and the oocyte, as well as in atretic follicles. Our results suggested that apoptosis in follicular cells occurred in greater numbers in infected mosquitoes than in uninfected ones during the second and third days of adult life and at the initiation step of vitellogenesis. CONCLUSIONS: The presence of Wolbachia leads to an increase of apoptosis occurrence in the ovaries of Cx. quinquefasciatus. Future studies should investigate if this augmented apoptosis frequency is the cause of the reduction in the number of eggs laid by Wolbachia-infected females. Follicular atresia is first reported in the previtellogenic period of oogenesis. Our findings may have implications for the use of Wolbachia as a mosquito and pathogens control strategy. PMID- 28841918 TI - Sexual behaviors among methadone maintenance patients in a mountainous area in northern Vietnam. AB - BACKGROUND: Methadone maintenance treatment (MMT) improves patients' ability to access HIV-related services and reduces needle sharing and other risky HIV related behaviors. However, patients may continue to engage in risky sexual practices. In this study, we evaluate sexual behaviors of MMT patients in a mountainous province in Northern Vietnam. METHODS: We explored the health status, MMT and substance use history, and sexual practices of 241 male MMT patients in Tuyen Quang province. Health status was investigated using the EuroQOL-5 Dimensions-5 Levels (EQ-5D-5 L). Multivariate logistic regression was employed to assess associated factors. RESULTS: Most patients (66.4%) reported having at least one sexual partner within the previous twelve months. Most of these partners were spouses or primary partners (72.6%). About 8.3% of patients had casual partners, and 5.8% had visited sex workers; of those who engaged in casual sexual relationships, 90.9% reported using condoms. Current drug use and living in a remote area were associated with an increased odd of having two or more sexual partners, while anxiety or depression was associated with lower odds. CONCLUSION: This study highlights a low proportion of having sexual risk behaviors among MMT patients in Vietnamese mountainous settings. Integrating education about safe sexual practices into MMT services, along with providing medical care and ensuring methadone treatment adherence, is an important component in HIV risk reduction for these patients who were at risk of unsafe sexual practices. PMID- 28841919 TI - Mesonephric adenocarcinoma of the uterine corpus with intracystic growth completely confined to the myometrium: a case report and literature review. AB - BACKGROUND: Mesonephric adenocarcinoma (MA) is a rare tumor believed to arise from mesonephric remnants occurring mostly in the uterine cervix and, to a lesser extent, the corpus. Since the first case report of MA in the corpus in 1995, only 16 cases have been reported in the English literature. A recent report suggested that MA originates in Mullerian tissue and exhibits the mesonephric differentiation phenotype. CASE PRESENTATION: An asymptomatic 61-year-old woman was referred to our hospital because of elevated levels of tumor markers. Imaging revealed an intramural lesion of the uterine corpus exhibiting fluorodeoxyglucose uptake. A total hysterectomy and bilateral salpingo-oophorectomy were performed. The tumor was completely confined to the corpus wall and was composed of an intracystic bulky component and an invasive component in the myometrial layer. The tumor exhibited a variety of growth patterns, including a characteristic tubular pattern with dense eosinophilic secretion reminiscent of the thyroid, as well as a variety of morphologies, such as acinar, papillary, and ductal structures. The structures were immunoreactive for CK7, vimentin, CD10, calretinin, PAX8, and GATA3 and almost completely negative for ER/PgR. CA125 and CA19-9 antigen expression was also detected. CONCLUSION: A case of MA with a unique growth pattern of an intracystic mass within the corpus wall is presented. The histogenesis and differential diagnoses are discussed. The histogenesis of MA is not yet clear. We hypothesize two different pathways involved: 1) direct development from the mesonephric remnants and/or 2) mesonephric transformation of Mullerian adenocarcinoma. PMID- 28841921 TI - Growing up HIV-positive in Uganda: "psychological immunodeficiency"? A qualitative study. AB - BACKGROUND: This study is part of a longitudinal study among children and adolescents with HIV in both urban and rural Uganda: 'Mental health among HIV infected CHildren and Adolescents in KAmpala and Masaka, Uganda (CHAKA)'. METHOD: The study is constructed of both quantitative and qualitative components. In this article we report a qualitative study on the experiences of 21 adolescents (twelve to seventeen years) living with HIV in Uganda. The purpose of the study was to investigate both the protective and the risk factors in HIV-infected adolescents' care environment in order to understand what might contribute to negative outcomes and what might provide a protective buffer against harmful life events. Semi-structured interviews with vignettes about mental disorders were employed and a phenomenological analysis was done. RESULTS: The findings uncovered that the adolescents' families were mostly characterized by instability and diffuse relationships that provided an insecure basis for secure attachment and emotional support. Even in stable and secure family environments, there was no guarantee for getting sufficient emotional support in order to develop a positive self-concept due to the fate being the only infected child in the family. Both secure attachment and positive self-concept are known psychological protective mechanisms that provide the individual with resilience. The adolescents in this study seemed hampered in the development of protective mechanisms and consequently seemed psychologically vulnerable and badly equipped for coping with challenges, which paves the way for the possible development of mental disorders. CONCLUSION: To change the focus towards strengthening the children and adolescents' development of psychological protective mechanisms implicates a change in focus from illness to health and has consequences for both treatment and prevention. Psychological health promotion must be systemic and aim at strengthening the family environment, but also to establish peer group support. PMID- 28841922 TI - From the Editor: A Message to Students of IR. PMID- 28841920 TI - Ipsilateral EEG mu rhythm reflects the excitability of uncrossed pathways projecting to shoulder muscles. AB - BACKGROUND: Motor planning, imagery or execution is associated with event-related desynchronization (ERD) of mu rhythm oscillations (8-13 Hz) recordable over sensorimotor areas using electroencephalography (EEG). It was shown that motor imagery involving distal muscles, e.g. finger movements, results in contralateral ERD correlating with increased excitability of the contralateral corticospinal tract (c-CST). Following the rationale that purposefully increasing c-CST excitability might facilitate motor recovery after stroke, ERD recently became an attractive target for brain-computer interface (BCI)-based neurorehabilitation training. It was unclear, however, whether ERD would also reflect excitability of the ipsilateral corticospinal tract (i-CST) that mainly innervates proximal muscles involved in e.g. shoulder movements. Such knowledge would be important to optimize and extend ERD-based BCI neurorehabilitation protocols, e.g. to restore shoulder movements after stroke. Here we used single-pulse transcranial magnetic stimulation (TMS) targeting the ipsilateral primary motor cortex to elicit motor evoked potentials (MEPs) of the trapezius muscle. To assess whether ERD reflects excitability of the i-CST, a correlation analysis between between MEP amplitudes and ipsilateral ERD was performed. METHODS: Experiment 1 consisted of a motor execution task during which 10 healthy volunteers performed elevations of the shoulder girdle or finger pinching while a 128-channel EEG was recorded. Experiment 2 consisted of a motor imagery task during which 16 healthy volunteers imagined shoulder girdle elevations or finger pinching while an EEG was recorded; the participants simultaneously received randomly timed, single-pulse TMS to the ipsilateral primary motor cortex. The spatial pattern and amplitude of ERD and the amplitude of the agonist muscle's TMS-induced MEPs were analyzed. RESULTS: ERDs occurred bilaterally during both execution and imagery of shoulder girdle elevations, but were lateralized to the contralateral hemisphere during finger pinching. We found that trapezius MEPs increased during motor imagery of shoulder elevations and correlated with ipsilateral ERD amplitudes. CONCLUSIONS: Ipsilateral ERD during execution and imagery of shoulder girdle elevations appears to reflect the excitability of uncrossed pathways projecting to the shoulder muscles. As such, ipsilateral ERD could be used for neurofeedback training of shoulder movement, aiming at reanimation of the i-CST. PMID- 28841923 TI - Peripherally Inserted Central Catheter Insertion in Conjoined Thoraco omphalopagus Twins. PMID- 28841924 TI - First Device to Market: Highlighting the Value of the US Early Feasibility Study Program. PMID- 28841925 TI - Increasing Role of Dual-Energy CT in Noninvasive Vascular Imaging. PMID- 28841926 TI - Endovascular Treatment of Inferior Vena Cava Agenesis Using the Azygos Vein. PMID- 28841927 TI - Fluoroscopic Radiation Exposure in Chemoembolization and Radioembolization: Results from a Prospective Randomized Study. PMID- 28841928 TI - Incidence of "Occult" Prostatopudendal Arterial Anastomoses during Prostatic Artery Embolization. PMID- 28841929 TI - Successful Prostatic Artery Embolization following UroLift Device Failure. PMID- 28841930 TI - Changes in Prostatic Artery Angiography with Balloon Occlusion. PMID- 28841931 TI - Renal Microwave Ablation Resulting in Ureteropelvic Junction Stricture Remote from the Ablation Site. PMID- 28841932 TI - CT-Guided Irreversible Electroporation for Locally Recurrent Prostate Cancer following Radical Prostatectomy and Salvage Radiation Therapy. PMID- 28841933 TI - Percutaneous Microwave Ablation of Hepatocellular Carcinoma Metastatic to a Mesocolic Lymph Node. PMID- 28841934 TI - Bladder Protection with Continuous Infusion of Warmed Saline Solution to Facilitate CT-Guided Cryoablation of Prostate Cancer with Extracapsular and Bladder Invasion. PMID- 28841935 TI - Pulmonary Embolism after Percutaneous Cryoablation for Lung Cancer: A Case Report. PMID- 28841936 TI - Incident of Stroke after Transradial Arterial Access for Subdiaphragmatic Intervention. PMID- 28841937 TI - Re: Endovascular Stroke Treatment of Acute Tandem Occlusion: A Single-Center Experience. PMID- 28841938 TI - Complex Endovascular Abdominal Aneurysm Repair with Fenestrated Endograft Insertion under Hypnosis and Local Anesthesia. PMID- 28841939 TI - Congenital Extrahepatic Portosystemic Shunt Embolization with the Use of a Duct Occluder in a Neonate with Liver Dysfunction and Hyperammonemia. PMID- 28841940 TI - Stent Fracture and Fragment Migration to Chordae Tendineae of the Tricuspid Valve after Transjugular Intrahepatic Portosystemic Shunt Procedure. PMID- 28841941 TI - Uterine Artery Embolization prior to Gravid Hysterectomy in the Setting of Invasive Placenta. PMID- 28841942 TI - Retrieval of an Essure Device from the Pulmonary Arterial System. PMID- 28841943 TI - Image-Guided Injection of Bone Allograft and Autologous Bone Marrow for the Treatment of Aneurysmal Bone Cyst of the Jaw. PMID- 28841944 TI - A Rare Complication of Percutaneous Transoral Vertebroplasty at C2: Cement Leakage within the Vertebral Artery. PMID- 28841945 TI - Percutaneous Endovascular Retrieval of a Migrated Permanent VenaTech LP Inferior Vena Cava Filter from the Right Ventricle. PMID- 28841946 TI - Inferior Vena Cava Filter with Pancreatic Penetration and Complex Retrieval Complicated by Renal Arterial Injury. PMID- 28841947 TI - Retained Nephrostomy String Causing Severe Flank Pain and Hematuria. PMID- 28841948 TI - Successful Loop Snare Salvage of Contralateral Glue Migration during Portal Vein Embolization. PMID- 28841949 TI - Endovascular Retrieval of a Retained Temporary Ventricular Support Device. PMID- 28841950 TI - Prone Transradial Renal Arteriography and Interventional Nephroscopy for the Visualization and Retrieval of Migrated Renal Embolization Coils Causing Flank Pain and Hydronephrosis. PMID- 28841951 TI - Percutaneous Suprapubic Cystolitholapaxy in Adult Patients with Previous Mitrofanoff Repair: Considerations for the Interventional Radiologist. PMID- 28841952 TI - Disposable Single-Use Ureteroscopy-Guided Nephroureteral Stent Placement in a Patient with Pyelovesicostomy Stricture and Failed Prior Nephroureteral Stent Placement. PMID- 28841953 TI - Intrastent Pseudoaneurysm following Endoscopic Biliary Stent Insertion. PMID- 28841954 TI - Ultrasound- and Fluoroscopic-Guided Embolization of a Bronchial Artery Pseudoaneurysm in a Patient with Lung Cancer. PMID- 28841955 TI - Successful Thoracic Duct Embolization for Treatment of an Iatrogenic Left Chylothorax in a Neonate after Repair of a Tracheoesophageal Fistula and Esophageal Atresia. PMID- 28841956 TI - Endolymphatic Ultrasound-Assisted Microvascular Plug Placement in a Patient with Thoracic Duct Leak after Esophagectomy. PMID- 28841957 TI - Endovascular Treatment of May-Thurner Syndrome-Related Symptomatic Venous Aneurysm. PMID- 28841958 TI - Collateral Damage: Catheterization of the Epidural Space during Deep Venous Thrombosis Thrombolysis. PMID- 28841959 TI - Re: Adjuvant Medications that Improve Survival after Locoregional Therapy. PMID- 28841960 TI - Reply to: "Adjuvant Medications that Improve Survival after Locoregional Therapy". PMID- 28841961 TI - Re: Bleeding Risk and Management in Interventional Procedures in Chronic Liver Disease. PMID- 28841962 TI - Reply to: "Re: Bleeding Risk and Management in Interventional Procedures in Chronic Liver Disease". PMID- 28841963 TI - Erratum. PMID- 28841964 TI - Improved voltammetric method for simultaneous determination of Pt and Rh using second derivative signal transformation - application to environmental samples. AB - The determination of Platinum-group elements (PGE) in relevant environmental matrices is a challenging task. Sensitive and accurate analytical procedures for simultaneous determination of Pt and Rh are still needed. In this study, we report for the first time on the use of second derivative signal transformation to the ultra-trace simultaneous determination of Pt and Rh by Adsorptive Cathodic Stripping Voltammetry (AdCSV). With that step, the ill-defined peaks typically observed in the original voltammograms are transformed into well-shaped peaks, resulting in accurate detection. The experimental conditions were investigated and optimised: a suitable electrolyte for both elements, with less reagents consumption, (0.25M H2SO4, 0.05M HCl, 0.01M FA and 0.5mM HZ), deposition time (td) and deposition potential (Ed). For td = 120s and Ed = -0.75V, linear relationships r > 0.999 were obtained in the concentration range up to 5.8ngL-1 (27 pM) for Pt and up to 3.4ngL-1 (34 pM) for Rh. Limits of detection were 0.2ngL 1 for Pt and 0.08ngL-1 for Rh. Lower values can be achieved by increasing the deposition time. Limits of quantification, LOQ, calculated as 3 times LOD, were 0.5ngL-1 for Pt and 0.2ngL-1 for Rh. The sensitivity of Pt was affected by elevated Zn concentrations, whereas a minor effect was observed for Rh. However, Pt and Rh determinations were not influenced using the standard addition method. Precision as intermediate precision and expressed as relative standard deviation, based on Pt and Rh spiked solutions and digested road dust CRM BCR-723 was 17% and 20% for Pt and Rh, respectively. Recoveries of CRM were around 90% for both elements. The method was successfully applied in the simultaneous determination of Pt and Rh in sediments from Tagus estuary and, for the first time, dissolved Rh was determined in water samples of a waste water treatment plant. Application of this technique in a multidisciplinary approach will be a relevant contribution to the current understanding of PGE cycle and fate in the environment. PMID- 28841965 TI - Fluorescent sensor systems based on nanostructured polymeric membranes for selective recognition of Aflatoxin B1. AB - Nanostructured polymeric membranes for selective recognition of aflatoxin B1 were synthesized in situ and used as highly sensitive recognition elements in the developed fluorescent sensor. Artificial binding sites capable of selective recognition of aflatoxin B1 were formed in the structure of the polymeric membranes using the method of molecular imprinting. A composition of molecularly imprinted polymer (MIP) membranes was optimized using the method of computational modeling. The MIP membranes were synthesized using the non-toxic close structural analogue of aflatoxin B1, ethyl-2-oxocyclopentanecarboxylate as a dummy template. The MIP membranes with the optimized composition demonstrated extremely high selectivity towards aflatoxin B1 (AFB1). Negligible binding of close structural analogues of AFB1 - aflatoxins B2 (AFB2), aflatoxin G2 (AFG2), and ochratoxin A (OTA) was demonstrated. Binding of AFB1 by the MIP membranes was investigated as a function of both type and concentration of the functional monomer in the initial monomer composition used for the membranes' synthesis, as well as sample composition. The conditions of the solid-phase extraction of the mycotoxin using the MIP membrane as a stationary phase (pH, ionic strength, buffer concentration, volume of the solution, ratio between water and organic solvent, filtration rate) were optimized. The fluorescent sensor system based on the optimized MIP membranes provided a possibility of AFB1 detection within the range 14-500ngmL-1 demonstrating detection limit (3?) of 14ngmL-1. The developed technique was successfully applied for the analysis of model solutions and waste waters from bread-making plants. PMID- 28841966 TI - Galvanostatic electrodeposition of copper nanoparticles on screen-printed carbon electrodes and their application for reducing sugars determination. AB - In this work, a novel method for the galvanostatic electrodeposition of copper nanoparticles on screen-printed carbon electrodes was developed. Nanoparticles of spherical morphology with sizes between 60 and 280nm were obtained. The electrocatalytic effect of these copper nanospheres towards the oxidation of different sugars was studied. Excellent analytical performance was obtained with the nanostructured sensor: low detection limits and wide linear ranges (1 10,000uM) were achieving for the different reducing sugars evaluated (glucose, fructose, arabinose, galactose, mannose, xylose) with very similar calibration slopes, which demonstrates the possibility of total sugar detection. The reproducibility of these sensors was 4.4% (intra-electrode) and 7.2% (inter electrode). The stability of the nanostructured electrodes was at least 30 days, even using the same device on different days. Several real samples (honey, orange juice and normal and sugar-free soft drinks) were evaluated to study the reliability of the nanostructured sensor. PMID- 28841967 TI - Colorimetric detection of thiocyanate based on inhibiting the catalytic activity of cystine-capped core-shell Au@Pt nanocatalysts. AB - In this work, core-shell Au@Pt nanocatalysts (Au@Pt NCs) with ultrathin Pt shell were synthesized and demonstrated high peroxidase-like activity. Thiocyanate ions (SCN-) were found to effectively inhibit the peroxidase-like activity of Au@Pt NCs, and the mechanism was discussed by the characterization of TEM, DLS, EPR and XPS, etc. The inhibition of the catalytic activity of Au@Pt NCs by SCN- was mainly due to the decreased ability of the Au@Pt NCs for capturing *OH radicals and the increased ratio of Pt2+ to Pt degrees on the surface of the Au@Pt NCs. A sensitive colorimetric detection of thiocyanate (SCN-) was developed, based on the activity inhibition of Au@Pt NCs by SCN-. Interestingly, cystine modification of Au@Pt NCs was found to significantly improve the selectivity of SCN- recognition. After optimization, a colorimetric assay for SCN- was established with a detection limit of 5.0nM and a broad linear calibration over the range of 20nM to 40uM. This assay has the advantages of highly sensitive, selective and low-cost. Moreover, this assay demonstrated highly potential application in the quantitative determination of SCN- in water and raw milk samples. PMID- 28841968 TI - Nanopore biosensor for sensitive and label-free nucleic acid detection based on hybridization chain reaction amplification. AB - A label-free nanopore biosensor for detection of DNA target is proposed utilizing hybridization chain reaction (HCR) strategy for signal amplification. The DNA target triggered HCR to form large DNA nanostructure inside the nanopore and out the nanopore membrane, which inducing the ionic current decrease effectively due to the blockage of the nanopore. The developed method achieves a desirable sensitivity of 30fM with a wide linear dynamic range from 0.1 to 10pM and demonstrated good application for real sample analysis. This work has great potential to be applied in the early diagnosis of gene-related diseases and provide a new paradigm for label-free nucleic acid amplification strategy in ultrasensitive nanopore biosensor. PMID- 28841969 TI - Kinetic study of niobium and tantalum hexameric forms and their substituted ions by capillary electrophoresis in alkaline medium. AB - In this work a capillary electrophoretic (CE) method is used for the kinetic study of the intermetallic substitutions in hexameric ions of two strategic metals, tantalum and niobium in an alkaline medium. Recently proposed processes for the production and analytical separation of tantalum and niobium that are faster, more economical and environmental friendly are based on the use of highly alkaline media. It was previously established that in these media, tantalum and niobium exist as hexameric species, HxTa6O19X-8 (Ta6) and HxNb6019x-8 (Nb6), which can be analysed with a CE method using an alkaline electrolyte and UV detection. However, when using the above method on an industrial sample a minor species that should correspond to the substituted Ta1Nb5 form was observed. The purpose of the present study is to probe, by means of CE, the kinetic of the formation of substituted niobate-tantalate ions, Ta6-xNbx (1 <= x <= 5), starting from mixtures of pure hexaniobate and hexatantalate ions. This study required the development of a new CE method allowing the separation of all the five substituted ions and their two non-substituted hexameric parent ions in less than seven minutes. In details, a previously developed separation method was transferred to a Beckman instrument and the separation improved by adjusting the total length, the applied voltage, the injection volume, the rinsing steps and the internal standard. The kinetic study shows that samples initially containing non-substituted hexameric forms of tantalum and niobium in a 1:1M ratio naturally form the five possible substituted species Ta6-xNbx (1 <= x <= 5) after only a few hours which may represent an issue for future Nb-Ta separation processes operated in alkaline media. The developed method was also transferred to an Agilent instrument and the kinetic study repeated. Results obtained with the Agilent instrument corroborate those obtained with the Beckman instrument. The proposed electrophoretic separation method lays the ground for new analytical techniques that could help assessing the presence of substituted species that can be deleterious for Nb-Ta purification processes. PMID- 28841970 TI - Semi-quantitative visual detection of loop mediated isothermal amplification (LAMP)-generated DNA by distance-based measurement on a paper device. AB - A distance-based paper analytical device (dPAD) for loop mediated isothermal amplification (LAMP) detection based on distance measurement was proposed. This approach relied on visual detection by the length of colour developed on the dPAD with reference to semi-quantitative determination of the initial amount of genomic DNA. In this communication, E. coli DNA was chosen as a template DNA for LAMP reaction. In accordance with the principle, the dPAD was immobilized by polyethylenimine (PEI), which is a strong cationic polymer, in the hydrophilic channel of the paper device. Hydroxynaphthol blue (HNB), a colourimetric indicator for monitoring the change of magnesium ion concentration in the LAMP reaction, was used to react with the immobilized PEI. The positive charges of PEI react with the negative charges of free HNB in the LAMP reaction, producing a blue colour deposit on the paper device. Consequently, the apparently visual distance appeared within 5min and length of distance correlated to the amount of DNA in the sample. The distance-based PAD for the visual detection of the LAMP reaction could quantify the initial concentration of genomic DNA as low as 4.14 * 103 copiesuL-1. This distance-based visual semi-quantitative platform is suitable for choice of LAMP detection method, particular in resource-limited settings because of the advantages of low cost, simple fabrication and operation, disposability and portable detection of the dPAD device. PMID- 28841971 TI - Strip-dried whole milk sampling technique for progesterone detection in cows by ELISA. AB - New sampling format of whole cows' milk in strip-dried form was proposed. Few methodological issues of whole milk progesterone ELISA using samples dried on a membrane carrier in a form of strip were investigated and optimized: width of a strip, shape of punched/cut-off part of membrane, sample application method. It was shown that distribution of the hormone along narrow strip was even except the initial part of a strip (the first 0.5 * 0.5cm piece) where recovered concentration of progesterone was higher. Storage stability of progesterone in strip-dried whole cows' milk samples at 4 degrees C, ambient temperature, 37 degrees C and 60 degrees C was investigated. Rising of the detected progesterone concentration over storage period at elevated temperatures was observed predominantly in milk samples with low hormone concentration (from non-pregnant cows). Strip-dried whole milk samples can be used for collection, transportation, storage and ELISA analysis of progesterone level which is correlated with reproductive status of cows. PMID- 28841972 TI - Determination of calcium and zinc in gluconates oral solution and blood samples by liquid cathode glow discharge-atomic emission spectrometry. AB - A novel flowing liquid cathode glow discharge (LCGD) was developed as an excitation source of the atomic emission spectrometry (AES) for the determination of Ca and Zn in digested calcium and zinc gluconates oral solution and blood samples, in which the glow discharge is produced between the electrolyte (as cathode) overflowing from a quartz capillary and the needle-like Pt anode. The electron temperature and electron density of LCGD were calculated at different discharge voltages. The discharge stability and parameters affecting the LCGD were investigated in detail. In addition, the measured results of real samples using LCGD-AES were verified by ICP-AES. The results showed that the optimized analytical conditions are pH = 1 HNO3 as supporting electrolyte, 4.5mLmin-1 solution flow rate. The power consumption of LCGD is 43.5-66.0W. The R2 and the RSD ranged from 630 to 680V are 0.9942-0.9995 and 0.49%-2.43%, respectively. The limits of detections (LODs) for Zn and Ca are 0.014-0.033 and 0.011-0.097mgL-1, respectively, which are in good agreement with the closed-type electrolyte cathode atmospheric glow discharge (ELCAD). The obtained results of Ca and Zn in real samples by LCGD-AES are basically consistent with the ICP-AES and reference value. The results suggested that LCGD-AES can provide an alternative analytical method for the detection of metal elements in biological and medical samples. PMID- 28841973 TI - Polydimethylsiloxane/MIL-100(Fe) coated stir bar sorptive extraction-high performance liquid chromatography for the determination of triazines in environmental water samples. AB - Polydimethylsiloxane (PDMS)/MIL-100(Fe) coated stir bar was prepared by sol gel technique, and good preparation reproducibility was achieved with relative standard deviations (RSDs) ranging from 2.6% to 7.5% (n=7) and 3.6% to 10.8% (n=7) for bar-to-bar and batch-to-batch, respectively. Compared with commercial PDMS coated stir bar (Gerstel) and PEG coated stir bar (Gerstel), the prepared PDMS/MIL-100(Fe) stir bar showed better extraction efficiency for target triazines compounds. It also exhibited relatively fast extraction/desorption kinetics and long lifespan. Based on it, a method of PDMS/MIL-100(Fe) coated stir bar sorptive extraction (SBSE)-high performance liquid chromatography-ultraviolet detector (HPLC-UV) was developed for the determination of six triazines (simazine, atrazine, prometon, ametryn, prometryne and prebane) in environmental water samples. Several parameters affecting SBSE of six target triazines including extraction time, stirring rate, sample pH, ionic strength, desorption solvent and desorption time were investigated. Under the optimal experimental conditions, the limits of detection (LODs, S/N=3) were found to be in the range of 0.021-0.079MUgL-1. The repeatability RSDs were in the range of 2.3-6.3% (n=7, c=0.5MUgL-1) and the enrichment factors (EFs) ranged from 51.1 to 102-fold (theoretical EF was 200-fold). The proposed method was applied to the analysis of target triazines in environmental water samples, with recoveries of 98.0-118% and 94.0-107% for spiked East Lake water and local pond water samples, respectively. PMID- 28841974 TI - Ultrasensitive electrochemical sensing platform based on graphene wrapping SnO2 nanocorals and autonomous cascade DNA duplication strategy. AB - In this work, a sensitive, universal and reusable electrochemical biosensor based on stannic oxide nanocorals-graphene hybrids (SnO2 NCs-Gr) is developed for target DNA detection by using two kinds of DNA enzymes for signal amplification through an autonomous cascade DNA duplication strategy. A hairpin probe is designed composing of a projecting part at the 3'-end as identification sequence for target, a recognition site for nicking endonuclease, and an 18-carbon shim to stop polymerization process. The designed DNA duplication-incision-replacement process is handled by KF polymerase and endonuclease, then combining with gold nanoparticles as signal carrier for further signal amplification. In the detection system, the electrochemical-chemical-chemical procedure, which uses ferrocene methanol, tris(2-carboxyethyl)phosphine and l-ascorbic acid 2-phosphate as oxidoreduction neurogen, deoxidizer and zymolyte, separately, is applied to amplify detection signal. Benefiting from the multiple signal amplification mechanism, the proposed sensor reveals a good linear connection between the peak current and logarithm of analyte concentration in range of 0.0001-1 * 10-11molL-1 with a detection limit of 1.25 * 10-17molL-1 (S/N=3). This assay also opens one promising strategy for ultrasensitive determination of other biological molecules for bioanalysis and biomedicine diagnostics. PMID- 28841975 TI - Highly sensitive antibody-aptamer sensor for vascular endothelial growth factor based on hybridization chain reaction and pH meter/indicator. AB - Vascular endothelial growth factor (VEGF) is a crucial signaling protein for the tumor growth and metastasis, which is also acted as the biomarkers for various diseases. In this research, we fabricate an aptamer-antibody sensor for point-of care test of VEGF. Firstly, target VEGF is captured by antibody immobilized on the microplate, and then binds with aptamer to form the sandwich structure. Next, with the assist of glucose oxidase (GOx)-functionalized ssDNAs, hybridization chain reaction occurs using the aptamer as the primer. Thus, GOx are greatly gathered on the microplate, which catalyzes the oxidization of glucose, leading to the pH change. As a result, the detect limit at a signal-to-noise was estimated to be 0.5pg/mL of target by pH meter, and 1.6pg/mL of VEGF was able to be distinguished by naked eyes. Meanwhile, this method has been used assay VEGF in the serum with the satisfactory results. PMID- 28841976 TI - A facile and high sensitive micro fluorimeter based on light emitting diode and photodiode. AB - A facile and high sensitive micro fluorimeter was developed and evaluated. It employed light emitting diode (LED) as light source, cuvette as detection cell, and photodiode (PD) as optoelectronic detector. Optical and electronic parameters were optimized and demonstrated. A high power LED was chosen, which could irradiate the inner area of the cuvette completely at the same time with divergence angle as small as possible. The optimum LED brought 2.5 times signal to-noise ratio (SNR) enhancement. Using reflector at the opposite direction of excitation light path doubled SNR. The amplifier circuit of PD was deeply investigated to achieve high sensitivity, low noise, and good stability. The limit of detection (LOD) of fluorescein isothiocyanate (FITC) and chlorophyll at SNR = 3 were 10pM ~ 0.004 ppb and 0.05 ppb, respectively. Basing on the principle structure, a portable fluorimeter for fungimycin detection was developed using a low power UV LED as light source. The LOD for aflatoxin B1 was 0.1 ppb. PMID- 28841977 TI - Aptamer-immobilized open tubular capillary column to capture circulating tumor cells for proteome analysis. AB - Circulating tumor cells hold the key to predicting the prognosis and discovering the therapeutic targets. Herein, we proposed a strategy to develop an aptamer immobilized open tubular capillary column by which SMMC-7721 human hepatoma cells (SMMC-7721 cells) could be captured with an over 70% of capture efficiency and a 3.0 +/- 0.2 of enrichment factor. Owing to the compatibility of the column, the captured cells by the column could be analyzed by LC-MS from protein level and 5 unique proteins of SMMC-7721 cells were identified which could be used as markers to identify SMMC-7721 cells when Jurkat T-leukemia cells (Jurkat cells) were employed as interfering cells. As the key component, the aptamer-immobilized column had the potential to be integrated into the platform for separating, enriching and characterizing rare cells simultaneously. PMID- 28841978 TI - Simultaneous determination of cadmium, lead and mercury ions at trace level by magnetic solid phase extraction with Fe@Ag@Dimercaptobenzene coupled to high performance liquid chromatography. AB - Pollution resulted from heavy metal ions have absorbed much attention, and it is of great importance to develop sensitive and simultaneous determination method for them with common technologies without highly sensitive instruments. We prepared a new and functional core-shell magnetic nano-material, Fe@Ag@dimercaptobenzene (Fe@Ag@DMB), by a one-step method with sodium borohydride as the reducing agent and transmission electron microscopy (TEM) and energy dispersive spectrometer (EDS) were used for characterisation. The mercapto functional groups on the newly synthesised magnetic nanoparticles could interact with Cd2+, Pb2+, and Hg2+ ions in water samples and then efficient extraction for Cd2+, Pb2+, and Hg2+ ions was achieved. DDTC-Na solution was a good elutent for elution of these ions from Fe@Ag@DMB nanoparticles. Based on these, a sensitive method was developed for simultaneous preconcentration and determination of the aforementioned ions using magnetic Fe@Ag@DMB nanoparticles as the magnetic solid phase extraction adsorbent prior to high performance liquid chromatography coupled with variable wavelength detection. Under the optimal conditions, the detection limits of the three metal ions were in the range of 0.011-0.031MUgL-1, and precisions were below 2.37% (n=6). The proposed method was evaluated with real water samples, and excellent spiked recoveries achieved indicated that the developed method would be a promising tool for monitoring these heavy metal ions in water samples. PMID- 28841979 TI - Quantification and size characterisation of silver nanoparticles in environmental aqueous samples and consumer products by single particle-ICPMS. AB - Single particle-inductively coupled plasma mass spectrometry (SP-ICPMS) is a promising technique able to generate the number based-particle size distribution (PSD) of nanoparticles (NPs) in aqueous suspensions. However, SP-ICPMS analysis is not consolidated as routine-technique yet and is not typically applied to real test samples with unknown composition. This work presents a methodology to detect, quantify and characterise the number-based PSD of Ag-NPs in different environmental aqueous samples (drinking and lake waters), aqueous samples derived from migration tests and consumer products using SP-ICPMS. The procedure is built from a pragmatic view and involves the analysis of serial dilutions of the original sample until no variation in the measured size values is observed while keeping particle counts proportional to the dilution applied. After evaluation of the analytical figures of merit, the SP-ICPMS method exhibited excellent linearity (r2>0.999) in the range (1-25) * 104 particlesmL-1 for 30, 50 and 80nm nominal size Ag-NPs standards. The precision in terms of repeatability was studied according to the RSDs of the measured size and particle number concentration values and a t-test (p = 95%) at the two intermediate concentration levels was applied to determine the bias of SP-ICPMS size values compared to reference values. The method showed good repeatability and an overall acceptable bias in the studied concentration range. The experimental minimum detectable size for Ag-NPs ranged between 12 and 15nm. Additionally, results derived from direct SP-ICPMS analysis were compared to the results conducted for fractions collected by asymmetric flow-field flow fractionation and supernatant fractions after centrifugal filtration. The method has been successfully applied to determine the presence of Ag-NPs in: lake water; tap water; tap water filtered by a filter jar; seven different liquid silver-based consumer products; and migration solutions (pure water and sweat simulant) from plasters. Results obtained by SP-ICPMS were supported by transmission electron microscopy and energy dispersive spectroscopy characterisation, suggesting that the proposed methodology can be applied as a positive screening test in the simultaneous quantification and size characterisation of Ag-NPs in samples of environmental interest. PMID- 28841980 TI - Electrochemical enzyme biosensors based on calcium phosphate materials for tyramine detection in food samples. AB - Electrochemical tyrosinase biosensors for tyramine determination were developed by the immobilization of the enzyme in calcium phosphate materials (CaPs) followed by cross-linking with glutaraldehyde. Tyramine was detected by the electrochemical reduction at -0.1V of the o- enzymatically-formed dopaquinone. Three different CaPs were explored as immobilization systems, monetite, brushite and brushite cement. Biosensors based on brushite matrices provide better analytical properties than the monetite one. Compared to brushite, a 10-fold increase of sensitivity was obtained with the brushite cement-based biosensor, which highlights the effect of brushite crystal formation in the presence of the enzyme in the biosensor performance. Several variables involved in the enzyme immobilization method such as glutaraldehyde cross-linking time, PPO/brushite ratio and thickness of the brushite-enzyme film were investigated. Furthermore, the effects of pH and temperature on biosensor performance were also optimized. Brushite cement-PPO-GA biosensor resulted in a reliable, highly sensitive, fast, inexpensive and easy analytical method for tyramine detection. Under optimal conditions (time of 15min, a ratio of 1.0 and 50MUg of the brushite-enzyme mixture, 20 degrees C and pH 6,0), a linear range of 5.8 * 10-7 to 1.6 * 10-5, sensitivity 1.50 * 103mAM-1 cm-2, detection limit, 4.85 * 10-8M and a response time, 6s were obtained. The suitability of the proposed biosensor to determine the tyramine content in cheese samples has been explored. The mean analytical recovery of added tyramine in gouda and brie cheeses were found to be 95.5+/-5.8 and 96.9+/-7.5 respectively. A study of the tyramine content evolution over the course of a week under inadequate storage showed the importance of monitoring the degradation of certain foods. PMID- 28841981 TI - Hydrogen bubble dynamic template fabrication of nanoporous Cu film supported by graphene nanaosheets: A highly sensitive sensor for detection of nitrite. AB - High surface area nanoporous Cu film (NPCF) has been successfully synthesized using a hydrogen bubble dynamic template on the graphene nanosheets (GNs) modified glassy carbon electrode (GCE). The effect of different synthesis conditions such as applied potential and deposition time on the NPCF morphology was investigated. The structure and constituent of the NPCF-GNs/GCE were characterized by scanning electron microscopy (SEM), energy-dispersive x-ray (EDX), X-ray diffraction (XRD), electrochemical impedance spectroscopy (EIS) and electrochemical methods. The study on electrocatalytic performance of the NPCF GNs/GCE demonstrated that this electrode has excellent catalytic activity toward nitrite oxidation. The quantitative measurement of nitrite by amperometric method showed a wide concentration range (0.1-100umolL-1) with a detection limit and a sensitivity of 8.87 * 10-8molL-1 and 3.1 AL/molcm2, respectively. The excellent electrochemical response and high sensitivity of the proposed electrode were attributed to the 3D structure of NPCF and the synergic effect of NPCF and GNs. Furthermore, this electrode showed some other advantages including good repeatability, high reproducibility, long-term stability and anti-interference performance toward nitrite sensing. The applicability of the proposed electrode was proved by successful determination of nitrite in real samples (tap water, river water and sausage samples). PMID- 28841982 TI - Dual-channel sensing strategy based on gold nanoparticles cooperating with carbon dots and hairpin structure for assaying RNA and DNA. AB - By employing the attractive performance of fluorescent carbon dots and the assistant of hairpin structure, an innovative dual-channel biosensor on the basis of gold nanoparticles (AuNPs) for detecting multiple nucleotide sequences has been successfully proposed. In brief, the fluorescence of carbon dots (CDs) was quenched in the absence of the targets, and the hairpin structure was hybridized with the AuNPs-DNA and resulted in recovering the fluorescence. Instead, the presence of breast cancer (BRCA1) RNA/DNA could specifically bind with its contrary sequence to release the CDs from AuNPs, hence leading to the fluorescence recovery as a positive signal. Again, the hairpin structure can be released in the presence of thymidine kinase (TK1) RNA/DNA, thus induced a fluorescence quenching accordingly. Subsequently, the prepared sensing model was applied to detect BRCA1 RNA/DNA respectively accompanied with a linear range of 4 120nM as well as a detection limit of 1.5nM and 2.1nM, and 10-120nM as well as a detection limit of 3.6nM and 4.5nM for TK1 RNA/DNA respectively. More importantly, this sensing model could assay any possible gene sequence or aptamer substrate complexes by appropriately programming. PMID- 28841983 TI - A colorimetric aptamer biosensor based on cationic polythiophene derivative as peroxidase mimetics for the ultrasensitive detection of thrombin. AB - A colorimetric assay for the ultrasensitive determination of thrombin was presented, in which the cationic polythiophene derivative was used as catalyst of the 3,3',5,5'-tetramethylbenzidine (TMB)-H2O2 reaction and the thrombin-binding aptamer (TBA) was used as inducing polymer's different conformation elements. It was found the cationic polythiophene derivative, poly[3-(3'-N,N,N-triethylamino 1'-propyloxy)-4-methyl-2,5-t-hiophene hydrochloride] (PMNT), can catalyze the oxidation reaction of TMB in the presence of H2O2 to produce a blue color solution. The catalytic activity of PMNT on the TMB-H2O2 reaction was closely relevant to the conformation of PMNT. The absorbance of TMB-H2O2 was distinctly increased in the presence of TBA. With the addition of thrombin, TBA interacted with thrombin to form a G-quadruplex structure. The conformational change weakened the catalytic activity of PMNT and resulted in a decrease in the absorbance. The colorimetric sensor could detect thrombin down to 4pM with high selectivity against other interfering proteins. This work is not only of importance for a better understanding of the unique properties of cationic polythiophenes derivative but also have great potential for medical diagnostics and therapy for human health. PMID- 28841984 TI - A simple and fast chromogenic reaction based on Ag3PO4/Ag nanocomposite for tumor marker detection. AB - Colorimetric assay is a powerful tool for detection of tumor markers with the outstanding advantages of visualization and simple analytical instruments. Herein, a simple and fast chromogenic reaction was developed based on Ag3PO4/Ag nanocomposite synthesized by one-step chemical bath method. And the Ag3PO4/Ag nanocomposite owned the ability of oxidizing of TMB under the acidic condition due to the hydrolytic action. The nanocomposite was characterized by transmission electron microscope (TEM), scanning electron microscope (SEM), X-ray powder diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Then, the colorimetric immunoassay was constructed by utilizing Ag3PO4/Ag nanocomposite as molecular labels for carcino embryonie antigen (CEA, UniProt accession number: P06731) detection. The blue color with gradient change was observed with the increasing of CEA concentrations. Under optimal conditions, the variation between absorbance values and CEA levels was linear in the range of 0.2ngmL-1 ~ 2.5ngmL-1 with the detection limit of 0.03ngmL-1. More importantly, the developed colorimetric immunoassay exhibited good selectivity, repeatability, stability and potential application in the real serum sample detection. PMID- 28841985 TI - In vitro selection of DNA aptamers against renal cell carcinoma using living cell SELEX. AB - Renal cell carcinoma (RCC) is the most common form of kidney cancer with poor prognosis. Early diagnosis of RCC would significantly improve patient prognosis and quality of life. In this work, we developed new aptamer probes for RCC by using cell-SELEX (systematic evolution of ligands by exponential enrichment) only after 12 rounds of selection, in which a clear cell renal cell carcinoma (ccRCC) cell line 786-O was used as target cell, and embryonic kidney cell line 293T as negative control cell. The selected aptamers were subjected to flow cytometry and laser confocal fluorescence microscopy to evaluate their binding affinity and selectivity. The dissociation constant Kd values of four selected aptamers are all in the nanomolar range. Aptamer W786-1 with the best binding affinity and a Kd value of 9.4 +/- 2.0nM was further optimized and its truncated sequence W786 1S showed considerable affinity to 786-O cells. The proteinase and temperature treatment experiment indicated that W786-1 could recognize the target 786-O cells through surface proteins, and remain good binding affinity and excellent selectivity under physiological conditions. Therefore, on the basis of its excellent targeting properties and functional versatility, W786-1 holds great potential to be used as a molecular probe for identifying and targeting RCC. PMID- 28841986 TI - Indirect Determination of Pentaerythritol Tetranitrate (PETN) with a gold nanoparticles-based colorimetric sensor. AB - Pentaerythritol tetranitrate (PETN) is the nitrate ester of pentaerythritol, used as an energetic and filling material for military and civilian purposes and rarely for terrorist actions. As there is no reliable nano-colorimetric method for PETN assay, we developed an indirect method based on the determination of nitrite, obtained by reduction of nitrate derived from the alkaline hydrolysis of PETN with H2O2. We colorimetrically determined the final product, nitrite, by both conventional Griess reaction and a recently developed gold nanoparticle-4 aminothiophenol-N-(1-naphthyl)-ethylenediamine (AuNP-4-ATP+NED) method. Nitramines (RDX and HMX), if present, could be degraded by alkaline hydrolysis, without affecting PETN. The analytical performance characteristics of the developed assays as molar absorptivity (epsilon), limits of detection (LOD) and quantification (LOQ) were: E=1.06*105 L mol-1 cm-1, LOD=0.03mgL-1 and LOQ=0.11mgL 1 for indirect Griess method; E=1.9*104Lmol-1 cm-1; LOD=0.12mgL-1 and LOQ=0.4mgL 1 for AuNP-4-ATP+NED method. Both methods were applied to a 1:1 (w/w) mixture of PETN and TNT (corresponding to the composition of military explosive 'Pentolite'). In order to eliminate the interference from TNT, the Meisenheimer anion of TNT formed in alkaline medium was retained on a strongly basic anion exchange resin column. As PETN had a very low solubility in water, common soil ions could be eliminated by prewashing the sample with water, or in acetone-water mixtures, Ca2+, K+, Cl-, SO42-, and NO3- could be tolerated at equal (1:1) mass ratios. Soil nitrates and nitrites, at a mass ratio of 50:1, could be separated from PETN with the aid of their insolubilities in acetone and of their retention affinity toward a strongly basic anion-exchange resin. The developed method was statistically validated against a reference GC-MS method. PMID- 28841987 TI - Determination of boron content and isotopic composition in gypsum by inductively coupled plasma optical emission spectroscopy and positive thermal ionization mass spectrometry using phase transformation. AB - As a stable isotope, boron plays an important role in hydrogeology, environmental geochemistry, ore deposit geochemistry and marine paleoclimatology. However, there is no report of boron isotopic composition in gypsum. This is mainly confined to complete dissolution of Gypsum by water or acid. In this study, gypsum was converted to calcium carbonate (CaCO3) with ammonium bicarbonate(NH4HCO3) by two steps at 50 degrees C. In every step, the mass ratio of NH4HCO3/CaSO4.2H2O was twice, and conversion rate reached more than 98%. Converted CaCO3 was totally dissolved with hydrochloric acid (the dissolution rate was over 99%). In order to overcome the difficulties of the matrix interference and the detection limit of Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), we use Amberlite IRA 743 resin to purify and enrichment the boron at first, then eluting boron from the resin with 10mL 0.1mol/L hydrochloric acid at 75 degrees C. The boron isotopic composition of natural gypsum samples was determined using positive thermal ionization mass spectrometry (P-TIMS). The boron isotopic composition of gypsum may be an excellent indicator for the formation environment. PMID- 28841988 TI - Surface radical chain-transfer reaction in deep eutectic solvents for preparation of silica-grafted stationary phases in hydrophilic interaction chromatography. AB - In this paper, deep eutectic solvents (DESs) were firstly used as new and green solvents for the preparation of polymer-grafted silica stationary phases. 1 Vinylimidazole and acrylic acid were homopolymerized and copolymerized on silica via surface radical chain-transfer reaction in the DESs. Three stationary phases including poly(1-vinylimidazole)-, poly(acrylic acid)-, poly(1-vinylimidazole-co acrylic acid)-grafted silica were obtained and characterized by elemental analysis and Fourier transform infrared spectroscopy. Their hydrophilic interaction chromatographic properties were investigated for separation of nucleosides, nucleobases, saccharides and amino acids. The retention changes of nucleosides and nucleobases on these columns were investigated under different chromatographic conditions including acetonitrile content, salt concentration, pH of mobile phase and column temperature. The repeatability of these columns was also investigated. The results demonstrate that DESs can be used as new media for the synthesis of silica-based stationary phases by homopolymerization and copolymerization on the surface of porous silica particles. PMID- 28841989 TI - Assessment of anti-inflammatory properties of extracts from Honeysuckle (Lonicera sp. L., Caprifoliaceae) by ATR-FTIR spectroscopy. AB - Inflammation is a hallmark of some of today's most life-threatening diseases such as arteriosclerosis, cancer, diabetes and Alzheimer's disease. Herbal medicines (HMs) are re-emerging resources in the fight against these conditions and for many of them, anti-inflammatory activity has been demonstrated. However, several aspects of HMs such as their multi-component character, natural variability and pharmacodynamic interactions (e.g. synergism) hamper identification of their bioactive constituents and thus the development of appropriate quality control (QC) workflows. In this study, we investigated the potential use of Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy as a tool to rapidly and non-destructively assess different anti-inflammatory properties of ethanolic extracts from various species of the Genus Lonicera (Caprifoliaceae). Reference measurements for multivariate calibration comprised in vitro bioactivity of crude extracts towards four key players of inflammation: Nitric oxide (NO), interleukin 8 (IL-8), peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kappaB). Multivariate analysis of variance (MANOVA) revealed a statistically significant, quantitative pattern-activity relationship between the extracts' ATR-FTIR spectra and their ability to modulate these targets in the corresponding cell models. Ensemble orthogonal partial least squares (OPLS) discriminant models were established for the identification of extracts exhibiting high and low activity with respect to their potential to suppress NO and IL-8 production. Predictions made on an independent test set revealed good generalizability of the models with overall sensitivity and specificity of 80% and 100%, respectively. Partial least squares (PLS) regression models were successfully established to predict the extracts' ability to suppress NO production and NF-kappaB activity with root mean squared errors of cross validation (RMSECV) of 8.7% and 0.05-fold activity, respectively. PMID- 28841990 TI - High-precision quantitation of a tuberculosis vaccine antigen with capillary-gel electrophoresis using an injection standard. AB - Analysis of proteinogenic vaccine antigens in a quality control environment requires an accurate, precise, and reliable method for protein separation and quantitation. While having multiple advantages over the classical SDS-PAGE, capillary gel electrophoresis (CGE) has not yet become a standard tool in vaccine antigen analysis. Here we report on development of a CGE-based method for quantitative analysis of a tuberculosis vaccine fusion antigen protein, H4, currently in clinical trials. We demonstrate that our method can monitor antigen purity and relative quantity with greater precision and accuracy versus SDS-PAGE. In addition, due to use of direct light-absorbance detection, the CGE method is suitable for absolute quantitation, an application for which SDS-PAGE is limited due to the need for staining and limited dynamic range of detection. To further improve the performance of our quantitation method, we introduced Bovine Serum Albumin (BSA) as an injection standard to correct for signal variance associated with the injected sample volume. We found that, for our specific application, BSA was more appropriate as an injection standard versus one provided in a commercial kit, in terms of precision and accuracy for quantitation of H4. In addition to providing better method performance versus SDS-PAGE, CGE is also faster and less resource-intensive. We conclude that CGE should be considered as a replacement for traditional SDS-PAGE methods for vaccine antigen quantitation in a quality control environment. PMID- 28841992 TI - Laser carved micro-crack channels in paper-based dilution devices. AB - We developed novel laser carved micro-crack (LCC) paper-based channels to significantly accelerate the liquid flow without an external pump. For the aqueous solutions they increased the flow velocity 59 times in 16% laser power-8 micro-cracks-LCC channel compared with it in solely-printed channels. All experimental data from both LCC and solely-printed channels were well-fitted by the time-distance quadratic trinomial that we developed on laser power and micro crack number. We designed and fabricated T-junction microstructures of LCCs. Further, the microfluidic paper-based analytical device (MUPAD) of LCC on dye mixing gradient and pH gradient were developed with the characteristics, fast self-acting transportation and high-performance mixing of liquid flows. In the dye mixing gradient the time cost was reduced from 2355s in the solely-printed one to only 123s in the five-stage of this LCC-MUPAD. It was useful for quick and long-distance transferences through the multiple units of MUPADs. Certainly, this LCC-MUPAD was inexpensive, disposable, portable and applicable to resource limited environments. PMID- 28841991 TI - Synthesis of permeable yolk-shell structured gadolinium-doped quantum dots as a potential nanoscale multimodal-visible delivery system. AB - Developing a nanoscale drug delivery system with magnetic resonance imaging (MRI)/fluorescence imaging (FL) visibility to optimize the delivery efficiency and therapeutic efficacy under image guidance has attracted great attentions in the area of nanomedicine. Herein, a novel permeable yolk-shell structured gadolinium-doped quantum dots nanocomposite was synthesized as a theranostic nanocarrier via an indirectly doping method. The as-prepared permeable nanoparticles with tunable color fluorescent emission, paramagnetic and accessible mesoporous channels could be developed as a novel nanomedical platform for integrated multimodal diagnosis and therapy. The hydrophilic nanocomposites exhibited tunable fluorescence as well as high longitudinal relaxivity (r1 = 17.32mM-1s-1) in water with good colloidal stability. In vivo animal experiments further verified CSSP could achieve FL/MRI dual modality imaging. The widely used antineoplastic anthracycline drug doxorubicin (DOX) was absorbed into the permeable nanospheres with 95.3% loading efficiency and released in a pH sensitive pattern. In vitro cancer cell cytotoxicity tests verified that the DOX loaded nanocomposites had enhanced cytotoxicity compared with free DOX at the same concentration. The as-prepared nanocomposites present great potential as MRI/FL-visible nanoscale drug carrier to realize imaging-guided personalized therapy. PMID- 28841993 TI - Gold coated porous silicon nanocomposite as a substrate for photoluminescence based immunosensor suitable for the determination of Aflatoxin B1. AB - A rapid and low cost photoluminescence (PL) immunosensor for the determination of low concentrations of Aflatoxin B1 (AFB1) has been developed. This immunosensor was based on porous silicon (PSi) covered by thin gold layer (Au) and modified by antibodies against AFB1 (anti-AFB1). PSi layer was formed on silicon substrate, then the surface of PSi was covered by 30nm layer of gold (PSi/Au) using electrochemical and chemical deposition methods and in such ways PSi/Au(El.) and PSi/Au(Chem.) structures were formed, respectively. In order to find PSi/Au the most efficiently suitable for PL-based sensor design, structure several different PSi/Au(El.) and PSi/Au(Chem.) structures were designed while using different conditions for electrochemical or chemical deposition of gold layer. It was shown that during the formation of PSi/Au structure crystalline Au nanoparticles uniformly coated the surface of the PSi pores. PL spectroscopy of PSi/Au nanocomposites was performed at room temperature and it showed a wide emission band centered at 700nm. Protein A was covalently immobilized on the surface of PSi/Au(El.) and PSi/Au(Chem.) forming PSi/Au(El.)/Protein-A and PSi/Au(Chem.)/Protein-A structures, respectively. In the next step PSi/Au(El.)/Protein-A and PSi/Au(Chem.)/Protein-A structures were modified by anti-AFB1 and in such way a structures (PSi/Au(El.)/Protein-A/anti-AFB1 and PSi/Au(Chem.)/Protein-A/anti-AFB1) sensitive towards AFB1 were designed. The PSi/Au(El.)/Protein-A/anti-AFB1- and PSi/Au(Chem.)/Protein-A/anti-AFB1-based immunosensors were tested in a wide range of AFB1 concentrations from 0.001 upon 100ng/ml. Interaction of AFB1 with PSi/Au(El.)/Protein-A/anti-AFB1- and PSi/Au(Chem.)/Protein-A/anti-AFB1-based structures resulted PL quenching. The highest sensitivity towards AFB1 was determined for PSi/Au(El.)/Protein-A/anti AFB1-based immunosensor and it was in the range of 0.01-10ng/ml. The applicability of PSi/Au-based structures as new substrates suitable for PL-based immunosensors is discussed. PMID- 28841994 TI - Use of fourier transform infrared spectroscopy to examine the Fe(II)-Catalyzed transformation of ferrihydrite. AB - The Fe(II)-catalyzed transformation of the poorly crystalline Fe(III) oxyhydroxide mineral, ferrihydrite (Fh), to more crystalline Fe(III) mineral species such as magnetite, goethite, and lepidocrocite has been quantitatively evaluated under various conditions using X-ray adsorption spectroscopy (XAS) and Fourier transform infrared (FTIR) spectroscopy. Using the peak height of signature FTIR peaks of sub-micron sized lepidocrocite and goethite references minerals, the FTIR results were comparable to the XAS results within experimental error. This was independent of whether the Fe(II)-catalyzed transformation was initiated by the Fe(III)-reducing bacterium Shewanella oneidensis MR-1 or by added ferrous ammonium sulfate in the presence or absence of lactate. Whilst the use of FTIR has not been previously employed to follow this transformation process, it has advantages relative to XAS including a lower sample requirement (approximately 30-fold lower), greater accessibility and greater safety of operation. Whilst problems with quantifying magnetite in the presence of lepidocrocite were identified in this study using reference Fe(III) oxyhydroxide suspensions, large amounts of magnetite were not produced during transformation under the conditions employed in this study. Reference spectra of lath-like nano goethite particles (with dimensions of approx. 10 * 50nm) also resulted in higher IR absorbance and a slight red-shift in signature peak positions relative to sub micron sized goethite particles with this shift potentially affecting the reliable quantification of samples of unknown size. Despite this, good agreement between the XAS and FTIR data for samples containing iron oxides undergoing continuous transformation was obtained suggesting that FTIR may be a convenient, inexpensive means of following such mineral transformations. PMID- 28841995 TI - Two of a kind but different: Luminescent carbon quantum dots from Citrus peels for iron and tartrazine sensing and cell imaging. AB - Citrus sinensis and Citrus limon peels were used to synthesize two different kinds of carbon quantum dots (CQDs) via an unsophisticated and inexpensive carbonization procedure. The proposed synthesis is straightforward and adheres to the principles of green chemistry since no organic solvents are used and no toxic by-products are formed, while the residual resources employed facilitate the large scale synthesis of dots. The Citrus sinensis and Citrus limon peels are proved to be excellent precursors for the synthesis of CQDs with highly practical applications. The CQDs display strong excitation-independent, blue fluorescence, which is stable over time. Splendid water dispersibility, photostability and stability over a wide range of pH are some of the main advantages of the CQDs, which enable them to be used as a fluorescent probes. Although many of their features are alike, our findings demonstrate that each kind of the CQDs lend itself to quite distinct analytical applications. The developed fluorescent probes possess high potential for sensitive and selective detection of Fe3+ (Citrus sinensis CQDs) and tartrazine (Citrus limon CQDs) via a quenching mechanism. The decrease in fluorescence intensity is in linear relationship with the concentrations of Fe3+ and tartrazine in the ranges of 0.01-1.0MUM and 0.6 23.5MUMU, respectively. Moreover, their low cytotoxicity reinforces their applicability towards cell bioimaging and intracellular detection of Fe3+, which were further studied. PMID- 28841996 TI - Disposable sputtered-bismuth screen-printed sensors for voltammetric monitoring of cadmium and lead in atmospheric particulate matter samples. AB - We report here the use of commercial screen-printed disposable sensors comprising a sputtered bismuth working electrode, a silver pseudo reference electrode and a carbon auxiliary electrode (whole set referred as BispSPE), as a new and advantageous alternative for reliable and convenient monitoring of Cd and Pb in atmospheric particulate matter (PM10 fraction) by anodic stripping voltammetry after acid digestion. After a detailed exploration of surface composition and depth profiles of the BispSPE by SEM, EDX, XPS and EIS, chemical and instrumental variables have been optimized to develop a reliable method capable of measuring Cd and Pb with detection limits of 11.8ngmL-1 and 6.1ngmL-1 respectively. These detection limits are useful for pollution monitoring of these elements in ambient air under the requirements of international health and environmental protection standards. The accuracy of the method was assessed by voltammetric measurements of Cd and Pb in ERM(r)-CZ120 Fine dust (PM10-like) and ERM(r) 1648a Urban Particulate Matter certified reference materials. The applicability of the method to Cd and Pb determination in real samples was demonstrated by analysis of PM10 samples from the air quality network in Extremadura, with a good correlation respect to the standard ICP-MS methodology. Our work constitutes the first reference about the use of disposable sensors based on BispSPE for the determination of heavy metals in atmospheric particulate matter samples. PMID- 28841997 TI - Radiometric evaluation of diglycolamide resins for the chromatographic separation of actinium from fission product lanthanides. AB - Actinium-225 is a potential Targeted Alpha Therapy (TAT) isotope. It can be generated with high energy (>= 100MeV) proton irradiation of thorium targets. The main challenge in the chemical recovery of 225Ac lies in the separation from thorium and many fission by-products most importantly radiolanthanides. We recently developed a separation strategy based on a combination of cation exchange and extraction chromatography to isolate and purify 225Ac. In this study, actinium and lanthanide equilibrium distribution coefficients and column elution behavior for both TODGA (N,N,N',N'-tetra-n-octyldiglycolamide) and TEHDGA (N,N,N',N'-tetrakis-2-ethylhexyldiglycolamide) were determined. Density functional theory (DFT) calculations were performed and were in agreement with experimental observations providing the foundation for understanding of the selectivity for Ac and lanthanides on different DGA (diglycolamide) based resins. The results of Gibbs energy (DeltaGaq) calculations confirm significantly higher selectivity of DGA based resins for LnIII over AcIII in the presence of nitrate. DFT calculations and experimental results reveal that Ac chemistry cannot be predicted from lanthanide behavior under comparable circumstances. PMID- 28841998 TI - Quantitation and biospecific identification of virus-like particles of human papillomavirus by capillary electrophoresis. AB - Capillary electrophoresis (CE) for HPV-VLP quantitation is a very interesting alternative technique compared to those currently used in viral analysis, such as SDS-PAGE, Western blot or protein assay that are destructive and semi quantitative or non specific. In this study, the quantitative performance of the CE method was evaluated. A main issue in virus quantitation is the absence of reference material. Therefore, the concentration of a HPV16-VLP sample produced in the laboratory was determined using ELISA with Gardasil(r), after adjuvant dissolution, as reference material and conformational H16.V5 antibody. HPV16-VLP concentration was found to influence particles electrophoretic mobility until a plateau was reached for concentrations <= 50ugml-1. As zeta potential is directly proportional to the electrophoretic mobility, it was measured at different HPV VLP concentrations and the results were in complete accordance with the measured electrophoretic mobilities. The concentration dependence of the electrophoretic mobility could be explained by an overlap of the electrical double layers of adjacent particles. The HPV16-VLP peak identity was demonstrated unequivocally by the study of HPV16-VLP/H16.V5 antibody complex formation using affinity CE. Finally, the CE method was successfully validated following the ICH Q2R1 guidelines. To overcome the sample heterogeneity issue, a well-designed sample preparation was used. Considering sample complexity, validation results were satisfactory with maximum repeatability and intermediate precision RSD of 12.2% and a maximum relative bias of 1.4%. PMID- 28841999 TI - Voltammetric detection of carbofuran determination using screen-printed carbon electrodes modified with gold nanoparticles and graphene oxide. AB - Carbofuran is a highly toxic pesticide that is heavily used in agriculture due to its high effectiveness and low cost. Improved methods that are simpler and lower cost are needed for carbofuran detection in food and agricultural samples. Herein, we describe the development of a unique electrochemical method for carbofuran-phenol, which is the main hydrolysis product of carbofuran. We have successfully developed a highly accurate and precise method in a portable size using a screen-printed carbon electrode (SPCE) that is modified with graphene oxide (GO) and gold nanoparticles (AuNPs). Consequently, the developed electrode is highly sensitive to and selective for carbofuran. Using the central composite design (CCD) approach, we optimized the method for analysis parameters including the electrode surface loadings of GO and AuNPs as well as the working solution pH. The method exhibited a wide linear range of 1-250uM for analyte detection using differential pulse voltammetry (DPV) on AuNPs/GO-SPCE under the optimized conditions. The limits of detection and quantitation were 0.22 and 0.72uM, respectively. In addition, we also report the application of the method for carbofuran determination in real cucumber and rice samples. This sensitive and selective carbofuran detection method is very promising for simple and low cost analysis in real agricultural fields. PMID- 28842001 TI - A novel label-free electrochemical immunosensor based on aldehyde-terminated ionic liquid. AB - In this paper, aldehyde-terminated ionic liquid was synthesized and used to fabricate a novel label-free electrochemical immunosensor for the determination of hepatitis B surface antigen. This sensor was formed from a gold electrode which was modified with a composite film containing the aldehyde-functionalized ionic liquid incorporated into nafion and anti-hepatitis B surface antigen antibody probes. Aldehyde-functionalized ionic liquid was used not only as a substrate for antibody immobilization, but also as a good material with high electrical conductivity, which greatly simplified the process of sensor fabrication. The proposed sensor exhibited a good performance in a linear range from 0.05 to 15ngmL-1 with a detection limit of 20pgmL-1 (S/N=3) and provided a novel strategy for clinical detection due to satisfying stability, selectivity and reproducibility. PMID- 28842000 TI - A novel colorimetric biosensor based on non-aggregated Au@Ag core-shell nanoparticles for methamphetamine and cocaine detection. AB - We report a novel colorimetric biosensor based on non-aggregation Au@Ag core shell nanoparticles to detect methamphetamine and cocaine. The biosensor consisted of a reporter probe (RP) that is a specific single-stranded DNA (ssDNA) sequence coated on Au@Ag nanoparticles, a capture probe (CP) conjugated with magnetic beads, and an illicit drug-binding DNA aptamer (Apt). Au@Ag nanoparticles were synthesized by seed growth and characterized by scanning electron microscope (SEM), high-resolution transmission electron microscopy (HR TEM), and UV-vis spectra. Methamphetamine (METH) was used as an example to evaluate the feasibility of the biosensor and to optimize the detection conditions. We demonstrated that this sensing platform was able to detect as low as 0.1nM (14.9ngL-1) METH with a negligible interference from other common illicit drugs. Various concentrations of METH were spiked into urines, and the biosensor yielded recoveries more than 83.1%. In addition, the biosensor also showed a high sensitivity to detect cocaine. These results demonstrated that our colorimetric sensor holds promise to be implemented as a visual sensing platform to detect multiple illicit drugs in biological samples and environmental matrices. PMID- 28842002 TI - Ultrasonic assisted dispersive liquid-liquid microextraction method based on deep eutectic solvent for speciation, preconcentration and determination of selenium species (IV) and (VI) in water and food samples. AB - A novel ultrasound-assisted liquid phase microextraction (UALPME) based on environmental friendly extractants, deep eutectic solvent (DES) was first time presented for speciation of selenium. In present study, five DES solvents of different composition was prepared and used as efficient extractive medium for hydrophobic chelate of Se(IV) with 3,3'-Diaminobenzidine (DAB). The total inorganic Se species were determined after pre-reduction of Se(VI) to Se(IV), prior to applying developed method. The concentration of Se(VI) was calculated by the difference of Se(IV) values and total selenium contents. The concentration of Se in DES rich phase was measured with electrothermal atomic absorption spectrometer (ETAAS). The effects of different parameters on extraction efficiency of study analyte, including pH, ligand concentration, type and volume of DES, sonication time, volumes tetrahydrofuran and aqueous samples were examined. At the optimum conditions, limit of detection and quantification, preconcentration factor, and relative standard deviation (RSD %) were determined as 4.61ngL-1, 15.4ngL-1, 50% and 4.1%, respectively. The accuracy of the presented method was confirmed by analysis of certified reference material and standard addition method for different water and ice tea samples. The developed method was effectively applied to real water and food samples. PMID- 28842003 TI - Cyclohexylamine as extraction solvent and chelating agent in extraction and preconcentration of some heavy metals in aqueous samples based on heat-induced homogeneous liquid-liquid extraction. AB - A new sample preparation method has been developed for extraction and preconcentration of some heavy metal cations in aqueous samples using cyclohexylamine-based homogeneous liquid-liquid microextraction. In the proposed method, cyclohexylamine was used as both the complexing agent and the extraction solvent. For this purpose, cyclohexylamine at uL level was initially added into an aqueous solution containing Co(II), Ni(II), and Cu(II) ions which was placed in a glass test tube. The mixture was shaken for forming a homogeneous solution. Then sodium chloride was added to the solution. After shaking manually again, the test tube was placed in a water bath thermostated at 70 degrees C. Due to lower solubility of cyclohexylamine at the elevated temperature, a cloudy solution was formed. The fine droplets of cyclohexylamine containing cation-cyclohexylamine complexes were collected on the top of the aqueous phase by centrifuging. The enriched analytes in the upper phase were determined by graphite furnace atomic absorption spectrometry. Several variables possibly affecting the extraction efficiency were investigated and optimized. Under the optimum conditions the calibration curves were linear in the ranges of 80-1000, 40-700, and 80-800ngL-1 for Co2+, Ni2+, and Cu2+, respectively. Repeatability of the proposed method, expressed as relative standard deviation, ranged from 3.3% to 5.2% (n = 6, C = 200ngL-1). Moreover, the obtained detection limits of the selected analytes were in the range of 15.3-37.7ngL-1. The accuracy of the developed procedure was verified by analyzing a certified reference material, namely NRCC-SLRS4 Riverine water. Finally, the proposed method was successfully applied for the simultaneous analysis of the selected analytes in environmental water samples. PMID- 28842004 TI - Application of silver nanoparticles and CdSe quantum dots sensitized with of C like lectin for detection of St. aureus. Comparison of various approaches. AB - C-type lectin from hen egg shell as a recognition ligand for detection of St. aureus was applied. Three approaches for detection of bacteria were used and the sensitivities of the assays were compared. Two of them included spherical and anisotropic silver nanoparticles sensitized by lectin. In these cases the optical changes as a result of interaction of sensitized nanoparticles with bacteria were measured. In the third approach hybrid system of CdSe quantum dots-anisotropic silver nanoparticles sensitized by lectin was applied. Here fluorescent changes as a result of resonance energy transfer between nanoparticles as consequence of their interaction with bacteria were measured. The data demonstrate that assays with spherical silver nanoparticles permit to detect St. aureus in the range of 6 * 104/mL-2 * 107/mL, anisotropic silver nanoparticles in the range of 2 * 105/mL 1 * 108/mL, CdSe-Ag hybrid system in the range of 6 * 103/mL-2 * 107/mL. The data demonstrate that hybrid system CdSe-Ag with resonance energy transfer provides the best sensitivity. PMID- 28842005 TI - New procedure of quantitative mapping of Ti and Al released from dental implant and Mg, Ca, Fe, Zn, Cu, Mn as physiological elements in oral mucosa by LA-ICP-MS. AB - A new procedure for determination of elements derived from titanium implants and physiological elements in soft tissues by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is presented. The analytical procedure was developed which involved preparation of in-house matrix matched solid standards with analyte addition based on certified reference material (CRM) MODAS-4 Cormorant Tissue. Addition of gelatin, serving as a binding agent, essentially improved physical properties of standards. Performance of the analytical method was assayed and validated by calculating parameters like precision, detection limits, trueness and recovery of analyte addition using additional CRM - ERM BB184 Bovine Muscle. Analyte addition was additionally confirmed by microwave digestion of solid standards and analysis by solution nebulization ICP-MS. The detection limits are in range 1.8MUgg-1 to 450MUgg-1 for Mn and Ca respectively. The precision values range from 7.3% to 42% for Al and Zn respectively. The estimated recoveries of analyte addition line within scope of 83%-153% for Mn and Cu respectively. Oral mucosa samples taken from patients treated with titanium dental implants were examined using developed analytical method. Standards and tissue samples were cryocut into 30um thin sections. LA-ICP-MS allowed to obtain two-dimensional maps of distribution of elements in tested samples which revealed high content of Ti and Al derived from implants. Photographs from optical microscope displayed numerous particles with um size in oral mucosa samples which suggests that they are residues from implantation procedure. PMID- 28842006 TI - Microcystin-LR label-free immunosensor based on exfoliated graphite nanoplatelets and silver nanoparticles. AB - This paper describes a simple, rapid and accurate label-free immunosensor for the determination of MC-LR in water samples. The anti-MC-LR was immobilized in a hybrid nanocomposite, comprised of exfoliated graphite nanoplatelets dispersed in a suspension of silver nanoparticles (AgNP-Nafion-xGnP), by adsorption. The nanomaterial obtained was then employed to prepare an immunosensor using a glassy carbon electrode (GCE) in one-step. Under optimized conditions, using square-wave voltammetry (SWV) and an incubation time of 10min, the immunosensor showed a linear relationship between the oxidation current and MC-LR concentration in the range of 0.5-5000ngmL-1 with a detection limit of 0.017ngmL-1. The immunosensor demonstrated good precision, with coefficients of variation of 4.5% (inter-day; n = 7) and 3.1% (intra-day; n = 5), and acceptable selectivity (low interference in the presence of potential interferents), indicating that it is suitable for analytical applications. The immunosensor was successfully applied in the determination of MC-LR in a water sample and this platform offers advantages when compared to other electrochemical sensors reported in the literature, especially with regard to the time of incubation. PMID- 28842007 TI - Highly sensitive amperometric biosensor for determination of NADH and ethanol based on Au-Ag nanoparticles/poly(L-Cysteine)/reduced graphene oxide nanocomposite. AB - This work presents the fabrication of a novel nicotinamide adenine dinucleotide (NADH) sensor using gold-silver bimetallic nanoparticles (Au-AgNPs), poly(L Cysteine) (P(L-Cys)) and electrochemically reduced graphene oxide (ERGO) modified glassy carbon electrode (GCE/Au-AgNPs/P(L-Cys)-ERGO). The composite electrode exhibited an excellent electrocatalytic response towards NADH at a low oxidation potential (+ 0.35V) and minimization of surface contamination due to the synergistic effects of the Au-AgNPs, polymer and ERGO. Under optimum conditions, modified sensors allowed the detection of NADH with a wide linear range from 0.083uM to 1.05mM with a low detection limit of 9.0nM (S/N = 3). Moreover, this modified electrode was also used as a sensitive ethanol biosensor, which was prepared with alcohol dehydrogenase (ADH) via glutaraldehyde, bovin serum albumin and nafion (Naf). There was a linear response for ethanol in the concentration range from 0.017 to 1.845mM with a low detection limit of 5.0uM (S/N = 3). The GCE/Au-AgNPs/P(L-Cys)-ERGO/ADH/Naf electrode can be successfully used for the determination of ethanol in different commercial beverages. PMID- 28842008 TI - The application of visible absorption spectroscopy to the analysis of uranium in aqueous solutions. AB - Through assay analysis into an excess of 1M H2SO4 at fixed temperature a technique has been developed for uranium concentration analysis by visible absorption spectroscopy over an assay concentration range of 1.8-13.4mgU/g. Once implemented for a particular spectrophotometer and set of spectroscopic cells this technique promises to provide more rapid results than a classical method such as Davies-Gray (DG) titration analysis. While not as accurate and precise as the DG method, a comparative analysis study reveals that the spectroscopic method can analyze for uranium in well characterized uranyl(VI) solution samples to within 0.3% of the DG results. For unknown uranium solutions in which sample purity is less well defined agreement between the developed spectroscopic method and DG analysis is within 0.5%. The technique can also be used to detect the presence of impurities that impact the colorimetric analysis, as confirmed through the analysis of ruthenium contamination. Finally, extending the technique to other assay solution, 1M HNO3, HCl and Na2CO3, has also been shown to be viable. Of the four aqueous media the carbonate solution yields the largest molar absorptivity value at the most intensely absorbing band, with the least impact of temperature. PMID- 28842009 TI - Sample preparation for arsenic speciation analysis in baby food by generation of substituted arsines with atomic absorption spectrometry detection. AB - A slurry sampling procedure for arsenic speciation analysis in baby food by arsane generation, cryogenic trapping and detection with atomic absorption spectrometry is presented. Several procedures were tested for slurry preparation, including different reagents (HNO3, HCl and tetramethylammonium hydroxide - TMAH) and their concentrations, water bath heating and ultrasound-assisted agitation. The best results for inorganic arsenic (iAs) and dimethylarsinate (DMA) were reached when using 3molL-1 HCl under heating and ultrasound-assisted agitation. The developed method was applied for the analysis of five porridge powder and six baby meal samples. The trueness of the method was checked with a certified reference material (CRM) of total arsenic (tAs), iAs and DMA in rice (ERM-BC211). Arsenic recoveries (mass balance) for all samples and CRM were performed by the determination of the tAs by inductively coupled plasma mass spectrometry (ICP-MS) after microwave-assisted digestion and its comparison against the sum of the results from the speciation analysis. The relative limits of detection were 0.44, 0.24 and 0.16ugkg-1 for iAs, methylarsonate and DMA, respectively. The concentrations of the most toxic arsenic species (iAs) in the analyzed baby food samples ranged between 4.2 and 99ugkg-1 which were below the limits of 300, 200 and 100ugkg-1 set by the Brazilian, Chinese and European legislation, respectively. PMID- 28842010 TI - A novel high throughput screening assay for binding affinities of perfluoroalkyl iodide for estrogen receptor alpha and beta isoforms. AB - Contaminants of emerging concern are continuously increasing, which makes it important to develop high throughput screening techniques for the evaluation of their potential biological effects, especially endocrine disrupting effects, which would directly influence the population dynamics in environment. A novel competitive binding assay based on enzyme fragmentation complementation technology was established to screen the binding affinities of emerging chemicals for estrogen receptor (ER) alpha or beta isoforms. Exogenous compounds could compete with the fragment (ED-ES) of genetically engineered beta-galactosidase enzyme (beta-gal) for the binding to ERalpha or beta, thus quantitatively altering the formation of enzymatically active beta-gal and the hydrolysis of luminescent substrate. According to the monitoring of luminescence curves and the optimization of ERalpha or beta concentrations, it was found that luminescent signals were sustainably emitted for 9h, and 40nM ERalpha or beta in the system would lead to the most sensitive luminescence response. Using 17beta-estrodiol (E2) and genistein as the representative estrogenic hormones, their binding affinities for ERalpha and beta were evaluated. The results were consistent with those determined by traditional methods, which confirmed the reliability of this competitive binding assay based on beta-gal. Four polyfluorinated iodine alkanes (PFIs) with specific structural characteristics in iodine substitution and carbon chain length were screened, and the results showed diverse binding affinities and different preferences of these chemicals to ERalpha or beta isoforms. The binding affinities of PFIs for ERalpha were consistent with the result from MVLN transcriptional reporter assay. Overall, the competitive binding assay presented in this study provided a promising alternative to high throughput screening of emerging chemicals with estrogenic effects, which would be important in explanation of their potential toxicological effects and human exposure risks. PMID- 28842011 TI - In vivo imaging of alkaline phosphatase in tumor-bearing mouse model by a promising near-infrared fluorescent probe. AB - Alkaline phosphatase (ALP), one of the important hydrolases, is associated with the progress of many diseases as a well-defined biomarker. Fluorescence imaging of ALP in living organisms is of great importance for biological studies. However, in vivo detection of ALP remains a great challenge because current fluorescent probes show short excitation and emission wavelength, which are not desired for in vivo fluorescence imaging. Herein we reported a near-infrared (NIR) fluorescent probe (NALP) for turn-on trapping of ALP activity in living cancer cells and tumors. NALP was composed of a NIR-emitting fluorophore as a reporter and phosphate as a triggered moiety. Phosphate group was directly tethered to the hydroxyl group of fluorophore, which prohibited the fluorescence. The probe exhibited a high selectivity and remarkable fluorescence turn-on response to ALP in aqueous solutions with a detection limit of 0.28U/L. Benefiting from NIR excitation and emission, high contrast on the imaging signal could be achieved in response to endogenous ALP activity. Impressively, not only we successfully used NALP for imaging of endogenous ALP activity in cancer cells, but also, applied it for fluorescence imaging of ALP in tumor tissues and living tumor xenograft in nude mice for the first time. The probe was expected to be promising tool for practical application in disease diagnosis on the roles of ALP in disease. PMID- 28842012 TI - Preparation of a TiO2-NH2 modified MALDI plate for on-plate simultaneous enrichment of phosphopeptides and glycopeptides. AB - In this work, a TiO2 film was prepared on a MALDI plate by atomic layer deposition (ALD) technique and then modified with -NH2. The obtained TiO2-NH2 modified plate was applied for on-plate simultaneous enrichment of phosphopeptides and glycopeptides. The ALD TiO2 film displayed quite uniform morphology, and attached firmly to the MALDI plate with rather stable physical and chemical properties, which resulted in fine stability of the plate in performance. The -NH2 groups offered the film better hydrophilicity and affinity toward glycopeptides. The on-plate simultaneous enrichment performance of the TiO2-NH2 modified plate was investigated by beta-casein digests, HRP digests and human serum. PMID- 28842013 TI - New methodologies in screening of antibiotic residues in animal-derived foods: Biosensors. AB - Antibiotics are leading medicine asset for fighting against microbial infection, but also one of the important causes of death worldwide. Many antibiotics used as therapeutics and growth promotion agents in animals can lead to antibiotic residues in animal-derived food which harm the health of people. Hence, it is vital to screen antibiotic residues in animal derived foods. Typical methods for screening antibiotic residues are based on microbiological growth inhibition and immunological analyses. However these two methods have some disadvantages, such as poor sensitive, lack of specificity and etc. Therefore, it is necessary to develop simple, more efficient and high sensitive screening methods of antibiotic residues. These assays have been introduced for the screening of numerous food samples. Biosensors are emerging methods, applied in screening antibiotic residues in animal-derived foods. Two types of biosensors, whole-cell based biosensors and surface plasmon resonance-based sensors have been extensively used. Their advantages include portability, small sample requirement, high sensitivity and good specificity over the traditional screening methods. PMID- 28842014 TI - White light reflectance spectroscopy biosensing system for fast quantitative prostate specific antigen determination in forensic samples. AB - A label-free biosensor based on white light reflectance spectroscopy for the determination of PSA as semen indicator in forensic samples is presented. The sensor is based on a two-step immunoassay which employs the same polyclonal anti PSA antibody as capture and detection antibody followed by reaction with streptavidin as a signal enhancement step. The whole assay time was set to 10min; 5min reaction of immobilized antibody with the PSA calibrators or the samples, 3min reaction with the biotinylated anti-PSA antibody and 2min reaction with streptavidin. Following this protocol, a detection limit of 0.5ng/mL was achieved and the assay's linear response range extended up to 500ng/mL. Thus, taking into account the quantification limit of 1.0ng/mL and the average PSA concentration in semen (0.2-5.5mg/mL), semen quantities of a few nanoliters could be detected. The accuracy of the sensor developed was demonstrated through recovery (% recovery ranged from 89.6 to 106) and semen dilution experiments. A linear correlation was found for semen dilutions ranging from 5000 to 360,000. The lack of interference by other bodily fluids was confirmed by analysing stains of blood, urine and saliva prior to and after the addition of semen. Finally, the sensor was evaluated by analysing 51 forensic casework samples which were also analysed with a semi-quantitative membrane strip test (Seratec(r) PSA), through microscopic detection of spermatozoa, and male DNA identification through detection of Y chromosome. The results obtained with the sensor were in excellent agreement with those provided by an immunoradiometric assay kit (PSA-RIACT) and in complete agreement with the findings using the membrane strip assay, spermatozoa and Y chromosome detection. The excellent analytical performance and small size of the instrument make the sensor developed an attractive tool for use in forensic evidence screening for semen detection. PMID- 28842015 TI - New chiral ligand exchange capillary electrophoresis system with chiral amino amide ionic liquids as ligands. AB - Using chiral amino amide ionic liquids as the ligands, a new chiral ligand exchange capillary electrophoresis method with Cu(II) as the central ion was constructed for enantioseparation of labeled D,L-amino acids. The effects of key parameters, including pH value of the running buffer, the ratio of Cu(II) to chiral amino amide ionic liquids, the concentration of complexes based on Cu(II) chiral amino amide ionic liquids were investigated. It has been observed that eight pairs of labeled D,L-amino acids could be baseline-separated with a running buffer of 15.0mM ammonium acetate, 10.0mM Cu(II) and 20.0mML-phenylalaninamide based ionic liquid at pH 5.0. The quantitation of D,L-amino acids was conducted and good linearity (r2 >= 0.964) was obtained. Furthermore, an assay for determining the enantiomeric purity of D,L-amino acids was developed and the possible enantiorecognition mechanism was discussed briefly. The results indicated that the chiral amino amide ionic liquids could play the role of ligands in chiral ligand exchange capillary electrophoresis system and exhibit great potential in chiral analysis. PMID- 28842016 TI - A simple and novel colorimetric assay for tyrosinase and inhibitor screening using 3,3',5,5'-tetramethylbenzidine as a chromogenic probe. AB - A novel colorimetric method for the detection of tyrosinase (TYR) and its inhibitor by taking utilization of Ag+-3,3',5,5'-tetramethylbenzidine (TMB) detection system has been proposed. Ag+ could oxidize TMB to oxidized TMB (oxTMB) and induce a blue color solution corresponding to an absorption peak centered at 652nm. The addition of dopamine (DA) could cause the reduction of oxTMB which resulted in the fading of the blue color and a decrease of the absorbance at 652nm. However, in the presence of TYR, DA could be oxidized to dopaquinone, which inhibited the reduction of oxTMB by DA, resulting in a blue color recovery and an increase of the absorbance at 652nm. Based on this finding, we propose a method to quantitatively detect TYR activity with the help of UV-vis spectroscopy. The developed assay is highly sensitive with a low detection limit of 0.010U/mL. More importantly, this method is fairly simple and inexpensive without the use of complicated nanomaterials. In addition, it constructs a useful platform for TYR inhibitor screening. PMID- 28842017 TI - Speciation of platinum by GFAAS using various possibilities of analytical signal enhancement. AB - A novel method for determination of platinum species by application of graphite furnace atomic absorption spectrometry (GFAAS) was developed. The principle of determination is the formation of platinum ion associates (IA) with SCN- and polymethine basic agent 1,3,3-trimethyl-2-[3-(1,3,3-trimethyl-1,3-dihydroindol-2 yliden)-propyl-1,3-dienyl]-3H-indolium chloride (TTDI), which can then be extracted by various organic solvents. Different options for analytical signal intensification (ultrasonic and microwave energy) were examined. The conditions found for ion associate formation and extraction have enabled the proposing of a new Pt(II) and Pt(IV) speciation process. These species can be reliably determined simultaneously at concentration ratios from 1:5 to 5:1. Moreover, the ion associates of platinum with TTDI can be extracted with toluene up to a volume ratio of aqueous and organic phases of Vaq:Vorg = 50:1. This fact for Pt determination using GFAAS means decreasing the limit of detection (LOD) from 7.1ugL-1 to 0.3ugL-1. The method was applied for Pt determination in a model and in spiked water samples. PMID- 28842018 TI - 3D printed device including disk-based solid-phase extraction for the automated speciation of iron using the multisyringe flow injection analysis technique. AB - The development of advanced manufacturing techniques is crucial for the design of novel analytical tools with unprecedented features. Advanced manufacturing, also known as 3D printing, has been explored for the first time to fabricate modular devices with integrated features for disk-based automated solid-phase extraction (SPE). A modular device integrating analyte oxidation, disk-based SPE and analyte complexation has been fabricated using stereolithographic 3D printing. The 3D printed device is directly connected to flow-based analytical instrumentation, replacing typical flow networks based on discrete elements. As proof of concept, the 3D printed device was implemented in a multisyringe flow injection analysis (MSFIA) system, and applied to the fully automated speciation, SPE and spectrophotometric quantification of Fe in water samples. The obtained limit of detection for total Fe determination was 7ng, with a dynamic linear range from 22ng to 2400ng Fe (3mL sample). An intra-day RSD of 4% (n = 12) and an inter-day RSD of 4.3% (n = 5, 3mL sample, different day with a different disk), were obtained. Incorporation of integrated 3D printed devices with automated flow based techniques showed improved sensitivity (85% increase on the measured peak height for the determination of total Fe) in comparison with analogous flow manifolds built from conventional tubing and connectors. Our work represents a step forward towards the improved reproducibility in the fabrication of manifolds for flow-based automated methods of analysis, which is especially relevant in the implementation of interlaboratory analysis. PMID- 28842019 TI - A label-free sensitive method for membrane protein detection based on aptamer and AgNCs transfer. AB - Recently, membrane proteins have been considered as candidate cancer biomarkers and drug targets, due to their important roles in numerous physiological processes. Therefore, a facile, sensitive and quantitative detection of the membrane proteins is crucial for better understanding their roles in cancer cells and further validating their function in clinical research. We report a highly facile and sensitive detection method for membrane proteins on living cells in situ based on membrane protein-triggered release of cytosine (C)-rich single stranded DNA (ssDNA) sequences, and the subsequent silver nanoclusters (AgNCs) transfer from polymer to C-rich ssDNA. The high-quantum yield and stable DNA AgNCs allow the accurate detection of membrane proteins with facile operations and a common fluorescence spectrophotometer. The detection of protein tyrosine kinase-7 (PTK7), a membrane protein model, displays a response range from 30pM to 2nM with a detection limit of 12pM. The expression of PTK7 on single Hela cell and CCRF-CEM cell was calculated to be 7.5 * 10-19mol and 1.8 * 10-18mol, respectively. Given the simple and facile operation of this method, this detection platform can be applied as a universal strategy for ultrasensitive detection of membrane protein on cell in situ. PMID- 28842020 TI - One-step synthesis of carboxyl-functionalized metal-organic framework with binary ligands for highly selective enrichment of N-linked glycopeptides. AB - Highly efficient and selective enrichment of glycopeptides from complex biosamples is vital prior to mass spectrometry analysis. In this work, a hydrophilic metal organic framework with free carboxylic groups (denoted as UiO 66-COOH) was synthesized in one step with binary ligands. Compared with pure UiO 66 with one ligand, UiO-66-COOH containing binary ligands demonstrated greater hydrophilicity and performed much better in selective enrichment of glycopeptides. The as-prepared material demonstrated excellent performance for selective enrichment of glycopeptides from tryptic digests of standard glycoproteins and practical biological samples. PMID- 28842021 TI - Stacking chip for quantitative bioanalysis. AB - This paper describes a microwell-based microdevice for performing quantitative bioanalysis. This microdevice combined the passive pumping by degassed polydimethylsiloxane (PDMS) with serial operations including solution dispensing, plates splitting and plates stacking. We name this microdevice "stacking chip". To use the stacking chip in quantitative bioanalysis, nanoliter solutions were first dispensed into the microwells through the degassed PDMS microchannels. Next, we split the microwell and microchannel plates assisted by the application of one drop of silicone oil, which resulted in a microwell array containing the reagent solutions. Microreactor arrays were formed by stacking the two microwell arrays containing the reagent solutions. With this microdevice, the enzymatic kinetics of alkaline phosphatase during the dissociation of the fluorescein diphosphate was measured and analyzed by the Michaelis-Menten model. The stacking chip is simple to fabricate and operate, and amenable to automation for high throughput analysis. PMID- 28842022 TI - A strategy of improving the imprinting effect of molecularly imprinted polymer: Effect of heterogeneous macromolecule crowding. AB - The topic in the present work is to prepare molecularly imprinted polymer (MIP) in heterogeneous crowding surrounding for improving imprinting effect. For the first time, heterogeneous crowding surrounding was made up of a tetrahydrofuran (THF) solution of low molecular weight polyethene glycol (PEG) and high molecular weight polystyrene (PS). The MIP prepared in heterogeneous crowding surrounding against procyanidin B2 can display apparent imprinting effect (imprinting factor of 5.13) in the situation of difficult imprinting at single crowding surrounding or non-crowding surrounding. The necessity of simultaneous use of low and high molecular weight crowding agents for enhanced imprinting effect was further proved. NMR peak shifts of active hydrogen of procyanidin B2 strongly suggested that the interaction between functional monomer and template can be enhanced due to the effect of heterogeneous crowding in the self-assembly process. The influence of molecular weight and amount of PEG, molecular weight of PS, as well as the ratio of procyanidin B2 to functional monomer on the imprinting factor was investigated. The MIP was then used to extract purify procyanidin B2 from extract of grape seed. The recovery of procyanidin B2 obtained was 87% with relative standard deviation of less than 5%. PMID- 28842023 TI - Portable kit for high-throughput analysis of polycyclic aromatic hydrocarbons using surface enhanced Raman scattering after dispersive liquid-liquid microextraction. AB - In this work, a portable kit was developed for convenient high-throughput trace analysis of polycyclic aromatic hydrocarbons (PAHs) using surface enhanced Raman scattering (SERS) after dispersive liquid-liquid microextraction (DLLME) process. This portable kit contains three sealed reagent tubes (labeled as T1, T2 and T3), a self-made well plate, and a portable Raman spectrometer. The reagent tube T1 contains a mixture of disperser solvent and extraction solvent, which involved a 2min sample pretreatment of DLLME process. The quick injection of solvents in tube T1 into the sample containing PAHs formed a cloudy solution immediately, which consists of fine droplets of extraction solvent dispersed entirely into aqueous phase. The enrichment factor was found to be 29.6. T2 and T3 contain methanol and 1-propanethiol-modified silver nanoparticles (PTH-Ag NPs), respectively. The liquid in the tube T3 was used to enhance the Raman signal of analytes on the self-made high-throughput micro reactor. A linear relationship between the concentration of pyrene and the relative Raman peak intensity was obtained (R2 = 0.993). The detection limit was 0.50MUgL-1 for pyrene. RSD of the high-throughput analysis of 12 samples was calculated as 4.8%. The ability of DLLME-SERS technique in the extraction of PAH isomers from water samples were investigated. The performance of DLLME-SERS in the recovery of pyrene from lake, spring and drinking water was also studied. PMID- 28842024 TI - Selenocystine modified screen-printed electrode as an alternative sensor for the voltammetric determination of metal ions. AB - A novel selenium based screen-printed electrode was developed based on the immobilization of selenocystine on aryl diazonium salt monolayers anchored to a carbon-nanofiber screen-printed electrode support (SeCyst-SPCNFE). SeCyst-SPCNFE was analytically compared to a screen-printed carbon nanofiber electrode modified with L-Cystine (Cyst-SPCNFE) for the determination of Pb(II) and Cd(II) by stripping voltammetric techniques. Their analytical performance suggests that SeCyst-SPCNFE could be a much better alternative for metal ion determination at trace levels than Cyst-SPCNFE. The proposed electrode was successfully applied for the simultaneous voltammetric determination of trace Pb(II) and Cd(II) in a wastewater reference material with a very high reproducibility (3.2%) and good trueness (2.6%). PMID- 28842025 TI - An integrated automatic system to evaluate U and Th dynamic lixiviation from solid matrices, and to extract/pre-concentrate leached analytes previous ICP-MS detection. AB - Leached fractions of U and Th from different environmental solid matrices were evaluated by an automatic system enabling the on-line lixiviation and extraction/pre-concentration of these two elements previous ICP-MS detection. UTEVA resin was used as selective extraction material. Ten leached fraction, using artificial rainwater (pH 5.4) as leaching agent, and a residual fraction were analyzed for each sample, allowing the study of behavior of U and Th in dynamic lixiviation conditions. Multivariate techniques have been employed for the efficient optimization of the independent variables that affect the lixiviation process. The system reached LODs of 0.1 and 0.7ngkg-1 of U and Th, respectively. The method was satisfactorily validated for three solid matrices, by the analysis of a soil reference material (IAEA-375), a certified sediment reference material (BCR- 320R) and a phosphogypsum reference material (MatControl CSN-CIEMAT 2008). Besides, environmental samples were analyzed, showing a similar behavior, i.e. the content of radionuclides decreases with the successive extractions. In all cases, the accumulative leached fraction of U and Th for different solid matrices studied (soil, sediment and phosphogypsum) were extremely low, up to 0.05% and 0.005% of U and Th, respectively. However, a great variability was observed in terms of mass concentration released, e.g. between 44 and 13,967ngUkg-1. PMID- 28842026 TI - Blue-emitting copper nanoparticles as a fluorescent probe for detection of cyanide ions. AB - A simple and green method for the determination of cyanide ions (CN-) has been developed which is based on copper nanoparticles (CuNPs) acting as a fluorescent probe in aqueous solutions. In this study, fluorescent CuNPs have been synthesized in the presence of ascorbic acid which acts both as a reducing and protecting agent. The preparation of CuNPs by this method is very simple, low cost, high yield, and reproducible. The prepared CuNPs have the small average diameter of 10nm and show a blue emission at 440nm. However, upon the addition of CN- into the CuNPs sensing system, its fluorescence was quenched considerably as a result of the strong interaction between cyanide and copper. Under optimized conditions, a good relationship was observed between the fluorescence quenching of the system and the concentration of CN- in the range of 0.5-18umolL-1 with a detection limit of 0.37umolL-1. In addition, the developed sensor has a high selectivity and simple operations. Furthermore, as a cost-effective and selective fluorescent probe, the CuNPs sensor was successfully employed for the detection of CN- ions in water samples. PMID- 28842027 TI - Long-term sub second-response monitoring of gaseous ammonia in ambient air by positive inhaling ion mobility spectrometry. AB - A real-time dynamic measurements of ammonia (NH3) is crucial for understanding the atmospheric nucleation process. A novel method was developed for on line monitoring at the sub-second time scale for the gaseous ammonia in ambient air for months, based on a positive inhaling ion mobility spectrometry (IMS) with a 63Ni ion source. The selective detection of NH3 was achieved using a high resolution IMS with an optimization of the drift tube temperature above 150 degrees C. This method improved the peak-to-peak resolution significantly, thus avoided the interferences of the adjacent peaks to the quantitative analysis of NH3. The time resolution of the IMS was less than 0.1s at a data averaging of 10 times. The limit of detection (LOD) achieved at sub-ppb level while a linear response of peak intensity versus concentration of NH3 in the range of 10-60ppb and 60-400ppb were obtained. The relative standard deviations (RSD), the confidence level and the errors were 1.06%, 95% and +/- 0.21ppb by measuring 100ppb NH3 for 100 times. The effect of ambient humidity could be greatly reduced by using the drift temperature of over 150 degrees C. At last, the application of measuring the NH3 concentration evolutions of Dalian city was performed from June 19 to December 3 in 2015. The results illustrated a potential method of using IMS for a real-time measuring atmospheric NH3 at an unprecedented accuracy and sensitivity with long-term stability. PMID- 28842028 TI - A method based on near-infrared spectroscopy for the in-situ determination of the ammonia concentration in ammonia/water mixtures in an absorber test bench. AB - This paper discusses the development and implementation of a method based on NIR spectroscopy for the in-situ determination of the ammonia mass fraction of ammonia/water mixtures in an absorber test bench. The calibration model was established using a static measuring system. A cell was designed and constructed to prepare and measure samples at the ammonia mass fractions (0.332-0.482), pressures (3.4-4.6), bar and temperatures (25.0-35.5) degrees C typical in absorption refrigeration systems. A quadratic model for absorbance at 1041nm was established and validated. The root-mean-square deviation (RMSD) of the results was 2.1%. To implement NIR spectroscopy in the absorber test bench, a new flow cell was designed. The calibration model was transferred and used in the conditions of the absorber test bench. In these experimental conditions, the model was statistically validated using density measurements as a reference method for measuring the ammonia mass fraction. The root-mean-square deviation between the ammonia mass fractions obtained using the two methods was 1.1%. PMID- 28842029 TI - Multi-element determination of metals and metalloids in waters and wastewaters, at trace concentration level, using electroanalytical stripping methods with environmentally friendly mercury free-electrodes: A review. AB - Nowadays, water is no longer regarded as an inexhaustible resource and the excessive release and proliferation of toxic metal(loid)s into aquatic environments has become a critical issue. Therefore, fast, accurate, simple, selective, sensitive and portable methodologies to detect multiple elements in natural waters is of paramount importance. Electrochemical stripping analysis is an efficient tool for trace metal(loid)s determinations and bring new prospects for answering the current environmental concerns. This review presents a survey of the advancements made between 2003 and 2016 on the development and application of non-toxic mercury free electrodes on the simultaneous analysis of metals and metalloids in waters and wastewaters by means of electroanalytical stripping techniques. The advantages, limitations, improvements and real applications of these "green" sensors are discussed from a critical point of view. PMID- 28842030 TI - Development of a nanostructured immunosensor for early and in situ detection of Xanthomonas arboricola in agricultural food production. AB - We report a microfluidic electrochemical immunosensor for Xanthomonas arboricola (XA) determination, based on the covalently immobilization of monoclonal anti-XA antibody (anti-XA) on a previously amino functionalized SBA-15 in situ synthesized in the central channel of a glass-poly(dimethylsiloxane) microfluidic immunosensor. The synthetized amino-SBA-15 was characterized by N2 adsorption desorption isotherm, scanning electron microscopy and infrared spectroscopy. XA was detected by a direct sandwich immunoassay through an alkaline phosphatase (AP) enzyme-labeled anti-XA conjugate. Later, the substrate p-aminophenyl phosphate was converted to p-aminophenol by AP. The enzymatic product was detected at +100mV on a sputtered gold electrode. The measured current was directly proportional to the level of XA in walnut trees samples. The linear range was from 5 * 102 to 1 * 104CFUmL-1. The detection limit was 1.5 * 102CFUmL 1, and the within- and between-assay coefficients of variation were below 5%. Microfluidic immunosensor is a very promising tool for the early and in situ diagnosis of XA in walnuts avoiding serious economic losses. PMID- 28842031 TI - Coupling sweeping-micellar electrokinetic chromatography with tandem mass spectrometry for the therapeutic monitoring of benzimidazoles in animal urine by dilute and shoot. AB - A new method based on micellar electrokinetic chromatography-tandem mass spectrometry (MEKC-MS/MS) has been developed for the identification and simultaneous quantification of thirteen benzimidazoles in animal urine. In order to obtain an appropriate separation with the highest sensitivity, different electrophoretic parameters were evaluated. Under optimum conditions, the separation was performed using ammonium perfluorooctanoate as volatile surfactant and electrophoretic buffer (50mM, pH 9). To increase the sensitivity, a stacking mode named sweeping was applied, using water as injection solvent at 50mbar for 75s, obtaining sensitivity enhancement factors from 50 to 181. The method was applied to different animal urine samples, including sheep, cow and goat. The sample treatment consisted of a 1:10 (v/v) dilution with water. Calibration using sheep urine samples can be used for both goat and cow urine samples with a relative bias below 25% and relative standard deviations lower than 8%. The limits of detection were below 70ugL-1. As a result, the applicability of this rapid, simple, sensitive, and environmentally friendly method for therapeutic drug monitoring of benzimidazoles based on the analysis of animal urine has been demonstrated. PMID- 28842032 TI - Rapid in vivo determination of fluoroquinolones in cultured puffer fish (Takifugu obscurus) muscle by solid-phase microextraction coupled with liquid chromatography-tandem mass spectrometry. AB - Fluoroquinolones (FQs) are a group of antimicrobial agents that have been widely used for therapeutic purposes in clinical medicine for human and veterinary diseases, as well as in aquaculture production. Their residues, however, may survive in foods of animal origin, thus causing health risks for human. In this study, a rapid and sensitive method based on in vivo solid-phase microextraction (SPME) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to detect the residues of five FQs in cultured puffer fish (Takifugu obscurus). In vitro fiber evaluation experiment demonstrated that, compared with the thicker polydimethylsiloxane (PDMS) coating (165um), the custom-made biocompatible C18-PAN fibers (45um) exhibited much higher extraction efficiencies towards FQs (approximately 9-31 times). The custom-made C18-PAN coating also possessed excellent reproducibility in fish muscle with the intra-fiber relative standard deviations (RSDs) ranging from 11.2% to 14.3% (n = 6) and inter-fiber RSDs ranging from 13.1% to 16.1% (n = 6), which was suitable for in vivo sampling. The custom-made SPME fibers were subsequently applied to determine fluoroquinolones in dorsal-epaxial muscle of living puffer fish. The accuracies were verified through the comparison with traditional liquid extraction (LE) method, and the sensitivities were demonstrated to be satisfying with the limits of detection (LODs) ranging from 0.3ngg-1 to 1.5ngg-1. In general, this study presented a convenient and high-efficient method to determine fluoroquinolones in puffer fish by in vivo sampling. PMID- 28842033 TI - Analysis of multiple mass spectrometry images from different Phaseolus vulgaris samples by multivariate curve resolution. AB - A new procedure based on the simultaneous analysis of multiple mass spectrometry images using multivariate curve resolution is presented in this work. Advantages of the application of the proposed approach are shown for three cases of plant studies demonstrating its potential usefulness in metabolomics studies, particularly in lipidomics. In the first dataset, a three stage germination time course process of green bean seeds is presented. The second example is a dose response study where the stem bases of a non-exposed plant are compared to those of plants exposed to increasing concentrations of the pesticide chlorpyrifos. Finally, the third study is the simultaneous analysis of several sequential transversal and longitudinal cuts of the same green bean plant stem segment. The analysis of these three examples required the comprehensive adaptation of different chemometric methodologies including data compression by selection of the regions of interest (ROI strategy), appropriate data normalization and baseline correction, all of them before MCR-ALS simultaneous image analysis of multiple samples and post processing of the achieved results. MCR-ALS resolved components provided spatial information about the changes in the spatial composition and distribution of the different lipids on the surface of the investigated samples. These results enabled the identification of single lipids and the clustering of those lipids that behaved similarly in the different images simultaneously analyzed. The proposed strategy for MSI analysis represents a step forward in the simultaneous analysis of multiple sets of images providing an improved recovery of both spatial and structural information in environmental and biomedical studies. PMID- 28842035 TI - Corrigendum to "Zinc/Aluminum layered double hydroxide-titanium dioxide composite nanosheet film as novel solid phase microextraction fiber for the gas chromatographic determination of valproic acid" [Talanta, Volume 103, 15 January 2013, Pages 207-213]. PMID- 28842034 TI - Biologically friendly room temperature ionic liquids and nanomaterials for the development of innovative enzymatic biosensors. AB - Main purpose of the work is assembling, testing and optimizing new disposable amperometric biosensors to analyze substances in different application fields as agribusiness, clinical chemistry and environment protection. Many kinds of modified electrodes have been prepared and tested to build portable devices to analyze quickly many analytes, in a simple and cost-effective manner. Bare electrodes of the screen-printed type, with silver as reference, have been used for modification. The glassy carbon electrodes with multi-walled carbon nanotubes or graphene or gold nanoparticles depositions were modified with generation IV ionic liquids. Choline as cation and amino acids, such as glycine, serine, phenylalanine and histidine, as anions have been employed for these ionic liquids. The presence of nanostructured materials on the electrode brings an increased contact surface between analytes and receptor and, consequently, an amplification of the amperometric signal and a better sensibility. Moreover the use of new ionic liquids of generation IV, biologically friendly and water soluble, improves the electronic transfer, facilitating and strengthening the redox reaction nearby the electrode. By immobilizing the proper enzymes onto the modified electrode surface, different compounds of analytical interest can be determined by means of sensitive, properly designed amperometric biosensors. Analytes such as antioxidant components in extra-virgin olive oils, alcohols in beverages and glucose in food matrices have been tested, using a suitable enzyme: microbial lipase, alcohol dehydrogenase and glucose oxidase, respectively. PMID- 28842036 TI - Corrigendum to "A novel dispersive micro solid phase extraction using zein nanoparticles as the sorbent combined with headspace solid phase micro-extraction to determine chlorophenols in water and honey samples by GC-ECD" [Talanta 128 (1 October 2014) 493-499]. PMID- 28842037 TI - Reduction of interferences in the determination of lanthanides, actinides and transition metals by an octopole collision/reaction cell inductively coupled plasma mass spectrometer - Application to the analysis of Chios mastic. AB - Lanthanides, actinides and transition metals have demonstrated the ability to be used as fingerprint for the specification of the authenticity and geographical origin of food commodities. Therefore, the existence of analytical methods for their determination is of great importance, since both producers and consumers could benefit. An inductively coupled plasma mass spectrometric (ICP-MS) method was developed and validated for the determination of these elements in a Protected Designation of Origin product, the Chios mastic gum. A multivariate strategy for the microwave digestion of mastic was carried out. Five factors were studied and optimized. Hold time, temperature and HF volume, were found to be the most critical factors, so further optimization was performed. Molecular oxide (MO+, MO2+) and hydroxide (MOH+) interferences were investigated. The capability of an octopole collision/reaction cell ICP-MS to attenuate or remove these interferences was studied. The effect of instrumental parameters on MO+/M+, MOH+/M+ and MO2+/M+ ratios was studied to ensure that observed changes were a result of alteration of the parameter and not due to random fluctuations. Moreover, the effect of kinetic energy discrimination to suppress these species was demonstrated. The energy losses of ions were measured from stopping curves and the estimation of collision cross sections was done. Efficiencies of He and H2 gases were compared and H2 was finally selected for all elements. The calculated recoveries were ranged between 70 and 70% and 104% and the relative standard deviations (intermediate precision) were generally under 16%. The limits of detection were 0.07ngg-1 (Dy, Th) - 1.4ngg-1 (Ce). PMID- 28842038 TI - "External" antibodies as the simplest tool for sensitive immunochromatographic tests. AB - The scheme of immunochromatographic competitive analysis with "external" specific antibodies is offered for the first time. The test strip includes all the necessary components for analysis (membranes, protein antigen conjugates, colored nanoparticles), except specific free unconjugated antibodies that are transferred to the buffer used for sample dilution. Thus, the concentrations of the antibodies and markers can be chosen independently, and dilution of the sample with buffer (a routine procedure for any immunochromatographic test) ensures pre incubation of the antibodies with the sample. Both factors increase the sensitivity of the test. The proposed scheme has been proven to be effective for the determination of deoxynivalenol and T-2 toxin; detection limits of 500pg/mL and 50pg/mL, respectively, were achieved. This is an order of magnitude lower than the limits of detection of traditional tests using the same reagents. The analysis was conducted in water-organic extracts (20% methanol); the duration of the analysis is 10min (it's the same time as for a traditional test). The proposed approach is universal, and it can be used to detect a variety of compounds. PMID- 28842039 TI - "Cork taint" responsible compounds. Determination of haloanisoles and halophenols in cork matrix: A review. AB - Analytical methods of haloanisoles and halophenols quantification in cork matrix are summarized in the current review. Sample-preparation and sample-treatment techniques have been compared and discussed from the perspective of their efficiency, time- and extractant-optimization, easiness of performance. Primary interest of these analyses usually addresses to 2,4,6-trichloroanisole (TCA), which is a major wine contaminant among haloanisoles. Two concepts of TCA determination are described in the review: releasable TCA and total TCA analyses. Chromatographic, bioanalytical and sensorial methods were compared according to their application in the cork industry and in scientific investigations. Finally, it was shown that modern analytical techniques are able to provide required sensitivity, selectivity and repeatability for haloanisoles and halophenols determination. PMID- 28842040 TI - Development of a HS-SPME-GC/MS protocol assisted by chemometric tools to study herbivore-induced volatiles in Myrcia splendens. AB - A headspace solid phase microextraction (HS-SPME) method combined with gas chromatography-mass spectrometry (GC/MS) was developed and optimized for extraction and analysis of volatile organic compounds (VOC) of leaves and galls of Myrcia splendens. Through a process of optimization of main factors affecting HS-SPME efficiency, the coating divivnilbenzene-carboxen-polydimethylsiloxane (DVB/Car/PDMS) was chosen as the optimum extraction phase, not only in terms of extraction efficiency, but also for its broader analyte coverage. Optimum extraction temperature was 30 degrees C, while an extraction time of 15min provided the best compromise between extraction efficiencies of lower and higher molecular weight compounds. The optimized protocol was demonstrated to be capable of sampling plant material with high reproducibility, considering that most classes of analytes met the 20% RSD FDA criterion. The optimized method was employed for the analysis of three classes of M. splendens samples, generating a final list of 65 tentatively identified VOC, including alcohols, aldehydes, esters, ketones, phenol derivatives, as well as mono and sesquiterpenes. Significant differences were evident amongst the volatile profiles obtained from non-galled leaves (NGL) and leaf-folding galls (LFG) of M. splendens. Several differences pertaining to amounts of alcohols and aldehydes were detected between samples, particularly regarding quantities of green leaf volatiles (GLV). Alcohols represented about 14% of compounds detected in gall samples, whereas in non-galled samples, alcohol content was below 5%. Phenolic derived compounds were virtually absent in reference samples, while in non-galled leaves and galls their content ranged around 0.2% and 0.4%, respectively. Likewise, methyl salicylate, a well-known signal of plant distress, amounted for 1.2% of the sample content of galls, whereas it was only present in trace levels in reference samples. Chemometric analysis based on Heatmap associated with Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA) provided a suitable tool to differentiate VOC profiles in vegetal material, and could open new perspectives and opportunities in agricultural and ecological studies for the detection and identification of herbivore-induced plant VOC emissions. PMID- 28842041 TI - Slurry sampling high-resolution continuum source electrothermal atomic absorption spectrometry for direct beryllium determination in soil and sediment samples after elimination of SiO interference by least-squares background correction. AB - In this work a simple, efficient, and environmentally-friendly method is proposed for determination of Be in soil and sediment samples employing slurry sampling and high-resolution continuum source electrothermal atomic absorption spectrometry (HR-CS-ETAAS). The spectral effects originating from SiO species were identified and successfully corrected by means of a mathematical correction algorithm. Fractional factorial design has been employed to assess the parameters affecting the analytical results and especially to help in the development of the slurry preparation and optimization of measuring conditions. The effects of seven analytical variables including particle size, concentration of glycerol and HNO3 for stabilization and analyte extraction, respectively, the effect of ultrasonic agitation for slurry homogenization, concentration of chemical modifier, pyrolysis and atomization temperature were investigated by a 27-3 replicate (n = 3) design. Using the optimized experimental conditions, the proposed method allowed the determination of Be with a detection limit being 0.016mgkg-1 and characteristic mass 1.3pg. Optimum results were obtained after preparing the slurries by weighing 100mg of a sample with particle size < 54um and adding 25mL of 20% w/w glycerol. The use of 1MUg Rh and 50MUg citric acid was found satisfactory for the analyte stabilization. Accurate data were obtained with the use of matrix-free calibration. The accuracy of the method was confirmed by analysis of two certified reference materials (NIST SRM 2702 Inorganics in Marine Sediment and IGI BIL-1 Baikal Bottom Silt) and by comparison of the results obtained for ten real samples by slurry sampling with those determined after microwave-assisted extraction by inductively coupled plasma time of flight mass spectrometry (TOF-ICP-MS). The reported method has a precision better than 7%. PMID- 28842044 TI - Preface to gastrointestinal polyps. PMID- 28842045 TI - Morphological classifications of gastrointestinal lesions. AB - In the era of spreading adoption of gastrointestinal endoscopy screening worldwide, endoscopists encounter an increasing number of complex lesions in the gastrointestinal tract. For decision-making on optimal treatment, precise lesion characterization is crucial. Especially the assessment of potential submucosal invasion is of utmost importance as this determines whether endoscopic removal is an option and which technique should be used. To describe a lesion and stratify for the risk of submucosal invasion, several morphological classification systems have been developed. In this manuscript, we thoroughly discuss a systematic approach for the endoscopic assessment of a lesion, which include location, size, Paris classification, lateral spreading tumor classification if applicable and evaluation of the surface pattern with advanced endoscopic imaging techniques. The use of advanced imaging techniques improves the characterization of mucosal surface patterns and helps to determine whether lesions are amenable to endoscopic resection. PMID- 28842046 TI - Histological and molecular classification of gastrointestinal polyps. AB - Endoscopic diagnosis and treatment for gastrointestinal polyps became widely available within the last decades. Exact terminology is important for further therapeutic steps, follow up or treatment. Gastroenterologists, Oncologists, Surgeons and Pathologists need to be aware of the most recent terminology to ensure proper risk assessment and subsequent treatment if necessary. This manuscript aims to list the variety of gastrointestinal polyps and the molecular background where appropriate. PMID- 28842047 TI - Evaluation and management of gastric epithelial polyps. AB - Gastric polyps include a wide spectrum of lesions with different histology and neoplastic potential. They are found in up to 6% of upper gastrointestinal endoscopy and are usually asymptomatic and incidentally diagnosed, being in the vast majority epithelial gastric polyps. Hyperplastic, fundic gland and adenomas are the most common types of gastric polyps and, although each type may have typical endoscopic appearances, they all must be sampled at the initial endoscopy for histological assessment. Also, the normal appearing gastric mucosa should be sampled to stage atrophic changes, rule out endoscopically non-visible dysplasia and to diagnose Helicobacter pylori. Polyposis syndromes that affect the stomach are rare but should be taken into account. Hamartomatous polyps can be found in Juvenile polyposis, Cowden syndrome and Peutz-Jeghers syndrome. On the other hand, multiple fundic gland polyps are present in the majority of patients with familial adenomatous polyposis. In this study we provide a comprehensive review on the evaluation and management of gastric epithelial polyps, in this way helping physicians to properly handle this type of lesions. PMID- 28842048 TI - Management of duodenal polyps. AB - Duodenal adenomas are the most common type of polyp arising from the duodenum. These adenomas can occur within and outside of genetic syndromes, and are broadly classified as non-ampullary or ampullary depending on their location. All adenomas have malignant potential and are therefore appropriately treated by endoscopic resection. However, the unique anatomical properties of the duodenum, namely its relatively thin and vascular walls, narrow luminal diameter and relationship to the ampulla and its associated pancreatic and biliary drainage, pose an increased degree of complexity for any endoscopic interventions in this area. This review will discuss the epidemiology of duodenal adenomas, their endoscopic detection and diagnosis, and techniques for safe and effective endoscopic resection of ampullary and non-ampullary lesions. PMID- 28842049 TI - Management of small bowel polyps: A literature review. AB - Despite the small bowel comprising 90% of the mucosal surface area of the gastrointestinal tract, it is a rare site for neoplasia and only accounts for a little over 3% of the tumors that arise in the digestive tract. Benign small bowel lesions include lipomas, lymphangiomas, leiomyomas, neurofibromas, nodular lymphoid hyperplasia and adenomas, many of which are precursors to malignant lesions. Several polyposis syndromes are associated with small bowel polyps as well, including familial adenomatous polyposis syndrome, lynch syndrome, Peutz Jeghers syndrome, Cowden syndrome and juvenile polyposis syndrome. Our aim was to review non-malignant small bowel polyps and discuss the prevalence, typical location, clinical presentation, diagnosis, endoscopic and histologic description and lastly management of each of these lesions. PMID- 28842050 TI - Hereditary or sporadic polyposis syndromes. AB - Polyposis syndromes are encountered in endoscopy practice, and are considered rare entities, accounting for <=1% of colorectal cancer. Polyposis can occur within inherited syndromes or as "sporadic" cases of unknown etiology. Their proper characterization is relevant for patient management, and should nowadays drive appropriate genetic tests which have a key role in clinical practice for driving surveillance and colorectal cancer prevention, enlarged to relatives. Polyposis classification is based upon polyp number and histology, familial and personal history. This review will explore the polyposis nosology and their genetic determinants in the emerging scenario of Next Generation Sequencing which allow testing multiples genes in parallel. This capability will likely continue to increase the range of polyposis predisposing genes, contributing to define new clinical entities. PMID- 28842052 TI - Polyp detection at colonoscopy: Endoscopist and technical factors. AB - The adenoma detection rate (ADR) has emerged as the most important quality measure in colonoscopy, as it predicts the risk of interval cancer after colonoscopy. Measuring and improving ADR is the central focus of the current quality movement in colonoscopy. High ADRs can be achieved by a colonoscopist with a thorough understanding of the wide range of endoscopic appearances of precancerous lesions in the colorectum, effective bowel preparation, and meticulous technique using high definition colonoscopes. The knowledgeable and effective examiner needs no adjunctive devices or techniques to achieve master level ADRs. However, measurement reveals that many colonoscopists have ADRs that are below recommended minimum thresholds or below master levels. These colonoscopists, and even master level performers, can choose from a variety of adjunctive tools to improve ADR. This review describes these tools according to whether they are non-device methods (e.g. double right colon examination, patient position change, water exchange), mucosal exposure devices (wide angle colonoscopy, fold flattening devices), and lesion highlighting techniques (e.g. chromoendoscopy, electronic chromoendoscopy). PMID- 28842051 TI - Epidemiology and risk factors of colorectal polyps. AB - The lifetime risk of colorectal cancer (CRC) in the Western world is around 5%. CRC commonly develops from precursor lesions termed polyps, classified as adenomatous or serrated polyps according to growth pattern. Despite the well known connection between polyps and cancer, most polyps will never develop into CRC. For those that do, the time until CRC development is generally thought of as >10 years. This gives opportunity for interventional strategies to prevent transformation into cancer. This article aims to provide an overview of the epidemiology of and risk factors for colorectal polyps in the average risk population, and will encompass the effect of age, gender, ethnicity, smoking, obesity, alcohol, physical activity, NSAIDs and dietary factors on colorectal polyps. PMID- 28842053 TI - Polyp characterization at colonoscopy: Clinical implications. AB - Although advancements in endoscopic imaging of colorectal mucosa have outstripped the pace of research in the field, the potential clinical applications of these novel technologies are promising. Chief among these is the ability to diagnose colorectal polyps in vivo. This feature appears most applicable to diminuitive polyps, which have very little malignant potential yet represent over 70% of resected polyps. In an ideal application, the capability to predict diminutive hyperplastic polyp histology in vivo precludes the need for excision whereas dimunitive adenomas do require excision, but not necessarily histopathologic analysis if the diagnosis is made in vivo with adequate confidence. However, the vast array of new advanced imaging modalities and polyp classification tools have been difficult to reconcile. We aim to highlight the current status of real-time colorectal polyp diagnosis and identify the barriers that remain to its widespread implementation. PMID- 28842054 TI - Adenoma detection rate and risk of colorectal cancer. AB - GOALS: The aim of this paper was to discuss association between adenoma detection rate (ADR) and interval colorectal cancer risk. BACKGROUND: Adenoma detection rate is being used as a benchmark quality measure for colonoscopy. There are three studies showing inverse association between ADR and interval colorectal cancer risk. One recent study reports significant impact of increased ADR on decreasing interval colorectal cancer risk. STUDY: We discussed evidence for using ADR as a quality measures in colonoscopy and flexible sigmoidoscopy. We revised three studies (Kaminski et al., N Engl J Med 2010; Corley et al., N Engl J Med 2014 and Rogal et al., Clin Gastroenterol Hepatol, 2013) analyzing association between ADR and interval colorectal cancer. We collated strengths and weaknesses of these studies with the perspective of clinical impact of their results. RESULTS: Kaminski et al. and Corley et al. reported inverse association between ADR at colonoscopy and interval colorectal cancer. Kaminski et al. showed that patients examined by endoscopists with ADR of less than 20% had over 10 times greater risk of interval colorectal cancer during the follow-up time than those examined by endoscopists with ADR >=20%. Additionally, Corley et al. showed that ADR >=28% resulted in a significantly lower risk of colorectal cancer death than ADR of less than 19%. In parallel, Rogal et al. reported similar association for flexible sigmoidoscopy, with 2.4 higher odds of interval colorectal cancer diagnosis during follow-up time in patients examined by endoscopists with distal ADR <7.2% than those with distal ADR >=7.2%. Apart from inevitable clinical importance of the studies, they are not without disadvantages. In Kaminski et al. study cohort and study endpoint are well defined, but there is lack of statistical power to provide more robust results. In Rogal et al. study cohort is well defined, but approximation of the study endpoint was used. Finally, Corley et al. study has both poorly defined study cohort and study endpoint, but has the highest statistical power of all three to detect the differences for both interval colorectal cancer and colorectal cancer death. CONCLUSION: Both, inverse relationship between ADR and ADR improvement and colorectal cancer risk and death reaffirm ADR as a crucial quality control parameter. PMID- 28842055 TI - Standardisation of polypectomy technique. AB - There are several approaches to polypectomy for sessile polyps <20 mm and for pedunculated polyps. Recent evidence is leading towards standardisation of polypectomy technique. Key recent polypectomy developments include: 1. Use of cold snare polypectomy (CSP) for sessile polyps <10 mm; 2. Use of hot snare polypectomy (HSP) following submucosal injection for sessile polyps sized 10-19 mm; 3. Piecemeal cold snare polypectomy (PCSP), with or without prior submucosal injection, for select sessile polyps sized 10-19 mm, where the potential risk for an adverse event is increased (e.g. polyps in the caecum or ascending colon, or patients with increased risk of post-polypectomy bleeding), and where the risk of submucosal invasion is low; 4. Avoidance of hot biopsy forceps (HBF); 5. Limiting the use of cold biopsy forceps (CBF) to the smallest of diminutive polyps, where CSP is not feasible; 6. Mechanical haemostasis prior to polypectomy for large pedunculated polyps with head >=20 mm or stalk >=10 mm. PMID- 28842056 TI - Colorectal endoscopic mucosal resection (EMR). AB - Colonoscopy has the benefit of detecting and treating precancerous adenomatous polyps and thus reduces mortality associated with CRC. Screening colonoscopy is the keystone for prevention of colorectal cancer. Over the last 20 years there has been increased in the management of large colorectal polyps from surgery to endoscopic removal techniques which is less invasive. Traditionally surgical resection was the treatment of choice for many years for larger polyps but colectomy poses significant morbidity of 14-46% and mortality of up to 7%. There are several advantages of endoscopic resection technique over surgery; it is less invasive, less expensive, has rapid recovery, and preserves the normal gut functions. In addition patient satisfaction and efficacy of EMR is higher with minor complications. Thus, this has facilitated the development of advanced resection technique for the treatment of large colorectal polyps called as endoscopic mucosal resection (EMR). PMID- 28842057 TI - Colorectal endoscopic submucosal dissection (ESD). AB - Endoscopic submucosal dissection (ESD) is an interventional procedure for en-bloc resection of gastrointestinal lesions. ESD is a challenging and can involve a reasonable degree of risk, therefore case selection is of crucial importance, especially in the colo-rectum. This procedure should be mainly used for dissection of lesions when there is a high suspicion of superficial malignant invasion; several classifications have been proposed in order to better identify lesions suitable for ESD. However, case selection is still an issue, since only about 8-10% of dissected lesions are superficially invading cancer and most of cases involve benign or massively invading cancer. In addition, significant differences have been reported between Asian and Western countries in regard to main outcomes, and therefore measures should be adopted as soon as possible to reduce this discrepancy. PMID- 28842059 TI - Steps Toward Sustainable Change in Advance Care Planning. PMID- 28842060 TI - After 4 Decades of Lupus Nephritis Trials, Is There a "Best" Therapy? PMID- 28842058 TI - Distribution of colorectal polyps: Implications for screening. AB - BACKGROUND: During the last decades data from different studies reported modifications of the topographic distribution of colorectal cancers (CRCs), with an increased frequency of tumours in proximal colonic segments. Given the documented link between adenomas and CRC, a proximal migration of adenomas over time could be expected as well. AIM: To evaluate available evidence about the prevalence of adenomas and of sessile serrated polyps across colonic segments, the changing trends in their distribution across the colon and the diagnostic performance of screening tests currently adopted in population based screening programs for lesions located in different colonic segments. METHODS: Literature search on PubMed, Embase, and Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects with reference to preferred reporting items for systematic reviews and meta-analysis (PRISMA), considering all adult human studies in English, published between January 2000 and February 2017. RESULTS: Cross-sectional analysis of endoscopy and pathology data-bases are consistently showing a trend toward an increase with age of the proportion of adenomas located in the proximal colon. Several observational studies analysed the site distribution of adenomas, testing the hypothesis of a proximal shift of these lesions, and most of them reported an increase in the proportion of right-sided adenomas over time, although a similar trend was not confirmed by others. Also the quality of the retrieved evidence was low. Both endoscopy and FIT are showing a different level of sensitivity for lesions arising in different colonic segments, depending also on screenees characteristics. CONCLUSION: Available evidence is supporting the hypothesis of an increase in the proportion of right sided adenomas with age, while a similar increase has not been reported for SSP/A, at least among subjects aged 50 or older. The trend toward a proximalization of colorectal adenomas over time, reported by some authors, likely results from improved diagnostic performances and/or the process of population ageing. PMID- 28842061 TI - Quiz: Acute Allograft Failure Nearly a Decade Posttransplantation. PMID- 28842062 TI - AJKD Atlas of Renal Pathology: CKD of Unknown Cause (CKDu); Mesoamerican Nephropathy. PMID- 28842063 TI - Evolving Trends in Human Papillomavirus Vaccination by Sex and Time: Implications for Clinicians and Interventionists. PMID- 28842064 TI - Out on Campus: Meeting the Mental Health Needs of Sexual and Gender Minority College Students. PMID- 28842065 TI - Abstinence-Only-Until-Marriage: An Updated Review of U.S. Policies and Programs and Their Impact. AB - Adolescence is marked by the emergence of human sexuality, sexual identity, and the initiation of intimate relations; within this context, abstinence from sexual intercourse can be a healthy choice. However, programs that promote abstinence only-until-marriage (AOUM) or sexual risk avoidance are scientifically and ethically problematic and-as such-have been widely rejected by medical and public health professionals. Although abstinence is theoretically effective, in actual practice, intentions to abstain from sexual activity often fail. Given a rising age at first marriage around the world, a rapidly declining percentage of young people remain abstinent until marriage. Promotion of AOUM policies by the U.S. government has undermined sexuality education in the United States and in U.S. foreign aid programs; funding for AOUM continues in the United States. The weight of scientific evidence finds that AOUM programs are not effective in delaying initiation of sexual intercourse or changing other sexual risk behaviors. AOUM programs, as defined by U.S. federal funding requirements, inherently withhold information about human sexuality and may provide medically inaccurate and stigmatizing information. Thus, AOUM programs threaten fundamental human rights to health, information, and life. Young people need access to accurate and comprehensive sexual health information to protect their health and lives. PMID- 28842068 TI - Cultivating Connectedness and Equity: A Call to Action for the Global Adolescent Health Community. PMID- 28842066 TI - Human Papillomavirus Vaccination: What Are the Reasons for Nonvaccination Among U.S. Adolescents? AB - PURPOSE: Human papillomavirus (HPV) vaccination is recommended for 11- to 12-year old U.S. adolescents. Unfortunately, HPV vaccine rates have been suboptimal. Parents are key decision agents regarding their adolescents' health; thus, it is necessary to understand their reasons for not vaccinating their adolescents. The purpose of this study was to compare parents' primary reasons for non-HPV vaccination by calendar year, sex of the child, and level of vaccine hesitancy. METHODS: The National Immunization Survey-Teen 2012-2015 was subset to parents who did not intend for their adolescent to receive the HPV vaccine in the next 12 months (N = 59,897). Survey-weighted logistic regression models assessed the impact of year, sex, and level of hesitancy on main reasons for nonvaccination. RESULTS: Not receiving a recommendation and lack of knowledge were significantly more likely to be the reasons for nonvaccination in 2012 and 2013 compared with 2015. The following reasons were significantly less likely to be reported for females compared with males: not recommended (odds ratio [OR] = .63, 95% confidence interval [CI], .58-.69) and lack of knowledge (OR = .86, 95% CI, .79 .94). In contrast, parents of females were more likely to state they were concerned about safety and side effects (OR = 2.19, 95% CI, 1.98-2.41). Differences in reasons for nonvaccination were observed between those who were unlikely and unsure regarding receiving the HPV vaccine. CONCLUSIONS: Findings indicate that U.S. parental attitudes about HPV vaccination have changed over time and reasons for nonvaccination vary based on the sex of the adolescent and the level of hesitancy of the parent. This information can shape how providers respond to parental concerns and HPV vaccine hesitancy. PMID- 28842067 TI - Prospective Associations of 12th-Grade Drinking Intensity and Age 19/20 Driving Related Consequences. AB - PURPOSE: The purpose of this study is to examine driving-related consequences associated with levels of drinking intensity among a national sample of young adult drinkers. METHODS: Data come from a nationally representative sample of 12th graders sampled annually in 2005-2014 with subsamples surveyed at age 19/20 years. Multivariable logistic regressions examined associations of 12th-grade drinking intensity (0-4, 5-9, 10-14, and 15+ drinks in a row) with driving consequences at age 19/20 years. RESULTS: Twelfth-grade binge drinkers (compared with nonbinge drinkers) were more likely to experience negative driving consequences at age 19/20 years. Among binge drinkers, 15+ drinkers (compared with 5-9 drinkers) in 12th grade had increased the risk of negative drinking consequences at age 19/20 years. CONCLUSIONS: These results suggest that while underage binge drinkers are at an increased risk for having driving consequences, those who engage in higher intensity drinking are at even greater risk for these consequences. High-intensity drinkers may require additional screening or intervention to reduce future driving-related consequences. PMID- 28842069 TI - The Use of Medication by Adolescents and Young Adults. AB - This paper articulates the Society for Adolescent Health and Medicine positions regarding access to, and use of, medications by adolescents and young adults (AYA). AYA encounter a significant number of medication-related challenges. System barriers such as supply disruption, cost, and complicated refill systems affect adherence and contribute to complications and long-term sequelae. AYA need to be able to access medications easily, confidentially, at minimal (or no) cost, and without stigma. Optimal use of medications should ideally result from a process negotiated through the triadic relationship between AYA, their parents/caregivers, and health professionals. This should be underpinned by access to developmentally appropriate information, support and education, including credible online sources developed to support AYA self-management. Self management should be facilitated by meaningful AYA and parent/caregiver involvement in decision-making so that medication regimens are built around the life and developmental context of the AYA and form an integral part of their transition to adult health services. In addition, there should be facilitated involvement of AYA in the development of, licensing of, and access to new medications, including clinical trials. The positions presented in this paper are a comprehensive set of recommendations to improve AYA access to, and use of, medications for chronic illness, contraception, and self-limiting conditions. PMID- 28842070 TI - Abstinence-Only-Until-Marriage Policies and Programs: An Updated Position Paper of the Society for Adolescent Health and Medicine. AB - Abstinence from sexual intercourse can be a healthy choice for adolescents, particularly if an adolescent is not ready to engage in sex. However, government programs exclusively promoting abstinence-only-until-marriage (AOUM) are problematic from scientific and ethical viewpoints. Most young people initiate sexual intercourse as adolescents or young adults, and given a rising age at first marriage around the globe, increasingly fewer adolescents wait until marriage to initiate sex. While theoretically fully protective, abstinence intentions often fail, as abstinence is not maintained. AOUM programs are not effective in delaying initiation of sexual intercourse or changing other behaviors. Conversely, many comprehensive sexuality education programs successfully delay initiation of sexual intercourse and reduce sexual risk behaviors. AOUM programs inherently provide incomplete information and are often neglectful to sexually active adolescents; lesbian, gay, bisexual, transgender, and questioning adolescents; pregnant and parenting adolescents; and survivors of sexual assault. Promotion of AOUM policies by the U.S. government has undermined sexuality education in the United States and in U.S. foreign aid programs to prevent HIV infection. In many U.S. communities, AOUM programs have replaced more comprehensive approaches to sexuality education. PMID- 28842071 TI - Invited commentary. PMID- 28842072 TI - Invited commentary. PMID- 28842073 TI - Disarticulation of the knee: Analysis of an extended database on survival, wound healing, and ambulation. AB - OBJECTIVE: This study analyzed survival of the amputee patients, wound healing, and ambulation after knee disarticulation (KD). METHODS: Between July 1989 and October 2015, 153 KDs in 138 patients were performed at Nij Smellinghe Hospital, Drachten. Data were retrieved from hospital medical records. Wound healing was analyzed using nonparametric tests. Ambulation was recorded according to the Special Interest Group Amputation Medicine Workgroup Amputation and Prosthetics mobility scale. RESULTS: Survival at 1, 6, and 12 months was 86%, 65%, and 55%, respectively. Wounds healed in 91% of patients. Wounds healed primarily in 57% of residual limbs, and healing was delayed in 33%. A transfemoral amputation (TFA) was performed in 10%. Patients with sagittal flaps had significantly poorer primary wound healing and delayed wound healing more often than patients with a dorsal-myocutaneous (dorsomyocutaneous) flap (P < .027). In total, 62% of patients were provided with a prosthesis. Preoperatively, 71% of the patients had intention to ambulate with prosthesis, of which 91% received prosthesis. Of these, 35% walked without the help of others. KD amputee patients who underwent a reamputation at the transfemoral level were significantly less ambulant than amputee patients who did not (P < .021). CONCLUSIONS: If feasible, the dorsomyocutaneous flap technique seems to be the treatment of choice in KD. Because the wound complication rate of the group with a dorsomyocutaneous flap and the percentage of amputee patients who received prosthesis after KD fell within the same range as TFA amputee patients, KD may be an appropriate alternative when surgeons consider a TFA. PMID- 28842074 TI - Partnerships between podiatrists and vascular surgeons in building effective wound care centers. AB - This practice memo, a collaborative effort between the Young Physicians' Program of the American Podiatric Medical Association and the Young Surgeons Committee of the Society for Vascular Surgery, is intended to aid podiatrists and vascular surgeons in the early years of their respective careers, especially those involved in the care of patients with chronic wounds. During these formative years, learning how to successfully establish an interprofessional partnership is crucial to provide the best possible care to this important population of patients. PMID- 28842075 TI - Visceral collateralization with symptomatic occlusion of celiomesenteric trunk. PMID- 28842076 TI - Data, guidelines, and practice of revascularization for claudication. PMID- 28842077 TI - Evolution and current use of technology for superficial femoral and popliteal artery interventions for claudication. AB - An important facet in caring for patients with claudication is the development of a plan for managing the technology available for superficial femoral artery (SFA) and popliteal artery interventions. Although this is a field in evolution, clinical experience and data are emerging that assist the clinician in making informed choices as to the best method of endovascular treatment. Algorithms for SFA and popliteal artery interventions are developing. Methods for assessing a wide range of technologies are discussed. This article reviews the evolution of technology for SFA and popliteal artery interventions, describes the recent developments in data and clinical experiences, and discusses some potential methods of device assessment and incorporation into clinical practice. PMID- 28842078 TI - Cost measurement and payment implications in the Quality Payment Program. PMID- 28842079 TI - A critical note on protamine use in carotid endarterectomy. PMID- 28842080 TI - Regarding "Carotid endarterectomy should not be based on consensus statement duplex criteria". PMID- 28842081 TI - Reply. PMID- 28842082 TI - Regarding "A randomized controlled trial and cost-effectiveness analysis of early cannulation arteriovenous grafts versus tunneled central venous catheters in patients requiring urgent vascular access for hemodialysis". PMID- 28842083 TI - Reply. PMID- 28842084 TI - Endoscopic Plantar Fasciotomy; Deep Fascial Versus Superficial Fascial Approach: A Prospective Randomized Study. AB - In the present randomized prospective study, 2 different surgical techniques of endoscopic plantar fascia release were compared. Of 547 patients with a diagnosis of plantar fasciitis, 46 with no response to conservative treatment for >=6 months were included. Of the 46 patients, 5 were lost to follow-up. In group 1 (n = 21), plantar fascia release was performed using a deep fascial approach (DFA), and in group 2 (n = 20), the superficial fascial approach (SFA) with a slotted cannula technique was used. Patients were evaluated using the American Orthopaedic Foot and Ankle Society Ankle Hindfoot scale and visual analog scale at baseline and 3 weeks and 3, 6, and 12 months after the initial surgery. At the final follow-up appointment, the Roles-Maudsley score was used to determine patient satisfaction. At the final follow-up examination, the mean American Orthopaedic Foot and Ankle Society Ankle-Hindfoot scale scores had increased from 53.12 to 83.68, with a decrease in the mean visual analog scale score from 7.95 to 1.65 noted. According to the Roles-Maudsley score, the success rate after 1 year was 90.47% for DFA group, 95% for the SFA group, and 92.68% for all patients. Although no significant difference was found between the final functional scores, better early postoperative scores were found in the SFA group. The mean duration of the procedure was measured as 27.22 +/- 9.41 minutes overall, 35 +/- 5.62 minutes in the DFA group, and 19.05 +/- 4.01 minutes in the SFA group. Two early and two late complications occurred in the DFA group with none reported in the SFA group. In conclusion, the SFA is a faster and safer method of endoscopic plantar fascia release with better early postoperative scores. PMID- 28842085 TI - What Is the Current Role and Factors for Success of the Journal Club in Podiatric Foot and Ankle Surgery Residency Training Programs? AB - The journal club (JC) is a traditional part of postgraduate medical education, although little has been written on its current role in podiatric surgical training programs. The goal of the present study was to determine how JCs are conducted and the factors associated with their success. Anonymous electronic surveys were distributed to all podiatric foot and ankle surgical training program directors in the United States with a valid e-mail address. A total of 202 surveys were initially e-mailed to training program directors, with a second and third round sent to those who did not respond. The eventual response rate was 47.5%. The variables associated with success included high faculty attendance, dissemination of articles in advance, and regularly scheduled meetings. Of the residency programs that responded, 39.0% provided some type of handout or supplemental session and 39.8% provided supplemental session or handouts regarding the process of critical review, epidemiology, or biostatistics. A structured review instrument or checklist was used to guide critical appraisal in 21.5% of the JCs, and 11.8% of the programs provided feedback to residents. The JC was perceived by residency directors to be valuable and worthy of maintaining. Residency directors perceived the following factors to be associated with a successful JC: faculty participation, a designated leader, mandatory attendance, dissemination of materials in advance, and regularly scheduled meetings. Areas cited for improvement included implementation of a structured review instrument, delineation of clear goals, and periodic evaluation. We believe these findings could aid residency directors interested in maximizing the educational benefits of their JC. PMID- 28842086 TI - Comparison of Time to Operation and Efficacies of Ultrasound-Guided Nerve Block and General Anesthesia in Emergency External Fixation of Lower Leg Fractures (AO 42, 43, 44). AB - The present randomized controlled trial evaluated the usefulness of ultrasound (US)-guided nerve block (NB) for emergency external fixation of lower leg fractures, by investigating the time required before surgery and the clinical results stratified by the anesthesia method (US-guided NB or general anesthesia [GA]). From June 2014 to April 2016, 40 patients who had undergone emergency surgery for external fixator application were enrolled in the present study. We measured the lead time before the start of surgery after the decision to perform emergency surgery in both groups. The US-guided NB group included 17 males (85%) and 3 females (15%), with a mean age of 55.6 (range 33 to 77) years. Of these 20 patients, 12 (60%) had comorbidities such as diabetes mellitus, hypertension, and kidney-related disease. Fracture type 42, 43, and 44 in the AO classification were observed in 3 (15%), 12 (60%), and 5 (25%) cases, respectively. The mean interval before emergency surgery was 4.3 (range 2 to 6.25) hours in the US guided NB group. In the GA group (n = 20 patients), the mean interval before emergency surgery was 9.4 (range 3 to 14) hours, and this difference was statistically significant (p < .001). In the US-guided NB group, no cases of anesthesia failure or unstable vital signs occurred during surgery. Also, no postoperative complications related to the anesthesia method, such as aggravation of the general condition, developed. In contrast, 1 case of postoperative atelectasis occurred in the GA group. Emergency external fixation with US-guided NB in patients with lower extremity trauma can be implemented in less time, regardless of the preoperative preparation, which is a requirement for GA. PMID- 28842087 TI - Management of Intra-Articular Calcaneal Fractures: Clinical Results of Reduction Technique Using a Bone Spreader. AB - The purpose of the present study was to examine the clinical results of surgery for intra-articular calcaneal fractures using a calcaneal locking plate and a bone spreader as a reduction tool. Ten patients with intra-articular calcaneal fractures were treated. An extended lateral approach was used. The reduction of the intra-articular fragments of the posterior facet was temporarily held using a bone spreader and Kirschner wires. Internal fixation was achieved with a locking calcaneal plate. Bohler's angle and Preiss' angle were assessed on the day of injury and the day of the final follow-up examination. The step off and gap of the posterior facet were assessed on the day of injury and the first week after surgery. The functional outcome was evaluated using the American Orthopaedic Foot and Ankle Society ankle hindfoot scale score. The mean Bohler's angle ranged from 2.1 degrees +/- 11.0 degrees to 30.4 degrees +/- 5.0 degrees (p < .0001), the mean Preiss' angle ranged from 23.5 degrees +/- 4.5 degrees to 15.5 degrees +/ 2.9 degrees (p < .0001), the mean step off ranged from 4.0 +/- 1.9 mm to 0.1 +/ 0.2 mm (p = .0002), and the mean gap ranged from 2.6 +/- 1.0 mm to 1.2 +/- 0.6 mm (p = .0035). The mean American Orthopaedic Foot and Ankle Society Ankle Hindfoot scale score was 89.2 (range 85 to 100) at a mean of 14.3 months after surgery. Our results suggest that a locking calcaneal plate can be used to restore and reduce an intra-articular calcaneal fracture and achieve good clinical results. PMID- 28842088 TI - Comparison of Completion Rates for SF-36 Compared With SF-12 Quality of Life Surveys at a Tertiary Urban Wound Center. AB - Patient-reported outcome measures derived from quality of life instruments are an important tool in monitoring disease progression and treatment response. Although a number of validated instruments are available, the Short Form-36 (SF-36) quality of life survey is the most widely used. It is imperative that the patients answer all the questions in this instrument for appropriate analysis and interpretation. It has been hypothesized that fewer questions (i.e., the Short Form-12 [SF-12]), will result in greater survey completion rates. The present study was a randomized prospective study comparing the completion rates for the SF-36 and SF-12 quality of life surveys. Patients presenting with a chronic wound were asked to complete the SF-36 or SF-12 survey. After an a priori power analysis was performed, the completion rates, patterns of skipped questions, and demographic information were analyzed using t tests for continuous variables or Fisher's exact test for categorical variables and both multivariate linear regression and logistic regression. A total of 59 subjects (30 completed the SF 12 and 29 completed the SF-36) participated in the present study. The SF-12 group had an 80% (24 of 30) completion rate compared with a 55% (16 of 29) completion rate for the SF-36 group (p < .05). However, the length of the survey did not affect the completion rate nor was a statistically detectable pattern of skipped questions found. College graduates were more likely to complete both surveys compared with high school graduates (p < .07). Although it is unclear why, our study results indicate that the SF-12 yields a higher total survey completion rate. However, completion appears independent of the shorter survey length. PMID- 28842089 TI - Experimental Comparison of the Clinical Measurement of Ankle Joint Dorsiflexion and Radiographic Tibiotalar Position. AB - Clinical measurement of ankle dorsiflexion is typically used to diagnose limited ankle range of motion. Controversy and a lack of clarity continue regarding the most accurate clinical method of measuring ankle joint dorsiflexion and the effect that the foot position (supinated, neutral, pronated) has on the true tibiotalar position. We investigated the effects of supinated, neutral and pronated foot positions on the clinical dorsiflexion measurements in 50 healthy subjects and compared these results to the radiographic measurement of tibiotalar joint position with the ankle maximally dorsiflexed in each of the 3 foot positions. Interrater reliability was confirmed to be adequate among the 3 clinicians of varied skill levels. Radiographic measurements of the tibiotalar position showed very little change in each of the 3 foot positions, with a total difference of 0.35 degrees between supination and pronation. However, we found a mean difference of 14 degrees of dorsiflexion in the clinical measurements between the pronated and supinated foot position, with a 9.08 degrees difference between the neutral and supinated positions. Motion of the foot between the neutral and supinated positions introduced an additional source of potential error from the measurement technique when using the neutral position as the standard, which has been recommended in the past. We recommend a supinated foot position as a more reliable foot position for measuring the clinical ankle joint range of motion and propose it as a potential standard. PMID- 28842090 TI - Comparison of Tibial Sesamoid Position on Anteroposterior and Axial Radiographs Before and After Triplane Tarsal Metatarsal Joint Arthrodesis. AB - We reviewed the radiographic results of a group of patients who had undergone triplane correctional tarsometatarsal arthrodesis for symptomatic hallux abducto valgus with metatarsus primus abducto valgus. Of the 21 feet included in the present review, 17 (81%) displayed radiographic findings of metatarsal pronation preoperatively based on axial sesamoid views and positive lateral round sign on anteroposterior radiographs. At a mean follow-up period of 5.2 +/- 1.6 months, a significant improvement in the tibial sesamoid position (TSP) on both anteroposterior (AP) and axial radiographs was measured. A negative metatarsal round sign, indicating correction of coronal plane metatarsal rotation, was observed in 20 of the 21 feet (95.2%) on AP radiographic evaluation. All 21 patients (100%) had obtained resolution of sesamoid subluxation on the sesamoid axial view at the final follow-up examination. The sesamoid axial position was consistently normal when the round sign was absent, and the TSP was in the normal range of 1 to 3 on the AP radiograph. Sesamoid subluxation from the normal position with the tibial sesamoid on or lateral to the crista was noted in 4 feet (19%) preoperatively and 0 feet postoperatively. This confirmed that lateral round sign of the first metatarsal head and a high TSP noted on the AP radiograph are both related to metatarsal pronation and can be corrected concurrently with coronal plane varus rotation of the first metatarsal as a part of the procedure. PMID- 28842091 TI - Ten-Year Follow-Up of Metatarsal Head Resurfacing Implants for Treatment of Hallux Rigidus. AB - Controversy remains regarding the use of arthroplasty versus arthrodesis in the surgical treatment of late-stage hallux rigidus. The purpose of our retrospective study was to report the long-term follow-up results of the metatarsal head resurfacing implant used for hemiarthroplasty. The patient assessments were conducted using the American Orthopaedic Foot and Ankle Society (AOFAS) metatarsophalangeal clinical rating system and a satisfaction questionnaire. A total of 59 consecutive implantations were performed from January 2005 to December 2009 at our institution. Of the 59 patients, 2 had died and 12 were lost to follow-up, for a 76.3% follow-up rate (45 of 59 procedures) at a mean of 117.67 (range 96 to 143) months. The mean overall AOFAS scale score was 90.6 +/- 7.6. The AOFAS pain scale score was 37.78 +/- 4.71. One implant was removed, and all remaining patients were happy with their outcome and would repeat the procedure on their other foot, if needed. A subset of patients from a previous mid-term study at our institution showed no significant change in the AOFAS scale scores. Of these 32 patients, 30 (93.75%) were available for follow-up examination at a mean of 122.62 (range 96 to 143) months. We were able to obtain long-term results for 32 implants (30 patients), resulting in a 10-year follow-up rate of 93.7%. With the minimal resection required for this implant, salvage arthrodesis remains a viable option if revision is needed. The surgical treatment of late-stage hallux rigidus with metatarsal head resurfacing allows for low-risk and excellent outcomes at long-term follow-up point. PMID- 28842092 TI - Iselin's Disease: A Systematic Review. AB - Iselin's disease was first described in 1912. It is a condition affecting the tuberosity of the base of the fifth metatarsal. It has been described as a traction apophysitis predominately affecting adolescents, in particular those who partake in regular sporting activity. The condition is rarely reported and likely to remain undiagnosed, possibly mistaken for a fracture. The present report reviewed the available published data to highlight this condition as a differential diagnosis in patients with fifth metatarsal pain. Investigations, treatments and outcomes into this condition are described, to support the management and diagnosis of this condition. PMID- 28842093 TI - Intraoperative Three-Dimensional Navigation for Talocalcaneal Coalition Resection. AB - Talocalcaneal tarsal coalitions are a common source of foot pain, stiffness, and deformity. These coalitions are treated symptomatically with rest and periods of immobilization. When those measures fail, surgical resection is attempted. This procedure is an anatomic challenge with the consequence of leaving residual coalition. The residual coalition primarily results from difficulty with intraoperative imaging because fluoroscopy does not provide adequate detail of this area. Some investigators have recommended intraoperative computed tomography after resection with reasonable results. We describe the combination of an intraoperative computed tomography with a navigated instrument system for resection of talocalcaneal coalitions. The use of a navigated probe and burr aids in defining the most anterior, posterior, and medial extents of the coalition. This technique reduces the morbidity, with less bone removed and preservation of intact subtalar articulations and allows for an efficient, thorough, and controlled resection. PMID- 28842094 TI - Case Study: Rare Case of Mantle Cell Lymphoma With Extranodal Involvement in the Foot. AB - Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that commonly affects extranodal sites. The most commonly affected sites are the bone marrow, gastrointestinal tract, Waldeyer's ring, lung, and pleura. We report the case of an 80-year-old diabetic male, in MCL remission, who presented with a small dome shaped nodule on his calf and an ipsilateral second digit non-healing ulceration after a traumatic fall. Despite surgical and conservative treatment, the wound worsened, resulting in histopathologic examination, which confirmed the presence of lymphocytes, indicating MCL relapse. This case was followed up for approximately 3 months until the patient died. Our case is an example of pedal manifestations of skin involvement of MCL, which, on consideration of the clinical manifestations also, can be confused with a nonhealing diabetic wound. The clinical significance of our case study is to assist in the diagnosis, management, and prognosis of a patient with MCL. PMID- 28842096 TI - Syndesmotic Injuries: Where Are We Now? Where Do We Need To Go? PMID- 28842095 TI - Functional Outcomes After Heel Pad Reconstruction: A Review of 7 Cases. AB - Sensate, durable heel pad reconstruction is challenging. The present study assessed the functional outcomes after heel pad reconstruction using various flap techniques at our institution. From June 2011 to June 2016 (5-year period), 7 consecutive patients underwent heel pad reconstruction for various etiologies, with 3 microvascular free flaps (42.9%; 2 musculocutaneous flaps [66.7%] and 1 contralateral medial plantar flap [33.3%]) and 4 local pedicle flaps (57.1%; 3 instep medial plantar artery flaps [75.0%] and 1 distally based reverse sural flap [25.0%]). The patient records and demographic data were reviewed, and surgically related information was obtained and analyzed. The subjective components of the American Orthopaedic Foot and Ankle Society hindfoot clinical ratings scale were used to evaluate the pain and functional outcomes. Sensation was assessed using Semmes-Weinstein monofilaments, and ulcer recurrence was recorded. The mean age of the patients was 41.7 (range 11 to 70) years, the mean defect size was 59 (range 12 to 270) cm2, and the mean follow-up duration was 22 (range 15 to 43) months. Complete flap survival was achieved without significant complications in all 7 patients. Patients treated with the sensate medial plantar artery flap recorded the highest mean American Orthopaedic Foot and Ankle Society score of 57.3 (maximum score of 60) and experienced a return of deep sensation at 6 (range 6 to 24) months and protective sensation at 1 year. This was followed by the reverse sural flap and the musculocutaneous flap. No recurrent heel ulceration was observed in our series of patients. In conclusion, the sensate medial plantar flap is a satisfactory method for coverage of small- to moderate size heel defects. PMID- 28842097 TI - Sports Medicine and the Foot and Ankle Surgeon. PMID- 28842098 TI - Should Sports Injuries and Surgeries Be "POLICED"? PMID- 28842100 TI - Functional Medium-Term Results After Autologous Matrix-Induced Chondrogenesis for Osteochondral Lesions of the Talus: A Five-Year Prospective Cohort Study: Gottschalk et al. PMID- 28842099 TI - Surgery for Tendinopathy of the Main Body of the Achilles Tendon: No Need to Look for New Solutions When the "Old Ones" Work, if Performed Well. PMID- 28842101 TI - Navicular Stress Fracture Outcomes in Athletes: Analysis of 62 Injuries. AB - The optimal treatment modalities for navicular stress fractures in athletes is currently unknown for this season-ending injury. The present study evaluated factors that might be significant and affect healing outcomes, specifically focusing on the return to activity (RTA) time and a decreased desired activity (DDA) after treatment in athletes. Such considerations included previous navicular stress fractures, patient demographic data and type of sport, and initiation time of treatment. The data from 59 patients with 62 fractures were prospectively analyzed from May 2005 through July 2016. The results showed a significant correlation between a previous navicular stress fracture and decreased desired activity. The average duration of symptoms before receiving definitive treatment was 8.8 months. Computed tomography as the initial imaging modality correlated positively with a correct diagnosis (1.00). In contrast, magnetic resonance imaging, when used initially, was only 71% accurate. Runners constituted most of the cohort at 38 (61.3%). Ten other athletes were involved in jumping sports. Of the 62 injuries, 21 (33.9%) were in elite or professional athletes, all of whom were able to RTA, with 1 patient, a 38-year-old world record holding runner, having a DDA. Seven refractures (11.2%) occurred an average >5 years after the initial injury, predominantly in those aged <21 years, none with previous surgery. Eight patients (12.9%) developed postinjury arthrosis, including 1 with DDA. Patients who underwent open reduction and internal fixation had a RTA of 4.56 months compared with those who had undergone nonoperative treatment, who had an average RTA of 3.97 months. Seven patients (11.2%) underwent screw removal and required a longer RTA. Overall, of the 62 injuries, the patients with 57 of the injuries (91.9%) were able to RTA at their preinjury level. PMID- 28842102 TI - Commentary on Navicular Stress Fracture Outcomes in Athletes: Analysis of 62 Injuries. PMID- 28842103 TI - Treatment of Plantar Fasciitis With Radial Soundwave "Early" Is Better Than After 6 Months: A Pilot Study. AB - Extracorporeal shock wave therapy/radial soundwave therapy has been predominantly used for chronic or recalcitrant plantar fasciitis with strong scientific evidence of reliable outcomes. Most of the studies included patients with plantar fasciitis with symptoms >6 months in duration. Only 2 known studies have investigated acute plantar fasciitis, which is <6 weeks in duration. They both found suboptimal results for the use of extracorporeal shock wave therapy. To the best of our knowledge, no studies have investigated radial soundwave therapy for the subacute stage or early stage of plantar fasciitis. Data were prospectively collected from 28 eligible patients who underwent radial soundwave therapy (RSWT) during a 9-month period in 2014. Of the 28 subjects, 14 were enrolled in the "early group" with a symptom duration of <3 months and 14 in the "standard/control" group with a symptom duration of >6 months. The pretreatment and posttreatment visual analog scale scores, Roles-Maudlsey scores, and activity level were recorded and compared. The early implementation of RSWT yielded comparable outcomes when compared with the standard group. RSWT is a valid treatment modality that can be implemented soon after the initial treatment options or first-phase treatment options have failed. Early treatment is more likely to allow for maintenance of patients' activity level. Also, waiting 6 months to treat plantar fasciitis with RSWT results in delays and inferior results. Early treatment is better for active and athletic patients. PMID- 28842104 TI - Assessment of the Resistance of Several Suture Techniques in Human Cadaver Achilles Tendons. AB - Many treatments are available for acute Achilles tendon ruptures, conservative and surgical, with none superior to another. For surgical treatment, one can use various techniques. Recent studies have shown that double stitches are superior to simple sutures. Therefore, in the present study, we sought to determine the suture technique that is the most resistant to rupture. We performed an experimental anatomic study with 27 fresh-frozen human cadaveric Achilles tendons obtained through the body donation program of the University of Barcelona, testing the maximum strength. We simulated a rupture by performing resection in the middle portion of the tendon, 4 cm proximal to the calcaneus insertion. We then evaluated the double Kessler, double Bunnell, Krackow, and percutaneous Ma and Griffith technique. We used absorbable suture (polydioxanone no. 1) with all the techniques. Traction was performed using a machine that pulls the tendon at 10 to 100 N in 1000 repetitive cycles. Statistical analysis was performed using the chi2 test and analysis of variance, with the 95% confidence intervals (p < .05). All repairs failed at the site of the suture knots, with none pulling out through the substance of the tendon. We found no significant differences among the different open suture techniques (p > .05). The Krackow suture presented with superior resistance, with a rupture rate 16.70% but with a mean elongation of 7.11 mm. The double Bunnell suture had the same rupture rate as the Krakow suture (16.70%) but with an inferior mean elongation of 4.53 mm. The Krackow and Bunnell suture were superior in endurance, strength of failure, and primary stability compared with the other suture types. However, the former presented with greater tendon elongation, although the difference was not statistically significant. Therefore, according to our findings and the published data, we recommend double Bunnell sutures for the surgical treatment of acute Achilles tendon rupture. PMID- 28842105 TI - Early Protected Weightbearing for Acute Ruptures of the Achilles Tendon: Do Commonly Used Orthoses Produce the Required Equinus? AB - Conservative "functional" management of acute Achilles tendon ruptures has become increasingly popular. Critical to this is the use of the walking orthosis, which positions the ankle in equinus to allow for early weightbearing. Our aim was to test whether 2 common orthoses achieved a satisfactory equinus position. A total of 11 sequentially treated Achilles tendon ruptures were assigned to either a fixed angle walking boot with wedges (FAWW) or an adjustable external equinus corrected brace (EEB). The lateral radiographs of the cast immobilized tendons showed a mean tibiotalar angle (TTA) of 56 degrees (range 54 degrees to 57 degrees ) and a mean tibio-first metatarsal angle (1MTA) of 74 degrees (range 62 degrees to 85 degrees ). The FAWW resulted in a mean TTA of 28 degrees (range 15 degrees to 35 degrees ) and 1MTA of 37 degrees (range 30 degrees to 45 degrees ). The EEB resulted in a TTA of 48 degrees (range 43 degrees to 45 degrees ) and 1MTA of 54 degrees (range 47 degrees to 57 degrees ). Ankle equinus was significantly greater with the EEB than with the FAWW (p < .05) and similar to that with an equinus cast. The use of wedges produced an equinus appearance through the midfoot but not at the ankle. We express caution in the use of the FAWW because it is unlikely to achieve sufficient ankle equinus to shorten the Achilles tendon. PMID- 28842106 TI - Electromagnetic Transduction Therapy for Achilles Tendinopathy: A Preliminary Report on a New Technology. AB - A parallel prospective feasibility study was performed on 53 patients with chronic mid-portion Achilles tendinopathy (age 44.7 +/- 9.1 years). Of the 53 patients, 28 (active group) were treated using a new electromagnetic (pulsed electromagnetic field) transduction therapy device (Cellactor(r) MT1) and heel cushions. The device produces an electromagnetic field of 80 milliTesla; a total of 8 treatments was performed within 4 weeks in an outpatient setting, without anesthesia, immobilization, or rest. A control group of 25 patients with a similar duration of symptoms was treated with heel cushions only. At the 12-week assessment point, the visual analog scale scores in both groups had significantly decreased, although the active group had significantly improved visual analog scale scores compared with those of the controls. The Role-Maudsley scores had also significantly improved in both the active and the control groups (p < .00001 and p = .0002, respectively). Electromagnetic transduction therapy could potentially be a useful modality for the treatment of Achilles tendinopathy. It should be compared with the current reference standard of extracorporeal shockwave therapy/radial soundwave therapy with similar level I, II, and III studies. PMID- 28842107 TI - Exercise and Diabetes: A Narrative Review. AB - Persons with diabetes might experience significant benefits through regular exercise. Not unlike the general population, those with diabetes could also lack motivation to participate in an exercise program. Often, those treating persons with diabetes lack training and/or interest in exercise prescription and are therefore unable to provide the needed information and encouragement. In many cases, reluctance to exercise could result from an inability to find an enjoyable exercise activity. Attempts to find activities that, not only provide effective aerobic challenges, but are also enjoyable to participate in are fraught with difficulty. Three electronic databases were searched in January 2017. Evidence for the merits of exercise for those with diabetes was robust. Numerous reports have addressed the degree of noncompliance to exercise recommendations and the barriers reported for this nonadherence. Additional studies concluded that most medical providers are deficient in formal training in the prescription of an exercise program. Newer studies are evaluating the effects of exercise and vitamin D supplementation and their interplay with diabetic peripheral neuropathy and ulceration. Exercise confers remarkable benefits to those with diabetes; however, the challenges to compelling patients with diabetes to exercise are formidable. An improved focus on exercise prescription and related motivation during provider training must be undertaken. PMID- 28842108 TI - Percutaneous Ultrasonic Tenotomy for Achilles Tendinopathy Is a Surgical Procedure With Similar Complications. AB - Percutaneous ultrasonic tenotomy is a relatively new treatment option for multiple types of tendinopathy. However, a paucity of high-level data is available on its use for chronic Achilles tendinosis. The present case series details the complications associated with the use of this technique. When considering percutaneous ultrasonic tenotomy, the surgeon should be cognizant that it is a surgical procedure with complications similar to those of other Achilles tendon surgeries. PMID- 28842109 TI - Treatment of Medial Tibial Stress Syndrome With Radial Soundwave Therapy in Elite Athletes: Current Evidence, Report on Two Cases, and Proposed Treatment Regimen. AB - Two case reports of high-level athletes with medial tibial stress syndrome (MTSS), 1 an Olympian with an actual stress fracture, are presented. Successful treatment included radial soundwave therapy, pneumatic leg braces, relative rest using an antigravity treadmill, and temporary foot orthoses. Radial soundwave therapy has a high level of evidence for treatment of MTSS. We also present recent evidence of the value of vitamin D assessment. Both patients had a successful outcome with minimal downtime. Finally, a suggested treatment regimen for MTSS is presented. PMID- 28842110 TI - Separating Pathways in the Extracellular ESCRT Service. PMID- 28842111 TI - Sex Disparities After Induction Chemoradiotherapy and Esophagogastrectomy for Esophageal Cancer. AB - BACKGROUND: The impact of sex on the outcomes of treatment for locally advanced esophageal carcinoma is unclear. This study analyzed the impact of sex on response to neoadjuvant chemoradiotherapy (nCRT), tumor recurrence, and survival. METHODS: From January 1990 through December 2013, female patients who received nCRT followed by esophagogastrectomy at 3 affiliated centers were compared with control male patients based on age, pretreatment clinical stage, histologic type, and surgical era. Only patients staged preoperatively with computed tomographic scans and endoscopic ultrasonography (EUS) were included. RESULTS: There were 366 patients (145 women and 221 men). The median female age was 64 years (range, 22 81 years), whereas male patients were 61 years (range, 33-82 years). The histologic type was adenocarcinoma in 105 (72%) women and 192 (87%) men, and it was squamous cell carcinoma in 40 (28%) women and 29 (13%) men (p = 0.005). Women were more likely to attain either a complete pathologic (CP) response or a nearly complete pathologic (NCP) response to induction therapy (84 [58%]) compared with men (103 [47%]; p = 0.034). Men had an 80% increased risk of recurrence (hazard ratio [HR], 1.80; 95% CI, 1.15-2.68; p = 0.008). There was no sex association with risk of death (p = 0.538). Irrespective of sex, a partial responder (relative to a complete or nearly complete responder) was 3 times more likely to have recurrence (HR, 2.96; 95% CI, 1.98-4.43; p < 0.001) and 2.5 times more likely to die (HR, 2.56; 95% CI, 1.88-3.48; p < 0.001). CONCLUSIONS: Female sex correlated with improved rates of achieving either a CP response or an NCP response after neoadjuvant chemotherapy and a smaller likelihood of experiencing tumor recurrence. Future efforts should be directed at understanding determinants of this sex disparity. PMID- 28842112 TI - RCR audit of compliance with UK guidelines for the prevention and detection of acute kidney injury in adult patients undergoing iodinated contrast media injections for CT. AB - AIM: To determine radiology departmental compliance with current UK guidance on contrast-induced acute kidney injury (CI-AKI) and to provide data on the incidence of clinically significant post-contrast AKI (PC-AKI) in computed tomography (CT) practice. MATERIALS AND METHODS: A questionnaire was sent to all UK acute National Health Service (NHS) providers (NHS boards in Scotland, local health boards in Wales, NHS trusts in England and health and social care trusts in Northern Ireland) to assess compliance of provider protocols with current UK guidelines for the prevention, recognition, and management of CI-AKI. Audit data were collected for 40 consecutive fit outpatients and 40 consecutive acutely unwell patients/inpatients from hospitals within each participating provider to assess clinical compliance. RESULTS: Eighty-nine of 172 (52%) health service providers responded, and data on 7,159 contrast-enhanced CT examinations were provided. Compliance with guidelines was poor with wide variation in clinical practice. The observed incidence of clinically significant (requiring treatment or resulting in death) PC-AKI was zero in 3,590 outpatients, although two patients developed AKI due to other causes (sepsis and progressive malignancy). Fourteen out of 3,569 (0.4%) patients in the inpatient group developed clinically significant PC-AKI, and a further 17 patients were identified who met the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI (Electronic Supplementary Material Appendix S1), but did not require active treatment, giving an overall incidence of AKI of 0.9%. In patients at high risk due to impaired renal function prior to the scan, there was no difference in the median serum creatinine (SCr) before and after contrast medium administration in either group. CONCLUSION: Health service provider protocols and clinical practice demonstrate poor compliance with current UK guidance on CI-AKI. A very low incidence of PC- AKI was demonstrated. PMID- 28842113 TI - Diffusion-weighted imaging in gynaecological malignancy. AB - Diffusion weighted imaging (DWI) has become an essential part of the gynaecological magnetic resonance imaging (MRI) protocol. DWI is used as an adjunct to conventional MRI sequences and has been shown to improve reporting accuracy in the imaging of gynaecological malignancy. In this review, we discuss the role of DWI in the diagnosis, staging, and assessment of treatment response of endometrial, cervical, and ovarian cancer. We also review the role of DWI in the assessment of the sonographically indeterminate ovarian lesion. Further, we highlight potential pitfalls that can beset the accurate interpretation of DWI in patients with gynaecological malignancy. PMID- 28842116 TI - No evidence of differences in color changes between walking bleach technique and inside-out technique in patients with nonvital discolored teeth. PMID- 28842115 TI - Slow-Growing Pink Papule. PMID- 28842117 TI - Bone scrapers may have similar rates of intraoperative complications as ultrasonic inserts when reducing cortical wall thickness during sinus floor elevation surgery. PMID- 28842114 TI - Intergenerational Effect of Maternal Exposure to Childhood Maltreatment on Newborn Brain Anatomy. AB - BACKGROUND: Childhood maltreatment (CM) confers deleterious long-term consequences, and growing evidence suggests some of these effects may be transmitted across generations. We examined the intergenerational effect of maternal CM exposure on child brain structure and also addressed the hypothesis that this effect may start during the child's intrauterine period of life. METHODS: A prospective longitudinal study was conducted in a clinical convenience sample of 80 mother-child dyads. Maternal CM exposure was assessed using the Childhood Trauma Questionnaire. Structural magnetic resonance imaging was employed to characterize newborn global and regional brain (tissue) volumes near the time of birth. RESULTS: CM exposure was reported by 35% of the women. Maternal CM exposure was associated with lower child intracranial volume (F1,70 = 6.84, p = .011), which was primarily due to a global difference in cortical gray matter (F1,70 = 9.10, p = .004). The effect was independent of potential confounding variables, including maternal socioeconomic status, obstetric complications, obesity, recent interpersonal violence, pre- and early postpartum stress, gestational age at birth, infant sex, and postnatal age at magnetic resonance imaging scan. The observed group difference between offspring of CM exposed mothers versus nonexposed mothers was 6%. CONCLUSIONS: These findings represent the first report to date associating maternal CM exposure with variation in newborn brain structure. These observations support our hypothesis of intergenerational transmission of the effects of maternal CM exposure on child brain development and suggest this effect may originate during the child's intrauterine period of life, which may have downstream neurodevelopmental consequences. PMID- 28842118 TI - Laser therapy seems to have benefits when used for treating oral pigmentation, yet there is no evidence of its relative effectiveness compared with other treatments. PMID- 28842119 TI - Direct light-activated resin-based composite restorations in posterior teeth seem to have a high clinical success rate and long-term survival. PMID- 28842120 TI - A desiccant agent as an adjuvant to scaling and root planing improves clinical parameters in patients with chronic periodontitis and good prognosis up to 1 year after treatment. PMID- 28842121 TI - Mineral trioxide aggregate likely to have a better success rate than calcium hydroxide in mature permanent teeth undergoing partial pulpotomy. PMID- 28842122 TI - Malonic acid based cationic lipids - The way to highly efficient DNA-carriers. AB - Cationic lipids play an important role as non-viral nucleic acid carriers in gene therapy since 3 decades. This review will introduce malonic acid derived cationic lipids as nucleic acid carriers which appeared in the literature dealing with lipofection 10years ago. The family of amino-functionalized branched fatty acid amides will be presented as well as different generations of malonic acid diamides. Both groups of cationic lipids yield lipid mixtures with highly efficient nucleic acid transfer activities in in-vitro cell culture models. The DNA transfer screening of lipid libraries with directed structural variations in the lipophilic as well as in the hydrophilic part of the amphiphiles yields structure/activity relationships. Furthermore, the detailed characterizations of selected lipid composites at the air/water interface and in bulk systems are summarized with regard to transfection determining physical-chemical properties. The findings are also discussed in comparison to results obtained with other families of cationic lipids. PMID- 28842123 TI - MiRNA-154-5p inhibits cell proliferation and metastasis by targeting PIWIL1 in glioblastoma. AB - MicroRNAs (miRNAs) play a critical role in glioblastoma initiation and progression. PIWIL1, a human homolog of the PIWI family, has a critical effect on glioblastoma progression. In present study, we found that the expression of miR 154-5p was significantly lower in glioblastoma. Our results suggested that the overexpression of miR-154-5p suppressed proliferation and metastasis, induced apoptosis, whereas inhibiting the expression of miR-154-5p significantly promoted proliferation and metastasis of glioblastoma. We further proved that miR-154-5p directly integrated with the 3'-UTR of PIWIL1 and reintroduction of PIWIL1 can rescue the phenotype changes induced by miR-154-5p. Taken together, our study reveals that miR-154-5p can counteract the malignant phenotypes of glioblastoma by targeting PIWIL1, which might be beneficial to reveal new therapeutic targets for glioblastoma. PMID- 28842124 TI - Phencyclidine-induced dysregulation of primary cilia in the rodent brain. AB - Significant roles of the primary cilia in the central nervous system have been reported in neural generation and cognitive functions. However, little is known about the possible pathological changes in brain primary cilia in neuropsychiatric disorders. To obtain an insight into the relationship between cilial dysregulation and schizophrenia, we presently investigated the effects of psychotomimetics, phencyclidine, MK-801 (dizocilpine), and methamphetamine, on morphological and molecular indices in the rodent brain. Using an immunohistochemical technique, we found that a subcutaneous injection of phencyclidine, an NMDA type glutamate receptor (NMDAR) antagonist, caused a reduction in the long axis length of a primary cilium in the CA1 region of the hippocampus without affecting that in the dentate gyrus and medial prefrontal cortex of rats and mice. The region-selective modulation of primary cilia was mimicked by another NMDAR antagonist, MK-801, but not by the indirect dopamine agonist methamphetamine. Furthermore, systemic administration of phencyclidine, but not methamphetamine, down-regulated mRNA expression of primary cilium morphology-related genes, including kif3a, 5-HTR6, RPGRIP1L, and TMEM67, and of genes composing the cilial Wnt/beta-catenin signaling pathway, beta-catenin, syn2 and Bcl-2, in the hippocampus, but not in the cerebral cortex of rats. These findings suggest that NMDAR hypofunction-induced dysregulation of CA1 primary cilia could be involved in the pathophysiology of dopamine transmission independent symptoms of schizophrenia. PMID- 28842125 TI - The role of miR-214 in cardiovascular diseases. AB - Cardiovascular disease (CVD) is the leading cause of death throughout the world. The increase in new patients every year leads to a demand for the identification of valid and novel prognostic and diagnostic biomarkers for the prevention and treatment of cardiovascular diseases. MicroRNAs (miRNAs) are critical endogenous small noncoding RNAs that negatively modulate gene expression by regulating its translation. miRNAs are implicated in most physiological processes of the heart and in the pathological progression of cardiovascular diseases. miR-214 is a deregulated miRNA in many pathological conditions, and it contributes to the pathogenesis of multiple human disorders, including cancer and cardiovascular diseases. miR-214 has dual functions in different cardiac pathological circumstances. However, it is considered as a promising marker in the prognosis, diagnosis and treatment of cardiovascular diseases. In this review, we discuss the role of miR-214 in various cardiac disease conditions, including ischaemic heart diseases, cardiac hypertrophy, pulmonary arterial hypertension (PAH), angiogenesis following vascular injury and heart failure. PMID- 28842126 TI - Immediate postpartum levonorgestrel intrauterine device insertion and breast feeding outcomes: a noninferiority randomized controlled trial. AB - BACKGROUND: Immediate postpartum levonorgestrel intrauterine device insertion is increasing in frequency in the United States, but few studies have investigated the effect of early placement on breast-feeding outcomes. OBJECTIVE: This study examined the effect of immediate vs delayed postpartum levonorgestrel intrauterine device insertion on breast-feeding outcomes. STUDY DESIGN: We conducted this noninferiority randomized controlled trial at the University of Utah and the University of New Mexico Health Sciences Centers from February 2014 through March 2016. Eligible women were pregnant and planned to breast-feed, spoke English or Spanish, were aged 18-40 years, and desired a levonorgestrel intrauterine device. Enrolled women were randomized 1:1 to immediate postpartum insertion or delayed insertion at 4-12 weeks' postpartum. Prespecified exclusion criteria included delivery <37.0 weeks' gestational age, chorioamnionitis, postpartum hemorrhage, contraindications to levonorgestrel intrauterine device insertion, and medical complications of pregnancy that could affect breast feeding. We conducted per-protocol analysis as the primary approach, as it is considered the standard for noninferiority studies; we also report the alternative intent-to-treat analysis. We powered the study for the primary outcome, breast-feeding continuation at 8 weeks, to detect a 15% noninferiority margin between groups, requiring 132 participants in each arm. The secondary study outcome, time to lactogenesis, used a validated measure, and was analyzed by survival analysis and log rank test. We followed up participants for ongoing data collection for 6 months. Only the data analysis team was blinded to the intervention. RESULTS: We met the enrollment target with 319 participants, but lost 34 prior to randomization and excluded an additional 26 for medical complications prior to delivery. The final analytic sample included 132 in the immediate group and 127 in the delayed group. Report of any breast-feeding at 8 weeks in the immediate group (79%; 95% confidence interval, 70-86%) was noninferior to that of the delayed group (84%; 95% confidence interval, 76-91%). The 5% difference in breast-feeding continuation at 8 weeks between the groups fell within the noninferiority margin (95% confidence interval, -5.6 to 15%). Time to lactogenesis (mean +/- SD) in the immediate group, 65.3 +/- 25.7 hours, was noninferior to that of the delayed group, 63.6 +/- 21.6 hours. The mean difference between groups was 1.7 hours (95% confidence interval, -4.8 to 8.2 hours), noninferior by log-rank test. A total of 24 intrauterine device expulsions occurred in the immediate group compared to 2 in the delayed group (19% vs 2%, P < .001), consistent with the known higher expulsion rate with immediate vs delayed postpartum intrauterine device insertion. No intrauterine device perforations occurred in either group. CONCLUSION: Our results of noninferior breast-feeding outcomes between women with immediate and delayed postpartum levonorgestrel intrauterine device insertion suggest that immediate postpartum intrauterine device insertion is an acceptable option for women planning to breast-feed and use the levonorgestrel intrauterine device. Expulsion rates are higher with immediate postpartum levonorgestrel intrauterine device insertion compared to delayed insertion, but this disadvantage may be outweighed by the advantages of immediate initiation of contraception. Providers should offer immediate postpartum intrauterine device insertion to breast-feeding women planning to use the levonorgestrel intrauterine device. PMID- 28842127 TI - Mechanistic insights into EgGST1, a Mu class glutathione S-transferase from the cestode parasite Echinococcus granulosus. AB - Glutathione transferases (GSTs) comprise a major detoxification system in helminth parasites, displaying both catalytic and non-catalytic activities. The kinetic mechanism of these enzymes is complex and depends on the isoenzyme which is being analyzed. Here, we characterized the kinetic mechanism of rEgGST1, a recombinant form of a cytosolic GST from Echinococcus granulosus (EgGST1), which is related to the Mu-class of mammalian enzymes, using the canonical substrates glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). Initial rate and product inhibition studies were consistent with a steady-state random sequential mechanism, where both substrates are bound to the enzyme before the products are released. Kinetic constants were also determined (pH 6.5 and 30 degrees C). Moreover, rEgGST1 lowered the pKa of GSH from 8.71 +/- 0.07 to 6.77 +/- 0.08, and enzyme-bound GSH reacted with CDNB 1 * 105 times faster than free GSH at pH 7.4. Finally, the dissociation of the enzyme-GSH complex was studied by means of intrinsic fluorescence, as well as that of the complex with the anthelminth drug mebendazole. This is the first report on mechanistic issues related to a helminth parasitic GST. PMID- 28842128 TI - Formulation optimization, characterization, and evaluation of in vitro cytotoxic potential of curcumin loaded solid lipid nanoparticles for improved anticancer activity. AB - The aim of the present research was to develop a novel, biocompatible, amenable to industrial scale up and affordable solid lipid nanoparticles (SLN) preparation of curcumin and evaluate the therapeutic efficacy in vitro using cancer cells. We have incorporated cholesterol as the lipid to prepare SLN along with the Poloxamer-188 as stabilizer. High shear homogenization was used to prepare the SLN and formulation was optimized using Quality by Design The optimized Chol CUR SLN exhibited a narrow size distribution with a particle size of 166.4+/-3.5nm. Percentage encapsulation (%EE) was found to be 76.9+/-1.9%. The SLN were further characterized by DSC, FTIR, XRD and drug release. In vitro cell studies in MDA-MB 231 (Human Breast cancer) cell line revealed that the Chol CUR SLN showed superior cytotoxicity and uptake in comparison to the free curcumin. Furthermore, Chol CUR SLN induced a significantly higher apoptosis compared to free CUR treatment. These results indicated that the curcumin encapsulated in Chol SLN was able to significantly improve the cytotoxic potential and induction of apoptosis in MDA-MB-231 cells. The promising result from our study could lead a further exploration of this nanoparticle formulation to be utilized clinically for cancer treatment. PMID- 28842129 TI - Leishmania tropica infected human lesions: Whole genome transcription profiling. AB - Leishmania (L.) tropica is the main causative agent of anthroponotic cutaneous leishmaniasis (CL) in Iran. Defining the host inflammatory response in the L. tropica lesions are crucial for the development of new treatment modalities. High throughput RNA sequencing provides a powerful method for characterization of the human gene expression profile in L. tropica lesions. Comparing the transcription profile of the L. tropica skin lesions with normal skin identified over 5000 differentially regulated genes. Gene set enrichment analysis indicated significant activation of key immunological pathways related to antigen processing and presentation. In addition, we observed a substantial upregulation of immunoglobulin genes in lesion samples, highlighting the remarkable involvement of B cells in the infection site. To our knowledge, this study is the first report to build a comprehensive picture of transcriptome changes in acute human skin lesions during infection by L. tropica. PMID- 28842130 TI - Proteolytic steps within signaling cascades make these signaling pathways irreversible. PMID- 28842131 TI - Co-resident plasmids travel together. AB - Conjugative plasmids encode genes that enable them to transfer, by conjugation, from a given host cell to another cell. Conjugative transfer, despite being an important feature of conjugative plasmids, is not constitutive for most plasmids, the reason being that genes involved in horizontal transfer are mostly repressed. Only upon their transient de-repression are plasmids able to transfer horizontally. If host cells harbour multiple plasmids, their simultaneous transfer depends on simultaneous transient de-repression of all plasmids. If de repression of different plasmids was random and independent events, simultaneous de-repression should be a rare event because the probability of simultaneous de repression would be the product of the probabilities of de-repression of each plasmid. Some previous observations support this hypothesis, while others show that co-transfer of plasmids is more frequent than this reasoning indicates. Here, we show that co-transfer of multiple plasmids mainly results from non independent events: the probability that all plasmids within a cell become de repressed is much higher than if de-repression of plasmids genes were independent. We found a simple model for the probability of co-transfer: the plasmid having the lowest conjugation rates is the one who limits co-transfer. In this sense, cells receiving the plasmid with the lower transfer rate also receive the other plasmid. If de-repression happens simultaneously on co-resident plasmids, common cues may stimulate de-repression of distinct plasmids. PMID- 28842132 TI - Conjugation efficiency depends on intra and intercellular interactions between distinct plasmids: Plasmids promote the immigration of other plasmids but repress co-colonizing plasmids. AB - Conjugative plasmids encode the genes responsible for the synthesis of conjugative pili and plasmid transfer. Expression of the conjugative machinery (including conjugative pili) may be costly to bacteria, not only due to the energetic/metabolic cost associated with their expression but also because they serve as receptors for certain viruses. Consequently, the presence of two plasmids in the same cell may be disadvantageous to each plasmid, because they may impose a higher fitness cost on the host. Therefore, plasmids may encode mechanisms to cope with co-resident plasmids. Moreover, it is possible that the transfer rate of a plasmid is affected by the presence of a distinct plasmid in the recipient cell. In this work, we measured transfer rates of twelve natural plasmids belonging to seven incompatibility groups in three situations, namely when: (i) donor cells contain a plasmid and recipient cells are plasmid-free; (ii) donor cells contain two unrelated plasmids and recipient cells are plasmid free; and (iii) half of the cells contain a given plasmid and the other half contain another, unrelated, plasmid. In the third situation, recipient cells of a plasmid are the donor cells of the other plasmid. We show that there are more negative interactions (reduction of a plasmid's conjugative efficiency) between plasmids if they reside in the same cell than if they reside in different cells. However, if plasmids interacted intercellularly, the transfer rate of one of the plasmids was often higher (when the unrelated conjugative plasmid was present in the recipient cell) than if the recipient cell was plasmid-free - a positive effect. Experimental data retrieved from the study of mutant plasmids not expressing conjugative pili on the cell surface suggest that positive effects result from a higher efficiency of mating pair formation. Overall, our results suggest that negative interactions are significantly more frequent when plasmids occupy the same cell. Such interactions may determine how antibiotic resistance disseminates in bacterial populations. PMID- 28842133 TI - Multiple plasmid interference - Pledging allegiance to my enemy's enemy. AB - As shown in the previous article, two distinct conjugative plasmids sometimes interact within bacterial cells, implicating changes of transfer rates. In most cases of interactions within bacteria, the transfer of one of the plasmids decreases. Less frequently, the transfer rate of one of the plasmids increases. Here we analyse what happens if three distinct conjugative plasmids colonize the same bacterial cell. Our aim is to understand how interactions between two plasmids affect the transfer rate of the third plasmid. After showing that plasmids interact in 59 out of 84 possible interactions we show that, with some exceptions, if the transfer rate of a plasmid decreases in the presence of a second plasmid, a decrease is also observed in the presence of a third plasmid. Moreover, if the conjugation rate of a plasmid increases in the presence of another, an increase is also observed if there is a third plasmid in the cell. Both types of interactions are mostly independent of the third plasmid's identity, even if sometimes the third plasmid quantitatively distorts the interaction of the other two plasmids. There is a bias towards negative intensifying interactions, which provide good news concerning the spread conjugative plasmids encoding antibiotic-resistance genes and virulence factors. PMID- 28842134 TI - Reciprocal complementation of bovine parainfluenza virus type 3 lacking either the membrane or fusion gene. AB - Two defective bovine parainfluenza virus type 3 (BPIV3) strains were generated, one lacking the membrane (M) protein gene and expressing EGFP (DeltaM-EGFP) and the other lacking the fusion (F) protein gene and expressing mStrawberry (DeltaF mSB), by supplying deficient proteins in trans. When Madin-Darby bovine kidney (MDBK) cells were co-infected with DeltaM-EGFP and DeltaF-mSB at a multiplicity of infection (MOI) of 0.1, complemented viruses were easily obtained. Complemented viruses grew as efficiently as wild-type BPIV3 and could be passaged in MDBK cell cultures even at an MOI of 0.01, possibly due to multiploid virus particles containing genomes of both DeltaM-EGFP and DeltaF-mSB. This reciprocal complementation method using two defective viruses would be useful to express large or multiple proteins in cell cultures using paramyxovirus vectors. PMID- 28842135 TI - New Series: SOHO 'State of the Art Updates and Next Questions'. PMID- 28842136 TI - Philadelphia Chromosome-like Acute Lymphoblastic Leukemia. AB - Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described B-cell precursor ALL with a gene expression profile and a high frequency of IKZF1 gene alteration similar to that of Ph-positive ALL. Its prevalence is approximately 12% in children, 21% in adolescents (16-20 years of age), and 20% to 24% in adults older than 40 years, with a peak (27%) in young adults 21 to 39 years old. It occurs more often in male individuals and patients with Down syndrome. Ph-like ALL is overrepresented in those with Hispanic ethnicity and is associated with inherited genetic variants in GATA3 (rs3824662). It is a clinically and biologically heterogeneous subtype of B-ALL. Although most patients with Ph-like ALL have positive minimal residual disease after remission induction and poor event-free survival, approximately 40% of pediatric patients responded well to chemotherapy and can be cured with relatively low intensity of treatment. The treatment outcome correlated negatively with increasing age at presentation. Ph-like ALL is characterized by a wide range of genetic alterations that dysregulate several cytokine receptor and kinase signaling pathways, including CRLF2 rearrangement in half of the cases and translocation of nonreceptor tyrosine kinases (predominantly ABL-class and Janus kinases). Patients with ABL-class fusions respond clinically to ABL1 tyrosine kinase inhibitors, whereas mutations activating the JAK-STAT pathway are amendable to treatment with JAK inhibitors in vitro or in preclinical models. Prospective studies are needed to determine if incorporation of tyrosine kinase inhibitor targeting kinase alterations into intensive chemotherapy regimens will improve outcome of patients with Ph-like ALL. PMID- 28842137 TI - Rituximab Improves the Outcome of Patients With Grade 3 Follicular Lymphoma Receiving Anthracycline-Based Therapy. AB - BACKGROUND: The combination of rituximab with chemotherapy has improved the outcome of patients with follicular lymphoma (FL). However, data on Grade 3 FL (FL3) and its subtypes are lacking. The aims of the study were to determine: (1) the clinical features and outcome of patients with FL3 treated with rituximab and anthracycline-based chemotherapy; and (2) the clinical significance of the 3 subtypes of FL3. PATIENTS AND METHODS: Eighty-seven patients with Grade 1/2 FL, 84 with FL3 including 46 FL3A, 17 FL3B, and 21 follicular large cleaved cell (FL3C), and 411 patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab and anthracycline-based chemotherapy, and a historical cohort of 167 patients with FL3 who received only anthracycline-based chemotherapy (FL3*) were included in this retrospective study. RESULTS: The FL3 group had a significantly better overall survival (OS) and event-free survival (EFS) compared with those with FL3* or DLBCL. No significant differences in OS were found among the 3 subtypes of FL3. However, patients with FL3B had a shorter EFS than those with FL3A and FL3C. Moreover, patients with FL3B had an outcome similar to those with DLBCL, whereas patients with FL3A and 3C had significantly better outcomes than those with DLBCL. Less than 50% of the patients with FL3B and less than 20% of the patients with FL3A and 3C have relapsed, and relapses were uncommon after 5 years. CONCLUSION: The use of rituximab with anthracycline-based chemotherapy significantly improved the survival of patients with FL3 and should be considered the benchmark by which other therapies for FL3 are evaluated in the future. PMID- 28842138 TI - Evaluation of Bortezomib-Induced Neuropathy Using Total Neuropathy Score (Reduced and Clinical Versions) and NCI CTCAE v4.0 in Newly Diagnosed Patients With Multiple Myeloma Receiving Bortezomib-Based Induction. AB - BACKGROUND: Bortezomib-induced peripheral neuropathy (BiPN) is a dose-limiting adverse effect of bortezomib-based therapy for multiple myeloma (MM). The reporting of BiPN is variable because of the use of different neuropathy scales. Most investigators use the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). PATIENTS AND METHODS: We prospectively evaluated the incidence of BiPN in treatment-naive patients with MM receiving weekly cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in 28-day cycles using 3 neuropathy scores: Total Neuropathy Score-reduced (TNSr) and -clinical (TNSc), and NCI CTCAE v4.0. RESULTS: Twenty-six patients received CyBorD. Twenty patients completed follow-up. The rates of occurrence of BiPN were as follows: TNSr - 55% (n = 11), TNSc - 40% (n = 8), and NCI CTCAE - 45% (n = 9). All 3 scales showed worsening after treatment (P < .01). When compared to BiPN by TNSr, sensitivities for NCI CTCAE and TNSc were 77.8% and 88.9%, respectively. Specificity was 63.3% for both NCI CTCAE and TNSc. Among 12 patients who did not have BiPN by NCI CTCAE scale, 41.7% (n = 5) and 16.7% (n = 2) patients satisfied the criteria for BiPN by TNSr and TNSc, respectively. The higher detection rate of neuropathy by TNSr and TNSc is probably due to increment in scores that are allotted for increase in anatomic extent of sensorimotor involvement, unlike the NCI CTCAE scale, which requires functional limitation for increase in grade. CONCLUSION: NCI CTCAE may be suboptimal in comparison to TNSr and TNSc in assessment of BiPN because it may miss worsening neuropathy without functional limitation. PMID- 28842139 TI - Daunorubicin 90 mg/m2 in Acute Myeloid Leukemia Induction: Increased Toxicity in Young Patients. AB - BACKGROUND: The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia for more than 3 decades. The clinical benefit of intensification of the daunorubicin dose to 90 mg/m2 has been supported by randomized trials. Based on these promising results, in 2010 we changed our induction protocol of acute myeloid leukemia, increasing the dose of daunorubicin. PATIENTS AND METHODS: We retrospectively analyzed the treatment outcome of patients treated with high-dose daunorubicin (90 mg/m2 on days 1-3) and cytosine arabinoside (200 mg/m2/day continuous infusion on days 1 7) compared with patients receiving 45 to 60 mg/m2 of daunorubicin. Twenty-six previously untreated patients younger than 60 years of age were included. Twelve received high-dose daunorubicin (HD) and 14 the low-dose (LD). Seventeen patients were in complete remission after 1 induction cycle. RESULTS: There was no overall difference in complete remission rate between HD and LD (66% vs. 64%; P = 1.0). Thirty-day induction mortality was 15.3% overall, with a nonsignificant difference between groups (25% vs. 7.1%; P = .3). Relapses were observed in 9 (53%) patients: 3 (37.5%) in the HD group and in 6 (66.6%) in the LD group (P = .34). Invasive fungal disease (41.6% vs. 0%; P = .012), creatinine elevation (P = .001), abdominal pain (33% vs. 0%; P = .033), and need for intensive care unit admission (33.3% vs. 0%; P = .033) were more frequent in the HD group. Four patients in the HD group developed neutropenic enterocolitis (P = .033). CONCLUSION: These data indicate that 90 mg/m2 of daunorubicin increased the toxicity compared with lower doses. PMID- 28842140 TI - Blastic Transformation in Mexican Population With Chronic Myelomonocytic Leukemia. AB - BACKGROUND: Chronic myelomonocytic leukemia (CMML) is the most aggressive of chronic leukemias, with short overall survival and a high transformation rate to acute leukemia. We investigated the factors related to blastic transformation in a Mexican population treated at a tertiary referral center. PATIENTS AND METHODS: The records of patients with a diagnosis of CMML from 2000 to 2015 were reviewed. A total of 54 patients were included, with a median age of 71 years and an overall survival of 16 months. The patients with incomplete data were excluded. IBM SPSS Statistics, version 21.0, software was used to perform the statistical analysis. RESULTS: The rate of blastic transformation was 33% (18 patients), and the interval time to progression was 9 months (range, 0-87 months). Comparing the patients who did not undergo blastic transformation to those who did, those with progression to acute leukemia tended to be younger (age, 58 vs. 71 years; P = .001), to have a greater peripheral blood blast count (>= 2% vs. 0%; P = .003), and were more likely to have immature myeloid precursors circulating in the peripheral blood (94% vs. 64%; P = .02). On multivariate analysis, younger age continued to be a statistically significant factor for progression (hazard ratio, 0.97; 95% confidence interval, 0.929-0.987). CONCLUSION: Mexican patients with CMML that progressed to overt acute leukemia were considerably younger, with a higher tumor burden and short overall survival. In this population, it is important to consider more aggressive treatment at diagnosis, focusing on high dose chemotherapy and hematopoietic stem cell transplantation within a short period. PMID- 28842141 TI - Defibrotide Use in Vincristine-induced Hepatic Sinusoidal Obstruction Syndrome. PMID- 28842142 TI - Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. AB - Many health benefits are attributed to vitamin D, with those findings supported mostly by observational outcome studies of relationships to serum 25 hydroxyvitamin D [25(OH)D]. However, many randomized controlled trials (RCTs) aiming to confirm those findings have failed, perhaps because serum 25(OH)D is an index of UVB exposure and non-vitamin D mechanisms or because disease reduces serum 25(OH)D content. But the most likely reason for that failure is inappropriate design, conduct, analysis, and interpretation of RCTs. Most RCTs used principles designed to test pharmaceutical drugs; that design incorporates the assumptions that the RCT is the sole source of the agent and that dose response relationships are linear. However, neither assumption is true for vitamin D, since neither vitamin D dose-responses or health outcome-serum 25(OH)D concentration relationships are linear-larger changes being induced with low rather than high baseline 25(OH)D values. Here, we propose a hybrid observational approach to vitamin D RCT design, based primarily on serum 25(OH)D concentration, requiring an understanding of serum 25(OH)D concentration-health outcome relationships, measuring baseline 25(OH)D values, recruiting non-replete subjects, measuring serum 25(OH)D during the trial for adjustment of supplemental doses for achievement of pretrial selection of target 25(OH)D values, where possible, and analyzing health outcomes in relation to those data rather than solely to vitamin D dosages. PMID- 28842143 TI - Gender Differences in the Trends of Hospitalizations for Acute Stroke Among Patients With Atrial Fibrillation in the United States: 2005 to 2014. AB - Female gender was included in stroke prediction algorithms in an attempt to improve anticoagulation rates in women with atrial fibrillation (AF). It is unclear if these efforts reduced stroke burden in women with AF. To bridge this literature gap, using the Nationwide Inpatient Sample, we assessed gender differences in the trends of hospitalizations for stroke among patients with AF in the United States in 2005 to 2014. International classification of diseases, 9th revision, clinical modification codes were used to abstract AF and stroke diagnoses. From 2005 to 2014, 18,413,291 hospitalizations of women with AF and 18,035,866 hospitalizations of men with AF were reported. Of these, 740,635 hospitalizations in women and 595,730 hospitalizations in men had stroke as the primary diagnosis. Age-adjusted stroke hospitalizations increased in women (443 per million in 2005 to 495 per million in 2014) as well as in men (351 per million in 2005 to 453 per million in 2014) (p trend < 0.001). Further, anticoagulation rates increased in women (11.5% in 2005 to 24.0% in 2014) as well as in men (11.7% in 2005 to 24.9% in 2014). Stroke hospitalizations involving anticoagulated patients with AF decreased in women (411 per million in 2005 to 347 per million in 2014) as well as in men (402 per million in 2005 to 311 per million in 2014) (p trend < 0.001). In conclusion, although we noted an increasing trend of stroke hospitalizations in both genders, it is reassuring to note that stroke hospitalizations involving anticoagulated patients with AF is decreasing in both genders and in particular among women. PMID- 28842144 TI - Timing of Susceptibility to Mortality and Heart Failure in Patients With Preexisting Atrial Fibrillation After Transcatheter Aortic Valve Implantation. AB - The relationship between cardiac rhythm and adverse events after transcatheter aortic valve implantation (TAVI) remains unclear. To compare the prognostic impact of preexisting atrial fibrillation (AF) and new-onset AF (NOAF) after TAVI, we assessed 1,124 patients (846 with sinus rhythm [SR], 49 with NOAF, and 229 with preexisting AF) who underwent TAVI with a balloon-expandable valve from October 2013 to April 2016. The incidences of all-cause death and rehospitalization for heart failure (HF) were retrospectively evaluated. The median follow-up period was 370 days (range 188 to 613). In the Kaplan-Meier analysis, the incidences of all-cause death and rehospitalization for HF were significantly higher in patients with preexisting AF than those in patients with NOAF and SR. The multivariable analysis showed that preexisting AF was significantly associated with increased all-cause death (hazard ratio [HR] 1.54; 95% confidence interval [CI] 1.02 to 2.34) and rehospitalization for HF (HR 2.94; 95% CI 1.75 to 4.93). The landmark analysis demonstrated that patients with preexisting AF had a significantly higher incidence of rehospitalization for HF within the first 6 months after TAVI (HR 4.04; 95% CI 2.23 to 7.32), and a higher incidence of all-cause death from 6 months to 2 years after TAVI (HR 2.12; 95% CI 1.15 to 3.90). Our study demonstrated that preexisting AF increased the risk of all-cause death and rehospitalization for HF after TAVI in comparison with NOAF or SR. Moreover, there was a specific timing of susceptibility to all-cause death and rehospitalization for HF after TAVI. PMID- 28842145 TI - Cost-Effectiveness of Multidisciplinary Management Program and Exercise Training Program in Heart Failure. AB - Heart failure causes significant health and financial burdens for patients and society. Multidisciplinary management program (MMP) and exercise training program (ETP) have been reported as cost-effective in improving health outcomes, yet no study has compared the 2 programs. We constructed a Markov model to simulate life year (LY) gained and total costs in usual care (UC), MMP, and ETP. The probability of transitions between states and healthcare costs were extracted from previous literature. We calculated the incremental cost-effectiveness ratio (ICER) over a 10-year horizon. Model robustness was assessed through 1-way and probabilistic sensitivity analyses. The expected LY for patients treated with UC, MMP, and ETP was 7.6, 8.2, and 8.4 years, respectively. From a societal perspective, the expected cost of MMP was $20,695, slightly higher than the cost of UC ($20,092). The cost of ETP was much higher ($48,378) because of its high implementation expense and the wage loss it incurred. The ICER of MMP versus UC was $976 per LY gained, and the ICER of ETP versus MMP was $165,702 per LY gained. The results indicated that, under current cost-effectiveness threshold, MMP is cost-effective compared with UC, and ETP is not cost-effective compared with MMP. However, ETP is cost-effective compared with MMP from a healthcare payer's perspective. PMID- 28842146 TI - Clinical and Prognostic Value of the Electrocardiogram in Patients With Acute Occlusion of the Left Circumflex Coronary Artery. AB - The utility of the electrocardiogram (ECG) in patients with acute left circumflex (LC) coronary occlusion is not established. This study aimed at determining the clinical, angiographic, and prognostic characteristics associated with the different patterns of ST-segment changes in patients with LC occlusion. A cohort of 314 patients with LC occlusion was categorized according to the admission ECG: (1) ST-segment elevation (ST-E, n=208), (2) isolated ST-segment depression in precordial leads (ST-D, n=62), and (3) negligible ST-segment changes (No-ST, n=44). Clinical variables, coronary angiography, and 30-day major adverse cardiac event (MACE) (in-hospital ventricular fibrillation, 1-month mortality, or heart failure) were compared among the three groups. As compared with No-ST, patients with ST-E or ST-D presented more advanced Killip class, higher troponin peak, lower LV ejection fraction, and were independently associated with MACE (odds ratio 5.43, 95% confidence interval 1.09 to 27.20 and odds ratio 3.39, 95% confidence interval 0.66 to 17.50, respectively). Patients with ST-D were tardily reperfused, had more often mitral regurgitation (23.1% vs 9.3% in ST-E and 3.3% in No-ST, p=0.03), and presented ST-segment elevation in leads V7 to V9 in 12 of 16 cases with available recordings. Culprit proximal LC predominated in ST-D (41.9%), distal LC in ST-E (42.8%), and obtuse marginal in No-ST (59.1%) (all p<0.01). The No-ST had smaller coronary vessels and more collaterals. In conclusion, the three ST-segment patterns of LC occlusion identify patients with different clinical, angiographic, and prognostic characteristics. Patients with ST-depression pattern require a prompt reperfusion therapy and could be better recognized by recording leads V7 to V9. PMID- 28842147 TI - Comparison of In-Hospital Outcomes After Percutaneous Revascularization for Peripheral Arterial Disease in Patients With a Body Mass Index of >30 kg/m2 Versus <=30 kg/m2 (from the National Inpatient Sample). AB - Obesity is an independent risk factor for cardiovascular disease and mortality which may affect the outcomes of patients with peripheral arterial disease (PAD). However, the exact role of obesity in patients with PAD who underwent percutaneous revascularization is not well defined. We sought to analyze in hospital outcomes and characteristics in obese patients who underwent percutaneous treatment for PAD. We identified study cohorts who underwent percutaneous treatment for PAD from 2012 to 2014 using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic and procedures codes specific for PAD and endovascular treatment. Endovascular treatment included a drug-eluting stent, a bare metal stent, and an atherectomy or angioplasty in the lower extremities. Obesity was defined as a body mass index of >30 kg/m2. Patients below 18 years of age were excluded. A total of 62,445 (weighted 312,225) patients were identified. The mean age was higher in the nonobese group (64.2 vs 69.0 years, p <=0.001). No difference existed in the primary outcome, in-hospital mortality, with the propensity score matched (1:10) analysis. Renal failure and the composite of complications were increased in obese patients. Percutaneous treatment of PAD was associated with increased length of stay (7.7 vs 7.0 days, p <=0.001) and median cost of hospitalization ($30,602 vs $28,692, p <=0.001) in obese patients. In conclusion, obesity did not impact in-hospital mortality in patients who underwent peripheral percutaneous revascularization. Increased adverse events, however, were seen in the obese population. The increased cost associated with the hospitalization of obese patients may be attributed to longer length of stay and greater complication. PMID- 28842148 TI - Immune and metabolic alterations following trauma and sepsis - An overview. PMID- 28842149 TI - The History of Japanese Anesthesiology. AB - Anesthesia in Japan has a 200-year history, beginning when Seishu Hanaoka first conducted surgery successfully under general anesthesia in 1804. Despite common belief, Hanaoka was not secretive about his technique using Mafutsusan, and he spawned a generation of Japanese anesthetists, including Gendai Kamada, author of several influential texts. Japanese anesthetists adopted inhalational techniques as they became available. In 1954, the Japanese Society of Anesthesiologists was established; in 1960, "Anesthesiology" was accredited by Japanese government as an officially approved medical specialty; and in 1963, board examinations were established to be an instructor of anesthesia. In 2011, the Japanese Museum of Anesthesiology opened in Kobe, with the mission to collect and preserve literature and equipment related to the history of Japanese anesthesia (Figure 1). PMID- 28842150 TI - Henry Jacob Bigelow: Scholar and Antischolar. PMID- 28842151 TI - Adoniram Judson Shurtleff: a Tragic Picture of Anesthetic Drug Abuse. AB - A previously unpublished carte-de-visit depicts Massachusetts dentist Adoniram Judson Shurtleff, who died at 41 years of age while abusing nitrous oxide in 1885. PMID- 28842152 TI - Edison Etheroscope. PMID- 28842153 TI - Perry Davis' Pain Killer: America's First Nationally Advertised Drug for Analgesia? AB - Perry Davis' Pain Killer, a combination of opium, alcohol, and other substances, was formulated in 1839 and marketed successfully worldwide within 4 decades as both an internal and external pain remedy. PMID- 28842154 TI - Correspondence Dated April 17, 1848, from Charles T. Jackson, MD, to John Snow, MD. AB - A previously unpublished four-page letter from Charles T. Jackson, MD, to John Snow, MD, was acquired in December 2016 by the Wood Library-Museum of Anesthesiology, Schaumburg, IL. The letter may be a draft or a copy of the letter which may have been sent to Snow in 1848. Jackson's letter to Snow does not reveal any significant new insight into the controversy over the discovery of etherization. A hitherto unknown meeting of Jackson's former chemistry student, Joseph Peabody, and John Snow, MD, was revealed in the letter. PMID- 28842155 TI - The History of One-Lung Anesthesia and the Double-Lumen Tube. AB - One-lung anesthesia presents many practical, anatomical, and physiological challenges to the anesthetist in modern day practice. The techniques and equipment that we use today have developed slowly over the course of the last century. The idea of isolated lung ventilation came from bronchospirometry studies by pioneering physiologists as early as 1871, and some of their original equipment was adapted for clinical use in the 1930s. Anesthetic techniques have generally been developed to facilitate surgical advances, and the development of double-lumen tubes is no exception. The development of the double-lumen tube was sporadic and occurred mainly to allow more complex thoracic procedures, mostly associated with suppurative lung disease. Once the need for independent ventilation of the lungs was identified in clinical practice, pioneers of the technique developed their own methods and often their own equipment. This led to the ability of the anesthetist to be able to control ventilation to each lung, including collapse of the operative lung and protection of the isolated lung against contamination. As these anesthetics became more reliable, the surgical scope for one-lung anesthesia began to broaden, and today one-lung ventilation is used to facilitate thoracic surgery, mainly on the lung, but also esophageal, thoracic wall, and mediastinal surgical procedures. PMID- 28842156 TI - Beyond Ether and Chloroform-A Major Breakthrough With Halothane. AB - BACKGROUND: The use of equipment powered by electricity in the operating room increased the risk of fires in the presence of flammable agents such as ether and cyclopropane. Chloroform was associated with cardiac arrhythmias and liver damage. The introduction of halothane in the late 1950s was heralded as a solution to many problems facing the specialty of anesthesia. We explore whether the manufacturer promptly reported halothane's adverse effects to regulatory agencies and practitioners. SOURCES: We consulted documents submitted by Ayerst Laboratories to federal authorities through the Freedom of Information Act, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Two major complications associated with the use of halothane, cardiac arrhythmias and the risk of hepatotoxicity, were disclosed by the manufacturer when the drug was first introduced to the US market. Reports appeared timely and complete; there was no apparent attempt to conceal or otherwise downplay these risks. CONCLUSION: The process of drug discovery and approval for clinical use has always been a lengthy, complex, and extremely expensive undertaking, with only a small minority of compounds receiving approval. The risk of adverse effects or drug interaction directly impacts commercial viability. In the case of halothane, the manufacturer disclosed major adverse effects, and the drug enjoyed decades of popularity until it was replaced by agents with a better drug profile. PMID- 28842157 TI - A UK Civil Aviation Authority protocol to allow pilots with insulin-treated diabetes to fly commercial aircraft. PMID- 28842158 TI - Issues with European guidelines for phenylketonuria. PMID- 28842159 TI - Issues with European guidelines for phenylketonuria - Authors' reply. PMID- 28842160 TI - Meta-analysis of artificial pancreas trials: methodological considerations - Authors' reply. PMID- 28842161 TI - Meta-analysis of artificial pancreas trials: methodological considerations. PMID- 28842162 TI - Correction to Lancet Diabetes Endocrinol 2017; 5: 524-33. PMID- 28842163 TI - Validated spectrophotometric and chromatographic methods for analysis of the recently approved hepatitis C antiviral combination ledipasvir and sofosbuvir. AB - This work describes five simple and reliable spectrophotometric and chromatographic methods for analysis of hepatitis C antiviral binary mixture of ledipasvir (LPV) and sofosbuvir (SBV). Method I is based on the use of Amax and derivative spectrophotometry with the zero-crossing technique where LPV was determined using its Amax and 1D amplitudes at 324 and 338nm respectively, while SBV was determined by measuring the 1D amplitudes at 276nm. Method II involves the application of the ratio spectra derivative spectrophotometry. For LPV, 12MUg/mL SBV was used as divisor and the 1DD amplitudes at 239.8nm were plotted against LPV concentrations; while by using 10MUg/mL LPV, the amplitudes at 279.2nm were found proportional to SBV concentrations. Method III depends on ratio-difference measurement where the peak to trough amplitudes between 229.2 and 268.4nm were measured and correlated to LPV concentration. Similarly, the amplitudes between 268.6 and 229.2nm in the SBV ratio spectra were recorded. For method IV, the two compounds were separated using HPTLC sheets of silica gel and a mobile phase composed of chloroform-methanol (94:6) followed by densitometric measurement of LPV and SBV spots at 331 and 267nm respectively. Method V depends on HPLC-DAD. Effective chromatographic separation was achieved using Thermohypersil C8 column (4.6*250mm, 5MUm) with a mobile phase consisting of 0.01M sodium dihydrogen phosphate (pH 2.5) and methanol (20:80) at a flow rate 1.2mL/min and detection at 332 and 262nm for LPV and SBV respectively. Analytical performance of the developed methods was validated according to the ICH guidelines with respect to linearity, ranges, precision, accuracy, detection and quantification limits. The validated methods were successfully applied to the simultaneous analysis of LPV and SBV in mixtures of different proportions and their combined tablet dosage form. PMID- 28842164 TI - Colorectal cancer screening in rural and poor-resourced communities. AB - To test the efficacy of a community-based intervention, Empowering Communities for Life (EC4L), designed to increase colorectal cancer (CRC) screening through fecal occult blood test (FOBT) in rural underserved communities in a randomized controlled trial. Participants were randomized into 3 groups (2 interventions and 1 control). Interventions were delivered by community lay health workers or by academic health professionals. The main outcome of interest was return rate of FOBT screening kit within 60 days. Participants included 330 screening-eligible adults. The overall return rate of FOBT kits within 60 days was 32%. The professional group (Arm 2) had the highest proportion of returned FOBTs within 60 days at 42% (n = 46/110), a significantly higher return rate than the lay group (Arm 1) [28%(n = 29/103);P = 0.0422] or control group (Arm 3) [25%(n = 29/117);P = 0.0099]. Thus, one arm (Arm 2) of our intervention produced significantly higher CRC screening through FOBT. Community-based participation partnered with academic health professionals enhanced CRC screening among rural and poor resourced communities. PMID- 28842165 TI - Chronic Kidney Disease, Basal Insulin Glargine, and Health Outcomes in People with Dysglycemia: The ORIGIN Study. AB - BACKGROUND: Early stages of chronic kidney disease are associated with an increased cardiovascular risk in patients with established type 2 diabetes and macrovascular disease. The role of early stages of chronic kidney disease on macrovascular outcomes in prediabetes and early type 2 diabetes mellitus is not known. In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, the introduction of insulin had no effect on cardiovascular outcomes compared with standard therapy. In this post hoc analysis of ORIGIN, we compared cardiovascular outcomes in subjects without to those with mild (Stages 1-2) or moderate chronic kidney disease (Stage 3). METHODS: Tauwo co-primary composite cardiovascular outcomes were assessed. The first was the composite end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes; and the second was a composite of any of these events plus a revascularization procedure, or hospitalization for heart failure. Several secondary outcomes were prespecified, including microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers. RESULTS: Complete renal function data were available in 12,174 of 12,537 ORIGIN participants. A total of 8114 (67%) had no chronic kidney disease, while 4060 (33%) had chronic kidney disease stage 1-3. When compared with nonchronic kidney disease participants, the risk of developing the composite primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in those with mild to moderate chronic kidney disease was 87% higher; hazard ratio (HR) 1.87; 95% confidence interval (CI), 1.71-2.04 (P < .0001). The presence of chronic kidney disease 1-3 was also associated with a greater than twofold higher risk for both all-cause mortality (HR 2.17; 95% CI, 1.98-2.38; P < .0001) and cardiovascular mortality (HR 2.39; 95% CI, 2.13-2.69; P < .0001). Moreover, patients with mild to moderate chronic kidney disease had significantly higher risk for nonfatal myocardial infarction (50%), nonfatal stroke (68%), any stroke (84%), the above composite primary end point plus revascularization or heart failure requiring hospitalization (59%), or a major coronary artery disease event (56%). Furthermore, in patients with chronic kidney disease and early diabetes mellitus type 2, the primary end point occurred 83% more frequently as compared with nonchronic kidney disease participants (HR 1.83; 95% CI, 1.67-2.01; P < .001) and in patients with prediabetes and chronic kidney disease 67% more frequently (HR 1.67; 95% CI,1.25 2.24; P < .001). CONCLUSIONS: In high-risk patients with dysglycemia (prediabetes and early diabetes), mild and moderate chronic kidney disease significantly increased cardiovascular events. PMID- 28842167 TI - Direct visualization of IgG4-related cholangiopathy. PMID- 28842166 TI - The NuRD complex-mediated p21 suppression facilitates chemoresistance in BRCA proficient breast cancer. AB - The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex play a role in silencing gene expression. CHD4, the core component of the NuRD complex, which cooperates with histone deacetylase in reducing tumor suppressor genes (TSGs). To dissect the mechanisms underlying cancer promotion, we clarify the role of CHD4 in cyclin-dependent kinase inhibitor protein p21. Here, our data indicates that CHD4 deficiency impairs the recruitments of HDAC1 to the p21 promoter. ~ 300bp proximal promoter region is responsible for CHD4-HDAC1 axis-mediated p21 transcriptional activity. For identifying the role of anti-cancer drug response, knockdown of p21 overcomes cisplatin and poly-(ADP-ribose) polymerase (PARP) inhibitor-mediated growth suppression in CHD4-depleted cells. Consistent with in vitro data, tissue of patients and bioinformatics approach also showed positive correlation between CHD4 and p21. Overall, our findings not only identify that CHD4 deficiency preferentially impairs cell survival via increasing the level of p21, but also establishes targeting CHD4 as a potential therapeutic implication in BRCA-proficient breast cancer treatment. PMID- 28842168 TI - Stent migration into the abdominal cavity after EUS-guided hepaticogastrostomy. PMID- 28842169 TI - Esophageal cryoablation using retrograde per-gastrostomy ventilation in a patient with pharyngoesophageal stenosis. PMID- 28842170 TI - Acute suppurative cholangitis due to an impacted pancreatic stone: a rare adverse event in the setting of chronic calcified pancreatitis. PMID- 28842171 TI - Colistin-induced autophagy and apoptosis involves the JNK-Bcl2-Bax signaling pathway and JNK-p53-ROS positive feedback loop in PC-12 cells. AB - Our recent study demonstrated neurotoxicity of colistin-induced autophagy and apoptosis in PC-12 cells, and that autophagy reached peak level at 12 h. In this study, we scrutinized the role of JNK in colistin-induced neurotoxicity and demonstrated the relationship among JNK, p53 and ROS in colistin treated PC-12 cells. Colistin-induced autophagy and apoptosis by JNK inhibition/activation were examined by western blotting, electron microscopy, and immunofluorescence/fluorescence microscopy. The results indicated that colistin induced JNK activation reached peak level at 12 h, while the highest levels of p Bcl2/Bcl2 were observed at 12 h and Bax/Bcl2 significantly increased in a time dependent manner. In PC-12 cells, inhibition of JNK by SP600125 (JNK inhibitor) resulted in significantly lower levels of autophagy upon colistin treatment, depending on the expression levels of Beclin1, LC3-II, p62 degradation and reduction in the number of autophagic vacuoles. In contrast, anisomycin pretreatment PC-12 cells led to upregulated autophagy. Especially, the highest levels of Beclin1 and p-Bcl2/Bcl2 were observed at 6 h, and Bax/Bcl2, cleaved caspase3 and cleaved-PARP significantly increased in a time-dependent manner. The results revealed that JNK activation mediated autophagy and apoptosis related to Beclin1-Bcl2 and Bax-Bcl2 complex in colistin-treated PC-12 cells. Silencing of p53 by siRNA before colistin treatment substantially reduced ROS production and transactivated JNK in PC-12 cells. Moreover, activation of JNK increased ROS generation in PC-12 cells. In conclusion, colistin-induced autophagy and apoptosis is correlated to JNK-Bcl2-Bax signaling pathway, and an interaction effect found between intracellular ROS level and JNK-p53 signaling pathway in apoptosis. PMID- 28842172 TI - Micropipette aspiration of the Pacinian corpuscle. AB - The Pacinian corpuscle (PC) is a cutaneous mechanoreceptor sensitive to high frequency vibrations (20-1000Hz). The PC is of importance due to its integral role in somatosensation and the critical need to understand PC function for haptic feedback system development. Previous theoretical and computational studies have modeled the physiological response of the PC to sustained or vibrating mechanical stimuli, but they have used estimates of the receptor's mechanical properties, which remain largely unmeasured. In this study, we used micropipette aspiration (MPA) to determine an apparent Young's modulus for PCs isolated from a cadaveric human hand. MPA was applied in increments of 5mm H2O (49Pa), and the change in protrusion length of the PC into the pipette was recorded. The protrusion length vs. suction pressure data were used to calculate the apparent Young's modulus. Using 10 PCs with long-axis lengths of 2.99+/ 0.41mm and short-axis lengths of 1.45+/-0.22mm, we calculated a Young's modulus of 1.40+/-0.86kPa. Our measurement is on the same order of magnitude as those approximated in previous models, which estimated the PC to be on the same order of magnitude as skin or isolated cells, so we recommend that a modulus in the kPa range be used in future studies. PMID- 28842173 TI - MicroRNAs and bioactive compounds on TLR/MAPK signaling in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune mediated joint disease with severe complications affecting 1% of the population worldwide. Although the exact mechanism underlying the aggravation of RA remains unknown, its occurrence can lead to joint degradation and functional disability. Recent evidences have shown that the aberrant expression of microRNAs (miRNAs) play a prominent role in the furtherance of RA. Over the last decade, various intensive studies have validated different microRNAs to be good candidates for diagnostic purposes and for monitoring the disease progression in various inflammatory diseases. A deeper understanding of the molecular mechanism through which miRNAs amplify the production of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and IL-17), pro inflammatory mediators, growth factors and MMPs will act as potential therapeutic targets. More importantly, several studies have briefly reported the crucial role of TLR dependent MAPK signaling pathway, which mediates the pathological features of RA. In this review, we summarize the recent findings and provide a detailed report of the molecular mechanism of microRNA along with the role of TLR/MAPK signaling pathway in RA. However, the major aim of this review is to correlate the aberrantly expressed microRNAs in TLR/MAPK pathway with various well reported bioactive compounds that can modulate these signaling pathways in rheumatoid arthritis. Targeting miRNA expression using specific bioactive compounds might be a potent and an effective target in RA treatment by suppressing the TLR/MAPK pathway. PMID- 28842174 TI - A fast and simple method for simultaneous measurements of 25(OH)D, 24,25(OH)2D and the Vitamin D Metabolite Ratio (VMR) in serum samples by LC-MS/MS. AB - BACKGROUND: Rapid, easy and reliable measurement of the major vitamin D metabolites is required in order to fulfill the needs of a clinical routine laboratory. To overcome these challenges, we have developed and validated a LC MS/MS method for the quantification of 25-hydroxyvitamin D2 and D3, epi-25 hydroxyvitamin D3 and 24,25-dihydroxyvitamin D3. METHODS: Sample preparation was based on precipitation and centrifugation of 100MUL of patient serum, followed by injection into the LC-MS/MS system. Samples from Vitamin D Standardization Program (n=80) and patient samples (n=281) have been compared with a reference LC MS/MS method. For the analytical validation NIST and Labquality quality control materials were used. RESULTS: Mean intra-assay and inter-assay imprecision were <6.0 and 6.4% and mean recoveries were within 95-104%. LOQ's were 0.5MUg/L for 24,25(OH)2D3, 1.1MUg/L for 25(OH)D3 and epi-25(OH)D3 and 1.7MUg/L for 25(OH)D2. A 3% bias obtained between the proposed and the reference method satisfies Vitamin D Standardization Program recommendations. CONCLUSIONS: We present a rapid, easy, reliable and cost-effective method completely adequate for routine testing, which permits the measurement of the ratio of 24,25-dihydroxyvitamin D to 25 hydroxyvitamin D, Vitamin D Metabolite Ratio (VMR), in serum samples. PMID- 28842175 TI - Metabonomics screening of serum identifies pyroglutamate as a diagnostic biomarker for nonalcoholic steatohepatitis. AB - OBJECTIVE: A key step in managing non-alcoholic fatty liver disease (NAFLD) is to differentiate nonalcoholic steatohepatitis (NASH) from simple steatosis (SS). METHOD: Serum samples were collected from three groups: NASH patients (N=21), SS patients (N=38) and healthy controls (N=31). High performance liquid chromatography-mass spectrometry (HPLC-MS) was used to analyse the metabolic profile of the serum samples. The acquired data were processed by multivariate principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) to identify novel metabolites. The potential biomarkers were quantitatively determined and their diagnostic power was further validated. RESULTS: A total of 56 metabolites were capable of distinguishing NASH from SS samples based on the OPLS-DA model. Pyroglutamate was found to be the most promising factor in distinguishing the NASH from SS groups. With an optimal cut-off value of 4.82mmol/L, the sensitivity and specificity of the diagnosis of NASH were 72% and 85%, respectively. The area under the receiver operating characteristic (AUROC) of the pyroglutamate levels of NASH versus SS patients was more than those of tumor necrosis factor-alpha, adiponectin and interleukin-8. CONCLUSION: These data suggest that pyroglutamate may be a new and useful biomarker for the diagnosis of NASH. PMID- 28842176 TI - Platelet-endothelial molecule SCUBE1 levels in patients with Behcet's disease: A preliminary study. PMID- 28842177 TI - Gross deletions in FBN1 results in variable phenotypes of Marfan syndrome. AB - BACKGROUND: A mutation in FBN1 is primarily attributed to Marfan syndrome (MFS). So far, >1800 unique FBN1 mutations have been identified, with the vast majority being single-nucleotide substitutions, small deletions, and insertions. The rearrangement of large fragments of FBN1 accounts for only 1.7% of all variants. The aim of this study was to investigate the characteristics of large genomic rearrangements in FBN1 among MFS patients and to evaluate the correlations between genotype and phenotype. METHODS: Systematic sequencing of the disease related genes FBN1, TGFBR1, and TGFBR2, was carried out previously for 26 unrelated patients with MFS. No small mutations were found. Subsequently, multiplex ligation-dependent probe amplification was performed for the detection of copy number variations in these patients. The breakpoints were determined by gap PCR and sequencing. Transcription level analysis was conducted in patients whose RNA sample was available. RESULTS: Four gross deletions were identified in FBN1. Three deletions (exons 6, 48-53, and 49-50) were predicted to be in-frame deletions; the remaining deletion (exons 1-36) was expected to induce the loss of one copy of the FBN1 gene. The breakpoints of these four deletions were cloned, and revealed deletion sizes of 16,551, 10,346, 4563, and 187,047bp, respectively. Patients with in-frame deletions of exons 48-53 and 49-50 showed severe clinical phenotypes; Patient with an exon 6 deletion showed mild potential MFS phenotypes. And the patient had classic MFS with a deletion of exons 1-36. CONCLUSIONS: We characterized four large genomic rearrangements in FBN1. FBN1 haploinsufficiency correlated with a classic MFS phenotype, while in-frame deletions between exons 24-53 of FBN1 tended to cause severe clinical phenotypes. PMID- 28842178 TI - Variance in estimated pairwise genetic distance under high versus low coverage sequencing: The contribution of linkage disequilibrium. AB - The mean pairwise genetic distance among haplotypes is an estimator of the population mutation rate theta and a standard measure of variation in a population. With the advent of next-generation sequencing (NGS) methods, this and other population parameters can be estimated under different modes of sampling. One approach is to sequence individual genomes with high coverage, and to calculate genetic distance over all sample pairs. The second approach, typically used for microbial samples or for tumor cells, is sequencing a large number of pooled genomes with very low individual coverage. With low coverage, pairwise genetic distances are calculated across independently sampled sites rather than across individual genomes. In this study, we show that the variance in genetic distance estimates is reduced with low coverage sampling if the mean pairwise linkage disequilibrium weighted by allele frequencies is positive. Practically, this means that if on average the most frequent alleles over pairs of loci are in positive linkage disequilibrium, low coverage sequencing results in improved estimates of theta, assuming similar per-site read depths. We show that this result holds under the expected distribution of allele frequencies and linkage disequilibria for an infinite sites model at mutation-drift equilibrium. From simulations, we find that the conditions for reduced variance only fail to hold in cases where variant alleles are few and at very low frequency. These results are applied to haplotype frequencies from a lung cancer tumor to compute the weighted linkage disequilibria and the expected error in estimated genetic distance using high versus low coverage. PMID- 28842180 TI - Purification of biomevalonate from fermentation broth and conversion of biomevalonate into biomevalonolactone. AB - Mevalonate (MVA) is a key compound of living organisms including bacteria, plants, and humans. MVA and mevalonolactone (MVL), a lactonized form of MVA, are important for pharmaceutical, cosmeceutical, and biotechnological applications. Although (R, S)-MVA with 50% enantiomeric purity is mainly produced by chemical synthesis, recently, microbial fermentation processes for MVA production have been considered as an alternative to the chemical synthesis because of high enantiomeric purity [(R)-MVA] and high titer. In the present study, bio-MVA produced by a fermentative process was decolorized by a charcoal-based method and then chemically transformed into bio-MVL without byproducts by means of phosphoric acid as an acid catalyst. The final bio-MVL was (R)-MVL with over 99% enantiomeric purity according to 1H NMR analysis. PMID- 28842179 TI - Roles of the F-domain in [FeFe] hydrogenase. AB - The role of accessory Fe-S clusters of the F-domain in the catalytic activity of M3-type [FeFe] hydrogenase and the contribution of each of the two Fe-S surface clusters in the intermolecular electron transfer from ferredoxin are both poorly understood. We designed, constructed, produced and spectroscopically, electrochemically and biochemically characterized three mutants of Clostridium acetobutylicum CaHydA hydrogenase with modified Fe-S clusters: two site-directed mutants, HydA_C100A and HydA_C48A missing the FS4C and the FS2 surface Fe-S clusters, respectively, and a HydA_DeltaDA mutant that completely lacks the F domain. Analysis of the mutant enzyme activities clearly demonstrated the importance of accessory clusters in retaining full enzyme activity at potentials around and higher than the equilibrium 2H+/H2 potential but not at the lowest potentials, where all enzymes have a similar turnover rate. Moreover, our results, combined with molecular modelling approaches, indicated that the FS2 cluster is the main gate for electron transfer from reduced ferredoxin. PMID- 28842181 TI - Splenic gammadelta T cell subsets can be separated by a novel mab specific for two CD45 isoforms. AB - CD45 isoforms have been identified in a variety of different species and mab against various isoforms have been instrumental to define cellular subsets. In the process of generating novel mab against chicken gammadelta T cells two mab with specificity for CD45 were identified and characterized. The analysis of the chicken CD45 genomic structure suggested three exons being involved in alternative splicing. We cloned and expressed the full length CD45 isoform and three shorter isoforms. While the 7D12 mab reacted with all of these isoforms, the 8B1 mab selectively reacted with two short isoforms lacking either exons 3 and 5 or exons 3, 5 and 6. As expected, the reactivity of 7D12 included all leukocyte subsets, also including thrombocytes. In contrast, the 8B1 mab only reacted with lymphocytes and monocytes. 8B1 expression was found on almost all blood alphabeta T cells, while a gammadelta T cell subset and virtually all B cells lacked 8B1 reactivity. The fraction of 8B1- alphabeta and gammadelta cells was larger in splenocytes as compared to PBL and there was also a population of 8B1+ splenic B cells. CD3 stimulation of splenic T cells resulted in upregulation of the 8B1 antigen on all T cells. Three-color immunofluorescence revealed differences in CD28 expression between the 8B1+ and 8B1- gammadelta T cell subsets with a higher CD28 expression level on 8B1- cells. The CD28 antigen was upregulated upon stimulation of the cells with IL-2 and IL-12. This novel mab will be a useful tool to further analyze chicken gammadelta T cells in more detail. PMID- 28842182 TI - The CC and CXC chemokine receptors in channel catfish (Ictalurus punctatus) and their involvement in disease and hypoxia responses. AB - Chemokines are vital regulators of cell mobilization for immune surveillance, inflammation, and development. Chemokines signal through binding to their receptors that are a superfamily of seven-transmembrane domain G-coupled receptors. Recently, a complete repertoire of both CC and CXC chemokines have been identified in channel catfish, but nothing is known about their receptors. In this study, a set of 29 CC chemokine receptor (CCR) genes and 8 CXC chemokine receptor (CXCR) genes were identified and annotated from the channel catfish genome. Extensive phylogenetic and comparative genomic analyses were conducted to annotate these genes, revealing fish-specific CC chemokine receptors, and lineage specific tandem duplications of chemokine receptors in the teleost genomes. With 29 genes, the channel catfish genome harbors the largest numbers of CC chemokine receptors among all the genomes characterized. Analysis of gene expression after bacterial infections indicated that the chemokine receptors were regulated in a gene-specific manner. Most differentially expressed chemokine receptors were up regulated after Edwardsiella ictaluri and Flavobacterium columnare infection. Among which, CXCR3 and CXCR4 were observed to participate in immune responses to both bacterial infections, indicating their potential roles in catfish immune activities. In addition, CXCR3.2 was significantly up-regulated in ESC susceptible fish, and CXCR4b was mildly induced in ESC-resistant fish, further supporting the significant roles of CXCR3 and CXCR4 in catfish immune responses. CXCR4b and CCR9a were both up-regulated not only after bacterial infection, but also after hypoxia stress, providing the linkage between bacterial infection and low oxygen stresses. These results should be valuable for comparative immunological studies and provide insights into their roles in disease and stress responses. PMID- 28842184 TI - Ring chromosome in myeloid neoplasms is associated with complex karyotype and disease progression. AB - Ring chromosome (RC) is a poorly understood genetic anomaly seen in myeloid neoplasms. This study aims to shed light on the clinical significance of this finding. We identified 96 cases of myeloid neoplasms with RC from 3 academic hospitals. Clinicopathologic features and overall (OS) and leukemia-free survival were reviewed and compared to cases of myeloid neoplasms lacking RC. We identified 59 acute myeloid leukemias (AML-RC) and 37 myelodysplastic syndromes (MDS-RC) with RC identified on routine karyotyping. Seventy-five percent of AML RC and 97% of MDS-RC had complex (>3 independent cytogenetic abnormalities) karyotypes. The median OS of AML-RC with complex karyotype was significantly shorter than AML-RC patients with a non-complex (<=3 independent cytogenetic abnormalities) karyotype (P=.001), but similar to AML patients with complex karyotype lacking RC (P=not significant). Compared to complex-karyotype MDS lacking RC, MDS-RC patients had shorter leukemia-free survival (P=.016) and a trend for shorter OS (P=.10). RCs were sometimes lost after therapy or appeared during disease relapse, suggesting that they may be associated with genetic instability. PMID- 28842183 TI - Pronounced and sustained cutaneous vasoconstriction during and following cyrotherapy treatment: Role of neurotransmitters released from sympathetic nerves. AB - Cryotherapy is a therapeutic technique using ice or cold water applied to the skin to manage soft tissue trauma and injury. While beneficial, there are some potentially detrimental side effects, such as pronounced vasoconstriction and tissue ischemia that are sustained for hours post-treatment. This study tested the hypothesis that this vasoconstriction is mediated by 1) activation of post synaptic alpha-adrenergic receptors and/or 2) activation of post-synaptic neuropeptide Y1 (NPY Y1) receptors. 8 subjects were fitted with a commercially available cryotherapy unit with a water perfused bladder on the lateral portion of the right calf. Participants were instrumented with four intradermal microdialysis probes beneath the bladder. The following conditions were applied at the four treatment sites: 1) control (Ringer solution), 2) combined post synaptic beta-adrenergic receptors and neuropeptide (NPY) Y1 receptors blockade (P+B site), 3) combined post-synaptic alpha-adrenergic receptor, beta-adrenergic receptor, and NPY Y1 receptor blockade (Y+P+B site), and 4) blockade of pre synaptic release of all neurotransmitters from the sympathetic nerves (BT site). Following thermoneutral baseline data collection, 1 degrees C water was perfused through the bladder for 30min, followed by passive rewarming for 60min. Skin temperature (Tskin) fell from ~34 degrees C to ~18.5 degrees C during active cooling across all sites and there was no difference between sites (P>0.05 vs. control for each site). During passive rewarming Tskin rose to a similar degree in all sites (P>0.05 relative to the end of cooling). In the first 20min of cooling %CVC was reduced at all sites however, this response was blunted in the BT and the Y+P+B sites (P>0.05 for all comparisons). By the end of cooling the degree of vasoconstriction was similar between sites with the exception that the reduction in %CVC in the Y+B+P site was less relative to the reduction in the control site. %CVC was unchanged in any of the sites during passive rewarming such that each remained similar to values obtained at the end of active cooling. These findings indicate that the initial vasoconstriction (i.e. within the 1st 20min) that occurs during cryotherapy induced local cooling is achieved via activation of post-synaptic alpha-adrenergic receptors; whereas nonadrenergic mechanisms predominate as the duration of cooling continues. The sustained vasoconstriction that occurs following cessation of the cooling stimulus does not appear to be related to activation of post-synaptic alpha-adrenergic receptors or NPY Y1 receptor. PMID- 28842185 TI - Early diagnosis of PI3Kdelta syndrome in a 2 years old girl with recurrent otitis and enlarged spleen. AB - Heterozygous gain of function mutations in the gene encoding p110delta subunit of PI3K have been recently associated with activated PI3K-delta syndrome (APDS), a novel combined immune deficiency characterized by recurrent sinopulmonary infections, lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. Here we report a dominant gain of function PIK3CD mutation (E1021K) in a patient presenting with recurrent otitis media, massive splenomegaly, and persistent EBV-viraemia. The immunological studies showed low IgA level, but normal IgM, IgG, and normal antibody response to diphtheria and tetanus toxoid vaccination. Analysis of B lymphocyte subsets revealed abnormal expansion of transitional B cells, and low percentage of switched CD27+IgD- and CD27+IgD+ memory B cells. Analysis of T cell compartment unveiled prevalence of terminally differentiated cells. This study suggests that PIK3CD gain of function mutations should be suspected despite incomplete phenotype in patients with early onset splenomegaly, persistent EBV viremia and abnormal B and T cell subsets despite normal IgG levels. Currently the optimal treatment is still debated, but prompt management can hopefully diminish incidence of severe long-lasting sequelae (i.e. bronchiectasis, ear and sinus damage). PMID- 28842186 TI - An altered blood-brain barrier contributes to brain iron accumulation and neuroinflammation in the 6-OHDA rat model of Parkinson's disease. AB - Brain iron accumulation is a common feature shared by several neurodegenerative disorders including Parkinson's disease. However, what produces this accumulation of iron is still unknown. In this study, the 6-hydroxydopamine (6-OHDA) hemi parkinsonian rat model was used to investigate abnormal iron accumulation in substantia nigra. We investigated three possible causes of iron accumulation; a compromised blood-brain barrier (BBB), abnormal expression of ferritin, and neuroinflammation. We identified alterations in the BBB subsequent to the injection of 6-OHDA using gadolinium-enhanced magnetic resonance imaging (MRI). Moreover, detection of extravasated IgG suggested that peripheral components are able to enter the brain through a leaky BBB. Presence of iron following dopamine cell degeneration was studied by MRI, which revealed hypointense signals in the substantia nigra. The presence of iron deposits was further validated in histological evaluations. Furthermore, iron inclusions were closely associated with active microglia and with increased levels of L-ferritin indicating a putative role for microglia and L-ferritin in brain iron accumulation and dopamine neurodegeneration. PMID- 28842188 TI - The changing aetiology of eosinophilia in migrants and returning travellers in the Hospital for Tropical Diseases, London 2002-2015: An observational study. AB - INTRODUCTION: Determining the cause of eosinophilia in patients returning from the tropics continues to present a diagnostic challenge. The history, symptoms and degree of eosinophilia are often poor predictors of eventual diagnosis, but helminths are an important cause. The current British Infection Association recommendations use travel history to guide investigation of eosinophilia. However the global burden of helminth disease and travel patterns have changed over the last 3 decades and guidelines based on previous epidemiology need to be reviewed in the light of current data. METHODS: Consecutive patients presenting with, or referred for, investigation of eosinophilia were identified prospectively. Case notes, laboratory results and electronic records were reviewed for demographic and clinical data. Patients with an eosinophil count >=0.50 * 109/L were included, and grouped based on lifetime history of travel to: West Africa, elsewhere in Africa, and the rest of the world. Results were compared to published data from 1997 to 2002 collected at the same centre. RESULTS: Of 410 patients who met the inclusion criteria, 407 had a documented travel history. Average yearly referrals for eosinophilia fell from 58 per year between 1997 and 2002, to 33 per year (2002-2015). The proportion of eosinophilia cases diagnosed with a parasitic cause fell from 64% to 50%, and yields for all parasitological investigations fell, the largest reduction in stool microscopy (20% yield to 9%) and day bloods for microfilariae (14% yield to 3%). Strongyloides stercoralis was the commonest diagnosis overall in our cohort, accounting for 50% of the total parasites diagnosed, and was present in 38% of patients from West Africa, 19% from rest of Africa, and 34% from rest of world; a relative increase compared to previous data. Schistosomiasis is slightly less common in those who had travelled to West Africa than the rest of Africa, and overall point prevalence has fallen from 33% (1997-2002) to 17% (2002-2015). Travellers were significantly less likely than patients who had immigrated to the UK to be diagnosed with any parasite (OR 0.54 95% CI 0.378-0.778 p = 0.0009). DISCUSSION: A parasitic cause will still be found in half of people returning from the tropics with an eosinophilia, but we observed a fall in the overall prevalence of parasitic diagnoses when compared with the earlier data. This may, in part, be explained by the impact of control programmes on the prevalence of parasites globally, especially filarial disease. S. stercoralis now represents the majority of parasites diagnosed in our cohort from all continents. We identified significantly higher rates of strongyloidiasis in immigrants than returning travellers. Despite the falling yields of stool microscopy and filarial serology the current guidelines based on travel history remain relevant with adequate yield. PMID- 28842187 TI - Connectome-scale functional intrinsic connectivity networks in macaques. AB - There have been extensive studies of intrinsic connectivity networks (ICNs) in the human brains using resting-state functional magnetic resonance imaging (fMRI) in the literature. However, the functional organization of ICNs in macaque brains has been less explored so far, despite growing interests in the field. In this work, we propose a computational framework to identify connectome-scale group wise consistent ICNs in macaques via sparse representation of whole-brain resting state fMRI data. Experimental results demonstrate that 70 group-wise consistent ICNs are successfully identified in macaque brains via the proposed framework. These 70 ICNs are interpreted based on two publicly available parcellation maps of macaque brains and our work significantly expand currently known macaque ICNs already reported in the literature. In general, this set of connectome-scale group-wise consistent ICNs can potentially benefit a variety of studies in the neuroscience and brain-mapping fields, and they provide a foundation to better understand brain evolution in the future. PMID- 28842189 TI - Daily rhythmicity of behavior of nine species of South American feral felids in captivity. AB - The authors analyzed the daily activity rhythms of the domestic cat and of eight of the ten feral felid species that are indigenous to South America. All species showed daily rhythmicity of activity in captivity under a natural light-dark cycle. The robustness of the rhythmicity varied from species to species, but the grand mean of 34% was within the range of robustness previously described for mammalian species ranging in size from mice to cattle. There was not a sharp division between diurnal and nocturnal felids. Instead, what was found was a gradient of diurnality going from the predominantly nocturnal margay (72% of activity counts during the night) to the predominantly diurnal jaguarundi (87% of activity counts during the day) with the remaining species lying in between these two extremes. The ecological implications of temporal niche variations are discussed. PMID- 28842190 TI - Mild exercise in female subjects impairs complex learning independent of hydration status and emotion. AB - INTRODUCTION: Depending on type, intensity and duration, exercise can have both beneficial and detrimental effects on cognitive function. The impact of exercise on learning and memory is also sensitive to hydration status, so we hypothesized that mild hypohydration induced with exercise, will adversely impact executive and complex memory function tasks and that these changes in cognitive function are independent of changes in emotion. METHODS: Using a cross over design, on separate days 11 women exercised on a recumbent bicycle. On day 1, women exercised to 1.5% hypohydration at 34 degrees C, and <10% rh, on day 2, water loss from sweating was replaced by drinking water (euhydration). Pre- and post euhydration and hypohydration, subjects underwent computer based cognitive tasks (simple, learning, memory, executive function) and visual analog testing to determine emotion. RESULTS: Exercise increased Groton Maze Learning Test errors within both conditions: [Pre: 41.5+/-11.8, Post: 46.8+/-12.4, and Pre: 41.9+/ 9.2, Post: 46.5+/-12.9, hypohydrated and euhydrated, respectively, Pre vs Post, ANOVA, time effect, P=0.007], a test of acquisition, storage, and use of new knowledge. None of the measures of emotion were affected by exercise under either hydration condition. CONCLUSIONS: A bout of mild aerobic exercise compromised performance on a complex learning and memory task, but this change was unaffected by hydration status or emotion. PMID- 28842191 TI - Removal of BCG artefact from concurrent fMRI-EEG recordings based on EMD and PCA. AB - BACKGROUND: Simultaneous electroencephalography (EEG) and functional magnetic resonance image (fMRI) acquisitions provide better insight into brain dynamics. Some artefacts due to simultaneous acquisition pose a threat to the quality of the data. One such problematic artefact is the ballistocardiogram (BCG) artefact. METHODS: We developed a hybrid algorithm that combines features of empirical mode decomposition (EMD) with principal component analysis (PCA) to reduce the BCG artefact. The algorithm does not require extra electrocardiogram (ECG) or electrooculogram (EOG) recordings to extract the BCG artefact. RESULTS: The method was tested with both simulated and real EEG data of 11 participants. From the simulated data, the similarity index between the extracted BCG and the simulated BCG showed the effectiveness of the proposed method in BCG removal. On the other hand, real data were recorded with two conditions, i.e. resting state (eyes closed dataset) and task influenced (event-related potentials (ERPs) dataset). Using qualitative (visual inspection) and quantitative (similarity index, improved normalized power spectrum (INPS) ratio, power spectrum, sample entropy (SE)) evaluation parameters, the assessment results showed that the proposed method can efficiently reduce the BCG artefact while preserving the neuronal signals. COMPARISON WITH EXISTING METHODS: Compared with conventional methods, namely, average artefact subtraction (AAS), optimal basis set (OBS) and combined independent component analysis and principal component analysis (ICA PCA), the statistical analyses of the results showed that the proposed method has better performance, and the differences were significant for all quantitative parameters except for the power and sample entropy. CONCLUSIONS: The proposed method does not require any reference signal, prior information or assumption to extract the BCG artefact. It will be very useful in circumstances where the reference signal is not available. PMID- 28842192 TI - Evaluation of the RumiWatchSystem for measuring grazing behaviour of cows. AB - Feeding behaviour is an important parameter of animal performance, health and welfare, as well as reflecting levels and quality of feed available. Previously, sensors were only used for measuring animal feeding behaviour in indoor housing systems. However, sensors such as the RumiWatchSystem can also monitor such behaviour continuously in pasture-based environments. Therefore, the aim of this study was to validate the RumiWatchSystem to record cow activity and feeding behaviour in a pasture-based system. The RumiWatchSystem was evaluated against visual observation across two different experiments. The time duration per hour at grazing, rumination, walking, standing and lying recorded by the RumiWatchSystem was compared to the visual observation data in Experiment 1. Concordance Correlation Coefficient (CCC) values of CCC=0.96 for grazing, CCC=0.99 for rumination, CCC=1.00 for standing and lying and CCC=0.92 for walking were obtained. The number of grazing and rumination bouts within one hour were also analysed resulting in Cohen's Kappa (kappa)=0.62 and kappa=0.86 for grazing and rumination bouts, respectively. Experiment 2 focused on the validation of grazing bites and rumination chews. The accordance between visual observation and automated measurement by the RumiWatchSystem was high with CCC=0.78 and CCC=0.94 for grazing bites and rumination chews, respectively. These results indicate that the RumiWatchSystem is a reliable sensor technology for observing cow activity and feeding behaviour in a pasture based milk production system, and may be used for research purposes in a grazing environment. PMID- 28842193 TI - Flow characterization and patch clamp dose responses using jet microfluidics in a tubeless microfluidic device. AB - BACKGROUND: Surface tension passive pumping is a way to actuate flow without the need for pumps, tubing or valves by using the pressure inside small drop to move liquid via a microfluidic channel. These types of tubeless devices have typically been used in cell biology. Herein we present the use of tubeless devices as a fluid exchange platform for patch clamp electrophysiology. NEW METHOD: Inertia from high-speed droplets and jets is used to create flow and perform on-the-fly mixing of solutions. These are then flowed over GABA transfected HEK cells under patch in order to perform a dose response analysis. RESULTS: TIRF imaging and electrical recordings are used to study the fluid exchange properties of the microfluidic device, resulting in 0-90% fluid exchange times of hundreds of milliseconds. COMSOL is used to model flow and fluid exchange within the device. Patch-clamping experiments show the ability to use high-speed passive pumping and its derivatives for studying peak dose responses, but not for studying ion channel kinetics. COMPARISON WITH EXISTING METHOD(S): Our system results in fluid exchange times slower than when using a standard 12-barrel application system and is not as stable as traditional methods, but it offers a new platform with added functionality. CONCLUSIONS: Surface tension passive pumping and tubeless devices can be used in a limited fashion for electrophysiology. Users may obtain peak dose responses but the system, in its current form, is not capable of fluid exchange fast enough to study the kinetics of most ion channels. PMID- 28842194 TI - Development of a head-mounted wireless microstimulator for deep brain stimulation in rats. AB - BACKGROUND: Commercial neurostimulators for clinical use are effective in patients; however they are too large and prohibitively expensive for preclinical studies. Thus, there is an urgent need of a small inexpensive and wireless microstimulator which is fully programmable in frequency, pulse width and amplitude for rodent experiments. NEW METHODS: Rats were subjected to a photothrombotic stroke of the right sensorimotor cortex and a microelectrode was implanted in the right mesencephalic locomotor region. The microstimulator was connected with the head plug of the rat. Three different stimulation frequencies were applied and different stimulating amplitudes were chosen. Under these conditions, gait velocity and locomotor behavior of six rats were examined on a beam. RESULTS: The head-mounted microstimulator allowed freedom in all motor activities performed spontaneously by the tested rats. Increasing either the frequency or the stimulating amplitude increased gait velocity and ameliorated locomotor behavior after stroke. COMPARISON WITH EXISTING METHODS: Other devices for DBS in rodents must be implanted under the skin or worn in an animal jacket on the back by the tested rat. Some available systems require even a tethering of the tested animal via a cable to an external stimulation system, which limits the freedom of movement. CONCLUSION: Here, we present a freely programmable microstimulator including DBS-typical stimulating parameters. The lightweight device is connected by a simple plug to the head allowing full freedom of movement and exchange of batteries for long-term experiments. The design of this stimulator is suitable for sophisticated behavior tests requiring balance and skilled walking. PMID- 28842195 TI - Effects of a combination of 3,4-methylenedioxymeth amphetamine and caffeine on real time stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry. AB - It is well documented that caffeine exacerbates the hyperthermia associated with acute exposure to 3,4-methylenedioxymethamphetamine (MDMA) in rats. Previous reports have also indicated that MDMA-related enhancement of dopamine release is exacerbated in the presence of caffeine. In the present study we have examined whether the effects of MDMA on real-time stimulated dopamine release, in the absence of uptake inhibition, are accentuated in the presence of caffeine. Isolated striatal slices from adult male Wistar rats were treated acutely with MDMA, caffeine, or a combination, and their effects on single and 5pulse stimulated dopamine release monitored using the technique of fast cyclic voltammetry. Caffeine at 10 or 100MUM had no significant effect on single pulse stimulated dopamine release. However 100MUM caffeine caused a significant peak increase in 5pulse stimulated dopamine release. Both 1 and 30MUM MDMA gave rise to a significant increase in both single and 5-pulse dopamine release and reuptake. A combination of 100MUM caffeine and 1 or 30MUM MDMA did not significantly enhance the effects of MDMA on single or 5pulse dopamine release and reuptake when compared to that applied alone. Utilizing single action potential dependent dopamine release, these results do not demonstrate a caffeine enhanced MDMA-induced dopamine release. PMID- 28842196 TI - Gonadal ecdysone titers are modulated by protein availability but do not impact protein appetite. AB - How animals survey internal nutrient availability to modulate specific appetites is currently largely unknown. Dietary proteins have a profound impact on the reproductive capacity and the selection of food sources in insects. When deprived of dietary proteins, insects stop producing eggs and develop strong protein appetites. In many adult insects, the ovaries are the site of synthesis of the ecdysone hormone. Therefore, an attractive hypothesis is that protein availability changes the gonadal production of ecdysone, which instructs the brain to increase its preference for yeast. We combine quantitative feeding assays, dietary manipulations, hormonal measurements, and genetic germline manipulations to test this hypothesis in Drosophila melanogaster. Our results show that upon yeast deprivation mated adult female Drosophila develop a strong yeast appetite and strongly reduce their egg production. This dietary manipulation also leads to a drastic reduction in ecdysone titers. However, the drop in ecdysone is not linked to the increase in yeast appetite as mutants with impaired oogenesis are able to adapt yeast intake to their nutrient state while displaying a constitutive low ecdysone titer. Interestingly, a low ecdysone titer is correlated with a lower level of overall food intake. Our data therefore show that in mated females the level of ecdysone reflects the level of protein in the diet and the physiological state of the ovaries. While the ovaries and ecdysone are unlikely to instruct the brain to develop a yeast appetite upon protein deprivation, they seem to be able to control overall food intake. PMID- 28842197 TI - Over-expression of a human CD62L ecto-domain and a potential role of RNA pseudoknot structures in recombinant protein expression. AB - L-selectin (CD62L) is an extracellular protein with a lectin-like domain that mediates rolling adhesion of leukocytes to vascular endothelial cell surfaces. Currently, there are no solved structures for the ectodomain of CD62L, nor of CD62L in complex with its ligand. We have developed a rapid mammalian recombinant protein expression system using an amplifiable glutamine synthase based vector. Here, we further developed and applied this method to express and purify the entire extracellular region of CD62L. This resulted in excess of 20 mg/L yield of recombinant CD62L. In an attempt to understand the different expression levels among four similar CD62L constructs that differ primarily in signal sequences, we calculated the presence of potential RNA pseudoknots in their signal sequences. The results showed the presence of pseudoknots involving the start codon and between the signal sequence and gene in the mRNA of the non-expressing constructs, suggesting a potential inhibitory role of RNA pseudoknots in recombinant protein expression. PMID- 28842198 TI - beta-d-glucan as an enteric delivery vehicle for probiotics. AB - Three strains of probiotics L. casei, L. acidophilus and B. bifidum were encapsulated in beta-d-glucan matrix using freeze drying technique in order to increase survivability during their journey through GI tract. The encapsulation efficiency (%) of beta-d-glucan varied significantly with Bifidobacteria showing low survival rate than Lactobacilli. SEM images revealed a partially collapsed structure with bacterial cells distributed randomly in the matrix. Further absorption band between 1300 and 900cm-1 in FTIR spectra shows the presence of bacterial proteins and nucleic acids. For encapsulated beta-d-glucan maximum degree of swelling was observed at pH 3 and 4, whereas when the pH value was increased to 6.5 the encapsulated beta-d-glucan started their disintegration. In vitro release studies revealed that the microcapsules start to dissolve upon entry to the small intestine where it is needed most. PMID- 28842199 TI - An inclusive physicochemical comparison of natural and synthetic chitin films. AB - Natural and synthetic chitin films, obtained from the same source were produced and their physicochemical properties were examined comparatively. Firstly, natural chitin film was obtained from elytra of an insect (Oryctes nasicornis L.) and purity of the obtained chitin film (degree of acetylation: 79+/-2%) was demonstrated by solid state 13C nuclear magnetic resonance (13C NMR). Then, the synthetic film was produced by dissolving of natural chitin film in LiCl-DMAc. The obtained natural and synthetic films were characterized by AFM, TGA, DSC, FTIR, mechanical properties, light transmission and contact angle. The analyses result demonstrated that natural chitin film lost very important properties such as high thermal stability, transparency, nanofibrous nature, tensile strength, Young's modulus and hydrophobicity after transforming the synthetic film. PMID- 28842200 TI - Flavonolignans reduce the response of blood platelet to collagen. AB - The primary biological function of platelets is to form hemostatic thrombi that prevent blood loss and maintain vascular integrity. These multi-responding cells are activated by different endogenous, physiological agonists due to the vast number of receptors present on the surface of the platelets. Collagen represents up to 40% of the total protein presented in the vessel wall and is the major activator of the platelets' response after tissue injury, and is the only matrix protein which supports both platelet adhesion and complete activation. The aim of our study was to determine the effects of three major flavonolignans (silybin, silychristin and silydianin) on collagen-induced blood platelets' activation, adhesion, aggregation and secretion of PF-4. We observed that depending on the dose, silychristin and silybin have anti-platelet properties observed as inhibition of collagen-induced activation (formation of blood platelet aggregates and microparticles, as well as decreased expression of P-selectin and activation of integrin alphaIIbbeta3), aggregation, adhesion and secretion of PF-4. These effects highlight the potential of silybin and silychristin as supplementation to prevent primary and secondary thrombotic events wherein excessive blood platelet response to a physiological agonist is observed. PMID- 28842201 TI - Production of cellulose nanocrystals from pistachio shells and their application for stabilizing Pickering emulsions. AB - This study presents isolation and characterization of cellulose nanocrystals (CNC) from pistachio shell and their application to stabilize Pickering emulsion. Pistachio shell (PS) is an agro-waste with an attractive source of cellulose. Alkali and bleaching treatments were performed for removing hemicellulose and lignin and purification of cellulose, while cellulose nanocrystals were obtained by acid hydrolysis. Hydrolysis using H2SO4 was very severe that led to formation of amorphous structures. While, hydrolysis reaction by HCl for 180min in concentration of 3M was recognized as the best conditions to extract CNCs with yield of 77.1% and crystallinity of 79.4%. FE-SEM images represented both rod like and spherical shapes of CNC and TEM image showed particles with mean diameter of 68.8+/-20.7nm. Chemical structure and thermal properties of CNC were characterized by FTIR and TGA analysis. In order to evaluate emulsifier ability of CNCs, different concentrations of CNCs were dispersed in an oil in water emulsions as the Pickering agent. By increasing the CNC concentration, stability of emulsions against heating, stresses and storage time enhanced while the mean diameter of oil droplets decreased. The results of this study indicated high potential of CNCs as an environmental friendly material for food emulsion preparation. PMID- 28842202 TI - Synthesis and characterisation of chitin from periwinkle (Tympanotonus fusatus (L.)) and snail (Lissachatina fulica (Bowdich)) shells. AB - This study characterizes chitin extracted from bio-sources of snail and periwinkle using varied combinations of acid and alkali concentrations. A three level factorial design of experiment with alkali and acid concentrations was used. FTIR, XRD and SEM were used to investigate the structural changes after treatments. Results reveal that both alkali and acid concentrations significantly affect the development of the functional groups and their intensities in the extracted chitin. A certain combination of concentration of acid and alkali can be used to obtain chitin with high degree of order (Crystallinity Index (CrI)>0.9) and a degree of de-acetylation (DD>50%). This results in combined high crystallinity and degree of de-acetylation. The study also established that certain combination of acid and alkali concentrations could lead to alpha to beta transformation in chitin structure. PMID- 28842203 TI - Analysis of the peptides detected in atopic dermatitis and various inflammatory diseases patients-derived sera. AB - Serum proteomics has been applied for the discovery and analysis of biomarkers related to human disease. Serum is an optimal source to identify proteins derived from diseased-tissue compartments. We recently established an integrative method to analyze highly basic proteins that remain unresolved by the general 2D-PAGE method. In this follow-up study, we successfully detected several disease associated proteins from sera samples obtained from patients with atopic dermatitis (AD). After proteomic analyses, target proteins were validated from AD patient-derived sera using ELISA or Western blotting methods We detected zinc finger CCHC domain containing 10 (ZCCHC10), peptidoglycan recognition protein L (PGRP-L), kininogen, alpha-1-antitrypsin, and hornerin proteins that are dysregulated in AD patient sera samples, which suggest effective approaches to methodologically analyze the serum proteome. Thus, the integrated proteomic method approach described here could be applicable for the detection of proteins associated with other human diseases. Our present study provides new insights into optimized serum proteomic techniques to understand systemic events of AD. PMID- 28842204 TI - Role of cardiolipin in stability of integral membrane proteins. AB - Cardiolipin (CL) is a unique phospholipid with a dimeric structure having four acyl chains and two phosphate groups found almost exclusively in certain membranes of bacteria and of mitochondria of eukaryotes. CL interacts with numerous proteins and has been implicated in function and stabilization of several integral membrane proteins (IMPs). While both functional and stabilization roles of CL in IMPs has been generally acknowledged, there are, in fact, only limited number of quantitative analysis that support this function of CL. This is likely caused by relatively complex determination of parameters characterizing stability of IMPs and particularly intricate assessment of role of specific phospholipids such as CL in IMPs stability. This review aims to summarize quantitative findings regarding stabilization role of CL in IMPs reported up to now. PMID- 28842205 TI - Effects of chronic exposure to octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane in the aging female Fischer 344 rat. AB - Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are used as intermediates or monomers in the synthesis of silicon-based polymers for industrial or consumer applications. D4 and D5 may remain as residual monomer in these polymers at less than 1000ppm and may therefore be present as a minor impurity in consumer products. For D5, in addition to the manufacture of polymers, its uses include intentional addition to consumer products, personal care products and some dry- cleaning solvents. Two-year rodent chronic bioassays were conducted with both substances and borderline increases in the incidence of uterine tumors were observed, specifically, benign uterine adenoma with D4 and adenocarcinoma with D5. The effects profile and induction of uterine tumors share some similarity with that seen with chronic exposure to dopamine agonists. The current study investigated the potential for D4 and D5 to elicit dopamine agonist like effects on estrous cyclicity. Separate groups of reproductively senescent female Fischer 344 rats (F344) were exposed via vapor inhalation to D4 (700ppm, 9.3mg/L) or D5 (160ppm, 2.1mg/L) or to a diet containing 0.0045, 0.045, or 4.5ppm pergolide mesylate (PM), a potent dopamine agonist used here as a reference substance, from 11 through 24 months of age. The primary focus was to characterize the effects of D4 and D5 exposure on estrous cyclicity relative to that observed with PM. As a monitoring effort, circulating endogenous estradiol, progesterone, prolactin and corticosterone levels were evaluated monthly. A blood sample from each rat was obtained via tail vein in the afternoon after the daily inhalation exposure period once every 4 weeks. Histomorphologic examination of the major organs including the reproductive tract was conducted on all animals at study termination. This study has shown that chronic exposure to D4 and D5 can affect cyclicity in the reproductively senescent F344 rat. For each substance the effect on cyclicity involved reduction in the incidence of pseudopregnancy with a shift toward cycles more typical of younger animals. D4 and D5 induced an increase in estrous cycle repetition whereas D4 also increased the incidence of extended estrus. These shifts resulted in animals entering proestrus/estrus significantly more times over the duration of the study than seen in the control group. Similar effects were observed with the reference substance, PM. However, distinct differences in the timing and magnitude of the effects on the estrous cycle and impact on prolactin, progesterone, estradiol, and corticosterone suggest that D4 and D5 are not classical dopamine agonists even though a similar increased incidence of proestrus/estrus was also observed with PM. These results may prove important with respect to understanding D4- and D5-induced uterine tumor response in the F344 rat, given the relationship between increased incidence of uterine endometrium stimulation by endogenous estrogen as a consequence of extended or more frequent proestrus/estrus, uterine tumor risk, and questions of relevance to humans. Recent publications have summarized the existing data on D4 and D5, with emphasis on exploring the biological relevance of the uterine tumors (Klaunig et al., 2016a,b; Franzen et al., 2017; Dekant and Klaunig, 2016; Dekant et al., 2017). The authors concluded that although the mode of action has not yet been fully established, the data, including the findings from this study, indicate that the D4- and D5-induced uterine tumors observed in the rodent chronic bioassays have no relevance for human risk characterization based not only on the distinct species differences in regulation of the reproductive systems, but also the high exposure levels and duration required for expression in rats. PMID- 28842206 TI - Potential neurotoxicity of prenatal exposure to sevoflurane on offspring: Metabolomics investigation on neurodevelopment and underlying mechanism. AB - Repeated or prolonged anesthesia to pregnant women disturbs neurodevelopment of developing infants, but its mechanism has not been elaborated absolutely. This study was conducted to investigate the mechanism of potential neurotoxicity on their offspring generation after sevoflurane anesthesia in adult animals during pregnancy based on metabolomics. 16 pregnant rats were equally assigned to sevoflurane group and control group, and serum samples were collected from their 7-day-old offspring for metabolomics analysis using ultra performance liquid chromatography coupled to time-of-flight mass spectrometry. Principal component analysis and partial least squares-discriminate analysis were used for pattern recognition, and pathway analysis was performed by MetaboAnalyst platform. 29 metabolites were discovered as neurotoxicity related-biomarkers, among which S Adenosylmethioninamine was inhibited dramatically after sevoflurane exposure. Prenatal exposure to sevoflurane led to a significant reduction in S Adenosylmethionine level, as shown by enzyme-linked immunosorbent assay. Pathway analysis highlighted that prenatal exposure to sevoflurane induced alteration in arginine/proline metabolism, cysteine/methionine metabolism, and so on. The most important altered metabolic pathway was arginine/proline metabolism. This study suggests that abnormal methylation and disturbed arginine/proline metabolism may crucially contribute to the mechanism with neurotoxicity on offspring generation after sevoflurane anesthesia in adult animals during pregnancy, and dietary supplement of S-Adenosylmethionine and modulating arginine/proline metabolism may be the potential therapeutic targets for protecting neurodevelopment from detrimental effects of prenatal exposure to inhalational anesthetics. PMID- 28842207 TI - Central administration of tert-butylhydroquinone attenuates hypertension via regulating Nrf2 signaling in the hypothalamic paraventricular nucleus of hypertensive rats. AB - Reactive oxygen species (ROS) in the paraventricular nucleus (PVN) play a pivotal role in the pathogenesis of hypertension. Nuclear factor E2-related factor-2 (Nrf2) is an important transcription factor that modulates cell antioxidant defense response against oxidative stress. The present study aimed to explore the efficacy of PVN administration of tert-butylhydroquinone (tBHQ), a selective Nrf2 activator, in hypertensive rats. 16-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used in this study. These rats were chronic bilateral PVN infusion of tBHQ (0.8MUg/day), or oxygen free radical scavenger tempol (20MUg/h), or vehicle for 2weeks. SHR rats had higher mean arterial pressure (MAP), plasma norepinephrine (NE) levels, and sympathetic nerve activity (RSNA) and lower PVN levels of Nrf2, hemeoxygenase-1 (HO-1), superoxide dismutase-1 (SOD1) and catalase (CAT) as compared with those in the WKY group. Bilateral PVN infusion of tBHQ or tempol significantly reduced MAP, RSNA, plasma NE levels in SHR rats. In addition, tBHQ treatment enhanced the nuclear accumulation of Nrf2 and increased the expression of HO-1, CAT and SOD1 in SHR rats. Furthermore, tBHQ attenuated PVN levels of ROS, the expression of proinflammatory cytokines and restored the imbalance of neurotransmitters in PVN. Knockdown of Nrf2 in the PVN by adeno-associated virus mediated small interfering RNA abrogated the protective effects of tBHQ on hypertension. These findings suggest that PVN administration of tBHQ can attenuate hypertension by activation of the Nrf2-mediated signaling pathway. PMID- 28842208 TI - Reclassification Rates of Patients Eligible for Active Surveillance After the Addition of Magnetic Resonance Imaging-Ultrasound Fusion Biopsy: An Analysis of 7 Widely Used Eligibility Criteria. AB - OBJECTIVES: To evaluate the impact of adding magnetic resonance imaging ultrasound (MRI-US) fusion biopsy cores to standard 12-core biopsy in selecting men for active surveillance (AS). MATERIALS AND METHODS: Among men undergoing a fusion biopsy for evaluation of prostate cancer, we selected men who were eligible for at least 1 of 7 different AS criteria based on the standard biopsy alone. We assessed each patient's eligibility for each AS criterion with and without the inclusion of fusion biopsy cores. The primary end point was the proportion of men who were initially eligible for AS but became ineligible after addition of the fusion biopsy cores. RESULTS: A total of 100 men were eligible for at least 1 AS criterion. After addition of fusion biopsy cores, the proportion of men who became ineligible for AS varied from 10.3% to 40.7%. Criteria that incorporated an absolute maximum number of cores positive had the highest rates of ineligibility. Using a percentage of cores positive helped to reduce the number of patients who would have been excluded. Combining the targeted biopsy cores into one, or taking the single core with the highest grade or volume did not appear to reduce the proportion of men who became ineligible. CONCLUSIONS: The addition of fusion biopsy to standard 12-core biopsy significantly increased the number of men who became ineligible for AS. Using the percent of cores positive, instead of an absolute number, allowed fewer exclusions. AS criteria may need to be updated to prevent the unnecessary exclusion of men due to an oversampling of low-risk disease. PMID- 28842209 TI - Longitudinal Gender Disparity in Female Urology Resident Primary Authorship at an American Urological Association Sectional Meeting. AB - OBJECTIVE: To further evaluate the academic representation of female urology residents in the United States, we reviewed abstracts from the Mid-Atlantic American Urological Association (MA-AUA) sectional meetings to determine if the recent increase in the number of female urology residents mirrored an increase in this group's abstract authorship. MATERIALS AND METHODS: Full text abstracts from the MA-AUA meetings were analyzed from 2008 to 2014 excluding 1 joint section meeting. First-author gender was determined by querying publicly available institutional websites, social media platforms, and the U.S. News & World Report. First-author gender was indeterminable in 10 abstracts based on search criteria and these were excluded. Individual abstracts were broadly categorized based on keywords into 1 of several topics. Chi-square statistical tests examined the relationship between first-authorship gender, publication year, and abstract category. RESULTS: The number of female urology residents in the MA-AUA increased over the study period. A total of 484 abstracts were analyzed. Three hundred ninety-three abstracts (81%) included a male first-author, whereas 81 abstracts (17%) included a female first-author. Female first-authorship ranged from 13% to 25% annually. Comparison of male-to-female first-authorship was statistically significant in all years evaluated (P <.001). There was a statistically significant difference between male and female first-authorship in all topic categories (P <.01), except Education/Other (P = .56). CONCLUSION: Despite continued gains and increasing female representation in urology, these data highlight significantly fewer female first-authors at the regional Mid-Atlantic section meetings. Larger studies are necessary to identify contributing factors and further areas for improvement toward decreasing gender imbalances within the academic community. PMID- 28842210 TI - Racial or Ethnic and Socioeconomic Disparities in Prostate Cancer Survivors' Prostate-specific Quality of Life. AB - OBJECTIVE: To conduct a prospective study to examine whether there are pretreatment and post-treatment disparities in urinary, sexual, and bowel quality of life (QOL) by race or ethnicity, education, or income in men with clinically localized prostate cancer (PCa.) METHODS: Participants (N = 1508; 81% white; 12% black; 7% Hispanic; 50% surgery; 27% radiotherapy; 23% active surveillance) completed the Expanded Prostate Cancer Index Composite measure of PCa-specific QOL prior to treatment, 6 weeks, 6, 12, 18, and 24 months after treatment. We analyzed pretreatment differences in QOL with multivariable linear regression and post-treatment differences with generalized estimating equation models. RESULTS: Blacks and Hispanics (compared with whites) and men with lower income had worse pretreatment urinary function; poorer and less educated men had worse pretreatment sexual function (P < .05). In adjusted models, among men treated surgically, blacks and Hispanics had worse bowel function compared with whites, and men with lower income experienced more sexual bother and slower recovery in urinary function. Not all racial or ethnic differences favored whites; blacks had higher sexual function than whites prior to surgery and improved faster after surgery. Blacks receiving radiotherapy had lower post-treatment bowel bother than whites (P < .05). CONCLUSION: Controlling for baseline QOL, there were some post treatment disparities in urinary and sexual QOL that suggest the need to investigate whether treatment quality and access to follow-up care is equitable. However, survivorship disparities may, to a greater extent, reflect disadvantages in baseline health that exacerbate QOL issues after treatment. PMID- 28842211 TI - The Effects of Population-based Prostate-specific Antigen Screening Beginning at Age 40. AB - OBJECTIVE: To evaluate population-based prostate cancer (CaP) testing of men in their 40s, given the paucity of prospective data evaluating the consequences of prostate-specific antigen (PSA) testing in younger men for CaP. MATERIALS AND METHODS: A total of 1052 men in their 40s were followed longitudinally for prostate outcomes, from 1990 to 2010. A random subset of 268 men was selected to undergo biennial CaP testing including PSA testing, transrectal ultrasound, and a digital rectal examination. A representative population of 609 men with a subset of 159 men who also began CaP testing in their 50s was also evaluated as a comparison group. Risk of prostate biopsy (PBx), CaP, or death from CaP was compared between CaP-tested and the routine-care population cohort. RESULTS: Median follow-up was 17.2 years. Men aged 40-49, who underwent CaP testing were 2.4 times more likely to undergo a PBx (hazard ratio [HR] 2.4 95% confidence interval [CI] 1.8-3.3) and 2.2 times more likely to be diagnosed with low-risk CaP (HR 2.2, 95% CI 1.12-4.0). Those initiating CaP testing a decade earlier were 2.2 times and 1.7 times more likely to be biopsied and be diagnosed with CaP for any given age (HR 2.2 95% CI 1.4-3.5 and 1.7 95% CI 1.1-2.7, respectively). CONCLUSION: CaP testing in men beginning at age 40 resulted in a significant increase in the risk of PBx and diagnosis of low-risk CaP, without a measurable reduction in risk of CaP-death in this low-risk population. However, given the natural history of CaP, a longer follow-up is needed to confirm this finding. PMID- 28842212 TI - Measles on the move. PMID- 28842213 TI - Measles in Pakistan: Time to make steps towards eradication. AB - World Health Organization (WHO) measles surveillance data report a reduction in cases of measles globally from 67,524 cases in 2015 to 16,846 in 2016, and a reduction in deaths from 546,800 to 114,900 during period of 2000-14. Pakistan is among the five nations where almost a million children did not receive their first dose of measles vaccination, and outbreaks of the disease resulted in 4386 cases in 2011, 14,687 cases in 2012 with 310 deaths. In 2013, about 25,401 cases of measles were reported and 321 affected children died. The measles vaccination coverage is very low in Pakistan for both 1st dose and booster dose. To prevent outbreaks of measles in Pakistan a national vaccination program should be launched side by side with a polio eradication program in each district and township and a campaign should be launched to educate parents on measles vaccination for childrens to reduce the measles case fatality rate. PMID- 28842214 TI - Travel-related acquisition of diarrhoeagenic bacteria, enteral viruses and parasites in a prospective cohort of 98 Dutch travellers. AB - BACKGROUND: Limited prospective data are available on the acquisition of viral, bacterial and parasitic diarrhoeagenic agents by healthy individuals during travel. METHODS: To determine the frequency of travel associated acquisition of 19 pathogens in 98 intercontinental travellers, qPCR was used to detect 8 viral pathogens, 6 bacterial enteric pathogens and 5 parasite species in faecal samples collected immediately before and after travel. RESULTS: We found high pre-travel carriage rates of Blastocystis spp. and Dientamoeba fragilis of 32% and 19% respectively. Pre-travel prevalences of all other tested pathogens were below 3%. Blastocystis spp. (10%), Plesiomonas shigelloides (7%), D. fragilis (6%) and Shigella spp. (5%) were the most frequently acquired pathogens and acquisition of enteral viruses and hepatitis E virus in this relatively small group of travellers was rare or non-existent. CONCLUSIONS: Our findings suggest that the role of viruses as the cause of persisting traveller's diarrhoea is limited and bacterial pathogens are more likely as a cause of traveller's diarrhoea. The substantial proportion of travellers carrying Blastocystis spp. and D. fragilis before travel warrants cautious interpretation of positive samples in returning travellers with gastrointestinal complaints. PMID- 28842215 TI - Cloning and expression of the recombinant crustacean hyperglycemic hormone isoform B2 (rCHH-B2) and its effects on the metabolism and osmoregulation of the Pacific white shrimp Litopenaeus vannamei. AB - Crustacean hyperglycemic hormones (CHHs) are multifunctional neuropeptides ubiquitous in crustaceans. In Litopenaeus vannamei, CHH-B2 is a CHH eyestalk isoform whose expression has been shown to vary with enviromental conditions, suggesting its relevance for ecophysiological performance of shrimp, controlling processes related to metabolism and osmo-ionic regulation. To study the involvement of CHH-B2 in these processes, we cloned and expressed a recombinant version with a free C-terminal glycine (rCHH-B2-Gly) in the methylotrophic yeast Pichia pastoris. The rCHH-B2-Gly peptide secreted to the culture medium was purified by RP-HPLC and used for in vivo glucose, triglyceride, and osmoregulation dose-response analyses with juvenile shrimp. The peptide was also amidated at the C-terminus using an alpha-amidating enzyme to produce rCHH-B2 amide. The shrimp showed a dose-dependent effect of rCHH-B2-Gly to hemolymph glucose and triglyceride levels, inducing maximal increases by injecting 500 and 1000pmol of hormone, respectively. Additionally, 10pmol of hormone was sufficient to reduce the hypo-osmoregulatory capacity of shrimp at 350/00. These findings suggest that CHH-B2 has regulatory roles in carbohydrate and lipid metabolism, and a potential involvement in osmoregulation of L. vannamei. Injection of 100pmol of rCHH-B2-amide increased glucose and triglyceride levels by 15 and 28%, respectively in comparison with rCHH-B2-Gly, suggesting an important role for the C-terminal amidation. Additionally, an in silico structural analysis done with the CHH-B1 and rCHH-B2-Gly peptides suggests that the C-terminal region may be relevant for the activity of the L. vannamei isoforms and explain the functional divergence from other crustacean CHH/CHH-like peptides. PMID- 28842216 TI - Egr2 enhances insulin resistance via JAK2/STAT3/SOCS-1 pathway in HepG2 cells treated with palmitate. AB - Insulin resistance is generally responsible for the pathogenesis of type 2 diabetes mellitus (T2DM). Early growth response proteins-2 (Egr2) has been reported to be able to increase the expression of the suppressors of cytokine signaling-1 (SOCS-1), and impair insulin signaling pathway through suppression of insulin receptor substrates (IRS), including IRS-1 and IRS-2. However, whether Egr2 is directly involved in the development of insulin resistance, and how its potential contributions to insulin resistance still remain unknown. Here, our present investigation found that the expression levels of Egr2 were up-regulated when insulin resistance occurs, and knockdown of Egr2 abolished the effect of insulin resistance in HepG2 cells induced with palmitate (PA). Importantly, inhibition of Egr2 decreased the expression of SOCS-1 as well as reduced phosphorylation of JAK2 and STAT3. And, our data indicated that silencing of Egr2 accelerated hepatic glucose uptake and reversed the impaired lipid metabolism upon insulin resistance. In summary, the present study confirms that Egr2 could deteriorate insulin resistance via the pathway of JAK2/STAT3/SOCS-1 and may shed light on resolving insulin resistance and further the pathogenesis of T2DM. PMID- 28842217 TI - Cytoskeleton-related regulation of primary cilia shortening mediated by melanin concentrating hormone receptor 1. AB - Primary cilia are specialized microtubule-based organelles. Their importance is highlighted by the gamut of ciliary diseases associated with various syndromes including diabetes and obesity. Primary cilia serve as signaling hubs through selective interactions with ion channels and conventional G-protein-coupled receptors (GPCRs). Melanin-concentrating hormone (MCH) receptor 1 (MCHR1), a key regulator of feeding, is selectively expressed in neuronal primary cilia in distinct regions of the mouse brain. We previously found that MCH acts on ciliary MCHR1 and induces cilia shortening through a Gi/o-dependent Akt pathway with no cell cycle progression. Many factors can participate in cilia length control. However, the mechanisms for how these molecules are relocated and coordinated to activate cilia shortening are poorly understood. In the present study, we investigated the role of cytoskeletal dynamics in regulating MCH-induced cilia shortening using clonal MCHR1-expressing hTERT-RPE1 cells. Pharmacological and biochemical approaches showed that cilia shortening mediated by MCH was associated with increased soluble cytosolic tubulin without changing the total tubulin amount. Enhanced F-actin fiber intensity was also observed in MCH-treated cells. The actions of various pharmacological agents revealed that coordinated actin machinery, especially actin polymerization, was required for MCHR1-mediated cilia shortening. A recent report indicated the existence of actin-regulated machinery for cilia shortening through GPCR agonist-dependent ectosome release. However, our live-cell imaging experiments showed that MCH progressively elicited cilia shortening without exclusion of fluorescence-positive material from the tip. Short cilia phenotypes have been associated with various metabolic disorders. Thus, the present findings may contribute toward better understanding of how the cytoskeleton is involved in the GPCR ligand-triggered cilia shortening with cell mechanical properties that underlies clinical manifestations such as obesity. PMID- 28842218 TI - Does Modality Matter? Palliative Care Unit Associated With More Cost-Avoidance Than Consultations. AB - CONTEXT: Inpatient palliative care (PC) is associated with reduced costs, but the optimal model for providing inpatient PC is unknown. OBJECTIVES: To estimate the effect of palliative care consultations (PCCs) and care in a palliative care unit (PCU) on cost of care, in comparison with usual care (UC) only and in comparison with each other. METHODS: Retrospective cohort study, using multinomial propensity scoring to control for observed confounding between treatment groups. Participants were adults admitted as inpatients between 2009 and 2015, with at least one of seven life-limiting conditions who died within a year of admission (N = 6761). RESULTS: PC within 10 days of admission is estimated to reduce costs compared with UC in the case of both PCU (-$6333; 95% CI: -7871 to -4795; P < 0.001) and PCC (-$3559; 95% CI: -5732 to -1387; P < 0.001). PCU is estimated to reduce costs compared with PCC (-$2774; 95% CI: -5107 to -441; P = 0.02) and length of stay compared with UC (-1.5 days; -2.2 to -0.9; P < 0.001). The comparatively larger effect of PCU over PCC is not observable when the treatment groups are restricted to those who received PC early in their admission (within six days). CONCLUSION: Both PCU and PCC are associated with lower hospital costs than UC. PCU is associated with a greater cost-avoidance effect than PCC, except where both interventions are provided early in the hospitalization. Both timely provision of PC for appropriate patients and creation of more PCUs may decrease hospital costs. PMID- 28842219 TI - Acculturation and Perceptions of a Good Death Among Japanese Americans and Japanese Living in the U.S. AB - CONTEXT: Acculturation is the phenomenon of the attitudinal changes of individuals who come into continuous contact with another culture. Despite the long history of Japanese immigration to America, little is known about the impact of acculturation on perceptions of a good death. OBJECTIVES: To examine differences in perceptions of a good cancer death among Japanese Americans (JA/A), Japanese living in America (J/A), and the Japanese living in Japan (J/J). METHODS: We administered surveys among JA/A and J/A and used historical J/J data for reference. Primary endpoint was the proportion of respondents who expressed the necessity of core and optional items of the Good Death Inventory. Group differences >=20% were deemed clinically important. RESULTS: In total, 441 survey responses in America and 2548 in Japan were obtained. More than 80% of respondents consistently considered nine of 10 core items necessary without significant group differences. No core item reached a >=20% group difference. Three of the eight optional items reached >=20% group difference: fighting against disease until one's last moment (49%, P < 0.0001; 52%, P < 0.0001; and 73% in JA/A, J/A, and J/J, respectively), knowing what to expect about one's condition in the future (83%, P < 0.0001; 80%, P < 0.0001; and 58%, respectively), and having faith (64%, P = 0.0548; 43%, P = 0.0127; and 38%, respectively). CONCLUSION: Although most core items of a good death were preserved throughout the levels of acculturation, perceptions of some optional items shifted away from Japanese attitudes as individuals became more acculturated. Understanding of different levels of acculturation may help clinicians provide culturally sensitive end-of-life care. PMID- 28842220 TI - Spiritual Needs and Perception of Quality of Care and Satisfaction With Care in Hematology/Medical Oncology Patients: A Multicultural Assessment. AB - CONTEXT: Assessment and response to patients' spiritual concerns are crucial components of high-quality supportive care. Better measures of spiritual needs across the cultural spectrum may help direct necessary interventions. OBJECTIVES: The objective of this study was to assess spiritual needs in a racially/ethnically and religiously mixed sample of hematology and oncology outpatients and examine the association between spiritual needs and perception of quality of care and satisfaction with care. METHODS: This is an observational study of 727 racially/ethnically and religiously diverse outpatients. Spiritual needs were measured using a validated, 23-item questionnaire, the Spiritual Needs Assessment for Patients. Scales were administered in four languages. RESULTS: Forty-four percent were white, 13% Hispanic, 25% black, and 14% Asian. English was the primary language for 57%; 59% considered themselves "spiritual but not religious." At least one spiritual need was reported by 79%. Forty-eight percent were comfortable having their physician inquire about spiritual needs. Compared with English-speaking patients, Russian-speaking patients reported lower spiritual needs (P = 0.003). Patients who considered themselves "spiritual but not religious" (P = 0.006) reported a higher level of spiritual needs. Higher spiritual needs were associated with less satisfaction with care (P = 0.018) and lower perception of quality of care (P = 0.002). CONCLUSION: Spiritual needs are common in an ethnically, religiously, and linguistically diverse cancer patient population but may differ by cultural background. High levels of spiritual need are associated with lower levels of satisfaction and diminished perception of quality of care. Training clinicians to address patients' spiritual concerns, with attention to cultural differences, may improve patients' experiences of care. PMID- 28842221 TI - Rapid and visual detection of Mycobacterium tuberculosis complex using recombinase polymerase amplification combined with lateral flow strips. AB - To definitively diagnose active pulmonary Tuberculosis (TB), Mycobacterium tuberculosis complex (MTBC) bacilli must be identified within clinical specimens from patients. In this study, we introduced a rapid and visual detection method of MTBC using recombinase polymerase amplification (RPA) combined with lateral flow (LF) strips. The LF-RPA assay, read results with naked eyes, could detect as few as 5 genome copies of M. tuberculosis H37Rv (ATCC 27294) per reaction and had no cross-reactions with other control bacteria even using excessive amount of template DNA. The system could work well at a broad range of temperature 25-45 degrees C and reach detectable level even within 5 min. When testing a total of 137 clinical specimens, the sensitivity and specificity of the LF-RPA assay were 100% (95% CI: 95.94%-100%) and 97.92% (95% CI: 88.93%-99.95%), respectively, compared to culture identification method. Therefore, the LF-RPA system we have demonstrated is a rapid, simple, robust method for MTBC detection which, subject to the availability of a suitable sample extraction method, has the potentiality to diagnose TB at the point-of-care testing. PMID- 28842223 TI - An essential role of Rieske domain oxygenase Neverland in the molting cycle of black tiger shrimp, Penaeus monodon. AB - Molting is an important process for development and growth in arthropods. In crustaceans, molt is regulated by ecdysteroids or molting hormones that are synthesized in Y-organs. However, ecdysteroid biosynthesis pathway in crustaceans and its participating enzymes have not been well studied so far. In this study, a Rieske domain oxygenase, the enzyme that acts as cholesterol 7,8-dehydrogenase by converting cholesterol to 7-dehydrocholesterol in the first step of the ecdysteroid biosynthesis was characterized in black tiger shrimp, Penaeus monodon. A full-length cDNA of P. monodon's Rieske domain oxygenase Neverland (PmNvd) was successfully cloned. The expression of PmNvd was dominantly found in the Y-organ, and changed during molting period. The PmNvd mRNA level was low in intermolt and early premolt stages, then dramatically increased in the mid premolt stage suggesting its role in molt regulation. The function of PmNvd in the molting process was investigated by RNAi approach. Silencing of PmNvd transcript in shrimp by specific double-stranded RNA (dsNvd) led to prolonged molt duration with abnormal molting progression, i.e. the molting process got stuck at early premolt stage. In addition, 20-hydroxyecdysone titer in the hemolymph of dsNvd-injected shrimp was significantly reduced compared with that in NaCl-injected shrimp. These evidences suggested a crucial role of PmNvd in molt progression, particularly during the initiation of premolt phase via the regulation of ecdysteroid production. PMID- 28842222 TI - Physical performance and movement-evoked pain profiles in community-dwelling individuals at risk for knee osteoarthritis. AB - BACKGROUND: Knee pain associated with osteoarthritis is a significant contributor to decreased physical function. Recent evidence supports the inter-individual heterogeneity associated with knee pain presentation, but whether there is similar heterogeneity in physical performance among these individuals has not been previously examined. The aim of the present study was to characterize the variability in physical performance profiles and the pain evoked by their performance (i.e., movement-evoked pain). METHODS: In a secondary analysis of the community-based study Understanding Pain and Limitations in Osteoarthritic Disease (UPLOAD), individuals (n=270) completed functional, pain, psychological, and somatosensory assessments. Hierarchical cluster analysis was used to derive physical function profiles that were subsequently compared across several clinical, psychological and experimental pain measures. RESULTS: Our results support the hypothesis that among persons with knee OA pain, three different physical performance profiles exist with varying degrees of movement-evoked pain. Even as all three groups experienced moderate to severe levels of spontaneous knee pain, those individuals with the most severe movement-evoked pain and lowest physical functional performance also had the least favorable psychological characteristics along with increased mechanical pain sensitivity and temporal summation. CONCLUSIONS: Our findings support the need for the assessment and consideration of movement-evoked pain during physical performance tasks as these have the potential to increase the value of functional and pain assessments clinically. The identification of the mechanisms driving pain burden within homogeneous groups of individuals will ultimately allow for targeted implementation of treatments consistent with a biopsychosocial model of pain. PMID- 28842224 TI - An efficient and assumption-free method to approximate protein level distribution in the two-states gene expression model. AB - Stochastic fluctuations at each step of gene expression might influence protein levels distributions across cell populations. However, current methods to model protein distribution of intrinsic gene expression dynamics are either computationally inefficient or rely on ad hoc assumptions, e.g., that the gene is always active. Taking advantage of the simple form of lower-order moments of distribution, we developed an efficient and assumption-free protein distribution approximation method (EFPD), for the two state gene expression model to accurately approximate the distribution. By EFPD, we computed nearly identical intensity of gene expression regulation at mRNA and protein level, implying a profound link between transcription and translation. Finally, by extending EFPD to approximate the distribution of protein level at any arbitrary temporal state, we proposed an explanation for the role of stochastic noise in gene expression in the context of a continuously changing environment. EFPD can be a powerful tool for modeling the particular molecular mechanisms of targeted gene expression pattern. PMID- 28842225 TI - Transvenous lead extraction at the time of cardiac implantable electronic device upgrade: Complexity, safety, and outcomes. AB - BACKGROUND: The practice of lead abandonment at the time of cardiac implantable electronic device upgrade remains a controversial topic but is affecting an increasing number of patients. Inherent risks include high-risk extractions of redundant leads when extraction is required at a later date. OBJECTIVES: We aimed to report our experience with transvenous lead extraction (TLE) at the time of device upgrade. METHODS: All consecutive TLE procedures at the time of device upgrade at the Cleveland Clinic between January 1, 1996 and December 31, 2012 were included (n = 503). Success and complications were defined according to the Heart Rhythm Society consensus document on TLE. RESULTS: There were a total of 984 leads in place, and 719 were targeted with extraction (589 pacer and 130 defibrillator leads, 63 of them being dual-coil leads). In all patients, TLEs aimed to avoid abandoning leads. Concomitant lead management issues included lead malfunction (15%), previously abandoned leads (9%), vascular access occlusion (6%), or leads on advisory (3%). In most procedures (75.4%), special extraction tools were needed. The complete procedural and clinical success rates were 96.6% and 97.2%, respectively. During planned extractions, damage of coexisting leads occurred in 19 patients (3.8%), eventually requiring extraction. The major and minor complication rates were 1% and 1.4%, respectively. CONCLUSION: In a high volume center, TLEs at the time of device upgrade were successful in the vast majority of patients with a low complication rate. PMID- 28842226 TI - Frozen Section Can "Sharpen" or "Sand Off" the Surgeon's Knife: 2 Case Illustrations with Skull Base Meningioma Mimics. AB - BACKGROUND: Lesions at the skull base warrant careful evaluation of imaging and meticulous preoperative planning. Unnecessary radical resection of these lesions could add to surgical morbidity. Occasionally, dural-based inflammatory or infectious lesions at this site radiologically mimic meningiomas, which are commonly encountered entities at this site. Not all lesions require excision, and it could be harmful in a few cases. CASE DESCRIPTION: Two patients had skull base lesions that resembled a meningioma on imaging, whereas frozen section in both cases differed from the preoperative diagnosis, showing an inflammatory lesion in the first case and invasive aspergillosis in the second case. Formalin-fixed, paraffin-embedded sections confirmed the frozen section diagnosis. Safe resection was performed in the first case, whereas surgery was abandoned and the patient was started on antifungal therapy in the second case. Both patients had a good outcome. CONCLUSIONS: This report underscores the usefulness of intraoperative frozen section to decide on a further course of treatment when faced with such unexpected situations. Frozen sections and crush smears hold great potential to avoid unwarranted surgical morbidity, particularly for skull base lesions. PMID- 28842227 TI - "Wait-and-See" Strategies for Newly Diagnosed Intracranial Meningiomas Based on the Risk of Future Observation Failure. AB - OBJECTIVE: To analyze factors affecting observation failure (Ob-F) of untreated intracranial meningiomas (IMs) and to develop a "wait-and-see" strategy for newly diagnosed IMs based on risk. METHODS: Factors affecting Ob-F (i.e., development of neurologic symptoms, significant growth, loss of opportunity to do radiosurgery, and tumor invasion into the adjacent sinus) were examined using a multivariate Cox proportional hazard model. The utility of the Asan Intracranial Meningiomas Scoring System (AIMSS) for screening out patients at risk for Ob-F was also analyzed. The "wait-and-see" strategy was based on the growth rate affecting the 5-year observation success (Ob-S) rate. RESULTS: Over 46.9 months, 77 of 232 patients (33.2%) experienced Ob-F. Larger tumors, preexisting neurologic symptoms, absence of calcification, and isointense/hyperintense signal were predictors of Ob-F. An AIMSS score of 4 for tumors <2.5 cm in diameter (P = 0.0002) and a score of 6 for tumors >=2.5 to <4.0 cm in diameter screened out tumors at risk for Ob-F (P = 0.0023). Initial growth rates of >=20%/year for tumors <2.5 cm (P < 0.0001) and >=1 cm3/year for tumors >=2.5 to <4.0 cm (P = 0.0019) were predictive of 5-year Ob-S rate; however, tumors >=4 cm tended to experience Ob-F, regardless of score group or growth rate. CONCLUSIONS: The AIMSS is helpful for screening out IMs at risk for Ob-F at the time of diagnosis. The initial growth rate after follow-up predicts the risk of future Ob-F in small- to medium- sized IMs. PMID- 28842228 TI - Microelectrode Recording-Guided Versus Intraoperative Magnetic Resonance Imaging Guided Subthalamic Nucleus Deep Brain Stimulation Surgery for Parkinson Disease: A 1-Year Follow-Up Study. AB - BACKGROUND: Microelectrode recording (MER) and intraoperative magnetic resonance imaging (iMRI) have been used in deep brain stimulation surgery for Parkinson disease (PD), but comparative methodology is lacking. Therefore, we compared the 1-year follow-up outcomes of MER-guided and iMRI-guided subthalamic nucleus (STN) deep brain stimulation (DBS) surgery in PD patients. METHODS: We conducted a review comparing PD patients who underwent MER-guided (n = 76, group A) and iMRI guided STN DBS surgery (n = 61, group B) in our institution. Pre- and postoperative assessments included Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score, Parkinson's Disease Questionnaire (PDQ-39), Mini-Mental State Examination (MMSE), levodopa equivalent daily doses (LEDDs), and magnetic resonance images. RESULTS: The mean magnitudes of electrode discrepancy were x = 1.1 +/- 0.2 mm, y = 1.3 +/- 0.3 mm, and z = 2.1 +/- 0.5 mm in group A and x = 1.3 +/- 0.4 mm, y = 1.2 +/- 0.2 mm, and z = 2.5 +/- 0.7 mm in group B. Significant differences were not found between 2 groups for x, y, or z (P = 0.34, P = 0.26, and P = 0.41, respectively). At 1 year, when levodopa was withdrawn for 12 hours, the UPDRS-III score improved by 66.3% +/- 13.5% in group A and 64.8% +/- 12.7% in group B (P = 0.24); the PDQ-39 summary index score improved by 49.7% +/- 14.3% in group A and 44.1% +/- 12.7% in group B (P = 0.16); the MMSE score improved by 4.2% +/- 2.1% in group A and 11.1% +/- 3.2% in group B (P = 0.43); and LEDDs decreased by 48.7% +/- 10.1% in group A and 56.9% +/- 12.0% in group B (P = 0.32). CONCLUSIONS: MER and iMRI both are effective ways to ensure adequate electrode placement in DBS surgery, but there is no superiority between both techniques, at least in terms of 1-year follow-up outcomes. PMID- 28842229 TI - Intraoperative Navigation Is Associated with Reduced Blood Loss During C1-C2 Posterior Cervical Fixation. AB - OBJECTIVE: Traumatic injuries, degenerative/rheumatologic conditions, tumors, or infections of the upper cervical spine may in certain circumstances require surgical stabilization. C1 lateral mass screws (Harms technique) in combination with C2 instrumentation (pars, pedicle, translaminar screws) have become a mainstay of surgical treatment. The surgical anatomy of the C1 lateral mass can be challenging especially with the robust venous plexus that often causes significant bleeding with exposure of the C1-C2 articular complex. The purpose of this study was to examine whether the use of navigation reduced intraoperative blood loss during atlantoaxial fixation. METHODS: We reviewed our institutional experience with atlantoaxial instrumentation with and without navigation from 2007 to 2016. We limited our cases to those requiring C1-C2 stabilization in traumatic and degenerative cases and not as part of more extensive surgical stabilizations. We identified 45 consecutive patients and compared intraoperative blood loss, need for transfusion, and time of procedure with and without the use of navigation. RESULTS: There was a significant reduction in the amount of intraoperative blood loss in the navigated (n = 20) versus non-navigated cases (n = 25). In addition, although the navigated cases initially were longer, currently there is no significant difference in the length of the cases. CONCLUSIONS: In our series, surgical navigation significantly reduced blood loss compared with non-navigated cases without increasing surgical time or risk of complication. Furthermore, navigation has the potential to reduce operative times due to a reduction in blood loss. PMID- 28842230 TI - Factors Predicting Ventricle Volume Increase After Aneurysmal Clipping in Patients with Subarachnoid Hemorrhage. AB - OBJECTIVE: Although many studies have evaluated risk factors associated with hydrocephalus after aneurysmal subarachnoid hemorrhage, specific ventricle volume changes after subarachnoid hemorrhage have not been evaluated. We sought to evaluate factors predicting ventricle volume enlargement in patients with aneurysmal subarachnoid hemorrhage by measuring ventricle volume with a validated, semiautomated tool. METHODS: Uni- and multivariable linear regression analyses were conducted with the follow-up ventricle volume as the dependent variable and the duration between subarachnoid hemorrhage occurrence and follow up imaging as the independent variable, classified by the use of various predictive factors. A logistic regression model was used to calculate the odds ratio for the greater ventricle volume group compared with the lower ventricle volume group based on predictive factors. RESULTS: We included 173 participants with a mean age of 55.5 years. Overall, an approximate increase in ventricle volume of 1.1 mL was observed daily within 60 days of clipping due to subarachnoid hemorrhage. In the multivariate logistic regression analysis, patients in the first and second tertile groups for body mass index showed approximately a 5.9- and 4.1-fold increased risk of greater follow-up ventricle volume, respectively, compared with the third tertile group for body mass index within 60 days of subarachnoid hemorrhage. CONCLUSIONS: We found that greater body mass index independently predicted suppression of ventricle volume growth, owing to maintenance of subarachnoid trabeculae structures after subarachnoid hemorrhage. Further studies are needed to confirm our findings. PMID- 28842231 TI - Evaluation of Correction of Radiologic Parameters (Angulation and Displacement) and Accuracy of C2 Pedicle Screw Placement in Unstable Hangman's Fracture with Intraoperative Computed Tomography-Based Navigation. AB - BACKGROUND: Opinions vary regarding optimal treatment of unstable hangman's fractures, including rigid orthosis and internal fixation. The anatomy of upper cervical spine is complex. The advent of intraoperative 3-dimensional navigation systems facilitates safe and accurate instrumentation. OBJECTIVE: To evaluate radiologic parameters of fracture morphology in unstable hangman's fracture in preoperative and postoperative period and accuracy of inserting axis pedicle screws by using intraoperative computed tomography-based navigation. METHODS: Fifteen patients with unstable hangman's fractures with age ranging from 17 years to 81 years were operated using computed tomography-based navigation from September 2011 to march 2016. Patient's age, sex, mechanism of injury, associated injuries, and neurologic status were noted. Clinical outcome, accuracy of screw insertion, preoperative and postoperative displacement, and angulation of C2 over C3 and bony fusion were assessed. RESULTS: Overall, 76 screws were inserted including 30 screws in C2 pedicle with 2 (2/60; 6.7%) malplaced screws in C2 pedicle. Mean follow-up period was 34 +/- 18 months (range 7-80 months). Mean hospital stay was 12.8 +/- 2.4 days. Mean preoperative and postoperative displacements were 4.09 mm +/- 1.78 mm and 1.82 mm +/- 1.14 mm respectively with a mean reduction of 2.27 mm +/- 1.49 mm. Mean preoperative angulation was 7.23 degrees +/- 11.96 degrees and postoperative angulation was 2.32 degrees +/- 4.77 degrees with a mean reduction of 5.11 degrees +/- 11.96 degrees . Bony fusion was achieved and rotation was preserved at C1-C2 joint in all cases. CONCLUSIONS: Intraoperative O-arm-based navigation is a safe, accurate, and effective tool for screw placement in patients with unstable hangman fracture and achieves good anatomical reduction. PMID- 28842232 TI - Endoscopic Third Ventriculostomy in Patients with Neurofibromatosis Type 1: A Multicenter International Experience. AB - BACKGROUND: Hydrocephalus in patients with neurofibromatosis (NF) type 1 is usually obstructive and may arise secondary to tumoral or nontumoral causes. Treatment of hydrocephalus in these patients is often challenging owing to combined pathologies and unique anatomic changes. The use of endoscopic third ventriculostomy (ETV) as treatment has rarely been described in this group. We aimed to characterize indications, considerations, and outcome of ETV in patients with NF 1 gathered in a multicenter international cohort. METHODS: Five centers participated in this retrospective study. Following institutional review board approval, data and images were collected. Patients of all ages with NF 1 who underwent ETV for treatment of obstructive hydrocephalus were included. Patients who had no postoperative radiologic or clinical follow-up were excluded. ETV failure was defined as recurrent clinical or radiologic signs of hydrocephalus. RESULTS: The study included 42 patients. Common etiologies for hydrocephalus were aqueductal/tectal tumor (31%), aqueductal web (26%), and aqueductal stenosis owing to NF-related changes (14%). Ten patients had a preoperative diagnosis of optic pathway glioma. ETV failures were identified in 6 patients within 1 month, in 3 patients within 9 months, and in 1 patient within 4 years. ETV was successful in 32 patients (76%) with a mean follow up of 59.4 months +/- 50.9 (range, 4 months to 15 years). CONCLUSIONS: ETV is a safe treatment for selected patients with NF 1 and obstructive hydrocephalus. Individual anatomic and pathologic aspects should be taken into consideration. PMID- 28842233 TI - Pattern of Corticospinal Projections Defined by Brain Mapping During Resective Epilepsy Surgery in a Patient with Congenital Hemiparesis and Intractable Epilepsy. AB - BACKGROUND: Congenital or early-onset brain structural lesions often cause contralateral hemiparesis, cognitive deficits, developmental delays, and seizures. Seizure is the most debilitating condition, as it greatly impairs quality of life in both the affected individuals and their caregivers and prevents them from active social participation. CASE DESCRIPTION: A 34-year-old man with hemiparesis and early-onset seizures since childhood owing to a congenital brain lesion developed intractable seizures in the last 2 years and was subsequently admitted for resective epileptic surgery. During the operation, we employed an innovative intraoperative neurophysiologic monitoring technique. In contrast to routine application for transcranial stimulation, we recorded compound muscle action potentials over the bilateral limb muscles simultaneously, instead of over the contralateral muscles only, to determine the patterns of the corticospinal projections. Transcranial stimulation over the bilateral hemispheres was applied before craniotomy, and direct cortical stimulation over the lesioned hemisphere was applied after craniotomy. By integrating both approaches, we could first identify the pattern of corticospinal projections before craniotomy and then accurately define the noneloquent area, which guided the resection to successfully accomplish the surgical goal. CONCLUSIONS: This technique is simple because no patient participation is required. We believe that it has the potential to replace conventional preoperative functional magnetic resonance imaging and transcranial magnetic stimulation in resective epilepsy surgery, particularly for young patients. Not only can it improve the safety of surgical procedures, but also it can help predict functional outcome. PMID- 28842234 TI - T1-T2 Herniated Disk Presenting with Horner Syndrome. AB - BACKGROUND: The incidence of thoracic disk herniation is estimated to be 1000 to 1,000,000. Upper thoracic disk herniation is an exceedingly rare pathology with unique neurologic features. We report a case of a young patient who presented with Horner syndrome caused by a T1-T2 disk herniation. CASE DESCRIPTION: A 34 year-old female patient was admitted to the emergency department presenting a sudden-onset history of ptosis and miosis on the left eye (Horner syndrome). She reported a 2-month history of neck, scapular, and medial left arm and forearm pain and numbness. The cervical magnetic resonance image showed a T1-T2 left disk herniation with intraforaminal compression of the T1 nerve root. A microdiskectomy was performed, and both left arm pain and Horner syndrome have completely regressed. CONCLUSIONS: Symptomatic T1-T2 disk herniation is an uncommon condition in a spine surgeon daily routine. The differential diagnosis for patients presenting upper limb pain and Horner's Syndrome should include upper thoracic disk herniation. Patients' outcomes can be excellent if an adequate surgical treatment is timely provided. PMID- 28842235 TI - Staged Endovascular Occlusion of a Posterior Communicating Artery-Cavernous Sinus Fistula and a Basilar Artery-Cavernous Sinus Fistula Associated with Traumatic Pseudoaneurysms: Technical Consideration and Literature Review. AB - BACKGROUND: Traumatic injury of the posterior communicating artery or the basilar artery causing arteriovenous fistulae is rare. CASE DESCRIPTION: Here we report an unusual case of the coincidence of a posterior communicating artery-cavernous sinus fistula and a basilar artery-cavernous sinus fistula associated with traumatic pseudoaneurysms of the posterior communicating and basilar arteries. The fistulas and pseudoaneurysms were obliterated completely after staged endovascular surgery via a transarterial and transvenous route. CONCLUSIONS: To our knowledge, this is the first such report worldwide. PMID- 28842236 TI - Treatment of Syringomyelia in Patients with Arachnoiditis at the Craniocervical Junction. AB - OBJECTIVE: Craniocervical junction arachnoiditis (CCJA) is an uncommon cause of syringomyelia. The pathophysiology of syrinx formation is uncertain, and the appropriate management unclear. A series of cases is reported to demonstrate variations in etiology, uniformity of functional cerebrospinal fluid obstruction at the foramen magnum, and results of surgical intervention. METHODS: We retrospectively analyzed the clinical and radiologic features of a consecutive series of patients treated for syringomyelia related to CCJA. RESULTS: Eight patients (5 male, 28-66 years old) were treated from 2000 to 2016. Magnetic resonance imaging demonstrated cervicothoracic syringomyelia in all cases, with the rostral extension of the syrinx suggesting communication with the fourth ventricle in all but one case. There was reduction of foramen magnum cerebrospinal fluid space in all cases, cerebellar ectopia in 5 cases, and fourth ventricular entrapment in 3 cases. Treatment consisted of posterior fossa decompression with either a GoreTex or pericranial patch graft. Six patients had a fourth-ventricle spinal subarachnoid shunt. Two patients had titanium mesh cranioplasty. The immediate postoperative period was associated with reduction in syrinx cavity size and improvement in neurologic symptoms in all cases. At follow up 10-60 months postoperatively, 3 patients exhibited recurrence of the syrinx and underwent successful reoperation at the craniocervical junction. One patient with persistence of the inferior component of the syrinx was treated with a syrinx-spinal subarachnoid shunt. CONCLUSIONS: Most syrinx cavities associated with CCJA communicate with the fourth ventricle. Posterior fossa decompression and fourth ventricle to spinal subarachnoid space shunting appears a reasonable treatment for this form of syringomyelia. PMID- 28842237 TI - Three-Dimensional Cortical Surface Reconstruction Versus Operative Findings: Their Similarity and Applications. AB - BACKGROUND: Three-dimensional cortical surface reconstruction (3DCSR) is an important tool for operations involving cerebral cortex, but data on its similarity to actual cortical architecture are lacking. In this study, the authors systematically tested the similarity between operative findings and 3DCSR built by a neuronavigation system and illustrated its applications. METHODS: The authors retrospectively retrieved operative photographs and 3DCSR of patients who underwent craniotomy with the aid of 3DCSR and asked 4 evaluators to perform a series of matching tests. Test 1 was to match 3DCSR and operative photographs. Test 2 was a repetition of test 1 to determine the consistency of matching ability. Test 3 was to match detailed anatomy of the 3DCSR with operative photographs. Scores on all tests were analyzed to measure the degree of similarity between 3DCSR and operative findings. The scores between patients with and without cortical distortion were compared to determine the impact of distortion on matching ability. RESULTS: Tests of similarity were performed on 22 patients. Mean scores of tests 1, 2, and 3 were 84.09%, 93.18%, and 89.77%, respectively. The Kappa statistic for agreement between test 1 and 2 ranged from 0.76 to 0.88. There was no statistically significant difference between average score of patients with and without cortical distortion in all tests. CONCLUSIONS: Authors have systematically demonstrated that 3DCSR built by neuronavigation system in this study provides detailed anatomy of cortical surface with a high degree of similarity to operative findings even in the presence of cortical distortion, leading to various applications beyond navigation alone. PMID- 28842238 TI - Comparison of Different Sequences of Magnetic Resonance Imaging and Ultrasonography with Nerve Conduction Studies in Peripheral Neuropathies. AB - BACKGROUND: Peripheral neuropathies refer to a group of disorders in which there is damage to the nerves of the peripheral nervous system. Electrophysiologic studies are the main stay for the diagnosis of peripheral neuropathies. However, direct visualization of the nerves is possible with exact localization of site of disease with high-resolution ultrasonography (USG) and 3-Tesla magnetic resonance imaging (MRI) scanner, and newer magnetic resonance (MR) sequences. METHODS: We performed a cross-sectional study including 55 patients and 64 nerves with upper limb peripheral neuropathies. All patients included underwent high-resolution focused USG of the nerves and MR neurography. A nerve conduction velocity study was performed for reference. RESULTS: The diagnostic confidence of the turbo spin echo T2-weighted (T2W) MR sequence was seen to be highest, with a sensitivity of 95.31%, whereas it was 81.25% for USG. Continuity of the nerve in patients with traumatic neuropathy was seen in 65.7% and 62.86% (22/35) nerves on MRI and USG, respectively. T1-weighted and T2W MR sequences were seen to be equally effective in establishing the continuity of the nerve. Increase in the caliber/thickening was seen in 77% of cases on MRI and 73.8% of cases on USG. Neuroma formation was seen equally on both MR and USG in 60.66%. We consistently found low fractional anisotropy (FA) values at the site of disease. CONCLUSIONS: USG is a sensitive technique to diagnose peripheral neuropathies and it should be used as a screening modality for focused MR to be performed later. Turbo spin echo T2W fast spin has the highest sensitivity to identify nerve disease and is comparable with nerve conduction studies. Among the newer sequences, diffusion tensor imaging should be performed to increase diagnostic confidence. PMID- 28842239 TI - Endoscopic Endonasal Odontoidectomy with Anterior C1 Arch Preservation in Rheumatoid Arthritis: Long-Term Follow-Up and Further Technical Improvement by Anterior Endoscopic C1-C2 Screw Fixation and Fusion. AB - OBJECTIVE: To examine the long-term outcomes (minimum of 4.5 years) of endoscopic endonasal odontoidectomy (EEO) with preservation of anterior C1 ring to treat irreducible ventral bulbo-medullary compressions in rheumatoid arthritis (RA) and to illustrate a novel technique of anterior pure endoscopic craniovertebral junction (CVJ) reconstruction and fusion. In fact, long-term clinical studies are still lacking to elucidate the effective role of EEO and whether it can obviate the need for posterior fixation. METHODS: From November 2008 to January 2012, clinical and radiologic data of 7 patients presenting with RA and associated irreducible bulbo-medullary compression treated with EEO were analyzed retrospectively. In all patients, decompression was achieved by EEO with anterior C1 arch preservation. In the last 2 patients, after EEO, we used the spared anterior C1 arch for reconstruction of anterior column of CVJ by positioning, under pure endoscopic guidance, autologous bone and 2 tricortical screws between the anterior arch of C1 and the residual odontoid. All patients were examined clinically with Ranawat classification and radiographically with computed tomography, magnetic resonance imaging, and dynamic radiography immediately after surgery and during follow-up. RESULTS: Adequate bulbo-medullary decompression with anterior C1 arch preservation was obtained in all cases. At follow-up (average, 66.2 months; range, 51-91 months) all patients experienced an improvement at least of one Ranawat classification level and presented no clinical or radiologic signs of instability. CONCLUSIONS: EEO with anterior C1 arch sparing provides satisfying long-term results for irreducible ventral CVJ lesions in RA. The preservation of anterior C1 arch and, when possible, the reconstruction of anterior CVJ can prevent the need for posterior fusion. PMID- 28842240 TI - Duty Hour Restrictions, Revisited: Second Year of FIRST Trial. PMID- 28842241 TI - Photodynamic diagnosis of visceral pleural invasion of lung cancer with a combination of 5-aminolevulinic acid and autofluorescence observation systems. AB - BACKGROUND: Visceral pleural invasion (PL) is a prognostic factor in lung cancer. In the lung, lymph flows along the pleura, in addition to the flow toward the pulmonary hilum just as the pulmonary arteries and veins run toward it. Even with the same tumor diameter, a PL1 or higher level of pleural invasion is indicative of a more advanced disease stage. Final diagnosis based on the PL level is made by pathological examination of excised specimens. However, if an intraoperative diagnosis can be established, proper selection of the surgical procedure can be made, and unnecessary surgeries for disseminated lesions can be avoided. We investigated optical diagnostic techniques for identifying the presence or absence of visceral pleural invasion in lung cancer by capitalizing on the phenomenon of 5-amino-levulinic acid (5-ALA) being metabolized to a photosensitizing substance or protoporphyrin IX within malignant tumors, generating red luminescence in response to excitation light. METHOD: This study included 38 patients with primary lung cancer who underwent surgery. They received 5-ALA (20mg/kg) orally 4h before surgery and then we assessed the presence or absence of pleural invasion using an autofluorescence observation system. At visceral pleural invasion sites, we were able to confirm tumor sites visualized in red with a clear border in contrast to the green autofluorescence generated in normal tissues. RESULT: Red luminescence could be confirmed in 100% of PL1-PL3 patients (14/14) and 41.6% of PL0 patients (10/24) with primary lung cancer. PL0 patients in whom visualization was possible were preoperatively diagnosed as having PL1 and many of them showed vascular channel invasion. The sensitivity, specificity, positive predictive value, and negative predictive value of this diagnostic technique were 100%, 58.0%, 63.1%, and 100%, respectively. Red fluorescence emission was observed significantly more often in pleural invasion cases. CONCLUSION: Accurate intraoperative diagnosis for visceral pleural invasion in lung cancer may contribute to determining the indications for limited operations such as segmental resection. In addition, accurate local diagnosis has the possibility of being applicable to photodynamic therapy. PMID- 28842242 TI - Letter in response to "the role of succinate and ROS in reperfusion injury - A critical appraisal" by Andrienko et al. PMID- 28842244 TI - Substance P receptor in the rat indusium griseum during postnatal development. AB - The presence of substance P (SP) receptor (Neurokinin-1 receptor, NK1R) in the indusium griseum (IG) and anterior hippocampal continuation (AHC) during postnatal development was studied by immunocytochemistry (ICC). NK1R immunopositive neurons (NK1RIP-n) first appeared in both areas on postnatal day (P) 5. From P5 onward, their distribution pattern was adult-like. In sagittal sections NK1RIP-n formed a narrow strip of neurons and dendrites that were located over the corpus callosum (cc); in coronal sections they were found in a roughly triangular area at the base of the cingulate cortex (Cg) on the dorsal surface of the cc. NK1RIP-n were also found in the AHC, which is considered as a subcallosal extension of the IG, located ventral to the genu of the cc. At all ages studied, IG NK1RIP-n sent dendrites to the contralateral IG, the underlying cc, and the Cg. Moreover, NK1RIP-n located in the Cg and the cc sent dendrites to the IG. The present findings are in line with previous ICC studies describing dopaminergic and serotoninergic afferents to the IG. Together these data suggest that, through NK1R, SP could play an important role in regulating the release mechanisms of these afferents and that it could be an important developmental factor. Notably, IG neurons could be activated by cortical and intracallosal afferents. PMID- 28842243 TI - The differential effects of unihemispheric and bihemispheric tDCS over the inferior frontal gyrus on proactive control. AB - This study examined the effects of bihemispheric and unihemispheric transcranial Direct Current Stimulation (tDCS) over the inferior frontal gyrus (IFG) on proactive control. Sixteen participants were randomized to receive (i) bihemispheric tDCS, with a 35cm2 anodal electrode of the right IFG and a 35cm2 cathode electrode of left IFG or (ii) unihemispheric tDCS, with a 35cm2 anodal electrode of the right IFG and a 100cm2 electrode of the left IFG or (iii) sham tDCS, while performing a prepotent inhibition task. There were significant speed accuracy tradeoff effects in terms of switch costs: unihemispheric tDCS significantly decreased the accuracy when compared to bihemispheric, and sham tDCS, while increased response time when comparing to bihemispheric and sham tDCS. The computational model showed a symmetrical field intensity for the bihemispheric tDCS montage, and an asymmetrical for the unihemispheric tDCS montage. This study confirms that unihemispheric tDCS over the rIFG has a significant impact on response inhibition. The lack of results of bihemispheric tDCS brings two important findings for this study: (i) left IFG seems to be also critically associated with inhibitory response control, and (ii) these results highlight the importance of considering the dual effects of tDCS when choosing the electrode montage. PMID- 28842245 TI - Silencing of FUS in the common marmoset (Callithrix jacchus) brain via stereotaxic injection of an adeno-associated virus encoding shRNA. AB - Fused in sarcoma (FUS) is an RNA binding protein that is involved in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To establish the common marmoset (Callithrix jacchus) as a model for FTLD, we generated a stereotaxic injection-based marmoset model of FUS-silencing. We designed shRNAs against the marmoset FUS gene and generated an AAV9 virus encoding the most effective shRNA against FUS (shFUS). The AAV encoding shFUS (AAV-shFUS) was introduced into the frontal cortex of young adult marmosets, whereas AAV encoding a control shRNA was injected into the contralateral side. We obtained approximately 70-80% silencing of FUS following AAV-shFUS injection. Interestingly, FUS-silencing provoked a proliferation of astrocytes and microglias. Since FTLD is characterized by various emotional deficits, it would be helpful to establish a marmoset model of FUS-silencing in various brain tissues for investigating the pathomechanism of higher cognitive and behavioral dysfunction. PMID- 28842246 TI - Mediterranean Dietary Pattern is Associated with Low Risk of Aggressive Prostate Cancer: MCC-Spain Study. AB - PURPOSE: We explored the association of the previously described Western, prudent and Mediterranean dietary patterns with prostate cancer risk by tumor aggressiveness and extension. MATERIALS AND METHODS: MCC-Spain (Multicase-Control Study on Common Tumors in Spain) is a population based, multicase-control study that was done in 7 Spanish provinces between September 2008 and December 2013. It collected anthropometric, epidemiological and dietary information on 754 histologically confirmed incident cases of prostate cancer and 1,277 controls 38 to 85 years old. Three previously identified dietary patterns, including Western, prudent and Mediterranean, were reconstructed using MCC-Spain data. The association of each pattern with prostate cancer risk was assessed by logistic regression models with random, province specific intercepts. Risk according to tumor aggressiveness (Gleason score 6 vs greater than 6) and extension (cT1-cT2a vs cT2b-cT4) was evaluated by multinomial regression models. RESULTS: High adherence to a Mediterranean dietary pattern rich not only in fruits and vegetables but also in fish, legumes and olive oil was specifically associated with a lower risk of Gleason score greater than 6 prostate cancer (quartile 3 vs 1 relative RR 0.66, 95% CI 0.46-0.96 and quartile 4 vs 1 relative RR 0.68, 95% CI 0.46-1.01, p-trend = 0.023) or with higher clinical stage (cT2b-T4 quartile 4 vs 1 relative RR 0.49, 95% CI 0.25-0.96, p-trend = 0.024). This association was not observed with the prudent pattern, which combines vegetables and fruits with low fat dairy products, whole grains and juices. The Western pattern did not show any association with prostate cancer risk. CONCLUSIONS: Nutritional recommendations for prostate cancer prevention should consider whole dietary patterns instead of individual foods. We found important differences between the Mediterranean dietary pattern, which was associated with a lower risk of aggressive prostate cancer, and Western and prudent dietary patterns, which had no relationship with prostate cancer risk. PMID- 28842247 TI - Treatment Patterns and Overall Survival Outcomes of Octogenarians with Muscle Invasive Cancer of the Bladder: An Analysis of the National Cancer Database. AB - PURPOSE: Elderly patients with muscle invasive bladder cancer can pose a therapeutic dilemma, given multiple comorbidities which may preclude surgery. In this registry based analysis we investigated treatment patterns and survival outcomes in this group of patients. MATERIALS AND METHODS: We queried the National Cancer Database for muscle invasive (cT2-T4aN0M0) bladder cancer in patients 80 years old or older who were diagnosed from 2004 to 2013. Patients included in study underwent transurethral resection of bladder tumor followed by radical cystectomy, radical cystectomy plus chemotherapy, radiation therapy alone, chemotherapy alone, chemoradiation or no treatment. We performed Kaplan Meier, log rank and multivariate Cox proportional hazards regression and propensity score matching. RESULTS: A total of 9,270 patients were identified with a median followup of 12.8 months. Median overall survival in patients treated with radical cystectomy alone was 23.2 months (95% CI 19.8-26.6), which was superior to that of chemotherapy alone or radiation therapy alone (p <0.0001). Those treated with chemoradiation had a median overall survival of 27.3 months (95% CI 25.0-29.7), which did not statistically differ from that of radical cystectomy alone (p = 0.39). Surgery plus chemotherapy showed the longest median overall survival of 34.5 months (95% CI 22.2-46.7, vs chemoradiation and radical cystectomy alone p <0.0001). On multivariate analysis and propensity score matching the best overall survival was seen in patients treated with surgery plus chemotherapy and there was no difference in overall survival between chemoradiation and radical cystectomy alone. CONCLUSIONS: In elderly patients with muscle invasive bladder cancer chemoradiation is an alternative definitive treatment strategy with survival equal to that of surgery alone and superior to that of chemotherapy alone or radiation therapy alone. If a patient was able to receive neoadjuvant or adjuvant chemotherapy with surgery, additional survival was observed in this nonrandomized study. PMID- 28842249 TI - Mitochondria and the eye diseases - Editorial. PMID- 28842248 TI - Two CYP82D Enzymes Function as Flavone Hydroxylases in the Biosynthesis of Root Specific 4'-Deoxyflavones in Scutellaria baicalensis. AB - Baicalein, wogonin, and their glycosides are major bioactive compounds found in the medicinal plant Scutellaria baicalensis Georgi. These flavones can induce apoptosis in a variety of cancer cell lines but have no effect on normal cells. Furthermore, they have many additional benefits for human health, such as anti oxidant, antiviral, and liver-protective properties. Here, we report the isolation and characterization of two CYP450 enzymes, SbCYP82D1.1 and SbCYP82D2, which function as the flavone 6-hydroxylase (F6H) and flavone 8-hydroxylase (F8H), respectively, in S. baicalensis. SbCYP82D1.1 has broad substrate specificity for flavones such as chrysin and apigenin and is responsible for biosynthesis of baicalein and scutellarein in roots and aerial parts of S. baicalensis, respectively. When the expression of SbCYP82D1.1 is knocked down, baicalin and baicalein levels are reduced significantly while chrysin glycosides accumulate in hairy roots. SbCYP82D2 is an F8H with high substrate specificity, accepting only chrysin as its substrate to produce norwogonin, although minor 6 hydroxylation activity can also be detected. Phylogenetic analysis suggested that SbCYP82D2 might have evolved from SbCYP82D1.1 via gene duplication followed by neofunctionalization, whereby the ancestral F6H activity is partially retained in the derived SbCYP82D2. PMID- 28842250 TI - RAP80 binds p32 to preserve the functional integrity of mitochondria. AB - RAP80, a member of the BRCA1-A complex, is a well-known crucial regulator of cell cycle checkpoint and DNA damage repair in the nucleus. However, it is still unclear whether Rap80 localizes to another region outside the nucleus and plays different roles with its partners. Here, we found mitochondrial p32 as a novel binding partner of RAP80 by using yeast two-hybrid screening. RAP80 directly binds the internal region of p32 through its arginine rich C-terminal domain. Based on the interaction, we showed that a subset of RAP80 localizes to mitochondria where p32 exists. Loss of function study revealed that RAP80 deficiency reduces the protein level of p32 and p32 dependent mitochondrial translating proteins such as Rieske and COX1. As a result, mitochondrial membrane potential and oxygen consumption are reduced in RAP80 knockdown cells, indicating mitochondrial dysfunction. Our study identifies a novel interaction between RAP80 and p32, which is important for preserving intact mitochondrial function. PMID- 28842251 TI - Sirt7 stabilizes rDNA heterochromatin through recruitment of DNMT1 and Sirt1. AB - Maintenance of highly compact heterochromatin at ribosomal DNA (rDNA) segments is essential to prevent homologous recombination between rDNA repeats and for preserving genomic stability and nucleolar architecture. Here, we investigated the role of Sirtuin 7 (Sirt7) in the regulation of rDNA chromatin structure, rDNA repeat stability and nucleolar organization. We found that Sirt7 mediates heterochromatin formation at rRNA genes through recruitment of DNA methyltransferase 1 and another member of the sirtuin family, Sirt1. Lack of Sirt7 leads to nucleolar fragmentation associated with hypomethylation of rDNA and hyperacetylation of histones at rDNA loci resulting in rDNA and genomic instability. Our findings suggest a novel role of Sirt7 in preventing cellular transformation by mediating maintenance of rDNA repeats and nucleolar integrity. PMID- 28842252 TI - E3 ubiquitin ligase DTX4 is required for adipogenic differentiation in 3T3-L1 preadipocytes cell line. AB - Deltex4 (DTX4) is a member of the Deltex family of proteins. To date several lines of evidences suggest that Deltex family of proteins is closely linked to cell development and cell differentiation. However, little is known about the role of DTX4 in adipogenic differentiation. In this study, we assessed the impact of DTX4 on adipogenic differentiation in vitro, we found that DTX4 protein expression gradually increased during adipogenic differentiation of 3T3-L1 preadipocytes cell line. While DTX4 stable knockdown by recombinant shRNA lentivirus (sh-DTX4) notably reduced the number of lipid droplets and down regulated the expression of adipogenic transcription factors C/EBPalpha and PPARgamma and adipogenic markers gene FABP4 and Adipsin. Besides, cell numbers and incorporation of 5-Ethynyl-2'-deoxyuridine (EdU) into cells were significantly decreased during mitotic clonal expansion (MCE) in sh-DTX4 cells postinduction. Furthermore, compared to recombinant shRNA lentivirus control group (sh-CON), the mRNA levels of Wnt signaling genes such as Wnt6, Wnt10b and beta-catenin, were obviously elevated in sh-DTX4 group at day 3 of postinduction. Taken together, our results indicate that DTX4 stable knockdown inhibits adipogenesis of 3T3-L1 cells through inhibiting C/EBPalpha and PPARgamma, arresting mitotic clonal expansion and regulating Wnt signaling pathway. PMID- 28842253 TI - Repression of ESR1 transcription by MYOD potentiates letrozole-resistance in ERalpha-positive breast cancer cells. AB - Transcriptional silencing of estrogen receptor alpha (ERalpha) expression is an important etiology contributing to the letrozole-resistance in ERalpha-positive breast cancer (BCa) cells, but the transcription factors responsible for this transcriptional repression remain largely unidentified. Here we report that the expression of the basic helix-loop-helix myogenic regulatory factor MYOD was abnormally up-regulated in letrozole-resistant BCa tissues and in experimentally induced letrozole-resistant BCa cells. Overexpression of the exogenous MYOD impaired ERalpha expression and potentiated letrozole-resistance in letrozole sensitive MCF7 cells, whereas MYOD knockdown could effectively restore ERalpha expression and thereby promote letrozole-sensitivity in letrozole-resistant MCF 7/LR cells. Mechanistically, MYOD was shown to be a potent corepressor of ESR1 transcription, and this transcriptional repression was significantly enhanced in the presence of letrozole treatment. Thus, targeted inhibition of MYOD may restore ERalpha level and lead to resensitization to letrozole-based hormone therapy, providing a novel therapeutic strategy for relapsed ERalpha-positive BCa patients. Our data also underscore an unexpected chemotherapeutic facet of MYOD, which may operate as a novel regulator of BCa biology. PMID- 28842254 TI - miR-1236-3p suppresses the migration and invasion by targeting KLF8 in lung adenocarcinoma A549 cells. AB - MicroRNAs (miRNAs) have a great effect on regulating tumor cell migration, invasion, proliferation and prognosis. However, the mechanism of miR-1236-3p on regulating carcinogenesis is still unknown. In this study, the expression of miR 1236-3p was lower in lung adenocarcinoma tissues than that in adjacent normal tissue. In lung adenocarcinoma A549 cell line, miR-1236-3p decreased ability of cell invasion and migration, furthermore, we show that KLF8 is targeted by miR 1236-3p, and expression of miR-1236-3p is negatively correlated with KLF8. Additionally, miR-1236-3p suppressed the expression of KLF8 and EMT (epithelial mesenchymal transition)-related genes. Overexpression of KLF8 can promote EMT related genes at protein level. In conclusion, our results support the fact that miR-1236-3p acts as a tumor inhibitor in lung adenocarcinoma by suppressing the activity of KLF8, and it may play a critical role in the diagnosis and treatment of lung cancer. PMID- 28842255 TI - Cyclin-dependent kinase 5 controls vasculogenic mimicry formation in non-small cell lung cancer via the FAK-AKT signaling pathway. AB - Vasculogenic mimicry (VM), an endothelial-independent tumor vascularization phenomenon representing functional tumor plasticity, might be the culprit behind the poor clinical outcome in classic antiangiogenesis treatment. However, the mechanism underlying VM needs to be elucidated. Cyclin-dependent kinase 5 (CDK5) has been recognized as a key factor in regulating migration and neuronal plasticity. Recently, CDK5 was associated with tumor migration and invasion and its expression levels correlated with poor clinical prognosis, indicating its important role in tumor cell plasticity. In this study, we determined the presence of VM network in the lung cancer cell line A549 by tube formation assay. Selective inhibition of CDK5 expression by roscovitine or siRNA significantly decreased VM formation in A549 cells both in vitro and in vivo and retarded tumor growth. To investigate the possible mechanism, we detected the downstream pathway of CDK5 by Western blotting and immunohistochemistry. We found that CDK5 silencing led to significant decrease in FAKSer732 and AKTSer472 phosphorylation level. Further studies showed that FAK knockdown impaired VM formation and deregulated cytoskeleton transformation of A549 cells. And these effects caused by FAK silence couldn't be reversed by adding CDK5 recombinant protein. This study indicates that CDK5 kinase activates the FAK/AKT signaling pathway to generate VM in a lung cancer cell line, which can help us develop potential therapeutic strategies against vessel-positive tumors. PMID- 28842256 TI - Quantitative analysis of chromatin accessibility in mouse embryonic fibroblasts. AB - Genomic DNA of eukaryotic cells is hierarchically packaged into chromatin by histones. The dynamic organization of chromatin fibers plays a critical role in the regulation of gene transcription and other DNA-associated biological processes. Recently, numerous approaches have been developed to map the chromatin organization by characterizing chromatin accessibilities in genome-wide. However, reliable methods to quantitatively map chromatin accessibility are not well established, especially not on a genome-wide scale. Here, we developed a modified MNase-seq for mouse embryonic fibroblasts, wherein chromatin was partially digested at multiple digestion times using micrococcal nuclease (MNase), allowing quantitative analysis of local yet genome-wide chromatin compaction. Our results provide strong evidence that the chromatin accessibility at promoter regions are positively correlated with gene activity. In conclusion, our assay is an ideal tool for the quantitative study of gene regulation in the perspective of chromatin accessibility. PMID- 28842257 TI - Antidepressant and pro-neurogenic effects of agmatine in a mouse model of stress induced by chronic exposure to corticosterone. AB - Agmatine is an endogenous neuromodulator that has been shown to have beneficial effects in the central nervous system, including antidepressant-like effects in animals. In this study, we investigated the ability of agmatine (0.1mg/kg, p.o.) and the conventional antidepressant fluoxetine (10mg/kg, p.o.) to reverse the behavioral effects and morphological alterations in the hippocampus of mice exposed to chronic corticosterone (20mg/kg, p.o.) treatment for a period of 21days as a model of stress and depressive-like behaviors. Chronic corticosterone treatment increased the immobility time in the tail suspension test (TST), but did not cause anhedonic-like and anxiety-related behaviors, as assessed with the splash test and the open field test (OFT), respectively. Of note, the depressive like behaviors induced by corticosterone were accompanied by a decrease in hippocampal cell proliferation, although no changes in hippocampal neuronal differentiation were observed. Our findings provide evidence that, similarly to fluoxetine, agmatine was able to reverse the corticosterone-induced depressive like behaviors in the TST as well as the deficits in hippocampal cell proliferation. Additionally, fluoxetine but not agmatine, increased hippocampal differentiation. Agmatine, similar to fluoxetine, was capable of increasing both dendritic arborization and length in the entire dentate hippocampus, an effect more evident in the ventral portion of the hippocampus, as assessed with the modified Sholl analysis. Altogether, our results suggest that the increase in hippocampal proliferation induced by agmatine may contribute, at least in part, to the antidepressant-like response of this compound in this mouse model of stress induced by chronic exposure to corticosterone. PMID- 28842258 TI - Children's Sleep Habits Questionnaire - Infant Version. AB - OBJECTIVES: This study proposed a version of the Children's Sleep Habits Questionnaire for infants under 12 months (CSHQ-I). METHODS: The sample was comprised of 299 infants, aged between 2 weeks and 12 months. RESULTS: Exploratory factor analysis revealed four subscales: Bedtime Resistance, Sleep Anxiety, Positive Sleep Habits, and Daytime Sleepiness. The CSHQ-I total scale presented good test-retest reliability and internal consistency. The CSHQ-I also showed good concurrent validity, with significant associations found between the CSHQ-I total scale and subscales and a measure of infant sleep-wake behaviors. CONCLUSIONS: The present study suggested the CSHQ-I as a reliable instrument to assess sleep problems in infants during the first year of life. PMID- 28842259 TI - A cytometric approach to follow variation and dynamics of the salivary microbiota. AB - Microbial flow cytometry is an established fast and economic technique for complex ecosystem studies and enables visualization of rapidly changing community structures by measuring characteristics of single microbial cells. Cytometric evaluation routines are available such as flowCyBar which are useful for automatic data processing. Here, a cytometric workflow was established which allows to routinely analyze salivary microbiomes on the example of ten oral healthy subjects. First, saliva was collected within a 3-month period, cytometrically analyzed and the evolution of the microbiomes followed as well as the calculation of their intra- and inter-subject similarity. Second, the respective microbiomes were stressed by exposition to high sugar or acid concentrations and immediate changes were recorded. Third, bactericide solutions were tested on their impact on the microbiomes. In all three set ups huge intra individual variations in cytometric community structures were found to be largely absent, even under stress, while inter-individual diversity was obvious. The bacterial cell counts of saliva samples were found to vary between 3.0*107 and 6.2*108 cells per sample and subject in undisturbed environments. The application of the two bactericides did not cause noteworthy diversity changes but the loss in cell numbers by about 50% was high after treatment. Illumina(r) sequencing of whole microbiomes or sorted sub-microbiomes revealed typical phyla such as Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes and Fusobacteria. This approach is useful for fast monitoring of individual salivary microbiomes and automatic calculation of intra- and inter-individual dynamic changes and variability and opens insight into ecological principles leading to their sustainment in their individual environment. PMID- 28842260 TI - Latent binocular function in amblyopia. AB - Recently, psychophysical studies have shown that humans with amblyopia do have binocular function that is not normally revealed due to dominant suppressive interactions under normal viewing conditions. Here we use magnetoencephalography (MEG) combined with dichoptic visual stimulation to investigate the underlying binocular function in humans with amblyopia for stimuli that, because of their temporal properties, would be expected to bypass suppressive effects and to reveal any underlying binocular function. We recorded contrast response functions in visual cortical area V1 of amblyopes and normal observers using a steady state visually evoked responses (SSVER) protocol. We used stimuli that were frequency tagged at 4Hz and 6Hz that allowed identification of the responses from each eye and were of a sufficiently high temporal frequency (>3Hz) to bypass suppression. To characterize binocular function, we compared dichoptic masking between the two eyes in normal and amblyopic participants as well as interocular phase differences in the two groups. We observed that the primary visual cortex responds less to the stimulation of the amblyopic eye compared to the fellow eye. The pattern of interaction in the amblyopic visual system however was not significantly different between the amblyopic and fellow eyes. However, the amblyopic suppressive interactions were lower than those observed in the binocular system of our normal observers. Furthermore, we identified an interocular processing delay of approximately 20ms in our amblyopic group. To conclude, when suppression is greatly reduced, such as the case with our stimulation above 3Hz, the amblyopic visual system exhibits a lack of binocular interactions. PMID- 28842261 TI - Updated meta-analysis of controlled observational studies: proton-pump inhibitors and risk of Clostridium difficile infection. AB - Attention has recently been directed toward a plausible link between Clostridium difficile infection (CDI) and proton-pump inhibitors (PPIs). However, the results of studies on the association between CDI and PPI remain controversial. We searched the literature databases from their inception to December 2016, without restriction of language, including all controlled observational studies examining the association between acid-suppressive therapy and CDI. Pooled analysis of 50 studies showed a significant association between PPI use and risk of developing CDI (odds ratio: 1.26; 95% confidence interval: 1.12-1.39) as compared with non users. When stratified by study patients, the relative risk of hospital-acquired CDI and community-associated CDI were 1.29 (1.14-1.44) and 1.17 (0.74-1.59). After restricting the studies according to hospital department, the relative risks of hospital-acquired CDI in ICUs and general wards were 1.43 (0.74-2.11) and 1.29 (1.13-1.45). By implementing cumulative meta-analysis, it was clear that earlier trials of CDI conducted in the early 2000s demonstrated a high degree of heterogeneity and a high percentage of negative results. Since 2011, the overall association between PPI use and risk of developing CDI has remained relatively stable within an effect size between OR 1.20 and 1.26. Our findings indicate a significant associated risk of incident CDI among PPI users, especially in general ward patients. The totality of evidence, when using cumulative meta analysis, showed that further trials are unlikely to overturn this positive result. Therefore establishing a guideline for the use of PPIs may help in future with the control of CDI. PMID- 28842262 TI - Blossoming vancomycin-resistant enterococci infections. PMID- 28842264 TI - Evaluation of antiviral activity of piperazine against Chikungunya virus targeting hydrophobic pocket of alphavirus capsid protein. AB - Small heterocyclic molecules such as piperazine are potential pharmacotherapeutic agents and binding of these molecules to the hydrophobic pocket of capsid protein (CP) offers a new perspective for therapeutic intervention. Here, we report the crystal structure of CP from Aura virus (AVCP) in complex with piperazine at 2.2 A resolution. Piperazine binds to the conserved hydrophobic pocket of CP where dioxane based antivirals bind. Comparative structural studies of the piperazine bound AVCP structure with the apo, active and dioxane-bound AVCP structures provide insights into the conformational variations in the pocket. Additionally, the molecular docking studies showed that piperazine binds into the hydrophobic pocket of Chikungunya virus CP (CVCP) with more affinity than with AVCP. Furthermore, the antiviral activity of piperazine against Chikungunya virus (CHIKV) was investigated by plaque reduction and immunofluorescence assays. The AVCP-piperazine complex may serve as a lead scaffold for structure-based design of piperazine derivatives as alphaviral inhibitors. The antiviral properties of piperazine provide its usefulness for further investigations towards the development of piperazine based anti-alphaviral drugs. PMID- 28842265 TI - Identification of broadly neutralizing monoclonal antibodies against Crimean Congo hemorrhagic fever virus. AB - Despite the serious public health impact of Crimean-Congo hemorrhagic fever (CCHF), the efficacy of antivirals targeting the causative agent, CCHF virus (CCHFV), remains debatable. Neutralizing monoclonal antibodies (MAbs) targeting the CCHFV glycoprotein Gc have been reported to protect mice against challenge with the prototype CCHFV strain, IbAr10200. However, due to extensive sequence diversity of CCHFV glycoproteins, it is unknown whether these MAbs neutralize other CCHFV strains. We initially used a CCHF virus-like particle (VLP) system to generate 11 VLP moieties, each possessing a glycoprotein from a genetically diverse CCHFV strain isolated in either Africa, Asia, the Middle East, or southeastern Europe. We used these VLPs in biosafety level 2 conditions to efficiently screen MAb cross-neutralization potency. Of the 16 MAbs tested, 3 (8A1, 11E7, and 30F7) demonstrated cross-neutralization activity with most CCHF VLPs, with 8A1 neutralizing all VLPs tested. Although binding studies suggest that none of the MAbs compete for the same epitope, combining 11E7, 30F7, or both 11E7 and 30F7 with 8A1 had no additive effect on increasing neutralization in this system. To confirm our findings from the VLP system, the 3 MAbs capable of strain cross-neutralization were confirmed to effectively neutralize 5 diverse CCHFV strains in vitro. Passaging CCHFV strains in the presence of sub neutralizing concentrations of MAbs did not generate escape mutants resistant to subsequent neutralization. This study demonstrates the utility of the VLP system for screening neutralizing MAbs against multiple CCHFV strains, and provides the first evidence that a single MAb can effectively neutralize a number of diverse CCHFV strains in vitro, which may lead to development of future CCHF therapeutics. PMID- 28842263 TI - Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription. AB - Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged "block and lock" approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clinical use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compound library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFalpha-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug. PMID- 28842266 TI - Rapamycin-induced autophagy restricts porcine epidemic diarrhea virus infectivity in porcine intestinal epithelial cells. AB - Porcine epidemic diarrhea virus (PEDV) invades porcine intestinal epithelial cells (IECs) and causes diarrhea and dehydration in pigs. In the present study, we showed a suppression of PEDV infection in porcine jejunum intestinal epithelial cells (IPEC-J2) by an increase in autophagy. Autophagy was activated by rapamycin at a dose that does not affect cell viability and tight junction permeability. The induction of autophagy was examined by LC3I/LC3II conversion. To confirm the autophagic-flux (entire autophagy pathway), autophagolysosomes were examined by an immunofluorescence assay. Pre-treatment with rapamycin significantly restricted not only a 1 h infection but also a longer infection (24 h) with PEDV, while this effect disappeared when autophagy was blocked. Co localization of PEDV and autophagosomes suggests that PEDV could be a target of autophagy. Moreover, alleviation of PEDV-induced cell death in IPEC-J2 cells pretreated with rapamycin demonstrates a protective effect of rapamycin against PEDV-induced epithelial cell death. Collectively, the present study suggests an early prevention against PEDV infection in IPEC-J2 cells via autophagy that might be an effective strategy for the restriction of PEDV, and opens up the possibility of the use of rapamycin in vivo as an effective prophylactic and prevention treatment. PMID- 28842267 TI - Medicinal properties of mangosteen (Garcinia mangostana L.): A comprehensive update. AB - Garcinia mangostana L. (Clusiaceae) is a tropical tree native to Southeast Asia known as mangosteen which fruits possess a distinctive and pleasant taste that has granted them the epithet of "queen of the fruits". The seeds and pericarps of the fruit have a long history of use in the traditional medicinal practices of the region, and beverages containing mangosteen pulp and pericarps are sold worldwide as nutritional supplements. The main phytochemicals present in the species are isoprenylated xanthones, a class of secondary metabolites with multiple reports of biological effects, such as antioxidant, pro-apoptotic, anti proliferative, antinociceptive, anti-inflammatory, neuroprotective, hypoglycemic and anti-obesity. The diversity of actions displayed by mangosteen xanthones shows that these compounds target multiple signaling pathways involved in different pathologies, and place them as valuable sources for developing new drugs to treat chronic and degenerative diseases. This review article presents a comprehensive update of the toxicological findings on animal models, and the preclinical anticancer, analgesic, neuroprotective, antidiabetic and hypolipidemic effects of G. mangostana L. extracts and its main isolates. Pharmacokinetics, drug delivery systems and reports on dose-finding human trials are also examined. PMID- 28842268 TI - The trait 'pessimism' does not interact with cognitive flexibility but makes rats more vulnerable to stress-induced motivational deficits: Results from the attentional set-shifting task. AB - In the present study, we have investigated the effects of the traits 'optimism' and 'pessimism' on cognitive flexibility in an animal model of depression based on chronic restraint stress. For this, first, we trained and tested the rats in a series of ambiguous-cue interpretation (ACI) tests, which allowed us to classify them as 'optimistic' or 'pessimistic'. Subsequently, we re-trained and re-tested the animals in the Attentional Set Shifting Task (ASST), which allowed evaluation of the differences between 'optimists' and 'pessimists' in terms of cognitive flexibility. Finally, we subjected half of the 'optimistic' and half of the 'pessimistic' rats to chronic (2 weeks) restraint stress and assessed the interaction between cognitive judgement bias and stress in the ASST. Although we did not observe statistically significant effects of the investigated traits and stress on cognitive flexibility, the 'pessimistic' animals subjected to chronic restraint stress showed significantly longer latencies to approach experimental rewards than their 'optimistic' conspecifics. This effect may indicate a stress induced motivational deficit that is specific to 'pessimistic' animals. The results of the present study, along with our previous reports, indicate that the trait 'pessimism' determines animals' vulnerability to stress. PMID- 28842269 TI - Evidence-based severity assessment: Impact of repeated versus single open-field testing on welfare in C57BL/6J mice. AB - According to current guidelines on animal experiments, a prospective assessment of the severity of each procedure is mandatory. However, so far, the classification of procedures into different severity categories mainly relies on theoretic considerations, since it is not entirely clear which of the various procedures compromise the welfare of animals, or, to what extent. Against this background, a systematic empirical investigation of the impact of each procedure, including behavioral testing, seems essential. Therefore, the present study was designed to elucidate the effects of repeated versus single testing on mouse welfare, using one of the most commonly used paradigms for behavioral phenotyping in behavioral neuroscience, the open-field test. In an independent groups design, laboratory mice (Mus musculus f. domestica) experienced either repeated, single, or no open-field testing - procedures that are assigned to different severity categories. Interestingly, testing experiences did not affect fecal corticosterone metabolites, body weights, elevated plus-maze or home cage behavior differentially. Thus, with respect to the assessed endocrinological, physical, and behavioral outcome measures, no signs of compromised welfare could be detected in mice that were tested in the open-field repeatedly, once, or, not at all. These findings challenge current classification guidelines and may, furthermore, stimulate systematic research on the severity of single procedures involving living animals. PMID- 28842270 TI - Games people play: How video games improve probabilistic learning. AB - Recent research suggests that video game playing is associated with many cognitive benefits. However, little is known about the neural mechanisms mediating such effects, especially with regard to probabilistic categorization learning, which is a widely unexplored area in gaming research. Therefore, the present study aimed to investigate the neural correlates of probabilistic classification learning in video gamers in comparison to non-gamers. Subjects were scanned in a 3T magnetic resonance imaging (MRI) scanner while performing a modified version of the weather prediction task. Behavioral data yielded evidence for better categorization performance of video gamers, particularly under conditions characterized by stronger uncertainty. Furthermore, a post experimental questionnaire showed that video gamers had acquired higher declarative knowledge about the card combinations and the related weather outcomes. Functional imaging data revealed for video gamers stronger activation clusters in the hippocampus, the precuneus, the cingulate gyrus and the middle temporal gyrus as well as in occipital visual areas and in areas related to attentional processes. All these areas are connected with each other and represent critical nodes for semantic memory, visual imagery and cognitive control. Apart from this, and in line with previous studies, both groups showed activation in brain areas that are related to attention and executive functions as well as in the basal ganglia and in memory-associated regions of the medial temporal lobe. These results suggest that playing video games might enhance the usage of declarative knowledge as well as hippocampal involvement and enhances overall learning performance during probabilistic learning. In contrast to non gamers, video gamers showed better categorization performance, independently of the uncertainty of the condition. PMID- 28842271 TI - Dopamine D1 receptor activation maintains motor coordination in injured rats but does not accelerate the recovery of the motor coordination deficit. AB - The sensorimotor cortex and the striatum are interconnected by the corticostriatal pathway, suggesting that cortical injury alters the striatal function that is associated with skilled movements and motor learning, which are functions that may be modulated by dopamine (DA). In this study, we explored motor coordination and balance in order to investigate whether the activation of D1 receptors (D1Rs) modulates functional recovery after cortical injury. The results of the beam-walking test showed motor deficit in the injured group at 24, 48 and 96h post-injury, and the recovery time was observed at 192h after cortical injury. In the sham and injured rats, systemic administration of the D1R antagonist SCH-23390 (1mg/kg) alone at 24, 48, 96 and 192h significantly (P<0.01) increased the motor deficit, while administration of the D1R agonist SKF-38393 alone (2, 3 and 4mg/kg) at 24, 48, 96 and 192h post-injury did not produce a significant difference; however, the co-administration of SKF-38393 and SCH-23390 prevented the antagonist-induced increase in the motor deficit. The cortical+striatal injury showed significantly increased the motor deficit at 24, 48, 96 and 192h post-injury (P<0.01) but did not show recovery at 192h. In conclusion, the administration of the D1R agonist did not accelerate the motor recovery, but the activation of D1Rs maintained motor coordination, confirming that an intact striatum may be necessary for achieving recovery. PMID- 28842272 TI - Pharmacotherapeutic potential of ginger and its compounds in age-related neurological disorders. AB - Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders with a risk that increases with aging. ANDs are generally characterized by common neuropathological conditions of the central nervous system, such as oxidative stress, neuroinflammation, and protein misfolding. Recently, efforts have been made to overcome ANDs because of the increase in age-dependent prevalence. Ginger, the rhizome of Zingiber officinale Roscoe, is a popular food spice and has a long history of use in traditional medicine for treating various disease symptoms. The structure-activity relationships of ginger phytochemicals show that ginger can be used to treat ANDs by targeting different ligand sites. This review shows that ginger and its constituents, such as 6-gingerol, 6-shogaol, 6-paradol, zingerone, and dehydrozingerone, are effective for ameliorating the neurological symptoms and pathological conditions of ANDs through by modulating cell death or cell survival signaling molecules. From this review, we conclude that the active ingredients in ginger have therapeutic potential in ANDs. PMID- 28842274 TI - Structural changes in socio-affective networks: Multi-modal MRI findings in long term meditation practitioners. AB - Our goal was to assess the effects of long-term mental training in socio affective skills on structural brain networks. We studied a group of long-term meditation practitioners (LTMs) who have focused on cultivating socio-affective skills using loving-kindness and compassion meditation for an average of 40k h, comparing these to meditation-naive controls. To maximize homogeneity of prior practice, LTMs were included only if they had undergone extensive full-time meditation retreats in the same center. MRI-based cortical thickness analysis revealed increased thickness in the LTM cohort relative to meditation-native controls in fronto-insular cortices. To identify functional networks relevant for the generation of socio-affective states, structural imaging analysis were complemented by fMRI analysis in LTMs, showing amplitude increases during a loving-kindness meditation session relative to non-meditative rest in multiple prefrontal and insular regions bilaterally. Importantly, functional findings partially overlapped with regions of cortical thickness increases in the left ventrolateral prefrontal cortex and anterior insula, suggesting that these regions may play a central role in the generation of emotional states relevant for the meditative practice. Our multi-modal MRI approach revealed structural changes in LTMs who have cultivated loving-kindness and compassion for a significant period of their life in functional networks activated by these practices. These preliminary cross-sectional findings motivate future longitudinal work studying brain plasticity following the regular practice of skills aiming at enhancing human altruism and prosocial motivation. PMID- 28842275 TI - Preferential isolation of Megasphaera elsdenii from pig feces. AB - Lactic acid produced by intestinal bacteria is fermented by lactate-utilizing bacteria. In this study, we developed a selective culture medium (KMI medium) for Megasphaera elsdenii, a lactate-utilizing bacterium that is abundant in pig intestines. Supplementation of the medium with lactate and beef extract powder was necessary for the preferential growth of M. elsdenii. In addition, we designed a species-specific primer set to detect M. elsdenii. When pig fecal samples were plated on KMI agar medium, approximately 60-100% of the resulting colonies tested positive using the M. elsdenii-specific PCR primers. In fact, nearly all of the large, yellow-white colonies that grew on the KMI agar medium tested positive by PCR with this primer set. The 16S rRNA gene sequences of three representative PCR-positive strains showed strong similarities to that of M. elsdenii ATCC 25940T (98.9-99.2% identity). These three strains were approximately 1.5 MUm sized cocci that were primarily arranged in pairs, as was observed for M. elsdenii JCM 1772T. The selective KMI medium and species-specific primer set developed in this study are useful for the isolation and detection of M. elsdenii and will be useful in research aimed at increasing our understanding of intestinal short-chain fatty acid metabolism in pigs. PMID- 28842276 TI - Toxic genes present a unique phylogenetic signature. AB - Horizontal gene transfer (HGT) is a major part of the evolution of Archaea and Bacteria, to the extent that the validity of the Tree of Life concept for prokaryotes has been seriously questioned. The patterns and routes of HGT remain a subject of intense study and debate. It was discovered that while several genes exhibit rampant HGT across the whole prokaryotic tree of life, others are lethal to certain organisms and therefore cannot be successfully transferred to them. We distinguish between these two classes of genes and show analytically that genes found to be toxic to a specific species (E. coli) also resist HGT in general. Several tools we employ show evidence to support that claim. One of those tools is the quartet plurality distribution (QPD), a mathematical tool that measures tendency to HGT over a large set of genes and species. When aggregated over a collection of genes, it can reveal important properties of this collection. We conclude that evidence of toxicity of certain genes to a wide variety of prokaryotes are revealed using the new tool of quartet plurality distribution. PMID- 28842277 TI - Olfactory discrimination and memory deficits in the Flinders Sensitive Line rodent model of depression. AB - Major Depressive Disorder (MDD) is a heterogeneous psychiatric disorder with broad symptomatic manifestations. The current study examined, for the first time, olfactory memory and discrimination in the Flinders Sensitive Line (FSL) rodent model of depression. Male FSL rats and controls were trained on an Olfactory Discrimination (OD) and a Social Interaction (SI) test. On the OD test, the FSL and controls performed similarly at the shortest inter-trial interval (5min), however, with extended delay of 30min, the FSLs had a recall and odour discrimination deficit. At the longest delay (60min) both groups performed poorly. The FSL rats i.) had a deficit in olfactory discrimination suggesting impairment in olfactory memory and recall; ii.) were less likely to socialize with unfamiliar rats. The data suggests that FSL animals have an impaired olfactory information processing capacity. PMID- 28842273 TI - Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets. AB - Asthma is a complex inflammatory disease characterized by airway inflammation and hyperresponsiveness. The mechanisms associated with the development and progression of asthma have been widely studied in multiple populations and animal models, and these have revealed involvement of various cell types and activation of intracellular signaling pathways that result in activation of inflammatory genes. Significant contributions of Toll-like-receptors (TLRs) and transcription factors such as NF-kB, have been reported as major contributors to inflammatory pathways. These have also recently been associated with mechanisms of oxidative biology. This is of important clinical significance as the observed inefficacy of current available treatments for severe asthma is widely attributed to oxidative stress. Therefore, targeting oxidizing molecules in conjunction with inflammatory mediators and transcription factors may present a novel therapeutic strategy for asthma. In this review, we summarize TLRs and NF-kB pathways in the context of exacerbation of asthma pathogenesis and oxidative biology, and we discuss the potential use of polyphenolic flavonoid compounds, known to target these pathways and possess antioxidant activity, as potential therapeutic agents for asthma. PMID- 28842278 TI - Discrimination of emotional prosodies in human neonates: A pilot fNIRS study. AB - Very early in development, vocal emotional cues are more critical than facial expressions in guiding infants' behavior. However, the processing of emotional prosody in the very early days of life is still far from clearly understood. To address the issue, this study used functional near-infrared spectroscopy to examine brain response of neonates when they passively listened to fearful, angry, happy and neutral prosodies. It was found that while the right temporal cortex (mainly located in the middle temporal gyrus and superior temporal gyrus) exhibited enhanced response to emotional, relative to neutral, prosody, a right parietal area (approximately located in the supramarginal gyrus) showed a heightened sensitivity to fearful, relative to happy and neutral, prosody. These findings highlight the crucial importance of the right hemisphere in the perception of emotional prosody in neonates. Furthermore, the result is consistent with the notion of a negativity bias, supporting the evolutionary importance of threatening information that could be processed at birth. PMID- 28842279 TI - Itch induces conditioned place aversion in mice. AB - Itch sensation consists of both sensory and emotional components. The molecular and cellular mechanisms underlying the transduction and transmission of itch sensation have been studied extensively in rodents. However, whether itch induces emotional responses in mice still remains unknown. We found that pruritogens induced conditioned place aversion (CPA) in mice, and that the CPA lasted for at least two weeks. Disruption of itch signal transmission by depletion of peripheral sensory fibers expressing TRPV1 (transient receptor potential vanilloid subfamily, member 1) attenuated chloroquine-induced CPA. Consistently, ablation of itch-specific neurons that express gastrin-releasing peptide receptor in the spinal cord also abolished itch-induced CPA, confirming that itch-induced CPA is dependent on the spinal itch circuit. Thus, these results demonstrate that itch can induce CPA in mice, which requires peripheral itch signal inputs. PMID- 28842280 TI - Electroacupuncture alleviates surgery-induced cognitive dysfunction by increasing alpha7-nAChR expression and inhibiting inflammatory pathway in aged rats. AB - Postoperative cognitive dysfunction (POCD) is a common disorder of cognitive functions in aged patients following anesthesia and surgery. alpha7-nicotinic acetylcholine receptors (alpha7-nAChR) plays a regulatory role in cognitive processes and is involved in cognitive deficits. This study aims to observe the effect of electroacupuncture (EA) on the cognitive function in aged POCD rats, and its regulation on expressions of hippocampal alpha7-nAChR and proinflammatory factors. Ninety healthy Sprague-Dawley male aged rats were randomly divided into three groups (each n=30): control group (sham operation), model group (partial hepatectomy), and electroacupuncture (EA) group. The cognitive function was detected by Morris water-maze test, and the changes of hippocampal expressions of alpha7-nAChR, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL 1beta) were detected by immunohistochemical method. Our results showed that compared with the model group, the EA group had significantly shorter escape latency and decreased crossing platform times at 1d, 3d and 7d after operation (P<0.05). alpha7-nAChR positive neurons in the hippocampus decreased and TNF alpha and IL-1beta positive neurons increased on postoperative days 1, 3 and 7. Compared with the model group, the alpha7-nAChR positive neurons were increased and TNF-alpha and IL-1beta positive neurons were decreased in the EA group at the same time points (P<0.05). In conclusion, the electroacupuncture regulation can improve the learning and memory abilities in POCD rats, and its mechanism may be related to upregulation of alpha7-nAChR and downregulation of TNF-alpha and IL 1beta in hippocampus. PMID- 28842281 TI - Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear. AB - The present study examined the pattern of activation of neurons that express dopamine receptors 1 and 2 (D1R and D2R), and parvalbumin (PV) in mice that underwent extinction of a fear memory. Adult male transgenic mice expressing D1R or D2R tagged with green fluorescent protein (GFP) were conditioned with 6 tone shock pairings. The following day they were randomly divided into one of four experimental groups: extinction, retrieval, context or handled. Extinction groups were exposed to 45 tone presentations, retrieval groups were exposed to 5 tone presentations and the context groups were exposed to the chamber without any tones. Ninety minutes following their assigned treatment, mice were perfused and brain tissue processed for Fos/GFP/PV immunohistochemistry. Quantification of immunoreactivity revealed that extinction resulted in changes in the infralimbic cortex including increased Fos expression and a decrease in the number of D2R+ cells compared to all other groups. Conversely, fear memory retrieval resulted in increased activation of D2R+ cells in the prelimbic cortex compared to all other groups. Additional changes were observed in the extinction and retrieval groups that were different to the handled group, but not to the context group, which highlights that there is overlapping neurocircuitry between extinction and retrieval of fear memory, as well as with context exposure. These results provide novel insights into the roles of specific dopamine receptor subtypes, which will be valuable for informing future research that aims to strengthen extinction learning via dopaminergic mechanisms. PMID- 28842282 TI - Detection and quantification of the plasmid-mediated mcr-1 gene conferring colistin resistance in wastewater. AB - There is a global concern about the increasing resistance of bacterial pathogens to colistin, an antibiotic of last resort for the treatment of multidrug resistant Gram-negative bacterial infections (e.g. carbapenemase-producing Enterobacteriaceae). In this study, an increasing prevalence of colistin resistance in raw and treated wastewater was demonstrated using a new developed SYBR Green-based real-time PCR assay for specific detection and quantification of the plasmid-mediated mcr-1 gene. Raw and treated wastewater samples were collected from a wastewater treatment plant in Girona (Spain) at two different time periods (November 2011-January 2012 and December 2016-February 2017). In both periods, the absolute abundance of the mcr-1 gene was significantly higher (P <0.05) in raw sewage samples, suggesting that conventional wastewater treatment reduces colistin-resistant bacteria. Moreover, the analysis revealed an increase from 1-2 orders of magnitude in the absolute abundance of mcr-1 between the studied periods (winter 2011 versus winter 2016, P <0.05), suggesting that colistin resistance has increased over time. This study gives evidence of the growing spread of mcr-1 and provides a real-time PCR assay for its rapid detection and quantification. PMID- 28842283 TI - Effect of combination therapy containing a high-dose carbapenem on mortality in patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection. AB - OBJECTIVES: To evaluate the impact of high-dose (HD) carbapenem-based combination therapy on clinical outcome in patients with monomicrobial carbapenem-resistant Klebsiella pneumoniae (CR-KP) bloodstream-infection (BSI). METHODS: Post hoc analysis of all adult patients with CR-KP BSI who were treated with a combination antibiotic regimen, collected over a six-year period in six large Italian teaching hospitals. To control for confounding effects of HD carbapenem combination on 14-day mortality, a multivariate Cox regression analysis was performed. Due to imbalances between patients, a propensity score for receiving HD carbapenem was added to the model. RESULTS: 595 patients with CR-KP BSI were analysed, 77% of isolates showed a carbapenem MIC >=16 mg/L, 428 (71.9%) received HD carbapenem-based combination therapy. Overall, 127 patients (21.3%) died within 14 days after BSI onset. Multivariate analysis showed the Charlson comorbidity index (HR 1.31, 95%CI 1.20-1.43, P <0.001), septic shock at BSI onset (HR 3.14, 95%CI 2.19-4.50, P <0.001), and colistin-resistant strain (HR 1.52, 95%CI 1.02-2.24, P = 0.03) were independently associated with 14-day mortality, whereas admission to surgical ward (HR 0.44, 95%CI 0.25-0.78, P = 0.005) and HD carbapenem use (HR 0.69, 95%CI 0.47-1.00, P = 0.05) were protective factors. When adjusted for the propensity score, HD carbapenem use showed a greater protective effect (HR 0.64, 95%CI 0.43-0.95, P = 0.03). Stratifying the model for carbapenem MIC, the benefit of HD carbapenem was also observed for strains with carbapenem MIC >=16 mg/L. CONCLUSIONS: In patients receiving combination therapy for CR-KP BSI, the use of HD carbapenem seems to be associated with better outcome, even in the presence of high-level carbapenem resistance. PMID- 28842284 TI - Penetration of polymeric nanoparticles loaded with an HIV-1 inhibitor peptide derived from GB virus C in a vaginal mucosa model. AB - Despite the great effort to decrease the HIV infectivity rate, current antiretroviral therapy has several weaknesses; poor bioavailability, development of drug resistance and poor ability to access tissues. However, molecules such as peptides have emerged asa new expectative to HIV eradication. The vaginal mucosa is the main spreading point of HIV. There are natural barriers such as the vaginal fluid which protects the vaginal epithelium from any foreign agents reaching it. This work has developed and characterized Nanoparticles (NPs) coated with glycol chitosan (GC), loaded with an HIV-1 inhibitor peptide (E2). In vitro release and ex vivo studies were carried out using the vaginal mucosa of swine and the peptide was determined by HPLC MS/MS validated method. Moreover, the peptide was labeled with 5(6)-carboxyfluoresceine and entrapped into the NPs to carried out in vivo studies and to evaluate the NPs penetration and toxicity in the vaginal mucosa of the swine. The mean size of the NPs, xi and the loading percentage were fundamental features for to reach the vaginal tissue and to release the peptide within intercellular space. The obtained results suggesting that the fusion inhibitor peptides loaded into the NPs coated with GC might be a new way to fight the HIV-1, due to the formulation might reach the human epithelial mucosa and release peptide without any side effects. PMID- 28842286 TI - Incidence and risk factors of acute kidney injury in the Japanese trauma population: A prospective cohort study. AB - INTRODUCTION: Previous studies have reported the prevalence and risk factors of acute kidney injury (AKI) in relatively young trauma patients. The aims of this study were to identify the prevalence and risk factors of AKI among older Japanese trauma patients. METHODS: We conducted a prospective observational study in the 8-bed intensive care unit (ICU) of a Japanese tertiary-care hospital. Participants comprised trauma patients aged 18 years or older admitted to the ICU. Our primary outcome was the incidence of AKI within 10days of admission, according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: Among 333 patients, 66 (19.8%) developed AKI (Stage 1, n=54; Stages 2, n=5; and Stage 3, n=7). Multivariate logistic regression analysis revealed that the incidence of AKI was associated with increased age (odds ratio (OR), 1.38; 95% confidence interval (CI), 1.15-1.65), male sex (OR, 2.06; 95%CI, 1.04-4.07), greater amount of red blood cell transfusions (OR, 1.61; 95%CI, 1.04-1.17), and presence of underlying chronic kidney disease (CKD) (OR, 3.97; 95%CI, 1.78-8.83). Length of stay in the ICU was significantly longer in patients with AKI (6days) than in those without (3days; p<0.001). Patients >=65 years old were more likely to develop AKI (26.2% vs 11.6%; p<0.001). No significant differences in ICU stay (median, 4 vs 4days; p=0.70), hospital stay (median, 24 vs 21days; p=0.45), or 28 day mortality (2.1% vs 1.4%; p=0.19) were evident between age groups. CONCLUSIONS: Approximately 20% of trauma patients developed AKI, and the elderly were more likely to develop AKI. Older age, male, greater units of red blood cell transfusions, and underlying CKD were associated with incidence of AKI. PMID- 28842285 TI - miR-93-5p/IFNAR1 axis promotes gastric cancer metastasis through activating the STAT3 signaling pathway. AB - Aberrant expression of microRNAs (miRNAs) plays an important role in gastric cancer (GC) development. miR-93-5p has shown opposing functions in different types of cancers, but the exact expression pattern and molecular mechanism of miR 93-5p in GC development remain to be elucidated. Here, we reported that miR-93-5p expression was increased in GC tissues compared with the adjacent normal tissues and that its overexpression was correlated with distant metastasis and poor survival in GC patients. miR-93-5p knockdown inhibited the migration, invasion and proliferation of GC cells in vitro and in vivo, while its overexpression displayed an opposite result. Using an mRNA microarray, we found that miR-93-5p significantly downregulated IFNAR1 expression in GC cells, which was further identified as a direct target of miR-93-5p. IFNAR1 knockdown promoted GC cell migration and invasion, but its restoration could rescue GC cell migration and invasion induced by miR-93-5p overexpression. Moreover, miR-93-5p-IFNAR1 axis increased MMP9 expression via STAT3 pathway in GC cells. Taken together, we reveal that miR-93-5p overexpression is associated with the poor survival of GC patients and miR-93-5p-IFNAR1 axis promotes GC metastasis through activation of STAT3 pathway. PMID- 28842287 TI - Determining potential of PMMA as a depot for rifampin to treat recalcitrant orthopaedic infections. AB - BACKGROUND: Open fractures are often complicated by infection. In cases of severe soft tissue and vascular injury, systemic antibiotics may be ineffective due to their inability to reach and provide direct antimicrobial activity to the zone of injury. High antibiotic concentrations within the wound can be achieved with reduced systemic toxicity by using local antibiotic delivery. As bacteria associated with musculoskeletal injuries frequently form biofilms, antibiotic selection is important. Herein, the use of rifampin, an antibiotic with activity against biofilms, delivered via polymethylmethacrylate (PMMA) beads is evaluated for use in a traumatic musculoskeletal wound model. METHODS: PMMA beads loaded with rifampin, or combinations of rifampin and vancomycin, were prepared and evaluated for time to curing, drug release kinetics in vitro, and infection prevention in vivo using a well-established rat model of musculoskeletal infection. A segmental bone defect was created and contaminated with methicillin susceptible Staphylococcus aureus (UAMS-1). Wounds were debrided, irrigated, and treated with PMMA beads, containing rifampin or combinations of rifampin plus vancomycin, following a 6-h (early) or 24-h (delayed) treatment. After 14days, tissue, implants, and beads were removed for bacterial quantification and assessed for rifampin resistance. RESULTS: There was a direct association between loaded concentration and release kinetics of the rifampin and vancomycin from PMMA beads. Higher rifampin concentrations delayed PMMA curing times. The addition of vancomycin to PMMA resulted in more rapid release of rifampin from beads. However, the highest concentration of rifampin loaded PMMA beads (10% wt/wt) was the only treatment to significantly reduce bacterial counts. No rifampin resistance was observed. CONCLUSION: Although higher concentrations of rifampin resulted in significant reductions of bacteria, these levels extended PMMA curing times and transformed PMMA material characteristics. While these characteristics make the material unsuitable for weight-bearing applications, such as total joint arthroplasty, the use of rifampin-loaded PMMA beads may be an effective intervention in a contaminated traumatic extremity wound due to its ability to eradicate biofilms. PMID- 28842288 TI - Effects of seeding adipose-derived stem cells on electrospun nanocomposite used as chest wall graft in a murine model. AB - OBJECTIVES: Malignant neoplasms infiltrating the chest wall often requires resection of the thoracic wall. To replace the defect, Gore-Tex(r) is usually employed as the gold standard material, however, Gore-Tex(r) is inert and not degradable. Novel materials are nowadays available which allow a full bio integration due to their non-toxic degradability. Additionally, stem cell seeding has the capacity to reduce inflammatory response towards such grafts, thus integrating it better into the host organism. PMID- 28842289 TI - Favorable and publicly funded studies are more likely to be published: a systematic review and meta-analysis. AB - OBJECTIVES: The aim of this study was to identify and quantify the characteristics of studies associated with the likelihood of publication. STUDY DESIGN AND SETTING: We searched for manuscripts that tracked cohorts of clinical studies ("cohorts") that from launch to publication. We explored the association of study characteristics with the probability of publication via traditional meta analyses and meta-regression using random effects models. RESULTS: The literature review identified 85 cohorts of studies that met our inclusion criteria. The probability of publication was significantly higher for studies whose characteristics were favorable (odds ratio [OR] = 2.04; 95% confidence interval [CI]: 1.62, 2.57) or statistically significant (OR = 2.07; 95% CI: 1.52, 2.81), had a multicenter design (OR = 1.32; 95% CI: 1.16, 1.45), and were of later regulatory phase (3/4 vs. 1/2, OR = 1.34; 95% CI: 1.14, 1.49). Industry funding was modestly associated with lower (OR = 0.81; 95% CI: 0.67, 0.99) probability of publication. An exploratory analysis of effect modification revealed that the effect of the study characteristic "favorable results" on likelihood for publication was stronger for industry-funded studies. CONCLUSION: The study characteristics of favorable and significant results were associated with greater probability of publication. PMID- 28842291 TI - RNA splicing: An ingenious gene self editing tool. PMID- 28842290 TI - Cherry-picking by trialists and meta-analysts can drive conclusions about intervention efficacy. AB - OBJECTIVES: The objective of this study was to determine whether disagreements among multiple data sources affect systematic reviews of randomized clinical trials (RCTs). STUDY DESIGN AND SETTING: Eligible RCTs examined gabapentin for neuropathic pain and quetiapine for bipolar depression, reported in public (e.g., journal articles) and nonpublic sources (clinical study reports [CSRs] and individual participant data [IPD]). RESULTS: We found 21 gabapentin RCTs (74 reports, 6 IPD) and 7 quetiapine RCTs (50 reports, 1 IPD); most were reported in journal articles (18/21 [86%] and 6/7 [86%], respectively). When available, CSRs contained the most trial design and risk of bias information. CSRs and IPD contained the most results. For the outcome domains "pain intensity" (gabapentin) and "depression" (quetiapine), we found single trials with 68 and 98 different meta-analyzable results, respectively; by purposefully selecting one meta analyzable result for each RCT, we could change the overall result for pain intensity from effective (standardized mean difference [SMD] = -0.45; 95% confidence interval [CI]: -0.63 to -0.27) to ineffective (SMD = -0.06; 95% CI: 0.24 to 0.12). We could change the effect for depression from a medium effect (SMD = -0.55; 95% CI: -0.85 to -0.25) to a small effect (SMD = -0.26; 95% CI: 0.41 to -0.1). CONCLUSIONS: Disagreements across data sources affect the effect size, statistical significance, and interpretation of trials and meta-analyses. PMID- 28842292 TI - Using game authoring platforms to develop screen-based simulated functional assessments in persons with executive dysfunction following traumatic brain injury. AB - The assessment of functional status is a critical component of clinical neuropsychological evaluations used for both diagnostic and therapeutic purposes in patients with cognitive brain disorders. There are, however, no widely adopted neuropsychological tests that are both ecologically valid and easily administered in daily clinical practice. This discrepancy is a roadblock to the widespread adoption of functional assessments. In this paper, we propose a novel approach using a serious game authoring platform (eAdventure) for creating screen-based simulated functional assessments. We created a naturalistic functional task that consisted of preparing a cup of tea (SBS-COT) and applied the assessment in a convenience sample of eight dyads of therapists/patients with mild executive dysfunction after traumatic brain injury. We had three main aims. First, we performed a comprehensive review of executive function assessment in activities of daily living. Second, we were interested in measuring the feasibility of this technology with respect to staffing, economic and technical requirements. Third, a serious game was administered to patients to study the feasibility of this technology in the clinical context (pre-screening test). In addition, quantitative (Technology Acceptance Model (TAM) questionnaires) and qualitative (semistructured interviews) evaluations were applied to obtain user input. Our results suggest that the staffing, economic and technical requirements of the SBS COT are feasible. The outcomes of the pre-screening test provide evidence that this technology is useful in the functional assessment of patients with executive dysfunction. In relation to subjective data, the TAM questionnaire showed good user acceptability from a professional perspective. Interview analyses with professionals and patients showed positive experiences related to the use of the SBS-COT. Our work indicates that the use of these types of authoring platforms could have positive long-term implications for neuropsychological research, opening the door to more reproducible, cooperative and efficient research by allowing the facilitated production, reuse and sharing of neuropsychological assessment tools. PMID- 28842294 TI - Bivalent role of intra-platelet serotonin in liver regeneration and tumor recurrence in humans. AB - BACKGROUND & AIMS: Besides its critical role during liver regeneration, serotonin (5-HT) has been found to act as a mitogenic factor in several neoplastic entities. Accordingly, we aimed to evaluate whether intra-platelet 5-HT (IP5-HT) was associated with oncological outcome after liver resection and concomitantly evaluate its ability to serve as a therapeutic target to promote liver regeneration. METHODS: A total of 96 patients undergoing liver resection for malignant liver tumors were prospectively included. Optimized plasma and serum preparation were performed and IP5-HT levels were determined. Patients were followed up for postoperative liver dysfunction (LD), morbidity, disease free and overall survival (OS). RESULTS: We found increased preoperative IP5-HT levels in patients with disease recurrence at 6 and 12months (p=0.046, p=0.020, respectively). In clear contrast, patients suffering from postoperative morbidity, severe morbidity or LD had significantly reduced IP5-HT levels (p=0.011, p=0.035, p=0.003, respectively). Patients with high IP5-HT levels (>134ng/ml) suffered from an increased incidence of postoperative disease recurrence at 6 and 12months (p=0.045, p=0.006, respectively) but exhibited a reduction in morbidity, severe morbidity, and LD (p=0.006, p=0.008, p=0.005, respectively). We confirmed these results in our two largest subgroups, demonstrating that they were independent of tumor type. This bivalent effect of IP5-HT was also reflected in patients receiving selective serotonin reuptake inhibitor treatment, who displayed a reduction in disease recurrence accompanied by an increase in postoperative morbidity. Yet, both early disease recurrence and morbidity worsened OS. CONCLUSION: Herein, we present first clinical evidence for IP5-HT being associated with early disease recurrence after liver resection in humans. Thus, pharmacological intervention at the level of platelets and platelet derived 5-HT to promote liver regeneration should be considered with caution. A careful definition of indications and timing is needed to promote liver regeneration without inducing deleterious effects. LAY SUMMARY: Preoperative intra-platelet serotonin (IP5-HT) levels seem to substantially affect patient outcomes after liver resection for liver tumors. While there is a narrow window of IP5-HT levels where liver regeneration and tumor progression is balanced, excessively high IP5-HT levels (>134ng/ml IP5-HT) lead to an increased incidence of early tumor recurrence and excessively low IP5-HT levels (<73ng/ml IP5-HT) lead to a higher rate of morbidity. Ultimately, overall survival is negatively affected by both postoperative early disease recurrence and morbidity. ClinicalTrials.gov-Identifier: NCT01700231. PMID- 28842293 TI - Temperament Is Associated With Outdoor Free Play in Young Children: A TARGet Kids! Study. AB - OBJECTIVE: Outdoor free play is important for preschoolers' physical activity, health, and development. Certain temperamental characteristics are associated with obesity, nutrition, and sedentary behaviors in preschoolers, but the relationship between temperament and outdoor play has not been examined. This study examined whether there is an association between temperament and outdoor play in young children. METHODS: Healthy children aged 1 to 5 years recruited to The Applied Research Group for Kids (TARGet Kids!), a community-based primary care research network, from July 2008 to September 2013 were included. Parent reported child temperament was assessed using the Childhood Behavior Questionnaire. Outdoor free play and other potential confounding variables were assessed through validated questionnaires. Multivariable linear regression was used to determine the association between temperament and outdoor play, adjusted for potential confounders. RESULTS: There were 3393 children with data on outdoor play. The association between negative affectivity and outdoor play was moderated by sex; in boys, for every 1-point increase in negative affectivity score, mean outdoor play decreased by 4.7 minutes per day. There was no significant association in girls. Surgency was associated with outdoor play; for every 1 point increase in surgency/extraversion, outdoor play increased by 4.6 minutes per day. CONCLUSIONS: Young children's temperamental characteristics were associated with their participation in outdoor free play. Consideration of temperament could enhance interventions and strategies to increase outdoor play in young children. Longitudinal studies are needed to elucidate the relationship between children's early temperament and physical activity. PMID- 28842295 TI - Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. AB - BACKGROUND & AIMS: Hepatic ischemia-reperfusion injury (IRI), characterized by exogenous antigen-independent local inflammation and hepatocellular death, represents a risk factor for acute and chronic rejection in liver transplantation. We aimed to investigate the molecular communication involved in the mechanism of liver IRI. METHODS: We analyzed human liver transplants, primary murine macrophage cell cultures and IR-stressed livers in myeloid-specific heme oxygenase-1 (HO-1) gene mutant mice, for anti-inflammatory and cytoprotective functions of macrophage-specific HO-1/SIRT1 (sirtuin 1)/p53 (tumor suppressor protein) signaling. RESULTS: Decreased HO-1 expression in human post-reperfusion liver transplant biopsies correlated with a deterioration in hepatocellular function (serum ALT; p<0.05) and inferior patient survival (p<0.05). In the low HO-1 liver transplant biopsy group, SIRT1/Arf (alternative reading frame)/p53/MDM2 (murine double minute 2) expression levels decreased (p<0.05) while cleaved caspase 3 and frequency of TUNEL+cells simultaneously increased (p<0.05). Immunofluorescence showed macrophages were the principal source of HO-1 in human and mouse IR-stressed livers. In vitro macrophage cultures revealed that HO-1 induction positively regulated SIRT1 signaling, whereas SIRT1-induced Arf inhibited ubiquitinating activity of MDM2 against p53, which in turn attenuated macrophage activation. In a murine model of hepatic warm IRI, myeloid-specific HO 1 deletion lacked SIRT1/p53, exacerbated liver inflammation and IR-hepatocellular death, whereas adjunctive SIRT1 activation restored p53 signaling and rescued livers from IR-damage. CONCLUSION: This bench-to-bedside study identifies a new class of macrophages activated via the HO-1-SIRT1-p53 signaling axis in the mechanism of hepatic sterile inflammation. This mechanism could be a target for novel therapeutic strategies in liver transplant recipients. LAY SUMMARY: Post transplant low macrophage HO-1 expression in human liver transplants correlates with reduced hepatocellular function and survival. HO-1 regulates macrophage activation via the SIRT1-p53 signaling network and regulates hepatocellular death in liver ischemia-reperfusion injury. Thus targeting this pathway in liver transplant recipients could be of therapeutic benefit. PMID- 28842296 TI - Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation. AB - BACKGROUND & AIMS: Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients. METHODS: Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain. RESULTS: In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p=0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT. CONCLUSIONS: Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need. LAY SUMMARY: Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need. PMID- 28842297 TI - Professor Samuel H. Yalkowsky: Scientist, Mentor, and Molecular Empath. PMID- 28842298 TI - Conformational Preference and Spectroscopical Characteristics of the Active Pharmaceutical Ingredient Levetiracetam. AB - The analysis of the possible conformers and the conformational change between solid and liquid states of a particular drug molecule are mandatory not only for describing reliably its spectroscopical properties but also for understanding the interaction with the receptor and its mechanism of action. Therefore, here we investigated the free-energy conformational landscape of levetiracetam (LEV) in gas phase as well as in water and ethanol, aiming to describe the 3-dimensional structure and energetic stability of its conformers. Twenty-two unique conformers were identified, and their energetic stability was determined at density functional theory B3LYP/6-31+G(2d,2p) level of theory. The 6 most stable monomers in water, within a relative free-energy window of 0.71 kcal mol-1 and clearly separated in energy from the remaining subset of 16 conformers, as well as the 3 most stable dimers were then used to compute the Boltzmann populations-averaged UV-Vis and NMR spectra of LEV. The conformational landscape in solution is distinctly different from that corresponding to gas phase, particularly due to the relative orientations of the butanamide group. Aiming to clarify the stability of the possible dimers of LEV, we also investigated computationally the structure of a set of 11 nonhydrated and hydrated homochiral hydrogen-bonded LEV dimers. PMID- 28842299 TI - Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid. AB - This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (<=320 MUg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid. PMID- 28842300 TI - Targeted Drug Delivery via Folate Receptors for the Treatment of Brain Cancer: Can the Promise Deliver? AB - Brain cancers are among the most lethal tumors due to their rapid development and poor prognosis. Despite the existing potential of novel therapeutic strategies for the treatment of brain cancer, the major remaining challenge associated with clinical translation is the lack of effective and safe delivery strategies to ensure drug transport to tumor tissues following systemic administration. Folate receptors, known to overexpress on different types of cancer cells, have been used to develop targeted delivery of therapeutic agents for cancer therapy. In this review, the potential of exploiting the folate receptor to achieve targeted cell-specific delivery of nanoparticles containing brain cancer therapeutics will be discussed in tandem with an analysis of the possible reasons for the current lack of clinical translation. PMID- 28842301 TI - Controlled and Localized Nitric Oxide Precursor Delivery From Chitosan Gels to Staphylococcus aureus Biofilms. AB - Extracellular polymeric substances in bacterial biofilms reduce the penetration of antimicrobials and give rise to extreme recalcitrance and treatment challenges for many persistent biofilms and associated infections. Nitric oxide (NO) is a promising alternative to conventional antimicrobials but is challenging to deliver at precise concentrations for significant periods in a convenient and nontoxic manner. Here we report a unique NO delivery platform by incorporating the NO precursor isosorbide mononitrate (ISMN) into chitosan gels to facilitate sustained ISMN release and effective delivery. The chitosan gels were characterized with respect to the drug release kinetics, rheological properties, as well as antimicrobial efficacy against biofilms of Staphylococcus aureus in the absence and presence of the antibiotic ciprofloxacin. Chitosan gels loaded with ISMN alone (CS-ISMN) showed comparable antimicrobial effects compared to blank chitosan gel (approximately 2 log10 reduction). However, there was strong synergy of CS-ISMN when combined with ciprofloxacin, that is, ~4 log10 reduction of bacterial colonies of CS-ISMN-CIP compared to the single treatments. These findings were confirmed by confocal imaging and highlight a potentially effective new way to overcome recalcitrant S aureus biofilms using NO precursors. PMID- 28842302 TI - Syringe Filling of High-Concentration mAb Formulation: Slow Suck-Back Pump Speed Prevented Filling Needle Clogging. AB - Partial and complete clogging of filling needles occurred during syringe filling of a high-concentration mAb formulation. This caused nonvertical liquid flow, which eventually led to the termination of filling. Overcoming this phenomenon was essential to ensure minimal fill weight variation, product waste, and manufacturing downtime. The liquid behavior inside the filling needle was studied using glass and stainless steel needles and demonstrated that effective suck-back control was critical for preventing needle clogging. A key finding of our work is that the suck-back pump speed was a critical factor to achieve an effective suck back. More specifically, a slow suck-back pump speed (<10 rpm; liquid flow rate, <5 mL/min) was essential to improve suck-back control inside the conventional stainless steel filling needles. In contrast, higher suck-back pump speeds (>10 rpm; liquid flow rate, >5 mL/min) resulted in downward product migration within the filling needle leading to formation of a liquid plug at the needle tip, which was prone to rapid drying. Slowing the suck-back pump speed in conjunction with modifying the suck-back volume was effective at consistently withdrawing product into the stainless steel filling needles and prevented needle clogging. PMID- 28842303 TI - Aspirin resistance are associated with long-term recurrent stroke events after ischaemic stroke. AB - OBJECTIVE: To investigate the prevalent of aspirin resistance (AR) in stroke and its association with recurrent stroke in 214 patients with ischemic stroke who were receiving aspirin before the stroke onset. METHODS: Two hundreds and fourteen acute stroke patients who previously received aspirin therapy (100mg/day for >=7days) were enrolled. Whole blood samples were collected for platelet aggregation testing. The result is expressed in aspirin reaction units (ARU). A cutoff of 550 ARU was used to determine the presence of AR. A follow-up period of 1year was performed to record stroke recurrence events. RESULTS: In this study, the median age was 68 years (IQR, 60-77 years), and 118 (55.1%) were men. A total of 43 of 214 enrolled patients (20.1%) were AR. ARU levels were significantly higher in patients with recurrence than those without (514[IQR: 466-592] vs. 454[IQR: 411-499]; P <0.001). The stroke recurrence distribution across the ARU quartiles ranged between 7.41% (first quartile) to 40.74% (fourth quartile). In multivariate analyses, the 3th and 4th quartile of ARU was significantly associated with stroke recurrence during the observation period compared to the 1st quartile group, and the adjusted risk increased by 215% (OR=3.15 [95% CI 1.96 4.33], P=0.007) and 322% (4.22[2.56-7.16], P<0.001). In multivariate logistic regression analysis, AR was associated with a higher risk of stroke recurrence, and the adjusted risk increased by 365% (OR=4.65; 95% CI=2.99-8.16; P<0.001). CONCLUSION: In conclusion, AR is not uncommon in Chinese stroke patients who receive anti-platelet medications. Patients with AR may have a greater risk of suffering stroke recurrence events. PMID- 28842304 TI - Establishment of a rhesus monkey model of chronic temporal lobe epilepsy using repetitive unilateral intra-amygdala kainic acid injections. AB - OBJECTIVE: Temporal lobe epilepsy (TLE) is a common type of acquired epilepsy refractory to medical treatment. As such, establishing animal models of this disease is critical to developing new and effective treatment modalities. Because of their small head size, rodents are not suitable for comprehensive electroencephalography (EEG) evaluation via scalp or subdural electrodes. Therefore, a larger primate model that closely recapitulates signs of TLE is needed; here we describe a rhesus monkey model resembling chronic TLE. METHODS: Eight monkeys were divided into two groups: kainic acid (KA) group (n=6) and saline control group (n=2). Intra-amygdala KA injections were performed biweekly via an Ommaya device until obvious epileptiform discharges were recorded. Video EEG recording was conducted intermittently throughout the experiment using both scalp and subdural electrodes. Brains were then analyzed for Nissl and glial fibrillary acid protein (GFAP) immunostaining. RESULTS: After 2-4 injections of KA (approximately 1.2-2.4mg, 0.12-0.24mg/kg), interictal epileptiform discharges (IEDs) were recorded in all KA-treated animals. Spontaneous recurrent seizures (SRSs) accompanied by symptoms mimicking temporal lobe absence (undetectable without EEG recording), but few mild motor signs, were recorded in 66.7% (four of six) KA-treated animals. Both IEDs and seizures indicated a primary epileptic zone in the right temporal region and contralateral discharges were later detected. Segmental pyramidal cell loss and gliosis were detected in the brain of a KA-treated monkey. CONCLUSIONS: Through a modified protocol of unilateral repetitive intra-amygdala KA injections, a rhesus monkey model with similar behavioral and brain electrical features as TLE was developed. PMID- 28842305 TI - Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression. AB - Major depression is a common neuropsychiatric disease with high lifetime prevalence and high incidence of suicide. This study aimed to evaluate the antidepressant effects of ginsenoside Rg2 in mice, and the possible mechanism was also determined. A single injection of both Rg2 (10 and 20mg/kg) and fluoxetine (positive control, 20mg/kg) induced notable antidepressant-like effects in the forced swim test and tail suspension test without affecting the locomotor activity of mice, and the tests were done 30min after the injection. Also, repeated daily treatment of Rg2 and fluoxetine for the last 2 weeks fully reversed the chronic mild stress (6 weeks)-induced depressive-like symptoms in mice. Moreover, western blot analysis showed that Rg2 administration significantly increased the BDNF signaling pathway in hippocampus. Importantly, the usage of TrkB shRNA fully blocked the antidepressant effects of Rg2 in mice. Collectively, these results suggest that Rg2 produces an antidepressant-like effect in mice which is mediated, at least in part, through promoting the hippocampal BDNF signaling pathway. PMID- 28842306 TI - Berberine attenuates depressive-like behaviors by suppressing neuro-inflammation in stressed mice. AB - Berberine, the major constituent alkaloid originally from the famous Chinese herb Huanglian (Coptis chinensis), has been shown to exert antidepressant-like effects in rodents. However, it is still not clear the involvement of neuro-inflammation suppression in the effects of berberine. The purpose of this study was to determine whether berberine affects the neuro-inflammation system in mice induced by chronic unpredictable mild stress (CUMS). Berberine was orally administrated in normal or CUMS mice for successive four weeks. Behavioral evaluation showed that berberine prevented the depressive deficits both in sucrose preference test and novelty-suppressed feeding test. The elevation of hippocampal pro inflammatory cytokines such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), as well as the activation of microglia were decreased by berberine. In addition, chronic berberine treatment inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) signaling pathway as the phosphorylated proteins of NF-kappaB, IkappaB kinase (IKK)alpha and IKKbeta in the hippocampus were suppressed after berberine administration. Furthermore, inducible nitric oxide synthase (iNOS), one downstream target of NF-kappaB signaling pathway was also inhibited by berberine. In conclusion, these findings suggest that administration of berberine could prevent depressive-like behaviors in CUMS mice by suppressing neuro-inflammation in the hippocampus. PMID- 28842307 TI - Febrile rhabdomyolysis of unknown origin in refugees coming from West Africa through the Mediterranean to Calabria, Italy. PMID- 28842308 TI - Void forming index: A new parameter for detecting microstructural transformation caused by powder agglomeration. AB - As powder agglomeration during storage causes a decrease in the performance of dry powder inhalers (DPIs), it is important to understand the properties of powder agglomeration in developing DPIs. Generally, powder agglomeration is caused by capillary force and crystalline transformation in conditions of higher humidity. It is, however, difficult to correlate crystalline transformation and powder agglomeration, especially when the crystalline transformation is limited. In this study, we focused on the application of inverse gas chromatography (iGC) to detect powder agglomeration directly. There was a slight change between the powder state and lactose agglomerates using powder X-ray diffraction, and dynamic vapor sorption. On the other hand, a change in pressure drop was found during measurement of lactose using iGC. After measurement by iGC, powdered lactose agglomerated. This finding suggests that a pressure drop is related to powder agglomeration and can be employed to detect the onset of powder agglomeration. Based on these findings, we propose a novel index-the Void Forming Index (VFI) which is related to the pressure drop with iGC. The VFI is a useful index in the evaluation of powder agglomeration, and will be especially useful during DPI development. PMID- 28842309 TI - Drug solubilization by complexation. AB - Drugs must possess some solubility in water to be therapeutically effective after oral or topical administration to the eye, and drugs must be soluble to be formulated as aqueous solutions for, for example, parenteral delivery. A variety of methods can be applied to enhance aqueous solubility of poorly soluble drugs one of which is the usage of solubilizing complexing agents. There are numerous types of complexes and some are more water-soluble than others. Coordination complexes consist of drugs that act as complexing agents (i.e. ligands) and metal ions (i.e. substrates). Examples of coordination complexes are some water-soluble tetracycline-metal ion complexes. Organic molecular complexes can consist of a small substrate (i.e. the drug) and a small (e.g., caffeine) or a large (e.g., polyvinylpyrrolidone) ligand. In inclusion complexes the substrate is partly or completely enveloped by the complexing agent (e.g., cyclodextrin). Finally, pharmacosomes are drug-phospholipid complexes that can not only enhance aqueous solubility of poorly soluble drugs but also their solubility in organic solvents. This is a mini-review of solubilizing complexing agents that are or can be used in pharmaceutical products. PMID- 28842310 TI - Designing optimal formulations for hot-melt coating. AB - Hot-melt coating (HMC) as a solvent-free technology grants faster and more economic coating processes with reduced risk of dissolving the drug during the process. Moreover, traditional coating equipment can be modified to enable the HMC process. Despite the indubitable advantages and feasibility of the process, HMC is not well-known to pharmaceutical industry and its employment is still limited. The main aspect hindering the widespread application of this technique is the need of materials alternative to the conventional polymeric coatings. The current work reviews the published HMC formulations and describes the properties that have led to their selection. As these materials are mainly solid lipid excipients, attention should be paid to their crystallization and solid state behavior, and their impact on the performance of coated drug products, particularly on the stable drug release profile. Although different drug release profiles can be easily tailored, much development work is needed to respond to the unmet requirements of a stable formulation. Ensuring stable solid-state behavior and providing a mechanistic understanding of the macroscopic properties are essential steps towards fulfilling these requirements and establishing of HMC as advanced coating technology for manufacturing of pharmaceutical products. PMID- 28842311 TI - Structure-based drug design of novel peptidomimetic cellulose derivatives as HCV NS3 protease inhibitors. AB - Hepatitis C Virus (HCV) represents a global health threat not only due to the large number of reported worldwide HCV infections, but also due to the absence of a reliable vaccine for its prevention. HCV NS3 protease is one of the most important targets for drug design aiming at the deactivation of HCV. In the present work, molecular docking simulations are carried out for suggested novel NS3 protease inhibitors applied to the Egyptian genotype 4. These inhibitors are modifications of dimer cellulose by adding a hexa-peptide to the cellulose at one of the positions 2, 3, 6, 2', 3' or 6'. Results show that the inhibitor compound with the hexa-peptide at position 6 shows significantly higher simulation docking score with HCV NS3 protease active site. This is supported by low total energy value of docking system, formation of two H-bonds with HCV NS3 protease active site residues, high binding affinity and increased stability in the interaction system. PMID- 28842312 TI - Desipramine rescues age-related phenotypes in depression-like rats induced by chronic mild stress. AB - AIMS: Our previous finding demonstrates that major depressive disorder can mediate accelerated aging in rats. Desipramine is a typical tricyclic antidepressant, and can provide neuroprotection and counteract depression-like behaviors. However, whether desipramine can rescue age-related phenotypes in depressed individuals is not understood. In the present study, we investigated the physiological function of desipramine on rescuing the age-related phenotypes in these animals. MAIN METHODS: The rats were induced by chronic mild stress paradigm, and the depression-like behaviors of rats were detected by sucrose intake test, open field test (OFT) and forced swimming test (FST). Then the depressed rats were treated by desipramine. KEY FINDINGS: Desipramine administration was effective in counteracting depression-like behaviors by increasing the sucrose solution intake, reducing the immobility time in the FST, and increasing total distance travelled and numbers of grid line crossed in the OFT. Moreover, desipramine treatment was able to reduce the oxidative damage to rat liver, and to increase the expression of telomerase reverse transcriptase (TERT), leading to correspondingly restored telomerase activity. SIGNIFICANCE: Our findings identify that one function of desipramine may partly be to rescue age-related phenotypes in depressed individuals induced by chronic stress. PMID- 28842313 TI - A facile approach to functionalizing cell membrane-coated nanoparticles with neurotoxin-derived peptide for brain-targeted drug delivery. AB - The blood brain barrier separates the circulating blood from the extracellular fluid in the central nervous system and thus presents an essential obstacle to brain transport of therapeutics. Herein, we report on an effective brain-targeted drug delivery system that combines a robust red blood cell membrane-coated nanoparticle (RBCNP) with a unique neurotoxin-derived targeting moiety. The RBCNPs retain the complex biological functions of natural cell membranes while exhibiting physicochemical properties that are suitable for effective drug delivery. CDX peptide is derived from candoxin and shows high binding affinity with nicotinic acetylcholine receptors (nAChRs) expressed on the surface of brain endothelial cells. Through a facile yet robust approach, we successfully incorporate DCDX peptides onto the surface of RBCNPs without compromising the peptide's brain targeting ability. The resulting DCDX-RBCNPs show promising brain targeting efficiency both in vitro and in vivo. Using a glioma mouse model, we demonstrate that doxorubicin-loaded DCDX-RBCNPs have superior therapeutic efficacy and markedly reduced toxicity as compared to the nontargeted drug formulations. While RBCNPs are used as a model system to evaluate the surface modification approach, the reported method can be readily generalized to various types of cell membrane-derived nanocarriers for broad medical applications. PMID- 28842314 TI - Oral delivery of Escherichia coli persistently infected with M2e-displaying bacteriophages partially protects against influenza A virus. AB - We describe a novel live oral vaccine type. Conceptually, this vaccine is based on a non-lytic, recombinant filamentous bacteriophage that displays an antigen of interest. To provide proof of concept we used the amino-terminal part of a conserved influenza A virus epitope, i.e. matrix protein 2 ectodomain (M2e) residues 2 to 16, as the antigen of interest. Rather than using the phages as purified virus-like particles as a vaccine, these phages were delivered to intestinal Peyer's patches as a live bacterium-phage combination that comprises Escherichia coli cells that conditionally express invasin derived from Yersinia pseudotuberculosis. Invasin-expressing E. coli cells were internalized by mammalian Hep-2 cells in vitro and adhered to mouse intestinal microfold (M) cells ex vivo. Invasin-expressing E. coli cells were permissive for recombinant filamentous bacteriophage f88 that displays M2e and became persistently infected. Oral administration of the live engineered E. coli-invasin-phage combination to mice induced M2e-specific serum IgG antibodies. Mice that had been immunized with invasin-expressing E. coli cells that carried M2e2-16 displaying fd phages seroconverted to M2e and showed partial protection against challenge with influenza A virus. Oral delivery of a live vaccine comprising a bacterial host that is targeted to Peyer's patches and is persistently infected with an antigen displaying phage, can thus be exploited as an oral vaccine. PMID- 28842315 TI - Bisphosphonate-functionalized coordination polymer nanoparticles for the treatment of bone metastatic breast cancer. AB - Bone is the most common organ affected by metastatic breast cancer. Targeting cancers within the bone remains a great challenge due to the inefficient delivery of therapeutic to bone. In this study, a polyethylene glycol (PEG) coated nanoparticles (NPs) made of a Zn2+ coordination polymer was linked with a bone seeking moiety, alendronate (ALN), to deliver cisplatin prodrug (DSP) to the bone. The particle sizes of this novel system, DSP-Zn@PEG-ALN NPs, were regulated by adjusting the volume ratio of water phase to oil phase in microemulsion. It was small enough (about 55nm) to extravasate through the clefts (80nm) of the bone's sinusoidal capillaries and localize into metastatic bones. DSP-Zn@PEG-ALN NPs showed much higher affinity for hydroxyapatite in vitro and bone in vivo than non-targeted DSP-Zn@PEG NPs and cisplatin. In addition, the in vivo biodistribution studies demonstrated that about 4-fold of platinum was delivered to the bone metastatic lesions than that in healthy bones by DSP-Zn@PEG-ALN NPs intravenously. Finally, DSP-Zn@PEG-ALN NPs not only inhibited the tumor growth efficiently but also reduced the osteocalastic bone destruction. Besides, DSP Zn@PEG-ALN NPs showed significantly reduced toxicity of cisplatin. These results indicate that the DSP-Zn@PEG-ALN NPs have a great potential in enhancing chemotherapeutic efficacy for the treatment of bone metastatic breast cancer. PMID- 28842316 TI - Protease-activatable cell-penetrating peptide possessing ROS-triggered phase transition for enhanced cancer therapy. AB - Reactive oxygen species (ROS)- or protease-responsive materials have been utilized as carriers in cancer therapies because ROS and specific proteases are overproduced in cancer cells. Methionine-based polypeptides containing a thioether group are promising candidates due to their ROS-responsiveness which provides a phase transition. Herein, we developed protease-activatable cell penetrating peptide containing a ROS-responsive methionine, a cell permeable lysine chain, and a matrix metalloproteinase (MMP)-cleavable linker. We designed a poly(l-methionine-block-l-lysine)-PLGLAG-PEG (MLMP) and doxorubicin (DOX) was loaded into the micelle core. The MLMP exhibited MMP-sensitive cleavage and ROS induced DOX release. Moreover, we confirmed efficient DOX delivery into cancer cells and induction of the apoptotic capability in vitro. In a bio-distribution study, IR-780 dye encapsulated MLMP showed superior tumor targetability with long retention. Furthermore, MLMP (DOX) exhibited outstanding tumor inhibition capability with non-toxicity compared to free DOX, indicating that dual stimuli MLMP has great potential as an anticancer drug delivery platform. PMID- 28842317 TI - Effective treatment of drug resistant recurrent breast tumors harboring cancer stem-like cells by staurosporine/epirubicin co-loaded polymeric micelles. AB - Breast cancer recurrence and resistance are associated with cancer stem-like cell (CSC) sub-populations. As conventional therapies fail to treat CSCs, institution of novel therapeutic strategies capable of eradicating both cancer cells and CSCs is central for achieving effective treatments with long-term survival. Here, we studied the ability of polymeric micelles cooperatively loading the cytotoxic drug epirubicin (Epi) and the CSC inhibitor staurosporine (STS) to treat breast tumors, particularly when tumors relapsed after chemotherapy. The STS/Epi-loaded micelles (STS/Epi/m) demonstrated potent therapeutic efficacy against both naive orthotopic 4T1-luc breast tumors and their recurrent Epi-resistant counterparts, significantly prolonging survival. This efficacy enhancement of STS/Epi/m was correlated with the ability of the micelles to suppress the CSC-associated sub populations of breast cancer, i.e. the aldehyde dehydrogenase-positive (ALDH+) population and the CD44+/CD24- fraction, in Epi-resistant cells and tumors. These results demonstrated STS/Epi/m as a promising strategy for effective management of breast cancer. PMID- 28842318 TI - Stimulus-responsive viral vectors for controlled delivery of therapeutics. AB - Virus-based therapies have gained momentum as the next generation of treatments for a variety of serious diseases. In order to make these therapies more controllable, stimulus-responsive viral vectors capable of sensing and responding to specific environmental inputs are currently being developed. A number of viruses naturally respond to endogenous stimuli, such as pH, redox, and proteases, which are present at different concentrations in diseases and at different organ and organelle sites. Additionally, rather than relying on natural viral properties, efforts are underway to engineer viruses to respond to endogenous stimuli in new ways as well as to exogenous stimuli, such as temperature, magnetic field, and optical light. Viruses with stimulus-responsive capabilities, either nature-evolved or human-engineered, will be reviewed to capture the current state of the field. Stimulus-responsive viral vector design considerations as well as gaps in current research efforts will be identified. PMID- 28842319 TI - Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib. AB - : Acquired drug resistance impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti cancer therapy. The lack of clinically effective therapies to overcome resistance represents an unmet need. Understanding the signalling that drives drug resistance will facilitate the development of new salvage therapies to treat patients with secondary TKI resistance. In this study, we utilise mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only 6% and 9.7% of the quantified phosphoproteome is altered upon the acquisition of pazopanib and dasatinib resistance, respectively. Pazopanib resistant cells display elevated phosphorylation in cytoskeletal regulatory pathways while dasatinib resistant cells show an upregulation of the insulin receptor/IGF-1R signalling pathway. Drug response profiling rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance. SIGNIFICANCE: Pazopanib and dasatinib are tyrosine kinase inhibitors (TKIs) approved for the treatment of multiple cancer types. Patients who are treated with these drugs are prone to the development of drug resistance and consequently tumour relapse. Here we use quantitative phosphoproteomics to characterise the signalling pathways which are enriched in cells that have acquired resistance to these two drugs. Furthermore, targeted drug screens were used to identify salvage therapies capable of overcoming pazopanib and dasatinib resistance. This data advances our understanding of the mechanisms of TKI resistance and highlights candidate targets for cancer therapy. PMID- 28842321 TI - Differential Day-Night Outcome to HSV-2 Cutaneous Infection. PMID- 28842320 TI - Skin Colonization by Staphylococcus aureus Precedes the Clinical Diagnosis of Atopic Dermatitis in Infancy. AB - Atopic dermatitis (AD) has a well-established association with skin colonization or infection by Staphylococcus aureus, which can exacerbate the disease. However, a causal relationship between specific changes in skin colonization during the first years of life and AD development still remains unclear. In this prospective birth cohort study, we aimed to characterize the association between skin colonization and AD development in 149 white infants with or without a family history of atopy. We assessed infants clinically and collected axillary and antecubital fossa skin swabs for culture-based analysis at birth and at seven time points over the first 2 years of life. We found that at age 3 months, S. aureus was more prevalent on the skin of infants who developed AD later on. S. aureus prevalence was increased on infants' skin at the time of AD onset and also 2 months before it, when compared with age-matched, unaffected infants. Furthermore, at AD onset, infants testing positive for S. aureus were younger than uncolonized subjects. In conclusion, our results suggest that specific changes in early-life skin colonization may actively contribute to clinical AD onset in infancy. PMID- 28842322 TI - Integrin alpha4beta1 and TLR4 Cooperate to Induce Fibrotic Gene Expression in Response to Fibronectin's EDA Domain. AB - Alternative splicing of fibronectin increases expression of the EDA+ isoform of fibronectin (EDA+Fn), a damage-associated molecular pattern molecule, which promotes fibro-inflammatory disease through the activation of toll-like receptors. Our studies indicate that the fibronectin EDA domain drives two waves of gene expression in human dermal fibroblasts. The first wave, seen at 2 hours, consisted of inflammatory genes, VCAM1, and tumor necrosis factor. The second wave, evaluated at 24 hours, was composed of the fibrosis-associated cytokines IL 10 and IL-13 and extracellular matrix genes fibronectin and osteopontin. Gene expression was coordinately regulated by the alpha4beta1 integrin and the innate immune receptor toll-like receptor 4. Additionally, we found a significant toll like receptor 4/alpha4beta1-dependent enrichment in the ratio of EDA+Fn to total fibronectin in response to EDA, consistent with EDA+Fn initiating further production of EDA+Fn. Our data also suggest that the EDA/alpha4beta1 integrin interaction primes the cell for an enhanced response to toll-like receptor 4 ligands. Our studies provide evidence that remodeling of the fibronectin matrix in injured or diseased tissue elicits an EDA-dependent fibro-inflammatory response in dermal fibroblasts. The data suggest a paradigm of damage-associated molecular pattern-based signaling whereby damage-associated molecular pattern binding integrins cooperate with innate immune receptors to stimulate inflammation and fibrosis. PMID- 28842323 TI - Associations of Statins and Diabetes with Diagnosis of Ulcerated Cutaneous Melanoma. AB - Ulcerated primary melanomas are associated with an inflammatory tumor microenvironment. We hypothesized that systemic proinflammatory states and anti inflammatory medications are also associated with a diagnosis of ulcerated melanoma. In a cross-sectional study of 787 patients with newly diagnosed clinical stage IB or II melanoma, we estimated odds ratios for the association of proinflammatory factors (high body mass index, diabetes, cardiovascular disease, hypertension, and smoking) or the use of anti-inflammatory medications (statins, aspirin, corticosteroids, and nonsteroidal anti-inflammatory drugs), with ulcerated primary melanoma using regression models and subgroup analyses to control for melanoma thickness and mitotic rate. On the basis of information from 194 patients with ulcerated and 593 patients with nonulcerated primary melanomas, regular statin users had lower likelihood of a diagnosis of ulcerated primary melanoma (odds ratio 0.67, 95% confidence interval 0.45-0.99), and this association remained after adjusting for age, sex, thickness, and mitosis. When analysis was limited to melanomas that were <=2 mm thick and had <=2 mitoses/mm2 (40 ulcerated; 289 without ulceration), patients with diabetes had significantly raised odds of diagnosis of ulcerated melanoma (odds ratio 2.90, 95% confidence interval 1.07-7.90), adjusted for age, sex, body mass index, and statin use. These findings support our hypotheses that statin use is inversely associated, and diabetes is positively associated, with ulcerated melanoma. PMID- 28842325 TI - C-Terminal Processing of Collagen XVII Induces Neoepitopes for Linear IgA Dermatosis Autoantibodies. AB - Transmembrane collagen XVII (COL17) is a hemidesmosomal component of basal keratinocytes that can be targeted by autoantibodies in autoimmune blistering disorders, including linear IgA dermatosis (LAD). COL17 can be physiologically cleaved within the juxtamembranous extracellular NC16A domain, and LAD autoantibodies preferentially react with the processed ectodomains, indicating that the processing induces neoepitopes. However, the details of how neoepitopes develop have not been elucidated. In this study, we show that C-terminal processing of COL17 also plays a role in inducing neoepitopes for LAD autoantibodies. First, the mAb hC17-ect15 targeting the 15th collagenous domain of COL17 was produced, which showed characteristics similar to LAD autoantibodies. The mAbs preferentially reacted with C-terminally deleted (up to 682 amino acids) recombinant COL17, suggesting that C-terminal processing shows neoepitopes on the 15th collagenous domain. The LAD autoantibodies also react with C-terminal deleted COL17. Therefore, neoepitopes for LAD autoantibodies also develop after C-terminal processing. Finally, the passive transfer of the mAb hC17-ect15 into human COL17-expressing transgenic mice failed to induce blistering disease, suggesting that neoepitope-targeting antibodies are not always pathogenic. In summary, this study shows that C-terminal processing induces dynamic structural changes and neoepitopes for LAD autoantibodies on COL17. PMID- 28842326 TI - Influence of Market Competition on Tetracycline Pricing and Impact of Price Increases on Clinician Prescribing Behavior. AB - Oral tetracyclines are commonly used for acne and other conditions. Recent generic price increases threaten access to these medications. Using the OptumInsight Clinformatics DataMart, we retrospectively evaluated the underlying factors behind these price increases for oral tetracylines using the framework of a competitive market and evaluated the impact of these price increases on prescribing practices. Between 2011 and 2013, the mean cost of doxycycline hyclate prescriptions increased from $7.16 to $139.89 and the mean out-of-pocket cost increased by $9.69. A comparable cost increase was not observed for doxycycline monohydrate or minocycline. There was no significant association between the cost of doxycycline hyclate and market concentration as assessed by the Herfindahl-Hirschman index (beta = 0.030, 95% confidence interval -0.019 to 0.079, P = 0.213) and the market was highly concentrated throughout the study period. The percentage of prescriptions for doxycycline hyclate decreased by 1.9% from 2011 to 2013. This dramatic increase in the cost of doxycycline hyclate is not easily explained using the framework of a competitive market, suggesting that noncompetitive market forces may be responsible. In addition, clinicians have not altered their prescribing behavior in response to this price increase, suggesting that clinician or pharmacy level interventions could potentially increase the use of less costly substitutes. PMID- 28842324 TI - Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma. AB - Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+ were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS+ with older age relative to the wild type (BRAF-/NRAS-) melanomas (all P < 0.05). Comparing specific BRAF subtypes to the wild type, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P < 0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (Pinteraction < 0.05) but inversely associated with BRAF V600K (Ptrend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS+, and wild-type melanomas. MC1R's associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAF V600E melanomagenesis. PMID- 28842328 TI - Melanocytes Sense Blue Light and Regulate Pigmentation through Opsin-3. AB - The shorter wavelengths of the visible light spectrum have been recently reported to induce a long-lasting hyperpigmentation but only in melano-competent individuals. Here, we provide evidence showing that OPN3 is the key sensor in melanocytes responsible for hyperpigmentation induced by the shorter wavelengths of visible light. The melanogenesis induced through OPN3 is calcium dependent and further activates CAMKII followed by CREB, extracellular signal-regulated kinase, and p38, leading to the phosphorylation of MITF and ultimately to the increase of the melanogenesis enzymes: tyrosinase and dopachrome tautomerase. Furthermore, blue light induces the formation of a protein complex that we showed to be formed by tyrosinase and dopachrome tautomerase. This multimeric tyrosinase/tyrosinase related protein complex is mainly formed in dark-skinned melanocytes and induces a sustained tyrosinase activity, thus explaining the long-lasting hyperpigmentation that is observed only in skin type III and higher after blue light irradiation. OPN3 thus functions as the sensor for visible light pigmentation. OPN3 and the multimeric tyrosinase/tyrosinase-related protein complex induced after its activation appear as new potential targets for regulating melanogenesis but also to protect dark skins against blue light in physiological conditions and in pigmentary disorders. PMID- 28842327 TI - Genome-Wide Analysis of Protein-Coding Variants in Leprosy. AB - Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 * 10-9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 * 10-8, OR = 4.75); three low frequency variants: rs76418789 in IL23R (P = 1.03 * 10-10, OR = 1.36), rs146466242 in FLG (P = 3.39 * 10-12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 * 10-6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 * 10-9, OR = 1.14) and rs181206 in IL27 (P = 1.08 * 10-7, OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases. PMID- 28842329 TI - Opioids' Effect on Healing of Venous Leg Ulcers. PMID- 28842330 TI - Nuclear Proteins and Apoptotic Bodies Are Found in the Lupus Band of Patients with Cutaneous Lupus Erythematosus. PMID- 28842331 TI - Corrigendum to "Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7" [Biochim. Biophys. Acta 1859(5) (2017) 835-844]. PMID- 28842332 TI - Tumor acidity-activatable manganese phosphate nanoplatform for amplification of photodynamic cancer therapy and magnetic resonance imaging. AB - : Amorphous biodegradable metal phosphate nanomaterials are considered to possess great potential in cancer theranostic application due to their promise in providing ultra-sensitive pH-responsive therapeutic benefits and diagnostic functions simultaneously. Here we report the synthesis of photosensitising and acriflavine-carrying amorphous porous manganese phosphate (PMP) nanoparticles with ultra-sensitive pH-responsive degradability and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1alpha/vascular endothelial growth factor (HIF1alpha/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Carboxymethyl dextran (CMD) is chemically anchored on the surface of porous manganese phosphate theranostic system through the pH-responsive boronate esters. Upon the stimulus of the tumor acid microenvironment, manganese phosphate disintegrates and releases Mn2+ ions rapidly, which are responsible for the magnetic resonance imaging (MRI) effect. Meanwhile, the released photosensitizer chlorin e6 (Ce6) produces ROS under irradiation while acriflavine (ACF) inhibits the HIF-1alpha/VEGF pathway during the burst release of VEGF in tumour induced by photodynamic therapy (PDT), resulting in increased therapeutic efficacy. Considering the strong pH responsivity, MRI signal amplification and drug release profile, the PMP nanoparticles offer new prospects for tumor acidity-activatable theranostic application by amplifying the PDT through inhibiting the HIF-1alpha /VEGF pathway timely while enhancing the MRI effect. STATEMENT OF SIGNIFICANCE: In this study, we report the synthesis of the tumor acidity-activatable amorphous porous manganese phosphate nanoparticles and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1alpha/vascular endothelial growth factor (HIF-1alpha/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Besides, upon the stimulus of the tumor acid microenvironment, the manganese phosphate nanoparticles finally disintegrate and release Mn2+ ions rapidly, which are responsible for the magnetic resonance imaging (MRI) effect. This nanoplatform is featured with distinctive advantages such as ultra pH-responsive drug release, MRI function and rational drug combination exploiting the blockage of the treatment escape signalling pathway. PMID- 28842333 TI - A theranostic dental pulp capping agent with improved MRI and CT contrast and biological properties. AB - : Different materials have been used for vital dental pulp treatment. Preferably a pulp capping agent should show appropriate biological performance, excellent handling properties, and a good imaging contrast. These features can be delivered into a single material through the combination of therapeutic and diagnostic agents (i.e. theranostic). Calcium phosphate based composites (CPCs) are potentially ideal candidate for pulp treatment, although poor imaging contrast and poor dentino-inductive properties are limiting their clinical use. In this study, a theranostic dental pulp capping agent was developed. First, imaging properties of the CPC were improved by using a core-shell structured dual contrast agent (csDCA) consisting of superparamagnetic iron oxide (SPIO) and colloidal gold, as MRI and CT contrast agent respectively. Second, biological properties were implemented by using a dentinogenic factor (i.e. bone morphogenetic protein 2, BMP-2). The obtained CPC/csDCA/BMP-2 composite was tested in vivo, as direct pulp capping agent, in a male Habsi goat incisor model. Our outcomes showed no relevant alteration of the handling and mechanical properties (e.g. setting time, injectability, and compressive strength) by the incorporation of csDCA particles. In vivo results proved MRI contrast enhancement up to 7weeks. Incisors treated with BMP-2 showed improved tertiary dentin deposition as well as faster cement degradation as measured by uCT assessment. In conclusion, the presented theranostic agent matches the imaging and regenerative requirements for pulp capping applications. STATEMENT OF SIGNIFICANCE: In this study, we combined diagnostic and therapeutic agents in order to developed a theranostic pulp capping agent with enhanced MRI and CT contrast and improved dentin regeneration ability. In our study we cover all the steps from material preparation, mechanical and in vitro characterization, to in vivo study in a goat dental model. To the best of our knowledge, this is the first time that a theranostic pulp capping material have been developed and tested in an in vivo animal model. Our promising results in term of imaging contrast enhancement and of induction of new dentin formation, open a new scenario in the development of innovative dental materials. PMID- 28842334 TI - The effects of surface processing on in-vivo corrosion of Nitinol stents in a porcine model. AB - : A major limitation with current assessments of corrosion in metallic medical devices is the lack of correlation between in-vitro and in-vivo corrosion performance. Therefore, the objective of this study was to elucidate the relationship between pitting corrosion measured by breakdown potentials (Eb) in ASTM F2129 testing and corrosion resistance in-vivo. Four groups of Nitinol stents were manufactured using different processing methods to create unique surface properties. The stents were implanted into iliac arteries of minipigs for six months and explanted for corrosion analysis. Scanning electron microscopy and energy dispersive X-ray spectrometry analyses indicated that stents with a thick complex thermal oxide (420nm) and high corrosion resistance in-vitro (Eb=975+/ 94mV) were free from detectable corrosion in-vivo and exhibited no changes in Ni/Ti ratio when compared to non-implanted controls. This result was also found in mechanically polished stents with a thin native oxide (4nm; Eb=767+/-226mV). In contrast, stents with a moderately thick thermal oxide (130nm) and low corrosion resistance in-vitro (Eb=111+/-63mV) possessed corrosion with associated surface microcracks in-vivo. In addition, Ni/Ti ratios in corroded regions were significantly lower compared to non-corroded adjacent areas on explanted stents. When stents were minimally processed (i.e. retained native tube oxide from the drawing process), a thick thermal oxide was present (399nm) with low in-vitro corrosion resistance (Eb=68+/-29mV) resulting in extensive in-vivo pitting. These findings demonstrate that functional corrosion testing combined with a detailed understanding of the surface characteristics of a Nitinol medical device can provide insight into in-vivo corrosion resistance. STATEMENT OF SIGNIFICANCE: Nitinol is a commonly used material in the medical device industry. However, correlations between surface processing of nitinol and in-vivo corrosion has yet to be established. Elucidating the link between in-vivo corrosion and pre clinical characterization can aid in improved prediction of clinical safety and performance of nitinol devices. We addressed this knowledge gap by fabricating nitinol stents to possess distinct surface properties and evaluating their corrosion susceptibility both in-vitro and after six months of in-vivo exposure. Relationships between stent processing, surface characterization, corrosion bench testing, and outcomes from explanted devices are discussed. These findings highlight the importance of surface characterization in nitinol devices and provide in-vitro pitting corrosion levels that can induce in-vivo corrosion in nitinol stents. PMID- 28842335 TI - Concurrently suppressing multidrug resistance and metastasis of breast cancer by co-delivery of paclitaxel and honokiol with pH-sensitive polymeric micelles. AB - : To concurrently suppress multidrug resistance (MDR) and metastasis of breast cancer cells, paclitaxel (PTX) and honokiol (HNK) were coencapsulated into pH sensitive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA). The physicochemical properties of dual drug-loaded PEOz-PLA micelles were characterized in size, drug loading and in vitro release. The efficiency of MDR reversal for the micelles was testified by synergetic enhancement of cytotoxicity and uptake by MCF-7/ADR cells. The flow cytometry and fluorescence polarization measurement results reinforced the conclusion that down-regulation of P-gp expression and increase of plasma membrane fluidity appeared to be possible mechanisms of MDR reversal by dual drug-loaded PEOz-PLA micelles. Further, the efficient inhibition of tumor metastasis by dual drug-loaded PEOz PLA micelles was demonstrated by in vitro anti-invasion and anti-migration assessment in MDA-MB-231 cells and in vivo bioluminescence imaging in nude mice. The suppression of MDR and metastasis by the micelles was assigned to synergistic effects of pH-triggered drug release and HNK/PEOz-PLA-aroused P-gp inhibition, and pH-triggered drug release and PTX/HNK-aroused MMPs inhibition, respectively. In conclusion, our findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis. STATEMENT OF SIGNIFICANCE: Multidrug resistance (MDR) and metastasis are considered to be two of the major barriers for successful chemotherapy. The combination of a chemotherapeutic drug with a modulator has emerged as a promising strategy for efficiently treating MDR cancer and preventing tumor metastasis. Herein, a dual drug (paclitaxel and honokiol)-loaded pH-sensitive polymeric micelle system based on PEOz-PLA was successfully fabricated to ensure that tumor MDR and metastasis could be concurrently suppressed, therefore achieving distinguishing endo/lysosomal pH from physiological pH by accelerating drug release and then enhancing the cytotoxicity of paclitaxel to drug-resistant tumor cells MCF-7/ADR by increasing cellular uptake of paclitaxel, preventing in vitro invasion and migration for MDA-MB-231 cells and in vivo metastasis in nude mice. Further, the mechanism of MDR reversal by dual drug-loaded PEOz-PLA micelles was elucidated to be down-regulation of P-gp expression and increase of plasma membrane fluidity of MCF-7/ADR cells. The present findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis. PMID- 28842336 TI - 7-Chloro-4-phenylsulfonyl quinoline, a new antinociceptive and anti-inflammatory molecule: Structural improvement of a quinoline derivate with pharmacological activity. AB - The present study was designed to examine the antinociceptive and anti inflammatory effects of 7-chloro-4-phenylsulfonyl quinoline (PSOQ). Mice were orally (p.o) pretreated with PSOQ (0.01-10 mg/kg), meloxicam (10 mg/kg), 30 min prior to the acetic acid, hot-plate and open field tests. PSOQ reduced abdominal writhing induced by acetic acid, while meloxicam presented no effect. The latency time in the hot-plate test and locomotor/exploratory activities in the open field test were not altered by treatments. In order to evaluate the gastric tolerability after oral administration of PSOQ or meloxicam (10 mg/kg), mice were fasted for 18 h prior to drug exposure. Four hours later, the development of lesions was assessed. PSOQ and meloxicam did not induce ulcer at the dose and time evaluated. Indeed, anti-inflammatory and anti-edematogenic properties of PSOQ were investigated. For this, animals were pretreated with PSOQ (0.01-50 mg/kg; p.o.), meloxicam (50 mg/kg; p.o.), 30 min prior to croton oil application. PSOQ and meloxicam (50 mg/kg) diminished the edema formation and myeloperoxidase activity induced by croton oil in the ear tissue. Taken together these data demonstrated that PSOQ exerts acute anti-inflammatory and antinociceptive actions, suggesting that it may represent an alternative in the development of future new therapeutic strategies. PMID- 28842337 TI - Development of a tool to assess the completeness of drug information sources for health care professionals: A Delphi study. AB - The aim of this study was to create a standard set of essential drug information items as a tool to assess the completeness of any type of drug information source, regardless of its length, using a Delphi consensus panel of European health care professionals. A compilation of drug-related information items was performed by searching several resources for health care professionals and a final list of 162 items was obtained. Fifty-seven experts in drug information from 23 different European countries were invited to participate in a three-round Delphi technique to obtain consensus on items considered essential and non essential content of information. Consensus for the first, second, and third rounds was defined as >=90%, >=80%, and >=75% agreement, respectively. Of the 57 experts invited, 32 completed the first round, 27 the second, and 29 the third. Consensus was achieved for 28.3% of the items in the first round, 49.3% in the second, and 58.3% in the third. The final cumulative consensus was 67.7% (n = 126) for items considered essential and 16.1% (n = 30) for items considered non essential. The final tool obtained to assess the completeness of drug information sources was composed by 126 essential items grouped into 11 sections. This tool allows for the comparison of different information sources for the same medicine and the information content for different medicines in the same source. PMID- 28842338 TI - Structure, proteome and genome of Sinorhizobium meliloti phage PhiM5: A virus with LUZ24-like morphology and a highly mosaic genome. AB - Bacteriophages of nitrogen-fixing rhizobial bacteria are revealing a wealth of novel structures, diverse enzyme combinations and genomic features. Here we report the cryo-EM structure of the phage capsid at 4.9-5.7A-resolution, the phage particle proteome, and the genome of the Sinorhizobium meliloti-infecting Podovirus PhiM5. This is the first structure of a phage with a capsid and capsid associated structural proteins related to those of the LUZ24-like viruses that infect Pseudomonas aeruginosa. Like many other Podoviruses, PhiM5 is a T=7 icosahedron with a smooth capsid and short, relatively featureless tail. Nonetheless, this group is phylogenetically quite distinct from Podoviruses of the well-characterized T7, P22, and epsilon 15 supergroups. Structurally, a distinct bridge of density that appears unique to PhiM5 reaches down the body of the coat protein to the extended loop that interacts with the next monomer in a hexamer, perhaps stabilizing the mature capsid. Further, the predicted tail fibers of PhiM5 are quite different from those of enteric bacteria phages, but have domains in common with other rhizophages. Genomically, PhiM5 is highly mosaic. The PhiM5 genome is 44,005bp with 357bp direct terminal repeats (DTRs) and 58 unique ORFs. Surprisingly, the capsid structural module, the tail module, the DNA-packaging terminase, the DNA replication module and the integrase each appear to be from a different lineage. One of the most unusual features of PhiM5 is its terminase whose large subunit is quite different from previously-described short-DTR-generating packaging machines and does not fit into any of the established phylogenetic groups. PMID- 28842339 TI - Gangjihwan, a polyherbal composition, inhibits fat accumulation through the modulation of lipogenic transcription factors SREBP1C, PPARgamma and C/EBPalpha. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gangjihwan (DF) which is composed of Ephedra intermedia, Lithospermum erythrorhizon, and Rheum palmatum has been used for the treatment of obesity in traditional medical clinics in Korea. AIM OF THE STUDY: This study was conducted to standardize DF and elucidate its mechanism of action for inhibiting fat accumulation in adipocytes and adipose tissues. MATERIALS AND METHODS: The herbal ingredients of DF were extracted in water, 30% ethanol or 70% ethanol and freeze-dried followed by HPLC analyses. 3T3-L1 adipocytes and high fat diet-induced obese mice were treated with each of the three DF preparations. Messenger RNA and protein expression levels were measured by real-time qPCR and Western blotting. RNA-Seq analyses were conducted to examine the effects of DF treatment on whole transcriptome of adipocyte. RESULTS: (-)-Ephedrine and (+) pseudoephedrine from E. intermedia, aloe-emodin and chrysophanol from R. palmatum and shikonin from L. erythrorhizon were identified as phytochemical components of DF. DF caused dose-dependent inhibition of fat accumulation in 3T3-L1 adipocytes. It also significantly reduced adipose tissue mass and adipocyte size in high-fat diet-induced obese mice. DF was found to down-regulate the expressions of the lipogenic transcription factors such as sterol regulatory element binding protein 1C (SREBP1C), peroxisome proliferator activated receptor gamma (PPARgamma), and CCAAT/enhancer binding protein alpha (C/EBPalpha). Among the three preparations of DF, the 70% ethanol extract was the most effective. RNA-Seq analyses showed that DF treatment decreased the expression levels of up-regulators and increased those of down-regulators of lipogenic transcription factors. CONCLUSIONS: DF preparations, among which 70% ethanol extract was the most effective, reduced fat accumulation in 3T3-L1 adipocytes and high-fat diet-induced obese mice through the down-regulation of lipogenic transcription factors SREBP1C, PPARgamma and C/EBPalpha. PMID- 28842340 TI - Investigation of association of chemical profiles with the tracheobronchial relaxant activity of Chinese medicinal herb Beimu derived from various Fritillaria species. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fritillariae Bulbus (Beimu in Chinese) is derived from the bulbus of many Fritillaria species (family Liliaceae), which has been used as an antitussive herb in traditional Chinese medicine for more than 2000 years. Due to the complexity of plant origins and significant variations in chemical profiles, the characterization of the profile of the major bioactive constituents and its association with pharmacological activity are important for the quality control of Beimu herbs from different origins. AIM OF THE STUDY: This study aims to investigate the distribution of major bioactive isosteroidal alkaloids in Beimu herbs of different origins and its correlation with the tracheobronchial relaxant activity. METHODS: Quantification of 7 main bioactive 5alpha-cevanine isosteroidal alkaloids, including ebeiedine, ebeiedinone, hupehenine, isoverticine, verticine, verticinone and imperialine, in 23 Fritillaria species was performed using gas chromatography. The relaxant effect of different extracts of 4 commonly used Beimu herbs, namely Zhe-Beimu (F. thunbergii Miq.), Chuan-Beimu (F. cirrhosa D. Don), Hubei-Beimu (F. hupehensis Hsiao et K. C. Hsia) and Yi-Beimu (F. pallidiflora Schrenk), was evaluated using rat isolated tracheal and bronchial preparations pre-contracted with carbachol, the well established in vitro antitussive model. RESULTS: Amongst 23 Fritillaria species detected, significant variations of the types and quantities of 7 major isosteroidal alkaloids were determined, which served as an important indicator for the classification of different Beimu herbs with distinct geographic distributions. Based on the type and quantity of these alkaloids, different origins of Beimu could be clearly clustered into several subgroups by principal component analysis. Furthermore, both crude alkaloid and water extracts of all 4 Beimu herbs showed a dose-dependent tracheobronchial relaxation with different potencies. The total content of alkaloids (weight adjusted based on the activity of individual alkaloids) in Beimu extracts significantly correlated with their tracheobronchial relaxation effects (r2 > 0.9, p < 0.001). CONCLUSIONS: The results demonstrated that the differences in chemical profile of major bioactive isosteroidal alkaloids and pharmacological activity of Beimu could be incorporated into a simple and unified method for quality control and potential prediction of activity of Beimu herbs from different origins. PMID- 28842341 TI - The genus Psiadia: Review of traditional uses, phytochemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Psiadia Jacq. ex. Willd. belongs to the Asteraceae family and includes more than 60 species. This genus grows in tropical and subtropical regions, being especially well represented in Madagascar and the Mascarene Islands (La Reunion, Mauritius and Rodrigues). Several Psiadia species have been used traditionally for their medicinal properties in Africa and the Mascarene Islands. Based on traditional knowledge, various phytochemical and pharmacological studies have been conducted. However there are no recent papers that provide an overview of the medicinal potential of Psiadia species. Therefore, the aim of this review is to provide a comprehensive summary of the botany, phytochemistry and pharmacology of Psiadia and to highlight the gaps in our knowledge for future research opportunities. MATERIALS AND METHODS: The available information on traditional uses, phytochemistry and biological activities of the genus Psiadia was collected from scientific databases through a search using the keyword 'Psiadia' in 'Google Scholar', 'Pubmed', 'Sciencedirect', 'SpringerLink', 'Web of Science', 'Wiley' and 'Scifinder'. Additionally, published books and unpublished Ph.D. and MSc. dissertations were consulted for botanical information and chemical composition. RESULTS: Historically, species of the genus Psiadia have been used to treat a wide range of ailments including abdominal pains, colds, fevers, bronchitis, asthma, rheumatoid arthritis, skin infections and liver disorders among others. Phytochemical works led to the isolation of flavonoids, phenylpropanoids, coumarins and terpenoids. Furthermore, phytochemical compositions of the essential oils of some species have been evaluated. Crude extracts, essential oils and isolated molecules showed in vitro pharmacological activities, such as antimicrobial, anti-viral, anti-inflammatory, antiplasmodial and antileishmanial activities. Crude extracts of Psiadia dentata and Psiadia arguta have specifically been found to be potentially useful for inhibition of growth of Plasmodium falciparum. However, pharmacological data on this particular genus is quite limited. Further research is necessary to determine the active compounds and the underlying mechanisms. PMID- 28842342 TI - Phytochemical analysis, molecular docking and antiamnesic effects of methanolic extract of Silybum marianum (L.) Gaertn seeds in scopolamine induced memory impairment in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Silybum marianum (L.) Gaertn and its main component silymarin have been extensively studied and have been found effective in various neurological disorders. AIMS OF THE STUDY: The aim of the current study is to identify phytoconstituents in the methanolic extract (Me. Ext) of Silybum marianum (L.) Gaertn seeds and to study in-vivo the anti-amnesic effects along with in vitro antioxidant and acetylcholinesterase (AChE) and buteryl cholinesterase (BChE) inhibition potential. Induced fir docking (IFD) results have confirmed that quercetin, morin and rutin showed good affinity when docked into AChE binding site. MATERIALS AND METHODS: The present study investigates the in-vitro AChE and BChE inhibition potential of the Me-Ext of Silybum marianum (L.) Gaertn at various concentrations (31.25, 62.50, 125, 250, 500, 1000ug/mL) using Ellman's spectrophotometric analysis, while antioxidant potential against DPPH and ABTS were determined using Brand-Williams spectrophotometric method. Furthermore, the in-vivo anti-amnesic effects of Me. Ext at the dose level of 50, 100 and 200mg/kg were also evaluated using scopolamine -induced memory impairment in mice in the novel object recognition test (NORT) and Y-maze test. RESULTS: The Me. Ext showed a concentration dependent inhibition of AChE and BChE with IC50 values of 110 and 130ug/mL respectively and antioxidant activity against DPPH and ABTS with IC50 values 280 and 220ug/mL, respectively. In mice, Me. Ext reversed the amnesia induced by scopolamine as indicated by a dose-dependent increase in spontaneous alternation performance in the Y-maze task (p< 0.05 versus scopolamine) and increase in the discrimination index in the NORT comparable to the standard drug donepezil 2mg/kg. HPLC-UV analysis showed the presence of quercetin, rutin and morin. Induced fit docking (IFD) was performed using quercetin, rutin and morin, Glide Gscore and IFD score of all compounds were consistent with their experimental AChE inhibitory activities. CONCLUSION: The results indicate that Silybum marianum (L.) Gaertn could be a new source for the isolation of phytoconstituents useful in cognition and memory disorders such as Alzheimer's disease. PMID- 28842343 TI - Australian children's perceptions of discretionary foods. AB - Energy-dense nutrient poor foods and drinks, often referred to as discretionary choices, can contribute a significant amount of energy, fat, sodium and sugar to the diet if consumed in large quantities. Currently many Australian children are consuming a diet that is characterised by large quantities of discretionary items. We undertook a qualitative study to gain a descriptive account of preadolescent children's attitudes and perceptions towards health and nutrition. A series of 6 focus groups and 14 individual semi-structured interviews were conducted with thirty-eight children aged 11-12 years, across three state government schools in a socially disadvantaged region of metropolitan South Australia. The naturalistic manner of qualitative inquiry led to several unintended yet highly pertinent emergent themes, including children's perceptions and practices surrounding discretionary food consumption. Our results indicate that while Australian guidelines recommend that discretionary foods are consumed 'only sometimes and in small amounts', children generally held a different belief with respect to what constituted 'sometimes'. Many children identified that discretionary foods should be consumed in moderation to maintain a balanced diet, yet reported consuming these foods frequently. Self-reported discretionary food consumption was grounded in socially constructed experiences valued by the children, who made situational attributions to foods and legitimised discretionary food consumption in certain contexts, for example during the weekend. Overall, there is variability between children's opinions about the acceptable frequency of consumption of discretionary foods compared with national guidelines. PMID- 28842344 TI - Allosteric modulation of nicotinic and GABAA receptor subtypes differentially modify autism-like behaviors in the BTBR mouse model. AB - Autism spectrum disorder (ASD) is associated with two core symptoms (social communication deficits and stereotyped repetitive behaviors) in addition to a number of comorbidities. There are no FDA-approved drugs for the core symptoms and the changes that underlie these behaviors are not fully understood. One hypothesis is an imbalance of the excitation (E)/inhibition (I) ratio with excessive E and diminished I occurring in specific neuronal circuits. Data suggests that both gamma-aminobutyric acidA (GABAA) and alpha7 nicotinic acetylcholine receptors (nAChRs) significantly impact E/I. BTBR T+tf/J (BTBR) mice are a model that display an autism-like phenotype with impaired social interaction and stereotyped behavior. A beta2/3-subunit containing GABAA receptor (GABAAR) subtype selective positive allosteric modulator (PAM), 2-261, and an alpha7 nAChR subtype selective PAM, AVL-3288, were tested in social approach and repetitive self-grooming paradigms. 2-261 was active in the social approach but not the self-grooming paradigm, whereas AVL-3288 was active in both. Neither compound impaired locomotor activity. Modulating alpha7 nAChRs alone may be sufficient to correct these behavioral and cognitive deficits. GABAergic and nicotinic compounds are already in various stages of clinical testing for treatment of the core symptoms and comorbidities associated with ASD. Our findings and those of others suggest that compounds that have selective activities at GABAAR subtypes and the alpha7 nAChR may address not only the core symptoms, but many of the associated comorbidities as well and warrant further investigation in other models of ASD. PMID- 28842345 TI - Temporal effect of manipulating NeuroD1 expression with the synthetic small molecule KHS101 on morphine contextual memory. AB - The treatment of opioid addiction is challenging because addicts are highly prone to relapse when the memory of the former drug experience is triggered by emotional or environmental cues. An emerging and promising concept in addiction biology is that by manipulating adult hippocampal neurogenesis, a phenomenon involved in learning and memory, drug reward-like behaviors and relapse can be attenuated. We tested a new synthetic compound, KHS101, in an animal model of drug-associated contextual memory. KHS101 has been reported to increase the expression of neurogenic differentiation 1 (NeuroD1), a transcription factor involved in adult neurogenesis, and to specifically induce neuronal differentiation both in vitro and in vivo. Our results indicated that the subcutaneous injection of 3 mg/kg KHS101 for 7 days before conditioned place preference (CPP) training prolonged CPP extinction, while the same treatment after training accelerated extinction. This effect paralleled that observed following temporally controlled, tetracycline-induced NeuroD1 overexpression. Furthermore, the effect of KHS101 may occur via its induction of NeuroD1 expression as demonstrated by the abolition of the KHS101-mediated modulation of morphine-induced CPP extinction after the stereotaxic injection of lentiviral NeuroD1 small interfering RNA into the dentate gyrus (DG) of the hippocampus. These results suggest that the KHS101-mediated modulation of neurogenesis at a critical stage of the conditioning or the extinction of an opioid-associated experience may disrupt the memory trace of the existing opioid-associated experience to facilitate the extinction of drug-associated contextual memory. This implies that KHS101 has therapeutic potential for the treatment of opioid addiction. PMID- 28842346 TI - Hydrogen sulfide-producing cystathionine gamma-lyase is critical in the progression of kidney fibrosis. AB - Cystathionine gamma-lyase (CSE), the last key enzyme of the transsulfuration pathway, is involved in the production of hydrogen sulfide (H2S) and glutathione (GSH), which regulate redox balance and act as important antioxidant molecules. Impairment of the H2S- and GSH-mediated antioxidant system is associated with the progression of chronic kidney disease (CKD), characterized by kidney fibrosis and dysfunction. Here, we evaluated the role of CSE in the progression of kidney fibrosis after unilateral ureteral obstruction (UUO) using mice deficient in the Cse gene. UUO of wild-type mice reduced the expression of H2S-producing enzymes, CSE, cystathionine beta-synthase, and 3-mercaptopyruvate sulfurtransferase in the obstructed kidneys, resulting in decreased H2S and GSH levels. Cse gene deletion lowered H2S and GSH levels in the kidneys. Deleting the Cse gene exacerbated the decrease in H2S and GSH levels and increase in superoxide formation and oxidative damage to proteins, lipids, and DNA in the kidneys after UUO, which were accompanied by greater kidney fibrosis, deposition of extracellular matrixes, expression of alpha-smooth muscle actin, tubular damage, and infiltration of inflammatory cells. Furthermore, Cse gene deletion exacerbated mitochondrial fragmentation and apoptosis of renal tubule cells after UUO. The data provided herein constitute in vivo evidence that Cse deficiency impairs renal the H2S- and GSH-producing activity and exacerbates UUO-induced kidney fibrosis. These data propose a novel therapeutic approach against CKD by regulating CSE and the transsulfuration pathway. PMID- 28842348 TI - Extracellular reactive oxygen species are generated by a plasma membrane oxidative phosphorylation system. AB - Although the oxidative phosphorylation (OXPHOS) system has been found in mitochondria and the plasma membrane of various mammalian cell lines, understanding the physiological functions of the plasma membrane OXPHOS system is challenging. Here, we demonstrated that OXPHOS I, II, III, IV and V subunits were expressed in the plasma membrane of HepG2 cells and primary mouse hepatocytes, as determined by non-permeabilized immunofluorescence, total internal reflection fluorescence (TIRF) microscopy, cell surface-biotin labeling and plasma membrane and lipid raft isolation. Next, we demonstrated that NADH administration generated extracellular superoxide and improved insulin signaling in HepG2 cells and primary mouse hepatocytes. The NADH-dependent generation of extracellular superoxide was prevented by knockdown of NDUFV-1, the first subunit of OXPHOS I receiving electrons from NADH and the NADH-improved insulin signaling was abolished by extracellular catalase. Thus, we conclude that the OXPHOS system in the plasma membrane may be required for the generation of extracellular ROS and the regulation of insulin signaling. PMID- 28842349 TI - Solid self-nanoemulsifying drug delivery systems for oral delivery of polypeptide k: Formulation, optimization, in-vitro and in-vivo antidiabetic evaluation. AB - Development of self-nanoemulsifying drug delivery systems (SNEDDS) of polypeptide k (PPK) is reported with the aim to achieve its oral delivery. Box-Behnken design (BBD) was adopted to develop and optimize the composition of SNEDDS. Oleoyl polyoxyl-6 glycerides (A), Tween 80 (B), and diethylene glycol monoethyl ether (C) were used as oil, surfactant and co-surfactant, respectively as independent variables. The effect of variation in their composition was observed on the mean droplet size (y1), polydispersity index (PDI) (y2), % drug loading (y3) and zeta potential (y4). As per the optimal design, seventeen SNEDDS prototypes were prepared. The optimized composition of SNEDDS formulation was 25% v/v Oleoyl polyoxyl-6 glycerides, 37% v/v Tween 80, 38% v/v diethylene glycol monoethyl ether, and 3% w/v PPK. The optimized formulation revealed values of y1, y2, y3, and y4 as 31.89nm, 0.16, 73.15%, and -15.65mV, respectively. Further the optimized liquid SNEDDS were solidified through spray drying using various hydrophilic and hydrophobic carriers. Among the various carriers, Aerosil 200 was found to provide desirable flow, compression, disintegration and dissolution properties. Both, liquid and solid-SNEDDS have shown release of >90% within 10min. The formulation was found stable with change in pH, dilution, temperature variation and freeze thaw cycles in terms of droplet size, zeta potential, drug precipitation and phase separation. Crystalline PPK was observed in amorphous state in solid SNEDDS when characterized through DSC and PXRD studies. The biochemical, hematological and histopathological results of streptozotocin induced diabetic rats shown promising antidiabetic potential of PPK loaded in SNEDDS at its both the doses (i.e. 400mg/kg and 800mg/kg) as compared to its naive form at both the doses. The study revealed successful formulation of SNEDDS for oral delivery of PPK. PMID- 28842350 TI - Dendrimer conjugated estramustine nanocrystalline 'Dendot': An effective inhibitor of DMBA-TPA induced papilloma formation in mouse. AB - Clinically approved anticancer drug estramustine mediates its function by impairing microtubule polymerization. However, the low aqueous solubility and high toxicity limit its anticancer activity via the oral route. Previously, efforts have been made to develop an enhanced water soluble form of estramustine as estramustine phosphate (EM) but acidic gastrointestinal pH breaks the phosphate derivative via oral administration. As an alternative approach, we have made an effort to enhance solubility and minimize toxicity in vivo by conjugating EM to a poly(amidoamine) (PAMAM) dendrimer, which generated the sustained release of dendrimer conjugate (DEM). To the best of our knowledge, for the first time, we report the direct proof of the nano-crystalline 'DenDot' of DEM on TEM image. The toxicity study showed that both EM and DEM were nontoxic up to 20mg/kg. A comparative anti-papilloma study was also performed with EM and dendrimer conjugates (DEM) using a two-stage mouse skin carcinogenesis model. We found that DEM was more effective in inhibiting skin tumor formation than EM. Histopathology and immunohistochemistry studies further indicated that DEM treatment increased cell apoptosis, and reduced epithelial hyperplasia, cell proliferation and inflammation in skin tissues of mice. In addition, the synthetic DEM conjugate inhibited skin tumor progression more effectively than EM. PMID- 28842351 TI - Screening of pharmacokinetic properties of fifty dihydropyrimidin(thi)one derivatives using a combo of in vitro and in silico assays. AB - The heterocycles dihydropyrimidin(thi)ones have been under intensive pharmacological research, but their pharmacokinetic properties remain almost unknown. Herein, fifty dihydropyrimidin(thi)ones were submitted to in vitro screening tests using parallel artificial membrane permeability assays (PAMPA) to evaluate their apparent permeability (Papp) through intestinal membrane and blood brain barrier models, and cell-based assays to assess their interference on the efflux transporter P-glycoprotein (P-gp). Moreover, a set of kinetic and toxicological parameters was also estimated employing a new computational tool, the pkCSM. The in vitro results suggested that 82% of the test compounds have good intestinal permeability (Papp>1.1*10-6cm/s), and 66% of these are also expected to exhibit good permeability through blood-brain barrier (Papp>2.0*10 6cm/s); these findings are consistent with a high transport rate by passive transcellular pathway. In both PAMPA models, thiourea derivatives presented higher Papp values than the respective urea analogues, which were further corroborated by in silico predictions. The in vitro results also suggested a low extent of plasma protein binding for all compounds (Papp<1.0*10-5cm/s), and these findings were also supported by in silico data (unbound fraction ranging from 0.13 to 0.59). In addition, although approximately half of the compounds did not modulate P-gp at the tested concentrations (10 and 50MUM), nine of them presented a trend to induce P-gp and particularly the chlorinated compounds exhibited a marked P-gp inhibition at 50MUM. Furthermore, the in silico predictions suggested that half of the compounds have hepatotoxic potential. Overall, within this group of compounds, the thiourea derivatives containing an unsubstituted or a monosubstituted (NO2, CH3, OCH3) phenyl ring attached to the position 4 of the dihydropyrimidine ring represented the most promising structures and should be considered in the subsequent studies of the development of new structurally related drug candidates. PMID- 28842347 TI - Extracellular superoxide dismutase and its role in cancer. AB - Reactive oxygen species (ROS) are increasingly recognized as critical determinants of cellular signaling and a strict balance of ROS levels must be maintained to ensure proper cellular function and survival. Notably, ROS is increased in cancer cells. The superoxide dismutase family plays an essential physiological role in mitigating deleterious effects of ROS. Due to the compartmentalization of ROS signaling, EcSOD, the only superoxide dismutase in the extracellular space, has unique characteristics and functions in cellular signal transduction. In comparison to the other two intracellular SODs, EcSOD is a relatively new comer in terms of its tumor suppressive role in cancer and the mechanisms involved are less well understood. Nevertheless, the degree of differential expression of this extracellular antioxidant in cancer versus normal cells/tissues is more pronounced and prevalent than the other SODs. A significant association of low EcSOD expression with reduced cancer patient survival further suggests that loss of extracellular redox regulation promotes a conducive microenvironment that favors cancer progression. The vast array of mechanisms reported in mediating deregulation of EcSOD expression, function, and cellular distribution also supports that loss of this extracellular antioxidant provides a selective advantage to cancer cells. Moreover, overexpression of EcSOD inhibits tumor growth and metastasis, indicating a role as a tumor suppressor. This review focuses on the current understanding of the mechanisms of deregulation and tumor suppressive function of EcSOD in cancer. PMID- 28842352 TI - Amino acid or peptide conjugates of acridine/acridone and quinoline/quinolone containing drugs. A critical examination of their clinical effectiveness within a twenty-year timeframe in antitumor chemotherapy and treatment of infectious diseases. AB - Acridines/acridones, quinolines/quinolones (chromophores) and their derivatives constitute extremely important family of compounds in current medicine. Great significance of the compounds is connected with antimicrobial and antitumor activities. Combining these features together in one drug seems to be long-term benefit, especially in oncology therapy. The attractiveness of the chromophore drugs is still enhanced by elimination their toxicity and improvement not only selectivity, specificity but also bioavailability. The best results are reached by conjugation to natural peptides. This paper highlights significant advance in the study of amino acid or peptide chromophore conjugates that provide highly encouraging data for novel drug development. The structures and clinical significance of amino acid or peptide chromophore conjugates are widely discussed. PMID- 28842353 TI - Experimental methods for flow and aerosol measurements in human airways and their replicas. AB - Recent developments in the prediction of local aerosol deposition in human lungs are driven by the fast development of computational simulations. Although such simulations provide results in unbeatable resolution, significant differences among distinct methods of calculation emphasize the need for highly precise experimental data in order to specify boundary conditions and for validation purposes. This paper reviews and critically evaluates available methods for the measurement of single and disperse two-phase flows for the study of respiratory airflow and deposition of inhaled particles, performed both in vivo and in replicas of airways. Limitations and possibilities associated with the experimental methods are discussed and aspects of the computational calculations that can be validated are indicated. The review classifies the methods into following categories: 1) point-wise and planar methods for velocimetry in the airways, 2) classic methods for the measurement of the regional distribution of inhaled particles, 3) standard medical imaging methods applicable to the measurement of the regional aerosol distribution and 4) emerging and nonconventional methods. All methods are described, applications in human airways studies are illustrated, and recommendations for the most useful applications of each method are given. PMID- 28842354 TI - Fatal stroke after Bothrops snakebite in the Amazonas state, Brazil: A case report. AB - Bothrops atrox is the snake responsible for the majority of snakebites in the Brazilian Amazon. Patients generally evolve to local manifestations such as edema, pain and ecchymoses. Systemic effects of B. atrox venom are usually restricted to blood incoagulability and spontaneous bleeding. However, in a few cases, bleeding in the central nervous system may occur, which can lead to sequels and deaths. Here, we report a case of a 59 year-old woman who presented edema, pain and ecchymoses on the right foot, headache, nausea, diarrhea, hypertension and blood incoagulability after the bite by Bothrops snake in the Brazilian Amazon. This case evolved with stroke resulting in death despite the antivenom and conservative therapy employed. In addition, we were able to identify the presence of venom in the patient's brain tissue after death. Direct action of toxins present in the snake's venom in the induction of systemic hemorrhage allied to blood incoagulability and hypertension presented by the patient could be involved in the mechanism of stroke in this case. PMID- 28842355 TI - First genetic characterization of Toxoplasma gondii infection in poultry meat intended for human consumption in eastern China. AB - Toxoplasma gondii can infect nearly all warm-blooded animals including birds. However, limited information on the molecular epidemiology and genotypes of T. gondii infecting poultry is available in China. Therefore, the present study characterized T. gondii genotypes in poultry meat in eastern China. During August 2015 and September 2016, muscle tissue samples collecting from 414 poultries (257 chickens, 115 ducks and 42 geese) in Shandong provinces were used to detect the T. gondii B1 gene by a semi-nested PCR, and the positive samples were genotyped at 10 nuclear loci (i.e., SAG1, alternative SAG2, 5'- and 3'-SAG2, SAG3, L358, BTUB, c22-8, GRA6, c29-2, PK1) and an apicoplast locus Apico by multi-locus PCR RFLP technology. Thirty-two (7.37%) samples from 414 poultry meat were T. gondii B1 gene positive. Chicken had the highest T. gondii prevalence (8.17%), followed by ducks (7.83%) and geese (4.76%). Furthermore, only one genotype (ToxoDB#9) was identified. This is the first genetic characterization of T. gondii isolates from poultry meat in Shandong province, eastern China and also the first report of genotype ToxoDB#9 was found in poultry in China, which provide basic data for the surveillance and control of T. gondii infection in poultry, other animals and humans. PMID- 28842356 TI - Impact of microRNAs on ischemic stroke: From pre- to post-disease. AB - Stroke is the number one cause of neurological dysfunction in adults and has a heavy socioeconomic burden worldwide. The etiological origins of ischemic stroke and resulting pathological processes are mediated by a multifaceted cascade of molecular mechanisms that are in part modulated by posttranscriptional activity. Accumulating evidence has revealed a role for microRNAs (miRNAs) as essential mediators of posttranscriptional gene silencing in both the physiology of brain development and pathology of ischemic stroke. In this review, we compile miRNAs that have been reported to regulate various stroke risk factors and pre-disease mechanisms, including hypertension, atherosclerosis, and diabetes, followed by an in-depth analysis of miRNAs in ischemic stroke pathogenesis, such as excitotoxicity, oxidative stress, inflammation, apoptosis, angiogenesis and neurogenesis. Since promoting or suppressing expression of miRNAs by specific pharmaceutical and non-pharmaceutical therapies may be beneficial to post-stroke recovery, we also highlight the potential therapeutic value of miRNAs in clinical settings. PMID- 28842357 TI - New alkenylated tetrahydropyran derivatives from the marine sediment-derived fungus Westerdykella dispersa and their bioactivities. AB - Six new alkenylated tetrahydropyran derivatives belonged to polyketides, designated as (12R,13R)-dihydroxylanomycinol (1), (12S,13S)-dihydroxylanomycinol (2), (12R,13S)-dihydroxylanomycinol (3) and (12S,13R)-dihydroxylanomycinol (4), (12S,13R)-N-acetyl-dihydroxylanomycin (5) and (12S,13S)-N-acetyl dihydroxylanomycin (6), together with one related known compound lanomycinol (7) were isolated from the liquid cultures of Westerdykella dispersa obtained from the marine sediments. Their structures and absolute configurations were determined on the basis of extensive analysis of NMR spectra combined with comparison of NMR data to those of known compound, and computational method via calculation of the electronic circular dichroism (ECD). The anti-agricultural pathogenic fungal and antibacterial activities of all isolated compounds were evaluated. Compounds 1-7 exhibited moderate antifungal activities selectively against tested fungal strains with minimum inhibitory concentration (MIC) values ranging from 12.5 to 50MUg/mL, and weak antibacterial activities selectively against tested antibacterial strains with MIC value at 100MUg/mL. PMID- 28842358 TI - HPLC, NMR based chemical profiling and biological characterisation of Indian propolis. AB - The present study aimed to investigate chemical profile, antioxidant and antimicrobial activities of Indian Melifera propolis (IMP) samples collected from 13 different states. Chemical characterisation of ethanolic extracts of IMP (EEMP) samples was carried out by using HPLC and 1HNMR spectroscopy. The antioxidant activity of EEMP samples was measured by DPPH, ABTS, and FRAP assay. Moreover, the antimicrobial activity of each EEMP sample tested against bacteria and yeast using a 96 well plate microdilution method. All EEMP samples had remarkable antioxidant and antimicrobial activities. The antioxidant potential of EEMP samples found to have a moderate positive correlation with their total phenolics and flavonoids content. Majority of EEMP samples had a minimum inhibitory concentration (MIC) <=1mg/mL against Staphylococcus aureus. Chemometric analysis of 1HNMR data indicated that brown, green, green-brown, red and red-brown coloured IMP samples were chemically distinct from each other, and showed two separate clusters for northern and southern states propolis samples. HPLC analysis confirmed phenethyl caffeate was most common and abundant compound in IMP samples among studied compounds. In conclusion, this study may be helpful for defining the quality of IMP as a raw material, and also in finished food and health care products. PMID- 28842359 TI - Isocoumarin derivatives from the endophytic fungus, Pestalotiopsis sp. AB - Five new isocoumarin derivatives, pestalactone A-C (1-3) and pestapyrone D-E (4 5), together with two known compounds (6-7) were isolated from the solid cultures of the endophytic fungus Pestalotiopsis sp. obtained from Photinia frasery. Their structures were mainly determined by extensive spectroscopic analysis, Mo2(OCOCH3)4-induced electronic circular dichroism (ECD), and ECD calculation. Compounds 1 and 2 were rare isocoumarin derivatives and derived from distinctive polyketide pathways. Compound 3 exhibited potent antifungal activity against Candida glabrata (ATCC 90030) with an MIC50 value of 3.49+/-0.21MUg/mL. PMID- 28842360 TI - Notch-out for breast cancer therapies. AB - Notch signalling is an evolutionarily highly conserved pathway that plays a crucial role during embryonic development and in tissue homeostasis maintenance during adult life. Abnormal Notch signalling has been implicated in several human genetic disorders and in multiple facets of cancer biology, including stem cell renewal, cancer cell proliferation, tumor angiogenesis and metastasis. Hence, Notch signalling has gained increasing attention as a potential therapeutic target for many disorders. gamma-secretase inhibitors (GSIs) were the first therapeutics used to inhibit pathological Notch signalling in various diseases, notably in oncology. Although GSIs show antitumor activity in advanced and metastatic cancer, the lack of substrate specificity and associated toxicity constitute significant limitations to their therapeutic use. Antibodies have emerged as powerful therapeutics due to their specificity, efficacy and safety, and remarkable success has been achieved with their use in immune-mediated diseases and cancer. This review describes the importance of the Notch pathway and its involvement in several pathologies, with a special focus on breast cancer. Moreover, the role of Notch and its ligands as promising therapeutic targets will be addressed, as well as therapeutic strategies being pursued for Notch modulation. PMID- 28842361 TI - Risk factors and molecular epidemiology of extended-spectrum beta-lactamase producing Klebsiella pneumoniae in Xiamen, China. AB - OBJECTIVES: The aim of this study was to evaluate the risk factors for pneumonia due to extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-KP) and to analyse the molecular epidemiology of ESBL-KP in Xiamen, China. METHODS: A case-control study was conducted at Zhongshan Hospital from January 2014 to August 2015. Medical records of patients with nosocomial pneumonia caused by K. pneumoniae were collected. A total of 40 cases with ESBL-KP infection and 90 controls with non-ESBL-KP infection were included. The sequence types (STs) of the 40 ESBL-KP strains were determined by multilocus sequence typing (MLST). RESULTS: Univariate analysis primarily revealed an association between the following seven risk factors and ESBL-KP infection (P<0.10): length of hospitalisation; use of cephalosporins; use of quinolones; presence of a nasogastric tube; presence of an intravenous catheter; mechanical ventilation; and cerebrospinal fluid drainage. Furthermore, multivariate analysis revealed that use of cephalosporins and presence of a nasogastric tube were independent risk factors for ESBL-KP infection (P<0.05), with adjusted odds ratios of 3.473 [95% confidence interval (CI) 1.105-10.911; P=0.033] and 2.488 (95% CI 1.083 5.715; P=0.032), respectively. MLST identified 28 STs. The main STs were ST23 (10.0%) and ST37 (10.0%); three novel STs were identified. CONCLUSIONS: Use of cephalosporins and presence of a nasogastric tube are independent risk factors for ESBL-KP infection. In addition, the discovery of three novel STs serves as a reminder to continuously monitor outbreaks of ESBL-KP infection. PMID- 28842362 TI - Determinants of short term fracture risk in patients with a recent history of low trauma non-vertebral fracture. AB - Low-trauma fractures tend to cluster in time, and subsequent fractures have a role in increased morbidity and mortality in osteoporotic patients. The aim of this study was to identify the risk factors of short-term subsequent non vertebral fracture (NVF). Patients were included from the Fracture Liaison Service (FLS) which provides assessment for osteoporosis to all in-hospital patients admitted for a low-trauma NVF in the Orthopaedics department. Location and date of occurrence of previous fractures, risk factors for osteoporosis and falls were collected. Bone mineral density was measured at the lumbar spine and total hip; presence of vertebral fractures was evaluated using vertebral fracture assessment (VFA). Nine hundred and fifty patients were included (84% women; 75+/ 12years), with a mean T-score at the femoral neck of -2.3+/-1.0. Four hundred and sixty eight (49%) patients were in the FLS because of a hip fracture. Using multivariable analysis, the risk of being in the FLS with a previous fracture <=3years before was associated with: history of fall in the year before the admission (OR=2.75, CI 95% 1.55-4.93), history of severe low-trauma NVF (OR=2.54; CI 95% 1.45-4.52), and BMI lower than 20kg/m2 (OR=2.45, CI 95% 1.25-4.87); age older than 78years-old was protective to the risk of re-fracture (OR=0.44, CI 95% 0.24-0.80). Some risk factors (age, history of fall and of previous severe non vertebral fracture) can help in the selection of patients at high risk of refracture, who should receive the highest priority for a treatment. PMID- 28842363 TI - Associations between body mass index across adult life and hip shapes at age 60 to 64: Evidence from the 1946 British birth cohort. AB - OBJECTIVE: To examine the associations of body mass index (BMI) across adulthood with hip shapes at age 60-64years. METHODS: Up to 1633 men and women from the MRC National Survey of Health and Development with repeat measures of BMI across adulthood and posterior-anterior dual-energy X-ray absorptiometry bone mineral density images of the proximal femur recorded at age 60-64 were included in analyses. Statistical shape modelling was applied to quantify independent variations in hip mode (HM), of which the first 6 were examined in relation to: i) BMI at each age of assessment; ii) BMI gain during different phases of adulthood; iii) age first overweight. RESULTS: Higher BMI at all ages (i.e. 15 to 60-64) and greater gains in BMI were associated with higher HM2 scores in both sexes (with positive HM2 values representing a shorter femoral neck and a wider and flatter femoral head). Similarly, younger age first overweight was associated with higher HM2 scores but only in men once current BMI was accounted for. In men, higher BMI at all ages was also associated with lower HM4 scores (with negative HM4 values representing a flatter femoral head, a wider neck and smaller neck shaft angle) but no associations with BMI gain or prolonged exposure to high BMI were found. Less consistent evidence of associations was found between BMI and the other four HMs. CONCLUSION: These results suggest that BMI across adulthood may be associated with specific variations in hip shapes in early old age. PMID- 28842364 TI - Femoral head trabecular micro-architecture in patients with osteoporotic hip fractures: Impact of bisphosphonate treatment. AB - INTRODUCTION: Bisphosphonates are effective in preventing osteoporotic fractures. However, their limited efficacy of bisphosphonates has been suggested as a result of these drugs, which prevent the resorption of bone without improving bone connectivity. The trabecular microarchitecture in patients with osteoporotic hip fractures was evaluated according to their history of bisphosphonate treatment (BT). METHODS: One hundred thirty-three patients with hip fractures admitted and treated between November 2014 and September 2016. The patients were divided into two groups based on whether they had received treatment with bisphosphonates for >3years or not [non-bisphosphonate-treated patients (NT)]. One-to-one propensity score matching generated 15 matched pairs of patients. Microstructural parameters of femoral head were measured by using micro-computed tomography (MUCT). Mechanical compression test (Young's modulus, yield strength, and maximum compressive force) was performed following MUCT. RESULTS: Trabecular bone pattern factor (1.15+/-0.7mm-1 versus 1.61+/-0.5mm-1, p=0.037) and specific bone surface (14.1+/-0.8mm-1 versus 15.4+/-1.9mm-1, p=0.050) were significantly lower in the BT group than in the NT group. Furthermore, Young's modulus was significantly higher in the BT group than in the NT group (72.14+/-30.75MPa versus 47.89+/ 29.89MPa, p=0.037). In both groups, trabecular bone pattern was the most closely correlated microstructural parameter to bone strength. Microstructural analysis demonstrated that bone connectivity was better preserved in the BT group than in the NT group. CONCLUSIONS: Bisphosphonate treatment preserves bone mass and bone quality. The factors influencing osteoporotic hip fractures in patients treated with bisphosphonates warrant further research. PMID- 28842365 TI - Spinal deformity changes in children with long-term vertical expandable prosthetic titanium rib treatment. AB - BACKGROUND CONTEXT: In several studies, vertical expandable prosthetic titanium rib (VEPTR) implants have shown good scoliosis control in children with the longest reported follow-up of 3.6 years. For growing rods, recent studies suggest a decreased efficiency of correction starting just after that time. To our knowledge, no long-term results of children with VEPTR treatment are available. PURPOSE: This study aimed to evaluate spinal deformity in scoliotic children and to investigate correction potential of VEPTR implants at several time points of treatment, particularly after long-term follow-up. STUDY DESIGN/SETTING: We performed a retrospective case series of 32 children with spinal deformity and VEPTR treatment with analysis of clinical and radiological data pre- and post VEPTR implantation and every 2 years during the follow-up period. PATIENT SAMPLE: Thirty-two patients with spinal deformity and VEPTR treatment comprised the patient sample. OUTCOME MEASURES: Patients had a primary VEPTR implantation due to spinal deformity and thoracic insufficiency syndrome and repeated lengthening procedures every 6 months. Clinical data were assessed and radiological parameters were analyzed. The main thoracic scoliotic curve and associated curves as well as kyphosis, lordosis, pelvic obliquity, and spinal length were measured in all radiographs until the end of VEPTR treatment or the last available examination. METHODS: Development of the different parameters during follow-up was evaluated and statistical analysis was performed with Statistica version 13.0. No funding was obtained for this study. The authors have no conflicts of interest to declare. RESULTS: Directly after VEPTR implantation, thoracic and lumbar curves corrected significantly, were stable at 2.8-year follow-up, and increased at 5.5-year follow-up, whereas cervical scoliosis was not affected by the treatment. The sagittal profile was initially improved both in kyphosis and lordosis. However, at 5.5-year follow-up, hyperkyphosis had deteriorated beyond the initial deformity. Pelvic obliquity was significantly restored especially in neuromuscular patients, and increasing spinal length was achieved within the 5.5 year follow-up. CONCLUSION: In children with spinal deformity, implantation of the VEPTR device sufficiently corrected the deformity in all planes. During long term follow-up, scoliosis increased slightly and was rather well controlled, whereas the implant system was not able to prevent deterioration of hyperkyphosis. Pelvic obliquity was well balanced and spinal lengthening was achieved during long-term follow-up. PMID- 28842366 TI - EUCAST proposes to change the definition and usefulness of the susceptibility category 'Intermediate'. PMID- 28842367 TI - The Acquisition and Extinction of Fear of Painful Touch: A Novel Tactile Fear Conditioning Paradigm. AB - : Fear of touch, due to allodynia and spontaneous pain, is not well understood. Experimental methods to advance this topic are lacking, and therefore we propose a novel tactile conditioning paradigm. Seventy-six pain-free participants underwent acquisition in a predictable as well as an unpredictable pain context. In the predictable context, vibrotactile stimulation was paired with painful electrocutaneous stimulation (simulating allodynia). In the unpredictable context, vibrotactile stimulation was unpaired with pain (simulating spontaneous pain). During an extinction phase, a cue exposure and context exposure group continued in the predictable and unpredictable context, respectively, without pain. A control group received continued acquisition in both contexts. Self reported fear and skin conductance responses, but not startle responses, showed fear of touch was acquired in the predictable context. Context-related startle responses showed contextual fear emerged in the unpredictable context, together with elevated self-reported fear and skin conductance responses evoked by the unpaired vibrotactile stimulations. Cue exposure reduced fear of touch, whereas context exposure reduced contextual fear. Thus, painful touch leads to increased fear, as does touch in the same context as unpredictable pain, and extinction protocols can reduce this fear. We conclude that tactile conditioning is valuable for investigating fear of touch and can advance our understanding of chronic pain. PERSPECTIVES: The acquisition and extinction of fear of touch was investigated in a clinical analog study using a novel tactile fear conditioning paradigm. The results have implications for research on the development and treatment of chronic pain conditions characterized by allodynia and spontaneous pain fluctuations. PMID- 28842368 TI - Validity of the Visual Trajectories Questionnaire for Pain. AB - : Researchers have identified trajectories of pain derived using statistical techniques on longitudinal data. These trajectories have potential to be of use clinically but the repeated data collection required is currently impractical for such situations. Our aim was to investigate the validity of a self-report (Visual Trajectories Questionnaire-Pain) for pain. Analysis included participants from 2 prospective cohorts of people seeking primary health care for back pain (n = 622). A question was developed asking people to classify their pain experience into one of a number of trajectories using visual and word descriptions. Overall 98% of participants completed the question; criterion validity was established by comparing self-report trajectories and trajectories derived using longitudinal latent class analysis, and construct validity was established by comparing responses to the questionnaire against an existing model of back pain stages. As expected variables such as pain intensity and widespreadness, other symptoms, and psychological distress showed an increasing trend of severity across trajectory categories in line with the hypothesized model. In conclusion, the self-report single-item Visual Trajectories Questionnaire-Pain is acceptable to patients and supported by evidence of face, criterion, and construct validity. Further research is needed to investigate the clinical usefulness of the question. PERSPECTIVE: This study provides a new questionnaire (Visual Trajectories Questionnaire-Pain) that captures the longitudinal state of a patient's pain experience. The Visual Trajectories Questionnaire-Pain has shown aspects of face, criterion, and construct validity, and has the potential to be clinically useful. PMID- 28842369 TI - Old Friends With New Faces: Are Sodium Channel Blockers the Future of Adjunct Pain Medication Management? AB - : Providers are being asked to decrease the emphasis and overutilization of long term opioid therapy, but many are left without proper guidance on appropriate utilization of nonopioid therapies. Furthermore, therapeutic options are quite limited and many providers lack confidence in distinguishing available alternatives. When first-line therapy has failed in a patient, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose among alternative agents, an understanding of pharmacology, pharmacokinetics, and efficacy in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine) for adjunct pain medication management including research updates in pharmacology, pharmacokinetics, and current evidence for pain along with promising areas of research. It is an evidence update for clinical use of sodium channel blockers, clarifies misconceptions regarding their use, and highlights emerging research for improved pain targets that justifies additional study. We performed a complete review of the literature using the search terms, "oxcarbazepine," "carbamazepine," and "eslicarbazepine" in conjunction with "pharmacokinetics," "adverse effects," "pharmacology," "voltage-gated sodium channel subtype," "neuropathic pain," "inflammatory pain," "metabolism," "epoxide metabolite formation," "drug interactions," "CYP450 interactions," "pain phenotype," and "chronic pain management." Databases searched included PubMed and Google Scholar. Package inserts were used for drug structure illustration, adverse reactions, and bioavailability. Pharmacology and pharmacokinetic data were taken from randomized controlled trials evaluating this area as well as in vitro published results. For validity, only peer-reviewed literature was included. Evidence for sodium channel blockers in chronic pain management was limited. This review focuses on highlighting the data available for the use of sodium channel blockers for certain pain syndromes as well as underutilized potential. Emerging literature on sodium channel subtypes and their connection to neuropathic, inflammatory, and mechanical pain transmission is elucidated. The authors also scrutinize literature surrounding the pharmacokinetics of oxcarbazepine and eslicarbazepine to provide clearer guidance to the significance of any drug interactions and refute assumptions made on the basis of structural similarity to carbamazepine and its known undesirable drug interactions. Side effect profiles are outlined and compared, emphasizing the differences between agents. Sodium channel blocker doses used in certain pain syndromes are outlined with a call for further research to better understand their place in chronic pain management. Identification of sodium channel subtypes with links to specific pain conditions and the ability to target them hints at the potential for truly individualized therapy. Sodium channel inhibitors are underutilized on the basis of available evidence, and emerging research has identified this area as promising for additional clinical trials to better guide clinical practice. PERSPECTIVE: This article provides a review of the pharmacology, evidence for pain management, and pharmacokinetics of oxcarbazepine, carbamazepine, and eslicarbazepine. There is a disparity in evidence using sodium channel blockers for pain and this article highlights the potential that is currently underutilized. The authors believe this will catalyze interest for further studies. PMID- 28842370 TI - The Effect of Preoperative Intra-Articular Methylprednisolone on Pain After TKA: A Randomized Double-Blinded Placebo Controlled Trial in Patients With High-Pain Knee Osteoarthritis and Sensitization. AB - : In a randomized, double-blind, placebo controlled trial, we investigated the postoperative analgesic effect of a single intra-articular injection of 40 mg methylprednisolone acetate (MP) administered 1 week before total knee arthroplasty (TKA). Forty-eight patients with high pain osteoarthritis (>=5 on a numeric rating scale during walk) and sensitization (pressure pain threshold <250 kPa), aged 50 to 80 years and scheduled for primary unilateral TKA under spinal anaesthesia were included. The primary outcome was the proportion of patients with moderate/severe pain during a 5-m walk test 24 hours postoperatively. Secondary outcomes included pain at 48 hours, during the first 14 days, sensitization (quantitative sensory testing with pressure pain threshold and wind up from temporal summation), and inflammatory changes (systemic C-reactive protein, intra-articular interleukin [IL]-6). No difference in the proportion of patients with moderate/severe pain was found between MP/placebo groups at 24 hours (67% and 74%, chi2 = .2, P = .63, odds ratio = .7, 95% confidence interval = .2-2.8) or at 48 hours (57% and 68%, chi2 = .5, P = .46, odds ratio = .6, 95% confidence interval = .2-2.3), and no difference between groups in postoperative sensitization was found (P > .4) despite reduced preoperative intra-articular inflammation (IL-6) in the MP group versus placebo (median change in IL-6 = -70 pg/mL, interquartile range = -466 to 0 vs. 32 pg/mL, interquartile range = -26 to 75, P = .029). Alternative central or peripheral analgesic interventions in this high-risk group are required. PERSPECTIVE: Peripherally driven inflammatory pain and nociceptive changes before TKA has been suggested to be a cause for increased acute postoperative pain. However, preoperative intra-articular MP in patients with high pain osteoarthritis and sensitization did not reduce acute post-TKA pain or sensitization despite a preoperative reduction of intra-articular inflammatory markers. PMID- 28842371 TI - Molecular cloning and functional characterization of interferon regulatory factor 7 of the barbel chub, Squaliobarbus curriculus. AB - The interferon regulatory factor 7 (IRF7) is a critical regulator of type-I interferon-dependent immune reaction that defense against virus. To investigate the antiviral function of IRF7 of barbel chub Squaliobarbus curriculus (ScIRF7), the cDNA of ScIRF7 was cloned and characterized. The full length cDNA of ScIRF7 was 1870 bp, consisted of 41 bp 5'-UTR, 560 bp 3'-UTR and a 1269 bp open reading frame (ORF). The ORF encoded 423 amino acids with a molecular weight of 49.426 KDa and a theoretical isoelectric point of 5.71. The putative ScIRF7 protein possesses typical domains of IRF family including a conserved N-terminal DBD binding domain (DBD), a C-terminal IRF association domain and a serine-rich domain. In the DBD, four tryptophans were found to be highly conserved among all species, whilst in another conserved tryptophan site of mammals, the corresponding amino acids were methionine for fishes. The expression level of ScIRF7 was highest in the spleen and lowest in the liver. The expression level of IFN-beta was highest in the gill and lowest in the liver. After GCRV infection, expression levels changes of ScIRF7 showed an overall tendency of firstly up regulation and then down-regulation in the spleen and the gill; and expression levels of ScIRF7 in peripheral blood lymphocyte at 24 h post-infection was highest among all time points. In pEGFP-ScIRF7 overexpressing cells, the mRNA level of ScIRF7 was firstly up-regulation and then down-regulation; and the expression of IFN-beta was significantly up-regulated at 12 h post-infection than that of control group (P < 0.05), which was significantly higher than those in pEGFP-N1 overexpressing cells. The results indicated that ScIRF7 may play a key role in immune responses of barbel chub Squaliobarbus curriculus against GCRV and may also functions in the Ctenopharyngodon idellus kidney cells. PMID- 28842372 TI - Various cellular responses of different shrimp haemocyte subpopulations to lipopolysaccharide stimulation. AB - Different haemocyte types have been reported to play diverse roles in immune defense of shrimp. To investigate the roles of the three haemocyte types [hyaline cells (HC), semigranular cells (SGC) and granular cells (GC)] of shrimp in immune responses against lipopolysaccharide (LPS), percentage, non-specific esterase activity (EA), reactive oxygen species (ROS) production and nitric oxide (NO) production of the three haemocyte subpopulations were analyzed in LPS-injected Penaeus monodon using flow cytometry. Results showed that percentage of HC increased after 3 h injection, and returned to the original level after 48 h. Proportion of SGC and GC reduced after 6-36 h and 3-12 h respectively, and recovered to the initial level after 48 and 24 h respectively. Loss of SGC and GC might be related to degranulation to release proPO system, and degranulation of GC seemed more sensitive to LPS stimulation. EA of both HC and SGC improved after 3-6 h injection, while EA of GC was induced after 3-24 h. No significant effect of LPS injection could be found in ROS production and NO production of HC. Enhanced ROS levels was observed in SGC and GC after 3-24 h and 3-36 h respectively, and NO production of SGC and GC improved after 3-48 h injection. These results demonstrated that SGC and GC possessed strong capabilities for LPS induced EA, ROS production and NO production, while HC only displayed EA response to LPS, suggesting that GC and SGC play the main role in immune defense of shrimp against Gram-negative bacteria. PMID- 28842373 TI - Ontogeny and modulation after PAMPs stimulation of beta-defensin, hepcidin, and piscidin antimicrobial peptides in meagre (Argyrosomus regius). AB - Antimicrobial peptides (AMPs), components of innate immunity, play an important role in protecting fish. In this study we report the molecular cloning of full open reading frames and characterization of expression of three AMP genes (beta defensin (defb), hepcidin (hep2), piscidin (pisc) in meagre (Argyrosomus regius). A phylogenetic analysis of the expressed sequences obtained shows the defensin isoform forms a clade with the other members of the beta class of this family, hepcidin corresponds to hepcidin 2, and piscidin corresponds to class I of its respective family. Gene expression profiles of AMPs was investigated, by means of quantification of mRNA in nine development stages, from 8 days post-hatching (dph) to accomplishment of juvenile form (120 dph). During development it was demonstrated defb, hep2, pisc were expressed in all stages of larval development and in juvenile tissues (kidney, spleen gut and gill). Moreover, expression patterns suggest the expression levels of theses AMPs are influenced by live prey (rotifer, Artemia) and first intake of commercial diet. Induction experiments in vivo (24 h) and in vitro (4, 12, 24 h) with PAMPs (LPS, poly (I:C), beta-glucan) revealed significant changes in gene expression of the three AMP genes, in kidney, spleen, gut and gill. However, expression profiles differed in magnitude and time course response. defb expression shows a similar trend in vivo and in vitro in kidney at 24 h after LPS and beta-glucan stimulation. The hep2 expression levels were up-regulated upon beta-glucan challenge in vivo, more in gut and gills than kidney, while in vitro hep2 expression was up-regulated in kidney cells by LPS, poly (I:C), beta-glucan (4 h). pisc expression was up regulated in kidney cells, splenocytes by beta-glucan, but in gill cells by poly (I:C) and beta-glucan in vivo. However, pisc expression was upregulated in kidney cells by beta-glucan and gill cells by LPS at 4 post-stimulation in vitro. These data suggest that AMPs play an important role in defense against pathogens, with each AMP having differing efficacies against specific types of microorganisms, although follow-up studies focusing on the biological activities in fish are needed. PMID- 28842374 TI - Immobilization of bacteriophage in wound-dressing nanostructure. AB - Opportunistic bacteria that cause life-threatening infections are still a central problem associated with a healthcare setting. Bacteriophage capsid immobilization on nanostructured polymers maximizes its tail exposure and looks promising in applications toward skin-infections as alternative to antibiotics standardly used. The main goal of this work was to investigate the covalent immobilization of vB_Pae_Kakheti25 bacteriophage capsid on polycaprolactone (PCL) nanofibers (non-woven textile), as a potential effective antimicrobial, laundry resistant and non-toxic dressing for biomedical use. Surface analyses showed that the immobilization of vB_Pae_Kakheti25 bacteriophage capsid on PCL nanofibres oriented bacteriophage tails to interact with bacteria. Furthermore, antimicrobial assays showed a very effective 6 log bacterial reduction, which was equivalent to 99.9999%, after immediate and 2 hours of contact, even following 25 washing cycles (due to covalent bond). The activity of PCL-vB_Pae_Kakheti25 against P. aeruginosa was immediate and its reduction was complete. PMID- 28842375 TI - MUC1 aptamer-capped mesoporous silica nanoparticles for controlled drug delivery and radio-imaging applications. AB - Mucin 1 (MUC1) is a cell surface protein overexpressed in breast cancer. Mesoporous silica nanoparticles (MSNs) loaded with safranin O, functionalized with aminopropyl groups and gated with the negatively charged MUC1 aptamer have been prepared (S1-apMUC1) for specific targeting and cargo release in tumoral versus non-tumoral cells. Confocal microscopy studies showed that the S1-apMUC1 nanoparticles were internalized in MDA-MB-231 breast cancer cells that overexpress MUC1 receptor with subsequent pore opening and cargo release. Interestingly, the MCF-10-A non-tumorigenic breast epithelial cell line that do not overexpress MUC1, showed reduced (S1-apMUC1) internalization. Negligible internalization was also found for S1-ap nanoparticles that contained a scrambled DNA sequence as gatekeeper. S2-apMUC1 nanoparticles (similar to S1-apMUC1 but loaded with doxorubicin) internalized in MDA-MB-231 cells and induced a remarkable reduction in cell viability. Moreover, S1-apMUC1 nanoparticles radio labeled with 99mTc (S1-apMUC1-Tc) showed a remarkable tumor targeting in in vivo studies with MDA-MB-231 tumor-bearing Balb/c mice. PMID- 28842376 TI - Theranostic poly(lactic-co-glycolic acid) nanoparticle for magnetic resonance/infrared fluorescence bimodal imaging and efficient siRNA delivery to macrophages and its evaluation in a kidney injury model. AB - In this work, a theranostic nanoparticle was developed for multimodal imaging and siRNA delivery. The core of the nanoparticles (NP) was formed by encapsulation of superparamagnetic iron oxides and indocyanine green in a PLGA matrix to serve as a multimodal probe for near-infrared (NIFR) and magnetic resonance (MR) imaging. The surface of the particle was coated with polyethylenimine (PEI) for siRNA delivery. Macrophages efficiently took up the nanoparticles and emitted strong NIFR and MR contrast. When transfected with siRNA targeting the pro-inflammatory enzyme cyclooxygenase-2 (COX-2), significant down-regulation of COX-2 was achieved in activated macrophages. Furthermore, after injection into a unilateral ureteral obstruction (UUO)-induced kidney injury model, NIFR and MRI imaging revealed accumulation of nanoparticles in the injury kidney. In addition, in vivo silencing of COX-2 was achieved by NP/PEI/siCOX-2, which further attenuated kidney injury. Our theranostic platform represents a promising approach for simultaneous diagnosis and treatment of inflammatory diseases. PMID- 28842377 TI - A dabigatran etexilate phospholipid complex nanoemulsion system for further oral bioavailability by reducing drug-leakage in the gastrointestinal tract. AB - Dabigatran etexilate (DE) is insoluble at neutral pH values but soluble at low pH values due to protonation, which is the major cause for the poor bioavailability of commercial DE products. Here, we first developed a DE nanoemulsion system and improved dissolution in simulated intestinal fluids by encapsulating DE into an oil phase, but 35.8% of the drug still leaked out. Further, we prepared a DE phospholipid complex (DE-PC) to enhance lipophilicity and solubility of DE. The resulting DE-PC nanoemulsions significantly (P<0.05) reduced drug leakage and subsequent precipitation. As a result, the relative bioavailability of DE-PC nanoemulsions increased to 147.3% and 606.6% compared to DE nanoemulsions and commercial DE products, respectively. Thus, the presently developed drug phospholipid complex nanoemulsion system is a promising drug delivery system for improving the oral bioavailability of pH-dependent soluble drugs. PMID- 28842378 TI - End-of-Life Discussions in Patients With Heart Failure. AB - BACKGROUND: Although guidelines call on clinicians to conduct regular conversations about advance care planning and end-of-life (EOL) preferences with patients with heart failure (HF), research suggests that physicians often avoid these discussions. METHODS AND RESULTS: From January 20, 2014, to January 18, 2016, Southeastern Minnesota residents hospitalized with acute decompensated HF (ADHF) at Mayo Clinic hospitals were enrolled into an observational cohort study that included the administration of face-to-face questionnaires. Risk of death (prognosis) was estimated using the Meta-analysis Global Group in Chronic Heart Failure score. Among 400 patients (mean age 77.7 years, 46% female, 48% preserved ejection fraction), only 69 (17%) reported previously discussing EOL wishes with their physician. Patients reporting EOL discussions more often had an advance directive (81% vs 66%; P = .009), recognized the term "hospice" (96% vs 87%; P = .027), and had more favorable attitudes of dying and hospice (P = .030). Resuscitation preferences and rates of completion of advance directives varied with prognosis, although patient-clinician EOL discussions did not. CONCLUSIONS: The majority of patients hospitalized with ADHF did not recall discussing their preferences for EOL care with their physician. This represents an important modifiable gap in the optimal longitudinal care of HF patients. PMID- 28842379 TI - Weblogs: A Complex Data Source for Qualitative Research. PMID- 28842380 TI - Brief Report: Patient Activation Among Urban Hospitalized Patients With Heart Failure. AB - BACKGROUND: Patient activation influences patients' ability to meaningfully engage in critical heart failure self-care. The purpose of this study was to identify whether patient activation is associated with patient-reported health outcomes in an urban and racially diverse inpatient sample of patients with heart failure. METHODS: We prospectively recruited patients with heart failure hospitalized at an urban academic medical center from October 2016 to May 2017 and measured patient activation, physical and affective symptoms, physical function, self-care, perceived control, and self-efficacy. Differences in patient reported health outcomes between low and high activation groups were compared with the use of linear regression models adjusting for age, sex, education, left ventricular ejection fraction, and New York Heart Association functional classification. RESULTS: A total of 96 patients completed the study (mean age 57 +/- 12.4 y); 39% identified as black and 35% as Latino, 35% were female, and 50% reported not having enough income to make ends meet. Based on the 4 levels of activation defined by the Patient Activation Measure-13, 22% of patients reported being "disengaged and overwhelmed," 14% were "becoming aware, but still struggling," 39% were "taking action," and 26% were "maintaining behaviors and pushing further." Higher patient activation was associated with better applied cognitive abilities, self-care behaviors, perceived control, and self-efficacy. CONCLUSION: Patient activation can be easily measured in hospitalized patients with heart failure and is associated with clinically meaningful patient-reported health outcomes. PMID- 28842381 TI - Clinical Decision Support for Heart Failure Referral-More Work, Better Outcomes? PMID- 28842382 TI - Varenicline promotes endothelial cell migration by lowering vascular endothelial cadherin levels via the activated alpha7 nicotinic acetylcholine receptor-mitogen activated protein kinase axis. AB - Varenicline is a widely used and effective drug for smoking cessation. Despite its efficacy, varenicline increases the risk of cardiovascular disease. We previously demonstrated that varenicline aggravates atherosclerotic plaque formation in apolipoprotein E knockout mice. However, little is known about its effects in vascular endothelial cells. Therefore, we examined whether varenicline promotes migration of human umbilical vein endothelial cells (HUVECs) using the Boyden chamber assay. Varenicline (100MUM) markedly promoted migration of HUVECs and decreased expression of vascular endothelial (VE)-cadherin, an endothelial adhesion molecule. Extracellular signal-regulated kinase (ERK), p38 and c-Jun N terminal kinase (JNK) signaling were markedly activated by varenicline. Methyllycaconitine (MLA; 100nM), an alpha7 nicotinic acetylcholine receptor (nAChR) antagonist, but not dihydro-beta-erythroidine hydrobromide (DHbetaE; 20MUM) blocked varenicline-stimulated migration and varenicline-activated ERK, p38 and JNK signaling in HUVECs. MLA (100nM), PD98059 (an ERK inhibitor; 20MUM), SB203580 (a p38 inhibitor; 20MUM) and SP600125 (a JNK inhibitor; 20MUM) also blocked cell migration and varenicline-induced downregulation of VE-cadherin expression in HUVECs. These findings suggest that varenicline promotes HUVEC migration by lowering VE-cadherin expression due to activated ERK/p38/JNK signaling through alpha7 nAChR. These processes probably contribute to varenicline-aggravated atherosclerotic plaque. Hence, an increased risk of cardiovascular events upon varenicline treatment might occur and must be considered in patients with cardiovascular diseases. PMID- 28842383 TI - Glucagon-like peptide 2 prevents down-regulation of intestinal multidrug resistance-associated protein 2 and P-glycoprotein in endotoxemic rats. AB - Multidrug resistance-associated protein 2 (Mrp2, ABCC2) and P-glycoprotein (P-gp, ABCB1) constitute essential components of the intestinal biochemical barrier that prevent incorporation of food contaminants, drugs or toxic metabolites into the blood stream. Endotoxemia induced in rats by administration of bacterial lipopolysaccharide (LPS) results in elevated intestinal permeability and toxicity of xenobiotics in part associated with down-regulation of expression and activity of Mrp2 and P-gp. We evaluated the protective effect of glucagon-like peptide 2 (GLP-2), a peptide hormone with enterotrophic properties, on Mrp2 and P-gp alterations induced by single i.p. injection of LPS (5mg/kg b.wt.) to rats. Two different protocols of GLP-2 administration, namely prevention and reversion, were examined. The prevention protocol consisted of 7s.c. injections of GLP-2 (125MUg/kg b.wt.) administered every 12h, starting 60h before LPS administration. The reversion protocol consisted of 2 doses of GLP-2, starting 3h after LPS injection. Intestinal samples were collected 24h after LPS administration and expression (protein and mRNA) and activity of Mrp2 were evaluated in proximal jejunum whereas those of P-gp were studied in ileum. GLP-2 completely neutralized down-regulation of expression of Mrp2 and P-gp and loss of their respective activities induced by LPS under prevention protocol. GLP-2 was also able to prevent internalization of both transporters from the apical membrane of the enterocyte to intracellular compartments, as detected by confocal microscopy. LPS induced an increase in IL-1beta and oxidized glutathione tissue levels, which were also counterbalanced by GLP-2 administration. In contrast, the reversion protocol failed to attenuate Mrp2 and P-gp down-regulation induced by LPS. We conclude that GLP-2 can prevent down-regulation of intestinal expression and activity of Mrp2 and P-gp in endotoxemic rats and that IL-1beta and oxidative stress constitute potential targets of GLP-2 protective effects. PMID- 28842384 TI - 3D MR fingerprinting with accelerated stack-of-spirals and hybrid sliding-window and GRAPPA reconstruction. AB - PURPOSE: Whole-brain high-resolution quantitative imaging is extremely encoding intensive, and its rapid and robust acquisition remains a challenge. Here we present a 3D MR fingerprinting (MRF) acquisition with a hybrid sliding-window (SW) and GRAPPA reconstruction strategy to obtain high-resolution T1, T2 and proton density (PD) maps with whole brain coverage in a clinically feasible timeframe. METHODS: 3D MRF data were acquired using a highly under-sampled stack of-spirals trajectory with a steady-state precession (FISP) sequence. For data reconstruction, kx-ky under-sampling was mitigated using SW combination along the temporal axis. Non-uniform fast Fourier transform (NUFFT) was then applied to create Cartesian k-space data that are fully-sampled in the in-plane direction, and Cartesian GRAPPA was performed to resolve kz under-sampling to create an alias-free SW dataset. T1, T2 and PD maps were then obtained using dictionary matching. RESULTS: Phantom study demonstrated that the proposed 3D-MRF acquisition/reconstruction method is able to produce quantitative maps that are consistent with conventional quantification techniques. Retrospectively under sampled in vivo acquisition revealed that SW + GRAPPA substantially improves quantification accuracy over the current state-of-the-art accelerated 3D MRF. Prospectively under-sampled in vivo study showed that whole brain T1, T2 and PD maps with 1 mm3 resolution could be obtained in 7.5 min. CONCLUSIONS: 3D MRF stack-of-spirals acquisition with hybrid SW + GRAPPA reconstruction may provide a feasible approach for rapid, high-resolution quantitative whole-brain imaging. PMID- 28842385 TI - Effects of spatial fMRI resolution on the classification of naturalistic movies. AB - Studies involving multivariate pattern analysis (MVPA) of BOLD fMRI data generally attribute the success of the information-theoretic approach to BOLD signal contrast on the fine spatial scale of millimeters facilitating the classification or decoding of perceptual stimuli. However, to date MVPA studies that have actually explored fMRI resolutions at less than 2 mm voxel size are rare and limited to small sets of unnatural stimuli (like visual gratings) as well as specific sub-regions of the brain, notably the primary somatosensory cortices. To investigate what spatial scale best supports high information extraction under more general conditions this study combined naturalistic movie stimuli with high-resolution fMRI at 7 T and linear discriminant analysis (LDA) of global and local BOLD signal patterns. Contrary to predictions, LDA and similar classifiers reached a maximum in classification accuracy (CA) at a smoothed resolution close to 3 mm, well above the 1.2 mm voxel size of the fMRI acquisition. Maximal CAs around 90% were contingent upon global fMRI signal patterns comprising 4 k-16 k of the most reactive voxels distributed sparsely throughout the occipital and ventro-temporal cortices. A Searchlight analysis of local fMRI patterns largely confirmed the global results, but also revealed a small subset of brain regions in early visual cortex showing limited increases in CA with higher resolution. Principal component analysis of the global and local fMRI signal patterns suggested that reproducible neuronal contributions were spatially auto-correlated and smooth, while other components of higher spatial frequency were likely related to physiological noise and responsible for the reduced CA at higher resolution. Systematic differences between experiments and subjects suggested that higher CA was significantly correlated with more consistent behavior revealed by eye tracking. Thus, the optimal resolution of fMRI data for MVPA was mainly limited by physiological noise of high spatial frequency as well as behavioral (in-)consistency. PMID- 28842387 TI - Is It All About Age or Personalized Haploidentical Hematopoietic Stem Cell Transplantation for Elderly Patients? PMID- 28842386 TI - Complementary contributions of concurrent EEG and fMRI connectivity for predicting structural connectivity. AB - While averaged dynamics of brain function are known to estimate the underlying structure, the exact relationship between large-scale function and structure remains an unsolved issue in network neuroscience. These complex functional dynamics, measured by EEG and fMRI, are thought to arise from a shared underlying structural architecture, which can be measured by diffusion MRI (dMRI). While simulation and data transformation (e.g. graph theory measures) have been proposed to refine the understanding of the underlying function-structure relationship, the potential complementary and/or independent contribution of EEG and fMRI to this relationship is still poorly understood. As such, we explored this relationship by analyzing the function-structure correlation in fourteen healthy subjects with simultaneous resting-state EEG-fMRI and dMRI acquisitions. We show that the combination of EEG and fMRI connectivity better explains dMRI connectivity and that this represents a genuine model improvement over fMRI-only models for both group-averaged connectivity matrices and at the individual level. Furthermore, this model improves the prediction within each resting-state network. The best model fit to underlying structure is mediated by fMRI and EEG delta connectivity in combination with Euclidean distance and interhemispheric connectivity with more local contributions of EEG-gamma at the scale of resting state networks. This highlights that the factors mediating the relationship between functional and structural metrics of connectivity are context and scale dependent, influenced by topological, geometric and architectural features. It also suggests that fMRI studies employing simultaneous EEG measures may characterize additional and essential parts of the underlying neuronal activity of the resting-state, which might be of special interest for both clinical studies and the investigation of resting-state dynamics. PMID- 28842388 TI - Exergames Encouraging Exploration of Hemineglected Space in Stroke Patients With Visuospatial Neglect: A Feasibility Study. AB - BACKGROUND: Use of exergames can complement conventional therapy and increase the amount and intensity of visuospatial neglect (VSN) training. A series of 9 exergames-games based on therapeutic principles-aimed at improving exploration of the neglected space for patients with VSN symptoms poststroke was developed and tested for its feasibility. OBJECTIVES: The goal was to determine the feasibility of the exergames with minimal supervision in terms of (1) implementation of the intervention, including adherence, attrition and safety, and (2) limited efficacy testing, aiming to document possible effects on VSN symptoms in a case series of patients early poststroke. METHODS: A total of 7 patients attended the 3-week exergames training program on a daily basis. Adherence of the patients was documented in a training diary. For attrition, the number of participants lost during the intervention was registered. Any adverse events related to the exergames intervention were noted to document safety. Changes in cognitive and spatial exploration skills were measured with the Zurich Maxi Mental Status Inventory and the Neglect Test. Additionally, we developed an Eye Tracker Neglect Test (ETNT) using an infrared camera to detect and measure neglect symptoms pre- and postintervention. RESULTS: The median was 14 out of 15 (93%) attended sessions, indicating that the adherence to the exergames training sessions was high. There were no adverse events and no drop-outs during the exergame intervention. The individual cognitive and spatial exploration skills slightly improved postintervention (P=.06 to P=.98) and continued improving at follow-up (P=.04 to P=.92) in 5 out of 7 (71%) patients. Calibration of the ETNT was rather error prone. The ETNT showed a trend for a slight median group improvement from 15 to 16 total located targets (+6%). CONCLUSIONS: The high adherence rate and absence of adverse events showed that these exergames were feasible and safe for the participants. The results of the amount of exergames use is promising for future applications and warrants further investigations-for example, in the home setting of patients to augment training frequency and intensity. The preliminary results indicate the potential of these exergames to cause improvements in cognitive and spatial exploration skills over the course of training for stroke patients with VSN symptoms. Thus, these exergames are proposed as a motivating training tool to complement usual care. The ETNT showed to be a promising assessment for quantifying spatial exploration skills. However, further adaptations are needed, especially regarding calibration issues, before its use can be justified in a larger study sample. PMID- 28842389 TI - Usability of a Culturally Informed mHealth Intervention for Symptoms of Anxiety and Depression: Feedback From Young Sexual Minority Men. AB - BACKGROUND: To date, we are aware of no interventions for anxiety and depression developed as mobile phone apps and tailored to young sexual minority men, a group especially at risk of anxiety and depression. We developed TODAY!, a culturally informed mobile phone intervention for young men who are attracted to men and who have clinically significant symptoms of anxiety or depression. The core of the intervention consists of daily psychoeducation informed by transdiagnostic cognitive behavioral therapy (CBT) and a set of tools to facilitate putting these concepts into action, with regular mood ratings that result in tailored feedback (eg, tips for current distress and visualizations of mood by context). OBJECTIVE: The aim of this study was to conduct usability testing to understand how young sexual minority men interact with the app, to inform later stages of intervention development. METHODS: Participants (n=9) were young sexual minority men aged 18 20 years (Mean=19.00, standard deviation [SD]=0.71; 44% black, 44% white, and 11.1% Latino), who endorsed at least mild depression and anxiety symptoms. Participants were recruited via flyers, emails to college lesbian, gay, bisexual, and transgender (LGBT) organizations, Web-based advertisements, another researcher's database of sexual minority youth interested in research participation, and word of mouth. During recorded interviews, participants were asked to think out loud while interacting with the TODAY! app on a mobile phone or with paper prototypes. Feedback identified from these recordings and from associated field notes were subjected to thematic analysis using a general inductive approach. To aid interpretation of results, methods and results are reported according to the consolidated criteria for reporting qualitative research (COREQ). RESULTS: Thematic analysis of usability feedback revealed a theme of general positive feedback, as well as six recurring themes that informed continued development: (1) functionality (eg, highlight new material when available), (2) personalization (eg, more tailored feedback), (3) presentation (eg, keep content brief), (4) aesthetics (eg, use brighter colors), (5) LGBT or youth content (eg, add content about coming out), and (6) barriers to use (eg, perceiving psychoeducation as homework). CONCLUSIONS: Feedback from usability testing was vital to understanding what young sexual minority men desire from a mobile phone intervention for symptoms of anxiety and depression and was used to inform the ongoing development of such an intervention. PMID- 28842390 TI - User Perspectives on Exergames Designed to Explore the Hemineglected Space for Stroke Patients With Visuospatial Neglect: Usability Study. AB - BACKGROUND: Visuospatial neglect due to stroke is characterized by the inability to perceive stimuli emerging in the area opposite to the side of brain damage. Besides adopting conventional rehabilitation methods to treat neglect symptoms, the use of virtual reality (VR) is becoming increasingly popular. We designed a series of 9 exergames aimed to improve exploration of the neglected side of space. When new VR interventions are designed, it is important to assess the usability aspects of such management strategies within the target population. To date, most studies used questionnaires to assess user satisfaction with the intervention or product being tested. However, only a combination of both quantitative and qualitative data allows a full picture of user perspective. OBJECTIVE: The purpose of this study was to quantitatively and qualitatively assess patient and therapist perspectives of a VR intervention based on the series of 9 exergames designed to explore hemineglected space. Specifically, we wanted to evaluate (1) perceived-user friendliness of the exergames, (2) attitude towards using the exergames, and (3) intention to use the exergames in the future. METHODS: A total of 19 participants (7 patients, 12 therapists) evaluated the exergames they had used 5 times a week during 3 weeks. The Technology Acceptance Model (TAM) questionnaire was filled out after the intervention. Based on those responses, we conducted focus group interviews (with therapists) and individual interviews (with patients). To analyze the TAM questionnaires, we used descriptive statistics. We adopted content and comparative analysis to analyze the interviews and drew illustration maps to analyze the focus group interviews. RESULTS: The therapists took a more critical stance with a mean TAM questionnaire total score of 48.6 (SD 4.5) compared to the patients who had a mean total score of 56.1 (SD 12.3). The perceived user-friendliness score was 5.6 (SD 1.4) for patients and 4.9 (SD 1.4) for therapists. The attitude towards using the exergames was rated 4.8 (SD 1.9) by patients and 3.6 (SD 1.4) by therapists, respectively. The intention to use the exergames in the future was rated 3.9 (SD 2.1) by patients and 3.7 (SD 1.8) by therapists. We gained information on how to improve the exergames in the interviews. CONCLUSIONS: Patients and therapists perceived the exergames as user-friendly; however, using the games further with the actual test version was not perceived as conceivable. The therapists were generally more critical towards future use than the patients. Therefore, involving both users to achieve acceptable and user-friendly versions of game based rehabilitation for the future is deemed crucial and warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT02353962; https://clinicaltrials.gov/ct2/show/NCT02353962 (Archived by WebCite at http://www.webcitation.org/6soxIJlAZ). PMID- 28842392 TI - Clinical Validation of Heart Rate Apps: Mixed-Methods Evaluation Study. AB - BACKGROUND: Photoplethysmography (PPG) is a proven way to measure heart rate (HR). This technology is already available in smartphones, which allows measuring HR only by using the smartphone. Given the widespread availability of smartphones, this creates a scalable way to enable mobile HR monitoring. An essential precondition is that these technologies are as reliable and accurate as the current clinical (gold) standards. At this moment, there is no consensus on a gold standard method for the validation of HR apps. This results in different validation processes that do not always reflect the veracious outcome of comparison. OBJECTIVE: The aim of this paper was to investigate and describe the necessary elements in validating and comparing HR apps versus standard technology. METHODS: The FibriCheck (Qompium) app was used in two separate prospective nonrandomized studies. In the first study, the HR of the FibriCheck app was consecutively compared with 2 different Food and Drug Administration (FDA)-cleared HR devices: the Nonin oximeter and the AliveCor Mobile ECG. In the second study, a next step in validation was performed by comparing the beat-to beat intervals of the FibriCheck app to a synchronized ECG recording. RESULTS: In the first study, the HR (BPM, beats per minute) of 88 random subjects consecutively measured with the 3 devices showed a correlation coefficient of .834 between FibriCheck and Nonin, .88 between FibriCheck and AliveCor, and .897 between Nonin and AliveCor. A single way analysis of variance (ANOVA; P=.61 was executed to test the hypothesis that there were no significant differences between the HRs as measured by the 3 devices. In the second study, 20,298 (ms) R R intervals (RRI)-peak-to-peak intervals (PPI) from 229 subjects were analyzed. This resulted in a positive correlation (rs=.993, root mean square deviation [RMSE]=23.04 ms, and normalized root mean square error [NRMSE]=0.012) between the PPI from FibriCheck and the RRI from the wearable ECG. There was no significant difference (P=.92) between these intervals. CONCLUSIONS: Our findings suggest that the most suitable method for the validation of an HR app is a simultaneous measurement of the HR by the smartphone app and an ECG system, compared on the basis of beat-to-beat analysis. This approach could lead to more correct assessments of the accuracy of HR apps. PMID- 28842391 TI - Developments in the Frequency of Ratings and Evaluation Tendencies: A Review of German Physician Rating Websites. AB - BACKGROUND: Physician rating websites (PRWs) have been developed to allow all patients to rate, comment, and discuss physicians' quality online as a source of information for others searching for a physician. At the beginning of 2010, a sample of 298 randomly selected physicians from the physician associations in Hamburg and Thuringia were searched for on 6 German PRWs to examine the frequency of ratings and evaluation tendencies. OBJECTIVE: The objective of this study was to examine (1) the number of identifiable physicians on German PRWs; (2) the number of rated physicians on German PRWs; (3) the average and maximum number of ratings per physician on German PRWs; (4) the average rating on German PRWs; (5) the website visitor ranking positions of German PRWs; and (6) how these data compare with 2010 results. METHODS: A random stratified sample of 298 selected physicians from the physician associations in Hamburg and Thuringia was generated. Every selected physician was searched for on the 6 PRWs (Jameda, Imedo, Docinsider, Esando, Topmedic, and Medfuhrer) used in the 2010 study and a PRW, Arztnavigator, launched by Allgemeine Ortskrankenkasse (AOK). RESULTS: The results were as follows: (1) Between 65.1% (194/298) on Imedo to 94.6% (282/298) on AOK-Arztnavigator of the physicians were identified on the selected PRWs. (2) Between 16.4% (49/298) on Esando to 83.2% (248/298) on Jameda of the sample had been rated at least once. (3) The average number of ratings per physician ranged from 1.2 (Esando) to 7.5 (AOK-Arztnavigator). The maximum number of ratings per physician ranged from 3 (Esando) to 115 (Docinsider), indicating an increase compared with the ratings of 2 to 27 in the 2010 study sample. (4) The average converted standardized rating (1=positive, 2=neutral, and 3=negative) ranged from 1.0 (Medfuhrer) to 1.2 (Jameda and Topmedic). (5) Only Jameda (position 317) and Medfuhrer (position 9796) were placed among the top 10,000 visited websites in Germany. CONCLUSIONS: Whereas there has been an overall increase in the number of ratings when summing up ratings from all 7 analyzed German PRWs, this represents an average addition of only 4 new ratings per physician in a year. The increase has also not been even across the PRWs, and it would be advisable for the users of PRWs to utilize a number of PRWs to ascertain the rating of any given physician. Further research is needed to identify barriers for patients to rate their physicians and to assist efforts to increase the number of ratings on PRWs to consequently improve the fairness and practical importance of PRWs. PMID- 28842393 TI - E6130, a Novel CX3C Chemokine Receptor 1 (CX3CR1) Modulator, Attenuates Mucosal Inflammation and Reduces CX3CR1+ Leukocyte Trafficking in Mice with Colitis. AB - The chemokine fractalkine (CX3C chemokine ligand 1; CX3CL1) and its receptor CX3CR1 are involved in the pathogenesis of several diseases, including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, rheumatoid arthritis, hepatitis, myositis, multiple sclerosis, renal ischemia, and atherosclerosis. There are no orally available agents that modulate the fractalkine/CX3CR1 axis. [(3S,4R)-1-[2-Chloro-6-(trifluoromethyl)benzyl]-3-{[1 (cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3 yl]acetic acid (2S)-hydroxy(phenyl)acetate (E6130) is an orally available highly selective modulator of CX3CR1 that may be effective for treatment of inflammatory bowel disease. We found that E6130 inhibited the fractalkine-induced chemotaxis of human peripheral blood natural killer cells (IC50 4.9 nM), most likely via E6130-induced down-regulation of CX3CR1 on the cell surface. E6130 had agonistic activity via CX3CR1 with respect to guanosine 5'-3-O-(thio)triphosphate binding in CX3CR1-expressing Chinese hamster ovary K1 (CHO-K1) membrane and had no antagonistic activity. Orally administered E6130 ameliorated several inflammatory bowel disease-related parameters in a murine CD4+CD45RBhigh T-cell-transfer colitis model and a murine oxazolone-induced colitis model. In the CD4+CD45RBhigh T-cell transfer model, E6130 inhibited the migration of CX3CR1+ immune cells and decreased the number of these cells in the gut mucosal membrane. These results suggest that E6130 is a promising therapeutic agent for treatment of inflammatory bowel disease. PMID- 28842394 TI - Transforming Growth Factor-beta1/Activin Receptor-like Kinase 5-Mediated Cell Migration is Dependent on the Protein Proteinase-Activated Receptor 2 but not on Proteinase-Activated Receptor 2-Stimulated Gq-Calcium Signaling. AB - Transforming growth factor-beta (TGF-beta), serine proteinases such as trypsin, and proteinase-activated receptor 2 (PAR2) promote tumor development by stimulating invasion and metastasis. Previously, we found that in cancer cells derived from pancreatic ductal adenocarcinoma (PDAC) PAR2 protein is necessary for TGF-beta1-dependent cell motility. Here, we show in the same cells that, conversely, the type I TGF-beta receptor activin receptor-like kinase 5 is dispensable for trypsin and PAR2 activating peptide (PAR2-AP)-induced migration. To reveal whether Gq-calcium signaling is a prerequisite for PAR2 to enhance TGF beta signaling, we investigated the effects of PAR2-APs, PAR2 mutation and PAR2 inhibitors on TGF-beta1-induced migration, reporter gene activity, and Smad activation. Stimulation of cells with PAR2-AP alone failed to enhance basal or TGF-beta1-induced C-terminal phosphorylation of Smad3, Smad-dependent activity of a luciferase reporter gene, and cell migration. Consistently, in complementary loss of function studies, abrogation of the PAR2-Gq-calcium signaling arm failed to suppress TGF-beta1-induced cell migration, reporter gene activity, and Smad3 activation. Together, our findings suggest that the calcium-regulating motif is not required for PAR2 to synergize with TGF-beta1 to promote cell motility. Additional experiments in PDAC cells revealed that PAR2 and TGF-beta1 synergy may involve TGF-beta1 induction of enzymes that cause autocrine cleavage/activation of PAR2, possibly through a biased signaling function. Our results suggest that although reducing PAR2 protein expression may potentially block TGF-beta's prooncogenic function, inhibiting PAR2-Gq-calcium signaling alone would not be sufficient to achieve this effect. PMID- 28842395 TI - Toilet humour with a message. PMID- 28842396 TI - Benefits of Dominance over Additive Models for the Estimation of Average Effects in the Presence of Dominance. AB - In quantitative genetics, the average effect at a single locus can be estimated by an additive (A) model, or an additive plus dominance (AD) model. In the presence of dominance, the AD-model is expected to be more accurate, because the A-model falsely assumes that residuals are independent and identically distributed. Our objective was to investigate the accuracy of an estimated average effect ([Formula: see text]) in the presence of dominance, using either a single locus A-model or AD-model. Estimation was based on a finite sample from a large population in Hardy-Weinberg equilibrium (HWE), and the root mean squared error of [Formula: see text] was calculated for several broad-sense heritabilities, sample sizes, and sizes of the dominance effect. Results show that with the A-model, both sampling deviations of genotype frequencies from HWE frequencies and sampling deviations of allele frequencies contributed to the error. With the AD-model, only sampling deviations of allele frequencies contributed to the error, provided that all three genotype classes were sampled. In the presence of dominance, the root mean squared error of [Formula: see text] with the AD-model was always smaller than with the A-model, even when the heritability was less than one. Remarkably, in the absence of dominance, there was no disadvantage of fitting dominance. In conclusion, the AD-model yields more accurate estimates of average effects from a finite sample, because it is more robust against sampling deviations from HWE frequencies than the A-model. Genetic models that include dominance, therefore, yield higher accuracies of estimated average effects than purely additive models when dominance is present. PMID- 28842397 TI - Lipocalins Are Required for Apical Extracellular Matrix Organization and Remodeling in Caenorhabditis elegans. AB - A lipid and glycoprotein-rich apical extracellular matrix (aECM) or glycocalyx lines exposed membranes in the body, and is particularly important to protect narrow tube integrity. Lipocalins ("fat cups") are small, secreted, cup-shaped proteins that bind and transport lipophilic cargo and are often found in luminal or aECM compartments such as mammalian plasma, urine, or tear film. Although some lipocalins can bind known aECM lipids and/or matrix metalloproteinases, it is not known if and how lipocalins affect aECM structure due to challenges in visualizing the aECM in most systems. Here we show that two Caenorhabditiselegans lipocalins, LPR-1 and LPR-3, have distinct functions in the precuticular glycocalyx of developing external epithelia. LPR-1 moves freely through luminal compartments, while LPR-3 stably localizes to a central layer of the membrane anchored glycocalyx, adjacent to the transient zona pellucida domain protein LET 653 Like LET-653 and other C. elegans glycocalyx components, these lipocalins are required to maintain the patency of the narrow excretory duct tube, and also affect multiple aspects of later cuticle organization. lpr-1 mutants cannot maintain a continuous excretory duct apical domain and have misshapen cuticle ridges (alae) and abnormal patterns of cuticular surface lipid staining. lpr-3 mutants cannot maintain a passable excretory duct lumen, properly degrade the eggshell, or shed old cuticle during molting, and they lack cuticle barrier function. Based on these phenotypes, we infer that both LPR-1 and LPR-3 are required to build a properly organized aECM, while LPR-3 additionally is needed for aECM clearance and remodeling. The C. elegans glycocalyx provides a powerful system, amenable to both genetic analysis and live imaging, for investigating how lipocalins and lipids affect aECM structure. PMID- 28842398 TI - ANCA Glomerulonephritis and Vasculitis. AB - ANCA vasculitis has an associated autoimmune response that produces ANCAs that induce distinct pathologic lesions. Pauci-immune necrotizing and crescentic GN is a frequent component of ANCA vasculitis. ANCA vasculitis is associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). A diagnosis of ANCA vasculitis should always specify the serotype as MPO-ANCA positive, PR3 ANCA positive, or ANCA-negative. To fully characterize a patient, the serotype also should be accompanied by the clinicopathologic variant if this can be determined: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or renal-limited vasculitis. ANCA vasculitis is most prevalent in individuals >50 years old. There are racial/ethnic and geographic influences on the prevalence, serotype frequencies, and clinicopathologic phenotypes. There is clinical, in vitro, and animal model evidence that ANCAs cause disease by activating neutrophils to attack small vessels. Immunomodulatory and immunosuppressive therapies are used to induce remission, maintain remission, and treat relapses. Over recent years, there have been major advances in optimizing treatment by minimizing toxic therapy and utilizing more targeted therapy. PMID- 28842399 TI - Inhibition of 12/15-Lipoxygenase Protects Against beta-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes. AB - Islet beta-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in beta-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate beta-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15 LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced beta-cell oxidative stress, and preservation of beta-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced beta-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of beta-cell dysfunction and glycemic deterioration in models of T1D. PMID- 28842401 TI - Cost-effectiveness of Obesity Interventions: Will We Know It When We See It? PMID- 28842400 TI - Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes. AB - Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin producing beta-cells. Insulin represents a key self-antigen in disease pathogenesis, as recent studies identified proinsulin-responding T cells from inflamed pancreatic islets of organ donors with recent-onset T1D. These cells respond to an insulin B-chain (InsB) epitope presented by the HLA-DQ8 molecule associated with high T1D risk. Understanding insulin-specific T-cell frequency and phenotype in peripheral blood is now critical. We constructed fluorescent InsB10-23:DQ8 tetramers, stained peripheral blood lymphocytes directly ex vivo, and show DQ8+ patients with T1D have increased tetramer+ CD4+ T cells compared with HLA-matched control subjects without diabetes. Patients with a shorter disease duration had higher frequencies of insulin-reactive CD4+ T cells, with most of these cells being antigen experienced. We also demonstrate that the number of insulin tetramer+ effector memory cells is directly correlated with insulin antibody titers, suggesting insulin-specific T- and B-cell interactions. Notably, one of four control subjects with tetramer+ cells was a first-degree relative who had insulin-specific cells with an effector memory phenotype, potentially representing an early marker of T-cell autoimmunity. Our results suggest that studying InsB10-23:DQ8 reactive T-cell frequency and phenotype may provide a biomarker of disease activity in patients with T1D and those at risk. PMID- 28842402 TI - Cost-effectiveness of Family-Based Obesity Treatment. AB - BACKGROUND AND OBJECTIVES: We translated family-based behavioral treatment (FBT) to treat children with overweight and obesity and their parents in the patient centered medical home. We reported greater reductions in child and parent weight at 6 and 24 months compared with an attention-controlled information control (IC) group. This article reports the cost-effectiveness of long-term weight change for FBT compared with IC. METHODS: Ninety-six children 2 to 5 years of age with overweight or obesity and with parents who had a BMI >=25 were randomly assigned to FBT or IC, and both received diet and activity education (12-month treatment and 12-month follow-up). Weight loss and cost-effectiveness were assessed at 24 months. Intention-to-treat, completers, and sensitivity analyses were performed. RESULTS: The average societal cost per family was $1629 for the FBT and $886 for the IC groups at 24 months. At 24 months, child percent over BMI (%OBMI) change decreased by 2.0 U in the FBT group versus an increase of 4.4 U in the IC group. Parents lost 6.0 vs 0.2 kg at 24 months in the FBT and IC groups, respectively. The incremental cost-effectiveness ratios (ICERs) for children and parents' %OBMI were $116.1 and $83.5 per U of %OBMI, respectively. Parental ICERs were also calculated for body weight and BMI and were $128.1 per 1, and $353.8/ per kilogram, respectively. ICER values for child %OBMI were similar in the intention to-treat group ($116.1/1 U decrease) compared with completers ($114.3). CONCLUSIONS: For families consisting of children and parents with overweight, FBT presents a more cost-effective alternative than an IC group. PMID- 28842403 TI - Use of a Smartphone App to Assess Neonatal Jaundice. AB - BACKGROUND: The assessment of jaundice in outpatient neonates is problematic. Visual assessment is inaccurate, and more exact methodologies are cumbersome and/or expensive. Our goal in this study was to assess the accuracy of a technology based on the analysis of digital images of newborns obtained using a smartphone application called BiliCam. METHODS: Paired BiliCam images and total serum bilirubin (TSB) levels were obtained in a diverse sample of newborns (<7 days old) at 7 sites across the United States. By using specialized software, data on color values in the images ("features") were extracted. Machine learning and regression analysis techniques were used to identify features for inclusion in models to predict an estimated bilirubin level for each newborn. The correlation between estimated bilirubin levels and TSB levels was calculated. In addition, the sensitivity and specificity of the estimated bilirubin levels in identifying newborns with high TSB levels were calculated by using 2 recommended decision rules for jaundice screening. RESULTS: Estimated bilirubin levels were calculated and compared with TSB levels in a diverse sample of 530 newborns (20.8% African American, 26.3% Hispanic, and 21.2% Asian American). The overall correlation was 0.91, and correlations among white, African American, Hispanic, and Asian American newborns were 0.92, 0.90, 0.91, and 0.88, respectively. The sensitivities of BiliCam in identifying newborns with high TSB levels were 84.6% and 100%, respectively, by using 2 decision rules; specificities were 75.1% and 76.4%, respectively. CONCLUSIONS: BiliCam provided accurate estimates of TSB values, demonstrating that an inexpensive technology that uses commodity smartphones could be used to effectively screen newborns for jaundice. PMID- 28842409 TI - Time of Day Differences in Neural Reward Functioning in Healthy Young Men. AB - Reward function appears to be modulated by the circadian system, but little is known about the neural basis of this interaction. Previous research suggests that the neural reward response may be different in the afternoon; however, the direction of this effect is contentious. Reward response may follow the diurnal rhythm in self-reported positive affect, peaking in the early afternoon. An alternative is that daily reward response represents a type of prediction error, with neural reward activation relatively high at times of day when rewards are unexpected (i.e., early and late in the day). The present study measured neural reward activation in the context of a validated reward task at 10.00 h, 14.00 h, and 19.00 h in healthy human males. A region of interest BOLD fMRI protocol was used to investigate the diurnal waveform of activation in reward-related brain regions. Multilevel modeling found, as expected, a highly significant quadratic time-of-day effect focusing on the left putamen (p < 0.001). Consistent with the "prediction error" hypothesis, activation was significantly higher at 10.00 h and 19.00 h compared with 14.00 h. It is provisionally concluded that the putamen may be particularly important in endogenous priming of reward motivation at different times of day, with the pattern of activation consistent with circadian-modulated reward expectancies in neural pathways (i.e., greater activation to reward stimuli at unexpected times of day). This study encourages further research into circadian modulation of reward and underscores the methodological importance of accounting for time of day in fMRI protocols.SIGNIFICANCE STATEMENT This is one of the first studies to use a repeated-measures imaging procedure to explore the diurnal rhythm of reward activation. Although self-reported reward (most often operationalized as positive affect) peaks in the afternoon, the present findings indicate that neural activation is lowest at this time. We conclude that the diurnal neural activation pattern may reflect a prediction error of the brain, where rewards at unexpected times (10.00 h and 19.00 h) elicit higher activation in reward brain regions than at expected (14.00 h) times. These data also have methodological significance, suggesting that there may be a time of day influence, which should be accounted for in neural reward studies. PMID- 28842410 TI - Impaired Feedforward Control and Enhanced Feedback Control of Speech in Patients with Cerebellar Degeneration. AB - The cerebellum has been hypothesized to form a crucial part of the speech motor control network. Evidence for this comes from patients with cerebellar damage, who exhibit a variety of speech deficits, as well as imaging studies showing cerebellar activation during speech production in healthy individuals. To date, the precise role of the cerebellum in speech motor control remains unclear, as it has been implicated in both anticipatory (feedforward) and reactive (feedback) control. Here, we assess both anticipatory and reactive aspects of speech motor control, comparing the performance of patients with cerebellar degeneration and matched controls. Experiment 1 tested feedforward control by examining speech adaptation across trials in response to a consistent perturbation of auditory feedback. Experiment 2 tested feedback control, examining online corrections in response to inconsistent perturbations of auditory feedback. Both male and female patients and controls were tested. The patients were impaired in adapting their feedforward control system relative to controls, exhibiting an attenuated anticipatory response to the perturbation. In contrast, the patients produced even larger compensatory responses than controls, suggesting an increased reliance on sensory feedback to guide speech articulation in this population. Together, these results suggest that the cerebellum is crucial for maintaining accurate feedforward control of speech, but relatively uninvolved in feedback control.SIGNIFICANCE STATEMENT Speech motor control is a complex activity that is thought to rely on both predictive, feedforward control as well as reactive, feedback control. While the cerebellum has been shown to be part of the speech motor control network, its functional contribution to feedback and feedforward control remains controversial. Here, we use real-time auditory perturbations of speech to show that patients with cerebellar degeneration are impaired in adapting feedforward control of speech but retain the ability to make online feedback corrections; indeed, the patients show an increased sensitivity to feedback. These results indicate that the cerebellum forms a crucial part of the feedforward control system for speech but is not essential for online, feedback control. PMID- 28842411 TI - Identified GABAergic and Glutamatergic Neurons in the Mouse Inferior Colliculus Share Similar Response Properties. AB - GABAergic neurons in the inferior colliculus (IC) play a critical role in auditory information processing, yet their responses to sound are unknown. Here, we used optogenetic methods to characterize the response properties of GABAergic and presumed glutamatergic neurons to sound in the IC. We found that responses to pure tones of both inhibitory and excitatory classes of neurons were similar in their thresholds, response latencies, rate-level functions, and frequency tuning, but GABAergic neurons may have higher spontaneous firing rates. In contrast to their responses to pure tones, the inhibitory and excitatory neurons differed in their ability to follow amplitude modulations. The responses of both cell classes were affected by their location regardless of the cell type, especially in terms of their frequency tuning. These results show that the synaptic domain, a unique organization of local neural circuits in the IC, may interact with all types of neurons to produce their ultimate response to sound.SIGNIFICANCE STATEMENT Although the inferior colliculus (IC) in the auditory midbrain is composed of different types of neurons, little is known about how these specific types of neurons respond to sound. Here, for the first time, we characterized the response properties of GABAergic and glutamatergic neurons in the IC. Both classes of neurons had diverse response properties to tones but were overall similar, except for the spontaneous activity and their ability to follow amplitude-modulated sound. Both classes of neurons may compose a basic local circuit that is replicated throughout the IC. Within each local circuit, the inputs to the local circuit may have a greater influence in determining the response properties to sound than the specific neuron types. PMID- 28842412 TI - Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor. AB - Genetically encoded voltage indicators create an opportunity to monitor electrical activity in defined sets of neurons as they participate in the complex patterns of coordinated electrical activity that underlie nervous system function. Taking full advantage of genetically encoded voltage indicators requires a generalized strategy for targeting the probe to genetically defined populations of cells. To this end, we have generated a mouse line with an optimized hybrid voltage sensor (hVOS) probe within a locus designed for efficient Cre recombinase-dependent expression. Crossing this mouse with Cre drivers generated double transgenics expressing hVOS probe in GABAergic, parvalbumin, and calretinin interneurons, as well as hilar mossy cells, new adult born neurons, and recently active neurons. In each case, imaging in brain slices from male or female animals revealed electrically evoked optical signals from multiple individual neurons in single trials. These imaging experiments revealed action potentials, dynamic aspects of dendritic integration, and trial-to-trial fluctuations in response latency. The rapid time response of hVOS imaging revealed action potentials with high temporal fidelity, and enabled accurate measurements of spike half-widths characteristic of each cell type. Simultaneous recording of rapid voltage changes in multiple neurons with a common genetic signature offers a powerful approach to the study of neural circuit function and the investigation of how neural networks encode, process, and store information.SIGNIFICANCE STATEMENT Genetically encoded voltage indicators hold great promise in the study of neural circuitry, but realizing their full potential depends on targeting the sensor to distinct cell types. Here we present a new mouse line that expresses a hybrid optical voltage sensor under the control of Cre recombinase. Crossing this line with Cre drivers generated double transgenic mice, which express this sensor in targeted cell types. In brain slices from these animals, single-trial hybrid optical voltage sensor recordings revealed voltage changes with submillisecond resolution in multiple neurons simultaneously. This imaging tool will allow for the study of the emergent properties of neural circuits and permit experimental tests of the roles of specific types of neurons in complex circuit activity. PMID- 28842413 TI - NF-kappaB Activation Protects Oligodendrocytes against Inflammation. AB - NF-kappaB is a key player in inflammatory diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the effects of NF-kappaB activation on oligodendrocytes in MS and EAE remain unknown. We generated a mouse model that expresses IkappaBalphaDeltaN, a super-suppressor of NF-kappaB, specifically in oligodendrocytes and demonstrated that IkappaBalphaDeltaN expression had no effect on oligodendrocytes under normal conditions (both sexes). Interestingly, we showed that oligodendrocyte-specific expression of IkappaBalphaDeltaN blocked NF-kappaB activation in oligodendrocytes and resulted in exacerbated oligodendrocyte death and hypomyelination in young, developing mice that express IFN-gamma ectopically in the CNS (both sexes). We also showed that NF-kappaB inactivation in oligodendrocytes aggravated IFN-gamma induced remyelinating oligodendrocyte death and remyelination failure in the cuprizone model (male mice). Moreover, we found that NF-kappaB inactivation in oligodendrocytes increased the susceptibility of mice to EAE (female mice). These findings imply the cytoprotective effects of NF-kappaB activation on oligodendrocytes in MS and EAE.SIGNIFICANCE STATEMENT Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. NF-kappaB is a major player in inflammatory diseases that acts by regulating inflammation and cell viability. Data indicate that NF-kappaB activation in inflammatory cells facilitates the development of MS. However, to date, attempts to understand the role of NF-kappaB activation in oligodendrocytes in MS have been unsuccessful. Herein, we generated a mouse model that allows for inactivation of NF-kappaB specifically in oligodendrocytes and then used this model to determine the precise role of NF kappaB activation in oligodendrocytes in models of MS. The results presented in this study represent the first demonstration that NF-kappaB activation acts cell autonomously to protect oligodendrocytes against inflammation in animal models of MS. PMID- 28842414 TI - The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism. AB - The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss of-function dat-1 mutations. Here, we report the identity of swip-13, which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function.SIGNIFICANCE STATEMENT Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly in vivo Using a forward genetic screen in the nematode Caenorhabditis elegans, we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide in vitro and in vivo evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that may contribute to risk for disorders linked to perturbed DA signaling. Targeting this pathway may be of value in the development of therapeutics in such disorders. PMID- 28842415 TI - Effect of Threat on Right dlPFC Activity during Behavioral Pattern Separation. AB - It has long been established that individuals with anxiety disorders tend to overgeneralize attributes of fearful stimuli to nonfearful stimuli, but there is little mechanistic understanding of the neural system that supports overgeneralization. To address this gap in our knowledge, this study examined effect of experimentally induced anxiety in humans on generalization using the behavioral pattern separation (BPS) paradigm. Healthy subjects of both sexes encoded and retrieved novel objects during periods of safety and threat of unpredictable shocks while we recorded brain activity with fMRI. During retrieval, subjects were instructed to differentiate among new, old, and altered images. We hypothesized that the hippocampus and dorsolateral prefrontal cortex (dlPFC) would play a key role in the effect of anxiety on BPS. The dlPFC, but not the hippocampus, showed increased activity for altered images compared with old images when retrieval occurred during periods of threat compared with safety. In addition, accuracy for altered items retrieved during threat was correlated with dlPFC activity. Together, these results suggest that overgeneralization in anxiety patients may be mediated by an inability to recruit the dlPFC, which mediates the cognitive control needed to overcome anxiety and differentiate between old and altered items during periods of threat.SIGNIFICANCE STATEMENT Anxiety and posttraumatic stress disorder patients generalize fear to nonfearful fear stimuli, making it difficult to regulate anxiety. Understanding how anxiety affects generalization is key to understanding the overgeneralization experienced by these patients. We examined this relationship in healthy subjects by studying how threat of shock affects neural responses to previously encountered stimuli. Although previous studies point to hippocampal involvement, we found that threat affected activity in the dorsolateral prefrontal cortex (dlPFC), rather than the hippocampus, when subjects encountered slightly altered versions of the previously encountered items. Importantly, this dlPFC activity predicted performance for these items. Together, these results suggest that the dlPFC is important for discrimination during elevated anxiety and that overgeneralization may reflect a deficit in dlPFC-mediated cognitive control. PMID- 28842417 TI - Synaptic Excitation in Spinal Motoneurons Alternates with Synaptic Inhibition and Is Balanced by Outward Rectification during Rhythmic Motor Network Activity. AB - Regular firing in spinal motoneurons of red-eared turtles (Trachemys scripta elegans, either sex) evoked by steady depolarization at rest is replaced by irregular firing during functional network activity. The transition caused by increased input conductance and synaptic fluctuations in membrane potential was suggested to originate from intense concurrent inhibition and excitation. We show that the conductance increase in motoneurons during functional network activity is mainly caused by intrinsic outward rectification near threshold for action potentials by activation of voltage and Ca2+ gated K channels. Intrinsic outward rectification facilitates spiking by focusing synaptic depolarization near threshold for action potentials. By direct recording of synaptic currents, we also show that motoneurons are activated by out-of-phase peaks in excitation and inhibition during network activity, whereas continuous low-level concurrent inhibition and excitation may contribute to irregular firing.SIGNIFICANCE STATEMENT Neurons embedded in active neural networks can enter a high-conductance state. High-conductance states were observed in spinal motoneurons during rhythmic motor behavior. Assuming no change in intrinsic conductance, it was suggested that the high-conductance state in motoneurons originated from balanced inhibition and excitation. In this study, we demonstrate that intrinsic outward rectification significantly contributes to the high-conductance state. Outward rectification balances synaptic excitation and maintains membrane potential near spike threshold. In addition, direct synaptic current recordings show out-of phase excitation and inhibition in motoneurons during rhythmic network activity. PMID- 28842416 TI - Synaptic Adhesion Molecule Pcdh-gammaC5 Mediates Synaptic Dysfunction in Alzheimer's Disease. AB - Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer's disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-gammaC5 (Pcdh-gammaC5), a member of clustered Pcdh-gamma subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh gammaC5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon beta-amyloid (Abeta) treatment, and in amyloid precursor protein (APP)/presenilin 1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experiments showed that Pcdh-gammaC5 modulates spontaneous synaptic currents and Abeta-induced synaptic alterations directly. Our results support a model in which Pcdh-gammaC5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-gammaC5 expression and associated synaptic dysfunction.SIGNIFICANCE STATEMENT Synaptic dysfunction is causal for Alzheimer's disease (AD). Here, we reveal a novel pathway that contributes GABAergic synaptic dysfunction in AD mediated by protocadherin-gammaC5. Our study not only identifies a new mechanism mediating excitatory/inhibitory balance in AD, but may also offer a new target for potential therapeutic intervention. PMID- 28842418 TI - Dedicated Hippocampal Inhibitory Networks for Locomotion and Immobility. AB - Network activity is strongly tied to animal movement; however, hippocampal circuits selectively engaged during locomotion or immobility remain poorly characterized. Here we examined whether distinct locomotor states are encoded differentially in genetically defined classes of hippocampal interneurons. To characterize the relationship between interneuron activity and movement, we used in vivo, two-photon calcium imaging in CA1 of male and female mice, as animals performed a virtual-reality (VR) track running task. We found that activity in most somatostatin-expressing and parvalbumin-expressing interneurons positively correlated with locomotion. Surprisingly, nearly one in five somatostatin or one in seven parvalbumin interneurons were inhibited during locomotion and activated during periods of immobility. Anatomically, the somata of somatostatin immobility activated neurons were smaller than those of movement-activated neurons. Furthermore, immobility-activated interneurons were distributed across cell layers, with somatostatin-expressing cells predominantly in stratum oriens and parvalbumin-expressing cells mostly in stratum pyramidale. Importantly, each cell's correlation between activity and movement was stable both over time and across VR environments. Our findings suggest that hippocampal interneuronal microcircuits are preferentially active during either movement or immobility periods. These inhibitory networks may regulate information flow in "labeled lines" within the hippocampus to process information during distinct behavioral states.SIGNIFICANCE STATEMENT The hippocampus is required for learning and memory. Movement controls network activity in the hippocampus but it's unclear how hippocampal neurons encode movement state. We investigated neural circuits active during locomotion and immobility and found interneurons were selectively active during movement or stopped periods, but not both. Each cell's response to locomotion was consistent across time and environments, suggesting there are separate dedicated circuits for processing information during locomotion and immobility. Understanding how the hippocampus switches between different network configurations may lead to therapeutic approaches to hippocampal-dependent dysfunctions, such as Alzheimer's disease or cognitive decline. PMID- 28842419 TI - Repulsive Guidance Molecule a (RGMa) Induces Neuropathological and Behavioral Changes That Closely Resemble Parkinson's Disease. AB - Repulsive guidance molecule member a (RGMa) is a membrane-associated or released guidance molecule that is involved in axon guidance, cell patterning, and cell survival. In our previous work, we showed that RGMa is significantly upregulated in the substantia nigra of patients with Parkinson's disease. Here we demonstrate the expression of RGMa in midbrain human dopaminergic (DA) neurons. To investigate whether RGMa might model aspects of the neuropathology of Parkinson's disease in mouse, we targeted RGMa to adult midbrain dopaminergic neurons using adeno-associated viral vectors. Overexpression of RGMa resulted in a progressive movement disorder, including motor coordination and imbalance, which is typical for a loss of DA release in the striatum. In line with this, RGMa induced selective degeneration of dopaminergic neurons in the substantia nigra (SN) and affected the integrity of the nigrostriatal system. The degeneration of dopaminergic neurons was accompanied by a strong microglia and astrocyte activation. The behavioral, molecular, and anatomical changes induced by RGMa in mice are remarkably similar to the clinical and neuropathological hallmarks of Parkinson's disease. Our data indicate that dysregulation of RGMa plays an important role in the pathology of Parkinson's disease, and antibody-mediated functional interference with RGMa may be a disease modifying treatment option.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is a neurodegenerative disease characterized by severe motor dysfunction due to progressive degeneration of mesencephalic dopaminergic (DA) neurons in the substantia nigra. To date, there is no regenerative treatment available. We previously showed that repulsive guidance molecule member a (RGMa) is upregulated in the substantia nigra of PD patients. Adeno-associated virus-mediated targeting of RGMa to mouse DA neurons showed that overexpression of this repulsive axon guidance and cell patterning cue models the behavioral and neuropathological characteristics of PD in a remarkable way. These findings have implications for therapy development as interfering with the function of this specific axon guidance cue may be beneficial to the survival of DA neurons. PMID- 28842421 TI - Effects of Selective Deafferentation on the Discharge Characteristics of Medial Rectus Motoneurons. AB - Medial rectus motoneurons receive two main pontine inputs: abducens internuclear neurons, whose axons course through the medial longitudinal fasciculus (MLF), and neurons in the lateral vestibular nucleus, whose axons project through the ascending tract of Deiters (ATD). Abducens internuclear neurons are responsible for conjugate gaze in the horizontal plane, whereas ATD neurons provide medial rectus motoneurons with a vestibular input comprising mainly head velocity. To reveal the relative contribution of each input to the oculomotor physiology, single-unit recordings from medial rectus motoneurons were obtained in the control situation and after selective deafferentation from cats with unilateral transection of either the MLF or the ATD. Both MLF and ATD transection produced similar short-term alterations in medial rectus motoneuron firing pattern, which were more drastic in MLF of animals. However, long-term recordings revealed important differences between the two types of lesion. Thus, while the effects of the MLF section were permanent, 2 months after ATD lesioning all motoneuronal firing parameters were similar to the control. These findings indicated a more relevant role of the MLF pathway in driving motoneuronal firing and evidenced compensatory mechanisms following the ATD lesion. Confocal immunocytochemistry revealed that MLF transection produced also a higher loss of synaptic boutons, mainly at the dendritic level. Moreover, 2 months after ATD transection, we observed an increase in synaptic coverage around motoneuron cell bodies compared with short-term data, which is indicative of a synaptogenic compensatory mechanism of the abducens internuclear pathway that could lead to the observed firing and morphological recovery.SIGNIFICANCE STATEMENT Eye movements rely on multiple neuronal circuits for appropriate performance. The abducens internuclear pathway through the medial longitudinal fascicle (MLF) and the vestibular neurons through the ascending tract of Deiters (ATD) are a dual system that supports the firing of medial rectus motoneurons. We report the effect of sectioning the MLF or the ATD pathway on the firing of medial rectus motoneurons, as well as the plastic mechanisms by which one input compensates for the lack of the other. This work shows that while the effects of MLF transection are permanent, the ATD section produces transitory effects. A mechanism based on axonal sprouting and occupancy of the vacant synaptic space due to deafferentation is the base for the mechanism of compensation on the medial rectus motoneuron. PMID- 28842420 TI - Conditional Deletion of Prnp Rescues Behavioral and Synaptic Deficits after Disease Onset in Transgenic Alzheimer's Disease. AB - Biochemical and genetic evidence implicate soluble oligomeric amyloid-beta (Abetao) in triggering Alzheimer's disease (AD) pathophysiology. Moreover, constitutive deletion of the Abetao-binding cellular prion protein (PrPC) prevents development of memory deficits in APPswe/PS1DeltaE9 mice, a model of familial AD. Here, we define the role of PrPC to rescue or halt established AD endophenotypes in a therapeutic disease-modifying time window after symptom onset. Deletion of Prnp at either 12 or 16 months of age fully reverses hippocampal synapse loss and completely rescues preexisting behavioral deficits by 17 months. In contrast, but consistent with a neuronal function for Abetao/PrPC signaling, plaque density, microgliosis, and astrocytosis are not altered. Degeneration of catecholaminergic neurons remains unchanged by PrPC reduction after disease onset. These results define the potential of targeting PrPC as a disease-modifying therapy for certain AD-related phenotypes after disease onset.SIGNIFICANCE STATEMENT The study presented here further elucidates our understanding of the soluble oligomeric amyloid-beta-Abetao-binding cellular prion protein (PrPC) signaling pathway in a familial form of Alzheimer's disease (AD) by implicating PrPC as a potential therapeutic target for AD. In particular, genetic deletion of Prnp rescued several familial AD (FAD)-associated phenotypes after disease onset in a mouse model of FAD. This study underscores the therapeutic potential of PrPC deletion given that patients already present symptoms at the time of diagnosis. PMID- 28842422 TI - Sepsis reveals compartment-specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes re-enter the cell cycle. AB - Cell production and death are tightly regulated in the rapidly renewing gut epithelium, with proliferation confined to crypts and apoptosis occurring in villi and crypts. This study sought to determine how stress alters these compartmentalized processes. Wild-type mice made septic via cecal ligation and puncture had decreased crypt proliferation and increased crypt and villus apoptosis. Fabpi-TAg mice expressing large T-antigen solely in villi had ectopic enterocyte proliferation with increased villus apoptosis in unmanipulated animals. Septic fabpi-TAg mice had an unexpected increase in villus proliferation compared with unmanipulated littermates, whereas crypt proliferation was decreased. Cell cycle regulators cyclin D1 and cyclin D2 were decreased in jejunal tissue in septic transgenic mice. In contrast, villus and crypt apoptosis were increased in septic fabpi-TAg mice. To examine the relationship between apoptosis and proliferation in a compartment-specific manner, fabpi-TAg mice were crossed with fabpl-Bcl-2 mice, resulting in expression of both genes in the villus but Bcl-2 alone in the crypt. Septic bi-transgenic animals had decreased crypt apoptosis but had a paradoxical increase in villus apoptosis compared with septic fabpi-TAg mice, associated with decreased proliferation in both compartments. Thus, sepsis unmasks compartment-specific proliferative and apoptotic regulation that is not present under homeostatic conditions.-Lyons, J. D., Klingensmith, N. J., Otani, S., Mittal, R., Liang, Z., Ford, M. L., Coopersmith, C. M. Sepsis reveals compartment-specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes re-enter the cell cycle. PMID- 28842423 TI - Activation of liver X receptor suppresses angiogenesis via induction of ApoD. AB - Liver X receptors (LXRs) are important sensors and regulators for cholesterol, fatty acid, and glucose. LXRs play essential roles in the development and progression of cardiovascular diseases. We examined the effects of T0901317, a potent LXR agonist, on angiogenesis of human umbilical vein endothelial cells (HUVECs). Treatment with T0901317 inhibited the tube formation and migration of HUVECs and reduced the in vivo angiogenesis, as determined by chorioallantoic membrane assay. T0901317 stimulated gene and protein expression of LXR target gene apolipoprotein D (ApoD). Overexpression of ApoD suppressed the tube formation of HUVECs. ApoD interacted with scavenger receptor class B member 1 (SR B1), while knockdown of SR-B1 blocked suppressive effects of T0901317 on HUVEC migration. T0901317 treatment or overexpression of ApoD lessened expression of proteins regulating angiogenesis, including phospho-eNOS S1177, phospho-Akt T308, phospho-Akt S473, eNOS, mammalian target of rapamycin, VEGF-A, VEGF-C, IL-8, RhoB, matrix metalloproteinase (MMP)-8, -9, and monocyte chemoattractant protein 1. Our study suggested that activation of LXR interferes with angiogenesis through induction of LXR target gene ApoD, which in turn suppresses PI3K-Akt-eNOS signaling, an essential pathway regulating angiogenesis. ApoD may be a potential therapeutic target for tumor angiogenesis.-Lai, C.-J., Cheng, H.-C., Lin, C.-Y., Huang, S.-H., Chen, T.-H., Chung, C.-J., Chang, C.-H., Wang, H.-D., Chuu, C.-P. Activation of liver X receptor suppresses angiogenesis via induction of ApoD. PMID- 28842425 TI - Photoacoustic imaging for in vivo quantification of placental oxygenation in mice. AB - Accurate analysis of placental and fetal oxygenation is critical during pregnancy. Photoacoustic imaging (PAI) combines laser technology with ultrasound in real time. We tested the sensitivity and accuracy of PAI for analysis of placental and fetal oxygen saturation (sO2) in mice. The placental labyrinth (L) had a higher sO2 than the junctional zone plus decidua region (JZ+D) in C57Bl/6 mice. Changing maternal O2 from 100 to 20% in C57Bl/6 mice lowered sO2 in these regions. C57Bl/6 mice were treated with the NO synthase inhibitor L-NG nitroarginine methyl ester (L-NAME) from gestational day (GD) 11 to GD18 to induce hypertension. L-NAME decreased sO2 in L and JZ+D at GD14 and GD18 in association with fetal growth restriction and higher blood pressure. Hypoxia inducible factor 1alpha immunostaining was higher in L-NAME vs control mice at GD14. Fetal sO2 levels were similar between l-NAME and control mice at GD14 and GD18. In contrast to untreated C57Bl/6, L-NAME decreased placental sO2 at GD14 and GD18 vs GD10 or GD12. Placental sO2 was lower in fetal growth restriction in an angiotensin-converting enzyme 2 knockout mouse model characterized by placental hypoxia. On phantom studies, patterns of sO2 measured directly correlated with those measured by PAI. In summary, PAI enables the detection of placental and fetal oxygenation during normal and pathologic pregnancies in mice. Yamaleyeva, L. M., Sun, Y., Bledsoe, T., Hoke, A., Gurley, S. B., Brosnihan, K. B. Photoacoustic imaging for in vivo quantification of placental oxygenation in mice. PMID- 28842426 TI - Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase-deficient mice on 129Sv/C57BL/6 background. AB - Exaggerated maternal immune responses must be strictly controlled to ensure a successful pregnancy. Neutrophil extracellular traps (NETs) have recently been implicated as a potential mechanism for promoting inflammation in pregnancy related disorders. In this study, we demonstrated that NETs play a key role in the pathogenesis of sphingosine kinase (Sphk)-mediated pregnancy loss. Perturbing the sphingolipid pathway by disrupting Sphk genes during pregnancy led to excessive NET formation exclusively at the fetomaternal interface and early fetal death. Neutrophils that formed NETs were characterized by histone hypercitrullination and peptidylarginine deiminase 4 (PAD4) overexpression. In addition, thrombus formation was enhanced in the decidua, but not in the plasma, of Sphk-deficient mice. Blocking NET formation with a PAD4 inhibitor protected Sphk-deficient mice from pregnancy loss. The PAD4 inhibition significantly reduced the expression of hypercitrullinated histone in neutrophils and ameliorated vascular injury in the decidua of Sphk-deficient mice. Moreover, NET formation was induced in human neutrophils stimulated with Sphk-deficient human decidual cells. Together, these findings indicate that targeting NETs might be a novel therapeutic strategy to treat idiopathic pregnancy loss in humans. Mizugishi, K., Yamashita, K. Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase-deficient mice on 129Sv/C57BL/6 background. PMID- 28842424 TI - Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways. AB - Our previous studies have found that Growth factor receptor-bound protein 2 associated binding protein 2 (Gab2)-a docking protein-governs the development of fatty liver disease. Here, we further demonstrate that Gab2 mediates hepatocarcinogenesis. Compared with a faint expression in para-carcinoma tissue, Gab2 was highly expressed in ~60-70% of human hepatocellular carcinoma (HCC) specimens. Deletion of Gab2 dramatically suppressed diethylnitrosamine-induced HCC in mice. The oncogenic effects of Gab2 in HepG2 cells were promoted by Gab2 overexpression but were rescued by Gab2 knockdown. Furthermore, Gab2 knockout in HepG2 cells restrained cell proliferation, migration and tumor growth in nude mice. Signaling pathway analysis with protein kinase inhibitors demonstrated that oncogenic regulation by Gab2 in hepatic cells involved multiple signaling molecules, including ERK, Akt, and Janus kinases (Jaks), especially those that mediate inflammatory signaling. IL-6 signaling was increased by Gab2 overexpression and impaired by Gab2 deletion via regulation of Jak2 and signal transducer and activator of transcription 3 phosphorylation and the expression of downstream genes, such as Bcl-2 (B-cell lymphoma 2), c-Myc, MMP7 (matrix metalloproteinase-7), and cyclin D1in vitro and in vivo These data indicate that Gab2 mediates the pathologic progression of HCC by integrating multiple signaling pathways and suggest that Gab2 might be a powerful therapeutic target for HCC. Cheng, J., Zhong, Y., Chen, S., Sun, Y., Huang, L., Kang, Y., Chen, B., Chen, G., Wang, F., Tian, Y., Liu, W., Feng, G.-S., Lu, Z. Gab2 mediates hepatocellular carcinogenesis by integrating multiple signaling pathways. PMID- 28842427 TI - Quantitative assessment of the degradation of aggregated TDP-43 mediated by the ubiquitin proteasome system and macroautophagy. AB - Amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions are neurodegenerative disorders that share the cytosolic deposition of TDP-43 (TAR DNA-binding protein 43) in the CNS. TDP-43 is well known as being actively degraded by both the proteasome and macroautophagy. The well-documented decrease in the efficiency of these clearance systems in aging and neurodegeneration, as well as the genetic evidence that many of the familial forms of TDP-43 proteinopathies involve genes that are associated with them, suggest that a failure of these protein degradation systems is a major factor that contributes to the onset of TDP-43-associated disorders. Here, we inserted preformed human TDP-43 aggregates in the cytosol of murine NSC34 and N2a cells in diffuse form and observed their degradation under conditions in which exogenous TDP-43 is not expressed and endogenous nuclear TDP-43 is not recruited, thereby allowing a time zero to be established in TDP-43 degradation and to observe its disposal kinetically and analytically. TDP-43 degradation was observed in the absence and presence of selective inhibitors and small interfering RNAs against the proteasome and autophagy. We found that cytosolic diffuse aggregates of TDP-43 can be distinguished in 3 different classes on the basis of their vulnerability to degradation, which contributed to the definition with previous reports-of a total of 6 distinct classes of misfolded TDP-43 species that range from soluble monomer to undegradable macroaggregates. We also found that the proteasome and macroautophagy-degradable pools of TDP-43 are fully distinguishable, rather than in equilibrium between them on the time scale required for degradation, and that a significant crosstalk exists between the 2 degradation processes.-Cascella, R., Fani, G., Capitini, C., Rusmini, P., Poletti, A., Cecchi, C., Chiti, F. Quantitative assessment of the degradation of aggregated TDP-43 mediated by the ubiquitin proteasome system and macroautophagy. PMID- 28842428 TI - Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. AB - Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic- and asparagine-treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knockdown of ASNS in steatotic hepatocytes restored autophagic flux. As a potential biomarker, increased serum p62/sequestosome 1 (SQSTM1) level was an independent risk factor for patients with steatosis and lobular inflammation. Impaired autophagy in NAFLD is elicited by defective lysosome acidification, which is caused by ASNS-induced asparagine synthesis under endoplasmic reticulum stress and subsequent retention of lysosomal calcium. p62/SQSTM1 could be used as a noninvasive biomarker in the diagnosis of NAFLD patients.-Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., To, K.-F., Wong, V. W. S., Chan, H. L. Y., Chan, M. T. V., Sung, J. J. Y., Wu, W. K. K., Yu, J. Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. PMID- 28842430 TI - Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin-dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways. AB - The protein tyrosine phosphatase nonreceptor type 12 (PTPN12) is a multifunctional protein and has elicited much research attention because its decreased protein level has been associated with poor prognosis of several types of cancers. Recently, we have solved the crystal structure of the phosphatase domain of PTPN12, which disclosed a specific PTPN12-insert-loop harboring a cyclin-dependent kinase 2 (CDK2) phosphorylation site. However, the functional significance of this phosphorylation is undefined. In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions. Phosphorylation of PTPN12 at the S19 site changed its substrate interface, and by doing so, selectively decreased its activity toward the human epidermal growth factor receptor 2 (HER2)- pY1196 site, but not other HER2 phosphorylation sites or other known PTPN12 substrates. A further in depth mechanism study revealed that the phosphorylation of PTPN12 by CDK2 impaired recruitment of the serine/threonine-protein kinase 1 (PAK1) to HER2, resulted in the blockade of the HER2-pY1196-PAK1-T423 signaling pathway, thus increased tumor cell motility. Taken together, our results identified a new phosphorylation-based substrate recognition mechanism of PTPN12 by CDK2, which orchestrated signaling crosstalk between the oncogenic CDK2 and HER2 pathways. The newly identified governing mechanism of the substrate selectivity of a particular phosphatase was previously unappreciated and exemplifies how a phospho network is precisely controlled in different cellular contexts.-Li, H., Yang, D., Ning, S., Xu, Y., Yang, F., Yin, R., Feng, T., Han, S., Guo, L., Zhang, P., Qu, W., Guo, R., Song, C., Xiao, P., Zhou, C., Xu, Z., Sun, J.-P., Yu, X. Switching of the substrate specificity of protein tyrosine phosphatase N12 by cyclin dependent kinase 2 phosphorylation orchestrating 2 oncogenic pathways. PMID- 28842431 TI - Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo. AB - Male exposure to cigarette smoke is associated with seminal defects and with congenital anomalies and childhood cancers in offspring. In mice, paternal exposure to cigarette smoke condensate (CSC) causes molecular defects in germ cells and phenotypic effects in their offspring. Here we used an ex vivo testicular explant model and in vivo exposure to determine the concentration at which CSC impairs spermatogenesis and offspring development. We explanted testis tissue at postnatal day (P)5.5 and cultured it until P11.5. Assessment of growth parameters by analyzing expression of cell-specific markers revealed that the explant system maintained structural and functional integrity. We exposed the P5.5 to -11.5 explants to various concentrations (40-160 ug/ml) of CSC and confirmed that nicotine in the CSC was metabolized to cotinine. We assessed various growth and differentiation parameters, as well as testosterone production, and observed that many spermatogenesis features were impaired at 160 ug/ml CSC. The same parameters were impaired by a similar CSC concentration in vivo Finally, females mated to males that were exposed to 160 ug/ml CSC neonatally had increased rates of pup resorption. We conclude that male exposure to CSC impairs offspring development and that the concentration at which CSC impairs spermatogenesis is similar in vivo and ex vivo. Given that the concentrations of CSC we used contained similar doses of nicotine as human smokers are exposed to, we argue that our model mimics human male reproductive effects of smoking.-Esakky, P., Hansen, D. A., Drury, A. M., Felder, P., Cusumano, A., Moley, K. H. Testicular cells exhibit similar molecular responses to cigarette smoke condensate ex vivo and in vivo. PMID- 28842429 TI - Anti-inflammatory effects of hypoxia-preconditioned human periodontal ligament cell secretome in an experimental model of multiple sclerosis: a key role of IL 37. AB - Recent research has widely investigated the anti-inflammatory effects of mesenchymal stem cells and their secretory products, termed the secretome, in the treatment of multiple sclerosis (MS). The present study examined the capacity of the conditioned medium (CM) from human periodontal ligament stem cells (hPLSCs) under hypoxia (H-hPDLSCs-CM) to suppress experimental autoimmune encephalomyelitis (EAE), a murine model of MS. To induce EAE, female C57BL/6 mice were immunized with myelin oligodendroglial glycoprotein peptide35-55 At the onset of symptoms, H-hPDLSCs-CM was infused via the tail vein of mice. Our results demonstrate the efficacy of H-hPDLSCs-CM treatment in diminishing clinical and histologic disease score. A key finding from this study is the marked expression of anti-inflammatory cytokine IL-37, paralleled by the suppression of proinflammatory cytokines in mice with EAE that were treated with H-hPDLSCs-CM. In addition, a consequent modulation of oxidative stress, autophagic, and apoptotic markers was observed in mice with EAE after hPDLSCs-CM administration. In addition, to provide additional evidence of the molecular mechanisms that underlie H-hPDLSCs-CM, we investigated its therapeutic action in scratch injury-exposed NSC-34 neurons, an in vitro model of injury. This model reproduces severe inflammation and oxidative stress conditions as observed after EAE damage. In vitro results corroborate the ability of hPDLSCs-CM to modulate inflammatory, oxidative stress, and apoptotic pathways. Taken together, our findings suggest H-hPDLSCs-CM as a new pharmacologic opportunity for the management of MS.-Giacoppo, S., Thangavelu, S. R., Diomede, F., Bramanti, P., Conti, P., Trubiani, O., Mazzon, E. Anti-inflammatory effects of hypoxia preconditioned human periodontal ligament cell secretome in an experimental model of multiple sclerosis: a key role of IL-37. PMID- 28842432 TI - Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity induced axonal degeneration. AB - NAD+ depletion is a common phenomenon in neurodegenerative pathologies. Excitotoxicity occurs in multiple neurologic disorders and NAD+ was shown to prevent neuronal degeneration in this process through mechanisms that remained to be determined. The activity of nicotinamide riboside (NR) in neuroprotective models and the recent description of extracellular conversion of NAD+ to NR prompted us to probe the effects of NAD+ and NR in protection against excitotoxicity. Here, we show that intracortical administration of NR but not NAD+ reduces brain damage induced by NMDA injection. Using cortical neurons, we found that provision of extracellular NR delays NMDA-induced axonal degeneration (AxD) much more strongly than extracellular NAD+ Moreover, the stronger effect of NR compared to NAD+ depends of axonal stress since in AxD induced by pharmacological inhibition of nicotinamide salvage, both NAD+ and NR prevent neuronal death and AxD in a manner that depends on internalization of NR. Taken together, our findings demonstrate that NR is a better neuroprotective agent than NAD+ in excitotoxicity-induced AxD and that axonal protection involves defending intracellular NAD+ homeostasis.-Vaur, P., Brugg, B., Mericskay, M., Li, Z., Schmidt, M. S., Vivien, D., Orset, C., Jacotot, E., Brenner, C., Duplus, E. Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity induced axonal degeneration. PMID- 28842433 TI - Multicohort analysis reveals baseline transcriptional predictors of influenza vaccination responses. AB - Annual influenza vaccinations are currently recommended for all individuals 6 months and older. Antibodies induced by vaccination are an important mechanism of protection against infection. Despite the overall public health success of influenza vaccination, many individuals fail to induce a substantial antibody response. Systems-level immune profiling studies have discerned associations between transcriptional and cell subset signatures with the success of antibody responses. However, existing signatures have relied on small cohorts and have not been validated in large independent studies. We leveraged multiple influenza vaccination cohorts spanning distinct geographical locations and seasons from the Human Immunology Project Consortium (HIPC) and the Center for Human Immunology (CHI) to identify baseline (i.e., before vaccination) predictive transcriptional signatures of influenza vaccination responses. Our multicohort analysis of HIPC data identified nine genes (RAB24, GRB2, DPP3, ACTB, MVP, DPP7, ARPC4, PLEKHB2, and ARRB1) and three gene modules that were significantly associated with the magnitude of the antibody response, and these associations were validated in the independent CHI cohort. These signatures were specific to young individuals, suggesting that distinct mechanisms underlie the lower vaccine response in older individuals. We found an inverse correlation between the effect size of signatures in young and older individuals. Although the presence of an inflammatory gene signature, for example, was associated with better antibody responses in young individuals, it was associated with worse responses in older individuals. These results point to the prospect of predicting antibody responses before vaccination and provide insights into the biological mechanisms underlying successful vaccination responses. PMID- 28842435 TI - Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis. AB - Impaired diabetic wound healing is associated with a dermal extracellular matrix protein profile favoring proteolysis; within the healing diabetic wound, this is represented by an increase in activated matrix metalloproteinase (MMPs). Treatment of diabetic wounds with mesenchymal stem cells (MSCs) has been shown to improve wound healing; however, there has not yet been an assessment of their ability to correct dysregulation of MMPs in diabetic wounds. Furthermore, there has been no prior assessment of the role of microRNA29b (miR-29b), an inhibitory regulatory molecule that targets MMP-9 mRNA. Using in vitro models of fibroblast coculture with MSCs and in vivo murine wound healing models, we tested the hypothesis that MSCs correct dysregulation of MMPs in a microRNA-29b-dependent mechanism. In this study, we first demonstrated that collagen I and III protein content is significantly reduced in diabetic wounds, and treatment with MSCs significantly improves collagen I content in both nondiabetic and diabetic wounds. We then found that MMP-9 gene expression and protein content were significantly upregulated in diabetic wounds, indicating elevated proteolysis. Treatment with MSCs resulted in a decrease in MMP-9 gene expression and protein content level in diabetic wounds 3 and 7 days after wounding. Zymographic analysis indicated that MSC treatment also decreased the amount of activated MMP 9 present in diabetic wounds. Furthermore, miR-29b expression was inversely associated with MMP-9 gene expression; miR-29b expression was decreased in diabetic wounds and diabetic fibroblast. Following treatment of diabetic wounds with MSCs, as well as in diabetic fibroblasts cocultured with MSCs, miR-29b was significantly increased. These findings suggest a potential mechanism through which MSCs enhance diabetic wound healing by improving collagen I content in diabetic wounds through decreasing MMP-9 expression and increasing miR-29b expression. PMID- 28842434 TI - Enhanced hemodynamic responses to angiotensin II in diabetes are associated with increased expression and activity of AT1 receptors in the afferent arteriole. AB - The prevalence of hypertension is about twofold higher in diabetic than in nondiabetic subjects. Hypertension aggravates the progression of diabetic complications, especially diabetic nephropathy. However, the mechanisms for the development of hypertension in diabetes have not been elucidated. We hypothesized that enhanced constrictive responsiveness of renal afferent arterioles (Af-Art) to angiotensin II (ANG II) mediated by ANG II type 1 (AT1) receptors contributes to the development of hypertension in diabetes. In response to an acute bolus intravenous injection of ANG II, alloxan-induced diabetic mice exhibited a higher mean arterial pressure (MAP) (119.1 +/- 3.8 vs. 106.2 +/- 3.5 mmHg) and a lower renal blood flow (0.25 +/- 0.07 vs. 0.52 +/- 0.14 ml/min) compared with nondiabetic mice. In response to chronic ANG II infusion, the MAP measured with telemetry increased by 55.8 +/- 6.5 mmHg in diabetic mice, but only by 32.3 +/- 3.8 mmHg in nondiabetic mice. The mRNA level of AT1 receptor increased by ~10 fold in isolated Af-Art of diabetic mice compared with nondiabetic mice, whereas ANG II type 2 (AT2) receptor expression did not change. The ANG II dose-response curve of the Af-Art was significantly enhanced in diabetic mice. Moreover, the AT1 receptor antagonist, losartan, blocked the ANG II-induced vasoconstriction in both diabetic mice and nondiabetic mice. In conclusion, we found enhanced expression of the AT1 receptor and exaggerated response to ANG II of the Af-Art in diabetes, which may contribute to the increased prevalence of hypertension in diabetes. PMID- 28842436 TI - Ca2+/calmodulin-dependent kinase II-dependent regulation of atrial myocyte late Na+ current, Ca2+ cycling, and excitability: a mathematical modeling study. AB - Atrial fibrillation (AF) affects more than three million people per year in the United States and is associated with high morbidity and mortality. Both electrical and structural remodeling contribute to AF, but the molecular pathways underlying AF pathogenesis are not well understood. Recently, a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the regulation of persistent "late" Na+ current ( INa,L) has been identified. Although INa,L inhibition is emerging as a potential antiarrhythmic strategy in patients with AF, little is known about the mechanism linking INa,L to atrial arrhythmogenesis. A computational approach was used to test the hypothesis that increased CaMKII activated INa,L in atrial myocytes disrupts Ca2+ homeostasis, promoting arrhythmogenic afterdepolarizations. Dynamic CaMKII activity and regulation of multiple downstream targets [ INa,L, L-type Ca2+ current, phospholamban, and the ryanodine receptor sarcoplasmic reticulum Ca2+-release channel (RyR2)] were incorporated into an existing well-validated computational model of the human atrial action potential. Model simulations showed that constitutive CaMKII dependent phosphorylation of Nav1.5 and the subsequent increase in INa,L effectively disrupt intracellular atrial myocyte ion homeostasis and CaMKII signaling. Specifically, increased INa,L promotes intracellular Ca2+ overload via forward-mode Na+/Ca2+ exchange activity, which greatly increases RyR2 open probability beyond that observed for CaMKII-dependent phosphorylation of RyR2 alone. Increased INa,L promotes atrial myocyte repolarization defects (afterdepolarizations and alternans) in the setting of acute beta-adrenergic stimulation. We anticipate that our modeling efforts will help identify new mechanisms for atrial NaV1.5 regulation with direct relevance for human AF. NEW & NOTEWORTHY Here, we present a novel computational model to study the effects of late Na+ current ( INa,L) in human atrial myocytes. Simulations predict that INa,L promotes intracellular accumulation of Ca2+, with subsequent dysregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling and ryanodine receptor 2-mediated Ca2+ release. Although INa,L plays a small role in regulating atrial myocyte excitability at baseline, CaMKII-dependent enhancement of the current promoted arrhythmogenic dynamics. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/camkii-dependent-regulation-of-atrial late-sodium-current-and-excitability/ . PMID- 28842437 TI - Hypoxia promotes primitive glycosaminoglycan-rich extracellular matrix composition in developing heart valves. AB - During postnatal heart valve development, glycosaminoglycan (GAG)-rich valve primordia transform into stratified valve leaflets composed of GAGs, fibrillar collagen, and elastin layers accompanied by decreased cell proliferation as well as thinning and elongation. The neonatal period is characterized by the transition from a uterine environment to atmospheric O2, but the role of changing O2 levels in valve extracellular matrix (ECM) composition or morphogenesis is not well characterized. Here, we show that tissue hypoxia decreases in mouse aortic valves in the days after birth, concomitant with ECM remodeling and cell cycle arrest of valve interstitial cells. The effects of hypoxia on late embryonic valve ECM composition, Sox9 expression, and cell proliferation were examined in chicken embryo aortic valve organ cultures. Maintenance of late embryonic chicken aortic valve organ cultures in a hypoxic environment promotes GAG expression, Sox9 nuclear localization, and indicators of hyaluronan remodeling but does not affect fibrillar collagen content or cell proliferation. Chronic hypoxia also promotes GAG accumulation in murine adult heart valves in vivo. Together, these results support a role for hypoxia in maintaining a primitive GAG-rich matrix in developing heart valves before birth and also in the induction of hyaluronan remodeling in adults.NEW & NOTEWORTHY Tissue hypoxia decreases in mouse aortic valves after birth, and exposure to hypoxia promotes glycosaminoglycan accumulation in cultured chicken embryo valves and adult murine heart valves. Thus, hypoxia maintains a primitive extracellular matrix during heart valve development and promotes extracellular matrix remodeling in adult mice, as occurs in myxomatous disease. PMID- 28842439 TI - Hypertrophic cardiomyopathy mutation in cardiac troponin T (R95H) attenuates length-dependent activation in guinea pig cardiac muscle fibers. AB - The central region of cardiac troponin T (TnT) is important for modulating the dynamics of muscle length-mediated cross-bridge recruitment. Therefore, hypertrophic cardiomyopathy mutations in the central region may affect cross bridge recruitment dynamics to alter myofilament Ca2+ sensitivity and length dependent activation of cardiac myofilaments. Given the importance of the central region of TnT for cardiac contractile dynamics, we studied if hypertrophic cardiomyopathy-linked mutation (TnTR94H)-induced effects on contractile function would be differently modulated by sarcomere length (SL). Recombinant wild-type TnT (TnTWT) and the guinea pig analog of the human R94H mutation (TnTR95H) were reconstituted into detergent-skinned cardiac muscle fibers from guinea pigs. Steady-state and dynamic contractile measurements were made at short and long SLs (1.9 and 2.3 um, respectively). Our results demonstrated that TnTR95H increased pCa50 (-log of free Ca2+ concentration) to a greater extent at short SL; TnTR95H increased pCa50 by 0.11 pCa units at short SL and 0.07 pCa units at long SL. The increase in pCa50 associated with an increase in SL from 1.9 to 2.3 um (DeltapCa50) was attenuated nearly twofold in TnTR95H fibers; DeltapCa50 was 0.09 pCa units for TnTWT fibers but only 0.05 pCa units for TnTR95H fibers. The SL dependency of rate constants of cross-bridge distortion dynamics and tension redevelopment was also blunted by TnTR95H Collectively, our observations on the SL dependency of pCa50 and rate constants of cross-bridge distortion dynamics and tension redevelopment suggest that mechanisms underlying the length-dependent activation cardiac myofilaments are attenuated by TnTR95HNEW & NOTEWORTHY Mutant cardiac troponin T (TnTR95H) differently affects myofilament Ca2+ sensitivity at short and long sarcomere length, indicating that mechanisms underlying length dependent activation are altered by TnTR95H TnTR95H enhances myofilament Ca2+ sensitivity to a greater extent at short sarcomere length, thus attenuating the length-dependent increase in myofilament Ca2+ sensitivity. PMID- 28842438 TI - Plastics and cardiovascular health: phthalates may disrupt heart rate variability and cardiovascular reactivity. AB - Plastics have revolutionized medical device technology, transformed hematological care, and facilitated modern cardiology procedures. Despite these advances, studies have shown that phthalate chemicals migrate out of plastic products and that these chemicals are bioactive. Recent epidemiological and research studies have suggested that phthalate exposure adversely affects cardiovascular function. Our objective was to assess the safety and biocompatibility of phthalate chemicals and resolve the impact on cardiovascular and autonomic physiology. Adult mice were implanted with radiofrequency transmitters to monitor heart rate variability, blood pressure, and autonomic regulation in response to di-2 ethylhexyl-phthalate (DEHP) exposure. DEHP-treated animals displayed a decrease in heart rate variability (-17% SD of normal beat-to-beat intervals and -36% high frequency power) and an exaggerated mean arterial pressure response to ganglionic blockade (31.5% via chlorisondamine). In response to a conditioned stressor, DEHP treated animals displayed enhanced cardiovascular reactivity (-56% SD major axis Poincare plot) and prolonged blood pressure recovery. Alterations in cardiac gene expression of endothelin-1, angiotensin-converting enzyme, and nitric oxide synthase may partly explain these cardiovascular alterations. This is the first study to show an association between phthalate chemicals that are used in medical devices with alterations in autonomic regulation, heart rate variability, and cardiovascular reactivity. Because changes in autonomic balance often precede clinical manifestations of hypertension, atherosclerosis, and conduction abnormalities, future studies are warranted to assess the downstream impact of plastic chemical exposure on end-organ function in sensitive patient populations. This study also highlights the importance of adopting safer biomaterials, chemicals, and/or surface coatings for use in medical devices.NEW & NOTEWORTHY Phthalates are widely used in the manufacturing of consumer and medical products. In the present study, di-2-ethylhexyl-phthalate exposure was associated with alterations in heart rate variability and cardiovascular reactivity. This highlights the importance of investigating the impact of phthalates on health and identifying suitable alternatives for medical device manufacturing. PMID- 28842440 TI - Age-related impairment of metabovascular coupling during cortical spreading depolarizations. PMID- 28842443 TI - X-linked myotubular myopathy: Living longer and awaiting treatment. PMID- 28842442 TI - RNA polymerase I, bending the rules? PMID- 28842441 TI - Carotid artery stenosis in hypertensive rats impairs dilatory pathways in parenchymal arterioles. AB - Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits. PMID- 28842444 TI - 1H-MRS metabolites and rate of beta-amyloid accumulation on serial PET in clinically normal adults. AB - OBJECTIVE: To assess whether noninvasive proton magnetic resonance spectroscopy (1H-MRS) tissue metabolite measurements at baseline can predict an increase in the rate of beta-amyloid (Abeta) accumulation on serial PET in clinically normal (CN) older adults. METHODS: Consecutive participants aged 60 years and older (n = 594) from the Mayo Clinic Study of Aging who were CN at baseline and who underwent 1H-MRS from the posterior cingulate voxel and longitudinal 11C Pittsburgh compound B (PiB)-PET were included. The rate of Abeta accumulation by serial cortical PiB standardized uptake value ratios was estimated as a function of baseline 1H-MRS metabolite ratios and time using mixed-effect models adjusted for age, sex, and APOE epsilon4. Effect of APOE epsilon4 on the relationship between baseline MRS and an increased rate of Abeta accumulation was also assessed. RESULTS: Among all participants, a higher myo-inositol (mI)/creatine (p = 0.011) and a lower N-acetylaspartate/mI (p = 0.006) at baseline were associated with an increased Abeta accumulation over time after adjusting for age, sex, and APOE epsilon4. APOE epsilon4 did not modify the association of baseline 1H-MRS metabolite ratios and rate of Abeta accumulation. However, APOE epsilon4 carriers accumulated Abeta faster than noncarriers regardless of the baseline Abeta load (p = 0.001). CONCLUSION: Among CN older adults, early metabolic alterations on 1H MRS and APOE epsilon4 status are independently associated with an increased rate of Abeta accumulation. Our findings could have important implications for early diagnosis and identification of individuals for secondary prevention trials, because an increased rate of Abeta accumulation in CN older adults may confer a higher risk for cognitive decline and mild cognitive impairment. PMID- 28842445 TI - Genetic epilepsy with febrile seizures plus: Refining the spectrum. AB - OBJECTIVE: Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum. METHODS: We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years. RESULTS: We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene. CONCLUSION: As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants. PMID- 28842446 TI - A natural history study of X-linked myotubular myopathy. AB - OBJECTIVE: To define the natural history of X-linked myotubular myopathy (MTM). METHODS: We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33). RESULTS: We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non-muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays. CONCLUSIONS: MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention. PMID- 28842448 TI - Dietary sodium intake: An etiologic dead end in multiple sclerosis. PMID- 28842447 TI - No association between dietary sodium intake and the risk of multiple sclerosis. AB - OBJECTIVE: To prospectively investigate the association between dietary sodium intake and multiple sclerosis (MS) risk. METHODS: In this cohort study, we assessed dietary sodium intake by a validated food frequency questionnaire administered every 4 years to 80,920 nurses in the Nurses' Health Study (NHS) (1984-2002) and to 94,511 in the Nurses' Health Study II (NHSII) (1991-2007), and calibrated it using data from a validation study. There were 479 new MS cases during follow-up. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the effect of energy-adjusted dietary sodium on MS risk, adjusting also for age, latitude of residence at age 15, ancestry, body mass index at age 18, supplemental vitamin D intake, cigarette smoking, and total energy intake in each cohort. The results in both cohorts were pooled using fixed effects models. RESULTS: Total dietary intake of sodium at baseline was not associated with MS risk (highest [medians: 3.2 g/d NHS; 3.5 g/d NHSII] vs lowest [medians: 2.5 g/d NHS; 2.8 g/d NHSII] quintile: HRpooled 0.98, 95% CI 0.74-1.30, p for trend = 0.75). Cumulative average sodium intake during follow-up was also not associated with MS risk (highest [medians: 3.3 g/d NHS; 3.4 g/d NHSII] vs lowest [medians: 2.7 g/d NHS; 2.8 g/d NHSII] quintile: HRpooled 1.02, 95% CI 0.76-1.37, p for trend = 0.76). Comparing more extreme sodium intake in deciles yielded similar results (p for trend = 0.95). CONCLUSIONS: Our findings suggest that higher dietary sodium intake does not increase the risk of developing MS. PMID- 28842451 TI - The "plus" side of epilepsy phenotyping. PMID- 28842449 TI - Effect of informed consent on patient characteristics in a stroke thrombolysis trial. AB - OBJECTIVE: To determine whether the manner of consent, i.e., informed consent by patients themselves or informed consent by proxy, affects clinical characteristics of samples of acute stroke patients enrolled in clinical trials. METHODS: We analyzed the manner of obtaining informed consent in the first 1,005 patients from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset running in 6 European countries. Patients providing informed consent by themselves were compared with patients enrolled by proxy consent. Baseline clinical measures were compared between groups. RESULTS: In 359 (35.7%) patients, informed consent was by proxy. Patients with proxy consent were older (median 71 vs 66 years, p < 0.0001) and had a higher frequency of arterial hypertension (58.2% vs 43.4%, p < 0.0001). They showed higher scores on the NIH Stroke Scale (median 11 vs 5, p < 0.0001) and more frequently aphasia (73.7% vs 20.0%, p < 0.0001). The rate of proxy consent varied among countries (p < 0.0001), ranging from 77.1% in Spain to 1.2% in Denmark. CONCLUSIONS: Patients recruited by proxy consent were older, had more severe strokes, and had higher prevalence of aphasia than those with capacity to give personal consent. Variations in the manner of consent across countries may influence trial results. CLINICALTRIALSGOV AND CLINICALTRIALSREGISTEREU IDENTIFIERS: NCT01525290 (clinicaltrials.gov); 2011 005906-32 (clinicaltrialsregister.eu). PMID- 28842450 TI - Neuroinflammation drives anxiety and depression in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To explore the inflammatory processes in the pathogenesis of psychiatric symptoms and the prognostic value of psychiatric comorbidities in multiple sclerosis (MS). METHODS: Four hundred five patients with relapsing remitting (RR) MS underwent psychiatric evaluation by means of Beck Depression Inventory II (BDI-II) and State/Trait Anxiety Inventory (STAI-Y). The inflammatory activity level was assessed by MRI. In a subset of 111 treatment naive patients, CSF levels of proinflammatory cytokines were determined. Correlation and regression analyses were performed to determine associations between variables. RESULTS: Relapsing patients demonstrated greater values of STAI-state and BDI-II compared with remitting patients but comparable trait anxiety scores. There were no significant differences in psychometric parameters between relapsing and asymptomatic MRI-active patients, highlighting the effect of subclinical inflammation on mood disturbances. A significant reduction of STAI state and BDI-II scores was recorded, along with the subsiding of neuroinflammation. Interleukin-2 CSF levels were found to correlate with STAI state, while tumor necrosis factor-alpha and interleukin-1beta correlated with BDI-II. Because emotional disorders were associated with subclinical inflammation, variations of the psychometric profile were able to detect subclinical reactivation earlier. In line with this, high STAI-state values considerably predicted the possibility of disease reactivation. CONCLUSIONS: Mood alterations are induced by intrathecal inflammation, even though not clinically apparent, and are able to predict inflammatory reactivations in RRMS. Inflammation is therefore a biological event, not less important than the traditional psychosocial factors, involved in mood disorders. PMID- 28842452 TI - Procoagulant imbalance in premenopausal women with chronic migraine. PMID- 28842453 TI - Comment: Capacity, consent, and country in acute stroke research. PMID- 28842454 TI - Coalition seeks solutions for clinician burnout. PMID- 28842456 TI - ASHP fellowship trains future association executives. PMID- 28842455 TI - Program teaches MTM-focused teams how to tell their stories. PMID- 28842457 TI - Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, April-June 2017. PMID- 28842458 TI - Education and certification of pharmacy technicians: A noble decision is long overdue. PMID- 28842459 TI - Polypharmacy: America's other drug problem. PMID- 28842460 TI - Reduction in warfarin effect associated with sofosbuvir-velpatasvir. PMID- 28842461 TI - Student participation in guiding the future of ambulatory care practice. PMID- 28842463 TI - Optimizing the contributions of technicians in pharmacy practice-moving the pharmacy profession forward. PMID- 28842462 TI - Improving employee engagement within a department of pharmacy. PMID- 28842465 TI - Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, April-June 2017. PMID- 28842467 TI - Role of Lymphocyte Subsets in the Immune Response to Primary B Cell-Derived Exosomes. AB - Exosomes are lipid nanovesicles released after fusion of the endosomal limiting membrane with the plasma membrane. In this study, we investigated the requirement for CD4 T cells, B cells, and NK cells to provide help for CD8 T cell-mediated response to B cell-derived exosomes. CTL responses to Ag-loaded exosomes were dependent on host MHC class I, with a critical role for splenic langerin+ CD8alpha+ dendritic cells (DCs) in exosomal Ag cross-presentation. In addition, there was an absolute dependence on the presence of CD4 T cells, CD8 T cells, and NK cells, where the loss of any one of these subsets led to a complete loss of CTL response. Interestingly, NK cell depletion experiments demonstrated a critical cutoff point for depletion efficacy, with low-level residual NK cells providing sufficient help to allow optimal CD8 T cell proliferative responses to exosomal protein. Despite the potential role for B cells in the response to B cell-derived exosomal proteins, B cell depletion did not alter the exosome induced CTL response. Similarly, a possible role for the BCR or circulating Ab in mediating CTL responses to B cell-derived exosomes was ruled out using DHLMP2A mice, which lack secreted and membrane-bound Ab, yet harbor marginal zone and follicular B cells. In contrast, CTL responses to DC-derived exosomes were significantly inhibited within Ab-deficient DHLMP2A mice compared with wild-type mice. However, this response was not restored upon serum transfer, implicating a role for the BCR, but not circulating Ab, in DC-derived exosome responses. PMID- 28842466 TI - IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-kappaB. AB - Group 3 innate lymphoid cells (ILC3s) are important regulators of the immune system, maintaining homeostasis in the presence of commensal bacteria, but activating immune defenses in response to microbial pathogens. ILC3s are a robust source of IL-22, a cytokine critical for stimulating the antimicrobial response. We sought to identify cytokines that can promote proliferation and induce or maintain IL-22 production by ILC3s and determine a molecular mechanism for this process. We identified IL-18 as a cytokine that cooperates with an ILC3 survival factor, IL-15, to induce proliferation of human ILC3s, as well as induce and maintain IL-22 production. To determine a mechanism of action, we examined the NF kappaB pathway, which is activated by IL-18 signaling. We found that the NF kappaB complex signaling component, p65, binds to the proximal region of the IL22 promoter and promotes transcriptional activity. Finally, we observed that CD11c+ dendritic cells expressing IL-18 are found in close proximity to ILC3s in human tonsils in situ. Therefore, we identify a new mechanism by which human ILC3s proliferate and produce IL-22, and identify NF-kappaB as a potential therapeutic target to be considered in pathologic states characterized by overproduction of IL-18 and/or IL-22. PMID- 28842468 TI - CXCL12-CXCR4 Axis Is Required for Contact-Mediated Human B Lymphoid and Plasmacytoid Dendritic Cell Differentiation but Not T Lymphoid Generation. AB - We investigated the involvement of CXCL12-CXCR4 interactions in human lymphohematopoiesis by coculture with telomerized human stromal cells. CXCR4 expression was low in CD34+CD38-CD45RA-CD10-CD7-CD19- immature hematopoietic stem/precursor cells (HSPCs) but higher in CD34+CD38-CD45RA+CD10+CD7+/-CD19- early lymphoid precursors and even higher in CD34+CD38+CD45RA+CD10+CD7-CD19+ pro B cells. Inhibition of the effect of stromal cell-produced CXCL12 by an anti CXCR4-blocking Ab suppressed the generation of CD45RA+CD10-CD7+CD19- early T lymphoid precursors (ETPs) and CD45RA+CD10+CD7-CD19+/- B lymphoid precursors on stromal cells, but it did not affect the generation of ETPs in conditioned medium of stromal cell cultures. Replating assays showed that contact with stromal cells was critical for HSPC-derived CD45RA+CD10+CD7-CD19- B lineage-biased precursors to differentiate into CD19+ pro-B cells, which was suppressed by the anti-CXCR4 Ab. Conversely, HSPC-derived ETPs possessed T and B lymphoid and monocytic differentiation potential; stromal cell contact was not required for their growth but rather promoted B lymphoid differentiation. The anti-CXCR4 Ab did not affect the growth of ETPs in conditioned medium, but it suppressed their B lymphoid differentiation on stromal cells. CD14-CD11c-HLA-DR+CD123highCD303+ plasmacytoid dendritic cells developed from HSPCs and ETPs exclusively in contact with stromal cells, which was suppressed by the anti-CXCR4 Ab. These data indicate that CXCL12 plays an essential role in stromal cell contact-mediated B lymphoid and plasmacytoid dendritic cell differentiation from immature hematopoietic and early T lymphoid precursors with a multilineage differentiation potential, but it does not participate in contact-independent generation of early T lymphoid precursors. PMID- 28842470 TI - IL15 Infusion of Cancer Patients Expands the Subpopulation of Cytotoxic CD56bright NK Cells and Increases NK-Cell Cytokine Release Capabilities. AB - The cytokine IL15 is required for survival and activation of natural killer (NK) cells as well as expansion of NK-cell populations. Here, we compare the effects of continuous IL15 infusions on NK-cell subpopulations in cancer patients. Infusions affected the CD56bright NK-cell subpopulation in that the expansion rates exceeded those of CD56dim NK-cell populations with a 350-fold increase in their total cell numbers compared with 20-fold expansion for the CD56dim subset. CD56bright NK cells responded with increased cytokine release to various stimuli, as expected given their immunoregulatory functions. Moreover, CD56bright NK cells gained the ability to kill various target cells at levels that are typical for CD56dim NK cells. Some increased cytotoxic activities were also observed for CD56dim NK cells. IL15 infusions induced expression changes on the surface of both NK-cell subsets, resulting in a previously undescribed and similar phenotype. These data suggest that IL15 infusions expand and arm CD56bright NK cells that alone or in combination with tumor-targeting antibodies may be useful in the treatment of cancer. Cancer Immunol Res; 5(10); 929-38. (c)2017 AACR. PMID- 28842471 TI - ISGylation - a key to lock the cell gates for preventing the spread of threats. AB - Interferon stimulated gene 15 (ISG15) is an ubiquitin-like protein whose expression and conjugation to targets (ISGylation) is induced by infection, interferon (IFN)-alpha and -beta, ischemia, DNA damage and aging. Attention has historically focused on the antiviral effects of ISGylation, which blocks the entry, replication or release of different intracellular pathogens. However, recently, new functions of ISGylation have emerged that implicate it in multiple cellular processes, such as DNA repair, autophagy, protein translation and exosome secretion. In this Review, we discuss the induction and conjugation of ISG15, as well as the functions of ISGylation in the prevention of infections and in cancer progression. We also offer a novel perspective with regard to the latest findings on this pathway, with special attention to the role of ISGylation in the inhibition of exosome secretion, which is mediated by fusion of multivesicular bodies with lysosomes. Finally, we propose that under conditions of stress or infection, ISGylation acts as a defense mechanism to inhibit normal protein translation by modifying protein kinase R (PKR, also known as EIF2AK2), while any newly synthesized proteins are being tagged and thus marked as potentially dangerous. Then, the endosomal system is re-directed towards protein degradation at the lysosome, to effectively 'lock' the cell gates and thus prevent the spread of pathogens, prions and deleterious aggregates through exosomes. PMID- 28842472 TI - The constriction and scission machineries involved in mitochondrial fission. AB - A key event in the evolution of eukaryotic cells was the engulfment of an aerobic bacterium by a larger anaerobic archaebacterium, leading to a close relationship between the host and the newly formed endosymbiont. Mitochondria, originating from this event, have evolved to be the main place of cellular ATP production. Maintaining elements of their independence, mitochondria undergo growth and division in the cell, thereby ensuring that new daughter cells inherit a mitochondrial complement. Mitochondrial division is also important for other processes, including quality control, mitochondrial (mt)DNA inheritance, transport and cell death. However, unlike bacterial fission, which uses a dynamin related protein to constrict the membrane at its inner face, mitochondria use dynamin and dynamin-related proteins to constrict the outer membrane from the cytosolic face. In this Review, we summarize the role of proteins from the dynamin superfamily in mitochondrial division. This includes recent findings highlighting that dynamin-2 (Dnm2) is involved in mitochondrial scission, which led to the reappraisal of the role of dynamin-related protein 1 (Drp1; also known as Dnm1l) and its outer membrane adaptors as components of the mitochondrial constriction machinery along with ER components and actin. PMID- 28842469 TI - A20 Restrains Thymic Regulatory T Cell Development. AB - Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (Treg) cells in the thymus. Activation of NF-kappaB transcription factors is critically required for Treg cell development, partly via initiating Foxp3 expression. NF-kappaB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4+ T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral Treg cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic Treg differentiation. A20-deficient thymic Treg cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-kappaB transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic Treg cells. Furthermore, we found that the increase in Treg cells in T cell-specific A20-deficient mice was already observed in CD4+ single-positive CD25+ GITR+ Foxp3 thymic Treg cell progenitors. Treg cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic Treg cell development. A20-deficient Treg cells efficiently suppressed effector T cell-mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural Treg cells in check, A20 thus integrates Treg cell activity and increased effector T cell survival into an efficient CD4+ T cell response. PMID- 28842473 TI - GMC appeals decision not to strike off doctor convicted of manslaughter. PMID- 28842474 TI - Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells. PMID- 28842475 TI - Shining a light on GPCR complexes. AB - The G protein-coupled receptor (GPCR) signaling pathways mediating information exchange across the cell membrane are central to a variety of biological processes and therapeutic strategies, but visualizing the molecular-level details of this exchange has been difficult for all but a few GPCR-G protein complexes. A study by Gao et al. now reports new strategies and tools to obtain receptor complexes in a near-native state, revealing insights into the gross conformational features of rhodopsin-transducin interactions and setting the stage for future studies. PMID- 28842476 TI - Spelunking for lipids in caveolae. AB - Phosphatidylserine (PtdSer) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) have been implicated in the maintenance of caveolae, but direct evidence that these lipids are required for normal caveolar structure and dynamics in living cells has been lacking. A new study by Fairn and colleagues uses sophisticated tools to perturb specific lipids in living cells to assess the consequences for caveolae. This study demonstrates disparate roles for these lipids in the stability and mobility of caveolae and points the way for future work to understand how these lipids contribute to the biology of caveolae. PMID- 28842477 TI - Tumor necrosis factor (TNF) signaling, but not TWEAK (TNF-like weak inducer of apoptosis)-triggered cIAP1 (cellular inhibitor of apoptosis protein 1) degradation, requires cIAP1 RING dimerization and E2 binding. PMID- 28842478 TI - Leucine-rich repeat-containing G protein-coupled receptor 4 facilitates vesicular stomatitis virus infection by binding vesicular stomatitis virus glycoprotein. AB - Vesicular stomatitis virus (VSV) and rabies and Chandipura viruses belong to the Rhabdovirus family. VSV is a common laboratory virus to study viral evolution and host immune responses to viral infection, and recombinant VSV-based vectors have been widely used for viral oncolysis, vaccination, and gene therapy. Although the tropism of VSV is broad, and its envelope glycoprotein G is often used for pseudotyping other viruses, the host cellular components involved in VSV infection remain unclear. Here, we demonstrate that the host protein leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is essential for VSV and VSV-G pseudotyped lentivirus (VSVG-LV) to infect susceptible cells. Accordingly, Lgr4-deficient mice had dramatically decreased VSV levels in the olfactory bulb. Furthermore, Lgr4 knockdown in RAW 264.7 cells also significantly suppressed VSV infection, and Lgr4 overexpression in RAW 264.7 cells enhanced VSV infection. Interestingly, only VSV infection relied on Lgr4, whereas infections with Newcastle disease virus, influenza A virus (A/WSN/33), and herpes simplex virus were unaffected by Lgr4 status. Of note, assays of virus entry, cell ELISA, immunoprecipitation, and surface plasmon resonance indicated that VSV bound susceptible cells via the Lgr4 extracellular domain. Pretreating cells with an Lgr4 antibody, soluble LGR4 extracellular domain, or R-spondin 1 blocked VSV infection by competitively inhibiting VSV binding to Lgr4. Taken together, the identification of Lgr4 as a VSV-specific host factor provides important insights into understanding VSV entry and its pathogenesis and lays the foundation for VSV based gene therapy and viral oncolytic therapeutics. PMID- 28842480 TI - The unique C terminus of the calcineurin isoform CNAbeta1 confers non-canonical regulation of enzyme activity by Ca2+ and calmodulin. AB - Calcineurin, the conserved Ca2+/calmodulin-regulated phosphatase and target of immunosuppressants, plays important roles in the circulatory, nervous, and immune systems. Calcineurin activity strictly depends on Ca2+ and Ca2+-bound calmodulin (Ca2+/CaM) to relieve autoinhibition of the catalytic subunit (CNA) by its C terminus. The C terminus contains two regulatory domains, the autoinhibitory domain (AID) and calmodulin-binding domain (CBD), which block the catalytic center and a conserved substrate-binding groove, respectively. However, this mechanism cannot apply to CNAbeta1, an atypical CNA isoform generated by alternative 3'-end processing, whose divergent C terminus shares the CBD common to all isoforms, but lacks the AID. We present the first biochemical characterization of CNAbeta1, which is ubiquitously expressed and conserved in vertebrates. We identify a distinct C-terminal autoinhibitory four-residue sequence in CNAbeta1, 462LAVP465, which competitively inhibits substrate dephosphorylation. In vitro and cell-based assays revealed that the CNAbeta1 containing holoenzyme, CNbeta1, is autoinhibited at a single site by either of two inhibitory regions, CBD and LAVP, which block substrate access to the substrate-binding groove. We found that the autoinhibitory segment (AIS), located within the CBD, is progressively removed by Ca2+ and Ca2+/CaM, whereas LAVP remains engaged. This regulatory strategy conferred higher basal and Ca2+ dependent activity to CNbeta1, decreasing its dependence on CaM, but also limited maximal enzyme activity through persistence of LAVP-mediated autoinhibiton during Ca2+/CaM stimulation. These regulatory properties may underlie observed differences between the biological activities of CNbeta1 and canonical CNbeta2. Our insights lay the groundwork for further studies of CNbeta1, whose physiological substrates are currently unknown. PMID- 28842479 TI - TNF-alpha promotes nuclear enrichment of the transcription factor TonEBP/NFAT5 to selectively control inflammatory but not osmoregulatory responses in nucleus pulposus cells. AB - Intervertebral disc degeneration (IDD) causes chronic back pain and is linked to production of proinflammatory molecules by nucleus pulposus (NP) and other disc cells. Activation of tonicity-responsive enhancer-binding protein (TonEBP)/NFAT5 by non-osmotic stimuli, including proinflammatory molecules, occurs in cells involved in immune response. However, whether inflammatory stimuli activate TonEBP in NP cells and whether TonEBP controls inflammation during IDD is unknown. We show that TNF-alpha, but not IL-1beta or LPS, promoted nuclear enrichment of TonEBP protein. However, TNF-alpha-mediated activation of TonEBP did not cause induction of osmoregulatory genes. RNA sequencing showed that 8.5% of TNF-alpha transcriptional responses were TonEBP-dependent and identified genes regulated by both TNF-alpha and TonEBP. These genes were over-enriched in pathways and diseases related to inflammatory response and inhibition of matrix metalloproteases. Based on RNA-sequencing results, we further investigated regulation of novel TonEBP targets CXCL1, CXCL2, and CXCL3 TonEBP acted synergistically with TNF-alpha and LPS to induce CXCL1-proximal promoter activity. Interestingly, this regulation required a highly conserved NF-kappaB binding site but not a predicted TonE, suggesting cross-talk between these two members of the Rel family. Finally, analysis of human NP tissue showed that TonEBP expression correlated with canonical osmoregulatory targets TauT/SLC6A6, SMIT/SLC5A3, and AR/AKR1B1, supporting in vitro findings that the inflammatory milieu during IDD does not interfere with TonEBP osmoregulation. In summary, whereas TonEBP participates in the proinflammatory response to TNF-alpha, therapeutic strategies targeting this transcription factor for treatment of disc disease must spare osmoprotective, prosurvival, and matrix homeostatic activities. PMID- 28842481 TI - Protonation-dependent stepped rotation of the F-type ATP synthase c-ring observed by single-molecule measurements. AB - The two opposed rotary molecular motors of the F0F1-ATP synthase work together to provide the majority of ATP in biological organisms. Rotation occurs in 120 degrees power strokes separated by dwells when F1 synthesizes or hydrolyzes ATP. F0 and F1 complexes connect via a central rotor stalk and a peripheral stator stalk. A major unresolved question is the mechanism in which the interaction between subunit-a and rotating subunit-c-ring in the F0 motor uses the flux of H+ across the membrane to induce clockwise rotation against the force of counterclockwise rotation driven by the F1-ATPase. In single-molecule measurements of F0F1 embedded in lipid bilayer nanodiscs, we observed that the ability of the F0 motor to form transient dwells increases with decreasing pH. Transient dwells can halt counterclockwise rotation powered by the F1-ATPase in steps equivalent to the rotation of single c-subunits in the c-ring of F0, and can push the common axle shared by the two motors clockwise by as much as one c subunit. Because the F0 proton half-channels that access the periplasm and the cytoplasm are exposed to the same pH, these data are consistent with the conclusion that the periplasmic half-channel is more easily protonated in a manner that halts ATPase-driven rotation by blocking ATPase-dependent proton pumping. The fit of transient dwell occurrence to the sum of three Gaussian curves suggests that the asymmetry of the three ATPase-dependent 120 degrees power strokes imposed by the relative positions of the central and peripheral stalks affects c-subunit stepping efficiency. PMID- 28842482 TI - Nuclear Gene 33/Mig6 regulates the DNA damage response through an ATM serine/threonine kinase-dependent mechanism. AB - Gene 33 (Mig6, ERRFI1) is an adaptor protein with multiple cellular functions. We recently linked Gene 33 to the DNA damage response (DDR) induced by hexavalent chromium (Cr(VI)), but the molecular mechanism remains unknown. Here we show that ectopic expression of Gene 33 triggers DDR in an ATM serine/threonine kinase (ATM)-dependent fashion and through pathways dependent or not dependent on ABL proto-oncogene 1 non-receptor tyrosine kinase (c-Abl). We observed the clear presence of Gene 33 in the nucleus and chromatin fractions of the cell. We also found that the nuclear localization of Gene 33 is regulated by its 14-3-3-binding domain and that the chromatin localization of Gene 33 is partially dependent on its ErbB-binding domain. Our data further indicated that Gene 33 may regulate the targeting of c-Abl to chromatin. Moreover, we observed a clear association of Gene 33 with histone H2AX and that ectopic expression of Gene 33 promotes the interaction between ATM and histone H2AX without triggering DNA damage. In summary, our results reveal nuclear functions of Gene 33 that regulate DDR. The nuclear localization of Gene 33 also provides a spatial explanation of the previously reported regulation of apoptosis by Gene 33 via the c-Abl/p73 pathway. On the basis of these findings and our previous studies, we propose that Gene 33 is a proximal regulator of DDR that promotes DNA repair. PMID- 28842483 TI - Cell-cell adhesion in metazoans relies on evolutionarily conserved features of the alpha-catenin.beta-catenin-binding interface. AB - Stable tissue integrity during embryonic development relies on the function of the cadherin.catenin complex (CCC). The Caenorhabditis elegans CCC is a useful paradigm for analyzing in vivo requirements for specific interactions among the core components of the CCC, and it provides a unique opportunity to examine evolutionarily conserved mechanisms that govern the interaction between alpha- and beta-catenin. HMP-1, unlike its mammalian homolog alpha-catenin, is constitutively monomeric, and its binding affinity for HMP-2/beta-catenin is higher than that of alpha-catenin for beta-catenin. A crystal structure shows that the HMP-1.HMP-2 complex forms a five-helical bundle structure distinct from the structure of the mammalian alpha-catenin.beta-catenin complex. Deletion analysis based on the crystal structure shows that the first helix of HMP-1 is necessary for binding HMP-2 avidly in vitro and for efficient recruitment of HMP 1 to adherens junctions in embryos. HMP-2 Ser-47 and Tyr-69 flank its binding interface with HMP-1, and we show that phosphomimetic mutations at these two sites decrease binding affinity of HMP-1 to HMP-2 by 40-100-fold in vitro. In vivo experiments using HMP-2 S47E and Y69E mutants showed that they are unable to rescue hmp-2(zu364) mutants, suggesting that phosphorylation of HMP-2 on Ser-47 and Tyr-69 could be important for regulating CCC formation in C. elegans Our data provide novel insights into how cadherin-dependent cell-cell adhesion is modulated in metazoans by conserved elements as well as features unique to specific organisms. PMID- 28842484 TI - Single-domain antibodies pinpoint potential targets within Shigella invasion plasmid antigen D of the needle tip complex for inhibition of type III secretion. AB - Numerous Gram-negative pathogens infect eukaryotes and use the type III secretion system (T3SS) to deliver effector proteins into host cells. One important T3SS feature is an extracellular needle with an associated tip complex responsible for assembly of a pore-forming translocon in the host cell membrane. Shigella spp. cause shigellosis, also called bacillary dysentery, and invade colonic epithelial cells via the T3SS. The tip complex of Shigella flexneri contains invasion plasmid antigen D (IpaD), which initially regulates secretion and provides a physical platform for the translocon pore. The tip complex represents a promising therapeutic target for many important T3SS-containing pathogens. Here, in an effort to further elucidate its function, we created a panel of single-VH domain antibodies (VHHs) that recognize distinct epitopes within IpaD. These VHHs recognized the in situ tip complex and modulated the infectious properties of Shigella Moreover, structural elucidation of several IpaD-VHH complexes provided critical insights into tip complex formation and function. Of note, one VHH heterodimer could reduce Shigella hemolytic activity by >80%. Our observations along with previous findings support the hypothesis that the hydrophobic translocator (IpaB in Shigella) likely binds to a region within the tip protein that is structurally conserved across all T3SS-possessing pathogens, suggesting potential therapeutic avenues for managing infections by these pathogens. PMID- 28842485 TI - The MukB-topoisomerase IV interaction is required for proper chromosome compaction. AB - The bacterial condensin MukB and the cellular decatenating enzyme topoisomerase IV interact. This interaction stimulates intramolecular reactions catalyzed by topoisomerase IV, supercoiled DNA relaxation, and DNA knotting but not intermolecular reactions such as decatenation of linked DNAs. We have demonstrated previously that MukB condenses DNA by sequestering negative supercoils and stabilizing topologically isolated loops in the DNA. We show here that the MukB-topoisomerase IV interaction stabilizes MukB on DNA, increasing the extent of DNA condensation without increasing the amount of MukB bound to the DNA. This effect does not require the catalytic activity of topoisomerase IV. Cells carrying a mukB mutant allele that encodes a protein that does not interact with topoisomerase IV exhibit severe nucleoid decompaction leading to chromosome segregation defects. These findings suggest that the MukB-topoisomerase IV complex may provide a scaffold for DNA condensation. PMID- 28842486 TI - The bacterial condensin MukB compacts DNA by sequestering supercoils and stabilizing topologically isolated loops. AB - MukB is a structural maintenance of chromosome-like protein required for DNA condensation. The complete condensin is a large tripartite complex of MukB, the kleisin, MukF, and an accessory protein, MukE. As found previously, MukB DNA condensation is a stepwise process. We have defined these steps topologically. They proceed first via the formation of negative supercoils that are sequestered by the protein followed by hinge-hinge interactions between MukB dimers that stabilize topologically isolated loops in the DNA. MukB itself is sufficient to mediate both of these topological alterations; neither ATP nor MukEF is required. We show that the MukB hinge region binds DNA and that this region of the protein is involved in sequestration of supercoils. Cells carrying mutations in the MukB hinge that reduce DNA condensation in vitro exhibit nucleoid decondensation in vivo. PMID- 28842487 TI - Loss of mucin-type O-glycans impairs the integrity of the glomerular filtration barrier in the mouse kidney. AB - The kidney's filtration activity is essential for removing toxins and waste products from the body. The vascular endothelial cells of the glomerulus are fenestrated, flattened, and surrounded by podocytes, specialized cells that support glomerular endothelial cells. Mucin-type core 1-derived O-glycans (O glycans) are highly expressed on both glomerular capillary endothelial cells and their supporting podocytes, but their biological role is unclear. Biosynthesis of core 1-derived O-glycans is catalyzed by the glycosyltransferase core 1 beta1,3 galactosyltransferase (C1galt1). Here we report that neonatal or adult mice with inducible deletion of C1galt1 (iC1galt1-/-) exhibit spontaneous proteinuria and rapidly progressing glomerulosclerosis. Ultrastructural analysis of the glomerular filtration barrier components revealed that loss of O-glycans results in altered podocyte foot processes. Further analysis indicated that O-glycan is essential for the normal signaling function of podocalyxin, a podocyte foot process-associated glycoprotein. Our results reveal a new function of O glycosylation in the integrity of the glomerular filtration barrier. PMID- 28842488 TI - Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel. AB - Cantu syndrome (CS) is a condition characterized by a range of anatomical defects, including cardiomegaly, hyperflexibility of the joints, hypertrichosis, and craniofacial dysmorphology. CS is associated with multiple missense mutations in the genes encoding the regulatory sulfonylurea receptor 2 (SUR2) subunits of the ATP-sensitive K+ (KATP) channel as well as two mutations (V65M and C176S) in the Kir6.1 (KCNJ8) subunit. Previous analysis of leucine and alanine substitutions at the Val-65-equivalent site (Val-64) in Kir6.2 indicated no major effects on channel function. In this study, we characterized the effects of both valine-to-methionine and valine-to-leucine substitutions at this position in both Kir6.1 and Kir6.2 using ion flux and patch clamp techniques. We report that methionine substitution, but not leucine substitution, results in increased open state stability and hence significantly reduced ATP sensitivity and a marked increase of channel activity in the intact cell irrespective of the identity of the coassembled SUR subunit. Sulfonylurea inhibitors, such as glibenclamide, are potential therapies for CS. However, as a consequence of the increased open state stability, both Kir6.1(V65M) and Kir6.2(V64M) mutations essentially abolish high affinity sensitivity to the KATP blocker glibenclamide in both intact cells and excised patches. This raises the possibility that, at least for some CS mutations, sulfonylurea therapy may not prove to be successful and highlights the need for detailed pharmacogenomic analyses of CS mutations. PMID- 28842489 TI - Structural basis of the PE-PPE protein interaction in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has developed multiple strategies to adapt to the human host. The five type VII secretion systems, ESX-1-5, direct the export of many virulence-promoting protein effectors across the complex mycobacterial cell wall. One class of ESX substrates is the PE-PPE family of proteins, which is unique to mycobacteria and essential for infection, antigenic variation, and host-pathogen interactions. The genome of Mtb encodes 168 PE-PPE proteins. Many of them are thought to be secreted through ESX-5 secretion system and to function in pairs. However, understanding of the specific pairing of PE-PPE proteins and their structure-function relationship is limited by the challenging purification of many PE-PPE proteins, and our knowledge of the PE-PPE interactions therefore has been restricted to the PE25 PPE41 pair and its complex with the ESX-5 secretion system chaperone EspG5. Here, we report the crystal structure of a new PE-PPE pair, PE8-PPE15, in complex with EspG5. Our structure revealed that the EspG5-binding sites on PPE15 are relatively conserved among Mtb PPE proteins, suggesting that EspG5-PPE15 represents a more typical model for EspG5-PPE interactions than EspG5-PPE41. A structural comparison with the PE25-PPE41 complex disclosed conformational changes in the four-helix bundle structure and a unique binding mode in the PE8 PPE15 pair. Moreover, homology-modeling and mutagenesis studies further delineated the molecular determinants of the specific PE-PPE interactions. These findings help develop an atomic algorithm of ESX-5 substrate recognition and PE PPE pairing. PMID- 28842491 TI - Conformational state interactions provide clues to the pharmacochaperone potential of serotonin transporter partial substrates. AB - Point mutations in SLC6 transporters cause misfolding, which can be remedied by pharmacochaperones. The serotonin transporter (SERT/SLC6A4) has a rich pharmacology including inhibitors, releasers (amphetamines, which promote the exchange mode), and more recently, discovered partial substrates. We hypothesized that partial substrates trapped the transporter in one or several states of the transport cycle. This conformational trapping may also be conducive to folding. We selected naphthylpropane-2-amines of the phenethylamine library (PAL) including the partial substrate PAL1045 and its congeners PAL287 and PAL1046. We analyzed their impact on the transport cycle of SERT by biochemical approaches and by electrophysiological recordings; substrate-induced peak currents and steady-state currents monitored the translocation of substrate and co-substrate Na+ across the lipid bilayer and the transport cycle, respectively. These experiments showed that PAL1045 and its congeners bound with different affinities (ranging from nm to MUm) to various conformational intermediates of SERT during the transport cycle. Consistent with the working hypothesis, PAL1045 was the most efficacious compound in restoring surface expression and transport activity to the folding-deficient mutant SERT-601PG602-AA. These experiments provide a proof of-principle for a rational search for pharmacochaperones, which may be useful to restore function to clinically relevant folding-deficient transporter mutants. PMID- 28842490 TI - A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity. AB - cis-Prenyltransferases (cis-PTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. In eukaryotes and archaea, cis-PT is the first enzyme committed to the synthesis of dolichyl phosphate, an obligate lipid carrier in protein glycosylation reactions. The homodimeric bacterial enzyme, undecaprenyl diphosphate synthase, generates 11 isoprene units and has been structurally and mechanistically characterized in great detail. Recently, we discovered that unlike undecaprenyl diphosphate synthase, mammalian cis-PT is a heteromer consisting of NgBR (Nus1) and hCIT (dehydrodolichol diphosphate synthase) subunits, and this composition has been confirmed in plants and fungal cis-PTs. Here, we establish the first purification system for heteromeric cis-PT and show that both NgBR and hCIT subunits function in catalysis and substrate binding. Finally, we identified a critical RXG sequence in the C-terminal tail of NgBR that is conserved and essential for enzyme activity across phyla. In summary, our findings show that eukaryotic cis-PT is composed of the NgBR and hCIT subunits. The strong conservation of the RXG motif among NgBR orthologs indicates that this subunit is critical for the synthesis of polyprenol diphosphates and cellular function. PMID- 28842492 TI - Introduction to the Thematic Minireview Series: Redox metabolism and signaling. AB - Life on oxygen predisposes cells to reactive oxygen species (ROS) generation by electron slippage in the electron transfer chain. Aerobic metabolism also generates superoxide (O2) and hydrogen peroxide (H2O2) as bona fide products in reactions involving 1- or 2-electron reduction of O2 Although often viewed as dangerous, ROS are now recognized as important messengers in redox signaling pathways. A delicate balance between needed versus excessive ROS production distinguishes health from an array of disease states. A collection of provocative reviews in this thematic series discusses the relative importance of mitochondrial sites for ROS production, ROS signaling-mediated regulation of cellular stress responses and thermogenesis, and how O2 deficiency leads to metabolic reprograming in cancer. PMID- 28842493 TI - Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions. AB - Mitochondrial production of superoxide and hydrogen peroxide is potentially important in cell signaling and disease. Eleven distinct mitochondrial sites that differ markedly in capacity are known to leak electrons to oxygen to produce O2 and/or H2O2 We discuss their contributions to O2/H2O2 production under native conditions in mitochondria oxidizing different substrates and in conditions mimicking physical exercise and the changes in their capacities after caloric restriction. We review the use of S1QELs and S3QELs, suppressors of mitochondrial O2/H2O2 generation that do not inhibit oxidative phosphorylation, as tools to characterize the contributions of specific sites in situ and in vivo. PMID- 28842494 TI - Cellular prion protein targets amyloid-beta fibril ends via its C-terminal domain to prevent elongation. AB - Oligomeric forms of the amyloid-beta (Abeta) peptide are thought to represent the primary synaptotoxic species underlying the neurodegenerative changes seen in Alzheimer's disease. It has been proposed that the cellular prion protein (PrPC) functions as a cell-surface receptor, which binds to Abeta oligomers and transduces their toxic effects. However, the molecular details of the PrPC-Abeta interaction remain uncertain. Here, we investigated the effect of PrPC on polymerization of Abeta under rigorously controlled conditions in which Abeta converts from a monomeric to a fibrillar state via a series of kinetically defined steps. We demonstrated that PrPC specifically inhibited elongation of Abeta fibrils, most likely by binding to the ends of growing fibrils. Surprisingly, this inhibitory effect required the globular C-terminal domain of PrPC, which has not been previously implicated in interactions with Abeta. Our results suggest that PrPC recognizes structural features common to both Abeta oligomers and fibril ends and that this interaction could contribute to the neurotoxic effect of Abeta aggregates. Additionally, our results identify the C terminus of PrPC as a new and potentially more druggable molecular target for treating Alzheimer's disease. PMID- 28842495 TI - Chimeric rabbit/human Fab antibodies against the hepatitis Be-antigen and their potential applications in assays, characterization, and therapy. AB - Hepatitis B virus (HBV) infection afflicts millions worldwide, causing cirrhosis and liver cancer. HBV e-antigen (HBeAg), a clinical marker for disease severity, is a soluble variant of the viral capsid protein. HBeAg is not required for viral replication but is implicated in establishing immune tolerance and chronic infection. The structure of recombinant e-antigen (rHBeAg) was recently determined, yet to date, the exact nature and quantitation of HBeAg still remain uncertain. Here, to further characterize HBeAg, we used phage display to produce a panel of chimeric rabbit/human monoclonal antibody fragments (both Fab and scFv) against rHBeAg. Several of the Fab/scFv, expressed in Escherichia coli, had unprecedentedly high binding affinities (Kd ~10-12 m) and high specificity. We used Fab/scFv in the context of an enzyme-linked immunosorbent assay (ELISA) for HBeAg quantification, which we compared with commercially available kits and verified with seroconversion panels, the WHO HBeAg standard, rHBeAg, and patient plasma samples. We found that the specificity and sensitivity are superior to those of existing commercial assays. To identify potential fine differences between rHBeAg and HBeAg, we used these Fabs in microscale immunoaffinity chromatography to purify HBeAg from individual patient plasmas. Western blotting and MS results indicated that rHBeAg and HBeAg are essentially structurally identical, although HBeAg from different patients exhibits minor carboxyl terminal heterogeneity. We discuss several potential applications for the humanized Fab/scFv. PMID- 28842496 TI - Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase. AB - Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch-mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin signaling in mouse embryonic fibroblasts as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism. PMID- 28842497 TI - The binding of activated Galphaq to phospholipase C-beta exhibits anomalous affinity. AB - Upon activation by the Gq family of Galpha subunits, Gbetagamma subunits, and some Rho family GTPases, phospholipase C-beta (PLC-beta) isoforms hydrolyze phosphatidylinositol 4,5-bisphosphate to the second messengers inositol 1,4,5 trisphosphate and diacylglycerol. PLC-beta isoforms also function as GTPase activating proteins, potentiating Gq deactivation. To elucidate the mechanism of this mutual regulation, we measured the thermodynamics and kinetics of PLC-beta3 binding to Galphaq FRET and fluorescence correlation spectroscopy, two physically distinct methods, both yielded Kd values of about 200 nm for PLC-beta3-Galphaq binding. This Kd is 50-100 times greater than the EC50 for Galphaq-mediated PLC beta3 activation and for the Galphaq GTPase-activating protein activity of PLC beta. The measured Kd was not altered either by the presence of phospholipid vesicles, phosphatidylinositol 4,5-bisphosphate and Ca2+, or by the identity of the fluorescent labels. FRET-based kinetic measurements were also consistent with a Kd of 200 nm We determined that PLC-beta3 hysteresis, whereby PLC-beta3 remains active for some time following either Galphaq-PLC-beta3 dissociation or PLC-beta3 potentiated Galphaq deactivation, is not sufficient to explain the observed discrepancy between EC50 and Kd These results indicate that the mechanism by which Galphaq and PLC-beta3 mutually regulate each other is far more complex than a simple, two-state allosteric model and instead is probably kinetically determined. PMID- 28842498 TI - Oxygen availability and metabolic reprogramming in cancer. AB - Hypoxia and dysregulated metabolism are defining features of solid tumors. How cancer cells adapt to low O2 has been illuminated by numerous studies, with "reprogrammed" metabolism being one of the most important mechanisms. This metabolic reprogramming not only promotes cancer cell plasticity, but also provides novel insights for treatment strategies. As the most studied O2 "sensor," hypoxia-inducible factor (HIF) is regarded as an important regulator of hypoxia-induced transcriptional responses. This minireview will summarize our current understanding of hypoxia-induced changes in cancer cell metabolism, with an initial focus on HIF-mediated effects, and will highlight how these metabolic alterations affect malignant phenotypes. PMID- 28842499 TI - Human copper transporter ATP7B (Wilson disease protein) forms stable dimers in vitro and in cells. AB - ATP7B is a copper-transporting P1B-type ATPase (Cu-ATPase) with an essential role in human physiology. Mutations in ATP7B cause the potentially fatal Wilson disease, and changes in ATP7B expression are observed in several cancers. Despite its physiologic importance, the biochemical information about ATP7B remains limited because of a complex multidomain organization of the protein. By analogy with the better characterized prokaryotic Cu-ATPases, ATP7B is assumed to be a single-chain monomer. We show that in eukaryotic cells, human ATP7B forms dimers that can be purified following solubilization. Deletion of the four N-terminal metal-binding domains, characteristic for human ATP7B, does not disrupt dimerization, i.e. the dimer interface is formed by the domains that are conserved among Cu-ATPases. Unlike the full-length ATP7B, which is targeted to the trans-Golgi network, 1-4DeltaMBD-7B is targeted primarily to vesicles. This result and the analysis of differentially tagged ATP7B variants indicate that the dimeric structure is retained during ATP7B trafficking between the intracellular compartments. Purified dimeric species of 1-4DeltaMBD-7B were characterized by a negative stain electron microscopy in the presence of ADP/MgCl2 Single-particle analysis yielded a low-resolution 3D model that provides the first insight into an overall architecture of a human Cu-ATPase, positions of the main domains, and a dimer interface. PMID- 28842500 TI - Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms. AB - Brown and beige adipose tissues can catabolize stored energy to generate heat, relying on the principal effector of thermogenesis: uncoupling protein 1 (UCP1). This unique capability could be leveraged as a therapy for metabolic disease. Numerous animal and cellular models have now demonstrated that mitochondrial reactive oxygen species (ROS) signal to support adipocyte thermogenic identity and function. Herein, we contextualize these findings within the established principles of redox signaling and mechanistic studies of UCP1 function. We provide a framework for understanding the role of mitochondrial ROS signaling in thermogenesis together with testable hypotheses for understanding mechanisms and developing therapies. PMID- 28842501 TI - Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress. AB - Transcription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2. PMID- 28842502 TI - BNGR-A25L and -A27 are two functional G protein-coupled receptors for CAPA periviscerokinin neuropeptides in the silkworm Bombyx mori. AB - CAPA peptides, such as periviscerokinin (PVK), are insect neuropeptides involved in many signaling pathways controlling, for example, metabolism, behavior, and reproduction. They are present in a large number of insects and, together with their cognate receptors, are important for research into approaches for improving insect control. However, the CAPA receptors in the silkworm (Bombyx mori) insect model are unknown. Here, we cloned cDNAs of two putative CAPA peptide receptor genes, BNGR-A27 and -A25, from the brain of B. mori larvae. We found that the predicted BNGR-A27 ORF encodes 450 amino acids and that one BNGR-A25 splice variant encodes a full-length isoform (BNGR-A25L) of 418 amino acid residues and another a short isoform (BNGR-A25S) of 341 amino acids with a truncated C terminal tail. Functional assays indicated that both BNGR-A25L and -A27 are activated by the PVK neuropeptides Bom-CAPA-PVK-1 and -PVK-2, leading to a significant increase in cAMP-response element-controlled luciferase activity and Ca2+ mobilization in a Gq inhibitor-sensitive manner. In contrast, BNGR-A25S was not significantly activated in response to the PVK peptides. Moreover, Bom-CAPA PVK-1 directly bound to BNGR-A25L and -A27, but not BNGR-A25S. Of note, CAPA-PVK mediated ERK1/2 phosphorylation and receptor internalization confirmed that BNGR A25L and -A27 are two canonical receptors for Bombyx CAPA-PVKs. However, BNGR A25S alone is a nonfunctional receptor but serves as a dominant-negative protein for BNGR-A25L. These results provide evidence that BNGR-A25L and -A27 are two functional Gq-coupled receptors for Bombyx CAPA-PVKs, enabling the further elucidation of the endocrinological roles of Bom-CAPA-PVKs and their receptors in insect biology. PMID- 28842503 TI - The C-terminal fibrinogen-like domain of angiopoietin-like 4 stimulates adipose tissue lipolysis and promotes energy expenditure. AB - Angptl4 (Angiopoietin-like 4) is a circulating protein secreted by white and brown adipose tissues and the liver. Structurally, Angptl4 contains an N-terminal coiled-coil domain (CCD) connected to a C-terminal fibrinogen-like domain (FLD) via a cleavable linker, and both full-length Angptl4 and its individual domains circulate in the bloodstream. Angptl4 inhibits extracellular lipoprotein lipase (LPL) activity and stimulates the lipolysis of triacylglycerol stored by adipocytes in the white adipose tissue (WAT). The former activity is furnished by the CCD, but the Angptl4 domain responsible for stimulating adipocyte lipolysis is unknown. We show here that the purified FLD of Angptl4 is sufficient to stimulate lipolysis in mouse primary adipocytes and that increasing circulating FLD levels in mice through adenovirus-mediated overexpression (Ad-FLD) not only induces WAT lipolysis in vivo but also reduces diet-induced obesity without affecting LPL activity. Intriguingly, reduced adiposity in Ad-FLD mice was associated with increased oxygen consumption, fat utilization, and the expression of thermogenic genes (Ucp1 and Ppargc1a) in subcutaneous WAT. Moreover, Ad-FLD mice exhibited increased glucose tolerance. Chronically enhancing WAT lipolysis could produce ectopic steatosis because of an overflow of lipids from the WAT to peripheral tissues; however, this did not occur when Ad-FLD mice were fed a high fat diet. Rather, these mice had reductions in both circulating triacylglycerol levels and the mRNA levels of lipogenic genes in the liver and skeletal muscle. We conclude that separating the FLD from the CCD-mediated LPL-inhibitory activity of full-length Angptl4 reveals lipolytic and thermogenic properties with therapeutic relevance to obesity and diabetes. PMID- 28842506 TI - Remote Control: Impacts of Peripheral Tumor Necrosis Factor-Alpha on Alzheimer Disease-Related Pathology. PMID- 28842504 TI - Functional defects in Clostridium difficile TcdB toxin uptake identify CSPG4 receptor-binding determinants. AB - Clostridium difficile is a major nosocomial pathogen that produces two exotoxins, TcdA and TcdB, with TcdB thought to be the primary determinant in human disease. TcdA and TcdB are large, multidomain proteins, each harboring a cytotoxic glucosyltransferase domain that is delivered into the cytosol from endosomes via a translocation domain after receptor-mediated endocytosis of toxins from the cell surface. Although there are currently no known host cell receptors for TcdA, three cell-surface receptors for TcdB have been identified: CSPG4, NECTIN3, and FZD1/2/7. The sites on TcdB that mediate binding to each receptor are not defined. Furthermore, it is not known whether the combined repetitive oligopeptide (CROP) domain is involved in or required for receptor binding. Here, in a screen designed to identify sites in TcdB that are essential for target cell intoxication, we identified a region at the junction of the translocation and the CROP domains that is implicated in CSPG4 binding. Using a series of C-terminal truncations, we show that the CSPG4-binding site on TcdB extends into the CROP domain, requiring three short repeats for binding and for full toxicity on CSPG4 expressing cells. Consistent with the location of the CSPG4-binding site on TcdB, we show that the anti-TcdB antibody bezlotoxumab, which binds partially within the first three short repeats, prevents CSPG4 binding to TcdB. In addition to establishing the binding region for CSPG4, this work ascribes for the first time a role in TcdB CROPs in receptor binding and further clarifies the relative roles of host receptors in TcdB pathogenesis. PMID- 28842505 TI - The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer. AB - Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene Mgat3 encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated N-linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells, also known as cancer stem cells. More specifically, we found that GnT-III expression regulates the levels and activation of the heavily glycosylated Notch receptor involved in normal and malignant development. Suppression of GnT-III in EOC cell lines and primary tumor-derived cells resulted in an inhibition of Notch signaling that was more potent than pharmacologic blockage of Notch activation via gamma-secretase inhibition. The inhibition resulted from the redirection of the Notch receptor to the lysosome, a novel mechanism. These findings demonstrate a new role for bisecting glycosylation in the control of Notch transport and demonstrate the therapeutic potential of inhibiting GnT-III as a treatment for controlling EOC growth and recurrence. PMID- 28842507 TI - Under What Circumstances Do Rostral Ventrolateral Medulla Neurons Support Blood Pressure? PMID- 28842508 TI - Two modes of targeting transposable elements by piRNA pathway in human testis. AB - PIWI proteins and their partner small RNAs, termed piRNAs, are known to control transposable elements (TEs) in the germline. Here, we provide evidence that in humans this control is exerted in two different modes. On the one hand, production of piRNAs specifically targeting evolutionarily youngest TEs (L1HS, L1PA2-L1PA6, LTR12C, SVA) is present both at prenatal and postnatal stages of spermatogenesis and is performed without involvement of piRNA clusters. On the other hand, at postnatal stages, piRNAs deriving from pachytene clusters target "older" TEs and thus complement cluster-independent piRNA production to achieve relevant targeting of virtually all TEs expressed in postnatal testis. We also find that converging transcription of antisense-oriented genes contributes to the origin of genic postnatal prepachytene clusters. Finally, while a fraction of pachytene piRNAs was previously shown to arise from long intergenic noncoding RNAs (lincRNAs, i.e., pachytene piRNA cluster primary transcripts), we ascertain that these are a specific set of lincRNAs that both possess distinguishing epigenetic features and are expressed exclusively in testis. PMID- 28842509 TI - An improved analysis methodology for translational profiling by microarray. AB - Translational regulation plays a central role in the global gene expression of a cell, and detection of such regulation has allowed deciphering of critical biological mechanisms. Genome-wide studies of the regulation of translation (translatome) performed on microarrays represent a substantial proportion of studies, alongside with recent advances in deep-sequencing methods. However, there has been a lack of development in specific processing methodologies that deal with the distinct nature of translatome array data. In this study, we confirm that polysome profiling yields skewed data and thus violates the conventional transcriptome analysis assumptions. Using a comprehensive simulation of translatome array data varying the percentage and symmetry of deregulation, we show that conventional analysis methods (Quantile and LOESS normalizations) and statistical tests failed, respectively, to correctly normalize the data and to identify correctly deregulated genes (DEGs). We thus propose a novel analysis methodology available as a CRAN package; Internal Control Analysis of Translatome (INCATome) based on a normalization tied to a group of invariant controls. We confirm that INCATome outperforms the other normalization methods and allows a stringent identification of DEGs. More importantly, INCATome implementation on a biological translatome data set (cells silenced for splicing factor PSF) resulted in the best normalization performance and an improved validation concordance for identification of true positive DEGs. Finally, we provide evidence that INCATome is able to infer novel biological pathways with superior discovery potential, thus confirming the benefits for researchers of implementing INCATome for future translatome studies as well as for existing data sets to generate novel avenues for research. PMID- 28842511 TI - Assessment Model to Identify Patients With Stroke With a High Possibility of Discharge to Home: A Retrospective Cohort Study. AB - BACKGROUND AND PURPOSE: Discharge planning for inpatients with acute stroke can enhance reasonable use of healthcare resources, as well as improve clinical outcomes and decrease financial burden of patients. Especially, prediction for discharge destination is crucial for discharge planning. This study aimed to develop an assessment model to identify patients with a high possibility of discharge to home after an acute stroke. METHODS: We reviewed the electronic medical records of 3200 patients with acute stroke who were admitted to a stroke center in Japan between January 1, 2011, and December 31, 2015. The outcome variable was the discharge destination of postacute stroke patients. The predictive variables were identified through logistic regression analysis. Data were divided into 2 data sets: the learning data set (n=2240) for developing the instrument and the test data set (n=960) for evaluating the predictive capability of the model. RESULTS: In all, 1548 (48%) patients were discharged to their homes. Multiple logistic regression analysis identified 5 predictive variables for discharge to home: living situation, type of stroke, functional independence measure motor score on admission, functional independence measure cognitive score on admission, and paresis. The assessment model showed a sensitivity of 85.0% and a specificity of 75.3% with an area under the curve equal to 0.88 (95% confidence interval, 0.86-0.89) when the cutoff point was 10. On evaluating the predictive capabilities, the model showed a sensitivity of 88.0% and a specificity of 68.7% with an area under the curve equal to 0.87 (95% confidence interval, 0.85-0.89). CONCLUSIONS: We have developed an assessment model for identifying patients with a high possibility of being discharged to their homes after an acute stroke. This model would be useful for health professionals to adequately plan patients' discharge soon after their admission. PMID- 28842510 TI - Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy. AB - Purpose: The combination of docetaxel chemotherapy and androgen deprivation therapy (ADT) has become a standard treatment for patients with metastatic prostate cancer. The recently accrued phase III CALGB 90203 trial was designed to investigate the clinical effectiveness of this treatment approach earlier in the disease. Specimens from this trial offer a unique opportunity to interrogate the acute molecular response to docetaxel and ADT and identify potential biomarkers.Experimental Design: We evaluated baseline clinical data, needle biopsies, and radical prostatectomy (RP) specimens from 52 (of 788) patients enrolled on CALGB 90203 at one high volume center. Pathology review, tumor and germline-targeted DNA sequencing (n = 72 genes), and expression profiling using NanoString platform (n = 163 genes) were performed to explore changes in critical prostate cancer pathways linked to aggression and resistance.Results: Three of 52 patients had only microfocal residual cancer at prostatectomy. The most common alterations included TMPRSS2-ERG fusion (n = 32), TP53 mutation or deletion (n = 11), PTEN deletion (n = 6), FOXA1 (n = 6), and SPOP (n = 4) mutation, with no significant enrichment in posttreated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was upregulation of both AR and AR-V7 expression as well as a subset of neuroendocrine and plasticity genes.Conclusions: These data support the feasibility of targeted and temporal genomic and transcriptome profiling of neoadjuvant-treated prostate cancer with limited formalin-fixed paraffin embedded tissue requirement. Characterization of the heterogeneity of treatment response and molecular outliers that arise posttreatment provides new insight into potential early markers of resistance. Clin Cancer Res; 23(22); 6802 11. (c)2017 AACR. PMID- 28842512 TI - Cerebral Microbleeds and the Risk of Incident Ischemic Stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy). AB - BACKGROUND AND PURPOSE: Cerebral microbleeds are associated with an increased risk of intracerebral hemorrhage. Recent data suggest that microbleeds may also predict the risk of incident ischemic stroke. However, these results were observed in elderly individuals undertaking various medications and for whom causes of microbleeds and ischemic stroke may differ. We aimed to test the relationship between the presence of microbleeds and incident stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)-a severe monogenic small vessel disease known to be responsible for both highly prevalent microbleeds and a high incidence of ischemic stroke in young patients. METHODS: We assessed microbleeds on baseline MRI in all 378 patients from the Paris-Munich cohort study. Incident ischemic strokes were recorded during 54 months. Survival analyses were used to test the relationship between microbleeds and incident ischemic stroke. RESULTS: Three hundred sixty-nine patients (mean age, 51.4+/-11.4 years) were followed-up during a median time of 39 months (interquartile range, 19 months). The risk of incident ischemic stroke was higher in patients with microbleeds than in patients without (35.8% versus 19.6%, hazard ratio, 1.87; 95% confidence interval, 1.16-3.01; P=0.009). These results persisted after adjustment for history of ischemic stroke, age, sex, vascular risk factors, and antiplatelet agents use (hazard ratio, 1.89; 95% confidence interval, 1.10-3.26; P=0.02). CONCLUSIONS: The presence of microbleeds is an independent risk marker of incident ischemic stroke in CADASIL, emphasizing the need to carefully interpret MRI data. PMID- 28842513 TI - Transcription and translation of APOL1 variants. AB - It is highly important to document the molecular alterations existing in normal cells prior to the onset of any disease. Knowledge of genetic mutations and associated molecular mechanisms will be helpful for better diagnosis and management of disease. The major focus of this commentary on providing understanding about the apolipoprotein 1 (APOL1) gene, the protein encoded by this gene (apoL1) and the mechanistic details regarding the role of apoL1 in the lysis of Trypanosoma brucei Information about APOL1 genetic variants, APOL1G1 and APOL1G2, is provided along with the association of these variants with hypertension-attributed end-stage renal disease (ESRD) and focal segmental glomerulosclerosis (FSGS). Moreover, this commentary presents a brief overview of how the authors of a recent Bioscience Reports article [Haque et al (2017) 37, BSR20160531, doi: 10.1042/BSR20160531] have evaluated the functional impact of G1 and G2 alleles on the transcription and translation of APOL1 mRNA. PMID- 28842514 TI - Impaired innate immune gene profiling in airway smooth muscle cells from chronic cough patients. AB - Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough. Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers. ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection. Supernatants were collected for multiplex analysis. Our results showed no significant differentially expressed genes (DEGs, false discovery rate (FDR) <0.05) between chronic cough and healthy non-cough ASMCs at baseline. Poly(I:C) stimulation resulted in 212 DEGs (>1.5 fold-change, FDR <0.05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers. The top up-regulated genes included chemokine (C-X-C motif) ligand (CXCL) 11 (CXCL11), CXCL10, chemokine (C-C motif) ligand (CCL) 5 (CCL5) and interferon induced protein 44 like (IFI44L) corresponding with inflammation and innate immune response pathways. ASMCs from cough subjects had enhanced activation of viral response pathways in response to poly(I:C) compared with healthy non-cough subjects, reduced activation of pathways involved in chronic inflammation and equivalent activation of neuroregulatory genes. The poly(I:C)-induced release of inflammatory mediators, including CXCL8, interleukin (IL)-6 and CXCL1, from ASMCs from cough patients was significantly impaired compared with healthy non-cough subjects. Addition of fluticasone propionate (FP) to poly(I:C)-treated ASMCs resulted in greater gene expression changes in healthy non-cough ASMCs. FP had a differential effect on poly(I:C)-induced mediator release between chronic cough and healthy non-cough volunteers. In conclusion, altered innate immune and inflammatory gene profiles within ASMCs, rather than infiltrating cells or nerves, may drive the cough response following respiratory viral infection. PMID- 28842515 TI - Predictive role of galectin-1 and integrin alpha5beta1 in cisplatin-based neoadjuvant chemotherapy of bulky squamous cervical cancer. AB - Although galectin-1 and integrin alpha5beta1 confer chemoresistance to certain types of cancer, whether their expression predicts the response to cisplatin based neoadjuvant chemotherapy (NACT) in squamous cervical cancer remains unclear. Paired tumor samples (pre- and post-chemotherapy) were obtained from 35 bulky squamous cervical cancer patients treated with cisplatin-based NACT and radical hysterectomy at our hospital between January 2007 and August 2014. The expression of galectin-1 and integrin alpha5beta1 in tumor cells and stromal cells was analyzed by immunohistochemistry. The correlation between galectin 1/integrin alpha5beta1 and apoptosis-associated markers was investigated by using the The Cancer Genome Atlas (TCGA) RNA-sequencing data. Seventeen patients were identified as chemotherapy responders and 18 as non-responders. Galectin-1 and integrin alpha5beta1-positive immunostaining was more frequently observed in stromal cells than its in tumor cells. The expression of galectin-1 and integrin alpha5beta1 in stromal and tumor cells was significantly down-regulated in postchemotherapy cervical cancer tissues. High levels of galectin-1 and integrin alpha5beta1 in stromal were associated with a negative chemotherapy response in squamous cervical cancer patients treated with cisplatin-based NACT. Additionally, the expression of galectin-1 and integrin alpha5 correlated negatively with caspase 3/caspase 8 by using the TCGA RNA-sequencing data. Galectin-1 and integrin alpha5beta1 expression in stromal may serve as a prediction of the responses to cisplatin-based NACT for patients with bulky squamous cervical cancer. Galectin-1 and integrin alpha5beta1 may be implicated in the development of chemoresistance in cervical cancer via suppressing apoptosis. PMID- 28842517 TI - Quantifying low-value care: a patient-centric versus service-centric lens. PMID- 28842516 TI - miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model. AB - A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir-miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir-miR-494, and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H2O2-induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H2O2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir-miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats (P<0.05 or 0.01). After H2O2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group (P<0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor (P<0.01). Moreover, HIRI + agomir-miR-494 rats exhibited significantly lower PTEN expression, and higher p AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN, leading to the activation of PI3K/AKT signaling pathway. PMID- 28842518 TI - Formalization of an antimicrobial stewardship program in a small community hospital. AB - PURPOSE: Results of a study to formalize an antimicrobial stewardship program (ASP) in a small community hospital are presented. METHODS: The formalization process began with a gap analysis of the hospital's antimicrobial services, followed by the development of a fully integrated, multipharmacist ASP. The impact was studied with an institutional review board-approved study design. Retrospective pre-ASP data were pulled from March 1 to June 30, 2012 and 2013 patient records; prospective post-ASP data were collected for March 1 to June 30, 2015. Analyses included descriptive and inferential statistics. RESULTS: No significant differences in age, percent of patients on antimicrobials, or length of stay were found between the 2 groups. The post-ASP period showed a 30.2% decrease in defined daily dose (DDD) per 1,000 patient-days for the 18 most frequently used parenteral antimicrobial agents (p < 0.001). For all nursing units except nursery, the vancomycin and piperacillin-tazobactam DDD per 1,000 patient-days decreased by 63% (p < 0.001) and 36% (p < 0.001), respectively. Mean antibiotic charges per patient-day decreased from $10.44 to $3.09 (p < 0.001) and from $18.04 to $11.29 (p < 0.001) for vancomycin and piperacillin-tazobactam, respectively. Pharmacist interventions increased from 19.3 per 1,000 patients to 104.3 per 1,000 patients. Deescalation of therapy was the most common intervention (46% and 29%) in both time periods. CONCLUSION: In a small community hospital, a new formalized ASP with pharmacists showed a decrease in the DDD per 1,000 patient-days and average antibiotic charges per patient-day for vancomycin and piperacillin-tazobactam within 4 months of implementation. The approach used to develop a formalized ASP could be used as an example for development in small community hospitals with similar resources. PMID- 28842519 TI - Effect of pharmacy management on turnaround time of 4-factor prothrombin complex concentrate. AB - PURPOSE: The change in turnaround time of 4-factor prothrombin complex concentrate (PCC) when managed by the pharmacy department compared to blood bank management was evaluated. METHODS: A retrospective analysis evaluated blood bank versus pharmacy management of PCC. Blood bank management was evaluated from November 2014 to November 2015, and pharmacy management was evaluated from December 2015 to July 2016. Chart review was performed on all patients who received PCC during these study periods. The primary outcome was the difference in median time from order entry to administration between management groups. Comparisons were made for the appropriateness of clinical use, length of stay, and discharge status. The primary outcome was analyzed using a Mann-Whitney U test. Secondary outcomes were analyzed using the chi-square test or Fisher's exact test. Descriptive statistics were utilized to analyze secondary outcomes. RESULTS: Forty-three patients received PCC in the blood bank group, and 22 patients received PCC in the pharmacy group. Median turnaround time of PCC was lower in the pharmacy group (43 minutes; interquartile range [IQR], 32-65 minutes) compared to the blood bank group (62 minutes; IQR; 39-110 minutes; p = 0.032). PCC use was clinically appropriate for 55% of patients (n = 12) in the pharmacy group compared with 37% of patients (n = 16) in the blood bank group (p = 0.182). There were no significant differences between the blood bank and pharmacy groups with regard to hospital length of stay or in-hospital mortality. CONCLUSION: Conversion of PCC management from the blood bank to the pharmacy was associated with a significant decrease in time to PCC administration. PMID- 28842520 TI - Improvement in immunosuppression therapy monitoring in organ transplant recipients. AB - PURPOSE: The results of a study to determine whether a technology-enabled pharmacist intervention improved immunosuppression monitoring in organ transplant recipients are presented. METHODS: This was a retrospective, longitudinal cohort study. Eligible patients included veteran solid organ transplant recipients receiving immunosuppression therapy from a Veterans Affairs Medical Center (VAMC) between July 1, 2013, and July 1, 2015. A clinical pharmacist used an electronic surveillance system to determine need for laboratory monitoring and engaged the recipients to obtain regular laboratory monitoring at the VAMC or an outside facility. The primary aim was to determine whether the intervention improved immunosuppression monitoring using an interrupted time series inquiry with segmented regression analysis. The secondary aim was to assess care coordination using descriptive statistics. RESULTS: A total of 110 veteran transplant recipients were included; 96% were male, 50% received kidney transplants, 36% received liver transplants, and 14% received thoracic transplants. During the 6 month initial intervention period, the rate of patients meeting minimum immunosuppression monitoring criteria increased by 4.7% per month (p < 0.001). The monthly rate of patients meeting immunosuppressant monitoring for tacrolimus, cyclosporine, and antimetabolites increased by 4.1% (p = 0.0013), 9.5% (p = 0.0442), and 1.5% (p = 0.0077), respectively. The clinical pharmacist performed 126 medication reconciliations, documented 259 outside laboratory values, and referred 9 patients to other providers. CONCLUSION: Clinical pharmacist intervention resulted in an increased number of patients with solid organ transplant meeting minimum immunosuppressant monitoring recommendations. PMID- 28842521 TI - Impact of a quality-assessment dashboard on the comprehensive review of pharmacist performance. AB - PURPOSE: The impact of a quality-assessment dashboard and individualized pharmacist performance feedback on the adherence of order verification was evaluated. METHODS: A before-and-after study was conducted at a 1,440-bed academic medical center. Adherence of order verification was defined as orders verified according to institution-derived, medication-related guidelines and policies. Formulas were developed to assess the adherence of verified orders to dosing guidelines using patient-specific height, weight, and serum creatinine clearance values from the electronic medical record at the time of pharmacist verification. A total of 5 medications were assessed by the formulas for adherence and displayed on the dashboard: ampicillin-sulbactam, ciprofloxacin, piperacillin-tazobactam, acyclovir, and enoxaparin. Adherence of order verification was assessed before (May 1-July 31, 2015) and after (November 1, 2015-January 31, 2016) individualized performance feedback was given based on trends identified by the quality-assessment dashboard. RESULTS: There was a significant increase in the overall adherence rate postintervention (90.1% versus 91.9%, p = 0.040). Among the 34 pharmacists who participated, the percentage of pharmacists with at least 90% overall adherence increased postintervention (52.9% versus 70.6%, p = 0.103). Time to verification was similar before and after the study intervention (median, 6.0 minutes; interquartile range, 3-13 minutes). The rate of documentation for nonadherent orders increased significantly postintervention (57.1% versus 68.5%, p = 0.019). CONCLUSION: The implementation of the quality-assessment dashboard, educational sessions, and individualized performance feedback significantly improved pharmacist order-verification adherence to institution-derived, medication-related guidelines and policies and the documentation rate of nonadherent orders. PMID- 28842522 TI - The Role of Hyperglycemia, Insulin Resistance, and Blood Pressure in Diabetes Associated Differences in Cognitive Performance-The Maastricht Study. AB - OBJECTIVE: To study to what extent differences in cognitive performance between individuals with different glucose metabolism status are potentially attributable to hyperglycemia, insulin resistance, and blood pressure-related variables. RESEARCH DESIGN AND METHODS: We used cross-sectional data from 2,531 participants from the Maastricht Study (mean age +/- SD, 60 +/- 8 years; 52% men; n = 666 with type 2 diabetes), all of whom completed a neuropsychological test battery. Hyperglycemia was assessed by a composite index of fasting glucose, postload glucose, glycated hemoglobin (HbA1c), and tissue advanced glycation end products; insulin resistance by the HOMA of insulin resistance index; and blood pressure related variables included 24-h ambulatory pressures, their weighted SDs, and the use of antihypertensive medication. Linear regression analyses were used to estimate mediating effects. RESULTS: After adjustment for age, sex, and education, individuals with type 2 diabetes, compared with those with normal glucose metabolism, performed worse in all cognitive domains (mean differences in composite z scores for memory -0.087, processing speed -0.196, executive function and attention -0.182; P values <0.032), whereas individuals with prediabetes did not. Diabetes-associated differences in processing speed and executive function and attention were largely explained by hyperglycemia (mediating effect 79.6% [bootstrapped 95% CI 36.6; 123.4] and 50.3% [0.6; 101.2], respectively) and, for processing speed, to a lesser extent by blood pressure-related variables (17.7% [5.6; 30.1]), but not by insulin resistance. None of the factors explained the differences in memory function. CONCLUSIONS: Our cross-sectional data suggest that early glycemic and blood pressure control, perhaps even in the prediabetic stage, may be promising therapeutic targets for the prevention of diabetes associated decrements in cognitive performance. PMID- 28842523 TI - What End Users and Stakeholders Want From Automated Insulin Delivery Systems. AB - OBJECTIVE: The purpose of this study was to rigorously explore psychosocial factors associated with automated insulin delivery systems among people living with type 1 diabetes. RESEARCH DESIGN AND METHODS: Across four sites in the U.S. and U.K., 284 participants completed structured interviews or focus groups on expectations, desired features, potential benefits, and perceived burdens of automated insulin delivery systems. Recorded audio files were transcribed and analyzed using NVivo. RESULTS: Three themes were identified as critical for uptake of automated insulin delivery: considerations of trust and control, system features, and concerns and barriers to adoption. Children and adolescents with type 1 diabetes primarily identified needs specific to their life stage and social contexts (e.g., school). Adults with type 1 diabetes, parents of youth with type 1 diabetes, and partners of adults with type 1 diabetes were most concerned about the accuracy, adaptability, and algorithm quality alongside expectations that systems stabilize glucose levels and reduce risk for long-term complications. CONCLUSIONS: Incorporating stakeholder perspectives on use of automated insulin delivery systems will improve the adoption of devices, quality of life, and likelihood of optimal health. Efforts to build trust in systems, optimize user-system interactions, and provide clear guidance about device capabilities and limitations may help potential users achieve optimal glycemic outcomes. PMID- 28842524 TI - Erratum. Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1alpha1-67 in Patients With Type 2 Diabetes. Diabetes Care 2017;40:1073-1081. PMID- 28842525 TI - Erratum. Response to Comment on Pathak et al. Severe Hypoglycemia Requiring Medical Intervention in a Large Cohort of Adults With Diabetes Receiving Care in U.S. Integrated Health Care Delivery Systems: 2005-2011. Diabetes Care 2016;39:363-370. Diabetes Care 2017;40:e26. PMID- 28842526 TI - Erratum. Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits. Diabetes Care 2015;38:1456-1466. PMID- 28842527 TI - Mechanisms contributing to cardiac remodelling. AB - Cardiac remodelling is classified as physiological (in response to growth, exercise and pregnancy) or pathological (in response to inflammation, ischaemia, ischaemia/reperfusion (I/R) injury, biomechanical stress, excess neurohormonal activation and excess afterload). Physiological remodelling of the heart is characterized by a fine-tuned and orchestrated process of beneficial adaptations. Pathological cardiac remodelling is the process of structural and functional changes in the left ventricle (LV) in response to internal or external cardiovascular damage or influence by pathogenic risk factors, and is a precursor of clinical heart failure (HF). Pathological remodelling is associated with fibrosis, inflammation and cellular dysfunction (e.g. abnormal cardiomyocyte/non cardiomyocyte interactions, oxidative stress, endoplasmic reticulum (ER) stress, autophagy alterations, impairment of metabolism and signalling pathways), leading to HF. This review describes the key molecular and cellular responses involved in pathological cardiac remodelling. PMID- 28842528 TI - The prospect of untreatable gonorrhoea. PMID- 28842529 TI - Structure of the Holliday junction: applications beyond recombination. AB - The Holliday junction (HJ) is an essential element in recombination and related mechanisms. The structure of this four-stranded DNA assembly, which is now well defined alone and in complex with proteins, has led to its applications in areas well outside of molecular recombination, including nanotechnology and biophysics. This minireview explores some interesting recent research on the HJ, as it has been adapted to design regular two- or three-dimensional lattices for crystal engineering, and more complex systems through DNA origami. In addition, the sequence dependence of the structure is discussed in terms how it can be applied to characterize the geometries and energies of various noncovalent interactions, including halogen bonds in oxidatively damaged (halogenated) bases and hydrogen bonds associated with the epigenetic 5-hydroxylmethylcytosine base. PMID- 28842530 TI - Visualising pattern recognition receptor signalling. AB - Signalling by pattern recognition receptors (PRRs) is critical for protecting the host against pathogens. Disruption of these signalling pathways has been implicated in many diseases ranging from infection susceptibility to cancer and autoimmune disease. Understanding how PRRs signal is of critical importance due to their potential as therapeutic targets to ameliorate symptoms of inflammatory diseases. The recent advances in microscopy, such as the discovery of fluorescent proteins and the breaking of the diffraction limit of light, offer a unique opportunity to visualise receptor signalling at a single protein level within living cells. Many different microscopy techniques have been developed and used for dissecting different aspects of PRR signalling pathways. This review will provide an overview of the main microscopy techniques used for dissecting these pathways with a focus on Toll-like receptor and NOD-like receptor signalling. PMID- 28842531 TI - Role of conformational change and K-path ligands in controlling cytochrome c oxidase activity. AB - Given the central role of cytochrome c oxidase (CcO) in health and disease, it is an increasingly important question as to how the activity and efficiency of this key enzyme are regulated to respond to a variety of metabolic states. The present paper summarizes evidence for two modes of regulation of activity: first, by redox-induced conformational changes involving the K-proton uptake path; and secondly, by ligand binding to a conserved site immediately adjacent to the entrance of the K-path that leads to the active site. Both these phenomena highlight the importance of the K-path in control of CcO. The redox-induced structural changes are seen in both the two-subunit and a new four-subunit crystal structure of bacterial CcO and suggest a gating mechanism to control access of protons to the active site. A conserved ligand-binding site, first discovered as a bile salt/steroid site in bacterial and mammalian oxidases, is observed to bind an array of ligands, including nucleotides, detergents, and other amphipathic molecules. Highly variable effects on activity, seen for these ligands and mutations at the K-path entrance, can be explained by differing abilities to inhibit or stimulate K-path proton uptake by preventing or allowing water organization. A new mutant form in which the K-path is blocked by substituting the conserved carboxyl with a tryptophan clarifies the singularity of the K-path entrance site. Further study in eukaryotic systems will determine the physiological significance and pharmacological potential of ligand binding and conformational change in CcO. PMID- 28842532 TI - The Arabidopsis Leucine-Rich Repeat Receptor Kinase BIR3 Negatively Regulates BAK1 Receptor Complex Formation and Stabilizes BAK1. AB - BAK1 is a coreceptor and positive regulator of multiple ligand binding leucine rich repeat receptor kinases (LRR-RKs) and is involved in brassinosteroid (BR) dependent growth and development, innate immunity, and cell death control. The BAK1-interacting LRR-RKs BIR2 and BIR3 were previously identified by proteomics analyses of in vivo BAK1 complexes. Here, we show that BAK1-related pathways such as innate immunity and cell death control are affected by BIR3 in Arabidopsis thaliana BIR3 also has a strong negative impact on BR signaling. BIR3 directly interacts with the BR receptor BRI1 and other ligand binding receptors and negatively regulates BR signaling by competitive inhibition of BRI1. BIR3 is released from BAK1 and BRI1 after ligand exposure and directly affects the formation of BAK1 complexes with BRI1 or FLAGELLIN SENSING2. Double mutants of bak1 and bir3 show spontaneous cell death and constitutive activation of defense responses. BAK1 and its closest homolog BKK1 interact with and are stabilized by BIR3, suggesting that bak1 bir3 double mutants mimic the spontaneous cell death phenotype observed in bak1 bkk1 mutants via destabilization of BIR3 target proteins. Our results provide evidence for a negative regulatory mechanism for BAK1 receptor complexes in which BIR3 interacts with BAK1 and inhibits ligand binding receptors to prevent BAK1 receptor complex formation. PMID- 28842535 TI - Journal Impact: Brave New World. PMID- 28842534 TI - Light and Ethylene Coordinately Regulate the Phosphate Starvation Response through Transcriptional Regulation of PHOSPHATE STARVATION RESPONSE1. AB - Plants have evolved an array of adaptive responses to low Pi availability, a process modulated by various external stimuli and endogenous growth regulatory signals. Little is known about how these signaling processes interact to produce an integrated response. Arabidopsis thaliana PHOSPHATE STARVATION RESPONSE1 (PHR1) encodes a conserved MYB-type transcription factor that is essential for programming Pi starvation-induced gene expression and downstream Pi starvation responses (PSRs). Here, we show that loss-of-function mutations in FHY3 and FAR1, encoding two positive regulators of phytochrome signaling, and in EIN3, encoding a master regulator of ethylene responses, cause attenuated PHR1 expression, whereas mutation in HY5, encoding another positive regulator of light signaling, causes increased PHR1 expression. FHY3, FAR1, HY5, and EIN3 directly bind to the PHR1 promoter through distinct cis-elements. FHY3, FAR1, and EIN3 activate, while HY5 represses, PHR1 expression. FHY3 directly interacts with EIN3, and HY5 suppresses the transcriptional activation activity of FHY3 and EIN3 on PHR1 Finally, both light and ethylene promote FHY3 protein accumulation, and ethylene blocks the light-promoted stabilization of HY5. Our results suggest that light and ethylene coordinately regulate PHR1 expression and PSRs through signaling convergence at the PHR1 promoter. PMID- 28842533 TI - Genomic Analysis of the DNA Replication Timing Program during Mitotic S Phase in Maize (Zea mays) Root Tips. AB - All plants and animals must replicate their DNA, using a regulated process to ensure that their genomes are completely and accurately replicated. DNA replication timing programs have been extensively studied in yeast and animal systems, but much less is known about the replication programs of plants. We report a novel adaptation of the "Repli-seq" assay for use in intact root tips of maize (Zea mays) that includes several different cell lineages and present whole genome replication timing profiles from cells in early, mid, and late S phase of the mitotic cell cycle. Maize root tips have a complex replication timing program, including regions of distinct early, mid, and late S replication that each constitute between 20 and 24% of the genome, as well as other loci corresponding to ~32% of the genome that exhibit replication activity in two different time windows. Analyses of genomic, transcriptional, and chromatin features of the euchromatic portion of the maize genome provide evidence for a gradient of early replicating, open chromatin that transitions gradually to less open and less transcriptionally active chromatin replicating in mid S phase. Our genomic level analysis also demonstrated that the centromere core replicates in mid S, before heavily compacted classical heterochromatin, including pericentromeres and knobs, which replicate during late S phase. PMID- 28842536 TI - A highly conserved basidiomycete peptide synthetase produces a trimeric hydroxamate siderophore. AB - The model white-rot basidiomycete Ceriporiopsis (Gelatoporia) subvermispora B encodes putative natural product biosynthesis genes. Among them is the gene for the seven-domain nonribosomal peptide synthetase CsNPS2. It is a member of the as yet uncharacterized fungal type VI siderophore synthetase family which is highly conserved and widely distributed among the basidiomycetes. These enzymes include only one adenylation (A) domain, i.e., one complete peptide synthetase module and two thiolation/condensation (T-C) di-domain partial modules which, together, constitute an AT1C1T2C2T3C3 domain setup. The full-length CsNPS2 enzyme (274.5 kDa) was heterologously produced as polyhistidine fusion in Aspergillus niger as soluble and active protein. N5-acetyl-N5-hydroxy-l-ornithine (l-AHO) and N5-cis anhydromevalonyl-N5 -hydroxy-l-ornithine (l-AMHO) were accepted as substrates, as assessed in vitro using the substrate-dependent [32P]ATP-pyrophosphate radioisotope exchange assay. Full-length holo-CsNPS2 catalyzed amide bond formation between three l-AHO molecules to release the linear l-AHO trimer, called basidioferrin, as product in vitro, which was verified by LC-HRESIMS. Phylogenetic analyses suggest that type VI family siderophore synthetases are widespread in mushrooms and have evolved in a common ancestor of basidiomycetes.Importance: The basidiomycete nonribosomal peptide synthetase CsNPS2 represents a member of a widely distributed but previously uninvestigated class (type VI) of fungal siderophore synthetases. Genes orthologous to CsNPS2 are highly conserved across various phylogenetic clades of the basidiomycetes. Hence, our work serves as a broadly applicable model for siderophore biosynthesis and iron metabolism in higher fungi. Also, our results on the amino acid substrate preference of CsNPS2 supports further understanding of the substrate selectivity of fungal adenylation domains. Methodologically, this report highlights the Aspergillus niger/SM-Xpress-based system as suitable platform to heterologously express multimodular basidiomycete biosynthesis enzymes in the > 250 kDa range in soluble and active form. PMID- 28842537 TI - Molecular Determinants of the Thickened Matrix in a Dual-Species Pseudomonas aeruginosa and Enterococcus faecalis Biofilm. AB - Biofilms are microbial communities that inhabit various surfaces and are surrounded by extracellular matrices (ECMs). Clinical microbiologists have shown that the majority of chronic infections are caused by biofilms, following the introduction of the first biofilm infection model by J. W. Costerton and colleagues (J. Lam, R. Chan, K. Lam, and J. W. Costerton, Infect Immun 28:546 556, 1980). However, treatments for chronic biofilm infections are still limited to surgical removal of the infected sites. Pseudomonas aeruginosa and Enterococcus faecalis are two frequently identified bacterial species in biofilm infections; nevertheless, the interactions between these two species, especially during biofilm growth, are not clearly understood. In this study, we observed phenotypic changes in a dual-species biofilm of P. aeruginosa and E. faecalis, including a dramatic increase in biofilm matrix thickness. For clear elucidation of the spatial distribution of the dual-species biofilm, P. aeruginosa and E. faecalis were labeled with red and green fluorescence, respectively. E. faecalis was located at the lower part of the dual-species biofilm, while P. aeruginosa developed a structured biofilm on the upper part. Mutants with altered exopolysaccharide (EPS) productions were constructed in order to determine the molecular basis for the synergistic effect of the dual-species biofilm. Increased biofilm matrix thickness was associated with EPSs, not extracellular DNA. In particular, Pel and Psl contributed to interspecies and intraspecies interactions, respectively, in the dual-species P. aeruginosa and E. faecalis biofilm. Accordingly, targeting Pel and Psl might be an effective part of eradicating P. aeruginosa polymicrobial biofilms.IMPORTANCE Chronic infection is a serious problem in the medical field. Scientists have observed that chronic infections are closely associated with biofilms, and the vast majority of infection-causing biofilms are polymicrobial. Many studies have reported that microbes in polymicrobial biofilms interact with each other and that the bacterial interactions result in elevated virulence, in terms of factors, such as infectivity and antibiotic resistance. Pseudomonas aeruginosa and Enterococcus faecalis are frequently isolated pathogens in chronic biofilm infections. Nevertheless, while both bacteria are known to be agents of numerous nosocomial infections and can cause serious diseases, interactions between the bacteria in biofilms have rarely been examined. In this investigation, we aimed to characterize P. aeruginosa and E. faecalis dual-species biofilms and to determine the molecular factors that cause synergistic effects, especially on the matrix thickening of the biofilm. We suspect that our findings will contribute to the development of more efficient methods for eradicating polymicrobial biofilm infections. PMID- 28842538 TI - In Bacillus subtilis, the SatA (Formerly YyaR) Acetyltransferase Detoxifies Streptothricin via Lysine Acetylation. AB - Soil is a complex niche, where survival of microorganisms is at risk due to the presence of antimicrobial agents. Many microbes chemically modify cytotoxic compounds to block their deleterious effects. Streptothricin is a broad-spectrum antibiotic produced by streptomycetes that affects Gram-positive and Gram negative bacteria alike. Here we identify the SatA (for streptothricin acetyltransferase A, formerly YyaR) enzyme of Bacillus subtilis as the mechanism used by this soil bacterium to detoxify streptothricin. B. subtilis strains lacking satA were susceptible to streptothricin. Ectopic expression of satA+ restored streptothricin resistance to B. subtilissatA (BsSatA) strains. Purified BsSatA acetylated streptothricin in vitro at the expense of acetyl-coenzyme A (acetyl-CoA). A single acetyl moiety transferred onto streptothricin by SatA blocked the toxic effects of the antibiotic. SatA bound streptothricin with high affinity (Kd [dissociation constant] = 1 MUM), and did not bind acetyl-CoA in the absence of streptothricin. Expression of B. subtilissatA+ in Salmonella enterica conferred streptothricin resistance, indicating that SatA was necessary and sufficient to detoxify streptothricin. Using this heterologous system, we showed that the SatA homologue from Bacillus anthracis also had streptothricin acetyltransferase activity. Our data highlight the physiological relevance of lysine acetylation for the survival of B. subtilis in the soil.IMPORTANCE Experimental support is provided for the functional assignment of gene products of the soil-dwelling bacilli Bacillus subtilis and Bacillus anthracis This study focuses on one enzyme that is necessary and sufficient to block the cytotoxic effects of a common soil antibiotic. The enzyme alluded to is a member of a family of proteins that are broadly distributed in all domains of life but poorly studied in B. subtilis and B. anthracis The initial characterization of the enzyme provides insights into its mechanism of catalysis. PMID- 28842539 TI - Dietary fibers and protective lactobacilli drive burrata cheese microbiome. AB - This study aimed at improving the functional attributes and shelf-life of burrata cheese by using protective lactobacilli (Lactobacillus plantarum LPAL and Lactobacillus rhamnosus LRB), fructoligosaccharides and inulin. Six burrata cheeses were made by using: i) the traditional protocol (control); ii) addition of 0.5% fructoligosaccharides and inulin (DF cheese); iii) protective lactobacilli in milk alone (PL cheese); iv) protective lactobacilli in milk and governing liquid (2PL cheese); v) protective lactobacilli in milk and dietary fibers (DF_PL cheese); and vi) protective lactobacilli in milk, governing liquid and dietary fibers (DF_2PL cheeses). As expected, DF, DF_PL and DF_2PL cheeses showed 1.5% of total fibers. Burrata cheeses produced by adding protective lactobacilli only in milk (PL and DF_PL) showed the lowest acidification during cheese-making and storage. Lactic and acetic acids and ethanol were found at the lowest concentration in these samples. Analyses of cultivable microbiota and microbiome showed that protective lactobacilli reduced the house microbiota components (e.g., Streptococcus thermophilus, Lactococcus lactis, Leuconostoc lactis) during cheese-making and storage. Protective lactobacilli slowed down the growth of staphylococci, coliforms and Pseudomonas sp. especially in early storage. According to the different microbiome assembly, burrata samples differed in peptide profiles and level of free amino acids. As shown by sensory analysis, the addition of protective lactobacilli in milk improved the flavor and increased the shelf-life of burrata cheese. Compared to cheeses made by culture protective only in milk, those containing cultures also in the governing liquid did not further prolong shelf-life and received lower acceptability scores by the panelist.IMPORTANCE This study provided more in-depth knowledge of the microbiome of burrata cheese and set-up a novel biotechnology using prebiotics dietary fibers and probiotic protective Lactobacillus plantarum LPAL and Lactobacillus rhamnosus LRB in milk. The biotechnology proposed in this study should be considered as an useful tools to improve the functional value of burrata cheese. The use of protective lactobacilli in milk enhanced flavor formation and shelf life of burrata cheese. PMID- 28842540 TI - Critical Synergistic Concentration of Lecithin Phospholipids Improves the Antimicrobial Activity of Eugenol against Escherichia coli. AB - In this study, the effect of individual lecithin phospholipids on the antimicrobial properties of eugenol against Escherichia coli C600 was investigated. We tested five major phospholipids common in soy or egg lecithin (1,2-dihexadecanoyl-sn-glycero-3-phosphocholine [DPPC], 1,2-dioctadecanoyl-sn glycero-3-phosphocholine [DSPC], 1,2-dihexadecanoyl-sn-glycero-3 phosphoethanolamine [DPPE], 1,2-dihexadecanoyl-sn-glycero-3-phosphate [sodium salt] [DPPA], and 1,2-dihexadecanoyl-sn-glycero-3-phospho-l-serine [DPPS]) and one synthetic cationic phospholipid (1,2-dioctadecanoyl-sn-glycero-3 ethylphosphocholine [18:0 EPC]). Among the six phospholipids, DPPC, DSPC, DPPE, DPPA, and the cationic 18:0 EPC showed critical synergistic concentrations that significantly improved the inactivation effect of eugenol against E. coli after 30 min of exposure. At the critical synergistic concentration, an additional ca. 0.4 to 1.9 log reduction (ca. 0.66 to 2.17 log CFU/ml reduction) in the microbial population was observed compared to eugenol-only (control) treatments (ca. 0.25 log reduction). In all cases, increasing the phospholipid amount above the critical synergistic concentration (which was different for each phospholipid) resulted in antimicrobial properties similar to those seen with the eugenol-only (control) treatments. DPPS did not affect the antimicrobial properties of eugenol at the tested concentrations. The critical synergistic concentration of phospholipids was correlated with their critical micelle concentrations (CMC).IMPORTANCE Essential oils (EOs) are naturally occurring antimicrobials, with limited use in food due to their hydrophobicity and strong aroma. Lecithin is used as a natural emulsifier to stabilize EOs in aqueous systems. We previously demonstrated that, within a narrow critical-concentration window, lecithin can synergistically enhance the antimicrobial properties of eugenol. Since lecithin is a mixture of different phospholipids, we aimed to identify which phospholipids are crucial for the observed synergistic effect. This research studied the bioactivity of lecithin phospholipids, contributing to a rational design in using lecithin to effectively control foodborne pathogens in foods. PMID- 28842541 TI - Environmental determinants of Vibrio parahaemolyticus in the Chesapeake Bay. AB - Vibrio parahaemolyticus naturally-occurs in brackish and marine waters and is one of the leading causes of seafood-borne illness. Previous work studying the ecology of V. parahaemolyticus is often limited in geographic extent and lacking a full range of environmental measures. This study used a unique, large dataset of surface water samples in the Chesapeake Bay (n=1,385) collected from 148 monitoring stations from 2007 to 2010. Water was analyzed for over 20 environmental parameters with additional meteorological and surrounding land use data. V. parahaemolyticus-specific genetic markers thermolabile hemolysin (tlh), thermostable direct hemolysin (tdh), and tdh-related hemolysin (trh) were assayed using quantitative PCR (qPCR), and interval-censored regression models with non linear effects were estimated to account for limits of detection and quantitation. tlh was detected in 19.6% of water samples; tdh or trh markers were not detected. Results confirmed previously reported positive associations for V. parahaemolyticus abundance with temperature and turbidity and negative associations with high salinity (> 10-230/00). Furthermore, the salinity relationship was determined to be a function of both low temperature and turbidity, with an increase of either nullifying the high salinity effect. Associations with dissolved oxygen and phosphate also appeared stronger when samples were taken nearby human developments. Renewed focus on the V. parahaemolyticus ecological paradigm is warranted to protect public health.ImportanceVibrio parahaemolyticus is one of the leading causes of seafood borne illness in the United States and across the globe. Exposure is often through consuming raw or undercooked shellfish. Given the natural presence of the bacterium in the marine environment, improved understanding of its environmental determinants is necessary for future preventative measures. This analysis of environmental Vibrio parahaemolyticus is one of only a few that utilize a large dataset measured over a wide geographic and temporal range. The analysis also includes a large number of environmental parameters for Vibrio modeling, many of which have previously only been tested sporadically, and some of which have not been considered before. The results of the analysis revealed previously unknown relationships between salinity, turbidity, and temperature that provide significant insight into the abundance and persistence of V.parahaemolyticus bacterium in the environment. This information will be essential for developing environmental forecast models for the bacterium. PMID- 28842542 TI - The Limnohabitans Genus Harbors Generalistic and Opportunistic Subtypes: Evidence from Spatiotemporal Succession in a Canyon-Shaped Reservoir. AB - We studied the diversity of Limnohabitans using reverse line blot hybridization with Limnohabitans lineage-specific probes in the freshwater canyon-shaped Rimov reservoir (Czech Republic). To examine the succession of distinct lineages, we performed (i) a study of an intensive spring sampling program at the lacustrine part of the Rimov reservoir (from ice melt through a phytoplankton peak to the clear-water phase), and (ii) a seasonal study (April to November) when the occurrence of distinct Limnohabitans lineages was related to the inherent longitudinal heterogeneity of the reservoir. Significant spatiotemporal changes in the compositions of distinct Limnohabitans lineages allowed for the identification of "generalists" that were always present throughout the whole season as well as "specialists" that appeared in the reservoir only for limited periods of time or irregularly. Our results indicate that some phytoplankton groups, such as cryptophytes or cyanobacteria, and zooplankton composition were the major factors modulating the distribution and dynamics of distinct Limnohabitans lineages. The highest Limnohabitans diversity was observed during the spring algal bloom, whereas the lowest was during the summer cyanobacterial bloom. The microdiversity also markedly increased upstream in the reservoir, being highest at the inflow, and thus likely reflecting strong influences of the watershed.IMPORTANCE The genus Limnohabitans is a typical freshwater bacterioplankton and is believed to play a significant role in inland freshwater habitats. This work is unique in detecting and tracing different closely related lineages of this bacterial genus in its natural conditions using the semiquantitative reverse line blot hybridization method and in discovering the factors influencing the microdiversity, subtype alternations, and seasonality. PMID- 28842543 TI - Lactolisterin BU, a Novel Class II Broad-Spectrum Bacteriocin from Lactococcus lactis subsp. lactis bv. diacetylactis BGBU1-4. AB - Lactococcus lactis subsp. lactis bv. diacetylactis BGBU1-4 produces a novel bacteriocin, lactolisterin BU, with strong antimicrobial activity against many species of Gram-positive bacteria, including important food spoilage and foodborne pathogens, such as Listeria monocytogenes, Staphylococcus aureus, Bacillus spp., and streptococci. Lactolisterin BU was extracted from the cell surface of BGBU1-4 by 2-propanol and purified to homogeneity by C18 solid-phase extraction and reversed-phase high-performance liquid chromatography. The molecular mass of the purified lactolisterin BU was 5,160.94 Da, and an internal fragment, AVSWAWQH, as determined by N-terminal sequencing, showed low-level similarity to existing antimicrobial peptides. Curing and transformation experiments revealed the presence of a corresponding bacteriocin operon on the smallest plasmid, pBU6 (6.2 kb), of strain BGBU1-4. Analysis of the bacteriocin operon revealed a leaderless bacteriocin of 43 amino acids that exhibited similarity to bacteriocin BHT-B (63%) from Streptococcus ratti, a bacteriocin with analogy to aureocin A.IMPORTANCE Lactolisterin BU, a broad-spectrum leaderless bacteriocin produced by L. lactis subsp. lactis bv. diacetylactis BGBU1-4, expresses strong antimicrobial activity against food spoilage and foodborne pathogens, such as Listeria monocytogenes, Staphylococcus aureus, Bacillus spp., and streptococci. Lactolisterin BU showed the highest similarity to aureocin-like bacteriocins produced by different bacteria. The operon for synthesis is located on the smallest plasmid, pBU6 (6.2 kb), of strain BGBU1-4, indicating possible horizontal transfer among producers. PMID- 28842544 TI - Probing the genome-scale metabolic landscape of Bordetella pertussis, the causative agent of whooping cough. AB - Whooping cough is a highly-contagious respiratory disease caused by Bordetella pertussis. Despite vaccination, its incidence has been rising alarmingly, and yet, the physiology of B. pertussis remains poorly understood. We combined genome scale metabolic reconstruction, a novel optimization algorithm and experimental data to probe the full metabolic potential of this pathogen, using strain Tohama I as a reference. Experimental validation showed that B. pertussis secretes a significant proportion of nitrogen as arginine and purine nucleosides, which may contribute to modulation of the host response. We also found that B. pertussis can be unexpectedly versatile, being able to metabolize many compounds while displaying minimal nutrient requirements. It can grow without cysteine - using inorganic sulfur sources such as thiosulfate - and it can grow on organic acids such as citrate or lactate as sole carbon sources, providing in vivo demonstration that its TCA cycle is functional. Although the metabolic reconstruction of eight additional strains indicates that the structural genes underlying this metabolic flexibility are widespread, experimental validation suggests a role of strain-specific regulatory mechanisms in shaping metabolic capabilities. Among five alternative strains tested, three were shown to grow on substrate combinations requiring a functional TCA cycle, but only one could use thiosulfate. Finally, the metabolic model was used to rationally design growth media with over two-fold improvements in pertussis toxin production. This study thus provides novel insights into B. pertussis physiology, and highlights the potential, but also limitations of models solely based on metabolic gene content.IMPORTANCE The metabolic capabilities of Bordetella pertussis - the causative agent of whooping cough - were investigated from a systems-level perspective. We constructed a comprehensive genome-scale metabolic model for B. pertussis, and challenged its predictions experimentally. This systems approach shed light on new potential host-microbe interactions, and allowed to rationally design novel growth media with over two-fold improvements in pertussis toxin production. Most importantly, we also uncovered the potential for metabolic flexibility of B. pertussis (significantly larger range of substrates than previously alleged; novel active pathways allowing growth in minimal, nearly mineral nutrient combinations where only the carbon source must be organic), although our results also highlight the importance of strain-specific regulatory determinants in shaping metabolic capabilities. Deciphering the underlying regulatory mechanisms appears crucial for a comprehensive understanding of B. pertussis's lifestyle and the epidemiology of whooping cough. The contribution of metabolic models in this context will require the extension of the genome-scale metabolic model to integrate this regulatory dimension. PMID- 28842545 TI - Oxygen-Inducible Conversion of Lactate to Acetate in Heterofermentative Lactobacillus brevis ATCC 367. AB - Lactobacillus brevis is an obligatory heterofermentative lactic acid bacterium that produces high levels of acetate, which improve the aerobic stability of silages against deterioration caused by yeasts and molds. However, the mechanism involved in acetate accumulation has yet to be elucidated. Here, experimental evidence indicated that aerobiosis resulted in the conversion of lactate to acetate after glucose exhaustion in L. brevis ATCC 367 (GenBank accession number NC_008497). To elucidate the conversion pathway, in silico analysis showed that lactate was first converted to pyruvate by the reverse catalytic reaction of lactate dehydrogenase (LDH); subsequently, pyruvate conversion to acetate might be mediated by pyruvate dehydrogenase (PDH) or pyruvate oxidase (POX). Transcriptional analysis indicated that the pdh and pox genes of L. brevis ATCC 367 were upregulated 37.92- and 18.32-fold, respectively, by oxygen and glucose exhaustion, corresponding to 5.32- and 2.35-fold increases in the respective enzyme activities. Compared with the wild-type strain, the transcription and enzymatic activity of PDH remained stable in the Deltapox mutant, while those of POX increased significantly in the Deltapdh mutant. More lactate but less acetate was produced in the Deltapdh mutant than in the wild-type and Deltapox mutant strains, and more H2O2 (a product of the POX pathway) was produced in the Deltapdh mutant. We speculated that the high levels of aerobic acetate accumulation in L. brevis ATCC 367 originated mainly from the reuse of lactate to produce pyruvate, which was further converted to acetate by the predominant and secondary functions of PDH and POX, respectively.IMPORTANCE PDH and POX are two possible key enzymes involved in aerobic acetate accumulation in lactic acid bacteria (LAB). It is currently thought that POX plays the major role in aerobic growth in homofermentative LAB and some heterofermentative LAB, while the impact of PDH remains unclear. In this study, we reported that both PDH and POX worked in the aerobic conversion of lactate to acetate in L. brevis ATCC 367, in dominant and secondary roles, respectively. Our findings will further develop the theory of aerobic metabolism by LAB. PMID- 28842546 TI - Mechanism for Restoration of Fertility in Hybrid Zygosaccharomyces rouxii Generated by Interspecies Hybridization. AB - The mechanism of whole-genome duplication (WGD) in yeast has been intensively studied because it has a large impact on yeast evolution. WGD has shaped the genomic architecture of modern Saccharomyces cerevisiae; however, the mechanism for restoring fertility after interspecies hybridization, which would be involved in the process of WGD, has not been thoroughly elucidated. In this study, we obtained a draft genome sequence of the salt-tolerant yeast Zygosaccharomyces rouxii NBRC110957 and revealed that it is a hybrid lineage of Z. rouxii (allodiploid) with two subgenomes equivalent to NBRC1876. Because this allodiploid yeast can mate with other allodiploid strains and form spores, it can be a good model of restoring fertility after interspecies hybridization. We observed that NBRC110957 and NBRC1876 contain six mating-type-like (MTL) loci. There are no large deletions or deleterious mutations in MTL loci, except for several-base-pair deletions in the X region in certain MTL loci. We also assigned only one mating-type (MAT) locus that exclusively determines mating types from six MTL loci. These results suggest that it is possible to recover mating competence regardless of whether cells lose one MAT locus through random gene loss by mitotically dividing after interspecies hybridization. Moreover, we propose that perturbation of gene expression and substantial breakdown of MAT heterozygosity caused by chromosomal rearrangement at MTL loci play roles in restoring the mating competence of allodiploids. This scenario can provide a mechanism for restoring fertility after interspecies hybridization that is compatible with random gene loss models and suggests genomic plasticity during WGD in yeast.IMPORTANCE A whole-genome duplication occurred in an ancestor of the baker's yeast Saccharomyces cerevisiae The origins of this complex and multifaceted process, which requires intra- or interspecies hybridization followed by dysfunction of one mating-type (MAT) locus to regain mating competence, has not been thoroughly elucidated. In this study, we provide a mechanism for regaining fertility in an interspecies hybrid, Zygosaccharomyces rouxii The draft genome sequence analysis and mating test showed that the Z. rouxii strain used in this study is an intact interspecies hybrid, suggesting that it is possible to recover fertility regardless of whether cells lose one MAT locus. PMID- 28842547 TI - The Arsenic Resistance-Associated Listeria Genomic Island LGI2 Exhibits Sequence and Integration Site Diversity and a Propensity for Three Listeria monocytogenes Clones with Enhanced Virulence. AB - In the foodborne pathogen Listeria monocytogenes, arsenic resistance is encountered primarily in serotype 4b clones considered to have enhanced virulence and is associated with an arsenic resistance gene cluster within a 35-kb chromosomal region, Listeria genomic island 2 (LGI2). LGI2 was first identified in strain Scott A and includes genes putatively involved in arsenic and cadmium resistance, DNA integration, conjugation, and pathogenicity. However, the genomic localization and sequence content of LGI2 remain poorly characterized. Here we investigated 85 arsenic-resistant L. monocytogenes strains, mostly of serotype 4b. All but one of the 70 serotype 4b strains belonged to clonal complex 1 (CC1), CC2, and CC4, three major clones associated with enhanced virulence. PCR analysis suggested that 53 strains (62.4%) harbored an island highly similar to LGI2 of Scott A, frequently (42/53) in the same location as Scott A (LMOf2365_2257 homolog). Random-primed PCR and whole-genome sequencing revealed seven novel insertion sites, mostly internal to chromosomal coding sequences, among strains harboring LGI2 outside the LMOf2365_2257 homolog. Interestingly, many CC1 strains harbored a noticeably diversified LGI2 (LGI2-1) in a unique location (LMOf2365_0902 homolog) and with a novel additional gene. With few exceptions, the tested LGI2 genes were not detected in arsenic-resistant strains of serogroup 1/2, which instead often harbored a Tn554-associated arsenic resistance determinant not encountered in serotype 4b. These findings indicate that in L. monocytogenes, LGI2 has a propensity for certain serotype 4b clones, exhibits content diversity, and is highly promiscuous, suggesting an ability to mobilize various accessory genes into diverse chromosomal loci.IMPORTANCEListeria monocytogenes is widely distributed in the environment and causes listeriosis, a foodborne disease with high mortality and morbidity. Arsenic and other heavy metals can powerfully shape the populations of human pathogens with pronounced environmental lifestyles such as L. monocytogenes Arsenic resistance is encountered primarily in certain serotype 4b clones considered to have enhanced virulence and is associated with a large chromosomal island, Listeria genomic island 2 (LGI2). LGI2 also harbors a cadmium resistance cassette and genes putatively involved in DNA integration, conjugation, and pathogenicity. Our findings indicate that LGI2 exhibits pronounced content plasticity and is capable of transferring various accessory genes into diverse chromosomal locations. LGI2 may serve as a paradigm on how exposure to a potent environmental toxicant such as arsenic may have dynamically selected for arsenic-resistant subpopulations in certain clones of L. monocytogenes which also contribute significantly to disease. PMID- 28842549 TI - Roles of miR319 and TCP Transcription Factors in Leaf Development. AB - Sophisticated regulation of gene expression, including microRNAs (miRNAs) and their target genes, is required for leaf differentiation, growth, and senescence. The impact of miR319 and its target TEOSINTE BRANCHED1, CYCLOIDEA, and PROLIFERATING CELL NUCLEAR ANTIGEN BINDING FACTOR (TCP) genes on leaf development has been extensively investigated, but the redundancies of these gene families often interfere with the evaluation of their function and regulation in the developmental context. Here, we present the genetic evidence of the involvement of the MIR319 and TCP gene families in Arabidopsis (Arabidopsis thaliana) leaf development. Single mutations in MIR319A and MIR319B genes moderately inhibited the formation of leaf serrations, whereas double mutations increased the extent of this inhibition and resulted in the formation of smooth leaves. Mutations in MIR319 and gain-of-function mutations in the TCP4 gene conferred resistance against miR319 and impaired the cotyledon boundary and leaf serration formation. These mutations functionally associated with CUP-SHAPED COTYLEDON genes, which regulate the cotyledon boundary and leaf serration formation. In contrast, loss of-function mutations in miR319-targeted and nontargeted TCP genes cooperatively induced the formation of serrated leaves in addition to changes in the levels of their downstream gene transcript. Taken together, these findings demonstrate that the MIR319 and TCP gene families underlie robust and multilayer control of leaf development. This study also provides a framework toward future researches on redundant miRNAs and transcription factors in Arabidopsis and crop plants. PMID- 28842550 TI - Sugar Potentiation of Fatty Acid and Triacylglycerol Accumulation. AB - Photosynthetically derived sugar provides carbon skeletons for lipid biosynthesis. We used mutants of Arabidopsis (Arabidopsis thaliana) and the expression of oleogenic factors to investigate relationships among sugar availability, lipid synthesis, and the accumulation of triacylglycerol (TAG) in leaf tissue. The adg1 mutation disables the small subunit of ADP-glucose pyrophosphorylase, the first step in starch synthesis, and the suc2 mutation disables a sucrose/proton symporter that facilitates sucrose loading from leaves into phloem. The adg1suc2 double mutant increases glucose plus sucrose content in leaves 80-fold relative to the wild type, total fatty acid (FA) content 1.8-fold to 8.3% dry weight, and TAG more than 10-fold to 1.2% dry weight. The WRINKLED1 transcription factor also accumulates to higher levels in these leaves, and the rate of FA synthesis increases by 58%. Adding tt4, which disables chalcone synthase, had little effect, but adding the tgd1 mutation, which disables an importer of lipids into plastids to create adg1suc2tt4tgd1, increased total leaf FA to 13.5% dry weight and TAG to 3.8% dry weight, demonstrating a synergistic effect upon combining these mutations. Combining adg1suc2 with the sdp1 mutation, deficient in the predominant TAG lipase, had little effect on total FA content but increased the TAG accumulation by 66% to 2% dry weight. Expression of the WRINKLED1 transcription factor, along with DIACYLGLYCEROL ACYLTRANSFERASE1 and the OLEOSIN1 oil body-associated protein, in the adg1suc2 mutant doubled leaf FA content and increased TAG content to 2.3% dry weight, a level 4.6-fold higher than that resulting from expression of the same factors in the wild type. PMID- 28842551 TI - Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy. AB - BACKGROUND Inducing mitochondrial dysfunction has been recently demonstrated to be an alternative therapeutic strategy for cancer treatment. Doxycycline is an antibiotic that has been shown to have anti-cancer activities in various cancers by way of targeting mitochondria. In this work, we examined whether doxycycline can be repurposed for glioblastoma treatment. MATERIAL AND METHODS The effects of doxycycline on the growth, survival, and mitochondrial metabolisms of glioblastoma were investigated. The efficacy of a combination of doxycycline with temozolomide was examined using xenograft mouse model in total number of 40 mice. RESULTS Doxycycline targeted glioblastoma cell lines, regardless of their origin, through inhibiting growth and inducing cell death, accompanied by a significant decrease in proliferating cell nuclear antigen (PCNA) and increase in cleaved caspase-3. In addition, doxycycline significantly sensitized glioblastoma cell response to temozolomide in vitro and in vivo. Mechanistically, doxycycline disrupted mitochondrial functions through decreasing mitochondrial membrane potential and mitochondrial respiration. Inducing mitochondrial dysfunctions by using doxycycline led to energy crisis, oxidative stress, and damage as shown by the decreased levels of ATP and the elevated levels of mitochondrial superoxide, intracellular ROS, 8-OHdG, protein carbonylation, and lipid peroxidation. An antioxidant N-acetyl-L-cysteine (NAC) significantly abolished the anti proliferative and pro-apoptotic effects of doxycycline, demonstrating that doxycycline acts on glioblastoma via inducing oxidative stress. CONCLUSIONS In our study, we show that the antibiotic doxycycline is effective in targeting glioblastoma through inducing mitochondrial dysfunctions and oxidative stress. Our work also demonstrated the importance of mitochondrial metabolism in glioblastoma. PMID- 28842552 TI - Modifying electron transfer between photoredox and organocatalytic units via framework interpenetration for beta-carbonyl functionalization. AB - Modifying electron transfer pathways is essential to controlling the regioselectivity of heterogeneous photochemical transformations relevant to saturated carbonyls, due to fixed catalytic sites. Here we show that the interpenetration of metal-organic frameworks that contain both photoredox and asymmetric catalytic units can adjust the separations and electron transfer process between them. The enforced close proximity between two active sites via framework interpenetration accelerates the electron transfer between the oxidized photosensitizer and enamine intermediate, enabling the generation of 5pie- beta enaminyl radicals before the intermediates couple with other active species, achieving beta-functionalized carbonyl products. The enriched benzoate and iminium groups in the catalysts provide a suitable Lewis-acid/base environment to stabilize the active radicals, allowing the protocol described to advance the beta-functionalization of saturated cyclic ketones with aryl ketones to deliver gamma-hydroxyketone motifs. The homochiral environment of the pores within the recyclable frameworks provides additional spatial constraints to enhance the regioselectivity and enantioselectivity.Metal organic frameworks are promising catalysts due to their porous structure and the possible incorporation of multiple active sites. Here, the authors show that interpenetrated metal-organic frameworks containing both a photocatalyst and an organocatalyst catalyse the beta-alkylation of carbonyl compounds. PMID- 28842553 TI - Changing Epidemic of HIV and Syphilis Among Resident and Migrant Men Who Have Sex with Men in Jiangsu, China. AB - Men who have sex with men (MSM) in China face high rates of HIV and syphilis infection exacerbated by internal migration. Studies on the differences of HIV and syphilis epidemics changing trends in high-risk behaviors and geographic distribution between resident and migrant MSM in Jiangsu, China were conducted. MSM were recruited from 14 surveillance sites in the serial cross-sectional study. Data on demographics, sexual behaviors, HIV and syphilis prevalence were collected. Participants were classified as residents or migrants based on household registration. During 2010-2014, 19,750 MSM were investigated. Engaged in anal sex (76.3% to 80.2%, P < 0.01) as well as received HIV-related services (72.1% to 79.2%, P < 0.01) were increasing. In contrast, engaged in commercial anal sex with males (7.4% to 5.0%, P < 0.01) and drug use (1.6% to 0.8%, P < 0.01) were decreasing. HIV prevalence ranged between 8.6% to 9.6%, while syphilis prevalence decreased over time (13.4-6.8%, P < 0.01). Further, we found that migrant MSM were more likely to engage in condomless anal sex, also had a higher HIV and syphilis prevalence than resident. During the study period, while syphilis prevalence decreased, higher rates of risk behaviors among migrant MSM called for targeted intervention strategies to reduce the HIV transmission. PMID- 28842555 TI - Hierarchically self-assembled hexagonal honeycomb and kagome superlattices of binary 1D colloids. AB - Synthesis of binary nanoparticle superlattices has attracted attention for a broad spectrum of potential applications. However, this has remained challenging for one-dimensional nanoparticle systems. In this study, we investigate the packing behavior of one-dimensional nanoparticles of different diameters into a hexagonally packed cylindrical micellar system and demonstrate that binary one dimensional nanoparticle superlattices of two different symmetries can be obtained by tuning particle diameter and mixing ratios. The hexagonal arrays of one-dimensional nanoparticles are embedded in the honeycomb lattices (for AB2 type) or kagome lattices (for AB3 type) of micellar cylinders. The maximization of free volume entropy is considered as the main driving force for the formation of superlattices, which is well supported by our theoretical free energy calculations. Our approach provides a route for fabricating binary one dimensional nanoparticle superlattices and may be applicable for inorganic one dimensional nanoparticle systems.Binary mixtures of 1D particles are rarely observed to cooperatively self-assemble into binary superlattices, as the particle types separate into phases. Here, the authors design a system that avoids phase separation, obtaining binary superlattices with different symmetries by simply tuning the particle diameter and mixture composition. PMID- 28842554 TI - CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression. AB - Impairment of intrinsic plasticity is involved in a range of neurological disorders such as epilepsy. However, how intrinsic excitability is regulated is still not fully understood. Here we report that the epigenetic factor Chromodomain Y-like (CDYL) protein is a critical regulator of the initiation and maintenance of intrinsic neuroplasticity by regulating voltage-gated ion channels in mouse brains. CDYL binds to a regulatory element in the intron region of SCN8A and mainly recruits H3K27me3 activity for transcriptional repression of the gene. Knockdown of CDYL in hippocampal neurons results in augmented Nav1.6 currents, lower neuronal threshold, and increased seizure susceptibility, whereas transgenic mice over-expressing CDYL exhibit higher neuronal threshold and are less prone to epileptogenesis. Finally, examination of human brain tissues reveals decreased CDYL and increased SCN8A in the temporal lobe epilepsy group. Together, our findings indicate CDYL is a critical player for experience dependent gene regulation in controlling intrinsic excitability.Alterations in intrinsic plasticity are important in epilepsy. Here the authors show that the epigenetic factor CDYL regulates the gene expression of the voltage gated sodium channel, Nav1.6, which contributes to seizures in a rat model of epilepsy. PMID- 28842556 TI - Social support helps protect against perinatal bonding failure and depression among mothers: a prospective cohort study. AB - Causal relationships between perinatal bonding failure, depression, and social support among mothers remain unclear. A total of 494 women (mean age 32.4 +/- 4.5 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), and the Japanese version of the Social Support Questionnaire in early pregnancy before week 25 (T1) and 1 month after delivery (T2). Our model of recursive structured equation modeling (SEM) showed acceptable fit (CMIN/df = 2.2, CFI = 0.97, and RMSEA = 0.05). It was revealed that: (1) a lower number of supportive persons at T1 significantly predicted both MIBQ and EPDS scores at T1 and T2; (2) at T1, poorer satisfaction with the social support received significantly predicted EPDS scores; (3) both MIBQ and EPDS scores at T1 significantly predicted their respective scores at T2. Out cohort study indicates that the number of individuals who are available to provide social support and the degree of satisfaction with the level of social support received during pregnancy have a great influence on bonding failure and depression in the postpartum period. These findings suggest that psychosocial interventions that focus on these two aspects of social support during pregnancy are effective in preventing bonding failure and depression in the postpartum period. PMID- 28842557 TI - Functionalized Non-vascular Nitinol Stent via Electropolymerized Polydopamine Thin Film Coating Loaded with Bortezomib Adjunct to Hyperthermia Therapy. AB - Gastrointestinal malignancies have been a tremendous problem in the medical field and cover a wide variety of parts of the system, (i.e. esophagus, duodenum, intestines, and rectum). Usually, these malignancies are treated with palliation with the use of non-vascular nitinol stents. However, stenting is not a perfect solution for these problems. While it can enhance the quality of life of the patient, in time the device will encounter problems such as re-occlusion due to the rapid growth of the tumor. In this study, we propose a functionalization technique using electropolymerization of polydopamine directly onto the nitinol stent struts for the combined application of hyperthermia and chemotherapy. The coating was characterized using FESEM, XPS, and FT-IR. Drug release studies show that facile release of the anticancer drug BTZ from the surface of the polydopamine-coated stent could be achieved by the dissociation between catechol groups of polydopamine and the boronic acid functionality of BTZ in a pH dependent manner. The anti-cancer property was also evaluated, and cytotoxicity on ESO26 and SNU-5 cancer cell lines were observed. Our results suggest that the introduced approach can be considered as a potential method for therapeutic stent application. PMID- 28842559 TI - Tau plasma levels in subjective cognitive decline: Results from the DELCODE study. AB - Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Abeta42 (r = 0.073; p = 0.634), tau (r = -0.179; p = 0.240), and p tau181 (r = -0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids. PMID- 28842558 TI - HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells. AB - B lymphocyte-induced maturation protein-1 (Blimp-1) ensures B-cell differentiation into the plasma cell stage, and its instability constitutes a crucial oncogenic element in certain aggressive cases of activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL). However, the underlying degradation mechanisms and their possible therapeutic relevance remain unexplored. Here, we show that N-terminal misfolding mutations in ABC-DLBCL render Blimp-1 protein susceptible to proteasome-mediated degradation but spare its transcription regulating activity. Mechanistically, whereas wild-type Blimp-1 metabolism is triggered in the nucleus through PML-mediated sumoylation, the degradation of lymphoma-associated mutants is accelerated by subversion of this pathway to Hrd1 mediated cytoplasmic sequestration and ubiquitination. Screening experiments identifies the heat shock protein 70 (HSP70) that selects Blimp-1 mutants for Hrd1 association, and HSP70 inhibition restores their nuclear accumulation and oncorepressor activities without disrupting normal B-cell maturation. Therefore, HSP70-Hrd1 axis represents a potential therapeutic target for restoring the oncorepressor activity of unstable lymphoma-associated Blimp-1 mutants.The transcriptional repressor Blimp-1 has an important role in B-cell differentiation. Here the authors show that lymphoma-associated Blimp-1 mutants are selectively recognized by HSP70-Hrd1, which leads to their accelerated degradation and propose HSP70 inhibition as a therapeutic approach for certain lymphomas. PMID- 28842560 TI - Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui. AB - Cells harboring latent HIV-1 pose a major obstacle to eradication of the virus. The 'shock and kill' strategy has been broadly explored to purge the latent reservoir; however, none of the current latency-reversing agents (LRAs) can safely and effectively activate the latent virus in patients. In this study, we report an ingenol derivative called EK-16A, isolated from the traditional Chinese medicinal herb Euphorbia kansui, which displays great potential in reactivating latent HIV-1. A comparison of the doses used to measure the potency indicated EK 16A to be 200-fold more potent than prostratin in reactivating HIV-1 from latently infected cell lines. EK-16A also outperformed prostratin in ex vivo studies on cells from HIV-1-infected individuals, while maintaining minimal cytotoxicity effects on cell viability and T cell activation. Furthermore, EK-16A exhibited synergy with other LRAs in reactivating latent HIV-1. Mechanistic studies indicated EK-16A to be a PKCgamma activator, which promoted both HIV-1 transcription initiation by NF-kappaB and elongation by P-TEFb signal pathways. Further investigations aimed to add this compound to the therapeutic arsenal for HIV-1 eradication are in the pipeline. PMID- 28842562 TI - Release of free-volume bubbles by cooperative-rearrangement regions during the deposition growth of a colloidal glass. AB - Vapor deposition can directly produce ultrastable glasses which are similar to conventional glasses aged over thousands of years. The highly mobile surface layer is believed to accelerate the ageing process of vapor-deposited glasses, but its microscopic kinetics have not been experimentally observed. Here we study the deposition growth kinetics of a two-dimensional colloidal glass at the single particle level using video microscopy. We observe that newly deposited particles in the surface layer (depth, d < 14 particles) relax via out-of-cage diffusions of individual particles, while particles in the deeper middle layer (14 < d ? 100 particles) relax via activation of cooperative-rearrangement regions. These cooperative-rearrangement regions are much larger, more anisotropic and occur more frequently than cooperative-rearrangement regions in the bulk (d ? 100 particles) or after deposition. Cooperative-rearrangement regions move towards the surface and released free-volume bubbles at the surface, while the particles within cooperative-rearrangement regions move towards the bulk, resulting in a more compact bulk glass.Vapor deposition can produce ultrastable glasses similar to conventional glasses aged over thousands of years. Here authors study deposition growth kinetics of a two-dimensional colloidal glass and report relatively frequent occurrence of large and anisotropic regions of cooperative rearrangements at intermediate depths from the surface. PMID- 28842561 TI - Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme. AB - Although catalytic mechanisms in natural enzymes are well understood, achieving the diverse palette of reaction chemistries in re-engineered native proteins has proved challenging. Wholesale modification of natural enzymes is potentially compromised by their intrinsic complexity, which often obscures the underlying principles governing biocatalytic efficiency. The maquette approach can circumvent this complexity by combining a robust de novo designed chassis with a design process that avoids atomistic mimicry of natural proteins. Here, we apply this method to the construction of a highly efficient, promiscuous, and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H2O2. The maquette exhibits kinetics that match and even surpass those of certain natural peroxidases, retains its activity at elevated temperature and in the presence of organic solvents, and provides a simple platform for interrogating catalytic intermediates common to natural heme containing enzymes.Catalytic mechanisms of enzymes are well understood, but achieving diverse reaction chemistries in re-engineered proteins can be difficult. Here the authors show a highly efficient and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H2O2. PMID- 28842563 TI - The Role of Periostin in the Occurrence and Progression of Eosinophilic Chronic Sinusitis with Nasal Polyps. AB - Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with different host defence responses. However, whether periostin and vascular endothelial growth factor (VEGF) are similarly impaired in patients with eosinophilic CRSwNP (ENP) and those with non-eosinophilic CRSwNP (nENP) remains unclear. We sought to evaluate the expression and possible modulation of periostin and VEGF, regulated on activation normal T expressed and secreted (RANTES) and eotaxin-2 in the polyp tissues from 30 patients with ENP and from 36 patients with nENP and in middle turbinate tissues from 12 control subjects. We found that ENP tissues exhibited a significantly increased expression of periostin and VEGF compared with tissues from patients with nENP and control subjects (P < 0.05, respectively). Accordingly, the expression of VEGF, RANTES, and eotaxin-2 in ENP fibroblasts was significantly up-regulated after stimulation with up-regulated periostin in vitro, but the expression of VEGF and RANTES was significantly inhibited by stimulation with down-regulated periostin. Our findings suggest that periostin might play an important role in the occurrence and progression of ENP and might be a potential therapeutic target. PMID- 28842564 TI - A probabilistic assessment of the rapidity of PETM onset. AB - Knowledge of the onset duration of the Paleocene-Eocene Thermal Maximum-the largest known greenhouse-gas-driven global warming event of the Cenozoic-is central to drawing inferences for future climate change. Single-foraminifera measurements of the associated carbon isotope excursion from Maud Rise (South Atlantic Ocean) are controversial, as they seem to indicate geologically instantaneous carbon release and anomalously long ocean mixing. Here, we fundamentally reinterpret this record and extract the likely PETM onset duration. First, we employ an Earth system model to illustrate how the response of ocean circulation to warming does not support the interpretation of instantaneous carbon release. Instead, we use a novel sediment-mixing model to show how changes in the relative population sizes of calcareous plankton, combined with sediment mixing, can explain the observations. Furthermore, for any plausible PETM onset duration and sampling methodology, we place a probability on not sampling an intermediate, syn-excursion isotopic value. Assuming mixed-layer carbonate production continued at Maud Rise, we deduce the PETM onset was likely <5 kyr.Single-foraminifera measurements of the PETM carbon isotope excursion from Maud Rise have been interpreted as indicating geologically instantaneous carbon release. Here, the authors explain these records using an Earth system model and a sediment-mixing model and extract the likely PETM onset duration. PMID- 28842565 TI - No difference in plasticity between different ploidy levels in the Mediterranean herb Mercurialis annua. AB - Increased phenotypic plasticity for a number of plant traits has been suggested as a possible reason for the success and spread of polyploids. One such trait is a plant's sex allocation (or gender), which influences its reproductive success directly as a function of the potentially heterogeneous mating prospects in the population. However, it is unknown how polyploidy per se might affect plasticity in a plant's sex allocation. Although there have been numerous comparisons between diploid and (usually) tetraploid taxa, we know very little about how elevated ploidy above the diploid level might affect plasticity. Here, we ask whether different ploidy levels > 2x express different plasticity in the ruderal plant Mercurialis annua. We grew tetraploid and hexaploid hermaphrodites under different levels of nutrient availability and compared their reaction norms for growth (above-ground biomass, SLA) and reproductive traits (reproductive effort, phenotypic gender). Overall, we found that an increase in ploidy level from 4x to 6x in M. annua is associated with an increase in the relative biomass allocated to seeds, measured as female reproductive effort. However, our study provides no support for the idea that increasing ploidy level increases the ability to express different phenotypes in response to changes in the environment. PMID- 28842566 TI - Improved Self-cleaning Properties of an Efficient and Easy to Scale up TiO2 Thin Films Prepared by Adsorptive Self-Assembly. AB - Transparent titania coatings have self-cleaning and anti-reflection properties (AR) that are of great importance to minimize soiling effect on photovoltaic modules. In this work, TiO2 nanocolloids prepared by polyol reduction method were successfully used as coating thin films onto borosilicate glass substrates via adsorptive self-assembly process. The nanocolloids were characterized by transmission electron microscopy and x-ray diffraction. The average particle size was around 2.6 nm. The films which have an average thickness of 76.2 nm and refractive index of 1.51 showed distinctive anti soiling properties under desert environment. The film surface topography, uniformity, wettability, thickness and refractive index were characterized using x-ray diffraction, atomic force microscopy, scanning electron microscopy, water contact angle measurements and ellipsometry. The self-cleaning properties were investigated by optical microscopy and UV-Vis spectroscopy. The optical images show 56% reduction of dust deposition rate over the coated surfaces compared with bare glass substrates after 7 days of soiling. The transmission optical spectra of these films collected at normal incidence angle show high anti-reflection properties with the coated substrates having transmission loss of less than 6% compared to bare clean glass. PMID- 28842568 TI - Toroidal response in all-dielectric metamaterials based on water. AB - We experimentally demonstrate for the first time the toroidal dipolar response in metamaterials based on clusters of cylindrical dielectric particles in microwave frequency range. Instead of expensive ceramic elements we used distilled water with permittivity at room temperature is about 75, while the dielectric loss tangent is not large at frequencies up to 4 GHz. Moreover, we show all-dielectric metamaterial consisting of water box with hollow tubes which is more practical for future applications. Our findings also demonstrate that the proposed ideas can be applicable in optics with low-index dielectrics. PMID- 28842567 TI - Insular atrophy at the prodromal stage of dementia with Lewy bodies: a VBM DARTEL study. AB - Diffuse atrophy including the insula was previously demonstrated in dementia with Lewy bodies (DLB) patients but little is known about the prodromal stage of DLB (pro-DLB). In this prospective study, we used SPM8-DARTEL to measure gray matter (GM) and white matter (WM) atrophy in pro-DLB patients (n = 54), prodromal Alzheimer's disease (pro-AD) patients (n = 16), DLB patients at the stage of dementia (mild-DLB) (n = 15), and Alzheimer's disease patients at the stage of dementia (mild-AD) (n = 28), and compared them with healthy elderly controls (HC, n = 22). Diminished GM volumes were found in bilateral insula in pro-DLB patients, a trend to significance in right hippocampus and parahippocampal gyrus in pro-AD patients, in left insula in mild-DLB patients, and in medial temporal lobes and insula in mild-AD patients. The comparison between prodromal groups did not showed any differences. The comparison between groups with dementia revealed atrophy around the left middle temporal gyrus in mild-AD patients. Reduced WM volume was observed in mild-DLB in the pons. The insula seems to be a key region in DLB as early as the prodromal stage. MRI studies looking at perfusion, and functional and anatomical connectivity are now needed to better understand the role of this region in DLB. PMID- 28842569 TI - An aldo-keto reductase is responsible for Fusarium toxin-degrading activity in a soil Sphingomonas strain. AB - Degradation of toxins by microorganisms is a promising approach for detoxification of agricultural products. Here, a bacterial strain, Sphingomonas S3-4, that has the ability to degrade the mycotoxin deoxynivalenol (DON) was isolated from wheat fields. Incubation of Fusarium-infected wheat grains with S3 4 completely eliminated DON. In S3-4 DON is catabolized into compounds with no detectable phytotoxicity, 3-oxo-DON and 3-epi-DON, via two sequential reactions. Comparative analysis of genome sequences from two DON-degrading strains, S3-4 and Devosia D17, and one non-DON-degrading strain, Sphingobium S26, combined with functional screening of a S3-4 genomic BAC library led to the discovery that a novel aldo/keto reductase superfamily member, AKR18A1, is responsible for oxidation of DON into 3-oxo-DON. DON-degrading activity is completely abolished in a mutant S3-4 strain where the AKR18A1 gene is disrupted. Recombinant AKR18A1 protein expressed in Escherichia coli catalyzed the reversible oxidation/reduction of DON at a wide range of pH values (7.5 to 11) and temperatures (10 to 50 degrees C). The S3-4 strain and recombinant AKR18A1 also catabolized zearalenone and the aldehydes glyoxal and methyglyoxal. The S3-4 strain and the AKR18A1 gene are promising agents for the control of Fusarium pathogens and detoxification of mycotoxins in plants and in food/feed products. PMID- 28842571 TI - Ultra-large single crystals by abnormal grain growth. AB - Producing a single crystal is expensive because of low mass productivity. Therefore, many metallic materials are being used in polycrystalline form, even though material properties are superior in a single crystal. Here we show that an extraordinarily large Cu-Al-Mn single crystal can be obtained by abnormal grain growth (AGG) induced by simple heat treatment with high mass productivity. In AGG, the sub-boundary energy introduced by cyclic heat treatment (CHT) is dominant in the driving pressure, and the grain boundary migration rate is accelerated by repeating the low-temperature CHT due to the increase of the sub boundary energy. With such treatment, fabrication of single crystal bars 70 cm in length is achieved. This result ensures that the range of applications of shape memory alloys will spread beyond small-sized devices to large-scale components and may enable new applications of single crystals in other metallic and ceramics materials having similar microstructural features.Growing large single crystals cheaply and reliably for structural applications remains challenging. Here, the authors combine accelerated abnormal grain growth and cyclic heat treatments to grow a superelastic shape memory alloy single crystal to 70 cm. PMID- 28842570 TI - Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. AB - Stimulation of TNFR1 by TNFalpha can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFalpha-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFalpha leads to RIPK1-independent apoptosis when NF-kappaB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1 mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1 independent apoptosis and necroptosis.TNFalpha can promote three distinct mechanisms of cell death: necroptosis, RIPK1-independent and dependent apoptosis. Here the authors show that TNFalpha-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this decision. PMID- 28842572 TI - Conformal metasurface-coated dielectric waveguides for highly confined broadband optical activity with simultaneous low-visibility and reduced crosstalk. AB - The ability to achieve simultaneous control over the various electromagnetic properties of dielectric waveguides, including mode confinement, polarization, scattering signature, and crosstalk, which are critical to system miniaturization, diversity in functionality, and non-invasive integration, has been a highly sought after yet elusive goal. Currently existing methods, which rely on three-dimensional artificial cores or claddings and/or structural chirality, provide efficient paths for obtaining either highly confined modes, optical activity, or a low-scattering signature, but at the expense of increased propagation loss, form factor and weight. Here, by tailoring the unique anisotropy and exploiting the inter-cell coupling of metasurface coatings, we report a unified approach for simultaneously controlling the diverse optical properties of dielectric waveguides. The experimentally demonstrated highly confined sub-wavelength dielectric waveguide with a low-visibility and broadband optical activity represents a transformative wave manipulation capability with far reaching implications, offering new pathways for future miniaturization of dielectric waveguide-based systems with simultaneous polarization and scattering control.Controlling all the optical properties of dielectric waveguides is a challenging task and often requires complicated core- and cladding designs. Here, Jiang et al. demonstrate that a thin metasurface coating can control several optical properties simultaneously over a broad frequency range. PMID- 28842573 TI - Giant magnetoresistance in lateral metallic nanostructures for spintronic applications. AB - In this letter, we discuss the shift observed in spintronics from the current perpendicular-to-plane geometry towards lateral geometries, illustrating the new opportunities offered by this configuration. Using CoFe-based all-metallic LSVs, we show that giant magnetoresistance variations of more than 10% can be obtained, competitive with the current-perpendicular-to-plane giant magnetoresistance. We then focus on the interest of being able to tailor freely the geometries. On the one hand, by tailoring the non-magnetic parts, we show that it is possible to enhance the spin signal of giant magnetoresistance structures. On the other hand, we show that tailoring the geometry of lateral structures allows creating a multilevel memory with high spin signals, by controlling the coercivity and shape anisotropy of the magnetic parts. Furthermore, we study a new device in which the magnetization direction of a nanodisk can be detected. We thus show that the ability to control the magnetic properties can be used to take advantage of all the spin degrees of freedom, which are usually occulted in current-perpendicular to-plane devices. This flexibility of lateral structures relatively to current perpendicular-to-plane structures is thus found to offer a new playground for the development of spintronic applications. PMID- 28842574 TI - Using the New CellCollector to Capture Circulating Tumor Cells from Blood in Different Groups of Pulmonary Disease: A Cohort Study. AB - Circulating tumor cells (CTCs) are promising biomarkers for clinical application. Cancer screening with Low-Dose Computed Tomography (LDCT) and CTC detections in pulmonary nodule patients has never been reported. The aim of this study was to explore the effectiveness of the combined methods to screen lung cancer. Out of 8313 volunteers screened by LDCT, 32 ground-glass nodules (GGNs) patients and 19 healthy volunteers were randomly selected. Meanwhile, 15 lung cancer patients also enrolled. CellCollector, a new CTC capturing device, was applied for CTCs detection. In GGNs group, five CTC positive patients with six CTCs were identified, 15.6% were positive (range, 1-2). In lung cancer group, 73.3% of the analyzed CellCollector cells were positive (range, 1-7) and no "CTC-like" events were detected in healthy group. All CTCs detected from GGNs group were isolated from the CellCollector functional domain and determined by whole genomic amplification for next-generation sequencing(NGS) analysis. NGS data showed that three cancer-related genes contained mutations in five CTC positive patients, including KIT, SMARCB1 and TP53 genes. In four patients, 16 mutation genes existed. Therefore, LDCT combined with CTC analysis by an in vivo device in high risk pulmonary nodule patients was a promising way to screen early stage lung cancer. PMID- 28842575 TI - Treatment patterns, efficacy and toxicity of regorafenib in gastrointestinal stromal tumour patients. AB - Regorafenib was approved as third-line therapy for advanced Gastrointestinal Stromal Tumour (GIST) at a starting dose of 160 mg daily 3 weeks on, 1 week off, based on improvement in progression free survival over placebo (4.8 vs. 0.9 months), but the response rate was low at 4.5%. Given the high toxicity rate in GIST patients, there is variability in the post-marketing dosing of regorafenib. We aimed to summarize our experience regarding prescribing patterns, efficacy and toxicity of regorafenib and determine the role of response assessment by Choi criteria in GIST patients. We included 28 patients who received regorafenib from our pharmacy. Baseline patient characteristics and treatment outcomes were recorded and an independent radiologist assessed response using Choi and RECIST. Seventy-nine percent of patients started at a 120 mg continuous daily dosing schedule, different from the standard intermittent dosing schedule. Grade 3/4 adverse events were experienced by 43% of patients. Median progression-free survival was 8.7 months. Continuous dosing with regorafenib at 120 mg daily is the preferred prescribing pattern and appears to be better tolerated and with comparable efficacy to the current standard dose. Similar to imatinib, the partial response rate for regorafenib by Choi (29%) was higher compared to RECIST (4%). PMID- 28842576 TI - Methods for estimating disease transmission rates: Evaluating the precision of Poisson regression and two novel methods. AB - Precise estimates of disease transmission rates are critical for epidemiological simulation models. Most often these rates must be estimated from longitudinal field data, which are costly and time-consuming to conduct. Consequently, measures to reduce cost like increased sampling intervals or subsampling of the population are implemented. To assess the impact of such measures we implement two different SIS models to simulate disease transmission: A simple closed population model and a realistic dairy herd including population dynamics. We analyze the accuracy of different methods for estimating the transmission rate. We use data from the two simulation models and vary the sampling intervals and the size of the population sampled. We devise two new methods to determine transmission rate, and compare these to the frequently used Poisson regression method in both epidemic and endemic situations. For most tested scenarios these new methods perform similar or better than Poisson regression, especially in the case of long sampling intervals. We conclude that transmission rate estimates are easily biased, which is important to take into account when using these rates in simulation models. PMID- 28842577 TI - Tumor-selective catalytic nanomedicine by nanocatalyst delivery. AB - Tumor cells metabolize in distinct pathways compared with most normal tissue cells. The resulting tumor microenvironment would provide characteristic physiochemical conditions for selective tumor modalities. Here we introduce a concept of sequential catalytic nanomedicine for efficient tumor therapy by designing and delivering biocompatible nanocatalysts into tumor sites. Natural glucose oxidase (GOD, enzyme catalyst) and ultrasmall Fe3O4 nanoparticles (inorganic nanozyme, Fenton reaction catalyst) have been integrated into the large pore-sized and biodegradable dendritic silica nanoparticles to fabricate the sequential nanocatalyst. GOD in sequential nanocatalyst could effectively deplete glucose in tumor cells, and meanwhile produce a considerable amount of H2O2 for subsequent Fenton-like reaction catalyzed by Fe3O4 nanoparticles in response to mild acidic tumor microenvironment. Highly toxic hydroxyl radicals are generated through these sequential catalytic reactions to trigger the apoptosis and death of tumor cells. The current work manifests a proof of concept of catalytic nanomedicine by approaching selectivity and efficiency concurrently for tumor therapeutics.The specific metabolism of cancer cells may allow for selective tumor therapeutics. Here, the authors show that a suitable combination of an enzyme and iron nanoparticles loaded on dendritic silica induces apoptosis of cancer cells in response to the glucose-reliant and mild acidic microenvironment. PMID- 28842578 TI - Three-dimensional Graphene with MoS 2 Nanohybrid as Potential Energy Storage/Transfer Device. AB - Portable and matured energy storage devices are in high demand for future flexible electronics. Flowery shaped MoS2 nanostructures with porous and flake like morphology was used to study the supercapacitive nature with specific capacitance (C sp ) of 169.37F/g, the energy density of 28.43 Wh/Kg and power density of 10.18 W/Kg. This nanoflower like architecture was decorated on 3D graphene on Graphite electrode to design the solid-state-supercapacitor prototype device of dimensions of 23.6 * 22.4 * 0.6 mm3 having considerable high Csp of 58.0F/g and energy density of 24.59 Wh/Kg, and power density of 8.8 W/Kg. Four fabricated supercapacitors were connected in series for real state practical demonstration using the light emitting diode that remains enlightened for 40 s by charging it only for 25 s. This study demonstrates the 3D-graphene/MoS2 nanohybrid has a quite high overall potential window nearly about 2.7 V (-1.5 to +1.2 V) in KOH-PVA medium which can be used for the development of solid-state supercapacitors thereby completely eliminating the need for any expensive ionic liquid mediums thus building an exciting potential for high-performance energy storage/transfer devices. PMID- 28842579 TI - Phase Behavior and Thermodynamic Model Parameters in Simulations of Extractive Distillation for Azeotrope Separation. AB - Extractive distillation (ED) processes for separating ternary mixtures of benzene cyclohexane-toluene with dimethyl formamide (DMF) and N-methyl-2-pyrrolidone (NMP) were studied using Aspen Plus and PRO/II simulators. The Aspen Plus built in binary interaction parameters for the toluene-DMF, benzene-NMP and cyclohexane NMP systems resulted in inaccurate phase behavior calculations. The vapor-liquid equilibrium (VLE) for the three binary systems was regressed to illustrate the importance of using accurate model parameters. The obtained binary interaction parameters described the phase behavior more accurately compared with the built in binary interaction parameters in Aspen Plus. In this study, the effects of the regressed and built-in binary interaction parameters on the ED process design are presented. The total annual cost (TAC) was calculated to further illustrate the importance of the regressed binary interaction parameters. The results show that phase behavior and thermodynamic model parameters should receive more attention during the research and development of ED processes. PMID- 28842580 TI - Dimerization in tailoring uptake efficacy of the HSV-1 derived membranotropic peptide gH625. AB - gH625 constitutes a promising delivery vehicle for the transport of therapeutic biomacromolecules across membrane barriers. We report an application of multivalency to create a complex nanosystem for delivery and to elucidate the mechanism of peptide-lipid bilayer interactions. Multivalency may offer a route to enhance gH625 cellular uptake as demonstrated by results obtained on dimers of gH625 by fluorescence spectroscopy, circular dichroism, and surface plasmon resonance. Moreover, using both phase contrast and light sheet fluorescence microscopy we were able to characterize and visualize for the first time the fusion of giant unilamellar vesicles caused by a membranotropic peptide. PMID- 28842581 TI - A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol. AB - Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34 PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25 ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10 mg, 10 mg and 20 mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was >72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was -0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored. PMID- 28842582 TI - Detecting Photosymbiosis in Fossil Scleractinian Corals. AB - The evolutionary success of reef-building corals is often attributed to photosymbiosis, a mutualistic relationship scleractinian corals developed with zooxanthellae; however, because zooxanthellae are not fossilized, it is difficult (and contentious) to determine whether ancient corals harbored symbionts. In this study, we analyze the delta15N of skeletal organic matrix in a suite of modern and fossil scleractinian corals (zooxanthellate- and azooxanthellate-like) with varying levels of diagenetic alteration. Significantly, we report the first analyses that distinguish shallow-water zooxanthellate and deep-water azooxanthellate fossil corals. Early Miocene (18-20 Ma) corals exhibit the same nitrogen isotopic ratio offset identified in modern corals. These results suggest that the coral organic matrix delta15N proxy can successfully be used to detect photosymbiosis in the fossil record. This proxy will significantly improve our ability to effectively define the evolutionary relationship between photosymbiosis and reef-building through space and time. For example, Late Triassic corals have symbiotic values, which tie photosymbiosis to major coral reef expansion. Furthermore, the early Miocene corals from Indonesia have low delta15N values relative to modern corals, implying that the west Pacific was a nutrient-depleted environment and that oligotrophy may have facilitated the diversification of the reef builders in the Coral Triangle. PMID- 28842583 TI - Responses of renal hemodynamics and tubular functions to acute sodium-glucose cotransporter 2 inhibitor administration in non-diabetic anesthetized rats. AB - The aim of this study is to examine the effects of acute administration of luseogliflozin, the sodium-glucose cotransporter 2 (SGLT2) inhibitor, on renal hemodynamics and tubular functions in anesthetized non-diabetic Sprague Dawley (SD) rats and 5/6 nephrectomized (Nx) SD rats. Renal blood flow (RBF), mean arterial pressure (MAP), and heart rate (HR) were continuously measured and urine was collected directly from the left ureter. Intraperitoneal injection of luseogliflozin (0.9 mg kg-1) did not change MAP, HR, RBF, or creatinine clearance (CrCl) in SD rats (n = 7). Luseogliflozin significantly increased urine volume, which was associated with significantly increased urinary glucose excretion rates (P < 0.001). Similarly, luseogliflozin significantly increased urinary sodium excretion (from 0.07 +/- 0.01 umol min-1 at baseline to 0.76 +/- 0.08 umol min-1 at 120 min; P < 0.001). Furthermore, luseogliflozin resulted in significantly increased urinary pH (P < 0.001) and decreased urinary osmolality and urea concentration (P < 0.001) in SD rats. Similarly, in Nx SD rats (n = 5-6), luseogliflozin significantly increased urine volume and urinary glucose excretion (P < 0.001) without altering MAP, HR, RBF, or CrCl. Luseogliflozin did not elicit any significant effects on the other urinary parameters in Nx SD rats. These data indicate that SGLT2 inhibitor elicits direct tubular effects in non-diabetic rats with normal renal functions. PMID- 28842584 TI - Probing charge transfer between molecular semiconductors and graphene. AB - The unique density of states and exceptionally low electrical noise allow graphene-based field effect devices to be utilized as extremely sensitive potentiometers for probing charge transfer with adsorbed species. On the other hand, molecular level alignment at the interface with electrodes can strongly influence the performance of organic-based devices. For this reason, interfacial band engineering is crucial for potential applications of graphene/organic semiconductor heterostructures. Here, we demonstrate charge transfer between graphene and two molecular semiconductors, parahexaphenyl and buckminsterfullerene C60. Through in-situ measurements, we directly probe the charge transfer as the interfacial dipoles are formed. It is found that the adsorbed molecules do not affect electron scattering rates in graphene, indicating that charge transfer is the main mechanism governing the level alignment. From the amount of transferred charge and the molecular coverage of the grown films, the amount of charge transferred per adsorbed molecule is estimated, indicating very weak interaction. PMID- 28842585 TI - Dynamics of resilience of wheat to drought in Australia from 1991-2010. AB - Although enhancing resilience is a well-recognized adaptation to climate change, little research has been undertaken on the dynamics of resilience. This occurs because complex relationships exist between adaptive capacity and resilience, and some issues also create challenges related to the construction, operation, and application of resilience. This study identified the dynamics of temporal, spatial changes of resilience found in a sample of wheat-drought resilience in Australia's wheat-sheep production zone during 1991-2010. I estimated resilience using principal component analysis, mapped resilience and its components, distinguished resilient and sensitive regions, and provided recommendations related to improving resilience. I frame that resilience is composed of social resilience including on- and off-site adaptive capacity as well as biophysical resilience including resistance and absorption. I found that resilience and its components have different temporal trends, spatial shifts and growth ratios in each region during different years, which results from complicated interactions, such as complementation and substitution among its components. In wheat-sheep zones, I recommend that identifying regional bottlenecks, science-policy engagement, and managing resilience components are the priorities for improving resilience. PMID- 28842586 TI - Spatially resolved investigation of all optical magnetization switching in TbFe alloys. AB - Optical control of magnetization using femtosecond laser without applying any external magnetic field offers the advantage of switching magnetic states at ultrashort time scales. Recently, all-optical helicity-dependent switching (AO HDS) has drawn a significant attention for potential information and data storage device applications. In this work, we employ element and magnetization sensitive photoemission electron microscopy (PEEM) to investigate the role of heating in AO HDS for thin films of the rare-earth transition-metal alloy TbFe. Spatially resolved measurements in a 3-5 MUm sized stationary laser spot demonstrate that AO-HDS is a local phenomenon in the vicinity of thermal demagnetization in a 'ring' shaped region. The efficiency of AO-HDS further depends on a local temperature profile around the demagnetized region and thermally activated domain wall motion. We also demonstrate that the thickness of the film determines the preferential switching direction for a particular helicity. PMID- 28842587 TI - Methylseleninic Acid Provided at Nutritional Selenium Levels Inhibits Angiogenesis by Down-regulating Integrin beta3 Signaling. AB - Targeting angiogenesis has emerged as a promising strategy for cancer treatment. Methylseleninic acid (MSA) is a metabolite of selenium (Se) in animal cells that exhibits anti-oxidative and anti-cancer activities at levels exceeding Se nutritional requirements. However, it remains unclear whether MSA exerts its effects on cancer prevention by influencing angiogenesis within Se nutritional levels. Herein, we demonstrate that MSA inhibited angiogenesis at 2 uM, which falls in the range of moderate Se nutritional status. We found that MSA treatments at 2 uM increased cell adherence, while inhibiting cell migration and tube formation of HUVECs in vitro. Moreover, MSA effectively inhibited the sprouts of mouse aortic rings and neoangiogenesis in chick embryo chorioallantoic membrane. We also found that MSA down-regulated integrin beta3 at the levels of mRNA and protein, and disrupted clustering of integrin beta3 on the cell surface. Additionally, results showed that MSA inhibited the phosphorylation of AKT, IkappaBalpha, and NFkappaB. Overall, our results suggest that exogenous MSA inhibited angiogenesis at nutritional Se levels not only by down-regulating the expression of integrin beta3 but also by disorganizing the clustering of integrin beta3, which further inhibited the phosphorylation involving AKT, IkappaBalpha, NFkappaB. These findings provide novel mechanistic insight into the function of MSA for regulating angiogenesis and suggest that MSA could be a potential candidate or adjuvant for anti-tumor therapy in clinical settings. PMID- 28842588 TI - Cancer-targeted Nucleic Acid Delivery and Quantum Dot Imaging Using EGF Receptor Aptamer-conjugated Lipid Nanoparticles. AB - Co-application of fluorescent quantum dot nanocrystals and therapeutics has recently become a promising theranostic methodology for cancer treatment. We developed a tumor-targeted lipid nanocarrier that demonstrates notable efficacy in gene delivery as well as tumor bio-imaging. Coupling of aptamer molecules against the EGF receptor (EGFR) to the distal termini of lipid nanoparticles provided the carrier with tumor-specific recognition capability. The cationic lipid component, referred to as O,O'-dimyristyl-N-lysyl glutamate (DMKE), was able to effectively complex with anionic small-interfering RNA (siRNA). The hydrophobic quantum dots (Q-dots) were effectively incorporated in hydrophobic lipid bilayers at an appropriate Q-dot to lipid ratio. In this study, we optimized the liposomal formula of aptamer-conjugated liposomes containing Q-dots and siRNA molecules (Apt-QLs). The anti-EGFR Apt-QLs exhibited remarkable EGFR dependent siRNA delivery as well as fluorescence imaging, which were analyzed in cultured cancer cells and tumor xenografts in mice. These results imply that the formulation of Apt-QLs could be widely utilized as a carrier for tumor-directed gene delivery and bio-imaging. PMID- 28842589 TI - Effects of scale of movement, detection probability, and true population density on common methods of estimating population density. AB - Knowledge of population density is necessary for effective management and conservation of wildlife, yet rarely are estimators compared in their robustness to effects of ecological and observational processes, which can greatly influence accuracy and precision of density estimates. In this study, we simulate biological and observational processes using empirical data to assess effects of animal scale of movement, true population density, and probability of detection on common density estimators. We also apply common data collection and analytical techniques in the field and evaluate their ability to estimate density of a globally widespread species. We find that animal scale of movement had the greatest impact on accuracy of estimators, although all estimators suffered reduced performance when detection probability was low, and we provide recommendations as to when each field and analytical technique is most appropriately employed. The large influence of scale of movement on estimator accuracy emphasizes the importance of effective post-hoc calculation of area sampled or use of methods that implicitly account for spatial variation. In particular, scale of movement impacted estimators substantially, such that area covered and spacing of detectors (e.g. cameras, traps, etc.) must reflect movement characteristics of the focal species to reduce bias in estimates of movement and thus density. PMID- 28842590 TI - DDX3 localizes to the centrosome and prevents multipolar mitosis by epigenetically and translationally modulating p53 expression. AB - The DEAD-box RNA helicase DDX3 plays divergent roles in tumorigenesis, however, its function in mitosis is unclear. Immunofluorescence indicated that DDX3 localized to centrosome throughout the cell cycle and colocalized with centrosome associated p53 during mitosis in HCT116 and U2OS cells. DDX3 depletion promoted chromosome misalignment, segregation defects and multipolar mitosis, eventually leading to G2/M delay and cell death. DDX3 prevented multipolar mitosis by inactivation and coalescence of supernumerary centrosomes. DDX3 silencing suppressed Ser15 phosphorylation of p53 which is required for p53 centrosomal localization. Additionally, knockout of p53 dramatically diminished the association of DDX3 with centrosome, which was rescued by overexpression of the centrosomal targeting-defective p53 S15A mutant, indicating that centrosomal localization of DDX3 is p53 dependent but not through centrosomal location of p53. Furthermore, DDX3 knockdown suppressed p53 transcription through activation of DNA methyltransferases (DNMTs) along with hypermethylation of p53 promoter and promoting the binding of repressive histone marks to p53 promoter. Moreover, DDX3 modulated p53 mRNA translation. Taken together, our study suggests that DDX3 regulates epigenetic transcriptional and translational activation of p53 and colocalizes with p53 at centrosome during mitosis to ensure proper mitotic progression and genome stability, which supports the tumor-suppressive role of DDX3. PMID- 28842591 TI - NogoA Neutralization Promotes Axonal Restoration After White Matter Injury In Subcortical Stroke. AB - Blocking axonal growth inhibitor NogoA has been of great interest for promoting axonal recovery from neurological diseases. The present study investigates the therapeutic effects of blocking NogoA, inducing functional recovery and promoting white matter repair in an experimental animal model of stroke. Adult male rats were subjected to white matter injury by subcortical ischemic stroke. Twenty-four hours after surgery, 250 ug of anti-NogoA or anti-IgG-1 were administered through the tail vein. The quantity of NogoA protein was determined by immunohistochemistry in the brain and peripheral organs. In addition, functional status, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers were analyzed. Moreover, an in vitro study was performed in order to strengthen the results obtained in vivo. A lower quantity of NogoA protein was found in the brain and peripheral organs of the animals that received anti-NogoA treatment. The animals receiving anti-NogoA treatment showed significantly better results in terms of functional recovery, fiber tract integrity, axonal sprouting and white matter repair markers compared with the control group at 28 days. White matter integrity was in part restored by antibody-mediated inhibition of NogoA administration in those animals that were subjected to an axonal injury by subcortical stroke. This white matter restoration triggered functional recovery. PMID- 28842592 TI - Neglected role of hydrogen sulfide in sulfur mustard poisoning: Keap1 S sulfhydration and subsequent Nrf2 pathway activation. AB - Sulfur mustard (SM) is a chemical warfare agent and a terrorism choice that targets various organs and tissues, especially lung tissues. Its toxic effects are tightly associated with oxidative stress. The signaling molecule hydrogen sulfide (H2S) protects the lungs against oxidative stress and activates the NF-E2 p45-related factor 2 (Nrf2) pathway. Here, we sought to establish whether endogenous H2S plays a role in SM induced lesion in mouse lungs and lung cells and whether endogenous H2S plays the role through Nrf2 pathway to protect against SM-induced oxidative damage. Furthermore, we also explored whether activation of Nrf2 by H2S involves sulfhydration of Kelch-like ECH-associated protein-1 (Keap1). Using a mouse model of SM-induced lung injury, we demonstrated that SM induced attenuation of the sulfide concentration was prevented by NaHS. Concomitantly, NaHS attenuates SM-induced oxidative stress. We also found that H2S enhanced Nrf2 nuclear translocation, and stimulated expression of Nrf2 targeted downstream protein and mRNA levels. Incubation of the lung cells with NaHS decreased SM-induced ROS production. Furthermore, we also found that H2S S sulfhydrated Keap1, which induced Nrf2 dissociation from Keap1, and enhanced Nrf2 nuclear translocation. Our data indicate that H2S is a critical, however, being long neglected signal molecule in SM-induced lung injury. PMID- 28842593 TI - Bacterial Community Structure in the Asian Rice Gall Midge Reveals a Varied Microbiome Rich in Proteobacteria. AB - The Asian rice gall midge (ARGM) has emerged as a model gall forming pest of rice. The ARGM infestation of rice results in failure of panicle formation and economic loss. Understanding the molecular basis of ARGM-rice interactions is very crucial in order to control this devastating pest of rice. The current investigation was devised to identify bacterial communities present in the ARGM and in addition the bacterial diversity in the maggots during their interaction with susceptible or resistant rice varieties. Sequencing of 16S rRNA bacterial gene (V3-V4 region) revealed differences in the microflora of the ARGM maggots feeding on susceptible or resistant rice hosts. Results revealed that Wolbachia was the predominant bacterium in pupae and adults while Pseudomonas was predominant in maggots. Further, we observed that members of proteobacteria were predominant across all the samples. There was high species diversity in maggots isolated from susceptible rice and a high representation of unclassified bacteria in maggots isolated from resistant rice. This is the first study that reports variation of microbiome of the ARGM, based on host phenotype from which it was isolated, and results suggest that these variations could have an important role in host's susceptibility. PMID- 28842594 TI - Serum fibronectin distinguishes the early stages of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, necessitating the discovery of serum markers for its early detection. In this study, a total of 180 serum samples from liver cirrhosis (LC), hepatocellular carcinoma (HCC) patients and paired samples of HCC patients who recovered (Recovery) were analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) to verify biomarkers. The three-fold crossvalidation was repeated 100 times in the training and test sets to evaluate statistical significance of 124 candidate proteins. This step resulted in 2 proteins that had an area under the receiver operating curve (AUROC) values >=0.800 in the training (n = 90) and test sets (n = 90). Specifically, fibronectin (FN1, WCGTTQNYDADQK), distinguished HCC from LC patients, with an AUROC value of 0.926 by logistic regression. A FN1 protein was selected for validation in an independent sample (n = 60) using enzyme-linked immunosorbent assay (ELISA). The combination of alpha fetoprotein (AFP) and FN1 improved the diagnostic performance and differentiated HCC patients with normal AFP levels. Our study has examined candidate markers for the benign disease state and malignancy and has followed up on the consequent recovery. Thus, improvement in the early detection of HCC by a 2-marker panel (AFP + FN1) might benefit HCC patients. PMID- 28842595 TI - Regulation of HGF-induced hepatocyte proliferation by the small GTPase Arf6 through the PIP2-producing enzyme PIP5K1A. AB - HGF and its receptor c-Met are critical molecules in various biological processes. Others and we have previously shown that the small GTPase Arf6 plays a pivotal role in HGF signaling in hepatocytes. However, the molecular mechanism of how Arf6 regulates HGF signaling is unclear. Here, we show that Arf6 plays an important role in HGF-stimulated hepatocyte proliferation and liver regeneration through the phosphatidylinositol 4,5-bisphosphate (PIP2)-producing enzyme PIP5K1A. We find that knockdown of Arf6 and PIP5K1A in HepG2 cells inhibits HGF stimulated proliferation, Akt activation, and generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and its precursor PIP2. Interestingly, PIP5K1A is recruited to c-Met upon HGF stimulation in an Arf6 activity-dependent manner. Finally, we show that hepatocyte proliferation and liver regeneration after partial hepatectomy are suppressed in Pip5k1a knockout mice. These results provide insight into the molecular mechanism for HGF-stimulated hepatocyte proliferation and liver regeneration: Arf6 recruits PIP5K1A to c-Met and activates it upon HGF stimulation to produce PIP2 and subsequently PIP3, which in turn activates Akt to promote hepatocyte proliferation, thereby accelerating liver regeneration after liver injury. PMID- 28842596 TI - Rational identification of aggregation hotspots based on secondary structure and amino acid hydrophobicity. AB - Insolubility of proteins expressed in the Escherichia coli expression system hinders the progress of both basic and applied research. Insoluble proteins contain residues that decrease their solubility (aggregation hotspots). Mutating these hotspots to optimal amino acids is expected to improve protein solubility. To date, however, the identification of these hotspots has proven difficult. In this study, using a combination of approaches involving directed evolution and primary sequence analysis, we found two rules to help inductively identify hotspots: the alpha-helix rule, which focuses on the hydrophobicity of amino acids in the alpha-helix structure, and the hydropathy contradiction rule, which focuses on the difference in hydrophobicity relative to the corresponding amino acid in the consensus protein. By properly applying these two rules, we succeeded in improving the probability that expressed proteins would be soluble. Our methods should facilitate research on various insoluble proteins that were previously difficult to study due to their low solubility. PMID- 28842597 TI - Intrinsic brain connectivity after partial sleep deprivation in young and older adults: results from the Stockholm Sleepy Brain study. AB - Sleep deprivation has been reported to affect intrinsic brain connectivity, notably reducing connectivity in the default mode network. Studies to date have however shown inconsistent effects, in many cases lacked monitoring of wakefulness, and largely included young participants. We investigated effects of sleep deprivation on intrinsic brain connectivity in young and older participants. Participants aged 20-30 (final n = 30) and 65-75 (final n = 23) years underwent partial sleep deprivation (3 h sleep) in a cross-over design, with two 8-minutes eyes-open resting state functional magnetic resonance imaging (fMRI) runs in each session, monitored by eye-tracking. We assessed intrinsic brain connectivity using independent components analysis (ICA) as well as seed region analyses of functional connectivity, and also analysed global signal variability, regional homogeneity, and the amplitude of low-frequency fluctuations. Sleep deprivation caused increased global signal variability. Changes in investigated resting state networks and in regional homogeneity were not statistically significant. Younger participants had higher connectivity in most examined networks, as well as higher regional homogeneity in areas including anterior and posterior cingulate cortex. In conclusion, we found that sleep deprivation caused increased global signal variability, and we speculate that this may be caused by wake-state instability. PMID- 28842598 TI - Perfused Three-dimensional Organotypic Culture of Human Cancer Cells for Therapeutic Evaluation. AB - Pharmaceutical research requires pre-clinical testing of new therapeutics using both in-vitro and in-vivo models. However, the species specificity of non-human in-vivo models and the inadequate recapitulation of physiological conditions in vitro are intrinsic weaknesses. Here we show that perfusion is a vital factor for engineered human tissues to recapitulate key aspects of the tumour microenvironment. Organotypic culture and human tumour explants were allowed to grow long-term (14-35 days) and phenotypic features of perfused microtumours compared with those in the static culture. Differentiation status and therapeutic responses were significantly different under perfusion, indicating a distinct biological response of cultures grown under static conditions. Furthermore, heterogeneous co-culture of tumour and endothelial cells demonstrated selective cell-killing under therapeutic perfusion versus episodic delivery. We present a perfused 3D microtumour culture platform that sustains a more physiological tissue state and increased viability for long-term analyses. This system has the potential to tackle the disadvantages inherit of conventional pharmaceutical models and is suitable for precision medicine screening of tumour explants, particularly in hard-to-treat cancer types such as brain cancer which suffer from a lack of clinical samples. PMID- 28842599 TI - Overexpression of miR-210 and its significance in ischemic tissue damage. AB - Hypoxia-induced miR-210 displays a pro-survival, cytoprotective and pro angiogenic role in several in vitro systems. In vivo, we previously found that miR-210 inhibition increases ischemic damage. Here we describe the generation of a versatile transgenic mouse model allowing the evaluation of miR-210 therapeutic potential in ischemic cardiovascular diseases. We generated a Tet-On miR-210 transgenic mouse strain (TG-210) by targeted transgenesis in the ROSA26 locus. To functionally validate miR-210 transgenic mice, hindlimb ischemia was induced by femoral artery dissection. Blood perfusion was evaluated by power Doppler while tissue damage and inflammation were assessed by histological evaluation. We found that miR-210 levels were rapidly increased in TG-210 mice upon doxycycline administration. miR-210 overexpression was maintained over time and remained within physiological levels in multiple tissues. When hindlimb ischemia was induced, miR-210 overexpression protected from both muscular and vascular ischemic damage, decreased inflammatory cells density and allowed to maintain a better calf perfusion. In conclusion, we generated and functionally validated a miR-210 transgenic mouse model. Albeit validated in the context of a specific cardiovascular ischemic disease, miR-210 transgenic mice may also represent a useful model to assess the function of miR-210 in other physio-pathological conditions. PMID- 28842600 TI - Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface. AB - Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential alpha- and beta-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the alpha- and beta-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets. PMID- 28842601 TI - A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNgamma. AB - Macrophage polarization plays an important role in tissue damage and repair. In this study, we show that Substance-P (SP) can directly induce M2 polarization of inflammatory macrophages. SP induced the differentiation of GM-CSF-differentiated pro-inflammatory macrophages into alternatively activated phagocytic M2 like macrophages (M2SP) through direct activation of the PI3K/Akt/mTOR/S6kinase pathway and induction of Arginase-1, CD163, and CD206, all of which were nullified by pretreatment with the neurokinin-1 receptor (NK-1R) antagonist RP67580 and specific signaling pathway inhibitors. M2SP were distinct from IL 4/IL-13-induced M2a and IL-10-induced M2c subtypes; they did not show STAT activation and exhibited high phagocytic and endothelial adhesive activity. Furthermore, SP had a dominant effect on M2 polarization over Interferon gamma (IFNgamma), a potent M1-skewing cytokine, and effectively induced the M2 phenotype in monocytes and the human THP-1 cell line. Finally, adoptively transferred M2SP migrated to a spinal cord injury (SCI) lesion site and improved functional recovery. Collectively, our findings show that SP, a neuropeptide, plays a role as a novel cytokine by inducing tissue-repairing M2SP macrophages and thus may be developed for pharmacological intervention in diseases involving chronic inflammation and acute injury. PMID- 28842602 TI - Solvent Assisted Tuning of Morphology of a Peptide-Perylenediimide Conjugate: Helical Fibers to Nano-Rings and their Differential Semiconductivity. AB - Understanding the regulatory factors of self-assembly processes is a necessity in order to modulate the nano-structures and their properties. Here, the self assembly mechanism of a peptide-perylenediimide (P-1) conjugate in mixed solvent systems of THF/water is studied and the semiconducting properties are correlated with the morphology. In THF, right handed helical fibers are formed while in 10% THF-water, the morphology changes to nano-rings along with a switch in the helicity to left-handed orientation. Experimental results combined with DFT calculations reveal the critical role of thermodynamic and kinetic factors to control these differential self-assembly processes. In THF, P-1 forms right handed helical fibers in a kinetically controlled fashion. In case of 10% THF water, the initial nucleation of the aggregate is controlled kinetically. Due to differential solubility of the molecule in these two solvents, elongation of the nuclei into fibers is restricted after a critical length leading to the formation of nano-rings which is governed by the thermodynamics. The helical fibers show superior semi-conducting property to the nano-rings as confirmed by conducting AFM and conventional I-V characteristics. PMID- 28842603 TI - Virtual histological assessment of the prenatal life history and age at death of the Upper Paleolithic fetus from Ostuni (Italy). AB - The fetal remains from the Ostuni 1 burial (Italy, ca 27 ka) represent a unique opportunity to explore the prenatal biological parameters, and to reconstruct the possible patho-biography, of a fetus (and its mother) in an Upper Paleolithic context. Phase-contrast synchrotron X-ray microtomography imaging of two deciduous tooth crowns and microfocus CT measurements of the right hemimandible of the Ostuni 1b fetus were performed at the SYRMEP beamline and at the TomoLab station of the Elettra - Sincrotrone laboratory (Trieste, Italy) in order to refine age at death and to report the enamel developmental history and dental tissue volumes for this fetal individual. The virtual histology allowed to estimate the age at death of the fetus at 31-33 gestational weeks. Three severe physiological stress episodes were also identified in the prenatal enamel. These stress episodes occurred during the last two months and half of pregnancy and may relate to the death of both individuals. Compared with modern prenatal standards, Os1b's skeletal development was advanced. This cautions against the use of modern skeletal and dental references for archaeological finds and emphasizes the need for more studies on prenatal archaeological skeletal samples. PMID- 28842604 TI - Neuroprotective effect of kinin B1 receptor activation in acute cerebral ischemia in diabetic mice. AB - Activation of the kallikrein-kinin system enhances cardiac and renal tolerance to ischemia. Here we investigated the effects of selective agonists of kinin B1 or B2 receptor (R) in brain ischemia-reperfusion in diabetic and non-diabetic mice. The role of endogenous kinins was assessed in tissue kallikrein deficient mice (TK-/-). Mice underwent 60min-middle cerebral artery occlusion (MCAO), eight weeks after type 1-diabetes induction. Treatment with B1R-, B2R-agonist or saline was started at reperfusion. Neurological deficit (ND), infarct size (IS), brain water content (BWC) were measured at day 0, 1 and 2 after injury. MCAO induced exaggerated ND, mortality and IS in diabetic mice. B2R-agonist increased ND and mortality to 60% and 80% in non-diabetic and diabetic mice respectively, by mechanisms involving hemodynamic failure and renal insufficiency. TK-/- mice displayed reduced ND and IS compared to wild-type littermate, consistent with suppression of B2R activity. B1R mRNA level increased in ischemic brain but B1R agonist had no effect on ND, mortality or IS in non-diabetic mice. In contrast, in diabetic mice, B1R-agonist tested at two doses significantly reduced ND by 42 52% and IS by 66-71%, without effect on BWC or renal function. This suggests potential therapeutic interest of B1R agonism for cerebral protection in diabetes. PMID- 28842605 TI - Deficient Insulin-mediated Upregulation of the Equilibrative Nucleoside Transporter 2 Contributes to Chronically Increased Adenosine in Diabetic Glomerulopathy. AB - Deficient insulin signaling is a key event mediating diabetic glomerulopathy. Additionally, diabetic kidney disease has been related to increased levels of adenosine. Therefore, we tested a link between insulin deficiency and dysregulated activity of the equilibrative nucleoside transporters (ENTs) responsible for controlling extracellular levels of adenosine. In ex vivo glomeruli, high D-glucose decreased nucleoside uptake mediated by ENT1 and ENT2 transporters, resulting in augmented extracellular levels of adenosine. This condition was reversed by exposure to insulin. Particularly, insulin through insulin receptor/PI3K pathway markedly upregulated ENT2 uptake activity to restores the extracellular basal level of adenosine. Using primary cultured rat podocytes as a cellular model, we found insulin was able to increase ENT2 maximal velocity of transport. Also, PI3K activity was necessary to maintain ENT2 protein levels in the long term. In glomeruli of streptozotocin-induced diabetic rats, insulin deficiency leads to decreased activity of ENT2 and chronically increased extracellular levels of adenosine. Treatment of diabetic rats with adenosine deaminase attenuated both the glomerular loss of nephrin and proteinuria. In conclusion, we evidenced ENT2 as a target of insulin signaling and sensitive to dysregulation in diabetes, leading to chronically increased extracellular adenosine levels and thereby setting conditions conducive to kidney injury. PMID- 28842606 TI - Optimal Translation Along a Circular mRNA. AB - The ribosome flow model on a ring (RFMR) is a deterministic model for ribosome flow along a circularized mRNA. We derive a new spectral representation for the optimal steady-state production rate and the corresponding optimal steady-state ribosomal density in the RFMR. This representation has several important advantages. First, it provides a simple and numerically stable algorithm for determining the optimal values even in very long rings. Second, it enables efficient computation of the sensitivity of the optimal production rate to small changes in the transition rates along the mRNA. Third, it implies that the optimal steady-state production rate is a strictly concave function of the transition rates. Maximizing the optimal steady-state production rate with respect to the rates under an affine constraint on the rates thus becomes a convex optimization problem that admits a unique solution. This solution can be determined numerically using highly efficient algorithms. This optimization problem is important, for example, when re-engineering heterologous genes in a host organism. We describe the implications of our results to this and other aspects of translation. PMID- 28842608 TI - A preclinical model for identifying rats at risk of alcohol use disorder. AB - Alcohol use is one of the world's leading causes of death and disease, although only a small proportion of individuals develop persistent alcohol use disorder (AUD). The identification of vulnerable individuals prior to their chronic intoxication remains of highest importance. We propose here to adapt current methodologies for identifying rats at risk of losing control over alcohol intake by modeling diagnostic criteria for AUD: inability to abstain during a signaled period of reward unavailability, increased motivation assessed in a progressive effortful task and persistent alcohol intake despite aversive foot shocks. Factor analysis showed that these three addiction criteria loaded on one underlying construct indicating that they represent a latent construct of addiction trait. Further, not only vulnerable rats displayed higher ethanol consumption, and higher preference for ethanol over sweetened solutions, but they also exhibited pre-existing higher anxiety as compared to resilient rats. In conclusion, the present preclinical model confirms that development of an addiction trait not only requires prolonged exposure to alcohol, but also depends on endophenotype like anxiety that predispose a minority of individuals to lose control over alcohol consumption. PMID- 28842607 TI - Retinal cell death dependent reactive proliferative gliosis in the mouse retina. AB - Neurodegeneration is a common starting point of reactive gliosis, which may have beneficial and detrimental consequences. It remains incompletely understood how distinctive pathologies and cell death processes differentially regulate glial responses. Muller glia (MG) in the retina are a prime model: Neurons are regenerated in some species, but in mammals there may be proliferative disorders and scarring. Here, we investigated the relationship between retinal damage and MG proliferation, which are both induced in a reproducible and temporal order in organotypic culture of EGF-treated mouse retina: Hypothermia pretreatment during eye dissection reduced neuronal cell death and MG proliferation; stab wounds increased both. Combined (but not separate) application of defined cell death signaling pathway inhibitors diminished neuronal cell death and maintained MG mitotically quiescent. The level of neuronal cell death determined MG activity, indicated by extracellular signal-regulated kinase (ERK) phosphorylation, and proliferation, both of which were abolished by EGFR inhibition. Our data suggest that retinal cell death, possibly either by programmed apoptosis or necrosis, primes MG to be able to transduce the EGFR-ERK activity required for cell proliferation. These results imply that cell death signaling pathways are potential targets for future therapies to prevent the proliferative gliosis frequently associated with certain neurodegenerative conditions. PMID- 28842609 TI - Nanoceria-mediated delivery of doxorubicin enhances the anti-tumour efficiency in ovarian cancer cells via apoptosis. AB - Nanocarriers are widely used for effective delivery of anticancer drugs to tumours with potential to improve cancer treatment. Here, we developed a nanoceria (CeO2)-based system for delivery of the anti-cancer drug doxorubicin (DOX) to human ovarian cancer cells. Negatively charged nanoceria could conjugate with the cationic DOX via electrostatic interaction under physiological conditions, forming DOX-loaded nanoceria (CeO2/DOX). CeO2/DOX particles displayed nearly spherical shapes, along with superior drug-loading content (22.41%), loading efficiency (99.51%), and higher cellular uptake and drug release behaviours compared to free DOX. Moreover, DOX was released faster from CeO2/DOX under reductive acidic conditions (pH 5.0, 10 mM glutathione) than under physiological conditions (pH 7.4). The initial intracellular DOX concentration was higher in the free DOX groups than in the CeO2/DOX groups, but quickly reduced to 25% of the initial concentration after 24-h culture. By contrast, CeO2/DOX showed sustained DOX release over time and maintained a high intracellular DOX concentration for up to 72 h. In vitro assays showed that CeO2/DOX exhibited higher cell proliferation inhibition and apoptosis compared with free DOX. These results highlight DOX-loaded nanoceria as a promising therapeutic agent for cancer treatment. PMID- 28842610 TI - Sofosbuvir protects Zika virus-infected mice from mortality, preventing short- and long-term sequelae. AB - Zika virus (ZIKV) causes significant public health concerns because of its association with congenital malformations, neurological disorders in adults, and, more recently, death. Considering the necessity to mitigate ZIKV-associated diseases, antiviral interventions are an urgent necessity. Sofosbuvir, a drug in clinical use against hepatitis C virus (HCV), is among the FDA-approved substances endowed with anti-ZIKV activity. In this work, we further investigated the in vivo activity of sofosbuvir against ZIKV. Neonatal Swiss mice were infected with ZIKV (2 * 107 PFU) and treated with sofosbuvir at 20 mg/kg/day, a concentration compatible with pre-clinical development of this drug. We found that sofosbuvir reduced acute levels of ZIKV from 60 to 90% in different anatomical compartments, such as the blood plasma, spleen, kidney, and brain. Early treatment with sofosbuvir doubled the percentage and time of survival of ZIKV-infected animals. Sofosbuvir also prevented the acute neuromotor impairment triggered by ZIKV. In the long-term behavioural analysis of ZIKV-associated sequelae, sofosbuvir prevented loss of hippocampal- and amygdala-dependent memory. Our results indicate that sofosbuvir inhibits ZIKV replication in vivo, which is consistent with the prospective necessity of antiviral drugs to treat ZIKV-infected individuals. PMID- 28842611 TI - Evidence-based tailoring of bioinformatics approaches to optimize methods that predict the effects of nonsynonymous amino acid substitutions in glucokinase. AB - Computational methods that allow predicting the effects of nonsynonymous substitutions are an integral part of exome studies. Here, we validated and improved their specificity by performing a comprehensive bioinformatics analysis combined with experimental and clinical data on a model of glucokinase (GCK): 8835 putative variations, including 515 disease-associated variations from 1596 families with diagnoses of monogenic diabetes (GCK-MODY) or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), and 126 variations with available or newly reported (19 variations) data on enzyme kinetics. We also proved that high frequency of disease-associated variations found in patients is closely related to their evolutionary conservation. The default set prediction methods predicted correctly the effects of only a part of the GCK-MODY-associated variations and completely failed to predict the normoglycemic or PHHI-associated variations. Therefore, we calculated evidence-based thresholds that improved significantly the specificity of predictions (<=75%). The combined prediction analysis even allowed to distinguish activating from inactivating variations and identified a group of putatively highly pathogenic variations (EVmutation score < 7.5 and SNAP2 score >70), which were surprisingly underrepresented among MODY patients and thus under negative selection during molecular evolution. We suggested and validated the first robust evidence-based thresholds, which allow improved, highly specific predictions of disease-associated GCK variations. PMID- 28842612 TI - Routes to probe Bismuth induced strong-coupling superconductivity in bimetallic BiIn alloys. AB - We report the observation of strong electron-phonon coupling in intergranular linked BiIn superconductors over an infinite range mediated by low-lying phonons. An enhanced superconducting transition temperature was observed from the magnetization, revealing a main diamagnetic Meissner state below TC(0) = 5.86(1) K and a critical field HC(0) = 1355(15) Oe with an In2Bi phase of the composite sample. The electron-phonon coupling to low lying phonons is found to be the leading mechanism for observed strong-coupling superconductivity in the BiIn system. Our findings suggest that In2Bi is in the strong-coupling region with TC(0) = 5.62(1) K, lambdaep = 1.45, omegaln = 45.92 K and alpha = 2.23. The estimated upper critical field can be well-described by a power law with alpha value higher than 2, consistent with the strong electron-phonon coupling. PMID- 28842613 TI - Accuracy of deep learning, a machine-learning technology, using ultra-wide-field fundus ophthalmoscopy for detecting rhegmatogenous retinal detachment. AB - Rhegmatogenous retinal detachment (RRD) is a serious condition that can lead to blindness; however, it is highly treatable with timely and appropriate treatment. Thus, early diagnosis and treatment of RRD is crucial. In this study, we applied deep learning, a machine-learning technology, to detect RRD using ultra-wide field fundus images and investigated its performance. In total, 411 images (329 for training and 82 for grading) from 407 RRD patients and 420 images (336 for training and 84 for grading) from 238 non-RRD patients were used in this study. The deep learning model demonstrated a high sensitivity of 97.6% [95% confidence interval (CI), 94.2-100%] and a high specificity of 96.5% (95% CI, 90.2-100%), and the area under the curve was 0.988 (95% CI, 0.981-0.995). This model can improve medical care in remote areas where eye clinics are not available by using ultra-wide-field fundus ophthalmoscopy for the accurate diagnosis of RRD. Early diagnosis of RRD can prevent blindness. PMID- 28842614 TI - Chemometric analysis of cow dung ash as an adsorbent for purifying biodiesel from waste cooking oil. AB - Taraditionally, the water-soluble contaminants of biodiesel are treated by water wash method. However, water wash method ends up in an aqueous effluent, which might then cause a harmful environmental impact. As a consequence, waterless purification of biodiesel has triggered primary interest in biodiesel manufacturing process. To address this issue, an endeavour has been made in this work to investigate the waterless purification of biodiesel from waste cooking oil using cow dung ash at different concentration of 1, 2, 3 and 4 wt/wt %. The optimum concentration of cow dung ash for biodiesel purification was found through chemometric analysis by comparing the Fourier transform infrared transmission (FTIR) spectral characteristics of cow dung ash with the water treated FTIR. It was observed from the experimental study that 1 wt/wt % of cow dung ash exhibited similar structural characteristics as that of traditional water treated method of biodiesel purification. Therefore, bio-waste cow dung ash is an effective adsorbent in purifying biodiesel analogous to traditional water washing technology. PMID- 28842615 TI - A Model of Exposure to Extreme Environmental Heat Uncovers the Human Transcriptome to Heat Stress. AB - The molecular mechanisms by which individuals subjected to environmental heat stress either recover or develop heat-related complications are not well understood. We analysed the changes in blood mononuclear gene expression patterns in human volunteers exposed to extreme heat in a sauna (temperature of 75.7 +/- 0.86 degrees C). Our analysis reveals that expression changes occur rapidly with no significant increase in core temperature and continue to amplify one hour after the end of heat stress. The reprogramed transcriptome was predominantly inhibitory, as more than two-thirds of the expressed genes were suppressed. The differentially expressed genes encoded proteins that function in stress associated pathways; including proteostasis, energy metabolism, cell growth and proliferation, and cell death, and survival. The transcriptome also included mitochondrial dysfunction, altered protein synthesis, and reduced expression of genes -related to immune function. The findings reveal the human transcriptomic response to heat and highlight changes that might underlie the health outcomes observed during heat waves. PMID- 28842616 TI - Spatial multi-scale relationships of ecosystem services: A case study using a geostatistical methodology. AB - Adequately understanding the spatial multi-scale relationships of ecosystem services (ES) is an important step for environmental management decision-making. Here, we used spatially explicit methods to estimate five critical ES (nitrogen and phosphorous purifications, crop production, water supply and soil retention) related to non-point source (NPS) pollution in the Taihu Basin region of eastern China. Then a factorial kriging analysis and stepwise multiple regression were performed to identify the spatial multi-scale relationships of ES and their dominant factors at each scale. The spatial variations in ES were characterized at the 12 km and 83 km scales and the result indicated that the relationships of these services were scale dependent. It was inferred that at the 12 km scale, ES were controlled by anthropogenic activities and their relationships were dependent on socio-economic factors. At the 83 km scale, we suggested that ES were primarily dominated by the physical environment. Moreover, the policy implications of ES relationships and their dominant factors were discussed for the multi-level governance of NPS pollution. Overall, this study presents an optimized approach to identifying ES relationships at multiple spatial scales and illustrates how appropriate information can help guide water management. PMID- 28842617 TI - Simultaneous Gene Delivery and Tracking through Preparation of Photo-Luminescent Nanoparticles Based on Graphene Quantum Dots and Chimeric Peptides. AB - Designing suitable nano-carriers for simultaneous gene delivery and tracking is in the research priorities of the molecular medicine. Non-toxic graphene quantum dots (GQDs) with two different (green and red) emission colors are synthesized by Hummer's method and characterized by UV-Vis, Photoluminescence (PL), Fourier Transform Infrared (FTIR) and Raman spectroscopies, Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The GQDs are conjugated with MPG-2H1 chimeric peptide and plasmid DNA (pDNA) by non-covalent interactions. Following conjugation, the average diameter of the prepared GQDs increased from 80 nm to 280 nm in complex structure, and the zeta-potential of the complex increased (from -36.87 to -2.56 mV). High transfection efficiency of the nano-carrier and results of confocal microscopy demonstrated that our construct can be considered as a nontoxic carrier with dual functions for gene delivery and nuclear targeting. PMID- 28842619 TI - Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. AB - Pepcan-12 (RVD-hemopressin; RVDPVNFKLLSH) is the major peptide of a family of endogenous peptide endocannabinoids (pepcans) shown to act as negative allosteric modulators (NAM) of cannabinoid CB1 receptors. Noradrenergic neurons have been identified to be a specific site of pepcan production. However, it remains unknown whether pepcans occur in the periphery and interact with peripheral CB2 cannabinoid receptors. Here, it is shown that pepcan-12 acts as a potent (K i value ~50 nM) hCB2 receptor positive allosteric modulator (PAM). It significantly potentiated the effects of CB2 receptor agonists, including the endocannabinoid 2 arachidonoyl glycerol (2-AG), for [35S]GTPgammaS binding and cAMP inhibition (5 10 fold). In mice, the putative precursor pepcan-23 (SALSDLHAHKLRVDPVNFKLLSH) was identified with pepcan-12 in brain, liver and kidney. Pepcan-12 was increased upon endotoxemia and ischemia reperfusion damage where CB2 receptors play a protective role. The adrenals are a major endocrine site of production/secretion of constitutive pepcan-12, as shown by its marked loss after adrenalectomy. However, upon I/R damage pepcan-12 was strongly increased in the liver (from ~100 pmol/g to ~500 pmol/g) independent of adrenals. The wide occurrence of this endogenous hormone-like CB2 receptor PAM, with unforeseen opposite allosteric effects on cannabinoid receptors, suggests its potential role in peripheral pathophysiological processes. PMID- 28842618 TI - fNIRS can robustly measure brain activity during memory encoding and retrieval in healthy subjects. AB - Early intervention in Alzheimer's Disease (AD) requires novel biomarkers that can capture changes in brain activity at an early stage. Current AD biomarkers are expensive and/or invasive and therefore unsuitable for use as screening tools, but a non-invasive, inexpensive, easily accessible screening method could be useful in both clinical and research settings. Prior studies suggest that especially paired-associate learning tasks may be useful in detecting the earliest memory impairment in AD. Here, we investigated the utility of functional Near Infrared Spectroscopy in measuring brain activity from prefrontal, parietal and temporal cortices of healthy adults (n = 19) during memory encoding and retrieval under a face-name paired-associate learning task. Our findings demonstrate that encoding of novel face-name pairs compared to baseline as well as compared to repeated face-name pairs resulted in significant activation in left dorsolateral prefrontal cortex while recalling resulted in activation in dorsolateral prefrontal cortex bilaterally. Moreover, brain response to recalling was significantly higher than encoding in medial, superior and middle frontal cortices for novel faces. Overall, this study shows that fNIRS can reliably measure cortical brain activation during a face-name paired-associate learning task. Future work will include similar measurements in populations with progressing memory deficits. PMID- 28842620 TI - Synthetic analogs of an Entamoeba histolytica glycolipid designed to combat intracellular Leishmania infection. AB - Intracellular pathogens belonging to the genus Leishmania have developed effective strategies that enable them to survive within host immune cells. Immunostimulatory compounds that counteract such immunological escape mechanisms represent promising treatment options for diseases. Here, we demonstrate that a lipopeptidephosphoglycan (LPPG) isolated from the membrane of a protozoan parasite, Entamoeba histolytica (Eh), shows considerable immunostimulatory effects targeted against Leishmania (L.) major, a representative species responsible for cutaneous leishmaniasis (CL). Treatment led to a marked reduction in the number of intracellular Leishmania parasites in vitro, and ameliorated CL in a mouse model. We next designed and synthesized analogs of the phosphatidylinositol anchors harbored by EhLPPG; two of these analogs reproduced the anti-leishmanial activity of the native compound by inducing production of pro-inflammatory cytokines. The use of such compounds, either alone or as a supportive option, might improve the currently unsatisfactory treatment of CL and other diseases caused by pathogen-manipulated immune responses. PMID- 28842621 TI - SOCS1 regulates hepatic regenerative response and provides prognostic makers for acute obstructive cholangitis. AB - Acute obstructive cholangitis (AOC) is a common and severe infectious diseases that occurs in an obstructed biliary system. The suppressors of cytokine signaling (SOCS) family include well-known negative regulators of cytokine receptor signaling. However, few studies have been conducted to determine their function in AOC. In this study, we showed that SOCS1 expression aberrantly changed and was associated with AOC prognosis in rat models. Decreased SOCS1 expression enhances regenerative response after biliary drainage (BD) resulting from AOC by upregulating hepatocyte growth factor (HGF) signaling. To detect SOCS1 expression in the liver less invasively and to predict the prognosis for AOC after BD, miR-221 and miR-222 were investigated. Ectopic SOCS1 expression indirectly decreases miR-221/222 expression through Met in vitro. An inverse correlation between SOCS1 expression and miR-221/222 expression in liver tissue or in serum was verified in rats. Serum from AOC patients showed that lower expression of circulating miR-221/222 after endoscopic nasobiliary drainage was associated with delayed restoration of liver function. Our results showed that SOCS1 regulates hepatic regenerative response, and indirectly detecting downstream molecules, such as miR-221/222, may provide prognostic makers for AOC. PMID- 28842622 TI - No evidence for manipulation of Anopheles gambiae, An. coluzzii and An. arabiensis host preference by Plasmodium falciparum. AB - Whether malaria parasites can manipulate mosquito host choice in ways that enhance parasite transmission toward suitable hosts and/or reduce mosquito attraction to unsuitable hosts (i.e. specific manipulation) is unknown. To address this question, we experimentally infected three species of mosquito vectors with wild isolates of the human malaria parasite Plasmodium falciparum, and examined the effects of immature and mature infections on mosquito behavioural responses to combinations of calf odour, human odour and outdoor air using a dual-port olfactometer. Regardless of parasite developmental stage and mosquito species, P. falciparum infection did not alter mosquito activation rate or their choice for human odours. The overall expression pattern of host choice of all three mosquito species was consistent with a high degree of anthropophily, with infected and uninfected individuals showing higher attraction toward human odour over calf odour, human odour over outdoor air, and outdoor air over calf odour. Our results suggest that, in this system, the parasite may not be able to manipulate the early long-range behavioural steps involved in the mosquito host feeding process. Future studies are required to test whether malaria parasites can modify their mosquito host choice at a shorter range to enhance transmission. PMID- 28842623 TI - Prevalence and risk factors associated with stroke in middle-aged and older Chinese: A community-based cross-sectional study. AB - Although the prevalence of stroke and its risk factors has been widely reported in some Western countries, information on essential stroke parameters is lacking in China, the most populous nation. A community-based cross-sectional study with 8,018 Chinese adults aged >=40 years was used to determine the prevalence of stroke and associated risk factors. Within the screened population, the prevalence of stroke was 2.21% for both sexes, 1.60% for females, and 3.18% for males. Prevalence increased with age in both sexes (P < 0.0001). In a multivariable model, factors significantly associated with stroke were increasing age (odds ratio [OR] = 1.87, 95% CI: 1.58-2.24), male gender (OR = 2.03, 95% CI: 1.42-2.90), family history of stroke (OR = 4.33, 95% CI: 2.89-6.49), history of hyperlipidemia (OR = 1.87, 95% CI 1.31-2.68), history of hypertension (OR = 1.47, 95% CI 1.02-2.12), and physical inactivity (OR = 1.74, 95% CI: 1.16-2.59). The findings indicate that stroke prevalence in middle-aged and older Chinese adults is higher in males than in females, and increases with age in both sexes. Population-based public health intervention programs and policies targeting hyperlipidemia and hypertension control and encouragement of physical activity should be highly prioritized for middle-aged and older adults in Shenzhen, China. PMID- 28842624 TI - Characterization and RNAi-mediated knockdown of Chitin Synthase A in the potato tuber moth, Phthorimaea operculella. AB - Chitin is a major component of insect exoskeleton, tracheal system and gut where it is synthesized by chitin synthase (CHS) enzymes. In this paper, we report the isolation and RNAi of chitin synthase A (PhoCHSA) from the potato tuber moth Phthorimaea operculella. The full-length cDNA of PhoCHSA is 5,627 bp with 4,689 bp open reading frame coding for 1,563 amino acids. Structural analysis of conceptual amino acid translation showed three distinct regions found in all known insect CHS proteins; N-terminus region having 9 transmembrane helices, middle catalytic region containing several conserved domains identified in insect CHS enzymes, and C-terminus region containing seven transmembrane spans. Phylogenetic analysis showed that PhoCHSA protein clustered with CHSA enzymes identified from insects from different insect orders. RNAi targeting three different regions of the gene showed different efficacy against potato tuber moth larvae and dsRNA targeting the 5' region has the highest efficacy. Results were verified by qRT-PCR which showed that dsRNA targeting the 5' region caused the highest reduction in PhoCHSA mRNA level. Our results show the importance of selecting the RNAi target region and that chitin synthase A can be a suitable RNAi target for the potato tuber moth control. PMID- 28842625 TI - Umbilical cord-derived mesenchymal stem cell extracts reduce colitis in mice by re-polarizing intestinal macrophages. AB - Human umbilical cord mesenchymal stem cells (hUC-MSCs), originating in Wharton's jelly, are multipotent stem cells that home to damaged tissues and can modulate the immune system. We examined whether administering extracts of MSCs (MSC-Ex) instead of MSCs could augment the beneficial effects of MSC therapy by overcoming the low homing efficiency of MSCs systemically administered in inflammatory bowel diseases (IBD). Dextran sodium sulfate-induced colitis model was established in C57BL/6 mice, and MSC-Ex was administered intraperitoneally. MSC-Ex reduced colitis, disease activity index (DAI), and histological colitis scores, and increased the body weight. Treatment with MSC-Ex completely blocked the induction of inflammatory cytokines, which were strongly detected in mice with colitis. MSC Ex shifted the macrophage functional phenotype from M1 to M2 by decreasing the levels of MCP1, CXCL9, and iNOS, but increasing the levels of IL-10, LIGHT, CCL1, and Arg-1. MSC-Ex recovered the destruction of the epithelial barrier in the differentiated Caco-2 cells in vitro. Treatment with MSC-Ex was more potent than that with MSC in reducing DAI, the histological score, and nitrite levels. These data strongly support that MSC-Ex treatment can be a potent approach to overcome severe refractory IBD. PMID- 28842626 TI - Multipole Modes Excitation of uncoupled dark Plasmons Resonators based on Frequency Selective Surface at X-band Frequency Regime. AB - In this report, we theoretically and experimentally demonstrates that multipole modes could be excited effectively in dark plasmonic resonators without introducing any other bright resonators at microwave range based on a two dimensional frequency selective surface (FSS) structure. These excited multipole resonances are closely related to the coupling strength between adjacent S-LSPs resonators (the periodicity of the FSS). The modes splitting effects and resonance frequencies of the excited multipole modes are regulated by changing the numbers of grooves and inner disk radius, both of which play significant roles in the excitation of the dark S-LSPs disk resonator at normal incidence. Moreover, the multipole resonances characteristics of dark S-LSPs resonators in the case of oblique incidence are also presented. Observation of such multipole resonances in dark S-LSPs without introducing extra bright resonance at normal/oblique incidence would find more potential applications in microwave and terahertz based sensors, plasmonic resonance devices and metamaterial devices. PMID- 28842627 TI - Enhancement of mesenchymal stem cell chondrogenesis with short-term low intensity pulsed electromagnetic fields. AB - Pulse electromagnetic fields (PEMFs) have been shown to recruit calcium-signaling cascades common to chondrogenesis. Here we document the effects of specified PEMF parameters over mesenchymal stem cells (MSC) chondrogenic differentiation. MSCs undergoing chondrogenesis are preferentially responsive to an electromagnetic efficacy window defined by field amplitude, duration and frequency of exposure. Contrary to conventional practice of administering prolonged and repetitive exposures to PEMFs, optimal chondrogenic outcome is achieved in response to brief (10 minutes), low intensity (2 mT) exposure to 6 ms bursts of magnetic pulses, at 15 Hz, administered only once at the onset of chondrogenic induction. By contrast, repeated exposures diminished chondrogenic outcome and could be attributed to calcium entry after the initial induction. Transient receptor potential (TRP) channels appear to mediate these aspects of PEMF stimulation, serving as a conduit for extracellular calcium. Preventing calcium entry during the repeated PEMF exposure with the co-administration of EGTA or TRP channel antagonists precluded the inhibition of differentiation. This study highlights the intricacies of calcium homeostasis during early chondrogenesis and the constraints that are placed on PEMF-based therapeutic strategies aimed at promoting MSC chondrogenesis. The demonstrated efficacy of our optimized PEMF regimens has clear clinical implications for future regenerative strategies for cartilage. PMID- 28842628 TI - Exciton-polariton Josephson junctions at finite temperatures. AB - We consider finite temperature effects in a non-standard Bose-Hubbard model for an exciton- polariton Josephson junction (JJ) that is characterised by complicated potential energy landscapes (PEL) consisting of sets of barriers and wells. We show that the transition between thermal activation (classical) and tunneling (quantum) regimes exhibits universal features of the first and second order phase transition (PT) depending on the PEL for two polariton condensates that might be described as transition from the thermal to the quantum annealing regime. In the presence of dissipation the relative phase of two condensates exhibits non-equilibrium PT from the quantum regime characterized by efficient tunneling of polaritons to the regime of permanent Josephson or Rabi oscillations, where the tunneling is suppressed, respectively. This analysis paves the way for the application of coupled polariton condensates for the realisation of a quantum annealing algorithm in presently experimentally accessible semiconductor microcavities possessing high (105 and more) Q-factors. PMID- 28842629 TI - Bone marrow-derived cells and their conditioned medium induce microvascular repair in uremic rats by stimulation of endogenous repair mechanisms. AB - The reduced number of circulating stem/progenitor cells that is found in chronic kidney disease (CKD) patients may contribute to impaired angiogenic repair and decreased capillary density in the heart. Cell therapy with bone marrow-derived cells (BMDCs) has been shown to induce positive effects on the microvasculature and cardiac function, most likely due to secretion of growth factors and cytokines, all of which are present in the conditioned medium (CM); however, this is controversial. Here we showed that treatment with BMDC or CM restored vascular density and decreased the extent of fibrosis in a rat model of CKD, the 5/6 nephrectomy. Engraftment and differentiation of exogenous BMDCs could not be detected. Yet CM led to the mobilization and infiltration of endogenous circulating cells into the heart. Cell recruitment was facilitated by the local expression of pro-inflammatory factors such as the macrophage chemoattractant protein-1, interleukin-6, and endothelial adhesion molecules. Consistently, in vitro assays showed that CM increased endothelial adhesiveness to circulating cells by upregulating the expression of adhesion molecules, and stimulated angiogenesis/endothelial tube formation. Overall, our results suggest that both treatments exert vasculoprotective effects on the heart of uremic rats by stimulating endogenous repair mechanisms. PMID- 28842630 TI - Results from 11C-metformin-PET scans, tissue analysis and cellular drug sensitivity assays questions the view that biguanides affects tumor respiration directly. AB - The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) may have anti-cancer effects. Biguanides suppress plasma growth factors, but nonetheless, the view that these mitochondrial inhibitors accumulate in tumor tissue to an extent that leads to severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm that biguanides inhibits cell proliferation by targeting respiration, but only at highly suprapharmacological concentrations due to low drug retention. Biodistribution/PET studies of 11C-labeled metformin (11C-METF) revealed that plasma bioavailability remained well below concentrations with metabolic/anti proliferative in vitro effects, following a high oral dose. Intraperitoneal administration resulted in higher drug concentrations, which affected metabolism in normal organs with high METF uptake (e.g., kidneys), but tumor drug retention peaked at low levels comparable to plasma levels and hypoxia was unaffected. Prolonged intraperitoneal treatment reduced tumor growth in two tumor models, however, the response did not reflect in vitro drug sensitivity, and tumor metabolism and hypoxia was unaffected. Our results do not support that direct inhibition of tumor cell respiration is responsible for reduced tumor growth, but future studies using 11C-METF-PET are warranted, preferably in neoplasia's originating from tissue with high drug transport capacity, to investigate the controversial idea of direct targeting. PMID- 28842632 TI - Ammonia plasma-treated electrospun polyacrylonitryle nanofibrous membrane: the robust substrate for protein immobilization through glutaraldhyde coupling chemistry for biosensor application. AB - The surface of polyacrylonitrile electrospun nanofibrous membrane (PAN NFM) was aminated by the ammonia plasma treatment. The content of amine groups has been estimated for different time of plasma treatment. The newly generated amine groups were successfully activated by glutaraldehyde (Ga) for the covalent attachment of the protein molecules on the NFM surface. Bio-functionalization of ammonia plasma treated PAN NFM was carried out by the primary antibodies (Ab) immobilization as a protein model through Ga coupling chemistry. For comparison, the immobilization of Ab was also performed through physical interactions. Attenuated total reflection-fourier transform infrared spectroscopy (ATR-FTIR) was used for the characterization of surface functional groups of PAN NFM after different modifications. The surface morphology of the NFM after immobilization was characterized using scanning electron microscope (SEM). The efficacy of Ab immobilization was estimated by enzyme-linked immuno sorbent assay (ELISA) method. X- Ray photoelectron spectroscopy (XPS) was performed to confirm the covalent immobilization of Ab on the modified PAN NFM. Results show that ammonia plasma treatment effectively increased the amount of Ab immobilization through Ga coupling chemistry. Our findings suggest that this is a versatile model for the preparation of stable bio-functionalized NFM which is applicable in different field of biomedical science. PMID- 28842631 TI - Elucidation of Dietary Polyphenolics as Potential Inhibitor of Microtubule Affinity Regulating Kinase 4: In silico and In vitro Studies. AB - Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase belonging to AMPK-like family, has recently become an important drug target against cancer and neurodegenerative disorders. In this study, we have evaluated different natural dietary polyphenolics including rutin, quercetin, ferulic acid, hesperidin, gallic acid and vanillin as MARK4 inhibitors. All compounds are primarily binds to the active site cavity of MARK4. In silico observations were further complemented by the fluorescence-binding studies and isothermal titration calorimetry (ITC) measurements. We found that rutin and vanillin bind to MARK4 with a reasonably high affinity. ATPase and tau-phosphorylation assay further suggesting that rutin and vanillin inhibit the enzyme activity of MARK4 to a great extent. Cell proliferation, ROS quantification and Annexin-V staining studies are clearly providing sufficient evidences for the apoptotic potential of rutin and vanillin. In conclusion, rutin and vanillin may be considered as potential inhibitors for MARK4 and further exploited to design novel therapeutic molecules against MARK4 associated diseases. PMID- 28842633 TI - Expression and role of VLA-1 in resident memory CD8 T cell responses to respiratory mucosal viral-vectored immunization against tuberculosis. AB - Lung resident memory T cells (TRM) characterized by selective expression of mucosal integrins VLA-1 (alpha1beta1) and CD103 (alphaEbeta7) are generated following primary respiratory viral infections. Despite recent progress, the generation of lung TRM and the role of mucosal integrins following viral vector respiratory mucosal immunization still remains poorly understood. Here by using a replication-defective viral vector tuberculosis vaccine, we show that lung Ag specific CD8 T cells express both VLA-1 and CD103 following respiratory mucosal immunization. However, VLA-1 and CD103 are acquired in differential tissue sites with the former acquired during T cell priming in the draining lymph nodes and the latter acquired after T cells entered the lung. Once in the lung, Ag-specific CD8 T cells continue to express VLA-1 at high levels through the effector/expansion, contraction, and memory phases of T cell responses. Using a functional VLA-1 blocking mAb, we show that VLA-1 is not required for trafficking of these cells to the lung, but it negatively regulates them in the contraction phase. Furthermore, VLA-1 plays a negligible role in the maintenance of these cells in the lung. Our study provides new information on vaccine-inducible lung TRM and shall help develop effective viral vector respiratory mucosal tuberculosis vaccination strategies. PMID- 28842634 TI - Holding of bovine blastocysts at suprazero temperatures using small molecules. AB - Although assisted reproductive technology (ART) currently exists, the only embryo preservation technology that is available is cryopreservation. In the present study, small molecules were used to hold embryos at room temperature. The basic medium for embryo holding for a short period of time at 4 degrees C, 10 degrees C and 20 degrees C consisted of 1% BSA non-cryopreservation medium (BNC) instead of fetal bovine serum. To maintain survival and prevent damage during embryo incubation, three candidate small molecules were selected-CHIR99021, Y-27632 and Thiazovivin-and their concentrations were optimized. The viability and hatching rate of embryos incubated at 10 degrees C were greater for Y-27632-BNC and CHIR99021+Y-27632-BNC compared to BNC. However, the rate was lower for Thiazovivin-BNC compared to BNC. Although there were no surviving embryos after incubation at 20 degrees C, the viability and hatching rate of embryos significantly increased in Y-27632-BNC and CHIR99021+Y-27632-BNC compared to BNC. The pregnancy rate of embryos incubated at 20 degrees C was also greater in the CHIR99021+Y-27632-BNC group compared to that in the frozen group. The mechanism by which small molecules enhance survival of embryos during incubation was investigated, and expression of heat shock protein 70 was observed to increase. The findings of this work may be useful in improving ART in the agricultural field. PMID- 28842635 TI - A robust superhydrophobic TiO2 NPs coated cellulose sponge for highly efficient oil-water separation. AB - Oil-water separation has recently become a worldwide concern because of the increasing oil spill accidents and industrial oily wastewater generation. Herein, a facile method with the combined superhydrophobic coating and adhesive was used to fabricate superhydrophobic TiO2 NPs coated cellulose sponge. The developed materials exhibited excellent superhydrophobicity (WCA = 171 degrees ) and superoleophilicity (OCA = 0 degrees ), which can separate a variety of oil-water mixtures, including chloroform, toluene, kerosene and other contaminations. A high separation efficiency up to 98.5% for chloroform-water mixture was achieved when used for gravity-driven oil/water separation test. More importantly, the as prepared samples exhibited excellent chemical stability and mechanical abrasion resistance even towards various corrosive oil/water mixtures (such as strong acid, alkali solution and salt-water environment) or a strong abrasion by aluminium oxide sandpaper of 600 mesh. In addition, the separation efficiency remained above 93% even after 40 scratch cycles, and the materials could be reused with a stable hydrophobicity, indicating a strong potential for industrial application. PMID- 28842636 TI - Strong electric wave response derived from the hybrid of lotus roots-like composites with tunable permittivity. AB - Lotus roots-like NiO/NiCo2O4 hybrids derived from Metal-organic frameworks (MOFs) are fabricated for the first time by using flake NiCo-MOF precursors as reactant templates. It was found that a thin sample consisting of 60 wt % NiO/NiCo2O4 hybrids in the wax matrix exhibited an effective microwave absorption bandwidth of 4.2 GHz at the thickness of 1.6 mm. The highest reflection loss of -47 dB was observed at 13.4 GHz for a sample with a thickness of 1.7 mm. Results obtained in this study indicate that hybrids of NiO and NiCo2O4 are promising microwave absorbing materials with adjustable permittivity, which can exhibit broad effective absorption bandwidth at low filler loading and thin thickness. PMID- 28842637 TI - Untargeted metabolomic analysis in naturally occurring canine diabetes mellitus identifies similarities to human Type 1 Diabetes. AB - While predominant as a disease entity, knowledge voids exist regarding the pathogenesis of canine diabetes. To test the hypothesis that diabetic dogs have similar metabolomic perturbations to humans with type 1 diabetes (T1D), we analyzed serum metabolomic profiles of breed- and body weight-matched, diabetic (n = 6) and healthy (n = 6) dogs by liquid chromatography-mass spectrometry (LC MS) profiling. We report distinct clustering of diabetic and control groups based on heat map analysis of known and unknown metabolites. Random forest classification identified 5/6 dogs per group correctly with overall out of bag error rate = 16.7%. Diabetic dogs demonstrated significant upregulation of glycolysis/gluconeogenesis intermediates (e.g., glucose/fructose, C6H12O6, keto hexose, deoxy-hexose, (P < 0.01)), with significant downregulation of tryptophan metabolism metabolites (e.g., picolinic acid, indoxyl sulfate, anthranilate, (P < 0.01)). Multiple amino acids (AA), AA metabolites, and bile acids were also significantly lower in diabetic versus healthy dogs (P < 0.05) with the exception of the branched chain AA valine, which was elevated in diabetic animals (P < 0.05). Metabolomic profiles in diabetic versus healthy dogs shared similarities with those reported in human T1D (e.g., alterations in glycolysis/gluconeogensis metabolites, bile acids, and elevated branched chain AA). Further studies are warranted to evaluate the utility of canine diabetes to provide novel mechanistic insights to the human disorder. PMID- 28842638 TI - Efficacy of Laropiprant in Minimizing Brain Injury Following Experimental Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is one of the most devastating and disabling forms of stroke, yet effective treatments are still lacking. Prostaglandins and their receptors have been implicated in playing vital roles in ICH outcomes. Recently, laropiprant, a DP1 receptor antagonist, has been used in combination with niacin to abolish the prostaglandin D2-(PGD2)-induced flushing. Here, we test the hypothesis that laropiprant limits bleeding and rescues the brain from ICH. Wildtype (WT) and DP1-/- mice were subjected ICH and neurologic deficits and hemorrhagic lesion outcomes were evaluated at 72 hours after the ICH. To test the therapeutic potential of laropiprant, WT mice subjected to ICH were treated with laropiprant at 1 hour after the ICH. The putative effect of laropiprant on limiting hematoma expansion was tested by an in vivo tail bleeding cessation method and an ex vivo coagulation method. Finally, the roles of laropiprant on gliosis and iron accumulation were also investigated. A significant decrease in the injury volume was observed in DP1-/- as well as laropiprant-treated WT mice. The tail bleeding time was significantly lower in laropiprant group as compared with the vehicle group. Significantly lower Iba-1 and Perls' iron staining in DP1 /- and laropiprant-treated WT groups were observed. Altogether, the data suggest that laropiprant treatment post-ICH attenuates brain damage by targeting primary as well as secondary injuries. PMID- 28842639 TI - Metabolomic Analysis Reveals Vitamin D-induced Decrease in Polyol Pathway and Subtle Modulation of Glycolysis in HEK293T Cells. AB - We combined 1H NMR metabolomics with functional and molecular biochemical assays to describe the metabolic changes elicited by vitamin D in HEK293T, an embryonic proliferative cell line adapted to high-glucose concentrations. Activation of the polyol pathway, was the most important consequence of cell exposure to high glucose concentration, resembling cells exposed to hyperglycemia. Vitamin D induced alterations in HEK293T cells metabolism, including a decrease in sorbitol, glycine, glutamate, guanine. Vitamin D modulated glycolysis by increasing phosphoglycerate mutase and decreasing enolase activities, changing carbon fate without changing glucose consumption, lactate export and Krebs cycle. The decrease in sorbitol intracellular concentration seems to be related to vitamin D regulated redox homeostasis and protection against oxidative stress, and helped maintaining the high proliferative phenotype, supported by the decrease in glycine and guanine and orotate concentration and increase in choline and phosphocholine concentration. The decrease in orotate and guanine indicated an increased biosynthesis of purine and pyrimidines. Vitamin D elicited metabolic alteration without changing cellular proliferation and mitochondrial respiration, but reclaiming reductive power. Our study may contribute to the understanding of the metabolic mechanism of vitamin D upon exposure to hyperglycemia, suggesting a role of protection against oxidative stress. PMID- 28842640 TI - Cross sectional evaluation of the gut-microbiome metabolome axis in an Italian cohort of IBD patients. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract of uncertain origin, which includes ulcerative colitis (UC) and Crohn's disease (CD). The composition of gut microbiota may change in IBD affected individuals, but whether dysbiosis is the cause or the consequence of inflammatory processes in the intestinal tissue is still unclear. Here, the composition of the microbiota and the metabolites in stool of 183 subjects (82 UC, 50 CD, and 51 healthy controls) were determined. The metabolites content and the microbiological profiles were significantly different between IBD and healthy subjects. In the IBD group, Firmicutes, Proteobacteria, Verrucomicrobia, and Fusobacteria were significantly increased, whereas Bacteroidetes and Cyanobacteria were decreased. At genus level Escherichia, Faecalibacterium, Streptococcus, Sutterella and Veillonella were increased, whereas Bacteroides, Flavobacterium, and Oscillospira decreased. Various metabolites including biogenic amines, amino acids, lipids, were significantly increased in IBD, while others, such as two B group vitamins, were decreased in IBD compared to healthy subjects. This study underlines the potential role of an inter-omics approach in understanding the metabolic pathways involved in IBD. The combined evaluation of metabolites and fecal microbiome can be useful to discriminate between healthy subjects and patients with IBD. PMID- 28842641 TI - Non-equilibrium plasma jet induced thermo-acoustic resistivity imaging for higher contrast and resolution. AB - A thermo-acoustic imaging modality induced by non-equilibrium atmospheric pressure plasma jet is reported. A tiny plasma jet is generated by a fast-rising pulsed dielectric barrier discharge and applied to the surface of the biological tissues. The pulsed conductive current induced by the conductive plasma jet is injected into the biological tissues. The Joule heating inside the tissue stimulates the ultrasound signals effectively. The amplitude of the ultrasound is related to the resistivity of the biological tissues near the contact point and takes the maximum at the certain conductivity of the certain frequency. Accordingly the thermo-acoustic resistivity imaging modality of high contrast and resolution is demonstrated theoretically and experimentally. PMID- 28842642 TI - Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I. AB - Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme alpha-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases. PMID- 28842643 TI - Dielectric collapse at the LaAlO3/SrTiO3 (001) heterointerface under applied electric field. AB - The fascinating interfacial transport properties at the LaAlO3/SrTiO3 heterointerface have led to intense investigations of this oxide system. Exploiting the large dielectric constant of SrTiO3 at low temperatures, tunability in the interfacial conductivity over a wide range has been demonstrated using a back-gate device geometry. In order to understand the effect of back-gating, it is crucial to assess the interface band structure and its evolution with external bias. In this study, we report measurements of the gate bias dependent interface band alignment, especially the confining potential profile, at the conducting LaAlO3/SrTiO3 (001) heterointerface using soft and hard x-ray photoemission spectroscopy in conjunction with detailed model simulations. Depth-profiling analysis incorporating the electric field dependent dielectric constant in SrTiO3 reveals that a significant potential drop on the SrTiO3 side of the interface occurs within ~2 nm of the interface under negative gate-bias. These results demonstrate gate control of the collapse of the dielectric permittivity at the interface, and explain the dramatic loss of electron mobility with back-gate depletion. PMID- 28842644 TI - Influence of synthesis parameters on CCVD growth of vertically aligned carbon nanotubes over aluminum substrate. AB - In the past two decades, important results have been achieved in the field of carbon nanotube (CNT) research, which revealed that carbon nanotubes have extremely good electrical and mechanical properties The range of applications widens more, if CNTs form a forest-like, vertically aligned structure (VACNT) Although, VACNT-conductive substrate structure could be very advantageous for various applications, to produce proper system without barrier films i.e. with good electrical contact is still a challenge. The aim of the current work is to develop a cheap and easy method for growing carbon nanotubes forests on conductive substrate with the CCVD (Catalytic Chemical Vapor Deposition) technique at 640 degrees C. The applied catalyst contained Fe and Co and was deposited via dip coating onto an aluminum substrate. In order to control the height of CNT forest several parameters were varied during the both catalyst layer fabrication (e.g. ink concentration, ink composition, dipping speed) and the CCVD synthesis (e.g. gas feeds, reaction time). As-prepared CNT forests were investigated with various methods such as scanning electron microscopy, Raman spectroscopy, and cyclic voltammetry. With such an easy process it was possible to tune both the height and the quality of carbon nanotube forests. PMID- 28842645 TI - Population mechanics: A mathematical framework to study T cell homeostasis. AB - Unlike other cell types, T cells do not form spatially arranged tissues, but move independently throughout the body. Accordingly, the number of T cells in the organism does not depend on physical constraints imposed by the shape or size of specific organs. Instead, it is determined by competition for interleukins. From the perspective of classical population dynamics, competition for resources seems to be at odds with the observed high clone diversity, leading to the so-called diversity paradox. In this work we make use of population mechanics, a non standard theoretical approach to T cell homeostasis that accounts for clone diversity as arising from competition for interleukins. The proposed models show that carrying capacities of T cell populations naturally emerge from the balance between interleukins production and consumption. These models also suggest remarkable functional differences in the maintenance of diversity in naive and memory pools. In particular, the distribution of memory clones would be biased towards clones activated more recently, or responding to more aggressive pathogenic threats. In contrast, permanence of naive T cell clones would be determined by their affinity for cognate antigens. From this viewpoint, positive and negative selection can be understood as mechanisms to maximize naive T cell diversity. PMID- 28842646 TI - A missense MT-ND5 mutation in differentiated Parkinson Disease cytoplasmic hybrid induces ROS-dependent DNA Damage Response amplified by DROSHA. AB - Genome integrity is continuously threatened by endogenous sources of DNA damage including reactive oxygen species (ROS) produced by cell metabolism. Factors of the RNA interference (RNAi) machinery have been recently involved in the cellular response to DNA damage (DDR) in proliferating cells. To investigate the impact of component of RNAi machinery on DDR activation in terminally differentiated cells, we exploited cytoplasmic hybrid (cybrid) cell lines in which mitochondria of sporadic Parkinson's disease patients repopulate neuroblastoma SH-SY5Y-Rho(0) cells. Upon differentiation into dopaminergic neuron-like cells, PD63 cybrid showed increased intracellular level of ROS and chronic DDR activation, compared to other cybrids with the same nuclear background. Importantly, DDR activation in these cells can be prevented by ROS scavenging treatment suggesting that ROS production is indeed causative of nuclear DNA damage. Sequence analysis of the mitogenomes identified a rare and heteroplasmic missense mutation affecting a highly conserved residue of the ND5-subunit of respiratory complex I, which accounts for ROS increase. We demonstrated that the assembly of nuclear DDR foci elicited by oxidative stress in these cells relies on DROSHA, providing the first evidence that components of RNAi machinery play a crucial role also in the mounting of ROS-induced DDR in non-replicating neuronal cells. PMID- 28842647 TI - Spatially destabilising effect of woody plant diversity on forest productivity in a subtropical mountain forest. AB - We used geographically weighted regression to investigate the relationship between biodiversity and the spatial stability of forest productivity (SSFP) in a subtropical mountain forest. We examined the effect of elevation on this relationship and on its spatial non-stationarity. We found that higher woody plant diversity reduced SSPF. Higher woody plant diversity strengthened the asynchrony of species responses to spatial heterogeneity of forest habitats, which contributed to SSFP, but reduced two factors that enhanced SSFP: species dominance and the spatial stability of the dominant species. The percentage of variation in SSFP explained by diversity measures was highest for the Shannon Wiener index, lowest for functional dispersion, and intermediate for species richness. The correlations of woody plant diversity with SSFP became stronger with elevation and varied among plots, indicating that the spatial non stationarity existed in the biodiversity-SSFP relationship. These correlations became weaker in most cases after controlling for elevation. Our results suggest that in the subtropical mountain forest higher woody plant diversity has a spatially destabilising effect on forest productivity, particularly at higher elevations. PMID- 28842648 TI - Size effects of lamellar twins on the strength and deformation mechanisms of nanocrystalline hcp cobalt. AB - Twins play an important role in the deformation of nanocrystalline (NC) metals. The size effects of {[Formula: see text]} tensile/{[Formula: see text]} compressive lamellar twins on the tensile strength and deformation mechanisms of NC hcp cobalt have been investigated by a series of large-scale molecular dynamics simulations. Unlike the size effects of twins on the strength for polycrystalline fcc metals, the strength of NC hcp cobalt with lamellar tensile/compressive twins monotonically increases with decreasing twin boundary spacing (TBS) and no softening stage is observed, which is due to the consistent deformation mechanisms no matter TBS is large or small. These consistent deformation mechanisms can be categorized into four types of strengthening mechanisms: (i) Partial basal dislocations nucleated from grain boundaries (GBs) or twin boundaries (TBs) intersecting with TBs/GBs; (ii) Phase transformation from hcp to fcc; (iii) partial edge dislocations nucleated from TBs intersecting with basal partial dislocations; (iv) Growth of the newly formed secondary tensile twins inside the primary compressive/tensile twins. The observed multiple twinning in MD simulations has also been confirmed by TEM after tensile testing in NC cobalt processed by severe plastic deformation. PMID- 28842649 TI - Structure-based drug discovery for combating influenza virus by targeting the PA PB1 interaction. AB - Influenza virus infections are serious public health concerns throughout the world. The development of compounds with novel mechanisms of action is urgently required due to the emergence of viruses with resistance to the currently approved anti-influenza viral drugs. We performed in silico screening using a structure-based drug discovery algorithm called Nagasaki University Docking Engine (NUDE), which is optimised for a GPU-based supercomputer (DEstination for Gpu Intensive MAchine; DEGIMA), by targeting influenza viral PA protein. The compounds selected by NUDE were tested for anti-influenza virus activity using a cell-based assay. The most potent compound, designated as PA-49, is a medium sized quinolinone derivative bearing a tetrazole moiety, and it inhibited the replication of influenza virus A/WSN/33 at a half maximal inhibitory concentration of 0.47 MUM. PA-49 has the ability to bind PA and its anti influenza activity was promising against various influenza strains, including a clinical isolate of A(H1N1)pdm09 and type B viruses. The docking simulation suggested that PA-49 interrupts the PA-PB1 interface where important amino acids are mostly conserved in the virus strains tested, suggesting the strain independent utility. Because our NUDE/DEGIMA system is rapid and efficient, it may help effective drug discovery against the influenza virus and other emerging viruses. PMID- 28842650 TI - Giardia's primitive GPL biosynthesis pathways with parasitic adaptation 'patches': implications for Giardia's evolutionary history and for finding targets against Giardiasis. AB - Giardia is a worldwide spread protozoan parasite colonizing in small intestines of vertebrates, causing Giardiasis. The controversy about whether it is an extremely primitive eukaryote or just a highly evolved parasite has become a fetter to its uses as a model for both evolutionary and parasitological studies for years. Glycerophospholipid (GPL) synthesis is a conserved essential cellular process, and thus may retain some original features reflecting its evolutionary position, and this process should also have undergone parasitic adaptation to suit Giardia's dietary lipid-rich environment. Thus, GPL synthesis pathways may be a perfect object to examine the controversy over Giardia. Here, we first clarified Giardia's previously confusing GPL synthesis by re-identifying a reliable set of GPL synthesis genes/enzymes. Then using phylogenetic and comparative genomic analyses, we revealed that these pathways turn out to be evolutionarily primitive ones, but with many secondary parasitic adaptation 'patches' including gene loss, rapid evolution, product relocation, and horizontal gene transfer. Therefore, modern Giardia should be a mosaic of 'primary primitivity' and 'secondary parasitic adaptability', and to make a distinction between the two categories of features would restart the studies of eukaryotic evolution and parasitic adaptation using Giardia as a model system. PMID- 28842652 TI - Application of color Doppler ultrasound combined with Doppler imaging artifacts in the diagnosis and estimate of congenital hypertrophic pyloric stenosis. AB - Congenital Hypertrophic Pyloric Stenosis (CHPS) is a disease condition that is caused as a result of pylorus wall hypertrophy and hyperplasia. In this study, we used color Doppler flow imaging (CDFI) and Doppler artifacts technique to observe the blood flow of hypertrophic pylorus tissue and the dynamic imaging of liquid passing through the pyloric canal in CHPS infants. 65 cases of CHPS infants and 50 infants without CHPS served as control group. We found that there were statistically significant differences between the blood flow grade of muscular layer and mucosal layer between CHPS and control infants, but no significant differences were observed in the same group. Doppler artifacts technique demonstrated the whole process of contrast agent flow through pyloric canal was directly observed in 35 of 65 subjects, and the internal diameter of the pyloric canal was 1.93 +/- 0.33mm.Conclusion that CDFI combined with color Doppler artifacts technique was proved to be effective to observe the distribution feature and blood flow grade in each layer of pyloric canal in CHPS patients. This method provides the evidence for judging the degree of pyloric stenosis clinically, and furnishes the basis of therapy along with its clinical significance and good application value. PMID- 28842651 TI - US-Guided Percutaneous Radiofrequency versus Microwave Ablation for Benign Thyroid Nodules: A Prospective Multicenter Study. AB - Compared with microwave ablation (MWA), percutaneous radiofrequency ablation (RFA) and laser ablation (LA) have been recommended as minimally invasive treatments for patients with symptomatic benign thyroid nodules (BTNs) because of the large number of clinical applications. This prospective multicenter study sought to evaluate the clinical outcomes of RFA and MWA for BTNs. In eight participating institutions, the total number of 1252 patients treated by RFA and MWA were 649 ones with 687 BTNs and 603 ones with 664 BTNs, respectively. The clinical outcomes including the nodular maximal diameter reduction ratio (MDRR), the nodular volume reduction ratio (VRR), and the incidence of complications were compared to evaluate the efficacy and safety of the two techniques. The results for the nodular MDRR and VRR in the RFA group were significantly better than those in the MWA group at 6 months and later follow-up, and the major complication rates of 4.78% and 6.63% in RFA and MWA groups showed no statistically significant differences. In conclusion, both RFA and MWA are safe and effective techniques for selected patients with symptomatic BTNs. The achieved MDRR and VRR in the RFA group were greater than those in the MWA group at 6 months and later follow-up. PMID- 28842653 TI - Procedural complication and long term outcomes after alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: data from China. AB - Data on procedural complications and long term survival after alcohol septal ablation (ASA) in Chinese patients with obstructive hypertrophic cardiomyopathy (HOCM) are lacking. We aimed to investigate long-term survival of HOCM patients after ASA and compared to the non-obstructive hypertrophic cardiomyopathy(NOHCM). A total of 233 patients with HOCM and a peak pressure gradient of >=50 mm Hg at rest or with provocation were consecutively enrolled from Fuwai Hospital in China between 2000 and 2012. Another 297 patients without left ventricular outflow tract obstruction were regarded as control group. Periprocedural mortality of ASA were low (0.89%). Periprocedural lethal ventricular arrhythmia occurred in 9 patients (4.0%). Alcohol volume (RR 1.44, 95% CI: 1.03-2.03, P = 0.034) and age <=40 years old (RR 4.63, 95% CI: 1.07-20.0, P = 0.040) were independent predictors for periprocedural lethal ventricular arrhythmia. The 10- year overall survival was 94.6% in the ASA group, similar with 92.9% in the NOHCM group (P = 0.930). In conclusion, periprocedural mortality and complications were rare in ASA. Long term survival after ASA were satisfactory and comparable to NOHCM. Patients under 40 years old should be more cautious undergoing ASA, for these patients were more likely to endure lethal ventricular arrhythmia during periprocedural period of ASA. PMID- 28842654 TI - Correlations between Gray Matter and White Matter Degeneration in Pure Alzheimer's Disease, Pure Subcortical Vascular Dementia, and Mixed Dementia. AB - Alzheimer's disease dementia (ADD) and subcortical vascular dementia (SVaD) both show cortical thinning and white matter (WM) microstructural changes. We evaluated different patterns of correlation between gray matter (GM) and WM microstructural changes in pure ADD, pure SVaD, and mixed dementia. We enrolled 40 Pittsburgh compound B (PiB) positive ADD patients without WM hyperintensities (pure ADD), 32 PiB negative SVaD patients (pure SVaD), 23 PiB positive SVaD patients (mixed dementia), and 56 normal controls. WM microstructural integrity was quantified using fractional anisotropy (FA), axial diffusivity (DA), and radial diffusivity (DR) values. We used sparse canonical correlation analysis to show correlated regions of cortical thinning and WM microstructural changes. In pure ADD patients, lower FA in the frontoparietal area correlated with cortical thinning in the left inferior parietal lobule and bilateral paracentral lobules. In pure SVaD patients, lower FA and higher DR across extensive WM regions correlated with cortical thinning in bilateral fronto-temporo-parietal regions. In mixed dementia patients, DR and DA changes across extensive WM regions correlated with cortical thinning in the bilateral fronto-temporo-parietal regions. Our findings showed that the relationships between GM and WM degeneration are distinct in pure ADD, pure SVaD, and mixed dementia, suggesting that different pathomechanisms underlie their correlations. PMID- 28842655 TI - The water kinetics of superabsorbent polymers during cement hydration and internal curing visualized and studied by NMR. AB - SuperAbsorbent Polymers (SAPs) can be applied as an admixture in cementitious materials. As the polymers are able to swell, they will absorb part of the mixing water and can then release that water back towards the cementitious matrix for internal curing. This is interesting in terms of autogenous shrinkage mitigation as the internal relative humidity is maintained. The mechanism is theoretically described by the Powers and Brownyard model, but the kinetics and water release still remain subject of detailed investigation. This paper uses Nuclear Magnetic Resonance (NMR) to study the release of water from the superabsorbent polymers towards the cementitious matrix during cement hydration. The release of water by the SAPs is monitored as a function of time and degree of hydration. The internal humidity is also monitored in time by means of sensitive relative-humidity sensors. PMID- 28842657 TI - REST, a master regulator of neurogenesis, evolved under strong positive selection in humans and in non human primates. AB - The transcriptional repressor REST regulates many neuronal genes by binding RE1 motifs. About one third of human RE1s are recently evolved and specific to primates. As changes in the activity of a transcription factor reverberate on its downstream targets, we assessed whether REST displays fast evolutionary rates in primates. We show that REST was targeted by very strong positive selection during primate evolution. Positive selection was also evident in the human lineage, with six selected sites located in a region that surrounds a VNTR in exon 4. Analysis of expression data indicated that REST brain expression peaks during aging in humans but not in other primates. Because a REST coding variant (rs3796529) was previously associated with protection from hippocampal atrophy in elderly subjects with mild cognitive impairment (MCI), we analyzed a cohort of Alzheimer disease (AD) continuum patients. Genotyping of two coding variants (rs3796529 and rs2227902) located in the region surrounding the VNTR indicated a role for rs2227902 in modulation of hippocampal volume loss, indirectly confirming a role for REST in neuroprotection. Experimental studies will be instrumental to determine the functional effect of positively selected sites in REST and the role of REST variants in neuropreservation/neurodegeneration. PMID- 28842656 TI - Deep Brain Stimulation of the subthalamic nucleus does not negatively affect social cognitive abilities of patients with Parkinson's disease. AB - Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a treatment option for patients with advanced idiopathic PD successful at alleviating disabling motor symptoms. Nevertheless, the effects of STN-DBS on cognitive functions remain controversial and few studies have investigated modification of social cognitive abilities in patients with PD treated with STN DBS. Here we expanded the typically-investigated spectrum of these abilities by simultaneously examining emotion recognition, and both affective and cognitive Theory of Mind (ToM). By means of a cross-sectional study, 20 patients with PD under dopaminergic replacement therapy, 18 patients with PD treated with STN-DBS, and 20 healthy controls performed the Ekman 60-Faces test, the full version of the Reading the Mind in the Eyes test, and the Protocol for the Attribution of Communicative Intentions. There were no differences between the PD groups (treated and not treated with STN-DBS) on any of the social cognitive tests. Our results suggest that patients with PD who are treated with STN-DBS do not experience detrimental effects on their social cognitive abilities. The present study, the first one examining a wide spectrum of social cognitive abilities after DBS of the STN, suggests that this surgical procedure can be considered safe from this standpoint. PMID- 28842658 TI - Src-mediated tyrosine phosphorylation of Protein Kinase D2 at focal adhesions regulates cell adhesion. AB - Dependent on their cellular localization, Protein Kinase D (PKD) enzymes regulate different processes including Golgi transport, cell signaling and response to oxidative stress. The localization of PKD within cells is mediated by interaction with different lipid or protein binding partners. With the example of PKD2, we here show that phosphorylation events can also contribute to localization of subcellular pools of this kinase. Specifically, in the present study, we show that tyrosine phosphorylation of PKD2 at residue Y87 defines its localization to the focal adhesions and leads to activation. This phosphorylation occurs downstream of RhoA signaling and is mediated via Src. Moreover, mutation of this residue blocks PKD2's interaction with Focal Adhesion Kinase (FAK). The presence and regulation of PKD2 at focal adhesions identifies a novel function for this kinase as a modulator of cell adhesion and migration. PMID- 28842660 TI - Time-of-Flight Three Dimensional Neutron Diffraction in Transmission Mode for Mapping Crystal Grain Structures. AB - The physical properties of polycrystalline materials depend on their microstructure, which is the nano- to centimeter scale arrangement of phases and defects in their interior. Such microstructure depends on the shape, crystallographic phase and orientation, and interfacing of the grains constituting the material. This article presents a new non-destructive 3D technique to study centimeter-sized bulk samples with a spatial resolution of hundred micrometers: time-of-flight three-dimensional neutron diffraction (ToF 3DND). Compared to existing analogous X-ray diffraction techniques, ToF 3DND enables studies of samples that can be both larger in size and made of heavier elements. Moreover, ToF 3DND facilitates the use of complicated sample environments. The basic ToF 3DND setup, utilizing an imaging detector with high spatial and temporal resolution, can easily be implemented at a time-of-flight neutron beamline. The technique was developed and tested with data collected at the Materials and Life Science Experimental Facility of the Japan Proton Accelerator Complex (J-PARC) for an iron sample. We successfully reconstructed the shape of 108 grains and developed an indexing procedure. The reconstruction algorithms have been validated by reconstructing two stacked Co-Ni-Ga single crystals, and by comparison with a grain map obtained by post-mortem electron backscatter diffraction (EBSD). PMID- 28842659 TI - HIV-1 envelope glycoprotein stimulates viral transcription and increases the infectivity of the progeny virus through the manipulation of cellular machinery. AB - During HIV infection, large amounts of progeny viral particles, including infectious virus and a large proportion of defective viral particles, are produced. Despite of the critical role of the infectious viruses in infection and pathogenesis in vivo, whether and how those defective viral particles, especially the virus-associated envelope glycoprotein (vEnv), would impact viral infection remains elusive. In this study, we investigated the effect of vEnv on HIV infected T cells and demonstrated that the vEnv was able to stimulate HIV transcription in HIV-infected cells, including peripheral blood mononuclear cells (PBMCs) isolated from HIV patients. This vEnv-mediated HIV transcription activation is mediated primarily through the interaction between vEnv and CD4/coreceptors (CCR5 or CXCR4). Through transcriptome analysis, we found that numerous cellular gene products involved in various signaling pathways were modulated by vEnv. Among them, we have further identified a cellular microRNA miR181A2, which is downregulated upon vEnv treatment, resulting in increased HIV LTR histone H3 acetylation and HIV transcription. Furthermore, we also found a vEnv-modulated cellular histone deacetylase, HDAC10, whose downregulation is associated with the increased infectivity of progeny viruses. Altogether, these findings provide evidence of the important role vEnv plays in modulating cellular environments and facilitating HIV expression and infection. PMID- 28842661 TI - Calcium (II) - and dipicolinic acid mediated-biostimulation of oil-bioremediation under multiple stresses by heat, oil and heavy metals. AB - The oil-producing Arabian Gulf states have hot summer seasons of about 7-month in length. Therefore, environmental oil spills should be bioremediated by the activity of indigenous, hydrocarbonoclastic (hydrocarbon-degrading) microorganisms with optimum growth at about 50 degrees C. Soils in such arid countries harbor thermophilic bacteria, whose oil-consumption potential is enhanced by calcium (II) - and dipicolinic acid (DPA)-supplement. Those organisms are, however, subjected to additional stresses including toxic effects of heavy metals that may be associated with the spilled oil. Our study highlighted the resistance of indigenous, thermophilic isolates to the heavy metals, mercury (II), cadmium (II), arsenic (II) and lead (II) at 50 degrees C. We also detected the uptake of heavy metals by 15 isolates at 50 degrees C, and identified the merA genes coding for Hg2+-resistance in 4 of the studied Hg2+-resistant isolates. Hg2+ was the most toxic metal and the metal toxicity was commonly higher in the presence of oil. The addition of Ca2+ and DPA enhanced the Hg2+ resistance among most of the isolates at 50 degrees C. Crude oil consumption at 50 degrees C by 4 selected isolates was inhibited by the tested heavy metals. However, Ca2+ and DPA limited this inhibition and enhanced oil-consumption, which exceeded by far the values in the control cultures. PMID- 28842662 TI - Low Tube Voltage Liver MDCT with Sinogram-Affirmed Iterative Reconstructions for the Detection of Hepatocellular Carcinoma. AB - Aim of this study was to compare low tube voltage computed tomography (80 kV) of the liver using iterative image reconstruction (SAFIRE) with standard computed tomography (120 kV) using filtered back-projection (FBP) for the detection of hepatocellular carcinoma (HCC). 46 patients (43 men) with 93 HCC confirmed by 3 T MRI with Gd-EOB-DPTA, in inconclusive cases combined with contrast-enhanced ultrasound, underwent dual-energy CT. The raw data of the 80 kV tube was reconstructed using the iterative reconstruction algorithm SAFIRE with two strengths (I3 and I5). The virtual 120 kV image data set was reconstructed using FBP. The CT images were reviewed to determine the lesion-to-liver contrast (LLC), the lesion contrast-to-noise ratio (CNR) and the sensitivity. The LLC (57.1/54.3 [I3/I5] vs. 34.9 [FBP]; p <= 0.01), CNR (3.67/4.45 [I3/I5] vs. 2.48 [FBP]; p < 0.01) and sensitivity (91.4%/88.2% [I3/I5] vs. 72.0% [FBP]; p <= 0.01) were significantly higher in the low-voltage protocol using SAFIRE. Therefore, low tube voltage CT using SAFIRE results in an increased lesion-to-liver contrast as well as an improved lesion contrast-to-noise ratio compared to FBP at 120 kV which results in a higher sensitivity for the detection of HCC. PMID- 28842663 TI - Structure and magnetic properties of icosahedral PdxAg13-x (x = 0-13) clusters. AB - In this article, we present a modified Velocity-Verlet algorithm that makes cluster system converge rapidly and accurately. By combining it with molecular dynamics simulations, we develop an effective global sampling method for extracting isomers of bimetallic clusters. Using this method, we obtain the isomers of icosahedral PdxAg13-x (x = 0-13). Additionally, using the first principle spin-polarized density functional theory approach, we find that each isomer still retains its icosahedral structure because of strong s-d orbital hybridization, and the cluster is more stable when a Pd atom is at the center of the cluster. With increasing x value, the magnetic moment decreases linearly from 5.0 MUB at x = 0, until reaching zero at x = 5, and then increases linearly up to 8.0 MUB at x = 13. By calculating the atom-projected density of states (PDOS), we reveal that the magnetic moment of PdxAg13-x mainly originates from s electrons of Ag when 0 <= x < 5, and d electrons of Pd when 5 < x <= 13. The PDOS results also show that the PdxAg13-x tends to transform from a semiconductor state to semi-metallic state when x gradually increases from 0 to 13. PMID- 28842664 TI - Evaluation of the Elecsys syphilis immunoassay for routine screening of serum samples in China. AB - We compared the performance of the Roche Diagnostics Elecsys immunoassay for the detection of Treponema pallidum specific antibodies in patient serum samples with that of the Abbott Laboratories Architect chemiluminescent microparticle immunoassay and the InTec and KHB enzyme-linked immunosorbent assays, which are commonly used in China. We tested 13,767 serum samples collected from 13 independent laboratories throughout China, which included samples from 999 previously confirmed syphilis cases and 158 'borderline' samples previously identified using the Architect, InTec, and KHB tests. The Mikrogen Syphilis Immunoblot was used to confirm positive test results. The consistency between the four different assays was 100%. The sensitivity of Elecsys immunoassay was 100% versus 98.26% for Architect, 99.11% for InTec; and 98.56% for KHB. The specificity of the Elecsys immunoassay was 99.81% versus 99.74% for Architect; 99.93% versus 99.80% for InTec; and 99.85% versus 99.77% for KHB. For borderline samples, the Elecsys immunoassay yielded no false-negative results and fewer false-positive results, compared to the other tests. Considering the ease-of-use, automation, high speed, and high throughput capacity of the Elecsys assay, the higher sensitivity and specificity indicate it is superior for routine screening of serum samples for syphilis diagnosis. PMID- 28842665 TI - Marked seasonality and high spatial variation in estuarine ciliates are driven by exchanges between the 'abundant' and 'intermediate' biospheres. AB - We examined the spatial and temporal variability of ciliate community in a subtropical estuary by rRNA and rDNA-based high throughput sequencing of 97 samples collected along the entire salinity gradient at two-month intervals in 2014. Community divided statistically into three groups: freshwater (salinity < 0.50/00), oligohaline and mesohaline (0.50/00 < salinity < 180/00), and polyhaline and euhaline (180/00 < salinity < 400/00). Across all three groups, salinity explained most of the community variability. Within each group, seasonal shifts in community formed cool (spring and winter) and warm (summer and autumn) subgroups, indicating that spatial variability overrode seasonal changes in determining community composition. Cool and warm groups showed opposite associations with temperature and prey proxies, suggesting distinct seasonal niche separation. The community reassembly of cool and warm groups was essentially due to transitions between intermediate (with relative abundance of 0.01-1%) and abundant (with relative abundance > 1%) OTUs. Further analyses demonstrated that the intermediate group not only encompassed comparable OTU richness to that of the total community and maintained high metabolic activity but also had the highest proportion in transition, either to abundance or rarity, thus offering a first view on how it varies across space and time and revealing the essential role it played in maintaining stability and functionality within the community. PMID- 28842667 TI - Relationship between initiation time of adjuvant chemotherapy and survival in ovarian cancer patients: a dose-response meta-analysis of cohort studies. AB - Although several studies have previously investigated the association between the initiation time of adjuvant chemotherapy and survival in ovarian cancer, inconsistencies remain about the issue. We searched PubMed and Web of Science through the May 24, 2017 to identify cohort studies that investigated the aforementioned topic. Fourteen studies with 59,569 ovarian cancer patients were included in this meta-analysis. We conducted meta-analyses comparing the longest and shortest initiation time of adjuvant chemotherapy and dose-response analyses to estimate summary hazards ratios (HRs) and 95% confidence intervals (CIs). A random-effects model was used to estimate HRs with 95% CIs. When comparing the longest with the shortest category of initiation time of adjuvant chemotherapy, the summary HR was 1.18 (95% CI: 1.06-1.32; I 2 = 17.6; n = 7) for overall survival. Additionally, significant dose-response association for overall survival was observed for each week delay (HR = 1.04; 95% CI: 1.00-1.09; I 2 = 9.05; n = 5). Notably, these findings were robust in prospective designed cohort studies as well as studies with advanced stage (FIGO III-IV) patients. No evidence of publication bias was observed. In conclusion, prolonged initiation time of adjuvant chemotherapy is associated with a decreased overall survival rate of ovarian cancer, especially in patients with advanced stage ovarian cancer. PMID- 28842666 TI - Impact of negative inotropic drugs on accuracy of diastolic stress echocardiography for evaluation of left ventricular filling pressure. AB - The ratio of early diastolic trans-mitral flow velocity to tissue-Doppler mitral annular early diastolic velocity (E/e'), and left ventricular end-diastolic pressure(LVEDP) have been shown to be correlated at rest, provided that patients are not on positive inotropic drugs. Data concerning the latter correlation during exercise stress are conflicting. Therefore, we investigated if use of negative inotropic drugs (NID), impacts the accuracy of E/e' as a surrogate for LVEDP during low-level exercise. An exercise(50 watts) during cardiac invasive hemodynamic monitoring and an exercise echocardiography were performed prospectively within 24 hours in 54 patients (81%male, 62 +/- 9years) with preserved LV Ejection-Fraction. Before exercise, the patients had scattered LVEDP (13.8 +/- 5.8 mmHg) and septal E/e' (8.7 +/- 2.7). Half of them were on NID, mainly betablockers(n = 26). The correlation between septal-E/e' and LVEDP was low for examinations performed at rest (r = 0.35,p = 0.01) with no significant impact of NID. For measurements performed at 50 Watts, NID had a significant impact on the association between septal-E/e'50 watts and LVEDP50 watts (beta = 0.28,p = 0.03). Correlation between septal-E/e'50 watts and LVEDP50 watts persisted in patients on NID (r = 0.61,p = 0.001) while it disappeared in the group of patients with no NID (r = 0.15,p = 0.47). NID use is an important confounding factor to take into consideration when assessing exercise LVFP using stress E/e' in patients with preserved LVEF. PMID- 28842668 TI - The E-cadherin/AmotL2 complex organizes actin filaments required for epithelial hexagonal packing and blastocyst hatching. AB - Epithelial cells connect via cell-cell junctions to form sheets of cells with separate cellular compartments. These cellular connections are essential for the generation of cellular forms and shapes consistent with organ function. Tissue modulation is dependent on the fine-tuning of mechanical forces that are transmitted in part through the actin connection to E-cadherin as well as other components in the adherens junctions. In this report we show that p100 amotL2 forms a complex with E-cadherin that associates with radial actin filaments connecting cells over multiple layers. Genetic inactivation or depletion of amotL2 in epithelial cells in vitro or zebrafish and mouse in vivo, resulted in the loss of contractile actin filaments and perturbed epithelial packing geometry. We further showed that AMOTL2 mRNA and protein was expressed in the trophectoderm of human and mouse blastocysts. Genetic inactivation of amotL2 did not affect cellular differentiation but blocked hatching of the blastocysts from the zona pellucida. These results were mimicked by treatment with the myosin II inhibitor blebbistatin. We propose that the tension generated by the E cadherin/AmotL2/actin filaments plays a crucial role in developmental processes such as epithelial geometrical packing as well as generation of forces required for blastocyst hatching. PMID- 28842669 TI - DNA analysis of traded shark fins and mobulid gill plates reveals a high proportion of species of conservation concern. AB - Continuously increasing demand for plant and animal products causes unsustainable depletion of biological resources. It is estimated that one-quarter of sharks and rays are threatened worldwide and although the global fin trade is widely recognized as a major driver, demand for meat, liver oil, and gill plates also represents a significant threat. This study used DNA barcoding and 16 S rRNA sequencing as a method to identify shark and ray species from dried fins and gill plates, obtained in Canada, China, and Sri Lanka. 129 fins and gill plates were analysed and searches on BOLD produced matches to 20 species of sharks and five species of rays or - in two cases - to a species pair. Twelve of the species found are listed or have been approved for listing in 2017 in the appendices of the Convention on International Trade in Endangered Species of Fauna and Flora (CITES), including the whale shark (Rhincodon typus), which was surprisingly found among both shark fin and gill plate samples. More than half of identified species fall under the IUCN Red List categories 'Endangered' and 'Vulnerable', raising further concerns about the impacts of this trade on the sustainability of these low productivity species. PMID- 28842670 TI - The cellular and molecular determinants of emphysematous destruction in COPD. AB - The introduction of microCT has made it possible to show that the terminal bronchioles are narrowed and destroyed before the onset of emphysematous destruction in COPD. This report extends those observations to the cellular and molecular level in the centrilobular phenotype of emphysematous destruction in lungs donated by persons with very severe COPD (n = 4) treated by lung transplantation with unused donor lungs (n = 4) serving as controls. These lung specimens provided companion samples to those previously examined by microCT (n = 61) that we examined using quantitative histology (n = 61) and gene expression profiling (n = 48). The histological analysis showed that remodeling and destruction of the bronchiolar and alveolar tissue is associated with macrophage, CD4, CD8, and B cell infiltration with increased formation of tertiary lymphoid organs. Moreover, gene set enrichment analysis showed that genes known to be expressed by natural killer (NK), lymphoid tissue inducer (LTi), and innate lymphoid cell 1 (ILC1) cells, but not ILC2 or ILC3 cells, were enriched in the expression profiles associated with CD4, CD8, and B cell infiltration. Based on these findings, we postulate that the centrilobular phenotype of emphysematous destruction COPD is driven by a Th1 response activated by infiltrating ILC1, NK, and LTi cells. PMID- 28842671 TI - Prevalence of hyperuricemia and its related risk factors among preschool children from China. AB - To estimate the prevalence of hyperuricemia and its major risk factors among Chinese preschool children. A cross-sectional survey was carried out in six central urban districts of Tianjin from March to June 2015. A cluster sampling was employed to obtain a random sample of preschool children. A total of 4073 children aged from 3 to 6 years participated in this survey. Logistic regression was used to obtain odds ratios and 95% confidence intervals. The overall mean serum uric acid concentrations was 243.0 +/- 53.2 MUmol/L, corresponding to a mean concentrations of 247.3 +/- 53.7 MUmol/L among boys and 238.3 +/- 52.4 MUmol/L among girls. The overall prevalence of serum uric acid >= 310 MUmol/L among children was 10.1%. Boys, obesity, diastolic blood pressure, and serum triglyceride concentrations were associated with the increased risk of hyperuricemia in univariable models, although the statistically significant association between diastolic blood pressure, serum triglyceride concentrations and hyperuricemia disappeared in multivariable models. The prevalence of hyperuricemia among children aged from 3 to 6 years was relatively high. Several metabolic syndrome components were associated with the risk of hyperuricemia. PMID- 28842672 TI - Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes. AB - Differentiation of certain cell types is followed by a downregulation of PARP1 expression. We show that the reduction in the abundance of PARP1 in hematopoietic progenitor cells and monocytes is tightly controlled by the cell cycle. The differentiation-associated cell cycle exit induces E2F1 replacement with E2F4 at the PARP1 promoter and the assembly of an E2F4-RBL2-HDAC1-BRM(SWI/SNF) repressor complex which deacetylates nucleosomes and compacts chromatin. In G1 arrested cells, PARP1 transcription is reduced by the recruitment of E2F1-RB1-HDAC1 EZH2(PRC2)-BRM/BRG1(SWI/SNF), which additionally trimethylates H3K27 and causes an even higher increase in nucleosome density. The re-establishment of an active chromatin structure by treating post-mitotic monocytes with the HDAC inhibitor and G1 arrested cells with a combination of HDAC and EZH2 inhibitors restores PARP1 expression completely but does not affect the interaction between the components of the repressor complex with chromatin. This suggests that RB1 and RBL2, as well as PRC2, SWI/SNF and HDAC1, do not interfere with the transcription machinery. Interestingly, reinstatement of PARP1 expression by the silencing of RBL2 or by the inhibition of HDACs in monocytes and by transfection with the PARP1 expression vector in differentiated THP-1 cells substantially increased transcription of pluripotency stem cell factors such as POU5F1, SOX2 and NANOG. PMID- 28842673 TI - Tensile properties of millimeter-long multi-walled carbon nanotubes. AB - There have been a number of theoretical and experimental studies on tensile properties of carbon nanotubes (CNT), reporting the Young's modulus of the individual CNT up to 1 TPa. Although CNT shows the promise to be used as reinforcement in a high modulus/strength composite material, it exhibits quite disappointing in terms of modulus or strength. Along with recent advance in CNT growth technique, we will be able to directly measure tensile properties of millimeter-long MWCNTs. This study firstly tackles the direct measurement of the tensile properties of millimeter-long MWCNTs that can be used as reinforcement in a composite system. A carefully designed tensile testing technique for the MWCNTs is developed, which allows us to obtain more accurate and reliable measured values. The average tensile strength and Young's modulus of the CNTs investigated in this study are measured to be 0.85 GPa and 34.65 GPa, respectively. Also, this work statistically investigates the effect of the CNT dimensions including length, diameter and volume on the tensile properties. To the best of our knowledge, this is the very first report on the tensile properties of macroscopically long and continuous CNTs. PMID- 28842674 TI - Hyperspectral data processing improves PpIX contrast during fluorescence guided surgery of human brain tumors. AB - Fluorescence guided surgery (FGS) using aminolevulinic-acid (ALA) induced protoporphyrin IX (PpIX) provides intraoperative visual contrast between normal and malignant tissue during resection of high grade gliomas. However, maps of the PpIX biodistribution within the surgical field based on either visual perception or the raw fluorescence emissions can be masked by background signals or distorted by variations in tissue optical properties. This study evaluates the impact of algorithmic processing of hyperspectral imaging acquisitions on the sensitivity and contrast of PpIX maps. Measurements in tissue-simulating phantoms showed that (I) spectral fitting enhanced PpIX sensitivity compared with visible or integrated fluorescence, (II) confidence-filtering automatically determined the lower limit of detection based on the strength of the PpIX spectral signature in the collected emission spectrum (0.014-0.041 MUg/ml in phantoms), and (III) optical-property corrected PpIX estimates were more highly correlated with independent probe measurements (r = 0.98) than with spectral fitting alone (r = 0.91) or integrated fluorescence (r = 0.82). Application to in vivo case examples from clinical neurosurgeries revealed changes to the localization and contrast of PpIX maps, making concentrations accessible that were not visually apparent. Adoption of these methods has the potential to maintain sensitive and accurate visualization of PpIX contrast over the course of surgery. PMID- 28842675 TI - Response of ecosystem CO2 fluxes to grazing intensities - a five-year experiment in the Hulunber meadow steppe of China. AB - Grazing is the primary land use in the Hulunber meadow steppe. However, the quantitative effects of grazing on ecosystem carbon dioxide (CO2) fluxes in this zone remain unclear. A controlled experiment was conducted from 2010 to 2014 to study the effects of six stocking rates on CO2 flux, and the results showed that there were significant differences in CO2 fluxes by year, treatment, and month. The effects of light and intermediate grazing remained relatively constant with grazing year, whereas the effects of heavy grazing increased substantially with grazing duration. CO2 flux significantly decreased with increasing grazing intensity and duration, and it was significantly positively correlated with rainfall, soil moisture (SM), the carbon to nitrogen ratio (C/N ratio), soil available phosphorus (SAP), soil NH4+-N, soil NO3-N, aboveground biomass (AGB), coverage, height, and litter and negatively correlated with air temperature, total soil N (TN) and microbial biomass N (MBN). A correspondence analysis showed that the main factors influencing changes in CO2 emissions under grazing were AGB, height, coverage, SM, NH4+-N and NO3-N. Increased rainfall and reduced grazing resulted in greater CO2 emissions. Our study provides important information to improve our understanding of the role of livestock grazing in GHG emissions. PMID- 28842676 TI - Efficacy and safety of different doses of cytarabine in consolidation therapy for adult acute myeloid leukemia patients: a network meta-analysis. AB - Cytarabine (Ara-C) in consolidation therapy played important role in preventing relapses for AML patients achieved complete remission, but the optimum dose remains elusive. In this network meta-analysis, we compared benefit and safety of high-, intermediate- and low-dose Ara-C [HDAraC (>2 g/m2, <=3 g/m2 twice daily), IDAraC (>=1 g/m2, <=2 g/m2 twice daily) and LDAraC (<1 g/m2 twice day)] in consolidation, based on ten randomized phase III/IV trials from 1994 to 2016, which included 4008 adult AML patients. According to the results, HDAraC in a dosage of 3 g/m2 twice daily significantly improved disease-free survival (DFS) compared with IDAraC [hazard rate (HR) 0.87, 95% CrI 0.79-0.97) and LDAraC (HR 0.86, 95% CrI 0.78-0.95). Subgroup analysis further showed that the DFS advantage of HDAraC is focused on the patients with favorable cytogenetics, but not the other cytogenetics. Compared with LDAraC, HDAraC (HR 6.04, 95% CrI 1.67-21.49) and IDAraC (HR 3.80, 95% CrI 1.05-12.85) were associated with higher risk of grade 3-4 non-haematological toxicity. However, no significant difference between HDAraC and IDAraC was found. These findings suggest that Ara-C in a dosage of 3 g/m2 twice daily provides maximal anti-relapse effect. PMID- 28842677 TI - GsCHX19.3, a member of cation/H+ exchanger superfamily from wild soybean contributes to high salinity and carbonate alkaline tolerance. AB - Cation/H+ exchangers (CHX) are characterized to be involved in plant growth, development and stress responses. Although soybean genome sequencing has been completed, the CHX family hasn't yet been systematically analyzed, especially in wild soybean. Here, through Hidden Markov Model search against Glycine soja proteome, 34 GsCHXs were identified and phylogenetically clustered into five groups. Members within each group showed high conservation in motif architecture. Interestingly, according to our previous RNA-seq data, only Group IVa members exhibited highly induced expression under carbonate alkaline stress. Among them, GsCHX19.3 displayed the greatest up-regulation in response to carbonate alkaline stress, which was further confirmed by quantitative real-time PCR analysis. We also observed the ubiquitous expression of GsCHX19.3 in different tissues and its localization on plasma membrane. Moreover, we found that GsCHX19.3 expression in AXT4K, a yeast mutant lacking four ion transporters conferred resistance to low K+ at alkali pH, as well as carbonate stress. Consistently, in Arabidopsis, GsCHX19.3 overexpression increased plant tolerance both to high salt and carbonate alkaline stresses. Furthermore, we also confirmed that GsCHX19.3 transgenic lines showed lower Na+ concentration but higher K+/Na+ values under salt-alkaline stress. Taken together, our findings indicated that GsCHX19.3 contributed to high salinity and carbonate alkaline tolerance. PMID- 28842678 TI - Sost deficiency led to a greater cortical bone formation response to mechanical loading and altered gene expression. AB - Bone adaptation optimizes mass and structure, but the mechano-response is already reduced at maturation. Downregulation of sclerostin was believed to be a mandatory step in mechano-adaptation, but in young mice it was shown that load induced formation can occur independent of sclerostin, a product of the Sost gene. We hypothesized that the bone formation and resorption response to loading is not affected by Sost deficiency, but is age-specific. Our findings indicate that the anabolic response to in vivo tibial loading was reduced at maturation in Sost Knockout (KO) and littermate control (LC) mice. Age affected all anabolic and catabolic parameters and altered Sost and Wnt target gene expression. While load-induced cortical resorption was similar between genotypes, loading-induced gains in mineralizing surface was enhanced in Sost KO compared to LC mice. Loading led to a downregulation in expression of the Wnt inhibitor Dkk1. Expression of Dkk1 was greater in both control and loaded limbs of Sost KO compared to LC mice suggesting a compensatory role in the absence of Sost. These data suggest physical activity could enhance bone mass concurrently with sclerostin-neutralizing antibodies, but treatment strategies should consider the influence of age on ultimate load-induced bone mass gains. PMID- 28842679 TI - Olfactory receptor 10J5 responding to alpha-cedrene regulates hepatic steatosis via the cAMP-PKA pathway. AB - Ectopic expression and functions of odorant receptors (ORs) in the human body have aroused much interest in the past decade. Mouse olfactory receptor 23 (MOR23, olfr16) and its human orthologue, OR10J5, have been found to be functionally expressed in several non-olfactory systems. Here, using MOR23- and OR10J5-expressing Hana3A cells, we identified alpha-cedrene, a natural compound that protects against hepatic steatosis in mice fed the high-fat diet, as a novel agonist of these receptors. In human hepatocytes, an RNA interference-mediated knockdown of OR10J5 increased intracellular lipid accumulation, along with upregulation of lipogenic genes and downregulation of genes related to fatty acid oxidation. alpha-Cedrene stimulation resulted in a significant reduction in lipid contents of human hepatocytes and reprogramming of metabolic signatures, which are mediated by OR10J5, as demonstrated by receptor knockdown experiments using RNA interference. Taken together, our findings show a crucial role of OR10J5 in the regulation of lipid accumulation in human hepatocytes. PMID- 28842680 TI - Small RNA profiles from Panax notoginseng roots differing in sizes reveal correlation between miR156 abundances and root biomass levels. AB - Plant genomes encode several classes of small regulatory RNAs (sRNAs) that play critical roles in both development and stress responses. Panax notoginseng (Burk.) F.H. Chen (P. notoginseng) is an important traditional Chinese herbal medicinal plant species for its haemostatic effects. Therefore, the root yield of P. notoginseng is a major economically important trait since the roots of P. notoginseng are the parts used to produce medicine. To identify sRNAs that are critical for the root biomass of P. notoginseng, we performed a comprehensive study of miRNA transcriptomes from P. notoginseng roots of different biomasses. We identified 675 conserved miRNAs, of which 180 pre-miRNAs are also identified, and three TAS3 loci in P. notoginseng. By using degradome sequencing, we identified 79 conserved miRNA:target or tasiRNA:target interactions, of which eight were further confirmed with the RLM 5'-RACE experiments. More importantly, our results revealed that a member of miR156 family and one of its SPL target genes have inverse expression levels, which is tightly correlated with greater root biomass contents. These results not only contributes to overall understanding of post-transcriptional gene regulation in roots of P. notoginseng but also could serve as markers for breeding P. notoginseng with greater root yield. PMID- 28842682 TI - Solar Open Flux Migration from Pole to Pole: Magnetic Field Reversal. AB - Coronal holes are solar regions with low soft X-ray or low extreme ultraviolet intensities. The magnetic fields from coronal holes extend far away from the Sun, and thus they are identified as regions with open magnetic field lines. Coronal holes are concentrated in the polar regions during the sunspot minimum phase, and spread to lower latitude during the rising phase of solar activity. In this work, we identify coronal holes with outward and inward open magnetic fluxes being in the opposite poles during solar quiet period. We find that during the sunspot rising phase, the outward and inward open fluxes perform pole-to-pole trans equatorial migrations in opposite directions. The migration of the open fluxes consists of three parts: open flux areas migrating across the equator, new open flux areas generated in the low latitude and migrating poleward, and new open flux areas locally generated in the polar region. All three components contribute to the reversal of magnetic polarity. The percentage of contribution from each component is different for different solar cycle. Our results also show that the sunspot number is positively correlated with the lower-latitude open magnetic flux area, but negatively correlated with the total open flux area. PMID- 28842681 TI - Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype. AB - Cyclooxygenase-2 (COX-2) triggers pro-inflammatory processes that can aggravate neuronal degeneration and functional impairments in many neurological conditions, mainly via producing prostaglandin E2 (PGE2) that activates four membrane receptors, EP1-EP4. However, which EP receptor is the culprit of COX-2/PGE2 mediated neuronal inflammation and degeneration remains largely unclear and presumably depends on the insult types and responding components. Herein, we demonstrated that COX-2 was induced and showed nuclear translocation in two neuronal cell lines - mouse Neuro-2a and human SH-SY5Y - after treatment with neurotoxin 6-hydroxydopamine (6-OHDA), leading to the biosynthesis of PGE2 and upregulation of pro-inflammatory cytokine interleukin-1beta. Inhibiting COX-2 or microsomal prostaglandin E synthase-1 suppressed the 6-OHDA-triggered PGE2 production in these cells. Treatment with PGE2 or EP2 selective agonist butaprost, but not EP4 agonist CAY10598, increased cAMP response in both cell lines. PGE2-initiated cAMP production in these cells was blocked by our recently developed novel selective EP2 antagonists - TG4-155 and TG6-10-1, but not by EP4 selective antagonist GW627368X. The 6-OHDA-promoted cytotoxicity was largely blocked by TG4-155, TG6-10-1 or COX-2 selective inhibitor celecoxib, but not by GW627368X. Our results suggest that PGE2 receptor EP2 is a key mediator of COX-2 activity-initiated cAMP signaling in Neuro-2a and SH-SY5Y cells following 6-OHDA treatment, and contributes to oxidopamine-mediated neurotoxicity. PMID- 28842683 TI - A novel ruthenium (II)-derived organometallic compound, TQ-6, potently inhibits platelet aggregation: Ex vivo and in vivo studies. AB - Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(eta6-cymene)2-(1H-benzoimidazol-2-yl) quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 uM) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca+2]i, P-selectin expression, FITC PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase Cgamma2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin beta3 phosphorylation stimulated by immobilized fibrinogen were diminished by TQ-6. Furthermore, TQ-6 had no effects in cyclic nucleotide formation. Moreover, TQ-6 substantially prolonged the closure time in whole blood, increased the occlusion time of thrombotic platelet plug formation and bleeding time in mice. In conclusion, TQ-6 has a novel role in inhibiting platelet activation through the inhibition of the agonist receptors-mediated inside-out signaling such as Src-Syk PLCgamma2 cascade and subsequent suppression of granule secretion, leading to disturb integrin alphaIIbbeta3-mediated outside-in signaling, and ultimately inhibiting platelet aggregation. Therefore, TQ-6 has potential to develop as a therapeutic agent for preventing or treating thromboembolic disorders. PMID- 28842684 TI - Plasmodium falciparum GPCR-like receptor SR25 mediates extracellular K+ sensing coupled to Ca2+ signaling and stress survival. AB - The malaria parasite Plasmodium falciparum is exposed, during its development, to major changes of ionic composition in its surrounding medium. We demonstrate that the P. falciparum serpentine-like receptor PfSR25 is a monovalent cation sensor capable of modulating Ca2+ signaling in the parasites. Changing from high (140 mM) to low (5.4 mM) KCl concentration triggers [Ca2+]cyt increase in isolated parasites and this Ca2+ rise is blocked either by phospholipase C (PLC) inhibition or by depleting the parasite's internal Ca2+ pools. This response persists even in the absence of free extracellular Ca2+ and cannot be elicited by addition of Na+, Mg2+ or Ca2+. However, when the PfSR25 gene was deleted, no effect on [Ca2+]cyt was observed in response to changing KCl concentration in the knocked out (PfSR25 -) parasite. Finally, we also demonstrate that: i) PfSR25 plays a role in parasite volume regulation, as hyperosmotic stress induces a significant decrease in parasite volume in wild type (wt), but not in PfSR25 - parasites; ii) parasites lacking PfSR25 show decreased parasitemia and metacaspase gene expression on exposure to the nitric oxide donor sodium nitroprusside (SNP) and iii), compared to PfSR25 - parasites, wt parasites showed a better survival in albumax-deprived condition. PMID- 28842685 TI - Universal linear-temperature resistivity: possible quantum diffusion transport in strongly correlated superconductors. AB - The strongly correlated electron fluids in high temperature cuprate superconductors demonstrate an anomalous linear temperature (T) dependent resistivity behavior, which persists to a wide temperature range without exhibiting saturation. As cooling down, those electron fluids lose the resistivity and condense into the superfluid. However, the origin of the linear-T resistivity behavior and its relationship to the strongly correlated superconductivity remain a mystery. Here we report a universal relation [Formula: see text], which bridges the slope of the linear-T-dependent resistivity (drho/dT) to the London penetration depth lambda L at zero temperature among cuprate superconductor Bi2Sr2CaCu2O8+delta and heavy fermion superconductors CeCoIn5, where MU 0 is vacuum permeability, k B is the Boltzmann constant and h is the reduced Planck constant. We extend this scaling relation to different systems and found that it holds for other cuprate, pnictide and heavy fermion superconductors as well, regardless of the significant differences in the strength of electronic correlations, transport directions, and doping levels. Our analysis suggests that the scaling relation in strongly correlated superconductors could be described as a hydrodynamic diffusive transport, with the diffusion coefficient (D) approaching the quantum limit D ~ h/m*, where m* is the quasi-particle effective mass. PMID- 28842686 TI - The validity and reliability of remote diabetic foot ulcer assessment using mobile phone images. AB - Despite their potential for telemedicine in diabetic foot ulcer treatment, diagnostic accuracy of assessment of diabetic foot ulcers using mobile phone images is unknown. Our aim was to determine the validity and reliability of remote diabetic foot ulcer assessment using mobile phone images. Fifty diabetic foot ulcers were assessed live and photographed. Five independent observers remotely assessed the mobile phone images twice for presence of nine clinical characteristics and three treatment decisions. Positive likelihood (LLR+) and negative likelihood (LLR-) ratios were calculated for validity. Multirater Randolph's and bi-rater Bennet kappa values were calculated for reliability. LLR+ ranged from 1.3-4.2; LLR- ranged from 0.13-0.88; the treatment decision 'peri wound debridement' was the only item with 'strong diagnostic evidence'. Inter observer reliability kappa ranged from 0.09-0.71; test-retest reliability from 0.45-0.86; the treatment decision 'peri-wound debridement' was the only item with 'adequate agreement'. In conclusion, mobile phone images had low validity and reliability for remote assessment of diabetic foot ulcers and should not be used as a stand-alone diagnostic instrument. Clinicians who use mobile phone images in clinical practice should obtain as much additional information as possible when making treatment decisions based on these images, and be cautious of the low diagnostic accuracy. PMID- 28842687 TI - Simultaneous emission of Gaussian-like and parabolic-like pulse waveforms in an erbium-doped dual-wavelength fiber laser. AB - We report on the observation of different pulse formation dynamics in a nonlinear polarization evolution (NPE)-based broadband erbium-doped fiber laser when the net cavity group-velocity dispersion (GVD) is managed to be close to zero. The fiber laser can generate pulses with a single wavelength or dual wavelengths by adjusting the waveplates. When the laser operates in dual-wavelength emission, the output pulses corresponding to the two wavelengths exhibit Gaussian- and parabolic-like waveforms, respectively, indicating that the laser can simultaneously operate in stretched-pulse and self-similar regimes. The generation of dual-wavelength emission with different pulse waveforms can be attributed to an overdriven NPE switch acting on a chirped broadband pulse and different dispersion mechanisms. These findings provide a good foundation for comprehensively studying pulse formation dynamics in laser cavities. PMID- 28842688 TI - Light-independent phospholipid scramblase activity of bacteriorhodopsin from Halobacterium salinarum. AB - The retinylidene protein bacteriorhodopsin (BR) is a heptahelical light-dependent proton pump found in the purple membrane of the archaeon Halobacterium salinarum. We now show that when reconstituted into large unilamellar vesicles, purified BR trimers exhibit light-independent lipid scramblase activity, thereby facilitating transbilayer exchange of phospholipids between the leaflets of the vesicle membrane at a rate >10,000 per trimer per second. This activity is comparable to that of recently described scramblases including bovine rhodopsin and fungal TMEM16 proteins. Specificity tests reveal that BR scrambles fluorescent analogues of common phospholipids but does not transport a glycosylated diphosphate isoprenoid lipid. In silico analyses suggest that membrane-exposed polar residues in transmembrane helices 1 and 2 of BR may provide the molecular basis for lipid translocation by coordinating the polar head-groups of transiting phospholipids. Consistent with this possibility, extensive coarse-grained molecular dynamics simulations of a BR trimer in an explicit phospholipid membrane revealed water penetration along transmembrane helix 1 with the cooperation of a polar residue (Y147 in transmembrane helix 5) in the adjacent protomer. These results suggest that the lipid translocation pathway may lie at or near the interface of the protomers of a BR trimer. PMID- 28842690 TI - Effects of surface defects on the mechanical properties of ZnO nanowires. AB - The elastic modulus of ZnO nanowires was measured using a resonance method based on laser Doppler effect and their fracture strains were determined via two-point bending with the aid of optical nanomanipulation. The elastic moduli of ZnO nanowires with diameters of 78 to 310 nm vary from 123 to 154 GPa, which are close to the bulk value of 140 GPa and independent of the diameters and surface defects. However, the fracture strains of the ZnO nanowires depend significantly on their diameters, increasing from 2.1% to 6.0% with the decrease in diameter from 316 to 114 nm. Post-mortem TEM analysis of the ends of the fractured nanowires revealed that fracture initiated at surface defects. The Weibull statistical analysis demonstrated that a greater defect depth led to a smaller fracture strain. The surface-defect dominated fracture should be an important consideration for the design and application of nanowire-based nanoelectromechanical systems. PMID- 28842689 TI - Altered expression of Tumor Necrosis Factor Alpha -Induced Protein 3 correlates with disease severity in Ulcerative Colitis. AB - Ulcerative colitis (UC), an inflammatory disorder of the colon arises from dysregulated immune response towards gut microbes. Transcription factor NFkappaB is a major regulatory component influencing mucosal inflammation. We evaluated expression of Tumor Necrosis Factor Alpha Induced Protein3 (TNFAIP3), the inhibitor of NFkappaB activation and its associated partners ITCH, RNF11 and Tax1BP1 in inflamed mucosa of UC patients. We found highly significant up regulated mRNA expression of TNFAIP3 that negatively correlated with disease activity in UC. mRNA levels of ITCH, RNF11 and Tax1BP1 were significantly down regulated. Significant positive correlation with disease activity was noted for Tax1BP1. All four genes showed significant down-regulation at protein level. mRNA levels of inducers of TNFAIP3 expression, NFkappaB p65 subunit and MAST3 was determined. There was significant increase in p65 mRNA expression and down regulated MAST3 expression. This suggested that increase in NFkappaB expression regulates TNFAIP3 levels. Deficiency of TNFAIP3 expression resulted in significant up-regulation of NFkappaB p65 sub-unit as well as its downstream genes such as iNOS, an inflammatory marker, inhibitors of apoptosis like cIAP2 and XIAP and mediators of anti-apoptotic signals TRAF1 and TRAF2. Taken together, decreased expression of TNFAIP3 and its partners contribute to inflammation and up-regulation of apoptosis inhibitors that may create microenvironment for colorectal cancer. PMID- 28842691 TI - Poly-Methyl Methacrylate/Polyvinyl Alcohol Copolymer Agents Applied on Diabetic Wound Dressing. AB - Due to the difficulty of healing chronic wound, in the process of changing dressing, secondary damage on the tissue caused by adhesion should be prevented. In this study, the new dressing of particle hydrogels synthesized with poly methyl methacrylate and poly-vinyl alcohol precursors were proposed. In addition, cell safety tests, animal's allergic stimulation, and animal's wound healing experiments were conducted for particle hydrogels. On one hand, in L929 cell experiment, the results of particle hydrogels extract 3-(4,5-Dimethylthiazol-2 yl)-2,5-diphenyl tetrazolium bromide tests and lactate dehydrogenase test trial show that there are no safety concerns over particle hydrogels. On the other hand, New Zealand white rabbits were chosen for skin sensitization tests in animal trials, which show the consistent results. At last, wound healing tests used diabetes induction with 10-week-old rats and three-month-old Landrace pigs, with the tissue histology. In short, through this experiment, it is found that in the early phase of the diabetic rats and pigs' wound healing, using particle hydrogels can enhance collagen formation, and achieve the goal of faster wound healing. PMID- 28842692 TI - Fe-based hybrid electrocatalysts for nonaqueous lithium-oxygen batteries. AB - Lithium-oxygen batteries promise high energy densities, but are confronted with challenges, such as high overpotentials and sudden death during discharge-charge cycling, because the oxygen electrode is covered with the insulating discharge product, Li2O2. Here, we synthesized low-cost Fe-based nanocomposites via an electrical wire pulse process, as a hybrid electrocatalyst for the oxygen electrode of Li-O2 batteries. Fe3O4-Fe nanohybrids-containing electrodes exhibited a high discharge capacity (13,890 mA h gc-1 at a current density of 500 mA gc-1), long cycle stability (100 cycles at a current rate of 500 mA gc-1 and fixed capacity regime of 1,000 mA h gc-1), and low overpotential (1.39 V at 40 cycles). This superior performance resulted from the good electrical conductivity of the Fe metal nanoparticles during discharge-charge cycling, which could enhance the oxygen reduction reaction and oxygen evolution reaction activities. We have demonstrated the increased electrical conductivity of the Fe3O4-Fe nanohybrids using electrochemical impedance spectroscopy. PMID- 28842693 TI - Fluorescent organic single crystals with elastic bending flexibility: 1,4 bis(thien-2-yl)-2,3,5,6-tetrafluorobenzene derivatives. AB - Organic single crystals with elastic bending flexibility are rare because they are generally brittle. We report here fluorescent organic single crystals based on thiophene-tetrafluorobenzene-thiophene derivatives, mainly 1,4-bis(thien-2-yl) 2,3,5,6-tetrafluorobenzene. Three derivatives were synthesized by Pd-catalyzed cross-coupling reactions (Stille or direct arylation pathways). The crystallization of the derivatives gave large (mm- or cm-scale) crystals. Two crystals of 1,4-bis(thien-2-yl)-2,3,5,6-tetrafluorobenzene, 1, and 1,4-bis(4 methylthien-2-yl)-2,3,5,6-tetrafluorobenzene, 3, bent under applied stress and quickly recovered its original shape upon relaxation. The other crystal of 1,4 bis(5-methylthien-2-yl)-2,3,5,6-tetrafluorobenzene, 2, showed brittle breakage under applied stress (normal behavior). Fibril lamella crystal structure based on criss-cross packed slip-stacked molecular wires and its structural integrity are important factors for the design and production of next generation crystal materials with elastic bending flexibility. Furthermore, mechanical bending relaxation resulted in reversible change of the morphology and fluorescence (mechanofluorochromism). Such bendable crystals would lead to the next generation solid-state fluorescent and/or semiconducting materials. PMID- 28842694 TI - Defect generation in Pd layers by 'smart' films with high H-affinity. AB - In this paper, we demonstrate that the microstructure and the surface of a thin palladium (Pd) film can be intentionally altered by the presence of a subjacent niobium (Nb) film. Depending on the thickness of the Nb film and on the hydrogen gas pressure, defects in the Pd film can be healed or created. To demonstrate this effect, Pd/Nb/sapphire (Al2O3) stacks are studied during hydrogen gas exposure at room temperature by using scanning tunneling microscopy (STM), X-ray diffraction (XRD) and environmental transmission electron microscopy (ETEM). STM shows that hydrogen-induced topography changes in the Nb films depend on the film thickness which affects the height of the Nb surface corrugations, their lateral size and distribution. XRD measurements show that these changes in the Nb hydride film influence the microstructure of the overlaying Pd film. ETEM reveals that the modifications of the Pd film occur due to the precipitation and growth of the Nb hydride phase. The appearance of new defects, interface and surface roughening is observed in the Pd film above locally grown Nb hydride grains. These results can open a new route to design 'smart' catalysts or membranes, which may accommodate their microstructure depending on the gaseous environment. PMID- 28842695 TI - Modeling acute toxicity of metal mixtures to wheat (Triticum aestivum L.) using the biotic ligand model-based toxic units method. AB - The combined toxic effects of copper (Cu) and cobalt (Co) were predicted using the biotic ligand model (BLM) for different concentrations of magnesium (Mg2+) and pH levels, with parameters derived from Cu-only and Co-only toxicity data. The BLM-based toxic unit (TU) approach was used for prediction. Higher activities of Mg2+ linearly increased the EC50 of Cu and Co, supporting the concept of competitive binding of Mg2+ and metal ions in toxic action. The effects of pH on Cu and Co toxicity were related not only to free Cu2+ and Co2+ activity, respectively, but also to inorganic metal complexes. Stability constants for the binding of Cu2+, CuHCO3+, CuCO3(aq), CuOH+, Mg2+, Co2+, CoHCO3+ and Mg2+ with biotic ligands were logK CuBL 5.87, [Formula: see text] 5.67, [Formula: see text] 5.44, logK CuOHBL 5.07, logK MgBL 2.93, logK CoBL 4.72, [Formula: see text] 5.81 and logK MgBL 3.84, respectively. The combinations of Cu and Co showed additive effects under different conditions. When compared with the FIAM-based TU model (root mean square error [RMSE = 16.31, R 2 = 0.84]), the BLM-based TU model fitted the observed effects better (RMSE = 6.70, R 2 = 0.97). The present study supports the BLM principles, which indicate that metal speciation and major cations competition need to be accounted for when predicting toxicity of both single metals and mixtures of metals. PMID- 28842696 TI - Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways. AB - Chronic myeloid leukemia (CML) is characterized by abnormal proliferation of myeloid cells which when untreated leads to bone marrow failure. Imatinib mesylate (IM) is the first line of therapy for treatment of CML and results in remission in most cases. However, a significant percentage of patients develop chemoresistance to IM, which might be due to the presence of chemoresistant cells in the bone marrow. In the current study, we explored the role of cell-cell interaction of CML cells with the bone marrow stromal cells in the development of chemoresistance in CML. We found that the stromal cells offered long-term chemoprotection to the CML cells from the apoptotic effect of IM. These stroma interacting CML cells were maintained in a non-proliferative stage and had increased ERK1/2 and SMAD1/8 phosphorylation levels. Prolonged interaction of CML cells with the stromal cells in the presence of IM resulted in the acquisition of stroma-free chemoresistance to IM treatment. However, inhibition of actin cytoskeleton, ERK1/2 and SMAD signaling abrogated the chemoresistance acquisition and sensitized the chemoresistant CML cells to IM induced apoptosis. PMID- 28842698 TI - Ultracompact bottom-up photonic crystal lasers on silicon-on-insulator. AB - Compact on-chip light sources lie at the heart of practical nanophotonic devices since chip-scale photonic circuits have been regarded as the next generation computing tools. In this work, we demonstrate room-temperature lasing in 7 * 7 InGaAs/InGaP core-shell nanopillar array photonic crystals with an ultracompact footprint of 2300 * 2300 nm2, which are monolithically grown on silicon-on insulator substrates. A strong lateral confinement is achieved by a photonic band edge mode, which is leading to a strong light-matter interaction in the 7 * 7 nanopillar array, and by choosing an appropriate thickness of a silicon-on insulator layer the band-edge mode can be trapped vertically in the nanopillars. The nanopillar array band-edge lasers exhibit single-mode operation, where the mode frequency is sensitive to the diameter of the nanopillars. Our demonstration represents an important first step towards developing practical and monolithic III-V photonic components on a silicon platform. PMID- 28842697 TI - Diversity of Amyloid-beta Proteoforms in the Alzheimer's Disease Brain. AB - Amyloid-beta (Abeta) plays a key role in the pathogenesis of Alzheimer's disease (AD), but little is known about the proteoforms present in AD brain. We used high resolution mass spectrometry to analyze intact Abeta from soluble aggregates and insoluble material in brains of six cases with severe dementia and pathologically confirmed AD. The soluble aggregates are especially relevant because they are believed to be the most toxic form of Abeta. We found a diversity of Abeta peptides, with 26 unique proteoforms including various N- and C-terminal truncations. N- and C-terminal truncations comprised 73% and 30%, respectively, of the total Abeta proteoforms detected. The Abeta proteoforms segregated between the soluble and more insoluble aggregates with N-terminal truncations predominating in the insoluble material and C- terminal truncations segregating into the soluble aggregates. In contrast, canonical Abeta comprised the minority of the identified proteoforms (15.3%) and did not distinguish between the soluble and more insoluble aggregates. The relative abundance of many truncated Abeta proteoforms did not correlate with post-mortem interval, suggesting they are not artefacts. This heterogeneity of Abeta proteoforms deepens our understanding of AD and offers many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development. PMID- 28842699 TI - Effects of drying and wetting cycles on the transformations of extraneous inorganic N to soil microbial residues. AB - The incorporation of extraneous nitrogen (N) into amino sugars (AS) could reflect the contribution of microbial residues to soil N transformation. Investigating the impact of drying-wetting (DW) on dynamics of newly-produced AS is critical because this represents microbial-driven N retention/losses in soil. A 36-day incubation of soil samples was conducted under different drying intensities, using 15N-labelled-(NH4)2SO4 as an N source together with/without glucose addition. There were multiple DW periods and they ranged from a constant moisture content treatment, to a one day drying (low-drying-intensity, LD), a two day drying (medium-drying-intensity, MD), or a three day drying event (severe-drying intensity, SD). The immobilization of added-N was restricted in DW when available carbon was not added, thus glucose addition increased the effect of DW on the incorporation of added-N into AS. The response of total 15N-AS to DW varied depending on drying intensities. The MD was beneficial to the incorporation of added-N into total 15N-AS, while total 15N-AS contents were low in SD treatment. The effect of DW on contribution of bacterial and fungal residues to N transformation was also related to drying intensities. Our study indicated that DW altered microbial transformation of added-N, and the effect was drying intensity-specific, and available carbon-dependent. PMID- 28842700 TI - EnSVMB: Metagenomics Fragments Classification using Ensemble SVM and BLAST. AB - Metagenomics brings in new discoveries and insights into the uncultured microbial world. One fundamental task in metagenomics analysis is to determine the taxonomy of raw sequence fragments. Modern sequencing technologies produce relatively short fragments and greatly increase the number of fragments, and thus make the taxonomic classification considerably more difficult than before. Therefore, fast and accurate techniques are called to classify large-scale fragments. We propose EnSVM (Ensemble Support Vector Machine) and its advanced method called EnSVMB (EnSVM with BLAST) to accurately classify fragments. EnSVM divides fragments into a large confident (or small diffident) set, based on whether the fragments get consistent (or inconsistent) predictions from linear SVMs trained with different k-mers. Empirical study shows that sensitivity and specificity of EnSVM on confident set are higher than 90% and 97%, but on diffident set are lower than 60% and 75%. To further improve the performance on diffident set, EnSVMB takes advantage of best hits of BLAST to reclassify fragments in that set. Experimental results show EnSVM can efficiently and effectively divide fragments into confident and diffident sets, and EnSVMB achieves higher accuracy, sensitivity and more true positives than related state-of-the-art methods and holds comparable specificity with the best of them. PMID- 28842701 TI - Drastic Improvement in Adhesion Property of Polytetrafluoroethylene (PTFE) via Heat-Assisted Plasma Treatment Using a Heater. AB - The heating effect on the adhesion property of plasma-treated polytetrafluoroethylene (PTFE) was examined. For this purpose, a PTFE sheet was plasma-treated at atmospheric pressure while heating using a halogen heater. When plasma-treated at 8.3 W/cm2 without using the heater (Low-P), the surface temperature of Low-P was about 95 degrees C. In contrast, when plasma-treated at 8.3 W/cm2 while using the heater (Low-P+Heater), the surface temperature of Low P+Heater was controlled to about 260 degrees C. Thermal compression of the plasma-treated PTFE with or without heating and isobutylene-isoprene rubber (IIR) was performed, and the adhesion strength of the IIR/PTFE assembly was measured via the T-peel test. The adhesion strengths of Low-P and Low-P+Heater were 0.12 and 2.3 N/mm, respectively. Cohesion failure of IIR occurred during the T-peel test because of its extremely high adhesion property. The surfaces of the plasma treated PTFE with or without heating were investigated by the measurements of electron spin resonance, X-ray photoelectron spectroscopy, nanoindentation, scanning electron microscopy, and scanning probe microscopy. These results indicated that heating during plasma treatment promotes the etching of the weak boundary layer (WBL) of PTFE, resulting in a sharp increase in the adhesion property of PTFE. PMID- 28842702 TI - Stigmasterol prevents glucolipotoxicity induced defects in glucose-stimulated insulin secretion. AB - Type 2 diabetes results from defects in both insulin sensitivity and insulin secretion. Elevated cholesterol content within pancreatic beta-cells has been shown to reduce beta-cell function and increase beta-cell apoptosis. Hyperglycemia and dyslipidemia contribute to glucolipotoxicity that leads to type 2 diabetes. Here we examined the capacity of glucolipotoxicity to induce free cholesterol accumulation in human pancreatic islets and the INS-1 insulinoma cell line. Glucolipotoxicity treatment increased free cholesterol in beta-cells, which was accompanied by increased reactive oxygen species (ROS) production and decreased insulin secretion. Addition of AAPH, a free radical generator, was able to increase filipin staining indicating a link between ROS production and increased cholesterol in beta-cells. We also showed the ability of stigmasterol, a common food-derived phytosterol with anti-atherosclerotic potential, to prevent the increase in both free cholesterol and ROS levels induced by glucolipotoxicity in INS-1 cells. Stigmasterol addition also inhibited early apoptosis, increased total insulin, promoted actin reorganization, and improved insulin secretion in cells exposed to glucolipotoxicity. Overall, these data indicate cholesterol accumulation as an underlying mechanism for glucolipotoxicity-induced defects in insulin secretion and stigmasterol treatment as a potential strategy to protect beta-cell function during diabetes progression. PMID- 28842703 TI - In situ repair of bone and cartilage defects using 3D scanning and 3D printing. AB - Three-dimensional (3D) printing is a rapidly emerging technology that promises to transform tissue engineering into a commercially successful biomedical industry. However, the use of robotic bioprinters alone is not sufficient for disease treatment. This study aimed to report the combined application of 3D scanning and 3D printing for treating bone and cartilage defects. Three different kinds of defect models were created to mimic three orthopedic diseases: large segmental defects of long bones, free-form fracture of femoral condyle, and International Cartilage Repair Society grade IV chondral lesion. Feasibility of in situ 3D bioprinting for these diseases was explored. The 3D digital models of samples with defects and corresponding healthy parts were obtained using high-resolution 3D scanning. The Boolean operation was used to achieve the shape of the defects, and then the target geometries were imported in a 3D bioprinter. Two kinds of photopolymerized hydrogels were synthesized as bioinks. Finally, the defects of bone and cartilage were restored perfectly in situ using 3D bioprinting. The results of this study suggested that 3D scanning and 3D bioprinting could provide another strategy for tissue engineering and regenerative medicine. PMID- 28842704 TI - Early markers of cardiovascular disease are associated with occupational exposure to polycyclic aromatic hydrocarbons. AB - Occupational exposure to soot, rich in polycyclic aromatic hydrocarbons (PAH), has been associated with increased risk of cardiovascular disease (CVD). However, our knowledge about PAH exposure and early markers of CVD remains limited. In this cross-sectional study of 151 chimney sweeps and 152 controls, we investigated occupational exposure to PAH and early markers of CVD. Blood pressure (BP) (chimney sweeps only), urinary PAH metabolites and serum biomarkers were measured (C-reactive protein, homocysteine, gamma-glutamyltransferase, cholesterol, HDL, LDL, and triglycerides). Chimney sweeps had up to 7 times higher concentrations of PAH metabolites in urine than controls (P < 0.001): median concentrations (adjusted for specific gravity) for 1-hydroxypyrene, 2 hydroxyphenanthrene, 3-hydroxybenzo[a]pyrene, and 3-hydroxybenzo[a]anthracene were 0.56 ug/L, 0.78 ug/L, 4.75 ng/L, and 6.28 ng/L, respectively. Compared with controls, chimney sweeps had increased homocysteine, cholesterol, and HDL (beta = 3.4 umol/L, 0.43 mmol/L, and 0.13 mmol/L, respectively, P <= 0.003, adjusted for age, BMI, and smoking). In chimney sweeps, PAH metabolites correlated positively with the percentage of soot sweeping (P < 0.001). 2-hydroxyphenanthrene, 3 hydroxybenzo[a]pyrene, and 3-hydroxybenzo[a]anthracene were positively associated with diastolic BP (P < 0.044, adjusted for age, BMI, and smoking). PAH exposure among chimney sweeps resulted in elevated levels of markers for CVD risk. These findings stress the need to reduce occupational exposure to PAH. PMID- 28842705 TI - The Legionella effector WipB is a translocated Ser/Thr phosphatase that targets the host lysosomal nutrient sensing machinery. AB - Legionella pneumophila infects human alveolar macrophages and is responsible for Legionnaire's disease, a severe form of pneumonia. L. pneumophila encodes more than 300 putative effectors, which are translocated into the host cell via the Dot/Icm type IV secretion system. These effectors highjack the host's cellular processes to allow bacterial intracellular growth and replication. Here we adopted a multidisciplinary approach to investigate WipB, a Dot/Icm effector of unknown function. The crystal structure of the N-terminal domain at 1.7 A resolution comprising residues 25 to 344 revealed that WipB harbours a Ser/Thr phosphatase domain related to the eukaryotic phospho-protein phosphatase (PPP) family. The C-terminal domain (residues 365-524) is sufficient to pilot the effector to acidified LAMP1-positive lysosomal compartments, where WipB interacts with the v-ATPase and the associated LAMTOR1 phosphoprotein, key components of the lysosomal nutrient sensing (LYNUS) apparatus that controls the mammalian target of rapamycin (mTORC1) kinase complex at the lysosomal surface. We propose that WipB is a lysosome-targeted phosphatase that modulates cellular nutrient sensing and the control of energy metabolism during Legionella infection. PMID- 28842706 TI - Probing the Hydrogen Enhanced Near-Field Emission of ITO without a Vacuum-Gap. AB - Electromagnetic fields produced by thermal fluctuation can excite the near-field optical states, creating the potential for thermal radiation orders of magnitude greater than what is predicted by Plank's blackbody theory. The typical schemes employed to probe the trapped electromagnetic energy of the near-field are with considerable technical challenges, suffering from scalability and high costs, hindering widespread use. A waveguide-based scheme relying on photon tunneling is presented as an alternate approach, as waveguides inherently provide a large density of channels for photons to tunnel to with the required k-vector matching and probability density overlap. The conducted experiments with a 10 nm indium tin oxide film, having plasmonic resonance in the 1500 nm wavelength range, show that the near-field EM radiation can be extracted to the far-field by establishing the mode of de-excitation to be that of photon tunneling to a nearby waveguide. Furthermore, it is also demonstrated that the thermally emitted energy is very sensitive to changes in the surface free electron density, a property that is unique to the near-field. In addition to the ease of implementation and scalability, the proposed waveguide-based extraction method does not require a vacuum-gap, which is a significant reduction in the required complexity. PMID- 28842707 TI - Superior Electronic Structure in Two-Dimensional MnPSe 3 /MoS2 van der Waals Heterostructures. AB - We explore the electronic structure of two-dimensional (2D) MnPSe3/MoS2 van der Waals (vdW) heterostructures based on density functional theory. A novel spin splitting at the valance band maximum of MnPSe3 appears in some specific stacking models due to Mn d orbital hybridization. The simultaneous spin and valley splitting can be achieved by interfacial coupling, which is attractive for manipulation of the valley and spin degrees of freedom. More importantly, due to the antiferromagnetic ordering of manganese, the opposite spin moments at K and K' valleys can be observed by transforming configurations, which realizes the tunable spin splitting states. Our theoretical work opens up the opportunities of valley and spin related applications of MnPSe3/MoS2 vdW heterostructures and offers a practical avenue for exploring novel devices based on the spin and valley degrees of freedom. PMID- 28842708 TI - Copper Induced Conformational Changes of Tripeptide Monolayer Based Impedimetric Biosensor. AB - Copper ions play a major role in biological processes. Abnormal Cu2+ ions concentrations are associated with various diseases, hence, can be used as diagnostic target. Monitoring copper ion is currently performed by non-portable, expensive and complicated to use equipment. We present a label free and a highly sensitive electrochemical ion-detecting biosensor based on a Gly-Gly-His tripeptide layer that chelate with Cu2+ ions. The proposed sensing mechanism is that the chelation results in conformational changes in the peptide that forms a denser insulating layer that prevents RedOx species transfer to the surface. This chelation event was monitored using various electrochemical methods and surface chemistry analysis and supported by theoretical calculations. We propose a highly sensitive ion-detection biosensor that can detect Cu2+ ions in the pM range with high SNR parameter. PMID- 28842711 TI - 3D Printing of Polymer-Bonded Rare-Earth Magnets With a Variable Magnetic Compound Fraction for a Predefined Stray Field. AB - Additive manufacturing of polymer-bonded magnets is a recently developed technique, for single-unit production, and for structures that have been impossible to manufacture previously. Also, new possibilities to create a specific stray field around the magnet are triggered. The current work presents a method to 3D print polymer-bonded magnets with a variable magnetic compound fraction distribution. This means the saturation magnetization can be adjusted during the printing process to obtain a required external field of the manufactured magnets. A low-cost, end-user 3D printer with a mixing extruder is used to mix permanent magnetic filaments with pure polyamide (PA12) filaments. The magnetic filaments are compounded, extruded, and characterized for the printing process. To deduce the quality of the manufactured magnets with a variable magnetic compound fraction, an inverse stray field framework is developed. The effectiveness of the printing process and the simulation method is shown. It can also be used to manufacture magnets that produce a predefined stray field in a given region. This opens new possibilities for magnetic sensor applications. This setup and simulation framework allows the design and manufacturing of polymer-bonded permanent magnets, which are impossible to create with conventional methods. PMID- 28842709 TI - The Parkinson's disease-associated GPR37 receptor interacts with striatal adenosine A2A receptor controlling its cell surface expression and function in vivo. AB - G protein-coupled receptor 37 (GPR37) is an orphan receptor associated to Parkinson's disease (PD) neuropathology. Here, we identified GPR37 as an inhibitor of adenosine A2A receptor (A2AR) cell surface expression and function in vivo. In addition, we showed that GPR37 and A2AR do oligomerize in the striatum. Thus, a close proximity of GPR37 and A2AR at the postsynaptic level of striatal synapses was observed by double-labelling post-embedding immunogold detection. Indeed, the direct receptor-receptor interaction was further substantiated by proximity ligation in situ assay. Interestingly, GPR37 deletion promoted striatal A2AR cell surface expression that correlated well with an increased A2AR agonist-mediated cAMP accumulation, both in primary striatal neurons and nerve terminals. Furthermore, GPR37-/- mice showed enhanced A2AR agonist-induced catalepsy and an increased response to A2AR antagonist-mediated locomotor activity. Overall, these results revealed a key role for GPR37 controlling A2AR biology in the striatum, which may be relevant for PD management. PMID- 28842710 TI - Preoperative prognostic nutritional index is a powerful predictor of prognosis in patients with stage III ovarian cancer. AB - Many established inflammation- and nutrition-related factors have been investigated as potential independent prognostic factors in various cancers, including the C-reactive protein/albumin ratio (CAR), lymphocyte/monocyte ratio (LMR), modified Glasgow prognostic score (mGPS), body mass index (BMI), and prognostic nutritional index (PNI). This study was performed to estimate the prognostic value of these factors in predicting survival and platinum resistance in ovarian cancer (OC), especially according to stage. Kaplan-Meier and multivariate analyses were performed to plot the survival curve and determine the independent prognostic factors. Additionally, the area under the receiver operating characteristic curve (AUC) was used to predict platinum resistance and prognosis by comparing the predictive ability of PNI and cancer antigen (CA)-125. In all patients, decreased PNI was significantly associated with platinum resistance and poor overall survival (OS) and progression-free survival (PFS). Regarding tumor stage, decreased PNI was significantly associated with poor PFS and OS only in stage III OC. Furthermore, the PNI also showed a significantly higher AUC value than CA-125 for predicting mortality and platinum resistance in all OC patients, but not in stage III patients. In conclusion, decreased PNI is a powerful predictor of a poor prognosis in OC, and especially for stage III cases. PMID- 28842712 TI - Biochips for Direct Detection and Identification of Bacteria in Blood Culture Like Conditions. AB - Bloodstream bacterial infections are life-threatening conditions necessitating prompt medical care. Rapid pathogen identification is essential for early setting of the best anti-infectious therapy. However, the bacterial load in blood samples from patients with bacteremia is too low and under the limit of detection of most methods for direct identification of bacteria. Therefore, a preliminary step enabling the bacterial multiplication is required. To do so, blood cultures still remain the gold standard before bacteremia diagnosis. Bacterial identification is then usually obtained within 24 to 48 hours -at least- after blood sampling. In the present work, the fast and direct identification of bacteria present in blood cultures is completed in less than 12 hours, during bacterial growth, using an antibody microarray coupled to a Surface Plasmon Resonance imager (SPRi). Less than one bacterium (Salmonella enterica serovar Enteritidis) per milliliter of blood sample is successfully detected and identified in blood volumes similar to blood tests collected in clinics (i.e. several milliliters). This proof of concept demonstrates the workability of our method for human samples, despite the highly complex intrinsic nature of unprocessed blood. Our label-free method then opens new perspectives for direct and faster bacterial identification in a larger range of clinical samples. PMID- 28842713 TI - In vitro blood cell viability profiling of polymers used in molecular assembly. AB - Biocompatible polymers have been extensively applied to molecular assembly techniques on a micro- and nanoscale to miniaturize functional devices for biomedical uses. However, cytotoxic assessments of developed devices are prone to partially focus on non-specific cells or cells associated with the specific applications. Thereby, since toxicity is dependent on the type of cells and protocols, we do not fully understand the relative toxicities of polymers. Additionally, we need to ensure the blood cell biocompatibility of developed devices prior to that of targeted cells because most of the devices contact the blood before reaching the targeted regions. Motivated by this issue, we focused on screening cytotoxicity of polymers widely used for the layer-by-layer assembly technique using human blood cells. Cytotoxicity at the early stage was investigated on twenty types of polymers (positively charged, negatively charged, or neutral) and ten combination forms via hemolysis, cell viability, and AnnexinV FITC/PI staining assays. We determined their effects on the cell membrane depending on their surface chemistry by molecular dynamics simulations. Furthermore, the toxicity of LbL-assembled nanofilms was assessed by measuring cell viability. Based on this report, researchers can produce nanofilms that are better suited for drug delivery and biomedical applications by reducing the possible cytotoxicity. PMID- 28842714 TI - Potential therapeutic targets for ALS: MIR206, MIR208b and MIR499 are modulated during disease progression in the skeletal muscle of patients. AB - Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons followed by muscle weakness, paralysis and death. The disease progression is extremely variable among patients, and reliable prognostic markers have not been identified. The aim of the study was to functionally characterize selected genes and microRNAs acting in the skeletal muscle of ALS patients, taking into account the duration and evolution of the disease, in order to obtain information regarding the muscle response to ALS progression. This prospective, longitudinal study enrolled 14 ALS patients and 24 age- and sex-matched healthy controls. Gene expression and histological analysis indicated an increase of MIR208B and MIR499 levels and the predominance of slow fibres, respectively, in the muscles of patients with a slower disease progression. A decreased expression of MIR206 and increased levels of HDAC4, during the progression of the disease were also observed. Taken together, our data suggest that the molecular signalling that regulates re-innervation and muscle regeneration is hampered during the progression of skeletal muscle impairment in ALS. This could provide precious hints towards defining prognostic protocols, and designing novel tailored therapeutic approaches, to improve ALS patients' care and delay disease progression. PMID- 28842715 TI - High Serum Levels of Malondialdehyde and 8-OHdG are both Associated with Early Cognitive Impairment in Patients with Acute Ischaemic Stroke. AB - Post-stroke cognitive impairment (PSCI) is an increasingly prevalent sequel after stroke that may associate with poor functional outcome and increased risk of recurrent stroke. We aimed to explore the relationship between oxidative stress biomarkers and the presence of PSCI. 193 first-ever acute ischaemic stroke patients were consecutively enrolled in the current study. The oxidative stress biomarkers malondialdehyde (MDA) and 8-hydroxydeoxyquanosine (8-OHdG) were measured within 24 h after admission. Cognition function was evaluated by the Mini-Mental State Examination (MMSE) at 1 month after stroke. Serum levels of 8 OHdG and MDA were both significantly higher in the PSCI (p < 0.001) compared with the non-PSCI group. Both the serum levels of both 8-OHdG and MDA were negatively correlated with the MMSE score. Receiver operating characteristic curve analysis was used to evaluate 8-OHdG and MDA as markers of a high risk of PSCI and produced area under curve values of 0.700 and 0.793. Adjusted logistic regression showed that serum 8-OHdG and MDA levels remained as independent markers of PSCI. High serum levels of malondialdehyde and 8-OHdG are associated with the presence of PSCI at 1 month after stroke. PMID- 28842716 TI - Pharmacological Inhibition of PTEN Aggravates Acute Kidney Injury. AB - Renal ischemia/reperfusion is a major cause of acute kidney injury. However, the pathogenic mechanisms underlying renal ischemia/reperfusion injury (IRI) are not fully defined. Here, we investigated the role of PTEN, a dual protein/lipid phosphatase, in the development of ischemic AKI in mice. Pharmacological inhibition of PTEN with bpV(HOpic) exacerbated renal dysfunction and promoted tubular damage in mice with IRI compared with vehicle-treated mice with IRI. PTEN inhibition enhanced tubular cell apoptosis in kidneys with IRI, which was associated with excessive caspase-3 activation. Furthermore, PTEN inhibition expanded the infiltration of neutrophils and macrophages into kidneys with IRI, which was accompanied by increased expression of the proinflammatory molecules. These results have demonstrated that PTEN plays a crucial role in the pathogenesis of ischemic acute kidney injury through regulating tubular cell apoptosis and inflammation suggesting PTEN could be a potential therapeutic target for acute kidney injury. PMID- 28842717 TI - Three-Dimensional Geometric Morphometric Analysis of Fossil Canid Mandibles and Skulls. AB - Much of the fossil record for dogs consists of mandibles. However, can fossil canid mandibles be reliably identified as dogs or wolves? 3D geometric morphometric analysis correctly classifies 99.5% of the modern dog and wolf mandibles. However, only 4 of 26 Ust'-Polui fossil mandibles, a Russian Arctic site occupied from 250BCE to 150CE, were identified as dogs and none of the 20 Ivolgin mandibles, an Iron Age site in southern Russia, were identified as dogs. Three of the Ust'-Polui mandibles and 8 of the Ivolgin mandibles were identified as wolves. In contrast, all 12 Ivolgin skulls and 5 Ust'-Polui skulls were clearly identified as dogs. Only the classification of the UP6571 skull as a dog (Dog Posterior Probability = 1.0) was not supported by the typical probability. Other evidence indicates these canids were domesticated: they were located within human dwellings, remains at both sites have butchery marks indicating that they were consumed, and isotope analysis of canid and human remains from Ust'-Polui demonstrate that both were consuming freshwater protein; indicating that the humans were feeding the canids. Our results demonstrate that the mandible may not evolve as rapidly as the cranium and the mandible is not reliable for identifying early dog fossils. PMID- 28842718 TI - Laser treatment in urogynaecology and the myth of the scientific evidence. PMID- 28842719 TI - Ten tips to facilitate understanding and clinical use of esophageal pressure manometry. PMID- 28842720 TI - A map of human circular RNAs in clinically relevant tissues. AB - Cellular circular RNAs (circRNAs) are generated by head-to-tail splicing and are present in all multicellular organisms studied so far. Recently, circRNAs have emerged as a large class of RNA which can function as post-transcriptional regulators. It has also been shown that many circRNAs are tissue- and stage specifically expressed. Moreover, the unusual stability and expression specificity make circRNAs important candidates for clinical biomarker research. Here, we present a circRNA expression resource of 20 human tissues highly relevant to disease-related research: vascular smooth muscle cells (VSMCs), human umbilical vein cells (HUVECs), artery endothelial cells (HUAECs), atrium, vena cava, neutrophils, platelets, cerebral cortex, placenta, and samples from mesenchymal stem cell differentiation. In eight different samples from a single donor, we found highly tissue-specific circRNA expression. Circular-to-linear RNA ratios revealed that many circRNAs were expressed higher than their linear host transcripts. Among the 71 validated circRNAs, we noticed potential biomarkers. In adenosine deaminase-deficient, severe combined immunodeficiency (ADA-SCID) patients and in Wiskott-Aldrich-Syndrome (WAS) patients' samples, we found evidence for differential circRNA expression of genes that are involved in the molecular pathogenesis of both phenotypes. Our findings underscore the need to assess circRNAs in mechanisms of human disease. KEY MESSAGES: circRNA resource catalog of 20 clinically relevant tissues. circRNA expression is highly tissue specific. circRNA transcripts are often more abundant than their linear host RNAs. circRNAs can be differentially expressed in disease-associated genes. PMID- 28842721 TI - Value and potential limitations of vertebral fracture assessment (VFA) compared to conventional spine radiography: experience from a fracture liaison service (FLS) and a meta-analysis. AB - : We evaluated the value of VFA in the identification of vertebral fractures using a retrospective study and a meta-analysis. Performance of VFA was adequate in the meta-analysis although this was not demonstrated in our centre. We recommend checking the performance of VFA tools before exclusively relying on this tool. INTRODUCTION: Vertebral fractures are traditionally diagnosed using conventional radiographs of the spine. Vertebral fracture assessment (VFA) has been advocated as an alternative tool in the diagnosis of these fractures. METHODS: We conducted a retrospective study as well as a systematic review and a meta-analysis to evaluate the performance of VFA compared to conventional spinal radiography in patients who had sustained a fracture and thus at risk for osteoporosis. A risk of bias analysis was also performed. RESULTS: The diagnostic study included 542 patients (25% male) with fractures. The sensitivity of low radiation VFA to detect a patient with a vertebral fracture >= Genant grade 2 was 0.77 and its specificity 0.80. Two hundred ninety-seven (55%) patients had >=1 and 135(25%) >=3 unevaluable vertebrae. The systematic review identified 16 studies including a total of 3238 subjects (19% male) with a mean age range of 45 to 74 years. Seven studies had a low risk of bias and 9 had an intermediate risk, mainly due to not consecutively including patients. The pooled sensitivity of VFA to detect a patient with a vertebral fracture >=Genant grade 2 was 0.84 (95% CI, 0.72-0.92) and specificity 0.90 (95% CI, 0.84-0.94). CONCLUSIONS: Our findings from the meta-analysis suggest an adequate performance of VFA for the detection of vertebral fractures. However, we could not demonstrate these findings in our center, especially the specificity. Our data advocate caution with exclusively relying on VFA in the assessment of vertebral fractures without identifying performance and potential limitations of the technique. PMID- 28842724 TI - Discussion of the Article "Effects of Fat Grafting Containing Stem Cells in Microstomia and Microcheilia Derived from Systemic Sclerosis" by Dr. Blezien and Colleagues. PMID- 28842722 TI - Glucose effectiveness, but not insulin sensitivity, is improved after short-term interval training in individuals with type 2 diabetes mellitus: a controlled, randomised, crossover trial. AB - AIMS/HYPOTHESIS: The role of glucose effectiveness (S G) in training-induced improvements in glucose metabolism in individuals with type 2 diabetes is unknown. The objectives and primary outcomes of this study were: (1) to assess the efficacy of interval walking training (IWT) and continuous walking training (CWT) on S G and insulin sensitivity (S I) in individuals with type 2 diabetes; and (2) to assess the association of changes in S G and S I with changes in glycaemic control. METHODS: Fourteen participants with type 2 diabetes underwent three trials (IWT, CWT and no training) in a crossover study. Exclusion criteria were exogenous insulin treatment, smoking, pregnancy, contraindications to structured physical activity and participation in recurrent training (>90 min/week). The trials were performed in a randomised order (computerised generated randomisation). IWT and CWT consisted of ten supervised treadmill walking sessions, each lasting 60 min, over 2 weeks. IWT was performed as repeated cycles of 3 min slow walking and 3 min fast walking (aiming for 54% and 89% of [Formula: see text], respectively, which was measured during the last minute of each interval), and CWT was performed aiming for a moderate walking speed (73% of [Formula: see text]). A two-step (pancreatic and hyperinsulinaemic) hyperglycaemic clamp was implemented before and after each trial. All data were collected in a hospitalised setting. Neither participants nor assessors were blinded to the trial interventions. RESULTS: Thirteen individuals completed all procedures and were included in the analyses. IWT improved S G (mean +/- SEM: 0.6 +/- 0.1 mg kg-1 min-1, p < 0.05) but not S I (p > 0.05), whereas CWT matched for energy expenditure and time duration improved neither S G nor S I (both p > 0.05). Changes in S G, but not in S I, were associated with changes in mean (beta = -0.62 +/- 0.23, r 2 = 0.17, p < 0.01) and maximum (beta = -1.18 +/- 0.52, r 2 = 0.12, p < 0.05) glucose levels during 24 h continuous glucose monitoring. CONCLUSIONS/INTERPRETATION: Two weeks of IWT, but not CWT, improves S G but not S I in individuals with type 2 diabetes. Moreover, changes in S G are associated with changes in glycaemic control. Therefore, increased S G is likely an important mechanism by which training improves glycaemic control in individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02320526 FUNDING: CFAS is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The study was further supported by grants from Diabetesforeningen, Augustinusfonden and Krista og Viggo Petersens Fond. CIM/CFAS is a member of DD2-the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant no. 09-067009 and 09 075724). PMID- 28842725 TI - [Diagnosis of non-epileptic paroxysmal disorders and epileptic seizures]. AB - Non-epileptic paroxysmal disorders may clinically manifest in a similar way to epileptic seizures and have to be considered in the differential diagnosis of epilepsy. Syncope, non-epileptic psychogenic seizures, paroxysmal movement disorders, migraine, transient ischemic attacks and parasomnia constitute the major differential diagnoses. A meticulous history and a third party description are useful for the differential diagnosis. Neurological, psychiatric and cardiological examinations are required for the correct differential diagnosis. The interictal electroencephalogram (EEG), which is normal in non-epileptic patients, is frequently normal in epileptic patients at the onset of seizures, but reaches a high sensitivity after repeated recordings. In equivocal cases EEG video monitoring and in the case of suspected cardiac asystole, event recorders are useful diagnostic tools. PMID- 28842726 TI - Laparoscopic D2 total gastrectomy and en-mass splenectomy and distal pancreatectomy for locally advanced proximal gastric cancer. AB - BACKGROUND: Safety and efficacy of laparoscopy surgery in locally Advanced Gastric Cancers (AGC) have not been proven by randomized control trials. Therefore, standard of care for AGC is still open surgery. Here, we are presenting a 64-year-old female with proximal gastric adenocarcinoma (close to cardio-oesophageal junction) adherent to tail of pancreas, who underwent D2 total gastrectomy en-mass distal pancreatectomy and splenectomy. METHODS: Five ports are entered into the peritoneal cavity (Three 10-12 mm and two 5 mm ports). Another 5 mm stab incision is made in the epigastrium for Nathanson Liver retractor. Standard D2 Gastrectomy was performed with en-mass removal of the spleen and body and tail of the pancreas. Roux-en-Y oesophago-jejunostomy (Hand sewn) and Jejuno-Jejunostomy reconstruction were performed laparoscopically. Hereby, we present a video of the above procedure. RESULTS: Total Operating time was 235 min. Post-operatively the patient was able to mobilize independently. Total Parenteral Nutrition (TPN) was started and continued until post-operative day (POD) 7 once gastrografin test and blue dye test both showed no anastomotic leak. Patient started on oral feeding and was discharged home well on POD 9. Histology showed poorly differentiated adenocarcinoma with pT3N3b (17 nodes out of 62 positive). CONCLUSION: Although laparoscopic D2 gastrectomy and en-mass distal pancreatectomy and splenectomy are feasible and safe in advanced gastric carcinoma, its oncological value has yet to be determined. PMID- 28842727 TI - Effect of vitamin D3 on bone turnover markers in critical illness: post hoc analysis from the VITdAL-ICU study. AB - : In this post hoc analysis of the VITdAL-ICU study, an RCT in critically ill adults with 25-hydroxyvitamin D levels <=20 ng/ml, vitamin D3 did not have a significant effect on beta-Crosslaps and osteocalcin. INTRODUCTION: Observational studies have shown accelerated bone loss in ICU survivors. A reversible contributor is vitamin D deficiency. In a post hoc analysis of the VITdAL-ICU study, we evaluated the effect of high-dose vitamin D3 on the bone turnover markers (BTM) beta-Crosslaps (CTX) and osteocalcin (OC). METHODS: The VITdAL-ICU study was a randomized, double-blind, placebo-controlled trial in critically ill adults with 25-hydroxyvitamin D levels <=20 ng/ml who received placebo or high dose vitamin D3 (a loading dose of 540,000 IU and starting 1 month after the loading dose five monthly maintenance doses of 90,000 IU). In this analysis on 289 survivors (209 telephone, 80 personal follow-up visits), BTM were analyzed on days 0, 3, 7, 28, and 180; self-reported falls and fractures were assessed. Bone mineral density (BMD) was measured after 6 months. RESULTS: At baseline, CTX was elevated; OC was low in both groups-after 6 months, both had returned to normal. There were no differences between groups concerning BTM, BMD, falls, or fractures. In linear mixed effects models, CTX and OC showed a significant change over time (p < 0.001, respectively), but there was no difference between the vitamin D and placebo group (p = 0.688 and p = 0.972, respectively). CONCLUSIONS: Vitamin D supplementation did not have a significant effect on BTM. Further studies should assess the effectiveness of vitamin D on musculoskeletal outcomes in ICU survivors. PMID- 28842729 TI - [On the road to psychiatric reform : Reconstructing the political preparation of the first Enquete Commission of the German Bundestag]. AB - BACKGROUND: The purpose of this paper is to analyze the political preparation of the Enquete Commission of the German Bundestag which aimed at assessing and improving the psychiatric and psychotherapeutic/psychosomatic care in the Federal Republic of Germany. METHODS: We performed a selective literature review and a hermeneutic analysis of political, parliamentary and administrative records from public archives which reflect and help reconstruct the run-up process to the so called Enquete of psychiatry. RESULTS: Literature and documents show how individual actors both in the mental health professions and politics bundled activities in the domains of psychiatry and mental health care as well as health/social politics; they helped to implement political, parliamentary and administrative steps leading up to the Enquete of the German Bundestag (1971 1975). In addition, the records and pertinent literature document the social, cultural and political developments in the Federal Republic of Germany which helped initiate the Enquete project. CONCLUSION: The Enquete was not a straightforward process and was also not tied to any moment. It fits more into the longer-term reform process of psychiatry in the Federal Republic of Germany. PMID- 28842728 TI - Discrepancy between bone density and bone material strength index in three siblings with Camurati-Engelmann disease. AB - : Camurati-Engelmann (CE) is a very rare disease affecting one in every million persons worldwide. It is characterized by an enlargement of long bones. We aimed to assess bone characteristics in three siblings with different tools. Even if there was an excess of bone density, quality seemed to be deteriorated. INTRODUCTION: CE disease is a rare monogenic disorder affecting approximately one in every million persons worldwide. It is mainly characterized by a progressive hyperostosis of the periosteum and endosteum of the diaphysis of long bones. Limited data are available about bone characteristics in these patients. In three siblings with CE disease, we aimed to assess bone mineral density (BMD) and trabecular bone score (TBS) by dual-energy X-ray absorptiometry (DXA) and material characteristics at tissue level using bone impact reference point indentation. METHODS: Clinical data were collected and a general laboratory workup was performed. At the lumbar spine and hip, BMD and TBS were measured using DXA imaging. Bone material strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. RESULTS: All three cases had densitometric values consistent with high bone mass (sum of Z-score at the lumbar spine and hip > 4). Hip BMD was extremely high in all three siblings at both total hip and femoral neck, while at the lumbar spine, two of them had normal values but the third again had very high BMD. TBS values were in the normal range. In contrast, BMSi measurements were at low or very low levels, compared with normal controls. CONCLUSION: Despite strikingly increased BMD and normal microarchitecture, BMSi is affected in patients with CE. Microindentation could be an appropriate tool for assessing bone fragility in these patients. Bone disease in this group of patients requires further study to better understand the underlying regulatory mechanisms and their alterations. PMID- 28842730 TI - Evidence-based prioritisation and enrichment of genes interacting with metformin in type 2 diabetes. AB - AIMS/HYPOTHESIS: There is an extensive body of literature suggesting the involvement of multiple loci in regulating the action of metformin; most findings lack replication, without which distinguishing true-positive from false-positive findings is difficult. To address this, we undertook evidence-based, multiple data integration to determine the validity of published evidence. METHODS: We (1) built a database of published data on gene-metformin interactions using an automated text-mining approach (n = 5963 publications), (2) generated evidence scores for each reported locus, (3) from which a rank-ordered gene set was generated, and (4) determined the extent to which this gene set was enriched for glycaemic response through replication analyses in a well-powered independent genome-wide association study (GWAS) dataset from the Genetics of Diabetes and Audit Research Tayside Study (GoDARTS). RESULTS: From the literature search, seven genes were identified that are related to the clinical outcomes of metformin. Fifteen genes were linked with either metformin pharmacokinetics or pharmacodynamics, and the expression profiles of a further 51 genes were found to be responsive to metformin. Gene-set enrichment analysis consisting of the three sets and two more composite sets derived from the above three showed no significant enrichment in four of the gene sets. However, we detected significant enrichment of genes in the least prioritised category (a gene set in which their expression is affected by metformin) with glycaemic response to metformin (p = 0.03). This gene set includes novel candidate genes such as SLC2A4 (p = 3.24 * 10 04) and G6PC (p = 4.77 * 10-04). CONCLUSIONS/INTERPRETATION: We have described a semi-automated text-mining and evidence-scoring algorithm that facilitates the organisation and extraction of useful information about gene-drug interactions. We further validated the output of this algorithm in a drug-response GWAS dataset, providing novel candidate loci for gene-metformin interactions. PMID- 28842731 TI - Implementing early physical rehabilitation and mobilisation in the ICU: institutional, clinician, and patient considerations. PMID- 28842732 TI - [Preclinical use of mild therapeutic hypothermia after cardiac arrest by the emergency services in Baden-Wurttemberg, Germany]. AB - BACKGROUND: During the last decade target temperature management has become an integral part of postresuscitation care. Within recent years there was a strong debate about the optimal target temperature, which might have effects on the preclinical induction of hypothermia. The present investigation focuses on the use of mild therapeutic hypothermia by emergency services in the state of Baden Wurttemberg (Germany) and compares it to results of a prior study in 2008. METHODS: Between April and August 2014 a questionnaire was sent to all senior emergency physicians of emergency services in Baden Wurttemberg. The survey period was April to August of 2014. Parts of the questionnaire were similar to a previous one in 2008, to ensure comparability to the former data; other parts were added to set new focuses. The data were analyzed in anonymized form. RESULTS: The response rate was 72.4% (97/134). Of the 97 sites which responded to the questionnaire significantly more use preclinical hypothermia, compared to 2008 (72.2% [70/97] vs. 41.7%); 62.9% (44/70) declare cooling resuscitated patients routinely (vs. 17.7% in 2008). Cold infusions (85.7%), icepacks (64.3%), passive cooling (37.1%), nasal cooling (2.9%) and cooling caps (1.4%) are used (multiple naming was possible). Sites that did not use mild therapeutic hypothermia stated the following reasons: lack of equipment, short transport time and missing data for the intervention. Four sites reported on complications with therapeutic hypothermia. CONCLUSION: The present investigation shows an increased use of preclinical cooling after cardiopulmonary resuscitation as compared to 2008. Therefore, recent discussions concerning the optimal target temperature in postresuscitation care did not result in a waiving of preclinical therapeutic strategies in Baden-Wurttemberg. The emergency services sites/locations estimated the complication rates of mild therapeutic hypothermia as very low. Lack of equipment seems to be the main reason to refuse the preclinical use of therapeutic hypothermia. In conclusion, preclinical mild therapeutic hypothermia has become an integral part in the standard care of resuscitated patients in Baden-Wurttemberg. PMID- 28842733 TI - Increasing alkali supplementation decreases urinary nitrogen excretion when adjusted for same day nitrogen intake. AB - : We examined whether escalating doses of potassium bicarbonate (KHCO3) supplements alter urinary nitrogen excretion expressed as a ratio to same day nitrogen intake (measure of muscle-protein breakdown). The ratio declined significantly from placebo to low to high dose of KHCO3 supplementation in older adults over 3 months, suggesting muscle-sparing. INTRODUCTION: Neutralization of dietary acid load with alkali supplementation (i.e., KHCO3) has been hypothesized to have muscle protein-sparing effects. In controlled feeding studies with fixed nitrogen (N) intake/day, 24-h urinary N excretion is a good marker of muscle breakdown. However, in studies with self-selected diets, changes in 24-h urinary N excretion can be influenced by shifts in N intake. METHODS: We evaluated changes in 24-h total urinary N excretion as a ratio of N excretion to concurrent N intake in 233 older men and women who participated in an 84-day KHCO3 supplementation randomized placebo-controlled trial. RESULTS: After adjustment for relevant cofactors, escalating doses of KHCO3 (1 mmol/kg/day [low] or 1.5 mmol/kg/day [high]) resulted in a progressive decline in urinary N excretion/N intake compared to placebo (overall P for trend = 0.042). The 84-day change in urinary N excretion/N intake in the high-dose KHCO3 group was statistically significantly lower compared to placebo (P = 0.012) but not compared to the low dose KHCO3 group (P = 0.276). The 84-day change in urinary N excretion/N intake in the low-dose KHCO3 group did not differ significantly from placebo (P = 0.145). CONCLUSIONS: Urinary N excretion expressed as ratio to same day N intake declined steadily with increasing doses of KHCO3 supplementation from low 1 mmol/kg/day to high 1.5 mmol/kg/day, suggesting a nitrogen-sparing effect. Compared to urinary N excretion alone, this ratio could be a more reasonable measure of muscle protein metabolism in large-scale long-term human studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT1475214. PMID- 28842734 TI - [Resection of main duct and mixed type IPMN >=5 mm]. AB - The incidence of cystic pancreatic lesions is steadily increasing due to the technical advances in imaging. Within the group of cystic pancreatic lesions intraductal papillary mucinous neoplasms (IPMNs) depict an important entity. Due to a possible progression to malignancy the clinical strategy has to be well chosen. For primary diagnostic work-up imaging by magnetic resonance imaging (MRI) with MR cholangiopancreatography (MRCP) and computed tomography (CT) scanning is recommended. Additional information can be gained by endosonography and a biopsy of the cystic lesion, allowing analysis of biomarkers, such as GNAS and KRAS mutation as wells as NLR. These can help to differentiate between IPMN and other cystic lesions although the clinical importance for the diagnosis of main duct (MD) and mixed IPMN is limited. The current guidelines (Fukuoka and EU guidelines) recommend resection of MD and mixed IPMN following oncological standards. For the definition of MD-IPMN, a duct dilatation between 5-10 mm is needed when following the current guidelines; however, current publications claim an even lower cut-off of >=5 mm due to the risk of malignant progression. Intraoperative frozen sections are recommended to evaluate the margins status and extended resection is recommended for residual high-grade dysplasia. Surveillance of potentially at risk patients is recommended at regular intervals of 6-12 months while patients with malignant IPMN should be followed according to pancreatic cancer protocols. A screening for extrapancreatic malignancy is not indicated. PMID- 28842735 TI - [Postoperative blood pressure alterations after carotid endarterectomy : Implications of different reconstruction methods]. AB - BACKGROUND: Postoperative blood pressure alterations after carotid endarterectomy (CEA) are associated with an increased risk of morbidity and mortality. OBJECTIVE: To outline the influence of the two commonly used surgical reconstruction techniques, conventional CEA with patch plasty (C-CEA) and eversion CEA (E-CEA), as well as the innovative carotid sinus-preserving eversion CEA (SP-E-CEA) technique on postoperative hemodynamics, taking the current scientific knowledge into consideration. METHODS: Assessment of the current clinical and scientific evidence on each operative technique found in the PubMed (NLM) database ranging from 1974 to 2017, excluding case reports. RESULTS: A total of 34 relevant papers as well as 1 meta-analysis, which scientifically dealt with the described topic were identified. The results of the studies and the meta-analysis showed that E-CEA correlates with an impairment of local baroreceptor functions as well as with an elevated need for vasodilators in the early postoperative phase, whereas C-CEA and SP-E-CEA seem to have a more favorable effect on the postoperative blood pressure. CONCLUSION: The CEA technique influences the postoperative blood pressure regulation, irrespective of the operative technique used. Accordingly, close blood pressure monitoring is recommended at least during the postoperative hospital stay. Further studies are mandatory to evaluate the importance of SP-E-CEA as an alternative to the classical E-CEA. PMID- 28842736 TI - [Minimally invasive and robot-assisted surgery for pancreatic cystic tumors]. AB - BACKGROUND: The indications for resection of pancreatic cystic lesions (PCL) are often complex and the operative risk has to be balanced against the risk of malignant transformation. The aim of the study was to provide a synopsis of the current treatment results of minimally invasive surgery for PCL. METHODS: A systematic literature search was performed using the Medline database (PubMed). Subsequently, the retrieved literature was selectively reviewed. RESULTS: No published prospective randomized controlled trials have yet addressed the comparison of open and minimally invasive surgery of PCL; however, retrospective case studies have demonstrated the feasibility, safety and a comparable morbidity after minimally invasive distal pancreatectomy (DP), pancreatoduodenectomy (PD), central (CP) or total pancreatectomy and enucleation. Whereas most DPs are performed laparoscopically, the experience of minimally invasive PD has been consolidated for the robot-assisted approach but is concentrated in only a few centers. The number of published reports on minimally invasive organ-sparing pancreas procedures (e. g. CP or enucleation) for PCL is scarce; however, the available (selected) results are promising. CONCLUSION: Minimally invasive surgery for PCL has the potential to reduce the operative trauma to the patients, while at the same time causing comparable or less morbidity. This requires an increasing specialization of complex minimally invasive resections. The clinical use of robotic systems will grow for the latter cases. A prospective registry of the results should be mandatory for quality management. PMID- 28842737 TI - Is the unadjusted ICU mortality a good indicator of quality of ICU care? PMID- 28842738 TI - A new LC-MS/MS bioanalytical method for perindopril and perindoprilat in human plasma and milk. AB - A first of its kind, simple, rapid, and sensitive liquid chromatography mass spectrometry (LC-MS/MS) method was developed and validated for quantification of perindopril and perindoprilat in both human plasma and breast milk. The analytes and internal standards (phenazone and acetyl salicylic acid) were extracted from biological matrices by protein precipitation. A Phenomenex(r) C-18 column was used to provide an appropriate chromatographic separation of the analytes, followed by detection with tandem mass spectrometry. Gradient chromatographic and mass spectrometric detection conditions with mobile phases (A: 5% methanol + 0.1% formic acid in water v/v, and B: 95% methanol + 0.1% formic acid in water v/v) were developed to achieve a LOQ of 0.5 ng/mL in both human plasma and milk. The method was suitable of evaluating clinical samples. The mass transition was followed as m/z 369.10/172.00 for perindopril, m/z 339.00/168.10 for perindoprilat, m/z 188.90/55.95 for phenazone, and m/z 179.04/137.02 for acetyl salicylic acid. The developed method was optimized and validated with a linear range of 0.1-200 ng/mL (r 2 = better than 0.99 for both perindopril and perindoprilat). The precision and accuracy values were within 15% CV. The overall recovery of the analytes was 80-110%. The method has good specificity and repeatability. Stability studies were conducted in both human plasma and bovine milk for up to 3 months, at the storage conditions of 25, 4, and -80 degrees C. PMID- 28842739 TI - Exploring metal artifact reduction using dual-energy CT with pre-metal and post metal implant cadaver comparison: are implant specific protocols needed? AB - OBJECTIVE: To quantify and optimize metal artifact reduction using virtual monochromatic dual-energy CT for different metal implants compared to non-metal reference scans. METHODS: Dual-energy CT scans of a pair of human cadaver limbs were acquired before and after implanting a titanium tibia plate, a stainless steel tibia plate and a titanium intramedullary nail respectively. Virtual monochromatic images were analyzed from 70 to 190 keV. Region-of-interest (ROI), used to determine fluctuations and inaccuracies in CT numbers of soft tissues and bone, were placed in muscle, fat, cortical bone and intramedullary tibia canal. RESULTS: The stainless-steel implant resulted in more pronounced metal artifacts compared to both titanium implants. CT number inaccuracies in 70 keV reference images were minimized at 130, 180 and 190 keV for the titanium tibia plate, stainless-steel tibia plate and titanium intramedullary nail respectively. Noise, measured as the standard deviation of pixels within a ROI, was minimized at 130, 150 and 140 keV for the titanium tibia plate, stainless-steel tibia plate and titanium intramedullary nail respectively. CONCLUSION: Tailoring dual-energy CT protocols using implant specific virtual monochromatic images minimizes fluctuations and inaccuracies in CT numbers in bone and soft tissues compared to non-metal reference scans. PMID- 28842740 TI - Lactococcus lactis as a safe and inexpensive source of bioactive silver composites. AB - This research develops a safe, inexpensive, and more accessible source for synthesis of silver nanoparticles. The bioactive silver composites synthesized by Lactococcus lactis 56 KY484989 (LCLB56-AgCs) were characterized by various physico-chemical techniques and investigated for their antimicrobial activity and cytotoxicity. The average amount of nanoparticles was 0.363 +/- 0.09 mg from 50 mL of culture medium. The synthesis efficiency varied from 71 to 85%. Synthesized silver nanoparticles with spherical in shape were found to be of 5-50 nm and average diameter 19 +/- 2 nm. Based on the shape of isotopic pattern of d electrons metals, the signals of silver isotopes [107Ag]+ at m/z 106.905 and [109Ag]+ at m/z 108.910 were confirmed. Moreover, LCLB56-AgCs exerted an inhibitory effect against all tested bacterial strains (Pseudomonas aeruginosa ATCC10145, Proteus mirabilis ATCC25933, Staphylococcus epidermidis ATCC49461, MSSA ATCC29213, and Staphylococcus aureus ATCC6338). More pronounced antimicrobial effect was noticed for 15 MUg/well. Minimum inhibitory concentration required to inhibite the growth of 90% organism (MIC90) of synthetized LCLB56-AgCs was in a range of 3.125-12.5 MUg/mL. The concentration at which the viability of the L929 cells was reduced to 50% was above 200 MUg/mL for LCLB56-AgNCs. These results open up possibilities for many applications of bioactive silver composites (BioAgCs) synthesized by L. lactis 56 in food and pharmaceutical industries. PMID- 28842741 TI - Response Assessment in Neuro-Oncology criteria, contrast enhancement and perfusion MRI for assessing progression in glioblastoma. AB - PURPOSE: The purpose of the study was to evaluate Response Assessment in Neuro Oncology (RANO) criteria in glioblastoma multiforme (GBM), with respect to the Macdonald criteria and changes in contrast-enhancement (CE) volume. Related variations in relative cerebral blood volume (rCBV) were investigated. METHODS: Forty-three patients diagnosed between 2006 and 2010 were included. All underwent surgical resection, followed by temozolomide-based chemoradiation. MR images were retrospectively reviewed. Times to progression (TTPs) according to RANO criteria, Macdonald criteria and increased CE volume (CE-3D) were compared, and the percentage change in the 75th percentile of rCBV (rCBV75) was evaluated. RESULTS: After a median follow-up of 22.7 months, a total of 39 patients had progressed according to RANO criteria, 32 according to CE-3D, and 42 according to Macdonald. Median TTPs were 6.4, 9.3, and 6.6 months, respectively. Overall agreement was 79.07% between RANO and CE-3D and 93.02% between RANO and Macdonald. The mean percentage change in rCBV75 at RANO progression onset was over 73% in 87.5% of patients. CONCLUSIONS: In conclusion, our findings suggest that CE-3D criterion is not yet suitable to assess progression in routine clinical practice. Indeed, the accurate threshold is still not well defined. To date, in our opinion, early detection of disease progression by RANO combined with advanced MRI imaging techniques like MRI perfusion and diffusion remains the best way to assess disease progression. Further investigations that would examine the impact of treatment modifications after progression determined by different criteria on overall survival would be of great value. PMID- 28842742 TI - In vitro, contrast agent-based evaluation of the influence of flow diverter size and position on intra-aneurysmal flow dynamics using syngo iFlow. AB - PURPOSE: Treatment of intracranial aneurysm with flow-diverting devices has become widespread in recent years. Despite that, intra-aneurysmal flow changes are yet not fully understood and can lead to different complications. Our aim was an in vitro contrast-based evaluation of the influence of flow diverter size and position on intra-aneurysmal flow dynamics. METHODS: Flow-diverting devices with different sizes (diameters 4.0, 4.5, and 6.0 mm) were deployed in seven silicone aneurysm models at different positions relative to the aneurysm neck (proximal, central, distal). Using syngo iFlow, we defined quantitative evaluation criteria based on contrast medium intensity and performed a flow evaluation. RESULTS: Intra-aneurysmal flows were heavily dependent on both size and position of flow diverting devices at the aneurysm neck. We observed a higher peak intensity delay and intra-aneurysmal washout delay with the centrally placed 4.0- and 4.5-mm device, respectively, compared to the proximal and distal positions. Especially distally placed 4.0-mm devices led to an earlier filling of the aneurysm and increased intra-aneurysmal contrast agent intensity compared to the parent vessel, due to a potential endoleak. CONCLUSIONS: Not only size but also position of flow-diverting devices have a considerable impact on the intra-aneurysmal flow dynamics. The suggested evaluation criteria allowed a quantitative comparison of flow-diverting effect using syngo iFlow and could represent an efficient tool for predicting flow diversion pre-procedurally. PMID- 28842743 TI - An improvement of miRNA extraction efficiency in human plasma. AB - MicroRNAs (miRNAs) are short noncoding RNA molecules that control the expression of mRNAs associated with various biological processes. Therefore, deregulated miRNAs play important roles in the pathogenesis of diseases. Numerous studies are aimed at discovering biomarkers of diseases or determining miRNA functions by monitoring circulating miRNAs in various biological sources such as plasma and urine. However, the analysis of miRNA in such fluids presents problems related to accuracy and reproducibility because of their low levels in biological fluids. Therefore, better extraction kits and more sensitive detection systems have been developed for improved and reproducible analysis of circulating miRNAs. However, new extraction methods are also needed to improve the yield of miRNAs for their reliable analysis from biological fluids. The combination of yeast transfer RNA (tRNA) and glycogen as carrier molecules and incubation durations were optimized to maximize extraction efficiency. The extraction recovery using a combination of yeast tRNA and glycogen was approximately threefold more than that by using glycogen or yeast tRNA alone. In addition, reproducible and accurate analysis of miRNAs can be carried out after extraction using a combination of yeast tRNA and glycogen without an impact on plasma components. Graphical abstract Steps of miRNA extraction in plasma. PMID- 28842744 TI - Multisite tumor sampling enhances the detection of intratumor heterogeneity at all different temporal stages of tumor evolution. AB - Intratumor heterogeneity (ITH) is an inherent process of tumor development that has received much attention in previous years, as it has become a major obstacle for the success of targeted therapies. ITH is also temporally unpredictable across tumor evolution, which makes its precise characterization even more problematic since detection success depends on the precise temporal snapshot at which ITH is analyzed. New and more efficient strategies for tumor sampling are needed to overcome these difficulties which currently rely entirely on the pathologist's interpretation. Recently, we showed that a new strategy, the multisite tumor sampling, works better than the routine sampling protocol for the ITH detection when the tumor time evolution was not taken into consideration. Here, we extend this work and compare the ITH detections of multisite tumor sampling and routine sampling protocols across tumor time evolution, and in particular, we provide in silico analyses of both strategies at early and late temporal stages for four different models of tumor evolution (linear, branched, neutral, and punctuated). Our results indicate that multisite tumor sampling outperforms routine protocols in detecting ITH at all different temporal stages of tumor evolution. We conclude that multisite tumor sampling is more advantageous than routine protocols in detecting intratumor heterogeneity. PMID- 28842745 TI - Diagnosis of long head of biceps tendinopathy in rotator cuff tear patients: correlation of imaging and arthroscopy data. AB - INTRODUCTION: The goal of this prospective study was to assess the reliability of pre-operative cross-sectional imaging for the diagnosis of long head of biceps (LHB) tendinopathy in patients with a rotator cuff tear. METHODS: Cross-sectional imaging with MRI or CT arthrography data from 25 patients operated upon because of a rotator cuff tear between 1 October 2015 and 1 April 2016 was analysed by one experienced orthopaedic surgeon, one experienced radiologist and one orthopaedic resident. The analysis consisted of determining whether the LHB was present, the extrinsic tendon abnormalities (dislocation, tendon coverage) and intrinsic abnormalities (fraying, inflammation, degeneration). These findings were then compared to intra-operative arthroscopy findings, which were used as the benchmark. The interobserver correlation between the three different examiners for the cross-sectional imaging analysis as well as the correlation between the imaging and arthroscopy data were determined. RESULTS: The correlation between the imaging and arthroscopy data was the highest (80%) for the determination of LHB dislocation from the bicipital groove. The other diagnostic elements (subluxation, coverage and tendon degeneration) were difficult to discern with preoperative imaging, and correlated poorly with the arthroscopy findings (45% to 65%). The interobserver correlation was moderate to strong for the diagnosis of extrinsic tendon abnormalities. It was low to moderate for intrinsic abnormalities. CONCLUSION: Except for LHB dislocation, pre operative imaging is not sufficient to make a reliable diagnosis of LHB tendinopathy. Arthroscopy remains the gold standard for the management of LHB tendinopathy, as diagnosed intra-operatively. PMID- 28842746 TI - Expression profiling and immunolocalization of Na+-D-glucose-cotransporter 1 in mice employing knockout mice as specificity control indicate novel locations and differences between mice and rats. AB - The expression and localization of sodium-D-glucose cotransporter SGLT1 (SLC5A1), which is involved in small intestinal glucose absorption and renal glucose reabsorption, is of high biomedical relevance because SGLT1 inhibitors are currently tested for antidiabetic therapy. In human and rat organs, detailed expression profiling of SGLT1/Sglt1 mRNA and immunolocalization of the transporter protein has been performed. Using polyspecific antibodies and preabsorption with antigenic peptide as specificity control, in several organs, different immunolocalizations of SGLT1/Sglt1 between human and rat were obtained. Because the preabsorption control does not exclude cross-reactivity with similar epitopes, some localizations remained ambiguous. In the present study, we performed an immunocytochemical localization of Sglt1 in various organs of mice. Specificities of the immunoreactions were evaluated using antibody preabsorption with the Sglt1 peptide and the respective organs of Sglt1 knockout mice. Because staining in some locations was abolished after antibody preabsorption but remained in the knockout mice, missing staining in knockout mice was used as specificity criterion. The immunolocalization in mouse was identical or similar to rat in many organs, including small intestine, liver, and kidney. However, the male-dominant renal Sglt1 protein expression in mice differed from the female dominant expression in rats, and localization in lung, heart, and brain observed in rats was not detected in mice. In mice, several novel locations of Sglt1, e.g., in eyes, tongue epithelial cells, pancreatic ducts, prostate, and periurethral glands were detected. Using end-point and quantitative RT-PCR in various organs, different Sglt1 expression in mice and rats was confirmed. PMID- 28842747 TI - Increased SOX2 expression in salivary gland carcinoma ex pleomorphic adenoma progression: an association with adverse outcome. AB - SOX2 is a regulatory factor of embryonic stem cells that has been implicated in carcinogenesis and cancer progression. We aimed to investigate the potential role of SOX2 in the stepwise progression from pleomorphic adenoma (PA) to invasive carcinoma ex pleomorphic adenoma (CXPA), evaluating its prognostic significance as well. Thirty PAs without malignant transformation and 25 CXPAs presenting both luminal or myoepithelial differentiation (7 intracapsular and 18 extracapsular) were evaluated immunohistochemically for SOX2 expression. Of these, 24 CXPAs (96%) were positive to SOX2, being 6 intracapsular carcinomas (85.7%) and all the 18 extracapsular carcinomas (100%). Residual PA areas and PA without malignant transformation were negative. High SOX2 expression levels (> 50% of positive cells) were correlated with high histological grade (p = 0.02), brisk mitotic activity (p = 0.01), advanced pT stage (p = 0.01), tumor recurrence (p = 0.01), and development of distant metastasis (p = 0.004). Still, overall survival rates were shorter in patients with extracapsular CXPA exhibiting diffuse SOX2 expression. These results suggest that SOX2 may play an important role in carcinogenesis and progression of CXPA and is also related with prognostic indicators in CXPAs with extracapsular invasion. Although direct therapeutic intervention in SOX2 may result in unwanted complications due to its constitutive functions, strategic approach to SOX2-related pathways may provide new therapeutic opportunities for patients with invasive CXPA. PMID- 28842748 TI - PD-L1 expression correlates with VEGF and microvessel density in patients with uniformly treated classical Hodgkin lymphoma. AB - Recent studies have reported the associations between programmed death-ligand 1 (PD-L1) or PD-L2/PD-1 pathways and pro-angiogenic genes including hypoxia inducible factors (HIFs) and vascular endothelial growth factor (VEGF) in several malignancies. However, no study has examined the relationship or prognostic implication of PD-L1, PD-L2, PD-1, VEGF expression, and microvessel density (MVD) in classical Hodgkin lymphoma (cHL) patients. Diagnostic tissues from 109 patients with doxorubicin, bleomycin, vinblastine, and dacarbazine-treated cHL were evaluated retrospectively by immunohistochemical analysis for PD-L1, PD-L2, PD-1, VEGF expression, and for CD31 expression as a measure of MVD. There was a positive correlation between PD-L1 and VEGF expression (P = 0.008) and additionally between PD-L2 and VEGF expression (P = 0.001). The mean MVD in tumors positive for both PD-L1 and VEGF was significantly (P = 0.022) higher than the mean MVD in tumors negative for both markers. High PD-1 expression group had lower (P = 0.019) 5-year overall survival rate than low PD-1 expression group. Multivariate analysis revealed that PD-1 was an independent prognostic factor for cHL with significance (P = 0.026). However, PD-L1, PD-L2, and VEGF expression had no prognostic impact. Our data confirmed the positive correlations between PD-L1, VEGF, or MVD. Our findings provided evidence supporting new therapeutic approaches including combinations of anti-PD-L1/PD-1 and anti-VEGF therapy in addition to the current standard regimen for cHL. PMID- 28842750 TI - [Requirements of neurologists for autopsies]. AB - BACKGROUND: In assuring the quality of the healthcare system, it is the intention of healthcare politics to raise the number of clinical autopsies. OBJECTIVE: What are the requirements of clinical neurologists for neuroautopsies and how can the post-mortem examiner cope with these requests? METHODS: Discussion on how the questions that arise with the most relevant neurological disease groups can be solved by post-mortem examination. RESULTS: The diagnostics of inflammatory, inflammatory demyelinating and demyelinating brain diseases, neurodegenerative diseases and neuromuscular diseases as well as central nervous system tumors necessitate the removal of specific brain regions, specific examination techniques, immunohistochemical investigations or specific samples taken for biochemical, molecular pathological or genetic investigations according to international published consensus criteria. It is the first priority in post mortem examinations to use all possible options and appraisals to identify patients with the aforementioned neurological diseases or suspected diseases early enough during the autopsy process that the tissue sampling, necessary for diagnosing the assumed diseases, will take place. CONCLUSION: Demands made on neuropathological investigations have increased tremendously, because of rapid progress in understanding chronic neurological diseases and the requirements of consensus criteria. To cope with expectations on neuropathological post-mortem investigations, a close collaboration should be established between clinical neurologists, post-mortem examiners and neuropathologists. PMID- 28842751 TI - Reply to the letter to the editor: Two-year results of treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy. PMID- 28842749 TI - Complement as a regulator of adaptive immunity. AB - The complement system is an ancient and evolutionarily conserved effector system comprising in mammals over 50 circulating and membrane bound proteins. Complement has long been described as belonging to the innate immune system; however, a number of recent studies have demonstrated its key role in the modulation of the adaptive immune response. This review does not set out to be an exhaustive list of the numerous interactions of the many complement components with adaptive immunity; rather, we will focus more precisely on the role of some complement molecules in the regulation of antigen presenting cells, as well as on their direct effect on the activation of the core adaptive immune cells, B and T lymphocytes. Recent reports on the local production and activation of complement proteins also suggest a major role in the control of effector responses. The crucial role of complement in adaptive immunity is further highlighted by several examples of dysregulation of these pathways in human diseases. PMID- 28842752 TI - Sexuality Among Women Treated for Breast Cancer: A Survey of Three Surgical Procedures. AB - BACKGROUND: The quality of life of Mexican patients with breast cancer has been studied, but female sexual function has only been explored superficially. The Female Sexual Function Index (FSFI) questionnaire has been validated as a tool to measure sexual function among women with cancer. However, no study in Mexico has been published. PURPOSE: To evaluate and compare female sexuality of breast cancer survivors treated with three surgical procedures. MATERIALS AND METHODS: This is a cross-sectional questionnaire survey applied in patients without active disease and free of any oncologic treatment who underwent conservative mastectomy, and mastectomy with and without reconstruction. Patients included in this study had no evidence of active disease after at least 2 years of postoperative follow-up and agreed to complete the FSFI questionnaire during a surveillance visit. RESULTS: Seventy-four patients were included: 37.8% had undergone conservative mastectomy, 29.7% radical mastectomy, and 32.4% radical mastectomy plus reconstruction. Patients in the radical mastectomy group were older than those in the other groups (p = 0.002). Female sexual dysfunction was observed in 34% of patients, but in patients who underwent radical mastectomy, it was 63% by contrast with 14 and 29% in women treated with conservative mastectomy and radical mastectomy with reconstruction (p = 0.001). CONCLUSIONS: We found a lower prevalence of female sexual dysfunction in patients treated with conservative mastectomy or reconstruction after radical mastectomy. Alternatively, radical mastectomy was offered to older patients, a condition that could contribute together with a loss of female perception to a higher prevalence of sexual dysfunction. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28842753 TI - [Autopsy rates in Germany]. AB - BACKGROUND: In 2015 the German professional Association of Pathologists conducted a survey to establish a baseline for an autopsy rate in Germany and to collect data from 2005-2014, as hospitals must meet a fixed autopsy quota to receive the supplementary payment for autopsies as stated in the law for hospital structure (KHSG 10.12.2015). MATERIAL AND METHODS: The survey comprised 12 questions and was sent to 450 institutes of pathology. The overall return rate was 38%. The data of the different institutional types was grouped and statistically analyzed. RESULTS: Of 86.416 reported autopsies on deceased adults in Germany from 2005 2014, 47% took place in university hospitals, 36% in local hospitals and 17% in privately run practices. Out of 4320 autopsies on deceased children and adolescents, the majority (83%) were performed at university hospitals, 8%, and 9%, respectively, at the other two entity types. Of the 14.047 fetal autopsies, 55% were done at university hospitals, 25% at other hospitals and 20% at private practices. From 2005 to 2014 the overall number of autopsies decreased by 30%, independently of the institute type. Within each group of institution types there was a wide range in numbers and rate of autopsies done per year: university hospitals total 0-428, quota of 3,4-19,4%; local hospitals 0-324, quota of 1,1 30,8%; private practices 0-268, quota 0,4-5,2%. CONCLUSION: To this day, there is no universal system to document and register hospital autopsy rates in Germany. Due to the high range of yearly autopsy rates even within the different groups of institute types, the threshold for the autopsy rate that must be met to obtain the supplementary payment should be low in the beginning. PMID- 28842755 TI - [Clinical autopsies]. PMID- 28842754 TI - Chen's Double Eyelid Fold Illusion: An Eye Size Assimilation Illusion Induced by a Supratarsal Fold in the Brow-Eye Unit, A Preliminary Report. AB - BACKGROUND: Double eyelidplasty can enhance the eye size and facial attractiveness of Asian individuals with single eyelids. The authors hypothesize that a supratarsal fold can induce an eye size assimilation illusion to enhance eye dimensions and aesthetics, and seek to define the optimum vertical proportion between a supratarsal fold and the eye fissure associated with maximal induction of the size assimilation illusion. METHODS: A photometric study of the replicated photographs of ten female Taiwanese patients after double eyelidplasty was designed. Each photograph was edited by shifting the supratarsal folds vertically at a regular fold/eye ratio increment of 0.1. The perceived attractiveness of edited photographs of each patient was rated by 100 adult observers using a score of 1-5. The palpebral parameters were measured and analyzed. RESULTS: The mean rating score increased gradually when a supratarsal fold was added and peaked when the fold/eye ratio was 0.3 and the mean Chen's double eyelid fold ratio was 0.631 +/- 0.023. After the peak, the mean score decreased gradually and was lower than the photograph without a fold when the fold/eye ratio exceeded 0.5 and the mean Chen's ratio exceeded 0.729 +/- 0.027. CONCLUSION: Within the optimal ranges of the fold/eye ratio and Chen's double eyelid fold ratio, eyes are perceived as larger and more attractive due to a hybrid presentation of two interdependent eye size assimilation illusions induced by a supratarsal fold in the brow-eye unit. "Chen's double eyelid fold illusion" is proposed to describe this complex visual phenomenon. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28842756 TI - The comorbidity of Axis I disorders in depressed pregnant women. AB - Depression during pregnancy is highly prevalent and is associated with increased risk of a variety of negative psychological and medical outcomes in both mothers and offspring. Antenatal depression often co-occurs with significant anxiety, potentially exacerbating morbidities for women and their children. However, screening during the antenatal period is frequently limited to assessment of depression so that other significant comorbid disorders may be missed. Follow-up assessment by clinicians has similarly focused primarily on detection of depressive symptoms. Anxiety, obsessive compulsive disorder, and post-traumatic stress disorder, among others, often go undetected in perinatal care settings, even when depression is identified. Failing to recognize these comorbid diagnoses may lead to inadequate treatment or only partial alleviation of distress. Consequently, screening for and assessment of comorbid disorders is warranted. In this study, 382 pregnant women (M age = 25.8 [SD = 5.3] years, 85.0% Caucasian) receiving care at a university hospital clinic and Maternal Mental Health Care centers in eastern Iowa and who screened positive for depression on the Beck Depression Inventory completed the Structured Clinical Interview for DSM-IV to assess comorbid mental health symptoms and diagnoses. Overall, findings demonstrate high rates of anxiety disorders among women both with and without current major depression, although depressed women reported higher rates of generalized anxiety disorder and post-traumatic stress disorder. Notably, however, incidence-specific symptoms were comparable across groups. Routine screening of both anxiety and depression during pregnancy should be conducted. PMID- 28842757 TI - Successful long-term outcome of pediatric liver-kidney transplantation: a single center study. AB - INTRODUCTION: Liver-kidney transplantation is a rare procedure in children, with just ten to 30 cases performed annually worldwide. The main indications are autosomal recessive polycystic liver-kidney disease and primary hyperoxaluria. This study aimed to report outcomes of liver-kidney transplantation in a cohort of pediatric patients. METHODS: We retrospectively analyzed all pediatric liver kidney transplantations performed in our center between September 2000 and August 2015. Patient data were obtained by reviewing inpatient and outpatient medical records and our transplant database. RESULTS: A total of 14 liver-kidney transplants were performed during the study period, with a median patient age and weight at transplant of 144.4 months (131.0-147.7) and 27.3 kg (12.0-45.1), respectively. The indications for liver-kidney transplants were autosomal recessive polycystic liver-kidney disease (8/14), primary hyperoxaluria -1 (5/14), and idiopathic portal hypertension with end-stage renal disease (1/14). Median time on waiting list was 8.5 months (5.7-17.3). All but two liver-kidney transplants were performed simultaneously. Patients with primary hyperoxaluria-1 tended to present a delayed recovery of renal function compared with patients transplanted for other indications (62.5 vs 6.5 days, respectively, P 0.076). Patients with liver-kidney transplants tended to present a lower risk of acute kidney rejection than patients transplanted with an isolated kidney transplant (7.2% vs 32.7%, respectively; P < 0.07). Patient and graft survival at 1, 3, and 5 years were 100%, 91.7%, 91.7%, and 91.7%, 83.3%, 83.3%, respectively. No other grafts were lost. CONCLUSION: Long-term results of liver-kidney transplants in children are encouraging, being comparable with those obtained in isolated liver transplantation. PMID- 28842758 TI - Utility of strain typing of Propionibacterium acnes in central nervous system and prosthetic joint infections to differentiate contamination from infection: a retrospective cohort. AB - The study aimed to retrospectively assess if strain typing of Propionibacterium acnes could help to distinguish between infection and contamination in isolates recovered from the central nervous system (CNS) and prosthetic joints (PJs). This was a retrospective cohort of all Propionibacterium species isolates from the Barnes-Jewish Hospital (St Louis, MO, USA) clinical microbiology laboratory from 2011 to 2014. Available frozen isolates were recovered, and strain type (IA-1, IA 2, IB, II, III, or nontypeable class A or B) was determined via polymerase chain reaction (PCR)-based methods. For CNS isolates, P. acnes was considered pathogenic if treating physicians administered >=7 days of directed antibiotic therapy against P. acnes. During the study period, Propionibacterium species was isolated from clinical cultures 411 times. 152 isolates were available for analysis. Of the 152 isolates, 140 were confirmed to be P. acnes, 61 of which were from the CNS (45 contaminants, 16 infections). Strain type IA-1 was more common (50.0%, 8 out of 16) among CNS infections than among contaminants (22.2%, 10 out of 45). For PJ isolates 61.3% (19 out of 31) met the criteria for infection. The predominant strain type for CNS infection was IA-1 and for PJ isolates, IB. Strain type IA-1 was isolated more often in patients with CNS infections, which may indicate a predilection of this strain type to cause CNS infection. Future research should prospectively evaluate strain typing as a means of assisting in the diagnosis of CNS infections and confirm our findings. PMID- 28842759 TI - Impact of secondhand smoking on disease activity in women with rheumatoid arthritis. AB - Smoking is an established risk factor for the development and severity of rheumatoid arthritis (RA) with prominent production of cytokines. The aim of the work was to study the possible effect of secondhand exposure on disease activity in non-smoking female RA patients. This cross-sectional study include 100 women with RA attending the rheumatology outpatient clinic and were grouped according to the non-smoking status into those not exposed to smoking and those considered secondhand smokers (SHS). Disease activity score in 28 joints (DAS28) was calculated and the patients' global assessment (PGA) score were assessed. The mean age of the patients was 45.2 +/- 12.1 years and disease duration was 8.3 +/- 6 years. Their DAS28 score was 4.3 +/- 0.93 with a PGA score of 1.47 +/- 1.36. Forty-seven of the patients were SHS and 53 were non-exposed. The secondhand smokers were significantly younger (41.6 +/- 11.7 years) than the non-smokers (48.3 +/- 11.6 years) (p = 0.005), and the DAS28 was significantly higher (4.6 +/ 0.84 versus 4.1 +/- 0.97; p = 0.02) compared to non-smokers. The disease duration and medications received were comparable. There is evidence pointing to the important role of secondhand smoking on disease activity in RA female patients. Studying the effect of secondhand smoking in view of the cytokine milieu could help confirm the relation to the disease pathogenesis. Taking into consideration the risk of cardiovascular disease and interplay with other potential factors should be well thought of. It is essential to draw patients' attention to the expected hazardous effect of passive smoking. PMID- 28842760 TI - Prevalence of vitamin D deficiency in chronic and subacute low back pain patients in India: a triple-arm controlled study. AB - Vitamin D is vital for musculoskeletal health and may be associated with subacute and chronic low back pain. The objective of this study was to estimate the prevalence of vitamin D deficiency among chronic low back pain (CLBP) and subacute low back pain (SLBP), and compare the same with healthy controls. This study was designed as triple-arm case-control study comprising of CLBP, SLBP, and controls. SLBP and CLBP cases were consecutively enrolled over 3 months of winter season from November 2016 to January 2017. Serum 25- (OH) vitamin D was estimated for the study subjects and categorical comparison of severity of vitamin D deficiency was done for the cases and controls. A total of 250 CLBP, 177 SLBP cases, and 248 controls were included in the study. Mean (+/- SD) serum vitamin D levels among CLBP, SLBP, and controls were 20.36 (+/- 12.56), 21.42 (+/- 13.20), and 20.84 (+/- 6.93) ng/ml respectively, the difference being statistically insignificant. There was no significant difference in the prevalence of vitamin D deficiency among CLBP, SLBP, and controls which was 53.6, 50.8, and 51.6% respectively, in the three arms. However, the categorical analysis revealed that CLBP and SLBP cases had a significantly higher prevalence of worse categories of vitamin D deficiency. Cases had significantly larger frequency (CLBP vs. controls, 43.6 vs 20.1%, P<0.001; SLBP vs. controls, 43.5 vs 20.1%, P = 0.001) of individuals with vitamin D levels <= 16 ng/ml (moderate deficiency upper threshold level). Thus, the severe forms of vitamin D deficiency may be causally associated with CLBP and SLBP. The results of the present study revealed that increasing severity of vitamin D deficiency may have a pathogenetic association with chronic low back pain and subacute low back pain. These results may prove to be of significance in framing of future management guidelines for the above clinical conditions. PMID- 28842761 TI - Inflammatory response and peritoneal contamination after transrectal natural orifice specimen extraction (NOSE) versus mini-laparotomy: a porcine in vivo study. AB - BACKGROUND: Transrectal natural orifice specimen extraction (NOSE) avoids abdominal organ retrieval during laparoscopic procedures and may reduce surgical trauma. However, this has not been proven clinically and transrectal peritoneal contamination is feared to cause infectious complications. This experimental study was designed to evaluate inflammatory response and peritoneal contamination after transrectal NOSE versus mini-laparotomy. METHODS: 24 German Landrace pigs underwent transrectal NOSE (N = 12) or mini-laparotomy (N = 12) for standardized extraction of water-instilled balloon. Blood samples were taken for analysis of leucocytes, CRP, IL-6, IL-10, and TNFalpha at 6, 12, 24, 48, 72 h as well as 7 and 14 days postoperatively. After 14 days laparoscopy was performed to inspect the abdomen and for microbiological swab sampling. RESULTS: Leucocytes were higher in the NOSE group at 72 h (19.3 +/- 3.9/nl vs. 15.8 +/- 4.2/nl, p = 0.046). IL-6 was lower in the NOSE group at day 7 (165 +/- 100/nl vs. 306 +/- 70/nl, p = 0.030). No difference was found comparing inflammatory parameters at all other time points. No difference was found regarding peritoneal contamination, which was 58.3% (7/12) in the NOSE group and 41.7% (5/12) in the MiniLap group (p = 0.414). CONCLUSIONS: The results suggest a pronounced acute inflammatory response after transrectal NOSE compared to mini-laparotomy, while late cytokine response seems to be less after transrectal NOSE, which may reflect less intense wound healing process. Using standardized rectal decontamination and endolumenal colon occlusion transrectal NOSE seems to be safe and comparable to mini-laparotomy with regard to peritoneal contamination. Clinical evidence is needed now to weight transrectal NOSE against mini-laparotomy during laparoscopic surgery. PMID- 28842762 TI - Hyperemesis gravidarum and the risk of emotional distress during and after pregnancy. AB - Hyperemesis gravidarum (HG) is a pregnancy condition characterised by severe nausea and vomiting. Previous studies have shown an association between HG and depressive symptoms during pregnancy, but little is known about the risk of maternal psychological distress following an HG pregnancy. The objective of the current study was therefore to assess the association between HG and emotional distress during and after pregnancy. This was a population-based pregnancy cohort study using data from the Norwegian Mother and Child Cohort Study. A total of 851/92,947 (0.9%) had HG. Emotional distress was measured by the Hopkins Symptom Checklist (SCL-5) in gestational weeks 17 and 32 and 6 and 18 months postpartum. The generalised estimating equations model was estimated for assessing time trends in emotional distress. Adjustments were made for previous HG, lifetime history of depression, maternal age, parity, BMI, smoking before pregnancy, physical activity, length of education, and pelvic girdle pain. Women with HG had higher odds for emotional distress than women without HG at the 17th (p < 0.001) and 32nd gestational weeks (p = 0.001) in addition to 6 months postpartum (p = 0.005) but not 18 months postpartum (p = 0.430). Adjusted odds for emotional distress varied significantly over time for women with and without HG (p = 0.035). Women with HG were more likely to report emotional distress compared to women without HG during pregnancy and 6 months postpartum, but the difference between the groups disappeared 18 months after birth. The results suggest that the increased risk of developing emotional distress may primarily be a consequence of HG. PMID- 28842763 TI - Development of a surgical training model for bilateral axillo-breast approach robotic thyroidectomy. AB - BACKGROUND: Bilateral axillo-breast approach robotic thyroidectomy (BABA RT) is an excellent surgical method, being oncologically safe and with anatomic views similar to those of open surgery. BABA RT, however, requires training and a learning curve for proficiency. We evaluated the educational effectiveness of a surgical training model for BABA RT, comparing objective BABA scores with scores on the da Vinci Skills Simulator (dVSS). METHODS: Medical students, surgical residents, and surgical fellows performed structured tasks with the BABA training model and dVSS under the same conditions. All tasks were videotaped. BABA scores were compared with dVSS scores and with objective evaluation scores (GEARS and OSATS). RESULTS: Eight medical students, ten surgical residents, and eight surgical fellows participated in this study. The educational effect of BABA training improved from one to two (p < 0.001), two to three (p = 0.003), and one to three (p < 0.001) procedures. Statistically significant differences were found when students were compared with residents (p = 0.025) and fellows (p < 0.001) in the BABA training model, and between students and fellows (p = 0.004) in dVSS. BABA scores showed similar distribution patterns in the three groups to GEARS and OSATS scores (p < 0.001 each). CONCLUSIONS: The BABA training model is an excellent educational tool for surgical residents and surgical fellows to learn and practice BABA RT. Assessment by BABA score yielded objective results comparable to those of traditional scoring methodologies. PMID- 28842764 TI - Prevalence and intensity of fleas parasitizing an isolated population of screaming hairy armadillo in Buenos Aires province, Argentina: host-related factors and temporal dynamics. AB - Fleas (Siphonaptera) of an isolated population of Chaetophractus vellerosus (Mammalia: Xenarthra) from Magdalena (Buenos Aires province) were studied, and their presence was associated with host-related factors (age, sex, weight, size, and physical condition) and temporal dynamics (seasonality and year). Three species of fleas were identified: Polygenis (Polygenis) platensis (Rhopalopsyllidae), Tunga penetrans (Tungidae), and Pulex irritans (Pulicidae). Prevalences were significant for year, season, and physical condition. Intensities were significantly different for year, physical condition, and weight. The intensities of fleas were higher in 2009 than in other years, probably because of lower rainfall than the annual average leading to extremely dry climatic conditions in 2008. Intensities decreased in individuals with major body weight and increased in individuals with poor physical condition. In this study, the dynamics of the flea community associated with an armadillo population is analyzed for the first time taking into account host-related factors and temporal dynamics, and also how these factors influence the community. PMID- 28842765 TI - SAGES technology and value assessment committee (TAVAC) safety and effectiveness analysis: LINX(r) reflux management system. PMID- 28842766 TI - Desmoid Tumor and Silicone Breast Implant Surgery: Is There Really a Connection? A Literature Review. AB - BACKGROUND: Desmoid tumors are borderline tumors of the connective tissue, arising in the musculo-aponeurotic stromal elements. A desmoid tumor (DT) has an infiltrative and locally aggressive growth pattern and usually does not metastasize; however, it has a high recurrence and complication rate. DT located in the breast (BDT) represents a rare extra-abdominal form. Recently, the presence of breast silicone implants was suggested by several researchers as a risk factor for developing BDT. OBJECTIVES: The goal of this review is to investigate the possible correlation between BDT and breast implant surgery. METHODS: We conducted a literature review of BDT-reported cases, associated with breast implant surgery. RESULTS: The search revealed 36 cases of BDT associated with silicone breast implants. CONCLUSIONS: Based on the reviewed data, the incidence of BDT following breast implant surgery is lower than BDT in the general population. At the moment, a possible association between breast implants and the development of breast desmoid tumors cannot be unequivocally confirmed. A world registry with accurate documentation of each case of BDT associated with breast implant surgery should be performed for future investigation. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28842767 TI - Surgical volume and conversion rate in laparoscopic hysterectomy: does volume matter? A multicenter retrospective cohort study. AB - BACKGROUND: A multicenter, retrospective, cohort study was conducted in the Netherlands. The aim was to evaluate whether surgical volume of laparoscopic hysterectomies (LHs) performed by proven skilled gynecologists had an impact on the conversion rate from laparoscopy to laparotomy. METHODS: In 14 hospitals, all LHs performed by 19 proven skilled gynecologists between 2007 and 2010 were included in the analysis. Surgical volume, conversion rate and type of conversion (reactive or strategic) were retrospectively assessed. To estimate the impact of surgical volume on the conversion rate, logistic regressions were performed. These regressions were adjusted for patient's age, Body Mass Index (BMI), ASA classification, previous abdominal surgery and the indication (malignant versus benign) for the LH. RESULTS: During the study period, 19 proven skilled gynecologists performed a total of 1051 LHs. Forty percent of the gynecologists performed over 20 LHs per year (median 17.3, range 5.4-49.5). Conversion to laparotomy occurred in 5.0% of all LHs (53 of 1051); 38 (3.6%) were strategic and 15 (1.4%) were reactive conversions. Performing over 20 LHs per year was significantly associated with a lower overall conversion rate (ORadjusted 0.43, 95% CI 0.24-0.77), a lower strategic conversion rate (ORadjusted 0.32, 95% CI 0.16-0.65), but not with a lower reactive conversion rate (ORadjusted 0.96, 95% CI 0.33-2.79). CONCLUSION: A higher annual surgical volume of LHs by proven skilled gynecologists is inversely related to the conversion rate to laparotomy, and results in a lower strategic conversion rate. PMID- 28842768 TI - Evaluation of blood adsorption onto dialysis membranes by time-of-flight secondary ion mass spectrometry and near-field infrared microscopy. AB - Blood adsorption onto the inside surface of hollow fiber dialysis membranes was investigated by means of time-of-flight secondary ion mass spectrometry (TOF SIMS) and near-field infrared microscopy (NFIR) in order to evaluate the biocompatibility and permeability of dialysis membranes. TOF-SIMS is useful for the imaging of particular molecules with a high spatial resolution of approximately 100 nm. In contrast, infrared spectra provide quantitative information and NFIR enables analysis with a high spatial resolution of less than 1 MUm, which is close to the resolution of TOF-SIMS. A comparison was made of one of the most widely used dialysis membranes made of polysulfone (PSf), that has an asymmetric and inhomogeneous pore structure, and a newly developed asymmetric cellulose triacetate (ATA) membrane that also has an asymmetric pore structure, even though the conventional cellulose triacetate membrane has a symmetric and homogeneous pore structure. As a result, it was demonstrated that blood adsorption on the inside surface of the ATA membrane is more reduced than that on the PSf membrane. Graphical abstract Analysis of blood adsorption on inside surface of hollow fiber membrane. PMID- 28842769 TI - Time-of-flight ion mobility spectrometry in combination with laser-induced fluorescence detection system. AB - A laser-induced fluorescence (LIF) was used as a complimentary detection system for time-of-flight ion mobility spectrometry (TOF-IMS). A LIF detection system is potentially faster than a conventional electrometer detector and can provide additional (to usual for IMS drift time) analytical information, namely wavelength of fluorescence maxima and fluorescence lifetime. Therefore, better discrimination ability can be expected. Additionally, the combination of IMS and LIF operates at atmospheric pressure. This allows fluorescence measurements of specified ions and ion clusters, which would not survive in a mass spectrometer. An IMS drift cell of open design with both the electrometer and LIF detectors was designed. The feasibility of IMS-LIF was demonstrated on the example of the Xanthene dye Rhodamine 6G (R6G). Electrospray was used as an ionization source. The release and desolvation of R6G ions from the electrospray with following IMS LIF analysis were demonstrated. The effects of experimental parameters (e.g., ion gate and drift voltages, distance to ESI emitter) are demonstrated and discussed. The obtained results are promising enough to ensure the potential of LIF as a complimentary/alternative detection system for time-of-flight ion mobility spectrometry. PMID- 28842770 TI - Dopamine-mediated immunoassay for bacteria detection. AB - Traditional enzyme-linked immunosorbent assay (ELISA) with sufficient sensing specificity is a useful analytical approach for the detection of toxicologically important substances in in vivo systems or complicated biological systems. Increasing worldwide demand for analyses of bacteria by signal amplification and increasing concern regarding their safe development and use require a simple, stable, and sensitive detection assay for target evaluation and clinical diagnosis. A sensitive and selective immunoassay for detection of bacteria is constructed that combines horseradish peroxidase (HRP)-catalyzed signal amplification with the strong linker of the polydopamine-biotin complex on the surface of solid substances or biomolecules. The incorporation of HRP labeling and amplification increases the detection sensitivity by about one to two orders of magnitude compared with conventional ELISA systems. A linear relationship between the response and the logarithm of the bacterial concentration was observed in the range from 1.5 * 102 to 1.5 * 107 colony-forming units per milliliter. This work demonstrates a new signal-amplification-based dopamine mediated process for the development of a sensitive method. This dopamine mediated immunoassay may be broadly applied in clinical diagnoses and for the monitoring of water environmental pollution. The approach proposed is distinct with simple protocols and easy processes, which allow it to be applied in a broad area. PMID- 28842771 TI - Pollution characteristics and ecological risk assessment of heavy metals in three land-use types on the southern Loess Plateau, China. AB - The accumulation of heavy metals in agricultural soils has been the subject of great concern because these metals have the potential to be transferred to soil solutions and subsequently accumulate in the food chain. To study the persistence of trace metals in crop and orchard soils, representative surface soil samples were collected from terrace farmland that had been cultivated for various numbers of years (3, 8, 12, 15, and >20 years), terrace orchard land that had been cultivated for various numbers of years (4, 7, 10, 12, 15, 18, 25, and >30 years), and slope farmland with various gradients (3 degrees , 5 degrees , 8 degrees , 12 degrees , 15 degrees , and 25 degrees ) and analyzed for heavy metals (As, Cr, Cu, Hg, Ni, and Zn). These samples were collected from Nihegou catchment of Chunhua county in the southern Loess Plateau of China. The six heavy metals demonstrated different trends with time or gradient in the three land-use types. The Cu and Zn contents of the soil were higher than the referee background values of the loessal soil, and the contents of Cr and Ni, and especially those of As and Hg, were lower. Cu was the only heavy metal that just met the Grade III Environmental Quality Standard for Soils of China, while the others reached grade I. Cu and Hg were considered contaminant factors and Hg was a moderate potential ecological risk factor in the catchment. Of the sites investigated, 89.5% fell into the category with a low degree of contamination (C d ) and rest were moderate, while all three land-use types had low potential ecological risk (RI). Changes of C d and RI were consistent with the cultivated time in the terrace farmland and terrace orchard land. Values of RI increased while C d decreased with the increasing of slope gradient in the slope farmland. Evaluating the ecological risk posed by heavy metals using more soil samples in a larger study area is necessary on the Loess Plateau of China. PMID- 28842772 TI - PDMS based multielectrode arrays for superior in-vitro retinal stimulation and recording. AB - Understanding of the neural response to electrical stimulation requires simultaneous recording from the various neurons of retina. Electrodes form the physical interface with the neural or retinal tissue. Successful retinal stimulation and recording demands conformal integration of these electrodes with the soft tissue to ensure establishment of proper electrical connection with the excitable tissue. Mechanical impedance of polydimethylsiloxane (PDMS) being compliant with that of retinal tissue, offers excellent potential as a substrate for metal electrodes. In this paper, Cr/Au micro electrodes with 200 MUm diameter were fabricated on rigid and flexible PDMS substrates under crack free condition. Spontaneous buckling of thin films over PDMS substrates improved electrode performance circumventing the fabrication issues faced over a buckled surface. Individual electrodes from the multielectrode arrays (MEAs) were examined with electrochemical impedance spectroscopy and cyclic voltammetry. Controlled fabrication process as described here generates buckles in the metal films leading to increased electrode surface area that increases the charge storage capacity and decreases the interface impedance of the metal electrodes. At 1 kHz, impedance was reduced from 490 +/- 27 kOmega to 246 +/- 19 kOmega and charge storage capacity was increased from 0.40 +/- 0.87 mC/cm2 to 2.1 +/- 0.87 mC/cm2. Neural spikes recorded with PDMS based electrodes from isolated retina also contained less noise as indicated by signal to noise ratio analysis. The present study established that the use of PDMS as a substrate for MEAs can enhance the performance of any thin film metal electrodes without incorporation of any coating layers or nanomaterials. PMID- 28842773 TI - Reduction of Framingham BMI score after rapid weight loss in severely obese subjects undergoing sleeve gastrectomy: a single institution experience. AB - BACKGROUND: There is vast evidence that supports the importance of obesity in the pathogenesis and progression of cardiovascular disease. Rapid weight loss induced by laparoscopic Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (LAGB) has proven beneficial. The aim of this study is to evaluate laparoscopic sleeve gastrectomy (LSG) as an alternative treatment modality and its impact on the Framingham-BMI 10-year risk score. METHODS: We retrospectively reviewed all patients that underwent bariatric surgery at our institution between 2010 and 2014. Patients who met the criteria for calculating the Framingham BMI 10-year risk score were included. Data collected included baseline demographics, perioperative parameters such as tobacco use, diagnosis of diabetes, treatment for hypertension, BMI and postoperative outcomes at 3 and 12 months. RESULTS: From our 1129 bariatric patients, 358 (31.7%) met criteria for the Framingham BMI 10-year risk score calculation. LSG was the most prevalent surgery 61.45% (N = 220) followed by LRYGB 22.06% (N = 79). Females composed 69% (N = 248) of our population. The average age for females was 52.3 +/- 10.8 years and for males 54.07 +/- 11.2 years. The initial Framingham 10-year score risk was significantly higher in males compared with females (36.16% +/- 22.3 vs. 16.97% +/- 15.6 (p < 0.001)). After 12-month follow-up, the absolute risk reduction in males was 11.58% (p < 0.001) and 6.17% in females (p < 0.001). The preoperative heart age was high in females and males (69.23 +/- 15.72 years and 73.55 +/- 13.55 years, respectively (p = 0.012)), and after 12 months it was reduced 7.19 years in females (p < 0.001) and 7.04 years in males (p < 0.001). The percentage of estimated BMI loss at 1 year was 64.43% in females and 60.69% in males. CONCLUSION: Sleeve gastrectomy has demonstrated to be an effective method of treatment for obesity. Our results suggest that rapid weight loss after LSG has a positive impact in the reduction of the 10-year cardiovascular disease risk. Further prospective studies may be needed to better assess these findings. PMID- 28842775 TI - MEMS measurements of single cell stiffness decay due to cyclic mechanical loading. AB - The goal of this study was to measure the mechanical stiffness of individual cells and to observe changes due to the application of repeated cell mechanical loads. 28 single baker's yeast cells (Saccharomyces cerevisiae) were fatigue tested and had their stiffness measured during repetitive loading cycles performed by a MEMS squeezer in aqueous media. Electrothermal micro-actuators compressed individual cells against a reference back spring; cell and spring motions were measured using a FFT image analysis technique with ~10 nm resolution. Cell stiffness was calculated based on measurements of cell elongation vs. applied force which resulted in stiffness values in the 2-10 N/m range. The effect of increased force was studied for cells mechanically cycled 37 times. Cell stiffness decreased as the force and the cycle number increased. After 37 loading cycles (~4 min), forces of 0.24, 0.29, 0.31, and 0.33 MUN caused stiffness drops of 5%, 13%, 31% and 41% respectively. Cells force was then set to 0.29 MUN and cells were tested over longer runs of 118 and 268 cycles. After 118 cycles (~12 min) cells experienced an average stiffness drop of 68%. After 268 cycles (~25 min) cells had a stiffness drop of 77%, and appeared to reach a stiffness plateau of 20-25% of the initial stiffness after approximately 200 cycles. PMID- 28842774 TI - The impact of bariatric surgery on insulin-treated type 2 diabetes patients. AB - INTRODUCTION: Bariatric surgery has been shown to lead to significant improvement in glucose homeostasis, resulting in greater rates of type 2 diabetes mellitus (T2DM) remission. While there is substantial evidence of the benefits of bariatric/metabolic surgery in obese diabetic patients on oral therapy (O-T2D), more evidence is necessary in the case of insulin-treated type 2 diabetes (I-T2D) patients and the selection of surgical procedure. METHODS: Analysis of the Ontario Bariatric Registry data was performed, comparing outcomes of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on insulin-treated versus non insulin-treated T2DM patients. We compared weight loss, medication use and remission rates during a 3-year follow up. RESULTS: A total of 3668 diabetic Bariatric Registry patients underwent surgery from Jan 2010 to Feb 2017, across 7 Bariatric Centers of Excellence in Ontario. Of these 2872 were O-T2D and 1187 were I-T2D. Weight loss was similar between the two groups at 3 years; with mean %WL of 30.1% for the insulin group vs. 28.3% non-insulin (p = 0.0673). At 3 years, 11.3% of the non-insulin and 59.6% of the insulin-dependent group were using anti-diabetic medication (p < 0.0001). Among insulin-dependent patients, RYGB showed greater reduction in insulin use with 26.5 and 40% compared to SG at 3 years. O-T2D patients experienced more complete diabetes remission, with 66.5 vs. 18.5% (p < 0.0001) at 3 years. Complete remission for I-T2D patients was higher in the RYGB group than SG (p < 0.0001) at years 1 and 2 (8.5 vs. 5.4% and 24.4 vs. 21.1%). The same trend was found regardless of insulin use; complete remission higher for RYGB at 1 and 2 years [50.7 vs. 39.8% (p < 0.0001), and 54.6 vs. 49.1% (p < 0.0001)]. CONCLUSION: While both RYGB and SG procedures provide effective treatment for I-T2D patients in terms of weight loss and diabetes, incidence of complete remission for insulin-dependent patients is higher with RYGB in earlier years. PMID- 28842776 TI - [Development of the sociolegal foundations for funding clinical autopsies]. PMID- 28842777 TI - Advances in metabolome information retrieval: turning chemistry into biology. Part II: biological information recovery. AB - This work reports the second part of a review intending to give the state of the art of major metabolic phenotyping strategies. It particularly deals with inherent advantages and limits regarding data analysis issues and biological information retrieval tools along with translational challenges. This Part starts with introducing the main data preprocessing strategies of the different metabolomics data. Then, it describes the main data analysis techniques including univariate and multivariate aspects. It also addresses the challenges related to metabolite annotation and characterization. Finally, functional analysis including pathway and network strategies are discussed. The last section of this review is devoted to practical considerations and current challenges and pathways to bring metabolomics into clinical environments. PMID- 28842779 TI - Polymer-based interconnection cables to integrate with flexible penetrating microelectrode arrays. AB - There have been various types of interconnection methods for neural interfacing electrodes, such as silicon ribbon cables, wire bonding and polymer-based cables. In this study, interconnection cables were developed for integration with a Flexible Penetrating Microelectrode Array (FPMA) that was previously developed for neural signal recording or stimulation. Polyimide and parylene C were selected as base materials for the interconnection cables as both materials can preserve the flexibility of the FPMA better than other interconnection methods such as silicon ribbon cable or wire bonding. We conducted durability tests to determine if the interconnection cables were suitable for in-vivo implantation, by long-term soaking of the cables in phosphate buffered saline solution. We measured the changes in impedance over time, and equivalent circuit models were used to analyze the electrochemical phenomena on the surface of the cables. Lastly, we implanted the cable-integrated electrodes device onto rabbit's sciatic nerve and recorded neural signals to prove the feasibility of the developed FPMA integration system. PMID- 28842778 TI - Refining the role of pegfilgrastim (a long-acting G-CSF) for prevention of chemotherapy-induced febrile neutropenia: consensus guidance recommendations. AB - PURPOSE: Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on granulocyte colony-stimulating factors (G-CSF) for prevention of FN, but guidance is unclear regarding use of short- vs long-acting G-CSF (e.g., filgrastim vs pegfilgrastim/lipegfilgrastim, respectively). An international panel of experts convened to develop guidance on appropriate use of pegfilgrastim for prevention of chemotherapy-induced FN. METHODS: Guidance recommendations were developed following a literature review, survey, evaluation of current practice, and an expert meeting. Consensus was established using an anonymous Delphi-based approach. RESULTS: Guidance recommendations for prevention of treatment-associated FN were as follows: for treatment with curative intent, maintenance of dose intensity using G-CSF to prevent dose delays/reduction should be standard of care; for treatment-associated FN risk >= 20%, short-acting G CSF/pegfilgrastim should be given from cycle 1 onwards; and for treatment associated FN risk < 20%, short-acting G-CSF/pegfilgrastim should be given if factors suggest overall risk (including treatment-related and patient-related risk factors) is >= 20%. It was agreed that pegfilgrastim and 11 days' filgrastim have similar efficacy and safety and that pegfilgrastim is preferred to < 11 days' filgrastim (and may be preferred to >= 11 days' filgrastim based on adherence and convenience); pegfilgrastim is not appropriate in weekly chemotherapy; in split-dose chemotherapy, pegfilgrastim is recommended 24 h after last chemotherapy dose; and during palliative chemotherapy, patient adherence and convenience may favor pegfilgrastim. CONCLUSION: In this era of targeted therapies, additional trials with G-CSF are still required. These recommendations should be used with existing guidelines to optimize pegfilgrastim use in clinical practice. PMID- 28842780 TI - Results of lateral ankle ligament repair surgery in one hundred and nineteen patients: do surgical method and arthroscopy timing matter? AB - PURPOSE: Ankle sprains are the most common athletic injury. One of five chronic lateral ankle instability patients will require surgery, making operative outcomes crucial. The purpose of this study is to determine if operative method influences failure and complication rates in chronic lateral ankle ligament repair surgery. METHODS: We retrospectively reviewed 119 cases (118 patients) of lateral ankle ligament surgery between 2006 and 2016. Patient charts and operative reports were examined for demographics, use and timing of ankle arthroscopy, ligament fixation method, type of surgical incision, presence of calcaneofibular ligament repair, and operative technique. Impact of operative methods on failure (one-year minimum follow-up) and complication outcomes was explored using Chi-square test of independence (or Fisher's exact test). Statistical significance was set at p less than .05. RESULTS: Mean age at surgery was 40 (range, 18-73) years. Mean follow-up was 51 (range, 12-260) weeks. Failure rate was 8.4% (10/89 cases) while complication rate was 17.6% (21/119). Failure rate did not differ significantly between any data subgroups (p > .05). Single stage arthroscopy was associated with a significantly lower complication rate (11%, 4/37) than double-stage arthroscopy (47%, 9/19) (p < .01) as was suture anchor ligament fixation (9%, 6/67) compared to direct suture ligament fixation (29%, 15/52) (p < .01). CONCLUSION: Failure rate was not impacted by any of the studied variables. Use of suture anchors and concurrent ankle arthroscopy may be favourable options to achieve fewer complications in chronic lateral ankle instability repair surgery. PMID- 28842781 TI - Closed-Suction Drains After Subcutaneous Mastectomy for Gynecomastia: Do They Reduce Complications? AB - BACKGROUND: In cases of refractory gynecomastia, surgical excision of excess glandular breast tissue is often warranted. Closed-suction drain placement is commonplace; however, the effect of drains on preventing complications after male breast surgery has not been fully elucidated in the literature. OBJECTIVE: To investigate the effect of drains on reducing seroma and hematoma after subcutaneous mastectomy for gynecomastia. METHODS: Retrospective chart review of patients undergoing subcutaneous mastectomy for gynecomastia over a 10-year period. Charts were reviewed for demographics, BMI, comorbidities, type of local anesthesia, specimen weight, use of liposuction, and placement of drains. Outcomes were determined by seroma or hematoma in the 30-day postoperative period. RESULTS: A total of 163 breasts were studied (group I = no-drain, n = 46; group II = drain, n = 117). Group I had a higher rate of clinically significant seromas requiring needle aspiration than group II (6.5 vs 0%, p = 0.0214). There was no difference in rates of hematoma (group I vs II, 2.2 vs 6.0%, p = 0.443) and total fluid collections (group I vs II, 19.6 vs 16.2%, p = 0.647). BMI, use of local anesthesia, specimen weight, and use of liposuction were not significantly associated with postoperative complications. CONCLUSIONS: Closed suction drains may reduce rates of clinically significant seromas requiring needle aspiration. Though drains carry their own pertinent adverse effects (e.g., patient discomfort and anxiety, cost, and additional clinic visits), there remains no universal standard of care and surgeon practices vary widely. Given the potential to reduce seroma rates, we recommend that surgeons consider placing drains and discuss with patients the benefits and risks of drains after surgical treatment of gynecomastia. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28842782 TI - Optimal post-operative radiation after soft-tissue sarcoma resection is achieved in less than two thirds of cases. AB - PURPOSE: Local control of soft tissue sarcomas frequently involves adjuvant radiation to the surgical resection. When opting for post-operative radiation, care should be taken that radiation is started within some reasonable time after the surgery. We were interested to the proportion of patients who did not recieve optimal post-operative radiation and the variables associated. METHODS: We retrospectively analyzed a series of 77 patients operated on for an extremity soft-tissue sarcoma and due for post-operative radiotherapy. Patients were considered to have received radiation optimally if radiation was started within 12 weeks of surgery. Variables associated with not receiving radiation optimally were looked for using univariable and multivariable regression models. RESULTS: Overall, 26 patients (34%; 95% CI: 23-45%) did not receive radiation optimally. Twenty (26%) did not start radiation within the 12-weeks mark and six (8%) could not have radiation at all. The main reason identified for not receiving radiation on time was the occurrence of a wound complication (14 (54%) patients). An increased body mass index (OR: 1.14; 95% CI: 1.02-1.26; p = 0.02) and an older age (OR: 1.55; 95% CI: 1.18-2.14; p = 0.04; of note, the OR are for a 10 year change) were significantly associated with not receiving radiation optimally. Patients with a social fragility (p = 0.04), metastatic spread at presentation (p = 0.04), and increased duration of surgery (p = 0.02) were more likely to develop a wound complication. CONCLUSIONS: About 34% of patients do not receive optimal post-operative radiation treatment. Older and obese patients have a higher risk of not receiving radiation optimally. The decision for pre- or post-operative radiation should account for these findings. PMID- 28842783 TI - Population genetics of IFITM3 in Portugal and Central Africa reveals a potential modifier of influenza severity. AB - Influenza epidemics are a serious global public health and economic problem. The IFITM3 allele (rs12252-C) was suggested as a population-based genetic risk factor for severe influenza virus infection by A(H1N1)pdm09. We analyzed the population genetics of IFITM3 variants in the Portuguese general population (n = 200) and Central Africans (largely Angolan) (n = 148) as well as its association to influenza severity in Portuguese patients (n = 41). Seven SNPs, within the 352 bp IFITM3 amplicon around rs12252, were identified. SNP distributions in the Portuguese appeared at an intermediate level between the Africans and other Europeans. According to HapMap, rs34481144 belongs to the same linkage disequilibrium (LD) block as rs12252 and is in strong LD with rs6421983. A negative association with severe relative to mild disease was observed for allele rs34481144-A, indicating a protective effect under the dominant model. Moreover, haplotype Hap4 with rs34481144-A, not including rs12252-C, was significantly associated to mild influenza. Conversely, although with borderline significance, haplotype Hap1 with rs34481144-G, not including rs12252-C, was associated to severe disease. Moreover, in comparison to the general Portuguese population, statistical significant differences in the frequencies of the protective allele rs34481144-A in the severe disease group, the deleterious Hap1 in the mild disease group, and the protective Hap4 in the severe disease group were observed. The population attributable risk (PAR) for the targeted rs34481144 allele or genotype was of 55.91 and 64.44% in the general population and the mildly infected individuals, respectively. Implication of these variants in disease phenotype needs further validation, namely through functional analysis as is discussed. PMID- 28842784 TI - Neutrophil extracellular traps may contribute to interstitial lung disease associated with anti-MDA5 autoantibody positive dermatomyositis. AB - In dermatomyositis (DM), anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody (autoAb) marks a subtype with low grade or absent muscle inflammation but frequent and rapidly progressive interstitial lung disease (ILD). The pathogenesis of ILD remains poorly unknown. The aim of the study is to explore whether neutrophil extracellular traps (NETs) are involved in the development of ILD in DM patients with anti-MDA5 autoAb. Patients with clinically amyopathic dermatomyositis (CADM, n = 20), classic dermatomyositis (cDM, n = 30), polymyositis (PM, n = 20), and healthy controls (HC, n = 20) were enrolled. Anti MDA5 autoantibody and Krebs von den Lungen-6 (KL-6) were detected by ELISA. Circulating levels of NETs were assessed by the quantification of both serum cell free DNA (cfDNA) and LL-37 (cathelicidin LL-37). Immunofluorescent staining was used to visualize NETs ex vivo. The elevated circulating NETs level was detected in DM patients with ILD complication. Compared to anti-MDA5 Ab- DM patients, anti MDA5 Ab+ DM patients had the higher concentrations of serum cfDNA (293 +/- 69 vs 252 +/- 63 ng/ml; P = 0.035) and serum LL-37 (0.6 +/- 1.0 vs 0.2 +/- 0.2 ng/ml; P = 0.026). Positive correlations were established between serum levels of cfDNA and KL-6 in DM patients (r s = 0.4422, P = 0.0003). anti-MDA5 Ab+ sera, other than anti-MDA5 Ab- sera, could induce greater numbers of normal neutrophils to form NETs in vitro. These data suggest that aberrant NETs formation may be involved in the pathogenesis of ILD in DM patients with anti-MDA5 autoAb. PMID- 28842785 TI - Effects of overfeeding and high-fat diet on cardiosomatic parameters and cardiac structures in young and adult zebrafish. AB - Obesity is a complex global health problem because it is a risk factor for multiple chronic pathologies such as cardiovascular, endocrine, metabolic, and neoplastic diseases. It is considered a multicausal disease, and one of the determining factors is nutritional imbalances, which include high-fat diets. In this paper, we use the zebrafish model to assess the impact of overfeeding and a high-fat diet in somatic and cardiac parameters in young and adult zebrafish. The results show that fish receiving a high-fat diet showed greater weight gain compared to fish receiving a standard fat diet. Additionally, changes in the heart, including increases in size, a change in the triangular shape of the ventricle to a globular shape, and an increase in the thickness of the trabeculae of the spongy myocardium were observed. These changes could be indicators of cardiovascular overload. The results show that there is a direct relationship between the intake of a high-fat diet and obesity, which in turn can induce cardiac changes, supporting the hypothesis of the relationship between high-fat diets and cardiovascular risk factors. Given the genetic similarity between zebrafish and humans, these results could be extrapolated to human beings, and the findings similarly highlight the importance of incorporating a balanced diet from the early life stages to reduce the risk of cardiovascular disease. PMID- 28842786 TI - Neutropenia in Patients with Common Variable Immunodeficiency: a Rare Event Associated with Severe Outcome. AB - BACKGROUND: Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID. METHODS: The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed. RESULTS: Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0 1400]*106/L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P < 0.05). Neutropenia was diagnosed for 10 patients before 22 years old. The most frequent symptoms, except infections, were autoimmune cytopenia, i.e., thrombopenia or anemia (11/16). Ten patients were affected with lymphoproliferative diseases. Two patients were in the infection only group and the others belonged to one or several other CVID groups. The median level of IgG was 2.6 g/L [0.35-4.4]. Most patients presented increased numbers of CD21low CD38low B cell, as already described in CVID autoimmune cytopenia group. Neutropenia was considered autoimmune in 11 cases. NGS for 52 genes of interest was performed on 8 patients. No deleterious mutations were found in LRBA, CTLA4, and PIK3. More than one potentially damaging variant in other genes associated with CVID were present in most patients arguing for a multigene process. CONCLUSION: Neutropenia is generally associated with another cytopenia and presumably of autoimmune origin during CVID. In the DEFI study, neutropenia is coupled with more severe clinical outcomes. It appears as an "alarm bell" considering patients' presentation and the high rate of deaths. Whole exome sequencing diagnosis should improve management. PMID- 28842787 TI - What are the Mechanisms Behind a Parasite-Induced Decline in Nestmate Recognition in Ants? AB - Social insects have developed sophisticated recognition skills to defend their nests against intruders. They do this by aggressively discriminating against non nestmates with deviant cuticular hydrocarbon (CHC) signatures. Studying nestmate recognition can be challenging as individual insects do not only vary in their discriminatory abilities, but also in their motivation to behave aggressively. To disentangle the influence of signaling and behavioral motivation on nestmate recognition, we investigated the ant Temnothorax nylanderi, where the presence of tapeworm-infected nestmates leads to reduced nestmate recognition among uninfected workers. The parasite-induced decline in nestmate recognition could be caused by higher intra-colonial cue diversity as tapeworm-infected workers are known to exhibit a modified hydrocarbon signature. This in turn may broaden the neuronal template of their nestmates, leading to a higher tolerance towards alien conspecifics. To test this hypothesis, we exchanged infected ants between colonies and analyzed their impact on CHC profiles of uninfected workers. We demonstrate that despite frequent grooming, which should promote the transfer of recognition cues, CHC profiles of uninfected workers neither changed in the presence of tapeworm-infected ants, nor did it increase cue diversity among uninfected nestmates within or between colonies. However, CHC profiles were systematically affected by the removal of nestmates and addition of non nestmates, independently from the ants' infection status. For example, when non nestmates were present workers expressed more dimethyl alkanes and higher overall CHC quantities, possibly to achieve a better distinction from non-nestmates. Workers showed clear task-specific profiles with tapeworm-infected workers resembling more closely young nurses than older foragers. Our results show that the parasite-induced decline in nestmate recognition is not due to increased recognition cue diversity or altered CHC profiles of uninfected workers, but behavioral changes might explain tolerance towards intruders. PMID- 28842788 TI - The Brazilian World Cup: too hot for soccer? AB - The main objective of this research was to analyze the climate data for the host cities of the soccer World Cup held in Brazil in June and July 2014. A great deal of criticism was expressed about the Brazilian climate in the national and international press and media in the run-up to the competition, suggesting that the air temperature and relative air humidity would be the main adversaries of the soccer teams, especially those from Europe, during the competition. An analysis of the weather was done at the places and times of each of the 64 matches held. A human thermal comfort index was calculated (discomfort index (DI)) for each of the matches in order to discover the real climatic conditions in the host cities during the 2014 World Cup and their potential influence on the teams and human comfort in general. During the 2014 World Cup, only two matches were played at temperatures above 30 degrees C, representing a negligible percentage of the total number of matches. The air temperature for over half the matches (53%) was 20-25 degrees C. The results showed the air temperature and relative humidity data analyzed here both individually and in the form of an index indicate that the World Cup held in Brazil in 2014 did not put any of the players at risk due to extreme heat. PMID- 28842789 TI - A comparison of therapeutic dosages of decitabine in treating myelodysplastic syndrome: a meta-analysis. AB - Decitabine is used to treat myelodysplastic syndrome (MDS). This meta-analysis evaluated the efficacy and safety of different dosing regimens of decitabine in treating intermediate and/or high-risk MDS. Medline, Cochrane, EMBASE, and Google Scholar databases were searched up to October 23, 2015. Randomized controlled trials, prospective, cohort, and case series studies were included. Fifteen studies were included with a total of 1378 patients. The decitabine 100 mg/m2/course dosing regimen had a greater overall response rate than the 60-75 mg/m2/course (51 vs. 25%; P = 0.003). It also had higher complete response rate compared with the 135 mg/m2/course regimen (24.2 vs.13.7%; P = 0.016). The three dosing regimens were similar with respect to bone marrow complete response and partial response and hematologic improvement (P values > 0.05). Decitabine 135 mg/m2/course regimen had similar hematologic improvement as best supportive care (P = 0.066). The incidence of neutropenia, thrombocytopenia, infections, and anemia was similar across treatment groups (range, 31 to 38%; P values >= 0.899). The 100 mg/m2/course decitabine regimen showed benefit with respect to overall response rate compared with the 60-75 mg/m2/course regimen, as well as greater improvement in complete response rate compared with the 135 mg/m2/course regimen. All three dosing regimens had similar frequency of adverse events. PMID- 28842790 TI - Clinical value of ambulatory blood pressure in pediatric patients after renal transplantation. AB - Hypertension is a highly prevalent co-morbidity in pediatric kidney transplant recipients. Undertreated hypertension is associated with cardiovascular complications and negatively impacts renal graft survival. Thus, the accurate measurement of blood pressure is of the utmost importance for the correct diagnosis and subsequent management of post-renal transplant hypertension. Data derived from the general population, and to a lesser extent from the pediatric population, indicates that ambulatory blood pressure monitoring (ABPM) is superior to blood pressure measurements taken in the clinical setting for the evaluation of true mean blood pressure, identification of patients requiring antihypertensive treatment, and in the prediction of cardiovascular outcome. This Educational Review will discuss the clinical value of ABPM in the identification of individual blood pressure phenotypes, i.e., normotension, new-onset hypertension, white-coat hypertension, masked hypertension, controlled blood pressure, and undertreated/uncontrolled hypertension in pediatric kidney transplant recipients. Finally, we examine the utility of performing repeated ABPM for treatment monitoring of post-renal transplant hypertension and on surrogate markers related to relevant clinical cardiovascular outcomes. Taken together, our review highlights the clinical value of the routine use of ABPM as a tool for identifying and monitoring hypertension in pediatric kidney transplant recipients. PMID- 28842791 TI - A plant growth-promoting symbiosis between Mycena galopus and Vaccinium corymbosum seedlings. AB - Typically, Mycena species are viewed as saprotrophic fungi. However, numerous detections of Mycena spp. in the roots of green plants suggest that a continuum from saprotrophy to biotrophy could exist. In particular, mycenoid species have repeatedly been found in Ericaceae plant roots. Our study asked whether (1) Mycena species are commonly found in the roots of green Ericaceae plants; (2) Mycena sequences are limited to a single group/lineage within the genus; and (3) a Mycena sp. can behave as a beneficial root associate with a typical ericoid mycorrhizal plant (Vaccinium corymbosum), regardless of how much external labile carbon is available. We detected Mycena sequences in roots of all sampled Ericaceae plants. Our Mycena sequences clustered in four different groups distributed across the Mycena genus. Only one group could be assigned with confidence to a named species (M. galopus). Our Mycena sequences clustered with other Mycena sequences detected in roots of ericoid mycorrhizal plant species collected throughout Europe, America, and Australia. An isolate of M. galopus promoted growth of V. corymbosum seedlings in vitro regardless of external carbon supply in the media. Seedlings inoculated with M. galopus grew as well as those inoculated with the ericoid mycorrhizal fungus Rhizoscyphus ericae. Surprisingly, this M. galopus isolate colonized Vaccinium roots and formed distinctive peg-like structures. Our results suggest that Mycena species might operate along a saprotroph-symbiotic continuum with a range of ericoid mycorrhizal plant species. We discuss our results in terms of fungal partner recruitment by Ericaceae plants. PMID- 28842792 TI - Measuring upper limb function in children with hemiparesis with 3D inertial sensors. AB - PURPOSE: Upper limb assessments in children with hemiparesis rely on clinical measurements, which despite standardization are prone to error. Recently, 3D movement analysis using optoelectronic setups has been used to measure upper limb movement, but generalization is hindered by time and cost. Body worn inertial sensors may provide a simple, cost-effective alternative. METHODS: We instrumented a subset of 30 participants in a mirror therapy clinical trial at baseline, post-treatment, and follow-up clinical assessments, with wireless inertial sensors positioned on the arms and trunk to monitor motion during reaching tasks. RESULTS: Inertial sensor measurements distinguished paretic and non-paretic limbs with significant differences (P < 0.01) in movement duration, power, range of angular velocity, elevation, and smoothness (normalized jerk index and spectral arc length). Inertial sensor measurements correlated with functional clinical tests (Melbourne Assessment 2); movement duration and complexity (Higuchi fractal dimension) showed moderate to strong negative correlations with clinical measures of amplitude, accuracy, and fluency. CONCLUSION: Inertial sensor measurements reliably identify paresis and correlate with clinical measurements; they can therefore provide a complementary dimension of assessment in clinical practice and during clinical trials aimed at improving upper limb function. PMID- 28842793 TI - Knee function after limb salvage surgery for malignant bone tumor: comparison of megaprosthesis and distal femur allograft with epiphysis sparing. AB - PURPOSE: Limb salvage surgery is increasingly used for the treatment of distal femur bone sarcomas. Total knee replacement using megaprosthesis and epiphysis sparing biologic reconstruction using an allograft are widely used in order to preserve joint motion. We aimed to compare the results of these procedures using gait analysis in patients undergoing limb salvage surgery. METHODS: Fifteen patients were included, nine undergoing allograft with epiphysis sparing (Allograft group) and six undergoing megaprosthesis (Megaprosthesis group). Every patient underwent a gait analysis using the Plug-in-Gait protocol. Spatiotemporal parameters, knee kinematics, and kinetics were compared between the two groups and a cohort of ten asymptomatic subjects. Knee function was assessed by the Gait Deviation Index (GDI) and the Gilette Gait Index (GGI). RESULTS: Both treatment groups showed decreased knee flexion during the loading response phase. Megaprosthesis patients showed a decreased knee flexion all along stance phase. There was no difference in gait pattern between the treatment groups. GDI was significantly lower in Megaprosthesis and Allograft patients when compared to controls (86.4 and 84.3 vs 94, all p < 0.05). This difference was not clinically relevant. CONCLUSION: Our study reveals that Megaprosthesis and Allograft patients did not show differences in gait patterns and global function. Even though Allograft and Megaprosthesis patients have significant changes in gait pattern, knee function is acceptable with effective gait mechanisms. Changes occur during stance phase and are due to the quadriceps weakness. The particular pattern of gait in Megaprosthesis patients could be a concern for prosthesis wear and should be investigated on this specific aspect. LEVEL OF EVIDENCE: 4. PMID- 28842794 TI - Analysis of the spatial-temporal variation characteristics of vegetative drought and its relationship with meteorological factors in China from 1982 to 2010. AB - Drought is a complex natural phenomenon that can cause reduced water supplies and can consequently have substantial effects on agriculture and socioeconomic activities. The objective of this study was to gain a better understanding of the spatial-temporal variation characteristics of vegetative drought and its relationship with meteorological factors in China. The Vegetation Condition Index (VCI) dataset calculated from NOAA/AVHRR images from 1982 to 2010 was used to analyse the spatial-temporal variation characteristics of vegetative drought in China. This study also examined the trends in meteorological factors and their influences on drought using monitoring data collected from 686 national ground meteorological stations. The results showed that the VCI appeared to slowly rise in China from 1982 to 2010. From 1982 to 1999, the VCI rose slowly. Then, around 2000, the VCI exhibited a severe fluctuation before it entered into a relatively stable stage. Drought frequencies in China were higher, showing a spatial distribution feature of "higher in the north and lower in the south". Based on the different levels of drought, the frequencies of mild and moderate drought in four geographical areas were higher, and the frequency of severe drought was higher only in ecologically vulnerable areas, such as the Tarim Basin and the Qaidam Basin. Drought was mainly influenced by meteorological factors, which differed regionally. In the northern region, the main influential factor was sunshine duration, while the other factors showed minimal effects. In the southern region and Tibetan Plateau, the main influential factors were sunshine duration and temperature. In the northwestern region, the main influential factors were wind velocity and station atmospheric pressure. PMID- 28842796 TI - Oncologic outcomes following laparoscopic colon cancer resection for T4 lesions: a case-control analysis of 7-years' experience. AB - BACKGROUND: According to many Societies' guidelines, patients presenting with clinical T4 colorectal cancer should conventionally be approached by a laparotomy. Results of emerging series are questioning this attitude. METHODS: We retrospectively analysed the oncologic outcomes of 147 patients operated on between June 2008 and September 2015 for histologically proven pT4 colon cancers. All patients were treated with curative intent, either by a laparoscopic or open "en bloc" resection. RESULTS: Median operative time, blood loss and hospital length of stay were significantly reduced in the laparoscopic group. Postoperative surgical complication rate and 30-day mortality did not significantly differ between the two groups ( p = 0.09 and p = 0.99, respectively). R1 resection rate and lymph nodes harvest, as well, did not remarkably differ when comparing the two groups. In the laparoscopic group, conversion rate was 19%. Long-term outcomes were not affected in patients who had undergone conversion. Five-year overall survival and disease-free survival did not significantly differ between the two groups (44.6% and 40.3% vs. 39.4% and 38.9%). Locally advanced stages (IIIB-IIIC) and R1 resections were detected as independent prognostic factors for overall survival. CONCLUSION: Laparoscopic approach might be safe and acceptable for locally advanced colon cancer and does not jeopardize the oncologic results. Conversion to open surgery should be a part of a strategy as it does not seem to adversely affect perioperative and long-term outcomes. We consider laparoscopy, in expert hands, the last diagnostic tool and the first therapeutic approach for well-selected locally advanced colon cancers. Larger prospective studies are needed to widely assess this issue. PMID- 28842797 TI - EPR in the USSR: the thorny path from birth to biological and chemical applications. AB - In 1944, electron paramagnetic resonance (EPR) was discovered by Evgenii Konstantinovich Zavoisky in the USSR (Union of the Soviet Socialist Republics). Since then, magnetic resonance methods have contributed invaluably to our knowledge in many areas of Life Sciences and Chemistry, and particularly in the area of photosynthesis research. However, the road of the magnetic resonance methods, as well as its acceptance in Life Sciences and Chemistry, was not smooth and prompt in the (former) USSR. We discuss the role played by many including Jakov K. Syrkin, Nikolai N. Semenov, Vladislav V. Voevodsky, Lev A. Blumenfeld, Peter L. Kapitza, and Alexander I. Shalnikov during the early stages of biological and chemical EPR spectroscopy in the USSR. PMID- 28842795 TI - X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. AB - An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition. PMID- 28842798 TI - Effects of different fertilizers on growth and nutrient uptake of Lolium multiflorum grown in Cd-contaminated soils. AB - This study aimed to explore the effects of different fertilizers and their combinations on growth and nutrient and Cd uptake of Lolium multiflorum. Compared with control treatment, chemical fertilizer, organic manure, and their conjunctions with biofertilizer increased shoot biomass. Biofertilizers were found to cause significant reductions in shoot biomass of plants grown in organic manure-treated and control soil. Decreased soil-available N and P and shoot N and K concentrations in biofertilizer amendment treatments indicated that plant growth and nutrient absorption might be negatively affected under nutrient deficiency conditions. Elevated shoot biomasses contributed to the highest shoot Cd contents in chemical fertilizer and chemical fertilizer + biofertilizer treatments among all treatments. But the maximum translocation efficiency occurred in biofertilizer + chemical fertilizer + organic manure treatment, followed by organic manure and chemical fertilizer + organic manure treatments. Based on the results, we can conclude that the application of only the biofertilizer Bacillus subtilis should be avoided in nutrient-limited soils. Chemical fertilizer application could benefit the amount of Cd in shoots, and organic manure application and its combinations could result in the higher translocation efficiency. PMID- 28842799 TI - Strategy to identify the causes and to solve a sludge granulation problem in methanogenic reactors: application to a full-scale plant treating cheese wastewater. AB - Granulation of biomass is at the basis of the operation of the most successful anaerobic systems (UASB, EGSB and IC reactors) applied worldwide for wastewater treatment. Despite of decades of studies of the biomass granulation process, it is still not fully understood and controlled. "Degranulation/lack of granulation" is a problem that occurs sometimes in anaerobic systems resulting often in heavy loss of biomass and poor treatment efficiencies or even complete reactor failure. Such a problem occurred in Mexico in two full-scale UASB reactors treating cheese wastewater. A close follow-up of the plant was performed to try to identify the factors responsible for the phenomenon. Basically, the list of possible causes to a granulation problem that were investigated can be classified amongst nutritional, i.e. related to wastewater composition (e.g. deficiency or excess of macronutrients or micronutrients, too high COD proportion due to proteins or volatile fatty acids, high ammonium, sulphate or fat concentrations), operational (excessive loading rate, sub- or over-optimal water upflow velocity) and structural (poor hydraulic design of the plant). Despite of an intensive search, the causes of the granulation problems could not be identified. The present case remains however an example of the strategy that must be followed to identify these causes and could be used as a guide for plant operators or consultants who are confronted with a similar situation independently of the type of wastewater. According to a large literature based on successful experiments at lab scale, an attempt to artificially granulate the industrial reactor biomass through the dosage of a cationic polymer was also tested but equally failed. Instead of promoting granulation, the dosage caused a heavy sludge flotation. This shows that the scaling of such a procedure from lab to real scale cannot be advised right away unless its operability at such a scale can be demonstrated. PMID- 28842800 TI - Reductive precipitation and removal of Cr(VI) from groundwaters by pipe flocculation-microfiltration. AB - Chromium (Cr(VI)) is a very toxic and carcinogenic element, which is widely present in groundwaters, mainly due to geogenic conditions. The limit of Cr(VI) in drinking water is expected to be reduced to 10 MUg/L in both the USA and the European Union. Recent literature findings indicated that the most efficient process in reducing Cr(VI) levels to below 10 MUg/L proved to be Cr(VI) reduction by Fe(II), by applying a molar ratio Fe(II)/Cr(VI) of around 9. In the present work, we investigated the reduction of Cr(VI) by Fe(II) in pipe flocculation reactors followed by filtration of insoluble products by microfiltration. The proposed technology involves re-circulation of a part of the sludge in the pipe reactors, in order to improve kinetics and efficiency of the process. The obtained results showed that with a Fe(II) dose of around 1 mg/L, Cr(VI) was reduced to below 10 MUg/L, by even an initial concentration as high as 300 MUg/L of Cr(VI), corresponding to a molar ratio Fe(II)/Cr(VI) of around 3, thus reducing the overall quantity of reductive reagents and of the produced sludge. This ratio was also confirmed by the XPS analysis, which also showed that Cr(VI) was reduced to Cr(III) and then precipitated either as Cr(OH)3 or associated with the produced iron oxides. PMID- 28842801 TI - Diffusion of robotic-assisted laparoscopic technology across specialties: a national study from 2008 to 2013. AB - INTRODUCTION: Robotic-assisted procedures were frequently found to have similar outcomes and indications to their laparoscopic counterparts, yet significant variation existed in the acceptance of robotic-assisted technology between surgical specialties and procedures. We performed a retrospective cohort study investigating factors associated with the adoption of robotic assistance across the United States from 2008 to 2013. METHODS: Using the Nationwide Inpatient Sample database, patient- and hospital-level variables were examined for differential distribution between robotic-assisted and conventional laparoscopic procedures. Multilevel logistic regression models were constructed to identify independent factors associated with robotic adoption. Furthermore, cases were stratified by procedure and specialty before being ranked according to proportion of robotic-assistance adoption. Correlation was examined between robotic assistance adoption and relative outcome in comparison with conventional laparoscopic procedures. RESULTS: The national robotic case volume doubled over the five-year period while a gradual decline in laparoscopic case volume was observed, resulting in an increase in the proportion of procedures performed with robotic assistance from 6.8 to 17%. Patients receiving robotic procedures were more likely to be younger, males, white, privately insured, more affluent, and with less comorbidities. These differences have been decreasing over the study period. The three specialties with the highest proportion of robotic-assisted laparoscopic procedures were urology (34.1%), gynecology (11.0%), and endocrine surgery (9.4%). However, no significant association existed between the frequency of robotic-assistance usage and relative outcome statistics such as mortality, charge, or length of stay. CONCLUSION: The variation in robotic-assistance adoption between specialties and procedures could not be attributable to clinical outcomes alone. Cultural readiness toward adopting new technology within specialty and target anatomic areas appear to be major determining factors influencing its adoption. PMID- 28842802 TI - Factors affecting the effectiveness and safety of submucosal tunneling endoscopic resection for esophageal submucosal tumors originating from the muscularis propria layer. AB - BACKGROUND AND AIMS: Submucosal tunneling endoscopic resection (STER) has been proved to be effective and safe for esophageal submucosal tumors (SMTs) originating from the muscularis propria (MP) layer. This study was aimed to further evaluate the effectiveness, safety, and influencing factors especially the types of mucosal incision of STER in a larger population. METHODS: A total of 89 patients undergoing STER with esophageal SMTs were retrospectively enrolled in this study from May 2012 to November 2016. Clinicopathological, endoscopic, and adverse events (AEs) data were collected and analyzed. Different incision methods were compared to evaluate the optimum incision method. RESULTS: There were 27 females and 62 males with mean age of 46.5 +/- 10.3 years. The medium size of the tumors was 16.0 mm (ranging 10.0-60.0 mm). Inverted T incisions were made in 29 (32.6%) patients, transverse incisions in 12 (13.5%) while longitudinal incisions in 48 (53.9%). En bloc resection was achieved in 70 (78.7%) patients. The residual rate was 1.1% (1/89), and no recurrence was noted even after piecemeal resection. The rate of AEs was 21.3% (19/89), and all of the AEs were cured without intervention or treated conservatively without the need for surgery. The en bloc resection rate was comparable among the three incision groups (P = 0.868); however, the incidence of AEs in the inverted T incision was lower than that in the longitudinal incision (P = 0.003). Fewer clips were used in the inverted T incision group than in the transverse incision group (P = 0.003). CONCLUSIONS: Although STER failed to achieve en bloc resection in 21.3% patients, it was still an effective therapy owing to low residual rate and no recurrence rate after piecemeal resection. STER was safe with no severe AEs; however, minor AEs were common. Inverted T incision seems to be the optimum entry point. PMID- 28842803 TI - A Multilevel Analysis of Individual, Health System, and Neighborhood Factors Associated with Depression within a Large Metropolitan Area. AB - Depression prevalence is known to vary by individual factors (gender, age, race, medical comorbidities) and by neighborhood factors (neighborhood deprivation). However, the combination of individual- and neighborhood-level data is rarely available to assess their relative contribution to variation in depression across neighborhoods. We geocoded depression diagnosis and demographic data from electronic health records for 165,600 patients seen in two large health systems serving the Denver population (Kaiser Permanente and Denver Health) to Denver's 144 census tracts, and combined these data with indices of neighborhood deprivation obtained from the American Community Survey. Non-linear mixed models examined the relationships between depression rates and individual and census tract variables, stratified by health system. We found higher depression rates associated with greater age, female gender, white race, medical comorbidities, and with lower rates of home owner occupancy, residential stability, and higher educational attainment, but not with economic disadvantage. Among the Denver Health cohort, higher depression rates were associated with higher crime rates and a lower percent of foreign born residents and single mother households. Our findings suggest that individual factors had the strongest associations with depression. Neighborhood risk factors associated with depression point to low community cohesion, while the role of education is more complex. Among the Denver Health cohort, language and cultural barriers and competing priorities may attenuate the recognition and treatment of depression. PMID- 28842804 TI - On understanding the chemical origin of band gaps. AB - Conceptual DFT and quantum chemical topology provide two different approaches based on the electron density to grasp chemical concepts. We present a model merging both approaches, in order to obtain physical properties from chemically meaningful fragments (bonds, lone pairs) in the solid. One way to do so is to use an energetic model that includes chemical quantities explicitly, so that the properties provided by conceptual DFT are directly related to the inherent organization of electrons within the regions provided by topological analysis. An example of such energy model is the bond charge model (BCM) by Parr and collaborators. Bonds within an ELF-BCM coupled approach present very stable chemical features, with a bond length of ca. 1 A and 2[Formula: see text]. Whereas the 2[Formula: see text] corroborate classical views of chemical bonding, the fact that bonds always expand along 1 A introduces the concept of geometrical transferability and enables estimating crystalline cell parameters. Moreover, combining these results with conceptual DFT enables deriving a model for the band gap where the chemical hardness of a solid is given by the bond properties, charge, length, and a Madelung factor, where the latter plays the major role. In short, the fundamental gap of zinc-blende solids can be understood as given by a 2[Formula: see text] bond particle asymmetrically located on a 1 A length box and electrostatically interacting with other bonds and with a core matrix. This description is able to provide semi-quantitative insight into the band gap of zinc-blende semiconductors and insulators on equal footing, as well as a relationship between band gap and compressibility. In other words, merging these different approaches to bonding enables to connect measurable macroscopic behavior with microscopic electronic structure properties and to obtain microscopic insight into the chemical origin of band gaps, whose prediction is still nowadays a difficult task. Graphical Abstract Conceptual DFT couples to quatum chemcial topology to explain the band gap of zinc-blende solids. PMID- 28842805 TI - The natural history of perforated marginal ulcers after gastric bypass surgery. AB - INTRODUCTION: Although perforated marginal ulcers (pMU) following Roux-en-Y Gastric Bypass (RYGB) represent a surgical emergency, the epidemiology and outcome of this condition is not well understood. The purpose of this study was to evaluate incidence of pMU following RYGB and assess the natural history of this complication. METHODS: The SPARCS administrative database was used to identify patients undergoing RYGB between 2005 and 2010. With the use of a unique identifier, we followed patients up to 2014 for subsequent admission and re intervention (repair or revision) for perforated MU. Groups were compared using Chi square tests with exact p values based on Monte Carlo simulation, t test with unequal variances, and the Wilcoxon rank-sum test when appropriate. RESULTS: We identified 35,080 RYGB patients; 292 patients (0.83%) developed pMU 937 (443 1546) days following RYGB [Median (Q1-Q3)]. Among these 292 patients, tobacco use was present in one-third of patients. Repair of the perforation was performed in 115 patients, while anastomotic revision was reported in 64. Patients who underwent revision were more likely to have respiratory complications. Hospital length of stay was significantly longer for patients managed with RYGB revision (Median, Q1-Q3:7, 5-14, vs 6, 4-7, days, p = 0.001). Recurrence of marginal ulcer was common after either intervention (26.09% for repair and 29.69% for revision, p = 0.726). CONCLUSION: Following RYGB, the incidence of pMU is small. Anastomotic revision for pMU is associated with prolonged length of stay compared to repair alone. Importantly, recurrence after intervention of pMU is common, suggesting possible value of a routine surveillance program for patients following pMU. PMID- 28842806 TI - Material Utilization of Organic Residues. AB - Each year, 1.3 billion tons of food waste is generated globally. This waste traces back to industrial and agricultural producers, bakeries, restaurants, and households. Furthermore, lignocellulosic materials, including grass clippings, leaves, bushes, shrubs, and woods, appear in large amounts. Depending on the region, organic waste is either composted, burned directly, or converted into biogas. All of the options set aside the fact that organic residues are valuable resources containing carbohydrates, lipids, proteins, and phosphorus. Firstly, it is clear that avoidance of organic residues is imperative. However, the residues that accumulate nonetheless should be utilized by material means before energy production is targeted. This review presents different processes for the microbial utilization of organic residues towards compounds that are of great importance for the bioeconomy. The focus thereby is on the challenges coming along with downstream processing when the utilization of organic residues is carried out decentralized. Furthermore, a future process for producing lactic acid from organic residues is sketched. PMID- 28842807 TI - Ceratomyxa azevedoi n. sp. (Myxozoa: Myxosporea) parasitizing the gallbladder of Lutjanus ehrenbergii in the Arabian Gulf. AB - A novel myxosporean species, Ceratomyxa azevedoi sp. n. is described from the gallbladder of the blackspot snapper, Lutjanus ehrenbergii (Peters), captured from the Arabian Gulf off Saudi Arabia. A total of 45 (26.8%) out of 168 fish specimens were found to be infected with Ceratomyxa azevedoi sp. n., the highest prevalence being observed in winter (42.9%, 18/42) and the lowest in autumn (11.9%, 5/42). Mature spores appeared as crescent to slightly elliptical-shaped, measuring 5-7 (6) MUm in length and 12 (10-14) MUm in thickness, with spherical polar capsules containing three polar filament coils. The morphometric and morphological comparison with similar species revealed the taxonomic novelty of this form, suggesting that it should be considered as new species. The phylogenetic analysis of C. azevedoi sp. n., based on partial SSU rDNA sequences, revealed close genetic relatedness to C. buri with 91.3% homogeneity and to C. hamour, with 90.1% homogeneity. PMID- 28842808 TI - Evaluation of DNA methylation and mRNA expression of heat shock proteins in thermal manipulated chicken. AB - Thermal manipulation during embryogenesis has been demonstrated to enhance the thermotolerance capacity of broilers through epigenetic modifications. Heat shock proteins (HSPs) are induced in response to stress for guarding cells against damage. The present study investigates the effect of thermal conditioning during embryogenesis and thermal challenge at 42 days of age on HSP gene and protein expression, DNA methylation and in vitro luciferase assay in brain tissue of Naked Neck (NN) and Punjab Broiler-2 (PB-2) chicken. On the 15th day of incubation, fertile eggs from two breeds, NN and PB-2, were randomly divided in to two groups: control (C)-eggs were incubated under standard incubation conditions, and thermal conditioning (TC)-eggs were exposed to higher incubation temperature (40.5 degrees C) for 3 h on the 15th, 16th, and 17th days of incubation. The chicks obtained from each group were further subdivided and reared under different environmental conditions from the 15th to the 42nd day as normal [N; 25 +/- 1 degrees C, 70% relative humidity (RH)] and heat exposed (HE; 35 +/- 1 degrees C, 50% RH) resulting in four treatment groups (CN, CHE, TCN, and TCHE). The results revealed that HSP promoter activity was stronger in CHE, which had lesser methylation and higher gene expression. The activity of promoter region was lesser in TCHE birds that were thermally manipulated at the embryonic stage, thus reflecting their stress-free condition. This was confirmed by the lower level of mRNA expression of all the HSP genes. In conclusion, thermal conditioning during embryogenesis has a positive impact and improves chicken thermotolerance capacity in postnatal life. PMID- 28842809 TI - beta-Catenin stabilization promotes proliferation and increase in cardiomyocyte number in chick embryonic epicardial explant culture. AB - Cardiomyocyte (CM) differentiation from proepicardial organ- (PEO) and embryonic epicardium (eEpi)-derived cells or EPDCs in a developing heart emerges as a wide interest in purview of cardiac repair and regenerative medicine. eEpi originates from the precursor PEO and EPDCs, which contribute to several cardiac cell types including smooth muscle cells, fibroblasts, endothelial cells, and CMs during cardiogenesis. Here in this report, we have analyzed several cardiac lineage specific marker gene expressions between PEO and eEpi cells. We have found that PEO-derived cells show increased level of CM lineage-specific marker gene expression compared to eEpi cells. Moreover, Wnt signaling activation results in increased level of CM-specific marker gene expression in both PEO and eEpi cells in culture. Interestingly, Wnt signaling activation also increases the number of proliferating and sarcomeric myosin (Mf20)-positive cells in eEpi explant culture. Together, this data suggests that eEpi cells as a source for CM differentiation and Wnt signaling mediator, beta-catenin, might play an important role in CM differentiation from eEpi cells in culture. PMID- 28842810 TI - Rectal Cancer in Patients Under 50 Years of Age. AB - BACKGROUND: General population screening for colorectal cancer starts at 50, and incidence rates of rectal cancer in patients over 50 years old are decreasing. However, incidence of rectal cancer under age 50 is increasing. This paper analyzes short-and long-term outcomes for rectal cancer patients under 50 years of age. METHODS: Retrospective analyses of consecutive patient cohort, who all received surgical treatment for primary rectal adenocarcinoma at a single institute were used in the study. Outcomes were stratified based on age under or over 50 at the time of surgery. RESULTS: A total of 582 patients was included, of whom 125 were younger than 50. ASA-score was higher for older patients, with no other significant differences in baseline characteristics. AJCC-staging, based on surgical pathology, differed significantly due to higher stage II-rate in the older group and higher stages III- and IV-rates in the younger group. Percentages of high-grade disease, small vessel-, and perineural invasion were higher for younger patients. Stage-for-stage oncologic survival analyses did not demonstrate a significant difference between younger and older patients. Additionally, an age under/over 50 did not have a significant effect in multivariable analyses for disease free-, and disease specific survival. CONCLUSIONS: Patients who present with rectal cancer under the age of 50 do not seem to have more aggressive disease, while they present with more advanced disease when compared to patients older than 50. Identifying young people at risk of developing rectal cancer and start screening earlier in a selective group might improve disease stage on presentation. PMID- 28842811 TI - Imaging of Claudin-4 in Pancreatic Ductal Adenocarcinoma Using a Radiolabelled Anti-Claudin-4 Monoclonal Antibody. AB - PURPOSE: Despite its widespread use, the positron emission tomography (PET) radiotracer 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) has been shown in clinical settings to be ineffective for improving early diagnosis of pancreatic ductal adenocarcinoma (PDAC). A promising biomarker for PDAC detection is the tight junction protein claudin-4. The purpose of this study was to evaluate a new single-photon emission computed tomography (SPECT) imaging agent, [111In]anti claudin-4 mAb, with regard to its ability to allow visualisation of claudin-4 in a xenograft and a genetically engineered mouse model of PDAC. PROCEDURES: The ability of [111In]anti-claudin-4 mAb to selectively target claudin-4 was assessed using two human xenograft tumour models with differential claudin-4 status in mice. [111In]anti-claudin-4 mAb was also used to detect PDAC development in genetically engineered KPC mice. The PDAC status of these mice was confirmed with [18F]FDG-PET, magnetic resonance imaging (MRI), histology, and immunofluorescence microscopy. RESULTS: High uptake of [111In]anti-claudin-4 mAb was observed in PDAC xenografts in mice, reaching 16.9 +/- 4.5 % of injected dose per gram (% ID/g) at 72 h post-injection. This uptake was mediated specifically by the expression of claudin-4. Uptake of [111In]anti-claudin-4 mAb also enabled clear visualisation of spontaneous PDAC formation in KPC mice. CONCLUSIONS: [111In]anti claudin-4 mAb allows non-invasive detection of claudin-4 upregulation during development of PDAC and could potentially be used to aid in the early detection and characterisation of this malignancy. PMID- 28842812 TI - Platelet Distribution Width to Platelet Count Ratio as an Index of Severity of Illness. AB - OBJECTIVE: To prospectively validate association between the ratio of platelet distribution width (PDW)/platelet count (PCT) and pediatric intensive care unit (PICU) mortality. METHODS: The study was done in the pediatric intensive care unit (PICU). Platelet indices in the first sample taken after admission were used. In this case control analysis, cases were the patients who died in PICU and the survivors served as controls. Consecutive 209 eligible patients over a period of 15 mo from January 2014 through March 2015 were included. Exposure was PDW/PC above 0.07. Of them 174 survived and 35 died. RESULTS: The mean PDW for survivors was 16.77 (+/-0.92) and for those who died it was 17.33 (+/-1.03) (p 0.0015). Mean platelet count (PC) for survivors was 3,46,000 (+/-1,64,700) and for those who died it was 1,75,800 (+/-1,61,500) (p < 0.001). PDW/PC for survivors was 0.12 (+/-0.46) and for those who died it was 0.336 (+/-0.53) (p 0.0014). Using the cut off of 0.07 for PDW/PC described by Golwala et al., 77.14% above the cut-off died, compared to 22.85% below that cut-off. The odds ratio (OR) for death was 10.6 (95% CI: 4.48 to 25.12). The area under the receiver operating curve (ROC) curve for PDW/PC ratio was 0.81. CONCLUSIONS: The ratio of PDW/PC, higher than 0.07 in the first sample after admission can be considered as an independent predictor of mortality with sensitivity and specificity of 77.1% and 77.5%, respectively. It may be a useful component for inclusion in composite scores for predicting mortality. PMID- 28842813 TI - Crying Infant. AB - Excessive crying is a common complaint in young infants, especially in those less than 3 mo of age. Altered circadian rhythm, immaturity of central nervous system and alteration of intestinal microbiota are some of the proposed mechanisms for this problem. Although it is commonly benign, crying can be the only clinical manifestation of many serious underlying illnesses, thus warranting careful clinical examination for ruling out organic causes. Urgent care clinics are best suited for evaluation and treatment of benign etiologies and promptly referring children with red flags to an emergency department. Routine investigations are not indicated in an afebrile infant with no signs of illness on history and physical examination. Excessive crying due to colic often results in parental stress and exhaustion. Treatment in such cases revolves more on reassuring the parents and avoiding drugs with uncertain action and potential side-effects. PMID- 28842815 TI - Congenital Fatal Diarrhea in Newborns. AB - Microvillus inclusion disease is a rare autosomal recessive disorder of intestinal epithelium causing intractable secretary diarrhea in the first two months of life and about 140 cases have been reported worldwide till now. Here authors report 2 cases of Microvillus inclusion disease (MVID) diagnosed in neonates by electron microscopy study of small intestinal biopsy. PMID- 28842814 TI - Protein Kinase C gamma Contributes to Central Sensitization in a Rat Model of Chronic Migraine. AB - Protein kinase C gamma (PKCgamma) is a critical regulator of central sensitization and is widely recognized to be involved in the pathogenesis of chronic migraine (CM). However, the function of PKCgamma in CM remains unknown. This study investigated the role of PKCgamma on pathogenesis of CM. We repeated infusions of inflammatory soup (IS) on the intact dura of conscious rats to model recurrent trigeminovascular or dural nociceptor activation assumed to occur in patients with CM. The von Frey test was then used to detect changes in pain threshold. QT-PCR, western blotting, and double immunofluorescence staining were performed to detect the expression and location of PKCgamma in the trigeminal nucleus caudalis (TNC) and the expressions of calcitonin gene-related peptide (CGRP), c-Fos, and phosphorylation level of GluR1 subunit at serine 831. Chelerythrine chloride (CHE) and phorbol 12-myristate 13-acetate (PMA) were administrated to investigate the role of PKCgamma in central sensitization. We found that repeated infusions of IS induced mechanical allodynia. PKCgamma was significantly increased in TNC after CM. Furthermore, inhibition of PKCgamma by CHE relieved allodynia and reduced the expression of CGRP and c-Fos. Activation of PKCgamma by PMA aggravated allodynia and increased the expression of CGRP and c-Fos. In addition, inhibition of PKCgamma reduced the phosphorylation level of GluR1; in contrast, activation of PKCgamma increased the phosphorylation level of GluR1. These results suggest PKCgamma-induced GluR1 phosphorylation might participate in central sensitization in a rat model of CM. We suggest that PKCgamma is a potential therapeutic target for CM. PMID- 28842816 TI - Single-Center Experience Implementing the LOINC-RSNA Radiology Playbook for Adult Abdomen/Pelvis CT and MR Procedures Using a Semi-Automated Method. AB - The LOINC-RSNA Radiology Playbook represents the future direction of standardization for radiology procedure names. We developed a software solution ("RadMatch") utilizing Python 2.7 and FuzzyWuzzy, an open-source fuzzy string matching algorithm created by SeatGeek, to implement the LOINC-RSNA Radiology Playbook for adult abdomen and pelvis CT and MR procedures performed at our institution. Execution of this semi-automated method resulted in the assignment of appropriate LOINC numbers to 86% of local CT procedures. For local MR procedures, appropriate LOINC numbers were assigned to 75% of these procedures whereas 12.5% of local MR procedures could only be partially mapped. For the standardized local procedures, only 63% of CT and 71% of MR procedures had corresponding RadLex Playbook identifier (RPID) codes in the LOINC-RSNA Radiology Playbook, which limited the utility of RPID codes. RadMatch is a semi-automated open-source software tool that can assist radiology departments seeking to standardize their radiology procedures via implementation of the LOINC-RSNA Radiology Playbook. PMID- 28842817 TI - Methamphetamine Induces TET1- and TET3-Dependent DNA Hydroxymethylation of Crh and Avp Genes in the Rat Nucleus Accumbens. AB - Methamphetamine (METH) addiction is a biopsychosocial disorder that is accompanied by multiple relapses even after prolonged abstinence, suggesting the possibilities of long-lasting maladaptive epigenetic changes in the brain. Here, we show that METH administration produced time-dependent increases in the expression of corticotropin-releasing hormone (Crh/Crf), arginine vasopressin (Avp), and cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt) mRNAs in the rat nucleus accumbens (NAc). Chromatin immunoprecipitation (ChIP) assays revealed that METH increased the abundance of phosphorylated CREB (pCREB) at the promoter of Cartpt but not at Avp or Crh DNA sequences. In contrast, METH produced DNA hypomethylation at sites near the Crh transcription start site (TSS) and at intragenic Avp sequences. METH also increased DNA hydroxymethylation at the Crh TSS and at intragenic Avp sites. In addition, METH increased the protein expression of ten-eleven-translocation enzymes that catalyze DNA hydroxymethylation. Importantly, METH increased TET1 binding at the Crh promoter and increased TET3 binding at Avp intragenic regions. We further tested the role of TET enzymes in METH-induced changes in gene expression by using the TET inhibitor, 1,5-isoquinolinediol (IQD), and found that IQD blocked METH-induced increases in Crh and Avp mRNA expression. Together, these results indicate that METH produced changes in neuropeptide transcription by both activation of the cAMP/CREB pathway and stimulation of TET-dependent DNA hydroxymethylation. These results provide molecular evidence for epigenetic controls of METH-induced changes in the expression of neuropeptides. PMID- 28842818 TI - Association between the MTHFR-C677T isoform and structure of sperm DNA. AB - PURPOSE: The aim of this study is to evaluate whether the MTHFR contribution to male decreased fertility can be attributable to anomalies in sperm nucleus DNA structure in relation to defective methylation. METHODS: The presence of MTHFR C677T, contributing at most for male infertility, was determined from a venous blood sample, using real-time polymerase chain reaction (PCR). Sperm DNA fragmentation (SDF) and sperm nucleus decondensation index (SDI) measurements were performed using acridine orange and flow cytometry. SDF and SDI of men MTHFR C677T heterozygous or homozygous were compared to a general population of hypo fertile patients RESULTS: SDF is not increased either in homozygous or heterozygous carriers of MTHFR C677T. In contrast, SDI is increased with a higher incidence in homozygous (p = 0.0006) than in heterozygous (p = 0.029) patients when compared with the control population. Using a critical threshold of 20% for either SDI or SDF assayed with our technique, the percentage of patients with results higher than this value is not significant with respect to fragmentation (0.128), but is significantly increased for decondensation (0.0003). CONCLUSIONS: Defective methylation linked to MTHFR may contribute to sperm pathogenesis via increased SDI. After DNA structure analysis, especially SDI, treatment with 5 methyl tetrahydrofolate (MTHF), the metabolite downstream from the action of MTHFR, should be recommended as a therapeutic approach. Patients with a high SDI should be tested for MTHFR isoforms as part of a healthcare policy. PMID- 28842820 TI - HIV Infection Is Not a Contraindication to Laparoscopic Sleeve Gastrectomy for Morbid Obesity. AB - BACKGROUND: The efficacy of antiretroviral therapy has made HIV a chronic condition. The prevalence of obesity in HIV positive patients has subsequently risen and is present in 6-34% of men and 21-30% of women (Keithley et al. J Assoc Nurses AIDS Care 20(4):260-74, 2009). Sleeve gastrectomy is a safe and effective procedure for weight loss in the general population, but having HIV may bring hesitation to performing bariatric surgery for some practitioners. OBJECTIVES: The aim of this study is to evaluate the safety and efficacy of laparoscopic sleeve gastrectomy (LSG) in patients with HIV. METHODS: A retrospective analysis of prospectively collected data of patients with HIV who underwent LSG at a community hospital by a single surgeon was performed. Nine patients with HIV underwent LSG. Primary outcomes include weight loss at 6 and 12 months and postoperative CD4 count and viral load. Secondary outcomes include alteration to antiretroviral therapy (ART). RESULTS: Our patients had a mean BMI of 46 (range 35-66) and were all well controlled on ART preoperatively. Mean weight loss at 12 months was 40 kg (range 21-55), with mean excess body weight loss 69% (range 42 112). There were no significant changes in CD4 counts, and all patients continued to have undetectable viral loads at 1 year postoperatively. One patient had a change in ART, which was unrelated to bariatric surgery. There were no complications in our patient group. CONCLUSION: This is the largest series to date evaluating sleeve gastrectomy in HIV-positive patients and further supports the safety and efficacy of sleeve gastrectomy in this patient population. PMID- 28842819 TI - Musculoskeletal Health in the Context of Spinal Cord Injury. AB - PURPOSE OF REVIEW: This review assembles recent understanding of the profound loss of muscle and bone in spinal cord injury (SCI). It is important to try to understand these changes, and the context in which they occur, because of their impact on the wellbeing of SC-injured individuals, and the urgent need for viable preventative therapies. RECENT FINDINGS: Recent research provides new understanding of the effects of age and systemic factors on the response of bone to loading, of relevance to attempts to provide load therapy for bone in SCI. The rapidly growing dataset describing the biochemical crosstalk between bone and muscle, and the cell and molecular biology of myokines signalling to bone and osteokines regulating muscle metabolism and mass, is reviewed. The ways in which this crosstalk may be altered in SCI is summarised. Therapeutic approaches to the catabolic changes in muscle and bone in SCI require a holistic understanding of their unique mechanical and biochemical context. PMID- 28842822 TI - Activation of Reactive MALDI Adduct Ions Enables Differentiation of Dihydroxylated Vitamin D Isomers. AB - Vitamin D compounds are secosteroids, which are best known for their role in bone health. More recent studies have shown that vitamin D metabolites and catabolites such as dihydroxylated species (e.g., 1,25- and 24,25-dihydroxyvitamin D3) play key roles in the pathologies of various diseases. Identification of these isomers by mass spectrometry is challenging and currently relies on liquid chromatography, as the isomers exhibit virtually identical product ion spectra under collision induced dissociation conditions. Here, we developed a simple MALDI-CID method that utilizes ion activation of reactive analyte/matrix adducts to distinguish isomeric dihydroxyvitamin D3 species, without the need for chromatography separation or chemical derivatization techniques. Specifically, reactive 1,5-diaminonaphthalene adducts of dihydroxyvitamin D3 compounds formed during MADI were activated and specific cleavages in the secosteroid's backbone structure were achieved that produced isomer-diagnostic fragment ions. Graphical Abstract ?. PMID- 28842821 TI - Association Between Obesity and Migraine in Women. AB - PURPOSE OF REVIEW: Migraine is a common and highly disabling condition that is particularly prevalent among women and especially women of reproductive age. The tremendous rise in adiposity in the Western world has led to an epidemic of obesity in women. The particular effects of obesity on women with migraine of various ages are the focus of this review. RECENT FINDINGS: Conflicting findings from various studies with different approaches and populations have made challenging definitive conclusions about associations between migraine and obesity. While the association between obesity and migraine frequency has been consistently demonstrated and obesity is considered a risk factor for progression from episodic to chronic migraine, the association between obesity and migraine prevalence is still somewhat debated and appears to be dependent on gender and age, with the most consistent effects observed in women younger than 55 years of age. Association between migraine and obesity is most commonly observed in women of reproductive age. The multimodal changes associated with age and hormonal change in women likely play a role in this relationship, as obesity does not appear to be related to migraine in women over 55 years of age. Future studies focusing on the migraine-obesity relationship in women should examine the effects of age, endogenous hormonal state, and exogenous hormones on migraine and obesity. PMID- 28842823 TI - In vitro toxicity of perfluorooctane sulfonate on rat liver hepatocytes: probability of distructive binding to CYP 2E1 and involvement of cellular proteolysis. AB - Perfluorooctanesulfonate (PFOS), an anthropogenic fluorosurfactant, is one of the most common global pollutants. PFOS is used in various consumer products to provide soil, oil, and water resistance to materials used in clothing, upholstery, and food packaging. PFOS is persistent, bioaccumulative, and toxic to mammalian species. In this study, the cellular mechanisms involved in PFOS hepatotoxicity were evaluated. For this purpose, we determined oxidative stress markers including cell lysis, ROS generation, lipid peroxidation, glutathione depletion, mitochondrial membrane potential decrease, lysosomal membrane leakiness, and cellular proteolysis. Our results demonstrated that PFOS liver cytotoxicity was associated with reactive oxygen species (ROS) formation and lipid peroxidation in isolated rat hepatocytes. Incubation of hepatocytes with PFOS caused rapid depletion of hepatocyte glutathione (GSH), an important marker of cellular oxidative stress. Most of the PFOS-induced GSH depletion could be attributed to the expulsion of glutathione disulfide (GSSG). PFOS hepatotoxicity was inhibited by antioxidants and ROS scavengers, mitochondrial permeability transition (MPT) pore sealing agents, and endocytosis inhibitors. Our results suggest that PFOS hepatotoxicity might be the result of oxidative stress-induced lysosomal membrane leakiness and cellular proteolysis in rat hepatocytes. PMID- 28842825 TI - ACMT and AACT Position Statement: Preventing Occupational Fentanyl and Fentanyl Analog Exposure to Emergency Responders. PMID- 28842824 TI - Protein Modifications with Ubiquitin as Response to Cerebral Ischemia-Reperfusion Injury. AB - Post-translational protein modifications present an elegant and energy efficient way to dynamically reprogram cellular protein properties and functions in response to homeostatic imbalance. One such protein modification is the tagging of proteins with the small modifier ubiquitin that can have an impact on protein stability, localization, interaction dynamics, and function. Ubiquitination is vital to any eukaryotic cell under physiological conditions, but even more important under stress including oxidative, genotoxic, and heat stress, where ubiquitination levels are drastically increased. Elevated levels of ubiquitin protein conjugates are also observed in the brain after focal and global cerebral ischemia. Post-ischemic ubiquitination is immediately induced with reperfusion and transiently detected in neurons with survival potential located in the peri infarct area. This review aims to critically discuss current knowledge and controversies on protein ubiquitination after cerebral ischemia, with special emphasis on potential mechanisms leading to elevated ubiquitination and on target identification. Further, possible functional implications of post-ischemic ubiquitination, including a relationship to SUMOylation, a neuroprotective modification, will be highlighted. The elevation in ubiquitinated proteins following cerebral ischemia is a greatly under-explored research area, the better understanding of which may contribute to the development of novel stroke therapies. PMID- 28842826 TI - Environmental Enrichment Reverses Tyrosine Kinase Inhibitor-Mediated Impairment Through BDNF-TrkB Pathway. AB - Exposure to an enriched environment (EE) has neuroprotective benefits and improves recovery from brain injury due to, among other, increased neurotrophic factor expression. Through these neurotrophins, important cortical and hippocampal changes occur. Vandetanib acts as a tyrosine kinase inhibitor of cell receptors, among others, the vascular endothelial growth factor receptor (VEGFR). Our aim was to investigate the effectiveness of EE counteracting cognitive and cellular effects after tyrosine kinase receptor blockade. Animals were reared under standard laboratory condition or EE; both groups received vandetanib or vehicle. Visuospatial learning was tested with Morris water maze. Neuronal, interneuronal, and vascular densities were measured by inmunohistochemistry and histochemistry techniques. Quantifications were performed in the hippocampus and in the visual cortex. Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), Akt, and Erk were measured by Western blot technique. Vandetanib produces a significant decrease in vascular and neuronal densities and reduction in the expression of molecules involved in survival and proliferation processes such as phospho-Akt/Akt and phospho-Erk/Erk. These results correlated to a cognitive impairment in visuospatial test. On the other hand, animals reared in an EE are able to reverse the negative effects, activating PI3K-AKT and MAP kinase pathways mediated by BDNF-TrkB binding. Present results provide novel and consistent evidences about the usefulness of living in EE as a strategy to improve deleterious effects of blocking neurotrophic pathways by vandetanib and the notable role of the BDNF-TrkB pathway to balance the neurovascular unit and cognitive effects. PMID- 28842827 TI - Nephronectin is Decreased in Metastatic Breast Carcinoma and Related to Metastatic Organs. AB - Breast cancer causes death mostly due to distant metastasis. During metastasis, cancer cells create new conditions in which normal tissue structure can be disturbed. Nephronectin, which is the primary ligand for alpha8beta1 integrin, plays an important role in kidney development. There are conflicting findings regarding its role in cancer progression and metastasis, especially in breast carcinoma. The aim of this study was to determine changes in nephronectin expression in primary tumor tissues and metastatic visceral organs, using metastatic and non-metastatic cell lines in a mouse model of breast cancer. In our study, 4T1-Liver Metastatic and 4T1-Heart Metastatic cells, originally derived from 4T1-murine breast carcinoma, and non-metastatic 67NR carcinoma cells were used. Cancer cells were injected orthotopically into the mammary gland of 8 10 week-old Balb-c mice. Primary tumors, lung, liver tissues were collected on 12th and 25th days after the tumor injection. Immunohistochemistry was used to determine expression of nephronectin in tissues. We also investigated the expression levels of the protein by using western blot technique. We found that lung and liver tissue of control animals (not-injected with tumor cells) expressed nephronectin which was lost in animals bearing metastatic tumor for 25 days. In accordance, nephronectin staining of lung and liver was preserved in animals injected with non-metastatic 67NR tumors. These results demonstrate that loss of nephronectin may play an important role in formation metastatic milieu for cancer cells. This is the first study demonstrating that tumor-induced loss of nephronectin expression in visceral organs in which metastatic growth takes place. PMID- 28842828 TI - A Biopsychological Model of Anti-drug PSA Processing: Developing Effective Persuasive Messages. AB - For the current study, we developed and tested a biopsychological model to combine research on psychological tension, the Limited Capacity Model of Motivated Mediated Message Processing, and the endocrine system to predict and understand how people process anti-drug PSAs. We predicted that co-presentation of pleasant and unpleasant information, vs. solely pleasant or unpleasant, will trigger evaluative tension about the target behavior in persuasive messages and result in a biological response (increase in cortisol, alpha amylase, and heart rate). In experiment 1, we assessed the impact of co-presentation of pleasant and unpleasant information in persuasive messages on evaluative tension (conceptualized as attitude ambivalence), in experiment 2, we explored the impact of co-presentation on endocrine system responses (salivary cortisol and alpha amylase), and in experiment 3, we assessed the impact of co-presentation on heart rate. Across all experiments, we demonstrated that co-presentation of pleasant and unpleasant information, vs. solely pleasant or unpleasant, in persuasive communications leads to increases in attitude ambivalence, salivary cortisol, salivary alpha amylase, and heart rate. Taken together, the results support the initial paths of our biopsychological model of persuasive message processing and indicate that including both pleasant and unpleasant information in a message impacts the viewer. We predict that increases in evaluative tension and biological responses will aid in memory and cognitive processing of the message. However, future research is needed to test that hypothesis. PMID- 28842829 TI - Psychiatric Hospitalization Among Adolescents. PMID- 28842831 TI - Simulating PDGF-Driven Glioma Growth and Invasion in an Anatomically Accurate Brain Domain. AB - Gliomas are the most common of all primary brain tumors. They are characterized by their diffuse infiltration of the brain tissue and are uniformly fatal, with glioblastoma being the most aggressive form of the disease. In recent years, the over-expression of platelet-derived growth factor (PDGF) has been shown to produce tumors in experimental rodent models that closely resemble this human disease, specifically the proneural subtype of glioblastoma. We have previously modeled this system, focusing on the key attribute of these experimental tumors the "recruitment" of oligodendroglial progenitor cells (OPCs) to participate in tumor formation by PDGF-expressing retrovirally transduced cells-in one dimension, with spherical symmetry. However, it has been observed that these recruitable progenitor cells are not uniformly distributed throughout the brain and that tumor cells migrate at different rates depending on the material properties in different regions of the brain. Here we model the differential diffusion of PDGF-expressing and recruited cell populations via a system of partial differential equations with spatially variable diffusion coefficients and solve the equations in two spatial dimensions on a mouse brain atlas using a flux differencing numerical approach. Simulations of our in silico model demonstrate qualitative agreement with the observed tumor distribution in the experimental animal system. Additionally, we show that while there are higher concentrations of OPCs in white matter, the level of recruitment of these plays little role in the appearance of "white matter disease," where the tumor shows a preponderance for white matter. Instead, simulations show that this is largely driven by the ratio of the diffusion rate in white matter as compared to gray. However, this ratio has less effect on the speed of tumor growth than does the degree of OPC recruitment in the tumor. It was observed that tumor simulations with greater degrees of recruitment grow faster and develop more nodular tumors than if there is no recruitment at all, similar to our prior results from implementing our model in one dimension. Combined, these results show that recruitment remains an important consideration in understanding and slowing glioma growth. PMID- 28842830 TI - Beneficial Effects of Delayed P7C3-A20 Treatment After Transient MCAO in Rats. AB - Despite ischemic stroke being the fifth leading cause of death in the USA, there are few therapeutic options available. We recently showed that the neuroprotective compound P7C3-A20 reduced brain atrophy, increased neurogenesis, and improved functional recovery when treatment was initiated immediately post reperfusion after a 90-min middle cerebral artery occlusion (MCAO). In the present study, we investigated a more clinically relevant therapeutic window for P7C3-A20 treatment after ischemic stroke. MCAO rats were administered P7C3-A20 for 1 week, beginning immediately or at a delayed point, 6 h post-reperfusion. Delayed P7C3-A20 treatment significantly improved stroke-induced sensorimotor deficits in motor coordination and symmetry, as well as cognitive deficits in hippocampal-dependent spatial learning, memory retention, and working memory. In the cerebral cortex, delayed P7C3-A20 treatment significantly increased tissue sparing 7 weeks after stroke and reduced hemispheric infarct volumes 48 h after reperfusion. Despite no reduction in striatal infarct volumes acutely, there was a significant increase in spared tissue volume chronically. In the hippocampus, only immediately treated P7C3-A20 animals had a significant increase in tissue sparing compared to vehicle-treated stroke animals. This structural protection translated into minimal hippocampal-dependent behavioral improvements with delayed P7C3-A20 treatment. However, all rats treated with delayed P7C3-A20 demonstrated a significant improvement in both sensorimotor tasks compared to vehicle controls, suggesting a somatosensory-driven recovery. These results demonstrate that P7C3-A20 improves chronic functional and histopathological outcomes after ischemic stroke with an extended therapeutic window. PMID- 28842832 TI - Perioperative management of antithrombotic therapy in patients receiving cardiovascular implantable electronic devices: a network meta-analysis. AB - PURPOSE: Network meta-analysis (NMA) has advantages including being able to simultaneously compare and rank multiple treatments over traditional meta analysis. We evaluated by a NMA the optimal antithrombotic strategy during the perioperative period of implantation of cardiovascular implantable electronic devices (CIEDs). METHODS: We performed a network meta-analysis of observational studies (cohort and case-control studies). The eligible studies tested the following antithrombotic therapy during the CIED placement: aspirin, clopidogrel, warfarin, novel oral anticoagulants (NOACs), and heparin bridging. RESULTS: Thirty-one observational studies with 119 study arms were included (41,174 patients receiving long-term antithrombotic therapy; median age, 72.6 years; 70.1% males; median follow-up, 3.6 years). Aspirin (4.26 [2.88-7.22]), warfarin (3.37 [2.17-5.23]), and clopidogrel (3.30 [1.49-5.88]) reduced the risk of bleeding as compared with heparin bridging, and there was no significance difference between continued NOACs and heparin bridging (0.67 [0.21-2.18]). The comparison of commonly used protocols in the management of anticoagulant therapy revealed that continued warfarin (0.38 [0.20-0.74]), continued NOACs (0.19 [0.04 0.89]), and heparin bridging therapy (0.01 [0.05-0.21]) increased the risk of bleeding as compared that of control, and continued warfarin (3.74 [1.96-7.16]), interrupted warfarin (4.89 [2.20-10.88]), and interrupted NOACs (12.5 [1.25-100]) reduced the risk of bleeding compared with that of heparin bridging. CONCLUSIONS: Among various antithrombotic drugs, aspirin had the lowest bleeding risk, followed by warfarin, clopidogrel and NOACs, and heparin, with the greatest bleeding risk. NOACs therapy appears safe and effective, and interrupted NOACs may be the optimal anticoagulation protocol for use during the perioperative period of CIED implantation. PMID- 28842834 TI - Knowing where is different from knowing what: Distinct response time profiles and accuracy effects for target location, orientation, and color probability. AB - When a location is cued, targets appearing at that location are detected more quickly. When a target feature is cued, targets bearing that feature are detected more quickly. These attentional cueing effects are only superficially similar. More detailed analyses find distinct temporal and accuracy profiles for the two different types of cues. This pattern parallels work with probability manipulations, where both feature and spatial probability are known to affect detection accuracy and reaction times. However, little has been done by way of comparing these effects. Are probability manipulations on space and features distinct? In a series of five experiments, we systematically varied spatial probability and feature probability along two dimensions (orientation or color). In addition, we decomposed response times into initiation and movement components. Targets appearing at the probable location were reported more quickly and more accurately regardless of whether the report was based on orientation or color. On the other hand, when either color probability or orientation probability was manipulated, response time and accuracy improvements were specific for that probable feature dimension. Decomposition of the response time benefits demonstrated that spatial probability only affected initiation times, whereas manipulations of feature probability affected both initiation and movement times. As detection was made more difficult, the two effects further diverged, with spatial probability disproportionally affecting initiation times and feature probability disproportionately affecting accuracy. In conclusion, all manipulations of probability, whether spatial or featural, affect detection. However, only feature probability affects perceptual precision, and precision effects are specific to the probable attribute. PMID- 28842833 TI - Ceramide and Its Related Neurochemical Networks as Targets for Some Brain Disorder Therapies. AB - Correlational and causal comparative research link ceramide (Cer), the precursor of complex sphingolipids, to some psychiatric (e.g., depression, schizophrenia (SZ), alcohol use disorder, and morphine antinociceptive tolerance) and neurological (e.g., Alzheimer's disease (AD), Parkinson disease (PD)) disorders. Cer generation can occur through the de novo synthesis pathway, the sphingomyelinase pathways, and the salvage pathway. The discoveries that plasma Cer concentration increase during depressive episodes in patients and that tricyclic and tetracyclic antidepressants functionally inhibit acid sphingomyelinase (ASM), the enzyme that catalyzes the degradation of sphingomyelin to Cer, have initiated a series of studies on the role of the ASM Cer system in depressive disorder. Disturbances in the metabolism of Cer or SM are associated with the occurrence of SZ and PD. In both PD and SZ patients, the elevated levels of Cer or SM in the brain regions were associated with the disease. AD patients showed also an abnormal metabolism of brain Cer at early stages of the disease which may suggest Cer as an AD biomarker. In plasma of AD patients and in AD transgenic mice, ASM activity was increased. In contrast, partial ASM inhibition of Abeta deposition improved memory deficits. Furthermore, in clinical and preclinical research, ethanol enhanced activation of ASM followed by Cer production. Limited data have shown that Cer plays an important role in the development of morphine antinociceptive tolerance. In summary, clinical and preclinical findings provide evidence that targeting the Cer system should be considered as an innovative translational strategy for some brain disorders. PMID- 28842836 TI - On the use of dorsiventral reflectance asymmetry of hornbeam (Carpinus betulus L.) leaves in air pollution estimation. AB - This study examines the role of dorsiventral leaf measurements in reflectance based air quality estimation. The dorsiventral asymmetry is used to describe the difference between the upper (adaxial) and lower (abaxial) leaf side. Spectral characteristics of dorsiventral asymmetry and both adaxial and abaxial leaf reflectance are investigated for a typical dicotyledonous species Carpinus betulus used in an urban environment. The link with traffic-related air pollution is established and the potential for monitoring of air quality is evaluated. We conclude that dorsiventral reflectance asymmetry is a factor that should not be ignored in canopy measurements and modeling. On the other hand, the benefits of dorsiventral asymmetry indices as a tool for reflectance-based air quality seem limited. PMID- 28842838 TI - MOSAIC: a web-interface for statistical analyses in ecotoxicology. AB - In ecotoxicology, bioassays are standardly conducted in order to measure acute or chronic effects of potentially toxic substances on reproduction, growth, and/or survival of living animals. MOSAIC, standing for MOdeling and StAtistical tools for ecotoxICology, is a user-friendly web interface dedicated to the mathematical and statistical modelling of such standard bioassay data. Its simple use makes MOSAIC a turnkey decision-making tool for ecotoxicologists and regulators. Without wasting time on extensive mathematical and statistical technicalities, users are provided with advanced and innovative methods for a valuable quantitative environmental risk assessment. MOSAIC is available at http://pbil.univ-lyon1.fr/software/mosaic/ . PMID- 28842837 TI - Study on the Interaction of the CpG Alternating DNA with CdTe Quantum Dots. AB - A novel sensitive method for detection of DNA methylation was developed with thioglycollic acid (TGA)-capped CdTe quantum dots (QDs) as fluorescence probes. Recognition of methylated DNA sites would be useful strategy due to the important roles of methylation in disease occurrence and developmental processes. DNA methylation occurs most often at cytosine-guanine sites (CpG dinucleotides) of gene promoters. The QDs significantly interacted with hybridized unmethylated and methylated DNA. The interaction of CpG rich methylated and unmethylated DNA hybrid with quantum dots as an optical probe has been investigated by fluorescence spectroscopy and electrophoresis assay. The fluorescence intensity of QDs was highly dependent to unmethylated and methylated DNA. Specific site of CpG islands of Adenomatous polyposis coli (APC), a well-studied tumor suppressor gene, was used as the detection target. Under optimum conditions, upon the addition of unmethylated dsDNA, the fluorescence intensity increased in linear range from 1.0 * 10- 10 to 1.0 * 10- 6M with detection limit of 6.2 * 10- 11 M and on the other hand, the intensity of QDs showed no changes with addition of methylated dsDNA. We also demonstrated that the unmethylated and methylated DNA and QDs complexes showed different mobility in electrophoresis assay. This easy and reliable method could distinguish between methylated and unmethylated DNA sequences. PMID- 28842839 TI - Six2 is involved in GATA1-mediated cell apoptosis in mouse embryonic kidney derived cell lines. AB - Six2 (Sine oculis homeobox 2), a homeodomain transcription factor, plays a crucial role in the regulation of mammalian nephrogenesis. It is also implicated in numerous biological functions, such as cell proliferation, apoptosis, and migration. However, the underlying regulatory mechanisms of Six2 remain largely unknown. In this study, we predicted that CRX, GATA1, HOXD8, and POU2F2 might target, binding to the promoter region of Six2 (~2000 bp) by bioinformatics analysis. Among the four genes, the predicted binding sequence of GATA1 is most highly conserved across species. Luciferase assays demonstrated that knockdown of GATA1 decreased the activity of Six2 promoter and qPCR result of Six2 expression was in consistent with this in 293T cells. Mutation of GATA1 binding sites of mSix2 promoter led to obvious decrease of the mSix2 promoter activity. Furthermore, knockdown of GATA1 decreased Six2 expression in mk3 cells and increased cell apoptosis of mk3 and mk4 compared with corresponding control cells, but this up-regulation can be rescued by Six2 overexpression. Our findings indicated that GATA1 may be a potential regulator of Six2-maintained population of nephron progenitor cells. PMID- 28842840 TI - Erratum to: Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies. PMID- 28842841 TI - High Risk of Depression in High-Income African American Boys. AB - BACKGROUND: Despite the well-established literature on the protective effect of socioeconomic status (SES) on physical and mental health, there are a few reports on poor mental health of blacks with high SES. Using a national sample, this study investigated the association between household income and risk of major depressive disorder (MDD) in black youth based on ethnicity, gender, and their intersection. METHODS: One thousand one hundred seventeen black adolescents (810 African Americans and 360 Caribbean blacks) were included in the current study. Household income was the main predictor. MDD (lifetime, 12-month, and 30-day) was the main outcome. Age was the covariate. Ethnicity and gender were the focal moderators. Logistic regressions were used for data analysis. RESULTS: In the pooled sample, household income was not associated with risk of MDD (lifetime, 12 month, or 30-day). We found significant interactions between income and gender on lifetime and 12-month MDD, suggesting a stronger protective effect of income on MDD for females than males. We also found significant interaction between income and ethnicity on 30-day MDD, suggesting stronger protective effect of income against MDD for Caribbean blacks than African Americans. In African American males, high household income was associated with higher risk of lifetime, 12 month, and 30-day MDD. For Caribbean black males and females, high household income was associated with lower odds of 30-day MDD. CONCLUSION: Findings suggest that ethnicity and gender influence how socioeconomic resources such as income are associated with MDD risk among black youth. Higher household income may be associated with higher risk of MDD for African American males. PMID- 28842842 TI - Using Bayesian regression to test hypotheses about relationships between parameters and covariates in cognitive models. AB - An important tool in the advancement of cognitive science are quantitative models that represent different cognitive variables in terms of model parameters. To evaluate such models, their parameters are typically tested for relationships with behavioral and physiological variables that are thought to reflect specific cognitive processes. However, many models do not come equipped with the statistical framework needed to relate model parameters to covariates. Instead, researchers often revert to classifying participants into groups depending on their values on the covariates, and subsequently comparing the estimated model parameters between these groups. Here we develop a comprehensive solution to the covariate problem in the form of a Bayesian regression framework. Our framework can be easily added to existing cognitive models and allows researchers to quantify the evidential support for relationships between covariates and model parameters using Bayes factors. Moreover, we present a simulation study that demonstrates the superiority of the Bayesian regression framework to the conventional classification-based approach. PMID- 28842843 TI - Utilization of Industrial Waste for the Production of Bio-Preservative from Bacillus licheniformis Me1 and Its Application in Milk and Milk-Based Food Products. AB - The bio-preservative efficacy of a partially purified antibacterial peptide (ppABP) produced by Bacillus licheniformis Me1 in an economical medium developed using agro-industry waste was evaluated by direct application in milk and milk based food products. The addition of ppABP in milk samples stored at 4 +/- 2 degrees C and 28 +/- 2 degrees C resulted in the growth inhibition of pathogens Listeria monocytogenes Scott A, Micrococcus luteus ATCC 9341, and Staphylococcus aureus FRI 722. The shelf life of milk samples with added ppABP increased to 4 days at 28 +/- 2 degrees C, whereas curdling and off-odor were noticed in samples without ppABP. Furthermore, the milk samples with ppABP were sensorily acceptable. Antilisterial effect was also observed in cheese and paneer samples treated with ppABP. These results clearly indicate that the ppABP of B. licheniformis Me1 can be utilized as a bio-preservative to control the growth of spoilage and pathogenic bacteria, thereby reducing the risk of food-borne diseases. PMID- 28842844 TI - Intestinal perforation after nivolumab immunotherapy for a malignant melanoma: a case report. AB - BACKGROUND: Nivolumab is a monoclonal antibody against programmed death 1 and has become a standard treatment of advanced melanoma because of its durable response and survival benefits. In this report, we present a case of severe intestinal perforation after nivolumab immunotherapy for malignant melanoma. CASE PRESENTATION: A 73-year-old man with stage IV malignant melanoma underwent nivolumab therapy. The patient presented to our hospital because of a progressing abdominal pain. Radiological evaluation revealed evidence of free intraperitoneal air. Therefore, we diagnosed the patient as having an intestinal perforation, which was successfully resolved after surgical treatment. CONCLUSION: Although intestinal perforation after nivolumab immunotherapy is rare, it can be severe and requires early diagnosis and emergency surgery to ensure a favorable prognosis. PMID- 28842845 TI - Gut Microbiota and Atherosclerosis. AB - PURPOSE OF REVIEW: Studies in microbiota-mediated health risks have gained traction in recent years since the compilation of the Human Microbiome Project. No longer do we believe that our gut microbiota is an inert set of microorganisms that reside in the body without consequence. In this review, we discuss the recent findings which further our understanding of the connection between the gut microbiota and the atherosclerosis. RECENT FINDINGS: We evaluate studies which illustrate the current understanding of the relationship between infection, immunity, altered metabolism, and bacterial products such as immune activators or dietary metabolites and their contributions to the development of atherosclerosis. In particular, we critically examine rec ent clinical and mechanistic findings for the novel microbiota-dependent dietary metabolite, trimethylamine N-oxide (TMAO), which has been implicated in atherosclerosis. These discoveries are now becoming integrated with advances in microbiota profiling which enhance our ability to interrogate the functional role of the gut microbiome and develop strategies for targeted therapeutics. The gut microbiota is a multi-faceted system that is unraveling novel contributors to the development and progression of atherosclerosis. In this review, we discuss historic and novel contributors while highlighting the TMAO story mainly as an example of the various paths taken beyond deciphering microbial composition to elucidate downstream mechanisms that promote (or protect from) atherogenesis in the hopes of translating these findings from bench to bedside. PMID- 28842846 TI - Previously Undescribed Antibacterial Polyketides from Heterotrophic Bacillus amyloliquefaciens Associated with Seaweed Padina gymnospora. AB - A heterotrophic marine bacterium Bacillus amyloliquefaciens isolated from seaweed Padina gymnospora exhibited broad spectra of antibacterial activities against pathogenic bacteria Aeromonas hydrophila, Vibrio harveyi, Vibrio vulnificus, and Vibrio parahaemolyticus. The seaweed-associated B. amyloliquefaciens was recognized to possess functional type I polyketide synthase-1 (pks-1) gene, and was used to isolate four homologous compounds with polyketide frameworks. The compounds were characterized as 11-(15-butyl-13-ethyl-tetrahydro-12-oxo-2H-pyran 13-yl) propyl-2-methylbenzoate (1), 9-(tetrahydro-12-isopropyl-11-oxofuran-10-yl) ethyl-4-ethoxy-2-hydroxybenzoate (2), 12-(aminomethyl)-11-hydroxyhexanyl-10 phenylpropanoate (3), and 7-(14-hydroxypropan-13-yl)-8-isobutyl-7,8 dihydrobenzo[c]oxepin-1(3H)-one (4) by comprehensive nuclear magnetic resonance and mass spectroscopic experiments. The compounds 1-4 displayed significant antibacterial activities against clinically important pathogens V. parahaemolyticus and V. vulnificus (inhibitory zone diameter of >=15 mm, 100 mcg on disk). The electronic and hydrophobic parameters appeared to hold a conspicuous part in directing the antibacterial properties of the compounds. This study revealed seaweed-associated B. amyloliquefaciens as potential source of antimicrobial polyketides for pharmaceutical applications. PMID- 28842847 TI - Visual adaptations of the eye of the gilthead sea bream (Sparus aurata). AB - The current investigation represents the morphological description of the adaptation of gilthead sea bream Sparus aurata to its environmental conditions. For the achievement of this study twelve mature fishes were used for gross, light and electron microscope examinations. The cornea is consists of three layers; an anterior stratified cuboidal epithelium, bowman layer, and a dermal stroma. A mucoid layer located between the dermal stroma and the anterior part of the scleral cornea, while the iridescent layer located between the anterior and the posterior scleral stroma. The retina is composed of ten layers. There are two areas of the retina; non-nervous and nervous. The non-nervous area is represented only by the thick pigmented epithelium layer. The retina has both rod and cone photoreceptors. The cones are differentiated into three types; single, double and triple cones. Rods inner segments contain numerous mitochondria while that of the cones has ellipsosomes. These ellipsosomes may function in condensing light in the outer segment. There is a clear correlation between ellipsosomes formation in the inner segment of cone and night condition. PMID- 28842848 TI - DEAD-box helicase 6 (DDX6) is a new negative regulator for milk synthesis and proliferation of bovine mammary epithelial cells. AB - Milk synthesis of bovine mammary gland is a complex biological process that is regulated by hormones and nutrients, but the mechanism of these regulations still needs further research. DEAD-box helicase 6 (DDX6) is an important member of the RNA helicase family, involved in the regulation of mRNA storage and translation in different systems, but its physiological role and mechanism are largely unclear. In this study, we describe DDX6 as a potentially novel negative regulator for milk synthesis and proliferation of bovine mammary epithelial cells (BMECs). Treatment of BMECs with amino acids (methionine or leucine) or hormones (estrogen or prolactin) decreased the expression of DDX6. DDX6 expression was lower in mammary tissues of lactation period than in mammary tissues of puberty and dry period. Notably, overexpressing DDX6 in BMECs significantly decreased milk synthesis, cell proliferation, and protein levels of p-mTOR, SREBP-1c, and cyclin D1, while inhibiting DDX6 had the opposite effect. Taken together, these results reveal that DDX6 is a new negative regulator to control milk synthesis and proliferation of BMECs. PMID- 28842849 TI - Temporal relations in hormone-withdrawal migraines and impact on prevention- a diary-based pilot study in combined hormonal contraceptive users. AB - BACKGROUND: Menstrually related migraine (MRM) in the hormone-free interval (HFI) of combined hormonal contraceptives (CHC) are according to the ICHD definition also estrogen withdrawal migraines (EWH). MRMs are less responsive to acute medication. Therefore short-term prevention, initiated 1-2 days before onset of the anticipated bleeding and continued for 6 days, is recommended. Such a long prophylactic triptan use might increase the risk for medication overuse headache in women suffering in addition from non-menstrual migraines. In CHC users onset of hormone decline is predictable. It is however unknown, whether the EWHs are rather associated with onset of hormone withdrawal or onset of bleeding. Improved understanding of this relation might contribute to better define and shorten the time interval for prevention. METHODS: For this observational diary-based pilot study we collected data from daily conducted headache diaries of CHC users with MRM in at least two of three cycles, visiting our clinic from 2009 to 2015. We analyzed frequency of migraines for each hormone free day, onset of migraine, onset of bleeding and the relation of migraine to onset of bleeding in the 7-day period following estrogen withdrawal. We identified in addition the onset of migraine attacks lasting more than 1 day (episodes). RESULTS: Forty patient charts met the inclusion criteria, what allowed us to analyze 103 cycles. The mean number of migraine days in the HFI was 2.2 +/- 1.6. Migraine started typically on days 1-5 and bleeding on days 3-5. In relation to first day of bleeding, migraines started on days -1 to 4. Almost half of the migraine attacks lasted longer than 24 h, despite the use of rescue medication. CONCLUSION: MRM in CHC users starts on bleeding days -1 to 4, what differs from findings in the natural cycle. Referring to the HFI interval migraine started mostly on days 1-5. According to these data, it seems to be reasonable to initiate short-term prevention at the last day of pill use or the first day of the HFI and continue for 5 days. PMID- 28842851 TI - Development and application of a self-report measure for assessing sensitive information disclosures across multiple modes. AB - Building on the literature that approaches self-disclosure as a decision-making process, we proposed a self-reported Sensitive Information Disclosure (SID) measure and tested the measure's reliability and validity in two studies across a variety of interview modes and settings. We used theory to identify potential dimensions of sensitive information disclosures, created potential scale items, performed two separate card sorts, and validated the resulting pool of items in two separate experiments. Participants answered the SID scale items following an interview involving sensitive information, potential risk, and after-disclosure vulnerability. Study 1 was a laboratory experiment conducted with 165 university students. Exploratory factor analysis results revealed a two-factor structure, Personal Discomfort and Revealing Personal Information. Study 2 replicated these procedures using confirmatory factor analysis to confirm the factor structure and demonstrate the scale's reliability and validity, with a sample of 77 students and 275 participants from Amazon's M-Turk. Together, these results demonstrate that the proposed 11-item SID scale has good convergent and discriminant validity as well as good reliability. A quasi-experimental application of the measure is illustrated using the substantive findings from Study 2. This research fills a gap in the literature by developing a topic-free scale to measure SID as a dependent variable. The ability to accurately measure sensitive information disclosure is an important and necessary step toward developing a more thorough understanding of how people feel and react when asked to provide personal information in diverse interview settings. PMID- 28842852 TI - Erratum to: Cross-modal working memory binding and L1-L2 word learning. PMID- 28842850 TI - A Flavonoid Glycoside Compound from Murraya paniculata (L.) Interrupts Metastatic Characteristics of A549 Cells by Regulating STAT3/NF-kappaB/COX-2 and EGFR Signaling Pathways. AB - Metastasis remains the leading cause of death from lung carcinoma. It is urgent to find safe and efficient pre-metastasis preventive agents for cancer survivors. We isolated a flavonoid glycoside, hexamethoxy flavanone-o-[rhamnopyranosyl-(1 -> 4)-rhamnopyranoside (HMFRR), from the traditional Chinese medicine (TCM) Murraya paniculata (L.) that can effectively inhibit the adhesion, migration, and invasion of lung adenocarcinoma A549 cells in vitro. Molecular and cellular studies demonstrated that HMFRR significantly downregulated the expressions of cell adhesion-related and invasion-related molecules such as integrin beta1, EGFR, COX-2, MMP-2, and MMP-9 proteins. Additionally, HMFRR effectively downregulated the expressions of epithelial-mesenchymal transition (EMT) markers (N-cadherin and vimentin) and upregulated that of E-cadherin. Moreover, these inhibitions were mediated by interrupting STAT3/NF-kappaB/COX-2 and EGFR/PI3K/AKT signaling pathways. Furthermore, HMFRR counteracted the expressions of cell adhesion molecules (ICAM-1, VCAM-1, and E-selectin) stimulated by interleukin 1beta in human pulmonary microvascular endothelial cells (HPMECs). As a result, HMFRR interrupted the adhesion of A549 cells to HPMECs. Collectively, these results indicate that HMFRR may become a good candidate for cancer metastatic chemopreventive agents by interrupting the STAT3/NF-kappaB/COX-2 and EGFR signaling pathways. PMID- 28842854 TI - PiSCES: Pictures with social context and emotional scenes with norms for emotional valence, intensity, and social engagement. AB - Picture databases are commonly used in experimental work on various aspects of emotion processing. However, existing standardized facial databases, typically used to explore emotion recognition, can be augmented with more contextual information for studying emotion and social perception. Moreover, the perception of social engagement, i.e., the degree of interaction or engagement inferred between the people in target pictures, has not been measured. In this paper, we describe the development of a database comprising 203 black-and-white line drawings depicting people within various situational contexts, and normed on perceived emotional valence, intensity, and social engagement, a new construct. Analyses of ratings collected from 62 young adults (30 females, 32 males; mean age 22 years) revealed the typical quadratic relationship between valence and intensity, i.e., stimuli that are more emotionally charged, whether positively or negatively valenced, are more intense than emotionally-neutral stimuli. Moreover, the results showed significant linear and quadratic relationships between valence and social engagement ratings, indicating that emotionally-charged social scenes were perceived as more engaging than emotionally-neutral social scenes. This new database will facilitate investigations of how people perceive and interpret social and emotional information in everyday interactions, and is offered as a resource to experimenters involved in social and/or emotional processing research. PMID- 28842853 TI - Assessing the presence of enrofloxacin and ciprofloxacin in piggery wastewater and their adsorption behaviour onto solid materials, with a newly developed chromatographic method. AB - Veterinary antibiotics could enter the environment after the application of manure or farm wastewater on soil as fertilizer. In this study, a UPLC-MS/MS analytical method was developed and validated for the simultaneous determination of enrofloxacin (ENR) and ciprofloxacin (CIP) at environmental relevant concentrations in piggery wastewater, piggery wastewater solids, agricultural soil and ground water with good performance characteristics. The method recovery for ENR and CIP was 94.2 and 89.9% in the filtered piggery wastewater, 81.3 and 82% in the wastewater solid material, 78.1 and 76.8% in the soil and 95.6 and 97.3% in the ground water. The Limit of Detection (LOD) and Limit of Quantification (LOQ) for ENR were 21 and 64 ng L-1 and for CIP was 18 and 54 ng L 1, respectively. The method was implemented to monitor ENR and CIP in the wastewater of a piggery facility in Cyprus which applied anaerobic treatment before the final disposal of the reclaimed water. The highest antibiotic concentrations were measured in the wastewater samples collected from the nursery, where ENR is continuously used, with average concentration 31.4 MUg L-1 for ENR and 16.0 MUg L-1 for CIP. After the anaerobic digester, the two antibiotics were found only on the solid matter of the treated wastewater with an average concentration of 1.7 MUg kg-1 for ENR and 1.0 MUg kg-1 for CIP. The antibiotics adsorption at pH = 7 on clay soil, quartz sand and on solid matter isolated from the piggery wastewater was found to be higher than 95% for all solid materials. The concentration of the antibiotics in soil samples taken from a field where reclaimed piggery wastewater was applied for 10 years and in samples of groundwater from a nearby well was found for all samples below the LOD. PMID- 28842855 TI - Diagnosis and Management of Autoimmune Pancreatitis. AB - OPINION STATEMENT: Although autoimmune pancreatitis is a relatively uncommon pancreatic disorder, it is an important consideration in the differential diagnosis of jaundice and pancreatic masses to avoid unnecessary surgical resection. The clinical diagnosis of autoimmune pancreatitis involves considering multiple pieces of information including the pancreatic imaging, serum IgG4 level, presence of characteristic other involvement, and histologic findings. Unlike other pancreatic disorders, this condition rapidly responds to treatment with steroids. In the more common disease subtype (type 1 autoimmune pancreatitis) disease relapses can occur necessitating the use of maintenance treatment with low-dose steroids, steroid-sparing immunomodulators, or rituximab. This chapter reviews the diagnosis and treatment of the autoimmune pancreatitis subtypes. PMID- 28842856 TI - The Need for Infant Mental Health Training for All Child and Adolescent Psychiatrists. PMID- 28842858 TI - Is pH Testing Necessary Before Antireflux Surgery in Patients with Endoscopic Erosive Esophagitis? AB - INTRODUCTION: The relationship between the Los Angeles (LA) grade of esophagitis and acid exposure by pH monitoring is unclear. The aim of this study was to correlate the results of pH testing in patients with esophagitis to determine at what LA grade of esophagitis a pH test is not necessary. METHODS: A retrospective review was performed of the records of all patients who underwent upper endoscopy and were found to have esophagitis graded using the LA system and who had pH monitoring from 2014 to 2016. An abnormal pH test was determined based on the DeMeester score. RESULTS: There were 56 patients with a median age of 57 years. Esophagitis was LA grade A in 19, B in 20, C in 15 and D in 2 patients. An abnormal pH score was present in 47 patients (84%). All patients with C or D esophagitis had an abnormal pH score compared to 79% and 75% of patients with A and B esophagitis, respectively. CONCLUSIONS: The presence of LA C or D esophagitis was always associated with increased esophageal acid exposure on pH testing and is proof of reflux disease. However, pH testing is recommended prior to antireflux surgery in patients with LA A or B esophagitis. PMID- 28842859 TI - Erratum to: aging affects the balance between goal-guided and habitual spatial attention. PMID- 28842857 TI - Characterization of Biaxial Stretch as an In Vitro Model of Traumatic Brain Injury to the Blood-Brain Barrier. AB - Traumatic brain injury (TBI) is one of the major causes of disability in the USA. It occurs when external mechanical forces induce brain damage that causes deformation of brain tissue. TBI is also associated with alterations of the blood brain barrier (BBB). Using primary rat brain microvascular endothelial cells as an in vitro BBB model, the effects of biaxial stretch were characterized at 5, 10, 15, 25, and 50% deformation using a commercially available system. The results were compared to the effects of mild and moderate TBI in vivo, induced by the weight-drop method in mice. In vitro, live/dead cells, lactate dehydrogenase (LDH) release, caspase 3/7 staining, and tight junction (TJ) protein expression were evaluated 24 h after a single stretch episode. In vivo, Evans blue extravasation, serum levels of S100beta, and TJ protein expression were evaluated. Stretch induced a deformation-dependent increase in LDH release, cell death, and activation of caspase 3/7, suggesting the induction of apoptosis. Interestingly, low magnitudes of deformation increased the expression of TJ proteins, likely in an attempt to compensate for stretch damage. High magnitudes of deformation decreased the expression of TJ proteins, suggesting that the damage was too severe to counteract. In vivo, mild TBI did not affect BBB permeability or the expression of TJ proteins. However, moderate TBI significantly increased BBB permeability and decreased the expression of these proteins, similar to the results obtained with a high magnitude deformation. These data support the use biaxial stretch as valuable tool in the study of TBI in vitro. PMID- 28842860 TI - Synergistic Effects of Genistein and Zinc on Bone Metabolism and the Femoral Metaphyseal Histomorphology in the Ovariectomized Rats. AB - In this study, we evaluated the synergistic effects of genistein and zinc on bone metabolism, bone mineral density, and the femoral metaphyseal histomorphology in the ovariectomized rats. Sixty female Sprague-Dawley rats, aged 13 weeks, were divided into sham-operated group (SHAM), ovariectomized group (OVX), genistein treated group (OVX-Gen), zinc-treated group (OVX-Zn), genistein combined zinc treated group (OVX-Gen-Zn), and 17beta-estradiol-treated group (OVX-E) (n = 10). Genistein, zinc, and 17beta-estradiol injections were started immediately after OVX and continued for 10 weeks. The OVX-Gen group was subcutaneous injections of genistein (5 mg/kg once every day). The OVX-Zn group was given intragastric ZnSO4 (0.25 mg/kg once every day) after bilateral ovariectomy. The OVX-Gen-Zn group was subcutaneous injections of genistein (5 mg/kg), at the same time intragastric ZnSO4 (0.25 mg/kg once every day). OVX-E group were intraperitoneally injected with 17beta-estradiol (10 MUg/kg) once every other day. The results showed that genistein and zinc did not alter body weight in OVX rats. The soluble ZnSO4 had no effect to uterus weight loss. Genistein and zinc supplementation significantly increased the BMD of the femur and lumbar spine in OVX rats (P < 0.05, vs. OVX control group). The BMD of the lumbar spine and femur in the OVX-Gen-Zn group is higher than that in the OVX-Gen and OVX-Zn groups (P < 0.05), and there were no differences of BMD among the OVX-Gen-Zn, OVX-E, and SHAM groups (P > 0.05). The femoral metaphyseal morphology and bone histomorphometric parameters revealed that the trabecular volume and thickness in the OVX-Gen-Zn and OVX-E groups were similar to that of SHAM group, and the OVX-Gen-Zn group had more trabecular volume than the OVX-Gen and OVX-Zn groups. Serum zinc was found to be significantly reduced in the OVX group when compared with SHAM. Serum zinc levels were enhanced in the OVX-Zn, OVX-Gen-Zn, and OVX-E groups and restored to normal levels. Serum calcium and serum phosphorus in the OVX-Gen-Zn group was greater than that in the OVX-Gen and OVX-Zn groups (P < 0.05); the serum calcium, phosphorus, and ALP in the OVX-Gen-Zn group were similar to that of SHAM and OVX E groups (P > 0.05). The OVX group had higher osteocalcin, CTX, and RANKL than the SHAM group (P < 0.01). They were lower in the OVX-Gen and OVX-Zn groups (P < 0.05), and they were significantly lower in the OVX-Gen-Zn and OVX-E groups, than in the OVX group. There were no significant differences of osteocalcin, CTX, and RANKL among the OVX-Gen-Zn, OVX-E, and SHAM groups (P > 0.05). OPG and OPG/RANKL ratios were significantly higher in the OVX-Gen and OVX-Zn groups than that in the OVX group (P < 0.05). The OPG and OPG/RANKL ratio in the OVX-Gen-Zn group is higher than that in the OVX-Gen and OVX-Zn groups (P < 0.05, vs. OVX-Gen group; P < 0.01, vs. OVX-Zn group). The differences of the OPG and OPG/RANKL ratios between the OVX-Gen-Zn, OVX-E, and the SHAM groups were not significant (P > 0.05). The results above indicate that the genistein and zinc have synergistic effects on both stimulation of bone formation and suppression of bone resorption in ovariectomized rats, thereby increasing bone mass. PMID- 28842861 TI - Our Truths. PMID- 28842862 TI - Neurotoxicity of the Cyanotoxin BMAA Through Axonal Degeneration and Intercellular Spreading. AB - beta-Methylamino-L-alanine (BMAA) is implicated in neurodegeneration and neurotoxicity, particularly in ALS-Parkinson Dementia Complex. Neurotoxic properties of BMAA have been partly elucidated, while its transcellular spreading capacity has not been examined. Using reconstructed neuronal networks in microfluidic chips, separating neuronal cells into two subcompartments-(1) the proximal, containing first-order neuronal soma and dendrites, and (2) a distal compartment, containing either only axons originating from first-order neurons or second-order striatal neurons-creates a cortico-striatal network. Using this system, we investigated the toxicity and spreading of BMAA in murine primary neurons. We used a newly developed antibody to detect BMAA in cells. After treatment with 10 MUM BMAA, the cyanotoxin was incorporated in first-degree neurons. We also observed a rapid trans-neuronal spread of BMAA to unexposed second-degree neurons in 48 h, followed by axonal degeneration, with limited somatic death. This in vitro study demonstrates BMAA axonal toxicity at sublethal concentrations and, for the first time, the transcellular spreading abilities of BMAA. This neuronal dying forward spread that could possibly be associated with progression of some neurodegenerative diseases especially amyotrophic lateral sclerosis. PMID- 28842864 TI - Mean size estimation yields left-side bias: Role of attention on perceptual averaging. AB - The human visual system can estimate mean size of a set of items effectively; however, little is known about whether information on each visual field contributes equally to the mean size estimation. In this study, we examined whether a left-side bias (LSB)-perceptual judgment tends to depend more heavily on left visual field's inputs-affects mean size estimation. Participants were instructed to estimate the mean size of 16 spots. In half of the trials, the mean size of the spots on the left side was larger than that on the right side (the left-larger condition) and vice versa (the right-larger condition). Our results illustrated an LSB: A larger estimated mean size was found in the left-larger condition than in the right-larger condition (Experiment 1), and the LSB vanished when participants' attention was effectively cued to the right side (Experiment 2b). Furthermore, the magnitude of LSB increased with stimulus-onset asynchrony (SOA), when spots on the left side were presented earlier than the right side. In contrast, the LSB vanished and then induced a reversed effect with SOA when spots on the right side were presented earlier (Experiment 3). This study offers the first piece of evidence suggesting that LSB does have a significant influence on mean size estimation of a group of items, which is induced by a leftward attentional bias that enhances the prior entry effect on the left side. PMID- 28842863 TI - An Analysis of Waves Underlying Grid Cell Firing in the Medial Enthorinal Cortex. AB - Layer II stellate cells in the medial enthorinal cortex (MEC) express hyperpolarisation-activated cyclic-nucleotide-gated (HCN) channels that allow for rebound spiking via an [Formula: see text] current in response to hyperpolarising synaptic input. A computational modelling study by Hasselmo (Philos. Trans. R. Soc. Lond. B, Biol. Sci. 369:20120523, 2013) showed that an inhibitory network of such cells can support periodic travelling waves with a period that is controlled by the dynamics of the [Formula: see text] current. Hasselmo has suggested that these waves can underlie the generation of grid cells, and that the known difference in [Formula: see text] resonance frequency along the dorsal to ventral axis can explain the observed size and spacing between grid cell firing fields. Here we develop a biophysical spiking model within a framework that allows for analytical tractability. We combine the simplicity of integrate-and-fire neurons with a piecewise linear caricature of the gating dynamics for HCN channels to develop a spiking neural field model of MEC. Using techniques primarily drawn from the field of nonsmooth dynamical systems we show how to construct periodic travelling waves, and in particular the dispersion curve that determines how wave speed varies as a function of period. This exhibits a wide range of long wavelength solutions, reinforcing the idea that rebound spiking is a candidate mechanism for generating grid cell firing patterns. Importantly we develop a wave stability analysis to show how the maximum allowed period is controlled by the dynamical properties of the [Formula: see text] current. Our theoretical work is validated by numerical simulations of the spiking model in both one and two dimensions. PMID- 28842865 TI - Leveraging the Family Influence of Women in Prostate Cancer Efforts Targeting African American Men. AB - BACKGROUND: Incidence rate of prostate cancer among African American (AA) men is 1.6 times that in White men. Prevention efforts in this population have typically been through faith-based organizations and barber shops, with a few including significant others. Culturally, women are known to have a strong influence in the AA family. The current study assessed prostate cancer knowledge and explored perceptions on the roles of women in prostate cancer prevention. METHODS: To assess prostate cancer knowledge, a 25-item questionnaire was administered to convenience samples of AA women (n = 297) and men (n = 199). Four focus groups were conducted to explore perceptions on the role of women in prostate cancer prevention. RESULTS: Men had a higher mean score (13.2; max of 25) than women (11.4) for knowledge of prostate cancer. For the men, higher knowledge scores were associated with having a family member diagnosed with prostate cancer and likelihood to engage healthcare providers about prostate cancer (p < 0.05). Themes from the focus groups included education/information resource, support and encouragement, instituting a "culture" of regular primary care, modeling healthcare-seeking behavior, surveillance and monitoring, motivation, and influencing diet. The major barrier to women engaging in the roles identified was limited knowledge. CONCLUSION: Including women in educational interventions may yield added benefits particularly in encouraging AA men to seek regular primary care. This affords men opportunities for dialog with healthcare providers about prostate cancer and informed decision making regarding screening. PMID- 28842866 TI - Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations. AB - Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T- B- NK-), thus underscoring the importance of functional purine metabolism for the development of the immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID. PMID- 28842867 TI - Observation oriented modeling revised from a statistical point of view. AB - Observation Oriented Modeling was proposed to overcome some of the problems in the application of statistical inference methods in the behavioral sciences. In this paper, we refine one part of this approach and show how it is connected to methods that are well known in statistical learning. Specifically, we argue that the Moore-Penrose pseudo inverse is superior to the initial solution from a statistical point of view. With this we also show that Observation Oriented Modeling can indeed be appropriate for some tasks in the analysis of observed data. To provide a practical example, we demonstrate the revised method by analyzing the effect of mindfulness training on attentional processes. PMID- 28842868 TI - Resident Perspectives on Work-Life Policies and Implications for Burnout. AB - OBJECTIVE: As resident burnout increases, there is a need for better awareness, resources, and interventions. Challenges in balancing work and life priorities have been implicated in contributing to physician burnout. Institutional work life policies (WLPs) are critical tools to meet work-life needs. This study investigates the influence of WLPs on residents' experiences. METHODS: The authors emailed a SurveyMonkey link to the APA chief resident and Minority Fellow listservs and directly to 94 psychiatry program directors and 52 fellowship directors nationwide to distribute a survey to residents regarding WLP use and barriers, as well as burnout. Estimated response rate was 12-23%. The authors assessed the anonymous responses using SPSS to evaluate for relationships between awareness of WLPs, perceptions/barriers surrounding their usage, and burnout. RESULTS: The authors analyzed 255 responses. Awareness and use of policies ranged from 2 to 33%. A prominent barrier to WLPs is that use results in shifting workload to co-residents (48% agree). Respondents who perceived leadership to view use of WLPs as a sign of weakness (16% agree) were less likely to use WLPs (t (89) = -3.52, p < 0.001, d = 0.61). Residents with burnout (41%) perceived vastly higher barriers to using WLPs as compared to those without burnout. CONCLUSIONS: This study supports the need for further investigation of WLPs to mitigate resident burnout and identifies important perceived barriers that affect the use of WLPs including low awareness, potential for shifting workload to co residents, and negative perceptions of leadership attitudes toward WLPs. PMID- 28842869 TI - Perceptual control models of pursuit manual tracking demonstrate individual specificity and parameter consistency. AB - Computational models that simulate individuals' movements in pursuit-tracking tasks have been used to elucidate mechanisms of human motor control. Whilst there is evidence that individuals demonstrate idiosyncratic control-tracking strategies, it remains unclear whether models can be sensitive to these idiosyncrasies. Perceptual control theory (PCT) provides a unique model architecture with an internally set reference value parameter, and can be optimized to fit an individual's tracking behavior. The current study investigated whether PCT models could show temporal stability and individual specificity over time. Twenty adults completed three blocks of 15 1-min, pursuit tracking trials. Two blocks (training and post-training) were completed in one session and the third was completed after 1 week (follow-up). The target moved in a one-dimensional, pseudorandom pattern. PCT models were optimized to the training data using a least-mean-squares algorithm, and validated with data from post-training and follow-up. We found significant inter-individual variability (partial eta2: .464-.697) and intra-individual consistency (Cronbach's alpha: .880-.976) in parameter estimates. Polynomial regression revealed that all model parameters, including the reference value parameter, contribute to simulation accuracy. Participants' tracking performances were significantly more accurately simulated by models developed from their own tracking data than by models developed from other participants' data. We conclude that PCT models can be optimized to simulate the performance of an individual and that the test-retest reliability of individual models is a necessary criterion for evaluating computational models of human performance. PMID- 28842870 TI - On Bayesian Testing of Additive Conjoint Measurement Axioms Using Synthetic Likelihood. AB - This article introduces a Bayesian method for testing the axioms of additive conjoint measurement. The method is based on an importance sampling algorithm that performs likelihood-free, approximate Bayesian inference using a synthetic likelihood to overcome the analytical intractability of this testing problem. This new method improves upon previous methods because it provides an omnibus test of the entire hierarchy of cancellation axioms, beyond double cancellation. It does so while accounting for the posterior uncertainty that is inherent in the empirical orderings that are implied by these axioms, together. The new method is illustrated through a test of the cancellation axioms on a classic survey data set, and through the analysis of simulated data. PMID- 28842871 TI - Homologous Recombineering to Generate Chromosomal Deletions in Escherichia coli. AB - Homologous recombination methods enable modifications to be made to the bacterial chromosome. Commonly, the lambda phage RED proteins are employed as a site specific recombinase system, to facilitate recombination of linear DNA fragments with targeted regions of the chromosome. Here we describe methods for the efficient delivery of linear DNA segments containing homology to the chromosome into the cell as substrates for the lambdaRED proteins. Combined with antibiotic selection and counterselection, we demonstrate that using this method facilitates accurate, rapid editing of the chromosome. PMID- 28842872 TI - Measuring In Vivo Supercoil Dynamics and Transcription Elongation Rates in Bacterial Chromosomes. AB - DNA gyrase is the only topoisomerase that can catalytically introduce negative supercoils into covalently closed DNA. The enzyme plays a critical role in many phases of DNA biochemistry. There are only a few methods that allow one to measure supercoiling in chromosomal DNA and analyze the role of gyrase in transcription and its interaction with the other three bacterial topoisomerases. Here, we provide molecular tools for measuring supercoil density in the chromosome and for connecting the dots between transcription and DNA topology. PMID- 28842873 TI - Revealing Sister Chromatid Interactions with the loxP/Cre Recombination Assay. AB - Sister chromatid cohesion is a transient state during replication in bacteria. It has been recently demonstrated that the extent of contact between cohesive sisters during the cell cycle is dependent on topoisomerase IV activity, suggesting that topological links hold sister chromatids together. In the present protocol, we describe a simple method to quantify the frequency of the contacts between two cohesive sister chromatids. This method relies on a site specific recombination assay between loxP sites upon Cre induction. PMID- 28842874 TI - Transposon Insertion Site Sequencing for Synthetic Lethal Screening. AB - Transposon insertion site sequencing (TIS) permits genome-wide, quantitative fitness assessment of individual genomic loci. In addition to the identification of essential genes in given growth conditions, TIS enables the elucidation of genetic networks such as synthetic lethal or suppressor gene combinations. Therefore, TIS becomes an exceptionally powerful tool for the high-throughput determination of genotype-phenotype relationships in bacteria. Here, we describe a protocol for the generation of high-density transposon insertion libraries and subsequent preparation of DNA samples for Illumina sequencing using the Gram negative bacterium Vibrio cholerae as an example. PMID- 28842875 TI - WGADseq: Whole Genome Affinity Determination of Protein-DNA Binding Sites. AB - We present a method through which one may monitor the relative binding affinity of a given protein to DNA motifs on the scale of a whole genome. Briefly, the protein of interest is incubated with fragmented genomic DNA and then affixed to a column. Washes with buffers containing low salt concentrations will remove nonbound DNA fragments, while stepwise washes with increasing salt concentrations will elute more specifically bound fragments. Massive sequencing is used to identify eluted DNA fragments and map them on the genome, which permits us to classify the different binding sites according to their affinity and determine corresponding consensus motifs (if any). PMID- 28842876 TI - High-Resolution Chromatin Immunoprecipitation: ChIP-Sequencing. AB - Chromatin immunoprecipitation (ChIP) coupled with next-generation sequencing (NGS) is widely used for studying the nucleoprotein components that are involved in the various cellular processes required for shaping the bacterial nucleoid. This methodology, termed ChIP-sequencing (ChIP-seq), enables the identification of the DNA targets of DNA binding proteins across genome-wide maps. Here, we describe the steps necessary to obtain short, specific, high-quality immunoprecipitated DNA prior to DNA library construction for NGS and high resolution ChIP-seq data. PMID- 28842877 TI - Generation and Analysis of Chromosomal Contact Maps of Bacteria. AB - This methods article described a protocol aiming at generating chromosome contact maps of bacterial species using a genome-wide derivative of the chromosome conformation capture (3C) technique. The approach is readily applicable on a broad variety of gram + and gram-bacterial species. It describes and addresses known caveats and technicalities associated with the technique, and should be of interest to any laboratory interested to perform a multiscale analysis of the genome structure of its species of interest. PMID- 28842878 TI - Nucleoid-Associated Proteins: Genome Level Occupancy and Expression Analysis. AB - The advent of Chromatin Immunoprecipitation sequencing (ChIP-Seq) has allowed the identification of genomic regions bound by a DNA binding protein in-vivo on a genome-wide scale. The impact of the DNA binding protein on gene expression can be addressed using transcriptome experiments in appropriate genetic settings. Overlaying the above two sources of data enables us to dissect the direct and indirect effects of a DNA binding protein on gene expression. Application of these techniques to Nucleoid Associated Proteins (NAPs) and Global Transcription Factors (GTFs) has underscored the complex relationship between DNA-protein interactions and gene expression change, highlighting the role of combinatorial control. Here, we demonstrate the usage of ChIP-Seq to infer binding properties and transcriptional effects of NAPs such as Fis and HNS, and the GTF CRP in the model organism Escherichia coli K12 MG1655 (E. coli). PMID- 28842879 TI - Isolation and Analysis of RNA Polymerase Supramolecular Complex with Associated Proteins. AB - Transcription machinery plays a central role in both the gene expression and nucleoid compaction. In this chapter we elaborate on the optimization of RNA polymerase purification protocol using a mild procedure with the purpose of preserving its native composition. This protocol combines protein extraction under non-denaturing conditions, heparin based affinity purification, and consequent BN-PAGE-SDS-PAGE separation. The outcome is an experimental procedure for screening RNA polymerase composition with associated proteins, in various bacterial strains or mutant backgrounds. With modifications in the column purification step, this procedure can be applied for isolation and identification of the components of other multi-protein complexes. PMID- 28842880 TI - A Chromosome Co-Entrapment Assay to Study Topological Protein-DNA Interactions. AB - Chromosome organization, DNA replication, and transcription are only some of the processes relying on dynamic and highly regulated protein-DNA interactions. Here, we describe a biochemical assay to study the molecular details of associations between ring-shaped protein complexes and chromosomes in the context of living cells. Any protein complex embracing chromosomal DNA can be enriched by this method, allowing for the underlying loading mechanisms to be investigated. PMID- 28842881 TI - Tethered Particle Motion Analysis of the DNA Binding Properties of Architectural Proteins. AB - Architectural DNA binding proteins are key to the organization and compaction of genomic DNA inside cells. Tethered Particle Motion (TPM) permits analysis of DNA conformation and detection of changes in conformation induced by such proteins at the single molecule level in vitro. As many individual protein-DNA complexes can be investigated in parallel, these experiments have high throughput. TPM is therefore well suited for characterization of the effects of protein-DNA stoichiometry and changes in physicochemical conditions (pH, osmolarity, and temperature). Here, we describe in detail how to perform Tethered Particle Motion experiments on complexes between DNA and architectural proteins to determine their structural and biochemical characteristics. PMID- 28842882 TI - Biochemical Analysis of Bacterial Condensins. AB - Condensins help establish compactness of bacterial chromosomes and assist in their segregation during cell growth and division. They act as elaborate macromolecular machines that organize the chromosome on a global scale and link it to the pan-cell dynamics. The mechanism of condensins in its entirety is yet to be elucidated. However, many aspects of condensin activity have been recuperated in vitro. This report described purification of the Escherichia coli condensin MukBEF, its reassembly from purified components, and reconstitution of DNA supercoiling and DNA bridging activities of the complex. PMID- 28842883 TI - Exploring Condensins with Magnetic Tweezers. AB - The signature activity of condensins as DNA reshaping machines is their ability to impose the giant loop architecture onto the chromosome. At the heart of this activity lies the propensity of the proteins to assemble into macromolecular clusters that bring distant DNA segments together. This gives rise to a rich dynamic behavior when the proteins are presented with the DNA substrate. The protocols in this section describe how the interaction between Escherichia coli condensin MukB and DNA proceeds in real time as observed using magnetic tweezers. PMID- 28842884 TI - Applications of Magnetic Tweezers to Studies of NAPs. AB - Nucleoid-associated proteins (NAPs) are important factors in shaping bacterial nucleoid and regulating global gene expression. A great deal of insights into NAPs can be obtained through studies using single DNA molecule, which has been made possible owing to recent rapid development of single-DNA manipulation techniques. These studies provide information on modes of binding to DNA, which shed light on the mechanism underlying the regulatory function of NAPs. In addition, how NAPs organize DNA and thus their contribution to chromosomal DNA packaging can be determined. In this chapter, we introduce transverse magnetic tweezers that allows for convenient manipulation of long DNA molecules, and its applications in studies of NAPs as exemplified by the E. coli H-NS protein. We describe how transverse magnetic tweezers is a powerful tool that can be used to characterize the DNA binding and organization modes of NAPs and how such information leads to better understanding of its roles in DNA packaging of bacterial nucleoid and transcription regulation. PMID- 28842885 TI - A User-Friendly DNA Modeling Software for the Interpretation of Cryo-Electron Microscopy Data. AB - The structural modeling of a macromolecular machine is like a "Lego" approach that is challenged when blocks, like proteins imported from the Protein Data Bank, are to be assembled with an element adopting a serpentine shape, such as DNA templates. DNA must then be built ex nihilo, but modeling approaches are either not user-friendly or very long and fastidious. In this method chapter we show how to use GraphiteLifeExplorer, a software with a simple graphical user interface that enables the sketching of free forms of DNA, of any length, at the atomic scale, as fast as drawing a line on a sheet of paper. We took as an example the nucleoprotein complex of DNA gyrase, a bacterial topoisomerase whose structure has been determined using cryo-electron microscopy (Cryo-EM). Using GraphiteLifeExplorer, we could model in one go a 155 bp long and twisted DNA duplex that wraps around DNA gyrase in the cryo-EM map, improving the quality and interpretation of the final model compared to the initially published data. PMID- 28842886 TI - Multilocus Imaging of the E. coli Chromosome by Fluorescent In Situ Hybridization. AB - Fluorescence in situ hybridization (FISH) is a widely used technique to detect and localize specific DNA or RNA sequences in cells. Although supplanted in many ways by fluorescently labeled DNA binding proteins, FISH remains the only cytological method to examine many genetic loci at once (up to six), and can be performed in any cell type and genotype. These advantages have proved invaluable in studying the spatial relationships between chromosome regions and the dynamics of chromosome segregation in bacteria. A detailed protocol for DNA FISH in E. coli is described. PMID- 28842887 TI - Imaging the Cell Cycle of Pathogen E. coli During Growth in Macrophage. AB - The study of the bacterial cell cycle at the single cell level can not only give insights on the fitness of the bacterial population but also reveal heterogeneous behavior. Typically, the DNA replication, the cell division, and the nucleoid conformation are appropriate representatives of the bacterial cell cycle. Because bacteria rapidly adapt their growth rate to environmental changes, the measure of cell cycle parameters gives valuable insights for the study of bacterial stress response or host-pathogen interactions. Here we describe methods to first introduce fluorescent fusion proteins and fluorescent tag within the chromosome of pathogenic bacteria to study these cell cycle steps; then to follow them within macrophages using a confocal spinning disk microscope. PMID- 28842888 TI - Measuring In Vivo Protein Dynamics Throughout the Cell Cycle Using Microfluidics. AB - Studying the dynamics of intracellular processes and investigating the interaction of individual macromolecules in live cells is one of the main objectives of cell biology. These macromolecules move, assemble, disassemble, and reorganize themselves in distinct manners under specific physiological conditions throughout the cell cycle. Therefore, in vivo experimental methods that enable the study of individual molecules inside cells at controlled culturing conditions have proved to be powerful tools to obtain insights into the molecular roles of these macromolecules and how their individual behavior influence cell physiology. The importance of controlled experimental conditions is enhanced when the investigated phenomenon covers long time periods, or perhaps multiple cell cycles. An example is the detection and quantification of proteins during bacterial DNA replication. Wide-field microscopy combined with microfluidics is a suitable technique for this. During fluorescence experiments, microfluidics offer well-defined cellular orientation and immobilization, flow and medium interchangeability, and high-throughput long-term experimentation of cells. Here we present a protocol for the combined use of wide-field microscopy and microfluidics for the study of proteins of the Escherichia coli DNA replication process. We discuss the preparation and application of a microfluidic device, data acquisition steps, and image analysis procedures to determine the stoichiometry and dynamics of a replisome component throughout the cell cycle of live bacterial cells. PMID- 28842889 TI - Imaging of Bacterial Chromosome Organization by 3D Super-Resolution Microscopy. AB - The bacterial nucleoid is highly organized, yet it is dynamically remodeled by cellular processes such as transcription, replication, or segregation. Many principles of nucleoid organization have remained obscure due to the inability of conventional microscopy methods to retrieve structural information beyond the diffraction limit of light. Structured illumination microscopy has recently been shown to provide new levels of spatial details on bacterial chromosome organization by surpassing the diffraction limit. Its ease of use and fast 3D multicolor capabilities make it a method of choice for imaging fluorescently labeled specimens at the nanoscale. We describe a simple high-throughput method for imaging bacterial chromosomes using this technique. PMID- 28842890 TI - Sequential Super-Resolution Imaging of Bacterial Regulatory Proteins: The Nucleoid and the Cell Membrane in Single, Fixed E. coli Cells. AB - Despite their small size and the lack of compartmentalization, bacteria exhibit a striking degree of cellular organization, both in time and space. During the last decade, a group of new microscopy techniques emerged, termed super-resolution microscopy or nanoscopy, which facilitate visualizing the organization of proteins in bacteria at the nanoscale. Single-molecule localization microscopy (SMLM) is especially well suited to reveal a wide range of new information regarding protein organization, interaction, and dynamics in single bacterial cells. Recent developments in click chemistry facilitate the visualization of bacterial chromatin with a resolution of ~20 nm, providing valuable information about the ultrastructure of bacterial nucleoids, especially at short generation times. In this chapter, we describe a simple-to-realize protocol that allows determining precise structural information of bacterial nucleoids in fixed cells, using direct stochastic optical reconstruction microscopy (dSTORM). In combination with quantitative photoactivated localization microscopy (PALM), the spatial relationship of proteins with the bacterial chromosome can be studied. The position of a protein of interest with respect to the nucleoids and the cell cylinder can be visualized by super-resolving the membrane using point accumulation for imaging in nanoscale topography (PAINT). The combination of the different SMLM techniques in a sequential workflow maximizes the information that can be extracted from single cells, while maintaining optimal imaging conditions for each technique. PMID- 28842891 TI - Procedures for Model-Guided Data Analysis of Chromosomal Loci Dynamics at Short Time Scales. AB - This chapter provides theoretical background and practical procedures for model guided analysis of mobility of chromosomal loci from movies of many single trajectories. We guide the reader through existing physical models and measurable quantities, illustrating how this knowledge is useful for the interpretation of the measurements. PMID- 28842892 TI - Isolation and Characterization of Bacterial Nucleoids in Microfluidic Devices. AB - We report methods for isolation of Escherichia coli nucleoids in microfluidic devices, allowing characterization of nucleoids during a controlled in vivo to in vitro transition. Biochemically, nucleoids are isolated by gentle osmotic lysis, which minimally perturbs nucleoid-associated proteins (NAPs). Biophysically, nucleoids are isolated in microfluidic chambers, which mimic confinement within the cell, as well as facilitate diffusive buffer exchange around nucleoids without subjecting them to flow. These methods can be used to characterize interactions between NAPs and whole nucleoids, and to investigate nucleoid structure and dynamics in confinement. We present protocols for isolation, quantification, and perturbation of nucleoids in microfluidic confinement. PMID- 28842893 TI - Modeling Bacterial DNA: Simulation of Self-Avoiding Supercoiled Worm-Like Chains Including Structural Transitions of the Helix. AB - Under supercoiling constraints, naked DNA, such as a large part of bacterial DNA, folds into braided structures called plectonemes. The double-helix can also undergo local structural transitions, leading to the formation of denaturation bubbles and other alternative structures. Various polymer models have been developed to capture these properties, with Monte-Carlo (MC) approaches dedicated to the inference of thermodynamic properties. In this chapter, we explain how to perform such Monte-Carlo simulations, following two objectives. On one hand, we present the self-avoiding supercoiled Worm-Like Chain (ssWLC) model, which is known to capture the folding properties of supercoiled DNA, and provide a detailed explanation of a standard MC simulation method. On the other hand, we explain how to extend this ssWLC model to include structural transitions of the helix. PMID- 28842894 TI - Molecular Dynamics Simulation of Supercoiled, Knotted, and Catenated DNA Molecules, Including Modeling of Action of DNA Gyrase. AB - A detailed protocol of molecular dynamics simulations of supercoiled DNA molecules that can be in addition knotted or catenated is described. We also describe how to model ongoing action of DNA gyrase that introduces negative supercoing into DNA molecules. The protocols provide detailed instructions about model parameters, equations of used potentials, simulation, and visualization. Implementation of the model into a frequently used molecular dynamics simulation environment, ESPResSo, is shown step by step. PMID- 28842895 TI - Skeletal Muscle Lysosomal Function via Cathepsin Activity Measurement. AB - Muscle wasting or cachexia is commonly associated with aging and many diseases such as cancer, infection, autoimmune disorders, and trauma. Decrease in muscle mass, or muscle atrophy, is often caused by dysfunction of protein proteolytic systems, such as lysosomes, which regulate protein turnover and homeostasis. Lysosomes contain many hydrolases and proteases and, thus, represent the major organelle that control protein turnover. Recently, lysosomes have emerged as a signaling hub to integrate cellular functions of nutrient sensing and metabolism, autophagy, phagocytosis, and endocytosis, which are all related to tissue homeostasis. In this chapter, we describe the protocol used to measure lysosomal proteinase (cathepsins) activity in the skeletal muscle. A better understanding of lysosomal function in muscle homeostasis is critical in developing new therapeutic approaches to prevent muscle wasting. PMID- 28842896 TI - Determination of Autophagy in the Caco-2 Spontaneously Differentiating Model of Intestinal Epithelial Cells. AB - The Caco-2 colorectal cancer cell line is widely used as a model for intestinal differentiation and barrier function. These cells, upon reaching confluency, spontaneously differentiate into enterocyte-like cells, synthesize intestinal enzymes, and form domes. Caco-2 cells also undergo autophagy in the course of differentiation. The criteria to establish the induction of autophagy in cells are already well established. Here, we describe the protocol for the spontaneous differentiation of Caco-2 cells and the detection of autophagy using Western blot, flow cytometry, and immunofluorescence. PMID- 28842897 TI - Initial gut microbiota structure affects sensitivity to DSS-induced colitis in a mouse model. AB - The dextran sulfate sodium (DSS)-induced colitis model is a widely applied mouse model, but controversial results have been obtained from experiments using the same mouse strain under the same conditions. Because the gut microbiota play an important role in DSS-induced colitis, it is essential to evaluate the influence of the initial gut microbiota in this model. Here, we identified significant variations in the initial gut microbiota of different batches of mice and found that the initial intestinal microbiota had a profound influence on DSS-induced colitis. We performed three independent trials using the same C57BL/6J mouse model with DSS treatment and used high-throughput 16S rRNA gene sequencing to analyze the gut microbiota. We found that the structure and composition of the gut microbiota in mice with severe colitis, as compared with mice with milder colon damage, had unique features, such as an increase in Akkermansia bacteria and a decrease in Barnesiella spp. Moreover, these varied gut bacteria in the different trials also showed different responses to DSS treatment. Our work suggests that, in studies using mouse models, the gut microbiota must be considered when examining mechanisms of diseases, to ensure that comparable results are obtained. PMID- 28842898 TI - Bisulfite Sequencing for DNA Methylation Analysis of Primary Muscle Stem Cells. AB - In skeletal muscle, DNA methylation contributes to the suppression of gene expression in several biological processes and diseases. A protocol for the detection of methylated cytosine was thus established based on methylation sensitive enzymes, immunoprecipitation, and bisulfite conversion. DNA methylation analysis, with bisulfite conversion and sequencing, enables the quantification of methylation at each single base position. Here, we describe a basic method of bisulfite sequencing that can be used to analyze local DNA methylation status to confirm genome-wide DNA methylation analysis or correlation of gene expression regulatory mechanisms. PMID- 28842899 TI - Whole Genome Chromatin IP-Sequencing (ChIP-Seq) in Skeletal Muscle Cells. AB - Transcriptional control of gene expression in skeletal muscle cell is involved in different processes ranging from muscle formation to regeneration. The identification of an increasing number of transcription factors, co-factors, and histone modifications has been greatly advanced by methods that allow studies of genome-wide chromatin-protein interactions. Chromatin immunoprecipitation with massively parallel DNA sequencing, or ChIP-seq, is a powerful tool for identifying binding sites of TFs/co-factors and histone modifications. The major steps of this technique involve immunoprecipitation of fragmented chromatin, followed by high-throughput sequencing to identify the protein bound regions genome-wide. Here, in this protocol, we will illustrate how the entire ChIP-seq is performed using global H3K27ac profiling in myoblast cells as an example. PMID- 28842900 TI - Analysis of RNA Expression in Adult Zebrafish Skeletal Muscle. AB - The zebrafish is an excellent vertebrate model system to investigate skeletal muscle development and disease. During early muscle formation the small size of the developing zebrafish allows for the characterization of gene expression in whole embryos. However, as the zebrafish develops, access to the underlying skeletal muscle is limited, requiring the skeletal muscle to be sectioned for a more detailed examination. Here, we describe a straightforward and effective method to prepare adult zebrafish skeletal muscle sections, preserving muscle morphology, to characterize gene expression in the zebrafish adult skeletal muscle. PMID- 28842901 TI - Targeted Lipidomic Analysis of Myoblasts by GC-MS and LC-MS/MS. AB - Lipids represent ~10% of the cell dry mass and play essential roles in membrane composition and physical properties, energy storage, and signaling pathways. In the developing or the regenerating skeletal muscle, modifications in the content or the flipping between leaflets of membrane lipid components can modulate the fusion capacity of myoblasts, thus constituting one of the regulatory mechanisms underlying myofiber growth. Recently, few genes controlling these qualitative and quantitative modifications have started to be unraveled. The precise functional characterization of these genes requires both qualitative and quantitative evaluations of a global lipid profile. Here, we describe a lipidomic protocol using mass spectrometry, allowing assessing the content of fatty acids, glycerophospholipids, and cholesterol in the routinely used C2C12 mouse myoblast cell line, or in primary cultures of mouse myoblasts. PMID- 28842902 TI - Measuring Mitochondrial Substrate Utilization in Skeletal Muscle Stem Cells. AB - Skeletal muscle stem cells (MuSCs) derived from the somatic mesoderm play a critical role in successful muscle regeneration following injury and trauma. MuSCs have been found to undergo rapid changes in metabolism following a change in cell state, such as that which occurs during the transition from quiescence to an actively proliferating state. There is mounting evidence that metabolism is critically important in the regulation of quiescence, activation, and differentiation and thus the development of new techniques that aim to further probe the metabolism of MuSCs is essential. The Seahorse XF Bioanalyzer is a powerful tool that simultaneously measures the extracellular rate of change in oxygen partial pressure and pH, providing a method to measure mitochondrial respiration and lactate production. In this chapter, we describe the use of key metabolic inhibitors that allow for the investigation of mitochondrial substrate utilization in primary MuSCs. PMID- 28842903 TI - Microcontact-Printed Hydrogel Microwell Arrays for Clonal Muscle Stem Cell Cultures. AB - Adult muscle stem cells (also called satellite cells) are an anatomically defined population of cells that are essential for muscle regeneration. In aging and dystrophic diseases, muscle stem cells (MuSCs) exhibit functional and molecular heterogeneity; therefore, single-cell assay technologies are critical to illuminate the mechanisms of pathological stem cell dysfunction. Here, we describe the process of generating mechanically tunable hydrogels with micro scale well features ("microwells") using micro-contact printing for clonal muscle stem cell culture assays. Microcontact printing (MUCP) is a simple and versatile method for generating cell culture substrates for micro-scale features for spatially restricting the cultures of single cells and their progeny. We explain how to use photolithography and polydimethylsiloxane casting to generate stamps capable of printing purified extracellular matrix proteins onto soft, hydrated poly(ethylene glycol) hydrogels to generate arrayed microwells in a defined pattern. We summarize methods to analyze the viability, migration, and differentiation of individual MuSC clones within hydrogel microwell cultures. PMID- 28842904 TI - Isolation, Culture, and Differentiation of Fibro/Adipogenic Progenitors (FAPs) from Skeletal Muscle. AB - Fibro/Adipogenic Progenitors (FAPs) are a multipotent progenitor population resident in skeletal muscle. During development and regeneration, FAPs provide trophic support to myogenic progenitors that is required for muscle fiber maturation and specification. FAPs also represent a major cellular source of fibrosis in degenerative disease states, highlighting them as a potential cellular target for anti-fibrotic muscle therapies. Effective and reproducible methods to isolate and culture highly purified FAP populations are therefore critical to further understand their biology. Here, we describe a fluorescent activated cell sorting (FACS) based protocol to isolate CD31-/CD45-/Integrin alpha7-/Sca1+ FAPs from murine skeletal muscle including details of tissue collection and enzymatic muscle digestion. We also incorporate optimized methods of expanding and differentiated FAPs in vitro. Together, this protocol provides a complete workflow to study skeletal muscle derived FAPs and compliments downstream analytical, drug screening, and disease modeling applications. PMID- 28842905 TI - Human Satellite Cell Isolation and Xenotransplantation. AB - Satellite cells are mononucleated cells of the skeletal muscle lineage that exist beneath the basal lamina juxtaposed to the sarcolemma of skeletal muscle fibers. It is widely accepted that satellite cells mediate skeletal muscle regeneration. Within the satellite cell pool of adult muscle are skeletal muscle stem cells (MuSCs), also called satellite stem cells, which fulfill criteria of tissue stem cells: They proliferate and their progeny either occupies the adult MuSC niche during self-renewal or differentiates to regenerate mature muscle fibers. Here, we describe robust methods for the isolation of enriched populations of human satellite cells containing MuSCs from fresh human muscle, utilizing mechanical and enzymatic dissociation and purification by fluorescence-activated cell sorting. We also describe a process for xenotransplantation of human satellite cells into mouse muscle by injection into irradiated, immunodeficient, mouse leg muscle with concurrent notexin or bupivacaine muscle injury to increase engraftment efficiency. The engraftment of human MuSCs and the formation of human muscle can then be analyzed by histological and immunofluorescence staining, or subjected to in vivo experimentation. PMID- 28842906 TI - Application of Split-GFP Reassembly Assay to Study Myogenesis and Myofusion In Vitro. AB - Green fluorescent protein (GFP) is composed of 11 beta-strands, and loses GFP signals, when divided into the N-terminal ten beta-strands (GFP1-10) and the C terminal last beta-strand (GFP11). However, when GFP1-10 and GFP11 encounter, they reassemble into the fluorescent GFP. We expressed GFP1-10 and blasticidin resistance gene product-fused GFP11 (BSR-GFP11) in C2C12 cells. Both the cell lines do not show GFP but when they undergo myogenesis and myofusion, GFP1-10 and BSR-GFP11 form the fluorescent complex in multi-nuclear myotubes, so that GFP signals reflect myogenesis and myofusion. PMID- 28842907 TI - Myogenic Maturation by Optical-Training in Cultured Skeletal Muscle Cells. AB - Optogenetic techniques are powerful tools for manipulating biological processes in identified cells using light under high temporal and spatial resolutions. Here, we describe an optogenetic training strategy to promote morphological maturation and functional development of skeletal muscle cells in vitro. Optical stimulation with a rhythmical frequency facilitates specific structural alignment of sarcomeric proteins. Optical stimulation also depolarizes the membrane potential, and induces contractile responses in synchrony with the given pattern of light pulses. These results suggest that optogenetic techniques can be employed to manipulate activity-dependent processes during myogenic development and control contraction of photosensitive skeletal muscle cells with high temporal and special precision. PMID- 28842908 TI - Fabrication of Micromolded Gelatin Hydrogels for Long-Term Culture of Aligned Skeletal Myotubes. AB - Cultured skeletal myotubes are a powerful in vitro system for identifying mechanisms of skeletal muscle development and disease. However, skeletal myotubes routinely delaminate from conventional culture substrates after approximately 1 week, which significantly hampers their utility for in vitro disease modeling and drug screening. To address this problem, we fabricated micromolded gelatin hydrogels as culture substrates that are more biomimetic than conventional substrates. On micromolded gelatin hydrogels, C2C12 skeletal myoblasts align and differentiate into skeletal myotubes that are stable in culture for multiple weeks. With this protocol, we detail three key steps: (1) Fabrication of micromolded gelatin hydrogels; (2) Culture of mouse C2C12 myoblasts and differentiation into myotubes; and (3) Quantification of myotube morphology. These substrates have many applications for skeletal muscle disease modeling and drug screening over longer time scales. PMID- 28842909 TI - Quantification of Embryonic Myofiber Development by Immunofluorescence. AB - Mammalian myogenesis occurs in two distinct phases, primary and secondary, which are temporally separated. The primary wave occurs shortly after somitogenesis producing embryonic myofibers. The secondary wave occurs after somitogenesis producing fetal myofibers that form adjacent to the embryonic myofibers. The myogenic cells that give rise to these two waves have distinct characteristics as do the myofibers they produce. The objective of this chapter is to describe our methods for quantifying embryonic and fetal myofiber development in mouse embryos using immunofluorescence. PMID- 28842910 TI - How to Wire the Diaphragm: Wholemount Staining Methods to Analyze Mammalian Respiratory Innervation. AB - Direct or indirect impairment of breathing in humans by diseases or environmental factors can either cause long-term disability and pain, or can ultimately result in death. Automatic respiratory centers in the brainstem control the highly structured process of breathing and signal to a specialized group of motor neurons in the cervical spinal cord that constitute the phrenic nerves. In mammals, the thoracic diaphragm separates the thorax from the abdomen and adopts the function of the primary respiratory musculature. Faithful innervation by the phrenic nerves is a prerequisite for correct functionality of this highly specialized musculature and thus, ultimately, the viability of the entire organism.To analyze the effects of diseases and genetic defects responsible for deleterious or lethal respiratory phenotypes, accurate imaging of respiratory innervation during embryonic development, e.g., in genetically modified mouse models enables the characterization of specific marker genes and pathways that underlie appropriate wiring of the diaphragm. Among the different available immunostaining techniques, wholemount staining methods provide the advantage of clear and faithful three-dimensional information about the location of the antigens of interest. In comparison to routine histological techniques, however, the researcher has to deal with technical challenges, such as antibody penetration, the stability and availability of the antigen, and clearing of the relevant tissue, and the need to be equipped with state-of-the-art microscope equipment.In this methodological chapter, we explain and share our expertise concerning wholemount processing of mouse embryos and thoracic diaphragms for the analysis of mammalian respiratory innervation. PMID- 28842911 TI - Membrane Repair Assay for Human Skeletal Muscle Cells. AB - The characterization of the membrane repair machinery in human skeletal muscle has become crucial, since it has been shown that some muscular dystrophies result from a defect of this fundamental physiological process. Deciphering membrane repair mechanism requires the development of methodologies allowing studying the response of skeletal muscle cells to sarcolemma damage and identifying candidate proteins playing a role in the membrane repair machinery. Here, we describe a protocol that is based on the creation of cell membrane disruption by infrared laser irradiation in human myotubes. Membrane disruption and repair are assayed by monitoring the incorporation into myotubes of the membrane probe FM1-43. This methodology has recently enabled us to show that Annexin-A5 is required for membrane repair in human skeletal muscle cells (Carmeille et al., Biochim Biophys Acta 1863:2267-2279, 2016). PMID- 28842912 TI - Cryoinjury Model for Tissue Injury and Repair in Bioengineered Human Striated Muscle. AB - Regenerative medicine aims to replace injured tissues to restore normal physiological function. One possibility for achieving this goal is to activate or enhance endogenous regenerative pathways. Therefore, human tissue regeneration models may be useful tools for the discovery and development of novel regenerative therapeutics. In this chapter, we describe methods for the generation of three-dimensional bioengineered striated muscle in vitro and a cryoinjury model that can be applied to these tissues. This technique enables mechanistic in vitro analysis of the endogenous regenerative response of human striated muscle to injury, which is not possible using other in vivo approaches. PMID- 28842913 TI - FAMILY CONFLICT MODERATES EARLY PARENT-CHILD BEHAVIORAL TRANSACTIONS. AB - The reciprocal transactions that shape early parent-child relationships are influenced by contextual stress, such as family conflict. Although family conflict is a salient stressor to the family system, few studies have considered how parent-child transactions vary according to exposure to family conflict. The present study examined how family conflict alters early parent-child behavioral transactions. We utilized three waves of data from a multisite longitudinal study of low-income families (N = 2, 876), child age 14 months, 24 months, and 36 months, to identify behavioral transactions of positive and negative maternal (supportiveness, negative regard) and child (engagement, negativity) behaviors. Results indicated that family conflict at 14 months diminished the positive association between maternal supportiveness and child engagement, and amplified the inverse association between maternal negativity and child engagement. Family conflict at 14 months also was associated with increased stability of child negativity and subsequent increased maternal negative regard at 36 months, in part via increases in 24-month child negativity. In sum, family conflict occurring early in childhood predicted and moderated behavioral transactions between young children and their mothers. PMID- 28842914 TI - Metabolic conditions and breast cancer risk among Los Angeles County Filipina Americans compared with Chinese and Japanese Americans. AB - Accumulating evidence suggests that the aggregation of common metabolic conditions (high blood pressure, diabetes and dyslipidemia) is a risk factor for breast cancer. Breast cancer incidence has risen steadily in Asian American women, and whether these metabolic conditions contribute to breast cancer risk in certain Asian American subgroups is unknown. We investigated the role of physician-diagnosed hypertension, high cholesterol and diabetes separately, and in combination, in relation to the risk of breast cancer in a population-based case-control study of 2,167 Asian Americans diagnosed with breast cancer and 2,035 age and ethnicity matched control women in Los Angeles County. Compared to Asian American women who did not have any of the metabolic conditions, those with 1, 2 or 3 conditions showed a steady increase in risk (respective odds ratios were 1.12, 1.42 and 1.62; P trend = 0.001) with adjustment for covariates including body mass index. Similar significant trends were observed in Filipina Americans (P trend = 0.021), postmenopausal women (P trend =0.001), Asian women who were born in the United States (US) (P trend = 0.052) and migrants who have lived in the US for at least 20 years (P trend = 0.004), but not migrants who lived in the US for <20 years (P trend = 0.64). These results suggest that westernization in lifestyle (diet and physical inactivity) and corresponding increase in adiposity have contributed to the rising prevalence of these metabolic conditions, which in turn, are associated with an increase in breast cancer. PMID- 28842915 TI - Roles of impaired intracellular calcium cycling in arrhythmogenicity of diabetic mouse model. AB - BACKGROUND: Diabetes mellitus is associated an increased risk of ventricular arrhythmias (VAs), but the underlying electrophysiological mechanisms are not fully explored. This study was aimed to test whether dynamic factors and Cai handling play roles in arrhythmogenesis of a diabetic animal model. METHODS: We used 26 db/db type 2 diabetes mice and 28 control mice in this study. VA inducibility was evaluated in vivo under isoflurane general anesthesia. The intracellular Ca2+ (Cai ) and membrane voltage (Vm ) signals of the Langendorff perfused mouse hearts were simultaneously recorded using the optical mapping technique. Action potential duration (APD), Cai dynamics conduction velocity (CV), and arrhythmogenic alternans were analyzed. Western blot was conducted to examine expressions of calcium handling and associated ion channels proteins. RESULTS: The diabetic db/db mice showed significantly increased VA inducibility and severity. Longer APD and Cai transient duration and slower Cai decay and CV in the db/db mice than these in the control ones were observed. Dynamic pacing showed increased incidence of spatially discordant alternans leading to more VA inducibility in the db/db mice. Western blot analyses revealed increased phosphorylated-Ca2+ /calmodulin-dependent protein kinase II protein expression and decreased ryanodine receptor protein expression, which probably underlay the molecular mechanisms of enhanced arrhythmogenicity in db/db mice. CONCLUSIONS: The type 2 diabetic mouse hearts show impaired repolarization, Cai handling homeostasis, and cardiac conduction reserve, leading to vulnerability of spatially discordant alternans development and induction of VA. Altered Cai handling protein expressions probably underlie the molecular mechanisms of arrhythmogenicity in the type 2 diabetes animal model. PMID- 28842916 TI - Impact of nitrogen source and supply level on growth, yield and nutritional value of two contrasting ecotypes of Cichorium spinosum L. grown hydroponically. AB - BACKGROUND: In the present study, two contrasting stamnagathi (Cichorium spinosum L.) ecotypes originating either from a mountainous or from a seaside habitat were grown hydroponically and supplied with a nutrient solution differing in the total N level (4 or 16 mmol L-1 ) and the N source (NH4+ -N/total-N: 0.05, 0.25 or 0.50). The aim was to search for genotypic differences in nitrogen nutrition. RESULTS: At commercial maturity, the dry weight of mountainous plants was higher than that of seaside plants. The shoot mineral concentrations were higher in seaside plants than in mountainous plants in both harvests. The leaf nitrate concentration was influenced by the levels of both total-N and NH4+ -N/total-N at both harvests, whereas plants with a seaside origin exhibited higher nitrate concentrations than those originating from a mountainous site in all total-N and NH4+ -N/total-N treatments. CONCLUSION: The two stamnagathi ecotypes differed considerably in their responses to nitrogen nutrition and tissue nitrate content. The mountainous ecotype was superior in terms of growth, tissue nitrate concentration and antioxidant capacity, whereas the seaside ecotype accumulated more nutrient microcations in leaves. A low total-N concentration (up to 4 mmol L 1 ) combined with a high NH4+ -N/total-N ratio (up to 0.05) could minimize tissue NO3- concentrations without compromising yield. (c) 2017 Society of Chemical Industry. PMID- 28842917 TI - Impact of race and gender on clinical outcomes of catheter ablation in patients with atrial fibrillation. AB - BACKGROUND: Radiofrequency catheter ablation (CA) is an effective treatment of drug-refractory atrial fibrillation (AF). However, the efficacy of CA by race and gender has not been well characterized. We sought to determine the impact of ethnicity and gender on clinical outcome following CA in patients with AF. METHODS: Patients who underwent CA for AF from September 2013 to April 2016 were included in this study. Patients were identified retrospectively and followed prospectively. RESULTS: A total of 118 patients (15.3% black and 78.8% white, 33% female) comprised the cohort, with mean age at ablation 63.4 +/- 10.4 years. Black patients were older at time of the procedure (65.4 vs 63.4 years old) and had more prevalent comorbidities, including hypertension (77.8% vs 63.4%), diabetes (33.3% vs 15.0%), chronic kidney disease (22.2% vs 7.5%), and lower left ventricular ejection fraction (51.8% vs 56.2%). Blacks also had significantly larger left atrial size (P = 0.03). Late recurrence of AF was similar between blacks and whites (33.3% vs 34.4%, P = 1) as well as between women and men (28.2% vs 36.7%, P = 0.41). Early recurrence was predictive of late recurrence in men (P < 0.001) but not in women (P = 0.48). Enlarged left atrium and early recurrence of AF were significant predictors for late recurrence of AF in the cohort. CONCLUSIONS: CA for AF is equally effective in black patients despite more prevalent comorbidity and increased left atrial size. Early recurrence of AF after CA was not predictive of late recurrence of AF in women but was in men. PMID- 28842918 TI - Who still remains at risk of arrhythmic death at time of implantable cardioverter defibrillator generator replacement? AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) is associated with reduction in arrhythmic mortality. However, at the time of generator replacement (GR) some patients had not experienced therapies and had a different clinical profile. Therefore, the risk-benefit ratio of ICD may have changed. Our aim was to determine the proportion of patients with ICD implanted in primary prevention that maintain guideline-derived indications at the time of GR and assess predictors of therapies in the postreplacement period. We evaluate the long-term benefit of ICD after GR in nonischemic cardiomyopathy (NICM) versus ischemic cardiomyopathy (ICM). METHODS: We included 141 patients undergoing GR from 11/2009 to 7/2015. Patients were divided into: G1 - guideline congruent indication for ICD at the time of GR (left ventricular ejection fraction [LVEF] <= 35% or appropriate therapies) and G2 - guideline incongruent indication (patients without appropriate therapies and LVEF >35%). We also compared ICD benefit between ICM and NICM patients. RESULTS: Maintenance of guideline-driven indications for ICD (G1) was present in 68% of patients and 32% had recovery of LVEF and no ICD therapies at the time of GR (G2). After GR, G2 patients showed a lower rate of appropriate therapies (3% vs 33%, P < 0.01). LVEF <= 35% was the only independent predictor of appropriate therapies (OR 12.0, P < 0.01). In multivariate analysis, etiology of heart failure did not predict the arrhythmic risk. CONCLUSION: At the time of GR, a significant proportion of patients no longer met guideline indications for ICD and their need for therapies is reduced. The etiology of heart failure did not predict freedom from therapies. PMID- 28842919 TI - A map of sensilla and neurons in the taste system of drosophila larvae. AB - In Drosophila melanogaster larvae, the prime site of external taste reception is the terminal organ (TO). Though investigation on the TO's implications in taste perception has been expanding rapidly, the sensilla of the TO have been essentially unexplored. In this study, we performed a systematic anatomical and molecular analysis of the TO. We precisely define morphological types of TO sensilla taking advantage of volume electron microscopy and 3D image analysis. We corroborate the presence of five external types of sensilla: papilla, pit, spot, knob, and modified papilla. Detailed 3D analysis of their structural organization allowed a finer discrimination into subtypes. We classify three subtypes of papilla and pit sensilla, respectively, and two subtypes of knob sensilla. Further, we determine the repertoire of receptor genes for each sensillum by analyzing GAL4 driver lines of Ir, Gr, Ppk, and Trp receptor genes. We construct a map of the TO, in which the receptor genes are mapped to neurons of individual sensilla. While modified papillum and spot sensilla are not labeled by any GAL4 driver, neurons of the pit, papilla, and knob type are labeled by partially overlapping but different subsets of GAL4 driver lines of the Ir, Gr, and Ppk gene family. The results suggest that pit, papilla and knob sensilla act in contact chemosensation. However, they likely do these employing different stimulus transduction mechanisms to sense the diverse chemicals of their environment. PMID- 28842920 TI - Various approaches to reach the pericardial space for arrhythmia mapping and ablation. PMID- 28842921 TI - Development of high-throughput and high sensitivity capillary gel electrophoresis platform method for Western, Eastern, and Venezuelan equine encephalitis (WEVEE) virus like particles (VLPs) purity determination and characterization. AB - In this paper, we describe development of a high-throughput, highly sensitive method based on Lab Chip CGE-SDS platform for purity determination and characterization of virus-like particle (VLP) vaccines. A capillary gel electrophoresis approach requiring about 41 s per sample for analysis and demonstrating sensitivity to protein initial concentrations as low as 20 MUg/mL, this method has been used previously to evaluate monoclonal antibodies, but this application for lot release assay of VLPs using this platform is unique. The method was qualified and shown to be accurate for the quantitation of VLP purity. Assay repeatability was confirmed to be less than 2% relative standard deviation of the mean (% RSD) with interday precision less than 2% RSD. The assay can evaluate purified VLPs in a concentration range of 20-249 MUg/mL for VEE and 20 250 MUg/mL for EEE and WEE VLPs. PMID- 28842923 TI - Astrocyte-driven plasticity contributes to environment-related changes of hippocampal oscillations. PMID- 28842922 TI - Surveillance of biting midges (Culicoides spp.) in Northern Ireland: influence of seasonality, surrounding habitat and livestock housing. AB - Biting midges, Culicoides spp. (Diptera: Ceratopogonidae), are important vectors of viral pathogens. Following the outbreak of bluetongue serotype 8 in Europe between 2006 and 2009, many Culicoides surveillance programmes were initiated to identify vector-active periods, in accordance with European Commission regulation 2007/1266/EC. This study utilized surveillance data from 4 years of continuous light-trapping at 14 sites in Northern Ireland. The number of captured Culicoides varied from none during the vector-free period (December-April) to more than 36 000 per night during peak activity in the summer. The Obsoletus group represented 75% of Culicoides collected and the Pulicaris group represented 21%. A total of 91% of Culicoides were female, of which 42% were parous. Abundance data, sex ratios and parous rates suggested that both the Obsoletus and Pulicaris groups underwent three generations/year. The Obsoletus group was associated with cattle rearing habitats and woodland, the Impunctatus group was found in habitats related to sheep rearing and the Pulicaris group were associated with both cattle and sheep. Housing did not reduce incursion of female Obsoletus group Culicoides but it did for males and for the Pulicaris group Culicoides. The influence of housing was strongly affected by time of year, probably reflecting the presence of livestock indoors/outdoors. PMID- 28842924 TI - Distribution of corticotropin-releasing factor (CRF) receptor binding in the mouse brain using a new, high-affinity radioligand, [125 I]-PD-Sauvagine. AB - The corticotropin-releasing factor (CRF) family of peptides includes CRF and three urocortins, which signal through two distinct G-protein coupled receptors, CRF1 and CRF2 . Although the cellular distribution of CRF receptor expression has been well characterized at the mRNA level, the localization of receptor protein, and, by inference, of functional receptors, has been limited by a lack of reliable immunohistochemical evidence. Recently, a CRF-related peptide, termed PD sauvagine, was isolated from the skin of the frog, Pachymedusa dacnicolor, and validated as a high-affinity ligand for CRF receptor studies. A radiolabeled analog, [125 I]-PD-sauvagine, with high signal-to-noise ratio, was used in autoradiographic studies to map the distribution of CRF receptor binding sites in the mouse brain. Through the use of receptor-deficient mice and subtype-specific antagonists, CRF1 and CRF2 binding sites were isolated, and found to be readily reconcilable with regional patterns of mRNA expression. Binding site distributions within a given structure sometimes differed from mRNA patterns, however, particularly in laminated structures of the isocortex, hippocampus, and cerebellum, presumably reflecting the trafficking of receptors to their operational homes on neuronal (mostly dendritic) processes. Binding patterns of [125 I]-PD-sauvagine provided independent assessments of controversial receptor localizations, failing to provide support for CRF1 expression in central autonomic components of the limbic forebrain, the locus coeruleus and cerebellar Purkinje cells, or for CRF2 in any aspect of the cerebellar cortex. Though lacking in ideal resolution, in vitro binding of the PD-sauvagine radioligand currently provides the most sensitive and accurate available tool for localizing CRF receptors in rodent brain. PMID- 28842925 TI - Polyphenol-rich pomegranate juice reduces IgE binding to cashew nut allergens. AB - BACKGROUND: Food allergy negatively impacts quality of life and can be life threatening. Cashew nuts can cause severe reactions in very small amounts, and they are included in a group of foods most commonly responsible for causing food allergy. Polyphenols and polyphenol-rich juices have been demonstrated to complex with peanut allergens. Here, the interaction between cashew nut allergens and polyphenol-rich juices is evaluated biochemically and immunologically. RESULTS: Various juices, including pomegranate (POM), blueberry (BB), and concord grape (CG) juices, were evaluated for polyphenol content and formation of polyphenol cashew allergen complexes. Among the various juices studied, POM juice showed a greater capacity to form complexes with cashew proteins. Dynamic light scattering (DLS) demonstrated a sharp increase in cashew protein extract particle size to around 3580 nm, and fewer cashew proteins were resolved by electrophoresis after treatment with POM juice. Immunoassays demonstrated reduced IgG and IgE binding to cashew allergens due to allergen precipitation by POM juice. These observations support the formation of complexes between polyphenol and cashew proteins that can prevent antibody recognition of cashew allergens through allergen precipitation. CONCLUSION: POM juice treatment of cashew extract effectively reduces antibody binding through allergen precipitation, and these findings could be applied to the development of less allergenic cashew nut products and oral immunotherapy. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. PMID- 28842926 TI - Synthesis of novel octyl sinapate to enhance antioxidant capacity of rapeseed linseed oil mixture. AB - BACKGROUND: Lipophilisation allows the formation of new functionalised antioxidants having beneficial properties compared to natural hydrophilic phenolic acids. Therefore, this work focused on the synthesis of lipophilic antioxidants, such as a new octyl sinapate, octyl caffeate and octyl ferulate using the modified Fischer esterification of selected hydroxycinnamic acids with 1-octanol. RESULTS: The lipophilic octyl sinapate was obtained for the first time with satisfactory yield (83%) after purification by column chromatography. The identity of the synthesised phenolipids was confirmed by chromatographic and spectroscopic analyses. Antioxidant capacity of phenolipids was determined by DPPH (IC50 = 35.87-52.24 MUg mL-1 ) and ABTS (IC50 = 39.45-48.72 MUg mL-1 ) methods and compared with IC50 values (7.37-35.30 MUg mL-1 and 7.55-41.67 MUg mL 1 , respectively) for well known antioxidants. The antioxidant capacity of rapeseed-linseed oil enriched with the purified esters was about two to 30 times higher in comparison with a non-supplemented oil. CONCLUSION: The novel octyl sinapate as well as octyl caffeate and octyl ferulate have antioxidant properties and lipophilic character, therefore they may be added to vegetable oils as potential antioxidants for tackling oxidative processes. (c) 2017 Society of Chemical Industry. PMID- 28842927 TI - Effect of pre-bloom leaf removal on grape aroma composition and wine sensory profile of Semillon cultivar. AB - BACKGROUND: Early leaf removal at pre-bloom is an innovative viticultural practice for regulating yield components and improving grape quality. The effects of this technique on vine performance, grape composition and wine sensory profile of Semillon variety were assessed. RESULTS: Pre-bloom leaf removal enhanced canopy porosity, total soluble solids in musts and reduced cluster compactness. This practice had a strong effect on glycoside aroma precursors, in particular by increasing glycoside terpenols and norisoprenoids. Metabolites of linalool were the most responsive to leaf removal. Wine produced from defoliated vines was preferred in tasting trials for its more intense fruity notes and mouthfeel attributes. CONCLUSION: Pre-bloom leaf removal is a powerful technique for modifying canopy microclimate, vine yield, grape composition and wine quality. The increase of glycoside aroma compounds in treated grapes has potential positive effect in improving the sensory profile of the resulting wines. (c) 2017 Society of Chemical Industry. PMID- 28842929 TI - The Effect of Rurality on Out-of-Hospital Cardiac Arrest Resuscitation Incidence: An Exploratory Study of a National Registry Utilizing a Categorical Approach. AB - PURPOSE: Variation in incidence is a universal feature of out-of-hospital cardiac arrest (OHCA). One potential source of variation is the rurality of the location where the OHCA incident occurs. While previous work has used a simple binary approach to define rurality, the purpose of this study was to use a categorical approach to quantify the impact of urban-rural classification on OHCA incidence in the Republic of Ireland. METHODS: The observed versus expected ratio of OHCA incidence where resuscitation was attempted for the period January 1, 2012, to December 31, 2014, was calculated for each of the 3,408 electoral divisions (ED). EDs were then classified into 1 of 6 urban-rural classes. Multilevel modeling was used to test for variation in incidence ratios (IR) across the urban-rural classes. FINDINGS: A total of 4,755 cases of adult OHCA, not witnessed by Emergency Medical Services, where resuscitation was attempted were included in the study. The number of EDs in each category was as follows: city (n = 477); town (n = 293); near village (n = 182); remote village (n = 84); near rural (n = 1,479); remote rural (n = 893). The IR per ED varied from 0 to 18.38 (EDs, n = 3,408). Multilevel modeling showed that 2.36% of variation in IR was due to urban rural classification. This dropped to 0.45% when adjusted for ED deprivation score and median distance to an ambulance station. The addition of other explanatory variables did not improve the model. CONCLUSION: OHCA variation in Ireland is limited and almost fully explained by area-level deprivation and proximity to ambulance stations. PMID- 28842928 TI - EARLY HEAD START FAMILIES' EXPERIENCES WITH STRESS: UNDERSTANDING VARIATIONS WITHIN A HIGH-RISK, LOW-INCOME SAMPLE. AB - The federal Early Head Start program provides a relevant context to examine families' experiences with stress since participants qualify on the basis of poverty and risk. Building on previous research that has shown variations in demographic and economic risks even among qualifying families, we examined possible variations in families' perceptions of stress. Family, parent, and child data were collected to measure stressors and risk across a variety of domains in families' everyday lives, primarily from self-report measures, but also including assay results from child cortisol samples. A cluster analysis was employed to examine potential differences among groups of Early Head Start families. Results showed that there were three distinct subgroups of families, with some families perceiving that they experienced very high levels of stress while others perceived much lower levels of stress despite also experiencing poverty and heightened risk. These findings have important implications in that they provide an initial step toward distinguishing differences in low-income families' experiences with stress, thereby informing interventions focused on promoting responsive caregiving as a possible mechanism to buffer the effects of family and social stressors on young children. PMID- 28842930 TI - Medication-Assisted Opioid Treatment Prescribers in Federally Qualified Health Centers: Capacity Lags in Rural Areas. AB - PURPOSE: This study explores correlates of on-site availability of substance use disorder treatment services in federally qualified health centers, including buprenorphine treatment that is critical to addressing the opioid epidemic. METHODS: We employed descriptive and multivariable analyses with weighted 2010 Assessment of Behavioral Health Services survey data and the 2010 Uniform Data System. FINDINGS: In 2010, 47.6% of health centers provided on-site substance use disorder treatment, 12.3% provided buprenorphine treatment for opioids, and 38.8% were interested in expanding buprenorphine availability. Urban health centers, those in the West, and health centers with electronic health records had higher odds of offering on-site substance use disorder treatment. Compared with on-site mental health treatment, substance use disorder treatment was available in fewer clinic sites within each organization. Health centers in rural areas had lower odds of providing on-site buprenorphine treatment (OR = 0.49, 95% CI: 0.26-0.94), and those in the South had lower odds of providing on-site buprenorphine treatment compared with health centers in other regions. Rural health centers had lower odds of expressing interest in expanding the availability of buprenorphine treatment (OR = 0.58, 95% CI: 0.35-0.97). CONCLUSIONS: Improving access to substance use disorder treatment in primary care is a critical part of the strategy to combat the opioid use disorder epidemic. These findings highlight the important role of health centers as portals of access to substance use disorder treatment services in underserved communities. Recent investments to expand treatment capacity in health centers will expand the availability of substance use disorder services, but urban/rural and regional disparities should be monitored. PMID- 28842931 TI - Changes in intestinal microbiota and their effects on allogeneic stem cell transplantation. AB - The human intestinal microbiota is essential for microbial homeostasis, regulation of metabolism, and intestinal immune tolerance. Rapidly evolving understanding of the importance of the microbiota implicates changes in the composition and function of intestinal microbial communities in an assortment of systemic conditions. Complications following allogeneic stem cell transplant now join the ever-expanding list of pathologic states regulated by intestinal microbiota. Dysbiosis, or disruption of the normal ecology of this microbiome, has been directly implicated in the pathogenesis of entities such as Clostridium difficile infections, graft-versus-host disease (GVHD), and most recently disease relapse, all of which are major causes of morbidity and mortality in patients undergoing allogeneic stem cell transplant. In this review, we elucidate the key origins of microbiotic alterations and discuss how dysbiosis influences complications following allogeneic stem cell transplant. Our emerging understanding of the importance of a balanced and diverse intestinal microbiota is prompting investigation into the appropriate treatment of dysbiosis, reliable and early detection of such, and ultimately its prevention in patients to improve the outcome following allogeneic hematopoietic stem cell transplant. PMID- 28842932 TI - Clinicopathological characteristics and outcomes of squamous cell carcinoma of the tongue in different age groups. AB - BACKGROUND: The clinicopathological features and outcomes of squamous cell carcinoma (SCC) of the tongue in patients of different age groups remain debatable. METHODS: Medical records of 457 patients with tongue SCC were reviewed, grouped by age, followed up, and compared. RESULTS: Sex and TNM stage showed no intergroup differences. Tongue SCC in patients <=30 years had the most advanced TNM classification and greatest proportion of poorly differentiation tumors. Both disease-free survival (DFS) and disease-specific survival (DSS) showed no statistically significant difference between the youngest and the oldest groups (P = .605 and P = .520). However, there was a tendency of higher death rate caused by recurrence or metastasis in the youngest group compared with the others (91.7% vs 75.4% and 77.4%). CONCLUSION: Young patients had a tendency of higher death rate caused by recurrence or metastasis than middle-age and older patients; therefore, a larger case sample is needed for further confirmation. PMID- 28842933 TI - Plasma stem cell factor levels are associated with risk of cardiovascular disease and death. AB - OBJECTIVE: Stem cell factor (SCF) is a key growth factor for several types of stem and progenitor cells. There is experimental evidence that such cells are of importance for maintaining the integrity of the cardiovascular system. We investigated the association between circulating levels of SCF and risk for development of cardiovascular events and death. METHODS: SCF was analysed by the proximity extension assay technique in plasma from 4742 subjects participating in the Malmo Diet and Cancer Study. Cardiovascular events and death were monitored through national registers with a mean follow-up time of 19.2 years. RESULTS: Subjects with high baseline levels of SCF had lower cardiovascular (n = 340) and all-cause mortality (n = 1159) as well as a lower risk of heart failure (n = 177), stroke (n = 318) and myocardial infarction (n = 452). Smoking, diabetes and high alcohol consumption were associated with lower levels of SCF. Single nucleotide polymorphisms in the gene region encoding PDX1 C-terminal inhibiting factor 1 (PCIF1) and matrix metalloproteinase-9 were associated with plasma SCF levels. The highest SCF quartile remained independently associated with a lower risk of a lower risk of cardiovascular [hazard ratio and 95% confidence interval 0.59 (0.43-0.81)] and all-cause mortality [0.68 (0.57-0.81)], heart failure [0.50 (0.31-0.80)] and stroke [0.66 (0.47-0.92)], but not with MI [0.96 (0.72-1.27)] as compared with the lowest quartile when adjusting for traditional cardiovascular risk factors in Cox proportional hazard regression models. CONCLUSIONS: This prospective population-based study demonstrates that subjects with high levels of SCF have a lower risk of cardiovascular events and death. The findings provide clinical support for a protective role of SCF in maintaining cardiovascular integrity. PMID- 28842934 TI - Sudden gains in the outpatient treatment of anorexia nervosa: A process-outcome study. AB - OBJECTIVE: Sudden gains (SGs), broadly defined as sudden symptom reductions occurring between two consecutive treatment sessions, have been associated with improved treatment outcomes in anxiety and depression. The present study is the first to formally define SGs in anorexia nervosa and explore the characteristics, demographic and baseline clinical predictors, and clinical impact of SGs in anorexia nervosa. METHOD: This is a secondary analysis of data from 89 outpatients with broadly defined anorexia nervosa who received one of two psychotherapeutic interventions as part of the MOSAIC trial (Schmidt et al., 2015). SGs were defined using session-by-session body mass index (BMI) measures. This study investigated whether SGs were associated with changes in BMI, eating disorder symptomology, general psychopathology, and psychosocial impairment between baseline and 6, 12, and 24 months follow-up. RESULTS: SGs, experienced by 61.8% of patients, mostly occurred during the early and middle phases of treatment. A larger proportion of SGs predicted larger increases in BMI between baseline and 6, 12, and 24 months follow-up. Amongst those experiencing at least one SG, fewer days between baseline and a patient's first SG predicted a larger increase in BMI between baseline and both 6 and 12 months follow-up. The proportion and timing of SGs did not predict changes in other outcome measures. DISCUSSION: SGs in BMI during the outpatient treatment of anorexia nervosa are clinically useful predictors of longer-term weight outcomes. PMID- 28842935 TI - Quantification of the salivary volume flow rate in the parotid duct using the time-spatial labeling inversion pulse (Time-SLIP) technique at MRI: A feasibility study. AB - BACKGROUND: We developed a method to quantify the volume flow rate (VFR) using the time-spatial labeling inversion pulse (Time-SLIP) technique to evaluate salivary function. PURPOSE/HYPOTHESIS: To investigate the accuracy of quantification of the salivary VFR using the Time-SLIP technique in phantoms and to examine the feasibility of its use in human subjects. STUDY TYPE: This was a prospective phantom and volunteer study. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: A phantom and 23 normal volunteers who fasted at least 2 hours study was performed. FIELD STRENGTH/SEQUENCE: Flow images of the phantom and the parotid duct of 23 volunteers were acquired on a 3T-MRI scanner using the Time-SLIP technique. ASSESSMENT: Hypothesizing that flow aggregates in the conducting duct, we measured the VFR on flow images. In the phantom study, the actual VFR (slow, medium, fast flow) was controlled by an automatic pump system and the measured VFR was compared with the actual VFR on flow images. In the human study we injected citric acid into the mouth of healthy volunteers to stimulate saliva secretion and recorded the VFR. STATISTICAL TESTS: As this study was a feasibility study, statistical tests were not performed. RESULTS: In the phantom study, the VFR at slow, medium, and fast flow was 5.7 +/- 0.4 (SD), 8.4 +/- 0.3, and 12.2 +/- 1.1 mm3 /sec, respectively. The error between the measured and actual VFR values was 2.8-3.7%. Salivary flow in the parotid duct was visualized in 22 of the 23 volunteers. The mean VFR was 8760 mm3 /10 min. DATA CONCLUSION: When salivary flow was stimulated with citric acid in normal volunteers, the salivary VFR could be obtained using the Time-SLIP technique. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:928-935. PMID- 28842936 TI - A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T-cell lymphomas. AB - The transcription factor GATA-3, highly expressed in many cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphomas (PTCL), confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-kappaB, we sought to determine the extent to which proteasomal inhibition impairs NF-kappaB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-kappaB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF-kappaB activation, and GATA-3 expression were observed preclinically in ixazomib-treated cells. Therefore, an investigator-initiated, single-center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF kappaB activation and GATA-3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF kappaB/GATA-3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents. PMID- 28842937 TI - Optimization of region-of-interest sampling strategies for hepatic MRI proton density fat fraction quantification. AB - BACKGROUND: Clinical trials utilizing proton density fat fraction (PDFF) as an imaging biomarker for hepatic steatosis have used a laborious region-of-interest (ROI) sampling strategy of placing an ROI in each hepatic segment. PURPOSE: To identify a strategy with the fewest ROIs that consistently achieves close agreement with the nine-ROI strategy. STUDY TYPE: Retrospective secondary analysis of prospectively acquired clinical research data. POPULATION: A total of 391 adults (173 men, 218 women) with known or suspected NAFLD. FIELD STRENGTH/SEQUENCE: Confounder-corrected chemical-shift-encoded 3T MRI using a 2D multiecho gradient-recalled echo technique. ASSESSMENT: An ROI was placed in each hepatic segment. Mean nine-ROI PDFF and segmental PDFF standard deviation were computed. Segmental and lobar PDFF were compared. PDFF was estimated using every combinatorial subset of ROIs and compared to the nine-ROI average. STATISTICAL TESTING: Mean nine-ROI PDFF and segmental PDFF standard deviation were summarized descriptively. Segmental PDFF was compared using a one-way analysis of variance, and lobar PDFF was compared using a paired t-test and a Bland-Altman analysis. The PDFF estimated by every subset of ROIs was informally compared to the nine ROI average using median intraclass correlation coefficients (ICCs) and Bland Altman analyses. RESULTS: The study population's mean whole-liver PDFF was 10.1 +/- 8.9% (range: 1.1-44.1%). Although there was no significant difference in average segmental (P = 0.452) or lobar (P = 0.154) PDFF, left and right lobe PDFF differed by at least 1.5 percentage points in 25.1% (98/391) of patients. Any strategy with >=4 ROIs had ICC >0.995. 115 of 126 four-ROI strategies (91%) had limits of agreement (LOA) <1.5%, including four-ROI strategies with two ROIs from each lobe, which all had LOA <1.5%. 14/36 (39%) of two-ROI strategies and 74/84 (88%) of three-ROI strategies had ICC >0.995, and 2/36 (6%) of two-ROI strategies and 46/84 (55%) of three-ROI strategies had LOA <1.5%. DATA CONCLUSION: Four-ROI sampling strategies with two ROIs in the left and right lobes achieve close agreement with nine-ROI PDFF. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:988-994. PMID- 28842938 TI - One-Step Reforming of CO2 and CH4 into High-Value Liquid Chemicals and Fuels at Room Temperature by Plasma-Driven Catalysis. AB - The conversion of CO2 with CH4 into liquid fuels and chemicals in a single-step catalytic process that bypasses the production of syngas remains a challenge. In this study, liquid fuels and chemicals (e.g., acetic acid, methanol, ethanol, and formaldehyde) were synthesized in a one-step process from CO2 and CH4 at room temperature (30 degrees C) and atmospheric pressure for the first time by using a novel plasma reactor with a water electrode. The total selectivity to oxygenates was approximately 50-60 %, with acetic acid being the major component at 40.2 % selectivity, the highest value reported for acetic acid thus far. Interestingly, the direct plasma synthesis of acetic acid from CH4 and CO2 is an ideal reaction with 100 % atom economy, but it is almost impossible by thermal catalysis owing to the significant thermodynamic barrier. The combination of plasma and catalyst in this process shows great potential for manipulating the distribution of liquid chemical products in a given process. PMID- 28842939 TI - A One-Dimensional Fluidic Nanogenerator with a High Power Conversion Efficiency. AB - Electricity generation from flowing water has been developed for over a century and plays a critical role in our lives. Generally, heavy and complex facilities are required for electricity generation, while using these technologies for applications that require a small size and high flexibility is difficult. Here, we developed a fluidic nanogenerator fiber from an aligned carbon nanotube sheet to generate electricity from any flowing water source in the environment as well as in the human body. The power conversion efficiency reached 23.3 %. The fluidic nanogenerator fiber was flexible and stretchable, and the high performance was well-maintained after deformation over 1 000 000 cycles. The fiber also offered unique and promising advantages, such as the ability to be woven into fabrics for large-scale applications. PMID- 28842940 TI - The impact of restrictions on neonicotinoid and fipronil insecticides on pest management in maize, oilseed rape and sunflower in eight European Union regions. AB - BACKGROUND: In 2013, the European Commission restricted the use of three neonicotinoids (clothianidin, imidacloprid and thiamethoxam) and the pyrazole fipronil, which are widely used to control early-season pests. Here, we used original farm survey data to examine the impact of the restrictions on pest management practices in eight regional case studies including maize, oilseed rape and sunflower in seven European Union (EU) countries. RESULTS: In four case studies, farmers switched to using untreated seeds as no alternative seed treatments were available. In three case studies, farmers switched to using unrestricted neonicotinoid- or pyrethroid-treated seeds. In five case studies, farmers increased the use of soil or foliar treatments, with pyrethroids as the principal insecticide class. Other changes in pest management practices ranged from increased sowing density to more frequent scouting for pests. Many farmers perceived that the time, cost and amount of insecticides required to protect crops increased, along with pest pressure. Alternative seed treatments were mostly perceived as being less effective than the restricted seed treatments. CONCLUSION: Farmers generally relied on alternative seed treatments or more soil/foliar treatments in the first growing season after the restrictions took effect. Further study is required to assess the effectiveness and sustainability of these alternatives compared with the restricted insecticides. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28842942 TI - Risk factors of age-related cataract in a Chinese adult population: the Taizhou Eye Study. AB - IMPORTANCE: Cataract risk factors data will provide epidemic evidence for cataract prevention. BACKGROUND: This study aimed to study the risk factors for age-related cataract in a Chinese adult population. DESIGN: This is a population based, cross-sectional study. PARTICIPANTS: A total of 10 234 eligible subjects >=45 years old (response rate: 78.1%) were included in the study. METHODS: We conducted detailed eye examinations including presenting visual acuity, best corrected visual acuity, slit lamp examination of lens opacities and fundus examination. Questionnaires about lifestyle were administered. Measurements of blood pressure, heart rate and body mass index were collected. Serological metabolic indicators, including fasting blood glucose, triglycerides, cholesterol, lipoprotein, were also evaluated. We used stepwise multivariate logistic regression model to evaluate the association of these risk factors with any cataract and subtypes of cataract. MAIN OUTCOME MEASURES: Odds ratios of risk factors for cataract were calculated. RESULTS: For any cataract, we found age, gender (female), increased outdoor activity, no outdoor eye protection, high myopia, high low-density lipoprotein, low high-density lipoprotein, lower education level and increased pickled food intake were independent risk factors. When further examined the risk factors of different subtypes of cataract, we found that these risk factors also existed, but there were slight differences among different subtypes. In addition, for cortical cataract, lower annual family income and high diastolic pressure were additional independent risk factors. CONCLUSIONS AND RELEVANCE: Reduced outdoor activity, outdoor eye protection, prevention of high myopia, higher education level, controlled blood pressure, improved high-density lipoprotein and low-density lipoprotein levels and reduced pickled food intake may help to reduce the risk of age-related cataract development. PMID- 28842941 TI - Characterization of early communicative behavior in mouse models of neurofibromatosis type 1. AB - : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss-of-function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45-60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal-separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/- mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAP CKO mice). We observed altered USV production in both models: Nf1+/- mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAP CKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole-brain serotonin was observed in Nf1+/- mice, but whole-brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD-relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44-58. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)-relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. PMID- 28842943 TI - To mdivi-1 or not to mdivi-1: Is that the question? AB - The fission/division and fusion of mitochondria are fundamental aspects of mitochondrial biology. The balance of fission and fusion sets the length of mitochondria in cells to serve their physiological requirements. The fission of mitochondria is markedly induced in many disease states and in response to cellular injury, resulting in the fragmentation of mitochondria into dysfunctional units. The mechanism that drives fission is dependent on the dynamin related protein 1 (Drp1) GTPase. mdivi-1 is a quinazolinone originally described as a selective inhibitor of Drp1, over other dynamin family members, and reported to inhibit mitochondrial fission. A recent study has challenged the activity of mdivi-1 as an inhibitor of Drp1. This study raises serious issues regarding the interpretation of data addressing the effects of mdivi-1 as reflective of the inhibition of Drp1 and thus fission. This commentary considers the evidence for and against mdivi-1 as an inhibitor of Drp1 and presents the following considerations; (1) the activity of mdivi-1 toward Drp1 GTPase activity requires further biochemical investigation, (2) as there is a large body of literature using mdivi-1 in vitro with effects as predicted for inhibition of Drp1 and mitochondrial fission, reviewed herein, the evidence is in favor of mdivi-1's originally described bioactivity, and (3) until the issue is resolved, experimental interpretations for the effects of mdivi-1 on inhibition of fission in cell and tissue experiments warrants stringent positive controls directly addressing the effects of mdivi-1 on fission. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1260-1268, 2017. PMID- 28842944 TI - High-throughput next-generation sequencing to genotype six classical HLA loci from 96 donors in a single MiSeq run. AB - Next generation sequencing (NGS) methods have been established as an efficient approach for HLA typing because unlike traditional Sanger sequencing, they provide unambiguous results at a reasonable cost. We previously developed a multi locus index method to genotype four HLA loci (A, B, C, and DRB1) on the Illumina MiSeq platform. We have now expanded this method to include two additional loci, HLA-DPB1 and DQB1. Contiguous full-length amplicons from 5'UTR through 3'UTR regions were generated using one long-range PCR reaction per locus for each of the six loci from 96 individuals of different ethnicities. The six amplicons from each donor were pooled, enzymatically fragmented and given a donor-specific index. This approach enabled sequencing of 576 loci from 96 individuals in a single MiSeq run. Donor-specific sequence reads were demultiplexed, and allele calls were generated from FASTQ files using commercially available software. Comparison to HLA genotypes generated from Sanger sequence-based typing (SBT) identified no discordances among any of the alleles analyzed in this study. Importantly, this method was able to resolve 22 DPB1 and 20 DQB1 alleles that were ambiguous with the SBT method. Furthermore, a novel allele in each of these two loci was identified, with the DQB1*05:01:24 allele having a frequency of greater than five percent. This method was subsequently validated against a blinded panel of 22 samples from the 17th International HLA and Immunogenetics Workshop. The flexibility of the method is further highlighted by successful genotyping of eight loci comprising all classical HLA loci for a subset of the samples. We now present a high-throughput, high-resolution, scalable NGS HLA typing method to accurately and efficiently genotype all classical HLA class I and II loci. PMID- 28842945 TI - Minimal iris touch excision: a novel surgical technique for local excision of iris melanoma. PMID- 28842946 TI - Anxiety and depression in adult outpatients with bronchiectasis: Associations with disease severity and health-related quality of life. AB - BACKGROUND: Anxiety and depression might frequently affect bronchiectasis patients, but data in Chinese patients, including their association with disease severity assessed with Bronchiectasis Severity Index (BSI) and FACED score, are limited. OBJECTIVE: To investigate the rate, risk factors, association with disease severity and impact of anxiety and depression on health-related quality of life (HRQoL) in adult outpatients with steady-state bronchiectasis. METHODS: This cross-sectional study included 163 outpatients (102 females; mean age, 45.8 years) and 80 healthy subjects (47 females; mean age, 47.1 years). Demographic, clinical indices, radiology, spirometry, aetiology, sputum bacteriology, Hospital Anxiety and Depression Scales (HADS), Pittsburgh Sleep Quality Index (PSQI) and St. George's Respiratory Questionnaire (SGRQ) were assessed. RESULTS: Patients with steady-state bronchiectasis had a higher rate of depression (HADS-depression >7) (30.1% vs 10.0%, P = .001) and anxiety (HADS-anxiety >7; 39.9% vs 6.3%, P < .001) compared with healthy subjects. Notably, no significant differences in the rate of anxiety and depression were found across different disease severity, assessed with BSI and FACED score (all P > .05). In multivariate model, factors associated with anxiety included younger age (OR = 1.05), education below college graduate (OR = 4.55) and sleep disturbance (PSQI >= 6; OR = 2.95); whereas sleep disturbance was the sole factor associated with depression (OR = 5.98). Patients with either depression or anxiety had more markedly impaired HRQoL affecting most domains than those without. CONCLUSIONS: Anxiety and depression are common in bronchiectasis and can negatively affect HRQoL, but not related to disease severity. Prompt assessment and treatment of these mental disorders, regardless of bronchiectasis severity, are advocated and might improve HRQoL. PMID- 28842947 TI - Protective effects of the egg stalk of Paratrioza sinica (Hemiptera: Psyllidae) at various angles and spacings against three predaceous coccinellids, Harmonia axyridis, Coccinella septempunctata and Hippodamia variegata (Coleoptera: Coccinellidae). AB - BACKGROUND: Paratrioza sinica is a major pest of wolfberry (Lycium barbarum). Coccinellids can effectively control various developmental stages of P. sinica but not the stalked egg. To investigate the protective role of egg stalks against the predaceous coccinellids Harmonia axyridis, Coccinella septempunctata and Hippodamia variegata, we studied the functional responses to, and effects of, two factors: the angle between the egg stalk and the leaf plane, and the spacing between egg stalks. RESULTS: The searching rate, handling time and theoretical maximum egg consumption of H. variegata were optimal among the three ladybug species. Egg consumption by coccinellids was maximum and minimum at stalk angles of 0 degrees and 90 degrees , respectively. The average reduction in the rate of egg consumption when the stalk angle was 90 degrees relative to 0 degrees was significantly smaller for larvae of coccinellids compared with adults, and for H. variegata compared with the other two species. Optimal spacing of eggs for consumption by predators varied with the predator species and their developmental stage, and was close to the body length of the predators. CONCLUSION: The egg stalk serves as a physical protection against predators. The evolutionary selective advantage of the egg stalk in providing protection against predators requires more attention. Appropriate selection of predators and irrigation strategies may improve control of P. sinica. (c) 2017 Society of Chemical Industry. PMID- 28842948 TI - Leveraging a CHO cell line toolkit to accelerate biotherapeutics into the clinic. AB - The Biogen upstream platform is capable of delivering equivalent quality material throughout the cell line generation process. This allows us to rapidly deliver high-quality biopharmaceuticals to patients with unmet medical needs. The drive to reduce time-to-market led the cell engineering group to develop an expression system that can enable this strategy. We have developed a clonal Chinese Hamster Ovary (CHO) host cell line that can routinely produce consistent antibody material at high titers throughout the cell line generation process. This host line enables faster delivery of early phase material through use of the highly productive stable pool or a mixture of high performance clones. Due to unique characteristics of this cell line, the product quality of material from early cell populations is very comparable to material from the final clones. This lends itself to a "fast-to-tox" strategy whereby toxicology studies can be performed with representative material from an earlier cell population, thus accelerating the clinical timelines. Our new clonal host offers robust and consistent performance that enables a highly productive, flexible process and faster preclinical timelines. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1468-1475, 2017. PMID- 28842950 TI - Glucagon receptor as a drug target: A witches' brew of eye of newt (peptides) and toe of frog (receptors). PMID- 28842949 TI - Dl-3-n-butylphthalide attenuates acute inflammatory activation in rats with spinal cord injury by inhibiting microglial TLR4/NF-kappaB signalling. AB - In this study, we examined the neuroprotective effects and anti-inflammatory properties of Dl-3-n-butylphthalide (NBP) in Sprague-Dawley (SD) rats following traumatic spinal cord injury (SCI) as well as microglia activation and inflammatory response both in vivo and in vitro. Our results showed that NBP improved the locomotor recovery of SD rats after SCI an significantly diminished the lesion cavity area of the spinal cord, apoptotic activity in neurons, and the number of TUNEL-positive cells at 7 days post-injury. NBP inhibited activation of microglia, diminished the release of inflammatory mediators, and reduced the upregulation of microglial TLR4/NF-kappaB expression at 1 day post-injury. In a co-culture system with BV-2 cells and PC12 cells, NBP significantly reduced the cytotoxicity of BV-2 cells following lipopolysaccharide (LPS) stimulation. In addition, NBP reduced the activation of BV-2 cells, diminished the release of inflammatory mediators, and inhibited microglial TLR4/NF-kappaB expression in BV 2 cells. Our findings demonstrate that NBP may have neuroprotective and anti inflammatory properties in the treatment of SCI by inhibiting the activation of microglia via TLR4/NF-kappaB signalling. PMID- 28842951 TI - Effect of potassium and manganese phosphites in the control of Pythium damping off in soybean: a feasible alternative to fungicide seed treatments. AB - BACKGROUND: Use of fungicide seed treatments for control of soybean soilborne diseases such as Pythium damping-off has increased worldwide. However, emergence of Pythium strains resistant to metalaxyl-M has prompted the need for alternative technologies to fungicides for damping-off control. The use of phosphites (Phis) has been proposed as a method to control oomycetes, but their use as seed treatments in soybean is limited by the lack of information on their efficacy. The effect of potassium (K) and manganese (Mn) Phis (as seed treatments) in the control of Pythium damping-off in soybean was evaluated in vitro and in vivo. In vitro, treated seeds and a control were placed on potato dextrose agar and the damping-off severity caused by Pythium aphanidermatum (Edson) Fitzpatrick, Pythium irregulare Buisman, and Pythium ultimum Trow was assessed 5 days after incubation using an ordinal scale. In vivo, treated seeds and a control were planted in polystyrene pots and emergence was evaluated 21 days after planting. RESULTS: Analysis of the in vitro data using a multinomial generalized linear model showed that the probabilities of non-germinated, dead seeds ranged from 0.64 to 1.00 in the control and from 0 to 0.13 in the Phi treatments in each of the Pythium species. Probabilities of seed germination without or with damping off symptoms were significantly higher for seeds treated with the Phi products than for the control. In the in vivo experiment, the Phi-based products increased seedling emergence by up to 29% on average compared with the untreated control. CONCLUSION: Mn and K Phis are feasible alternatives as seed treatments to control Pythium damping-off in soybean. This study is the first, worldwide, to document the efficacy of K and Mn Phis in the control of soybean Pythium damping-off. (c) 2017 Society of Chemical Industry. PMID- 28842952 TI - Sequence-based typing of a novel HLA-DRB1 allele, HLA-DRB1*14:32:03, in a Chinese individual. AB - HLA-DRB1*14:32:03 has one synonymous nucleotide change from HLA-DRB1*14:32:02at nucleotide 303 (codon 72 Arginine). PMID- 28842953 TI - Novel Body Shape Descriptors for Abdominal Adiposity Prediction Using Magnetic Resonance Images and Stereovision Body Images. AB - OBJECTIVE: The purpose of this study was to design novel shape descriptors based on three-dimensional (3D) body images and to use these parameters to establish prediction models for abdominal adiposity. METHODS: Sixty-six men and fifty-five women were recruited for abdominal magnetic resonance imaging (MRI) and 3D whole body imaging. Volumes of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured from MRI sequences by using a fully automated algorithm. The shape descriptors were measured on the 3D body images by using the software developed in this study. Multiple regression analysis was employed on the training data set (70% of the total participants) to develop predictive models for VAT and SAT, with potential predictors selected from age, BMI, and the body shape descriptors. The validation data set (30%) was used for the validation of the predictive models. RESULTS: Thirteen body shape descriptors exhibited high correlations (P < 0.01) with abdominal adiposity. The optimal predictive equations for VAT and SAT were determined separately for men and women. CONCLUSIONS: Novel body shape descriptors defined on 3D body images can effectively predict abdominal adiposity quantified by MRI. PMID- 28842955 TI - Sex During Pregnancy. PMID- 28842954 TI - MiR-155 inhibits proliferation and invasion by directly targeting PDCD4 in non small cell lung cancer. AB - BACKGROUND: MicroRNAs are often abnormally expressed in human non-small cell lung cancer (NSCLC) and are thought to play a critical role in the emergence or maintenance of NSCLC by binding to its target messenger RNA. We assessed the effects of miR-155 on cell proliferation and invasion to elucidate the role played by miR-155/PDCD4 in NSCLC. METHODS: Quantitative reverse transcription PCR, Western blotting, and cell counting kit-8, luciferase, and transwell invasion assays were conducted on a normal human bronchial epithelial cell line (BEAS-2B) and three NSCLC cell lines (SPC-A-1, A549, and H2170). RESULTS: We confirmed that miR-155 was upregulated, while PDCD4 messenger RNA and protein levels were downregulated in NSCLC cell lines. miR-155 negatively regulated PDCD4 at both transcriptional and post-transcriptional levels. Moreover, PDCD4 was forecast as an assumed target of miR-155 using bioinformatic methods and we demonstrated that PDCD4 was a direct target of miR-155 using luciferase reporter assays. Furthermore, PDCD4 overexpression could restrain NSCLC proliferation and invasion induced by miR-155. CONCLUSION: Our results collectively demonstrate that miR-155 exerts an oncogenic role in NSCLC by directly targeting PDCD4. PMID- 28842956 TI - Clinical and social characteristics associated with reduced visual acuity at presentation in Australian patients with neovascular age-related macular degeneration: a prospective study from a long-term observational data set. The Fight Retinal Blindness! Project. AB - IMPORTANCE: Identifying variables that influence presenting visual acuity (VA) in patients with neovascular age-related macular degeneration (nAMD) is important because it is a strong predictor of long-term outcomes. BACKGROUND: To assess the clinical and social characteristics associated with low presenting VA in nAMD patients. DESIGN: The present study is a cross-sectional analysis from a prospective, observational database. PARTICIPANTS: We identified 3242 treatment naive patients from 54 Australian practices in the Fight Retinal Blindness! registry. METHODS: Age, gender, ethnicity and VA were recorded at the baseline visit. Socio-economic status was determined using the Australian Bureau of Statistics socio-economic indexes for areas. MAIN OUTCOME MEASURES: Association between clinical and socio-economic characteristics with presenting VA was identified. RESULTS: Poor VA (<=35 letters) in the presenting eye was associated with older age (adjusted odds ratio [AOR]: 1.33 for patients aged >=80 years vs. <80 years [95% confidence interval, CI: 1.04, 1.71]), treatment at a public practice (AOR: 1.91 for public vs. private practices [95% CI: 1.46, 2.50]) and intermediate (36-69 letters) VA in the fellow eye (AOR: 0.67 [95% CI: 0.47, 0.95] and 0.64 [95% CI: 0.48, 0.85] for poor [<=35 letters] and good [>=70 letters] VA vs. intermediate VA in the fellow eye). Gender, ethnicity and socio-economic status were not independently associated with VA at presentation. CONCLUSIONS AND RELEVANCE: Poor presenting vision is detrimental to the long-term outcomes of nAMD. Poor presentation of nAMD in Australia may not be related to socio-economic circumstances, but due to systems of care. Further research is warranted to determine why patients at public practices present with worse vision compared with private practices in Australia. PMID- 28842957 TI - Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: From Mechanisms to Novel Test Methods. AB - Endocrine-disrupting chemicals (EDCs) are man-made chemicals that interfere with hormonal signalling pathways. They are used in, for example, production of common household materials, in resin-based medical supplies and in pesticides. Thus, they are environmentally ubiquitous and human beings and wildlife are exposed to them on a daily basis. Early-life exposure to EDCs has been associated with later life adversities such as obesity, diabetes and cancer. Mechanisms underlying such associations are unknown but are likely to be mediated by epigenetic changes induced by EDCs. Epigenetics is the study of changes in gene function that are heritable but do not entail a change in DNA sequence. EDCs have been shown to affect epigenetic marks such as DNA methylation and histone modifications. The scope of this article was to review today's knowledge about mechanisms involved in EDC-induced epigenetic changes and to discuss how this knowledge could be used for designing novel methods addressing epigenetic effects of EDCs. PMID- 28842958 TI - Enhanced diastereoselective synthesis of t-Butyl 6-cyano-(3R,5R) dihydroxyhexanoate by using aldo-keto reductase and glucose dehydrogenase co producing engineered Escherichia coli. AB - t-Butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-2) is a key chiral diol precursor of atorvastatin calcium (Lipitor(r)). We have constructed a Kluyveromyces lactis aldo-keto reductase mutant KlAKR-Y295W/W296L (KlAKRm) by rational design in previous research, which displayed high activity and excellent diastereoselectivity (dep > 99.5%) toward t-butyl 6-cyano-(5R)-hydroxy-3 oxohexanoate ((5R)-1). To realize in situ cofactor regeneration, a robust KlAKRm and Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) co-producer E. coli BL 21(DE3) pETDuet-esgdh (MCS1)/pET-28b (+)-klakrm was constructed in this work. Under the optimized conditions, AKR and GDH activities of E. coli BL 21(DE3) pETDuet-esgdh (MCS1)/pET-28b (+)-klakrm peaked at 249.9 U/g DCW (dry cellular weight) and 29100 U/g DCW, respectively. It completely converted (5R)-1 at substrate loading size of up to 60.0 g/L (5R)-1 in the absence of exogenous NADH, which was one-fifth higher than that of the separately prepared KlAKRm and EsGDH under the same conditions. In this manner, a biocatalytic process for (3R,5R)-2 with productivity of 243.2 kg/m3 d was developed. Compared with the combination of separate expressed KlAKRm with EsGDH, co-expression of KlAKRm and EsGDH has the advantages of alleviating cell cultivation burden and elevating substrate load. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1235-1242, 2017. PMID- 28842959 TI - Mechanical, chemical and biological damage modes within head-neck tapers of CoCrMo and Ti6Al4V contemporary hip replacements. AB - Total hip replacement (THR) failure due to mechanically assisted crevice corrosion within modular head-neck taper junctions remains a major concern. Several processes leading to the generation of detrimental corrosion products have been reported in first generation modular devices. Contemporary junctions differ in their geometries, surface finishes, and head alloy. This study specifically provides an overview for CoCrMo/CoCrMo and CoCrMo/Ti6Al4V head-neck contemporary junctions. A retrieval study of 364 retrieved THRs was conducted which included visual examination and determination of damage scores, as well as the examination of damage features using scanning electron microscopy. Different separately occurring or overlapping damage modes were identified that appeared to be either mechanically or chemically dominated. Mechanically dominated damage features included plastic deformation, fretting, and material transfer, whereas chemically dominate damage included pitting corrosion, etching, intergranular corrosion, phase boundary corrosion, and column damage. Etching associated cellular activity was also observed. Furthermore, fretting corrosion, formation of thick oxide films, and imprinting were observed which appeared to be the result of both mechanical and chemical processes. The occurrence and extent of damage caused by different modes was shown to depend on the material, the material couple, and alloy microstructure. In order to minimize THR failure due to material degradation within modular junctions, it is important to distinguish different damage modes, determine their cause, and identify appropriate counter measures, which may differ depending on the material, specific microstructural alloy features, and design factors such as surface topography. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1672-1685, 2018. PMID- 28842960 TI - Preoperative risk stratification of 646 cataract cases at Waikato Hospital, New Zealand. PMID- 28842961 TI - High nymphal host density and mortality negatively impact parasitoid complex during an insect herbivore outbreak. AB - Insect herbivore outbreaks frequently occur and this may be due to factors that restrict top-down control by parasitoids, for example, host-parasitoid asynchrony, hyperparasitization, resource limitation and climate. Few studies have examined host-parasitoid density relationships during an insect herbivore outbreak in a natural ecosystem with diverse parasitoids. We studied parasitization patterns of Cardiaspina psyllids during an outbreak in a Eucalyptus woodland. First, we established the trophic roles of the parasitoids through a species-specific multiplex PCR approach on mummies from which parasitoids emerged. Then, we assessed host-parasitoid density relationships across three spatial scales (leaf, tree and site) over one year. We detected four endoparasitoid species of the family Encyrtidae (Hymenoptera); two primary parasitoid and one heteronomous hyperparasitoid Psyllaephagus species (the latter with female development as a primary parasitoid and male development as a hyperparasitoid), and the hyperparasitoid Coccidoctonus psyllae. Parasitoid development was host-synchronized, although synchrony between sites appeared constrained during winter (due to temperature differences). Parasitization was predominantly driven by one primary parasitoid species and was mostly inversely host-density dependent across the spatial scales. Hyperparasitization by C. psyllae was psyllid-density dependent at the site scale, however, this only impacted the rarer primary parasitoid. High larval parasitoid mortality due to density-dependent nymphal psyllid mortality (a consequence of resource limitation) compounded by a summer heat wave was incorporated in the assessment and resulted in density independence of host-parasitoid relationships. As such, high larval parasitoid mortality during insect herbivore outbreaks may contribute to the absence of host density-dependent parasitization during outbreak events. PMID- 28842962 TI - Response to "Statistical analysis of data from limiting dilution cloning to assess monoclonality in generating manufacturing cell lines". PMID- 28842963 TI - Metal release and cell biological compatibility of beta-type Ti-40Nb containing indium. AB - Small indium (In) additions up to 5 wt % to the beta-type Ti-40Nb alloy effectively improve its mechanical biofunctionality. The impact on its biocompatibility is addressed in this work. Comparative electrochemical polarization studies and inductively coupled plasma optical emission spectrometry analyses were conducted in Tris-buffered saline (on the basis of 150 mM NaCl) with pH 7.6 and 2.0 at 310 +/- 1 K with Ti-6Al-4V as reference. The metal ion releases from beta-type alloys were generally very low, for example, those of In3+ ions from (Ti-40Nb)-4In specimens were below 6 * 10-7 mmol/cm2 . X-ray photoelectron spectroscopy revealed the passivation mainly by Ti- and Nb-oxides with traces of In-oxides as the dominating surface process. In vitro studies demonstrate a better human bone marrow stromal cells (hBMSC) activity on the beta type alloys in comparison to CP-Ti (grade 2), which is mainly due to their high Nb content. At 24 h after seeding on (Ti-40Nb)-4In the metabolic activity of hBMSC was 1.5-fold higher and after 11 days, the tissue non-specific alkaline phosphatase activity was 1.8-fold higher relative to values for CP-Ti. Surface treatments, like chemical etching or plasma oxidation, change the surface topography and the thickness and composition of the oxide layers, but they are not effective in further improving the cell response. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1686-1697, 2018. PMID- 28842964 TI - Corrigendum to: Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. PMID- 28842965 TI - Erratum to: Noggin-Mediated Retinal Induction Reveals a Novel Interplay Between Bone Morphogenetic Protein Inhibition, Transforming Growth Factor beta, and Sonic Hedgehog Signaling. PMID- 28842966 TI - Autonomy support and autonomous motivation in the outpatient treatment of adults with an eating disorder. AB - OBJECTIVE: Across diverse clinical problems, therapists' autonomy support has been found to increase patients' autonomous motivation for change. Being self motivated has, in turn, been linked to superior treatment response. In people undergoing outpatient eating disorder (ED) treatment, we examined associations among ratings of autonomy support received from therapists and other carers, self reported engagement in therapy, and clinical outcomes. METHOD: Ninety-seven women with anorexia nervosa, bulimia nervosa, or a related ED provided measures of motivational status and clinical symptoms at the beginning and end of time limited (12-16 weeks) segments of specialized treatment. At mid-treatment, patients also rated the extent to which they perceived their individual therapists, group therapists, group-therapy peers, family members, friends, and romantic partners as being autonomy supportive. RESULTS: Overall, multiple regression analyses indicated autonomy support to moderate (rather than mediate) the link between initial autonomous motivation and later change in autonomous motivation-with results indicating that, independently of ED diagnosis or treatment intensity, greater perceived autonomy support (from therapists and nontherapists alike) coincided with larger increases in autonomous motivation over the course of therapy. In turn, higher autonomous motivation at end-of therapy coincided with larger reductions in eating symptoms. DISCUSSION: Findings suggest that the experience of autonomy support (from therapists and nontherapists) is associated with increasing motivation in people undergoing ED treatment, and that becoming self-motivated is linked to better outcomes. Such results indicate that support from therapists, relatives, and peers can favorably influence personal engagement in individuals undergoing ED treatment. PMID- 28842968 TI - Insulin Mediated Activation of PI3K/Akt Signalling Pathway Modifies the Proteomic Cargo of Extracellular Vesicles. AB - Epidemiological studies suggest that diabetes and obesity increases the risk of colorectal cancer (CRC) and lowers the patient survival rate. An important attribute in diabetes and obesity is the presence of high levels of growth factors including insulin in blood which can activate the PI3K/Akt signalling pathway. Dysregulation of PI3K/Akt signalling pathway leads to sustained proliferative signals thereby allowing the cells susceptible to cancer. Extracellular vesicles (EVs), secreted nanovesicles of endocytic origin, are implicated in mediating the transfer of oncogenic cargo in the tumour microenvironment. In this study, CRC cells were treated with insulin to activate PI3K/Akt signaling pathway. Insulin treatment significantly increased the number of EVs secreted by CRC cells. Furthermore, pAkt was exclusively packaged in EVs secreted by PI3K/Akt activated cells. Quantitative proteomics analysis confirmed that the protein cargo of EVs are modified upon activation of PI3K/Akt signaling pathway. Bioinformatics analysis highlighted the enrichment of proteins implicated in cell proliferation in EVs secreted by PI3K/Akt activated cells. Furthermore, incubation of EVs secreted by PI3K/Akt activated cells induced proliferation in recipient CRC cells. These findings suggest that EVs can amplify the signal provided by the growth factors in the tumor microenvironment and hence aid in cancer progression. PMID- 28842967 TI - Zeolite-loaded alginate-chitosan hydrogel beads as a topical hemostat. AB - Hemorrhage is the leading cause of preventable death after a traumatic injury, and the largest contributor to loss of productive years of life. Hemostatic agents accelerate hemostasis and help control hemorrhage by concentrating coagulation factors, acting as procoagulants and/or interacting with erythrocytes and platelets. Hydrogel composites offer a platform for targeting both mechanical and biological hemostatic mechanisms. The goal of this work was to develop hydrogel particles composed of chitosan, alginate, and zeolite, and to assess their potential to promote blood coagulation via multiple mechanisms: erythrocyte adhesion, factor concentration, and the ability to serve as a mechanical barrier to blood loss. Several particle compositions were synthesized and characterized. Hydrogel bead composition was optimized to achieve the highest swelling capacity, greatest erythrocyte adhesion, and minimal in vitro cytotoxicity. These results suggest a polymer hydrogel-aluminosilicate composite material may serve as a platform for an effective hemostatic agent that incorporates multiple mechanisms of action. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1662-1671, 2018. PMID- 28842969 TI - Pleuroparenchymal fibroelastosis in heterogeneous clinical conditions: Clinicopathologic analysis of 7 cases. AB - BACKGROUND AND AIMS: Pleuroparenchymal fibroelastosis (PPFE) is classified as a rare idiopathic interstitial pneumonia, and its clinicopathologic features remain unclear. We sought to investigate the clinical, radiologic, and pathologic features of patients with histologically proven PPFE. METHODS: Seven patients who had histologic features of PPFE that were definitive or consistent with PPFE were included. Clinical data and radiologic findings of chest computed tomography were obtained. Histologic evaluation was performed by 2 pathologists. RESULTS: Four patients had elevated serum autoantibodies, 3 had a history of organ transplantation, and 1 had acute Aspergillus infection. All patients had various degrees of restrictive patterns on pulmonary function tests. Histologic examination revealed a variable extent of PPFE. Fibroblastic foci, patchy lymphocytic infiltration, and pneumothorax were observed, but these findings were nonspecific. Radiologically, PPFE lesions were distributed diffusely, rather than being limited to the upper lungs. CONCLUSIONS: PPFE seems to be a histologic finding that may partly overlap with other chronic lung diseases. There can be various underlying clinical states. PMID- 28842970 TI - Steroid profile and IRMS analysis of musk administration for doping control. AB - Musk, the dried secretion of the musk pod (sac) of adult male musk deer, has been used as traditional Chinese Medicine (TCM) in China and south-east Asian countries for thousands of years. Due to the anabolic steroid component in this TCM, musk preparations have been included in the list of medical products containing prohibited substances employed for doping by the State Food and Drug Administration of China. The application of musk pod formulation was claimed to be responsible for some adverse analytical findings (AAFs) in the 2011 FIFA Women's World Cup. Our preliminary study has suggested that musk ingestion did not lead to AAFs of doping control with the single dosage of 100 mg. However, the influences of musk administration in large and multi dosage are still unclear. The aim of this study is to further investigate the influences of musk administration for doping control. Wild and domestic deer musk samples were collected. The concentrations and delta13 C-values of steroids in musk were analyzed. In an excretion study, 200 and 100 mg of wild and domestic deer musk samples were administrated by 29 subjects, respectively. Fluctuations in steroid profile could be observed, and the ratio of 5alpha-androstane-3alpha,17beta-diol to 5beta-androstane-3alpha,17beta-diol was more sensitive than other parameters. In the IRMS test, the ?Deltadelta13 C-value between endogenous reference compound and etiocholanolone was a sensitive parameter, and AAFs were obtained. It is the first time to confirm with excretion study that musk administration could lead to positive result of doping control. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28842972 TI - What Do Implanted Cardiac Monitors Reveal About Atrial Fibrillation? PMID- 28842971 TI - The impact of pediatric obesity on hospitalized children with lower respiratory tract infections in the United States. AB - OBJECTIVE: Obesity is the most common public health problem and is a clinically complicating risk factor among hospitalized children. The impact of pediatric obesity on the severity and morbidity of lower respiratory tract infections remains unclear. MATERIALS AND METHODS: We conducted a retrospective cohort study of bronchitis and pneumonia among children aged 2-20 years using hospital discharge records. The data were obtained from the Kid's Inpatient Database in 2003, 2006, 2009, and 2012, and were weighted to estimate the number of hospitalizations in the United States. We used the International Classification of Diseases, Ninth Revision, Clinical Modification code (278.0*) to classify whether the patient was obese or not. We investigated the associations between pediatric obesity and use of mechanical ventilation using multivariable logistic regression model. In addition, we ascertained the relationships between pediatric obesity, comorbid blood stream infections, mean healthcare cost, and length of hospital stay. RESULTS: We estimated a total of 133 602 hospitalizations with pneumonia and bronchitis among children aged between 2 and 20 years. Obesity was significantly associated with use of mechanical ventilation (adjusted OR 2.90, 95% CI 2.15-3.90), comorbid bacteremia or septicemia (adjusted OR 1.58, 95% CI 1.03-2.44), elevated healthcare costs (adjusted difference $383, 95%CI $276 $476), and prolonged length of hospital stay (difference 0.32 days, 95%CI 0.23 0.40 days), after adjusting for patient and hospital characteristics using multivariable logistic regression models. CONCLUSIONS: Pediatric obesity is an independent risk factor for severity and morbidity among pediatric patients with lower respiratory tract infections. These findings suggest the importance of obesity prevention for pediatric populations. PMID- 28842973 TI - Incidence of Previously Undiagnosed Atrial Fibrillation Using Insertable Cardiac Monitors in a High-Risk Population: The REVEAL AF Study. AB - Importance: In approximately 20% of atrial fibrillation (AF)-related ischemic strokes, stroke is the first clinical manifestation of AF. Strategies are needed to identify and therapeutically address previously undetected AF. Objective: To quantify the incidence of AF in patients at high risk for but without previously known AF using an insertable cardiac monitor. Design, Setting, and Participants: This prospective, single-arm, multicenter study was conducted from November 2012 to January 2017. Visits took place at 57 centers in the United States and Europe. Patients with a CHADS2 score of 3 or greater (or 2 with at least 1 additional risk factor) were enrolled. Approximately 90% had nonspecific symptoms potentially compatible with AF, such as fatigue, dyspnea, and/or palpitations. Exposures: Patients underwent monitoring with an insertable cardiac monitor for 18 to 30 months. Main Outcomes and Measures: The primary end point was adjudicated AF lasting 6 or more minutes and was assessed at 18 months. Other analyses included detection rates at points from 30 days to 30 months and among CHADS2 score subgroups. Median time from insertion to detection and the percentage of patients subsequently prescribed oral anticoagulation therapy was also determined. Results: A total of 446 patients were enrolled; 233 (52.2%) were male, and the mean (SD) age was 71.5 (9.9) years. A total of 385 patients (86.3%) received an insertable cardiac monitor, met the primary analysis cohort definition, and were observed for a mean (SD) period of 22.5 (7.7) months. The detection rate of AF lasting 6 or more minutes at 18 months was 29.3%. Detection rates at 30 days and 6, 12, 24, and 30 months were 6.2%, 20.4%, 27.1%, 33.6%, and 40.0%, respectively. At 18 months, AF incidence was similar among patients with CHADS2 scores of 2 (24.7%; 95% CI, 17.3-31.4), 3 (32.7%; 95% CI, 23.8-40.7), and 4 or greater (31.7%; 95% CI, 22.0-40.3) (P = .23). Median (interquartile) time from device insertion to first AF episode detection was 123 (41-330) days. Of patients meeting the primary end point, 13 (10.2%) had 1 or more episodes lasting 24 hours or longer, and oral anticoagulation therapy was prescribed for 72 patients (56.3%). Conclusions and Relevance: The incidence of previously undiagnosed AF may be substantial in patients with risk factors for AF and stroke. Atrial fibrillation would have gone undetected in most patients had monitoring been limited to 30 days. Further trials regarding the value of detecting subclinical AF and of prophylactic therapies are warranted. Trial Registration: clinicaltrials.gov Identifier: NCT01727297. PMID- 28842974 TI - Economics of Inhaled Oxygen Use as an Acute Therapy for Cluster Headache in the United States of America. AB - BACKGROUND: Cluster headache (CH) is a primary headache disorder associated with low levels of diagnosis and high unmet medical need. The pain attacks, associated anxiety, and fear in anticipation of the attacks are extremely debilitating to a patient with CH. For acute therapy, treatment guidelines recommend inhalation of high flow oxygen during the period of an attack. However, the use of oxygen for treatment of CH remains largely underutilized. OBJECTIVES: The objectives of the study, which covered each of the US states, were to map the current market landscape of medical grade oxygen for use in CH and to develop a cost simulator based on a patient's needs and geography. METHODS: Desk research was undertaken to obtain price lists and product catalogs from wholesale and retail suppliers of medical grade oxygen across all US states. Base case scenarios for chronic and episodic forms of CH were assumed. A cost simulator was used to calculate the cost of oxygen use using inputs including the state in USA, tank size and price, exacerbations per year, duration of exacerbation, attacks per day, flow rate and duration of flow. Information was also collected to determine if healthcare insurers covered the costs of home oxygen use for CH. RESULTS: Out of the 42 US states where pricing information of medical grade oxygen was available from suppliers, in 38 states the annual cost of high-flow oxygen for a patient with episodic CH was estimated to be <$1000. In 39 states, the annual cost of high flow oxygen for a patient with chronic CH was estimated to be <$5000. Most of the home oxygen suppliers were familiar with CH and stocked the special non rebreather masks and regulators necessary for this condition. It was found that many of the private commercial healthcare insurance providers reimbursed the cost of oxygen use for CH. However, the US Centers for Medicare and Medicaid Services (CMS) maintains there is insufficient evidence for coverage and continues to deny coverage for US Medicare and Medicaid patients. CONCLUSIONS: Results from our study showed that the current costs for oxygen use as an acute therapy in CH are not prohibitively expensive for patients and healthcare insurance providers. Apart from CMS, many insurers do reimburse the cost of oxygen use for CH. Our study suggests that further research is needed to determine if a lack of physician awareness about treatments and ways to prescribe are barriers for patients to access the high-flow oxygen treatment. PMID- 28842975 TI - MATERNAL INTERACTION QUALITY MODERATES EFFECTS OF PRENATAL MATERNAL EMOTIONAL SYMPTOMS ON GIRLS' INTERNALIZING PROBLEMS. AB - The role of mother-infant interaction quality is studied in the relation between prenatal maternal emotional symptoms and child behavioral problems. Healthy pregnant, Dutch women (N = 96, M = 31.6, SD = 3.3) were allocated to the "exposed group" (n = 46), consisting of mothers with high levels of prenatal feelings of anxiety and depression, or the "low-exposed group" (n = 50), consisting of mothers with normal levels of depressive or anxious symptoms during pregnancy. When the children (49 girls, 47 boys) were 23 to 60 months of age (M = 39.0, SD = 9.6), parents completed the Child Behavior Checklist (T.M. Achenbach & L.A. Rescorla, ), and mother-child interaction quality during a home visit was rated using the Emotional Availability Scales. There were no differences in mother child interaction quality between the prenatally exposed and low-exposed groups. Girls exposed to high prenatal emotional symptoms showed more internalizing problems, if maternal interaction quality was less optimal. No significant effects were found for boys. PMID- 28842976 TI - Safety and efficacy of a novel three-dimensional magnetic resonance imaging model for uterine incision in placenta previa. AB - OBJECTIVE: To assess a novel three-dimensional (3D) magnetic resonance imaging (MRI) model for determining position of uterine incision during cesarean delivery among patients with placenta previa. METHODS: A prospective study was conducted among women with singleton pregnancies complicated by placenta previa who delivered by cesarean at a hospital in China between January 1, 2014, and January 1, 2016. Patients chose whether to undergo 3D MRI modeling to guide uterine incision (study group) or the standard intervention (control group). Medical records were reviewed to collect data on maternal, neonatal, and operative characteristics. RESULTS: Among 134 women enrolled, 45 were in the study group and 89 in the control group. When compared with the control group, patients in the study group experienced less intraoperative blood loss (678.65 +/- 649.54 vs 933.96 +/- 695.25 mL; P=0.042) and shorter operative times (65.13 +/- 27.38 vs 86.88 +/- 54.43 minutes; P=0.013). Fewer patients in the study group received transfusions (11 [24%] vs 38 [43%]; P=0.038). No between-group differences were found for hysterectomy rate, hospitalization days and cost, or neonatal outcomes. CONCLUSION: Uterine incision guided by a 3D MRI model could improve maternal outcomes during cesarean delivery, including reductions in intraoperative blood loss, transfusion frequency, and operative time. PMID- 28842977 TI - Clinical outcomes after external cephalic version with spinal anesthesia after failure of a first attempt without anesthesia. AB - OBJECTIVE: To determine whether repeat external cephalic version (ECV) with spinal anesthesia affects clinical outcomes and cesarean delivery rates. METHODS: A retrospective study was conducted using data collected at one hospital in Israel between January 1, 2009, and December 31, 2015. Women with non-vertex singleton pregnancies (>=37 weeks) who had a failed ECV attempt without spinal anesthesia were included in the analysis. All women were offered a repeat ECV with spinal anesthesia. Outcomes assessed were rates of vertex presentation at delivery, successful repeat ECV, and cesarean delivery. RESULTS: Overall, 145 of 213 ECV attempts without spinal anesthesia were successful. Of the 68 women with a failed attempt, 5 (7%) experienced spontaneous version and 18 (26%) delivered at another institution or went into spontaneous labor. Among the remaining 45 women, 28 (62%) agreed to a repeat ECV with spinal anesthesia; 11 (39%) of these procedures were successful. All 11 women experienced vertex presentation at delivery versus none of the 17 women who refused repeat ECV (P=0.003). The cesarean delivery rate was 64% (18/28) versus 100% (17/17), respectively (P=0.007). CONCLUSION: Repeat ECV with spinal anesthesia after a failed first attempt without spinal anesthesia increased vertex presentation at birth and decreased the rate of cesarean delivery. PMID- 28842978 TI - The lasso technique for endoscopic suture lateralization in bilateral vocal fold immobility. PMID- 28842979 TI - Epicardial ablation utilizing remote magnetic navigation in a patient with Brugada syndrome and inferior early repolarization. AB - We report a case of epicardial ablation in a combined Brugada and inferior early repolarization syndrome patient with recurrent defibrillator therapy for spontaneous ventricular fibrillation. Electroanatomic mapping and ablation were achieved with remote magnetic navigation. Highly fractionated electrograms were seen epicardially in the anterior right ventricular outflow tract (RVOT) and at the anterior-inferior right ventricle. Ablation of the RVOT region resulted in resolution Brugada pattern electrocardiogram. The inferior early repolarization persisted despite ablation of the inferior right ventricular epicardium. Our patient remained event free at 12-months follow-up. PMID- 28842981 TI - Effect of botulinum toxin on inducibility and maintenance of atrial fibrillation in ovine myocardial tissue: Response to letter to the editor. PMID- 28842980 TI - Escherichia coli "TatExpress" strains super-secrete human growth hormone into the bacterial periplasm by the Tat pathway. AB - Numerous high-value proteins are secreted into the Escherichia coli periplasm by the General Secretory (Sec) pathway, but Sec-based production chassis cannot handle many potential target proteins. The Tat pathway offers a promising alternative because it transports fully folded proteins; however, yields have been too low for commercial use. To facilitate Tat export, we have engineered the TatExpress series of super-secreting strains by introducing the strong inducible bacterial promoter, ptac, upstream of the chromosomal tatABCD operon, to drive its expression in E. coli strains commonly used by industry (e.g., W3110 and BL21). This modification significantly improves the Tat-dependent secretion of human growth hormone (hGH) into the bacterial periplasm, to the extent that secreted hGH is the dominant periplasmic protein after only 1 hr induction. TatExpress strains accumulate in excess of 30 mg L-1 periplasmic recombinant hGH, even in shake flask cultures. A second target protein, an scFv, is also shown to be exported at much higher rates in TatExpress strains. PMID- 28842983 TI - SUNCT in a Patient With Multiple Sclerosis: A Case Report. PMID- 28842982 TI - Novel Therapeutic Targets Against Spreading Depression. AB - Migraine is among the most prevalent and disabling neurological diseases in the world. Cortical spreading depression (SD) is an intense wave of neuronal and glial depolarization underlying migraine aura, and a headache trigger, which has been used as an experimental platform for drug screening in migraine. Here, we provide an overview of novel therapeutic targets that show promise to suppress SD, such as acid-sensing ion channels, casein kinase Idelta, P2X7-pannexin 1 complex, and neuromodulation, and outline the experimental models and essential quality measures for rigorous and reproducible efficacy testing. PMID- 28842984 TI - Desynchronization by cardiac resynchronization device related to automatic sensing test. PMID- 28842986 TI - Biosimilars: Key regulatory considerations and similarity assessment tools. AB - A biosimilar drug is defined in the US Food and Drug Administration (FDA) guidance document as a biopharmaceutical that is highly similar to an already licensed biologic product (referred to as the reference product) notwithstanding minor differences in clinically inactive components and for which there are no clinically meaningful differences in purity, potency, and safety between the two products. The development of biosimilars is a challenging, multistep process. Typically, the assessment of similarity involves comprehensive structural and functional characterization throughout the development of the biosimilar in an iterative manner and, if required by the local regulatory authority, an in vivo nonclinical evaluation, all conducted with direct comparison to the reference product. In addition, comparative clinical pharmacology studies are conducted with the reference product. The approval of biosimilars is highly regulated although varied across the globe in terms of nomenclature and the precise criteria for demonstrating similarity. Despite varied regulatory requirements, differences between the proposed biosimilar and the reference product must be supported by strong scientific evidence that these differences are not clinically meaningful. This review discusses the challenges faced by pharmaceutical companies in the development of biosimilars. PMID- 28842987 TI - Surface energy and viscoelasticity influence caramel adhesiveness. AB - : Adhesion is an important textural attribute that directs consumer eating patterns and behaviors and can be a negative attribute during food processing. The objectives of this study were to modify caramel formulation and compare adhesion to different materials to quantify the influence of surface energetics and viscoelasticity on caramel adhesiveness. Mechanical adhesion was viewed in the context of pressure sensitive tack theory, where adhesion is controlled by viscoelasticity of the adhesive material and the surface energy relationship of material and probe. Caramel samples varied in total amount of fat and protein, and mechanical adhesion was measured using a series of materials with total surface energies of 39.7-53.2 mJ/m2 . Adhesiveness decreased as fat and protein content increased, with a significant effect of total surface energy. Viscoelasticity was modeled using creep recovery data fit to a four-element Burger mechanistic model. Burger model parameters representing retarded elasticity correlated strongly with adhesiveness. The results suggest two zones of adhesion based on formulation, one driven by both surface energy relationships most notably dispersive and total surface energy-and viscoelasticity, and the other driven solely by viscoelasticity. PRACTICAL APPLICATIONS: Relationships between mechanical properties and adhesion have been explored but are still not well understood, and could aid in the design of food products with a controlled level of adhesion. The results of this study indicate the importance of considering material surface energy when measuring mechanical adhesion or texture profile analysis. Understanding the relationships between viscoelastic behavior and adhesion can be used to make inferences on perceived texture. PMID- 28842988 TI - Ultrasonographic observations of the fetal brain in the first 100 pregnant women with Zika virus infection in Trinidad and Tobago. AB - OBJECTIVE: To evaluate the fetal brain in pregnant women infected with Zika virus in a limited-resource setting. METHODS: In an observational study in Trinidad and Tobago, 100 pregnant women infected with Zika virus who were referred for fetal medicine services provided by a single clinician were enrolled from March 31 to September 2, 2016. Two-dimensional ultrasonography was undertaken. RESULTS: The women were aged 17-41 years (mean 27.5 +/- 5.7). Six cases of fetal brain abnormalities consistent with Zika infection were detected before 26 gestational weeks. The gestational period at infection and time of presentation ranged, respectively, from 7+3 to 16+0 weeks and from 23+2 to 25+5 weeks. In all cases, centiles of the biparietal diameter and head circumference decreased progressively over time to below the third centile. The skull contour appeared irregular, owing to collapse or overlap of the fetal skull bones. In four cases, brain anomalies were not obvious on the transabdominal scan but were diagnosed on the transvaginal scan. In a further two cases, brain abnormalities presented after 26 weeks of gestation. CONCLUSION: Overall, 8.0% of women infected with Zika virus had fetuses with brain abnormalities suggestive of Zika congenital syndrome. Six cases were detected before 26 weeks and two cases after 26 weeks. PMID- 28842989 TI - Consulting Dr. Google: Quality of Online Resources About Tympanostomy Tube Placement. AB - OBJECTIVE: Tympanostomy tube (TT) placement is common in children; however, family-centeredness and utility of online information used for decision making and understanding is unknown. We evaluate the quality of leading Internet resources describing TT placement. STUDY DESIGN: Cross-sectional descriptive design. METHODS: We performed a Google (Menlo Park, CA) search for terms related to TTs. We defined quality using scaled readability measures (Flesch Reading Ease and Flesch-Kincaid Grade-Level), understandability and actionability (Patient Education Materials Assessment Tool), shared decision-making centrality (Center for Medicare and Medicaid Services informed consent guidelines), and clinical practice guideline (CPG) compatibility. Three reviewers coded each measure. Fleiss kappa interrater reliability analysis was performed. RESULTS: Ten most frequently encountered websites were analyzed. One of 10 met national health literacy standards (mean 10th-grade level reading, median 9th, range 6-15th). All sites were understandable (mean understandability 81.9%, range 73%-92%). Most had low actionability scores (7 of 10, median 47%, mean 44.6%, range 0-80). Shared decision-making centrality was high (mean 5, range 4-6), but most did not list alternative treatment options. Although CPG compatibility was high (mean 3.4, range 1-4), many websites contained inconsistent recommendations about tube duration, follow-up, and water precautions. There was inter-rater agreement for understandability scoring (kappa = 0.20; P = 0.02). CONCLUSION: Internet resources about TT placement vary in quality pertaining to health literacy, principles of shared decision making, and consistency with practice guidelines. With growing emphasis on patient-/family-centered engagement in healthcare decision making, standardization of content and improved usability of educational materials for common surgical procedures in children such as tympanostomy tube placement should be a public health priority. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:496-501, 2018. PMID- 28842990 TI - Migraine Prophylaxis and Acute Treatment Patterns Among Commercially Insured Patients in the United States. AB - OBJECTIVES: To describe prophylactic and acute medication treatment patterns, including timing, medication type, and duration of use in migraine patients initiating prophylaxis. BACKGROUND: Patients with migraine can be treated with acute and prophylactic therapies. Current treatment options for migraine prophylaxis are associated with poor tolerability and low adherence and persistence. METHODS: This retrospective cohort study used the Truven Health Analytics MarketScan(r) Research Databases to identify adults in the United States with a migraine diagnosis who initiated migraine prophylactic medication (index event) between January 1, 2008, and December 31, 2011. Prescribed prophylactic medications evaluated included topiramate, beta-blockers, and tricyclic antidepressants. Patients were required to have 12 months of pre- and post-index continuous enrollment. Patient characteristics, migraine-specific prescribed prophylactic treatment patterns (including gaps in therapy, treatment switches, and additions of index medications), and prescribed acute medication utilization were assessed. RESULTS: The study population comprised 107,122 patients, with 52,275 (49%) initiating topiramate, 22,658 (21%) initiating beta blockers, and 32,189 (30%) initiating tricyclic antidepressants. Mean (SD) age was 41 (12) years and 83% were female. Persistence with migraine prophylactic medication was low; 81% of patients had gaps of >90 days in their migraine prophylaxis in the first year. The gap in therapy occurred early in treatment (mean, 95 days), and only 10% of patients restarted prophylactic therapy within that year. Switching from index medication to another prophylactic medication or adding prophylaxis was uncommon (13% and 5%, respectively). One year after initiating prophylaxis, 65% of patients were not receiving any prophylactic therapies. Most patients initiating migraine prophylaxis also utilized acute treatments (81%); opioid use was more frequent than triptan use (53% vs 48%) and was common (40%) among patients without other chronic pain conditions (eg, arthritis, fibromyalgia, and lower back pain). CONCLUSION: Patients with migraine who initiated prophylactic therapy had poor persistence with early gaps in therapy, were unlikely to switch prophylactic treatments, and most discontinued prophylaxis by the end of the first year. PMID- 28842991 TI - The amniotic fluid as a source of mesenchymal stem cells with lung-specific characteristics. AB - The amniotic fluid is a clinically accessible source of mesenchymal stem cells (AF-MSC) during gestation, which enables autologous cellular therapy for perinatal disorders. The origin of AF-MSC remains elusive: renal and neuronal progenitors have been isolated from the AF-MSC pool, yet no cells with pulmonary characteristics. We analyzed gene expression of pulmonary and renal markers of 212 clonal lines of AF-MSC isolated from amniocentesis samples. AF-MSC were cultured on dishes coated with extracellular matrix (ECM) proteins from decellularized fetal rabbit lungs. In vivo differentiation potential of AF-MSC that expressed markers suggestive of lung fate was tested by renal subcapsular injections in immunodeficient mice. Of all the isolated AF-MSC lines, 26% were positive for lung endodermal markers FOXA2 and NKX2.1 and lacked expression of renal markers (KSP). This AF-MSC subpopulation expressed other lung-specific factors, including IRX1, P63, FOXP2, LGR6, SFTC, and PDPN. Pulmonary marker expression decreased over passages when AF-MSC were cultured under conventional conditions, yet remained more stable when culturing the cells on lung ECM-coated dishes. Renal subcapsular injection of AF-MSC expressing lung-specific markers resulted in engrafted cells that were SPTB positive. These data suggest that FOXA2+/NKX2.1+/KSP- AF-MSC lines have lung characteristics which are supported by culture on lung ECM-coated dishes. PMID- 28842992 TI - Recombinant RNA Polymerase from Geobacillus sp. GHH01 as tool for rapid generation of metagenomic RNAs using in vitro technologies. AB - The exciting promises of functional metagenomics for the efficient discovery of novel biomolecules from nature are often hindered by factors associated with expression hosts. Aiming to shift functional metagenomics to a host independent innovative system, we here report on the cloning, heterologous expression, and reconstitution of an RNA polymerase (RNAP) from the thermophilic Geobacillus sp. GHH01 and in vitro transcription thereafter. The five genes coding for RNAP subunits, a house keeping sigma factor and two transcription elongation factors were cloned and over expressed as His6 -tagged and/ or tag-free proteins. Purified subunits were reconstituted into a functional polymerase through either the classical method of denaturation and subsequent renaturation or through a new resource and time efficient thermo-reconstitution method which takes advantage of the subunits' temperature stability. Additionally, all subunits were cloned into a single vector system for a co-expression and in vivo reconstitution to the RNAP core enzyme. Both the core and holoenzyme form of the RNAP exhibited a robust transcription activity and were stable up to a temperature of 55 degrees C close to their fullest activity. The Geobacillus RNAP showed a remarkable in vitro transcription profile recognizing DNA template sequences of diverse bacteria and archaea as well as metagenomic samples. Coupled with a subsequent in vitro translation step, this recombinant transcription system could allow a new, clone free, and functional metagenomic screening approach. PMID- 28842993 TI - Three-dimensional tissue-engineered skeletal muscle for laryngeal reconstruction. AB - OBJECTIVE: There is an unmet need for tissue-engineered three-dimensional (3D) muscle constructs for laryngeal reconstruction. Functional engineered muscle could be used to repair postoncologic or traumatic defects or to medialize the vocal fold in cases of paresis/paralysis. Autologous, organized, engineered muscle that has adequate bulk integrates into host tissue and restores function currently does not exist. METHODS: Primary skeletal muscle progenitor cells (MPCs) were isolated from F344 rats. Three-dimensional muscle constructs were created by encapsulating MPCs via flow alignment in a customized collagen formulation and cultured under passive tension. Muscle-specific immunohistochemistry and confocal microscopy were used to evaluate muscle tissue differentiation. After 2 weeks of culture, muscle constructs were implanted into surgically created defects in the rat larynx. Postmortem function testing and histology was performed at 1 and 3 months. RESULTS: Immunohistochemistry with confocal microscopy demonstrated well-differentiated myotubes, which were well aligned and distributed throughout the engineered construct in vitro. There was evidence of restoration of normal laryngeal function at 1 month postoperative, as indicated by safe swallow (no aspiration events), weight gain, and excellent animal survival. Postmortem specimens demonstrated functional muscle contraction on ex vivo testing, and histology confirmed integration into host tissue. CONCLUSION: This is the first study to demonstrate that functional, 3D tissue engineered skeletal muscle can be developed from primary MPCs and standardized oligomeric collagen. Collectively, these findings may have tremendous clinical implications for autologous laryngeal muscle repair and reconstruction. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:603-609, 2018. PMID- 28842994 TI - Safety and immunogenicity of the novel seasonal preservative- and adjuvant-free influenza vaccine: Blind, randomized, and placebo-controlled trial. AB - The producers of influenza vaccines are not capable today to meet the global demand for an influenza vaccine in case of pandemic, so the World Health Organization recommends to develop the own influenza vaccine production in each country. A domestic preservative- and adjuvant-free trivalent split vaccine against seasonal influenza was developed at the Research Institute for Biological Safety Problems. The paper presents the results of assessing safety and immunogenicity of the influenza split vaccine after single immunization of healthy volunteers aged 18-50 years in the course of Phase I Clinical Trials. This study was randomized, blind, and placebo-controlled. The volunteers were intramuscularly vaccinated with a dose of split vaccine or placebo. The study has shown that all local and systemic reactions had low degree of manifestation and short-term character, so there was no need in medication. Serious side effects were not observed. On day 21 post vaccination the portion of vaccinated persons with fourfold seroconversions to influenza A/H1N1pdm09 virus was 100.0%, to influenza A/H3N2 virus-95.5%, to influenza B virus-81.8%, and in placebo group this index was 0%. Seroprotection rates against influenza A/H1N1pdm09, A/H3N2 and B viruses were 95.5, 86.3, and 72.7%, respectively. Geometric mean titers (GMT) of antibodies by day 21 post vaccination reached 175.7 for influenza A/H1N1pdm09 virus, 64.2 for influenza A/H3N2 virus, and 37.6 for influenza B virus; in placebo group GMT growth was not observed. So, the seasonal influenza split vaccine is well tolerated and fits all immunogenicity criteria for human influenza vaccines. PMID- 28842995 TI - Hepatitis C virus genotypes in the Middle East and North Africa: Distribution, diversity, and patterns. AB - Our objective was to characterize the distribution, diversity and patterns of hepatitis C virus (HCV) genotypes in the Middle East and North Africa (MENA). Source of data was a database of HCV genotype studies in MENA populated using a series of systematic literature searches. Pooled mean proportions were estimated for each genotype and by country using DerSimonian-Laird random-effects meta analyses. Genotype diversity within countries was assessed using Shannon Diversity Index. Number of chronic infections by genotype and country was calculated using the pooled proportions and country-specific numbers of chronic infection. Analyses were conducted on 338 genotype studies including 82 257 genotyped individuals. Genotype 1 was dominant (>=50%) in Algeria, Iran, Morocco, Oman, Tunisia, and UAE, and was overall ubiquitous across the region. Genotype 2 was common (10-50%) in Algeria, Bahrain, Libya, and Morocco. Genotype 3 was dominant in Afghanistan and Pakistan. Genotype 4 was dominant in Egypt, Iraq, Jordan, Palestine, Qatar, Saudi Arabia, and Syria. Genotypes 5, 6, and 7 had limited or no presence across countries. Genotype diversity varied immensely throughout MENA. Weighted by population size, MENA's chronic infections were highest among genotype 3, followed by genotype 4, genotype 1, genotype 2, genotype 5, and genotype 6. Despite ubiquitous presence of genotype 1, the vast majority of chronic infections were of genotypes 3 or 4, because of the sizable epidemics in Pakistan and Egypt. Three sub-regional patterns were identified: genotype 3 pattern centered in Pakistan, genotype 4 pattern centered in Egypt, and genotype 1 pattern ubiquitous in most MENA countries. PMID- 28842996 TI - Use of pharyngeal packs in functional endoscopic sinus surgery: A randomized controlled trial. AB - OBJECTIVE: To determine if pharyngeal packs have an effect on postoperative pain and postoperative nausea and vomiting in functional endoscopic sinus surgery (FESS). STUDY DESIGN: Forty-six patients scheduled for routine endoscopic sinus surgery were recruited into this study. The patients were randomly allocated to have or to not have pharyngeal packing prior to surgery. METHODS: The placement of pharyngeal packs during FESS is controversial. Theoretically, pharyngeal packs may prevent postoperative nausea and vomiting by preventing ingestion of blood during sinus surgery. However, prior studies have not conclusively demonstrated this to be the case in FESS. Pharyngeal packs have been associated with complications including throat pain, aspiration, and death. The objective of this randomized control trial was to determine if pharyngeal packs have an effect on postoperative throat pain, nausea, and vomiting in order to determine their importance during FESS. Patients were blinded to intervention. Postoperatively, throat pain and nausea/vomiting scores were recorded. RESULTS: There was no significant difference in mean throat pain at 4 hours following surgery (P = 0.860). At 24 hours after surgery, patients without pharyngeal packing experienced more pain than those who had a throat pack placed (P = 0.002). There was no significant difference in the level of nausea at 4 hours after surgery (P = 0.315) or at 24 hours after surgery (P = 0.315). CONCLUSION: We recommend against the routine use of placing pharyngeal packs during FESS. LEVEL OF EVIDENCE: 1b. Laryngoscope, 127:2460-2465, 2017. PMID- 28842997 TI - Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir. AB - Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks. PMID- 28842998 TI - Postoperative IPTH compared with IPTH gradient as predictors of post thyroidectomy hypocalcemia. AB - OBJECTIVES/HYPOTHESIS: Predicting patients' risk for hypocalcemia after thyroidectomy may allow for same-day discharge. This study was designed to compare postoperative intact parathyroid hormone (IPTH) alone with percentage change in IPTH (IPTH gradient) in predicting post-thyroidectomy hypocalcemia. STUDY DESIGN: Retrospective cohort study. METHODS: Patients undergoing total thyroidectomy by the senior author from May 2015 to May 2016 were included. Serum IPTH was measured preoperatively and 1 hour postoperatively, and IPTH gradient was calculated. Postoperative hypocalcemia was mild (>=8.0, <8.4) or severe (<8.0 and/or hypocalcemic symptoms). Postoperative IPTH and IPTH gradient were compared with hypocalcemia using logistic regression. Receiver operating characteristic analysis of IPTH measures as predictors of hypocalcemia was performed, and the area under the curve (AUC) was calculated. RESULTS: Overall, 119 patients were included. Forty-seven percent of the patients developed postoperative hypocalcemia, including 26 (22%) with mild and 30 (25%) with severe hypocalcemia. Thirteen patients had hypocalcemic symptoms. Median IPTH gradient and postoperative IPTH each differed significantly by category of hypocalcemia (P < .001). Higher IPTH gradient was significantly associated with odds of severe and symptomatic hypocalcemia (adjusted odds ratio [aOR]: 1.21, 95% confidence interval [CI]: 1.06-1.39 and aOR: 1.34, 95% CI: 1.05-1.71 per 10% increase), whereas lower postoperative IPTH was not (aOR: 1.27, 95% CI: 0.95-1.68 and aOR: 1.44, 95% CI: 0.90-2.31 per 10 pg/mL decrease). The AUC for predicting severe hypocalcemia was nonsignificantly higher for IPTH gradient than postoperative IPTH (AUC = 0.77 vs. 0.69, P = .10). The AUC for predicting symptomatic hypocalcemia was significantly higher for IPTH gradient (AUC = 0.75 vs. 0.72, P = .03). CONCLUSIONS: Our results suggest that the IPTH gradient may be more useful than postoperative IPTH alone in predicting risk of post-thyroidectomy hypocalcemia. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:769-774, 2018. PMID- 28842999 TI - Rethinking the laryngopharyngeal reflux treatment algorithm: Evaluating an alternate empiric dosing regimen and considering up-front, pH-impedance, and manometry testing to minimize cost in treating suspect laryngopharyngeal reflux disease. AB - OBJECTIVES/HYPOTHESIS: Empiric proton pump inhibitor (PPI) trials for laryngopharyngeal reflux (LPR) are common. A majority of the patients respond to acid suppression. This work intends to evaluate once-daily, 40 mg omeprazole and once-nightly, 300 mg ranitidine (QD/QHS) dosing as an alternative regimen, and use this study's cohort to evaluate empiric regimens prescribed for LPR as compared to up-front testing with pH impedance multichannel intraluminal impedance (MII) with dual pH probes and high-resolution manometry (HRM) for potential cost minimization. STUDY DESIGN: Retrospective cohort review and cost minimization study. METHODS: A chart review identified patients diagnosed with LPR. All subjects were treated sequentially and outcomes recorded. Initial QD/QHS dosing increased after 3 months to BID if no improvement and ultimately prescribed MII and HRM if they failed BID dosing. Decision tree diagrams were constructed to determine costs of two empiric regimens and up-front MII and HRM. RESULTS: Ninety-seven subjects met the criteria. Responders and nonresponders to empiric therapy were identified. Seventy-two subjects (74%) responded. Forty eight (67% of responders and 49% of all) improved with QD/QHS dosing. Forty-nine (51%) subjects escalated to BID dosing. Twenty-four subjects (33% of responders and 25% of all) improved on BID therapy. Twenty-five subjects (26%) did not respond to acid suppression. Average weighted cost was $1,897.00 per patient for up-front testing, $3,033.00 for initial BID, and $3,366.00 for initial QD/QHS. CONCLUSIONS: An alternate QD/QHS regimen improved the majority who presented with presumed LPR. Cost estimates demonstrate that the QD/QHS regimen was more expensive than the initial BID high-dose PPI for 6 months. Overall per-patient cost appears less with up-front MII and HRM. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:S1-S13, 2017. PMID- 28843000 TI - Cascading effect in bioprocessing-The impact of mild hypothermia on CHO cell behavior and host cell protein composition. AB - A major challenge in downstream purification of monoclonal antibodies (mAb) is the removal of host cell proteins (HCPs). Previous studies have shown that cell culture conditions significantly impact the HCP content at harvest. However, it is currently unclear how process conditions affect physiological changes in the host cell population, and how these changes, in turn, cascade down to change the HCP profile. We examined how temperature downshift (TDS) to mild hypothermia affects key upstream performance indicators, that is antibody titre, HCP concentration and HCP species, across the cell culture decline phase and at harvest through the lens of changes in cellular behavior. Mild hypothermic conditions introduced on day 5 of fed-batch Chinese hamster ovary (CHO) cell bioreactors resulted in a lower cell proliferation rate but larger percentages of healthier cells across the cell culture decline phase compared to bioreactors maintained at standard physiological temperature. Moreover, the onset of apoptosis was less evident in mild hypothermic cultures. Consequently, mild hypothermic cultures took an extra 5 days to reach an integral viable cell concentration (IVCC) and antibody yield similar to that of the control at standard physiological temperature. When cell viability dropped below 80%, mild hypothermic cell cultures had a reduced variety of HCP species by 36%, including approximately 44% and 27% lower proteases and chaperones, respectively, despite having similar HCP concentration. This study suggests that TDS may be a good strategy to provide cleaner downstream feedstocks by reducing the variety of HCPs and to maintain product integrity by reducing the number of proteases and chaperones. PMID- 28843001 TI - Cell-free production of a therapeutic protein: Expression, purification, and characterization of recombinant streptokinase using a CHO lysate. AB - The use of cell-free systems to produce recombinant proteins has grown rapidly over the past decade. In particular, cell-free protein synthesis (CFPS) systems based on mammalian cells provide alternative methods for the production of many proteins, including those that contain disulfide bonds, glycosylation, and complex structures such as monoclonal antibodies. In the present study, we show robust production of turbo green fluorescent protein (tGFP) and streptokinase in a cell-free system using instrumented mini-bioreactors for highly reproducible protein production. We achieved recombinant protein production (~600 MUg/ml of tGFP and 500 MUg/ml streptokinase) in 2.5 hr of expression time, comparable to previously reported yields for cell-free protein expression. Also, we demonstrate the use of two different affinity tags for product capture and compare those to a tag-free self-cleaving intein capture technology. The intein purification method provided a product recovery of 86%, compared with 52% for conventionally tagged proteins, while resulting in a 30% increase in total units of activity of purified recombinant streptokinase compared with conventionally tagged proteins. These promising beneficial features combined with the intein technology makes feasible the development of dose-level production of therapeutic proteins at the point-of-care. PMID- 28843002 TI - HCV avidity as a tool for detection of recent HCV infection: Sensitivity depends on HCV genotype. AB - Accurate detection of incident hepatitis C virus (HCV) infection is required to target and evaluate public health interventions, but acute infection is largely asymptomatic and difficult to detect using traditional methods. Our aim was to evaluate a previously developed HCV avidity assay to distinguish acute from chronic HCV infection. Plasma samples collected from recent seroconversion subjects in two large Australian cohorts were tested using the avidity assay, and the avidity index (AI) was calculated. Demographic and clinical characteristics of patients with low/high AI were compared via logistic regression. Sensitivity and specificity of the assay for recent infection and the mean duration of recent infection (MDRI) were estimated stratified by HCV genotype. Avidity was assessed in 567 samples (from 215 participants), including 304 with viraemia (defined as >=250 IU/mL). An inverse relationship between AI and infection duration was found in viraemic samples only. The adjusted odds of a low AI (<30%) decreased with infection duration (odds ratio [OR] per week of 0.93; 95% CI:0.89-0.97), and were lower for G1 compared with G3 samples (OR = 0.14; 95% CI:0.05-0.39). Defining recent infection as <26 weeks, sensitivity (at AI cut-off of 20%) was estimated at 48% (95% CI:39-56%), 36% (95% CI:20-52%), and 65% (95% CI:54-75%) and MDRI was 116, 83, and 152 days for all genotypes, G1, and G3, respectively. Specificity (>=52 weeks infection duration, all genotypes) was 96% (95% CI:90-98%). HCV avidity testing has utility for detecting recent HCV infection in patients, and for assessing progress in reaching incidence targets for eliminating transmission, but variation in assay performance across genotype should be recognized. PMID- 28843003 TI - Effect of TLR10 (2322A/G, 720A/C, and 992T/A) polymorphisms on the pathogenesis of Crimean Congo hemorrhagic fever disease. AB - Crimean Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the Crimean Congo hemorrhagic fever virus (CCHFV). Toll-like receptors (TLRs) are type 1 transmembrane proteins of immune cells that play a critical role in innate and adaptive immunity. The present study first time aims to investigate the relation between TLR10 gene polymorphisms (720A/C, 992T/A, and 2322A/G), severity/non-severity, fatality/non-fatality, and CCFH disease by using PCR-RFLP assay in a Turkish population. TLR10 720A/C polymorphism was determined to be statistically significant both genotype and allele frequency (P = 0,011, P = 0.015, respectively). TLR10 992T/A polymorphism was found statistically significant relationships between patient and control (P = 0.026) and individual with AA genotype have approximately three times greater risk than TT genotype (OR = 2.93). There was not a significant difference in 2322A/G genotype distribution (P = 0.152). There were also statistically significant associations between both TLR10 992T/A and 2322A/G polymorphism and patient mortality (P = 0.001 and P = 0.008, respectively). We have not found statistically any linkage among TLR10 haplotype, but individual AAA and GAT haplotype have higher risk than individual AAT haplotype (OR = 3.22, OR = 1.93, respectively). Consequently, this study shows that pathogenesis of CCHF disease is associated with the TLR10 720A/C and 992T/A polymorphisms. There is a statistically significant association in fatal/non-fatal patients with TLR10 720A/C and 992T/A. The TLR10 992AA genotype might increase and TLR10 720CC genotype might decrease susceptibility to pathogenesis of CCHF disease. TLR 10 polymorphisms may be also an important biomarker for CCHF susceptibility and fatality rate. PMID- 28843004 TI - Single nucleotide polymorphisms rs911160 in AURKA and rs2289590 in AURKB mitotic checkpoint genes contribute to gastric cancer susceptibility. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) in mitotic checkpoint genes could confer increased susceptibility to gastric cancer (GC). We investigated the association of Aurora kinase A (AURKA), Aurora kinase B (AURKB), Aurora kinase C (AURKC), Polo-like kinase 1 (PLK1) and Budding uninhibited by benzimidazol 3, yeast (BUB3) gene polymorphisms with GC risk. MATERIALS AND METHODS: Genotyping of 6 SNPs in AURKA (rs911160 and rs8173), AURKB (rs2289590), AURKC (rs11084490), PLK1 (rs42873), and BUB3 (rs7897156) was performed using TaqMan genotyping assays. RESULTS: Our study demonstrated that rs911160 (AURKA) heterozygous genotype was associated with an increased GC risk (OR = 1.50, 95% CI = 1.01-2.22, P = 0.043). Analysis of rs911160 (AURKA) showed significant association with an increased risk for intestinal type GC (OR = 1.80, 95%CI = 1.01-3.21, P = 0.040) and the risk was significantly higher in women than men (OR = 2.65, 95%CI = 1.02 6.87, P = 0.033). SNP rs2289590 in AURKB might contribute to susceptibility for the development of gastric cancer, particularly in women (OR = 2.08, 95% CI = 1.05-4.09, P = 0.032). CONCLUSION: Our findings suggested that AURKA (rs911160) and AURKB (rs2289590) polymorphisms could affect GC risk. Further validation studies in larger and multi-ethnical populations are needed to elucidate their functional impact on the development of GC. Environ. Mol. Mutagen. 58:701-711, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28843005 TI - Reconstruction of midface defects with the osteocutaneous radial forearm flap: Evaluation of long term outcomes including patient reported quality of life. AB - BACKGROUND: Maxillectomy defects significantly impair quality of life. Prosthetics can overcome some of these issues, but has limitations. The role of the osteocutaneous radial forearm free flap (OC-RFFF) has been established for reconstruction of smaller maxillectomy defects, but its role in larger defects is not well defined. We aim to evaluate outcomes after midface reconstruction utilizing the OC-RFFF. METHODS: Retrospective review of prospective database collected between 2005 and 2014 of midface reconstruction using OC-RFFF in a tertiary care centre. Donor site complications and acute and long-term recipient site complications were measured. Health related quality of life was assessed using the University of Washington Quality of Life (UW-QOL) Questionnaire. RESULTS: A total of 68 midface defects were reconstructed using the OC-RFFF. Acute recipient site complications included three flap failures (4%), and two additional microvascular revision cases for vascular compromise. Late recipient complications included fistula (n = 10, 14%), ectropion (n = 7, 10%), diplopia (n = 6, 9%) and exposed hardware (n = 5, 7%). Resection of cheek skin or orbital rim correlated with orbital complications. The incidence of fistula was not affected by defect size or prior radiation. There were two donor site infections and no instances of forearm fracture. Patients undergoing OC-RFFF repair had mean scores for UW-QOL outcomes higher than published rates of obturator quality of life. CONCLUSION: The OC-RFFF is suited to a variety of midface defects and can be combined with hardware to reconstruct the orbital floor. Recipient site complications are common, but donor site morbidity is low and outcomes, including HR-QOL, are acceptable. PMID- 28843006 TI - Interaction between optineurin and Rab1a regulates autophagosome formation in neuroblastoma cells. AB - Optineurin (OPTN) is an autophagy receptor protein that has been implicated in glaucoma and amyotrophic lateral sclerosis. OPTN-mediated autophagy is a complex process involving many autophagy-regulating proteins. Autophagy plays a critical role in removing damaged organelles, intracellular pathogens, and protein aggregates to maintain cellular homeostasis. We identified Ypt1 as a novel interaction partner of OPTN by performing a large-scale yeast-human two-hybrid assay. Coimmunoprecipitation assay showed that OPTN interacted with Rab1, the mammalian homolog of yeast Ypt1, in N2a mouse neuroblastoma cell line. We confirmed this interaction by confocal microscopy showing intracellular colocalization of the two proteins. We observed that a zinc finger domain of OPTN is important for Rab1a binding. Rab1a activity is also required for the binding with OPTN. The role of the OPTN-Rab1a complex in neuronal autophagy was determined by measuring the translocation of microtubule-associated protein light chain 3-EGFP to autophagosomes. In N2a cells, OPTN-induced autophagosome formation was inhibited by Rab1a knockdown, indicating the important role of OPTN Rab1a interaction in neuronal autophagy processes. Similarly, in N2a cells overexpressing Rab1a, serum starvation-induced formation of autophagosome was enhanced, while OPTN knockdown reduced the Rab1a-induced autophagy. These results show that the OPTN-Rab1a complex modulates autophagosome formation in neuroblastoma cells. PMID- 28843007 TI - Bcl-2 protects TK6 cells against hydroquinone-induced apoptosis through PARP-1 cytoplasm translocation and stabilizing mitochondrial membrane potential. AB - B cell leukemia/lymphoma-2 (Bcl-2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl-2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)-induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration-dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker gamma-H2AX, and production of the DNA damage-responsive enzyme poly(ADP-ribose)polymerase-1 (PARP-1). Exposure of TK6 cells to HQ leads to an increase in Bcl-2 and co-localization with PARP-1 in the cytoplasm. Inhibition of Bcl-2 using the BH3 mimetic, ABT-737, suppressed the PARP-1 nuclear to cytoplasm translocation and sensitized TK6 cells to HQ-induced apoptosis through depolarization of the MMP. Western blot analysis indicated that ABT-737 combined with HQ increased the levels of cleaved PARP and gamma-H2AX, but significantly decreased the level of P53. Thus, ABT-737 can influence PARP-1 translocation and induce apoptosis via mitochondria-mediated apoptotic pathway, independently of P53. In addition, we found that knockdown of PARP-1 attenuated the HQ-induced production of cleaved PARP and P53. These results identify Bcl-2 as a protective mediator of HQ-induced apoptosis and show that upregulation of Bcl-2 helps to localize PARP-1 to the cytoplasm and stabilize MMP. Environ. Mol. Mutagen. 59:49-59, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28843008 TI - Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABAA R alpha1/GABAA R alpha2 ratio. AB - Exposure of neonatal rat to sevoflurane leads to neurodegeneration and deficits of spatial learning and memory in adulthood. However, the underlying mechanisms remain unclear. The type A gamma-aminobutyric acid receptor (GABAA R) is a target receptor for sevoflurane. The present study intends to investigate the changes in GABAA R alpha1/alpha2 expression and its relationship with the neurotoxicity effect due to sevoflurane in neonatal rats. After a dose-response curve was constructed to determine minimum alveolar concentration (MAC) and safety was guaranteed in our 7-day-old neonatal rat pup mode, we conducted two studies among the following groups: (A) the control group; (B) the sham anesthesia group; and (C) the sevoflurane anesthesia group and all three groups were treated in the same way as the model. First, poly(ADP-ribose) polymerase-1 protein (PARP-1) expression was determined in the different brain areas at 6 hr after anesthesia. Second, the expression of PARP-1 and GABAA R alpha1/GABAA R alpha2 in the hippocampus area was tested by Western blotting at 6 hr, 24 hr, and 72 hr after anesthesia in all three groups. After 4 hr, with 0.8 MAC (2.1%) sevoflurane anesthesia, the PARP-1 expression was significantly higher in the hippocampus than the other brain areas (p < .05). Compared with Groups A and B, the expression of PARP-1 in the hippocampus of Group C significantly increased at 6 hr after sevoflurane exposure (216% +/- 15%, p < .05), and the ratio of the alpha1/alpha2 subunit of GABAA R surged at 6 hr (126% +/- 6%), 24 hr (127% +/- 8%), and 72 hr (183% +/- 22%) after sevoflurane exposure in the hippocampus (p < .05). Our study showed that sevoflurane exposure of 0.8 MAC (2.1%)/4 hr was a suitable model for 7-day-old rats. And the exposure to sevoflurane could induce the apoptosis of neurons in the early stage, which may be related to the transmission from GABAA R alpha2 to GABAA R alpha1. PMID- 28843009 TI - Directional DBS increases side-effect thresholds-A prospective, double-blind trial. AB - OBJECTIVE: The objective of this study was to investigate whether directional deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease (PD) offers increased therapeutic windows, side-effect thresholds, and clinical benefit. METHODS: In 10 patients, 20 monopolar reviews were conducted in a prospective, randomized, double-blind design to identify the best stimulation directions and compare them to conventional circular DBS regarding side-effect thresholds, motor improvement, and therapeutic window. In addition, circular and best-directional DBS were directly compared in a short-term crossover. Motor outcome was also assessed after an open-label follow-up of 3 to 6 months. RESULTS: Stimulation in the individual best direction resulted in significantly larger therapeutic windows, higher side-effect thresholds, and more improvement in hand rotation than circular DBS. Rigidity and finger tapping did not respond differentially to the stimulation conditions. There was no difference in motor efficacy or stimulation amplitudes between directional and circular DBS in the short-term crossover. Follow-up evaluations 3 to 6 months after implantation revealed improvements in motor outcome and medication reduction comparable to other DBS studies with a majority of patients remaining with a directional setting. CONCLUSION: Directional DBS can increase side-effect thresholds while achieving clinical benefit comparable to conventional DBS. Whether directional DBS improves long-term clinical outcome needs to be investigated in the future. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28843010 TI - Telomerase activity, telomere length and hTERT DNA methylation in peripheral blood mononuclear cells from monozygotic twins with discordant smoking habits. AB - Increased telomerase expression has been implicated in the pathogenesis of lung cancer and, since the primary cause of lung cancer is smoking, an association between telomerase reactivation and tobacco smoke has been proposed. In this work an investigation has been performed to assess the relationship between tobacco smoke exposure and telomerase activity (TA) in peripheral blood mononuclear cells of healthy smokers. The methylation status of the catalytic subunit of telomerase hTERT was concurrently investigated to assess the possible association between epigenetic modifications of hTERT and TA. Besides, the association between smoke and telomere length (TL) has been evaluated. Healthy monozygotic twins with discordant smoking habits were selected as study population to minimize inter individual differences because of demographic characteristics and genetic heterogeneity. Statistically significant higher values of TA and TL were observed in smokers compared to nonsmoker co-twins. The multivariate analysis of data showed, besides smoking habits (P = 0.02), an influence of gender (P = 0.006) and BMI (P = 0.001) on TA and a borderline effect of gender (P = 0.05) on TL. DNA methylation analysis, focused on 100 CpG sites mapping in hTERT, highlighted nine CpG sites differentially methylated in smokers. When co-twins were contrasted, selecting as variables the intra-twin difference in TA and hTERT DNA methylation, a statistically significant inverse correlation (P = 0.003) was observed between TA and DNA methylation at the cg05521538 site. In conclusion, these results indicate an association of tobacco smoke with TA and TL and suggest a possible association between smoke-induced epigenetic effects and TA in healthy smokers. Environ. Mol. Mutagen. 58:551-559, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28843011 TI - The bipedicled medial plantar flap: Vascular enhancement of a reverse flow Y-V medial plantar flap by the inclusion of a metatarsal artery perforator for the reconstruction of a forefoot defect-A case report. AB - The pedicled medial plantar (MP) flap is an optimal solution for defects involving the weight-bearing areas of the foot. However, venous congestion is a frequently encountered complication, especially with the reverse-flow variants of the flap, and several strategies have been reported in literature both to prevent and to manage it. In this article, we present the use of a medial plantar flap based distally on the lateral plantar artery with the adjunct of an extra metatarsal perforator from the dorsalis pedis artery as a vascular enhancement to avoid the venous congestion and to improve the overall circulation. This bipedicled flap was successfully advanced to cover a 5 * 3 cm soft-tissue defect located at the level of the first and second metatarsal heads of the right foot resulting from the excision of a squamous cell carcinoma in an 80-year-old male patient with a history of cardiovascular disease. The postoperative course was uneventful. The patient was discharged 7 days after the operation and was able to walk after 6 weeks wearing normal shoes. We believe that preserving plantar metatarsal perforators during the harvesting of an MP flap based distally on the lateral plantar artery may be a precious adjunct as it increases blood supply, especially the venous drainage of the flap. PMID- 28843012 TI - The main beam correction term in kinetic energy release from metastable peaks. AB - The correction term for the precursor ion signal width in determination of kinetic energy release is reviewed, and the correction term is formally derived. The derived correction term differs from the traditionally applied term. An experimental finding substantiates the inaccuracy in the latter. The application of the "T-value" to study kinetic energy release is found preferable to kinetic energy release distributions when the metastable peaks are slim and simple Gaussians. For electronically predissociated systems, a "borderline zero" kinetic energy release can be directly interpreted in reaction dynamics with strong curvature in the reaction coordinate. PMID- 28843014 TI - How does parkinson's disease begin? Perspectives on neuroanatomical pathways, prions, and histology. AB - Parkinson's disease (PD) is a multisystem disorder with involvement of the peripheral nervous system. Misfolding and aggregation of alpha-synuclein is central to the pathogenesis of PD, and it has been postulated that the disease may originate in olfactory and gastrointestinal nerve terminals. The prion-like behavior of alpha-synuclein has been convincingly demonstrated in vitro and in animal models of PD. Lewy-type pathology have been detected in peripheral organs many years prior to PD diagnosis, and 2 independent studies have now suggested that truncal vagotomy may be protective against the disorder. Other lines of evidence are difficult to reconcile with a peripheral onset of PD, most importantly the relative scarcity of post mortem cases with isolated gastrointestinal alpha-synuclein pathology without concomitant CNS pathology. This Scientific Perspectives article revisits some important topics with implications for the dual-hit hypothesis. An account of the neuroanatomical pathways necessary for stereotypical alpha-synuclein spreading is presented. Parallels to the existing knowledge on true prion disorders, including Creutzfeld Jakob disease, are examined. Finally, the vagotomy studies and the somewhat inconsistent findings in the growing literature on peripheral alpha-synuclein pathology are discussed. It is concluded that the dual-hit hypothesis remains a potential explanation for PD pathogenesis, but several issues need to be resolved before more firm conclusions can be drawn. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28843013 TI - It's not just the basal ganglia: Cerebellum as a target for dystonia therapeutics. AB - Dystonia is a common movement disorder that devastates the lives of many patients, but the etiology of this disorder remains poorly understood. Dystonia has traditionally been considered a disorder of the basal ganglia. However, growing evidence suggests that the cerebellum may be involved in certain types of dystonia, raising several questions. Can different types of dystonia be classified as either a basal ganglia disorder or a cerebellar disorder? Is dystonia a network disorder that involves the cerebellum and basal ganglia? If dystonia is a network disorder, how can we target treatments to alleviate symptoms in patients? A recent study by Chen et al, using the pharmacological mouse model of rapid-onset dystonia parkinsonism, has provided some insight into these important questions. They showed that the cerebellum can directly modulate basal ganglia activity through a short latency cerebello-thalamo-basal ganglia pathway. Further, this article and others have provided evidence that in some cases, aberrant cerebello-basal ganglia communication can be involved in dystonia. In this review we examine the evidence for the involvement of the cerebellum and cerebello-basal ganglia interactions in dystonia. We conclude that there is ample evidence to suggest that the cerebellum plays a role in some dystonias, including the early-onset primary torsion dystonia DYT1 and that further studies examining the role of this brain region and its interaction with the basal ganglia in dystonia are warranted. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28843015 TI - Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in parkinson's disease patients. AB - BACKGROUND: Reduced beta-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's disease patients, suggesting that lower beta-glucocerebrosidase activity is a key feature in the pathogenesis of PD. The objectives of this study were to confirm whether there is reduced beta-glucocerebrosidase activity in the CSF of GBA1 mutation carrier and noncarrier PD patients and verify if other lysosomal enzymes show altered activity in the CSF. METHODS: CSF beta-glucocerebrosidase, cathepsin D, and beta hexosaminidase activities were measured in 79 PD and 61 healthy controls from the BioFIND cohort. The whole GBA1 gene was sequenced. RESULTS: Enzyme activities were normalized according to CSF protein content (specific activity). beta glucocerebrosidase specific activity was significantly decreased in PD versus controls (-28%, P < 0.001). GBA1 mutations were found in 10 of 79 PD patients (12.7%) and 3 of 61 controls (4.9%). GBA1 mutation carrier PD patients showed significantly lower beta-glucocerebrosidase specific activity versus noncarriers. beta-glucocerebrosidase specific activity was also decreased in noncarrier PD patients versus controls (-25%, P < 0.001). Cathepsin D specific activity was lower in PD versus controls (-21%, P < 0.001). beta-Hexosaminidase showed a similar trend. beta-Glucocerebrosidase specific activity fairly discriminated PD from controls (area under the curve, 0.72; sensitivity, 0.67; specificity, 0.77). A combination of beta-glucocerebrosidase, cathepsin D, and beta-hexosaminidase improved diagnostic accuracy (area under the curve, 0.77; sensitivity, 0.71; specificity, 0.85). Lower beta-glucocerebrosidase and beta-hexosaminidase specific activities were associated with worse cognitive performance. CONCLUSIONS: CSF beta-glucocerebrosidase activity is reduced in PD patients independent of their GBA1 mutation carrier status. Cathepsin D and beta hexosaminidase were also decreased. The possible link between altered CSF lysosomal enzyme activities and cognitive decline deserves further investigation. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28843016 TI - Directional leads for deep brain stimulation: Opportunities and challenges. PMID- 28843017 TI - Motor hyperactivity of the iron-deficient rat - an animal model of restless legs syndrome. AB - BACKGROUND: Abnormal striatal dopamine transmission has been hypothesized to cause restless legs syndrome. Dopaminergic drugs are commonly used to treat restless legs syndrome. However, they cause adverse effects with long-term use. An animal model would allow the systematic testing of potential therapeutic drugs. A high prevalence of restless legs syndrome has been reported in iron deficient anemic patients. We hypothesized that the iron-deficient animal would exhibit signs similar to those in restless legs syndrome patients. METHODS: After baseline polysomnographic recordings, iron-deficient rats received pramipexole injection. Then, iron-deficient rats were fed a standard rodent diet, and polysomnographic recording were performed for 2 days each week for 4 weeks. RESULTS: Iron-deficient rats have low hematocrit levels and show signs of restless legs syndrome: sleep fragmentation and periodic leg movements in wake and in slow-wave sleep. Iron-deficient rats had a positive response to pramipexole treatment. After the iron-deficient rats were fed the standard rodent diet, hematocrit returned to normal levels, and sleep quality improved, with increased average duration of wake and slow-wave sleep episodes. Periodic leg movements decreased during both waking and sleep. Hematocrit levels positively correlated with the average duration of episodes in wake and in slow-wave sleep and negatively correlated with periodic leg movements in wake and in sleep. Western blot analysis showed that striatal dopamine transporter levels were higher in iron-deficient rats. CONCLUSIONS: The iron-deficient rat is a useful animal model of iron-deficient anemic restless legs syndrome. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28843018 TI - Browning in apples: Exploring the biochemical basis of an easily-observable phenotype. AB - Many fruits and vegetables undergo browning when they are cut and the tissue is exposed to the air. This is due to the activity of the enzyme polyphenol oxidase (PPO, EC 1.14.18.1) with endogenous substrates. In this laboratory experiment, students prepare slices of different varieties of apples and assess the rate of browning. They make a simple extract of the apple tissue and measure the activity of PPO using 3,4-dihydroxy-l-phenylalanine (l-DOPA) as substrate. They determine the protein concentration of the extract with the Bradford Coomassie Blue reagent and calculate the specific activity of PPO. Finally, the students measure the total concentration of the potential substrates for PPO with the Folin-Ciocalteau phenol reagent using a gallic acid standard curve. By comparing the tendency of the apples to turn brown, the specific activity of PPO, and the concentration of potential substrates, they can assess the biochemical basis of the browning phenotype. This experiment can be done as a series of weekly laboratory exercises, as an intensive 1-week laboratory project, or as the basis of an extended student research investigation. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):76-82, 2018. PMID- 28843019 TI - Brain calcification in a CSF1R mutation carrier precedes white matter degeneration. PMID- 28843020 TI - Clinicopathologic discrepancies in a population-based incidence study of parkinsonism in olmsted county: 1991-2010. AB - OBJECTIVE: The purpose of this study was to examine the discrepancies between the clinical diagnosis of parkinsonism and neuropathological findings in a population based cohort with parkinsonian disorders. BACKGROUND: The specific clinical diagnosis of parkinsonism is challenging, and definite confirmation requires neuropathological evaluation. Currently, autopsies are seldom performed, and most brain autopsies represent atypical or diagnostically unresolved cases. METHODS: We used a defined population-based incidence cohort with clinical parkinsonism (n = 669) from the Rochester Epidemiology Project in Olmsted County, Minnesota, 1991 2010. We reviewed reports of all patients who underwent neuropathologic examination at autopsy (n = 60; 9%) and applied consensus pathologic guidelines for neurodegenerative disease diagnosis. RESULTS: Among the 60 patients examined pathologically, the median time from the last recorded clinical diagnosis to death was 7 years (range from 2 to 17 years). Clinical-pathological concordance was found in 52 cases (86.7%), whereas 8 (13.3%) had a clinical-pathological discrepancy. Four patients with a clinical diagnosis of idiopathic Parkinson's disease had no pathological evidence of Lewy bodies or alpha-synucleinopathy; of these, pathological diagnoses were Alzheimer's disease (2 cases), progressive supranuclear palsy (1 case), and vascular parkinsonism (1 case). Two patients with clinical diagnoses of "dementia with Lewy bodies" and one patient with an "unspecified parkinsonism" had a pathological diagnosis of Alzheimer's disease without concomitant alpha-synuclein lesions. One patient with clinically diagnosed "progressive supranuclear palsy" had indeterminate pathological findings without alpha-synuclein or Abeta- or tau-immunoreactive lesions at autopsy. CONCLUSIONS: Overall, the clinical diagnoses of parkinsonian subtypes had good concordance with pathological confirmation (86.7%). However, clinical pathological discrepancies were documented in 13.3%. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28843021 TI - The nasal and gut microbiome in Parkinson's disease and idiopathic rapid eye movement sleep behavior disorder. AB - BACKGROUND: Increasing evidence connects the gut microbiota and the onset and/or phenotype of Parkinson's disease (PD). Differences in the abundances of specific bacterial taxa have been reported in PD patients. It is, however, unknown whether these differences can be observed in individuals at high risk, for example, with idiopathic rapid eye movement sleep behavior disorder, a prodromal condition of alpha-synuclein aggregation disorders including PD. OBJECTIVES: To compare microbiota in carefully preserved nasal wash and stool samples of subjects with idiopathic rapid eye movement sleep behavior disorder, manifest PD, and healthy individuals. METHODS: Microbiota of flash-frozen stool and nasal wash samples from 76 PD patients, 21 idiopathic rapid eye movement sleep behavior disorder patients, and 78 healthy controls were assessed by 16S and 18S ribosomal RNA amplicon sequencing. Seventy variables, related to demographics, clinical parameters including nonmotor symptoms, and sample processing, were analyzed in relation to microbiome variability and controlled differential analyses were performed. RESULTS: Differentially abundant gut microbes, such as Akkermansia, were observed in PD, but no strong differences in nasal microbiota. Eighty percent of the differential gut microbes in PD versus healthy controls showed similar trends in idiopathic rapid eye movement sleep behavior disorder, for example, Anaerotruncus and several Bacteroides spp., and correlated with nonmotor symptoms. Metagenomic sequencing of select samples enabled the reconstruction of genomes of so far uncharacterized differentially abundant organisms. CONCLUSION: Our study reveals differential abundances of gut microbial taxa in PD and its prodrome idiopathic rapid eye movement sleep behavior disorder in comparison to the healthy controls, and highlights the potential of metagenomics to identify and characterize microbial taxa, which are enriched or depleted in PD and/or idiopathic rapid eye movement sleep behavior disorder. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28843022 TI - Distinct metabolomic signature in cerebrospinal fluid in early parkinson's disease. AB - OBJECTIVE: The purpose of this study was to profile cerebrospinal fluid (CSF) from early-stage PD patients for disease-related metabolic changes and to determine a robust biomarker signature for early-stage PD diagnosis. METHODS: By applying a non-targeted and mass spectrometry-driven approach, we investigated the CSF metabolome of 44 early-stage sporadic PD patients yet without treatment (DeNoPa cohort). We compared all detected metabolite levels with those measured in CSF of 43 age- and gender-matched healthy controls. After this analysis, we validated the results in an independent PD study cohort (Tubingen cohort). RESULTS: We identified that dehydroascorbic acid levels were significantly lower and fructose, mannose, and threonic acid levels were significantly higher (P < .05) in PD patients when compared with healthy controls. These changes reflect pathological oxidative stress responses, as well as protein glycation/glycosylation reactions in PD. Using a machine learning approach based on logistic regression, we successfully predicted the origin (PD patients vs healthy controls) in a second (n = 18) as well as in a third and completely independent validation set (n = 36). The biomarker signature is composed of the three markers-mannose, threonic acid, and fructose-and allows for sample classification with a sensitivity of 0.790 and a specificity of 0.800. CONCLUSION: We identified PD-specific metabolic changes in CSF that were associated with antioxidative stress response, glycation, and inflammation. Our results disentangle the complexity of the CSF metabolome to unravel metabolome changes related to early-stage PD. The detected biomarkers help understanding PD pathogenesis and can be applied as biomarkers to increase clinical diagnosis accuracy and patient care in early-stage PD. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28843023 TI - Physiological and Metabolomic Analysis of Issatchenkia orientalis MTY1 With Multiple Tolerance for Cellulosic Bioethanol Production. AB - Yeast with multiple tolerance onto harsh conditions has a number of advantages for bioethanol production. In this study, an alcohol yeast of Issatchenkia orientalis MTY1 is isolated in a Korean winery and its multiple tolerance against high temperature and acidic conditions is characterized in microaerobic batch cultures and by metabolomic analysis. In a series of batch cultures using 100 g L 1 glucose, I. orientalis MTY1 possesses wider growth ranges at pH 2-8 and 30-45 degrees C than a conventional yeast of Saccharomyces cerevisiae D452-2. Moreover, I. orientalis MTY1 showes higher cell growth and ethanol productivity in the presence of acetic acid or furfural than S. cerevisiae D452-2. I. orientalis MTY1 produces 41.4 g L-1 ethanol with 1.5 g L-1 h-1 productivity at 42 degrees C and pH 4.2 in the presence of 4 g L-1 acetic acid, whereas a thermo-tolerant yeast of Kluyvermyces marxianus ATCC36907 does not grow. By metabolomics by GC-TOF MS and statistical analysis of 125 metabolite peaks, it is revealed that the thermo tolerance of I. orientalis MTY1 might be ascribed to higher contents of unsaturated fatty acids, purines and pyrimidines than S. cerevisiae D452-2. Conclusively, I. orientalis MTY1 could be a potent workhorse with multiple tolerance against harsh conditions considered in cellulosic bioethanol production. PMID- 28843024 TI - NaMYB8 regulates distinct, optimally distributed herbivore defense traits. AB - When herbivores attack, plants specifically reconfigure their metabolism. Herbivory on the wild tobacco Nicotiana attenuata strongly induces the R2R3 MYB transcriptional activator MYB8, which was reported to specifically regulate the accumulation of phenolamides (PAs). We discovered that transcriptional regulation of trypsin protease inhibitors (TPIs) and a threonine deaminase (TD) also depend on MYB8 expression. Induced distributions of PAs, TD and TPIs all meet predictions of optimal defense theory: their leaf concentrations increase with the fitness value and the probability of attack of the tissue. Therefore, we suggest that these defensive compounds have evolved to be co-regulated by MYB8. PMID- 28843025 TI - Concomitant coronary artery disease and its management in patients referred to transcatheter aortic valve implantation: Insights from the POL-TAVI Registry. AB - BACKGROUND: Coronary artery disease (CAD) and degenerative aortic stenosis often coexist. However, the impact of CAD and its management on the prognosis after transcatheter aortic valve implantation (TAVI) remains uncertain. We sought to evaluate the impact of obstructive CAD, SYNTAX score (Ss), and percutaneous coronary intervention (PCI) prior to TAVI on short-term outcome. METHODS: Overall, 896 patients who underwent TAVI after heart team decision was included. Pre-procedural angiograms were analysed to calculate baseline Ss (bSs) and residual Ss (rSs). Baseline, procedural and follow-up data up to 30 days was acquired from the national POL-TAVI registry. RESULTS: Patients with obstructive CAD at baseline (n = 462, 52%) had higher mortality as compared with the remaining (8.7 vs. 5.1%, log-rank P = 0.039). Also, after correction for confounding factors obstructive CAD was identified as independent predictor of mortality (hazard ratio [HR] 1.74, 95% confidence intervals [CIs] 1.03-2.94, P = 0.037). In obstructive CAD, neither bSs (AUC 0.47, CI 0.38-0.56, P = 0.47) nor rSs (AUC 0.47, CI 0.30-0.64, P = 0.72 for those undergoing PCI and AUC 0.48, CI 0.37-0.59, P = 0.75 for the remaining) was predictive of mortality. When revascularization status was considered, patients with PCI prior to TAVI had similar outcome as those without obstructive CAD at baseline (7.7 vs. 5.1%, log rank P = 0.23) with no negative impact on mortality (HR 1.13, CI 0.62-2.09, P = 0.69). CONCLUSIONS: In conclusion, obstructive CAD at baseline evaluation for TAVI has independent negative impact on short-term prognosis. However, neither baseline nor residual Ss values have prognostic ability in patients undergoing TAVI. Revascularization prior to TAVI seems to improve survival to levels comparable with patients without obstructive CAD at baseline. PMID- 28843026 TI - Insect-plant-pathogen interactions as shaped by future climate: effects on biology, distribution, and implications for agriculture. AB - Carbon dioxide (CO2 ) is the main anthropogenic gas which has drastically increased since the industrial revolution, and current concentrations are projected to double by the end of this century. As a consequence, elevated CO2 is expected to alter the earths' climate, increase global temperatures and change weather patterns. This is likely to have both direct and indirect impacts on plants, insect pests, plant pathogens and their distribution, and is therefore problematic for the security of future food production. This review summarizes the latest findings and highlights current knowledge gaps regarding the influence of climate change on insect, plant and pathogen interactions with an emphasis on agriculture and food production. Direct effects of climate change, including increased CO2 concentration, temperature, patterns of rainfall and severe weather events that impact insects (namely vectors of plant pathogens) are discussed. Elevated CO2 and temperature, together with plant pathogen infection, can considerably change plant biochemistry and therefore plant defense responses. This can have substantial consequences on insect fecundity, feeding rates, survival, population size, and dispersal. Generally, changes in host plant quality due to elevated CO2 (e.g., carbon to nitrogen ratios in C3 plants) negatively affect insect pests. However, compensatory feeding, increased population size and distribution have also been reported for some agricultural insect pests. This underlines the importance of additional research on more targeted, individual insect-plant scenarios at specific locations to fully understand the impact of a changing climate on insect-plant-pathogen interactions. PMID- 28843027 TI - LC-MS-sMRM Method Development and Validation of Different Classes of Pain Panel Drugs and Analysis of Clinical Urine Samples. AB - Urine Drug Testing (UDT) is an important analytical/bio-analytical technique that has inevitably become an integral and vital part of a testing program for diagnostic purposes. This manuscript presents a tailor-made LC-MS/MS quantitative assay method development and validation for a custom group of 33 pain panel drugs and their metabolites belonging to different classes (opiates, opioids, benzodiazepines, illicit, amphetamines, etc.) that are prescribed in pain management and depressant therapies. The LC-MS/MS method incorporates two experiments to enhance the sensitivity of the assay and has a run time of about 7 min. with no prior purification of the samples required and a flow rate of 0.7 mL/min. The method also includes the second stage metabolites for some drugs that belong to different classes but have first stage similar metabolic pathways that will enable to correctly identify the right drug or to flag the drug that might be due to specimen tampering. Some real case examples and difficulties in peak picking were provided with some of the analytes in subject samples. Finally, the method was deliberated with some randomly selected de-identified clinical subject samples, and the data evaluated from "direct dilute and shoot analysis" and after "glucuronide hydrolysis" were compared. This method is now used to run routinely more than 100 clinical subjects samples on a daily basis. This article is protected by copyright. All rights reserved. PMID- 28843028 TI - Magnetic dispersive solid-phase extraction based on modified magnetic nanoparticles for the detection of cocaine and cocaine metabolites in human urine by high-performance liquid chromatography-mass spectrometry. AB - An easy-to-handle magnetic dispersive solid-phase extraction procedure was developed for preconcentration and extraction of cocaine and cocaine metabolites in human urine. Divinyl benzene and vinyl pyrrolidone functionalized silanized Fe3 O4 nanoparticles were synthesized and used as adsorbents in this procedure. Scanning electron microscopy, vibrating sample magnetometry, and infrared spectroscopy were employed to characterize the modified adsorbents. A high performance liquid chromatography with mass spectrometry method for determination of cocaine and its metabolites in human urine sample has been developed with pretreatment of the samples by magnetic dispersive solid-phase extraction. The obtained results demonstrated the higher extraction capacity of the prepared nanoparticles with recoveries between 75.1 to 105.7% and correlation coefficients higher than 0.9971. The limits of detection for the cocaine and cocaine metabolites were 0.09-1.10 ng/mL. The proposed magnetic dispersive solid-phase extraction method provided a rapid, environmentally friendly and magnetic stuff recyclable approach and it was confirmed that the prepared adsorbents material was a kind of highly effective extraction materials for the trace cocaine and cocaine metabolites analyses in human urine. PMID- 28843029 TI - A retrospective analysis of 538 sinonasal fungus ball cases treated at a single tertiary medical center in Korea (1996-2015). AB - BACKGROUND: Sinonasal fungus ball (FB) is a type of noninvasive fungal rhinosinusitis affecting immunocompetent hosts. FB, previously considered rare, has been reported with increasing frequency. We reviewed our experience of 538 cases over the past 20 years. METHODS: We retrospectively examined clinical records including clinical presentations, radiological findings, management, and outcomes of FB patients who have undergone surgery for treatment. The number of FB patients who underwent endoscopic sinus surgery (ESS) was calculated annually. Causal relationships between structural variations and FB were also investigated. RESULTS: The number of FB patients who underwent sinus surgery has increased. The mean age was 58.3 years, and the gender ratio was approximately 2 (female): 1 (male). While the most common presenting symptoms of maxillary sinus FB patients were nasal symptoms, such as postnasal drip and nasal obstruction, sphenoid sinus FB patients presented with headache mostly. On computed tomography (CT) scans, the most common finding was intralesional hyperdensity (77.3%). There was no significant correlation between the presence of FB and structural variations (nasal septal deviation, concha bullosa, Haller cell). Median follow-up period of the patients was 11 months. Recurrence or residual disease occurred in only 6 (1.1%) cases. CONCLUSION: The number of FB patients who underwent surgery has increased steadily over the past 20 years. FB should be considered in patients with unilateral nasal symptoms and unexplained headaches. A preoperative CT scan is an essential tool in making diagnosis easier and faster. Endoscopic surgery is the treatment of choice, with a low morbidity and recurrence rate. PMID- 28843030 TI - Simultaneously Enhancing the Stability and Catalytic Activity of Multimeric Lysine Decarboxylase CadA by Engineering Interface Regions for Enzymatic Production of Cadaverine at High Concentration of Lysine. AB - Cadaverine (1,5-diaminopentane) is a major source of many industrial polyamides such as nylon and chelating agents. Currently, cadaverine is produced by the microbial fermentation of glucose to lysine, which is then decarboxylated by lysine decarboxylase (CadA). However, utilizing CadA for cadaverine production causes enzyme instability. In order to stabilize the CadA homo-decamer structure for in vitro decarboxylation reaction, mutants are designed. Of the four disulfide bond mutants in the multimeric interfacial region, B1 (F14C/K44C) showed a 216-folds increase in the half-life of CadA at 60 degrees C. On top of B1, another round of mutant screening is performed around F14C and K44C to generate B1/L7M/N8G, which is then examined for cadaverine production (2M lysine and 10% v/v of cell-extract at 50 degrees C). The reaction pH increased from 4.9 to 8.3, and the final titer of the mutant is 157 g L-1 , that is, 76.7% conversion yield in 9.5 h, whereas the wild-type gave 119 g L-1 , that is, 58.2% conversion yield in 9.5 h. PMID- 28843031 TI - Diabetes primary prevention program: New insights from data analysis of recruitment period. AB - BACKGROUND: Primary Prevention of Diabetes Program in Buenos Aires Province evaluates the effectiveness of adopting healthy lifestyle to prevent type 2 diabetes (T2D) in people at high risk of developing it. We aimed to present preliminary data analysis of FINDRISC and laboratory measurements taken during recruitment of people for the Primary Prevention of Diabetes Program in Buenos Aires Province in the cities of La Plata, Berisso, and Ensenada, Argentina. METHODS: People were recruited through population approach (house-to-house survey by FINDRISC in randomized areas) and opportunistic approach (FINDRISC completed by participants during consultations for nonrelated prediabetes/diabetes symptoms in public and private primary care centres of cities involved). In people with FINDRISC score >= 13 points, we evaluated blood concentrations of HbA1c , creatinine, lipids, and an oral glucose tolerance test (OGTT). RESULTS: Approximately 3415 individuals completed the FINDRISC populational survey and 344 the opportunistic survey; 43% of the 2 groups scored over 13 points; 2.8 and 75.4% of them, respectively, took the prescribed OGTT. Approximately 53.7% of the OGTT showed normal values and 5.2% unknown T2D. The remaining cases showed 69.5% impaired fasting glucose, 13.6% impaired glucose tolerance, and 16.9% both impairments. HbA1c values showed significant differences compared with normal glucose tolerance (4.96 +/- 0.43%), prediabetes (5.28 +/- 0.51%), and T2D (5.60 +/- 0.51%). Participants with prediabetes and T2D showed a predominant increase in low-density lipoprotein-cholesterol values. In prediabetes, >50% showed insulin resistance. CONCLUSIONS: People with prediabetes/T2D had dyslipidemia associated with insulin resistance, which promotes the development of T2D and cardiovascular disease. Thus, it merits its appropriate treatment. PMID- 28843032 TI - Regulatory network and genetic interactions established by OsMADS34 in rice inflorescence and spikelet morphogenesis. AB - Grasses display highly diversified inflorescence architectures that differ in the arrangement of spikelets and flowers and determine cereal yields. However, the molecular basis underlying grass inflorescence morphogenesis remains largely unknown. Here we investigate the role of a functionally diversified SEPALLATA MADS-box transcription factor, OsMADS34, in regulating rice (Oryza sativa L.) inflorescence and spikelet development. Microarray analysis showed that, at the very early stages of inflorescence formation, dysfunction of OsMADS34 caused altered expression of 379 genes that are associated with protein modification and degradation, transcriptional regulation, signaling and metabolism activity. Genetic analysis revealed that OsMADS34 controls different aspects of inflorescence structure, branching and meristem activity synergistically with LAX PANICLE1 (LAX1) and FLORAL ORGAN NUMBER4 (FON4), as evidenced by the enhanced phenotypes of osmads34 lax1 and osmads34 fon4 compared with the single mutants. Additionally, double mutant between osmads34 and the sterile lemma defective mutant elongated empty glume (ele) displayed an enhanced phenotype, that is, longer and wider sterile lemmas that were converted into lemma/palea-like organs, suggesting that ELE and OsMADS34 synergistically control the sterile lemma development. OsMADS34 may act together with OsMADS15 in controlling sterile lemma development. Collectively, these findings provide insights into the regulatory function of OsMADS34 in rice inflorescence and spikelet development. PMID- 28843033 TI - Hemodynamic analysis of a novel bioresorbable scaffold in porcine coronary artery model. AB - BACKGROUND: The shear stress distribution assessment can provide useful insights for the hemodynamic performance of the implanted stent/scaffold. Our aim was to investigate the effect of a novel bioresorbable scaffold, Mirage on local hemodynamics in animal models. METHOD: The main epicardial coronary arteries of 7 healthy mini-pigs were implanted with 11 Mirage Microfiber sirolimus-eluting Bioresorbable Scaffolds (MMSES). Optical coherence tomography (OCT) was performed post scaffold implantation and the obtained images were fused with angiographic data to reconstruct the coronary artery anatomy. Blood flow simulation was performed and Endothelial Shear Stress(ESS) distribution was estimated for each of the 11 scaffolds. ESS data were extracted in each circumferential 5-degree subunit of each cross-section in the scaffolded segment. The generalized linear mixed-effect analysis was implemented for the comparison of ESS in two scaffold groups; 150-um strut thickness MMSES and 125-um strut thickness MMSES. RESULTS: ESS was significantly higher in MMSES (150 um) [0.85(0.49-1.40) Pa], compared to MMSES (125 um) [0.68(0.35-1.18) Pa]. Both MMSES (150 um) and MMSES (125 um) revealed low recirculation zone percentages per luminal surface area [3.17% +/- 1.97% in MMSES (150 um), 2.71% +/- 1.32% in MMSES (125 um)]. CONCLUSION: Thinner strut Mirage scaffolds induced lower shear stress due to the small size vessels treated as compared to the thick strut version of the Mirage which was implanted in relatively bigger size vessels. Vessel size should be taken into account in planning BRS implantation. Small vessels may not get benefit from BRS implantation even with a streamlined strut profile. This pilot study warrants comparative assessment with commercially available bioresorbable scaffolds. PMID- 28843034 TI - Changing psychosocial determinants of physical activity and diet in women with a history of gestational diabetes mellitus. AB - BACKGROUND: To investigate how a behavioural lifestyle intervention influences psychosocial determinants of physical activity and dietary behaviours in a population at risk of type 2 diabetes (T2DM). METHODS: Fifty-nine women with a body mass index of >=25 kg/m2 and a history of gestational diabetes mellitus (GDM) participated in a randomized controlled study. The intervention group (n = 29) received 2 face-to-face and 5 telephone lifestyle-counselling sessions with a health professional. The control group (n = 30) received care as usual. At baseline and 6 months, psychosocial determinants related to physical activity and diet were measured with a self-administrated questionnaire. Linear regression analyses were applied to test for intervention effects. RESULTS: The intervention was effective in improving social support (beta = 3.5, P < 0.001; beta = 2.1, P = 0.02), modifying self-efficacy (beta = -2.2, P = 0.02; beta = -4.3, P < 0.001), and reducing barriers (beta = -3.5, P = 0.01; beta = -3.8, P = 0.01) for, respectively, physical activity and diet from baseline to 6-month follow-up in the intervention group compared with the control group. The intervention reduced the following barriers to a physically active lifestyle: lack of energy and lack of motivation. Physical activity barriers like lack of time and lack of childcare were unchanged. The intervention reduced the following barriers to a healthy diet: lack of time, costs, having unhealthy snacks at home, and having cravings for sweets. CONCLUSION: This lifestyle intervention influenced psychosocial determinants relevant for overweight women with a history of gestational diabetes mellitus (GDM) in prevention of T2DM. PMID- 28843035 TI - Risk prediction of post-hepatectomy liver failure in patients with perihilar cholangiocarcinoma. AB - BACKGROUND AND AIM: In most patients with perihilar cholangiocarcinoma (PHCC), major hepatectomy and extrahepatic bile duct resection are needed for surgical radicality, and a high risk of hepatic insufficiency exists. This study aims to develop a prediction model for post-hepatectomy liver failure (PHLF) in patients with PHCC. METHODS: A total of 143 patients who underwent major liver resection and extrahepatic bile duct resection for PHCC between October 2001 and December 2013 were included. Clinically relevant PHLF was defined as liver failure corresponding to grade B or C of the International Study Group of Liver Surgery criteria. Multivariate logistic regression was used to develop the PHLF risk model. Model performance was evaluated internally using the area under the curve analysis (discrimination) after 1000 bootstrap resampling and the Hosmer-Lemeshow goodness-of-fit test (calibration). RESULTS: Post-hepatectomy liver failure occurred in 43.4% of patients (n = 62). In multivariate analysis, PHLF was significantly associated with future liver remnant ratio (odds ratio [OR] per 10% = 0.68, 95% confidence interval [CI] 0.51-0.88), intraoperative blood loss (OR per 1 L = 1.82, 95% CI 1.11-3.17), and preoperative prothrombin time > 1.20 (OR = 3.22, 95% CI 1.15-9.97). The PHLF risk score model showed good discrimination (area under the curve = 0.708, 95% CI 0.623-0.793) and calibration (P = 0.227). CONCLUSIONS: The risk model proposed in this study accurately predicted PHLF in patients with PHCC. This offers surgeons a practical guide to quantitative risk assessment of hepatic insufficiency and aids decision-making in surgical treatment and perioperative management. PMID- 28843036 TI - Breast reconstruction with DIEP and SIEA flaps in patients with prior abdominal liposuction. AB - INTRODUCTION: Suction-assisted lipectomy (SAL) has been considered a relative contraindication for autologous breast reconstruction due to reservations about size and integrity of perforator vessels. Such patients are often not considered ideal candidates for breast reconstruction utilizing deep inferior epigastric perforator (DIEP) and superficial inferior epigastric artery (SIEA) flaps. The aim of this article is to describe our experience with these flaps after SAL. METHODS: Retrospectively, patient charts from 2005 to 2015 were analyzed and 9 patients (13 flaps) were identified who received breast reconstruction after prior donor-site SAL. Eight patients underwent DIEP and 1 patient an SIEA flap breast reconstruction. The patients' average age was 47.7 (ranging 33-64) years and their BMI 26.0 (ranging 21.1-36.5). Preoperative radiologic studies were obtained for all patients via either Doppler ultrasound or cross-sectional imaging to assess abdominal perforators. Abdominal SAL took place between 2 and 20 years before reconstruction. RESULTS: On average, 2.4 (ranging 1-4) perforators with a mean diameter of 0.68 mm (ranging 0.2-2.5 mm) were included per DIEP flap and anastomosed to the internal mammary arteries. Median follow-up period was 1.2 (ranging 0.5-9.6) years without any flap loss, flap necrosis, hematoma, or unplanned reoperation. One breast seroma and one fat necrosis occurred. All patients had a successful reconstruction and finished treatment at our institution. CONCLUSION: Our results show that DIEP and SIEA flaps are safe and effective options for breast reconstruction in patients with previous abdominal SAL. Extensive preoperative patient evaluation and perforator imaging is important in identifying suitable candidates within this patient population. PMID- 28843037 TI - Performance of the in vitro transgene mutation assay in MutaMouse FE1 cells: Evaluation of nine misleading ("False") positive chemicals. AB - The screening of chemicals for the protection of human health and the environment requires the assessment of genetic toxicity. However, existing, internationally accepted in vitro mammalian genotoxicity tests have been criticized for their low specificity (i.e. high frequency of "false" or "misleading" positive results for compounds that are negative in vivo). An in vitro transgene mutation assay has been established that uses a metabolically competent cell line derived from MutaMouse lung (i.e. FE1 cells). Mutation scoring employs the well-characterized lacZ positive selection system, and the assay is proposed as an alternative in vitro assessment tool. In this study, the performance of the FE1 cell assay was evaluated by examining responses to nine non-DNA-reactive chemicals that previously elicited misleading positive results in other mammalian cell genotoxicity assays. FE1 cells were exposed to concentrations up to approximately 10 mM and/or concentrations that yielded approximately 80-90% cytotoxicity (as measured by relative increase in cell count). The assay demonstrated excellent specificity; exposures to the chemicals examined did not yield any positive responses even when tested in the presence of an exogenous metabolic activation system (i.e. S9) or with an extended sampling time. These results indicate that the FE1 cell mutagenicity assay is an effective and practical alternative to traditional mammalian cell gene mutation assays. The development and validation of effective in vitro tools such as the MutaMouse FE1 cell assay will contribute to international efforts to reduce, refine, and replace experimental animals for toxicity assessment. Environ. Mol. Mutagen. 58:582-591, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28843038 TI - In Response to "Changing the surgical dogma in frontal sinus trauma: transnasal endoscopic repair" by Grayson et al. PMID- 28843039 TI - TNF, TNF inducers, and TNFR2 agonists: A new path to type 1 diabetes treatment. AB - In the past decade, interest in the century-old tuberculosis vaccine, bacillus Calmette-Guerin (BCG), has been revived for potential new therapeutic uses in type 1 diabetes and other forms of autoimmunity. Diverse clinical trials are now proving the value of BCG in prevention and treatment of type 1 diabetes, in the treatment of new onset multiple sclerosis and other immune conditions. BCG contains the avirulent tuberculosis strain Mycobacterium bovis, a vaccine originally developed for tuberculosis prevention. BCG induces a host response that is driven in part by tumour necrosis factor (TNF). Induction of TNF through BCG vaccination or through selective agonism of TNF receptor 2 (TNFR2) has 2 desired cellular immune effects: (1) selective death of autoreactive T cells and (2) expansion of beneficial regulatory T cells (Tregs). In human clinical trials in both type 1 diabetes and multiple sclerosis, administration of the BCG vaccine to diseased adults has shown great promise. In a Phase I trial in advanced type 1 diabetes (mean duration of diabetes 15 years), 2 BCG vaccinations spaced 4 weeks apart selectively eliminated autoreactive T cells, induced beneficial Tregs, and allowed for a transient and small restoration of insulin production. The advancing global clinical trials using BCG combined with mechanistic data on BCGs induction of Tregs suggest value in this generic agent and possible immune reversal of the type 1 diabetic autoimmune process. PMID- 28843040 TI - Prospects for Bio-Industrial Application of an Extremely Alkaline Mannanase From Bacillus subtilis subsp. inaquosorum CSB31. AB - Mannan-degrading enzymes have been growing interest in bio-industrial applications, such as the pulp and paper, food, and pharmaceutical industries. In this study, an extremely alkaline mannanase (MnB31) is produced by Bacillus subtilis subsp. inaquosorum CSB31. MnB31 is purified to 17.92-fold with a 21.51% yield and specific activity of 1,796.13 U mg-1 by anion-exchange and gel filtration column chromatography. The biochemical characterization of MnB31 is performed, and the results are as follows: molecular weight of ~47 kDa with an optimum temperature of 60 degrees C and pH of 12.5. The enzyme is strongly activated by Co2+ , Mn2+ , Na+ , and K+ , and inhibited by Zn2+ , Ni2+ , and Mg2+ . Halo-tolerance (10% NaCl), urea stability (3 M), and protease resistance are also observed. The kinetic parameters of MnB31 are found to be Km of 0.043 mg ml 1 , and Vmax of 1,046 +/- 3.605 U mg-1 , respectively. In addition, the thermodynamical parameters are investigated; the activation energy (Ea ) is found to be 31.36 kJ mol-1 with a Kcat value of 156.9 * 104 s-1 , DeltaH (28.59 kJ mol 1 ), DeltaG (42.38 kJ mol-1 ), DeltaS (-41.39 J mol-1 K-1 ), Q10 (1.40), DeltaGE S (-8.697 kJ mol-1 ), and DeltaGE-T (-48.22 kJ mol-1 ). These results suggest that MnB31 has potential bio-industrial application, due to its greater hydrolytic efficiency and feasibility of enzymatic reaction. PMID- 28843041 TI - The social hippocampus. AB - The concept of cognitive map has been proposed as a way to organize our experiences and guide behavior across all domains of cognition. The hippocampus has been identified as the neural substrate supporting cognitive maps for navigating physical space. Recent evidence is broadening the role of the hippocampus into mapping other manner of spaces. Here we focus on the case of social space as a candidate for hippocampal representation because it combines multiple continuous dimensions and requires dynamic navigation through social contexts. We present evidence for the role of the hippocampus in (1) supporting social memory, (2) representing different dimensions of social space, (3) tracking dynamic social behavior, (4) maintaining a flexible map allowing adaptation to new social contexts, and (5) maladaptive social behavior across psychiatric disorders. To do so, we explore evidence across species including birds, rodents, nonhuman primates and humans, indicating hippocampal involvement in a range of social processes. Review of previous findings in a manner predicted by the cognitive map supports the existence of systematic mapping of social space by the hippocampus. Evidence for hippocampal social maps complements findings from other abstract domains, such as auditory, temporal and conceptual, allowing successful navigation through many domains of everyday life. PMID- 28843042 TI - Effect of Type of Protein-Based Microcapsules and Storage at Various Ambient Temperatures on the Survival and Heat Tolerance of Spray Dried Lactobacillus acidophilus. AB - The aims of this study were to evaluate the effect of types of protein-based microcapsules and storage at various ambient temperatures on the survival of Lactobacillus acidophilus during exposure to simulated gastrointestinal tract and on the change in thermo-tolerance during heating treatment. The encapsulating materials were prepared using emulsions of protein (sodium caseinate, soy protein isolate, or pea protein), vegetable oil, and glucose, with maltodextrin was used as a wall material. The formulations were heated at 90 degrees C for 30 min to develop Maillard substances prior to being incorporated with L. acidophilus. The mixtures were then spray dried. The microspheres were stored at 25, 30, and 35 degrees C for 8 wk and examined every 4 wk. The addition of proteins as encapsulating materials demonstrated a significant protective effect (P < 0.05) as compared to the control sample. Sodium caseinate and soy protein isolate appeared more effective than pea protein in protecting the bacteria after spray drying and during the storage at different room temperatures. Storage at 35 degrees C resulted in a significant decrease in survival at end of storage period regardless the type of encapsulating materials. The addition of protein-based materials also enhanced the survival of L. acidophilus during exposure to simulated gastrointestinal condition as compared to the control. After spray drying and after 0th wk storage, casein, soy protein isolate, and pea protein based formulations protected the bacteria during heat treatment. In fact, a significant decrease in thermal tolerance was inevitable after 2 wk of storage at 25 degrees C. PMID- 28843043 TI - Parents' traces in life: When and how parents are presented in spontaneous life narratives. AB - OBJECTIVE: Although parents are acknowledged to be a part of their children's personality and narrative identity and to remain important across the life span, narrative personality research has not yet explored the spontaneous presentation of parents in life stories. Therefore, this study examined longitudinally the place given to parents when crafting one's life narrative and how this changes with age. Furthermore, in contrast to prior studies, we focused on spontaneous mentions of parents. METHOD: We investigated how often parents are mentioned in life narratives of six age groups spanning from age 8 to 69, how the parental relationship is evaluated, whether narrators express understanding of their parents, and whether they respond to parental values. RESULTS: People of all ages dedicated a substantial part of their life narratives to their parents and evaluated their relationship with them in an increasingly differentiated manner. Parents were increasingly perceived as individuals beyond their parental nurturing role. Until late in life, individuals reflect on values and opinions that were transferred to them by their parents. CONCLUSIONS: Parents hold a consistent place in life narratives, emphasizing their importance for narrative identity. Results are discussed in terms of lifelong child-parent relationships. Directions for future research are outlined. PMID- 28843044 TI - Novel MRI and CT compatible stereotactic brain biopsy system in dogs using patient-specific facemasks. AB - OBJECTIVE: The objective of this pilot study was to describe the application and first preliminary data of a novel MRI and CT compatible patient-specific facemask for stereotactic brain biopsy of intracranial lesions in dogs. METHODS: Five client-owned dogs presenting for neurological deficits consistent with forebrain disease were included in the study. All dogs had MRI findings consistent with an intracranial lesion. Using images obtained from either MRI or CT, a virtual three dimensional model of each dog's face was generated. The contact surface of each dog's face was selected for facemask design and a target point for biopsy was chosen using specialised software and toolkits. A patient-specific facemask with an attached biopsy port with premeasured and preselected trajectory was then fabricated by a 3D printer. The facemasks were sterilised and used intraoperatively to obtain biopsy samples. Biopsy samples were submitted for both cytological and histopathological evaluation. RESULTS: The diagnostic yield based on specific histological diagnosis was 80%. The one case in which a histological diagnosis could not be confirmed had a cytological interpretation consistent with meningioma. No major complications were observed during or immediately after brain biopsy and all dogs were discharged from the hospital within 72 hours postprocedure. CLINICAL SIGNIFICANCE: In conclusion, patient-specific facemasks appear to be a safe and effective method of brain biopsy in dogs, with minimal complications observed. PMID- 28843045 TI - Hippocampal mechanisms in impaired spatial learning and memory in male offspring of rats fed a low-protein isocaloric diet in pregnancy and/or lactation. AB - Maternal nutritional challenges during fetal and neonatal development result in developmental programming of multiple offspring organ systems including brain maturation and function. A maternal low-protein diet during pregnancy and lactation impairs associative learning and motivation. We evaluated effects of a maternal low-protein diet during gestation and/or lactation on male offspring spatial learning and hippocampal neural structure. Control mothers (C) ate 20% casein and restricted mothers (R) 10% casein, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second lactation diet). We evaluated the behavior of young adult male offspring around postnatal day 110. Corticosterone and ACTH were measured. Males were tested for 2 days in the Morris water maze (MWM). Stratum lucidum mossy fiber (MF) area, total and spine type in basal dendrites of stratum oriens in the hippocampal CA3 field were measured. Corticosterone and ACTH were higher in RR vs. CC. In the MWM acquisition test CC offspring required two, RC three, and CR seven sessions to learn the maze. RR did not learn in eight trials. In a retention test 24 h later, RR, CR, and RC spent more time locating the platform and performed fewer target zone entries than CC. RR and RC offspring spent less time in the target zone than CC. MF area, total, and thin spines were lower in RR, CR, and RC than CC. Mushroom spines were lower in RR and RC than CC. Stubby spines were higher in RR, CR, and RC than CC. We conclude that maternal low-protein diet impairs spatial acquisition and memory retention in male offspring, and that alterations in hippocampal presynaptic (MF), postsynaptic (spines) elements and higher glucocorticoid levels are potential mechanisms to explain these learning and memory deficits. PMID- 28843046 TI - Characterizing the role of the hippocampus during episodic simulation and encoding. AB - The hippocampus has been consistently associated with episodic simulation (i.e., the mental construction of a possible future episode). In a recent study, we identified an anterior-posterior temporal dissociation within the hippocampus during simulation. Specifically, transient simulation-related activity occurred in relatively posterior portions of the hippocampus and sustained activity occurred in anterior portions. In line with previous theoretical proposals of hippocampal function during simulation, the posterior hippocampal activity was interpreted as reflecting a transient retrieval process for the episodic details necessary to construct an episode. In contrast, the sustained anterior hippocampal activity was interpreted as reflecting the continual recruitment of encoding and/or relational processing associated with a simulation. In the present study, we provide a direct test of these interpretations by conducting a subsequent memory analysis of our previously published data to assess whether successful encoding during episodic simulation is associated with the anterior hippocampus. Analyses revealed a subsequent memory effect (i.e., later remembered > later forgotten simulations) in the anterior hippocampus. The subsequent memory effect was transient and not sustained. Taken together, the current findings provide further support for a component process model of hippocampal function during simulation. That is, unique regions of the hippocampus support dissociable processes during simulation, which include the transient retrieval of episodic information, the sustained binding of such information into a coherent episode, and the transient encoding of that episode for later retrieval. PMID- 28843047 TI - Dysregulation of LIMK-1/cofilin-1 pathway: A possible basis for alteration of neuronal morphology in experimental cerebral malaria. AB - OBJECTIVE: Loss of cognition even after survival is the salient feature of cerebral malaria (CM). Currently, the fate of neuronal morphology is not studied at the ultrastructural level in CM. Recent studies suggest that maintenance of neuronal morphology and dendritic spine density (actin dynamics in particular) are essential for proper cognitive function. LIMK-1/cofilin-1 signaling pathway is known to be involved in the maintenance of actin dynamics through regulation of cofilin-1, and in executing learning and memory functions. METHODS: Using an experimental mouse model, we analyzed the behavioral parameters of asymptomatic mice with CM by performing a rapid murine coma and behavior scale experiment. We performed Golgi-Cox staining to assess neuronal morphology, dendritic spine density, and arborization in brain cortex subjected to Plasmodium berghei ANKA infection compared to asymptomatic, anemic, and control groups. We studied the neural gene expression pattern of LIMK-1, cofilin-1, and beta-actin in all the experimental groups by semiquantitative and quantitative polymerase chain reaction followed by immunoblotting and immunofluorescence. RESULTS: We observed significant loss of dendritic spine density, abnormal spine morphology, reduced dendritic arborization, and extensive dendritic varicosities in the cortical neurons of CM-infected brain. Furthermore, these observations correlated with diminished protein levels of LIMK-1, cofilin-1, phospho-cofilin-1, and beta-actin in the whole brain lysates as well as formation of actin-cofilin rods in the brain sections of symptomatic mice with CM. INTERPRETATION: Overall, our findings suggest that the altered neuronal morphology and dysregulation of LIMK-1/cofilin 1 pathway could affect the cognitive outcome after experimental CM. Therefore, this study could help to establish newer therapeutic strategies addressing long term cognitive impairment after CM. Ann Neurol 2017;82:429-443. PMID- 28843048 TI - Stereoselective determination of dufulin in watermelon under field conditions using chiral ultra high performance liquid chromatography with high-resolution mass spectrometry. AB - An effective and sensitive chiral analytical method was established to investigate the stereoselective dissipation of rac-dufulin in watermelon using ultra high performance liquid chromatography with a superchiral S-OD chiral column (4.6 * 150 mm i.d., 5 MUm) coupled with high-resolution mass spectrometry. To optimize the pretreatment method for detecting rac-dufulin in the three matrixes, different extraction solvents, extractant volumes, extraction times, and absorbents were investigated to improve extraction efficiency. Moreover, analysis of variance was used to perform method validation for determination of the two dufulin enantiomers in the three matrixes. Using the optimized method, good linearity was obtained (determination coefficient > 0.999). The limits of detection and quantification of the two dufulin enantiomers in soil, watermelon, and pulp were 0.15 and 0.5 MUg/kg, respectively. The average recoveries of the two enantiomers in the three matrixes at four spiked levels ranged from 75.0 to 107.8%, with intra- and inter-day relative standard deviations of 0.4-10.4%. In field trials, the R enantiomer was preferentially dissipated in watermelon. These method validation results confirmed that the developed method was convenient and reliable for the stereoselective determination of enantiomers of rac-dufulin in watermelon. PMID- 28843049 TI - Effect of Interferon-gamma Polymorphisms on Ankylosing Spondylitis: A Case Control Study. AB - BACKGROUND This research aimed to explore the effects of interferon-gamma (IFN gamma) polymorphisms and expression profile on susceptibility to ankylosing spondylitis (AS) in a Chinese population. MATERIAL AND METHODS Blood samples were collected from 89 AS patients and 106 healthy controls. IFN-gamma polymorphisms were genotyped by polymerase chain reaction (PCR) and sequencing methods. The genotype distribution of polymorphism in the control group was detected by Hardy Weinberg equilibrium (HWE). Odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using the chi2 test to evaluate the association between AS susceptibility and IFN-gamma polymorphisms. Moreover, serum IFN-gamma level was measured by ELISA. RESULTS rs1861493 and rs2430561 polymorphisms were conformed to be in HWE in genotypes distribution of the control group (P>0.05 for both). However, only TT genotype and T allele of rs2430561 presented significantly higher frequencies in AS patients than in healthy controls (P=0.04 and 0.03, respectively), indicating that they obviously increased the risk of AS in a Chinese population (OR=2.54, 95%CI=1.01-6.40; OR=1.60, 95%CI=1.04-2.46). In AS patients, serum IFN-gamma level was higher than in controls, and its expression patterns showed significant association with genotypes of rs2430561. CONCLUSIONS IFN-gamma rs2430561 polymorphism may contribute to the risk of AS through influencing IFN-gamma expression. PMID- 28843051 TI - Environmental Mutagenesis and Genomics Society 48th Annual Meeting. PMID- 28843050 TI - Sirolimus therapy in the treatment of pseudomyogenic hemangioendothelioma. AB - Pseudomyogenic hemangioendothelioma (PMH) is a rare, mostly indolent vascular tumor. Extensive cases are treated with amputation as chemotherapy seems to be ineffective. Recently, promising results were published using mammalian target of rapamycin (mTOR) inhibitors in tumors of vascular origin. Here, we present a case of a child with advanced PMH relapsing after surgery and chemotherapy. Sirolimus achieved significant clinical improvement and stabilization of the lesions without any remarkable toxicity. This case contributes to the growing evidence regarding the efficacy of mTOR inhibitors, such as sirolimus, in multifocal PMH. PMID- 28843052 TI - Hypercalcaemia secondary to ectopic parathyroid hormone expression in an adolescent with metastatic alveolar rhabdomyosarcoma. AB - We report the case of a 14-year-old male with metastatic alveolar rhabdomyosarcoma, presenting with hypercalcaemia (3.89 mmol/l) and elevated parathyroid hormone (PTH) level (10.2 pmol/l). Imaging demonstrated extensive bony lytic damage, with "floating teeth" in the mandible. Normalisation of calcium levels and bony reformation of the mandible occurred following chemotherapy; PTH levels decreased initially but remained above normal levels. Imaging did not demonstrate any evidence of parathyroid abnormality. Tumour ectopic PTH secretion is a very rare cause of hypercalcaemia of malignancy in children. Hypercalcaemia with an elevated PTH, in the absence of parathyroid related cause, should prompt investigation for underlying malignancy. PMID- 28843053 TI - Oral health and hematopoietic stem cell transplantation: A longitudinal evaluation of the first 28 days. AB - BACKGROUND: Mucositis is well described after pediatric hematopoietic stem cell transplant (HSCT) but other aspects of oral health such as dental plaque and gingivitis are poorly understood. The aim of this study was to describe dental plaque, gingivitis, and mucositis early after HSCT. METHODS: We conducted a prospective longitudinal observational study to describe dental plaque, gingivitis, and mucositis in the peritransplant period. We conducted comprehensive oral evaluations that included the Miyazaki tongue coating, modified simplified oral hygiene, modified gingivitis of Suomi and Barbano, and mucosal ulceration indices at baseline on days 0, +7, +14, and +28. RESULTS: Data were collected from 19 patients with a median age of 8.0 years (5.1-12.8) at time of HSCT. Sixteen patients (85%) had plaque accumulation that progressively worsened, 16 (85%) developed severe gingival inflammation, 13 (68%) developed mucositis, and 11 (58%) had oral ulcerations. All oral indices worsened from baseline during the study period. Gingivitis and oral plaque persisted in most patients at day +28 while mucositis and oral ulcerations slightly improved. DISCUSSION: Gingivitis, dental plaque, mucositis, and oral ulcerations are common after HSCT. Additional studies are needed to ascertain methods that decrease plaque and gingivitis development and severity. PMID- 28843054 TI - High-dose treatment for malignant rhabdoid tumor of the kidney: No evidence for improved survival-The Gesellschaft fur Padiatrische Onkologie und Hamatologie (GPOH) experience. AB - BACKGROUND: Malignant rhabdoid tumor of the kidney (MRTK) is the most aggressive childhood renal tumor with overall survival (OS) rates ranging from 22% to 42%. Whether high-dose chemotherapy with autologous stem-cell transplantation (HDSCT) in an intensive first-line treatment offers additional benefit is an ongoing discussion. METHODS: A retrospective analysis of all 58 patients with MRTK from Austria, Switzerland, and Germany treated in the framework of consecutive, prospective renal/rhabdoid tumor studies SIOP9/GPO, SIOP93-01/GPOH (where SIOP is International Society of Pediatric Oncology and GPOH is German Society of Pediatric Oncology and Hematology), SIOP2001/GPOH, and European Rhabdoid Tumor Registry from 1991 to 2014. RESULTS: Median age at diagnosis was 11 months. Fifty percent of patients had metastases or multifocal disease at diagnosis (Stage IV). Local stage distribution was as follows: not done/I/II/III-1/6/11/40. Fifteen (26%) patients underwent upfront surgery. Thirty-seven (64%) patients achieved a complete remission, 17 (29%) relapsed, 34 (59%) died of disease progression, and two (3%) died of treatment-related complication. Mean time to the first event was 3.5 months. Two-year EFS/OS (where EFS is event-free survival) for the whole group was 37 +/- 6%/38 +/- 6%. Metastases/multifocal disease, younger age, and local stage III were associated with significantly inferior survival. Eleven (19%) patients underwent HDSCT (carboplatin + thiotepa, n = 6; carboplatin + etoposide + melphalan, n = 4; others, n = 1); 2-year OS in this group was 60 +/- 15% compared to 34 +/- 8% in the non-HDSCT group (P = 0.064). However, the time needed from radiologic to histologic diagnosis, stem-cell harvest, and HDSCT must also be taken into account to avoid selection bias by excluding the highest risk group with early progression (<90 days). Thus, 2-year EFS only for patients without progression until day 90 was 60 +/- 16% consolidated by HDSCT compared to 62 +/- 11% without (P = 0.8). CONCLUSION: Our retrospective analysis suggests comparable outcomes for patients with and without HDSCT, if adjusted for early disease progression. PMID- 28843056 TI - Microplastics in the aquatic environment-Perspectives on the scope of the problem. PMID- 28843055 TI - Exercise right heart catheterization for pulmonary hypertension identified on screening echocardiography in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. AB - Pulmonary hypertension, determined noninvasively by tricuspid regurgitant jet velocity on Doppler echocardiography, was previously identified in 25% of long term survivors who received chest-directed radiotherapy. To validate noninvasively defined pulmonary hypertension, survivors (mean age 48 years), exposed to chest radiotherapy, underwent right heart catheterization with planned cardiopulmonary exercise testing during catheterization. Eight participants had an elevated mean pulmonary artery pressure at rest (>=25 mm Hg) or with subsequent exercise (>30 mm Hg), evidence of hemodynamically confirmed pulmonary hypertension by right heart catheterization. Cardiopulmonary exercise testing further defined the magnitude and etiology of cardiopulmonary limitations in this life-threatening late effect. PMID- 28843057 TI - Methylammonium lead chloride: A sensitive sample for an accurate NMR thermometer. AB - A new solid-state nuclear magnetic resonance (NMR) thermometry sample is proposed. The 207Pb NMR chemical shift of a lead halide perovskite, methylammonium lead chloride (MAPbCl3) is very sensitive to temperature, 0.905+/ 0.010ppmK-1. The response to temperature is linear over a wide temperature range, from its tetragonal to cubic phase transition at 178K to >410K, making it an ideal standard for temperature calibrations in this range. Because the 207Pb NMR lineshape for MAPbCl3 appears symmetric, the sample is ideal for calibration of variable temperature NMR data acquired for spinning or non-spinning samples. A frequency-ratio method is proposed for referencing 207Pb chemical shifts, based on the 1H and 13C frequencies of the methylammonium cation, which are used asan internal standard. Finally, this new NMR thermometer has been used to measure the degree of frictional heating asa function of spinning frequency for a series of MAS rotors ranging in outer diameter from 1.3 to 7.0mm. As expected, the largest diameter rotors are more susceptible to frictional heating, but lower diameter rotors are subjected to higher frictional heating temperatures as they are typically spun at much higher spinning frequencies. PMID- 28843058 TI - Strong-coupling induced damping of spin-echo modulations in magic-angle-spinning NMR: Implications for J coupling measurements in disordered solids. AB - In the context of improving J coupling measurements in disordered solids, strong coupling effects have been investigated in the spin-echo and refocused INADEQUATE spin-echo (REINE) modulations of three- and four-spin systems under magic-angle spinning (MAS), using density matrix simulations and solid-state NMR experiments on a cadmium phosphate glass. Analytical models are developed for the different modulation regimes, which are shown to be distinguishable in practice using Akaike's information criterion. REINE modulations are shown to be free of the damping that occurs for spin-echo modulations when the observed spin has the same isotropic chemical shift as its neighbour. Damping also occurs when the observed spin is bonded to a strongly-coupled pair. For mid-chain units, the presence of both direct and relayed damping makes both REINE and spin-echo modulations impossible to interpret quantitatively. We nonetheless outline how a qualitative comparison of the modulation curves can provide valuable information on disordered networks, possibly also pertaining to dynamic effects therein. PMID- 28843059 TI - Birth weight and its association with blood pressure and nutritional status in adolescents. AB - OBJECTIVE: The management of children with low birth weight is not the same in countries with different resources. The authors assessed the association of birth weight with blood pressure and nutritional status in a representative sample of adolescents from a Brazilian state, aiming to identify possible consequences of these differences. METHODS: A cross-sectional school-based study was conducted with adolescents (12-18 years) enrolled in public and private schools. Birth weight, office blood pressure, home blood pressure measurements, and nutritional status (body mass index, height z-score for the age, and waist circumference) were assessed. The association of birth weight with the outcomes (blood pressure, height, body mass index, and waist circumference) was studied through univariate and multivariable linear regression models. RESULTS: A total of 829 adolescents with a mean age of 14.6+/-1.62 years were included; 43.3% were male, and 37.0% from private schools. The prevalence of low birth weight was 8.7%. Mild low height prevalence was higher among those adolescents with low/insufficient birth weight when compared to those with normal/high birth weight (11.7 vs. 4.2%; p<0.001). In the multiple linear regression analysis, for each increase of 100g in birth weight, height increased by 0.28cm (95% CI: 0.18-0.37; p<0.01). Birth weight did not influence office blood pressure and home blood pressure, body mass index, or waist circumference of adolescents. CONCLUSIONS: Birth weight was directly associated to height, but not associated to blood pressure, body mass index, and waist circumference in adolescents from an urban area of a developing country. PMID- 28843060 TI - Aggregation of risk indicators to cardiometabolic and musculoskeletal health in Brazilian adolescents in the periods 2008/09 and 2013/14. AB - OBJECTIVE: To assess the occurrence of an aggregate risk to cardiometabolic and musculoskeletal health of Brazilian adolescents in the period 2008/09 and 2013/14 and to identify whether there are differences in risk between the genders and in these periods. METHODS: This was a trend epidemiological study with a quantitative approach, consisting of a voluntary sample of adolescents from 16 Brazilian states. Data were extracted from the database of Brazil Sports Project (Projeto Esporte Brasil). Health-related physical fitness was evaluated based on body mass index, cardiorespiratory fitness, flexibility, and abdominal strength/resistance. Descriptive analysis, chi-squared test, and Poisson log regression were used for the statistical treatment. RESULTS: In the years 2008/09, 14.6% of Brazilian youngsters showed an aggregate risk to cardiometabolic health and 17.1% an aggregate risk for musculoskeletal indicators, whereas in 2013/14, the values of the risk indicators were, respectively 40.0% and 22.4%. It was observed that, in the years 2013/14, the risk to the cardiometabolic health of boys was 2.51 times greater than in 2008/09, while for girls, a three-fold increase in risk was observed. Concerning musculoskeletal health, girls showed a 2.21 risk of being in the risk zone in 2013/14 when compared with 2008/09. CONCLUSION: The occurrence of an aggregate risk to the cardiometabolic and musculoskeletal health of Brazilian adolescents increased in the 2008/09 and 2013/14 periods. Regarding gender, an increase in the cardiometabolic and musculoskeletal risk between these periods was observed in girls. As for boys, an increase was observed only in cardiometabolic risk. PMID- 28843061 TI - Cross-cultural adaptation and validation of the Karitane Parenting Confidence Scale of maternal confidence assessment for use in Brazil. AB - OBJECTIVES: To transculturally adapt and validate the Karitane Parenting Confidence Scale to the Brazilian Portuguese language and culture and verify the combination of the results with the maternal sociodemographic characteristics. METHODOLOGY: This is a validation and transcultural adaptation nestled in a longitudinal and observational study in Porto Alegre, RS, Brazil, assessing mother-infant pairs from different gestational and perinatal environments. The original authors authorized the translation into Brazilian Portuguese, unified version creation, back-translation, analysis by specialists, final version implementation, and acceptance. Cronbach's alpha analysis was performed. The Kruskal-Wallis test with post-hoc Dunn's test was used to compare the study groups. Socioeconomic and demographic characteristics, obtained through a questionnaire in the first 24-48h of the newborns' life, were associated with maternal results by the Brazilian version of the scale, using Spearman's correlation and Mann-Whitney's test. RESULTS: The sample consisted of 251 postpartum women, with the confidence maternal questionnaire being applied at 15 days postpartum. The median score of the mothers' confidence was 40.00 (37.00 43.00). The protocol obtained a Cronbach's alpha of 0.717. There were significant weak positive correlations between maternal confidence and age (p=0.013, r=0.157) and between maternal confidence and schooling (p=0.048, r=0.125). Additionally, a significant association was observed between maternal confidence and parity (p=0.030). CONCLUSION: The transcultural adaptation and validation of the confidence maternal questionnaire into Brazilian Portuguese language and culture showed good reliability for this sample. The results of its use demonstrated that maternal confidence was associated with schooling, age and parity. PMID- 28843062 TI - Impulse oscillometry and obesity in children. AB - OBJECTIVE: To compare impulse oscillometry system parameters of normal-weight children with overweight and obese children. METHOD: All participants were submitted to the evaluation of lung function (spirometry and impulse oscillometry) following the American Thoracic Society standards. The evaluation of respiratory mechanics was performed using the JaegerTM MasterScreenTM Impulse Oscillometry System (Erich Jaeger, Germany), three tests were recorded, with acquisition for at least 20seconds. RESULTS: The study included 81 children (30 in the control group, 21 in the overweight group, and 30 the in obesity group), matched for age and sex. Regarding spirometry data, obesity group showed higher numerical values in relation to the control group; however, there were no significant differences among the three groups. For impulse oscillometry parameters, there was a difference between control group and obesity group for respiratory impedance (p=0.036), resistance at 5hertz (p=0.026), resonant frequency (p=0.029), and reactance area (p=0.014). For the parameters expressed in percentage of predicted, there were differences in resistance at 5 hertz, resonant frequency, and reactance area between control group and obesity group. CONCLUSIONS: Obese children showed increased oscillometry parameters values representative of airway obstruction, compared to normal-weight children. Changes in some oscillometry parameters can already be observed in overweight school-aged children. PMID- 28843063 TI - In situ depot comprising phase-change materials that can sustainably release a gasotransmitter H2S to treat diabetic wounds. AB - Patients with diabetes mellitus are prone to develop refractory wounds. They exhibit reduced synthesis and levels of circulating hydrogen sulfide (H2S), which is an ephemeral gaseous molecule. Physiologically, H2S is an endogenous gasotransmitter with multiple biological functions. An emulsion method is utilized to prepare a microparticle system that comprises phase-change materials with a nearly constant temperature of phase transitions to encapsulate sodium hydrosulfide (NaHS), a highly water-labile H2S donor. An emulsion technique that can minimize the loss of water-labile active compounds during emulsification must be developed. The as-prepared microparticles (NaHS@MPs) provide an in situ depot for the sustained release of exogenous H2S under physiological conditions. The sustained release of H2S promotes several cell behaviors, including epidermal/endothelial cell proliferation and migration, as well as angiogenesis, by extending the activation of cellular ERK1/2 and p38, accelerating the healing of full-thickness wounds in diabetic mice. These experimental results reveal the strong potential of NaHS@MPs for the sustained release of H2S for the treatment of diabetic wounds. PMID- 28843065 TI - Self-assembled N-cadherin mimetic peptide hydrogels promote the chondrogenesis of mesenchymal stem cells through inhibition of canonical Wnt/beta-catenin signaling. AB - N-cadherin, a transmembrane protein and major component of adherens junction, mediates cell-cell interactions and intracellular signaling that are important to the regulation of cell behaviors and organ development. Previous studies have identified mimetic peptides that possess similar bioactivity as that of N cadherin, which promotes chondrogenesis of human mesenchymal stem cells (hMSCs); however, the molecular mechanism remains unknown. In this study, we combined the N-cadherin mimetic peptide (HAVDI) with the self-assembling KLD-12 peptide: the resultant peptide is capable of self-assembling into hydrogels functionalized with N-cadherin peptide in phosphate-buffered saline (PBS) at 37 degrees C. Encapsulation of hMSCs in these hydrogels showed enhanced expression of chondrogenic marker genes and deposition of cartilage specific extracellular matrix rich in proteoglycan and Type II Collagen compared to control hydrogels, with a scrambled-sequence peptide after 14 days of chondrogenic culture. Furthermore, western blot showed a significantly higher expression of active glycogen synthase kinase-3beta (GSK-3beta), which phosphorylates beta-catenin and facilitates ubiquitin-mediated degradation, as well as a lower expression of beta catenin and LEF1 in the N-cadherin peptide hydrogels versus controls. Immunofluorescence staining revealed significantly less nuclear localization of beta-catenin in N-cadherin mimetic peptide hydrogels. Our findings suggest that N cadherin peptide hydrogels suppress canonical Wnt signaling in hMSCs by reducing beta-catenin nuclear translocation and the associated transcriptional activity of beta-catenin/LEF-1/TCF complex, thereby enhancing the chondrogenesis of hMSCs. Our biomimetic self-assembled peptide hydrogels can serve as a tailorable and versatile three-dimensional culture platform to investigate the effect of biofunctionalization on stem cell behavior. PMID- 28843064 TI - Mechanically dynamic PDMS substrates to investigate changing cell environments. AB - Mechanics of the extracellular matrix (ECM) play a pivotal role in governing cell behavior, such as cell spreading and differentiation. ECM mechanics have been recapitulated primarily in elastic hydrogels, including with dynamic properties to mimic complex behaviors (e.g., fibrosis); however, these dynamic hydrogels fail to introduce the viscoelastic nature of many tissues. Here, we developed a two-step crosslinking strategy to first form (via platinum-catalyzed crosslinking) networks of polydimethylsiloxane (PDMS) and then to increase PDMS crosslinking (via thiol-ene click reaction) in a temporally-controlled manner. This photoinitiated reaction increased the compressive modulus of PDMS up to 10 fold within minutes and was conducted under cytocompatible conditions. With stiffening, cells displayed increased spreading, changing from ~1300 to 1900 MUm2 and from ~2700 to 4600 MUm2 for fibroblasts and mesenchymal stem cells, respectively. In addition, higher myofibroblast activation (from ~2 to 20%) for cardiac fibroblasts was observed with increasing PDMS substrate stiffness. These results indicate a cellular response to changes in PDMS substrate mechanics, along with a demonstration of a mechanically dynamic and photoresponsive PDMS substrate platform to model the dynamic behavior of ECM. PMID- 28843066 TI - Deriving vascular smooth muscle cells from mesenchymal stromal cells: Evolving differentiation strategies and current understanding of their mechanisms. AB - Vascular smooth muscle cells (VSMCs) play essential roles in regulating blood vessel form and function. Regeneration of functional vascular smooth muscle tissue to repair vascular diseases is an area of intense research in tissue engineering and regenerative medicine. For functional vascular smooth muscle tissue regeneration to become a practical therapy over the next decade, the field will need to have access to VSMC sources that are effective, robust and safe. While pluripotent stem cells hold good future promise to this end, more immediate translation is expected to come from approaches that generate functional VSMCs from adult sources of multipotent adipose-derived and bone marrow-derived mesenchymal stromal cells (ASCs and BMSCs). The research to this end is extensive and is dominated by studies relating to classical biochemical signalling molecules used to induce differentiation of ASCs and BMSCs. However, prolonged use of the biochemical induction factors is costly and can cause potential endotoxin contamination in the culture. Over recent years several non-traditional differentiation approaches have been devised to mimic defined aspects of the native micro-environment in which VSMCs reside to contribute to the differentiation of VSMC-like cells from ASCs and BMSCs. In this review, the promises and limitations of several non-traditional culture approaches (e.g., co culture, biomechanical, and biomaterial stimuli) targeting VSMC differentiation are discussed. The extensive crosstalk between the underlying signalling cascades are delineated and put into a translational context. It is expected that this review will not only provide significant insight into VSMC differentiation strategies for vascular smooth muscle tissue engineering applications, but will also highlight the fundamental importance of engineering the cellular microenvironment on multiple scales (with consideration of different combinatorial pathways) in order to direct cell differentiation fate and obtain cells of a desired and stable phenotype. These strategies may ultimately be applied to different sources of stem cells in the future for a range of biomaterial and tissue engineering disciplines. PMID- 28843067 TI - Elevated modified shock index in early sepsis is associated with myocardial dysfunction and mortality. AB - PURPOSE: The aim of this study was to explore the association of an elevated modified shock index (MSI) in sepsis and myocardial dysfunction. METHODS: This single center exploratory retrospective cohort study was conducted at Mayo Clinic from 2011 to 2014. It includes adults admitted to the medical intensive care unit with severe sepsis or septic shock. The time MSI>1.3, area under the curve, in the first 6h was assessed using logistic regression for primary outcomes of myocardial dysfunction and depression and secondary outcomes including mortality and SOFA score. RESULTS: Overall 578 individuals met inclusion criteria, 169 (29%) developed myocardial dysfunction and 23 (4%) myocardial depression. Adjusted for age, gender, Charlson score, and baseline APACHE 3 score, area MSI>1.3 was associated with increased odds of myocardial dysfunction (OR 1.10, 95% CI 1.00-1.21; p=0.058) and depression (OR 1.28, 95% CI 1.07-1.53; p=0.007). Associations were also seen with ICU mortality (OR 1.17, 95% CI 1.04-1.32; p=0.011), hospital mortality (OR 1.13, 95% CI 1.02-1.25; p=0.025) and SOFA score. CONCLUSION: Elevated modified shock index during early sepsis is associated with the development of myocardial dysfunction and depression, SOFA score and mortality. PMID- 28843068 TI - Identification of intronic-splice site mutations in GATA4 gene in Indian patients with congenital heart disease. AB - Congenital Heart Disease (CHD) is the most common birth defect among congenital anomalies that arise before birth. GATA4 transcription factor plays an important role in foetal heart development. Mutational analysis of GATA4 gene in CHD patients revealed five known heterozygous mutations (p.T355S, p.S377G, p.V380M, p.P394T and p.D425N) identified in exons 5 and 6 regions and fifteen intronic variants in the non-coding regions (g.76885T>C/Y,g.76937G>S, g.78343G>R, g.83073T>Y, g.83271C>A/M, g.83318G>K, g.83415G>R, g.83502A>C/M, g.84991G>R, g.85294C>Y, g.85342C>T/Y, g.86268A>R, g.87409G>A/R, g.87725T>Y, g.87813A>T/W). In silico analysis of these intronic variants identified two potential branch point mutations (g.83271C>A/M, g.86268A>R) and predicted effects of these on intronic splice sites as enhancer and silencer motifs. This study attempts to correlate the pattern of intronic variants of GATA4 gene which might provide new insights to unravel the possible molecular etiology of CHD. PMID- 28843069 TI - New onset status epilepticus in older patients: Clinical characteristics and outcome. AB - PURPOSE: We here evaluated (1) the differential characteristics of status epilepticus (SE) in older (>=60 years) compared to younger adults (18-59 years). In particular, we were interested in (2) the proportion and characteristics of new onset SE in patients with no history of epilepsy (NOSE) in older compared to younger adults, and (3) predictive parameters for clinical outcome in older subjects with NOSE. METHODS: We performed a monocentric retrospective analysis of all adult patients (>=18years) admitted with SE to our tertiary care centre over a period of 10 years (2006-2015) to evaluate clinical characteristics and short time outcome at discharge. RESULTS: One-hundred-thirty-five patients with SE were included in the study. Mean age at onset was 64 years (range 21-90), eighty-seven of the patients (64%) were older than 60 years. In 76 patients (56%), SE occurred as NOSE, sixty-seven percent of them were aged >=60 years. There was no age dependent predominance for NOSE. NOSE was not a relevant outcome predictor, especially regarding age-related subgroups. Older patients with NOSE had less frequently general tonic clonic SE (GTCSE; p=0.001) and were more often female (p=0.01). Regarding outcome parameters and risk factors in older patients with NOSE, unfavourable outcome was associated with infections during in-hospital treatment (0.04), extended stay in ICU (p=0.001), and generally in hospital (p<0.001). CONCLUSION: In our cohort, older patients represented the predominant subgroup in patients with SE. Older patients suffered more often from non convulsive semiology and had a less favourable short-time outcome. NOSE was not a predictive outcome parameter in older patients. Data suggest that avoiding infections should have a priority because higher infection rates were associated with unfavourable outcome. PMID- 28843070 TI - Multi-attribute, multi-alternative models of choice: Choice, reaction time, and process tracing. AB - The first aim of this research is to compare computational models of multi alternative, multi-attribute choice when attribute values are explicit. The choice predictions of utility (standard random utility & weighted valuation), heuristic (elimination-by-aspects, lexicographic, & maximum attribute value), and dynamic (multi-alternative decision field theory, MDFT, & a version of the multi attribute linear ballistic accumulator, MLBA) models are contrasted on both preferential and risky choice data. Using both maximum likelihood and cross validation fit measures on choice data, the utility and dynamic models are preferred over the heuristic models for risky choice, with a slight overall advantage for the MLBA for preferential choice. The response time predictions of these models (except the MDFT) are then tested. Although the MLBA accurately predicts response time distributions, it only weakly accounts for stimulus-level differences. The other models completely fail to account for stimulus-level differences. Process tracing measures, i.e., eye and mouse tracking, were also collected. None of the qualitative predictions of the models are completely supported by that data. These results suggest that the models may not appropriately represent the interaction of attention and preference formation. To overcome this potential shortcoming, the second aim of this research is to test preference-formation assumptions, independently of attention, by developing the models of attentional sampling (MAS) model family which incorporates the empirical gaze patterns into a sequential sampling framework. An MAS variant that includes attribute values, but only updates the currently viewed alternative and does not contrast values across alternatives, performs well in both experiments. Overall, the results support the dynamic models, but point to the need to incorporate a framework that more accurately reflects the relationship between attention and the preference-formation process. PMID- 28843072 TI - Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. PMID- 28843071 TI - RNA-seq based transcriptomic analysis of CPPU treated grape berries and emission of volatile compounds. AB - Grapevine (Vitis vinifera L.) is considered to be one of the most popular and widespread fruit crops in the world. Numerous value added products are prepared from grape fruit and investments are being made to establish new viticulture region (Hoff et al., 2017; Imran et al., 2017). CPPU [forchlorfenuron N-(2-chloro 4-pyridyl)-N-phenylurea] is a synthetic cytokine-like plant regulator which promotes grape berry set and development. The influence of CPPU [forchlorfenuron N-(2-chloro-4-pyridyl)-N-phenylurea] on berry development of 'Shine Muscat' (Vitis labruscana Bailey*V vinifera L.) grapes was evaluated under field conditions. A concentration response was observed over a range of 0, 5, and 10 mgL-1 CPPU that was applied to fruitlets (mean diameter 6mm) at 2 weeks after full bloom. Gas-chromatography mass-spectrometry (GC-MS) revealed that volatile compounds such as terpenoids and aromatics; especially linalool, geraniol and benzyl alcohols, were greatly reduced in CPPU-treated grapes. In contrast, aliphatics, such as hexanol, were increased in CPPU-treated berries. RNA sequencing (RNA-Seq) was conducted to identify differentially expressed genes (DEGs) that were induced by CPPU, especially those related to volatile biosynthesis. A total of 494, 1237, and 1085 DEGs were detected in CPPU0-vs CPPU5, CPPU0-vs-CPPU10, and CPPU5-vs-CPPU10 treatments, respectively. The results were compared against two databases (Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)) to annotate gene descriptions and assign a pathway to each gene. GO covers three domains: biological processes, molecular functions and cellular components. Pathway enrichment annotation demonstrated that highly ranked genes were associated with the fatty acid degradation and biosynthesis, phenylpropanoid metabolism and biosynthesis, carotenoid biosynthesis, and plant hormone signal transduction. Analysis with qRT-PCR of twelve selected transcripts validated the data obtained by RNA-seq. Additionally, we also found that genes such as CCDs (carotenoid cleavage dioxygenase), LOX (lipoxygenase), GGDP reductase (geranylgeranyl diphosphate reductase), PAL (phenylalanine ammonia lyase) and some hormones related genes, were closely involved in the formation of volatiles compounds in CPPU treated berries. In summary, our results provide the first sequential transcriptomic atlas of CPPU treated grape berries which significantly increases our understanding of volatile metabolites and biosynthesis pathways in grape affected by CPPU. PMID- 28843073 TI - The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements. PMID- 28843074 TI - Effects of military service and deployment on clinical symptomatology: The role of trauma exposure and social support. AB - The Marine Resiliency Study-II examined changes in symptomatology across a deployment cycle to Afghanistan. U.S. Servicemembers (N = 1041) received clinical testing at two time points either bracketing a deployment (855) or not (186). Factor analyses were used to generate summary and change scores from Time 1 to Time 2. A between-subject design was used to examine changes across the deployment cycle with deployment (low-trauma, high-trauma, and non-deployed) and social support (low vs. high) as the grouping variables. Insomnia increased post deployment regardless of deployment trauma (std. effect for high-trauma and low trauma = 0.39 and 0.26, respectively). Only the high-trauma group showed increased PTSD symptoms and non-perspective-taking (std. effect = 0.40 and 0.30, respectively), while low-trauma showed decreased anxiety symptoms after deployment (std. effect = -0.17). These associations also depend on social support, with std. effects ranging from -0.22 to 0.51. When the groups were compared, the high-trauma deployed group showed significantly worse PTSD and non perspective-taking than all other groups. Similar to studies in other military divisions, increased clinical symptoms were associated with high deployment stress in active duty Servicemembers, and social support shows promise as a moderator of said association. PMID- 28843075 TI - Expression of adiponectin and its receptors (AdipoR1 and AdipoR2) in goat ovary and its effect on oocyte nuclear maturation in vitro. AB - Adiponectin is an adipokine secreted primarily by adipocytes and is involved in the control of male and female reproductive functions. Circulating levels of adiponectin are inversely correlated with body fat mass, and its biological effects are predominantly mediated through two receptors, AdipoR1 and AdipoR2. The aim of the present study was to verify the expression of the adiponectin system (adiponectin and its receptors, AdipoR1 and AdipoR2) in goat ovary using qPCR and immunohistochemistry analyses and further investigate the in vitro effects of recombinant adiponectin (5 MUg/mL and 10 MUg/mL) on goat oocyte nuclear maturation. We demonstrated that the mRNA and proteins of the adiponectin system are present in goat ovary. Gene and protein expression of AdipoR1 and AdipoR2 was detected in follicular cells (oocyte, cumulus, granulosa and theca) of small and large antral follicles, while adiponectin mRNA was not detected in oocytes from small and large follicles or in large follicle cumulus cells. Finally, addition of various concentrations of adiponectin in maturation medium affected the number of oocytes that reached metaphase II. In conclusion, in the present study, we detected expression of adiponectin and its receptors AdipoR1 and AdipoR2 in goat ovarian follicles. Furthermore, we demonstrated that recombinant adiponectin increases nuclear maturation of goat oocytes in vitro. PMID- 28843076 TI - Epididymal alpha-l-fucosidase and its possible role in remodelling the surface of bull spermatozoa. AB - The mammalian epididymis provides an appropriate environment for sperm maturation. During the epididymal transit, spermatozoa undergo biochemical and morphological changes that lead to the acquisition of the fertilizing capacity. In this study we analysed the fucosylation status of membrane glycoproteins in the spermatozoa obtained from different regions of the bull epididymis. High amounts of fucose were detected on caput spermatozoa (R.F.I. = 1010 +/- 20.35), mostly located in the post-acrosome zone. A significant decrease in the fucose levels was detected toward the cauda (R.F.I. = 540.5 +/- 49.93) (P < 0.05). This decrease was in line with the increased activity of alpha-l-fucosidase in the cauda fluid. In sperm from the cauda, the defucosylation occurred in some proteins, whereas others showed higher fucosylation rates. A significant decrease of fucose in the gametes was observed upon incubation of crude cauda fluid with caput spermatozoa (from R.F.I. = 1.45 +/- 0.08 to 1.06 +/- 0.03) (P < 0.05) indicating that the alpha-l-fucosidase present in the epididymal fluid is active on spermatozoa. Moreover, this effect was blocked with specific enzyme inhibitors. These results provide direct evidence that the alpha-l-fucosidase from epididymal fluid participates in the fucose removal from spermatozoa, as a step of sperm maturation in the bull epididymis. PMID- 28843077 TI - Effects of maternal history of depression and early life maltreatment on children's health-related quality of life. AB - BACKGROUND: There is a well-established link between maternal depression and child mental health. Similar effects have been found for maternal history of early life maltreatment (ELM). However, studies investigating the relationship of children's quality of life and maternal depression are scarce and none have been conducted for the association with maternal ELM. The aim of the present study was to investigate the effects of maternal history of ELM and depression on children's health-related quality of life and to identify mediating factors accounting for these effects. METHODS: Our study involved 194 mothers with and without history of depression and/or ELM and their children between five and 12 years. Children's health-related quality of life was assessed by maternal proxy- and child self-ratings using the KIDSCREEN. We considered maternal sensitivity and maternal parenting stress as potential mediators. RESULTS: We found an effect of maternal history of depression but not of maternal history of ELM on health related quality of life. Maternal stress and sensitivity mediated the effects of maternal depression on child global health-related quality of life, as well as on the dimensions Autonomy & Parent Relation, School Environment (maternal and child rating), and Physical Wellbeing (child rating). LIMITATION: Due to the cross sectional design of the study, causal interpretations must be made with caution. Some scales yielded low internal consistency. CONCLUSIONS: Maternal impairments in areas of parenting which possibly developed during acute depression persist even after remission of acute affective symptoms. Interventions should target parenting stress and sensitivity in parents with prior depression. PMID- 28843078 TI - Impact of early and recent stress on white matter microstructure in major depressive disorder. AB - BACKGROUND: Major Depressive Disorder (MDD) is a worldwide-spread pathology, characterized by lifetime-recurrent episodes. Adverse childhood experiences (ACE) increase the lifetime risk of developing depression and affect the structure of the brain. Recent stressful events (RSE) can trigger the onset of depressive episodes, and affect grey matter volume. The aim of our study is to analyse the effect of both early and recent stress events on white matter microstructure in MDD patients and healthy volunteers. METHODS: Sixty-five MDD inpatients and fifty nine healthy controls underwent MRI acquisition of diffusion tensor images with a 3.0T scanner. Severity of ACE and RSE was rated, respectively, on the Risky Families Questionnaire and on the Social Readjustment Rating Scale. RESULTS: A significant effect of diagnosis was observed, with MDD subjects showing reduced fractional anisotropy (FA) and axial diffusivity (AD) compared to healthy controls in all the major association, projection and commissural tracts. In patients with MDD, but not in healthy controls, both ACE and RSE correlated with measures of WM microstructure: ACE correlated negatively with AD and MD, whereas RSE correlated negatively with FA. LIMITATIONS: The two diagnostic groups differed for age and education, previous and current medications, and treatment periods. CONCLUSIONS: Exposure to both early and recent stress exerts a widespread effect on WM microstructure of MDD patients, with a different impact possibly depending from the developmental period in which the stress has occurred. PMID- 28843079 TI - Investigating the role of hopelessness in the relationship between PTSD symptom change and suicidality. AB - BACKGROUND: This study served as an initial investigation of the role hopelessness may play in the relationship between PTSD symptom change and suicide intent, among a trauma-exposed, treatment-seeking sample. We explored whether the effect of PTSD symptom change on self-reported likelihood of a future suicide attempt (FSA) varies as a function of pre-treatment hopelessness, and whether reductions in hopelessness serve as a mechanism through which PTSD symptom change influences FSA likelihood. METHODS: Data was collected from participants (N = 159) in a larger randomized clinical trial of a suicide risk-factor intervention. Self-report questionnaires assessed hopelessness, PTSD symptoms, depression symptoms, and FSA likelihood at pre-treatment and one-month follow-up. RESULTS: Pre-treatment hopelessness emerged as a significant moderator, such that overall PTSD symptom reductions were related to overall decreases in FSA likelihood among those at or above (but not those below) the sample mean of pre-treatment hopelessness. In a subsample of individuals who reported FSA likelihood > 0 and elevated hopelessness at pre-treatment, overall pre-treatment-to-month-one reductions in hopelessness significantly mediated the relationship between overall PTSD symptom reductions and decreased FSA likelihood during this same time period, even after accounting for depression symptom changes. LIMITATIONS: Data were limited to self-report measures (i.e., hopelessness, FSA likelihood). The intervention was not PTSD-specific. Mediation analyses were strictly statistical due to overlapping time-points. CONCLUSIONS: This preliminary investigation suggests pre-treatment hopelessness may serve to identify trauma exposed individuals for whom PTSD treatment would significantly reduce FSA likelihood. Moreover, reductions in FSA likelihood during treatment may be due in part to reduced hopelessness. PMID- 28843080 TI - Association between hypovitaminosis D and cognitive inhibition impairment during major depression episode. AB - BACKGROUND: Major depressive episode (MDE) has been associated with cognitive functioning alteration and hypovitaminosis D (hypoVD), but the relationship between hypoVD, depression, and cognition is not well understood. We aimed to compare patient with MDE with or without hypoVD in regard of cognitive functioning. METHODS: 91 patients (38.5 years old, 65.9% female) with MDE were included in a cross-sectional study and were evaluated with a complete cognitive battery. None of the participants were medicated at the time of the inclusion. Serum 25-hydroxyvitamin D was measured using LC-MS/MS method, and hypovitaminosis was defined as 25OHD < 50nmol/L. Covariates were gender, season of dosage, first MDE onset, age, body mass index and depression severity RESULTS: Patients with hypoVD demonstrated a higher stroop intereference index time underscoring that means low cognitive inhibition ability. Mutiple logistic regression confirmed that hypoVD was significantly associated with high stroop interference time index after controlling by gender, season of dosage, first MDE onset, age, body mass index and depression severity. CONCLUSION: Our results suggest that patient with MDE having hypoVD may be more prone to cognitive impairment. PMID- 28843081 TI - Cumulative childhood trauma, emotion regulation, dissociation, and behavior problems in school-aged sexual abuse victims. AB - BACKGROUND: Child sexual abuse is associated with a plethora of devastating repercussions. A significant number of sexually abused children are likely to experience other forms of maltreatment that can seriously affect their emotion regulation abilities and impede on their development. The aim of the study was to test emotion regulation and dissociation as mediators in the association between cumulative childhood trauma and internalized and externalized behavior problems in child victims of sexual abuse. METHODS: Participants were 309 sexually abused children (203 girls and 106 boys; Mean age = 9.07) and their non-offending parent. Medical and clinical files were coded for cumulative childhood trauma. At initial evaluation (T1), parents completed measures assessing children's emotion regulation abilities and dissociation. At Time 2 (T2), parents completed a measure assessing children's behavior problems. Mediation analyses were conducted with emotion regulation and dissociation as sequential mediators using Mplus software. RESULTS: Findings revealed that cumulative childhood trauma affects both internalized and externalized behavior problems through three mediation paths: emotion regulation alone, dissociation alone, and through a path combining emotion regulation and dissociation. LIMITATIONS: Both emotion regulation and dissociation were assessed at T1 and thus the temporal sequencing of mediators remains to be ascertained through a longitudinal design. All measures were completed by the parents. CONCLUSIONS: Clinicians should routinely screen for other childhood trauma in vulnerable clienteles. In order to tackle behavior problems, clinical interventions for sexually abused youth need to address emotion regulation competencies and dissociation. PMID- 28843082 TI - Attitudes toward placebo-controlled clinical trials among depressed patients in Japan. AB - BACKGROUND: Placebo-controlled clinical trials are the standard in the design of clinical studies for the licensing of new drugs. Medical and ethical concerns regarding placebo use still exist in clinical trials of depressed patients. The aim of this study was to investigate the attitudes toward placebo-controlled clinical trials and to assess factors related to the willingness to participate in such trials among depressed patients in Japan. METHODS: A total of 206 depressed patients aged 49.5 +/- 15.7 years (mean +/- SD) who were admitted to three psychiatric hospitals were recruited for a cross-sectional study from June 2015 to March 2016. After a thorough explanation of the placebo, the study participants completed a brief 14-item questionnaire developed to evaluate patients' attitudes regarding possible participation in placebo-controlled clinical trials. The Quick Inventory of Depressive Symptomatology was also administered to assess depressive symptoms. RESULTS: The results indicated that 47% of the patients would be willing to participate in a placebo-controlled clinical trial. Expectations for the improvement of disease, desire to receive more medical care, encouragement by family or friends, and desire to support the development of new drugs were associated with the willingness to participate in such trials, whereas a belief that additional time would be required for medical examinations and fear of exacerbation of symptoms due to placebo use were associated with non-participation. LIMITATIONS: Patients were asked about possible participation in placebo-controlled clinical trials. CONCLUSIONS: Less than half of the respondents were willing to participate in placebo-controlled clinical trials. Attitudes toward participation in a placebo-controlled clinical trial need to be considered when deciding whether to conduct such a trial. PMID- 28843083 TI - Tobacco toxicant exposure in cigarette smokers who use or do not use other tobacco products. AB - BACKGROUND: Non-cigarette other tobacco products (OTP; e.g., cigarillos, little cigars) are typically used in combination with cigarettes, but limited data exists on the tobacco toxicant exposure profiles of dual cigarette-OTP (Cig-OTP) users. This study examined biomarkers of nicotine and carcinogen exposure in cigarette smokers who used or did not use OTP. METHODS: 111 Cig-OTP and 111 cigarette only (Cig Only) users who smoked equivalent cigarettes per day were matched on age (< 40, >=40), race (African American, White), and gender. Participants reported past 7-day daily use of cigarettes and OTP and provided urine for nicotine, cotinine, total nicotine equivalents (TNE) and total NNAL concentrations. RESULTS: Cig-OTP users reported greater past 7-day tobacco use (15.9 versus 13.0 products/day, p<0.01) but had significantly lower creatinine normalized nicotine (606 versus 1301ng/mg), cotinine (1063 versus 2125ng/mg), TNE (28 versus 57 nmol/mg) and NNAL (251 versus 343pg/mg) than Cig Only users (p<0.001). CONCLUSIONS: Cig-OTP users had lower levels of nicotine and metabolites of a lung carcinogen relative to Cig-Only users, but concentrations of toxicants among Cig-OTP users were still at levels that place smokers at great risk from the detrimental health effects of smoking. IMPACT: Our study finds that nicotine and carcinogen exposure in Cig-OTP users are lower compared to cigarette only users, but still likely to be associated with substantial harm. A better understanding of why toxicant levels may be lower in Cig-OTP is an important area for future study. PMID- 28843084 TI - Assessing electronic cigarette effects and regulatory impact: Challenges with user self-reported device power. AB - BACKGROUND: Electronic cigarettes (ECIGs) aerosolize liquids for user inhalation that usually contain nicotine. ECIG nicotine emission is determined, in part, by user behavior, liquid nicotine concentration, and electrical power. Whether users are able to report accurately nicotine concentration and device electrical power has not been evaluated. This study's purpose was to examine if ECIG users could provide data relevant to understanding ECIG nicotine emission, particularly liquid nicotine concentration (mg/ml) as well as battery voltage (V) and heater resistance (ohms, Omega) - needed to calculate power (watts, W). METHODS: Adult ECIG users (N=165) were recruited from Los Angeles, CA for research studies examining the effects of ECIG use. We asked all participants who visited the laboratory to report liquid nicotine concentration, V, and Omega. RESULTS: Liquid nicotine concentration was reported by 89.7% (mean=9.5mg/ml, SD=7.3), and responses were consistent with the distribution of liquids available in commonly marketed products. The majority could not report voltage (51.5%) or resistance (63.6%). Of the 40 participants (24.8%) who reported voltage and resistance, there was a substantial power range (2.2-32,670W) the upper limit of which exceeds that of the highest ECIG reported by any user to our knowledge (i.e., 2512W). If 2512W is taken as the upper limit, only 30 (18.2%) reported valid results (mean 237.3W, SD=370.6; range=2.2-1705.3W). CONCLUSIONS: Laboratory, survey, and other researchers interested in understanding ECIG effects to inform users and policymakers may need to use methods other than user self-report to obtain information regarding device power. PMID- 28843085 TI - The influence of groups and alcohol consumption on individual risk-taking. AB - BACKGROUND: Research addressing the influence of alcohol and groups on risky behaviour has yielded contradictory findings regarding the extent to which intoxicated groups exaggerate or minimise risk-taking. Previous work has examined the effect of intoxication on risk-taking focusing on collective group decision making, and to date the influence of alcohol consumption and groups on individual risk-taking has yet to be explored experimentally. The current study therefore examined the impact of intoxication and groups on individual risk-taking. METHODS: In a mixed design, 99 social drinkers (62 female) attended an experimental session individually (N=48) or in groups of three (N=51). Individuals completed the study in isolation while groups were tested in the same room. Participants completed two behavioural measures of risk-taking: Balloon Analogue Risk Task (BART) and Stoplight Task (SLT), both before and following consumption of an alcoholic (0.6g/kg males, 0.5g/kg females) or a placebo beverage. RESULTS: Those who participated in groups took significantly more risks in both tasks than those in isolation. Alcohol did not increase risk-taking on either risk-taking tasks. However, those who consumed placebo were significantly less risky on the SLT, compared to baseline. No interactions were found between context and beverage on risk-taking. CONCLUSION: The findings do not support a combined effect of alcohol and groups on individual risk-taking. Rather, results indicate that risk-taking behaviour is influenced by peer presence regardless of alcohol consumption. Targeting the influence of groups (above those of alcohol) may hold promise for reducing risk-taking behaviours in drinking environments. PMID- 28843086 TI - Occurrence of illicit drugs in water and wastewater and their removal during wastewater treatment. AB - This review critically evaluates the types and concentrations of key illicit drugs (cocaine, amphetamines, cannabinoids, opioids and their metabolites) found in wastewater, surface water and drinking water sources worldwide and what is known on the effectiveness of wastewater treatment in removing such compounds. It is also important to amass information on the trends in specific drug use as well as the sources of such compounds that enter the environment and we review current international knowledge on this. There are regional differences in the types and quantities of illicit drug consumption and this is reflected in the quantities detected in water. Generally, the levels of illicit drugs in wastewater effluents are lower than in raw influent, indicating that the majority of compounds can be at least partially removed by conventional treatment processes such as activated sludge or trickling filters. However, the literature also indicates that it is too simplistic to assume non-detection equates to drug removal and/or mitigation of associated risks, as there is evidence that some compounds may avoid detection via inadequate sampling and/or analysis protocols, or through conversion to transformation products. Partitioning of drugs from the water to the solids fraction (sludge/biosolids) may also simply shift the potential risk burden to a different environmental compartment and the review found no information on drug stability and persistence in biosolids. Generally speaking, activated sludge-type processes appear to offer better removal efficacy across a range of substances, but the lack of detail in many studies makes it difficult to comment on the most effective process configurations and operations. There is also a paucity of information on the removal effectiveness of alternative treatment processes. Research is also required on natural removal processes in both water and sediments that may over time facilitate further removal of these compounds in receiving environments. PMID- 28843087 TI - Are there mode-specific and fatigue-related electromechanical delay responses for maximal isokinetic and isometric muscle actions? AB - This study used a combined electromyographic, mechanomyographic, and force approach to identify electromechanical delay (EMD) from the onsets of the electromyographic to force signals (EMDE-F), onsets of the electromyographic to mechanomyogrpahic signals (EMDE-M), and onsets of mechanomyographic to force signals (EMDM-F). The purposes of the current study were to examine: (1) differences in EMDE-M, EMDM-F, and EMDE-F from the vastus lateralis between maximal isokinetic and maximal concentric isometric leg extensions; and (2) the effects of fatigue and recovery on EMDE-M, EMDM-F, and EMDE-F. These EMD measures were obtained from twelve men during maximal concentric isokinetic and isometric leg extensions pretest, posttest, and after 3-min and 5-min of recovery from 25 maximal isokinetic leg extensions at 60 degrees s-1. The results indicated no differences between maximal isokinetic and isometric muscle actions for EMDE-M, EMDM-F, or EMDE-F during the pretest, posttest, 3-min recovery, and 5-min recovery measurements. These findings support the comparison of voluntary EMD measures between studies with different modes of exercise as long as the methodology for the determination of EMD are consistent. There were, however, fatigue-induced pretest to posttest increases in EMDE-M, EMDM-F, and EMDE-F which remained elongated after 3-min of recovery, but returned to pretest values after 5-min of recovery. PMID- 28843088 TI - Neural predictors of substance use disorders in Young adulthood. AB - Offspring from multiplex, alcohol-dependent families are at heightened risk for substance use disorders (SUDs) in adolescence and young adulthood. These high risk offspring have also been shown to have atypical structure and function of brain regions implicated in emotion regulation, social cognition, and reward processing. This study assessed the relationship between amygdala and orbitofrontal cortex (OFC) volumes obtained in adolescence and SUD outcomes in young adulthood among high-risk offspring and low-risk controls. A total of 78 participants (40 high-risk; 38 low-risk) from a longitudinal family study, ages 8 19, underwent magnetic resonance imaging; volumes of the amygdala and OFC were obtained with manual tracing. SUD outcomes were assessed at approximately yearly intervals. Cox regression survival analyses were used to assess the effect of regional brain volumes on SUD outcomes. The ratio of OFC to amygdala volume significantly predicted SUD survival time across the sample; reduction in survival time was seen in those with smaller ratios for both high-risk and low risk groups. Morphology of prefrontal relative to limbic regions in adolescence prospectively predicts age of onset for substance use disorders. PMID- 28843089 TI - Evaluation of the Precision ID Identity Panel for the Ion TorrentTM PGMTM sequencer. AB - In cases where only a partial or incomplete STR profile is obtained from a sample, information contained in single nucleotide polymorphisms (SNPs) can prove informative for human identification. Thermo Fisher Scientific, which developed the high throughput Ion TorrentTM PGMTM sequencer, released the Precision ID Identity Panel, a multiplex SNP panel for human identity. We evaluated the reproducibility and sensitivity of this multiplex, which contains primers for the amplification of 90 autosomal SNPs and 34 Y-clade SNPs. The manufacturer's protocol was tested using five commercially available pure native DNAs and six forensic type samples at a range of DNA input amounts (0.2-1.0ng; n, 90). In addition to analyzing the data using the manufacturer's software, HID SNP Genotyper (v4.3.1), we also used CLC Genomics Workbench (Qiagen). Although library yields and templating of ion sphere particles (ISPs) were low, downstream sequencing was still successful. Across all samples, only 1.5% of all possible quality control (QC) flags were raised by both the plugin QC filter and CLC; 85% of those flags were raised as the SNP had a major allele frequency outside the thresholds specified by the manufacturer. For the remaining SNPs, coverage of >1500 X and >780 X was obtained for autosomal and Y-clade SNPs respectively, and 100% congruence among genotype calls from both analysis programs was observed. Our results demonstrate that it is possible to obtain reliable and reproducible genotypes using the Precision ID Identity Panel, when using low quantities (>=0.2ng) of either pure native DNA or forensic type DNA samples. PMID- 28843090 TI - Neural network for regression problems with reduced training sets. AB - Although they are powerful and successful in many applications, artificial neural networks (ANNs) typically do not perform well with complex problems that have a limited number of training cases. Often, collecting additional training data may not be feasible or may be costly. Thus, this work presents a new radial-basis network (RBN) design that overcomes the limitations of using ANNs to accurately model regression problems with minimal training data. This new design involves a multi-stage training process that couples an orthogonal least squares (OLS) technique with gradient-based optimization. New termination criteria are also introduced to improve accuracy. In addition, the algorithms are designed to require minimal heuristic parameters, thus improving ease of use and consistency in performance. The proposed approach is tested with experimental and practical regression problems, and the results are compared with those from typical network models. The results show that the new design demonstrates improved accuracy with reduced dependence on the amount of training data. As demonstrated, this new ANN provides a platform for approximating potentially slow but high-fidelity computational models, and thus fostering inter-model connectivity and multi-scale modeling. PMID- 28843091 TI - Fast DCNN based on FWT, intelligent dropout and layer skipping for image retrieval. AB - Deep Convolutional Neural Network (DCNN) can be marked as a powerful tool for object and image classification and retrieval. However, the training stage of such networks is highly consuming in terms of storage space and time. Also, the optimization is still a challenging subject. In this paper, we propose a fast DCNN based on Fast Wavelet Transform (FWT), intelligent dropout and layer skipping. The proposed approach led to improve the image retrieval accuracy as well as the searching time. This was possible thanks to three key advantages: First, the rapid way to compute the features using FWT. Second, the proposed intelligent dropout method is based on whether or not a unit is efficiently and not randomly selected. Third, it is possible to classify the image using efficient units of earlier layer(s) and skipping all the subsequent hidden layers directly to the output layer. Our experiments were performed on CIFAR-10 and MNIST datasets and the obtained results are very promising. PMID- 28843092 TI - A patch-based convolutional neural network for remote sensing image classification. AB - Availability of accurate land cover information over large areas is essential to the global environment sustainability; digital classification using medium resolution remote sensing data would provide an effective method to generate the required land cover information. However, low accuracy of existing per-pixel based classification methods for medium-resolution data is a fundamental limiting factor. While convolutional neural networks (CNNs) with deep layers have achieved unprecedented improvements in object recognition applications that rely on fine image structures, they cannot be applied directly to medium-resolution data due to lack of such fine structures. In this paper, considering the spatial relation of a pixel to its neighborhood, we propose a new deep patch-based CNN system tailored for medium-resolution remote sensing data. The system is designed by incorporating distinctive characteristics of medium-resolution data; in particular, the system computes patch-based samples from multidimensional top of atmosphere reflectance data. With a test site from the Florida Everglades area (with a size of 771 square kilometers), the proposed new system has outperformed pixel-based neural network, pixel-based CNN and patch-based neural network by 24.36%, 24.23% and 11.52%, respectively, in overall classification accuracy. By combining the proposed deep CNN and the huge collection of medium-resolution remote sensing data, we believe that much more accurate land cover datasets can be produced over large areas. PMID- 28843093 TI - Model-data comparison of high frequency compressional wave attenuation in water saturated granular medium with bimodal grain size distribution. AB - Several acoustic models, such as the poro-elastic model, visco-elastic model, and multiple scattering model, have been used for describing the dispersion relation in a porous granular medium. However, these models are based on continuum or scattering theory, and therefore cannot explain the broadband measurements in cases where scattering and non-scattering losses co-exist. Additionally, since the models assume that the porous granular medium consists of grains of identical size (unimodal size distribution), the models does not account for the behavior of wave dispersion in a medium that has a distribution of differing grain sizes. As an alternative approach, this study proposes a new broadband attenuation model that describes the high frequency dispersion relation for the p-wave in the case of elastic grain scatterers existing in the background fluid medium. The broadband model combines the Biot-Stoll plus grain contact squirt and shear flow (BICSQS) model and the quasicrystalline approximation (QCA) multiple scattering model. Additionally, distribution of grain size effect is examined rudimentarily through consideration of bimodal grain size distribution. Through the quantitative analysis of the broadband model and measured data, it is shown that the model can explain the attenuation dependencies of frequency and grain size distribution for a water-saturated granular medium in the frequency range from 350kHz to 1.1MHz. This study can be applied to the high frequency acoustic SONAR modeling and design in the water-saturated environment. PMID- 28843094 TI - MERS coronavirus nsp1 participates in an efficient propagation through a specific interaction with viral RNA. AB - MERS-CoV is the only lethal human CoV still endemic in the Arabian Peninsula and neither vaccine nor therapeutics against MERS-CoV infection is available. The nsp1 of CoV is thought to be a major virulence factor because it suppresses protein synthesis through the degradation of host mRNA. In contrast, viral RNA circumvents the nsp1-mediated translational shutoff for an efficient propagation. In this study, we identified amino acid residue in MERS-CoV nsp1 that differ from those of SARS-CoV nsp1, and that appear to be crucial for circumventing the translational shutoff. In addition, reverse genetics analysis suggested the presence of a cis-acting element at the 5'-terminus of the nsp1-coding region, which contributes to the specific recognition of viral RNA that is required for an efficient viral replication. Our results suggest the CoVs share a common mechanism for circumventing the nsp1-mediated translational shutoff. PMID- 28843095 TI - Truck-involved crashes injury severity analysis for different lighting conditions on rural and urban roadways. AB - This paper investigates factors affecting injury severity of crashes involving trucks for different lighting conditions on rural and urban roadways. It uses 2009-2013 Ohio crash data from the Highway Safety Information System. The explanatory factors include the occupant, vehicle, collision, roadway, temporal and environmental characteristics. Six separate mixed logit models were developed considering three lighting conditions (daylight, dark, and dark-lighted) on two area types (rural and urban). A series of log-likelihood ratio tests were conducted to validate that these six separate models by lighting conditions and area types are warranted. The model results suggest major differences in both the combination and the magnitude of impact of variables included in each model. Some variables were significant only in one lighting condition but not in other conditions. Similarly, some variables were found to be significant in one area type but not in other area type. These differences show that the different lighting conditions and area types do in fact have different contributing effects on injury severity in truck-involved crashes, further highlighting the importance of examining crashes based on lighting conditions on rural and urban roadways. Age and gender of occupant (who is the most severely injured in a crash), truck types, AADT, speed, and weather condition were found to be factors that have significantly different levels of impact on injury severity in truck-involved crashes. PMID- 28843096 TI - Insect succession on pig carcasses using different exposure time - A preliminary study in Guangzhou, China. AB - The exposure time of carcasses in insect succession studies are generally not consistent and more than 40% studies start in the morning. How such an arrangement affects the succession of insects is worth evaluating. In this study, six piglet carcasses (15-17 kg) were exposed at 6 time points during the day: 11:00, 15:00, 19:00, 23:00, 03:00 and 07:00 on July 20th-July 21st 2006 in Guangzhou, China to investigate the potential effects of the time of day of carcass exposure on body decomposition and insect succession, and also to provide fundamental data on insect succession in summer for this area. The results showed that there were negligible differences in the decay process among the carcasses. We found the carcasses synchronized their decay stage after entering the bloated stage on July 21st. All 6 carcasses entered the remains stage on August 3rd (approximately 14 d after carcass placement). The carcasses yielded 30 species of arthropods, representing 3 orders and 12 families, and no obvious differences were found in species composition between the carcasses. However, we found that there were significant differences in the arrival and colonization of Calliphoridae. We found two batches of Chrysomya megacephala (Fabricius) larvae with significant differences in body length and instar on the carcasses placed at the site at 11:00, 15:00 and 19:00. By contrast, there was only one batch of C. megacephala larvae having similar body length and instar on the carcasses placed at the site at 23:00, 03:00 and 07:00. These observations have potential use for estimating the postmortem interval in forensic entomology. PMID- 28843097 TI - Writer identification: A comparative study across three world major languages. AB - This paper presents a review on the state of the art in offline text-independent writer identification methods for three major languages, namely English, Chinese and Arabic, which were published in literatures from 2011 till 2016. For ease of discussions, we grouped the techniques into three categories: texture-, structure , and allograph-based. Results are analysed, compared and tabulated along with datasets used for fair and just comparisons. It is observed that during that period, there are significant progresses achieved on English and Arabic; however, the growth on Chinese is rather slow and far from satisfactory in comparison to its wide usage. This is due to its complex writing structure. Meanwhile, issues on datasets used by previous studies are also highlighted because the size matter - accuracy of the writer identification deteriorates as database size increases. PMID- 28843098 TI - Prevalence and characteristics of inhalational and dermal palytoxin exposures reported to the National Poison Data System in the U.S. AB - INTRODUCTION: Palytoxin, produced by unicellular microalgae, is one of the most potent toxins known. Human exposure results most prominently through oral, dermal, and inhalational contact. There is no current data on the prevalence of cases in the United States. METHODS: This study reviewed human inhalational and dermal exposures to palytoxin via records from the National Poison Data System from 2000 to 2014. RESULTS: There were 171 cases reported, the majority occurred at a residence and experienced minor respiratory or dermal symptoms and recovered without any major sequelae or fatalities. Ten patients required admission to an intensive care unit. CONCLUSION: The incidence of palytoxin exposure is low but significant symptoms can occur. PMID- 28843099 TI - Self-defense of Escherichia coli against damages caused by nanoalumina. AB - Although studies showed effects of nanoalumina (nano-Al2O3) on Escherichia coli, no study completely provides understanding on how bacterial cells respond to damages, especially on how they initiate self-defense. In this study, we showed three types of responses of E. coli to damages caused by nano-Al2O3. Live, dead, and injured, bacteria showed improved survival rates reaching 104%, 116%, and 104% after exposure to 0.1, 1, and 10mmol/L of nano-Al2O3 respectively. Survival rates improved from 100% to 114%, corresponding to an exposure time of 0-9h, and from 100% to 127%, corresponding to 0-1000MUg/L Al3+. Improvements were noted in survival rates of E. coli K12 MG1655, HB101, DH5alpha, and K12 MG1655 ?lexA treated by nano-Al2O3 in Luria-Bertani (LB) exposure system or K12 MG1655 in LB, normal saline(NS) and H2O exposure system. Bacterial cells transformed from long rods to ellipsoidal or nearly spherical as form of self-preservation mechanism; this phenomenon may be related to changes in membrane potential induced by free Al3+ released from nano-Al2O3 particles. Molecular mechanism of this response involved inhibited gene expression of sythesis and metabolism of carbohydrates, lipids and proteins. Findings presented in this study may improve understanding of potential danger of nanomaterials and control their spread to environmen. PMID- 28843100 TI - Differential tissue regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) and cannabinoid receptor 1 (CB1) gene transcription pathways by diethylene glycol dibenzoate (DEGB): preliminary observations in a seabream (Sparus aurata) in vivo model. AB - Today a variety of endocrine disrupting chemicals (EDCs) are recognized in the group of metabolic disruptors, a wide range of environmental contaminants that alter energy balance regulation by affecting the peroxisome proliferator activated receptor (PPAR)/retinoid X receptor (RXR) pathway. Herein, we investigated the effect of diethylene glycol dibenzoate (DEGB), a dibenzoate based plasticizer used as alternative to phthalates, on the expression of key genes involved in lipid metabolism and energy balance by using Sparus aurata juveniles as models. We also evaluated the correlation between cannabinoid receptor 1 (CB1) and PPARalpha transcriptional patterns in both liver and brain tissues. Exposure to the highest DEGB concentration differentially modulated PPARalpha/CB1 transcriptional pathways in liver/brain tissues of seabream. We hypothesize that, at peripheral level (i.e. liver), DEGB acts as PPARalpha agonist resulting in a potential stimulation of key lipolytic genes and a concomitant down-regulation of endocannabinoid metabolic enzyme genes. PMID- 28843101 TI - Modelling the impact of targeted anthelmintic treatment of cattle on dung fauna. AB - The insecticidal properties of many anthelmintics pose a risk to dung fauna through the effects of drug residues in dung on the activity, oviposition and development of dung-dwelling invertebrates. Reductions in dung fauna numbers can inhibit dung degradation, which may impact biodiversity and nutrient cycling on farms. A simulation model was created to predict the impact of antiparasitic drugs on cattle dung fauna, and calibrated using published data on the dung breeding fly Scathophaga stercoraria. This model was then tested under different effective dung drug concentrations (EC) and proportions of treated cattle (PT) to determine the impact under different application regimens. EC accounted for 12.9% of the observed variation in S. stercoraria population size, whilst PT accounted for 54.9%. The model outputs indicate that the tendency within veterinary medicine for targeted selective treatments (TST), in order to attenuate selection for drug resistance in parasite populations, will decrease the negative impacts of treatments on dung fauna populations by providing population refugia. This provides novel evidence for the benefits of TST regimens on local food webs, relative to whole-herd treatments. The model outputs were used to create a risk graph for stakeholders to use to estimate risk of anthelminthic toxicity to dung fauna. PMID- 28843102 TI - Assessment of exposure to pesticides in rural workers in southern of Minas Gerais, Brazil. AB - The aim of the study was to assess of occupational exposure to pesticides in rural workers using genotoxicity test, bioindicators and clinical evaluation. Blood, urine and buccal samples from persons, rural workers exposed to a complex mixture of pesticides with organophosphates (n=94) and without organophosphates (n=94) were collected to compare the activities of cholinesterases, the levels of urinary dialkyl phosphates, genotoxicity data, from a cytome assay. Biomarkers were analysed by traditional/published methods Control group consisted of 50 other persons, non- occupationally exposed to pesticides from the city of Alfenas, Minas Gerais, Brazil. All subjects underwent a clinical evaluation. In the group exposed to organophosphates, the activity of acetylcholinesterase, butyrylcholinesterase and total cholinesterase was lower by 63.8%, 12.8%, and 14.8%, respectively, and 92.6% of the group had dialkyl phosphates present in their urine. The cytome assay was used to measure biomarkers of DNA damage (micronuclei and/or elimination of nuclear material by budding), cytokinetic defects (binucleated cells), and proliferative potential (basal cell) and/or cell death (condensed chromatin, karyorrhectic, pyknotic, and karyolytic cells). The group exposed to organophosphates showed significant changes in all these parameters compared to the control group and showed significant changes in budding, condensed chromatin and karyolytic cells compared with the group non exposed to organophosphates. Data from the clinical evaluation showed significant changes in the central nervous, respiratory and auditory systems. The studied biomarkers are able to distinguish occupational and environmental exposure to pesticides and the data showed hazardous exposure to organophosphates and afforded valuable data to estimate the risk to cancer development. PMID- 28843103 TI - Synthesis and bioimaging of biodegradable red fluorescent organic nanoparticles with aggregation-induced emission characteristics. AB - Fluorescent organic nanoparticles (FONs) with aggregation-induced emission (AIE) features have recently emerged as promising fluorescent probes for biomedical applications owing to their excellent optical properties, designability and biocompatibility. Significant progress has been made recently for synthesis and biomedical applications of these AIE-active FONs. However, only very limited reports have demonstrated the fabrication of biodegradable AIE-active FONs with red fluorescence emission. In this study, a novel strategy has been developed for the preparation of biodegradable AIE-active polyurethanes (PUs) through a two step polymerization, in which the diisocyanate-terminated polyethylene glycol (NCO-PEG-NCO) was synthesized and subsequently conjugated with diamine-containing AIE dye (NH2-Phe-NH2). The successful synthesis of AIE-active Phe-PEG2000 PUs is evidenced by a series of characterization techniques. Because of the formation of AIE-active amphiphilic PUs, the final copolymers can self-assemble into spherical nanoparticles, which exhibit strong luminescence and high water dispersion. The biological evaluation results suggest that the AIE-active Phe-PEG2000 FONs possess low toxicity and desirable cell permeability. Therefore, we anticipate that these AIE-active FONs with biodegradable potential will trigger much research enthusiasm and effort toward the creation of new AIE-active materials with improved properties for various biomedical applications. PMID- 28843104 TI - Surface roughness induced superhydrophobicity of graphene foam for oil-water separation. AB - Surface free energy and roughness are two predominant factors governing the hydrophilicity/hydrophobicity of materials. This paper reported the surface roughness induced hydrophobicity of graphene foam by incorporating silica nanoparticles onto graphene sheet via a sol-gel method and subsequent modification using silane. Various techniques were employed to characterize the morphology, composition and surface properties of sample. The results showed that the as-prepared graphene foam exhibited a superhydrophobic surface with a high water contact angle of 156 degrees , as well as superoleophilicity with excellent adsorption capacities for a variety of oil compounds. Benefiting from the integration of enhancement on the surface roughness and reduction on the surface free energy of material, the graphene foam developed in this study had the capability to effectively separate oil-water mixture with excellent stability and recyclability. PMID- 28843105 TI - Polymer-entanglement-driven coassembly of hybrid superparamagnetic nanoparticles: Tunable structures and flexible functionalization. AB - In this study, we report a facile and versatile strategy for preparing a type of pH-responsive superparamagnetic hybrid coassemblies featuring a series of controls over the morphology and multi-functionalization simultaneously and efficiently. Via the entanglement interactions, the combine of fixed PEG-b-P4VP modified Fe3O4 NPs (D-Fe3O4@mPEG-b-P4VP) and different well-designed free PEG-b P4VP, which are analogous to two amphiphiles, contributes these hybrid superstructures with multiple, well-defined morphologies and targeted fluorescent properties. In contrast to other studies, our work overcame several defects (e.g., interior NPs' randomness, cumbersome assembly parameter adjustment and functionalization) of the conventional assembly of modified inorganic NPs and demonstrated that this coassembly strategy can be used as a versatile tool for the controllable assembly of other NPs or polymers. Finally, taking the coassembly C1 as a desirable drug delivery carrier, good biocompatibility and pH triggered drug release were successfully verified. The current study indicated that these magnetic coassemblies are promising as multifunctional and multipurpose carriers in biological, medical, catalytic, and coating applications. PMID- 28843106 TI - Probing pi-pi stacking modulation of g-C3N4/graphene heterojunctions and corresponding role of graphene on photocatalytic activity. AB - The photoelectrochemical properties of g-C3N4 sheet are modified by the pi-pi stacking interaction with graphene, and the corresponding role of graphene on the surface chemical reactions is investigated by density functional theory. The calculated cohesive energies and the lattice mismatch energies indicate that g C3N4 and graphene are in parallel contact and can form a stable heterojunction. According to our calculated energy band structures and work functions of g C3N4/graphene heterojunctions, the band edge modulations by graphene are discussed and corresponding photoinduced charge transfer processes are analyzed in detail. It is found that the incorporating of graphene into g-C3N4 facilitates the separation of photoinduced e-/h+ pairs and the oxidation capacity enhancement of the photoinduced holes with the downshifting of the valence band edge of g C3N4 layer. It is identified that the inhomogeneous onsite energies between interlayer and the band edge modulations are induced by the inhomogeneous charge redistribution between interlayer caused by graphene. Further, the initial dynamic reaction processes of oxygen atoms in g-C3N4/graphene heterojunctions also confirm the significant role of graphene on the surface chemical reactions. PMID- 28843107 TI - pH-sensitive nanogels with ortho ester linkages prepared via thiol-ene click chemistry for efficient intracellular drug release. AB - pH-sensitive nanogels with ortho ester linkages were conveniently prepared through reaction of thiol-ene click chemistry. Through adjusting feed reactant ratios and concentrations of ortho ester diacrylamide (OEAM), pentaerythritol tetra(3-mercaptopropionate) (PT), and methoxyl poly(ethyleneglycol) acrylate (mPEGA), the size of the nanogels could be controlled at 100-200nm with relatively narrow size distributions. The nanogels with size of 149.1+/-17.7nm (designed as NG) were verified by proton nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), dynamic laser scattering (DLS) and transmission electron microscopy (TEM). Doxorubicin (DOX) was loaded into NG with high drug loading efficiency up to 73.7%. In vitro drug release studies showed that up to 75.9% DOX from NG was released in 24h at pH 5.0 because of hydrolysis of ortho ester. Cellular uptake studies confirmed that DOX-loaded NG (NG/DOX) could be readily internalized by two-dimensional cells, resulting in efficient antitumor efficiency of cancer cells. Three-dimensional (3D) multicellular tumor spheroids (MCTS) as in vitro tumor model was used to further evaluate the antitumor effect of NG/DOX. The results demonstrated that NG/DOX showed a significantly enhanced penetration and growth inhibition in 3D multicellular tumor spheroids (MCTS), compared to free DOX. PMID- 28843108 TI - NiO nanoparticles on graphene nanosheets at different calcination temperatures as effective electrocatalysts for urea electro-oxidation in alkaline medium. AB - NiO nanoparticles were supported on graphene nanosheets (NiO/Gr) through coprecipitation step of Ni(OH)2 species, followed by calcination at different temperature values. The formed nanocomposites were characterized by employing X ray diffraction (XRD) and transmission electron microscopy (TEM) to investigate their crystalline structure and morphology. The effect of varying the calcination temperature during the preparation of NiO/Gr electrocatalyst on some kinetic parameters in 0.5M NaOH solution was studied. The electrocatalytic activity of synthesized electrocatalysts was examined for urea electro-oxidation reaction in alkaline solution using cyclic voltammetry, chronoamperometry and electrochemical impedance spectroscopy. Among the fabricated NiO/Gr electrocatalysts, the one that was heated at 200 degrees C exhibited the highest urea oxidation current density value with most stable performance for long time. PMID- 28843109 TI - Adsorption of crystal violet dye onto a mesoporous ZSM-5 zeolite synthetized using chitin as template. AB - HYPOTHESIS: ZSM-5 zeolite is an efficient adsorbent for several compounds. However, is a microporous material, and consequently, is little efficient for large dye molecules. In order to make ZSM-5 zeolite a mesoporous material with ability to adsorb dyes, the use of chitin (low-cost biopolymer) as template in the synthesis route can be an alternative. EXPERIMENTS: ZSM-5 zeolites were synthetized using a nucleating gel as structure-directing agent for the material formation, followed by the chitin insertion (or not), homogenization and hydrothermal treatment. The obtained zeolites (ZSM-5 and chitin/ZSM-5) from these different methods were characterized. The potential of ZSM-5 and chitin/ZSM-5 zeolites to adsorb crystal violet dye (CV) was evaluated in batch mode, considering the effects of adsorbent dosage and pH. Equilibrium, thermodynamic and kinetic studies were also performed. FINDINGS: The use of chitin in the synthesis route provided the following improvements on the ZSM-5 structure: (i) the mesopores volume increased from 0.027 (ZSM-5) to 0.142cm3g-1 (chitin/ZSM-5); (ii) the pore diameter increased from 1.97 (ZSM-5) to 22.49nm (chitin/ZSM-5); (iii) the porosity was increased and the crystallinity was decreased. For both, ZSM-5 and chitin/ZSM-5, the CV adsorption was favored with adsorbent dosage of 2.0gL-1 and pH of 7.5. The pseudo-second order model was suitable to represent the adsorption kinetics and, the Langmuir model was adequate to represent the equilibrium. The maximum adsorption capacity increased from 141.8 (ZSM-5) to 1217.3mgg-1 (chitin/ZSM-5). The adsorption was spontaneous, favorable and endothermic. PMID- 28843110 TI - Cytomegalovirus reactivation in lymphoma and myeloma patients undergoing autologous peripheral blood stem cell transplantation. AB - BACKGROUND: Cytomegalovirus reactivation is often diagnosed in allogeneic hematopoietic cell transplant recipients and therefore could lead to CMV-related disease, involving many organs in these immunocompromised patients. In contrast, few studies investigated CMV reactivation and end-organ disease in patients undergoing Autologous Peripheral Blood Stem Cell Transplant (ASCT) since they are considered at low risk for both reactivation and disease. OBJECTIVES: The primary outcome of the analysis was to understand the difference in incidence of CMV reactivation between MM and Lymphoma patients. Secondary outcomes included the difference between MM and Lymphoma patients when considering the effect of CMV reactivation on transplant related mortality (TRM) overall survival (OS) progression free survival (PFS), risk factors for reactivation, and median time to reactivation. STUDY DESIGN: In this report, we retrospectively compared the incidence, risk factors, and outcome of CMV reactivation in adult patients with Myeloma (MM) and Lymphoma undergoing ASCT at the American university of Beirut Medical Center in Lebanon (AUBMC). A total of 324 consecutive ASCT were performed between January 2005 and March 2016. Serial weekly monitoring for CMV quantification was done using a quantitative PCR, starting from transplantation until the hospital discharge and afterwards based on the clinical symptoms in cases of clinical suspicion of reactivation after discharge from the hospital. RESULTS: The cumulative incidence of CMV reactivation was 16% (n=53) with a median time of 16 (range, 4-242) days after ASCT. The incidence of reactivation was significantly higher in the MM (22%) and NHL (20%) groups, when compared to the HL (4%) (P=0.001). There was a higher incidence of CMV reactivation according to age (>=50 vs <=50 years) with higher incidence in the older population 24% vs 10% respectively (p=0.0043). The mean time to CMV reactivation was significantly higher in the NHL group with a mean of 53.7days when compared to the HL and MM groups with mean 19.75days and 12.66 (range, 4-34) days respectively (P=0.003). Twenty-two patients (76%) and three patients (75%) patients required specific antiviral therapy in the MM group and HL groups respectively; which was significantly higher (P<0.001) then the NHL group with 13 (65%) patients requiring specific antiviral therapy. Five patients (1.5%) developed CMV disease at a median of 60days (range, 7-107) post ASCT: there was significant difference in the mean-time to reactivation based on disease type MM versus lymphoma 10 versus 33days (P=0.007). In multivariate analysis, a higher age was associated with an increased risk of CMV reactivation; MM and NHL had higher risk of CMV reactivation when compared to HL, and progressive disease at transplant was associated with increased risk of CMV reactivation. After a median follow-up of 21.5 months (range: 1-125), there was no significant impact on PFS, however there was significant decrease in OS of lymphoma patients who had CMV reactivation when compared to those without CMV reactivation (204 and 112days respectively P=0.045). TRM increased from 1.1% in patients with no CMV reactivation to 13% in patients with CMV reactivation (P=0.003). CONCLUSION: Our data suggests that CMV reactivation is not uncommon in ASCT recipients and may contribute to increase TRM. MM patients may have a higher incidence, of CMV reactivation with more anti viral treatment requirements when compared to lymphoma patients, especially in older population. PMID- 28843111 TI - Exploitation of a surrogate host, Saccharomyces cerevisiae, to identify cellular targets and develop novel antiviral approaches. AB - Plant RNA viruses are widespread pathogens that need to interact intricately with their hosts to co-opt numerous cellular factors to facilitate their replication. Currently, there are only a limited number of plant resistance genes against a limited number of viruses. To develop novel antiviral approaches, the interaction network between the given virus and the host cell could be targeted. Yeast (Saccharomyces cerevisiae) has been developed as a surrogate host for tomato bushy stunt virus (TBSV), allowing systematic genome-wide screens to identify both susceptibility and restriction factors for TBSV. Importantly, pro-viral or antiviral functions of several of the characterized yeast proteins have been validated in plant hosts. This paper describes how yeast susceptibility and restriction factors of TBSV could be used as antiviral approaches. The gained knowledge on host factors could lead to novel, inducible, broad-range, and durable antiviral tools against plant viruses. PMID- 28843112 TI - Bio-behavioral synchrony promotes the development of conceptualized emotions. AB - As adults, we have structured conceptual representations of our emotions that help us to make sense of and regulate our ongoing affective experience. The ability to use emotion concepts is critical to make predictions about the world and choose appropriate action, such as 'I am afraid, and going to run away' or 'I am hungry and going to eat'. Thus, emotion concepts have an important role in helping us maintain our ongoing physiological balance, or allostasis. We will suggest here that infants can learn emotion concepts for the purpose of allostasis regulation, and that conceptualization is key component in emotional development. Moreover, we will suggest that social dyads facilitate concept learning because of a robust evolutionary feature seen in newborns of social species: they cannot survive alone and depend on conspecifics for allostasis regulation. Such social dependency creates a robust driving force for social learning of emotion concepts, and makes the social dyad, which is designed to regulate the infant's allostasis, an optimal medium for concept learning. In line with that, we will review evidence showing that the neural reference space for emotion overlaps with neural circuits that support allostasis (striatum, amygdala, and hypothalamus) and conceptualization (medial prefrontal cortex, posterior cingulate cortex), and that their developmental trajectories are interrelated, and depend on synchronous social care. PMID- 28843113 TI - Adverse events in veterans affairs inpatient psychiatric units: Staff perspectives on contributing and protective factors. AB - OBJECTIVES: This study sought to identify risk factors and protective factors in hospital-based mental health settings in the Veterans Health Administration (VHA), with the goal of informing interventions to improve care of persons with serious mental illness. METHODS: Twenty key informants from a stratified sample of 7 VHA inpatient psychiatric units were interviewed to gain their insights on causes of patient safety events and the factors that constrain or facilitate patient safety efforts. RESULTS: Respondents identified threats to patient safety at the system-, provider-, and patient-levels. Protective factors that, when in place, made patient safety events less likely to occur included: promoting a culture of safety; advocating for patient-centeredness; and engaging administrators and organizational leadership to champion these changes. CONCLUSIONS: Findings highlight the impact of systems-level policies and procedures on safety in inpatient mental health care. Engaging all stakeholders, including patients, in patient safety efforts and establishing a culture of safety will help improve the quality of inpatient psychiatric care. Successful implementation of changes require the knowledge of local experts most closely involved in patient care, as well as support and buy-in from organizational leadership. PMID- 28843114 TI - Clinical and radiological predictors of outcome in tubercular meningitis: A prospective study of 209 patients. AB - OBJECTIVES: The predictors of poor outcome in tuberculous meningitis (TBM) remain to be delineated. We determined role of various clinical, radiological and cerebrospinal fluid (CSF) parameters in prediction of outcome in TBM. PATIENTS AND METHODS: Current study was a prospective observational study including 209 patients of TBM. All patients underwent detailed evaluation including Gadolinium enhanced Magnetic resonance imaging (GdMRI) of brain as well as tests to detect evidence of tuberculosis elsewhere in body. They also underwent GdMRI at three and nine month follow up. All patients received treatment as per standard guidelines. RESULTS: Mean age was 30.4+/-13.8years. 139 (66.5%) patients had definite TBM while 70 (34.5%) had highly probable TBM. 53 (25.4%) patients died. On univariate analysis, longer duration of illness, altered sensorium, stage III TBM, hydrocephalus and exudates correlated with poor outcome. On multivariate analysis presence of hydrocephalus (p=0.003; OR=3.2; 95% CI=1.5-6.7) and stage III TBM (p<0.0001; OR=8.7; 95% CI=3.7-20.2) correlated with higher risk of mortality. In addition, there was significant positive association between presence of hydrocephalus (p=0.05; OR=2.2; 95% CI=0.97-5.1), stage III TBM (p<0.0001; OR=28; 95% CI=4.9-158) and presence of altered sensorium (p=0.05; OR=22; 95% CI=0.99-4.8) with either death or survival with severe disability. CONCLUSIONS: It is possible to prognosticate TBM using a combination of clinical and radiological. The duration of illness (65.9+/-92days) before diagnosis of TBM continues to be unacceptably long and this stresses on need to educate primary care physicians about TBM. Future studies where intensity and duration of treatment is guided by these cues may help in sorting out some of the most difficult questions in TBM, namely duration of antitubercular therapy as well as dose and duration of steroid therapy etc. PMID- 28843115 TI - Double-level isthmic spondylolisthesis treated with posterior lumbar interbody fusion: A review of 32 cases. AB - OBJECTIVE: The incidence of double-level isthmic spondylolisthesis is rare. The aim of this study is to evaluate the short-term functional and radiological outcomes of surgical treatment for double-level isthmic spondylolisthesis. PATIENTS AND METHODS: Between 2004 and 2014, thirty-two patients with double level isthmic spondylolisthesis who underwent posterior lumbar interbody fusion (PLIF) with autogenous bone chips were reviewed retrospectively. The clinical outcomes were measured by VAS (Visual analog scale) and JOA(Japanese Orthopedic Association) score. RESULTS: At an average follow-up of 2.8 years, the mean score on the VAS of back pain and sciatica decreased from 6.48 and 4.26 points preoperatively to 1.82 and 1.10 points at final follow-up, respectively. The average JOA score improved from 13.8+/-3.1 preoperative to 25.6+/-1.3 (range, 17 28) points postoperative. The average recovery rate was 77.6%. The good and excellent rate was 84.3% (27/32). The fusion rate was 87.5% (28/32). Changes in disc height, degree of listhesis, whole lumbar lordosis, and sacral inclination between the pre- and postoperative periods were significant. CONCLUSIONS: Our findings suggest that PLIF with autogenous bone chips for double-level isthmic spondylolisthesis could yield good functional short-term results. It seems to be a viable approach in the treatment of double-level isthmic spondylolisthesis. PMID- 28843116 TI - Biomonitoring of mercury in hair of breastfeeding mothers living in the Valencian Region (Spain). Levels and predictors of exposure. AB - This study focused on the evaluation of the levels of total mercury in hair among 120 breastfeeding mothers aged 20 to 45 -. The concentrations of Hg ranged from 0.07 to 6.87 MUg/g with a geometric mean (GM) of 1.22 MUg/g. This GM is six times higher than the average internal exposure of mothers from other 17 European countries (0.225 MUg/g). Near 70% of mothers presented levels of Hg above the USA EPA internal exposure guideline of 1 MUg/g, and 27% exceeded the EFSA health based guidance value of 1.9 MUg/g. The multivariate regression analysis revealed that age, smoking and fish consumption (sword fish, small fat fish, small lean fish) were the major predictors of mercury in hair. PMID- 28843117 TI - Identification of endocrine active disinfection by-products (DBPs) that bind to the androgen receptor. AB - The formation of disinfection by-products (DBPs) in drinking water occurs when chemical disinfectants such as chlorine and chloramine react with natural organic matter and anthropogenic pollutants. Some DBPs have been linked to bladder cancer and infertility; however, the underlying mechanism of action is unknown. One possibility is disruption of the endocrine system, with DBPs binding to the androgen receptor and subsequently altering gene expression. Using the androgen receptor-binding assay and in silico molecular docking, the binding affinity of 21 suspected and known DBPs were tested individually at concentrations over the range 0.1 nM-2 mM. 14 DBPs were found to bind at IC50 values ranging from 1.86 mM for 2,3-dichloropropionamide to 13.5 MUM for 3,4,5,6-tetrachloro-benzoquinone as compared to the positive control, 4-n-nonylphenol which bound at 31.6 MUM. Since DBPs are present in drinking waters as mixtures, the question of how IC50 values for individual DBPs might be affected by the presence of other chemicals is addressed. Seven of the chemicals with the strongest binding affinities and one chemical with no binding affinity were tested in binary mixtures with 4-n nonylphenol, a known androgenic chemical found in some surface waters. In these binary mixtures, concentration additive binding was observed. While typical levels of individual androgenic DBPs in drinking water are below their measured IC50 values, their combined binding abilities in mixtures could be a source of androgen disruption. PMID- 28843119 TI - Biofilm of Escherichia coli O157:H7 on cantaloupe surface is resistant to lauroyl arginate ethyl and sodium hypochlorite. AB - Biofilms formed by Escherichia coli O157:H7 on cantaloupe rind were characterized in this study. Cantaloupe rind pieces inoculated with E. coli O157:H7 B6-914 was sampled after 2, 12, and 24h incubation for imaging with cryo-scanning electron microscopy (Cryo-SEM) or treating with lauroyl arginate ethyl (LAE) or sodium hypochlorite (SHC). Cryo-SEM images showed that E. coli O157:H7 formed a biofilm within 12h on the rind surface. For rind samples treated with LAE or SHC, the residual cell counts were significantly different (p<0.05) between 2 and 12h incubation, and between 2 and 24h of incubation. For the 2h incubation samples, E. coli O157:H7 was undetectable (>5-log reduction) after treatment with 2000MUg/mL of LAE or SHC. In contrast, for 12h incubation samples, 2000MUg/mL of LAE or SHC could only achieve 1.74 or 1.86-log reduction, respectively. The study showed the low efficacy of LAE and SHC on cantaloupe rind surface to reduce the E. coli biofilm, suggesting the needs for cantaloupe cleaning methods beyond washing with conventional antimicrobial agents. PMID- 28843118 TI - Antimicrobial evaluation of novel poly-lactic acid based nanocomposites incorporated with bioactive compounds in-vitro and in refrigerated vacuum-packed cooked sausages. AB - Biodegradability and antimicrobial activity of food packaging materials are among the most attractive parameters in modern food industries. In order to develop biodegradable poly-lactic acid (PLA) film to antibacterial nanocomposites, different concentration of Zataria multiflora Bioss. essential oil (ZME), propolis ethanolic extract (PEE) and cellulose nanofiber (CNF) were incorporated to the polymer by solvent casting method. The resulting films were characterized by mechanical and physical tests and their antimicrobial application was evaluated in-vitro against four common foodborne pathogens and in vacuum-packed cooked sausages during refrigerated storage. Mechanical examination revealed that addition of ZME and PEE made films more flexible and incorporation of CNF improved almost all mechanical parameters tested. Moreover, according to physical analysis, incorporation of 0.5% v/v ZME to the composite primary solutions improved water vapor permeability of the resulting films. Almost all of the active films were effective against the tested bacteria except for PLA/PEE films, and maximum antibacterial effects recorded for the films containing both ZME and PEE. Based on the microbiological and sensory evaluation of the sausages, all of the PLA/1%ZME/PEE composites increased the shelf life to >40days. The results indicate that incorporation of natural antimicrobial substances such as ZME and PEE to packaging material could be an interesting approach in development of active packaging material without significant negative effect on polymer technical properties. PMID- 28843120 TI - Evaluation of pulsed light treatments on inactivation of Salmonella on blueberries and its impact on shelf-life and quality attributes. AB - Blueberry have a short shelf life when fully ripe and susceptible to contamination of various pathogens. Our study investigated the effect of pulsed light (PL) on inactivation of Salmonella on blueberries and its impact on shelf life, quality attributes and health-benefit compounds of blueberries. Dry PL (6J/cm2) and water-assisted PL (samples were agitated in water during PL treatment; 9J/cm2) along with two controls, dry control (untreated) and water assisted control (water washing without PL), were applied to blueberries with subsequent storages at room temperature (3days) or 5 degrees C (7days). For Salmonella inactivation, dry PL treatment achieved 0.9 and 0.6 log reduction of Salmonella for spot and dip inoculation, respectively; while the water-assisted PL treatment reduced Salmonella by 4.4 log and 0.8 log for spot and dip inoculation, respectively. The water-assisted PL treatment resulted in Salmonella populations significantly lower than the dry control after storage regardless of the storage temperature and inoculation method. Neither dry nor water-assisted PL treatments improved the shelf life of blueberries even though direct inactivation of natural yeasts and molds were achieved. Surface lightness was instantly reduced after both dry and water-assisted PL treatments. Compared with the dry control, the two PL treatments did not reduce the firmness of blueberries. Weight loss was increased for the dry PL treated samples, but not for the water-assisted PL treatment for both storage conditions. Delayed anthocyanins accumulation and reduced total antioxidant activity were induced by both PL treatments at the end of storage at room temperature, while slight enhancement in total phenolics content was achieved by water-assisted PL treatment. In conclusion, the water assisted PL treatment could effectively decontaminate Salmonella on blueberries while showed minimal or no impact on the shelf-life, quality attributes and health-benefit compounds of blueberries. PL processing parameters need to be further evaluated and optimized before possible application in the blueberry industry. PMID- 28843121 TI - Exploring the microbial origins of p-cresol and its co-occurrence pattern in the Chinese liquor-making process. AB - The compound p-cresol is the major off-odor and toxic component of strong aroma type Chinese liquor. To trace its origin, the p-cresol contents in the liquor making process were detected by gas chromatography-mass spectrometry. The prokaryotic communities involved in the process were revealed by 16S rRNA gene MiSeq sequencing. The results showed that the microbial diversity and concentration of p-cresol in pit mud significantly increased with increased pit depth. Canonical correspondence analysis further revealed that p-cresol was positively correlated with the genera Aminobacterium, Clostridium, Sedimentibacter and Syntrophomonas. On investigating potential p-cresol producers, we obtained 11 species from pit mud samples using selective culture media. Clostridium butyricum, Clostridium tyrobutyricum, Clostridium aminovalericum and Eubacterium contortum were confirmed to possess the capacity for p-cresol production. Moreover, based on volatile compounds data, these strains were assigned to the same clusters characterized by the high abundance of butanoic acid and p-cresol. Furthermore, 24 pairs of significant correlations were identified from 14 genera using co-occurrence network analysis. Clostridium was the hub in pit mud and could be inhibited by increasing levels of Lactobacillus. These findings represented a step forward for controlling p-cresol in a complex microbial community of Chinese liquor. PMID- 28843122 TI - Lactobionic acid enhances the synergistic effect of nisin and thymol against Listeria monocytogenes Scott A in tryptic soy broth and milk. AB - Listeria monocytogenes is a Gram-positive opportunistic human pathogen and it remains a significant cause of foodborne illnesses. A variety of natural and synthetic compounds have been studied to inhibit the growth of L. monocytogenes in foods. Antimicrobial combinations with synergistic antilisterial properties can reduce the dose of each antimicrobial, which can be further enhanced by chelating compounds. Therefore, the objective of this study was to determine antilisterial properties of binary or ternary combinations of lactobionic acid (LBA), nisin, and thymol in tryptic soy broth (TSB), 2% reduced-fat milk, and whole milk. The results showed that the minimum inhibitory concentration (MIC) of nisin, thymol and LBA was 125IU/mL, 0.25mg/mL, and 10mg/mL, respectively. The ternary combination was the most effective in reducing MICs of antimicrobials, with the MIC of nisin, thymol, and LBA being 31.25IU/mL, 0.0625mg/mL, and 1.25mg/mL, respectively. In TSB with 0.6% yeast extract, L. monocytogenes grew in individual or binary antimicrobial treatments of 31.25IU/mL nisin, 0.0625mg/mL thymol, and 1.25mg/mL LBA within 24h at 32 degrees C, while it was completely inhibited by the ternary combination. In 2% reduced-fat milk at 21 degrees C, the ternary combination of nisin, thymol, and LBA at respective concentrations of 250IU/mL, 2mg/mL, and 10mg/mL completely inhibited the bacterium to below the detection limit in 72h while >2log (CFU/mL) bacteria was still detected in all the binary combinations after 120h. In whole milk, the combination of 500IU/mL nisin, 2mg/mL thymol, and 10mg/mL LBA reduced bacteria to around 2log (CFU/mL) in 4h at 21 degrees C, and no bacterial recovery was observed after 5 d. This study suggested the potential of the ternary combination of nisin, thymol and LBA for food preservation. PMID- 28843123 TI - Antimicrobial efficacy of Cinnamomum javanicum plant extract against Listeria monocytogenes and its application potential with smoked salmon. AB - Extracts from medicinal plants have been reported to possess good antimicrobial properties, but a majority of them remain unexplored. This study aimed at identifying a novel plant extract with antimicrobial activity, to validate its efficacy in food model, and to elucidate its composition and antimicrobial mechanism. A total of 125 plant extracts were screened, and Cinnamomum javanicum leaf and stem extract showed potential antimicrobial activity against Listeria monocytogenes (MIC=0.13mg/mL). Total phenolic content of the extract was 78.3mg GAE/g extract and its antioxidant activity was 57.2-326.5mg TE/g extract. When applied on cold smoked salmon, strong strain-dependent antimicrobial effectiveness was observed, with L. monocytogenes LM2 (serotype 4b) and LM8 (serotype 3a) being more resistant compared to SSA81 (serotype 1/2a). High extract concentration (16mg/mL) was needed to inhibit or reduce the growth of L. monocytogenes on smoked salmon, which resulted in surface color change. GC-MS revealed that eucalyptol (25.54 area%) was the most abundant compound in the crude extract. Both crude extract and eucalyptol induced significant membrane damages in treated L. monocytogenes. These results suggest anti-L. monocytogenes activity of C. javanicum plant extract, identified its major volatile components, and elucidated its membrane-damaging antimicrobial mechanisms. PMID- 28843124 TI - Impact of the reusing of food manufacturing wastewater for irrigation in a closed system on the microbiological quality of the food crops. AB - In order to evaluate if the reuse of food industry treated wastewater is compatible for irrigation of food crops, without increased health risk, in the present study a cropping system, in which ground water and treated wastewater were used for irrigation of tomato and broccoli, during consecutive crop seasons was monitored. Water, crop environment and final products were monitored for microbial indicators and pathogenic bacteria, by conventional and molecular methods. The microbial quality of the irrigation waters influenced sporadically the presence of microbial indicators in soil. No water sample was found positive for pathogenic bacteria, independently from the source. Salmonella spp. and Listeria monocytogenes were detected in soil samples, independently from the irrigation water source. No pathogen was found to contaminate tomato plants, while Listeria monocytogenes and E. coli O157:H7 were detected on broccoli plant, but when final produce were harvested, no pathogen was detected on edible part. The level of microbial indicators and detection of pathogenic bacteria in field and plant was not dependent upon wastewater used. Our results, suggest that reuse of food industry wastewater for irrigation of agricultural crop can be applied without significant increase of potential health risk related to microbial quality. PMID- 28843125 TI - Combination of essential oil compounds and phenolic acids against Escherichia coli O157:H7 in vitro and in dry-fermented sausage production. AB - Escherichia coli O157:H7 is a foodborne pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. The low dose of infection and severity of the disease represent a concern to public health. Natural compounds have been widely applied as food additives to replace synthetic preservatives. The aim of this study was to determine the efficiency of essential oil compounds (EOCs) in combination with phenolic acids (PA) in vitro and in dry-fermented sausage production. Minimum Inhibitory Concentration (MIC) and Fractional Inhibitory Concentration index (FICindex) were determined for a 5-strain mixture of E. coli O157:H7. Batches of sausage tainted with E. coli O157:H7 were produced using Pediococcus pentosaceus UM 116P and Staphylococcus carnosus UM 123M as starter cultures. The best combination of EOCs and PAs found in vitro was used as an additive. Chemical-physical and microbiological analyses were evaluated weekly from day 0 to 35 after production. Sensory evaluation (texture, odor, flavor, appearance and overall evaluation) of E. coli-free sausages was conducted using a 9-point hedonic scale with 56 untrained volunteers. The MIC values of allyl isothiocyanate (AITC), carvacrol (CAR), ferulic acid (FA), o-coumaric acid (CA) and p-hydroxybenzoic acid (AHB) were, respectively, 0.25; 1.3; 5.12; 18.27; and 37mM. AITC combined with CA had a synergistic effect (FICindex=0.25) and together they were applied in the production of dry fermented sausage at concentrations of 10* FIC and 20* FIC. Aw had no significant difference among treatments, whereas the pH of 10* FIC and 20* FIC were higher than the control. E. coli O157:H7 was reduced by >5logCFU/g with 20* FIC after 21d, and by 2.8logCFU/g with 10* FIC after 35d. Sensory analysis showed that the combination of AITC and omicron coumaric acid in both treatments presented lower scores in the 5 categories when compared to the control, but none of the parameters received a negative score. This study demonstrated that the combination of AITC and omicron-coumaric acid at 20* FIC reduced E. coli O157:H7 in compliance with the North American legislation, but adjustments in the dose are necessary to improve the sensory characteristics of the final product. PMID- 28843126 TI - Pre-procedural neutrophil-to-lymphocyte ratio and long-term cardiac outcomes after percutaneous coronary intervention for stable coronary artery disease. AB - BACKGROUND AND AIMS: An elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with worse clinical outcomes in patients with acute coronary syndrome. However, the long-term prognostic value of NLR in stable coronary artery disease (CAD) after percutaneous coronary intervention (PCI) has not been fully investigated. The aim of this study was to determine whether NLR is an independent predictor of long-term cardiac outcomes after PCI. METHODS: A total of 2070 patients with CAD who underwent elective PCI were enrolled in the study. Patients were divided into three groups by NLR tertile (<1.7, 1.7-2.5, and 2.5<). Incidences of all-cause death and cardiac death were evaluated. RESULTS: During follow-up (median, 7.4 years), 300 patients (14.5%) died. Kaplan-Meier curves revealed ongoing divergence in rates of all-cause death and cardiac death among tertiles (both log-rank p < 0.01). In multivariate analysis, using the lowest tertile as reference, the highest tertile remained significantly associated with greater incidences of all-cause death (hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.29-2.34; p = 0.0002). Continuous NLR values were also an independent predictor of all-cause death (HR, 1.87 per log NLR 1 increase; 95% CI, 1.50-2.32; p < 0.0001) and cardiac death (HR, 2.11; 95% CI, 1.46-3.05; p < 0.0001). Adding NLR values to a baseline model with established risk factors improved the C-index (p = 0.002), net reclassification improvement (p = 0.008) and integrated discrimination improvement (p = 0.0001) for all-cause death. CONCLUSIONS: Elevated NLR was an independent predictor of long-term cardiovascular outcomes after elective PCI. Assessing pre-PCI NLR may be useful for risk stratification of stable CAD. PMID- 28843127 TI - How do academic stress and leisure activities influence college students' emotional well-being? A daily diary investigation. AB - China has one of the largest bodies of college students who face growing academic stress that influences their well-being. Using a daily diary method in a group of Chinese college students (n = 139, mean age = 19.50 years, 27% males) who reported their daily positive and negative emotion consecutively for two weeks, this study investigated the dynamic relations between daily academic stress, leisure activities engagement, and emotion, and further examined the moderation of sex on these links. The results showed that at both between- and within-person level, academic stress was positively associated with negative emotion, and leisure activities engagement was positively associated with positive emotion. The association between leisure activities engagement and positive emotion were stronger among female students than among male students. These results suggest that effectively reducing academic stress and actively engaging in leisure activities are both important in promoting and enhancing daily emotional well being. PMID- 28843128 TI - Effect of neck flexor muscle activation on impact velocity of the head during backward falls in young adults. AB - Falls are a common cause of traumatic brain injuries (TBI) across the lifespan. A proposed but untested hypothesis is that neck muscle activation influences impact severity and risk for TBI during a fall. We conducted backward falling experiments to test whether activation of the neck flexor muscles facilitates the avoidance of head impact, and reduces impact velocity if the head contacts the ground. Young adults (n=8) fell from standing onto a 30cm thick gymnastics mat while wearing a helmet. Participants were instructed to fall backward and (a) prevent their head from impacting the mat ("no head impact" trials); (b) allow their head to impact the mat, but with minimal impact severity ("soft impact" trials); and (c) allow their head to impact the mat, while inhibiting efforts to reduce impact severity ("hard impact" trials). Trial type associated with peak magnitude of electromyographic activity of the sternocleidomastoid (SCM) muscles (p<0.017), and with the vertical and horizontal velocity of the head at impact (p<0.001). Peak SCM activations, expressed as percent maximal voluntary isometric contraction (%MVIC), averaged 75.3, 67.5, and 44.5%MVIC in "no head impact", "soft impact", and "hard impact" trials, respectively. When compared to "soft impact" trials, vertical impact velocities in "hard impact" trials averaged 87% greater (3.23 versus 1.73m/s) and horizontal velocities averaged 83% greater (2.74 versus 1.50m/s). For every 10% increase in SCM %MVIC, vertical impact velocity decreased 0.24m/s and horizontal velocity decreased 0.22m/s. We conclude that SCM activation contributes to the prevention and modulation of head impact severity during backward falls. PMID- 28843129 TI - Self-rated health, generalized trust, and the Affordable Care Act: A US panel study, 2006-2014. AB - Previous research shows that generalized trust, the belief that most people can be trusted, is conducive to people's health. However, only recently have longitudinal studies suggested an additional reciprocal pathway from health back to trust. Drawing on a diverse body of literature that shows how egalitarian social policy contributes to the promotion of generalized trust, we hypothesize that this other 'reverse' pathway could be sensitive to health insurance context. Drawing on nationally representative US panel data from the General Social Survey, we examine whether the Affordable Care Act of 2010 could have had influence on the deteriorating impact of worsening self-rated health (SRH) on generalized trust. Firstly, using two-wave panel data (2008-2010, N = 1403) and employing random effects regression models, we show that a lack of health insurance coverage negatively determines generalized trust in the United States. However, this association is attenuated when additionally controlling for (perceived) income inequality. Secondly, utilizing data from two separate three wave panel studies from the US General Social Survey (2006-10; N = 1652; 2010 2014; N = 1187), we employ fixed-effects linear regression analyses to control for unobserved heterogeneity from time-invariant factors. We demonstrate that worsening SRH was a stronger predictor for a decrease in generalized trust prior (2006-2010) to the implementation of the Affordable Care Act. Further, the negative effect of fair/poor SRH seen in the 2006-2010 data becomes attenuated in the 2010-2014 panel data. We thus find evidence for a substantial weakening of the previously established negative impact of decreasing SRH on generalized trust, coinciding with the most significant US healthcare reforms in decades. Social policy and healthcare policy implications are discussed. PMID- 28843130 TI - The observed and perceived neighborhood environment and physical activity among urban-dwelling adults: The moderating role of depressive symptoms. AB - RATIONALE: Physical environmental features of neighborhoods are associated with physical activity, but the influence of mental health factors, such as depression, on these associations is poorly understood. OBJECTIVE: We examined whether the perceived neighborhood environment mediated associations between the observed neighborhood environment and physical activity, and whether these associations were moderated by depressive symptoms. METHODS: Data consisted of systematic social observations of 343 neighborhoods and resident surveys. Participants' (N = 2969) mean age was 41.9 +/- 16.2 years, 60.2% were female, and 67.9% were non-White. We conducted multiple linear regression and tests for mediation and moderated mediation. RESULTS: Observed recreation facilities, commercial destinations, physical disorder, and physical deterioration were indirectly associated with walking via perceived neighborhood environment variables. Observed recreation facilities was indirectly and positively associated with leisure-time physical activity via perceived park access, and indirectly and inversely associated with walking and leisure-time physical activity via perceived traffic danger, but only among participants with low depressive symptom scores. Observed recreation facilities was indirectly and inversely associated, and observed physical disorder and physical deterioration were indirectly and positively associated with walking via perceived disorder, but only among participants with high depressive symptom scores. CONCLUSION: Depressive symptoms affected the strength and direction of associations between the observed neighborhood environment and physical activity via residents' perceptions. PMID- 28843131 TI - Left hemispheric breakdown of LTP-like cortico-cortical plasticity in schizophrenic patients. AB - OBJECTIVE: Altered cortical connectivity and plasticity seems to be asymmetrical between the hemispheres in patients with schizophrenia (SCZ). We evaluated long term potentiation (LTP) in parietal-frontal circuits of both hemispheres using a cortico-cortical Paired Associative Stimulation (cc-PAS) protocol testing the rules of Hebbian-like spike timing dependent plasticity (SPTD). METHODS: 12 SCZ and 12 healthy subjects (HS) underwent a cc-PAS protocol to activate, by means of paired pulses of transcranial magnetic stimulation (TMS), the short-latency connection between posterior parietal cortex (PPC) and primary motor cortex (M1) of both hemispheres. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. RESULTS: While HS showed a similar time course of LTP-like plasticity in the two hemispheres, SCZ revealed a weaker late-LTP-like plasticity in the left compared to the right hemisphere after cc-PAS protocol. CONCLUSIONS: SCZ failed to show the typical long-lasting increase of M1 excitability observed after cc-PAS protocol in both hemispheres, with a greater reduction in the left one. SIGNIFICANCE: Our findings provide novel neurophysiological evidence for an asymmetric impairment of the left parietal-frontal network in SCZ patients. PMID- 28843132 TI - Henry, where have you lost your Self? AB - The Self is a complex construct encompassing distinct components, including episodic and semantic autobiographical memory, the Self-concept, and the subjective sense of Self, which highest level consists of Self-awareness. The neuro-anatomical correlates are complex, and it is debated as to whether a common region could support these different components of the Self, with a particular interest for the cortical midline structures and the medial prefrontal cortex (MPFC). Alzheimer's disease (AD) constitutes an interesting model for the study of Self as autobiographical memory typically deteriorates as the disease progresses. Here, we report the unexpected case of Henry, a patient with MCI due to AD who was unable to produce any personal autobiographical memories, nor describe his Self-concept, had a poor personal semantic memory, and disclosed unusual anosognosia for this stage of the disease. His cognitive performance was compared to a group of matched AD patients and a group of healthy controls confirming that the main components of his Self were degraded. We hypothesized that it was due to a marked atrophy within the cortical midline, as visually assessed on his MRI. We further elucidated these findings through Voxel-based morphometry analysis, which confirmed a significant atrophy of the MPFC that was specific to this patient. Moreover, this revealed significant atrophy within the bilateral insular cortex. Given the stage of the disease, the degradation of the Self is unlikely to be accounted for by deficient mnemonic processes, especially as the presence of discrete temporal atrophy was noted. We suggest that this specific pattern of MPFC and insular atrophy is responsible for the systematic collapse of the patient's Self, through the breakdown of the subjective sense of Self, which is proposed as a prerequisite to all other components, according to the model proposed by Prebble, Addis, and Tippett (2013). PMID- 28843133 TI - Potassium improves photosynthetic tolerance to and recovery from episodic drought stress in functional leaves of cotton (Gossypium hirsutum L.). AB - To investigate whether potassium (K) application enhances the potential of cotton (Gossypium hirsutum L.) plants to maintain physiological functions during drought and recovery, low K-sensitive (Siza 3) and -tolerant (Simian 3) cotton cultivars were exposed to three K rates (0, 150, and 300 K2O kg ha-1) and either well watered conditions or severe drought stress followed by a recovery period. Under drought stress, cotton plants showed a substantial decline in leaf water potential, stomatal conductance, photosynthetic rate, and the maximum and actual quantum yield of PSII, resulting in greater non-photochemical quenching and lipid peroxidation as compared to well-watered plants. However, plants under K application not only showed less of a decline in these traits but also displayed greater potential to recover after rewatering as compared to the plants without K application. Plants receiving K application showed lower lipid peroxidation, higher antioxidant enzyme activities, and increased proline accumulation as compared to plants without K application. Significant relationships between rates of photosynthetic recovery and K application were observed. The cultivar Siza 3 exhibited a more positive response to K application than Simian 3. The results suggest that K application enhances the cotton plant's potential to maintain functionality under drought and facilitates recovery after rewatering. PMID- 28843134 TI - RdreB1BI enhances drought tolerance by activating AQP-related genes in transgenic strawberry. AB - The dehydration-responsive element binding protein (DREB) family of transcription factors is associated with abiotic stress responses during plant growth and development. This study focussed on the subfamily member DREB1B, which was initially described as highly and specifically responsive to low temperature. However, here it is shown that DREB1B is not only involved in cold tolerance but also other abiotic stress tolerances, such as that of drought. To further understand the genetic improvement effects of the drought tolerance provided by RdreB1BI in transgenic strawberry, drought stress responses of transgenic plants were evaluated at the morphological, physiological, and transcriptional levels. Transactivation assays revealed that RdreB1BI could activate the FvPIP2;1 like 1 promoter. RdreB1BI transgenic plants showed enhanced drought tolerance on the basis of lower rates of electrolyte leakage (EL), higher relative water content (RWC), and less stomatal aperture as well as increased peroxidase (POD) and superoxide dismutase (SOD) activities and less malondialdehyde (MDA) accumulation. The transgenic plants also accumulated higher levels of drought related regulatory genes and functional gene transcripts, including those of PIP, NAC, RD22, ABI, and NCED. Together, these results demonstrate that RdreB1BI plays an essential role in the regulation of the drought stress response. DREB1B transcription constitutes a useful strategy to exploit in transgenic plants for coping with abiotic stresses, at least cold and drought stresses. The approach may be helpful for genetic engineering horticultural plants to have increased environmental adaptations. PMID- 28843135 TI - Effects of exposure to nano and bulk sized TiO2 and CuO in Lemna minor. AB - Nanoparticles of TiO2 and CuO are among most commonly used nanoparticles, and elevated concentrations of them are expected to be found in all environments, including aquatic. A standard growth inhibition test ISO/CD 20079 was used to determine the toxicity of nano sized and larger micro sized (bulk) particles in the concentrations of 0.1, 1, 10, 100 and 1000 MUM CuO and TiO2 on common duckweed (Lemna minor L.). Both nano and bulk CuO particles caused changes in the structure and function of treated plants. The number of fronds and colonies decreased by as much as 78%, the length of roots and fronds decreased by 99% and 14%, respectively. Furthermore, photochemical efficiency was reduced by up to 35%, and the activities of antioxidative enzymes guaiacol peroxidase, ascorbate peroxidase and glutathione reductase increased by more than 240%. The altered physiological state of the CuO exposed plants was also reflected in the elevated occurrence of necrosis and bleaching in the duckweed colonies. Nano sized particles of CuO proved more phytotoxic than bulk particles, and the effects of both studied CuO sizes were concentration dependent. On the other hand, both bulk and nano sized particles of TiO2 caused no severe phytotoxic effects, there was no concentration dependence and they could be considered as non-harmful to common duckweed. PMID- 28843136 TI - Correlates of weight-related quality of life among individuals with binge eating disorder before and after cognitive behavioral therapy. AB - Individuals with obesity and binge eating disorder (BED) report poorer weight related quality of life (WRQOL) compared to individuals with obesity alone. Cognitive behavioral therapy (CBT), the best available treatment for BED, does not consistently produce weight loss or improvements in weight QOL. The purpose of the current study was to examine baseline and longitudinal associations between eating-related and psychosocial variables and dimensions of weight QOL. We examined associations between predictor variables, including body mass index (BMI), eating disorder (ED) psychopathology, and psychosocial factors, in relation to three dimensions of WRQOL among 171 patients whom received CBT for BED. Participants completed interviews and self-report measures at baseline prior to CBT and at end of treatment. At baseline the following associations were significant: BMI, ED psychopathology, and self-esteem were associated with weight related self-esteem; gender, BMI, and self-esteem were associated with weight related public distress (i.e., stigma and worry in public because of one's weight); and age, BMI, and ED psychopathology were associated with weight-related physical function. At end of treatment, the following associations were significant: changes in ED psychopathology and coping predicted weight-related self-esteem; changes in coping and self-esteem predicted weight-related public distress; and changes in BMI and subjective binge eating predicted weight-related physical function. Overall, changes in a number of ED and associated symptoms were associated with improvements in WRQOL. PMID- 28843137 TI - Fake news of baby booms 9months after major sporting events distorts the public's understanding of early human development science. AB - INTRODUCTION: In France on 27/6/16, Iceland's men's national football team won 2 1, knocking England out of the UEFA European Championship. RESULT: Nine months after this momentous Icelandic victory, Asgeir Petur Porvaldsson a medical doctor in Iceland, posted a tweet in jest suggesting that a baby boom had occurred as a result of increased celebratory coital activity following the win. The media covered this widely but statistical analysis shows otherwise and this was confirmed by the original tweet source. DISCUSSION: Given the increase in fake scientific news, it is especially important for scientists to correct misinformation lest the public loses trust in science or gains a distorted understanding of known facts. PMID- 28843138 TI - Usefulness of the Infant Driven Scale in the early identification of preterm infants at risk for delayed oral feeding independency. AB - BACKGROUND: Very preterm infants frequently experience difficulties in achieving feeding independency. The availability of feeding assessment instruments has been recommended to evaluate an infant's readiness for oral feeding and enable preterm infants' caregivers to document each infant's feeding readiness and advancements. AIMS: To investigate the implementation of the Infant Driven Scale in neonatal intensive care units and to identify a cut off value associated with delayed feeding independency. STUDY DESIGN: Prospective, observational, single-centre study. SUBJECTS: A total of 47 infants born at a gestational age<=32weeks, consecutively admitted to a tertiary neonatal unit between July 2015 and March 2016. OUTCOMES MEASURES: The infant's feeding readiness and the postmenstrual age at achievement of feeding independency. RESULTS: Mean postmenstrual age at feeding independency was 35.6+/-1.34weeks. A linear regression analysis showed that a score<=8 at 32weeks of postmenstrual age was associated with a delay of 1.8weeks in achieving feeding independency. CONCLUSION: The Infant Driven Scale appears to be a useful additional instrument for the assessment of preterm infants' oral feeding readiness and the early identification of the infants at risk for delayed feeding independency. PMID- 28843139 TI - Sources, distribution, bioavailability, toxicity, and risk assessment of heavy metal(loid)s in complementary medicines. AB - The last few decades have seen the rise of alternative medical approaches including the use of herbal supplements, natural products, and traditional medicines, which are collectively known as 'Complementary medicines'. However, there are increasing concerns on the safety and health benefits of these medicines. One of the main hazards with the use of complementary medicines is the presence of heavy metal(loid)s such as arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg). This review deals with the characteristics of complementary medicines in terms of heavy metal(loid)s sources, distribution, bioavailability, toxicity, and human risk assessment. The heavy metal(loid)s in these medicines are derived from uptake by medicinal plants, cross-contamination during processing, and therapeutic input of metal(loid)s. This paper discusses the distribution of heavy metal(loid)s in these medicines, in terms of their nature, concentration, and speciation. The importance of determining bioavailability towards human health risk assessment was emphasized by the need to estimate daily intake of heavy metal(loid)s in complementary medicines. The review ends with selected case studies of heavy metal(loid) toxicity from complementary medicines with specific reference to As, Cd, Pb, and Hg. The future research opportunities mentioned in the conclusion of review will help researchers to explore new avenues, methodologies, and approaches to the issue of heavy metal(loid)s in complementary medicines, thereby generating new regulations and proposing fresh approach towards safe use of these medicines. PMID- 28843140 TI - Prenatal and postnatal exposure to organophosphate pesticides and childhood neurodevelopment in Shandong, China. AB - BACKGROUND: Although studies in laboratory animals demonstrate neurodevelopmental deficits caused by prenatal or postnatal organophosphate pesticide (OP) exposure, there is limited evidence on effects induced by not only prenatal but also postnatal exposure of children to OPs. METHODS: We measured diethylphosphate (DE), dimethylphosphate (DM), and total dialkylphosphate (DAP) metabolites in maternal and child urine at 12 and 24months of age and examined their relationship with developmental quotients (DQs) in 12-month-old infants and 24 month-old children in Shandong, China. RESULTS: The median concentrations of total DAP metabolites (DAPs) in child urine [371.97nmol/g creatinine (12-month old infants), 538.64nmol/g creatinine (24-month-old children)] were higher than those in maternal urine (352.67nmol/g creatinine). Prenatal OP exposure was negatively associated with 24-month-old children's DQs, especially among boys. A 10-fold increase in prenatal DEs and DAPs was associated with a 2.59- and 2.49 point decrease in social domain DQ scores in 24-month-old children (n=262), respectively. However, positive association of postnatal exposure to OPs and 24 month-old children's DQs was observed (n=237). Neither prenatal nor postnatal exposure to OPs was related to 12-month-old infants' DQs. CONCLUSIONS: These data suggested that prenatal OP exposure could adversely affect children's neurodevelopment at 24months of age, especially among boys. The prenatal period might be a critical window of OP exposure. In view of the positive association with postnatal OP exposure, it is necessary to interpret findings with caution. PMID- 28843142 TI - Legacy and alternative halogenated flame retardants in human milk in Europe: Implications for children's health. AB - In this study, 10 polybrominated diphenyl ethers (PBDEs) and 19 alternative halogenated flame retardants (AFRs) were determined in >450 human milk samples across three European countries, representing northern, western and eastern Europe. This study provides first insights into the occurrence of selected AFRs in mother milk samples and compares them among three European countries. Sums of median concentrations of the most frequently detected PBDEs were 2.16, 0.88 and 0.45ngg-1 lipid weight (lw) in Norway, the Netherlands and Slovakia, respectively. The sum of the concentrations of AFRs ranged from 0.14 to 0.25ngg 1lw in all countries, which was 2 to 15 times less compared to Sigma7PBDEs. The Penta-BDE replacement, bis(2-ethylhexyl) tetrabromophthalate, BEH-TEBP, was present at the greatest concentrations of any of the AFRs and in some samples exceeded concentrations of BDE 47 and BDE 153. Four AFRs including bromobenzenes (hexabromobenzene, pentabromobenzene, pentabromotoluene) and another Penta-BDE replacement (2-ethylhexyl-2,3,4,5-tetrabromobenzoate, EH-TBB) were detected in >42% of all human milk samples. Because of the potential developmental neurotoxicity of the halogenated flame retardants, infant dietary intakes via breastfeeding were estimated; in four cases the intakes of BDE 47 exceeded the reference dose indicating that the present concentrations may pose a risk for children. PMID- 28843141 TI - DNA methylation and exposure to ambient air pollution in two prospective cohorts. AB - Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes. This study included blood-derived DNA methylation (Illumina HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available. Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation. Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses. PMID- 28843143 TI - Effects of oral versus long-acting antipsychotics on social functioning: A psychiatrists' survey in India. AB - BACKGROUND: Schizophrenia is associated with functional challenges for patients; relapses in schizophrenia may lead to increased treatment costs and poor quality of life. OBJECTIVE: This SUSTAIN-I study was conducted to establish psychiatrists' perspective on impact of long-acting injectables (LAIs) antipsychotics on the socio-economic and functional burden of schizophrenia. METHODS: This cross-sectional, survey-based study was conducted in 5 cities in India. Psychiatrists (>=5years of experience) working in clinics, psychiatric, government hospitals and rehabilitation centers were included and administered a specially designed questionnaire to elicit information on their clinical practice and prescription patterns. Perceived treatment costs for LAI versus oral antipsychotic treatments (OATs) and relapse rates were assessed. Descriptive statistics were used to summarize results. RESULTS: Total 31 physicians completed this survey. In acute phase, OAT prescription was higher whereas chronic patients were treated with either OATs or LAIs. Treatment with LAIs was the preferred treatment in 9% of chronic cases. Reduced relapse rates were observed with LAI treatment: 12% patients on LAIs relapsed as compared with 60% patients on OATs. Monthly medication cost for oral medications was lower ($8-$17) than short-acting injectables ($22-$50). For chronic cases, atypical antipsychotics cost (oral: $11.7-25, LAI: $150-167) was higher than typical antipsychotics (oral: $4-5, LAI: $5-25). Of the total expenses incurred, cost for hospital admissions was the largest component (78%). CONCLUSION: Despite enhanced treatment adherence and potential to lower risk of rehospitalizations from relapse, LAIs are not the preferred treatment choice for patients with schizophrenia in India, owing to their perceived high costs. PMID- 28843144 TI - Disulfiram induced psychosis: Revisiting an age-old entity. PMID- 28843145 TI - Presence of Salmonella and Escherichia coli O157 on the hide, and presence of Salmonella, Escherichia coli O157 and Campylobacter in feces from small-ruminant (goat and lamb) samples collected in the United States, Bahamas and Mexico. AB - The objective of this study was to evaluate the frequency of Salmonella and E. coli O157 found on the hides, as well as presence of Salmonella, Campylobacter and E. coli O157 found in small-ruminant fecal samples from abattoirs and farms in California, New Mexico, Texas, Mexico and the Bahamas. In small-ruminant fecal samples, overall organism presence was identified as 13.9% Salmonella (n=532), 15.3% E. coli O157 (n=477) and 80.7% Campylobacter (n=176). Overall, on small ruminant hide surfaces, Salmonella frequency was 17.1% (N=339) and E. coli O157 was detected at 1.5% (n=266). The overall lower detection (P<0.0001) of E. coli O157 from hide samples (1.5%) when compared to presence in fecal samples (15.3%), is not consistent with trends expected. Results from this study can be used to better understand and potentially control pathogens in small-ruminants utilized for meat and milk. PMID- 28843146 TI - Chia and oat emulsion gels as new animal fat replacers and healthy bioactive sources in fresh sausage formulation. AB - This paper examines the effect of emulsion gels (EG) prepared with chia (CEG) and oats (OEG) used as animal fat replacers in reduced-fat fresh sausages (longaniza) (LRF) during chilled storage. Reduced-fat samples were reformulated with CEG and OEG, (LRF/CEG and LRF/OEG respectively). Normal (LNF/P) and reduced-fat (LRF/P) (all-pork-fat) sausages were used as controls. Nutritional composition and microbiological, technological and sensory characteristics of sausages were evaluated. The presence of an EG affected (P<0.05) the concentrations of some minerals and amino acids in sausages. CEG improved MUFA and PUFA contents. Cooking loss was lower (P<0.05) in LRF/CEG and LRF/OEG than in the controls. Of all the reduced-fat samples, Kramer shear force values (KSF) were highest (P<0.05) in the ones containing an EG. KSF generally increased (P<0.05) over storage in all samples. The microbial count was significantly affected by the use of CEG. Sensory properties were affected by the incorporation of an EG, but all sausages were judged acceptable. PMID- 28843147 TI - Examining co-occurring and pure relational and physical victimization in early childhood. AB - The current study took a novel approach to examining peer victimization experiences on a continuum in early childhood. A bifactor approach was used to examine co-occurring victimization as well as the relative contribution of subtypes of victimization, including both physical and relational victimization. To date, no known research has examined co-occurring victimization in early childhood. The fit of a bifactor model, as well as the utility of the model in testing associations with internalizing problems, was examined. The short-term longitudinal study (N=231; 109 girls; Mage=47.46months, SD=7.35) found support for a hierarchical structure of victimization, including co-occurrence and "pure" victimization dimensions, in early childhood. Regression analyses supported that both co-occurring victimization and relational victimization were associated with internalizing adjustment outcomes. These associations differed by gender. A bifactor model may be a useful statistical technique to address the common finding of co-occurrence of victimization to better understand peer harassment experiences and risk for adjustment problems. PMID- 28843148 TI - Therapeutic effects of Syzygium mundagam bark methanol extract on type-2 diabetic complications in rats. AB - Plants are considered as one of the best sources of diabetic therapy. Being a reliable and sustainable medicinal hub, this study directs the use of Syzygium mundagam in exploring the antidiabetic property. Streptozotocin-Nicotinamide (STZ NA) induced diabetic rats were treated with Syzygium mundagam bark methanol extract (SMBM). Based on acute toxicity study, the doses of the extract were fixed as 100 and 200mg/kg. Glibenclamide was used as reference drug. The blood glucose level and body weight of the rats were monitored for 28days. After the treatment, rats were sacrificed and the blood biochemical, serum and histopathological parameters were analysed. The in vivo antioxidant levels in liver and kidney were also estimated. SMBM extract (200mg/kg) could significantly reduce the blood glucose level from 580.60mg/dL to 237.60mg/dL on day 28. An accelerated reduction in body weight was observed in diabetic control rats and inhibited by the extract during the study. The haematological parameters were normal compared to normal rats. The values of serum parameters like triglycerides, high-density lipoprotein (HDL), cholesterol and very low-density lipoprotein (VLDL) were close to the values of normal rats. After the treatment, Superoxide dismutase (SOD), Glutathione (GSH) and Glutathione reductase (GR) levels in liver and kidney were found accountable for their antioxidant properties during diabetic condition. The degree of protection set by SMBM extract was clear enough in the histopathology of liver, kidney and pancreas. The phenolic compounds studied in SMBM can be related to these activities. This study proves the ability of Syzygium mundagam to combat the diabetic condition and provides an insight on hidden properties of plants which can be utilized as novel drugs for existing disease complications. PMID- 28843149 TI - Berberine chloride ameliorates oxidative stress, inflammation and apoptosis in the pancreas of Streptozotocin induced diabetic rats. AB - Berberine chloride (BC) has been widely used as an unprescribed oral drug in China for the treatment of various diseases, and it is an active ingredient in many traditionally used medicinal plants. The present study was undertaken to evaluate the beneficial effects of BC on oxidative stress, inflammation and apoptosis in the pancreas of Streptozotocin (STZ) induced diabetic rats. Diabetes was induced in the male Wistar albino rats using a single intraperitoneal injection of STZ of 40mg/kg b.w. Diabetic rats were treated with BC (50mg/kg b.w) for 45days. Oral administration of BC showed significant reduction of the blood glucose, glycated hemoglobin (HbAlc) and increased the plasma insulin, hemoglobin (Hb) and body weight. Lipid peroxidation marker LOOH and TBARS levels were reduced while SOD, CAT, GPx, GSH, vitamin E and vitamin C levels were increased in the pancreas. A significant reduction of pro-inflammatory mediators (TNF alpha, NF-kappaB, phospho-NF-kappaB-p65, COX-2 and iNOS) and pro-apoptotic proteins (caspase-8, t-Bid, Bax, cytochrome-c and cleaved caspase-3), and elevation of anti-apoptotic protein Bcl-2, anti-inflammatory mediator IL-10 and GLUT-2 in were observed in BC treated diabetic rats. Thus, the present study demonstrated that BC has anti-hyperglycemic, antioxidant, anti-inflammatory and anti-apoptotic activities in STZ induced diabetic rats. PMID- 28843150 TI - Neuroprotective effect of liquiritin against neuropathic pain induced by chronic constriction injury of the sciatic nerve in mice. AB - Managing of neuropathic pain remains clinically challenging because the existing pharmacotherapies are either ineffective or non-specific. Therefore, developing novel alternatives is essential for better treatment. Liquiritin is an active component extracted from Glycyrrhizae radix and has potential neuroprotective action. This study aimed to investigate the protective efficacy of liquiritin on chronic constriction injury (CCI)-induced neuropathic pain in mice. Liquiritin (30, 60, and 120mg/kg) and pregabalin (40mg/kg) were administered intragastrically for 7 consecutive days starting on the 8th day post-surgery. Behavioral parameters and sciatic functional index were assessed on days 0, 7, 8, 10, 12, and 14. Electrophysiological and histopathological changes were analyzed on the 14th day. Immunofluorescence and Western blot were used to evaluate the expression of glial cells and the protein levels of inflammatory cytokines in the spinal cord, respectively. Results showed that liquiritin dose-dependently reduced hyperalgesia and allodynia and increased the sciatic functional index and motor nerve conduction velocities. Moreover, liquiritin restored the injured axon and myelin sheath, inhibited the activation of astrocyte and microglia, down regulated the pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin (IL-6, and IL-1beta), and simultaneously up-regulated the anti-inflammatory cytokine IL-10. Our study revealed that liquiritin exerted a neuroprotective effect on CCI-induced neuropathic pain, which might be attributed to its direct protective effect on damaged nerves and its anti inflammatory activity at the level of the spinal cord. Therefore, liquiritin shows promise as a compound for the development of novel analgesic agents that can be used to effectively treat intractable neuropathic pain. PMID- 28843152 TI - Reverse electrodialysis performed at pilot plant scale: Evaluation of redox processes and simultaneous generation of electric energy and treatment of wastewater. AB - This paper describes the experimental campaign carried out with a reverse electrodialysis (RED) demonstration plant (Marsala, Italy) with the main aims of: (i) evaluating the effect of various operating parameters, including the redox processes, on the system performances; (ii) using the plant for the simultaneous generation of electric energy and treatment of wastewater. The prototype (44 * 44 cm2, 500 cell pairs) was tested using both real (brackish water and brine) and artificial solutions. Tests with two different electrode rinse solutions (with or without iron redox couples) were performed. In agreement with the data obtained in the laboratory, the presence of iron ions contributes positively to the power production. The effect of flow rates in the electrode and saline compartments, as well as aging of the electrode rinse solution was also investigated. The possibility to remove an organic pollutant (the azoic dye Acid Orange 7) from the electrode solution was tested, obtaining a very fast and total removal of the pollutant. This experimental campaign represents the first demonstration in a real environment of the abilities of a RED plant to treat wastewater, thus giving useful indications for the spreading of RED technology in the near future. PMID- 28843151 TI - Reduced levels of methyltransferase DNMT2 sensitize human fibroblasts to oxidative stress and DNA damage that is accompanied by changes in proliferation related miRNA expression. AB - Methyltransferase DNMT2 is suggested to be involved in the regulation of numerous processes, however its biological significance and underlying molecular mechanisms remain elusive. In the present study, we have used WI-38 and BJ human fibroblasts as an in vitro model system to investigate the effects of siRNA-based DNMT2 silencing. DNMT2-depleted cells were found to be sensitive to oxidative stress conditions as judged by increased production of reactive oxygen species and susceptible to DNA damage that resulted in the inhibition of cell proliferation. DNMT2 silencing promoted upregulation of proliferation-related and tumor suppressor miRNAs, namely miR-28-3p, miR-34a-3p, miR-30b-5p, miR-29b-3p, miR-200c-3p, miR-28-5p, miR-379-5p, miR-382-5p, miR-194-5p, miR-193b-3p and miR 409-3p. Moreover, DNMT2 silencing induced cellular senescence and DNMT2 levels were elevated in replicatively senescent cells. Taken together, we found that DNMT2 may take part in the regulation of cell proliferation and longevity in human fibroblasts and speculate that the manipulation of DNMT2 levels that limits cell proliferation may be potentially useful anticancer strategy. PMID- 28843153 TI - Inactivation of three genera of dominant fungal spores in groundwater using chlorine dioxide: Effectiveness, influencing factors, and mechanisms. AB - Fungi in aquatic environments received more attention recently; therefore, the characteristics of inactivation of fungal spores by widely used disinfectants are quite important. Nonetheless, the inactivation efficacy of fungal spores by chlorine dioxide is poorly known. In this study, the effectiveness of chlorine dioxide at inactivation of three dominant genera of fungal spores isolated from drinking groundwater and the effects of pH, temperature, chlorine dioxide concentration, and humic acid were evaluated. The inactivation mechanisms were explored by analyzing the leakage of intracellular substances, the increase in extracellular adenosine triphosphate (ATP), deoxyribonucleic acid (DNA), and proteins as well as the changes in spore morphology. The kinetics of inactivation by chlorine dioxide fitted the Chick-Watson model, and different fungal species showed different resistance to chlorine dioxide inactivation, which was in the following order: Cladosporium sp.>Trichoderma sp. >Penicillium sp., which are much more resistant than Escherichia coli. Regarding the three genera of fungal spores used in this study, chlorine dioxide was more effective at inactivation of fungal spores than chlorine. The effect of disinfectant concentration and temperature was positive, and the impact of pH levels (6.0 and 7.0) was insignificant, whereas the influence of water matrices on the inactivation efficiency was negative. The increased concentration of characteristic extracellular substances and changes of spore morphology were observed after inactivation with chlorine dioxide and were due to cell wall and cell membrane damage in fungal spores, causing the leakage of intracellular substances and death of a fungal spore. PMID- 28843154 TI - Numerical analysis of wall shear stress in ascending aorta before tearing in type A aortic dissection. AB - Although the incidence of many cardiovascular diseases has declined as medical treatments have improved, the prevalence of aortic dissection (AD) has increased. Compared to type B dissections, type A dissections are more severe, and most patients with type A dissections require surgical treatment. The objective of this study was to investigate the relationships between the wall shear stress (WSS) on the aortic endothelium and the frequent tearing positions using computational fluid dynamics. Five type A dissection cases and two normal aortas were included in the study. First, the structures of the aortas before the type A dissection were reconstructed on the basis of the original imaging data. Analyses of flow in the reconstructed premorbid structures reveals that the rupture positions in three of the five cases corresponded to the area of maximum elevated WSS. Moreover, the WSS at the junction of the aortic arch and descending aorta was found to be elevated, which is considered to be related to the locally disturbed helical flow. Meanwhile, the highest WSS in the patients with premorbid AD was found to be almost double that of the control group. Due to the noticeable morphological differences between the AD cases and the control group, the WSSs in the premorbid structures without vasodilation in the ascending part were estimated. The computational results revealed that the WSS was lower in the aorta without vasodilation, but the pressure drop in this situation was higher than that with vasodilation in the ascending aorta. Significant differences were seen between the AD cases and the control group in the angles of the side branches of the aortic arch and its bending degree. Dilation of the ascending aorta and alterations in the branching angles may be the key determinants of a high WSS that leads to type A dissection. Greater tortuosity of the aortic arch leads to stronger helical flow through the distal aortic arch, which may be related to tears in this region. PMID- 28843155 TI - Do complaints of everyday cognitive failures in high schizotypy relate to emotional working memory deficits in the lab? AB - BACKGROUND: Individuals high on schizotypy complain of increased cognitive failures in everyday life. However, the neuropsychological performance of this group does not consistently indicate underlying ability deficits. It is possible that current neuropsychological tests lack ecological validity. Given the increased affective reactivity of high schizotypes, they may be more sensitive to emotional content interfering with cognitive ability. This study sought to explore whether an affective n-back working memory task would elicit impaired performance in schizotypy, echoing complaints concerning real world cognition. METHODS: 127 healthy participants completed self-report measures of schizotypy and cognitive failures and an affective n-back working memory task. This task was varied across three levels of load (1- to 3-back) and four types of stimulus emotion (neutral, fearful, happy, sad). Differences between high (n=39) and low (n=48) schizotypy groups on performance outcomes of hits and false alarms were examined, with emotion and load as within-groups variables. RESULTS: As expected, high schizotypes reported heightened vulnerability to cognitive failures. They also demonstrated a relative working memory impairment for emotional versus neutral stimuli, whereas low schizotypes did not. High schizotypes performed most poorly in response to fearful stimuli. For false alarms, there was an interaction between schizotypy, load, and emotion, such that high schizotypy was associated with deficits in response to fearful stimuli only at higher levels of task difficulty. Inclusion of self-reported cognitive failures did not account for this. CONCLUSION: These findings suggest that the "gap" between subjective and objective cognition in schizotypy may reflect the heightened emotional demands associated with cognitive functioning in the real world, although other factors also seem to play a role. There is a need to improve the ecological validity of objective assessments, whilst also recognizing that self-reported cognitive failures tap into a range of factors difficult to assess in the lab, including emotion. Cognitive interventions for at-risk individuals will likely be more beneficial if they address emotional processing alongside other aspects of cognition. PMID- 28843156 TI - Small molecule AT7867 proliferates PDX1-expressing pancreatic progenitor cells derived from human pluripotent stem cells. AB - While pancreatic islet transplantation achieves insulin independence in type 1 diabetes (T1D) patients, its widespread application is limited by donor tissue scarcity. Pancreatic progenitor cells (PPCs) give rise to all cell types in the pancreas during development. PPCs derived from human pluripotent stem cells have been shown to differentiate into functional beta cells both in vitro and in vivo, and to reverse hyperglycemia, at least in mice. Therefore, PPCs have great potential to serve as an alternative cell source for cell therapy, and the identification of compounds that facilitate PPC proliferation could provide stable and large-scale pancreatic cell preparation systems in clinical settings. Here, we developed and performed cell-based screens to identify small molecules that induce the proliferation of hiPSC-derived PDX1-expressing PPCs. The screening identified AT7867, which promoted PPC proliferation approximately five fold within six days through the maintenance of a high Ki67+ cell ratio. The induced proliferation by AT7867 does not result in DNA damage, as revealed by pHH2AX staining, and is observed specifically in PPCs but not other cell types. The established platform utilizing small molecules for PPC proliferation may contribute to the development of cell therapy for T1D using a regenerative medicine approach. PMID- 28843157 TI - Epidermal growth factor as a mechanosensitizer in human bone marrow stromal cells. AB - Epidermal growth factors (EGFs) e.g. EGF, heparin-binding EGF and transforming growth factor alpha and their receptors e.g. EGFR and ErbB2 control proinflammatory signaling and modulate proliferation in bone marrow stromal cells (BMSC). Interleukin-6 and interleukin-8 are EGF targets and participate in the inflammatory phase of bone regeneration via non-canonical wnt signaling. BMSC differentiation is also influenced by mechanical strain-related activation of ERK1/2 and AP-1, but the role of EGFR signaling in mechanotransduction is unclear. We investigated the effects of EGFR signaling in telomerase-immortalized BMSC, transfected with a luciferase reporter, comprising a mechanoresponsive AP1 element, using ligands, neutralizing antibodies and EGFR inhibitors on mechanotransduction and we found that EGF via EGFR increased the response to mechanical strain. Results were confirmed by qPCR analysis of mechanoresponsive genes. EGF-responsive interleukin-6 and interleukin-8 were synergistically enhanced by EGF stimulation and mechanical strain. We show here in immortalized and primary BMSC that EGFR signaling enhances mechanotransduction, indicating that the EGF system is a mechanosensitizer in BMSC. Alterations in mechanosensitivity and -adaptation are contributors to age-related diseases like osteoporosis and the identification of a suitable mechanosensitizer could be beneficial. The role of the synergism of these signaling cascades in physiology and disease remains to be unraveled. PMID- 28843158 TI - Development of bone seeker radiopharmaceuticals by Scandium-47 and estimation of human absorbed dose. AB - In this study labeling EDTMP (ethylenediamine tetra(methylene phosphonic acid)) and HEDP (Hydroxyethylidene-1, 1-Diphosphonic Acid) as the carrier ligands with Scandium-47 were investigated. The biokinetics of the bone seeking of labeled ligands with Scandium-47 were assessed by measuring the skeletal absorbed dose and then the mice data extrapolated to human absorbed dose and compared with the 186/188Rhenium-HEDP, 153Samarium-EDTMP dosimetry data estimated by other researchers. Because the availability of 47Sc was limited we performed some preliminary studies using 46Sc. PMID- 28843159 TI - Measurement of formation cross-section of 99Mo from the 98Mo(n,gamma) and 100Mo(n,2n) reactions. AB - The formation cross-section of medical isotope 99Mo from the 98Mo(n,gamma) reaction at the neutron energy of 0.025eV and from the 100Mo(n,2n) reaction at the neutron energies of 11.9 and 15.75MeV have been determined by using activation and off-line gamma-ray spectrometric technique. The thermal neutron energy of 0.025eV was used from the reactor critical facility at BARC, Mumbai, whereas the average neutron energies of 11.9 and 15.75MeV were generated using 7Li(p,n) reaction in the Pelletron facility at TIFR, Mumbai. The experimentally determined cross-sections were compared with the evaluated nuclear data libraries of ENDF/B-VII.1, CENDL-3.1, JENDL-4.0 and JEFF-3.2 and are found to be in close agreement. The 100Mo(n,2n)99Mo reaction cross-sections were also calculated theoretically by using TALYS-1.8 and EMPIRE-3.2 computer codes and compared with the experimental data. PMID- 28843160 TI - Comparison of dicentric dose response curves of 6MV LINAC X-rays and 60Co gamma rays for biodosimetry application. AB - In vitro Dicentric (DC) dose response curves of 6MV X-rays (3Gy/min) and 60Co gamma-rays (0.63Gy/min) were generated and compared (intra-laboratory) to understand their similarities and differences. Human peripheral blood samples exposed to ten different doses (0, 0.05, 0.1, 0.25, 0.5, 1, 2, 3, 4 and 5Gy) of 6MV X-rays and 60Co gamma-rays were subjected to Dicentric Chromosome Assay (DCA) and dicentrics, excess acentric fragments (AF) and chromatid breaks (CB) were scored. Totally about 31,553 metaphase spreads were scored for the purpose. Dose response curves of both radiation qualities were almost same except for a 13.8% higher beta value for 6MV X-rays. However, blind tests results revealed that both these curves are biologically equivalent and exhibited good dose prediction accuracy for the entire dose range. This demonstrated the feasibility of interchangeable use of these curves in biodosimetry. Consequently it has been suggested that LINAC facilities worldwide can be roped in for biodosimetry capacity augmentation towards managing nuclear emergency situations involving gamma-radiation exposures. PMID- 28843161 TI - Ruxolitinib for the management of myelofibrosis: Results of an international physician survey. AB - BACKGROUND: Ruxolitinib is established as treatment for symptomatic myeloproliferative neoplasm (MPN)-associated myelofibrosis. The strict inclusion and exclusion criteria and dose modification rules that applied to the COMFORTI and II studies that led to the licensing of ruxolitinib are not always applicable to routine clinical practice. Thus physicians now face decisions regarding ruxolitinib use that were not addressed in these pivotal trials. METHODS: We performed an online survey of hematologists practicing in Europe, Israel, the United Kingdom and the United States. Demographic details regarding the physicians and their practice as relates to MPNs were collected. Management decisions pertaining to the use of ruxolitinib were obtained regarding 10 clinical scenarios relating to anemia, thrombocytopenia, frailty, infection and lack or loss of response to ruxolitnib in MF patients. RESULTS: 140 physicians responded to the survey. There were marked differences regarding their decisions for ruxolitinib administration in MF patients with or developing anemia or thrombocytopenia. Similarly there was little consensus regarding management of patients refractory or losing a response to ruxolitinib. There were differences between "MPN-focused" and "non-MPN-focused" physicians in certain areas. CONCLUSION: Physician practices regarding management of MF patients experiencing ruxolitinib-related toxicities or in whom response to the drug is lost was variable. This was true of "MPN-focused" and "non-MPN-focused" physicians in certain cases. Physician education and experience in using ruxolitinib may improve patient management. PMID- 28843163 TI - Electromiography comparison of distal and proximal lower limb muscle activity patterns during external perturbation in subjects with and without functional ankle instability. AB - Ankle sprain is one of the most common injuries among athletes and the general population. Most ankle injuries commonly affect the lateral ligament complex. Changes in postural sway and hip abductor muscle strength may be generated after inversion ankle sprain. Therefore, the consequences of ankle injury may affect proximal structures of the lower limb. The aim is to describe and compare the activity patterns of distal and proximal lower limb muscles following external perturbation in individuals with and without functional ankle instability. The sample consisted of 16 women with functional ankle instability and 18 healthy women were recruited to participate in this research. The external perturbation via body jacket using surface electromyography, amplitude and onset of muscle activity of gluteus maximums, gluteus medius, tibialis anterior, and peroneus longus was recorded and analyzed during external perturbation. There were differences between the onset of muscles activity due to perturbation direction in the two groups (healthy and functional ankle instability). In the healthy group, there were statistically significant differences in amplitude of proximal muscle activity with distal muscle activity during front perturbation with eyes open and closed. In the functional ankle instability group; there were statistically significant differences in amplitude of proximal muscle activity with distal muscle activity during perturbation of the front and back with eyes open. There were statistically significant differences in the onset of muscle activity and amplitude of muscle activity, with-in and between groups (P<0.05). Therefore, in the presence of functional ankle instability, activation patterns of the lower limb proximal muscles may be altered. PMID- 28843162 TI - Antiproliferative metabolites from the Northern African endemic plant Daucus virgatus (Apiaceae). AB - Chemical analysis of the dichloromethane fraction obtained from aerial parts of the Northern African endemic plant Daucus virgatus led to the isolation of three previously undescribed sesquiterpenoids, namely the daucane vaginatin B, a eudesmane and the elemane elemavirgolide, along with five known metabolites. The structures of these compounds were determined by a detailed MS and NMR analysis and they were evaluated for antiproliferative activity against three human cell lines, A375 (melanoma), MCF-7 (breast adenocarcinoma), and HACAT (keratinocyte). The phytoalexin 6-methoxymellein revealed a previously unreported antiproliferative activity, while the eudesmane and the elemane derivatives exhibited a selective activity (SI = 11.1 and 3.3, respectively) against melanoma tumor cell lines. PMID- 28843164 TI - Concrete and cement composites used for radioactive waste deposition. AB - This review article presents the current state-of-knowledge of the use of cementitious materials for radioactive waste disposal. An overview of radwaste management processes with respect to the classification of the waste type is given. The application of cementitious materials for waste disposal is divided into two main lines: i) as a matrix for direct immobilization of treated waste form; and ii) as an engineered barrier of secondary protection in the form of concrete or grout. In the first part the immobilization mechanisms of the waste by cement hydration products is briefly described and an up-to date knowledge about the performance of different cementitious materials is given, including both traditional cements and alternative binder systems. The advantages, disadvantages as well as gaps in the base of information in relation to individual materials are stated. The following part of the article is aimed at description of multi-barrier systems for intermediate level waste repositories. It provides examples of proposed concepts by countries with advanced waste management programmes. In the paper summary, the good knowledge of the material durability due to its vast experience from civil engineering is highlighted however with the urge for specific approach during design and construction of a repository in terms of stringent safety requirements. PMID- 28843165 TI - Calculations of individual doses for Techa River Cohort members exposed to atmospheric radioiodine from Mayak releases. AB - Time-dependent thyroid doses were reconstructed for over 29,000 Techa River Cohort members living near the Mayak production facilities from 131I released to the atmosphere for all relevant exposure pathways. The calculational approach uses four general steps: 1) construct estimates of releases of 131I to the air from production facilities; 2) model the transport of 131I in the air and subsequent deposition on the ground and vegetation; 3) model the accumulation of 131I in environmental media; and 4) calculate individualized doses. The dose calculations are implemented in a Monte Carlo framework that produces best estimates and confidence intervals of dose time-histories. Other radionuclide contributors to thyroid dose were evaluated. The 131I contribution was 75-99% of the thyroid dose. The mean total thyroid dose for cohort members was 193 mGy and the median was 53 mGy. Thyroid doses for about 3% of cohort members were larger than 1 Gy. About 7% of children born in 1940-1950 had doses larger than 1 Gy. The uncertainty in the 131I dose estimates is low enough for this approach to be used in regional epidemiological studies. PMID- 28843167 TI - The health benefits of nature-based solutions to urbanization challenges for children and the elderly - A systematic review. AB - Urban green and blue spaces promote health by offering areas for physical activity, stress relief, and social interaction, which may be considered as cultural ecosystem services. They also provide a number of regulating ecosystem services that can be regarded as nature-based solutions to mitigate impacts from urbanization-induced challenges. Urban trees and other vegetation provide cooling through shade and evapotranspiration, which reduce the impact of the urban heat island on hot summer days. Urban vegetation may improve air quality by removing air pollutants. Open areas in cities, such as parks, gardens, playgrounds and cemeteries, are unsealed spaces that also improve infiltration during extreme precipitation events providing water regulating functions. All these services have the potential to improve the health of urban residents, particularly of specific vulnerable groups such as children and the elderly. The aim of this paper is to provide an overview of the current state of evidence on the relationship between the health of children and the elderly and urban green and blue spaces that can account as nature-based solutions to urbanization-induced challenges. We discuss potential confounding factors and refer to the different green space metrics used to identify associations to health. From the results, we cannot conclude on a universal protective health effect of urban green and blue spaces for children and the elderly. While the association trend is positive, the results remain inconclusive, context dependent and are partly overridden by socioeconomic confounders. However, the research area is consistently increasing, and we advance important prospects for future research on urban green and blue spaces in the face of global challenges such as urbanization. PMID- 28843166 TI - Occupation and mammographic density: A population-based study (DDM-Occup). AB - INTRODUCTION: High mammographic density is one of the main risk factors for breast cancer. Although several occupations have been associated with breast cancer, there are no previous occupational studies exploring the association with mammographic density. Our objective was to identify occupations associated with high mammographic density in Spanish female workers. METHODS: We conducted a population-based cross-sectional study of occupational determinants of high mammographic density in Spain, based on 1476 women, aged 45-68 years, recruited from seven screening centers within the Spanish Breast Cancer Screening Program network. Reproductive, family, personal, and occupational history data were collected. The latest occupation of each woman was collected and coded according to the 1994 National Classification of Occupations. Mammographic density was assessed from the cranio-caudal mammogram of the left breast using a semi automated computer-assisted tool. Association between mammographic density and occupation was evaluated by using mixed linear regression models, using log transformed percentage of mammographic density as dependent variable. Models were adjusted for age, body mass index, menopausal status, parity, smoking, alcohol intake, educational level, type of mammography, first-degree relative with breast cancer, and hormonal replacement therapy use. Screening center and professional reader were included as random effects terms. RESULTS: Mammographic density was higher, although non-statistically significant, among secondary school teachers (ebeta = 1.41; 95%CI = 0.98-2.03) and nurses (ebeta = 1.23; 95%CI = 0.96-1.59), whereas workers engaged in the care of people (ebeta = 0.81; 95%CI = 0.66-1.00) and housewives (ebeta = 0.87; 95%CI = 0.79-0.95) showed an inverse association with mammographic density. A positive trend for every 5 years working as secondary school teachers was also detected (p-value = 0.035). CONCLUSIONS: Nurses and secondary school teachers were the occupations with the highest mammographic density in our study, showing the latter a positive trend with duration of employment. Future studies are necessary to confirm if these results are due to chance or are the result of a true association whose causal hypothesis is, for the moment, unknown. PMID- 28843168 TI - Immobilization of Cr(VI) by hydrated Portland cement pastes with and without calcium sulfate. AB - This work aims to illustrate the impact of high concentrations of Cr(VI) (based on Na2CrO4) on the hydration assembly and microstructural development of hydrated Portland cement, and the results also present the role of calcium sulfate on the immobilization of Cr(VI) in Portland cement. The results showed that the immobilization of Cr(VI) in hydrated Portland cement was attributed to the formation of CrO4-U phase, an analogue of SO4-U phase (3CaO.Al2O3.CaSO4.0.5Na2SO4.15H2O). The growth of CrO4-U phase on the surface of clinker particles formed a diffusion barrier and hence increased the setting time. Increasing the calcium sulfate dosage impaired the Cr(VI) immobilization due to the competition between CrO42- and SO42- integrated into the U phase. The generalized acid neutralization capacity (GANC) test indicated that the Cr(VI) leaching behavior was a function of the leachate pH value. As the pH decreased to 11.8, the CrO4-U phase was converted quickly to CrO4-ettringite, which generated a slight increase in Cr(VI) concentration. The most leaching sector, approximately 89.3% of added Cr (1wt% of cement), was found in the pH range 11.8 10.5 due to the dissolution of secondary CrO4-ettringite. It could also be shown that the C-S-H had little chemical binding for Cr(VI). PMID- 28843169 TI - The low single nucleotide polymorphism heritability of plasma and saliva cortisol levels. AB - Cortisol is an important stress hormone affected by a variety of biological and environmental factors, such as the circadian rhythm, exercise and psychological stress. Cortisol is mostly measured using blood or saliva samples. A number of genetic variants have been found to contribute to cortisol levels with these methods. While the effects of several specific single genetic variants is known, the joint genome-wide contribution to cortisol levels is unclear. Our aim was to estimate the amount of cortisol variance explained by common single nucleotide polymorphisms, i.e. the SNP heritability, using a variety of cortisol measures, cohorts and analysis approaches. We analyzed morning plasma (n=5705) and saliva levels (n=1717), as well as diurnal saliva levels (n=1541), in the Rotterdam Study using genomic restricted maximum likelihood estimation. Additionally, linkage disequilibrium score regression was fitted on the results of genome-wide association studies (GWAS) performed by the CORNET consortium on morning plasma cortisol (n=12,597) and saliva cortisol (n=7703). No significant SNP heritability was detected for any cortisol measure, sample or analysis approach. Point estimates ranged from 0% to 9%. Morning plasma cortisol in the CORNET cohorts, the sample with the most power, had a 6% [95%CI: 0-13%] SNP heritability. The results consistently suggest a low SNP heritability of these acute and short-term measures of cortisol. The low SNP heritability may reflect the substantial environmental and, in particular, situational component of these cortisol measures. Future GWAS will require very large sample sizes. Alternatively, more long-term cortisol measures such as hair cortisol samples are needed to discover further genetic pathways regulating cortisol concentrations. PMID- 28843170 TI - Glutaredoxin 1 (GRX1) inhibits oxidative stress and apoptosis of chondrocytes by regulating CREB/HO-1 in osteoarthritis. AB - GRX1 (glutaredoxin1), a sulfhydryl disulfide oxidoreductase, is involved in many cellular processes, including anti-oxidation, anti-apoptosis, and regulation of cell differentiation. However, the role of GRX1 in the oxidative stress and apoptosis of osteoarthritis chondrocytes remains unclear, prompting the current study. Protein and mRNA expressions were measured by Western blot and RT-qPCR. Oxidative stress was detected by the measurement of MDA and SOD contents. Cells apoptosis were detected by Annexin V-FITC/PI and caspase-3 activity assays. We found that the mRNA and protein expressions of GRX1 were significantly down regulated in osteoarthritis tissues and cells. GRX1 overexpression increased the mRNA and protein expression of CREB and HO-1. Meanwhile, GRX1 overexpression inhibited oxidative stress and apoptosis in osteoarthritis chondrocytes. Furthermore, we found that GRX1 overexpression regulated HO-1 by increasing CREB, and that HO-1 regulated oxidative stress and apoptosis in osteoarthritis chondrocytes. Thus, GRX1 overexpression constrains oxidative stress and apoptosis in osteoarthritis chondrocytes by regulating CREB/HO-1, providing a novel insight into the molecular mechanism and potential treatment of osteoarthritis. PMID- 28843171 TI - The F0F1 ATP synthase regulates human neutrophil migration through cytoplasmic proton extrusion coupled with ATP generation. AB - Cytoplasmic alkalinization and extracellular adenosine triphosphate (ATP) signals are required for migration of chemokineactivated neutrophils, but the precise functions remain unclear. In this work, the effect of the plasma membrane expressed F0F1-ATP synthase (FATPase) on human neutrophils was examined. We found F-ATPase to be involved in cytoplasm proton extrusion and extracellular ATP generation. Oligomycin A, an F-ATPase inhibitor that blocks proton transfer, inhibited cytoplasmic alkalinization, extracellular ATP generation, adhesion and chemotaxis in N-formyl-Met-Leu-Phe (fMLP)-stimulated neutrophils; however, adenosine diphosphate (ADP), a substrate and activator of F-ATPase, had the opposite effect. Further analysis revealed that cell surface F-ATPase can translocate to the leading edge of directional fMLP-stimulated neutrophils toward ADP hydrolyzed from pannexin 1 channel-released ATP, followed by F-ATPase catalyzed ATP regeneration using ADP and protons transferred from the cytoplasm. Therefore, the membrane-expressed F-ATPase regulates human neutrophil migration via cytoplasm proton extrusion and extracellular ATP generation. PMID- 28843172 TI - Cognitive interventions in patients with dementia living in long-term care facilities: Systematic review and meta-analysis. AB - BACKGROUND: Previous reviews and meta-analyses demonstrated effects of cognitive interventions in dementia, but none specifically considered residents with dementia in long-term care (LTC) facilities. OBJECTIVE: To analyse the efficacy of cognitive interventions in institutionalised individuals with dementia. METHODS: After identifying 27 articles, a systematic review was performed. A meta analysis was calculated for 15 studies of the randomized controlled trials regarding effects on relevant outcomes. Fixed-effects meta-analyses were conducted using standardized mean differences (SMD) of changes from baseline pooled using the inverse variance method. RESULTS: When comparing cognitive interventions to passive control groups, the meta-analysis revealed significant moderate effects on global cognition (SMD=0.47, 95% CI 0.27-0.67), autobiographical memory (0.67, 0.02-1.31), and behavioral and psychological symptoms in dementia (BPSD; 0.71, 0.06-1.36). Significant small effects were detected for quality of life (QoL; 0.37, 0.05-0.70). Moderate effects on activities of daily living (0.28; -0.02 to 0.58) failed to reach significance; no effects were found on depression (0.22; -0.08 to 0.51). Significant moderate effects of global cognition (0.55; 0.22-0.89) and depression (0.64; 0.21-1.07) were also found for cognitive interventions contrasting active control groups. No harmful events related to the participation in the interventions were observed. CONCLUSION: Cognitive interventions are safe and effective for residents with dementia in LTC. However, while it seems clear that cognitive benefits can specifially be assigned to these forms of intervention, further research is necessary to clarify whether the effects on BPSD and QoL reflect unspecific changes due to additional attention. Furthermore, future studies will have to determine which intervention type yields the largest benefits. PMID- 28843173 TI - Validated LC-MS/MS method for the simultaneous determination of rotigotine and its prodrug in rat plasma and an application to pharmacokinetics and biological conversion in vitro. AB - Rotigotine behenate (RGTB), a long chain alkyl ester of the prodrug of rotigotine (RGT), has been synthesized for use in a sustained delivery system. The aim of the present report was to develop and validate a simple, sensitive and reliable LC-MS/MS method for the simultaneous determination of RGT and its prodrug RGTB in rat plasma samples. Detection was performed on a 1290 Infinity UPLC coupled Triple Quad 4500 mass spectrometer operated in positive MRM mode using an Eclipse XDB-CN chromatography column (2.1mm*100mm, 3.5MUm) by isocratic elution using a 0.2% formic acid aqueous solution and acetonitrile, with stable isotope labeled RGT as an internal standard. The sample preparation method employed 50MUL of a plasma sample and liquid-liquid extraction with a mixture of diethyl ether dichloromethane (3:2, v/v) as the extraction solvent. The proposed method was fully validated by assessing its specificity, linearity, precision and accuracy, recovery, matrix effects and stability. Good linearity was found within the range of 0.1-10.0ng/mL for both analytes (r>0.996). This method was successfully applied to a pharmacokinetic study of a slow release RGTB formulation in rats following a single intramuscular injection and biological conversion in vitro. PMID- 28843174 TI - Quantification of gabapentin polymorphs in gabapentin/excipient mixtures using solid state 13C NMR spectroscopy and X-ray powder diffraction. AB - Gabapentin was used as a model pharmaceutical compound with susceptibility to polymorphic transformation as a function of environmental and mechanical stress. The utility of 13C CP/MAS NMR and XRPD as stability-indicating methods to quantify polymorphic transformation kinetics was investigated. Polymorphic Form II and III were distinguishable based on their chemical shift and distinct diffraction peak differences. Reproducible and accurate quantification of polymorphic composition in the presence of selected excipients was demonstrated using both signals from 13C CP/MAS NMR spectra and XRPD patterns. The effect of excipients on polymorphic transformations (Form II->III) was determined by measuring the transformation after co-milling. Both 13C CP/MAS NMR and XRPD were capable of measuring polymorphic composition in co-milled excipient mixtures without excipient peak interference. The amounts of Form III present in co-milled mixtures containing colloidal silicon dioxide, starch, hydroxy propyl cellulose and dibasic calcium phosphate were 8.7, 21, 33, and 39mol%, respectively. A quenching procedure for obtaining 13C CP/MAS NMR spectra and environmentally controlled XRPD were devised to determine polymorphic transformation kinetics of co-milled excipient mixtures during storage. PMID- 28843175 TI - Who's uncivil to who? Perceptions of incivility in pre-licensure nursing programs. AB - The purpose of this study was to determine if there were differences in the perceptions of uncivil behaviors among nursing students and faculty according to pre-licensure nursing program types, and if there were any relationships in reported uncivil behaviors to the variables of age, gender, ethnic/racial background, and parental level of education. The sample was a convenience sample of 159 pre-licensure senior nursing students and 14 nursing faculty from four schools of nursing in the northeastern United States: two Bachelor of Science in Nursing (BSN) programs, one Associate Degree in Nursing (ADN) program, and one hospital-based diploma nursing program. The nursing students and nursing faculty were administered a mixed method, validated survey instrument, the Incivility in Nursing Education (INE) Survey (Clark et al., 2009). The results of the survey identified similarities and differences between the BSN, ADN, and diploma nursing programs for both the perceptions and experiences of uncivil behaviors, however no significant differences were found between the demographic variables and the occurrence of uncivil behaviors. PMID- 28843176 TI - Risk of second primary cancers among patients with a first primary gastric cancer: A population-based study in North Portugal. AB - BACKGROUND: The growing number of incident cases of gastric cancer along with improved survival result in a rising population of survivors at risk of second primary cancers (SPC). We estimated the cumulative incidence of metachronous (diagnosed >2months after first primary cancer [FPC]) SPC in gastric FPC patients and compared the incidence of metachronous SPC with that expected in the general population. METHODS: A cohort of gastric FPC patients from the North Region Cancer Registry of Portugal, diagnosed in 2000-2006 (n=7427) was followed to 31 December 2010 for synchronous and metachronous SPCs. Cumulative incidence of metachronous SPCs taking into account death as a competing event and standardized incidence ratios (SIR) of metachronous SPCs were estimated. RESULTS: Overall, 331 (4.5%) patients developed an SPC (26.9% synchronous and 73.1% metachronous). Over half of the SPCs occurred in digestive organs. Among men, the most frequent were colon, prostate, and trachea, bronchus and lung; in women, colon, breast and thyroid were the most common. The 10-year cumulative incidence of metachronous SPC for males was 5.7% and for females 3.5%. The SIR for all cancers was 1.30 in males and 1.20 in females. Among both sexes, significantly higher SIRs were observed for cancers of the oesophagus (males: 4.99; females: 8.03), small intestine (males: 11.04; females: 13.09) and colon (males: 2.42; females: 2.58). CONCLUSIONS: Patients with a gastric FPC were found to be at increased risk of developing SPC, mainly in digestive organs, when compared to the general population. Close surveillance of these patients may allow early detection of SPC. PMID- 28843177 TI - Is there a socioeconomic variation in survival from renal tumours in children and young people resident in northern England (1968-2012)? AB - BACKGROUND: Despite strong evidence of a social gradient in cancer survival among UK adults, studies in children and young people remain inconclusive and have not included renal tumours. This study investigated the relationship between socioeconomic status and survival from renal tumours among children and young people. PROCEDURE: Kaplan-Meier estimation and Cox regression were used to analyse survival for all 209 renal tumours in children and young people (0-24 years) diagnosed 1968-2012 and registered by a specialist population-based registry. Sociodemographic and clinicopathologic variables, including paternal occupation at birth, were also analysed. RESULTS: No significant disparity in overall renal tumour and Wilms tumour (WT) survival was observed according to paternal social class [p=0.988 and 0.808, respectively]. The strongest predictor of survival was stage, with late stage (III-IV) disease having a 4-fold higher risk of death compared to early stage (I-II) disease [p<0.001]. Similarly, high mortality-risk was seen for late stage WT in children aged 0-14 years (Hazard Ratio=6.37; 95% CI=2.60-15.59). CONCLUSIONS: This study did not detect a significant social gradient in renal tumour survival. The identification of tumour stage as a strong predictor of survival irrespective of age, necessitates the development of appropriate public health interventions that target early diagnosis and treatment. PMID- 28843178 TI - Esculentoside A exerts anti-inflammatory activity in microglial cells. AB - Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. This study was designed to evaluate the pharmacological effects of EsA on lipopolysaccharide (LPS)-stimulated BV2 microglia and primary microglia cells. Our results indicated that EsA pretreatment significantly decreased LPS-induced production of Nitric Oxide (NO) and Prostaglandin E2 (PGE2) and impeded LPS mediated upregulation of pro-inflammatory mediators' expression such as nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-12 (IL-12) and tumor necrosis factor-a (TNF alpha) in both BV2 microglia and primary microglia cells. Moreover, EsA markedly suppressed nuclear factor-kappaB p65 (NF-kappaB p65) translocation by blocking IkappaB-alpha phosphorylation and degradation in LPS-treated BV2 cells. EsA also decreased phosphorylation level of mitogen-activated protein kinases (MAPKs) and inhibited NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome mediated caspase-1 activation in LPS-stimulated BV2 cells. Additionally, EsA decreased beta-amyloid1-42 (Abeta1-42)-induced production of TNF-alpha, IL-1beta and IL-6 in primary microglia. Thus, EsA might be a promising therapeutic agent for alleviating neuroinflammatory diseases. PMID- 28843179 TI - Propofol inhibits NF-kappaB activation to ameliorate airway inflammation in ovalbumin (OVA)-induced allergic asthma mice. AB - Propofol, one of the most commonly used intravenous anesthetic agents, has been reported to have anti-inflammatory property. However, the anti-allergic inflammation effect of propofol and its underlying molecular mechanisms have not been elucidated. In the present study, we aim to investigate the roles of NF-kB activation in propofol anti-asthma effect on OVA-induced allergic airway inflammation in mice. In a standard experimental asthma model, Balb/c mice were sensitized with ovalbumin, treated with propofol (50,100,150mg/kg) or a vehicle control 1h before OVA challenge. Blood samples, bronchoalveolar lavage fluid (BALF) and lung tissues were harvested after measurement of airway hyperresponsiveness. Results revealed that propofol not only significantly inhibit airway hyperresponsiveness, but also inhibited the production of Th2 cytokines, NO, Ova-specific IgE and eotaxin. Histological studies indicated that propofol significantly attenuated OVA-induced inflammatory cell infiltration in the peribronchial areas and mucus hypersecretion. Meanwhile, our results indicated that propofol was found to inhibit NF-kB activation in OVA-Induced mice. Furthermore, propofol significantly reduced the TNF-alpha-induced NF-kB activation in A549 cells. In conclusion, our study suggested that propofol effectively reduced allergic airway inflammation by inhibiting NF-kB activation and could thus be used as a therapy for allergic asthma. PMID- 28843180 TI - Photoactivation provides a mechanistic explanation for pan-assay interference behaviour of 2-aminopyrroles in lipoxygenase inhibition. AB - Human 15-lipoxygenase-1 (h-15-LOX-1) is a promising drug target in inflammation and cancer. In this study substitution-oriented screening (SOS) has been used to identify compounds with a 2-aminopyrrole scaffold as inhibitors for h-15-LOX-1. The observed structure activity relationships (SAR) proved to be relatively flat. IC50's for the most potent inhibitor of the series did not surpass 6.3 MUM and the enzyme kinetics demonstrated uncompetitive inhibition. Based on this, we hypothesized that the investigated 2-aminopyrroles are pan assay interference compounds (PAINS) with photoactivation via a radical mechanism. Our results demonstrated clear photoactivation of h-15-LOX-1 inhibition under UV and visible light. In addition, the investigated 2-aminopyrroles decreased viability of cultured human hepatocarcinoma cells HCC-1.2 in a dose-dependent manner with LD50 ranging from 0.55 +/- 0.15 MUM (21B10) to 2.75 +/- 0.91 MUM (22). Taken together, this indicates that photoactivation can play an important role in the biological activity of compounds with a 2-amino-pyrrole scaffold as investigated here. PMID- 28843181 TI - Early prenatal androgen exposure reduces testes size and sperm concentration in sheep without altering neuroendocrine differentiation and masculine sexual behavior. AB - Prenatal androgens are largely responsible for growth and differentiation of the genital tract and testis and for organization of the control mechanisms regulating male reproductive physiology and behavior. The aim of the present study was to evaluate the impact of inappropriate exposure to excess testosterone (T) during the first trimester of fetal development on the reproductive function, sexual behavior, and fertility potential of rams. We found that biweekly maternal T propionate (100 mg) treatment administered from Day 30-58 of gestation significantly decreased (P < 0.05) postpubertal scrotal circumference and sperm concentration. Prenatal T exposure did not alter ejaculate volume, sperm motility and morphology or testis morphology. There was, however, a trend for more T exposed rams than controls to be classified as unsatisfactory potential breeders during breeding soundness examinations. Postnatal serum T concentrations were not affected by prenatal T exposure, nor was the expression of key testicular genes essential for spermatogenesis and steroidogenesis. Basal serum LH did not differ between treatment groups, nor did pituitary responsiveness to GnRH. T-exposed rams, like control males, exhibited vigorous libido and were sexually attracted to estrous females. In summary, these results suggest that exposure to exogenous T during the first trimester of gestation can negatively impact spermatogenesis and compromise the reproductive fitness of rams. PMID- 28843182 TI - Propylparaben suppresses epileptiform activity in hippocampal CA1 pyramidal cells in vitro. AB - Epilepsy is a highly prevalent neurological disorder. Additionally, a percentage of patients do not respond to conventional antiepileptic drugs. Therefore, drugs for epilepsy control are still being developed. In the present study, the effect of propylparaben (PPB) in the epileptiform activity induced by 4-aminopyridine in hippocampal CA1 pyramidal neurons was evaluated using individual recordings in current-clamp mode. Results indicated that PPB suppressed the epileptiform activity in registered neurons. This effect disappeared when PPB was removed from the solution of incubation. In contrast, phenytoin only reduced the firing frequency without abolishing epileptiform activity. Our results indicate that PPB exerts an antiepileptic effect on CA1 pyramidal neurons in vitro. Therefore, PPB may represent an effective antiepileptic compound. PMID- 28843183 TI - Automated approaches for band gap mapping in STEM-EELS. AB - Band gap variations in thin film structures, across grain boundaries, and in embedded nanoparticles are of increasing interest in the materials science community. As many common experimental techniques for measuring band gaps do not have the spatial resolution needed to observe these variations directly, probe corrected Scanning Transmission Electron Microscope (STEM) with monochromated Electron Energy-Loss Spectroscopy (EELS) is a promising method for studying band gaps of such features. However, extraction of band gaps from EELS data sets usually requires heavy user involvement, and makes the analysis of large data sets challenging. Here we develop and present methods for automated extraction of band gap maps from large STEM-EELS data sets with high spatial resolution while preserving high accuracy and precision. PMID- 28843185 TI - Effects of flexible and rigid rocker profiles on in-shoe pressure. AB - Rocker profiles are commonly used in the prevention of diabetic foot ulcers. Rockers are mostly stiffened to restrict toe plantarflexion to ensure proper offloading. It is also described that toe dorsiflexion should be restricted. However, the difference in effect on plantar pressure between rigid rockers that restrict this motion and flexible rockers that do not is unknown. In-shoe plantar pressure data were collected for a control shoe and the same shoe with rigid and flexible rockers with the apex positioned at 50% and 60%. For 29 healthy female adults peak plantar pressure (PP), maximum mean pressure (MMP) and force-time integral (FTI) were determined for seven regions of the foot. Generalized estimate equation was used to analyse the effect of the different shoes on the outcome measures for these regions. Compared to the control shoe a significant increase of PP and FTI was found at the first toe for both rigid rockers and the flexible rocker with the apex positioned at 60%, while MMP was significantly increased in rockers with an apex position of 60% (p<0.001). PP at the first toe was significantly lower in flexible rockers when compared to rigid rockers (p<0.001). For both central and lateral forefoot PP and MMP were significantly more reduced in rigid rockers (p<0.001), while for the medial forefoot no differences were found. The use of rigid rockers results in larger reductions of forefoot plantar pressures, but in worse increase of plantar pressures at the first toe compared to rockers that allow toe dorsiflexion. PMID- 28843184 TI - Evaluation of survival across several treatment lines in metastatic colorectal cancer: Analysis of the FIRE-3 trial (AIO KRK0306). AB - BACKGROUND: We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment. PATIENTS AND METHODS: OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time. RESULTS: The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS-intention-to-treat (ITT)/all-RAS wild type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44-0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35-0.75]). CONCLUSION: The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves. PMID- 28843186 TI - Backward compared to forward over ground gait retraining have additional benefits for gait in individuals with mild to moderate Parkinson's disease: A randomized controlled trial. AB - Over ground gait retraining in the reverse direction has shown to be beneficial for neurological rehabilitation, but has not yet been investigated in Parkinson's disease (PD). Backwards walking (BW) might be a useful training alternative to improve PD gait and possibly reduce fall risk during complex multi-directional daily activities. The primary aim was to compare the effect of an eight-week forward (FWG) and backwards (BWG) gait retraining program on gait parameters in PD individuals. Twenty-nine participants (aged 71.0+/-8.8years; UPDRS-III 38.1+/ 12.3; H&Y 2.7+/-0.5) were randomly assigned to either the control (FWG; n=14) or experimental group (BWG; n=15). Baseline measures included disease severity (UPDRS III), global cognition (MoCA) and depression (PHQ-9). Outcome measures were selected gait variables on the 10m-instrumented-walk-test (i10mWT) assessed before and after the interventions. Both groups improved usual gait speed (FWG: p=0.03, d=0.35; BWG: p<0.01, d=0.35) and height-normalized gait speed (FWG: p=0.04, d=0.35; BWG: p<0.01, d=0.57). Additionally, the BWG demonstrated improved cadence (p<0.01, d=0.67) and stride length (SL; p=0.02, d=0.39). Both interventions were effective to improved gait speed sufficiently to independently navigate in the community. PMID- 28843187 TI - Biodiversity of soil bacteria exposed to sub-lethal concentrations of phosphonium based ionic liquids: Effects of toxicity and biodegradation. AB - Little is known about the effect of ionic liquids (ILs) on the structure of soil microbial communities and resulting biodiversity. Therefore, we studied the influence of six trihexyl(tetradecyl)phosphonium ILs (with either bromide or various organic anions) at sublethal concentrations on the structure of microbial community present in an urban park soil in 100-day microcosm experiments. The biodiversity decreased in all samples (Shannon's index decreased from 1.75 down to 0.74 and OTU's number decreased from 1399 down to 965) with the largest decrease observed in the microcosms spiked with ILs where biodegradation extent was higher than 80%. (i.e. [P66614][Br] and [P66614][2,4,4]). Despite this general decrease in biodiversity, which can be explained by ecotoxic effect of the ILs, the microbial community in the microcosms was enriched with Gram negative hydrocarbon-degrading genera e.g. Sphingomonas. It is hypothesized that, in addition to toxicity, the observed decrease in biodiversity and change in the microbial community structure may be explained by the primary biodegradation of the ILs or their metabolites by the mentioned genera, which outcompeted other microorganisms unable to degrade ILs or their metabolites. Thus, the introduction of phosphonium-based ILs into soils at sub-lethal concentrations may result not only in a decrease in biodiversity due to toxic effects, but also in enrichment with ILs-degrading bacteria. PMID- 28843188 TI - A comparative study to evaluate natural attenuation, mycoaugmentation, phytoremediation, and microbial-assisted phytoremediation strategies for the bioremediation of an aged PAH-polluted soil. AB - Biological treatments are considered an environmentally option to clean-up polluted soil with polycyclic aromatic hydrocarbons (PAHs). A pot experiment was conducted to comparatively evaluate four different strategies, including natural attenuation (NA), mycoaugmentation (M) by using Crucibulum leave, phytoremediation (P) using maize plants, and microbial-assisted phytoremediation (MAP) for the bioremediation of an aged PAH-polluted soil at 180 days. The P treatment had higher affinity degrading 2-3 and 4 ring compounds than NA and M treatments, respectively. However, M and P treatments were more efficient in regards to naphthalene, indeno[l,2,3-c,d]pyrene and benzo[g,h,i]perylene degradation respect to NA. However, 4, 5-6 rings undergo a strong decline during the microbe-assisted phytoremediation, being the treatment which determined the highest rates of PAHs degradation. Sixteen PAH compounds, except fluorene and dibenzo[a,h]anthracene, were found in maize roots, whereas the naphthalene, phenanthrene, anthracene, fluoranthene, and pyrene were accumulated in the shoots, in both P and MAP treatments. However, higher PAH content in maize biomass was achieved during the MAP treatment respect to P treatment. The bioconversion and translocation factors were less than 1, indicating that phystabilization/phytodegradation processes occurred rather than phytoextraction. The microbial biomass, activity and ergosterol content were significantly boosted in the MAP treatment respect to the other treatments at 180 days. Ours results demonstrated that maize-C. laeve association was the most profitable technique for the treatment of an aged PAH-polluted soil when compared to other bioremediation approaches. PMID- 28843189 TI - Bacterial mediated alleviation of heavy metal stress and decreased accumulation of metals in plant tissues: Mechanisms and future prospects. AB - Heavy metal pollution of agricultural soils is one of main concerns causing some of the different ecological and environmental problems. Excess accumulation of these metals in soil has changed microbial community (e.g., structure, function, and diversity), deteriorated soil, decreased the growth and yield of plant, and entered into the food chain. Plants' tolerance to heavy metal stress needs to be improved in order to allow growth of crops with minimum or no accumulation of heavy metals in edible parts of plant that satisfy safe food demands for the world's rapidly increasing population. It is well known that PGPRs (plant growth promoting rhizobacteria) enhance crop productivity and plant resistance to heavy metal stress. Many recent reports describe the application of heavy metal resistant-PGPRs to enhance agricultural yields without accumulation of metal in plant tissues. This review provides information about the mechanisms possessed by heavy metal resistant-PGPRs that ameliorate heavy metal stress to plants and decrease the accumulation of these metals in plant, and finally gives some perspectives for research on these bacteria in agriculture in the future. PMID- 28843190 TI - Using species-specific enriched stable isotopes to study the effect of fresh mercury inputs in soil-earthworm systems. AB - The fate of mercury (Hg) in the soil-earthworm system is still far from being fully understood, especially regarding recurrent and challenging questions about the importance of the reactivity of exogenous Hg species. Thus, to predict the potential effect of Hg inputs in terrestrial ecosystems, it is necessary to evaluate separately the reactivity of the endogenous and exogenous Hg species and, for this purpose, the use of enriched stable isotope tracers is a promising tool. In the present work, earthworms (Lumbricus terrestris) were exposed to historically Hg contaminated soils from the Almaden mining district, Spain. The soils were either non-spiked, which contain only endogenous or native Hg naturally occurring in the soil, or spiked with isotopically enriched inorganic Hg (199IHg), representing exogenous or spiked Hg apart from the native one. The differential reactivity of endogenous and exogenous Hg in the soil conditioned the processes of methylation, mobilization, and assimilation of inorganic Hg by earthworms. Both endogenous and exogenous Hg species also behave distinctly regarding their bioaccumulation in earthworms, as suggested by the bioaccumulation factors, being the endogenous methylmercury (MeHg) the species more readily bioaccumulated by earthworms and in a higher extent. To the best of our knowledge, this work demonstrates for the first time the potential of enriched stable isotopes to study the effects of fresh Hg inputs in soil earthworm systems. The findings of this work can be taken as a case study on the dynamics of Hg species in complex terrestrial systems and open a new door for future experiments. PMID- 28843191 TI - A short history of RubisCO: the rise and fall (?) of Nature's predominant CO2 fixing enzyme. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO) is arguably one of the most abundant proteins in the biosphere and a key enzyme in the global carbon cycle. Although RubisCO has been intensively studied, its evolutionary origins and rise as Nature's most dominant carbon dioxide (CO2)-fixing enzyme still remain in the dark. In this review we will bring together biochemical, structural, physiological, microbiological, as well as phylogenetic data to speculate on the evolutionary roots of the CO2-fixation reaction of RubisCO, the emergence of RubisCO-based autotrophic CO2-fixation in the context of the Calvin Benson-Bassham cycle, and the further evolution of RubisCO into the 'RubisCOsome', a complex of various proteins assembling and interacting with the enzyme to improve its operational capacity (functionality) under different biological and environmental conditions. PMID- 28843192 TI - Systems and synthetic biology for the biotechnological application of cyanobacteria. AB - Cyanobacteria are the only prokaryotes that perform oxygenic photosynthesis. Their evolutionary relation to plastids in eukaryotic phototrophs and their increasing utilization as green cell factories initiated the use of systems biology approaches early on. For select model strains, extensive 'omics' data sets have been generated, and genome-wide models have been elucidated. Moreover, the results obtained may be used for the optimization of cyanobacterial metabolism, which can direct the biotechnological production of biofuels or chemical feedstock. Synthetic biology approaches permit the rational construction of novel metabolic pathways that are based on the combination of multiple enzymatic activities of different origins. In addition, the manipulation of whole metabolic networks by CRISPR-based and sRNA-based technologies with multiple parallel targets will further stimulate the use of cyanobacteria for diverse applications in basic research and biotechnology. PMID- 28843193 TI - Meteorological analysis of symptom data for people with seasonal affective disorder. AB - It is thought that variation in natural light levels affect people with Seasonal Affective Disorder (SAD). Several meteorological factors related to luminance can be forecast but little is known about which factors are most indicative of worsening SAD symptoms. The aim of this meteorological analysis is to determine which factors are linked to SAD symptoms. The symptoms of 291 individuals with SAD in and near Groningen have been evaluated over the period 2003-2009. Meteorological factors linked to periods of low natural light (sunshine, global radiation, horizontal visibility, cloud cover and mist) and others (temperature, humidity and pressure) were obtained from weather observation stations. A Bayesian zero adjusted auto-correlated multilevel Poisson model was carried out to assess which variables influence the SAD symptom score BDI-II. The outcome of the study suggests that the variable sunshine duration, for both the current and previous week, and global radiation for the previous week, are significantly linked to SAD symptoms. PMID- 28843195 TI - Core-size regulated aggregation/disaggregation of citrate-coated gold nanoparticles (5-50nm) and dissolved organic matter: Extinction, emission, and scattering evidence. AB - Knowledge of the interactions between gold nanoparticles (GNPs) and dissolved organic matter (DOM) is significant in the development of detection devices for environmental sensing, studies of environmental fate and transport, and advances in antifouling water treatment membranes. The specific objective of this research was to spectroscopically investigate the fundamental interactions between citrate stabilized gold nanoparticles (CT-GNPs) and DOM. Studies indicated that 30 and 50nm diameter GNPs promoted disaggregation of the DOM. This result-disaggregation of an environmentally important polyelectrolyte-will be quite useful regarding antifouling properties in water treatment and water-based sensing applications. Furthermore, resonance Rayleigh scattering results showed significant enhancement in the UV range which can be useful to characterize DOM and can be exploited as an analytical tool to better sense and improve our comprehension of nanomaterial interactions with environmental systems. CT-GNPs having core size diameters of 5, 10, 30, and 50nm were studied in the absence and presence of added DOM at 2 and 8 ppm at low ionic strength and near neutral pH (6.0-6.5) approximating surface water conditions. Interactions were monitored by cross-interpretation among ultraviolet (UV)-visible extinction spectroscopy, excitation-emission matrix (EEM) spectroscopy (emission and Rayleigh scattering), and dynamic light scattering (DLS). This comprehensive combination of spectroscopic analyses lends new insights into the antifouling behavior of GNPs. The CT-GNP-5 and -10 controls emitted light and aggregated. In contrast, the CT-GNP-30 and CT-GNP-50 controls scattered light intensely, but did not aggregate and did not emit light. The presence of any CT-GNP did not affect the extinction spectra of DOM, and the presence of DOM did not affect the extinction spectra of the CT-GNPs. The emission spectra (visible range) differed only slightly between calculated and actual mixtures of CT-GNP-5 or -10 with DOM, whereas emissions for mixtures of CT GNP-30 or -50 with DOM were enhanced at the surface plasmon resonance (SPR) wavelength. The emission spectra (ultraviolet range) for protein-like constituents of DOM were quenched. Resonance Rayleigh scattering (RRS) was more intense for the CT-GNP-30 and -50 than for the CT-GNP-5 and -10 controls. Intensity-based DLS particle size distributions (PSDs) of DOM controls, CT-GNP-5 and -10nm controls, and 5- and 10nm GNP-DOM mixtures exhibited multimodal aggregation. Analyses of CT-GNP-5 and CT-GNP-10nm mixtures with DOM indicated overcoating of DOM molecules occurred in close proximity (<10nm) to GNPs, whereas similar overcoating was not supported for the CT-GNP-30 or -50 mixtures with DOM. These fundamental observations can be exploited to improve our comprehension of nanomaterial interactions with environmental systems. PMID- 28843194 TI - Bioengineered II-VI semiconductor quantum dot-carboxymethylcellulose nanoconjugates as multifunctional fluorescent nanoprobes for bioimaging live cells. AB - Colloidal semiconductor quantum dots (QDs) are light-emitting ultra-small nanoparticles, which have emerged as a new class of nanoprobes with unique optical properties for bioimaging and biomedical diagnostic. However, to be used for most biomedical applications the biocompatibility and water-solubility are mandatory that can achieved through surface modification forming QD nanoconjugates. In this study, semiconductor II-VI quantum dots of type MX (M=Cd, Pb, Zn, X=S) were directly synthesized in aqueous media and at room temperature using carboxymethylcellulose sodium salt (CMC) behaving simultaneously as stabilizing and surface biofunctional ligand. These nanoconjugates were extensively characterized using UV-visible spectroscopy, photoluminescence spectroscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, dynamic light scattering and zeta potential. The results demonstrated that the biopolymer was effective on nucleating and stabilizing the colloidal nanocrystals of CdS, ZnS, and PbS with the average diameter ranging from 2.0 to 5.0nm depending on the composition of the semiconductor core, which showed quantum-size confinement effect. These QD/polysaccharide conjugates showed luminescent activity from UV visible to near-infrared range of the spectra under violet laser excitation. Moreover, the bioassays performed proved that these novel nanoconjugates were biocompatible and behaved as composition-dependent fluorescent nanoprobes for in vitro live cell bioimaging with very promising perspectives to be used in numerous biomedical applications and nanomedicine. PMID- 28843196 TI - Fast classification of hazelnut cultivars through portable infrared spectroscopy and chemometrics. AB - The authentication and traceability of hazelnuts is very important for both the consumer and the food industry, to safeguard the protected varieties and the food quality. This study investigates the use of a portable FTIR spectrometer coupled to multivariate statistical analysis for the classification of raw hazelnuts. The method discriminates hazelnuts from different origins/cultivars based on differences of the signal intensities of their IR spectra. The multivariate classification methods, namely principal component analysis (PCA) followed by linear discriminant analysis (LDA) and partial least square discriminant analysis (PLS-DA), with or without variable selection, allowed a very good discrimination among the groups, with PLS-DA coupled to variable selection providing the best results. Due to the fast analysis, high sensitivity, simplicity and no sample preparation, the proposed analytical methodology could be successfully used to verify the cultivar of hazelnuts, and the analysis can be performed quickly and directly on site. PMID- 28843198 TI - Synergistic effect of casein glycomacropeptide on sodium caseinate foaming properties. AB - Several strategies to improve the interfacial properties and foaming properties of proteins may be developed; among them, the use of mixtures of biopolymers that exhibit synergistic interactions. The aim of the present work was to evaluate the effect of casein glycomacropeptide (CMP) on foaming and surface properties of sodium caseinate (NaCas) and to establish the role of protein interactions in the aqueous phase. To this end particles size, interfacial and foaming properties of CMP, NaCas and NaCas-CMP mixtures at pH 5.5 and 7 were determined. At both pH, the interaction between CMP and NaCas induced a decrease in the aggregation state of NaCas. Single CMP foams showed the highest and NaCas the lowest foam overrun (FO) and the mixture exhibited intermediate values. CMP foam quickly drained. The drainage profile of mixed foams was closer to NaCas foams; at pH 5.5, mixed foams drained even slower than NaCas foam, exhibiting a synergistic performance. Additionally, a strong synergism was observed on the collapse of mixed foams at pH 5.5. Finally, a model to explain the synergistic effect observed on foaming properties in CMP-NaCas mixtures has been proposed; the reduced aggregation state of NaCas in the presence of CMP, made it more efficient for foam stabilization. PMID- 28843197 TI - Novel ratiometric surface-enhanced raman spectroscopy aptasensor for sensitive and reproducible sensing of Hg2. AB - It is important to precisely monitor mercury (II) ions (Hg2+) for environment protection and human health monitoring. Although many strategies have been developed in the past decades, there still remains a challenge for developing an ultrasensitive, simple and reliable approach to detect Hg2+. Herein, we report a ratiometric surface-enhanced Raman scattering (SERS) aptasensor by employing aptamer-modified Au@Ag core-shell nanoparticles (Au@Ag NPs) as highly functional sensing probes, allowing for ultrasensitive detection of Hg2+. In principle, the thiolated 5'-Cy3 labeled aptamer probe (Cy3-aptamer) is firstly immobilized on the SERS substrate surface and then hybridizes with the 5'-Rox labeled complementary DNA (cDNA) to form a rigid double-stranded DNA (dsDNA), in which the Cy3 and Rox Raman labels are used to produce the ratiometric Raman signals. In the presence of Hg2+, the aptamer DNA turns into the thymine (T)-Hg2+-T mediated hairpin structure, leading to the dissociation of dsDNA. As a result, the Rox labels are away from the Au@Ag NP SERS substrate while Cy3 labels are close to it. Therefore, the intensity of SERS signal from Cy3 labels increases while that from Rox labels decreases. The ratio between the Raman intensities of Cy3 labels and Rox labels is linear with Hg2+ concentrations in the range from 0.001 to 1.0nM, and the limit of detection is estimated to be 0.4pM. The proposed strategy provides a new rapid, simple and reliable approach for sensitive detection of Hg2+ and may create a universal methodology for developing analogous aptasensors for a wide range of other analytes determination. PMID- 28843199 TI - Thiol-ene miniemulsion polymerization of a biobased monomer for biomedical applications. AB - Herein, we present the synthesis and characterization of poly(thioether-ester) nanoparticles via thiol-ene miniemulsion polymerization using a biobased alpha,omega-diene diester monomer, namely dianhydro-d-glucityl diundec-10-enoate (DGU), synthesized from 10-undecenoic acid (derived from castor oil) and isosorbide (derived from starch). DGU was copolymerized with 1,4-butanedithiol by thiol-ene miniemulsion polymerization resulting in waterborne poly(thioether ester) particles with diameter around 200nm. Polymers with number average molecular weight up to 11kDa were obtained via miniemulsion polymerization. DSC and XRD analyses indicated a semi-crystalline polymer with a degree of crystallinity of at least 20% and Tm around 68 degrees C. In addition, Coumarin 6 was encapsulated in the polymer particles with efficiency up to 98%. Nanoparticles presented biocompatibility in murine fibroblast (L929) and uterine colon cancer (HeLa) cells. The substantial cellular uptake of poly(thioether ester) nanoparticles by HeLa cells suggests a potential use in uterine colon cancer treatment. PMID- 28843200 TI - Cartilage oligomeric matrix protein improves in vivo cartilage regeneration and compression modulus by enhancing matrix assembly and synthesis. AB - Cartilage oligomeric matrix protein (COMP), an abundant cartilage extracellular matrix protein, plays an important role in mesenchymal chondrogenesis. To test our hypothesis that COMP could promote tissue engineering cartilage regeneration as well as improve cartilaginous mechanical properties, COMP gene transfected rabbit bone marrow mesenchymal stem cells (BMSCs) were used for chondrogenic differentiation in vitro and were implanted with biphasic scaffolds into osteochondral defects of New Zealand white rabbit trochlear grooves for cartilage regeneration in vivo. In vitro, over expressed COMP could enhance the chondrogenic differentiation and ECM secretion of BMSCs. After euthanasia at 12 weeks post implantation, macroscopic observation, histological staining, mechanical tests and micro-CT were performed for the assessment of repaired cartilage. Overexpression of COMP leads to more newly formed hyaline cartilage and significantly improved mechanical property. These results demonstrated the significant role of COMP in the cartilage regeneration in vivo and offered inspiring advantage of COMP in the application of tissue engineering. PMID- 28843201 TI - Layer-by-layer assembly and functionalization of nanobentonite with nanopolyaniline and oleic acid to remove divalent Zn, Co,65Zn, and 60Co from water and radioactive wastewater. AB - A novel material was designed using layer-by-layer functionalization of nanobentonite with nanopolyaniline and oleic acid to produce an efficient NBent NPA-OA nanosorbent to adsorb the divalent ionic Zn/Co and their radioisotopes 65Zn/60Co from tap water and radioactive wastewater. The new nanosorbent was characterized by Fourier-transform-infrared (FT-IR), thermal gravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), high resolution transmission electron microscopy (HR-TEM) and determination of surface area. The NBent-NPA-OA particle size was ranged between 9.45 and 33.60nm according to HR-TEM analysis. The FT-IR exhibited several characteristic absorption peaks due to the existence of deposited layers of nanopolyaniline and oleic acid on the surface of nanobentonite surface. Different experimental parameters including, initial pH, contact time, nanosorbent, initial concentration of the target metals and interfering ions were varied, investigated and optimized to evaluate the removal efficiency of the divalent ionic Zn/Co from their solutions by the action of NBent-NPA-OA nanosorbent. The collected batch equilibrium results confirmed the efficiency of newly functionalized NBent-NPA-OA nanosorbent to uptake the divalent ionic Zn/Co from their solutions (10.0mL of 0.01mol/L) with maximum capacity values 2.916 and 1.960mmolg-1, respectively using 5.0mg nanosorbent, pH 6.0 and 20min contact reaction time. The multistage microcolumn system was successfully implemented to remove the divalent ionic Zn/Co from tap water in addition to their radioisotopes 65Zn/60Co from radioactive wastewater. The current study refers to an excellent recovery and the removal percent of the radioisotopes 65Zn (96.4) and 60Co (92.7%) using NBent-NPA OA nanosorbent. PMID- 28843202 TI - Microplastic pollution in the surface waters of the Bohai Sea, China. AB - The ubiquitous presence and persistency of microplastics in aquatic environments is of particular concern because these pollutants represent an increasing threat to marine organisms and ecosystems. An identification of the patterns of microplastic distribution will help to understand the scale of their potential effect on the environment and on organisms. In this study, the occurrence and distribution of microplastics in the Bohai Sea are reported for the first time. We sampled floating microplastics at 11 stations in the Bohai Sea using a 330 MUm trawling net in August 2016. The abundance, composition, size, shape and color of collected debris samples were analyzed after pretreatment. The average microplastic concentration was 0.33 +/- 0.34 particles/m3. Micro-Fourier transform infrared spectroscopy analysis showed that the main types of microplastics were polyethylene, polypropylene, and polystyrene. As the size of the plastics decreased, the percentage of polypropylene increased, whereas the percentages of polyethylene and polystyrene decreased. Plastic fragments, lines, and films accounted for most of the collected samples. Accumulation at some stations could be associated with transport and retention mechanisms that are linked to wind and the dynamics of the rim current, as well as different sources of the plastics. PMID- 28843204 TI - Toxicity of emerging antifouling biocides to non-target freshwater organisms from three trophic levels. AB - Antifouling (AF) systems provide the most cost-effective protection against biofouling. Several AF biocides have, however, caused deleterious effects in the environment. Subsequently, new compounds have emerged that claim to be more environment-friendly, but studies on their toxicity and environmental risk are necessary in order to ensure safety. This work aimed to assess the toxicity of three emerging AF biocides, tralopyril, triphenylborane pyridine (TPBP) and capsaicin, towards non-target freshwater organisms representing three trophic levels: algae (Chlamydomonas reinhardtii), crustacean (Daphnia magna) and fish (Danio rerio). From the three tested biocides, tralopyril had the strongest inhibitory effect on C. reinhardtii growth, effective quantum yield and adenosine triphosphate (ATP) content. TPBP caused sub-lethal effects at high concentrations (100 and 250MUgL-1), and capsaicin had no significant effects on algae. In the D. magna acute immobilisation test, the most toxic compound was TPBP. However, tralopyril has a short half-life and quickly degrades in water. With exposure solution renewals, tralopyril's toxicity was similar to TPBP. Capsaicin did not cause any effects on daphnids. In the zebrafish embryo toxicity test (zFET) the most toxic compound was tralopyril with a 120h - LC50 of 5MUgL-1. TPBP's 120h - LC50 was 447.5MUgL-1. Capsaicin did not cause mortality in zebrafish up to 1mgL 1. Sub-lethal effects on the proteome of zebrafish embryos were analysed for tralopyril and TPBP. Both general stress-related and compound-specific protein changes were observed. Five proteins involved in energy metabolism, eye structure and cell differentiation were commonly regulated by both compounds. Tralopyril specifically induced the upregulation of 6 proteins implicated in energy metabolism, cytoskeleton, cell division and mRNA splicing whilst TPBP lead to the upregulation of 3 proteins involved in cytoskeleton, cell growth and protein folding. An ecological risk characterization was performed for a hypothetical freshwater marina. This analysis identified capsaicin as an environment-friendly compound while tralopyril and TPBP seem to pose a risk to freshwater ecosystems. Noneless, more studies on the characterization of the toxicity, behaviour and fate of these AF biocides in the environment are necessary since this information directly affects the outcome of the risk assessment. PMID- 28843203 TI - Mitigation of Cd accumulation in paddy rice (Oryza sativa L.) by Fe fertilization. AB - Cadmium uptake in rice is believed to be mediated by the Fe transport system. Phyto-available Cd can be changed by Fe fertilization of substrates. This work investigated whether and how Fe fertilization affects mitigation of Cd accumulation in paddy rice. A 90-d soil column experiment was conducted to study the change of Cd and Fe availability in soil after Fe fertilization (ionic and chelated Fe). A low-Cd accumulating cultivar (TY116) and a high-Cd accumulating cultivar (JY841) were grown in two Cd-polluted paddy soils amended with chelated Fe fertilizers. Additionally, both cultivars were grown in hydroponics to compare Fe-related gene expression in EDDHAFe-deficient and EDDHAFe-sufficient roots. The column experiment showed that EDTANa2Fe(II) and EDDHAFe(III) fertilization had a better mitigation effect on soil Cd availability compared to FeSO4.7H2O. Moreover, the field experiment demonstrated that these two chelated fertilizations could reduce Cd concentrations in brown rice by up to 80%. Iron concentrations in the brown rice were elevated by Fe chelates. Compared to EDDHAFe(III), EDTANa2Fe(II) fertilization had a stronger mitigation effect by generating more EDTANa2Cd(II) in the soil solution to decrease phyto-available Cd in the soil. While EDDHAFe(III) fertilization could increase soil pH and decrease soil Eh which contributed to decreasing phyto-available Cd in a contaminated soil. In the hydroponic experiment, Fe sufficiency significantly reduced Cd concentrations in above-ground organs. In some cases, the expression of OsIRT1, OsNRAMP1 and OsNRAMP5 was inhibited under Fe sufficiency relative to Fe deficiency conditions. These results suggest that mitigation of rice Cd by Fe chelate fertilization results from a decrease in available Cd in substrates and the inhibition of the expression of several Fe-related genes in the IRT and NRAMP families. PMID- 28843205 TI - Social class, leaders and leadership: a critical review and suggestions for development. AB - The consideration of social class in leadership research presents many exciting directions for research. In this review, we describe and summarize how social class research has been applied to the study of leaders and the leadership process, noting that while evidence suggests those from higher social classes are more likely to occupy formal leader roles in organizations, there is little evidence suggesting that they are more effective in these roles than those from lower social classes. We conclude with a discussion of important, unanswered theoretical questions about how social class relates to the process of leadership most notably, whether those from different classes internalize different beliefs and expectations about how people in leader and follower roles should act, and how matches or mismatches in those beliefs and expectations shape leader-follower interactions and outcomes. PMID- 28843206 TI - Leveraging cultural differences to promote educational equality. AB - This paper theorizes that academic interventions will be maximally effective when they are culturally grounded. Culturally grounded interventions acknowledge cultural differences and validate multiple cultural models in a given context. This review highlights the importance of considering culture in academic interventions and draws upon the culture cycle framework to provide a blueprint for those interested in building more efficacious interventions. Specifically, the paper reviews literature in education and psychology to argue: first, when working-class and racial minority students' cultural models are not valued in mainstream academic domains, these students underperform; and second, many current academic interventions intended to improve working-class and racial minority students' academic outcomes could be further enhanced by cultural grounding. PMID- 28843207 TI - Resisting distraction and response inhibition trigger similar enhancements of future performance. AB - Resisting distraction and response inhibition are crucial aspects of cognitive control. Interestingly, each of these abilities transiently improves just after it is utilized. Competing views differ, however, as to whether utilizing either of these abilities (e.g., resisting distraction) enhances future performance involving the other ability (e.g., response inhibition). To distinguish between these views, we combined a Stroop-like task that requires resisting distraction with a restraint variant of the stop-signal task that requires response inhibition. We observed similar sequential-trial effects (i.e., performance enhancements) following trials in which participants (a) resisted distraction (i.e., incongruent go trials) and (b) inhibited a response (i.e., congruent stop trials). First, the congruency effect in go trials, which indexes overall distractibility, was smaller after both incongruent go trials and congruent stop trials than it was after congruent go trials. Second, stop failures were less frequent after both incongruent go trials and congruent stop trials than after congruent go trials. A control experiment ruled out the possibility that perceptual conflict or surprise engendered by occasional stop signals triggers sequential-trial effects independent of stopping. Thus, our findings support a novel, integrated view in which resisting distraction and response inhibition trigger similar sequential enhancements of future performance. PMID- 28843208 TI - Color and alcohol removal for the simultaneous detection of amino acids and sugars in wine by two-dimensional ion chromatography. AB - An effective pretreatment method for wine color removal by a PS-DVB SPE cartridge and online alcohol elimination by valve switching was presented. The optimum parameters for color removal were investigated: 40-MUm and 100A poly (styrene) divinylbenzene (PS-DVB) (0.4g) was selected as the color removal material and 5mL of ethanol (10%) as the elution solvent for sample pretreatment under given condition. Moreover, an accurate and automated two-dimensional ion chromatography method for the simultaneous detection of amino acids and sugars was achieved with two valves after injection without alcohol interference. The method had a mean correlation coefficient of >0.99 and a repeatability of 0.92%-4.30% for eight replicates. The mean recovery of six red wine samples were 97.6%, 96.6%, 96.1%, 95.9%, 97.3% and 96.4% respectively. And this method successfully analyzed the amino acid and sugar contents of six wine samples of different origins. PMID- 28843210 TI - Systematic review of unmet healthcare needs in patients with epilepsy. AB - OBJECTIVE: Patients with epilepsy (PWE) are more likely to have unmet healthcare needs than the general population. This systematic review assessed the reasons for unmet needs in PWE. METHODS: Medline, Embase, PsycINFO, Cochrane, and Web of Science databases were searched using keywords relating to unmet healthcare needs, treatment barriers, and access to care. The search included all countries, adult and pediatric populations, survey and qualitative studies, but excluded non English articles and articles published before 2001. Reasons for unmet needs were extracted. RESULTS: Nineteen survey and 22 qualitative studies were included. Three survey and five qualitative studies excluded patients with comorbidities. There were twice as many studies on unmet mental healthcare needs than unmet physical care needs in PWE. Poor availability of health services, accessibility issues, and lack of health information contributed to unmet needs in both Western and developing countries. Lack of health services, long wait lists, uncoordinated care, and difficulty getting needed health information were prevalent in the United States (US) as well as countries with a universal healthcare system. However, unmet needs due to costs of care were reported more commonly in studies from the US. SIGNIFICANCE: This systematic review identified reasons for unmet needs in PWE across different countries, which will inform specific interventions required to address these unmet needs. Unmet needs may have been underestimated due to exclusion of PWE with comorbidities in some studies. Additional studies are needed to understand the contribution of comorbidities on unmet needs and their interaction with caregiver and family factors. PMID- 28843209 TI - Stream segregation of concurrent speech and the verbal transformation effect: Influence of fundamental frequency and lateralization cues. AB - Repeating a recorded word produces verbal transformations (VTs); perceptual regrouping of acoustic-phonetic elements may contribute to this effect. The influence of fundamental frequency (F0) and lateralization grouping cues was explored by presenting two concurrent sequences of the same word resynthesized on different F0s (100 and 178 Hz). In experiment 1, listeners monitored both sequences simultaneously, reporting for each any change in stimulus identity. Three lateralization conditions were used - diotic, +/-680-MUs interaural time difference, and dichotic. Results were similar for the first two conditions, but fewer forms and later initial transformations were reported in the dichotic condition. This suggests that large lateralization differences per se have little effect - rather, there are more possibilities for regrouping when each ear receives both sequences. In the dichotic condition, VTs reported for one sequence were also more independent of those reported for the other. Experiment 2 used diotic stimuli and explored the effect of the number of sequences presented and monitored. The most forms and earliest transformations were reported when two sequences were presented but only one was monitored, indicating that high task demands decreased reporting of VTs for concurrent sequences. Overall, these findings support the idea that perceptual regrouping contributes to the VT effect. PMID- 28843211 TI - Predictive coding: A contemporary view on the burden of normality and forced normalization in individuals undergoing epilepsy surgery. AB - Following epilepsy surgery, a good psychosocial outcome is not necessarily contingent on a good seizure outcome. Increasingly, it is believed that "successful" surgery is a combination of both an acceptable and expected seizure status as well as the individual's perception of improvements in quality of life (QOL). The factors that create this optimal outcome remain an ongoing area of research in the epilepsy community. That being said, there have been some major breakthroughs in observing and understanding poor outcomes seen in a subset of postoperative patients with epilepsy. Characteristics of burden of normality and forced normalization are two phenomena that have been evident in cases of poor postoperative outcomes. In this review, we provide a summary of research and concepts used to explain these poor QOL outcomes for a seemingly successful surgery and suggest a contemporary view in understanding the mechanism of forced normalization through understanding the brain as a predictive organ. Using such a predictive coding model together with recommendations of other studies, we suggest the crucial need for a preoperative intervention addressing patient predictions and expectations to optimize on the benefits achievable through epilepsy surgery. PMID- 28843212 TI - The influence of endophenotypic, disease-specific, and environmental variables on the expression of anxiety in pediatric epilepsy. AB - Children and adolescents with epilepsy often show higher rates of anxiety, which carries an increased risk for reduced health-related quality of life (HRQOL). The current study assessed the role of parental psychiatric history (i.e., anxiety, depression, and/or bipolar disorder) on the rate of anxiety features in youth seen in a tertiary epilepsy clinic. Data included parental ratings on the Behavior Assessment System for Children (BASC-2) and the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire for 180 children and adolescents (mean age=11.40, SD=3.98). Our results identified clinically elevated anxiety ratings in nearly half the sample (47%) with previous psychiatric history endorsed by 48% of parents. The effect of parental psychiatric history on youth anxiety was found to be significant and associated with a threefold increase in the rate of youth anxiety features. This risk increased to fourfold in refractory epilepsy, and the impact of family psychiatric history is greater in adolescent females and in families that report higher levels of stress. In those families who reported no psychiatric history, anxiety was best predicted by epilepsy-specific factors above and beyond sociodemographic factors. Parental psychiatric history was also identified as a significant risk factor for diminished patient HRQOL, even after accounting for seizure control. These findings highlight the impact of family and epilepsy factors on psychological functioning and offer further support for the strong relationship between parental adjustment and child outcome in pediatric epilepsy. PMID- 28843213 TI - Response shift in parents' assessment of health-related quality of life of children with new-onset epilepsy. AB - OBJECTIVE: Diagnosis of epilepsy is known to impact health-related quality of life (HRQOL) of children with new-onset epilepsy and can also influence their conceptualization and valuation of HRQOL construct, also known as response shift. This study investigates the presence of response shift in a cohort of children with new-onset epilepsy. METHODS: Data are from the HEalth-Related QUality of Life in children with Epilepsy Study, a prospective cohort study of 373 children with new-onset epilepsy. Hypotheses about the presence of reconceptualization, reprioritization, and recalibration response shift were tested in the Quality of Life in Childhood Epilepsy (QOLCE-55) Questionnaire, a parent-reported, disease specific HRQOL measure, using Oort's structural equation model between baseline and 1-year follow-up. Model fit was assessed using log-likelihood ratio test, root mean square error of approximation, and comparative fit index. RESULTS: Small positive uniform recalibration response shift effects were observed on physical, emotional, and social functioning domains of the QOLCE-55, but negligibly small negative nonuniform recalibration response shift effect was observed on social functioning domain. There was no significant change in overall QOLCE-55 scores over time after adjusting for response shift effects. SIGNIFICANCE: Parents of children with new-onset epilepsy are likely to positively recalibrate (upward bias) their assessments of their children's HRQOL over a 1-year period after diagnosis. This study highlights the potential benefits of response shift as a desired consequence in parents' perception of changes in HRQOL of children with new-onset epilepsy. PMID- 28843214 TI - Constructing fine-granularity functional brain network atlases via deep convolutional autoencoder. AB - State-of-the-art functional brain network reconstruction methods such as independent component analysis (ICA) or sparse coding of whole-brain fMRI data can effectively infer many thousands of volumetric brain network maps from a large number of human brains. However, due to the variability of individual brain networks and the large scale of such networks needed for statistically meaningful group-level analysis, it is still a challenging and open problem to derive group wise common networks as network atlases. Inspired by the superior spatial pattern description ability of the deep convolutional neural networks (CNNs), a novel deep 3D convolutional autoencoder (CAE) network is designed here to extract spatial brain network features effectively, based on which an Apache Spark enabled computational framework is developed for fast clustering of larger number of network maps into fine-granularity atlases. To evaluate this framework, 10 resting state networks (RSNs) were manually labeled from the sparsely decomposed networks of Human Connectome Project (HCP) fMRI data and 5275 network training samples were obtained, in total. Then the deep CAE models are trained by these functional networks' spatial maps, and the learned features are used to refine the original 10 RSNs into 17 network atlases that possess fine-granularity functional network patterns. Interestingly, it turned out that some manually mislabeled outliers in training networks can be corrected by the deep CAE derived features. More importantly, fine granularities of networks can be identified and they reveal unique network patterns specific to different brain task states. By further applying this method to a dataset of mild traumatic brain injury study, it shows that the technique can effectively identify abnormal small networks in brain injury patients in comparison with controls. In general, our work presents a promising deep learning and big data analysis solution for modeling functional connectomes, with fine granularities, based on fMRI data. PMID- 28843215 TI - Understanding participation of children with cerebral palsy in family and recreational activities. AB - AIMS: The primary aim of this study was to determine the effect of age, sex, gross motor, manual ability, and communication functions on the frequency and enjoyment of children's participation in family and recreational activities. The secondary aim was to determine the relationships between motor and communication functions and participation. METHODS: Participants were 694 children, 1.5-12 years old, with cerebral palsy (CP) and their parents across the US and Canada. Parents rated children's frequency and enjoyment of participation using the Child Engagement in Daily Life measure. Parents and therapists identified children's level of function using Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS). RESULTS: Differences in frequency and enjoyment of participation were found based on children's GMFCS, MACS, and CFCS levels but not age or sex. Children with higher gross motor, manual, and communication functions had higher frequency and enjoyment of participation, compared to children with lower functions. Frequency of participation was associated with GMFCS and CFCS levels whereas enjoyment of participation was only associated with CFCS level. IMPLICATIONS: Knowledge of child's gross motor, manual ability, and communication functions of children with CP is important when setting goals and planning interventions for participation. PMID- 28843216 TI - Current Trends in Management of Oral Mucositis in Cancer Treatment AB - Oral Mucositis (OM) is among the most common and dreaded toxicities of cancer therapy. It occurs in almost allpatients who receive radiation therapy in which areas of oral and oropharyngeal mucosa are included in the treatmentfield. With the advent of chemotherapy in 1940 and its extended clinical legacy, it is only within the past two decadeor so that mucositis' complex pathobiology has become fully appreciated. There are still many unanswered questionsabout the risk factors for developing OM, but historically, risk factors have been attributed to both therapy and patientm characteristics. One thing that has been consistent from the initial descriptions of its clinical manifestations hasbeen the frustration on the part of clinicians and patients with the scarcity of therapeutic options to prevent or treat thecondition, or effectively ameliorate the symptoms. Clinicians, researchers and those involved in oral and periodontalmedicine should join hand in hand in persuit of understanding and developing treatment strategies for treatment ofinflammatory conditions like OM in oncology. This will lead to development of effective treatments and reducing theburden of OM and other inflammatory conditions in oncology. PMID- 28843217 TI - Systematic Review of Hospital Based Cancer Registries (HBCRs): Necessary Tool to Improve Quality of Care in CancerPatients AB - Introduction: Incidence and mortality rate of cancer is increasing in all countries including low and middle-incomecountries. Hospital based cancer registry (HBCR) is an important tool for administration purpose and improvementof the quality of care. It is also important resource for population based cancer registries. In this study we reviewedHBCRs in different countries. Methods: We searched the published literature using the MEDLINE (PubMed), Googlescholar, Scopus, ProQuest and Google. We also reviewed websites of the HBCRs in different countries. The searchwas carried out based on proper keywords in English for all motor engines including "hospital-based", "clinical" and"data quality" combined with "registry", "cancer" and "tumor" including all subheadings. We reviewed objectives,developer institutions, minimum datasets, data sources, quality control indicators and processes. Results: In total wefound 163 papers in the first step. After screening of the titles, abstracts and the full texts, 14 papers remained foranalysis. Analysis of the 14 papers showed that the improvement of the quality of the care were the most importantobjectives among the registries. HBCRs collect information about patients, tumor diagnosis, treatment and follow-up.Generally, indicators such as completeness and validity were used for quality control. Conclusion: Because of theincreases in cancer burden in the world, more attention is needed to be paid on cancer surveillance systems, includingHBCRs. We evaluated and highlighted the importance and characteristics HBCRs and believe that this paper wouldhelp the hospitals and policy makers for planning and establishment of new HBCRs. We suggest the establishment ofa worldwide network for coordination and collaboration between HBCRs. PMID- 28843218 TI - Clinicopathologic Findings and Treatment Outcome of Laryngectomized Patients with Laryngeal Cancer and Hypopharyngeal Cancer: An Experience in Thailand AB - Objective: To evaluate the clinicopathologic findings and treatment outcome in laryngectomized patients withlaryngeal cancer and hypopharyngeal cancer. Materials and Methods: The authors retrospectively reviewed themedical records of 212 patients who had been newly diagnosed and treated with laryngectomy between January 2000and December 2010. The age, gender, clinical manifestations, associated predisposing condition, tumor WHO grade,AJCC tumor stage, maximum tumor size, anatomical involvement, type of surgery, postoperative sequelae, treatment andtherapeutic outcome were analyzed. Results: The present study included laryngeal cancer (n = 155) and hypopharyngealcancer (n = 57). The patients' age ranged from 38 to 84 years, with the mean age of 62.08+/-9.67 years. The commonclinical presentations were hoarseness (73.6%), cervical lymphadenopathy (35.8%), sorethroat (22.2%), and odynophagia(14.6%). The laryngeal cancer commonly involves true vocal cord (86.5%), anterior commissure (65.8%), false vocalcord (56.8%), laryngeal ventricle (53.5%), subglottis (47.1%), and paraglotic space (35.5%), respectively. Fifty-threepercent of cases had stage IV cancer. The most common postoperative surgical sequela was hypothyroidism (77.8%).The overall 5-year survivals for laryngeal cancer and hypopharyngeal cancer were 55% and 9%, respectively. The 5-yearsurvival for node negative cases was 61.8% versus 17% for node-positive cases (p< 0.001). AJCC stage of laryngealcancer and hypopharyngeal cancer was a significant predictor of 5-year survival (p< 0.001 and p = 0.004, respectively).Conclusions: The advanced AJCC stage, advanced T stage, advanced N stage, extracapsular tumor spread, and tumorinvasion of false vocal cord, epiglottis, preepiglottic space, paraglottic space, thyroid cartilage, cricothyroid membranewere found to significantly augment the decrease of 5-year survival in laryngeal cancer. Only advanced AJCC stagewas significantly associated with 5-year survival rate in hypopharyngeal cancer. PMID- 28843219 TI - Molecular Response to Imatinib and Its Correlation with mRNA Expression Levels of Imatinib Influx Transporter (OCT1) in Indian Chronic Myeloid Leukemia Patients AB - Background and objectives: Imatinib mesylate is approved for the treatment of Chronic Myeloid Leukemia (CML).About 20% of patients with CML do not respond to treatment with Imatinib either initially or because of acquiredresistance. In addition to mutated BCR-ABL1 kinase, the organic cation transporter1 (OCT1, encoded by SLC22A1) hasbeen considered to contribute to Imatinib resistance in patients with chronic myeloid leukemia (CML). OCT1 has beenreported to be the main influx transporter involved in Imatinib uptake into CML cells. To date, only a few studies havebeen reported on involvement of influx transporters in development of Imatinib resistance. Therefore this study wasaimed to determine the expression level of Imatinib uptake transporter (OCT1) in CML patients and to correlate this levelwith molecular response. Methods: One hundred fifty eight patients on Imatinib were considered for gene expressionanalysis study for OCT1 gene. Total RNA was extracted from peripheral blood mononuclear cells. ComplementaryDNAs (cDNAs) were synthesized and Real Time Polymerase Chain Reaction (RQ-PCR) was performed. Results:High OCT1 expression was present in 81 (51.8%) patients and low OCT1 expression was in 77 (48.7%) patients. LowSokal risk score group have a significantly high OCT1 expression (p=0.048). The rate of molecular response was higherin those with high OCT1 expression than in those with low OCT1 expression (p=0.05). Both event-free survival andmedian overall survival were significantly shorter in patients with low OCT1 expressions when compared to the patientswith high OCT1 expression (p=0.03 and p=0.05). Conclusions: Our findings demonstrated that the mRNA expressionlevel of OCT1 was significantly correlated with molecular response in CML patients. Based on these findings, presentstudy believes that the pre-therapeutic higher expression of OCT1 may help to predict response to imatinib therapy inCML patients. PMID- 28843220 TI - Association of C-myc and p53 Gene Expression and Polymorphisms with Hepatitis C (HCV) Chronic Infection, Cirrhosis and Hepatocellular Carcinoma (HCC) Stages inEgypt AB - The aim of this study is to investigate c-myc and p53 gene expression and polymorphisms in different stages ofHCV infection,. Expression levels of c-myc and p53 were evaluated by RT-PCR and polymorphisms were determinedby PCR-RFLP in 60 HCV patients classified into chronic infection, cirrhosis and HCC groups along with 30 controls.c-myc gene expression significant increased through the stages as compared to the control level (1.17, 1.82, 3.33 and 0.32,respectively), whereas p53 significantly declined (4,375, 3,842, 525 and 5,498, respectively). The C-myc CC genotypewas predominant in the HCC group (90%) to a greater extent than in the cirrhosis, chronic infection and control cases(80%, 20% and 10%, respectively), while the GG genotype was predominant in controls (83%, as compared to 65%,10% and 10%). The CG genotype was most common in chronic infection (15%). The p53 PP genotype predominatedin controls (87%, with 15%, 10% and 20%, respectively, for the three stages) while the AA genotype demonstratedonly slight increase to HCC (13%, 25% and 30%, respectively) and PA genotype was predominant in cirrhosis cases(90%). These findings reveal that c myc and p53 gene expression and polymorphisms may be considered as promisingsensitive genetic biomarkers for progression of HCV infection. PMID- 28843221 TI - Role of Multidetector Computed Tomography in Evaluation of Ovarian Lesions in Women Clinically Suspected of Malignancy AB - Objective: To determine the diagnostic accuracy of multidetector computed tomography (MDCT) in the evaluationof ovarian carcinoma using histopathology as the gold standard. Methods: This prospective cross-sectional study wasconducted at Department of Radiology, Dow international medical college, DUHS, Karachi from December 2015 toApril 2016. All patients of 30-60 years of age who were referred for CT a scan of the abdomen and pelvis with clinicalsuspicion of malignant ovarian cancer were included. A total of 158 cases were assessed with signs and symptomsof weight loss and an abdominal or pelvic mass detected on examination by a physician. Results: The mean age was42.7 +/-10.3 years (range 30-60). The largest group (46, 29.1%) presented with Stage 0 disease. The mean duration ofsymptoms was 4.06 +/-1.39 months (range 1-6). Taking histopathology as the gold standard the sensitivity, specificity,NPV, PPV and overall diagnostic accuracy values for MDCT were 95.6%, 97.3%, 93.5%, 97.3% and 96.8%, respectively.Conclusion: MDCT showed high accuracy in differentiating benign and malignant lesions and as well as staging ofmalignant cases which should be very helpful in management of ovarian disease. PMID- 28843222 TI - Accuracy of Cervical Visual Inspection with Acetic Acid Guide for 4-Quadrant Random Cervical Biopsies by GeneralPractitioners in Women with Abnormal Pap Smears AB - Objective: To study the performance of visual inspection with acetic acid plus 4 quadrant cervical biopsy (V4B)by general practitioners in detecting high grade cervical lesion, compared to highest histopathologic grade from theAmerican Society for Colposcopy and Cervical Pathology American Society for Colposcopy and Cervical Pathology(ASCCP) 2013 work up guidelines. Materials and methods: Patients with abnormal cervical cytologic screeningresults suggesting low grade lesions underwent V4B by general practitioners followed by colposcopy on the same daybases on ASCCP 2013 guidelines. Those with Pap smears indicative of high grade lesions or cervical cancer were sentto V4B before confirmed diagnosis and and therapeutic excisional procedures.Predictive performance of V4B wasevaluated against the reference diagnosis. Results: Compared with the reference diagnosis in 100 of patients, V4Bby general practitioners had sensitivity, specificity, PPV, and NPV of 67.9%, 100%, 100%, and 88.9%, respectively.There were 11.1% false negatives with no false positives. No complications were observed following this technique.Conclusion: Overall, V4B by general practitioners demonstrates moderate accuracy when compared with definitediagnosis by colposcopy and/or LEEP. This novel strategy performed better in those with low grade lesions on cervicalcytological screening. PMID- 28843224 TI - Survival in Good Performance Malignant Pleural Mesothelioma Patients; Prognostic Factors and Predictors of Response AB - Purpose: Malignant pleural mesothelioma (MPM) has a poor prognosis in general. Here we sought to evaluateprognostic factors and predictors of response to chemotherapy in good performance (PS=0-I) patients. Methods: Weretrospectively reviewed our database and enrolled patients with MPM who received platinum containing chemotherapy(2012-2014). Clinico-pathological and laboratory data were retrieved and Cox and logistic regression multivariateanalyses (MVA) were respectively used to identify predictors of survival and response to chemotherapy. Comparisonof good vs poor performance status (PS>=II) was accomplished using the Chi (X2) test. Kaplan-Meier survival curveswere also obtained and propensity-score matching was performed for survival comparison. Results: Among 114 patientslisted during the study period, 82 had good PS=0-I (median age 45years, 43 men, 30 smokers, median weight=77Kg,pretreatment haemoglobin (Hb) level=12g/dL, platelet count=372,000/MUL, leukocytes=9,700/MUL, neutrophils=6,100/MUL,lymphocytes=1,890/MUL and neutrophil/lymphocyte ratio (NLR)=3.60 ). Some 65 had asbestosis, 23 had chronic disease,55 (67.1%) were responders to platinum containing first line chemotherapy. A total of 49 (59.8%) had epithelial MPM.Median-OS and PFS in good PS cases were 17 and 9 months, respectively, as compared to 16 and 8 months for thepoor PS group. After matching, better OS was observed among good PS vs poor PS patients (p=0.024) but there wasno PFS difference (p=0.176). Significant decrease in PFS was observed among those with advanced nodal N disease(median PFS in N0 and N+ was 10 and 5 months, respectively), non-responders (p=0.012), NLR (p=0.026) and thosewith an epithelial pathology (p=0.062). MVA demonstrated that advanced (N) status (p=0.015), being a non-responder(p<0.001), NLR (p=0.015) and smoking (p=0.07) adversely affected the prognosis. The only predictor of responsewas absence of metastasis (M0; p=0.04). Conclusions: In addition to previously recognized factors, like nodal status,response, smoking and NLR, better median survival was evident in our patients with a good PS. Early detection beforedevelopment of metastasis warrants greater focus to allow better responses to be obtained. PMID- 28843223 TI - Synchronous and Metachronous Malignant Epithelial and Lymphoid Tumors: a Clinicopathologic Study of 10 Patientsfrom a Major Tertiary Care Center in Pakistan AB - Case reports and case series documenting unfortunate patients with more than one malignant neoplasm are rarebut well established. While majority of such patients have two malignancies, cases with three or even four malignantneoplasms in the same patient have been published in literature. A number of factors influencing carcinogenesis have beenimplicated in such cases including exposure to large amounts of radiation, chemotherapy for the original malignancy;prolonged history of heavy smoking and exposure to other environmental carcinogens; aging; and underlying geneticalterations. Concomitant multiple malignant neoplasms may be synchronous-two or more malignant neoplasmshistologically distinct from each other, arising in the same site and detected simultaneously (for example during the samehospital admission) or detected one after the other in sequence in a period less than 6 months; or metachronous-two ormore malignant neoplasms of similar or distinct histologic type detected at different times (after an interval of greaterthan 6 months) in different anatomic sites. Any combination of malignant tumors can occur in the same patient forexample carcinomas with other carcinomas, carcinomas with Non-Hodgkin or Hodgkin lymphomas, carcinomas withmesotheliomas, carcinomas with sarcomas etc. We have reported several cases with multiple malignancies during ourpractice, and these cases were composed of the different combinations described above. The aim of the present studyis to document 10 such cases of combined carcinoma and Non Hodgkin lymphoma in the same patient which werediagnosed in our section. PMID- 28843225 TI - Managing the Axilla in Early Breast Cancer. Impact of ACOSOG Z0011 Trial in Changing Practices in a Low MiddleIncome Country AB - Objective: To determine the impact of the trial on surgeon practice patterns at our institution. Methodology:A comparison of patients undergoing surgery for early breast cancer before and after the implementation of the newguidelines was done. We adopted the new guidelines in April 2015. Patients meeting Z0011 inclusion criteria wereidentified. For group A (Pre Z0011) patients operated between Jan to Dec 2013 were studied. And for Group B (PostZ0011) patients operated between July 2014 to Jun 2015 were included. Clinicopathologic data were comparedbetween the two groups. Results: There were 318 patients with clinical T1 2 tumors planned for breast conservation.68% patients had T1 tumor and 32% had T2. 92% of the patients had IDCa. There were 150 patients in the pre-Z0011group and 168 post-Z0011. 68% of the patients in Group A were ER+ve while 70% in group B. 38 (25.7 %) patientswere sentinel lymph node (SLN) positive in the pre-Z0011 group versus 34 (21 %) post-Z0011 (p = 0.392). BeforeZ0011 100 % (38/38) of SLN positive patients underwent axillary node dissection (ALND) versus 17 % (6/34) afterZ0011 (p < 0.01). Median no of SLNs identified in group A were 1.3 and group B were 1.4. There was a decrease inmedian operative times of the two groups (80 vs. 60 min, p < 0.01). There was a significant decrease in the overallhospital stay of sentinel lymph node positive patients in between the two groups (2.1 days vs 1.3 days p value < 0.01).Conclusions: Implemention of Z0011 guidelines has resulted in significant short term advantages in terms of reducedaxiilary dissections, shorter operative times and shoter hospital stays. PMID- 28843226 TI - Pregnancy Outcomes after Conservative Surgery for Early-Stage Ovarian Neoplasms AB - Objective: This retrospective, single institute study aimed to evaluate pregnancy and oncologic outcomes inreproductive-age Thai women with early-stage ovarian neoplasms undergoing conservative surgical treatment.Methods: Medical records of 84 women of reproductive age (15-45 years) with histologically confirmed early stage(IA-IIC) borderline ovarian tumors or cancers who had undergone conservative surgery between January 2003 andDecember 2012 were retrospectively reviewed. Results: The mean age of patients at diagnosis was 28.0 years (SD 7.2).Histologically, 30 (35.7%) had borderline ovarian tumors, 28 (33.3%) epithelial cancers, 22 (26.2%) malignant germ celltumors, and 4 (4.8%) sex cord stromal tumors. Thirty-five women (41.7%) had complete surgical staging performed,whereas 49 (58.3%) underwent an incomplete staging procedure. Thirty four patients (40.5%) received postoperativechemotherapy. Among 29 patients subsequently attempting pregnancy, 15 conceived successfully (51.7%). Pregnancyoutcomes were one spontaneous abortion and 14 viable births. There were no serious adverse obstetric and neonataloutcomes among women with documented live births and no reported fetal abnormalities. Pregnancy rates were notimpacted by surgical staging (53.8% vs 50.0%, p=0.837) or adjuvant chemotherapy (55.6% vs 50.0%, p=0.782). The5-year disease-free survival was 91.0% and pregnancy after conservative surgery did not affect progression-free survival(p=0.194). Conclusion: Conservative surgery with or without appropriate adjuvant chemotherapy can be offered toyoung women with early-stage ovarian neoplasms who wish to preserve their fertility potential. PMID- 28843227 TI - Investigating the Quality of Life and the Related Factors in Iranian Women with Breast Cancer AB - Introduction: Nowadays breast cancer is the most important factor concerning the women's health which can affectthe quality of life (QOL). This study was performed with aim to investigate the QOL and the related factors in Iranianwomen diagnosed with breast cancer in 2014-2015. Methods: This cross-sectional study was performed on 94 womenwith breast cancer who were selected by convenience sampling in Mashhad, Iran from 2014-2015. The data werecollected through Demographic and Clinical Questionnaire and EORTC QLQ-C30.V3 Standard Questionnaire. Datawas analyzed by SPSS software (version 18) and also descriptive statistics and linear regression analysis. P<0.05 wasconsidered statistically significant. Results: The mean of total score for the quality of life was 71.45+/- 22.28. In the areaof the symptoms of disease, the highest score belonged to insomnia (22.73+/- 14.89) and fatigue (19.81+/- 14.42). In thefunctional area, physical and emotional scales accounted for the highest (91.35+/-9.67) and lowest (78.55+/-2.84) scores,respectively. The results of multiple regression analysis showed that the variables of age, social status, radiotherapy,and hormone therapy are effective factors in the QOL. Conclusion: Breast cancer can affect the women's QOL.Therefore, efforts to promote the QOL in breast cancer patients is considered as one of the most important topics inwomen's health care. This requires more attention to identify various aspects of life and find effective ways to promoteand improve the QOL in these patients. PMID- 28843228 TI - Prospective Evaluation of Quality of Life in Patients Undergoing Primary Surgery for Oral Cancer: Preoperative and Postoperative Analysis AB - Background: The purpose of the present study was to compare the preoperative and postoperative health relatedquality of life (HRQoL) of a sample of patients undergoing primary surgery for oral cancer in 2012-13. Materialsand Methods: A cross-sectional, prospective study of 54 patients in a Brazilian population was performed. HRQoLwas measured preoperatively (after histopathological diagnosis) and postoperatively (2 months after surgery) usingthe University of Washington Quality of Life Questionnaire (UW-QOL). Clinicopathological, sociodemographic andlifestyle data were collected. Results: Surgery had a negative impact on most HRQoL domains, but pain, mood andanxiety scores were significantly improved. Most patients rated their health-related and overall postoperative HRQoLas good or very good. Conclusions: The UW-QOL was efficient at measuring HRQoL in our sample of patients withoral cancer. Surgery had a negative impact on HRQoL, especially due to sequelae affecting the stomatognathic system,yet patients classified their postoperative health-related and overall QoL as positive. Qualitative studies are necessaryfor confirmation of our results and further exploration. PMID- 28843229 TI - Homeodomain Protein Transforming Growth Factor Beta-Induced Factor 2 Like, X Linked Function in Colon Adenocarcinoma Cells AB - Background: TGIF2LX (transforming growth factor beta-induced factor 2 like, X linked) is a homeodomain (HD)protein that has been implicated in the negative regulation of cell signaling pathways. The aim of this study was toinvestigate the possible functions of TGIF2LX in colon adenocarcinoma cells. Methods: The human SW48 cell linewas transfected with cDNA for the wild-type TGIF2LX gene and gene/protein over-expression was confirmed bymicroscopic analysis, real time RT PCR and Western blotting techniques. In vitro cell proliferation was evaluated byMTT and BrdU assays. After developing a colon tumor model in nude mice, immunohistochemical (IHC) staining oftumor tissue was carried out for Ki-67 (proliferation) and CD34 (angiogenesis) markers. To predict potential proteinpartners of TGIF2LX, in-silico analysis was also conducted. Results: Obtained results showed over-expression ofTGIF2LX as a potential transcription factor could inhibit either proliferation or angiogenesis (P<0.05) in colon tumors.In-silico results predicted interaction of TGIF2LX with other proteins considered important for cellular development.Conclusions: Our findings provided evidence of molecular mechanisms by which TGIF2LX could act as a tumorsuppressor in colon adenocarcinoma cells. Thus, this gene may potentially be a promising option for colon cancergene-based therapeutic strategies. PMID- 28843230 TI - Perioperative Liver Function after Hepatectomy in a Tertiary University Hospital in Damascus AB - Background: Liver resection is the only viable therapeutic treatment option for several neoplastic entities of the liver.Although, the number of resectable patients is increasing in Syria, liver failure is still a major complication affectingmortality and morbidity rates. Methods: Between 2009 and 2016, 104 patients undergoing liver resection in DamascusUniversity Faculty of Medicine were retrospectively analyzed. Liver function tests were conducted before surgery (ps)and in the perioperative period (po) and comparisons were performed with division into anatomic VS non-anatomicor malignant VS non-malignant groups. Results: Liver synthetic, excretory and detoxifying functions deterioratedafter liver resection (INR ps 'presurgery'=1.129 po 'perioperative'=1.426 P<0.001, TP ps=7.426 po=5.581 P<0.001,ALB ps=4.204 po=3.242 P<0.001, T-Bill ps=0.061 po=0.136 P<0.001) and liver cell necrosis increased after resection(ALT ps=27.597 po=200.221 P<0.001, AST ps=33.395 po=190.553 P<0.001). There was no significant difference inliver functions when we compared anatomic VS non-anatomic groups or malignant VS non-malignant groups, butliver cell necrosis was higher with malignancies (ALT malignant group=236.475 non-malignant group=89.5 P=0.002,AST malignant group=222.644 non-malignant group=101.125 P=0.001). Conclusion: Although liver resection affectsliver function significantly, no differences in outcomes were found between anatomic VS non anatomic or malignantVS non-malignant groups. PMID- 28843231 TI - Association of Cervical Cancer Screening with Knowledge of Risk Factors, Access to Health Related Information, Health Profiles, and Health Competence Beliefs among Community-Dwelling Women in Japan AB - Objective: The aim of this study was to evaluate the past attendance for cervical cancer screening with knowledgeof risk factors, access to health-related information, health profiles and health competence beliefs among Japanesewomen. Methods: Women ages 25, 30, 35, 40, 45, 50, 55, and 60 were contacted cross sectionally as part of a projectfor the Japanese Ministry of Health, Labour and Welfare in Nikaho, Akita prefecture Japan between June 2010 andMarch 2011, and 249 women were analyzed for the current study. The questionnaire asked about past cervical cancerscreening. Knowledge of each cervical cancer risk factor was determined on a four-point scale. A barriers to informationaccess scale was utilized to assess the degree of difficulty in accessing health-related information. Health profiles weremeasured using the EuroQOL EQ-5D. Perceived health competence was measured using a scale (PHCS). The associationwas evaluated with odds ratios with 95% confidence interval were calculated from a logistic regression analysis afteradjustment for age and potential confounders. The trend across the level was also assessed. Results: Women who knewthat sexual intercourse at young age was a risk factor were significantly more likely to have participated in cervicalcancer screening sometime in their lives (p for trend =0.02). Women who had pain/discomfort and those who hadanxiety/depression were significantly more likely to have participated in cervical screening within the past two years(odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.04-3.94; OR: 2.32, 95% CI: 1.05-5.16, respectively). Womenwith higher PHCS were significantly more likely to have attended for cervical screened at some point in their lives(p=0.04). Conclusion: This study observed that specific knowledge of cervical cancer risk factors, health profiles andPHCS were associated with the past attendance for cervical cancer screening among women in a community. Furtherresearches are warranted. PMID- 28843232 TI - Colorectal Cancer and Precancerous Lesions Associated with Ulcerative Colitis in Thailand AB - Background: Ulcerative colitis(UC) is important risk factor of colorectal cancer. Many evidences from westerncountries confirmed this relationship but limited studies were reported in ASEAN. This study was aimed to investigateprevalence, clinical presentations, endoscopic findings, histopathology, disease progression and risk for colorectalcancer(CRC) of UC patients in Thailand. Methods: We conducted a retrospective cohort study using computer database from Thammasat University Hospital, Pathumthani, Thailand between September 2011 and December 2015,follow-up through May 2016. Diagnosis of UC was confirmed by histopathology and whole clinical course. Results:We identified 6,082 patients who diagnosed with colitis during the study period. Of whom, only 22 patients(<1%)was confirmed of UC. Male to female ratio was 13:9 (mean age of 47.2 years). Clinical presentations were bloodydiarrhea in 86.4%, watery diarrhea in 31.8% and abdominal pain in 59.1%. According to Montreal classification, diseaseextensions were ulcerative proctitis in 22.7%, distal UC in 50%, and pancolitis in 27.3%. Disease grading was mildin 31.8%, moderate in 9.1%, and severe in 59.1%. The prevalence of precancerous lesions were 2/22 patients(9.1%).There was no definite invasive colorectal cancer patient during study period. However, history of malnutrition wassignificantly higher in patients with dysplasia than those without dysplastic lesions(50%vs.0%, P-value=0.045). Therewas no difference in duration and disease extension between 2 groups. Interestingly, subgroup analysis demonstratedthat pancolitis was significantly more common in female than male (55.6%vs.7.7%,P-value=0.02,OR=15.0, 95%CI=1.3-169.9). Furthermore, patients' age> 35 years had significantly more severe colitis than younger group (81.25%vs.0%,P value=0.0006) Conclusions: Although UC is rare disease in ASEAN, precancerous lesions for CRC were notuncommon. UC with pancolitis was common in female whereas severe colitis was common in elderly patients. Properscreening program and careful surveillance for precancerous lesions in patients at risk might be appropriate approachfor early detection and improvement the treatment outcome. PMID- 28843233 TI - Increasing Awareness of Gynecologic Cancer Risks and Symptoms among Asian, Native Hawaiian and Pacific Islander Women in the US-Associated Pacific Island Jurisdictions AB - Background: Gynecologic cancers are common among Asian/Native Hawaiian/Pacific Islander (A/NH/PI) women.Prevention is important in United States associated Pacific Island jurisdictions (USAPIJ) because there are limitedresources to treat cancer. The objective of this study was to educate A/NH/PI women and providers about evidence-basedinterventions to prevent and control gynecologic cancers in Yap, one of four major islands comprising the FederatedStates of Micronesia (FSM). This was done through a partnership between Inside Knowledge: Get The Facts AboutGynecologic Cancer national campaign and the Yap comprehensive cancer control program, both funded by the Centerfor Disease Control and Prevention (CDC). Methods: Inside Knowledge educational materials were obtained from theCDC website and used in facilitated educational sessions. Sessions were planned according to leading health educationtheories, and were implemented and led by local Yap public health practitioners. Pre- and post-session surveys were usedto assess changes in gynecologic cancer awareness, confidence and behavioral intentions related to prevention/earlydetection for gynecologic cancer. Results: Twenty-nine providers and 326 adult women participated in sessions. Allparticipants demonstrated significant increases in knowledge across all measured domains post-session. Public knowledgethat HPV causes cervical, vulvar and vaginal cancer increased from 4.9% pre-session to 51.4% post-session (p<0.0001);provider knowledge increased from 17.2% to 96.6% (p<0.0001). Significantly more women identified smoking as acervical cancer risk factor post session (increased from 53.8% to 98.7% [p<0.0001]). An average of 61.4% of providerssaid they were extremely or somewhat confident in their gynecologic cancer knowledge pre-session compared to 91.7%post-session. Conclusion: Targeted education about gynecologic cancer symptoms and risk factors can be effective atincreasing awareness, behavioral intention, confidence and knowledge. These increases can lead to more widespreadprevention of these five cancers. PMID- 28843234 TI - Neem Seed Oil Induces Apoptosis in MCF-7 and MDA MB-231 Human Breast Cancer Cells AB - Background: In traditional Indian medicine, azadirachta indica (neem) is known for its wide range of medicinalproperties. Various parts of neem tree including its fruit, seed, bark, leaves, and root have been shown to possessantiseptic, antiviral, antipyretic, anti-inflammatory, antiulcer, antimalarial, antifungal and anticancer activity. Materialsand Methods: MCF-7 and MDA MB-231 cells were exposed to various concentrations of 2% ethanolic solution of NSO(1-30 MUl/ml) and further processed for cell viability, cell cycle and apoptosis analysis. In addition, cells were analyzedfor alteration in Mitochondrial Membrane Potential (MMP) and generation of Reactive Oxygen Species (ROS) usingJC-1 and DCFDA staining respectively. Results: NSO give 50% inhibition at 10 MUl/ml and 20 MUl/ml concentrationin MCF-7 and MDA MB-231 cells respectively and, arrests cells at G0/G1 phase in both the cell types. There was asignificant alteration in mitochondrial membrane potential that leads to the generation of ROS and induction of apoptosisin NSO treated MCF-7 and MDA MB-231 cells. Conclusion: The results showed that NSO inhibits the growth ofhuman breast cancer cells via induction of apoptosis and G1 phase arrest. Collectively these results suggest that NSOcould potentially be used in the management of breast cancer. PMID- 28843235 TI - Association of the Single Nucleotide Polymorphisms of the Genes Encoding IL-2 and IFN-gamma With Febrile Seizure. AB - Inflammatory elements and genetics have major roles in febrile seizures (FS) pathogenesis. Seventy patients were enrolled and compared with 139 controls. The allele and genotype frequency of the IL-2 gene at -330 and +166 positions and the IFN-gamma at +874 position were determined. A significant positive association with GG genotype at position -330 in the patient group was found (P=0.003). Further, a positive association was detected in simple and complex FS groups at the same position (P=0.03, P=0.004). IL-2 GT haplotype was significantly more common in the patients compared to controls (P=0.0008). Higher frequency of GT haplotype was detected in simple FS patients in comparison to controls (P=0.0003). Contrary, IL-2 TG haplotype frequency was lower in complex FS group (P=0.005). Overrepresentation of certain alleles, genotypes and haplotypes in IL 2 gene in FS patients could predispose individuals to this disease. PMID- 28843236 TI - A Practical Non-Extraction Direct Liquid Chromatography Method for Determination of Thiopurine S-Methyltransferase Activity in Inflammatory Bowel Disease. AB - Thiopurine drugs remain pivotal therapies for the wide varieties of diseases such as inflammatory bowel disease (IBD). Here, thiopurine S-methyltransferase (TPMT) phenotype, the main metabolizing enzyme of thiopurine-drugs, was studied. This is for the first time that TPMT activity is measured in Iranian IBD patients. We used an improved direct liquid chromatography assay without need for solvent extraction and minimize excess labor handling making it ideal for use in routine referral medical centers. TPMT activity in whole blood was determined by a non extraction HPLC method. We evaluated 427 individuals including 215 IBD patients and 212 unrelated healthy individuals as control group from Iran's western population. TPMT phenotyping of this study demonstrated no frequency for deficient, 2.8 % for low and 97.2% for normal activity, which is different with results of other studies. There was a significant negative correlation between TPMT activities as calculated based on nmol/grHb/h and the Hb-levels in IBD and control groups (r= -0.54, P<0.001 and r= -0.27, P<0.001), respectively. Interestingly a significant positive correlation between Hb levels and TPMT activities were seen when the activity calculated in mU/L in IBD patients and control subjects (r=0.14, P=0.05 and r=0.43, P<0.001), respectively. We strongly suggest the use of international unit (mU/L) is more appropriate than nmol6MTG/grHb/h for expressing TPMT-activity in IBD patients. In addition, in comparison with other providers of TPMT test activity and centers around the world the risk of toxicity is much lower after utilizing thiopurine drugs for IBD patients in this region. PMID- 28843237 TI - Concomitant Transurethral and Transvaginal-Periurethral Injection of Autologous Adipose Derived Stem Cells for Treatment of Female Stress Urinary Incontinence: A Phase One Clinical Trial. AB - Stress urinary incontinence is a common medical problem among women. The urethral closure complex and/or the supportive mechanisms are responsible for incontinence in the majority of patients. Several surgical procedures with different degrees of invasiveness and outcomes have been reported to treat the problem. Although most of these procedures are reasonably effective, a general trend towards the study of natural and biocompatible tissues is emerging over popular synthetic materials. Here we report our experience of autologous adipose-derived stem cells transplantation into the periurethral region as a new method of stress urinary incontinence treatment. Ten women with symptoms of stress urinary incontinence were treated by injections of autologous adipose-derived stem cells into the periurethral region via transurethral and transvaginal approach under urethroscopic observation. This report presents the short-term outcome of the patients. The outcome measured by pad test results, ICIQ-SF scores, and Qmax. The mean age of the participants was 45.8+/-8.7 years. Urinary incontinence significantly decreased through the first two, 6 and 24 weeks after the injection therapy. The difference was significant in pad test results (P<0.001) and ICIQ-SF scores (P<0.001), especially comparing results between 2 and 6 weeks and among 6 and 24 weeks, but not for 2 and 6 weeks compared to each other. Surprisingly, Qmax showed improvement after the study period (means 32.6 vs. 35.7; P=0.002). This study showed that injection of the autologous adipose-derived stem cells to the periurethral region is a safe, yet short-term effective treatment option for stress urinary incontinence. Further studies with longer follow up are needed to confirm its long term efficacy. PMID- 28843238 TI - Assessment of the Prevalence and Risk Factors Associated With Glucocorticoid Induced Diabetes Mellitus in Pemphigus Vulgaris Patients. AB - Pemphigus vulgaris is a chronic autoimmune disease and glucocorticoids are one of the main treatments. Our study investigates the prevalence and associated factors of glucocorticoid-induced diabetes mellitus in these patients under different glucocorticoid regimens. 36 patients with first diagnosed Pemphigus vulgaris based on pathological and direct immunofluorescence findings who had received different glucocorticoid regimens (1-2 mg/kg oral or 1-2 mg/kg oral with 1g methylprednisolone pulse daily for 3 consecutive days with or without azathioprine) were evaluated during 2014-2016. Our study found that 22.2% of patients had impaired fasting glucose and incidence of corticosteroid-induced diabetes mellitus was 22.2% with no difference between oral and pulse therapy of corticosteroid. The first day after pulse therapy 19 patients of 21 had post bolus hyperglycemia that 36% of them became diabetic after 8 weeks. None of the variables, including age, BMI, HbA1c, LDL, HDL, TG, cholesterol, family history and blood pressure were associated with diabetes. Pretreatment FBS was the factor that would increase the likelihood of glucocorticoid-induced diabetes mellitus, 42.2% of patients with pretreatment FBS 100-126 developed diabetes in comparison with 17.2% in normal pretreatment FBS. Although the group who received azathioprine was associated with increased incidence of diabetes, the overall corticosteroid dose in this group was significantly higher than the other group (P=0.012), and controversy with other studies could be because of difference in corticosteroid dosage and small number of patients. The incidence of diabetes was not different between the group with glucocorticoid pulses and oral prednisolone without pulse therapy. Higher pretreatment FBS can be related to increased incidence of diabetes, but results from this study due to small number of patients are preliminary and multicenter studies are needed. PMID- 28843239 TI - Evaluation of Cognitive Functions in Iranian Children and Adolescents With Diabetes Mellitus. AB - Diabetes in children and adolescents is a chronic condition with an expanding trend in the community. Several studies have shown cognitive dysfunctions are the most important side effects of diabetes among individuals of younger ages. Due to cultural differences and their impact on cognitive issues, the authors decided to assess the cognitive functions of Iranian children and adolescents with diabetes. Cognitive functions including memory, attention and executive functions were evaluated in 62 diabetic children and adolescents and healthy peers using CANTAB cognitive tests. Other data such as demographic, school performance and medical information were collected by questionnaires. Except in the case of few variables in RVP, SSP and SST, no significant difference exists between diabetic children and the control group in terms of different cognitive domains. But cognitive variables, especially in PRM, SWM and SOC test, has been shown to be deteriorated with increasing HbA1C values in serum levels. Diabetes has no impact on the cognitive functioning of children provided by maintaining a glycemic control. It is proposed that the adoption of appropriate parenting styles and family and social support can prevent cognitive changes in children with diabetes. PMID- 28843240 TI - Smoking Discriminately Changes the Serum Active and Non-Active Forms of Vitamin B12. AB - Smoking may modify the appetite, and consequently affect nutrient intake and serum micronutrients. The effect of smoking on vitamin B12 status has been considered in several studies. The research proposed that organic nitrites, nitro oxide, cyanides, and isocyanides of cigarette smoke interfere with vitamin B12 metabolism, and convert it to inactive forms. This research was carried out to determine the serum level of active and inactive forms of vitamin B12 in male smokers in comparison with male nonsmokers. This is a case-control study, in which the participants were 85 male smokers and 85 male nonsmokers. The serum levels of total and active form of vitamin B12 were measured. Dietary intake was recorded by a quantitative food frequency questionnaire and one-day 24-hour dietary recall method. Independent two sample T test was used to compare quantitative variables between the case and control groups. The serum level of total vitamin B12 was not significantly different between two groups, but serum level of active form of vitamin B12 in the smoking group was significantly lower than non-smoking group (P<0.001). This is one of the first studies that evaluated the serum level of active form of vitamin B12 in smokers in the Iranian community. The results of this study identified that serum level of total vitamin B12 might be not different between smoking and non-smoking people, but the function of this vitamin is disturbed in the body of smokers through the reduction of serum level of active form of vitamin B12. PMID- 28843241 TI - Does Adding Intravenous Phosphorus to Parenteral Nutrition Has Any Effects on Calcium and Phosphorus Metabolism and Bone Mineral Content in Preterm Neonates? AB - The use of parenteral nutritional supplementation of phosphorus may lead to exhibit higher plasma phosphate concentrations and less radiological features in premature neonates susceptible to osteopenia. The present study aimed to assess the beneficial effects of adding intravenous phosphorus to total parenteral nutrition (TPN) on calcium and phosphorus metabolism in preterm neonates by measuring bone mineral content. This open-labeled randomized clinical trial was conducted on premature neonates who were hospitalized at NICU. The neonates were randomly assigned to two groups received TPN with intravenous sodium glycerophosphate or Glycophos (1.5 mmol/kg/day) or TPN without sodium glycerophosphate. At the end of the four weeks of treatment, the presence of osteopenia was examined using DEXA Scan. After completing treatment protocols, the group received TPN with intravenous Glycophos had significantly lower serum alkaline phosphatase (360+/-60 versus 762+/-71, P<0.001), as well as higher serum calcium to creatinine ratio (1.6+/-0.3 versus 0.44+/-0.13, P<0.001) compared to the control group received TPN without Glycophos. Those who received TPN with intravenous Glycophos experienced more increase in bone mineral density than those in control group (0.13+/-0.01 versus 0.10+/-0.02, P<0.001). There was no significant difference in serum calcium and serum vitamin D between the case and control groups. Adding intravenous sodium glycerophosphate to TPN in premature neonates can compensate the lack of bone mineral content and help to prevent osteopenia. PMID- 28843242 TI - Relationship Between Vitamin D Deficiency and Markers of Metabolic Syndrome Among Overweight and Obese Adults. AB - In recent years, metabolic syndrome, obesity, diabetes and cardiovascular disease has had a tremendous elevation growth. Many studies have demonstrated negative correlation between vitamin D deficiency and indexes of metabolic syndrome in obese patients. This study was designed to find the relation between vitamin D deficiency and markers of metabolic syndrome among overweight and obese adults referred to obesity center of Shahid Sadoughi hospital in 2014. Eighty-nine overweight and obese adults (79 women and 10 men), who 13 subjects were overweight and 76 subjects were obese were recruited in this cross-sectional study. Total cholesterol, high-density lipoprotein cholesterol, triglyceride, plasma glucose and vitamin D were measured. IDF criteria were used for identifying subjects with metabolic syndrome. Demographic questionnaire was completed. Statistical analysis was performed using SPSS version 16.0. Fisher exact test, logistic regression, and Spearman correlation coefficient were used. The frequency of vitamin D deficiency was 93.2%. According to IDF criteria, the frequency of metabolic syndrome was 36%. There was no significant relationship between vitamin D deficiency and metabolic syndrome. Among metabolic syndrome indicators, there was a significant direct relationship between vitamin D level with FBS (P=0.013) and SBP (P=0.023). There was no significant relationship between vitamin D deficiency and metabolic syndrome. Due to the lack of relationship between vitamin D deficiency and metabolic syndrome, small number of participants in this study and very low case of normal vitamin D level, further studies are needed. PMID- 28843243 TI - Incidental Finding of Intercostal Artery Aneurysm During Coarctation Surgery. AB - Intercostal artery aneurysms (ICAA) are very rare vascular complication of coarctation. The most cases are asymptomatic and could be found incidentally during thoracotomy for others vascular pathology or may present with fatal problems such as rupture that is leading to bleeding and hypovolemic shock. Intercostal artery aneurysm most commonly accompanies with neurofibromatosis, aortic coarctation, or in chest trauma. We report a 10-year-old girl who complained of lower extremities pain and hypertension for a few months. His final diagnosis was coarctation of the aorta. She was scheduled for thoracotomy and coarctation repair by resection and end to end anastomosis. During thoracotomy at lateral side of coarctation, an ICAA distal to coarctation site was seen that by a collateral artery connects to its upper intercostals artery. The patient was treated by ligation and resection of the affected intercostal artery and subsequent coarctation repair. The postoperative course was uneventful and, she was discharged on 7th postoperative day. PMID- 28843244 TI - In Vitro Leukoagglutination: A Rare Hematological Cause of Spurious Leukopenia. AB - Leukopenia secondary to leukocytic agglutination is caused by an ethylene diamine tetra acetic acid (EDTA) which may appear in both benign and malignant states. Ethylene diamine tetra acetic acid induced platelets clumping in peripheral blood has been well established, but invitro leukocytic aggregation is very rarest hematological finding. Pseudo-leukopenia resulting from leukoagglutinins has been reported in the cirrhotic state, infections, autoimmune disorders, uremia, in immunosuppressed state or in various malignancies. Though the condition seems to be benign but very important to be detected as these artifactual findings lead to unnecessary investigations and remarkably changed the overall management plan. Here we report the case of a young patient with this rare finding who was admitted to our hospital with progressive labor pains. The analysis of ethylene diaminetetraacetic acid (EDTA), anticoagulated blood was done on automated hematology analyzer reveals leukopenia. The peripheral smear examination revealed multiple aggregates of leukocytes. On repeat sampling in citrate anticoagulant, the complete blood count showed total leukocytic count of 16.5x109/L with absolute neutrophilic count of 11.5x109/L. This is a rare case of spurious leukopenia secondary to in-vitro leukocytic agglutination provoked by EDTA anticoagulant. PMID- 28843245 TI - An Uncommon Complication of Streptokinase: Large Spontaneous Iliopsoas Hematoma. AB - Streptokinase is a fibrinolytic agent that enhances plasmin activation and is used in selected patients with acute ST elevation myocardial infarction (STEMI). Similar to the other thrombolytics, a common side effect is bleeding, especially from venous puncture sites. Here, we present a case of acute anterior wall STEMI complicated by large spontaneous iliopsoas hematoma after streptokinase administration. With conservative management, the course of the disease was uneventful, and the patient was discharged with no symptom and no clinically important sequel. PMID- 28843246 TI - Vital Sign Assessment Directives Have Not Associated With Diagnostic Validity. PMID- 28843247 TI - Corrigendum to: "Subarachnoid Space Transplantation of Schwann and/or Olfactory Ensheathing Cells Following Severe Spinal Cord Injury Fails to Improve Locomotor Recovery in Rats" [Acta Med Iran 2016;54(9):562-569]. PMID- 28843248 TI - Moringa oleifera Root Induces Cancer Apoptosis more Effectively than Leave Nanocomposites and Its Free Counterpart AB - Medicinal plants are important elements of indigenous medical system that have persisted in developing countries.Many of the botanical chemo-preventions currently used as potent anticancer agents. However, some importantanticancer agents are still extracted from plants because they cannot be synthesized chemically on a commercial scaledue to their complex structures that often contain several chiral centers. The aim of this study was to test differentextracts from the Moringa oleifera leaves (ML), its PLGA-CS-PEG nanocomposites (MLn), as well as root core (Rc)and outer (Ro) parts for activity against hepatocarcinoma HepG2, breast MCF7, and colorectal HCT 116/ Caco-2 cellsin vitro. Nano-composites were prepared and characterized. Then, the nanocomposites and the free counterparts werescreened on different propagated cancer cell lines. The underlying cytotoxic impact was followed using apoptosismeasurements. All extracts kill the different cancer cells with different ratios, but intriguingly, the root core extract couldkill the majority of cancer cells (approximately 70-80%), while sparing normal BHK-21 cells with minimal inhibitoryeffect (approximately 30-40%). Apoptotic cell increment came to confirm the cytotoxic effects of these extracts onHCT 116 cells (Rc: 212% and Ro: 180%, respectively) and HepG2 cells (ML: 567.5% and MLn: 608%, respectively)compared to control (100%) mechanistically wise. Moringa oleifera nanocomposites may have potential for use as anatural source of anti-cancer compounds. PMID- 28843249 TI - Cancer Prevalence in Aichi, Japan for 2012: Estimates Based on Incidence and Survival Data from Population-Based Cancer Registry AB - Background: Cancer is the leading cause of death among both men and women in Japan. Monitoring cancerprevalence is important because prevalence data play a critical role in the development and implementation of healthpolicy. We estimated cancer prevalence in 2012 based on cancer incidence and 5-year survival rate in Aichi Prefectureusing data from a population-based cancer registry, the Aichi Cancer Registry, which covers 7.4 million people.Methods: The annual number of incident cases between 2008 and 2012 was used. Survival data of patients diagnosed in2006-2008 and followed up until the end of 2012 were selected for survival analysis. Cancer prevalence was estimatedfrom incidence and year specific survival probabilities. Cancer prevalence was stratified by sex, cancer site (25 majorcancers), and age group at diagnosis. Results: The estimated prevalence for all cancers in 2012 was 68,013 casesamong men, 52,490 cases among women, with 120,503 cases for both sexes. Colorectal cancer was the most incidentcancer with 6,654 cases, accounting for 16.0% of overall incident cases, followed by stomach cancer with 5,749 cases(13.8%) and lung cancer with 5,593 cases (13.4%). Prostate cancer was the most prevalent among men, accounting for21.5%, followed by colorectal and stomach cancers. Breast cancer was the most prevalent among women, accountingfor 28.6%, followed by colorectal, stomach, and uterine cancers. Conclusion: This study provides cancer prevalencedata that could serve as useful essential information for local governments in cancer management, to carry out morepractical and reasonable countermeasures for cancer. PMID- 28843250 TI - The Association between Lifestyle, Occupational, and Reproductive Factors and Colorectal Cancer Risk AB - Objective: Association of lifestyle, reproductive and environmental factors has been investigated with increasedrisk of colorectal cancer in different studies. We explored evidence and investigated association between various riskfactors and colorectal cancer. Methods: This case- control study was conducted 155 colorectal cancer patients and 150hospital-controls. We obtained detailed lifestyle, occupational, reproductive information from both groups. Chi-Squaretest and Logistic regression model were used to evaluate the risk factors of colorectal cancer. Results: The resultsshowed that frequent intake of fruits, chicken, fish and alcohol drinking were associated with risk for colorectal cancer.Agricultural occupation (OR=7.003, 95% CI=2.19-22.38) and industrial exposure (OR=1.97, 95% CI=0.91-4.22) wereassociated significantly with risk for colorectal cancer. Regarding reproductive factors, women who reported less than3 pregnancies was associated with an increased risk of colorectal carcinoma (OR=2.88, 95% CI=1.15 7.17). We didnot find significant association between other reproductive factors and colorectal cancer risk in women after adjustingfor demographic factors. Conclusion: In this case-control study we observed that agricultural occupation, industrialexposure and high consumption of fish and less than 3 pregnancies in women were associated with an increased riskof colorectal carcinoma. PMID- 28843251 TI - Investigating Factors Associated with FOBT Screening for Colorectal Cancer Based on the Components of Health BeliefModel and Social Support AB - Introduction: This study aimed to investigate the factors associated with FOBT screening for colorectal cancerbased on the components of Health Belief Model and social support in Fasa City, Fars Province, Iran. Materials andMethods: This was a cross-sectional study carried out on 240 subjects in people of Fasa city who had 50 years old andabove. The subjects in this study were assigned to two groups of 120 patients. The first group included people over 50years, who referred to the diagnostic laboratories for doing FOBT, but the second group included people aged 50 yearsand above who did not refer to a laboratory for doing FOBT and were assessed by questionnaires at home. Data werecollected through a questionnaire based on health belief model and perceived social support. Results: The referringgroup included 61.3 percent women and 38.7 percent men, with a mean age of 65.24 +/- 8.01. The non-referring groupincluded 59.7 percent women and 40.3 percent men, with a mean age of 64.21 +/-7.53 (p=0.24). In the referring group,64.2 percent had undergone FOBT in the past year, while in the non referring group only 12.72percent had done so(p=0.001).The results showed that the referring group obtained higher scores on awareness about CRC and ways toprevent it, and on HBM Model constructs, and social support compared to the non referring group (p<0.001). In addition,the referring group reported significantly lower Perceived Barriers compared to the non-referring group (p<0.001).Conclusion: The results showed significant differences between the two groups in terms of HBM components andperceived social support for doing FOBT. Therefore, theory-based educational interventions can be used to increaseindividuals' Perceived Severity, Perceived Susceptibility, and Perceived Benefits and reduce their Perceived Barriersin order to empower and encourage people to perform FOBT. PMID- 28843252 TI - Overexpression of Antiangiogenic Vascular Endothelial Growth Factor Isoform and Splicing Regulatory Factors in Oral, Laryngeal and Pharyngeal Squamous Cell Carcinomas AB - Background: Overexpression of proangiogenic vascular endothelial growth factor A family VEGFAxxx is associatedwith tumor growth and metastasis. The role of the alternatively spliced antiangiogenic family VEGFAxxxb is poorlyinvestigated in head and neck squamous cell carcinomas (HNSCCs). The antiangiogenic isoform binds to bevacizumaband its expression level could influence the treatment response and progression-free survival. In this study, the relativeexpression of VEGFAxxx and VEGFA165b isoforms and splicing regulatory factors genes was investigated in a seriesof HNSCCs. Methods: VEGFAxxx, VEGFA165b, SRSF6, SRSF5, SRSF1 and SRPK1 gene expression was quantified byquantitative real time PCR in 53 tissue samples obtained by surgery from HNSCC patients. Protein expression wasevaluated by immunohistochemistry. Results: VEGFAxxx and VEGFA165b were overexpressed in HNSCCs. Elevatedprotein expression was also confirmed. However, VEGFA isoforms demonstrated differential expression according toanatomical sites. VEGFAxxx was overexpressed in pharyngeal tumors while the VEGFA165b isoform was up-regulatedin oral tumors. The VEGFA165b isoform was also positively correlated with expression of the splicing regulatory genesSRSF1, SRSF6 and SRSF5. Conclusions: We concluded that VEGFAxxx and VEGFA165b isoforms are overexpressed inHNSCCs and the splicing regulatory factors SRSF1, SRSF6, SRSF5 and SRPK1 may contribute to alternative splicing ofthe VEGFA gene. The findings for the differential expression of the antiangiogenic isoform in HNSCCs could facilitateeffective therapeutic strategies for the management of these tumors. PMID- 28843253 TI - Plasma Calcitonin Levels and miRNA323 Expression in Medullary Thyroid Carcinoma Patients with or without RET Mutation AB - Background: Medullary thyroid cancer (MTC) is an endocrine tumor featuring parafollicular or C-cell differentiation,with calcitonin as a specific biomarker in MTC diagnosis. Germline mutations in the RET proto-oncogene are consideredresponsible for its familial occurrence and somatic mutations can cause sporadic lesions. MicroRNAs can act asoncogenes or tumor suppressors by inhibiting the expression of target genes.. The aim of this study was to investigaterelationships between plasma levels of calcitonin and miRNA323 expression in MTC patients with or without RETmutation. Methods: In this cross sectional study, MTC lesions (based on pathological confirmation) were investigated.Genomic DNA was extracted and Exons 10 and 11 of RET were genotyped using PCR-sequencing. Division was intotwo groups of 43 cases each with or without mutation. Plasma levels of calcitonin were determined in both. Results:miRNA323 was measured using real-time-PCR. After performing normality tests, independent T-tests and MannWhitney tests were used for the statistical comparison of parametric and nonparametric data, respectively. Plasmalevels of calcitonin were significantly higher in MTC cases without a RET mutation compared to those with a mutation.Conclusion: There was no significant difference between the two groups regarding the expression of miRNA323 sothat this parameter could not be used as a bio-index germ line mutations in MTCs. However, determination of calcitoninlevels in plasma might be helpful in this regard. PMID- 28843254 TI - Evaluation of miR-711 as Novel Biomarker in Prostate Cancer Progression AB - Objective: MicroRNAs (miRs) are class of small non-coding regulatory RNA aberrantly expressed in various typesof malignancies including prostate cancer and serves as potential targets to develop new diagnostic and therapeuticstrategies. In this quiet we investigated miRNAs expression profile in benign prostatic hyperplasia (BPH) and prostatecancer (PCa) tissue samples and correlated their expression with clinicopathological parameters. Methodology: ThemiRNAs expression profile as well as their validation has been done by using Microarray and RT-PCR, respectively.Additionally, we also tried to speculate microRNA-mRNA regulatory module through computational target predictionsby using Targetscan, Miranda and MirWalk and obtained results were analysed through DAVID software. Result: Weobserved that miR-711 is significantly deregulated in BPH and PCa, compared to controls. The lower expression ofmiR-711 was found to be significantly associated with high Gleason score and metastatic disease. Furthermore, thecomputational target prediction analysis explored miR-711 association to various cancer cells signalling cascade keymolecules associated with cancer cell survival.Conclusion: From our observations we suggest that miR 711 may playa critical role in PCa progression, regulation of various cancer cell survival signalling cascades and that it may be avaluable biomarker for prediction of metastatic disease and poor prognosis in PCa. PMID- 28843255 TI - Development of a Colorectal Cancer Screening Intervention for Iranian Adults: Appling Intervention Mapping AB - Background: While the incidence rate of the colorectal cancer (CRC) has been increasing over the last threedecades in Iran, very limited interventions to increase CRC screening have been developed for Iranian population.The purpose of this study was to describe the use of Intervention Mapping (IM) for applying theory and evidence andconsidering local contexts to develop a CRC screening program among adults in Iran. Materials and Methods: FromApril 2014 to July 2016 following the IM process, six steps were formulated and implemented. First a need assessmentwas conducted involving relevant stakeholders and using focus groups discussions (n=10), individual interviews(n=20), and a household survey (n= 480). Then a matrix of change objectives was developed for each behavioraloutcome and theoretical methods and their practical applications were identified to guide intervention development andimplementation. A multi-component intervention was developed and piloted. Decision on suitable parts of interventionwas made based on feedback of pilot study. Finally, evaluation plan including process and outcome evaluation wasgenerated and conducted to inform future scale up. Results: The needs assessment highlighted factors affecting CRCscreening including knowledge, self efficacy, social support and perceived benefit and barriers (financial problems,fear of detection of cancer and etc). Results of needs assessment were used to develop next steps IM. The programutilized methods like information delivery, modeling, and persuasion. Practical applications included video presentation,group discussion, role playing and postcards.This program was assessed through a cluster-randomized controlledtrial. Results showed that there were significant differences in CRC screening uptake between intervention groups andcontrol (P<0.001). Conclusions: IM is a useful process in the design of a theory-based intervention addressing CRCscreening among Iranian population. PMID- 28843257 TI - BRAF, KRAS and PIK3CA Mutation and Sensitivity to Trastuzumab in Breast Cancer Cell Line Model AB - Studies show that approximately 20% of all breast cancer patients have a breast tumor that tests positive for HumanEpidermal Growth Factor Receptor 2, otherwise known as the HER2 gene. As such, treatments for breast cancerusually include drugs that target HER2. The drug Trastuzumab is a recombinant antibody that has been approved bythe FDA for the treatment of these HER2 positive breast cancers. However, researchers have found that mutations inassociated genes, PIK3CA and KRAS, can cause the tumor to become resistant to Trastuzumab. The purpose of thisarticle is to evaluate the sensitivity of the cancer cell lines to the drug Trastuzumab and investigate how this sensitivityis compromised by the PIK3CA, KRAS and BRAF gene mutations. Trastuzumab responsiveness was evaluated inbreast cancer cell lines by treating the lines with an optimal concentration of the drug followed by a proliferation assayof the cell lines in the presence of monoclonal antibodies. We determined the optimum concentration of Trastuzumab tobe 7 MUg/well. The BRAF and KRAS mutated cell line, MDA-MB-231, showed the least sensitivity after being treatedwith trastuzumab when compared to the sensitivity of the PIK3CA mutated cell lines, MCF-7 and MDA-MB-361, andthe KRAS/ BRAF/ PIK3CA cell line, MDA-MB-453. Clinical observations show that mutations in BRAF and KRASgenes in breast cancer cells do lower the responsiveness of Trastuzumab drug treatments. PMID- 28843256 TI - Naja Naja Oxiana Venom Fraction Selectively Induces ROS-Mediated Apoptosis in Human Colorectal Tumor Cells by Directly Targeting Mitochondria AB - Objective: To investigate the selective effect of Naja naja oxiana crude venom and its fractions on human colorectalcancer mitochondria to activate apoptosis signaling. Methods: Cells and mitochondria isolated from human cancerousand normal colorectal tissues exposed to N. oxiana crude venom and its fractions obtained from size-exclusionchromatography and then mitochondrial parameters related to up-stream cell death signalling such as reactive oxygenspecies formation, MMP, mitochondrial swelling, cytochrome c release and ATP content as mitochondrial parametersand activation of caspase3 and finally apoptosis/necrosis % were then assayed as cellular parameters. Result: Ourfindings indicated that crude venom (15, 30 and 60 MUg/ml) and fraction 3; F3; (10, 20 and 40 MUg/ml) of N. Oxianavenom induced a significant (p<0.05) increase of reactive oxygen species level, swelling of mitochondria, collapseof mitochondrial membrane potential (MMP), release of cytochrome c, activated caspase3 and decrease ATP contentonly in colon cancer tissue group but not from the healthy colon tissue group. Our results also showed that fraction 3of venom decreased the percentage of viable cells and induced apoptosis in cancerous colorectal cells. Conclusion:F3 fraction of N. Oxiana venom is a suitable candidate for further studies as a new drug treatment of colorectal cancerdue to its high capacity for induction of apoptosis signaling via mitochondrial pathway. PMID- 28843258 TI - CD24 and Nanog expression in Stem Cells in Glioblastoma: Correlation with Response to Chemoradiation and Overall Survival AB - Background and aim: Glioblastoma (GBM) is one of the most common and aggressive brain tumors with amedian survival of 12-14 months. The aim of present study was to evaluate the gene expression profile of stem cellmarkers Nanog and CD24 in GBM and to determine its relationship to outcome in terms of treatment response andoverall survival. Material and methods: This was a retrospective as well as retrospective study which included 51histologically confirmed cases of GBM. Expression of CD24, and Nanog was evaluated by RT-PCR. Control tissueincluded debrided brain tissue from open head injury cases. All cases of GBM underwent total surgical resection andsubsequently chemotherapy. Immediate treatment response was evaluated at 3 months using Response EvaluationCriteria In Solid Tumors (RECIST) guidelines and overall survival was measured at 36 months. Result: As comparedto control gene, expression of CD24 and Nanog was seen to be unregulated to 24.5% and 31.7% respectively. However,the difference in mean expression of cases and controls was not statistically significant. Correlation between expressionsof these two markers was also not statistically significant. On univariate cox regression analysis, cases with >2 foldexpression of CD24 and Nanog had significantly poor survival as compared to those with <2 fold expression. Onmultivariate analysis > 2 fold CD24 expression had a statistically significant correlation with poor survival. Conclusion:An overexpression of CD24 by more than two fold was associated with poor overall survival in GBM. Poor survivalmay be related to increased "stemness" of tumour cells. Targeted therapy inclusive of drugs targeting stem cells directlyor indirectly may be a promising therapeutic option. PMID- 28843259 TI - The Effect of Health Belief Model-Based Education through Telegram Instant Messaging Services on Pap smear performance AB - Background: Pap smear is an effective screening method for early detection of cervical cancer. This study aimed toinvestigate the effect of education based on Health Belief Model (HBM) through Telegram instant messaging serviceson the Pap smear test. Material and methods: This research was a quasi-experimental study which was performed on106 eligible women (48 participants in the intervention group and 47 participants in the control group). The patients inboth groups completed the written consent form and questionnaires at the beginning of the study. In intervention group,the educational content based on HBM was regularly sent via Telegram during one month. After education and threemonths later, both groups completed questionnaires. Then, the data was analyzed with using SPSS version 22. Results:The findings showed that the two groups at first were similar in demographic characteristics. In the intervention group,the mean difference of the scores before and immediate post training on the knowledge and all of the constructs weresignificant (P<0.001). Also, the mean difference of the scores before and three months after training on knowledge andall of the constructs (except for perceived barriers) has increased and about the perceived barriers this difference hasdecreased significantly compared to the score before the training. In the control group, changes in knowledge and otherconstructs were not significant in during the study. Within the three months after the training, 23 participants (47.9%) inthe intervention group, and 4 participants (5.8%) in the control group performed Pap smear which indicates a statisticallysignificant difference (P<0.001). Conclusion: With regard to the individuals' access to mobile phone, content postedby Telegram on the HBM-based education affects the women's belief and behavior regarding Pap smear test. PMID- 28843260 TI - Neutrophil/Lymphocyte and Platelet/Lymphocyte Ratios are Not Different among Breast Cancer Subtypes AB - Background: Breast cancer is a heterogeneous complex of diseases comprising different subtypes that have differenttreatment responses and clinical outcomes. Systemic inflammation is known to be associated with poor prognosis inmany types of cancer. The neutrophil / lymphocyte ratio (NLR) and platelet / lymphocyte ratio (PLR) are factors usedas indicators of inflammation. In this study, we evaluated NLR and PLR ratios in breast cancer subtypes. Methods: Atotal of 255 breast cancer patients were evaluated retrospectively. Patients were classified into three subtypes: estrogenreceptor (ER)- or progesterone receptor (PR) positive tumors were classified as luminal tumors; human epidermalgrowth factor receptor-2 (HER2)-overexpressed and ER-negative tumors were classified as HER2 positive tumors;and ER, PR, and HER2-negative tumors were classified as triple negative tumors. The NLR and PLR were calculated.Results: The median NLR and PLR were 3 (0.37-37,1) and 137 (37.1-421.3), respectively. 66.7% of the patientswere luminal type, 19.2% were HER2 positive, and 14.1% were triple negative. NLR was not associated with grade(p: 0.412), lymphovascular invasion (p: 0.326), tumor size (p: 0.232) and metastatic lymph node involvement (p: 0.406).PLR was higher in the patients with lymph node metastasis than in those without lymph node metastasis (p: 0.03).The NLR was 2 in the luminal group, 1.8 in the HER2-positive group, and 1.9 in the triple-negative group, but thedifferences were not significant(p: 0.051). PLR was 141 in the luminal group, 136 in the HER2-positive group, and130 in the triple-negative group, but the differences were not significant. Conclusion: We could not find any significantdifferences for NLR and PLR according to breast cancer subtypes. PMID- 28843261 TI - Effect of Frequency and Duration of Tobacco Use on Oral Mucosal Lesions - A Cross Sectional Study among Tobacco Users in Hyderabad, India AB - Purpose: Tobacco use is one of the most important risk factors for the development of oral mucosal lesions includingoral pre-cancer and cancer. The type and location of the lesion varies with the type of tobacco used, the way it isused, and the frequency and duration of use. Hence, the present study aimed to determine the effect of frequency andduration of tobacco use on oral mucosal lesions among tobacco users in Hyderabad city. Materials and Methods: Across sectional study was carried out among 280 tobacco users who were categorized into smokers, chewers and mixedgroups according to the habit. One forty subjects diagnosed with Oral Mucosal Lesions, designated as cases and Oneforty lesion free controls, frequency matched for age, gender, habit and family income were assessed. The study protocolincluded a visual oral soft tissue examination and a questionnaire-based interview. Statistical analysis was done usingChi square test and t- test. Multiple logistic regression analysis was done to assess the association of the variables withlesions. Results: Oral submucous fibrosis (18%) was the most common oral mucosal lesion followed by Leukoplakia(14%) and Smoker's palate (12%). Dose-response relationships were observed for both duration and frequency ofhabits on the risk of oral mucosal lesions. However, it was significant only for frequency of the habit. A significantpositive correlation was observed between occurrence of lesion and those with no education (p=0.005). Conclusion:The study revealed that frequency and duration of tobacco use was associated with the risk of oral mucosal lesions. PMID- 28843262 TI - Cytological Features Associated with Ureaplasma Urealyticum in Pap Cervical Smear AB - Purpose: Ureaplasma urealyticum is associated with several obstetric complications and increases the importanceof risk management in pregnant women. Furthermore, U. urealyticum has been identified as a cofactor that interactswith human papillomavirus infection in cervical cancer onset. The aim of this study was to assess specific cytologicalfeatures of U. urealyticum infection in Pap smears to determine whether additional microbiological testing should beperformed for pregnant women with a high possibility of U. urealyticum infection. Methods: Liquid-based cytologyspecimens (LBC) from cervical swabs of a total of 55 women, including 33 pregnant women who were negative forintraepithelial lesion or malignancy (NILM) on Pap testing and with U. urealyticum diagnosed without any otherinfectious microbes and 22 U. urealyticum-negative controls, were used in this study. We evaluated the localizationof U. urealyticum by immunofluorescence, cytological features of secondary changes in squamous cells caused byinflammation, and the specimen background in Pap smears. Results: Based on analysis of Pap smears, a significantrelationship was observed between U. urealyticum infection and cannonballs (p < 0.05) as well as predominance ofcoccoid bacteria (p < 0.05). A large number of U. urealyticum were detected in cannonballs by immunofluorescence.Conclusion: In the present study, cytological features in Pap smears of U. urealyticum infected samples, which havehardly been understood thus far, were assessed. The cytological features included cannonballs and predominance ofcoccoid bacteria. Our results might help in determining whether additional microbiological testing should be performedfor pregnant women with a high possibility of U. urealyticum infection. PMID- 28843263 TI - Adjuvant Therapy with Silibinin Improves the Efficacy of Paclitaxel and Cisplatin in MCF-7 Breast Cancer Cells AB - Herbal-derived medicines have introduced as sources of novel drugs due to minimum systemic side effects. Silibininas a flavonoid compound has showed with effective chemotherapeutic effects on different cancers. Here, we investigatedthe impact of combination therapy of silibinin, with paclitaxel and cisplatin in inhibition of proliferation and inductionof apoptosis in MCF-7 cells. Cell proliferation was assessed by MTT assay and the percentage of apoptotic cells wasmeasured using flowcytometric assay. Understand of molecular mechanism of this combination related to apoptoticpathway were evaluated by Real Time RT-PCR assays. The IC50 values for silibinin, paclitaxel and cisplatin were160 +/- 22.2 MUM, 33.7 +/- 4.2 nM and 3.2 +/- 0.5 MUM, respectively. Paclitaxel and cisplatin induced higher percentage ofapoptosis in MCF-7 (P < 0.05). Treatment of cell line with combination of silibinin and paclitaxel or cisplatin showedenhanced early apoptosis 56% and 61%, respectively (P < 0.05). Gene expression patterns demonstrated a significantdecrease in anti-apoptotic Bcl-2 with increase in pro apoptotic Bax, P53, BRCA1 and ATM mRNA levels. Takentogether combination therapy of breast cancer cells by applying paclitaxel or cisplatin with silibinin synergisticallyincreases the anti-proliferative effect of single agents. PMID- 28843264 TI - Active Expression of Human Tissue Plasminogen Activator (t-PA) c-DNA from Pulmonary Metastases in the Methylotrophic Yeast Pichia Pastoris KM71H Strain AB - Background: Human tissue-type plasminogen activator (t-PA) is a key protease of the trypsin family. It catalyzesthe activation of zymogen plasminogen to the fibrin-degrading proteinase, plasmin, leading to digestion of fibrin clots.The recombinant enzyme produced by recombinant technology issued to dissolve blood clots in treatment of varioushuman diseases such as coronary artery thrombosis, pulmonary embolism, acute ischemic stroke (AIS). Pichia pastorisexpression system is a unique system for the production of high level of recombinant proteins. GS115 and KM71Hare two kinds of Pichia pastoris strains whilst production of recombinant proteins in these strains is not predictable.The aim of the study was evaluation of t-PA expression in KM71H strains. Methods: In this study, the cDNA of thet-PA gene was amplified by PCR, sequenced and cloned into Pichia pastoris KM71H host strain using pPICZalphaAexpression vector that allows methanol-induced expression and secretion of the protein. Results: Dot blotting resultsconfirmed the presence oft-PA in the cell supernatant. Western blotting test revealed the approximate size of 70 KDa forrecombinant t-PA. Quantitative ELISA experiment showed 810 MUg/L of t-PA in the supernatant samples. Zymographyanalysis confirmed the proteolytic activity and biological function of the expressed recombinant t PA. Conclusions:Correspondingly, Pichia pastoris KM71H is an appropriate strain for production of active recombinant protein. PMID- 28843265 TI - Poly-L-Lysine Inhibits Tumor Angiogenesis and Induces Apoptosis in Ehrlich Ascites Carcinoma and in Sarcoma S-180 Tumor AB - Background: This study focuses on the role of Poly-L-lysine (PLL), an essential amino acid, on molecular changesof tumor angiogenesis suppression, pro-apoptotic and anti-apoptotic gene expression after treatment on Ehrlich ascitescarcinoma (EAC) and solid sarcoma-180 tumor cells bearing mice. Materials and Methods: The cell viability wascarried out using MTT assay. The antitumor activity was evaluated by treatment with PLL at 20 and 40mg/kg/b.w dosesfor 14 days in EAC ascites tumor and 21 days for Sarcoma-180 solid tumor model. Several tumor evaluation studies,haematological and biochemical parameters were estimated. Importantly, the tumor cell apoptosis was assessed usingmicroscopic observations, DNA fragmentation assay, Flow cytometric analysis, cell-cycle and electron microscopicstudy, following which, the expression of several signal proteins related to pro-apoptosis, anti-apoptosis and tumorangiogenesis were quantified using western blotting and immunohistochemistry study. Results: Precisely, PLL hadcytotoxic effect on K562; A549; U937 and B16F10 cancer cells. Significant decreases in liquid and solid tumors andincreased life span of treated mice were observed (P<0.05). Typical morphological changes, apoptosis bleb phenomenonand sub-G1 cell cycle arrests revealed that PLL promoted apoptotic cell death. Western blot and immunohistochemistryconfirms, PLL activated apoptotic signalling cascades through down regulation of Bcl-2 and CD31 protein and upregulationof Bax and p53 proteins. The anti-angiogenic effects were also accompanied with decreased VEGF expressionand reduced peritoneal-angiogenesis and microvessel density. Conclusions: The antitumor and antitumor-angiogenicactivity of PLL was confirmed from all the results via up and down regulation of relevant signal proteins reported inthis publication. PMID- 28843266 TI - Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia AB - Background: Deviation of host immune response by engagement of inhibitory receptors is one of the well-knownmechanisms of tumor cells for immune evasion and survival. PD-1/PD-L1 and Tim-3/Gal-9 axes are two majorpathways in this area which their contribution has been documented in a variety of malignancies. In this study, Gal-9and PD-L1 expression was investigated in leukemic cells from patients with Chronic Lymphocytic Leukemia (CLL).Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 25 untreated CLL patients and 15 sex andage-matched healthy controls. CLL patients were classified into different clinical stages based on the Rai staging system.Total RNA was extracted from all samples and applied for cDNA synthesis. Relative expression of Gal-9 and PD L1mRNA was determined by Real-Time PCR using beta-actin as a housekeeping gene. Results: Gal-9 and PD-L1 mRNA wassignificantly more expressed in CLL patients compared to healthy controls (p<0.0001 and p=0.005, respectively). CLLpatients in advanced clinical stages showed higher expression of Gal-9 and PD-L1 in comparison to patients in earlyclinical stages (p<0.0001 and p=0.004, respectively). Conclusion: Our promising results regarding over-expression ofGal 9 and PD-L1 in CLL patients call future complementary studies to more evaluate and confirm these pathways forimmunotherapy approaches of this malignancy. Upregulation of both Gal-9 and PD-L1 in CLL patients with advancedclinical stages introduces them as useful prognostic biomarkers for disease progression. PMID- 28843267 TI - Screening for Circulating Tumour Cells Allows Early Detection of Cancer and Monitoring of Treatment Effectiveness: An Observational Study AB - Background: Circulating-Tumour-Cells (CTC) provide a blood biomarker for early carcinogenesis, cancerprogression and treatment effectiveness. An increase in CTCs is associated with cancer progression, a CTC decreasewith cancer containment or remission. Several technologies have been developed to identify CTC, including thevalidated Isolation-by-Size-of-Epithelial-Tumour (ISET, Rarecells) technology, combining blood filtration andmicroscopy using standard histo-pathological criteria. Methods: This observational study compared CTC count tocancer status and cancer risk, by monitoring treatment effectiveness in cancer patients and by screening for CTC inasymptomatic patients with risk factors, including family history of cancer. Results: Between Sept-2014 and Dec-2016we undertook 600 CTC tests (542 patients), including 50% screening requests of patients without cancer diagnosis butwith risk factors. CTC were detected in all cancer patients (n=277, 100%), and in half of the asymptomatic patientsscreened (50%, 132 out-of 265 patients). Follow-up tests including scans, scheduled within 1-10 months of positiveCTC tests, found early cancerous lesions in 20% of screened patients. In 50% of male patients with CTC and normalPSA (prostate-specific-antigen) levels, PSMA-PET scans revealed increased uptake in the prostate, indicative of earlyprostate cancer. Other types of cancers detected by CTC screening and subsequent scans included early breast, ovarian,lung, or renal cancer. Patients with CTC were advised on integrative approaches including immune-stimulating andanti-carcinogenic nutritional therapies. CTC repeat tests were available in 10% of patients with detected CTC (40 outof409 patients, n=98 CTC tests) to assess treatment effectiveness, suggesting nutritional therapies to be beneficial inreducing CTC count. Conclusions: CTC screening provided a highly sensitive biomarker for the early detection ofcancer, with higher CTC counts being associated with higher risk of malignancy. CTC monitoring over time indicatedtreatment effectiveness. Nutrients with anti-carcinogenic properties could reduce CTC count, and included curcumin,garlic, green tea, grape seed, modified citrus pectin, and medicinal mushroom extract. PMID- 28843268 TI - Effects of a Phosphoinositide-3-Kinase Inhibitor on Anaplastic Thyroid Cancer Stem Cells AB - Background: Thyroidectomy, radioactive iodine therapy, chemotherapy, or their combination are treatmentsof choice for thyroid cancers. However, cancer stem cells (CSCs) may become resistant to therapy, and mutationsin somatic genes affect radioiodine uptake. This study determined the effect of a phosphoinositide 3-kinase (PI3K)inhibitor on anaplastic thyroid CSCs. Materials and Methods: The magnetic-activated cell sorting assay was usedfor segregating CD133-positive CSCs from three anaplastic thyroid carcinoma (ATC) cell lines (C643, SW1736, and8305C). After confirming the cells' purity by flow cytometry, they were treated with 5, 10, 20, or 25 MUM LY294002,a PI3K inhibitor, and then evaluated at 24 and 48 h. The sodium-iodide symporter (NIS) mRNA level was determinedusing the quantitative real-time polymerase chain reaction. NIS protein expression was evaluated using western blotting.Results: The PI3K inhibitor, at different concentrations and times, increased the NIS mRNA level (1.30-6.17-fold,P < 0.0001). If the NIS mRNA level in LY294002-treated CD133-positive CSCs was increased more than 2-fold, theNIS protein content was detectable. Conclusions: CD133-positive CSCs isolated from ATC cell lines expressed NISmRNA and protein after PI3K inhibition. Our findings suggest that molecularly targeted CSC therapy may improvethe treatment efficacy of aggressive cancers like ATC. PMID- 28843269 TI - Survival of Patients with Thyroid Cancer in Yazd, Iran AB - Background: Thyroid cancer is the most common endocrine related malignancy in the world. This cancer hasincreased during recent years in Iran and is the11th most common malignancy in Iranian population. Survival of patientswith thyroid carcinoma in the different geographic areas within Iran is not clear. The present study aimed to estimatesurvival of patients suffering from thyroid cancer in Yazd, Iran. Methods: In this retrospective cohort study, data werecollected from 80 patients with thyroid cancer registered in Shohadaye Kargar and Shahid Sadoughy hospitals in Yazdbetween March 2001 and March 2012. The Kaplan-Meier analysis was used for estimation of survival over time andCox regression method was performed for calculating hazard ratios according to demographic and risk variables.Results: Survival rates at the end of 1, 3, and 5 years in thyroid cancer patients were 99%, 96%, and 91%, respectively.A statistically significant correlation was found between stage of disease, type of cancer and survival time of patients(p<0.05). The worst survival was in peoples with the anaplastic type and stage IV of thyroid carcinoma. Conclusion:The survival of patients with thyroid carcinoma was higher than some areas in Iran. Since type and stage of thyroidcancer were the important factors in survival time, screening of people for cancer diagnosis in early stages, it seemsto improve survival of patients. Radioactive iodine therapy can increase the survival rate in patients suffering fromthyroid malignancy. PMID- 28843270 TI - Thioredoxin-Interact ing-Pro t e in [TXNIP] and Transglutaminase 2 [TGM2] Expression in Meningiomas of Different Grades and the Role of Their Expression inMeningioma Recurrence and Prognosis AB - Background: Meningiomas are common central nervous system (CNS) tumors that account for thirty percent ofprimary intracranial tumors.. The accuracy of predicting meningioma recurrence and progression is not enough. So, thereis a real need for discovering recent factors for identification of the relapse risk, progression rates, which patients willneed aggressive treatment and predicting and improving patients' survival. Thioredoxin-interacting-protein [TXNIP]is an alpha-arrestin-protein family member that is mapped on chromosome 1-q21-22 and is found to participate incellular redox reactions regulations and control. Transglutaminase 2 (TGM2) is a transglutaminase enzyme familymember that is found in many human cells, it may act as an enzyme, a structural protein and also has multiple rolesin many cellular activities. Aim of our study: It was to explore the expression of TXNIP, TGM2 and Ki-67 usingimmunohistochemistry in different pathological grades of meningiomas, and to investigate the relevance betweentheir expressions, clinicopathological criteria, disease recurrence and prognosis of meningioma patients. Methods: weincluded 50 cases of meningioma of different pathological grades; all patients were managed according to their gradeby surgery alone, with radiotherapy or combined modalities. Sections from paraffin blocks prepared from samples of allpatients stained by TXNIP, TGM2 and Ki-67 using immunohistochemistry. Results: high expression of TXNIP in 28out of 50 (56%) cases of meningioma of different pathological grades and was positively correlated with meningiomalower grade, low KI labeling index (p=0.000), adequacy of resection, negatively correlated with high incidence ofrecurrence after surgery and it was negatively correlated with meningioma higher pathological grades (p=0.000). Wedetected high expression of TGM2 in 21 out of 50 (42%) cases of meningioma and it was positively correlated withmeningioma higher grade (p= 0.002), high KI labeling index (p=0.000), high incidence of recurrence after surgery,progression to higher pathological grades and was negatively correlated with adequacy of resection of meningioma(p=0.000). Conclusion: There is inverse relation between both [TXNIP and TGM2 expression in meningiomas and thecombination of decreased expression of TXNIP and increased expression of TGM2 could predict risk of meningiomarecurrence and progression in to higher pathological grades. PMID- 28843271 TI - Vitamin D Proliferates Vaginal Epithelium through RhoA Expression in Postmenopausal Atrophic Vagina tissue. AB - Postmenopausal atrophic vagina (PAV) is the thinning of the walls of the vagina and decreased lugae of the vagina. PAV is caused by decreased estrogen levels in postmenopausal women. However, the harmful effects of hormone replacement therapy (HRT) have resulted in considerable caution in its use. Various estrogen agonist treatment options are available. Vitamin D is influences the regulation of differentiation and proliferation of various cells, especially tissues lining stratified squamous epithelium, such as the vaginal epithelium. In this study, we hypothesized that vitamin D could provide an alternative and a safe treatment option for PAV by promoting the proliferation and differentiation of the vaginal epithelium. Thirty six patients were enrolled in this case-control study. Vitamin D associated proteins in a vitamin D and sex hormone treated vaginal epithelial cell line as well as normal and PAV tissues were measured. To confirm of cell-to cell junction protein expression, cell line and tissue studies included RT-PCR, immunohistochemistry staining, and immunoblot analyses. The expression of cell-to cell junction proteins was higher in women with symptoms of atrophic vagina tissue compared to women without the symptoms. Vitamin D stimulated the proliferation of the vaginal epithelium by activating p-RhoA and Erzin through the vitamin D receptor (VDR). The results suggest that vitamin D positively regulates cell-to-cell junction by increasing the VDR/p-RhoA/p-Ezrin pathway. This is the first study to verify the relationship of the expression of RhoA and Ezrin proteins in vaginal tissue of PAV. PMID- 28843275 TI - AsMA Annual Award Winners. PMID- 28843276 TI - Peak BMP Responses in the Drosophila Embryo Are Dependent on the Activation of Integrin Signaling. PMID- 28843273 TI - Fusion anomaly of the pancreatic tail and spleen: a case report. AB - BACKGROUND: Splenopancreatic fusion is a rare anomaly that is often associated with trisomy 13. Its diagnosis can be important in patients scheduled to undergo distal pancreatectomy or splenectomy, to avoid possible intraoperative or postoperative complications. CASE PRESENTATION: An 82-year-old Japanese man was referred to our hospital for further evaluation and treatment for a solitary hepatocellular carcinoma based on liver cirrhosis. Triple-phase contrast-enhanced multidetector-row computed tomography and magnetic resonance imaging showed a splenopancreatic fusion as well as a solitary hepatocellular carcinoma in segment VIII of his liver. CONCLUSIONS: Fusion of the pancreatic tail and spleen is a rare and asymptomatic anomaly. Its detection can be improved by the use of multidetector computed tomography or magnetic resonance imaging. PMID- 28843272 TI - Inhibition of the DevSR Two-Component System by Overexpression of Mycobacterium tuberculosis PknB in Mycobacterium smegmatis. AB - The DevSR (DosSR) two-component system, which is a major regulatory system involved in oxygen sensing in mycobacteria, plays an important role in hypoxic induction of many genes in mycobacteria. We demonstrated that overexpression of the kinase domain of Mycobacterium tuberculosis (Mtb) PknB inhibited transcriptional activity of the DevR response regulator in Mycobacterium smegmatis and that this inhibitory effect was exerted through phosphorylation of DevR on Thr180 within its DNA-binding domain. Moreover, the purified kinase domain of Mtb PknB significantly phosphorylated RegX3, NarL, KdpE, TrcR, DosR, and MtrA response regulators of Mtb that contain the Thr residues corresponding to Thr180 of DevR in their DNA-binding domains, implying that transcriptional activities of these response regulators might also be inhibited when the kinase domain of PknB is overexpressed. PMID- 28843277 TI - Population of Monocyte-Derived Macrophages. PMID- 28843278 TI - NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. PMID- 28843279 TI - Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. PMID- 28843280 TI - A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy. PMID- 28843281 TI - TRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding. PMID- 28843282 TI - Correction. PMID- 28843283 TI - The Proteomic Landscape of Triple-Negative Breast Cancer. PMID- 28843284 TI - The Dnmt3L ADD Domain Controls Cytosine Methylation Establishment during Spermatogenesis. PMID- 28843285 TI - Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human. PMID- 28843287 TI - An S-Acylation Switch of Conserved G Domain Cysteines Is Required for Polarity Signaling by ROP GTPases. PMID- 28843286 TI - Integrative Clinical Genomics of Advanced Prostate Cancer. PMID- 28843288 TI - The Role of Recent Admixture in Forming the Contemporary West Eurasian Genomic Landscape. PMID- 28843289 TI - All Spiking, Sustained ON Displaced Amacrine Cells Receive Gap-Junction Input from Melanopsin Ganglion Cells. PMID- 28843291 TI - European Society for Dermatological Research (ESDR): Shifting Scope and Expanding Boundaries, Promoting Cutaneous Biology Research across Europe and beyond. PMID- 28843290 TI - Safe Return to Driving After Volar Plating of Distal Radius Fractures. AB - PURPOSE: A major concern for patients following distal radius fracture fixation is when they can resume driving. This decision has medical, legal, and safety considerations, but there are no evidence-based guidelines to assist the surgeon. The goal of this study was to observe when patients are capable of safely resuming driving following surgical fixation of the distal radius. METHODS: Patients undergoing volar plating of a distal radius fracture were prospectively enrolled. At approximately 2 and 4 weeks after surgery, patients were administered a driving examination on a closed course and given a subjective questionnaire including visual analog scale scores. All basic functions of vehicle operation were evaluated. Successful completion indicated they would pass a driving evaluation. RESULTS: Twenty-three patients were enrolled. Sixteen (69.5%) passed their first attempt (average of 18.4 days from surgery), another 4 (17.4%) passed their second attempt (31.3 days from surgery), and 3 did not complete the second examination. Patients who failed relied too much on their nonsurgical hand, were not able to control the steering wheel with 2 hands, and reported pain and insecurity when using the operative hand. Of those who passed the second attempt, the first failure was universally attributed to pain. Fifteen patients reported a return to independent driving prior to the first examination (average, 11.3 days). Of the 7 who failed, 6 reported they could control the car in an emergency, and 2 reported they would not feel safe with daily driving. Maximum pain while driving on the visual analog scale was 2.4 of 10 among those who failed compared with 1.3 among those who passed. CONCLUSIONS: Most patients could safely return to driving within 3 weeks of surgery. Pain was the primary limiting factor affecting driving ability. Safe return to driving may be warranted within 3 weeks of distal radius volar plate fixation in some patients. Persistent pain is likely the most important obstacle to a safe return to driving. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 28843292 TI - More Than Many: How to Manage the Most Frequent Cancer? AB - Leiter et al. report on the increasing incidence of keratinocyte cancers in Germany. The true population burden is even larger then reported, because many of these new patients will develop multiple keratinocyte cancers. Keratinocyte cancer puts a large burden on health care systems worldwide. Prevention and management strategies are needed to maintain high quality of care for all patients. PMID- 28843293 TI - Langerhans Cells Orchestrate TFH-Dependent Humoral Immunity. AB - T follicular helper cells contribute to the development of long-lasting humoral immunity by germinal center formation. Somatic hypermutation and affinity maturation take place in germinal centers leading to the generation of memory B cells and plasma cells. As such, T follicular helper cells impact immunodeficiencies, autoimmunity, and cancer. This necessitates further understanding of how T follicular helper cells are regulated in health and disease. The current study by Levin et al. builds on prior work to further substantiate a critical role for skin migratory dendritic cells and in particular Langerhans cells at governing T follicular helper and germinal center formation after intradermal immunization with HIV p24-coated polylactic acid nanoparticles. PMID- 28843294 TI - Metabo-miR: miR-211 Regulates Mitochondrial Energy Metabolism in Vitiligo. AB - The study by Sahoo et al. established miR-211 as a critical regulator of cellular metabolism in vitiligo cells. miR-211, which is expressed from the transient receptor potential melastatin 1 intronic region, regulates oxidative phosphorylation and mitochondrial energy metabolism in vitiligo. Loss of miR-211 in melanocytes was shown to alter expression patterns of newly identified target genes, and those that regulate respiratory functions in melanocytes are among them. This study highlights the importance of miR-211 for the melanocyte biology and development of vitiligo. PMID- 28843295 TI - Novel Mutations Involving NF-kappaB and B-Cell Signaling Pathways in Primary Cutaneous Large B-Cell Lymphoma, Leg-Type and Comparison with Sezary Syndrome. AB - Multiple genomic mutations, especially those involving the NF-kappaB pathway, have been characterized in primary cutaneous large B-cell lymphoma, leg type. However, its genomic profiling remains limited given its rarity. In a recent study, Mareschal et al. performed next-generation sequencing and whole-exome sequencing, identifying new driver genes while also confirming the role of myeloid differentiation primary response gene 88 in the molecular pathogenesis of the disease. PMID- 28843296 TI - Research Techniques Made Simple: Bioinformatics for Genome-Scale Biology. AB - High-throughput biology presents unique opportunities and challenges for dermatological research. Drawing on a small handful of exemplary studies, we review some of the major lessons of these new technologies. We caution against several common errors and introduce helpful statistical concepts that may be unfamiliar to researchers without experience in bioinformatics. We recommend specific software tools that can aid dermatologists at varying levels of computational literacy, including platforms with command line and graphical user interfaces. The future of dermatology lies in integrative research, in which clinicians, laboratory scientists, and data analysts come together to plan, execute, and publish their work in open forums that promote critical discussion and reproducibility. In this article, we offer guidelines that we hope will steer researchers toward best practices for this new and dynamic era of data intensive dermatology. PMID- 28843297 TI - SnapshotDx Quiz: September 2017. PMID- 28843298 TI - Cells to Surgery Quiz: September 2017. PMID- 28843299 TI - Remember to play and play to remember. PMID- 28843300 TI - Dietary guidelines for inborn errors of metabolism. PMID- 28843301 TI - 50 Years Ago in The Journal of Pediatrics: Brain Scan in a Patient with Herpes Simplex Encephalitis. PMID- 28843302 TI - 50 Years Ago in The Journal of Pediatrics: Effects of Hypoxemia, Hypercarbia, Acidosis, and Reduced Pulmonary Blood Flow on the Surfactant Fetal Lamb Lung. PMID- 28843303 TI - Medical Progress Series: Bronchopulmonary Dysplasia at 50 Years-An Introduction. PMID- 28843304 TI - Children with intellectual disabilities: taking care of our weak. PMID- 28843305 TI - Do you know what SUDEP is? PMID- 28843306 TI - USPSTF celiac disease screening recommendations. PMID- 28843307 TI - Response to name may enhance autism spectrum disorder screening. PMID- 28843308 TI - Most children labeled as penicillin allergic are at low risk for true penicillin allergy. PMID- 28843309 TI - Perfusion index, in addition to pulse oximetry may enhance detection of neonatal severe congenital heart disease. PMID- 28843310 TI - The Quick-Wee infant urine collection method. PMID- 28843311 TI - 50 Years Ago in The Journal of Pediatrics: Cellular Growth of Human Placenta. PMID- 28843312 TI - Corrigendum to: "Bacteroides fragilis RecA protein overexpression causes resistance to metronidazole." [Res. Microbiol. 161 (5) (2010) 346-354]. PMID- 28843313 TI - Plant Hormones: Key Players in Gut Microbiota and Human Diseases? AB - It is well established that plant hormones such as auxins, cytokinins (CKs), and abscisic acid (ABA) not only govern important plant physiological traits but are key players in plant-microbe interactions. A poorly appreciated fact, however, is that both microbes and animals produce and perceive plant hormones and their mimics. Moreover, dietary plant hormones impact on human physiological process such as glucose assimilation, inflammation, and cell division. This leads us to wonder whether plant hormones could ensure functions in microbes per se as well as in animal-microbe interactions. We propose here and explore the hypothesis that plant hormones play roles in animal-microbiota relationships, with consequences for human health. PMID- 28843314 TI - Corrigendum to "Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery" [Drug Discov. Today 19 (2014), 171 182. PMID- 28843315 TI - Corrigendum to "d-Arginine as a neuroprotective amino acid: promising outcomes for neurological diseases" [Drug Discov. Today 19 (2014) 627-636]. PMID- 28843316 TI - Erratum: Laccase-based dye decolorization using agro-wastes: comment on Santhanam et al.: [Trends in Biotechnology 30 (2012) 361-362]. PMID- 28843317 TI - Corrigendum to "A simple Fourier filter for suppression of the missing wedge ray artefacts in single-axis electron tomographic reconstructions" [J. Struct. Biol. 186(1) (2014) 141-152]. PMID- 28843318 TI - September 2017 Featured Articles, Volume 225. PMID- 28843319 TI - Correction. PMID- 28843320 TI - Corrigendum to "The conserved Fanconi anemia nuclease Fan1 and the SUMO E3 ligase Pli1 act in two novel Pso2-independent pathways of DNA interstrand crosslink repair in yeast" [DNA Repair 12 (December (12)) (2013) 1011-1023]. PMID- 28843321 TI - Corrigendum to "Disruption of the potassium channel regulatory subunit KCNE2 causes iron-deficient anemia" [Experimental Hematology, Vol. 42, Issue 12, p1053 1058.e1]. PMID- 28843322 TI - Latest-Generation Transcatheter Aortic Valve Replacement Devices and Procedures. AB - Transcatheter aortic valve replacement (TAVR) is a well-established treatment for patients with severe symptomatic aortic stenosis who are at high or prohibitive surgical risk. More recently, TAVR has emerged as a valid alternative to surgical aortic valve replacement for treating intermediate-risk patients, and several studies are currently evaluating the role of TAVR in low-risk patients. Transcatheter heart valve (THV) technologies have evolved considerably over time, and important iterations have been implemented in many of the latest-generation devices to (1) reduce the size and improve delivery system properties; (2) improve valve deployment, repositioning, and retrievability; and (3) reduce paravalvular leaks. This article reviews the main characteristics of, and clinical results associated with, the newer-generation THVs while providing an overview of novel TAVR indications. PMID- 28843323 TI - Should TAVR Replace Surgery for Aortic Stenosis in Low- to Intermediate-Risk Patients? AB - Transcatheter aortic valve replacement (TAVR) was initially envisioned as a less invasive option for patients with severe symptomatic aortic stenosis who either were not candidates or were very high-risk candidates for surgical aortic valve replacement (SAVR). Based on data from the original Placement of Aortic Transcatheter Valve (PARTNER) trials as well as the CoreValve Pivotal trials, TAVR is now approved and accepted in the treatment of severe symptomatic aortic stenosis in extreme-risk and high-risk patient populations. Thus far, the randomized controlled trial data for TAVR have been noninferior or even superior to both medical therapy and SAVR. Recently, the US Food and Drug Administration expanded the indications for 2 balloon-expandable devices, and CE Mark status was awarded to a self-expanding device for use in patients at intermediate risk. Given all the data, the logical next step is to study low-risk patient groups. Anecdotal and nonrandomized data have been conflicting when comparing TAVR to SAVR in low-risk patients. Two low-risk randomized trials have started in the United States, and ultimately these trials will determine the feasibility of TAVR as an acceptable alternative to SAVR in low-risk patients with severe aortic stenosis. PMID- 28843324 TI - Minimally Invasive Heart Valve Surgery. AB - Minimally invasive valve surgery represents a recent and significant advance in modern heart surgery. Indeed, many less invasive approaches for both the aortic and mitral valves have been developed in the past 2 decades. These procedures were hypothesized to result in less operative trauma, which might translate into better patient outcomes. However, this clinical benefit remains controversial in the literature. The aim of this review is to discuss the evidence surrounding minimally invasive heart valve surgery in the current era. A systematic search of the literature from 2006-2016 was performed looking for articles reporting early or late outcomes after minimally invasive valve surgery. Less invasive valve surgery is safe and provides long-term surgical outcomes similar to those of standard sternotomy. In addition, these approaches result in a reduction in overall hospital length of stay and may mitigate the risk of early morbidity mainly postoperative bleeding, transfusions, and ventilation duration. PMID- 28843325 TI - Pulmonary Valve Procedures Late After Repair of Tetralogy of Fallot: Current Perspectives and Contemporary Approaches to Management. AB - Few topics in adult congenital heart disease have approached the level of scrutiny bestowed on pulmonary valve replacement (PVR) strategies late after tetralogy of Fallot (TOF) repair. Despite the successes of primary surgery for TOF, there is a growing group of adults with residual right ventricular outflow tract and pulmonary valve dysfunction. Patients with residual chronic pulmonic regurgitation as a consequence of earlier surgery can later develop symptoms of exercise intolerance and complications including heart failure, tachyarrhythmias, and sudden cardiac death. Optimal timing of PVR has sparked debate, which has catalyzed increasing research efforts over the past decade. Although performance of PVR in the absence of symptoms is currently on the basis of the rationale that achievement of complete reverse remodelling is highly desirable, whether this approach results in improvement in patient outcomes in the long-term has yet to be shown. Surgical PVR and percutaneous pulmonary valve intervention are different techniques with specific advantages and disadvantages that require careful consideration for each individual patient, alongside the need for requisite reinterventions over the course of a patient's lifetime. Criteria pertaining to referral strategies are ever being refined as newer technologies for percutaneous therapies continue to evolve. In this article we review the literature surrounding the indications for, the optimal timing of, and the approaches to pulmonary valve procedures in adults with previously repaired TOF. PMID- 28843326 TI - Valve Interventions in Utero: Understanding the Timing, Indications, and Approaches. AB - Efficient use of fetal echocardiography has enabled early detection of congenital heart disease and of its often irreversible complications, such as ventricular hypoplasia in case of severe stenosis of the semilunar valves. Experience of the past 25 years has proved that balloon dilatation of the severely stenotic or atretic valve in fetuses as early as the 23rd week of gestation is technically feasible with a learning curve. Reported results regarding the ultimate biventricular circulation outcome after fetal valve intervention are at best controversial, with the desired improvements in the quality of life and cost benefits of the postnatal treatment being as yet unconfirmed. Despite acute hemodynamic success with a relatively low rate of fetal complications, the number of suitable candidates for the fetal valve intervention remains low. High valvular tissue plasticity in the fetus and difficulties of assessing the point of no return of the myocardial damage often makes the success of fetal valve intervention short-lived and unpredictable. Hopefully, future refinements of the equipment, imaging, and biodegradable tissue regeneration materials will lead to better results of the fetal valve interventions beyond their technical success. PMID- 28843327 TI - Role of Computational Modelling in Planning and Executing Interventional Procedures for Congenital Heart Disease. AB - Increasingly, computational modelling and numerical simulations are used to help plan complex surgical and interventional cardiovascular procedures in children and young adults with congenital heart disease. From its origins more than 30 years ago, surgical planning with analysis of flow hemodynamics and energy loss/efficiency has helped design and implement many modifications to existing techniques. On the basis of patient-specific medical imaging, surgical planning allows accurate model production that can then be manipulated in a virtual surgical environment, with the proposed solutions finally tested with advanced computational fluid dynamics to evaluate the results. Applications include a broad range of congenital heart disease, including patients with single-ventricle anatomy undergoing staged palliation, those with arch obstruction, with double outlet right ventricle, or with tetralogy of Fallot. In the present work, we focus on clinical applications of this exciting field. We describe the framework for these techniques, including brief descriptions of the engineering principles applied and the interaction between "benchtop" data with medical decision-making. We highlight some early insights learned from pioneers over the past few decades, including refinements in Fontan baffle geometries and configurations. Finally, we offer a glimpse into exciting advances that are presently being explored, including use of modelling for transcatheter interventions. In this era of personalized medicine, computational modelling and surgical planning allows patient-specific tailoring of interventions to optimize clinical outcomes. PMID- 28843328 TI - Transcatheter vs Surgical Aortic Valve Replacement for Aortic Stenosis in Low Intermediate Risk Patients: A Meta-analysis. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) has emerged as the treatment of choice for patients with severe aortic stenosis at high surgical risk; the role of TAVR compared with surgical aortic valve replacement (SAVR) in the low-intermediate surgical risk population remains uncertain. Our primary objective was to determine differences in 30-day and late mortality in patients treated with TAVR compared with SAVR at low-intermediate risk (Society of Thoracic Surgeons Predicted Risk of Mortality < 10%). METHODS: Medline and Embase were searched from 2010 to March 2017 for studies that compared TAVR with SAVR in the low-intermediate surgical risk population, restricted to randomized clinical trials and matched observational studies. Two investigators independently abstracted the data and a random effects meta-analysis was performed. RESULTS: Four randomized clinical trials (n = 4042) and 9 propensity score-matched observational studies (n = 4192) were included in the meta-analysis (n = 8234). There was no difference in 30-day mortality between TAVR and SAVR (3.2% vs 3.1%, pooled risk ratio: 1.02; 95% confidence interval, 0.80-1.30; P = 0.89; I2 = 0%) or mortality at a median of 1.5-year follow-up (incident rate ratio: 1.01; 95% confidence interval, 0.90-1.15; P = 0.83; I2 = 0%). There was a higher risk of pacemaker implantation and greater than trace aortic insufficiency in the TAVR group whereas the risk of early stroke, atrial fibrillation, acute kidney injury, cardiogenic shock, and major bleeding was higher in the SAVR group. CONCLUSIONS: Although there was no difference in 30-day and late mortality, the rate of complications differed between TAVR and SAVR in the low-intermediate surgical risk population. PMID- 28843329 TI - Safety and Feasibility of the Transcatheter Approach to Create a Reverse Potts Shunt in Children With Idiopathic Pulmonary Arterial Hypertension. AB - BACKGROUND: The reversed Potts shunt improves right ventricular (RV) function in patients with suprasystemic pulmonary arterial hypertension (PAH). The proximity of the left pulmonary artery (LPA) to the descending aorta (DAo) permits the creation of a transcatheter connection. We sought to assess the safety, feasibility, and hemodynamic efficacy of the transcatheter Potts shunt (TPS) in children. METHODS: The TPS procedure was performed using radiofrequency energy for vessel perforation and deployment of a covered stent to connect the DAo and LPA. Procedural details and clinical follow-up data were collected prospectively. RESULTS: A TPS was successfully created in 6 children (mean age, 11.0 +/- 4.2 years) with drug-refractory suprasystemic PAH and deteriorating RV function. All patients exhibited nearly complete equalization of aortic and pulmonary pressures and improvement in RV contractility within days after TPS placement. Two patients with pre-existing severe biventricular dysfunction and pericardial effusion experienced acute low-output states immediately after shunt creation because of sudden reductions in left ventricular (LV) preload, resulting in cardiac arrest, irreversible brain damage, and death. Stent dislodgement and embolization into the iliac artery occurred in 1 patient. The stent was successfully secured and followed by placement of a second stent at the target location. The procedure was uncomplicated in 4 patients, who remain alive after a mean follow-up of 10 +/- 2.6 months. Intravenous vasodilator therapy was weaned uneventfully after TPS in 3 patients. CONCLUSIONS: TPS creation in children is feasible and results in hemodynamic improvement. Further insights into high-risk markers, such as reduced preprocedural LV function and preload reserves, are important for guiding patient selection. PMID- 28843330 TI - Adult Congenital Heart Disease Intervention: The Canadian Landscape. AB - Once considered a childhood disease, the number of adults living with congenital heart disease (CHD) has now exceeded the number of pediatric patients. The landscape of percutaneous intervention for adult congenital heart disease (ACHD) has evolved over the past decade and has yet to be characterized in Canada. The aim of this study was to begin to understand the current infrastructure underlying ACHD interventions in Canada and to characterize the type and number of interventions being carried out across the country. A cross-sectional national survey was distributed by e-mail to all cardiac catheterization laboratory directors in 2015. All Canadian laboratories involved in ACHD interventions responded, encompassing 19 institutions spanning 69 cardiac catheterization laboratories. A total of 1451 percutaneous interventions were recorded. Nationwide, the most common simple ACHD interventions were for atrial septal defect and patent foramen ovale closures. The most common ACHD interventions of increased complexity were for coarctation stenting and transcatheter pulmonary valve implantation. There was a marked clustering of procedures in Ontario, Quebec, British Columbia, and Alberta in keeping with Canada's population-density distribution. A total of 23 ACHD operators were identified, half of whom had ACHD specific fellowship training. These data can be used as a starting point to inform the present state of affairs in the area and lay the groundwork for further work to assess resource allocation and human resource planning for the care of patients with ACHD in Canada. PMID- 28843331 TI - Computed Tomographic and Fluoroscopic Image Fusion for Pulmonary Vein Stenosis Stenting. PMID- 28843332 TI - Atypical Chest Pain and a Blood Blister: More Than Meets the Eye. PMID- 28843333 TI - Erratum to "Dietary restriction delays aging, but not neuronal dysfunction, in Drosophila models of Alzheimer's disease." [Neurobiol. Aging 32 (2011) 1977 1989]. PMID- 28843334 TI - Re. "Cardiac imaging evaluation is mandatory in patients with anorexia nervosa": Author's response. PMID- 28843335 TI - The identification of Meyerozyma guilliermondii from blood cultures and surveillance samples in a university hospital in Northeast Turkey: A ten-year survey. AB - Meyerozyma (Pichia) guilliermondii exists in human skin and mucosal surface microflora. It can cause severe fungal infections like candidemia, which is an opportunistic pathogen. One hundred and forty-one M. guilliermondii isolates, consisting of 122 blood culture isolates, belonging to 126 patients; 13 total parenteral nutrition solution isolates; and two rectal swab isolates were identified according to carbohydrate assimilation reactions in a university hospital in Turkey between January 2006 and December 2015. Following Candida albicans (34.0%) and C. parapsilosis (21.2%), the third yeast species most commonly isolated from blood cultures in the Farabi Hospital was M. guilliermondii (20.6%). The patients were hospitalised in 27 different departments. A total of 50% of the patients were in pediatric departments, 49.2% were in intensive care units, and 17.2% were in haematology-oncology departments. Molecular identification of the isolates was performed using DNA sequence analysis of ribosomal ITS gene regions and IGS amplification-AluI fingerprinting (IGSAF). With molecular identification, 140 isolates were identified as M. guilliermondii and one isolate was identified as Candida membranifaciens. It was observed that the ITS1 region specifically helps in identifying these species. It was demonstrated that biochemical and molecular methods were 99.3% consistent in identifying M. guilliermondii. The Wild-Type (WT) Minimum Inhibitory Concentrations (MICs) distribution of fluconazole, voriconazole, itraconazole, and flucytosine were determined using the Sensititre YeastOne YO2V system after 24h of incubation. One M. guilliermondii strain was determined to be non-WT for fluconazole, voriconazole, itraconazole and flucytosine. In total, three M. guilliermondii strains, for fluconazole, were determined to be non-WT in this study. PMID- 28843336 TI - The effect of Trimetazidine and Diazoxide on immunomodulatory activity of human embryonic stem cell-derived mesenchymal stem cell secretome. AB - Comprehensive proteome profiling of the factors secreted by mesenchymal stem cells (MSCs), referred to as secretome, revealed that it consists of cytokines, chemokines, growth factors, extracellular matrix proteins, and components of regeneration, vascularization, and hematopoiesis pathways. Harnessing this MSC secretome for therapeutic applications requires the optimization of production of secretary molecules. A variety of preconditioning methods have been introduced, which subject cells to stimulatory molecules to create the preferred response and stimulate persistent effects. Pharmacological preconditioning uses small molecules and drugs to increase survival of MSCs after transplantation or prolong release of effective secretary factors such as cytokines that improve immune system responses. In this study, we investigated the effect of secretome of human embryonic-derived mesenchymal stem cells (hESC-MSCs) preconditioned with Trimetazidine (TMZ) and Diazoxide (DZ) on immunomodulatory efficiency of these cells in LPS-induced peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from human peripheral blood and treated with concentrated hESC-MSC derived conditioned medium and then, the secreted levels of IL-10, TNFalpha and IL-1beta were assessed by ELISA after induction with LPS. The results showed that TMZ and DZ-conditioned medium significantly enhanced immunomodulatory potential of hESC-MSCs by increasing the secretion of IL-10, TNFalpha and IL-1beta from LPS induced PBMCs. We also found that hESC-MSCs did not secrete mentioned cytokines prior to or after the preconditioning with TMZ and DZ. In conclusion, our results implied that TMZ and DZ can be used to promote the immunomodulatory effects of hESC-MSC secretome. It is obvious that for applying of these findings in clinical demands, the potency of different pre-conditioned MSCs secretome on immune response needs to be more clarified. PMID- 28843338 TI - Trauma and the structuring of complex care: Back to the settlements? Commentary on Thompson-Lastad et al. (2017). PMID- 28843337 TI - Up-regulation of TRAF2 Suppresses Neuronal Apoptosis after Rat Spinal Cord Injury. AB - Tumor necrosis factor receptor-associated factor 2 (TRAF2) for signal transduction of the cell death receptor is well established. However, the role of TRAF2 in spinal cord injury (SCI) remains unclear. In this study, we detected the dynamic change patterns of TRAF2 expression using an acute spinal cord contusion (SCC) model in adult rats. Western blot analysis and immunohistochemistry identified significant upregulation of TRAF2 after SCI. Double-immunofluorescent staining demonstrated that the upregulated TRAF2 was found predominantly in neurons. Moreover, colocalization of TRAF2 with active caspase-3/-8 was detected in NeuN-positive cells. In vitro, we analyzed the association of TRAF2 with active caspase-3/8 on PC12 cells by western blot analysis, which paralleled the in vivo data. Knockdown ofTRAF2 with siRNA demonstrated its probable anti apoptotic role in the process of neuronal apoptosis after SCI. To summarize, we have revealed for the first time the temporal and spatial expression profile of TRAF2 in SCI. Our data suggest that upregulation of TRAF2 triggered by trauma plays an important role in suppressing neuronal apoptosis after SCI. PMID- 28843339 TI - Chronic urinary retention after radical cystectomy and orthotopic neobladder in women: Risk factors and relation to time. AB - PURPOSE: To investigate the long-term cumulative incidence of chronic urinary retention (CUR) after radical cystectomy (RC) and orthotopic neobladder (ONB) in women and the possible risk factors. MATERIAL AND METHODS: We retrospectively analyzed a prospectively evaluated cohort of women for whom RC and ONB were performed. Patients in CUR were evaluated for the cumulative incidence of CUR using Kaplan-Meier curve and for the possible risk factors using log rank and Cox regression analysis. RESULTS: A total of 234 women with mean age +/- SD of 52.3 +/- 9 years and a median (range) of follow-up of 92 (12-247) months were included. The incidence of CUR increased with time, where 12 (5.2%), 21 (8.97%), 35 (14.9%), 53 (22.6%), and 56 (24%) patients started clean intermittent catheterization in 1, 2, 2 to 5 years, 5 to 10 years, and after 10 years of follow-up, respectively. In univariate and multivariate analysis, diabetes mellitus and urethral Kock pouch were independent predictors of CUR development (HR [95% CI] = 2.45 [1.2-5.1], and 2.1 [1.05-4.2], P = 0.01 and 0.03, respectively). Genital- sparing RC and surgical modification to provide pouch back support were independent factors that reduce CUR development (HR [95% CI] = 9.3 [1.25-69.9], and 2.1 [1.19-3.9], P = 0.02 and 0.01, respectively). CONCLUSION: The incidence of CUR after RC and ONB in women increases with time even after 10 years of follow-up. Presence of diabetes mellitus increases the risk of CUR development. Genital-sparing RC and modification to prevent CUR reduced the likelihood of CUR development. PMID- 28843340 TI - Human TLR gene family members are differentially expressed in patients with urothelial carcinoma of the bladder. AB - PURPOSE: Toll-like receptors (TLRs) have an important role in the activation of both innate and adaptive immunity in response to pathogens and endogenous danger signals from damaged or dying cells. The aim of this study was to determine the relationship between urothelial carcinoma (UC) and TLR expression. BASIC PROCEDURES: Real-time polymerase chain reaction evaluation was made of the messenger RNA expression of TLRs 1-10 in 24 UC samples and 46 nontumoral bladder tissue samples. The levels of proinflammatory cytokines (IL-1beta, IL-6, and IL 8) in the urine samples were also determined with enzyme-linked immunosorbent assay. MAIN FINDINGS: TLR2-7 and TLR10 expressions were significantly higher in UC than in the control group (P<0.05 for all comparisons). No concordance was found between matched tumor tissue and urine samples in terms of TLR expression. IL-1beta, IL-6, and IL-8 levels were significantly higher in urine specimens of patients with UC (P = 0.033, P = 0.001, and P = 0.008, respectively). PRINCIPAL CONCLUSIONS: The results of this study demonstrated that the TLR gene expression profiles reflect the heterogeneity within UC. These results might also prompt further investigation to better understand the role of the TLR gene family expression in the tumor progression of UC. PMID- 28843342 TI - Readability of online materials for Dupuytren's contracture. AB - STUDY DESIGN: Descriptive. BACKGROUND: Dupuytren's contracture is a common disorder involving fibrosis of the palmar fascia. As patients are increasingly using online materials to gather health care information, it is imperative to assess the readability and appropriateness of this content. The recommended grade level for patient educational materials is seventh to eighth grade according to the National Institutes of Health. This study aims to assess the readability and content of online patient resources for Dupuytren's contracture. PURPOSE OF THE STUDY: Evaluate readability of online patient education materials for Dupuytren's contracture. METHODS: The largest public search engine, Google, was queried using the term "Dupuytren's contracture surgery" on February 26, 2016. Location filters were disabled, and sponsored results were excluded to avoid any inadvertent search bias. The 10 most popular Web sites were identified, and all relevant patient-directed information within 1 click from the original site was downloaded and saved as plain text. Readability was analyzed using 6 established analyses (Readable.io, Added Bytes, Ltd, UK). RESULTS: Analysis of 10 Web sites demonstrates an average grade level of at least 11th grade (Flesch-Kincaid grade level, 10.2; Gunning-Fog grade level, 13.1; Coleman-Liau grade level, 14.4; Simple Measure of Gobbledygook grade level, 10.0; automated readability grade level, 9.7; and average grade level, 11.5). Overall Flesch-Kincaid reading ease index was 46.4, which is difficult. No single article was at the recommended reading level. CONCLUSIONS: Online materials available for treatment of Dupuytren's contracture are above recommended reading levels and do not include a comprehensive explanation of treatment options, which may negatively impact decision making in patients seeking treatment for this condition. Surgeons and hand therapists alike should be cognizant of available online patient materials and make efforts to develop and provide more appropriate materials. LEVEL OF EVIDENCE: V. PMID- 28843341 TI - Artificial grammar learning in vascular and progressive non-fluent aphasias. AB - Patients with non-fluent aphasias display impairments of expressive and receptive grammar. This has been attributed to deficits in processing configurational and hierarchical sequencing relationships. This hypothesis had not been formally tested. It was also controversial whether impairments are specific to language, or reflect domain general deficits in processing structured auditory sequences. Here we used an artificial grammar learning paradigm to compare the abilities of controls to participants with agrammatic aphasia of two different aetiologies: stroke and frontotemporal dementia. Ten patients with non-fluent variant primary progressive aphasia (nfvPPA), 12 with non-fluent aphasia due to stroke, and 11 controls implicitly learned a novel mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships. We compared response profiles for otherwise identical sequences of speech tokens (nonsense words) and tone sweeps. In all three groups the ability to detect grammatical violations varied with sequence complexity, with performance improving over time and being better for adjacent than non-adjacent relationships. Patients performed less well than controls overall, and this was related more strongly to aphasia severity than to aetiology. All groups improved with practice and performed well at a control task of detecting oddball nonwords. Crucially, group differences did not interact with sequence complexity, demonstrating that aphasic patients were not disproportionately impaired on complex structures. Hierarchical cluster analysis revealed that response patterns were very similar across all three groups, but very different between the nonsense word and tone tasks, despite identical artificial grammar structures. Overall, we demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently. The similarity of profiles of discriminatory abilities and rule learning across groups suggests that insights from previous studies of implicit sequence learning in vascular aphasia are likely to prove applicable in nfvPPA. PMID- 28843344 TI - Novel common variants associated with body mass index and coronary artery disease detected using a pleiotropic cFDR method. AB - Genome-wide association studies (GWAS) have been successfully applied in identifying single nucleotide polymorphisms (SNPs) associated with body mass index (BMI) and coronary heart disease (CAD). However, the SNPs to date can only explain a small percentage of the genetic variances of traits. Here, we applied a genetic pleiotropic conditional false discovery rate (cFDR) method that combines summary statistic p values from different multi-center GWAS datasets, to detect common genetic variants associated with these two traits. The enrichment of SNPs associated with BMI and CAD was assessed by conditional Q-Q plots and the common variants were identified by the cFDR method. By applying the cFDR level of 0.05, 7 variants were identified to be associated with CAD (2 variants being novel), 34 variants associated with BMI (11 variants being novel), and 3 variants associated with both BMI and CAD (2 variants being novel). The SNP rs653178 (ATXN2) is noteworthy as this variant was replicated in an independent analysis. SNP rs12411886 (CNNM2) and rs794356 (HIP1) were of note as the annotated genes may be associated with processes that are functionally important in lipid metabolism. In conclusion, the cFDR method identified novel variants associated with BMI and/or CAD by effectively incorporating different GWAS datasets. PMID- 28843345 TI - Cyclosporine-immunosuppression does not affect survival of transplanted skin derived precursor Schwann cells in the injured rat spinal cord. AB - A major goal of Schwann cell (SC) transplantation for spinal cord injury (SCI) is to fill the injury site to create a bridge for regenerating axons. However, transplantation of peripheral nerve SCs requires an invasive biopsy, which may result in nerve damage and donor site morbidity. SCs derived from multipotent stem cells found in skin dermis (SKP-SCs) are a promising alternative. Regardless of source, loss of grafted SCs post-grafting is an issue in studies of regeneration, with survival rates ranging from ~1 to 20% after >=6 weeks in rodent models of SCI. Immune rejection has been implicated in these low survival rates. Therefore, our aim was to explore the role of the immune response on grafted SKP-SC survival in Fischer rats with a spinal hemisection injury. We compared SKP-SC survival 6 weeks post-transplantation in: (I) cyclosporine immunosuppressed rats (n=8), (II) immunocompetent rats (n=9), and (III) rats of a different sub-strain than the SKP-SC donor rats (n=7). SKP-SC survival was similar in all groups, suggesting immune rejection was not a main factor in SKP SC loss observed in this study. SKP-SCs were consistently found on laminin expressed at the injury site, indicating detachment-mediated apoptosis (i.e., anoikis) might play a major role in grafted cell loss. PMID- 28843346 TI - Beyond the critical point: An overview of excitotoxicity, calcium overload and the downstream consequences. AB - Over the past several decades, an overwhelming body of research has greatly expanded our understanding of the mechanisms underlying excitotoxicity in brain ischemia as well as in many chronic neurodegenerative diseases. The identification of an array of molecular targets has opened avenues for neuroprotective strategies and, consequently, has sparked considerable interest for their attractive therapeutic means as pharmacological options. The purpose of this work is to provide a general overview of neuronal excitotoxicity and the inevitable downstream consequences of Ca2+ overload. We also discuss the contribution of Ca2+ transporters in excitotoxicity. This article is part of a Special Issue entitled "Calcium Pumps and Exchangers in Neuronal Injury and Neurodegeneration". PMID- 28843347 TI - Poly(glycerol adipate) - indomethacin drug conjugates - synthesis and in vitro characterization. AB - The linear biodegradable polyester poly(glycerol adipate) (PGA) was synthesized via enzymatic polycondensation using lipase B from Candida antarctica (CAL-B). Every monomer unit of PGA possesses a pendant hydroxyl group which is responsible for the hydrophilic character and moisture swelling. These OH groups were esterified to different degrees with the anti-inflammatory drug indomethacin in order to create a prodrug with a pH-sensitive linker for modified drug release. The structure of the conjugates was determined via ATR FT-IR spectroscopy, NMR spectroscopy, GPC and UV/VIS spectroscopy. The physical properties of polymers with different drug load were investigated using DSC, contact angle measurements and oscillatory rheology. Drug release was monitored over one month in vitro. A very slow, but continuous release was observed in PBS. Slightly acidic conditions and lipase activity are accelerating the indomethacin release. Therefore, poly(glycerol adipate) - indomethacin conjugates are promising prodrugs for the local sustained release of indomethacin. PMID- 28843343 TI - The 3 Cs of Antibiotic Allergy-Classification, Cross-Reactivity, and Collaboration. AB - Antibiotic allergy labeling is highly prevalent and negatively impacts patient outcomes and antibiotic appropriateness. Reducing the prevalence and burden of antibiotic allergies requires the engagement of key stakeholders such as allergists, immunologists, pharmacists, and infectious diseases physicians. To help address this burden of antibiotic allergy overlabeling, we review 3 key antibiotic allergy domains: (1) antibiotic allergy classification, (2) antibiotic cross-reactivity, and (3) multidisciplinary collaboration. We review the available evidence and research gaps of currently used adverse drug reaction classification systems, antibiotic allergy cross-reactivity, and current and future models of antibiotic allergy care. PMID- 28843348 TI - From smart materials to advanced drug delivery systems. PMID- 28843349 TI - Effects of crystal habit on the sticking propensity of ibuprofen-A case study. AB - This study demonstrates the effect of active pharmaceutical ingredient (API) particle habit on the sticking propensity of ibuprofen. Four diverse crystal habits with similar physico chemical properties are reported and the sticking propensity was found to increase with shape regularity. The surface energy of the extreme habits were shown to be different where particles that were more regular in shape exhibited surface energies of 9mJ/m2 higher than those that were needle like in habit. Computational and experimental data reveals that the increase in surface energy of the regular shaped particles can be attributed to the increase in the specific (polar) component, which is due to greater presence of faces which contain the carboxylic acid functionality at the surface. The increase in the specific energy component is shown to correlate with the sticking propensity of ibuprofen. It is proposed that investigation of the chemical causality of sticking, for this API and others, using the techniques demonstrated in this paper will be of increasing importance. PMID- 28843350 TI - Kyasanur forest disease: Another flavivirus requiring more research? Results of a bibliometric assessment. PMID- 28843351 TI - Effect of Polysorbate 20 and Polysorbate 80 on the Higher-Order Structure of a Monoclonal Antibody and Its Fab and Fc Fragments Probed Using 2D Nuclear Magnetic Resonance Spectroscopy. AB - We examined how polysorbate 20 (PS20; Tween 20) and polysorbate 80 (PS80; Tween 80) affect the higher-order structure of a monoclonal antibody (mAb) and its antigen-binding (Fab) and crystallizable (Fc) fragments, using near-UV circular dichroism and 2D nuclear magnetic resonance (NMR). Both polysorbates bind to the mAb with submillimolar affinity. Binding causes significant changes in the tertiary structure of mAb with no changes in its secondary structure. 2D 13C-1H methyl NMR indicates that with increasing concentration of polysorbates, the Fab region showed a decrease in crosspeak volumes. In addition to volume changes, PS20 caused significant changes in the chemical shifts compared to no changes in the case of PS80. No such changes in crosspeak volumes or chemical shifts were observed in the case of Fc region, indicating that polysorbates predominantly affect the Fab region compared to the Fc region. This differential effect of polysorbates on the Fab and Fc regions was because of the lesser thermodynamic stability of the Fab compared to the Fc. These results further indicate that PS80 is the preferred polysorbate for this mAb formulation, because it offers higher protection against aggregation, causes lesser structural perturbation, and has weaker binding affinity with fewer binding sites compared to PS20. PMID- 28843353 TI - Corrigendum to "Ethical language and decision-making for prenatally diagnosed lethal malformations" [Semin Fetal Neonatal Med 19 (5) (2014) 306-311]. PMID- 28843352 TI - Effects of rehabilitation training on apoptosis of nerve cells and the recovery of neural and motor functions in rats with ischemic stroke through the PI3K/Akt and Nrf2/ARE signaling pathways. AB - This study was designed in order to investigate the effects between rehabilitation training on the apoptosis of nerve cells and the recovery of neural and motor functions of rats with ischemic stroke by way of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and nuclear factor E2 related factor 2/antioxidant responsive element (Nrf2/ARE) signaling pathways. In total, 110 healthy adult male Sprague-Dawley (SD) rats were selected in order to take part in this study. Ninety SD rats were used in order to establish the middle cerebral artery occlusion (MCAO), among which 80 rats were randomly assigned as part of the natural recovery, natural recovery+Rp-PI3K (the rats injected with PI3K/Akt inhibitor LY294002), rehabilitation training, and rehabilitation training+Rp-PI3K groups. Meanwhile, 20 rats were selected as part of the sham operation group. The neural and motor functions of these rats were evaluated using a balance beam test and the Bederson score. The mRNA expressions of PI3K, Akt, Nrf2 and HO-1 were measured using an RT-qPCR. The protein expressions of PI3K, p-PI3K, Akt, p-Akt, Nrf2 and HO-1 were also detected by using western blotting and the immunohistochemistry process. The cell cycle and cell apoptosis were detected by using a flow cytometry and TUNEL assay. The sham operation group exhibited lower neural and motor function scores than other groups. At the 7, 14, and 21 d marks of this study, the neural and motor function scores were increased in the natural recovery, natural recovery+Rp-PI3K, and rehabilitation training+Rp-PI3K groups in comparison with the rehabilitation training group but found to be decreased in the natural recovery group in comparison with the natural recovery+Rp-PI3K group. In comparison with the sham operation group, expressions of PI3K, Nrf2 and HO-1, and proportions of p PI3K/PI3K and p-Akt/Akt were all higher in the natural recovery, rehabilitation training, and rehabilitation training+Rp-PI3K groups. Same trends were found in the rehabilitation training group in comparison with the natural recovery and rehabilitation training+Rp-PI3K groups, as well as in the natural recovery group in comparison with the natural recovery+Rp-PI3K group. In comparison with the sham operation and rehabilitation training groups, hippocampal nerve cells at G1 phase and the cells apoptosis were both elevated in the other three groups which were found to be decreased in the natural recovery group in comparison with the natural recovery+Rp-PI3K group. Our results indicated that the rehabilitation training can inhibit the apoptosis of nerve cells as well as promote the recovery of both neural Rehabilitation training in rats with IS. PMID- 28843354 TI - Reply. PMID- 28843355 TI - The Blind Firing Squad. PMID- 28843356 TI - Heterogeneity in Definitions of Endpoints for Clinical Trials of Ulcerative Colitis: A Systematic Review for Development of a Core Outcome Set. AB - BACKGROUND & AIMS: Advances in development of therapeutic agents for ulcerative colitis (UC) have been paralleled by innovations in trial design. It would be useful to identify a core outcome set, to standardize outcome definitions for efficacy and safety in clinical trials. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled randomized controlled trials of patients with UC. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017, for placebo-controlled randomized controlled trials of adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. We collected information on efficacy and safety outcomes, definitions, and measurement tools, stratified by decade of publication. RESULTS: We analyzed data from 83 randomized controlled trials (68 induction and 15 maintenance) comprising 17,737 patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the UC Disease Activity Index and Mayo Clinic Score were frequently used to determine clinical response or remission. We found substantial variation in definitions of clinical or composite-clinical endpoints, with more than 50 definitions of response or remission. Endoscopic factors, histologic features, and fecal or serum biomarkers were used to determine outcomes in 83.1% (69 of 83), 24.1% (20 of 83), and 24.1% (20 of 83) of trials, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints were found. Patient reported efficacy and quality-of-life outcomes were described in 25 trials (30.1%) and safety outcomes were reported in 77 trials (92.8%). CONCLUSION: In a systematic review, we found that despite recent advances in clinical trials methods, there is a great deal of variation in definitions of endpoints, including response and remission, in randomized controlled trials of patients with UC. Researchers should identify a core set of outcomes to standardize efficacy and safety reporting in UC clinical trials. PMID- 28843358 TI - Baseline and On-Treatment Characteristics of Serum Tumor Markers in Stage IV Oncogene-Addicted Adenocarcinoma of the Lung. AB - INTRODUCTION: The role of serum tumor markers in the modern management of advanced NSCLC remains poorly described. METHODS: A single-center retrospective analysis of available carcinoembryonic antigen, CA125, CA19.9, and CA27.29 levels at baseline and during treatment of stage IV lung adenocarcinoma by oncogenic driver was conducted. RESULTS: A total of 142 patients were analyzed (60 with anaplastic lymphoma kinase gene [ALK] rearrangement, 50 with EGFR mutation, four with ROS1 rearrangement, and 29 with KRAS mutation). Of these, 82% had at least one marker (95% if all four markers were measured), with CA27.29 being the most commonly increased and CA19.9 the rarest. Only CA27.29 differed significantly by oncogene (it was less common in KRAS) (p = 0.016). The median times to nadir during tyrosine kinase inhibitor (TKI) therapy in EGFR and ALK cases were 16.4 and 20 weeks, respectively. Of the 41 patients with EGFR mutation or ALK or ROS1 rearrangement, 24 (59%) demonstrated an initial increase within the first 4 weeks of TKI therapy, 58% of whom then had their levels fall below baseline. An increase in marker level of 10% or more from nadir occurred in 53% of systemic and 22% of central nervous system-only progression. CONCLUSIONS: Serum tumor markers are frequently increased in lung adenocarcinoma regardless of driver oncogene. Changes within the first 4 weeks of therapy may be misleading. Progression is associated with marker increases, especially in sites other than the central nervous system. PMID- 28843357 TI - The Role of Thoracic Surgery in the Therapeutic Management of Metastatic Non Small Cell Lung Cancer. AB - INTRODUCTION: In most patients with NSCLC, the disease is diagnosed in an advanced stage, the prognosis is poor, and survival is typically measured in months. Standard therapeutic treatment regimens for patients with stage IV NSCLC typically include chemotherapy and palliative radiation. Despite newer regimens that may include molecularly targeted therapy and immunotherapy, the overall 5 year survival for stage IV disease remains low at 4% to 6%. Although therapeutic surgery is performed in a minority of cases, accumulating data suggest that thoracic surgery may play several beneficial roles for these patients. METHODS: In this narrative review, we summarize the literature on surgical intervention in the multimodality management of stage IV NSCLC, focusing on the potential evidence for and against therapeutic or curative intent procedures to affect outcomes for patients with oligometastatic disease and pleural metastasis. RESULTS: In selected patients, surgical resection can result in a 5-year survival rate of 30% to 50%, but this is heavily influenced by the presence of mediastinal nodal disease, which should be evaluated before therapeutic surgical procedures are undertaken. Additionally, diagnostic or palliative surgical procedures can play an important role in the personalized management of stage IV disease. These data suggest that for carefully selected patients with advanced stage NSCLC, surgical intervention can be an important component of combined modality treatment. CONCLUSIONS: Given the advances in molecular targeted therapy and immunotherapy, further studies should focus on the possible use of surgery as a strategy of therapeutic "consolidation" for appropriately selected patients with stage IV NSCLC who are receiving combined modality care. PMID- 28843359 TI - Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non-Small Cell Lung Cancer. AB - INTRODUCTION: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has demonstrated efficacy in tumors harboring the EGFR T790M resistance mutation. Inevitably, resistance to third-generation inhibitors results in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. On the basis of preclinical data, we report what is the first known case of a patient harboring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib. METHODS: On development of progressive disease after multiple therapies, the patient's plasma was sequenced using the Oncomine Lung cfDNA Assay (Thermo Fisher Scientific, Waltham, MA). Subsequent monitoring of circulating tumor DNA in plasma was performed by droplet digital polymerase chain reaction. RESULTS: Sequencing showed that the T790M and C797S mutations were in trans. Within 2 weeks of commencement of combination therapy, rapid clinical improvement occurred. Accompanying this, a rapid decline in the C797S mutation subclone in plasma was detected. However, the levels of the EGFR exon 19 deletion driver mutation and the T790M resistance mutation in the circulating tumor DNA continued to rise and the patient died from progressive disease 6 weeks after commencement of combination therapy. There were no adverse events seen with the combination therapy. CONCLUSION: This is, to the best of our knowledge, the first reported case of combination EGFR tyrosine kinase inhibitor therapy tailored to the allelic conformation of T790M and C797S mutation that resulted in brief clinical improvement without toxicity. PMID- 28843360 TI - Prognostic Value of Primary Tumor Volume Changes on kV-CBCT during Definitive Chemoradiotherapy for Stage III Non-Small Cell Lung Cancer. AB - INTRODUCTION: Kilovoltge cone beam computed tomography (kV-CBCT) allows for tumor localization and response assessment during definitive chemoradiotherapy for locally advanced NSCLC. We hypothesize that significant tumor volume loss occurs early during radiotherapy and that the extent of volume loss correlates with clinical outcomes. METHODS: A total of 52 patients with locally advanced NSCLC treated with definitive chemoradiotherapy were reviewed. kV-CBCT images were used to contour primary gross tumor volumes at four time points during treatment. Patients were dichotomized according to absolute and relative volume changes at each time point. Statistical analyses were performed to evaluate correlations between volume changes and clinical outcomes. RESULTS: The median gross tumor volumes were 77.1, 48.3, 42.5, and 29.9 cm3 for fractions 1, 11, 21, and final, respectively. Greater relative volume loss between fractions 1 and 21 correlated with improved distant control (hazard ratio [HR] = 0.35, 95% confidence interval [CI]: 0.13-0.94, p = 0.038) and overall survival (HR = 0.40, 95% CI: 0.16-0.98, p = 0.046). Greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.17-0.88, p = 0.02) and trended toward improved overall survival (HR = 0.43, 95% CI: 0.17-1.06, p = 0.07). On multivariate analysis, greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.16-0.97, p = 0.041) and overall survival (HR = 0.31, 95% CI: 0.11-0.88, p = 0.027). CONCLUSIONS: Significant primary tumor volume loss occurs early during radiotherapy for locally advanced NSCLC. Greater relative tumor volume loss during treatment correlates with improved disease control and overall survival. Thus, kV-CBCT has potential to be used as a practical prognostic imaging marker. PMID- 28843361 TI - Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma. AB - INTRODUCTION: Although lung cancer is generally thought to be environmentally provoked, anecdotal familial clustering has been reported, suggesting that there may be genetic susceptibility factors. We systematically tested whether germline mutations in eight candidate genes may be risk factors for lung adenocarcinoma. METHODS: We studied lung adenocarcinoma cases for which germline sequence data had been generated as part of The Cancer Genome Atlas project but had not been previously analyzed. We selected eight genes, ATM serine/threonine kinase gene (ATM), BRCA2, DNA repair associated gene (BRCA2), checkpoint kinase 2 gene (CHEK2), EGFR, parkin RBR E3 ubiquitin protein ligase gene (PARK2), telomerase reverse transcriptase gene (TERT), tumor protein p53 gene (TP53), and Yes associated protein 1 gene (YAP1), on the basis of prior anecdotal association with lung cancer or genome-wide association studies. RESULTS: Among 555 lung adenocarcinoma cases, we detected 14 pathogenic mutations in five genes; they occurred at a frequency of 2.5% and represented an OR of 66 (95% confidence interval: 33-125, p < 0.0001 [chi-square test]). The mutations fell most commonly in ATM (50%), followed by TP53, BRCA2, EGFR, and PARK2. Most (86%) of these variants had been reported in other familial cancer syndromes. Another 12 cases (2%) carried ultrarare variants that were predicted to be deleterious by three protein prediction programs; these most frequently involved ATM and BRCA2. CONCLUSIONS: A subset of patients with lung adenocarcinoma, at least 2.5% to 4.5%, carry germline variants that have been linked to cancer risk in Mendelian syndromes. The genes fall most frequently in DNA repair pathways. Our data indicate that patients with lung adenocarcinoma, similar to other solid tumors, include a subset of patients with inherited susceptibility. PMID- 28843362 TI - National Cancer Database Report on Pneumonectomy Versus Lung-Sparing Surgery for Malignant Pleural Mesothelioma. AB - INTRODUCTION: Controversy exists regarding the optimal surgical technique for malignant pleural mesothelioma (MPM). We evaluated national practice patterns and outcomes of MPM treated with extrapleural pneumonectomy (EPP) versus lung-sparing extended pleurectomy/decortication (P/D). METHODS: The National Cancer Database was queried for patients with newly diagnosed MPM undergoing EPP or P/D. Multivariable logistic regression ascertained clinical factors independently associated with P/D receipt. Kaplan-Meier analysis was used to evaluate overall survival (OS) between cohorts; multivariable Cox proportional hazards modeling was used to evaluate factors associated with OS. Survival was then evaluated between propensity-matched populations. RESULTS: Overall, 1307 patients (271 undergoing EPP [21%] and 1036 undergoing P/D [79%]) met the criteria. Patients receiving P/D were older (p = 0.028), whereas those undergoing EPP were more likely to live in a rural area (p = 0.044), live farther from the treating facility (p = 0.039), and receive treatment at an academic center (p = 0.050). There were no differences between cohorts in 30-day readmission or mortality (all p > 0.05). The median OS times in the EPP and P/D groups were 19 versus 16 months, respectively (p = 0.120); no differences were observed after propensity matching (p = 0.540). CONCLUSIONS: In this largest analysis of its kind to date, findings from this contemporary cohort demonstrate that P/D comprised most surgical procedures for MPM. Procedure type was influenced by sociodemographic and geographical factors, without observed differences in survival or postoperative mortality and readmission rates between techniques. PMID- 28843363 TI - Pembrolizumab-Induced Encephalopathy: A Review of Neurological Toxicities with Immune Checkpoint Inhibitors. AB - The use of immune checkpoint inhibitor (ICI) therapy in the treatment of solid organ malignancies is becoming increasingly common. This has prompted the recognition of a new class of immune-related adverse effects (irAEs) stemming from the upregulation of T-cell activity causing autoimmunity. Neurological irAEs are a rare complication of ICIs that can lead to long-term morbidity. We report a rare case of encephalopathy after treatment with pembrolizumab, to which the patient achieved durable disease response despite discontinuation of therapy. We also review the pathophysiology, incidence, clinical presentation, diagnosis, and management of neurotoxicity secondary to ICIs. Treatment requires early administration of high-dose corticosteroids, and cessation of ICI therapy is often necessary after grade 3 or 4 irAEs. However, early data suggest that neurological irAEs correlate with a favorable disease response. Consideration should also be given to the optimal duration of ICI therapy to minimize the risk of toxicity and optimize health care expenditure. PMID- 28843364 TI - Reliability of the Minimum Basic Data Set as an Epidemiological Tool in Tuberculosis. PMID- 28843365 TI - Mediastinitis After Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration of a Follicular Dendritic Cell Sarcoma. PMID- 28843366 TI - Corrigendum to "Knemometry Assessment of Short-term Growth in Children with Asthma Receiving Fluticasone Furoate for 2 Weeks: A Randomized, Placebo controlled, Cross-over Trial" Clin Ther 2017;39:1191-1199. PMID- 28843367 TI - Transcatheter Tricuspid Valve-in-Valve Intervention for Degenerative Bioprosthetic Tricuspid Valve Disease. AB - Isolated reoperative tricuspid valve replacement is one of the highest risk operations classified in the Society of Thoracic Surgeons registry, particularly in the setting of preexisting right ventricular dysfunction. Transcatheter tricuspid valve-in-valve implantation represents an attractive alternative to redo surgery in patients with tricuspid bioprosthetic valve degeneration who are considered high-risk or unsuitable surgical candidates. In this review article, the authors discuss the emergence of transcatheter tricuspid valve-in-valve therapy, preprocedural echocardiographic assessment of tricuspid bioprosthetic valve dysfunction, periprocedural imaging required for tricuspid valve-in-valve implantation, and postprocedural assessment of tricuspid transcatheter device function. PMID- 28843368 TI - Echocardiographic Epicardial Adipose Tissue Thickness Is Associated with Symptomatic Coronary Vasospasm during Provocative Testing. AB - BACKGROUND: Epicardial adipose tissue (EAT) is the ectopic visceral fat surrounding the heart, which plays an important role in atherosclerosis of the coronary arteries via endothelial damage. Several studies have also suggested that vasospasm with angina (VSA) causes endothelial dysfunction in the coronary arteries. The aim of this study was to evaluate the thickness of EAT in the anterior interventricular groove (EAT-AIG) using echocardiography in patients who had no obstructive coronary artery disease and were suspected of having VSA. METHODS: Sixty-five patients who underwent intracoronary acetylcholine provocation testing for clinical indications were prospectively enrolled. VSA was diagnosed by coronary artery stenosis increase of >90% and the presentation of chest pain with ischemic changes on electrocardiography. RESULTS: Subjects were divided into two groups, with and without significant coronary spasm (VSA group, 30 patients; non-VSA group, 35 patients), consistent with acetylcholine provocation testing. EAT-AIG thickness was significantly greater in the VSA group than in the non-VSA group (8.2 +/- 2.7 vs 6.1 +/- 2.5 mm, P = .002). By receiver operating characteristic analysis, EAT-AIG thickness had a high C statistic (area under the curve = 0.81, P < .001) after adjustment for conventional risk factors (smoking, diabetes mellitus, and dyslipidemia). EAT-AIG thickness had incremental diagnostic value over other conventional risk factors (area under the curve = 0.81 vs 0.64, P for comparison = .020). CONCLUSIONS: EAT-AIG thickness, which is noninvasively and easily measured using transthoracic echocardiography, can be one of multiple clinical variables associated with VSA. PMID- 28843369 TI - Microbial ecology of cereal vinegar fermentation: insights for driving the ecosystem function. AB - Over thousands of years, humans have mastered the natural vinegar fermentation technique of cultivating functional microbiota on different raw materials. Functional microbial communities that form reproducibly on non-autoclaved raw materials through repeated batch acetic acid fermentation underpin the flavour development of traditional cereal vinegars. However, how to modulate rationally and optimise the metabolic function of these naturally engineered acidic ecosystems remains unclear. Exploring two key minorities in a vinegar ecosystem, including microbial functions (e.g., flavour and aroma synthesis) and microbial strains, is a crucial step for the vinegar industry to modulate the metabolic function of vinegar microbiota, to monitor the fermentation process, and to maintain the flavour quality of final product. PMID- 28843370 TI - A Phase 2 Study of Preoperative Capecitabine and Concomitant Radiation in Women With Advanced Breast Cancer. AB - PURPOSE: To examine the response rate of gross chemo-refractory breast cancer treated with concurrent capecitabine (CAP) and radiation therapy in a prospective Phase II study. METHODS AND MATERIALS: Breast cancer patients with inoperable disease after chemotherapy, residual nodal disease after definitive surgical resection, unresectable chest wall or nodal recurrence after a prior mastectomy, or oligometastatic disease were eligible. Response by RECIST criteria was assessed after 45 Gy. Conversion to operable, locoregional control, and grade >=3 toxicities were assessed. The first 9 patients received CAP 825 mg/m2 twice daily continuously. Because of toxicity, subsequent patients received CAP only on radiation days. Kaplan-Meier analysis was used to estimate overall survival (OS) and locoregional recurrence-free survival. RESULTS: From 2009 to 2012, 32 patients were accrued; 26 received protocol-specified treatment. Median follow-up was 12.9 months (interquartile range, 7.10-42.9 months). Nineteen patients (73%) had partial or complete response. Fourteen patients (53.9%) experienced grade 3 non-dermatitis toxicity (7 of 9 continuous dosing). Three of four inoperable patients converted to operable. One-year actuarial OS in the treated cohort was 54%. The trial was stopped early after interim analysis suggested futility independent of response. Treatment was deemed futile (ie, conversion to operable but M1 disease immediately postoperatively) in 9 of 10 patients with triple negative (TN) versus 6 of 16 with non-TN disease (P=.014). Median OS and 1-year locoregional recurrence-free survival among non-TN versus TN patients was 22.8 versus 5.1 months, and 63% versus 20% (P=.007). CONCLUSIONS: Capecitabine can be safely administered on radiation days with careful clinical monitoring and was associated with encouraging response in this chemo-refractory cohort. However, patients with TN breast cancer had poor outcomes even when response was achieved. Further study in non-TN patients may be warranted. PMID- 28843371 TI - Pencil Beam Algorithms Are Unsuitable for Proton Dose Calculations in Lung. AB - PURPOSE: To compare analytic and Monte Carlo-based algorithms for proton dose calculations in the lung, benchmarked against anthropomorphic lung phantom measurements. METHODS AND MATERIALS: A heterogeneous anthropomorphic moving lung phantom has been irradiated at numerous proton therapy centers. At 5 centers the treatment plan could be calculated with both an analytic and Monte Carlo algorithm. The doses calculated in the treatment plans were compared with the doses delivered to the phantoms, which were measured using thermoluminescent dosimeters and film. Point doses were compared, as were planar doses using a gamma analysis. RESULTS: The analytic algorithms overestimated the dose to the center of the target by an average of 7.2%, whereas the Monte Carlo algorithms were within 1.6% of the physical measurements on average. In some regions of the target volume, the analytic algorithm calculations differed from the measurement by up to 31% in the internal gross target volume (iGTV) (46% in the planning target volume), over-predicting the dose. All comparisons showed a region of at least 15% dose discrepancy within the iGTV between the analytic calculation and the measured dose. The Monte Carlo algorithm recalculations showed dramatically improved agreement with the measured doses, showing mean agreement within 4% for all cases and a maximum difference of 12% within the iGTV. CONCLUSIONS: Analytic algorithms often do a poor job predicting proton dose in lung tumors, over predicting the dose to the target by up to 46%, and should not be used unless extensive validation counters the consistent results of the present study. Monte Carlo algorithms showed dramatically improved agreement with physical measurements and should be implemented to better reflect actual delivered dose distributions. PMID- 28843372 TI - Multisource Rotating Shield Brachytherapy Apparatus for Prostate Cancer. AB - PURPOSE: Our purpose is to present a novel multisource rotating shield brachytherapy (RSBT) apparatus for the simultaneous precise angular and linear positioning of partially shielded 153Gd brachytherapy sources in interstitial needles for the treatment of locally advanced prostate cancer. It is designed to lower the dose to nearby healthy tissues, the urethra in particular, relative to conventional high-dose-rate brachytherapy techniques. METHODS AND MATERIALS: Following needle implantation through the patient template, an angular drive mechanism is docked to the patient template. Each needle is coupled to a multisource afterloader catheter by a connector passing through a shaft. The shafts are rotated about their axes by translating a moving template between 2 stationary templates. The shafts' surfaces and moving template holes are helically threaded with the same pattern such that translation of the moving template causes simultaneous rotation of the shafts. The rotation of each shaft is mechanically transmitted to the catheter-source-shield combination, inside the needles, via several key-keyway pairs. The catheter angles are simultaneously incremented throughout treatment, and only a single 360 degrees rotation of all catheters is needed for a full treatment. For each rotation angle, source depth in each needle is controlled by a multisource afterloader, which is proposed as an array of belt-driven linear actuators, each of which drives a wire that controls catheter depth in a needle. RESULTS: Treatment plans demonstrated that RSBT with the proposed apparatus reduced urethral D0.1cm3 (the minimum dose delivered to the hottest 0.1cm3 of the urethra) below that of conventional high dose-rate brachytherapy by 31% for urethral dose gradient volume within 3 mm of the urethra surface. Treatment time to deliver 20 Gy with the proposed multisource RSBT apparatus by use of nineteen 62.4-GBq 153Gd sources was 122 minutes. CONCLUSIONS: The proposed RSBT delivery apparatus enables a mechanically feasible urethra-sparing treatment technique for prostate cancer in a clinically reasonable time frame. PMID- 28843373 TI - Prospective Clinical Implementation of a Novel Magnetic Resonance Tracking Device for Real-Time Brachytherapy Catheter Positioning. AB - PURPOSE: We designed and built dedicated active magnetic resonance (MR)-tracked (MRTR) stylets. We explored the role of MRTR in a prospective clinical trial. METHODS AND MATERIALS: Eleven gynecologic cancer patients underwent MRTR to rapidly optimize interstitial catheter placement. MRTR catheter tip location and orientation were computed and overlaid on images displayed on in-room monitors at rates of 6 to 16 frames per second. Three modes of actively tracked navigation were analyzed: coarse navigation to the approximate region around the tumor; fine tuning, bringing the stylets to the desired location; and pullback, with MRTR stylets rapidly withdrawn from within the catheters, providing catheter trajectories for radiation treatment planning (RTP). Catheters with conventional stylets were inserted, forming baseline locations. MRTR stylets were substituted, and catheter navigation was performed by a clinician working inside the MRI bore, using monitor feedback. RESULTS: Coarse navigation allowed repositioning of the MRTR catheters tips by 16 mm (mean), relative to baseline, in 14 +/- 5 s/catheter (mean +/- standard deviation [SD]). The fine-tuning mode repositioned the catheter tips by a further 12 mm, in 24 +/- 17 s/catheter. Pullback mode provided catheter trajectories with RTP point resolution of ~1.5 mm, in 1 to 9 s/catheter. CONCLUSIONS: MRTR-based navigation resulted in rapid and optimal placement of interstitial brachytherapy catheters. Catheters were repositioned compared with the initial insertion without tracking. In pullback mode, catheter trajectories matched computed tomographic precision, enabling their use for RTP. PMID- 28843374 TI - The Results of Low-Dose Total Skin Electron Beam Radiation Therapy (TSEB) in Patients With Mycosis Fungoides From the UK Cutaneous Lymphoma Group. AB - PURPOSE: Total skin electron beam radiation therapy (TSEB) is a very effective treatment of mycosis fungoides. Following reports of similar durations of response to lower doses of TSEB, a low-dose schedule of TSEB was introduced in the United Kingdom. METHODS AND MATERIALS: A protocol of 12 Gy in 8 fractions over a period of 2 weeks was agreed on by use of the Stanford University technique. Data were collected prospectively, and the results were analyzed according to the European Organisation for Research and Treatment of Cancer International Society for Cutaneous Lymphomas endpoints (EORTC-ISCL). Toxicity was scored according to CTCAE v4.0 (Common Terminology Criteria for Adverse Events version 4.0). RESULTS: One hundred three patients received treatment, with a median follow-up period of 20.6 months (range, 3.3-53 months). Of these patients, 54 had stage IB disease, 33 had stage IIB, 12 had stage III, and 4 had stage IV. The median age was 68 years (range, 26-91 years). The complete response rate was 18%, the partial response rate was 69%, stable disease was present in 8%, and progression on treatment was found in 5%. In the patients who had a complete response, the median time to relapse was 7.3 months. The median response duration was 11.8 months. Median progression-free survival for all patients was 13.2 months. It was significantly longer, at 26.5 months, in patients with stage IB disease compared with 11.3 months in patients with stage IIB (P=.003; hazard ratio, 2.66) and 10.2 months in patients with stage III (P=.002; hazard ratio, 4.62). The treatment was well tolerated with lower toxicity than higher-dose schedules. CONCLUSIONS: The low-dose TSEB schedule of 12 Gy in 8 fractions over a period of 2 weeks is well tolerated and is an effective option for patients with mycosis fungoides. PMID- 28843376 TI - Validation of the Eighth AJCC New Substages for Bladder Cancer Among Different Staging Contexts. AB - OBJECTIVES: To validate the prognostic value of the new American Joint Committee on Cancer (AJCC) staging system (eighth edition) among different staging contexts (clinical vs. pathologic). METHODS: Surveillance, Epidemiology, and End Results (SEER) database (2010-2014) was accessed through SEER*Stat program and both AJCC seventh and eighth edition stages were assigned for each patient. Overall and cancer-specific survival analyses according to both editions were conducted through Kaplan-Meier analysis. Concordance index (c-index) was assessed for each edition. RESULTS: A total of 7074 patients with pathologically staged and 26,698 with clinically staged urinary bladder carcinoma were identified in the period from 2010 to 2014. Among patients with pathologically staged disease without neoadjuvant treatment, P values for all pairwise comparisons among different stages (according to AJCC seventh and eighth systems) were significant for both overall and cancer-specific survivals (< .01). Moreover, within the same cohort, c-index (using death from urinary bladder cancer as the dependent variable) for AJCC seventh system was 0.714 (SE 0.008; 95% CI, 0.699-0.729); whereas the c index for the AJCC eighth system was 0.718 (SE 0.008; 95% CI, 0.702-0.733). Likewise, among patients with clinically staged disease, P values for all pairwise comparisons among different AJCC eighth stages were significant for overall survival (< .05) except for stage IIIA versus stage IIIB; whereas P values for all pairwise comparisons among different AJCC eighth stages were significant for cancer-specific survival (P < .05). CONCLUSION: This analysis supports the prognostic relevance of the added substages described within AJCC eighth edition stages III and IV for clinically staged and pathologically staged disease without neoadjuvant treatment. PMID- 28843375 TI - MR-OPERA: A Multicenter/Multivendor Validation of Magnetic Resonance Imaging-Only Prostate Treatment Planning Using Synthetic Computed Tomography Images. AB - PURPOSE: To validate the dosimetric accuracy and clinical robustness of a commercially available software for magnetic resonance (MR) to synthetic computed tomography (sCT) conversion, in an MR imaging-only workflow for 170 prostate cancer patients. METHODS AND MATERIALS: The 4 participating centers had MriPlanner (Spectronic Medical), an atlas-based sCT generation software, installed as a cloud-based service. A T2-weighted MR sequence, covering the body contour, was added to the clinical protocol. The MR images were sent from the MR scanner workstation to the MriPlanner platform. The sCT was automatically returned to the treatment planning system. Four MR scanners and 2 magnetic field strengths were included in the study. For each patient, a CT-treatment plan was created and approved according to clinical practice. The sCT was rigidly registered to the CT, and the clinical treatment plan was recalculated on the sCT. The dose distributions from the CT plan and the sCT plan were compared according to a set of dose-volume histogram parameters and gamma evaluation. Treatment techniques included volumetric modulated arc therapy, intensity modulated radiation therapy, and conventional treatment using 2 treatment planning systems and different dose calculation algorithms. RESULTS: The overall (multicenter/multivendor) mean dose differences between sCT and CT dose distributions were below 0.3% for all evaluated organs and targets. Gamma evaluation showed a mean pass rate of 99.12% (0.63%, 1 SD) in the complete body volume and 99.97% (0.13%, 1 SD) in the planning target volume using a 2%/2-mm global gamma criteria. CONCLUSIONS: Results of the study show that the sCT conversion method can be used clinically, with minimal differences between sCT and CT dose distributions for target and relevant organs at risk. The small differences seen are consistent between centers, indicating that an MR imaging only workflow using MriPlanner is robust for a variety of field strengths, vendors, and treatment techniques. PMID- 28843377 TI - Favorable Gleason 3 + 4 Prostate Cancer Shows Comparable Outcomes With Gleason 3 + 3 Prostate Cancer: Implications for the Expansion of Selection Criteria for Active Surveillance. AB - BACKGROUND: To investigate the feasibility of active surveillance (AS) in biopsy Gleason score (GS) 3 + 4 prostate cancer (PCa), we compared the outcomes of biopsy GS 3 + 3 and 3 + 4 PCa after radical prostatectomy. PATIENTS AND METHODS: We analyzed the data of 1491 patients undergoing radical prostatectomy for biopsy GS 3 + 3 or 3 + 4 PCa who fulfilled the low-risk criteria of the National Comprehensive Cancer Network guidelines regardless of GS. The favorable GS 3 + 4 group was defined as having core involvement <= 50%, prostate-specific antigen density <= 0.2 ng/mL/cm3, and number of positive cores <= 2 (maximal 1 core of GS 3 + 4). RESULTS: The GS 3 + 4 group showed significantly worse pathologic outcomes, including pathologic GS, pathologic stage, and seminal vesicle invasion rate (all P < .001), as well as worse biochemical recurrence-free survival (P < .001) than the GS 3 + 3 group. However, the favorable GS 3 + 4 subgroup showed no significant differences in the pathologic outcomes (all P > .05) and in biochemical recurrence-free survival (P = .817) compared to the GS 3 + 3 group. CONCLUSION: Despite the application of low-risk criteria, GS 3 + 4 PCa patients showed significantly worse outcomes than GS 3 + 3 patients. However, favorable GS 3 + 4 patients showed comparable clinicopathologic outcomes with GS 3 + 3 patients, suggesting possible expansion of AS for the favorable GS 3 + 4 group. PMID- 28843378 TI - Reply to the letter "Does vital exhaustion enhance our ability to predict type 2 diabetes?" written by Dr. Renzo Bianchi and Dr. Eric Laurent. PMID- 28843379 TI - Corrigendum to "Retinal thinning in Gaucher disease patients and carriers: Results of a pilot study" [Mol. Genet. Metab. 109 (2013) 221-223]. PMID- 28843380 TI - The impact of intensity-modulated radiation therapy plan normalization in the postprostatectomy setting-does it matter? AB - The International Commission on Radiation Units & Measurements -83 recommends prescribing intensity-modulated radiation therapy (IMRT) in a dose-volume manner. Despite this, clinical variation still exists in how prostate IMRT plans are prescribed. This study aims to investigate the impact of different plan normalization methods for postprostatectomy IMRT. IMRT treatment plans were created retrospectively for 20 postprostatectomy patients. These were normalized such that the dose received by 98% (D98) of the planning target volume (PTV) was equal to 100% of the prescribed dose. All plans were individually optimized to achieve target coverage and organ at risk (OAR) dose constraints. Each patient's plan was then copied and normalized such that the mean dose (Dmean) received by the PTV was equal to 100% of the prescribed dose. The International Commission on Radiation Units & Measurements -83 recommended dosimetric end points were extracted for targets and Quantitative Analyses of Normal Tissue Effects in the Clinic or Radiation Therapy Oncology Group 0534 end points extracted for OARs. Statistical analysis using the Wilcoxon signed-rank test to measure the difference between data from plans normalized to D98 and Dmean was conducted. Extracted dosimetric end points of the targets and OARs were significantly higher in plans normalized to D98 than Dmean (p < 0.05) with the exceptions of D2 of the rectum and right femoral head. Normalization impacts on dosimetric end points of a plan. Hence, reporting the normalization method used is necessary to allow for meaningful interpretation of IMRT dosimetric studies. PMID- 28843381 TI - Corrigendum to "Treatment of Breast and Prostate Cancer by Hypofractionated Radiotherapy: Potential Risks and Benefits" [Clin Oncol 27 (7) (2015) 420-426]. PMID- 28843382 TI - Performing the Parryscope technique gently for office tubal patency assessment. AB - OBJECTIVE: To demonstrate a novel approach to office tubal patency assessment through infusing air into saline during flexible office hysteroscopy. We also provide data addressing pain and patient experience relative to hysterosalpingography (HSG). DESIGN: Video presentation of clinical technique with supportive crossover data (Canadian Task Force classification II-1). Its University of Mississippi Medical Center Institutional Review Board protocol number is 2013-0230. SETTING: Academic hospital. PATIENT(S): Women undergoing office hysteroscopy and ultrasound, with a subset also having HSG. INTERVENTION(S): Air infusion into saline during office hysteroscopy. MAIN OUTCOME MEASURE(S): The focus is on demonstrating how the technique appears and is performed, with supplemental Likert data addressing subjective pain and preference relative to HSG. RESULT(S): When performed as described, this office technique has 98.3%-100% sensitivity to tubal occlusion and 83.7% specificity. The gentle technique is central to accurate outcomes, which is facilitated through use of a small-caliber (<3 mm), flexible hysteroscope and avoiding uterine overdistention. Patients are far more likely to report maximum discomfort with HSG. Among patients who also had HSG, 92% somewhat or strongly prefer hysteroscopic assessment. Also, 96% of patients reporting maximum discomfort with HSG had mild to no discomfort with the described technique. CONCLUSION(S): Air infused saline at flexible office hysteroscopy can accurately, gently, and rapidly assess tubal patency. Coupled with strong patient preference for this technique over HSG, it is a promising option for evaluating fertility. CLINICAL TRAIL REGISTRATION NUMBER: NCT02005263. PMID- 28843383 TI - IL-10-592 polymorphism is associated with IL-10 expression and severity of enterovirus 71 infection in chinese children. AB - BACKGROUND: Enterovirus 71 (EV71) infection results in some severe complications with high mortality and disability in Hand, Foot and Mouth Disease (HFMD) in children. Recent studies have shown that cytokine genetic predispositions have associations with both the development of EV71 infection and severity of HFMD. OBJECTIVE: This study was designed to investigate whether the IL-10-592 polymorphism is associated with IL-10 levels and disease severity in Chinese children with EV71 infection. STUDY DESIGN: In patients selected, there were 378 cases with EV71 infection (including 291 mild cases, 70 severe cases and 17 critical cases), as well as 406 health controls. EV71 in serum was tested by RT PCR, and IL-10-592 genotype was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis techniques. RESULT: The IL-10 592C allele was observed with higher frequency in patients with critical EV71 infection (70.59%) compared with severe EV71 infection (41.43%, P<0.01), mild EV71 infection (43.81%, P<0.01) and healthy children (44.46%, P<0.01). The blood IL-10 levels of critical cases were significantly higher than severe cases, mild cases, and healthy children. Among all of the four groups, IL-10 levels in patients with genotype AA were significantly lower than those with genotypes AC+CC (t=4.86, P<0.05; t=2.30, P<0.05; t=3.44, P<0.05; t=5.58, P<0.05). CONCLUSION: IL-10-592C allele is associated with IL-10 expressions and the severity of EV71 infection in Chinese patients. PMID- 28843384 TI - Staging of recent HIV-1 infection using Geenius rapid confirmatory assay compared to INNO-LIA, New Lav and Blot 2.2 assays. AB - BACKGROUND: Besides confirmation of HIV seropositivity, Western Blot (WB) assays play an important role for identification of recent infection based on incomplete antibody reactivity and lack of p31 band. OBJECTIVES: We evaluated the capacities of the GeeniusTM HIV1/2 Confirmatory Assay (Bio-Rad), a new generation rapid confirmatory assay based on immune-chromatography and automated reading, for staging of HIV-1 infection. STUDY DESIGN: Sixteen samples collected during early HIV-1 infections (Fiebig stage III-VI) were tested using the Geenius assay, and compared to HIV Blot 2.2 WB assay (MP Diagnostics), New Lav Blot I WB assay (Bio Rad) and INNO-LIATM HIV I/II Score Dot Blot assay (Fujirebio). Results obtained with Geenius and INNO LIA in 47 newly diagnosed chronic HIV-1 infections were also compared. RESULTS: The p24 band was less frequently detected in early HIV-1 infections using the Geenius (3/16) compared to the New Lav (15/16, p<0.0001), INNO-LIA (13/16, p=0.0011), and Blot 2.2 (13/16, p=0.0011). Testing samples collected during chronic infection allowed to confirm that p31 band and complete Gag, Pol, Env profiles were less frequently observed using the Geenius assay compared to the INNO LIA assay (p=0.027 for p31, and p=0.0015 for complete profile). CONCLUSIONS: The Geenius assay is a simple and rapid test showing a high sensitivity to detect Env bands and to confirm HIV-1 seropositivity during the early phases of infection. However, this test is less suitable for distinguishing between later stages of acute and chronic infections because of a reduced sensitivity to detect the p31 and p24 bands compared to INNO LIA and New Lav assays. PMID- 28843385 TI - Erratum. PMID- 28843387 TI - On self-reported measurements: an epidemiologic perspective. PMID- 28843388 TI - Response. PMID- 28843389 TI - Impact Factor: A Curious and Capricious Metric. PMID- 28843390 TI - A mathematical model of cellular swelling in Neuromyelitis optica. AB - Neuromyelitis Optica (NMO) is a severe neuro-inflammatory disease of the central nervous system characterized by predominant damage to the optic nerve and of the spinal cord. The pathogenic antibody found in the majority of patients targets the AQP4 channels on astrocytic endfeet and causes the cells to swell. Although, the pathophysiology of the disease is broadly known, there are no specific targeted treatments for this process clinically available nor accurate prognostic markers both during attacks and for predicting long term neuronal damage. This lack is, in part, due to the rarity of the disease and its relatively recent pathogenic clarity. Hence, the ability to mathematically model the progress of the condition to test prospective therapies in silico would be a step forward. This paper combines state of the art models of cellular metabolism and cytotoxic oedema in neurons and astrocytes and augments it with a detailed characterization of water transport across the cellular membrane. In particular, we capture the process of perforation of the cell through the human complement cascade and resulting water and ionic fluxes. Simulating NMO by injecting its antibody and human complement into the extracellular space showed a 25% increase of the astrocytic volume after 12 h from onset. Most of the volume change occurred during the first 30 min of simulation with a peak volume change of 38%. The model was further adapted to simulate the therapeutic potential of CD59. It was found that there is a threshold of CD59 concentration that can prevent the swelling of astrocytes. Since the astrocyte volume changes mostly during the first hour, further experimental work should focus on this time scale to provide data for further model refinement and validation. PMID- 28843392 TI - Pro-social behaviour of ants depends on their ecological niche-Rescue actions in species from tropical and temperate regions. AB - Some ants display rescue behaviour, which is performed by nearby nestmates and directed at individuals in danger. Here, using several ant species, we demonstrate that rescue behaviour expression matches predicted occurrences based on certain aspects of species' ecological niches. Rescue occurred in sand dwelling ants exposed both to co-occurring antlion larvae, representing the threat of being captured by a predator, and to nest cave-ins, representing the threat of being trapped in a collapsed nest chamber. Rescue also occurred in forest groundcover ants exposed to certain entrapment situations. However, rescue never occurred in species associated with open plains, which nest in hardened soils and forage largely on herbaceous plants, or in ants living in close mutualistic relationships with their host plants. In addition, because we tested each species in two types of tests, antlion larva capture tests and artificial entrapment tests, we highlight the importance of accounting for test context in studying rescue behaviour expression. PMID- 28843391 TI - [Management of bone and mineral metabolism disorders before the dialysis stage remains still perfectible. Data from the French Phosphorus and Calcium Survey Photo-Graphe]. AB - Only limited data is available on the management of the chronic kidney disease associated bone and mineral metabolism disorder (CKD-MBD) in the pre-dialysis stages of CKD in France. A better knowledge of current management habits could lead to an improvement in the implementation of international recommendations (KDIGO). The 3rd version of the French Phosphorus and Calcium Survey Photo-Graphe (Sanofi) included a cohort of CKD stages 4 and 5 patients, whose aim was to examine the prevalence of CKD-MBD and the quality of its management in patients under the care of 62 nephrologists from over 20 geographical regions in France. The study started in October 2011, i.e. one year after patient enrollment. We examined in particular the percentage of patients presenting with laboratory parameter abnormalities indicative of CKD-MBD who were not receiving adequate treatment. A total of 456 patients with CKD stage 4 and 154 with CKD stage 5 were studied. Their mean age was 72.9+/-14.2 years, and male/female ratio was 58/42. KDIGO targets of serum PTH for CKD stages 4 and 5 were not achieved in respectively 80 and 84% of the patients, for serum calcium in 8 and 22% and for serum phosphate in 12 and 46%. As a potential explanation, insufficient therapy was estimated to account for respectively 45 and 60% of insufficiently controlled secondary hyperparathyroidism, and for 36% of persistent hyperphosphatemia in stage 5. It should be noted that 55.5 and 57.5% of patients were receiving native vitamin D. In this national observatory, the management of CKD-MBD stages 4 and 5 appears suboptimal, especially as regards the control of secondary hyperparathyroidism, which remained untreated in nearly 50% of the patients. Hyperphosphatemia was also common and inadequately controlled in CKD stage 5. To improve the management of CKD-MBD, nephrologists need to be more aware of the importance of aiming for recommended laboratory targets and how this can be achieved. PMID- 28843394 TI - Effect of Heart Failure Secondary to Ischemic Cardiomyopathy on Body Weight and Blood Pressure. AB - Both the obesity paradox and blood pressure (BP) paradox remain ill defined. Because both obesity and hypertension are well-known predictors of coronary artery disease (CAD) and acute heart failure (HF), in the present study, we compared the obesity paradox and the BP paradox between patients with acute HF with and without a history of CAD. A multicenter retrospective study was conducted on 3,204 consecutive patients with acute HF. Potential risk factors for in-hospital mortality were selected by univariate analyses; multivariate Cox regression analysis with backward stepwise selection was then used to identify significant factors. Kaplan-Meier survival curves and log-rank testing were used to compare in-hospital mortality between groups. Across the study cohort, 27% of patients had a history of CAD, and the all-cause in-hospital mortality rate was 5%. In-hospital mortality was significantly lower for patients with obesity than in those without obesity (log-rank, p = 0.033). However, this obesity paradox disappeared in the group with HF and CAD (log-rank, p = 0.740). In contrast, in hospital mortality was significantly lower for patients with high BP at admission, regardless of the presence of a history of CAD (log-rank, p <0.001 for both groups). In conclusion, a history of CAD canceled the obesity paradox in patients with acute HF, whereas the BP paradox persisted regardless of a history of CAD. PMID- 28843393 TI - Prospective Assessment of Frailty Using the Fried Criteria in Patients Undergoing Left Ventricular Assist Device Therapy. AB - Frail patients are more prone to adverse events after cardiac surgery, particularly after implantation of left ventricular assist devices. Thus, frailty assessment may help identify patients unlikely to benefit from left ventricular assist device therapy. The purpose was to establish a suitable measure of frailty in adults with end-stage heart failure. In a prospective cohort of 75 patients (age 58 +/- 12 years) with end-stage heart failure, we assessed the association between frailty (5-component Fried criteria) and the composite primary outcome of inpatient mortality or prolonged length of stay, as well as extubation status, time on ventilator, discharge status, and long-term mortality. Fried frailty criteria were met in 44 (59%) patients, but there was no association with the primary outcome (p = 0.10). However, an abridged set of 3 criteria (exhaustion, inactivity, and grip strength) was predictive of the primary outcome (odds ratio 2.9, 95% confidence interval 1.1 to 7.4), and of time to extubation and time to discharge. In patients with advanced heart failure, the 5-component Fried criteria may not be optimally sensitive to clinical differences. In conclusion, an abridged set of 3 frailty criteria was predictive of the primary outcome and several secondary outcomes, and may therefore be a clinically useful tool in this population. PMID- 28843395 TI - Patient Engagement Following Acute Myocardial Infarction and Its Influence on Outcomes. AB - The Patient Activation Measure (PAM) is a validated assessment tool that evaluates how engaged patients are in their own health care. The more engaged or "activated" patients are, the higher the score and the more likely they are to adhere to medical therapy and make healthy lifestyle choices. Little is known regarding patient activation in patients after an acute myocardial infarction. From March 2016 to December 2016, we administered PAM surveys to patients after myocardial infarction at the time of a clinic visit scheduled within 10 days of hospital discharge. Demographic and outcome data were collected. The primary outcome was defined as a composite end point of major medication errors, emergency department visits, and/or unplanned readmission. The secondary outcome was continued tobacco use after discharge. A total of 93 patients were enrolled and 39 (42%) were positive for the primary outcome. PAM scores ranged from 40.9 to 100 (median 62.6, interquartile range 56.0 to 72.1). In multivariable analysis, adjusting for age, gender, and burden of co-morbidities, patients with lower PAM scores were more likely to have the primary outcome (odds ratio 1.063, 95% confidence interval 1.020 to 1.109, p = 0.0041). Patients with lower PAM scores also were more likely to continue to use tobacco after discharge (odds ratio 1.060, 95% confidence interval 1.005 to 1.118, p = 0.0325). In conclusion, we found an association between lower PAM scores and subsequent adverse clinical outcomes, including unplanned readmissions. Further investigation into the potential effect of education and coaching interventions in patients with low PAM scores after acute myocardial infarction is warranted. PMID- 28843397 TI - Experimental validation of a 4D dose calculation routine for pencil beam scanning proton therapy. AB - Respiratory induced organ motion poses a major challenge for high-precision radiotherapy such as pencil beam scanning proton therapy (PBS). In order to employ PBS for target regions affected by respiratory motion, the implementation of dedicated motion mitigation techniques should be considered and residual uncertainties need to be assessed. For the latter purpose, a routine simulating the delivery of a scanned proton beam to a moving target was developed and implemented in the commercial treatment planning system RayStation. The time structure of the beam delivery was extracted from electronic irradiation protocols of the delivery system. Alternatively to electronic irradiation protocols, an empirical time model of the beam delivery was created to allow for prospective estimations of interplay effects between target motion and pencil beam scanning. The experimental validation of the routine was performed using a two-dimensional ionization chamber array and a dynamic phantom. A 4D CT data set, including 10 respiratory phases, provided the spatial temporal information about the phantom motion. The dosimetric comparison of the measured and the calculated dose distribution yielded gamma pass rates above 96% using a 3% dose difference and a 3mm distance to agreement criterion. Thus, a tool for the evaluation of interplay effects is available in a clinical software environment and patient specific quality assurance can be extended to dynamic treatment scenarios. PMID- 28843396 TI - Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility. AB - The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains(n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb susceptible L. (V.) panamensis. Our results substantiate that different mechanisms of drug resistance operate in laboratory adapted and clinical Leishmania strains, and provide evidence that parasite-mediated modulation of host cell gene expression of molecules involved in drug transport and metabolism could contribute to the mechanisms of drug resistance and susceptibility in Leishmania. PMID- 28843398 TI - Effect of HPV E6/E7 siRNA with Chemotherapeutic Agents on the Regulation of TP53/E2F Dynamic Behavior for Cell Fate Decisions. AB - Toxicity and resistance remain major challenges for advanced or recurrent cervical cancer therapies, as treatment requires high doses of chemotherapeutic agents. Restoration of TP53 and hypophosphorylated-retinoblastoma (pRB) proteins by human papillomavirus (HPV) E6/E7 siRNA sensitizes HPV-positive cervical cancer cells toward chemotherapeutic agents. Here, we investigated the therapeutic effects of E6/E7 siRNA on the dynamic behavior of TP53 and RB/E2F signaling networks in deciding the cell fate. The synergistic effect of HPV E6/E7 siRNA pool (SP) with chemotherapeutic agents on TP53 and RB/E2F signaling, proliferation, and apoptosis was analyzed in vitro and in vivo. Compared to the E6/E7 SP alone, E6/E7 SP with cisplatin treatment effectively restored TP53 and RB/E2F signaling and contributes to differences in cell fate, such as apoptosis or cell cycle arrest. We also developed a cellular dynamics model that includes TP53-RB/E2F dynamics and cell proliferation profiles, and confirmed its utility for investigating E6/E7 siRNA-based combination regimens. Using a dual reporter system, we further confirmed the cross talk between TP53 and RB/E2F signaling mechanisms. Treatment of E6/E7 SP cationic liposome (i.v.) with cisplatin and paclitaxel (i.p.) potentially inhibited tumor growth in BALB/c-nude mice. Altogether, our findings suggest that stabilization of TP53 and the RB/E2F repressor complex by E6/E7 SP combined with low-dose chemotherapy can effectively suppress tumor growth. PMID- 28843400 TI - Big data and surgery: The digital revolution continues. PMID- 28843399 TI - Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia. AB - B acute lymphoblastic leukemia (B-ALL) cells are distinctively vulnerable to endoplasmic reticulum (ER) stress. Recently, inhibition of p97 was shown to induce ER stress and subsequently cell death in solid tumors and in multiple myeloma. We investigated the role of a novel, orally available, p97 inhibitor (CB 5083; Cleave Biosciences) in B-ALL. CB-5083 induced a significant reduction in viability in 10 human B-ALL cell lines, harboring the most common fusion-genes involved in pediatric and adult B-ALL, with IC50s ranging from 0.34 to 0.76 MUM. Moreover, CB-5083 significantly reduced the colony formation of OP1 and NALM6 cells. Early and strong induction of apoptosis was demonstrated in BALL1 and OP1 cells, together with a robust cleavage of PARP. CB-5083 induced ER stress, as documented through: 1) prominent expression of chaperones (GRP78, GRP94, PDI, DNAJC3, and DNAJB9); 2) increased activation of IRE1-alpha, as demonstrated by the splicing of XBP1; and 3) activation of PERK, which resulted in a significant overexpression of CHOP, and its downstream genes. CB-5083 reduced the viability also in GRP78-/-, GRP94-/-, and XBP1-/- cells, suggesting that none of these proteins alone was strictly required for CB-5083 activity. Moreover, we showed that the absence of XBP1 (XBP1-/-) increased the sensitivity to CB-5083, leading to the hypothesis that XBP1 splicing counteracts the activity of CB-5083, probably mitigating ER stress. Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 cells. In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL. PMID- 28843401 TI - Dystonia: Then and now. AB - INTRODUCTION: Dystonia is a rare disorder that has undergone extensive scientific investigation leading to a transformation of understanding over the past century. METHODS: This manuscript was prepared through a review of relevant literature for each topic. RESULTS: Historically dystonia was considered the manifestation of psychiatric disorders. Subsequently, investigations have firmly established this as a neurological disorder. Though electrophysiological and imaging, dystonia is thought to arise from a loss inhibition of motor programs, defective sensorimotor integration and abnormal plasticity. The genetic studies in dystonia have revealed the hereditary nature of many forms of familial dystonia. Treatment of dystonia has focused primarily on botulinum toxin for focal and segmental dystonia and deep brain stimulation of the globus pallidus interna for generalized and medically refractory focal dystonia. CONCLUSION: The progress in dystonia in the past century has revised the concepts of this disorder, increased knowledge of genetics and underlying pathophysiology, and provides new therapeutic targets. To promote future research the development of diagnostic criteria, biomarkers and validated rating scales for each form of dystonia is essential. PMID- 28843402 TI - Temporomandibular joint reconstruction with stock and custom-made devices: Indications and results of a 14-year experience. AB - PURPOSE: Temporomandibular joint (TMJ) reconstruction with alloplastic implants is a reliable, safe and effective treatment option for selected debilitating pathologies of the TMJ. This study retrospectively analyzes our 14-year experience in total alloplastic reconstruction of the TMJ using stock and custom Biomet prostheses. Indications, results and rationale for the choice of stock and custom-made devices are discussed. MATERIAL AND METHODS: Patients were enrolled in the study who underwent single-stage alloplastic total joint replacement from January 2000 to October 2014. The subjective and objective variables were as follows: TMJ pain, diet, jaw function, maximum interincisal opening (MIO), quality of life and occlusion. The minimum follow-up was 12 months. RESULTS: A total of 38 patients (55 joints) met the inclusion criteria and were enrolled in the study. Of the patients, 25 underwent Biomet total joint reconstruction system with stock prosthesis, 12 patients underwent total joint reconstruction system with custom made (patient matched) prosthesis, and 1 patient underwent bilateral total joint reconstruction using stock system on one side and custom system on the other side. The following adverse events and complications were recorded: bleeding, 2 cases; malocclusion, 1 case; postoperative infection with prosthesis removal, 1 case; heterotopic bone formation, 1 case; and contralateral TMJ overload in unilateral cases, 1 case. The occlusion was habitual unchanged in 29 of 38 cases. In 1 patient occlusion worsened with less stable functional contact. The patient refused postoperative orthodontic treatment. In 8 patients, a concomitant orthognatic procedure was planned in order to improve the occlusion. In all these patients, the occlusion improved. Quality of life and MIO relevantly improved in all cases. CONCLUSIONS: This study supports the use of total joint reconstruction for end-stage TMJ disease. Both stock and custom implants allow consistent results, but there are precise indications for the use of custom implants. PMID- 28843403 TI - Piezoelectric versus conventional techniques for orthognathic surgery: Systematic review and meta-analysis. AB - PURPOSE: The purpose of this study was to perform a systematic review and meta analysis of complications after orthognathic surgery comparing piezo-surgery with conventional osteotomy. METHODS: We conducted this study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We performed a systematic search of PubMed, Scopus, Science Direct, Lilacs, Cochrane Central Register of Controlled Trials, Google Scholar, and OpenThesis to identify randomized and nonrandomized controlled trials (RCTs and nRCTs, respectively) comparing patient outcomes (operative time, intraoperative blood loss, postoperative swelling, pain, neurosensitivity) after orthognathic surgery by piezoelectric or conventional osteotomy. We pooled individual results of continuous and dichotomous outcome data using the mean difference (MD) and risk difference (RD) with the 95% confidence interval, respectively. RESULTS: Three RCTs and five nRCTs were selected. No difference in operative time was observed between piezo-surgery and conventional osteotomies. We found a decrease of intraoperative blood loss with piezo-surgery (MD -128 mL; P < 0.001) and a pooled difference in severe blood loss of 35% (P = 0.008) favouring piezo surgery. Based on pooled individual results of studies evaluating neurosensitivity by clinical neurosensory testing, our meta-analysis showed a pooled difference in severe nerve disturbance of 25% (P < 0.0001) favouring piezo surgery. Test for subgroup differences (I2 = 26.6%) indicated that follow-up time may have an effect on neurosensory disturbance. We found differences between piezo-surgery and conventional osteotomy at 3 months (RD 28%; P < 0.001) and 6 months (RD 15%; P = 0.001) after surgery. Meta-analyses for pain and swelling were not performed because of a lack of sufficient studies. CONCLUSION: Currently available evidence suggests that piezo-surgery has favorable effects on complications associated with orthognathic surgery, including reductions in intraoperative blood loss and severe nerve disturbance. PMID- 28843405 TI - Intracanal temperature changes during bone preparations close to and penetrating the inferior alveolar canal: Drills versus piezosurgery. AB - PURPOSE: The aim of this in vitro study was to investigate temperature increases in the inferior alveolar canal (IAC), when different bone preparation methods approximate and penetrate the IAC. MATERIALS AND METHODS: In pig mandible, buccal bone removals were performed until the neurovascular bundle became visible. Temperatures were registered with thermocouple probes and with infrared thermometer. Preparations were performed with diamond drills (DD), tungsten carbide drills (TCD), piezoelectric diamond sphere (PT_D) and saw (PT_S) tips, and a combined preparation method was also performed whereby the superficial three-fourths of the bone was removed with TCD and the deepest one-fourth of the bone with PT_D (TCD + PT_D_7 degrees C) or PT_S (TCD + PT_S_7 degrees C), using cooled irrigation (7 degrees C). RESULTS: Preparations using room temperature irrigation caused significantly less heat on the bone surface than in the IAC. Piezosurgery in the IAC produced significantly higher temperatures (>13 degrees C) than the drills (<4 degrees C). Heat productions of the piezoelectric tips were reduced significantly by applying the combined bone removal methods. The speed of PT_S and TCD + PT_S_7 degrees C were comparable to the speed of TCD, whereas TCD + PT_D_7 degrees C was found to be significantly slower. CONCLUSION: The speed of piezosurgery is comparable to that of the drills; however, it produces the highest, potentially nerve-harming temperatures. To eliminate the heat consequences during piezosurgery in the IAC, the use of cooled irrigation at 7 degrees C and predrilling is recommended. PMID- 28843404 TI - Morphometric analysis of temporomandibular joint elements. AB - PURPOSE: To study the morphology of temporomandibular joint (TMJ) elements and examine the feasibility of a novel biofidelic articular disc casting technique. METHODS: 18 formalin-fixed cadavers (77.8% female, 22.2% male) with mean (SD) death age of 71.9 (13.7) years were used for this study. In each specimen the masseter muscle, mandibular ramus, and articular disc were dissected bilaterally and measured for length, width, and thickness. All anatomic measurements were made using a digital slide caliper (Hawk Inc., Cleveland, OH). Further, a novel method for the creation of biofidelic articular disc models was established through trial and error. Models were measured for accuracy against their biological counterparts. RESULTS: Left articular disc length and thickness were inversely correlated (r = -0.58, p < 0.049). Direct correlations existed between right disc and ramus thickness (r = 0.56, p < 0.039), masseter length and thickness (r = 0.59, p < 0.009), and masseter width and thickness (r = 0.66, p < 0.003). Comparison of the model measurements with their biological counterparts found no significant differences. DISCUSSION: These observed correlations between elements of the TMJ hold relevance for oral-maxillofacial surgeons and researchers examining disorders of the TMJ. Additionally, our casting technique proved accurate in modeling human articular discs. PMID- 28843407 TI - The feasibility of cold atmospheric plasma in the treatment of complicated wounds in cranio-maxillo-facial surgery. AB - BACKGROUND: Compromised wound healing in cranio-maxillo-facial surgery is a threat to the patient's rehabilitation. Therapy of chronic and/or infected wounds is time- and cost-consuming, burdensome and occasionally futile. Cold atmospheric plasma is a new approach that promises to overcome these limitations. The aim of this proof-of-concept study was to evaluate the clinical outcome of cold plasma irradiation in patients with impaired wound healing who are refractory to conservative wound therapy and/or revision surgery. MATERIALS AND METHODS: We enrolled six patients (mean age: 63.5 years; SD 8.8 years; 1 female and 5 males) who experienced various cranio-maxillo-facial surgical procedures and suffered from wound healing disturbances. In addition to established wound care, all wounds were irradiated with cold atmospheric plasma. The primary outcome variable was the attainment of complete wound closure. RESULTS: In all patients, complete remission in terms of wound closure was observed within a mean time of 15.5 weeks (range: 4-38 weeks). No undesirable side effects were observed, and no inflammation or infection occurred after cold plasma initiation. CONCLUSION: The use of cold atmospheric plasma might offer a reliable, conservative treatment option in complicated wound healing disturbances in cranio-maxillo-facial surgery. PMID- 28843406 TI - Do patients with malocclusion have a higher prevalence of temporomandibular disorders than controls both before and after orthognathic surgery? A systematic review and meta-analysis. AB - PURPOSE: The aim of this study was to identify, through meta-analysis, whether patients who require orthognathic surgery have a higher prevalence of temporomandibular disorders (TMDs) than controls, both before treatment and after. MATERIAL AND METHODS: A systematic review and meta-analysis were conducted based on PRISMA guidelines, to address the study purposes. A search of major databases through PubMed, EMBASE, and Cochrane CENTRAL was performed to locate all pertinent articles published from inception to June 2016. Inclusion criteria were controlled clinical studies, either prospective or retrospective, and case control studies comparing preoperative and postoperative signs and symptoms of TMDs in patients who undergo orthognathic surgery to those of a healthy volunteer population with no dentofacial deformities. The predictor variables were patients with dentofacial deformities who underwent orthognathic surgery and patients with no dentofacial deformities and with good maxillomandibular relations and normal occlusion. The outcomes variables were the weighted, prevalence rate (proportion) in signs and symptoms of TMDs in patients with dentofacial deformities and risk ratio (RR) of signs and symptoms of TMDs before and after orthognathic surgery, compared to the control group. RESULTS: A total of 542 patients enrolled in 6 studies were included in this analysis. The overall pooled weighted rate or prevalence of TMDs for orthognathic surgery patients preoperatively was 32.5% (95% CI = 26.7%-38.9%). There was a significant difference between the 2 groups with respect to TMDs before surgery, but no significant difference in TMDs after surgery. The RR for patients who had dentofacial deformities before orthognathic surgery compared with a control group was 1.634 (95% CI = 1.216-2.194; P = 0.001). The RR for patients after orthognathic surgery compared with a control group was 1.262 (0.718; 95% CI = 0.805-1.979; P = 0.311). CONCLUSION: The results of this study show that patients who are going to have a correction of their malocclusion by orthodontics and orthognathic surgery have a significant incidence of TMDs when compared to a control population, but that after treatment, the incidence of TMDs does not differ from a control population. The reasons for these findings are not clear. PMID- 28843408 TI - Tackling mumps in a public health setting: loopholes in disease surveillance. PMID- 28843409 TI - Defining binge drinking: young drinkers' perceptions of risky alcohol consumption. PMID- 28843410 TI - Health system barriers and enablers to early access to breast cancer screening, detection, and diagnosis: a global analysis applied to the MENA region. AB - OBJECTIVES: To identify barriers and enablers that impact access to early screening, detection, and diagnosis of breast cancer both globally and more specifically in the Middle East and North Africa (MENA) region (with a specific focus on Egypt, Jordan, Oman, Saudi Arabia, United Arab Emirates [UAE], and Kuwait) with a specific focus on the health system. STUDY DESIGN: A systematic review of literature. METHODS: We conducted a systematic reviewing using the PRISMA methodology. We searched PubMed, Global Index Medicus, and EMBASE for studies on 'breast cancer', 'breast neoplasm,' or 'screening, early detection, and early diagnosis' as well as key words related to the following barriers: religion, culture, health literacy, lack of knowledge/awareness/understanding, attitudes, fatalism/fear, shame/embarrassment, and physician gender from January 1, 2000 until September 1, 2016. Two independent reviewers screened both titles and abstracts. The application of inclusion and exclusion criteria yielded a final list of articles. A conceptual framework was used to guide the thematic analysis and examine health system barriers and enablers to breast cancer screening at the broader macro health system level, at the health provider level, and the individual level. The analysis was conducted globally and in the MENA region. RESULTS: A total of 11,936 references were identified through the initial search strategy, of which 55 were included in the final thematic analysis. The results found the following barriers and enablers to access to breast cancer screening at the health system level, the health provider level, and the individual level: health system structures such as health insurance and care coordination systems, costs, time concerns, provider characteristics including gender of the provider, quality of care issues, medical concerns, and fear. In addition, the following seven barriers and enablers were identified at the health system or provider level as significantly impacting screening for breast cancer: (1) access to insurance, (2) physician recommendation, (3) physician gender, (4) provider characteristics, (5) having a regular provider, (6) fear of the system or procedure, and (7) knowledge of the health system. More specifically, the largest increased odds for having a mammogram was from having insurance, having a physician recommendation, type of provider (mainly gynecologist), and having regular contact with a physician. Clinical breast examinations were increased by having insurance and having regular contact with a physician. The eight studies identified from the MENA region identified barriers to breast cancer screening related to service quality, fear of pain and of cancer itself, female versus male provider, having a physician recommend the screen, cost issues as well as time and convenience of the services. CONCLUSIONS: There are a number of system changes that can be made to remove barriers to breast cancer screening. Some of these system changes apply directly to MENA countries. A larger health system assessment of a country is warranted to determine which health system changes should be made to most efficiently and effectively improve access to breast cancer screening. PMID- 28843411 TI - The activin receptor is stimulated in the skeleton, vasculature, heart, and kidney during chronic kidney disease. AB - We examined activin receptor type IIA (ActRIIA) activation in chronic kidney disease (CKD) by signal analysis and inhibition in mice with Alport syndrome using the ActRIIA ligand trap RAP-011 initiated in 75-day-old Alport mice. At 200 days of age, there was severe CKD and associated Mineral and Bone Disorder (CKD MBD), consisting of osteodystrophy, vascular calcification, cardiac hypertrophy, hyperphosphatemia, hyperparathyroidism, elevated FGF23, and reduced klotho. The CKD-induced bone resorption and osteoblast dysfunction was reversed, and bone formation was increased by RAP-011. ActRIIA inhibition prevented the formation of calcium apatite deposits in the aortic adventitia and tunica media and significantly decreased the mean aortic calcium concentration from 0.59 in untreated to 0.36 mg/g in treated Alport mice. Aortic ActRIIA stimulation in untreated mice increased p-Smad2 levels and the transcription of sm22alpha and alphaSMA. ActRIIA inhibition reversed aortic expression of the osteoblast transition markers Runx2 and osterix. Heart weight was significantly increased by 26% in untreated mice but remained normal during RAP-011 treatment. In 150-day old mice, GFR was significantly reduced by 55%, but only by 30% in the RAP-011 treated group. In 200-day-old mice, the mean BUN was 100 mg/dl in untreated mice compared to 60 mg/dl in the treated group. In the kidneys of 200-day-old mice, ActRIIA and p-Smad2 were induced and MCP-1, fibronectin, and interstitial fibrosis were stimulated; all were attenuated by RAP-011 treatment. Hence, the activation of ActRIIA signaling during early CKD contributes to the CKD-MBD components of osteodystrophy and cardiovascular disease and to renal fibrosis. Thus, the inhibition of ActRIIA signaling is efficacious in improving and delaying CKD-MBD in this model of Alport syndrome. PMID- 28843413 TI - Accelerated long-term forgetting and autobiographical memory disorders in temporal lobe epilepsy: One entity or two? AB - Temporal lobe epilepsy (TLE) is a type of epilepsy that often has a negative impact on patients' memory. Despite the importance of patients' complaints in this regard, the difficulties described by these patients are often not easy to demonstrate through a standard neuropsychological assessment. Accelerated long term forgetting and autobiographical memory disorders are the two main memory impairments reported in the literature in patients with TLE. However, the methods used by different authors to evaluate long-term memory and autobiographical memory are heterogeneous. This heterogeneity can lead to differences in the observed results as well as how they are interpreted. Yet, despite the methodological differences, objectification of such memory deficits appears to be both specific and robust within this patient population. Analysis of the literature shows that accelerated long-term forgetting and autobiographical memory disorders share the same clinical characteristics. This leads to the assumption that they are, in fact, only one entity and that their evaluation may be done through a single procedure. Our proposal is to place this evaluation within the context of memory consolidation disorders. With such a perspective, evaluation of accelerated forgetting in autobiographical memory should consist of identifying a disorder in the formation and/or recovery of new memory traces. PMID- 28843412 TI - Single-tubule RNA-Seq uncovers signaling mechanisms that defend against hyponatremia in SIADH. AB - In the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatremia is limited by onset of vasopressin-escape caused by loss of the water channel aquaporin-2 in the renal collecting duct despite high circulating vasopressin. Here, we use the methods of systems biology in a well-established rat model of SIADH to identify signaling pathways activated at the onset of vasopressin-escape. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical collecting ducts of vasopressin-treated rats at 1, 2, and 4 days after initiation of oral water loading in comparison to time-control rats without water loading. The time-dependent mRNA abundance changes were mapped to gene sets associated with curated canonical signaling pathways and revealed evidence of perturbation of transforming growth factor beta signaling and epithelial-to-mesenchymal transition on Day 1 of water loading simultaneous with the initial fall in Aqp2 gene expression. On Day 2 of water loading, transcriptomic changes mapped to Notch signaling and the transition from G0 into the cell cycle but arrest at the G2/M stage. There was no evidence of cell proliferation or altered principal or intercalated cell numbers. Exposure of vasopressin-treated cultured mpkCCD cells to transforming growth factor beta resulted in a virtually complete loss of aquaporin-2. Thus, there is a partial epithelial-to-mesenchymal transition during vasopressin escape with a subsequent shift from quiescence into the cell cycle with eventual arrest and loss of aquaporin-2. PMID- 28843414 TI - Disentangling conscious from unconscious cognitive processing with event-related EEG potentials. AB - By looking for properties of consciousness, cognitive neuroscience studies have dramatically enlarged the scope of unconscious cognitive processing. This emerging knowledge inspired the development of new approaches allowing clinicians to probe and disentangle conscious from unconscious cognitive processes in non communicating brain-injured patients both in terms of behaviour and brain activity. This information is extremely valuable in order to improve diagnosis and prognosis in such patients both at acute and chronic settings. Reciprocally, the growing observations coming from such patients suffering from disorders of consciousness provide valuable constraints to theoretical models of consciousness. In this review we chose to illustrate these recent developments by focusing on brain signals recorded with EEG at bedside in response to auditory stimuli. More precisely, we present the respective EEG markers of unconscious and conscious processing of two classes of auditory stimuli (sounds and words). We show that in both cases, conscious access to the corresponding representation (e.g.: auditory regularity and verbal semantic content) share a similar neural signature (P3b and P600/LPC) that can be distinguished from unconscious processing occurring during an earlier stage (MMN and N400). We propose a two stage serial model of processing and discuss how unconscious and conscious signatures can be measured at bedside providing relevant informations for both diagnosis and prognosis of consciousness recovery. These two examples emphasize how fruitful can be the bidirectional approach exploring cognition in healthy subjects and in brain-damaged patients. PMID- 28843415 TI - Complexity vs. unity in unilateral spatial neglect. AB - Unilateral spatial neglect constitutes a heterogeneous syndrome characterized by two main entangled components: a contralesional bias of spatial attention orientation; and impaired building and/or exploration of mental representations of space. These two components are present in different subtypes of unilateral spatial neglect (visual, auditory, somatosensory, motor, allocentric, egocentric, personal, representational and productive manifestations). Detailed anatomical and clinical analyses of these conditions and their underlying disorders show the complexity of spatial cognitive deficits and the difficulty of proposing just one explanation. This complexity is in contrast, however, to the widely acknowledged effectiveness of rehabilitation of the various symptoms and subtypes of unilateral spatial neglect, exemplified in the case of prism adaptation. These common effects are reflections of the unity of the physiotherapeutic mechanisms behind the higher brain functions related to multisensory integration and spatial representations, whereas the paradoxical aspects of unilateral spatial neglect emphasize the need for a greater understanding of spatial cognitive disorders. PMID- 28843416 TI - Visual agnosia and focal brain injury. AB - Visual agnosia encompasses all disorders of visual recognition within a selective visual modality not due to an impairment of elementary visual processing or other cognitive deficit. Based on a sequential dichotomy between the perceptual and memory systems, two different categories of visual object agnosia are usually considered: 'apperceptive agnosia' and 'associative agnosia'. Impaired visual recognition within a single category of stimuli is also reported in: (i) visual object agnosia of the ventral pathway, such as prosopagnosia (for faces), pure alexia (for words), or topographagnosia (for landmarks); (ii) visual spatial agnosia of the dorsal pathway, such as cerebral akinetopsia (for movement), or orientation agnosia (for the placement of objects in space). Focal brain injuries provide a unique opportunity to better understand regional brain function, particularly with the use of effective statistical approaches such as voxel-based lesion-symptom mapping (VLSM). The aim of the present work was twofold: (i) to review the various agnosia categories according to the traditional visual dual pathway model; and (ii) to better assess the anatomical network underlying visual recognition through lesion-mapping studies correlating neuroanatomical and clinical outcomes. PMID- 28843417 TI - Evaluation of primitive ground water supplies as a risk factor for the development of major waterborne zoonosis in Egyptian children living in rural areas. AB - BACKGROUND: Endemic waterborne zoonosis frequently occurs in both developed and less developed countries. Thus, bio-surveillance of waterborne zoonosis is a "necessity" for the implementation of effective preventive public health measures in Egyptian rural areas. The primitive individual water supplies created by the rural agriculture population, primarily from ground water, usually maximize the customers' exposure to impurity pathogens via diffused humans and animal excreta or wastages. The current study aimed to evaluate the frequency of zoonotic pathogens within the infiltrated untreated ground water supplies with an assessment of the impact of such biohazards on children living in the studied Egyptian rural areas. METHODS: A total of 796 stool samples were collected from children under 10 years of age from the Abulnomorous (401) and Shabramant (395) villages in Giza, Egypt, and two hundred forty five ground water samples were collected from various individual home water supplies (ground pumps) within two rural Egyptian localities, namely, the Abulnomorous (128) and Shabramant (117) villages. All the samples were examined for the identification of bacterial, fungal and parasitic zoonosis. RESULTS: The isolation of Campylobacter jejuni, Escherichia coli, Salmonella typhi and Shigella spp. was documented in the following frequencies in the water and stool samples of symptomatic children (11.4% and 5.2%), (6.9% and 2.9%), (13.9% and 6.4%) and (4.5% and 2.3%), respectively. Candida albicans and Cryptococcus neoformans were detected in the examined water and morbid stool samples at (7.8% and 2.9%) and (1.6% and 0%), respectively. Additionally, the existence of parasites, including Entamoeba histolytica (5.7% and 4%), Giardia lamblia (9% and 1.7%) and Cryptosporidium oocysts (15.1% and 3.5%), was determined. Regarding Toxoplasma gondii, sporulated oocysts were detected in the ground water (2.9%). The prevalence of diarrhea among the examined children in Abulnomorous was higher (24.7%) than those living in Shabramant (18.7%), which might be attributable to the higher presentation of associated social and environmental risk factors in Abulnomorous than in Shabramant with significant differences P<=0.05. Additionally, the ground water analysis showed that the water samples collected from Abulnomorous (83.0%) were more polluted than those from Shabramant (74.3%). CONCLUSIONS: The results confirm human biohazards through rural individual water supplies and reflect the need for public health education regarding the correct use of drinking ground water only after effective treatment through filtration and/or boiling. PMID- 28843419 TI - Utility of intracardiac echocardiography during transvenous lead extraction. AB - BACKGROUND: Transvenous lead extraction (TLE) carries a significant risk of intraprocedural complications. Phased-array intracardiac echocardiography (ICE) is widely used during cardiac procedures; however, its utility during TLE has not been well described. OBJECTIVE: We sought to define the utility of ICE imaging during TLE. METHODS: Fifty patients referred for TLE were included. Patients underwent ICE imaging before and throughout TLE. Clinical characteristics of the patients, ICE findings, and procedural outcomes were collected and analyzed. RESULTS: Of the 50 patients, 18 (36%) were found to have visible binding sites in the ICE field of view; 13 (26%) had intracardiac binding sites only, and 5 (10%) had both superior vena cava (SVC) and intracardiac binding sites. Lead-adherent echodensities (LAEs) were found in 36 patients (72%), of whom 7 (14%) had bacteremia. Patients with SVC and/or intracardiac binding sites were more likely to have a complex extraction, defined as that requiring the use of internal jugular or femoral venous access, advancement of extraction apparatus beyond the SVC, disruption of lead structure during the procedure, or resulting in major complications (56% vs 0%; P <= .0001). CONCLUSION: ICE imaging during TLE can be used to assess the presence of lead binding sites, LAEs, and procedural complications. LAEs were found in the majority of patients, mostly in the absence of bacteremia. The presence of ICE-detected lead binding sites is predictive of a more complex extraction procedure. PMID- 28843420 TI - Profound differences in prognostic impact of left ventricular reverse remodeling after cardiac resynchronization therapy relate to heart failure etiology. AB - BACKGROUND: An ischemic etiology of heart failure (HF) has been associated with reduced left ventricular reverse remodeling after cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to assess the relationship between the etiology of HF and reverse remodeling and outcome after CRT. METHODS: Consecutive patients undergoing CRT implantation between October 1, 2008 and August 14, 2015 were retrospectively evaluated. Coronary angiography classified ischemic vs nonischemic etiology. Reverse remodeling was defined as the changes in left ventricular ejection fraction (LVEF) after 6 months. Clinical outcome was assessed 1 year after implantation using a combined end point of all cause mortality and HF readmission. RESULTS: A total of 685 patients were included (300/385 for ischemic/nonischemic etiology). Compared with patients with ischemic cardiomyopathy, patients with nonischemic cardiomyopathy exhibited a greater degree of improvement in LVEF (8.4% +/- 10.4% vs 15.8% +/- 12.3%; P < .001). After correcting for differences, an ischemic etiology of HF predicted less reverse remodeling (P < .001) and a higher rate of mortality or HF readmission (hazard ratio 1.63; 95% confidence interval [CI] 1.12-2.73; P = .011). Nevertheless, in comparison to a greater degree of improvement in LVEF, a lesser degree of improvement in LVEF (0%-5%) was associated with a higher risk of all-cause mortality and HF hospitalization in patients with nonischemic cardiomyopathy (odds ratio 9.78; 95% CI 1.95-49.04; P = .006) but not in patients with ischemic cardiomyopathy (odds ratio 3.58; 95% CI 0.85-15.18; P = .083). The most accurate cutoff for improvement in LVEF predicting good clinical outcome was 5.5% in ischemic cardiomyopathy vs 10.5% in nonischemic cardiomyopathy. CONCLUSION: CRT results in reverse remodeling in both patients with ischemic and nonischemic cardiomyopathy, but to a lesser extent in the former. Patients with an ischemic etiology are at an intrinsically higher risk of mortality and HF hospitalization, but derive benefit on outcome at a lesser degree of reverse remodeling. PMID- 28843418 TI - Successful ventricular tachycardia ablation in patients with electrical storm reduces recurrences and improves survival. AB - OBJECTIVE: The purpose of this study was to evaluate the characteristics and outcome of patients undergoing ablation after electrical storm (ES). METHODS: Clinical and procedural characteristics, ventricular tachycardia (VT) recurrence, and mortality rates from 1940 patients undergoing VT ablation were compared between patients with and without ES. RESULTS: The group of 677 patients with ES (34.9%) were older, were more frequently men, and had a lower ejection fraction, more advanced heart failure, and a higher prevalence of cardiovascular comorbidities as compared with those without ES (86.1% patients with ES had >=2 comorbidities vs 71.4%; P < .001). Patients with ES had more inducible VTs (2.5 +/- 1.8 vs 1.9 +/- 1.9; P < .001), required longer procedures (296.1 +/- 119.1 minutes vs 265.7 +/- 110.3 minutes; P < .001), and had a higher in-hospital mortality (42 deaths [6.2%] vs 18 deaths [1.4%]; P < .001). At 1-year follow-up, patients with ES experienced a higher risk of VT recurrence and mortality (32.1% vs 22.6% and 20.1% vs 8.5%; long-rank, P < .001 for both). Among patients with ES, those without any inducible VT after ablation had a higher survival rate (86.3%) than did those with nonclinical VTs only (72.9%), those with clinical VTs inducible at programmed electrical stimulation (51.2%), and not-tested patients (65.0%) (long-rank, P < .001 for all). In multivariate analysis, ES remained an independent predictor of in-hospital mortality, VT recurrence, and 1-year mortality (P < .001). CONCLUSION: Patients with ES have a high risk of VT recurrence and mortality. Patient and procedure characteristics are consistent with advanced cardiac disease and longer and more complex procedures. In patients with ES, acute procedural success is associated with a significant reduction in VT recurrence and improved 1-year survival. PMID- 28843421 TI - Inflammation, scarring, and atrioventricular nodal reentrant tachycardia. PMID- 28843422 TI - Redirecting T cells with Chimeric Antigen Receptor (CAR) for the treatment of childhood acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Nowadays the survival rate is around 85%. Nevertheless, an urgent clinical need is still represented by primary refractory and relapsed patients who do not significantly benefit from standard approaches, including chemo-radiotherapy and hematopoietic stem cell transplantation (HSCT). For this reason, immunotherapy has so far represented a challenging novel treatment opportunity, including, as the most validated therapeutic options, cancer vaccines, donor-lymphocyte infusions and tumor-specific immune effector cells. More recently, unexpected positive clinical results in ALL have been achieved by application of gene engineered chimeric antigen expressing (CAR) T cells. Several CAR designs across different trials have generated similar response rates, with Complete Response (CR) of 60-90% at 1 month and an Event-Free Survival (EFS) of 70% at 6 months. Relevant challenges anyway remain to be addressed, such as amelioration of technical, cost and feasibility aspects of cell and gene manipulation and the necessity to face the occurrence of relapse mechanisms. This review describes the state of the art of ALL immunotherapies, the novelties in terms of gene manipulation approaches and the problems emerged from early clinical studies. We describe and discuss the process of clinical translation, including the design of a cell manufacturing protocol, vector production and regulatory issues. Multiple antigen targeting and combination of CAR T cells with molecular targeted drugs have also been evaluated as latest strategies to prevail over immune-evasion. PMID- 28843423 TI - Neural circuit adaptations during drug withdrawal - Spotlight on the lateral habenula. AB - Withdrawal after drug intake triggers a wealth of affective states including negative feelings reminiscent of depressive symptoms. This negative state can ultimately be crucial for relapse, a hallmark of addiction. Adaptations in a wide number of neuronal circuits underlie aspects of drug withdrawal, however causality between cellular modifications within these systems and precise behavioral phenotypes remains poorly described. Recent advances point to an instrumental role of the lateral habenula in driving depressive-like states during drug withdrawal. In this review we will discuss the general behavioral features of drug withdrawal, the importance of plasticity mechanisms in the mesolimbic systems, and the latest discoveries highlighting the implications of lateral habenula in drug addiction. We will further stress how specific interventions in the lateral habenula efficiently ameliorate depressive symptoms. Altogether, this work aims to provide a general knowledge on the cellular and circuit basis underlying drug withdrawal, ultimately speculating on potential treatment for precise aspects of addiction. PMID- 28843424 TI - The molecular mechanisms controlling morphogenesis and wiring of the habenula. AB - The habenula is an evolutionarily conserved brain region comprising bilaterally paired nuclei that plays a key role in processing reward information and mediating aversive responses to negative stimuli. An important aspect underlying habenula function is relaying information between forebrain and mid- and hindbrain areas. This is mediated by its complex organization into multiple subdomains and corresponding complexity in circuit organization. Additionally, in many species habenular nuclei display left-right differences at the anatomical and functional level. In order to ensure proper functional organization of habenular circuitry, sophisticated molecular programs control the morphogenesis and wiring of the habenula during development. Knowledge of how these mechanisms shape the habenula is crucial for obtaining a complete understanding of this brain region and can provide invaluable tools to study habenula evolution and function. In this review we will discuss how these molecular mechanisms pattern the early embryonic nervous system and control the formation of the habenula, how they shape its asymmetric organization, and how these mechanisms ensure proper wiring of the habenular circuit. Finally, we will address unexplored aspects of habenula development and how these may direct future research. PMID- 28843426 TI - Erratum to "The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism" [Neurobiol. Aging 36 (2015) 1221.e1-1221.e6]. PMID- 28843427 TI - ? PMID- 28843428 TI - Association of matrix metalloproteinase-3 gene 5A/6A polymorphism with the recurrence of ischemic stroke: A prospective observational study. AB - Studies have demonstrated that matrix metalloproteinase-3 (MMP-3) is involved in the development and progression of atherosclerosis. However, there is no information available on the association of MMP-3 5A/6A polymorphism with recurrent ischemic stroke (IS) in different IS subtypes. We investigated the potential associations between MMP-3 serum level and -1171 5A/6A polymorphism and the recurrence of IS in a Chinese population. Consecutive acute first-ever IS patients were enrolled between August 2008 and October 2013. The genotypes of MMP 3 5A/6A polymorphism were determined using polymerase chain reaction-restriction fragment length polymorphism. IS recurrence was monitored after the index event and multivariate Cox proportional hazards model was constructed to identify factors related to future IS recurrence. A total of 1282 eligible patients were enrolled. During a 2-year follow-up period, 157 (12.25%) patients had recurrent events. MMP-3 level was significantly higher in patients with 5A/6A or 5A/5A genotype (22.72+/-7.29ng/ul) than in patients with 6A/6A genotype (20.48+/ 7.58ng/ul), P<0.001. No interaction between MMP-3 5A/6A polymorphism and the risk of recurrence in total IS patients was found. The variant 5A/6A+5A/5A genotype and the 5A allele were significantly associated with a high risk of recurrence for large-artery atherosclerosis (LAA) (multivariate-adjusted, P=0.002, 0.001, respectively), but not for small-artery occlusion and cardioembolism. Our finding showed that MMP-3 5A/6A may be a useful biomarker for predicting recurrence for LAA stroke patients and 5A allele carrier may bear a higher risk of recurrence among patients with the subtype of LAA. PMID- 28843425 TI - Does being drunk or high cause HIV sexual risk behavior? A systematic review of drug administration studies. AB - HIV sexual risk behavior is broadly associated with substance use. Yet critical questions remain regarding the potential causal link between substance use (e.g., intoxication) and HIV sexual risk behavior. The present systematic review was designed to examine and synthesize the existing literature regarding the effects of substance administration on HIV sexual risk behavior. Randomized controlled experiments investigating substance administration and HIV sexual risk behavior (e.g., likelihood of condom use in a casual sex scenario) were included. Across five databases, 2750 titles/abstracts were examined and forty-three total peer reviewed published manuscripts qualified (few were multi-study manuscripts, and those details are outlined in the text). The majority of articles investigated the causal role of acute alcohol administration on HIV sexual risk behavior, although one article investigated the effects of acute THC administration, one the effects of acute cocaine administration, and two the effects of buspirone. The results of this review suggest a causal role in acute alcohol intoxication increasing HIV sexual risk decision-making. Although evidence is limited with other substances, cocaine administration also appears to increase sexual risk, while acute cannabis and buspirone maintenance may decrease sexual risk. In the case of alcohol intoxication, the pharmacological effects independently contribute to HIV sexual risk decision-making, and these effects are exacerbated by alcohol expectancies, increased arousal, and delay to condom availability. Comparisons across studies showed that cocaine led to greater self-reported sexual arousal than alcohol, potentially suggesting a different risk profile. HIV prevention measures should take these substance administration effects into account. Increasing the amount of freely and easily accessible condoms to the public may attenuate the influence of acute intoxication on HIV sexual risk decision-making. PMID- 28843429 TI - Ultracompact states of native proteins. AB - A statistical analysis of circa 20,000 X-ray structures evidenced the effects of temperature of data collection on protein intramolecular distances and degree of compaction. Identical chains with data collected at cryogenic ultralow temperatures (<=160K) showed a radius of gyration (Rg) significantly smaller than at moderate temperatures (>=240K). Furthermore, the analysis revealed the existence of structures with a Rg significantly smaller than expected for cryogenic temperatures. In these ultracompact cases, the unusually small Rg could not be specifically attributed to any experimental parameter or crystal features. Ultracompaction involves most atoms and results in their displacement toward the center of the molecule. Ultracompact structures on average have significantly shorter van der Waals and hydrogen bonds than expected for ultralow temperature structures. In addition, the number of van der Waals contacts was larger in ultracompact than in ultralow temperature structures. The structure of these ultracompact states was analyzed in detail and the implication and possible causes of the phenomenon are discussed. PMID- 28843430 TI - Adaptive terminal sliding mode control for hypersonic flight vehicles with strictly lower convex function based nonlinear disturbance observer. AB - In this paper, the altitude and velocity tracking control of a generic hypersonic flight vehicle (HFV) is considered. A novel adaptive terminal sliding mode controller (ATSMC) with strictly lower convex function based nonlinear disturbance observer (SDOB) is proposed for the longitudinal dynamics of HFV in presence of both parametric uncertainties and external disturbances. First, for the sake of enhancing the anti-interference capability, SDOB is presented to estimate and compensate the equivalent disturbances by introducing a strictly lower convex function. Next, the SDOB based ATSMC (SDOB-ATSMC) is proposed to guarantee the system outputs track the reference trajectory. Then, stability of the proposed control scheme is analyzed by the Lyapunov function method. Compared with other HFV control approaches, key novelties of SDOB-ATSMC are that a novel SDOB is proposed and drawn into the (virtual) control laws to compensate the disturbances and that several adaptive laws are used to deal with the differential explosion problem. Finally, it is illustrated by the simulation results that the new method exhibits an excellent robustness and a better disturbance rejection performance than the convention approach. PMID- 28843431 TI - Design and implementation of a control structure for quality products in a crude oil atmospheric distillation column. AB - In recent years, interest for petrochemical processes has been increasing, especially in refinement area. However, the high variability in the dynamic characteristics present in the atmospheric distillation column poses a challenge to obtain quality products. To improve distillates quality in spite of the changes in the input crude oil composition, this paper details a new design of a control strategy in a conventional crude oil distillation plant defined using formal interaction analysis tools. The process dynamic and its control are simulated on Aspen HYSYS(r) dynamic environment under real operating conditions. The simulation results are compared against a typical control strategy commonly used in crude oil atmospheric distillation columns. PMID- 28843432 TI - WITHDRAWN: Association of Baseline Body Composition With Incomplete Immune Response After Highly Active Antiretroviral Therapy in Chinese HIV-Infected Adults. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28843433 TI - HDAC inhibitors: A new promising drug class in anti-aging research. AB - In the last years, epigenetic regulation of gene expression is regarded as an important factor involved in a broad spectrum of aging-associated processes including loss of physical activity, frailty and genomic instability, and in development of various pathological conditions such as atherosclerosis, type 2 diabetes, cancer, immune deficits and neurodegenerative diseases. Accordingly, inhibitors of the members of superfamilies of histone deacetylases (HDACs) have been proposed, among other drugs targeting epigenetic pathways, as a promising type of therapeutics that is able to combat aging and its manifestations. The main focus of this article is a review of the literature describing the healthspan-promoting and life-extending effects of inhibitors of HDAC activity in both animal and clinical studies. PMID- 28843434 TI - When Patients and Their Families Feel Like Hostages to Health Care. AB - Patients are often reluctant to assert their interests in the presence of clinicians, whom they see as experts. The higher the stakes of a health decision, the more entrenched the socially sanctioned roles of patient and clinician can become. As a result, many patients are susceptible to "hostage bargaining syndrome" (HBS), whereby they behave as if negotiating for their health from a position of fear and confusion. It may manifest as understating a concern, asking for less than what is desired or needed, or even remaining silent against one's better judgment. When HBS persists and escalates, a patient may succumb to learned helplessness, making his or her authentic involvement in shared decision making almost impossible. To subvert HBS and prevent learned helplessness, clinicians must aim to be sensitive to the power imbalance inherent in the clinician-patient relationship. They should then actively and mindfully pursue shared decision making by helping patients trust that it is safe to communicate their concerns and priorities, ask questions about the available clinical options, and contribute knowledge of self to clinical decisions about their care. Hostage bargaining syndrome is an insidious psychosocial dynamic that can compromise quality of care, but clinicians often have the power to arrest it and reverse it by appreciating, paradoxically, how patients' perceptions of their power as experts play a central role in the care they provide. PMID- 28843435 TI - Role of specialized DNA polymerases in the limitation of replicative stress and DNA damage transmission. AB - Replication stress is a strong and early driving force for genomic instability and tumor development. Beside replicative DNA polymerases, an emerging group of specialized DNA polymerases is involved in the technical assistance of the replication machinery in order to prevent replicative stress and its deleterious consequences. During S-phase, altered progression of the replication fork by endogenous or exogenous impediments induces replicative stress, causing cells to reach mitosis with genomic regions not fully duplicated. Recently, specific mechanisms to resolve replication intermediates during mitosis with the aim of limiting DNA damage transmission to daughter cells have been identified. In this review, we detail the two major actions of specialized DNA polymerases that limit DNA damage transmission: the prevention of replicative stress by non-B DNA replication and the recovery of stalled replication forks. PMID- 28843436 TI - Improved vectors for Agrobacterium mediated genetic manipulation of Hypholoma spp. and other homobasidiomycetes. AB - The basidiomycete fungi Hypholoma fasciculare and H. sublateritium are both prolific producers of sesquiterpenes and triterpenes, some of which have relevant pharmaceutical properties. Although H. sublateritium has been transformed in the past, the low reported efficiencies highlighted the need for establishing an effective simple transformation system for these valuable species. We have optimized Agrobacterium tumefaciens-mediated transformation through testing various parameters in these two Hypholoma species, showing that a mixture of homogenized mycelia and Agrobacterium (strain LBA4404) co-cultivated for 84h at 25 degrees C is optimal for efficient transformation in these basidiomycetes. This study also reveals the requirements for transgene expression, with the first report of GFP expression in these Hypholoma, the need for an intron for such transgene expression, and further demonstrates the functionality of the expression vector by its use in Clitopilus passeckerianus. This development of transformation system and expression constructs, can facilitate further genetic investigation such as gene functionality in these fungi. PMID- 28843438 TI - Inflammation, substance use, psychopathology, and cognition in phase 1 of the clinical antipsychotic trials of intervention effectiveness study. AB - INTRODUCTION: Schizophrenia has been associated with aberrant blood levels of inflammatory markers. However, patients with comorbid illicit drug use have been inadequately studied with respect to immune function. Furthermore, associations between inflammatory markers, psychopathology, and cognition have been inconsistently considered. We investigated relationships between inflammatory markers, comorbid marijuana and cocaine use, and psychopathology and cognition in patients with schizophrenia. METHOD: For subjects with available fasting data from the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial, inflammatory markers were investigated as predictors of psychopathology and cognition in patients with and without comorbid marijuana or cocaine use, using linear regression models controlling for potential confounding factors. RESULTS: Compared to subjects with a negative urine drug screen (UDS), marijuana use was a predictor of higher lymphocytes and E-selectin, and lower leptin (p<=0.04 for each); cocaine use was a predictor of higher adiponectin (p=0.04). In subjects with marijuana use, lower WBC and higher IL-6 were predictors of higher PANSS total score (p<0.05 for each). In subjects with cocaine use, lower total and differential WBC were predictors of higher PANSS total score (p<0.04 for each). In younger, non-obese subjects with a negative UDS, higher monocytes and IL-6 were predictors of PANSS total score (p<0.04 for each). CONCLUSIONS: Our findings provide additional evidence that inflammation may be associated with psychopathology and cognition in some patients with schizophrenia. Furthermore, there is preliminary evidence for differential effects of comorbid marijuana and cocaine use on these relationships. PMID- 28843437 TI - Deficits in visual working-memory capacity and general cognition in African Americans with psychosis. AB - On average, patients with psychosis perform worse than controls on visual change detection tasks, implying that psychosis is associated with reduced capacity of visual working memory (WM). In the present study, 79 patients diagnosed with various psychotic disorders and 166 controls, all African Americans, completed a change-detection task and several other neurocognitive measures. The aims of the study were to (1) determine whether we could observe a between-group difference in performance on the change-detection task in this sample; (2) establish whether such a difference could be specifically attributed to reduced WM capacity (k); and (3) estimate k in the context of the general cognitive deficit in psychosis. Consistent with previous studies, patients performed worse than controls on the change-detection task, on average. Bayesian hierarchical cognitive modeling of the data suggested that this between-group difference was driven by reduced k in patients, rather than differences in other psychologically meaningful model parameters (guessing behavior and lapse rate). Using the same modeling framework, we estimated the effect of psychosis on k while controlling for general intellectual ability (g, obtained from the other neurocognitive measures). The results suggested that reduced k in patients was stronger than predicted by the between-group difference in g. Moreover, a mediation analysis suggested that the relationship between psychosis and g (i.e., the general cognitive deficit) was mediated by k. The results were consistent with the idea that reduced k is a specific deficit in psychosis, which contributes to the general cognitive deficit. PMID- 28843439 TI - Symbiotic Dinoflagellate Functional Diversity Mediates Coral Survival under Ecological Crisis. AB - Coral reefs have entered an era of 'ecological crisis' as climate change drives catastrophic reef loss worldwide. Coral growth and stress susceptibility are regulated by their endosymbiotic dinoflagellates (genus Symbiodinium). The phylogenetic diversity of Symbiodinium frequently corresponds to patterns of coral health and survival, but knowledge of functional diversity is ultimately necessary to reconcile broader ecological success over space and time. We explore here functional traits underpinning the complex biology of Symbiodinium that spans free-living algae to coral endosymbionts. In doing so we propose a mechanistic framework integrating the primary traits of resource acquisition and utilisation as a means to explain Symbiodinium functional diversity and to resolve the role of Symbiodinium in driving the stability of coral reefs under an uncertain future. PMID- 28843440 TI - The expression of pluripotency and neuronal differentiation markers under the influence of electromagnetic field and nitric oxide. AB - Nitric oxide (NO) is a diatomic free radical compound that as a secondary messenger contributes to cell physiological functions and its variations influence proteins activity and triggering intracellular signaling cascades. Low frequency electromagnetic field (EMF) alters the cell biology such as cell differentiation by targeting the plasma membrane and entering force to the ions and small electrical ligands. The effect of these chemical (NO) and physical (EMF) factors on the expression of the stemness and neuronal differentiation markers in rat bone marrow mesenchymal stem cells (BMSC) was investigated. The cells were treated with low (50micromolar) and high (1mM) concentrations of Deta NO as a NO donor molecule and 50Hz low frequency EMF. The expression of pluripotency and neuronal differentiation genes and proteins was investigated using real time qPCR and Immunocytochemistry techniques. The simultaneous treatment of EMF with NO (1mM) led to the down-regulation of stemness markers expression and up-regulation of neuronal differentiation markers expression. Cell proliferation decreased and cell morphology changed which caused the majority of cells obtains neuronal protein markers in their cytoplasm. The decrease in the expression of neuronal differentiation Nestin and DCX markers without any change in the expression of pluripotency Oct4 marker (treated with low concentration of NO) indicates protection of stemness state in these cells. Treatment with NO demonstrated a double behavior. NO low concentration helped the cells protect the stemness state but NO high concentration plus EMF pushed cells into differentiation pathway. PMID- 28843441 TI - Urticaria by thiamine (vitamin B1). PMID- 28843442 TI - Availability of information on young onset dementia for patients and carers in six European countries. AB - OBJECTIVES: To identify information available in six European countries (England, France, Germany, Netherlands, Portugal, Sweden) that addresses the specific needs of people with young onset dementia (YOD) and their carers, and identify gaps. METHODS: Search of websites of organisations with potential interest in dementia. Narrative synthesis and comparative analysis. RESULTS: 21 sources of information were identified (Netherlands 6, England 6, France 3, Germany 2, Portugal 2, Sweden 2); 11 were from voluntary sector organisations. Sources dedicated to YOD were limited (4 websites, 4 books); all other YOD information was sub-entries in generic dementia sources, difficult to locate and with limited coverage of relevant topics. Gaps related to implications of living with YOD in Germany, Portugal and Sweden. CONCLUSION: Availability of information varies among countries, some having no dedicated source and incomplete coverage of issues of importance to YOD. PRACTICAL IMPLICATIONS: Information is an important means of supporting carers; their needs change as the condition progresses. A comprehensive resource collating key information is needed so that the issues that differentiate the specific needs of people living with YOD from those of people with dementia in older age are available and easily located. PMID- 28843444 TI - Association between vitamin D deficiency and adverse outcomes in critically ill adult patients. PMID- 28843445 TI - Concordance of the new ESPEN criteria with low phase angle in defining early stages of malnutrition in cardiac surgery. AB - BACKGROUND & AIMS: The aim of this study was to evaluate the incidence of malnutrition (MN) in cardiac surgery patients by implementing the new ESPEN diagnostic criteria and to determine whether these criteria are concordant with the bioelectrical impedance analysis (BIA) provided phase angle (PA) in predicting early stages of malnutrition. METHODS: A prospective study was conducted in a tertiary hospital. The nutritional state of the cardiac surgery patients was evaluated one day prior to cardiac surgery using the malnutrition screening tools NRS-2002, MUST and SF-MNA, and bioelectrical impedance analysis. Patients at risk of malnutrition were further studied in accordance with the ESPEN malnutrition diagnostic criteria. A BIA provided PA value of less than the 15th percentile of the age and gender group was set as a theoretical marker of early malnutrition. ROC AUC (receiver operating characteristic area under curve) analysis and other parameters were calculated to determine the concordance between the new ESPEN malnutrition diagnostic criteria and a low PA. RESULTS: The study comprised 549 enrolled cardiac surgery patients. MN or risk of MN in accordance with at least one nutritional status assessment tool was diagnosed in 372 (67.75%) patients. MN, according to the new ESPEN malnutrition diagnostic criteria, was only diagnosed in 31 (5.6%) patients. Low PA was detected in 124 patients (22.6%), providing a higher MN rate. The ROC analysis and other concordance parameters showed that the new ESPEN diagnostic criteria (AUC 0.560, p = 0.042) were not concordant with a low PA. CONCLUSION: Fewer patients are classified as malnourished by the new ESPEN definition as those identified by the BIA provided PA. Incorporation of the BIA provided PA into the new ESPEN definition may aid to diagnose the early stages of MN in the field of cardiac surgery. PMID- 28843446 TI - Looking for fairer societies, can hard sciences help?: Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida and Nisrine Outada. PMID- 28843447 TI - Influence of spinopelvic alignment and morphology on deviation in the course of the psoas major muscle. AB - BACKGROUND: In some people, the psoas major rises laterally or anteriorly at the L4/5 disc level and detaches from the most posterior aspect of the disc despite the absence of transitional vertebrae; this is called the "rising psoas sign." There are no reports of the relationship between spinopelvic parameters and rising psoas sign. The objective of this study was to investigate the relationship between spinopelvic parameters and deviations in the location and shape of psoas major muscle at the L4/5 disc level. METHODS: We investigated the preoperative location and shape of both psoas major muscles in 64 patients treated with lateral lumbar interbody fusion. Spinopelvic parameters were measured on X-ray films. The morphology of psoas major at the L4/5 disc level was investigated with magnetic resonance images. The morphological measurements were normalized by the anteroposterior diameter of the center of the L4 vertebral body, which was measured by computed tomography. The rising psoas sign was classified into 2 types: bilateral or unilateral. RESULTS: The pelvic incidence (PI) was significantly larger for the bilateral type than the others (normal and unilateral types) (60.2 +/- 11.0 vs. 46.7 +/- 8.7, p < 0.001). The PI correlated significantly with the normalized anteroposterior diameter of the pelvis (R = 0.66, p < 0.001). The receiver-operator characteristic curve showed an optimal cutoff value of PI = 54, with 75% sensitivity and 78.5% specificity. The coronal L1-4 Cobb angle was significantly larger in the unilateral type than the others (normal and bilateral types) (p < 0.0001). In the unilateral type, the Cobb angle in the recumbent position correlated significantly with the normalized distance of the lateral deviation of psoas major (R = 0.60, p = 0.0085). CONCLUSION: The rising psoas sign was related to a higher PI and lumbar scoliosis. It was firstly elucidated that the spinopelvic alignment and morphology influence the deviation of the course of the psoas major muscle. STUDY DESIGN: A retrospective morphological study. PMID- 28843443 TI - Dietary magnesium intake and risk of incident coronary heart disease in men: A prospective cohort study. AB - BACKGROUND & AIMS: The associations between dietary magnesium intake and stroke and coronary heart disease (CHD) incidences are inconsistent and not established in Asian. We aimed to determine the association between dietary magnesium intake and the risk of stroke and CHD in a Japanese population. SUBJECTS/METHODS: We studied 85,293 Japanese subjects by questionnaire at baseline (age 45-74 years, without cardiovascular disease or cancer in 1995 and 1998 for Cohorts I and II, respectively). The participants were followed until the end of 2009 and 2010 in Cohorts I and II, respectively. Dietary magnesium intake was estimated from a self-administered 138-item food-frequency questionnaire. RESULTS: After 1,305,738 person-years of follow-up, 4110 strokes and 1283 cases of CHD were documented. The multivariable-adjusted hazard ratios (HRs, 95% confidence intervals, 95%CIs) of CHD for the fourth and fifth quintiles of dietary magnesium intake were 0.70 (0.50-0.99) and 0.66 (0.44-0.97) in men (P for trend = 0.036), respectively, and third quintile of dietary magnesium intake was 0.61 (0.39-0.96) in women (P for trend = 0.241), compared with the lowest quintile in men and women. We observed no decreased risks of incident stroke in men or women with higher dietary magnesium intakes. CONCLUSIONS: Higher dietary magnesium intake was associated with a reduced risk of CHD in Japanese men. PMID- 28843448 TI - Cardiorespiratory fitness and future risk of pneumonia: a long-term prospective cohort study. AB - PURPOSE: We aimed to assess the prospective association of cardiorespiratory fitness (CRF) with the risk of pneumonia. METHODS: Cardiorespiratory fitness, as measured by maximal oxygen uptake, was assessed using a respiratory gas exchange analyzer in 2244 middle-aged men in the Kuopio Ischemic Heart Disease cohort. We corrected for within-person variability in CRF levels using data from repeat measurements taken several years apart. RESULTS: During a median follow-up of 25.8 years, 369 men received a hospital diagnosis of pneumonia. The age-adjusted regression dilution ratio of CRF was 0.58 (95% confidence interval: 0.53-0.63). Cardiorespiratory fitness was linearly associated with pneumonia risk. The hazard ratio (95% confidence interval) for pneumonia per 1 standard deviation increase in CRF in analysis adjusted for several risk factors for pneumonia was 0.77 (0.68 0.87). The association remained consistent on additional adjustment for total energy intake, socioeconomic status, physical activity, and C-reactive protein 0.82 (0.72-0.94). The corresponding adjusted hazard ratios (95% confidence intervals) were 0.58 (0.41-0.80) and 0.67 (0.48-0.95) respectively, when comparing the extreme quartiles of CRF levels. CONCLUSIONS: Our findings indicate a graded inverse and independent association between CRF and the future risk of pneumonia in a general male population. PMID- 28843449 TI - Functional reach of older adults: normative reference values based on new and published data. AB - OBJECTIVES: To provide normative reference values for the standing functional reach test for older adults. DESIGN: Observational study and meta-analysis of data from published studies. SETTING: Clinical Research Center. PARTICIPANTS: Older adults: 199 hypertensive from INFINITY study and 7535 from consolidation of INFINITY and 20 other studies. MAIN OUTCOME MEASURE: Functional reach. RESULTS: The mean (standard deviation) for functional reach for the hypertensive older adults was 27.5 (7.2) cm. For the consolidated sample of older adults, a random effects model determined a weighted mean (standard error) functional reach of 27.2 (0.9) cm with a 95% confidence interval of 25.5 to 28.9cm. CONCLUSION: Pending the availability of data from a large population-based study, the summary data presented herein can serve as a reasonable estimate of normal functional reach for older adults. PMID- 28843451 TI - Physiotherapy interventions for people with dementia and a hip fracture-a scoping review of the literature. AB - BACKGROUND: People with dementia are 2.7 times more likely to suffer a hip fracture than those without and their management is estimated to cost L0.92 billion per year. Yet there has been little focus on the effectiveness of interventions for this population. OBJECTIVE: The aim of this scoping review was to summarise the current available evidence for physiotherapy interventions for people with dementia who fracture their hip as well as to identify gaps in the literature that may require further research. DATA SOURCES: A systematic search of the following databases was undertaken-TRIP, CINAHL, Amed, Embase, PEDro, PsycINFO, Cochrane Library, Open Grey, Ethos, ISRCTN, Proquest, PROSPERO and UK Clinical Trials Gateway. STUDY SELECTION: Articles were included if they described an intervention which is considered within the scope of a physiotherapist and targeted those with both a hip fracture and dementia. SYNTHESIS METHODS: A narrative summary was then undertaken to describe the current state of the literature. RESULTS: Twenty six studies were included, of which thirteen were observational, six RCTs, two qualitative, two surveys and three systematic reviews. Only nine studies focused explicitly on physiotherapy interventions. CONCLUSION: The findings of this scoping review suggest there is limited evidence to guide physiotherapists in the management of people with dementia who fracture their hip. No evidence was found about perceptions or experiences of patients in this group or of the physiotherapists involved in their care. Further research is needed to develop and evaluate physiotherapy interventions for people with dementia who fracture their hip. PMID- 28843450 TI - Symptoms of chronic fatigue syndrome/myalgic encephalopathy are not determined by activity pacing when measured by the chronic pain coping inventory. AB - OBJECTIVES: Chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) is a chronic illness which can cause significant fatigue, pain and disability. Activity pacing is frequently advocated as a beneficial coping strategy, however, it is unclear whether pacing is significantly associated with symptoms in people with CFS/ME. The first aim of this study was therefore to explore the cross-sectional associations between pacing and levels of pain, disability and fatigue. The second aim was to explore whether changes in activity pacing following participation in a symptom management programme were related to changes in clinical outcomes. DESIGN: Cross-sectional study exploring the relationships between pacing, pain, disability and fatigue (n=114) and pre-post treatment longitudinal study of a cohort of patients participating in a symptom management programme (n=35). SETTING: Out-patient physiotherapy CFS/ME service. PARTICIPANTS: One-hundred and fourteen adult patients with CFS/ME. MAIN OUTCOME MEASURES: Pacing was assessed using the chronic pain coping inventory. Pain was measured using a Numeric Pain Rating Scale, fatigue with the Chalder Fatigue Scale and disability with the Fibromyalgia Impact Questionnaire. RESULTS: No significant associations were observed between activity pacing and levels of pain, disability or fatigue. Likewise, changes in pacing were not significantly associated with changes in pain, disability or fatigue following treatment. CONCLUSIONS: Activity pacing does not appear to be a significant determinant of pain, fatigue or disability in people with CFS/ME when measured with the chronic pain coping index. Consequently, the utility and measurement of pacing require further investigation. PMID- 28843452 TI - The microbiome as a key regulator of brain, behavior and immunity: Commentary on the 2017 named series. AB - The focus on the microbiome for the 2017 Named Series in Brain, Behavior, and Immunity reflects the rapidly growing interest in commensal microbes and the effects that they can have on physiological processes often studied in PsychoNeuroImmunology Research. The studies included in this Named Series show that commensal microbes can impact immune system activity, as well as brain and behavioral processes across the lifespan, and are involved in behavioral and immunological responses to social stresses. The studies also show that dietary effects on brain, behavior, and immunity often involve alterations of the gut microbiota. Thus, diet can be used therapeutically for diseases and conditions involving the brain, behavior, and immunity, as can treatment with both pre- and probiotics. While this has been widely tested in animal models, fewer studies have focused on pre- and probiotic treatment in humans. The studies in this Named Series highlight the challenges of probiotic research in human populations, but also highlight the future promise of probiotics for human health. While emotional disorders, such as anxiety and depression have been often been linked to alterations in the gut microbiota, studies in this Named Series identify new domains involving interactions between the microbiota, brain, behavior, and immunity, including schizophrenia, traumatic brain injury, and stroke. As a whole, this collection of work demonstrates the importance of the microbiome in regulating key aspects of immunity, brain, and behavior, and provides important rationale for extending the work so that findings can be translated into clinical practice. PMID- 28843453 TI - Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia. AB - Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB1 and CB2 receptors, which may form heteromeric complexes (CB1-CB2Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-gamma-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB1 and circa 20 fold for CB2), whereas receptor levels were similar for CB1 and markedly upregulated for CB2; CB1 CB2Hets were also upregulated. Unlike in resting cells, CB2 receptors became robustly coupled to Gi in activated cells, in which CB1-CB2Hets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with beta-amyloid (Abeta1-42). Microglial activation markers were detected in the striatum of a Parkinson's disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant beta amyloid precursor protein (APPSw,Ind) mice, a transgenic Alzheimer's disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APPSw,Ind and in cells from control animals activated using LPS plus IFN-gamma. Expression of CB1-CB2Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB1-CB2Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB1-CB2 heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases. PMID- 28843454 TI - Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach. AB - BACKGROUND: Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. MAIN FINDINGS: Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. CONCLUSIONS: This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. PMID- 28843455 TI - End-of-Life Experience of Older Adults Dying of End-Stage Renal Disease: A Comparison With Cancer. AB - CONTEXT: Older adults with end-stage renal disease (ESRD) are a rapidly growing group of seriously ill patients. Yet, despite a mortality rate almost twice that of cancer, less is known about the impact of ESRD on patients' end-of-life experience. OBJECTIVE: To compare the end-of-life experience of older adults who died of ESRD vs. cancer. METHODS: We used data from the Health and Retirement Study, a nationally representative survey of older adults. Our sample included 1883 Health and Retirement Study participants who died of cancer or ESRD between 2000 and 2010 and their family respondents. We compared advance care planning, treatment intensity, and symptoms between the two groups and used propensity score weighting to adjust for differences by diagnosis. RESULTS: Among propensity weighted cohorts, older adults with ESRD, compared with similar patients with cancer, were less likely to have end-of-life instructions (adjusted proportions 38.5% vs. 49.7%; P = 0.005) and were more likely to die in the hospital (53.5% vs. 29.0%; P < 0.001) and to use the intensive care unit in the last two years of life (57.1% vs. 37.0%; P < 0.001). Decedents with ESRD and cancer had similarly high rates of moderate or severe pain (53.7% vs. 57.8%; P = 0.34) and all other symptoms. CONCLUSION: Older adults dying of ESRD had lower rates of advance care planning and higher treatment intensity near the end of life than similar patients dying of cancer; both groups had similarly high rates of symptoms. Efforts are needed to make treatment more supportive and alleviate suffering for older adults with ESRD and their families near the end of life. PMID- 28843456 TI - Prescribing Non-Opioid Drugs in End-Stage Kidney Disease. AB - Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles (hq@palliativedrugs.com). PMID- 28843457 TI - Development and Validation of a Family Meeting Assessment Tool (FMAT). AB - CONTEXT: A cornerstone procedure in Palliative Medicine is to perform family meetings. Learning how to lead a family meeting is an important skill for physicians and others who care for patients with serious illnesses and their families. There is limited evidence on how to assess best practice behaviors during end-of-life family meetings. OBJECTIVES: Our aim was to develop and validate an observational tool to assess trainees' ability to lead a simulated end-of-life family meeting. METHODS: Building on evidence from published studies and accrediting agency guidelines, an expert panel at our institution developed the Family Meeting Assessment Tool. All fourth-year medical students (MS4) and eight geriatric and palliative medicine fellows (GPFs) were invited to participate in a Family Meeting Objective Structured Clinical Examination, where each trainee assumed the physician role leading a complex family meeting. Two evaluators observed and rated randomly chosen students' performances using the Family Meeting Assessment Tool during the examination. Inter-rater reliability was measured using percent agreement. Internal consistency was measured using Cronbach alpha. RESULTS: A total of 141 trainees (MS4 = 133 and GPF = 8) and 26 interdisciplinary evaluators participated in the study. Internal reliability (Cronbach alpha) of the tool was 0.85. Number of trainees rated by two evaluators was 210 (MS4 = 202 and GPF = 8). Rater agreement was 84%. Composite scores, on average, were significantly higher for fellows than for medical students (P < 0.001). CONCLUSION: Expert-based content, high inter-rater reliability, good internal consistency, and ability to predict educational level provided initial evidence for construct validity for this novel assessment tool. PMID- 28843458 TI - A Systematic Review of the Patient- and Carer-Related Factors Affecting the Experience of Pain for Advanced Cancer Patients Cared for at Home. AB - CONTEXT: Effective pain management is a priority in the palliative care of advanced cancer patients. A body of research is emerging examining the factors that influence the management and experience of pain for such individuals. Identifying such factors should allow for the development of targeted interventions to improve pain management in the home while ultimately reducing unnecessary suffering for the patient. OBJECTIVES: The objective of this study was to identify relevant patient- and carer-related factors which have an effect on the pain experienced by advanced cancer patients cared for at home. METHOD: This is a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement guidelines. Studies were retrieved from the CINAHL, MEDLINE, and Web of Science and assessed independently by two reviewers with discrepancies assessed by a third before quality assessment and data extraction. A narrative synthesis was produced. RESULTS: Our search strategy produced 720 hits, of which 10 studies were retained for the final analysis. The factors identified included carer knowledge of cancer pain management, carer burden, carer and patient distress, pain rating disparity, patient well-being, patient depression, patient affective experience, patient body image, and satisfaction with palliative/medical care. All factors identified are supported by only some evidence with many having only been explored in single studies. CONCLUSIONS: There is a lack of quantitative research in the area of factors influencing the experience of pain for advanced cancer patients cared for at home. Such findings would be useful in developing theories of change that would underpin interventions aimed at improving pain outcomes for this population. PMID- 28843459 TI - Site and type of craniopharyngiomas impact differently on 24-hour circadian rhythms and surgical outcome. A neurophysiological evaluation. AB - This study aimed to quantify 24h body core temperature (BcT degrees ) and sleep wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24h BcT degrees and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24h BcT degrees rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24h BcT degrees remained pathological in only one out of six cases, returned to normal in two and improved in three. 24h BcT degrees rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT degrees rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome. PMID- 28843460 TI - Safety Threats During the Care of Infants with Hypoglycemic Seizures in the Emergency Department: A Multicenter, Simulation-Based Prospective Cohort Study. AB - BACKGROUND: Errors in the timely diagnosis and treatment of infants with hypoglycemic seizures can lead to significant patient harm. It is challenging to precisely measure medical errors that occur during high-stakes/low-frequency events. Simulation can be used to assess risk and identify errors. OBJECTIVE: We hypothesized that general emergency departments (GEDs) would have higher rates of deviations from best practices (errors) compared to pediatric emergency departments (PEDs) when managing an infant with hypoglycemic seizures. METHODS: This multicenter simulation-based prospective cohort study was conducted in GEDs and PEDs. In situ simulation was used to measure deviations from best practices during management of an infant with hypoglycemic seizures by inter-professional teams. Seven variables were measured: five nonpharmacologic (i.e., delays in airway assessment, checking dextrose, starting infusion, verbalizing disposition) and two pharmacologic (incorrect dextrose dose and incorrect dextrose concentration). The primary aim was to describe and compare the frequency and types of errors between GEDs and PEDs. RESULTS: Fifty-eight teams from 30 hospitals (22 GEDs, 8 PEDs) were enrolled. Pharmacologic errors occurred more often in GEDs compared to PEDs (p = 0.043), while nonpharmacologic errors were uncommon in both groups. Errors more frequent in GEDs related to incorrect dextrose concentration (60% vs. 88%; p = 0.025), incorrect dose (20% vs. 56%; p = 0.033), and failure to start maintenance dextrose (33% vs. 65%; p = 0.040). CONCLUSIONS: During the simulated care of an infant with hypoglycemic seizures, errors were more frequent in GEDs compared to PEDs. Decreasing annual pediatric patient volume was the best predictor of errors on regression analysis. PMID- 28843462 TI - Binding mode analysis, dynamic simulation and binding free energy calculations of the MurF ligase from Acinetobacter baumannii. AB - MurF ligase catalyzes the final cytoplasmic step of bacterial peptidoglycan biosynthesis and, as such, is a validated target for therapeutic intervention. Herein, we performed molecular docking to identify putative inhibitors of Acinetobacter baumannii MurF (AbMurF). Based on comparative docking analysis, compound 114 (ethyl pyridine substituted 3-cyanothiophene) was predicted to potentially be the most active ligand. Computational pharmacokinetic characterization of drug-likeness of the compound showed it to fulfil all the parameters of Muegge and the MDDR rule. A molecular dynamic simulation of 114 indicated the complex to be stable on the basis of an average root mean square deviation (RMSD) value of 2.09A for the ligand. The stability of the complex was further supported by root mean square fluctuation (RMSF), beta factor and radius of gyration values. Analyzing the complex using radial distribution function (RDF) and a novel analytical tool termed the axial frequency distribution (AFD) illustrated that after simulation the ligand is positioned in close vicinity of the protein active site where Thr42 and Asp43 participate in hydrogen bonding and stabilization of the complex. Binding free energy calculations based on the Poisson-Boltzmann or Generalized-Born Surface Area Continuum Solvation (MM(PB/GB)SA) method indicated the van der Waals contribution to the overall binding energy of the complex to be dominant along with electrostatic contributions involving the hot spot amino acids from the protein active site. The present results indicate that the screened compound 114 may act as a parent structure for designing potent derivatives against AbMurF in specific and MurF of other bacterial pathogens in general. PMID- 28843461 TI - A New Rule for Terminating Resuscitation of Out-of-Hospital Cardiac Arrest Patients in Japan: A Prospective Study. AB - BACKGROUND: The American Heart Association and European Resuscitation Council guidelines for cardiopulmonary resuscitation present rules for termination of resuscitation (TOR) in cases of out-of-hospital cardiac arrest (OHCA). In Japan, only doctors are legally allowed TOR in OHCA cases. OBJECTIVE: This study aimed to develop a new TOR rule that suits the actual situations of the Japanese emergency medical services system. METHODS: Five different combinations of the TOR rule criteria were compared regarding specificity and positive predictive value (PPV) for 1-month survival with unfavorable neurologic outcomes. The criteria were unwitnessed by emergency medical service personnel, unwitnessed by bystanders, initial unshockable rhythm in the field, initial asystole in the field, no shock delivered, no prehospital return of spontaneous circulation, unshockable rhythm at hospital arrival, and asystole at hospital arrival. RESULTS: A total of 13,291 cases were included. The following combination provided the highest specificity and PPV for predicting 1-month unfavorable neurologic outcomes and death: unwitnessed by bystanders, initial asystole in the field, and asystole at hospital arrival. The specificity and PPV for the combination of the three criteria for predicting 1-month unfavorable neurologic outcomes were 0.992 and 0.999, and for predicting death at 1 month after OHCA were 0.986 and 0.998, respectively. CONCLUSIONS: OHCA patients fulfilling the criteria unwitnessed by bystanders and asystole in the field and at hospital arrival had universally poor outcomes. Termination of resuscitation after hospital arrival for these patients may decrease unwarranted treatments. PMID- 28843463 TI - Liposomal bupivacaine versus interscalene nerve block for pain control after total shoulder arthroplasty: A systematic review and meta-analysis. AB - OBJECTIVE: To illustrate the efficacy liposomal bupivacaine versus interscalene nerve block for pain management after total shoulder arthroplasty. METHODS: A systematic search was performed in Medline, PubMed, Embase, ScienceDirect and the Cochrane Library. Data on patients prepared for total shoulder arthroplasty in studies that compared liposomal bupivacaine versus interscalene nerve block were retrieved. The endpoints were the visual analogue scale (VAS) and opioid consumption. Fixed/random effect model was used according to the heterogeneity tested by I2 statistic. Software of Stata 11.0 was used for pooling the final outcomes. RESULTS: Four randomized controlled trials (RCTs) including 510 patients met the inclusion criteria. The present meta-analysis indicated that there were no significant differences between groups in terms of VAS score at 12 h, 24 h, and 48 h (p > 0.05). No significant differences were found regarding to opioid consumption at postoperative 12 h, 24 h and 48 h (p > 0.05). CONCLUSION: Compared with interscalene nerve block, liposomal bupivacaine had comparative effectiveness on reducing both pain scores and opioid consumption. Higher quality RCTs are required for further research. PMID- 28843464 TI - Translating New Imaging Technologies to Clinical Practice. AB - Radiology continues to benefit from constant innovation and technological advances. However, for promising new imaging technologies to reach widespread clinical practice, several milestones must be met. These include regulatory approval, early clinical evaluation, payer reimbursement, and broader marketplace adoption. Successful implementation of new imaging tests into clinical practice requires active stakeholder engagement and a focus on demonstrating clinical value during each phase of translation. PMID- 28843465 TI - Coronary Artery Calcium Imaging in the ROBINSCA Trial: Rationale, Design, and Technical Background. AB - RATIONALE AND OBJECTIVES: To describe the rationale, design, and technical background of coronary artery calcium (CAC) imaging in the large-scale population based cardiovascular disease screening trial (Risk Or Benefit IN Screening for CArdiovascular Diseases [ROBINSCA]). MATERIALS AND METHODS: First, literature search was performed to review the logistics, setup, and settings of previously performed CAC imaging studies, and current clinical CAC imaging protocols of participating centers in the ROBINSCA trial were evaluated. A second literature search was performed to evaluate the impact of computed tomography parameter settings on CAC score. RESULTS: Based on literature reviews and experts opinion an imaging protocol accompanied by data management protocol was created for ROBINSCA. The imaging protocol should consist of a fixed tube voltage, individually tailored tube current setting, mid-diastolic electrocardiography triggering, fixed field-of-view, fixed reconstruction kernel, fixed slice thickness, overlapping reconstruction and without iterative reconstruction. The analysis of scans is performed with one type and version of CAC scoring software, by two dedicated and experienced researchers. The data management protocol describes the organization of data handling between the coordinating center, participating centers, and core analysis center. CONCLUSION: In this paper we describe the rationale and technical considerations to be taken in developing CAC imaging protocol, and we present a detailed protocol that can be implemented for CAC screening purposes. PMID- 28843466 TI - MatriDerm Decreases Donor Site Morbidity After Radial Forearm Free Flap Harvest in Transgender Surgery. AB - BACKGROUND: Phalloplasty with the radial forearm free flap is associated with a large donor site defect. AIM: To compare two methods of donor site closure for functional and cosmetic long-term results: full-thickness skin grafting vs split thickness skin grafting with MatriDerm. METHODS: Thirty-seven transgender patients had a neophallus created from a radial forearm free flap, and all were operated on by the same senior surgeon. Eight patients had their donor site defect closed by total skin grafting and 29 patients, operated on after 2009, received a split-thickness skin graft with MatriDerm closure. All 37 patients were evaluated by questionnaire and by careful clinical examination. Pressure perception was assessed with the Semmes-Weinstein monofilament test. Sensory recovery, skin quality, and cosmetic result also were compared. The contralateral arm was used as the control. OUTCOMES: Pressure perception values showed better sensory return in the MatriDerm group. Split-thickness skin grafting with MatriDerm achieved superior results in skin sensibility, superficial radial nerve recovery, and cosmetic aspect. RESULTS: Our findings support the hypothesis that MatriDerm can be used to preserve sensory function and decrease morbidity of the donor site. CLINICAL IMPLICATIONS: The use of a dermal substitute decreases the morbidity of the forearm free flap donor site. STRENGTHS AND LIMITATIONS: The strength of this study is its retrospective nature conducted of a prospectively maintained database of 37 consecutive radial forearm free flaps with superimposable dimensions and location performed by the same surgeon, thus limiting biases. A limitation is its small sample (particularly for the control group). CONCLUSION: Our experience showed that the combination of a split thickness skin graft with MatriDerm substantially decreases postoperative complications at the donor site defect on the forearm of transgender patients. Watfa W, di Summa PG, Meuli J, et al. MatriDerm Decreases Donor Site Morbidity After Radial Forearm Free Flap Harvest in Transgender Surgery. J Sex Med 2017;14:1277-1284. PMID- 28843467 TI - The importance of evidence to maintain the health of military service members. PMID- 28843468 TI - Equipping military nurses with evidence to care for the wounded. PMID- 28843469 TI - A Genotype-First Approach for Clinical and Genetic Evaluation of Wolcott-Rallison Syndrome in a Large Cohort of Iranian Children With Neonatal Diabetes. AB - OBJECTIVE: Wolcott-Rallison syndrome (WRS) is an extremely rare autosomal recessive condition, characterized by permanent neonatal diabetes mellitus (PNDM) associated with skeletal dysplasia, growth retardation and liver dysfunction. WRS is caused by biallelic mutations in the gene encoding eukaryotic translation initiation factor 2alpha kinase 3 (EIF2AK3). METHODS: As part of a comprehensive study on clinical and genetic investigation of neonatal diabetes in an Iranian population, 60 unrelated Iranian subjects referred with PNDM were analyzed. All the probands were screened for KCNJ11, INS, ABCC8 and EIF2AK3 using a polymerase chain reaction-based sequencing approach. RESULTS: We identified 9 different variants in EIF2AK3 in 11 unrelated Iranian probands, of which 5 variants were shown to be novel and not reported previously. The diagnosis of WRS was made by molecular genetic testing and confirmed by clinical re-evaluation of the subjects. Clinical follow up of the affected individuals shows that in at least some of them, PNDM was associated with short stature, failure to thrive, neurodevelopmental delay, epilepsy and hepatic and renal dysfunction. There was a strong family history of neonatal diabetes in the families of the probands with a high mortality rate. CONCLUSION: WRS is a common cause of PNDM in children of consanguineous parents. Furthermore, clinical diagnosis of WRS would have been delayed or possibly missed without genetic testing because this study shows that the associated features of WRS might be obscured by a diagnosis of PNDM. Therefore EIF2AK3 should be considered for any infant and young child with PNDM, particularly if the parents are related. PMID- 28843470 TI - Pediatric Type 1 Diabetes: Patients' and Caregivers' Perceptions of Glycemic Control. AB - OBJECTIVES: (1) to describe pediatric patients with T1D and their caregivers' perceptions of measures of glycemic control (hemoglobin [A1C] and blood glucose [BG] levels) and (2) to determine the relationship between patients' and caregivers' perceptions of measures of glycemic control with actual A1C levels and adherence to diabetes self-care behaviors. METHODS: Patients (8 to 18 years) with T1D and caregivers completed questionnaires that queried their perceptions of (1) what the A1C level assesses, (2) the ideal A1C target, and (3) the ideal BG range. Point-of-care A1C levels were measured for each patient. They also completed the Self-Care Inventory Revised (SCI-R) to assess adherence to diabetes self-care behaviors. RESULTS: Among 253 dyads, the frequencies of patients compared to caregivers who could accurately describe what the A1C level assesses, identify the ideal A1C target, and identify the ideal BG range were 20 vs. 66, 31 vs. 56, and 72 vs. 76%, respectively. Patients' accuracy in reporting ideal targets for glycemic control was significantly associated with caregivers' accuracy. There was a trend for lower median A1C levels in patients who were part of a dyad wherein both had accurate perceptions of glycemic control. CONCLUSIONS: Patients and caregivers had accurate knowledge of ideal BG range but were less knowledgeable about the meaning of A1C levels and ideal A1C targets. Nevertheless, whether glycemic control was perceived as an A1C measurement or a BG range, A1C levels trended lower for patients when both they and their caregivers had accurate perceptions of glycemic control. PMID- 28843471 TI - Should the Clinical Criteria for Suspecting Glucokinase Mutation-Related Hyperglycemia (MODY-2) Be Revisited During Pregnancy? PMID- 28843472 TI - Response to the Letter to the Editor From Dr. Spence, "Egg Consumption and Cardiovascular Risk". PMID- 28843473 TI - Choosing the Best Therapy for Your Patients in Today's Diabetes World. PMID- 28843474 TI - Response to the Letter to the Editor From Dr. Kawada, "Predictors of Serum Adiponectin in Patients With Prediabetes and Type 2 Diabetes". PMID- 28843475 TI - Endoscopic treatment of urethrodeferential reflux in children. AB - INTRODUCTION: Urethrodeferential reflux is an underdiagnosed condition, and there is no consensus on its treatment. Our objective is to show our experience in the minimally invasive treatment of this disease using endoscopy. MATERIAL AND METHODS: We present 8 patients with recurrent suppurative orchitis due to urethrodeferential reflux treated endoscopically during the period 2008-2013. All patients presented unilateral orchitis. The minimum number of episodes of orchitis per patient prior to the operation was 3. The endoscopic treatment consists of ureteroscopy, locating the ejaculatory orifices and conducting an intraoperative contrast study to demonstrate the urethrodeferential reflux. Subejaculatory dextranomer/hyaluronic acid was subsequently injected in all the cases. RESULTS: The mean surgical time was 15min, and the procedure was outpatient for all patients. There were no postoperative complications, and the patients had good clinical progression. Only one case required a second injection of dextranomer/hyaluronic acid. The follow-up of these patients showed a complete resolution of the epididymitis and good testicular development, with a follow-up longer than 4 years in all cases. CONCLUSION: We propose this form of treatment as a minimally invasive, easily reproducible alternative that shows good long term results in our small series of patients. PMID- 28843476 TI - Corrections. PMID- 28843477 TI - Unusual osteolytic lesion of the jaw. PMID- 28843478 TI - Chronic alcohol consumption regulates the expression of poly immunoglobulin receptor (pIgR) and secretory IgA in the gut. AB - The effect of ethanol (EtOH) on the gut immune system was analyzed using an experimental model previously described, where EtOH was provided ad libitum in the drinking water in a 20% w/v concentration for up to 12weeks. Dendritic cells, T cells and macrophages were analyzed in Peyer's patches and the small intestines using flow cytometry. Cytokine and immunoglobulin levels were analyzed in sera, feces, and homogenates from small and large intestines and lungs. Decreases in the proportion of T cells and alterations in dendritic cells and macrophages were observed after EtOH treatment. Levels of immunoglobulin A (IgA) increased in tissue homogenates but decreased in small intestine fecal contents. Meanwhile poly-immunoglobulin receptor (pIgR) levels decreased in tissue homogenates and fecal contents. Levels of cytokines associated with the regulation of pIgR expression decreased for IL-10 and TGF-beta, and increased for IFN-gamma and IL 17 in the small intestine. The data indicate that chronic EtOH consumption disrupts the homeostasis of the mucosal immune system by altering the phenotype and functionality of multiple immune cell types, leading to a diminished secretion of SIgA, due to pIgR expression decreased. PMID- 28843479 TI - Chreods, homeorhesis and biofields: Finding the right path for science through Daoism. AB - C.H. Waddington's concepts of 'chreods' (canalized paths of development) and 'homeorhesis' (the tendency to return to a path), each associated with 'morphogenetic fields', were conceived by him as a contribution to complexity theory. Subsequent developments in complexity theory have largely ignored Waddington's work and efforts to advance it. Waddington explained the development of the concept of chreod as the influence on his work of Alfred North Whitehead's process philosophy, notably, the concept of concrescence as a self-causing process. Processes were recognized as having their own dynamics, rather than being explicable through their components or external agents. Whitehead recognized the tendency to think only in terms of such 'substances' as a bias of European thought, claiming in his own philosophy 'to approximate more to some strains of Indian, or Chinese, thought, than to western Asiatic, or European, thought.' Significantly, the theoretical biologist who comes closest to advancing Waddington's research program, also marginalized, is Mae-Wan Ho. Noting this bias, and embracing Whitehead's and Waddington's efforts to free biology from assumptions dominating Western thought to advance an ontology of creative causal processes, I will show how later developments of complexity theory, most importantly, Goodwin's work on oscillations, temporality and morphology, Vitiello's dissipative quantum brain dynamics, Salthe's work on hierarchy theory, biosemiotics inspired by Peirce and von Uexkull, Robert Rosen's work on anticipatory systems, together with category theory and biomathics, can augment while being augmented by Waddington's work, while further advancing Mae-Wan Ho's radical research program with its quest to understand the reality of consciousness. PMID- 28843480 TI - Conjoined Tendon Transfer for Traumatic Anterior Glenohumeral Instability in Patients With Large Bony Defects and Anterior Capsulolabral Deficiency. AB - PURPOSE: To report outcomes of a conjoined tendon transfer procedure in a small case series of young active patients of various activity levels with recurrent traumatic anterior shoulder instability. METHODS: A retrospective chart review identified 10 consecutive patients who underwent conjoined tendon transfer (8 open and 2 arthroscopic) for anterior glenohumeral instability from January 2009 through December 2012. The indications were traumatic anterior shoulder instability with 25% or greater anterior glenoid bone loss, engaging Hill-Sachs lesion, or absent anterior-inferior labral tissue with anterior capsular tissue that did not readily hold sutures or a combination of these deficiencies. Patients did not undergo the procedure if they had healthy capsulolabral tissue and small bony defects or if they competed in high-level collision sports or were overhead throwers. The American Shoulder and Elbow Surgeons (ASES) questionnaire and a physical examination were completed preoperatively. Postoperatively, patients answered questions about shoulder stability and completed ASES and Western Ontario Shoulder Index questionnaires. A physical examination was performed postoperatively to assess range of motion. RESULTS: Of 10 patients, 9 were available for follow-up. The mean age was 33.0 years (range, 18-51 years) at the time of surgery. Eight of nine patients underwent a physical examination at 31.3 +/- 10.5 months (range, 24-58 months) postoperatively. There were no revisions or complications except for recurrent instability in 1 patient who underwent the arthroscopic procedure and reported gross deviation from the postoperative protocol. The ASES score improved significantly (62.8 +/- 21.2 at baseline vs 89.2 +/- 11.5 at final follow-up, P = .01). The postoperative Western Ontario Shoulder Index score was 74.5 +/- 19.7. No significant change was found in external rotation in 90 degrees of abduction (80.6 degrees +/- 12.9 degrees at baseline vs 88.4 degrees +/- 6.1 degrees at final follow-up, P = .11) or in flexion (145.6 degrees +/- 14.9 degrees at baseline vs 153.1 degrees +/- 16.4 degrees at final follow-up, P = .19). All patients returned to their previous activity level. CONCLUSIONS: Stability was restored and no significant range-of motion loss was observed in noncollision athletes who underwent conjoined tendon transfer. Recurrent instability occurred in 1 patient who underwent the arthroscopic procedure. There were no other complications. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28843481 TI - Prevalence of Borrelia miyamotoi and Borrelia burgdorferi sensu lato in questing ticks from a recreational coniferous forest of East Saxony, Germany. AB - The hard tick Ixodes ricinus is the most important vector of tick-transmitted pathogens in Europe, frequently occurring in urban parks and greenbelts utilized for recreational activities. This species is the most common vector of the causative agents of Lyme borreliosis in Europe. Similarly, the species spreads Borrelia miyamotoi, causing a relapsing-fever like illness. A total of 1774 Ixodes ricinus (50 females, 68 males, 840 nymphs and 818 larvae) were collected with flagging between March and September 2014 in a coniferous forest patch in Niederkaina near the town of Bautzen in Saxony, Germany. To measure questing tick density a time-based density estimating method was utilized. From each month, a total of 100 adults and nymphal ticks and all larvae (pools of 10 individuals per tube/month) were selected for the molecular analyses. For simultaneous detection of B. burgdorferi s.l. and B. miyamotoi a duplex real-time PCR targeting the flaB locus was performed. Prevalence of B. burgdorferi s.l. was 9.4% (female: 6%, male: 2.9%, nymph: 12.2%, larva: 0%) and minimum prevalence of B. miyamotoi was 1.2% (female: 0%, male: 4.3%, nymph: 2.8%, larva: 0.1%) in the 714 samples with real-time polymerase chain reaction. A real-time PCR reaction was utilized first to target the histone-like protein gene (hbb) of B. burgdorferi s.l., a hemi nested outer surface protein (ospA) gene conventional PCR was then performed followed by a restriction enzyme analysis to distinguish B. burgdorferi s.l. genospecies. Seven B. afzelii, one B. burgdorferi s.s., one B. bavariensis and four B. miyamotoi infections were confirmed. Prevalence of Lyme borreliosis spirochetes was significantly higher in nymphs than in adults (p<0.01, Fisher exact test) probably due to the diluting effect of the local roe deer population. Our data highlight the potential risk of human infection with the emerging pathogen B. miyamotoi within the study area. PMID- 28843482 TI - Should we continue to perform single-port laparoscopic cholecystectomy? PMID- 28843483 TI - Guidelines for Developing Successful Short Advanced Courses in Systems Medicine and Systems Biology. AB - Systems medicine and systems biology have inherent educational challenges. These have largely been addressed either by providing new masters programs or by redesigning undergraduate programs. In contrast, short courses can respond to a different need: they can provide condensed updates for professionals across academia, the clinic, and industry. These courses have received less attention. Here, we share our experiences in developing and providing such courses to current and future leaders in systems biology and systems medicine. We present guidelines for how to reproduce our courses, and we offer suggestions for how to select students who will nurture an interdisciplinary learning environment and thrive there. PMID- 28843484 TI - Cell-Cycle Position of Single MYC-Driven Cancer Cells Dictates Their Susceptibility to a Chemotherapeutic Drug. AB - While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G1 phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle. PMID- 28843485 TI - Novel Transfer of Care Sign-out Assessment Tool in a Pediatric Emergency Department. AB - OBJECTIVE: Transfer of care sign-outs (TOCS) for admissions from a pediatric emergency department have unique challenges. Standardized and reliable assessment tools for TOCS remain elusive. We describe the development, reliability, and validity of a TOCS assessment tool. METHODS: Video recordings of resident TOCS were assessed to capture 4 domains: completeness, synopsis, foresight, and professionalism. In phase 1, 56 TOCS were used to modify the tool and improve reliability. In phase 2, 91 TOCS were used to examine validity. Analyses included Cronbach's alpha for internal structure, intraclass correlation and Cohen's kappa for interrater reliability, Pearson's correlation for relationships between variables, and 95% confidence interval of the mean for resident group comparisons. RESULTS: Cronbach's alpha was 0.52 for internal structure of the tool's subjective rating scale. Intraclass correlation for the subjective rating scale items ranged from 0.70 to 0.80. Cohen's kappa for most objective checklist items ranged from 0.43 to 1. Content completeness was significantly correlated with synopsis, foresight, and professionalism (Pearson's r ranged from 0.36 to 0.62, P values were <0.001). House staff senior residents scored higher (on average) than interns and rotating senior residents in synopsis and foresight. Also, house staff interns scored higher (on average) than rotating senior residents in professionalism. House staff senior residents scored higher (on average) than rotating senior residents in content completeness. CONCLUSIONS: We provide validity evidence to support using scores from the TOCS tool to assess higher-level transfer of care comprehension and communication by pediatric emergency department residents and to test interventions to improve TOCS. PMID- 28843486 TI - Children With Medical Complexity: A Web-Based Multimedia Curriculum Assessing Pediatric Residents Across North America. AB - OBJECTIVE: No standardized curricula exist for training residents in the special needs of children with medical complexity. We assessed resident satisfaction, knowledge, and behavior after implementing a novel online curriculum composed of multimedia modules on care of children with medical complexity utilizing virtual simulation. METHODS: We conducted a randomized controlled trial of residents across North America. A Web-based curriculum of 6 self-paced, interactive, multimedia modules was developed. Readings for each topic served as the control curriculum. Residents were randomized to 1 of 2 groups, each completing 3 modules and 3 sets of readings that were mutually exclusive. Outcomes included resident scores on satisfaction, knowledge-based assessments, and virtual simulation activities. RESULTS: Four hundred forty-two residents from 56 training programs enrolled in the curriculum, 229 of whom completed it and were included in the analysis. Subjects were more likely to report comfort with all topics if they reviewed modules compared to readings (P <= .01 for all 6 topics). Posttest knowledge scores were significantly higher than pretest scores overall (mean increase in score 17.7%; 95% confidence interval 16.0, 19.4), and the mean pre post score increase for modules was significantly higher than readings (20.9% vs 15.4%, P < .001). Mean scores on the verbal handoff virtual simulation increased by 1.1 points (95% confidence interval 0.2, 2.0, P = .02). There were no significant differences found in pre-post performance for the device-related emergency virtual simulation. CONCLUSIONS: There was high satisfaction, significant knowledge acquisition, and specific behavior change after participating in this innovative online curriculum. This is the first multisite, randomized trial assessing satisfaction, knowledge impact, and behavior change in a virtually simulated environment with pediatric trainees. PMID- 28843488 TI - Objective Measures of Psoriasis Severity Predict Mortality: A Prospective Population-Based Cohort Study. PMID- 28843487 TI - STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network. AB - Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma. PMID- 28843489 TI - [Early drop-outs and retentions in substance abuse outpatient clinics: a cross sectional comparative study of factors that increase or decrease adherence]. AB - AIM: The aim of this study is to define the risk factors associated with early discharge in out-patients clinics. DESIGN: Cross-sectional and observational study. SETTING: Substance abuse clinics in Girona (Catalonia, Spain). PARTICIPANTS: A total of 264 individuals were included in the sample, and 34.8% of them abandoned the process within two months of starting the therapy (n=92). PROCEDURE: Clinical and socio-demographic variables of the clinical history were compared between participants with/without adherence. MAIN MEASUREMENTS: The Student t test was used to measure the comparison, and the chi-squared test was used for the analysis of qualitative variables. A binary logistic regression model was adjusted, with adherence as the dependent variable. RESULTS: The results indicated that attending the appointments unaccompanied (OR=3.13), being female (OR=2.44), having cocaine related issues (OR=1.14), and being younger (OR=0.89) are the factors which increase the risk early abandonment. Contrarily, being referred to specialists from a Primary Health Centre reduces the risk (OR=0.28). CONCLUSIONS: It is concluded that special attention must be devoted to the patients' families, women, and young patients. Moreover, the appropriate coordination between specialist services and basic services increases adherence to treatment among drug users. PMID- 28843490 TI - [Application of the Smoking Scale for Primary Care (ETAP) in clinical practice]. AB - OBJECTIVE: To determine if the ETAP smoking scale, which measures accumulated exposure to tobacco, both actively and passively, is applicable and effective in the clinical practice of Primary Care for the prevention of acute myocardial infarction (AMI). Location Barranco Grande Health Centre in Tenerife, Spain. DESIGN: A study of 61 cases (AMI) and 144 controls. Sampling with random start, without matching. COR-II curves were analysed, and effectiveness was estimated using sensitivity and negative predictive value (NPV). A questionnaire was provided to participating family physicians on the applicability of ETAP in the clinic. RESULTS: The opinion of the participating physicians was unanimously favourable. ETAP was easy to use in the clinic, required less than 3min per patient, and was useful to reinforce the preventive intervention. The ETAP COR-II curve showed that 20years of exposure was the best cut-off point, with an area under the curve of 0.70 (95%CI: 0.62-0.78), and a combination of sensitivity (98%) and NPV (96%) for AMI. When stratifying age and gender, all groups achieved sensitivities and NPVs close to 100%, except for men aged >=55years, in whom the NPV fell to 75%. CONCLUSIONS: The results indicate that ETAP is a valid tool that can be applied and be effective in the clinical practice of Primary Care for the prevention of AMI related to smoking exposure. PMID- 28843491 TI - Recognition and management of common, rare, and novel serum protein electrophoresis and immunofixation interferences. AB - Protein electrophoresis and immunofixation are subject to a variety of analytical interferences that may affect monoclonal protein diagnostics performed in the context of monoclonal gammopathies. Interferences include endogenous substances, such as hemoglobin and fibrinogen, and exogenous compounds, such as radiocontrast dyes, antibiotics, and monoclonal antibody therapies. General approaches to managing interferences begin with recognition of the problem. Provided herein are examples of common, rare, and novel interferences with the goal of providing a comprehensive overview. With each example, specific methods and strategies are provided to manage analytical interferences to ensure that interpretative reports are accurate. Longstanding and newer technologies are also described to contextualize where interferences may be identified and avoided. PMID- 28843492 TI - Effects of gasoline and ethanol-gasoline exhaust exposure on human bronchial epithelial and natural killer cells in vitro. AB - Air pollution exposure, including passenger car emissions, may cause substantial respiratory health effects and cancer death. In western countries, the majority of passenger cars are driven by gasoline fuel. Recently, new motor technologies and ethanol fuels have been introduced to the market, but potential health effects have not been thoroughly investigated. We developed and verified a coculture model composed of bronchial epithelial cells (ECs) and natural killer cells (NKs) mimicking the human airways to compare toxic effects between pure gasoline (E0) and ethanol-gasoline-blend (E85, 85% ethanol, 15% gasoline) exhaust emitted from a flexfuel gasoline car. We drove a steady state cycle, exposed ECs for 6h and added NKs. We assessed exhaust effects in ECs alone and in cocultures by RT-PCR, flow cytometry, and oxidative stress assay. We found no toxic effects after exposure to E0 or E85 compared to air controls. Comparison between E0 and E85 exposure showed a weak association for less oxidative DNA damage after E85 exposure compared to E0. Our results indicate that short-term exposure to gasoline exhaust may have no major toxic effects in ECs and NKs and that ethanol as part of fuel for gasoline cars may be favorable. PMID- 28843493 TI - Utilization of iPSC-derived human neurons for high-throughput drug-induced peripheral neuropathy screening. AB - As the number of cancer survivors continues to grow, awareness of long-term toxicities and impact on quality of life after chemotherapy treatment in cancer survivors has intensified. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common side effects of modern chemotherapy. Animal models are used to study peripheral neuropathy and predict human risk; however, such models are labor-intensive and limited translatability between species has become a major challenge. Moreover, the mechanisms underlying CIPN have not been precisely determined and few human neuronal models to study CIPN exist. Here, we have developed a high-throughput drug-induced neurotoxicity screening model using human iPSC-derived peripheral-like neurons to study the effect of chemotherapy agents on neuronal health and morphology using high content imaging measurements (neurite length and neuronal cell viability). We utilized this model to test various classes of chemotherapeutic agents with known clinical liability to cause peripheral neuropathy such as platinum agents, taxanes, vinca alkaloids, proteasome inhibitors, and anti-angiogenic compounds. The model was sensitive to compounds that cause interference in microtubule dynamics, especially the taxane, epothilone, and vinca alkaloids. Conversely, the model was not sensitive to platinum and anti-angiogenic chemotherapeutics; compounds that are not reported to act directly on neuronal processes. In summary, we believe this model has utility for high-throughput screening and prediction of human risk for CIPN for novel chemotherapeutics. PMID- 28843494 TI - Phosphorylation of Lbx1 controls lateral myoblast migration into the limb. AB - The migration of limb myogenic precursors from limb level somites to their ultimate site of differentiation in the limb is a paradigmatic example of a set of dynamic and orchestrated migratory cell behaviours. The homeobox containing transcription factor ladybird homeobox 1 (Lbx1) is a central regulator of limb myoblast migration, null mutations of Lbx1 result in severe disruptions to limb muscle formation, particularly in the distal region of the limb in mice (Gross et al., 2000). As such Lbx1 has been hypothesized to control lateral migration of myoblasts into the distal limb anlage. It acts as a core regulator of the limb myoblast migration machinery, controlled by Pax3. A secondary role for Lbx1 in the differentiation and commitment of limb musculature has also been proposed (Brohmann et al., 2000; Uchiyama et al., 2000). Here we show that lateral migration, but not differentiation or commitment of limb myoblasts, is controlled by the phosphorylation of three adjacent serine residues of LBX1. Electroporation of limb level somites in the chick embryo with a dephosphomimetic form of Lbx1 results in a specific defect in the lateral migration of limb myoblasts. Although the initial delamination and migration of myoblasts is unaffected, migration into the distal limb bud is severely disrupted. Interestingly, myoblasts undergo normal differentiation independent of their migratory status, suggesting that the differentiation potential of hypaxial muscle is not regulated by the phosphorylation state of LBX1. Furthermore, we show that FGF8 and ERK mediated signal transduction, both critical regulators of the developing limb bud, have the capacity to induce the phosphorylation of LBX1 at these residues. Overall, this suggests a mechanism whereby the phosphorylation of LBX1, potentially through FGF8 and ERK signalling, controls the lateral migration of myoblasts into the distal limb bud. PMID- 28843495 TI - High-intensity interval versus moderate-intensity continuous training: Superior metabolic benefits in diet-induced obesity mice. AB - AIMS: Exercise is beneficial in obesity, however, the debate about the value of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) has been long lasting. Therefore, here we have compared the possible beneficial effects of two different exercise training regimes in a mouse model of diet-induced obesity (DIO). MATERIALS AND METHODS: Following 7wk. on high fat diet (HFD), ten-week-old male ICR mice (n=30) were assigned to HIIT, distance-matched MICT or remained sedentary for the next 8 constitutive weeks while maintaining the dietary treatments. Age-matched sedentary mice with standard diet were used as a control (n=10). Exercise was performed on a motorized treadmill for 5days a week. KEY FINDINGS: Both modes of exercise ameliorated adiposity and related metabolic dysfunction induced by HFD and sedentary lifestyle, while mice following HIIT exhibited significantly lower body weight, percentage of fat mass and smaller adipocyte size. HIIT was more favorable in preventing liver lipid accumulation by restoring mRNA levels of genes involved in hepatic lipogenesis (SREBP1, ACC1, FAS) and beta-oxidation (PPARalpha, CPT1a, HAD). In addition, HIIT was more efficient in mitigating adipose tissue inflammation and insulin insensitivity, partly dependent on abrogating phosphorylation of JNK/IRS1 (Ser307) pathway. Moreover, only HIIT led to pronounced beige adipocyte recruitment in inguinal subcutaneous adipose tissue. SIGNIFICANCE: We conclude that HIIT contribute a more favorable regulation of metabolic dysfunctions in DIO mice compared with MICT. PMID- 28843496 TI - Specific immune responses in mice following subchronic exposure to acetamiprid. AB - AIMS: Acetamiprid (ACE) is an insecticide of the neonicotinoid family, the most widely used in the world. Herein, we assessed the effect of ACE on either the humoral or cellular immune responses of rodents. We also evaluated the role of curcumin in the restoration of altered immune responses after ACE treatment. METHODS: Five groups of five Swiss Albino mice were immunized intraperitoneally with the recombinant form of CFP32, a virulence factor of Mycobacterium tuberculosis. One group received ACE (5mg/kg) during 61days, a second one received ACE associated with curcumin (100mg/kg). Three control groups were included; one untreated, the second received corn oil and the third received curcumin alone. The humoral immune response was assessed by ELISA testing the anti-rCFP32 antibody concentrations in the serum. The cellular immune response was assessed by analyzing the cellular proliferation of the splenocytes stimulated in vitro by a mitogen or rCFP32. RESULTS: The ACE-treated mice showed a significant immunosuppression of the specific humoral response with a restorative effect of curcumin when administered with ACE. Similarly, ACE significantly decreased the level of splenocyte proliferation after either a non specific or a specific activation. Curcumin partially restores the antigen specific cellular immune response. Moreover, when administered alone, curcumin significantly inhibits the proliferative responses to the mitogen confirming its anti-mitogenic effect. Histological analysis showed alteration of spleens of mice exposed to ACE. SIGNIFICANCE: Altogether, our data indicated that ACE could potentially be harmful to the immune system. PMID- 28843497 TI - Long noncoding RNA UCA1 promotes tumour metastasis by inducing GRK2 degradation in gastric cancer. AB - Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) regulate gene and protein expression by exerting an influence on transcriptional and post transcriptional processes. Here, we report that the lncRNA UCA1 increases the metastatic ability of gastric cancer (GC) cells by regulating GRK2 protein stability by promoting Cbl-c-mediated GRK2 ubiquitination and degradation. This process then activates the ERK-MMP9 signalling pathway. Furthermore, we demonstrate that GRK2 is downregulated in GC cells and that silencing of GRK2 might cause similar phenotypic changes and signalling pathway activation as those induced by elevated UCA1 in GC cells. Our results suggest that UCA1 might function as a mediator of protein ubiquitination and may be a promising molecular target for GC therapy. PMID- 28843498 TI - The relationship between education debt and career choices in professional programs: The case of dentistry. AB - BACKGROUND: The authors examined the relationship between education debt and career choice, particularly dentists' decisions to specialize, participate in public health insurance programs, and join dental management service organizations (DMSOs). METHODS: The authors used data from the American Dental Association 2015 office database, which contains dentist demographic information and identifies dentists who participate in public health insurance programs for pediatric dental care services. The authors merged this database with the 2002 2015 American Dental Association Survey of Dental Graduates, which contains information about education debt, to assess the relationship between education debt and career choices. The authors used probit and multinomial logit models to determine the relationships among education debt, demographic characteristics, and dentist career choices. RESULTS: For each $10,000 increase in education debt, dentists were 0.9% more likely to join a DMSO (relative risk ratio, 1.009; 95% confidence interval, 1.0021 to 1.0164) and 0.6% less likely to join a non-DMSO group practice (relative risk ratio, 0.994; 95% confidence interval, 0.9897 to 0.9987) over a solo practice. Education debt did not have a statistically significant association with the decision to participate in public health insurance programs, but it did have a statistically significant association with the decision to specialize. CONCLUSIONS: Education debt had a modest association with some career choices among dentists. Demographic characteristics, such as race and sex, had a greater association. PRACTICAL IMPLICATIONS: Dental education debt has increased substantially in recent years. Debt had only a modest association with some career choices. Policy makers could consider this when considering education debt relief. PMID- 28843499 TI - Intrapocket topical anesthetic versus injected anesthetic for pain control during scaling and root planing in adult patients: Systematic review and meta-analysis. AB - BACKGROUND: In this systematic review and meta-analysis, the authors evaluated the pain during scaling and root planing with use of topical anesthetic versus that with the use of injected anesthetic in adult patients. TYPES OF STUDIES REVIEWED: The authors searched 6 databases for randomized clinical trials in which the investigators compared the clinical effectiveness of intrapocket and injectable anesthetics. The primary outcome was the risk of developing pain or intensity of pain. Quality assessment followed the guidelines from the Cochrane Collaboration's risk-of-bias tool. The authors performed meta-analyses on studies considered at low and unclear risk of bias. RESULTS: From 976 articles identified, 6 remained in the qualitative synthesis (4 at low and 2 at unclear risk of bias). Injected anesthetic produced lower pain intensity than did anesthetic gel (P = .03) and required less rescue anesthetic than did topical anesthetic (P < .0001). There was no difference in patient preference (P = .09). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Injected anesthetic decreased the intensity of pain and the need for rescue anesthetic during scaling and root planing, but the risk of developing pain yielded similar results for injected and topical anesthetics. PMID- 28843500 TI - Mandibular implant-retained overdenture relining procedure with an attachment system: A step-by-step demonstration of the technique. AB - BACKGROUND AND OVERVIEW: Because of continuous alveolar bone resorption, implant retained overdentures need to be relined. The purpose of this study was to describe a method for relining an implant-retained overdenture. CASE DESCRIPTION: The authors present a step-by-step technique. A 65-year-old patient sought care for trauma and pain in the oral mucosa underneath his mandibular implant-retained overdenture. The overdenture had been fabricated 4 years previously. In addition, the patient mentioned the denture's lack of stability during function. On the basis of the patient's dental history, and clinical and radiographic examination results, the authors found alveolar bone resorption. CONCLUSIONS AND PRACTICAL IMPLICATIONS: In this case report, the authors describe the technique, analyze the procedure of implant-retained overdenture relining with a Locator attachment system (Locator abutment, H3, SP MB SZL03 for internal hex implants; MIS Seven), and describe how to restore the contact of the denture base with the denture bearing tissues. The goal of this technique for the general dentist is to eliminate patients' tissue trauma and pain and increase the stability and support of the prosthesis. PMID- 28843501 TI - Real-time imaging reveals unique heterogeneous population features in insect cell cultures. AB - Heterogeneity of cellular populations has been frequently observed. We used live cell imaging to follow Sf9 insect cells before and after infection with baculovirus, to understand population dynamics. It was possible to identify in real time cells with distinctive phenotypes. Mobile cells with an elongated bipolar shape were observed. They extended pseudopods and actively moved about the culture surface. The presence of actively moving elongated cells increased when cultures were subjected to oxygen limiting or excessive conditions, suggesting that stress triggered differentiation of cells to the mobile phenotype. A dual reporter baculovirus (DRBac), coding for two fluorescent proteins under promoters with different temporality, was designed to follow sequential phenomena through infection. Oxygen limitation reduced the number of cells that expressed the reporter proteins, possibly because it reduced the efficiency of baculovirus infection. Elongated cells did not show signs of infection. To our knowledge, this is the first time that actively moving cells are observed in real time in Sf9 cultures, which had distinctive responses towards infection. Anoxia was identified as a factor that modulates baculovirus infection. Results open a new approach for understanding the insect-cell baculovirus system. Particular cellular phenotypes with unique traits can be isolated for specific applications. PMID- 28843502 TI - A novel geminivirus identified in tomato and cleome plants sampled in Brazil. AB - Viruses in the family Geminiviridae have single-stranded DNA genomes encapsulated in geminate icosahedral particles. High throughput sequencing (HTS) for metagenomic approaches are being extensively used for the identification of known and novel viruses. Using a HTS approach, we identified a novel geminivirus in a tomato (Solanum lycopersicum) sample and a Cleome sp. sample collected in the midwest region of Brazil. The genomes from the two samples share 99.96% identity and ~61-63% to genomes in the genus Capulavirus. The novel virus has been tentatively named tomato associated geminivirus 1 (TaGV1). No visual symptoms were observed in the field tomato plant or in the inoculated Nicotiana benthamiana where the virus established a systemic infection. The replication associated protein of TaGV1 is most similar to that encoded by capulaviruses (sharing 62-70% identity), whereas the CP is most similar to that of tomato pseudo curly top virus (sharing ~31% identity). In the TaGV1 positive Cleome sp. sample, begomovirus DNA A and B components were also detected sharing 96% and 90% sequence identity to cleome leaf crumple virus DNA A and B components, respectively. Using a HTS approach, we identified TaGV1 in tomato and Cleome sp. samples and this is the first report of a geminivirus that is non-begomovirus in Brazil. PMID- 28843503 TI - Cyp7a1 is continuously increased with disrupted Fxr-mediated feedback inhibition in hypercholesterolemic TALLYHO/Jng mice. AB - TALLYHO/Jng (TH) mice reveal hypercholesterolemia at an early age before their plasma glucose levels have increased. The increased plasma cholesterol should be related to bile acids (BAs) metabolism, because cholesterol is the precursor of BAs and BAs change cholesterol metabolism in a feedback manner. We analyzed the BAs pool size, BAs composition, and expression levels of several proteins that have key roles in BAs synthesis, excretion, and reabsorption and compared them to those of C57BL/6 (B6) mice to study BAs metabolism in TH mice. TH mice exhibited an increased total BAs pool size, increased BAs content in the cecum feces, and an increased ratio of muricholic acid (MCA)/cholic acid (CA). The mRNA and protein levels of cholesterol 7 alpha-hydroxylase (Cyp7a1) and the ATP-binding cassette sub-family G member 5 (Abcg5) were elevated in the liver but not in the apical sodium bile acid transporter (Asbt) and organic solute transporters (Osts) in the ileum. These results indicate that synthesis and the excretion of BAs from the liver to the gallbladder might be elevated, but the reabsorption rate of BAs in the ileum might be reduced. The declined expression of fibroblast growth factor 15 (Fgf15) and fibroblast growth factor receptor 4 (Fgfr4) was respectively identified in the ileum and the liver, indicating the disrupted feedback inhibition of Cyp7a1. Consequently, hypercholesterolemia in TH mice might increase the BAs amounts via the interrupted Fxr/Fgf15/Fgfr4-mediated feedback regulation of Cyp7a1. PMID- 28843504 TI - Mammalian enzymes responsible for the biosynthesis of N-acylethanolamines. AB - Bioactive N-acylethanolamines (NAEs) are ethanolamides of long-chain fatty acids, including palmitoylethanolamide, oleoylethanolamide and anandamide. In animal tissues, NAEs are biosynthesized from membrane phospholipids. The classical "transacylation-phosphodiesterase" pathway proceeds via N-acyl phosphatidylethanolamine (NAPE), which involves the actions of two enzymes, NAPE generating Ca2+-dependent N-acyltransferase (Ca-NAT) and NAPE-hydrolyzing phospholipase D (NAPE-PLD). Recent identification of Ca-NAT as E isoform of cytosolic phospholipase A2 enabled the further molecular biological approaches toward this enzyme. In addition, Ca2+-independent NAPE formation was shown to occur by N-acyltransferase activity of a group of proteins named phospholipase A/acyltransferases (PLAAT)-1-5. The analysis of NAPE-PLD-deficient mice confirmed that NAEs can be produced through multi-step pathways bypassing NAPE-PLD. The NAPE-PLD-independent pathways involved three members of the glycerophosphodiesterase (GDE) family (GDE1, GDE4 and GDE7) as well as alpha/beta hydrolase domain-containing protein (ABHD)4. In this review article, we will focus on recent progress made and latest insights in the enzymes involved in NAE synthesis and their further characterization. PMID- 28843505 TI - The clinical case: validity, values and strategies to approach its writing. AB - The case report is used to communicate the experience acquired by its authors with a patient. Although its relevance has been doubted, the case report deserves to be vindicated and contextualized. We review the case report's historical tradition, recent evolution and current formats. We describe its utility as a scientific tool, a continuing education resource and an aid to diagnosis. We reflect on the teaching potential its writing entails. Finally, we provide strategies to address the writing of a radiological case report. PMID- 28843506 TI - The influence of anatomic total shoulder arthroplasty using a subscapularis tenotomy on shoulder strength. AB - BACKGROUND AND HYPOTHESIS: There is limited evidence describing the influence of total shoulder arthroplasty on strength. The hypothesis was that after total shoulder arthroplasty, strength would improve compared with the preoperative state but remain inferior to that of the nonoperative shoulder. An additional aim was to determine whether strength improvement was associated with improvements in outcome scores and motion. MATERIALS AND METHODS: Thirty-six patients underwent total shoulder arthroplasty, with 31 patients (86%) having 1 year of follow-up for all outcomes. Patient-determined outcomes (Western Ontario Osteoarthritis of the Shoulder score; Disabilities of the Arm, Shoulder and Hand score; Single Assessment Numeric Evaluation rating; and shoulder activity level), range of motion, and strength were assessed. Isometric strength was determined for scaption and external rotation, as well as the liftoff test, belly-press test, and bear-hug test. RESULTS: All strength measures improved, with significant increases in external rotation, the liftoff test, and the bear-hug test, but remained inferior to the nonoperative-side strength. Improved strength in the belly-press test was associated with greater improvement in Single Assessment Numeric Evaluation scores. Improvements in scaption and belly-press testing were associated with improvements in active flexion. Strength improvements in the liftoff test were associated with improved internal rotation in 90 degrees of abduction. Patients with improvements in strength had improvements in their shoulder activity level from baseline to final follow-up, whereas patients without improved strength test findings did not have improved shoulder activity levels. CONCLUSIONS: Total shoulder arthroplasty improved external rotation, liftoff, and bear-hug strength testing. Operative shoulder strength remained inferior to strength of the nonoperative shoulder. Patients with improvements in strength were more likely to have greater improvements in outcome scores and range of motion. Improvements in the shoulder activity level after anatomic total shoulder arthroplasty may be dependent on improvements in strength. PMID- 28843507 TI - Purification of metal-dependent lysine deacetylases with consistently high activity. AB - Metal-dependent lysine deacetylases (KDACs) are involved in regulation of numerous biological and disease processes through control of post-translational acetylation. Characterization of KDAC activity and substrate identification is complicated by inconsistent activity of prepared enzyme and a range of multi-step purifications. We describe a simplified protocol based on two-step affinity chromatography. The purification method is appropriate for use regardless of expression host, and we demonstrate purification of several representative members of the KDAC family as well as a selection of mutated variants. The purified proteins are highly active and consistent across preparations. PMID- 28843508 TI - [Purchase of local foods for school meals in Andalusia, the Canary Islands and the Principality of Asturias (Spain)]. AB - OBJECTIVE: To explore and compare the characteristics of Primary Education Centres (PEC) in Andalusia, the Canary Islands and the Principality of Asturias depending on whether or not they make local food purchases (LFP) for school meals and to explore the opinion of cafeteria managers about the benefits and challenges of this type of purchase. METHOD: Information on the characteristics of 186 PECs and opinions of cafeteria managers about the benefits/challenges of LFP was collected through an electronic questionnaire. Data were stratified according to how the products were purchased (LFP: yes/no), and the chi square test was applied. RESULTS: 38.2% of the PECs studied make LFP. This is more frequent in rural areas (51.0 with self-managed cafeterias (80.0%), and their own kitchen (65.5%). These centres have less expensive menus than their peers (69.8%), participate more frequently in healthy eating programmes (81.5%) and purchase more organic food products (65.8%). According to the majority of the participants whose centres engage in LFP, the benefits include: supporting the local economy (97.2%), the offer of fresh foods (97.2%) and environmental sustainability (93.0%). The challenges include: productive capacity of the region (50.7%), the seasonal variation in food production (71.8%), and the lack of support (42.3%) and information from the government (46.5%). CONCLUSION: The location of the centres, the management of the cafeteria and the availability of a kitchen on site can influence the development of LFP in schools. Government support could help to integrate LFP in schools, improving school meals at a lower economic and environmental cost. PMID- 28843509 TI - Walking speed decline in older adults is associated with elevated pro-BDNF in plasma extracellular vesicles. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is produced by cleavage of proBDNF, and BDNF and proBDNF may play antagonistic roles in nervous system development, learning, memory and neuronal stress resistance. BDNF and proBDNF are present in blood, but the origin and relative contributions of soluble and extracellular vesicle (EV)-associated levels are unknown. METHODS: In this study we used validated immunoassays to measure proBDNF and BDNF levels in plasma, total plasma EVs and a subpopulation of EVs enriched for neuronal origin (expressing the neuronal marker L1CAM) in 150 Baltimore Longitudinal Study of Aging participants with and without decline in walking speed (reflecting aging associated motor decline). RESULTS: Levels of BDNF and proBDNF were highest in L1CAM+ EVs. Participants with walking speed decline had higher levels of proBDNF in L1CAM+ EVs compared to non-decliners, but no differences in proBDNF levels in plasma and total EV. CONCLUSIONS: Our findings suggest that levels of proBDNF and BDNF in circulating L1CAM+ EVs might be used as biomarkers for conditions involving altered BDNF signaling. PMID- 28843510 TI - An alternative model for studying age-associated metabolic complications: Senescence-accelerated mouse prone 8. AB - Rodent animal models take at least 18months to develop aging phenotypes for researchers to investigate the mechanism of age-related metabolic complications. Senescence-accelerated mouse prone 8 (SAMP8) shortens the process of aging and may facilitate an alternative model for studying age-related insulin resistance. The short-lived strain SAMP8 and two long-lived strains SAM resistant 1 (SAMR1) mice and C57BL/6 mice at 12 (young) and 40weeks old (old) were used in the present study. Glucose tolerance test, histology and signaling pathways involved in lipid metabolism in adipose tissue and liver and key components of insulin signaling pathway in the skeletal muscle were determined in these three strains. We found that short-lived SAMP8 mice developed symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance in association with adipocyte hypertrophy and ectopic lipid accumulation in liver and muscle at 40-wk.-old. Significantly increased serum IL-6, leptin, and resistin levels and adipogenic transcription factor PPARgamma and macrophage marker F4/80 mRNA expression in adipose tissues were observed in old SAMP8 mice, compared with that in young SAMP8 mice. Marked increases in SREBP1 and PPARgamma and a decrease in PPARalpha at mRNA level in accordance with activation of mTOR/Akt pathway were contributed to hepatic lipid accumulation in old SAMP8 mice. Down-regulation of insulin signaling pathway including IRbeta, IRS1, and AS160 at protein level in skeletal muscle was observed in old SAMP8 mice. At 40 wk.-old, both long-lived SAMR1 and C57BL/6 mice have not been fully developed age related metabolic disorders including insulin resistance and visceral fat expansion in line with fewer defects in lipid metabolism and skeletal muscle insulin signaling pathway. In conclusion, our data suggest the suitability of the SAMP8 mice as a model for studying age-related metabolic complications. PMID- 28843511 TI - The relationship between reproductive and biochemical ageing at the time of the menopausal transition. AB - The biochemical ageing status of women in the menopausal transition was studied using quantitative analysis of age- and autophagy-related gene activities (CDC42 and MAP1LC3 genes were selected as target genes). Free estradiol and progesterone levels in saliva were estimated. General linear models were used to determine the relationship between lifestyle, health status, socioeconomic factors and CDC42 and MAP1LC3 gene expression levels. Gene expression analysis revealed (1) an increasing expression of CDC42 gene after 45years in women, (2) expression level of CDC42 gene associated with menopausal status, (3) while endocrine status was found to associate with the expression of both of the studied age-related genes, (4) the "never used hormonal contraceptives" and "obese nutritional status" were the strongest factors for increased level of age-related gene expressions, and (5) changes in gene expression levels by ageing should be studied by considering not only chronological, but also biological ages. Gene expression profile of ageing has mostly been studied in model systems or human blood samples, but rarely in human saliva samples. The concordance of results between the present and former gene expression analyses, and the simplicity of saliva sample collection emphasizes the importance of saliva tissue samples in gene expression analyses especially in epidemiological surveys. PMID- 28843512 TI - Diversity of culturable yeasts associated with zoanthids from Brazilian reef and its relation with anthropogenic disturbance. AB - Some of the main threats to coral reefs come from human actions on marine environment, such as tourism, overfishing and pollution from urban development. While several studies have demonstrated an association between bacteria and corals, demonstrating how these communities react to different anthropogenic stressors, yeast communities associated with corals have received far less attention from researchers. The aim of this work was therefore to describe cultivable yeasts associated with three coral species and to evaluate the influence of sewage discharge on yeasts community. We obtained 130 isolates, mostly belonging to phylum Ascomycota and many of them had previously been isolated from human samples or are considered pathogens. The mycobiota was more similar among corals collected from the same reef, indicating that the composition of reef yeast community is more influenced by environmental conditions than host species. We suggest further studies to elucidate which factors are most influential on the composition of the coral-associated yeast community. PMID- 28843513 TI - Discrepancies Between Pathological Tumor Responses and Estimations of Complete Response by Magnetic Resonance Imaging After Neoadjuvant Chemotherapy Differ by Breast Cancer Subtype. AB - INTRODUCTION: The influence of breast cancer (BC) subtype in discrepancies between pathologic complete response (pCR) and complete response by magnetic resonance imaging (MRI-CR) after neoadjuvant chemotherapy (NAC) have not been discussed well. We evaluated the association between BC subtype and pCR or only residual in situ lesion without invasive cancer (pCR/in situ+) in patients with MRI-CR (positive predictive value [PPV]). MATERIAL AND METHODS: From the data of 716 patients with primary BC who were diagnosed with invasive cancer and treated with NAC and then surgery from January 2009 to May 2014 at St. Luke's International Hospital, 180 patients were determined to have MRI-CR by retrospective chart review. BC subtypes at baseline were classified into 6 subtypes, as strong estrogen receptor (ER++), moderately positive ER (ER+), negative ER (ER-), and HER2 status expression. RESULTS: Three subtypes had PPV (pCR) >= 50%: ER-/HER2+ (56.3%, 27/48), ER-/HER2- (57.6%, 34/59), and ER+/HER2+ (56.2%, 9/16). However, PPV (pCR) for the ER++/HER2- and ER++/HER2+ subtypes was < 30%; notably, only 12.0% (3/25) for the ER++/HER2- subtype, which was significantly low (P < .001) compared with ER++/HER2- and other subtypes. PPV (pCR/in situ+) was significantly low at 20.0% in the ER++/HER2- subtype (P < .001 compared with other subtypes). PPV (pCR/in situ+) in other subtypes was collectively greater than 60%, and was 91.7% in the ER-/HER2+ subtype. CONCLUSION: We should interpret carefully MRI-CR of NAC to evaluate residual disease for ER++/HER2- BC. PMID- 28843514 TI - Inequalities in cervical cancer screening utilisation and results: A comparison between Italian natives and immigrants from disadvantaged countries. AB - Cervical cancer screening underutilisation is documented among immigrants from poor countries and it is associated to an augmented risk for severe lesions. In a cohort of 1,410,364 Italian women and 200,491 immigrants from poor countries differences in screening participation and results were investigated. Participation rate was lower for immigrants than for Italians: 43.98% versus 48.59% (chi(1): p<0.001). This gap increased with age (ptrend<0.0001). Some socio demographic factors negatively influenced immigrants' participation. Illiteracy (OR=0.75) versus secondary school, being single (OR=0.71) versus attached, first screens (OR=0.67) versus subsequent ones. Although the interaction between educational and professional levels showed that graduated immigrant women conducting an intellectual job have a higher inclination towards screening than their Italian peers (OR=1.43 vs OR=1.04). The Standardised Detection Ratio (SDR) suggested a frequency of severe lesions nearly double among immigrants in first screens (SDR=1.94; 95% CI: 1.82-2.08) and even higher (SDR=2.53; 95% CI: 2.35 2.73) for Central/Eastern Europeans. Multi-component interventions involving both patients and providers offer the greatest potential to increase cervical cancer screening uptake within foreign-born populations. So immigrant-specific interventions are needed for some immigrant groups, like Central/Eastern Europeans who are at higher risk of cervical lesions and, together with Asians and Africans, showed a poor attitude towards cancer prevention. PMID- 28843516 TI - Measuring sarcoidosis around the world: Using the same ruler. PMID- 28843515 TI - Estimating Tanzania's National Met and Unmet Blood Demand From a Survey of a Representative Sample of Hospitals. AB - Estimating blood demand to determine collection goals challenges many low-income countries. We sampled Tanzanian hospitals to estimate national blood demand. A representative sample based on probability proportional to size sampling of 42 of 273 (15%) Tanzanian transfusing hospitals was selected. Blood bank registers, patient medical records, and blood component disposition records were reviewed prospectively from June to September 2013 to determine the number of components requested and the number and proportion issued, not issued due to nonavailability, and not issued for other reasons. Data were estimated for an annual national estimate. Of an estimated 278 371 components requested in 2013, 6648 (2.4%) were not issued due to nonavailability, 34 591 (12.4%) were not issued for other reasons, and 244 535 (87.8%) were issued. Of these 278 371 components, 86 753 (31.2%) were requested by adult medical, 74 499 (26.8%) by pediatric medical, and 57 312 (20.6%) by obstetric units. In these 3 units, the proportion of units not issued due to nonavailability was 1.8%. Private (4.1%) and large (6%) hospitals had the largest proportion of units not issued because of nonavailability. Of 244 535 issued components, 91 690 (37.5%) were collected, tested, and issued from blood banks that are not part of the Tanzania National Blood Transfusion Services (TNBTS). Nearly 98% of blood component demand was met. However, a large portion of the blood supply for the hospitals came from non TNBTS blood banks. TNBTS could increase availability of safe blood through assuring the quality of donor selection and donation testing at non-TNBTS blood banks. PMID- 28843517 TI - Pulmonary rehabilitation at primary care - The results of a local survey. PMID- 28843519 TI - MicroRNA profiles of fibroblasts derived from in vivo fertilized and fat-1 transgenic cattle. AB - Fat-1 transgenic cattle have high levels of omega-3 fatty acids, which regulate several genes in fatty acid metabolism. In the current study, fibroblasts derived from in vivo fertilized (Ferti) and fat-1 transgenic (TG) Luxi cattle (Bos taurus), a local breed in China, were cultured and their miRNA expression was characterized. Expression of 352 known miRNAs differed in cells from Ferti and TG cattle: 83 miRNAs were found to be specifically expressed in cells from Ferti cattle while 23 miRNAs were found to be specifically expressed in cells from TG cattle. Novel differences in miRNA expression were also found in cells from Ferti and TG cattle. The identity of seven differentially expressed miRNAs was verified using quantitative real-time PCR, and target genes were identified computationally. GO and KEGG analysis revealed that these miRNAs were involved in seven major biological pathways, including metabolism, MAPK signaling, calcium signaling, purine metabolism, ubiquitin mediated proteolysis, pyrimidine metabolism, and the cell cycle. Overexpression of one of these miRNAs, miR-21-5p, was found to suppress expression of fibroblast growth factor 10 (FGF10) and adipose triglyceride lipase (ATGL) in fibroblasts from TG cattle and 3T3-L1 pre adipocytes. Conversely, knockdown of miR-21-5p stimulated expression. Together, these results suggest that miRNAs potentially play a role in expression of lipogenic and lipolytic genes as well as in synthesis of omega-3 fatty acids facilitated by fat-1. PMID- 28843518 TI - Management of Factor Xa inhibitor-associated life-threatening major hemorrhage: A retrospective multi-center analysis. AB - BACKGROUND: Factor Xa (FXa) inhibitors, used for stroke prevention in atrial fibrillation and venous thromboembolism treatment and prevention, are the dominant non-Vitamin K oral anticoagulants on the market. While major bleeding may be less common with these agents compared to warfarin, it is always a risk, and little has been published on the most serious bleeding scenarios. This study describes a cohort of patients with FXa inhibitor-associated life-threatening bleeding events, their clinical characteristics, interventions and outcomes. METHODS: We performed a retrospective, 5-center review of FXa inhibitor-treated major bleeding patients. Investigators identified potential cases by cross referencing ICD-9/10 codes for hemorrhage with medication lists. Investigators selected cases they deemed to require immediate reversal of coagulopathy, and reviewed charts for characteristics, reversal strategies and other interventions, and outcomes. RESULTS: A total of 56 charts met the inclusion criteria for the retrospective cohort, including 29 (52%) gastrointestinal bleeds (GIB), 19 (34%) intracranial hemorrhages (ICH) and 8 (14%) others. Twenty-four (43%) patients received various factor or plasma products, and the remainder received supportive care. Thirty-day mortality was 21% (n=12). Re-anticoagulation within 30-days occurred in 23 (41%) patients. Thromboembolic events (TEEs) occurred in 6 (11%) patients. No differences were observed in outcomes by treatment strategy. CONCLUSIONS: This cohort of FXa inhibitor-associated major bleeding scenarios deemed appropriate for acute anticoagulant reversal illustrates the variable approaches in the absence of a specific reversal agent. PMID- 28843520 TI - The long non-coding RNA MIAT regulates zinc finger E-box binding homeobox 1 expression by sponging miR-150 and promoteing cell invasion in non-small-cell lung cancer. AB - The myocardial infarction associated transcript (MIAT), a long non-coding RNA (lncRNA), was originally identified as a candidate gene for myocardial infarction, and was recently shown to participate in the progression of cancer and the process of metastasis. However, the biological role of MIAT and the underlying mechanisms that mediate its role in non-small-cell lung cancer (NSCLC) remain unclear. Here, we have shown that the expression of MIAT in NSCLC tissues was upregulated. Knockdown of MIAT substantially inhibited the invasive ability of NSCLC cells. Moreover, the knockdown of MIAT significantly downregulated the expression of the zinc finger E-box binding homeobox 1 (ZEB1), that was upregulated in NSCLC and that promoted cell invasion. Rather than by direct interactions, we found that MIAT indirectly regulated ZEB1 expression through sponging and suppressing microRNA (miR)-150, which represses ZEB1 and interacts with MIAT in a sequence-specific manner. Thus, MIAT may inhibit ZEB1 expression and promote cell invasion of NSCLC cells via the miR-150/ZEB1 pathway. Taken together, our findings suggested that MIAT plays an oncogenic role in NSCLC through the ZEB1 signaling pathway by sponging miR-150, and MIAT may therefore serve as a valuable prognostic biomarker and therapeutic target for NSCLC. PMID- 28843522 TI - WITHDRAWN: An analysis of the gene interaction networks identifying the role of PARP1 in metastasis of non-small cell lung cancer. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28843521 TI - Curcumin suppresses proliferation and in vitro invasion of human prostate cancer stem cells by ceRNA effect of miR-145 and lncRNA-ROR. AB - Many studies have demonstrated that curcumin can effectively inhibit the proliferation, invasion, and tumorigenesis of prostate cancer cells in vitro and in vivo. In this study, CD44+/CD133+ human prostate cancer stem cells (HuPCaSCs) were isolated from the prostate cancer cell lines Du145 and 22RV1. Curcumin treatment of these cells resulted in the inhibition of in vitro proliferation and invasion, and cell cycle arrest. The expression levels of cell cycle proteins (Ccnd1 and Cdk4) and stem cell markers (Oct4, CD44, and CD133) were decreased in curcumin-treated HuPCaSCs. Microarray analysis and northern blotting assays indicated that miR-145 was overexpressed in curcumin-treated HuPCaSCs. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, bioinformatics analysis and luciferase activity assays showed that the lncRNA-ROR and Oct4 mRNA both contain miR-145 binding sites, and Oct4 and lncRNA-ROR directly compete for microRNA binding. Curcumin induced high miR-145 expression and inhibited the expression of lncRNA-ROR. The tumorigenicity of curcumin- treated HuPCaSCs in nude mice was significantly reduced. In summary, reducing the expression of endogenous lncRNA-ROR could effectively increase the available concentration of miR-145 in HuPCaSCs, where miR-145 prevents cell proliferation by decreasing Oct4 expression. In particular, we hypothesized that lncRNA-ROR may act as a ceRNA, effectively becoming a sink for miR-145, thereby activating the derepression of core transcription factors Oct4. Thus, curcumin suppresses the proliferation, in vitro invasion, and tumorigenicity of HuPCaSCs through ceRNA effect of miR-145 and lncRNA-ROR caused. PMID- 28843523 TI - Use of an Exercise Technology in Post-Acute Care of a Skilled Nursing Facility: A Feasibility Study. AB - OBJECTIVES: Use of exercise technologies has benefits for community-dwelling older adults in terms of improved gait and balance. But research on the feasibility of use of exercise technologies in various geriatric health care settings is lacking. Hence, the current study examined the feasibility of implementing an exercise technology intended to augment rehabilitation in patients receiving post-acute care (PAC) in a skilled nursing facility (SNF). We focused on 3 indicators of feasibility: extent of usage (including predictors of more intense use), patients' acceptability of the technology, and limited efficacy. DESIGN: Cross-sectional study with data from patients' electronic medical records (EMR), exercise technology portal, and patient interviews. SETTING: SNF. PARTICIPANTS: A sample of post-acute patients (n = 237). MEASUREMENTS: Sociodemographic and health-related variables, time spent using the technology, and 8 items of the Physical Activity Enjoyment Scale (PACES). RESULTS: Average time spent using the technology varied greatly (range, 1-460 minutes). A regression analysis showed that patients who had a longer length of stay (beta = .01, P < .05) and were younger (beta = -0.01, P < .05) spent significantly more time using the technology. Acceptability of technology was high among patients. Finally, patients who used the technology had lower 30-day rehospitalization rates. CONCLUSION: Exercise technology is feasible to use in supporting rehabilitation in patients receiving PAC in a SNF and seems to have beneficial effects. PMID- 28843524 TI - Homocysteine, Tryptophan, and Cognition in the Very Old. PMID- 28843525 TI - Important Care and Activity Preferences in a Nationally Representative Sample of Nursing Home Residents. AB - OBJECTIVES: Person-centered care (PCC), which considers nursing home resident preferences in care delivery, has been linked to important outcomes such as improved quality of life, resident satisfaction with care, and mood and reduced behavioral symptoms for residents with dementia. Delivery of PCC fundamentally relies on knowledge of resident preferences. The Minimum Data Set (MDS) 3.0 Preference Assessment Tool (PAT) is a standardized, abbreviated assessment that facilitates systematic examination of preferences from a population of nursing home residents. However, it is unknown how well the PAT discriminates preferences across residents or items. The purpose of this study was to use MDS 3.0 PAT data to describe (1) overall resident preferences, (2) variation in preferences across items, and (3) variation in preferences across residents. DATA: Data from admission MDS assessments between October 1, 2011 and December 31, 2011 were used for this study. SAMPLE: A nationally representative sample of 244,718 residents over the age of 65 years who were able to complete the resident interview version of preference, cognition, and depression assessments were included. MEASUREMENTS: Importance ratings of 16 daily care and activity preferences were the primary outcome measures. Resident factors including function (MDS Activities of Daily Living-Long Form), depression (Patient Health Questionnaire-9), cognitive impairment (Brief Interview for Mental Status), and sociodemographics (age, race, sex, and marital status) were used as predictors of important preferences. ANALYSIS: Overall preferences were examined using descriptive statistics. Proportional differences tests were used to describe variation across items. Logistic regression was used to describe variation in preferences across residents. RESULTS: The majority of residents rated all 16 preferences important. However, there was variation across items and residents. Involvement of family in care and individualizing daily care and activities were rated important by the largest proportion of residents. Several resident factors including cognitive impairment, depression, sex, and race were significant predictors of preferences. CONCLUSIONS: Findings demonstrate the PAT captures variation in preferences across items and residents. Residents with possible depression and cognitive impairment were less likely to rate preferences important than residents without those conditions. Non-Caucasian and male residents reported some preferences differently than Caucasian and female residents. Additional assessment and care planning may be important for these residents. More research is needed to determine the factors that influence preferences and the ways to incorporate them into care. PMID- 28843526 TI - Validation of the Korean Version of the SARC-F Questionnaire to Assess Sarcopenia: Korean Frailty and Aging Cohort Study. AB - OBJECTIVES: The SARC-F is a simple sarcopenia screening tool comprising 5 assessment items: strength, assistance walking, rising from a chair, climbing stairs, and falls. The present study aimed to examine the validation of the Korean version of SARC-F for elderly individuals residing in communities. SETTING AND PARTICIPANTS: From the first year baseline data of Korean Frailty and Aging Cohort Study, a total of 1222 elderly individuals (70 years and older) who met the study's selection criteria were included in the analysis. MEASUREMENTS: The SARC-F was translated into the Korean language in a culturally responsive way. The total score was calculated by adding the scores on the 5 items. The participants were divided into 2 groups according to the total score (SARC-F <4 vs SARC-F >=4), and its correlations with various factors including walking speed, hand grip, ability to perform everyday activities, and health-related quality of life, were examined by sex. In addition, the tool's validity was analyzed by comparing it with the European, international, and Asian sarcopenia working group diagnostic criteria for sarcopenia. RESULTS: The prevalence of sarcopenia according to the SARC-F was 4.2% in among men and 15.3% in women. The sensitivity of the SARC-F was low compared with the European, international, and Asian criteria of sarcopenia [male (M): 11%-60%, female (F): 28%-34%]. However, SARC-F showed a high specificity (M: 96.6%-98%, F: 85%-87.7%) and a high negative predictive value (M: 89.2%-99.3%, F: 88.5%-98.4%). The participants in the SARC-F >=4 group had poorer grip strength, slower walking speed, poorer physical performance, poorer cognitive function, and a lower quality of life (a high EuroQol-5 dimension score) than the participants in the SARC-F <4 group. CONCLUSIONS: The Korean language version of SARC-F showed a high specificity and high negative predictive value. As such, the tool is useful for briefly ruling out sarcopenia in a clinical setting. In addition, diagnosis of sarcopenia using the SARC-F was found to be associated with physical performance, cognitive function, and the quality of life. PMID- 28843527 TI - Factors Associated With the Trend of Physical and Chemical Restraint Use Among Long-Term Care Facility Residents in Hong Kong: Data From an 11-Year Observational Study. AB - BACKGROUND: Negative effects of restraint use have been well-documented. However, the prevalence of restraints use has been high in long-term care facilities in Hong Kong compared with other countries and this goes against the basic principles of ethical and compassionate care for older people. The present study aimed to review the change in the prevalence of physical and chemical restraint use in long-term care facilities (LTCFs) over a period of 11 years in Hong Kong and to identify the major factors associated with their use. METHODS: This is an observational study with data obtained from the Hong Kong Longitudinal Study on LTCF Residents between 2005 and 2015. Trained assessors (nurses, social workers, and therapists) used the Minimum Data Set Resident Assessment Instrument to collect the data from 10 residential LTCFs. Physical restraint was defined as the use of any of the following: full bedside rails on all open sides of bed, other types of bedside rails used, trunk restraint, limb restraint, or the use of chair to prevent rising during the past 7 days. Chemical restraint was defined as the use of any of the following medications: antipsychotic, antianxiety, or hypnotic agents during past 7 days, excluding elder residents with a diagnosis of psychiatric illness. OUTCOMES: Annual prevalence of restraint use over 11 years and factors that were associated with the use of physical and chemical restraints. RESULTS: We analyzed the data for 2896 older people (978 male individuals, mean age = 83.3 years). Between 2005 and 2015, the prevalence of restraint use was as follows: physical restraint use increased from 52.7% to 70.2%; chemical restraint use increased from 15.9% to 21.78%; and either physical or chemical restraint use increased from 57.9% to 75.7%. Physical restraint use was independently associated with older age, impaired activities of daily living or cognitive function, bowel and bladder incontinence, dementia, and negative mood. Chemical restraint use was independently associated with older age, falls, bladder incontinence, use of feeding tube, dementia, poor cognitive function, delirium, behavioral problems, and negative mood. The increasing time-trend of physical but not chemical restraint use remained significant after adjusting for other factors as mentioned above (coefficient = 0.092, P < .001). CONCLUSIONS: Use of physical and chemical restraint was highly prevalent among LTCF residents in Hong Kong, with an increasing trend over a period of 11 years, especially targeting the most physically and cognitively frail older people. Appropriate healthcare staff education and policy change are urgently needed to ensure personal care that is characterized by respect, dignity, empathy, and compassion for the older generation. PMID- 28843528 TI - Cognitive Frailty: Far From Clinical and Research Adoption. PMID- 28843529 TI - Assessment of acute sublethal effects of clothianidin on motor function of honeybee workers using video-tracking analysis. AB - Sublethal impacts of pesticides on the locomotor activity might occur to different degrees and could escape visual observation. Therefore, our objective is the utilization of video-tracking to quantify how the acute oral exposure to different doses (0.1-2ng/bee) of the neonicotinoid "clothianidin" influences the locomotor activity of honeybees in a time course experiment. The total distance moved, resting time as well as the duration and frequency of bouts of laying upside down are measured. Our results show that bees exposed to acute sublethal doses of clothianidin exhibit a significant increase in the total distance moved after 30 and 60min of the treatment at the highest dose (2ng/bee). Nevertheless, a reduction of the total distance is observed at this dose 90min post-treatment compared to the distance of the same group after 30min, where the treated bees show an arched abdomen and start to lose their postural control. The treated bees with 1ng clothianidin show a significant increase in total distance moved over the experimental period. Moreover, a reduction in the resting time and increase of the duration and frequency of bouts of laying upside down at these doses are found. Furthermore, significant effects on the tested parameters are observed at the dose (0.5ng/bee) first at 60min post-treatment compared to untreated bees. The lowest dose (0.1ng/bee) has non-significant effects on the motor activity of honeybees compared to untreated bees over the experimental period. PMID- 28843530 TI - Root-induced changes of Zn and Pb dynamics in the rhizosphere of sunflower with different plant growth promoting treatments in a heavily contaminated soil. AB - Root induced changes are deemed to have an important role in the success of remediation techniques in contaminated soils. Here, the effects of two nano particles [SiO2 and zeolite] with an application rate of 200mgkg-1, and two bacteria [Bacillus safensis FO-036b(T) and Pseudomonas fluorescens p.f.169] in the rhizosphere of sunflower on Zn and Pb dynamics were studied in greenhouse conditions. The treatments reduced the exchangeable Zn (from 13.68% to 30.82%) and Pb (from 10.34% to 25.92%) in the rhizosphere compared to the control. The EC and microbial respiration/population of the rhizosphere and bulk soil had an opposite trend with the exchangeable fraction of Zn and Pb, but dissolved organic carbon followed a similar trend with the more bioavailable fractions. As a result, the accumulation of Pb and Zn in the plant tissues was significantly (p < 0.05) reduced by the application of amendments, which might be due to the shift of the metals to immobile forms induced by the nature of the treatments and changes in the rhizosphere process. The empirical conditions of this research produced the intensification of the rhizosphere process because the findings highlight those changes in the rhizosphere EC, pH and dissolved organic carbon can affect the efficiency of zeolite/SiO2 NPs and bacteria to immobilize Pb and Zn in the soil, depending on the chemical character of the metals and the treatments. Generally, the affinity of the biotic treatment for Pb was more than the abiotic and conversely, the abiotic treatment showed a higher ability to immobilize Zn than the biotic treatment. PMID- 28843531 TI - Testing lagoonal sediments with early life stages of the copepod Acartia tonsa (Dana): An approach to assess sediment toxicity in the Venice Lagoon. AB - The early-life stages of development of the calanoid copepod Acartia tonsa from egg to copepodite I is proposed as an endpoint for assessing sediment toxicity by exposing newly released eggs directly onto the sediment-water interface. A preliminary study of 5 sediment samples collected in the lagoon of Venice highlighted that the larval development rate (LDR) and the early-life stages (ELS) mortality endpoints with A. tonsa are more sensitive than the standard amphipod mortality test; moreover LDR resulted in a more reliable endpoint than ELS mortality, due to the interference of the sediment with the recovery of unhatched eggs and dead larvae. The LDR data collected in a definitive study of 48 sediment samples from the Venice Lagoon has been analysed together with the preliminary data to evaluate the statistical performances of the bioassay (among replicate variance and minimum significant difference between samples and control) and to investigate the possible correlation with sediment chemistry and physical properties. The results showed that statistical performances of the LDR test with A. tonsa correspond with the outcomes of other tests applied to the sediment-water interface (Strongylocentrotus purpuratus embryotoxicity test), sediments (Neanthes arenaceodentata survival and growth test) and porewater (S. purpuratus); the LDR endpoint did, however, show a slightly higher variance as compared with other tests used in the Lagoon of Venice, such as 10-d amphipod lethality test and larval development with sea urchin and bivalves embryos. Sediment toxicity data highlighted the high sensitivity and the clear ability of the larval development to discriminate among sediments characterized by different levels of contamination. The data of the definitive study evidenced that inhibition of the larval development was not affected by grain-size and the organic carbon content of the sediment; in contrast, a strong correlation between inhibition of the larval development and the sediment concentrations of some metals (Cu, Hg, Pb, Zn), acid-volatile sulphides (AVS), polychlorinated biphenyls (PCBs) and polynuclear aromatic hydrocarbons (PAHs) was found. No correlation was found with DDTs, hexachlorobenzene and organotin compounds. PMID- 28843532 TI - The medical threat of mamba envenoming in sub-Saharan Africa revealed by genus wide analysis of venom composition, toxicity and antivenomics profiling of available antivenoms. AB - : Mambas (genus Dendroaspis) are among the most feared of the medically important elapid snakes found in sub-Saharan Africa, but many facets of their biology, including the diversity of venom composition, remain relatively understudied. Here, we present a reconstruction of mamba phylogeny, alongside genus-wide venom gland transcriptomic and high-resolution top-down venomic analyses. Whereas the green mambas, D. viridis, D. angusticeps, D. j. jamesoni and D. j. kaimosae, express 3FTx-predominant venoms, black mamba (D. polylepis) venom is dominated by dendrotoxins I and K. The divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas makes it plausible that this major difference in venom composition is due to dietary variation. The pattern of intrageneric venom variability across Dendroaspis represented a valuable opportunity to investigate, in a genus-wide context, the variant toxicity of the venom, and the degree of paraspecific cross-reactivity between antivenoms and mamba venoms. To this end, the immunological profiles of the five mamba venoms were assessed against a panel of commercial antivenoms generated for the sub Saharan Africa market. This study provides a genus-wide overview of which available antivenoms may be more efficacious in neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the notably different potency and pharmacological profiles of Dendroaspis venoms at locus resolution. This understanding will allow selection and design of toxin immunogens with a view to generating a safer and more efficacious pan-specific antivenom against any mamba envenomation. BIOLOGICAL SIGNIFICANCE: The mambas (genus Dendroaspis) comprise five especially notorious medically important venomous snakes endemic to sub-Saharan Africa. Their highly potent venoms comprise a high diversity of pharmacologically active peptides, including extremely rapid-acting neurotoxins. Previous studies on mamba venoms have focused on the biochemical and pharmacological characterisation of their most relevant toxins to rationalize the common neurological and neuromuscular symptoms of envenomings caused by these species, but there has been little work on overall venom composition or comparisons between them. Only very recently an overview of the composition of the venom of two Dendroaspis species, D. angusticeps and D. polylepis, has been unveiled through venomics approaches. Here we present the first genus-wide transcriptomic-proteomic analysis of mamba venom composition. The transcriptomic analyses described in this paper have contributed 29 (D. polylepis), 23 (D. angusticeps), 40 (D. viridis), 25 (D. j. jamesoni) and 21 (D. j. kaimosae), novel full-length toxin sequences to the non-redundant Dendroaspis sequence database. The mamba genus-wide venomic analysis demonstrated that major D. polylepis venom components are Kunitz-fold family toxins. This feature is unique in relation to the relatively conserved three-finger toxin (3FTx) dominated venom compositions of the green mambas. Venom variation was interpreted in the context of dietary variation due to the divergent terrestrial ecology of D. polylepis compared to the arboreal niche occupied by all other mambas. Additionally, the degree of cross-reactivity conservation of mamba venoms was assessed by antivenomics against a panel of commercial antivenoms generated for the sub-Saharan Africa market. This study provides a genus-wide overview to infer which available antivenoms may be capable of neutralising human envenomings caused by mambas, irrespective of the species responsible. The information gathered in this study lays the foundations for rationalising the pharmacological profiles of mamba venoms at locus resolution. This understanding will contribute to the generation of a safer and more efficacious pan-Dendroaspis therapeutic antivenom against any mamba envenomation. PMID- 28843533 TI - The molecular mechanism and post-transcriptional regulation characteristic of Tetragenococcus halophilus acclimation to osmotic stress revealed by quantitative proteomics. AB - : Tetragenococcus halophilus is a moderate halophilic bacterium which was widely used in fermentation processes, growing in a broad range of salinity conditions, and can survive a saturated 26.47% w/w NaCl concentration. However, the mechanism of this outstanding ability to acclimate to extracellular osmotic stress still remains unknown. The current study firstly conducted a quantitative proteomic analysis to identify alterations of the cellular proteome under both hypo-osmotic and hyper-osmotic stress conditions. A total of 1405 proteins were identified and differentially accumulated proteins were analyzed, further functional annotations were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The results revealed that both hypo- and hyper-osmotic stresses have prominent impacts on the synthesis of proteins involving in multiple cellular functions. Further analyses of the differentially accumulated proteins suggested that the adaptation strategies T. halophilus applies to deal with hypo- and hyper-osmotic stress conditions may be distinct. Comparison of the differentially accumulated proteins in both transcriptomic and proteomic study indicated the existence of post-transcriptional modification during salinity adaptation of T. halophilus. The current study generated a proteomic atlas of differentially accumulated proteins under both hypo- and hyper-osmotic stress conditions, provided an overview of the molecular mechanism of osmotic acclimation of T. halophilus. SIGNIFICANCE: The current study aimed to reveal how the moderately halophilic Tetragenococcus halophilus adapt to extracellular salinity stress, which is the first proteomic study analyzing the differences in proteome of Tetragenococcus halophilus between hypo- and hyper-osmotic stress to our knowledge. By analyzing the differences in the accumulating levels of the proteome via isobaric labeling based quantitative proteomic study, we identified proteins with significantly different accumulation levels which may play important roles in the adaptation process to extracellular salinity stress. Examining the cellular functions of these proteins according to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, a draft view of how the bacterium act to acclimate to osmotic stress has been drawn. Further analysis revealing the differences between the transcriptome and proteome suggested that some proteins may undergo post-transcriptional regulation during acclimation process, which still remains unstudied and needs further investigations. The results of the current study can help researchers to gain insights and further reveal the halophilic mechanism of halophiles. PMID- 28843534 TI - SalivaPRINT Toolkit - Protein profile evaluation and phenotype stratification. AB - : The value of the molecular information obtained from saliva is dependent on the use of in vitro and in silico techniques. The main proteins of saliva when separated by capillary electrophoresis enable the establishment of individual profiles with characteristic patterns reflecting each individual phenotype. Different physiological or pathological conditions may be identified by specific protein profiles. The association of each profile to the particular protein composition provides clues as to which biological processes are compromised in each situation. Patient stratification according to different phenotypes often within a particular disease spectrum is especially important for the management of individuals carrying multiple diseases and requiring personalized interventions. In this work we present the SalivaPRINT Toolkit, which enables the analysis of protein profile patterns and patient phenotyping. Additionally, the SalivaPRINT Toolkit allows the identification of molecular weight ranges altered in a particular condition and therefore potentially involved in the underlying dysregulated mechanisms. This tutorial introduces the use of the SalivaPRINT Toolkit command line interface (https://github.com/salivatec/SalivaPRINT) as an independent tool for electrophoretic protein profile evaluation. It provides a detailed overview of its functionalities, illustrated by the application to the analysis of profiles obtained from a healthy population versus a population affected with inflammatory conditions. BIOLOGICAL SIGNIFICANCE: We present SalivaPRINT, which serves as a patient characterization tool to identify molecular weights related with particular conditions and, from there, find proteins, which may be involved in the underlying dysregulated cellular mechanisms. The proposed analysis strategy has the potential to boost personalized diagnosis. To our knowledge this is the first independent tool for electrophoretic protein profile evaluation and is crucial when a large number of complex electrophoretic profiles needs to be compared and classified. PMID- 28843535 TI - Swimming Against the Stream: Is Surgery Worthwhile in Women with Deep Infiltrating Endometriosis and Pregnancy Intention? PMID- 28843536 TI - Resectoscopic Surgery for Polyps and Myomas: A Review of the Literature. AB - Resectoscopic surgery is routinely performed to remove endometrial polyps and uterine myomas. A search of Medline, PubMed, and the Cochrane Library was conducted through November 2016 for studies written in English, regardless of sample size or study type. The studies were then filtered by selecting those evaluating resectoscopic surgery. An analysis of peer-reviewed, published literature was performed to examine the clinical application of this treatment modality on patients requiring polypectomy and myomectomy. Different surgical techniques were also compared: hysteroscopy with scissors, forceps, or a cold loop; resectoscopy with radiofrequency energy; and mechanical resection. The literature finds that operative time during resectoscopic surgery is significantly longer than with mechanical resection. Resectoscopic myomectomy, however, may be necessary for removal of larger or more deeply embedded myomas. Ultimately, both techniques result in symptom resolution and a low recurrence rate. PMID- 28843537 TI - Sophia Observation withdrawal Symptoms-Paediatric Delirium scale: A tool for early screening of delirium in the PICU. AB - BACKGROUND: Delirium in critically ill children is a severe neuropsychiatric disorder which has gained increased attention from clinicians. Early identification of delirium is essential for successful management. The Sophia Observation withdrawal Symptoms-Paediatric Delirium (SOS-PD) scale was developed to detect Paediatric Delirium (PD) at an early stage. OBJECTIVE: The aim of this study was to determine the measurement properties of the PD component of the SOS PD scale in critically ill children. METHODS: A prospective, observational study was performed in patients aged 3 months or older and admitted for more than 48h. These patients were assessed with the SOS-PD scale three times a day. If the SOS PD total score was 4 or higher in two consecutive observations, the child psychiatrist was consulted to assess the diagnosis of PD using the Diagnostic and Statistical Manual-IV criteria as the "gold standard". The child psychiatrist was blinded to outcomes of the SOS-PD. The interrater reliability of the SOS-PD between the care-giving nurse and a researcher was calculated with the intraclass correlation coefficient (ICC). RESULTS: A total of 2088 assessments were performed in 146 children (median age 49 months; IQR 13-140). The ICC of 16 paired nurse-researcher observations was 0.90 (95% CI 0.70-0.96). We compared 63 diagnoses of the child psychiatrist versus SOS-PD assessments in 14 patients, in 13 of whom the diagnosis of PD was confirmed. The sensitivity was 96.8% (95% CI 80.4-99.5%) and the specificity was 92.0% (95% CI 59.7-98.9%). CONCLUSIONS: The SOS-PD scale shows promising validity for early screening of PD. Further evidence should be obtained from an international multicentre study. PMID- 28843538 TI - Neurophysiological evidence for enhanced tactile acuity in early blindness in some but not all haptic tasks. AB - Previous research assessing the presence of enhanced tactile skills in early blind (EB) population obtained conflicting results. Most of the studies relied on behavioral measures with which different mechanisms leading to the same outcome go unnoticed. Moreover, the scarce electrophysiological research that has been conducted focused exclusively on the processing of microgeometric properties. To clarify the extent of superior tactile abilities in EBs using high-density multichannel electrophysiological recordings, the present study compared the electrophysiological correlates of EBs and sighted controls (CON) in two tactile discrimination tasks that targeted microgeometric (texture) and macrogeometric (shape) properties. After a restricted exploration (haptic glance), participants judged whether a touched stimulus corresponded to an expected stimulus whose name had been previously presented aurally. In the texture discrimination task, differences between groups emerged at ~75 ms (early perceptual processing stages) whereas we found no between-group differences during shape discrimination. Furthermore, for the first time, we were able to determine the latency at which EBs started to discriminate micro- (EB: 170 ms; CON: 230 ms) and macrogeometric (EB: 250 ms; CON: 270 ms) properties. Altogether, the results suggest different electrophysiological signatures during texture (but not shape) discrimination in EBs, possibly due to cortical reorganization in occipital areas and their increased connectivity with S1. PMID- 28843539 TI - Neuroanatomical foundations of delayed reward discounting decision making. AB - Resolving tradeoffs between smaller immediate rewards and larger delayed rewards is ubiquitous in daily life and steep discounting of future rewards is associated with several psychiatric conditions. This form of decision-making is referred to as delayed reward discounting (DRD) and the features of brain structure associated with DRD are not well understood. The current study characterized the relationship between gray matter volume (GMV) and DRD in a sample of 1038 healthy adults (54.7% female) using cortical parcellation, subcortical segmentation, and voxelwise cortical surface-based group analyses. The results indicate that steeper DRD was significantly associated with lower total cortical GMV, but not subcortical GMV. In parcellation analyses, less GMV in 20 discrete cortical regions was associated with steeper DRD. Of these regions, only GMV in the middle temporal gyrus (MTG) and entorhinal cortex (EC) were uniquely associated with DRD. Voxelwise surface-based analyses corroborated these findings, again revealing significant associations between steeper DRD and less GMV in the MTG and EC. To inform the roles of MTG and EC in DRD, connectivity analysis of resting state data (N = 1003) using seed regions from the structural findings was conducted. This revealed that spontaneous activity in the MTG and EC was correlated with activation in the ventromedial prefrontal cortex, posterior cingulate cortex, and inferior parietal lobule, regions associated with the default mode network, which involves prospection, self-reflective thinking and mental simulation. Furthermore, meta-analytic co-activation analysis using Neurosynth revealed a similar pattern across 11,406 task-fMRI studies. Collectively, these findings provide robust evidence that morphometric characteristics of the temporal lobe are associated with DRD preferences and suggest it may be because of their role in mental activities in common with default mode activity. PMID- 28843540 TI - Pattern component modeling: A flexible approach for understanding the representational structure of brain activity patterns. AB - Representational models specify how complex patterns of neural activity relate to visual stimuli, motor actions, or abstract thoughts. Here we review pattern component modeling (PCM), a practical Bayesian approach for evaluating such models. Similar to encoding models, PCM evaluates the ability of models to predict novel brain activity patterns. In contrast to encoding models, however, the activity of individual voxels across conditions (activity profiles) are not directly fitted. Rather, PCM integrates over all possible activity profiles and computes the marginal likelihood of the data under the activity profile distribution specified by the representational model. By using an analytical expression for the marginal likelihood, PCM allows the fitting of flexible representational models, in which the relative strength and form of the encoded feature spaces can be estimated from the data. We present here a number of different ways in which such flexible representational models can be specified, and how models of different complexity can be compared. We then provide a number of practical examples from our recent work in motor control, ranging from fixed models to more complex non-linear models of brain representations. The code for the fitting and cross-validation of representational models is provided in an open-source software toolbox. PMID- 28843541 TI - Immune development and environment: lessons from Amish and Hutterite children. AB - Children who grow up in traditional farm environments are protected from developing asthma and allergy. This 'farm effect' can be largely explained by the child's early life contact with farm animals, in particular cows, and their microbes. Our studies in Amish and Hutterite school children living on farms in the U.S. have further demonstrated that this protection is mediated through innate immune pathways. Although very similar with respect to ancestry and many lifestyle factors that are associated with asthma risk, Amish and Hutterites follow farming practices that are associated with profound differences in the levels of house dust endotoxin, in the prevalence of asthma and atopy among school children, and in the proportions, phenotypes, and functions of immune cells from these children. In this review, we will consider our studies in Amish and Hutterites children in the context of the many previous studies in European farm children and discuss how these studies have advanced our understanding of the asthma-protective 'farm effect'. PMID- 28843542 TI - Effects of GABA microinjection into dorsal raphe nucleus on behavior and activity of lateral habenular neurons in mice. AB - The dorsal raphe nucleus (DRN) is a key site for 5-hydroxytryptamine (5-HT) synthesis and release. DRN dysfunction has been implicated in several stress related disorders, including depression and anxiety. The lateral habenular nucleus (LHb) has been shown to inhibit the activity of DRN 5-HT neurons, and thus the LHb-DRN pathway plays an important role in the pathogenesis of depression. Although it is known that the LHb also receives the projection from the 5-HT neuron in the DRN, whether 5-HT neurons in the DRN can influence activity of the LHb in vivo and whether this effect is related to the induced behavioral changes have not been investigated. In the current study, we determined how injecting gamma-aminobutyric acid (GABA) into the DRN to inhibit 5 HT neurons affected behavior and the changes in the activity of LHb neurons in mice. We found that GABA injection into the DRN induced depression-like behavior in mice, as indicated by increased immobility time, and decreased climbing time in the forced swimming test and the tail suspension test, decreased time spent in the center and total distance moved in the open field test. Using extracellular single unit recording, we showed that the firing rate of LHb neurons decreased after GABA microinjection into the DRN. Further, c-Fos expression in LHb neurons was inhibited. Together our results indicate that inhibition of DRN 5-HT neurons can cause decreased LHb activity and depression-like behavior in mice, however this depression-like behavior could be independent of the LHb activity. The observed decrease in LHb activity is probably due to the presence of a negative feedback loop between the DRN and the LHb, which may play a role in maintaining emotional homeostasis. PMID- 28843543 TI - Microglia and macrophages differ in their inflammatory profile after permanent brain ischemia. AB - We studied the expression of pro- and anti-inflammatory molecules in microglia and infiltrating monocyte-derived macrophages after permanent Middle Cerebral Artery Occlusion (pMCAO). LysM-EGFP knock-in mice were used to distinguish between these two cell types, as peripheral myeloid cells are LysM-EGFP+, while microglia are not. This was confirmed with P2ry12 (a microglial specific marker), Iba-1 and EGFP immunostaining. The peak of LysM-EGFP+ myeloid cell infiltration was 72h post-ischemia, and were distributed evenly in the lesion core, surrounded by a dense region of microglia. Flow cytometry showed that a higher percentage of microglia expressed TNF-alpha at 3 (24.3% vs 1.4%) and 7 (18.8% vs 3.4%) days post-pMCAO as compared to infiltrating macrophages. Microglia and macrophages were purified by fluorescence activated cell sorting 72h post-ischemia to assess the mRNA expression of inflammatory markers. Macrophages upregulated expression of mRNA for arginase-1 (Arg-1) by 1000-fold, and IL-1beta by 90-fold as compared to microglia. At the protein level, a significantly number of macrophages expressed Arg-1, while few if any microglia expressed Arg-1. However, IL-1beta protein was not detected in macrophages by flow cytometry or immunofluorescence labeling of tissue sections. It was, however, detected in astrocytes along the lesion border. A PCR-array screen of 84 inflammatory genes revealed that pro inflammatory chemokines and cytokines were predominantly upregulated in macrophages but down-regulated in microglia in the ischemic brain. Our results show clear differences in the inflammatory expression profiles between microglia and macrophages 72h post-ischemia which may shape repair and pro-regenerative mechanisms after stroke. PMID- 28843544 TI - Occurrence of norovirus infection in an asymptomatic population in Indonesia. AB - Norovirus (NoV) is a major cause of nonbacterial acute gastroenteritis worldwide in all age groups, and asymptomatic individuals may contribute to NoV transmission as a reservoir. Nonetheless, little information is available regarding asymptomatic NoV infection in Indonesia. We performed an epidemiological analysis of NoV infection among asymptomatic healthy volunteers in the city of Surabaya, Indonesia (population ~2.75 million). A total of 512 stool samples from 18 individuals (age range 20-42years) collected from July 2015 to June 2016 were examined. The detection of NoV and the genotype classification were carried out by a reverse transcription-polymerase chain reaction (RT-PCR) direct sequencing method. NoV was detected in 14 of the 512 stool samples (2.7%), with 7 individuals (38.9%) having at least 1 positive stool sample. All 14 of the NoV strains detected belonged to genogroup GII. The phylogenetic analysis indicated that 10 strains (71.4%) were grouped with GII.2, 2 (14.3%) were GII.17, 1 was GII.4 Sydney 2012, and 1 was GII.1. The circulation of GII.Pg/GII.1 and GII.Pe/GII.4 Sydney 2012 recombinant variants was detected among an asymptomatic population in Surabaya, Indonesia. Of the 7 positive individuals, 2 were repeatedly infected with the same strain and heterogenous strains. Taken together, our results suggest that the excretion of NoV from healthy individuals is one of the sources of NoV outbreak. PMID- 28843546 TI - Ljungan/Sebokele-like picornavirus in birds of prey, common kestrel (Falco tinnunculus) and red-footed falcon (F. vespertinus). AB - Ljungan and Sebokele viruses are thought to be rodent-borne (picorna)viruses in the genus Parechovirus. Using random amplification and next generation sequencing method a novel Ljungan/Sebokele-like picornavirus was identified in birds of prey. Viral RNA was detected in total of 1 (9%) of the 11 and 2 (28.6%) of the 7 faecal samples from common kestrels and red-footed falcons in Hungary, respectively. High faecal viral RNA load (4.77*106 genomic copies/ml) measured by qPCR. The complete genome of picornavirus strain falcon/HA18_080/2014/HUN (KY645497) is 7964-nucleotide (nt) long including a 867-nt 5'end and a 101-nt 3'end (excluding the poly(A)-tail). Falcon/HA18_080/2014/HUN has type-II IRES related to hunnivirus IRES, encodes a polyprotein lacking a leader protein, a VP0 maturation cleavage site and it predicted to encode three 2A proteins (2A1NPG?P, 2A2NPG?P and 2A3H-Box/NC), two of them end with 'ribosome-skipping' sites (DxExNPG?P). Sequence analyses indicated that the ORF1 (6996nt) polyprotein (2331 amino acid - aa) of falcon/HA18_080/2014/HUN shares the highest aa identity, 59% and 57%, to the corresponding polyproteins of Ljungan and Sebokele viruses. This study reports the identification and complete genome characterization of a novel Ljungan/Sebokele-like picornavirus in faeces of birds of prey which suggests that the genetic diversity and the potential host species spectrum of Ljungan/Sebokele like viruses in genus Parechovirus are wider than previously thought. PMID- 28843547 TI - The arms race between man and Mycobacterium tuberculosis: Time to regroup. AB - An arms race is an appropriate metaphor to use for the interaction of man and Mycobacterium tuberculosis (M.tb) through the millennia. Estimates of the time of infection of modern humans with M.tb often pre-date the Out-of-Africa migration. Humans have adapted to the changing environment during the migration with respect to climate, food sources and encounters with local pathogens. More recently, there has been adaptation to the demographic changes brought about in the majority of the human population by the Neolithic revolution. By chance and/or selection, specific variants in immune defence have arisen in different population groups. These select for M.tb strains more fit to cause disease and be transmitted, sometimes by exploiting defence systems effective on other bacteria. The different selection pressures on the M.tb lineages carried by specific human groups have resulted in a worldwide M.tb population that is geographically structured according to the humans historically found there. A similar structure is seen with pathogens such as M. leprae and Helicobacter pylori. Modern M.tb strains have emerged which may be more fit, such as the Beijing lineage, leading to their rapid spread both in the areas where they arose, and into new areas after recent introduction. The speed at which this is occurring is outpacing coevolution for the time being. By using the results of genome wide and other association studies, as well as admixture mapping and 'natural experiments' in areas where both a number of populations, admixed populations, and a variety of M.tb strains occur, we can investigate the forces that have driven the coevolution of man and M.tb. The diversity of human and bacterial genetic background may be used in the future to discover and target the specific host pathogen interactions leading to tuberculosis diseases, which suggests the potential for rational design of vaccines and host-directed therapies. PMID- 28843545 TI - Subtype analysis of zoonotic pathogen Cryptosporidium skunk genotype. AB - Cryptosporidium skunk genotype is a zoonotic pathogen commonly identified in surface water. Thus far, no subtyping tool exists for characterizing its transmission in humans and animals and transport in environment. In this study, a subtyping tool based on the 60kDa glycoprotein (gp60) gene previously developed for Cryptosporidium chipmunk genotype I was used in the characterization of Cryptosporidium skunk genotype in animal and storm runoff samples from a watershed in New York. Altogether, 17 positive samples from this watershed and 5 human and animal specimens from other areas were analyzed. We identified 14 subtypes of Cryptosporidium skunk genotype, 11 of which were seen in the watershed. In phylogenetic analysis, these subtypes belonged to 4 subtype families (XVIa, XVIb, XVIc, and XVId). No host-adapted subtypes were identified and the two subtypes in humans were genetically similar to some in raccoons, otters, and storm runoff samples from the watershed. The characteristics of gp60 protein sequences of the Cryptosporidium skunk genotype are similar to those of other Cryptosporidium species, but only its XVIb subtype family has a putative furin cleavage site. This subtyping tool might be useful in characterizing Cryptosporidium skunk genotype in clinical and environmental samples. PMID- 28843548 TI - Arthroscopic Deltoid Repair: A Technical Tip. AB - Deltoid ligament repair can be challenging, and implementation of an arthroscopic method can be useful in terms of minimizing morbidity associated with open dissection, as long as the repair is effective and durable. In this brief report, we describe a method of arthroscopic deltoid ligament repair that we have found to be useful. PMID- 28843549 TI - Defining Talar Head and Neck Pathology: The Malvern Classification System. AB - Talar fractures account for <1% of all fractures in the body and 3% to 6% of pedal fractures. Of these fractures, avulsion and neck fractures represent the most and second most common type, respectively. Several classification systems exist for talar fractures of the talar dome (Berndt-Hardy), talar neck dislocation (Hawkins), and talar body (Sneppen) anatomic locations. Although diverse, they are not all encompassing for fracture patterns of the talus. Another set of pathologic issues occur about the talar head and neck region that can be seen in the clinical setting. Thus, a new classification system (Malvern classification system for talar head/neck fractures) was devised and defined for this location. The system represents a comprehensive review of the available published data and synthesis into an organized classification system. PMID- 28843550 TI - Lisfranc Joint Ligament Complex Reconstruction: A Promising Solution for Missed, Delayed, or Chronic Lisfranc Injury Without Arthritis. AB - The current classifications of "Lisfranc injury" can be purely ligamentous (low grade midfoot sprains) or involve the osseous and articular structures (high grade Lisfranc fracture displacements). The first type is often difficult to detect. If these patients are not properly treated, long-term disability can result. The rate of missed or delayed diagnoses has ranged from 13% to 24%, primarily owing to the subtlety of the radiographic findings. This is relatively more common in cases of subtle ligamentous injury (19%). The aim of the present report was to provide a new technique for missed or delayed Lisfranc injury without degenerative local signs. The Lisfranc ligament complex reconstruction is performed with a gracilis tendon graft and is protected by temporary screw fixation. We performed this technique in 3 patients. All 3 patients obtained good results, have been able to resume their previous activities, and have stated they would undergo this type of procedure again. The minimum follow-up length was 2 years. PMID- 28843551 TI - Calcaneocuboid Distraction Arthrodesis With Synthetic Bone Grafts: Preliminary Results of an Innovative Bone Grafting Procedure in 13 Patients. AB - Calcaneocuboid distraction arthrodesis (CCDA) is regarded as an effective method for reconstructing adult-acquired flatfoot deformity. In the present study, we present our experience with newly developed rigid beta-tricalcium phosphate wedges to treat CCDA to better understand the outcomes of this synthetic bone grafting procedure. A total of 13 feet in 13 patients underwent CCDA with synthetic bone grafts. One male (7.69%) and 12 females (92.31%), with a mean age of 65.07 +/- 11.83 (range 36 to 77) years, were followed up for a mean duration of 32.76 +/- 12.81 (range 18 to 55) months. Successful graft union was postoperatively obtained in 12 of the 13 feet (92.31%). The mean preoperative visual analog scale and American Orthopaedic Foot and Ankle Society scale score were 7.97 +/- 1.52 (range 5.4 to 10) and 54.46 +/- 14.72 (range 18 to 75), respectively. These scores improved to 1.52 +/- 1.78 (range 0 to 6.2) and 85.46 +/- 13.38 (range 50 to 97) postoperatively (p = .001 for both comparisons). On radiographic analysis, the talonavicular coverage angle, first metatarsal talar angle, calcaneal pitch, and heel alignment angle had significantly improved (p = .001, p = .028, p = .006, and p = .001, respectively). The use of bone graft substitutes in CCDA is a viable treatment option for reconstructing flexible flatfoot deformity. Although good clinical and radiographic outcomes were obtained, our method is even more challenging than conventional methods and should be used with caution. Rigid locking fixation with a long period of protected weightbearing is highly recommended to attain uneventful bone healing. PMID- 28843552 TI - Calibration transfer of a Raman spectroscopic quantification method for the assessment of liquid detergent compositions between two at-line instruments installed at two liquid detergent production plants. AB - Calibration transfer of partial least squares (PLS) quantification models is established between two Raman spectrometers located at two liquid detergent production plants. As full recalibration of existing calibration models is time consuming, labour-intensive and costly, it is investigated whether the use of mathematical correction methods requiring only a handful of standardization samples can overcome the dissimilarities in spectral response observed between both measurement systems. Univariate and multivariate standardization approaches are investigated, ranging from simple slope/bias correction (SBC), local centring (LC) and single wavelength standardization (SWS) to more complex direct standardization (DS) and piecewise direct standardization (PDS). The results of these five calibration transfer methods are compared reciprocally, as well as with regard to a full recalibration. Four PLS quantification models, each predicting the concentration of one of the four main ingredients in the studied liquid detergent composition, are aimed at transferring. Accuracy profiles are established from the original and transferred quantification models for validation purposes. A reliable representation of the calibration models performance before and after transfer is thus established, based on beta expectation tolerance intervals. For each transferred model, it is investigated whether every future measurement that will be performed in routine will be close enough to the unknown true value of the sample. From this validation, it is concluded that instrument standardization is successful for three out of four investigated calibration models using multivariate (DS and PDS) transfer approaches. The fourth transferred PLS model could not be validated over the investigated concentration range, due to a lack of precision of the slave instrument. Comparing these transfer results to a full recalibration on the slave instrument allows comparison of the predictive power of both Raman systems and leads to the formulation of guidelines for further standardization projects. It is concluded that it is essential to evaluate the performance of the slave instrument prior to transfer, even when it is theoretically identical to the master apparatus. PMID- 28843553 TI - Comparison of a disposable sorptive sampler with thermal desorption in a gas chromatographic inlet, or in a dedicated thermal desorber, to conventional stir bar sorptive extraction-thermal desorption for the determination of micropollutants in water. AB - The presence of micropollutants in the aquatic environment is a worldwide environmental concern. The diversity of micropollutants and the low concentration levels at which they may occur in the aquatic environment have greatly complicated the analysis and detection of these chemicals. Two sorptive extraction samplers and two thermal desorption methods for the detection of micropollutants in water were compared. A low-cost, disposable, in-house made sorptive extraction sampler was compared to SBSE using a commercial Twister sorptive sampler. Both samplers consisted of polydimethylsiloxane (PDMS) as a sorptive medium to concentrate micropollutants. Direct thermal desorption of the disposable samplers in the inlet of a GC was compared to conventional thermal desorption using a commercial thermal desorber system (TDS). Comprehensive gas chromatography coupled to time-of-flight mass spectrometry (GC * GC-TOFMS) was used for compound separation and identification. Ten micropollutants, representing a range of heterogeneous compounds, were selected to evaluate the performance of the methods. The in-house constructed sampler, with its associated benefits of low-cost and disposability, gave results comparable to commercial SBSE. Direct thermal desorption of the disposable sampler in the inlet of a GC eliminated the need for expensive consumable cryogenics and total analysis time was greatly reduced as a lengthy desorption temperature programme was not required. Limits of detection for the methods ranged from 0.0010 ng L-1 to 0.19 ng L-1. For most compounds, the mean (n = 3) recoveries ranged from 85% to 129% and the % relative standard deviation (% RSD) ranged from 1% to 58% with the majority of the analytes having a %RSD of less than 30%. PMID- 28843554 TI - Comprehensive study of buffer systems and local pH effects in electromembrane extraction. AB - Different phosphate-, acetate- and formate buffers in the pH range 2.0-6.8 were tested for electromembrane extraction (EME) in a 96-well system. The five basic drugs haloperidol, loperamide, methadone, nortriptyline, and pethidine were selected as model analytes. The EME performance was tested with respect to extraction recovery, extraction current and pH-stability. The analytes were extracted from 200 MUL buffer, through a 100 MUm thick supported liquid membrane (SLM) of 2-nitrophenyl octyl ether (NPOE) immobilized in the pores of filters in a 96-well plate, and into 100 MUL buffer acceptor phase. The extraction voltage was 50 V and the extraction time was 10 min. The acceptor phase was analyzed by HPLC-UV. The extraction current was <=6 MUA with all buffers, and pH was effectively stabilized during EME using buffers as donor (sample) and acceptor phase. For buffers with pH <= 4.8 as acceptor phase, the extraction recoveries were in the range 66-97% and with RSD <15%. With pH in the range 5.8-6.8 in the acceptor phase, the extraction recoveries decreased and were in the range 21-62%. This was attributed to elevated pH conditions in the acceptor/SLM interface. The presence of elevated pH conditions was visualized with phenolphthalein as pH sensitive color indicator. Increasing the buffer strength from 10 to 500 mM in an attempt to offset the elevated pH conditions gave no improvement, and elevated pH conditions remained. Elevated pH conditions in the acceptor/SLM interface were also observed when voltage was increased, and when NPOE was replaced with tributyl phosphate as SLM. The presence of elevated pH conditions close to the SLM in EME was discussed for the first time, and this information is highly important for future development of EME. PMID- 28843555 TI - A novel multi-hyphenated analytical method to simultaneously determine xanthine oxidase inhibitors and superoxide anion scavengers in natural products. AB - Natural products, such as rosmarinic acid and apigenin, can act as xanthine oxidase inhibitors (XOIs) as well as superoxide anion scavengers, and have potential for treatment of diseases associated with high uric acid levels and oxidative stress. However, efficient simultaneous screening of these two bioactivities in natural products has been challenging. We have developed a novel method by assembling a multi-hyphenated high performance liquid chromatography (HPLC) system that combines a photo-diode array, chemiluminescence detector and a HPLC system with a variable wavelength detector, to simultaneously detect components that act as both XOIs and superoxide anion scavengers in natural products. Superoxide anion scavenging activity in the analyte was measured by on line chemiluminescence chromatography based on pyrogallol-luminol oxidation, while xanthine oxidase inhibitory activity was determined by semi-on-line HPLC analysis. After optimizing multiple elements, including chromatographic conditions (e.g., organic solvent concentration and mobile phase pH), concentrations of xanthine/xanthine oxidase and reaction temperature, our validated analytical method was capable of mixed sample analysis. The final results from our method are presented in an easily understood visual format including comprehensive bioactivity data of natural products. PMID- 28843556 TI - A new technique for probing chirality via photoelectron circular dichroism. AB - We present a proof-of-principle approach for discriminating chiral enantiomers based on the phenomenon of multiphoton photoelectron circular dichroism. A novel stereo detection setup was used to measure the number of photoelectrons emitted from chiral molecules in directions parallel or anti-parallel to the propagation of the ionising femtosecond laser pulses. In this study, we show how these asymmetries in the ketones camphor and fenchone depend upon the ellipticity of the laser pulses and the enantiomeric excess of the sample. By using a high repetition rate femtosecond laser, enantiomer excesses with uncertainties at the few-percent level could be measured in close to real-time. As the instrument is compact, and commercial turnkey femtosecond lasers are readily available, the development of a stand-alone chiral analysis instrument for a range of applications is now possible. PMID- 28843557 TI - Development and validation of an ultra-high performance liquid chromatographic high resolution Q-Orbitrap mass spectrometric method for the simultaneous determination of steroidal endocrine disrupting compounds in aquatic matrices. AB - The lack of adequate strategies for monitoring endocrine disrupting compounds (EDCs) in the aquatic environment is emphasized in the European Water Framework Directive. In this context, a new UHPLC-HR-Q-Orbirtrap-MS multi-residue method was developed for the simultaneous measurement of 70 steroidal EDCs in two aquatic matrices, i.e. sea and fresh water. First, an instrumental APCI-UHPLC-HR Q-Orbitrap-MS was devised for separating and detecting the EDC isomers and mass analogues, within 12.5 min per run. Next, an appropriate extraction was statistically optimised using a three-strep workflow (95% confidence interval, p > 0.05); including fractional factorial resolution IV, simplex lattice, and response surface methodological designs. The fitness-for-purpose of the method was demonstrated through successful validation at relevant environmental concentrations, i.e. the low nano- and picogram range. Method quantification limits ranged for the androgens (n = 33), oestrogens (n = 14), progestins (n = 12), and corticosteroids (n = 11) between, respectively, 0.13 and 5.00 ng L-1, 0.25 and 5.00 ng L-1, 0.13 and 2.50 ng L-1, and 0.50 and 5.00 ng L-1. Good linearity (R2 >= 0.99) and no lack of fit was observed (95% confidence interval, p > 0.05) for the 70 steroidal EDCs. In addition, good recovery (95-109%) and satisfactory repeatability (RSD < 8.5%, n = 18) and reproducibility (RSD < 10.5%, n = 12) were obtained. Finally, the applicability of the multi-residue method was demonstrated by measuring steroidal EDC in 28 sea water samples collected from four different locations during fall 2016 and winter 2017. Regarding the sea water samples, all the classes were ubiquitously present and included different metabolites, transformation product and or degradation products from the parent EDCs (n = 43). PMID- 28843559 TI - An amplified fluorescent aptasensor based on single-stranded DNA binding protein, copper and silica nanoparticles for sensitive detection of interferon-gamma. AB - It is great significance to identify interferon-gamma (IFN-gamma), as a biological marker for diagnosis of latent tuberculosis, in serum samples. In this paper, a novel fluorescent aptasensor was fabricated and applied for sensitive and specific detection of IFN-gamma. This biosensor was based on hairpin structure of oligonucleotide, single-stranded DNA-binding protein (SSB), copper nanoparticles (CuNPs) and silica nanoparticles coated with streptavidin (SNPs Streptavidin). The presences of double-stranded DNA (dsDNA) region and poly thymine (T) in the hairpin structure of the oligonucleotide, SSB and SNPs streptavidin caused IFN-gamma determination with high selectivity and sensitivity. Upon addition of IFN-gamma, the hairpin structure of the oligonucleotide was disassembled and therefore, poly T strand interacted with SSB and a weak fluorescence signal was obtained. Without introduction of IFN-gamma, the hairpin structure of oligonucleotide was preserved and fluorescent CuNPs were formed on the stem region of hairpin structure of oligonucleotide, resulting in strong fluorescence intensity. Under optimal conditions, concentration as low as 1 pg/mL IFN-gamma could be detected, with a linear range between 10 pg/mL and 4 ng/mL. The presented method was further performed for detection of IFN-gamma in the spiked human serum samples and the recoveries were 92.52%-98.32%, showing the great potential of the proposed analytical method in biomedical analysis. PMID- 28843558 TI - Targeted quantification of lipid mediators in skeletal muscles using restricted access media-based trap-and-elute liquid chromatography-mass spectrometry. AB - Lipid mediators (LMs) are a class of bioactive metabolites of the essential polyunsaturated fatty acids (PUFA), which are involved in many physiological processes. Their quantification in biological samples is critical for understanding their functions in lifestyle and chronic diseases, such as diabetes, as well allergies, cancers, and in aging processes. We developed a rapid, and sensitive LC-MS/MS method to quantify the concentrations of 14 lipid mediators of interest in mouse skeletal muscle tissue without time-consuming liquid-liquid or solid-phase extractions. A restricted-access media (RAM) based trap was used prior to LC-MS as cleanup process to prevent the analytical column from clogging and deterioration. The system enabled automatic removal of residual proteins and other biological interferences presented in the tissue extracts; the target analytes were retained in the trap and then eluted to an analytical column for separation. Matrix evaluation tests demonstrated that the use of the combined RAM trap and chromatographic separation efficiently eliminated the biological or chemical matrix interferences typically encountered in bioanalytical analysis. Using 14 LM standards and 12 corresponding deuterated compounds as internal standards, the five-point calibration curves, established over the concentration range of 0.031-320 ng mL-1, demonstrated good linearity of r2 > 0.9903 (0.9903 0.9983). The lower detection limits obtained were 0.016, 0.031, 0.062, and 0.31 ng mL-1 (0.5, 1, 2, and 10 pg on column), respectively, depending on the specific compounds. Good accuracy (87.1-114.5%) and precision (<13.4%) of the method were observed for low, medium, and high concentration quality control samples. The method was applied to measure the amount of 14 target LMs in mouse skeletal muscle tissues. All 14 analytes in this study were successfully detected and quantified in the gastrocnemius muscle samples, which provided crucial information for both age and gender-related aspects of LMs signaling in skeletal muscles previously unknown. This method could be applied to advance the understanding of skeletal muscle pathophysiology to study the role of LMs in health and disease. Furthermore, we will expand the application of this methodology to humans and other tissues/matrices in the near future. PMID- 28843560 TI - Smartphone coupled handheld array reader for real-time toxic gas detection. AB - Smartphones and related accessories are rapidly expanding their applications in various fields. Herein we developed a smartphone coupled handheld array reader with the integration of complementary metal oxide (CMOS) image sensor for detecting various toxic gases by colorimetric monitoring approach. In this study, toxic gases such as hydrogen fluoride (HF), chlorine (Cl2), ammonia (NH3), and formaldehyde (CH2O) were detected using titanium nanoparticles (TiO2 NPs) blended poly (vinyl alcohol) (PVA) hydrogel test strips, which were patterned with chemically responsive dyes. The dye colors changed based on acid-base reactions, and the colorimetric reader monitored the array strips and mapped them in the form of chrominance data. The observed signals transferred to a smartphone that displays the detected toxic gases and their exposure levels with the aid of the smartphone app "Toxic Gas Detection". The colorimetric array reader was precisely constructed with an auto-calibration system to minimize potential errors. Various concentration of toxic gases (0.5-10 ppm) were analyzed and achieved the detection limit of 1 ppm for each gas. Also, various analytical performance including sensitivity, stability, selectivity, and reproducibility analysis proved the reliability and accuracy of the detection system. Additionally, the smartphone app can be installed on any type of tablet, laptop, or other portable device. This study proved that smartphone coupled colorimetric array reader is a suitable system for detecting various toxic gases, chemicals and biochemical analysis with real-time monitoring approach. PMID- 28843561 TI - Fluorescent aptasensor for antibiotic detection using magnetic bead composites coated with gold nanoparticles and a nicking enzyme. AB - Antibiotic abuse has been bringing serious pollution in water, which is closely related to human health. It is desirable to develop a new strategy for antibiotic detection. To address this problem, a sensitive fluorescent aptasensor for antibiotic detection was developed by utilizing gold nanoparticles modified magnetic bead composites (AuNPs/MBs) and nicking enzyme. AuNPs/MBs were synthesized with the help of polyethylenimine (PEI). The prepared AuNPs/MBs acted as dual-functional scaffolds that owned excellent magnetic separation capacity and strong covalent bio-conjugation. The non-specifically absorbed aptamers in AuNPs/MBs were less than that in MBs. Hence, the fluorescent aptasensor based on AuNPs/MBs show a better signal to background ratio than that based on carboxyl modified magnetic beads (MBs). In this work, ampicillin was employed as a model analyte. In the presence of ampicillin, the specific binding between ampicillin and aptamer induced structure-switching that led to the release of partial complementary DNA (cDNA) of aptamer. Then, the released cDNA initiated the cycle of nicking enzyme assisted signal amplification (NEASA). Therefore, a large amount of taqman probes were cleaved and fluorescence signal was amplified. The prepared fluorescent aptasensor bring sensitive detection in range of 0.1-100 ng mL-1 with the limit of detection of 0.07 ng mL-1. Furthermore, this aptasensor was also successfully applied in real sample detection with acceptable accuracy. The fluorescent aptasensor provides a promising method for efficient, rapid and sensitive antibiotic detection. PMID- 28843562 TI - Fabrication of a novel impedimetric sensor based on l-Cysteine/Cu(II) modified gold electrode for sensitive determination of ampyra. AB - This paper presents a novel impedimetric sensor for the sensitive determination of ampyra (Am) based on the l-Cysteine/Cu (II) modified gold electrode (Cu (II)/L Cys/AuE). This novel sensing layer was characterized by different techniques, including atomic force microscopy (AFM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Am determination by conventional electrochemical methods is not possible, because of its high redox overpotential. Therefore, [Fe(CN)6]3-/4- was used as a redox probe for the impedimetric determination of Am. Under the optimized conditions, the calibration curve for Am concentration was linear in the range 0.010-40.0 nM with a detection limit of 0.0028 nM. The practical applicability of the proposed sensor was examined by evaluating the detection of Am in biological fluids and pharmaceutical samples with satisfied recoveries. Therefore, the prepared sensor can hold great promise for fast, simple and sensitive detection of Am in various real samples. PMID- 28843563 TI - Plasmonic substrates for surface enhanced Raman scattering. AB - As an advanced analytical tool, surface-enhanced Raman scattering (SERS) has broad applications in identification of colorants in paints and glazes, hazard detection to ensure food safety, biomedicine and diagnosis, environmental monitoring, detection of explosives and forensic science. In this review, main types of plasmonic substrates, which include solid substrate with metallic nanostructures and chemically synthesized noble metal colloids, and their fabrication methods are reviewed. The design principles for fabrication of ultrasensitive plasmonic substrates for SERS are presented on the basis of published literature. Finally, various applications of SERS substrates are described, indicating the potential of this technique in practical applications. As an ultrasensitive detection method, SERS is at the core of a rapidly expanding research field. PMID- 28843564 TI - A long-lived ferrocene-conjugated iridium(III) complex for sensitive turn-on luminescence detection of traces of DMSO in water and human serum. AB - The development of an efficient sensor for the determination of the DMSO content in aqueous solution is highly desirable in a number of chemical industries. Presented herein is a ferrocene-conjugated iridium(III) complex, which exhibits remarkable capability to detect traces of DMSO (<1% v/v) in aqueous solution through a turn-on luminescence sensing mechanism. The extraordinary sensitivity and selectivity of this newly developed complex for DMSO renders it as one of the most powerful DMSO sensors known. PMID- 28843565 TI - Multi-stimuli responsive copper nanoclusters with bright red luminescence for quantifying acid phosphatase activity via redox-controlled luminescence switch. AB - Thiolate-protected copper nanoclusers (CuNCs) are emerging as a promising class of luminescent materials since its unique optical properties such as aggregation induced emission (AIE) and intriguing molecular-like behavior have been explored for sensing application. In this work, multi-stimuli responsive property of CuNCs was first investigated in depth and further adopted to develop a reliable and sensitive ACP assay. Penicilamine-capped CuNCs from a facile one-pot synthesis possess bright red luminescence and distinctive multi-stimuli responsive behaviors. Its sensitive and reversible response in luminescence to pH and temperature is originated from its inherent AIE property, and can be constructed as luminescent nanoswitches controlled by these external stimuli for precisely monitoring the change of environmental pH or temperature. The specific redox responsive behavior of CuNC aggregates is found from severe luminescence quenching in the presence of a small amount of ferric or silver ions, and this sensitive response in luminescence to the preceding species is proved to be due to the conversion of Cu(II) from copper atoms with lower valence inside CuNCs. The luminescence switch of CuNC aggregates controlled by specific external potentials is further utilized to design a novel detection strategy for ACP activity. The great difference in luminescence quenching of CuNCs induced by iron(III) pyrophosphate (FePPi2) complex and free ferric ions enables us to quantitatively monitor ACP level by the luminescence change as variation of ACP activity in the assay solution. This assay is able to detect ACP level as lower as 0.8 U/L, and covers a broad linear scope of 100.0 U/L. This work reports redox responsive property of CuNCs and its underlying nature due to the oxidation of its interior copper atoms, and provides a sensitive assay method for ACP activity which is sufficiently sensitive for practical measurement in real samples. PMID- 28843566 TI - Partial filling affinity capillary electrophoresis as a useful tool for fragment based drug discovery: A proof of concept on thrombin. AB - With the emergence of more challenging targets, a relatively new approach, fragment-based drug discovery (FBDD), proved its efficacy and gained increasing importance in the pharmaceutical industry. FBDD identifies low molecular-weight (MW) ligands (fragments) that bind to biologically important macromolecules, then a structure-guided fragment growing or merging approach is performed, contributing to the quality of the lead. However, to select the appropriate fragment to be evolved, sensitive analytical screening methods must be used to measure the affinity in the MUM or even mM range. In this particular context, we developed a robust and selective partial filling affinity CE (ACE) method for the direct binding screening of a small fragment library in order to identify new thrombin inhibitors. To demonstrate the accuracy of our assay, the complex dissociation constants of three known thrombin inhibitors, namely benzamidine, p aminobenzamidine and nafamostat were determined and found to be in good concordance with the previously reported values. Finally, the screening of a small library was performed and demonstrated the high discriminatory power of our method towards weak binders compared to classical spectrophotometric activity assay, proving the interest of our method in the context of FBDD. PMID- 28843567 TI - Saturated fatty acid determination method using paired ion electrospray ionization mass spectrometry coupled with capillary electrophoresis. AB - A sensitive and selective capillary electrophoresis-mass spectrometry (CE-MS) method for determination of saturated fatty acids (FAs) was developed by using dicationic ion-pairing reagents forming singly charged complexes with anionic FAs. For negative ESI detection, 21 anionic FAs at pH 10 were separated using ammonium formate buffer containing 40% acetonitrile modifier in normal polarity mode in CE by optimizing various parameters. This method showed good separation efficiency, but the sensitivity of the method to short-chain fatty acids was quite low, causing acetic and propionic acids to be undetectable even at 100 mgL 1 in negative ESI-MS detection. Out of the four dicationic ion-pairing reagents tested, N,N'-dibutyl 1,1'-pentylenedipyrrolidium infused through a sheath-liquid ion source during CE separation was the best reagent regarding improved sensitivity and favorably complexed with anionic FAs for detection in positive ion ESI-MS. The monovalent complex showed improved ionization efficiency, providing the limits of detection (LODs) for 15 FAs ranging from 0.13 to 2.88 MUg/mL and good linearity (R2 > 0.99) up to 150 MUg/mL. Compared to the negative detection results, the effect was remarkable for the detection of short- and medium-chain fatty acids. The optimized CE-paired ion electrospray (PIESI)-MS method was utilized for the determination of FAs in cheese and coffee with simple pretreatment. This method may be extended for sensitive analysis of unsaturated fatty acids. PMID- 28843568 TI - Corrigendum to "Separate screening of brominated and chlorinated dioxins in field samples using in vitro reporter gene assays with rat and mouse hepatoma cell lines" [ACA 975 (2017) 86-95]. PMID- 28843569 TI - Review of geometries and coating materials in solid phase microextraction: Opportunities, limitations, and future perspectives. AB - The development of new support and geometries of solid phase microextraction (SPME), including metal fiber assemblies, coated-tip, and thin film microextraction (TFME) (i.e. self-supported, fabric and blade supported), as well as their effects on diffusion and extraction rate of analytes were discussed in the current review. Application of main techniques widely used for preparation of a variety of coating materials of SPME, including sol-gel technique, electrochemical and electrospinning methods as well as the available commercial coatings, were presented. Advantages and limitations of each technique from several aspects, such as range of application, biocompatibility, availability in different geometrical configurations, method of preparation, incorporation of various materials to tune the coating properties, and thermal and physical stability, were also investigated. Future perspectives of each technique to improve the efficiency and stability of the coatings were also summarized. Some interesting materials including ionic liquids (ILs), metal organic frameworks (MOFs) and particle loaded coatings were briefly presented. PMID- 28843570 TI - A novel absolute quantitative imaging strategy of iron, copper and zinc in brain tissues by Isotope Dilution Laser Ablation ICP-MS. AB - Isotope Dilution Laser Ablation ICP-MS (ID-LA-ICP-MS), because of its impressive spatial resolution capacity and precise means for quantification, is one of the most promising tools for in-situ quantitative imaging of trace elements in biological samples. In the ID-LA-ICP-MS strategy for tissue section, the tissue must be maintained intact during the whole sample preparation process. Therefore, how to homogeneously distribute enriched isotope spike on tissue section and how to confirm isotope equilibration between sample and spike are two important challenges. In this study, we reported a novel quantitative imaging strategy for biological thin section based on ID-LA-ICP-MS. To distribute the enriched isotope spikes on tissue section homogeneously, a "border" was constructed to make spike droplet stay on the tissue for isotope exchange. Laser ablation and isotope exchange parameters were also investigated to obtain optimal ID-LA-ICP-MS conditions. The prepared homogeneous in-house standard was used to validate the ID-LA-ICP-MS approach and good agreement with the bulk analysis was achieved. On this basis, quantitative imaging of Fe, Cu and Zn in real mouse brain of Alzheimer's Disease (AD) were measured by the improved methodology. Assessment of the method for real sample was undertaken by comparison of the LA-ICP-MS data with that obtained by micro-XRF. Moreover, comparative analysis of elements distribution and immunohistochemical markers in AD mouse brain was also carried out. The similar distributional patterns demonstrated that the proposed methodology is potential to investigate the correlation of biomarker heterogeneity and elements distribution, and may be useful to understand such complex brain mechanisms in the future. PMID- 28843571 TI - Selection of robust variables for transfer of classification models employing the successive projections algorithm. AB - Multivariate models have been widely used in analytical problems involving quantitative and qualitative analyzes. However, there are cases in which a model is not applicable to spectra of samples obtained under new experimental conditions or in an instrument not involved in the modeling step. A solution to this problem is the transfer of multivariate models, usually performed using standardization of the spectral responses or enhancement of the robustness of the model. This present paper proposes two new criteria for selection of robust variables for classification transfer employing the successive projections algorithm (SPA). These variables are then used to build models based on linear discriminant analysis (LDA) with low sensitivity with respect to the differences between the responses of the instruments involved. For this purpose, transfer samples are included in the calculation of the cost for each subset of variables under consideration. The proposed methods are evaluated for two case studies involving identification of adulteration of extra virgin olive oil (EVOO) and hydrated ethyl alcohol fuel (HEAF) using UV-Vis and NIR spectroscopy, respectively. In both cases, similar or better classification transfer results (obtained for a test set measured on the secondary instrument) employing the two criteria were obtained in comparison with direct standardization (DS) and piecewise direct standardization (PDS). For the UV-Vis data, both proposed criteria achieved the correct classification rate (CCR) of 85%, while the best CCR obtained for the standardization methods was 81% for DS. For the NIR data, 92.5% of CCR was obtained by both criteria as well as DS. The results demonstrated the possibility of using either of the criteria proposed for building robust models as an alternative to the standardization of spectral responses for transfer of classification. PMID- 28843572 TI - A TiO2 nanosheet-g-C3N4 composite photoelectrochemical enzyme biosensor excitable by visible irradiation. AB - In this work, g-C3N4 and TiO2 nanosheets were synergistically employed as a novel composite for developing a scaffold of a photoelectrochemical enzyme biosensor. In this way, we have improved the poor visible light excitation of TiO2 and retarded the photo-generated charge recombination on g-C3N4 to achieve an enhanced response at the photoelectrochemical biosensor, compared to that generated by the corresponding biosensors consisting of each individual component. Using glucose oxidase as a model enzyme, the biosensor was demonstrated to show strong visible light activity towards the enzyme mediated glucose oxidation. We have also observed a 350% enhanced photocurrent compared to that at a g-C3N4 based ITO electrode. In addition, the high specific surface area and excellent biocompatibility of TiO2 nanosheets have also positively contributed to the performance of the photoelectrochemical enzyme biosensor with a 0.05-16 mM linear range and a 0.01 mM glucose detection limit. PMID- 28843573 TI - Comparative study of carbon fiber structure on the electrocatalytic performance of ZIF-67. AB - In this study, novel ZIF-67@carbon fiber composites were fabricated by a simple and facile approach. In order to explore the influence of carbon fiber structure on enhancing the electrocatalytic efficiency of the ZIF-67, different structural carbon fibers (hollow porous carbon fiber (PCF) and solid carbon fiber (SCF)) were used for preparing ZIF-67/carbon fiber catalysts. ZIF-67/carbon fiber composites were characterized via X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, X ray photoelectron spectroscopy and electrochemical methods. Thanks to excellent hollow structural characteristic of PCF, ZIF-67/PCF possesses more exposed active sites, smaller particle size of ZIF-67, better conductivity, electrochemical stability, more mass transport channels as well as superior electrocatalytic abilities than ZIF-67/SCF. Furthermore, ZIF-67/PCF(1:1) sample-modified glassy carbon electrode presents a linear range to nitrobenzene that is composed by two line segments, i.e. from 0.3 to 50 MUM with a sensitivity of 454.7 MUA mM-1 and from 50 to 390 MUM with a sensitivity of 132.0 MUA mM-1, and a low detection limit of 0.16 MUM. It also exhibits a wide linear response to l-cysteine in the range of 5-160 MUM and 160-1580 MUM with a rapidly response within 1.0 s as well as high catalytic rate constant, good stability and anti-interference ability. Our work provides useful information for searching and choosing carbon materials with excellent structure benefit to electrochemical applications. PMID- 28843574 TI - The 7-factor hybrid model of DSM-5 PTSD symptoms and alcohol consumption and consequences in a national sample of trauma-exposed veterans. AB - The purpose of the present study was to investigate associations between the 7 factor hybrid model of DSM-5 posttraumatic stress disorder (PTSD) symptoms, which includes intrusions, avoidance, negative affect, anhedonia, externalizing behaviors, anxious arousal, and dysphoric arousal symptoms, and alcohol consumption and consequences. A nationally representative sample of 916 trauma exposed U.S. military veterans were administered the Trauma History Screen, PTSD Checklist-5, and Alcohol Use Disorders Identification Test. Confirmatory factor analyses were conducted to determine associations between the 7-factor hybrid model of PTSD symptoms, and alcohol consumption and consequences. Results revealed that lifetime dysphoric arousal (r=0.31), negative affect (r=0.30), and anhedonia (r=0.29) symptom clusters were most strongly associated with past-year alcohol consequences. No significant associations were observed for alcohol consumption. While the cross-sectional study design does not allow one to ascertain causative associations between PTSD factors and alcohol consumption and consequences, results generally align with the self-medication hypothesis, as PTSD factors reflecting internalizing were most strongly related to alcohol related consequences. These results underscore the importance of assessing for alcohol use problems in veterans who score highly on PTSD symptoms reflecting internalizing symptomatology. PMID- 28843575 TI - Can less be more? Open trial of a stepped care approach for child and adolescent anxiety disorders. AB - This open trial presents a stepped care treatment approach for youths with anxiety disorders. In Step 1, 124 youths (65 girls; M age=9.7years) participated in a low intensity computer administered attention bias modification (ABM) protocol. Statistically significant reductions in youth anxiety severity were found following Step 1. Youths and parents were then given the option to not continue with further treatment or step up to a higher intensity cognitive behavioral therapy (CBT) protocol (Step 2). Of 112 youths who completed Step 1, 67 (59.8%) discontinued treatment and 45 (40.2%) stepped up. Co-occurring ADHD and higher anxiety severity at baseline were significantly associated with the decision to step up. Of those youths who completed Step 2, additional statistically significant reductions in youth anxiety severity were found. Across the entire protocol, 68.6% of youths were rated as either very much improved or much improved on the Clinical Global Impressions-Improvement scale. In a hypothetical comparison in which all youths received CBT alone, the stepped care protocol resulted in approximately 50% less time in treatment sessions. These findings support the promise of initiating youth anxiety disorder treatment with low intensity treatment and then stepping up to higher intensity treatment as needed. PMID- 28843576 TI - Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis. AB - BACKGROUND: HIV and herpes simplex virus type 2 (HSV-2) infections cause a substantial global disease burden and are epidemiologically correlated. Two previous systematic reviews of the association between HSV-2 and HIV found evidence that HSV-2 infection increases the risk of HIV acquisition, but these reviews are now more than a decade old. METHODS: For this systematic review and meta-analysis, we searched PubMed, MEDLINE, and Embase (from Jan 1, 2003, to May 25, 2017) to identify studies investigating the risk of HIV acquisition after exposure to HSV-2 infection, either at baseline (prevalent HSV-2 infection) or during follow-up (incident HSV-2 infection). Studies were included if they were a cohort study, controlled trial, or case-control study (including case-control studies nested within a cohort study or clinical trial); if they assessed the effect of pre-existing HSV-2 infection on HIV acquisition; and if they determined the HSV-2 infection status of study participants with a type-specific assay. We calculated pooled random-effect estimates of the association between prevalent or incident HSV-2 infection and HIV seroconversion. We also extended previous investigations through detailed meta-regression and subgroup analyses. In particular, we investigated the effect of sex and risk group (general population vs higher-risk populations) on the relative risk (RR) of HIV acquisition after prevalent or incident HSV-2 infection. Higher-risk populations included female sex workers and their clients, men who have sex with men, serodiscordant couples, and attendees of sexually transmitted infection clinics. FINDINGS: We identified 57 longitudinal studies exploring the association between HSV-2 and HIV. HIV acquisition was almost tripled in the presence of prevalent HSV-2 infection among general populations (adjusted RR 2.7, 95% CI 2.2-3.4; number of estimates [Ne]=22) and was roughly doubled among higher-risk populations (1.7, 1.4-2.1; Ne=25). Incident HSV-2 infection in general populations was associated with the highest risk of acquisition of HIV (4.7, 2.2-10.1; Ne=6). Adjustment for confounders at the study level was often incomplete but did not significantly affect the results. We found moderate heterogeneity across study estimates, which was explained by risk group, world region, and HSV-2 exposure type (prevalent vs incident). INTERPRETATION: We found evidence that HSV-2 infection increases the risk of HIV acquisition. This finding has important implications for management of individuals diagnosed with HSV-2 infection, particularly for those who are newly infected. Interventions targeting HSV-2, such as new HSV vaccines, have the potential for additional benefit against HIV, which could be particularly powerful in regions with a high incidence of co-infection. FUNDING: World Health Organization. PMID- 28843577 TI - Measuring progress on preventing pneumonia deaths: are we there yet? PMID- 28843579 TI - A fresh look at an old problem. PMID- 28843578 TI - Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the Global Burden of Disease Study 2015. AB - BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2015 provides an up-to-date analysis of the burden of lower respiratory tract infections (LRIs) in 195 countries. This study assesses cases, deaths, and aetiologies spanning the past 25 years and shows how the burden of LRI has changed in people of all ages. METHODS: We estimated LRI mortality by age, sex, geography, and year using a modelling platform shared across most causes of death in the GBD 2015 study called the Cause of Death Ensemble model. We modelled LRI morbidity, including incidence and prevalence, using a meta-regression platform called DisMod-MR. We estimated aetiologies for LRI using two different counterfactual approaches, the first for viral pathogens, which incorporates the aetiology-specific risk of LRI and the prevalence of the aetiology in LRI episodes, and the second for bacterial pathogens, which uses a vaccine-probe approach. We used the Socio-demographic Index, which is a summary indicator derived from measures of income per capita, educational attainment, and fertility, to assess trends in LRI-related mortality. The two leading risk factors for LRI disability-adjusted life-years (DALYs), childhood undernutrition and air pollution, were used in a decomposition analysis to establish the relative contribution of changes in LRI DALYs. FINDINGS: In 2015, we estimated that LRIs caused 2.74 million deaths (95% uncertainty interval [UI] 2.50 million to 2.86 million) and 103.0 million DALYs (95% UI 96.1 million to 109.1 million). LRIs have a disproportionate effect on children younger than 5 years, responsible for 704 000 deaths (95% UI 651 000-763 000) and 60.6 million DALYs (95UI 56.0 65.6). Between 2005 and 2015, the number of deaths due to LRI decreased by 36.9% (95% UI 31.6 to 42.0) in children younger than 5 years, and by 3.2% (95% UI -0.4 to 6.9) in all ages. Pneumococcal pneumonia caused 55.4% of LRI deaths in all ages, totalling 1 517 388 deaths (95% UI 857 940-2 183 791). Between 2005 and 2015, improvements in air pollution exposure were responsible for a 4.3% reduction in LRI DALYs and improvements in childhood undernutrition were responsible for an 8.9% reduction. INTERPRETATION: LRIs are the leading infectious cause of death and the fifth-leading cause of death overall; they are the second-leading cause of DALYs. At the global level, the burden of LRIs has decreased dramatically in the last 10 years in children younger than 5 years, although the burden in people older than 70 years has increased in many regions. LRI remains a largely preventable disease and cause of death, and continued efforts to decrease indoor and ambient air pollution, improve childhood nutrition, and scale up the use of the pneumococcal conjugate vaccine in children and adults will be essential in reducing the global burden of LRI. FUNDING: Bill & Melinda Gates Foundation. PMID- 28843580 TI - A biodegradable non-covered self-expandable stent to treat pancreatic duct strictures in chronic pancreatitis: a proof of principle. AB - BACKGROUND AND AIMS: In chronic pancreatitis (CP), fibrotic pancreatic duct (PD) strictures pose a therapeutic challenge, because endoscopic dilatation requires multiple procedures with suboptimal results. Biodegradable self-expandable stents (BD-SESs) may serve as an alternative in this setting. METHODS: Patients with CP were eligible for this proof-of-principle study if at least 6 months of endoscopic dilatation with plastic stents had failed to resolve their PD stricture. The non-covered BD-SESs were expected to degrade within 3 to 6 months. Patients were followed at 3-monthly intervals for 1 year. Placement success and safety were the primary outcome parameters. Stricture resolution was assessed by ERCP after 6 months. RESULTS: BD-SESs were successfully placed in all 19 patients without adverse events. In 2 cases, stent occlusion with sludge and stones was treated by a balloon swipe. One stent disintegrated during this procedure, after which placement of the plastic stent was resumed. A hyperplastic response was observed in 2 patients but did not result in functional obstruction. Stricture resolution was accomplished in 11 patients (technical success rate 58%). Six patients required further treatment of their PD stricture, 4 endoscopically and 2 surgically. Three additional patients underwent surgery for other reasons: 2 Whipple procedures for CP-related adverse events and one tail resection for an intraductal papillary mucinous neoplasm. The remaining 10 patients did not require further PD drainage (clinical success rate 52%). CONCLUSIONS: These preliminary results show that BD-SESs are safe to use and able to resolve fibrotic PD strictures in CP. These encouraging outcomes warrant further testing. PMID- 28843581 TI - EUS-guided drainage of postsurgical fluid collections using lumen-apposing metal stents: a multicenter study. AB - BACKGROUND AND AIMS: Postsurgical fluid collections (PSFCs) are traditionally drained either percutaneously or surgically. Endoscopic drainage offers several advantages compared with either percutaneous or surgical approaches, including avoiding repeat surgery or the need to have a percutaneous drain in place for weeks. There are very little data regarding the use of lumen-apposing metal stents (LAMSs) in the drainage of PSFCs. We aim to study the technical and clinical success and adverse events (AEs) of using LAMSs in the drainage of PSFCs. METHODS: Collaborators from 8 centers retrospectively reviewed their endoscopic databases to find procedures using LAMSs for drainage of PSFCs. Technical success (successful placement of LAMSs into the fluid collection), clinical success (complete resolution of the fluid collection on repeat imaging or endoscopy), and intraprocedure and postprocedure AEs were measured. RESULTS: Forty-seven patients were identified with PSFCs after various surgeries. Thirteen patients had failed previous percutaneous or surgical drainage attempts. Fluid collections averaged 78.6 mm (range, 47-150 mm) in size. The most common site of stent placement was transgastric, followed by rectum and duodenum. Technical success rate was 93.6% and clinical success rate 89.3%. The intraprocedural AE rate was 4.25% and postprocedural AE rate 6.4%. There was 1 death unrelated to the procedure. CONCLUSIONS: The use of LAMSs to drain PSFCs has a high technical and clinical success rate with low AEs. For collections that are favorably located adjacent to the stomach, duodenum, or rectum, LAMS placement is a viable alternative to repeat surgery or percutaneous drainage. PMID- 28843582 TI - Diagnosis and predictors of sessile serrated adenoma after educational training in a large, community-based, integrated healthcare setting. AB - BACKGROUND AND AIMS: Sessile serrated adenomas (SSAs) are precursors of 15% to 30% of colorectal cancers but are frequently underdiagnosed. We sought to measure the SSA detection rate (SDR) and predictors of SSA detection after educational training for community gastroenterologists and pathologists. METHODS: Colonoscopy and pathology data (2010-2014) from 3 medical centers at Kaiser Permanente Northern California were accessed electronically. Gastroenterologists and pathologists attended a training session on SSA diagnosis in 2012. Mean SDRs and patient-level predictors of SSA detection post-training (2013-2014) were investigated. RESULTS: Mean SDRs increased from .6% in 2010-2012 to 3.7% in 2013 2014. The increase in the detection of proximal SSAs was accompanied by a decrease in the detection of proximal hyperplastic polyps (HPs). Among 34,161 colonoscopies performed in 2013 to 2014, SDRs for screening, fecal immunochemical test positivity, surveillance, and diagnostic indication were 4.2%, 4.5%, 4.9%, and 3.0%, respectively. SSA detection was lower among Asians (adjusted odds ratio [aOR], .46; 95% confidence interval [CI], .31-.69) and Hispanics (aOR, .59; 95% CI, .36-.95) compared with non-Hispanic whites and higher among patients with synchronous conventional adenoma (aOR, 1.46; 95% CI, 1.15-1.86), HP (aOR, 1.74; 95% CI, 1.30-2.34), and current smokers (aOR, 1.78; 95% CI, 1.17-2.72). SDRs varied widely among experienced gastroenterologists, even after training (1.1% 8.1%). There was a moderately strong correlation between adenoma detection rate (ADR) and SDR for any SSA (r = .64, P = .0003) and for right-sided SSAs (r = .71, P < .0001). CONCLUSIONS: Educational training significantly increased the detection of SSA, but a wide variation in SDR remained across gastroenterologists. SSA detection was inversely associated with Asian and Hispanic race/ethnicity and positively associated with the presence of conventional adenoma, HP, and current smoking. There was a moderately strong correlation between ADR and SDR. PMID- 28843583 TI - Long-term outcomes of EUS-guided choledochoduodenostomy using a lumen-apposing metal stent for malignant distal biliary obstruction: a prospective multicenter study. AB - BACKGROUND AND AIMS: EUS-guided choledochoduodenostomy (EUS-CDS) using conventional tubular stents has been successfully performed. However, EUS-CDS carries a high risk of bile leakage with attendant adverse events. This study aimed to prospectively evaluate the long-term outcome of EUS-CDS using a dedicated lumen-apposing metal stent (LAMS). METHODS: Nineteen patients (mean age, 70.6 years; 12 men) with unresectable malignant diseases were treated in 5 tertiary referral centers. EUS-CDS was performed using a fully covered LAMS with a cautery-enhanced delivery system for EUS-CDS. RESULTS: All stents were successfully deployed without any adverse events. Jaundice improved in 79% of the patients within 7 days and finally in 95%. In 95% of patients the stents remained in good anastomotic position without migration or dislocation during the follow up period (median, 184 days; range, 12-819). One patient had a fever the day after stent placement. During the follow-up period 5 patients had secondary stent obstruction because of food residue (n = 2), kinking (n = 1), suspected tumor ingrowth (n = 1), and spontaneous dislodgement (n = 1). Five patients developed obstruction in the second portion of the duodenum. The overall adverse event rate was 36.8% (7/19), mostly with mild severity. CONCLUSIONS: This study revealed that the novel dedicated LAMS used has high technical and clinical success rates for EUS-CDS. The adverse events and patency rates are inferior to the historically reported data of a conventional transpapillary metal stent. Development of a more suitable dedicated LAMS is anticipated. PMID- 28843584 TI - Esophageal triamcinolone acetonide-filling method: a novel procedure to prevent stenosis after extensive esophageal endoscopic submucosal dissection (with videos). AB - BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) for extensive esophageal carcinomas may cause severe stenosis requiring endoscopic balloon dilations (EBDs). A standard prevention method has not been established. We propose the esophageal triamcinolone acetonide (TA)-filling method as a novel local steroid administration procedure. METHODS: We enrolled 22 consecutive patients with early esophageal cancer who were treated using either subcircumferential or circumferential ESD (15 and 7 procedures, respectively) in this case series. Esophageal TA filling was performed on the day after ESD and 1 week later and was performed again if mild stenosis was found on follow-up. EBD with TA filling was performed only for severe stenosis that prevented endoscope passage. The primary endpoint was the incidence of severe stenosis. Secondary endpoints were the total number of EBDs and additional TA filling, dysphagia score, time to stenosis and to complete re-epithelialization, and any adverse events. RESULTS: The incidence of severe stenosis was 4.5% (1/22; confidence interval, .1%-22.8%), and EBD was performed 2 times in 1 patient. Mild stenosis was found in 9 patients. Additional TA filling was performed in 45.5% of patients (10/22; median, 5 times; range, 1-13). The dysphagia score deteriorated to 1 to 2 in 31.8% (7/22) but showed a final score of 0 after complete re-epithelialization in 90.9% (20/22). The median time to stenosis was 3 weeks (range, 3-4) and that to complete re-epithelialization was 7 weeks (range, 4-36). No severe adverse events occurred. CONCLUSIONS: The esophageal TA-filling method is highly effective for preventing severe stenosis after extensive esophageal ESD. PMID- 28843585 TI - Metallic coil and N-butyl-2-cyanoacrylate for closure of pancreatic duct leak (with video). AB - BACKGROUND AND AIMS: Pancreatic fistula is a challenging yet common adverse event of partial pancreatectomy. Our objective is to determine the feasibility of endoscopic closure of a pancreatic fistula using a combination of a metallic coil and N-butyl-2-cyanoacrylate (NBCA) glue. METHODS: A patient with a postoperative pancreatic stump leak recalcitrant to conservative management and pancreatic duct stent placement underwent endoscopic/fluoroscopic placement of a metallic coil in the pancreatic duct followed by injection of .5 mL NBCA and lipiodol mixture directed at the coil. The patient's clinical condition, Jackson-Pratt (JP) drain output, and pancreatic enzyme content were monitored daily after the procedure. RESULTS: The patient's clinical condition improved. JP drain output and amylase/lipase levels progressively decreased to resolution within 7 days of the procedure. No adverse events occurred as a result of the procedure. CONCLUSIONS: Endoscopic closure of pancreatic fistula with a metallic coil and NBCA glue is feasible and may be a useful modality for treatment of refractory postpancreatectomy-related fistula. PMID- 28843586 TI - A single-operator learning curve analysis for the endoscopic sleeve gastroplasty. AB - BACKGROUND AND AIMS: Endoscopic sleeve gastroplasty (ESG) is a novel, incisionless technique for gastric volume reduction to promote weight loss. Our aim was to describe the learning curve for performing ESG using a prospective case series. METHODS: Using a prospective case series design, we analyzed the first 128 consecutive patients at a tertiary care academic medical center who underwent ESG performed by a single operator from August 2013 to December 2016. Efficiency (refining performance to decrease procedure time) and mastery (absence of outliers) for performing ESG was evaluated by using a penalized basis-spline regression and cumulative sum analysis. RESULTS: Efficiency for ESG was attained after 38 ESGs, with mastery after 55 procedures. At 12 months, the mean percent total body weight loss was 15.8% (standard deviation, 9.47%). A total of 71.7% of patients achieved successful weight loss. When using multiple linear regression analysis, both number of sutures and baseline weight were significantly associated with procedure time. Other patient characteristics, such as age, sex, and race, did not significantly affect procedure time. In addition, number of sutures, baseline weight, and endoscopist achieving efficiency were not correlated with successful weight loss at 12 months. CONCLUSIONS: Mastery of ESG by a single operator is suggested after sufficient endoscopic experience and may help guide widespread clinical adaptability. PMID- 28843587 TI - Effectiveness of endoscopic treatments for colonic diverticular bleeding. AB - BACKGROUND AND AIMS: Several endoscopic modalities have been used for the treatment of colonic diverticular bleeding (CDB). The aim of this study was to evaluate the effectiveness of endoscopic treatment for CDB. METHODS: We performed a systematic review and meta-analysis of the English literature. Main outcomes were initial hemostasis, early recurrent bleeding (recurrent bleeding within 30 days after endoscopic treatment), and need for transcatheter arterial embolization (TAE) or surgery. Proportions were collected from each study and were used to calculate pooled estimates. Heterogeneity was evaluated by I2. RESULTS: Sixteen studies (384 patients with CDB) were included. Pooled estimates of initial hemostasis were coagulation, 1.00 (95% CI, .91-1.00) (I2 = .0%); clipping, .99 (95% CI, .97-1.00) (I2 = .0%); and ligation, .99 (95% CI, .95-1.00) (I2 = .0%). Pooled estimates of early recurrent bleeding were coagulation, .21(95% CI, .01-.51) (I2 = 61.2%); clipping, .19 (95% CI, .07-.35) (I2 = 77.3%); and ligation, .09 (95% CI, .04-.15) (I2 = .0%). Pooled estimates of need for TAE or surgery were coagulation, .18 (95% CI, .00-.61) (I2 = 68.9%); clipping, .08 (95% CI, .03-.16) (I2 = 36.8%); and ligation, .00 (95% CI, .00-.01) (I2 = .0%). The proportion of need for TAE or surgery in the ligation group was significantly lower than that in the clipping group (P = .003) and marginally lower than in the coagulation group (P = .086). No significant difference was found between coagulation and clipping groups (P = .44). CONCLUSIONS: Ligation therapy was more effective compared with clipping to avoid TAE or surgery. Coagulation, clipping, and ligation were equivocal in terms of effectiveness for initial hemostasis and preventing early recurrent bleeding. PMID- 28843588 TI - Mental contamination: The effects of religiosity. AB - BACKGROUND AND OBJECTIVES: Mental contamination, which occurs in the absence of contact with a contaminant, has a moral element. Previous studies evoked feelings of mental contamination via listening to a scenario, which described a non consensual kiss. Since mental contamination has a moral element, we tested the effects of the level of religiosity on feelings of mental contamination and related variables in an experimental design. METHODS: Female undergraduates of high religiosity (n = 48) and low religiosity (n = 44) were randomly assigned to listen to one of two audio recordings involving a consensual or non-consensual kiss from a man described as moral. RESULTS: Mental contamination feelings were evoked successfully in both groups. Effects of scenario condition and religiosity level were seen in mental contamination and related negative feelings. Participants who imagined a non-consensual kiss reported greatest feelings of mental contamination, and internal and external negative feelings. More importantly, high religiosity resulted in greater feelings of mental contamination, internal negative feelings, as well as urges to wash and actual washing behaviors. LIMITATIONS: The current study was conducted on non-clinical Muslim females. This limits the generalization of the findings to the wider population. CONCLUSIONS: Mental contamination and related feelings can be seen in different forms at different levels of religiosity. PMID- 28843589 TI - Hemorrhage risk with transjugular intrahepatic portosystemic shunt (TIPS) insertion at the main portal vein bifurcation with stent grafts. AB - PURPOSE: The purpose of this study was to assess the incidence of major hemorrhage after transjugular intrahepatic portosystemic shunt (TIPS) insertion using a stent graft at the main portal vein bifurcation. PATIENTS AND METHODS: TIPS insertion using stent grafts was performed in 215 patients due to non variceal hemorrhage indications. There were 137 men and 78 women, with a mean age of 57 years+/-10.6 (SD) (range: 19-90 years). Based on retrospective review of portal venograms, TIPS inserted within 5mm from the portal vein bifurcation were considered "bifurcation TIPS", while those inserted 2cm or greater from the bifurcation were considered intrahepatic. Suspicion for acute major periprocedural hemorrhage were categorized as low, moderate, and high, based on the number of signs of hemorrhage. RESULTS: Of 215 TIPS inserted for purposes other than hemorrhage, the TIPS was inserted at the portal bifurcation in 41 patients (29 men, 12 women; mean age, 55.9+/-11.7 (SD); range: 26-79 years) and intrahepatic in 62 patients (37 men, 25 women; mean age, 57.6+/-10.6 (SD), range: 34-82 years), whereas 112 were indeterminate in location. No active extravasations were identified on post-TIPS portal venograms. Suspicion for acute major hemorrhage was moderate or high in 3/41 (7%) of patients in the TIPS bifurcation group compared to 5/62 (8%) in the intrahepatic TIPS group (P>0.99). There were no significant differences in 30-day mortality rates (1/41 [2%] and 3/62 [5%] respectively; P> 0.99). No deaths or interventions were attributed to acute hemorrhage. CONCLUSION: TIPS insertion at the portal bifurcation with stent grafts did not incur an elevated risk of hemorrhagic complications. PMID- 28843590 TI - Expanding the borders: Image-guided procedures for the treatment of musculoskeletal tumors. AB - Interventional radiology has revolutionized the local management of bone tumours, offering new minimal invasive alternatives to surgery and radiotherapy. Its role has continuously increased over the past years for the treatment of benign tumors and also of some malignant ones, especially in palliative situations. The development of protective techniques and new ablative technologies, such as cryoablation, contributes to expand the role of the interventional radiologist to new fields of applications in musculoskeletal oncology. PMID- 28843591 TI - My Fitness Pal calorie tracker usage in the eating disorders. AB - Mobile phone and tablet usage has become a part of modern life. Mobile applications that count calories, such as My Fitness Pal, are frequently employed on a daily basis. Recent research has shown that in undergraduates, calorie tracking is associated with eating disorder pathology. In the current study (N=105 individuals diagnosed with an eating disorder), we assessed usage of My Fitness Pal to track calories. We also assessed perceptions that My Fitness Pal contributed to eating disorder symptoms and if these perceptions were associated with eating disorder symptoms. We found that a substantial percentage (~75%) of participants used My Fitness Pal and that 73% of these users perceived the app as contributing to their eating disorder. Furthermore, we found that these perceptions were correlated with eating disorder symptoms. This research suggests that My Fitness Pal is widely used in an eating disorder population and is perceived as contributing to eating disorder symptoms. Further research is needed to clarify the role calorie tracking applications play within a sample of individuals with eating disorders. PMID- 28843592 TI - Longitudinal impact of weight misperception and intent to change weight on body mass index of adolescents and young adults with overweight or obesity. AB - OBJECTIVE: Accurate perception of one's weight status is believed to be necessary to motivate weight loss intention and subsequent weight loss among those with overweight/obesity. This proposed pathway, however, is understudied in longitudinal research. This study examined the indirect effect of weight change intention on the relationship between weight status perception and BMI change among adolescents with overweight/obesity. METHODS: Participants included 2664 adolescents with overweight/obesity (52% female) from the National Longitudinal Study of Adolescent Health. Longitudinal associations between Wave II weight status perception (accurate versus misperception) and intent to change weight (i.e., gain, lose, stay the same) on BMI change (Wave II-Wave IV) were examined using multiple linear regression. Indirect effects of weight change intention were investigated using the Monte Carlo method. Analyses were stratified by gender. RESULTS: Accurate perceivers (81.0% female; 60.1% male) were more likely than misperceivers (i.e., perception of "about the right weight") to report weight loss intention (p<0.001). Among females, weight status misperception and weight loss intention individually were associated with smaller (beta=-1.37, 95% CI [-2.64, -0.10]) and greater (beta=1.18, 95% CI [0.11, 2.25]) BMI gains, respectively. Among males, fully adjusted models suggested that weight status misperception was associated with significantly smaller gains in BMI over time (beta=-1.51, 95% CI [-2.38, -0.63]). Weight change intention did not emerge as an indirect effect for either gender. CONCLUSIONS: Although weight status misperception was protective against weight gain, weight change intention did not provide an explanation for this relationship. PMID- 28843593 TI - Surgical management of temporal bone osteoradionecrosis: Single surgeon experience of 47 cases. AB - PURPOSE: To report the outcomes of 47 patients with temporal bone osteoradionecrosis treated primarily with surgical resection in order to analyze whether flap type and hyperbaric oxygen use affect wound breakdown. MATERIALS AND METHODS: Between January 1998 and January 2016, 47 patients were treated for temporal bone osteoradionecrosis with surgery. Some patients were also treated with hyperbaric oxygen. Resection of grossly necrotic temporal bone was followed by immediate reconstruction with local, regional, or free flaps. Minimum follow up was 6months. If patients had breakdown of their initial reconstructions, secondary reconstruction was performed with either a regional or free flap. During the post-operative period, wound breakdown, flap complications, and patient survival were noted. RESULTS: 30 patients developed ORN from primary radiotherapy while 17 had post-operative radiation. It was found that wound breakdown was significantly associated with type of flap reconstruction (p=0.02) with local flap reconstruction portending a poorer prognosis. Hyperbaric oxygen was not associated with decreased wound breakdown (p=0.5). CONCLUSIONS: Surgical treatment can be an effective treatment for temporal bone osteoradionecrosis, without hyperbaric oxygen providing any additional benefit. Reconstruction with regional or free flaps may be a more reliable method to resurface defects compared to local flaps. PMID- 28843594 TI - Safety assessment of the dietary supplement OxyELITETM Pro (New Formula) in inbred and outbred mouse strains. AB - Herbal dietary supplements have gained wide acceptance as alternatives to conventional therapeutic agents despite concerns regarding their efficacy and safety. In 2013, a spate of severe liver injuries across the United States was linked to the dietary supplement OxyELITE Pro-New Formula (OEP-NF), a multi ingredient product marketed for weight loss and exercise performance enhancement. The principal goal of this study was to assess the hepatotoxic potential of OEP NF in outbred and inbred mouse models. In an acute toxicity study, significant mortality was observed after administering 10X and 3X mouse-equivalent doses (MED) of OEP-NF, respectively. Increases in liver/body weight ratio, ALT and AST were observed in female B6C3F1 mice after gavaging 2X and 1.5X MED of OEP-NF. Similar findings were observed in a 90-day feeding study. These alterations were paralleled by altered expression of gene- and microRNA-signatures of hepatotoxicity, including Cd36, Nqo1, Aldoa, Txnrd1, Scd1 and Ccng1, as well as miR-192, miR-193a and miR-125b and were most pronounced in female B6C3F1 mice. Body weight loss, observed at week 1, was followed by weight gain throughout the feeding studies. These findings bolster safety and efficacy concerns for OEP-NF, and argue strongly for implementation of pre-market toxicity studies within the dietary supplement industry. PMID- 28843595 TI - Ginsenosides Rd and Re co-treatments improve rotenone-induced oxidative stress and mitochondrial impairment in SH-SY5Y neuroblastoma cells. AB - Oxidative stress and mitochondrial dysfunction play key roles in Parkinson's disease (PD) initiation and progression. Ginsenosides are major compounds of Ginseng species and they are responsible for pharmacological activity. The aim of this study was to investigate the potential neuroprotective effects and mechanism of the major ginsenosides Rd and Re in rotenone-induced oxidative stress model in human neuroblastoma SH-SY5Y cells. Co-treatments with both ginsenosides inhibited the increased intracellular ROS production and by-products lipid peroxidation accumulation caused by rotenone. Moreover, these ginsenosides upregulated SOD and aconitase enzymes activities, and glutathione system; these antioxidant properties are related to Nrf2 induction and radical scavenger effect. Additionally, the results showed that both Rd and Re attenuated the extent of depolarization of mitochondrial membrane potential and restored calcium levels. Furthermore, these compounds prevented apoptosis by modulating Bax and Bcl-2 proteins and inhibiting cytochrome c release and caspase-3 activation. The ginsenoside Rd resulted to be more active than ginsenoside Re. These findings highlighted the efficacy of these compounds as neuroprotectant compounds for PD prevention and treatment through reducing oxidative stress, improving mitochondrial integrity and functions, and inhibiting apoptosis. PMID- 28843597 TI - Molecular dynamics simulations and applications in computational toxicology and nanotoxicology. AB - Nanotoxicology studies toxicity of nanomaterials and has been widely applied in biomedical researches to explore toxicity of various biological systems. Investigating biological systems through in vivo and in vitro methods is expensive and time taking. Therefore, computational toxicology, a multi discipline field that utilizes computational power and algorithms to examine toxicology of biological systems, has gained attractions to scientists. Molecular dynamics (MD) simulations of biomolecules such as proteins and DNA are popular for understanding of interactions between biological systems and chemicals in computational toxicology. In this paper, we review MD simulation methods, protocol for running MD simulations and their applications in studies of toxicity and nanotechnology. We also briefly summarize some popular software tools for execution of MD simulations. PMID- 28843596 TI - Cytochrome P450-2E1 is involved in aging-related kidney damage in mice through increased nitroxidative stress. AB - The aim of this study was to investigate the role of cytochrome P450-2E1 (CYP2E1) in aging-dependent kidney damage since it is poorly understood. Young (7 weeks) and aged female (16-17 months old) wild-type (WT) and Cyp2e1-null mice were used. Kidney histology showed that aged WT mice exhibited typical signs of kidney aging such as cell vacuolation, inflammatory cell infiltration, cellular apoptosis, glomerulonephropathy, and fibrosis, along with significantly elevated levels of renal TNF-alpha and serum creatinine than all other groups. Furthermore, the highest levels of renal hydrogen peroxide, protein carbonylation and nitration were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of iNOS and mitochondrial nitroxidative stress through altered amounts and activities of the mitochondrial complex proteins and significantly reduced levels of the antioxidant glutathione (GSH). In contrast, the aged Cyp2e1-null mice exhibited significantly higher antioxidant capacity with elevated heme oxygenase-1 and catalase activities compared to all other groups, while maintaining normal GSH levels with significantly less mitochondrial nitroxidative stress compared to the aged WT mice. Thus, CYP2E1 is important in causing aging-related kidney damage most likely through increasing nitroxidative stress and that CYP2E1 could be a potential target in preventing aging-related kidney diseases. PMID- 28843598 TI - Health effects of feeding genetically modified (GM) crops to livestock animals: A review. AB - A large share of genetically modified (GM) crops grown worldwide is processed into livestock feed. Feed safety of GM crops is primarily based on compositional equivalence with near-isogenic cultivars and experimental trials in rodents. However, feeding studies in target animals add to the evaluation of GM crops with respect to animal health. This review aimed to evaluate the possible health effects of feeding GM crops to livestock by reviewing scientific publications on experimental studies in ruminants, pigs, and poultry in which at least one of the following health parameters was investigated: body condition score, organ weight, haematology, serum biochemistry, histopathology, clinical examination, immune response, or gastrointestinal microbiota. In most experiments, either Bt (Bacillus thuringiensis) maize, Roundup Ready (RR) soybean, or both were fed to livestock animals. Significant differences (P<0.05) in health parameters were most often observed when animals were fed Bt maize, although most effects measured were unlikely to be of biological significance and were within normal biological ranges. Health effects of RR soybean were only observed in one experimental study with broilers. Based on this literature review, we conclude that there is no clear evidence that feed composed of first generation GM crops has adverse effects on animal health. PMID- 28843600 TI - Reply to: Microwave thermosphereTM ablation in the multimodal management of colorectal cancer liver metastasis'. PMID- 28843599 TI - The pathophysiology of Fabry disease. AB - Fabry disease is a lysosomal condition with systemic clinical expression, caused by the tissue deposit of globotriaosylceramide, due to a deficit in its degradation. As with most lysosomal diseases, the presence of a mutation in a gene does not explain the pathophysiological disorders shown by patients. We conducted a comprehensive review of the pathogenic mechanisms that occur in Fabry disease. PMID- 28843601 TI - Preliminary evaluation of UF-5000 Body Fluid Mode for automated cerebrospinal fluid cell counting. AB - BACKGROUND: Cellular analysis of cerebrospinal fluid (CSF) provides important diagnostic information in various medical conditions. The aim of this study was to evaluate the application of Sysmex UF-5000 body fluid mode in cytometric analysis of CSF compared to Light Microscopic (LM). METHODS: Eighty-one consecutive CSF samples were analyzed by UF-5000 body fluid mode and by LM. The study also included the evaluation of: limit of Blank (LoB), limit of Detection (LoD), limit of Quantitation (LoQ), carryover and linearity. RESULTS: For total nucleated cells (TNC-UF) and white blood cells (WBC-UF) LoB, LoD and LoQ were 1*106cells/L, 1.8*106cells/L and 1.9*106cells/L respectively. For red blood cells (RBC) LoB was 2*106cells/L, LoD was 3.5*106cells/L and LoQ was 14*106cells/L respectively. Linearity was excellent, carryover was negligible. The agreement between UF-5000 body fluid mode parameters and manual cell counts was good in all CSF samples with bias ranged between -0.5 and 25.1*106cells/L. The ROC curve analysis showed an area under curve of 0.99 for both TNC-UF and WBC-UF parameters. CONCLUSIONS: The UF-5000 body fluid mode offers rapid and accurate counts in clinically relevant concentration ranges, replacing the LM for most samples. However, in samples with abnormal cell counts or with abnormal scattergram the need for microscopic review remains. PMID- 28843602 TI - An organically modified silica aerogel for online in-tube solid-phase microextraction. AB - Aerogels have received considerable attentions because of its porous, high specific surface, unique properties and environmental friendliness. In this work, an organically modified silica aerogel was functionalized on the basalt fibers (BFs) and filled into a poly(ether ether ketone) (PEEK) tube, which was coupled with high performance liquid chromatography (HPLC) for in-tube solid-phase microextraction (IT-SPME). The aerogel was characterized by scanning electron microscopy (SEM) and fourier transform infrared spectrometry (FT-IR). The extraction efficiency of the tube was systematically investigated and shown enrichment factors from 2346 to 3132. An automated, sensitive and selective method was developed for the determination of five estrogens. The linear range was from 0.03 to 100MUgL-1 with correlation coefficients (r) higher than 0.9989, and low detection limits (LODs) were 0.01-0.05MUgL-1. The relative standard deviations (RSDs) for intra-day and inter-day were less than 4.5% and 6.7% (n=6), respectively. Finally, the analysis method was successfully applied to detect estrogens in sewage and emollient water samples. PMID- 28843603 TI - Editorial Comment. PMID- 28843604 TI - Author Reply. PMID- 28843605 TI - The Right Ventricle: A Rags-to-Riches Story. PMID- 28843606 TI - Impact of Low Tidal Volumes During One-Lung Ventilation. A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: The link between ventilation strategies and perioperative outcomes remains one of the fundamental paradigms of thoracic anaesthesia. During one-lung ventilation (OLV), one lung is excluded from gas exchange and ventilation is directed at the dependent lung. The authors hypothesised that the use of low tidal volumes (VT) during OLV provides adequate gas exchange and improves postoperative outcome. DESIGN: Meta-analysis of randomized clinical trials. SETTING: Thoracic surgery. PARTICIPANTS: Patients undergoing OLV. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors performed a meta-analysis of all randomized trials on low versus high VT during OLV in patients undergoing thoracic surgery. Outcomes of the study were gas exchange and airway pressures during and after OLV, postoperative pulmonary complications (PPCs), and hospital stay (HLOS). Fourteen randomized trials were selected, but only a few of them contained one outcome of interest. Low VT was associated with lower arterial oxygen tension, lower airway pressures, and higher arterial carbon dioxide tension at specific time points during OLV. Low VT was associated with preserved gas exchange after OLV, lower incidence of pulmonary infiltrations, and acute respiratory distress syndrome. Incidences of PPCs and HLOS were similar. CONCLUSIONS: The use of low VT reduces airway pressure but worsens gas exchange during OLV. Preservation of postoperative oxygenation and reduction in infiltrates suggest a lung-protective modality with no demonstrable impact on PPCs and HLOS. PMID- 28843607 TI - Patients Discharged From the Intensive Care Unit on a Dopamine Infusion-A Retrospective, Observational Study. AB - OBJECTIVE: To assess the safety of discharging cardiac surgical patients from the intensive care unit (ICU) to wards while the patients are still receiving a dopamine infusion. DESIGN: Retrospective, observational study. SETTING: Cardiothoracic ICU of a tertiary academic hospital in the United Kingdom. PARTICIPANTS: The study comprised all cardiac surgical patients older than 18 years and admitted between September 1, 2015 and September 16, 2016 to the ICU and subsequently discharged to a surgical ward. Patients were divided in the following 2 groups: a dopamine group with patients discharged with a dopamine infusion and a control group with patients discharged without any dopamine infusion. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The hospital mortality rate was comparable in both groups (0.7% in the dopamine group v 0.2% in the control group [p = 0.11]), despite that the median logistic EuroSCORE was significantly higher in the dopamine group (7.0 v 3.8 [p < 0.01]). The ICU readmission rate was higher in the dopamine group (6.6% v 2.4%; p < 0.01). ICU and hospital lengths of stay were longer in the dopamine group (1.7 v 0.9 days [p < 0.01] and 11.4 v 8.0 days [p < 0.01], respectively). CONCLUSIONS: Despite a higher ICU readmission rate, ICU discharge of patients on dopamine infusion was not associated with increased mortality. PMID- 28843608 TI - Cardiac Reverse Remodeling in Heart Failure: Is There a Role for Epidural in the Current Treatment Landscape? PMID- 28843609 TI - Event-related potential N270 as an index of social information conflict in explicit processing. AB - As N270 has been widely shown to be sensitive to nonsocial information conflict, the present study investigated whether social information conflict can elicit increased N270 in either explicit or implicit processing conditions. Gender stereotype-related picture-word pairs and picture-word pairs in specific colors were used as social and nonsocial information, respectively. Participants performed an explicit task based on the S1-S2 paradigm in Study 1, and both social and nonsocial information conditions elicited larger N270 than the no conflict condition. In Study 2, participants performed a word judgment task that was modified from the S1-S2 paradigm of Study 1. However, neither social information nor nonsocial information elicited larger N270 within the conflict condition. Social trials generally elicited a more negative ERP waveform than nonsocial trials overall. These findings suggest that N270 may reflect the processing of social information conflict only in explicit conditions and also that the cognitive basis of N270 is thus a general but explicit processing of working memory representation conflict. PMID- 28843610 TI - Role of the DNA repair glycosylase OGG1 in the activation of murine splenocytes. AB - OGG1 (8-oxoguanine-DNA glycosylase) is the major DNA repair glycosylase removing the premutagenic DNA base modification 8-oxo-7,8-dihydroguanine (8-oxoG) from the genome of mammalian cells. In addition, there is accumulating evidence that OGG1 and its substrate 8-oxoG might function in the regulation of certain genes, which could account for an attenuated immune response observed in Ogg1-/- mice in several settings. Indications for at least two different mechanisms have been obtained. Thus, OGG1 could either act as an ancillary transcription factor cooperating with the lysine-specific demethylase LSD1 or as an activator of small GTPases. Here, we analysed the activation by lipopolysaccaride (LPS) of primary splenocytes obtained from two different Ogg1-/- mouse strains. We found that the induction of TNF-alpha expression was reduced in splenocytes (in particular macrophages) of both Ogg1-/- strains. Notably, an inhibitor of LSD1, OG-L002, reduced the induction of TNF-alpha mRNA in splenocytes from wild-type mice to the level observed in splenocytes from Ogg1-/- mice and had no influence in the latter cells. In contrast, inhibitors of the MAP kinases p38 and JNK as well as the antioxidant N-acetylcysteine attenuated the LPS-stimulated TNF-alpha expression both in the absence and presence of OGG1. The free base 8-oxo-7,8 dihydroguanine had no influence on the TNF-alpha expression in the splenocytes. The data demonstrate that OGG1 plays a role in an LSD1-dependent pathway of LPS induced macrophage activation in mice. PMID- 28843611 TI - Function and structure-based screening of compounds, peptides and proteins to identify drug candidates. AB - Drug discovery in simple words is all about finding small molecular compounds that possess the potential to interact with specific bio-macromolecules, mainly proteins, thereby bringing a desired effect in the functioning of the target molecules. Virtual screening of large compound libraries using computational approaches has come up as a great alternative to cost and labor-intensive high throughput screening carried out in laboratories. Virtual high-throughput screening enormously reduces the number of compounds for systematic analysis using biochemical assays before entering the clinical trials. Here, we first give a brief overview of the rationale behind virtual screening, types of virtual screening - structure-based, ligand-based and inverse virtual screening, and challenges that need to be addressed to improve the existing strategies. Subsequently, we describe the methodology adopted for virtual screening of small molecules, peptides and proteins. Finally, we use few case studies to provide a better insight to the application of computer-aided high-throughput screening. PMID- 28843612 TI - Genomic regulation of type 2 diabetes endophenotypes: Contribution from genetic studies in the Goto-Kakizaki rat. AB - The inbred Goto-Kakizaki (GK) rat strain is a unique model of spontaneous type 2 diabetes mellitus caused by naturally occurring genetic variants that have been selectively isolated from an outbred colony of Wistar rats. Genetic and genomic studies in experimental crosses and congenic strains of the GK have shed light on the complex etiopathogenesis of diabetes phenotypes in this model. Diabetes related phenotypes in the GK are under polygenic control and distinct genetic loci regulate glucose tolerance, insulin secretion, beta-cell mass and plasma lipids. Metabolome and transcriptome profiling data in GK crosses and congenics, combined with GK genome resequencing, have resulted in a comprehensive landscape of genomic regulations of metabolism that can disentangle causal relationships between GK variants and diabetes phenotypes. Application of systems biology and systems genetics in the GK has contributed to improve our understanding of the fundamental mechanisms regulating metabolism. The wealth of physiological, genetic and genomic information in this strain makes it one of the most powerful model systems to improve our understanding of genetic regulations of metabolism and for testing therapeutic solutions for diabetes. PMID- 28843613 TI - Evolution of inhibitor-resistant natural mutant forms of HIV-1 protease probed by pre-steady state kinetic analysis. AB - Pre-steady state kinetic analysis of mechanistic features of substrate binding and processing is crucial for insight into the evolution of inhibitor-resistant forms of HIV-1 protease. These data may provide a correct vector for rational drug design assuming possible intrinsic dynamic effects. These data should also give some clues to the molecular mechanism of protease action and resistance to inhibitors. Here we report pre-steady state kinetics of the interaction of wild type or mutant forms of HIV-1 protease with a FRET-labeled peptide. The three stage "minimal" kinetic scheme with first and second reversible steps of substrate binding and with following irreversible peptide cleavage step adequately described experimental data. For the first time, a set of "elementary" kinetic parameters of wild type HIV-1 protease and its natural mutant inhibitor resistant forms MDR-HM, ANAM-11 and prDRV4 were compared. Inhibitors of the first and second generation were used to estimate the inhibitory effects on HIV-1 protease activity. The resulting set of kinetic data supported that the mutant forms are kinetically unaffected by inhibitors of the first generation, proving their functional resistance to these compounds. The second generation inhibitor darunavir inhibited mutant forms MDR-HM and ANAM-11, but was ineffective against prDRV4. Our kinetic data revealed that these inhibitors induced different conformational changes in the enzyme and, thereby they have different mode of binding in the enzyme active site. These data confirmed hypothesis that the driving force of the inhibitor-resistance evolution is disruption of enzyme inhibitor complex by changing of the contact network in the inhibitor binding site. PMID- 28843614 TI - An integrative appraisal of the hormonal and metabolic changes induced by acute stress using king penguins as a model. AB - A large number of studies have focused on the reactivity of the hypothalamic pituitaryadrenal (HPA) axis and the consequences of glucocorticoids (GC) in mediating life-history trade-offs. Although short-term increases in GCs are viewed as adaptive, mobilizing energy substrates allowing animals to deal with impending threats (e.g. stimulating hepatic gluconeogenesis, stimulating lipolysis, mobilizing amino acids), few studies have actually measured the exact time-course of substrate mobilisation in response to acute stress in natural conditions. We evaluated the hormonal and metabolic components of the stress response to acute stress in 32 free-living king penguins (Aptenodytes patagonicus). We monitored changes in blood GCs (corticosterone, CORT), glucose, lactate, ketone bodies (beta-hydroxybutyrate), non-esterified fatty acids, and uric acid in response to a standardized capture-restraint protocol lasting for up to 90min. Furthermore, we tested whether the vigilance status of the animal (alert or asleep) affected its perception of the capture, thereby modulating the hormonal and metabolic stress responses. The time course of energy mobilisation followed the characteristic pattern expected from laboratory and theoretical models, with a rapid depletion of those energy stores linked to rapid adrenergic responses (i.e. glucose and ketone bodies), followed by a mobilisation of energy stores associated with the sustained longer-term GC response (i.e. fats and protein stores). HPA reactivity was generally slower than reported in other birds, and there was high inter-individual variability. Sleeping birds had higher GC and glucose responses to acute stress, suggesting a more rapid mobilization of energy stores. Our results highlight the importance of considering HPA and metabolic responses to acute stress against species-specific life history and ecological relevant backgrounds. PMID- 28843615 TI - Faecal glucocorticoid metabolite monitoring as a measure of physiological stress in captive and wild vervet monkeys. AB - The development of non-invasive techniques to analyse physiological stress in mammalian species has revolutionised field-based endocrinology. However, careful validation of the methods used to determine faecal glucocorticoid metabolite (fGCM) and other hormone concentrations are required on a species- and sex specific basis. In this study, we performed an adrenocorticotropic hormone (ACTH) stimulation test on four (two male and two female) captive vervet monkeys (Chlorocebus pygerythrus) to determine the most appropriate enzyme immunoassay (EIA) from a suite of available EIAs. Furthermore, we took advantage of a potentially stressful event in our wild vervet population from Samara Private Game Reserve, South Africa, to examine if an alpha-beta female rank reversal increases the physiological stress of those individuals directly involved, as well as other group members. Both our physiological and biological validation studies revealed that a cortisol assay was the most appropriate EIA for monitoring fGCM alterations in vervet monkeys. In addition, we found that the observed rank-reversal had no significant effect on the physiological stress levels of uninvolved group members. Our study highlights that physiological validation is imperative and, where possible, should be conducted in parallel with a carefully considered biologically-relevant test under natural conditions. Overall, our results provide a necessary step for future studies to examine physiological stress of vervet monkeys via fGCM monitoring by validating a suitable EIA for this species. This paves the way for future research into the health and welfare of both captive and wild vervet monkeys, and will allow researchers to assess the behavioural, social and ecological correlates of physiological stress levels of this species. PMID- 28843616 TI - Safety and efficacy of pirfenidone in severe Idiopathic Pulmonary Fibrosis: A real-world observational study. AB - BACKGROUND: Pirfenidone is a novel anti-fibrotic drug that has shown efficacy in five randomized multicenter clinical trials enrolling patients with Idiopathic Pulmonary Fibrosis of mild-to-moderate disease severity. Scarce data supports the use of pirfenidone in IPF patients with more advanced disease. OBJECTIVE: To investigate the safety and efficacy profile of pirfenidone in IPF patients with severe lung function impairment. PATIENTS AND METHODS: This was a retrospective study enrolling patients with advanced IPF (FVC%predicted < 50% and/or (DLco%predicted <35%) receiving pirfenidone for at least 6 months. RESULTS: Between September 2011 and March 2013, we identified 43 patients with severe IPF (baseline meanFVC%predicted+/-SD: 63.8 +/- 20.3, meanDLCO%predicted: 27.3 +/- 8.2), of mean age+/-SD: 66.3 + 9.7, 34 males (81%) that received pirfenidone (2.403 mg/daily) for one year. Pirfenidone treatment was associated with a trend towards decrease in functional decline compared to 6-months before treatment initiation but failed to show any benefit after one year of treatment (DeltaFVC: 3.3 +/- 4.6 vs 0.49 +/- 11.4 and vs. -5.8 +/- 11.8, p = 0.06 and p = 0.04, respectively and DeltaDLCO: -13.3 +/- 15.2 vs. -10.1 +/- 16.6 and vs. 28.3 +/- 19.2, p = 0.39 and p = 0.002, respectively). Gastrointestinal disorders (34.9%), fatigue (23.2%) and photosensitivity (18.6%) were the most common adverse events. Adverse events led to treatment discontinuation in 9 patients (20.9%) and dose reduction in 14 (32.5%). CONCLUSION: Pirfenidone appears to be safe when administered in patients with advanced IPF. Pirfenidone efficacy in IPF patients with severe lung function impairment may diminish after 6 months of treatment. PMID- 28843617 TI - Model-based clinical pharmacology profiling and exposure-response relationships of the efficacy and biomarker of lebrikizumab in patients with moderate-to-severe asthma. AB - Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV1], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day-1 for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV1 and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate. Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV1 and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL 13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients. PMID- 28843618 TI - Feasibility of UltraFast Doppler in Post-operative Evaluation of Hepatic Artery in Recipients following Liver Transplantation. AB - To determine the feasibility of using UltraFast Doppler in post-operative evaluation of the hepatic artery (HA) after liver transplantation (LT), we evaluated 283 simultaneous conventional and UltraFast Doppler sessions in 126 recipients over a 2-mo period after LT, using an Aixplorer scanner The Doppler indexes of the HA (peak systolic velocity [PSV], end-diastolic velocity [EDV], resistive index [RI] and systolic acceleration time [SAT]) by retrospective analysis of retrieved waves from UltraFast Doppler clips were compared with those obtained by conventional spectral Doppler. Correlation, performance in diagnosing the pathologic wave, examination time and reproducibility were evaluated. The PSV, EDV, RI and SAT of spectral and UltraFast Doppler measurements exhibited excellent correlation with favorable diagnostic performance. During the bedside examination, the mean time spent for UltraFast clip storing was significantly shorter than that for conventional Doppler US measurements. Both conventional and UltraFast Doppler exhibited good to excellent inter-analysis consistency. In conclusion, compared with conventional spectral Doppler, UltraFast Doppler values correlated excellently and yielded acceptable pathologic wave diagnostic performance with reduced examination time at the bedside and excellent reproducibility. PMID- 28843619 TI - Pilot Investigation into the Use of an Anthropomorphic Breast Sonography Phantom as a Training and Assessment Tool. AB - A device for the training and quantitative assessment of the competency of trainee radiologists in the technically challenging area of breast sonography was developed and evaluated. Currently, suitable commercially available devices are lacking, and there is a growing realization that the reliance on direct exposure to patients for learning may not represent best practice from either the trainees' or patients' perspective. Three devices (PI, PII and PIII) were designed to produce very realistic sonographic images of breast morphology with a range of embedded pathologies. The pilot evaluation used a case study research design to evaluate the role of the anthropomorphic breast sonography training device in training and assessment in a clinical environment. Through the case study, it was possible to evaluate the process and relationships when using this type of training intervention for a small group of radiology resident trainees. The investigation involved a baseline assessment of trainees' (n = 4) ability to detect and characterize all lesions in PI, followed by a 4-wk training period on PII and a post-training assessment using PIII. The evaluation revealed an improvement of 30% +/- 8% in the trainee's performance from pre- to post training. It was expected that the performance of the trainees would improve as the training phantom described in this study aligns with the learning theory of constructivism and fits the ideal specifications of a medical training device in terms of its realism and facilitation of self-directed learning and deliberate practice of the trainees. The device provides a useful platform upon which training and assessment can be facilitated. PMID- 28843620 TI - The Combination of Glycolytic Inhibitor 2-Deoxyglucose and Microbubbles Increases the Effect of 5-Aminolevulinic Acid-Sonodynamic Therapy in Liver Cancer Cells. AB - Sonodynamic therapy (SDT) overcomes the shortcoming of photodynamic therapy in the treatment of cancer. Previous studies indicated that the glycolysis inhibitor 2-deoxyglucose (2-DG) potentiated photodynamic therapy induced tumor cell death and microbubbles (MBs) improved the SDT performance. We hypothesized that the combination of 2-DG and MBs will increase the effect of 5-aminolevulinic acid (ALA)-SDT in HepG2 liver cancer cells. When cells were treated with 5-min ALA-SDT and 2-mmol/L 2-DG, the cell survival rate decreased to 73.0 +/- 7.1% and 75.2 +/- 7.9%, respectively. Furthermore, 2 mmol/L 2-DG increased 5-min ALA-SDT induced growth inhibition and augmented ALA-SDT induced cell apoptotic rate from 9.8 +/- 0.7% to 17.4 +/- 2.2%. In the combination group (2-DG and ALA-SDT group), HepG2 cells possessed typical apoptotic characters. 2-DG also increased ALA-SDT associated intracellular reactive oxygen species generation and loss of mitochondrial membrane potential. Moreover, SonoVue MBs had stimulatory function on cell viability inhibition, apoptosis, reactive oxygen species production and mitochondrial membrane potential loss for combination treatment. This study suggests a promising therapeutic strategy using a combination of 2-DG, MBs and ALA-SDT for treating liver cancer. PMID- 28843622 TI - Peripheral physiological responses to subliminally presented negative affective stimuli: A systematic review. AB - Negative affective information may be presented outside of awareness and change physiological activity. By increasing peripheral physiological activity, subliminally presented negative affective information may contribute to the development of disease. The current systematic review evaluated 65 studies in which negative affective stimuli were presented subliminally to a healthy sample while cardiovascular, electrodermal, electromyographical, hormonal, or immunological activity was measured. Overall, 41% of the tested contrasts indicated significant increases due to negative affective stimuli compared to control stimuli. These effects were most pronounced in fear-conditioning studies measuring skin conductance response amplitude and priming studies measuring systolic blood pressure. However, across the included studies the methodology varied substantially and the number of contrasts per physiological parameter was limited. Thus, although some evidence exists that subliminally presented negative affective stimuli can induce adverse peripheral physiological changes, this has not yet been addressed sufficiently. PMID- 28843621 TI - Early detection of HIV infection and of asymptomatic sexually transmitted infections among men who have sex with men. AB - OBJECTIVE: To provide data on incidence of early diagnosis of HIV infections and define prevalence and incidence of asymptomatic sexually transmitted infections (STI) in men who have sex with men (MSM). METHODS: We assessed a prospective cohort study of HIV-uninfected MSM at high risk for HIV infection. Participants were selected through a risk-assessment questionnaire, and they were screened for HIV infection (quarterly) and for other STI (yearly): syphilis, and hepatitis A, B and C (serology); Chlamydia trachomatis and Neisseria gonorrhoeae in penis and rectum; and human papillomavirus in anus and mouth (PCR). RESULTS: Between November 2009 and October 2012, a total of 258 HIV-uninfected MSM at high risk for HIV infection were included and followed up for a median of 2 years (interquartile range 1.4, 2.5). Nineteen acute HIV infections were diagnosed (incidence, 3.9 per 100 person-years). Prevalence of STI at baseline was follows: syphilis 8.4% (95% confidence interval (CI) 5.4-12.7); hepatitis C virus (HCV) 2.0% (95% CI 0.7-4.8); C. trachomatis in penis 3.2% (95% CI 1.5-6.5) and in rectum 6.5% (95% CI 3.9-10.5); N. gonorrhoeae in penis 2.0% (95% CI 0.8-5.0) and in rectum 6.1% (95% CI 3.6-10.1); human papillomavirus in anal canal 75.7% (95% CI 68.8-81.5) and in mouth 3.8% (95% CI 1.8-7.7). CONCLUSIONS: The implementation of the Check-Ear Project in a MSM community centre allowed for the identification of early HIV infections and asymptomatic STI among MSM. The high incidence of HIV infections and the high prevalence of STI strongly support the recommendation of periodic screenings among sexually active MSM. PMID- 28843623 TI - Antimicrobial peptides human LL-37 and beta-defensin-3 modulate the expression of nerve elongation factors in human epidermal keratinocytes. PMID- 28843624 TI - Sorafenib stimulates human skin type mast cell degranulation and maturation. AB - BACKGROUND: Sorafenib is a multi-kinase inhibitor for treating advanced hepatocellular and renal cell carcinomas by targeting various types of receptors and signaling molecules, including vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and Raf-1. Sorafenib may cause diverse cutaneous adverse reactions, including hand-foot reaction, facial and scalp eruptions, alopecia and pruritus. However, the mechanism of these adverse effects has not been well-investigated. OBJECTIVE: Mast cells (MCs) are reported to be associated with various types of skin diseases. To investigate the mechanism of sorafenib-induced cutaneous adverse effects, we focused on MCs in situ. METHODS: We evaluated skin samples of organ cultured normal human skin treated with sorafenib using c-Kit, tryptase, and stem cell factor (SCF), Ki-67, and TUNEL immunohistochemistry as well as quantitative real-time polymerase chain reaction to evaluate MC number, degranulation, proliferation, and apoptosis in situ. RESULTS: Sorafenib significantly increased the number and degranulation of skin type MCs compared with the vehicle-treated control group in situ. However, sorafenib did not affect MC proliferation and apoptosis, suggesting that it stimulated MC maturation from resident precursors. Furthermore, sorafenib increased SCF expression in situ. The increase in MC number by sorafenib was abrogated by co-administration of SCF neutralizing antibody or the phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, but not the mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, PD98059. This suggests that SCF is involved in sorafenib induced MC maturation. In addition, the compensatory upregulation of PI3K signaling from inhibition of MAPK signaling by sorafenib might stimulate MC maturation in situ. We also evaluated MCs within the skin samples from patients with drug eruptions by sorafenib administration. The total and degranuated MCs number as well as SCF expression was significantly increased compared to healthy individuals. CONCLUSION: Our results contribute to a better understanding of the mechanism by which sorafenib induces adverse cutaneous reactions via activation of skin-type MC degranulation and maturation. This activation appears to be related to PI3K signaling and SCF production, which could be a new targets for treating sorafenib-induced adverse reactions. PMID- 28843625 TI - Prevalence and predictors of distress associated with completion of an online survey assessing mental health and suicidality in the community. AB - While there is evidence that mental health surveys do not typically increase distress, limited research has examined distress in online surveys. The study investigated whether completion of a 60-min online community-based mental health survey (n = 3620) was associated with reliable increases in psychological distress. 2.5% of respondents had a reliable increase in distress, compared to 5.0% with a reliable decrease, and decreased distress overall across the sample (Cohen's d = -0.22, p < 0.001). Initial depression/anxiety symptoms were associated with increased distress, but suicidality was not. Online mental health surveys are associated with low prevalence of increased distress. PMID- 28843626 TI - Animal Hoarding Disorder: A new psychopathology? AB - This study aimed to characterize the sociodemographic profile of animal hoarders in a southern city of Brazil. In addition, it aimed to propose Animal Hoarding Disorder as a new nosological category, distinct from Hoarding Disorder. Thirty three individuals with Animal Hoarding Disorder, 73% female and 60% elderly, composed the sample. The average age of the sample was 61.39 years (SD = 12.69) and the average period that individuals hoarded or lived with a large number of animals was 23.09 years (SD = 15.98.) It was observed that 56.7% of the sample hoarded other inanimate objects, besides the animals. The total number of hoarded animals was 1.357 and the average number of animals per hoarder was approximately 41 (SD = 24.41). Significant differences between hoarding disorder and animal hoarding are discussed. Unlike hoarded objects, hoarded animals generally do not obstruct domicile environments. The processes of disengaging from or donating animals also differ from those of object hoarding, since there is an affectional bond with lives and not with unanimated objects. In this sense, the characterization of Animal Hoarding Disorder as a new mental disorder may arouse great interest from both clinical professionals and researchers. PMID- 28843627 TI - Rumination and PTSD symptoms among trauma-exposed Latinos in primary care: Is mindful attention helpful? AB - The present investigation examined the moderating role of mindful attention in the relation between rumination and posttraumatic stress (PTS) symptoms (i.e., re experiencing, avoidance, arousal, and total PTSD symptoms) among trauma-exposed Latinos in a primary care medical setting. It was hypothesized that mindful attention would moderate, or lessen, the relation between rumination and all facets of PTS, even after controlling for clinically relevant covariates. Participants included 182 trauma-exposed adult Latinos (89.0% female; Mage = 37.8, SD = 10.6% and 95.1% reported Spanish as their first language) attending a community-based integrated healthcare clinic in the Southwestern United States. Mindful attention was a significant moderator of relations between rumination and all PTS facets. Specifically, rumination and PTSD symptoms were significantly related yet only in the context of low (vs. high) levels of mindful attention. Mindfulness-based skills may offer incremental value to established treatment protocols for traumatic stress, especially when high levels of rumination are present. Rumination may also serve to identify those who are at greatest risk for developing PTSD after trauma exposure and, therefore, most likely to benefit from mindfulness-based strategies. PMID- 28843628 TI - Association between physiological oscillations in self-esteem, narcissism and internet addiction: A cross-sectional study. AB - Internet addiction is a novel and relatively uninvestigated form of dependence that is fairly common in adolescent population. Previous research has indicated that it may be associated with other mental health problems, such as dysthymic mood and narcissistic behavior. In our study, we tested the existence and strength of relationship between Internet addiction, self-esteem and narcissism in a student population. On a sample of 244 students, we also investigated social networking activities, such as number of self-portrait photographs ("selfies"), and their potential connection with self-esteem and narcissism. Each participant completed a questionnaire consisting of Young Internet Addiction Test, Rosenberg Self-Esteem scale, and Narcissistic Personality Inventory. There was a statistically significant negative correlation between internet addiction score and self-esteem. Internet addiction increased as self-esteem decreased and vice versa. On the other hand, there was a positive correlation between internet addiction and narcissism. NPI score and number of self-portrait photographs (selfies) on Facebook were also in a positive relationship. Conversely, NPI score increased as the self-esteem decreased. The results of the study are in accordance with our previous findings on Internet use and mental health, confirming that Internet addiction is a potentially a serious public health problem. PMID- 28843629 TI - Mental health on screen: A DSM-5 dissection of portrayals of autism spectrum disorders in film and TV. AB - Portrayals of characters with autism spectrum disorders (ASD) in films and TV series are subject to intense debate over whether such representations are accurate. Inaccurate portrayals are a concern as they may lead to increased stereotypes toward the condition. We investigate whether portrayals of characters with autism spectrum disorder in film and TV-series align with DSM-5 diagnostic criteria. Our data show that characters present a full range of characteristics described in the DSM-5. The meaning of this finding is discussed in relation to potential educational value of on screen portrayals and the notion of authenticity in representing the autistic experience. PMID- 28843630 TI - Moral disengagement and callous unemotional traits configurations in adolescents with disruptive behavior disorder: A person-oriented approach. AB - The interplay between Callous Unemotional Traits (CU) and Moral Disengagement (MD) was examined in a sample of 90 adolescents with Disruptive Behavior Disorders. Using a person-centered approach, three CU and MD configurations were identified, attesting the strong relationship between these two moral dimensions. However, for some adolescents, CU and MD do not 'move together'. Practical implications are discussed in terms of assessment and intervention. PMID- 28843631 TI - Structural coverage of the proteome for pharmaceutical applications. AB - Structure-based computational drug discovery efforts have traditionally focused on the structure of a single, well-known drug target. Important applications, such as target deconvolution and the analysis of polypharmacology, require proteome-scale molecular docking and have been inaccessible to structure-based in silico approaches. One important reason for this inaccessibility was that the structure of most proteins was not known. Lately, this 'structure gap' has been closing rapidly, and proteome-scale molecular docking seems within reach. Here, we survey the current state of structural coverage of the human genome and find that coverage is truly proteome-wide, both overall and in most pharmaceutically relevant categories of proteins. The time is right for structure-based approaches to target deconvolution and polypharmacology. PMID- 28843632 TI - The Warburg effect and glucose-derived cancer theranostics. AB - Tumor cells are known for their propensity to proliferate uncontrollably and generate multitudes of metastatic masses at the advanced stages of cancer. During this progression, tumor cells switch their energy source from mitochondrial oxidative phosphorylation to a glucose-dependent glycolytic pathway, despite the availability of oxygen. Consequently, tumor cells increase their metabolic rates as well as glucose uptake to maintain their proliferation. This atypical metabolic phenomenon is known as the Warburg effect, which has been recognized as a hallmark of cancer and serves as a promising target for diagnosis and therapy of cancer. In this review, we summarize the current advances toward the development of glucose-derived therapeutic and diagnostic agents (theranostics) of cancer. PMID- 28843633 TI - Quality Improvement Project: Replacing the Numeric Rating Scale with a Clinically Aligned Pain Assessment (CAPA) Tool. AB - CAPA is a multifaceted pain assessment tool that was adopted at a large tertiary Midwest hospital to replace the numeric scale for adult patients who could self report their pain experience. This article describes the process of implementation and the effect on patient satisfaction scores. Use of the tool is supported by the premise that pain assessment entails more than just pain intensity and that assessment is an exchange of meaning between patients and clinicians dependent on internal and external factors. Implementation of the tool was a transformative process resulting in modest increases in patient satisfaction scores with pain management. Patient reports that "staff did everything to manage pain" had the biggest gains and were sustained for more than 2 years. The CAPA tool meets regulatory requirements for pain assessment. PMID- 28843634 TI - Beyond the Pain Scale: Provider Communication and Staffing Predictive of Patients' Satisfaction with Pain Control. AB - This paper examined hospital characteristics, staffing, and nursing care factors associated with patient perception of poor pain control by conducting a secondary analysis of the Hospital Consumer Assessment of Health Care Providers Systems (HCAHPS) survey in California, Massachusetts, and New York hospitals. Analysis of variance was used to analyze the relationship between nurse, hospitalist, physician, and resident staffing and patients' perception of pain control. Twenty one factors correlated with patients' reports of pain control were included in the stepwise linear regression analysis. Patients' perception of pain control significantly improved with higher numbers of registered nurses (p = .045), nursing staff (p = .005), and hospitalists (p = .035) and worsened with higher numbers of residents or interns (p = .010). Six predictors explained 79% of the variance in patients' self-reports of pain control. Four factors increased the likelihood that patients reported their pain was poorly controlled: (1) patients did not receive help as soon as they wanted (p < .001), (2) poor nurse communication (p < .001), (3) poor medication education (p < .001), and (4) teaching hospitals (p < .001). Two factors decreased the likelihood that patients reported their pain was poorly controlled: (1) higher numbers of nursing staff (p = .001) and (2) nonprofit hospitals (p = .001). Nurse staffing and nurse-patient communication are highly predictive of patients' perception of pain management. In teaching hospitals, with rotating intern/resident assignments, patients reported less satisfaction with pain management. This study provides new evidence for the importance of continuity of care in controlling the pain of hospitalized patients. PMID- 28843635 TI - Can We Quickly and Thoroughly Assess Pain with the PACSLAC-II? A Convergent Validity Study in Long-Term Care Residents Suffering from Dementia. AB - A previous study found that the modified version of the Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC-II) is a valid tool to assess pain in elderly individuals suffering from dementia and who are unable to communicate verbally. The primary objective of this study was to confirm the convergent validity of the PACSLAC-II using direct evaluation of long-term care residents in real-life situations, using two other well-validated pain assessment scales (i.e., PACSLAC and Pain Assessment in Advanced Dementia [PAINAD]). A secondary objective was to document and compare the time required to complete and score each assessment scale. During two potentially painful procedures (i.e., transfer/mobilization), 46 long-term care residents (mean age = 83 +/- 10 years) suffering from dementia were observed by three independent evaluators, each using one of the assessment scales (randomly assigned). Correlational analyses and analysis of variance were used to evaluate the association between each scale and to compare scoring time. The PACSLAC (r = 0.61) and the PAINAD (r = 0.65) were both moderately associated with the PACSLAC-II (all p values < .001). The PAINAD's average scoring time (63 +/- 19 seconds) was lower than the PACSLAC-II's (96 +/- 2 seconds), which was lower than the PACSLAC's (135 +/- 53 seconds) (all p values < .001). These results suggest that the PACSLAC-II is a valid tool for assessing pain in individuals with dementia. The time required to complete and score the PACSLAC-II was reasonable, supporting its usefulness in clinical settings. PMID- 28843636 TI - Management of Sickle Cell Pain Using Pregabalin: A Pilot Study. AB - Sickle cell disease (SCD) pain may have a neuropathic component. Adjuvant drugs used to treat neuropathic pain have not been studied for the treatment of adults with SCD. To determine the safety and feasibility of using pregabalin for chronic SCD pain. A randomized, controlled, double-blind pilot study. Based on random assignment, participants were treated with pregabalin or placebo control for 3 months with monthly follow-up visits. Participants were recruited from the University of Illinois Hospital and Health Sciences System outpatient SCD clinic. Participants/Subjects: A total of 22 participants with SCD (21 African American, 1 other) were included 16 women aged 18-82 (mean age 33.1 +/- 9.9). PAINReportIt, Leeds Assessment of Neuropathic Signs and Symptoms, Neuropathic Pain Symptom Inventory, and Short Form 36 Health Survey were completed. Adverse effects were minimal. Mean scores for average pain intensity, composite pain index, and neuropathic pain revealed a reduction for pregabalin and placebo control groups. Although the between-group differences were not significant, sustained reduction in pain over time within the pregabalin group indicated promising effects of pregabalin for SCD pain. Mean quality-of-life scores increased slightly over time (representing better quality of life) in 7 of 8 domains for the pregabalin group and decreased in 4 of 8 domains for the placebo control group. Small sample size made it difficult to interpret quality-of-life findings. This pilot study provided sufficient evidence that further investigation of pregabalin's potential efficacy for treatment of chronic SCD pain in adults is warranted. PMID- 28843637 TI - The Characteristics of Pain in Patients Diagnosed with Depression and Heart Failure. AB - Heart failure (HF) is a costly and growing health problem that is routinely complicated by chronic pain and depression. The purpose of this paper is to describe the characteristics of pain and pain management in depressed HF patients. In this descriptive cross-sectional study, we analyzed data from 62 participants with depression and class II-IV HF. Study variables of interest were collected from the Brief Pain Inventory, Beck Depression Inventory, and Rand-36. Almost all participants (98%) had some pain in the past month and most had pain in the last 24 hours (66%). The median pain score was 4 (0-10 scale) with the majority reporting moderate to severe pain. The median pain interference score was 4.42 (0-10 scale) with the majority reporting moderate to extreme interference. Medication to treat pain was used by all participants who reported pain, with only 5% also using nonpharmacologic treatment. The majority of participants reported moderate or severe pain while also having moderate to extreme pain interference. Nonpharmacologic pain treatments were severely underused. Women were more likely to have higher levels of pain intensity and more pain interference than men, suggesting that additional screening for the impact of pain is especially important in women. The wide variety of body areas affected, along with moderate to high intensity pain and considerable interference scores reported, indicate that pain was ineffectively treated. Nonpharmacologic treatments should be considered to decrease the impact of pain. PMID- 28843638 TI - Local vibration inhibits H-reflex but does not compromise manual dexterity and does not increase tremor. AB - The present work aimed at investigating the effects of local vibration on upper limb postural and kinetic tremor, on manual dexterity and on spinal reflex excitability. Previous studies have demonstrated a decrease in spinal reflex excitability and in force fluctuations in the lower limb but an increase in force fluctuation in the upper limbs. As hand steadiness is of vital importance in many daily-based tasks, and local vibration may also be applied in movement disorders, we decided to further explore this phenomenon. Ten healthy volunteers (26+/ 3years) were tested for H reflex, postural and kinetic tremor and manual dexterity through a Purdue test. EMG was recorded from flexor carpi radialis (FCR) and extensor digitorum communis (EDC). Measurements were repeated at baseline, after a control period during which no vibration was delivered and after vibration. Intervention consisted in holding for two minutes a vibrating handle (frequency 75Hz, displacement~7mm), control consisted in holding for two minutes the same handle powered off. Reflex excitability decreased after vibration whilst postural tremor and manual dexterity were not affected. Peak kinetic tremor frequency increased from baseline to control measurements (P=0.002). Co-activation EDC/FCR increased from control to vibration (P=0.021). These results show that two minutes local vibration lead to a decrease in spinal excitability, did not compromise manual dexterity and did not increase tremor; however, in contrast with expectations, tremor did not decrease. It is suggested that vibration activated several mechanisms with opposite effects, which resulted in a neutral outcome on postural and kinetic tremor. PMID- 28843639 TI - Characteristics of the Most Recently Awarded Magnetic Resonance Imaging Patents in the United States. AB - PURPOSE: To characterize recent magnetic resonance imaging (MRI) technical development and innovation based on data regarding MRI-related patents awarded in 2016. METHODS: The US Patent and Trademark Office website was searched for patents awarded in 2016 and an abstract containing "magnetic resonance." Patent characteristics were summarized. An MRI physicist classified patents' themes. RESULTS: A total of 423 MRI-related patents were awarded in 2016. Among these, 29% had 1 inventor, 24% had 2 inventors, and 47% had >=2 inventors. Mean interval between patents being filed and awarded was 1389 +/- 559days (range: 167-4029). Most common countries of patents' first assignee were USA (40%), Germany (24%), Netherlands (10%), and Japan (10%). In all, 3% included assignees with different countries (most common collaborators USA and Germany). Patents' first assignee had an industry affiliation in 76% vs an academic affiliation in 21% (4% indeterminate); and 3% had industry-academia collaboration. Patents' most common themes were coils (n = 77), sequence design (n = 65), and noncoil scanner hardware (n = 41). These top themes were similar for USA, international, and industry-based patents; however, for academic-based patents, the most common themes were sequence design, reconstruction, and exogenous agents. Less common themes included image analysis, postprocessing, spectroscopy, relaxometry, diffusion, motion correction, radiation therapy, implants, wireless devices, and positron emission tomography-MRI. CONCLUSION: Most MRI-related patents were by non-US inventors. A large majority had industry affiliation; minimal industry academic collaborationwas observed. Patents from industry and academic inventors had distinct top focuses: hardware and software, respectively. Awarenessofthe most recent years' MRI patents may provide insights into forthcoming clinical translations and help guide ongoing research and entrepreneurism. PMID- 28843640 TI - Takayasu's arteritis: A new era is approaching. PMID- 28843641 TI - A study on the colonization of Pneumocystis jirovecii among outpatients during cancer chemotherapy and among healthy smokers. AB - AIMS: Pneumocystis Jirovecii (PJ) is regarded as an agent of fungal infection and in cases of pneumocystis pneumonia (PCP) in immune-compromised patients including cancer patients. It is not clear what kinds of cancer, treatments, and environment need prophylaxis for PCP. In this study, we have analyzed the detectability of PJ DNA from sputum, and discussed prophylaxis and risk factors regarding PCP. METHODS: A total of forty-nine materials (twenty-four from outpatients during cancer chemotherapies and twenty-five from healthy control subjects) was collected. Their PJ DNAs were amplified using nested PCR with specific primers of the PJ gene (the mitochondrial small subunit rRNA gene). RESULTS: PJ DNA was detectable in 46% of specimens (sputum) from cancer patients during chemotherapies, and incidences of not significantly different among types of cancer and chemotherapy regimens. Prophylactic use of Sulfamethoxazole/Trimetoprim (ST) reduced the detection of PJ DNA. Detection of PJ DNA is not high among healthy non-smokers (20%) and high among healthy smokers (47%). CONCLUSIONS: Prophylactic use of ST may be necessary for cancer patients during chemotherapies. Also, smoking may be associated with PJ colonization in the airway and air vesicles, and may increase the mortality rate for PCP. All patients undergoing cancer chemotherapies should cease smoking. PMID- 28843642 TI - The effect of glass fiber posts and ribbons on the fracture strength of teeth with flared root canals restored using composite resin post and cores. AB - PURPOSE: This study evaluated the fracture strength and mode of failure of structurally compromised teeth with flared root canals restored using composite resin with four different systems. METHODS: Sixty endodontically treated bovine teeth were uniformly shaped to simulate human mandibular premolars with flared root canals. The roots were divided into four groups of 15 specimens each based on the type of restoration: composite resin core only (control), glass fiber post, cylindroid glass fiber ribbons, and glass fiber post and ribbons. All specimens were loaded until fracture occurred using a universal testing machine. Average fracture loads were compared with a one-way ANOVA and Tukey HSD test (alpha=.05). The modes of failure were observed and the Fisher exact test and Bonferroni correction were used for statistical analysis. RESULTS: The fiber post and ribbon group (1035.70N) and the fiber ribbon group (881.77N) showed significantly higher fracture strength than the controls (567.97N) (p<.05). The fiber post and ribbon group also showed significantly higher fracture strength than the fiber post group (769.40N). Almost all specimens showed unrestorable root fractures (p<.008). The control group had a significantly higher ratio of core sectional fractures (p<.017). CONCLUSIONS: Cylindroid glass fiber ribbons significantly increased the fracture strength of the composite resin post and cores in the case of the dentin within the thin root canal wall. Based on the results, this study recommends the combined use of glass fiber post and ribbons. PMID- 28843643 TI - The prospective use of biochar as adsorption matrix - A review from a lifecycle perspective. AB - Biochar is obtained from the thermochemical conversion of biomass in an oxygen limited environment. Beyond its use for soil amendment and carbon sequestration, other value-added applications, such as a green environmental sorbent for different types of pollutants, are also of increasing interest. This paper reviews the available literature on the use of various feedstocks for biochar production as an initial step to compile the required inventory data from material flow data analysis. The environmental evaluation of different schemes of biochar production in a life cycle perspective reports the environmental impacts of the different alternatives, with more sustainable profiles than the use of activated carbon as conventional adsorption material. Moreover, most systems were validated as negative carbon processes with favorable performance regarding climate change mitigation. In particular, materials based on lignocellulosic waste were responsible for the highest environmental benefits, mainly due to their largest energy potential in comparison with other feedstocks. PMID- 28843644 TI - Corrigendum to "Systemic inflammation alters central 5-HT function as determined by pharmacological MRI" [Neuroimage 75 (2013) 177-186]. PMID- 28843645 TI - [Effectiveness of aqueous extracts of aromatic and medicinal plants against tomato grey mould in Morocco]. AB - Grey mould is a major disease threatening the Moroccan tomato; this disease is often controlled by fungicides. However, the latter are a real danger to human health and environment. Thus, this study is part of the research of harmless alternatives such extracts of aromatic and medicinal plants (Lavandula officinalis, Thymus vulgaris, Cymbopogon citratus, and Melissa officinalis). In this study, the extracts of four medicinal and aromatic plants were tested for their antifungal potency in vitro and in vivo in order to select the most effective. The results show that, in vitro, the Lavandula officinalis, Thymus vulgaris and Cymbopogon citratus aqueous extracts all possess significant antifungal activity, whereas Melissa officinalis shows the least effective. Also in vivo only the aqueous extract of Cymbopogon citratus proves most effective against B. cinerea on tomato fruit. The test of the plants confirms that aqueous extracts of Cymbopogon citratus and Thymus vulgaris are most effective, while the aqueous extracts of Melissa officinalis and Lavandula officinalis always seem to be the least effective. Therefore, the aqueous extracts of Cymbopogon citratus and Thymus vulgaris are the most envisaged for the biological control of grey mould. PMID- 28843646 TI - Characterizing the effect of endocrine disruptors on human health: The role of epidemiological cohorts. AB - Research on endocrine disruptors (EDs) developed from numerous disciplines. In this concert of disciplines, epidemiology is central to inform on the relevance for humans of mechanisms and dose-response functions identified in animals, to characterize the health impact (number of attributable disease cases), the cost associated with ED exposure, and the efficiency of the measures taken to limit exposure. Here, we present epidemiological tools to draw valid inference regarding effects of potential EDs. Epidemiology is generally observational, requiring care to control confounding bias. Many potential EDs have a short biological half-life; approaches relying on repeated biospecimens sampling allow limiting exposure misclassification and the resulting bias. For non-persistent compounds, couple-child cohorts are a central study design. Cohorts can now rely on molecular biology approaches to characterize exposures and intermediate pathways, which corresponds to the advent of molecular epidemiology and allows stronger interactions between epidemiology, toxicology, and molecular epidemiology to characterize the health effects of EDs. PMID- 28843647 TI - [Non surgical chronic thromboembolic pulmonary hypertension in a subject with antiphospholipid syndrome]. PMID- 28843648 TI - 5-gene differential expression predicts stability of human intestinal allografts. AB - In intestinal allografts, endoscopy and histology detect the injury once changes in the bowel wall architecture have occurred. We aimed to identify a molecular signature that could predict early deterioration, within histologically indistinguishable biopsies with "minimal changes" (MC) pathology. Sixty biopsies from 12 adult recipients were longitudinally taken during 8years post-transplant. They were classified as either stable (STA) or non-stable (NSTA) according to the prospectively recorded number, frequency and severity of rejection events of the allograft. In a discovery set of MC samples analyzed by RNA-Seq, 816 genes were differentially expressed in STA vs NSTA biopsies. A group of 5 genes (ADH1C, SLC39A4, CYP4F2, OPTN and PDZK1) correctly classified all NSTA biopsies in the discovery set and all STA biopsies from an independent set. These results were validated by qPCR in a new group of MC biopsies. Based on a logistic regression model, a cutoff of 0.28 predicted the probability of being a NSTA biopsy with 85% sensitivity and 69% specificity. In conclusion, by analyzing MC samples early after transplantation, the expression of a 5-gene set may predict the evolution of the bowel allograft. This prognostic biomarker may be of help to personalize care of the intestinal transplant recipient. PMID- 28843649 TI - Change in nomenclature for the immunologic synapse from Troxis Necrosis to trogocytosis. AB - The immunologic synapse mechanism of liver necrosis was termed Troxis Necrosis meaning "nibbling". (Wang MX et al. and French SW. Exp Mol Pathol 2001, 71: 137 146). This mechanism of liver injury was first named "Piecemeal Necrosis" by Hans Popper. It is involved in autoimmune hepatitis, HCV, HBV, primary biliary cirrhosis and steatohepatitis. This process involves the T cell receptor (TCR) which binds to the hepatocyte antigen presenting major histocompatibility complex (MHC) on the hepatocytic plasma membrane which quickly leads to the removal of the complex from the liver and uptake by the CD4 lymphocyte. This process is performed by the immunologic synapse now called trogocytosis meaning "gnaw" (Martinez-Martin N et al., Immunity 2011, 35: 208-222 and Dustin ML, Cancer Immunol Res 2014, 2: 1023-1033). The repeated episodes of uptake of the hepatocyte bite by bite causes the hepatocyte to slowly disappear like the Cheshire cat. This immunological synapse process is also involved in drug hepatitis, Hashimoto's thyroiditis, type I diabetes, autoimmune adrenalitis, autoimmune gastritis and cancer therapy. Treatment of Alzheimer's disease is also now being studied with PD-L1 antibody as used in the treatment of cancer allowing recruitment of disease modifying leukocytes to the sites of brain pathology (Schwartz M. Science 2017, 357: 254-255). Acknowledgement: Supported by a Grant from NIAAAUO1-021898. PMID- 28843650 TI - Relationship of metabolic syndrome and its components with thyroid dysfunction in Algerian patients. AB - AIMS: The aim of this study is to evaluate the prevalence of the metabolic syndrome and its compounds in subjects with different thyroid status. MATERIALS AND METHODS: A prospective cross-sectional study was conducted in the internal medicine department at El Okbi Hospital of Guelma (East of Algeria) from January 2014 to September 2015. Eighty six patients attending the specialist consultation for suspected thyroid disorders were included in the study. Gender; blood pressure; body mass index; and serum levels of fasting glucose, total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol, and triglyceride were compared between subjects with hypothyroidism, hyperthyroidism and euthyroidism. RESULTS AND CONCLUSION: Thyroid dysfunction was found in 59.3% (n=42) patients, hypothyroidism (45.3%) was the major thyroid dysfunction followed by hyperthyroidism (14.0%). Overall, the prevalence of metabolic syndrome was 48.8% (n=42). Subjects with hypothyroidism had significantly higher level of BMI, WC, TC, LDL-C, and higher prevalence of abdominal obesity (84.6%, p<0.01) and hypertension (51.2%, p<0.05). The hyperthyroid group had significantly lower level of TC, LDL-C and HDL-C but a higher level of SBP and UA. Furthermore, abdominal obesity, hypertension and low HDL-C level were the most common metabolic syndrome compounds found in the hyperthyroid group compared to the euthyroid group. We found a positive association between TSH level and the prevalence of the metabolic syndrome. PMID- 28843651 TI - Recognition and Prevention of Nosocomial Malnutrition: A Review and A Call to Action! AB - Nosocomial malnutrition in hospitalized adults is a morbid, costly, and potentially preventable and treatable problem. Although recognized as contributing to many serious complications of hospitalization, malnutrition is often missed when present on admission and rarely diagnosed if it occurs during hospital stay. Many routine clinical practices such as holding nutrition for testing or failing to address poor intake, when added to acute inflammatory disease states, cause rapid deterioration in nutritional status in up to 70% of inpatients. Malnutrition during hospitalization is associated with increased mortality for years after discharge. In addition, unrecognized (and under-coded) malnutrition is associated with potential lost revenues for hospital systems. Low cost interventions of recognizing at-risk patients and providing adequate nutrition have the potential to improve patient outcomes and reduce health care costs. Physicians must champion implementation of these interventions, using guidance from national organizations. PMID- 28843652 TI - Using High-Sensitivity Cardiac Troponin T for Acute Cardiac Care. AB - The recent approval of the fifth-generation cardiac troponin T assay, which has characteristics clinically of a high-sensitivity assay, has led to concern that the problems of increased sensitivity will be greater than the benefits. This will not be the case if cardiology, emergency medicine, and laboratory medicine combine to develop procedures for use of the assay. We advocate sex-specific 99th percentile upper reference limit values of 15 ng/L for men and 10 ng/L for women. We suggest a 2-hour rule-out strategy, including a value less than the 99th percentile upper reference limit and the lack of a change in values of <4 ng/L. Those with values >100 ng/L and or a changing pattern of values >=10 ng/L are a population much more likely to have acute myocardial infarction. Most of the increment in elevated values will occur not in those with acute coronary problems but in those with primary cardiac disease like heart failure and those with primary noncardiac problems. The former belong on a cardiac service because they are at high risk. The latter should have therapy on the service most apt to provide optimal care for their primary diagnosis, with cardiac consultation as needed. PMID- 28843653 TI - Characterization of folate receptor alpha (FRalpha) expression in archival tumor and biopsy samples from relapsed epithelial ovarian cancer patients: A phase I expansion study of the FRalpha-targeting antibody-drug conjugate mirvetuximab soravtansine. AB - PURPOSE: To characterize folate receptor alpha (FRalpha) expression in archival and fresh biopsy tumor samples from relapsed ovarian cancer patients. METHODS: Patients with ovarian tumors amenable to biopsy were eligible to enroll. Eligibility included a minimum requirement of FRalpha positivity in archival tumor samples (>=25% of cells with >=2+ staining intensity). Patients received mirvetuximab soravtansine at 6mg/kg once every 3weeks. Core needle biopsies were collected before and after treatment and FRalpha levels assessed by immunohistochemistry. Descriptive statistics were used to summarize the association between receptor expression and response. RESULTS: Twenty-seven heavily pre-treated patients were enrolled. Six individuals (22%) did not have evaluable pre-treatment biopsies due to insufficient tumor cells. The concordance of FRalpha expression in archival and biopsy tissues was 71%, and no major shifts in receptor expression were seen in matched pre- and post-treatment biopsy samples. Adverse events were generally mild (<=grade 2) with keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common treatment-related toxicities. The confirmed objective response rate (ORR) was 22%, including two complete responses and four partial responses. Superior efficacy measures were observed in the subset of patients with the highest FRalpha levels (ORR, 31%; progression-free survival, 5.4months). CONCLUSION: Concordance of FRalpha expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRalpha expression was associated with greater antitumor activity. PMID- 28843654 TI - PDF-ECG in clinical practice: A model for long-term preservation of digital 12 lead ECG data. AB - BACKGROUND: In clinical practice, data archiving of resting 12-lead electrocardiograms (ECGs) is mainly achieved by storing a PDF report in the hospital electronic health record (EHR). When available, digital ECG source data (raw samples) are only retained within the ECG management system. OBJECTIVE: The widespread availability of the ECG source data would undoubtedly permit successive analysis and facilitate longitudinal studies, with both scientific and diagnostic benefits. METHODS & RESULTS: PDF-ECG is a hybrid archival format which allows to store in the same file both the standard graphical report of an ECG together with its source ECG data (waveforms). Using PDF-ECG as a model to address the challenge of ECG data portability, long-term archiving and documentation, a real-world proof-of-concept test was conducted in a northern Italy hospital. A set of volunteers undertook a basic ECG using routine hospital equipment and the source data captured. Using dedicated web services, PDF-ECG documents were then generated and seamlessly uploaded in the hospital EHR, replacing the standard PDF reports automatically generated at the time of acquisition. Finally, the PDF-ECG files could be successfully retrieved and re analyzed. CONCLUSION: Adding PDF-ECG to an existing EHR had a minimal impact on the hospital's workflow, while preserving the ECG digital data. PMID- 28843657 TI - "Empirical" retreatment of patients with chronic hepatitis C who failed a first direct-acting antiviral-based regimen. PMID- 28843655 TI - Phantom Limbs, Neuroprosthetics, and the Developmental Origins of Embodiment. AB - Amputees who wish to rid themselves of a phantom limb must weaken the neural representation of the absent limb. Conversely, amputees who wish to replace a lost limb must assimilate a neuroprosthetic with the existing neural representation. Whether we wish to remove a phantom limb or assimilate a synthetic one, we will benefit from knowing more about the developmental process that enables embodiment. A potentially critical contributor to that process is the spontaneous activity - in the form of limb twitches - that occurs exclusively and abundantly during active (REM) sleep, a particularly prominent state in early development. The sensorimotor circuits activated by twitching limbs, and the developmental context in which activation occurs, could provide a roadmap for creating neuroprosthetics that feel as if they are part of the body. PMID- 28843656 TI - Disease outcomes in a cohort of women in Ireland infected by hepatitis C contaminated anti-D immunoglobulin during 1970s. AB - BACKGROUND & AIM: In the mid-1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotype 1b infection, following administration of contaminated anti-D immunoglobulin in 1977-79. We aimed to describe their disease history and estimate the effect of selected host and treatment factors on disease progression. METHODS: We conducted a cohort study on the women infected with HCV. Information was collected from records at seven HCV treatment centres on demographics, treatment and health outcomes up to the 31st December 2013. We calculated cumulative incidence, case fatality, and sub hazard ratios (SHR) for disease progression using competing risks regression. RESULTS: Six hundred and eighty-two patients were included in the study. Among the chronically infected patients (n=374), 35% completed interferon-based antiviral treatment; 42% of whom had a sustained virological response. At the end of 2013, 19%, 1.9%, and 4.9% of chronically infected patients had developed cirrhosis, hepatocellular carcinoma, and liver-related death, respectively, compared with 10%, 0.8%, and 2.4% at the end of 2008. At the end of 2013, 321 (86%) of the chronically infected patients remained alive, 247 (77%) of whom were still chronically infected. Factors associated with increased cirrhosis rates included high alcohol intake (aSHR=4.9 [2.5-9.5]) and diabetes mellitus (aSHR=5.0 [2.9-8.8]). CONCLUSIONS: Development of liver-related outcomes accelerated with time, with the risk of cirrhosis, hepatocellular carcinoma, and liver-related death doubling in the last five years of follow-up, particularly in women with high alcohol consumption and diabetes mellitus. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of alcohol, and that data be collected on this cohort after a further five years to analyse the effect of subsequent antiviral treatment during this rapidly evolving period in HCV treatment history. LAY SUMMARY: In the mid-1990s, a group of women were diagnosed with chronic hepatitis C virus (HCV) infection following receipt of contaminated anti-D immunoglobulin between 1977 and 1979 in Ireland. Seventy-two (19%) developed cirrhosis and 18 had died from liver-related causes (5%) after 36years of infection. Disease progression accelerated in the last five years of follow-up, particularly in women with diabetes mellitus and high alcohol consumption. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of high alcohol consumption. PMID- 28843658 TI - Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. AB - BACKGROUND & AIMS: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in hepatocellular carcinoma (HCC) and study their intra- and inter-tumor distribution in advanced lesions. METHODS: A total of 151 samples representing the multistep process of hepatocarcinogenesis were analyzed by targeted-sequencing and a single nucleotide polymorphism array. Genes altered in early lesions (31 dysplastic nodules [DNs] and 38 small HCCs [sHCC]) were defined as trunk. Their distribution was explored in: a) different regions of large tumors (43 regions, 21 tumors), and b) different nodules of the same patient (39 tumors, 17 patients). Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. RESULTS: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events and at least one was present in 51% of sHCCs. Around 90% of mutations in these genes were ubiquitous among different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs; 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. CONCLUSIONS: Trunk events in early stages (TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC. LAY SUMMARY: Trunk alterations arise at early stages of cancer and are shared among all malignant cells of the tumor. In order to identify trunk alterations in HCC, we characterized early stages of hepatocarcinogenesis represented by dysplastic nodules and small lesions. Mutations in TERT, TP53 and CTNNB1 genes were the most frequent. Analyses in more advanced lesions showed that mutations in these same genes were shared between different regions of the same tumor and between primary and metastatic tumors, suggesting their trunk role in this disease. PMID- 28843659 TI - Laparoscopic graduated cardiomyotomy with anterior fundoplication as treatment for achalasia: experience of 48 cases. AB - INTRODUCTION AND AIMS: At the Upper Gastrointestinal Tract Clinic of the Hospital General de Mexico, achalasia treatment has been standarized through strictly graduated cardiomyotomy. This procedure guarantees a complete myotomy for the satisfactory resolution of dysphagia, a characteristic symptom of achalasia. To ensure the inclusion of the entire lower esophageal sphincter, an 8cm Penrose drain is placed at the surgical site 6cm above the gastroesophageal junction and 2cm in a caudal direction, for accurate laparoscopic measuring. The aim of our study was to evaluate the results of this technique. MATERIALS AND METHODS: A descriptive, retrospective, longitudinal, and observational study was conducted on a cohort of patients diagnosed with achalasia at the Upper Gastrointestinal Tract Clinic of the Hospital General de Mexico "Dr. Eduardo Liceaga". RESULTS: The study included 48 patients, 40 of whom had no prior surgical treatment and 8 that presented with recurrence. Forty-seven patients (97.9%) underwent a laparoscopic procedure and conversion to open surgery was required in 2 of them (4.25% conversion rate). Postoperative progression was satisfactory in all cases, with mean oral diet commencement at 52h and mean hospital stay of 5.7 days. No recurrence was registered during the mean follow-up period of 35.75 months and there were no deaths. CONCLUSIONS: Laparoscopic graduated (strictly measured) cardiomyotomy with anterior fundoplication is a reproducible, efficacious, and safe option for the surgical treatment of achalasia. PMID- 28843660 TI - Response to Dr. Tobar-Marcillo and his coauthors: "Chemoprophylaxis in the prevention of Clostridium difficile infection: Still a ways to go". PMID- 28843661 TI - Reproductive losses caused by the ingestion of Poincianella pyramidalis in sheep. AB - Malformations have been observed in sheep and goats in the Brazilian semiarid region in areas where Poincianella pyramidalis is dominant. The objective of this trial was to determine whether Poincianella pyramidalis causes reproductive changes in pregnant sheep. Sixteen non-pregnant sheep were mated with two rams. After confirmation of the pregnancy by ultrasonography on the 18th day after mating, pregnant sheep were randomly divided into four groups (#1, 2, 3, and 4), with four animals each. Sheep received roughage in an amount equivalent to 2% of their body weight, mixed with 0%, 10%, 20% and 40% of dried leaves of P. pyramidalis for groups 1, 2, 3 and 4, respectively. In Groups 1 and 2, all animals lambed normally. In Group 3 (20% P. pyramidalis in the roughage), one lamb was born with arthrogryposis and three sheep gave birth to premature weak lambs within 128, 132, and 133 days of gestation. In Group 4 (40% P. pyramidalis in the roughage), one sheep lambed a normal lamb; another ewe had embryonic mortality after seven days of plant consumption, and two aborted on days 103 and 144 of pregnancy. One of the aborted fetuses was normal and the other showed arthrogryposis and prognathism. These results suggest that P. pyramidalis causes embryonic deaths, abortions, and malformations in sheep. Grazing pregnant sheep in areas where this plant is dominant should be avoided, and roughage for confined pregnant females should not contain more than 10% P. pyramidalis. PMID- 28843663 TI - Risk factors and outcomes of critically ill patients with acute brain failure: A novel end point. AB - OBJECTIVE: To determine the incidence, risk factors and outcomes of acute brain failure (ABF) in a mixed medical and surgical cohort of critically ill patients and its effect on ICU & hospital mortality. DESIGN: Observational electronic medical record (EMR) based retrospective cohort study of critically ill patients admitted to the ICU between 2006 and 2013. SETTING: Tertiary academic medical center. PATIENTS: Consecutive adult (>18years) critically ill patients admitted to medical and surgical ICUs. Patients admitted to the Neuroscience, Pediatric and Neonatal ICUs were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ABF was defined by the presence of delirium (positive CAM-ICU) or depressed level of consciousness (by abnormal GCS and FOUR scores) in the absence of deep sedation (RASS<-3). Severity of ABF was categorized as grade I if there was delirium with GCS consistently >8 and grade II if the GCS was <=8 with or without delirium during the ICU hospitalization. ABF duration was not used for this study. Univariate and multivariable analyses were used to access the factors associated with the development of ABF and its effect on short and long term mortality. Of 67,333 ICU patients included in the analysis, ABF was present in 30,610 (44.6%). Patients with ABF had an isolated delirium in 1985 (6.5%) patients, isolated depressed consciousness in 18,323 (59.9%), and both delirium and depressed consciousness in 10,302 (33.6%) patients. When adjusted for comorbidities and severity of illness ABF was associated with increased hospital (OR 3.47; 95% CI 3.19-3.79), and at one year (OR 2.36; 95% CI 2.24-2.50) mortality. Both hospital and one year mortality correlated with the increased severity of ABF. The factors most strongly associated with ABF were pre-admission dementia (OR 7.86; 95% CI 6.15-10.19) and invasive ventilation (OR 2.32; 95% CI 2.24-2.40) but older age, female sex, presence of liver disease, renal failure, diabetes mellitus, malignancy and COPD were also associated with increased risk of ABF. CONCLUSIONS: ABF is a common complication of critical illness and is associated with increased short and long term mortality. The risk of ABF was particularly high in older patients with baseline dementia, COPD, diabetes, liver and renal disease and those treated with invasive mechanical ventilation. PMID- 28843662 TI - The effect of early renal replacement therapy guided by plasma neutrophil gelatinase associated lipocalin on outcome of acute kidney injury: A feasibility study. AB - PURPOSE: The optimal time and the parameter utilized for decision to initiate renal replacement therapy (RRT) in acute kidney injury (AKI) are still controversial. Recently, high levels of plasma NGAL (pNGAL) has been strongly correlated with poor AKI outcome. This is a feasibility study conducted to test whether early RRT initiation guided by pNGAL could improve AKI outcome. MATERIAL AND METHODS: The study comprised of triage trial and interventional trial running subsequently. As a guide for triage to RRT, we measured pNGAL at the enrollment time. Forty patients with pNGAL>=400ng/mL (high pNGAL group) were randomized to 'early' or 'standard' group. Patients with pNGAL<400ng/mL (n=20) were defined as low pNGAL group. RESULTS: The triggering pNGAL selected AKI patients with more severity of illness and worse clinical outcome. However, in high pNGAL group, early RRT did not result in different 28-day mortality from the standard group. The median numbers of day free from mechanical ventilation were significantly higher in the early RRT group. CONCLUSIONS: Our finding suggested that it was feasible to use pNGAL to triage severe AKI patients. However, early initiation of RRT in this high risk group did not affect the 28-day mortality. PMID- 28843664 TI - Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis. AB - PURPOSE: One of the pathophysiological processes in sepsis is endothelial dysfunction, which leads to disseminated intravascular coagulation (DIC). Syndecan-1 is a major structural component of the endothelium and plays a key role in endothelial function. The purpose of this study was to assess the value of syndecan-1 as a predictive marker for DIC in sepsis. METHODS: We performed a prospective observational study of patients with sepsis from February 2014 to July 2015. Serial change of hemostatic markers, anticoagulant and fibrinolytic markers (antithrombin, PAI-1), endothelial markers (syndecan-1, VCAM-1, E selectin), and inflammatory markers (IL-1beta, IL-6, IL-8, HMGB-1, histone-H3) were analyzed. Clinical data including APACHE II, SOFA, and DIC scores and 28-day mortality were also evaluated. RESULTS: During the study, 39 septic patients and 15 healthy controls were included. Syndecan-1 levels were significantly increased in the septic patients compared with the healthy controls. Of the septic patients, non-survivors had higher syndecan-1 levels than did the survivors on days 1, 2, and 4. Significant correlations on day 1 were found between syndecan-1 levels and APACHE II, SOFA, and DIC scores, hemostatic markers, IL-1beta, IL-8, and PAI-1. Syndecan-1 levels on day 1 were also significantly higher in patients with than without DIC and had strong discriminative power for the prediction of both DIC development and subsequent mortality, with AUCs of 0.79 and 0.85, respectively. CONCLUSION: Syndecan-1 levels were associated with not only the severity of illness and mortality but also DIC development in sepsis, suggesting that syndecan-1 could be a predictive marker of DIC. PMID- 28843665 TI - Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure. AB - BACKGROUND: Cirrhotic patients have complex haemostatic abnormalities. Current evidence suggests stable cirrhotic (SC) patients have a "re-balanced" haemostatic state. However, limited data exists in acute decompensated (AD) or acute on chronic liver failure (ACLF) patients. METHODS: We utilised thrombin generation analysis, fibrinolysis assessment, and evaluation of haemostatic parameters to assess haemostasis in liver disease of progressive severity. RESULTS: The study cohorts were comprised of: SC, n=8; AD n=44; ACLF, n=17; and Healthy Control (HC), n=35. There was a progressive increase across the cohorts in INR (p=0.0001), Factor VIII (p=0.0001) and VWF levels (p=0.0001) and a correspondingly decrease in anti-thrombin (p=0.0001), ADAMTS-13 (p=0.01) and fibrinogen levels (p=0.0001). In the presence of thrombomodulin, thrombin generation was equivalent or significantly higher in all the cohorts compared to HC (p=0.0001). Compared to AD, ACLF had a lower ETP (p=0.002) and thrombin peak (p=0.0001). There was no significant difference across the cohorts in clot lysis time (p=0.07), although compared to HC, AD had a significantly shorter lysis time (p=0.001). CONCLUSIONS: Our cohorts, despite significant differences in haemostatic parameters, displayed intact thrombin generation but progressive hypo functional clot stability and potentially but not universal hyper-functional haemostasis. PMID- 28843666 TI - CA1 inactivation impairs episodic-like memory in rats. AB - Episodic memory was initially believed to be unique to humans. However, studies demonstrate that nonhuman species discriminate items based on the triad what, where and when. Here we addressed the role of the dorsal hippocampal subfield CA1 in an integrative what-where-when task in Wistar rats. We performed bilateral inactivation of dorsal CA1 with the GABAA agonist muscimol previously to the task. As expected, sham-operated animals recollected an integrative memory for objects (what), their places (where) and temporal order (when). However, the inactivation of CA1 impaired the performance of the three components of episodic like memory. In addition, total time of objects exploration and distance traveled were not different between groups, indicating that rats had similar levels of motivation, thus, alterations in exploration does not account for impaired locomotor performance. Altogether, our data provides evidence that CA1 plays an important role in episodic-like memory. PMID- 28843667 TI - The specific localization of advanced glycation end-products (AGEs) in rat pancreatic islets. AB - Advanced glycation end-products (AGEs) are produced by non-enzymatic glycation between protein and reducing sugar such as glucose. Although glyceraldehyde derived AGEs (Glycer-AGEs), one of the AGEs subspecies, have been reported to be involved in the pathogenesis of various age-relating diseases such as diabetes mellitus or arteriosclerosis, little is known about the pathological and physiological mechanism of AGEs in vivo. In present study, we produced 4 kinds of polyclonal antibodies against AGEs subspecies and investigated the localization of AGEs-modified proteins in rat peripheral tissues, making use of these antibodies. We found that Glycer-AGEs and methylglyoxal-derived AGEs (MGO-AGEs) were present in pancreatic islets of healthy rats, distinguished clearly into the pancreatic alpha and beta cells, respectively. Although streptozotocin-induced diabetic rats suffered from remarkable impairment of pancreatic islets, the localization and deposit levels of the Glycer- and MGO-AGEs were not altered in the remaining alpha and beta cells. Remarkably, the MGO-AGEs in pancreatic beta cells were localized into the insulin-secretory granules. These results suggest that the cell-specific localization of AGEs-modified proteins are presence generally in healthy peripheral tissues, involved in physiological intracellular roles, such as a post-translational modulator contributing to the secretory and/or maturational functions of insulin. PMID- 28843668 TI - Phagocytes, Antibiotics, and Self-Limiting Bacterial Infections. AB - Most antibiotic use in humans is to reduce the magnitude and term of morbidity of acute, community-acquired infections in immune competent patients, rather than to save lives. Thanks to phagocytic leucocytes and other host defenses, the vast majority of these infections are self-limiting. Nevertheless, there has been a negligible amount of consideration of the contribution of phagocytosis and other host defenses in the research for, and the design of, antibiotic treatment regimens, which hyper-emphasizes antibiotics as if they were the sole mechanism responsible for the clearance of infections. Here, we critically review this approach and its limitations. With the aid of a heuristic mathematical model, we postulate that if the rate of phagocytosis is great enough, for acute, normally self-limiting infections, then (i) antibiotics with different pharmacodynamic properties would be similarly effective, (ii) low doses of antibiotics can be as effective as high doses, and (iii) neither phenotypic nor inherited antibiotic resistance generated during therapy are likely to lead to treatment failure. PMID- 28843669 TI - Visualization of IAV Genomes at the Single-Cell Level. AB - Different influenza A viruses (IAVs) infect the same cell in a host, and can subsequently produce new viruses through genome reassortment. By combining padlock probe RNA labeling with a single-cell analysis, a new approach effectively captures IAV genome trafficking and defines a time window for genome reassortment from same-cell coinfections. PMID- 28843670 TI - Temperature dependence of hydroxyl radical reactions with chloramine species in aqueous solution. AB - The absolute temperature-dependent kinetics for the reaction between hydroxyl radicals and the chloramine water disinfectant species monochloramine (NH2Cl), as well as dichloramine (NHCl2) and trichloramine (NCl3), have been determined using electron pulse radiolysis and transient absorption spectroscopy. These radical reaction rate constants were fast, with values of 6.06 * 108, 2.57 * 108, and 1.67 * 108 M-1 s-1 at 25 degrees C for NH2Cl, NHCl2, and NCl3, respectively. The corresponding temperature dependence of these reaction rate constants, measured over the range 10-40 degrees C, is well-described by the transformed Arrhenius equations:giving activation energies of 8.57 +/- 0.58, 6.11 +/- 0.40, and 5.77 +/ 0.72 kJ mol-1 for these three chloramines, respectively. These data will aid water utilities in predicting hydroxyl radical partitioning and chemical contaminant removal efficiencies under real-world advanced oxidation process treatment conditions. PMID- 28843671 TI - Expanding Francisella models: Pairing up the soil amoeba Dictyostelium with aquatic Francisella. AB - The bacterial genus Francisella comprises highly pathogenic species that infect mammals, arthropods, fish and protists. Understanding virulence and host defense mechanisms of Francisella infection relies on multiple animal and cellular model systems. In this review, we want to summarize the most commonly used Francisella host model platforms and highlight novel, alternative model systems using aquatic Francisella species. Established mouse and macrophage models contributed extensively to our understanding of Francisella infection. However, murine and human cells display significant differences in their response to Francisella infection. The zebrafish and the amoeba Dictyostelium are well-established model systems for host-pathogen interactions and open up opportunities to investigate bacterial virulence and host defense. Comparisons between model systems using human and fish pathogenic Francisella species revealed shared virulence strategies and pathology between them. Hence, zebrafish and Dictyostelium might complement current model systems to find new vaccine candidates and contribute to our understanding of Francisella infection. PMID- 28843672 TI - In vitro metal catalyzed oxidative stress in DAH7PS: Methionine modification leads to structure destabilization and induce amorphous aggregation. AB - The first committed step of the shikimate pathway is catalyzed by a metalloenzyme 3-deoxy-d-arabino-heptulosonate-7-phosphate synthase (DAH7PS), which exhibits vulnerability to the oxidative stress. DAH7PS undergoes inactivation in multiple ways in the presence of redox metal, H2O2, and superoxide. The molecular mechanism and susceptibility of its inactivation might differ in different organisms and are presently unclear. In the present work, we have cloned, expressed and purified a DAH7PS from Providencia alcalifaciens (PaDAH7PS). The oligomeric state and effect of redox metal treatment on its stability were analyzed through the size exclusion chromatography. The FTIR, MALDI-TOF/TOF-MS studies revealed that methionine residues were modified to methionine sulfoxide in PaDAH7PS. During oxidation, PaDAH7PS is altered into partially folded protein and unfolded states as determined by CD and Fluorescence studies. A significant loss in enzymatic activity of PaDAH7PS was determined and the formation of amorphous aggregates was visualized using AFM imaging and also confirmed by ThT binding based assay. This is the first report where we have shown a hexameric DAH7PS and the methionine residues of PaDAH7PS get oxidize in the presence of oxidative stress. The partially folded and unfolded oligomeric states with high beta-content of PaDAH7PS might be the critical precursors for aggregation. PMID- 28843673 TI - Glycation induced conformational alterations in caprine brain cystatin (CBC) leads to aggregation via passage through a partially folded state. AB - Glycation induced advanced glycation end products (AGEs) of proteins formed as a result of Maillard reaction is currently at the heart of a number of pathological conditions. The formation of chemically stable AGEs can permanently alter protein structure and function; hence can serve as an implication in long term complications. Cystatins with high amyloidogenic inclination are implicated in various diseases including cancer and neurodegenerative conditions. The aggregates of cystatin purified from caprine brain have been studied on addition of glucose and ribose using UV absorption, fluorescence emission, circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). In the present study AGEs have been monitored and characterized. CBC was incubated for varying time intervals up to 41days in the presence of 17 and 100mM each of glucose and ribose. Ribose at both the concentrations was found to be more potent glycating agent as compared to glucose at these concentrations which is evident from UV and fluorescence spectroscopic studies. Altered intrinsic and high ANS fluorescence for 100mM and 17mM sugar concentrations respectively, suggested the existence of molten globule state of CBC. Glycated CBC as AGEs and aggregates were observed on day 27 and 41 respectively. Formation of AGEs was confirmed by employing AGEs specific fluorescence studies. CBC aggregates confirmed the presence of beta-sheet structure as shown by far-UV CD, dye binding assay and transmission electron microscopy (TEM). Current study is of immense importance as cystatin is a potential candidate of amyloidogenic tendency and a potent endogenous regulator of thiol proteases; hence serves to be an attractive model to study amyloidogenesis of brain cysteine protease inhibitor. PMID- 28843674 TI - Collagen-fucoidan blend film with the potential to induce fibroblast proliferation for regenerative applications. AB - Collagen is a unique protein abundantly present in the connective tissues of mammals and widely used for biomaterial preparation. In this study, we synthesized and characterized collagen-fucoidan blend films for tissue regenerative properties. Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) were used for thermal analysis of the blend films, and the films exhibited higher thermal stability and denaturation temperature (Td) than those of native collagen due to intramolecular hydrogen bonding interaction between collagen and fucoidan, which was analyzed by FTIR spectroscopy. Morphological evaluation of these films using Scanning Electron Microscopy (SEM) showed smaller pore size than the control. Moreover, fucoidan protects collagen against enzymatic degradation and thereby increases the structural stability of collagen. Further, the in vitro studies of the synthesized films showed that they effectively facilitated the proliferation and migration of fibroblast cells without exhibiting toxicity. These study results suggested that the collagen fucoidan blend films are a favorable substrate for growth of fibroblast cells, and may have great potential for tissue engineering applications. PMID- 28843675 TI - Aerosol furosemide for dyspnea: High-dose controlled delivery does not improve effectiveness. AB - Published studies have shown great variability in response when aerosolized furosemide has been tested as a palliative treatment for dyspnea. We hypothesized that a higher furosemide dose with controlled aerosol administration would produce consistent dyspnea relief. We optimized deposition by controlling inspiratory flow (300-500mL/s) and tidal volume (15% predicted vital capacity) while delivering 3.4MUm aerosol from either saline or 80mg of furosemide. We induced dyspnea in healthy subjects by varying inspired PCO2 while restricting minute ventilation. Subjects rated "Breathing Discomfort" on a Visual Analog Scale (BDVAS, 100% Full Scale=intolerable). At the PETCO2 producing 60% BDVAS pre treatment, furosemide produced a clinically meaningful reduction of BDVAS (i.e., >20% FS) in 5/11 subjects; saline reduced dyspnea in 3/11 subjects; neither treatment worsened dyspnea in any subject. Furosemide and saline treatment effects were not statistically different. There were no significant adverse events. Higher furosemide dose and controlled delivery did not improve consistency of treatment effect compared with prior studies. PMID- 28843676 TI - Ventilatory response to carbon monoxide during exercise in hypoxia and hypercapnia. AB - We tested if the addition of CO to inspired gases with different inspired O2 and CO2 fractions (FIO2 and FICO2) stimulates ventilation at rest or during submaximal exercise. We measured minute ventilation (VE) in goats breathing combinations of FIO2 ranging from 0.21 to 0.06 and FICO2 from 0 to 0.05, both with and without inspired CO resulting in carboxyhemoglobin fractions (FHbCO) of 0.02 (no CO added), 0.15, or 0.45. We did this while they stood on a treadmill, walked at 1.4, or trotted at 2.5ms-1. Hypoxia, hypercapnia, and exercise, alone and in combination, increased ventilation compared to breathing air at rest. Both elevated FHbCO increased VE compared with ambient FHbCO during exercise (increases of 1.50 and 5.53mls-1kg-1 for FHbCO 0.15 and 0.45, respectively; P=0.035), but not at rest (P=0.958), when the ventilatory effects of FIO2 and FICO2 are factored out. Additionally, FHbCO 0.45 (but not 0.15) increased VE compared to FHbCO 0.02 for all FIO2 and FICO2 when the ventilatory effects of exercise are factored out. Taken together, these data suggest that exercise intensity and FHbCO dose interact to stimulate ventilation during exercise. PMID- 28843677 TI - NADPH oxidase activity: Spectrophotometric determination of superoxide using pyrogallol red. AB - A simple and fast spectrophotometric methodology able to quantify superoxide released by NADPH oxidase from differentiated promyelocytic leukaemia (HL-60) cells using pyrogallol red is described.The latter is based on the known stoichiometry of the reaction between superoxide and pyrogallol red and the inability of pyrogallol red to react with hydrogen peroxide. In addition, we developed a 96-wells microplate-based method able to determine NADPH oxidase activity. Using this method, we determined pharmacological properties of the NADPH oxidase inhibitors VAS2870 and diphenyleneiodonium and the obtained IC50 values were in good agreement with previous reported data. NOX2 is highly expressed in differentiated promyelocytic leukaemia cells, whereas other isoforms are not detected or expressed at low amounts. Likewise, this methodology may be a useful assay for NOX2 inhibitor screening. NADPH oxidases are involved in several physiological and pathological processes, rendering its pharmacological modulation an attractive research target. In this context, this simple assay can be used for NADPH oxidase inhibitor screening as well as aiding in the study of different biological conditions that involve NADPH oxidase activity. PMID- 28843678 TI - Supplementation of vitamin E, selenium and increased energy allowance mitigates the transition stress and improves postpartum reproductive performance in the crossbred cow. AB - Dairy cow undergoes tremendous physiological challenges during the transition period leading to negative energy balance (NEBAL), impaired immunity and oxidative stress that ultimately compromises the postpartum fertility. Accordingly, we investigated the effects of antioxidant supplementation and increased energy allowance on transition stress and fertility of crossbred cow. Advanced pregnant crossbred cows (n = 26) of 2-4 parity and lactation potential of >10 L/day were divided into two equal groups (n = 13 cows/group). Cows were fed diets either (i) supplemented with vitamin E (80 IU/kg DM), Selenium (Se; 0.3 mg/kg DM) and increased energy allowance in the form of 20% additional concentrate (TRT) or (ii) basal diet without any supplementation as control (CON). Vitamin E and Se were supplemented with wheat flour bolus from -4 to 8 week of calving whereas energy allowance was increased from 2 to 8 week of calving on daily basis to individual animal (where 0 is day of calving). Blood samples were collected on weekly interval from -4 to 8 week of calving. Oxidative stress was assessed by estimation of malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase (CAT). Immunity level was assessed via estimation of phagocytic activity (PA) of granulocytes and lymphocyte proliferation assay (LPA). Postpartum fertility was assessed by interval to first postpartum estrus (day) and pregnancy rate. Cows in TRT had a significantly lower MDA, higher TAC and decreased activity of SOD and CAT than that of CON (P < 0.05). Phagocytic activity increased at -1, 0 and 3-8 weeks postpartum (P < 0.05) while LPA showed difference (P < 0.05) at parturition, week 4 and 8 postpartum. Marked improvement in the fertility was recorded in terms of early resumption of postpartum estrus (P < 0.001) and higher pregnancy rate (P < 0.05). PMID- 28843679 TI - Phase-coherence classification: A new wavelet-based method to separate local field potentials into local (in)coherent and volume-conducted components. AB - BACKGROUND: Local field potentials (LFP) reflect the integrated electrophysiological activity of large neuron populations and may thus reflect the dynamics of spatially and functionally different networks. NEW METHOD: We introduce the wavelet-based phase-coherence classification (PCC), which separates LFP into volume-conducted, local incoherent and local coherent components. It allows to compute power spectral densities for each component associated with local or remote electrophysiological activity. RESULTS: We use synthetic time series to estimate optimal parameters for the application to LFP from within the subthalamic nucleus of eight Parkinson patients. With PCC we identify multiple local tremor clusters and quantify the relative power of local and volume conducted components. We analyze the electrophysiological response to an apomorphine injection during rest and hold. Here we show medication-induced significant decrease of incoherent activity in the low beta band and increase of coherent activity in the high beta band. On medication significant movement induced changes occur in the high beta band of the local coherent signal. It increases during isometric hold tasks and decreases during phasic wrist movement. COMPARISON WITH EXISTING METHODS: The power spectra of local PCC components is compared to bipolar recordings. In contrast to bipolar recordings PCC can distinguish local incoherent and coherent signals. We further compare our results with classification based on the imaginary part of coherency and the weighted phase lag index. CONCLUSIONS: The low and high beta band are more susceptible to medication- and movement-related changes reflected by incoherent and local coherent activity, respectively. PCC components may thus reflect functionally different networks. PMID- 28843680 TI - Genome-wide association and pathway-based analysis using latent variables related to milk protein composition and cheesemaking traits in dairy cattle. AB - The aim of this study was to perform genome-wide associations (GWAS) and gene-set enrichment analyses with protein composition and cheesemaking-related latent variables (factors; F) in a cohort of 1,011 Italian Brown Swiss cows. Factor analysis was applied to identify latent structures of 26 phenotypes related to bovine milk quantity and quality, protein fractions [alphaS1-, alphaS2-, beta-, and kappa-casein (CN), beta-lactoglobulin, and alpha-lactalbumin (alpha-LA)], coagulation and curd firming at time t (CFt) measures, and cheese properties [cheese yield (%CY) and nutrients recovery in the curd] of individual cows. Ten orthogonal F were extracted, explaining 74% of the original variability. Factor 1%CY underlined the %CY characteristics, F2CFt was related to the CFt process parameters, F3Yield was considered as descriptor of milk and solids yield, whereas F4Cheese N underscored the presence of nitrogenous compounds (N) into the cheese. Four more F were related to the milk caseins (F5alphaS1-beta-CN, F7beta kappa-CN, F8alphaS2-CN, and F9alphaS1-CN-Ph) and 1 F was linked to the whey protein (F10alpha-LA); 1 F underlined the udder health status (F6Udder health). All cows were genotyped with the Illumina BovineSNP50 Bead Chip v.2 (Illumina Inc., San Diego, CA). Single marker regression GWAS were fitted. Gene-set enrichment analysis was run on GWAS results, using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases, to reveal ontologies or pathways associated with the F. All F but F3Yield showed significance in GWAS. Signals in 10 Bos taurus autosomes (BTA) were detected. High peaks on BTA6 (~87 Mbp) were found for F6beta-kappa-CN, F5alphaS1-beta-CN, and at the tail of BTA11 (~104 Mbp) for F4Cheese N. Gene-set enrichment analyses showed significant results (false discovery rate at 5%) for F8alphaS2-CN, F1%CY, F4Cheese N, and F10alpha-LA. For F8alphaS2-CN, 33 Gene Ontology terms and 3 Kyoto Encyclopedia of Genes and Genomes categories were enriched, including terms related to ion transport and homeostasis, neuron function or part, and GnRH signaling pathway. Our results support the feasibility of factor analysis as a dimension reduction technique in genomic studies and evidenced a potential key role of alphaS2-CN in milk quality and composition. PMID- 28843681 TI - Effect of genetic and nongenetic factors on chemical composition of individual milk samples from dromedary camels (Camelus dromedarius) under intensive management. AB - The aims of the present study were to monitor the changes in gross chemical composition of individual dromedary camel milk over a 5-yr period, to provide reference values, and to determine the effect of genetic and nongenetic factors influencing camel milk composition under intensive management. A total of 1,528 lactating dromedary camels were included in the study. Animals were fed a constant diet and were milked twice a day in a herringbone parlor. Milk samples were collected at monthly intervals using a sampling device and then fat, protein, lactose, total solids (TS), and solids-nonfat (SNF) concentrations of raw camel milk were determined with an automatic milk analyzer. For each milk sample, production parameters were recorded and quantities (grams) of milk constituents were calculated. The overall mean quantity and fat, protein, lactose, SNF, and TS concentrations of the morning milk were 4.0 kg, 2.58%, 2.95%, 4.19%, 8.08%, and 10.46%, respectively. Milk quantity showed a positive correlation with lactose and a negative correlation with all other components. Parity exerted a strong effect on all milk parameters. Primiparous dromedaries (n = 60) produced less milk with higher concentrations of components than did multiparous animals (n = 1,468). Milk composition varied among the 7 breeds tested, but none of the genotypes was found to be superior to the others in this respect. We detected a significant, yet small calf sex-biased difference in milk yield and composition. Stage of lactation and season strongly influenced milk yield and all milk components. We also found a significant interaction between month postpartum (mPP) and month of the year. The concentration of all milk components decreased from 1 to 5 mPP. Later, lactose concentration and quantity continued to decrease parallel with decreasing milk production. The concentration of other components showed a temporary increase in mid lactation, from 6 to 11 mPP, and in late lactation, from 18 to 23 mPP. Mean fat, protein, SNF, and TS concentrations showed a high seasonal variation (9.5 to 28.7%), with the lowest and highest values being measured during summer and winter, respectively. This seasonal variation was independent of nutrition and may reflect an endogenous circannual rhythm. We observed a noticeable variation among years. Dromedary camels could provide a useful in vivo model to study the homeorhetic regulation of mammary cell function by endogenous and environmental factors. PMID- 28843682 TI - Herd-level prevalence of selected endemic infectious diseases of dairy cows in Great Britain. AB - To implement appropriate and effective disease control programs at the national level, up-to-date and unbiased information on disease frequency is needed. The aim of this study was to estimate the prevalence of selected endemic infectious diseases in the population of dairy herds in Great Britain. Bulk milk tank (BMT) samples from 225 randomly selected dairy farms, stratified by region and herd size, were tested for antibodies against bovine viral diarrhea virus (BVDV), bovine herpesvirus type 1, Mycobacterium avium ssp. paratuberculosis, Leptospira Hardjo, Salmonella spp., Coxiella burnetii, Fasciola hepatica, Neospora caninum, and Ostertagia ostertagi. Furthermore, the presence of BVDV, C. burnetii, and Chlamydia-like organisms was determined by PCR. The apparent herd prevalence was estimated as a weighted proportion of positive herds. The true prevalence was calculated when a test was used with known test characteristics for the cut-off value used. Among unvaccinated herds, the true prevalence of BMT antibodies against BVDV was estimated at 66% [95% confidence interval (CI): 56-77%], M. avium ssp. paratuberculosis 68% (95% CI: 59-77%), bovine herpesvirus type 1 62% (95% CI: 52-73%), Leptospira Hardjo 47% (95% CI: 34-60%), and Salmonella spp. 48% (95% CI: 39-56%). The apparent prevalence of BMT antibodies against C. burnetii was 80% (95% CI: 75-85%), F. hepatica 55% (95% CI: 48-62%), N. caninum 46% (95% CI: 38-54%), and O. ostertagi 95% (95% CI: 91-98%). The BVDV, C. burnetii, and Chlamydia-like antigens were detected in 5 (95% CI: 2-9%), 29 (95% CI: 21-36%), and 31% (95% CI: 24-38%) of herds, respectively. Our results show that dairy cows across GB are frequently exposed to the studied pathogens, which are endemic at high levels with some geographical variations. These prevalence estimates provide a much-needed basis to assess whether nationwide control programs for the studied pathogens are justified by their potential economic, environmental, and public health implications. Should surveillance and control programs be initiated, the estimates presented here are a baseline against which progress can be assessed. PMID- 28843683 TI - Effect of substituting soybean meal and canola cake with dried distillers grains with solubles at 2 dietary crude protein levels on feed intake, milk production, and milk quality in dairy cows. AB - Dried distillers grain with solubles (DDGS) is an alternative source of feed protein for dairy cows. Previous studies found that DDGS, based on grains other than corn, can substitute for soybean meal and canola cake as a dietary protein source without reducing milk production or quality. As societal concerns exist, and in many areas strict regulation, regarding nitrogen excretion from dairy cows, the dairy industry has focused on reducing dietary protein level and nitrogen excretion. In the present study, we investigated the use of DDGS as a protein source, at a marginally low dietary crude protein (CP) levels, in a grass clover and corn silage-based ration. The experiment involved 24 Holstein cows and 2 protein sources (DDGS or soybean-canola mixture) fed at 2 levels of CP (14 or 16%) in a 4 * 4 Latin square design. The aim of this study was to evaluate the effect of both protein source and protein level on feed intake, milk yield, and milk quality. The results indicated that feed intake, milk yield, and protein in milk increased when the protein level in the ration was 16% CP compared with 14%. We found no effect of substituting the soybean-canola mixture with DDGS. Moreover, no sensory problems were observed when comparing fresh milk with stored milk, and milk taste was unaffected by DDGS. Milk from cows fed DDGS had a slightly higher content of linoleic acid and conjugated linoleic acid (CLA 9-11), and lower content of C11 to C17 fatty acids than cows fed diets with the soybean canola mixture. Cows fed the diets with 16% CP produced milk with higher oleic acids and lower palmitic acid content than cows fed 14% CP diets. To conclude, DDGS can substitute for a soybean-canola mixture without affecting feed intake, milk yield and quality, or sensory quality. Under the conditions of this experiment, feeding 16% CP compared with 14% CP in the ration can increase feed intake and milk production. PMID- 28843684 TI - Short communication: Supplementation of fructo-oligosaccharides does not improve insulin sensitivity in heavy veal calves fed different sources of carbohydrates. AB - Heavy veal calves (4-6 mo old) often develop problems with insulin sensitivity. This could lead to metabolic disorders and impaired animal growth performance. Studies in various animal species have shown that the supplementation of short chain fructo-oligosaccharides (scFOS) can improve insulin sensitivity. We therefore studied the effects of scFOS supplementation on insulin sensitivity in heavy veal calves. Forty male Holstein-Friesian calves (BW = 190 +/- 2.9 kg; age = 162 +/- 1.4 d at the start of the trial) were fed either a control milk replacer (MR) diet or a diet in which one-third of the lactose was replaced by glucose, fructose, or glycerol for 10 wk prior to the start of the trial. At the start of the trial, calves were subjected to a frequently sampled intravenous glucose tolerance test to assess whole-body insulin sensitivity (muscle and hepatic insulin sensitivity). Calves within each dietary treatment group were ranked based on their insulin sensitivity value. Half of the calves received scFOS (12 mg/kg of BW) with the MR for 6 wk (supplementation was equally distributed over the insulin sensitivity range). Subsequently, a second frequently sampled intravenous glucose tolerance test was conducted to assess the effect of scFOS. In addition, fasting plasma levels of glucose, insulin, triglycerides, and cholesterol were determined to calculate the quantitative insulin sensitivity check index and triglyceride:high-density lipoprotein cholesterol ratio (fasting indicators of insulin sensitivity). Whole-body insulin sensitivity was low at the start of the trial and remained low in all groups [1.0 +/- 0.1 and 0.8 +/- 0.1 (mU/L)-1 . min-1 on average, respectively]. Supplementation of scFOS did not improve insulin sensitivity in any of the treatment groups. The quantitative insulin sensitivity check index and the triglyceride:high-density lipoprotein cholesterol ratio also did not differ between scFOS and non-scFOS calves and averaged 0.326 +/- 0.003 and 0.088 +/- 0.004, respectively, at the end of the trial. We conclude that scFOS supplementation does not improve insulin sensitivity in heavy veal calves regardless of the carbohydrate composition of the MR. This is in contrast to other animals (e.g., dogs and horses), where scFOS supplementation did improve insulin sensitivity. The absence of an effect of scFOS might be related to the dosage or to metabolic differences between ruminants and nonruminants. Increasing evidence indicates that dietary interventions in veal calves have little or no effect on insulin sensitivity, possibly because of low levels of insulin sensitivity. PMID- 28843685 TI - pH influences hydrolysis of sodium polyphosphate in dairy matrices and the structure of processed cheese. AB - We investigated the effect of pH (5.2 to 6.8) on the hydrolysis of a sodium polyphosphate in water, milk, calcium caseinate, and spreadable processed cheese, as well as the effect of pH on the cheese structure. Monitoring of the hydrolysis in water and the different milk matrices was carried out using 31P nuclear magnetic resonance technique. In general, the decrease in pH increased the hydrolysis of polyphosphates in all matrices. The presence of calcium in milk increased the rate of hydrolysis. Hydrolysis in milk was higher than in calcium caseinate, probably due to lower molecular mobility in concentrated systems with high viscosity. Increasing the pH decreased the hardness and adhesiveness of the cheeses. At low pH (5.2 and 5.6), the cheeses presented a granular structure, although, at more neutral pH (6.0 to 6.8), the structure was continuous, homogeneous, and more fluid. These results highlight the importance of precise pH control in the manufacture of processed cheeses. PMID- 28843686 TI - Fertility, survival, and conformation of Montbeliarde * Holstein and Viking Red * Holstein crossbred cows compared with pure Holstein cows during first lactation in 8 commercial dairy herds. AB - Montbeliarde (MO) * Holstein (HO) and Viking Red (VR) * HO crossbred cows were compared with pure HO cows in 8 large, high-performance dairy herds in Minnesota. All cows calved for the first time from December 2010 to April 2014. Fertility and survival traits were calculated from records of insemination, pregnancy diagnosis, calving, and disposal that were recorded via management software. Body condition score and conformation were subjectively scored once during early lactation by trained evaluators. The analysis of survival to 60 d in milk included 536 MO * HO, 560 VR * HO, and 1,033 HO cows during first lactation. Cows analyzed for other fertility, survival, and conformation traits had up to 13% fewer cows available for analysis. The first service conception rate of the crossbred cows (both types combined) increased 7%, as did the conception rate across the first 5 inseminations, compared with the HO cows during first lactation. Furthermore, the combined crossbred cows (2.11 +/- 0.05) had fewer times bred than HO cows (2.30 +/- 0.05) and 10 fewer d open compared with their HO herdmates. Across the 8 herds, breed groups did not differ for survival to 60 d in milk; however, the superior fertility of the crossbred cows allowed an increased proportion of the combined crossbreds (71 +/- 1.5%) to calve a second time within 14 mo compared with the HO cows (63 +/- 1.5%). For survival to second calving, the combined crossbred cows had 4% superior survival compared with the HO cows. The MO * HO and VR * HO crossbred cows both had increased body condition score (+0.50 +/- 0.02 and +0.25 +/- 0.02, respectively) but shorter stature and less body depth than HO cows. The MO * HO cows had less set to the hock and a steeper foot angle than the HO cows, and the VR * HO cows had more set to the hock with a similar foot angle to the HO cows. The combined crossbred cows had less udder clearance from the hock than HO cows, more width between both front and rear teats, and longer teat length than the HO cows; however, the frequency of first-lactation cows culled for udder conformation was uniformly low (<1%) across the breed groups. PMID- 28843687 TI - Short communication: Sensitive detection of norbixin in dried dairy ingredients at concentrations of less than 1 part per billion. AB - Norbixin is the water-soluble carotenoid in annatto extracts used in the cheese industry to color Cheddar cheese. The purpose of norbixin is to provide cheese color, but norbixin is also present in the whey stream and contaminates dried dairy ingredients. Regulatory restrictions dictate that norbixin cannot be present in dairy ingredients destined for infant formula or ingredients entering different international markets. Thus, there is a need for the detection and quantification of norbixin at very low levels in dried dairy ingredients to confirm its absence. A rapid method for norbixin evaluation exists, but it does not have the sensitivity required to confirm norbixin absence at very low levels in compliance with existing regulations. The current method has a limit of detection of 2.7 MUg/kg and a limit of quantification of 3.5 MUg/kg. The purpose of this study was to develop a method to extract and concentrate norbixin for quantification in dried dairy ingredients below 1 MUg/kg (1 ppb). A reverse-phase solid-phase extraction column step was applied in the new method to concentrate and quantify norbixin from liquid and dried WPC80 (whey protein concentrate with 80% protein), WPC34 (WPC, 34% protein), permeate, and lactose. Samples were evaluated by both methods for comparison. The established method was able to quantify norbixin in whey proteins and permeates (9.39 MUg/kg to 2.35 mg/kg) but was unable to detect norbixin in suspect powdered lactose samples. The newly developed method had similar performance to the established method for whey proteins and permeates but was also able to detect norbixin in powdered lactose samples. The proposed method had a >90% recovery in lactose samples and a limit of detection of 28 ppt (ng/kg) and a limit of quantification of 94 ppt (ng/kg). The developed method provides detection and quantification of norbixin for dairy ingredients that have a concentration of <1 ppb. PMID- 28843688 TI - The genetic and biological basis of feed efficiency in mid-lactation Holstein dairy cows. AB - The objective of this study was to identify genomic regions and candidate genes associated with feed efficiency in lactating Holstein cows. In total, 4,916 cows with actual or imputed genotypes for 60,671 single nucleotide polymorphisms having individual feed intake, milk yield, milk composition, and body weight records were used in this study. Cows were from research herds located in the United States, Canada, the Netherlands, and the United Kingdom. Feed efficiency, defined as residual feed intake (RFI), was calculated within location as the residual of the regression of dry matter intake (DMI) on milk energy (MilkE), metabolic body weight (MBW), change in body weight, and systematic effects. For RFI, DMI, MilkE, and MBW, bivariate analyses were performed considering each trait as a separate trait within parity group to estimate variance components and genetic correlations between them. Animal relationships were established using a genomic relationship matrix. Genome-wide association studies were performed separately by parity group for RFI, DMI, MilkE, and MBW using the Bayes B method with a prior assumption that 1% of single nucleotide polymorphisms have a nonzero effect. One-megabase windows with greatest percentage of the total genetic variation explained by the markers (TGVM) were identified, and adjacent windows with large proportion of the TGVM were combined and reanalyzed. Heritability estimates for RFI were 0.14 (+/-0.03; +/-SE) in primiparous cows and 0.13 (+/ 0.03) in multiparous cows. Genetic correlations between primiparous and multiparous cows were 0.76 for RFI, 0.78 for DMI, 0.92 for MBW, and 0.61 for MilkE. No single 1-Mb window explained a significant proportion of the TGVM for RFI; however, after combining windows, significance was met on Bos taurus autosome 27 in primiparous cows, and nearly reached on Bos taurus autosome 4 in multiparous cows. Among other genes, these regions contain beta-3 adrenergic receptor and the physiological candidate gene, leptin, respectively. Between the 2 parity groups, 3 of the 10 windows with the largest effects on DMI neighbored windows affecting RFI, but were not in the top 10 regions for MilkE or MBW. This result suggests a genetic basis for feed intake that is unrelated to energy consumption required for milk production or expected maintenance as determined by MBW. In conclusion, feed efficiency measured as RFI is a polygenic trait exhibiting a dynamic genetic basis and genetic variation distinct from that underlying expected maintenance requirements and milk energy output. PMID- 28843689 TI - In vitro gas and methane production of silages from whole-plant corn harvested at 4 different stages of maturity and a comparison with in vivo methane production. AB - The current study investigated the relationship between in vitro and in vivo CH4 production by cows fed corn silage (CS)-based rations. In vivo CH4 production was measured in climate respiration chambers using 8 rumen-cannulated Holstein Friesian cows. In vitro CH4 production was measured using rumen fluid from the 8 cows that were fully adapted to their respective experimental rations. The animals were grouped in 2 blocks, and randomly assigned to 1 of the 4 total mixed rations (TMR) that consisted of 75% experimental CS, 20% concentrate, and 5% wheat straw [dry matter (DM) basis]. The experimental CS were prepared from whole plant corn that was harvested at either a very early (25% DM), early (28% DM), medium (32% DM), or late (40% DM) stage of maturity. The 4 experimental TMR and the corresponding CS served as substrate in 2 separate in vitro runs (each run representing 1 block of 4 animals) using rumen fluid from cows fed the TMR in question. No relationship was found between in vivo CH4 production and in vitro CH4 production measured at various time points between 2 and 48 h. None of the in vitro gas production (GP) and CH4 production parameters was influenced by an interaction between substrate and origin of rumen fluid. In vitro measured 48-h GP was not affected by the maturity of whole-plant corn, irrespective whether CS alone or as part of TMR was incubated in adapted rumen inoculum. Incubation of the experimental TMR did not affect the kinetics parameters associated with gas or CH4 production, but when CS alone was incubated the asymptote of GP of the soluble fraction was slightly decreased with increasing maturity of CS at harvest. In vitro CH4 production expressed as a percent of total gas was not affected by the maturity of whole-plant corn at harvest. Several in vitro parameters were significantly affected (GP) or tended to be affected (CH4) by diet fed to donor cows. It was concluded that the current in vitro technique is not suitable to predict in vivo CH4 production from CS-based rations. PMID- 28843690 TI - Process efficiency of casein separation from milk using polymeric spiral-wound microfiltration membranes. AB - Microfiltration is largely used to separate casein micelles from milk serum proteins (SP) to produce a casein-enriched retentate for cheese making and a permeate enriched in native SP. Skim milk microfiltration is typically performed with ceramic membranes and little information is available about the efficiency of spiral-wound (SW) membranes. We determined the effect of SW membrane pore size (0.1 and 0.2 um) on milk protein separation in total recirculation mode with a transmembrane pressure gradient to evaluate the separation efficiency of milk proteins and energy consumption after repeated concentration and diafiltration (DF). Results obtained in total recirculation mode demonstrated that pore size diameter had no effect on the permeate flux, but a drastic loss of casein was observed in permeate for the 0.2-um SW membrane. Concentration-DF experiments (concentration factor of 3.0* with 2 sequential DF) were performed with the optimal 0.1-um SW membrane. We compared these results to previous data we generated with the 0.1-um graded permeability (GP) membrane. Whereas casein rejection was similar for both membranes, SP rejection was higher for the 0.1-um SW membrane (rejection coefficient of 0.75 to 0.79 for the 0.1-um SW membrane versus 0.46 to 0.49 for the GP membrane). The 0.1-um SW membrane consumed less energy (0.015-0.024 kWh/kg of permeate collected) than the GP membrane (0.077 0.143 kWh/kg of permeate collected). A techno-economic evaluation led us to conclude that the 0.1-um SW membranes may represent a better option to concentrate casein for cheese milk; however, the GP membrane has greater permeability and its longer lifetime (about 10 yr) potentially makes it an interesting option. PMID- 28843691 TI - Dietary supplementation with dried olive pomace in dairy cows modifies the composition of fatty acids and the aromatic profile in milk and related cheese. AB - This study aimed to evaluate the effect of dietary integration of dried olive pomace (DOP), a by-product of olive oil separation, on nutritional and aromatic properties of milk and cheese. Twenty dairy cows were divided into 2 groups that were balanced for milk yield, parity, and days in milk. The control group was fed a conventional diet (20 kg of dry matter/head per day), whereas the experimental group (EG) received the conventional diet supplemented with DOP as 10% of dry matter. During the trial, milk yield was recorded and the samples of milk, cheese, total mixed rations, and DOP were collected and analyzed to determine the chemical-nutritional composition and aromatic profile. Atherogenic and thrombogenic indices were calculated on the basis of the fatty acid (FA) profile of milk and cheese. Data were analyzed according to the mixed model for milk yield and chemical composition, including cows nested within treatment as a random effect, whereas the general linear model was used for the analysis of cheese parameters. Differences were assessed by Tukey's test. The EG diet had a lower content of palmitic, stearic, and linoleic acids and a higher level of oleic acid compared with the control. Dietary DOP integration did not affect milk yield and composition with the exception of protein content, which was greater in EG and significantly affected by diet and period. Instead, period was found to be significant for fat and casein in both groups. Dietary supplementation with DOP modified the FA profile of milk and cheese. There was a decrease in short- and medium-chain FA, but significance was achieved only for palmitic acid. The stearic, isomer trans of oleic (in particular vaccenic acid), oleic, and isomer trans of linoleic acids significantly increased. Monounsaturated FA increased in EG milk and cheese and saturated FA were significantly lower, whereas no difference was marked between the groups regarding level of polyunsaturated FA. Supplementation with DOP reduced atherogenic and thrombogenic indices and increased conjugated linoleic acid in both milk and cheese. The free fatty acids, ketones, lactones, esters, and phenylalanine catabolites were increased in raw milk, whereas only leucine metabolism was affected by diet in pasteurized milk cheese at both 1 and 30 d of ripening. The present results pointed out that DOP supplementation may improve the nutritional and nutraceutical properties and modify the aroma of milk and derived cheese. PMID- 28843692 TI - Invited review: A perspective on the future of genomic selection in dairy cattle. AB - Genomic evaluation has been successfully implemented in the United States, Canada, Great Britain, Ireland, New Zealand, Australia, France, the Netherlands, Germany, and the Scandinavian countries. Adoption of this technology in the major dairy producing countries has led to significant changes in the worldwide dairy industry. Gradual elimination of the progeny test system has led to a reduction in the number of sires with daughter records and fewer genetic ties between years. As genotyping costs decrease, the number of cows genotyped will continue to increase, and these records will become the basic data used to compute genomic evaluations, most likely via application of "single-step" methodologies. Although genomic selection has been successful in increasing rates of genetic gain, we still know very little about the genetic architecture of quantitative variation. Apparently, a very large number of genes affect nearly all economic traits, in accordance with the infinitesimal model for quantitative traits. Less emphasis in selection goals will be placed on milk production traits, and more on health, reproduction, and efficiency traits and on environmentally friendly production with reduced waste and gas emission. Genetic variance for economic traits is maintained by the increase in frequency of rare alleles, new mutations, and changes in selection goals and management. Thus, it is unlikely that a selection plateau will be reached in the near future. PMID- 28843693 TI - Leukocyte profile, gene expression, acute phase response, and metabolite status of cows with sole hemorrhages. AB - Sole hemorrhages result from disruption to normal claw horn formation and are caused by a variety of internal and external factors. Evidence suggests that they are painful, although they do not usually cause clinical lameness and are difficult to detect by observing cow gait. Little is known about how or whether sole hemorrhages affect the cow systemically. This study compared hematology profile, leukocyte gene expression, and physiological responses of cows with no/mild hemorrhages (category 1; n = 17), moderate hemorrhages (category 2; n = 18), and severe hemorrhages (category 3; n = 12). At approximately 100 d in milk, all cows in the study herd (n = 374) were locomotion scored before hoof examination. The cows included in the study were not clinically lame and had no other hoof disorder. Blood samples were taken from all cows within 24 h of selection. Leukocyte counts were obtained using an automated cell counter, cortisol and dehydroepiandrosterone (DHEA) concentration by ELISA, and plasma haptoglobin, urea, total protein, creatine kinase and glucose were analyzed on a clinical chemistry analyzer. Expression of 16 genes associated with lameness or stress were estimated using real-time quantitative PCR. Data from cows within each category were compared using the Mixed procedure in SAS (version 9.3; SAS Institute Inc., Cary, NC). Fixed effects included hemorrhage severity category and lactation number, with days in milk and body condition score included as covariates. Locomotion score worsened as sole hemorrhage category worsened. Locomotion score of category 1 cows tended to be lower than that of category 2 cows and was lower than that of category 3 cows. The locomotion score of category 3 cows was also greater than that of categories 1 and 2 combined. Category had no effect on leukocyte number, on any of the individual leukocyte cell numbers or percentages, cortisol or DHEA concentration, cortisol:DHEA ratio, or relative expression of any of the genes investigated, and we detected no differences in plasma glucose, protein, or creatine kinase concentrations between categories. However, category 3 cows had greater plasma concentrations of haptoglobin and tended to have lesser concentrations of plasma urea than category 1 and 2 cows. The differences in gait between cows with no or minor sole hemorrhages and cows with severe hemorrhages indicate that hemorrhages may be associated with discomfort or pain. Nevertheless, the only physiological measure that changed with increasing locomotion score was plasma haptoglobin concentration. Haptoglobin has previously been found to be elevated in lame cows, and thus shows promise as a marker for limb pain. PMID- 28843694 TI - The global regulator CodY responds to oxidative stress by the regulation of glutathione biosynthesis in Streptococcus thermophilus. AB - CodYst is a global transcriptional regulator that modulates the metabolic network in Streptococcus thermophilus ST2017. In this study, experimental data showed that the cell survival of the codYst defective mutant obviously declined at the presence of 10 mM H2O2, suggesting CodYst was involved in response to the oxidative stress. To investigate this phenomenon, transcriptome analysis and real time-quantitative PCR were performed and the results indicated that the transcriptional level of a bifunctional glutathione synthetase gene (gshF) was downregulated by about 3-fold in the codYst defective mutant, along with a decrease by 20% of the glutathione yield compared with the wild-type in minimal chemical defined medium, whereas half of the viable cells remained after H2O2 challenge. In vitro gel shift assays showed that the purified CodYst could bind to the promoter region of gshF, with a conserved CodYst box, confirming the regulation of CodYst on the gshF gene. To our knowledge, this is first report of CodYst in response to oxidative stress mediated by the regulation of gshF in S. thermophilus. PMID- 28843695 TI - Effect of hormonal and energy-related factors on plasma adiponectin in transition dairy cows. AB - In transition dairy cows, plasma levels of the insulin-sensitizing hormone adiponectin fall to a nadir at parturition and recover in early lactation. The transition period is also characterized by rapid changes in metabolic and hormonal factors implicated in other species as positive regulators of adiponectin production (i.e., negative energy balance, lipid mobilization) and others as negative regulators (i.e., reduced leptin and insulin and increased growth hormone and plasma fatty acids). To assess the role of onset of negative energy balance and lipid mobilization after parturition, dairy cows were either milked thrice daily (lactating) or never milked (nonlactating) for up to 4 wk after parturition. Plasma adiponectin was 21% higher across time in nonlactating than lactating cows. Moreover, nonlactating cows recovered plasma adiponectin at similar rates as lactating cows even though they failed to lose body condition. Next, we assessed the ability of individual hormones to alter plasma adiponectin in transition dairy cows. In the first experiment, dairy cows received a constant 96-h intravenous infusion of either saline or recombinant human leptin starting on d 8 of lactation. In the second experiment, dairy cows were studied in late pregnancy (LP, starting on prepartum d -31) and again in early lactation (EL, starting on d 7 postpartum) during a 66-h period of basal sampling followed by 48 h of hyperinsulinemic-euglycemia. In the third experiment, cows were studied either in LP (starting on d -40 prepartum) or EL (starting on d 7 postpartum) during a 3-h period of basal sampling followed by 5 d of bovine somatotropin treatment. Plasma adiponectin was reduced by an average of 21% in EL relative to LP in these experiments, but neither leptin, insulin, or growth hormone treatment affected adiponectin in LP or EL. Finally, the possibility that plasma fatty acids repress plasma adiponectin was evaluated by intravenous infusion of a lipid emulsion in nonpregnant, nonlactating cows in the absence or presence of glucagon for 16 consecutive hours. The intralipid infusion increased plasma fatty acid concentration from 102 to over 570 uM within 3 h but had no effect on plasma adiponectin irrespective of presence or absence of glucagon. Overall, these data suggest that energy balance around parturition may regulate plasma adiponectin but do not support roles for lipid mobilization or sustained changes in the plasma concentration of leptin, insulin, growth hormone, or fatty acids. PMID- 28843697 TI - Reply to the letter to the editor regarding "Comment on an evaluation of oxidative and nitrosative stress in children-who-stutter and its relationship to severity". PMID- 28843696 TI - NGF protects endothelial cells from indomethacin-induced injury through activation of mitochondria and upregulation of IGF-1. AB - BACKGROUND/AIMS: Endothelial cells (ECs) lining blood vessels are critical for delivery of oxygen and nutrients to all tissues and organs and play a crucial role in the regeneration of blood vessel following tissue injury. ECs are also major targets of injury by a variety of noxious factors [e.g., ethanol and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin, diclofenac], especially in gastric mucosa that has direct exposure to these agents. In this study, we investigated whether nerve growth factor (NGF) can protect gastric microvascular ECs (GECs) from injury by indomethacin (INDO) and the mechanisms involved. METHODS: GECs were isolated from rat gastric mucosa and pre-treated with either vehicle or NGF (100ng/ml) for 30min to 4h followed by treatment with vehicle or 0.25mM INDO for 4h. STUDIES: 1) cell viability using Calcein AM live cell tracking dye, 2) mitochondrial structure and function using MitoTracker, molecular probe that stains mitochondria in live cells in a manner dependent on mitochondrial membrane potential (MMP), 3) in vitro angiogenesis - endothelial tube formation on Matrigel, 4) expression and subcellular localization of NGF receptor, TrkA, and 5) expression of IGF-1 protein. RESULTS: Treatment with INDO reduced GEC viability and in vitro angiogenesis and induced mitochondrial injury and MMP depolarization. NGF pre-treatment protected GECs from INDO-induced injury preventing both INDO-induced MMP depolarization and reduced in vitro angiogenesis. The NGF high affinity receptor, TrkA, was localized in GECs to both cell membrane and mitochondria. NGF treatment of GECs also resulted in increased IGF-1 protein expression. CONCLUSIONS: 1) NGF protects GECs against IND-induced injury. 2) Mitochondria are major targets of both INDO induced injury and NGF afforded protection of GECs. 3) TrkA expression in the mitochondria of GECs indicates that the protection afforded by NGF is partly mediated by its direct action on mitochondria. 4) NGF prevents MMP depolarization and increases expression of IGF-1 protein in GECs. These studies indicate that NGF may play a protective role against injury to GECs; and, that maintenance of mitochondrial structure and function is one of the mechanisms. PMID- 28843698 TI - Statistical verification on the effect of hearing loss on speech-evoked auditory brainstem response. PMID- 28843699 TI - Differential dose absorptions for various biological tissue equivalent materials using Gafchromic XR-QA2 film in diagnostic radiology. AB - Phantoms are devices that simulate human tissues including soft tissues, lungs, and bones in medical and health physics. The purpose of this work was to investigate the differential dose absorption in several commercially available low-cost materials as substitutes to human tissues using Gafchromic XR-QA2 film. The measurement of absorbed dose by different materials of various densities was made using the film to establish the relationship between the absorbed dose and the material density. Materials investigated included soft board materials, Perspex, chicken bone, Jeltrate, chalk, cow bone, marble, and aluminum, which have varying densities from 0.26 to 2.67gcm-3. The absorbed dose increased as the density and atomic number of the material increased. The absorbed dose to the density can be well represented by a polynomial function for the materials used. PMID- 28843700 TI - Glucose metabolism in bone. AB - The adult human skeleton is a multifunctional organ undergoing constant remodeling through the opposing activities of the bone-resorbing osteoclast and the bone-forming osteoblast. The exquisite balance between bone resorption and bone formation is responsible for bone homeostasis in healthy adults. However, evidence has emerged that such a balance is likely disrupted in diabetes where systemic glucose metabolism is dysregulated, resulting in increased bone frailty and osteoporotic fractures. These findings therefore underscore the significance of understanding the role and regulation of glucose metabolism in bone under both normal and pathological conditions. Recent studies have shed new light on the metabolic plasticity and the critical functions of glucose metabolism during osteoclast and osteoblast differentiation. Moreover, these studies have begun to identify intersections between glucose metabolism and the growth factors and transcription factors previously known to regulate osteoblasts and osteoclasts. Here we summarize the current knowledge in the nascent field, and suggest that a fundamental understanding of glucose metabolic pathways in the critical bone cell types may open new avenues for developing novel bone therapeutics. PMID- 28843701 TI - Fine particulate matter exposure induces cell cycle arrest and inhibits migration and invasion of human extravillous trophoblast, as determined by an iTRAQ-based quantitative proteomics strategy. AB - Long-term exposure to fine particulate matter (PM2.5) may cause adverse pregnancy outcomes but the mechanisms are not clear. Our research confirms that PM2.5 induced DNA damage, and inhibited cell proliferation in HTR-8/SVneo cells, presenting in a dose- and time-dependent manners. Using quantitative proteomics, the 182 and 486 differentially expressed proteins in cells treated with 120MUgml 1 PM2.5 for 24 and 48h were involved in many critical biological processes, including of cell proliferation, response to DNA damage, regulation of small GTPase mediated signal transduction, and etc. Further validation indicated that PM2.5 blocked the cell cycle at the G2/M phase through activation of the ATR Cyclin E1/Cdk6 pathway, and it reduced the migration and invasion by upregulating TIMP1 and TIMP2 expression and downregulating Collagen I expression. Our findings were consistent with the observed effects of PM2.5 on cell cycle arrest and inhibition of migration and invasion in human extravillous trophoblast. PMID- 28843702 TI - Quantum dots mediated embryotoxicity via placental damage. AB - The increasing use of nanoparticles in consumer products raises the concerns of their safety. This study investigated the biological effects of quantum dots (QD) exposure to rats during pregnancy. CdTe QD were injected on the 13th gestation day. Morphological features of 121 fetuses and histological analysis of placentas were performed on the 20th gestation day. The results showed that QD exhibit dose dependent embryotoxicity: survival rates of fetuses were 97% (5mg/kg dose), 86% (10mg/kg dose) and 43% (20mg/kg dose). QD exposure also resulted in the reduction of fetal body length and mass, disturbed ossification of limbs and caused placental tissue damage. QD exhibit no teratogenic effects at the applied doses. It is hypothesized that embryogenesis was impeded due to the placental damage rather than QD penetration and accumulation in the fetuses. To conclude, mothers should be protected from QD exposure during pregnancy. PMID- 28843703 TI - Asymmetric DNA methylation between sister chromatids of metaphase chromosomes in mouse embryos upon bisphenol A action. AB - Earlier we showed that asymmetric methylation of sister chromatids (AMSC) was a specific characteristic of differentiation potency, and supposed that AMSC could be a useful marker of environmental impact connected with differentiation and/or dedifferentiation. Here we investigated the level of AMSC in chromosomes and the nuclei methylation in mouse preimplantation and postimplantation embryos, in comparison with the undifferentiated cells of mouse embryonal carcinoma cell line F9, and human differentiated HEK293 cells upon BPA influence. We found that exposure of mouse preimplantation embryos to BPA caused a significant decrease in the level of AMSC in chromosomes and the nuclei methylation. The BPA exposure of potentially differentiating F9 cells had no any influence on DNA methylation in nuclei but significantly decreased the number of AMSC. The level of DNA methylation and AMSC in HEK293 cells were not also changed. These data indicate that BPA exerts significant influence on differentiating and potentially differentiable cells. The most sensitive BPA targets are preimplantation embryos and stem cells. PMID- 28843704 TI - Anogenital distance: A longitudinal evaluation of its variants and indices in boys and girls of Sonora, Mexico. AB - There is no consensus on which anogenital distance (AGD) variant to use and how to adjust it by body size in humans. This study quantitatively evaluated AGD variants and body size adjustments to determine which would be the best choice. AGD variants, height, and weight were measured on five occasions during the first year of life of 307 infants. The ratio of anoscrotal distance (ASD) in boys and anofourchette distance (AFD) in girls increased from 1.9 at birth to 2.3 at 12 months of age. Each AGD variant was divided by each body size variable to generate different indices. Such indices were standardized to make them comparable when analyzing their performance through mixed models. ASD and AFD adjusted by height generated precise (p<0.05) AGD indices: 0.4-0.5 and 0.2, respectively. Results suggest that the best body size adjustment for all AGD variants in the first year of life is height. PMID- 28843705 TI - Recurrent conjunctival atypical fibroxanthoma in Pigmentosum Xeroderma. AB - CASE REPORT: A 7 year-old boy with Xeroderma Pigmentosum (XP) and who presents a recurrent conjunctival atypical fibroxanthoma after two surgeries. This is the third procedure and the patient is treated with a surgical excision of the tumour and cryotherapy at the surgical bed. Due to the risk of recurrence, topical Mitomycin C 0,02% was added at post-operative care achieving a good clinical outcome. DISCUSSION: Surgical exeresis with cryotherapy and topical Mitomycin C is an effective treatment for a case of an atypical fibroxanthoma with a high potential for recurrence and invasion. An ophthalmologic follow-up is required for these patients, as well as general paediatric care and support aids. PMID- 28843706 TI - Variation of facet joint orientation and tropism in lumbar degenerative spondylolisthesis and disc herniation at L4-L5: A systematic review and meta analysis. AB - Although degenerative spondylolisthesis (DS) and lumber disc herniation (LDH) are common causes of back pain, the associations between the lumbar facet joint angle orientation and tropism in these conditions are still contentious. The objective of the meta-analysis was to identify the role of facet joint orientation and tropism on the development of lumbar degenerative disease, including DS and LDH. Electronic searches of PubMed and Embase were conducted up to April 2017. P value<0.05 was regarded as significant. Seventeen studies were included in this meta-analysis. Depending on the analysis, patients with DS have more sagittal orientated facet joints compared with control subjects (weighted mean difference [WMD] -10.5, 95% confidence interval [CI] -11.71 to -8.60; P<0.00001). We also found that DS patients have more remarkable facet joint tropism (WMD 1.84, 95% CI 0.77-2.91; P=0.0007). No significant correlation was observed between facet joint angle with LDH. There is a possibility that morphological deformity of facet joints could be associated with accelerated degeneration of stabilizing structures and affect the progress of DS. Our conclusion did not support the correlation between LDH and abnormalities of the facet joint. We tend to assume that the mechanics related to biomechanical changes in LDH disease progress might be more sophisticated. PMID- 28843707 TI - Cerebral pseudo-tumoral neuro-Behcet: Histological demonstration of an inflammatory and vascular disease. PMID- 28843709 TI - PD-L1 in breast cancer: comparative analysis of 3 different antibodies. AB - The interaction of programmed cell death-1 and its ligand-1 (PD-L1) serves as a regulatory check against excessive immune response to antigen and autoimmunity. We compared the performance of 3 different PD-L1 antibodies (Ventana SP263, Dako 22C3, and BioCare RbMCAL10 antibodies) in 136 invasive ductal carcinoma specimens including 43 primary, 48 locally metastatic, and 46 distantly metastatic diseases. PD-L1 expression was correlated with clinicopathologic parameters including tumor size, grade, lymphovascular invasion, estrogen receptor, progesterone receptor, HER2, Ki67, molecular type, and triple-negative status. There was excellent agreement between the 3 antibodies, with highly significant kappa values (P<=.001). PD-L1 expression was more likely to be associated with higher tumor grade and estrogen receptor-negative, progesterone receptor negative, triple-negative, and highly proliferative tumors (P<.001). When we studied PD-L1 expression at 0, 1%-9%, 10%-49%, and >=50% cutoff points by the 3 antibodies, there were 20 discordant cases between the antibodies. Sixteen were of inconsequential impact as far as low and high PD-L1 expression. The 4 differences between antibodies did exhibit an interesting pattern of expression, where there was a general agreement between the BioCare and Ventana antibodies with consistently higher PD-L1 expression compared with the Dako antibody. Given the high concordance, it is not surprising that all 3 antibodies demonstrated the same associations with all pathologic and clinical parameters studied. Standardization studies to identify reliable biomarkers that help in patient selection for immune therapy to improve the risk-benefit ratio for these drugs are still needed. PMID- 28843708 TI - Synthesis and biological evaluation of pyridinium-functionalized carbazole derivatives as promising antibacterial agents. AB - Various pyridinium-functionalized carbazole derivatives were constructed by coupling the key fragments of carbazole skeleton and pyridinium nucleus in a single molecular architecture. Antibacterial bioassays revealed that some of the title compounds displayed impressive bioactivities against plant pathogens such as Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri with minimal EC50 values of up to 0.4, 0.3, and 0.3mg/L, respectively. These bioactivities were achieved by systematically tuning and optimizing bridging linker, alkyl length of the tailor, and substituents on the carbazole scaffold. Compared with the bioactivity of the lead compound (AP-10), antibacterial efficacy dramatically increased by approximately 13-, 104- and 21 fold. This finding suggested that these compounds can serve as new lead compounds in research on antibacterial chemotherapy. PMID- 28843710 TI - Renal collision tumor composed of oncocytoma and mucinous tubular and spindle cell carcinoma: case report of an unprecedented entity. AB - Primary renal collision tumors composed of 2 histologically distinct components are rare with only isolated case reports in the medical literature. Oncocytoma is a benign renal neoplasm, which is thought to originate from distal tubular epithelial cells. Mucinous tubular and spindle cell carcinoma (MTSCC) of kidney is a rare, relatively recently described renal neoplasm that was first included in the 2004 World Health Organization renal cell carcinoma (RCC) classification as a distinct entity. Current studies suggest that the tumor originates from the proximal nephron, although it is still controversial. The presence of concurrent oncocytoma with conventional (clear cell) RCC, chromophobe RCC, and papillary RCC has been previously described. However, the association of oncocytoma with MTSCC has not yet been reported to our knowledge. Herein, we report the first case of a renal collision tumor composed of oncocytoma and MTSCC. PMID- 28843711 TI - Utility of Sox10 labeling in metastatic breast carcinomas. AB - Sox10 labeling by immunohistochemistry has been primarily reported in tumors of neural crest origin, such as nerve sheath tumors and melanoma. However, Sox10 also labels primary breast carcinomas, particularly those with the basal-like, triple-negative phenotype. However, the utility of Sox10 labeling in metastatic breast carcinomas has not been reported. Here, we prospectively evaluated Sox10 labeling in surgically resected metastatic breast carcinomas from 26 patients sampled on tissue microarrays. In this cohort, Sox10 labeling was seen in 3 metastatic breast carcinomas (12%), all of which were grade III, triple-negative ductal carcinomas metastatic to the brain (n=2) or lung (n=1). Overall, 38% of triple-negative metastases were Sox10 positive, compared to 0% of estrogen receptor (ER)+ or human epidermal growth factor 2 (HER-2) + metastases (P=.045). In addition, we retrospectively reviewed the use of Sox10 immunohistochemistry in metastatic carcinomas in our clinical practice. We identified 21 cases from January 2012-July 2017 in which Sox10 immunohistochemistry was ordered on clinical sign-out in the work-up of a metastatic carcinoma as being of possible breast origin. Overall, Sox10 labeled 57% (n=12) of all evaluated metastatic carcinomas. All of the Sox10+ tumors were ER-, such that 71% of ER- carcinomas were Sox10+ in comparison to 0% of ER+ carcinomas (P=0.049). In conclusion, the differential diagnosis of a Sox10+ malignancy of unknown origin should not be limited to metastatic melanoma. Sox10 labeling is seen in a subset of metastatic triple-negative breast carcinomas, supporting its use as a marker of breast origin in this setting. PMID- 28843712 TI - Atypical mitoses in pleomorphic lipomas. PMID- 28843713 TI - Postablation neuroma of the myometrium-a report of 5 cases. AB - When hysterectomy is performed for chronic pelvic pain, routine pathology examination often provides no explanation. However, analysis of small uterine nerves using immunostains may help to address this deficiency. Small uterine nerves tend to be sparse or absent in wide areas of normal myometrium. Some studies of uterine nerves have suggested that endometriosis, adenomyosis, and fibroids are not inherently painful, with increased small nerves in the inner uterine wall associated with the history of pelvic pain. Although such areas may appear normal on hematoxylin and eosin (H&E), we have found a subtle inner wall lesion termed inner myometrial elastosis, best detected with trichrome or elastic stains, which may be a reaction to microscopic tears of inner myometrium. Such tears may induce increased inner wall innervation via the generation of nerve growth factor in granulation tissue. In the course of studying uterine nerves with immunostains, we found 5 cases with florid nerve proliferation, after deep endometrial ablation for abnormal uterine bleeding led to increased pelvic pain. We suggest that immunostains for postablation neuromas should be done in hysterectomies when pelvic pain increases after endometrial ablation. This may offer gynecologists and their patients an objective finding with a rational, scientific explanation for the pelvic pain. PMID- 28843714 TI - Pancreatectomy with venous resection for pT3 head adenocarcinoma: Perioperative outcomes, recurrence pattern and prognostic implications of histologically confirmed vascular infiltration. AB - BACKGROUND: The outcomes of pancreatectomy with superior mesenteric vein (SMV) or portal vein (PV) resection have been mixed. This study investigated the morbidity and mortality profile after SMV-PV resection in comparison with standard pancreatectomy. Furthermore, we assessed whether tumors with histologically proven SMV-PV infiltration differ from other pT3 neoplasms in terms of recurrence pattern and survival. METHODS: All patients with a pT3 head adenocarcinoma resected from 2000 to 2013 were analyzed retrospectively. In the SMV-PV resection group, information on venous wall status was obtained through pathologic reports. Standard statistical methods were used for data analysis. RESULTS: The study population consisted of 651 patients, of whom 81 (12.4%) underwent synchronous SMV-PV resection. Venous resection was not associated with a higher rate of postoperative complications (60.5% versus 50.2%) and mortality (1.2% versus 1.1%) in comparison with standard pancreatectomy. Vascular infiltration was confirmed pathologically in 56/81 patients (69.1%). The median disease-specific survival of the entire population was 27 months (95% CI 24.6-29.3), with a 5-year survival rate of 20.5%. The median recurrence-free survival was 18 months (95% CI 15.0 20.9). On multivariate analysis, ASA score, preoperative pain, Ca 19-9 levels, tumor grade, R-status, lymph-vascular invasion, N-status, and adjuvant therapy resulted to be survival predictors. Similarly, Ca 19.9 levels, R-status, and N status were predictors of recurrence. SMV-PV infiltration was not a significant prognostic factor. CONCLUSION: Morbidity and mortality rates of pancreatectomy with SMV-PV resection are comparable with standard pancreatectomy. Pancreatic head adenocarcinoma with histologically confirmed SMV-PV infiltration does not segregate prognostically from other pT3 tumors. PMID- 28843715 TI - Safety and efficacy of angioembolisation followed by endoscopic ultrasound guided transmural drainage for pancreatic fluid collections associated with arterial pseudoaneurysm. AB - BACKGROUND AND AIMS: Arterial pseudoaneurysms associated with pancreatic fluid collections (PFC's) are serious complication of pancreatitis. There is insufficient data on safety of endoscopic ultrasound (EUS) guided drainage in these patients. AIM: To retrospectively analyze results of combination of angioembolisation followed by EUS guided transmural drainage of PFC's associated with pseudoaneurysms. METHODS: Retrospective analysis of data base of eight patients (all males; mean age: 36.9 + 9.2 years; age range: 26-51 years) who underwent angioembolisation of pseudoaneurysm followed by EUS guided transmural drainage of the PFC's. RESULTS: The median size of PFC was 6.5 cm (range 5-14 cm) with 7 patients having acute pancreatitis and one patient having idiopathic chronic pancreatitis. The etiology for acute pancreatitis was alcohol in 5 patients, trauma and gall stones in one patient each. Six patients had walled off pancreatic necrosis (WOPN) and 2 had pseudocysts. The pseudoaneurysm was located in splenic artery (5 patients), gastro-duodenal artery (2) and short gastric artery (1). All patients underwent successful digital subtraction angiography followed by angioembolisation. EUS guided transmural drainage was successfully done through stomach in 7 patients and via duodenum in one patient. The PFC's resolved in 3.9 + 2.5 weeks with no recurrence of either PFC or bleed over a follow up period of up to 24 months. No significant complications were observed in any patient. CONCLUSIONS: Arterial pseudoaneurysms associated with PFC's can be successfully and safely treated with combination of initial radiological obliteration of the pseudoaneurysm followed by EUS guided transmural drainage. PMID- 28843716 TI - Outcome following osteosynthesis or primary arthrodesis of calcaneal fractures: A cross-sectional cohort study. AB - BACKGROUND: Calcaneal fractures are uncommon and have a substantial impact on hindfoot function and quality of life. Several surgical treatment options are available; both in surgical approach and type of operation. The aim of this study was to compare functional outcome and quality of life following ORIF and primary arthrodesis. Furthermore, predictors of worse functional outcome were explored. METHODS: A retrospective cross-sectional cohort study was performed in patients with surgical fixation of a calcaneal fracture with a minimum follow-up of 18 months. Patients received ORIF through the 1) Extended Lateral Approach (ELA), 2) Sinus Tarsi Approach (STA) or 3) primary arthrodesis via STA. Participants were presented a questionnaire containing demographics, the AOFAS hindfoot scale, Foot Function Index, SF-36, EQ-5D and patient satisfaction. RESULTS: In total 95 patients participated in this study. The three groups were comparable regarding patient characteristics. A median score of 74.5 points on the AOFAS hindfoot scale and 11.9 on the FFI was found for the entire group. There were no statistically significant differences between patients with ORIF of primary arthrodesis. Patients scored a median of 49.0 on the Physical Component Scale of the SF-36 and 55.4 on the Mental Component Scale. On the EQ-5D patients scored a median of 0.8 points. Again no statistically significant differences were observed between the three subgroups. Socio-economic status was the only statistically significant predictor of worse functional outcome (beta: 4.06, 95% CI: 0.50-7.62) after multivariable analysis. INTERPRETATION: Good midterm outcomes following in terms of functional outcome and in quality of life are observed. We observed no statistical significant difference in functional outcome between patients with ORIF and patients with primary arthrodesis. The only predictor of worse functional outcome is a lower socio-economic status. PMID- 28843717 TI - Variables associated with pulmonary thromboembolism in injured patients: A systematic review. AB - BACKGROUND: Pulmonary thromboembolism (PTE) is a dangerous complication of traumatic injury, with varied risk profiles and treatment options. This review aims to describe reported incidence and variables associated with PTE among severely injured patients. METHODS: Searches were conducted using PubMed, Cochrane and MEDLINE. Relevant studies were identified by two independent reviewers based on predetermined inclusion criteria. Incidence of PTE was the primary outcome measure. Variables associated with PTE was the secondary outcome measure. The Newcastle-Ottawa Scale was used to assess quality of included studies. RESULTS: There were eight studies that satisfied inclusion criteria. The diagnosed incidence of PTE in these populations ranged from 0.35 to 24%. The most common variables associated with PTE were pelvic or lower limb injury, chest injury, higher total Injury Severity Score, male sex and age. Variables that were less commonly associated with PTE were previous warfarin use, head injury, high serum lactate, soft tissue injury, more than one operation, more than three days on a ventilator, presence of a subclavian central venous catheter, need for a blood transfusion, systolic blood pressure <90mmHg, abdominal injury, presence of a deep venous thrombosis, inferior vena cava filter placement and isolated liver spleen or spinal injuries. CONCLUSIONS: The reported incidence of PTE after major trauma is variable and dependent on inclusion criteria, diagnostic criteria and study design. Identified variables differed to those reported for venous thromboembolism in other populations. It is difficult to predict populations at risk of clinically significant PTE following injury using available evidence. Further studies linked to patient-specific variables will assist in more precise risk-stratification and interventions. PMID- 28843718 TI - Prospective randomized study evaluating the effects of PerClot(r) (Polysaccharide Hemostatic System) application in patients with high bleeding risk undergoing cardiac rhythm device implantation. AB - BACKGROUND: Thus far, the topic hemostatic agent PerClot(r) is used for surgical procedures. Data about the use of PerClot(r) for cardiac-rhythm-devices (CRD) implantation are missing. The aim of this study was to evaluate the safety and efficacy of PerClot(r) in patients with high bleeding risk. METHODS AND RESULTS: In this prospective randomized study we planned to include 150 patients admitted for CRD-Implantation receiving anticoagulation and/or dual-antiplatelet-therapy. Participants were randomized to receive PerClot(r) versus standard-of-care. The primary endpoint was the incidence of pocket hematoma. Safety endpoint was pocket infection. After a planned safety-interim-analysis the study was terminated early because of safety concerns. 51 patients were included. The two groups were comparable with regard to age (73+/-11years vs. 74+/-10years; p=0.71), CHA2DS2VASc (3.6+/-1.5 vs. 4.0+/-1.5; p=0.27) and HASBLED-Score (2.4+/-1.1 vs. 2.5+/-1.0; p=0.98), CRD or procedure type, anticoagulant or anti-platelet therapy. The use of PerClot(r) resulted in a higher incidence of postoperative fever (7 (28%) vs. 0 (0%); p=0.004), higher C-Reactive Protein (66.1+/-50.5mg/l vs. 25.9+/-22.5mg/l; p=0.002); and higher postoperative white blood cell count (13.5+/-4.3/nl vs. 8.8+/-2.6/nl; p<0.001). Hematoma formation did not differ significantly (p=0.14). Reoperation was not necessary in any patient. CONCLUSION: This first randomized controlled study for the topical use of the hemostatic agent PerClot(r) in CRD implantation was terminated early by the safety monitoring board because of an augmented rate of fever and inflammatory markers in the PerClot(r) group. The addition of PerClot(r) does not suggest a benefit with regard to the frequency of pocket hematoma. PMID- 28843719 TI - Incidence, risk factors, and mortality of neonatal and late-onset dilated cardiomyopathy associated with cardiac neonatal lupus. AB - BACKGROUND: Dilated cardiomyopathy (DCM), a well-known complication of cardiac neonatal lupus, is associated with high mortality rate. Its risk factors remain unclear. METHODS: We analyzed occurrence of postnatal DCM among children with high-degree congenital heart block (CHB) and mothers with anti-SSA and/or anti SSB antibodies. RESULTS: Among 187 neonates with CHB, 35 (18.8%, one missing data) had DCM and 22 (11.8%) died during a median follow-up of 7years [range: birth-36years]. On multivariate analysis, factors associated with postnatal DCM were in utero DCM (P=0.0199; HR=3.13 [95% CI: 1.20-8.16]), non-European origin (P=0.0052; HR=4.10 [95% CI: 1.81-9.28]) and pacemaker implantation (P=0.0013; HR=5.48 [95% CI: 1.94-15.47]). Postnatal DCM could be categorized in two subgroups: neonatal DCM (n=13, diagnosed at a median age of 0day [birth-4days]) and late-onset DCM (n=22, diagnosed at a median age of 15.2months [3.6months 22.8years]). Factors associated with neonatal DCM were in utero DCM, hydrops, endocardial fibroelastosis and pericardial effusion, whereas those associated with late-onset DCM were non-European origin, in utero mitral valve insufficiency, and pacemaker implantation. Fluorinated steroids showed no protective effect against late-onset DCM (P=0.27; HR=1.65 [95% CI: 0.63-4.25]). Probability of survival at 10years was 23.1% for newborns diagnosed neonatally with DCM, 53.9% for those who developed late-onset DCM, and 98.6% for those without DCM. CONCLUSION: Neonatal and late-onset DCM appear to be two different entities. None of the known risk factors associated with neonatal DCM predicted late-onset DCM. Long-term follow-up of cardiac function is warranted in all children with CHB. PMID- 28843720 TI - The utility of arginine-citrulline stable isotope tracer infusion technique in the assessment of nitric oxide production in MELAS syndrome. PMID- 28843721 TI - Letter to the Editor RE: Incidence of Torsade de Pointes in a tertiary hospital population by Vandael et al. PMID- 28843723 TI - Re: Guest Editorial Ann Kinnear Women and Birth 30 (2017) 168. PMID- 28843722 TI - Macrophage cell-derived exosomes/staphylococcal enterotoxin B against fibrosarcoma tumor. AB - Targeted immune therapies are a modern approach to harness the immunity to treat cancer patients. Exosomes (EXOs) are nano-vesicles used for drug delivery in cancer treatment. We aimed to assess the effectiveness of novel designed EXO structures for immunotherapy alone and in combination with other components in animal models. EXO derived from untreated macrophage (EXO), WEHI-164 cell lysate treated EXO (EXOLys), HSP70 enriched WEHI-164 cell lysate treated EXO (EXOHSP70), Naloxone (NLX) treated EXO (EXONLX), Propranolol (PRP) treated EXO (EXOPRP) and staphylococcal enterotoxin B (SEB) anchored to three kinds of EXOs designated as EXO/SEB, EXOLys/SEB, EXOHSP70/SEB were purified from J774 cell line. To determine the therapeutic effect of these novel constructed nano-vesicles, the animals were immunized with different types of EXOs at weekly intervals for three consecutive weeks and in the fourth week the WEHI-164 tumor cells were injected. Finally, the splenocyte proliferation was examined by MTT assay and tumor growth was also determined in each group. We observed that EXOHSP was more effective than EXO and EXOLys to decrease the number of tumor cells and to stimulate immune responses in animal models (P < 0.05). In SEB-anchored EXO group, EXOHSP70/SEB has the potency to stimulate immune responses more efficiently than EXO/SEB and EXOLys/SEB and the tumor was not palpable until 28th day which may refer to synergistic effect of HSP70 and SEB on immunity. In EXONLX treated mice proliferative response decreased significantly compared to control group (P > 0.05) and the tumor number was constant within a period of 28 days and EXOPRP may delay the occurrence of the fibrosarcoma tumor; After development of fibrosarcoma the number of tumors diminished over the studied period of time. Our results demonstrate that HSP70 enriched EXO is an effective immunoadjuvant in cancer immunotherapy and causes tumor regression in animal model. PMID- 28843724 TI - Working class conservatism: a system justification perspective. AB - Working class conservatism is a perennial issue in social science, but researchers have struggled to provide an adequate characterization. In social psychology, the question has too often been framed in 'either/or' terms of whether the disadvantaged are more or less likely to support the status quo than the advantaged. This is a crude rendering of the issue obscuring the fact that even if most working class voters are not conservative, millions are-and conservatives could not win elections without their support. System justification theory highlights epistemic, existential, and relational needs to reduce uncertainty, threat, and social discord that are shared by everyone-and that promote conservative attitudes. I summarize qualitative and quantitative evidence of system justification among the disadvantaged and consider prospects for more constructive political activity. PMID- 28843725 TI - Social class & risk preferences and behavior. AB - This paper reviews recent work regarding the link between one's societal ranking (or social class), and risk preferences and behavior. While the topic of social class and its relationship to risk has been studied only tentatively in psychology, preliminary evidence suggests that experiences with rank, access to resources, and movement between classes have a meaningful impact on people's risk preferences and behaviors. Yet, a clear pattern of results remains elusive. Some studies suggest that lower social class standing is related to risk aversion, while others suggest it is related to risk taking. These mixed results highlight the need for future research that examines when and why lower social class standing is related to more or less risky decisions. By shedding light on this important phenomenon, the hope is to offer intervention opportunities that influence policies and mitigate inequality. PMID- 28843726 TI - Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging. AB - BACKGROUND: Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [18F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several quantitative FMISO-PET parameters were identified as potential prognostic biomarkers. Here we present the results of the prospective validation cohort, and the overall results of the study. METHODS: FMISO-PET/CT images of further 25 HNSCC patients were acquired at four time-points before and during radiochemotherapy (RCHT). Peak standardised uptake value, tumour-to-background ratio, and hypoxic volume were analysed. The impact of the potential prognostic parameters on loco-regional tumour control (LRC) was validated by the concordance index (ci) using univariable and multivariable Cox models based on the exploration cohort. Log-rank tests were employed to compare the endpoint between risk groups. RESULTS: The two cohorts differed significantly in several baseline parameters, e.g., tumour volume, hypoxic volume, HPV status, and intercurrent death. Validation was successful for several FMISO-PET parameters and showed the highest performance (ci=0.77-0.81) after weeks 1 and 2 of treatment. Cut-off values for the FMISO-PET parameters could be validated after week 2 of RCHT. Median values for the residual hypoxic volume, defined as the ratio of the hypoxic volume in week 2 of RCHT and at baseline, stratified patients into groups of significantly different LRC when applied to the respective other cohort. CONCLUSION: Our study validates that residual tumour hypoxia during radiochemotherapy is a major driver of therapy resistance of HNSCC, and that hypoxia after the second week of treatment measured by FMISO-PET may serve as biomarker for selection of patients at high risk of loco-regional recurrence after state-of-the art radiochemotherapy. PMID- 28843727 TI - Hypofractionated radiation therapy for basal and squamous cell skin cancer: A meta-analysis. AB - PURPOSE: To characterize the cosmetic outcomes and local recurrence (LR) rates of various hypofractionated radiation therapy (RT) regimens for skin basal and squamous cell cancers (BCCs/SCCs). METHODS: A PICOS/PRISMA/MOOSE selection protocol was performed to identify 344 articles published between 1985-2016 evaluating patients with T1-2 N0 SCCs/BCCs treated with definitive RT. Biologically equivalent doses with alpha/beta=3 (BED3s) were calculated. The primary endpoint was post-treatment cosmesis. Mixed effects regression models were used to estimate weighted linear relationships between BED3 and cosmetic outcomes. RESULTS: A total of 21 studies were identified detailing the treatment of 9729 skin BCC/SCC patients, across seven countries, with external beam RT (n=9255) or brachytherapy (n=474). Median follow-up was 36months (range: 12-77). Median dose was 45Gy/11 fractions (interquartile range: 37.5Gy/6-55Gy/18) at 4Gy/fraction (interquartile range: 2.5-6Gy); most hypofractionated 18.75Gy/1. There was a trend to decreased "good" cosmesis with higher total dose: -3.4% "good" cosmesis/10Gy BED3, p=0.01. Similarly, there was a trend to increased "fair" cosmesis with higher dose: +3.8% "fair" cosmesis/10Gy BED3,p=0.006. At a BED3 of 100Gy, the expected rate of "good" cosmesis is 79% (95% confidence interval: 70%, 88%). Hypofractionated schedules produced similar cosmesis to conventionally fractionated schedules, at the same BED3. Fewer than 8% of patients experienced "poor" cosmesis, independent of dose or fractionation regimen. CONCLUSION: Hypofractionated RT has favorable cosmesis for patients with skin BCCs/SCCs. We recommend clinicians consider these commonly-used regimens, which all have BED3 of ~100Gy: 50Gy/15 fractions, 36.75Gy/7 fractions, or 35Gy/5 fractions, as they result in "good" cosmesis in 80% of patients. PMID- 28843728 TI - Evidence for proton tunneling and a transient covalent flavin-substrate adduct in choline oxidase S101A. AB - The effect of temperature on the reaction of alcohol oxidation catalyzed by choline oxidase was investigated with the S101A variant of choline oxidase. Anaerobic enzyme reduction in a stopped-flow spectrophotometer was biphasic using either choline or 1,2-[2H4]-choline as a substrate. The limiting rate constants klim1 and klim2 at saturating substrate were well separated (klim1/klim2>9), and were >15-fold slower than for wild-type choline oxidase. Solvent deuterium kinetic isotope effects (KIEs) ~4 established that klim1 probes the proton transfer from the substrate hydroxyl to a catalytic base. Primary substrate deuterium KIEs >=7 demonstrated that klim2 reports on hydride transfer from the choline alkoxide to the flavin. Between 15 degrees C and 39 degrees C the klim1 and klim2 values increased with increasing temperature, allowing for the analyses of H+ and H- transfers using Eyring and Arrhenius formalisms. Temperature independent KIE on the klim1 value (H2Oklim1/D2Oklim1) suggests that proton transfer occurs within a highly reorganized tunneling-ready-state with a narrow distribution of donor-acceptor distances. Eyring analysis of the klim2 value gave lines with the slope(choline)>slope(D-choline), suggesting kinetic complexity. Spectral evidence for the transient occurrence of a covalent flavin-substrate adduct during the first phase of the anaerobic reaction of S101A CHO with choline is presented, supporting the notion that an important role of amino acid residues in the active site of flavin-dependent enzymes is to eliminate alternative reactions of the versatile enzyme-bound flavin for the reaction that needs to be catalyzed. PMID- 28843729 TI - Depression and marijuana use disorder symptoms among current marijuana users. AB - BACKGROUND: Depression is one of the most consistent risk factors implicated in both the course of escalating substance use behaviors and in the development of substance dependence symptoms, including those associated with marijuana use. In the present study, we evaluate if depression is associated with marijuana use disorder symptoms across the continuum of marijuana use frequency. METHODS: Data were drawn from six annual surveys of the National Survey of Drug Use and Health to include adults who reported using marijuana at least once in the past 30days (N=28,557). RESULTS: After statistical control for sociodemographic characteristics and substance use behaviors including marijuana use, alcohol use, smoking, and use of illicit substances other than marijuana, depression was positively and significantly associated with each of the marijuana use disorder symptoms as well as the symptom total score. Adult marijuana users with depression were consistently more likely to experience marijuana use disorder symptoms and a larger number of symptoms, with the magnitude and direction of the relationship generally consistent across all levels of marijuana use frequency from 1day used in the past month to daily marijuana use. CONCLUSIONS: Depression is a consistent risk factor for marijuana use disorder symptoms over and above exposure to marijuana suggesting that depressed individuals may represent an important subgroup in need of targeted substance use intervention. PMID- 28843730 TI - Substance use disorders among immigrants in the United States: A research update. AB - INTRODUCTION: There is a critical need for the most current information available on the prevalence of substance use disorders (SUD) among immigrants vis-a-vis that of individuals born in the United States (US). We report the prevalence of SUDs among immigrants from major world regions and top immigrant-sending countries, and assess key moderators (i.e., age, gender, family income, age of migration, time in US) of the relationship between immigrant status and SUD risk. METHOD: The data source used for the present study is the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III, 2012-2013), a nationally representative survey of 36,309 civilian, non-institutionalized adults ages 18 and older in the US. Logistic regression was employed to examine the relationship between immigrant status and SUD risk. RESULTS: Immigrants were found to be substantially less likely than US-born individuals to be diagnosed with a past year or lifetime SUD, including alcohol, cannabis, cocaine, and opioid use disorders. These findings held across major world region and among immigrants from the top-ten immigrant sending nations, and across differences in age, gender, family income, age of migration, and time spent in the US. CONCLUSIONS: Results from the present study provide up-to-date and cogent evidence that immigrants use alcohol and drugs, and meet criteria for SUDs, at far lower rates than do US-born individuals. Moreover, we provide new evidence that the protective effect of nativity holds for immigrants from an array of global regions and sending countries, and across key demographic and migration-related differences. PMID- 28843731 TI - Ethanol-induced autonomic responses and risk taking increase in young adults with a positive family history of alcohol problems. AB - The mechanisms that underlie the greater prevalence of alcohol use disorders in individuals with a positive family history (FH+) of alcohol abuse are still under investigation. These subjects may exhibit differential sensitivity to alcohol's effects on psychomotor stimulation and impulsivity. Alcohol-induced psychomotor stimulation, measured as the heart rate (HR) response, is a proxy for the positive rewarding effects of the drug. We analyzed alcohol-induced effects on time perception (Time Production Task), risk taking (Balloon Analogue Risk Task [BART]), and HR in FH+ and FH- participants. In the FH+ and FH- groups, women and men received 0.6 and 0.7g/kg alcohol, respectively. The alcohol dose yielded a breath alcohol concentration of 0.08% throughout the experiment. The control groups received placebo, and the subjective perception of alcohol intoxication was assessed. Alcohol intoxication significantly increased HR and the adjusted average number of pumps on the BART (a measure of risk taking) in FH+ men and women but not in FH- participants. Behavioral impulsivity was unaffected by alcohol or a FH of alcohol abuse. FH- but not FH+ participants who received alcohol reported significantly greater subjective perception of alcohol's effects than their placebo counterparts. These results indicate that FH+ individuals presented heightened sensitivity to alcohol-induced HR stimulation and alcohol induced risk taking compared with their FH- counterparts. FH+ subjects, however, were insensitive to the subjective effects of alcohol. This idiosyncratic response pattern may be a likely pathway by which a FH of alcohol problems promotes alcohol drinking. PMID- 28843733 TI - Co-delivery of oxygen and erlotinib by aptamer-modified liposomal complexes to reverse hypoxia-induced drug resistance in lung cancer. AB - Tumor hypoxia is a common feature of the tumor microenvironment and has been regarded as one of the key factors in driving the emergence of drug resistance in solid tumors. To surmount the hypoxia-associated drug resistance, we fabricated the novel multifunctional liposomal complexes (ACLEP) that could co-deliver oxygen and molecular targeted drug to overcome the hypoxia-induced drug resistance in lung cancer. The ACLEP were fabricated with liposomes anchored with anti-EGFR aptamer-conjugated chitosan to co-administrate erlotinib and PFOB to EGFR-overexpressing non-small-cell lung cancer. Our results showed that the ACLEP possessed desired physicochemistry, good biostability and controlled drug release. The entrapped PFOB in nanoparticle facilitated the uptake of ACLEP in either normoxia or hypoxic condition. Comparing to those nanoparticles loading erlotinib alone, our innovative oxygen/therapeutic co-delivery system showed a promising outcome in fighting against hypoxia-evoked erotinib resistance both in vitro and in vivo. Hence, this work presents a potent drug delivery platform to overcome hypoxia-induced chemotherapy resistance. PMID- 28843734 TI - An alternative approach to the decision threshold. AB - Two effects were identified that induce the dependence of the decision threshold on the uncertainty of the conversion factor. With the first effect, the conversion factor influences the decision threshold directly, through its variability. With the second effect, the variability of the conversion factor influences the decision threshold only when it is not evaluated for the null measurement. Then, the variability of the conversion factor influences the value of the measurand, where the decision threshold is evaluated. Both effects are explained and evaluated. PMID- 28843732 TI - Multiscale design and synthesis of biomimetic gradient protein/biosilica composites for interfacial tissue engineering. AB - Continuous gradients present at tissue interfaces such as osteochondral systems, reflect complex tissue functions and involve changes in extracellular matrix compositions, cell types and mechanical properties. New and versatile biomaterial strategies are needed to create suitable biomimetic engineered grafts for interfacial tissue engineering. Silk protein-based composites, coupled with selective peptides with mineralization domains, were utilized to mimic the soft to-hard transition in osteochondral interfaces. The gradient composites supported tunable mineralization and mechanical properties corresponding to the spatial concentration gradient of the mineralization domains (R5 peptide). The composite system exhibited continuous transitions in terms of composition, structure and mechanical properties, as well as cytocompatibility and biodegradability. The gradient silicified silk/R5 composites promoted and regulated osteogenic differentiation of human mesenchymal stem cells in an osteoinductive environment in vitro. The cells differentiated along the composites in a manner consistent with the R5-gradient profile. This novel biomimetic gradient biomaterial design offers a useful approach to meet a broad range of needs in regenerative medicine. PMID- 28843735 TI - Investigation of gamma-gamma coincidence counting using the National Nuclear Array (NANA) as a primary standard. AB - The National Physical Laboratory has recently been in the process of commissioning a multi-detector gamma ray array - the National Nuclear Array (NANA). In this study we have sought to exploit the NANA and the excellent timing characteristics of its intrinsic LaBr3(Ce) scintillation detectors for use as a primary standardisation system. For this initial investigation, the absolute standardisation of 60Co has been performed by the gamma-gamma coincidence technique using NANA and the result compared to the established 4pi(LS)-gamma Digital Coincidence Counting (DCC) system. The effect of the angular correlation of the stretched E2 transitions emitted from the 4+->2+->0 states of 60Ni on the activity determined by NANA was observed between the pairs of detectors. Corrections for these angular correlations were derived through Monte Carlo simulations. An activity per unit mass by NANA of 330.8 (10) kBqg-1 for the 60Co solution was determined. There was no significant statistical difference between the results of NANA and the 4pi(LS)-gamma DCC, with a relative difference of 0.04% observed. This study shows that NANA can be used as a primary standard. PMID- 28843736 TI - Outdoor blue spaces, human health and well-being: A systematic review of quantitative studies. AB - BACKGROUND: A growing number of quantitative studies have investigated the potential benefits of outdoor blue spaces (lakes, rivers, sea, etc) and human health, but there is not yet a systematic review synthesizing this evidence. OBJECTIVES: To systematically review the current quantitative evidence on human health and well-being benefits of outdoor blue spaces. METHODS: Following PRISMA guidelines for reporting systematic reviews and meta-analysis, observational and experimental quantitative studies focusing on both residential and non residential outdoor blue space exposure were searched using specific keywords. RESULTS: In total 35 studies were included in the current systematic review, most of them being classified as of "good quality" (N=22). The balance of evidence suggested a positive association between greater exposure to outdoor blue spaces and both benefits to mental health and well-being (N=12 studies) and levels of physical activity (N=13 studies). The evidence of an association between outdoor blue space exposure and general health (N=6 studies), obesity (N=8 studies) and cardiovascular (N=4 studies) and related outcomes was less consistent. CONCLUSIONS: Although encouraging, there remains relatively few studies and a large degree of heterogeneity in terms of study design, exposure metrics and outcome measures, making synthesis difficult. Further research is needed using longitudinal research and natural experiments, preferably across a broader range of countries, to better understand the causal associations between blue spaces, health and wellbeing. PMID- 28843737 TI - Toxic effects of triclosan on a zebrafish (Danio rerio) liver cell line, ZFL. AB - Triclosan (TCS, 5-chloro-2-(2,4-dichlorophenoxy) phenol) is an antimicrobial agent widely used in personal care products. It has been detected in surface water, soil, aquatic species, and even humans. In this study, we used zebrafish (Danio rerio) as a model to test the hypothesis that TCS exhibits toxic effects by interacting with thyroid hormone receptor beta (TRbeta) and aryl hydrocarbon receptor (AhR) and by inducing the transcription of thyroid hormone (TH) associated genes and affecting phase I and phase II enzymes. The median lethal concentrations (LC50) of TCS in zebrafish embryos/larvae and a zebrafish liver cell line (ZFL) were first determined. Hatched larvae were most sensitive to TCS exposure, with LC50 values ranging from 1.26 to 1.46MUM for 96h after hatching exposure. The major effect of TCS was delayed hatching which occurred from 1.13MUM. The constructed GFP-zfTRbeta fusion protein revealed the subcellular location of zfTRbeta as the nucleus in both T3-induced and uninduced states, adding to the difficulty of studying TCS action on thyroid hormone receptors in ZFL cells. TCS had neither agonistic nor antagonistic effects on zfTRbetaLBD or AhR from the reporter gene systems. Ethoxyresorufin-o-deethylase (EROD) assay suggested that TCS is a weak P4501a (Cyp1a) agonist at 5MUM and that it inhibits cytochrome Cyp1a activity induced by benzo(a)pyrene (BaP). In time course-based mRNA profiling in ZFL cells, 4-h exposure to TCS caused a significant (up to 37.5 fold) inhibition of Cyp1a at 2.5MUM. An overall inhibition of liver phase I and II gene transcription at 4h exposure indicates the possible quick catabolism of TCS. Our findings suggest that TCS is not a TH mimic that affects TH-related gene expression. The impairment of Cyp1a mRNA expression could be due to stimulation by other stressors such as oxidative stress, warranting further investigation into the underlying mechanism in zebrafish. PMID- 28843739 TI - Reply. PMID- 28843738 TI - Exposure of spermatozoa to dibutyl phthalate induces abnormal embryonic development in a marine invertebrate Galeolaria caespitosa (Polychaeta: Serpulidae). AB - In this study, we have investigated the impact of dibutyl phthalate (DBP) on early embryogenesis in a sessile marine invertebrate, Galeolaria caespitosa. DBP was found to induce sperm dysfunction as well as impaired and defective embryogenesis characterised by a particular pattern of abnormality. Thus, after the first cleavage, one blastomere in these abnormal embryos was able to carry out further mitoses, while the other arrested. Analysis of microtubules, chromosomes and actin filaments demonstrated that the mitotic spindles in the abnormal embryos were irregularly bent, shortened and unable to anchor to the cortex, resulting in the defective segregation of chromosomes. Within the non dividing blastomeres, karyokinesis was found to continue at a slow pace as indicated by the presence of multiple sets of abnormal mitotic spindles. However, cytokinesis had been disrupted in these arrested cells due to a failure to assemble the contractile actin ring, as a result of which one pole of the embryos remained as one large, undivided cell. DBP was found to suppress the activity of superoxide dismutase in spermatozoa and, in association with this change, DBP treated cells experienced oxidative stress as indicated by the presence of lipid aldehydes, such as 4-hydroxynonenal (4-HNE) in the sperm acrosome and neck. Adduction of lipid aldehydes at the level of the acrosome would be expected to impede the acrosome reaction and account for the significant decrease in fertilisation rates. 4-HNE generated as a consequence of lipid peroxidation in the sperm neck resulted in alkylation of the sperm centrioles. Such paternally damaged centrioles were inherited by the embryos and disrupted cytoskeletal protein organisation during early cleavage, generating the observed abnormalities in embryonic development. This research emphasises the vulnerability of spermatozoa to oxidative damage and highlights novel potential mechanisms for reproductive toxicity involving the alkylation of subcellular structures in spermatozoa by lipid aldehydes. PMID- 28843740 TI - Trends in perception of risk of regular marijuana use among US pregnant and nonpregnant reproductive-aged women. PMID- 28843741 TI - A pilot study in using deep learning to predict limited life expectancy in women with recurrent cervical cancer. PMID- 28843742 TI - Postoperative maintenance levonorgestrel-releasing intrauterine system and endometrioma recurrence: a randomized controlled study. PMID- 28843743 TI - Vulvar zoster. PMID- 28843744 TI - Description of two species of caenomorphid ciliates (Ciliophora, Armophorea): Morphology and molecular phylogeny. AB - Most species in the anaerobic ciliate family Caenomorphidae Poche, 1913 lack detailed descriptions based on modern morphologic and molecular methods. In this report, two species, Caenomorpha medusula Perty, 1852 and Sulfonecta uniserialis (Levander, 1894) Jankowski, 1978, were isolated from freshwater anaerobic sediments in Qingdao, China. Another population of C. medusula was recorded from Boise, Idaho, USA. We reinvestigated live morphology, ciliature, and the small subunit (SSU) rRNA gene sequence of both species. The current study supports the opinion of Jankowski that, due to the variation in macronuclear nodule number, this character is of limited taxonomic significance in C. medusula. Scanning electronic micrographs clearly reveal that this species has one posterior spine. The China population of Sulfonecta uniserialis corresponds well with previously described populations in having a single macronucleus, a complex posterior spine, and one bell kinety. Our phylogenetic analyses reveal that the Caenomorphidae is monophyletic. However, the placement of the family is uncertain as it forms a closer relationship with the Litostomatea but with only a medium support value. PMID- 28843745 TI - Structural, mechanical and chemical evaluation of molar-incisor hypomineralization-affected enamel: A systematic review. AB - OBJECTIVES: To systematically assess and contrast reported differences in microstructure, mineral density, mechanical and chemical properties between molar incisor-hypomineralization-affected (MIH) enamel and unaffected enamel. METHODS: Studies on extracted human teeth, clinically diagnosed with MIH, reporting on the microstructure, mechanical properties or the chemical composition and comparing them to unaffected enamel were reviewed. Electronic databases (PubMed, Embase and Google Scholar) were screened; hand searches and cross-referencing were also performed. RESULTS: Twenty-two studies were included. Fifteen studies on a total of 201 teeth investigated the structural properties, including ten (141 teeth) on microstructure and seven (60 teeth) on mineral density; six (29 teeth) investigated the mechanical properties and eleven (87 teeth) investigated the chemical properties of MIH-affected enamel and compared them to unaffected enamel. Studies unambiguously found a reduction in mineral quantity and quality (reduced Ca and P content), reduction of hardness and modulus of elasticity (also in the clinically sound-appearing enamel bordering the MIH-lesion), an increase in porosity, carbon/carbonate concentrations and protein content compared to unaffected enamel. FINDINGS: were ambiguous with regard to the extent of the lesion through the enamel to the enamel-dentin junction, the Ca/P ratio and the association between clinical appearance and defect severity. CONCLUSIONS: There is an understanding of the changes related to MIH-affected enamel. The association of these changes with the clinical appearance and resulting implications for clinical management are unclear. CLINICAL SIGNIFICANCE: MIH affected enamel is greatly different from unaffected enamel. This has implications for management strategies. The possibility of correlating the clinical appearance of MIH-affected enamel with the severity of enamel changes and deducing clinical concepts (risk stratification etc.) is limited. PMID- 28843746 TI - Cytological and histological changes in the urothelium produced by electromotive drug administration (EMDA) and by the combination of intravescical hyperthermia and chemotherapy (thermochemotherapy). AB - The treatment of non muscle-invasive bladder cancer (NMIBC) encompasses a range of different procedures. Electromotive drug administration (EMDA) and chemo hyperthermia (C-HT; Synergo) represent a minimally-invasive methods of intravesical instillation of therapeutic agents as mitomycin C (MMC). We selected patients with high grade NMIBC, BCG non responder, treated with EMDA/MMC and C HT/MMC and we also examined the morphological changes in urine cytology samples. During the period from 2012 to 2014, 110 patients with high grade NMIBC, BCG refractory were selected. All cases examined were classified according to The Paris System Classification as negative for high urothelial carcinoma (NHGUC) or atypical urothelial cells (AUC) with a mean of follow-up of 15 months and the cytological diagnosis were confirmed by histological biopsies. In particular 50 patients were treated with EMDA/MMC and 60 patients underwent to C-HT/MMC. The morphological changes were evaluated in urine samples processed by Thin Prep method. In the 50 patients treated with EMDA/MMC, 35 samples were classified as NHGUC and 15 cases were classified as AUC, while in the 60 patients treated with C-HT/MMC, 43 samples were NHGUC and 17 cases were classified AUC. The increase of cellularity and nuclear size with the alteration of nuclear/cytoplasmatic ratio (N/C) were common in patients treated with EMDA/MMC and C-HT/MMC without clinical and histological evidence of recurrence of neoplasia. The hyperchromasia and irregular nuclear chromatin were rarely observed. The irregular nuclear membrane rarely identified in urine cytology after EMDA/MMC treatment, is a feature present in patients C-HT/MMC treated. PMID- 28843747 TI - Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) in a young female athlete at 36 weeks gestation: a case report. AB - A 26year old east African professional athlete presented to the obstetric clinic for a routine visit at 36 weeks gestation. She had a history of Right Ventricular Outflow Tract - Ventricular Tachycardia (RVOT-VT) with an episode of cardiac arrest in the past, and had been treated with ablation 4 years earlier. Her current visit was uneventful, her pregnancy progressing normally. Following the visit she went to a local restaurant where she suffered a cardiac arrest that was unresponsive to therapy. Chest compressions were continued from the time of her collapse until an emergency caesarian section was performed, delivering a healthy female infant. At autopsy a focal area of subtle pallor and myocardial thinning was present at the apex of the right ventricle. Histology showed myocyte degeneration and loss with focal full thickness replacement of myocardium by adipose tissue, consistent with the fatty form of arrhythmogenic right ventricular cardiomyopathy (ARVC). Molecular studies revealed a variant of unknown significance in the MYBPC3 gene, but no variant known to be associated with ARVC. In view of the subtlety of the lesion on gross examination this diagnosis could have been easily missed, emphasizing the importance of performing histologic examination of subtle gross cardiac lesions. PMID- 28843748 TI - Exploration of the pathways and interaction network involved in bladder cancer cell line with knockdown of Opa interacting protein 5. AB - OBJECTIVES: In our previous study, we displayed that knockdown of Opa interacting protein 5 (OIP5) inhibited cell growth, disturbed cell cycle and increased cell apoptosis in bladder cancer (BC) cell line. Our present study aimed to explore the underlying pathways and interaction network involved in the roles of OIP5 in BC. METHODS: Microarray analysis was conducted to obtain mRNA expression profiling of OIP5 knockdown (shOIP5) and control (shCtrl) BC cell lines. Bioinformatics analyses were performed including differentially expressed mRNAs (DEGs) identification, protein-protein interaction network construction, biological functions of prediction and ingenuity pathways analysis (IPA). Western Blotting (WB) was subjected to validate the protein expression levels of candidate DEGs in shOIP5 BC cell line. RESULTS: Respective 255 up- and 184 down regulated DEGs were identified in shOIP5 group compared with shCtrl group. In the PPI network, CAND1 and MYC had the highest connectivity with DEGs. 439 DEGs were significantly enriched in inflammatory response, regulation of cell proliferation, Toll-like receptor signaling pathway, cytokine-cytokine receptor interaction and bladder cancer. In the disease and function enrichment, DEGs were obviously involved in cellular movement, cellular growth and proliferation, cancer, inflammatory response, cell death and survival. In the OIP5 regulatory network, CDH2, IRS1, IRAK3, ID1, TNF, IL6, ITGA6, MYC and SOD2 interacted with OIP5. The WB validation results were compatible with our bioinformatics analyses. CONCLUSIONS: OIP5 interaction network might function as an oncogene in BC progression based on aberrant inflammatory responses. Our study might provide valuable information for investigation of tumorigenesis mechanism in BC. PMID- 28843749 TI - Evaluation of expression of genes CADM1, TWIST1 and CDH1 by immunohistochemestry in melanocytic lesions. AB - AIM: Malignant melanoma is an aggressive disease and its incidence is increasing worldwide. Genetic predisposition and exposure to environmental factors, especially sunlight, are risk factors. Histopathologic distinction between nevi and melanomas can be difficult. It is anticipated that the evaluation of the immunohistochemical expression of some genes could contribute to the differential diagnosis of questionable histologically lesions. The objective of this study was to investigate wether the evaluation of the immunohistochemical expression of genes CADM1, TWIST1 and CDH1 (E-cadherin), that take part in mechanisms of cell adhesion and epithelial-mesenchymal transition, contributes to the differential diagnosis of melanocytic lesions difficult to diagnose. MATERIALS AND METHODS: Retrospective cross-sectional study based on immunohistochemistry analysis of samples of 30 dysplastic compound melanocytic nevi, 30 melanomas less than 1.0mm thick and 30 melanomas more than 1.0mm thick, diagnosed between 2013 and 2016. A score was used to evaluate color intensity and percentage of cells stained. RESULT: There were significant reductions in the expression of the genes CADM1 and CDH1 in melanomas (below and above 1.00mm of thickness) and in melanomas more than 1.0mm thick, respectively, compared to dysplastic compund melanocytic nevi. There was also lower expression of the genes CADM1 and CDH1 in melanomas greater than 1.0mm thick compared to melanomas less than 1.0mm. The gene TWIST1 showed no significant difference in expression between groups. CONCLUSION: These findings allow us to conclude that the immunohistochemical expression of CADM1 has the potential to contribute as an auxiliary tool to the differential diagnosis between nevi and melanomas. PMID- 28843750 TI - Autophagy analysis in oral carcinogenesis. AB - OBJECTIVE: The aim of this study was to evaluate the levels of autophagy in oral leukoplakia and squamous cell carcinoma and to correlate with clinical pathological features, as well as, the evolution of these lesions. METHODOLOGY: 7 Normal oral mucosa, 51 oral leukoplakias, and 120 oral squamous cell carcinomas (OSCC) were included in the study. Histological sections of the mucosa and leukoplakias were evaluated throughout their length, while the carcinomas were evaluated using Tissue Microarray. After the immunohistochemical technique, LC3 II positive cells were quantified in the different epithelial layers of the mucosa and leukoplakias and in the microarrays of the squamous cell carcinomas. The correlation between positive cells with the different clinical-pathological variables and with the evolution of the lesions was tested using the t test, ANOVA, and Kaplan-Meier survival analysis. RESULTS: We observed increased levels of autophagy in the oral squamous cell carcinomas (p<0.001) in relation to the other groups, but without any association with poorer evolution or survival of these patients. Among the leukoplakias, we observed a higher percentage of positive cells in the intermediate layer of the dysplastic leukoplakias (p=0.0319) and in the basal layer of lesions with poorer evolution (p=0.0133). CONCLUSION: The levels of autophagy increased during the process of oral carcinogenesis and are correlated with poorer behavior of the leukoplakias. PMID- 28843751 TI - Thyroid transcription factor-1 promotes lymph node metastasis by inducing lymphangiogenesis in ovarian carcinoma. AB - AIMS AND BACKGROUND: Thyroid transcription factor-1 (TTF-1) expression is widely considered a specific marker for lung and thyroid carcinomas and plays an important role in angiogenesis in lung cancer. However, it can occasionally be expressed in other malignancies, including ovarian carcinomas, and the mechanism of TTF-1 in lymphatic metastasis of ovarian carcinomas is still unclear. This study aimed to define the TTF-1 expression and lymph vessel density (LVD) in ovarian carcinomas and look for their correlations with clinicopathological features. METHODS: We examined the incidence of thyroid transcription factor 1 expression (clone SPT24) and lymph vessel density (LVD) quantified through D2-40 by immunohistochemistry from 110 primary ovarian carcinomas and 40 benign ovarian tumor as controls in Chinese patients. RESULTS: Thyroid transcription factor 1 was detected in 28 primary ovarian carcinomas (25.5%), which was significantly higher than its expression in benign ovarian tumor. TTF-1 expression was correlated with tumor FIGO stage,T stage and lymphatic metastasis. Moreover, LVD was associated with tumor FIGO stage, TNM stage. Furthermore, the LVD counts in group of TTF-1 positive expression were higher than in group of TTF-1 negative expression. CONCLUSIONS: These findings indicated the occasional expression of TTF-1 immunoreactivity of ovarian carcinomas should be considered in the evaluation of neoplasms of unknown primary origin and TTF-1 might be involved in lymph node metastasis of ovarian carcinomas in the presence of lymphangiogenesis. PMID- 28843752 TI - Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets. AB - A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment. PMID- 28843753 TI - Anaerobic digestion/co-digestion kinetic potentials of different agro-industrial wastes: A comparative batch study for C/N optimisation. AB - Anaerobic digestion (AD) of different agro-industrial wastes and their co digestion potential has been exhaustively studied in this research. It explores variation of feedstock characteristics such as biodegradability and methane potential during AD and anaerobic co-digestion (ACoD) of chicken litter (CL) with yoghurt whey (YW), organic fraction of municipal solid waste (OFMSW), hay grass (HG) and wheat straw (WS) under mesophilic conditions. Comparative performance was made at different loading concentrations (2%, 3% and 4% VS) with 1:2g/g VS of substrate to inoculum and carrying C/N ratio. Among different kinetic models, the AD of single substrates showed better fit to the modified Gompertz model (R2: 0.93-0.997) indicating variation in lag phase and methane production rate depend on the substrate characteristics. During ACoD, the methane yield improved by 9 85% through the addition of two, three or four substrates due to the synergistic effect asa result of increased biodegradability and optimum conditions (such asC/N ratio). A surface (optimisation) model indicated that maximum methane production can be achieved by blending chicken litter (30-35%) and a (65-70%) mixture of yoghurt whey, hay and wheat straw with aC/N ratio of (26-27.5). PMID- 28843754 TI - Thoracic Intradural-Extramedullary Epidermoid Tumor: The Relevance for Resection of Classic Subarachnoid Space Microsurgical Anatomy in Modern Spinal Surgery. Technical Note and Review of the Literature. AB - BACKGROUND: Intradural epidermoid tumors of the spinal cord are commonly associated with spinal cord dysraphism or invasive procedures. We report the particular relationships between spinal subarachnoid compartments and thoracic intradural-extramedullary epidermoid tumor, highlighting the relevant anatomic changes that may influence microsurgery. METHODS: A 40-year-old woman from compressive myelopathy owing to a thoracic epidermoid tumor extending from T3 to T4 and not associated with spina bifida, trauma, previous surgery, or lumbar spinal puncture underwent microsurgical excision. Accurate tumor membrane dissection, respecting spinal arachnoidal compartments, was performed. Reposition of a laminoplasty plateau helped in restoring thoracic spine anatomic integrity. RESULTS: Safe gross total tumor resection was achieved. Complete neurologic recovery as well as absence of recurrent tumor was documented at 4-year follow up. A literature review revealed only 2 other cases of "isolated" thoracic spine epidermoid tumor. However, description of the relationship between tumor membranes and spinal subarachnoid compartments was not available in either case. CONCLUSIONS: A thorough knowledge of spinal subarachnoid space anatomy is helpful to distinguish between tumor membranes and arachnoidal planes and to achieve a safe and complete resection to avoid recurrences. PMID- 28843755 TI - Association of Perforator Infarction with Clinical Courses and Outcomes Following Surgical Clipping of Ruptured Anterior Communicating Artery Aneurysms. AB - BACKGROUND: Perforator infarction is a procedure-related complication of surgical clipping of ruptured anterior communicating artery (ACoA) aneurysms. Patients with perforator infarction may present with specific clinical features. The aim of this study was to elucidate incidence, risk factors, clinical course, and outcomes of perforator infarction following surgical clipping of ruptured ACoA aneurysms. METHODS: Retrospective analysis was performed of 104 patients from a single-center, observational cohort database who underwent surgical clipping for ruptured ACoA aneurysm. Risk factors of perforator infarction were identified. Correlation of perforator infarction with clinical course during hospitalization was investigated, focusing on dysfunction of hypothalamus and cerebral limbic system. We also evaluated any associations between perforator infarction and poor outcomes. RESULTS: Perforator infarction was observed in 24 (23.1%) patients. Use of temporary clip (P = 0.019, chi2 test) and intraoperative rupture (P < 0.001, chi2 test) were significantly associated with perforator infarction. Patients with perforator infarction had increased likelihood of hyponatremia (odds ratio 6.41 [95% confidence interval 2.27-18.1], P < 0.001) and insufficient oral intake (odds ratio 6.53 [95% confidence interval 1.80-23.7], P = 0.004) in the subacute stage of subarachnoid hemorrhage by multivariate analyses. Perforator infarction was an independent risk factor of poor functional outcomes at 3 months (modified Rankin Scale score 3-6; odds ratio 5.29 [95% confidence interval 1.62-17.2], P = 0.006). CONCLUSIONS: Perforator infarction following surgical clipping of ruptured ACoA aneurysms caused region-specific complications, including hyponatremia and insufficient oral intake, and was associated with poor functional outcomes. PMID- 28843756 TI - Recurrent Perimesencephalic Nonaneurysmal Subarachnoid Hemorrhage: Case Report and Review of the Literature. AB - BACKGROUND: Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSAH) is a benign form of subarachnoid hemorrhage (SAH) with a favorable prognosis. The risk of recurrent hemorrhage of this benign entity is extremely low. CASE DESCRIPTION: We describe a rare case of recurrent, spontaneous PNSAH in a 56-year-old man. This hypertensive patient suffered a recurrent episode of PNSAH 1 month after its first ictus, suggesting rebleeding can still occur in the setting of PNSAH; however, the risk is much less than that in aneurysmal SAH. No source of the hemorrhage was identified in the imaging examinations, even with the performance of a 6-vessel angiography. CONCLUSIONS: Despite the PNSAH owning benign clinical manifestations and a favorable outcome, this distinct case of recurrent PNSAH demonstrated that the risk of recurrent hemorrhage of PNSAH does exist, although it is rather low. A conservative approach with close follow-up is still warranted for PNSAH patients. PMID- 28843757 TI - Changing Operating Room Culture: Implementation of a Postoperative Debrief and Improved Safety Culture. AB - BACKGROUND: Patient safety is foundational to neurosurgical care. Postprocedural "debrief" checklists have been proposed to improve patient safety, but data about their use in neurosurgery are limited. Here, we implemented an initiative to routinely perform postoperative debriefs and evaluated the impact of debriefing on operating room (OR) safety culture. METHODS: A 10-question safety attitude questionnaire (SAQ) was sent to neurosurgical OR staff at a major academic medical center before and 18 months after the implementation of a postoperative debriefing initiative. Rates of debrief compliance and changes in attitudes before and after the survey were evaluated. The survey used a Likert scale and analyzed with standard statistical methods. RESULTS: After the debrief initiative, the rate of debriefing increased from 51% to 86% of cases for the neurosurgery service. Baseline SAQ responses found that neurosurgeons had a more favorable perception of OR safety than did anesthesiologists and nurses. After implementation of the postoperative debriefing process, perceptions of OR safety significantly improved for neurosurgeons, anesthesiologists, and nurses. Furthermore, the disparity between nurses and surgeons was no longer significant. After debrief implementation, neurosurgical OR staff had improved perceptions of patient safety compared with surgical services that did not commonly perform debriefing. Debriefing identified OR efficiency concerns in 26.9% of cases, and prevention of potential adverse events/near misses was reported in 8% of cases. CONCLUSIONS: Postoperative debriefing can be effectively introduced into the OR and improves the safety culture after implementation. Debriefing is an effective tool to identify OR inefficiencies and potential adverse events. PMID- 28843758 TI - New Technique for Chiasmapexy Using Iliac Crest Bone Graft: 2 Cases of Visual Impairment Caused by Empty Sella Syndrome. AB - BACKGROUND: Chiasmapexy is used to treat empty sella syndrome, and various materials are used for the elevation of the optic chiasm. However, the use of artificial substances may have the risk of graft infection, and fat and muscle may be absorbed over the long term after surgery. In addition, bone and cartilage may be unavailable in adequate amounts. Here, we describe a new technique for chiasmapexy using an iliac crest bone graft. CASE DESCRIPTION: The first patient was a 71-year-old woman who had undergone transsphenoidal surgery twice for the treatment of pituitary adenoma and Rathke cleft cyst. The optic chiasm collapsed after the second surgery and her visual field worsened gradually. We performed chiasmapexy using fat, fascia, and a septal mucosal flap, but the optic chiasm did not remain in the normal position because of graft shrinkage. Finally, we used an iliac crest bone graft, which resulted in good visual function. The second patient was a 58-year-old man who was incidentally diagnosed with empty sella syndrome. The patient's bitemporal hemianopia gradually progressed. As in the first case, we used an iliac crest bone graft, which halted the deterioration of visual function after chiasmapexy. CONCLUSIONS: The advantages of iliac bone are that it is less likely to absorb and become infected than synthetic materials. This method may be suitable for reoperative cases, especially those wherein the septal cartilage has been removed in a previous surgery. This method will halt visual deterioration and may be one of the considerable options for chiasmapexy operations. PMID- 28843759 TI - Hybrid Technique for the Treatment of Refractory Vertebrobasilar Insufficiencies. AB - BACKGROUND: Tortuous or occluded vertebral arteries (VAs) can make the endovascular treatment of vertebrobasilar insufficiency impractical. Bypass surgery is an option, but a craniotomy of the posterior fossa is complicated when physiologic vessels must be abandoned. We report 3 cases of refractory vertebrobasilar insufficiency with different presentations requiring problematic approaches in which the patients were treated by different hybrid strategies. CASE DESCRIPTION: Patient 1 had severe stenosis of right VA ostium with right V1 segment tortuosity and was treated by right VA ostium transposition during which the proximal subclavian artery was blocked by a balloon guide catheter. Patient 2 had severe stenosis of the basilar artery and bilateral VA tortuosity. The V1 segment was exposed and cut open so that an available approach for endovascular procedures was created. Patient 3 had bilateral VA occlusion. After exposure of the left V1 segment, recanalization of the left VA was performed by an interventional radiologist and surgeon working together. All patients had improved hemodynamics and symptoms alleviated without major complications. CONCLUSIONS: For refractory vertebrobasilar insufficiencies, hybrid operations that combine surgical manipulation of the V1 segment and endovascular techniques can be safe and effective. PMID- 28843760 TI - VITOM 3D: Preliminary Experience in Cranial Surgery. AB - BACKGROUND: Optimal vision and ergonomics are important factors contributing to achievement of good results during neurosurgical interventions. The operating microscope and the endoscope have partially filled the gap between the need for good surgical vision and maintenance of a comfortable posture during surgery. Recently, a new technology called video-assisted telescope operating monitor or exoscope has been used in cranial surgery. The main drawback with previous prototypes was lack of stereopsis. We present the first case report of cranial surgery performed using the VITOM 3D, an exoscope conjugating 4K resolution view and three-dimensional technology, and discuss advantages and disadvantages compared with the operating microscope. CASE DESCRIPTION: A 50-year-old patient with vertigo and headache linked to a petrous ridge meningioma underwent surgery using the VITOM 3D. Complete removal of the tumor and resolution of symptoms were achieved. The telescope was maintained over the surgical field for the duration of the procedure; a video monitor was placed at 2 m from the surgeons; and a control unit allowed focusing, magnification, and repositioning of the camera. CONCLUSIONS: VITOM 3D is a video system that has overcome the lack of stereopsis, a major drawback of previous exoscope models. It has many advantages regarding ergonomics, versatility, and depth of field compared with the operating microscope, but the holder arm and the mechanism of repositioning, refocusing, and magnification need to be ameliorated. Surgeons should continue to use the technology they feel confident with, unless a distinct advantage with newer technologies can be demonstrated. PMID- 28843761 TI - Percutaneous Biopsy of Lesions in the Cavernous Sinus: A Systematic Review. AB - BACKGROUND: A wide variety of lesions may develop in the cavernous sinus region, including tumors or pseudotumors of inflammatory origin. Sometimes imaging is insufficient to ascertain a pathologic diagnosis. Percutaneous biopsy performed through the foramen ovale route may aid therapeutic decision making, avoiding unnecessary open surgery when lesions are confirmed to be nonsurgical or unresectable. We conducted a systematic review to determine the efficacy of percutaneous biopsy of cavernous sinus lesions. METHOD: A systematic search in PubMed, LILACS, Web of Science, and Scopus yielded 4495 potentially eligible abstracts. Fourteen studies describing 75 biopsy procedures for lesions in the cavernous sinus region were reviewed. The primary outcome measure was diagnostic success. Data were analyzed according to standard systemic review techniques. RESULTS: A diagnosis was obtained in 65 of the 75 cases described in the literature. Among all series, only 3 patients had permanent deficits. No individual studies reported mortality. The histopathologic evaluation revealed neoplastic diseases in 58 lesions. Meningiomas were found in 26 biopsy samples. Nonneoplastic diseases, originating from infectious, inflammatory, or deposition diseases, accounted for 6 biopsy samples. CONCLUSIONS: Percutaneous biopsy of cavernous sinus lesions is effective for diagnosis. Biopsy can be performed in patients with cavernous sinus masses, especially when neuroimaging fails to provide sufficient histopathologic data. PMID- 28843762 TI - Preventing Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage with Aggressive Cisternal Clot Removal and Nicardipine. AB - BACKGROUND: A subarachnoid clot is the strongest predictor of cerebral vasospasm. Our purpose was to analyze the relationship between the number of postoperative cisternal clots and cerebral vasospasm and to assess the efficacy of surgical clot removal. METHODS: The subjects were 158 patients with aneurysmal subarachnoid hemorrhage. All patients underwent clipping with cisternal clot removal. The preoperative and postoperative number of clots was analyzed semiquantitatively using computed tomography, and cerebral vasospasm and its severity were analyzed using magnetic resonance angiography in a blind fashion. Factors related to cerebral vasospasm and poor outcome were analyzed retrospectively. Poor outcome was defined as modified Rankin Scale (mRS) score of 3 or greater. RESULTS: Symptomatic cerebral vasospasm (SCV) was observed in 6 patients (3.8%). Angiographic vasospasm (AVS) was observed in 38 patients (24.1%). One year after the operation, 82.9% of patients had an mRS score of 0-2. The postoperative number of clots was significantly (P < 0.005) related to SCV (adjusted odds ratio [OR], 6.447; 95% confidence interval [CI], 2.063-20.146), AVS (OR, 2.634; 95% CI, 1.467-4.728), and poor outcome (OR, 2.103; 95% CI, 1.104 4.007). Poor outcome was also related to age over 65 (OR, 6.658; 95% CI, 2.389 18.559) and World Federation of Neurosurgical Societies scale grade (OR, 1.732; 95% CI, 1.248-2.403). CONCLUSIONS: Surgically removing as many clots as possible in the acute stage can decrease SCV and reduce AVS severity. Irrigation should be performed on all approachable cisterns. PMID- 28843763 TI - Metastatic Basal Cell Adenocarcinoma of Submandibular Gland to the Spine: An Extremely Rare Condition. AB - BACKGROUND: Basal cell adenocarcinomas are rare malignant neoplasms of salivary glands, accounting for <1% of salivary gland tumors. Few cases of distant metastases have been reported. CASE DESCRIPTION: A 50-year-old Thai man was diagnosed with basal cell adenocarcinoma of the submandibular gland with pulmonary and cervical spine metastases with progressive myelopathy. He was treated with wide surgical resection of the soft tissue tumor and modified radical neck dissection, anterior cervical total corpectomy with fusion combined with posterior decompression and fusion of the cervical spine, and surgical wound coverage by anterolateral thigh free tissue transfer, followed by adjuvant radiotherapy. At 18-month follow-up, the patient remained in good condition, and no signs of local recurrence or contiguous spreading were detected. Postoperative radiographs showed solid osseous fusion without loss of correction or implant failure. CONCLUSIONS: This case highlighted an extremely rare condition of metastatic basal cell adenocarcinoma of the submandibular gland to the lung and spine, which, to our knowledge, has not been previously reported in the literature. PMID- 28843764 TI - More Learning in Less Time: Optimizing the Resident Educational Experience with Limited Clinical and Educational Work Hours. AB - OBJECTIVE: Resident education in the United States and elsewhere has undergone significant changes in recent years owing to work hour restrictions, requiring didactics to fit within a limited schedule, while being increasingly effective at accomplishing educational goals. METHODS: A single small program experience in improving the didactic experience of residents is described. RESULTS: Focused mentorship, curricula for intangibles, asynchronous education, and independent curricula all are useful tools in resident education. CONCLUSIONS: Residents can be exposed to both clinical material and specialty-specific mores using focused and intentional educational techniques. PMID- 28843765 TI - To Stimulate or Inhibit? That Is the Question for the Function of Abscisic Acid. AB - Physiologically, abscisic acid (ABA) is believed to be a general inhibitor of plant growth, including during the crucial early development of seedlings. However, this view contradicts many reports of stimulatory effects of ABA that, so far, have not been considered in the debate concerning ABA's function in plant development. To address this apparent contradiction, we propose a hypothetical mechanism to explain how ABA might contribute to the promotion of cell expansion. We wish to overturn conventional views on ABA's role during juvenile plant development and put forward the idea that, as for other phytohormones, the role of ABA is determined by dose and sensitivity and ranges from stimulatory to inhibitory effects. PMID- 28843766 TI - Exploiting DELLA Signaling in Cereals. AB - The spectacular yield increases in rice and wheat during the green revolution were partly realized by reduced gibberellin (GA) synthesis or sensitivity, both causing the accumulation of DELLA proteins. Although insights into the regulation of plant growth and development by DELLA proteins advanced rapidly in arabidopsis (Arabidopsis thaliana), DELLA-mediated regulation of downstream responses in cereals has received little attention to date. Furthermore, translating this research from arabidopsis to cereals is challenging given their different growth patterns and our phylogenetic analysis which reveals that DELLA-related DGLLA proteins exist in cereals but not in arabidopsis. Therefore, understanding the molecular basis of DELLA function in cereals holds great potential to improve yield. In this review, we propose to extend the focus of DELLA functional research to cereals, and highlight the appropriate tools that are now available to achieve this. PMID- 28843767 TI - Carfilzomib versus bortezomib: no longer an ENDEAVOR. PMID- 28843769 TI - A new technique for creating a neo-umbilicus in abdominoplasty. AB - BACKGROUND: The umbilicus is an essential feature of the abdomen. In this article, we describe a new technique for creating a neo-umbilicus in abdominoplasty. METHODS: Thirty consecutive women underwent abdominoplasty with our new technique for recreating the navel. The new navel is created at the midpoint between the xiphoid process and pubic symphysis by defatting a cylinder of fat tissue as far as the dermis that is then sutured to the rectus muscle to enable it to "take" in the same way as a total skin graft and form a hollow, which will be the new navel. Patients were divided into three groups according to BMI (group A < 25; group B 25-29.9; group C >= 30). Results were rated on a scale of 0-10 by external observers and by the patients. Complications were recorded. RESULTS: Groups B and C obtained median scores of 10/10 from both the external raters and patients (range 1), while group A obtained median scores of 6/10 and 7/10, respectively (ranges 6 and 5). CONCLUSIONS: Our new technique presents a series of advantages: it allows the positioning of the new navel in any location, it does not create periumbilical scarring, and it can be used in cases in which the original pedicle and vascularization of the navel cannot be preserved. It appears to achieve good aesthetic results and high levels of satisfaction among patients; however, it is less effective in very thin patients whose navel remains flat due to the lack of adipose tissue. PMID- 28843768 TI - Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. AB - BACKGROUND: The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups. METHODS: ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1.3 mg/m2) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients. FINDINGS: Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47.6 months (95% CI 42.5-not evaluable) in the carfilzomib group versus 40.0 months (32.6-42.3) in the bortezomib group (hazard ratio 0.791 [95% CI 0.648 0.964], one-sided p=0.010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment related deaths occurred in five (1%) of 463 patients in the carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two (<1%) of 456 patients in the bortezomib group (cardiac arrest [n=1] and pneumonia [n=1]). INTERPRETATION: Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease. FUNDING: Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary. PMID- 28843770 TI - Natural history of intracranial aneurysms in autosomal dominant polycystic kidney disease. AB - : Autosomal-dominant polycystic kidney disease (ADPKD) is a relatively frequent genetic disorder that is associated with increased prevalence of intracranial aneurysms (IAs). However, evidence on the natural history of IAs in ADPKD is suboptimal. That leads to difficulties in development of recommendations on surveillance on patients with IAs in their medical history, or the need for repeat imaging for IAs in those with a negative result of the initial screening. The aim of the article is to present our experience on the natural history of IAs in ADPKD patients. MATERIAL AND METHODS: Thirty-four ADPKD patients, managed at our outpatient department, with imaging for intracranial aneurysms performed at least twice, were included into present retrospective analysis. RESULTS: Among 8 patients with an IA in their medical history, no new IA was observed during 93 patient-years of follow-up. In 6 patients with untreated, unruptured IAs, IA growth was observed in 2 cases during 32 patient-years of follow-up. Finally, among 20 patients with a negative result of initial screening, 2 new IAs were noticed during 115 patient-years of follow-up, including 1 patient with a positive family history for an IA, and 1 patient without a family history. CONCLUSIONS: Our observations support repeat imaging for IAs in patients with ADPKD, positive family history of IA, and negative result of initial screening. Additionally, efforts should be made to develop clinical and/or laboratory risk factors for IAs development in ADPKD patients without family history of IA, which enable to identify patients who should undergo repeat imaging for IAs. PMID- 28843771 TI - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) - A Polish family with novel SACS mutations. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare hereditary ataxia, characterized by the triad of early-onset cerebellar ataxia, peripheral sensorimotor neuropathy and lower limb spasticity. Although ARSACS is increasingly reported worldwide, we present the first Polish family with a comprehensive clinical and neuropsychological assessment, harboring two novel mutations in the SACS gene. Our results demonstrate the variability in cognitive and behavioral profiles in ARSACS, which is in line with other heredodegenerative ataxias. One should be aware of ARSACS in cases of autosomally recessive inherited ataxias without common mutations. PMID- 28843772 TI - Gamasoidosis (bird mite dermatitis): A case series in a family. PMID- 28843773 TI - Rooted in the Community: Assessing the Reintegration Effects of Agriculture on Rural Veterans. AB - OBJECTIVE: To assess the effect of a veteran-oriented community agricultural initiative on transitioning rural veterans. DESIGN: Convergent mixed-method program evaluation. SETTING: Veteran-oriented farm-to-market community agricultural initiative. PARTICIPANTS: Veterans (N=43) who were members of the community agricultural initiative. MAIN OUTCOME MEASURES: Health, well-being, and reintegration were assessed by self-reported data from interviews, a demographic survey, a validated health quality of life measure (Veterans RAND-12 [VR-12]), a validated reintegration measure (Military to Civilian Questionnaire), and a general satisfaction survey. RESULTS: Veteran participants were primarily white (88.4%, n=38) and men (74.4%, n=32), and most had a service-connected disability rating (58.2%, n=25). Qualitative and quantitative data revealed that the veterans participating in this community agricultural initiative experienced health and reintegration benefits. Results on the Military to Civilian Questionnaire, VR-12, and satisfaction survey suggest that participating in this community agricultural initiative contributed to improved mental, physical, and emotional health and vocational skills, community connectedness, and interpersonal communication. Qualitative interviews supported quantitative findings and revealed that participating in the community agricultural initiative provided veterans with a sense of satisfaction, a sense of belonging, and helped decrease the stigma surrounding their veteran status. CONCLUSIONS: Veterans who participate in this community agricultural initiative reported general improvements in physical and mental health, including improvements in sleep, nutrition, and exercise, and decreases in anxiety, pain, depression, and medication and substance use, all known factors which effect veteran reintegration. PMID- 28843774 TI - Putting the new ILAE classification of focal cortical dysplasia into practice in western China. AB - PURPOSE: To re-examine drug-resistant epilepsy cases using the revised 2011 ILAE classification of focal cortical dysplasia (FCD). METHODS: Patients with drug resistant epilepsy who have undergone epilepsy surgery in West China Hospital between July 2012 and Jun 2014 were included. Clinical histories, pathological diagnoses, and surgical outcomes were reviewed. A questionnaire was developed to investigate the clinical practice of the new classification. A short-term training program on FCD was carried out to improve pathological diagnosis accuracy. RESULTS: 260 consecutive cases (177 male and 83 female) were included. Pathological diagnosis was changed in 70 cases (26.9%) after re-examination. The five most common pathological types were hippocampal sclerosis (19.2%, 50/260), brain tumors (17.7%, 46/260), vascular malformations (16.2%, 42/260), glial scars (11.2%, 29/260) and FCD (10.0%, 26/260). The most common subtype of isolated FCD was FCD IIb (53.8%, 14/26), followed by FCD IIa (42.3%, 11/26) and FCD Ib (3.8%, 1/26). In addition, forty-five cases were diagnosed as associated FCD type III (17.3%, 45/260). Half of patients with FCD achieved Engel class I at two-year follow-up. Questionnaire investigation suggested most participant pathologists lack sufficient knowledge on the new classification. The diagnostic sensitivity for different FCD subtypes was significantly improved by two to six folds after short-term training. CONCLUSIONS: FCD is an important etiology of drug-resistant epilepsy in western China. It is essential to provide continuing trainings to improve diagnostic precision of FCD in developing countries. PMID- 28843776 TI - Examining the Value of Video Visits to Patients in an Outpatient Urology Clinic. AB - OBJECTIVE: To examine the value that urologic patients place on video visits before the implementation of a telemedicine program at our institution's outpatient urology clinic. METHODS: We conducted an on-site survey at a tertiary medical center's outpatient urology clinic over a 3-month period. Our survey questions assessed patient access to technology needed for video visits, patients' perceptions about video visits, the amount patients would be willing to pay out-of-pocket for video visits, and total time patients expect to spend during a standard clinic visit. RESULTS: We completed 108 surveys of adult patients. Of the patients, 94% owned a device that could be used for a video visit. The median level of patient interest in video visits was reported as 72 out of 100 (interquartile range: 51.25; scale: 0-100,) with a statistically significant difference in interest level across different age groups (P = .022). The median amount patients reported they were willing to pay out-of-pocket for video visits was $20 (interquartile range: $39.25, max: $174). CONCLUSION: The vast majority of patients in our outpatient urology clinic possess the technology necessary to engage in video visits. Patients are highly interested in video visits and report a willingness to share in the costs of these visits. Given that a portion of patients travel long distances for specialty clinic visits, video visits have the potential to substantially improve the patient experience. PMID- 28843775 TI - Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-kappaB signaling pathway in secondary hyperparathyroidism. AB - Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1-34). In Caco-2 cells, PTH (1-34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13-34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-kappaB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-kappaB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment. PMID- 28843777 TI - Feasibility of Intracorporeal Robotic-Assisted Laparoscopic Appendiceal Interposition for Ureteral Stricture Disease: A Case Report. AB - OBJECTIVE: To describe a robotic-assisted laparoscopic (RAL) technique for using the appendix to repair ureteral stricture disease MATERIALS AND METHODS: A case of a patient presenting with a 5-cm obliterative right ureteral stricture was reviewed, and surgical technique, complications, and outcomes were reported. RESULTS: Our patient developed a right-sided 5-cm obliterative ureteral stricture secondary to recurrent stone disease and pyelonephritis. He underwent an uncomplicated RAL repair of his stricture with interposition of the appendix between the 2 segments of ureter. Operative time was just over 6 hours, blood loss was minimal, and there were no complications. A 10-month follow-up showed resolution of hydronephrosis with no flank pain. CONCLUSION: We report our initial experience with this procedure and believe that RAL appendiceal interposition for ureteral stricture disease presents an excellent option for reconstruction. PMID- 28843778 TI - Elimination of dysfunctional mitochondria through mitophagy suppresses benzo[a]pyrene-induced apoptosis. AB - Mitophagy, a special type of autophagy, plays an important role in the mitochondria quality control and cellular homeostasis. In this study, we examined the molecular mechanism of mitophagy induction with benzo[a]pyrene (B[a]P), a ubiquitous polycyclic aromatic hydrocarbon, which acts as a prosurvival response against apoptotic cell death. Our study showed that B[a]P displayed higher cytotoxicity in autophagy-deficient HaCaT cells as compared to control. Further, we showed that B[a]P triggered the Beclin-1-dependent autophagy through the mammalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK) pathway. Moreover, our study indicated that the B[a]P-induced autophagy was initiated through the activation of cytochrome P450 1B1 (CYP1B1) and the aryl hydrocarbon receptor (AhR) in HaCaT cells. Intriguingly, the B[a]P-induced Beclin-1-mediated mitophagy was suppressed in CYP1B1 and AhR knockdown HaCaT cells, indicating a crucial role of B[a]P activation in the mitophagy induction to regulate cell death. B[a]P was shown to increase the mitochondrial dysfunction and decrease the mitochondrial membrane potential, resulting in depletion of ATP level along with the inhibition of the oxygen consumption rate in HaCaT cells. Importantly, the supplementation of methyl pyruvate compensated for the B[a]P-induced drop in the ATP level and mitigated the reactive oxygen species burden and autophagy. Mechanistically, B[a]P inhibited the manganese superoxide dismutase (MnSOD) activity and we found that the activated mitochondrial CYP1B1 interacted with MnSOD, inflicting mitophagy to protect from B[a]P-induced apoptosis. In summary, our study reveals mitophagy induction as a cellular protection mechanism against B[a]P-triggered toxicity and carcinogenesis. PMID- 28843779 TI - Endogenous, regulatory cysteine sulfenylation of ERK kinases in response to proliferative signals. AB - ERK-dependent signaling is key to many pathways through which extracellular signals are transduced into cell-fate decisions. One conundrum is the way in which disparate signals induce specific responses through a common, ERK-dependent kinase cascade. While studies have revealed intricate ways of controlling ERK signaling through spatiotemporal localization and phosphorylation dynamics, additional modes of ERK regulation undoubtedly remain to be discovered. We hypothesized that fine-tuning of ERK signaling could occur by cysteine oxidation. We report that ERK is actively and directly oxidized by signal-generated H2O2 during proliferative signaling, and that ERK oxidation occurs downstream of a variety of receptor classes tested in four cell lines. Furthermore, within the tested cell lines and proliferative signals, we observed that both activation loop-phosphorylated and non-phosphorylated ERK undergo sulfenylation in cells and that dynamics of ERK sulfenylation is dependent on the cell growth conditions prior to stimulation. We also tested the effect of endogenous ERK oxidation on kinase activity and report that phosphotransfer reactions are reversibly inhibited by oxidation by as much as 80-90%, underscoring the importance of considering this additional modification when assessing ERK activation in response to extracellular signals. PMID- 28843781 TI - Biochemical composition of marine monogenean parasite eggs. AB - This study on the eggs of the tropical monogenean Neobenedenia girellae presents the first detailed quantitative biochemical information of a marine parasite species' eggs. Moisture and protein composed the majority of the contents of freshly laid eggs (79.12+/-0.82 and 11.51+/-0.49% respectively) followed by lipid (2.50+/-0.15%). Lipids were composed of approximately equal amounts of saturated, monounsaturated, and polyunsaturated fatty acids and the predominant lipid class was triacylglycerol (33.82+/-1.20%). This study represents a fundamental step towards a better understanding of the early life biology of this important species of parasite. PMID- 28843782 TI - Rodent-free cyclical transmission of Trypanosoma brucei brucei. AB - We provide a simple protocol enabling cyclical transmission of Trypanosoma brucei brucei to be performed without the need for mammals. These procedures have two advantages: they are in line with 3R principles of animal use - replace, refine, reduce - and may enable more laboratories to study the complete life cycle. PMID- 28843780 TI - Epidemiology of estrogen and dementia in women with Down syndrome. AB - Several lines of investigation have shown a protective role for estrogen in Alzheimer's disease through a number of biological actions. This review examines studies of the role of estrogen-related factors in age at onset and risk for Alzheimer's disease in women with Down syndrome, a population at high risk for early onset of dementia. The studies are consistent in showing that early age at menopause and that low levels of endogenous bioavailable estradiol in postmenopausal women with Down syndrome are associated with earlier age at onset and overall risk for dementia. Polymorphisms in genes associated with estrogen receptor activity and in genes for estrogen biosynthesis affecting endogenous estrogen are related to age at onset and cumulative incidence of dementia, and may serve as biomarkers of risk. To date, no clinical trials of estrogen or hormone replacement therapy (ERT/HRT) have been published for women with Down syndrome. While findings from clinical trials of ERT or HRT for dementia have generally been negative among women in the neurotypical population, the short interval between menopause and onset of cognitive decline, together with a more positive balance between potential benefits and risks, suggests an opportunity to evaluate the efficacy of ERT/HRT for delaying or preventing dementia in this high risk population, although questions concerning the optimal formulation and timing of the hormone therapy are not yet resolved. PMID- 28843783 TI - What are the likely IVF/ICSI outcomes if there is a discrepancy between serum AMH and FSH levels? A multicenter retrospective study. AB - OBJECTIVE: The principal outcome was to assess the ovarian response to controlled hyperstimulation during in vitro fertilization (IVF) with or without micro injection (ICSI) in patients whom ovarian reserve testing revealed a discrepancy between the serum levels of FSH and AMH. The secondary outcome was to determine whether AMH and FSH profiles could predict the IVF/ICSI response. STUDY DESIGN: This was a multicenter, retrospective study analysing all controlled ovarian hyperstimulation cycles with attempted fresh embryo transfer(s) carried out during IVF/ICSI treatment and in which the AMH level had been assayed between January 01, 2008 and December 31, 2011. This enabled us to form 2 control groups (NOR, normal ovarian reserve: normal AMH and FSH and DOR, diminished ovarian reserve: diminished AMH, increased FSH) and 2 study groups (DAMH: diminished AMH, normal FSH and NAMH: normal AMH, increased FSH). The principal assessment criterion was quantitative ovarian response to stimulation defined by the mean number of oocytes punctured, the secondary assessment criterion the qualitative response to stimulation defined by the pregnancy rate per cycle. RESULTS: We were able to analyse 1803 stimulation cycles. The mean number of oocytes punctured was significantly reduced in the DAMH and DOR groups compared to the NAMH and NOR groups (5.2+/-3.9 and 4.1+/-3.3 vs. 11.5+/-7 and 9.5+/-5.6, respectively [P<0.01]). The pregnancy rate per initiated cycle was significantly reduced in the DAMH and DOR groups compared to the NAMH and NOR groups (20% and 24% vs. 32 and 35%, respectively [P<0.01]). Live birth rates did not differ between the groups however. Multivariate analysis with logistic regression revealed that AMH, FSH and age independently had an effect on the number of oocytes punctured, although the effect exerted by AMH seemed to be preponderant (OR: 2.75: 95%CI [2.39-3.19]). AMH appeared to be the sole factor independently predictive of pregnancy per cycle. CONCLUSION: The serum AMH level appears to provide an additional item of discriminatory information, which should not be overlooked. Ovarian reserve work-up should include routine AMH assay. PMID- 28843784 TI - How many differentially expressed genes: A perspective from the comparison of genotypic and phenotypic distances. AB - Identifying differentially expressed genes is critical in microarray data analysis. Many methods have been developed by combining p-value, fold-change, and various statistical models to determine these genes. When using these methods, it is necessary to set up various pre-determined cutoff values. However, many of these cutoff values are somewhat arbitrary and may not have clear connections to biology. In this study, a genetic distance method based on gene expression level was developed to analyze eight sets of microarray data extracted from the GEO database. Since the genes used in distance calculation have been ranked by fold change, the genetic distance becomes more stable when adding more genes in the calculation, indicating there is an optimal set of genes which are sufficient to characterize the stable difference between samples. This set of genes is differentially expressed genes representing both the genotypic and phenotypic differences between samples. PMID- 28843785 TI - HIF-1alpha coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress. AB - Hypoxia inducible factor 1 alpha (HIF-1alpha) regulates a diverse range of pathophysiological processes. It has been demonstrated previously that HIF-1alpha plays a role in the pathogenesis of steatosis mediating the effects of excessive nutritional insults. In the present study we investigated the role of HIF-1alpha in trans-activating the seven in absentia homolog 1 (SIAH1) gene and the underlying mechanism. We report that in response to nutritional stress, SIAH1 expression was up-regulated in the liver in mice and in cultured hepatocytes. In the meantime, HIF-1alpha started to occupy the SIAH1 promoter. Depletion of HIF 1alpha with siRNA or inhibition of HIF-1alpha with chetomin abrogated the induction of SIAH1 expression. HIF-1alpha knockdown or inhibition paralleled epigenetic alterations surrounding the SIAH1 promoter characterized by the loss of acetylated histone H3 and trimethylated H3K4 as well as the acquisition of dimethylated H3K9. Further analyses revealed that HIF-1alpha interacted with and recruited the histone demethylase KDM3A to the SIAH1 promoter to activate transcription. HIF-1alpha also mediated the crosstalk between KDM3A and p300. Depletion of KDM3A coincided with the loss of SIAH1 induction and the accumulation of dimethylated H3K9 surrounding the SIAH1 promoter. Interestingly, KDM3A expression was also up-regulated by nutritional stress in a HIF-1alpha dependent manner. Together, our data uncover a novel epigenetic pathway that may contribute to the regulation of SIAH1 expression and the pathogenesis of steatosis. PMID- 28843786 TI - Use of M2e ELISAs for longitudinal surveillance of commercial poultry in Indonesia vaccinated against highly pathogenic avian influenza. AB - In countries where highly pathogenic avian influenza virus (HPAIV) H5N1 is endemic and controlled by vaccination, post-vaccination serological monitoring is essential to differentiate vaccinated poultry from those that are infected. The objectives of this study were to validate two experimental ELISAs that detect antibodies raised against the M2e protein of avian influenza virus that can be used for DIVA purposes. Results from the sM2e and tM2e ELISAs were compared with other conventional tests for the detection of H5N1influenza virus (virus isolation and RT-PCR) using samples collected from 16 commercial flocks in Indonesia. These comprised vaccinated layers aged between 18 and 68 weeks old that were sampled at ten-weekly intervals. A small number of sera were positive in sM2e and tM2e ELISA, 14 (0.6%) and 17 (0.7%) respectively, with low OD420 (0.1 0.3), but only 4 sera were positive in both tests. At the flock level, the incidence of M2e positive sera was low (4%), well below previously established minimum of 40% for an HPAIV H5N1-infected flock. Conventional M and H5 gene RT PCRs indicated that none of 16 flocks were infected at any time during the study. No virus was isolated from any of the 480 pooled swab samples, except from one, for which the combined data analysis suggest to be the result of a laboratory cross-contamination. Clinical disease, mortalities or reduction in production performance, indicative of field H5N1 challenge, were not observed either in any of the flocks. Birds from two surveyed flocks, challenged in the laboratory with an Indonesian HPAIV H5N1 developed M2e antibodies in 50% and 55% of surviving birds with OD420 in the range of 0.35-1.47 in tM2e ELISA, confirming the validity of the criteria established for use of M2e ELISA for DIVA purposes. Overall these results showed that the tM2e ELISA could be a useful monitoring tool to ascertain freedom from H5N1 infections in vaccinated commercial poultry. PMID- 28843787 TI - A rapid ultrasound particle agglutination method for HIV antibody detection: Comparison with conventional rapid HIV tests. AB - We present the results of the feasibility and preliminary studies on analytical performance of a rapid test for detection of human immunodeficiency virus (HIV) antibodies in human serum or plasma that is an important advance in detecting HIV infection. Current methods for rapid testing of antibodies against HIV are qualitative and exhibit poor sensitivity (limit of detection). In this paper, we describe an ultrasound particle agglutination (UPA) method that leads to a significant increase of the sensitivity of conventional latex agglutination tests for HIV antibody detection in human serum or plasma. The UPA method is based on the use of: 1) a dual mode ultrasound, wherein a first single-frequency mode is used to accelerate the latex agglutination process, and then a second swept frequency mode of sonication is used to disintegrate non-specifically bound aggregates; and 2) a numerical assessment of results of the agglutination process. The numerical assessment is carried out by optical detection and analysis of moving patterns in the resonator cell during the swept-frequency mode. The single-step UPA method is rapid and more sensitive than the three commercial rapid HIV test kits analyzed in the study: analytical sensitivity of the new UPA method was found to be 510-, 115-, and 80-fold higher than that for CapillusTM, MultispotTM and Uni-GoldTM Recombigen HIV antibody rapid test kits, respectively. The newly developed UPA method opens up additional possibilities for detection of a number of clinically significant markers in point-of-care settings. PMID- 28843788 TI - Concentration and quantification of somatic and F+ coliphages from recreational waters. AB - Somatic and F+ coliphages are promising alternative fecal indicators, but current detection methods are hindered by lower levels of coliphages in surface waters compared to traditional bacterial fecal indicators. We evaluated the ability of dead-end hollow fiber ultrafiltration (D- HFUF) and single agar layer (SAL) procedure to concentrate and enumerate coliphages from 1L and 10L volumes of ambient surface waters (lake, river, marine), river water with varying turbidities (3.74-118.7 NTU), and a simulated combined sewer overflow (CSO) event. Percentage recoveries for surface waters were 40-79% (somatic) and 35-94% (F+). The method performed equally well in all three matrices at 1L volumes, but percent recoveries were significantly higher in marine waters at 10L volumes when compared to freshwater. Percent recoveries at 1L and 10L were similar, except in river water where recoveries were significantly lower at higher volume. In highly turbid waters, D-HFUF-SAL had a recovery range of 25-77% (somatic) and 21-80% (F+). The method produced detectable levels of coliphages in diluted wastewater and in unspiked surface waters, emphasizing its applicability to CSO events and highlighting its utility in recovery of low coliphage densities from surface waters. Thus D-HFUF-SAL is a good candidate method for routine water quality monitoring of coliphages. PMID- 28843789 TI - In vitro particulate and in vivo drug retention study of a novel polyethylene oxide formulation for drug-coated balloons. AB - OBJECTIVE: The purpose of this study was to investigate the newly developed drug coated balloon (DCB) using polyethylene oxide (PEO) as a platform and to compare it directly with a commercially available DCB in a preclinical experimental setting. METHODS: The PEO balloon was characterized for coating morphology and degree of paclitaxel (PAT) crystallinity. PAT tissue levels were then measured up to 30 days in a healthy porcine model (10 swine, 20 vessels) after treatment with either a PEO balloon or a commercially available DCB. An in vitro bench-top model was used to compare the particulates released from the PEO balloon and commercially available DCB. RESULTS: The coating on the PEO balloon was smooth and homogeneous with PAT in its amorphous state. From the porcine survival study, the PAT tissue levels were comparable between PEO balloon and commercially available DCB after 7 days of treatment. Both the PEO balloon and the commercially available DCB retained therapeutic drug up to 30 days. During the simulated in vitro model, the PEO balloon shed significantly fewer particulates that were smaller than those of the commercially available DCB. Most important, the PEO balloon shed 25 times fewer large particulates than the commercially available DCB. CONCLUSIONS: The amorphous PAT in the PEO balloon provided comparable drug tissue retention levels to those of the commercially available DCB and fewer particulates. Thus prepared PEO balloon proved to be safe and effective in the preclinical experimental setting. The clinical outcomes of these findings need further investigation. PMID- 28843790 TI - Circulating biomarkers are not associated with endoleaks after endovascular repair of abdominal aortic aneurysms. AB - OBJECTIVE: Endoleak is a common complication of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) but can be detected only through prolonged follow-up with repeated aortic imaging. This study examined the potential for circulating matrix metalloproteinase 9 (MMP9), osteoprotegerin (OPG), D-dimer, homocysteine (HCY), and C-reactive protein (CRP) to act as diagnostic markers for endoleak in AAA patients undergoing elective EVAR. METHODS: Linear mixed-effects models were constructed to assess differences in AAA diameter after EVAR between groups of patients who did and did not develop endoleak during follow-up, adjusting for potential confounders. Circulating MMP9, OPG, D-dimer, HCY, and CRP concentrations were measured in preoperative and postoperative plasma samples. The association of these markers with endoleak diagnosis was assessed using linear mixed effects adjusted as before. The potential for each marker to diagnose endoleak was assessed using receiver operating characteristic curves. RESULTS: Seventy-five patients were included in the study, 24 of whom developed an endoleak during follow-up. Patients with an endoleak had significantly larger AAA sac diameters than those who did not have an endoleak. None of the assessed markers showed a significant association with endoleak. This was confirmed through receiver operating characteristic curve analyses indicating poor diagnostic ability for all markers. CONCLUSIONS: Circulating concentrations of MMP9, OPG, D-dimer, HCY, and CRP were not associated with endoleak in patients undergoing EVAR in this study. PMID- 28843791 TI - Low total psoas area as scored in the clinic setting independently predicts midterm mortality after endovascular aneurysm repair in male patients. AB - OBJECTIVE: Preoperative sarcopenia is an established risk factor for poor outcomes after surgery. Methods for assessing sarcopenia are either complex, time consuming, or poorly validated. We aimed to assess the interobserver reliability of scoring psoas area at the level of the L3 vertebra and to evaluate whether sarcopenia scored by this simple and rapid method correlated with other fitness scoring methods or impacted on mortality and duration of stay for patients undergoing endovascular aneurysm repair (EVAR). METHODS: We had access to 191 preoperative computed tomography scans of patients who underwent EVAR. For each scan the axial slice at the most caudal level of the L3 vertebra was extracted. Three observers independently calculated the combined cross-sectional area of the left and right psoas muscle at this level. Interobserver variability was calculated as per Band and Altman. Psoas area was normalized for patient height with sarcopenia defined as total psoas area of <500 mm2/m2. The effect of sarcopenia on patient survival was assessed using Cox proportional hazards models. Kaplan-Meier curves are also presented. RESULTS: Interobserver reliability of scoring psoas area was acceptable (reproducibility coefficient as percent of mean for each observer pair: 7.92%, 7.95%, and 14.33%). Sarcopenic patients had poorer survival (hazard ratio, 2.37; P = .011) and an increased hospital duration of stay (4.0 days vs 3.0 days; P = .008) when compared with nonsarcopenic patients. Sarcopenic patients were more likely to self-report as unfit (12.4% vs 33.3%; P = .004). Sarcopenia did not correlate with an increased rate of postprocedure complications. CONCLUSIONS: Psoas area scoring has good interobserver reliability. Preoperative sarcopenia as defined by psoas area was associated with poorer survival and of longer length of stay. As all patients being worked up for an endovascular aortic aneurysm repair will undergo a computed tomography scan, this method is a rapid and effective way to highlight patients in the clinic setting who have an increased risk of morbidity and mortality after EVAR. PMID- 28843792 TI - Ultrasensitive electrochemical detection of tumor cells based on multiple layer CdS quantum dots-functionalized polystyrene microspheres and graphene oxide - polyaniline composite. AB - In this work, a novel ultrasensitive electrochemical biosensor was developed for the detection of K562 cell by a signal amplification strategy based on multiple layer CdS QDs functionalized polystyrene microspheres(PS) as bioprobe and graphene oxide(GO) -polyaniline(PANI) composite as modified materials of capture electrode. Due to electrostatic force of different charge, CdS QDs were decorated on the surface of PS by PDDA (poly(diallyldimethyl-ammonium chloride)) through a layer-by-layer(LBL) assemble technology, in which the structure of multiple layer CdS QDs increased the detection signal intensity. Moreover, GO-PANI composite not only enhanced the electron transfer rate, but also increased tumor cells load ratio. The resulting electrochemical biosensor was used to detect K562 cells with a lower detection limit of 3 cellsmL-1 (S/N = 3) and a wider linear range from 10 to 1.0 * 107 cellsmL-1. This sensor was also used for mannosyl groups on HeLa cells and Hct116 cells, which showed high specificity and sensitivity. This signal amplification strategy would provide a novel approach for detection, diagnosis and treatment for tumor cells. PMID- 28843793 TI - Construction of an ultrasensitive non-enzymatic sensor to investigate the dynamic process of superoxide anion release from living cells. AB - In this work, a novel non-enzymatic superoxide anion (O2*-) sensor was constructed based on Ag nanoparticles (NPs) / poly (amidoamine) (PAMAM) dendrimers and used to investigate the dynamic process of O2*- release from living cells. The AgNPs/PAMAM nanohybrids were characterized by transmission electron microscopy (TEM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The fabricated electrode exhibited excellent catalytic activity toward the reaction of O2*- with a super low detection limit (LOD) of 2.530 * 10-13M (S/N = 3) and wide linear range of 8 orders of magnitude. It could fulfill the requirement of real-time measurement O2*- released from living cells. Furthermore, zymosan was chosen as the stimulant to induce O2*- generation from cancer cells (rat adrenal medulla pheochromocytoma cell (PC12)). The electrochemical experiment results indicated that the levels of intracellular O2* depended on the amount of Zymosan. A large amount of O2*- generated in the living cells by added heavy stimulant could damage cells seriously. More importantly, a vitro simulation experiment confirmed the role of superoxide dismutase (SOD) for the first time because it could maintain the O2*- concentration at a normal physiological range. These findings are of great significance for evaluating the metabolic processes of O2*- in the biological system, and this work has the tremendous potential application in clinical diagnostics to assess oxidative stress. PMID- 28843794 TI - Photochemical, thermal, biological and long-term degradation of celecoxib in river water. Degradation products and adsorption to sediment. AB - Celecoxib is an anti-inflammatory drug with antibacterial activity whose fate in surface water is unknown. Thus, some assays have been conducted under forced biological, photochemical and thermal conditions, and non-forced conditions, to establish its persistence and degradation products in river water. The results suggest that celecoxib dissolved in river water is not biologically degraded while it is minimally altered after its exposure to sunlight or high temperature (70 degrees C). Only the irradiation at 254nm promotes its complete degradation. Celecoxib is degraded about 3%, in 36 weeks, when water was kept at room temperature and the exposure to sunlight was partially limited as it happens inside a body of water. Residues were monitored by ultra-pressure liquid chromatography/quadrupole time-of-flight/mass spectrometry after solid-phase extraction; eleven degradation products were detected and the structures of nine of them were unequivocally proposed from the molecular formulae and fragmentation observed in high-resolution tandem mass spectra. The long-term transformation products under non-forced conditions were 4-[5-(4-methylphenyl)-3 (trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonic acid, 4-[1-(4-sulfoaminephenyl) 3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoic acid and a hydroxylated derivative. The degradation over time in presence of sediment was monitored, being slightly higher, about 4%. The adsorption equilibrium constants of celecoxib and degradation products on river sediment were estimated. PMID- 28843795 TI - Sustainable magnet-responsive nanomaterials for the removal of arsenic from contaminated water. AB - In this study, chitosan and bio-based substances (BBS) obtained from composted biowaste were used as stabilizers for the synthesis of magnet-sensitive nanoparticles (NPs) via coprecipitation method. A pyrolysis treatment was carried out on both biopolymers at 550 degrees C, and their consequent conversion into a carbon matrix was followed by means of different physicochemical characterization techniques (mainly FTIR spectroscopy and XRD), whereas magnetic properties were evaluated by magnetization curves. The prepared materials were tested in water remediation processes from arsenic (As) species (both inorganic and organic forms). These tests, explained by means of the most common adsorption models, evidenced that the best performances were reached by both materials obtained after pyrolysis treatments, pointing out the promising application of such magnet sensitive materials as easy-recoverable tools for water purification treatments. PMID- 28843796 TI - Development of bioreactors for comparative study of natural attenuation, biostimulation, and bioaugmentation of petroleum-hydrocarbon contaminated soil. AB - Bioremediation of soil and groundwater sites contaminated by petroleum hydrocarbons is known as a technically viable, cost-effective, and environmentally sustainable technology. The purpose of this study is to investigate laboratory-scale bioremediation of petroleum-hydrocarbon contaminated soil through development of eight bioreactors, two bioreactors for each bioremediation mode. The modes were: (1) natural attenuation (NA); (2) biostimulation (BS) with oxygen and nutrients; (3) bioaugmentation (BA) with hydrocarbon degrading isolates; (4) a combination of biostimulation and bioaugmentation (BS-BA). Total petroleum hydrocarbons (TPH) mass balance over the bioreactors showed about 2% of initial 20,000mgkg-soil-1 TPH was removed by advection due to synthetic groundwater which was flowing through the soil, and the rest of decrease in TPH was caused by biodegradation. The BS-BA mode showed the highest TPH biodegradation percentage (89.7+/-0.3%) compared to the NA (51.4+/-0.6%), BS (81.9+/-0.3%) and BA (62.9+/-0.5%) modes. Furthermore, an increase in microbial population was another evidence of TPH biodegradation by microorganism. Reaction rate data from each bioremediation mode were fitted with a first-order reaction rate model. The Monod kinetic constants including maximum specific growth rate of microorganisms (MUmax) and substrate concentration at half-velocity constant (Ks) were estimated for each bioremediation modes. PMID- 28843797 TI - Risk-based underground pipeline safety management considering corrosion effect. AB - Due to the long term usage and irregular maintenance for corrosion checks, catastrophic accidents have been increasing in underground pipelines. In this study, a new safety management methodology of underground pipeline, risk-based pipeline management, is introduced reflecting corrosion effect. First, principle of the risk-based pipeline management is presented compared with an original method, qualitative measure. It is distinguished from the qualitative measure by reflecting societal risk and corrosion in safety management of underground pipeline. And then, it is applied to an existing underground propylene pipeline in Ulsan Industrial Complex, South Korea. The consequence analysis is based on real information, and the frequency analysis reflects degree of corrosion. For calculation of corrosion rate, direct current voltage gradient (DCVG) and close interval potential survey (CIPS) are conducted. As a result of applying the risk based pipeline management, risk integral is reduced by 56.8% compared to the qualitative measure. Finally, sensitivity analysis is conducted on variables, which affect the risk of the pipeline. This study would contribute to introduce quantitative measure to pipeline management and increase safety of pipeline. PMID- 28843798 TI - Ruthenium oxides supported on heterostructured CoPO-MCF materials for catalytic oxidation of vinyl chloride emissions. AB - A novel heterostructured material, cobalt phosphate-SiO2 mesostructured cellular foams (CoPO-MCF), was successfully synthesized by in situ growth. The material was characterized by X-ray diffraction (XRD), nitrogen sorption, temperature programmed reduction (H2-TPR and CO-TPR), temperature-programmed desorption of NH3 (NH3-TPD), and X-ray photoelectron spectroscopy (XPS). A ruthenium precursor was readily introduced and highly dispersed on the CoPO nanophases of the CoPO MCF through an impregnation method. The resulting Ru/CoPO-MCF catalyst exhibited high catalytic activity for the oxidation of vinyl chloride (VC). The results of three consecutive runs and long-term tests showed high stability of the Ru/CoPO MCF for the catalytic oxidation of VC. The unique heterostructures of the CoPO MCF not only improve the reducibility and acidity of the MCF but also strengthen the interaction between ruthenium oxide nanoparticles and the CoPO-MCF support, which contributes to the enhanced catalytic performance. PMID- 28843799 TI - Increased obesity risks for being an only child in China: findings from a nationally representative study of 19,487 children. AB - OBJECTIVES: Given the rapid demographic transition and obesity growth in China, it is important to study how the large only-child population (~100 million) might contribute to the obesity epidemic. This study evaluated associations of only child status with weight and energy expenditure-related behaviors in China and examined how the associations may vary by sex and urbanicity. STUDY DESIGN: Secondary analyses of nationally representative cross-sectional data from China Education Panel Survey: Junior Cohorts 2013-14, which included 19,487 students from 112 middle schools in 28 regions across China. METHODS: We used propensity score-weighted multilevel models to test associations between only-child status and weight outcomes. RESULTS: Compared with sibling-sons, only-sons had higher body mass index (BMI) (Beta = 0.32, P < 0.05) and higher risks of overweight (OR = 1.24, 95% CI = [1.07-1.45]) and obesity (OR = 1.29, 95% CI = [1.02-1.64]); and spent less time on TV watching (Incidence rate ratio (IRR) = 0.89, 95% CI = [0.81 0.98]), internet use (IRR = 0.87, 95% CI = [0.79-0.96]), after-school sports (IRR = 0.91, 95% CI = [0.83-0.99]), and household chores (IRR = 0.85, 95% CI = [0.80 0.92]). Overweight/obesity risks for only-sons were particularly pronounced in urban China, where only-sons were 36% more likely to be overweight and 43% more likely to be obese than sibling-sons. Only-daughters had a higher risk of obesity (OR = 1.43, 95% CI = [1.01-2.04]) than sibling-daughters. However, the association was not significant for either urban girls or rural girls examined separately. Only-daughters in rural areas spent less time helping with household chores (IRR = 0.88, 95% CI = [0.80-0.97]) than sibling-daughters. CONCLUSIONS: Future childhood obesity interventions should pay special attention targeting the large young only-child population in China. PMID- 28843800 TI - Striatal synapses, circuits, and Parkinson's disease. AB - The striatum is a hub in the basal ganglia circuitry controlling goal directed actions and habits. The loss of its dopaminergic (DAergic) innervation in Parkinson's disease (PD) disrupts the ability of the two principal striatal projection systems to respond appropriately to cortical and thalamic signals, resulting in the hypokinetic features of the disease. New tools to study brain circuitry have led to significant advances in our understanding of striatal circuits and how they adapt in PD models. This short review summarizes some of these recent studies and the gaps that remain to be filled. PMID- 28843801 TI - Endovascular Stroke Treatment of Patients Over 80 Years Old: Cumulative Evidence from the "Real World". AB - BACKGROUND: Evidence on stent retriever-based thrombectomy (SRT) efficacy in elderly patients is controversial. This study aimed to analyze safety and efficacy outcomes in octogenarians submitted to SRT. METHODS: Analysis was based on a prospective observational registry of patients with stroke because of anterior circulation large-vessel occlusion treated with SRT at our center between January 2015 and September 2016. Patients were dichotomized into 2 age groups: <=80 and >80 years old. Outcomes at 90 days were assessed: "excellent outcome" (a modified Rankin scale [mRs] score of 0-1) and "good outcome" (a mRs score of 0-2). RESULTS: A total of 141 patients were included: 35 (24.8%) >80 years old and 106 (71.2%) <=80 years old; 43.4% of patients in the younger group and 25.7% of patients in the older group achieved an "excellent outcome." A "good outcome" was achieved in 65.1% of patients in the younger group, and 60% of patients in the older group; crude odds ratio (OR) for "excellent outcome" was 0.452 (P = .067). Crude OR for "good outcome" was 0.804 (P = .587). After adjusting for gender, National Institutes of Health Stroke Scale score at admission, Alberta Stroke Program Early CT Score, and thrombolysis, the OR was 0.450 (P = .100) and 1.217 (P = .686) for "excellent" and "good" outcomes, respectively. CONCLUSIONS: In this cohort, 60% of elderly patients regained functional independence at 3 months after SRT. Although age may be a prognostic factor, patients should not be excluded from SRT based on age criteria. PMID- 28843802 TI - A Recurrent Case of Ischemic Stroke Caused by Vasospasm due to Giant Cell Arteritis. AB - A 73-year-old man was admitted with sudden right upper-limb weakness. He had a temporal headache on the left side and had a 4-month history of fever. Meandering of the left temporal artery (TA) with induration and high inflammatory responses (white blood cell count 22,500 per microliter, C-reactive protein 35.0 mg/dL, and elevated sedimentation rate [ESR] 80 mm/h) were observed. Glycometabolism and lipid metabolism were normal, and autoimmune antibodies were negative. Cultivation tests revealed no bacteria in either blood culture or cerebrospinal fluid. Brain magnetic resonance imaging (MRI) showed ischemic lesion in the left frontal lobe, while magnetic resonance angiography (MRA) and carotid ultrasonography showed unstable plaque lesions in the left extracranial internal carotid artery (ICA). According to reported criteria (age > 50 years, new onset of headache, abnormality of the TA, and raised ESR), we diagnosed giant cell arteritis (GCA) with acute ischemic stroke (IS) and gave the patient antithrombotic therapy (aspirin 100 mg, cilostazol 200 mg). After admission, hemiparesis progressed but fluctuated. Subsequent MRI showed new lesions in the left watershed area. MRA also showed vasospasm in the middle cerebral artery and C5 portion of the ICA. Considering the correlation with GCA pathophysiology, oral prednisolone therapy was administered. Steroid therapy has prevented stroke recurrence and improved the symptoms and vasospasm. We wish to emphasize that GCA can induce IS via vasospasm, and steroid therapy is recommended. PMID- 28843804 TI - Intra-Arterial Alteplase Thrombolysis during Mechanical Thrombectomy for Acute Ischemic Stroke. AB - BACKGROUND: Intra-arterial alteplase (IA tPA) is commonly used during mechanical thrombectomy for acute ischemic stroke in patients with large-vessel occlusion, but specific indications and applications for its use remain undefined. METHODS: We analyzed 40 patients who underwent stent-retriever mechanical thrombectomy, 28 of whom received adjunctive IA tPA. To our knowledge, this is the largest cohort with this concomitant treatment reported in the literature in the post-mechanical thrombectomy trial era. RESULTS: Between patients with and without IA tPA, rates of hemorrhagic conversion, neurologic outcome, and mortality were equivalent, with a trend toward improved angiographic revascularization observed in the IA tPA group. CONCLUSIONS: IA tPA is a safe adjunct to mechanical thrombectomy, and more investigation is warranted to understand ideal indications and dosage methodologies. PMID- 28843803 TI - Downregulation of Apolipoprotein-E and Apolipoprotein-J in Moyamoya Disease-A Proteome Analysis of Cerebrospinal Fluid. AB - BACKGROUND AND PURPOSE: Genetic factors are closely involved in the etiology of moyamoya disease (MMD). However, its postgenomic mechanisms are still unknown. This study was aimed to identify specific biomarkers in the cerebrospinal fluid (CSF) of patients with MMD, using quantitative proteome technique. METHODS: This study included 10 patients with MMD and 4 controls. The CSF was collected without blood contamination during surgery. A comparative 2-dimensional gel electrophoresis study (2D-PAGE) was performed. Protein spots that showed significant differences between moyamoya patients and controls were selected for further analysis by mass spectrometry. RESULTS: On 2D-PAGE, 2 proteins were significantly upregulated, and 2 other proteins were downregulated in the CSF of MMD. Further mass spectrometry analysis revealed that haptoglobin and alpha-1-B glycoprotein (A1BG) were upregulated. On the other hand, apolipoprotein-E (apoE), apoE precursor, and apolipoprotein-J (apoJ) were significantly downregulated in the CSF of MMD. The observed probability-based MOWSE score was 72 for haptoglobin (P <.05), 521 for A1BG (P <.05), 62 for apoE (P <.05), 72 for apoE precursor (P <.05), and 112 for apoJ (P <.05). CONCLUSION: Although the role of A1BG in the central nervous system is still unknown, the overexpressed haptoglobin may indicate the inflammation and/or angiogenesis in MMD. The downregulation of apoE and apoJ strongly suggests a critical role of lipid metabolism in the development and progression of MMD. These proteins may be novel biomarkers in shedding light on the pathogenesis of MMD, although further studies would be warranted. PMID- 28843805 TI - Superior Microvascular Perfusion of Infused Liposome-Encapsulated Hemoglobin Prior to Reductions in Infarctions after Transient Focal Cerebral Ischemia. AB - BACKGROUND: The development of cerebral infarction after transient ischemia is attributed to postischemic delayed hypoperfusion in the microvascular region. In the present study, we assessed the microvascular perfusion capacity of infused liposome-encapsulated hemoglobin (LEH) in a therapeutic approach for transient middle cerebral artery occlusion (tMCAO). METHODS: Two-hour middle cerebral artery occlusion rats were immediately subjected to intra-arterial infusion of LEH (LEH group) or saline (vehicle group) or no treatment (control group), and then to recanalization. Neurological findings, infarct and edema progression, microvascular endothelial dysfunction, and inflammatory reactions were compared between the 3 groups after 24 hours of reperfusion. Microvascular perfusion in the early phase of reperfusion was evaluated by hemoglobin immunohistochemistry and transmission electron microscopy. RESULTS: The LEH group achieved significantly better results in all items evaluated than the other groups. Hemoglobin immunohistochemistry revealed that the number of hemoglobin-positive microvessels was significantly greater in the LEH group than in the other groups (P < .01), with microvascular perfusion being more likely in narrow microvessels (<=5 um in diameter). An electron microscopic examination revealed that microvessels in the control group were compressed and narrowed by swollen astrocyte end-feet, whereas those in the LEH group had a less deformed appearance and contained LEH particles and erythrocytes. CONCLUSION: The results of the present study demonstrated that the infusion of LEH reduced infarctions after tMCAO with more hemoglobin-positive and less deformed microvessels at the early phase of reperfusion, suggesting that the superiority of the microvascular perfusion of LEH mediates its neuroprotective effects. PMID- 28843806 TI - Treatment of Cryptogenic Stroke with Active Cancer with a New Oral Anticoagulant. AB - BACKGROUND: Low-molecular weight heparin (LMWH) was shown to be effective and safe in treating venous thromboembolism, and generally used for stroke in cancer patients, but its effects on stroke are unclear. We compared clinical outcomes between LMWH and new oral anticoagulant (NOAC) in patients with cancer-related stroke. METHODS: We enrolled patients with cryptogenic ischemic stroke with active cancer who were treated with LMWH or NOAC between May 2012 and June 2015. The clinical outcomes, including early neurologic deterioration, early radiologic recurrence, 3-month modified Rankin scale score, 90-day mortality, cardio cerebrovascular recurrence, and bleeding complications, were compared. RESULTS: Among 48 patients, 7 patients were treated with NOAC, and the remaining 41 patients with LMWH. Overall, the participants presented poor outcomes, including 20 (42%) early neurologic deteriorations, 28 (58%) early radiologic recurrences, 34 (71%) poor modified Rankin scale scores, 27 (56%) 90-day mortality events, 24 (50%) cardio-cerebrovascular recurrences, and 18 (38%) bleeding complications, that led to a change or temporary hold in medication in 12 cases. No statistical differences were found between the 2 groups in terms of demographic, clinical, or cardiovascular risk factors and clinical outcomes. CONCLUSIONS: NOAC showed the similar clinical outcomes and safety compared with LMWH in the treatment of cryptogenic ischemic stroke in active cancer patients. PMID- 28843807 TI - A comparative study of procedures for binding of aflatoxin M1 to Lactobacillus rhamnosus GG. AB - Several strains of lactic acid bacteria (LAB), frequently used in food fermentation and preservation, have been reported to bind different types of toxins in liquid media. This study was carried out to investigate the effect of different concentrations of Lactobacillus rhamnosus GG (ATCC 53103) to bind aflatoxin M1 (AFM1) in liquid media. AFM1 binding was tested following repetitive washes or filtration procedures in combination with additional treatments such as heating, pipetting, and centrifugation. The mixture of L. rhamnosus GG and AFM1 was incubated for 18h at 37 degrees C and the binding efficiency was determined by quantifying the unbound AFM1 using HPLC. The stability of the complexes viable bacteria-AFM1 and heat treated bacteria-AFM1 was tested. Depending on the bacterial concentration and procedure used, the percentages of bound AFM1 by L. rhamnosus GG varied from as low as undetectable to as high as 63%. The highest reduction in the level of unbound AFM1 was recorded for the five washes procedure that involved heating and pipetting. Results also showed that binding was partially reversible and AFM1 was released after repeated washes. These findings highlight the effect of different treatments on the binding of AFM1 to L. rhamnosus GG in liquid matrix. PMID- 28843808 TI - How, not whether: contributions of others in the development of infant helping. AB - Young children's helping behaviors emerge and develop through everyday interactions with others. This paper proposes to sidestep the dichotomy between socialization and biological processes in research on early helping: The question is not whether but how others contribute to the development of infant helping. To answer this question, it is necessary to broaden conceptions of how others may contribute to the development of helping beyond explicit teaching and rewards. Recent experimental and observational research indicates that family members scaffold helping from the first year of life and that specific forms of scaffolding influences the development of helping. The roles of others appear to vary with child age and across communities and are responsive to children's social initiatives. PMID- 28843809 TI - Cis- and trans-acting lncRNAs in pluripotency and reprogramming. AB - Pervasive transcription in mammalian genomes produces thousands of long noncoding RNA (lncRNA) transcripts. Although they have been implicated in diverse biological processes, the functional relevance of most lncRNAs remains unknown. Recent studies reveal the prevalence of lncRNA-mediated cis regulation on nearby transcription. In this review, we summarize cis- and trans-acting lncRNAs involved in stem cell pluripotency and reprogramming, highlighting the role of regulatory lncRNAs in providing an additional layer of complexity to the regulation of genes that govern cell fate during development. PMID- 28843810 TI - Variability of human pluripotent stem cell lines. AB - Human pluripotent stem cells derived from embryos (human Embryonic Stem Cells or hESCs) or generated by direct reprogramming of somatic cells (human Induced Pluripotent Stem Cells or hiPSCs) can proliferate almost indefinitely in vitro while maintaining the capacity to differentiate into a broad diversity of cell types. These two properties (self-renewal and pluripotency) confers human pluripotent stem cells a unique interest for clinical applications since they could allow the production of infinite quantities of cells for disease modelling, drug screening and cell based therapy. However, recent studies have clearly established that human pluripotent stem cell lines can display variable capacity to differentiate into specific lineages. Consequently, the development of universal protocols of differentiation which could work efficiently with any human pluripotent cell line is complicated substantially. As a consequence, each protocol needs to be adapted to every cell line thereby limiting large scale applications and precluding personalised therapies. Here, we summarise our knowledge concerning the origin of this variability and describe potential solutions currently available to bypass this major challenge. PMID- 28843811 TI - Super resolution imaging of chromatin in pluripotency, differentiation, and reprogramming. AB - Chromatin fiber organization is essential for gene function in all cell types. Moreover it helps to determine cell fate in embryonic/adult stem cells and in somatic cells undergoing reprogramming to pluripotency. Until now the diffraction limit of light has limited the inspection of the chromatin fiber organization to a level sufficient to understand how it impacts gene function. The development of advanced microscopy methods, such as single molecule localization microscopy, has largely opened a new field of research providing us with the tools to visualize and quantitatively analyze chromatin fiber organization and thus gene activity at nanoscale resolution in single cells. PMID- 28843812 TI - Resistance of human plasmacytoid dendritic CAL-1 cells to infection with lymphocytic choriomeningitis virus (LCMV) is caused by restricted virus cell entry, which is overcome by contact of CAL-1 cells with LCMV-infected cells. AB - Plasmacytoid dendritic cells (pDCs), a main source of type I interferon in response to viral infection, are an early cell target during lymphocytic choriomeningitis virus (LCMV) infection, which has been associated with the LCMV's ability to establish chronic infections. Human blood-derived pDCs have been reported to be refractory to ex vivo LCMV infection. In the present study we show that human pDC CAL-1 cells are refractory to infection with cell-free LCMV, but highly susceptible to infection with recombinant LCMVs carrying the surface glycoprotein of VSV, indicating that LCMV infection of CAL-1 cells is restricted at the cell entry step. Co-culture of uninfected CAL-1 cells with LCMV-infected HEK293 cells enabled LCMV to infect CAL-1 cells. This cell-to-cell spread required direct cell-cell contact and did not involve exosome pathway. Our findings indicate the presence of a novel entry pathway utilized by LCMV to infect pDC. PMID- 28843813 TI - Live baculovirus acts as a strong B and T cell adjuvant for monomeric and oligomeric protein antigens. AB - Recombinant proteins produced by baculovirus (BV) expression systems contain residual BV after crude purification. We studied adjuvant effect of BV on antibody and T cell responses against two model antigens, monomeric ovalbumin (OVA) protein and oligomeric norovirus (NoV) virus-like particles (VLPs). BALB/c mice were immunized intradermally with OVA alone or OVA formulated with live or inactivated BV, and VLP formulations comprised of chromatographically purified NoV GII.4 VLPs alone or mixed with BV, or of crude purified VLPs containing BV impurities from expression system. Live BV improved immunogenicity of NoV VLPs, sparing VLP dose up to 10-fold. Moreover, soluble OVA protein induced IgG2a antibodies and T cell response only when co-administered with live BV. BV adjuvant effect was completely abrogated by removal or inactivation of BV. These findings support the usage of crude purified proteins containing residual BV as vaccine antigens. PMID- 28843814 TI - Interaction of 2A proteinase of human rhinovirus genetic group A with eIF4E is required for eIF4G cleavage during infection. AB - In enteroviruses, the inhibition of protein synthesis from capped host cell mRNA is catalyzed by the virally encoded 2A proteinase (2Apro), which cleaves eukaryotic initiation factors (eIF) 4GI and 4GII. Despite much investigation, the exact mechanism of 2Apro cleavage remains however unclear. Here, we identify the domains responsible for the eIF4E/HRV2 2Apro interaction using molecular modelling and describe mutations that impair this interaction and delay in vitro cleavage of eIF4G isoforms. Furthermore, we produced HRV1A viruses bearing the mutation L17R, Y32A or Y86A in the 2Apro sequence. All three viruses showed reduced yield and were appreciably delayed during infection in eIF4GI cleavage. Thus, we propose for genetic group A HRVs that the eIF4E/2Apro interaction is essential for successful viral replication. In contrast, HRV4 2Apro and coxsackievirus B4 2Apro failed to form complexes with eIF4E, suggesting that the mechanism of eIF4G isoform cleavage in these and related viruses is different. PMID- 28843816 TI - Recent exposure to linezolid is strongly associated with the isolation of linezolid-resistant coagulase-negative staphylococci in patients with related infection or colonisation: a case-control study in an intensive care unit. PMID- 28843815 TI - Nucleoside reverse transcriptase inhibitors induced hepatocellular mitochondrial DNA lesions and compensatory enhancement of mitochondrial function and DNA repair. AB - Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of combined antiretroviral therapy (cART) and are widely used in anti-human immunodeficiency virus (HIV) therapy. Long-term administration of NRTIs can result in mitochondrial dysfunction in certain HIV-1-infected patients. However, NRTI associated liver mitochondrial toxicity is not well known. Herein, the liver autopsy of acquired immune deficiency syndrome (AIDS) patients and the liver tissues of mice with 12 months of NRTI exposure were used to identify NRTI associated liver toxicity with immunofluorescence, quantitative real-time polymerase chain reaction (qPCR), Amplex red and horseradish peroxidase, and cloning and sequencing. Laser capture microdissection was used to capture hepatocytes from liver tissues. We observed DNA oxidative damage and mitochondrial DNA (mtDNA) loss in the livers of AIDS patients, and cART patients had higher DNA oxidative damage and lower DNA repair function in liver tissues than non-cART patients. We also observed liver oxidative damage, increased DNA repair and mtDNA loss in mice with exposure to four different NRTIs for 12 months, and hepatocytes had no more mtDNA loss than liver tissues. Although NRTIs could induce mitochondrial hydrogen peroxide production, increased mitochondrial oxygen consumption was found with a Clark-type electrode. The captured hepatocytes had greater diversity in their mtDNA D-loop, dehydrogenase subunit1 (ND1) and ND4 than the controls. Long-term NRTI exposure induced single nucleotide variation in hepatocellular mtDNA D-loop, ND1 and ND4. Our findings indicate that NRTIs can induce liver mtDNA lesions, but simultaneously enhance mitochondrial function and mtDNA repair. PMID- 28843817 TI - A novel resistance gene, lnu(H), conferring resistance to lincosamides in Riemerella anatipestifer CH-2. AB - The Gram-negative bacterium Riemerella anatipestifer CH-2 is resistant to lincosamides, having a lincomycin (LCM) minimum inhibitory concentration (MIC) of 128 ug/mL. The G148_1775 gene of R. anatipestifer CH-2, designated lnu(H), encodes a 260-amino acid protein with <=41% identity to other reported lincosamide nucleotidylyltransferases. Escherichia coli RosettaTM (DE3) containing the pBAD24-lnu(H) plasmid showed four- and two-fold increases in the MICs of LCM and clindamycin (CLI), respectively. A kinetic assay of the purified Lnu(H) enzyme for LCM and CLI showed that the protein could inactive lincosamides. Mass spectrometry analysis demonstrated that the Lnu(H) enzyme catalysed adenylylation of lincosamides. In addition, an lnu(H) gene deletion strain exhibited 512- and 32-fold decreases in LCM and CLI MICs, respectively. The wild-type level of lincosamide resistance could be restored by complementation with a shuttle plasmid carrying the lnu(H) gene. The transformant R. anatipestifer ATCC 11845 [lnu(H)] acquired by natural transformation also exhibited high-level lincosamide resistance. Moreover, among 175 R. anatipestifer field isolates, 56 (32.0%) were positive for the lnu(H) gene by PCR. In conclusion, Lnu(H) is a novel lincosamide nucleotidylyltransferase that inactivates LCM and CLI by nucleotidylylation, thus conferring high-level lincosamide resistance to R. anatipestifer CH-2. PMID- 28843818 TI - Perillyl alcohol exhibits in vitro inhibitory activity against Plasmodium falciparum and protects against experimental cerebral malaria. AB - The development of new drugs is one of the strategies to control malaria. Isoprenoid biosynthesis in Plasmodium falciparum is an essential pathway for parasite survival, and is therefore a potential target for new antimalarial drugs. Indeed, plant-derived secondary metabolites, such as terpenes, exhibit antimalarial activity in vitro by inhibiting isoprenoid biosynthesis in P. falciparum. In this study, the in vitro antiplasmodial activity of perillyl alcohol (POH) was evaluated, along with its in vitro toxicity and its effect on the isoprenylation process. In addition, the efficacy of intranasally administered POH in preventing Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM) was determined. The 50% inhibitory concentrations of POH for 3D7 and K1 P. falciparum were 4.8 uM and 10.4 uM, respectively. POH inhibited farnesylation of 20-37 kDa proteins in P. falciparum (3D7), but no toxic effects in Vero cells were observed. A 500 mg/kg/d dose of POH had no effect on P. berghei ANKA parasitaemia, but showed marked efficacy in preventing ECM development (70% survival compared with 30% for untreated animals). This effect was associated with the downregulation of cerebrovascular inflammation and damage, with marked decreases in brain leucocyte accumulation and the incidence of brain microhaemorrhage. POH also downregulated interleukin (IL)-10, IL-6, tumour necrosis factor-alpha, interferon-gamma, IL-12 and monocyte chemoattractant protein-1 levels in the brain and spleen. In conclusion, POH shows antiplasmodial activity in vitro and, despite there being no evidence of antiplasmodial activity in vivo following intranasal administration, POH prevented cerebrovascular inflammation/damage and expression of pro-inflammatory cytokines. PMID- 28843819 TI - Eradication of methicillin-resistant Staphylococcus aureus (MRSA) throat carriage: a randomised trial comparing topical treatment with rifampicin-based systemic therapy. AB - Eradication of methicillin-resistant Staphylococcus aureus (MRSA) colonisation may prevent transmission of strains between patients and reduces the risk of clinical infection. Colonisation of the throat is associated with prolonged carriage and is more difficult to eradicate. An open randomised study was conducted to evaluate two eradication protocols. Patients with pharyngeal carriage of MRSA were enrolled at six Swedish centres during 4 years. One treatment group received oral rifampicin and either clindamycin or trimethoprim/sulfamethoxazole (SXT) for 7 days in combination with nasal mupirocin. Patients in the other group were treated with nasal mupirocin only. Patients in the same household were randomised together. Both groups followed a hygiene protocol including chlorhexidine washing. Cultures from the nares, perineum and throat were taken at baseline and then at 2 weeks, 2 months and 6 months after the end of treatment. A total of 28 patients received rifampicin based systemic antibiotics and 24 subjects received mupirocin only. At follow-up 6 months after the end of treatment, 61% of patients and 50% of households in the systemic antibiotics group had culture results negative for MRSA. Significantly less patients (12%) and households (10%) became decolonised in the group receiving topical treatment only. A combination of rifampicin and either clindamycin or SXT was more effective in eliminating pharyngeal MRSA carriage compared with topical treatment with mupirocin only. PMID- 28843820 TI - Multiple pathways towards reduced membrane potential and concomitant reduction in aminoglycoside susceptibility in Staphylococcus aureus. AB - Staphylococcus aureus is responsible for life-threatening and difficult-to-treat infections worldwide and antimicrobial resistance is an increasing concern. Whilst acquired resistance has been widely studied, little is known of the contributions from chromosomal determinants that upon inactivation may reduce the susceptibility of S. aureus to antibiotics. The aim of this study was to identify genetic determinants that upon inactivation reduce aminoglycoside susceptibility in S. aureus. The Nebraska Transposon Mutant Library of 1920 single-gene inactivations in S. aureus strain JE2 was screened for reduced susceptibility to gentamicin. Nine mutants were confirmed by Etest to display between 2- and 16 fold reduced susceptibility to this antibiotic. All of the identified genes were associated with the electron transport chain and energy metabolism. Four mutant strains (menD, hemB, aroC and SAUSA300_0355) conferred the largest decrease in gentamicin susceptibility and three exhibited a small colony variant phenotype, whereas the remaining mutants (qoxA, qoxB, qoxC, ndh and hemX) displayed colony morphology similar to the wild-type. All of the mutants, except hemX, displayed reduced membrane potential suggesting that reduced uptake of gentamicin is the predominant mechanism leading to reduced susceptibility. The results of this study demonstrate that S. aureus possesses multiple genes that upon inactivation by mutagenesis reduce the membrane potential and thereby reduce the lethal activity of gentamicin. PMID- 28843821 TI - Activity of 2-(quinolin-4-yloxy)acetamides in Mycobacterium tuberculosis clinical isolates and identification of their molecular target by whole-genome sequencing. AB - The 2-(quinolin-4-yloxy)acetamides (QOAs) have been reported to be promising molecules for tuberculosis treatment. Recent studies demonstrated their potent antimycobacterial activity, biological stability and synergism with rifampicin. The identification of the molecular target is an essential step towards the development of a novel drug candidate. Here, we report the target identification of the QOAs. We found that these compounds are active against Mycobacterium tuberculosis clinical isolates resistant to isoniazid, rifampicin, ethambutol, streptomycin and ethionamide. The initial evidence that DNA gyrase might be the target of QOAs, based on high minimum inhibitory concentration (MIC) values against ofloxacin-resistant clinical isolates and structural similarities with fluoroquinolones, was discarded by experiments performed with M. tuberculosis GyrA point mutant, DNA gyrase supercoiling inhibition assay and overexpression of DNA gyrase. We selected spontaneous mutants for our lead compound 21 and observed that these strains were also resistant to all QOA derivatives. The genomes of the spontaneous mutants were sequenced, and the results revealed a single mutation in qcrB gene (T313A), which indicates that the QOAs target the cytochrome bc1 complex. The protein-compound interaction was further investigated by molecular docking. These findings reinforce the relevance of these compounds as promising candidates for the treatment of multidrug-resistant tuberculosis. PMID- 28843822 TI - Clofazimine protects against Mycobacterium tuberculosis dissemination in the central nervous system following aerosol challenge in a murine model. AB - Tuberculosis (TB) has been the scourge of the human race for many decades, claiming countless number of lives. This is further complicated by the ability of Mycobacterium tuberculosis to infect extrapulmonary sites, specifically the brain. These extrapulmonary forms of TB are difficult to treat owing to problems associated with drug delivery across the blood-brain barrier. Linezolid (LIN) and clofazimine (CFZ) are two of the more promising anti-TB drugs in recent times. In this study, BALB/c mice were aerosol-infected with M. tuberculosis H37Rv and were treated for 4 weeks with LIN [100 mg/kg body weight (BW)] or CFZ (100 mg/kg BW). Concurrently, it was investigated whether an aerosol TB infection would lead to dissemination of TB bacilli into the brain. Post-treatment brain and lung CFUs were determined together with serum, lung and brain drug concentrations. CFZ displayed a strong bactericidal effect in the lung, whilst LIN had a bacteriostatic effect. Mycobacterium tuberculosis appeared at 2 weeks post infection in the untreated group (2.38 +/- 0.43 log10 CFU) and more surprisingly at 3 weeks post-infection in the LIN-treated group (1.14 +/- 0.99 log10 CFU). TB bacilli could not be detected in the brains of the CFZ-treated group. To the best of our knowledge, this is the first study showing the appearance of M. tuberculosis in the brain following a murine aerosol TB infection. This study may advocate the use of CFZ as prophylactic treatment to prevent the development of extrapulmonary TB of the central nervous system using a two-pronged approach. PMID- 28843823 TI - Inhibitory and bactericidal effect of Artilysin(r) Art-175 against colistin resistant mcr-1-positive Escherichia coli isolates. PMID- 28843824 TI - Venous thromboembolism and vascular access thrombosis in patients with end-stage renal disease on maintenance hemodialysis: Cross-sectional results of the Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemoDIalysis (VIVALDI). AB - BACKGROUND: Patients with end-stage renal disease (ESRD) on maintenance hemodialysis (HD) are at risk for occurrence of vascular access thrombosis and venous thromboembolism (VTE). Understanding the extent of these complications and identifying risk factors can help improve management strategies. METHODS: Adult HD patients were cross-sectionally recruited into the Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemoDIalysis (VIVALDI). In this investigation, retrospective data on the incidence and risk of VTE and vascular access thrombosis was analyzed using logistic regression and negative binomial regression for counts of vascular access thrombosis episodes. RESULTS: The analysis includes 626 patients on HD, which constitutes 73% of the total HD population in Vienna, Austria. One-hundred-seventy-eight patients (28.4%) had 275 vascular access thrombosis events during 2463.1 patient-years on HD, corresponding to an incidence rate (IR) of 111.6 events per 1000 patient-years on HD. In the multivariable negative binomial regression model, we found that patients suffered from vascular access thrombosis 2.5 times more often (IR ratio 2.63, 95% confidence interval [CI] 1.48-4.68, p=0.001) if toxic nephropathy was their cause of ESRD (n=28, 4.5%) compared to patients with other causes of ESRD. Sixty-one patients (9.7%) had a history of VTE and the IR of VTE events during the time on HD was 10.9 per 1000 patient-years on HD (women: IR 15.1, men IR 8.6). Female sex (odds ratio [OR] 1.90, 95%CI 1.07-3.36, p=0.029) and atrial fibrillation (OR 2.00, 95%CI 1.10-3.64, p=0.023) were independently associated with VTE. CONCLUSIONS: Thromboembolic events including vascular access thrombosis and VTE are frequent complications in patients on HD. Risk evaluation for thromboembolism, including sex and clinical parameters, may identify high-risk patients and improve their clinical management. PMID- 28843825 TI - Implementation of a rapid HIT immunoassay at a university hospital - Retrospective analysis of HIT laboratory orders in patients with thrombocytopenia. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a rare cause of thrombocytopenia and a potentially life-threatening adverse drug reaction. Clinical overdiagnosis of HIT results in costly laboratory tests and anticoagulation. Criteria and algorithms for diagnosis are established, but their translation into clinical practice is still challenging. STUDY DESIGN AND METHODS: In a retrospective approach we studied all HIT related laboratory test requests within four years and evaluated data before (1st period, 24month) and after (2nd period, 24month) replacing particle gel immunoassay (PaGIA) and enzyme linked immunosorbent assay (ELISA) by a chemiluminescent immunoassay (CLIA). HIT was confirmed by heparin-induced platelet activation (HIPA) test. Clinical pretest probability for HIT using an implemented simplified 4Ts score and platelet count were evaluated. Costs for laboratory tests and alternative anticoagulation were calculated. RESULTS: In 1850 patients with suspected HIT, 2327 laboratory orders were performed. In 87.2% of these orders an intermediate/high simplified 4Ts score was found. Thrombocytopenia was present in 87.1%. After replacing PaGIA and ELISA by CLIA the number of immunological and functional laboratory tests was reduced by 38.2%. The number of positive HIT immunoassays declined from 22.6% to 6.0%, while the number of positive HIPA tests among positive immunological tests increased by 19%. Altogether, acute HIT was confirmed in 59 patients. A decline in the use of alternative anticoagulants was observed in the 2nd period. CONCLUSION: Our study shows that in a university hospital setting HIT is well-known, but diagnosis requires a precise laboratory confirmation. Replacing PaGIA and ELISA by CLIA did not influence laboratory order behavior but results in reduced overall costs for laboratory diagnostics and alternative anticoagulation. PMID- 28843826 TI - Zoledronic acid, an FPPS inhibitor, ameliorates liver steatosis through inhibiting hepatic de novo lipogenesis. AB - Currently, there is no standard therapy for non-alcoholic fatty liver disease (NAFLD), and statins have been developed as a first-line pharmaceutical therapeutic option for NAFLD-associated dyslipidemia. However, prolonged statins therapy has side effects, as statins inhibit HMG-CoA reductase, an enzyme at the very beginning of the mevalonate pathway. Here, we found that zoledronic acid (ZA), an inhibitor of farnesyl diphosphate synthase in the downstream mevalonate pathway, could attenuate hepatic lipid accumulation and improve liver injury in both high-fat diet-induced C57BL/6J mice and ob/ob mice. Moreover, the hepatic lipid metabolism was largely inhibited after ZA administration in high-fat diet induced obese mice. Mechanically, ZA inhibited SREBP-1c-mediated de novo lipogenesis through suppressing RhoA activation via decreasing farnesyl diphosphate and geranylgeranyl diphosphate levels. In conclusion, our data provide a novel application of ZA in improving hepatic steatosis. PMID- 28843827 TI - PTPN21 protects PC12 cell against oxygen-glucose deprivation by activating cdk5 through ERK1/2 signaling pathway. AB - PTPN21, a cytosolic non-receptor tyrosine phosphatase isolated from human skeletal muscle, was reported to promote neuronal survival. Nevertheless, it is not clear whether PTPN21 plays a role in hypoxia ischemia-induced neuronal injury. A proper understanding of the PTPN21 mechanism in neuron growth regulation is limited. In this study, we investigated the neuroprotective effects and potential mechanism of PTPN21 on oxygen glucose deprivation (OGD)-injured PC12 cells. The ischemic stroke model of PC12 cells was made by OGD for 2h, after transfection of the PTPN21 siRNA and pcDNA 3.1 PTPN21(+). Cell viability was tested using the MTT and CCK-8 assay. Apoptotic cells were estimated by Annexin V FITC/PI staining and caspase-3 activity using the Caspase-3 Assay Kit; the PTPN21, cdk5, ERK1/2 and p-ERK1/2 levels were estimated by qRT-PCR and Western blot. We found that the PTPN21 markedly increased cell viability, inhibited apoptosis. We also found that PTPN21 inhibited caspase-3 activity and down regulating the Bax/Bcl-2 ratio. Furthermore, the expression of cdk5 protein was up-regulated by PTPN21 by activating ERK1/2 signaling pathway. Finally, our results showed that cdk5 siRNA or ERK1/2 signaling inhibitor PD98059 attenuated the accelerative effect of pcDNA3.1 PTPN21(+) on cell proliferation and apoptosis in PC12 cells. In short, it appears that PTPN21 may protect the PC12 from ischemia injury by upregulating cdk5 via ERK1/2 signaling pathway. PMID- 28843828 TI - Vinpocetine mitigates proteinuria and podocytes injury in a rat model of diabetic nephropathy. AB - Podocyte injury and glomerular basement membrane thickening have been considered as essential pathophysiological events in diabetic nephropathy. The aim of this study was to investigate the possible beneficial effects of vinpocetine on diabetes-associated renal damage. Male Wistar rats were made diabetic by injection of streptozotocin (STZ). Diabetic rats were treated with vinpocetine in a dose of 20mg/kg/day for 6 weeks. Treatment with vinpocetine resulted in a marked decrease in the levels of blood glucose, glycosylated haemoglobin, creatinine, blood urea nitrogen, urinary albumin and albumin/creatinine ratio along with an elevation in creatinine clearance rate. The renal contents of advanced glycation end-products, interleukin-10, tissue growth factor-beta, nuclear factor (NF)-kappaB and Ras-related C3 botulinum toxin substrate 1 (Rac 1) were decreased. Renal nephrin and podocin contents were increased and their mRNA expressions were replenished in vinpocetine-treated rats. Moreover, administration of vinpocetine showed improvements in oxidative status as well as renal glomerular and tubular structures. The current investigation revealed that vinpocetine ameliorated the STZ-induced renal damage. This beneficial effect could be attributed to its antioxidant and antihyperglycemic effects parallel to its ability to inhibit NF-kappaB which eventually modulated cytokines production as well as nephrin and podocin proteins expression. PMID- 28843829 TI - Learning representations for the early detection of sepsis with deep neural networks. AB - BACKGROUND: Sepsis is one of the leading causes of death in intensive care unit patients. Early detection of sepsis is vital because mortality increases as the sepsis stage worsens. OBJECTIVE: This study aimed to develop detection models for the early stage of sepsis using deep learning methodologies, and to compare the feasibility and performance of the new deep learning methodology with those of the regression method with conventional temporal feature extraction. METHOD: Study group selection adhered to the InSight model. The results of the deep learning-based models and the InSight model were compared. RESULTS: With deep feedforward networks, the area under the ROC curve (AUC) of the models were 0.887 and 0.915 for the InSight and the new feature sets, respectively. For the model with the combined feature set, the AUC was the same as that of the basic feature set (0.915). For the long short-term memory model, only the basic feature set was applied and the AUC improved to 0.929 compared with the existing 0.887 of the InSight model. CONCLUSIONS: The contributions of this paper can be summarized in three ways: (i) improved performance without feature extraction using domain knowledge, (ii) verification of feature extraction capability of deep neural networks through comparison with reference features, and (iii) improved performance with feedforward neural networks using long short-term memory, a neural network architecture that can learn sequential patterns. PMID- 28843830 TI - Mechanical model of orthopaedic drilling for augmented-haptics-based training. AB - In this study, augmented-haptic feedback is used to combine a physical object with virtual elements in order to simulate anatomic variability in bone. This requires generating levels of force/torque consistent with clinical bone drilling, which exceed the capabilities of commercially available haptic devices. Accurate total force generation is facilitated by a predictive model of axial force during simulated orthopaedic drilling. This model is informed by kinematic data collected while drilling into synthetic bone samples using an instrumented linkage attached to the orthopaedic drill. Axial force is measured using a force sensor incorporated into the bone fixture. A nonlinear function, relating force to axial position and velocity, was used to fit the data. The normalized root mean-square error (RMSE) of forces predicted by the model compared to those measured experimentally was 0.11 N across various bones with significant differences in geometry and density. This suggests that a predictive model can be used to capture relevant variations in the thickness and hardness of cortical and cancellous bone. The practical performance of this approach is measured using the Phantom Premium haptic device, with some required customizations. PMID- 28843832 TI - Magnetic Compression Anastomosis (Magnamosis): First-In-Human Trial. AB - BACKGROUND: Magnetic compression anastomosis (magnamosis) uses a pair of self centering magnetic Harrison Rings to create an intestinal anastomosis without sutures or staples. We report the first-in-human case series using this unique device. STUDY DESIGN: We conducted a prospective, single-center, first-in-human pilot trial to evaluate the feasibility and safety of creating an intestinal anastomosis using the Magnamosis device. Adult patients requiring any intestinal anastomosis to restore bowel continuity were eligible for inclusion. For each procedure, 1 Harrison Ring was placed in the lumen of each intestinal segment. The rings were brought together and mated, and left to form a side to side, functional end to end anastomosis. Device movement was monitored with serial x rays until it was passed in the stool. Patients were monitored for adverse effects with routine clinic appointments, as well as questionnaires. RESULTS: Five patients have undergone small bowel anastomosis with the Magnamosis device. All 5 patients had severe systemic disease and underwent complex open urinary reconstruction procedures, with the device used to restore small bowel continuity after isolation of an ileal segment. All devices passed without obstruction or pain. No patients have had any complications related to their anastomosis, including anastomotic leaks, bleeding, or stricture at median follow-up of 13 months. CONCLUSIONS: In this initial case series from the first-in-human trial of the Magnamosis device, the device was successfully placed and effectively formed a side to side, functional end to end small bowel anastomosis in all 5 patients. No patients have had any anastomotic complications at intermediate follow-up. PMID- 28843831 TI - ImmunoPET imaging of tissue factor expression in pancreatic cancer with 89Zr-Df ALT-836. AB - Overexpression of tissue factor (TF) has been associated with increased tumor growth, tumor angiogenesis, and metastatic potential in many malignancies, including pancreatic cancer. Additionally, high TF expression was shown to strongly correlate with poor prognoses and decreased survival in pancreatic cancer patients. Herein, we exploited the potential targeting of TF for positron emission tomography (PET) imaging of pancreatic cancer. The TF-targeted tracer was developed through radiolabeling of the anti-human TF monoclonal antibody (ALT 836) with 89Zr. The tracer was characterized by fluorescence microscopy and flow cytometry assays in BXPC-3 and PANC-1 cells, two pancreatic cancer cell lines with high and low TF expression levels, respectively. Non-invasive PET scans were acquired in tumor-bearing mice injected with 89Zr-Df-ALT-836. Additionally, ex vivo biodistribution, blocking, and histological studies were performed to establish the affinity and specificity of 89Zr-Df-ALT-836 for TF in vivo. 89Zr labeling of Df-ALT-836 was achieved in high yield and good specific activity. Flow cytometry and microscopy studies revealed no detectable difference in TF binding affinity between ALT-836 and Df-ALT-836 in vitro. Longitudinal PET scans unveiled a lasting and prominent 89Zr-Df-ALT-836 uptake in BXPC-3 tumors (peak at 31.5+/-6.0%ID/g at 48h post-injection; n=3), which was significantly abrogated (2.3+/-0.5%ID/g at 48h post-injection; n=3) when mice were pre-injected with a blocking dose (50mg/kg) of unlabeled ALT-836. Ex vivo biodistribution data confirmed the accuracy of the PET results, and histological analysis correlated high tumor uptake with in situ TF expression. Taken together, these results attest to the excellent affinity and TF-specificity of 89Zr-Df-ALT-836. With elevated, persistent, and specific accumulation in TF-positive BXPC-3 tumors, PET imaging using 89Zr-Df-ALT-836 promises to open new avenues for improving future diagnosis, stratification, and treatment response assessment in pancreatic cancer patients. PMID- 28843834 TI - Correction. PMID- 28843833 TI - Strain-specific differences in the development of neuronal excitability in the mouse ventral nucleus of the trapezoid body. AB - This investigation compared the development of neuronal excitability in the ventral nucleus of the trapezoid body (VNTB) between two strains of mice with differing progression rates for age-related hearing loss. In contrast to CBA/Ca (CBA) mice, the C57BL/6J (C57) strain are subject to hearing loss from a younger age and are more prone to damage from sound over-exposure. Higher firing rates in the medial olivocochlear system (MOC) are associated with protection from loud sounds and these cells are located in the VNTB. We postulated that reduced neuronal firing of the MOC in C57 mice could contribute to hearing loss in this strain by reducing efferent protection. Whole cell patch clamp was used to compare the electrical properties of VNTB neurons from the two strains initially in two age groups: before and after hearing onset at ~ P9 and ~P16, respectively. Prior to hearing onset VNTB neurons electrophysiological properties were identical in both strains, but started to diverge after hearing onset. One week after hearing onset VNTB neurons of C57 mice had larger amplitude action potentials but in contrast to CBA mice, their waveform failed to accelerate with increasing age, consistent with the faster inactivation of voltage-gated potassium currents in C57 VNTB neurons. The lower frequency action potential firing of C57 VNTB neurons at P16 was maintained to P28, indicating that this change was not a developmental delay. We conclude that C57 VNTB neurons fire at lower frequencies than in the CBA strain, supporting the hypothesis that reduced MOC firing could contribute to the greater hearing loss of the C57 strain. PMID- 28843835 TI - Corrections. PMID- 28843836 TI - Correction. PMID- 28843837 TI - How useful is ultrasound guidance for internal jugular venous access in children? AB - PURPOSE: The aim of this study was to determine whether US reduces number of puncture attempts, procedure time, and complication rate during IJV access in children. METHODS: A prospective study was performed in children (age <=18years) admitted to our institution, from September 2013 to July 2014, with indications for central venous access. Patients meeting the inclusion criteria were randomized to the US-guided or control groups. The same physician performed all IJV cannulations in both groups. The end-points for comparison were: length of time to venous access, number of attempts, and rate of complications. RESULTS: Fifty-one patients were included: 23 in the US-guided group and 28 in the control group. There were no between-group differences in weight, age, or sex. In the US guided group, the number of punctures needed to achieve IJV access (median [interquartile range], 3 [2-5] vs. 1 [1, 2]; P<0.001), time to achievement of venous access, and complication rate (39% vs. 4.3%, P<0.009) were significantly lower. CONCLUSION: US guidance is a useful adjunct to central venous access in children, facilitating the procedure, decreasing time to cannulation, and increasing safety. TYPE OF STUDY: Prospective randomized study. LEVEL OF EVIDENCE: 1. PMID- 28843839 TI - Tracking the Penetration of Plasma Reactive Species in Tissue Models. AB - Electrically generated cold atmospheric plasma is being intensively researched for novel applications in biology and medicine. Significant attention is being given to reactive oxygen and nitrogen species (RONS), initially generated upon plasma-air interactions, and subsequently delivered to biological systems. Effects of plasma exposure are observed to millimeter depths within tissue. However, the exact nature of the initial plasma-tissue interactions remains unknown, including RONS speciation and delivery depth, or how plasma-derived RONS intervene in biological processes. Herein, we focus on current research using tissue and cell models to learn more about the plasma delivery of RONS into biological environments. We argue that this research is vital in underpinning the knowledge required to realize the full potential of plasma in biology and medicine. PMID- 28843838 TI - Parsing learning in networks using brain-machine interfaces. AB - Brain-machine interfaces (BMIs) define new ways to interact with our environment and hold great promise for clinical therapies. Motor BMIs, for instance, re-route neural activity to control movements of a new effector and could restore movement to people with paralysis. Increasing experience shows that interfacing with the brain inevitably changes the brain. BMIs engage and depend on a wide array of innate learning mechanisms to produce meaningful behavior. BMIs precisely define the information streams into and out of the brain, but engage wide-spread learning. We take a network perspective and review existing observations of learning in motor BMIs to show that BMIs engage multiple learning mechanisms distributed across neural networks. Recent studies demonstrate the advantages of BMI for parsing this learning and its underlying neural mechanisms. BMIs therefore provide a powerful tool for studying the neural mechanisms of learning that highlights the critical role of learning in engineered neural therapies. PMID- 28843840 TI - Structure-activity relationships and molecular docking of thirteen synthesized flavonoids as horseradish peroxidase inhibitors. AB - For the first time, the structure-activity relationships of thirteen synthesized flavonoids have been investigated by evaluating their ability to modulate horseradish peroxidase (HRP) catalytic activity. Indeed, a modified spectrophotometrically method was carried out and optimized using 4 methylcatechol (4-MC) as peroxidase co-substrate. The results show that these flavonoids exhibit a great capacity to inhibit peroxidase with Ki values ranged from 0.14+/-0.01 to 65+/-0.04mM. Molecular docking has been achieved using Auto Dock Vina program to discuss the nature of interactions and the mechanism of inhibition. According to the docking results, all the flavonoids have shown great binding affinity to peroxidase. These molecular modeling studies suggested that pyran-4-one cycle acts as an inhibition key for peroxidase. Therefore, potent peroxidase inhibitors are flavonoids with these structural requirements: the presence of the hydroxyl (OH) group in 7, 5 and 4' positions and the absence of the methoxy (O-CH3) group. Apigenin contributed better in HRP inhibitory activity. The present study has shown that the studied flavonoids could be promising HRP inhibitors, which can help in developing new molecules to control thyroid diseases. PMID- 28843841 TI - Relationship between time post-ovulation and progesterone on oocyte maturation and pregnancy in canine cloning. AB - Canine oocytes ovulated at prophase complete meiosis and continue to develop in presence of a high progesterone concentration in the oviduct. Considering that meiotic competence of canine oocyte is accomplished in the oviductal environment, we postulate that hormonal milieu resulting from the circulating progesterone concentration may affect oocyte maturation and early development of embryos. From 237 oocyte donors, 2620 oocytes were collected and their meiotic status and morphology were determined. To determine optimal characteristics of the mature oocytes subjected to nuclear transfer, a proportion of the meiotic status of the oocytes were classified in reference to time post-ovulation as well as progesterone (P4) level. A high proportion of matured oocytes were collected from >126h (55.5%) post-ovulation or 40-50ngmL-1 (46.4%) group compared to the other groups. Of the oocyte donors that provided mature oocytes in vivo, there was no correlation between serum progesterone of donors and time post ovulation, however, time post-ovulation were significantly shorter for <30ng/mL group (P<0.05). Using mature oocytes, 1161 cloned embryos were reconstructed and transferred into 77 surrogates. In order to determine the relationship between pregnancy performance and serum progesterone level, embryos were transferred into surrogates showing various P4 serum levels. The highest pregnancy (31.8%) and live birth cloning efficacy (2.2%) rates were observed when the embryos were transferred into surrogates with circulating P4 levels were from 40 to 50ngmL-1. In conclusion, measurement of circulating progesterone of female dog could be a suitable an indicator of the optimal time to collect quality oocyte and to select surrogates for cloning. PMID- 28843842 TI - Association between change in brain gray matter volume, cognition, and depression severity: Pre- and post- antidepressant pharmacotherapy for late-life depression. AB - Late-life depression (LLD) is associated with cognitive impairments and reduced gray matter volume (GMV); however the mechanisms underlying this association are not well understood. The goal of this study was to characterize changes in depression severity, cognitive function, and brain structure associated with pharmacologic antidepressant treatment for LLD. We administered a detailed neurocognitive battery and conducted structural magnetic resonance imaging (MRI) on 26 individuals with LLD, pre-/post-a 12-week treatment trial with venlafaxine. After calculating changes in cognitive performance, GMV, and depression severity, we calculated Pearson's correlations, performed permutation testing, and false discovery rate correction. We found that loss of GMV over 12 weeks in the superior orbital frontal gyrus was associated with less improvement in depression severity and that increased GMV in the same was associated with greater improvement in depression severity. We detected no associations between changes in cognitive performance and improvements in either depressive symptoms or changes in GMV. PMID- 28843843 TI - Evidence for altered cell membrane lipid composition in postmortem prefrontal white matter in bipolar disorder and schizophrenia. AB - Brain imaging suggests that white matter abnormalities, including compromised white matter integrity in the frontal lobe, are shared across bipolar disorder (BD) and schizophrenia (SCZ). However, the precise molecular and cellular correlates remain to be elucidated. Given evidence for widespread alterations in cell membrane lipid composition in both disorders, we sought to investigate whether lipid composition is disturbed in frontal white matter in SCZ and BD. The phospholipids phosphatidylethanolamine (PE) and phosphatidylcholine (PC) were quantified in white matter adjacent to the dorsolateral prefrontal cortex in subjects with BD (n = 34), SCZ (n = 35), and non-psychiatric controls (n = 35) using high-pressure liquid chromatography. Individual fatty acid species and plasmalogens were then quantified separately in PE and PC fractions by gas liquid chromatography. PC was significantly lower in the BD group, compared to controls. The fatty acids PE22:0, PE24:1 and PE20:2n6 were higher, and PC20:4n6, PE22:5n6 and PC22:5n6 lower in the BD group, relative to the control group. PE22:1 was higher and PC20:3n6, PE22:5n6 and PC22:5n6 lower in the SCZ group, compared to the control group. These data provide evidence for altered lipid composition in white matter in both BD and SCZ. Changes in white matter lipid composition could ultimately contribute to dysfunction of frontal white matter circuits in SCZ and BD. PMID- 28843844 TI - Cognitive decline in Huntington's disease expansion gene carriers. AB - BACKGROUND: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown. OBJECTIVE: The aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline. METHODS: In the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage. RESULTS: There was significant cognitive decline on all administered tasks throughout pre motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset. The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time. CONCLUSION: Cognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline. PMID- 28843845 TI - Synthesis, pH dependent, plasma and enzymatic stability of bergenin prodrugs for potential use against rheumatoid arthritis. AB - Bergenin is a unique C-glycoside natural product possessing anti-inflammatory and anti-arthritic activity. It is hydrophilic molecule and stable under acidic conditions however is unstable at neutral-basic pH conditions. The rate of degradation is directly proportional to the increase in pH which might be one of the reasons for its low oral bioavailability. Thus, herein our objective was to improve its stability using prodrug strategy. Various ester and ether prodrugs were synthesized and studied for lipophilicity, chemical stability and enzymatic hydrolysis in plasma/esterase. The stability of synthesized prodrugs was evaluated in buffers at different pH, in biorelevant media such as SGF, SIF, rat plasma and in esterase enzyme. All prodrugs displayed significantly improved lipophilicity compared with bergenin, which was in accordance with the criteria of drug-like compounds. Acetyl ester 4a2 appeared to be the most promising prodrug as it remained stable at gastric/intestinal pH and was completely transformed to the parent compound bergenin in plasma as desired for an ideal prodrug. The data presented herein, will help in designing stable prodrugs of unstable molecules with desired physicochemical properties in structurally similar chemotypes. PMID- 28843846 TI - Sport concussion assessment tool-Third edition normative reference values for professional Rugby Union players. AB - OBJECTIVES: To establish normative reference data for the SCAT3 in professional Rugby Union players. DESIGN: A cross sectional study in professional Rugby Union players competing in national and international professional competitions between 2015 and 2016. METHODS: The SCAT3 was administered pre-season or prior to tournaments. Data was collected electronically using a custom tablet application. SCAT3 subcomponents distributions were described and normative ranges determined using percentile cut-offs for average, unusually low/high, and extremely low/high scores. The association between player characteristics and performance in SCAT3 subcomponents was also investigated in exploratory analyses. RESULTS: A total of 3611 professional Rugby Union players were included. The most common baseline symptom was fatigue (14%). The symptom score median (md) was 0 (interquartile range (IQR)=0-1). Symptom severity md was 0 (IQR=0-1). The md of the SAC score was 28 (IQR=26-29). The md of the MBESS was 2 (IQR=0-4). The Tandem gait md was 11.1s (IQR=10.0-12.7s). Upper limb coordination was normal in 98.4%. Younger age and lower educational level were associated with worse performance on delayed recall and reverse month sub-components of the SCAT3 (p<0.0001). No statistically significant differences in SCAT3 subcomponents were evident across gender. CONCLUSIONS: Representative normative reference values for the SCAT3 among professional Rugby Union players are provided. Baseline performance on concentration and delayed recall tests may be lower in younger athletes or in those with lower educational level. PMID- 28843847 TI - Skin Transcriptomes of common bottlenose dolphins (Tursiops truncatus) from the northern Gulf of Mexico and southeastern U.S. Atlantic coasts. AB - Common bottlenose dolphins serve as sentinels for the health of their coastal environments as they are susceptible to health impacts from anthropogenic inputs through both direct exposure and food web magnification. Remote biopsy samples have been widely used to reveal contaminant burdens in free-ranging bottlenose dolphins, but do not address the health consequences of this exposure. To gain insight into whether remote biopsies can also identify health impacts associated with contaminant burdens, we employed RNA sequencing (RNA-seq) to interrogate the transcriptomes of remote skin biopsies from 116 bottlenose dolphins from the northern Gulf of Mexico and southeastern U.S. Atlantic coasts. Gene expression was analyzed using principal component analysis, differential expression testing, and gene co-expression networks, and the results correlated to season, location, and contaminant burden. Season had a significant impact, with over 60% of genes differentially expressed between spring/summer and winter months. Geographic location exhibited lesser effects on the transcriptome, with 23.5% of genes differentially expressed between the northern Gulf of Mexico and the southeastern U.S. Atlantic locations. Despite a large overlap between the seasonal and geographical gene sets, the pathways altered in the observed gene expression profiles were somewhat distinct. Co-regulated gene modules and differential expression analysis both identified epidermal development and cellular architecture pathways to be expressed at lower levels in animals from the northern Gulf of Mexico. Although contaminant burdens measured were not significantly different between regions, some correlation with contaminant loads in individuals was observed among co-expressed gene modules, but these did not include classical detoxification pathways. Instead, this study identified other, possibly downstream pathways, including those involved in cellular architecture, immune response, and oxidative stress, that may prove to be contaminant responsive markers in bottlenose dolphin skin. PMID- 28843848 TI - Depressive-like neurochemical and behavioral markers of Parkinson's disease after 6-OHDA administered unilaterally to the rat medial forebrain bundle. AB - BACKGROUND: Although Parkinson's disease (PD) is characterized by progressive neurodegeneration of multiple neurotransmitter systems, 6-hydroxydopamine (6 OHDA) as a model substance is mainly used to selectively damage the nigrostriatal dopaminergic neurons and induce parkinsonian-like motor disturbances in rats. We hypothesized that high doses of this neurotoxin affecting other monoaminergic systems may also evoke the depressive-like behavior. METHODS: The impact of 6 OHDA (8, 12, 16MUg/4MUl) administered unilaterally into the medial forebrain bundle on the sucrose solution intake (a measure of anhedonia) and on the tissue levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the striatum (STR), substantia nigra (SN), prefrontal cortex (PFC) and hippocampus (HIP) was examined in rats pretreated or non-pretreated with desipramine. RESULTS: The highest dose of 6-OHDA reduced the preference for 3% sucrose solution both in rats without and with desipramine pretreatment. All used doses of 6-OHDA dramatically decreased DA content in the studied brain structures on the ipsilateral side. NA levels were severely decreased in the ipsilateral STR, HIP and PFC of rats non-pretreated with desipramine and to a much lesser extent in those pretreated with desipramine. In the SN, moderate decreases in NA level were found both in rats pretreated and non-pretreated with desipramine. Higher doses of 6-OHDA reduced 5-HT content in the ipsilateral STR, HIP and PFC, but not in the SN, only in rats non-pretreated with desipramine. CONCLUSIONS: Administration of the highest dose of 6-OHDA without desipramine pretreatment evoked neurochemical and behavioral changes resembling the advanced PD with coexisting depression. PMID- 28843849 TI - Contamination incidents in the pre-analytical phase of forensic DNA analysis in Austria-Statistics of 17 years. AB - Forensic DNA analyses have become more and more sensitive in the past years. With the ability to generate DNA profiles even from minute amounts of cellular material also the possibility to detect DNA on trace material that originates from persons not linked to the crime event, such as crime scene investigators, increases. The contamination of crime scene samples can lead to false positive results and misinterpretation that can cause deceptive investigations. In this work we continue a study of 2010 that compared the number of detected contamination incidents that were caused in the pre-analytical phase of forensic DNA analysis with the number of crime scene samples analyzed by our laboratory. Within the past 17 years we were able to detect a total of 347 contamination incidents caused by police officers in approximately 46,000 trace samples to their origin (0.75%). Additionally we demonstrate the usefulness of reference profile databases that contain DNA profiles of police officers to detect contamination incidents of trace material. PMID- 28843850 TI - Substance use disorders in adolescent and young adult relatives of probands with bipolar disorder: What drives the increased risk? AB - BACKGROUND: Adults with bipolar disorder (BD) have higher rates of substance use disorders (SUDs) compared to the general population. SUD rates in young offspring/relatives of BD probands, as well as factors which drive those rates, are not as well-characterized. METHODS: We aimed to examine SUD prevalence among adolescent/young adult offspring and relatives of probands with and without BD. Data were collected from five sites in the US and Australia during 2006-2011. Youth offspring/relatives ("Relatives of BD probands;" n=267; mean age=16.8years; +/-2.9S.D.), identified through a proband family member with DSM-IV BD (Type I or II), were compared to offspring/relatives of control probands ("relatives of control probands;" n=149; mean age=17.4years; +/-2.9S.D.). Logistic regression with generalized estimating equations was used to compare the groups across a range of substance use and SUD variables. Odds ratios were calculated for lifetime prevalence of substance outcomes. RESULTS: Bivariate analyses showed DSM IV SUDs were more prevalent among relatives of BD probands than among relatives of control probands (29% vs. 18%; p=0.01). Generalized estimating equation models showed BD mood and childhood-onset externalizing disorders in adolescent and young adult relatives to each significantly increase the odds (OR=2.80-3.17; p<0.02) for the development of several substance variables among all relatives, whereas the risk of SUDs in relatives was not increased when the relatives had no mood or externalizing disorders themselves. CONCLUSION: Relatives of BD probands with lifetime mood and externalizing disorders report more substance use/SUDs than relatives of control probands. In contrast, SUD outcomes in relatives of BD probands without mood or externalizing disorders were no different from control relatives without psychopathology. Early recognition and treatment of psychiatric disorders may lead to less substance use in this highly vulnerable population. PMID- 28843851 TI - 1,3-dichloro-2-propanol induced lipid accumulation in HepG2 cells through cAMP/protein kinase A and AMP-activated protein kinase pathways via Gi/o-coupled receptors. AB - 1,3-dichloro-2-propanol (1,3-DCP) is a food born hepatoxic chloropropanol contaminant that has been detected in a wide range of foods. In the present study, we investigated the effects and mechanisms of 1,3-DCP on lipid accumulation in HepG2 cells. The data showed 1,3-DCP significantly increased intracellular content of triglyceride (TG) and total cholesterol (TC) at 0.5 2MUg/mL. Further results showed that 1,3-DCP greatly decreased cyclic AMP (cAMP) level. In addition, 1,3-DCP inhibited PKA and AMPK signaling pathway, but had no influence on intracellular calcium and regulated proteins. Moreover, Gi/o protein inhibitor PTX significantly inhibited 1,3-DCP induced decrease of cAMP, p-PKA and p-AMPK expression. Furthermore, 1,3-DCP significantly decreased GPR41 and GPR43 expression, but had no effect on GPR109B.Thus, we concluded that 1,3-DCP induced lipid accumulation in HepG2 cells through cAMP/PKA and AMPK signaling pathways via Gi/o-coupled receptor. PMID- 28843852 TI - Blood pressure in indoor and outdoor workers. AB - INTRODUCTION: The aim of our study is to evaluate the changes in systolic and diastolic blood pressure in two occupational categories: outdoor workers (traffic policemen and environment technicians) and indoor workers. MATERIALS AND METHODS: The study was conducted comparing the results obtained from three samples of male workers: 175 outdoor traffic policemen, 175 outdoor environment technicians and 175 indoor workers. The outdoor and indoor groups were made comparable by age, length of service, body mass index, alcohol consumption, smoking status. RESULTS: The mean values of systolic and diastolic blood pressure were found higher in traffic policemen and technicians than in indoor workers, as well as higher values of systolic blood pressure in traffic policemen than in technicians. CONCLUSIONS: The results suggest that outdoor working affects the blood pressure, contributing to an increased cardiovascular risk. PMID- 28843853 TI - The development of monoclonal anti-ADAMTS18 antibodies with precise validation of ADAMTS18 post-translational modification status in living organisms. AB - ADAMTS18 is a member of a secreted Zn-metalloproteinase ADAMTS family, and has been implicated in development, hemostasis, and various malignancies. It has thus far proven difficult to resolve its post-translational modification status, cleaved forms, and splice variants in living organisms due to the lack of specific antibodies available to characterize this enzyme. In this study, we develop six murine monoclonal antibodies (mAbs) against different functional regions of ADAMTS18 using hybridoma technology. These mAbs exhibit cross recognition between ADAMTS18 and the homology domain of its family members. Using the tissues from Adamts18 knockout (KO) mice, we find that two of these mAbs (N-3 and C-5) precisely identify five significantly attenuated bands located at 180, 135, 95, 72, and 45 kDa. These bands represent the forms of ADAMTS18 that potentially exist in the tissues. These mAbs will provide a useful tool to investigate the ADAMTS18's biologic significance in the tissues. PMID- 28843854 TI - Neuromedin U precursor-related peptide (NURP) exerts neuromedin U-like sympathetic nerve action in the rat. AB - It has been suggested that novel peptide that is produced from the neuromedin U (NMU) precursor may exist, as this precursor contains multiple consensus sequences for proteolytic processing. Recently, we identified two mature novel peptides comprising 33 and 36 residues in the rat brain, which were designated neuromedin U precursor-related peptide (NURP) 33 and 36. In the present study, we compared the roles of NURP33 and 36 with that of NMU, as neither activates the NMU receptors. Immunoreactivity for NMU and NURPs was widely present in the central nervous system and showed a similar distribution. Intracerebroventricular (icv) injection of NURP33 in rats increased locomotor activity, energy expenditure, heart rate and back surface temperature (BS-T), similarly to NMU or NURP36. NMU treatment reduced food intake, but NURP33 did not. Pretreatment with the beta3 blocker, SR59230A, and the cyclooxygenase blocker, indomethacin, inhibited the NURP33- or NMU-induced increase of BS-T. In addition, icv injection of NURP33 or NMU increased the expression of mRNA for cyclooxygenase 2 in the hypothalamus and for uncoupling protein 1 in the brown adipose tissue. These results suggest that although NURP33 and 36 do not activate the NMU receptors, they might exert NMU-like sympathetic nerve action in the brain. PMID- 28843855 TI - Metformin protects against retinal cell death in diabetic mice. AB - Retinal degeneration is an early feature of diabetic retinopathy, the major cause of blindness in the developed world. Here we investigated how the widely used antidiabetic drug metformin reduces retinal injury in diabetic mice. Metformin was orally administered to control mice or mice with streptozotocin-induced diabetes. Western blot analysis showed that levels of O-linked beta-N acetylglucosamine (O-GlcNAc) transferase (OGT) and other related proteins such as carbohydrate-responsive element-binding protein (ChREBP) and thioredoxin interacting protein (TXNIP) were significantly increased, and nuclear factor kappaB (NF-kappaB) and poly (ADP-ribose) polymerase (PARP) were activated in the diabetic retinas or retinal pigment epithelial (RPE) cells exposed to high glucose compared to controls. More importantly, RPE cells exposed to high glucose and treated with thiamet-G had higher levels of those proteins, demonstrating the role of elevated O-GlcNAcylation. Double immunofluorescence analysis revealed increased co-localization of terminal deoxynucleotide transferase-mediated dUTP nick-end labelling (TUNEL)-positive ganglion cells and OGT, ChREBP, TXNIP, or NF kappaB in diabetic retinas compared to control retinas. Co-immunoprecipitation analysis showed that interaction between OGT and ChREBP or NF-kappaB was increased in diabetic retinas compared to control retinas, and this was accompanied by more cell death. Notably, metformin attenuated the increases in protein levels; reduced co-localization of TUNEL-positive ganglion cells and OGT, ChREBP, TXNIP, or NF-kappaB; and reduced interaction between OGT and ChREBP or NF kappaB. Our results indicate that OGT inhibition might be one of the mechanisms by which metformin decreases retinal cell death. PMID- 28843856 TI - HTNV-induced upregulation of miR-146a in HUVECs promotes viral infection by modulating pro-inflammatory cytokine release. AB - Increasing research has shown a link between viruses and miRNAs, such as miRNA 146a, in regulating virus infection and replication. In the current study, the association between miR-146a and hantaan virus (HTNV) infection in human umbilical vein endothelial cells (HUVECs) was investigated, with a focus on examining the expression of pro-inflammatory cytokines. The results showed that HTNV infection promoted the production of miR-146a in HUVECs and activated nuclear factor-kappaB (NF-kappaB) signaling, along with the upregulation of pro inflammatory cytokines, including interleukin 8 (IL-8), C-C Motif Chemokine Ligand 5 (CCL5, also RANTES), interferon-inducible protein-10 (IP-10) and interferon beta (IFN-beta). Moreover, miR-146a exhibited a negative regulatory effect on the NF-kappaB pathway. Accordingly, a miR-146a inhibitor increased the expression of IL-8, CCL5, IP-10 and IFN-beta, whereas a miR-146a mimic reduced the levels of these cytokines. Consequently, exogenous transduction of miR-146a significantly enhanced HTNV replication in HUVEC cells. We also discovered that viral proteins (NP/GP) contributed to miR-146a expression via enhancement the activity of miR-146a promoter. In conclusion, these results imply the negative regulation of miR-146a on the production of HTNV-induced pro-inflammatory cytokines contributes to virus replication, which suggest that miR-146a may be regarded as a novel therapeutic target for HTNV infection. PMID- 28843857 TI - Anti-tumor activity of KNTC2 siRNA in orthotopic tumor model mice of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is still one of the major causes of cancer-related death. Kinetochore-associated protein 2 (KNTC2) is specifically upregulated in tumor tissues of HCC patients and recognized as a potential candidate target for the treatment of HCC. However, the relationship between KNTC2 and in vivo tumor growth of HCC is not yet fully understood. Here we encapsulated KNTC2 siRNAs into a lipid nanoparticle (LNP) and investigated their knockdown activity, target engagement marker, anti-tumor activity and hepatotoxicity in an orthotopic HCC model mice of Hep3B-luc cells. Single i.v. administration of KNTC2 siRNA-LNP specifically suppressed the expression levels of both human KNTC2 mRNA and mouse Kntc2 mRNA in tumor tissues. Phosphorylation levels of histone H3 (HH3) at serine 10 in tumor tissues were increased by KNTC2 siRNA-LNP. Repeated administration of KNTC2 siRNA-LNP (twice a week) specifically inhibited the growth of tumor tissues without increasing the plasma AST and ALT levels. Their growth inhibitory activities were consistent with knockdown activities. These data strongly indicated that KNTC2 is a promising target for the treatment of HCC and that phosphorylated HH3 at serine 10 is one of the target engagement markers for KNTC2. PMID- 28843858 TI - TLR7 deficiency contributes to attenuated diabetic retinopathy via inhibition of inflammatory response. AB - Diabetic retinopathy (DR) is a major microvascular complication of diabetes, resulting in neuronal dysfunction, retinal vascular leakage, and apoptosis within the retina. Innate immunity plays an important role in the pathogenesis of type 2 diabetes (T2D) and related complications. The toll-like receptors (TLRs), central to innate immunity, are essential participants in the progression and pathogenesis of the disease and its complications. In the study, streptozotocin (STZ) was combined with whole-body hypoxia for quicker induction of early-stage diabetic retinopathy (DR) in the wild type (WT) and TLR7-knockout (KO) C57BL/6 mice. The effects of TLR7 were also investigated in fructose-treated retinal pigment epithelial (RPE) cells. In the retinas of WT/DR mice, abnormal a-wave and b-wave activity, hyperfluorescence, and reduced retinal thickness were observed. DR development was associated with enhanced TLR7 expression, whose deletion dramatically reduced VEGF expression levels. And the secretion of pro inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-18 and IL-12, was highly reduced by TLR7 deficiency in DR mice. Consistently, WT/DR mice exhibited higher phosphorylation of IkappaB kinase alpha (IKKalpha), inhibitor of NF-kappaB alpha (IkappaBalpha) and nuclear factor kappaB (NF-kappaB), which were found to be down-regulated in KO/DR mice. Similarly, DR-induced mitogen-activated protein kinases (MAPKs) activation was blocked by TLR7-knockout. In vitro, fructose incubation-triggered inflammation was reversed by TLR7 knockdown, accompanied with inactivated NF kappaB and MAPKs pathways. And reduced reactive oxygen species (ROS) generation was observed in TLR7-knockdown cells with fructose treatment. Together, inhibiting TLR7 suppressed diabetic retinopathy by reducing inflammation and suggested a potential application in clinics. PMID- 28843859 TI - Aortic pseudoaneurysm after endarterectomy for small aorta syndrome. AB - INTRODUCTION: Small Aorta Syndrome (SAS) or hypoplastic aorto-iliac syndrome is a rare pathology of the aorta that affects almost exclusively young or middle-aged women and is characterized by smaller dimension of the aorta and iliac axes. Etiopathogenesis is unclear and many factors have been invoked. The smaller caliber of the aorta and iliac arteries may predispose to aorto-iliac occlusive disease development. In the past aorto-iliac endarterectomy (AE) with patch closure was utilized as an alternative to surgical bypass in order to correct steno-obstructive syndromes affecting carriers of SAS. Little is known about long term outcomes of this type of surgery. PRESENTATION OF THE CASE: During investigations for acute colecystitis, an aortic pseudoaneurysm (PA) was diagnosed by ultrasound in a 73 old year woman. She was submitted twenty-two years ago for SAS with disabling claudication to aortic endarterectomy (AE) with patch graft insertion. Considering all the vascular options available she was submitted to open surgery with replacement of the aortic bifurcation. DISCUSSION: Aortic PA is a relatively common complication after bypass surgery but is rarely observed after AE. It requires prompt intervention to prevent subsequent complications such as rupture, thrombosis, distal embolism or aorto-enteric fistula. CONCLUSION: Endovascular treatment for aortic PA should be always considered the treatment of choice but the open surgical option was preferred in this particular case because of the small diameters of the iliac accesses, making them unsuitable for an endovascular approach. PMID- 28843860 TI - Swallowing dysfunction in elderly trauma patients. AB - PURPOSE: Newly diagnosed swallowing dysfunction is rare, with an incidence <1% in hospitalized patients. The purpose of this study was to evaluate the incidence and clinical characteristics of dysphagia in elderly trauma patients specifically. METHODS: Patients >=75years who had newly diagnosed swallowing dysfunction were identified by retrospective review of our institutional trauma database from 2009-2012. A comparison group without dysphagia was also identified that was matched by age, gender, injury mechanism, and injury severity score (ISS). Relevant demographics, injury characteristics, and potential factors associated with dysphagia were collected. RESULTS: 1323 patients met criteria. Of these, 56(4.2%) had newly identified dysphagia. Cases and controls were similar in regards to regional injury pattern (AIS). Patients with dysphagia had a mean Charlson Comorbidity Index (CCI) of 3.7 vs. 1.9 for patients without dysphagia (p<0.01). Patients with dysphagia also had longer hospital (11.4 vs. 5.8days, p<0.01) and ICU LOS (5.6 vs 1.9days, p<0.01). On multivariable regression, CCI greater than 3 (OR 7.2, p<0.001), in-hospital complications (OR 9.6, p<0.01), and ICU LOS greater than 2days (OR 1.5, p<0.05) were independently associated with the diagnosis of dysphagia. CONCLUSIONS: Elderly trauma patients with a high comorbidity burden or with prolonged ICU lengths of stay should be screened for dysphagia. PMID- 28843861 TI - Shoot regeneration: a journey from acquisition of competence to completion. AB - Plants display an extraordinary ability to regenerate complete shoot systems from a tissue fragment or even from a single cell. Upregulation of the determinants of pluripotency during a precise window of time in response to external inductive cues is a key decisive factor for shoot regeneration. A burst of recent studies has begun to provide an understanding of signaling molecules that are instrumental in the making of the regenerative mass, as well as the developmental regulators that are seminal in shaping the pluripotent state. Here, we discuss how signaling molecules, waves of mutually exclusive stem cell regulators and epigenetic modifiers could contribute to cellular heterogeneity in an island of regenerative mass, thus leading to de novo shoot regeneration. PMID- 28843862 TI - Altered synaptic phospholipid signaling in PRG-1 deficient mice induces exploratory behavior and motor hyperactivity resembling psychiatric disorders. AB - Plasticity related gene 1 (PRG-1) is a neuron specific membrane protein located at the postsynaptic density of glutamatergic synapses. PRG-1 modulates signaling pathways of phosphorylated lipid substrates such as lysophosphatidic acid (LPA). Deletion of PRG-1 increases presynaptic glutamate release probability leading to neuronal over-excitation. However, due to its cortical expression, PRG-1 deficiency leading to increased glutamatergic transmission is supposed to also affect motor pathways. We therefore analyzed the effects of PRG-1 function on exploratory and motor behavior using homozygous PRG-1 knockout (PRG-1-/-) mice and PRG-1/LPA2-receptor double knockout (PRG-1-/-/LPA2-/-) mice in two open field settings of different size and assessing motor behavior in the Rota Rod test. PRG 1-/- mice displayed significantly longer path lengths and higher running speed in both open field conditions. In addition, PRG-1-/- mice spent significantly longer time in the larger open field and displayed rearing and self-grooming behavior. Furthermore PRG-1-/- mice displayed stereotypical behavior resembling phenotypes of psychiatric disorders in the smaller sized open field arena. Altogether, this behavior is similar to the stereotypical behavior observed in animal models for psychiatric disease of autistic spectrum disorders which reflects a disrupted balance between glutamatergic and GABAergic synapses. These differences indicate an altered excitation/inhibition balance in neuronal circuits in PRG-1-/- mice as recently shown in the somatosensory cortex [38]. In contrast, PRG-1-/-/LPA2-/- did not show significant changes in behavior in the open field suggesting that these specific alterations were abolished when the LPA2-receptor was lacking. Our findings indicate that PRG-1 deficiency led to over-excitability caused by an altered LPA/LPA2-R signaling inducing a behavioral phenotype typically observed in animal models for psychiatric disorders. PMID- 28843863 TI - Administration of riluzole to the basolateral amygdala facilitates fear extinction in rats. AB - A general understanding exists that inhibition of glutamatergic neurotransmission in the basolateral amygdala (BLA) impairs fear extinction in rodents. Surprisingly, we recently found that systemic administration of riluzole, which has been shown to inhibit the glutamatergic system, facilitates extinction learning in rats with a preconditioned contextual fear response. However, the mechanisms underlying this paradoxical effect of riluzole remain unclear. In this study, adult male Wistar rats were bilaterally cannulated in the BLA to examine the effects of intra-BLA administration of riluzole. We also compared the effects of riluzole with those of d-cycloserine, a partial agonist at the glycine-binding region of the N-methyl-d-aspartate (NMDA) receptor. In this study, intra-BLA administration of either riluzole or d-cycloserine facilitated extinction learning of contextual fear in conditioned rats. In addition, both riluzole and d cycloserine enhanced the acquisition of recognition memory in the same model. However, intra-BLA injections of riluzole, but not d-cycloserine, had a potent anxiolytic-like effect when investigated using an elevated plus-maze test. Our findings suggest that riluzole-induced facilitation of extinction learning in rats with a preconditioned contextual fear reflects an indirect effect, resulting from the intra-BLA administration of the drug, and might not be directly related to inhibition of glutamatergic signaling. Further research is needed to clarify the mechanisms underlying the paradoxical effect of riluzole on fear extinction learning observed in this study. PMID- 28843864 TI - Sustained release of intravitreal flurbiprofen from a novel drug-in-liposome-in hydrogel formulation. AB - A novel Flurbiprofen (FLB)-in-liposome-in-hydrogel formulation was developed, as a method to sustain the release and increase the ocular bioavailability of FLB following intravitreal injection. For this, FLB loading into liposomes was optimized and liposomes were entrapped in thermosensitive hydrogels consisted of Pluronic F-127 (P). FLB solution, liposomes, and FLB dissolved in hydrogel were also used as control formulations. Actively loaded liposomes were found to be optimal for high FLB loading and small size, while in vitro studies revealed that P concentration of 18% (w/v) was best to retain the integrity of the hydrogel dispersed liposome, compared to a 20% concentration. The in vitro release of FLB was significantly sustained when FLB-liposomes were dispersed in the hydrogel compared to hydrogel dissolved FLB, as well as the other control formulations. In vivo studies were carried out in pigmented rabbits which were injected through a 27G needle with 1mg/mL FLB in the different formulation-types. Ophthalmic examinations after intravitreal injection of all FLB formulations, revealed no evidence of inflammation, hemorrhage, uveitis or endophthalmitis. Pharmacokinetic analysis results confirm that the hybrid drug delivery system increases the bioavailability (by 1.9 times compared to solution), and extends the presence of the drug in the vitreous cavity, while liposome and hydrogel formulations demonstrate intermediate performance. Furthermore the hybrid system increases MRT of FLB in aqueous humor and retina/choroid tissues, compared to all the control formulations. Currently the potential therapeutic advances of FLB sustained release formulations for IVT administration are being evaluated. PMID- 28843865 TI - Drug-device combination approaches for delivery to the eye. AB - While the eye is readily accessible from the outside of the body, it is a rather isolated organ with a number of barriers and elimination mechanisms in place to protect it from the environment, rendering efficient treatment difficult. To enhance drug delivery to the eye, a number of drug-device combinations have been investigated over recent decades, increasing drug retention and permeation while also allowing for sustained drug release over prolonged periods. This article will summarize recent combination systems investigated for the treatment of anterior and posterior segment conditions. PMID- 28843866 TI - Comparing two different techniques of rectus sheath block after single port laparoscopic surgery in benign adnexal mass patients: Surgical versus ultrasonography guidance-A randomized, single-blind, case-controlled study. AB - OBJECTIVE: The purpose of this study was to compare the analgesic effect of surgical bilateral rectus sheath block (BRSB) and ultrasonography-guidance BRSB in patients undergoing single port laparoscopic surgery (SPLS) for ovarian cyst. STUDY DESIGN: Seventy-five patients were randomly allocated into three groups: the control and ultrasound (US)-guidance group (n=25, each) received BRSB with 10ml of normal saline or 0.5% ropivacaine bilaterally under US guidance at the end of surgery, respectively; the surgical group (n=25) received BRSB with10ml of 0.5% ropivacaine bilaterally just before suturing the surgical site. All patients received intravenous fentanyl 50MUg for postoperative pain before emergence from anesthesia. Additional self-administered fentanyl and pain intensity were measured at postoperative 1, 6, 10 and 24h. RESULTS: Demographic characteristics showed no significant group-wise differences. The cumulative amount of fentanyl delivered was significantly lower in the US-guidance and surgical BRSB groups (189.20MUg and 187.68MUg, respectively) than the control group (286.40MUg) on postoperative day 1 (P<0.001). At 24h, the median pain score was significantly lower only in the surgical BRSB group. In addition, opioid-related side effects were decreased in patients who received BRSB (control group 36% vs. US-guidance BRSB group 24% vs. surgical BRSB group 12%). CONCLUSIONS: Both US-guided and surgical BRSB were effective for pain control in patients undergoing SPLS. Thus, surgical BRSB can be performed by gynecologists intra-operatively, for post operative pain management. PMID- 28843867 TI - Prevalence of sexual dysfunction in infertile versus fertile couples. AB - OBJECTIVES: The primary aim of this study was to test the hypothesis that sexual dysfunction is higher in infertile females in relation to normal healthy women through comparing total and sexual domains scores in both groups. The secondary objectives were: to determine factors affecting occurrence of female sexual dysfunction (FSD) in all sample and to determine factors affecting the different sexual domain scores within the infertile group. STUDY DESIGN: This cross sectional study was done at Cairo University Hospital. 200 infertile and 200 control females were evaluated using the Female Sexual Function Index (FSFI) questionnaire. Total score less than 26.55 signified sexual dysfunction. Husbands were evaluated by Sexual Health Inventory for Men (SHIM) questionnaire. A score less than 22 signified erectile dysfunction (ED). RESULTS: Proportion of females with sexual dysfunction was higher in the infertile versus control group (47% versus 30%, 95%CI for the difference: 8%, 26%, p-value:<0.001). Total, orgasm, satisfaction and pain scores were significantly lower in infertile versus control group (mean+/-SD: 26.8+/-3.8 versus 27.9+/-3.5, p-value: 0.003; 4.2+/-0.7 versus 4.6+/-0.6, p-value: 0.01; 4.9+/-0.5 versus 5.2+/-0.5, p-value: 0.004 and 3.9+/ 0.9 versus 4.4+/-0.7, p-value:<0.001 respectively). Husband SHIM erectile score was significantly lower in the infertile group (median score (range): 19 (5, 25) versus 22 (12, 25), p-value: 0.001). After adjustment for 15factors by logistic regression, the odds ratio of having FSD was 2.6 (95%CI: 1.5, 4.5, p-value: 0.001) in the infertile relative to control females. Secondary (versus primary) infertility was negatively correlated with arousal score (B (95%CI): -0.6 (-0.02, -1.2), p-value: 0.003) while duration of infertility was negatively correlated with arousal, satisfaction and pain domains scores (B (95%CI): -0.2 (-0.08, 0.32), p-value: 0.04; -0.2 (-0.1, -0.3), p-value: 0.005; -0.2 (-0.06, -0.34), p value: 0.03 respectively). CONCLUSION: sexual dysfunction is more prevalent in infertile versus control group. Infertility clinicians should be aware of this problem to assess and treat their patients to improve their quality of life. PMID- 28843868 TI - Recessions and health revisited: New findings for working age adults. AB - A series of influential papers have documented that state level mortality rates decrease during economic downturns. In this paper, we estimate the effect of education specific unemployment rates on mortality, which provide a more exact measure of the likelihood of being directly impacted by a recession. We find that the unemployment rate of an education group in a given state is positively related to mortality in that group. A 1% increase in the group-specific unemployment rate is associated with an approximately 0.015% increase in the group-specific mortality rate, which is consistent with the hypothesis that, while state-level unemployment may have indirect health benefits, being personally affected by a recession has a detrimental effect on health. PMID- 28843869 TI - Development of a radioligand for imaging V1a vasopressin receptors with PET. AB - A series of vasopressin receptor V1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3 yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6 yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with 11C for PET studies. [11CH3](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (~2% ID/g tissue) and specifically (30 34%) labeled V1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [11CH3](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V1a receptor. PMID- 28843871 TI - Untangling the complex relationships between symptoms of schizophrenia and emotion dynamics in daily life: Findings from an experience sampling pilot study. AB - The unfolding of emotions over time (i.e., emotion dynamics) has been characterized by baseline, intraindividual variability and regulatory tendency (return time to baseline after deflection). Mounting evidence suggests that compared to healthy individuals, individuals with schizophrenia are characterized by a more negatively valenced baseline and a higher intraindividual variability. However, the regulatory tendency has not been investigated in schizophrenia so far. We hypothesize that the severity of positive symptoms is linked to increased emotional variability and that the severity of negative symptoms is associated with an increased regulatory tendency. Fifteen individuals diagnosed with schizophrenia took part in this pilot experience sampling study and reported their emotional state ten times a day. The dynamics of valence and arousal and their relationship with symptomatology were estimated with the DynAffect model. Regulatory tendency in valence and arousal was positively associated with negative symptom severity and negatively associated with positive symptom severity. However, the severity of positive symptoms was not credibly associated with the variability of valence. The study only partly corroborates findings on increased stress reactivity in schizophrenia, which might be due to the small sample size. However, results suggest that negative symptoms could stem from over regulated emotion dynamics, which may impede goal-directed behavior. PMID- 28843870 TI - Trauma and traumatic stress in a sample of pregnant women. AB - OBJECTIVE: To examine the construct validity of the 9 item Traumatic Events Questionnaire (TEQ) and to evaluate the extent to which experiences of trauma assessed using the TEQ are associated with symptoms of psychiatric disorders among 3342 pregnant women in Lima, Peru. METHODS: Symptoms of depression were assessed using the Patient Health Questionnaire-9 (PHQ-9) and Edinburgh Postnatal Depression Scale (EPDS) while the PTSD Checklist-civilian (PCL-C) and Generalized Anxiety Disorder-7 (GAD-7) were used to assess symptoms of PTSD and generalized anxiety. Hierarchical logistic regression procedures were used to evaluate relations between TEQ and symptoms of psychiatric disorders. RESULTS: The majority of participants (87.8%) experienced at least one traumatic event (mean = 2.5 events). The trauma occurrence score was moderately correlated with symptoms of PTSD (PCL-C: rho = 0.38, P-value < 0.0001), depression (EPDS: rho = 0.31, P value < 0.0001; PHQ-9: rho = 0.20, P-value < 0.0001), and GAD (GAD-7: rho = 0.29, P-value < 0.0001). Stronger correlations were observed between the trauma intensity score with symptoms of psychiatric disorders (PCL-C: rho = 0.49, P value < 0.0001; EPDS: rho = 0.36, P-value < 0.0001; PHQ-9: rho = 0.31, P-value < 0.0001; GAD-7: rho = 0.39, P-value < 0.0001). CONCLUSION: Given the high burden of trauma experiences and the enduring adverse consequences on maternal and child health, there is an urgent need for integrating evidence-based trauma informed care programs in obstetrical practices serving Peruvian patients. PMID- 28843872 TI - Does grandchild care influence grandparents' self-rated health? Evidence from a fixed effects approach. AB - The present study aims to identify, whether and how supplementary grandchild care is causally related to grandparents' self-rated health (SRH). Based on longitudinal data drawn from the German Aging Survey (DEAS; 2008-2014), I compare the results of pooled OLS, pooled OLS with lagged dependant variables (POLS-LD), random and fixed effects (RE, FE) panel regression. The results show that there is a positive but small association between supplementary grandchild care and SRH in POLS, POLS-LD, and RE models. However, the fixed effects model shows that the intrapersonal change in grandchild care does not cause a change in grandparents' SRH. The FE findings indicate that supplementary grandchild care in Germany does not have a causal impact on grandparents' SRH, suggesting that models with between-variation components overestimate the influence of grandchild care on grandparents' health because they do not control for unobserved (time-constant) heterogeneity. PMID- 28843874 TI - Alternative futures: Fields, boundaries, and divergent professionalisation strategies within the Chiropractic profession. AB - Sociological studies of the complementary and alternative medicine (CAM) occupations have documented the professionalisation strategies these groups use to establish boundaries between themselves and their competitors, including seeking educational accreditation and statutory regulation/licensure. Chiropractic has been particularly successful at professionalising and in Australia and the UK it is taught within public universities. Recent events have threatened chiropractic's university foothold, however, showing that professionalisation needs to be understood as an ongoing process of negotiation. Based on interviews with chiropractors in Australia and the UK, this paper examines the professionalisation strategies deployed by chiropractors within and outside of the university. Highly divergent strategies are identified across different sectors of the profession, relating to defining the chiropractic paradigm, directing education and constructing professional identity. In each domain, chiropractic academics tended to prioritise building the evidence base and becoming more aligned with medicine and other allied health professions. Although some practitioners supported this agenda, others strove to preserve chiropractic's vitalistic philosophy and professional distinction. Following Bourdieu, these intra-professional struggles are interpreted as occurring within a field in which chiropractors compete for different forms of capital, pulled by two opposing poles. The differing orientations and strategies pursued at the two poles of the field point to a number of possible futures for this CAM profession, including a potential split within the profession itself. PMID- 28843873 TI - The Islamification of antiretroviral therapy: Reconciling HIV treatment and religion in northern Nigeria. AB - Access and adherence to antiretroviral therapy (ART) are essential to HIV treatment success and epidemic control. This article is about how HIV-positive Muslims and providers balance ART with religious tenets and obligations. I conducted 17 months of multi-site ethnographic research between 2007 and 2010, including participant-observation in an urban HIV clinic in Kano, Nigeria and a support group for people living with HIV, as well as in-depth interviews with 30 HIV-positive men and 30 key informants with caregiving, clinical, or policy roles related to HIV/AIDS. Patients migrated from Islamic prophetic medicine to ART when it became more widely available in the mid-2000s through the U.S. PEPFAR program. At the same time, a conceptual shift occurred away from considering HIV immediately curable through spiritual and herbal-based Islamic prophetic medicine toward considering HIV as a chronic infection that requires adherence to daily pill regimens. Hope for a complete cure and encouragement from some Islamic prophetic healers resulted in some patients forgoing ART. Patients and providers adapted biomedical treatment guidelines to minimize disruption to religious practices also considered essential to Muslims' wellbeing, irrespective of HIV status. Providers discouraged patients on second-line ART from fasting because such patients had fewer treatment options and, often, poorer health. However, patients' medication adherence was affected by the desire to fulfill fasting obligations and to avoid questions from family and friends unaware of their HIV positive status. This study is one of few ethnographic accounts of HIV treatment in a Muslim-majority society and contributes to understanding the significance of religion for HIV treatment in northern Nigeria. It has implications for public health programming and clinical approaches to HIV treatment in medically pluralistic Muslim societies. PMID- 28843875 TI - Cardiovascular causes of maternal sudden death. Sudden arrhythmic death syndrome is leading cause in UK. PMID- 28843876 TI - 2D FTIR correlation spectroscopy and EPR analysis of Urtica dioica leaves from areas of different environmental pollution. AB - Leaves of Urtica dioica collected from two areas of different environmental pollution were analysed by fourier transform infrared spectroscopy (FTIR) and electron paramagnetic resonance (EPR) spectroscopy. Analysis of FTIR spectra allows to describe main component of plant like proteins, lipids and carbohydrates. Although the FTIR spectra of plants from these two geographical locations of different environmental pollution appear to be relatively similar, 2D correlation shows completely different patterns. Synchronous and asynchronous correlation maps showed sequences of changes occurring during development of plant, manly in Amide I and Amide II, lignin, lipids and cellulose. In addition, 2D analysis revealed another sequence of changes as the function of plant growth depending on the degree of the environmental pollution. Two various kinds of paramagnetic species, transition metal ions (Mn(II), Fe(III)) and stable organic radicals (chlorophyll, semiquinone, tyrosyl and carbon centered) were found in leaves of nettle collected at different stages of development and growing in clean and polluted environment. In plants growing in polluted area the injuries of protein molecules bonding metal ions and the disturbances of photosynthesis and redox equilibrium in cells, as well as instability of polysaccharide structure of cell walls were observed. PMID- 28843877 TI - Interaction of anesthetic molecules with alpha-helix and polyproline II extended helix of long-chain poly-l-lysine. AB - The effect of halothane, enflurane, sevoflurane, and isoflurane molecules, as volatile anesthetics, on the alpha-helices and polyproline II extended helices (PPII) of long-chain poly-l-lysine (PLL) were studied using Fourier-transform infrared and vibrational circular dichroism spectroscopy. Uncharged and charged alpha-helices, as well as charged extended PPII helices, were subjected to anesthetic actions in solvents with different pD values or methanol to water ratios. A crucial factor responsible for hindering the anesthetic-PLL interactions is shown to be the ionization of amino groups of the PLL side chains. The alpha-helix to beta-sheet transition was triggered only for the uncharged alpha-helical structures of PLL by the nonpolar anesthetics under study. PMID- 28843878 TI - An efficient, cost effective, sensing behaviour liquid-liquid extraction and spectrophotometric determination of copper(II) incorporated with 4-(4' chlorobenzylideneimino)-3-methyl-5-mercapto-1, 2, 4-triazole: Analysis of food samples, leafy vegetables, fertilizers and environmental samples. AB - The aim of the present work is to develop an efficient, simple and selective moreover cost-effective method for the extractive spectrophotometric determination of copper(II) by using the Schiff base 4-(4' chlorobenzylideneimino)-3-methyl-5-mercapto-1, 2, 4-triazole [CBIMMT]. This chromogenic reagent forms a yellow coloured complex with copper(II) in acetate buffer at pH4.2. The copper(II) complex with ligand is instantly extracted into chloroform and shows a maximum absorbance at 414nm which remains stable for >48h. The composition of extracted complex is found to be 1:2 [copper(II): reagent] which was ascertained using Job's method of continuous variation, mole ratio method and slope ratio method. Under optimal conditions, the copper(II) complex in chloroform adheres to Beer's law up to 17.5MUgmL-1 of copper(II). The optimum concentration range obtained from Ringbom's plot is from 5MUgmL-1 to 17.5MUgmL-1. The molar absorptivity, Sandell's sensitivity and enrichment factor of the extracted copper(II) chelate are 0.33813*104Lmol-1cm-1, 0.01996MUgcm-2 and 2.49 respectively. In the extraction of copper(II), several affecting factors including the solution pH, ligand concentration, equilibrium time, effect of foreign ions are optimized. The interfering effects of various cations and anions were also studied and use of masking agents enhances the selectivity of the method. The chromogenic sulphur containing reagent, 4-(4'-chlorobenzylideneimino) 3-methyl-5-mercapto-1, 2, 4-triazole has been synthesized in a single step with high purity and yield. The synthesized reagent has been successfully applied first time for determination of copper(II). The reagent forms stable chelate with copper(II) in buffer medium instantly and quantitatively extracted in chloroform within a minute. The method is successfully applied for the determination of copper(II) in various synthetic mixtures, complexes, fertilizers, environmental samples such as food samples, leafy vegetables, and water samples. The results are compared with those obtained with a reference procedure. Good agreement was attained. All the obtained results are indicative of a convenient, fast method for the extraction and quantification of micro levels of copper(II) from various environmental matrices without use of sophisticated instrumentation and procedure. The method showed a relative standard deviation of 0.42%. PMID- 28843879 TI - Influence of vibronic contribution on light harvesting efficiency of NKX-2587 derivatives with oligothiophene as pi-conjugated linker. AB - Based on the NKX-2587 molecule we designed ten sensitizers with 1-10 thiophene moieties to investigate how the number of thiophene unit in the spacer influences the absorption spectra of sensitizer in dye sensitized solar cells (DSSCs). The parameters of short-circuit current density (Jsc), open circuit voltage (Voc), the light harvesting efficiency (LHE), injection driving force (?Ginject), and transferred electron number (nc), were calculated and discussed in detail. Results indicated that the increasing of thiophene units makes for the enhancement of oscillator strengths (f), although the red shift of vertical electronic absorption spectra is small. For the designed sensitizers with 1-5 thiophene units, their DeltaGinject and nc raise gradually with the increasing of thiophene number. However, for those sensitizers with 6-10 thiophene units, the DeltaGinject and nc decrease continuously with the increasing of thiophene units. In order to study how the oligothiophene as pi-conjugated linker affects light harvesting efficiency of DSSCs, the vibrationally resolved electronic spectra of five metal-free NKX-2587 derivatives with 1-5 thiophene units were simulated within the Franck-Condon approximation including the Herzberg-Teller and Duschinsky effects. The present theoretical results provided helpful guidance for understanding the sources of spectral intensities of dye molecules, and a valuable method for rational design of new molecules to improve the energy conversion efficiency (eta) of DSSCs. PMID- 28843880 TI - Non-destructive prediction of protein content in wheat using NIRS. AB - A steady and accurate model used for quality detection depends on precise data and appropriate analytical methods. In this study, the authors applied partial least square regression (PLSR) to construct a model based on the spectral data measured to predict the protein content in wheat, and proposed a new method, global search method, to select PLSR components. In order to select representative and universal samples for modeling, Monte Carlo cross validation (MCCV) was proposed as a tool to detect outliers, and identified 4 outlier samples. Additionally, improved simulated annealing (ISA) combined with PLSR was employed to select most effective variables from spectral data, the data's dimensionality reduced from 100 to 57, and the standard error of prediction (SEP) decreased from 0.0716 to 0.0565 for prediction set, as well as the correlation coefficients (R2) between the predicted and actual protein content of wheat increased from 0.9989 to 0.9994. In order to reduce the dimensionality of the data further, successive projections algorithm (SPA) was then used, the combination of these two methods was called ISA-SPA. The results indicated that calibration model built using ISA-SPA on 14 effective variables achieved the optimal performance for prediction of protein content in wheat comparing with other developed PLSR models (ISA or SPA) by comprehensively considering the accuracy, robustness, and complexity of models. The coefficient of determination increased to 0.9986 and the SEP decreased to 0.0528, respectively. PMID- 28843881 TI - Biophysical and computational characterization of vandetanib-lysozyme interaction. AB - Interaction of an anticancer drug, vandetanib (VDB) with a ligand transporter, lysozyme (LYZ) was explored using multispectroscopic techniques, such as fluorescence, absorption and circular dichroism along with computational analysis. Fluorescence data and absorption results confirmed VDB-LYZ complexation. VDB-induced quenching was characterized as static quenching based on inverse correlation of KSV with temperature as well as kq values. The complex was characterized by the weak binding constant (Ka=4.96-3.14*103M-1). Thermodynamic data (DeltaS=+12.82Jmol-1K-1; DeltaH=-16.73kJmol-1) of VDB-LYZ interaction revealed participation of hydrophobic and van der Waals forces along with hydrogen bonds in VDB-LYZ complexation. Microenvironmental perturbations around tryptophan and tyrosine residues as well as secondary and tertiary structural alterations in LYZ upon addition of VDB were evident from the 3-D fluorescence, far- and near-UV CD spectral analyses, respectively. Interestingly, addition of VDB to LYZ significantly increased protein's thermostability. Molecular docking results suggested the location of VDB binding site near the LYZ active site while molecular dynamics simulation results suggested stability of VDB-LYZ complex. Presence of Mg2+, Ba2+ and Zn2+ was found to interfere with VDB LYZ interaction. PMID- 28843882 TI - Influence of various bonding techniques on the fracture strength of thin CAD/CAM fabricated occlusal glass-ceramic veneers. AB - OBJECTIVES: To evaluate the efficiency of immediate dentin sealing and the effects of different bonding protocols on the fracture strength of CAD/CAM occlusal veneers bonded to exposed dentin. METHODS: Ninety-six extracted maxillary premolars were initially divided into three main groups with 32 specimens each: without immediate dentin sealing, immediate dentin sealing/total etching and immediate dentin sealing/selective etching. Teeth were identically prepared in the dentin to receive occlusal veneers of 0.8mm thickness, milled from lithium disilicate ceramic blocks (IPS e.max CAD). Each main group was later subdivided, according to the pre-cementation surface etching protocol (total/selective), into two subgroups with 16 specimens each. All restorations were adhesively bonded using a resin cement (Variolink Esthetic). Half of the specimens of each subgroup were subjected to thermo-dynamic loading in a chewing simulator with 1,200,000 cycles at 10kg load. The other half and the surviving specimens were subjected to quasi-static loading until failure. Statistical analysis was performed using three-way ANOVA and Tukey's post-hoc tests. RESULTS: All specimens except one survived the artificial aging. A significantly higher fracture strength of restorations (p <= 0.001) was obtained when immediate dentin sealing was followed regardless of the etching method with values ranging from a minimum of 1122 +/- 336N to a maximum of 1853 +/- 333N. Neither the pre cementation treatment nor the artificial aging had a statistical significant effect on the fracture strength. SIGNIFICANCE: Immediate dentin sealing protocol is recommended whenever dentin is exposed during the preparation for thin glass ceramic occlusal veneers. PMID- 28843883 TI - Fatigue strength of yttria-stabilized zirconia polycrystals: Effects of grinding, polishing, glazing, and heat treatment. AB - This study aimed to evaluate and compare the effect of different surface post processing treatments (polishing, heat treatment, glazing, polishing + heat treatment and polishing + glazing) on the superficial characteristics (micromorphology and roughness), phase transformation and fatigue strength of a Y TZP ceramic ground with diamond bur. Discs of Y-TZP ceramic were manufactured (ISO:6872-2015; final dimensions of 15mm in diameter and 1.2 +/- 0.2mm in thickness) and randomly allocated according to the surface condition: Ctrl - as sintered; Gr - ground with coarse diamond bur; Gr+HT - ground and subjected to the heat treatment; Gr+Pol - ground and polished; Gr+Pol+HT - ground, polished and heat treated; Gr+Gl - ground and glazed; Gr+Pol+Gl - ground, polished and glazed. The following analyses were performed: roughness (n = 25), surface topography (n = 2), phase transformation (n = 2) and fatigue strength by staircase method (n = 20). All treatments influenced to some extent the surface characteristics of Y-TZP, being that polishing reduced the surface roughness, the m-phase content and improved the fatigue strength; glazing led to the lowest roughness values (Ra and Rz), although it showed the worst fatigue strength; heat treatment showed limited effect on surface roughness, led to complete reversion of the existing m-phase content to t-phase, without enhancing fatigue performance. Thus, a polishing protocol after clinic adjustment (grinding) of monolithic restorations based on polycrystalline zirconia material is mandatory for surface characteristics and fatigue performance improvements. PMID- 28843884 TI - A multi-year study of tillage and amendment effects on compacted soils. AB - Constructing roads and buildings often involves removal of topsoil, grading, and traffic from heavy machinery. The result is exposed, compacted subsoil with low infiltration rate (IR), which hinders post-construction vegetation establishment and generates significant runoff, similar to impervious surfaces. Our goal was to assess tillage and adding amendments for improving density and maintaining perviousness of subsoils compacted during construction. The effects of tillage with and without amendments on (1) soil compaction, (2) IR, and (3) vegetative growth at five sites in North Carolina, USA were evaluated over a period of up to 32 months. The sites, representing a range of soil conditions, were located at three geographic regions; one in the Sandhills (located in Coastal Plain), one in the mountains, and three in the Piedmont. Amendments varied by site and included: (1) compost, (2) cross-linked polyacrylamide (xPAM), and (3) gypsum. Bulk density (BD) and soil penetration resistance (PR) tests were used to characterize soil physical condition. The IR was measured using a Cornell Sprinkle Infiltrometer. Vegetative growth was evaluated by measuring shoot mass and vegetative cover at all sites and root density at the Piedmont sites. Tillage decreased BD and PR compared to the compacted soil at four out of five sites for observations ranging from 24 to 32 months. Compost was applied to four sites prior to tillage and reduced BD in two of them compared to tillage alone. The IR in the tilled plots was maintained at about 3-10 times that of the compacted soil among the five sites over the monitoring periods. Adding amendments did not increase IR relative to tillage alone except at one Piedmont site, where compost and xPAM increased IR at 12 months and compost at 24 months after site establishment. Vegetative responses to tillage and amendments were inconsistent across sites. Results suggest that tillage is a viable option to reduce bulk density and increase infiltration for areas with compacted soils where vegetation is to be established, and that the effect is maintained for at least several years. PMID- 28843885 TI - The impact of treatment for head and neck cancer on positive psychological change within a year of completing treatment. AB - Head and neck cancer carries a high level of morbidity and mortality. So why could anyone find having such a disease a positive event? The adversity hypothesis of "what doesn't kill you makes you stronger" suggests that people can use adversity to develop as human beings. This positive psychological change has received little attention in relation to head and neck cancer. Responses to the Silver Lining Questionnaire, University of Washington Quality of Life Questionnaire, and Short-Form 12 were collected from a postal survey, 3 to 12 months after the completion of treatment for head and neck cancer. Fifty-two (63%) people returned the survey and were included in the analysis. Time since completion of therapy did not show any relationship with positive psychological change. Tumour stage and treatment regimen both had a relationship with positive change. Participants with lower stage tumours had higher levels of positive change than those with tumours of higher stages. Participants who had surgery alone reported more positive change than those who had surgery with radiotherapy. A social factor related to greater change was being married or living with a partner when compared to living alone. Further research would aid the identification of bio-psychosocial factors that influence the development of positive psychological change and inform the development of rehabilitation interventions. PMID- 28843887 TI - Pediatric emergency. PMID- 28843886 TI - Childhood maltreatment is associated with gray matter volume abnormalities in patients with first-episode depression. AB - Previous neuroimaging studies suggest that childhood maltreatment (CM) can affect brain function and structure and constitutes a potent risk of developing depression. The present study attempts to differentiate the effect of CM from the impact of depression diagnosis on brain structure. Eighty-four patients with first-episode depression and 84 controls participated in this study. All subjects underwent a structural magnetic resonance imaging (MRI) scan. Voxel-based morphometric analysis of variance (ANOVA), between-group comparison, and regression analyses were performed on a whole-brain level to identify the unbiased effects of CM and depression on brain structure. Our data showed different main effects of CM and depression on brain structure separately: the significant main effect of CM on fronto-limbic areas, visual cortex and cerebellum, and the main effect of depression on orbitofrontal regions and bilateral temporal lobes. The maltreatment-by-diagnosis interaction effect was found located on the bilateral prefrontal cortex. The CM severity was negatively related with the inferior occipital volume and positively with volumes in the left dorsolateral prefrontal cortex, right caudate, and left middle temporal gyrus. This study suggested that early life stress like CM is associated with structural abnormalities of the fronto-limbic regions that are commonly regarded as the psychopathological consequence of depression. The effect of CM on brain structure should be considered in future neuroimaging research of depression. PMID- 28843888 TI - Seed priming by sodium nitroprusside improves salt tolerance in wheat (Triticum aestivum L.) by enhancing physiological and biochemical parameters. AB - The germination, seedling vigor, crop establishment and yield of agronomically important crops is negatively affected by soil salinity. The current study aimed to investigate the ability of exogenous fertigation by sodium nitroprusside (SNP) to induce salt tolerance in four high yielding wheat cultivars (Sahar-06, Punjab 11, Millat-11 and Galaxy-13) that differ in their response to salt stress in terms of biomass production, oxidative defense mechanisms and grain yield. Three levels of SNP (0, 0.1 and 0.2 mM) were used for seed soaking. During soaking the seeds were kept in the dark. After soaking for 12 h the seeds were air-dried for 5 h before sowing. Salinity caused a significant reduction in biomass and grain yield, while it increased proline (Pro), ascorbic acid (AsA), hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents. Cultivar Sahar-06 and Galaxy-13 were found more tolerant to salinity based on shoot length root fresh and dry wights, 100 grain weight, decreased MDA and H2O2 accumulation, phenolic and ascorbic acid (AsA) contents, accumulation of proline, activities of SOD, POD and CAT as compared to the other cultivars. Seed priming with SNP was effective in reducing the adverse effects of salt stress induced oxidative stress on plant biomass and grain yield in all the studied wheat cultivars, but maximum amelioration of salt stress tolerance by SNP treatment was found in cv. Sahar-06. The increased salt tolerance in wheat plants by SNP seed priming might be due to the role of NO in improving seed vigor and germination and early establishment of seedlings with better growth. 0.1 mM SNP was found the most effective in improving salt tolerance, as compared to other SNP concentations. Exogenous SNP fertigation increased the activities of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) and the contents of AsA, Pro and total phenolics content (TPC) in the salt stressed wheat plants. Our data indicate that SNP-priming induced salt tolerance by up-regulating the antioxidative defense mechanisms resulting in better biomass production and grain yield. PMID- 28843889 TI - Physiological and antioxidant responses of winter wheat cultivars to strigolactone and salicylic acid in drought. AB - Strigolactones are considered as important regulators of plant growth and development. Recently positive regulatory influence of strigolactones in plant in response to drought and salt stress has been revealed. Salicylic acid, a phytohormone, has reported to be involved in a number of stress responses such as pathogen infection, UV irradiation, salinity and drought. Considering the concealed role of strigolactones in agronomic crops drought tolerance and possible interaction among salicylic acid and strigolactone, we investigated the effects of exogenous application of GR24 and salicylic acid on two winter wheat cultivars under drought conditions. Foliar GR24 and salicylic acid were applied on drought sensitive and drought tolerant winter wheat cultivars at tillering and anthesis stages in 40% and 80% of field capacity moisture levels. Strigolactones and salicylic acid treated plants showed higher tolerance to drought stress with regard to lower electrolyte leakage and higher relative water content, leaf stomatal limitation, membrane stability index and antioxidant enzyme activities. Salicylic acid application dampened malondialdehyde content in wheat plants. Drought tolerance of wheat plants were intensified in most of the cases when theses phytohormones were used together, suggesting a possible interaction between salicylic acid and strigolactones in drought situations. PMID- 28843890 TI - Prospective relations between intrusive parenting and child behavior problems: Differential moderation by parasympathetic nervous system regulation and child sex. AB - This study examined children's parasympathetic nervous system (PNS) regulation, which was indexed by respiratory sinus arrhythmia (RSA) during rest, reactivity, and recovery episodes, and sex as moderators of predicted relations between observed intrusive parenting and later observer-rated child behavior problems. Child-caregiver dyads (N=250; 50% girls; 46% Latino/a) completed a series of laboratory assessments yielding independent measures of intrusive parenting at age 4, PNS regulation at age 6, and child behavior problems at age 8. Results indicated that intrusive parenting was related to more internalizing problems among boys who showed low RSA reactivity (i.e., PNS withdrawal from pre-startle to startle challenge), but RSA reactivity did not moderate this relation among girls. Interestingly, RSA recovery (i.e., PNS activation from startle challenge to post-startle) moderated these relations differently for boys and girls. For girls with relatively low RSA post-startle (i.e., less recovery), intrusive parenting was positively related to both internalizing and externalizing problems. However, the reverse was true for boys, such that there was a significant positive relation between intrusive parenting and later externalizing problems among boys who evidenced relatively high RSA post-startle (i.e., more recovery). Findings provide evidence for the moderation of intrusive caregiving effects by children's PNS regulation while highlighting the differential patterning of these relations across distinct phases of the regulatory response and as a function of child sex. PMID- 28843891 TI - Gender differences in glucose homeostasis and diabetes. AB - Some aspects of glucose homeostasis are regulated differently in males and females. This review discusses the most fundamental gender differences in glucose homeostasis and diabetes. These include the prevalence of impaired fasting glucose and impaired glucose tolerance, the prevalence and incidence of type 2 and type 1 diabetes, and the sex-specific effects of testosterone and estrogen deficiency and excess. These gender-specific differences in glucose homeostasis represent a source of factors that should be studied to develop gender-based therapeutic avenues for diabetes. PMID- 28843892 TI - Anti-inflammatory effect of stem bark of Paulownia tomentosa Steud. in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and LPS-induced murine model of acute lung injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves, bark, and flowers of Paulownia tomentosa Steud. have been widely used as a traditional medicine in East Asia to treat inflammatory and infectious diseases. AIM OF THE STUDY: We investigated the protective effect of the methanol stem bark extract of P. tomentosa using an animal model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). MATERIALS AND METHODS: The UPLC Q-TOF-MS profiles for the methanol extract of P. tomentosa stem bark showed that verbascoside and isoverbascoside were the predominant compounds. Raw 264.7 cells were used for inhibitory effects of cytokine production in vitro. C57BL/6N mice were administered intranasally with LPS (10MUg/per mouse) to induce ALI. H&E staining was used to evaluate histological changes in the lung. RESULTS: Treatment with P. tomentosa stem bark extract (PTBE) suppressed the production of IL-6 and TNF-alpha in LPS-stimulated RAW 264.7 macrophages, and the recruitment of neutrophils and macrophages in the BALF of mice with LPS-induced ALI. PTBE also decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines in the BALF. PTBE reduced the levels of nitric oxide (NO) in the serum and of inducible nitric oxide synthase (iNOS) in the lung of ALI mice. PTBE also attenuated the infiltration of inflammatory cells and the expression of monocyte chemoattractant protein-1 (MCP 1) in the lung. In addition, PTBE suppressed the activation of NF-kappaB and the reduced expression of superoxide dismutase 3 (SOD3) in the lung. CONCLUSION: The results suggest that PTBE has a protective effect on LPS-induced ALI. PMID- 28843893 TI - Chemopreventive and remediation effect of Adansonia digitata L. Baobab (Bombacaceae) stem bark extracts in mouse model malaria. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Adansonia digitata L. Baobab (Bombacaceae) solvent extracts have been reported to possess medicinal properties and are currently been used traditionally for the treatment of malaria and several other diseases and infection; however few reports exist in literature that provides supportive scientific evidence in favour of its medicinal use. AIM OF THE STUDY: This study investigated the efficacy of Adansonia digitata stem bark extract in offering protection against experimental malaria and also examined its remediation effect when administered after established infection. MATERIALS AND METHODS: Weanling albino mice were used in the study. The mice were transfected intraperitonially with an inoculums size of 1* 107 of chloroquine susceptible strain of plasmodium berghei infected erythrocytes. Mechanisms of action of the extract were investigated by measuring the degree of tissue peroxidation and tissue antioxidant status. Severity of malaria was determined by measuring the serum C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and serum and tissue Alkaline phosphatase (ALP) activity. RESULTS: There was a significant increase in serum CRP, TNF-alpha concentrations and serum and tissue ALP activity in the control mice following Plasmodium berghei infection. All the treatment had effect on the growth of Plasmodium berghei parasites in mice. The extracts showed a significant dose dependent increase packed cell volume (PCV), percentage chemosupression/clearance and a significant decrease in percentage parasitemia at the two doses when administered after established infection. Methanolic extract (MEAD) at 400mg/kg exhibited the highest chemosupressive activity. The extract significantly reduced the degree of tissue peroxidation, increased the level of reduced glutathione (GSH), catalase and superoxide dismutase activity. Administration of the extract after established infection reduced serum CRP and TNF-alpha concentrations and serum and tissue ALP activity. CONCLUSION: Our study suggests that Adansonia digitata protects against Plasmodium berghei induced-malaria, and that administration of the extract after established infection reduced malaria progression. PMID- 28843894 TI - Modulation of gene expression by nutritional state and hormones in Bombyx larvae in relation to its growth period. AB - Insect growth and development are mainly regulated via synchronization of many extrinsic and intrinsic factors such as nutrition and hormones. Previously we have demonstrated that larval growth period influences the effect of insulin on the accumulation of glycogen in the fat body of Bombyx larvae. In the present study we demonstrate that Bombyx larvae at the terminal growth period (TGP, after critical weight) had a significantly greater increase in the expression level of Akt in the fat body than at the active growth period (AGP, before critical weight). The larvae at TGP also showed an increase in the expression level of ecdysone receptors (EcRB1 and USP1) and ecdysone-induced early genes (E75A and broad). The treatment of bovine insulin and methoprene to larvae at AGP induced the transcript levels of Akt, irrespective of the nutritional status of the larvae. However, in larvae at TGP, insulin repressed the transcript level of Akt. On contrary, 20-hydroxyecdysone (20E) induced the expression level of Akt in TGP larvae, but at feeding only. Insulin and 20E thus showed an antagonistic action on the Akt expression level in TGP larvae under feeding. The studies thus showed that larval growth period influences the expression level of Akt and ecdysone receptors in Bombyx. Further, the growth period and nutrition modulate the effect of exogenous hormones on Akt expression. PMID- 28843895 TI - Dechlorinating bacteria are abundant but anaerobic dechlorination of weathered polychlorinated dibenzo-p-dioxins and dibenzofurans in contaminated sediments is limited. AB - The potential for microbial dechlorination of the weathered polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) was determined in sediments with historical contamination by the chlorophenol wood preservative Ky-5 and its associated dimeric impurities. Sediments were collected from four sites of the Kymijoki River in South-Eastern Finland located at 0, 20, 30, and 60 km downstream from the source of contamination, and at a reference site. We examined the congener profiles of historical PCDD/Fs, including non-2,3,7,8-substituted congeners, and determined the dechlorination potential in sediments at the different sites of the river. The measured mean total concentrations for 2,3,7,8 PCDD/Fs were extremely high, 1200 mg/kg dw, at the most contaminated site, Kuusankoski. The mean concentrations for the predominant 2,3,7,8-congeners were 1,2,3,4,6,7,8-HpCDF 780 mg/kg dw, and for OCDF 380 mg/kg dw at Kuusankoski. At all other study sites of the river the mean total concentrations for 2,3,7,8 PCDD/Fs varied between 9 and 96 mg/kg dw, (6-80 mg/kg dw for 1,2,3,4,6,7,8-HpCDF, 3-13 mg/kg dw for OCDF). The sediment PCDD/F composition was similar to that of Ky-5, indicating that no or only minimal biodegradation of PCDD/F congeners has occurred in the river sediments over the last few decades since the contamination events. Microbes capable of PCDD/F dechlorination were present at all study sites based on Dehalococcoides-like Chloroflexi community determination and dechlorination of spiked 1,2,3,4-tetrachlorodibenzofuran. However, no substantial changes in the relative abundances of PCDD/Fs were observed over 2.5 years in laboratory microcosm studies, indicating that anaerobic dechlorination of weathered PCDD/Fs was limited over the course of the experiment. Therefore, concentrations of weathered PCDD/Fs in the sediments of the Kymijoki River are expected to remain at the same level for decades or centuries with further migration towards the Baltic Sea. PMID- 28843896 TI - Brominated flame retardants (BFRs) in eggs from birds of prey from Southern Germany, 2014. AB - In Southern Germany, peregrine falcons (Falco peregrinus), which almost exclusively prey on other birds, are top predators of the terrestrial food chain. These animals accumulate persistent organic pollutants (POPs) and halogenated flame retardants (HFRs) with mothers transferring these lipophilic contaminants to their eggs. Here we analyzed unhatched eggs of eleven peregrine falcons and six of other species, and report concentrations of polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCD), hexabromobenzene (HBB), 2,3-dibromopropyl 2,4,6-tribromophenyl ether (DPTE) and its metabolites, pentabromoethylbenzene (PBEB), pentabromotoluene (PBT), and tribromophenol (TBP). The extract of one purified peregrine falcon egg sample was comprehensively analyzed in a non-target (NT) approach by gas chromatography with mass spectrometry in the electron capture negative ion mode. A total of ~400 polyhalogenated compounds were detected, among them dechloranes and possibly transformation products, two tetrabrominated metabolites of PBT and several compounds unknown to us which could not be identified. PMID- 28843897 TI - Management of oil spill contamination in the Gulf of Patras caused by an accidental subsea blowout. AB - A methodology is presented and applied to assess the oil contamination probability in the Gulf of Patras and the environmental impacts on the environmentally sensitive area of Mesolongi - Aitoliko coastal lagoons, and to examine the effectiveness of response systems. The procedure consists of the following steps: (1) Determination of the computational domain and the main areas of interest, (2) determination of the drilling sites and oil release characteristics, (3) selection of the simulation periods and collection of environmental data, (4) identification of the species of interest and their characteristics, (5) performance of stochastic calculations and oil contamination probability analysis, (6) determination of the worst-cases, (7) determination of the characteristics of response systems, (8) performance of deterministic calculations, and (9) assessment of the impact of oil spill in the areas of interest. Stochastic calculations that were performed for three typical seasonal weather variations of the year 2015, three oil release sites and specific oil characteristics, showed that there is a considerable probability of oil pollution that reaches 30% in the Mesolongi - Aitoliko lagoons. Based on a simplified approach regarding the characteristic of the sensitive birds and fish in the lagoons, deterministic calculations showed that 78-90% of the bird population and 2-4% of the fish population are expected to be contaminated in the case of an oil spill without any intervention. The use of dispersants reduced the amount of stranded oil by approximately 16-21% and the contaminated bird population of the lagoons to approximately 70%; however, the affected fish population increased to 6-8.5% due to the higher oil concentration in the water column. Mechanical recovery with skimmers "cleaned" almost 10% of the released oil quantity, but it did not have any noticeable effect on the stranded oil and the impacted bird and fish populations. PMID- 28843898 TI - Role of heavy metals in structuring the microbial community associated with particulate matter in a tropical estuary. AB - Particulate matter (PM), which are chemically and biochemically complicated particles, accommodate a plethora of microorganisms. In the present study, we report the influence of heavy metal pollution on the abundance and community structure of archaea and bacteria associated with PM samples collected from polluted and non-polluted regions of Cochin Estuary (CE), Southwest coast of India. We observed an accumulation of heavy metals in PM collected from CE, and their concentrations were in the order Fe > Zn > Mn > Cr > Pb > Cu > Cd > Co > Ni. Zinc was a major pollutant in the water (4.36-130.50 MUgL-1) and in the particulate matter (765.5-8451.28 MUgg-1). Heavy metals, Cd, Co, and Pb were recorded in the particulate matter, although they were below detectable limits in the water column. Statistical analysis showed a positive influence of particulate organic carbon, nitrogen, PM-Pb, PM-Zn and PM-Fe on the abundance of PM-archaea and PM-bacteria. The abundance of archaea and bacteria were ten times less in PM compared with planktonic ones. The abundance of PM-archaea ranged between 4.27 and 9.50 * 107and 2.73 to 3.85 * 107 cellsL-1 respectively for the wet and dry season, while that of PM-bacteria was between 1.14 and 6.72 * 108 cellsL-1 for both seasons. Community structure of PM-bacteria varied between polluted and non polluted stations, while their abundance does not show a drastic difference. This could be attributed to the selective enrichment of bacteria by heavy metals in PM. Such enrichment may only promote the growth of metal resistant archaea and bacteria, which may not participate in the processing of PM. In such cases, the PM may remain without remineralization in the system arresting the food web dynamics and biogeochemical cycles. PMID- 28843899 TI - Size-segregated aerosol in a hot-spot pollution urban area: Chemical composition and three-way source apportionment. AB - In this work, a comprehensive characterisation and source apportionment of size segregated aerosol collected using a multistage cascade impactor was performed. The samples were collected during wintertime in Milan (Italy), which is located in the Po Valley, one of the main pollution hot-spot areas in Europe. For every sampling, size-segregated mass concentration, elemental and ionic composition, and levoglucosan concentration were determined. Size-segregated data were inverted using the program MICRON to identify and quantify modal contributions of all the measured components. The detailed chemical characterisation allowed the application of a three-way (3-D) receptor model (implemented using Multilinear Engine) for size-segregated source apportionment and chemical profiles identification. It is noteworthy that - as far as we know - this is the first time that three-way source apportionment is attempted using data of aerosol collected by traditional cascade impactors. Seven factors were identified: wood burning, industry, resuspended dust, regional aerosol, construction works, traffic 1, and traffic 2. Further insights into size-segregated factor profiles suggested that the traffic 1 factor can be associated to diesel vehicles and traffic 2 to gasoline vehicles. The regional aerosol factor resulted to be the main contributor (nearly 50%) to the droplet mode (accumulation sub-mode with modal diameter in the range 0.5-1 MUm), whereas the overall contribution from the two factors related to traffic was the most important one in the other size modes (34-41%). The results showed that applying a 3-D receptor model to size segregated samples allows identifying factors of local and regional origin while receptor modelling on integrated PM fractions usually singles out factors characterised by primary (e.g. industry, traffic, soil dust) and secondary (e.g. ammonium sulphate and nitrate) origin. Furthermore, the results suggested that the information on size-segregated chemical composition in different size classes was exploited by the model to relate primary emissions to rapidly-formed secondary compounds. PMID- 28843900 TI - Source tagging modeling study of heavy haze episodes under complex regional transport processes over Wuhan megacity, Central China. AB - Wuhan as a megacity of Central China was suffering from severe particulate matter pollution according to previous observation studies, however, the mechanism behind the pollution formation especially the impact of regional chemical transport is still unclear. This study, carried out on the Nested Air Quality Prediction Modeling System (NAQPMS) coupled with an on-line source-tagging module, explores different roles regional transport had in two strong haze episodes over Wuhan in October 2014 and quantitatively assesses the contributions from local and regional sources to PM2.5 concentration. Validation of predictions based on observations shows modeling system good skills in reproducing key meteorological and chemical features. The first short-time haze episode occurred on 12 October under strong northerly winds, with a hourly PM2.5 peak of 180 MUg m 3, and was found to be caused primarily by the long-range transport from the northern regions, which contributed 60.6% of the episode's PM2.5 concentration (versus a total of 32.7% from sources in and near Wuhan). The second episode lasted from the 15-20 October under stable regional large-scale synoptic conditions and weak winds, and had an hourly PM2.5 peak of 231.0 MUg m-3. In this episode, both the long-distance transport from far regions and short-range transport from the Wuhan-cluster were the primary causes of the haze episode and account for 24.8% and 29.2% of the PM2.5 concentration respectively. Therefore, regional transport acts as a crucial driver of haze pollution over Wuhan through not only long-range transfer of pollutants, but also short-range aerosol movement under specific meteorological conditions. The present findings highlight the important role of regional transport in urban haze formation and indicate that the joint control of multi city-clusters are needed to reduce the particulate pollution level in Wuhan. PMID- 28843901 TI - Fate of oxygenated intermediates in solar irradiated diluted bitumen mixed with saltwater. AB - Two types of diluted bitumen (dilbit) and a light crude oil spiked onto the surface of saltwater were irradiated with natural solar light in Ottawa to assess the impact of sunlight to the fate of oxygenated intermediates. Oxygenated components, including carbonyl polycyclic aromatic hydrocarbons (PAHs) and acidic polar fractions (naphthenic acid fraction compounds, NAFCs), were identified after periods of solar exposure under both winter and summer conditions. Carbonyl PAHs and NAFCs were formed in both seasons; however, light crude and summer irradiation produced higher abundance of them than dilbits and winter exposure. The formed NAFCs were abundant with the congeners containing a heteroatom of oxygen only (Oo species), accompanied by the minor amounts of sulfur- and nitrogen-containing acids. The produced Oo species were predominant with the congeners with light molecular weight, high degree of saturation and heavy oxygen numbers. For both carbonyl PAHs and NAFCs, their abundance continually increased throughout the period of winter exposure. In the summer, some carbonyl PAHs and all Oo species increased during the early exposure period; then they decreased with continued exposure for most oils, illustrating their transitional nature. Oxygenated intermediates thus appear to have been created through the photo oxidation of non-to medium-polar petroleum hydrocarbons or the intermediates of aldehydes or ketones (O1). Oil properties, the duration of exposure, exposure season and the chemical structure of these intermediates are critical factors controlling their fate through photo-oxidation. The observed chemical changes highlight the effects of sunlight on the potential behavior, fate and impact of spilled oil, with the creation of new resin group compounds and the reduction of aromatics and saturates. These results also imply that the ecological effects of spilled oil, after ageing in sunlight, depend on the specific oil involved and the environmental conditions. PMID- 28843902 TI - Relationship between chronobiological thyrotropin and prolactin responses to protirelin (TRH) and suicidal behavior in depressed patients. AB - BACKGROUND: So far, investigations of the relationships between suicidality and the activity of the thyrotropic and lactotropic axes are scarce and have yielded conflicting results. METHODS: We studied the thyrotropin (TSH) and prolactin (PRL) responses to 0800h and 2300h protirelin (TRH) stimulation tests, carried out on the same day, in 122 euthyroid DSM-5 major depressed inpatients with suicidal behavior disorder (SBD) (either current [n=71], or in early remission [n=51]); and 50 healthy hospitalized controls. RESULTS: Baseline TSH and PRL measurements did not differ across the 3 groups. In SBDs in early remission, the TSH and PRL responses to TRH tests (expressed as the maximum increment above baseline value after TRH [Delta]) were indistinguishable from controls. Current SBDs showed (1) lower 2300h-DeltaTSH and lower DeltaDeltaTSH values (differences between 2300h-DeltaTSH and 0800h-DeltaTSH) than controls and SBDs in early remission; and (2) lower baseline free thyroxine (FT4B) levels than controls. In the current SBD group, DeltaDeltaPRL values (differences between 2300h-DeltaPRL and 0800h-DeltaPRL) were correlated negatively with lethality. Moreover, in current SBDs (1) violent suicide attempters (n=15) showed lower FT4B levels, lower TSH-TRH responses (both at 0800h and 2300h), and lower DeltaDeltaTSH and DeltaDeltaPRL values than controls, while (2) non-violent suicide attempters (n=56) showed lower DeltaDeltaTSH values than controls and higher TSH-TRH responses (both at 0800h and 2300h) than violent suicide attempters. CONCLUSIONS: Our results suggest that central TRH secretion is not altered in depressed patients with SBD in early remission. The findings that current SBDs exhibit both decreased FT4B levels and decreased evening TSH responses (and consequently, decreased DeltaDeltaTSH values) support the hypothesis that hypothalamic TRH drive is reduced-leading to an impaired TSH resynthesis in the pituitary during the day after the morning TRH challenge. In violent suicide attempters, the marked abnormalities of TRH test responses might indicate a greatest reduction in hypothalamic TRH drive. These results further strengthen the possibility that a deficit in central TRH function may play a key role in the pathogenesis of suicidal behavior. PMID- 28843903 TI - Amygdala volume and hypothalamic-pituitary-adrenal axis reactivity to social stress. AB - The amygdala plays a central role in emotional processing and has an activating influence on the hypothalamic-pituitary-adrenal (HPA) axis. Structural changes in the amygdala have been associated with early adversity and, in principle, may contribute to the later emergence of emotional pathologies by influencing the way that the brain responds to stress provocation. The present study examined the relationship between amygdala volumes and cortisol secretion in response to a social stressor among young adults who were or were not exposed to maternal postnatal depression (PND) early in development (referred to as PND offspring and controls, respectively). Hierarchical Linear Modelling (HLM) revealed that, on a sample-wide level, there was no evidence of a relationship between total amygdala volume, or the volume of the right or left hemisphere amygdala taken separately, and cortisol reactivity. Unexpectedly, for PND offspring, larger right hemisphere amygdala volume was associated with lower cortisol reactivity in response to stress, an effect that was not apparent in control offspring. We conclude that the relationship between amygdala volumes and stress reactivity may not be as clear as previous models suggested. PMID- 28843904 TI - Regulation of epithelial cell expressed C3 in the intestine - Relevance for the pathophysiology of inflammatory bowel disease? AB - The complement system not only plays a critical role in efficient detection and clearance of bacteria, but also in intestinal immune homeostasis as mice deficient for key complement components display enhanced intestinal inflammation upon experimental colitis. Because underlying molecular mechanisms for this observation are unclear, we investigated the crosstalk between intestinal epithelial cells (IEC), bacteria and the complement system in the course of chronic colitis. Surprisingly, mouse intestinal epithelial cell lines constitutively express high mRNA levels of complement component 3 (C3), Toll-like receptor 2 (Tlr2) and Tlr4. Stimulation of these cells with lipopolysaccharide (LPS), but not with flagellin, LD-muramyldipeptide or peptidoglycan, triggered increased C3 expression, secretion and activation. Stimulation of the C3aR on these cell lines with C3a resulted in an increase of LPS-triggered pro inflammatory response. Tissue biopsies from C57BL/6J mice revealed higher expression of C3, Tlr1, Tlr2 and Tlr4 in colonic primary IECs (pIECs) compared to ileal pIECs, while in germ-free mice no differences in C3 protein expression was observed. In DSS-induced chronic colitis mouse models, C3 mRNA expression was upregulated in colonic biopsies and ileal pIECs with elevated C3 protein in the lamina propria, IECs and the mucus. Notably, increased C3b opsonization of mucosa attached bacteria and decreased fecal full-length C3 protein was observed in DSS treated compared to untreated mice. Of significant interest, non-inflamed and inflamed colonic biopsy samples from CD but not UC patients displayed exacerbated C3 expression compared to controls. These findings suggest that a novel TLR4-C3 axis could control the intestinal immune response during chronic colitis. PMID- 28843905 TI - Role of neuropilin-2 in the immune system. AB - Neuropilins (NRPs) are single transmembrane receptors with short cytoplasmic tails and are dependent on receptors like VEGF receptors or Plexins for signal transduction. NRPs are known to be important in angiogenesis, lymphangiogenesis, and axon guidance. The Neuropilin-family consists of two members, Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). They are up to 44 % homologous and conserved in all vertebrates. High levels of NRP2 are found on immune cells. Current research is very limited regarding the functions of NRP2 on these cells. Recent evidence suggests that NRP2 is important for migration, antigen presentation, phagocytosis and cell-cell contact within the immune system. Additionally, posttranslational NRP2 modifications like polysialylation are crucial for the function of some immune cells. This review is an overview about expression and functions of NRP2 in the immune system. PMID- 28843906 TI - Imaging surface acoustic wave dynamics in semiconducting polymers by scanning ultrafast electron microscopy. AB - Understanding the mechanical properties of organic semiconductors is essential to their electronic and photovoltaic applications. Despite a large volume of research directed toward elucidating the chemical, physical and electronic properties of these materials, little attention has been directed toward understanding their thermo-mechanical behavior. Here, we report the ultrafast imaging of surface acoustic waves (SAWs) on the surface of the Poly(3 hexylthiophene-2,5-diyl) (P3HT) thin film at the picosecond and nanosecond timescales. We then use these images to measure the propagation velocity of SAWs, which we then employ to determine the Young's modulus of P3HT. We further validate our experimental observation by performing a semi-empirical transient thermoelastic finite element analysis. Our findings demonstrate the potential of ultrafast electron microscopy to not only probe charge carrier dynamics in materials as previously reported, but also to measure their mechanical properties with great accuracy. This is particularly important when in situ characterization of stiffness for thin devices and nanomaterials is required. PMID- 28843908 TI - Alpinumisoflavone radiosensitizes esophageal squamous cell carcinoma through inducing apoptosis and cell cycle arrest. AB - Radiotherapy remains a mainstream treatment for patients with unresectable and locally advanced esophageal squamous cell carcinoma (ESCC). However, intrinsic radioresistance of ESCC tumors has largely compromised the efficacy of radiotherapy. The following study investigates the potential radiosensitizing effect of alpinumisoflavone (AIF) and explores its underlying mechanisms in ESCC. Briefly, our results showed that AIF could significantly increase radiosensitivity of ESCC cells both in vitro and in vivo, by increasing the effect of AIF on irradiation-induced DNA damage, apoptosis and cell cycle arrest. Mechanically, AIF aggravated irradiation-induced ROS generation in ESCC cells, which occurred via suppressing the expression of nuclear transcription factor Nrf2 and Nrf2-driven antioxidant molecule NQO-1 and HO-1. Collectively, we concluded that AIF functions as a potent radiosensitizer in human ESCC. PMID- 28843907 TI - CCL28 chemokine: An anchoring point bridging innate and adaptive immunity. AB - Chemokines are an extensive family of small proteins which, in conjunction with their receptors, guide the chemotactic activity of various immune cells throughout the body. CCL28, beta- or CC chemokine, is involved in the host immunity at various epithelial and mucosal linings. The unique roles of CCL28 in several facets of immune responses have attracted considerable attention and may represent a promising approach to combat various infections. CCL28 displays a broad spectrum of antimicrobial activity against gram-negative and gram-positive bacteria, as well as fungi. Here, we will summarize various research findings regarding the antimicrobial activity of CCL28 and the relevant mechanisms behind it. We will explore how the structure of CCL28 is involved with this activity and how this function may have evolved. CCL28 displays strong homing capabilities for B and T cells at several mucosal and epithelial sites, and orchestrates the trafficking and functioning of lymphocytes. The chemotactic and immunomodulatory features of CCL28 through the interactions with its chemokine receptors, CCR10 and CCR3, will also be discussed in detail. Thus, in this review, we emphasize the dual properties of CCL28 and suggest its role as an anchoring point bridging the innate and adaptive immunity. PMID- 28843909 TI - RSF1 functions as an oncogene in osteosarcoma and is regulated by XIST/miR-193a 3p axis. AB - RSF1 (HBXAP), is a member of ATP-dependent chromatin remodeling factor. Dysregulated RSF1 has been reported to be related to tumor progression. However, the function of RSF1 in osteosarcoma (OS) remains unclear. In this study, we showed that RSF1 expression was upregulated in OS cells. RSF1 inhibition suppressed OS cell proliferation and invasion. We further showed that MAPK/Erk signaling pathway was inactivated by RSF1 suppression. In addition, RSF1 was identified as a direct target of miR-193a-3p. Clinically, RSF1 was increased and associated with advanced clinical features and poor overall survival of OS patients. MiR-193a-3p expression was decreased and associated with advanced clinical features and poor overall survival of OS patients. In addition, we found that miR-193a-3p was negatively correlated with RSF1 expression in OS tissues. Moreover, our data showed that XIST could function as competing endogenous RNA to repress miR-193a-3p, which regulated its downstream target RSF1. In conclusion, our findings demonstrated that the XIST/miR-193a-3p/RSF1 axis might contribute to the progression and act as a therapeutic target of OS patients. PMID- 28843910 TI - Diacerein inhibits Estradiol-benzoate induced cervical hyperkeratosis in female rats. AB - Cervical hyperkeratosis is a common gynecological lesion and usually caused by inflammation or trauma. We investigated the effect of Diacerein on Estradiol benzoate-induced cervical hyperkeratosis. Diacerein (50mg/kg/day) was given orally to rats for 4 weeks in the presence or absence of cervical hyperkeratosis induced by intramuscular injection of Estradiol benzoate (60MUg/100g) 3 times per week for 4 weeks. We measured the serum levels of total cholesterol, uterine weights, uterine tissue malondialdehyde, total nitrites, superoxide dismutase activity, caspase-3, interleukin-1b immunoexpression and histopathology. Our results showed that Estradiol benzoate succeeded to induce cervical hyperkeratosis which was detected by typical histopathological changes. In addition; there was significant reduction in superoxide dismutase levels and caspase-3 immunoexpression but significant increase in serum total cholesterol, malondialdehyde, total nitrites and interleukin-1b immunoexpression. Diacerein could improve all measured parameters to normal levels. It markedly prevented cervical hyperkeratosis through its anti-inflammatory (IL-1b receptor inhibitor), antioxidant and anti-apoptotic effects. PMID- 28843911 TI - Resveratrol and diabetes: A critical review of clinical studies. AB - Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. The disease results from the defects of insulin secretion and/or action. Resveratrol is a non-flavonoid polyphenol that naturally occurs as phytoalexin. The shell and stem of Vitis vinifera L. (Vitaceae) are the richest source of this compound. In addition to various in vitro and in vivo studies revealing the effectiveness of resveratrol in DM, there are many clinical trials indicating that resveratrol has the potential to benefit in DM patients. The therapeutic action of this compound in relation to diabetes is complex and involves in several beneficial roles. In view of this, clinical studies are necessary to elucidate these roles. In the near future, the use of resveratrol, alone or in combination with current anti diabetic therapies, might be a conventional approach to effectively manage DM or its complications. This mini-review provides a critical overview of currently available clinical studies examining the effects of resveratrol in DM last decade. PMID- 28843912 TI - Capture of anti-coagulant active ingredients from Moutan Cortex by platelet immobilized chromatography and evaluation of anticoagulant activity in rats. AB - Moutan Cortex (MC) is a well-known Chinese medicine for promoting blood circulation and relieving blood stasis. The intent of this study was to evaluate the anticoagulant activity of MC and capture the bioactive compounds by platelet immobilized chromatography. Sprague Dawley (SD) rats were randomly divided into the control group, aspirin group and MC group (1.25, 2.5, 5g/kg/d). Coagulation system and platelet activity were investigated to evaluate the anti-coagulation effect of MC. The effective components of MC were captured by platelet immobilized chromatography. High performance liquid chromatography-diode array detection (HPLC-DAD) and liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) analysis were used to identify the binding ingredients. Meanwhile, the efficacy of active ingredients was assessed through inhibiting platelet adhesion and regulating the expression of platelet related proteins. Principal findings showed that 2.5g/kg/d MC significantly prolonged thrombin time (TT) and 5g/kg/d MC significantly prolonged TT and prothrombin time (PT). MC exhibited an inhibitory potency on adenosine diphosphate-induced platelet aggregation. Four active compounds were found by platelet immobilized chromatography including oxypaeoniflorin, tetragalloylglucose, pentagalloyl glucose and benzoylpaeoniflorin; these active ingredients significantly up-regulated the expression of hsp-70 and coronin-1B, reduced the ratio of adhesion platelets. These results suggest that MC markedly promoted blood circulation and relieved blood stasis by inhibiting platelet activation, as an anti-coagulant, elucidating its potential capacity to treat cardiovascular diseases. PMID- 28843913 TI - Paraquat exposure-induced Parkinson's disease-like symptoms and oxidative stress in Drosophila melanogaster: Neuroprotective effect of Bougainvillea glabra Choisy. AB - Extracts from the leaves of Bougainvillea glabra Choisy are used in traditional medicines, but their actions on the central nervous system have not been studied. In the present study, we investigated the potential neuroprotective effects of Bougainvillea glabra Choisy leaf extract (BG extract) against paraquat (PQ) induced neurotoxicity. Male adult wild-type flies (1- 4days old) were exposed to PQ (3.5mM) and/or BG extract (120MUg/mL) through food for 4days. PQ-fed flies had decreased locomotor capacity in negative geotaxis and crossing number assays and had a higher incidence of mortality than the control group. PQ neurotoxicity was also associated with a marked decrease in dopamine levels and increase in acetylcholinesterase (AChE) activity, reactive oxygen species (ROS) production and lipid peroxidation. Co-exposure to BG extract prevented mortality, and dopamine depletion, improved locomotor performance and decreased AChE activity, ROS production and lipid peroxidation. GC-MS and HPLC analyses of BG extract revealed the presence of many antioxidant compounds such as phytol, alpha,gamma tocopherol, squalene, stigmasterol, geranylgeraniol, quercetin, and caffeic, vanillic, coumaric, ferulic acids. Our results showed neuroprotective effects of BG extract, reflecting the presence of antioxidant compounds. Thus, we suggested that B. glabra leaves could be considered an effective agent in the prevention of neurological disorders, where dopamine depletion and/or oxidative stress are involved, as in Parkinson's disease (PD). PMID- 28843914 TI - The association between low level of high-density lipoprotein cholesterol and mood disorder using time-dependent analysis. AB - BACKGROUND: Although many studies have identified factors associated with mood disorder, the association between high-density lipoprotein cholesterol (HDL-C) and mood disorder is still controversial. The aim of our study was to evaluate the association between low HDL-C and onset of mood disorder in Korea based on different cut-off levels. METHODS: We used National Health Examinations Service cohort data from 2009 to 2013. We used time-dependent Cox regression analysis to evaluate the association between low level of HDL-C and onset of mood disorder. Hazard ratios (HRs) for onset of mood disorder were estimated for 1- to 2-year time intervals, starting at the first health examination and accounting for the duration until the next health examination. RESULTS: A total of 400,803 participants (male: 220,573; female: 180,230) were included in our study. A total of 4576 (2.07%) males and 7598 (4.22%) females developed mood disorder. Based on dyslipidemia (< 40mg/dL), low level of HDL-C was associated with the risk of mood disorder in both male and female, however, only females showed statistically significant (HR: 1.097, 95% CI: 1.012-1.189). Based on quartile-based approach, females with low levels of HDL-C (< 47mg/dL) and males with high levels of HDL-C (>= 59mg/dL) were associated with subsequent risk of mood disorder. CONCLUSIONS: Our findings suggest that level of HDL-C is associated with potential risk factors in mood disorder. However, a flexible threshold value in HDL-C level would be needed to evaluate the subsequent risk of mood disorder. Thus, further studies are needed to help improve the mental health in susceptible individuals. PMID- 28843915 TI - Effects of traumatic experiences on obsessive-compulsive and internalizing symptoms: The role of avoidance and mindfulness. AB - BACKGROUND: Trauma exposure is associated with adverse psychological outcomes including anxiety, depression, and obsessive-compulsive (OC) symptoms. Adolescence is increasingly recognized as a period of vulnerability for the onset of these types of psychological symptoms. The current study explored the mediating roles of experiential avoidance and mindfulness processes in the association between retrospective reports of childhood trauma and current internalizing and OC symptoms in adolescents. METHOD: A group of at-risk adolescents (N = 51) and a group of college students (N = 400) reported on childhood trauma, experiential avoidance, mindfulness, anxiety, depressive, and OC symptoms. Mediation analyses were performed to examine the mechanistic roles of avoidance and mindfulness in the association between trauma and internalizing and OC-specific symptoms. RESULTS: In the group of at-risk adolescents, experiential avoidance and mindfulness both significantly mediated the association between childhood trauma and OC symptoms. In the college student sample, experiential avoidance mediated the association between trauma and OC symptoms. Experiential avoidance, as well as the observe, act with awareness, and nonjudgmental facets of mindfulness all significantly mediated the association between trauma and internalizing symptoms. LIMITATIONS: The group of at-risk adolescents was small, and the college student group was demographically homogeneous. All data was self-report and cross-sectional. CONCLUSION: The current study demonstrated that experiential avoidance and mindfulness processes may be the mechanisms through which the association between trauma and obsessive compulsive and trauma and internalizing symptoms exist in adolescents. These findings provide potential targets for clinical intervention to improve outcomes for adolescents who have experienced trauma. PMID- 28843916 TI - Anxiety disorders and childhood maltreatment as predictors of outcome in bipolar disorder. AB - BACKGROUND: Comorbid anxiety disorders and childhood maltreatment have each been linked with unfavourable outcomes in people with bipolar disorder. Because childhood maltreatment is associated with anxiety disorders in this population, their respective predictive value remains to be determined. METHODS: In 174 adults with bipolar disorder, we assessed childhood maltreatment using the Childhood Trauma Questionnaire and lifetime anxiety disorders with the MINI International Neuropsychiatric Interview. We constructed an overall index of severity of bipolar disorder as a sum of six indicators (unemployment, psychotic symptoms, more than five manic episodes, more than five depressive episodes, suicide attempt, and hospital admission). We tested the relationship between childhood maltreatment, the number of anxiety disorders and the overall severity index using ordered logistic regression. RESULTS: The number of lifetime anxiety disorders was associated with the overall severity index (OR = 1.43, 95%CI = 1.01 2.04, p = 0.047). This relationship was only slightly attenuated when controlled for childhood maltreatment (OR = 1.39, 95%CI = 0.97-2.00, p = 0.069). The relationship between childhood maltreatment and the overall severity index was not statistically significant (OR = 1.26, 95%CI = 0.92-1.74, p = 0.151). Secondary analyses revealed that childhood maltreatment was associated with suicide attempts (OR = 1.70, 95%CI = 1.15-2.51, p = 0.008) and obsessive compulsive disorder was associated with the overall severity index (OR = 9.56, 95%CI = 2.20-41.47, p = 0.003). LIMITATIONS: This was a cross-sectional study with a moderate-sized sample recruited from a specialist program. CONCLUSIONS: While comorbid anxiety disorders are associated with the overall severity of bipolar disorder, childhood maltreatment is specifically associated with suicide attempts. Clinicians should systematically assess both factors. Interventions to improve outcomes of people with bipolar disorder with comorbid anxiety disorders and history of childhood maltreatment are needed. PMID- 28843917 TI - Subjective versus objective evening chronotypes in bipolar disorder. AB - BACKGROUND: Disturbed sleep timing is common in bipolar disorder (BD). However, most research is based upon self-reports. We examined relationships between subjective versus objective assessments of sleep timing in BD patients versus controls. METHODS: We studied 61 individuals with bipolar I or II disorder and 61 healthy controls. Structured clinical interviews assessed psychiatric diagnoses, and clinician-administered scales assessed current mood symptom severity. For subjective chronotype, we used the Composite Scale of Morningness (CSM) questionnaire, using original and modified (1, 3/4, 2/3, and 1/2 SD below mean CSM score) thresholds to define evening chronotype. Objective chronotype was calculated as the percentage of nights (50%, 66.7%, 75%, or 90% of all nights) with sleep interval midpoints at or before (non-evening chronotype) vs. after (evening chronotype) 04:15:00 (4:15:00a.m.), based on 25-50 days of continuous actigraph data. RESULTS: BD participants and controls differed significantly with respect to CSM mean scores and CSM evening chronotypes using modified, but not original, thresholds. Groups also differed significantly with respect to chronotype based on sleep interval midpoint means, and based on the threshold of 75% of sleep intervals with midpoints after 04:15:00. Subjective and objective chronotypes correlated significantly with one another. Twenty-one consecutive intervals were needed to yield an evening chronotype classification match of >= 95% with that made using the 75% of sleep intervals threshold. LIMITATIONS: Limited sample size/generalizability. CONCLUSIONS: Subjective and objective chronotype measurements were correlated with one another in participants with BD. Using population-specific thresholds, participants with BD had a later chronotype than controls. PMID- 28843918 TI - The safety and tolerability of cariprazine in patients with manic or mixed episodes associated with bipolar I disorder: A 16-week open-label study. AB - BACKGROUND: We evaluated the safety/tolerability of longer-term open-label treatment with cariprazine in patients who had responded to cariprazine for acute bipolar mania. METHODS: In this multinational, multicenter study, open-label, flexible-dose, cariprazine 3-12mg/d was administered for up to 16 weeks to patients (18-65 years) with bipolar mania. Safety evaluations included adverse events (AEs), laboratory values, vital signs, and extrapyramidal symptom (EPS) scales. Symptom change was evaluated by Young Mania Rating Scale (YMRS) total score change from baseline using the last observation carried forward approach. RESULTS: Of the 402 patients taking cariprazine, 33% completed the trial; the most frequent reasons for discontinuation were withdrawal of consent (20%), AEs (16%), and protocol violation (14%). Most common AEs leading to discontinuation were akathisia (4.7%) and depression (1.5%). Mean treatment duration was 57.7 days; mean cariprazine dose was 6.2mg/d. The incidence of serious AEs was 7.5% (most common: mania [2.2%], depression [1.2%]); 83.3% had treatment-emergent AEs, including akathisia (32.6%), headache (16.7%), constipation (10.7%), and nausea (10.4%). Mean body weight increased <1kg; 9.3% had >=7% weight gain; 5.7% had sedation; 3% had somnolence. Mean changes in laboratory values, vital signs, ECGs, and ophthalmology parameters were not clinically significant. Mean YMRS total score decreased by -15.2 at week 16. LIMITATIONS: Uncontrolled, open-label design. CONCLUSIONS: Open-label cariprazine 3-12 (mean 6.2) mg/d for up to 16 weeks was generally well tolerated, with low (<10%) rates of sedation and >=7% weight gain. Although akathisia occurred in 33%, it yielded discontinuation in <5%. PMID- 28843919 TI - Gene copy number variation and protein overexpression of EGFR and HER2 in distal extrahepatic cholangiocarcinoma. AB - EGFR and HER2 are among the most promising therapeutic targets in solid cancers. The expression status of EGFR and HER2 are associated with the prognosis, and with a number of clinicopathological factors, in many cancers. However, few studies have examined this association in distal extrahepatic cholangiocarcinoma (EHCC). Therefore, we investigated EGFR and HER2 protein expression and gene copy number variation (CNV) in distal EHCC. We also studied the association of these factors with clinicopathological parameters and prognosis. Immunostaining, using antibodies against EGFR and HER2, was performed on 84 cases of distal EHCC. All positive (3+) and equivocal (2+) EGFR and HER2 expression cases, together with randomly selected negative (1+ and 0) cases, were evaluated for EGFR and HER2 CNV. Among distal EHCC samples, 6.0% (n=5) were positive (3+) for EGFR expression and 6.0% (n=5) were equivocal (2+). HER2 expression was positively identified in 2.4% of samples (n=2), and was equivocal in 1.2% of samples (n=1). All cases of positive EGFR expression showed amplification (n=1) or high polysomy (n=4) involving the EGFR gene; three cases (60%) of equivocal EGFR expression showed high polysomy of the EGFR gene. All cases of positive or equivocal HER2 expression (n=3, 3.6%) showed amplification of the HER2 gene. In univariate analysis, EGFR expression and CNV were associated with shorter cancer-specific overall survival (p=0.003 and p=0.018, respectively). Multivariate analysis also showed that EGFR CNV was a significant prognostic factor in distal EHCC (p=0.015). Although further study is warranted, our findings suggest that EGFR expression and CNV are factors associated with poor prognosis, and that anticancer therapeutics against EGFR and HER2 receptors may be promising therapeutic options for patients with distal EHCC. PMID- 28843920 TI - Tumour infiltrating lymphocytes are predictors of lymph node metastasis in early gastric cancers. AB - Lymph node metastasis (LNM) is an important factor for predicting prognosis and selecting appropriate treatment in early gastric cancers (EGCs). We investigated the histopathological and microenvironmental predictors of LNM in EGCs. We retrieved 43 cases of EGC without LNM and 59 cases with LNM. Clinicopathological variables and tumour-infiltrating lymphocytes (TILs), Crohn's-like lymphoid reaction (CLR), tumour stromal percentage (TSP), and FOXA1 expression were evaluated and correlated with LNM. Among the 102 cases, 68 cases (66.7%) had low TILs and 34 cases (33.3%) had high TILs. High TILs were significantly correlated with the absence of LNM (p<0.001), less extent of invasion (p=0.004), absence of LVI (p=0.035), conspicuous CLR (p<0.001), and the absence of TSP (p=0.009). Conspicuous CLR was observed in 47 cases (46.1%) and TSP was present in 17 cases (16.7%) and neither was correlated with LNM. High FOXA1 expression was significantly associated with presence of LNM, low TILs, and submucosal invasion. In multivariate analysis, low TILs (p=0.023), LVI (p=0.008), and submucosal invasion (p=0.001) were independent predictive factors for LNM in EGCs. Evaluation of TILs in biopsied or endoscopically resected EGC specimens may help to predict LNM and select subsequent proper treatment modalities and follow-up. PMID- 28843921 TI - A Schiff base/quaternary ammonium salt bifunctional graphene oxide as an efficient adsorbent for removal of Th(IV)/U(VI). AB - A novel approach for facile covalent functionalization of graphene oxide (GO) was proposed in the present study in order to effectively avoid necessary anhydrous conditions and the usage of harsh reagents during the chemical functionalization of GO. Herein, a GO derivative that was functionalized with a primary amine derivative bearing a positively charged quaternary ammonium group, GO-S, was synthesized through a Schiff base condensation reaction between the amine groups of the primary amine derivative and the aldehyde groups of GO. The introduction of the quaternary ammonium groups can prevent GO from stacking and improve the dispersibility of GO after modification. The formation of imine bonds (NCH) between the primary amine and GO has been confirmed by Fourier transform infrared and X-ray photoelectron spectroscopy. The GO-S demonstrated good dispersion stability in aqueous medium and also exhibited better adsorption performance than GO for Th(IV) and U(VI), with a maximum thorium adsorption capacity of 2.22mmol/g and a maximum uranium adsorption capacity of 0.83mmol/g, suggesting a great potential for the application of graphene oxide-based materials for facilitating the removal of Th(IV) and U(VI) from nuclear waste solutions. PMID- 28843922 TI - Gold nanoparticle-gated mesoporous silica as redox-triggered drug delivery for chemo-photothermal synergistic therapy. AB - In this paper, a redox-triggered drug delivery system of DOX/MSN-Au was prepared for chemo-photothermal synergistic therapy. The ultra-small gold nanoparticles (NPs) were appended to the openings of mesoporous silica nanoparticles (MSN) by Au-S bonds as the gatekeepers. Meanwhile, the gold NPs could be heated to high temperature by the near infrared (NIR) light irradiation, which is conducive to photothermal therapy. X-ray photoelectron spectroscopy (XPS) and Fourier Transform Infrared Spectrometer (FT-IR) spectra confirmed the formation of MSN-SH and MSN-Au. An in vitro NIR-induced photothermal study indicated that MSN-Au possessed concentration-dependent and power-dependent photothermal conversion capacity. Doxorubicin (DOX) was selected as the model drug loaded in the MSN. In vitro drug release showed that DOX released faster in the presence of glutathione (GSH) or NIR laser irradiation than without GSH or NIR irradiation, which suggested that the system had potentials for redox-responsive and NIR-triggered drug release. Confocal Laser Scanning Microscope (CLSM) was performed to evaluate the cellular uptake performance of DOX/MSN-Au. The cytotoxicity assay indicated that DOX/MSN-Au had a synergistic therapeutic effect by the combination of chemotherapy and photothermal therapy. This work suggested that MSN-Au could be explored as a redox-triggered drug delivery system for the chemo-photothermal synergistic therapy. PMID- 28843923 TI - Epoxy-silica/clay nanocomposite for silver-based antibacterial thin coatings: Synthesis and structural characterization. AB - Development of new functional coatings in the field of health care, as antibacterial applications, deals with a straight control of the diffusive properties that rules the releasing of the active component. In this work, the development of a silver-rich nanocomposite thin coating, loaded with organically modified clay nanoparticles, is presented. The synthesis process included an environment-friendly silanization process of clay nanoparticles (Laponite(r) S482) with (3-glycidoxypropyl)trimethoxysilane (GPTMS) and the further hydrolytic condensation with tetraethoxysilane (TEOS). Silanization process and the obtained coatings were analysed by Fourier transformed infrared spectroscopy, UV-visible spectroscopy, X-ray diffraction, thermogravimetric curves and scanning electron microscopy. The silanization process of clay nanoparticles with the organically reactive alkyl alkoxysilane, allowed to stabilize and exfoliate the clay nanosheets within a hybrid organic-inorganic sol-gel material. Ring opening of grafted epoxy groups carried to an increasing of the basal spacing, of intercalated clay nanosheets, from 1.3 to 1.8nm. Moreover, incorporation of organically modified clay nanosheets introduced a significant stabilization on the development of silver nanoparticles inside the structure of the nanocomposite coating, retaining the silver inside the coating material and restricting the growing of silver nanoparticles on the surface of the coating. Antibacterial behaviour, against E. coli cultures, performed through agar diffusion tests, provided promising results that allow assuming that the studied nanocomposite coating serves as a reservoir of ionic silver, permitting the antibacterial effect. PMID- 28843924 TI - Hydrous ZrO2 decorated polyaniline nanofibres: Synthesis, characterization and application as an efficient adsorbent for water defluoridation. AB - A new hybrid material comprising hydrous zirconium oxide (HZrO2) supported onto polyaniline (PANI) nanofibres (HZrO2@PANI NFs) was prepared via the precipitation of HZrO2 onto as-synthesized PANI NFs and tested for its defluoridation capabilities. The developed adsorbent (HZrO2@PANI NFs) was fully characterized by FTIR, BET, XRD, SEM-EDX, TEM-(S)TEM, XPS, and zeta potential measurements. HZrO2@PANI NFs achieved 2-fold BET surface area ~86.64 m2/gas compared to PANI NFs ~44.72 m2/g, implying that the incorporation of HZrO2 onto the PANI nanofibres enhanced the available surface area for effective fluoride adsorption. Moreover, HZrO2@PANI NFs was found to be effective over a wide pH range (3-9) as designated by its high pHpzc ~9.8. The adsorption kinetics obeyed the pseudo second-order model well with equilibrium attainment in 30min. Adsorption isotherm was best described by the Langmuir model and the maximum adsorption capacities obtained were 83.23 and 28.77mg/g at pH 3 and 6.5, respectively, which is superior to most ZrO2 based adsorbents reported in the literature and better than that of native PANI. Furthermore, the developed adsorbent manifested quite a selective fluoride uptake at pH 3 as compared to pH 6.5+/-0.1 wherein significant chemical affinity competition was presented by phosphate ions followed by bicarbonate and sulfate. The recyclability of HZrO2@PANI NFs for four cycles and its applicability to fluoride spiked ground water has also been demonstrated. The adsorption mechanism was interpreted with the help of FTIR, XPS and Zeta potential analysis and the results revealed the involvement of both anion exchange and electrostatic attraction in the adsorption of F- ions. Thus, a new efficient adsorbent with reasonably high adsorption capacity and superior pH tolerance has been developed for fluoride removal. PMID- 28843925 TI - Nickel(0) nanoparticles supported on bare or coated cobalt ferrite as highly active, magnetically isolable and reusable catalyst for hydrolytic dehydrogenation of ammonia borane. AB - Nickel(0) nanoparticles supported on cobalt ferrite (Ni0/CoFe2O4), polydopamine coated cobalt ferrite (Ni0/PDA-CoFe2O4) or silica coated cobalt ferrite (Ni0/SiO2 CoFe2O4) are prepared and used as catalysts in hydrogen generation from the hydrolysis of ammonia borane at room temperature. Ni0/CoFe2O4 (4.0% wt. Ni) shows the highest catalytic activity with a TOF value of 38.3min-1 in hydrogen generation from the hydrolysis of ammonia borane at 25.0+/-0.1 degrees C. However, the initial catalytic activity of Ni0/CoFe2O4 catalyst is not preserved in subsequent runs of hydrolysis. Coating the surface of cobalt ferrite support with polydopamine or silica leads to a significant improvement in the stability of catalysts. The TOF values of Ni0/PDA-CoFe2O4 and Ni0/SiO2-CoFe2O4 are found to be 7.6 and 5.3min-1, respectively, at 25.0+/-0.1 degrees C. Ni0/PDA-CoFe2O4 catalyst shows high reusability as compared to the Ni0/CoFe2O4 and Ni0/SiO2 CoFe2O4 catalysts in hydrolytic dehydrogenation of ammonia borane at room temperature. All the catalysts are characterized by using a combination of various advanced analytical techniques. The results reveal that nickel nanoparticles with an average size of 12.3+/-0.7nm are well dispersed on the surface of PDA-CoFe2O4. . PMID- 28843926 TI - Nanosized amine-rich spheres embedded polymeric beads for Cr (VI) removal. AB - Porous matrix immobilization is considered as an effective approach to address the engineering challenges during practical application of nanoadsorbent. In this work, polyethersulfone (PES) beads with diameter of around 2.5mm, in which nanosized amine-rich polymer spheres (APSs) with particle size of ~400nm are immobilized, are fabricated via phase inversion route. APSs-PES beads possess asymmetric and hierarchical structure with an exterior porous surface dense layer and numerous inner interpenetrating fingerlike channels, which promote the transportation of molecule and prevent the leaching of nanoadsorbents. The well distributed APSs with nitrogen-containing functional groups provide abundant adsorption sites. The cooperative attributing of the hierarchical structure and APSs demmonstrates enhanced Cr (VI) adsorption efficiency. The adsorption capacity of Cr (VI) is 243.9mg/g at 298K by Langmuir fitting. The effects of pH, temperature, the ratio of adsorbents and coexisting ionic are further studied in detail. The Cr (VI) removal mechanism is further explored by the combination of SEM, XPS, FTIR measurements and the adsorption parameters, further revealing the synergistic contribution of electrostatic attraction and reduction process. Therefore, this kind of adsorbents may show promising prospects on elimination of hazardous Cr (VI) in wastewater treatment. PMID- 28843927 TI - Palladium nanoparticles embedded on mesoporous TiO2 material (Pd@MTiO2) as an efficient heterogeneous catalyst for Suzuki-Coupling reactions in water medium. AB - An efficient and recyclable catalytic system composed of palladium nanoparticles embedded over mesoporous TiO2 material (Pd@MTiO2) has been synthesized and its catalytic activity has been explored in Suzuki-Miyaura cross-coupling reaction of aryl halides in water medium. This catalytic system is a very simple and highly active protocol for carrying out the Suzuki coupling of aryl bromide and aryl chloride with boronic acids, which proceed smoothly in excellent yields under mild reaction conditions. Powder X-ray diffraction (XRD), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FT-IR), and N2 sorption studies are used to characterize the Pd@MTiO2 material. Environmentally friendly reaction conditions, high product yield, tolerance of variety of functionalities in the reactants and reusability suggested future potential of Pd@MTiO2 for the synthesis of a wide range of biaryl compounds. PMID- 28843928 TI - Preparation of black-pearl reduced graphene oxide-sodium alginate hydrogel microspheres for adsorbing organic pollutants. AB - The black-pearl reduced graphene oxide-sodium alginate (rGO-SA) hydrogel microspheres are prepared by the external emulsification and thermal reduction method, which are characterized by scanning electron microscope (SEM) and X-ray Diffraction (XRD). Sodium alginate (SA) serves as a template to form a 3D porous network structure, which can prevent the agglomeration and restacking of rGO sheets efficiently. The size of hydrogel microsphere can be controlled by adjusting the size of the liquid drop. The effects of rGO content (wt%), contact time, initial concentration of phenol, adsorption temperature and adsorption dose on the adsorption capacity of rGO-SA microspheres are investigated. The kinetics and isotherm data are well described by the pseudo-second-order kinetic model and the Langmuir equation, respectively. Thermodynamic results demonstrate the spontaneous and endothermic nature of adsorption. This rGO-SA microsphere exhibits the favorable adsorption performance for phenol, BPA and tetracycline. The rGO-SA microsphere might be a potential candidate for efficient adsorbents in water treatment. PMID- 28843929 TI - Direct surface grafting of mesoporous silica nanoparticles with phospholipid choline-containing copolymers through chain transfer free radical polymerization and their controlled drug delivery. AB - Mesoporous silica nanoparticles have attracted considerable research attention due to their various applications. Surface modification of these mesoporous silica nanoparticles with polymers not only can improve their water dispersity but can also endow several new functions, such as drug loading and delivery or targeting capability. In this work, we report a novel strategy for the direct surface grafting of phospholipid choline-containing copolymers onto Santa Barbara Amorphous-15 (SBA-15) through surface-initiated chain transfer free radical polymerization. The SBA-15 was synthesized by hydrolysis of tetraethoxysilane in the presence of poly(ethylene glycol)-block-poly(propylene glycol)-block poly(ethylene glycol) (P123) under acidic synthetic conditions. Next, SBA-15 was subsequently modified with thiol groups by co-condensation with gamma mercaptopropyltrimethoxysilane to obtain SBA-15-SH. Finally, the copolymers were grafted on SBA-15-SH through chain transfer free radical polymerization using 2 methacryloyloxy ethyl phosphorylcholine (MPC) and itaconic acid (IA) as monomers. The SBA-15-based polymer composites (SBA-15-SH-poly(MPC-co-IA)) were used as matrices for controlled release of cisplatin (CDDP). The data from a series of characterization techniques indicated that the monomers were successfully grafted onto SBA-15. The resultant SBA-15-SH-poly(MPC-co-IA) composites showed many remarkable physicochemical properties, such as high water dispersity, desirable biocompatibility and high drug loading capacity. These features provide the SBA 15-SH-poly(MPC-co-IA) composites with considerable potential for biomedical applications. PMID- 28843930 TI - Gait and its components in typically developing preschoolers. AB - OBJECTIVES: To determine whether key spatio-temporal components of gait can be identified in children who are preschoolers. Subsequently the obtained components were correlated to results of functional balance tests to determine which of them are related to balance control. METHODS: Thirty-three typically developing children performed gait on treadmill at three speeds (range 2-4.5km/h), the Pediatric Balance Scale (PBS) and the Timed Up and Go test (TUG). Principal component analysis (PCA) with varimax rotation was performed to detect relations between means and variability of step time, -length and -width, walking speed, age, BMI and leg length. Pearson correlation coefficients between the principal components and z-scores of the PBS and TUG were calculated. RESULTS: PCA revealed three principal components. The first component, maturation, showed high loadings for mean step length (0.911), age (0.897), walking speed (0.895), leg length (0.874) and step time variability (-0.672) explaining 37.57% of the variance. The second component, variability of gait, loaded with step length variability (0.819) and step width variability (0.818), explaining 18.02% of the variance. The third component, robustness, showed high loadings for mean step time (0.729), BMI (0.668) and mean step width (0.521), explaining 13.89% of the variance. A significant weak correlation was found between robustness and z-scores of the PBS (r=0.230, p=0.005). CONCLUSIONS: It seems that the key spatio-temporal component robustness is complementary to functional balance tests, suggesting its relevance in the assessment of balance control in preschoolers. PMID- 28843931 TI - Subdural empyema as a complication of odontogenic maxillary sinusitis. PMID- 28843932 TI - Hypervolemia, hypoalbuminemia and mitral calcification as markers of cardiovascular risk in peritoneal dialysis patients. AB - INTRODUCTION: Mortality in patients with end-stage renal disease is higher than in the general population. This is linked to traditional and non-traditional cardiovascular (CV) risk factors, as well as with risk factors associated with end-stage renal disease itself. The aim of this study is to identify CV risk markers in patients beginning peritoneal dialysis (PD) and their association with CV events and CV mortality. METHODS: This was a retrospective cohort study of 112 incident PD patients, in which demographic, clinical and laboratory parameters, valvular calcifications, types of PD solutions, hospitalizations, CV events and death were analyzed. Occurrence of CV events or death due to a CV event after PD initiation was defined as the primary endpoint. The use of icodextrin solution was taken as a marker of hypervolemia. RESULTS: Mean age was 53.7+/-16.1 years. Patients were treated with PD for 29.3+/-17.4 months. Eighteen patients (16.1%) had valvular calcifications at baseline, 15 patients (13.4%) had major CV events and 11 patients (9.8%) died from CV-related causes. Cox proportional hazards analysis of CV events or CV-related mortality revealed that mitral calcification, use of icodextrin solution and low albumin were independent predictors of CV events or mortality. CONCLUSIONS: Traditional CV risk factors appear to have little impact on CV complications in PD patients. Nevertheless, hypervolemia, hypoalbuminemia and mitral calcifications were independent predictors of CV events or mortality in this group of patients. PMID- 28843933 TI - Manipulation of induced resistance to viruses. AB - Induced resistance against plant viruses has been studied for many years. However, with the exception of RNA silencing, induced resistance to viruses remains mechanistically less well understood than for other plant pathogens. In contrast, the induction processes involved in induced resistance, comprising basal resistance signaling, effector-triggered immunity, and phytohormone pathways, have been increasingly well characterized in recent years. This has allowed induced resistance to viruses to be placed in a broader conceptual framework linking it to other defense systems, which we discuss in this review. We also discuss the range of agents, including chemicals and beneficial microorganisms and application methods that can be used to induce resistance to viruses. PMID- 28843935 TI - Erratum. PMID- 28843934 TI - Ag-4-ATP-MWCNT electrode modified with dsDNA as label-free electrochemical sensor for the detection of daunorubicin anticancer drug. AB - This paper describes the synthesis of Ag-4-ATP-MWCNT nanocomposite and its use as a modifier of working electrode. The surface of the electrochemical Ag-4-ATP MWCNT electrode was modified with a double-stranded DNA (dsDNA) to detect daunorubicin-DNA interactions. Differential pulse voltammetry was applied to develop an electroanalytical procedure for the determination of daunorubicin and evaluate its interaction with dsDNA immobilized on the electrode surface. After the optimization of operational parameters, the linear dependence of the peak current on the daunorubicin concentration was observed in the range of 0.10*10-8 to 1.00*10-5molL-1, with the detection and quantification limits of 3.00*10-10 and 1.00*10-9molL-1, respectively. The proposed biosensor was successfully applied to validate its capability for the determination of daunorubicin in human serum and urine samples. PMID- 28843936 TI - Robust hybrid enzyme nanoreactor mediated plasmonic sensing strategy for ultrasensitive screening of anti-diabetic drug. AB - Enzyme inhibition based drug screening strategy has been widely employed for new drug discovery. But this strategy faces some challenges in practical application especially for the trace active compound screening from natural products such as the stability of enzyme and the sensitivity of screening approach. Inspired by the above, we for the first time demonstrate the self-assembly of alpha glucosidase (GAA) and glucose oxidase (GOx) into one multi-enzymes-inorganic nanoreactor with hierarchical structure (flower shape). The hybrid enzyme nanoreactor enjoys the merits including the character of assembly line, the enhanced enzymatic activity and robust stability. The flower shape of enzyme nanoreactor possessed a bigger specific surface area, facilitating the trace GAA inhibitor detection. Based on the above, we proposed an enzyme nanoreactor mediated plasmonic sensing strategy for anti-diabetic drug screening. First, maltose was chosen as the substrate for GAA and the generated glucose were immediately utilized by GOx to generate H2O2, and finally, H2O2 etched the Ag nanoprism to round nanodiscs, resulting in the blue shift of surface plasmon resonance (SPR) absorption band. With the aid of hybrid enzyme nanoreactor guided SPR, the ultrasensitive screening of GAA inhibitor (i.e. anti-diabetic drug) can be realized with the detection limit of 5nM for acarbose. The proposed approach was successfully utilized for GAA inhibitor screening from natural products. We anticipate that the proposed sensing method may provide new insights and inspirations in the enzyme inhibition based drug discovery and clinical diagnosis. PMID- 28843937 TI - Determination of protein-unbound, active rifampicin in serum by ultrafiltration and Ultra Performance Liquid Chromatography with UV detection. A method suitable for standard and high doses of rifampicin. AB - Rifampicin is the most important antibiotic in use for the treatment of tuberculosis (TB). Preclinical and clinical data suggest that higher doses of rifampicin, resulting in disproportionally higher systemic exposures to the drug, are more effective. Serum concentrations of rifampicin are the intermediary link between the dose administered and eventual response and only protein-unbound (free) rifampicin is pharmacologically active. The objective of this work was to develop an ultra performance liquid chromatography assay for protein-unbound rifampicin in serum with ultrafiltration, carried out at a sample temperature of 37 degrees C, suitable for measurement of concentrations achieved after currently used and higher doses of rifampicin. Human serum was equilibrated at 37 degrees C and ultrafiltrated at the same temperature in a Centrifree YM-30 ultrafiltration device, followed by dilution of the ultrafiltrate with methanol and ascorbic acid. Unbound rifampicin was analyzed using ultra performance liquid chromatography with a BEH C18 column, isocratic elution and ultra-violet (UV) detection. The run time was 5min. The assay was linear over the concentration range of 0.065-26mg/L rifampicin in ultrafiltrate. Accuracies for measurement of rifampicin in ultrafiltrate were 97% and 102% at the higher and lower limits of quantitation. Accuracy of the ultrafiltration process cannot be established, as it is not possible to spike blank serum with known amounts of protein-unbound rifampicin. Within- and between-day precision of the method including ultrafiltration as well as after ultrafiltration were within prespecified limits (CV<10%). Dilution of the ultrafiltrate with methanol and ascorbic acid kept rifampicin in solution and prevented it from degradation. Rifampicin loss during the ultrafiltration process and variation in analytical results when using two different batches of ultrafiltration devices were both limited. Processed ultrafiltrate samples were stable for 3days in the autosampler. The developed method can be applied in pharmacokinetic research, studying exposure-response relationships for rifampicin when administered at higher than currently used doses. PMID- 28843938 TI - Assessing the chemical contamination dynamics in a mixed land use stream system. AB - Traditionally, the monitoring of streams for chemical and ecological status has been limited to surface water concentrations, where the dominant focus has been on general water quality and the risk for eutrophication. Mixed land use stream systems, comprising urban areas and agricultural production, are challenging to assess with multiple chemical stressors impacting stream corridors. New approaches are urgently needed for identifying relevant sources, pathways and potential impacts for implementation of suitable source management and remedial measures. We developed a method for risk assessing chemical stressors in these systems and applied the approach to a 16-km groundwater-fed stream corridor (Grindsted, Denmark). Three methods were combined: (i) in-stream contaminant mass discharge for source quantification, (ii) Toxic Units and (iii) environmental standards. An evaluation of the chemical quality of all three stream compartments - stream water, hyporheic zone, streambed sediment - made it possible to link chemical stressors to their respective sources and obtain new knowledge about source composition and origin. Moreover, toxic unit estimation and comparison to environmental standards revealed the stream water quality was substantially impaired by both geogenic and diffuse anthropogenic sources of metals along the entire corridor, while the streambed was less impacted. Quantification of the contaminant mass discharge originating from a former pharmaceutical factory revealed that several 100 kgs of chlorinated ethenes and pharmaceutical compounds discharge into the stream every year. The strongly reduced redox conditions in the plume result in high concentrations of dissolved iron and additionally release arsenic, generating the complex contaminant mixture found in the narrow discharge zone. The fingerprint of the plume was observed in the stream several km downgradient, while nutrients, inorganics and pesticides played a minor role for the stream health. The results emphasize that future investigations should include multiple compounds and stream compartments, and highlight the need for holistic approaches when risk assessing these dynamic systems. PMID- 28843939 TI - The influence of normal and high ultimate muscle pH on the microbiology and colour stability of previously frozen black wildebeest (Connochaetes gnou) meat. AB - Changes in pH, colour and microbiological counts were investigated in previously frozen Biceps femoris (BF) muscles from black wildebeest. Samples were stored under vacuum at refrigerated conditions (4.2+/-0.8 degrees C) for 12days. Seven BF muscles had a high pH (DFD) (pH>=6) and five had a normal pH (pH<6). Overtime the pH of DFD did not significantly change whilst that of normal pH meat decreased. Browning under anaerobic storage conditions was seen, more for normal meat than DFD meat. Initial total viable counts, lactic acid bacteria and coliform counts from samples with normal pH, were significantly higher than counts from the DFD samples. However, overtime DFD meat showed a faster increase for all microorganisms tested compared to normal pH meat. Overall, this study revealed that DFD meat can have a shorter shelf-life than normal pH meat stored at 4.2+/-0.8 degrees C. PMID- 28843940 TI - Programming Merino lambs by early feed restriction reduces growth rates and increases fat accretion during the fattening period with no effect on meat quality traits. AB - The objective of the study was to determine the effect of early feed restriction on carcass and meat quality traits in Merino lambs. Twenty-four male Merino lambs (4.81+/-0.256kg) were assigned to two groups (12 animals in each group). The first group (ad libitum, ADL) was kept permanently with the dams. The second group (restricted, RES) was milk-restricted. After weaning (15kg), daily feed intake of all lambs was identical, but a lower gain: feed ratio was recorded in the RES group (0.320 vs. 0.261; P<0.001). After animals were slaughtered (27kg), lower ultimate pH and reduced yellow colouration of subcutaneous fat was recorded in meat from the RES lambs when compared to ADL group, whereas a trend towards a significant increment of intramuscular fat content and no effect on meat quality traits was observed in the RES lambs. Early feed restriction may be useful to increase intramuscular fat accretion in Merino lambs during the fattening period. PMID- 28843941 TI - Botulinum Neurotoxin and Its Potential Role in the Treatment of Erectile Dysfunction. AB - INTRODUCTION: Botulinum toxin type A (BoNT-A) has been used to treat several striated and smooth muscle disorders. During the past year, human and animal studies conducted in Egypt and Canada by two different groups of investigators have suggested a possible role for the intracavernosal injection of BoNT-A in the treatment of erectile dysfunction (ED). AIM: To discuss BoNT-A and its current medical uses, the rationale for its new potential use in the treatment of ED, and the available evidence and concerns. METHODS: A literature search was conducted. This review was based on the available studies presented at the European Society for Sexual Medicine, Sexual Medicine Society of North America, and International Society for Sexual Medicine meetings in 2016 by the two groups. MAIN OUTCOME MEASURES: Sinusoidal diameter; penile color Doppler study; Erection Hardness Score; Sexual Health Inventory for Men questionnaire; and Sexual Encounter Profile questions 2 and 3. RESULTS: Two human studies conducted by the authors and two animal studies (one from the authors' group and one from Canada) were reviewed. These seemed to suggest generally favorable outcomes with the use of BoNT-A in the treatment of ED. CONCLUSION: BoNT-A could be a potential therapy for ED. In addition to the findings of the three pilot studies, larger multicenter trials need to be conducted to further explore the true therapeutic efficacy and clinical safety of BoNT-A in the treatment of ED. Ghanem H, Raheem AA, AbdelRahman IFS, et al. Botulinum Neurotoxin and Its Potential Role in the Treatment of Erectile Dysfunction. Sex Med Rev 2018;6:135-142. PMID- 28843942 TI - Sexual Function in Women Suffering From Genitourinary Syndrome of Menopause Treated With Fractionated CO2 Laser. AB - INTRODUCTION: Genitourinary syndrome of menopause (GSM) has a significant impact on the trophism of the genital and lower urinary tracts and can considerably impair sexual function. Fractional CO2 laser has a regenerative effect on vulvovaginal tissue trophism after menopause. AIM: To review the available literature on the effect of fractional CO2 laser on the sexual function of postmenopausal women affected by GSM. METHODS: A database search was carried out using the terms CO2laser, vaginal atrophy, sexual function, dyspareunia, and genitourinary syndrome of menopause and excluding studies using other types of laser or including breast cancer survivors with vulvovaginal atrophy. For statistical analysis, the estimated overall laser effect was computed (when at least two studies were involved) and data type of generic inverse variance was computed using inverse variance as the statistical method, a random-effects model, and the difference in means as an effect measurement. MAIN OUTCOME MEASURES: Different methods of evaluating sexual function were reported and studies were grouped and analyzed accordingly. Subjective assessment for dyspareunia was evaluated with a 10-point visual analog scale. Patient-reported outcome for an overall perception of sexual function was evaluated with a Likert scale. The Female Sexual Function Index was used as a condition-specific questionnaire. RESULTS: Six articles were considered for this review. A total of 273 women (mean age = 57.8 years) were treated with the same protocol in all studies. Compared with baseline, at the end of the treatment, dyspareunia significantly decreased in severity (P < .001), and the patient's perception of overall sexual function showed a statistically significant improvement (P < .001). At the last follow-up visit, the Female Sexual Function Index score for each single domain and overall score was significantly better than at entry (P < .001). CONCLUSION: Fractional CO2 laser can improve sexual function in postmenopausal women affected by GSM by restoring a better trophism in the lower genitourinary tract. Salvatore S, Pitsouni E, Del Deo F, et al. Sexual Function in Women Suffering From Genitourinary Syndrome of Menopause Treated With Fractionated CO2Laser. Sex Med Rev 2017;5:486-494. PMID- 28843943 TI - Evaluation of contact precautions for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. AB - BACKGROUND: There are limited controlled data demonstrating contact precautions (CPs) prevent methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE) infections in endemic settings. We evaluated changes in hospital-acquired MRSA and VRE infections after discontinuing CPs for these organisms. METHODS: This is a retrospective study done at an 800-bed teaching hospital in urban Detroit. CPs for MRSA and VRE were discontinued hospital-wide in 2013. Data on MRSA and VRE catheter-associated urinary tract infections (CAUTIs), ventilator-associated pneumonia (VAP), central line-associated bloodstream infections (CLABSIs), surgical site infections (SSIs), and hospital acquired MRSA bacteremia (HA-MRSAB) rates were compared before and after CPs discontinuation. RESULTS: There were 36,907 and 40,439 patients hospitalized during the two 12-month periods: CPs and no CPs. Infection rates in the CPs and no-CPs periods were as follows: (1) MRSA infections: VAP, 0.13 versus 0.11 (P = .84); CLABSI, 0.11 versus 0.19 (P = .45); SSI, 0 versus 0.14 (P = .50); and CAUTI, 0.025 versus 0.033 (P = .84); (2) VRE infections: CAUTI, 0.27 versus 0.13 (P = .19) and CLABSI, 0.29 versus 0.3 (P = .94); and (3) HA-MRSAB rates: 0.14 versus 0.11 (P = .55), respectively. CONCLUSIONS: Discontinuation of CPs did not adversely impact endemic MRSA and VRE infection rates. PMID- 28843944 TI - At most hospitals in the state of Iowa, most surgeons' daily lists of elective cases include only 1 or 2 cases: Individual surgeons' percentage operating room utilization is a consistently unreliable metric. AB - STUDY OBJECTIVE: Percentage utilization of operating room (OR) time is not an appropriate endpoint for planning additional OR time for surgeons with high caseloads, and cannot be measured accurately for surgeons with low caseloads. Nonetheless, many OR directors claim that their hospitals make decisions based on individual surgeons' OR utilizations. This incongruity could be explained by the OR managers considering the earlier mathematical studies, performed using data from a few large teaching hospitals, as irrelevant to their hospitals. The important mathematical parameter for the prior observations is the percentage of surgeon lists of elective cases that include 1 or 2 cases; "list" meaning a combination of surgeon, hospital, and date. We measure the incidence among many hospitals. DESIGN: Observational cohort study. SETTING: 117 hospitals in Iowa from July 2013 through September 2015. SUBJECTS: Surgeons with same identifier among hospitals. MEASUREMENTS: Surgeon lists of cases including at least one outpatient surgical case, so that Relative Value Units (RVU's) could be measured. MAIN RESULTS: Averaging among hospitals in Iowa, more than half of the surgeons' lists included 1 or 2 cases (77%; P<0.00001 vs. 50%). Approximately half had 1 case (54%; P=0.0012 vs. 50%). These percentages exceeded 50% even though nearly all the surgeons operated at just 1 hospital on days with at least 1 case (97.74%; P<0.00001 vs. 50%). The cases were not of long durations; among the 82,928 lists with 1 case, the median was 6 intraoperative RVUs (e.g., adult inguinal herniorrhaphy). CONCLUSIONS: Accurate confidence intervals for raw or adjusted utilizations are so wide for individual surgeons that decisions based on utilization are equivalent to decisions based on random error. The implication of the current study is generalizability of that finding from the largest teaching hospital in the state to the other hospitals in the state. PMID- 28843945 TI - The Foundational Public Health Services as a Framework for Estimating Spending. AB - INTRODUCTION: In support of the nation's effort to address rising healthcare costs and improve healthcare outcomes, the National Academy of Medicine called for a minimum package of public health services available in every community to protect and improve population health and identification of the resources needed to make these services universally available. In response, the Foundational Public Health Services (FPHS) framework was developed to outline a basic set of public health programs and capabilities. Although the FPHS is considered a useful public health practice tool, cost estimation for providing the FPHS is in its infancy. This is in part due to inability to estimate total costs of individual public health services and programs. This research begins to address this knowledge gap. METHODS: FPHS formed the basis of a coding framework used in 2013 2016 to code 1.9 million U.S. Census Bureau State Finance non-hospital expenditure records from 49 states from 2000 to 2013. Results were used to develop estimates of state governmental FPHS spending. RESULTS: FPHS spending constituted 36% of total state governmental non-hospital health spending from 2008 to 2013. The largest proportion of FPHS spending was on maternal/child health and the smallest proportion of spending was on access and linkage to clinical care. CONCLUSIONS: This research is an important step in response to the National Academy of Medicine's call for estimating the resources needed to provide the FPHS. Such estimates allow for spending comparisons across states and may inform future research to assess and evaluate FPHS spending impacts. PMID- 28843946 TI - Corrigendum to "Ferroportin disease: A systematic meta-analysis of clinical and molecular findings" J. Hepatol. 2010 Nov;53(5):941-949. PMID- 28843947 TI - Corrigendum to "The independent effects of fatigue and UDCA therapy on mortality in primary biliary cirrhosis: Results of a 9 year cohort follow-up" J. Hepatol. 2010 Nov; 53(5):911-917. PMID- 28843948 TI - The value of simulation-based learning in pre-licensure nurse education: A state of-the-art review and meta-analysis. AB - Simulation modalities are numerous in nursing education, with a need to reveal their range and impact. We reviewed current evidence for effectiveness of medium to high fidelity simulation as an education mode in pre-licensure/pre registration nurse education. A state-of-the-art review and meta-analyses was conducted based on a systematic search of publications in English between 2010 and 2015. Of 72 included studies, 43 were quantitative primary studies (mainly quasi-experimental designs), 13 were qualitative studies and 16 were reviews of literature. Forty of 43 primary studies reported benefits to student learning, and student satisfaction was high. Simulation programs provided multi-modal ways of learning. A meta-analysis (8 studies, n = 652 participants) identified that simulation programs significantly improved clinical knowledge from baseline. The weighted mean increase was 5.0 points (CI: 3.25-6.82) on a knowledge measure. Other objectively rated measures (eg, trained observers with checklists) were few. Reported subjective measures such as confidence and satisfaction when used alone have a strong potential for results bias. Studies presented valid empirical evidence, but larger studies are required. Simulation programs in pre-licensure nursing curricula demonstrate innovation and excellence. The programs should be shared across the discipline to facilitate development of multimodal learning for both pre-licensure and postgraduate nurses. PMID- 28843949 TI - Continuous-flow, implantable biventricular assist device as bridge to cardiac transplantation in a small child with restrictive cardiomyopathy. PMID- 28843950 TI - An evaluation of knowledge and attitudes toward epilepsy in Eastern Turkey. AB - PURPOSE: This study was designed to determine the knowledge and attitudes regarding epilepsy among individuals in eastern Turkey. METHOD: This descriptive study involved 530 healthy individuals who came to the Research and Application Hospital of Ataturk University in Erzurum, Turkey. A questionnaire and the epilepsy knowledge and attitude scale were administered to collect data. Mann Whitney U, Kruskal-Wallis, and Spearman's correlation tests were used to analyze the data. RESULTS: The participants' epilepsy knowledge mean score was 6.34 (SD=3.71), and their attitude mean score was 50.22 (SD=11.17). There was a positive (r=0.404) correlation between the knowledge and the attitude scores (p<0.001), and negative correlations between age and the knowledge (p=0.036) and the attitude scores (p<0.001). The mean knowledge and attitude scores were higher for the participants who were high school and university graduates, had expenses equal to income, and lived in nuclear families and in the city center (p<0.001). Civil servants and housewives had significantly higher mean knowledge scores, and students had significantly higher mean attitude scores (p<0.001). Significantly higher knowledge and attitude mean scores were also found for those who knew patients with epilepsy, had witnessed epileptic seizures, obtained information from healthcare personnel, and did not believe that epilepsy was associated with religion (p<0.001). CONCLUSIONS: The study participants had low knowledge about epilepsy but displayed positive attitudes toward it. Higher knowledge positively affected attitude, and younger individuals had greater knowledge and, thus, more positive attitudes. Women, civil servants, and housewives had higher knowledge, whereas singles and students had better attitudes. The participants who had high educational levels and expenses equal to income and lived in nuclear families and the city center had more knowledge and displayed more positive attitudes. Greater knowledge and more positive attitudes were also found among the participants who knew patients with epilepsy, had witnessed epileptic seizures, obtained the information from healthcare personnel, and did not believe that epilepsy was associated with religion. PMID- 28843951 TI - Partnering to support the next generation of epilepsy researchers. PMID- 28843952 TI - A national survey of natural radionuclides in soils and terrestrial radiation exposure in Iran. AB - In the past, some efforts have been made for measuring natural radioactivity and evaluating public exposure to natural radiation in certain areas of Iran especially in well-known High Level Natural Radiation Areas (HLNRA) in Ramsar and Mahallat. However, the information on radionuclide concentrations, and, consequently, terrestrial radiation exposure for many other areas are not available. There was therefore a need for a systematic and nation-wide survey. For this purpose, 979 soil samples from 31 provinces were collected. The activity concentrations of 40K, 226Ra and 232Th were measured by HPGe detector. The average activity concentrations for Iran were found to be 457.7 Bq/kg for 40K, 24.3 Bq/kg for 226Ra and 25.8 Bq/kg for 232Th. Results were compared with previous regional or provincial surveys. The population-weighted average outdoor and indoor annual effective dose due to external exposure to terrestrial sources of radiation are 0.06 mSv and 0.33 mSv, respectively. It was shown that there is a significant correlation between the activity concentrations of 232Th and 40K in soil. In addition, the results of chi square tests show normal and lognormal distributions cannot be considered for the frequency distributions of activity concentration of 232Th and 226 Ra while 40K has a normal distribution. PMID- 28843953 TI - Adipose tissue inflammation in obesity: a metabolic or immune response? AB - Adipose tissue is not only a reservoir for energy, but also an immune organ. In the context of obesity, the development of insulin resistance is now recognised to be initiated by inflammation of the adipose tissue. However, the primary events triggering this inflammation are still unclear, as a complex combination of endocrine and immune factors act to regulate this adipose tissue microenvironment. Below we discuss the different factors involved and how they affect the biology of the adipose tissue in obesity. PMID- 28843954 TI - Right Upper Quadrant Pain in a 47-Year-Old Woman. PMID- 28843956 TI - A Large Retroperitoneal Mass in an Asymptomatic 22-Year-Old Man. PMID- 28843955 TI - Predictors of Use of Monitored Anesthesia Care for Outpatient Gastrointestinal Endoscopy in a Capitated Payment System. AB - BACKGROUND & AIMS: Use of monitored anesthesia care (MAC) for gastrointestinal endoscopy has increased in the Veterans Health Administration (VHA) as in fee-for service environments, despite the absence of financial incentives. We investigated factors associated with use of MAC in an integrated health care delivery system with a capitated payment model. METHODS: We performed a retrospective cohort study using multilevel logistic regression, with MAC use modeled as a function of procedure year, patient- and provider-level factors, and facility effects. We collected data from 2,091,590 veterans who underwent outpatient esophagogastroduodenoscopy and/or colonoscopy during fiscal years 2000 2013 at 133 facilities. RESULTS: The adjusted rate of MAC use in the VHA increased 17% per year (odds ratio for increase, 1.17; 95% confidence interval, 1.09-1.27) from fiscal year 2000 through 2013. The most rapid increase occurred starting in 2011. VHA use of MAC was associated with patient-level factors that included obesity, obstructive sleep apnea, higher comorbidity, and use of prescription opioids and/or benzodiazepines, although the magnitude of these effects was small. Provider-level and facility factors were also associated with use of MAC, although again the magnitude of these associations was small. Unmeasured facility-level effects had the greatest effect on the trend of MAC use. CONCLUSIONS: In a retrospective study of veterans who underwent outpatient esophagogastroduodenoscopy and/or colonoscopy from fiscal year 2000 through 2013, we found that even in a capitated system, patient factors are only weakly associated with use of MAC. Facility-level effects are the most prominent factor influencing increasing use of MAC. Future studies should focus on better defining the role of MAC and facility and organizational factors that affect choice of endoscopic sedation. It will also be important to align resources and incentives to promote appropriate allocation of MAC based on clinically meaningful patient factors. PMID- 28843957 TI - Association of Aneuploidy and Flat Dysplasia With Development of High-Grade Dysplasia or Colorectal Cancer in Patients With Inflammatory Bowel Disease. AB - There is controversy over how to best manage patients with inflammatory bowel disease and flat low-grade dysplasia (fLGD) in the colon. We performed a retrospective analysis of formalin-fixed paraffin-embedded colon tissues with fLGD from 37 patients undergoing surveillance colonoscopy for inflammatory bowel disease from 1990 to 2015 at the University of California at San Francisco Medical Center, to determine whether detection of aneuploidy is associated with later development of high-grade dysplasia (HGD) or colorectal cancer. Medical data were collected from the patients for a mean follow-up time of 37 months. Using flow cytometry analysis of paraffin-embedded colon tissue, we detected aneuploidy in 15 of 37 samples with fLGD (40.5%). By comparison, aneuploidy was detected in 14 of 15 samples with flat HGD (93.3%) and 2 of 45 samples that were negative for dysplasia (4.4%). The univariate hazard ratio for subsequent detection of HGD or colorectal cancer in patients with fLGD and aneuploidy was 5.3 (95% CI, 1.542-24.121) within a mean follow-up time of 37 months. The presence of aneuploidy therefore identifies patients with fLGD in colon tissue who have an increased risk for HGD or colorectal cancer and may provide supportive evidence to a morphologic impression or suspicion of flat HGD. PMID- 28843958 TI - Avoiding Surgical Skill Decay: A Systematic Review on the Spacing of Training Sessions. AB - OBJECTIVE: Spreading training sessions over time instead of training in just 1 session leads to an improvement of long-term retention for factual knowledge. However, it is not clear whether this would also apply to surgical skills. Thus, we performed a systematic review to find out whether spacing training sessions would also improve long-term retention of surgical skills. DESIGN: We searched the Medline, PsycINFO, Embase, Eric, and Web of Science online databases. We only included articles that were randomized trials with a sample of medical trainees acquiring surgical motor skills in which the spacing effect was reported. The quality and bias of the articles were assessed using the Cochrane Collaboration's risk of bias assessment tool. RESULTS: With respect to the spacing effect, 1955 articles were retrieved. After removing duplicates and articles that did not meet the inclusion criteria, 11 articles remained. The overall quality of the experiments was "moderate." Trainees in the spaced condition scored higher in a retention test than students in the massed condition. CONCLUSIONS: Our systematic review showed evidence that spacing training sessions improves long-term surgical skills retention when compared to massed practice. However, the optimal gap between the re-study sessions is unclear. PMID- 28843959 TI - TEAM: A Low-Cost Alternative to ATLS for Providing Trauma Care Teaching in Haiti. AB - OBJECTIVE: Trauma resuscitation protocols have unified the care of trauma patients and significantly improved outcomes. However, the success of the Advanced Trauma Life Support course is difficult to reproduce in developing countries due to set-up costs, limitations of resources, and variations of practice. The objective of this study is to assess the Trauma Evaluation and Management (TEAM) course as a low-cost alternative for trauma resuscitation teaching in Low and Middle Income Countries (LMIC). DESIGN: As part of the Team Broken Earth initiative, TEAM course was provided to the health care professionals in Haiti. At its conclusion, participants were asked to complete a survey evaluating the course. Qualitative and quantitative data were analyzed to evaluate the perception of the course. SETTING: The course was provided in Port au-Prince, Haiti. PARTICIPANTS: A total of 80 health care professionals participated in the course. Response was obtained from 69 participants, which comprised of 32 physicians, 10 Emergency Medical Technicians (EMT), 22 nurses, and 5 medical trainees. RESULTS: The course was well received by physicians, nurses, and EMT with an average score of 90.6%. Question analysis revealed a lower satisfaction of physicians for the course manual and teaching materials, and information related to decisions for transfer of patients. EMT consistently felt that the course was not tailored to their learning and practice needs. Written feedback demonstrated several areas of weaknesses including need for improvements in translations, hands-on practice, and educational materials. CONCLUSIONS: Overall, the TEAM course was well received. Analysis demonstrated a need for adjustments specific to LMIC including a focus on prehospital assessment, increased nursing responsibilities, and unavailability of specialist's referrals. Team Broken Earth intends to take these findings into consideration and continue to provide the TEAM course to other LMIC. PMID- 28843961 TI - ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration. AB - Activating transcription factor 4 (ATF4), an endoplasmic reticulum stress inducible transcription factor, plays important roles in cancer progression and resistance to therapy. However, no report is available about its roles in endometrial cancer (EC). In this study, we found that ATF4 is commonly expressed in EC cell lines. Loss-of-function studies in two EC cell lines showed that ATF4 knockdown suppresses tumor growth of EC in vivo without influencing cell proliferation in vitro. And xenograft tumors derived from ATF4-knockdown cells had reduced M2 macrophage infiltration. In clinical specimens, ATF4-high expressing tumors indeed contained more macrophage infiltration compared to those with lower ATF4 expression. Moreover, we identified that ATF4-mediated chemokine CCL2 expression ultimately results in macrophage infiltration and tumor growth of EC. Taken together, our findings suggest that ATF4 contributes to tumor growth of EC by promoting CCL2 and subsequent recruitment of macrophage, and that ATF4/CCL2 axis might be a potential therapeutic target for EC. PMID- 28843960 TI - Interfacial degradation of adhesive composite restorations mediated by oral biofilms and mechanical challenge in an extracted tooth model of secondary caries. AB - OBJECTIVE: To study the combined effect of simulated occlusal loading and plaque derived biofilm on the interfacial integrity of dental composite restorations, and to explore whether the effects are modulated by the incorporation of sucrose. METHODS: MOD-class-II restorations were prepared in third molars. Half of the specimens (n=27) were subjected to 200,000 cycles of mechanical loading using an artificial oral environment (ART). Then, both groups of specimens (fatigued and non-fatigued) were divided into three subgroups for testing in CDC-reactors under the following conditions: no biofilm (Control), biofilm with no sucrose (BNS) and biofilm pulsed with sucrose (BWS). BNS and BWS reactors were incubated with a multispecies inoculum from a single plaque donor whereas the control reactor was not. The BWS reactor was pulsed with sucrose five times a day. The biofilm challenges were repeated sequentially for 12 weeks. pH was recorded for each run. Specimens were examined for demineralization with micro-CT and load capacity by fast fracture test. RESULTS: Demineralization next to the restorations was only detectable in BWS teeth. Fracture loads were significantly reduced by the concomitant presence of biofilm and sucrose, regardless of whether cyclic mechanical loading was applied. Cyclic loading reduced fracture loads under all reactor conditions, but the reduction was not statistically significant. CONCLUSIONS: Sucrose pulsing was required to induce biofilm-mediated degradation of the adhesive interface. We have presented a comprehensive and clinically relevant model to study the effects of mechanical loading and microbial challenge on the interfacial integrity of dental restorations. PMID- 28843963 TI - Intraventricular conduction disturbances: are we just looking at the tip of the iceberg? PMID- 28843962 TI - Inhibition of angiotension II type 1 receptor reduced human endothelial inflammation induced by low shear stress. AB - Low shear stress (LSS)-induced endothelial inflammation is the basis for the development of atherosclerosis. However, the mechanism underlying LSS-induced inflammation is not well understood. The angiotensin II type 1 receptor (AT1R), a component of the renin-angiotensin system, participates in atherosclerotic plaque progression. The aim of this study was to investigate the role of AT1R in LSS induced endothelial activation. Using immunohistochemistry, we noted significant increases in AT1R, vascular endothelial adhesion cell-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) expression in the inner curvature of the aortic arch in C57BL/6 mice compared to the descending aorta in these mice. Moreover, western blotting revealed that these LSS-induced increases in AT1R, ICAM1 and VCAM1 expression were time dependent. However, the expression of these proteins was significantly abolished by treatment with the AT1R antagonist Losartan (1MUM) or AT1R small interfering RNA (siRNA). AT1R inhibition significantly suppressed extracellular signal-regulated kinase 1/2 (ERK) upregulation, which also resulted in decreases in ICAM1 and VCAM1 protein expression. These findings demonstrate that LSS induces endothelial inflammation via AT1R/ERK signaling and that Losartan has beneficial effects on endothelial inflammation. PMID- 28843964 TI - Chitosan encapsulation of essential oil "cocktails" with well-defined binary Zn(II)-Schiff base species targeting antibacterial medicinal nanotechnology. AB - The advent of biodegradable nanomaterials with enhanced antibacterial activity stands as a challenge to the global research community. In an attempt to pursue the development of novel antibacterial medicinal nanotechnology, we herein a) synthesized ionic-gelated chitosan nanoparticles, b) compared and evaluated the antibacterial activity of essential oils extracted from nine different herbs (Greek origin) and their combinations with a well-defined antibacterial Zn(II) Schiff base compound, and c) encapsulated the most effective hybrid combination of Zn(II)-essential oils inside the chitosan matrix, thereby targeting well formulated nanoparticles of distinct biological impact. The empty and loaded chitosan nanoparticles were physicochemically characterized by FT-IR, Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), with the entrapment and drug release studies being conducted through UV-Visible and atomic absorption techniques. The antimicrobial properties of the novel hybrid materials were demonstrated against Gram positive (S. aureus, B. subtilis, and B. cereus) and Gram negative (E. coli and X. campestris) bacteria using modified agar diffusion methods. The collective physicochemical profile of the hybrid Zn(II) essential oil cocktails, formulated so as to achieve optimal activity when loaded to chitosan nanoparticles, signifies the importance of design in the development of efficient nanomedicinal pharmaceuticals a) based on both natural products and biogenic metal ionic cofactors, and b) targeting bacterial infections and drug resistance. PMID- 28843965 TI - A systematic review of balance and fall risk assessments with mobile phone technology. AB - Falls are a major health concern for older adults. Preventative measures can help reduce the incidence and severity of falls. Methods for assessing balance and fall risk factors are necessary to effectively implement preventative measures. Research groups are currently developing mobile applications to enable seniors, caregivers, and clinicians to monitor balance and fall risk. The following systematic review assesses the current state of mobile health apps for testing balance as a fall risk factor. Thirteen studies were identified and included in the review and analyzed based on study design, population, sample size, measures of balance, main outcome measures, and evaluation of validity and reliability. All studies successfully tested their applications, but only 38% evaluated the validity, and 23% evaluated the reliability of their applications. Of those, all applications were found to accurately and reliably measure balance on select variables. Four of the 13 studies included special populations groups. Out of the 13 studies, 12 reported clinicians as their intended user and seven reported seniors as their intended user. Further research should examine the validity of mobile health applications as well as report on the application's usability. PMID- 28843966 TI - Comprehensive analysis of the volume of bone for grafting that can be harvested from iliac crest donor sites. AB - Our aim was to calculate the volumes of cancellous, cortical, and corticocancellous bone that can be harvested as a graft from the anterior and posterior iliac crests using 3-dimensional computed tomography (CT) and software in a living adult population. We selected random CT scans of the pelvis from 31 men and 29 women from the Department of Radiology imaging database. CT data in DICOM file format were imported into Mimics software. The anterior iliac crest and posterior iliac crest bone graft-harvested boundaries were measured. The volume of the 3-dimensional cortical and cancellous bone grafts was measured using the Mimics software. There were significant differences in all comparisons between the anterior and posterior iliac crest, except for volumes of cortical bone. More cancellous and total corticocancellous bone can be harvested from the posterior than the anterior iliac crest, together with similar or smaller volumes of cortical bone. Sex, but not age, is an important factor in terms of the amount of bone that can be harvested, with a wide range of volumes individually from both iliac crests. PMID- 28843967 TI - Distance-dependent accuracy in Le Fort I maxillary repositioning procedures. AB - It has been hypothesised that, in maxillary repositioning procedures, longer distances correlate with less accurate transfers and particularly the repositioning forces of facial skin and muscles that increase exponentially. However, this has not to our knowledge been confirmed. The purpose of this study was to search for differences in the accuracy of transfer from maxillary repositioning procedures parallel to the three orthogonal planes and with respect to three different anatomical landmarks of the first molar left and right (M1L and M1R) and the first incisor (I). Cone-beam computed tomography (CT) datasets taken before and after operation for 92 patients who had Le Fort I maxillary repositioning procedures were aligned to measure the changes in the maxillary position in the axial, sagittal, and transverse directions. Differences between planned distances and those achieved were calculated and analysed with Pearsons correlation coefficient. The strongest significant correlations between the extent of planned repositioning distances and achieved differences (error) were detected in the sagittal plane for the anatomical landmarks of the right (M1R) and left first molar (M1L). Correlations became weaker if a limited planned distance ranging from 0-4mm was compared with a complete observed range that reached up to 12mm. Our results show for the first time to our knowledge that the accuracy of transfer of wafer-based maxillary positioning procedures depends on the distance being moved. Longer distances correlate with less accuracy, particularly in the sagittal plane and in the first molar region. PMID- 28843968 TI - Pitfalls in monitoring of the facial nerve during operations for parotid cancer. PMID- 28843969 TI - Split internal jugular vein: surgical and radiological implications. PMID- 28843970 TI - Scarless total maxillectomy: midfacial degloving with extended transconjunctival retrocaruncular approach. PMID- 28843971 TI - Hard neck lumps: a review of uncommon and sometimes overlooked causes of these worrying presentations. AB - While a neck lump is a common presentation that can raise suspicion of a potentially serious underlying disease, a hard lump, though less common, may be even more concerning for the patient, and prompt urgent investigation. Metastatic squamous cell carcinoma is the commonest underlying diagnosis that must be excluded, but other diseases or even normal anatomy of the neck can be associated with lumps that are hard or bony. Many of these presentations are relatively rare and may not be familiar to oral and maxillofacial surgeons (OMFS) (particularly more junior clinicians) as a differential diagnosis of a hard neck mass. We have reviewed these lesions to raise awareness of possible unusual causes, particularly when patients are not initially examined in a specialist neck lump clinic where ultrasound is readily available. PMID- 28843972 TI - What determines the fruit and vegetables intake of primary school children? - An analysis of personal and social determinants. AB - The high prevalence of childhood obesity is a major concern in developed and developing countries. An increase in fruit and vegetable (F&V) intake is perceived as one of the numerous strategies to prevent and reduce the risk of adiposity. The purpose of this study was to investigate the relevance of personal and social determinants in explaining children's F&V intake. Written questionnaire data were collected from 702 parent-child pairs that included 3rd and 4th graders (aged 7 to 10) and their parents. Children's F&V intake was recorded over three food records. Hierarchical linear regression models were applied to assess the impact of personal and social determinants on children's F&V intake. Regression models focusing on personal and social determinants revealed that the most promising personal determinants pertained to the knowledge of different types of F&V and preferences for F&V. Moreover, an exclusive focus on social determinants indicated that parental modeling and peer influence had significant and positive relationships with children's F&V intake, whereas verbal directives to eat F&V exhibited a significant and negative relationship. In combination, the following four personal and social determinants were demonstrated to be significant: knowledge of different types of F&V, preferences for F&V and parental modeling, all of which had positive relationships, and verbal directives to eat F&V, which had a negative impact. The results identify important associative determinants of children's F&V intake. These are in part personal and in part social and are shown by our analysis to be of equal and perhaps mutual importance. Therefore, we suggest that interventions aimed at improving children's F&V intake should address children's preferences for F&V, impart knowledge concerning the variety of F&V and encourage parents to act as role models. PMID- 28843973 TI - Acute effects of monosodium glutamate addition to whey protein on appetite, food intake, blood glucose, insulin and gut hormones in healthy young men. AB - AIMS: This study investigated the effects of adding monosodium glutamate (MSG) to carrot soup with or without whey protein, on subjective appetite, food intake (FI) and satiety hormones in healthy young men. METHODS: Two experiments were conducted using a repeated-measures, within-subject, crossover design. In exp-1 healthy young men (n = 28) consumed water alone (500 mL), or carrot soup (500 g) with or without MSG (5 g, 1% w/w) or whey protein enriched (36 g) carrot soup with or without MSG (5 g, 1% w/w). Subjective appetite was measured post treatment and FI measured at a meal at 120 min. In exp-2 (n = 15) the same treatments except for water were used. In addition to subjective appetite and FI, blood glucose, insulin, glucose like peptide 1 (GLP-1), C-peptide and ghrelin were measured. RESULTS: Adding MSG to carrot soup or whey protein enriched carrot soup did not affect FI. However, in exp-1 the addition of both MSG and protein increased fullness, and when MSG was added to carrot soup reduced desire to eat. In exp-2, average post-treatment appetite (5-120 min) was lower after carrot soup with MSG and protein than all other treatments (P < 0.05). In exp-2, carrot soup with MSG and protein, but not with protein alone, increased post-treatment insulin and C-peptide, and lowered blood glucose in comparison to carrot soup with no additions (P < 0.05). CONCLUSION: Adding MSG alone, or in combination with whey protein, to carrot soups did not affect FI. However, MSG increased fullness and reduced desire to eat, as well as subjective appetite, and when added to protein decreased blood glucose and increased insulin and C-peptide, offering some support for the hypothesis that MSG in the gut signals protein consumption. PMID- 28843974 TI - Acute effects of video-game playing versus television viewing on stress markers and food intake in overweight and obese young men: A randomised controlled trial. AB - BACKGROUND: Sedentary or near-sedentary activities are associated with overweight/obesity in epidemiological studies. This has traditionally been attributed to physical activity displacement. A little-explored area is whether behavioural stresses alter sensations of appetite and eating behaviour. We examined whether behaviours conducted seated (television viewing, video gaming) induce different eating patterns, associated with differential levels of stress response. METHODS AND FINDINGS: We conducted a randomized controlled trial in 72 overweight/obese adult males, assigned to three groups (24 per group): (i) non violent television (control group); (ii) non-violent game (FIFA); (iii) violent game (Call of Duty). Following a standardized breakfast, the 1-h intervention was followed by 25-min rest, with sweet and savoury snacks and drinks available ad libitum. Stress markers (heart rate, blood pressure, visual analogue scale (VAS)) were measured throughout. Heart rate, systolic blood pressure, and stress by VAS were significantly higher (p < 0.05) playing video games than watching non violent television, though the two game groups did not differ. Considered separately, only the violent video game group consumed more energy (Delta = 208.3 kcal, 95%CI 16, 400), sweet foods (Delta = 25.9 g, 95%CI 9.9, 41.9) and saturated fat (Delta = 4.36 g, 95%CI 0.76, 7.96) than controls. CONCLUSION: Playing video games in overweight/obese adult males is associated with an acute stress response relative to watching non-violent television, associated with greater subsequent food intake. These findings highlight the need to focus on the metabolic effects, as well as the energy costs, of activities involving sitting in relation to obesity risk. PMID- 28843975 TI - Buckled Thyroid Cartilage: An Anatomic Variant. AB - OBJECTIVE: Anatomic abnormalities in the larynx can cause significant and bothersome symptoms. Identified here is an anatomical variant of the thyroid cartilage. STUDY DESIGN: This study is a retrospective case series of 11 subjects diagnosed with an anatomic variant of the thyroid cartilage. METHODS: Patients with an anatomic inward buckling of the thyroid cartilage, termed here as buckled thyroid cartilage, were identified through a 20-year retrospective chart review of a tertiary care laryngology practice. RESULTS: We describe 11 patients with fullness or asymmetry in the area of the false vocal fold and an associated inward buckling of the thyroid cartilage on computed tomography scan. All patients presented with a bothersome voice-related complaint. The most common presenting complaints were hoarseness (54%), globus sensation (45%), or vocal fatigue (27%). One patient was found to have a history of known laryngeal trauma. Surgical correction through an external approach on one patient was successfully performed with subsequent resolution of symptoms. CONCLUSION: We postulate that deformity and protrusion of the false vocal fold can result in a dampening effect on the vibratory capacity of the vocal fold that can lead to symptomatic hoarseness and vocal fatigue. Buckled thyroid cartilage is, therefore, an important anatomical variant to be aware of and be able to recognize. PMID- 28843976 TI - Novel approaches to support breast cancer survivorship care models. AB - The delivery of cancer survivorship care has been increasingly recognized as an area of healthcare in need of improvement. Several survivorship care models have previously been described in the literature. Yet, there is growing evidence that current models are both unsustainable for the future and fail to meet the diverse needs of cancer survivors. As a result, there has been an emphasis on developing innovative models of survivorship care that are accessible to patients and improve outcomes. Proposed solutions to address these concerns include enhanced collaboration and communication among care providers as well as incorporating the use of technology for survivorship care delivery. This article reviews existing models of survivorship care and describes future approaches to improve the care of breast cancer survivors. PMID- 28843977 TI - Atomic force microscopy of RNA: State of the art and recent advancements. AB - The atomic force microscope (AFM) has become a powerful tool for the visualization, probing and manipulation of RNA at the single molecule level. AFM measurements can be carried out in buffer solution in a physiological medium, which is crucial to study the structure and function of biomolecules, also allowing studying them at work. Imaging the specimen in its native state is a great advantage compared to other high resolution methods such as electron microscopy and X-ray diffraction. There is no need to stain, freeze or crystallize biological samples. Moreover, compared to NMR spectroscopy for instance, for AFM studies the size of the biomolecules is not limiting. Consequently the AFM allows one also to investigate larger RNA molecules. In particular, structural studies of nucleic acids and assemblies thereof, have been carried out by AFM routinely including ssRNA, dsRNA and nucleoprotein complexes thereof, as well as RNA aggregates and 2D RNA assemblies. These are becoming increasingly important as novel unique building blocks in the emerging field of RNA nanotechnology. In particular by AFM unique information can be obtained on these RNA based assemblies. Moreover, the AFM is of fundamental relevance to study biological relevant RNA interactions and dynamics. In this short review a brief overview will be given on structural studies that have been done related to AFM topographic imaging of RNA, RNA assemblies and aggregates. Finally, an overview on AFM beyond imaging will be provided. This includes force spectroscopy of RNA under physiological conditions in aqueous buffer to probe RNA interaction with proteins and ligands as well as other AFM tip based RNA probing. Important applications include the detection and quantification of RNA in biological samples. A selection of recent highlights and breakthroughs will be provided related to structural and functional studies by AFM. The main intention of this short review to provide the reader with a flavor of what AFM is able to contribute to RNA research and engineering. PMID- 28843979 TI - Regulation of a minimal transcriptome by repeat domain proteins. AB - Repeat proteins regulate the expression of the mammalian mitochondrial genome at the level of transcription, processing, maturation, and translation. Defects in the regulation of mitochondrial gene expression due to mutations in genes encoding repeat proteins can lead to mitochondrial dysfunction and disease, however the molecular mechanisms that regulate mitochondrial gene expression and how defects in these processes cause disease still remains poorly understood. Recently solved crystal structures, characterisation of the new genetic models, and use of RNA sequencing (RNA-Seq) technologies have greatly expanded our current understanding of mitochondrial repeat proteins and biology. PMID- 28843978 TI - Primary cilia: Cell and molecular mechanosensors directing whole tissue function. AB - Primary cilia are immotile, microtubule-based organelles extending from the surface of nearly every mammalian cell. Mechanical stimulation causes deflection of the primary cilium, initiating downstream signaling cascades to the rest of the cell. The cilium forms a unique subcellular microdomain, and defects in ciliary protein composition or physical structure have been associated with a myriad of human pathologies. In this review, we discuss the importance of ciliary mechanotransduction at the cell and tissue level, and how furthering our molecular understanding of primary cilia mechanobiology may lead to therapeutic strategies to treat human diseases. PMID- 28843981 TI - Nitrate uptake and its regulation in relation to improving nitrogen use efficiency in cereals. AB - On average less than half of the applied N is captured by crops, thus there is scope and need to improve N uptake in cereals. With nitrate (NO3-) being the main form of N available to cereal crops there has been a significant global research effort to understand plant NO3- uptake. Despite this, our knowledge of the NO3- uptake system is not sufficient to easily target ways to improve NO3- uptake. Based on this there is an identified need to better understand the NO3- uptake system and the signalling molecules that modulate it. With strong transcriptional control governing the NO3- uptake system, we also need new leads for modulating transcription of NO3- transporter genes. PMID- 28843982 TI - Late Presentation of Popliteal Angiosarcoma After Previously Treated Popliteal Artery Aneurysm. PMID- 28843980 TI - ESCRT-dependent control of membrane remodelling during cell division. AB - The Endosomal Sorting Complex Required for Transport (ESCRT) proteins form an evolutionarily conserved membrane remodelling machinery. Identified originally for their role in cargo sorting and remodelling of endosomal membranes during yeast vacuolar sorting, an extensive body of work now implicates a sub-complex of this machinery (ESCRT-III), as a transplantable membrane fission machinery that is dispatched to various cellular locations to achieve a topologically unique membrane separation. Surprisingly, several ESCRT-III-regulated processes occur during cell division, when cells undergo a dramatic and co-ordinated remodelling of their membranes to allow the physical processes of division to occur. The ESCRT machinery functions in regeneration of the nuclear envelope during open mitosis and in the abscission phase of cytokinesis, where daughter cells are separated from each other in the last act of division. Roles for the ESCRT machinery in cell division are conserved as far back as Archaea, suggesting that the ancestral role of these proteins was as a membrane remodelling machinery that facilitated division and that was co-opted throughout evolution to perform a variety of other cell biological functions. Here, we will explore the function and regulation of the ESCRT machinery in cell division. PMID- 28843983 TI - Commentary on "Cryopreserved Cadaveric Arterial Allograft for Arterial Reconstruction in Patients with Prosthetic Graft Infection". PMID- 28843984 TI - Arteriovenous Fistulae for Haemodialysis: A Systematic Review and Meta-analysis of Efficacy and Safety Outcomes. AB - BACKGROUND: Arteriovenous fistulae are the currently recommended gold standard vascular access modality for haemodialysis because of their prolonged patency, improved durability, and low risk of infection for those that mature. However, notable disadvantages are observed in terms of protracted maturation time, associated high rates of catheter use, and substantial abandonment rates. The aim of this study was to quantitatively summarize the outcomes of fistula patency, infection, maturation, and abandonment published in the scientific literature. METHODS: This was a systematic review and meta-analyses of studies evaluating fistula outcomes. Literature searches were conducted in multiple databases to identify observational and interventional studies of mean fistula patency rates at 1 year, infection risk, maturation time, and abandonment. Digitisation software was used to simulate individual patient level data from Kaplan-Meier survival plots. RESULTS: Over 8000 studies were reviewed, and from these, 318 studies were included comprising 62,712 accesses. For fistulas the primary unassisted, primary assisted, and secondary patency rates at one year were 64%, 73% and 79% respectively, however not all fistulas reported as patent could be confirmed as being clinically useful for dialysis (i.e. functional patency). For fistulas that were reported as mature, mean time to maturation was 3.5 months, however only 26% of created fistulas were reported as mature at 6 months and 21% of fistulas were abandoned without use. Overall risk of infection in fistula patients was 4.1% and the overall rate per 100 access days was 0.018. CONCLUSIONS: Reported fistula patency rates may overstate their potential clinical utility when time to maturation, maturation rate, abandonment and infection are considered. Protracted maturation times, abandonment and infection all have a significant impact on evaluating the clinical utility of fistula creation. A rigorous and consistent set of outcomes definitions for hemodialysis access are necessary to clarify factors contributing to fistula success and the clinical consequence of fistula failure. PMID- 28843985 TI - Laparoscopic sleeve gastrectomy for diabetics - 5-year outcomes. AB - OBJECTIVE: Although the laparoscopic sleeve gastrectomy (SG) is increasingly performed for morbid obesity, gastric bypass is still considered by many to be the gold standard procedure for obese diabetic patients. The aim of this study was to assess the long-term results of SG in morbidly obese patients with type 2 diabetes. METHODS: Diabetic patients who underwent SG at a single center between 2009 and 2011 were included. Outcomes assessed included postoperative complications, weight loss, and resolution or improvement in co-morbidities with an emphasis on diabetes, including glycated hemoglobin (HbA1C) and medication status. RESULTS: Fifty-one diabetic patients underwent SG, 35 females and 16 males, with a collective mean age of 49 years and a mean body mass index of 43.2 kg/m2. On average, patients had had diabetes for 5.4 +/- 7.3 years before surgery. Mean HbA1C and fasting glucose levels were 7.9 +/- 1.6% and 166.9 +/- 63 mg/dL, respectively. Eleven patients (22%) were insulin dependent at the time of surgery. Average body mass index at a mean follow-up of 5 years after surgery was 34.4 +/- 5.8 kg/m2, with an average HbA1C of 6.6 +/- 1% and an average fasting glucose of 123 +/- 60 mg/dL. Only 3 patients remained insulin dependent. CONCLUSION: SG offers retainable weight loss results, accompanied by longstanding resolution or improvement of diabetes. Prospective, randomized controlled studies are warranted to better compare long-term outcomes between SG and gastric bypass. PMID- 28843986 TI - Bile acid physiology as the potential driver for the sustained metabolic improvements with bariatric surgery. PMID- 28843987 TI - Integrating disclosure support into family HIV care. PMID- 28843988 TI - The Amagugu intervention for disclosure of maternal HIV to uninfected primary school-aged children in South Africa: a randomised controlled trial. AB - BACKGROUND: Increasing populations of children who are HIV-exposed but uninfected will face the challenge of disclosure of parental HIV infection status. We aimed to test the efficacy of an intervention to increase maternal HIV-disclosure to primary school-aged HIV-uninfected children. METHODS: This randomised controlled trial was done at the Africa Health Research Institute in KwaZulu-Natal, South Africa. Women who had tested HIV positive at least 6 months prior, had initiated HIV treatment or been enrolled in pretreatment HIV care, and had an HIV uninfected child (aged 6-10 years) were randomly allocated to either the Amagugu intervention or enhanced standard of care, using a computerised algorithm based on simple randomisation and equal probabilities of being assigned to each group. Lay counsellors delivered the Amagugu intervention, which included six home-based counselling sessions of 1-2 h and materials and activities to support HIV disclosure and parent-led health promotion. The enhanced standard of care included one clinic-based counselling session. Outcome measures at 3 months, 6 months, and 9 months post baseline were done by follow-up assessors who were masked to participants' group and counsellor allocation. The primary outcome was maternal HIV disclosure (full [using the word HIV], partial [using the word virus], or none) at 9 months post baseline. We did the analysis in the intention to-treat population. This study is registered with ClinicalTrials.gov (NCT01922882). FINDINGS: Between July 1, 2013, and Dec 31, 2014, we randomly assigned 464 participants to the Amagugu intervention (n=235) or enhanced standard of care (n=229). 428 (92%) participants completed the 9 month assessment by Sept 3, 2015. Disclosure at any level was more common in the Amagugu intervention group (n=204 [87%]) than in the enhanced standard-of-care group (n=128 [56%]; adjusted odds ratio 9.88, 95% CI 5.55-17.57; p<0.0001). Full disclosure was also more common in the Amagugu intervention group (n=150 [64%]) than in the enhanced standard-of-care group (n=98 [43%]; 4.13, 2.80-6.11; p<0.0001). Treatment-unrelated adverse effects were reported for 17 participants in the Amagugu intervention group versus six in the enhanced standard-of-care group; adverse effects included domestic violence (five [2%] in the Amagugu intervention group vs one [<1%] in the enhanced standard-of-care group), sexual assault (four [2%] vs one [<1%]), participant illness or death (four [2%] vs four [2%]), and family member illness or death (four [2%] vs none). No treatment related deaths occurred. INTERPRETATION: The lay-counsellor-driven Amagugu intervention to aid parental disclosure has potential for wide-scale implementation after further effectiveness research and could be adapted to other target populations and other diseases. Further follow-up and effectiveness research is required. FUNDING: National Institutes of Health. PMID- 28843990 TI - Effect of diet and maternal education on allergies among preschool children: A case-control study. AB - INTRODUCTION: The prevalence of asthma and allergy has increased among children. This increase in prevalence might be related to dietary patterns. AIMS: The present epidemiological study investigated the relationship between the consumption of fruit, vegetables, nuts, meat and fish, and the prevalence of wheeze, asthma, and eczema among preschool children. METHODS: This nested case control study included 1489 children aged 4-6 years and residing in Kaunas city, Lithuania. The subjects were recruited to the KANC newborn cohort study during 2007-2009. Parents' responses to questionnaires were used to collect information on allergic diseases, diet, and other variables. The association between dietary patterns and children's allergic diseases were tested by using logistic regressions, after adjustment for maternal education level, smoking during pregnancy, parental asthma, children's sex, parity, and antibiotic usage during the first year of life. RESULTS: In this study, 83.3% of all children consumed fresh fruit and/or vegetables at least three times per week. A significantly lower adjusted odds ratio (aOR) of wheeze was found among children who ate fruit than among those who did not (aOR: 0.48; 95% CI: 0.22-0.96). The consumption of nuts was also associated with a lower 61% risk of eczema among 4-6 years old children. CONCLUSION: The results indicated a beneficial effect of a frequent consumption of fresh fruit and nuts on the prevalence of allergies among children. These results might have important implications for children's health. PMID- 28843989 TI - Distinct Mechanism Evolved for Mycobacterial RNA Polymerase and Topoisomerase I Protein-Protein Interaction. AB - We report here a distinct mechanism of interaction between topoisomerase I and RNA polymerase in Mycobacterium tuberculosis and Mycobacterium smegmatis that has evolved independently from the previously characterized interaction between bacterial topoisomerase I and RNA polymerase. Bacterial DNA topoisomerase I is responsible for preventing the hyper-negative supercoiling of genomic DNA. The association of topoisomerase I with RNA polymerase during transcription elongation could efficiently relieve transcription-driven negative supercoiling. Our results demonstrate a direct physical interaction between the C-terminal domains of topoisomerase I (TopoI-CTDs) and the beta' subunit of RNA polymerase of M. smegmatis in the absence of DNA. The TopoI-CTDs in mycobacteria are evolutionarily unrelated in amino acid sequence and three-dimensional structure to the TopoI-CTD found in the majority of bacterial species outside Actinobacteria, including Escherichia coli. The functional interaction between topoisomerase I and RNA polymerase has evolved independently in mycobacteria and E. coli, with distinctively different structural elements of TopoI-CTD utilized for this protein-protein interaction. Zinc ribbon motifs in E. coli TopoI-CTD are involved in the interaction with RNA polymerase. For M. smegmatis TopoI-CTD, a 27 amino-acid tail that is rich in basic residues at the C-terminal end is responsible for the interaction with RNA polymerase. Overexpression of recombinant TopoI-CTD in M. smegmatis competed with the endogenous topoisomerase I for protein-protein interactions with RNA polymerase. The TopoI-CTD overexpression resulted in decreased survival following treatment with antibiotics and hydrogen peroxide, supporting the importance of the protein protein interaction between topoisomerase I and RNA polymerase during stress response of mycobacteria. PMID- 28843991 TI - Imbalanced immune responses involving inflammatory molecules and immune-related pathways in the lung of acute and subchronic arsenic-exposed mice. AB - Inorganic arsenic has been claimed to increase the risk of pulmonary diseases through ingestion, as opposed to inhalation, which makes it a unique and intriguing environmental toxicant. However, the immunotoxic effects of lung, one of the targets of arsenic exposure, have not been extensively investigated in vivo. In the present study, we first confirmed that 2.5, 5 and 10mg/kg NaAsO2 orally for 24h dose-dependently triggered the infiltration of neutrophils, lymphocytes and macrophages in BALF. Not only the transcription activity, but also the secretion of proinflammatory cytokines IL-1beta, IL-6 and TNF-alpha were consistently raised in the lung and BALF of acute arsenic-exposed mice. Acute oral administration of NaAsO2 also raised pulmonary MPO activity and mRNA levels of chemokine Mip-2 and Mcp-1. Meanwhile, obvious histopathological damages with inflammatory cells infiltration and erythrocyte aggregation around the capillaries were verified in the lung of mice drank arsenic-rich water freely for 3 months. Furthermore, we affirmed notable disturbance of CD4+ T-cell differentiation in the lung of acute arsenic-exposed mice, as demonstrated by up regulated mRNA levels of regulator Gata3 and cytokine Il-4 of Th2, enhanced Foxp3 and Il-10 of Treg, down-regulated T-bet and Ifn-gamma of Th1, as well as lessened Ror-gammat and Il-23 of Th17. However, impressive elevation of cytokine Ifn-gamma and Il-23, as well as moderate enhancement of Il-4 and Il-10 were found in the lung by subchronic arsenic administration. Finally, our present study demonstrated that both a single and sustained arsenic exposure prominently increased the expression of immune-related p38, JNK, ERK1/2 and NF-kappaB proteins in the lung tissue. While disrupting the pulmonary redox homeostasis by increasing MDA levels, exhausting GSH and impaired enzyme activities of CAT and GSH-Px, antioxidant regulator NRF2 and its downstream targets HO-1 and GSTO1/2 were also up-regulated by both acute and subchronic arsenic treatment. Conclusively, our present study demonstrated both acute and subchronic oral administration of arsenic triggers multiple pulmonary immune responses involving inflammatory molecules and T-cell differentiation, which might be closely associated with the imbalanced redox status and activation of immune-related MAPKs, NF-kappaB and anti-inflammatory NRF2 pathways. PMID- 28843992 TI - Tracking MET de-addiction in lung cancer: A road towards the oncogenic target. AB - The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) asa group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype. Nevertheless, although different mechanisms eliciting the aberrant MET-associated oncogenic stimulus have been detected in lung cancer (such as gene amplification, increased gene copy number, mutations and MET/HGF overexpression), to date no clinically impactful results have been achieved with anti-MET tyrosine kinase inhibitors and monoclonal antibodies in the context of an unselected or MET enriched population. Recently, MET exon 14 splicing abnormalities have been identified asa potential oncogenic target in lung cancer, able to drive the activity of MET inhibitors in molecularly selected patients. In this paper, the major advancement and drawbacks of MET history in lung cancer are reviewed, underlying the renewed scientific euphoria related to the recent identification of MET exon 14 splicing variants asan actionable oncogenic target. PMID- 28843994 TI - NRG-1beta exerts neuroprotective effects against ischemia reperfusion-induced injury in rats through the JNK signaling pathway. AB - BACKGROUND: Neuregulin-1beta (NRG-1beta) has great potential to be developed into therapeutics for neuroprotection. The aim of the current study was to analyze the effects and possible signaling pathway of NRG-1beta on brain tissues in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). METHODS: In order to observe the protective effect of NRG-1beta on MCAO/R, the neurological deficit and infarct volume were measured using a modified neurological severity score (mNSS) test and by triphenyl tetrazolium chloride (TTC) staining. In order to detect the antagonistic effect of NRG-1beta on nerve cells and the blood-brain barrier (BBB), the morphology and structure of cortical brain tissues were observed by Evans Blue (EB) staining, hematoxylin-eosin (H&E) and Nissl staining, in situ cell death detection kit, and transmission electron microscopy (TEM). In order to investigate whether NRG-1beta exhibited a significant neuroprotective effect via the JNK signaling pathway, the activity of JNK and the levels of phospho-MKK4, phospho-JNK, pan-JNK and phospho-c-Jun were tested using a JNK activity screening kit, immunofluorescent labeling, and western blot analysis, respectively. RESULTS: In the NRG-1beta treatment group, accompanied with a decrease in JNK activity, the protein levels of phospho-JNK, phospho-MKK4 and phospho-c-Jun decreased, the ischemia-induced apoptosis decreased, the abnormal morphological structures of nerve cells were ameliorated, the integrity of the BBB was restored, and infarct volume was reduced. At the same time, neurological function was significantly recovered. CONCLUSION: NRG-1beta exerts a neuroprotective effect through the JNK signaling pathway in MCAO/R rats. PMID- 28843995 TI - What's left of the mirror illusion when the mirror can no longer be seen? Bilateral integration of proprioceptive afferents! AB - Recent data suggest that manipulating the muscle afferents of one arm affects both ipsilateral and contralateral perceptual estimates. Here, we used the mirror paradigm to study the bimanual integration of kinesthetic muscle afferents. The reflection of a moving hand in a mirror positioned in the sagittal plane creates an illusion of symmetrical bimanual movement. Although vision clearly has a role in kinesthesia, its role in the mirror illusion might have been overestimated. Conversely, the role of bimanual integration of muscle afferents might have been underestimated. We hypothesized that muscle-proprioceptive afferents of the passively displaced arm (the image of which was reflected in the mirror) are involved in this illusion. We evoked in 19 healthy adult participants the mirror illusion by displacing passively their left arm, the image of which was reflected in the mirror. Once participants experienced the illusion that their hidden right arm was moving, we then either occluded their view of the mirror (using occlusive glasses) and/or prevent the passive left arm displacement. Participants' illusion characteristics (duration and kinematic) under these conditions were compared with classical mirror illusion (without visual occlusion). We found that as long as the arm was still moving, the kinesthetic illusion decayed slowly after visual occlusion. These findings suggest that the mirror illusion results from the combination of visuo-proprioceptive signals from the two arms and is not purely visual in origin. Our findings also support the more general concept whereby proprioceptive afferents are integrated bilaterally for the purpose of kinesthesia during bimanual tasks. PMID- 28843996 TI - Neural correlates of visuo-tactile crossmodal paired-associate learning and memory in humans. AB - Studies have indicated that a cortical sensory system is capable of processing information from different sensory modalities. However, it still remains unclear when and how a cortical system integrates and retains information across sensory modalities during learning. Here we investigated the neural dynamics underlying crossmodal associations and memory by recording event-related potentials (ERPs) when human participants performed visuo-tactile (crossmodal) and visuo-visual (unimodal) paired-associate (PA) learning tasks. In a trial of the tasks, the participants were required to explore and learn the relationship (paired or non paired) between two successive stimuli. EEG recordings revealed dynamic ERP changes during participants' learning of paired-associations. Specifically, (1) the frontal N400 component showed learning-related changes in both unimodal and crossmodal tasks but did not show any significant difference between these two tasks, while the central P400 displayed both learning changes and task differences; (2) a late posterior negative slow wave (LPN) showed the learning effect only in the crossmodal task; (3) alpha-band oscillations appeared to be involved in crossmodal working memory. Additional behavioral experiments suggested that these ERP components were not relevant to the participants' familiarity with stimuli per se. Further, by shortening the delay length (from 1300ms to 400ms or 200 ms) between the first and second stimulus in the crossmodal task, declines in participants' task performance were observed accordingly. Taken together, these results provide insights into the cortical plasticity (induced by PA learning) of neural networks involved in crossmodal associations in working memory. PMID- 28843997 TI - Representation of tactile scenes in the rodent barrel cortex. AB - After half a century of research, the sensory features coded by neurons of the rodent barrel cortex remain poorly understood. Still, views of the sensory representation of whisker information are increasingly shifting from a labeled line representation of single-whisker deflections to a selectivity for specific elements of the complex statistics of the multi-whisker deflection patterns that take place during spontaneous rodent behavior - so called natural tactile scenes. Here we review the current knowledge regarding the coding of patterns of whisker stimuli by barrel cortex neurons, from responses to single-whisker deflections to the representation of complex tactile scenes. A number of multi-whisker tunings have already been identified, including center-surround feature extraction, angular tuning during edge-like multi-whisker deflections, and even tuning to specific statistical properties of the tactile scene such as the level of correlation across whiskers. However, a more general model of the representation of multi-whisker information in the barrel cortex is still missing. This is in part because of the lack of a human intuition regarding the perception emerging from a whisker system, but also because in contrast to other primary sensory cortices such as the visual cortex, the spatial feature selectivity of barrel cortex neurons rests on highly nonlinear interactions that remained hidden to classical receptive field approaches. PMID- 28843993 TI - Circuits in the rodent brainstem that control whisking in concert with other orofacial motor actions. AB - The world view of rodents is largely determined by sensation on two length scales. One is within the animal's peri-personal space; sensorimotor control on this scale involves active movements of the nose, tongue, head, and vibrissa, along with sniffing to determine olfactory clues. The second scale involves the detection of more distant space through vision and audition; these detection processes also impact repositioning of the head, eyes, and ears. Here we focus on orofacial motor actions, primarily vibrissa-based touch but including nose twitching, head bobbing, and licking, that control sensation at short, peri personal distances. The orofacial nuclei for control of the motor plants, as well as primary and secondary sensory nuclei associated with these motor actions, lie within the hindbrain. The current data support three themes: First, the position of the sensors is determined by the summation of two drive signals, i.e., a fast rhythmic component and an evolving orienting component. Second, the rhythmic component is coordinated across all orofacial motor actions and is phase-locked to sniffing as the animal explores. Reverse engineering reveals that the preBotzinger inspiratory complex provides the reset to the relevant premotor oscillators. Third, direct feedback from somatosensory trigeminal nuclei can rapidly alter motion of the sensors. This feedback is disynaptic and can be tuned by high-level inputs. A holistic model for the coordination of orofacial motor actions into behaviors will encompass feedback pathways through the midbrain and forebrain, as well as hindbrain areas. PMID- 28843998 TI - What the whiskers tell the brain. AB - A fundamental question in the investigation of any sensory system is what physical signals drive its sensory neurons during natural behavior. Surprisingly, in the whisker system, it is only recently that answers to this question have emerged. Here, we review the key developments, focussing mainly on the first stage of the ascending pathway - the primary whisker afferents (PWAs). We first consider a biomechanical framework, which describes the fundamental mechanical forces acting on the whiskers during active sensation. We then discuss technical progress that has allowed such mechanical variables to be estimated in awake, behaving animals. We discuss past electrophysiological evidence concerning how PWAs function and reinterpret it within the biomechanical framework. Finally, we consider recent studies of PWAs in awake, behaving animals and compare the results to related studies of the cortex. We argue that understanding 'what the whiskers tell the brain' sheds valuable light on the computational functions of downstream neural circuits, in particular, the barrel cortex. PMID- 28843999 TI - Predicting clinical symptoms of attention deficit hyperactivity disorder based on temporal patterns between and within intrinsic connectivity networks. AB - Attention deficit hyperactivity disorder (ADHD) is a common brain disorder with high prevalence in school-age children. Previously developed machine learning based methods have discriminated patients with ADHD from normal controls by providing label information of the disease for individuals. Inattention and impulsivity are the two most significant clinical symptoms of ADHD. However, predicting clinical symptoms (i.e., inattention and impulsivity) is a challenging task based on neuroimaging data. The goal of this study is twofold: to build predictive models for clinical symptoms of ADHD based on resting-state fMRI and to mine brain networks for predictive patterns of inattention and impulsivity. To achieve this goal, a cohort of 74 boys with ADHD and a cohort of 69 age-matched normal controls were recruited from the ADHD-200 Consortium. Both structural and resting-state fMRI images were obtained for each participant. Temporal patterns between and within intrinsic connectivity networks (ICNs) were applied as raw features in the predictive models. Specifically, sample entropy was taken asan intra-ICN feature, and phase synchronization (PS) was used asan inter-ICN feature. The predictive models were based on the least absolute shrinkage and selectionator operator (LASSO) algorithm. The performance of the predictive model for inattention is r=0.79 (p<10-8), and the performance of the predictive model for impulsivity is r=0.48 (p<10-8). The ICN-related predictive patterns may provide valuable information for investigating the brain network mechanisms of ADHD. In summary, the predictive models for clinical symptoms could be beneficial for personalizing ADHD medications. PMID- 28844000 TI - Epigallocatechin gallate induces extracellular degradation of amyloid beta protein by increasing neprilysin secretion from astrocytes through activation of ERK and PI3K pathways. AB - Amyloid-beta (Abeta) production and clearance in the brain is a crucial focus of investigations into the pathogenesis of Alzheimer disease. Imbalance between production and clearance leads to accumulation of Abeta. The important Abeta degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), and defective enzyme expression may facilitate Abeta deposition in sporadic late-onset AD patients. It has been suggested that epigallocatechin gallate (EGCG), a member of the catechin family, might be an effective treatment for AD, because it has been shown to elevate NEP expression. Therefore, we examined whether catechins, which are functional components of common foods, could regulate the degradation of Abeta by inducing NEP and IDE expression. We also investigated the role of catechins in activating intracellular signal transduction in astrocytes. Treatment of cultured rat astrocytes with EGCG significantly reduced the expression of NEP, but not IDE, in a concentration- and time-dependent manner. NEP expression in cultured astrocytes was suppressed by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3 kinase (PI3K), and reduced NEP expression was accompanied by an increase of NEP release into the extracellular space (culture medium). Moreover, culture medium from EGCG-treated astrocytes facilitated the degradation of exogenous Abeta. These results suggest that EGCG may have a beneficial effect on AD by activating ERK-and PI3K-mediated pathways in astrocytes, thus increasing astrocyte secretion of NEP and facilitating degradation of Abeta. PMID- 28844001 TI - Activation of 5-HT2A Receptors Restores KCC2 Function and Reduces Neuropathic Pain after Spinal Cord Injury. AB - Downregulation of the potassium chloride cotransporter type 2 (KCC2) after a spinal cord injury (SCI) disinhibits motoneurons and dorsal horn interneurons causing spasticity and neuropathic pain, respectively. We showed recently (Bos et al., 2013) that specific activation of 5-HT2A receptors by TCB-2 [(4-bromo-3,6 dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide] upregulates KCC2 function, restores motoneuronal inhibition and reduces SCI-induced spasticity. Here, we tested the potential analgesic effect of TCB-2 on central (thoracic hemisection) and peripheral [spared nerve injury (SNI)] neuropathic pain. We found mechanical and thermal hyperalgesia reduced by an acute administration of TCB-2 in rats with SCI. This analgesic effect was associated with an increase in dorsal horn membrane KCC2 expression and was prevented by pharmacological blockade of KCC2 with an intrathecal injection of DIOA [(dihydroindenyl)oxy]alkanoic acid]. In contrast, the SNI-induced neuropathic pain was not attenuated by TCB-2 although there was a slight increase of membrane KCC2 expression in the dorsal horn ipsilateral to the lesion. Up-regulation of KCC2 function by targeting 5-HT2A receptors, therefore, has therapeutic potential in the treatment of neuropathic pain induced by SCI but not by SNI. PMID- 28844002 TI - Expression of Ski and its role in astrocyte proliferation and migration. AB - Ski, as an evolutionarily conserved protein, is a versatile transcriptional regulator which widely distributes in various tissues and species. Recently, we have demonstrated for the first time that Ski was strikingly up-regulated in reactive astrocytes after spinal cord injury (SCI) in vivo, which indicates that maybe Ski is a new molecule that controls astrocytes' biological properties after SCI. However, the accurate distributions and functions of Ski in astrocytes after central nervous system (CNS) injury are still unclear. Astrocytes were collected from rats' cerebral cortex. To elucidate the expression and role of Ski in reactive astrocytes, we performed an activated astrocytes model induced by LPS and scratch injury in vitro. Our results showed that Ski gradually increased and reached a peak at 4days, then declined at 6days after induction by LPS. Up regulation of Ski was accompanied with the increase in proliferation-related proteins including PCNA, CDK4 and CyclinD1. Furthermore, immunofluorescent staining analysis also demonstrated a highly positive relationship between Ski and GFAP, PCNA in astrocytes. These results indicated that Ski might play an important role in astrocyte proliferation. To further explore the role of Ski, astrocytes were transfected with Ski-specific small interfering RNA (siRNA). We found that the primary activated astrocytes' proliferation decreased significantly after transfection with Ski-specific siRNA. Surprisingly, Ski knockdown also weakened the primary astrocyte migration. Based on the above, we could conclude that Ski might play a crucial role in astrocyte proliferation and migration. This discovery might contribute to a promising therapeutic intervention in CNS injury. PMID- 28844003 TI - The Effect of Contact Force on the Responses of Tactile Nerve Fibers to Scanned Textures. AB - The perception of fine textures relies on highly precise and repeatable spiking patterns evoked in tactile afferents. These patterns have been shown to depend not only on the surface microstructure and material but also on the speed at which it moves across the skin. Interestingly, the perception of texture is independent of scanning speed, implying the existence of downstream neural mechanisms that correct for scanning speed in interpreting texture signals from the periphery. What force is applied during texture exploration also has negligible effects on how the surface is perceived, but the consequences of changes in contact force on the neural responses to texture have not been described. In the present study, we measure the signals evoked in tactile afferents of macaques to a diverse set of textures scanned across the skin at two different contact forces and find that responses are largely independent of contact force over the range tested. We conclude that the force invariance of texture perception reflects the force independence of texture representations in the nerve. PMID- 28844004 TI - Altered intrinsic and synaptic properties of lumbosacral dorsal horn neurons in a mouse model of colitis. AB - Visceral pain in inflammatory and functional gastrointestinal conditions is a major clinical problem. The exact mechanisms underlying the development of pain, during and after visceral inflammation are unknown. However, clinical and pre clinical evidence suggests plasticity within the spinal cord dorsal horn is a contributing factor. Here we use an in vivo preparation and patch-clamp electrophysiology to test whether the synaptic and intrinsic properties of superficial dorsal horn (SDH) neurons are altered 5days after the induction of mild colitis in adult male mice (i.e. during acute inflammation of the colon). Whole-cell recordings were made from lumbosacral (L6-S1) superficial dorsal horn neurons (SDH), in animals under isoflurane anesthesia. Noxious colorectal distension (CRD) was used to identify SDH neurons with colonic inputs, while stimulation of the hind paw and tail was employed to assess convergent cutaneous input. Following inflammation, a significantly increased proportion of SDH neurons received both colonic and cutaneous inputs, compared to neurons in naive animals. In addition, the nature and magnitude of responses to CRD and cutaneous stimulation differed in inflamed animals, as was spontaneous excitatory synaptic drive. Conversely, several measures of intrinsic excitability were altered in a manner that would decrease SDH network excitability following colitis. We propose that during inflammation, sensitization of colonic afferents results in increased signaling to the SDH. This is accompanied by plasticity in SDH neurons whereby their intrinsic properties are changed to compensate for altered afferent activity. PMID- 28844005 TI - Synaptic potentiation mediated by L-type voltage-dependent calcium channels mediates the antidepressive effects of lateral habenula stimulation. AB - Although deep-brain stimulation (DBS) of the lateral habenula (LHb) has been successfully applied to treatment-resistant depression for years, the mechanism is still unclear. Previous researches have demonstrated that LHb-DBS elevates brain monoamine neurotransmitters. However, these changes do not account for the treatment efficacy on treatment-resistant depression, or the rapid behavioral effects in rats; the evidence suggests that altered synaptic potentiation may contribute to the treatment effects. We applied LHb-DBS in a rat model of learned helplessness (LH) and analyzed mammalian target of rapamycin (mTOR) phosphorylation. We also assessed related electrophysiological changes after LHb DBS in vitro. LHb-DBS reversed depression-like behaviors in sucrose preference and forced swim tests in rats with LH. Additionally, mTOR phosphorylation significantly increased and field population excitatory postsynaptic potentials increased in the hippocampus. These effects were blocked by the L-type voltage dependent calcium channel (L-VDCC) antagonist, nifedipine. Furthermore, in vitro LHb-DBS increased both the frequency and width of spontaneous spikes generated by CA1 pyramidal neurons, which contribute to Ca2+ influx through L-VDCC. Our findings suggest that L-VDCC-mediated synaptic potentiation underlies the antidepressant effects of LHb-DBS, and suggest that astrocytic regulation of Ca2+ influx and associated synaptic changes maybe novel targets for developing antidepressant treatments. PMID- 28844006 TI - Tau45-230 association with the cytoskeleton and membrane-bound organelles: Functional implications in neurodegeneration. AB - The dysregulation of posttranslational modifications of the microtubule associated protein (MAP) tau plays a key role in Alzheimer's disease (AD) and related disorders. Thus, we have previously shown that beta amyloid (Abeta) induced neurotoxicity was mediated, at least in part, by tau cleavage into the tau45-230 fragment. However, the mechanisms underlying the toxicity of tau45-230 remain unknown. To get insights into such mechanisms, we first determined the subcellular localization of this tau fragment in hippocampal neurons. Tau45-230 was easily detectable in cell bodies and processes extended by these neurons. In addition, cell extraction experiments performed using Triton X-100 and saponin showed that a pool of tau45-230 was associated with the cytoskeleton and the cytoskeleton plus membrane-bound organelles, respectively, in cultured hippocampal neurons. Furthermore, they suggested that these associations were independent of the presence of full-length tau. We also assessed whether this tau fragment could alter axonal transport. Our results indicated that tau45-230 significantly reduced the number of organelles transported along hippocampal axons. This altered axonal transport did not correlate with changes in the total number of organelles present in these cells or in motor protein levels. Together these results suggested that tau45-230 could exert its toxic effects by partially blocking axonal transport along microtubules thus contributing to the early pathology of AD. PMID- 28844007 TI - Striatal activity during reactive inhibition is related to the expectation of stop-signals. AB - Successful response inhibition relies on the suppression of motor cortex activity. The striatum has previously been linked to motor cortex suppression during the act of inhibition (reactive), but activation was also seen during anticipation of stop signals (proactive). More specifically, striatal activation increased with a higher stop probability. Using functional magnetic resonance imaging with specific regions of interest, we investigate for the first time whether activation in the striatum during reactive inhibition is related to previously formed expectations. We used a modified stop-signal response task in which subjects were asked trial by trial, after being presented a stop-signal probability cue, whether they actually expected a stop to occur. This enabled us to investigate the subjective expectation of a stop signal during each trial. We found that striatal activity during reactive inhibition was higher when subjects expected stop signals. These results help explain conflicting findings of previous studies on the association between striatal activation and inhibition, since we demonstrate a crucial role of the subjects' expectation of a stop signal and thus their ability to prepare for a stop in advance. In conclusion, the current results show for the first time that striatal contributions to reactive response inhibition are, in part, related to subjective anticipation. PMID- 28844008 TI - Delay discounting is predicted by scale-free dynamics of default mode network and salience network. AB - Resting-state functional Magnetic Resonance Imaging (rs-fMRI) is frequently used as a powerful technology to detect individual differences in many cognitive functions. Recently, some studies have explored the association between scale free dynamic properties of resting-state brain activation and individual personality traits. However, little is known about whether the scale-free dynamics of resting-state function networks is associated with delay discounting. To address this question, we calculated the Hurst exponent which quantifies long term memory of the time series in resting-state networks (RSNs) identified via independent component analysis (ICA) and examined what relationship between delay discounting and the Hurst exponent of RSNs is. ICA results showed that entire nine RSNs were successfully recognized and extracted from independent components. After controlling some covariates, including gender, age, education, personality and trait anxiety, partial correlation analysis revealed that the Hurst exponent in default mode network (DMN) and salience network (SN) was positively correlated with the delay discounting rates. No significant correlation between delay discounting and mean Hurst exponent of the whole brain was found. Thus, our results suggest the individual delay discounting is associated with the dynamics of inner-network interactions in the DMN and SN, and highlight the crucial role of scale-free dynamic properties of function networks on intertemporal choice. PMID- 28844009 TI - Anatomical and electrophysiological characterization of a population of dI6 interneurons in the neonatal mouse spinal cord. AB - The locomotor central pattern generator is a neural network located in the ventral aspect of the caudal spinal cord that underlies stepping in mammals. While many genetically defined interneurons that are thought to comprise this neural network have been identified and characterized, the dI6 cells- which express the transcription factors WT1 and/or DMRT3- are one population that settle in this region, are active during locomotion, whose function is poorly understood. These cells were originally hypothesized to be commissural premotor interneurons, however evidence in support of this is sparse. Here we characterize this population of cells using the TgDbx1Cre;R26EFP;Dbx1LacZ transgenic mouse line, which has been shown to be an effective marker of dI6 interneurons. We show dI6 cells to be abundant in laminae VII and VIII along the entire spinal cord and provide evidence that subtypes outside the WT1/DMRT3 expressing dI6 cells may exist. Retrograde tracing experiments indicate that the majority of dI6 cells project descending axons, and some make monosynaptic or disynaptic contacts onto motoneurons on either side of the spinal cord. Analysis of their activity during non-resetting deletions, which occur during bouts of fictive locomotion, suggests that these cells are involved in both locomotor rhythm generation and pattern formation. This study provides a thorough characterization of the dI6 cells labeled in the TgDbx1Cre;R26EFP;Dbx1LacZ transgenic mouse, and supports previous work suggesting that these cells play multiple roles during locomotor activity. PMID- 28844010 TI - Multimodal sensor-based weight drop spinal cord impact system for large animals. AB - BACKGROUND CONTEXT: A conventional weight drop spinal cord (SC) impact system for large animals is composed of a high-speed video camera, a vision system, and other things. However, a camera with high speed at over 5,000 frames per second (FPS) is very expensive. In addition, the use of the vision system involves complex pattern recognition algorithms and accurate arrangement of the camera and the target. PURPOSE: The purpose of this study was to develop a large animal spinal cord injury (SCI) modeling system using a multimodal sensor instead of a high-speed video camera and vision system. Another objective of this study was to demonstrate the possibility of the developed system to measure the impact parameters in the experiments using different stiffness materials and an in vivo porcine SC. STUDY DESIGN: A multimodal sensor-based SCI impact system was developed for large animals. The experiments to measure SC impact parameters were then performed using three different stiffness materials and a Yucatan miniature pig to verify the performance of system developed. METHODS: A comparative experiment was performed using three different stiffness materials such as high density (HD) sponge, rubber, and clay to demonstrate the system and perform measurement for impact parameters such as impact velocity, impulsive force, and maximally compressed displacement reflecting physical properties of materials. In the animal experiment, a female Yucatan miniature pig of 60-kg weight was used. Impact conditions for all experiments were fixed at freefalling object mass of 50 g and height of 20 cm. RESULTS: In the impact test, measured impact velocities were almost the same for the three different stiffness materials at 1.84+/-0.0153 m/s. Impulsive forces for the three materials of rubber, HD sponge, and clay were 50.88 N, 32.35 N, and 6.68 N, respectively. Maximally compressed displacements for rubber, HD sponge, and clay were 1.93 mm, 3.35 mm, and 15.01 mm, respectively. In the pig experiment, impact velocity, impulsive force, and maximally compressed dural displacement were measured at 1.84 m/s, 13.35 N, and 3.04 mm, respectively. After 3 days from the experiment, paralysis was confirmed for the lower half body of the experimental pig. CONCLUSIONS: Through experiments, it was verified that our proposed system could be used to measure the SC impact parameters and induce SCI for large animals. PMID- 28844011 TI - The pharmacokinetics of racemic MDPV and its (R) and (S) enantiomers in female and male rats. AB - BACKGROUND: These studies investigated the serum pharmacokinetic (PK) profile of racemic (3,4)-methylenedioxypyrovalerone [(R,S)-MDPV)] and its (R)- and (S) enantiomers in female and male Sprague Dawley rats. METHODS: Intravenous (R,S) MDPV (3 and 5.6mg/kg) and single enantiomer of (R)- and (S)-MDPV (1.5mg/kg) were administered to both sexes for PK studies. Intraperitoneal (ip) bioavailability was determined at 3mg/kg (R,S)-MDPV. Locomotor activity studies were conducted after ip treatment with saline and 0.3-5.6mg/kg of (R,S)-MDPV. RESULTS: PK values after iv (R,S)-MDPV showed a significant (p<0.05) sex-dependent differences in the volume of distribution at steady state (Vdss) for (R)- and (R,S)-MDPV at both (R,S)-MDPV doses. The female S/R enantiomeric ratios for area under the concentration time curve (AUCinf) and clearance were significantly lower and higher, respectively, than values determined in males. Importantly, there was no evidence of in vivo inversion of (R)-MDPV or (S)-MDPV to its antipode. There were, however, significant sex-dependent differences in volume of distribution after administration of the (R)-enantiomer. Bioavailability studies of ip (R,S) MDPV showed greater variability and significantly greater bioavailability in male rats. Accordingly, there was a significantly greater maximal distance traveled measurement in male rats at a 3.0mg/kg dose. CONCLUSION: PK sex differences in (R,S)-MDPV and enantiomers were most apparent in volume of distribution, which could be caused by differences in drug blood and tissue protein binding. The increased magnitude and variance in ip bioavailability in male compared to female rats could lead to sex-dependent differences in the pharmacological action caused by active enantiomer (S)-MDPV. PMID- 28844013 TI - Abuse liability of intravenous buprenorphine vs. buprenorphine/naloxone: Importance of absolute naloxone amount. AB - BACKGROUND: This study sought to determine the relative importance of a range of Bup/Nx doses compared to Bup alone in producing subjective and reinforcing effects. METHODS: Heroin-using volunteers (n=13) were transitioned onto daily oral hydromorphone (40mg). Laboratory sessions assessed the reinforcing and subjective effects of intravenous (IV) doses of Bup (1.51, 2.16, 6.15, and 8.64mg) and Bup/Nx (1.51/0.44, 2.16/0.61, 6.15/1.71, and 8.64/2.44mg). Placebo (Pbo), heroin (25mg) and Nx (0.3mg) were tested as neutral, positive, and negative controls, respectively. RESULTS: IV Bup alone was self-administered substantially less than IV heroin, though the two largest doses of Bup produced positive subjective effects, drug "Liking" (0-100mm), which were comparable to heroin (mean difference: Heroin vs Bup 6.15mg: -3.4mm, Heroin vs Bup 8.64mg: 11.3mm). All indicators of abuse potential seen with IV Bup alone were substantially decreased with the addition of Nx. All Bup/Nx combinations produced ratings of aversive effects, "Bad", which were comparable to, or greater than IV, Nx. On three of the four measures of aversive effects, the largest difference is seen with the 8.64 vs 8.64/2.44 condition. CONCLUSIONS: This study further demonstrates the ability of the Bup/Nx combination to deter IV use. Although none of the Bup/Nx combinations showed indications of abuse potential, formulations with larger absolute Nx, may be less abusable as they precipitate a greater degree of withdrawal. PMID- 28844012 TI - Smoking-related outcomes and associations with tobacco-free policy in addiction treatment, 2015-2016. AB - OBJECTIVE: This study assessed changes in smoking-related outcomes in two cross sectional samples of clients enrolled in addiction treatment and whether tobacco free grounds policies were associated with smoking-related outcomes. METHOD: Clients in 25 programs were surveyed in 2015 (N=1176) and 2016 (N=1055). The samples were compared on smoking prevalence, cigarettes per day (CPD), thinking of quitting, past year quit attempts, staff and clients smoking together, attitudes towards quitting, and tobacco-related services. Second, programs with (n=6) and without (n=17) tobacco-free grounds at both time points were compared on smoking-related outcomes. Last, we examined changes in these measures for two programs that adopted tobacco-free grounds between 2015 and 2016. RESULTS: There was one difference across years, such that the mean score for the tobacco Program Service scale increased from 2.37 to 2.48 (p=0.043, effect size=0.02). In programs with tobacco-free grounds policies, compared to those without, both CPD and the rate of staff and clients smoking together were significantly lower. In the two programs where tobacco-free grounds were implemented during study years, client smoking prevalence decreased (92.5% v. 67.6%, p=0.005), the rate of staff and clients smoking together decreased (35.6% v. 4.2%, p=0.031), mean CPD decreased (10.62v. 8.24, p<0.001) and mean tobacco services received by clients increased (2.08v. 3.05, p<0.001). CONCLUSION: Addiction treatment programs, and agencies responsible for licensing, regulating and funding these programs, should implement tobacco-free grounds policies. PMID- 28844014 TI - Changes in smoking status among a longitudinal cohort of gay, bisexual, and other men who have sex with men in Vancouver, Canada. AB - BACKGROUND: Cigarette smoking is common among gay, bisexual, and other men who have sex with men (GBMSM) and most of the mortality gap between HIV-positive and HIV-negative individuals is attributable to smoking. METHODS: We recruited sexually active HIV-positive and HIV-negative GBMSM age >=16 years using respondent-driven sampling. Study visits occurred every six months for up to four years and included a computer-assisted self-interview and clinical assessment. We conducted bivariate analyses to compare factors associated with "never", "former", "daily", or "non-daily" smoking at baseline and longitudinal mixed effects models to examine factors associated with cessation and (re)initiation. RESULTS: 774 participants completed a baseline visit and 525 enrolled in the cohort and completed at least one follow-up visit. At baseline, the median age was 34 years and 31.5% were daily smokers. In follow-up (median=2.5years), 116 daily or non-daily smokers (41%) quit at least once and of these, 101 (87%) remained former smokers at their last visit. Smoking cessation was positively associated with incomes >=$60,000 and self-reported excellent health. Alcohol use, ecstasy use, and having a partner who smokes were associated with decreased odds of cessation. Substance use (cannabis, GHB, and crystal methamphetamine) and having a partner who smokes were positively associated with increasing to/resuming daily smoking. HIV-positive GBMSM were more likely to smoke but not more likely to quit. CONCLUSIONS: Targeted, culturally relevant smoking cessation resources are needed, especially for HIV-positive GBMSM. Engaging couples in cessation interventions may be useful. PMID- 28844015 TI - Impact of gene-expression profiling in patients with early breast cancer when applied outside the guideline directed indication area. AB - PURPOSE: In Dutch guidelines, gene expression profiles (GEP) are indicated in estrogen receptor positive early breast cancer patients in whom benefit of chemotherapy (CT) is uncertain based on traditional prognostic factors alone. Aim of the present study is to assess the use and impact of GEP on administration of adjuvant CT in breast cancer patients who have according to national guidelines a clear indication to either use or withhold adjuvant chemotherapy (clinical high or low risk). METHODS: Clinical low- and high-risk patients, according to Dutch breast cancer guidelines, diagnosed between 2011 and 2014 were selected from the Netherlands Cancer Registry. Influence of GEP use and GEP test result on CT administration was assessed with logistic regression. RESULTS: Overall, 26,425 patients were identified; 4.8% of patients with clinical low risk (444/9354), 7.5% of the patients with a clinical high risk (1281/17,071) received a GEP. GEP use was associated with significantly increased odds of CT administration in clinical low-risk patients (OR = 2.12 95% CI: 1.44-3.11). In clinical high-risk patients, GEP use was associated with a decreased frequency of CT administration (OR = 0.55, 95% CI: 0.48-0.63). Adherence to the GEP result was higher in clinical high-risk patients with a discordant GEP result as compared to clinical low-risk patients with a discordant GEP result: 71.7% vs. 52.2%, respectively. CONCLUSION: GEP is frequently used outside the indicated area and significantly influenced the administration of adjuvant CT, although adherence to the test result was limited. PMID- 28844016 TI - Breast cancer in young women and prognosis: How important are proliferation markers? AB - AIM: Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis. METHODS: Distant disease-free survival (DDFS) was studied in 504 women aged <40 years and 383 women aged >=40 years from a population-based cohort. Information on patient characteristics, treatment and follow-up was collected from medical records. Tissue microarrays were produced for analysis of oestrogen receptor, progesterone receptor (PR), Her2, Ki-67 and cyclins. RESULTS: Young women with luminal tumours had significantly higher expression of Ki-67 and cyclins. Proliferation markers were prognostic only within this subtype. Ki-67 was a prognostic indicator only in young women with luminal PR+ tumours. The optimal cut-off for Ki-67 varied by age. High expression of cyclin E1 conferred a better DDFS in women aged <40 years with luminal PR- tumours (hazard ratio [HR] 0.47 [0.24-0.92]). Age <40 years was an independent risk factor of DDFS exclusively in women with luminal B PR+ tumours (HR 2.35 [1.22-4.50]). Young women with luminal B PR- tumours expressing low cyclin E1 had a six-fold risk of distant disease compared with luminal A (HR 6.21 [2.17-17.6]). CONCLUSIONS: The higher expression of proliferation markers in young women does not have a strong impact on prognosis. Ki-67 is only prognostic in the subgroup of young women with luminal PR+ tumours. The only cyclin adding prognostic value beyond subtype is cyclin E1. Age is an independent prognostic factor only in women with luminal B PR+ tumours. PMID- 28844017 TI - Assessment of Response of Kidney Tumors to Rapamycin and Atorvastatin in Tsc1+/- Mice. AB - Atorvastatin is widely used to lower blood cholesterol and to reduce risk of cardiovascular disease-associated complications. Epidemiological investigations and preclinical studies suggest that statins such as atorvastatin have antitumor activity for various types of cancer. Tuberous sclerosis (TSC) is a tumor syndrome caused by TSC1 or TSC2 mutations that lead to aberrant activation of mTOR and tumor formation in multiple organs. Previous studies have demonstrated that atorvastatin selectively suppressed growth and proliferation of mouse Tsc2 null embryonic fibroblasts through inhibition of mTOR. However, atorvastatin alone did not reduce tumor burden in the liver and kidneys of Tsc2+/- mice as assessed by histological analysis, and no combination therapy of rapamycin and atorvastatin has been tried. In this study, we used T2-weighted magnetic resonance imaging to track changes in tumor number and size in the kidneys of a Tsc1+/- mouse model and to assess the efficacy of rapamycin and atorvastatin alone and as a combination therapy. We found that rapamycin alone or rapamycin combined with atorvastatin significantly reduced tumor burden, while atorvastatin alone did not. Combined therapy with rapamycin and atorvastatin appeared to be more effective for treating renal tumors than rapamycin alone, but the difference was not statistically significant. We conclude that combined therapy with rapamycin and atorvastatin is unlikely to provide additional benefit over rapamycin as a single agent in the treatment of Tsc-associated renal tumors. PMID- 28844018 TI - Induction Chemotherapy Has No Prognostic Value in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Chronic Hepatitis B Infection in the IMRT Era. AB - BACKGROUND: The effectiveness of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) over CCRT alone in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and chronic hepatitis B infection in the intensity-modulated radiotherapy (IMRT) era is unknown. PATIENTS AND METHODS: A total of 249 patients with stage T1-2 N2-3 or T3-4 N1-3 NPC and chronic hepatitis B infection treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) was employed to balance covariates; 140 patients were propensity-matched (1:1 basis). Survival outcomes in the IC+CCRT and CCRT groups were compared using the Kaplan-Meier method, log-rank test and Cox proportional hazards model. RESULTS: No significant survival differences were observed between IC+CCRT and CCRT (5-year overall survival, 88.3% vs. 82.2%; P=.484; disease-free survival, 73.9% vs. 75.2%; P=.643; distant metastasis-free survival, 84.1% vs. 85.1%; P=.781; and locoregional failure-free survival, 87.9% vs. 85.1%; P=.834). After adjusting for known prognostic factors in multivariate analysis, IC was not an independent prognostic factor for any outcome (all P>.05); subgroup analysis based on T category (T1-2/T3-4), N category (N0-1/N2 3), and overall stage (III/IV) confirmed these results. The incidence of hepatic function damage in the IC+CCRT and CCRT groups was not significantly different. CONCLUSION: IC+CCRT leads to comparable survival outcomes and hepatic function damage compared to CCRT alone in patients with locoregionally advanced NPC with chronic hepatitis B infection in the IMRT era. Further investigations are warranted. PMID- 28844019 TI - The Functional Roles of the MDM2 Splice Variants P2-MDM2-10 and MDM2-?5 in Breast Cancer Cells. AB - BACKGROUND: MDM2 is a negative regulator of p53 and is upregulated in numerous human cancers. While different MDM2 splice variants have been observed in both normal tissues and malignant cells, their functions are poorly understood. METHODS: We evaluated the effect of MDM2 splice variants by overexpression in MCF 7 cells and analyses of expression of downstream genes (qPCR and Western blot), subcellular localization (immunofluorescence), cell cycle assays (Nucleocounter3000), apoptosis analysis (Annexin V detection), and induction of senescence (beta-galactosidase analysis). RESULTS: In a screen for MDM2 splice variants in MCF-7 breast cancer cells, extended with data from healthy leukocytes, we found P2-MDM2-10 and MDM2-Delta5 to be the splice variants expressed at highest levels. Contrasting MDM2 full-length protein, we found normal tissue expression levels of P2-MDM2-10 and MDM2-Delta5 to be highest in individuals harboring the promoter SNP309TT genotype. While we detected no protein product coded for by MDM2-Delta5, the P2-MDM2-10 variant generated a protein markedly more stable than MDM2-FL. Both splice variants were significantly upregulated in stressed cells (P=4.3 * 10-4 and P=7.1 * 10-4, respectively). Notably, chemotherapy treatment and overexpression of P2-MDM2-10 or MDM2-Delta5 both lead to increased mRNA levels of the endogenous MDM2-FL (P=.039 and P=.070, respectively) but also the proapoptotic gene PUMA (P=.010 and P=.033, respectively), accompanied by induction of apoptosis and repression of senescence. CONCLUSION: We found P2-MDM2-10 and MDM2-Delta5 to have distinct biological functions in breast cancer cells. GENERAL SIGNIFICANCE: Alternative splicing may influence the oncogenic effects of the MDM2 gene. PMID- 28844020 TI - Biocomputational identification and validation of novel microRNAs predicted from bubaline whole genome shotgun sequences. AB - MicroRNAs (miRNAs) are small (19-25 base long), non-coding RNAs that regulate post-transcriptional gene expression by cleaving targeted mRNAs in several eukaryotes. The miRNAs play vital roles in multiple biological and metabolic processes, including developmental timing, signal transduction, cell maintenance and differentiation, diseases and cancers. Experimental identification of microRNAs is expensive and lab-intensive. Alternatively, computational approaches for predicting putative miRNAs from genomic or exomic sequences rely on features of miRNAs viz. secondary structures, sequence conservation, minimum free energy index (MFEI) etc. To date, not a single miRNA has been identified in bubaline (Bubalus bubalis), which is an economically important livestock. The present study aims at predicting the putative miRNAs of buffalo using comparative computational approach from buffalo whole genome shotgun sequencing data (INSDC: AWWX00000000.1). The sequences were blasted against the known mammalian miRNA. The obtained miRNAs were then passed through a series of filtration criteria to obtain the set of predicted (putative and novel) bubaline miRNA. Eight miRNAs were selected based on lowest E-value and validated by real time PCR (SYBR green chemistry) using RNU6 as endogenous control. The results from different trails of real time PCR shows that out of selected 8 miRNAs, only 2 (hsa-miR-1277-5p; bta miR-2285b) are not expressed in bubaline PBMCs. The potential target genes based on their sequence complementarities were then predicted using miRanda. This work is the first report on prediction of bubaline miRNA from whole genome sequencing data followed by experimental validation. The finding could pave the way to future studies in economically important traits in buffalo. PMID- 28844021 TI - TLR2, TLR3 and TLR5 regulation of pro-inflammatory and pro-labour mediators in human primary myometrial cells. AB - Preterm birth continues to be a significant global health care issue, due to our lack of understanding of the mechanisms that drive human labour and delivery. Toll-like receptors (TLRs) are essential in triggering an inflammatory response in human gestational tissues, leading to the production of pro-inflammatory and pro-labour mediators, and thus preterm birth. The aims of this study were to determine whether the adaptor molecules associated with TLR2, TLR3 and TLR5 signalling are involved in human myometrium. Primary human myometrial cells were transfected with siRNA against TIRAP, IRAK1, IRAK4, TAK1and stimulated with bacterial product fsl-1 (TLR2); TRIF, TRADD, TRAF6, RIP1, TAK1 and stimulated with dsRNA viral analogue poly(I:C) (TLR3); IRAK1, IRAK4, TAK1 and stimulated with bacterial product flagellin (TLR5), and assayed for production of pro inflammatory and pro-labour mediators. Cells transfected with TIRAP, IRAK1, IRAK4 or TAK1 all showed a decrease in fsl-1-induced expression of cytokines (IL 1alpha, IL-1beta, IL-6), chemokines (GRO-alpha, IL-8, MCP-1), adhesion molecule ICAM-1, cyclooxygenase (COX)-2 mRNA and release of PGF2alpha and MMP-9 expression. Cells transfected with TRIF, TRAF6, RIP1 or TAK1 all decreased production of poly(I:C)-induced IL-1alpha, IL-1beta, IL-6, GRO-alpha, IL-8, MCP 1, ICAM-1 and MMP-9 expression. Cells transfected with IRAK1, IRAK4 or TAK1 all showed decreased expression of flagellin-induced cytokine and chemokine expression, ICAM-1 and MMP-9 expression. Lastly, transfection with these siRNAs decreased fsl-1, poly(I:C) and flagellin-induced NF-kappaB transcriptional activity. Our study signifies that these adaptor molecules are necessary for the proper production of cytokines, chemokines and pro-labour mediators after TLR ligation. PMID- 28844022 TI - Sleep in children with Angelman syndrome: Parental concerns and priorities. AB - Angelman syndrome is a rare genetic syndrome, in which sleep disturbances are reported for 20-80% of individuals (Williams et al., 2006). This interview study delineated parental perceptions of sleep problems experienced by children with Angelman syndrome and the impact on parental sleep quality, health and wellbeing. The nature of desired interventions was also explored. Semi-structured interviews were completed with parents of 50 children, aged 16 months-15 years with Angelman syndrome who experienced current or historic sleep problems; predominantly night waking and settling problems. Parents were concerned by the impact of their child's sleep quality upon their own ability to function during the day. The importance of considering parental experiences was evidenced by variability in coping e.g. despite the persistence of sleep problems 20% of parents did not feel the need for any additional support. Amongst a range of types of further support desired, 27% cited further support with a behavioural intervention, and information about the trajectory of sleep problems in Angelman syndrome (18%). The results suggest that behavioural interventions supporting both children and parents in improving their sleep quality and well-being, and longitudinal research into sleep problems should be prioritised. PMID- 28844023 TI - State of the art: 40 years of percutaneous cardiac intervention. PMID- 28844024 TI - Critical reflection on postgraduate learning: education through sharing. PMID- 28844025 TI - An interview with Professor Stephan Achenbach, Chairman ESC Congress Programme Committee 2016-2018. PMID- 28844026 TI - State of the art: coronary angiography. AB - In the early days of coronary angiography, the precise quantification of luminal narrowing was challenging. The introduction of balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]) by Andreas Gruntzig in 1977 was perhaps the greatest incentive to the development of quantitative coronary angiography (QCA). QCA has played a crucial role in evaluating interventional techniques and assessing the results of new technologies. With the advent of drug-eluting stents (DES), QCA metrics such as late lumen loss and diameter stenosis (restenosis) proved to be instrumental in assessing new technologies. Refinements in QCA with the advent of dedicated bifurcation analysis and three-dimensional (3D) QCA have broadened the application of QCA. Beyond angiographic metrics, new developments in the field of QCA have introduced the functional component in the assessment of coronary lesions. Angiography-derived fractional flow reserve (FFR) may be a good tool for diagnosing ischaemia-producing lesions in patients with non-complex coronary artery disease. Furthermore, the incremental functional information can be used to expand the traditional late lumen loss (LLL) and restenosis concepts. PMID- 28844027 TI - State of the art: role of intravascular imaging in the evolution of percutaneous coronary intervention - a 30-year review. AB - It has been 40 years since percutaneous coronary intervention (PCI) was introduced into the clinical setting. Over these years significant advances in device technology and the invention of new therapeutic strategies have broadened its applications in the clinical arena, rendering this treatment the first-line therapy for patients with obstructive coronary artery disease. The evolution of PCI would not have been possible without intravascular imaging which provided unique insights about coronary artery pathology, enabled evaluation of vessel wall response following PCI and allowed meticulous evaluation of the advantages and limitations of emerging devices. This review article appraises the role of intravascular imaging in the evolution of PCI, summarises the findings of invasive imaging studies that examined the efficacy of new therapies and endovascular devices, presents the evidence that supports its use in current clinical practice and discusses its future potential in PCI. PMID- 28844028 TI - State of the art: non-invasive imaging in ischaemic heart disease. AB - Evaluation of non-invasive imaging modalities is shifting to an assessment of their effect on clinical outcomes rather than of their diagnostic accuracy. For this reason, we present the most useful and commonly used non-invasive tests in the clinical scenario of patients with suspected or already known coronary artery disease in terms of their diagnostic accuracy and prognostic stratification. Each of the four sections, dedicated to a single imaging method (echocardiography, coronary computed tomography angiography, nuclear imaging and cardiac magnetic resonance), describes its early clinical applications, the main current indications and the more promising future field of interest. PMID- 28844029 TI - State of the art: pressure wire and coronary functional assessment. AB - The pressure wire has revolutionised cardiology by moving the focus of revascularisation from anatomy to physiology. This review provides a comprehensive viewpoint on the foundations of the field of intracoronary physiology, with emphasis on the development and clinical evidence of fractional flow reserve (FFR). Additionally, we critically appraise clinical decision making based on the evolving area of resting coronary physiology. The emerging role of coronary flow reserve and its complementariness with FFR is also discussed, and the importance of the invasive assessment of the coronary microcirculation in outlining prognosis is put into perspective. Overall, this review summarises the capacity of invasive coronary physiology indices to guide revascularisation and to discriminate patients at high risk of an adverse cardiovascular outcome. PMID- 28844030 TI - State of the art: balloon catheter technologies - drug-coated balloon. AB - Four decades after its introduction into clinical practice, coronary balloon angioplasty is still used during most coronary interventions. Conventional balloon angioplasty is frequently used to predilate complex or severe lesions and remains of major value to optimise the results of stent implantation. Plain balloon angioplasty is still used alone in some anatomic scenarios where stent implantation is not desirable (very small vessels or diffuse lesions, large resistant thrombus burden, side branches of bifurcations). However, this technique is hampered by a relatively high restenosis risk. Recently, drug-coated balloons (DCB) have been shown to provide an attractive new tool for the "leave nothing behind" strategy. Many studies have demonstrated that DCB are indeed safe and effective. Evidence of the value of DCB in patients with ISR is overwhelming. DCB are attractive for selected de novo coronary lesions (small vessels, diffuse disease, side branches). DCB have also gained major evidence supporting their clinical efficacy in the peripheral arterial territory. Further studies are required to elucidate the relative value of DCB compared with alternative strategies (namely new-generation drug-eluting stents) in different clinical and anatomic scenarios. PMID- 28844031 TI - State of the art: evolving concepts in the treatment of heavily calcified and undilatable coronary stenoses - from debulking to plaque modification, a 40-year long journey. AB - Since the first balloon angioplasty by Andreas Gruntzig 40 years ago, interventional cardiology has witnessed the introduction of countless tools and techniques that have significantly contributed to broadening the application of percutaneous coronary interventions (PCI) in unprecedented anatomic settings. Heavily calcified, fibrotic coronary stenosis has traditionally represented a very challenging scenario for PCI, and a very common indication for surgical revascularisation. This was mostly due to the difficulty in adequately dilating these lesions and/or to the inability to deliver and implant stents appropriately, which is often associated with high rates of procedural complications and suboptimal long-term clinical outcomes. Thanks to dedicated cutting and scoring balloons and to atherectomy devices, the treatment of most fibrotic and heavily calcified stenoses has become feasible and safe. Interventional cardiologists have learned how best to apply these tools through better patient and lesion selection, and also as a result of improved technology and techniques. In this review, we describe a 40-year-long journey that has evolved from the initial stand-alone debulking strategy to the currently applied coronary plaque modification, with the main objective of optimising drug-eluting stent delivery and implantation, translating into significantly improved patient outcomes. PMID- 28844032 TI - State of the art: coronary artery stents - past, present and future. AB - The first percutaneous coronary intervention (PCI) was performed in September 1977 by Andreas Gruntzig using a rudimentary balloon angioplasty catheter mounted on a fixed wire. PCI was immediately recognised as a potential breakthrough in cardiovascular medicine, but uptake in clinical practice was limited by unpredictable acute outcomes and a need for surgical standby. The introduction of bare metal stents (BMS) in the 1980s improved procedure reproducibility and clinical outcomes through a permanent scaffolding of the coronary vessel, preventing abrupt occlusion and acute recoil. It was the introduction of drug eluting stents (DES) at the beginning of this century, however, that allowed PCI to become one of the most frequently performed therapeutic interventions in medicine, primarily by addressing the issue of in-stent restenosis. DES technology has improved considerably since, with iterative developments of the stent metallic backbone, the polymer coating, and the released antiproliferative agents impacting on the safety and efficacy profile of these devices in a meaningful way. Overall, the impressive technological advances in metallic coronary stents have revolutionised the treatment of ischaemic heart disease over the last 40 years. The aim of the present article is to provide an overview of past, present, and future aspects of coronary stent technologies. PMID- 28844033 TI - State of the art: duration of dual antiplatelet therapy after percutaneous coronary intervention and coronary stent implantation - past, present and future perspectives. AB - Evidence from studies published more than 10 years ago suggested that patients receiving first-generation drug-eluting stents (DES) needed dual antiplatelet therapy (DAPT) for at least 12 months. Current evidence from randomised controlled trials (RCT) reported within the past five years suggests that patients with stable ischaemic heart disease who receive newer-generation DES need DAPT for a minimum of three to six months. Patients who undergo stenting for an acute coronary syndrome benefit from DAPT for at least 12 months, but a Bayesian network meta-analysis confirms that extending DAPT beyond 12 months confers a trade-off between reduced ischaemic events and increased bleeding. However, the network meta-analysis finds no credible increase in all-cause mortality if DAPT is lengthened from three to six months to 12 months (posterior median odds ratio [OR] 0.98; 95% Bayesian credible interval [BCI]: 0.73-1.43), from 12 months to 18-48 months (OR 0.87; 95% BCI: 0.64-1.17), or from three to six months to 18-48 months (OR 0.86; 95% BCI: 0.63-1.21). Future investigation should focus on identifying scoring systems that have excellent discrimination and calibration. Although predictive models should be incorporated into systems of care, most decisions about DAPT duration will be based on clinical judgement and patient preference. PMID- 28844034 TI - State of the art: the inception, advent and future of fully bioresorbable scaffolds. AB - To overcome the limitations of metallic stents, the development of the bioresorbable vascular scaffold started about 30 years ago. Researchers anticipated a transformative revolution from "vascular reparative therapy" by BRS at the beginning of its development. To date, there are five commercially available bioresorbable scaffolds which have already gained CE mark. However, recent studies, including randomised trials and meta-analyses evaluating clinical results of BRS, have raised concerns about the safety and efficacy of the device in the first few years prior to its complete bioresorption, compared to contemporary metallic DES. As one of the efforts to address these concerns, the impact of implantation technique was investigated. In addition, there are several aspects to be improved such as mechanical integrity, strut configuration, and late structural discontinuity. Intensive researches into the underlying causes of the greater device thrombosis rates with BRS have stimulated improvement of implantation technique and the development of next-generation BRS. Just as we have witnessed the evolution from first- to second-generation metallic DES, we anticipate that future generations of BRS with thinner struts and enhanced mechanical properties will result in substantially improved intermediate-term outcomes and safety. PMID- 28844035 TI - State of the art: optimal medical therapy - competing with or complementary to revascularisation in patients with coronary artery disease? AB - The role of coronary revascularisation with PCI and CABG in patients with stable and unstable coronary artery disease (CAD) is well established and there is a general consensus among guidelines as regards the indications for coronary revascularisation. Although revascularisation has undoubtedly revolutionised the treatment of CAD, it is vital to understand the recent advances and importance of the concomitant use of evidence-based optimal medical therapy (OMT). In contemporary practice, OMT should include an antiplatelet agent (or dual antiplatelet therapy when indicated) and a lipid-lowering drug for all patients, and a beta-blocker and an ACE inhibitor (or angiotensin receptor blocker) for the vast majority of patients, along with addressing cardiac risk factors and lifestyle management. OMT is the recommended initial choice for patients with stable angina pectoris, and the indication for revascularisation would be persistence of symptoms despite OMT and/or improvement of prognosis. For patients with acute coronary syndromes or those who underwent coronary revascularisation with either PCI or CABG, long-term use of OMT improves clinical outcomes and prognosis. PMID- 28844036 TI - From state-of-the-art cell therapy to endogenous cardiac repair. AB - Clinical heart failure prevention and contemporary therapy often involve breaking the vicious cycle of global haemodynamic consequences of myocardial decay. The lack of effective regenerative therapies results in a primary focus on preventing further deterioration of cardiac performance. The cellular transplantation hypothesis has been evaluated in many different preclinical models and a handful of important clinical trials. The primary expectation that cellular transplants will be embedded into failing myocardium and fuse with existing functioning cells appears unlikely. A multitude of cellular formulas, access routes and clinical surrogate endpoints for evaluation add to the complexity of cellular therapies. Several recent large clinical trials have provided insights into both the regenerative potential and clinical improvement from non-regenerative mechanisms. Initiating endogenous repair seems to be another meaningful alternative to recover structural integrity in myocardial injury. This option may be achieved using a transcoronary sinus catheter intervention, implying the understanding of basic principles in biology. With intermittent reduction of outflow in cardiac veins (PICSO), vascular cells appear to be activated and restart a programme similar to pathways in the developing heart. Structural regeneration may be possible without requiring exogenous agents, or a combination of both approaches may become clinical reality in the next decade. PMID- 28844037 TI - Targeting the anterior superior iliac spine yields significantly longer bone marrow cores. AB - : Pathologists and haematologists generally agree that the length of the biopsy core is a good surrogate for the diagnostic quality of the bone marrow. Previous studies suggested that the angulation of the biopsy needle from the posterior superior iliac spine (PSIS) could influence the length of the biopsy cores, targeting the anterior superior iliac spine (ASIS) from the PSIS would yield longer specimens than the traditional angulation technique (TAT), where the biopsy needle is directed straight in, perpendicular to the plane of the back. Twenty five adult haematology patients were prospectively recruited by haematologists-in-training (HITs), who were trained to target the ASIS using a lateral angulationtechnique (LAT). The mean length of biopsy cores was 16 mm and that was significantly longer (p=0.003) than a comparable group of bone marrow biopsies previously obtained by HITs using the TAT approach. These results support the LAT as a new standard of haematology practice. TRIAL REGISTRATION NUMBER: NCT 02524613. PMID- 28844038 TI - Unrestricted faecal calprotectin testing performs poorly in the diagnosis of inflammatory bowel disease in patients in primary care. AB - BACKGROUND: Faecal calprotectin (FC) measurement distinguishes patients with inflammatory bowel disease (IBD) from those with irritable bowel syndrome but evidence of its performance in primary care is limited. AIMS: To assess the yield of IBD from FC testing in primary care. METHODS: Retrospective review of hospital records to assess the outcome following FC testing in primary care. Investigations for all patients undergoing FC testing in a single laboratory for 6 months from 1 October 2013 to 28 February 2014 were reviewed. RESULTS: 410 patients (162 male; median age 42; range 16-91) were included. FC>50 ug/g was considered positive (FC+). 148/410 (36.1%; median age 44 (17-91)) were FC+ (median FC 116.5 ug/g (51-1770)). 122/148 FC-positive patients (82.4%) underwent further investigation. 97 (65.5%) underwent lower gastrointestinal endoscopy (LGIE), of which 7 (7.2%) had IBD. 49/262 (18.7%) FC-negative (FC-) patients (FC <=50 ug/g) (median age 47 (19-76)) also underwent LGIE, of whom 3 (6.1%) had IBD.IBD was diagnosed in 11/410 (2.7%; 4 ulcerative colitis, 3 Crohn's disease, 4 microscopic colitis). 8/11 were FC+ (range 67-1170) and 3 FC-. At a 50 ug/g threshold, sensitivity for detecting IBD was 72.7%, specificity 64.9%, positive predictive value (PPV) 5.41% and negative predictive value 98.9%. Increasing the threshold to 100 ug/g reduced the sensitivity of the test for detecting IBD to 54.6%. CONCLUSIONS: FC testing in primary care has low sensitivity and specificity with poor PPV for diagnosing IBD. Its use needs to be directed to those with a higher pretest probability of disease. Local services and laboratories should advise general practitioners accordingly. PMID- 28844039 TI - Relationship between non-technical skills and technical performance during cardiopulmonary resuscitation: does stress have an influence? AB - BACKGROUND: Non-technical skills, such as task management, leadership, situational awareness, communication and decision-making refer to cognitive, behavioural and social skills that contribute to safe and efficient team performance. The importance of these skills during cardiopulmonary resuscitation (CPR) is increasingly emphasised. Nonetheless, the relationship between non technical skills and technical performance is poorly understood. We hypothesise that non-technical skills become increasingly important under stressful conditions when individuals are distracted from their tasks, and investigated the relationship between non-technical and technical skills under control conditions and when external stressors are present. METHODS: In this simulator-based randomised cross-over study, 30 anaesthesiologists and anaesthesia residents from the VU University Medical Center, Amsterdam, the Netherlands, participated in two different CPR scenarios in random order. In one scenario, external stressors (radio noise and a distractive scripted family member) were added, while the other scenario without stressors served as control condition. Non-technical performance of the team leader and technical performance of the team were measured using the 'Anaesthetists' Non-technical Skill' score and a recently developed technical skills score. Analysis of variance and Pearson correlation coefficients were used for statistical analyses. RESULTS: Non-technical performance declined when external stressors were present (adjusted mean difference 3.9 points, 95% CI 2.4 to 5.5 points). A significant correlation between non-technical and technical performance scores was observed when external stressors were present (r=0.67, 95% CI 0.40 to 0.83, p<0.001), while no evidence for such a relationship was observed under control conditions (r=0.15, 95% CI 0.22 to 0.49, p=0.42). This was equally true for all individual domains of the non-technical performance score (task management, team working, situation awareness, decision-making). CONCLUSIONS: During CPR with external stressors, the team's technical performance is related to the non-technical skills of the team leader. This may have important implications for training of CPR teams. PMID- 28844040 TI - Rhino-orbito-cerebral mucormycosis: recovery against the odds. AB - A 22-year-old woman presented with diabetic ketoacidosis, acute right eye blindness and complete ophthalmoplegia. Despite early suspicion and treatment for rhino-orbito-cerebral mucormycosis, her extensive spread of infection led to right internal carotid artery occlusion and cavernous sinus thrombosis, right sided cerebral watershed infarctions and large abscesses in her right cerebellum, temporal lobe and pons. She underwent surgical removal of her right eye, paranasal sinuses, maxilla and palate, suboccipital craniectomy and shunting for hydrocephalus. Despite the grave prognosis, she has gradually improved and has remained on antifungal treatment for the 18 months since presentation. We discuss the factors that may have influenced her recovery. The case highlights the aggressive nature of rhino-orbito-cerebral mucormycosis, the need for multiple surgeries and the ethical issues in managing such patients. PMID- 28844041 TI - How to use pen and paper tasks to aid tremor diagnosis in the clinic. AB - When a patient presents with tremor, it can be useful to perform a few simple pen and paper tests. In this article, we explain how to maximise the value of handwriting and of drawing Archimedes spirals and straight lines as clinical assessments. These tasks take a matter of seconds to complete but provide a wealth of information that supplements the standard physical examination. They aid the diagnosis of a tremor disorder and can contribute to its longitudinal monitoring. Watching the patient's upper limb while they write and draw may reveal abnormalities such as bradykinesia, dystonic posturing and distractibility. The finished script and drawings can then be evaluated for frequency, amplitude, direction and symmetry of oscillatory pen movements and for overall scale of penmanship. Essential, dystonic, functional and parkinsonian tremor each has a characteristic pattern of abnormality on these pen and paper tests. PMID- 28844043 TI - Opportunities and barriers to STI testing in community health centres in China: a nationwide survey. AB - BACKGROUND: China has strengthened its primary care workforce and implemented a wide network of community health centres (CHCs). However, STI testing and management are not currently included in the 'Essential Package of Primary Health Care in China'. Legislation change to encourage STI service delivery would be important, but it is also critical to determine if there are also provider related opportunities and barriers for implementing effective STI programmes through CHCs if future legislation were to change. METHODS: A national representative survey was conducted between September and December 2015 in a stratified random sample of 180 CHCs based in 20 cities in China. Primary care practitioners (PCPs) provided information on current experiences of STI testing as well as the barriers and facilitators for STI testing in CHCs. Multivariate logistic regression was conducted to determine factors associated with PCPs performing STI testing. RESULTS: 3580 out of 4146 (86%) invited PCPs from 158 CHCs completed the survey. The majority (85%, 95% CI 84% to 87%) of doctors stated that STI testing was an important part of healthcare. However, less than a third (29%, 95% CI 27% to 31%) would perform an STI test if the patients asked. Barriers for performing STI testing included lack of training, concerns about reimbursement, concerns about damage to clinics' reputations and the stigma against key populations. Respondents who reported that they would perform an STI test were likely to be younger, received a bachelor degree or higher, received specific training in STIs, believed that STI test was an important part of healthcare or had resources to perform STI testing. CONCLUSIONS: There is potential for improving STI management in China through upskilling the primary care workforce in CHCs. Specific training in STIs is needed, and other structural, logistical and attitudinal barriers are needed to be addressed. PMID- 28844044 TI - The antibiotic management of gonorrhoea in Ontario, Canada following multiple changes in guidelines: an interrupted time-series analysis. AB - OBJECTIVE: This study assessed adherence with first-line gonorrhoea treatment recommendations in Ontario, Canada, following recent guideline changes due to antibiotic resistance. METHODS: We used interrupted times-series analyses to analyse treatment data for cases of uncomplicated gonorrhoea reported in Ontario, Canada, between January 2006 and May 2014. We assessed adherence with first-line treatment according to the guidelines in place at the time and the use of specific antibiotics over time. We used the introduction of new recommendations in the Canadian Guidelines for Sexually Transmitted Infections in 2008 and 2011 and the release of the province of Ontario's Guidelines for the Treatment and Management of Gonococcal Infections in Ontario in 2013 as interruptions in the time-series analysis. RESULTS: Overall, 34 287 gonorrhoea cases were reported between 1 January 2006 and 31 May 2014. Treatment data were available for 32 312 (94.2%). Our analysis included 32 272 (94.1%) cases without either a conjunctival or disseminated infection. Following the release of the 2011 recommendations, adherence with first-line recommendations immediately decreased to below 30%. Adherence slowly increased but did not reach baseline levels before the 2013 guidelines were released. Following release of the 2013 guidelines, adherence again decreased; adherence is slowly recovering but by May 2014, was only approximately 60%. CONCLUSIONS: Due to concerns about antibiotic resistance, gonorrhoea treatment guidelines need to be updated regularly and rapidly adopted in practice. Our study showed poor adherence following dissemination of updated guidelines. Over a year after the latest Ontario guidelines were released, 40% of patients did not receive first-line treatment, putting them at risk of treatment failure and potentially promoting further drug resistance. Greater attention should be devoted to dissemination and implementation of new guidelines. PMID- 28844045 TI - Language matters: a linguist's view on medicine. PMID- 28844046 TI - Paracrine effects of mesenchymal stem cells on the activation of keratocytes. AB - AIMS: The purpose of this study is to investigate the impact of mesenchymal stem cell (MSC)-derived soluble factors on the function of keratocytes, with a particular focus on the processes involved in wound healing, including keratocyte activation, migration and proliferation as well as extracellular matrix (ECM) synthesis. METHODS: Primary cultured rabbit keratocytes were treated with MSC conditioned medium (MSC-CM). The paracrine factors released by bone marrow MSCs were examined by ELISA. Time-lapse microscope was used to examine wound closure in vitro. Mouse model of corneal injury was made by epithelial scraping after ethanol injury. RESULTS: MSC-CM significantly increased the wound closure rate of corneal stromal cells in vitro. This enhancement of wound closure by MSC-CM was due to the promotion of cell migration. MSC-CM enhanced keratocyte survival following ethanol injury via inhibiting apoptosis. The expression of ECM component genes in keratocytes was upregulated by MSC-CM. In addition, MSC-CM promoted corneal epithelial wound healing following chemical injury. A number of wound healing mediators were detected in MSC-CM, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), transforming growth factor beta 1 (TGFbeta1), interleukin 8 (IL8), interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1). CONCLUSION: MSC secretes certain factors that accelerate corneal re-epithelialisation. The paracrine effects of MSC on corneal wound healing including improvements in cell viability, migration and ECM formation. PMID- 28844047 TI - Cumulative retention rate of adalimumab in patients with Behcet's disease-related uveitis: a four-year follow-up study. AB - BACKGROUND/AIMS: Adalimumab (ADA) has been shown to be an effective treatment for Behcet's disease (BD)-related uveitis. We aimed at evaluating the cumulative retention rate of ADA during a 48-month follow-up period in patients with BD related uveitis, the impact of a concomitant use of disease modifying anti rheumatic drugs (DMARDs) on ADA retention rate, and differences according to the various lines of biologic therapy (ie, first- vs second-line or more). Predictive factors of response to ADA were also investigated. METHODS: We enrolled patients diagnosed with BD-related uveitis and treated with ADA between January 2009 and December 2016. Cumulative survival rates were studied using the Kaplan-Meier plot, while the log-rank (Mantel-Cox) test was used to compare survival curves. Statistical analysis was performed to identify differences according to the response to ADA. RESULTS: 54 consecutive patients (82 eyes) were eligible for analysis. The drug retention rate at 12- and 48-month follow-up was 76.9% and 63.5%, respectively. No statistically significant differences were identified according to the use of concomitant DMARDs (p=0.27) and to the different lines of ADA treatment (p=0.37). No significant differences were found between patients continuing and discontinuing ADA in terms of age (p=0.24), age at BD onset (p=0.81), age at uveitis onset (p=0.56), overall BD duration (p=0.055), uveitis duration (p=0.46), human leucocyte antigen-B51 positivity (p=0.51), and gender (p=0.47). CONCLUSIONS: ADA retention rate in BD-related uveitis is excellent and is not affected by the concomitant use of DMARDs or by the different lines of biological therapy. Negative prognostic factors for BD uveitis do not impact ADA efficacy. PMID- 28844048 TI - Traumatic brain injury, dry eye and comorbid pain diagnoses in US veterans. AB - AIMS: The purpose of the study is to evaluate the relationship between dry eye (DE) and pain diagnoses in US veterans with and without traumatic brain injury (TBI). METHODS: Retrospective cohort study of veterans who were seen in the Veterans Administration Hospital (VA) between 1 January 2010 and 31 December 2014. Veterans were separated into two groups by the presence or absence of an International Classification of Diseases, Ninth Revision diagnosis of TBI and assessed for DE and other comorbidities. A dendrogram was used to investigate the linkage between TBI, DE, chronic pain and other comorbid conditions. RESULTS: Of the 3 265 894 veterans seen during the 5-year period, 3.97% carried a diagnosis of TBI. Veterans with TBI were more likely to have a diagnosis of DE compared with their counterparts without TBI (37.2% vs 29.1%, p<0.0005). The association was stronger between TBI and ocular pain (OR 3.08; 95% CI 3.03 to 3.13) compared with tear film dysfunction (OR 1.09; 95% CI 1.07 to 1.10). Those with TBI were also about twice as likely to have a diagnosis of chronic pain, headache, depression or post-traumatic stress disorder compared with their counterparts without TBI. Cluster analysis of TBI, DE and pain diagnoses of interest revealed that central pain syndrome, cluster headache, sicca syndrome, keratoconjunctivitis sicca and late effect of injury to the nervous system (as can be seen after TBI) were all closely clustered together. CONCLUSIONS: DE and pain disorders occur at higher frequencies in patients with a diagnosis of TBI, suggesting a common underlying pathophysiology. PMID- 28844049 TI - Pterygia are indicators of an increased risk of developing cutaneous melanomas. AB - AIM: To investigate whether pterygium is an indicator of an increased risk of cutaneous melanoma (CM). METHODS: A matched-cohort study, using linked health administrative data sets to identify all hospital-treated pterygium in Western Australia (WA) between 1979 and 2014. We identified pterygium cases from hospital diagnosis and/or procedure International Classification of Diseases 9th revision (ICD-9) and 10th revision (ICD-10) codes and matched cases by age, sex and residential postcode to WA Electoral Roll controls with no known history of pterygium. Both cohorts were linked to the WA Cancer Registry and the WA Deaths Registry. RESULTS: 23 625 people had pterygium treatment (64% male) in WA hospitals. The median age for pterygium diagnosis and/or treatment was 49 years (range 14-96). There were significantly more CM cases in the pterygium cohort compared with the control cohort (1083 vs 874; p<0.001). In a logistic regression analysis, there was a 24% increase in the odds of developing a CM in the pterygium cohort, compared with controls, after controlling for other predictors (OR 1.24, 95% CI 1.1 to 1.4). The incident rate ratio (IRR) of a malignant CM diagnosis was 20% greater in people who had treatment for a pterygium compared with controls (IRR 1.2, 95% CI 1.0 to 1.4). CONCLUSION: The presence of a pterygium indicates a significantly increased risk of developing a CM. Eye care providers who see patients with developing pterygia should advise these patients of this increased risk and recommend regular skin surveillance. PMID- 28844050 TI - Intravitreal topotecan in the management of refractory and recurrent vitreous seeds in retinoblastoma. AB - BACKGROUND/AIM: To evaluate the efficacy of intravitreal topotecan for refractory or recurrent vitreous seeds in retinoblastoma. METHODS: Intravitreal injection of topotecan hydrochloride (30 ug/0.15 mL) was provided every 3 weeks by the safety enhanced technique. RESULTS: The study included 17 consecutive patients with retinoblastoma with refractory or recurrent vitreous seeds. Five eyes (29%) belonged to International Classification of Retinoblastoma group C and 12 eyes (71%) belonged to group D. Primary treatment included triple drug intravenous chemotherapy for a mean of 10 cycles (median, 9 cycles; range, 6-18 cycles). Fifteen patients (88%) had undergone 56 periocular carboplatin injections with a mean of 4 injections (median, 3 injections; range, 1-8 injections), concurrent with intravenous chemotherapy. A total of 53 intravitreal topotecan injections were performed in 17 eyes of 17 consecutive patients with refractory or recurrent vitreous seeds with a mean of 3 injections (median, 3 injections; range, 2-6 injections). Complete regression of vitreous seeds was achieved in 17 of 17 eyes (100%). At a mean follow-up of 23.8 months (median, 24 months; range, 15.1-34.1 months), one eye (6%) with a recurrent retinal tumour needed enucleation, and the rest of the 16 eyes (94%) maintained complete regression. Final visual acuity could be reliably assessed in all 16 eyes (100%), of whom 12 eyes (75%) had visual acuity >=20/200. None of the patients developed ocular or systemic complications. CONCLUSION: Three-weekly intravitreal topotecan appears effective and safe in controlling focal or diffuse refractory or recurrent vitreous seeds in retinoblastoma. PMID- 28844051 TI - Active surveillance of choroidal neovascularisation in children: incidence, aetiology and management findings from a national study in the UK. AB - BACKGROUND/AIMS: To determine the UK incidence, demographics, aetiology, management and visual outcome for children developing choroidal neovascularisation (CNV). METHODS: A prospective population-based observational study of routine practice via the British Ophthalmological Surveillance Unit between January 2012 and December 2013 with subsequent 1-year follow-up in children under 16 years old with newly diagnosed CNV. RESULTS: Twenty-seven children with CNV were reported. The UK estimated annual incidence for those aged 16 and under was 0.21 per 100 000 (95% CI 0.133 to 0.299). The mean age was 11.1 years (SD 3.9, range 4-16). Fourteen were female. Seventy-seven per cent (22 patients) were Caucasian British. Twenty-three children (85%) had unilateral disease. The most common aetiology included inflammatory retinochoroidopathy (n=9), optic disc abnormalities (n=9) and idiopathic (n=5). Optical coherence tomography was performed in all cases and fundus fluorescein angiography in 61%. Management included observation only (n=10), anti-vascular endothelial growth factor (anti-VEGF) injection of bevacizumab (n=14) or ranibizumab (n=2), or both (n=1), and additional use of oral (n=1) and local (periocular n=2 and intravitreal n=2) steroids in five children with inflammatory retinochoroidopathy. The mean number of anti-VEGF injections was 2+/-1, with eight patients receiving only one injection. The mean (SD) best corrected visual acuity in LogMAR was 0.91 (0.53) at presentation and 0.74 (0.53) at 1-year follow up (p=0.09). CONCLUSION: This is the first population-based prospective study of CNV in children. This is a rare disorder with a poor visual prognosis irrespective of CNV location and the use of anti-VEGF therapy. PMID- 28844052 TI - Multicentred international review of orbital exenteration and reconstruction in oculoplastic and orbit practice. AB - BACKGROUND: Orbital exenteration is a disfiguring procedure reserved for life threatening malignancies. This study examines the clinical course and outcomes of a large series of patients who underwent orbital exenteration for malignant periocular neoplasms. METHODS: This is a retrospective review of patients who underwent orbital exenteration from 1 July 2005 to 30 June 2015 at four tertiary referral centres in the USA, Australia and Canada. Demographics, indication for surgery, pathology, surgical technique, reconstruction type and outcomes were reviewed. RESULTS: Orbital exenteration was performed on 102 patients. The mean age at surgery was 67.5 years. The most common malignant tumours encountered were squamous cell carcinoma, melanoma and basal cell carcinoma. Seventy-six patients (75%) underwent reconstruction with a local myocutaneous flap, twelve with partial-thickness skin grafts (PTSG), or split skin graft, two had a free flap, and one had a dermis fat graft. Sixteen patients had combined procedures of two of the above. Complete removal of the tumour was achieved with clear margins in 81 cases. Of all patients, 72% were alive at 48 months or more. CONCLUSION: The majority of orbital exenterations performed in this series were secondary to periocular malignancies with unsuccessful/insufficient previous treatments. Regional myocutaneous flaps, PTSG, full-thickness skin grafts and dermis fat grafts were all highly effective and durable reconstructive options, and were able to withstand radiation therapy without complications. PMID- 28844053 TI - Non-invasive method of monitoring retinal vasculitis in patients with birdshot chorioretinopathy using optical coherence tomography. AB - BACKGROUND/AIMS: To investigate the utility of using montaged optical coherence tomography (OCT) thickness maps to monitor perivascular thickness as a marker of vasculitic activity in patients with large-vessel retinal vasculitis. METHODS: This is a retrospective cohort study of 22 eyes of 11 patients with a history of retinal vasculitis associated with birdshot chorioretinopathy (BCR). Patients had serial spectral domain 6*6 mm cube OCT scans centred on the fovea, optic nerve and proximal branches of the superior and inferior retinal vessels. OCT thickness change maps for each respective region were analysed. Changes in perivascular thickness were confirmed by assessing vasculitic activity on fluorescein angiography (FA), when clinically indicated. RESULTS: In three patients, montaged OCT scans were acquired at diagnosis and serially through initial treatment. In all three patients, montaged OCT demonstrated reduced perivascular thickening with oral prednisone treatment, which was confirmed by FA showing reduced vascular leakage in both eyes. Eight patients had serial montaged OCT scans after diagnosis and initial treatment of BCR. Four of these patients showed fluctuations in perivascular thickness during flares and treatment that were confirmed by either increased or decreased vascular leakage on FA. The other four patients remained quiet on their immunosuppressive treatment regimens, and no changes in perivascular thickness were detected. CONCLUSIONS: Evaluating large vessel perivascular thickness on OCT scans may be a useful method for non invasively monitoring posterior pole large-vessel retinal vasculitis. PMID- 28844054 TI - Developing clinical guidelines with scant evidence approaches taken and lessons learnt. PMID- 28844055 TI - What is MR spectroscopy? AB - 1H-Magnetic Resonance Spectroscopy (MRS) is a novel advanced imaging technique used as an adjunct to MRI to reveal complementary non-invasive information about the biochemical composition of imaged tissue. Clinical uses in paediatrics include aiding diagnosis of brain tumours, neonatal disorders such as hypoxic ischaemic encephalopathy, inherited metabolic diseases, traumatic brain injury, demyelinating conditions and infectious brain lesions. MRS has potential to improve diagnosis and treatment monitoring of childhood brain tumours and other CNS diseases, facilitate biopsy and surgical planning, and provide prognostic biomarkers. MRS is employed as a research tool outside the brain in liver disease and disorders of muscle metabolism. The range of clinical uses is likely to increase with growing evidence for added value. Multicentre trials are needed to definitively establish the benefits of MRS in specific clinical scenarios and integrate this promising new technique into routine practice to improve patient care. This article gives a brief overview of MRS and its potential clinical applications, and addresses challenges surrounding translation into practice. PMID- 28844056 TI - Fifteen-minute consultation: Assessment, surveillance and management of hemihypertrophy. AB - This article aims to provide a structured and concise guide for the general paediatrician managing a child with hemihypertrophy. Hemihypertrophy is a relatively uncommon condition. The significance is that a proportion of those affected are at risk of developing malignancies in childhood. For these children regular surveillance is required. We have outlined how one might assess and investigate a child presenting with hemihypertrophy. We have also formulated a practicable surveillance strategy which is in line with the current Royal College of Paediatrics and Child Health (RCPCH) guideline 'Wilms' tumour surveillance in at-risk children'. PMID- 28844057 TI - Complexity of defining death: organismal death does not mean the cessation of all biological life. PMID- 28844058 TI - Molecular epidemiology of Pseudomonas aeruginosa in an unsegregated bronchiectasis cohort sharing hospital facilities with a cystic fibrosis cohort. AB - While Pseudomonas aeruginosa (PA) cross-infection is well documented among patients with cystic fibrosis (CF), the equivalent risk among patients with non CF bronchiectasis (NCFB) is unclear, particularly those managed alongside patients with CF. We performed analysis of PA within a single centre that manages an unsegregated NCFB cohort alongside a segregated CF cohort. We found no evidence of cross-infection between the two cohorts or within the segregated CF cohort. However, within the unsegregated NCFB cohort, evidence of cross-infection was found between three (of 46) patients. While we do not presently advocate any change in the management of our NCFB cohort, longitudinal surveillance is clearly warranted. PMID- 28844059 TI - Do donors matter? Short telomeres and survival after lung transplant. PMID- 28844060 TI - Diagnostic accuracy of interleukin 27 for tuberculous pleural effusion: two prospective studies and one meta-analysis. AB - BACKGROUND: Accurate differentiating diagnosis is essential for choosing treatment for exudative pleural effusions. OBJECTIVE: To establish the diagnostic accuracy of interleukin 27 for tuberculous pleural effusion (TPE). METHODS: First, the concentrations of pleural interleukin 27, interferon-gamma and adenosine deaminase were compared between 51 patients with TPE and 103 with non TPEs (Beijing cohort), and their diagnostic values were evaluated. These were further verified in another independent population (Wuhan cohort, n=120). In the second part of the study, we performed a meta-analysis. RESULTS: With a cut-off value of 591.4 ng/L in the Beijing cohort, the area under the curve, sensitivity, specificity, positive predictive value and negative predictive value of interleukin 27 to diagnose TPE were 0.983 (95% CI 0.947 to 0.997), 96.1% (86.5% to 99.5%), 99.0% (94.7% to 100%), 98.0 (89.4 to 99.9) and 98.1 (93.3 to 99.8), respectively. Excellent diagnostic accuracy of interleukin 27 was also found in the Wuhan cohort and was further confirmed in the meta-analysis. The diagnostic performance of interleukin 27 was comparable to that of interferon-gamma and was more accurate than that of adenosine deaminase. Since the post-test probability of a negative result was always <0.1%, a negative test was considered to exclude TPE in all tuberculosis prevalence settings. CONCLUSIONS: Interleukin 27 can be used to diagnose TPE in a high prevalence setting, and a negative result can also be reliably used to rule out TPE in all prevalence settings. PMID- 28844061 TI - Father-infant skin-to-skin contact appears to be beneficial, however paternal experiences of this need to be explored. PMID- 28844062 TI - Motion video-based quantitative analysis of the 'lifting-thrusting' method: a comparison between teachers and students of acupuncture. AB - OBJECTIVE: To compare objective measures of needle manipulation between students and teachers of acupuncture using motion video analysis technology, to help support instructional acupuncture education. METHODS: A total of 30 teachers and 60 students participated in this study. Acupuncture needles were inserted at LI11 and motion videos were recorded for three subtypes of 'lifting-thrusting' manipulation: (1) 'mild reinforcing-attenuating'; (2) 'reinforcing'; and (3) 'attenuating'. The videos were analysed using Simi Motion 3D software to acquire the movement parameters of four trace marks: 'thumb tip'; 'forefinger tip'; 'forefinger middle joint'; and 'forefinger base joint'. Differences between the two groups were compared using t-tests, X2 tests and/or rank-sum tests. RESULTS: Changes in the near-end interphalangeal joint were positively associated with a range of movement along the X axis. Motion parameters for the thumb tip, the proximal interphalangeal (PIP) joint of the forefinger and the X axis shaft swing near the end of the forefinger in the teacher group were higher than those in the student group. The teacher group featured smaller trough dispersion and smaller crest dispersion during 'reinforcing' and 'attenuating' manipulations, respectively. CONCLUSIONS: The 'lifting-thrusting' manipulation could be simplified as a fixed-axis rotation using metacarpophalangeal joints in the thumb and forefinger as the shaft centre. Teachers opened at a larger angular variation for the PIP during the lifting and thrusting processes with better spatial control. Temporal control was similar between groups and therefore appears easier to grasp. Repetitive training might be helpful for improving athletic and spatial stability during needle manipulation. PMID- 28844063 TI - Perceived benefits of utilising acupuncture by reason for use among US adults. PMID- 28844064 TI - CETP inhibition improves the lipid profile but has no effect on clinical cardiovascular outcomes in high-risk patients. PMID- 28844065 TI - Effect of childhood coeliac disease on ninth grade school performance: evidence from a population-based study. AB - BACKGROUND: Coeliac disease might affect school performance due to its effect on cognitive performance and related health consequences that might increase school absenteeism. The aim of this study was to investigate whether children with coeliac disease performed differently on completion of ninth grade in school compared with children without coeliac disease. METHODS: Analysis was performed on a population of 445 669 children born in Sweden between 1991 and 1994 of whom 1767 were diagnosed with coeliac disease. School performance at ninth grade was the outcome and coeliac disease was the exposure. Other covariates included sex, Apgar score at 5 min, small for gestational age, year of birth, family type, parental education and income. RESULTS: There was no association between coeliac disease and school performance at ninth grade (adjusted coefficient -2.4, 95% CI 5.1 to 0.4). A weak association was established between late coeliac diagnosis and higher grades, but this disappeared after adjusting for parent socioeconomic conditions. Being small for gestational age affected performance negatively (adjusted coefficient -6.9, 95% CI 8.0 to 5.7). Grade scores were significantly lower in children living with a single parent (adjusted coefficient -20.6, 95% CI 20.9 to 20.2), compared with those with married/cohabiting parents. A positive association was found between scores at ninth grade and parental education and income. CONCLUSION: Coeliac disease diagnosis during childhood is not associated with poor school performance at ninth grade. PMID- 28844066 TI - Extrapolation or controlled trials in paediatrics: the current dilemma. PMID- 28844067 TI - Cerebellar lobule atrophy and disability in progressive MS. AB - OBJECTIVE: To investigate global and lobular cerebellar volumetries in patients with progressive multiple sclerosis (MS), testing the contribution of cerebellar lobular atrophy to both motor and cognitive performances. METHODS: Eighty-two patients with progressive MS and 46 healthy controls (HC) were enrolled in this cross-sectional study. Clinical evaluation included motor and cognitive testing: Expanded Disability Status Scale, cerebellar Functional System score, Timed 25 Foot Walk Test, 9-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT) and California Verbal Learning Test II (CVLT). Cerebellar volumes were automatically obtained using the Spatially Unbiased Infratentorial Toolbox. A hierarchical multiple linear regression analysis was performed to assess the relationship between MRI variables of supratentorial and cerebellar damage (grey matter fraction, T2 lesion volume, metrics of cerebellar atrophy and cerebellar lesion volume) and motor/cognitive scores. RESULTS: Patients with MS exhibited lower cerebellar volumes compared with HC. Regression analysis showed that cerebellar metrics accounted for extra variance in both motor and cognitive performances, with cerebellar lesion volume, cerebellar Lobules VI, Crus I and VIIIa atrophy being independent predictors of 9 HPT, SDMT, BVMT and CVLT performances. CONCLUSIONS: Atrophy of specific cerebellar lobules explains different aspects of motor and cognitive disability in patients with progressive MS. Investigation of cerebellar involvement provides further insight into the pathophysiological basis of clinical disability in progressive MS. PMID- 28844068 TI - Dimethyl fumarate: a possible exit strategy from natalizumab treatment in patients with multiple sclerosis at risk for severe adverse events. AB - INTRODUCTION: Among disease-modifying treatments for multiple sclerosis, natalizumab (NTZ) is highly effective, well tolerated and generally safe. Major concerns regard the risk of developing progressive multifocal leukoencephalopathy (PML), and the occurrence of rebounds or disease activity after its discontinuation. The aim of this study was to explore the efficacy of dimethyl fumarate (DMF) in preventing disease reactivation after NTZ discontinuation. METHODS: Thirty-nine patients with relapsing remitting multiple sclerosis, at high risk of PML, were switched from NTZ to DMF and underwent neurological and 3T MRI monitoring for 2 years. Clinical and MRI data regarding the 2-year period preceding NTZ treatment, the 2 years of NTZ treatment and the 2 years of DMF were collected. RESULTS: During the DMF phase, among the 39 patients, one or more relapses occurred in five patients (12.8%), increased disability progression in 4 (10.3%) and MRI activity in 8 (20.5%). Post-NTZ rebound effect was observed only in one patient. Overall, only two dropouts (one rebound activity and one gastrointestinal side effect) were registered and almost 80% of the patients have still no evidence of disease activity at the end of DMF treatment. The multiple linear regression model revealed that the number of relapses and MRI parameters before DMF treatment were good predictors of disease activity during treatment with DMF. DISCUSSION: DMF appeared generally safe and no carryover PML among investigated cases was observed. Although DMF did not eliminate the possibility of disease reactivation, it seems anyway a promising drug for those patients who shall discontinue NTZ. The clinical and radiological activity preceding the DMF treatment might be used as a prognostic marker of therapy response. PMID- 28844069 TI - Acute demyelinating polyneuropathy induced by nivolumab. PMID- 28844071 TI - Corticolimbic structural alterations linked to health status and trait anxiety in functional neurological disorder. AB - OBJECTIVE: Affective symptoms influence health status (health-related quality of life) in functional neurological disorder (FND), and the salience network is implicated in the pathophysiology of FND and mood/anxiety disorders. We hypothesised that self-reported health status and affective symptoms would map onto salience network regions and that patients with FND would show decreased insular volumes compared with controls. METHODS: This voxel-based morphometry study investigated volumetric differences in 26 patients with FND (21 women, 5 men; mean age=40.3+/-11.5) compared with 27 healthy controls (22 women, 5 men; mean age=40.5+/-10.8). Post hoc analyses stratified patients with FND by mental and physical health scores (Short Form Health Survey-36). Within-group analyses investigated associations with mental health, physical health, trait anxiety and depression in patients with FND. RESULTS: There were no volumetric differences between the complete FND cohort and controls. In stratified analyses, however, patients with FND reporting the most severe physical health impairments showed reduced left anterior insular volume compared with controls. In within-group analyses, impaired mental health and elevated trait anxiety were associated with increased right amygdalar volumes in patients with FND. The relationship between amygdalar volume and mental health, driven by emotional well-being deficits and role limitations due to emotional problems, was independent of sensorimotor functional neurological symptom severity and motor FND subtype. In secondary within-group analyses, increased periaqueductal grey volume was associated with role limitations due to emotional problems. Impaired physical functioning correlated with decreased left anterior insular volumes. CONCLUSIONS: These findings support roles for several regions of the salience network in the pathophysiology of FND. PMID- 28844072 TI - Update in diagnosis and management of primary aldosteronism. AB - Primary aldosteronism (PA) is a group of disorders in which aldosterone is excessively produced. These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis. The prevalence of PA ranges from 5% to 12% around the globe, and the most common causes are adrenal adenoma and adrenal hyperplasia. The importance of PA recognition arises from the fact that it can have a remarkably adverse cardiovascular and renal impact, which can even result in death. The aldosterone-to-renin ratio (ARR) is the election test for screening PA, and one of the confirmatory tests, such as oral sodium loading (OSL) or saline infusion test (SIT), is in general necessary to confirm the diagnosis. The distinction between adrenal hyperplasia (AH) or aldosterone-producing adenoma (APA) is essential to select the appropriate treatment. Therefore, in order to identify the subtype of PA, imaging exams such as computed tomography or magnetic ressonance imaging, and/or invasive investigation such as adrenal catheterization must be performed. According to the subtype of PA, optimal treatment - surgical for APA or pharmacological for AH, with drugs like spironolactone and amiloride - must be offered. PMID- 28844073 TI - The effects of dry ice exposure on plasma pH and coagulation analyses. AB - BACKGROUND: We recently observed that exposure to dry ice lowered sample pH and increased clotting times in lupus anticoagulant analyses, and that such changes could be prevented by placing samples at -80 degrees C after dry ice exposure. In the current study, we sought to evaluate the effects of dry ice exposure on pH and various commonly used coagulation analyses. METHODS: Citrated plasma from 30 healthy blood donors was allocated to four preanalytical regimes: (1) immediate analysis of fresh plasma or (2) storage at -20 degrees C; (3) storage at -20 degrees C followed by dry ice exposure for 24 h or (4) storage at -20 degrees C followed by dry ice exposure for 24 h and storage at -80 degrees C for 24 h before analysis. Analyses of pH, prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), antithrombin, fibrinogen, protein C and protein S was performed. RESULTS: Samples exposed to dry ice had significantly lower pH, prolonged clotting times in PT-INR, APTT and fibrinogen analyses as well as lower levels of protein C, than samples not exposed to dry ice. These changes in coagulation analyses were not present if samples were stored at -80 degrees C for 24 h after dry ice exposure. Antithrombin and protein S were not significantly affected by dry ice exposure. CONCLUSIONS: Dry ice exposure lowered sample pH and affected various coagulation analyses. These effects were avoided by storing samples at -80 degrees C for 24 h after dry ice exposure. PMID- 28844070 TI - The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice. AB - Cerebral amyloid angiopathy (CAA) has never been more relevant. The last 5 years have seen a rapid increase in publications and research in the field, with the development of new biomarkers for the disease, thanks to advances in MRI, amyloid positron emission tomography and cerebrospinal fluid biomarker analysis. The inadvertent development of CAA-like pathology in patients treated with amyloid beta immunotherapy for Alzheimer's disease has highlighted the importance of establishing how and why CAA develops; without this information, the use of these treatments may be unnecessarily restricted. Our understanding of the clinical and radiological spectrum of CAA has continued to evolve, and there are new insights into the independent impact that CAA has on cognition in the context of ageing and intracerebral haemorrhage, as well as in Alzheimer's and other dementias. While the association between CAA and lobar intracerebral haemorrhage (with its high recurrence risk) is now well recognised, a number of management dilemmas remain, particularly when considering the use of antithrombotics, anticoagulants and statins. The Boston criteria for CAA, in use in one form or another for the last 20 years, are now being reviewed to reflect these new wide-ranging clinical and radiological findings. This review aims to provide a 5-year update on these recent advances, as well as a look towards future directions for CAA research and clinical practice. PMID- 28844074 TI - Leptocarpin Suppresses Proliferation, Migration, and Invasion of Human Osteosarcoma by Targeting Type-1 Insulin-Like Growth Factor Receptor (IGF-1R). AB - BACKGROUND Leptocarpin (LTC) has drawn much attention for suppressing tumor growth or reducing inflammation. However, the effect of LTC on osteosarcoma has rarely been reported. Our object was to determine whether LTC suppresses MG63 cell proliferation, migration, and invasion, and whether type-1 insulin-like growth factor receptor (IGF-1R) is one of the targets in LTC suppressing osteosarcoma. MATERIAL AND METHODS Cytotoxicity of LTC was performed by use of a cell-counting kit-8 (CCK-8). RNA interference (RNAi) or pEABE-bleo IGF-1R plasmid were used for silencing or overexpressing IGF-1R, Western blot (WB) analysis was used for IGF-1R expression, CCK-8 for proliferation, and transwell assay for migration and invasion. RESULTS LTC (23.533 MUM) treatment for 48 h was taken as the 50% inhibiting concentration (IC50), which significantly (P<0.05) suppressed MG63 cells proliferation, migration, and invasion. LTC (IC50) obviously inhibited IGF-1R expression in MG63 cells, with similar effect to small interfering RNA (siRNA), while pEABE-bleo IGF-1R transfection overexpressed IGF-1R. siRNA silencing IGF-1R suppressed MG63 cells proliferation, migration, and invasion, while pEABE-bleo IGF-1R transfection was significantly (P<0.05) promoted. With or without siRNA or pEABE-bleo IGF-1R transfection, LTC (IC50) suppressed MG63 cells proliferation, migration, and invasion. The effect of LTC (IC50) combined with siRNA on suppressing MG63 cells proliferation, migration, and invasion was more obvious, while the effect of LTC (IC50) combined with pEABE-bleo IGF-1R transfection was less significant (P<0.05). CONCLUSIONS LTC suppressed osteosarcoma proliferation, migration, and invasion by inhibiting IGF-1R expression. IGF-1R is one of the targets in LTC suppressing osteosarcoma. PMID- 28844075 TI - HRCT findings of childhood follicular bronchiolitis. AB - BACKGROUND: Follicular bronchiolitis is a lymphoproliferative form of interstitial lung disease (ILD) defined by the presence of peribronchial lymphoid follicles. Follicular bronchiolitis has been associated with viral infection, autoimmune disease and immunodeficiency. The most common clinical manifestation is respiratory distress in infancy followed by a prolonged course with gradual improvement. We found no reports of systematic review of high-resolution computed tomography (HRCT) findings in pediatric follicular bronchiolitis. OBJECTIVE: The purpose of this study was to describe the HRCT findings of follicular bronchiolitis in children and correlate these imaging findings with histopathology. MATERIALS AND METHODS: A 5-year retrospective review of all pathology-proven cases of follicular bronchiolitis was performed. Inclusion criteria were age <18 years and an HRCT within 6 months of lung biopsy. HRCTs were reviewed by three observers and scored using the system previously described by Brody et al. RESULTS: Six patients met the inclusion criteria with age range at HRCT of 7-82 months (median: 39.5 months). Pulmonary nodules (n=6) were the most common HRCT finding followed by focal consolidation (n=5), bronchiectasis (n=4) and lymphadenopathy (n=3). Tree and bud opacities and nodules on CT correlated with interstitial lymphocytic infiltrates and discrete lymphoid follicles on pathology. CONCLUSION: The salient HRCT findings of childhood follicular bronchiolitis are bilateral, lower lung zone predominant pulmonary nodules and bronchiectasis with infantile onset of symptoms. These characteristic HRCT findings help differentiate follicular bronchiolitis from other forms of infantile onset ILD. PMID- 28844077 TI - Erratum to: The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review. PMID- 28844076 TI - Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic. AB - PURPOSE OF REVIEW: Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity. RECENT FINDINGS: Here, we will briefly review evidence that PTSD might be a "synaptic disconnection syndrome" and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics. PMID- 28844078 TI - Long-term effects of radiation therapy on white matter of the corpus callosum: a diffusion tensor imaging study in children. AB - BACKGROUND: Despite improving survival rates, children are at risk for long-term cognitive and behavioral difficulties following the diagnosis and treatment of a brain tumor. Surgery, chemotherapy and radiation therapy have all been shown to impact the developing brain, especially the white matter. OBJECTIVE: The purpose of this study was to determine the long-term effects of radiation therapy on white matter integrity, as measured by diffusion tensor imaging, in pediatric brain tumor patients 2 years after the end of radiation treatment, while controlling for surgical interventions. MATERIALS AND METHODS: We evaluated diffusion tensor imaging performed at two time points: a baseline 3 to 12 months after surgery and a follow-up approximately 2 years later in pediatric brain tumor patients. A region of interest analysis was performed within three regions of the corpus callosum. Diffusion tensor metrics were determined for participants (n=22) who underwent surgical tumor resection and radiation therapy and demographically matched with participants (n=22) who received surgical tumor resection only. RESULTS: Analysis revealed that 2 years after treatment, the radiation treated group exhibited significantly lower fractional anisotropy and significantly higher radial diffusivity within the body of the corpus callosum compared to the group that did not receive radiation. CONCLUSION: The findings indicate that pediatric brain tumor patients treated with radiation therapy may be at greater risk of experiencing long-term damage to the body of the corpus callosum than those treated with surgery alone. PMID- 28844080 TI - Synthetic MRI showed increased myelin partial volume in the white matter of a patient with Sturge-Weber syndrome. PMID- 28844079 TI - Gout and Metabolic Syndrome: a Tangled Web. AB - PURPOSE OF REVIEW: The complexity of gout continues to unravel with each new investigation. Gout sits at the intersection of multiple intrinsically complex processes, and its prevalence, impact on healthcare costs, and association with important co-morbidities make it increasingly relevant. The association between gout and type 2 diabetes, hypertension, hyperlipidemia, cardiovascular disease, renal disease, and obesity suggest that either gout, or its necessary precursor hyperuricemia, may play an important role in the manifestations of the metabolic syndrome. In this review, we analyze the complex interconnections between gout and metabolic syndrome, by reviewing gout's physiologic and epidemiologic relationships with its major co-morbidities. RECENT FINDINGS: Increasing evidence supports gout's association with metabolic syndrome. More specifically, both human studies and animal models suggest that hyperuricemia may play a role in promoting inflammation, hypertension and cardiovascular disease, adipogenesis and lipogenesis, insulin and glucose dysregulation, and liver disease. Fructose ingestion is associated with increased rates of hypertension, weight gain, impaired glucose tolerance, and dyslipidemia and is a key driver of urate biosynthesis. AMP kinase (AMPK) is a central regulator of processes that tend to mitigate against the metabolic syndrome. Within hepatocytes, leukocytes, and other cells, a fructose/urate metabolic loop drives key inhibitors of AMPK, including AMP deaminase and fructokinase, that may tilt the balance toward metabolic syndrome progression. Preliminary evidence suggests that agents that block the intracellular synthesis of urate may restore AMPK activity and help maintain metabolic homeostasis. Gout is both an inflammatory and a metabolic disease. With further investigation of urate's role, the possibility of proper gout management additionally mitigating metabolic syndrome is an evolving and important question. PMID- 28844081 TI - Comparison of global metabolite extraction strategies for soybeans using UHPLC HRMS. AB - Metabolism, downstream effectors of genomics, transcriptomics, and proteomics, can determine the potential of phenotype of an organism including plants. Profiling the global scenario of metabolism requires optimization of different solvent extraction methods. Here, we report an approach comparing three different metabolite extraction strategies, including ammonium acetate/methanol (AAM), water/methanol (WM), and sodium phosphate/methanol (PM) in soybean plant using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Interestingly, both AAM and WM methods were found to cover a wider range of metabolites and provide better detection of molecular features than the PM method. Various clustering analyses based on multivariate statistical tools revealed that both AAM and WM methods showed tight and overlapping extraction strategy compared with the PM method. Using MatLab-based Mahalanobis distance (D M) calculation, statistically significant score plot separation was observed between AAM and PM, as well as WM and PM. However, no significant separation was observed between AAM and WM, which is expected from the overlap of principal component scores for these two methods. Using differential metabolite expression analysis, we identified that a large number of metabolites were extracted at a significantly higher level using AAM vs. PM. These comparative extraction methods suggest that AAM can effectively be applied for an LC/MS-based plant metabolomics profile study. Graphical abstract Step-by step outline of three different metabolite extraction methods and data analysis. PMID- 28844082 TI - Molecular Data and the IPSS-R: How Mutational Burden Can Affect Prognostication in MDS. AB - PURPOSE OF REVIEW: The purpose of this study is to review established prognostic models in myelodysplastic syndromes (MDS) and describe how molecular data can be used to improve patient risk stratification. RECENT FINDINGS: Somatic mutations are common in MDS and are associated with disease features including outcomes. Several recurrently mutated genes have prognostic significance independent of risk stratification tools used in practice. However, this prognostic impact can depend on the clinicogenetic context in which mutations occur. Qualitatively, SF3B1 mutations appear favorable only in patients with < 5% bone marrow blasts while mutations of several genes, including ASXL1, SRSF2, U2AF1, NRAS, and IDH2, appear adverse in this context. Mutations of TP53, RUNX1, and EZH2 appear adverse regardless of blast percentage. Consensus on how to best incorporate mutations into risk assessment is still being developed. Somatic mutations can refine risk stratification and improve the accuracy of existing prognostic models, often upstaging or downstaging patients across the boundary of higher- and lower-risk MDS. PMID- 28844084 TI - Wireless induction coils embedded in diamond for power transfer in medical implants. AB - Wireless power and data transfer to medical implants is a research area where improvements in current state-of-the-art technologies are needed owing to the continuing efforts for miniaturization. At present, lithographical patterning of evaporated metals is widely used for miniature coil fabrication. This method produces coils that are limited to low micron or nanometer thicknesses leading to high impedance values and thus limiting their potential quality. In the present work we describe a novel technique, whereby trenches were milled into a diamond substrate and filled with silver active braze alloy, enabling the manufacture of small, high cross-section, low impedance microcoils capable of transferring up to 10 mW of power up to a distance of 6 mm. As a substitute for a metallic braze line used for hermetic sealing, a continuous metal loop when placed parallel and close to the coil surface reduced power transfer efficiency by 43%, but not significantly, when placed perpendicular to the microcoil surface. Encapsulation of the coil by growth of a further layer of diamond reduced the quality factor by an average of 38%, which can be largely avoided by prior oxygen plasma treatment. Furthermore, an accelerated ageing test after encapsulation showed that these coils are long lasting. Our results thus collectively highlight the feasibility of fabricating a high-cross section, biocompatible and long lasting miniaturized microcoil that could be used in either a neural recording or neuromuscular stimulation device. PMID- 28844083 TI - Alcohol Use as a Comorbidity and Precipitant of Primary Headache: Review and Meta analysis. AB - PURPOSE OF REVIEW: In contrast to well-established relationships between headache and affective disorders, the role of alcohol use in primary headache disorders is less clear. This paper provides a narrative overview of research on alcohol use disorders (AUDs) in primary headache and presents a meta-analysis of the role of alcohol as a trigger (precipitant) of headache. RECENT FINDINGS: The majority of studies on AUDs in headache have failed to find evidence that migraine or tension type headache (TTH) is associated with increased risk for AUDs or problematic alcohol use. The meta-analysis indicated that 22% (95% CI: 17-29%) of individuals with primary headache endorsed alcohol as a trigger. No differences were found between individuals with migraine (with or without aura) or TTH. Odds of endorsing red wine as a trigger were over 3 times greater than odds of endorsing beer. An absence of increased risk for AUDs among those with primary headache may be attributable to alcohol's role in precipitating headache attacks for some susceptible individuals. Roughly one fifth of headache sufferers believe alcohol precipitates at least some of their attacks. Considerable study heterogeneity limits fine-grained comparisons across studies and suggests needs for more standardized methods for studying alcohol-headache relationships and rigorous experimental designs. PMID- 28844087 TI - Follow-up recommendations: the challenge, the opportunity and our future. PMID- 28844086 TI - Caregiving and mutuality among long-term colorectal cancer survivors with ostomies: qualitative study. AB - PURPOSE: The cancer caregiving literature focuses on the early phases of survivorship, but caregiving can continue for decades when cancer creates disability. Survivors with an ostomy following colorectal cancer (CRC) have caregiving needs that may last decades. Mutuality has been identified as a relationship component that can affect caregiving. This paper discusses how mutuality may affect long-term ostomy caregiving. METHODS: We conducted semi structured, in-depth interviews with 31 long-term CRC survivors with ostomies and their primary informal caregivers. Interviewees were members of an integrated health care delivery system in the USA. We used inductive theme analysis techniques to analyze the interviews. RESULTS: Most survivors were 71 years of age or older (67%), female (55%), and with some college education (54%). Two thirds lived with and received care from spouses. Caregiving ranged from minimal support to intimate assistance with daily ostomy care. While some survivors received caregiving far beyond what was needed, others did not receive adequate caregiving for their health care needs. Low mutuality created challenges for ostomy caregiving. CONCLUSIONS: Mutuality impacts the quality of caregiving, and this quality may change over time, depending on various factors. Emotional feedback and amplification is the proposed mechanism by which mutuality may shift over time. Survivorship care should include assessment and support of mutuality as a resource to enhance health outcomes and quality of life for survivors with long-term caregiving needs and their caregivers. Appropriate questionnaires can be identified or developed to assess mutuality over the survivorship trajectory. PMID- 28844085 TI - Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: a Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia? AB - Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult.PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1alpha (HIF 1alpha) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD+ exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-kappaB subunit p65, overexpression of the pro inflammatory cytokines IL-1beta and TNF-alpha, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth. PMID- 28844088 TI - Familial Chilblain Lupus - What Can We Learn from Type I Interferonopathies? AB - PURPOSE OF REVIEW: Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms. RECENT FINDINGS: There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described. These genes are involved in the process of the detection of intracellular DNA, and their mutation results in an increased production of type I interferons and their gene products, resulting in auto inflammation and auto-immunity. JAK inhibitors have been successfully used to treat this disorder. Familial chilblain is a rare disorder with very distinct clinical signs. Its pathophysiological mechanism gives insight into the process of interferon-induced inflammation in auto-immune diseases. PMID- 28844089 TI - Reasons for and predictors of acute hospitalization versus elective outpatient implantable cardioverter-defibrillator implantation and subsequent differential clinical outcomes. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) implantation is often an elective outpatient procedure, but previous studies have shown that approximately 30% are performed during acute hospitalizations. PURPOSE: This study aims to identify predictors of acute hospitalization versus elective outpatient ICD implantation and evaluate differential clinical outcomes. METHODS: We studied 327 first-time ICD recipients between 2011 and 2015. All patients receiving a primary prevention ICD were optimized on guideline directed medical therapy (GDMT) prior to consideration for device implantation. Using multivariate logistic regression, we examined predictors of ICD implantation during acute hospitalization. Cox proportional hazard regression was used adjusting for patient characteristics to examine associations with clinical outcomes including complications, device therapy, heart failure re-admission, and death. RESULTS: Of all patients, 132 (40.3%) underwent ICD implantation during acute hospitalization, most frequently performed for secondary prevention (n = 76, 57.6%). The most common reason for acute hospitalization ICD implantation in primary prevention patients was an indication for pacing (n = 20, 35.7%). In multivariable adjusted models, secondary prevention indication, non-single chamber device, NYHA class IV symptoms, lower diastolic blood pressure, higher BUN, and lower hemoglobin were significant predictors of ICD implantation during an acute hospitalization. In univariate analysis, acute hospitalization ICD implantation was associated with a higher risk of heart failure re-admission (HR = 1.6, 95% CI 1.1-2.4) and mortality (HR = 3.0, 95% CI 1.1-8.0) but no difference in risk of ICD therapy (HR = 1.4, 95% CI 0.9-2.3) or adverse events (HR = 1.1, 95% CI 0.6-2.1). After multivariable adjustment for potential confounders, all outcomes were no different between acute hospitalization versus elective outpatient ICD recipients. CONCLUSIONS: Among first-time ICD recipients, specific clinical characteristics predicted acute hospitalization ICD implantation. After adjustment for potential confounders, acute hospitalization ICD implantation was not associated with increased risk of morbidity or mortality. PMID- 28844090 TI - Role of TRIM33 in Wnt signaling during mesendoderm differentiation. AB - Tripartite motif 33 (TRIM33), a member of the transcription intermediate factor 1 (TIF1) family of transcription cofactors, mediates transforming growth factor beta (TGF-beta) signaling through its PHD-Bromo cassette in mesendoderm differentiation during early mouse embryonic development. However, the role of the TRIM33 RING domain in embryonic differentiation is less clear. Here, we report that TRIM33 mediates Wnt signaling by directly regulating the expression of a specific subset of Wnt target genes, and this action is independent of its RING domain. We show that TRIM33 interacts with beta-catenin, a central player in Wnt signaling in mouse embryonic stem cells (mESCs). In contrast to previous reports in cancer cell lines, the RING domain does not appear to function as the E3 ligase for beta-catenin, since neither knockout nor overexpression of TRIM33 had an effect on beta-catenin protein levels in mESCs. Furthermore, we show that although TRIM33 seems to be dispensable for Wnt signaling through a reporter assay, loss of TRIM33 significantly impairs the expression of a subset of Wnt target genes, including Mixl1, in a Wnt signaling-dependent manner. Together, our results indicate that TRIM33 regulates Wnt signaling independent of the E3 ligase activity of its RING domain for beta-catenin in mESCs. PMID- 28844091 TI - Two sampling strategies for an overview of pesticide contamination in an agriculture-extensive headwater stream. AB - Two headwaters located in southwest France were monitored for 3 and 2 years (Auvezere and Aixette watershed, respectively) with two sampling strategies: grab and passive sampling with polar organic chemical integrative sampler (POCIS). These watersheds are rural and characterized by agricultural areas with similar breeding practices, except that the Auvezere watershed contains apple production for agricultural diversification and the downstream portion of the Aixette watershed is in a peri-urban area. The agricultural activities of both are extensive, i.e., with limited supply of fertilizer and pesticides. The sampling strategies used here give specific information: grab samples for higher pesticide content and POCIS for contamination background noise and number of compounds found. Agricultural catchments in small headwater streams are characterized by a background noise of pesticide contamination in the range of 20-70 ng/L, but there may also be transient and high-peak pesticide contamination (2000-3000 ng/L) caused by rain events, poor use of pesticides, and/or the small size of the water body. This study demonstrates that between two specific runoff events, contamination was low; hence the importance of passive sampler use. While the peak pesticide concentrations seen here are a toxicity risk for aquatic life, the pesticide background noise of single compounds do not pose obvious acute nor chronic risks; however, this study did not consider the risk from synergistic "cocktail" effects. Proper tools and sampling strategies may link watershed activities (agricultural, non-agricultural) to pesticides detected in the water, and data from both grab and passive samples can contribute to discussions on environmental effects in headwaters, an area of great importance for biodiversity. PMID- 28844092 TI - Retrospective review of effectiveness and safety of intravenous ferric carboxymaltose given to children with iron deficiency anaemia in one UK tertiary centre. AB - : In the paediatric population, ferric carboxymaltose (FCM) is only licenced for use in children older than 14 years, and the data in younger children remains scarce. We retrospectively reviewed data of all paediatric patients less than 14 years old who had received FCM infusion from August 2011 to June 2015 at the John Radcliffe Hospital (Oxford University Hospitals), UK. The patient demographics, significant medical history, FCM dose, and blood investigations (pre-FCM and post FCM) were reviewed. Of the 51 children, 41 had inflammatory bowel disease. There were 24 girls and 27 boys, aged 1 to 13 years, mean (SD) weight 28.4 (13.6) kg. Fifteen patients received at least one more course of FCM up to 35 months later. The time interval between pre-FCM and post-FCM investigations was 1 to 8 months. An improved, median (range) rise in blood indices following one FCM infusion was haemoglobin 2.7 (- 2.4 to 7) g/dL, serum iron 6.6 (- 0.6 to 21.1) MUmol/L, and transferrin saturation 14 (- 14 to 38)%. No adverse outcomes were documented. CONCLUSIONS: FCM was effective in increasing the key blood indices with no adverse outcomes in children less than 14 years of age, with a range of different conditions, majority with gastrointestinal disorders such as IBD. What is Known: * Ferric carboxymaltose (FCM) given via the intravenous (IV) route has been used widely in adults for the treatment of iron deficiency anaemia. * Sparse data exists on FCM use in paediatric population, including young children What is New: * FCM infusion should be considered as a means of iron administration in the paediatric population less than 14 years of age * No adverse outcomes were recorded following FCM in a young paediatric population (less than 14 years of age); the majority of whom had gastrointestinal disorders. PMID- 28844093 TI - Alpha-Linolenic Acid Treatment Reduces the Contusion and Prevents the Development of Anxiety-Like Behavior Induced by a Mild Traumatic Brain Injury in Rats. AB - Approximately, 1.7 million Americans suffer a TBI annually and TBI is a major cause of death and disability. The majority of the TBI cases are of the mild type and while most patients recover completely from mild TBI (mTBI) about 10% result in persistent symptoms and some result in lifelong disability. Anxiety disorders are the second most common diagnosis post-TBI. Of note, TBI-induced anxiety disorders are difficult to treat and remain a chronic condition suggesting that new therapies are needed. Previous work from our laboratory demonstrated that a mild TBI induced an anxiety-like phenotype, a key feature of the human condition, associated with loss of GABAergic interneurons and hyperexcitability in the basolateral amygdala (BLA) in rodents 7 and 30 days after a controlled cortical impact (CCI) injury. We now confirm that animals display significantly increased anxiety-like behavior 30 days after CCI. The anxiety-like behavior was associated with a significant loss of GABAergic interneurons and significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor-mediated inhibitory postsynaptic currents (IPSCs) in the BLA. Significantly, subchronic treatment with alpha-linolenic acid (ALA) after CCI prevents the development of anxiety-like behavior, the loss of GABAergic interneurons, hyperexcitability in the BLA and reduces the impact injury. Taken together, administration of ALA after CCI is a potent therapy against the neuropathology and pathophysiological effects of mTBI in the BLA. PMID- 28844094 TI - Optical coherence tomography as a marker of vision in children with optic pathway gliomas. AB - PURPOSE: Optic pathway gliomas (OPG) represent an important cause of visual loss in pediatric population. The indication of treatment is based on clinical or neuroimaging progression. Visual acuity loss is the most important symptom of disease progression, but children with OPG are frequently unable to complete the testing of visual function. Optical coherence tomography (OCT) was suggested as an objective tool for visual assessment. A literature review was performed in order to determine the role of retinal OCT as a surrogate marker of vision in children with OPG. METHODS: The search was performed using PubMed, Embase, and Web of Science databases and was restricted to articles published in English between 2000 and 2016, with a minimum of ten participants enrolled. RESULTS: Eleven studies met the eligibility criteria and were included in the present review. Both neurofibromatosis-1 associated and sporadic OPG were investigated. CONCLUSIONS: Retinal OCT is a promising tool to be considered as a screening or follow-up test in children with OPG, and further multicenter research is encouraged. PMID- 28844095 TI - Pancreatic Panniculitis and Polyarthritis. AB - PURPOSE OF REVIEW: Polyarthritis can have numerous reasons and may thus constitute a challenge for differential diagnosis. One rare potential reason for sterile polyarthritis is underlying pancreatic disease with systemic hyperlipasemia, most often accompanied by painful skin lesions caused by a subcutaneous inflammatory process known as panniculitis. Systematic evidence on pancreatic panniculitis and polyarthritis is limited, particularly regarding its feature as facultative paraneoplasia with underlying intra- or even extra pancreatic malignancy. Therefore, we will summarize the current knowledge about this orphan disease including epidemiological, pathophysiological, diagnostic, and treatment aspects in the present review. RECENT FINDINGS: Although direct evidence is lacking, it is highly probable that pancreatic polyarthritis and panniculitis are caused by peripheral lipolytic activity of lipase systemically circulating due to benign (e.g., acute or chronic pancreatitis) or malign (e.g., acinar cell carcinoma (ACC) or adenocarcinoma) pancreatic disease. In the latter case, pancreatic polyarthritis and panniculitis are associated with poor outcome. Pancreatic polyarthritis and panniculitis should always be included into diagnostic considerations, and once suspected, a thorough work-up to identify the underlying disease has to be performed. PMID- 28844096 TI - Dispersion of magnetic graphene oxide nanoparticles coated with a deep eutectic solvent using ultrasound assistance for preconcentration of methadone in biological and water samples followed by GC-FID and GC-MS. AB - Magnetic graphene nanoparticles coated with a new deep eutectic solvent (Fe3O4@GO DES) were developed for efficient preconcentration of methadone. The extracted methadone was then analyzed by gas chromatography-flame ionization detection (GC FID) or gas chromatography-mass spectrometry (GC-MS). Fe3O4@GO-DES were characterized by Fourier transform IR and X-ray diffraction techniques. Ultrasound was used to enhance the dispersion of the sorbent, with a high extraction recovery. Some parameters affecting the extraction recovery, such as pH, type of deep eutectic solvent, sample volume, amount of sorbent, extraction time, and type of eluent, were investigated. Under optimum conditions, the method developed was linear in the concentration range from 3 to 45,000 MUg L-1 for GC FID and from 0.1 to 500 MUg L-1 for GC-MS, with a detection limit of 0.8 MUg L-1 for GC-FID and 0.03 MUg L-1 for GC-MS. The relative standard deviations (n = 6) as the intraday and interday precisions of the methadone spike at a concentration of 100 MUg L-1 were 5.8% and 8.4% respectively for GC-FID. The preconcentration factor was 250. Relative recoveries from spiked plasma, urine, and water samples ranged from 95.1% to 101.5%. PMID- 28844097 TI - Letter in Reply to Arno et al. "Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism". PMID- 28844098 TI - The toxic influence of dibromoacetic acid on the hippocampus and pre-frontal cortex of rat: involvement of neuroinflammation response and oxidative stress. AB - Dibromoacetic acid (DBA) exsits in drinking water as a by-product of disinfection as a result of chlorination or ozonation processes. Hippocampus and pre-frontal cortex are the key structures in memory formation and weanling babies are more sensitive to environmental toxicant than adults, so this study was conducted to evaluate the potential neurotoxicity effects of DBA exposure when administered intragastrically for 4 weeks to weanling Sprague-Dawley rats, at concentration of 0, 20, 50, 125 mg/kg via the neurobehavioral and neurochemical effects. Results indicated that animals weight gain and food consumption were not significantly affected by DBA. However, morris water maze test showed varying degrees of changes between control and high-dose group. Additionally, the level of malondialdehyde (MDA) and generation of reactive oxygen species (ROS) in the hippocampus and pre-frontal cortex of rats increased significantly. The activities of total superoxide dismutase (SOD) and the glutathione (GSH) content in the hippocampus and pre-frontal cortex of rats decreased significantly after treatment with DBA. Treatment with DBA increased the protein and mRNA expression of Iba-1, NF-kappaB, TNF-alpha, IL-6, IL-1beta and HO-1 in the hippocampus and pre-frontal cortex of rats. These data suggested that DBA had a toxic influence on the hippocampus and pre-frontal cortex of rats, and that the mechanism of toxicity might be associated with the neuroinflammation response and oxidative stress. PMID- 28844099 TI - Epigenetic silencing of PRSS3 provides growth and metastasis advantage for human hepatocellular carcinoma. AB - : Protease, serine, 3 (PRSS3), a member of the trypsin family of serine proteases, has been shown to be aberrantly expressed in several cancer types and to play important roles in tumor progression and metastasis. However, the expression and function of PRSS3 gene in hepatocellular carcinoma (HCC) remain unclear. Here we found that PRSS3 expression was decreased in human HCC cell lines and HCC surgical specimens. This was associated with intragenic methylation of PRSS3 gene. Treatment with DNA methyltransferase inhibitor 5-aza-2' deoxycytidine and/or histone deacetylase inhibitor trichostatin A restored PRSS3 expression in HCC cell lines. Ectopic overexpression of PRSS3 gene in HCC cell lines significantly suppressed cell proliferation and colony formation and arrested cell cycle at G1/S phase, accompanied with downregulation of cyclin D1 (CCND1)/CDK4 and cyclin E1 (CCNE1)/CDK2 complexes. Moreover, PRSS3 overexpression in HCC cells inhibited HCC cell migration and invasion with downregulation of matrix metallopeptidase 2 (MMP2). Further study showed that PRSS3 overexpression diminished the phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase signaling protein, mitogen-activated protein kinase kinase 1 (MEK1)/mitogen-activated protein kinase kinase 2 (MEK2) and extracellular-signal related kinase 1 (ERK1)/extracellular-signal related kinase 2 (ERK2), in HCC cells. In contrast, knockdown of PRSS3 by small interfering RNA resulted in opposite effects on an HCC cell line SNU-387 which constitutively expresses PRSS3. These results demonstrate that downregulation of PRSS3 by intragenic hypermethylation provides growth and metastasis advantage to HCC cells. The clinical relevance of PRSS3 to human HCC was shown by the intragenic methylation of PRSS3 in HCC specimens and its association with poor tumor differentiation in patients with HCC. Thus, PRSS3 is a potential prognostic biomarker and an epigenetic target for intervention of human HCC. KEY MESSAGES: * PRSS3 is downregulated by intragenic hypermethylation in HCC. * Epigenetic silencing of PRSS3 facilitates growth, migration, and invasion of HCC. * PRSS3 intragenic methylation has implication in diagnosis of HCC. PMID- 28844100 TI - Physical symptoms in very young children assessed for sexual abuse: a mixed method analysis from the ASAC study. AB - : So far, a recognizable pattern of clinical symptoms for child sexual abuse (CSA), especially in young male children, is lacking. To improve early recognition of CSA, we reviewed physical complaints, physical examination, and tests on sexually transmitted infections (STIs) in confirmed victims (predominantly preschool boys) of CSA from the Amsterdam sexual abuse case (ASAC). We retrospectively analyzed the outcomes of the primary assessment using mixed methods: descriptive analysis of physical complaints, physical exams, and STI tests from medical files and a qualitative analysis on expert's interpretations of physical complaints and children's behavior during physical examination. We included 54 confirmed CSA victims, median age 3.2 (0-6) years, 43 boys (80%), and 11 girls (20%). Physical complaints were reported in 50%, of which gastrointestinal and anogenital complaints were most common. None of the children showed CSA-specific genital signs at physical examination. Most prominent finding during physical examination was a deviant behavioral response (anxiety, withdrawal, too outgoing) in 15 children (28%), especially in children who experienced anal/vaginal penetration. Testing for STIs was negative. CONCLUSION: Physical complaints and physical signs at examinations were non specific for CSA. Deviant behavioral reactions during physical examination were the most prominent finding. Precise observation of a child's behavior during physical examination is needed. What is known * Child sexual abuse (CSA) affects many children on both the short and the long term but remains unrecognized in most cases. * So far, there is a lack of studies on symptom patterns of CSA in male, preschool children. What is new * None of the children showed CSA-specific findings at physical and anogenital examination; STIs were not found in the confirmed victims of CSA. * The most prominent finding was the deviant behavioral response of the children examined, especially in children who experienced anal/vaginal penetration; therefore, precise observation of a child's behavior during physical examination is a crucial part of the evaluation of suspected CSA. PMID- 28844101 TI - Monitoring of selected pharmaceuticals in surface waters of Croatia. AB - Sulfonamides, macrolides, torasemide, fumagillin, and chloramphenicol were simultaneously analyzed in surface water samples by using solid-phase extraction (SPE) and reversed-phase (RP) liquid chromatography-electrospray tandem mass spectrometry (LC-ESI-MS/MS). In the pre-concentration and clean-up process, the pH value of samples and volume of the solvent for extraction of analytes from cartridge were optimized. Extraction recoveries were high with values in the range from 62 to 115%. Limits of quantification (LoQ) were in the range from 0.02 to 0.2 MUg L-1. Repeatability of the method was evaluated at LoQ and expressed as relative standard deviation (RSD). Calculated RSDs were low with values in the range from 2.4 to 14.5%. The method was successfully applied for analysis of surface water real samples. Samples were collected along the rivers in Croatia on four sampling sites in 2012 in Danube catchment areas, 19 sampling sites in Danube and Adriatic catchment areas in 2013, and another 19 places in 2014. Altogether, 20 target compounds were analyzed in 148 water samples and detected in 31 samples in range (0.1-5.3) MUg L-1 or in 20.1% of samples. The most frequent and highest concentrations were detected for macrolide antibiotics. This is the first attempt of such monitoring in surface waters in Croatia. PMID- 28844102 TI - Kubrick's The Shining and the erased myopathic face. PMID- 28844103 TI - The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance. AB - : Pseudomonas aeruginosa is an important opportunistic pathogen that has become a serious problem due to increased rates of antibiotic resistance. Due to this along with a dearth in novel antibiotic development, especially against Gram negative pathogens, new therapeutic strategies are needed to prevent a post antibiotic era. Here, we describe the importance of the vacJ/Mla pathway in resisting bactericidal actions of the host innate immune response. P. aeruginosa tn5 transposon mutants in genes from the VacJ/Mla pathway showed increased susceptibility to killing by the host cathelicidin antimicrobial peptide, LL-37, when compared to the wild-type parent strain. The P. aeruginosa vacJ - mutant demonstrated increased membrane permeability upon damage as well as sensitivity to killing in the presence of the detergent sodium dodecyl sulfate and the divalent cation chelator EDTA. When exposed to human whole blood and serum complement, the vacJ - mutant was killed more rapidly when compared to the wild type parent strain and complemented mutant. Finally, in an in vivo mouse lung infection model, infection with the vacJ - mutant resulted in reduced mortality, lower bacterial burden, and reduced lung damage when compared to the wild-type strain. This study highlights the potential in therapeutically targeting the VacJ/Mla pathway in sensitizing P. aeruginosa to killing by the host innate immune response. KEY MESSAGES: * The Mla pathway regulates outer membrane dynamics in human pathogen Pseudomonas aeruginosa (PA). * Disruption of Mla pathway gene vacJ sensitizes PA to host cathelicidin antimicrobial peptide LL-37. * Loss of vacJ expression renders PA more sensitive to human whole blood and serum killing. * Loss of vacJ expression reduces PA survival and virulence in a murine lung infection model. * The Mla pathway merits exploration as a pharmacologic target to sensitize PA to host innate immunity. PMID- 28844105 TI - The Floccular Syndrome: Dynamic Changes in Eye Movements and Vestibulo-ocular Reflex in Isolated Infarction of the Cerebellar Flocculus. AB - The cerebellar flocculus is a critical structure involved in the control of eye movements. Both static and dynamic abnormalities of the vestibulo-ocular reflex (VOR) have been described in animals with experimental lesions of the flocculus/paraflocculus complex. In humans, lesions restricted to the flocculus are rare so they can become an exceptional model to contrast with the clinical features in experimental animals or in patients with more generalized cerebellar diseases. Here, we examined a 67-year-old patient with an acute vestibular syndrome due to an isolated infarct of the right flocculus. We evaluated him multiple times over 6 months-to follow the changes in eye movements and vestibular function-with caloric testing, video-oculography and head-impulse testing, and the anatomical changes on imaging. Acutely, he had an ipsilateral beating spontaneous nystagmus, bilateral gaze-evoked nystagmus, borderline impaired smooth pursuit, and a complete contraversive ocular tilt reaction. The VOR gain was reduced for head impulses directed contralateral to the lesion, and there was also an ipsilesional caloric weakness. All abnormalities progressively improved at follow-up visits but with a considerable reduction in volume of the affected flocculus on imaging. The vestibular and ocular motor findings, qualitatively similar to a previously reported patient, further clarify the "acute floccular syndrome" in humans. We also add new information about the pattern of recovery from such a lesion with corresponding changes in the size of the affected flocculus on imaging. PMID- 28844104 TI - Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer's Disease. AB - Neprilysin (NPL), the rate-limiting enzyme for amyloid beta peptide (AbetaP), appears to play a crucial role in the pathogenesis of Alzheimer's disease (AD). Since mesenchymal stem cells (MSCs) and/or cerebrolysin (CBL, a combination of neurotrophic factors and active peptide fragments) have neuroprotective effects in various CNS disorders, we examined nanowired delivery of MSCs and CBL on NPL content and brain pathology in AD using a rat model. AD-like symptoms were produced by intraventricular (i.c.v.) administration of AbetaP (1-40) in the left lateral ventricle (250 ng/10 MUl, once daily) for 4 weeks. After 30 days, the rats were examined for NPL and AbetaP concentrations in the brain and related pathology. Co-administration of TiO2-nanowired MSCs (106 cells) with 2.5 ml/kg CBL (i.v.) once daily for 1 week after 2 weeks of AbetaP infusion significantly increased the NPL in the hippocampus (400 pg/g) from the untreated control group (120 pg/g; control 420 +/- 8 pg/g brain) along with a significant decrease in the AbetaP deposition (45 pg/g from untreated control 75 pg/g; saline control 40 +/- 4 pg/g). Interestingly, these changes were much less evident when the MSCs or CBL treatment was given alone. Neuronal damages, gliosis, and myelin vesiculation were also markedly reduced by the combined treatment of TiO2, MSCs, and CBL in AD. These observations are the first to show that co-administration of TiO2 nanowired CBL and MSCs has superior neuroprotective effects in AD probably due to increasing the brain NPL level effectively, not reported earlier. PMID- 28844106 TI - Determination of the content of selected elements in medieval waterlogged oak wood from the Lednica Lake-a case study. AB - The content of selected elements: Al, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, P, Pb, Sb, Si, Ti, V and Zn was determined in archaeological waterlogged oak wood from the Lednica Lake by using the inductively coupled plasma optical emission spectrometry (ICP-OES) method. The concentration of metals (especially heavy metals) in wood is typically specified to characterise this material and evaluate the possibility to use it for industrial purposes. In case of waterlogged archaeological wood intended for further research on new methods of conservation, such an analysis is important for other reasons. As it has been confirmed by numerous conservators and researchers, the presence of metal compounds is a serious problem not only due to their destructive influence on wood tissue but also from a conservation/re-conservation perspective. Metal containing chemicals may influence conservation treatments by reacting with substances used for wood conservation and causing irreversible damage to wooden objects. Therefore, while developing new solutions for wood conservation, a broad knowledge not only on the state of wood preservation and deterioration but also on interacting chemical factors is required. The results of the research clearly show that content of minerals in waterlogged wood excavated from the bottom of the Lednica Lake considerably exceeded the average percentage of these elements in contemporary wood, which is associated with the mineralisation process. Moreover, variability in metal content was observed between waterlogged and contemporary wood. In waterlogged wood, the highest concentrations of Ca, Fe, Mg and P were observed, while in contemporary oak wood the predominant concentrations of K, Ca, Mn and Si were determined. Statistical analysis showed the variability in content of elements between different archaeological wood zones and contemporary wood. On the basis of the results obtained, it could be concluded that the studied waterlogged wood acted as an adsorbent of elements from water and sediments. High content of metal ions can be an impediment in developing new formulations for conservation, while using this wood as an experimental material. Therefore, while planning to use new chemicals as conservation agents, the possible interactions between chemicals and metals must be taken into consideration. PMID- 28844107 TI - Impacts of a care process model and inpatient electrophysiology service on cardiovascular implantable electronic device infections: a preliminary evaluation. AB - PURPOSE: Cardiovascular implantable electronic device infection (CIEDI) rates are rising. To improve outcomes, our institution developed an online care process model (CPM) and a specialized inpatient heart rhythm service (HRS). METHODS: This retrospective review compared hospital length of stay (LOS), mortality, and times to subspecialty consultation and procedures before and after CPM and HRS availability. RESULTS: CPM use was associated with shortened time to surgical consultation (median 2 days post-CPM vs. 3 days pre-CPM, p = 0.0152), pocket closure (median 4 vs. 5 days, p < 0.0001), and days to new CIED implant (median 7 vs. 8 days, p = 0.0126). Post-HRS patients were more likely to have a surgical consultation (OR 7.01, 95% CI 1.56-31.5, p = 0.011) and shortened time to pocket closure (coefficient - 2.21 days, 95% CI - 3.33 to - 1.09, p < 0.001), compared to pre-HRS. CONCLUSIONS: The CPM and HRS were associated with favorable outcomes, but further integration of CPM features into hospital workflow is needed. PMID- 28844108 TI - Are holocentrics doomed to change? Limited chromosome number variation in Rhynchospora Vahl (Cyperaceae). AB - Karyotype evolution in species with non-localised centromeres (holocentric chromosomes) is usually very dynamic and associated with recurrent fission and fusion (also termed agmatoploidy/symploidy) events. In Rhynchospora (Cyperaceae), one of the most species-rich sedge genera, all analysed species have holocentric chromosomes and their numbers range from 2n = 4 to 2n = 84. Agmatoploidy/symploidy and polyploidy were suggested as the main processes in the reshuffling of Rhynchospora karyotypes, although testing different scenarios of chromosome number evolution in a phylogenetic framework has not been attempted until now. Here, we used maximum likelihood and model-based analyses, in combination with genome size estimation and ribosomal DNA distribution, to understand chromosome evolution in Rhynchospora. Overall, chromosome number variation showed a significant phylogenetic signal and the majority of the lineages maintained a karyotype of 2n = 10 (~48% of the species), the most likely candidate for the ancestral number of the genus. Higher and lower chromosome numbers were restricted to specific clades, whilst polyploidy and/or fusion/fission events were present in specific branches. Variation in genome size and ribosomal DNA site number showed no correlation with ploidy level or chromosome number. Although different mechanisms of karyotype evolution (polyploidy, fusion and fission) seem to be acting in distinct lineages, the degree of chromosome variation and the main mechanisms involved are comparable to those found in some monocentric genera and lower than expected for a holocentric genus. PMID- 28844109 TI - Intratumoral Heterogeneity of Somatic Mutations for NRIP1, DOK1, ULK1, ULK2, DLGAP3, PARD3 and PRKCI in Colon Cancers. AB - Both NRIP1 and DOK1 genes are considered candidate tumor suppressor genes (TSGs). Also, cell polarity-related genes PARD3, PRKCI and DLGAP3, and autophagy-related genes ULK1 and ULK2 genes are considered to play crucial roles in tumorigenesis. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 harbored 18 (22.8%), 2 (2.5%), 2 (2.5%), 2 (2.5%), 5 (6.3%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. We also studied ITH for the frameshift mutations in 16 cases of CRCs and detected that the frameshift mutations of NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 showed regional ITH in 5 (31.3%), 2 (12.5%), 0 (0%), 0 (0%), 1 (6.3%), 1 (6.3%) and 3 (18.8%) cases, respectively. Our data exhibit that candidate cancer-related genes NRIP1, DOK1, PARD3, PRKCI, DLGAP3, ULK1 and ULK2 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC. PMID- 28844110 TI - Transcriptome comparison identifies potential biomarkers of spine and skull base chordomas. AB - Chordomas are rare, slowly growing, locally aggressive bone neoplasms that arise from embryonic remnants of the notochord, showing dual epithelial-mesenchymal differentiation. The high plasticity probably is the main reason for the high variety in phenotypes of chordoma, from its high heterogeneity on a cellular level to its subtype variations depending on tissue location, with its potential to develop from an inactive quiescent form to an aggressive cancer with extreme adaptability and resistance to drugs and other treatments. Gene expression profiles of formalin-fixed, paraffin-embedded skull chordoma, spine chordoma, and normal tissue specimens were generated and compared. Using strict criteria, we identified 222 differentially expressed transcripts unique to skull base chordoma, 261 unique to spine chordoma, and 192 common to both chordoma subtypes. Further analysis of these three groups of transcripts allowed the selection of three subsets of highly differentially expressed genes as potential biomarkers, disease drivers, and therapeutic targets in both chordoma subtypes. Immunohistochemistry revealed LMX1A to be dominant in skull base chordoma, SALL3 to be unique to spine chordoma, and T to be common to both chordoma subtypes. In both chordoma subtypes, the genes with the highest expression were predominantly development-related genes, mostly transcription factors. Our findings indicate that these developmental genes play important oncogenic roles in chordoma, mainly causing high plasticity and resistance to therapy in both these cancer subtypes but also determining their differentiation status and proliferation activity, pointing to features expected of heterogeneous stem cell-like tissues with similarities to their notochord origins. PMID- 28844111 TI - Development of a novel intra-abdominal pressure transducer for large scale clinical studies. AB - Intra-abdominal pressure may be one of the few modifiable risk factors associated with developing a pelvic floor disorder. With one in eight women having surgery to correct a pelvic floor disorder in their lifetimes, intra-abdominal pressure may be a key to understanding the disease etiology and how to mitigate its occurrence and progression. Many traditional methods of intra-abdominal pressure measurement have limitations in data quality, environment of use, and patient comfort. We have modified a previously reported intravaginal pressure transducer that has been shown to overcome other intra-abdominal pressure measurement technique limitations (Coleman et al. 2012). Our modifications to the intravaginal pressure transducer make it easier to use, less costly, and more reliable than previous designs, while maintaining accuracy, integrity, and quality of data. This device has been used in over 400 participants to date as part of one of the most comprehensive studies examining the relationship between intra-abdominal pressure and pelvic floor disorders. PMID- 28844112 TI - Reactive Oxygen Species Produced by a Photodynamic Effect Induced Calcium Signal in Neurons and Astrocytes. AB - Photodynamic therapy (PDT) leads to production of reactive oxygen species (ROS) and cell destruction due to oxidative stress. We used photodynamic effect of photosensitizer radachlorin to unravel the effect of photo-induced oxidative stress on the calcium signal and lipid peroxidation in primary culture of cortical neurons and astrocytes using live cell imaging. We have found that irradiation in presence of 200 nM of radachlorin induces calcium signal in primary neurons and astrocytes. Photo-induced neuronal calcium signal depends on internal calcium stores as it was still observed in calcium-free medium and could be blocked by depletion of endoplasmic reticulum (ER) stores with inhibitor of sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) thapsigargin. Both inhibitors of phospholipase C activity U73122 and water-soluble analogue of vitamin E Trolox suppressed calcium response activated by PDT. We have also observed that the photodynamic effect of radachlorin induces lipid peroxidation in neurons and astrocytes. This data demonstrate that lipid peroxidation induced by PDT in neurons and astrocytes leads to activation of phospholipase C that results in production of inositol 1,4,5-trisphosphate (IP3). PMID- 28844113 TI - Effect of UV irradiation on aflatoxin reduction: a cytotoxicity evaluation study using human hepatoma cell line. AB - In this proof-of-concept study, the efficacy of a medium-pressure UV (MPUV) lamp source to reduce the concentrations of aflatoxin B1, aflatoxin B2, and aflatoxin G1 (AFB1, AFB2, and AFG1) in pure water is investigated. Irradiation experiments were conducted using a collimated beam system operating between 200 to 360 nm. The optical absorbance of the solution and the irradiance of the lamp are considered in calculating the average fluence rate. Based on these factors, the UV dose was quantified as a product of average fluence rate and treatment time. Known concentrations of aflatoxins were spiked in water and irradiated at UV doses ranging from 0, 1.22, 2.44, 3.66, and 4.88 J cm-2. The concentration of aflatoxins was determined by HPLC with fluorescence detection. LC-MS/MS product ion scans were used to identify and semi-quantify degraded products of AFB1, AFB2, and AFG1. It was observed that UV irradiation significantly reduced aflatoxins in pure water (p < 0.05). Irradiation doses of 4.88 J cm-2 reduced concentrations 67.22% for AFG1, 29.77% for AFB2, and 98.25% for AFB1 (p < 0.05). Using this technique, an overall reduction of total aflatoxin content of ~95% (p < 0.05) was achieved. We hypothesize that the formation of OH radicals initiated by UV light may have caused photolysis of AFB1, AFB2, and AFG1 molecules. In cell culture studies, our results demonstrated that the increase of UV dosage decreased the aflatoxin-induced cytotoxicity in HepG2 cells. Therefore, our research finding suggests that UV irradiation can be used as an effective technique for the reduction of aflatoxins. PMID- 28844114 TI - The clinicopathologic spectrum of mature aggressive B cell lymphomas. AB - Our understanding of mature aggressive B cell lymphomas has evolved significantly in the last years as reflected in the 2016 update of the WHO lymphoma classification. A main topic of the 2016 European Association for Haematopathology/Society of Hematopathology lymphoma workshop in Basel therefore was the clinicopathological spectrum of mature aggressive B cell lymphomas with the exception of conventional diffuse large B cell lymphoma. In this review, we summarize two sessions dedicated to "high-grade B cell lymphomas, with MYC and BCL2 and/or BCL6 rearrangements (so-called double/triple-hit lymphomas)" and "high-grade B cell lymphomas, NOS" as defined in the 2016 update of the WHO lymphoma classification, Burkitt lymphoma and related neoplasms, and terminally differentiated aggressive B cell lymphomas. One focus was on cases of Burkitt lymphoma with unusual clinical features such as spontaneous regression or association with immunosuppression, and the new provisional category of Burkitt like lymphoma with 11q aberration. The large numbers of cases submitted for the new high-grade categories with or without genetic "double/triple hit" demonstrated the broad clinical and pathological spectrum of this group and gave ample opportunity for discussion. In this review, current definitions and our understanding of the main high-grade categories, potential problem areas, and suggestions for the immunophenotypic and genetic work-up of these neoplasms are discussed and illustrated by many interesting and challenging cases submitted to the workshop. PMID- 28844115 TI - In reply to: letter to the editor entitled: primary pure lymphoepithelioma-like carcinoma of the ureter. PMID- 28844116 TI - Cardiometabolic Disorders in Psoriatic Disease. AB - PURPOSE OF REVIEW: Patients with psoriasis and psoriatic arthritis, collectively termed psoriatic disease (PsD), are at an increased risk of developing cardiovascular diseases (CVD). The purpose if this manuscript is to review recent evidence about the epidemiology and underlying mechanisms of CVD in psoriatic patients and approaches to improve the management of these comorbidities. RECENT FINDINGS: Studies have shown that CVD risk is independent of traditional cardiovascular risk factors and is related to the systemic inflammatory nature of PsD. The use of surrogate markers, such as imaging of subclinical atherosclerosis, allows detection of patients at high cardiovascular risk before the occurrence of clinical events. These modalities could be clinically useful as clinical cardiovascular risk algorithms, such as the Framingham Risk Score, and have been shown to underestimate the actual cardiovascular risk in patients with PsD. Additional challenges related to the management of CVD in psoriatic patients include the underdiagnosis and undertreatment of traditional cardiovascular risk factors in rheumatology, dermatology and primary care setting. Effective measures used to control PsD, such as tumour necrosis factor inhibitors and methotrexate, has been associated with reduced cardiovascular risk in psoriatic patients. These findings highlight the importance of controlling disease activity as potential target that could lead to reduced cardiovascular risk. Together this highlights the importance of optimization of cardiovascular risk stratification and management of cardiovascular risk factors in patients with PsD. PMID- 28844117 TI - Well-Differentiated Thyroid Cancer Neovasculature Expresses Prostate-Specific Membrane Antigen-a Possible Novel Therapeutic Target. AB - Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein receptor, is highly expressed in prostate cancer and in the tumor neovasculature of colon, breast, and adrenocortical tumors. Here, we analyzed PSMA expression in the neovasculature of various thyroid cancer subtypes and assessed whether PSMA expression is correlated with aggressive behavior. From a prospectively maintained database, we evaluated 91 samples from 68 patients, including 37 primary differentiated thyroid cancers (DTCs) [11 classic papillary (cPTC), 9 follicular-variant (FvPTC), 11 follicular (FTC), 6 radioactive iodine-refractory (RAIR)], 5 anaplastic (ATC) carcinomas, 9 distant and 12 lymph node metastases, 21 benign thyroid nodules, and 7 normal thyroid specimens. Formalin-fixed paraffin-embedded tissue blocks were immunostained for vascular endothelial marker CD31 and PSMA with proper controls. PSMA expression was not detected in normal thyroid tissue. DTC tumors demonstrated a significantly higher PSMA expression, in regard to both intensity and percentage of vessels stained, than benign tumors (p < 0.001). Among the histologic subtypes, cPTC, FTC, and RAIR carcinomas demonstrated the highest percent of moderate to strong PSMA staining. PSMA expression was seen more frequently in specimens from distant metastases (100%) compared with specimens from only lymph node metastases (67%). PSMA is significantly overexpressed in the neovasculature of DTCs compared with normal and benign thyroid nodules specifically with increased expression in RAIR carcinomas and distant metastases. PSMA should be further explored as a novel therapeutic target for metastatic and RAIR carcinomas. PMID- 28844118 TI - MDCO-216 Does Not Induce Adverse Immunostimulation, in Contrast to Its Predecessor ETC-216. AB - PURPOSE: Aim of this study was to demonstrate that MDCO-216 (human recombinant Apolipoprotein A-I Milano) does not induce adverse immunostimulation, in contrast to its predecessor, ETC-216, which was thought to contain host cell proteins (HCPs) that elicited an inflammatory reaction. METHODS: Data were taken from a clinical trial in which 24 healthy volunteers (HV) and 24 patients with proven stable coronary artery disease (sCAD) received a single intravenous dose of MDCO 216, ranging 5-40 mg/kg. Additionally, whole blood from 35 HV, 35 sCAD patients and 35 patients requiring acute coronary intervention (aCAD group) was stimulated ex vivo with MDCO-216 and ETC-216. RESULTS: No inflammatory reaction was observed in HV and sCAD patients following MDCO-216 treatment, judging by body temperature, white cell counts, neutrophil counts, C-reactive protein, circulating cytokines (IL-6, TNF-alpha), and adverse events. In the ex vivo experiment, the geometric means (SD) of the ratio of MDCO-216 stimulated IL-6 over background levels were 0.8 (1.9), 0.7 (1.5), 1.0 (2.0) for respectively HV, sCAD, aCAD. The corresponding ETC-216 stimulated values were 15.8 (2.9), 9.5 (3.6), 3.8 (4.0). TNF-alpha results were comparable. Because many ETC-216 stimulated samples had cytokine concentrations >ULOQ, ratios were categorised and marginal homogeneity of the contingency table (MDCO-216 versus ETC-216) was assessed with the Stuart-Maxwell test. P-values were <=0.0005 for all populations. CONCLUSIONS: MDCO-216 did not induce adverse immunostimulation in HV and sCAD patients, in contrast to ETC-216. Results from the ex vivo stimulation suggests the same holds true for aCAD patients. PMID- 28844119 TI - The Role of HINT1 in Methamphetamine-Induced Conditioned Place Preference. AB - Drug addiction is a chronically relapsing disorder in humans; yet, the underlying mechanism remained unclear. Recent studies suggested that the histidine triad nucleotide binding protein 1 (HINT1) may play significant roles in diverse neuropsychiatric diseases including drug addiction. In our present study, we used different batches of mice to establish the different stages of methamphetamine (METH)-induced conditioned place preference (CPP) to explore the dynamic changes throughout the process of addiction in different brain regions, including prefrontal cortex (PFC), nucleus accumbens (NAc), corpus striatum (CPu), and hippocampus (Hip). We found that in NAc of the METH group mice, the HINT1 expression level initially increased after acquisition phases, and then dropped to the normal level after extinction phase, and again increased after reinstatement phase. However, there was no statistical difference in the HINT1 expression level in other three encephalic regions (PFC, CPu, and Hip). Therefore, the HINT1 protein, particularly in the NAc, plays a vital role in the METH-induced CPP. However, the precise mechanisms will require further investigation. PMID- 28844120 TI - Development of a biodegradable flow resisting polymer membrane for a novel glaucoma microstent. AB - Within this paper we analyzed the technical feasibility of a novel microstent for glaucoma therapy. For lowering of intraocular pressure, the flexible polyurethane (PUR) implant is designed to drain aqueous humour from the anterior chamber of the eye into subconjunctival, or alternatively suprachoroidal, space. The microstent includes a biodegradable, flow resisting polymer membrane serving as temporary flow resistance for the prevention of early postoperative hypotony. A biodegradable local drug delivery (LDD)-device was designed to prevent fibrous encapsulation. Biodegradable components were made of flexible, nonwoven membranes of Poly(4-hydroxybutyrate) (P(4HB)). Polymer samples and microstent prototypes were manufactured by means of dip coating, electrospinning and femtosecond-laser micromachining and characterized in vitro with regard to structural and fluid mechanical properties, degradation behavior and drug release. Bending stiffness of PUR-tubing (62.53 +/- 7.57 mN mm2) is comparable to conventional glaucoma drainage devices in a tube-plate design. Microstent prototypes yield a flow resistance of 2.4 +/- 0.6 mmHg/MUl min-1 which is close to the aspired value corresponding to physiological pressure (15 mmHg) and aqueous humour flow (2 MUl min-1) conditions inside the eye. Degradation of electrospun P(4HB) specimens was found to be almost completely finished after six months in vitro. Within this time frame, flow capacity of the microstent increases, which is beneficial to compensate potentially increasing flow resistance of fibrous tissue in vivo. Fast drug release of the LDD-device was found. One microstent prototype was implanted into a porcine eye ex vivo. Future preclinical studies will allow further information about Microstent performance. PMID- 28844121 TI - A rapid LC-MS/MS method for the determination of moniliformin and occurrence of this mycotoxin in maize products from the Bavarian market. AB - A simple LC-MS/MS method was developed for the determination of moniliformin (MON) in maize and applied for the analysis of samples within the official food surveillance. The homogenized samples were extracted with acetonitrile/water 50/50 (v/v) which proved to have the highest extraction efficiency compared to other tested solvents. The centrifuged extracts were diluted with acetonitrile and were measured after chromatographic separation by HILIC (hydrophobic interaction liquid chromatography)-HPLC without any cleanup (dilute and shoot approach). The LOD and LOQ achieved by this procedure were 2.6 and 8.8 MUg/kg, respectively. Thirty-nine samples of popcorn, maize meal, and semolina were collected in 2014 and 2015 at mills, cinemas, wholesale, and retail from the Bavarian market (Germany). The rate of contamination with MON was very high (97%) with levels ranging between the LOD and 847 MUg/kg. The mean level was 118 MUg/kg and the median, 39 MUg/kg. The maximum value was detected in maize meal. The results are discussed with respect to possible health implications for the consumer. PMID- 28844122 TI - Clinical significance of radiation-induced liver disease after stereotactic body radiation therapy for hepatocellular carcinoma. AB - BACKGROUND/AIMS: The aim of this study was to investigate parameters that predict radiation-induced liver disease (RILD) following stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to identify the clinical significance of RILD. METHODS: We retrospectively reviewed the medical records of 117 HCC patients who were treated by SBRT from March 2011 to February 2015. RILD was defined as elevated liver transaminases more than five times the upper normal limit or a worsening of Child-Pugh (CP) score by 2 within 3 months after SBRT. All patients were assessed at 1 month and every 3 months after SBRT. RESULTS: Median follow-up was 22.5 months (range, 3 to 56) after SBRT. RILD was developed in 29 of the 117 patients (24.7%). On univariate analysis, significant predictive factors of RILD were pretreatment CP score (p < 0.001) and normal liver volume (p = 0.002). Multivariate analysis showed that CP score was a significant predictor of RILD (p < 0.001). The incidence of RILD increased above a CP score of 6 remarkably. The rate of recovery from RILD decreased significantly above a CP score of 8. Survival analysis showed that CP score was an independent prognostic factor of overall survival (p = 0.001). CONCLUSION: CP score is a significant factor to predict RILD in patients with chronic liver disease. RILD can be tolerated by patients with a CP score <= 7. However, careful monitoring of liver function is needed for patients with a CP score 7 after SBRT. PMID- 28844124 TI - Analysis of Kudoa septempunctata as a cause of foodborne illness and its associated differential diagnosis. PMID- 28844123 TI - Use of hypnotics and the risk of or mortality from heart disease: a meta-analysis of observational studies. AB - Background/Aims: Some observational epidemiologic studies have reported conflicting results on the relationship between hypnotics use and the risk of developing and/or dying from heart disease. We investigated these associations using a meta-analysis of available literatures. METHODS: We searched the databases PubMed and EMBASE, along with the bibliographies of relevant articles to find additional publications in February 2016. RESULTS: Of 495 articles satisfying our initial criteria, two case-control studies and six cohort studies met our inclusion criteria and were included in the final analyses. Compared with never having used any kind of hypnotics, the odds ratio for overall use was 0.84 for risk of or mortality from heart disease (95% confidence interval, 0.79 to 0.89) in a random-effects meta-analysis of all eight studies. With respect to the geographical region, use of hypnotics was associated with a decreased risk or mortality of heart disease in Asia but not in Western countries. Among various types of sleep medications, zolpidem showed a decreased risk (-29%) of developing or dying from heart disease, but benzodiazepines were related with an increased risk (80%) of or mortality from heart disease. Conclusions: The current meta analysis of observational epidemiological studies suggested an evidence of association between hypnotics use and a decreased risk of heart disease. PMID- 28844125 TI - Stem Cell Therapy for Avascular Necrosis of Femoral Head in Sickle Cell Disease: Report of 11 Cases and Review of Literature. AB - Background and Objective: Sickle cell disease (SCD) is quite common in eastern Saudi Arabia and Avascular necrosis of femoral head (ANFH) occurs in 30% of the young patients leading to early joint arthroplasty. This study was conducted to assess the benefits of injection of osteoblasts in the avascular lesions of the head of femur. Patients and Methods: A preset technique was used, 10 CC of bone marrow aspiration was performed under local anesthesia and aseptic technique. Osteoblasts were separated from the bone marrow cells. The avascular area was drilled and 10 million osteoblasts were transplanted at the lesion site. Patients were seen in the out patient clinic after two weeks for removal of the suture and addressed the questionnaire and examined for the range of movement. The follow up MRI was performed at 4 months. Results: The average age was 20.2+/-3.9 years. The mean hemoglobin S was 81.6+/-4.8 percent. Quality of Life Score for Chronic Hip Disease was assessed and found at 8.6 (1 being the severe limitation and 10 being normal), whereas Harris hip score improved from 41.7+/-5.1 to 88.93+/-3.6 (p < 0.001). MRI of pre and post osteoblast implantation showed robust new bone formation and disappearance of the avascular lesions. Conclusions: The short term results were good and we believe the injection of osteoblast in the avascular lesion of head of femur is a less invasive procedure devoid of any untoward complications and merits such treatment in large patient group with longer follow up. PMID- 28844126 TI - The Effect of Different Routes of Injection of Bone Marrow Mesenchymal Stem Cells on Parotid Glands of Rats Receiving Cisplatin: A Comparative Study. AB - Background and Objectives: Cisplatin is a powerful antitumor chemotherapeutic agent that is widely used in the treatment of many cancers but it has many side effects on many organs including salivary glands. Bone marrow is considered to be a rich environment that comprises many types of stem cells of which BMSCs (Bone marrow mesenchymal stem cells) are the most studied with potentiality to differentiate into many cell types. This study was conducted to evaluate the effect of different routes of injection of BMSCs on parotid glands of rats receiving cisplatin. Methods and Results: Sprague-Dawley rats were divided into 3 groups: a negative control group receiving phosphate buffered saline, a positive control group receiving cisplatin, and an experimental group where rats received cisplatin and then received iron oxide-labeled BMSCs by either intravenous or intraparotid routes or both. Animals were sacrificed at periods of 3,6,10 and 15 days after cisplatin injection, then histological, ultrastructural and immunohistochemical studies were done. The experimental stem cell treated group showed better histological features and increased PCNA proliferation index when compared to the control. The systemic and combination groups showed better results than the local group. Iron oxide-labeled cells were detected with Prussian blue stain. Conclusions: This study proved that BMSCs can improve cisplatin induced cytotoxicity in parotid glands. Systemic administration showed to have a better effect than local intraparotid administration and comparable effect to combined administration. PMID- 28844127 TI - Direct Conversion of Human Umbilical Cord Blood into Induced Neural Stem Cells with SOX2 and HMGA2. AB - Recent advances have shown the direct reprogramming of mouse and human fibroblasts into induced neural stem cells (iNSCs) without passing through an intermediate pluripotent state. Thus, direct reprogramming strategy possibly provides a safe and homogeneous cellular platform. However, the applications of iNSCs for regenerative medicine are limited by the restricted availability of cell sources. Human umbilical cord blood (hUCB) cells hold great potential in that immunotyped hUCB units can be immediately obtained from public banks. Moreover, hUCB samples do not require invasive procedures during collection or an extensive culture period prior to reprogramming. We recently reported that somatic cells can be directly converted into iNSCs with high efficiency and a short turnaround time. Here, we describe the detailed method for the generation of iNSCs derived from hUCB (hUCB iNSCs) using the lineage-specific transcription factors SOX2 and HMGA2. The protocol for deriving iNSC-like colonies takes 1~2 weeks and establishment of homogenous hUCB iNSCs takes additional 2 weeks. Established hUCB iNSCs are clonally expandable and multipotent producing neurons and glia. Our study provides an accessible method for generating hUCB iNSCs, contributing development of in vitro neuropathological model systems. PMID- 28844128 TI - A Simple Method to Isolate and Expand Human Umbilical Cord Derived Mesenchymal Stem Cells: Using Explant Method and Umbilical Cord Blood Serum. AB - Background and Objectives: Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from umbilical cords and are therapeutically used because of their ability to differentiate into various types of cells, in addition to their immunosuppressive and anti-inflammatory properties. Fetal bovine serum (FBS), considered as the standard additive when isolating and culturing MSCs, has a major limitation related to its animal origin. Here, we employed a simple and economically efficient protocol to isolate MSCs from human umbilical cord tissues without using digestive enzymes and replacing FBS with umbilical cord blood serum (CBS). Methods and Results: MSCs were isolated by culturing umbilical cord pieces in CBS or FBS supplemented media. Expansion and proliferation kinetics of cells isolated by explant method in the presence of either FBS or CBS were measured, with morphology and multi-differentiation potential of expanded cells characterized by flow cytometry, RT-PCR, and immunofluorescence. MSCs maintained morphology, immunophenotyping, multi differentiation potential, and self-renewal ability, with better proliferation rates for cells cultured in CBS compared to FBS supplement media. Conclusions: We here present a simple, reliable and efficient method to isolate MSCs from umbilical cord tissues, where cells maintained proliferation, differentiation potential and immunophenotyping properties and could be efficiently expanded for clinical applications. PMID- 28844129 TI - Glaucoma, Stem Cells, and Gene Therapy: Where Are We Now? AB - Glaucoma is the second most common cause of blindness, affecting 70~80 million people around the world. The death of retinal ganglion cells (RGCs) is the main cause of blindness related to this disease. Current therapies do not provide enough protection and regeneration of RGCs. A novel opportunity for treatment of glaucoma is application of technologies related to stem cell and gene therapy. In this perspective we will thus focus on emerging approaches to glaucoma treatment including stem cells and gene therapy. PMID- 28844130 TI - Proteomic Analysis of Human Adipose Derived Stem Cells during Small Molecule Chemical Stimulated Pre-neuronal Differentiation. AB - Background: Adipose derived stem cells (ADSCs) are acquired from abdominal liposuction yielding a thousand fold more stem cells per millilitre than those from bone marrow. A large research void exists as to whether ADSCs are capable of transdermal differentiation toward neuronal phenotypes. Previous studies have investigated the use of chemical cocktails with varying inconclusive results. Methods: Human ADSCs were treated with a chemical stimulant, beta mercaptoethanol, to direct them toward a neuronal-like lineage within 24 hours. Quantitative proteomics using iTRAQ was then performed to ascertain protein abundance differences between ADSCs, beta-mercaptoethanol treated ADSCs and a glioblastoma cell line. Results: The soluble proteome of ADSCs differentiated for 12 hours and 24 hours was significantly different from basal ADSCs and control cells, expressing a number of remodeling, neuroprotective and neuroproliferative proteins. However toward the later time point presented stress and shock related proteins were observed to be up regulated with a large down regulation of structural proteins. Cytokine profiles support a large cellular remodeling shift as well indicating cellular distress. Conclusion: The earlier time point indicates an initiation of differentiation. At the latter time point there is a vast loss of cell population during treatment. At 24 hours drastically decreased cytokine profiles and overexpression of stress proteins reveal that exposure to beta-mercaptoethanol beyond 24 hours may not be suitable for clinical application as our results indicate that the cells are in trauma whilst producing neuronal like morphologies. The shorter treatment time is promising, indicating a reducing agent has fast acting potential to initiate neuronal differentiation of ADSCs. PMID- 28844131 TI - One Novel Multiple-Target Plasmid Reference Molecule Targeting Eight Genetically Modified Canola Events for Genetically Modified Canola Detection. AB - Multiple-target plasmid DNA reference materials have been generated and utilized as good substitutes of matrix-based reference materials in the analysis of genetically modified organisms (GMOs). Herein, we report the construction of one multiple-target plasmid reference molecule, pCAN, which harbors eight GM canola event-specific sequences (RF1, RF2, MS1, MS8, Topas 19/2, Oxy235, RT73, and T45) and a partial sequence of the canola endogenous reference gene PEP. The applicability of this plasmid reference material in qualitative and quantitative PCR assays of the eight GM canola events was evaluated, including the analysis of specificity, limit of detection (LOD), limit of quantification (LOQ), and performance of pCAN in the analysis of various canola samples, etc. The LODs are 15 copies for RF2, MS1, and RT73 assays using pCAN as the calibrator and 10 genome copies for the other events. The LOQ in each event-specific real-time PCR assay is 20 copies. In quantitative real-time PCR analysis, the PCR efficiencies of all event-specific and PEP assays are between 91% and 97%, and the squared regression coefficients (R2) are all higher than 0.99. The quantification bias values varied from 0.47% to 20.68% with relative standard deviation (RSD) from 1.06% to 24.61% in the quantification of simulated samples. Furthermore, 10 practical canola samples sampled from imported shipments in the port of Shanghai, China, were analyzed employing pCAN as the calibrator, and the results were comparable with those assays using commercial certified materials as the calibrator. Concluding from these results, we believe that this newly developed pCAN plasmid is one good candidate for being a plasmid DNA reference material in the detection and quantification of the eight GM canola events in routine analysis. PMID- 28844132 TI - Single-Cell Microfluidics to Study the Effects of Genome Deletion on Bacterial Growth Behavior. AB - By directly monitoring single cell growth in a microfluidic platform, we interrogated genome-deletion effects in Escherichia coli strains. We compared the growth dynamics of a wild type strain with a clean genome strain, and their derived mutants at the single-cell level. A decreased average growth rate and extended average lag time were found for the clean genome strain, compared to those of the wild type strain. Direct correlation between the growth rate and lag time of individual cells showed that the clean genome population was more heterogeneous. Cell culturability (the ratio of growing cells to the sum of growing and nongrowing cells) of the clean genome population was also lower. Interestingly, after the random mutations induced by a glucose starvation treatment, for the clean genome population mutants that had survived the competition of chemostat culture, each parameter markedly improved (i.e., the average growth rate and cell culturability increased, and the lag time and heterogeneity decreased). However, this effect was not seen in the wild type strain; the wild type mutants cultured in a chemostat retained a high diversity of growth phenotypes. These results suggest that quasi-essential genes that were deleted in the clean genome might be required to retain a diversity of growth characteristics at the individual cell level under environmental stress. These observations highlight that single-cell microfluidics can reveal subtle individual cellular responses, enabling in-depth understanding of the population. PMID- 28844133 TI - Determining the Probability of Achieving a Successful Quantitative Analysis for Gas Chromatography-Mass Spectrometry. AB - A new approach is presented to determine the probability of achieving a successful quantitative analysis for gas chromatography coupled with mass spectrometry (GC-MS). The proposed theory is based upon a probabilistic description of peak overlap in GC-MS separations to determine the probability of obtaining a successful quantitative analysis, which has its lower limit of chromatographic resolution Rs at some minimum chemometric resolution, Rs*; that is to say, successful quantitative analysis can be achieved when Rs >= Rs*. The value of Rs* must be experimentally determined and is dependent on the chemometric method to be applied. The approach presented makes use of the assumption that analyte peaks are independent and randomly distributed across the separation space or are at least locally random, namely, that each analyte represents an independent Bernoulli random variable, which is then used to predict the binomial probability of successful quantitative analysis. The theoretical framework is based on the chromatographic-saturation factor and chemometric-enhanced peak capacity. For a given separation, the probability of quantitative success can be improved via two pathways, a chromatographic efficiency pathway that reduces the saturation of the sample and a chemometric pathway that reduces Rs* and improves the chemometric-enhanced peak capacity. This theory is demonstrated through a simulation-based study to approximate the resolution limit, Rs*, of multivariate curve resolution-alternating least-squares (MCR-ALS). For this study, Rs* was determined to be ~0.3, and depending on the analytical expectations for the quantitative bias and the obtained mass-spectral match value, a lower value of Rs* ~ 0.2 may be achievable. PMID- 28844134 TI - Highly Versatile beta-C(sp3)-H Iodination of Ketones Using a Practical Auxiliary. AB - The first example of palladium(II)-catalyzed beta-C(sp3)-H iodination of a wide range of ketones using a commercially available aminooxyacetic acid auxiliary has been achieved. This L, X-type directing group overcomes the limitations of the transient directing group approach for C(sp3)-H functionalization of ketones. Practical advantages of this method include simple installation of the auxiliary without chromatography, exceptional tolerance of alpha-functional groups, as well as alkenes and alkynes, and rapid access to diverse sterically hindered quaternary centers. PMID- 28844135 TI - Confinement Phenomenon Effect on the CO2 Absorption Working Capacity in Ionic Liquids Immobilized into Porous Solid Supports. AB - In this work, the CO2 absorption working capacity and solubility in ionic liquids immobilized into porous solid materials (substrates) were studied both experimentally and theoretically. The CO2 absorption working capacity in the immobilized ionic liquids was measured experimentally. It was found that the CO2 absorption working capacity and solubility increased up to 10-fold compared to that in the bulk ionic liquids when the film thickness was nearly 2.5 nm in the [HMIm][NTf2] immobilized in the P25. Meanwhile, a new model was proposed to describe the Gibbs free energy of CO2 in the immobilized ionic liquids, and both macro- and microanalyses of the CO2 solubility in the confined ionic liquids were conducted. The theoretical investigations reveal that the substrate has a crucial effect on the gas solubility in the ionic liquid immobilized into the substrates, and the model performance was approved with a consideration of the substrate effect. PMID- 28844136 TI - Synthesis of Highly Oxygenated Carbocycles by Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems. AB - Densely substituted and highly oxygenated carbocycles are challenging targets for synthesis. In particular, those possessing numerous contiguous, fully substituted carbon atoms (i.e., tertiary alcohols and quaternary centers) are often not accessible in a direct fashion, necessitating the strategic decoupling of ring formation from the establishment of functionality about the system. Here, we describe an approach to the construction of highly oxygenated mono-, di-, and polycyclic carbocycles from the reaction of disubstituted alkynes with beta- or gamma-dicarbonyl systems. These processes embrace a variant of metallacycle mediated annulation chemistry where initial alkyne-carbonyl coupling is followed by a second, now intramolecular, stereoselective C-C bond-forming event. In addition to revealing the basic reactivity pattern in intermolecular settings, we demonstrate that this class of reactivity is quite powerful in a fully intramolecular context and, when terminated by a stereoselective oxidation process, can be used to generate polycyclic systems containing a fully substituted and highly oxygenated five-membered ring. PMID- 28844137 TI - Upconversion Nanoprobes for the Ratiometric Luminescent Sensing of Nitric Oxide. AB - By taking advantage of the optical properties of upconversion nanoparticles (UCNPs), we have designed a luminescence ratiometric nanosensor for measuring nitric oxide (NO) in biological fluids, live cells, and tissues. This nanoconjugate consists of a UCNP core with two strong fluorescence emission peaks at 540 and 656 nm as the upconversion fluorophore, NO-reactive rhodamine B derived molecules (RdMs) encapsulated within the mesopores of the mSiO2 shell, and a beta-cyclodextrin (betaCD) layer on the exterior of the particle. Reaction of the analyte with the O-phenylenediamine of the RdM induces opening of the spiro-ring and is accompanied by an appearance of a strong rhodamine B (RdB) absorption band between 500 and 600 nm, which has spectral overlap with the green emission (540 nm) of the UCNPs. This results in an increase in the I656/I540 ratio and quantitatively correlates with [NO]. The assay is validated under clean buffer conditions as well as inserum and liver tissue slices obtained from mouse models. PMID- 28844138 TI - TiO2 Nanoparticle-Induced Oxidation of the Plasma Membrane: Importance of the Protein Corona. AB - Titanium dioxide (TiO2) nanoparticles, used as pigments and photocatalysts, are widely present in modern society. Inhalation or ingestion of these nanoparticles can lead to cellular-level interactions. We examined the very first step in this cellular interaction, the effect of TiO2 nanoparticles on the lipids of the plasma membrane. Within 12 h of TiO2 nanoparticle exposure, the lipids of the plasma membrane were oxidized, determined with a malondialdehyde assay. Lipid peroxidation was inhibited by surface passivation of the TiO2 nanoparticles, incubation with an antioxidant (Trolox), and the presence of serum proteins in solution. Subsequent experiments determined that serum proteins adsorbed on the surface of the TiO2 nanoparticles, forming a protein corona, inhibit lipid peroxidation. Super-resolution fluorescence microscopy showed that these serum proteins were clustered on the nanoparticle surface. These protein clusters slow lipid peroxidation, but by 24 h, the level of lipid peroxidation is similar, independent of the protein corona or free serum proteins. Additionally, over 24 h, this corona of proteins was displaced from the nanoparticle surface by free proteins in solution. Overall, these experiments provide the first mechanistic investigation of plasma membrane oxidation by TiO2 nanoparticles, in the absence of UV light and as a function of the protein corona, approximating a physiological environment. PMID- 28844139 TI - Ultrasensitive Immunochromatographic Strip for Fast Screening of 27 Sulfonamides in Honey and Pork Liver Samples Based on a Monoclonal Antibody. AB - Group-specific monoclonal antibodies (Mabs) with selectivity for 27 sulfonamides were developed based on new combinations of immunogen and coating antigen. The Mab was able to recognize 27 sulfonamides with 50% inhibition concentration (IC50) values ranging from 0.15 to 15.38 MUg/L. In particular, the IC50 values for five sulfonamides (sulfamethazine, sulfaquinoxaline, sulfamonomethoxine, sulfadimethoxine, and sulfamethoxazole) were 0.51, 0.15, 0.56, 0.54, and 2.14 MUg/L, respectively. On the basis of the Mab, an immunochromatographic lateral flow strip test was established for rapid screening of sulfonamides in honey samples. The visual limit of detection of the strip test for most sulfonamides in spiked honey samples was below 10 MUg/kg, satisfying the requirements of authorities. Positive honey and pork liver samples, which had been confirmed by high-performance liquid chromatography/mass spectrometry, were used to validate the reliability of the proposed strip test. The immunochromatographic lateral flow strip test provides a rapid and convenient method for fast screening of sulfonamides in honey samples. PMID- 28844140 TI - Chirality-Selective Functionalization of Semiconducting Carbon Nanotubes with a Reactivity-Switchable Molecule. AB - Chirality-selective functionalization of semiconducting single-walled carbon nanotubes (SWCNTs) has been a difficult synthetic goal for more than a decade. Here we describe an on-demand covalent chemistry to address this intriguing challenge. Our approach involves the synthesis and isolation of a chemically inert diazoether isomer that can be switched to its reactive form in situ by modulation of the thermodynamic barrier to isomerization with pH and visible light that resonates with the optical frequency of the nanotube. We found that it is possible to completely inhibit the reaction in the absence of light, as determined by the limit of sensitive defect photoluminescence (less than 0.01% of the carbon atoms are bonded to a functional group). This optically driven diazoether chemistry makes it possible to selectively functionalize a specific SWCNT chirality within a mixture. Even for two chiralities that are nearly identical in diameter and electronic structure, (6,5)- and (7,3)-SWCNTs, we are able to activate the diazoether compound to functionalize the less reactive (7,3) SWCNTs, driving the chemical reaction to near exclusion of the (6,5)-SWCNTs. This work opens opportunities to chemically tailor SWCNTs at the single chirality level for nanotube sorting, on-chip passivation, and nanoscale lithography. PMID- 28844142 TI - Generation and Reactivity Studies of Diarylmethyl Radical Pairs in Crystalline Tetraarylacetones via Laser Flash Photolysis Using Nanocrystalline Suspensions. AB - The nanosecond electronic spectra and kinetics of the radical pairs from various crystalline tetraarylacetones were obtained using transmission laser flash photolysis methods by taking advantage of aqueous nanocrystalline suspensions in the presence of submicellar CTAB, which acts as a surface passivator. After showing that all tetraarylacetones react efficiently by a photodecarbonylation reaction in the crystalline state, we were able to detect the intermediate radical pairs within the ca. 8 ns laser pulse of our laser setup. We showed that the solid-state spectra of the radical pairs are very similar to those detected in solution, with lambdamax in the 330-360 nm range. Kinetics in the solid state was observed to be biexponential and impervious to the presence of oxygen or variations in laser power. A relatively short-lived component (0.3-1.7 MUs) accounts for only 3-8% of the total decay with a longer-lived component having a time constant in the range of 40-90 MUs depending on the nature of the substituents. PMID- 28844143 TI - Simultaneous Enantioselective Determination of the Chiral Fungicide Prothioconazole and Its Major Chiral Metabolite Prothioconazole-Desthio in Food and Environmental Samples by Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry. AB - An efficient and sensitive chiral analytical method was established for the determination of the chiral fungicide prothioconazole and its major chiral metabolite prothioconazole-desthio in agricultural and environmental samples using ultraperformance liquid chromatography-tandem mass spectrometry. The optical rotation and absolute configuration of enantiomers were identified by optical rotation detector and electronic circular dichroism spectra. The elution order of prothioconazole and its chiral metabolite enantiomers was R-(+) prothioconazole-desthio, S-(-)-prothioconazole-desthio, R-(-)-prothioconazole, and S-(+)-prothioconazole. The mean recoveries from the samples was 71.8-102.0% with intraday relative standard deviations (RSDs) of 0.3-11.9% and interday RSDs of 0.9-10.6%. The formation of prothioconazole-desthio was studied in soil under field conditions and enantioselective degradation was observed for chiral prothioconazole. Remarkable enantioselective degradation was observed: R prothioconazole degraded preferentially with EF values from 0.48 to 0.37. Although prothioconazole-desthio is the most remarkably bioactive metabolite, no obvious enantioselective behavior was observed in soil. These results may help to systematically evaluate prothioconazole and its metabolites in food and environmental safety. PMID- 28844141 TI - Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi. AB - Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5 amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease. PMID- 28844144 TI - Convergent Theoretical Prediction of Reactive Oxidant Structures in Diiron Arylamine Oxygenases AurF and CmlI: Peroxo or Hydroperoxo? AB - AurF and CmlI are currently the only two known diiron arylamine oxygenases. On the basis of extensive quantum mechanical/molecular mechanical (QM/MM) spectroscopic and mechanistic modelings, here we predict that the key oxygenated intermediates in AurF and CmlI, so-called P, are uniformly hydroperoxo species having similar structures. As a basis for mechanistic unification in AurF and CmlI, the proposed diferric-hydroperoxo P is calculated to be able to promote the arylamine N-oxygenation with highly accessible kinetics. This convergent MU eta0:eta2 structural assignment of P's in AurF and CmlI can rationalize many conundrums for P, including the different Mossbauer spectroscopic parameters, low O-O vibrational frequency, ambiphilic reactivity, and inertness toward C-H activation. In view of the very limited knowledge about hydroperoxo species in diiron enzymes, the novel diferric-hydroperoxo-mediated N-oxygenation mechanism revealed in this work opens up a new avenue for understanding the O2 activation mode in nature. For elucidating the structures of transient oxidants for diiron enzymes, the promising approach of QM/MM Mossbauer spectroscopic modeling is highlighted as a key problem solver in mechanistic enzymatic research. PMID- 28844145 TI - Identification of Biomarkers Associated with the Rearing Practices, Carcass Characteristics, and Beef Quality: An Integrative Approach. AB - Data from birth to slaughter of cull cows allowed using a PCA-based approach coupled with the iterative K-means algorithm the identification of three rearing practices classes. The classes were different in their carcass characteristics. Old cows raised mainly on pasture have better carcass characteristics, while having an equivalent tenderness, juiciness, flavor, intramuscular fat content, and pHu to those fattened with hay or haylage. The Longissimus thoracis muscle of the cows raised on pasture (with high physical activity) showed greater proportions of IIA fibers at the expense of the fast IIX ones. Accordingly, the meat of these animals have better color characteristics. Superoxide dismutase (SOD1) and alphaB-crystallin quantified by Dot-Blot were the only other biomarkers to be more abundant in "Grass" class compared to "Hay" and "Haylage" classes. The relationships between the biomarkers and the 6 carcass and 11 meat quality traits were investigated using multiple regression analyses per rearing practices. The associations were rearing practice class and phenotype trait dependent. ICDH and TP53 were common for the three classes, but the direction of their entrance was different. In addition, rearing practices and carcass traits were not related with Hsp70-Grp75 and MU-calpain abundances. The other relationships were specific for two or one rearing practices class. The rearing practices dependency of the relationships was also found with meat quality traits. Certain proteins were for the first time related with some beef quality traits. MyHC-IIx, PGM1, Hsp40, ICDH, and Hsp70-Grp75 were common for the three rearing practices classes and retained to explain at list one beef quality trait. A positive relationship was found between PGM1 and hue angle irrespective of rearing practices class. This study confirms once again that production-related traits in livestock are the result of sophisticated biological processes finely orchestrated during the life of the animal and soon after slaughter. PMID- 28844146 TI - A Novel Recombinant Form of HIV-1 CRF01_AE/CRF07_BC Identified by Near Full Length Genome in Shaanxi, China. AB - Recently multiple kinds of unique recombinant forms of HIV-1 CRF01_AE/CRF07_BC were identified in China. In this study, we report another near full-length genome of a novel recombinant form (SN121) between CRF01_AE and CRF07_BC from an HIV-1-infected male through heterosexual behavior in Shaanxi province, China. The analysis of SN121 showed that the genome composed of seven interlaced segments, including three CRF07_BC and four CRF01_AE segments with CRF01_AE as the backbone. Six breakpoints were observed in the pol and env gene regions, which are different from the previously identified CRF01_AE/07_BC recombinant forms in China. This novel emerging recombinant form suggested the complicated genetic diversity and the active local transmission of HIV-1 in Shaanxi province. Further monitoring should be performed to elucidate the possible molecular evolution of this novel recombinant form. PMID- 28844147 TI - Costal and Auricular Cartilage Grafts for Nasal Reconstruction: An Anatomic Analysis. AB - OBJECTIVES: The aim of this study was to measure the length, width, and surface area of costal and auricular cartilage harvested for grafting in rhinoplasty and nasal reconstruction. We also compared the sizes of ear cartilage grafts harvested from the anterior and posterior approaches. METHODS: Fifty-eight nasal reconstructive surgeries requiring rib or ear cartilage were performed by 2 facial plastic surgeons from February 2015 through January 2016. Among the 57 cases that met inclusion criteria, they comprised of 33 costal cartilage grafts and 24 auricular cartilage grafts (17 via anterior approach and 7 via posterior approach). RESULTS: The mean length, width, and surface area for the auricular cartilage grafts were 3.39 cm, 1.22 cm, and 4.38 cm2, respectively. The mean length, width, and surface area of the costal cartilage grafts were 4.21 cm, 1.46 cm, and 17.87 cm2, respectively. The differences in length, width, and surface area between the anterior versus posterior approach groups were all statistically significant. CONCLUSIONS: In our study, ear cartilage grafts harvested from the posterior approach had significantly greater length, width, and surface area. While this analysis has several limitations, it sets quantitative norms for costal and auricular cartilage harvest that can aid in surgical planning. PMID- 28844148 TI - The Association of Apolipoprotein E Gene Polymorphism With Cognitive Performance in Nondemented Polish Adults Aged 55 to 75. AB - The epsilon4 allele of the apolipoprotein E (APOE) gene is known as a risk factor for dementia. How APOE epsilon polymorphism affects cognitive performance in nondemented aging subjects remains less clear. In this study, the relationship between APOE status and cognitive performance across various cognitive domains in adults aged 55 to 75 years ( n = 74) without dementia was investigated. E4 carriers ( n = 11) performed worse versus noncarriers on forward Digit Span and delayed recall of the Rey-Osterrieth complex figure. General linear model analysis revealed a small but significant main effect of epsilon4 on Rey Osterrieth complex figure delayed recall. Comparing epsilon2 carriers, epsilon3 homozygotes, and epsilon4 carriers, epsilon3/epsilon3 performed significantly better on Trail Making Test part B and derived score Trail Making Test B-A. The findings support the relation between the APOE epsilon polymorphism and visual memory, short-term auditory memory, visuospatial attention, and executive functions in an aging sample without dementia. PMID- 28844149 TI - Effects of Working Couple's Retirement Sequence on Satisfaction in Patriarchal Culture Country: Probing on Gender Difference. AB - We examined the effects of the differences in the retirement sequence (i.e., who retires first between spouses) on satisfaction in Korea of patriarchal culture. Our empirical study demonstrates that households where men retired first had a much lower satisfaction than households where women retired first. In addition, men were found to show lower satisfaction than wives in both households where women retire first and the households where men retire first. Retirement sequence affecting their satisfaction at the point when only one of the spouses is retired continues to affect their satisfaction after both of them are retired. This means that the difference in the couple's retirement sequence has an ongoing effect on their later happiness. The analysis of the effect of a couple's retirement sequence on the satisfaction in their old life may be useful for improving an individual and couples' quality of life in countries with similar cultures. PMID- 28844150 TI - Evidence for Altered Glutamine Metabolism in Human Immunodeficiency Virus Type 1 Infected Primary Human CD4+ T Cells. AB - Glutamine is a conditionally essential amino acid that is an important metabolic resource for proliferating tissues by acting as a proteinogenic amino acid, a nitrogen donor for biosynthetic reactions and as a substrate for the citric acid or tricarboxylic acid cycle. The human immunodeficiency virus type 1 (HIV-1) productively infects activated CD4+ T cells that are known to require glutamine for proliferation and for carrying out effector functions. As a virus, HIV-1 is furthermore entirely dependent on host metabolism to support its replication. In this study, we compared HIV-1 infected with uninfected activated primary human CD4+ T cells with regard to glutamine metabolism. We report that glutamine concentrations are elevated in HIV-1-infected cells and that glutamine is important to support HIV-1 replication, although the latter is closely linked to the glutamine dependency of cell survival. Metabolic tracer experiments showed that entry of glutamine-derived carbon into the citric acid cycle is unaffected by HIV-1 infection, but that there is an increase in the secretion of glutamine derived glutamic acid from HIV-1-infected cells. Western blotting of key enzymes that metabolize glutamine revealed marked differences in the expression of glutaminase isoforms, KGA and CAG, as well as the PPAT enzyme that targets glutamine-derived nitrogen toward nucleotide synthesis. Altogether, this demonstrates that infection of CD4+ T cells with HIV-1 leads to considerable changes in the cellular glutamine metabolism. PMID- 28844151 TI - High-Dose Acyclovir for Cytomegalovirus Prophylaxis in Seropositive Abdominal Transplant Recipients. AB - BACKGROUND: Following abdominal solid organ transplant (aSOT), valganciclovir (VGC) is recommended for cytomegalovirus (CMV) prophylaxis. This agent is associated with efficacy concerns, toxicity, and emergence of ganciclovir resistance. OBJECTIVE: To evaluate the incidence of high-dose acyclovir (HD-A) prophylaxis failure in seropositive aSOT recipients (R+). METHODS: This was a retrospective, single-center study of R+ transplanted without lymphocyte depleting induction between January 1, 2000, and June 30, 2013, discharged with 3 months of HD-A prophylaxis (800 mg 4 times daily). The primary outcome was incidence of prophylaxis failure. Secondary outcomes were incidence of biopsy proven tissue-invasive disease and prophylaxis failure for each allograft subgroup. RESULTS: A total of 1525 patients met inclusion criteria: 944 renal (RTX), 108 simultaneous pancreas-kidneys (SPK), 462 liver (LTX), and 11 pancreas (PTX) transplant recipients. The composite rate of HD-A prophylaxis failure was 7%; incidence of tissue-invasive disease was 0.4%. Failure rates were 4.5%, 6.1%, 11%, and 20% in the RTX, SPK, LTX, and PTX populations, respectively; tissue invasive disease rates were 0.2%, 0%, 0.7%, and 10%. Failure occurred more frequently in the LTX and PTX populations ( P < 0.0001, HR = 2.6; P = 0.04 HR = 4.4). Incidence of tissue-invasive disease was minimal and not different in the RTX, LTX and SPK populations ( P = 0.34). When evaluating recipients of seronegative allografts (D-), the composite failure rate was 3.4% with no significant difference between allograft subgroups ( P = 0.45). CONCLUSION: HD-A may be a reasonable prophylaxis alternative for D-/R+ recipients, in the absence of lymphocyte-depleting induction, if low incidence viremia is tolerable. Future studies are needed to determine the long-term impact of CMV viremia in the setting of this prophylaxis approach. PMID- 28844152 TI - Lagging skills contribute to challenging behaviors in children with autism spectrum disorder without intellectual disability. AB - Many children with autism spectrum disorder display challenging behaviors. These behaviors are not limited to those with cognitive and/or language impairments. The Collaborative and Proactive Solutions framework proposes that challenging behaviors result from an incompatibility between environmental demands and a child's "lagging skills." The primary Collaborative and Proactive Solutions lagging skills-executive function, emotion regulation, language, and social skills-are often areas of weakness for individuals with autism spectrum disorder. The purpose of this study was to evaluate whether these lagging skills are associated with challenging behaviors in youth with autism spectrum disorder without intellectual disability. Parents of 182 youth with autism spectrum disorder (6-15 years) completed measures of their children's challenging behaviors, executive function, language, emotion regulation, and social skills. We tested whether the Collaborative and Proactive Solutions lagging skills predicted challenging behaviors using multiple linear regression. The Collaborative and Proactive Solutions lagging skills explained significant variance in participants' challenging behaviors. The Depression (emotion regulation), Inhibit (executive function), and Sameness (executive function) scales emerged as significant predictors. Impairments in emotion regulation and executive function may contribute substantially to aggressive and oppositional behaviors in school-age youth with autism spectrum disorder without intellectual disability. Treatment for challenging behaviors in this group may consider targeting the incompatibility between environmental demands and a child's lagging skills. PMID- 28844153 TI - Determinants and outcome of cardiogenic shock in patients with Takotsubo syndrome. PMID- 28844154 TI - Vancomycin Prophylaxis for Prevention of Clostridium difficile Infection Recurrence in Renal Transplant Patients. AB - BACKGROUND: Incidence of primary and recurrent Clostridium difficile infection (CDI) is higher in solid-organ transplant recipients than in the average hospitalized patient. Strategies for preventing recurrent CDI are limited. Prophylaxis with oral vancomycin (VPPx) for preventing recurrent CDI may be beneficial, but there is limited evidence supporting its use. OBJECTIVE: To examine the impact of VPPx (125 mg twice daily) for the prevention of recurrent CDI in renal transplant recipients (RTX) receiving high-risk broad spectrum antibiotics (BSAs). METHODS: Adult RTX with history of CDI, hospitalized with receipt of BSAs during a unit-specific CDI outbreak period-January 1, 2012, to December 31, 2015-were divided into 2 matched cohorts: patients who received VPPx concomitantly with BSAs and patients who did not. The primary objective was incidence of CDI recurrence, defined as CDI occurring <=30 days after receipt of BSAs but >=48 hours after beginning VPPx. Univariate analysis was performed. RESULTS: Baseline characteristics were similar; however, the VPPx group had more severe primary CDI and were receiving BSAs for more severe infections. There were no cases of CDI recurrence in the VPPx group (0% [0/12] vs 8% [2/24], P = 0.54). CONCLUSION: Although sufficient power was not obtained to detect statistically significant differences between the intervention and control groups, a 0% incidence of recurrent CDI while receiving VPPx in this high-risk patient population is compelling because it pertains to the avoidance of CDI-related morbidity and mortality in transplant recipients. Future prospective studies are needed to better evaluate the impact of this preventive strategy. PMID- 28844155 TI - Effects of aliskiren on mortality, cardiovascular outcomes and adverse events in patients with diabetes and cardiovascular disease or risk: A systematic review and meta-analysis of 13,395 patients. AB - BACKGROUND: Aliskiren was shown to increase adverse events in patients with diabetes and concomitant renin-angiotensin blockade. We aim to investigate the efficacy and safety of aliskiren in patients with diabetes and increased cardiovascular risk or established cardiovascular disease. METHODS: MEDLINE and Embase were searched for prospective studies comparing addition of aliskiren to standard medical therapy in patients with diabetes and cardiovascular disease, or ?1 additional cardiovascular risk factor (hypertension, abnormal lipid profile, microalbuminuria/proteinuria, chronic kidney disease). Relative risk for efficacy (all-cause mortality, combined cardiovascular mortality and hospitalisation) and safety (hyperkalaemia, hypotension, renal impairment) outcomes was calculated. RESULTS: Of 2151 studies identified in the search, seven studies enrolling 13,395 patients were included. Aliskiren had no effect on all-cause mortality (relative risk: 1.05, 95% confidence interval: 0.90 to 1.24, p = 0.53), or combined cardiovascular mortality or heart failure hospitalisation (relative risk: 1.07, 95% confidence interval: 0.81 to 1.40, p = 0.64). Patients receiving aliskiren had a greater risk of developing hyperkalaemia (relative risk: 1.32, 95% confidence interval: 1.14 to 1.53, p = 0.0003) and renal impairment (relative risk: 1.15, 95% confidence interval: 1.02 to 1.30, p = 0.03), but not hypotension. CONCLUSION: Patients with diabetes and cardiovascular disease or cardiovascular risk do not benefit from the addition of aliskiren to standard medical therapy. Detrimental safety profile in pooled analysis supports current warnings. PMID- 28844156 TI - Performance of Single-Use FlexorVue vs Reusable BoaVision Ureteroscope for Visualization of Calices and Stone Extraction in an Artificial Kidney Model. AB - PURPOSE: To evaluate and compare Flexor(r)VueTM, a semidisposable endoscopic deflection system with disposable ureteral sheath and reusable visualization source, and a nondisposable fiber optic ureteroscope in a standard in vitro setting. MATERIALS AND METHODS: FlexorVue and a reusable fiber optic flexible ureteroscope were each tested in an artificial kidney model. The experimental setup included the visualization of colored pearls and the extraction of calculi with two different extraction devices (NCircle(r) and NGage(r)). The procedures were performed by six experienced surgeons. Visualization time, access to calices, successful stone retraction, and time required were recorded. In addition, the surgeons' workload and subjective performance were determined according to the National Aeronautics and Space Administration-task load index (NASA-TLX). We referred to the Likert scale to assess maneuverability, handling, and image quality. RESULTS: Nearly all calices (99%) were correctly identified using the reusable scope, indicating full kidney access, whereas 74% of the calices were visualized using FlexorVue, of which 81% were correctly identified. Access to the lower poles of the kidney model was significantly less likely with the disposable device, and time to completion was significantly longer (755 s vs 153 s, p < 0.001). The stone clearance success rate with the disposable device was 23% using the NGage and 13% using the NCircle basket. Overall NASA-TLX scores were significantly higher using FlexorVue. The conventional reusable device also demonstrated superior maneuverability, handling, and image quality. CONCLUSIONS: FlexorVue offers a semidisposable deflecting endoscopic system allowing basic ureteroscopic and cystoscopic procedures. For its use as an addition or replacement for current reusable scopes, it requires substantial technical improvements. PMID- 28844157 TI - Validation of genetic predictors of late radiation-induced morbidity in prostate cancer patients. AB - INTRODUCTION: Normal tissue morbidity sets the dose limit for radiotherapy (RT) in cancer treatment and has importance for quality of life for cancer survivors. A previous study of prostate cancer patients treated with RT generated clinical data for radiation-induced morbidity measured by anorectal physiological methods and validated questionnaires. Other studies have identified genetic predictors associated with late radiation-induced morbidity outcome. We have expanded biobank material aiming to validate single nucleotide polymorphisms (SNPs) and a gene expression classifier with endpoints on patient-reported outcomes and biomechanical properties of the anorectum from our cohort matching originally published endpoints. MATERIALS AND METHODS: The present cohort of prostate cancer patients was treated with RT curative intent in 1999-2007. Nine SNPs associated with late radiation-induced morbidity were tested in 96 patients (rs2788612, rs1800629, rs264663, rs2682585, rs2268363, rs1801516, rs13035033, rs7120482 and rs17779457). A validated gene expression profile predictive of resistance to radiation-induced skin fibrosis was tested in 42 patients. An RT-induced anorectal dysfunction score (RT-ARD) served as a fibrosis-surrogate and a measure of overall radiation-induced morbidity. RESULTS: The lowest p-value found in the genotype analyses was for SNP rs2682585 minor allele (A) in the FSHR gene and the RT-ARD score with odds ratios (OR) = 1.76; 95% CI (0.98-3.17) p = .06, which was out of concordance with original data showing a protective effect of the minor allele. The gene expression profile in patients classified as fibrosis-resistant was associated with high RT-ARD scores OR 4.18; 95% CI (1.1-16.6), p = .04 conflicting with the hypothesis that fibrosis-resistant patients would experience lower RT-ARD scores. CONCLUSIONS: We aimed to validate nine SNPs and a gene expression classifier in a cohort of prostate cancer patients with unique scoring of radiation-induced morbidity. One significant association was found, pointing to the opposite direction of originally published data. We conclude that the material was not able to validate previously published genetic predictors of radiation-induced morbidity. PMID- 28844158 TI - Editorial Comment on: Prevalence of Protective Shielding Utilization for Radiation Dose Reduction in Adult Patients Undergoing Body Scanning Using Computed Tomography by Safiullah et al. PMID- 28844159 TI - Do Video-EEG Monitoring Findings in ICU Patients With Acute Stroke Predict Development of Seizures and Survival During Follow-up? AB - PURPOSE: Ischemic or hemorrhagic stroke are among the most common causes of seizures, especially in the elderly. EEG is the only technique that can detect epileptiform abnormalities (EA) and nonconvulsive status epilepticus (NCSE), which may negatively affect recovery of these patients. Herein we aimed to investigate the potential predictive value of long-term EEG findings in terms of poststroke seizures (PSS) and survival, in stroke patients followed up in the neurological intensive care unit (NICU). METHODS: Video-EEG reports of stroke patients (ischemic and hemorrhagic) hospitalized between 2009 and 2014 in our NICU were reviewed. Patients with <2 months of survival were excluded. Follow-up data were obtained via telephone calls or patient charts. The correlation between EEG findings and early (<=1 week) and late seizure (>1 week) occurrence, recurrent seizure development, outcome, and survival were analyzed statistically. RESULTS: Overall 50 patients (27 female, 23 male; age, 26-85 years) were included in the final analysis. Almost 60% developed PSS (~2/3 were early). There was no difference between ischemic versus hemorrhagic stroke patients ( P = .72). Recurrent seizures were more common in the late seizure group ( P < .001). EAs occurred in one-third of the study cohort. This finding did not predict seizure development ( P = .93) or survival ( P = .61). CONCLUSION: PSS are a frequent finding in stroke patients followed up in NICU. EAs are not uncommon, but do not predict seizure occurrence or survival. PMID- 28844160 TI - The Nature of EEG Reactivity to Light, Sound, and Pain Stimulation in Neurosurgical Comatose Patients Evaluated by a Quantitative Method. AB - EEG reactivity (EEG-R) is regarded as an important parameter in coma prognosis but knowledge is sparse on the nature of EEG changes due to different kinds of stimulation and their prognostic significance. EEG-R was quantified in a study of 39 comatose neurosurgical patients. Six 30-second standardized visual, auditory, and painful stimulations were applied. EEG-R in the delta, theta, alpha, and beta band was normalized in z-scores as the power of a stimulation epoch relative to average power of 6 resting epochs. Outcome measure was 3 months Glasgow Outcome Scale. Increase in EEG activity was related to poor outcome, was more common (13.4% of tests), and grew continuously during the 30-second stimulation epoch. Decrease in EEG activity was related to good outcome, was rarer (2.5%), and peaked around 15 seconds. Pain was the most provocative stimulation (20.4%) followed by sound (8.7%) and eye-opening (6.7%). Discrimination between good (n = 6) and poor (n = 33) outcome was best in the theta and alpha bands for pain stimulation in the first 10-20 seconds and for sound stimulation in the first 5 to 10 seconds, eye-opening did not discriminate. Increase in activity predicted poor outcome with a high specificity 100% (CI = 52%-100%) and a modest sensitivity of 39% (CI = 23%-58%). Decrease in activity predicted good outcome with a high specificity of 100% (CI = 87%-100%) and a modest sensitivity of 33% (CI = 6%-76%). This quantitative study reveals new knowledge about the nature of EEG-R, which contribute to the development of more reliable and objective clinical procedures for outcome prediction. PMID- 28844161 TI - Maturation of Binocular, Monocular Grating Acuity and of the Visual Interocular Difference in the First 2 Years of Life. AB - The sweep visual evoked potential method (sVEP) is a powerful tool for measurement of visual acuity in infants. Despite the applicability and reliability of the technique in measuring visual functions the understanding of sVEP acuity maturation and how interocular difference of acuity develops in early infancy, as well as the availability of normality ranges, are rare in the literature. We measured binocular and monocular sVEPS acuities in 481 healthy infants aged from birth to 24 months without ophthalmological diseases. Binocular sVEP acuity was significantly higher than monocular visual acuities for almost all ages. Maturation of monocular sVEP acuity showed 2 longer critical periods while binocular acuity showed three maturation periods in the same age range. We found a systematic variation of the mean interocular acuity difference (IAD) range according to age from 1.45 cpd at birth to 0.31 cpd at 24 months. An additional contribution was the determination of sVEP acuity norms for the entire age range. We conclude that binocular and monocular sVEP acuities have distinct growth curves reflecting different maturation profiles for each function. Differences in IAD range shorten according to age and they should be considered in using the sVEP acuity measurements for clinical diagnosis as amblyopia. PMID- 28844162 TI - The association of measures of the serotonin system, personality, alcohol use, and smoking with risk-taking traffic behavior in adolescents in a longitudinal study. AB - Studies on the neurobiological basis of risk-taking behavior have most often focused on the serotonin system. The promoter region of the gene encoding the serotonin transporter contains a polymorphic site (5-HTTLPR) that is important for the transcriptional activity, and studies have demonstrated its association with brain activity and behavior. Another molecular mechanism that reflects the capacity of the central serotonin system is the activity of the enzyme monoamine oxidase (MAO) as measured in platelets. The purpose of the present study was to examine how measures of the serotonin system (platelet MAO activity and the 5 HTTLPR polymorphism), personality variables, alcohol use and smoking are associated with risk-taking traffic behavior in schoolchildren through late adolescence. The younger cohort of the longitudinal Estonian Children Personality Behaviour and Health Study (originally n = 583) filled in questionnaires about personality traits, smoking status, alcohol use and traffic behavior at age 15 and 18 years. From venous blood samples, platelet MAO activity was measured radioenzymatically and 5-HTTLPR was genotyped. During late adolescence, subjects with lower platelet MAO activity were more likely to belong to the high-risk traffic behavior group. Male 5-HTTLPRs'-allele carriers were more likely to belong to the high-risk traffic behavior group compared to the l'/l' homozygotes. Other variables predicting risk group were alcohol use, smoking and Maladaptive impulsivity.The results suggest that lower capacity of the serotoninergic system is associated with more risky traffic behavior during late adolescence, but possibly by different mechanisms in boys and girls. PMID- 28844164 TI - Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis. AB - INTRODUCTION: Fingolimod was the first oral and the first in class disease modifying treatment in multiple sclerosis that acts as sphingosine-1-phospathe receptor agonist. Since approval in 2010 there is a growing experience with fingolimod use in clinical practice, but also next-generation sphingosin-1 receptor agonists in ongoing clinical trials. Growing evidence demonstrates additional effects beyond impact on lymphocyte circulation, highlighting further promising targets in multiple sclerosis therapy. Areas covered: Here we present a systematic review using PubMed database searching and expert opinion on fingolimod use in clinical practice. Long-term data of initial clinical trials and post-marketing evaluations including long-term efficacy, safety, tolerability and management especially within growing disease modifying treatment options and pre-treatment constellation in multiple sclerosis patients are critically discussed. Furthermore novel findings in mechanism of actions and prospective on additional use in progressive forms in multiple sclerosis are presented. Expert opinion: There is an extensive long-term experience on fingolimod use in clinical practice demonstrating the favorable benefit-risk of this drug. Using a defined risk management approach experienced MS clinicians should apply fingolimod after critical choice of patients and review of clinical aspects. Further studies are essential to discuss additional benefit in progressive forms in multiple sclerosis. PMID- 28844163 TI - A Qualitative Study of the Experiences of Parents With an Adult Child Who Has a Severe Disease: Existential Questions Will Be Raised. AB - A prominent existential concept is that elderly parents should naturally become severely ill or die before a younger person does. If the reverse should happen, it may influence the parent's existential view of life. The aim of this study was to investigate the existential issues during illness time. This was a qualitative study with in-depth interviews and was conducted in a University Hospital in western Sweden. Eleven parents agreed to participate in individual interviews at baseline and 1 year later. The total number of interviews completed was 19. The study identified 5 areas according to an existential perspective: life took the wrong path, the age of the child, difficult to see the child as sick, worrying about the child, and the relationship with the adult child. Existential questions are often present in those circumstances and can be raised in conversations with parents. Existential questions began to arise for the parent when the child was diagnosed with the severe illness. The situation of having a severely ill child caused both fear and anxiety that the worst-case scenario they could imagine, that the child will die, might happen. Further research is required on this rarely investigated subject of having an adult child with a severe disease. PMID- 28844165 TI - Really does temperature reduction and norepinephrine have similar effects on the energy metabolism in rat brown adipose tissue? AB - CONTEXT: Heat generation by brown adipose tissue (BAT) in response to temperature reduction seems to be entirely related to sympathetic nervous stimulation. OBJECTIVE: To analyse if temperature reduction and norepinephrine may differently affect the expression of proteins related to energy metabolism in BAT. MATERIALS AND METHODS: Isolated rats BAT was incubated with/without norepinephrine (10-6 mol/L, 24 h at 32 degrees C and 37 degrees C). RESULTS: In BAT, 32 degrees C increased the protein expression levels of carnitine palmitoyltransferase-I and II, mitochondrial uncoupling protein-1 (UCP-1) and the expression and activity of lactate dehydrogenase. Mitochondrial F1-ATP synthase alpha-chain expression was decreased at 32 degrees C compared to 37 degrees C. Norepinephrine and at 32 degrees C exposure, UCP-1 expression was increased but cytochrome-c oxidase and F1-ATP synthase alpha-chain expression was reduced with respect to 37 degrees C. DISCUSSION: Sympathetic stimulation seems not to be the only factor associated with heat generation. CONCLUSIONS: Temperature reduction by itself exerts some different effects on the expression of proteins related to the energy metabolism than norepinephrine. PMID- 28844166 TI - Nurses' Burnout: The Influence of Leader Empowering Behaviors, Work Conditions, and Demographic Traits. AB - Nurse burnout is a widespread phenomenon characterized by a reduction in nurses' energy that manifests in emotional exhaustion, lack of motivation, and feelings of frustration and may lead to reductions in work efficacy. This study was conducted to assess the level of burnout among Jordanian nurses and to investigate the influence of leader empowering behaviors (LEBs) on nurses' feelings of burnout in an endeavor to improve nursing work outcomes. A cross sectional and correlational design was used. Leader Empowering Behaviors Scale and the Maslach Burnout Inventory (MBI) were employed to collect data from 407 registered nurses, recruited from 11 hospitals in Jordan. The Jordanian nurses exhibited high levels of burnout as demonstrated by their high scores for Emotional Exhaustion (EE) and Depersonalization (DP) and moderate scores for Personal Accomplishment (PA). Factors related to work conditions, nurses' demographic traits, and LEBs were significantly correlated with the burnout categories. A stepwise regression model-exposed 4 factors predicted EE: hospital type, nurses' work shift, providing autonomy, and fostering participation in decision making. Gender, fostering participation in decision making, and department type were responsible for 5.9% of the DP variance, whereas facilitating goal attainment and nursing experience accounted for 8.3% of the PA variance. This study highlights the importance of the role of nurse leaders in improving work conditions and empowering and motivating nurses to decrease nurses' feelings of burnout, reduce turnover rates, and improve the quality of nursing care. PMID- 28844167 TI - Epidemiological study of failures of the Jaipur Foot. AB - OBJECTIVE: The purpose of this study was to examine effects of usage and demographics on damage to the Jaipur Foot prosthesis as well as the epidemiology and etiology of amputations performed at Santokba Durlabjhi Memorial Hospital (SDMH) in Jaipur, India. DESIGN: Total time spent standing, total time spent wearing and total distance walked were compared against severity and location of damage to the prosthesis. Time between initial fitting and follow-up visit for damaged prosthetic was also considered in this analysis. A novel damage severity scale based on prosthesis functionality is presented along with a damage location legend. RESULTS: Patients from 10 different states and two territories throughout India were included in the study. No main effects were found to be statistically significant in predicting severity or location of damage. Only the interaction between a patient's total time spent standing and their total time spent wearing the prosthesis as well as the interaction between a patient's total time spent standing and total distance walked was significant in predicting location of damage to the Jaipur Foot (p = .0327, p = .0278, respectively). CONCLUSIONS: The lack of significant usage factor effect on damage severity or location could support previous findings that lack standardization in materials and manufacturing processes, which is the major drawback of the Jaipur Foot. Implications for Rehabilitation The Jaipur Foot is a safe, reliable and stable product as no abrupt breakage or sudden falls causing injury to the patient were noted. Hence, it is a safe rehabilitation device for lost limbs. The population can squat and sit cross-legged while wearing the prosthetic foot and it does not affect damage severity or location of damage, allowing for these activities to be performed while rehabilitating. The manufacturing of the foot needs to be standardized to improve life of foot. Total time spent standing, total time spent wearing and total distance walked were not predictive of severity or location of damage to the prosthesis, hence providing patient guidelines for activity during rehabilitation. PMID- 28844168 TI - Effects of heart rate reduction with ivabradine on the international index of erectile function (IIEF-5) in patients with heart failure. AB - INTRODUCTION: The presence of concomitant erectile dysfunction (ED) with heart failure (HF) is not surprising, because endothelial dysfunction is pathophysiologic signature of both ED and HF. ED significantly and adversely affects quality of life in patients with HF. It was demonstrated that ivabradine treatment can improve endothelial function and ED in experimental models. In this study, we aimed to determine the effect of ivabradine treatment on ED in patients with HF via International Index of Erectile Function (IIEF-5) questionaire. MATERIAL AND METHODS: Consequently, 29 patients, between 18 and 70 years of age, male with chronic HF known for at least 1 year, New York Heart Association functional class I-II, left ventricule ejection fraction less than 40%, in sinus rhythm with a resting HR of at least 70 beats per minute (b.p.m.), who were intended to be treated with ivabradine according to the decision of their physicians were evaluated to determine ED. We used the Turkish version of the IIEF-5 questionnaire to evaluate ED on the last 6-month period. Twenty-four of 29 patients who scored <=21 were considered to have ED and included to the study. IIEF-5 scores for each question and domains were calculated for all responders at baseline and at 6-month follow-up visit in order to determine any effect of ivabradine treatment on ED in patients with HF. RESULTS: According to the data of survey, Cronbach's alpha coeffient for all of the patients who were included into the study were 0.84 and detected highly reliable. IEFF-5 questionnaire scores increased significantly (p = .003) after the ivabradine treatment, on the contrary, significant decrease in HR was revealed as expected. HR is decreased steadily after ivabradine treatment and mean decrease in HR was 11.5 +/- 9.4 in this study population. Likewise, negative correlation was demonstrated between decrease in HR (p < .001) and increase in IEFF-5 scores (p = .003). CONCLUSION: Although lack of patients with HF have been evaluated in this study population, initial results seem promising that ivabradine has favorable effects on ED. These findings were postulated to be dependent exclusively on HR reduction. As a sequel, cardiologist should avoid neglecting ED to improve medical compliance as well as quality of life in patients with heart failure. This pilot study provide some data for further randomized controlled studies. PMID- 28844169 TI - Efficacy, Safety, and Durability of 532 nm Laser Photovaporization of the Prostate with GreenLight 180 W XPS in Men with Acute Urinary Retention. AB - OBJECTIVE: We assessed the effectiveness and durability of 532 nm laser photovaporization with GreenLight XPS in men with and without preoperative urinary retention. MATERIALS AND METHODS: From 2010 to 2017 we prospectively studied men who underwent photovaporization of the prostate (PVP) for obstructive lower urinary tract symptoms (LUTS) secondary to BPH. The cohort was retrospectively divided into those with catheter dependent retention and those with elective PVP. Primary endpoints were catheter-free rate and improvement in quality of life (QoL) scores, international prostate symptom score (IPSS), maximum urinary flow rate (Qmax), and postvoid residual (PVR). The secondary endpoints of the study were complication outcomes as defined by the standardized Clavien-Dindo grading system. RESULTS: One hundred thirty-seven men with preoperative retention and 195 men without preoperative retention underwent PVP. Men with preoperative retention were older (70 years vs 66 years; p < 0.001), had a higher American Society of Anesthesiology (ASA) score, and had a higher prevalence of neurologic disease (8% vs 2.6%; p = 0.04). These men also had a larger prostate volume (76 cc vs 69 cc; p < 0.001) and higher prostate specific antigen (5 ng/mL vs 2.7 ng/mL; p < 0.001) than those without retention. Patients with preoperative retention also had higher preoperative baseline IPSS and QoL score. After PVP they improved to values similar to those without retention, with durability up to 24 months. After PVP, men in preoperative retention had similar rates to fail their first void trial (18.2% vs 10.3%, p = 0.053). There was a 96% catheter-free rate in the men with preoperative retention. The rate of complication was higher in the nonretention group, specifically at 90 days (35.4% vs 21.2%; p = 0.009), with almost all the complications being Clavien-Dindo grade 2. CONCLUSION: PVP is an effective, safe, and durable treatment for men in acute urinary retention (AUR) with a catheter-free rate of 96%. The improvement is similar to those who did not present in AUR. PMID- 28844170 TI - Non-healthcare costs of hepatitis C: a systematic review. AB - INTRODUCTION: There is an increasing interest in the indirect (or non-healthcare) costs of hepatitis C virus (HCV). Areas covered: Systematic review of original studies on the non-healthcare costs of HCV published in English or Spanish between January 2000 and March 2017. 19 studies addressing non-healthcare cost of HCV were included in the analysis. All studies but one contain treatments with monotherapy or dual therapy prior to the recent introduction of innovative and highly effective direct acting antivirals (DAAs). Five studies estimate the incremental non-healthcare cost of HCV with a control group, which is regarded as high-quality methodology. The incremental annual non-healthcare costs of HCV in untreated patients compared with non-HCV patients are ?4,209 in the US, and taking data from 5 European countries costs range from ?280 in the UK to ?659 in France. Expert commentary: Available studies may be underestimating the true burden of non-healthcare costs for HCV as they are all partial studies, mainly including absenteeism and premature mortality estimates. Moreover, there is a need for studies addressing non-healthcare costs of HCV in settings where new treatments with DAAs have been implemented, as they are probably changing the current and future burden of the disease. PMID- 28844171 TI - A clinical decision-making algorithm for penicillin allergy. AB - BACKGROUND: About 10% of subjects report suspected penicillin allergy, but 85-90% of these patients are not truly allergic and could safely receive beta-lactam antibiotics Objective: To design and validate a clinical decision-making algorithm, based on anamnesis (chronology, severity, and duration of the suspected allergic reactions) and reaching a 100% sensitivity and negative predictive value, to assess allergy risk related to a penicillin prescription in general practise. STUDY DESIGN AND METHODS: All patients were included prospectively and explorated based on ENDA/EAACI recommendations. Results of penicillin allergy work-up (gold standard) were compared with results of the algorithm. RESULTS: Allergological work-up diagnosed penicillin hypersensitivity in 41/259 patients (15.8%) [95% CI: 11.5-20.3]. Three of these patients were diagnosed as having immediate-type hypersensitivity to penicillin, but had been misdiagnosed as low risk patients using the clinical algorithm. Thus, the sensitivity and negative predictive value of the algorithm were 92.7% [95% CI: 80.1-98.5] and 96.3% [95% CI: 89.6-99.2], respectively, and the probability that a patient with true penicillin allergy had been misclassified was 3.7% [95% CI: 0.8-10.4]. CONCLUSIONS: Although the risk of misclassification is low, we cannot recommend the use of this algorithm in general practice. However, the algorithm can be useful in emergency situations in hospital settings. Key messages True penicillin allergy is considerably lower than alleged penicillin allergy (15.8%; 41 of the 259 patients with suspected penicillin allergy). A clinical algorithm based on the patient's clinical history of the supposed allergic event to penicillin misclassified 3/41 (3.7%) truly allergic patients. PMID- 28844172 TI - Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery. AB - Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC-MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports. PMID- 28844173 TI - Clinical Application of Whole Genome Array Improves the Diagnosis of Pediatric Brain Tumors. AB - Pediatric brain tumors are the leading cause of childhood cancer mortality. Recurring genetic abnormalities play an essential role in the diagnosis and prognosis of pediatric brain tumors. However, clinical workup has not routinely included whole genome assessment. Here, we present high resolution whole genome array results in 11 pediatric brain tumors. Array identified clinically relevant abnormalities in all samples. Copy number aberrations with targeted therapy implication, GOPC-ROS1 fusion, CDK4 amplification, and NF1 deletion, were detected in 3 cases. In addition, array detected recurring genetic abnormalities, including KIAA1549-BRAF fusion, 19q13.42 amplification, i(17q), and monosomy 6, which assisted accurate histological diagnosis in pediatric brain tumors. In conclusion, our results show that whole genome high-resolution array detects diagnostic and treatment-relevant copy number abnormalities in pediatric brain tumors. PMID- 28844174 TI - Novel reverse electrodialysis-driven iontophoretic system for topical and transdermal delivery of poorly permeable therapeutic agents. AB - Topical and transdermal drug delivery has great potential in non-invasive and non oral administration of poorly bioavailable therapeutic agents. However, due to the barrier function of the stratum corneum, the drugs that can be clinically feasible candidates for topical and transdermal delivery have been limited to small-sized lipophilic molecules. Previously, we fabricated a novel iontophoretic system using reverse electrodialysis (RED) technology (RED system). However, no study has demonstrated its utility in topical and/or transdermal delivery of poorly permeable therapeutic agents. In this study, we report the topical delivery of fluorescein isothiocyanate (FITC)-hyaluronic acid (FITC-HA) and vitamin C and the transdermal delivery of lopinavir using our newly developed RED system in the in vitro hairless mouse skin and in vivo Sprague-Dawley rat models. The RED system significantly enhanced the efficiency of topical HA and vitamin C and transdermal lopinavir delivery. Moreover, the efficiency and safety of transdermal delivery using the RED system were comparable with those of a commercial ketoprofen patch formulation. Thus, the RED system can be a potential topical and transdermal delivery system for various poorly bioavailable pharmaceuticals including HA, vitamin C, and lopinavir. PMID- 28844175 TI - Diaphragm and Intercostal Muscle Activity after Mid-Cervical Spinal Cord Contusion in the Rat. AB - The present study was designed to investigate the diaphragm and intercostal muscle activity after unilateral mid-cervical spinal cord contusion in rats. Electromyogram (EMG) activity of the bilateral diaphragm and T2 intercostal muscle was measured in anesthetized and spontaneously breathing rats. Unilateral mid-cervical contusion caused an immediate reduction in inspiratory bursting in the bilateral diaphragm and intercostal muscles. From 3 days to 8 weeks post contusion, contused animals displayed significantly lower tidal volume than uninjured animals, regardless of the time point after injury. The burst amplitude of the contralateral diaphragm EMG was augmented in contused animals at 3 days post-injury. When the data were normalized by the maximal response during hypoxic hypercapnic challenge (12-13% O2, 3-4% CO2), the ipsilateral diaphragm EMG of contused animals was greater than that of uninjured animals at 3 days and 2 weeks post-injury. Moreover, hypoxia-hypercapnia-induced increases in ipsilateral diaphragm EMG activity were blunted in contused animals at 2 weeks post-injury, but recovered at 8 weeks post-injury. Bilateral diaphragm EMG activity in contused animals was comparable to uninjured animals at 8 weeks post-injury. Notably, intercostal muscle activity was not substantially changed by mid cervical spinal cord contusion from 3 days to 8 weeks post-contusion. These results suggest that mid-cervical spinal contusion induces a compensatory increase in contralateral diaphragmatic activity and greater utilization of a percentage of maximal inspiratory activity in the ipsilateral diaphragm. The maintenance of intercostal muscle activity may enable the animal to sustain essential breathing capacity after cervical spinal cord injury. PMID- 28844176 TI - An Important Step for Thrombocardiology. PMID- 28844177 TI - Targeting Inflammation in Coronary Artery Disease. PMID- 28844178 TI - Human hemoglobin adsorption onto colloidal cerium oxide nanoparticles: a new model based on zeta potential and spectroscopy measurements. AB - The nanoparticle (NP)-induced conformational changes of protein and NP agglomeration have gained a remarkable interest in medical and biotechnological fields. Herein, the effect of human hemoglobin (Hb) on the colloidal stability of cerium oxide NP (CNP) was investigated by dynamic light scattering (DLS), zeta potential, and TEM analysis. In addition, the effect of CNP on the heme degradation and structural changes of Hb was studied using fluorescence, circular dichroism (CD), and UV-visible (UV-vis) spectroscopic methods. DLS and TEM analysis showed that the presence of Hb can increase the mean diameter of CNP. Zeta potential measurements revealed that CNP demonstrated a higher charge distribution relative to CNP/Hb complex. Besides, fluorescence studies indicated that two fluorescent heme degradation products are revealed during the interaction of CNP with Hb. Near UV-CD spectroscopy also showed that the microenvironmental changes of heme groups occur after interaction of Hb with CNP. The result of thermal behavior of Hb confirmed the structural changes of protein, which referred to decrease in the Hb stability in the presence of CNP. Indeed, the finding related to structural and functional changes of Hb induced by CNP may be crucial to obtain information regarding the side effects of NPs. Finally, this data reveal much insight into the effects of the interaction on protein structural changes and NP agglomeration, and can correlate the zeta potential of NP-protein complexes with the nature of the principle NP-protein interaction. PMID- 28844179 TI - Noninvasive Absolute Electron Paramagnetic Resonance Oxygen Imaging for the Assessment of Tissue Graft Oxygenation. AB - Oxygen is the single most important molecule for sustaining life and, therefore, an important variable in tissue engineering and regenerative medicine. It has been shown that the change in oxygen concentration in an artificial or tissue engineered graft affects cell survival, differentiation, and tissue growth in profound ways. However, at present, there are no reliable methods to map partial oxygen pressure (pO2) in growing artificial tissues. Here, we adapt and test the suitability of electron paramagnetic resonance oxygen imaging (EPROI) in assessing tissue graft oxygenation in vitro. EPROI is an established method to assess absolute pO2 and has been widely applied to study tumor hypoxia in small animals. In this study, we demonstrate the feasibility of EPROI in evaluating oxygen dynamics in tissue grafts. We measured oxygen concentration in mesenchymal stem cell (MSC)-seeded polylactic-co-glycolic acid (PLGA) scaffolds with variable porosity. The pO2 maps of these scaffolds showed that the mean pO2 inside the scaffolds was smaller than the ambient air pO2 (21% oxygen, 160 torr) and was gradually increased with increasing pore size. We assessed the local oxygen dynamics of the MSC-seeded osteogenic scaffold made from collagen-chitosan hydrogels in a partially sealed Eppendorf tube. The change in pO2 values as a function of time inside the graft showed that the cells had used available oxygen within first 2 h of the experiment and then went to a dormant low oxygen consumption state until the oxygen supply was reestablished. Collectively, these data suggest that EPROI could be successfully used for mapping pO2 in tissue engineered grafts. The knowledge of tissue graft oxygenation may be used to improve scaffold design and to assess the tissue viability and growth. PMID- 28844180 TI - Position and orientation of gallated proanthocyanidins in lipid bilayer membranes: influence of polymerization degree and linkage type. AB - It is well known that the biological activity of gallated proanthocyanidins (PAs) is highly structure-dependent. Polymerization degree (DP) and linkage types affect their biological activity greatly. Positions and orientations of gallated PAs in lipid bilayer reveal their structure-function activity at the molecular level. The present work aimed at determining the locations and orientations of epigallocatechin-3-gallate (EGCG) and its derivatives: A-type and B-type EGCG dimers and trimers in 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) and 1 palmitoyl-2-oleoyl phosphatidylethanolamine (POPE) lipid bilayer via molecular dynamic (MD) simulations. The results showed that EGCG and its derivatives localized in the lipid bilayer or on the bilayer/water interface. Their penetration depths and orientations depended on both DP and linkage types. The penetration depths decreased with the increase of DP, sequencing to be EGCG > EGCG dimers > EGCG trimers. Spatially stretched A-type PAs could form more hydrogen bonds (H-bonds) with deep oxygen atoms of lipid bilayer and have higher affinity to the lipid bilayer than B-type PAs. Our results will provide an explicit evidence for PAs' distinct biological activities. PMID- 28844181 TI - Changes in Pressure, Hemodynamics, and Metabolism within the Spinal Cord during the First 7 Days after Injury Using a Porcine Model. AB - Traumatic spinal cord injury (SCI) triggers many perturbations within the injured cord, such as decreased perfusion, reduced tissue oxygenation, increased hydrostatic pressure, and disrupted bioenergetics. While much attention is directed to neuroprotective interventions that might alleviate these early pathophysiologic responses to traumatic injury, the temporo-spatial characteristics of these responses within the injured cord are not well documented. In this study, we utilized our Yucatan mini-pig model of traumatic SCI to characterize intraparenchymal hemodynamic and metabolic changes within the spinal cord for 1 week post-injury. Animals were subjected to a contusion/compression SCI at T10. Prior to injury, probes for microdialysis and the measurement of spinal cord blood flow (SCBF), oxygenation (in partial pressure of oxygen; PaPO2), and hydrostatic pressure were inserted into the spinal cord 0.2 and 2.2 cm from the injury site. Measurements occurred under anesthesia for 4 h post-injury, after which the animals were recovered and measurements continued for 7 days. Close to the lesion (0.2 cm), SCBF levels decreased immediately after SCI, followed by an increase in the subsequent days. Similarly, PaPO2 plummeted, where levels remained diminished for up to 7 days post-injury. Lactate/pyruvate (L/P) ratio increased within minutes. Further away from the injury site (2.2 cm), L/P ratio also gradually increased. Hydrostatic pressure remained consistently elevated for days and negatively correlated with changes in SCBF. An imbalance between SCBF and tissue metabolism also was observed, resulting in metabolic stress and insufficient oxygen levels. Taken together, traumatic SCI resulted in an expanding area of ischemia/hypoxia, with ongoing physiological perturbations sustained out to 7 days post-injury. This suggests that our clinical practice of hemodynamically supporting patients out to 7 days post-injury may fail to address persistent ischemia within the injured cord. A detailed understanding of these pathophysiological mechanisms after SCI is essential to promote best practices for acute SCI patients. PMID- 28844182 TI - Modulation of the earliest visual evoked potential by attention: now you see it, now you don't. AB - Baumgartner and colleagues (this issue) report a replication of an ERP study by Kelly, Gomez-Ramirez, and Foxe (2008). Unlike the original authors, they failed to observe a significant modulation of the C1 by visuo-spatial attention. They conclude that initial afferent processing in V1 is impermeable to visuo-spatial attention. Although their study, like any replication effort, is valuable and important, there are some uncertainties at the methodological and statistical levels suggesting that the absence of evidence is not evidence of absence in the present case. PMID- 28844183 TI - Attenuation of Oxidative Damage by Coenzyme Q10 Loaded Nanoemulsion Through Oral Route for the Management of Parkinson's Disease. AB - Coenzyme Q10 (CoQ10) is a well-known antioxidant molecule which is used in the treatment of neurodegenerative disorders, but due to poor solubility it suffers with the drawback of low oral bioavailability. The aim of present study was to prepare and characterize CoQ10 loaded nanoemulsion to improve the oral bioavailability. Prepared formulation was studied for droplet size, polydispersity index (PDI), percentage transmittance, refractive index, viscosity, zeta potential, surface morphology by transmission electron microscopy, and in vitro release study. Optimized formulation (A10) showed spherical droplets with mean diameter of 60.00 +/- 15 nm, PDI of 0.121 +/- 0.053, and zeta potential values of -24.40 +/- 0.16 mV. Prepared nanoemulsion exhibited good transmittance (100.50% +/- 0.86%), refractive index (1.41 +/- 0.02), and viscosity (30.54 +/- 2.86 cP). Various behavioral tests like forced swimming test, locomotor activity test, catalepsy, muscle coordination test, and akinesia test performed in haloperidol challenged rats and treated with CoQ10 nanoemulsion significantly improved the behavioral activities in comparison to CoQ10 suspension by reducing nigrostriatal dopamine depletion and thereby helping in the treatment of Parkinson's disease. Biochemical estimation data showed that CoQ10 nanoemulsion was helpful in elevating the decreased content of glutathione and reducing the increased content of thiobarbituric acid reactive substances. Improved CoQ10 release was obtained with nanoemulsions. Pharmacokinetic study results revealed that nanoemulsion exhibited 1.81 times enhancement in bioavailability in comparison to CoQ10 suspension. PMID- 28844185 TI - Language as a determinant of participation rates in Finnish health examination surveys. AB - AIM: A high participation rate is considered as a prerequisite for representative survey results, especially when it is known that non-participation is selective. In many countries migration is increasing and the proportion of people speaking other language(s) than the official language(s) of the country is also increasing. How does this affect survey participation rates? METHODS: Data from four cross-sectional health examination surveys (the FINRISK Study) were used to evaluate the effect of the registered mother tongue to participation in the survey. RESULTS: Finland has two official languages (Finnish and Swedish). Between 1997 and 2012, the proportion of the population with some other language as their registered mother tongue has increased significantly. Participation rates in the health surveys have been highest among the Finnish language group (68% in men in 1997 and 76% in women in 1997), while lowest among the foreign language group (43% in men in 1997 and 57% in women in 1997). In 2012, the participation rates had declined in all language groups: for men, 58%, 62% and 41% for Finnish, Swedish and foreign groups respectively, and for women 68%, 75% and 56%. CONCLUSIONS: The participation rate for the foreign language group was significantly lower than for the Finnish and Swedish groups. In future surveys it will be important to include actions to promote participation, e.g. providing survey material in several languages. These actions will increase costs but will be essential to ensure high participation rates and reliable results for the total population. PMID- 28844184 TI - The Argentinian mother-and-child contaminant study: a cross-sectional study among delivering women in the cities of Ushuaia and Salta. AB - Several ongoing international multidisciplinary projects have examined linkages between environmental chemicals and health. In contrast to Arctic regions, information for the Southern Hemisphere is scarce. Because of the inherent practice of pesticide utilisation and mismanagement, food security is potentially threatened. The most vulnerable period in human life occurs during pregnancy and early childhood, thus a focus on the body burdens of PTS in pregnant or delivering women is warranted. The current study was designed to investigate health risks related to exposure to PTS and food security in two regions of Argentina (Ushuaia and Salta). Our aims were to quantify concentrations of organic and inorganic toxins in serum or whole blood of delivering women and to collect pertinent dietary and medical information. The overall study design, the basic demographic features and essential clinical chemistry findings are described in the current paper. The socioeconomic differences between the two study areas were evident. On average, the women in Ushuaia were 4 years older than those in Salta (28.8 vs. 24.7 years). Respectively, the proportion of current smokers was 4.5 vs. 9.6%; and Salta had a higher birth rate, with 15.6% being para four or more. Saltanean women reported longer breastfeeding periods. Caesarean sections were more frequent in Ushuaia, with 43% of Caesarean deliveries compared with only 6% in Salta. Employment was high in both communities. Recognised environmental pollution sources in the vicinity of participant dwellings were widespread in Salta (56.1%) compared to Ushuaia (9%). The use of pesticides for insect control in homes was most common in Salta (80%). There is an urgent need for a comprehensive assessment of exposures in areas of the Southern Hemisphere. Our data set and the planned publications of observed concentrations of inorganic and organic environmental contaminants in both mothers and their newborns will contribute to this objective. PMID- 28844186 TI - Austerity and the new age of population health? AB - The Great Recession of 2007-2008 saw the largest period of economic downturn since the Second World War or the Great Depression of the 1930s. Recessions, however, tend not to have a significant impact on population health. Rather it is how society and governments respond to a recession that has a larger impact on their populations. The dominant political response to the Great Recession was the introduction of austerity programmes aimed at reducing the size of the state. In this Commentary, I briefly review the state of evidence on the changes in population health during austerity. Although the negative impact of austerity on overall population health has been well documented across Europe, there remains a paucity of evidence on within-country differences in health. The slowing down of improvements in life expectancy, correlated to the level of austerity, raises uncomfortable questions as to whether we are beginning to transition from the era of consistently improving population health to a new age characterised by an instability in population health largely dictated by the social and political determinants of health. PMID- 28844187 TI - Evaluation of Oxidative Status in Patients With Chronic Periodontitis and Polycystic Ovary Syndrome: A Cross-Sectional Study. AB - BACKGROUND: The aim of the present study was to investigate the salivary and serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) levels as well as total antioxidant status (TAS), in females with chronic periodontitis (CP) and polycystic ovary syndrome (PCOS), compared to healthy females. METHODS: Four groups, each consisting of 22 individuals, respectively women with both PCOS and CP (PCOSCP), systemically healthy women with CP (CP), periodontally healthy women with PCOS (PCOSPH) and periodontally and systemically healthy women (PH). Demographic and clinical periodontal parameters were measured. Oxidative parameters were evaluated in serum and salivary samples. RESULTS: Salivary 8-OHdG levels in the PCOSCP and CP groups were statistically higher than those in both the PCOSPH and the PH groups (p<0.05). There was no statistical difference between the PCOSCP, CP and PCOSPH groups in salivary MDA and TAS levels(p>0.05). The highest serum 8-OHdG and MDA levels and the lowest serum TAS levels were seen in the PCOSCP group (p<0.05). Serum 8-OHdG and MDA levels in the PCOSPH group were higher than those in both systemically healthy groups (PH, CP)(p<0,05). The salivary TAS levels were highest (p<0.05) in the PH group. There was no statistical difference between the CP and PCOSPH groups, but serum TAS levels were lower than those in the PH group(p<0.05). CONCLUSIONS: CP, which led to an increase in serum and salivary 8-OHdG and MDA levels and a decrease in serum TAS levels in PCOS patients, contributed to increased oxidative stress.This effect was more prominent in serum levels than in salivary levels. PMID- 28844188 TI - Transcriptome of Healthy Gingival Tissue from Edentulous Sites in Patients with a History of Aggressive Periodontitis. AB - BACKGROUND: This study evaluated the transcriptome of healthy gingival tissue from edentulous sites in patients with a history of generalized aggressive periodontitis (GAgP), chronic periodontitis (CP) and in patients with no history of periodontitis (H), using microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. METHODS: Healthy gingival tissue from edentulous sites was taken from GAgP (n =12), CP (n=12) and H (n=12) patients. Initially, total RNA from 4 tissues samples per group was employed in transcriptomic microarray analysis. Differential gene expression (fold-change), gene ontology (GO; biological process) and pathway analyses were performed. Genes that were differentially expressed and showing a significant role on altered pathways were validated by qRT-PCR analysis on 12 samples per group. RESULTS: In total, 270 probes sets and 50 GO groups were differentially expressed (up regulated or down-regulated) between GAgP and H. Natural killer cell receptors and other genes related to the immune system were up-regulated in GAgP, while genes with functions in neural processes and in proliferation/differentiation of keratinocytes were under-expressed. There were 220 probe sets and 75 GO groups that were differentially expressed when comparing CP and GAgP. CP was characterized by the increased expression of genes related to responses to external stimuli and an under-expression of immune system-related genes. qRT-PCR analysis confirmed the microarray results, that KIR2DL4, IL6 and SELE were highly expressed in GAgP than CP or H patients. CONCLUSION: This study demonstrates differences in the transcriptome of healthy gingival tissue from edentulous sites from GAgP when compared with that of H or CP patients. PMID- 28844189 TI - Prevalence of Comorbidities in Periodontitis Patients Compared to the General Austrian Population. AB - BACKGROUND: To analyze the prevalence and impact of comorbidities in patients with periodontitis in Austria. METHODS: The prevalence of comorbidities was evaluated in 1199 patients with periodontitis (median age: 49, range: 14-83 years). These data were compared to an age and sex matched randomly selected cohort of the Austrian population by an unconditional logistic regression model. RESULTS: Comorbidities were found in 821/1199=68.5% patients. Allergies had the highest prevalence (29.2%), followed by hypertension (19.4%), musculoskeletal (11.2%), and endocrine disorders (9.7%). Chronic pulmonary disorders (no influenza/pneumonia) were associated with a higher approximal plaque-index (72% versus 63%, p=0.02). No association between characteristics of periodontitis and comorbidities was observed. The prevalence of allergies (29.2% vs. 22.9%) and pulmonary disorders (8.5% vs 4.3%) was significantly higher in periodontitis patients compared to the Austrian population (p<0.001), whereas asthma (1.5% vs. 5.6%), cardiovascular disorders (1.8% vs. 10.5%), depression (7.1% vs. 10.4%), headache (1.3% vs. 20%), hyperlipidemia (6.4% vs. 14.8%), hypertension (14.2% vs. 24.5%), musculoskeletal disorders (11.2% vs. 41.7%), and osteoporosis (2.8% vs. 5.1%) were found less frequently (p<0.001). No differences were observed for cancer, diabetes-mellitus, gastrointestinal disorders and psychiatric disorders (p=0.95, p=0.76, p=0.68, p=0.23, respectively). CONCLUSION(S): In Austria the majority of patients with periodontitis present with comorbidities and the adjusted prevalence differs significantly from the general population. PMID- 28844190 TI - Smoking May Lead to Marginal Bone Loss Around Non-Submerged Implants During Bone Healing by Altering Salivary Microbiome: A Prospective Study. AB - BACKGROUND: This prospective and controlled study elucidates the impact of smoking on the salivary microbiome and its further influence on marginal bone loss (MBL) around an implant during a 3-month bone-healing period. METHODS: Saliva samples were collected preoperatively from 20 periodontally healthy patients with single-tooth replacement in the posterior mandible (smokers [n = 10] and non-smokers [n = 10]). Sequencing of 16S recombinant RNA gene amplicons was used to characterize the salivary microbiome. Each patient received implant surgery after oral clinical assessment, and MBL around the implant was measured during a 3-month healing period. RESULTS: In total, 871,389 sequences were compared against the Human Oral Microbiome Database for bacterial identification. Microbial signatures of smokers exhibited lower diversity and richness, with a significant decrease in uncultured species. The phyla Gracilibacteria and Saccharibacteria showed a significant decrease in smokers. The genera Streptococcus, Lachnoanaerobaculum, Stomatobaculum, and Eubacterium were significantly increased in smokers, whereas Selenomonas, Selenomonas [G-3], and Catonella were significantly decreased. Specifically, Porphyromonas gingivalis was significantly more abundant in smokers, which was positively related to the severity of MBL during bone healing. CONCLUSIONS: Smoking shapes the salivary microbiome in states of clinical health, and further may influence MBL during bone healing by creating high at-risk-for-harm communities. Understanding of the distinctly divergent oral microbiome in smokers and non-smokers is a base for personalized therapeutics for this high-risk cohort and also a base for further study on the pathologic mechanisms. PMID- 28844191 TI - Microbiologic Response to Periodontal Therapy and Multivariable Prediction of Clinical Outcome. AB - BACKGROUND: This study assesses the microbiologic effects of a two-phase antimicrobial periodontal therapy and tested microbiologic, clinical, and biologic markers as prognostic indicators for clinical success. METHODS: Eighty patients with chronic or aggressive periodontitis received periodontal treatment supplemented with 375 mg amoxicillin plus 500 mg metronidazole, three times daily for 7 days. In group A, antibiotics were given during the first non-surgical phase (T1); in group B, antibiotics were given during the second surgical phase (T2). Six microorganisms, group assignment, demographic and clinical variables, peak values of 15 cytokines, and nine acute-phase proteins in serum were evaluated as potential predictors of at least one site with probing depth (PD) >4 mm and bleeding on probing (BOP) at 12 months post-therapy. RESULTS: T1 decreased the counts of Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia (Pi), and Treponema denticola significantly more in group A than group B. Aggregatibacter actinomycetemcomitans and Parvimonas micra (Pm) showed a significant decrease only if the treatment was supplemented with antibiotics, i.e., T1 in group A, or T2 in group B. After T2, differences between groups were no longer significant. A multivariable model including four parameters revealed a predictive value of Pm (odds ratio [OR] = 4.38, P = 0.02) and Pi (OR = 3.44, P = 0.049) and yielded moderate accuracy for predicting the treatment outcome (area under the curve = 0.72). Host-derived factors and treatment sequence were not significantly associated with the outcome. CONCLUSIONS: Long-term microbiologic outcomes of periodontal therapy with adjunctive antibiotics either in T1 or T2 were similar. Detection of Pm before therapy was a predictor for persistence of sites with PD >4 mm and BOP at 12 months post-treatment. PMID- 28844194 TI - Procedural Anticoagulation in Myocardial Infarction. PMID- 28844195 TI - Is Oxygen Therapy Beneficial in Acute Myocardial Infarction? Simple Question, Complicated Mechanism, Simple Answer. PMID- 28844196 TI - Atypical femoral fracture associated with bone-modifying agent for bone metastasis of breast cancer: A report of two cases. AB - Atypical femoral fractures (AFFs) are recently observed as a complication of long term bone-modifying agent (BMA; bisphosphonate or denosumab) therapy for bone metastases. We describe the cases of two women diagnosed with breast cancer who developed incomplete AFF associated with BMAs prescribed for bone metastases. Radiographs of their femurs revealed thickening of the lateral subtrochanteric cortex, and tomosynthesis revealed a visible fracture line in the thickened cortex. They were initially treated with conservative management; however, the incomplete fracture resulted in a complete fracture. These cases highlight two major implications. First, symptomatic incomplete AFF associated with BMAs prescribed for bone metastases should be treated with surgical prophylaxis, given the fact that fracture healing is expected to require a longer duration and an incomplete fracture might potentially progress to a complete fracture during long term conservative management. Second, tomosynthesis is useful in identifying radiolucent fracture lines that are reliable predictors of fracture propagation. PMID- 28844197 TI - Functional outcome of extra-articular distal humerus fracture fixation using a single locking plate: A retrospective study. AB - PURPOSE: The optimal method for fixation of extra-articular distal humerus factures poses a management dilemma. Although various plate configurations have been proposed, anatomic shaped extra-articular distal humerus locking plates have emerged as a viable solution for these complex injuries. We assessed clinico radiologic outcome in our retrospective case series of extra-articular distal humerus fractures managed with these plates. METHODS: Forty-five patients of extra-articular distal humerus fractures, who were operated at our level 1 trauma centre between January, 2012 and December, 2016, were identified. After exclusion, 36 patients were available for the final assessment. All patients were operated with the triceps-reflecting modified posterior approach. Regular clinico radiologic follow-up was done evaluating elbow functionality, fracture union, secondary displacement, non-union, implant failure and any complications; Mayo Elbow Performance score (MEPS) was used for the final functional assessment. RESULTS: Twenty-four (66.7%) male and 12 (33.3%) female patients constituted the study group, who had an average follow-up of 15 months. Preoperatively three patients and post-operatively one patient had radial nerve palsy; all had neurapraxia and recovered completely. Overall, 34 (94.4%) patients were adjudged to have complete radiological union within 3 months; 2 (5.5%) patients developed non-union. Mean flexion achieved was 122.9 degrees +/- 23 degrees , and mean extension was -4.03 degrees +/- 6.5 degrees ; 1 patient with head injury developed flexion deformity of 45 degrees . Average MEPS at the final follow-up was 90.8 degrees +/- 9.9 degrees . CONCLUSION: Stable reconstruction and early initiation of physiotherapy are utilitarian to envision optimal outcome; the use of precontoured extra-articular distal humerus locking plates has yielded satisfactory results with minimal complications in our hands. PMID- 28844198 TI - Medial external fixation for staged treatment of closed calcaneus fractures: Surgical technique and case series. AB - The derangement in calcaneal morphology after a fracture can be significant and is often associated with severe soft tissue envelop problems. Medial calcaneal external fixation is useful for early restoration of calcaneal morphology and the corresponding soft tissue envelop. When performed in a stepwise fashion, external fixation can successfully restore normal calcaneal height, length, width, and coronal plane alignment. For severely displaced joint depression and broken tongue-type calcaneus fractures where open treatment is the preferred strategy, early external fixation restores the normal soft tissue tension, allows a stable environment for soft tissue recovery, and facilitates the definitive operation by restoring and maintaining overall calcaneal architecture. We describe the stepwise approach to calcaneal reduction and external fixation and report a case series demonstrating this method is safe and effective for staged management of severely displaced calcaneus fractures. PMID- 28844199 TI - Cryopreservation versus fresh frozen meniscal allograft: A biomechanical comparative analysis. AB - Meniscal allograft transplantation may be a better alternative for the treatment of irreparable meniscal injury compared to other forms of treatment. However, it remains to be seen whether the use fresh frozen allograft is better than cryopreserved allograft in treating this type of injury. We hypothesized that cryopreserved meniscal allograft would work better in maintaining the original biomechanical properties compared to fresh frozen ones, due to the lower amount of damage it incurs during the storage process. We examined young and healthy human menisci obtained from orthopedic oncology patients who underwent resection surgeries around the knee. The menisci obtained were preserved via cryopreservation and deep-freezing process. Traction tests were carried out on the menisci after 6 weeks of preservation. Twelve pairs ( N = 24) of menisci were divided equally into two groups, cryopreservation and deep frozen. There were six males and six female menisci donors for this study. The age range was between 15 and 35 years old (24.9 +/- 8.6 years). Cryopreserved specimens had a higher ultimate tensile strength (UTS; 8.2 +/- 1.3 Mpa vs. 13.3 +/- 1.7 Mpa: p < 0.05) and elastic modulus (61.7 +/- 27.6 Mpa vs. 87.0 +/- 44.10 Mpa: p < 0.05) compared to the fresh frozen specimens. There was a significant difference in UTS ( p < 0.05) between the two groups but no significant difference in their elastic modulus ( p > 0.05). The elastic modulus of the preserved meniscus was similar to fresh normal menisci taken from other studies (60-120 Mpa; cryopreserved (87.0 +/ 44.1) and fresh frozen (61.7 +/- 27.5)). Cryopreserved menisci had a higher elastic modulus and point of rupture (UTS) compared to fresh frozen menisci. Cryopreservation proved to be a significantly better method of preservation, among the two methods of preservation in this study. PMID- 28844200 TI - Oxygen Therapy in Suspected Acute Myocardial Infarction. AB - BACKGROUND: The clinical effect of routine oxygen therapy in patients with suspected acute myocardial infarction who do not have hypoxemia at baseline is uncertain. METHODS: In this registry-based randomized clinical trial, we used nationwide Swedish registries for patient enrollment and data collection. Patients with suspected myocardial infarction and an oxygen saturation of 90% or higher were randomly assigned to receive either supplemental oxygen (6 liters per minute for 6 to 12 hours, delivered through an open face mask) or ambient air. RESULTS: A total of 6629 patients were enrolled. The median duration of oxygen therapy was 11.6 hours, and the median oxygen saturation at the end of the treatment period was 99% among patients assigned to oxygen and 97% among patients assigned to ambient air. Hypoxemia developed in 62 patients (1.9%) in the oxygen group, as compared with 254 patients (7.7%) in the ambient-air group. The median of the highest troponin level during hospitalization was 946.5 ng per liter in the oxygen group and 983.0 ng per liter in the ambient-air group. The primary end point of death from any cause within 1 year after randomization occurred in 5.0% of patients (166 of 3311) assigned to oxygen and in 5.1% of patients (168 of 3318) assigned to ambient air (hazard ratio, 0.97; 95% confidence interval [CI], 0.79 to 1.21; P=0.80). Rehospitalization with myocardial infarction within 1 year occurred in 126 patients (3.8%) assigned to oxygen and in 111 patients (3.3%) assigned to ambient air (hazard ratio, 1.13; 95% CI, 0.88 to 1.46; P=0.33). The results were consistent across all predefined subgroups. CONCLUSIONS: Routine use of supplemental oxygen in patients with suspected myocardial infarction who did not have hypoxemia was not found to reduce 1-year all-cause mortality. (Funded by the Swedish Heart-Lung Foundation and others; DETO2X-AMI ClinicalTrials.gov number, NCT01787110 .). PMID- 28844201 TI - Bivalirudin versus Heparin Monotherapy in Myocardial Infarction. AB - BACKGROUND: The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors. METHODS: In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y12 inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up. RESULTS: A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P=0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P=0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P=0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P=0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P=0.76). CONCLUSIONS: Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others; VALIDATE-SWEDEHEART ClinicalTrialsRegister.eu number, 2012 005260-10 ; ClinicalTrials.gov number, NCT02311231 .). PMID- 28844203 TI - Neonatal renal and inferior vena cava thrombosis associated with fetal thrombotic vasculopathy: a case report. AB - BACKGROUND: Fetal thrombotic vasculopathy is a described placental diagnosis associated with adverse perinatal outcomes. It may also predispose children to somatic thromboembolic events. As far as we know, this is the first case of inferior vena cava thrombosis associated with fetal thrombotic vasculopathy in a completely asymptomatic newborn. CASE PRESENTATION: We report the case of an asymptomatic, full-term Turkish male neonate delivered at 39 weeks of gestation diagnosed as having thrombosis of the renal vein and inferior vena cava. Diagnosis was guided only by the presence of edematous umbilical cord with macroscopic signs of clotting and, subsequently, microscopic features of the placenta, suggesting fetal thrombotic vasculopathy. CONCLUSIONS: Thrombosis of the renal and inferior vena cava in our healthy, asymptomatic full-term neonate is clearly associated with fetal thrombotic vasculopathy. The diagnosis of thrombosis in this neonate was incidental. This suggests that fetal thrombotic vasculopathy may cause unrecognized neonatal thrombosis. Untreated neonatal thrombosis may later compromise growth and function of the involved organs; therefore, maintaining a high index of suspicion based on thrombotic vasculopathy is paramount. PMID- 28844204 TI - Ocular metastasis from breast carcinoma simulating anterior scleritis: a case report. AB - BACKGROUND: Breast cancer is one of the commonest sources of ocular metastasis. Patients with ocular metastatic disease can present with a variable clinical picture. Patients with a history of breast cancer presenting with any eye symptom should be evaluated with consideration of ocular metastasis. CASE PRESENTATION: We report a case of ocular metastasis in a 46-year-old Brahmin woman presenting with right eye pain. She had been treated for stage IIIc left-sided breast cancer 2 years ago with six cycles of chemotherapy with docetaxel, adriamycin, and cyclophosphamide after undergoing modified radical mastectomy. An ophthalmic examination revealed a tender subconjunctival swelling superotemporally on retracting right upper eyelid. This finding alone indicated anterior scleritis. On examining fundus under mydriasis, an amelanotic subretinal mass could be visualized in the posterior pole superotemporal to macula. An orbital magnetic resonance imaging revealed a mass of 2 * 1 cm in size in the subretinal space of her right eye. Computed tomography of her chest was then done and showed multiple metastases in both lungs. CONCLUSION: This case report highlights the fact that any unusual ocular presentation, even one simulating anterior scleritis, in a patient with a history of breast cancer should raise suspicion of metastasis. PMID- 28844202 TI - Distinct unfolded protein responses mitigate or mediate effects of nonlethal deprivation of C. elegans sleep in different tissues. AB - BACKGROUND: Disrupting sleep during development leads to lasting deficits in chordates and arthropods. To address lasting impacts of sleep deprivation in Caenorhabditis elegans, we established a nonlethal deprivation protocol. RESULTS: Deprivation triggered protective insulin-like signaling and two unfolded protein responses (UPRs): the mitochondrial (UPRmt) and the endoplasmic reticulum (UPRER) responses. While the latter is known to be triggered by sleep deprivation in rodent and insect brains, the former was not strongly associated with sleep deprivation previously. We show that deprivation results in a feeding defect when the UPRmt is deficient and in UPRER-dependent germ cell apoptosis. In addition, when the UPRER is deficient, deprivation causes excess twitching in vulval muscles, mirroring a trend caused by loss of egg-laying command neurons. CONCLUSIONS: These data show that nonlethal deprivation of C. elegans sleep causes proteotoxic stress. Unless mitigated, distinct types of deprivation induced proteotoxicity can lead to anatomically and genetically separable lasting defects. The relative importance of different UPRs post-deprivation likely reflects functional, developmental, and genetic differences between the respective tissues and circuits. PMID- 28844205 TI - Ultrasound-guided central venous catheter placement: a structured review and recommendations for clinical practice. AB - The use of ultrasound (US) has been proposed to reduce the number of complications and to increase the safety and quality of central venous catheter (CVC) placement. In this review, we describe the rationale for the use of US during CVC placement, the basic principles of this technique, and the current evidence and existing guidelines for its use. In addition, we recommend a structured approach for US-guided central venous access for clinical practice. Static and real-time US can be used to visualize the anatomy and patency of the target vein in a short-axis and a long-axis view. US-guided needle advancement can be performed in an "out-of-plane" and an "in-plane" technique. There is clear evidence that US offers gains in safety and quality during CVC placement in the internal jugular vein. For the subclavian and femoral veins, US offers small gains in safety and quality. Based on the available evidence from clinical studies, several guidelines from medical societies strongly recommend the use of US for CVC placement in the internal jugular vein. Data from survey studies show that there is still a gap between the existing evidence and guidelines and the use of US in clinical practice. For clinical practice, we recommend a six-step systematic approach for US-guided central venous access that includes assessing the target vein (anatomy and vessel localization, vessel patency), using real time US guidance for puncture of the vein, and confirming the correct needle, wire, and catheter position in the vein. To achieve the best skill level for CVC placement the knowledge from anatomic landmark techniques and the knowledge from US-guided CVC placement need to be combined and integrated. PMID- 28844193 TI - Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. AB - BACKGROUND: Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding. METHODS: In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (>=80 years of age; >=70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. RESULTS: The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups. CONCLUSIONS: Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864 .). PMID- 28844206 TI - Gestational diabetes mellitus-right person, right treatment, right time? AB - BACKGROUND: Personalised treatment that is uniquely tailored to an individual's phenotype has become a key goal of clinical and pharmaceutical development across many, particularly chronic, diseases. For type 2 diabetes, the importance of the underlying clinical heterogeneity of the condition is emphasised and a range of treatments are now available, with personalised approaches being developed. While a close connection between risk factors for type 2 diabetes and gestational diabetes has long been acknowledged, stratification of screening, treatment and obstetric intervention remains in its infancy. CONCLUSIONS: Although there have been major advances in our understanding of glucose tolerance in pregnancy and of the benefits of treatment of gestational diabetes, we argue that far more vigorous approaches are needed to enable development of companion diagnostics, and to ensure the efficacious and safe use of novel therapeutic agents and strategies to improve outcomes in this common condition. PMID- 28844208 TI - Health policy and systems research collaboration pathways: lessons from a network science analysis. AB - BACKGROUND: The 2004 Mexico Declaration, and subsequent World Health Assembly resolutions, proposed a concerted support for the global development of health policy and systems research (HPSR). This included coordination across partners and advocates for the field of HPSR to monitor the development of the field, while promoting decision-making power and implementing responsibilities in low- and middle-income countries (LMICs). METHODS: We used a network science approach to examine the structural properties of the HPSR co-authorship network across country economic groups in the PubMed citation database from 1990 to 2015. This analysis summarises the evolution of the publication, co-authorship and citation networks within HPSR. RESULTS: This method allows identification of several features otherwise not apparent. The co-authorship network has evolved steadily from 1990 to 2015 in terms of number of publications, but more importantly, in terms of co-authorship network connectedness. Our analysis suggests that, despite growth in the contribution from low-income countries to HPSR literature, co authorship remains highly localised. Lower middle-income countries have made progress toward global connectivity through diversified collaboration with various institutions and regions. Global connectivity of the upper middle-income countries (UpperMICs) are almost on par with high-income countries (HICs), indicating the transition of this group of countries toward becoming major contributors to the field. CONCLUSIONS: Network analysis allows examination of the connectedness among the HSPR community. Initially (early 1990s), research groups operated almost exclusively independently and, despite the topic being specifically on health policy in LMICs, HICs provided lead authorship. Since the early 1990s, the network has evolved significantly. In the full set analysis (1990-2015), for the first time in HPSR history, more than half of the authors are connected and lead authorship from UpperMICs is on par with that of HICs. This demonstrates the shift in participation and influence toward regions which HPSR primarily serves. Understanding these interactions can highlight the current strengths and future opportunities for identifying new strategies to enhance collaboration and support capacity-building efforts for HPSR. PMID- 28844207 TI - A novel presentation of Mycobacterium avium complex in a recipient of a lung transplant: a case report. AB - BACKGROUND: Lung transplantation remains an important potential therapeutic option for end-stage lung disease. It can improve quality of life and in some cases be a life-lengthening therapy. Despite the possible benefits, there are also many potential complications following transplantation. Here we describe a novel presentation of nontuberculous mycobacterium manifesting as an endobronchial mass developing 4 years after lung transplantation. CASE PRESENTATION: A 66-year-old African-American woman presented with progressive dyspnea, cough, and persistent wheezing of 2 months' duration. She had a distant history of breast cancer and received bilateral lung transplantation due to end stage pulmonary fibrosis 4 years prior to her current presentation. She denied fevers, but did endorse night sweats. She had diffuse expiratory wheezing on auscultation. Chest computed tomography imaging showed an endobronchial soft tissue lesion nearly occluding the left mainstem bronchus, which was concerning for endobronchial carcinoma. Rigid bronchoscopy demonstrated a fibrinous mass protruding into the left mainstem proximal to the anastomosis. A pathology report noted fragments of partially necrotic granulation tissue in addition to scant fragments of focally ulcerated bronchial mucosa. Both the tissue culture and bronchial wash stained positively for acid-fast bacilli and grew Mycobacterium avium complex. CONCLUSIONS: Nontuberculous mycobacterium pulmonary disease is common post lung transplant and risk factors are related to immunosuppression and history of structural lung disease. Mycobacterium avium complex presenting as an endobronchial lesion in a patient post lung transplant is a novel presentation. PMID- 28844209 TI - The indeterminable resilience of the fascial system. AB - The most recent information on fascial tissue indicates that there are not fascial layers, but polyhedral microvacuoles of connective tissue, which connect the body systems and, by hosting specialized cells, permit several functions, such as motor, nervous, vascular and visceral. These microvacuoles (a repetition of polyhedral units of connective fibrils) under internal or external tension change shape and can manage the movement variations, regulating different body functions and ensuring the maintenance of efficiency of the body systems. Their plasticity is based on perfect functional chaos: it is not possible to determine the motion vectors of the different fibrils, which differ in behavior and orientation; this strategy confers to the fascial continuum the maximum level of adaptability in response to the changing internal and external conditions of the cell. The present commentary deals with this concept, providing clinical examples of different disease patterns, providing contrary examples in which this adaptability does not occur, and lastly suggesting considerations for the approach to manipulative therapy of the fascial tissue. The fascial continuum is like a flock of birds flying together without a predetermined logic and maintaining their individuality at the same time. PMID- 28844210 TI - A history of standardization in the English translation of traditional Chinese medicine terminology. AB - In order to facilitate and propose further international standardization of traditional Chinese medicine (TCM) terminology, this article applies methods of historiography, philology and descriptive study to divide the history of TCM into three phases, based on representative experts and social events; to illustrate different aspects of these experts and their translation principles and standards and to discuss associated factors and inherent problems. The authors find that the development of a terminology standard for TCM has generally progressed from early approaches that were ill-suited to the contemporary needs to culturally and professionally referenced approaches, from uncoordinated research to systematic studies, and from individual works to collaborative endeavors. The present international standards of TCM terminology have been attained through the work of numerous scholars and experts in the history of the field. The authors are optimistic that a more comprehensive and recognized standard will come out soon. PMID- 28844211 TI - Effectiveness of Myrtus communis in the treatment of hemorrhoids. AB - Myrtus communis is an important plant in the treatment of many different diseases. The aim of this review was to determine the importance of M. communis essential oil in the treatment of hemorrhoids. For preparing this manuscript, the information was extracted from different resources. The results of clinical studies showed that M. communis essential oil (lotion or ointment) can significantly improve bleeding, permanent pain, pain during defecation, anal irritation, anal itching and anal heaviness in patients with hemorrhoids types I and II. M. communis was also effective in treating patients who did not respond to current chemical treatments (anti-hemorrhoids ointment). Further clinical studies should look into designing a suppository form of M. communis essential oil and compare its effect with the lotion and ointment forms. PMID- 28844212 TI - A cross-sectional study of complementary and alternative medicine use in patients with coagulation disorders in Southern Iran. AB - OBJECTIVE: Complementary and alternative medicine (CAM) use has an increasing trend around the world. Despite the wild application of CAM in patients with coagulation disorders, its efficacy is still questioned by many studies. The aim of this study was to determine the frequency and types of CAM usage, and the factors affecting CAM use among patients with bleeding disorders. METHODS: This cross-sectional study investigated the usage of CAM with a standard validated questionnaire in coagulopathic patients who were referred to Dastgheib Hospital, an educational therapeutic center affiliated to the Shiraz University of Medical Sciences in Shiraz, Southern Iran. RESULTS: Between December 2015 and May 2016, 75 patients were included in this survey. Severe hemophilia A and rare bleeding disorders were the most frequent among our participants. Overall, nearly half of the studied population (49.3%) used at least one CAM product or practices. The most common products were multivitamin (29.3%), followed by folic acid (21.3%) and chamomile (12%). 32% of the patients resorted to faith healing. The main reasons of using CAM were reported to be increased general health, correction of anemia and thrombocytopenia and control of bleeding tendency. CONCLUSION: CAM is being used frequently in patients with coagulation disorders like many other chronic illnesses all around the world. Due to emerging concern regarding the safety and possible interaction with the conventional medicine, it is necessary to develop basic data about the hematologic effects of these methods in order to use them more safely. PMID- 28844213 TI - Effects of rhubarb (Rheum ribes L.) syrup on dysenteric diarrhea in children: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Rheum ribes L. is a plant native to China, Iran, Turkey, India, and a few other countries. Antidiarrheal activity is considered to be one of its important properties according to various systems of traditional medicine. An increasing rate of bacterial resistance to antibiotics has led to treatment failure in some cases of shigellosis in children, and underlines a need for safe, efficient and valid options. OBJECTIVE: The purpose of this study is to evaluate the efficacy of R. ribes syrup as a complementary medicine for treatment of shigellosis in children. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This randomized, double-blind, placebo-controlled trial started with a group of 150 children aged between 12-72 months with suspected Shigella dysentery. R. ribes syrup or placebo syrup was administered to the intervention and control groups, respectively for 5 days. In addition, the standard antibiotic treatment (ceftriaxone for the first 3 days and cefixime syrup for 2 further days) was administered to both groups. MAIN OUTCOME MEASURES: Body temperature, abdominal pain, need for antipyretics, defecation frequency, stool volume and consistency and microscopic stool examination were recorded as outcome measures. Any observed adverse effects were also recorded. RESULTS: Mean duration of fever and diarrhea in the R. ribes group was significantly lower than that in the placebo group (P = 0.016 and 0.001, respectively). In addition, patients in the R. ribes group showed shorter duration of need for antipyretics and shorter duration of abdominal pain (P = 0.012 and 0.001, respectively). However, there were no significant differences between the two groups regarding the microscopic stool analyses. Furthermore, no adverse effect was reported. CONCLUSION: R. ribes syrup can be recommended as a complementary treatment for children with Shigella dysentery. TRIAL REGISTRATION: Iranian Registry of Clinical Trial: IRCT2014070518356N1. PMID- 28844214 TI - Efficacy of topical chamomile on the incidence of phlebitis due to an amiodarone infusion in coronary care patients: a double-blind, randomized controlled trial. AB - BACKGROUND: Amiodarone is a useful antiarrhythmic drug. Phlebitis, caused by intravenous amiodarone, is common in patients in coronary care units (CCUs). OBJECTIVE: The aim of this study was to evaluate the effect of topical chamomile on the incidence of phlebitis due to the administration of an amiodarone infusion into the peripheral vein. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This was a randomized, double-blind clinical trial, conducted on 40 patients (n = 20 per group) in two groups-an intervention group (chamomile ointment) and a control group (lanoline, as a placebo), hospitalized in the CCUs and undergoing an amiodarone infusion into the peripheral vein over 24 h. Following the cannulation and commencement of the infusion, placebo or chamomile ointment was rubbed in, up to 10 cm superior to the catheter and repeated every eight hours for three days. The cannula site was then assessed based on the phlebitis checklist. MAIN OUTCOME MEASURES: The incidence and time of occurrence of phlebitis, relative risk, severity of phlebitis were the main outcome measures. RESULTS: Nineteen patients (19/20) in the control group had phlebitis on the first day of the study and one patient (20/20) on the second day. In the intervention group, phlebitis occurred in 13 cases (13/20) on the first day and another two (2/7) was found on the second day. The incidence of phlebitis was significantly different between two groups (P = 0.023). The cumulative incidence of phlebitis in the intervention group (15/20) is significantly later and lower than that in the control group (20/20) during two days (P = 0.008). Two patients in the intervention group did not develop phlebitis at all during the 3-day study. Also, the relative risk of phlebitis in the two groups was 0.68 (P = 0.008 5). A significant difference was not observed with regard to phlebitis severity in both groups. CONCLUSION: It seems that phlebitis occurred to a lesser extent and at a later time frame in the intervention group compared to control group. Topical chamomile may be effective in decreasing the incidence of phlebitis due to an amiodarone infusion. TRIAL REGISTRATION: This protocol was registered in the Iranian Registry of Clinical Trials (IRCT2014042017361N1). PMID- 28844215 TI - Antinociceptive and anti-inflammatory activities of leaf extracts from Annona tomentosa R.E.Fr. AB - OBJECTIVE: Annona tomentosa R.E.Fr is a species not endemic to Brazil that belongs to the phytogeographic areas of the Amazon, Cerrado and Pantanal. Popularly known as "araticum rasteiro" or "araticum de moita", A. tomentosa is edible and tea made from the leaves has been used as an anti-inflammatory by native communities. There is no scientific evidence for these uses of A. tomentosa, especially those related to the control of pain and inflammation. For this reason, in the present study we evaluated the antinociceptive and anti inflammatory activities of partitions from the methanolic extract of A. tomentosa leaves (A. tomentosa leaf methanolic extract (ATFM) in hexane partition: ATFM-H; ATFM in dichloromethane partition: ATFM-D; ATFM in ethyl acetate partition: ATFM Ac; ATFM in butanol partition: ATFM-B) in mice. METHODS: The antinociceptive effects of leaf extracts from A. tomentosa were evaluated by abdominal writhing and tail-flick tests, while the anti-inflammatory effects were evaluated by paw oedema and air-pouch tests. The locomotor activity was evaluated with the open field test. Furthermore, we evaluated the possible action mechanism of A. tomentosa, using naloxone, nitro-L-arginine methyl ester, glibenclamide, atropine, naltrindole and norbinaltorphimine in tail-flick tests. The productions of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta were also evaluated. RESULTS: The chromatographic fractionation of the partitions of the methanolic extract from the leaves of A. tomentosa revealed the presence of diterpenes, flavonoids, and steroids compounds. From the analysis of the hexane partition kaurenoic acid was identified as the major component. ATFM-H and ATFM-D had a significant antinociceptive effect in acute pain models in mice. The ATFM-H showed central antinociceptive effect from the involvement of the delta opioid receptors, without causing alterations in the locomotor activity of the mice, while ATFM-D was effective in decreasing paw oedema and TNF-alpha and IL-1beta production. CONCLUSION: These results demonstrate that leaf extracts from A. tomentosa present antinociceptive and anti-inflammatory effects that can to be used in relieving algesic and inflammatory conditions. PMID- 28844216 TI - Antioxidant defense system induced by cysteine-stabilized peptide fraction of aqueous extract of Morinda lucida leaf in selected tissues of Plasmodium berghei infected mice. AB - OBJECTIVE: This study evaluated the responses of some antioxidant parameters in selected tissues of Plasmodium berghei-infected mice treated with cysteine stabilized peptide fraction (CSPF) of aqueous extract of Morinda lucida leaf. METHODS: Fifty-six mice were randomly divided into seven groups. Group A (normal control) was uninfected and received 5% dimethyl sulfoxide (DMSO). Mice in Groups B (negative control), C, D, E and F were inoculated with P. berghei NK65 and were administered with 5% DMSO and 15.63, 31.25, 61.5 and 125 mg/kg body weight of CSPF respectively. Group G animals, were also inoculated with P. berghei NK65, and received 20 mg/kg body weight of chloroquine. The administration lasted for three days, after which malondialdehyde (MDA) concentration and various antioxidant parameters in selected tissues of mice were determined on days 4 and 8 post-inoculation. RESULTS: The results revealed that MDA concentration was significantly increased (P < 0.05) in the tissues of the negative control and chloroquine-treated groups. The increased MDA concentration was reduced by CSPF in a dose-dependent manner, which was significant (P < 0.05) at higher doses. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and the concentration of reduced glutathione were significantly reduced (P < 0.05) in the tissues of the negative control animals compared to the normal controls. This observed reduction in the negative control animals was reverted in a dose-dependent manner in infected animals given CSPF, even to the range of the normal controls at highest dose, as did chloroquine. CONCLUSION: The results suggest that CSPF of M. lucida leaf extract may induce the antioxidant defense system in vivo against Plasmodium species infection. PMID- 28844217 TI - Helicobacter pylori outer membrane protein Q genotypes and their susceptibility to anti-adhesive phytotherapeutic agents. AB - OBJECTIVE: Helicobacter pylori is a Gram-negative organism. Its outer membrane protein Q (HopQ) mediates host-pathogen interactions; HopQ genotypes 1 and 2 are found associating with gastroduodenal pathologies. The authors measured the anti adhesion effects of the extracts of Abelmoschus esculentus, Zingiber officinale, Trachyspermum ammi, Glycyrrhiza glabra, Curcuma longa and Capsicum annum against HopQ genotypes and H. pylori cytotoxin-associated gene A (CagA). METHODS: DNA was extracted by polymerase chain reaction of the HopQ genotypes (i.e., type 1, type 2 and CagA) from 115 H. pylori strains. The effect of the extracts from selected dietary ingredients was determined using a gastric adenocarcinoma cell line and a quantitative DNA fragmentation assay. The anti-adhesive effect of these extracts on H. pylori was tested using an anti-adhesion analysis. RESULTS: C. annum, C. longa and A. esculentus showed prominent anti-adhesion effects with resultant values of 17.3% +/- 2.9%, 14.6% +/- 3.7%, 13.8% +/- 3.6%, respectively, against HopQ type 1 and 13.1% +/- 1.7%, 12.1% +/- 2%, 11.1% +/- 1.6%, respectively, against HopQ type 2. C. longa (93%), C. annum (89%) and A. esculentus (75%) had better anti-adhesive activity against H. pylori with HopQ type 1 compared to HopQ type 2 with respective values of 70%, 64% and 51%. Extracts of C. annum (14.7% +/ 4.1%), A. esculentus (12.3% +/- 4.1%) and Z. officinale (8.4% +/- 2.8%) had an anti-adhesion effect against CagA-positive H. pylori strains compared to CagA negative strains. CONCLUSION: The anti-adhesion properties of the tested phytotherapeutic dietary ingredients were varied with HopQ genotypes. HopQ type 1 was found to be more sensitive to extracts of C. annum, C. longa and A. esculentus compared to the HopQ type 2 genotype. PMID- 28844218 TI - Leech therapy in treatment of cutaneous leishmaniasis: a case report. PMID- 28844219 TI - Static solid-state 2H NMR methods in studies of protein side-chain dynamics. AB - In this review, we discuss the experimental static deuteron NMR techniques and computational approaches most useful for the investigation of side-chain dynamics in protein systems. Focus is placed on the interpretation of line shape and relaxation data within the framework of motional modeling. We consider both jump and diffusion models and apply them to uncover glassy behaviors, conformational exchange and dynamical transitions in proteins. Applications are chosen from globular and membrane proteins, amyloid fibrils, peptide adsorbed on surfaces and proteins specific to connective tissues. PMID- 28844220 TI - Self-diffusion studies by intra- and inter-molecular spin-lattice relaxometry using field-cycling: Liquids, plastic crystals, porous media, and polymer segments. AB - Field-cycling NMR relaxometry is a well-established technique for probing molecular dynamics in a frequency range from typically a few kHz up to several tens of MHz. For the interpretation of relaxometry data, it is quite often assumed that the spin-lattice relaxation process is of an intra-molecular nature so that rotational fluctuations dominate. However, dipolar interactions as the main type of couplings between protons and other dipolar species without quadrupole moments can imply appreciable inter-molecular contributions. These fluctuate due to translational displacements and to a lesser degree also by rotational reorientations in the short-range limit. The analysis of the inter molecular proton spin-lattice relaxation rate thus permits one to evaluate self diffusion variables such as the diffusion coefficient or the mean square displacement on a time scale from nanoseconds to several hundreds of microseconds. Numerous applications to solvents, plastic crystals and polymers will be reviewed. The technique is of particular interest for polymer dynamics since inter-molecular spin-lattice relaxation diffusometry bridges the time scales of quasi-elastic neutron scattering and field-gradient NMR diffusometry. This is just the range where model-specific intra-coil mechanisms are assumed to occur. They are expected to reveal themselves by characteristic power laws for the time-dependence of the mean-square segment displacement. These can be favorably tested on this basis. Results reported in the literature will be compared with theoretical predictions. On the other hand, there is a second way for translational diffusion phenomena to affect the spin-lattice relaxation dispersion. If rotational diffusion of molecules is restricted, translational diffusion properties can be deduced even from molecular reorientation dynamics detected by intra-molecular spin-lattice relaxation. This sort of scenario will be relevant for adsorbates on surfaces or polymer segments under entanglement and chain connectivity constraints. Under such conditions, reorientations will be correlated with translational displacements leading to the so-called RMTD relaxation process (reorientation mediated by translational displacements). Applications to porous glasses, protein solutions, lipid bilayers, and clays will be discussed. Finally, we will address the intriguing fact that the various time limits of the segment mean-square displacement of polymers in some cases perfectly reproduce predictions of the tube/reptation model whereas the reorientation dynamics suggests strongly deviating power laws. PMID- 28844221 TI - MRI of chemical reactions and processes. AB - As magnetic resonance imaging (MRI) can spatially resolve a wealth of molecular information available from nuclear magnetic resonance (NMR), it is able to non invasively visualise the composition, properties and reactions of a broad range of spatially-heterogeneous molecular systems. Hence, MRI is increasingly finding applications in the study of chemical reactions and processes in a diverse range of environments and technologies. This article will explain the basic principles of MRI and how it can be used to visualise chemical composition and molecular properties, providing an overview of the variety of information available. Examples are drawn from the disciplines of chemistry, chemical engineering, environmental science, physics, electrochemistry and materials science. The review introduces a range of techniques used to produce image contrast, along with the chemical and molecular insight accessible through them. Methods for mapping the distribution of chemical species, using chemical shift imaging or spatially-resolved spectroscopy, are reviewed, as well as methods for visualising physical state, temperature, current density, flow velocities and molecular diffusion. Strategies for imaging materials with low signal intensity, such as those containing gases or low sensitivity nuclei, using compressed sensing, para hydrogen or polarisation transfer, are discussed. Systems are presented which encapsulate the diversity of chemical and physical parameters observable by MRI, including one- and two-phase flow in porous media, chemical pattern formation, phase transformations and hydrodynamic (fingering) instabilities. Lastly, the emerging area of electrochemical MRI is discussed, with studies presented on the visualisation of electrochemical deposition and dissolution processes during corrosion and the operation of batteries, supercapacitors and fuel cells. PMID- 28844223 TI - AAE Position Statement: AAE Guidance on the Use of Systemic Antibiotics in Endodontics. PMID- 28844224 TI - Reply. PMID- 28844225 TI - Vascular Endothelial Growth Factor-loaded Bioresorbable Delivery System for Pulp Regeneration. PMID- 28844227 TI - Corrigendum. PMID- 28844226 TI - Commentary. PMID- 28844228 TI - Optimizing Care Transitions: Adapting Evidence-Informed Solutions to Local Contexts. PMID- 28844222 TI - Recent advances in parallel imaging for MRI. AB - Magnetic Resonance Imaging (MRI) is an essential technology in modern medicine. However, one of its main drawbacks is the long scan time needed to localize the MR signal in space to generate an image. This review article summarizes some basic principles and recent developments in parallel imaging, a class of image reconstruction techniques for shortening scan time. First, the fundamentals of MRI data acquisition are covered, including the concepts of k-space, undersampling, and aliasing. It is demonstrated that scan time can be reduced by sampling a smaller number of phase encoding lines in k-space; however, without further processing, the resulting images will be degraded by aliasing artifacts. Nearly all modern clinical scanners acquire data from multiple independent receiver coil arrays. Parallel imaging methods exploit properties of these coil arrays to separate aliased pixels in the image domain or to estimate missing k space data using knowledge of nearby acquired k-space points. Three parallel imaging methods-SENSE, GRAPPA, and SPIRiT-are described in detail, since they are employed clinically and form the foundation for more advanced methods. These techniques can be extended to non-Cartesian sampling patterns, where the collected k-space points do not fall on a rectangular grid. Non-Cartesian acquisitions have several beneficial properties, the most important being the appearance of incoherent aliasing artifacts. Recent advances in simultaneous multi-slice imaging are presented next, which use parallel imaging to disentangle images of several slices that have been acquired at once. Parallel imaging can also be employed to accelerate 3D MRI, in which a contiguous volume is scanned rather than sequential slices. Another class of phase-constrained parallel imaging methods takes advantage of both image magnitude and phase to achieve better reconstruction performance. Finally, some applications are presented of parallel imaging being used to accelerate MR Spectroscopic Imaging. PMID- 28844229 TI - Understanding Facilitators and Barriers to Care Transitions: Insights from Project ACHIEVE Site Visits. AB - BACKGROUND: Care transitions between clinicians or settings are often fragmented and marked by adverse events. To increase patient safety and deliver more efficient and effective health care, new ways to optimize these transitions need to be identified. A study was conducted to delineate facilitators and barriers to implementation of transitional care services at health systems that may have been adopted or adapted from published evidence-based models. METHODS: From March 2015 through December 2015, site visits were conducted across the United States at 22 health care organizations-community hospitals, academic medical centers, integrated health systems, and broader community partnerships. At each site, direct observation and document review were conducted, as were semistructured interviews with a total of 810 participants (5 to 57 participants per site) representing various stakeholder groups, including management and leadership, transitional care team members, internal stakeholders, community partners, patients, and family caregivers. RESULTS: Facilitators of effective care transitions included collaborating within and beyond the organization, tailoring care to patients and caregivers, and generating buy-in among staff. Commonly reported barriers included poor integration of transitional care services, unmet patient or caregiver needs, underutilized services, and lack of physician buy-in. CONCLUSION: True community partnership, high-quality communication, patient and family engagement, and ongoing evaluation and adaptation of transitional care strategies are ultimately needed to facilitate effective care transitions. Health care organizations can strategically prioritize transitional care service delivery through staffing decisions, by making transitional care part of the organization's formal board agenda, and by incentivizing excellence in providing transitional care services. PMID- 28844230 TI - High-Performing Health Care Delivery Systems: High Performance Toward What Purpose? PMID- 28844231 TI - What Defines a High-Performing Health Care Delivery System: A Systematic Review. AB - BACKGROUND: Purchasers, payers, and policy makers are increasingly measuring and rewarding high-performing health systems, which use a variety of definitions of high performance, yet it is unclear if a consistently applied definition exists. A systematic review was conducted to determine if there is a commonly used, agreed-on definition of what constitutes a "high-performing" health care delivery system. METHODS: Searches were conducted for English-language articles defining high performance with respect to a health care system or organization in PubMed and WorldCat databases from 2005 to 2015 and the New York Academy of Medicine Grey Literature Report from 1999 to 2016. The entity/condition to which the definition was applied was extracted from included articles. The number and type of dimensions used to define high performance within and across articles was tabulated and the number and type of metrics used by performance dimension and by article was calculated. RESULTS: No consistent definition of a high-performing health care system or organization was identified. High performance was variably defined across different dimensions, including quality (93% of articles), cost (67%), access (35%), equity (26%), patient experience (21%), and patient safety (18%). Most articles used more than one dimension to define high performance (75%), but only five used five or more dimensions. The most commonly paired dimensions were quality and cost (63%). CONCLUSION: The absence of a consistent definition of what constitutes high performance and how to measure it hinders our ability to compare and reward health care delivery systems on performance, underscoring the need to develop a consistent definition of high performance. PMID- 28844232 TI - A Multicomponent Fall Prevention Strategy Reduces Falls at an Academic Medical Center. AB - BACKGROUND: While the reduction in fall rates has not kept pace with the reduction of other hospital-acquired conditions, patient safety research and quality improvement (QI) initiatives at the system and hospital levels have achieved positive results and provide insights into potentially effective risk reduction strategies. An academic medical center developed a QI-based multicomponent strategy for fall prevention and pilot tested it for six months in three high-risk units-the Neuroscience Acute Care Unit, the Myelosuppression/Stem Cell Transplant Unit, and the Acute Care for the Elderly Unit-before implementing and evaluating the strategy hospitalwide. METHODS: The multicomponent fall strategy was evaluated using a pre-post study design. The main outcome measures were falls and falls with harm measured in events per 1,000 patient-days. Fall rates were monitored and compared for three classes of falls: (1) accidental, (2) anticipated physiologic, and (3) unanticipated physiologic. RESULTS: Statistical process control charts showed that the pilot units had achieved significant reductions in falls with harm during the last five months of data collection. Wald test and segmented regression analyses revealed significant improvements in pooled postintervention fall rates, stratified by fall type. The hospitalwide implementation of the program resulted in a 47% overall reduction in falls in the postintervention period. CONCLUSION: A fall prevention strategy that targeted the spectrum of risk factors produced measurable improvement in fall rates and rates of patient harm. Hospitals must continue developing, rigorously testing, and sharing their results and experiences in implementing and sustaining multicomponent fall prevention strategies. PMID- 28844233 TI - Do Hospitals Support Second Victims? Collective Insights From Patient Safety Leaders in Maryland. AB - BACKGROUND: Second victims-defined as health care providers who are emotionally traumatized after a patient adverse event-may not receive needed emotional support. Although most health care organizations have an employee assistance program (EAP), second victims may be reluctant to access this service because of worries about confidentiality. A study was conducted to describe the extent to which organizational support for second victims is perceived as desirable by patient safety officers in acute care hospitals in Maryland and to identify existing support programs. METHODS: Semistructured interviews (using existing and newly developed questions) were conducted with 43 patient safety representatives from 38 of the 46 acute care hospitals in Maryland (83% response rate). RESULTS: All but one of the responding hospitals offered EAP services to their employees, but there were gaps in the services provided related to timeliness, EAP staff's ability to relate to clinical providers, and physical accessibility. There were no valid measures in place to assess the effectiveness of EAP services. Participants identified a need for peer support, both for the second victim and potentially for individuals who provide that support. Six (16%) of the 38 hospitals had second victim support programs, which varied in structure, accessibility, and outcomes, while an additional 5 hospitals (13%) were developing such a program. CONCLUSION: Patient safety officers thought their organizations should reevaluate the support currently provided by their EAPs, and consider additional peer support mechanisms. Future research is needed to evaluate the effectiveness of these programs. PMID- 28844234 TI - Using Simulation to Improve Systems-Based Practices. AB - BACKGROUND: Ensuring the safe, effective management of patients requires efficient processes of care within a smoothly operating system in which highly reliable teams of talented, skilled health care providers are able to use the vast array of high-technology resources and intensive care techniques available. Simulation can play a unique role in exploring and improving the complex perioperative system by proactively identifying latent safety threats and mitigating their damage to ensure that all those who work in this critical health care environment can provide optimal levels of patient care. METHODS: A panel of five experts from a wide range of institutions was brought together to discuss the added value of simulation-based training for improving systems-based aspects of the perioperative service line. Panelists shared the way in which simulation was demonstrated at their institutions. The themes discussed by each panel member were delineated into four avenues through which simulation-based techniques have been used. RESULTS: Simulation-based techniques are being used in (1) testing new clinical workspaces and facilities before they open to identify potential latent conditions; (2) practicing how to identify the deteriorating patient and escalate care in an effective manner; (3) performing prospective root cause analyses to address system weaknesses leading to sentinel events; and (4) evaluating the efficiency and effectiveness of the electronic health record in the perioperative setting. CONCLUSION: This focused review of simulation-based interventions to test and improve components of the perioperative microsystem, which includes literature that has emerged since the panel's presentation, highlights the broad based utility of simulation-based technologies in health care. PMID- 28844235 TI - Improving Pain Management and Safe Use of Opioids: A Call for Papers. PMID- 28844236 TI - Sensitivity and specificity prediction of the buccal micronucleus cytome assay in end-stage renal disease patients on dialysis: A case-control study. AB - Patients with end-stage renal disease (ESRD) require hemodialysis. However, dialysis therapy may cause genomic damage due to increased oxidative stress. Non invasive assessment of genotoxicity may be helpful for developing management strategies. We applied the buccal micronucleus cytome (BMCyt) assay to ESRD patients on dialysis. Patients (n=35, age 52+/-2 year) on dialysis therapy (20.9+/-0.8months) had low glomerular filtration rates (GFR=5.00+/ 0.36ml/min/1.73m2); controls (n=21, age 51+/-2 year) were healthy adults with no known recent illnesses or exposures. Patients had significantly increased chromosome damage: clastogenic/aneugenic events (frequency of cells with MN), cellproliferation (basal cells), cytokinesis defects (binucleated cells), and celldeath (pyknotic cells); Repair Index was lower in the patient group. Receiver Operator Characteristic (ROC) curve analysis showed that cells with MN were the best predictor for discriminating between patients and controls. Other predictivebiomarkers were the frequencies of basal, binucleated,and pyknotic. PMID- 28844237 TI - Genotoxicity testing: Comparison of the gammaH2AX focus assay with the alkaline and neutral comet assays. AB - Genotoxicity testing relies on the quantitative measurement of adverse effects, such as chromosome aberrations, micronuclei, and mutations, resulting from primary DNA damage. Ideally, assays will detect DNA damage and cellular responses with high sensitivity, reliability, and throughput. Several novel genotoxicity assays may fulfill these requirements, including the comet assay and the more recently developed gammaH2AX assay. Although they are thought to be specific for genotoxicants, a systematic comparison of the assays has not yet been undertaken. In the present study, we compare the gammaH2AX focus assay with the alkaline and neutral versions of the comet assay, as to their sensitivities and limitations for detection of genetic damage. We investigated the dose-response relationships of gammaH2AX foci and comet tail intensities at various times following treatment with four prototypical genotoxicants, methyl methanesulfonate (MMS), N-methyl-N' nitro-N-nitrosoguanidine (MNNG), mitomycin C, and hydrogen peroxide (H2O2) and we tested whether there is a correlation between the endpoints, i.e., alkali-labile sites and DNA strand breaks on the one hand and the cell's response to DNA double strand breaks and blocked replication forks on the other. Induction of gammaH2AX foci gave a linear dose response and all agents tested were positive in the assay. The increase in comet tail intensity was also a function of dose; however, mitomycin C was almost completely ineffective in the comet assay, and the doses needed to achieve a significant effect were somewhat higher for some treatments in the comet assay than in the gammaH2AX foci assay, which was confirmed by threshold analysis. There was high correlation between tail intensity and gammaH2AX foci for MMS and H2O2, less for MNNG, and none for mitomycin C. From this we infer that the gammaH2AX foci assay is more reliable, sensitive, and robust than the comet assay for detecting genotoxicant-induced DNA damage. PMID- 28844238 TI - Mechanisms of chromosomal aberrations induced by sesamin metabolites in Chinese hamster lung cells. AB - Sesamin is a major lignan in sesame seeds and oil. We previously demonstrated that sesamin induces chromosomal aberrations (CA) in Chinese hamster lung (CHL/IU) cells in the presence of a metabolic activation system (S9 mix), although no genotoxicity was detected in vivo. To clarify the mechanism of CA induction by sesamin, we identified its principal active metabolite. A mono catechol derivative, [2-(3,4-methylenedioxyphenyl)-6-(3,4-dihydroxyphenyl)-3,7 dioxabi-cyclo[3.3.0]octane (SC-1)], was previously identified in culture medium when sesamin was incubated with S9 mix. In the present study, we show that SC-1 induces CA in CHL/IU cells but not in human hepatoblastoma (HepG2) cells. SC-1 was unstable in culture medium. Addition of glutathione (GSH) to the incubation mixture decreased the rate of decomposition and also suppressed induction of CA in CHL/IU cells. These results indicate that SC-1 itself may not contribute to the induction of CA. Two GSH adducts of SC-1 were identified when SC-1 was incubated with GSH, suggesting that SC-1 was converted to the semiquinone/quinone form and then conjugated with GSH in the culture medium. Sodium sulfite (a quinone-responsive compound) also suppressed CA induction by SC-1. These findings strongly suggest that SC-1 is oxidized to semiquinone/quinone derivatives extracellularly in culture medium, that these derivatives are responsible for the induction of CA in CHL/IU cells, and therefore that the positive results obtained with sesamin in in vitro CA tests using CHL/IU cells may not be relevant to the assessment of in vivo activity. PMID- 28844239 TI - Personal samplers of bioavailable pesticides integrated with a hair follicle assay of DNA damage to assess environmental exposures and their associated risks in children. AB - Agriculture in the United States employs youth ages ten and older in work environments with high pesticide levels. Younger children in rural areas may also be affected by indirect pesticide exposures. The long-term effects of pesticides on health and development are difficult to assess and poorly understood. Yet, epidemiologic studies suggest associations with cancer as well as cognitive deficits. We report a practical and cost-effective approach to assess environmental pesticide exposures and their biological consequences in children. Our approach combines silicone wristband personal samplers and DNA damage quantification from hair follicles, and was tested as part of a community-based participatory research (CBPR) project involving ten Latino children from farmworker households in North Carolina. Our study documents high acceptance among Latino children and their caregivers of these noninvasive sampling methods. The personal samplers detected organophosphates, organochlorines, and pyrethroids in the majority of the participants (70%, 90%, 80%, respectively). Pesticides were detected in all participant samplers, with an average of 6.2+/-2.4 detections/participant sampler. DNA damage in epithelial cells from the sheath and bulb of plucked hairs follicles was quantified by immunostaining 53BP1-labled DNA repair foci. This method is sensitive, as shown by dose response analyses to gamma radiations where the lowest dose tested (0.1Gy) led to significant increased 53BP1 foci density. Immunolabeling of DNA repair foci has significant advantages over the comet assay in that specific regions of the follicles can be analyzed. In this cohort of child participants, significant association was found between the number of pesticide detections and DNA damage in the papilla region of the hairs. We anticipate that this monitoring approach of bioavailable pesticides and genotoxicity will enhance our knowledge of the biological effects of pesticides to guide education programs and safety policies. PMID- 28844241 TI - Is mobile phone radiation genotoxic? An analysis of micronucleus frequency in exfoliated buccal cells. AB - Electromagnetic fields (EMF) are classified as "possibly carcinogenic" by the International Agency for Research on Cancer (IARC). Some publications have reported associations between EMF exposure and DNA damage, but many other studies contradict such findings. Cytomorphological changes, such as micronuclei (MN), indicative of genomic damage, are biomarkers of genotoxicity. To test whether mobile phone-associated EMF exposure affects the MN frequency in exfoliated buccal cells, we obtained cells smears from the left and right inner cheeks of healthy mobile phone users, aged 18-30 (n=86), who also completed a characterization survey. MN frequencies were tested for potential confounding factors and for duration of phone use and preferential side of mobile phone use. No relationship was observed between MN frequency and duration of mobile phone use in daily calls. Cells ipsilateral to mobile phone use did not present a statistically significantly higher MN frequency, compared to cells contralateral to exposure. A highly statistically significant (p<0.0001) increase in MN frequency was found in subjects reporting regular exposure to genotoxic agents. Therefore, our results suggest that mobile phone-associated EMF do not to induce MN formation in buccal cells at the observed exposure levels. PMID- 28844240 TI - Developmental toxicity and DNA damaging properties of silver nanoparticles in the catfish (Clarias gariepinus). AB - Although, silver nanoparticles (AgNPs) are used in many different products, little information is known about their toxicity in tropical fish embryos. Therefore, this study evaluated the developmental toxicity of waterborne silver nanoparticles in embryos of Clarias gariepinus. Embryos were treated with (0, 25, 50, 75ng/L silver nanoparticles) in water up to 144h postfertilization stage (PFS). Results revealed various morphological malformations including notochord curvature and edema. The mortality rate, malformations, and DNA fragmentation in embryos exposed to silver nanoparticles increased in a dose- and embryonic stage dependent manner. The total antioxidant capacity and the activity of catalase in embryos exposed to 25ng/L silver nanoparticles were decreased significantly while the total antioxidant capacity and the activity of catalase were insignificantly increased with increasing concentrations in the embryos from 24 to 144 h-PFS exposed to 50 and 75ng/L silver nanoparticles. Lipid peroxidation values showed fluctuations with doses of silver nanoparticles. Histopathological lesions including severely distorted and wrinkled notochord were observed. The current data propose that the toxicity of silver nanoparticles in C. gariepinus embryos is caused by oxidative stress and genotoxicity. PMID- 28844242 TI - The DREME Network: Research and Interventions in Early Childhood Mathematics. AB - The DREME Network was created to advance the field of early mathematics research and improves the opportunities to develop math competencies offered to children birth through age 8 years, with an emphasis on the preschool years. All four main Network projects will have implications for interventions. Section 1 introduces the Network and its four projects. The remainder of the chapter focuses on one of these four projects, Making More of Math (MMM), in depth. MMM is directly developing an intervention for children, based on selecting high-quality instructional activities culled from the burgeoning curriculum resources. We first report a review of 457 activities from 6 research-based curricula, which describes the number of activities by content focus, type (nature), and setting of each activity. Given the interest in higher-order thinking skills and self regulation, we then identified activities that had the potential to, develop both mathematics and executive function (EF) proficiencies. We rated these, selecting the top 10 for extensive coding by mathematics content and EF processes addressed. We find a wide divergence across curricula in all these categories and provide comprehensive reports for those interested in selecting, using, or developing early mathematics curricula. PMID- 28844243 TI - Coaching in Early Mathematics. AB - Falling scores in math have prompted a renewed interest in math instruction at early ages. By their own admission, early childhood educators are generally underprepared and not always comfortable teaching math. Professional development (PD) in early mathematics is widely considered a main way to increase teachers' skills and efficacy (e.g., Guskey, 2000; Hyson & Woods, 2014; Munby, Russell, & Martin, 2001; Piasta, Logan, Pelatti, Capps, & Petrill, 2015; Richardson & Placier, 2001; Sarama, Clements, Wolfe, & Spitler, 2016; Sarama & DiBiase, 2004; Zaslow, 2014). However, it has been documented that stand-alone PD is not as effective in changing practice (e.g., Biancarosa & Bryk, 2011; Garet et al., 2008; Guskey, 2000; Hyson & Woods, 2014; Institute of Medicine and National Research Council, 2015; Joyce & Showers, 2002; Zaslow, 2014). Site-embedded ongoing support in the form of coaching or mentoring has been shown to be critical for successful implementation (Neuman & Cunningham, 2009; Powell, Diamond, Burchinal, & Koehler, 2010). In this chapter, we describe coaching models and abstract characteristics of effective coaching from the research. With this background, we provide an in-depth view of the coaching aspect of two large empirical studies in early mathematics. We introduce the theoretical framework from which the coaching models for these projects were developed and describe the research on which they were based. We then summarize how the planned models were instantiated and challenges to their implementation within each project. In the final section, we summarize what we have learned and described implications and challenges for the field. PMID- 28844244 TI - Notice, Explore, and Talk About Mathematics: Making a Positive Difference for Preschool Children, Families, and Educators in Australian Communities That Experience Multiple Disadvantages. AB - Let's Count is a preschool mathematics intervention implemented by The Smith Family from 2012 to the present in "disadvantaged" communities across Australia. It is based on current mathematics and early childhood education research and aligns with the Australian Early Years Learning Framework. Let's Count has been shown to be effective in enhancing mathematics learning and dispositions of young children, early childhood educators, and families through a longitudinal evaluation undertaken from 2012 to 2015. In this chapter, the authors explore the development, implementation, and evaluation of Let's Count and highlight the importance of adults noticing, exploring, and talking about children's mathematics. The findings from the longitudinal evaluation of Let's Count suggest that when adults notice children's mathematics, then children's learning thrives, and the positive dispositions and confidence of parents and educators increase. Let's Count has made a positive difference for many children and adults across Australia. PMID- 28844245 TI - Designing Studies to Test Causal Questions About Early Math: The Development of Making Pre-K Count. AB - A growing literature has demonstrated that early math skills are associated with later outcomes for children. This research has generated interest in improving children's early math competencies as a pathway to improved outcomes for children in elementary school. The Making Pre-K Count study was designed to test the effects of an early math intervention for preschoolers. Its design was unique in that, in addition to causally testing the effects of early math skills, it also allowed for the examination of a number of additional questions about scale-up, the influence of contextual factors and the counterfactual environment, the mechanism of long-term fade-out, and the role of measurement in early childhood intervention findings. This chapter outlines some of the design considerations and decisions put in place to create a rigorous test of the causal effects of early math skills that is also able to answer these questions in early childhood mathematics and intervention. The study serves as a potential model for how to advance science in the fields of preschool intervention and early mathematics. PMID- 28844246 TI - Interventions for Primary School Children With Difficulties in Mathematics. AB - Difficulty with arithmetic is a common problem for children and adults, though there has been some work on the topic for a surprisingly long time. This chapter will review some of the research that has been done over the years on interventions with primary school children. Interventions can be of various levels of intensiveness, ranging from whole-class approaches that take account of individual differences through small-group and limited-time individual interventions to extended-time individual interventions. Interventions discussed here include those involving peer tuition and group collaboration; those involving board and computer games; and those that involve assessing children's strengths and weaknesses in different components of mathematics; and targeting remedial activities to the assessed weaknesses. Most of the interventions discussed in this chapter specifically involve mathematics (usually mainly arithmetic), but there is also some discussion of attempts to improve mathematics by training children in domain-general skills, including Piagetian operations, metacognition, and executive functions. PMID- 28844247 TI - Early Executive Function and Mathematics Relations: Correlation Does Not Ensure Concordance. AB - In this chapter, we address one potentially overlooked component of the relation between executive function (EF) skills and early mathematics, a relation for which there is widespread empirical support. Evidence for this relation has, thus far, been largely correlational. Here we emphasize that because positive correlations do not guarantee concordance among all members of a sample or population, a small but meaningful number of children may either fare well in mathematics despite poor EF skills, or may have strong EF skills despite weak mathematics skills. We propose that attention to different profiles of discordance for EF and mathematics may help identify individualized learning needs for students at risk for mathematics difficulties and disabilities. PMID- 28844248 TI - The Use of Concrete Experiences in Early Childhood Mathematics Instruction. AB - Addressed are four key issues regarding concrete instruction: What is concrete? What is a worthwhile concrete experience? How can concrete experiences be used effectively in early childhood mathematics instruction? Is there evidence such experiences work? I argue that concrete experiences are those that build on what is familiar to a child and can involve objects, verbal analogies, or virtual images. The use of manipulatives or computer games, for instance, does not in itself guarantee an educational experience. Such experiences are worthwhile if they target and further learning (e.g., help children extend their informal knowledge or use their informal knowledge to understand and learn formal knowledge). A crucial guideline for the effective use of concrete experience is Dewey's principle of interaction-external factors (e.g., instructional activities) need to mesh with internal factors (readiness, interest). Cognitive views of concrete materials, such as the cognitive alignment perspective and dual representation hypothesis, provide useful guidance about external factors but do not adequately take into account internal factors and their interaction with external factors. Research on the effectiveness of concrete experience is inconclusive because it frequently overlooks internal factors. PMID- 28844249 TI - Interventions in Early Mathematics: Avoiding Pollution and Dilution. AB - Although specific interventions in early mathematics have been successful, few have been brought to scale successfully, especially across the challenging diversity of populations and contexts in the early childhood system in the United States. In this chapter, we analyze a theoretically based scale-up model for early mathematics that was designed to avoid the pollution and dilution that often plagues efforts to achieve broad success. We elaborate the theoretical framework by noting the junctures that are susceptible to dilution or pollution. Then we expatiate the model's guidelines to describe specifically how they were designed and implemented to mitigate pollution and dilution. Finally, we provide evidence regarding the success of these efforts. PMID- 28844250 TI - Preface. PMID- 28844251 TI - Sports Dietetics: Impact Beyond Playing Fields. PMID- 28844252 TI - Back to Basics: All About MyPlate Food Groups. PMID- 28844253 TI - What Is the Latest Recommendation Regarding Calcium Supplements? PMID- 28844254 TI - Perspectives on paramagnetic NMR from a life sciences infrastructure. AB - The effects arising in NMR spectroscopy because of the presence of unpaired electrons, collectively referred to as "paramagnetic NMR" have attracted increasing attention over the last decades. From the standpoint of the structural and mechanistic biology, paramagnetic NMR provides long range restraints that can be used to assess the accuracy of crystal structures in solution and to improve them by simultaneous refinements through NMR and X-ray data. These restraints also provide information on structure rearrangements and conformational variability in biomolecular systems. Theoretical improvements in quantum chemistry calculations can nowadays allow for accurate calculations of the paramagnetic data from a molecular structural model, thus providing a tool to refine the metal coordination environment by matching the paramagnetic effects observed far away from the metal. Furthermore, the availability of an improved technology (higher fields and faster magic angle spinning) has promoted paramagnetic NMR applications in the fast-growing area of biomolecular solid state NMR. Major improvements in dynamic nuclear polarization have been recently achieved, especially through the exploitation of the Overhauser effect occurring through the contact-driven relaxation mechanism: the very large enhancement of the 13C signal observed in a variety of liquid organic compounds at high fields is expected to open up new perspectives for applications of solution NMR. PMID- 28844255 TI - Journal Performance Report. PMID- 28844256 TI - Woman With Coffee Ground Emesis. PMID- 28844257 TI - Peripartum Patient With Epigastric Pain. PMID- 28844258 TI - Debriefing: An Expert Panel's How-to Guide. PMID- 28844259 TI - The Black Cloud of Christmas. PMID- 28844260 TI - All in One Minute: Eulogy for a Pedestrian and Well-being for Us. PMID- 28844262 TI - Clinical Decision Aids or Clinician Gestalt? Hard to Know Which Is Better: September 2017 Annals of Emergency Medicine Journal Club. PMID- 28844261 TI - Code White. PMID- 28844263 TI - Young Adult Male in a Coma. PMID- 28844264 TI - Middle-Aged Female With Chest Pain. PMID- 28844265 TI - Boy With Muscle Spasms. PMID- 28844267 TI - Selfieeeeeeee! PMID- 28844266 TI - Male With Severe Headache. PMID- 28844268 TI - Swarming: A New Model to Optimize Efficiency and Education in an Academic Emergency Department. PMID- 28844269 TI - Not So Fast: The Downsides of Rapid Test Ordering at Triage. PMID- 28844270 TI - In reply. PMID- 28844271 TI - Discriminatory Value of Orthostatic Vital Signs in the Emergency Department Evaluation of Syncope. PMID- 28844272 TI - Guidelines for the Use of Transesophageal Echocardiography (TEE) in the ED for Cardiac Arrest. PMID- 28844273 TI - Prior Authorization. PMID- 28844274 TI - Civil Commitment. PMID- 28844275 TI - Health Courts. PMID- 28844276 TI - Physician Credentialing and Delineation of Clinical Privileges in Emergency Medicine. PMID- 28844277 TI - Optimizing the Treatment of Acute Pain in the Emergency Department. PMID- 28844278 TI - Boy With Fever and Cough. PMID- 28844279 TI - Man With Suprapubic Pain. PMID- 28844280 TI - Man With Shortness of Breath. PMID- 28844281 TI - For Every Manuscript, a Journal? PMID- 28844282 TI - Brugada phenocopy during right coronary artery dissection. AB - CASE PRESENTATION: A 68-year-old female presented with non-ST-segment elevation myocardial infarction, and urgency coronary angiography was performed. The procedure was complicated with right coronary artery dissection leading to type-1 Brugada ECG pattern. DISCUSSION: Brugada phenocopies (BrP) are clinical entities that present with electrocardiograms identical to those found in Brugada Syndrome (BrS) but are the result of different medical conditions. This report provides evidence that atypical causes of myocardial ischemia may induce BrP. Appropriate electrocardiogram and clinical differentiation of Brugada phenocopy from true Brugada syndrome may prevent unnecessary treatments. Although patients with true high-risk BrS are candidates for ICD therapy, the natural history of BrP remains unknown and seems to be more benign, depending on the severity of the underlying condition. PMID- 28844284 TI - Hormesis and homeopathy: a step forward. PMID- 28844285 TI - Zincum metallicum research: an international scientific collaboration in homeopathy. PMID- 28844283 TI - All Wrapped Up: Environmental Effects on Myelination. AB - To date, studies have demonstrated the dynamic influence of exogenous environmental stimuli on multiple regions of the brain. This environmental influence positively and negatively impacts programs governing myelination, and acts on myelinating oligodendrocyte (OL) cells across the human lifespan. Developmentally, environmental manipulation of OL progenitor cells (OPCs) has profound effects on the establishment of functional cognitive, sensory, and motor programs. Furthermore, central nervous system (CNS) myelin remains an adaptive entity in adulthood, sensitive to environmentally induced structural changes. Here, we discuss the role of environmental stimuli on mechanisms governing programs of CNS myelination under normal and pathological conditions. Importantly, we highlight how these extrinsic cues can influence the intrinsic power of myelin plasticity to promote functional recovery. PMID- 28844286 TI - Metal nanoparticle induced hormetic activation: a novel mechanism of homeopathic medicines. AB - BACKGROUND: High-potency homeopathic remedies, 30c and 200c have enormous dilution factors of 1060 and 10400 respectively. Therefore, the presence of physical entities in them is inconceivable. As a result, their efficacy is highly debated and often dismissed as a placebo. Despite several hypotheses postulated to explain the claimed homeopathic efficacy, none have satisfactorily answered the qualms of the sceptics. Against all beliefs and principles of conventional dilution, we have shown that nanoparticles (NPs) of the starting metals are unequivocally found in the 30c and 200c remedies at concentrations of a few pg/ml. In this paper, our aim was to answer the important question of whether such negligible metal concentrations elicit a biological response. METHODS: Metal based homeopathic medicines (30c and 200c) were analysed at doses between 0.003%v/v and 10%v/v in in-vitro HepG2 cell-line. Upon treatment, cell response was estimated by MTT assay, FACS and total intracellular protein. Experiments were performed to discern whether the hormesis was a cell-activation or a proliferation effect. RESULTS: Remedies at doses containing a few femtograms/ml levels of the starting metals induced a proliferation-independent hormetic activation by increasing the intracellular protein synthesis. The metal concentrations (at fg/ml) were a billion-fold lower than the studies with synthetic NPs (at MUg/ml). Further, we also highlight a few plausible mechanisms initiating a hormetic response at a billion-fold lower dose. CONCLUSIONS: Hormetic activation has been shown for the first time with standard homeopathic high-potency remedies. These findings should have a profound effect in understanding these extreme dilutions from a biological perspective. PMID- 28844287 TI - Reproducibility of the effects of homeopathically potentised Argentum nitricum on the growth of Lemna gibba L. in a randomised and blinded bioassay. AB - BACKGROUND: A previous study reported a significant statistical interaction between experiment date and treatment effect of Argentum nitricum 14x-30x on the growth rate of duckweed (Lemna gibba L.). The aim of the present study was to investigate the stability of the test system and intra-laboratory reproducibility of the effects found. METHODS: Duckweed was treated with A. nitricum potencies (14x-30x) as well as succussed and unsuccussed water controls. The outcome parameter area-related growth rate for day 0-7 was determined by a computerised image analysis system in two series of independent randomised and blinded experiments. Systematic negative control (SNC) experiments were carried out to investigate test system stability. Statistical analysis was performed with full two-way analysis of variance (ANOVA) and protected Fisher's Least Significant Difference (LSD) test. RESULTS: In the first repetition series we found a significant treatment effect (p = 0.016), while in the second series no effect was observed. The negative control experiments showed that the experimental system was stable. An a posteriori subgroup analysis concerning gibbosity revealed the importance of this growth state of L. gibba for successful reproduction of the statistically significant interaction in the original study; flat: no interaction (p = 0.762); slight gibbosity: no interaction (p = 0.356); medium gibbosity: significant interaction (p = 0.031), high gibbosity: highly significant interaction (p = 0.005). CONCLUSIONS: With the original study design (disregarding gibbosity status of L. gibba) results of the original study could not be reproduced sensu stricto. We conclude that the growth state gibbosity is crucial for successful reproduction of the original study. Different physiological states of the test organisms used for bioassays for homeopathic basic research must carefully be considered. PMID- 28844288 TI - Generalisability of prognostic factor research: further analysis of data from the IIPCOS2 study. AB - Prognostic factor research is important as it helps in refining diagnosis, taking clinical and therapeutic decisions, enhances the design and analysis of intervention trials and helps to identify targets for new interventions that aim to modify the course of a disease. Prognostic factor research in homeopathy can be done by applying Bayes' theorem. This paper considers Bayes' theorem; Likelihood Ratio, conditional probability and research in subpopulations of a condition with examples. We analysed the likelihood ratios for 11 homeopathic medicines for the symptom 'cough' and other upper respiratory tract symptoms, based on data from the IIPCOS2 study. This yielded useful information since several medicines, including Belladonna, had LR >1 for cough, indicating that cough is not an indication for this medicine. The implications for improving homeopathic prescribing are discussed. PMID- 28844289 TI - Structural and thermal analyses of zinc and lactose in homeopathic triturated systems. AB - BACKGROUND: A series of different experimental approaches was applied in Zincum metallicum (Zinc met.) samples and lactose controls. Experiments were designed to elucidate the effect of zinc trituration and dynamization on physicochemical properties of homeopathic formulations, using lactose as excipient. METHODS: Zinc met. potencies (Zinc met 1-3c) were triturated and dynamized using lactose as excipient, according to Brazilian Homeopathic Pharmacopoeia. Lactose samples (LAC 1-3c) were also prepared following the same protocol and used as controls. The samples were analyzed structurally by Atomic Absorption Spectroscopy (AAS), X-ray Diffraction (XRD), Transmission Electron Microscopy (TEM) with Energy Dispersive X-ray Spectroscopy (EDX) and Scanning Electron Microscopy (SEM), and thermodynamically by Thermogravimetry (TG) and Differential Scanning Calorimetry (DSC). RESULTS: AAS analysis detected 97.0 % of zinc in the raw material, 0.75 % (Zinc met 1c) and 0.02% (Zinc met 2c). XRD analysis showed that inter-atomic crystalline spacing of lactose was not modified by dynamization. Amorphous and crystalline lactose spheres and particles, respectively, were observed by TEM in all samples, with mean size from 200 to 800 nm. EDX obtained with TEM identified zinc presence throughout the amorphous matter but individualized zinc particles were not observed. SEM images obtained from dynamized samples (LAC 1c and Zinc met 1c) with electron backscattering could not identify zinc metal grains. The dynamization process induced Derivatives of Thermal Gravimetric (DTg) peak modification, which was previously centered near 158 degrees C to lactose, to a range from 140 to 170 degrees C, suggesting the dynamization process modifies the temperature range of water aggregation. Thermal phenomena were analyzed and visualized by Analysis of Variance (ANOVA) and Principal Component Analysis (PCA) statistics. Both indicated that fusion enthalpy of dynamized samples (DynLAC 1 3c; DynZn 1-3c) increased 30.68 J/g in comparison to non-dynamized lactose (LAC; p < 0.05). CONCLUSIONS: Our results suggested no structural changes due to the trituration and dynamization process. However, TG and DSC analyses permit the differentiation of dynamized and non-dynamized groups, suggesting the dynamization process induced a significant increase in the degradation heat. These results call for further calorimetric studies with other homeopathic dilutions and other methodologies, to better understand the dynamics of these systems. PMID- 28844290 TI - Differential effects of Zincum metallicum on cell models. AB - INTRODUCTION: Zinc is an essential trace element necessary for life. Traditional and complementary medicines use zinc-based formulations to treat different classes of diseases. Basic research on homeopathic preparations of zinc are rare and there are a few published clinical cases describing its effects on patients. The use of cell-based models in drug screening is a reliable source of evidence. METHODS: We sought to investigate experimental end-points using cell-based models to determine the effects of dilutions of Zincum metallicum prepared according to the Brazilian Homeopathic Pharmacopoeia. Murine RAW 264.7 macrophages and melanoma B16-F10 cell lines were cultured according to standard procedures. Cells were treated with either 5c, 6c or 30c Zincum metallicum and control cells with its respective vehicle (5c, 6c, or 30c Lactose). Macrophage activation by CD54 immunolabeling and intracellular reactive oxygen species (ROS) using DCFH-DA (2,7 dichlorodihydrofluorescein diacetate) were detected by flow cytometry. Phagocytic capacity (endocytic index) was quantified by light microscopy. Features of melanoma cells were analyzed by colorimetric assays to determine melanin content and cell proliferation rate. All obtained data were submitted to normality test followed by statistical analysis. RESULTS: Zincum metallicum 6c shifted high ROS producing macrophages to a low ROS-producing phenotype. Macrophage CD54 expression was increased by Zincum metallicum 5c. No changes in endocytic index were observed. Melanoma cells were not affected by any treatment we tested. CONCLUSIONS: Differing responses and non-linearity were found on macrophages challenged with Zincum metallicum at high dilutions. No changes in melanoma cells were observed. Customised assays using target cells can be useful to investigate high-dilution effects. Other cell types and conditions should be explored. PMID- 28844291 TI - Could the study of cavitation luminescence be useful in high dilution research? AB - Cavitation in agitated liquids has been discussed for over five decades as a phenomenon that could play a role in the appearance of structural changes in the solvent of potentised dilutions. However, its lack of specificity as well as the absence of experimental confirmation have so far confined the idea to theory. The light emission associated with cavitational bubble collapse can be used to detect and study cavitation in fluids. The phenomenon has been extensively studied when driven by ultrasound, where it is called sonoluminescence. Sonoluminescence spectra reflect extremely high temperature and pressure in the collapsing bubbles and are parameter sensitive. This article tries to examine whether, despite objections and difficulties, the detection or the study of cavitational luminescence in solutions during potentisation could be useful as a physical tool in high dilution research. PMID- 28844292 TI - Comparison of plantar pressure distribution in patients with hallux valgus and healthy matched controls. AB - BACKGROUND: Detailed information regarding differences in plantar pressure distribution between hallux valgus and healthy feet is unavailable. The purposes of the present study were to clarify the characteristics of the plantar pressure distribution in patients with hallux valgus compared with healthy matched controls and to determine whether hallux valgus leads to dysfunction of the great toe during walking. METHODS: The study consisted of 25 patients with symptomatic moderate-to-severe hallux valgus (HV group) and 13 healthy matched volunteers (C group) without hallux valgus. All patients and volunteers were women. The HV and C groups did not differ significantly in age, height, weight, and body mass index. Plantar pressure during walking was measured using F-scan. The plantar aspect of the foot was divided into eight regions. The peak pressure (Peak-P), maximum force (Max-F), contact time (Con-T), contact area (Con-A), and force time integral (FTI) were measured in each region. RESULTS: The Peak-P of the great toe did not differ significantly between the HV and C groups. However, all other parameters: Max-F, Con-T, Con-A, and FTI of the great toe in the HV group were significantly lower than in the C group. In the central forefoot, the Peak-P and Max-F in the HV group were significantly higher than in the C group. CONCLUSION: The present study demonstrated that a moderate-to-severe hallux valgus deformity leads to dysfunction of the great toe during walking and may increase mechanical loading on the central forefoot. PMID- 28844293 TI - The effect of maropitant on intraoperative isoflurane requirements and postoperative nausea and vomiting in dogs: a randomized clinical trial. AB - OBJECTIVE: To establish if preoperative maropitant significantly reduced intraoperative isoflurane requirements and reduced clinical signs associated with postoperative nausea and vomiting (PONV) in dogs. STUDY DESIGN: Randomized clinical trial. ANIMALS: Twenty-four healthy, client-owned dogs undergoing routine ovariohysterectomy. METHODS: Premedication involved acepromazine (0.03 mg kg-1) combined with methadone (0.3 mg kg-1) intramuscularly 45 minutes before anaesthetic induction with intravenous (IV) propofol, dosed to effect. Meloxicam (0.2 mg kg-1) was administered intravenously. Dogs were randomly assigned to administration of saline (group S; 0.1 mL kg-1, n=12) or maropitant (group M; 1 mg kg-1, n=12) subcutaneously at time of premedication. Methadone (0.1 mg kg-1 IV) was repeated 4 hours later. Anaesthesia was maintained with isoflurane in oxygen, dosed to effect by an observer unaware of group allocation. The dogs were assessed hourly, starting 1 hour postoperatively, using the short form of the Glasgow Composite Pain Score (GCPS), and for ptyalism and signs attributable to PONV [score from 0 (none) to 3 (severe)] by blinded observers. Owners completed a questionnaire at the postoperative recheck. RESULTS: Overall mean+/-standard deviation end-tidal isoflurane percentage was lower in group M (1.19+/-0.26%) than group S (1.44+/-0.23%) (p=0.022), but was not significantly different between groups at specific noxious events (skin incision, ovarian pedicle clamp application, cervical clamp application, wound closure). Cardiorespiratory variables and postoperative GCPS were not significantly different between groups. Overall, 50% of dogs displayed signs attributable to PONV, with no difference in PONV scores between groups (p=0.198). No difference in anaesthetic recovery was noted by owners between groups. CONCLUSIONS: Maropitant reduced overall intraoperative isoflurane requirements but did not affect the incidence of PONV. CLINICAL RELEVANCE: Maropitant provided no significant benefits to dogs undergoing ovariohysterectomy with this anaesthetic and analgesic protocol, although clinically significant reductions in isoflurane requirements were noted. PMID- 28844294 TI - Cervical Spine Collar Removal by Emergency Room Nurses: A Quality Improvement Project. AB - INTRODUCTION: The Canadian C-Spine Rule (CCR) is a clinical decision aid to facilitate the safe removal of cervical collars in the alert, orientated, low risk adult trauma patient. Few health care settings have assessed initiatives to train charge nurses to use the CCR. This practice improvement project conducted in a secondary trauma center in Canada aimed to (1) train charge nurses of the emergency room to use the CCR, (2) monitor its use throughout the project period, and (3) compare the assessments of the charge nurses with those of emergency physicians. METHODS: The project began with the creation of an interdisciplinary team. Clinical guidelines were established by the interdisciplinary project team. Nine charge nurses of the emergency room were then trained to use the CCR (3 on each 8-hour shift). The use of the CCR was monitored throughout the project period, from June 1 to October 5, 2016. RESULTS: The 3 aims of this practice improvement project were attained successfully. Over a 5-month period, 114 patients were assessed with the CCR. Charge nurses removed the cervical collars for 54 of 114 patients (47%). A perfect agreement rate (114 of 114 patients, 100%) was attained between the assessments of the nurses and those of physicians. DISCUSSION: This project shows that the charge nurses of a secondary trauma center can use the CCR safely on alert, orientated, and low-risk adult trauma patients as demonstrated by the agreement in the assessments of emergency room nurses and physicians. PMID- 28844296 TI - Safety in the use of antidepressants: Vortioxetine-induce hyponatremia in a case report. PMID- 28844295 TI - Concentrations in plasma clozapine levels in schizophrenic and schizoaffective patients. AB - INTRODUCTION: There is great variability in plasma levels of clozapine. The objective of this study is to know the characteristics of patients treated with clozapine and the relationship between them and the variability of plasma levels. MATERIAL AND METHODS: Descriptive, cross-sectional study of all patients currently treated with clozapine in a Psychiatric Service with a diagnosis of schizophrenic psychosis or schizoaffective disorder. The present study assessed physical situation, psychopathology and functionality of the patients and explored the associations and correlations between clinical variables and plasma levels. RESULTS: We studied 39 patients, predominantly men, with negative and depressive symptoms and cardiovascular risk factors (metabolic syndrome and smoking). Significant variability in dose and even greater in clozapine levels were observed. The levels of clozapine at equal doses/kg of body weight were higher in non-smokers, they had positive correlation with BMI and negative correlation with systolic BP, disruptive behaviors and number of cigarettes consumed. CONCLUSION: Plasma level monitoring clozapine is an important tool to avoid clozapine plasma levels monitoring and minimize undesirable clinical situations (metabolic syndrome, sedation, negative symptoms and functional impairment). It is also important to control the effects of a smoking habit for optimum drug bioavailability. PMID- 28844297 TI - Measures of visual hallucinations: Review and recommendations. AB - BACKGROUND: Studies designed to investigate visual hallucinations (VH) require reliable and valid measures that can appropriately capture peoples' experiences. This review aimed to assess the psychometric rigour and usefulness of VH measures. METHOD: A systematic literature search was carried out against inclusion criteria (e.g. more than one specific question on VH, measures for adults in clinical and non-clinical populations). Eighteen measures were identified and rated against an adapted evaluation grid, which included essential criteria such as clear purpose and definition, psychometric properties including reliability and validity, and appropriate exploration of visual hallucinations. RESULTS: Measures could be categorised into 3 groups; those for general psychotic symptoms, those for all hallucinations, or those specifically for visual hallucinations. With one exception (the North East Visual Hallucinations Inventory), the measures were considered to be limited as they often targeted one population and hence lacked generalisability, or were limited in the characteristics of the visions that were described, or that psychometric properties were not adequately evaluated. CONCLUSIONS: Measures of VH require further development. The need to establish a clearer definition of VH is essential to provide clarity and consistency within research and practice. Measures need to demonstrate good psychometric properties to indicate robustness whilst being sensitive to change to help in the evaluation of treatments. Other recommendations include developing cross-cultural measures and involving service users in item development. PMID- 28844298 TI - UV-vis degradation of alpha-tocopherol in a model system and in a cosmetic emulsion-Structural elucidation of photoproducts and toxicological consequences. AB - The UV-vis photodegradation of alpha-tocopherol was investigated in a model system and in a cosmetic emulsion. Both gas chromatography coupled with tandem mass spectrometry (GC-MS/MS) and high performance liquid chromatography coupled with ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry (LC-UHR-MS) were used for photoproducts structural identification. Nine photoproduct families were detected and identified based on their mass spectra and additional experiments with alpha-tocopherol-d9; phototransformation mechanisms were postulated to rationalize their formation under irradiation. In silico QSAR (Quantitative Structure Activity Relationship) toxicity predictions were conducted with the Toxicity Estimation Software Tool (T.E.S.T.). Low oral rat LD50 values of 466.78mgkg-1 and 467.9mgkg-1 were predicted for some photoproducts, indicating a potential toxicity more than 10 times greater that of alpha-tocopherol (5742.54mgkg-1). In vitro assays on Vibrio fischeri bacteria showed that the global ecotoxicity of the alpha-tocopherol solution significantly increases with irradiation time. One identified product should contribute to this ecotoxicity enhancement since in silico estimations for D. magna provide a LC50 value 4 times lower than that of the parent molecule. PMID- 28844299 TI - Glycoform analysis of alpha1-acid glycoprotein based on capillary electrophoresis and electrophoretic injection. AB - A method based on capillary electrophoresis (CE) with electrophoretic injection and absorbance detection was developed for the direct analysis of AGP glycoforms in human serum. Electrophoretic injection of AGP was performed in the reversed polarity mode of CE with a capillary coated with poly(ethylene oxide) and that had minimal electroosmotic flow. This situation created an essentially stationary interface between the sample and running buffer during injection and sample stacking. This approach allowed an 11,000-fold increase in sample loading for a 5min injection versus hydrodynamic injection and without introducing any significant levels of extra band-broadening. This method was used with sample pretreatment methods based on acid precipitation and desalting to examine AGP glycoforms in only 65MUL of serum. A limit of detection of 2.1-11.3nM was obtained for the major AGP glycoform bands in serum, and the sample pretreatment method gave a recovery of 72.3-80.9% for these glycoforms. The precision for the migration times was +/-0.08-0.13% and the precision for the peak areas was +/ 0.34-1.18% when using serum samples and an internal standard. This method was used for both normal pooled serum and serum from individuals with systemic lupus erythematosus. Results were obtained in a separation time of 25min and allowed the comparison of up to eleven glycoform bands in these samples. A similar approach may be useful in examining additional glycoproteins in serum or other types of biological samples. PMID- 28844300 TI - Preparation and evaluation of an adsorbent based on poly (muconic acid-co divinylbenzene/ethylenedimethacrylate) for multiple monolithic fiber solid-phase microextraction of tetracycline antibiotics. AB - To extract tetracycline antibiotics (TAs) effectively, a new adsorbent based on poly (muconic acid-co-divinylbenzene/ethylenedimethacrylate) monolith was fabricated and used as the extraction medium of multiple monolithic fiber solid phase microextraction (MD/MF-SPME). The effect of the fabrication parameters on extraction efficiency was studied thoroughly. Elemental analysis, infrared spectroscopy, scanning electron microscopy and mercury intrusion porosimetry were used to check the physicochemical properties of the adsorbent. Some key parameters that affect the extraction performance of MD/MF-SPME for TAs were investigated systematically. Under the optimized experimental conditions, the prepared adsorbent could effectively extract the TAs through multiple interactions. At the same time, a simple and sensitive method for monitoring trace TAs in honey samples was developed by coupling MD/MF-SPME with high performance liquid chromatography tandem mass spectrometry detection (MD/MF-SPME HPLC-MS/MS). The limits of detection (S/N=3) for target compounds were in the range of 7.3-17.1ng/kg. The intra-day and inter-day precision (relative standard deviations, n=4, %) at 0.5MUg/kg and 20.0MUg/kg spiking concentrations were 5.0 9.5% and 3.6-10.0%, respectively. The mean recoveries of the target TAs in the real honey samples were between 70.5-111.0%. PMID- 28844301 TI - Electrophoretic deposition of graphene oxide onto carbon fibers for in-tube solid phase microextraction. AB - Carbon fibers (CFs) were functionalized with graphene oxide (GO) by an electrophoretic deposition (EPD) method for in-tube solid-phase microextraction (SPME). GO-CFs were filled into a poly(ether ether ketone) (PEEK) tube to obtain a fibers-in-tube SPME device, which was connected with high performance liquid chromatography (HPLC) equipment to build online SPME-HPLC system. Compared with CFs, GO-CFs presented obviously better extraction performance, due to excellent adsorption property and large surface area of GO. Using ten polycyclic aromatic hydrocarbons (PAHs) as model analytes, the important extraction conditions were optimized, such as sample flow rate, extraction time, organic solvent content and desorption time. An online analysis method was established with wide linear range (0.01-50MUgL-1) and low detection limits (0.001-0.004MUgL-1). Good sensitivity resulted from high enrichment factors (1133-3840) of GO-CFs in-tube device towards PAHs. The analysis method was used to online determination of PAHs in wastewater samples. Some target analytes were detected and relative recoveries were in the range of 90.2-112%. It is obvious that the proposed GO-CFs in-tube device was an efficient extraction device, and EPD could be used to develop nanomaterials functionalized sorbents for sample preparation. PMID- 28844302 TI - Interrelations between body mass index, frailty, and clinical adverse events in older community-dwelling women: The EPIDOS cohort study. AB - BACKGROUND: The hypothesis of reverse epidemiology holds that, obesity may reduce the risk of clinical adverse events in older subjects. However, this association is controversial and rarely explored according to the underlying health status. We tested this phenomenon by assessing the association between body mass index (BMI) and clinical adverse events in community dwelling older women according to their frailty status. METHODS: EPIDOS is a multicenter prospective cohort of community-dwelling women aged 75 and older recruited between 1992 and 1994. At baseline, we collected demographics, BMI (<21 kg/m2: underweight; 21-24.9: normal weight; 25-29.9: overweight and >=30: obesity), frailty through Fried model, and clinical characteristics. All-cause mortality, falls, hip fractures, and hospital admission were collected within 5 years of follow-up and were analyzed using univariate and multivariate survival analysis by using Kaplan-Meier methods and Cox Hazard Proportional models. RESULTS: Of 6662 women (mean age, 80.4 years), 11.6%; 95% Confidence Interval (95% CI) CI [10.8%-12.3%] were frail. By multivariate analysis, the risk of death in frail women (compared to not-frail normal weight women) decreases with increase of BMI: adjusted Hazard Ratio (aHR)frail-underweight = 2.04 [1.23-3.39]; aHRfrail-normal weight = 3.07 [2.21 4.26]; aHRfrail-overweight = 1.83 [1.31-2.56]; aHRfrail-obese = 1.76 [1.15-2.70]; p < 0.001. Frail overweight and obese women had a significant lower risk of death than frail normal-weight women (p = 0.004). Similar features were found for fall risk and hip fracture and for not-frail women. The relative risks of hospital admission for normal weight, overweight and obese frail women were similar (aHRfrail-normal weight = 1.50 [1.22-1.84], aHR frail-overweight =1.48 [1.26 1.74] and aHR frail-obese =1.53 [1.24-1.89], respectively). CONCLUSION: Our results suggest that overweight and obesity reduce the risks of clinical adverse events in frail community-dwelling older women and that frailty definition through Fried model had to be re-calibrated for overweight and obese individuals. PMID- 28844303 TI - Calcaneal Ewing's Sarcoma With Skip Metastases to Tarsals and Lymph Node Involvement: A Case Report. AB - Ewing's sarcoma (ES) represents the second most common primary malignant tumor of bone of children and occurs rarely in the bones of the foot. Dissemination to regional lymph nodes and skip metastases to adjacent bones are thought to be uncommon. We report a case of a 19-year-old female with the diagnosis of ES of the right calcaneus. Six months earlier, she had presented to the hospital with a history of ankle sprain and was treated with analgesics and ice application. Despite the treatment, the pain over the ankle persisted, her foot swelled progressively, and a mass evolved on the lateral side of the foot. She was referred to our clinic for further treatment options. Radiography and magnetic resonance imaging revealed an expansile mass originating from the calcaneus with talar and cuboidal skip metastases, with concomitant popliteal and inguinal lymph node involvement. The diagnosis was confirmed by histopathologic evaluation after Tru-Cut biopsy. Below-the-knee amputation with popliteal and inguinal lymph node dissection was performed after neoadjuvant chemotherapy. The postoperative first year follow-up data for the patient showed no evidence of metastasis. The calcaneus is a rare location for the development of ES. A few patients with ES will present with skip metastases to adjacent juxtaarticular bones or regional lymph node involvement. Therefore, the present study has presented a unique case of ES with a rare anatomic location and an unusual metastatic pattern. PMID- 28844304 TI - 46-Year-Old Man With Lower Back Pain. PMID- 28844305 TI - Regenerative Endodontics for Adult Patients. AB - The goal of endodontics is to save teeth. Since inception, endodontic treatments are performed to obturate disinfected root canals with inert materials such as gutta-percha. Although teeth can be saved after successful endodontic treatments, they are devitalized and therefore susceptible to reinfections and fractures. The American Association of Endodontists (AAE) has made a tremendous effort to revitalize disinfected immature permanent teeth in children and adolescents with diagnoses including pulp necrosis or apical periodontitis. The American Dental Association (ADA) in 2011 issued several clinical codes for regenerative endodontic procedures or apical revascularization in necrotic immature permanent teeth in children and adolescents. These AAE and ADA initiatives have stimulated robust interest in devising a multitude of tissue engineering approaches for dental pulp and dentin regeneration. Can the concept of regenerative endodontics be extended to revitalize mature permanent teeth with diagnoses including irreversible pulpitis and/or pulp necrosis in adults? The present article was written not only to summarize emerging findings to revitalize mature permanent teeth in adult patients but also to identify challenges and strategies that focus on realizing the goal of regenerative endodontics in adults. We further present clinical cases and describe the biological basis of potential regenerative endodontic procedures in adults. This article explores the frequently asked question if regenerative endodontic therapies should be developed for dental pulp and/or dentin regeneration in adults, who consist of the great majority of endodontic patients. PMID- 28844306 TI - Signaling Molecules and Pulp Regeneration. AB - Signaling molecules play an essential role in tissue engineering because they regulate regenerative processes. Evidence exists from animal studies that single molecules such as members of the transforming growth factor beta superfamily and factors that induce the growth of blood vessels (vascular endothelial growth factor), nerves (brain-derived neurotrophic factor), or fibroblasts (fibroblast growth factor) may induce reparative dentin formation. Mainly the formation of atubular dentin (osteodentin) has been described after the application of single molecules or combinations of recombinant growth factors on healthy exposed pulps or in pulp regeneration. Generally, such preparations have not received regulatory approval on the market so far. Only the use of granulocyte colony stimulating factors together with cell transplantation is presently tested clinically. Besides approaches with only 1 or few combined molecules, the exploitation of tissue-derived growth factors depicts a third promising way in dental pulp tissue engineering. Preparations such as platelet-rich plasma or platelet-rich fibrin provide a multitude of endogenous signaling molecules, and special regulatory approval for the market does not seem necessary. Furthermore, dentin is a perfect reservoir of signaling molecules that can be mobilized by treatment with demineralizing agents such as EDTA. This conditions the dentin surface and allows for contact differentiation of pulp stem cells into odontoblastlike cells, protects dentin from resorption, and enhances cell growth as well as attachment to dentin. By ultrasonic activation, signaling molecules can be further released from EDTA pretreated dentin into saline, thus avoiding cytotoxic EDTA in the final preparation. The use of dentin-derived growth factors offers a number of advantages because they are locally available and presumably are most fit to induce signaling processes in dental pulp. However, better characterization and standardization of the procedures are required. PMID- 28844307 TI - Clinical Evidence for Regenerative Endodontic Procedures: Immediate versus Delayed Induction? AB - Clinicians face many challenges when treating immature permanent teeth in young patients. Immediate blood clot induction can be a successful option as described by some case reports. No experimental studies or clinical trials have addressed this question. We have designed a clinical trial in which we hypothesized that there is no difference in success between immediate or delayed induction protocols. After confirmation of pulpal necrosis, patients were randomized. In the delayed group, 15 teeth were treated following the American Association of Endodontists guidelines, and calcium hydroxide was used as the intracanal medication. In the immediate group, 13 teeth had a blood clot inducted at the first appointment. The teeth were evaluated after 1, 3, and 12 months. Three independent evaluators assessed the periapical healing. The Pearson chi-square test or the Fisher exact test was used to compare the success rates between the 2 groups. Currently, of the 25 recruited patients (28 teeth), 19 have completed their 12-month follow-up. The group with delayed induction had a 71% success rate, and the group with immediate induction had a 33% success rate. In most cases (79%), trauma was the etiology. All successful cases started at stage 9 of root development (Nolla), and the majority showed healing type 2. Determination of the stage of root formation and etiology are possible critical factors for any therapeutic decision. In summary, it is early to conclude or suggest any of the protocols. Clearly, much more data are needed before sample size requirements can be met. PMID- 28844308 TI - Inflammation and Regeneration in the Dentin-pulp Complex: Net Gain or Net Loss? AB - The balance between the immune/inflammatory and regenerative responses in the diseased pulp is central to the clinical outcome, and this response is unique within the body because of its tissue site. Cariogenic bacteria invade the dentin and pulp tissues, triggering molecular and cellular events dependent on the disease stage. At the early onset, odontoblasts respond to bacterial components in an attempt to protect the tooth's hard and soft tissues and limit disease progression. However, as disease advances, the odontoblasts die, and cells central to the pulp core, including resident immune cells, pulpal fibroblasts, endothelial cells, and stem cells, respond to the bacterial challenge via their expression of a range of pattern recognition receptors that identify pathogen associated molecular patterns. Subsequently, recruitment and activation occurs of a range of immune cell types, including neutrophils, macrophages, and T and B cells, which are attracted to the diseased site by cytokine/chemokine chemotactic gradients initially generated by resident pulpal cells. Although these cells aim to disinfect the tooth, their extravasation, migration, and antibacterial activity (eg, release of reactive oxygen species [ROS]) along with the bacterial toxins cause pulp damage and impede tissue regeneration processes. Recently, a novel bacterial killing mechanism termed neutrophil extracellular traps (NETs) has also been described that uses ROS signaling and results in cellular DNA extrusion. The NETs are decorated with antimicrobial peptides (AMPs), and their interaction with bacteria results in microbial entrapment and death. Recent data show that NETs can be stimulated by bacteria associated with endodontic infections, and they may be present in inflamed pulp tissue. Interestingly, some bacteria associated with pulpal infections express deoxyribonuclease enzymes, which may enable their evasion of NETs. Furthermore, although NETs aim to localize and kill invading bacteria using AMPs and histones, limiting the spread of the infection, data also indicate that NETs can exacerbate inflammation and their components are cytotoxic. This review considers the potential role of NETs within pulpal infections and how these structures may influence the pulp's vitality and regenerative responses. PMID- 28844309 TI - Microbial Modulation of Stem Cells and Future Directions in Regenerative Endodontics. AB - Regenerative endodontic procedures (REPs) have been shown to promote the resolution of signs and symptoms of disease and increase survival compared with traditional treatment procedures. However, there is still variable predictability of continued root development and evidence that the tissues formed do not recapitulate the native pulp-dentin complex. There is growing evidence that the apical papilla is capable of surviving prolonged endodontic infection and apical periodontitis and that it represents a rich source of undifferentiated mesenchymal stem cells in REPs. The survival and proper differentiation of stem cells transferred into infected root canals are fraught with challenges. Residual antigens, such as lipopolysaccharides, have been shown to be present in dentin even after adequate chemomechanical debridement. These antigens have a profound effect on stem cell fate by modulating their proliferative capacity and postdifferentiation phenotype. Thus, root canals must be detoxified in addition to disinfection. There is a strong need for translational studies that incorporate all aspects of tissue engineering in endodontics in models that include an existing infection to promote further advancement of the field. This is particularly important to make REPs more predictable when treating immature teeth in young patients. Importantly, regenerative procedures could eventually promote tooth longevity in our aging population. Lessons learned from translational studies that best mimic the clinical challenges could be evaluated in pragmatic clinical trials to determine the effectiveness of these procedures to promote desirable patient-centered outcomes. PMID- 28844311 TI - Mitigating the Barriers to a Culture of Quality and Safety in Radiation Oncology. PMID- 28844310 TI - Altered plasma protein glycosylation in a mouse model of depression and in patients with major depression. AB - BACKGROUND: Glycosylation is a common posttranslational modification in protein biosynthesis that is implicated in several disease states. It has been reported that specific protein glycan structures are useful as biomarkers for cancer and some neuropsychiatric diseases; however, the relationship between plasma protein glycosylation and major depressive disorder (MDD) has not been investigated to date. The aim of this study was to determine whether plasma protein glycan structures are altered in depression using a stress-based mouse model and samples from patients with MDD. METHODS: We used chronic ultra-mildly stressed mice that were untreated or treated with imipramine as mouse models of depression and remission, respectively. We also made comparisons between samples from depressed and remitted patients with MDD. Protein glycosylation was analyzed using a lectin microarray that included 45 lectins with binding affinities for various glycan structures. RESULTS: Sia-alpha2-6Gal/GalNAc was a commonly altered glycan structure in both depression model mice and patients with MDD. Moreover, the expression of ST6GALNAC2 was decreased in leukocytes from patients with MDD. LIMITATIONS: Our study samples were small and we did not identify specific alpha2 6Gal/GalNAc-sialylated proteins. CONCLUSIONS: The glycan structure Sia-alpha2 6GalNAc in plasma protein and ST6GALNAC2 expression in peripheral leukocytes may have utility as candidate biomarkers for the clinical diagnosis and monitoring of MDD. PMID- 28844312 TI - [Obstructive sleep apnoea syndrome]. AB - INTRODUCTION: Obstructive sleep apnoea (OSA) is highly prevalent in children and a major public health problem. An attempt is made to determine the clinical and polysomnographic presentation of paediatric OSA in our area. PATIENTS AND METHODS: Retrospective descriptive study of sleep tests conducted on children up to 14 years-old from 1999 to 2012 in the Sleep Unit of the University Hospital of Albacete. Age, gender, anthropometric, clinical data, indication and variables of sleep study, treatment, and outcomes were collected. RESULTS: The study included 234 children. OSA was found in 71.8%, with 42.3% moderate and 44.6% severe. The majority were male (60.7%) and the mean age 5 was years, of whom 78% were pre school or school age. There was overweight/obesity in 44%, with 93.4% snoring, apnoea 84.5%, and 5.4% daytime sleepiness. There were 23 polysomnographies and 145 polygraphies, with a median apnoea/hypopnoea index (AHI) of 10, Sat.O2 minimum 84%, desaturation index 8, and mean sleep supine 53.65% and supine events 57.61%. Treatment was lifestyle modifications 29.2%, CPAP 6%, and surgery 42.9%. Improved snoring and/or apnoea 69.4%, and weight 32.4% of overweight/obesity children. CONCLUSIONS: Most of the studied children had a pathological AHI. Almost half were overweight/obese, and a high percentage had moderate-severe OSA. Most frequent treatment was surgery. The clinical outcome was favourable in almost 70%. Less than a third with OSA and overweight/obesity improved weight. PMID- 28844313 TI - Chemoprophylaxis in the prevention of Clostridium difficile infection: Still a ways to go. PMID- 28844314 TI - Acute kidney injury in acute-on-chronic liver failure: where does hepatorenal syndrome fit? AB - Renal dysfunction occurs in 25% to 50% of patients with cirrhosis admitted to the hospital with an acute episode of hepatic decompensation and may be due to underlying chronic kidney disease, an acute deterioration, or both. An acute deterioration in renal function in cirrhotic patients is now collectively referred to as acute kidney injury (AKI), which has been subclassified into different grades of severity that identify prognostic groups. Acute-on-chronic liver failure is characterized by acute hepatic and/or extrahepatic organ failure driven by a dysregulated immune response and systemic inflammatory response. AKI is also one of the defining features of ACLF and a major component in grading the severity of acute-on-chronic liver failure. As such, the pattern of AKI now observed in patients admitted to the hospital with acutely decompensated liver disease is likely to be one of inflammatory kidney injury including acute tubular injury (referred in this review as non-hepatorenal syndrome [HRS]-AKI) rather than HRS. As the management and supportive treatment of non-HRS-AKI potentially differ from those of HRS, then from the nephrology perspective, it is important to distinguish between non-HRS-AKI and HRS-AKI when reviewing patients with acute on-chronic liver failure and AKI, so that appropriate and early management can be instituted. PMID- 28844315 TI - Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders. AB - Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment individualized to the patient's phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes. PMID- 28844316 TI - Identifying early pathogenic events during vascular calcification in uremic rats. AB - Vascular calcification in chronic kidney disease is a very complex process traditionally explained in multifactorial terms. Here we sought to clarify relevance of the diverse agents acting on vascular calcification in uremic rats and distinguish between initiating and complicating factors. After 5/6 nephrectomy, rats were fed a 1.2% phosphorus diet and analyzed at different time points. The earliest changes observed in the aortic wall were noticed 11 weeks after nephrectomy: increased Wnt inhibitor Dkk1 mRNA expression and tissue non specific alkaline phosphatase (TNAP) expression and activity. First deposits of aortic calcium were observed after 12 weeks in areas of TNAP expression. Increased mRNA expressions of Runx2, BMP2, Pit1, Pit2, HOXA10, PHOSPHO1, Fetuin A, ANKH, OPN, Klotho, cathepsin S, MMP2, and ENPP1 were also found after TNAP changes. Increased plasma concentrations of activin A and FGF23 were observed already at 11 weeks post-nephrectomy, while plasma PTH and phosphorus only increased after 20 weeks. Plasma pyrophosphate decreased after 20 weeks, but aortic pyrophosphate was not modified, nor was the aortic expression of MGP, Msx2, several carbonic anhydrases, osteoprotegerin, parathyroid hormone receptor 1, annexins II and V, and CD39. Thus, increased TNAP and Dkk1 expression in the aorta precedes initial calcium deposition, and this increase is only preceded by elevations in circulating FGF23 and activin A. The expression of other agents involved in vascular calcification only changes at later stages of chronic kidney disease, in a complex branching pattern that requires further clarification. PMID- 28844317 TI - Short daily-, nocturnal- and conventional-home hemodialysis have similar patient and treatment survival. AB - Home hemodialysis (HHD) has many benefits, but less is known about relative outcomes when comparing different home-based hemodialysis modalities. Here, we compare patient and treatment survival for patients receiving short daily HHD (2 3 hours/5 plus sessions per week), nocturnal HHD (6-8 hours/5 plus sessions per week) and conventional HHD (3-6 hours/2-4 sessions per week). A nationally representative cohort of Canadian HHD patients from 1996-2012 was studied. The primary outcome was death or treatment failure (defined as a permanent return to in-center hemodialysis or peritoneal dialysis) using an intention to treat analysis and death-censored treatment failure as a secondary outcome. The cohort consisted of 600, 508 and 202 patients receiving conventional, nocturnal, and short daily HHD, respectively. Conventional-HHD patients were more likely to use dialysis catheter access (43%) versus nocturnal or short daily HHD (32% and 31%, respectively). Although point estimates were in favor of both therapies, after multivariable adjustment for patient and center factors, there was no statistically significant reduction in the relative hazard for the death/treatment failure composite comparing nocturnal to conventional HHD (hazard ratio 0.83 [95% confidence interval 0.66-1.03]) or short daily to conventional HHD (0.84, 0.63-1.12). Among those with information on vascular access, patients receiving nocturnal HHD had a relative improvement in death-censored treatment survival (0.75, 0.57-0.98). Thus, in this national cohort of HHD patients, those receiving short daily and nocturnal HHD had similar patient/treatment survival compared with patients receiving conventional HHD. PMID- 28844318 TI - Tolerability of the SQ Tree SLIT Tablet in Adults. AB - PURPOSE: The tree pollen sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) is being developed for the treatment of tree pollen induced allergic rhinitis with or without conjunctivitis. The objective of this Phase I trial was to investigate the tolerability and acceptable dose range of the SQ tree SLIT-tablet in adults with allergic rhinoconjunctivitis. METHODS: The trial was a randomized, double blind, placebo-controlled, dose escalation Phase I trial that included 70 adults (aged 19-61 years) with birch pollen-induced rhinoconjunctivitis with or without mild to moderate asthma. The trial included 6 different dosage groups that were randomized 3:1 to active treatment or placebo once daily for 28 days. Adverse events (AEs) were coded in the Medical Dictionary for Regulatory Activities by medically qualified personnel. Immunologic assessments included IgE and IgE blocking factor. FINDINGS: Most (96%) reported AEs were mild, and only 5 severe events (0.2%) were reported. The most frequently reported investigational medicinal product-related AEs were oral pruritus, ear pruritus, mouth edema, sensation of foreign body, throat irritation, pharyngolaryngeal pain, dry throat, tongue blistering, eye pruritus, and headache. The trial included doses ranging from 1 to 24 development units (DU), and the mean number of investigational medicinal product-related AEs per participant was highest in the 24 DU group. The 12 and 24 DU doses induced statistically significant changes from baseline compared with placebo in birch specific IgE and IgE-blocking factor. IMPLICATIONS: The trial found that doses up to 12 DU of the SQ tree SLIT tablet have a tolerability profile suitable for at-home administration. An immunomodulatory effect was found for all doses included in the trial, and doses up to 12 DU were thus chosen for further clinical development of the SQ tree SLIT tablet. EudraCT identifier: 2007-003234-42. PMID- 28844319 TI - Review of Extraskeletal Activity on Tc-99m Methylene Diphosphonate Bone Scintigraphy and Value of Cross-Sectional and SPECT-CT Imaging Correlation. AB - Recognizing the different mechanisms and imaging appearance of extraskeletal Tc 99m methylene diphosphonate uptake enhances the diagnostic value of bone scan interpretation. In this article, we present a pictorial review of the different mechanisms of extraskeletal Tc-99m methylene diphosphonate uptake on bone scintigraphy including neoplastic, inflammatory, ischemic, traumatic, excretory, and iatrogenic. We also illustrate through case examples the added value of correlation with cross-sectional and single photon emission computed tomography and computed tomography imaging in localizing and characterizing challenging cases of extraskeletal uptake. PMID- 28844320 TI - [Notice of expert for modality and prescriptions limits of local estrogenotherapy for urinairy inconfinence in women]. AB - OBJECTIVE: To develop a consensus of experts on the use of local estrogens in female urinary incontinence. MATERIAL AND METHOD: Following a formalized consensus method (DELPHI), a questionnaire was produced and sent to a first round and then to a second round of experts. The questionnaire consisted of proposals for recommendations for the use of local estrogens in the context of female urinary incontinence. The Survey Monkey(r) survey software allowed the questionnaire to be distributed and the answers obtained to be analyzed. RESULTS: Eight experts responded to the first round questionnaire. Seven formulations were deleted, 3 amended and 4 added to the first round questionnaire following expert advice. Twenty-six experts replied to the second round questionnaire, 24 of which were complete. Ten of the 21 proposals were approved at more than 80%, including five with strong agreement regarding the recognized benefit of local estrogens in urinary incontinence due to overactive bladder, the absence of data from the literature to demonstrate over-risk of hormone-dependent cancer under local estrogens and the need for follow-up of patients under this treatment. Six proposals were not the subject of a consensus and concerned the prescription modalities (maximum duration, effective minimum dose, prescription before surgery for incontinence). CONCLUSION: Although local estrogens did not have regulatory approval in urinary incontinence, more than 80% of these experts recognized their benefit in the management of urinary incontinence in women with vulvo-vaginal atrophy, particularly in the case of urinary urge incontinence. LEVEL OF PROOF: 4. PMID- 28844321 TI - Red blood cell folate concentrations and coronary heart disease prevalence: A cross-sectional study based on 1999-2012 National Health and Nutrition Examination Survey. AB - BACKGROUND AND AIM: Folate is involved in a number of metabolic pathways. Red blood cell (RBC) folate is a well-established indicator of folate intake. However, studies focused on the association between RBC folate and coronary heart disease (CHD) are limited. The aim of the current study was to investigate the effect of RBC folate concentrations on the presence of CHD in a nationally representative sample of American adults. METHODS AND RESULTS: In the 1999-2012 National Health and Nutrition Examination Survey (NHANES), 22,499 subjects aged 30-74 years with RBC folate concentrations, CHD status and responses to co variates questions were included; 822 (3.65%) participants were identified as having CHD. Bio-Rad Quanta Phase II radioassay and microbiological assay were used to measure RBC folate concentrations. Firstly, we treated RBC folate as a categorical variable, based on RBC folate tertiles, and used logistic regression analysis to display the RBC folate and CHD relationship. Secondly, we explored associations using a combination of restricted cubic spline and logistic regression models, stratified by sex. After adjusting for several well established traditional CHD risk factors, RBC folate was positively related to CHD presence in the total population and the association was more pronounced among males than females. A J-shaped pattern was observed in RBC folate concentrations for females. CONCLUSION: Elevated RBC folate concentrations were associated with higher CHD risk. Further investigation is needed to test the association in large-scale follow-up studies. PMID- 28844322 TI - Incidence, Risk Factors, and Outcomes of Retinal Detachment after Pediatric Cataract Surgery. AB - PURPOSE: To report the incidence of, and to estimate the long-term risk and predisposing factors and the surgical outcomes for, retinal detachment (RD) after pediatric cataract surgery. DESIGN: Retrospective consecutive interventional case series. PARTICIPANTS: During the study period 1996 to 2007 at a tertiary eye care institute, 481 eyes of 295 children aged below 16 years with no other ocular and systemic anomalies who underwent lensectomy, posterior capsulorrhexis, and anterior vitrectomy combined with primary intraocular lens implantation were included. The median follow-up was 66 months. METHODS: Kaplan-Meier estimates and Cox proportional hazard regression model were used for estimating cumulative risk and hazard ratio (HR), respectively. Difference between measured preoperative axial length and age-matched mean axial length (prior studies) was calculated, and was defined as age-adjusted axial length difference (ALD) (minus and plus denotes myopia and hypermetropia, respectively). MAIN OUTCOME MEASURES: Cumulative risk and potential risk factors for RD. RESULTS: Of the total, 12 eyes of 9 children developed RD after cataract surgery, with a median time of 70 months. The overall risk of RD was 5.5% at 10 years after cataract surgery. All 9 children were male. The multi-adjusted HR associated with increased risk of RD was 12.42 (95% confidence interval [CI], 2.91-53.01; P = 0.001) for eyes of children with intellectual disability and 21.93 (95% CI, 2.95-162.80; P = 0.003) for eyes of children with age-adjusted ALD < -1 mm (myopic). Retinal break associated with induction of posterior vitreous detachment was the most common (8 eyes) cause of RD. No surgical intervention was done in 2 eyes. Scleral buckle and vitrectomy combined with belt buckle were performed in 4 and 6 eyes, respectively. At final follow-up, 5 and 9 eyes had a visual acuity better than or equal to 6/18 and 6/60, respectively. CONCLUSIONS: A 5.5% risk for RD is estimated for the first 10 years after cataract surgery in children with no known ocular and systemic anomalies. The risk significantly increases in a male, myopic, and intellectual disabled child. We emphasize the need for regular and long-term follow-up after pediatric cataract surgery. PMID- 28844323 TI - Idiopathic Acute Exudative Polymorphous Vitelliform Maculopathy: Clinical Spectrum and Multimodal Imaging Characteristics. AB - PURPOSE: To describe clinical findings in patients with acute exudative polymorphous vitelliform maculopathy (AEPVM). DESIGN: Retrospective, observational, multicenter case series review. PARTICIPANTS: Consecutive patients diagnosed with idiopathic AEPVM. METHODS: Review of clinical charts, multimodal imaging, electrophysiologic findings, and genetic findings in previously unpublished patients and review of the literature. MAIN OUTCOME MEASURES: Clinical features of idiopathic AEPVM and differential diagnosis. RESULTS: Eighteen patients (age range, 21-74 years) with typical features of AEPVM, including initial localized, serous detachments followed by the development of characteristic yellow-white deposits in the vitelliform space. Over time, this hyperautofluorescent material gravitated within the larger lesions, resulting in typical curvilinear deposits characteristic of later stages. Symptoms and clinical findings lasted from weeks to several years. Some patients showed previously undescribed features such as fluorescein-negative intraretinal cystic changes, choroidal neovascularization, serous retinal elevations mimicking retinal folds, increased choroidal thickness, lack of rapid visual recovery, and recurrence years after complete resolution of initial manifestations. CONCLUSIONS: Acute exudative polymorphous vitelliform maculopathy can present with a more variable natural course than previously described. Paraneoplastic retinopathy and autosomal recessive bestrophinopathy closely resemble AEPVM, necessitating medical and hereditary evaluation to exclude these clinical possibilities. This series of patients with AEPVM expands the clinical spectrum of the disorder, including demographics, clinical manifestations, imaging features, natural course, and visual prognosis. PMID- 28844324 TI - [Cerebral tuberculosis presenting as cranial nerve III palsy: Case report]. PMID- 28844325 TI - [Visual outcomes four years after small incision lenticule extraction (SMILE) surgery on highly myopic eyes [French version]]. AB - OBJECTIVE: To determine whether the visual outcomes of the refractive surgery technique, small incision lenticule extraction (SMILE), are stable, effective, and predictable for high myopia over a four-year period. RESEARCH DESIGN: This is a retrospective study. The data were collected between March 2012 and July 2016. PARTICIPANTS: Two hundred and forty-eight patients participated in the study; that is, 496 eyes: 140 eyes of 70 patients (52 women/18 men) were classified in the highly myopic group (refraction measured in spherical equivalent [RMSE]>-6D), and 356 eyes of 178 patients (98 women/80 men) in the control group (RMSE<=-6D). Follow-up tests were conducted immediately post-operatively (D+1), after three months, after one year, and after four years. Refraction, uncorrected visual acuity (UCVA), and best visual corrected acuity (BCVA) were measured. The highly myopic group (HMG) contained more women, and astigmatism was higher for this group than for the control group (CG). PRIMARY AND SECONDARY STUDY CRITERIA: These are BCVA, refractive stability, the index of safety (SI: BCVA preoperatively D+1/BCVA postoperatively), and predictability (the percentage of eyes within+/-0.5 D of the target). RESULTS: In both groups, UCVA was better after the fourth year than it was immediately after the procedure (HMG: P=0.001; CG: P=0.001). Although it differed at one year (P=0.01), the groups' refractive stability tended to converge over four years (P=0.138). Both groups' SI was identical in the four follow-up tests (P=0.734 at D+1; P=0.07 at M+1; P=0.160 at M3 and Y1; and P=0.274 at Y4). For the HMG, SI stability was attained after three months (1.00+/-0.1); whereas it was attained after one month (0.91+/-0.11) for the CG. Four years after the surgery, we observed that 87 % of the operated eyes in the HMG were within 0.5 D of the target. CONCLUSION: SMILE is a good refractive surgery technique for treating high myopia. It yields stable, safe, effective, and predictable results over four years. PMID- 28844326 TI - [Comparison of anatomic and functional results between Z6 femtosecond laser assisted and manual trephination in deep anterior lamellar keratoplasty for advanced keratoconus [French version]]. AB - The management of severe keratoconus requires corneal transplantation, for which the gold standard is deep anterior lamellar keratoplasty (DALK), preserving the healthy Descemet's membrane and endothelium. The safety and reproducibility of corneal cuts have been improved by the evolution of femtosecond lasers in refractive surgery, and femtosecond laser in DALK would seem to provide the same advantages over the manual method. In our retrospective study, we compare functional and anatomical results of femtosecond assisted DALK versus manual trephination DALK in patients with keratoconus in stage 4 of the Krumeich classification. It is a retrospective study including all patients with stage 4 keratoconus who underwent femtosecond laser assisted DALK between November 2012 and November 2015 in Nantes hospital. We compared those patients to a group of patients who underwent manual DALK in the same period, paired by age and maximal keratometry. We assessed visual acuity, pachymetry, endothelial cell density (specular microscopy), and keratometry before surgery and at 4, 8 and 12 months of follow-up. Laser settings and intraoperative complications were recorded. Nineteen patients underwent surgery by femtosecond assisted DALK, 6 women and 12 men with average age 30.2+/-10.8 years at transplantation. They were paired with a group of 17 patients who underwent manual DALK in order to compare results. Before surgery, mean visual acuity in the femtosecond group was 0.90 logMAR versus 0.89 logMAR in the manual group, showing no statistically significant difference (P=0.96). Both groups were similar in terms of preoperative age, mean keratometry, pachymetry and endothelial cell density. Average visual acuity post surgery was 0.27, 0.26; and 0.14 logMAR for femtosecond DALK versus 0.27, 0.17 et 0.25 for manual DALK at 4, 8 and 12 months follow-up, respectively showing no statistically significant difference. After surgery, at 4, 8 and 12 months, mean pachymetry was similar in both groups, and average endothelial cell density was 2390 cells/mm2 in femtoDALK versus 2531 cells/mm2 in manual DALK at 12 months of follow-up, showing no statistically significant difference (P=0.5726). The rate of Descemet's membrane microperforations during the procedure was low and similar for both groups. Our study allows for a 12 month follow-up, with assessment of visual recovery, anatomical result and endothelial safety in a sample of 19 femtosecond laser assisted DALK with no statistical significant difference versus the manual trephination group. Femtosecond laser allows for increased reproducibility of the DALK procedure without reducing adverse effects during surgery. Femtosecond laser seems to improve the technique of the DALK procedure, and future developments could improve the reproducibility of DALK even further. A medical economics study would be necessary to determine the cost effectiveness of femtosecond laser assisted DALK. PMID- 28844327 TI - Pacific Proving Grounds radioisotope imprint in the Philippine Sea sediments. AB - Radionuclide concentrations were studied in sediment cores taken at the continental slope of the Philippine Sea off Mindanao Island in the equatorial Western Pacific. High resolution deposition records of anthropogenic radionuclides were collected at this site. Excess 210Pb together with excess 228Th and anthropogenic radionuclides provided information about accumulation rates. Concentrations of Am and Pu isotopes were detected by gamma spectrometry, alpha spectrometry and ICP-MS. The Pu ratios indicate a high portion (minimum of 60%) of Pu from the Pacific Proving Grounds (PPG). This implies that the transport of PPG derived plutonium with the Mindanao Current southward is similarly effective as the previously known transport towards the north with the Kuroshio Current. The record is compared to other studies from northwest Pacific marginal seas and Lombok basin in the Indonesian Archipelago. The sediment core top was found to contain a 6 cm thick layer dominated by terrestrial organic matter, which was interpreted as a result of the 2012 Typhoon Pablo-related fast deposition. PMID- 28844328 TI - New fossils of Australopithecus anamensis from Kanapoi, West Turkana, Kenya (2012 2015). AB - Kanapoi, Kenya, has yielded the earliest evidence of the genus Australopithecus, Australopithecus anamensis. Renewed fieldwork from 2012 through 2015 yielded 18 new fossils attributable to this species. The new specimens include the second maxillary fragment known from a Kanapoi hominin and the first from a relatively young adult. The new maxilla has the distinctive rounded nasal aperture margin characteristic of A. anamensis. A second partial proximal tibia from the site is the first postcranial element from a small A. anamensis individual. A new partial mandible and complete mandibular dentition display distinctive Kanapoi hominin morphology, but the mandible displays a larger trigonid on its fourth premolar than any known so far. Two new complete sets of mandibular incisors are also notably large, especially the lateral ones, a distinctive feature of A. anamensis compared with Australopithecus afarensis. The new fossils also highlight the distinctive morphology of Kanapoi A. anamensis compared to later hominins. PMID- 28844330 TI - A randomised controlled trial evaluating the utility of a patient Decision Aid to improve clinical trial (RAVES 08.03) related decision-making. AB - BACKGROUND AND PURPOSE: Randomised controlled trials (RCTs) are considered the 'gold-standard' for evaluating medical treatments. However, patients and clinicians report difficulties with informed consent and recruitment. We evaluated the utility of a Decision Aid (DA) in reducing RCT-related decisional conflict, and improving RCT knowledge and recruitment. MATERIALS AND METHODS: Potential participants for a radiotherapy RCT were invited to participate in the current study. Participants were randomised to receive the RCT's participant information sheet with or without a DA. Questionnaires were administered at baseline, one and six months. The primary outcome measure was decisional conflict. Secondary outcome measures included knowledge regarding and recruitment to the RCT. RESULTS: 129 men were randomised to the DA (63) and control (66) arms. Decisional conflict was significantly lower over 6-months (p=0.048) in the DA arm. Knowledge regarding the RCT was significantly higher at 6months (p=0.033) in the DA arm. 20.6% of the DA arm (13 of 63) and 9% of the control arm (6 of 66) entered the RCT. CONCLUSIONS: This study demonstrates the utility of a DA in reducing decisional conflict and improving trial knowledge in men with cancer who are making decisions regarding RCT participation. PMID- 28844329 TI - An XAS investigation of the nickel site structure in the transcriptional regulator InrS. AB - InrS (Internal nickel-responsive Sensor) is a transcriptional repressor of the nickel exporter NrsD and de-represses expression of the exporter upon binding Ni(II) ions. Although a crystal structure of apo-InrS has been reported, no structure of the protein with metal ions bound is available. Herein we report the results of metal site structural investigations of Ni(II) and Cu(II) complexes of InrS using X-ray absorption spectroscopy (XAS) that are complementary to data available from the apo-InrS crystal structure, and are consistent with a planar four-coordinate [Ni(His)2(Cys)2] structure, where the ligands are derived from the side chains of His21, Cys53, His78, and Cys82. Coordination of Cu(II) to InrS forms a nearly identical planar four-coordinate complex that is consistent with a simple replacement of the Ni(II) center by Cu(II). PMID- 28844331 TI - Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes. AB - BACKGROUND: 90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown. METHODS: All radiotherapy treatments delivered in a curative setting over seven years were extracted from the local electronic health record and linked to cancer registry data. 90DM rates were assessed and factors associated with this outcome were investigated using logistic regression. Cause of death was identified retrospectively further characterising the cause of 90DM. RESULTS: Overall 90DM was 1.25%. Levels varied widely with diagnosis (0.20 5.45%). Age (OR 1.066, 1.043-1.073), year of treatment (OR 0.900, 0.841-0.969) and diagnosis were significantly associated with 90DM on multi-variable logistic regression. Cause of death varied with diagnosis; 50.0% post-operative in rectal cancer, 40.4% treatment-related in head and neck cancer, 59.4% disease progression in lung cancer. CONCLUSION: Despite the drive to report centre level comparative outcomes, this study demonstrates that 90DM cannot be adopted routinely asa clinical indicator due to significant population heterogeneity and low event rates. Further national investigation is needed to develop a meaningful robust indicator to deliver appropriate comparisons and drive improvements in care. PMID- 28844332 TI - The Ambystoma tigrinum virus (ATV) RNase III gene can modulate host PKR activation and interferon production. AB - The iridovirus RNase III gene is one of 26 conserved core genes among the family Iridoviridae. Initial studies suggest this viral protein functions to suppress RNA interference pathways that may attack viral RNA during infection. Therefore, to determine if the Ambystoma tigrinum virus (ATV) RNase III-like gene (ORF 25R) can modulate the host innate immune response fish and human cells ectopically expressing 25R were treated with polyI:C and monitored for interferon synthesis and phosphorylation of eIF2alpha and PKR. We found a decrease in cellular IFN production and modulation of the PKR pathway. In addition, ATV deleted of the RNase III gene (ATVDelta25R) shows reduced pathogenicity in tiger salamanders. Collectively our data suggest that the ATV 25R protein is a pathogenesis factor that may function to help evade the host's immune response by masking activators of the IFN pathway. PMID- 28844333 TI - Foot exercises and foot orthoses are more effective than knee focused exercises in individuals with patellofemoral pain. AB - OBJECTIVES: To examine the effect of knee targeted exercises compared to knee targeted exercises combined with foot targeted exercises and foot orthoses in patients with patellofemoral pain. DESIGN: Forty adult individuals (28 women, 12 men) diagnosed with patellofemoral pain and screened for excessive calcaneal eversion were randomized to knee targeted exercises or knee targeted exercises combined with foot targeted exercise and orthoses. METHODS: The knee targeted exercises were prescribed during three supervised consultations. Individuals were instructed to perform the exercises 3 times per week during a 12-week period. The foot targeted exercises were prescribed for 2 times per week for 12 weeks with one session per week being supervised by a physiotherapist. The primary outcome was the subscale "pain" in the Knee Injury and Osteoarthritis Outcome Score (KOOS) at 4 months. RESULTS: Individuals randomized to knee targeted exercises combined with foot targeted exercises and foot orthoses had 8.9 points (95%CI: 0.4; 17.4) - NNT=3 (2-16) larger improvement in KOOS pain at the primary endpoint. CONCLUSIONS: The addition of foot targeted exercises and foot orthoses for 12 weeks was more effective than knee targeted exercises alone in individuals with patellofemoral pain. The effect was apparent after 4 months, but not significantly different after 12 months. PMID- 28844334 TI - Response to Letter to the Editor "Risk stratification in acute coronary syndromes: Graced by a new score?" PMID- 28844335 TI - Sacubitril/valsartan: An important piece in the therapeutic puzzle of heart failure. AB - Sacubitril/valsartan (LCZ696), a supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, was recently approved in the EU and the USA for the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF) (NYHA class II IV). Inhibition of chronically activated neurohormonal pathways (the renin angiotensin-aldosterone system [RAAS] and sympathetic nervous system [SNS]) is central to the treatment of chronic HFrEF. Furthermore, enhancement of the natriuretic peptide (NP) system, with favorable cardiovascular (CV) and renal effects in HF, is a desirable therapeutic goal to complement RAAS and SNS blockade. Sacubitril/valsartan represents a novel pharmacological approach that acts by enhancing the NP system via inhibition of neprilysin (an enzyme that degrades NPs) and by suppressing the RAAS via AT1 receptor blockade, thereby producing more effective neurohormonal modulation than can be achieved with RAAS inhibition alone. In the large, randomized, double-blind PARADIGM-HF trial, replacement of an angiotensin-converting enzyme inhibitor (ACEI) (enalapril) with sacubitril/valsartan resulted in a significant improvement in morbidity and mortality in patients with HFrEF. Sacubitril/valsartan was superior to enalapril in reducing the risk of CV death or HF hospitalization (composite primary endpoint) and all-cause death, and in limiting progression of HF. Sacubitril/valsartan was generally well tolerated, with a comparable safety profile to enalapril; symptomatic hypotension was more common with sacubitril/valsartan, whereas renal dysfunction, hyperkalemia and cough were less common compared with enalapril. In summary, sacubitril/valsartan is a superior alternative to ACEIs/ARBs in the treatment of HFrEF, a recommendation that is reflected in many HF guidelines. PMID- 28844336 TI - When not to use meta-analysis: Analysing the meta-analyses on vitamin D in critical care. PMID- 28844337 TI - Temporomandibular joint reconstruction after condylar fracture complication related to osteosynthesis material. AB - Total condylar resorption and the failure of bone synthesis material as postoperative complications of condyle fracture are seldom reported in the literature. When these occur, they may severely limit temporomandibular joint (TMJ) function. In such cases, a reconstruction of the joint is indicated, which can be achieved by means of an alloplastic prosthesis. This article reports a rare case of impaction of osteosynthesis material in the region of the base of the skull associated with a mandibular condyle fracture treated with rigid internal fixation, which resulted in complications. There was progression to condylar resorption, requiring an alloplastic TMJ reconstruction, which was performed in a single surgical session. PMID- 28844338 TI - Delayed blastocyst formation or an extra day culture increases apoptosis in pig blastocysts. AB - In the present study, the timing was examined of blastocyst collection/formation or of how the duration of post-blastulation culture affected the quality and developmental competence of in vitro-produced pig parthenogenetic embryos. The earliest apoptotic signals were observed at the morula stage while the earliest cytoplasmic fragmentation was observed before the 4- to 8-cell stage of embryo development. Nuclear condensation was detected in morulae and blastocysts, but not all condensed nuclei were positive for the apoptotic signal (TUNEL staining). The mean blastocyst diameter increased with delayed blastocyst collection or extended post-blastulation culture, but decreased with delayed blastocyst formation. Delayed blastocyst collection/formation or an additional day of post blastulation culture increased the frequencies of apoptosis, condensed nuclei, and low quality blastocysts (those showing a nuclear destruction that negated counting of the nuclei); increased the expression of the pro-apoptotic BAX gene; and reduced the ratio of ICM (inner cell mass) cells to TE (trophectoderm) cells. In addition, delayed blastocyst formation decreased POU5F1 gene expression. These results suggest that a delay in blastocyst collection/formation or an additional day of culture could increase the incidence of apoptosis, decrease the ICM:TE cell ratio, and influence the gene expression and diameter of blastocysts derived from in vitro-produced pig embryos. These findings provide a useful reference for improving the quality of in vitro-produced embryos. PMID- 28844339 TI - Advances in Merkel cell carcinoma from a pathologist's perspective. AB - Merkel cell carcinoma (MCC) is a rarely made but potentially devastating diagnosis. While local disease might be cured by surgery and radiotherapy, advanced disease is usually rapidly progressive and fatal. Until very recently, the only approach to metastatic MCC was cytotoxic chemotherapy with results so disappointing that current treatment guidelines discourage its use and recommend clinical trial as a more viable treatment option. Fortunately, recent advances in the understanding of the molecular pathogenesis of this tumour have produced a wide variety of experimental treatments for MCC, some of which are quite promising. The most current information regarding the diagnosis, staging, management of this tumour is briefly presented as well as new insights into the molecular basis of MCC and therapeutic approaches to MCC. PMID- 28844340 TI - Recent acquisitions on oxyprenylated secondary metabolites as anti-inflammatory agents. AB - Oxyprenylated secondary metabolites from plants, fungi, and bacteria, and their semisynthetic derivatives have been subject of growing interest during the last decade. Such natural products in fact have been discovered as potentially novel lead compounds for a series of pharmacological activities, mainly in terms of anti-cancer and anti-inflammatory ones. Especially during the last 5 years, a wider panel of prenyloxy secondary metabolites have been investigated from chemical and biological points of view and these include benzoic acids, alcohols, aldehydes, chalcones, anthraquinones, 1,4-naphthoquinones, other than the well known oxyprenylated ferulic acid and coumarin derivatives. The aim of this comprehensive review is to focus on the anti-inflammatory properties and related mechanisms of action of selected classes of oxyprenylated naturally occurring compounds and their semisynthetic analogues covering the literature period from 2011 to 2017. In vitro and in vivo data on their pharmacological activity triggering different pathways of the overall inflammatory machinery as well as structure activity relationship acquisitions will be summarized in order to make a detailed survey of the most recent reports on the potential of the title compounds as a novel class of anti-inflammatory agents. PMID- 28844341 TI - Comparing three treponemal tests for syphilis screening. AB - We compared the performance and ease of use for three high-throughput treponemal immunoassays: Phoenix Biotech Trep-Sure Total Antibody EIA, Siemens ADVIA(r) Centaur Syphilis Assay, and DiaSorin LIAISON(r) Treponema Assay. One thousand serum samples submitted for routine screening were used in this study. Each assay demonstrated comparable sensitivity, specificity, and percent agreement (98-100%) compared with Treponema pallidum particle agglutination (TP-PA). Thus, treponemal immunoassays are an acceptable alternative for syphilis screening or confirmatory testing. Batch sizes and technologist active time varied between each treponemal immunoassay; the chemiluminescence platforms offered significantly greater ability to batch (random access vs. fixed batch sizes) in less time. When we compared the results obtained using a reverse algorithm approach to those obtained using a traditional algorithm, we found that the reverse algorithm identified 38 additional seropositive individuals that were not detected using the traditional algorithm. Clinical evaluation was useful for resolving cases with discordant serology. PMID- 28844342 TI - Relation of Mycobacterium tuberculosis mutations at katG315 and inhA-15 with drug resistance profile, genetic background, and clustering in Argentina. AB - We analyzed 362 isoniazid-resistant clinical isolates of Mycobacterium tuberculosis obtained countrywide for the presence of mutation at katG315 and inhA-15 in relation to genotype, pattern of phenotypic resistance to other drugs, and ability to spread. We found the following mutation frequencies: katG315MUT/inhA-15wt 53.0%, katG315wt/inhA-15MUT 27.4%, katG315wt/inhA-15wt 19.3%, and katG315MUT/inhA-15MUT only 0.3%. Mutation at katG315 associated with the LAM superfamily; mutation at inhA-15 associated with the S family and the T1 Tuscany genotype; the combination katG315wt/inhA-15wt associated with the T1 Ghana genotype. Isolates harboring katG315MUT/inhA-15wt tended to accumulate resistance to other drugs and were more frequently found in cluster; isolates harboring katG315wt/inhA-15wt were more frequently found as orphan isolates. Although epidemiological and host factors could also be modulating the events observed, in Argentina, the systematic genotyping of drug resistant clinical isolates could help to predict an enhanced risk of transmission and a propensity to develop resistance to increasing numbers of drugs. PMID- 28844343 TI - Inclusion of elderly or frail patients in randomized controlled trials of targeted therapies for the treatment of metastatic colorectal cancer: A systematic review. AB - Treatment of metastatic colorectal cancer (mCRC) has been modified since the launching of targeted therapies. Colorectal cancer (CRC) is common in elderly patients; their representation in randomized controlled trials (RCTs) is thus crucial. This study aimed to evaluate and quantify the inclusion of elderly/frail patients in RCTs of targeted therapies in mCRC. A systematic review using Medline, Scopus, Cochrane Database and ISI Web of Science was performed to identify all phase II/III RCTs of bevacizumab, cetuximab, panitumumab, regorafenib and aflibercept in mCRC until January 2015. Two reviewers independently performed studies selection, and data extraction. The protocol was registered in Prospero (CRD42015016163). Among 1,369, identified publications, 54 RCTs were selected. Nine RCTs (17%) excluded elderly patients; median age of the included population was <65years old in 50 RCTs (93%). Twenty RCTs (37%) excluded frail patients, and many RCTs excluded patients with uncontrolled hypertension or heart failure, patients treated with specific drugs (mainly anticoagulants), and patients with inadequate creatinine clearance. Elderly/frail patients are underrepresented in RCTs studying targeted therapies in mCRC, and those elderly patients included in RCTs do not reflect well the general elderly population with mCRC because of the exclusion criteria. RCTs results concerning targeted therapies can be inferred only to relatively healthy elderly subjects. PMID- 28844192 TI - Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. AB - BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .). PMID- 28844344 TI - Patellofemoral Contact Pressures After Patellar Distalization: A Biomechanical Study. AB - PURPOSE: To measure the patellofemoral contact pressure in early flexion after a tibial tubercle distalization osteotomy. METHODS: Ten matched-pair fresh-frozen cadaveric knees were studied. The average Blackburne-Peel ratio of the native knees was 0.91. The knees were placed on a testing rig, with a fixed femur and tibia mobile through 90 degrees of flexion. Individual quadriceps heads and the iliotibial band were separated and loaded with 205 N in anatomic directions using a weighted pulley system. A straight tubercle distalization osteotomy of 1 cm was performed and fixed with screws, with and without a lateral release. Patellofemoral contact pressures were measured at 0 degrees , 10 degrees , 20 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees of flexion using pressure-sensitive films on the medial trochlea and lateral trochlea. Contact force, area, and pressure were measured in the following states: (1) in the native knee, (2) after distalization, and (3) after distalization with lateral release. RESULTS: The average Blackburne-Peel ratio after distalization was 0.64. Tibial tubercle distalization resulted in a 6-fold increase in mean contact pressure at 0 degrees (0.15 MPa vs 0.90 MPa, P < .001) and a 55% increase at 10 degrees of flexion (0.70 MPa vs 1.09 MPa, P = .02). Mean contact pressure was similar from 20 degrees to 90 degrees of flexion (P > .1). After distalization, the total contact area was significantly higher at 0 degrees of flexion (17.7 mm2 vs 58.4 mm2, P = .02). Lateral release after distalization did not significantly change contact pressure (P > .21). CONCLUSIONS: Our results suggest that patella baja, as a result of excessive patellar distalization, can cause increased patellofemoral contact pressures during early flexion at 0 degrees and 10 degrees . No changes were seen in contact pressure from 20 degrees to 90 degrees . CLINICAL RELEVANCE: Care should be taken to prevent excessive distalization of the patella to avoid patella baja and increased patellofemoral contact pressures during early flexion. PMID- 28844348 TI - Suspension of Disbelief in Simulation-Based Transesophageal Echocardiographic Training: Are We There? PMID- 28844347 TI - Corrigendum to "Less-favourable prognosis for low-risk endometrial cancer patients with a discordant pre- versus post-operative risk stratification" [Eur J Cancer 78 (2017) 82-90]. PMID- 28844350 TI - High incidence of body image dissatisfaction in pregnancy and the postnatal period: Associations with depression, anxiety, body mass index and weight gain during pregnancy. AB - This study aimed to delineate the prevalence of body image dissatisfaction in pregnant women and parturients in relation to depression and anxiety symptoms. We assessed 126 pregnant women during the third trimester and 2-3days and 4-6weeks after delivery using the Body Image Scale (BIS). Many pregnant participants (34.1%) showed body image dissatisfaction (BIS score <=3) which was associated with current antenatal depression, severity of depression, a lifetime history of mood disorders, trait anxiety, body mass index (BMI) and weight gain during pregnancy. The BIS score improved after delivery but was still associated with depression, lifetime history of mood disorders, age, BMI and weight gain during pregnancy. These findings suggest that about a third of pregnant women have a body image disturbance which is strongly associated with current and a life history of clinical depression and anxiety symptoms. Medical personnel should be alert to detect body image dissatisfaction in pregnant women because it may indicate an underlying mood disorder. PMID- 28844349 TI - Association between contraceptive use and socio-demographic factors of young fecund women in Bangladesh. AB - OBJECTIVE: This study aimed to explore the association between socio-demographic factors and contraceptive use among fecund women under 25years old. METHODS: This study utilized a cross-sectional data (n=3744) extracted from the Bangladesh Demographic and Health Survey 2011. Differences in the use of contraceptives by socio-demographic characteristics were assessed by chi2 analyses. Binary logistic regression was used to identify the determinants of contraceptive use among young women. RESULTS: This study observed that 71% fecund women aged below 25years used contraceptives. Getting family planning (FP) methods from FP workers increases the likelihood of using contraceptives among young women because outreach activities by FP workers and accessibility of FP related information pave the way of using contraceptives. Husband-wife joint participation in decision making on health care increases the likelihood of using contraceptives. Participation of women in decision making on health care could be achieved by promoting higher education and gainful employment for women. CONCLUSIONS: Reproductive and sex education should be introduced in schools to prepare the young for healthy and responsible living. Moreover, policy makers should focus on developing negotiation skills in young women by creating educational and employment opportunities since husband-wife joint participation in decision making increases contraceptive use. PMID- 28844345 TI - The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP. AB - Sudden unexpected death in epilepsy (SUDEP) is a significant public health burden. The mechanisms of SUDEP are elusive, although cardiorespiratory dysfunction is a likely contributor. Clinical and animal studies indicate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death in many SUDEP cases. Our prior studies demonstrated that intraperitoneal (IP) injection of atomoxetine, a norepinephrine reuptake inhibitor (NRI) widely used to treat attention deficit hyperactivity disorder, suppresses S-IRA in DBA/1 mice. In the current study, we injected atomoxetine intracerebroventricularly (ICV) and measured its effect on S-IRA in DBA/1 mice to determine its central effects. Additionally, to test our hypothesis that atomoxetine reduces S-IRA via altering cardiorespiratory function, we examined the effect of atomoxetine on respiratory and cardiac function using non-invasive plethysmography and ECG in anesthetized DBA/1 mice, and on blood pressure and heart rate using a tail-cuff system in conscious DBA/1 mice. ICV administration of atomoxetine at 200-250nmol significantly reduced S-IRA evoked by acoustic stimulation in DBA/1 mice, consistent with a central atomoxetine effect on S-IRA. Peripheral atomoxetine administration at a dosage that reduces S-IRA (15mg/kg, IP) slightly increased basal ventilation and the ventilatory response to 7% CO2, but exerted no effect on heart rate in anesthetized DBA/1 mice. IP injection of atomoxetine produced no effect on the heart rate and blood pressures in conscious mice. These data suggest that atomoxetine suppresses S-IRA through direct effects on the CNS and potentially through enhanced lung ventilation in DBA/1 mice. PMID- 28844352 TI - Unmet/met need for contraception and self-reported abortion in Ghana. AB - BACKGROUND: Unmet need for contraception in several sub-Saharan African countries, including Ghana, remains high, with implications for unintended pregnancies and unsafe abortion, associated maternal morbidity and mortality. In this paper, we analysed for any associations between unmet/met need for contraception and the prevalence of abortion. METHODS: The paper utilizes the 2014 Ghana Demographic Health Survey dataset. Applying descriptive statistics initially, and later, a binary logistic regression, we estimate two different models, taking into account, unmet/met need for contraception (Model 1) and a multivariable one comprising socioeconomic, spatial, cultural and demographic behaviour variables (Model 2) to test the associations between unmet/met need for contraception in Ghana. RESULTS: One-fourth (25%) of sampled women in 2014 had ever had an abortion. The bivariate results showed that women who reported "no unmet" considerably tended to report abortion more than the reference category - not married and no sex in the last 30days. The elevated odds among respondents who indicated "no unmet need" persisted even after controlling for all the relevant confounders. Relatedly, unlike women with an unmet need for spacing, women who desired to limit childbearing had a slightly higher tendency to report an abortion. CONCLUSION: The linkage between unmet need for contraception appears more complex, particularly when the connections are explored post-abortion. Thus, while an abortion episode is most likely due to unintended pregnancy, contraception may still not be used, after an abortion, probably because of failure, side effects or simply, a dislike for any method. PMID- 28844351 TI - Associations between women's perceptions of domestic violence and contraceptive use in seven countries in West and Central Africa. AB - OBJECTIVES: This study examined associations of women's attitudes toward domestic violence (DV) and contraceptive use in West and Central Africa. STUDY DESIGN: We used data from the Multiple Indicator Cluster Surveys for women in seven countries in West and Central Africa (2009-2011, n=80,055). MAIN OUTCOME MEASURE: We measured contraceptive use as none, traditional, or modern contraceptives. DV approval was measured as no, low, or high tolerance of wife beating. Multinomial logistic regression estimated odds of using traditional or modern methods versus none, adjusting for age, education, wealth, residence, parity, marital structure, spousal age-difference, and religion. RESULTS: Many women had no or low DV tolerance (41%, 44%, respectively); most used no contraception (81%). In adjusted results, women with low DV tolerance had lower odds of using traditional contraceptive methods (odds ratio, OR=0.87; 95% confidence interval, CI: 0.78 0.98) or modern methods (OR=0.86; 95% CI: 0.78-0.95) compared to women with no tolerance. Women with high DV tolerance had 28% lower odds of traditional contraceptive use (95% CI: 0.60-0.90), and 38% lower odds of modern contraceptive use (95% CI: 0.59-0.88) compared to women with no tolerance. CONCLUSION: The high prevalence of DV approval may threaten the success of programs aimed at improving women's reproductive health, including contraceptive use. PMID- 28844346 TI - Psychological Well-being's Link with Cardiovascular Health in Older Adults. AB - INTRODUCTION: Favorable cardiovascular health (FCH) is associated with healthy longevity and reduced cardiovascular mortality risk. However, limited work has investigated the distribution of FCH in older age or considered the antecedents of FCH. Based on prior work linking psychological well-being with cardiovascular endpoints, higher psychological well-being was hypothesized to be associated with increased likelihood of maintaining FCH over time. METHODS: Data were from the English Longitudinal Study of Ageing. The first study wave (2002-2003) included men and women aged >=50 years. The analytic sample (N=4,925) was restricted to individuals without baseline cardiovascular disease and with clinical data from three follow-ups through 2013. Psychological well-being was assessed with 17 items from the Control, Autonomy, Satisfaction, and Pleasure scale. FCH was defined as being a non-smoker, diabetes-free, and having healthy levels of blood pressure, cholesterol, and BMI (FCH scores ranged from 0-5). Statistical analyses conducted in 2016-2017 used linear mixed models to examine associations between psychological well-being and FCH scores over time. Secondary analyses examined cardiovascular-related mortality. RESULTS: Only 1% of participants had achieved complete FCH at study baseline. Adjusting for sociodemographic factors and depression, greater psychological well-being was associated with higher FCH scores across time (beta=0.05, 95% CI=0.02, 0.08), but not rate of change in FCH. Psychological well-being was also associated with a 29% reduced risk of cardiovascular-related mortality in multivariable-adjusted models. CONCLUSIONS: Findings suggest that psychological well-being is associated with having FCH at older ages, and add to knowledge of assets that may increase likelihood of healthy aging. PMID- 28844354 TI - The degree of suffering among pregnant women with a history of violence, help seeking, and police reporting. AB - OBJECTIVES: To explore the degree of self-reported suffering following violent incidents and the prevalence of police reporting as well as other help-seeking behaviour among women in early pregnancy with history of violence. STUDY DESIGN: A cross-sectional design. 1939 pregnant women>=18years were recruited prospectively between March 2012 and September 2013 in south-west Sweden. Of those, 761 (39.5%) reported having a history of violence, and they comprised the cohort investigated in the present study. Descriptive statistics, Chi-square analysis, and T-test were used for the statistical calculations. RESULTS: More than four of five women (80.5%) having a history of emotional abuse (n=374), more than half (52.4%) having history of physical abuse (n=561), and almost three of four (70.6%) who experienced sexual abuse (n=302) reported in the early second trimester of their pregnancy that they still suffered from their experience. Of those women who had experienced emotional, physical, and sexual abuse, 10.5%, 25.1%, and 18.0%, respectively, had never disclosed their experiences to anyone. At most, a quarter of the abused women had reported a violent incident to the police. CONCLUSIONS: All midwives and other actors who meet women with experience of abuse need to have increased knowledge about the long-term consequences of all types of abuse. Increased routine questioning of pregnant women about history of violence would help to prevent experiences of violence from affecting pregnancy and childbirth negatively and facilitate the provision of help and support. PMID- 28844353 TI - A systematic review of interventions for Hispanic women with or at risk of Gestational diabetes mellitus (GDM). AB - BACKGROUND AND OBJECTIVE: Gestational Diabetes Mellitus (GDM) is a serious health concern for pregnant women, with Hispanic women at particular risk for developing the condition. The aim of this review was to critically examine GDM intervention programs for Hispanic women, in the United States of America (US). METHODS: English and Spanish electronic databases were searched for relevant studies published between 1995 and 2015. Eligible study designs included randomized controlled trial, pre/post-test and quasi experimental methods. RESULTS: Findings indicated that there was a dearth of literature reporting on GDM interventions for Hispanic women and just seven papers met inclusion criteria. These seven studies were included in the review and they reported on interventions for: (1) pregnant women at high risk of developing GDM; (2) pregnant women with GDM. Results suggest that a combination of intensive counselling over a prolonged period of time, together with a low calorie, possibly low glycemic index diet, produces best results. CONCLUSION: The review found that intensive nutritional counselling approaches which promote low calorie/low GI diets appear to be most effective in BGL management in this population. Interventions that are delivered in Spanish and culturally tailored may be more acceptable to participants. More research is needed to develop suitable interventions to improve GDM management among Hispanic women. PMID- 28844355 TI - Do family planning messages improve antenatal care utilization? Evidence from Tajikistan. AB - OBJECTIVE: We assess the effects of TV family planning messages on the frequency and timing of antenatal care utilization in Tajikistan. Instrumental variable regressions are used with Tajikistan's 2012 nationally-representative Demographic and Health Survey to address confounding bias. METHODS: For the continuous outcome variable, number of antenatal visits, we use the instrumental variable linear two-stage least square (2SLS). For the binary outcome variable, the first antenatal visit made during the first trimester of pregnancy, we use instrumental variable biprobit. RESULTS: As suggested by 2SLS results, women who had been exposed to family planning messages on TV made additional 1.2 antenatal visits. As indicated by the biprobit results, exposure to TV family planning messages increases the likelihood of early initiation of ANC by 11 percentage points. CONCLUSION: Family planning messages on TV has strong direct positive impact on antenatal care utilization in Tajikistan. PMID- 28844357 TI - A critical review of the birth plan use in Catalonia. AB - INTRODUCTION: The birth plan allows the woman to express her expectations and needs with regards to the childbearing continuum but its use has been debated in the clinical context and in published literature. The birth plan was first introduced in the Spanish Health Service in 2008 through the Strategy for the Care in Normal Childbirth. In Catalonia, the Normal Childbirth Care Programme has promoted the use of birth plans in hospitals participating in this Programme. OBJECTIVE: This works describes and analyses the birth plans produced by the participating hospitals in order to gather knowledge about the options available to women. METHOD: Qualitative study in which the content of birth plans is systematically and quantitatively described in order to evaluate options available to women. The final sample includes all the birth plans provided by 30 Catalonian public hospitals. Following an initial assessment, it was decided to devise a grading scale which allowed to code and assign a value to each of the items contained in the birth plans. RESULTS: Three different types of birth plan are identified: a) those which present a list of items with no (or very little) associated explanations, b) list of items with some explanations and c) plans without items which only explain normal working practices in the hospital and/or protocols. PMID- 28844356 TI - Minimal clinically important difference for pain on the VAS scale and the relation to quality of life in women with endometriosis. AB - OBJECTIVES: The minimal important difference can be helpful in interpreting data from clinical trials. The objective of the study was to calculate the minimal important difference for improvement on the VAS scale for women with endometriosis. STUDY DESIGN: A prospective study was conducted to evaluate the effect of pertubation with lignocaine on dysmenorrhea and quality of life in women with endometriosis. Data collected in the trial were used for additional analyses in the present descriptive study. Eligible women (n=37) had endometriosis with pain>VAS 50mm (visual analogue scale). MAIN OUTCOME MEASURES: In a questionnaire, women evaluated their maximum pain on the VAS- scale during every menstrual period before and after treatment. They also estimated the changes in overall pain level by answering the response categories "much better", "somewhat better", "about the same", "somewhat worse" or "much worse". The women were grouped according to their own estimation of change in pain intensity after four months. The minimal important differences for change on the VAS scale correlate to the mean change for women who felt "somewhat better" (n=18) excluding those who were pain free (n=2). RESULTS: The minimal important difference for improvement on the VAS scale was found to be -39mm and/or -49%. CONCLUSION: If the patients have a pain level of at least 50mm on VAS scale at inclusion, the cut off for success in clinical trials is suggested to be defined as an either >40mm or a >50% decrease on VAS scale. Trial registry ClinicalTrials.gov Identifier: NCT01329796. PMID- 28844358 TI - How do youth with experience of violence victimization and/or risk drinking perceive routine inquiry about violence and alcohol consumption in Swedish youth clinics? A qualitative study. AB - OBJECTIVE: To explore perceptions and experiences among youth who underwent structured questions about violence victimization and alcohol consumption when visiting Swedish youth clinics. METHODS: This study is part of a larger research project examining the effect of including routine inquiry about violence victimization and alcohol consumption for youth visiting youth clinics. Fifteen youth with experiences of victimization and/or risk drinking (AUDIT-C>=5) were interviewed. Content analysis was used. RESULTS: The findings were grouped into three main categories: The first; "Disclosure - talking about violence" reflected the participants' experiences of being asked about victimization. Participants were in favor of routine inquiry about violence victimization, even when questions caused distress. The questions helped participants reflect on prior victimization and process what had happened to them. The second; "Influence on the life situation" demonstrated that many of the participants still were effected by prior victimization, but also how talking about violence sometimes led to the possibility of initiating change such as leaving a destructive relationship or starting therapy. In the third; "One's own alcohol consumption in black and white" participants considered it natural to be asked about alcohol consumption. However, most participants did not consider their drinking problematic, even when told they exceeded guidelines. They viewed risk drinking in terms of immediate consequences rather than in quantity or frequency of alcohol intake. CONCLUSION: Routine inquiry about violence victimization and risk drinking at youth clinics was well received. Questions about violence helped participants to interpret and process prior victimization and sometimes initiated change. PMID- 28844359 TI - Trends and consequences of the technocratic paradigm of childbirth in Portugal: A population-based analysis of birth conditions and social characteristics of parents. AB - OBJECTIVE: The aim of this paper is to analyse the evolution of birth conditions in Portugal and to establish a correspondence between maternity care and the socio-economic characteristics of new mothers. METHODS: A multivariate quantitative analysis (Multiple Correspondence Analysis and Cluster Analysis) was used, based on official quantitative data from different surveys. RESULTS: There is a consistent trend to a technocratic model of birth in the Portuguese context, where socio-economic characteristics appear to influence fertility rates and birth conditions. The evolution of birth conditions in Portugal reveal the institutionalisation of birth, with a strong presence of doctors, a higher frequency of births on certain weekdays, an increase in the proportion of births in private hospitals and an increase in the frequency of caesarean sections. There is an association between higher social status and more medicalised forms of assistance in childbirth. Women with higher levels of education, aged between 30 and 39years and who were married tended to be distinguished from the population of Portuguese women as a whole by three factors: birth in a hospital, the standardisation of pregnancy duration and the presence of a doctor at the birth. Women's educational and professional status also appears to influence their adoption of alternative models of birth, however, such as home birth. DISCUSSION: Limiting the study of childbirth to its medical aspects leaves important dimensions out of the analysis: women's perception of birth-related risks associated with the medicalised offer of maternity care, and the implications of this childbirth paradigm for health outcomes and for future care. PMID- 28844360 TI - Marital violence and sexually transmitted infections among women in post revolution Egypt. AB - OBJECTIVES: To explore the relationship between past year physical or sexual partner violence against women and women's self-report of sexually transmitted infection (STI) symptoms in post-revolution Egypt; and to examine the effects of men's and women's risky sexual behavioural characteristics and structural dimensions of poverty and gender inequality on this relationship. STUDY DESIGN: This study uses the nationally representative cross-sectional demographic and health survey data conducted in 2014. Multivariate logistic regression was used to assess the relationship between past year partner violence and self-report of STI symptoms among currently married women. MAIN OUTCOME MEASURES: women's self report of STI was based on their responses to three questions; whether in the past year they had: got a disease through sexual contact?, a genital sore or ulcer?, or a bad smelling abnormal genital discharge? Women who gave an affirmative response to one or more of these questions were assumed to self report STI. RESULTS: Almost one-third of women self-reported symptoms of STI. Fourteen percent of women reported they had experienced physical or sexual violence by a male partner in the past 12months. Abused women had a 2.76 times higher odds of self-reported STI symptoms (95% CI 2.25-3.38). The significant relationship between self-reported STI and past year partner violence against women did not alter when adjusting for men's and women's behavioural characteristics and factors related to poverty and gender inequality. CONCLUSIONS: Public health interventions that address women's sexual and reproductive health need to consider violence response and prevention strategies. PMID- 28844361 TI - A randomized controlled study comparing internet-based cognitive behavioral therapy and counselling by standard care for fear of birth - A study protocol. AB - Fear of birth is a concern that requires evidence based treatment. The aim of this study is to present the protocol of a randomized controlled multi-center trial to compare internet-based cognitive therapy with counseling as standard care for pregnant women reporting fear of birth. Participants will be recruited in mid-pregnancy. Women who score 60 or above on the Fear of Birth Scale will be offered to participate in this study. Data will be collected by questionnaires including validated instruments at baseline and follow-ups at gestational weeks 30 and 36, two months and one year after birth. The primary outcome will be level of fear of birth measured with the Fear of Birth Scale at 36 weeks of gestation. Secondary outcome measures are level of fear of birth at two months and one year after giving birth, preferences for mode of birth, requests for elective cesarean section, compliance and satisfaction with treatment and birth outcomes. A power calculation based on a 20% reduction of fear implies that approximately 200 will be included in the trial. The study outlined in this protocol will be the first randomized controlled trial comparing internet-based cognitive therapy with counseling for women reporting fear of birth. An effective treatment may result in better overall health for women with fear of birth and a reduction in cesarean sections for non-medical reasons. Evidence regarding treatment options of fear of birth will also provide a greater choice for women. PMID- 28844362 TI - Fathers' experience of starting family life with an infant born prematurely due to mothers' severe illness. AB - OBJECTIVE: To describe fathers' experiences of starting family life with an infant delivered prematurely out of necessity of saving the mother's and infant's lives due to the mother's severe preeclampsia. METHODS: A descriptive, qualitative design was used. Six fathers were interviewed twice: from 6 to 24 days and from 4 to 22 weeks after delivery. Data were transcribed verbatim and analyzed using a reflective lifeworld research approach. RESULTS: The essence of the fathers' experiences of establishing a family with a seriously ill mother and a premature infant can be described as a process of becoming a family through reflection on life and death in a context of separation. The essence specifically comprised the following constituents: (1) starting fatherhood facing existential issues, (2) connecting the family, (3) becoming familiar with your infant, and (4) becoming a father in a public area. CONCLUSIONS: The fathers were able to develop their relationship to their infants; this emphasizes the importance of the fathers being able to spend their time in the NICU. The privacy of the fathers were more or less challenged, health professionals should be aware of individualize their approach to the fathers. The study reveals that family life started with separation. Health professionals should try to ensure that the family should be together. Mutual guidelines between the wards that treats mother and child should be implemented. When new mother and child-centers are planned a family friendly environment should be prioritized. PMID- 28844363 TI - Change of lifestyle habits - Motivation and ability reported by pregnant women in northern Sweden. AB - BACKGROUND: Pregnant women are generally more motivated to change their lifestyle habits compared with non-pregnant women. However, the ability to change these habits depends on the motivation to change. This study describes pregnant women's self-reported motivation and ability to change lifestyle habits and their relation to body mass index (BMI), self-rated health, educational level and country of origin. METHODS: This cross-sectional study combined data from the Maternal Health Care Register in Vasterbotten (MHCR-VB) and the Salut Programme Register (Salut-R). Data were collected from 3,868 pregnant residents in Vasterbotten County (northern Sweden) between 2011 and 2012. Chi-square test, two independent samples t-test and univariate and multivariate logistic regression were performed. RESULTS: Most of the pregnant women (61.3%) were satisfied with their self-reported lifestyle habits irrespective of BMI, self-rated health, educational level, and country of origin. Many reported that they wanted to increase their physical activity, improve their dietary habits, and reduce their weight. In general, they estimated their ability to change their lifestyle habits as equal to their motivation of change. Women who reported a large or very large motivation to change their lifestyle habits were characterized by higher BMI and higher educational level. CONCLUSIONS: Most of the participating pregnant women were satisfied with their lifestyle habits, although they reported being further motivated to change some of them. Health care professionals encountering fertile and pregnant women may have a unique opportunity to support and promote lifestyle changes, taking into account women's motivation for change. Future research should focus on factors that motivate pregnant women to change their lifestyle, explore barriers for change of lifestyle and how support best may be provided to pregnant women. In addition, studies on lifestyle and motivation for lifestyle change from non-Nordic countries are called for. PMID- 28844364 TI - Factors related to choice of place of birth in a district in Nepal. AB - OBJECTIVE: In Nepal, both percentage of women giving birth at health facility and proportion of birth assisted by skilled birth attendant is very low. The purpose of this research was to identify predictors for choice of place of birth: either at home, primary health care facility (including birthing centres) or at tertiary health care facilites (hospitals and clinics). METHODS: A cross-sectional household survey was conducted in seven village development committee of a district lying in plain area of Nepal: Nawalparasi. A structured interview questionnaire was developed and administered face-to-face. Descriptive analysis along with chi-square test and multinomial logistic regression was used to identify the predictors of giving birth at a health care facility. RESULTS: Women were significantly more likely to give birth at health care facilities compared to home if the distance was less than one hour, belonged to advantaged caste, had radio, television and motorbike/scooter, decision maker for place of birth was husband, reported their frequency of antenatal (ANC) visits at 4 or more and belonged to age group 15-19. CONCLUSION: The analysis indicates that husbands of women giving birth influence the choice of place of birth. The findings highlight importance of having four or more ANC visits to the health institutions and that it should be located within one-hour walking distance. Inequity in utilisation of childbirth services at health institutions exists as showed by low utilisation of such services by disadvantaged caste. PMID- 28844365 TI - The relationship between history of hormonal contraceptive use and iron status among women in Tanzania: A population-based study. AB - OBJECTIVES: Approximately 30% of the Tanzanian women in the reproductive age group are iron deficient. At population-level, there is a dearth of research on the relationship between hormonal contraceptive use and iron deficiency. The study objective was to examine the relationship between history of hormonal contraceptive use and iron status among women in Tanzania. STUDY DESIGN: We conducted a cross-sectional study analysis including 4186 women who participated in the population-based 2010 Tanzania Demographic and Health Survey. MAIN OUTCOME MEASURE: Iron status determined by iron deficiency, anemia, and iron deficiency anemia. RESULTS: Almost 19.0% women reported history of hormonal contraceptive use. Nearly, 30.0%, 39.5%, and 14.3% women had iron deficiency, anemia and iron deficiency anemia respectively. History of hormonal contraceptive use was negatively associated with iron deficiency, anemia and iron deficiency anemia, independent of potential confounders. Compared to non-users, the multivariable adjusted odds ratio OR (95% CI) among hormonal contraceptive users was 0.73 (0.56 0.94, p<0.05) for iron deficiency, 0.58 (0.46-0.72, p<0.001) for anemia, and 0.53 (0.37-0.74; p<0.001) for iron deficiency anemia. Longer duration of hormonal contraceptive use (>2years) had lesser odds of iron deficiency 0.63 (0.43-0.91, p for trend 0.005), anemia 0.51 (0.36-0.73, p for trend <0.001) and iron deficiency anemia 0.35 (0.19-0.65, p for trend <0.001). CONCLUSION: Our finding has important implications for educating healthcare providers and women about additional nutritional benefits of the use of hormonal contraceptives. PMID- 28844366 TI - Syringomyelia associated with cervical spondylotic myelopathy causing canal stenosis. A rare association. AB - BACKGROUND: Although cervical spondylosis is extremely common, only few cases with associated syrinx have been reported. Depending on review of two large data bases, we report this case series. In addition, we evaluated the posterior decompression as the management option in treatment of this rare condition. MATERIALS AND METHODS: Data of all cases with cervical spondylosis and canal stenosis that sought medical advice or needed decompressive laminectomy/laminoplasty between the years 2006 and 2015 were checked in manually. Perioperative data, together with follow up were reviewed. RESULTS: Out of five cases found in the reviewed data; four cases undergone posterior decompression (laminectomy in two cases and laminoplasty in the other). One case refused surgery. Along mean follow up period of 6.25 months; three cases improved markedly, while in one case no improvement occurred. CONCLUSION: Cervical spondylotic myelopathy can rarely cause syringomyelia. Posterior decompression would be the preferable management option with clinical improvement of most of the cases. PMID- 28844367 TI - Apathy in drug-naive patients with Parkinson's disease. AB - OBJECTIVE: The aim of this study is to explore the prevalence and clinical correlates of apathy in early-stage Parkinson's disease (PD) from a cohort of Chinese patients. METHODS: A cross-sectional analysis of 133 treatment-naive PD patients was conducted. Each subject was categorized as PD with or without apathy using the Lille Apathy Rating Scale (LARS). RESULTS: Of 133 patients, 30 PD patients (22.56%) reported apathy, of whom 23 (17.29%) did not have concomitant depression. The stepwise binary logistic regression model indicated that the lower Frontal assessment battery (FAB) score (OR = 0.623, 95% CI = 0.466-0.834, P = 0.001), the higher sleep/fatigue score from the Non-Motor Symptoms Scale (NMSS) (OR = 1.171, 95% CI = 1.071-1.279, P = 0.001), the higher Hamilton Depression Rating Scale including 24 items (HAMD-24) score (OR = 1.112, 95% CI = 1.005 1.230, P = 0.039) and the higher Unified Parkinson's Disease Rating Scale (UPDRS) part III score (OR = 1.119, 95% CI = 1.045-1.198, P = 0.001) were associated with apathy. No significant associations were found between apathy and other parameters such as age, sex distribution, disease duration, anxiety, Fatigue Severity Scale (FSS) score, Montreal Cognitive Assessment (MOCA) score and remaining domain scores for NMSS. CONCLUSIONS: Apathy is not rare (22.56%) in Chinese treatment-naive PD patients. Apathy in PD is not only related to the severity of motor symptoms of the disease but also to some non-motor symptoms, such as executive dysfunction, depression and sleep disturbances. PMID- 28844368 TI - Advances in rapid drug detection technology. AB - Spurious/Falsely-labeled/Falsified/Counterfeit (SFFC)drugs have become a major threat to public health, especially in rural areas of developing countries.The goal of this review is to provide an overview of rapid detection technologies for counterfeits recently reported, such as Near Infrared Spectroscopy, Near Infrared Chemical Imaging, Raman Spectroscopy, X-Ray Fluorescence, X-RayPowder Diffraction, Ion Mobility Spectrometry, Ion MobilityMass Spectrometry,Isotope Ratio Mass Spectrometry and visual analytical methods The advantages of each of these detection methods are introduced. Examples of characterization of SFFC drugs using the detection technology mentioned are presented. In addition, new characteristics and trends of SFFC drugs are listed and the solution is discussed. PMID- 28844369 TI - Metabolism studies of chiral pesticides: A critical review. AB - The consumption of pesticides worldwide has been growing in recent decades, and consequently the exposure of humans and other animals to them as well. However, even though it is known that chiral pesticides can behave stereoselectively, the knowledge about the risks to human health and the environment is scarce. Among the pesticides registered to date, approximately 30% have at least one center of asymmetry, and just 7% of them are currently marketed as a pure stereoisomer or as an enriched mixture of the active stereoisomer. There are several in vitro, in vivo, and in silico models available to evaluate the enantioselective metabolism of chiral pesticides aiming ecotoxicological and risk assessment. Therefore, this paper intends to provide a critical view of the metabolism of chiral pesticides in non-target species, including humans, and discuss their implications, as well as, conduct a review of the analytical techniques employed for in vitro and in vivo metabolism studies of chiral pesticides. PMID- 28844370 TI - Technology: Is There Sufficient Evidence to Change Practice in Point-of-Care Management of Coagulopathy? AB - Currently, hemostasis is one of the most widely researched topics in perioperative medicine. As investigators learn more about the complexity of coagulation, developing tests with the ability to rapidly monitor coagulation and guide targeted therapy is the key to optimizing hemostasis management. There is mounting evidence that algorithmic transfusion using point-of-care (POC) testing can reduce red cell and platelet transfusions and major bleeding after cardiac surgery. Integrating these tests during cardiac surgery and trauma management is especially important because these groups use the most blood products within a health system and the risks of transfusion are well documented. Currently, numerous POC tests are available for evaluating hemostasis. The purpose of this review is to provide a comprehensive evaluation of the current evidence surrounding the most common POC testing devices in practice for managing coagulation. PMID- 28844372 TI - Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for >=24 weeks in Europe. AB - BACKGROUND: Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. OBJECTIVE: To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. DESIGN, SETTING, AND PARTICIPANTS: Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after >=24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. INTERVENTION: Patients received enzalutamide 160mg/d orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. RESULTS AND LIMITATIONS: Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naive. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1 8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. CONCLUSIONS: Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following >=24 wk of abiraterone acetate plus prednisone treatment. PATIENT SUMMARY: Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy, received enzalutamide. Although cross-resistance between the two agents was observed in a majority of patients, some still benefited from enzalutamide treatment. PMID- 28844371 TI - Active Surveillance Versus Watchful Waiting for Localized Prostate Cancer: A Model to Inform Decisions. AB - BACKGROUND: An increasing proportion of prostate cancer is being managed conservatively. However, there are no randomized trials or consensus regarding the optimal follow-up strategy. OBJECTIVE: To compare life expectancy and quality of life between watchful waiting (WW) versus different strategies of active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: A Markov model was created for US men starting at age 50, diagnosed with localized prostate cancer who chose conservative management by WW or AS using different testing protocols (prostate specific antigen every 3-6 mo, biopsy every 1-5 yr, or magnetic resonance imaging based). Transition probabilities and utilities were obtained from the literature. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes were life years and quality-adjusted life years (QALYs). Secondary outcomes include radical treatment, metastasis, and prostate cancer death. RESULTS AND LIMITATIONS: All AS strategies yielded more life years compared with WW. Lifetime risks of prostate cancer death and metastasis were, respectively, 5.42% and 6.40% with AS versus 8.72% and 10.30% with WW. AS yielded more QALYs than WW except in cohorts age >65 yr at diagnosis, or when treatment-related complications were long term. The preferred follow-up strategy was also sensitive to whether people value short term over long-term benefits (time preference). Depending on the AS protocol, 30 41% underwent radical treatment within 10 yr. Extending the surveillance biopsy interval from 1 to 5 yr reduced life years slightly, with a 0.26 difference in QALYs. CONCLUSIONS: AS extends life more than WW, particularly for men with higher-risk features, but this is partly offset by the decrement in quality of life since many men eventually receive treatment. PATIENT SUMMARY: More intensive active surveillance protocols extend life more than watchful waiting, but this is partly offset by decrements in quality of life from subsequent treatment. PMID- 28844373 TI - Blood derived eye drops for the treatment of cornea and ocular surface diseases. AB - The use of blood derived eye drops for the treatment of ocular surface disorders has become increasingly popular in recent years. The mechanism of action is the stimulation of cellular proliferation and migration by supplying an active mixture of growth factors and cytokines at the ocular surface, thus mimicking the function of the lacking natural tears. Blood derived eye drops have been used in the last decades for the treatment of a variety of ocular surface diseases, including mainly dry eye disease, persistent corneal epithelial defect, corneal ulcer, ocular surface burn, recurrent corneal erosion and limbal stem-cell deficiency. Among overall blood derived eye drops, both autologous (from the patients themselves) and homologous (from donors) products exist, with different advantages and disadvantages. Autologous serum, obtained from the patient's own peripheral blood, is the first introduced and most commonly used product. Despite several randomized clinical trials showed its safety and efficacy, a recent Cochraine meta-analysis failed to show significant results due to low evidence. Homologous sources including allogeneic serum obtained from healthy donors, and umbilical cord blood serum collected at the time of delivery, are efficient alternatives, especially when autologous serum therapy is contraindicated or not appropriate. Platelet-derived eye drops are prepared and used in various but poor standardized preparations, namely platelet-rich plasma, plasma rich in growth factors, and platelet lysate. Future perspectives of blood-derived products include the introduction of tailored eye drops, screened for the proper content of growth factors and cytokines according to each patient and ocular surface disease. PMID- 28844374 TI - Urinary tract infection surveillance in residential aged care. AB - OBJECTIVES: The aim of this research was to determine the prevalence of urinary tract infections (UTIs) in 2 aged care homes (ACHs) and examine the extent to which presumed UTIs met the 2012 McGeer infection surveillance definitions. DESIGN: Retrospective observational study. SETTING: Two ACHs: a 30-bed facility and a 100-bed facility PARTICIPANTS: Residents of the 2 ACHs diagnosed with UTI. METHODS: A retrospective review was conducted of UTIs clinically diagnosed at the 2 facilities over a 16-month period, utilizing surveillance and microbiologic data, resident progress notes, and medication charts. This data was reviewed to determine how many diagnosed UTIs met the revised McGeer definitions. RESULTS: Overall, 119 UTIs were diagnosed in 57 residents over 16 months. Only 7 of the diagnosed UTIs met the McGeer definitions. Forty-seven did not meet the clinical evidence, 17 did not meet the microbiologic evidence, and 48 did not meet either surveillance criteria. CONCLUSIONS: This study demonstrated the disparity between the clinical diagnosis of UTI and the surveillance definitions for UTI, and highlights the limitations of the McGeer definitions in those with cognitive or communication deficits. There is an urgent need for antimicrobial stewardship programs and education in the ACH setting. PMID- 28844375 TI - High mortality rate associated with KPC-producing Enterobacter cloacae in a Brazilian hospital. AB - We describe a clonal dissemination of KPC-producing Enterobacter cloacae in a Brazilian hospital. Patients diagnosed with theses isolates showed high mortality rate (41.8%) and were associated with previous use of antibiotics and urinary catheterization. Therefore, infection control measures and use of stricter antibiotic policies are required to control the spread of these organisms. PMID- 28844376 TI - Successful strategy to decrease indwelling catheter utilization rates in an academic medical intensive care unit. AB - BACKGROUND: Duration of indwelling urinary catheterization is an important risk factor for urinary tract infections. We devised a strategy to decrease the utilization of indwelling urinary catheters (IUCs). We also highlight the challenges of managing critically ill patients without IUCs and demonstrate some of the initiatives that we undertook to overcome these challenges. METHODS: A retrospective observational outcomes review was performed in an adult medical intensive care unit (ICU) between January 2012 and December 2016. This period included a baseline and series of intervals, whereby different aspects of the strategies were implemented. IUC utilization ratio and catheter-associated urinary tract infection (CAUTI) rates were calculated. RESULTS: Our IUC utilization ratio had a statistically significant decrease from 0.92 (baseline) to 0.28 (after 3 interventions) (P < .0001). Similarly, CAUTI rates had a statistically significant decrease from 5.47 (baseline) to 1.08 (after 3 intervention) (P = .0134). These rates sustained a statistically significant difference over the 2-year follow-up period from the last intervention. Incontinence-associated dermatitis (IAD) was identified as a potential complication of not using an IUC. There was no statistically significant change in the IAD rates during 2013-2016. CONCLUSIONS: Our interventions demonstrated that aggressive and comprehensive IUC restriction protocol and provider training can lead to a successful decrease in IUC use, leading to a lower IUC utilization ratio and CAUTI rate in a large complex academic ICU setting. PMID- 28844377 TI - The virus defeating Madam Mim. PMID- 28844378 TI - Nasal methicillin-resistant Staphylococcus aureus screening in patients with pneumonia: A powerful antimicrobial stewardship tool. PMID- 28844379 TI - Multiple interventions in a postanesthesia care unit: Impact on hand hygiene compliance. PMID- 28844380 TI - Prognostic factors of health care-associated bloodstream infection in adult patients >=40 years of age. AB - We investigated 401 geriatric patients and 453 middle-aged patients with health care-associated bloodstream infection (HABSI) at a medical center during January December 2014. Compared with middle-aged patients, the geriatric group had higher 30-day mortality (31.2% vs 23.4%, P = .01). Body mass index, serum albumin concentration, Charlson comorbidity index score, vancomycin-resistant Enterococcus bacteremia, and high C-reactive protein levels predict poor outcomes for HABSI among adult patients. PMID- 28844381 TI - Assessment of half-mask elastomeric respirator and powered air-purifying respirator reprocessing for an influenza pandemic. AB - BACKGROUND: Health care facilities are considering the use of reusable respiratory protective devices (RPDs) to mitigate a potential N95 filtering facepiece respirator shortage caused by an influenza pandemic. US regulators are also considering stockpiling reusable RPDs for pandemic preparedness, but limited data exist on the effectiveness of cleaning and disinfection of these devices. This study defines reprocessing protocols and evaluates their effectiveness against a pandemic influenza strain in a laboratory setting. METHODS: Five half mask elastomeric respirator models and 3 powered air-purifying respirator models were contaminated with influenza virus and artificial skin oil on multiple surfaces. RPDs were then manually treated with 1 of 2 methods: cleaned or cleaned and disinfected. Presence of viable influenza was determined via swab sampling and a median tissue culture infectious dose assay. RESULTS: Across 41 RPD surfaces, a mean log reduction in viable influenza of 4.54 +/- 0.97 log10 median tissue culture infectious dose was achieved for all treated surfaces, which included both cleaned and cleaned and disinfected surfaces. CONCLUSIONS: The methods defined as part of this study are effective for eliminating viable influenza in the presence of artificial skin oil on most of the RPD surfaces tested. Material type and RPD design should be considered when implementing RPD reprocessing protocols. PMID- 28844382 TI - Antibacterial effect and proposed mechanism of action of a topical surgical adhesive. AB - BACKGROUND: Medical adhesives effectively hold closed approximated skin edges of wounds from surgical incisions, including punctures from minimally invasive surgery. In addition, they have been reported to be antibacterial against gram positive bacteria. METHODS: Using membrane filtration to capture all organisms after contact with 2-octyl cyanoacrylate product for 3 minutes, we quantified the number of survivors. Controls were performed to rule out that the noted level of kill was caused by carryover product in the test system. RESULTS: We found that the product kills >7 logs of gram-positive and gram-negative bacteria. The mechanism of action for the antibacterial effect is described as a function of very low water content. CONCLUSIONS: As an antibacterial agent, the risk of nosocomial infection is greatly diminished, and an uneventful clinical result is facilitated. Bacterial growth cannot occur in the formulation and on contact death rapidly ensues as cellular water diffuses from the cell into the product. PMID- 28844383 TI - Contact patterns during cleaning of vomitus: A simulation study. AB - BACKGROUND: Environmental service workers cleaning bodily fluids may transfer pathogens through the environment and to themselves through contacts. METHODS: Participants with experience in cleaning of hospital environments were asked to clean simulated vomitus using normal practices in a simulated patient room while being videorecorded. Contacts with environmental surfaces and self were later observed. RESULTS: In 21 experimental trials with 7 participants, environmental surfaces were contacted 26.8 times per trial, at a frequency of 266 contacts per hour, on average. Self-contact occurred in 9 of 21 trials, and involved 1-18 contacts, mostly to the upper body. The recommended protocol of cleaning bodily fluids was followed by a minority of participants (2 of 7), and was associated with fewer surface contacts, improved cleaning quality, and different tool use. Participants used different cleaning practices, but each employed similar practices each time they performed an experimental trial. CONCLUSIONS: Training in the use of the recommended protocol may standardize cleaning practices and reduce the number of surface contacts. PMID- 28844384 TI - Implementation and evaluation of an automated surveillance system to detect hospital outbreak. AB - BACKGROUND: The timely identification of a cluster is a critical requirement for infection prevention and control (IPC) departments because these events may represent transmission of pathogens within the health care setting. Given the issues with manual review of hospital infections, a surveillance system to detect clusters in health care settings must use automated data capture, validated statistical methods, and include all significant pathogens, antimicrobial susceptibility patterns, patient care locations, and health care teams. METHODS: We describe the use of SaTScan statistical software to identify clusters, WHONET software to manage microbiology laboratory data, and electronic health record data to create a comprehensive outbreak detection system in our hospital. We also evaluated the system using the Centers for Disease Control and Prevention's guidelines. RESULTS: During an 8-month surveillance time period, 168 clusters were detected, 45 of which met criteria for investigation, and 6 were considered transmission events. The system was felt to be flexible, timely, accepted by the department and hospital, useful, and sensitive, but it required significant resources and has a low positive predictive value. CONCLUSIONS: WHONET-SaTScan is a useful addition to a robust IPC program. Although the resources required were significant, this prospective, real-time cluster detection surveillance system represents an improvement over historical methods. We detected several episodes of transmission which would have eluded us previously, and allowed us to focus infection prevention efforts and improve patient safety. PMID- 28844385 TI - Synthesis of some monosaccharide-related ester derivatives as insecticidal and acaricidal agents. AB - To develop natural-product-based pesticidal agents, a series of monosaccharide related ester derivatives (17a-q and 18a-f), glucose (xylose)-piperic acid/piperic acid-like conjugates, were synthesized. Three-dimensional structures of compounds 17b, 17g, 17h, and 17n were unambiguously determined by single crystal X-ray diffraction. Especially compounds 18e and 18f exhibited the most potent insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus. Their structure-activity relationships were also discussed. PMID- 28844387 TI - Synthesis and biological evaluation of a new series of cinnamic acid amide derivatives as potent haemostatic agents containing a 2-aminothiazole substructure. AB - Ten new cinnamic acid derivatives containing a 2-aminothiazole substructure were designed and synthesized. This series of compounds exhibited good thermostabilities as demonstrated by thermogravimetric analysis. In coagulation assays (prothrombin time, activated partial thromboplastin time and thrombin time) in vitro, most compounds demonstrated excellent activities to promote blood coagulation. Among the studied series, compounds N1, N4, N5 and W5 exhibited a significant coagulation activity. Further studies indicated that compound N5 (IC50=1.87MUmol/L) displayed the most suitable efficacy of promoting platelet aggregation than the clinically used haemostatic drug etamsylate (IC50=46.22MUmol/L). Furthermore, the relationship between the functional groups of the compounds and the corresponding blood coagulant activity was explored in this study. PMID- 28844388 TI - Cation exchange assisted binding-elution strategy for enzymatic synthesis of human milk oligosaccharides (HMOs). AB - A cation exchange assisted binding-elution (BE) strategy for enzymatic synthesis of human milk oligosaccharides (HMOs) was developed. An amino linker was used to provide the cation ion under acidic condition which can be readily bound to cation exchange resin and then eluted off by saturated ammonium bicarbonate. Ammonium bicarbonate in the collections was easily removed by vacuum evaporation. This strategy circumvented the incompatible issue between glycosyltransferases and solid support or large polymers, and no purification was needed for intermediate products. With current approach, polyLacNAc backbones of HMOs and fucosylated HMOs were synthesized smoothly. PMID- 28844386 TI - Modified biphenyl Hsp90 C-terminal inhibitors for the treatment of cancer. AB - Heat Shock Protein 90 (Hsp90) is a molecular chaperone under clinical investigation for the treatment of neurodegenerative diseases and cancer. Neuroprotective Hsp90 C-terminal inhibitors (novologues) contain a biaryl ring system, and include KU-596, which was modified and investigated for potential anti-cancer activity. Incorporation of a benzamide group onto the biaryl novologues in lieu of the acetamide yielded compounds that manifest anti-cancer activity. Further exploration of the central phenyl ring led to compounds with enhanced anti-proliferative activity. The design, synthesis, and evaluation of these new analogs against breast and prostate cancer cell lines is reported herein, where it was found that 8b and 10 manifest potent anti-proliferative activity and a robust degradation of Hsp90 client-dependent proteins. PMID- 28844389 TI - Synthesis and biological evaluations of new nitric oxide-anti-inflammatory drug hybrids. AB - Three novel series of nitroso derivatives (11-15), isoxazolopyrazoles (17a-c) and isoxazolo[3,4-d]pyridazines (18a-c) were prepared from the hydroxyimoyl chloride 10. In vitro COX1?2 inhibition activities were evaluated, both of 17b and 18a proved a promising inhibitory activity with IC50=1.12, 0.78MUM in sequent. Carrageenan induced Paw edema, ulcer liability, nitric oxide (NO) release and histopathological study were determined. Most of the prepared compounds showed excellent activities. Reactions of 2-aminopyridine and enaminone with hydroxyimoyl chloride 10 were investigated and proved by 2D NMR. Molecular docking for most active compounds was operated giving a hint for compound receptor interactions. PMID- 28844390 TI - Photodynamic inactivation of multiresistant bacteria (KPC) using zinc(II)phthalocyanines. AB - The worldwide increase in antibiotic resistance has led to search of alternatives anti-microbial therapies such as photodynamic inactivation. The aim of this paper was to evaluate the photodynamic activity in vitro of a neutral and two cationic Zn phthalocyanines. Their photokilling activity was tested on Escherichia coli ATCC 25922 and Klebsiella pneumoniae Carbapenemase (KPC)-producing. After treating bacteria with phthalocyanines, the cultures were irradiated with white light. As a result, the bacteria were inactivated in presence of cationic phthalocyanines. The photoinactivation was dependent of the irradiation time and phthalocyanine concentration. The most effective photosensitizer on KPC-producing was Zinc(II)tetramethyltetrapyridino[2,3-b:2',3'-g:2",3"-l:2''',3''' q]porphyrazinium methylsulfate (ZnTM2,3PyPz). After irradiation using the water soluble ZnTM2,3PyPz (3MUM) the viability of KPC (30min of irradiation) and E. coli (10min of irradiation) decreased ~99.995%. PMID- 28844391 TI - 1-Thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives as antitumor agents. AB - A class of substituted 1-thiazol-2-yl-N-3-methyl-1H-pyrozole-5-carboxylic acid derivatives was found to have potent anti-proliferative activity against a broad range of tumor cell lines. A compound from this class (14) was profiled across a broad panel of hematologic and solid tumor cancer cell lines demonstrating cell cycle arrest at the G0/G1 interphase and has potent anti-proliferative activity against a distinct and select set of cancer cell types with no observed effects on normal human cells. An example is the selective inhibition of human B-cell lymphoma cell line (BJAB). Compound 14 was orally bioavailable and tolerated well in mice. Synthesis and structure activity relationships (SAR) in this series of compounds are discussed. PMID- 28844392 TI - Lazarus Syndrome With Crizotinib in a Non-Small Cell Lung Cancer Patient With ROS1 Rearrangement and Disseminated Intravascular Coagulation. PMID- 28844393 TI - Pure apraxia of speech due to infarct in premotor cortex. AB - Apraxia of speech (AOS) is now recognized as an articulation disorder distinct from dysarthria and aphasia. Various lesions have been associated with AOS in studies that are limited in precise localization due to variability in size and type of pathology. We present a case of pure AOS in setting of an acute stroke to localize more precisely than ever before the brain area responsible for AOS, dorsal premotor cortex (dPMC). The dPMC is in unique position to plan and coordinate speech production by virtue of its connection with nearby motor cortex harboring corticobulbar tract, supplementary motor area, inferior frontal operculum, and temporo-parietal area via the dorsal stream of dual-stream model of speech processing. The role of dPMC is further supported as part of dorsal stream in the dual-stream model of speech processing as well as controller in the hierarchical state feedback control model. PMID- 28844394 TI - Seasonal trophic ecology of the dominant Antarctic coral Malacobelemnon daytoni (Octocorallia, Pennatulacea, Kophobelemnidae). AB - Antarctic ecosystems present highly marked seasonal patterns in energy input, which in turn determines the biology and ecology of marine invertebrate species. This relationship is stronger at lower levels of the food web, while upper levels may be less dependent on primary production pulses. The pennatulid Malacobelemnon daytoni, is one of the most abundant species in Potter Cove, Antarctica. In order to assess its trophic ecology and energetic strategies, its biochemical (carbohydrates, proteins and lipids), Fatty Acid (FA) and Stable Isotope (SI) (delta15N and delta13C) compositions were studied over a year-round period. The FA and SI profiles suggest an omnivorous diet and opportunistic feeding strategy for the species. These results, together with biochemical analysis (higher lipid and carbohydrate concentration observed in July and October 2009), support the hypothesis that resuspension events may be an important source of energy, reducing the seasonality of food depletion periods in winter. The evidence presented here gives us a better insight into the success that this species has in Potter Cove and under the current environmental changes experienced by the Antarctic Peninsula. PMID- 28844395 TI - [A case of gonococcal arthritis: Diagnostic difficulties and usefulness of synovial fluid PCR]. AB - INTRODUCTION: The incidence of Neisseria gonorrhoeae septic arthritis remains low in the general population. Its clinical and microbiological diagnostic remains difficult. CASE REPORT: We report a 44-year-old man who presented with a monoarthritis of the right ankle. The diagnosis of gonoccocal septic arthritis was obtained by PCR from the joint fluid. Treatment with ceftriaxone was effective. CONCLUSION: In patients with high risk of N. gonorrhoeae infection, PCR for detection of gonorrhea in synovial fluid could potentially facilitate the diagnostic of gonococcal septic arthritis. PMID- 28844396 TI - [Extensive cutaneous lesions]. PMID- 28844398 TI - Using the patients concerns inventory for distress screening in post-treatment head and neck cancer survivors. AB - PURPOSE: Cancer patients can experience significant distress during their cancer trajectory, which impacts upon clinical outcomes and quality of life. Screening for distress using holistic assessments can help identify and address unmet concerns/needs. The purpose of this study was to evaluate the relationship between concerns and distress, and the impact of distress on clinic outcomes in post-treatment head and neck cancer patients. METHODS: 170 patients attending routine follow-up clinics were prospectively recruited. All patients completed the Patient Concerns Inventory (PCI) and the Distress thermometer (DT) at preconsultation. RESULTS: The rate of significant distress (i.e. DT cut-off score >=4) was 36% (62/170). Significantly distressed patients selected more items overall than patients without distress (mean, median (QR) of 5.40, 5 (2-8) vs 2.61, 2 (0-4), p < 0.001). Significant distress was most strongly associated with Physical and Functional well-being (p < 0.001) and Psychological and Emotional well-being domains (p = 0.001). On balance, very little difference was noted between cut-off points of either >=4 or >=5 PCI items of concern selected. Both cut-off points demonstrated an acceptable level of sensitivity, specificity and predictive values for significant distress. Consultations were longer with increasing numbers of concerns. CONCLUSIONS: Just over one-third of patients are significantly distressed. They were more likely to express a higher number of concerns. A cutoff score >=4 or >=5 PCI items selected can identify those at risk of significant distress. Concerns causing significant distress were related to emotional/psychological issues and physical function. PMID- 28844397 TI - Functional considerations in ALPPS - consequences for clinical management. AB - BACKGROUND: Since perioperative morbidity and mortality in ALPPS are extraordinarily high, a deeper understanding of actual liver function during the procedure is essential to make the approach safer. METHODS: Data from 17 patients who underwent ALLPS were analyzed regarding their course of liver function capacity assessed with the LiMAx test and compared to an equal-sized matched cohort of patients that underwent PVE. RESULTS: A comparison of LiMAx prior to and following ALPPS Step I (330 [258-385] vs. 197 [144-224] MUg/kg/h, p = 0.003) and prior to and following PVE (386 [330-519] vs. 378 [336-455] MUg/kg/h, p = 0.534) demonstrated a significant drop in function after ALLPS. A volume/function analysis predicting FLR function regarding step II revealed an excellent correlation of predicted versus assessed postoperative liver function with a mean relative difference of 9 (-6 to 18)% and an ICC of 0.905 (123 [74-138] vs. 107 [77-175] MUg/kg/h, p = 0.310). CONCLUSIONS: We provide evidence that liver function capacity is significantly impaired due to ALPPS step I. This is particularly notable when compared to PVE. Our data also shows that the portal ligated liver lobe still continues to contribute significantly to overall liver function. Therefore, FLR function after step II is still predictable by volume/function analysis. PMID- 28844399 TI - Design of a nationwide survey on palliative care for end-stage heart failure in Japan. AB - BACKGROUND: The term palliative care has historically been associated with support for individuals with advanced incurable cancer, so cardiologists and cardiac nurses may be unfamiliar with its principles and practice. However, palliative care is now a part of end-stage heart failure management. We conducted the first nationwide survey to investigate the status of palliative care for heart failure in Japan. METHODS AND RESULTS: A self-reported questionnaire was mailed to all Japanese Circulation Society - authorized cardiology training hospitals (n=1004) in August 2016. The response deadline was December 2016. The survey focused on the following topics: basic information about the facility and multidisciplinary team, patient symptoms for palliative care, positive outcomes after providing palliative care, drug therapy as palliative care for patients with heart failure, advance care planning with patients and their families, and impediments to providing palliative care to patients with heart failure. The results of the survey will be reported in detail elsewhere. CONCLUSIONS: Current guidelines on palliative care do not specifically address what team members should be involved, what drugs should be used, or when palliative care should be started. This survey collected information to improve the quality of palliative care and provide more specialized palliative care within the limits of resources. PMID- 28844400 TI - meso-Dihydroguaiaretic acid derivatives with antibacterial and antimycobacterial activity. AB - Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium. Additionally, nineteen meso-DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50ug/mL. Seven meso-DGA derivatives bearing amino-ethers (26-31 and 33) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25ug/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N-ethylpiperidine moieties in meso-31) resulted essential to significantly increase the antimycobacterial properties of parent meso-DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies. PMID- 28844401 TI - Lipase-catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one derivatives by a one-pot dynamic kinetic resolution/intramolecular Diels-Alder reaction: Total synthesis of (-)-himbacine. AB - One-pot sequential reactions using the acyl moieties installed by enzymatic dynamic kinetic resolution of alcohols have been little investigated. In this work, the acryloyl moiety installed via the lipase/oxovanadium combo-catalyzed dynamic kinetic resolution of a racemic dienol [4-(cyclohex-1-en-1-yl)but-3-en-2 ol or 1-(cyclohex-1-en-1-yl)but-2-en-1-ol] with a (Z)-3-(phenylsulfonyl)acrylate underwent an intramolecular Diels-Alder reaction in a one-pot procedure to produce an optically active naphtho[2,3-c]furan-1(3H)-one derivative (98% ee). This method was successfully applied to the asymmetric total synthesis of (-) himbacine. PMID- 28844402 TI - Gastroprotective and mucosa homeostatic activities of coconut milk and water on experimentally induced gastropathies in male wistar rats. AB - In this biphasic study, 45 male wistar rats were divided into 9 groups. In Phase 1, Group 1 was treated with normal saline and served as the overall control, group 2 was treated with 95% Ethanol and represents the ulcer control, groups 3 and 4 received coconut water (CW; 4ml/100g BWt) and milk (CM; 4ml/100g BWt) for 4weeks while group 5 received Omeprazole (Omep; 20mg/kg BWt) during terminal week. 95% Ethanol-induced ulceration followed the treatments in all except group 1. In the second phase, Group 1 was the overall control, group 2 served as ulcer control by receiving acetic acid only, group 3 received coconut milk, and group 4 received omep. CM and omep were administered post-ulcer induction for 3 and 6days twice daily. Blood collection after 1hour was through cardiac puncture for haemocytometry, and gastric tissues harvested for histopathological investigations. Results showed significantly reduced ulcer score and gastric lesion index in Omep, CW and CM groups compared to ulcer control. WBC, neutrophil, lymphocyte counts in Omep, CW and CM groups were significantly reduced compared to ulcer and overall control groups. C-reactive protein was significantly reduced in CM compared to control. Neutrophil Infiltration score reduced while mucus cell density increased significantly in Omep; CM compared to control. EGFR and CD 31 assessment revealed significantly higher expressions in coconut-milk group compared to the ulcer control. We conclude that the protective effects of coconut (water and milk) is expressed by inflammation suppression, upregulation of mucus cell population and catalyses mucosa homeostasis via angiogenesis and mucosal cell proliferation following mucosa. erosion. PMID- 28844403 TI - Sepsis and Acute Myeloid Leukemia: A Population-Level Study of Comparative Outcomes of Patients Discharged From Texas Hospitals. AB - BACKGROUND: In the United States, approximately 750,000 cases of sepsis occur annually, and 28% to 50% of affected people die. Treatment is costly, often involving admission to the intensive care unit and prolonged hospitalization. We evaluated outcomes of patients with acute myeloid leukemia (AML) and sepsis in Texas. PATIENTS AND METHODS: We conducted a population-based cohort study of adults discharged from Texas hospitals during 2011, using ICD-9-CM codes and the Texas Inpatient Data Collection. RESULTS: A total of 2,173,776 adults were discharged from hospitals in Texas, and 5501 (0.25%) had a diagnosis of AML. Among patients with AML, 40% were >= 65 years old, and 52% were men. The rate of sepsis for AML patients was 16% compared to 4% for non-AML patients. Among patients with AML, sepsis was associated with pneumonia, acute renal failure, and hematologic dysfunctions in 34%, 32%, and 29% of discharges, respectively. Median length of stay, intensive care unit admission rate, and median hospital charges per stay for patients with AML and sepsis were 13 days (range, 1-133 days), 72%, and $122,333, respectively. Among in-hospital deaths due to sepsis, mortality was 30% in AML patients compared to 21% in non-AML patients. CONCLUSION: Patients with AML had a higher sepsis incidence and higher mortality rates overall, especially in relation to stem-cell transplant recipients and those with other types of cancer. Clinical trials are needed to determine whether early intervention or treatment in specialized centers could improve outcomes and reduce costs of care, particularly in the management of serious complications such as sepsis. PMID- 28844404 TI - Uncomplicated. PMID- 28844405 TI - Genetic and epigenetic risks of assisted reproduction. AB - Assisted reproductive technology (ART) is used primarily for infertility treatments to achieve pregnancy and involves procedures such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and cryopreservation. Moreover, preimplantation genetic diagnosis (PGD) of ART is used in couples for genetic reasons. In ART treatments, gametes and zygotes are exposed to a series of non-physiological processes and culture media. Although the majority of children born with this treatment are healthy, some concerns remain regarding the safety of this technology. Animal studies and follow-up studies of ART-borne children suggested that ART was associated with an increased incidence of genetic, physical, or developmental abnormalities, although there are also observations that contradict these findings. As IVF, ICSI, frozen-thawed embryo transfer, and PGD manipulate gametes and embryo at a time that is important for reprogramming, they may affect epigenetic stability, leading to gamete/embryo origins of adult diseases. In fact, ART offspring have been reported to have an increased risk of gamete/embryo origins of adult diseases, such as early-onset diabetes, cardiovascular disease, and so on. In this review, we will discuss evidence related to genetic, especially epigenetic, risks of assisted reproduction. PMID- 28844406 TI - Patients' values and preferences and communication about life expectancy: Combining honesty and hope. PMID- 28844407 TI - Novel hemagglutinin nanoparticle influenza vaccine with Matrix-MTM adjuvant induces hemagglutination inhibition, neutralizing, and protective responses in ferrets against homologous and drifted A(H3N2) subtypes. AB - Influenza viruses frequently acquire mutations undergoing antigenic drift necessitating annual evaluation of vaccine strains. Highly conserved epitopes have been identified in the hemagglutinin (HA) head and stem regions, however, current influenza vaccines induce only limited responses to these conserved sites. Here, we describe a novel seasonal recombinant HA nanoparticle influenza vaccine (NIV) formulated with a saponin-based adjuvant, Matrix-MTM. NIV induced hemagglutination inhibition (HAI) and microneutralizing (MN) antibodies against a broad range of influenza A(H3N2) subtypes. In a comparison of NIV against standard-dose and high-dose inactivated influenza vaccines (IIV and IIV-HD, respectively) in ferrets NIV elicited HAI and MN responses exceeding those induced by IIV-HD against homologous A(H3N2) by 7 fold, A(H1N1) by 26 fold, and B strain viruses by 2 fold. NIV also induced MN responses against all historic A/H3N2 strains tested, spanning more than a decade of viral evolution from the 2000-2017 influenza seasons whereas IIV and IIV-HD induced HAI and MN responses were largely directed against the homologous A(H3N2), A(H1N1), and B virus strains. NIV induced superior protection compared to IIV and IIV-HD in ferrets challenged with a homologous or 10-year drifted influenza A(H3N2) strain. HAI positive and HAI negative neutralizing monoclonal antibodies derived from mice immunized with NIV were active against homologous and drifted influenza A(H3N2) strains. Taken together these observations suggest that NIV can induce responses to one or more highly conserved HA head and stem epitopes and result in highly neutralizing antibodies against both homologous and drift strains. PMID- 28844408 TI - Genotype distribution of Group A rotavirus from southern India, 2005-2016. AB - Diarrheal disease due to Group A rotaviruses remain a leading cause of mortality and morbidity in the less developed parts of the world. India has started a phased roll out of rotavirus vaccine in the national immunization program. This analysis summarizes the rotavirus genotype strain distribution pre-vaccine introduction in Vellore, India from December 2005 to June 2016. Rotavirus was responsible for 32% of all diarrheal admission to the hospital. G2P[4] was the predominant strain in the initial years and was gradually replaced by G1P[8]. The emergence of G9P[4] replacing G9P[8], and the detection of G12 strains over several years were documented. There was no clear seasonality of disease. These data form the baseline to monitor genotype distribution post-vaccine introduction in Tamil Nadu. PMID- 28844409 TI - Immunotherapy in liver transplantation. PMID- 28844410 TI - Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/beta-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial. AB - BACKGROUND: There is currently no anti-fibrotic drug therapy available to treat hepatitis C virus (HCV) cirrhosis. The aim of this study was to assess the safety, tolerability, and anti-fibrotic effect of PRI-724, a small-molecule modulator of Wnt signaling, in patients with HCV cirrhosis. METHODS: In this single-center, open-label, phase 1 trial, we sequentially enrolled patients with HCV cirrhosis who were classified as Child-Pugh (CP) class A or B. PRI-724 was administered as a continuous intravenous infusion of 10, 40, or 160mg/m2/day for six cycles of 1week on and 1week off. The primary endpoints were frequency and severity of adverse events. The secondary endpoint was efficacy of PRI-724 in treating cirrhosis based on CP score and liver biopsy. This study is registered with ClinicalTrials.gov (no. NCT02195440). FINDINGS: Between Sept 3, 2014 and May 2, 2016, 14 patients were enrolled: CP class A:B, 6:8; median age, 62 (range: 43 to 74) years; male:female, 10:4. Twelve of the 14 patients completed six cycles of treatment; one was withdrawn from the study due to possible study drug-related liver injury (grade 3) in the 160mg/m2/day dose cohort and one withdrew for personal reasons. Serious adverse events occurred in three patients [21% (3/14)], one of which was possibly related to PRI-724. The most common adverse events were nausea [29% (4/14)] and fatigue [21% (3/14)]. After PRI-724 administration, the CP scores worsened by 1 point in two patients in the 10mg/m2/day cohort, improved in three patients at 1, 1, and 2 points in the 40mg/m2/day cohort, and improved in one patient by 3 points in the 160mg/m2/day cohort. The histology activity index scores of the liver tissue improved in two patients and exacerbated in two patients in the 10mg/m2/day cohort, and improved in one patient in the 40mg/m2/day cohort. INTERPRETATION: This study showed that administration of 10 or 40mg/m2/day intravenous PRI-724 over 12weeks was well-tolerated by patients with HCV cirrhosis; however, liver injury as a possible related serious adverse event was observed in the 160mg/m2/day cohort. FUNDING SOURCE: AMED. PMID- 28844411 TI - Chlamydia Anti-apoptosis - A By-product of Metabolic Reprogramming? PMID- 28844412 TI - Fetal Hemoglobin is Associated with Peripheral Oxygen Saturation in Sickle Cell Disease in Tanzania. AB - Fetal hemoglobin (HbF) and peripheral hemoglobin oxygen saturation (SpO2) both predict clinical severity in sickle cell disease (SCD), while reticulocytosis is associated with vasculopathy, but there are few data on mechanisms. HbF, SpO2 and routine clinical and laboratory measures were available in a Tanzanian cohort of 1175 SCD individuals aged>=5years and the association with SpO2 (as response variable transformed to a Poisson distribution) was assessed by negative binomial model with age and sex as covariates. Increase in HbF was associated with increased SpO2 (rate ratio, RR=1.19; 95% confidence intervals [CI] 1.04, 1.37 per natural log unit of HbF; p=0.0004). In univariable analysis, SpO2 was inversely associated with age, reticulocyte count, and log (total bilirubin) and directly with pulse, SBP, hemoglobin, and log(HbF). In multivariable regression log(HbF) (RR 1.191; 95%CI 1.04, 1.37; p=0.013), pulse (RR 1.01; 95%CI 1.00, 1.01; p=0.026), SBP (RR 1.008; 95%CI 1.00, 1.02; p=0.014), and hemoglobin (1.120; 95%CI 1.05, 1.19; p=0.001) were positively and independently associated with SpO2 while reticulocyte count (RR 0.985; 95%CI 0.97, 0.99; p=0.019) was independently inversely associated with SpO2. In SCD, improving SpO2, in part through cardiovascular compensation and associated with reduced reticulocytosis, may be a mechanism by which HbF reduces disease severity. PMID- 28844413 TI - Analysis and management of implant-prosthetic complications: Description of a diagnostic and therapeutic algorithm with a clinical case. AB - PATIENT: A 65-year-old non-smoker man with stabilized chronic periodontitis and in good general health conditions presented to our observation. The patient reported crown mobility, gingival inflammation and localized pain, corresponding to the mandibular right first molar rehabilitated with a cement-retained implant crown. This clinical situation suspected a fracture of an implant-prosthetic component. Through the described diagnostic algorithm, an abutment hexagon fracture was revealed. Thus, a minimally invasive treatment was carried out in order to use the residual implant-prosthetic components for a new implant prosthetic rehabilitation. DISCUSSION: Fractures of implant-prosthetic components are clinical occurrences that may result in irreversible failures. The main causes of a possible fracture are dependent on biomechanical considerations and production processes of implant-prosthetic components. The respect of the rigorous planning and the employment of the implant-prosthetic devices of the same manufacturer are recommended. CONCLUSIONS: Specific employments and protocols have to be offered in order to manage the fractures of implant prosthetic components. This work showed that through the described diagnostic and therapeutic algorithm, the clinician can be guided towards a proper diagnosis and a correct management of the cases where a fracture of implant-prosthetic components may occur. PMID- 28844414 TI - Childhood community-acquired pneumonia: A review of etiology- and antimicrobial treatment studies. AB - Community acquired pneumonia (CAP) is a leading cause of childhood morbidity worldwide. Because of the rising antimicrobial resistance rates and adverse effects of childhood antibiotic use on the developing microbiome, rational prescribing of antibiotics for CAP is important. This review summarizes and critically reflects on the available evidence for the epidemiology, etiology and antimicrobial management of childhood CAP. Larger prospective studies on antimicrobial management derive mostly from low- or middle-income countries as they have the highest burden of CAP. Optimal antimicrobial management depends on the etiology, age, local vaccination policies and resistance patterns. As long as non-rapid surrogate markers are used to distinguish viral- from bacterial pneumonia, the management is probably suboptimal. For a young child with signs of non-severe pneumonia (with or without wheezing), watchful waiting is recommended because of probable viral etiology. For children with more severe CAP with fever, a five-day oral amoxicillin course would be the first choice therapy and dosage will depend on local resistance rates. There is no clear evidence yet for superiority of a macrolide-based regimen for all ages. For cases with CAP requiring hospitalization, several studies have shown that narrow-spectrum IV beta-lactam therapy is as effective as a broad-spectrum cephalosporin therapy. For most severe disease, broad-spectrum therapy with or without a macrolide is suggested. In case of empyema, rapid IV-to-oral switch seems to be equivalent to prolonged IV treatment. PMID- 28844415 TI - Novel curved surface preparation technique for knee resurfacing. AB - Conventional tools are incapable of preparing the curved articular surface geometry required during cartilage repair procedures. A novel curved surface preparation technique was proposed and tested to provide an accurate low-cost solution. Three shapes of samples, with flat, 30 mm radius and 60 mm radius surfaces, were manufactured from foam bone substitute for testing. Registering guides and cutting guides were designed and 3-D printed to fit onto the foam samples. A rotational cutting tool with an adapter was used to prepare the surfaces following the guidance slots in the cutting guides. The accuracies of the positions and shapes of the prepared cavities were measured using a digital calliper, and the surface depth accuracy was measured using a 3-D scanner. The mean shape and position errors were both approximately +/- 0.5 mm and the mean surface depth error ranged from 0 to 0.3 mm, range - 0.3 to + 0.45 mm 95% CI. This study showed that the technique was able to prepare a curved surface accurately; with some modification it can be used to prepare the knee surface for cartilage repair. PMID- 28844416 TI - [Relationship between cost systems and hospital expenditure]. AB - OBJECTIVE: To analyze the relationship between the degree of development of hospital cost systems (CS) implemented by the regional health services (RHS) and the variation in unit cost of hospitals in Spanish National Health Service (NHS) between 2010 and 2013 and to identify other explanatory factors of this variation. METHODS: A database of NHS hospitals was constructed from exclusively public sources. Using a multilevel regression model, explaining factors of the variation in unit cost (cost per weighted unit of activity [WAU]) of a sample of 170 hospitals were analyzed. RESULTS: The variables representative of the degree of development of CS are associated in a negative and significant way with the variation of the cost per WAU. It is observed that if a high-level development CS is used the cost variation per WAU would be reduced by close to 3.2%. There is also a negative and significant relationship between the variation in the cost per WAU and the variations in the percentage of high technology and the hospital occupancy rate. On the other hand, the variations in the average cost of personnel and in the number of workers per 100 beds are associated in a positive and significant way with the variation of the cost per WAU. CONCLUSION: In the period analysed, during which the main health expenditure adjustment was made, the control in hospital unit cost is associated not only with spending cuts but also with aspects related to their management, such as the implementation of more developed CS. PMID- 28844417 TI - Downwards Vertical Attention Bias in Conversion Disorder vs Controls: A Pilot Study. AB - BACKGROUND: Conversion disorder (CD) is a largely enigmatic disorder, one that requires a thorough ruling-out process. Prior research suggests that metaphors and conceptualization are rooted in physical experience, and that we interpret our affective world through metaphors. Spatial metaphors (interaction of affect and vertical space) are a prominent example of the grounding of metaphors. This is a relatively unpaved direction of research of CD. OBJECTIVES: The present pilot study sought to explore this view by investigating the "healthy is up, sick is down" spatial metaphors (e.g., "fell ill" and "top shape") in patients with CD, examining the correlation between the processing of bodily-related words, CD, and vertical space. We hypothesized that patients with CD, who experience their bodies as ill, will demonstrate a downwards bias when processing bodily-related words; corresponding to the "healthy is up, sick is down" spatial metaphor. METHODS: A total of 8 female patients (ages M-38.13 SD-10.44) and 42 female controls (ages M-36.4 SD-14.57) performed a visual attention task. Participants were asked to identify a spatial probe at the top or the bottom of a screen, following either a bodily related (e.g., arm) or non-bodily related (e.g., clock) prime word. RESULTS: As predicted, when processing bodily-related words, patients with CD demonstrated a downwards attention bias. Moreover, the higher the patient's level of somatization, the faster the patient detected lower (vs upper) spatial targets. CONCLUSIONS: This study suggests that the changed health paradigm of patients with CD is grounded in sensorimotor perception. Further research could propose new diagnostic and treatment options for CD. PMID- 28844418 TI - Early results of Latitude primary total elbow replacement with a minimum follow up of 2 years. AB - BACKGROUND: The aim of this study was to present outcomes of primary Latitude total elbow replacement (TER) with a minimum follow-up of 2 years. METHODS: A retrospective cohort study was undertaken with prospective outcome data collection for the latest outcome. Included were 63 consecutive primary Latitude TERs in 58 patients performed during a period of 5 years at a specialist orthopedic hospital. RESULTS: The mean age of the patients was 62 years (33-85 years). Five primary TERs (4 patients) were lost to follow-up. The primary diagnosis was rheumatoid arthritis in 49, osteoarthritis in 8, and trauma in 6 elbows. The mean flexion-extension arc was 75 degrees preoperatively and 97 degrees postoperatively. Mean postoperative Elbex pain score was 19/100, and function score was 37/100. Mean postoperative scores were 42/100 for the Quick Disabilities of the Arm, Shoulder, and Hand and 38/50 for the elbow-specific American Shoulder and Elbow Surgeons assessment. Four patients died of unrelated causes, and 8 of 63 underwent further surgical intervention, including explantation and conversion from unlinked to linked implant. On radiographic review of 41 surviving TERs, aseptic radiologic loosening was observed of the humeral component in 4 elbows and of the ulnar component in 9. Seven elbows had no radial component, and of the remaining 34 elbows, 16 (47%) had signs of loosening of the radial implant. Complications included 1 heterotopic ossification, 1 olecranon fracture, and 3 further procedures for ulnar nerve entrapment. CONCLUSION: The results indicate that the early outcome of Latitude TER is comparable to that of other prostheses. There is concern about early radiologic loosening of the radial component. PMID- 28844419 TI - Pediatric elbow arthroscopy: indications and safety. AB - BACKGROUND: Elbow arthroscopy is a minimally invasive means by which to treat a variety of acute and chronic elbow conditions. Although the safety and efficacy is well documented in the adult population, comparatively little information is available about the role of elbow arthroscopy in the pediatric population. This study reports the indications for and safety of elbow arthroscopy in a series of pediatric patients. METHODS: A retrospective review was performed from 2001 to 2015 of a surgical database at a single institution. All elbow arthroscopies performed in patients aged 18 years and younger were reviewed. Indications for surgery, perioperative and postoperative complications, further surgical intervention, and descriptive demographic information were recorded. RESULTS: We identified 64 elbow arthroscopic procedures in 59 patients. The average age at the time of surgery was 11.8 years. Indications for the arthroscopic surgery included contracture release (45.3%), closed reduction and fixation for fracture (20.3%), treatment of osteochondritis dissecans (20.3%), diagnostic arthroscopy (7.8%), and debridement (6.3%). The overall complication rate was 17.2%, with a major and minor complication rate of 6.3% and 10.9%, respectively. CONCLUSION: Elbow arthroscopy has applications in the pediatric population with an acceptable safety profile. The techniques and indications continue to evolve. PMID- 28844420 TI - A prospective randomized controlled trial to identify the optimal postoperative pain management in shoulder arthroplasty: liposomal bupivacaine versus continuous interscalene catheter. AB - BACKGROUND: Shoulder arthroplasty is the fastest growing joint replacement surgery in the United States, and optimal postoperative pain management is critical to optimize outcomes for these surgeries. Liposomal bupivacaine (LB) has gained popularity for its potential to provide extended postoperative pain relief with possibly fewer side effects. The goal of this study was to assess the impact of LB compared with continuous interscalene nerve block (CISB) in terms of postoperative pain control, outpatient pain scores, and patient-reported and functional outcomes after shoulder arthroplasty surgery. METHODS: A prospective randomized controlled clinical trial compared consecutive patients undergoing shoulder arthroplasty treated with CISB vs. LB with a single bolus interscalene block. The primary outcome measures included pain assessment up to 24 hours after surgery; in addition, all doses and times of narcotics administered during the inpatient stay were recorded. Patient-reported outcome measures for pain, satisfaction, and functional outcomes were recorded postoperatively. RESULTS: A total of 70 of 74 consecutive patients who underwent shoulder arthroplasty were included in the study. The LB group had equivalent narcotic use, pain scores, and time to first narcotic rescue compared with the CISB group within the first 24 hours (P > .05). The LB group had higher American Shoulder and Elbow Surgeons score and Penn Shoulder Score at final follow-up. There was an increased number of complications and cost for the CISB group. CONCLUSION: This prospective randomized controlled trial demonstrated that LB provides excellent postoperative pain relief for shoulder arthroplasty patients. In addition, LB had fewer complications and lower cost, making it a promising addition to a multimodal pain regimen for shoulder arthroplasty. PMID- 28844422 TI - Dietary supplementation with essence of chicken enhances daily oscillations in plasma glucocorticoid levels and behavioral adaptation to the phase-shifted environmental light-dark cycle in mice. AB - Maintenance of circadian rhythms is essential to many aspects of human health, including metabolism and neurological and psychiatric well-being. Chronic disruption of circadian clock function is implicated in increasing the risk of metabolic syndrome, cardiovascular events and development of cancers. However, there are little approaches to reinforce the function of circadian clock for prevention of these diseases. Essence of Chicken (EC) is a nutritional supplement that is traditionally made by extracting water soluble substances derived from cooking the whole chicken. In this study, we found that dietary supplementation with EC enhanced circadian oscillation of glucocorticoid secretion in mice, and this was accompanied by enhancement of circadian oscillation in the adrenal expression of steroidogenic acute regulatory (StAR) protein that mediates the rate-limiting step of glucocorticoid synthesis. Furthermore, EC facilitated re entrainment of behavioral rhythm in mice when phase of the light-dark cycle was suddenly advanced. These results suggest that intake of EC has enhancement effect on circadian clock function in mice, which may contribute to sustain health and also offer new preventive strategies against circadian-related diseases. PMID- 28844421 TI - Adolescent clavicle nonunions: potential risk factors and surgical management. AB - BACKGROUND: Clavicle nonunions in adolescent patients are exceedingly rare. The purpose of this study was to evaluate a series of clavicle nonunions from a pediatric multicenter study group to assess potential risk factors and treatment outcomes. METHODS: A retrospective review of all clavicle nonunions in patients younger than 19 years was performed at 9 pediatric hospitals between 2006 and 2016. Demographic and surgical data were documented. Radiographs were evaluated for initial fracture classification, displacement, shortening, angulation, and nonunion type. Clinical outcomes were evaluated, including rate of healing, time to union, return to sports, and complications. Risk factors for nonunion were assessed by comparing the study cohort with a separate cohort of age-matched patients with a diaphyseal clavicle fracture. RESULTS: There were 25 nonunions (mean age, 14.5 years; range, 10.0-18.9 years) identified, all of which underwent surgical fixation. Most fractures were completely displaced (68%) initially, but 21% were partially displaced and 11% were nondisplaced. Bone grafting was performed in 24 of 25 cases, typically using the hypertrophic callus. Radiographic healing was achieved in 96% of cases. One patient (4%) required 2 additional procedures to achieve union. The primary risk factor for development of a nonunion was a previous history of an ipsilateral clavicle fracture. CONCLUSIONS: Clavicle nonunions can occur in the adolescent population but are an uncommon clinical entity. The majority occur in male patients with displaced fractures, many of whom have sustained previous fractures of the same clavicle. High rates of union were achieved with plate fixation and the use of bone graft. PMID- 28844423 TI - Dosing-time-dependent effect of rivaroxaban on coagulation activity in rats. AB - The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X (FX), might be influenced by its dosing time because the activity of the coagulofibrinolytic system exhibits daily rhythmicity. In rats, FX activity follows a 24-h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase. Consistent with these findings, a single dose of rivaroxaban had a stronger inhibitory effect on FX activity after dosing at the beginning of the light phase than after dosing at the beginning of the dark phase. A similar chronopharmacological effect was seen in a quantitative model of venous stasis thrombosis. In comparison, the dosing time had minimal influence on the pharmacokinetics of rivaroxaban. These data indicate that the anticoagulant effect of rivaroxaban is influenced by the dosing time. Further studies should confirm this finding in a clinical setting. PMID- 28844424 TI - Analysis of proarrhythmic potential of an atypical antipsychotic drug paliperidone in the halothane-anesthetized dogs. AB - Fatal cases with the use of atypical antipsychotic drug paliperidone have been reported; however, there was no clinical report describing paliperidone-induced torsade de pointes. In this study we assessed its electropharmacological effects together with its proarrhythmic potential in intravenous doses of 0.03, 0.3 and 3 mg/kg using the halothane-anesthetized dogs (n = 5), which could provide approximately 2, 20 and 200 times higher peak plasma drug concentrations than its therapeutic level, respectively. Paliperidone exerted potent vasodilator effect resulting in hypotension, which may be largely explained by its alpha1 adrenoceptor blocking action. In vivo electrophysiological results suggest that paliperidone may inhibit human ether-a-go-go-related gene K+ channel in a dose related manner and modestly suppress Na+ channel in the in situ heart. The high dose of paliperidone may have some potential to induce early afterdepolarization that can trigger lethal ventricular arrhythmias, whereas the low and middle doses lack such proarrhythmic possibility, indicating that at least 20 times higher plasma concentration may be considered to be safe. PMID- 28844425 TI - Amygdala activation as a marker for selective attention toward neutral faces in a chronic traumatic brain injury population. AB - There has been great interest in characterizing the response of the amygdala to emotional faces, especially in the context of social cognition. Although amygdala activation is most often associated with fearful or angry stimuli, there is considerable evidence that the response of the amygdala to neutral faces is both robust and reliable. This characteristic of amygdala function is of particular interest in the context of assessing populations with executive function deficits, such as traumatic brain injuries, which can be evaluated using fMRI attention modulation tasks that evaluate prefrontal control over representations, notably faces. The current study tested the hypothesis that the amygdala may serve as a marker of selective attention to neutral faces. Using fMRI, we gathered data within a chronic traumatic brain injury population. Blood Oxygenation Level Dependent (BOLD) signal change within the left and right amygdalae and fusiform face areas was measured while participants viewed neutral faces and scenes, under conditions requiring participants to (1) categorize pictures of faces and scenes, (2) selectively attend to either faces or scenes, or (3) attend to both faces and scenes. Findings revealed that the amygdala is an effective marker for selective attention to neutral faces and, furthermore, it was more face-specific than the fusiform face area. PMID- 28844426 TI - [The REDSIAM network]. AB - The French national health database (SNIIRAM) proved to be very useful for epidemiology, health economics, evaluation, surveillance or public health. However, it is a complex database requiring important resources and expertise for being used. The REDSIAM network has been set up for promoting the collaboration of teams working on the Sniiram. The main aim of REDSIAM is to develop and validate methods for analyzing the Sniiram database for research, surveillance, evaluation and public health purposes by sharing the knowledge and experience of specialized teams in the fields of diseases identification from the Sniiram data. The work conducted within the network is devoted to the development and the validation of algorithms using Sniiram data for identifying specific diseases. The REDSIAM governance includes the Steering Committee composed of the main organizations in charge of producing and using the Sniiram data, the Bureau and the Technical Committee. The network is organized in thematic working groups focused on specific pathological domains, and a charter defines the rules for participation in the network, the functioning of the thematic working groups, the rules for publishing and making available algorithms. The articles in this special issue of the journal present the first results of some of the thematic working groups. PMID- 28844427 TI - Diagnosing Myocarditis in the Absence of Leukocyte Infiltration: A Complementary Approach. PMID- 28844429 TI - Incorporating the Patient into Urologic Cancer Research. AB - Patient engagement in research has been increasingly prioritized by funders and adopted by health researchers. In this Seminars issue, we explore several different mechanisms of engagement in the reciprocal relationship between patients and researchers. This includes the generation of understandable patient health information, how patients engage in treatment decision-making for urologic cancers, patient involvement in the development of research ideas and research design, and patient engagement in their personalized survivorship care. PMID- 28844428 TI - A Case of Cardiogenic Shock Secondary to Complement-Mediated Myopericarditis From Influenza B Infection. AB - Influenza B is a rare cause of myocarditis that is usually caused by histiocytic and mononuclear cellular infiltrates. We describe a 22-year-old female patient presenting with fulminant myopericarditis secondary to influenza B infection that deteriorated to cardiogenic shock. Endomyocardial biopsy results yielded myocardial necrosis through complement-mediated cellular injury without evidence of interstitial infiltrates. The rare cause of this patient's disease, along with the unique pathologic findings, are an important reminder of the diversity of potential findings in myocarditis. PMID- 28844430 TI - Child Maltreatment Screening and Anticipatory Guidance: A Description of Pediatric Nurse Practitioner Practice Behaviors. AB - INTRODUCTION: Given the number of children affected by child maltreatment and the dire consequences that can develop, prompt identification of child maltreatment is crucial. The purpose of this study was to describe pediatric nurse practitioner (PNP) practice behaviors related to screening and providing anticipatory guidance for child maltreatment and its psychosocial risk factors. METHOD: The Risk Assessment Survey was developed for this study by 12 PNPs, all of whom were members of NAPNAP's Child Maltreatment Special Interest Group to ensure face validity; all 12 PNPs were content experts in child maltreatment. The content of the survey was derived from key characteristics from the evidence on child maltreatment. The survey was emailed to the more than 8500 NAPNAP members. RESULTS: Two hundred forty-three PNPs responded to the survey, which represents a response rate of 3%. Approximately half of the participants (n = 121; 51%) stated that they never/rarely ask parents questions about domestic violence, more than one-fourth (n = 71; 30%) reported that they never/rarely ask parents questions about discipline, and half of the responding PNPs (n = 120; 50%) reported that they perform an ano-genital exam at well visits. DISCUSSION: This study demonstrates that a significant number of PNPs do not routinely screen for child maltreatment and psychosocial risk factors. This is especially true in regards to sexual abuse screening and anticipatory guidance. PMID- 28844431 TI - Accounting for group differences in study retention in a randomized trial of specialized treatment for first episode psychosis. AB - BACKGROUND: Schizophrenia is a chronic disabling disorder for which current treatments are only partially effective. While the evaluation of novel interventions is a high priority, loss to follow-up is a major threat to validity. METHODS: Pattern mixture modeling is a statistical technique that incorporates information on patterns of retention that may bias comparisons between randomized treatment groups. This study used pattern mixture mixed model (PMMM) in the analysis of outcomes of a two-year cluster-randomized trial, the Recovery after an Initial Schizophrenia Episode-Early Treatment Program, which compared a coordinated specialty care intervention called NAVIGATE to usual community care (CC). PMM-adjusted outcome differences between NAVIGATE and CC were estimated by the weighted-average of effects across the retention patterns. RESULTS: Compared to the original analysis, PMMM improved model fit and the estimated effectiveness of NAVIGATE as compared to CC. On the Quality of Life Scale NAVIGATE effectiveness increased by 1.50 points (25.4%); on the Positive and Negative Syndrome Scale, by 1.72 points (39.8%), and on the Calgary Depression Scale by 0.49 points (62.1%). PMMM did not improve model fit for employment days, substance use days, or hospital days. CONCLUSION: Use of PMMM improved model fit and increased the estimated differences between NAVIGATE and CC for major outcomes. Patients with differential retention patterns may have different outcome trajectories. PMMM is a useful tool for addressing potential biases arising from these differences. PMID- 28844432 TI - Do trauma-focussed psychological interventions have an effect on psychotic symptoms? A systematic review and meta-analysis. AB - There is growing recognition of the relationship between trauma, posttraumatic stress disorder (PTSD) and psychosis. There may be overlaps in causal mechanisms involved in the development of PTSD and psychosis following traumatic or adverse events. Trauma-focussed treatments found to be effective in treating PTSD may therefore represent a new direction in the psychological treatment of psychosis. This systematic review examined the literature on trauma-focussed treatments conducted with people with schizophrenia spectrum or psychotic disorders to determine effects on psychotic symptoms. Secondary outcomes were symptoms of PTSD, depression and anxiety. Twenty-five studies were included in the review, with 12 being included in the meta-analysis. Trauma-focussed treatments had a small, significant effect (g=0.31, CI [0.55, 0.06]) on positive symptoms immediately post-treatment, but the significance and magnitude of this effect was not maintained at follow-up (g=0.18, CI [0.42, -0.06]). Trauma-focussed treatments also had a small effect on delusions at both post-treatment (g=0.37, CI [0.87, -0.12]) and follow-up (g=0.38, CI [0.67, 0.10]), but this only reached significance at follow-up. Effects on hallucinations and negative symptoms were small and non-significant. Effects on PTSD symptoms were also small (post treatment g=0.21, CI [0.70, -0.27], follow up g=0.31, CI [0.62, 0.00]) and only met significance at follow-up. No significant effects were found on symptoms of depression and anxiety. Results show promising effects of trauma-focussed treatments for the positive symptoms of psychosis, however further studies developing and evaluating trauma-focussed treatments for trauma-related psychotic symptoms are needed. PMID- 28844433 TI - Temporal stability of self-disorders and longitudinal unfolding of symptom dimensions: A complementary analysis. PMID- 28844434 TI - Targeting recovery in first episode psychosis: The importance of neurocognition and premorbid adjustment in a 3-year longitudinal study. AB - INTRODUCTION: Recovery in psychotic disorders remains a major challenge across mental health. Identifying predictors of recovery in first psychotic episodes is a priority in order to increase knowledge on underlying mechanisms of the illness and to obtain objective severity markers at initial phases. In this study we gathered sociodemographic, clinical and cognitive data to explore predictive variables of recovery after three years follow-up in a sample of 399 patients with a first episode of psychosis (FEP). MATERIAL AND METHOD: This is a longitudinal study including patients with a FEP. A dichotomic variable of recovery was created according to symptomatic and functional outcome after 3years follow-up. Significant variables in univariate analysis were entered into a binary logistic regression to obtain a multivariate prediction model of recovery. RESULTS: The predictive model was statistically significant and classified an overall of 76% of patients correctly, specifically 86.7% of patients that would not recover and 55% of the patients that would recover. From all the variables that where significantly different between recovered and not recovered patients, only speed of processing, executive functions and premorbid adjustment were found to be significant predictors of recovery. DISCUSSION: This study provides evidence that the degree of basal impairment in cognitive functions related to the Prefrontal Cortex and a worst premorbid adaptation predict in a significant way which patients are less likely to recover three years after a FEP. PMID- 28844435 TI - Maternal infection and anemia as prenatal predisposing factors for schizophrenia: The link with zinc deficiency. PMID- 28844437 TI - Product quality and microbial dynamics during vermicomposting and maturation of compost from pig manure. AB - This research evaluates, through microbial dynamics, the use of earthworms Eisenia andrei for maturation of pre-composted pig manure in comparison with maturation under static conditions and with vermicomposting of fresh pig manure. Therefore, two substrates were used (fresh and pre-composted pig manure) and four treatments were developed: fresh manure vermicomposting, control of fresh manure without earthworms, pre-composting followed by vermicomposting and static maturation of pre-composted manure. In order to determine the microbial dynamics, the enzymatic activities and profiles of phospholipid fatty acids (PLFAs) were evaluated over a 112-days period. Physicochemical and biological parameters of the obtained products were also analyzed. The presence of earthworms significantly reduced (p<0.05) microbial biomass and all the microbial groups (Gram+bacteria, Gram-bacteria, and fungi) in both substrates. The enzymatic activities (cellulase, beta-glucosidase and acid phosphatase) behaved in a significantly distinctive manner (p<0.05) depending on the treatment. Microbial communities had significant correlations (p<0.05) with hydrolytic activities during static maturation of pre-composted manure. This indicates a direct effect of microbiota evolution on the degradative processes; however, complex earthworm microbiota interactions were established in the presence of E. andrei. After earthworms' removal from vermicompost of fresh substrate at 70day, an increase in Gram + (4.4 times), Gram - (3.8 times) and fungi (2.8 times) were observed and, although the vermicompost achieved quality values, it is necessary to optimize the vermicompost aging phase period to improve the stability. Static maturation presented stability on microbial dynamics that indicated a slow degradation of organic compounds so that, maturation of pre-composted manure through vermicomposting is better option. PMID- 28844436 TI - Psychosis subgroups differ in intrinsic neural activity but not task-specific processing. AB - Individuals with psychosis often show high levels of intrinsic, or nonspecific, neural activity, but attenuated stimulus-specific activity. Clementz et al. (2016) proposed that one subgroup of psychosis cases has accentuated intrinsic activity (Biotype-2's) and a different subgroup (Biotype-1's) has diminished intrinsic activity, with both groups exhibiting varying degrees of cognitive deficits. This model was studied by assessing neural activity in psychosis probands (N=105) during baseline and a 5second period in preparation for a pro /anti-saccade task. Steady-state stimuli allowed real-time assessment of modulation of visuocortical investment to different target locations. Psychosis probands as a whole showed poor antisaccade performance. As expected, Biotype-1 showed diminished intrinsic neural activity and the worst behavior, and Biotype-2 showed accentuated intrinsic activity and less deviant behavior. Both of these groups also exhibited less dynamic oscillatory phase synchrony. Biotype-3 showed no neurophysiological differences from healthy individuals, despite a history of psychosis. Interestingly, all psychosis subgroups showed normal (i.e., not different from healthy) preparatory modulation of visuocortical investment as a function of cognitive demands, despite varying levels of task performance. Similar analyses conducted subgrouping cases by psychotic symptomatology revealed fewer and less consistent differences, including no intrinsic activity differences between any clinical subgroup and healthy individuals. This study illustrates that (i) differences in intrinsic neural activity may be a fundamental characteristic of psychosis and need to be evaluated separately from stimulus-specific responses, and (ii) grouping patients based on multidimensional classification using neurobiological data may have advantages for resolving heterogeneity and clarifying illness mechanisms relative to traditional psychiatric diagnoses. PMID- 28844438 TI - Air gasification of biogas-derived digestate in a downdraft fixed bed gasifier. AB - Digestate is a byproduct from biomass anaerobic digestion process. Gasification of dried digestate to produce gasesous product might be a promising route. In this work, air gasification of digestate with high ash content was performed in a downdraft fixed bed gasifier at temperature varying from 600 degrees C to 800 degrees C and air equivalence ratio (ER) ranging from 0.25 to 0.30. The ash melting properties were firstly detected by the Intelligent Ash Melting Point Test, and the by-products (biochar and ash) were analyzed. The results showed that no ash slagging was observed and therefore it is feasible to operate digestate gasification under 800 degrees C and ER ranging from 0.25 to 0.30. High temperature favored gas production, 800 degrees C is proposed for digestate gasification in the present study. ER with a medium value improved gas quality and cold gas efficiency (CGE), and the optimal LHV of 4.78MJ/Nm3 and CGE of 67.01% were obtained with ER of 0.28. High ER favored the increase of gas yield and decrease of tar concentration, and the optimal gas yield of 2.15 Nm3/kg and tar concentration of 1.61g/Nm3 were achieved with ER of 0.30. Improved molar ratio of H2/CO varying from 1.03 to 1.08 was obtained at 800 degrees C, indicating gaseous product has the potential for chemical synthesis processes (1

=F2) and cirrhosis (=F4), ElastPQ had better diagnostic accuracy (AUC = 0.929 and 0.834, respectively) than APRI (AUC = 0.656 and 0.618, respectively) (p < 0.05), and was similar to TE (AUC = 0.915 and 0.879, respectively). ElastPQ is a promising ultrasound-based imaging technique for evaluation of liver fibrosis, with a diagnostic accuracy comparable to that of TE. PMID- 28844465 TI - B-Mode Ultrasound Combined with Color Doppler and Strain Elastography in the Diagnosis of Non-mass Breast Lesions: A Prospective Study. AB - Non-mass breast lesions on ultrasound (US) are areas without an associated mass. The purpose of this study was to evaluate whether combining B-mode US with color Doppler US and strain elastography (SE) improves US differentiation between benign and malignant non-mass breast lesions and the decision for biopsy. In this prospective study, three different radiologists analyzed the US images of 77 non mass lesions independently and recorded Breast Imaging Reporting and Data System (BI-RADS) categories for four data sets. The image characteristics and BI-RADS categories of the four data sets were analyzed by another radiologist. The final diagnosis was made on the basis of pathologic findings. Values for area under the receiver operating curve (AUC), sensitivity, specificity and accuracy were compared among the data sets. The AUC of B-mode US combined with both color Doppler US and SE was greater than that of B-mode US alone (0.666 vs. 0.828) (p = 0.011). The specificity of making the decision for biopsy increased from 6.5% to 38.7% when B-mode US was combined with color Doppler and SE, without a statistically significant change in sensitivity (p < 0.001). Combined use of color Doppler and SE could improve the diagnostic value of B-mode US in distinguishing benign from malignant non-mass breast lesions and the specificity of making the decision for biopsy of non-mass breast lesions. PMID- 28844466 TI - Fuzzy mutual information based grouping and new fitness function for PSO in selection of miRNAs in cancer. AB - MicroRNAs (miRNA) are one of the important regulators of cell division and also responsible for cancer development. Among the discovered miRNAs, not all are important for cancer detection. In this regard a fuzzy mutual information (FMI) based grouping and miRNA selection method (FMIGS) is developed to identify the miRNAs responsible for a particular cancer. First, the miRNAs are ranked and divided into several groups. Then the most important group is selected among the generated groups. Both the steps viz., ranking of miRNAs and selection of the most relevant group of miRNAs, are performed using FMI. Here the number of groups is automatically determined by the grouping method. After the selection process, redundant miRNAs are removed from the selected set of miRNAs as per user's necessity. In a part of the investigation we proposed a FMI based particle swarm optimization (PSO) method for selecting relevant miRNAs, where FMI is used as a fitness function to determine the fitness of the particles. The effectiveness of FMIGS and FMI based PSO is tested on five data sets and their efficiency in selecting relevant miRNAs are demonstrated. The superior performance of FMIGS to some existing methods are established and the biological significance of the selected miRNAs is observed by the findings of the biological investigation and publicly available pathway analysis tools. The source code related to our investigation is available at http://www.jayanta.droppages.com/FMIGS.html. PMID- 28844468 TI - Discussion. PMID- 28844467 TI - Patient selection and perioperative outcomes of bypass and endovascular intervention as first revascularization strategy for infrainguinal arterial disease. AB - OBJECTIVE: The optimal initial revascularization strategy remains uncertain for patients with peripheral arterial disease. The purpose of this study was to evaluate current nationwide selection and perioperative outcomes of patients undergoing bypass or endovascular intervention for infrainguinal disease in those with no prior ipsilateral revascularization. METHODS: Patients undergoing nonemergent first-time infrainguinal revascularization were identified in the Targeted Vascular module of the National Surgical Quality Improvement Program (NSQIP) for 2011 to 2014 and stratified by symptom status (chronic limb threatening ischemia [CLTI] or claudication). Patients treated with endovascular intervention were compared with those who underwent bypass. Multivariable logistic regression was used to evaluate current selection of patients and to establish independent associations between first-time procedures and postoperative outcomes. RESULTS: Of 5998 first-time infrainguinal revascularizations performed, 3193 were bypass procedures (63% for CLTI) and 2805 were endovascular interventions (64% for CLTI). Current patient characteristics associated with an endovascular-first approach as opposed to bypass-first in CLTI patients were age >=80 years, tissue loss, nonsmoking, functional dependence, diabetes, dialysis, and tibial lesions, whereas age >=80 years, nonwhite race, nonsmoking, diabetes, and tibial lesions were associated with an endovascular approach for claudication. In comparing first-time endovascular intervention with bypass, there was no difference in 30-day mortality in CLTI patients (univariate: 2.1% vs 2.2%; adjusted: odds ratio [OR], 0.7; 95% confidence interval [CI], 0.4 1.1) or claudication patients (0.3% vs 0.6%). Among CLTI patients, endovascular first intervention was associated with lower rates of major adverse cardiovascular event (3.6% vs 4.7%; OR, 0.6; 95% CI, 0.4-0.9), surgical site infection (0.9% vs 7.7%; OR, 0.1; 95% CI, 0.1-0.2), bleeding (8.5% vs 17%; OR, 0.4; 95% CI, 0.3-0.5), unplanned reoperation (13% vs 17%; OR, 0.7; 95% CI, 0.5 0.8), and unplanned readmission (17% vs 18%; OR, 0.8; 95% CI, 0.7-0.9). Patients with claudication undergoing endovascular-first intervention also had lower rates of major adverse cardiovascular event (0.8% vs 1.6%; OR, 0.4; 95% CI, 0.2-0.95), surgical site infection (0.7% vs 6.6%; OR, 0.1; 95% CI, 0.04-0.2), bleeding (2.3% vs 6.0%; OR, 0.3; 95% CI, 0.2-0.5), unplanned reoperation (4.3% vs 6.6%; OR, 0.6; 95% CI, 0.4-0.9), and unplanned readmission (5.9% vs 9.0%; OR, 0.6; 95% CI, 0.4 0.8). Conversely, endovascular-first intervention was associated with a higher rate of secondary revascularizations within 30 days for CLTI (4.3% vs 3.1%; OR, 1.6; 95% CI, 1.04-2.3) but not for claudication (2.6% vs 1.9%; OR, 1.7; 95% CI, 0.9-3.4). CONCLUSIONS: An endovascular-first approach as a revascularization strategy for infrainguinal disease was associated with substantially lower early morbidity but not mortality, at the cost of higher rates of postoperative secondary revascularizations. As a national representation of first-time revascularizations, this study highlights the early endovascular perioperative benefit, although more robust long-term data are needed to adopt either one strategy or the other in select patients with peripheral arterial disease. PMID- 28844469 TI - A systematic review of primary endovascular repair of the ascending aorta. AB - OBJECTIVE: Endovascular repair of the ascending aorta is currently limited to patients at high surgical risk with aortic diseases originating above the sinotubular junction. A number of different endovascular technologies and approaches have been used, although no consensus exists regarding a standardized technique. To better understand real-world endovascular approaches to the ascending aorta, we performed a comprehensive review of the types of endovascular aortic stents and associated vascular access used in repair of the ascending aorta. METHODS: A search of the MEDLINE database was conducted from January 1, 1995, through January 31, 2017, with the search term "ascending aortic stent." Studies involving endovascular stenting in which the primary therapy was confined exclusively to the ascending aorta were included. Studies involving hybrid arch procedures and surgical replacement of the ascending aorta associated with aortic stenting were excluded. The type of aortic stent, underlying aortic disease, and surgical approach were recorded along with outcomes, need for reinterventions, and follow-up. RESULTS: A total of 46 publications that focused on primary endovascular repair of the ascending aorta were identified. Thirteen different aortic stent grafts of various designs were used in 118 total patients. The most commonly used device types were thoracic stents (n = 84 [71.2%]) along with abdominal cuffs (n = 13 [11%]) and custom-made grafts (n = 12 [10.2%]). The most commonly treated aortic disease was type A aortic dissection (n = 59 [50%]), followed by aortic pseudoaneurysm (n = 35 [29.7%]), aortic aneurysm (n = 6 [5.1%]), penetrating atherosclerotic ulcer (n = 5 [4.2%]), and acute aortic rupture (n = 3 [2.5%]). Femoral arterial access was used in 62.7% of patients (n = 74); transapical (n = 17 [14.4%]), carotid (n = 15 [12.7%]), and axillary (n = 8 [6.8%]) approaches were also used. The overall type I endoleak rate was 18.6% (n = 22), with 11 patients (9.3%) requiring reintervention. Other complications included all-cause mortality (n = 18 [15.2%]), conversions to open surgery (n = 4 [3.4%]), and cerebrovascular complications (n = 4 [3.4%]). Aorta-related mortality was 5% (n = 6), and average follow-up was 17.2 months. CONCLUSIONS: Despite the absence of a dedicated aortic stent graft for the ascending aorta, patients with a range of ascending aortic diseases are being successfully treated by endovascular technologies. For optimal outcomes, patient selection is critical to align aortic anatomy with the limited device sizing options, and it should be reserved for patients at high surgical risk. PMID- 28844470 TI - High hemoglobin A1c associated with increased adverse limb events in peripheral arterial disease patients undergoing revascularization. AB - OBJECTIVE: Diabetes and peripheral arterial disease (PAD) are independently associated with increased risk of amputation. However, the effect of poor glycemic control on adverse limb events has not been studied. We examined the effects of poor glycemic control (high hemoglobin A1c level) on the risk of amputation and modified major adverse limb events (mMALEs) after lower extremity revascularization. METHODS: Patients undergoing PAD revascularization who had hemoglobin A1c (HbA1c) levels available within 6 months were identified in the Veterans Affairs database of 2003 to 2014 (N = 26,799). The diagnosis of preoperative diabetes mellitus (PreopDM) was defined using diabetes diagnosis codes and evidence of treatment. Amputation and mMALE risk was compared for HbA1c levels using Kaplan-Meier analysis. Cox proportional hazards models were created to assess the effect of high HbA1c levels on amputation and mMALE (adjusted for age, gender, race, socioeconomic status, comorbidities, cholesterol levels, creatinine concentration, suprainguinal or infrainguinal procedure, open or endovascular procedure, severity of PAD, year of cohort entry, and medications) for all patients and stratified by PreopDM. RESULTS: High HbA1c levels were present in 33.2% of the cohort, whereas 59.9% had PreopDM. Amputations occurred in 4359 (16.3%) patients, and 10,580 (39.5%) had mMALE. Kaplan-Meier curves showed the worst outcomes in patient with PreopDM and high HbA1c levels. In the Cox model, incremental HbA1c levels of 6.1% to 7.0%, 7.1% to 8.0%, and >8% were associated with 26% (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.15 1.39), 53% (HR, 1.53; 95% CI, 1.37-1.7), and 105% (HR, 2.05; 95% CI, 1.87-2.26) higher risk of amputation, respectively. Similarly, the risk of mMALE also increased by 5% (HR, 1.05; 95% CI, 0.99-1.11), 21% (HR, 1.21; 95% CI, 1.13-1.29), and 33% (HR, 1.33, 95% CI, 1.25-1.42) with worsening HbA1c levels of 6.1% to 7.0%, 7.1% to 8.0%, and >8%, respectively (vs HbA1c <=6.0%). In stratified analysis by established PreopDM, the relative risk of amputation or mMALE was much higher with poor glycemic control (HbA1c >7.0%) in patients without PreopDM. CONCLUSIONS: PAD patients with worse perioperative glycemic control have a significantly higher risk of amputation and mMALE. Incremental increases in HbA1c levels are associated with higher hazards of adverse limb outcomes independent of PreopDM status. Poor glycemic control (HbA1c >7.0%) in patients without a PreopDM diagnosis carries twice the relative risk of amputation and mMALE than in those with good glycemic control. These results suggest that screening of diabetic status and better management of glycemic control could be a target for improvement of perioperative and long-term outcomes in PAD patients. PMID- 28844471 TI - Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes. AB - The immunological mechanism(s) of action whereby teplizumab preserves C-peptide levels in the progression of patients with recent onset type 1 diabetes (T1D) is still not well understood. In the present study, we evaluated the kinetics of T cell modulation in peripheral blood following two 14-day courses of teplizumab therapy one year apart in recent onset T1D participants in the AbATE clinical trial. Transient rises in PD-1+Foxp3+ Treg and potentially anergic (CD57-KLRG1-PD 1+) cells in the circulating CD4 T cell compartment were paralleled by more profound increases in circulating CD8 T cells with traits of exhaustion (CD57 KLRG1+PD-1+, TIGIT+KLRG1+, and persistent down-modulation of CD127). The observed phenotypic changes across cell types were associated with favorable response to treatment in the subgroup of study participants that did not develop anti-drug antibodies after the first course of therapy. These findings provide new insights on the duration and complexity of T cell modulation with teplizumab therapy in recent onset T1D, and in addition, suggest that coordinated immune mechanisms of tolerance that favor CD4 Treg function and restrain CD4 non-Treg and CD8 T cell activation may contribute to treatment success. PMID- 28844472 TI - Epithelial Monolayers Coalesce on a Viscoelastic Substrate through Redistribution of Vinculin. AB - The mechanical properties of the microenvironment play a large role in influencing cellular behavior. In particular, the tradeoff between substrate viscosity and elasticity on collective cell migration by adherent cells is highly physiologically relevant, but remains poorly understood. To investigate the specific effects of viscous substrates, we plated epithelial monolayers onto polydimethylsiloxane substrata with a range of viscosities and elasticities. We found that on viscoelastic substrates the monolayers underwent rapid and coordinated movement to generate cell-free areas. To understand the molecular mechanism of this coordinated movement, we imaged various structural and signaling proteins at cell-cell and cell-matrix junctions. Through quantitative image analysis of monolayer disruption and subcellular protein redistribution, we show that the mechanosensor protein, vinculin, is necessary and sufficient for this viscous response, during which it is lost from focal adhesions and recruited by the cadherin complex to intercellular junctions. In addition, the viscous response is dependent upon and enhanced by actomyosin contractility. Our results implicate vinculin translocation in a molecular switching mechanism that senses substrate viscoelasticity and associates with actomyosin contractility. PMID- 28844474 TI - Clinical performance assessment tools in physiotherapy practice education: a systematic review. AB - BACKGROUND: Clinical performance assessment tools (CPATs) used in physiotherapy practice education need to be psychometrically sound and appropriate for use in all clinical settings in order to provide an accurate reflection of a student's readiness for clinical practice. Current evidence to support the use of existing assessment tools is inconsistent. OBJECTIVES: To conduct a systematic review synthesising evidence relating to the psychometric and edumetric properties of CPATS used in physiotherapy practice education. DATA SOURCES: An electronic search of Web of Science, SCOPUS, Academic Search Complete, AMED, Biomedical Reference Collection, British Education Index, CINAHL plus, Education Full Text, ERIC, General Science Full Text, Google Scholar, MEDLINE, UK and Ireland Reference Centre databases was conducted identifying English language papers published in this subject area from 1985 to 2015. STUDY SELECTION: 20 papers were identified representing 14 assessment tools. DATA EXTRACTION AND SYNTHESIS: Two reviewers evaluated selected papers using a validated framework (Swing et al., 2009). RESULTS: Evidence of psychometric testing was inconsistent and varied in quality. Reporting of edumetric properties was unpredictable in spite of its importance in busy clinical environments. No Class 1 recommendation was made for any of the CPATs, and no CPAT scored higher than Level C evidence. CONCLUSIONS: Findings demonstrate poor reporting of psychometric and edumetric properties of CPATs reviewed. A more robust approach is required when designing CPATs. Collaborative endeavour within the physiotherapy profession and interprofessionally may be key to further developments in this area and may help strengthen the rigour of such assessment processes. PMID- 28844476 TI - Research misconduct and the INTERGROWTH-21st study. PMID- 28844473 TI - The Challenge of Interpreting Glutamate-Receptor Ion-Channel Structures. AB - Ion channels activated by glutamate mediate excitatory synaptic transmission in the central nervous system. Similar to other ligand-gated ion channels, their gating cycle begins with transitions from a ligand-free closed state to glutamate bound active and desensitized states. In an attempt to reveal the molecular mechanisms underlying gating, numerous structures for glutamate receptors have been solved in complexes with agonists, antagonists, allosteric modulators, and auxiliary proteins. The embarrassingly rich library of structures emerging from this work reveals very dynamic molecules with a more complex conformational spectrum than anticipated from functional studies. Unanticipated conformations solved for complexes with competitive antagonists and a lack of understanding of the structural basis for ion channel subconductance states further highlight challenges that have yet to be addressed. PMID- 28844475 TI - Soft tissue plasmacytomas in multiple myeloma. PMID- 28844477 TI - Rigging Innate Immunity against the Flu. PMID- 28844478 TI - [Descriptive and comparative study of cardiovascular risk factors and physical activity in patients with acute coronary syndrome]. AB - AIM: To analyse several cardiovascular risk factors by means of the physical activity performed by patients with acute coronary syndrome (ACS). DESIGN: Cross sectional study. LOCATION: Cardiovascular prevention service (Health Department, Valencia, Spain). PARTICIPANTS: The study included 401 individuals with acute coronary syndrome and discharged from hospital 2-3months before the assessment. The inclusion criteria included age between 30 and 80years-old, no contraindication for physical activity, and no previous participation in cardiac rehabilitation programmes. MAIN MEASUREMENTS: Metabolic equivalent MET (Kcal/Kg) was calculated, based on the type of activity, frequency, duration and intensity. Participants were divided into two groups: sedentary group (<10METs/week) and physically active group (>=10METs/week). Several variables associated with cardiovascular risk factors were assessed: body mass index (BMI), waist circumference, lipid profile, blood glucose, and arterial pressure. RESULTS: The mean consumption was 8.24+/-12.5METs/week. Prevalent factors were overweight (77.05%), and dyslipidaemia (64.3%), whilst 64.8% were sedentary. The physically active group showed differences when compared to sedentary group in triglycerides (146.53+/-72.8 vs. 166.94+/-104.8mg/dL; 95%CI; P=.031), and BMI (27.65+/-3.86 vs. 28.50+/-4.38kg/m2; 95%CI; P=.045). CONCLUSION: Physical activity was performed by a limited number of patients with ACS, with a prevalence of overweight and dyslipidaemia. Being physically active improved triglycerides levels and BMI. Therefore, health promotion from Primary Care and encouraging physical activity amongst patients with ACS is crucial. PMID- 28844479 TI - [Talking about chronic pain]. PMID- 28844480 TI - [Information on the risk of drugs in pregnancy: New regulation of the Food and Drug Administration]. PMID- 28844481 TI - Tert-butylhydroquinone attenuates oxidative stress and inflammation in hypothalamic paraventricular nucleus in high salt-induced hypertension. AB - Excessive oxidative stress and inflammation in hypothalamic paraventricular nucleus (PVN) are implicated in the pathogenesis of hypertension. It is reported that tert-butylhydroquinone (tBHQ), a nuclear factor erythroid 2-related factor 2(Nrf2)-inducer, has a variety of pharmacological activities such as anti oxidation and anti-inflammatory effect. The objective of this study was to investigate the effects of tBHQ in high salt induced hypertension and to identify whether the beneficial effects were induced by inhibiting PVN oxidative stress and inflammation. Male Sprague-Dawley rats were fed with high salt diet (HS, 8% NaCl) or normal salt diet (NS, 0.3% NaCl). These rats were administration of tBHQ (150mg/kg/d) by oral gavage for 16 weeks. Our results showed that high salt intake resulted in higher mean arterial pressure, cardiac hypertrophy as well as increased plasma level of norepinephrine and interleukin (IL)-1beta, IL-6 compared with NS rats. It increased PVN level of reactive oxygen species, gp91phox, IL-1beta, IL-6, p-IKKbeta and nuclear factor-kappa B (NF-kappaB) activity, decreased PVN level of Nrf2 and Cu/Zn-SOD. Chronic administration of tBHQ significantly attenuated these changes in HS rats. These data suggest that the protective effects of tBHQ in salt induced hypertension are partly due to inhibiting oxidative stress and inflammation in PVN. PMID- 28844482 TI - Impact of selective serotonin reuptake inhibitors on neural crest stem cell formation. AB - The use of antidepressants in pregnant women is rising, with rates up to 7.5% in the United States. Selective serotonin reuptake inhibitors (SSRIs) are currently the most common antidepressant prescribed to pregnant women. The teratogenic effects of SSRI exposure are debated because of discrepancies in epidemiological studies. As an alternative to epidemiological and animal studies, human embryonic stem cell research (hESC) provides a human-based experimental model to examine the risks of prenatal SSRI exposure. Neural crest stem cells (NCSCs) play an important role in craniofacial and cardiac development as precursors to craniofacial bones and heart septa. This study examines the effects of paroxetine (Paxil) and sertraline (Zoloft) exposure on proliferation, migration, and AP 2alpha protein expression of NCSC in vitro. hESCs were exposed to paroxetine and sertraline at three concentrations while undergoing directed differentiation into NCSCs. Our results indicate exposure to paroxetine significantly increased proliferation, migration, and AP-2alpha protein expression in NCSCs. Exposure to sertraline significantly decreased proliferation and significantly increased AP 2alpha protein expression in NCSC. This evidence suggests paroxetine and sertraline alter normal NCSC behavior and may thereby disrupt cardiac and craniofacial development. PMID- 28844483 TI - Serum microRNA-122-3p, microRNA-194-5p and microRNA-5099 are potential toxicological biomarkers for the hepatotoxicity induced by Airpotato yam. AB - Airpotato yam (the rhizome of Dioscorea bulbifera L.) is traditionally used to treat thyroid disease and various cancers in China. However, it was found to cause hepatotoxicity during clinical practice. This study aims to identify candidate serum microRNAs (miRNAs) as diagnostic biomarkers for the liver injury induced by Airpotato yam. The results of serum alanine/aspartate aminotransferase (ALT/AST) showed the remarkable hepatotoxicity induced by ethyl acetate fraction of Airpotato yam (EF) (450mg/kg) and diosbulbin B (DB) (300mg/kg) in mice. The results of miRNAs chip analysis showed that the expression of 28 and 37 serum miRNAs was obviously altered in EF- and DB-treated mice, respectively. Among these miRNAs, miRNA-122-3p, miR-194-3p and miR-5099 have passed the further validation in serum from both EF- and DB-treated mice. Moreover, the expression of miRNA-122-3p and miRNA-194-5p was significantly increased in EF (375mg/kg) treated mice with no significant elevation of serum ALT/AST activity. Only the expression of serum miRNA-5099 was not altered in the liver injury induced by acetaminophen (APAP), monocrotaline (MCT) or toosendanin (TSN). In conclusion, this study demonstrated that miR-122-3p and miRNA-194-5p were two sensitive biomarkers, and miR-5099 might be a specific biomarker for reflecting the liver injury induced by Airpotato yam. PMID- 28844484 TI - TLR2 Arg677Trp but not TLR2 -196 to -174 ins/del and Arg753Gln polymorphism alter the risk of peptic ulcer in north of Iran. AB - BACKGROUND: Most polymorphisms that occur in TLR-2 are associated with gastrointestinal disorders such as peptic ulcer disease (PUD). Hence, in current study, association between TLR2-196 to -174 ins/del, Arg753Gln and Arg677Trp polymorphisms and risk of PUD development in north of Iran was evaluated. METHODS: This case-control study included 50 patients with PUD as cases and 50 people without peptic ulcer as control group. Blood and endoscopic biopsies were collected. Helicobacter pylori infection was screened by rapid urease test, specific IgG measurement and specific PCR for glmM gene. Then, TLR2-196 to -174 ins/del polymorphism was assessed by using allele-specific PCR. The Arg753Gln and Arg677Trp polymorphism in TLR2 gene were analyzed by the PCR-restriction fragment length polymorphism (RFLP). RESULTS: There was no significant difference in the allele and genotype frequencies of polymorphisms in the TLR2-196 to -174 ins/ins and Arg753Gln genes between controls and patients, respectively. However, an association with increased risk for PUD was observed for polymorphism TLR-2 Arg677Trp (odds ratio [OR] = 7.9; 95% confidence interval [CI] = 0.94-67.5). Further analysis showed that H. pylori infection was associated with a significant difference in genotype and allele frequencies of TLR2-196 to -174 ins/ins and Arg753Gln polymorphism, respectively. Furthermore, there was no association between variant haplotypes and PUD development in H. pylori infected subjects. However, no association was detected between gender and genotypic frequencies of all polymorphisms in TLR2. CONCLUSION: Our findings showed that TLR2 Arg677Trp polymorphism and H. pylori infection may play crucial roles in peptic ulcer development respectively in north of Iran. PMID- 28844485 TI - Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-analysis of Noncoding Variation in Metabochip Data. AB - Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies can aid the discovery of disease associated genetic variants, especially those with unknown function and located outside protein-coding regions. Direct incorporation of one functional annotation as weight in existing dispersion and burden tests can suffer substantial loss of power when the functional annotation is not predictive of the risk status of a variant. Here, we have developed unified tests that can utilize multiple functional annotations simultaneously for integrative association analysis with efficient computational techniques. We show that the proposed tests significantly improve power when variant risk status can be predicted by functional annotations. Importantly, when functional annotations are not predictive of risk status, the proposed tests incur only minimal loss of power in relation to existing dispersion and burden tests, and under certain circumstances they can even have improved power by learning a weight that better approximates the underlying disease model in a data-adaptive manner. The tests can be constructed with summary statistics of existing dispersion and burden tests for sequencing data, therefore allowing meta-analysis of multiple studies without sharing individual-level data. We applied the proposed tests to a meta-analysis of noncoding rare variants in Metabochip data on 12,281 individuals from eight studies for lipid traits. By incorporating the Eigen functional score, we detected significant associations between noncoding rare variants in SLC22A3 and low-density lipoprotein and total cholesterol, associations that are missed by standard dispersion and burden tests. PMID- 28844486 TI - Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping. AB - During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics (NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA, techniques currently unavailable for routine clinical practice. Here, we present monogenic NIPD (MG-NIPD), which requires a blood sample from both parents, for targeted locus amplification (TLA)-based phasing of heterozygous variants selectively at a gene of interest. Capture probes-based targeted sequencing of cfDNA from the pregnant mother and a tailored statistical analysis enables predicting fetal gene inheritance. MG-NIPD was validated for 18 pregnancies, focusing on CFTR, CYP21A2, and HBB. In all cases we could predict the inherited alleles with >98% confidence, even at relatively early stages (8 weeks) of pregnancy. This prediction and the accuracy of parental haplotyping was confirmed by sequencing of fetal material obtained by parallel invasive procedures. MG-NIPD is a robust method that requires standard instrumentation and can be implemented in any clinic to provide families carrying a severe monogenic disease with a prenatal diagnostic test based on a simple blood draw. PMID- 28844487 TI - A Scalable Bayesian Method for Integrating Functional Information in Genome-wide Association Studies. AB - Genome-wide association studies (GWASs) have identified many complex loci. However, most loci reside in noncoding regions and have unknown biological functions. Integrative analysis that incorporates known functional information into GWASs can help elucidate the underlying biological mechanisms and prioritize important functional variants. Hence, we develop a flexible Bayesian variable selection model with efficient computational techniques for such integrative analysis. Different from previous approaches, our method models the effect-size distribution and probability of causality for variants with different annotations and jointly models genome-wide variants to account for linkage disequilibrium (LD), thus prioritizing associations based on the quantification of the annotations and allowing for multiple associated variants per locus. Our method dramatically improves both computational speed and posterior sampling convergence by taking advantage of the block-wise LD structures in human genomes. In simulations, our method accurately quantifies the functional enrichment and performs more powerfully for prioritizing the true associations than alternative methods, where the power gain is especially apparent when multiple associated variants in LD reside in the same locus. We applied our method to an in-depth GWAS of age-related macular degeneration with 33,976 individuals and 9,857,286 variants. We find the strongest enrichment for causality among non-synonymous variants (54* more likely to be causal, 1.4* larger effect sizes) and variants in transcription, repressed Polycomb, and enhancer regions, as well as identify five additional candidate loci beyond the 32 known AMD risk loci. In conclusion, our method is shown to efficiently integrate functional information in GWASs, helping identify functional associated-variants and underlying biology. PMID- 28844489 TI - Analysis of lipid raft molecules in the living brain slices. AB - Neuronal plasma membrane has been thought to retain a lot of lipid raft components which play important roles in the neural function. Although the biochemical analyses of lipid raft using brain tissues have been extensively carried out in the past 20 years, many of their experimental conditions do not coincide with those of standard neuroscience researches such as neurophysiology and neuropharmacology. Hence, the physiological methods for lipid raft analysis that can be compatible with general neuroscience have been required. Herein, we developed a system to physiologically analyze ganglioside GM1-enriched lipid rafts in brain tissues using the "Enzyme-Mediated Activation of Radical Sources (EMARS)" method that we reported (Kotani N. et al. Proc. Natl. Acad. Sci. U S A 105, 7405-7409 (2008)). The EMARS method was applied to acute brain slices prepared from mouse brains in aCSF solution using the EMARS probe, HRP-conjugated cholera toxin subunit B, which recognizes ganglioside GM1. The membrane molecules present in the GM1-enriched lipid rafts were then labeled with fluorescein under the physiological condition. The fluorescein-tagged lipid raft molecules called "EMARS products" distributed differentially among various parts of the brain. On the other hand, appreciable differences were not detected among segments along the longitudinal axis of the hippocampus. We further developed a device to label the lipid raft molecules in acute hippocampal slices under two different physiological conditions to detect dynamics of the lipid raft molecules during neural excitation. Using this device, several cell membrane molecules including Thy1, known as a lipid raft resident molecule in neurons, were confirmed by the EMARS method in living hippocampal slices. PMID- 28844490 TI - Decalogue of the Spanish Society of Arteriosclerosis to reduce therapeutic inertia. AB - Therapeutic inertia (TI) is defined as the failure of the physician to initiate or intensify a treatment when the therapeutic goal has not been achieved. TI can be of 2types: inertia due to lack of prescription of drugs and inertia in the absence of control of a risk factor. The consequences of TI are poor control of risk factors, an increase in potentially preventable events and an increase in costs. There are factors of the doctor himself, the patient and the care organization that determine the presence of TI. Ten measures are proposed to reduce TI: to promote continuing education, to define clearly therapeutic objectives, to establish audits, to implement computerized medical records with alerts, to encourage research in this field, to disseminate clinical practice guidelines, to create motivational incentives, to organize care, to improve the doctor-patient relationship and to involve other health care providers. PMID- 28844488 TI - The Genetic Legacy of Zoroastrianism in Iran and India: Insights into Population Structure, Gene Flow, and Selection. AB - Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these migrations. Here we present genome-wide autosomal, Y chromosome, and mitochondrial DNA data from Iranian and Indian Zoroastrians and neighboring modern-day Indian and Iranian populations and conduct a comprehensive genome-wide genetic analysis in these groups. Using powerful haplotype-based techniques, we find that Zoroastrians in Iran and India have increased genetic homogeneity relative to other sampled groups in their respective countries, consistent with their current practices of endogamy. Despite this, we infer that Indian Zoroastrians (Parsis) intermixed with local groups sometime after their arrival in India, dating this mixture to 690-1390 CE and providing strong evidence that Iranian Zoroastrian ancestry was maintained primarily through the male line. By making use of the rich information in DNA from ancient human remains, we also highlight admixture in the ancestors of Iranian Zoroastrians dated to 570 BCE-746 CE, older than admixture seen in any other sampled Iranian group, consistent with a long-standing isolation of Zoroastrians from outside groups. Finally, we report results, and challenges, from a genome-wide scan to identify genomic regions showing signatures of positive selection in present-day Zoroastrians that might correlate to the prevalence of particular diseases among these communities. PMID- 28844491 TI - Assessing nurses' adherence to a central line maintenance care checklist on a pediatric inpatient unit. AB - Adherence to evidence-based central line maintenance practices remains a challenge, particularly in complex patient populations. Using an evidence-based observational checklist, areas of nonadherence were identified and a focused educational intervention was developed, resulting in improved adherence across all aspects of the central line maintenance care bundle. PMID- 28844492 TI - Low prevalence of colonization with multidrug-resistant gram-negative bacteria in long-term care facilities in Graz, Austria. AB - BACKGROUND: Residents in long-term care facilities (LTCFs) are increasingly found to be an important reservoir of multidrug-resistant gram-negative (MRGN) bacteria. AIMS: We aimed to determine colonization by MRGN bacteria over 6 months in LTCFs and geriatric wards in Graz, Austria, and to evaluate risk factors for such colonization. METHODS: During August 2015, we conducted a point-prevalence survey at LTCFs and geriatric wards of the Geriatric Health Centers of the City of Graz. Inguinal and perianal swabs were taken from 137 patients and screened for MRGN using standard procedures. Six months after the initial investigation all colonized patients were sampled again and use of antibiotics, hospital admissions, and mortality was registered. Genetic relatedness of MRGN bacteria was evaluated. RESULTS: We detected 12 patients harboring MRGN isolates (prevalence, 8.7%). Overall inguinal colonization was 5.1%. After 6 months, only 2 out of 12 patients were still colonized. Presence of a urinary catheter was associated with a higher risk of MRGN colonization (odds ratio [OR], 17.5; 95% CI, 1.6-192). Chronic wounds and gastrostomy were also risk factors of MRGN colonization (OR, 10.7; 95% CI, 1.6-69.3 and OR, 18.3; 95% CI, 2.4-139.4, respectively). There was no difference in mortality between colonized and noncolonized patients. CONCLUSIONS: Prevalence of colonization with MRGN bacteria was low in patients in LTCFs and geriatric wards in Graz, Austria. PMID- 28844493 TI - Recent advances in JAK3 inhibition: Isoform selectivity by covalent cysteine targeting. AB - Janus kinases (JAKs) are a family of four cytosolic protein kinases with a high degree of structural similarity. Due to its very restricted role in immune regulation, JAK3 was promoted as an excellent target for immunosuppression for more than a decade, but clinical validation of this concept is still elusive. During the last years, speculation arose that kinase activity of JAK1, which cooperates with JAK3 in cytokine receptor signaling, may have a dominant role over the one of JAK3. Until recently, however, this issue could not be appropriately addressed due to a lack of highly isoform-selective tool compounds. With the recent resurgence of covalent drugs, targeting of a specific cysteine that distinguishes JAK3 from other JAK family members became an attractive design option. By applying this strategy, a set of JAK3 inhibitors with excellent selectivity against other JAK isoforms and the kinome was developed during the last three years and used to decipher JAK3-dependent signaling. The data obtained with these tool compounds demonstrates that selective JAK3 inhibition is sufficient to block downstream signaling. Since one of these inhibitors is currently under evaluation in phase II clinical studies against several inflammatory disorders, it will soon become apparent whether selective JAK3 inhibition translates into clinical efficacy. PMID- 28844494 TI - Conchal contractility after inferior turbinate hypertrophy treatment:A prospective, randomized clinical trial. AB - OBJECTIVE: The aim of this study is to evaluate the effects of these two methods (Nasal corticosteroids (NCS) and radiofrequency (RF) application) on conchal contractility utilizing objective rhinologic measurement parameters. METHODS: 82 patients were presented with the complaint of nasal obstruction and diagnosed with inferior turbinate hypertrophy and were included in the study. Patients in Group 1 received NCS for 12weeks. Patients in Group 2 were administered RF to their inferior turbinates. Acoustic rhinometry and rhinomanometry tests with and without decongestant were performed. RESULTS: In the evaluation of the contractility difference of rhinometry parameters, there was not a significant difference among pre and postoperative acoustic rhinometric parameters in Group 1. Whereas in Group 2, postoperative contractility difference was significantly decreased compared to preoperative values. In the evaluation of the contractility difference of rhinomanometric parameters, no significant difference was found between pre and postoperative values in Group 1. However, postoperative contractility difference was significantly decreased compared to preoperative values in Group 2 in terms. CONCLUSION: Because the RF procedure produces fibrosis in the vascular tissues, inferior turbinates do not have a shrinking response to decongestant administration. Administration of NCS administration maintains the contractility function compared to RF application. PMID- 28844496 TI - Epinephrine use as a measure of successful food allergy management. PMID- 28844495 TI - Metastatic squamous cell carcinoma to the superior cervical ganglion mimicking a retropharyngeal lymph node. AB - BACKGROUND: Metastasis of squamous cell carcinoma (SCC) to the superior cervical ganglion (SCG) has never been reported. Its anatomic location may easily be mistaken for a retropharyngeal lymph node. We present the first case of SCC metastasis to the SCG. METHODS: We report a case of a 69year-old never smoking male, who presented with right retropharyngeal PETCT-avid disease following chemoradiation for squamous cell carcinoma of the tonsil. He was brought to the operating room for resection, intraoperative radiation and reconstruction. RESULTS: Intraoperatively, visualization and frozen section confirmed squamous cell carcinoma located in the superior cervical ganglion. The ganglion was resected, intraoperative radiation was given and the patient was reconstructed with a radial forearm free flap. Postoperatively, the patient displayed features of a Horner's syndrome. CONCLUSIONS: The superior cervical ganglion may be mistaken for a retropharyngeal lymph node. Although extremely rare, these entities may be differentiated on the basis of radiological studies. PMID- 28844497 TI - Reply. PMID- 28844498 TI - ACT IV: the final act for rindopepimut? PMID- 28844500 TI - Right atrial function and prognosis in idiopathic pulmonary arterial hypertension. AB - AIM: To determine whether right atrial (RA) function has prognostic value in patients with idiopathic pulmonary arterial hypertension (PAH). METHODS AND RESULTS: Overall, 104 patients (70 female, mean age 58+/-13years) with idiopathic PAH underwent standard Doppler echocardiography and strain and strain rate (SR) analysis before right heart catheterization. At a mean follow-up of 22+/-7months, 30 patients (29%) had clinical worsening. On Cox multivariable proportional hazards regression analysis, RA reservoir function measured as peak longitudinal SR (hazard ratio [HR] 0.5; P<0.0001), RA area (HR 1.2; P<0.01), right ventricular (RV) SR (HR 0.6; P<0.0001), cardiac index (HR 0.79; P<0.01), and mixed venous oxygen saturation (HR 0.82; P<0.01) were found to be independent correlates of cardiac events. A RA SR reservoir cut-off value of <1.2s-1 and a RV SR cut-off value of <1s-1 well identified patients at higher risk of clinical worsening (sensitivity 85.5%; specificity 90.4%; test accuracy 88.8%). In particular, event rates and mean survival time free of clinical worsening were: 6.1% and 23.5+/ 2.2months in patients with normal RA and RV SR; 45% and 20.9+/-5.5months in patients with impaired RA and normal RV SR; 56.2% and 17.7+/-6.6months in patients with normal RA and impaired RV SR; and 87.5% and 12.9+/-7.6months in patients with impairment of both RA and RV SR. CONCLUSION: Our data suggest that RA function has prognostic value in idiopathic PAH, where a poorer RA function, as explored by strain and SR analysis, is associated with a worse outcome. PMID- 28844501 TI - ONX-0914, a selective inhibitor of immunoproteasome, ameliorates experimental autoimmune myasthenia gravis by modulating humoral response. AB - Accumulating evidence shows that the immunoproteasome participates in the immune response, beyond its initial role in the protein degradation. Here, we tested the effects of the selective immunoproteasome inhibitor, ONX-0914, on experimental autoimmune myasthenia gravis (EAMG). We found that ONX-0914 ameliorated the severity of ongoing EAMG by reducing the autoantibody affinity, accompanied with decreased Tfh cells and antigen presenting cells. Also it reduced the percentage of Th17 cells and inhibited the secretion of IL-17. Our data indicated ONX-0914 may bring benefit for MG therapy. PMID- 28844502 TI - Prenatal stress affects viability, activation, and chemokine signaling in astroglial cultures. AB - CXCL12/SDF-1alpha and CX3CL1/fractalkine are constitutively expressed in the brain, which indicates their significant functions. Emerging evidence highlights the role of astrocytes and the immune system in the pathophysiology of stress related disorders. The aim of this study was to assess whether prenatal stress affects chemokine signaling, cell viability/activation, and the iNOS pathway in astroglial cultures. Our results showed that prenatal stress lowered astrocyte viability and simultaneously increased GFAP expression. Furthermore, CX3CL1 production and the CXCL12/CXCR4-7 axis were also altered by prenatal stress. Taken together, malfunctions caused by prenatal stress may adversely influence brain development, leading to long-term effects on adult brain function and behavior. PMID- 28844503 TI - Absence of the neurogenesis-dependent nuclear receptor TLX induces inflammation in the hippocampus. AB - The orphan nuclear receptor TLX (Nr2e1) is a key regulator of hippocampal neurogenesis. Impaired adult hippocampal neurogenesis has been reported in neurodegenerative and psychiatric conditions including dementia and stress related depression. Neuroinflammation is also implicated in the neuropathology of these disorders, and has been shown to negatively affect hippocampal neurogenesis. To investigate a role for TLX in hippocampal neuroinflammation, we assessed microglial activation in the hippocampus of mice with a spontaneous deletion of TLX. Results from our study suggest that a lack of TLX is implicated in deregulation of microglial phenotype and that consequently, the survival and function of newborn cells in the hippocampus is impaired. TLX may be an important target in understanding inflammatory-associated impairments in neurogenesis. PMID- 28844499 TI - Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. AB - BACKGROUND: Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. METHODS: In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 MUg admixed with 150 MUg GM-CSF) or control (100 MUg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150-200 mg/m2 for 5 of 28 days) for 6-12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour <2 cm2 post chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. FINDINGS: Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20.1 months (95% CI 18.5-22.1) in the rindopepimut group versus 20.0 months (18.1-21.9) in the control group (HR 1.01, 95% CI 0.79-1.30; p=0.93). The most common grade 3-4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one-a pulmonary embolism in a 64-year-old male patient after 11 months of treatment-was assessed as potentially related to rindopepimut. INTERPRETATION: Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. FUNDING: Celldex Therapeutics, Inc. PMID- 28844504 TI - Unsuspected Critical Illness Among Emergency Department Patients Presenting for Acute Alcohol Intoxication. AB - STUDY OBJECTIVE: Emergency department (ED) visits for acute alcohol intoxication are common, but this population is at risk for decompensation and occult critical illness. The purpose of this study is to describe the incidence and predictors of unsuspected critical illness among patients with acute alcohol intoxication. METHODS: This was a retrospective observational study of ED patients from 2011 to 2016 with acute alcohol intoxication. The study cohort included patients presenting for alcohol intoxication, whose initial assessment was uncomplicated alcohol intoxication without any other active acute medical or traumatic complaints. The primary outcome was defined as the unanticipated subsequent use of critical care resources during the encounter or admission to an ICU. We investigated potential predictors for this outcome with generalized estimating equations. RESULTS: We identified 31,364 eligible patient encounters (median age 38 years; 71% men; median breath alcohol concentration 234 mg/dL); 325 encounters (1%) used critical care resources. The most common diagnoses per 1,000 ED encounters were acute hypoxic respiratory failure (3.1), alcohol withdrawal (1.7), sepsis or infection (1.1), and intracranial hemorrhage (1.0). Three patients sustained a cardiac arrest. Presence of the following had an increased adjusted odds ratio (aOR) of developing critical illness: hypoglycemia (aOR 9.2), hypotension (aOR 3.8), tachycardia (aOR 1.8), fever (aOR 7.6), hypoxia (aOR 3.8), hypothermia (aOR 4.2), and parenteral sedation (aOR 2.4). The initial blood alcohol concentration aOR was 1.0. CONCLUSION: Critical care resources were used for 1% of ED patients with alcohol intoxication who were initially assessed by physicians to have low risk. Abnormal vital signs, hypoglycemia, and chemical sedation were associated with increased odds of critical illness. PMID- 28844505 TI - Using resting-state fMRI to assess the effect of aerobic exercise on functional connectivity of the DLPFC in older overweight adults. AB - Cardiovascular fitness is thought to exert beneficial effects on brain function and might delay the onset of cognitive decline. Empirical evidence of exercise induced cognitive enhancement, however, has not been conclusive, possibly due to short intervention times in clinical trials. Resting-state functional connectivity (RSFC) has been proposed asan early indicator for intervention induced changes. Here, we conducted a study in which healthy older overweight subjects took either part in a moderate aerobic exercise program over 6months (AE group; n=11) or control condition of non-aerobic stretching and toning (NAE group; n=18). While cognitive and gray matter volume changes were rather small (i.e., appeared only in certain sub-scores without Bonferroni correction for multiple comparisons or using small volume correction), we found significantly increased RSFC after training between dorsolateral prefrontal cortex and superior parietal gyrus/precuneus in the AE compared to the NAE group. This intervention study demonstrates an exercise-induced modulation of RSFC between key structures of the executive control and default mode networks, which might mediate an interaction between task-positive and task-negative brain activation required for task switching. Results further emphasize the value of RSFC asa sensitive biomarker for detecting early intervention-related cognitive improvements in clinical trials. PMID- 28844506 TI - [Stereotactic body radiation therapy for hepatic malignancies: Organs at risk, uncertainties margins, doses]. AB - Stereotactic body radiation therapy for primary and metastatic hepatic malignancies can be performed in association and/or as an alternative to surgery and radiofrequency. The consequences of the great number of techniques available are heterogeneity in contouring, dose prescription and in determination of dose constraints for organs at risk. The objective of this paper is to improve the quality and safety and to help the diffusion of this technique for a majority of patients. In 2016, the French Society of Radiation Oncology (SFRO) published guidelines for external radiotherapy and brachytherapy ("Recorad"). This paper is an update of these recommendations considering recent publications. PMID- 28844507 TI - Accuracy of FNAC and CT in the differentiation of benign and malignant parotid tumours in a case series. AB - INTRODUCTION: Parotid tumours, in addition to the wide variety of types, are histologically complex. Differentiating between benign and malignant tumours in preoperative diagnosis is important in deciding the type of surgery required. Fine needle aspiration cytology (FNAC) is a simple, quick, low-cost, low-invasive and well-tolerated tool used in the preoperative diagnosis of these tumours. MATERIAL AND METHODS: we calculated the sensitivity, specificity, predictive positive value (PPV) and negative predictive value (NPV) of FNAC and computed tomography (CT) in the differentiation of benign and malignant parotid tumours operated between 2010 to 2014 in the oral and maxillofacial surgery department of the University Hospital Miguel Servet. RESULTS: The sensitivity of FNAC is 50%, while the specificity is high, at 98.7%. FNAC offers high reliability in the diagnosis of malignant tumours, despite its low sensitivity. However, when the diagnosis is indeterminate or benign, other than pleomorphic adenoma or Whartin tumour, the reliability to exclude malignancy decreases. CONCLUSION: The low sensitivity of FNAC to differentiate malignant from benign parotid tumours, means that we cannot rule out other diagnostic tests, clinical symptoms and especially the intraoperative vision of each surgeon. Especially when the diagnosis is indeterminate. Nevertheless, it is a technique used in a systematised way and helps in pre-surgical decision-making. PMID- 28844508 TI - Effect of the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Evolocumab on Glycemia, Body Weight, and New-Onset Diabetes Mellitus. AB - Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [ 0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment. PMID- 28844509 TI - Mortality Rates and Length of Stay in Patients With Acute Non-ST Segment Elevation Myocardial Infarction Hospitalized for Noncardiac Conditions on Surgical Versus Nonsurgical Services. AB - Patients hospitalized for noncardiac conditions often experience increased levels of stress and hemodynamic challenges, making them susceptible to acute coronary events. The clinical features, management strategy, and outcomes of inpatient non ST segment elevation myocardial infarction (NSTEMI) have not been described. This single-center retrospective study identified patients with inpatient NSTEMI from the University of North Carolina Hospitals discharge database in February 2008 to April 2014 using International Classification of Diseases, Ninth Revision (ICD-9) codes. This process generated an initial list of 485 cases that were subsequently manually reviewed. The associations of cardiac catheterization with in-hospital mortality and length of stay were analyzed using multivariable logistic regression and multiple linear regression. A total of 302 patients were confirmed to have inpatient NSTEMI, with 154 patients admitted to surgical and 148 admitted to nonsurgical services. The in-hospital mortality rate of patients with inpatient NSTEMI was high (19%). Patients with inpatient NSTEMI who underwent cardiac catheterization had lower in-hospital mortality rates than those who did not undergo cardiac catheterization (6% vs 25%; adjusted odds ratio 0.19, 95% confidence interval 0.07 to 0.50) and were discharged 6.8 days earlier (95% confidence interval 2.3 to 11.2 days). Inpatient NSTEMIs on surgical services compared with nonsurgical services were more likely to generate cardiology consultation (96% vs 62%, p <0.0001) and left heart catheterization (41% vs 24%, p = 0.002), with similar rates of revascularization (56% vs 56%, p = 1.0). In conclusion, both nonsurgical and surgical patients with inpatient NSTEMI who underwent invasive management had lower in-hospital mortality rates and shorter lengths of stay. PMID- 28844510 TI - Meta-Analysis of Effectiveness and Safety of Oral Anticoagulants in Atrial Fibrillation With Focus on Apixaban. AB - We performed a meta-analysis of data on the effectiveness and safety of apixaban compared with other oral anticoagulants (warfarin or rivaroxaban or dabigatran or edoxaban) for stroke prevention in atrial fibrillation (AF) in different settings of randomized controlled trials, real-world studies, and radiofrequency ablation (RFA). Thirty studies were searched in PubMed, the Cochrane Library, and Clinicaltrials.gov databases reporting comparative effectiveness and safety of apixaban with warfarin (n = 23), rivaroxaban (n = 12), dabigatran (n = 13), or edoxaban (n = 2) for stroke prevention in AF. In real-world estimates, apixaban was similar to warfarin for the prevention of stroke or systematic thromboembolism (hazard ratio 0.93, 95% CI 0.71 to 1.14, I2 = 82.9%, N = 7), and safer than warfarin in the risks of major bleeding (hazard ratio 0.62, 95% CI 0.54 to 0.70, I2 = 18.7%, N = 9) in patients with AF. The risk of stroke or thromboembolism with apixaban was similar to rivaroxaban, dabigatran, and edoxaban in the settings of real-world studies and RFA. Major bleeding with apixaban was generally lower than rivaroxaban (relative risks 0.45, 95% CI 0.38 to 0.53, I2 = 0%, N = 5) and similar to dabigatran in real-world studies (relative risks 1.44, 95% CI 0.33 to 6.30, I2 = 97.7%, N = 5), but similar to rivaroxaban, dabigatran, and edoxaban in RFA. In conclusion, our meta-analysis provides a comprehensive estimate of the effectiveness and safety of apixaban compared with other oral anticoagulants (warfarin, rivaroxaban, dabigatran, and edoxaban) in patients with AF in different settings of randomized controlled trial, real-world studies, and RFA. PMID- 28844511 TI - Prognostic Significance of Change in the Left Ventricular Ejection Fraction After Transcatheter Aortic Valve Implantation in Patients With Severe Aortic Stenosis and Left Ventricular Dysfunction. AB - Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis compared with patients with preserved LVEF. To evaluate the impact of early LVEF recovery in patients with baseline dysfunction on clinical outcomes after transcatheter aortic valve implantation (TAVI), we included all consecutive patients who underwent TAVI from the Italian ClinicalService registry with an LVEF of <=45% at baseline who had 1-month LVEF data. Patients who experienced a previous coronary artery bypass graft, a previous valve replacement, or a previous myocardial infarction were excluded from the analysis. Therefore, 131 patients with an improvement in LVEF of <10% (no-R group) were compared with 121 patients with an improvement in LVEF of >=10% (R group). The primary end point was the rate of death of any cause. Multivariable analysis was performed to determine independent predictors of lack in LVEF recovery. Early LVEF recovery occurred in 48% of the patients, generally before discharge. One-year all-cause mortality and major adverse cardiac and cerebrovascular events were significantly higher in the no-early recovery group (log rank test p = 0.005 and p = 0.003, respectively). Baseline severe left ventricular dysfunction and previous percutaneous coronary intervention were identified as independent predictors to warn the lack of improvement in LVEF. In conclusion, nearly 50% of patients with preoperative left ventricular dysfunction demonstrated a significant early improvement in LVEF after TAVI. Lack of early LVEF recovery is associated with a worse clinical outcome and is most likely among patients with a severely abnormal baseline LVEF and a previous percutaneous coronary intervention. PMID- 28844512 TI - Meta-Analysis of Usefulness of Anticoagulation After Transcatheter Aortic Valve Implantation. AB - Since the advent of bioprosthetic valves, the implications of long-term anticoagulation after valve replacement are unclear. There are very little data on outcomes of long-term anticoagulation after transcatheter aortic valve implantation (TAVI). Our aim was to conduct a systematic review of literature regarding anticoagulation after TAVI. The existing literature on anticoagulation after bioprosthetic valve replacement was thoroughly reviewed, including the most recent American College of Cardiology/American Heart Association 2017 guidelines for management of valvular disease, which is based on sparse, nonrandomized retrospective data. A systematic review of MEDLINE, EMBASE, and Cochrane CENTRAL databases was conducted to retrieve articles reporting outcomes on anticoagulation after TAVI, and 5 articles were retrieved. Pooled analysis revealed lower bleeding rates in the anticoagulated group (22% vs 35%, p = 0.006). Stroke and mortality were inconsistently reported by the studies. The data regarding outcomes of patients on anticoagulation after TAVI are sparse. Systematic collection of anticoagulation data in the existing registries and future trials should be strongly considered in patients undergoing TAVI. PMID- 28844513 TI - Outcomes of Nonagenarians Admitted to the Cardiac Intensive Care Unit by the Elders Risk Assessment Score for Long-Term Mortality Risk Stratification. AB - There are limited data on outcomes of older adults admitted to cardiac intensive care units (CICU), and there are no data on outcomes after admission to the CICU in nonagenarians. Our purpose was to identify whether the Elders Risk Assessment (ERA) index could risk stratify older adults after CICU admission. We retrospectively identified 453 nonagenarians admitted to the CICU between 2004 and 2013. End points included mortality, length of stay, incidence of delirium, and discharge disposition. Average age of the cohort was 92 +/- 2 years, and the average ERA score was 13 +/- 6. A total of 258 patients were female (57%). Most common admission indication was acute decompensated heart failure (57%) followed by acute myocardial infarction (49%). Loss of independence was observed after CICU admission, with 66% of patients living independently before admission, decreasing to 47% at discharge. Overall length of stay was 6 +/- 5 days and CICU stay was 2 +/- 2 days. Fifteen percent of patients died before hospital discharge. Median survival was 452 (interquartile range 40 to 1,371) days. ERA score effectively predicted survival (log-rank test, p = 0.002). ERA score of 16 or greater and ERA score of 9 to 15 were both associated with increased risk of mortality compared with the reference (score 4 to 8): hazard ratio 2.00, 95% confidence interval 1.37 to 2.90, p = 0.003, and hazard ratio 1.48, 95% confidence interval 1.06 to 2.08, p = 0.02, respectively. In conclusion, nonagenarians admitted to CICU experience reasonable outcomes. The ERA score effectively risk stratifies nonagenarians admitted to the CICU and may help with identification of vulnerable patients at risk of adverse outcomes. PMID- 28844516 TI - Myocardial Infarction and N-Terminal Pro-Brain Natriuretic Peptide. PMID- 28844514 TI - Comparison of the CHA2DS2-VASc, CHADS2, HAS-BLED, ORBIT, and ATRIA Risk Scores in Predicting Non-Vitamin K Antagonist Oral Anticoagulants-Associated Bleeding in Patients With Atrial Fibrillation. AB - The increasing adoption of non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF) necessitates a reassessment of bleeding risk scores. Because known risk factors for bleeding are largely the same as for stroke, we hypothesize that stroke risk scores could also be used to identify patients with high bleeding risks. We aimed to compare the performance of 2 stroke risk scores (Congestive Heart failure, hypertension, Age >=75 [doubled], Diabetes, Stroke [doubled], Vascular disease, Age 65-74, and Sex [female] [CHA2DS2-VASc] and Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] [CHADS2]) and 3 bleeding risk scores (hypertension, abnormal renal/liver function [1 point each], stroke, bleeding history or predisposition, labile INR, elderly [.65 years], drugs/alcohol concomitantly [1 point each] [HAS BLED], Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT], and AnTicoagulation and Risk factors In Atrial fibrillation [ATRIA]) in predicting major and intracranial bleeding. Using a large US commercial insurance database, we identified 39,539 patients with nonvalvular AF who started NOACs between October 1, 2010 and June 30, 2015. The performance of risk scores was compared using C-statistic and net reclassification improvement (NRI). Over a total of 22,583 person-years, 665 patients (2.94% per year) had major bleeding, including 74 intracranial hemorrhages (0.33% per year). For the prediction of major bleeding, CHA2DS2-VASc had the highest C-statistic both as a continuous score (C-statistic 0.68) and as a categorical score (C-statistic 0.65). For the prediction of intracranial bleeding, CHADS2 had the highest C-statistic both as a continuous score (C-statistic 0.66) and as a categorical score (C-statistic 0.66). There were no statistically significant differences between scores based on NRI. In conclusion, CHA2DS2-VASc, CHADS2, HAS-BLED, ORBIT, and ATRIA had similar, albeit modest, performance in predicting NOAC-associated bleeding in patients with AF. Careful assessment and active management of bleeding risk factors may be warranted in all patients on NOACs who have high stroke risk scores. PMID- 28844515 TI - Relation of Carotid Intima-Media Thickness to Cardiovascular Events in Black Americans (From the Jackson Heart Study). AB - Although several prospective studies have reported independent relations between carotid intima-media thickness (CIMT) and risk of incident cardiovascular diseases (CVD) in primarily non-African-American (AA) cohorts, the utility of CIMT values for the prediction of incident coronary heart disease and stroke events in blacks remain unclear. At the baseline examination (2000 to 2004) of the Jackson Heart Study, AA adults 21 to 94 years of age (mean 54) underwent bilateral far-wall CIMT measurement (mean 0.76 mm). Incident CVD events were then assessed over 7 to 11 years of follow-up (2000 to 2011) from samples of 2,463 women (107 CVD events) and 1,338 men (64 CVD events) who were free of clinical CVD at baseline. Each 0.2-mm increase in CIMT was associated with age-adjusted incident CVD hazard ratios of 1.4 (95% confidence interval 1.2, 1.5) for women and 1.3 (1.1, 1.6) for men. Classification accuracy improved only slightly when comparing multivariable models that used traditional risk factors alone with models that added CIMT: C-statistics 0.837 (0.794, 0.881) versus 0.842 (0.798, 0.886) in women and 0.754 (0.683, 0.826) versus 0.763 (0.701, 0.825) in men. Similarly, risk reclassification was only mildly improved by adding CIMT: Net Reclassification Index 0.13 (p = 0.05) and 0.05 (p = 0.50) for women and men, respectively; Integrated Discrimination Improvement 0.02 (p = 0.02) and 0.01 (p = 0.26) for women and men, respectively. In conclusion, CIMT was associated with incident CVD but provided modest incremental improvement in risk reclassification beyond traditional risk factors in a community-based AA cohort. PMID- 28844517 TI - Coronary Computed Tomographic Angiography-Derived Fractional Flow Reserve Based on Machine Learning for Risk Stratification of Non-Culprit Coronary Narrowings in Patients with Acute Coronary Syndrome. AB - This study investigated the prognostic value of coronary computed tomography angiography (cCTA)-derived fractional flow reserve (CT-FFR) in patients with acute coronary syndrome (ACS) and multivessel disease to gauge significance and guide management of non-culprit lesions. We retrospectively analyzed data of 48 patients (56 +/- 10 years, 60% men) who were admitted for symptoms suggestive of ACS and underwent dual-source cCTA followed by invasive coronary angiography with culprit lesion intervention. Culprit lesions were retrospectively identified on cCTA using images obtained during invasive coronary angiography. Non-culprit lesions with >=25% luminal stenosis and deferred intervention were evaluated using a machine learning CT-FFR algorithm to determine lesion-specific ischemia (CT-FFR <=0.80). Follow-up was performed. CT-FFR identified lesion-specific ischemia in 23 of 81 non-culprit lesions. After a median follow-up of 19.5 months, 14 patients (29%) had major adverse cardiac events (MACE). Univariate Cox regression analysis revealed that CT-FFR <=0.80 (hazard ratio [HR] 3.77 [95% confidence interval 1.16 to 12.29], p = 0.027), Framingham risk score (FRS) (HR 2.96 [1.01 to 7.63], p = 0.038), and a CAD-RADS classification >=3 (HR 3.12 [1.03 to 10.17], p = 0.051) were predictors of MACE. In a risk-adjusted model controlling for FRS and CAD-RADS >=3, CT-FFR <=0.80 remained a predictor of MACE (1.56 [1.01 to 2.83], p = 0.048). Receiver operating characteristics analysis including FRS, CAD-RADS >= 3, and CT-FFR <=0.80 (area under the curve 0.78) showed incremental discriminatory power over FRS alone (area under the curve 0.66, p = 0.032). CT-FFR of non-culprit lesions in patients with ACS and multivessel disease adds prognostic value to identify risk of future MACE. PMID- 28844518 TI - Usefulness of Sodium Bicarbonate for the Prevention of Contrast-Induced Nephropathy in Patients Undergoing Cardiac Resynchronization Therapy. AB - The use of contrast media during cardiac resynchronization therapy (CRT) devices implantation is associated with the risk of contrast-induced nephropathy (CIN). The aim of this study was to evaluate the possible beneficial role of periprocedural intravenous volume expansion with isotonic saline and sodium bicarbonate solution in patients who undergo CRT implantation. Eligible patients were randomly assigned in a 1:1 ratio to receive hydration plus one-sixth molar sodium bicarbonate (study group) or not (control group). Primary end point was CIN incidence. Secondary end points were (1) a combined end point of death, heart transplantation, or hospitalization for heart failure at 12 months, (2) incidence of death, and (3) the need for renal replacement therapy at 12 months. Final analysis was performed with 93 patients. In the hydration group CIN incidence was significantly reduced related to control group (0% vs 11%, p = 0.02). There was a trend to reduce the combined end point in hydration group (12.5% vs 22%, p = 0.14). Finally, CIN incidence was related to a higher 12 months mortality (25% vs 7%, p = 0.03). In conclusion, CIN incidence was 11% in a nonselected population of patients receiving a CRT device. CIN appearance could be reduced by using a hydration protocol based on sodium bicarbonate and isotonic saline. PMID- 28844519 TI - Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). AB - Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as >=50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 +/ 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography. PMID- 28844520 TI - Predictors of Technical Failure in Transradial Coronary Angiography and Intervention. AB - Transradial access for coronary angiography and intervention is preferred over the femoral approach but can be technically challenging. Identification of predictors of transradial access failure is important, especially in the context of acute coronary syndromes. We therefore retrospectively analyzed 13,095 consecutive patients (66 +/- 12 years, 64% male) in whom transradial access was attempted for coronary angiography or intervention to identify predictors of transradial access failure. Angiograms and patient files were systematically reviewed to analyze patient characteristics associated with failure. Transradial access failure rate was 6.8% (909 of 13,095). Patients with transradial access failure were more frequently female (9.5% vs 5.5%; p <0.001), significantly older (68 +/- 12 vs 66 +/- 12 years, p <0.001), and had a smaller body surface area (1.89 +/- 0.21 vs 1.94 +/- 0.2 m2; p <0.001). Transradial failure was not significantly more frequent in ST-elevation myocardial infarction versus other patients (8.1% vs 6.9%, p = 0.195). After multivariable adjustment, only female sex (odds ratio [OR] 1.44, p <0.001), higher patient age (OR 1.01/year, p = 0.002), and lower height (OR 0.98/cm, p = 0.004) independently predicted transradial access failure. In conclusion, female sex, higher age, and smaller height independently predict transradial access failure in coronary angiography and intervention. Failure rate in ST-elevation myocardial infarction is not significantly increased. PMID- 28844521 TI - Direct Modulation of the Guard Cell Outward-Rectifying Potassium Channel (GORK) by Abscisic Acid. PMID- 28844523 TI - Editorial overview: Emotion. PMID- 28844522 TI - Patient priorities and the doorknob phenomenon in primary care: Can technology improve disclosure of patient stressors? AB - OBJECTIVE: Patients with multiple chronic conditions face many stressors (e.g. financial, safety, transportation stressors) that are rarely prioritized for discussion with the primary care provider (PCP). In this pilot randomized controlled trial we examined the effects of a novel technology-based intervention called Customized Care on stressor disclosure. METHODS: The main outcomes were stressor disclosure, patient confidence and activation, as assessed by self report and observational methods (transcribed and coded audio-recordings of the office visit). RESULTS: Sixty patients were enrolled. Compared with care as usual, intervention patients were 6 times more likely to disclose stressors to the PCP (OR=6.16, 95% CI [1.53, 24.81], p=0.011) and reported greater stressor disclosure confidence (exp[B]=1.06, 95% CI [1.01, 1.12], p=0.028). No differences were found in patient activation or the length of the office visit. CONCLUSION: Customized Care improved the likelihood of stressor disclosure without affecting the length of the PCP visit. PRACTICE IMPLICATIONS: Brief technology-based interventions, like Customized Care could be made available through patient portals, or on smart phones, to prime patient-PCP discussion about difficult subjects, thereby improving the patient experience and efficiency of the visit. PMID- 28844524 TI - Mechanical thrombectomy for pediatric acute stroke and ventricular assist device. AB - BACKGROUND: Certain pediatric populations have increased risk of ischemic strokes, including those with cardiac disease and those dependent on mechanical circulatory devices such as ventricular assist devices. Due to their need for chronic anticoagulation, patients with mechanical circulatory devices are not candidates for systemic thrombolysis and thus treatment of acute ischemic stroke is limited. CASE: A 9-year-old boy with a ventricular assist device presented with acute onset of dense right hemiparesis, global aphasia, and a pediatric NIHSS score of 23. Vessel imaging showed an occlusive proximal left middle cerebral artery thrombus successfully removed via mechanical thrombectomy within 4.5h of symptom onset. His pediatric NIHSS 72h after presentation was 3. CONCLUSIONS: This case represents only the third report of successful mechanical thrombectomy for acute ischemic stroke in a pediatric patient with a ventricular assist device and the first using the Trevo stent retriever system. Our patient's excellent outcome highlights mechanical thrombectomy as a potential therapeutic option for children with ventricular assist devices experiencing acute neurological changes and radiologic evidence of proximal vessel occlusion. PMID- 28844525 TI - Oral Antidiabetic Agents and Cardiovascular Outcomes. AB - Cardiovascular disease is the leading cause of morbidity and mortality among patients with type 2 diabetes; however, a direct protective effect of tight glycemic control remains unproven. In fact, until 2008, when concerns related to rosiglitazone prompted regulatory agencies to mandate assessment of cardiovascular safety of new antidiabetic agents, little was known about how these medications affected cardiovascular outcomes. Since then, there has been a considerable increase in the number of cardiovascular trials, which employ a noninferiority design and focus on high-risk populations to establish safety in the shortest time possible. In this article, we summarize the 4 major cardiovascular outcome trials of oral antidiabetic agents, completed so far. These include 3 dipeptidyl peptidase-4 inhibitors (saxagliptin, alogliptin, and sitagliptin) and 1 sodium-glucose cotransporter-2 inhibitor (empagliflozin). We briefly discuss potential mechanisms, limitations, and provide an overview of the ongoing studies in this field. PMID- 28844526 TI - In Vivo Magnetic Recording of Neuronal Activity. AB - Neuronal activity generates ionic flows and thereby both magnetic fields and electric potential differences, i.e., voltages. Voltage measurements are widely used but suffer from isolating and smearing properties of tissue between source and sensor, are blind to ionic flow direction, and reflect the difference between two electrodes, complicating interpretation. Magnetic field measurements could overcome these limitations but have been essentially limited to magnetoencephalography (MEG), using centimeter-sized, helium-cooled extracranial sensors. Here, we report on in vivo magnetic recordings of neuronal activity from visual cortex of cats with magnetrodes, specially developed needle-shaped probes carrying micron-sized, non-cooled magnetic sensors based on spin electronics. Event-related magnetic fields inside the neuropil were on the order of several nanoteslas, informing MEG source models and efforts for magnetic field measurements through MRI. Though the signal-to-noise ratio is still inferior to electrophysiology, this proof of concept demonstrates the potential to exploit the fundamental advantages of magnetophysiology. PMID- 28844527 TI - A systematic review and meta-analysis of cold in situ perfusion and preservation for pancreas transplantation. AB - BACKGROUND: This study aimed to identify the most effective solution for in situ perfusion/preservation of the pancreas in donation after brain death donors, in addition to optimal in situ flush volume(s) and route(s) during pancreas procurement. METHODS: Embase, Medline and Cochrane databases were utilized (1980 2017). Articles comparing graft outcomes between two or more different perfusion/preservation fluids (University of Wisconsin (UW), histidine-tryptophan ketoglutarate (HTK) and/or Celsior) were compared using random effects models where appropriate. RESULTS: Thirteen articles were included (939 transplants). Confidence in available evidence was low. A higher serum peak lipase (standardized mean difference 0.47, 95% CI 0.23-0.71, I2 = 0) was observed in pancreatic grafts perfused/preserved with HTK compared to UW, but there were no differences in one-month pancreas allograft survivals or early thrombotic graft loss rates. Similarly, there were no significant differences in the rates of graft pancreatitis, thrombosis and graft survival between UW and Celsior solutions, and between aortic-only and dual aorto-portal perfusion. CONCLUSION: UW cold perfusion may reduce peak serum lipase, but no quality evidence suggested UW cold perfusion improves graft survival and reduces thrombosis rates. Further research is needed to establish longer-term graft outcomes, the comparative efficacy of Celsior, and ideal perfusion volumes. PMID- 28844529 TI - Membranous ventricular septum aneurysm, differentiated from sinus of valsalva aneurysm using cardiac CT. PMID- 28844528 TI - Association between implantation depth assessed by computed tomography and new onset conduction disturbances after transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is often associated with intraventricular conduction disturbances. We aimed to determine the association between implantation depth assessed by multidetector computed tomography (MDCT) and new-onset conduction abnormalities after TAVR. METHODS: Retrospective single-center study including patients consecutively submitted to TAVR, between August/2007 and October/2016, who underwent routine MDCT 3 months after the procedure. The endpoint of conduction disturbances included permanent pacemaker implantation and/or new-onset left bundle-branch block. Implantation depth was determined as the distance between the ventricular end of the prothesis and the native ring, at the level of the non-coronary cusp. RESULTS: 138 patients were included (female gender 52.2%, mean age 78.7 +/- 6.9 years). The EuroSCORE II was 4.0 +/- 3.9% and 57.2% were treated with self-expanding prosthesis. The endpoint of conduction abnormalities was found in 45.7% (n = 63). The implantation depth was greater in the group with conduction disturbances (7.7 vs 6.4 mm, p = 0.006). Chronic obstructive pulmonary disease, oversizing and implantation depth were independent predictors of conduction abnormalities. Implantation depth had an AUC of 0.64 (p = 0.004) for the prediction of conduction abnormalities and a cut-off value of 7.1 mm predicted the composed endpoint with a sensitivity and specificity of 65% and 70%, respectively. CONCLUSIONS: Implantation depth assessed by MDCT is associated with new-onset conduction disturbances after TAVR. In patients with conduction abnormalities, which do not qualify for the immediate implantation of pacemaker, the assessment of implantation depth by MDCT may be an additional marker of risk to aid decision making. PMID- 28844530 TI - Landmark-guided subclavian vein catheterization by palpating the subclavian artery. PMID- 28844531 TI - Influence of greater occipital nerve block on pain severity in migraine patients: A systematic review and meta-analysis. AB - AIMS: Greater occipital nerve (GON) block may be a promising approach to treat migraine. However, the results remained controversial. We conducted a systematic review and meta-analysis to explore the efficacy of GON block in migraine patients. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the efficacy of GON block versus placebo in migraine patients were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. Meta-analysis was performed using the random-effect model. RESULTS: Six RCTs were included in the meta-analysis. Overall, compared with control intervention in migraine patients, GON block intervention was found to significantly reduce pain score (Std. mean difference= 0.51; 95% CI=-0.81 to -0.21; P=0.0008), number of headache days (Std. mean difference=-0.68; 95% CI=-1.02 to -0.35; P<0.0001), and medication consumption (Std. mean difference=-0.35; 95% CI=-0.67 to -0.02; P=0.04), but demonstrated no influence on duration of headache per four weeks (Std. mean difference=-0.07; 95% CI=-0.41 to 0.27; P=0.70). CONCLUSIONS: Compared to control intervention, GON block intervention can significantly alleviate pain, reduce the number of headache days and medication consumption, but have no significant influence on the duration of headache per four weeks for migraine patients. PMID- 28844532 TI - Esophageal perforation due to blunt chest trauma: Difficult diagnosis because of coexisting severe disturbance of consciousness. AB - Esophageal perforation due to blunt trauma is a rare clinical condition, and the diagnosis is often difficult because patients have few specific symptoms. Delayed diagnosis may result in a fatal clinical course due to mediastinitis and subsequent sepsis. In this article, we describe a 26-year-old man with esophageal perforation due to blunt chest trauma resulting from a motor vehicle accident. Because a severe disturbance of consciousness masked the patient's trauma-induced thoracic symptoms, we required 11h to diagnose the esophageal perforation. Therefore, the patient developed septic shock due to mediastinitis. However, his subsequent clinical course was good because of prompt combined therapy involving surgical repair and medical treatment after the diagnosis. PMID- 28844533 TI - Irisin stimulates gonadotropins gene expression in tilapia (Oreochromis niloticus) pituitary cells. AB - The link between energy metabolism and reproduction is well known in vertebrates. Irisin, the product of fibronectin type III domain-containing protein 5 (FNDC5) gene, plays an important role in energy homeostasis. However, biological actions of irisin on reproduction remain elusive. To address this gap, we examined the direct effects of irisin on luteinizing hormone beta (LHbeta) and follicle stimulating hormone beta (FSHbeta) gene expression in tilapia pituitary cells. As a first step, the transcripts of FNDC5 were detected in the proximal pars distalis (PPD), but not in the rostral pars distalis (RPD) and neurointermediate lobe (NIL) of the tilapia pituitary by RT-PCR. In the tilapia pituitary, irisin immunoreactive signals were also detected in PPD region. In primary cultures of tilapia pituitary cells, irisin was effective in stimulating both LHbeta and FSHbeta mRNA levels in vivo and in vitro. In cultured pituitary cells of tilapia, removal of endogenous irisin by immunoneutralization using irisin antiserum inhibited LHbeta and FSHbeta gene expression. Salmon gonadotrophin releasing hormone (sGnRH) increased LHbeta and FSHbeta mRNA levels in tilapia pituitary but these stimulatory actions were not either enhanced by treatment with irisin or blocked by irisin antiserum. Furthermore, the stimulation on LHbeta and FSHbeta mRNA expression was coincident with the enhancement of LHbeta and FSHbeta mRNA stability after irisin treatment. These results provide evidence that irisin may serve as a novel intrapituitary factor maintaining gonadotropins gene expression in tilapia pituitary. PMID- 28844535 TI - WITHDRAWN: Outcomes of laparoscopic inguinal herniorrhaphy in female pediatric patients, particularly those with ovarian hernias. PMID- 28844534 TI - Eggshell matrix proteins OC-116, OC-17 and OCX36 in hen's sperm storage tubules. AB - While uterine epithelium secretes eggshell matrix proteins to regulate eggshell structural organization, uterovaginal junction (UVJ) epithelium supports sperm storage in tubules (SST). Here, we examined the presence of OCX36, OC-116 and OC 17 eggshell matrix proteins in SSTs. Two experimental lines of hens displaying either a long (F+ line) or a short (F- line) potential to store sperm were used, before and 24h after insemination. Using immunohistochemistry and western blot, we analyzed the presence of OC-116, OC-17 and OCX36 proteins in the SSTs. Using lectin and calcium staining, we examined the presence in SSTs of Gal/GalNAc (Galactose/N-acetylgalactosamine) and Glc/GlcNAc (Glucose/N-acetylglucosamine) glycans, as well as calcium ions. Our results indicate that in both F+ and F- hens, the eggshell matrix proteins OC-116 and OCX36 were identified in SST cells and lumen, in contact with spermatozoa. The OC-17 protein was found associated with calcium in F+ and F- hens, only in the SST lumen 24h after insemination. Glycans Gal/GalNAc and Glc/GlcNAc were found to be more abundant in the apical cytoplasmic area of the SST cells of F+ hens than in that of F- hens after insemination. This is the first report demonstrating the presence in SSTs of the OC-116, OC-17 and OCX36 eggshell matrix proteins, and their concomitant presence with Gal/GalNAc and Glc/GlcNAc glycans, as well as with calcium. Our results suggest that the OC-116, OC-17 and OCX36 eggshell matrix proteins may be involved in sperm storage. PMID- 28844536 TI - US pediatric trauma patient unplanned 30-day readmissions. AB - PURPOSE: We sought to determine readmission rates and risk factors for acutely injured pediatric trauma patients. METHODS: We produced 30-day unplanned readmission rates for pediatric trauma patients using the 2013 National Readmission Database (NRD). RESULTS: In US pediatric trauma patients, 1.7% had unplanned readmissions within 30days. The readmission rate for patients with index operating room procedures was no higher at 1.8%. Higher readmission rates were seen in patients with injury severity scores (ISS)=16-24 (3.4%) and ISS >=25 (4.9%). Higher rates were also seen in patients with LOS beyond a week, severe abdominal and pelvic region injuries (3.0%), crushing (2.8%) and firearm injuries (4.5%), and in patients with fluid and electrolyte disorders (3.9%). The most common readmission principal diagnoses were injury, musculoskeletal/integumentary diagnoses and infection. Nearly 39% of readmitted patients required readmission operative procedures. Most common were operations on the musculoskeletal system (23.9% of all readmitted patients), the integumentary system (8.6%), the nervous system (6.6%), and digestive system (2.5%). CONCLUSIONS: Overall, the readmission rate for pediatric trauma patients was low. Measures of injury severity, specifically length of stay, were most useful in identifying those who would benefit from targeted care coordination resources. LEVEL OF EVIDENCE: This is a Level III retrospective comparative study. PMID- 28844537 TI - Baroreflex autonomic control in human spinal cord injury: Physiology, measurement, and potential alterations. AB - The arterial baroreflex is a primary regulator of autonomic outflow to effectively regulate acute changes in blood pressure. After a spinal cord injury (SCI), regulation of autonomic function is disrupted, although the damage of the autonomic pathways may not necessarily be related to the severity of injury (i.e. level and completeness). Nonetheless, it can be assumed that there would be greater loss of sympathetic innervation with higher level of injury and that cardiac parasympathetic control would remain intact regardless of injury level. In those with SCI, impaired baroreflex regulation has implications not only for adequate pressure regulation, but also for long term cardiovascular health. In this review, we discuss the expected impact ofan SCI on baroreflex control and the studies that have investigated baroreflex sensitivity in this population. The data generally indicates that baroreflex sensitivity is lesser in those with chronic injuries. However, these findings are counter to the expected effect of an SCI and hence may indicate that the effect of an SCI on baroreflex control might be secondary to long term deconditioning and/or vascular stiffening of baroreceptive arteries. Furthermore, the alterations in the ability to regulate pressure do not impact the relationship between spontaneous heart rate and blood pressure variabilities. In addition, those with SCI are not adequately able to control blood pressure changes in response to orthostasis, resulting in frank hypotension in a significant proportion of those with high level injuries. PMID- 28844538 TI - Corrigendum to "HPV vaccines-A review of the first decade" [Gynecol. Oncol. 146 (2017) 196-204]. PMID- 28844539 TI - FDA ovarian cancer clinical trial endpoints workshop: A Society of Gynecologic Oncology White Paper. PMID- 28844540 TI - Gynecologic melanomas: A clinicopathologic and molecular analysis. AB - OBJECTIVE: Melanoma originating from gynecologic sites (MOGS), including the vulva, vagina, and cervix, is a rare and aggressive form of melanoma with poor long-term clinical outcome. The clinicopathologic features of vulvar and non vulvar tumors remain relatively understudied, and in contrast to cutaneous melanomas at non-sun-exposed sites, MOGS typically do not harbor BRAF mutations. Thus, we sought to analyze the clinicopathologic and molecular features of MOGS. METHODS: A large retrospective cohort of patients with MOGS (n=59) at a single large academic institution over a 28-year period was identified. Associations among clinicopathologic characteristics were assessed via standard statistical approaches, and clinical outcome was examined using Cox regression analysis. Sanger sequencing was utilized to identify mutations in hotspot regions of BRAF, KIT, NRAS, and CTNNB1. RESULTS: Tumors involving the vagina and/or cervix (non vulvar) are significantly associated with high-risk clinicopathologic features, including increased tumor thickness, ulceration, positive resection margins, lymph node metastasis, and poor long-term clinical outcome (with increased risk of death due to disease). The aggressive clinical behavior of non-vulvar tumors is independent of advanced clinical stage and lymph node metastasis in multivariate analysis. Targeted molecular analysis confirms an overall low rate of oncogenic mutations in our MOGS cohort, although KIT mutations (particularly in exon 11) are relatively enriched. CONCLUSIONS: Overall, our results show that non-vulvar MOGS are aggressive tumors with poor long-term clinical outcome and indicate that few targeted therapeutic options are currently available to patients with MOGS. PMID- 28844541 TI - A phase 1 study to evaluate the safety and pharmacokinetics of MEDI8852, an anti influenza A monoclonal antibody, in healthy adult volunteers. AB - MEDI8852 is an IgG1 kappa monoclonal antibody that is being developed to treat patients hospitalized with influenza A. We evaluated the safety and tolerability, pharmacokinetics, and anti-drug antibodies (ADA) of a single intravenous dose of MEDI8852 in healthy adult volunteers (NCT02350751). Forty subjects were randomized to receive either MEDI8852 (250, 750, 1,500, or 3000 mg) (n = 32) or placebo (n = 8) on day 1. Dose escalation was based on cumulative safety data through day 8. Subjects were followed through day 101 for safety, pharmacokinetics, and ADA. Treatment-emergent adverse events (TEAEs) were comparable (37.5%; 37.5%); all TEAEs were mild (grade 1) or moderate (grade 2) in severity. The most frequently reported TEAEs were headache (9.4%, 12.5%) and hypoglycemia (12.5%, 12.5%); all subjects with hypoglycemia were asymptomatic and did not require treatment. No subjects discontinued the study due to a TEAE. Mean area under the curve from time 0 to last sampling time point, area under the curve from time 0 to infinity, and observed maximum concentration for MEDI8852 were dose proportional. The terminal half-life ranged from 19.4 to 22.6 days. No ADAs were detected. A population pharmacokinetic model demonstrated good concentration separation between the 750- and 3000-mg dose groups. PMID- 28844542 TI - Comments on Validation of Serial Alberta Stroke Program Early CT Score as an Outcome Predictor in Thrombolyzed Stroke Patients. PMID- 28844543 TI - Association of Cumulative Exposure to Resting Heart Rate with Risk of Stroke in General Population: The Kailuan Cohort Study. AB - BACKGROUND AND PURPOSE: It remains unclear whether resting heart rate (RHR), particularly cumulative exposure to resting heart rate (cumRHR), is associated with stroke. The aim of our study was to prospectively explore the relationship between cumRHR and stroke morbidity. MATERIALS AND METHODS: The Kailuan study is a prospective longitudinal cohort study on cerebrovascular events and cardiovascular factors. Hazard ratios (HRs) with 95% confidence interval (CI) were calculated using a Cox competing risk model. RESULTS: A total of 46,568 participants were included in the final analysis. In the observation population, we identified 851 stroke events and 1012 incident death cases in the 4.98 +/- .51 year followed-up. Each 46.74 (beats/min) * year increase in heart rate was associated with a 12% increase in the risk of stroke (HR = 1.12, 95% CI = 1.05 1.20). In the categorical model, the highest quartile had an increased risk of stroke (HR = 1.43, 95% CI = 1.13-1.81), compared with the bottom quartile. Gender and age had no interaction with cumRHR for the risk of stroke. CONCLUSION: Increase of exposure to cumulative heart rate is independently associated with a higher risk of stroke in the general population. PMID- 28844544 TI - Case of 78-Year-Old Male with Cerebral Gas Embolism Associated with Combined Pulmonary Fibrosis and Emphysema. AB - Cerebral gas embolism (CGE) from the thoracic cavity is commonly associated with invasive procedures, and cases of spontaneous CGE are rare. A 78-year-old man presented with severe spontaneous CGE associated with combined pulmonary fibrosis and emphysema (CPFE). To the best of our knowledge, the comorbidity of CGE in a CPFE patient has not been documented until now. The patient became unconscious with left hemiparesis at approximately 2 a.m. Computed tomography scan revealed minute air densities scattered in the deep white matter of the right frontal lobe. The patient died on the sixth day of hospitalization. We postulated that CGE can be classified as either arterial CGE or retrogradely infused venous CGE. To differentiate between these two, the distribution of air densities provided useful information in our case. We assumed that the air was infused through the pulmonary vein to the left atrium of the heart, resulting in arterial CGE. A review of the literature further suggests that an upright position at the time of a CGE attack might be related to the retrogradely infused venous origin of the air, whereas arterial CGE may more likely occur when the patient is lying down. PMID- 28844546 TI - Etiological Classification of Stroke in Patients with Chagas Disease Using TOAST, Causative Classification System TOAST, and ASCOD Phenotyping. AB - BACKGROUND: Cardioembolism is considered a major pathophysiological mechanism in patients with ischemic stroke (IS) and Chagas disease (CD). However, a previous study reported that other stroke subtypes are present in more than 40% of CD patients according to the TOAST classification. Therefore, the aim of our study was to evaluate the etiologic classification of stroke in patients with CD using the Causative Classification System (CCS), the ASCOD, and the TOAST classifications in a prospective cohort of patients. METHODS: Patients evaluated in our outpatient clinic from 2012 to 2015 with IS and CD were included and underwent full investigation for stroke etiology. TOAST, CCS TOAST, and the ASCOD classifications were compared. FINDINGS: We Included 32 patients (18 men; mean age 62.7 +/-10.1 years). A total of 93.8% had at least 1 vascular risk factor; the most frequent was hypertension (87.5%). According to TOAST, we defined 87.5% as having cardioembolic stroke, being 9.4% as large-artery atherosclerotic (LAA) and 3.1% as undetermined cause. Using the CCS TOAST, 62.5% were classified as cardioaortic embolism evident and 15.6% as possible, 6.3% as small artery occlusion evident and 3.1% as probable, and 12.5% as LAA evident. When ASCOD phenotyping was applied, atherosclerosis was present in 50.1% of patients (A1 = 6.3%, A3 = 43.8%), cardiac pathology in 84.4% (C1 = 62.5%, C2 = 15.6%, C3 = 6.3%), and small-vessel disease in 66% (S1 = 9.4%, S2 = 3.1%, S3 = 3.1%). FINDINGS: In conclusion, the use of the CCS and the ASCOD phenotyping in patients with CD confirmed a high frequency of cardioembolic IS but also showed that other etiologies are prevalent, such as large-artery atherosclerosis and small-vessel occlusion. PMID- 28844545 TI - The Risk of Neurological Dysfunctions after Deep Hypothermic Circulatory Arrest with Retrograde Cerebral Perfusion. AB - OBJECTIVE: Retrograde cerebral perfusion (RCP) is a brain protection technique that is adopted generally for anticipated short periods of deep hypothermic circulatory arrest (DHCA). However, the real impact of this technique on cerebral protection during DHCA remains a controversial issue. METHODS: For 344 (59.5%) of 578 consecutive patients (mean age, 66.9 +/- 10.9 years) who underwent cardiovascular surgery under DHCA at the present authors' institution (1999 2015), RCP was the sole technique of cerebral protection that was adopted in addition to deep hypothermia. Surgery of the thoracic aorta was performed in 95.9% of these RCP patients; in 92 cases there was an aortic arch involvement. Outcomes were reviewed retrospectively. The focus was on postoperative neurological dysfunctions. RESULTS: There were 33 (9.6%) in-hospital deaths. Thirty-one (9%) patients had permanent neurological dysfunctions and 66 (19.1%) transitory neurological dysfunctions alone. Age older than 74 years (odds ratio [OR], 1.88, P = .023), surgery for acute aortic dissection (OR, 2.57; P = .0009), and DHCA time longer than 25 minutes (OR, 2.44; P = .0021) were predictors of neurological dysfunctions. The 10-year nonparametric estimate of freedom from all cause death was 61.8% (95% confidence interval, 57.8%-65.8%). Permanent postoperative neurological dysfunctions were risk factors for cardiac or cerebrovascular death (hazard ratio, 2.6; P = .039) even after an adjusted survival analysis (P < .04). CONCLUSIONS: According to the study findings, RCP, in addition to deep hypothermia, combines with a low risk of neurological dysfunctions provided that DHCA length is 25 minutes or less. Permanent postoperative neurological dysfunctions are predictors of poor late survival. PMID- 28844547 TI - Right Heart Failure as a Risk for Stroke in Patients with Chronic Obstructive Pulmonary Disease: A Case-Control Study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition characterized by complex lesions of the lungs and other organs as well as a progressive obstruction of the airway. In COPD patients, heart failure (HF) is associated with worse conditions such as inflammation, arterial stiffness, and increased risk mortality. However, the association of HF, COPD, and stroke are unclear; the examination of the role of HF, especially right HF, about increased risk of stroke in COPD patients has not been studied. We aimed to determine if right HF is a risk factor for stroke in patients with COPD. MATERIALS AND METHODS: A case-control study of patients with COPD was carried out. The cases were defined as COPD patients with ischemic stroke and control COPD patients without stroke. RESULTS: A total of 162 patients with COPD were analyzed: COPD with stroke (n = 35) and COPD alone (n = 127). COPD patients with right HF were at a greater risk of stroke compared with patients without right HF (odds ratio 3.03, 95% confidence interval 1.13-10.12, p = .044) adjusted for confounding factors. CONCLUSIONS: Right HF is an independent risk factor for stroke, probably because of cerebrovascular stasis secondary to congestion of the superior vena cava. PMID- 28844548 TI - Direct Common Carotid Artery Puncture for Endovascular Treatment of Acute Large Vessel Ischemic Stroke in a Patient with Aortic Coarctation. AB - Coarctation of the aorta is a condition that typically presents in childhood as a congenital malformation. This report describes a case of acute right middle cerebral artery ischemic stroke, which occurred in a patient with aortic coarctation that remained undiagnosed until her eighth decade. Complex anatomical variant presented a significant technical challenge in establishing endovascular access for mechanical thrombectomy using standard femoral, brachial, or radial artery approaches. Direct right common carotid puncture was performed successfully with subsequent reperfusion and full neurological recovery. Direct carotid artery puncture represents an alternative to standard transfemoral access in the event of stroke in a patient with difficult anatomy. PMID- 28844549 TI - Pancreatic heterotropia in wall of extra-hepatic choledochal cysts: A retrospective analysis of thirteen of such cases from north India. AB - INTRODUCTION: Heterotopic pancreas (HP) has rarely been identified in the wall of choledochal cyst (CC). METHODS: Retrospectively we screened 200 excised specimens of CC received at our Institute over a period of last eight years and looked for presence of HP rests in them. All the specimens were processed in their entirety. RESULT: HP was identified in the wall of 13 (6.5%) CCs, out of which 11 were Heinrich Type 2, and two were Heinrich Type 1. In half of the cases peribiliary mucous glands were observed intermingled with the HP rests. Features of chronic fibrosing pancreatitis were identified in these rests, with ulceration of overlying cyst lining. CONCLUSIONS: HP rests in the wall of CC though rare; their coexistence with peribiliary glands may possibly indicate their common embryonic origin. As a common site of inflammation, HP rest may be one of the common causes of CC. PMID- 28844550 TI - The development of a massive open online course during the 2014-15 Ebola virus disease epidemic. AB - PURPOSE: Timely training was urgently needed at the onset of the 2014 Ebola virus disease epidemic. Massive open online courses (MOOCs) have grown in popularity, though little is known about their utility in time-sensitive situations, including infectious disease outbreaks. METHODS: We created the first English language massive open online course on Ebola virus disease. Designed by a team representing various units of Emory University and six partner institutions, the six module course was aimed at a global general audience but also relevant for health care professionals. RESULTS: Over 7,000 learners from 170 countries participated in the initial course offering. More than a third of learners were from emerging economies, including seven percent from Africa, and another 13% from countries outside the United States who received individuals requiring treatment for Ebola virus disease. CONCLUSIONS: Creating and producing the first English language MOOC on EVD in a short time period required effective collaboration and strong coordination between subject matter and course development experts from Emory. Through these collaborative efforts, the development team was able to provide urgently needed training and educational materials while the epidemic of EVD continued to radiate through West Africa. PMID- 28844551 TI - Safety and efficacy of high-dose enteral, intravenous, and transdermal clonidine for the acute management of severe intractable childhood dystonia and status dystonicus: An illustrative case-series. AB - OBJECTIVE: Acute dystonia in children is distressing, painful and can progress to life-threatening status dystonicus. Typical management involves benzodiazepines which can result in respiratory depression requiring PICU admission. Clonidine is less respiratory-depressant, and by facilitating sleep, switches dystonia off. It can also be administered via enteral, continuous intravenous infusion, and transdermal slow release routes. We describe the dose range and safety profile of clonidine management in a case-series of children with severe acute exacerbation of dystonia in a tertiary hospital setting. METHODS: The management of 5 children (3 female, age range 8-14 years) suffering from an acute exacerbation of secondary dystonia requiring hospital admission at the Evelina London Children's Hospital was reviewed. The average and maximum dose of clonidine in mcg/kg/h and routes of administration were recorded for each day of hospital admission. Co administration of any other medical treatments for dystonia and their route of administration were also recorded. Cardiovascular and respiratory clinical status were measured by recording the daily mean and maximum Paediatric Early Warning Scores (PEWS). RESULTS: Clonidine was administered via enteral, intravenous, and transdermal routes at a median dose of 2.5 mcg/kg/h (range 0.1-9 mcg/kg/h). Administration of high dose clonidine was associated with decreased use of benzodiazepines, morphine, and propofol: avoiding invasive respiratory support for 3/4 cases during admission. Clonidine doses via all routes of administration did not correlate with poorer PEWS scores (p = 0.839). Both high dose intravenous and transdermal clonidine where found to be effective. CONCLUSIONS: High dose clonidine administered via different routes can be used in the acute management of severe exacerbations of dystonia. Its use in our cohort was not associated with significant cardio-respiratory depression even at doses as high as 9 mcg/kg/h. PMID- 28844552 TI - Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events. AB - OBJECTIVE/BACKGROUND: The objective was to observe for 1 year all patients in Norway operated on for symptomatic carotid stenosis with respect to (i) the time from the index event to surgery and neurological events during this time; (ii) the level in the healthcare system causing delay of surgical treatment; and (iii) the possible relationship between peri-operative use of platelet inhibitors and neurological events while awaiting surgery. METHODS: This was a prospective national multicentre study of a consecutive series of symptomatic patients. Patients were eligible for inclusion when referred for surgery. An index event was defined as the neurological event prompting contact with the healthcare system. All 15 departments in Norway performing carotid endarterectomy (CEA) participated. RESULTS: Three hundred and seventy one patients were eligible for inclusion between 1 April 2014 and 31 March 2015, and 368 patients (99.2%) were included. Fifty-four percent of the patients contacted their general practitioner on the day of the index event. Primary healthcare referred 84.2% of the patients to hospital on the same day as examined. In hospital median time from admission to referral for vascular surgery was 3 days. Median time between referral to the operating unit and actual CEA was 5 days. Overall, 61.7% of the patients were operated on within 2 weeks of the index event. Twelve patients (3.3%) suffered a new neurological event while awaiting surgery. The percentage of patients on dual antiplatelet therapy was lower (25.0%) in this group than among the other patients (62.6%) (p = .008). The combined 30 day mortality and stroke rate was 3.8%. CONCLUSION: This national study with almost complete inclusion and follow up shows that the delays occur mainly at patient level and in hospital. The delay is associated with new neurological events. Dual antiplatelet therapy is associated with reduced risk of having a new neurological event before surgery. PMID- 28844553 TI - The impact of symptom burden on the health status of service members with extremity trauma. AB - BACKGROUND: Service members injured in combat undergo repeated surgeries and long recoveries following a traumatic injury that produce a myriad of physical and psychological symptoms. PURPOSE: To describe the severity of pain, sleep disturbance, depression, and anxiety in service members with extremity trauma sustained during combat operations at the time of discharge from the hospital and to evaluate for differences in health status between those with and without symptom burden. METHOD: Descriptive study of 130 United States Army service members. DISCUSSION: More than 80% of the service members were classified as having symptom burden. Service members who reported one or more clinically meaningful levels of pain, sleep disturbance, depression, or anxiety reported significantly worse health status compared to those without symptom burden. CONCLUSIONS: Service members with extremity trauma experience clinically significant levels of pain, sleep disturbance, depression, and/or anxiety at the time of discharge from the hospital. The greater the service members' symptom burden, the worse their reported health status. PMID- 28844554 TI - Twenty-five years of supporting military nurses through research. PMID- 28844555 TI - Mitomycin-C and urethral dilatation: A safe, effective, and minimally invasive procedure for recurrent vesicourethral anastomotic stenoses. AB - PURPOSE: To report the safety and efficacy of mitomycin-C (MMC) injection followed by urethral dilatation for the treatment of recurrent vesicourethral anastomotic stenosis (VUAS) post-radical prostatectomy, and to report the outcome for patients treated for concomitant postprostatectomy incontinence. MATERIALS AND METHODS: A total of 29 patients with postprostatectomy incontinence and diagnosed with recurrent VUAS were recruited between March 2009 and January 2014 in this longitudinal case series. Under sedation, MMC was injected at the 3, 6, and 9 o'clock position, followed by urethral dilatation to 26F. Cystoscopy was performed to evaluate for patency at set intervals. Patients had the possibility to receive a salvage MMC injection if recurrence was noted. Patients with resolved VUAS were offered an anti-incontinence surgery. RESULTS: Median (interquartile range [IQR]) patient age was 67 years (63-72). Overall, 17 patients had >=2 prior treatments for the VUAS (median = 2, IQR: 1-3 treatments); 23 patients (79%) had a patent bladder neck at the 12 months follow-up cystoscopy after a single MMC injection and dilatation. Overall, 3 patients opted for a salvage MMC injection for recurrence, and 2 of those were salvaged, improving the success rate to 86%. No adverse events were reported. Overall, 20 patients (69%) opted for an anti-incontinence surgery, and all were either cured or improved of their incontinence after a median (IQR) follow-up of 58 months (48-77). CONCLUSIONS: MMC injection with urethral dilatation is a safe, effective, and minimally invasive treatment option for recurrent VUAS after radical prostatectomy. Favorable long-term results can be expected even after anti incontinence procedures. PMID- 28844556 TI - Nocturnal motor activity and light exposure: Objective actigraphy-based marks of melancholic and non-melancholic depressive disorder. Brief report. AB - Differentiation of melancholic (MEL) and non-melancholic (N-MEL) depression results from subjective assessment of psychomotor disturbance, which obscures their accurate diagnosis. CORE instrument assigned participants with severe or refractory depression to MEL or N-MEL group. Participants underwent 7 days of actigraphy. Data was fitted to a cosinusoidal curve corresponding to a 24-h rhythm. Nocturnal activity was significantly higher in N-MEL. ROC curve shows that average night activity discriminate participants with 71% sensitivity and 100% specificity (area under the curve = 0.84). Actigraphy contribute to the objective differentiation of depression subtypes, and have implications for research on their neurobiology and clinical management. PMID- 28844557 TI - Five factor model personality traits relate to adult attention deficit/hyperactivity disorder but not to their distinct neurocognitive profiles. AB - Deficits in multiple neuropsychological domains and specific personality profiles have been observed in attention-deficit/hyperactivity disorder (ADHD). In this study we investigated whether personality traits are related to neurocognitive profiles in adults with ADHD. Neuropsychological performance and Five Factor Model (FFM) personality traits were measured in adults with ADHD (n = 133) and healthy controls (n = 132). Three neuropsychological profiles, derived from previous community detection analyses, were investigated for personality trait differences. Irrespective of cognitive profile, participants with ADHD showed significantly higher Neuroticism and lower Extraversion, Agreeableness, and Conscientiousness than healthy controls. Only the FFM personality factor Openness differed significantly between the three profiles. Higher Openness was more common in those with aberrant attention and inhibition than those with increased delay discounting and atypical working memory / verbal fluency. The results suggest that the personality trait Openness, but not any other FFM factor, is linked to neurocognitive profiles in ADHD. ADHD symptoms rather than profiles of cognitive impairment have associations with personality traits. PMID- 28844558 TI - Cancer prevalence in Israeli men and women with schizophrenia. AB - The aim of this cross-sectional study was to compare cancer prevalence rates among patients with schizophrenia to those of the non-schizophrenia population. The study population included members of Clalit Health Services aged 25 to 74 years and all data was taken from patients' electronic health records. Of the 2,060,314 members who were included in the study, 32,748 had a diagnosis of schizophrenia. Cancer prevalence rates in women with and without schizophrenia were 491 per 10,000 and 439 per 10,000, respectively; in men, cancer prevalence rates were 226 per 10,000 and 296 per 10,000, respectively. The age-adjusted prevalence rate of all-type cancer was significantly lower among men with schizophrenia, compared to men without schizophrenia; specifically, men with schizophrenia had a lower rate of prostate cancer, and of cancers in the "other" category, compared to men without schizophrenia. Reduced cancer rates in men with schizophrenia may reflect under-diagnosis of some cancer types, likely due to insufficient medical attention. An effort to improve screening regimes should be made. PMID- 28844559 TI - A randomized, sham-controlled study of maintenance rTMS for treatment-resistant depression (TRD). AB - A few open-labeled studies have investigated the use of maintenance rTMS to prevent relapse for treatment-resistant depression (TRD) after rTMS treatment. We aim to assess the benefits of maintenance rTMS treatment for TRD patients who respond to rTMS treatment using a randomized, double-blind controlled design. Fifty eight TRD patients received rTMS over one month in an open-labeled design study (phase I). Responder patients were then randomized into active and sham high-frequency rTMS groups for the subsequent eleven months (phase II). The regularity of sessions was gradually reduced. The antidepressant effect of rTMS was evaluated using the Hamilton Depression Rating Scale (HDRS). Intention-to treat analysis was performed to assess the effectiveness of maintenance sessions. Of the 58 patients included, 35 patients were responders after one month of active rTMS (phase I), and 17 patients were randomized for the maintenance sessions (phase II). The delta HDRS scores demonstrated a significant improvement between the first month and the fourth month in active group in comparison with sham group (phase II). There was no significant difference between these two groups for other periods of time. Repetitive TMS could represent a novel strategy for preventing relapse in TRD patients who respond to rTMS treatment. These results should be confirmed in a larger sample. PMID- 28844560 TI - Physical activity is associated with the physical, psychological, social and environmental quality of life in people with mental health problems in a low resource setting. AB - There is a growing recognition of the importance of encouraging patients with mental health problems to become more active as an efficacious strategy to reduce the disability-associated burden. The aim of the current study was to investigate if there are differences in quality of life (QoL) outcomes between people with mental health problems that do and do not meet the recommendations of 150min per week of physical activity. 109 (36?) Ugandan in- and outpatients (mean age = 34.2 +/- 10.2 years) (depression = 7, bipolar disorder = 31, schizophrenia = 21, alcohol use disorder = 50) completed the Physical Activity Vital Sign (PAVS) method and World Health Organization Quality of Life Assessment brief version. Those who did not achieve the minimum physical activity recommendations as assessed by the PAVS (n = 63) had a lower physical, psychological, social and environmental QoL. The current data offer further evidence that the PAVS method might be an important risk identification tool in people with mental health problems. The feasibility and acceptability of the PAVS may help promote the importance of physical activity assessment and prescription as a core part of the treatment of mental health problems in LMICs. PMID- 28844561 TI - Increased risk of concurrent hepatitis C among Male patients with schizophrenia. AB - Prior studies attempted to explore the association between schizophrenia and hepatitis C virus (HCV). However, their conclusions were inconsistent. This study aimed to examine the association of schizophrenia with HCV using a population based dataset in Taiwan. There were 6097 patients with schizophrenia and 6097 sex and age-matched comparison patients without schizophrenia included in this study. We defined the dependent variable of interest as whether or not a patient had received a diagnosis of HCV. We found that of the sampled patients, 2.1% of patients with schizophrenia and 1.4% of comparison patients had concurrent HCV. We further found that schizophrenia was not significantly associated with concurrent HCV after adjusting for sex, age, urbanization level, geographic region, monthly income, and drug abuse. However, of the sampled male patients, the adjusted odds of concurrent hepatitis C for patients with schizophrenia were 1.72-times higher than the odds of concurrent HCV among comparison patients. We failed to observe this association among female sampled patients. We concluded that schizophrenia was not significantly associated with concurrent HCV. However, of the sampled male patients, the risk of concurrent HCV among patients with schizophrenia was higher than comparison patients. PMID- 28844562 TI - Utilization of cardiovascular medicines and cardiovascular mortality in Lithuania, Sweden and Norway in 2003-2012. AB - OBJECTIVE: The aim of this ecological study was to evaluate whether any changes in cardiovascular (CV) medicine utilization, population, socioeconomic and health system factors were associated with CV mortality in Lithuania, Sweden and Norway in 2003-2012. MATERIALS AND METHODS: CV drug utilization was calculated using the Anatomical Therapeutic Chemical/Defined Daily Dose (DDD) methodology and expressed as a number of DDD per 1000 inhabitants per day (DDD/TID). The CV age standardized death rate (CV-SDR) and risk factors data were obtained from the WHO, EUROSTAT, and FAOSTAT databases. The multiple linear regression model was used for modeling outcome measures - the relationship between the CV-SDR and CV medicine utilization including socioeconomic (GDP, unemployment and divorce rate), population (alcohol consumption, smoking and amount of kcal per day, consumption of fruit and vegetables, health status self-evaluation) and health system factors (number of hospital beds, practicing physicians and health care expenditure). RESULTS: The higher CV medicine utilization in Sweden (307-455 DDD/TID, P<0.001) and Norway (306-394 DDD/TID, P<0.001) was associated with a definite decline in CV-SDR (in Norway from 215 to 146 and in Sweden from 233 to 174). In Lithuania, the increasing but lower consumption of CV medicines (135-360 DDD/TID, P<0.001) and twice higher CV-SDR (from 541 to 447) was registered. A significant inverse correlation was observed between CV-SDR and DDD/TID. We found a strong association between the DDD/TID and the CV-SDR (R2=0.67, P<0.001). There was a strong correlation between CV-SDR and nine factors (P<0.05), except the number of practicing physicians, amount of kcal per day. There was a strong correlation between DDD/TID and nine factors (P<0.05), except the unemployment rate and amount of kcal per day. Association between an increase in the use of medicines and a decrease in CV-SDR was stronger in the case of higher alcohol consumption, higher number of available beds in hospitals and the lower unemployment rate. CONCLUSIONS: We confirmed the strong negative correlation between CV medicine utilization and CV mortality in all countries. The strong correlation was found between CV-SDR and nine factors, also between the use of CV medicines and nine factors. The impact of factors on the medicines induced decrease in CV-SDR showed the stronger influence in case of lower unemployment, higher alcohol consumption and higher number of beds for hospitalization. PMID- 28844563 TI - Psychological and physical well-being of Lithuanian youth: Relation to emotional intelligence. AB - OBJECTIVE: The objective of this article is to unveil the ways in which the emotional intelligence (EI) of a young person is linked with subjective assessment of physical state, depressiveness, anxiety, and psychological well being, as well as to determine whether these factors are reliable predictors of EI constituents. MATERIALS AND METHODS: The study was conducted using an original EI test (EI-DARL-V1/V2), which consisted of a traditional 73-item questionnaire; tasks of emotional, social and interpersonal situations; and identification of emotions in facial expressions (pictures). Questionnaire items were multiplexed into 5 subscales using multi-step factor analysis. Special questionnaires were devised and presented to participants together with the EI questionnaire in order to assess subjective assessment of physical and mental health, depressiveness, anxiety, and psychological well-being. There were 1430 participants from various regions of Lithuania who participated in the study. The age of participants varied from 17 to 27 years. RESULTS: Established inverse linear correlation showed that those participants who experienced certain somatic symptoms or unpleasant psychological states had lower EI; a particularly strong correlation was observed between poor subjective assessment of health and understanding and control of one's own emotions. Depressed and anxious participants possessed poorer understanding and ability to regulate emotions of others as well as their own. Also, these participants performed worse when resolving emotional, social, and interpersonal situations. A direct relationship between EI and psychological well-being was established according to three EI indexes i.e. (a) understanding of own emotions; (b) understanding of emotions of other people; (c) control of emotions of others. As perception of psychological well-being increased, participants were able to understand emotions of others better and demonstrated even better ability to understand and control their own emotions. The study failed to determine whether emotion recognition from non-verbal signs (face pictures) was related to at least one of the previously mentioned indexes. CONCLUSIONS: The study revealed that the factors such as subjective assessment of physical and mental health, depressiveness, anxiety, and psychological well-being were reliable predictors of certain EI indexes. PMID- 28844564 TI - Families on adult intensive care units: Are they really satisfied? A literature review. AB - OBJECTIVES: Family satisfaction in intensive care units (ICU) is of increasing relevance for family-centred cared. The objective of this review was to explore the characteristics of studies that have used questionnaires to measure the satisfaction of family members of ICU patients. REVIEW METHODS: A literature review was performed for studies evaluating family satisfaction in the ICU, independent of design. The following data were obtained for each selected article: publication year, country of origin, design, number of family members, instrument for family satisfaction, instrument score range, response rate, moment at which satisfaction was evaluated, and average level of reported satisfaction. DATA SOURCES: The following databases were systematically searched: PubMed, CINAHL, ProQuest Nursing, ProQuest Social Science, ProQuest Psychology, Science Direct, PsycINFO, LILACS, and Scielo. RESULTS: Thirty-seven articles met inclusion criteria, showing high levels of family satisfaction. Among these, nine different questionnaires were identified. In 31.6% of the studies, family satisfaction was evaluated during the ICU stay, whereas 36.9% did not report the evaluation moment. The mean response rate was 65.5%, and response rates greater than 70% were found only in 28.2% of the studies. CONCLUSIONS: High satisfaction levels among family members of ICU patients must be contextualised in light of questionnaire heterogeneity, low response rates, and variability in the moment at which family satisfaction is evaluated. The creation of methodological standards for evaluating and reporting family satisfaction could facilitate comparing results between investigations in this field. PMID- 28844565 TI - Within/between-session reliability and agreement of lumbopelvic kinematics in the sagittal plane during functional movement control tasks in healthy persons. AB - A lack of adequate lumbopelvic movement control has been suggested as an underlying mechanism contributing to the development and persistence of low back pain and lower limb pathologies. The purpose of this study was to assess the within and between session reliability (i.e. the ability to discriminate between subjects), and the agreement (i.e. whether scores are identical on repeated measures) of lumbopelvic kinematics in the sagittal plane during functional movement control tasks. Kinematics were measured with a portable inertial measurement unit system. Twenty healthy subjects (mean age = 22 (+/-3.6) years, 15 females) performed four tasks on two occasions, five to seven days apart: standing bow (SB), lifting a box from the floor (LIFT), stance-to-sit-to-stance (SIT) and placing a box on an overhead shelf (OVERH). Participants were asked to keep the lumbar spine in a neutral lordosis during the tasks. The maximal deviations from the neutral starting position for the lumbar spine and hip were calculated. Intraclass correlations (ICCs), standard errors of measurement (SEM), minimal detectable changes and 95% limits of agreement were used to assess reliability and agreement. SB and LIFT were substantially reliable (ICC = 0.89 0.96), SIT was moderately to substantially reliable (ICC = 0.69-0.92) and OVERH was fairly to moderately reliable (ICC = 0.40-0.67). SEMs ranged between 1.1 degrees and 3.1 degrees for the lumbar spine and between 0.7 degrees and 4.8 degrees for the hip. Based on the substantial reliability and acceptable agreement, SB and LIFT are most appropriate to quantify lumbopelvic movement control during functional tasks. PMID- 28844566 TI - Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model. AB - OBJECTIVE: Aiming to delineate novel neuro-immune mechanisms for NGF/TrkA signalling in osteoarthritis (OA) pain, we evaluated inflammatory changes in the knee joints following injection of monoiodoacetate (MIA) in mice carrying a TrkA receptor mutation (P782S; TrkA KI mice). METHOD: In behavioural studies we monitored mechanical hypersensitivity following intra-articular MIA and oral prostaglandin D2 (PGD2) synthase inhibitor treatments. In immunohistochemical studies we quantified joint mast cell numbers, calcitonin gene-related peptide expression in synovia and dorsal root ganglia, spinal cord neuron activation and microgliosis. We quantified joint leukocyte infiltration by flow cytometry analysis, and PGD2 generation and cyclooxygenase-2 (COX-2) expression in mast cell lines by ELISA and Western blot. RESULTS: In TrkA KI mice we observed rapid development of mechanical hypersensitivity and amplification of dorsal horn neurons and microglia activation 7 days after MIA. In TrkA KI knee joints we detected significant leukocyte infiltration and mast cells located in the vicinity of synovial nociceptive fibres. We demonstrated that mast cells exposure to NGF results in up-regulation of COX-2 and increase of PGD2 production. Finally, we observed that a PGD2 synthase inhibitor prevented MIA-mechanical hypersensitivity in TrkA KI, at doses which were ineffective in wild type (WT) mice. CONCLUSION: Using the TrkA KI mouse model, we delineated a novel neuro immune pathway and suggest that NGF-induced production of PGD2 in joint mast cells is critical for referred mechanical hypersensitivity in OA, probably through the activation of PGD2 receptor 1 in nociceptors: TrkA blockade in mast cells constitutes a potential target for OA pain. PMID- 28844567 TI - Editorial: from theory to practice - the challenges of compositional MRI in osteoarthritis research. PMID- 28844568 TI - Radiographic measurements of the hip joint and their associations with hip pain in Japanese men and women: the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. AB - OBJECTIVE: To investigate radiographic measurements of the hip joint and their associations with hip pain, and the prevalence of acetabular dysplasia defined by radiographic measurements of the hip joint in Japanese men and women using the large-scale population-based cohort of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study. METHODS: From the baseline survey of the ROAD study (cross-sectional study), 2963 participants (1040 men, 1923 women; mean age, 70.2 years) were analyzed. All participants underwent radiographic examinations of both hips using an anteroposterior view under weight-bearing. Minimum joint space width (mJSW), central-edge (CE) angle, acetabular depth-to-width ratio (ADR), and acetabular head index (AHI) were measured. Associations between these radiographic measurements and hip pain were assessed by calculating odds ratios (ORs) using multivariable logistic-regression analysis. Acetabular dysplasia was defined as a CE angle <20 degrees . RESULTS: Mean radiographic measurements of the hip joint for men were: mJSW, 3.8 mm; CE angle, 30.6 degrees ; ADR, 262.1 per 1000; and AHI, 81.4%. For women, these values were: mJSW, 3.4 mm; CE angle, 29.9 degrees ; ADR, 262.7 per 1000; and AHI, 81.2%. Associations were seen between hip pain and each of mJSW, CE angle, ADR, and AHI (OR 4.52, 95% confidence interval 3.45-5.97; 1.14, 1.11-1.18; 1.31, 1.24 1.40; and 1.15, 1.12-1.18, respectively). Acetabular dysplasia showed an overall prevalence of 13.9%, and was significantly more prevalent in women than in men (P = 0.012). CONCLUSION: The present study of radiographic measurements of the hip joint showed that mJSW, CE angle, ADR, and AHI were associated with hip pain. PMID- 28844569 TI - Tattoo associated retinochoroiditis. AB - CLINICAL CASE: A young woman was referred to our offices with impairment of visual acuity after she received a third tattoo on her arm. Systemic medical and laboratory work-up were performed in order to exclude an infectious agent or inflammatory disease. A yellowish juxtafoveal lesion in left eye along with a plaque-like outer retinal disruption and focal pigmentary defects was assessed using multi-modal diagnostic imaging. DISCUSSION: Ophthalmologists treating uveitis should consider this uncommon association and question patients regarding tattoos and tattoo inflammation given the rise of subjects undergoing artistic tattooing. PMID- 28844570 TI - Re: Mandibular wing osteotomy: technical modification. PMID- 28844571 TI - Customised instrument to retract alveolar subperiosteal flap during the placement of dental implants: new technique. PMID- 28844572 TI - Re: Re: Mandibular Wing Osteotomy: technical modification. PMID- 28844573 TI - If trainers regularly validate trainees' eLogbook records, they will spot a trainee who is not keeping theirs up-to-date. PMID- 28844574 TI - Weekday of gastrectomy for cancer in relation to mortality and oncological outcomes - A Dutch population-based cohort study. AB - BACKGROUND: Some studies demonstrate that high-complex surgeries performed later in the week are associated with higher postoperative mortality and worse long term survival. The aim of this cohort study was to determine whether weekday influences outcomes in patients undergoing gastrectomy for cancer. METHODS: All patients who underwent a curative gastrectomy for cancer (2006-2014) were selected from the nationwide population-based Netherlands Cancer Registry. Weekday was analyzed as categorized (Monday-Tuesday versus Wednesday-Friday) and discrete variable (Monday-Friday). The influence of weekday on postoperative 30- and 90-day mortality, and oncological outcomes (lymph node yield, radicality rate and overall survival) was assessed with multivariable logistic and Cox regression analyses. RESULTS: A total of 3.776 patients were included with a median overall survival of 26.7 months [range 0-120]. The 30- and 90-day mortality were 5% and 8% respectively, median lymph node yield was 13 [range 0-87], and radicality rate was 87%. In multivariable analysis, no influence of weekday was found on postoperative mortality (p > 0.05), on R0 resection rates (p > 0.05), nor on overall survival (Monday-Friday, HR 1.03, 95%CI 1.01-1.04, p = 0.111; Wednesday Friday vs. Monday-Tuesday, HR 1.05, 95%CI 0.96-1.14, p = 0.307). The lymph node yield was significantly lower later in the week compared to earlier (Monday Friday, OR 0.94, 95%CI 0.89-0.99, p = 0.013; Wednesday-Friday vs. Monday-Tuesday OR 0.83, 95%CI 0.71-0.96, p = 0.010), which was most apparent in recent years of surgery. CONCLUSION: Gastric cancer surgery can be performed safely throughout the week regarding postoperative mortality, radicality and overall survival. A point of concern is a reduced lymph node yield later in the week. PMID- 28844576 TI - Author response re. "Mediterranean diet to prevent/treat nonalcoholic fatty liver disease in children: A promising approach". PMID- 28844575 TI - Weight regain in patients with symptoms of post-bariatric surgery hypoglycemia. AB - BACKGROUND: Weight regain (WR) and symptoms of post-bariatric surgery hypoglycemia (PBSH) are metabolic complications observed in a subset of postbariatric patients. Whether hypoglycemic symptoms are an important driver of increased caloric intake and WR after bariatric surgery is unknown. OBJECTIVE: This study aims to determine whether patients with PBSH symptoms have greater odds for WR. SETTING: Tertiary academic hospital. METHODS: Patients who underwent Roux-en-Y gastric bypass or sleeve gastrectomy at our tertiary academic hospital from August 2008 to August 2012 were mailed a survey, from which weight trajectory and PBSH symptoms were assessed. Percent WR was calculated as 100*(current weight-nadir weight)/(preoperative weight-nadir weight) and was compared between dates of survey completion and bariatric surgery. The primary outcome was WR>=10%, as a reflection of the median WR among respondents. Multivariable logistic regression was used to determine clinical factors that indicate greater odds for WR>=10% at the P<.05 level. RESULTS: Of 1119 potential patients, 428 respondents (40.6%) were eligible for analysis. WR was observed in 79.2% (n = 339), while 20.8% (n = 89) experienced either weight loss or no WR at a mean of 40.6+/-14.5 months. Median WR was 10.8% (interquartile range, 5.6 19.4). Odds of WR>=10% was significantly increased in those who experienced PBSH symptoms (odds ratio [OR] = 1.66; 95% confidence interval [CI]: 1.04-2.65), reported less adherence to nutritional guideline (OR = 2.36; 95% CI: 1.52-3.67), and had a longer time since surgery (OR = 1.05; 95% CI: 1.03-1.07). CONCLUSIONS: We found evidence that the presence of PBSH symptoms was associated with WR. Future studies should elucidate the role of hypoglycemia among other factors in post-bariatric surgery WR. PMID- 28844577 TI - Perioperative safety of laparoscopic versus robotic gastric bypass: a propensity matched analysis of early experience. AB - BACKGROUND: The role of robotic assistance for gastric bypass remains controversial. Using a large nationwide cohort, we compared early outcomes after robotic Roux-en-Y gastric bypass (Robot-RYGB) with the laparoscopic technique (LRYGB). OBJECTIVE: This study aimed to use a bariatric-specific, large, nationwide cohort with several years of data to compare the early postoperative outcomes of the Robot-RYGB and LRYGB. SETTING: Nationwide register-based cohort study. METHODS: The Bariatric Outcomes Longitudinal Database from 2007 to 2012 was used to identify patients who underwent nonrevisional Robot-RYGB or LRYGB. Propensity matching was used to account for differences in age, body mass index, sex, American Society of Anesthesiologists classification, multiple preoperative co-morbidities, and procedural year. A second propensity score was calculated with adjustment of operative time in addition to the other adjusted variables. RESULTS: We identified 137,455 patients who underwent Robot-RYGB (n = 2415) or LRYGB (n = 135,040) with a mean body mass index of 47.1 +/- 8.4 kg/m2 and age of 45.4 +/- 11.7 years. In the propensity-matched cohorts, there were 30-day differences in operative time (150.2 +/- 72.5 versus 111.8 +/- 47.6, P<.001); 30 day rates of reoperation (4.8% versus 3.1%, P = .002); 90-day rates of reoperation (8.8% versus 5.3%, P<.001), complication (15.8% versus 12.5%, P = .001), readmission (8.5% versus 6.4%, P = .005), stricture (3.5% versus 2.0%, P = .001), ulceration (1.2% versus .6%, P = .034), nausea or emesis (6.4% versus 4.36%, P = .001), and anastomotic leak (1.6% versus .2%, P<.001) when comparing Robot-RYGB with LRYGB. After including operative time in propensity matching, there were no significant differences in rates of 30-day readmission or ulceration or 90-day readmission or ulceration; all other differences remained significant. CONCLUSIONS: Despite controlling for patient characteristics, patients undergoing Robot-RYGB developed higher rates of early morbidity compared with LRYGB, suggesting LRYGB may provide improved postoperative outcomes. Further studies are needed to definitively compare these 2 operative approaches. PMID- 28844578 TI - Productivity Over All. PMID- 28844579 TI - Editorial Comment. PMID- 28844580 TI - Author Reply. PMID- 28844581 TI - Corrigendum to "Predictors of Nodal Upstaging in Clinical Node Negative Patients With Penile Carcinoma: A National Cancer Database Analysis"[Urology 96 (2016) 29 34]. PMID- 28844582 TI - Outcomes of Isolated Radial Osteotomy for Volar Distal Radioulnar Joint Instability Following Radial Malunion in Children. AB - PURPOSE: The radius bone has a slight dorsoradial bow that allows for full forearm pronosupination around the ulna. However, radial malunion can lead to reversal of the radial bow and subsequent volar instability of the distal radioulnar joint (DRUJ), predominantly in supination. This study assessed the outcomes of corrective radial osteotomy for volar DRUJ instability after radial malunion in children. METHODS: The charts of 7 children (2 boys and 5 girls) treated with corrective radial osteotomy for volar DRUJ instability after a radius fracture or deformity were reviewed. Demographic, diagnostic, treatment, and complication information was collected for each patient. Radiographs at initial injury, fracture union, diagnosis of DRUJ instability, and final follow up were reviewed for radiographic measurements of radial deformity and subsequent correction. RESULTS: Fractures included 4 distal radius, 2 proximal radius, and 1 plastic deformation of the radial shaft. Volar DRUJ instability was diagnosed an average of 2.7 years (range, 1-6 years) after fracture at an average age of 13.6 years (range, 12-17 years). Two of 7 patients had persistent symptoms despite having undergone previous soft tissue surgery for DRUJ instability. Radial osteotomy was performed on all patients (3 dorsal and 4 volar approaches), with an average sagittal plane correction of 23 degrees +/- 10 degrees (range, 14 degrees to 40 degrees ). Osteotomy site varied (3 proximal third, 1 middle third, and 3 distal third) based on the apex of maximal deformity. Patients were observed an average of 2.3 years (range, 1.0-5.7 years). At final follow-up, all patients had a stable DRUJ and no patient required soft tissue stabilization. CONCLUSIONS: Apex volar malunion of radial fractures may result in volar instability of the DRUJ. Radial osteotomy restored the normal apex dorsal radial bow and effectively stabilized the DRUJ without the need for soft tissue repair. Osteotomy should be tailored to the specific site of radiographic deformity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 28844583 TI - Pharmacy performance while providing continuous medication monitoring. AB - OBJECTIVES: The aim of this work was to assess the effects of continuous medication monitoring (CoMM) on: 1) total costs of care; 2) proportion of days covered (PDC) rates; and 3) use of high-risk medications by older patients. DESIGN: Cohort design. SETTING AND PARTICIPANTS: A reimbursed CoMM program was implemented in a community pharmacy to manage problems with medications being dispensed to beneficiaries of a commercial insurer. Pharmacists assessed medications being dispensed, interacted with patients in the pharmacy, and documented their actions. Claims data compared the pharmacy performance for 3 study groups after 12 months of CoMM: group 1, patients with prescriptions dispensed only at the study pharmacy; group 2, patients with prescriptions dispensed from the study pharmacy and other pharmacies; and group 3, patients with no prescriptions dispensed by the study pharmacy. For the analyses, individuals in group 1 (CoMM-only group) were matched with those in group 2 and group 3 by age band, gender, risk category, and utilization band. MAIN OUTCOME MEASURES: The variables of interest were per-member per-month total health care costs, medication adherence (PDC), and the use of high-risk medications in older adults. RESULTS: At 12 months, per-member per-month total costs of care were significantly lower (P < 0.05) for group 1 versus group 2 ($309 difference) and for group 1 versus group 3 ($298 difference). At 12 months the average PDC for group 1 was significantly higher than for group 2 (3.8% difference) and group 3 (2.6% difference). No significant differences were found in the use of high-risk medications. CONCLUSION: A CoMM program in a community pharmacy was associated with lower total costs of care and better medication adherence. Paying pharmacists to proactively address the safety, effectiveness, and adherence of medications at the time of dispensing can support optimization of medication therapy. PMID- 28844584 TI - Consistency of psychotropic drug-drug interactions listed in drug monographs. AB - BACKGROUND: With an increasing prevalence of psychotropic polypharmacy, clinicians depend on drug-drug interaction (DDI) references to ensure safe regimens, but the consistency of such information is frequently questioned. OBJECTIVES: To evaluate the consistency of psychotropic DDIs documented in Clinical Pharmacology (CP), Micromedex (MM), and Lexicomp (LC) and summarize consistent psychotropic DDIs. METHODS: In May 2016, we extracted severe or major psychotropic DDIs for 102 psychotropic drugs, including central nervous system (CNS) stimulants, antidepressants, an antimanic agent (lithium), antipsychotics, anticonvulsants, and anxiolytics-sedatives-hypnotics from CP, MM, and LC. We then summarized the psychotropic DDIs that were included in all 3 references and with evidence quality of "excellent" or "good" based on MM. RESULTS: We identified 1496, 938, and 1006 unique severe or major psychotropic DDIs from CP, MM, and LC, respectively. Common adverse effects related to psychotropic DDIs include increased or decreased effectiveness, CNS depression, neurotoxicity, QT prolongation, serotonin syndrome, and multiple adverse effects. Among these interactions, only 371 psychotropic DDIs were documented in all 3 references, 59 of which had "excellent" or "good" quality of evidence based on MM. CONCLUSION: The consistency of psychotropic DDI documentation across CP, MM, and LC is poor. DDI documentations need standards that would encourage consistency among drug information references. The list of the 59 DDIs may be useful in the assessment of psychotropic polypharmacy and highlighting DDI alerts in clinical practice. PMID- 28844585 TI - Arsenic Exposure From Drinking Water and the Incidence of CKD in Low to Moderate Exposed Areas of Taiwan: A 14-Year Prospective Study. AB - BACKGROUND: Arsenic exposure is associated with decreased kidney function. The association between low to moderate arsenic exposure and kidney disease has not been fully clarified. STUDY DESIGN: The association between arsenic exposure from drinking water and chronic kidney disease (CKD) was examined in a long-term prospective observational study. SETTING & PARTICIPANTS: 6,093 participants 40 years and older were recruited from arseniasis-endemic areas in northeastern Taiwan. Arsenic levels were 28.0, 92.8, and 295.7MUg/L at the 50th, 75th, and 90th percentiles, respectively. PREDICTOR: Well-water arsenic and urinary total arsenic (inorganic plus methylated arsenic species) concentrations, adjusted for urinary creatinine concentration. OUTCOMES: Kidney diseases (ICD-9 codes: 250.4, 274.1, 283.11, 403.*1, 404.*2, 404.*3, 440.1, 442.1, 447.3, or 580-589) and CKD (ICD-9 code: 585) ascertained using Taiwan's National Health Insurance database 1998 to 2011. MEASUREMENTS: HRs contrasting CKD risk across arsenic exposure levels were estimated using Cox regression. Prevalence ORs for proteinuria (protein excretion >= 200mg/g) comparing quartiles of total urinary arsenic concentrations were estimated using logistic regression. RESULTS: We identified 1,104 incident kidney disease cases, including 447 CKD cases (incidence rates, 166.5 and 67.4 per 104 person-years, respectively). A dose-dependent association between well-water arsenic concentrations and kidney diseases was observed after adjusting for age, sex, education, body mass index, cigarette smoking, alcohol consumption, and analgesic use. Using arsenic concentration <= 10.0MUg/L as reference, multivariable-adjusted HRs for incident CKD were 1.12 (95% CI, 0.88 1.42), 1.33 (95% CI, 1.03-1.72), and 1.33 (95% CI, 1.00-1.77) for arsenic concentrations of 10.1 to 49.9, 50.0 to 149.9, and >=150.0MUg/L, respectively (P for trend=0.02). The association between arsenic concentration and kidney diseases was stronger for women (P for interaction=0.06). Arsenic values in the range of 50th to 75th and 75th to 100th percentiles of total urinary arsenic concentrations were associated with 50% and 67% higher prevalences, respectively, of proteinuria. LIMITATIONS: Kidney diseases and CKD outcomes were based on diagnostic codes. Glomerular filtration rates were not available. Other heavy metals were not measured. CONCLUSIONS: This study describes the temporal relationship between arsenic concentrations >= 10MUg/L in drinking water and CKD. A dose-dependent association between well-water arsenic concentration and kidney diseases was observed. Higher creatinine-adjusted urinary total arsenic concentrations were associated with a higher prevalence of proteinuria. PMID- 28844587 TI - Suicidal hanging resulting in decapitation: A case report and review of the literature. AB - Decapitation following suicidal hanging is rarely encountered in forensic practice. The authors report a case of suicidal hanging resulting in decapitation following a fall of 5m. This case is compared with 30 cases found in the literature. Several factors including type of rope, skin abrasion, level of the severed vertebrae, thyroid cartilage and hyoid bone injuries and vital signs are studied. The force applied to the neck and the kinetic energy were calculated. The kinetic energy (ranging from 1820 to 7310J) takes into account the weight of the victim but also the length of the rope (height of the fall). The speed of the body as it is stopped by the rope ranged between 6.49 and 14.01ms-1. PMID- 28844586 TI - Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury. AB - BACKGROUND: The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown. STUDY DESIGN: Cross-sectional analysis from multicenter prospective cohort. SETTINGS & PARTICIPANTS: Hospitalized deceased kidney donors on whom kidney biopsies were performed at the time of organ procurement for histologic evaluation. PREDICTORS: (1) AKI diagnosed by change in Scr concentration during donor hospitalization and (2) concentrations of urinary biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], liver-type fatty acid-binding protein [L-FABP], interleukin 18 [IL-18], and kidney injury molecule 1 [KIM-1]) measured at organ procurement. OUTCOME: Histologic acute tubular injury. RESULTS: Of 581 donors, 98 (17%) had mild acute tubular injury and 57 (10%) had severe acute tubular injury. Overall, Scr-based AKI had poor diagnostic performance for identifying histologic acute tubular injury and 49% of donors with severe acute tubular injury did not have AKI. The area under the receiver operating characteristic curve (AUROC) of change in Scr concentration for diagnosing severe acute tubular injury was 0.58 (95% CI, 0.49-0.67) and for any acute tubular injury was 0.52 (95% CI, 0.45-0.58). Compared with Scr concentration, NGAL concentration demonstrated higher AUROC for diagnosing both severe acute tubular injury (0.67; 95% CI, 0.60-0.74; P=0.03) and any acute tubular injury (0.60; 95% CI, 0.55-0.66; P=0.005). In donors who did not have Scr-based AKI, NGAL concentrations were higher with increasing severities of acute tubular injury (subclinical AKI). However, compared with Scr concentration, AUROCs for acute tubular injury diagnosis were not significantly higher for urinary L-FABP, IL-18, or KIM-1. LIMITATIONS: The spectrum of AKI cause in deceased donors may be different from that of a general hospitalized population. CONCLUSIONS: Concentrations of Scr and kidney injury biomarkers (L FABP, IL-18, and KIM-1) lack accuracy for diagnosing acute tubular injury in hospitalized deceased donors. Although urinary NGAL concentration had slightly higher discrimination for acute tubular injury than did Scr concentration, its overall AUROC was still modest. PMID- 28844588 TI - A Review of Cardiac Rehabilitation Delivery Around the World. AB - Herein, 28 publications describing cardiac rehabilitation (CR) delivery in 50 of the 113 countries globally suspected to deliver it are reviewed, to characterize the nature of services. Government funding was the main source of CR reimbursement in most countries (73%), with private and patient funding in about 1/4 of cases. Myocardial infarction patients and those having revascularization were commonly served. The main professions delivering CR were physicians, nurses, and physiotherapists. Programs offered a median of 20 sessions, although this varied. Most programs offered the core components of exercise training, patient education and nutrition counselling. Alternative models were not commonly offered. Lack of human and/or financial resources as well as space constraints were reported as the major barriers to delivery. Overall, CR delivery has been characterized in less than half of the countries where it is offered. The nature of services delivered is fairly consistent with major CR guidelines and statements. PMID- 28844590 TI - Surgical approaches, anaesthetic management and outcome in pediatric superior mediastinal tumors. AB - BACKGROUND: Pediatric superior mediastinal tumors are a heterogeneous group of tumors with marked variation in pathology and extension. We reviewed our experience with different surgical approaches to tumors originating from or extending to superior mediastinum in pediatrics. PATIENTS AND METHODS: The medical records of all patients who had undergone resection for superior mediastinal tumors in Children's Cancer Hospital - Egypt, between January 2008 to December 2015, were reviewed for demographic data, clinico-pathological features, radiologic findings, operative techniques and outcome. RESULTS: The study included 20 patients. Diagnosis included: germ cell tumors (n=8), neuroblastoma (n=4), soft tissue sarcoma (n=3), thymolipoma (n=2), infantile fibromatosis (n=1), calcifying fibrous tumor (n=1), and thymic carcinoma (n=1). Tumor extension was divided into tumors extending unilaterally to one hemithorax (n=9), tumors extending bilaterally to both hemithoraces (n=4), and cervico thoracic junction tumors (n=7). Extended lateral thoracotomy was used in 8 patients. Other approaches included trapdoor (n=5), clamshell (n=4), cervical approach (n=2) and double level lateral thoracotomy (n=1). There was no perioperative mortality, and postoperative morbidity was 20%. At the end of December 2016, 15 patients were alive free of disease, 5 patients developed local and/ or distant relapse. CONCLUSION: Pediatric superior mediastinal tumors could be divided into 3 groups according to tumor extension. Each group has an optimum surgical approach that achieves the best exposure for adequate resection. However, further research is needed to confirm the conclusion as this was a descriptive study and the sample size was too small for valid statistical analysis. PMID- 28844589 TI - Impact of CYP1A1, GSTP1 and XRCC1 genes polymorphisms on toxicity and response to chemotherapy in childhood acute lymphoblastic leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The interindividual genetic variations in drug metabolizing enzymes and DNA repair genes influence the efficacy and toxicity of numerous chemotherapeutic drugs affecting the treatment outcome. AIM OF THE WORK: The aim of the study was to investigate the impact of drug metabolizing CYP1, GSTP1 and DNA repair (XRCC1) genes polymorphisms on the toxicity and response to chemotherapy in childhood ALL. PATIENTS AND METHODOLOGY: Ninety seven ALL pediatric patients were genotyped for CYP1A1, GSTP1 ILe105Val and XRCC1 Arg194Tryp single nucleotide polymorphisms (SNPs) using PCR-RFLP. RESULTS: No statistically significant differences were observed between the wild and variant (homozygous and heterozygous) genotypes of the polymorphisms studied in CYP1A1, GSTP1 or XRCC1 genes regarding age, total leukocyte count, immunophenotyping, cytogenetic or risk group. The SNPs in CYP1A1, GSTP1 and XRCC1 genes did not show significant association with complete remission (CR) rate, overall survival (OS) or event free survival (EFS). However, XRCC1 Arg194Trp SNP was associated with higher drug toxicity; carriers of variant genotypes (CT and TT) had a significantly higher frequency of myelosuppression compared to those with the wild CC genotype (21/43[48.8%]) compared to (14/54[25.9%]) (p=0.020). The analysis of the combined effect of studied SNPs did not show any significant association with patient outcome. CONCLUSION: Our study reported a significant association between the DNA repair gene polymorphism and myelosuppression in childhood ALL patients. Adjustment of the dose of chemotherapeutic agents according to XRCC1 Arg194Trp polymorphism may improve outcome in cases with risk of toxicity. PMID- 28844591 TI - Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy-induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy. AB - BACKGROUND: Neurokinin-1 receptor antagonists, such as aprepitant are currently emerging as powerful prophylactic agents for chemotherapy-induced nausea and vomiting (CINV). Therefore, it is important to adjust the anti-emetic regimens based on personal risk factors of the patient, duration of the chemotherapy regimen and cost-effectiveness. PURPOSE: To determine the efficacy of the 3-day aprepitant along with ondansetron and dexamethasone in controlling CINV in patients with large B cell lymphoma receiving multiday-cisplatin regimen chemotherapy. METHODS: This is a pilot prospective cross-over trial. Patients were allocated to either aprepitant 125mg on day 1 and 80mg on days 2 & 3 or placebo in the first 2 cycles, with crossover to the opposite treatment in the 3rd and 4th cycles. The primary end point was complete response (CR) of both acute (days 1-5) and delayed (days 6-8) CINV. CR means neither to develop emetic episodes nor to use rescue anti-emetics medication. RESULTS: Twelve of the 15 patients recruited for the study were fully evaluable and completed 4 cycles of ESHAP regimen with a total of 48 cycles given. In the cycles with aprepitant and those without the CR were 83.3% and 0% respectively (p<0.05). Patients receiving aprepitant in the first 2 cycles recorded less nausea in subsequent cycles that were given without aprepitant. This was not statistically significant. CONCLUSION: This triple anti-emetic regimen showed efficacy in controlling the multi-day cisplatin-induced nausea and vomiting. Further randomized controlled trials are needed to compare between 3-day and 7-day aprepitant for multi-day cisplatin regimens. PMID- 28844592 TI - Adjuvant radiotherapy after radical cystectomy and ileal orthotopic neobladder. PMID- 28844593 TI - Alveolar soft part sarcoma of orbit: A rare diagnosis. AB - OBJECTIVE: Alveolar soft part sarcoma (ASPS) is an aggressive, rare tumour with unique morphological and histopathological features. METHODS: We report a rare case of orbital ASPS and its management in a young male who presented with painless proptosis and progressive loss of vision. RESULT: Twenty-two year male presented with a history of gradually increasing proptosis with loss of vision since 12months. He underwent radical re-excision of mass with right orbital exenteration and reconstruction using temporalis muscle flap. Adjuvant radiotherapy to a dose of 64Gy in 32 fractions over 6.5weeks was planned in view of positive surgical margins. Patient is free of disease and currently under follow up in multidisciplinary clinic. CONCLUSION: Function preserving surgery remains the standard treatment approach in localised disease however the complex anatomy and locally aggressive nature makes it difficult to achieve clear surgical margin. Adjuvant radiotherapy has shown to improve local control in patients with positive surgical margins. PMID- 28844595 TI - Cognitive impairments associated with alterations in synaptic proteins induced by the genetic loss of adenosine A2A receptors in mice. AB - The study of psychiatric disorders usually focuses on emotional symptoms assessment. However, cognitive deficiencies frequently constitute the core symptoms, are often poorly controlled and handicap individual's quality of life. Adenosine receptors, through the control of both dopamine and glutamate systems, have been implicated in the pathophysiology of several psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder. Indeed, clinical data indicate that poorly responsive schizophrenia patients treated with adenosine adjuvants show improved treatment outcomes. The A2A adenosine receptor subtype (A2AR) is highly expressed in brain areas controlling cognition and motivational responses including the striatum, hippocampus and cerebral cortex. Accordingly, we study the role of A2AR in the regulation of cognitive processes based on a complete cognitive behavioural analysis coupled with the assessment of neurogenesis and sub-synaptic protein expression in adult and middle-aged A2AR constitutional knockout mice and wild-type littermates. Our results show overall cognitive impairments in A2AR knockout mice associated with a decrease in new born hippocampal neuron proliferation and concomitant changes in synaptic protein expression, in both the prefrontal cortex and the hippocampus. These results suggest a deficient adenosine signalling in cognitive processes, thus providing new opportunities for the therapeutic management of cognitive deficits associated with psychiatric disorders. PMID- 28844594 TI - YidC Insertase of Escherichia coli: Water Accessibility and Membrane Shaping. AB - The YidC/Oxa1/Alb3 family of membrane proteins function to insert proteins into membranes in bacteria, mitochondria, and chloroplasts. Recent X-ray structures of YidC from Bacillus halodurans and Escherichia coli revealed a hydrophilic groove that is accessible from the lipid bilayer and the cytoplasm. Here, we explore the water accessibility within the conserved core region of the E. coli YidC using in vivo cysteine alkylation scanning and molecular dynamics (MD) simulations of YidC in POPE/POPG membranes. As expected from the structure, YidC possesses an aqueous membrane cavity localized to the membrane inner leaflet. Both the scanning data and the MD simulations show that the lipid-exposed transmembrane helices 3, 4, and 5 are short, leading to membrane thinning around YidC. Close examination of the MD data reveals previously unrecognized structural features that are likely important for protein stability and function. PMID- 28844596 TI - Chronic treatments with a 5-HT4 receptor agonist decrease amyloid pathology in the entorhinal cortex and learning and memory deficits in the 5xFAD mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT4 receptors (5-HT4Rs) seems very promising. 5-HT4R agonists exert pro-cognitive effects, inhibit amyloid-beta peptide (Abeta) production and therefore directly and positively impact AD progression. In the present work, we investigated the effects of RS 67333, a partial 5-HT4R agonist, after chronic administration in the 5xFAD mouse model of AD. 5xFAD male mice and their wild type (WT) male littermates received either RS 67333 or vehicle solution i.p., twice a week, for 2 or 4 months. Cognitive performance was evaluated in a hippocampal-dependent behavioral task, the olfactory tubing maze (OTM). Mice were then sacrificed to evaluate the metabolism of the amyloid precursor protein (APP), amyloidosis and neuroinflammatory processes. No beneficial effects of RS 67333 were observed in 5xFAD mice after 2 months of treatment, while 5xFAD mice treated for 4 months showed better cognitive abilities compared to vehicle-treated 5xFAD mice. The beneficial effects of RS 67333 on learning and memory correlated with the decrease in both amyloid plaque load and neuroinflammation, more specifically in the entorhinal cortex. The most significant improvements in learning and memory and reduction of pathology stigmata were observed after the 4-month administration of RS 67333, demonstrating that treatment duration is important to alleviate amyloidosis and glial reactivity, particularly in the entorhinal cortex. These results confirm the 5-HT4R as a promising target for AD pathogenesis and highlight the need for further investigations to characterize fully the underlying mechanisms of action. PMID- 28844597 TI - Idiopathic pulmonary hemosiderosis: Hemorrhagic flare after 6 years of remission. PMID- 28844598 TI - Exceptional Response to Nivolumab Rechallenge in Metastatic Renal Cell Carcinoma with Parallel Changes in Genomic Profile. PMID- 28844599 TI - Generic Imatinib Therapy Among Jordanians: An Observational Assessment of Efficacy and Safety in Routine Clinical Practice. AB - INTRODUCTION: Generic imatinib therapy is being globally considered owing to cost considerations. However, evidence of its efficacy and safety in Middle Eastern clinical settings is scarce. PATIENTS AND METHODS: The efficacy and safety of generic imatinib (Cemivil) were assessed among Jordanian patients diagnosed with chronic myeloid leukemia using an observational, multicenter, prospective study design. Responses were defined using European LeukemiaNet 2009 guidelines and assessed by complete blood counts, fluorescence in situ hybridization, and real time quantitative polymerase chain reaction. RESULTS: All patients (N = 91) were adults with chronic myeloid leukemia treated with generic imatinib 400 mg/day. Thirty-three patients received generic imatinib as first-line therapy, and 58 switched from patented imatinib to generic imatinib after a median of 4.5 years (range, 0.5-13.6 years) of imatinib therapy. The majority (85%; n = 28) of the first-line patients achieved complete hematologic response within 3 months of starting generic imatinib therapy (100% after 6 months [n = 33]). The 12-month major molecular response rate in the intention-to-treat population was 45%. The 12-month major molecular response rate was 88% for patients who switched therapy. The 12-month progression-free and overall survival rates were 92% and 100%, respectively. Most (85%; n = 144) adverse events were mild. Frequencies of drug related adverse events were similar to patented imatinib. CONCLUSION: This study suggests that the efficacy and safety of generic imatinib in this Middle Eastern population in routine clinical practice are comparable to patented imatinib, and to that of the global population. PMID- 28844600 TI - Prostate-specific Antigen Parameters and Prostate Health Index Enhance Prostate Cancer Prediction With the In-bore 3-T Magnetic Resonance Imaging-guided Transrectal Targeted Prostate Biopsy After Negative 12-Core Biopsy. AB - OBJECTIVE: To assess prostate cancer (PCa) detection and prediction by combining the in-bore magnetic resonance imaging-guided transrectal targeted prostate biopsy (MRGB) with prostate-specific antigen (PSA) parameters and the Prostate Health Index (PHI) in case of negative 12-core standard biopsy. MATERIALS AND METHODS: A total of 112 men (2014-2016) underwent 3-T multiparametric magnetic resonance imaging and subsequent MRGB of Prostate Imaging-Reporting and Data System (PI-RADS) lesions 3-5. Ancillary PSA parameters (PSA ratio [%fPSA] and PSA density [PSAD]) and the PHI and PHI density (PHID) were recorded. With these parameters in combination with MRGB, PCa prediction was calculated. RESULTS: The most common lesions biopsied were PI-RADS 4 (66%), located in the peripheral zone (64%), in the middle (58%) and anterior (65%) sections of the prostate, and 13 mm (IQR 10-15) in size. PCa was found in 62 (55%) patients (28% Gleason score >=7). PSAD (0.15 vs 0.21; P = .0051), %fPSA (16 vs 13; P = .0191), PHI (45 vs 69; P < .0001), PHID (0.7 vs 1.5; P < .0001), and prostate volume (56 mL vs 45 mL; P = .0073) were significantly different in patients with PCa and those without PCa. PHI and PHID were the strongest predictors of PCa with areas under the curve of 0.79 and 0.77, respectively. Using optimal thresholds of 59 and 0.79, PHI and PHID were 69% and 84% sensitive and 82% and62% specific for PCa, respectively. CONCLUSION: Following negative standard biopsy of the prostate, the MRGB achieved an overall PCa detection rate of 55% in patients with PI-RADS 3-5 lesions. By considering PHI and PHID, 82% and 62% of unnecessary biopsies could have been avoided, failing to detect 31% and 16% of cancers. PMID- 28844601 TI - Thoracic Quantitative Computed Tomography (QCT) Can Sensitively Monitor Bone Mineral Metabolism: Comparison of Thoracic QCT vs Lumbar QCT and Dual-energy X ray Absorptiometry in Detection of Age-relative Change in Bone Mineral Density. AB - RATIONALE AND OBJECTIVE: Sensitive detection of bone mineral density (BMD) change is a key issue to monitor and evaluate the individual bone health status, as well as bone metabolism and bone mineral status. The ability to use thoracic quantitative computed tomography (QCT) to detect the annual change of BMD remains unclear. We aimed to investigate the sensitivity in detecting age-related bone mineral loss using the thoracic QCT from the electrocardiographically gated heart scans in comparison to whole-body dual-energy X-ray absorptiometry (DXA) and standard lumbar QCT. MATERIALS AND METHODS: A total of 121 asymptomatic patients' imaging data, including DXA whole body scan, cardiac CT scan, and abdomen scans were analyzed. The BMD of the thoracolumbar spine, upper, and lower extremities were measured using QCT and DXA, respectively. The age-related annual rate of bone density loss was computed and compared to the thoracic and lumbar QCT, as well DXA measures. RESULTS: The age-related annual rate of bone loss with QCT was -0.70 mg/mL3 (-0.75%/y) in women, -0.83 mg/mL3 (-0.86%/y) in men in the thoracic and the lumbar trabecular QCT, respectively. Compared to the QCT, DXA demonstrates a lower annual rate of bone loss in the area of BMD measurement (P < .05 in all, excluding legs of women) in -0.45, -0.42, -0.67, and -0.46 in women, in -0.32, -0.02, -0.12, and -0.08 in men for thoracic, lumbar, leg, and arm, respectively. CONCLUSION: We conclude that the thoracic and the lumbar QCT provide a similar and more sensitive method for detecting bone mineral loss when compared to DXA. PMID- 28844602 TI - Further Investigation on High-intensity Focused Ultrasound (HIFU) Treatment for Thyroid Nodules: Effectiveness Related to Baseline Volumes. AB - RATIONALE AND OBJECTIVES: Several minimally invasive thermal techniques have been developed for the treatment of benign thyroid nodules. A new technique for this indication is high-intensity focused ultrasound (HIFU). The aim of this study was to assess effectiveness in varying preablative nodule volumes and whether outcome patterns that were reported during studies with other thermal ablative procedures for thyroid nodule ablation would also apply to HIFU. MATERIALS AND METHODS: Over the last 2 years, 19 nodules in 15 patients (12 women) whose average age was 58.7 years (36-80) were treated with HIFU in an ambulatory setting. Patients with more than one nodule were treated in multiple sessions on the same day. The mean nodule volume was 2.56 mL (range 0.13-7.67 mL). The therapeutic ultrasound probe (Echopulse THC900888-H) used in this series functions with a frequency of 3 MHz, reaching temperatures of approximately 80 degrees C-90 degrees C and delivering an energy ranging from 87.6 to 320.3 J per sonication. To assess the effectiveness of thermal ablation, nodular volume was measured at baseline and at 3-month follow-up. The end point of the study was the volume reduction assessment after 3 months' follow-up. Therapeutic success was defined as volume reduction of more than 50% compared to baseline. This study was retrospectively analyzed using the Wilcoxon signed rank test and Kendall tau. RESULTS: The median percentage volume reduction of all 19 nodules after 3 months was 58%. An inverse correlation between preablative nodular volume and percentage volume shrinking was found (tau = -0.46, P < .05). Therapeutic success was achieved in 10 out of 19 patients (53%). CONCLUSIONS: HIFU of benign thyroid nodules can be carried out as an alternative therapy for nodules <=3 mL if patients are refusing surgery or radioiodine therapy. PMID- 28844603 TI - T2 Star-weighted Angiography (SWAN) Allows to Concomitantly Assess the Prostate Contour While Detecting Fiducials Before MR-based Intensity-modulated Radiation Therapy in Prostate Carcinoma. AB - PURPOSE: To evaluate the performance of T2 star-weighted angiography (SWAN) to concomitantly assess the prostate contour while detecting fiducials before magnetic resonance (MR)-based intensity-modulated radiation therapy (IMRT) in prostate carcinoma. MATERIALS AND METHODS: Forty patients (mean age: 73.1 +/- 7.5 years; average Gleason score: 7 +/- 1; average prostate-specific antigen: 14.7 +/ 11.6 ng/mL) underwent MR and computed tomography imaging before fiducial-based IMRT. MR protocol included SWAN, T2-weighted (T2w) and diffusion-weighted imaging in a first group (n = 20) and SWAN, T2w and T2-star weighted imaging in a second group (n = 20). In group 1, the depiction of fiducials, image sharpness and visibility of prostate boundaries were independently evaluated by 2 readers on SWAN, T2w or diffusion-weighted images. In group 2, a similar evaluation was performed by 2 other readers on SWAN and T2-star images only. Depiction of fiducials was compared to computed tomography findings. RESULTS: The median scores of visibility of prostate boundaries, image sharpness and depiction of fiducials by SWAN were above average to excellent for all readers. In group 1, readers correctly located 56 of 57 (98.2%) and 47 of 57 (82.5%) fiducials, respectively; and 50 of 51 (98%), and 48 of 51 (88.2%) fiducials in group 2, respectively. CONCLUSION: By allowing adequate visualization of the prostate boundaries and high depiction of fiducial markers concomitantly, SWAN might be used for treatment planning of IMRT. The use of this sequence might simplify the registration process and limit any errors associated with image fusion. PMID- 28844604 TI - Starting a sentinel node service for melanoma: Is there a role for predictive nomograms? PMID- 28844605 TI - Isometric shoulder strength in young swimmers. AB - OBJECTIVES: The prevalence of shoulder pain in young swimmers is high. Shoulder rotation strength and the ratio of internal to external rotation strength have been reported as potential modifiable risk factors associated with shoulder pain. However, relative strength measures in elevated positions, which include flexion and extension, have not been established for the young swimmer. The aim of this study was to establish clinically useful, normative shoulder strength measures and ratios for swimmers (14-20 years) without shoulder pain. DESIGN: Cross sectional, observational study. METHODS: Swimmers (N=85) without a recent history of shoulder pain underwent strength testing of shoulder flexion and extension (in 140 degrees abduction); and internal and external rotation (in 90 degrees abduction). Strength tests were performed in supine using a hand-held dynamometer and values normalised to body weight. Descriptive statistics were calculated for strength and strength ratios (flexion:extension and internal:external rotation). Differences between groups (based on gender, history of pain, test and arm dominance) were explored using independent and paired t tests. RESULTS: Normative shoulder strength values and ratios were established for young swimmers. There was a significant difference (p<0.002) in relative strength between males and females for all tests with no differences in strength ratios. Relative strength of the dominant and non-dominant shoulders (except for extension); and for swimmers with and without a history of shoulder pain was not significantly different. CONCLUSIONS: A normal shoulder strength profile for the young swimmer has been established which provides a valuable reference for the clinician assessing shoulder strength in this population. PMID- 28844606 TI - AMPK activation: Role in the signaling pathways of neuroinflammation and neurodegeneration. AB - Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status and has been reported to be involved in chronic inflammatory disorders. AMPK is expressed in immune cells, such as dendritic cells, macrophages, lymphocytes and neutrophils, and is an important regulator of inflammatory responses through the regulation of complex signaling networks in part by inhibiting downstream cascade pathways, such as nuclear factor kB, which is a key regulator of innate immunity and inflammation, as well as acting as a negative regulator of toll-like receptors. Recent data suggest that AMPK dysregulation may participate in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and neuropathies. However, there are conflicting reports on the benefits or detrimental effects of AMPK in distinct pathological conditions. This paper offers a review of the recent literature on the pharmacological modulation of the AMPK system as a potential molecular target in the management of neurodegenerative diseases. PMID- 28844607 TI - Is voice therapy effective for the treatment of dysphonic patients with benign vocal fold lesions? AB - OBJECTIVE: To update our knowledge regarding the effectiveness of voice therapy for the treatment of vocal disturbance associated with benign vocal fold lesions, including vocal polyps, nodules and cysts, and for determining the utility of voice therapy in treating organic voice disorders, while highlighting problems for the future development of this clinical field. METHODS: We conducted a review of the most recent literature on the therapeutic effects of voice therapy, vocal hygiene education or direct vocal training on vocal quality, the lesion appearance and discomfort felt by patients due to the clinical entity of benign vocal fold mass lesions. RESULTS: Although voice therapy is principally indicated for the treatment of functional dysphonia without any organic abnormalities in the vocal folds, a number of clinicians have attempted to perform voice therapy even in dysphonic patients with benign mass lesions in the vocal folds. The two major possible reasons for the effectiveness of voice therapy on vocal disturbance associated with benign vocal fold lesions are hypothesized to be the regression of lesions and the correction of excessive/inappropriate muscle contraction of the phonatory organs. According to the current literature, a substantial proportion of vocal polyps certainly tend to shrink after voice therapy, but whether or not the regression results from voice therapy, vocal hygiene education or a natural cure is unclear at present due to the lack of controlled studies comparing two groups with and without interventions. Regarding vocal nodules, no studies have investigated the effectiveness of voice therapy using proper experimental methodology. Vocal cysts are difficult to cure by voice therapy without surgical excision according to previous studies. Evidences remains insufficient to support the use of voice therapy against benign vocal fold lesions. CONCLUSION: Evidences at present is therefore still insufficient to support the use of voice therapy for the treatment of benign vocal fold lesions. PMID- 28844608 TI - Risk factors for the occurrence of epistaxis: Prospective study. AB - OBJECTIVE: Analyse and compare the characteristics of patients with epistaxis admitted to the otolaryngology emergency department with those provided by a control group. Establish a model to identify epistaxis predictive factors. METHODS: Prospective analysis of 283 consecutive adults, admitted to the otolaryngology emergency department of a tertiary referral centre between 25 January and 25 February 2014. Comparison of gender, age, co-morbidities, usual medication, history of epistaxis or nasal trauma, presence of septal deviation and blood pressure value on admission, between the elements that were admitted to the emergency due to epistaxis (group 1) and a group composed of patients with other symptoms (group 2). Intergroup variations were analyzed using t student and chi-square tests. Multivariate logistic regression and a receiver operating characteristic curve were used to establish a predictive model and test its suitability. RESULTS: Male gender (OR=2.57, 95% CI 1.1-6.0, p=0.029), older age (OR=1.03, 95% CI 1.0-1.1, p=0.002), existence of peripheral vascular disease (OR=13.47, 95% CI 1.9-95.3, p=0.009), cardiovascular disease (OR=3.91, 95% CI 1.6 9.7, p=0.003) and previous history of epistaxis (OR=5.53, 95% CI 2.5-12.1, p<0.001) were predictors of epistaxis when adjusted for the presence of elevated blood pressure, history of hypertension, cerebrovascular disease and chronic use of anticoagulants or antiplatelet drugs. The model revealed a good applicability (area under the curve of 0.852). CONCLUSIONS: The only predictive factors of admission to the emergency department due to epistaxis were male gender, older age, peripheral vascular disease, cardiovascular disease and history of epistaxis. PMID- 28844610 TI - Corrigendum to "Safety evaluation of a milk-based protein powder produced by a novel manufacturing technique" [Food Chem. Toxicol. 103 (2017) 86-101]. PMID- 28844609 TI - A case of ectopic salivary gland of the larynx. AB - A 46-year-old man presented with sore throat. Laryngoscopic findings revealed a smooth yellow mass occupying the anterior portion of the false vocal fold on the left side. The authors performed biopsy under general anesthesia. The histopathological diagnosis was ectopic salivary gland. Because salivary glands are usually not found under the false vocal fold mucosa, ectopic salivary gland of the larynx was diagnosed. It is necessary to consider the possibility of ectopic salivary gland for mass lesions if swelling of the provisional vocal cord is found. PMID- 28844611 TI - In vitro evaluation of percutaneous drainage catheters: Flow related to connections and liquid characteristics. AB - PURPOSE: To evaluate the effect of catheter connections on drainage catheters' flow rate. MATERIALS AND METHOD: The in vitro model used commercially available catheters (8.5-F, 10.2-F, 12-F, and 14-F), connections - Luer-lok (2.33mm inner diameter), and stopcocks (1.33mm, 2.00mm, and 2.67mm inner diameters), water, ultrasound gel, textured vegetable protein (TVP) 2-mm particles, and collection bags. Plain water, viscous fluid (30% ultrasound gel solution in water), or water/viscous fluid with TVP were placed in collection bags and drained by gravity through each of the catheters and each connection. The flow rate was measured, recorded, and compared for each catheter and each connection as well as to the control flow rate of the catheters without connections. Ten one-minute trials were performed, and the mean flow rates were analyzed using Student t-test and Pearson correlation coefficient. RESULTS: Flow rate was significantly decreased in the 12-F and 14-F catheters with all stopcock and Luer-Lok connections with both water and viscous fluids. There was no significant reduction in flow for the 8.5-F and 10.2-F catheters with the 2.00-mm, 2.33-mm, and 2.67-mm connections; flow rate was significantly decreased in the 8.5-F and 10.2-F catheters with the 1.33-mm connection. A majority of trials with particulate fluid became occluded, and no consistent pattern between connections could be made. CONCLUSION: This in vitro study suggests that stopcock and Luer Lok connections limit catheter flow rate when their inner diameter is less than that of the drainage catheter. PMID- 28844612 TI - Percutaneous image-guided biopsies of small renal tumors: Current practice and perspectives. AB - Percutaneous image-guided biopsies help better select patients with renal tumors smaller than 4cm. These biopsies are performed to reduce the risks of overtreatment and to discriminate between patients who need ablation therapy and those who require active surveillance. Percutaneous image-guided biopsies are effective for a definitive diagnosis with little risk of complications when cautions are observed. With the current addition of multiparametric imaging, standardized biopsy protocols may further help adapt therapeutic decisions. The aim of this review is to report the current indications and techniques of biopsy performed in case of small solid renal masses and to clarify the optimal conditions for the realization of these biopsies. PMID- 28844613 TI - Percutaneous thermal ablation of lung tumors - Radiofrequency, microwave and cryotherapy: Where are we going? AB - Main indications of percutaneous pulmonary thermal ablation are early stage non small cell lung carcinoma (NSCLC) for patients who are not amenable to surgery and slow-evolving localized metastatic disease, either spontaneous or following a general treatment. Radiofrequency ablation (RFA) is the most evaluated technique. This technique offers a local control rate ranging between 80 and 90% for tumors <3cm in diameter. Other more recently used ablation techniques such as microwaves and cryotherapy could overcome some limitations of RFA. One common characteristic of these techniques is an excellent tolerance with very few complications. This article reviews the differences between these techniques when applied to lung tumors, indications, results and complications. Future potential associations with immunotherapy will be discussed. PMID- 28844614 TI - Responsiveness of gait analysis parameters in a cohort of 71 CMT subjects. AB - Detection of worsening in the slowly progressive Charcot-Marie-Tooth disease (CMT) is difficult. As previous clinical scales showed low responsiveness, novel outcome measures are under study, including innovative approaches such as quantitative muscle MRI and instrumented movement analysis. Since gait analysis proved able to reliably quantify CMT locomotor deficits, we aimed to explore whether it can be a sensitive-to-change outcome measure in CMT studies. Clinical and biomechanical evaluations were performed in 71 CMT subjects at baseline and after a mean (+/-sd) of 28.9 +/- 9.5 months. Locomotor tasks included natural walking, ascending and descending steps. Instrumented analysis of such tasks provided indexes related to muscle strength (kinetic parameters) and joint movement (kinematic parameters). Parameter responsiveness was expressed as Standardized Response Mean (SRM). Considering the whole CMT group, several parameters showed moderate responsiveness; subgrouping subjects according to disease severity allowed reaching high responsiveness (SRM >0.80). CMT Examination Score showed moderate responsiveness (SRM 0.53) in the minimally affected group; kinematic parameters were more responsive in this group, whereas kinetic parameters in the most severely affected one. Biomechanical parameters can represent suitable outcome measures for CMT by showing moderate-to-high responsiveness. These data suggest that appropriate selection of patient population and outcome measures is crucial for clinical trials' design. PMID- 28844615 TI - Anti-JCV antibody serostatus and longitudinal evaluation in a Portuguese Multiple Sclerosis population. AB - Multiple Sclerosis (MS) treatment with natalizumab is associated with Progressive Multifocal Leukoencephalopathy (PML). The risk of PML being related to the anti JCV antibody index is well established, but there is less known about seroconversion rates in natalizumab-treated patients and longitudinal variation in the anti-JCV antibody index. Our objective was to assess anti-JCV antibody prevalence in an MS population and to evaluate the evolution of the anti-JCV antibody index in natalizumab-treated patients. To assess anti-JCV antibody prevalence, we included all patients who had the anti-JCV antibody test in our consultation, regardless of the treatment. To evaluate the evolution of the anti JCV antibody index and seroconversion, only natalizumab-treated patients with at least two samples were selected. Demographic characteristics were evaluated. From a total of 371 patients included, 68.19% (n=253) were seropositive for anti-JCV antibodies (JCV+). There was a significant difference in anti-JCV antibody seropositivity concerning gender (male 76.27% vs. female 64.43%, p=0.023), but not age. To evaluate seroconversion, 85 patients who were initially seronegative (JCV-) were selected. The annual rate of seroconversion in the first two years was stable, but after that there was a significant increase with treatment duration (rho=0.90, p=0.037): in the first year it was 5.88% (n=5/85); in the second, 5.71% (n=4/70); in the third, 6.82% (n=3/44); in the fourth, 10.34% (n=3/29); and in the fifth, 15.0% (n=3/20). The mean index variability was higher in patients who experienced seroconversion (1.16+/-0.97), followed by JCV+ patients (0.44+/-0.48), compared to JCV- patients (0.08+/-0.05). In conclusion, anti-JCV antibody prevalence in our population is comparable to other reported cohorts. The seroconversion rate increased with treatment duration. We found a high fluctuation in the antibody index in JCV+ patients. PMID- 28844616 TI - MicroRNA-21 promotes bone mesenchymal stem cells migration in vitro by activating PI3K/Akt/MMPs pathway. AB - MicroRNA-21 (miR-21) contributes to anti-apoptosis in bone marrow mesenchymal stem cells (BMSC), but its role in the migration of BMSCs remains vague. The aim of this study was to determine the possible effect of miR-21 on regulating BMSCs directional migration and the expression of MMP-2/MMP-9 in BMSCs in vitro. BMSCs were successfully infected with miR-21-up lentivirus. Cell migration using Transwell assay indicated that upregulated expression of miR-21 could significantly promote BMSCs migration. Western blot analysis indicated that miR 21 significantly upregulated the expression of MMP-2 and MMP-9, which were related to metastasis-associated genes. GM6001, the specific MMPs inhibitor, abrogated the upregulated expression of MMP-2/MMP-9 and abolished the positive effect of miR-21 on promoting BMSCs migration. Meanwhile, miR-21 significantly enhanced Akt phosphorylation, as measured by Western blot analysis. LY294002, an inhibitor of Akt activation, abrogated the phosphorylation of Akt and abolished the positive effect of miR-21 on promoting BMSCs migration and upregulating MMP 2/MMP-9 expression. These results suggest that miR-21 contributes to BMSCs migration by upregulating MMP-2/MMP-9, potentially via the PI3K/Akt pathway. PMID- 28844617 TI - Spinal extradural arteriovenous fistulas with retrograde intradural venous drainage: Diagnostic features in digital subtraction angiography and time resolved magnetic resonance angiography. AB - Spinal extradural arteriovenous fistulas (AVFs) may be more difficult to prospectively identify than dural AVFs because they are less common than dural AVFs. The primary purpose was to further characterize the diagnostic imaging of spinal extradural AVFs with intradural retrograde venous drainage. The magnetic resonance (MR) imaging and angiographic results of 23 patients with suspected spinal dural AVFs were analyzed in order to distinguish dural and extradural AVFs. The diagnostic accuracy of MR angiography was retrospectively compared between dural and extradural AVFs. All 23 patients showed high intensity in the spinal cord on T2-weighted MR images. Eighteen out of 23 patients were diagnosed with dural AVFs, while the remaining 5 were diagnosed with extradural AVFs by angiography. Extradural AVFs were fed by a branch of the segmental artery to the vertebral body, characterized by a fistula located in the ventral extradural space, and drained retrogradely via an epidural venous pouch into intradural veins. The segmental artery was localized within 1 vertebral level using MRA in 12 out of 18 patients (67%) with dural AVFs and in 1 out of 5 patients (20%) with extradural AVFs (p=0.09). The reasons behind the lower accuracy was mainly the image misinterpretation. Congestion of the spinal cord in spinal extradural AVFs with intradural retrograde venous drainage was similar to that in dural AVFs, whereas its angioarchitecture differed from that of dural AVFs. A clearer understanding of the imaging features of extradural AVFs is important for improving the diagnostic accuracy and clarifying treatment targets. PMID- 28844618 TI - Impact of pain and pain subtypes on the quality of life of patients with Parkinson's disease. AB - Pain is a frequent and troublesome non-motor symptom of Parkinson's disease (PD) and has a negative impact on quality of life (QoL). The aim of this study was to investigate the relative impact of pain or a specific pain subtype on the QoL of patients with PD. We included 161 patients with PD. Pain was assessed using the patients' descriptions, a structured interview, and a detailed neurological examination. QoL was assessed using the 39-item Parkinson's Disease Questionnaire (PDQ-39). One hundred and twenty (74.5%) patients with PD had chronic pain. Musculoskeletal pain was the most prevalent type, followed by radicular/neuropathic, dystonic, and central pain. PD patients with pain, regardless of the pain subtype, had a worse PDQ-39 score than those without pain. Multivariate regression analysis after adjusting for disease-related factors and motor characteristics showed that younger PD onset age and the high scores of part II of Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, and Visual Analogue Scale were significant predictors of the poor PDQ-39 score. Pain along with depression, poor activities of daily living, and younger age of PD symptom onset are associated with poor QoL. All subtypes of pain affect QoL of patients with PD. Pain should be considered during the management of patients with PD. PMID- 28844619 TI - Combined upper cervical canal stenosis and cervical ossification of the posterior longitudinal ligament resulting in myelopathy: A case series and literature review. AB - Combined upper cervical canal stenosis and cervical ossification of the posterior longitudinal ligament (OPLL) is an under-recognized disorder. The objective of the present study was to investigate the radiological manifestations and surgical outcomes of this disease combination. Between May 2011 and July 2014, we studied the radiological manifestations of 18 cases of combined upper cervical canal stenosis and cervical OPLL. Appropriate decompression procedures were performed and the clinical outcomes were evaluated using a visual analog scale (VAS) and the Japanese Orthopedic Association (JOA) scoring system. Radiological outcomes, including the space available for the spinal cord (SAC) at the cephalad-adjacent level, occupying ratio of OPLL, and cervical sagittal alignment, were measured. We found that the etiologies of upper cervical canal stenosis included craniovertebral junction deformity, atlantoaxial subluxation, and OPLL extending to the C2 level. The radiological features of OPLL varied. Postoperatively, all patients showed evidence of improvement in their VAS and JOA scores. The radiological results were satisfactory in terms of the SAC at the cephalad adjacent level, occupying ratio of OPLL, and cervical alignment. We found that the radiological manifestations of combined upper cervical canal stenosis and cervical OPLL varied among patients. Satisfactory results can be achieved by applying appropriate decompression techniques. PMID- 28844620 TI - Whole exome sequencing: Uncovering causal genetic variants for ocular diseases. AB - Identification of causal genetic defects for human diseases took a significant leap when the first generation DNA sequencing technologies enabled biologists extract sequence-based genetic information from living beings. However, these sequencing methods had unavoidable constraints of throughput, scalability, rapidity, and resolution. In this direction, next-generation sequencing (NGS) since the time of its advent has revolutionized the process of gene discovery for both monogenic and multifactorial genetic diseases. Among several variations of NGS, whole exome sequencing (WES) has emerged as a smart strategy that enables identification of disease causing variants present within the coding region of the human genome. The current review focuses primarily on the application of WES in identification of causal variants for ocular diseases. WES has successfully revealed pathogenic variants in a variety of ocular diseases such as retinal degenerations, refractive errors, lens diseases, corneal dystrophies, and developmental ocular defects. It has demonstrated immense potential for molecular diagnosis of genetic ocular diseases. WES has been extensively used in Mendelian and complex cases, familial and sporadic cases, simplex and multiplex cases, and syndromic and non-syndromic cases of ocular diseases. Although many such ocular diseases have been investigated using WES, reports indicate that it has been employed overwhelmingly for heterogeneous retinal degenerations. WES, within a short period of time, has proved to be a cost-effective and promising approach for understanding the genetic basis of ocular diseases. PMID- 28844621 TI - Serious and actionable risks, plus disclosure: Investigating an alternative approach for presenting risk information in prescription drug television advertisements. AB - BACKGROUND: Broadcast direct-to-consumer (DTC) prescription drug ads that present product claims are required to also present the product's major risks. Debate exists regarding how much information should be included in these major risk statements. Some argue that such statements expose people to unnecessary amounts of information, while others argue that they leave out important information. OBJECTIVES: Examine the impact of type of risk statement (unedited versus serious and actionable risks only) and a disclosure indicating that not all risks are presented on consumers' ability to remember the important risks and benefits of a drug following exposure to a DTC television advertisement (ad). Risk and benefit perceptions, ad-prompted actions, recognition of the disclosure statement, and evaluations of both the disclosure and risk statement were also examined. METHODS: A web-based experiment was conducted in which US adults who self reported as having depression (N = 500), insomnia (N = 500), or high cholesterol (N = 500) were randomly assigned to view one of four versions of the television ad, and then complete a questionnaire. RESULTS: The type of risk statement had a significant effect on risk recall and recognition, benefit recognition, perceived risk severity (depression condition only), and perceived benefit magnitude (high cholesterol condition only). Disclosure recognition (using bias-corrected scores) ranged from 63% to 70% across the three illness samples. CONCLUSIONS: The revised risk statement improved overall processing of the television ad, as evidenced by improved risk recall and recognition and improved benefit recognition. Further, the presence of the disclosure did not adversely affect consumers' processing of drug risk and benefit information. Therefore, limiting the risks presented in DTC television ads and including a disclosure alerting consumers that not all risks are presented may be an effective strategy for communicating product risks. PMID- 28844622 TI - From transitions to transformation - A study of pharmacists developing patient centered communication skills. AB - BACKGROUND: Pharmacists' communication with patients often focuses on technical aspects of advice giving, while limiting socio-emotional content. To develop pharmacists' patient-centered communication a learning and practice module integrating motivational interviewing (MI) was designed for an online postgraduate program, and its impact on their self-described practice evaluated. OBJECTIVES: To investigate whether training in patient-centered communication changes pharmacists' perceptions of communicating with patients, and how any changes in their communication style influenced interactions and relationships with patients. METHODS: A descriptive, qualitative study analyzing reflective journal entries detailing pharmacists' experiences of implementing patient centered communication in practice was designed, evaluating reflections on initial patient interactions after training and 9-12 weeks later. Using the framework method of content and thematic analysis, an evaluation framework was devised that integrated communication, change and learning theories. Reflections were categorized within the framework as transitional (e.g. using good communication skills), transactional (e.g. using MI techniques, achieving reciprocity) or transformational (e.g. describing transformative learning, changing frames of reference in understanding of patient-centeredness). Differences between the first and last journal entries were evaluated and analyzed using descriptive statistics. RESULTS: Eighty-nine pharmacists provided two reflective journal entries for evaluation. Over 9-12 weeks, pharmacists described a change in their perspective of patient-centeredness, how they expanded the socio-emotional aspects of communication and succeeded in difficult conversations. When applying the thematic evaluation framework to initial journal entries, 38 (42%) of reflections fell within the transitional category, 51 (58%) were deemed transactional and none transformational. This changed to 10 (11%) transitional, 45 (51%) transactional and 34 (38%) transformational. Differences were observed between journal entries from pharmacists who studied completely online and those who also attended a workshop. CONCLUSION: Learning and practicing techniques of MI and person-focused communication changed many pharmacists' frames of reference in regards to patient-centeredness and their self-reported communication style with patients. PMID- 28844623 TI - Development and Field Test of an Audit Tool and Tracer Methodology for Clinician Assessment of Quality in End-of-Life Care. AB - CONTEXT: Quality improvement in end-of-life care generally acquires data from charts or caregivers. "Tracer" methodology, which assesses real-time information from multiple sources, may provide complementary information. OBJECTIVES: The objective of this study was to develop a valid brief audit tool that can guide assessment and rate care when used in a clinician tracer to evaluate the quality of care for the dying patient. METHODS: To identify items for a brief audit tool, 248 items were created to evaluate overall quality, quality in specific content areas (e.g., symptom management), and specific practices. Collected into three instruments, these items were used to interview professional caregivers and evaluate the charts of hospitalized patients who died. Evidence that this information could be validly captured using a small number of items was obtained through factor analyses, canonical correlations, and group comparisons. A nurse manager field tested tracer methodology using candidate items to evaluate the care provided to other patients who died. RESULTS: The survey of 145 deaths provided chart data and data from 445 interviews (26 physicians, 108 nurses, 18 social workers, and nine chaplains). The analyses yielded evidence of construct validity for a small number of items, demonstrating significant correlations between these items and content areas identified as latent variables in factor analyses. Criterion validity was suggested by significant differences in the ratings on these items between the palliative care unit and other units. The field test evaluated 127 deaths, demonstrated the feasibility of tracer methodology, and informed reworking of the candidate items into the 14-item Tracer EoLC v1. CONCLUSION: The Tracer EoLC v1 can be used with tracer methodology to guide the assessment and rate the quality of end-of-life care. PMID- 28844624 TI - Symptom Distress Among Diverse Patients Referred for Community-Based Palliative Care: Sociodemographic and Medical Correlates. AB - CONTEXT: Community-based palliative care programs are appearing in the U.S. Many of these programs, particularly those in large cities, serve highly diverse populations. Information about the sources of variation in the conditions that drive illness burden, like symptom distress, may be useful in program planning. OBJECTIVES: To characterize variation in symptom distress among highly diverse patients referred for palliative care in an urban setting. METHODS: This is a retrospective cross-sectional survey of data obtained from patients at the time of enrollment in a community-based palliative care program. Symptom distress was measured using the Condensed Memorial Symptom Assessment Scale. Severe distress was defined as reporting either "quite a bit"/"very much" or "frequently"/"almost constantly" for one or more symptoms. Multivariate analysis evaluated the associations between symptom distress and sources of patient variability. RESULTS: Patients (n = 1532) were aged 72.2 years on average; 60.0% were women, 56.4% were African-American or Hispanic, and 30.8% were non-English speaking. Most had cancer or congestive heart failure (68.6%); 90.2% had a Karnofsky Performance Status score of 40-70. The most prevalent symptoms were fatigue (71.8%), pain (47.3%), and sadness (41.6%); the most distressing symptoms were fatigue (58.5%), worrying (54.8%), and weight loss (52.1%). In multivariate analyses, Caucasian race, non-Asian language, low Karnofsky Performance Status scores, and cancer diagnosis predicted severe symptom distress. CONCLUSION: In a diverse urban population receiving community-based palliative care, symptoms were highly prevalent and distressing, and both sociodemographic and medical factors predicted severe distress. Program planning should consider the needs of subpopulations at risk for high symptom burden. PMID- 28844625 TI - Lupus Nephritis Associated With Cytoplasmic Anti-neutrophil Cytoplasmic Antibodies. PMID- 28844626 TI - Associations of Tumor Necrosis Factor-alpha and Interleukin-1beta Levels and Polymorphisms with Post-Stroke Depression. AB - OBJECTIVE: Proinflammatory cytokines have been implicated in the pathophysiology of post-stroke depression (PSD), and their production levels are influenced by the transcriptional activity of genetic polymorphisms. The present study aimed to investigate the roles of tumor necrosis factor (TNF)-alpha and interleukin (IL) 1beta in the serum on the risk of PSD while taking into account the TNF-alpha 850C/T and -308G/A polymorphisms and the IL-1beta -511C/T and +3953C/T polymorphisms. METHODS: A total of 286 patients were evaluated at 2 weeks post stroke and 222 (78%) of these patients were followed up 1 year later. Depressive (major or minor) disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria during both examinations; evaluations of cytokine concentrations and polymorphisms and demographic and clinical covariates were performed at 2 weeks. The effects of TNF alpha and IL-1beta concentrations and genotypes on PSD status were investigated using multivariate logistic regression models. RESULTS: Higher TNF-alpha levels were associated with PSD at 2 weeks in the presence of the -850T allele with a significant interaction term; higher IL-1beta levels were associated with PSD at 2 weeks in the presence of the -511T allele with a borderline significant interaction term and with any +3953C/T polymorphism without a significant interaction term. No associations were found with PSD at 1 year. CONCLUSIONS: These findings indicate the important roles that TNF-alpha and IL-1beta serum levels play regarding the risk of PSD, particularly during the acute phase of stroke and in patients with genetic susceptibility. PMID- 28844627 TI - Retrieved Magnesia-Stabilized Zirconia Femoral Heads Exhibit Minimal Roughening and Abrasive Potential. AB - BACKGROUND: The degradation of ceramic femoral heads made of yttria-stabilized zirconia (Y-TZP) because of tetragonal-to-monoclinic phase transformation in vivo is well-described, whereas magnesia-stabilized zirconia (Mg-PSZ) ceramics resist phase transformation in a warm aqueous environment. The purpose of this study was to evaluate phase transformation, changes in surface topography, and roughness parameters, including changes in surface polarity and abrasiveness, among retrieved zirconia femoral heads. METHODS: A total of 69 Y-TZP and 86 Mg-PSZ retrieved femoral heads were examined, with 5 never-implanted heads of each type as controls. Selected heads were scanned by x-ray diffraction, to measure % monoclinic phase. All heads were scanned by optical profilometry to find visual evidence of degradation and to measure surface roughness, surface polarity, and the functional roughness parameters. Monoclinic phase % and roughness data were plotted vs time in vivo. RESULTS: Visual evidence of phase transformation was observed among Y-TZP femoral heads, and some exhibited pitting. Y-TZP femoral heads roughened and become more abrasive in vivo, although those made by CeramTec exhibited less degradation than those by Morgan and Saint Gobain. In contrast, Mg PSZ heads did not exhibit pitting, undergo phase transformation, or roughen in vivo, and retained a negative surface polarity. CONCLUSION: All Y-TZP femoral heads exhibited increased phase transformation with time in vivo, although not all Y-TZP heads exhibited catastrophic roughening. No phase transformation was observed on Mg-PSZ femoral heads after up to 19.2 years in vivo. The lack of degradation among Mg-PSZ retrievals suggests a lower wear potential in joint replacement. PMID- 28844628 TI - Revision Total Knee Arthroplasty in Octogenarians: An Analysis of 957 Cases. AB - BACKGROUND: The number of octogenarians undergoing revision total knee arthroplasty (TKA) is increasing. However, there has been a lack of studies investigating the perioperative course and safety of revision TKA performed in this potentially vulnerable population in a large patient population. The purpose of this study is to compare complications following revision TKA between octogenarians and 2 younger patient populations (<70 and 70-79 year olds). METHODS: Patients who underwent revision TKA were identified in the 2005-2015 National Surgical Quality Improvement Program database and stratified into 3 age groups: <70, 70-79, and >=80 years. Baseline preoperative and intraoperative characteristics were compared between the 3 groups. Propensity score matched comparisons were then performed for 30-day perioperative complications, length of hospital stay, and readmissions. RESULTS: This study included 6523 (<70 years), 2509 (70-79 years), and 957 octogenarian patients who underwent revision TKA. After propensity matching, statistical analysis revealed only higher rates of blood transfusion and slightly longer length of stay in octogenarians compared to <70 year olds. Similarly, octogenarians had only higher rates of blood transfusion and slightly longer length of stay compared to 70-79 year olds. Notably, there were no differences in mortality or readmission between octogenarians compared to younger populations. CONCLUSION: These data suggest that revision TKA can safely be considered for octogenarians with the observation of higher rates of blood transfusion and slightly longer length of stay compared to younger populations. Octogenarian patients need not be discouraged from revision TKA solely based on their advanced age. PMID- 28844629 TI - Total Hip Arthroplasty After In Situ Fixation of Minimally Displaced Femoral Neck Fractures in Elderly Patients. AB - BACKGROUND: In situ screw fixation remains the most common treatment for minimally displaced femoral neck fractures (FNFs). Total hip arthroplasty (THA) can be used as a salvage procedure, but the results of conversion THA in this population have not been evaluated. The goals of this study were to evaluate (1) unique complications associated with conversion THA, (2) implant survivorship free of revision and reoperation, (3) radiographic results, and (4) clinical outcomes in patients undergoing conversion THA after in situ fixation of nondisplaced FNFs. METHODS: Between 2000 and 2014, 62 consecutive patients >65 years of age who underwent THA after in situ fixation of minimally displaced FNFs were identified. Indications were osteonecrosis (44%), post traumatic/degenerative arthritis (35%), and nonunion (21%). Mean age was 78 years, and 73% patients were women. Mean follow-up was 5.5 years. RESULTS: One patient was revised for aseptic femoral loosening at 11 years. One patient underwent debridement and modular component exchange at 10 years for acute hematogenous periprosthetic joint infection. Two patients underwent acute reoperation without component exchange (one superficial wound infection, one hematoma evacuation). Survivorship free of reoperation for any indication was 97% at 5 years. No patients with surviving implants had radiographic evidence of loosening at 5 years. Harris hip scores improved from 35-85 (P < .01) after THA. CONCLUSION: Conversion THA was associated with clinical improvement, a low rate of complications, and excellent implant durability. Risks of loosening, dislocation, and periprosthetic fracture can be minimized with appropriate operative strategies and perioperative management. PMID- 28844630 TI - Do Porous Tantalum Metaphyseal Cones Improve Outcomes in Revision Total Knee Arthroplasty? AB - BACKGROUND: Some authors have advocated for use of porous tantalum metaphyseal cones to manage bone defects during revision total knee arthroplasty (TKA). The purpose of this study is to compare results with porous metaphyseal cones to results with traditional hybrid stem fixation in revision TKA. METHODS: Forty nine patients undergoing revision TKA with femoral and/or tibial metaphyseal cones (39 tibial only, 3 femoral only, 7 both) were matched by surgical indication to 49 patients undergoing revision TKA with a traditional hybrid stem (non-cone) technique. Clinical and radiographic outcomes were compared at a minimum of two-year follow-up (mean 3.5 years) with adjustment for baseline characteristics. RESULTS: Pre-revision bone defects and most baseline demographics were similar between the cone and non-cone cohorts suggesting appropriate matching. Patients in the non-cone cohort had greater pre- to post operative increases in Knee Society Score (37.2 +/- 18.6 vs 28.4 +/- 17.8, P = .010) and Knee Society Functional Score (30.4 +/- 24.3 vs 13.1 +/- 27.6, P = .003). The cohorts did not differ with respect to complications, subsequent reoperation, subsequent revision, patient satisfaction, tibial overhang, the presence of radio-sclerotic lines, cortical hypertrophy around the stems, or tibial subsidence. CONCLUSION: In this series, metaphyseal cones were not associated with superior outcomes at short-term follow-up. Given the increased cost associated with use of cones compared to traditional techniques, this study cannot support the routine use of metaphyseal cones in revision TKA. Longer-term follow-up will be necessary to determine if construct durability differs over the long term. PMID- 28844631 TI - Improving Value in Total Hip and Knee Arthroplasty: The Role of High Volume Hospitals. AB - BACKGROUND: Recent healthcare reform efforts have focused on improving the quality of total joint replacement care while reducing overall costs. The purpose of this study is to determine if higher volume centers have lower costs and better outcomes than lower volume hospitals. METHODS: We queried the Centers for Medicare and Medicaid Services (CMS) Inpatient Charge Data and identified 2702 hospitals that performed a total of 458,259 primary arthroplasty procedures in 2014. Centers were defined as low (performing <100 total joint arthroplasty [TJA] per year) or high volume and mean total hospital-specific charges and inpatient payments were obtained. Patient satisfaction scores as well 30-day risk-adjusted complication and readmission scores were obtained from the multiyear CMS Hospital Compare database. RESULTS: Of all the hospitals, 1263 (47%) hospitals were classified as low volume and performed 60,895 (12%) TJA cases. Higher volume hospitals had lower mean total hospital-specific charges ($56,323 vs $60,950, P < .001) and mean Medicare inpatient payments ($12,131 vs $13,289, P < .001). Higher volume facilities had a lower complication score (2.96 vs 3.16, P = .015), and a better CMS hospital star rating (3.14 vs 2.89, P < .001). When controlling for hospital geographic and demographic factors, lower volume hospitals are more likely to be in the upper quartile of inpatient Medicare costs (odds ratio 2.127, 95% confidence interval 1.726-2.621, P < .001). CONCLUSION: Hospitals that perform <100 TJA cases per year may benefit from adopting the practices of higher volume centers in order to improve quality and reduce costs. PMID- 28844632 TI - Patient Dissatisfaction Following Total Knee Arthroplasty: A Systematic Review of the Literature. AB - BACKGROUND: Dissatisfaction following total knee arthroplasty (TKA) is common. Approximately 20% of patients report dissatisfaction following primary TKA. This systematic literature review explores key factors affecting patient dissatisfaction following TKA. METHODS: Six literature databases published between 2005 and 1 January 2016 were searched using 3 key search phrases. Papers were included if the study investigated patient dissatisfaction in primary unilateral or bilateral TKA. Information from each article was categorized to the domains of socioeconomic, preoperative, intraoperative, and postoperative factors affecting patient dissatisfaction. RESULTS: This review found that patient dissatisfaction pertains to several key factors. Patient expectations prior to surgery, the degree of improvement in knee function, and pain relief following surgery were commonly cited in the literature. Fewer associations were found in the socioeconomic and surgical domains. CONCLUSION: Identifying who may be dissatisfied after their TKA is mystifying; however, we note several strategies that target factors whereby an association exists. Further research is needed to better quantify dissatisfaction, so that the causal links underpinning dissatisfaction can be more fully appreciated and strategies employed to target them. PMID- 28844633 TI - Corrigendum to 'A Comparison of Modular Tapered Versus Modular Cylindrical Stems for Complex Femoral Revisions' [Journal of Arthroplasty 28 Suppl. 1 (2013) 71 73]. PMID- 28844634 TI - Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management. AB - Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015-16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities. PMID- 28844635 TI - Vaccine exemptions and the kindergarten vaccination coverage gap. AB - BACKGROUND: Vaccination requirements for kindergarten entry vary by state, but all states require 2 doses of measles containing vaccine (MCV) at kindergarten entry. OBJECTIVE: To assess (i) national MCV vaccination coverage for children who had attended kindergarten; (ii) the extent to which undervaccination after kindergarten entry is attributable to parents' requests for an exemption; (iii) the extent to which undervaccinated children had missed opportunities to be administered missing vaccine doses among children whose parent did not request an exemption; and (iv) the vaccination coverage gap between the "highest achievable" MCV coverage and actual MCV coverage among children who had attended kindergarten. METHODS: A national survey of 1465 parents of 5-7year-old children was conducted during October 2013 through March 2014. Vaccination coverage estimates are based provider-reported vaccination histories. Children have a "missed opportunity" for MCV if they were not up-to-date and if there were dates on which other vaccines were administered but not MCV. The "highest achievable" MCV vaccination coverage rate is 100% minus the sum of the percentages of (i) undervaccinated children with parents who requested an exemption; and (ii) undervaccinated children with parents who did not request an exemption and whose vaccination statuses were assessed during a kindergarten grace period or period when they were provisionally enrolled in kindergarten. RESULTS: Among all children undervaccinated for MCV, 2.7% were attributable to having a parent who requested an exemption. Among children who were undervaccinated for MCV and whose parent did not request an exemption, 41.6% had a missed opportunity for MCV. The highest achievable MCV coverage was 98.6%, actual MCV coverage was 90.9%, and the kindergarten vaccination gap was 7.7%. CONCLUSION: Vaccination coverage may be increased by schools fully implementing state kindergarten vaccination laws, and by providers assessing children's vaccination status at every clinic visit, and administering missed vaccine doses. PMID- 28844636 TI - Factors associated with routine childhood vaccine uptake and reasons for non vaccination in India: 1998-2008. AB - BACKGROUND: Despite almost three decades of the Universal Immunization Program in India, a little more than half the children aged 12-23months receive the full schedule of routine vaccinations. We examined socio-demographic factors associated with partial-vaccination and non-vaccination and the reasons for non vaccination among Indian children during 1998 and 2008. METHODS: Data from three consecutive, nationally-representative, District Level Household and Facility Surveys (1998-99, 2002-04 and 2007-08) were pooled. Multinomial logistic regression was used to identify individual and household level socio-demographic variables associated with the child's vaccination status. The mother's reported reasons for non-vaccination were analyzed qualitatively, adapting from a previously published framework. RESULTS: The pooled dataset contained information on 178,473 children 12-23months of age; 53%, 32% and 15% were fully vaccinated, partially vaccinated and unvaccinated respectively. Compared with the 1998-1999 survey, children in the 2007-2008 survey were less likely to be unvaccinated (Adjusted Prevalence Odds Ratio (aPOR): 0.92, 95%CI=0.86-0.98) but more likely to be partially vaccinated (aPOR: 1.58, 95%CI=1.52-1.65). Vaccination status was inversely associated with female gender, Muslim religion, lower caste, urban residence and maternal characteristics such as lower educational attainment, non institutional delivery, fewer antenatal care visits and non-receipt of maternal tetanus vaccination. The mother's reported reasons for non-vaccination indicated gaps in awareness, acceptance and affordability (financial and non-financial costs) related to routine vaccinations. CONCLUSIONS: Persisting socio-demographic disparities related to partial-vaccination and non-vaccination were associated with important childhood, maternal and household characteristics. Further research investigating the causal pathways through which maternal and social characteristics influence decision-making for childhood vaccinations is needed to improve uptake of routine vaccination in India. Also, efforts to increase uptake should address parental fears related to vaccination to improve trust in government health services as part of ongoing social mobilization and communication strategies. PMID- 28844637 TI - Response to "Risperidone and sulpiride: Brands vs generics". PMID- 28844638 TI - A state-independent network of depressive, negative and positive symptoms in male patients with schizophrenia spectrum disorders. AB - Depressive symptoms occur frequently in patients with schizophrenia. Several factor analytical studies investigated the associations between positive, negative and depressive symptoms and reported difficulties differentiating between these symptom domains. Here, we argue that a network approach may offer insights into these associations, by exploring interrelations between symptoms. The aims of current study were to I) construct a network of positive, negative and depressive symptoms in male patients with schizophrenia to investigate interactions between individual symptoms; II) identify the most central symptoms within this network and III) examine group-level differences in network connectivity between remitted and non-remitted patients. We computed a network of depressive, positive and negative symptoms in a sample of 470 male patients diagnosed with a psychotic disorder. Depressive symptoms were assessed with the Calgary Depression Rating Scale for Schizophrenia, while psychotic symptoms were assessed with the Positive and Negative Syndrome Scale. Networks of male patients who fulfilled remission criteria (Andreasen et al., 2005) and non-remitters for psychosis were compared. Our results indicate that depressive symptoms are mostly associated with suicidality and may act as moderator between psychotic symptoms and suicidality. In addition, 'depressed mood', 'observed depression', 'poor rapport', 'stereotyped thinking' and 'delusions' were central symptoms within the network. Finally, although remitted male patients had a similar network structure compared to non-remitters the networks differed significantly in terms of global strength. In conclusion, clinical symptoms of schizophrenia were linked in a stable way, independent of symptomatic remission while the number of connections appears to be dependent on remission status. PMID- 28844639 TI - Rapid vs. slow antipsychotic initiation in schizophrenia: A systematic review and meta-analysis. AB - BACKGROUND: How antipsychotics should be initiated/titrated in patients with acute schizophrenia as well as patients undergoing an antipsychotic switch remains a question. METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched. Randomized controlled trials examining rapid vs. slow antipsychotic initiation in patients with schizophrenia were selected. Data on study discontinuation, psychopathology, extrapyramidal symptoms (EPS), and treatment-emergent adverse events (TEAEs) were extracted and synthesized in studies including clinically different populations of acute patients and stable patients undergoing an antipsychotic switch. RESULTS: Among 11 studies that met eligibility criteria, 8 and 3 studies involving 809 and 777 patients were identified as acute patient studies and stable patient switching studies, respectively. Rapid antipsychotic initiation was not significantly different from slow antipsychotic initiation in acute patient studies for all cause study discontinuation, while the former was significantly inferior to the latter in stable patient switching studies (N=3, n=777, RR=1.45, 95% CI=1.05 2.00, P=0.02). In contrast, rapid initiation was significantly superior to slow initiation for all psychopathology outcomes including the PANSS/BPRS total score (N=3, n=336, SMD=-0.28, 95% CI=-0.51--0.05, P=0.02) in acute patient studies, but not different in stable patient switching studies. Any other outcomes except for nausea did not significantly differ between the 2 groups. CONCLUSIONS: Rapid initiation of antipsychotics may represent a reasonable option for the treatment of acute schizophrenia, while slower initiation may be a safer strategy when switching antipsychotics in stable schizophrenia. Because of the low to very low quality of evidence, findings should be considered preliminary. PMID- 28844640 TI - Early Versus Late Canalicular Laceration Repair Outcomes. AB - PURPOSE: To determine whether delayed repair of traumatic canalicular laceration affects the final outcome. DESIGN: Retrospective case series. METHODS: The medical records of 334 patients who underwent primary traumatic canalicular laceration repair were retrospectively reviewed. Patients were divided into 2 groups according to the surgical timing within 48 hours (early) or after 48 hours (delayed). The anatomic results were compared between these 2 groups. The causes of delayed repair and the mean operation time were also analyzed. RESULTS: There were 23 failed cases among 301 patients (7.6%) who had a repair within 48 hours and 3 failed cases among 33 patients (9.1%) who had a repair after 48 hours (P = .732). The mean operation time was 62 minutes in the early group and 66.3 minutes in the delayed group, which showed no significant difference (P = .371). The major cause of delayed surgery was traumatic brain injury, followed by facial or orbital fracture, long bone fracture, and chest injury. CONCLUSIONS: Delayed canalicular repair in unstable patients did not lead to poor results. An elective scheduling surgery, instead of an urgent repair, is feasible for an experienced surgeon. PMID- 28844641 TI - Performance of an iPad Application to Detect Moderate and Advanced Visual Field Loss in Nepal. AB - PURPOSE: To evaluate the accuracy and efficiency of Visual Fields Easy (VFE), a free iPad app, for performing suprathreshold perimetric screening. DESIGN: Prospective, cross-sectional validation study. METHODS: We performed screening visual fields using a calibrated iPad 2 with the VFE application on 206 subjects (411 eyes): 210 normal (NL), 183 glaucoma (GL), and 18 diabetic retinopathy (DR) at Tilganga Institute of Ophthalmology, Kathmandu, Nepal. We correlated the results with a Humphrey Field Analyzer using 24-2 SITA Standard tests on 373 of these eyes (198 NL, 160 GL, 15 DR). RESULTS: The number of missed locations on the VFE correlated with mean deviation (MD, r = 0.79), pattern standard deviation (PSD, r = 0.60), and number of locations that were worse than the 95% confidence limits for total deviation (r = 0.51) and pattern deviation (r = 0.68) using SITA Standard. iPad suprathreshold perimetry was able to detect most visual field deficits with moderate (MD of -6 to -12 dB) and advanced (MD worse than -12 dB) loss, but had greater difficulty in detecting early (MD better than -6 dB) loss, primarily owing to an elevated false-positive response rate. The average time to perform the Visual Fields Easy test was 3 minutes, 18 seconds (standard deviation = 16.88 seconds). DISCUSSION: The Visual Fields Easy test procedure is a portable, fast, effective procedure for detecting moderate and advanced visual field loss. Improvements are currently underway to monitor eye and head tracking during testing, reduce testing time, improve performance, and eliminate the need to touch the video screen surface. PMID- 28844642 TI - Function and Evolution of Vibrato-like Frequency Modulation in Mammals. AB - Why do distantly related mammals like sheep, giant pandas, and fur seals produce bleats that are characterized by vibrato-like fundamental frequency (F0) modulation? To answer this question, we used psychoacoustic tests and comparative analyses to investigate whether this distinctive vocal feature has evolved to improve the perception of formants, key acoustic components of animal calls that encode important information about the caller's size and identity [1]. Psychoacoustic tests on humans confirmed that vibrato-like F0 modulation improves the ability of listeners to detect differences in the formant patterns of synthetic bleat-like stimuli. Subsequent phylogenetically controlled comparative analyses revealed that vibrato-like F0 modulation has evolved independently in six mammalian orders in vocal signals with relatively high F0 and, therefore, low spectral density (i.e., less harmonic overtones). We also found that mammals modulate the vibrato in these calls over greater frequency extents when the number of harmonic overtones per formant is low, suggesting that this is a mechanism to improve formant perception in calls with low spectral density. Our findings constitute the first evidence that formant perception in non-speech sounds is improved by fundamental frequency modulation and provide a mechanism for the convergent evolution of bleat-like calls in mammals. They also indicate that selection pressures for animals to transmit important information encoded by formant frequencies (on size and identity, for example) are likely to have been a key driver in the evolution of mammal vocal diversity. PMID- 28844643 TI - Dopamine Regulation of GABAA Receptors Contributes to Light/Dark Modulation of the ON-Cone Bipolar Cell Receptive Field Surround in the Retina. AB - Cone bipolar cells are interneurons that receive synaptic input from cone photoreceptor cells and provide the output of the first synaptic layer of the retina. These cells exhibit center-surround receptive fields, a prototype of lateral inhibition between neighboring sensory cells in which stimulation of the receptive field center excites the cell whereas stimulation of the surrounding region laterally inhibits the cell. This fundamental sensory coding mechanism facilitates spatial discrimination and detection of stimulus edges. However, although it is well established that the receptive field surround is strongest when ambient or background illumination is most intense, e.g., at midday, and that the surround is minimal following maintained darkness, the synaptic mechanisms that produce and modulate the surround have not been resolved. Using electrical recording of bipolar cells under experimental conditions in which the cells exhibited surround light responses, and light and electron microscopic immunocytochemistry, we show in the rabbit retina that bright-light-induced activation of dopamine D1 receptors located on ON-center cone bipolar cell dendrites increases the expression and activity of GABAA receptors on the dendrites of the cells and that surround light responses depend on endogenous GABAA receptor activation. We also show that maintained darkness and D1 receptor blockade following maintained illumination and D1 receptor activation result in minimal GABAA receptor expression and activity and greatly diminished surrounds. Modulation of the D1/GABAA receptor signaling pathway of ON-cBC dendrites by the ambient light level facilitates detection of spatial details on bright days and large dim objects on moonless nights. PMID- 28844644 TI - Role of Corticotropin-Releasing Factor in Cerebellar Motor Control and Ataxia. AB - Cerebellar ataxia, characterized by motor incoordination, postural instability, and gait abnormality [1-3], greatly affects daily activities and quality of life. Although accumulating genetic and non-genetic etiological factors have been revealed [4-7], effective therapies for cerebellar ataxia are still lacking. Intriguingly, corticotropin-releasing factor (CRF), a peptide hormone and neurotransmitter [8, 9], is considered a putative neurotransmitter in the olivo cerebellar system [10-14]. Notably, decreased levels of CRF in the inferior olive (IO), the sole origin of cerebellar climbing fibers, have been reported in patients with spinocerebellar degeneration or olivopontocerebellar atrophy [15, 16], yet little is known about the exact role of CRF in cerebellar motor coordination and ataxia. Here we report that deficiency of CRF in the olivo cerebellar system induces ataxia-like motor abnormalities. CRFergic neurons in the IO project directly to the cerebellar nuclei, the ultimate integration and output node of the cerebellum, and CRF selectively excites glutamatergic projection neurons rather than GABAergic neurons in the cerebellar interpositus nucleus (IN) via two CRF receptors, CRFR1 and CRFR2, and their downstream inward rectifier K+ channel and/or hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. Furthermore, CRF promotes cerebellar motor coordination and rescues ataxic motor deficits. The findings define a previously unknown role for CRF in the olivo-cerebellar system in the control of gait, posture, and motor coordination, and provide new insight into the etiology, pathophysiology, and treatment strategy of cerebellar ataxia. PMID- 28844646 TI - Counteracting Ascarosides Act through Distinct Neurons to Determine the Sexual Identity of C. elegans Pheromones. AB - Sex pheromones facilitate reproduction by attracting potential mates and altering their behavior and physiology. In C. elegans, males and hermaphrodites secrete similar blends of pheromone molecules, two of which are present in different relative concentrations: ascr#3, which is more abundant in hermaphrodites, and ascr#10, which is more abundant in males. It is not currently understood how this compositional difference results in sex-specific effects, for example, the slower aging of the hermaphrodite germline in the presence of physiologically relevant concentrations of male pheromones. Here we report three key elements of the mechanism responsible for this phenomenon. First, ascr#3 counters the activity of ascr#10. This antagonism decreases the magnitude and the sensitivity of the hermaphrodite response to the male pheromone, restricting it to situations in which the presence of a male could be inferred with high confidence. Second, hermaphrodites recognize pheromone as male if the concentration of ascr#10 is higher than that of ascr#3. Third, the response to ascr#10 requires TRPV channel function in the ADL neurons and the daf-7 signaling from the ASI neurons, whereas the response to ascr#3 relies on cyclic guanosine monophosphate (cGMP)-gated channels and activity of the ASJ, AWB, and AWC neurons. These results argue that the counteracting activities of distinct neuronal circuits determine the sexual identity of the pheromone. The parallels between this mechanism and other signaling systems suggest that diverse organisms may perform particular neuronal computations using similar general principles. PMID- 28844645 TI - Direct Electrical Stimulation in the Human Brain Disrupts Melody Processing. AB - Prior research using functional magnetic resonance imaging (fMRI) [1-4] and behavioral studies of patients with acquired or congenital amusia [5-8] suggest that the right posterior superior temporal gyrus (STG) in the human brain is specialized for aspects of music processing (for review, see [9-12]). Intracranial electrical brain stimulation in awake neurosurgery patients is a powerful means to determine the computations supported by specific brain regions and networks [13-21] because it provides reversible causal evidence with high spatial resolution (for review, see [22, 23]). Prior intracranial stimulation or cortical cooling studies have investigated musical abilities related to reading music scores [13, 14] and singing familiar songs [24, 25]. However, individuals with amusia (congenitally, or from a brain injury) have difficulty humming melodies but can be spared for singing familiar songs with familiar lyrics [26]. Here we report a detailed study of a musician with a low-grade tumor in the right temporal lobe. Functional MRI was used pre-operatively to localize music processing to the right STG, and the patient subsequently underwent awake intraoperative mapping using direct electrical stimulation during a melody repetition task. Stimulation of the right STG induced "music arrest" and errors in pitch but did not affect language processing. These findings provide causal evidence for the functional segregation of music and language processing in the human brain and confirm a specific role of the right STG in melody processing. VIDEO ABSTRACT. PMID- 28844647 TI - Unmasking Transcriptional Heterogeneity in Senescent Cells. AB - Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5-8], and organismal aging [9]. The senescence program is variably characterized by several non-exclusive markers, including constitutive DNA damage response (DDR) signaling, senescence-associated beta-galactosidase (SA-betagal) activity, increased expression of the cyclin dependent kinase (CDK) inhibitors p16INK4A (CDKN2A) and p21CIP1 (CDKN1A), increased secretion of many bio-active factors (the senescence-associated secretory phenotype, or SASP), and reduced expression of the nuclear lamina protein LaminB1 (LMNB1) [1]. Many senescence-associated markers result from altered transcription, but the senescent phenotype is variable, and methods for clearly identifying senescent cells are lacking [10]. Here, we characterize the heterogeneity of the senescence program using numerous whole-transcriptome datasets generated by us or publicly available. We identify transcriptome signatures associated with specific senescence-inducing stresses or senescent cell types and identify and validate genes that are commonly differentially regulated. We also show that the senescent phenotype is dynamic, changing at varying intervals after senescence induction. Identifying novel transcriptome signatures to detect any type of senescent cell or to discriminate among diverse senescence programs is an attractive strategy for determining the diverse biological roles of senescent cells and developing specific drug targets. PMID- 28844648 TI - Drosophila PAF1 Modulates PIWI/piRNA Silencing Capacity. AB - To test the directness of factors in initiating PIWI-directed gene silencing, we employed a Piwi-interacting RNA (piRNA)-targeted reporter assay in Drosophila ovary somatic sheet (OSS) cells [1]. This assay confirmed direct silencing roles for piRNA biogenesis factors and PIWI-associated factors [2-12] but suggested that chromatin-modifying proteins may act downstream of the initial silencing event. Our data also revealed that RNA-polymerase-II-associated proteins like PAF1 and RTF1 antagonize PIWI-directed silencing. PAF1 knockdown enhances PIWI silencing of reporters when piRNAs target the transcript region proximal to the promoter. Loss of PAF1 suppresses endogenous transposable element (TE) transcript maturation, whereas a subset of gene transcripts and long-non-coding RNAs adjacent to TE insertions are affected by PAF1 knockdown in a similar fashion to piRNA-targeted reporters. Additionally, transcription activation at specific TEs and TE-adjacent loci during PIWI knockdown is suppressed when PIWI and PAF1 levels are both reduced. Our study suggests a mechanistic conservation between fission yeast PAF1 repressing AGO1/small interfering RNA (siRNA)-directed silencing [13, 14] and Drosophila PAF1 opposing PIWI/piRNA-directed silencing. PMID- 28844650 TI - Characterization of FaDu-R, a radioresistant head and neck cancer cell line, and cancer stem cells. AB - OBJECTIVES: The aim of this study was to evaluate the impact of CSC on insensitivity to radiotherapy in HNSCC. METHODS: A radioresistant cell line, FaDu R, was established using fractionated ionizing radiation. Cells with high and low CD44/ALDH activity were isolated. RESULTS: FaDu-R cells demonstrated significantly increased cell viability after radiation exposure compared with parental cells. CD44high/ALDHhigh FaDu-R cells demonstrated significantly faster wound closure (p<0.05) and more efficient invasion (p<0.05) compared to the CD44high/ALDHhigh FaDu cells or the CD44low/ALDHlow FaDu-R cells. There was a significant difference in tumor volume between the CD44high/ALDHhigh FaDu-R cells and the CD44high/ALDHhigh FaDu cells (p<0.05) as well as the CD44low/ALDHlow FaDu R cells (p<0.05). CONCLUSION: Cancer stem cells (CSC) were associated with invasion and tumorigenesis in a radioresistant head and neck squamous cell carcinoma (HNSCC) cell line. This concept might help to improve the understanding of these mechanisms and to develop drugs that can overcome radioresistance during radiotherapy. PMID- 28844651 TI - Gender Perception After Raising Vowel Fundamental and Formant Frequencies: Considerations for Oral Resonance Research. AB - OBJECTIVES: Voice feminization therapy for male-to-female transgender women typically targets increasing fundamental frequency (F0). Increasing vowel formant frequencies (FFs) has also been proposed. To better understand formant conditions that shift listeners' perception of gender from male to "not-male," individual and combined vowel FFs were incrementally raised, whereas F0 was held constant at a gender-ambiguous level. METHODS: The study used a prospective, experimental group design. Using a customized MATLAB program, vowels (/i/, /ae/, /alpha/, and /u/) spoken by an adult were manipulated by isolating and increasing FF1-3 until they matched those of a woman. Listeners heard randomized samples and perceptually categorized each as male, female, or gender neutral. The latter two choices were combined and labeled not-male. RESULTS: Chi-square analyses revealed that listeners rated samples as not-male for /alpha/ and /ae/ with all three formants shifted or individual formants shifted at >60%. Individual analysis of vowels, formants, and shifted FF using Kruskal-Wallis revealed a statistical significance for vowels only. CONCLUSIONS: Results suggest that voice was convincingly perceived as not-male, for vowels characterized by a high F1 frequency, and that raising FFs for all four vowels increased (in varying amounts) the perception of voice femininity beyond that of raising F0 alone. PMID- 28844649 TI - Post-operative mortality, missed care and nurse staffing in nine countries: A cross-sectional study. AB - BACKGROUND: Variation in post-operative mortality rates has been associated with differences in registered nurse staffing levels. When nurse staffing levels are lower there is also a higher incidence of necessary but missed nursing care. Missed nursing care may be a significant predictor of patient mortality following surgery. AIM: Examine if missed nursing care mediates the observed association between nurse staffing levels and mortality. METHOD: Data from the RN4CAST study (2009-2011) combined routinely collected data on 422,730 surgical patients from 300 general acute hospitals in 9 countries, with survey data from 26,516 registered nurses, to examine associations between nurses' staffing, missed care and 30-day in-patient mortality. Staffing and missed care measures were derived from the nurse survey. A generalized estimation approach was used to examine the relationship between first staffing, and then missed care, on mortality. Bayesian methods were used to test for mediation. RESULTS: Nurse staffing and missed nursing care were significantly associated with 30-day case-mix adjusted mortality. An increase in a nurse's workload by one patient and a 10% increase in the percent of missed nursing care were associated with a 7% (OR 1.068, 95% CI 1.031-1.106) and 16% (OR 1.159 95% CI 1.039-1.294) increase in the odds of a patient dying within 30days of admission respectively. Mediation analysis shows an association between nurse staffing and missed care and a subsequent association between missed care and mortality. CONCLUSION: Missed nursing care, which is highly related to nurse staffing, is associated with increased odds of patients dying in hospital following common surgical procedures. The analyses support the hypothesis that missed nursing care mediates the relationship between registered nurse staffing and risk of patient mortality. Measuring missed care may provide an 'early warning' indicator of higher risk for poor patient outcomes. PMID- 28844652 TI - Spanish validation of the adult Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS): relevance of clinical subtypes. AB - INTRODUCTION: Adult attention deficit hyperactivity disorder (ADHD) has a prevalence between 2.5% and 4% of the general adult population. Over the past few decades, self-report measures have been developed for the current evaluation of adult ADHD. The ADHD-RS is a 18-items scale self-report version for assessing symptoms for ADHD DSM-IV. A validation of Spanish version of the ADHD-RS was performed. MATERIAL AND METHOD: The sample consisted of 304 adult with ADHD and 94 controls. A case control study was carried out (adult ADHD vs. non ADHD). The diagnosis of ADHD was evaluated with the Structured Clinical Interview for DSM-IV (SCID-I) and the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID-II). To determinate the internal validity of the two dimensions structure of ADHD-RS an exploratory factor analysis was performed. The alpha-coefficients were taken as a measure of the internal consistency of the dimensions considered. A logistic regression study was carried out to evaluate the model in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV). RESULTS: Average age was 33.29 (SD=10.50) and 66% of subjects were men (there were no significant differences between the two groups). Factor analysis was done with a principal component analysis followed by a normalized varimax rotation. The Kaiser-Meyer-Olkin measure of sampling adequacy tests was .868 (remarkable) and the Bartlett's test of sphericity was 2 (153)=1,835.76, P<.0005, indicating the appropriateness of the factor analysis. This two-factor model accounted for 37.81% of the explained variance. The alpha-coefficient of the two factors was .84 and .82. The original strategy proposed 24 point for cut-off: sensitivity (81.9%), specificity (74.7%), PPV (50.0%), NPV (93.0%), kappa coefficient .78 and area under the curve (AUC) .89. The new score strategy proposed by our group suggests different cut-off for different clinical presentations. The 24 point is the best cut-off for ADHD combined presentation: sensitivity (81.9%), specificity (87.3%), PPV (78.6%), NPV (89.4%), kappa coefficient .88 and AUC .94, and 21 point is the best cut-off for ADHD predominantly inattentive presentation: sensitivity (70.2%), specificity (76.1%), PPV (71.7%), NPV (74.8%), kappa coefficient .88 and AUC .94. CONCLUSIONS: In this study, the Spanish version of the ADHD-RS is a valid scale to discriminate between ADHD adults and controls. The new proposed score strategy suggests the relevance of clinical presentations in the different cut-offs selected. PMID- 28844653 TI - No evidence of an immune adjustment in response to a parasitoid threat in Lobesia botrana larvae. AB - Immune function is a key determinant of an organism's fitness, and natural insect populations are highly variable for this trait, mainly due to environmental heterogeneity and pathogen diversity. We previously reported a positive correlation between infection prevalence by parasitoids and host immunity in natural populations of the vineyard pest Lobesia botrana. Here, we tested whether this correlation reflects a plastic adjustment of host immunity in response to the local presence of parasites. To this end, we measured immunity of non parasitized L. botrana larvae exposed, respectively, to one of the two most common species of parasitoids in vineyards, over 6days. Larvae were able to sense the parasitoid through visual, chemical, or mechanical cues, but contact larvae parasitoid were excluded. Contrary to our hypothesis, we found that L. botrana larvae did not increase their immune defenses in the presence of parasitoids, despite their ability to sense a potential threat. Our results therefore suggest that the positive correlation between infection prevalence by parasitoids and L. botrana immunity among natural populations may result from micro-evolutionary changes resulting from long-term local selection pressures imposed by parasitoids in wild populations rather than plastic adjustments of immunity. PMID- 28844654 TI - Appetitive olfactory learning and memory in the honeybee depend on sugar reward identity. AB - One of the most important tasks of the brain is to learn and remember information associated with food. Studies in mice and Drosophila have shown that sugar rewards must be metabolisable to form lasting memories, but few other animals have been studied. Here, we trained adult, worker honeybees (Apis mellifera) in two olfactory tasks (massed and spaced conditioning) known to affect memory formation to test how the schedule of reinforcement and the nature of a sugar reward affected learning and memory. The antennae and mouthparts of honeybees were most sensitive to sucrose but glucose and fructose were equally phagostimulatory. Whether or not bees could learn the tasks depended on sugar identity and concentration. However, only bees rewarded with glucose or sucrose formed robust long-term memory. This was true for bees trained in both the massed and spaced conditioning tasks. Honeybees fed with glucose or fructose exhibited a surge in haemolymph sugar of greater than 120mM within 30s that remained elevated for as long as 20min after a single feeding event. For bees fed with sucrose, this change in haemolymph glucose and fructose occurred with a 30s delay. Our data showed that olfactory learning in honeybees was affected by sugar identity and concentration, but that olfactory memory was most strongly affected by sugar identity. Taken together, these data suggest that the neural mechanisms involved in memory formation sense rapid changes in haemolymph glucose that occur during and after conditioning. PMID- 28844655 TI - A missed diagnosis of multiple intraocular foreign bodies for 21 years. AB - A 30-year-old patient went to the emergency department because of a chemical burn to the left eye more than 10 days ago by toilet cleanser. Surprisingly, a small piece of glass was found in the inferior anterior chamber in the same eye. The visual acuity was counting fingers. There was conjunctival congestion, corneal oedema and Descemet's membrane striae. And there was also a corneal leukoma around 4 to 5 o'clock. Through repeated questioning he recalled that he was injured by an exploded light bulb around 21 years ago. He was asymptomatic until he saw "something moving" in front of the left eye one month ago. Computed tomography (CT) scanning, ultrasonography, ultrasound biomicroscopy (UBM), anterior segment optical coherence tomography (AS-OCT) verified the presence of multiple intraocular foreign bodies (IOFBs) in the anterior chamber and vitreous cavity. B-scan verified the IOFB in the vitreous cavity. Thus, he was diagnosed with corneal chemical burn, IOFBs and corneal leukoma of the left eye. The IOFB in the anterior chamber was removed through surgery. An attempt was made to remove the IOFB in the vitreous cavity with electromagnet, but it was not successful. Vitrectomy could not be performed as it was hindered by the opacity of cornea. After surgery, the visual acuity remained counting fingers and the corneal oedema still existed. This case is a reminder that a detailed history taking, a thorough physical examination and modern imaging techniques are beneficial for establishing the diagnosis and treatment of IOFBs. PMID- 28844657 TI - Cytoplasmic and Nuclear TAZ Exert Distinct Functions in Regulating Primed Pluripotency. AB - Mouse epiblast stem cells (mEpiSCs) and human embryonic stem cells (hESCs) are primed pluripotent stem cells whose self-renewal can be maintained through cytoplasmic stabilization and retention of beta-catenin. The underlying mechanism, however, remains largely unknown. Here, we show that cytoplasmic beta catenin interacts with and retains TAZ, a Hippo pathway effector, in the cytoplasm. Cytoplasmic retention of TAZ promotes mEpiSC self-renewal in the absence of nuclear beta-catenin, whereas nuclear translocation of TAZ induces mEpiSC differentiation. TAZ is dispensable for naive mouse embryonic stem cell (mESC) self-renewal but required for the proper conversion of mESCs to mEpiSCs. The self-renewal of hESCs, like that of mEpiSCs, can also be maintained through the cytoplasmic retention of beta-catenin and TAZ. Our study indicates that how TAZ regulates cell fate depends on not only the cell type but also its subcellular localization. PMID- 28844656 TI - Methylome Analysis of Human Bone Marrow MSCs Reveals Extensive Age- and Culture Induced Changes at Distal Regulatory Elements. AB - Human bone marrow stromal cells, or mesenchymal stem cells (BM-MSCs), need expansion prior to use as cell-based therapies in immunological and tissue repair applications. Aging and expansion of BM-MSCs induce epigenetic changes that can impact therapeutic outcomes. By applying sequencing-based methods, we reveal that the breadth of DNA methylation dynamics associated with aging and expansion is greater than previously reported. Methylation changes are enriched at known distal transcription factor binding sites such as enhancer elements, instead of CpG-rich regions, and are associated with changes in gene expression. From this, we constructed hypo- and hypermethylation-specific regulatory networks, including a sub-network of BM-MSC master regulators and their predicted target genes, and identified putatively disrupted signaling pathways. Our genome-wide analyses provide a broader overview of age- and expansion-induced DNA methylation changes and a better understanding of the extent to which these changes alter gene expression and functionality of human BM-MSCs. PMID- 28844658 TI - Direct Reprogramming of Resident NG2 Glia into Neurons with Properties of Fast Spiking Parvalbumin-Containing Interneurons. AB - Converting resident glia into functional and subtype-specific neurons in vivo by delivering reprogramming genes directly to the brain provides a step forward toward the possibility of treating brain injuries or diseases. To date, it has been possible to obtain GABAergic and glutamatergic neurons via in vivo conversion, but the precise phenotype of these cells has not yet been analyzed in detail. Here, we show that neurons reprogrammed using Ascl1, Lmx1a, and Nurr1 functionally mature and integrate into existing brain circuitry and that the majority of the reprogrammed neurons have properties of fast-spiking, parvalbumin containing interneurons. When testing different combinations of genes for neural conversion with a focus on pro-neural genes and dopamine fate determinants, we found that functional neurons can be generated using different gene combinations and in different brain regions and that most of the reprogrammed neurons become interneurons, independently of the combination of reprogramming factors used. PMID- 28844659 TI - Recapitulation of Human Retinal Development from Human Pluripotent Stem Cells Generates Transplantable Populations of Cone Photoreceptors. AB - Transplantation of rod photoreceptors, derived either from neonatal retinae or pluripotent stem cells (PSCs), can restore rod-mediated visual function in murine models of inherited blindness. However, humans depend more upon cone photoreceptors that are required for daylight, color, and high-acuity vision. Indeed, macular retinopathies involving loss of cones are leading causes of blindness. An essential step for developing stem cell-based therapies for maculopathies is the ability to generate transplantable human cones from renewable sources. Here, we report a modified 2D/3D protocol for generating hPSC derived neural retinal vesicles with well-formed ONL-like structures containing cones and rods bearing inner segments and connecting cilia, nascent outer segments, and presynaptic structures. This differentiation system recapitulates human photoreceptor development, allowing the isolation and transplantation of a pure population of stage-matched cones. Purified human long/medium cones survive and become incorporated within the adult mouse retina, supporting the potential of photoreceptor transplantation for treating retinal degeneration. PMID- 28844661 TI - [Wellen's syndrome: much more than a T-wave]. PMID- 28844660 TI - Dermatopontin in Bone Marrow Extracellular Matrix Regulates Adherence but Is Dispensable for Murine Hematopoietic Cell Maintenance. AB - The hematopoietic marrow microenvironment is composed of multiple cell types embedded in an extracellular matrix (ECM). We have explored marrow ECM using mass spectrometry and found dermatopontin (DPT), a small non-collagenous ECM protein, to be present. We found that DPT cooperates with other ECM proteins to promote hematopoietic cell adherence in vitro on plastic as well as OP9 stromal cells. We generated constitutional DPT-/- mice that were viable and had no peripheral lympho-hematopoietic abnormalities. The composition of the marrow of wild-type and DPT-/- mice was equivalent in terms of cellularity, CFU-C, LSK (Lineage-, SCA 1+, KIT+), and LSK-SLAM (LSK, CD48-, CD150+) frequencies. These data suggest that DPT fosters adherence but is not required for steady-state hematopoiesis in vivo. There are likely overlapping cellular adhesion mechanisms that can compensate to maintain the hematopoietic niche in the absence of DPT. PMID- 28844662 TI - Goal impact influences the evaluative component of performance monitoring: Evidence from ERPs. AB - Successful performance monitoring (PM) requires continuous assessment of context and action outcomes. Electrophysiological studies have reliably identified event related potential (ERP) markers for evaluative feedback processing during PM: the Feedback-Related Negativity (FRN) and P3 components. The functional significance of FRN remains debated in the literature, with recent research suggesting that feedback's goal relevance can account for FRN (amplitude) modulation, apart from its valence or expectedness alone. Extending this account, the present study assessed whether graded differentiations in feedback's relevance or importance to one's goal (referred to as goal impact) would influence PM at the FRN (and P3) level. To this end, we ran a within-subject crossover design experiment in which 40 participants completed two standard cognitive control tasks (Go/No Go and Simon), while 64-channel electroencephalography was recorded. Critically, both tasks entailed similar reward processing but systematically varied in goal impact assignment (high vs. low), manipulated through their supposed diagnosticity for daily life functioning and activation of social comparison. ERP results showed that goal impact reliably modulated FRN in a general manner. Irrespective of feedback valence, it was overall less negative in the high compared to the low impact condition, suggesting a general decrease in feedback monitoring in the former compared to the latter condition. These findings lend support to the idea that PM is best conceived operating not solely based on motor cues, but is shaped by motivational demands. PMID- 28844663 TI - Radiological assessment of the placement of Essure(r) in order to reduce hysterosalpingography: Pelvic X-ray versus combined pelvic X-ray and ultrasound. AB - OBJECTIVE: Three months after hysteroscopic sterilisation with Essure(r), a confirmation test is required to evaluate the correct location of the inserts. The test may be conducted using a pelvic ultrasound (2D or 3D) or an abdominal X ray. Should the location not look satisfactory on these tests, a follow-up hysterosalpingography (HSG) would be required. The objective of our study is to assess whether the Essure(r) 3-month confirmation test using a single X-ray or a combination of X-ray and ultrasound could reduce the use of HSG. STUDY DESIGN: This retrospective study examined patients who underwent birth control Essure(r) procedure between 2009 and 2015 in the Gynaecological Surgery Department at the Regional University Hospital Centre (CHRU) in Lille. We divided patients into two groups based on the imaging tests performed: single X-ray (2009-2010) versus X ray and pelvic ultrasound (2014-2015). We then compared the results of the imaging tests and the use of HSG between the two groups. RESULTS: One hundred and thirty-four patients were tested, of which 60 (44.8%) using a single X-ray and 74 (55.2%) using a combination of X-ray and ultrasound. We note that the combined X ray/ultrasound test reduces significantly the number of HSG performed (26.7% versus 12.2%, P=0.04). CONCLUSION: Compared to a single X-ray, the combination of X-ray and ultrasound enables to significantly limit the use of HSG. PMID- 28844664 TI - Research misconduct and the INTERGROWTH-21st study. PMID- 28844665 TI - DjhnRNPA2/B1-like gene is required for planarian regeneration and tissue homeostasis. AB - The hnRNPs play important roles in physiological processes in eukaryotic organisms by regulation of pre-mRNA after transcription, including pre-mRNA splicing, mRNA stability, DNA replication and repair and telomere maintenance and so on. However, it remains unclear about the specific functions of these genes. In this study, the full-length cDNA sequence of hnRNPA2/B1-like was first cloned from Dugesia japonica, and its roles were investigated by WISH and RNAi. The results showed that: (1) DjhnRNPA2/B1-like was highly conserved during animal evolution; (2) DjhnRNPA2/B1-like mRNA was mainly distributed each side of the body in intact worms and regenerative blastemas, and its expression levels were up-regulated on days 0 and 5 after amputation; (3) the intact and regenerating worms gradually lysed or lost regeneration capacity after DjhnRNPA2/B1-like RNAi; and (4) DjhnRNPA2/B1-like expression is induced by temperature and heavy metal ion stress. The data suggests that DjhnRNPA2/B1-like is a multiple functional gene, it plays important roles in regeneration and homeostatic maintenance and it is also involved in stress responses in planarians. Our work provides basic data for the study of regenerative mechanism and stress responses in freshwater planarians. PMID- 28844666 TI - Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol. AB - Dyslipidemia is a major contributor to the increased cardiovascular disease and mortality associated with obesity and type 2 diabetes. We hypothesized that variation in expression of adipose tissue transcripts is associated with serum lipid concentrations in African Americans (AAs), and common genetic variants regulate expression levels of these transcripts. Fasting serum lipid levels, genome-wide transcript expression profiles of subcutaneous adipose tissue, and genome-wide SNP genotypes were analyzed in a cohort of non-diabetic AAs (N=250). Serum triglyceride (TRIG) and high density lipoprotein-cholesterol (HDL-C) levels were associated (FDR<0.01) with expression level of 1021 and 1875 adipose tissue transcripts, respectively, but none associated with total cholesterol or LDL-C levels. Serum HDL-C-associated transcripts were enriched for salient biological pathways, including branched-chain amino acid degradation, and oxidative phosphorylation. Genes in immuno-inflammatory pathways were activated among individuals with higher serum TRIG levels. We identified significant cis regulatory SNPs (cis-eSNPs) for 449 serum lipid-associated transcripts in adipose tissue. The cis-eSNPs of 12 genes were nominally associated (p<0.001) with serum lipid level in genome wide association studies in Global Lipids Genetics Consortium (GLGC) cohorts. Allelic effect direction of cis-eSNPs on expression of MARCH2, BEST1 and TMEM258 matched with effect direction of these SNP alleles on serum TRIG or HDL-C levels in GLGC cohorts. These data suggest that expressions of serum lipid-associated transcripts in adipose tissue are dependent on common cis-eSNPs in African Americans. Thus, genetically-mediated transcriptional regulation in adipose tissue may play a role in reducing HDL-C and increasing TRIG in serum. PMID- 28844667 TI - Thioredoxin-1, redox factor-1 and thioredoxin-interacting protein, mRNAs are differentially expressed in Multiple Sclerosis patients exposed and non-exposed to interferon and immunosuppressive treatments. AB - BACKGROUND: Oxidative stress is closely linked to inflammation in neurodegenerative diseases. We aimed to investigate the expression of redox system genes in Multiple Sclerosis (MS) patients either exposed or not exposed to conventional treatments. METHODS: Forty-four MS patients were divided into three groups: newly diagnosed (Group 1), receiving interferon (Group 2) and receiving immunosuppressive drugs (Group 3). Also, 15 healthy controls were enrolled. The mRNA expression of TRX1, TXNRD1, TRX2, TXNRD2, TXNIP, and APEX1 genes in peripheral blood mononuclear cells (PBMCs) was assessed by relative quantitative real-time PCR. Also, serum level of Trx1 was measured by ELISA. RESULTS: Serum level of Trx1 in the newly diagnosed MS patients was significantly higher compared to the healthy controls (P=0.013). Likewise, TRX1 and APEX1 expressions were significantly higher in the newly diagnosed patients compared to controls (P=0.003 and P=0.042), patients under interferon treatment (P=0.003 and P=0.013), and patients received immunosuppressants (P=0.001 and P=0.025). Furthermore, TXNIP expression in MS patients (either group 1, group 2, or group 3) was significantly lower than that in the control group (P=0.017, P=0.002, and P=0.022 respectively). The expression of TXNRD1, TRX2, and TXNRD2 did not show any significant difference between the control and the MS patient (P>0.05). CONCLUSIONS: Our data showed that redox system elements are differentially expressed in newly diagnosed MS patients, or patients receiving either interferon or immunosuppressive treatments. However, much more studies are required to confirm our findings and clarify the underlying mechanisms. PMID- 28844668 TI - Transcriptomic analysis of flower development in tea (Camellia sinensis (L.)). AB - Flowering is a critical and complicated process in plant development, involving interactions of numerous endogenous and environmental factors, but little is known about the complex network regulating flower development in tea plants. In this study, de novo transcriptome assembly and gene expression analysis using Illumina sequencing technology were performed. Transcriptomic analysis assembles gene-related information involved in reproductive growth of C. sinensis. Gene Ontology (GO) analysis of the annotated unigenes revealed that the majority of sequenced genes were associated with metabolic and cellular processes, cell and cell parts, catalytic activity and binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that metabolic pathways, biosynthesis of secondary metabolites, and plant hormone signal transduction were enriched among the DEGs. Furthermore, 207 flowering-associated unigenes were identified from our database. Some transcription factors, such as WRKY, ERF, bHLH, MYB and MADS-box were shown to be up-regulated in floral transition, which might play the role of progression of flowering. Furthermore, 14 genes were selected for confirmation of expression levels using quantitative real-time PCR (qRT-PCR). The comprehensive transcriptomic analysis presents fundamental information on the genes and pathways which are involved in flower development in C. sinensis. Our data also provided a useful database for further research of tea and other species of plants. PMID- 28844669 TI - Polymorphisms in autophagy related genes and the coal workers' pneumoconiosis in a Chinese population. AB - Autophagy is an evolutionary conserved intracellular degradation/recycling system that is essential for cellular homeostasis. Dysregulation of this process leads to a number of disorders, including pulmonary fibrosis. However, the genetic association between singe nucleotide polymorphisms of autophagy related genes (ATGs) and the risk of coal workers' pneumoconiosis has not been reported yet. Total of 7 SNPs in ATGs (ATG16, ATG12, ATG5, ATG10) were investigated for their roles in CWP by a case-control study which including 705 CWP patients and 703 control subjects. Genotyping were performed by the Sequenom Mass ARRAY system. Luciferase assays were taken to test the effects of rs26538 C>T on the activity of ATG12 in the promoter. Our data showed that ATG10 rs1864182 GT genotype was associated with a decreased risk of CWP compared with TT genotype (OR=0.42, 95% CI=0.33-0.54, P=0.001). Another 2 SNPs (rs26538, rs510432) were also with the marked decreases in the risk of CWP under recessive models (OR=0.58, 95% CI=0.40 0.83, P=0.002 for rs26538; OR=0.74, 95% CI=0.57-0.97, P=0.040 for rs510432). Luciferase assays in two different cell lines revealed that the rs26538 C>T substitution could reduce the expression of ATG12. Taken together, we identified three SNPs in ATGs, which implicated the development of CWP. Further studies are warranted to validate these findings. PMID- 28844670 TI - Goose FMO3 gene cloning, tissue expression profiling, polymorphism detection and association analysis with trimethylamine level in the egg yolk. AB - Flavin-containing monooxygenase 3 (FMO3) plays a critical role in catalyzing the conversion of trimethylamine (TMA) to trimethylamine-N-oxide (TMAO) in vivo. Despite the well-documented association between FMO3 mutations and a 'fishy' off flavor eggs in chicken and quail, little information is available regarding the molecular characteristic of goose (Anser cygnoides) FMO3 and its relationship with the yolk TMA content. To fill these gaps, we cloned the full-length cDNA sequence of goose FMO3, which comprised 1851bp encoding 531 amino acids. FMO3 mRNA was dramatically expressed in liver than in other tissues in the geese. Eight single nucleotide polymorphisms (SNPs) were detected in the entire coding region. The CC genotype at the T669C site, GG at the A723G site, and AA at the G734A site of FMO3 were highly significantly associated with elevated TMA content in goose egg yolk (P<0.001). Carriers of the A allele of G734A or C allele of T885C had yolk TMA content that had a high probability of being elevated after feeding with additional choline chloride (P=0.0429, OR=4.1300, 95%CI=1.0390 16.4270, and P=0.0251, OR=4.6060, 95%CI=1.1620-18.2620, respectively). This work lays a foundation for studying the function of FMO3 and yolk TMA content in goose. However, studies using larger sample sizes and more goose breeds are required to determine whether the fishy off-flavor trait exists in goose. PMID- 28844671 TI - Transcriptional profiling of human femoral mesenchymal stem cells in osteoporosis and its association with adipogenesis. AB - Genetic alterations are major contributing factors in the development of osteoporosis. Osteoblasts and adipocytes share a common origin, mesenchymal stem cells (MSCs), and their genetic determinants might be important in the relationship between osteoporosis and obesity. In the present study, we aimed to isolate differentially expressed genes (DEGs) in osteoporosis and normal controls using human MSCs, and elucidate the common pathways and genes related to osteoporosis and adipogenesis. Human MSCs were obtained from the bone marrow of femurs from postmenopausal women during orthopedic surgeries. RNA sequencing (RNA seq) was carried out using next-generation sequencing (NGS) technology. DEGs were identified using RNA-seq data. Ingenuity pathway analysis (IPA) was used to elucidate the common pathway related to osteoporosis and adipogenesis. Candidate genes for the common pathway were validated with other independent osteoporosis and obese subjects using RT-PCR (reverse transcription-polymerase chain reaction) analysis. Fifty-three DEGs were identified between postmenopausal osteoporosis patients and normal bone mineral density (BMD) controls. Most of the genetic changes were related to the differentiation of cells. The nuclear receptor subfamily 4 group A (NR4A) family was identified as possible common genes related to osteogenesis and adipogenesis. The expression level of the mRNA of NR4A1 was significantly higher in osteoporosis patients than in controls (p=0.018). The expression level of the mRNA of NR4A2 was significantly higher in obese patients than in controls (p=0.041). Some genetic changes in MSCs are involved in the pathophysiology of osteoporosis. The NR4A family might comprise common genes related to osteoporosis and obesity. PMID- 28844672 TI - Oocyte-like cells induced from CD34-positive mouse hair follicle stem cells in vitro. PMID- 28844674 TI - Automated anesthesia delivery systems in cardiac surgical patients with left ventricular dysfunction: All systems go? PMID- 28844676 TI - In vivo expression of a short peptide designed from late embryogenesis abundant protein for enhancing abiotic stress tolerance in Escherichia coli. AB - In vivo functional analyses of a late embryogenesis abundant (LEA) short peptide expressed in recombinant Escherichia coli BL21 (DE3) were carried out under abiotic stress (salt, heat, and cold) conditions. Our LEA peptide was derived from the Polypedilum vanderplanki group 3 LEA protein based on distinctive conserved amino acid motif sequences. We focused on high-salt (5% and 7% NaCl) concentrations to evaluate the functional relevance of the peptide under abiotic salt stress. E. coli transformants expressing the LEA peptide showed higher cell viability than the control not expressing the peptide when transferred to a medium containing 5% and 7% NaCl; cells expressing LEA peptide showed a higher number of colony-forming units per dilution under the high salt stress condition. Moreover, expression of the LEA peptide resulted in greater cell survival under heat (48 degrees C) and cold (4 degrees C) stress. These results suggest that LEA short peptide co-expression could be useful for developing genetically modified organisms and in applications to prevent E. coli cell death under high salt, heat, and cold stress. PMID- 28844675 TI - Let-7i attenuates human brain microvascular endothelial cell damage in oxygen glucose deprivation model by decreasing toll-like receptor 4 expression. AB - The let-7 family of microRNAs (miRNAs) plays an important role on endothelial cell function. However, there have been few studies on their role under ischemic conditions. In this study, we demonstrate that let-7i, belonging to the let-7 family, rescues human brain microvascular endothelial cells (HBMECs) in an oxygen glucose deprivation (OGD) model. Our data show that the expression of let-7 family miRNAs was downregulated after OGD. Overexpression of let-7i significantly alleviated cell death and improved survival of OGD-treated HBMECs. Let-7i also protected permeability in an in vitro blood brain barrier (BBB) model. Further, let-7i downregulated the expression of toll-like receptor 4 (TLR4), an inflammation trigger. Moreover, overexpression of let-7i decreased matrix metallopeptidase 9 (MMP9) and inducible nitric oxide synthase (iNOS) expression under OGD. Upon silencing TLR4 expression in HBMECs, the anti-inflammatory effect of let-7i was abolished. Our research suggests that let-7i promotes OGD-induced inflammation via downregulating TLR4 expression. PMID- 28844677 TI - Procyanidin B2 ameliorates carrageenan-induced chronic nonbacterial prostatitis in rats via anti-inflammatory and activation of the Nrf2 pathway. AB - Prostatitis is one of the most prevalent problems in andriatry and urinary surgery. In the present study, we evaluated the effect of procyanidin B2 (PB) on carrageenan-induced chronic nonbacterial prostatitis in rats. Results showed that PB significantly decreased the prostatic index and enhanced the body weight inhibited by carrageenan. Biochemical results revealed that PB significantly lowered the prostatic specific antigen (PSA) and alleviated oxidative stress in serum. The levels of TNF-alpha, IL-6, and IL-10 in prostatic homogenate were also significantly decreased after PB treatment. We also found evidence that PB treatment reversed the suppression of Nrf2 nuclear translocation, and increased the expressions of NQO1 and HO-1 in the prostate glands. In conclusion, treatment with PB attenuates carrageenan-induced chronic nonbacterial prostatitis via anti inflammatory and activation of the Nrf2 pathway. PMID- 28844678 TI - Antioxidant, anti-inflammatory, antiproliferative and antimycobacterial activities of the essential oil of Psidium guineense Sw. and spathulenol. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leaves from Psidium guineense Sw. are used in popular medicine for the treatment of inflammatory disease. However, there is no scientific evidence demonstrating this activity. AIM OF THE STUDY: To evaluate the antioxidant, anti-inflammatory, antiproliferative and antimycobacterial activities of the essential oil of P. guineense and spathulenol (a major constituent). The study was conducted in part to provide evidence supporting the ethnobotanical use of the leaves of this species. MATERIAL AND METHODS: The essential oil (EOPG) was extracted from the leaves of P. guineense by hydrodistillation and analysed by gas chromatography-mass spectrometry (GC-MS). The major compound, spathulenol (PG-1), was isolated in a chromatographic column and characterized by nuclear magnetic resonance (NMR). EOPG and PG-1 were evaluated in vitro for antioxidant activity by DPPH, ABTS and MDA methods; anti inflammatory potential was assessed using two models, including pleurisy and oedema, in mice. The impact of EOPG and PG-1 on cell proliferation was determined via spectrophotometric quantification of the cellular protein content using a sulforhodamine B assay, and anti-Mycobacterium tuberculosis activity was determined using the REMA method. RESULTS: A total of 38 components were identified from the EOPG, with the sesquiterpenic alcohol spathulenol (PG-1) (80.7%) being the major constituent. EOPG and PG-1 exhibited the highest antioxidant activities in the DPPH and MDA system compared with reference standard, with IC50 values ranging from 26.13 to 85.60MUg/mL. Oral administration of EOPG and PG-1 showed significant inhibition in the Cg-induced mice paw oedema and pleurisy model. The EOPG (GI50 = 0.89MUg/mL) and PG-1 (GI50 = 49.30MUg/mL) were particularly effective against the ovarian cancer cell line. Both showed moderate antimycobacterial activity. CONCLUSION: For the first time, this study demonstrated the antioxidant, anti-inflammatory, antiproliferative and antimycobacterial properties of the essential oil of P. guineense (leaves were collected in Dourados-MS) and spathulenol, collaborating the etnhopharmacologycal use of this plant due to its an anti-inflammatory effect. PMID- 28844679 TI - Syzygium cumini leaf extract inhibits LDL oxidation, but does not protect the liproprotein from glycation. AB - ETNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels is a plant widely used in folk medicine to treat diabetes mellitus (DM). The tea from its leaves is frequently used by diabetics for lowering hyperglycemia. There is a close relationship between DM and atherosclerosis, a chronic immuno-inflammatory disease, were the early stages encompass oxidative and glycative modifications in the structure of low density lipoprotein (LDL). AIM OF THIS STUDY: To investigate the potential protective effects of aqueous-leaf extract from Syzygium cumini (S.cExt) against CuSO4-induced oxidation and methylglyoxal (MG)-induced glycation of human LDL in vitro. MATERIALS AND METHODS: LDL oxidative changes were evaluated by measuring conjugated dienes (CD) formation, thiobarbituric acid reactive substances (TBARS) levels, quenching of tryptophan (Trp) fluorescence and structural modifications in LDL particle. In LDL glycated by MG (glyLDL), we determined the levels of fluorescent advanced glycation end products (AGEs) and mobility by agarose gel electrophoresis. RESULTS: S.cExt blocked oxidative events induced by CuSO4 in human LDL, plasma and serum. Fourier transform infrared spectroscopy (FT-IR) revealed that specific regions of apoB100 were oxidized by CuSO4 in human LDL and that S.cExt reduced these oxidations. Unlike, the increased AGEs levels and eletrophoretic mobility observed in LDL MG-glycated were not modified by S.cExt. CONCLUSION: The findings herein indicate that S.cExt could be tested in atherogenesis models as potential protective agent against LDL oxidation. PMID- 28844680 TI - Korean red ginseng (Panax ginseng) inhibits obesity and improves lipid metabolism in high fat diet-fed castrated mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Korean red ginseng (Panax ginseng C.A. Meyer, Araliaceae) has been historically used as a traditional drug for the prevention and treatment of most ageing-related diseases, such as obesity, dyslipidemia, diabetes, and cardiovascular disease. Elderly men with testosterone deficiency are strongly associated with many of the aforementioned metabolic diseases. The aim of this study was to determine the effects of ginseng on obesity and lipid metabolism in a mouse model of testosterone deficiency (castrated C57BL/6J mice). MATERIALS AND METHODS: The effects of ginseng extract (GE) on obesity and lipid metabolism in high-fat diet (HFD)-fed castrated C57BL/6J mice were examined using hematoxylin and eosin staining, serum lipid analysis, and quantitative real-time polymerase chain reaction (PCR). The effects of GE, ginsenosides, and testosterone on adipogenesis were measured using Oil Red O staining, XTT assay, and real-time PCR. RESULTS: Compared with HFD mice, mice receiving HFD supplemented with GE (HFD-GE) for 8 weeks showed decreased body weight, adipose tissue mass, and adipocyte size without affecting food intake. Serum levels of triglycerides and total cholesterol were lowered in HFD-GE mice than in HFD mice. GE also markedly reduced HFD-induced hepatic lipid accumulation. Concomitantly, HFD-GE decreased mRNA expression of adipogenesis-related genes (SREBP-1C, PPARgamma, FAS, SCD1, and ACC1) in visceral adipose tissues compared with HFD alone. Consistent with the in vivo data, GE and major active ginsenosides (Rb1 and Rg1) decreased lipid accumulation and mRNA expression of PPARgamma, C/EBPalpha, and SCD1 in 3T3-L1 adipocytes compared with control. Similarly, testosterone also decreased lipid accumulation and mRNA levels of PPARgamma, C/EBPalpha, and SCD1. These inhibitory effects were further increased by co treatment of GE or ginsenosides with testosterone. CONCLUSIONS: Our results demonstrate that ginseng can inhibit obesity and dyslipidemia in HFD-fed castrated mice, possibly by inhibiting adipogenic gene expression. In addition, our results indicate that ginseng may act like testosterone to inhibit adipogenesis, suggesting that ginseng may be able to prevent obesity, hyperlipidemia, and hepatic steatosis in men with testosterone deficiency. PMID- 28844681 TI - Dynamic hip system blade versus cannulated compression screw for the treatment of femoral neck fractures: A retrospective study. AB - OBJECTIVE: The aim of this study was to compare clinical outcomes of patients with femoral neck fractures treated with the dynamic hip system blade (DHS-BLADE) or cannulated compression screws. METHODS: Eighty-six patients with femoral neck fractures were treated by closed reduction internal fixation with a DHS-BLADE (n = 42; 18 males and 24 females; mean age: 56.3 years (37-87)) or cannulated compression screws (n = 44; 20 males and 24 females; mean age: 53.8 years (26 83)) between March 2011 and August 2013. The groups were compared with Harris hip score, operation time, surgical blood loss, incision size, hospital stay, and related complications. RESULTS: The average follow-up time was 27 months (range, 24-36 months). There was no significant difference for the operation time, incision size, hospital stay, and Harris hip score between the groups. Also, no statistically significant differences in the rates of nonunion (4.5% vs. 0) and avascular necrosis of the femoral head (9.1% vs. 7.1%) were observed. However, the screw group experienced significantly less surgical blood loss (32.4 +/- 24.7 ml) than the blade group (87.2 +/- 46.6 ml; P = 0.041). The incidence of femoral neck shortening above 10 mm in the screw group was significantly higher than that in the blade group (15.9% vs. 2.4%, P = 0.031). The blade group had a significantly lower incidence of screw migration than the screw group (4.8% vs. 22.7%, P = 0.016). CONCLUSION: The DHS-BLADE and cannulated compression screws might be equally effective in terms of postoperative fracture union. However, the DHS-BLADE has advantages over cannulated compression screws for preventing femoral neck shortening, screw migration, and cut-out. LEVEL OF EVIDENCE: Level III, Therapeutic study. PMID- 28844682 TI - Transfer of the lesser tuberosity for reverse Hill-Sachs lesions after neglected posterior dislocations of the shoulder: A retrospective clinical study of 13 cases. AB - OBJECTIVE: This study aimed to present middle-term functional and radiological outcomes of the transfer of the lesser tuberosity in the management of reverse Hill-Sachs lesions following posterior dislocations of the shoulder. PATIENTS AND METHODS: With a diagnosis of neglected posterior shoulder dislocation (8 locked, 5 recurrent), 13 male patients (age range: 28-72; mean age: 39.3 years) who underwent the transfer of the lesser tuberosity due to reverse Hill-Sachs lesions, were retrospectively reviewed based on functional and radiological data. The etiologies were: epilepsy in 9 patients, a traffic accident in 2 patients, and fall in 2 patients. To assess the patients' functional level, American Shoulder and Elbow Surgeons (ASES) and Constant Scores were used, and the patients' range of motion at the last follow-up was measured. To evaluate the development of arthrosis, the final follow-up control plain radiographs were examined. The average size of the defects calculated from the axial computed tomography sets was 27% (range: 20%-40%). RESULTS: The average length of follow up was 30 months (range: 12-67 months). At the last follow-up visit, the main ASES and Constant Scores were 78 and 85, respectively, and the average degrees of flexion, abduction, and external rotation were 163 degrees , 151 degrees , and 70 degrees respectively. The concentric reduction was observed postoperatively. CONCLUSION: McLaughlin procedure appears to be a safe and effective method in the treatment of neglected posterior shoulder dislocations with reverse Hill-Sachs lesion. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 28844683 TI - The most appropriate perfusate pH for ex vivo hypothermic organ perfusion: A hypothesis. PMID- 28844684 TI - Characterization of N-Acetyl-Tryptophan Degradation in Protein Therapeutic Formulations. AB - N-Acetyl-tryptophan (NAT) is used as a stabilizer for preparations of human serum albumin and has more recently been demonstrated to provide oxidative protection for labile Trp residues in monoclonal antibodies. As a component in the formulations of protein therapeutics, NAT is sacrificially degraded; therefore, understanding the identity and quantity of NAT degradants potentially formed in these drug products is essential to understanding the potential patient impact of this additive. Here, we report a simple reversed-phase chromatography approach that allows systematic investigation of NAT degradation in relevant formulations under stressed conditions. Screening a panel of NAT-containing samples following a variety of forced stress conditions led to a range of NAT degradation from minimal (3%) to significant (83%). NAT degradants were observed to be largely conserved between oxidative and thermal stress conditions. Online mass spectrometry and standard compound synthesis allowed for identification of the major degradants in the stressed sample panel. NAT degradation was minimal under recommended storage conditions and in relevant thermal stress conditions for a representative protein therapeutic drug product, suggesting that NAT is stable under normal manufacturing, storage, and handling conditions. This work supports the use of NAT as an antioxidant in liquid drug product formulations. PMID- 28844685 TI - FERM domain phosphorylation and endogenous 3'UTR are not essential for regulating the function and subcellular localization of polarity protein Crumbs. PMID- 28844686 TI - Changes in white cell estimates and plasma chemistry measurements following oral or external dosing of double-crested cormorants, Phalacocorax auritus, with artificially weathered MC252 oil. AB - Scoping studies were designed whereby double-crested cormorants (Phalacocorax auritus) were dosed with artificially weathered Deepwater Horizon (DWH) oil either daily through oil injected feeder fish, or by application of oil directly to feathers every three days. Preening results in oil ingestion, and may be an effective means of orally dosing birds with toxicant to improve our understanding of the full range of physiological effects of oral oil ingestion on birds. Blood samples collected every 5-6 days were analyzed for a number of clinical endpoints including white blood cell (WBC) estimates and differential cell counts. Plasma biochemical evaluations were performed for changes associated with oil toxicity. Oral dosing and application of oil to feathers resulted in clinical signs and statistically significant changes in a number of biochemical endpoints consistent with petroleum exposure. In orally dosed birds there were statistically significant decreases in aspartate amino transferase (AST) and gamma glutamyl transferase (GGT) activities, calcium, chloride, cholesterol, glucose, and total protein concentrations, and increases in plasma urea, uric acid, and phosphorus concentrations. Plasma electrophoresis endpoints (pre-albumin, albumin, alpha-2 globulin, beta globulin, and gamma globulin concentrations and albumin: globulin ratios) were decreased in orally dosed birds. Birds with external oil had increases in urea, creatinine, uric acid, creatine kinase (CK), glutamate dehydrogenase (GLDH), phosphorus, calcium, chloride, potassium, albumin, alpha-1 globulin and alpha-2 globulin. Decreases were observed in AST, beta globulin and glucose. WBC also differed between treatments; however, this was in part driven by monocytosis present in the externally oiled birds prior to oil treatment. PMID- 28844687 TI - Experience and Satisfaction With a Multidisciplinary Care Unit for Patients With Psoriasis and Psoriatic Arthritis. AB - OBJECTIVE: To describe patient's characteristics, the activity and patient's satisfaction with a multidisciplinary care unit in patients with psoriasis and psoriatic arthritis (PsA). METHODS: A retrospective medical records review of patients with psoriasis or PsA attended in a multidisciplinary care unit was performed. Included patients were contacted to fulfill a satisfaction questionnaire. A specific electronic database was set up. Data regarding to patients and their baseline characteristics and the activity of the unit were collected. Descriptive analysis were performed. RESULTS: A total of 112 patients with 154 visits were included in almost 3 years, 54% women, with a mean age of 51 years, 43.7% presented hyperlipidemia and 30.4% arterial hypertension. Half of patients were referred due to diagnostic doubts and the other half for therapeutic problems. After the evaluation of the patients, 66 patients (58.9%) met diagnostic criteria for PsA, and 13 (11.6%) of an inflammatory disease other than PsA, and 95% came back to their usual physician. The most ordered test were laboratory tests (75.6% of patients), followed by X-rays in 57 patients (51.3%). In general the number of patients with different treatments increased, and 55.4% and 42% of patients changed their topic and systemic treatments respectively. The level of satisfaction was very high and all of patients considered that their disease was better controlled in this multidisciplinary care unit. CONCLUSIONS: This multidisciplinary care unit has improved the care and satisfaction of patients with psoriasis or PsA, and increased collaboration between rheumatology and dermatology departments. PMID- 28844688 TI - Primary Sjogren's syndrome and pregnancy: A report of 18 cases. AB - : Primary Sjogren's syndrome (pSS) is a condition that predominantly affects women. Reports of pregnancy outcome in these patients are limited and contradictory. OBJECTIVE: To describe pregnancy characteristics and outcomes and newborn morbidity in women with pSS. MATERIAL AND METHODS: We included women with pSS who became pregnant after the onset of the symptoms of the disease. Clinical and serological characteristics, risk factors and previous maternal comorbidities are described. For each pregnancy in a woman with pSS, we recorded pregnancy course and outcome and newborn condition. RESULTS: We assessed 11 patients with 18 pregnancies after the onset of pSS symptoms. All of them presented FAN +; 10 anti-Ro / SSA + and 7 anti-La / SSB +. The mean age in years at the onset of symptoms was 24.9 (SD 6.9) and at the time of pregnancy was 30.3 (SD 5.4). Thirteen pregnancies happened before the diagnosis, reporting only one miscarriage. Two preterm births, 1 case of oligohydramnios, 2 of premature membrane rupture and 2 low birthweight babies were reported after the onset of pSS symptoms. There was 1 newborn with congenital atrioventricular block and another with neonatal cutaneous lupus. All the women with pregnancy complications (n=6) had anti-Ro/SSA antibodies. CONCLUSIONS: Almost half of the pregnancies assessed in women with pSS were associated with complications not attributable to factors other than the disease. PMID- 28844690 TI - Recent developments on algal biochar production and characterization. AB - Algal biomass is known as a promising sustainable feedstock for the production of biofuels and other valuable products. However, since last decade, massive amount of interests have turned to converting algal biomass into biochar. Due to their high nutrient content and ion-exchange capacity, algal biochars can be used as soil amendment for agriculture purposes or adsorbents in wastewater treatment for the removal of organic or inorganic pollutants. This review describes the conventional (e.g., slow and microwave-assisted pyrolysis) and newly developed (e.g., hydrothermal carbonization and torrefaction) methods used for the synthesis of algae-based biochars. The characterization of algal biochar and a comparison between algal biochar with biochar produced from other feedstocks are also presented. This review aims to provide updated information on the development of algal biochar in terms of the production methods and the characterization of its physical and chemical properties to justify and to expand their potential applications. PMID- 28844689 TI - Effects of concentration and gas flow rate on the removal of gas-phase toluene and xylene mixture in a compost biofilter. AB - The aim of this work was to study the performance of a compost/ceramic bead biofilter (6:4 v/v) for the removal of gas-phase toluene and xylene at different inlet loading rates (ILR). The inlet toluene (or) xylene concentrations were varied from 0.1 to 1.5gm-3, at gas flow rates of 0.024, 0.048 and 0.072m3h-1, respectively, corresponding to total ILR varying between 7 and 213gm-3h-1. Although there was mutual inhibition, xylene removal was severely inhibited by the presence of toluene than toluene removal by the presence of xylene. The biofilter was also exposed to transient variations such as prolonged periods of shutdown (30days) and shock loads to envisage the response and recuperating ability of the biofilter. The maximum elimination capacity (EC) for toluene and xylene were 29.2 and 16.4gm-3h-1, respectively, at inlet loads of 53.8 and 43.7gm 3h-1. PMID- 28844691 TI - Performance assessment of aeration and radial oxygen loss assisted cathode based integrated constructed wetland-microbial fuel cell systems. AB - The present study explores low-cost cathode development possibility using radial oxygen loss (ROL) of Canna indica plants and intermittent aeration (IA) for wastewater treatment and electricity generation in constructed wetland-microbial fuel cell (CW-MFC) system. Two CW-MFC microcosms were developed. Amongst them, one microcosm was planted with Canna indica plants for evaluating the ROL dependent cathode reaction (CW-MFC dependent on ROL) and another microcosm was equipped with intermittent aeration for evaluating the intermittent aeration dependent cathode reaction (CW-MFC with additional IA). The CW-MFC with additional IA has achieved 78.71% and 53.23%, and CW-MFC dependent on ROL has achieved 72.17% and 46.77% COD removal from synthetic wastewater containing glucose loads of 0.7gL-1and 2.0gL-1, respectively. The maximum power density of 31.04mWm-3 and 19.60mWm-3 was achieved in CW-MFC with additional IA and CW-MFC dependent on ROL, respectively. PMID- 28844693 TI - Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation. AB - An emerging family of innate lymphoid cells (termed ILCs) has an essential role in the initiation and regulation of inflammation. However, it is still unclear how ILCs are regulated in the duration of intestinal inflammation. Here, we identify a regulatory subpopulation of ILCs (called ILCregs) that exists in the gut and harbors a unique gene identity that is distinct from that of ILCs or regulatory T cells (Tregs). During inflammatory stimulation, ILCregs can be induced in the intestine and suppress the activation of ILC1s and ILC3s via secretion of IL-10, leading to protection against innate intestinal inflammation. Moreover, TGF-beta1 is induced by ILCregs during the innate intestinal inflammation, and autocrine TGF-beta1 sustains the maintenance and expansion of ILCregs. Therefore, ILCregs play an inhibitory role in the innate immune response, favoring the resolution of intestinal inflammation. PMID- 28844692 TI - A Broad-Spectrum Inhibitor of CRISPR-Cas9. AB - CRISPR-Cas9 proteins function within bacterial immune systems to target and destroy invasive DNA and have been harnessed as a robust technology for genome editing. Small bacteriophage-encoded anti-CRISPR proteins (Acrs) can inactivate Cas9, providing an efficient off switch for Cas9-based applications. Here, we show that two Acrs, AcrIIC1 and AcrIIC3, inhibit Cas9 by distinct strategies. AcrIIC1 is a broad-spectrum Cas9 inhibitor that prevents DNA cutting by multiple divergent Cas9 orthologs through direct binding to the conserved HNH catalytic domain of Cas9. A crystal structure of an AcrIIC1-Cas9 HNH domain complex shows how AcrIIC1 traps Cas9 in a DNA-bound but catalytically inactive state. By contrast, AcrIIC3 blocks activity of a single Cas9 ortholog and induces Cas9 dimerization while preventing binding to the target DNA. These two orthogonal mechanisms allow for separate control of Cas9 target binding and cleavage and suggest applications to allow DNA binding while preventing DNA cutting by Cas9. PMID- 28844694 TI - Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain. AB - Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs. PMID- 28844695 TI - Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2. AB - The respiratory megacomplex represents the highest-order assembly of respiratory chain complexes, and it allows mitochondria to respond to energy-requiring conditions. To understand its architecture, we examined the human respiratory chain megacomplex-I2III2IV2 (MCI2III2IV2) with 140 subunits and a subset of associated cofactors using cryo-electron microscopy. The MCI2III2IV2 forms a circular structure with the dimeric CIII located in the center, where it is surrounded by two copies each of CI and CIV. Two cytochrome c (Cyt.c) molecules are positioned to accept electrons on the surface of the c1 state CIII dimer. Analyses indicate that CII could insert into the gaps between CI and CIV to form a closed ring, which we termed the electron transport chain supercomplex. The structure not only reveals the precise assignment of individual subunits of human CI and CIII, but also enables future in-depth analysis of the electron transport chain as a whole. PMID- 28844696 TI - Endoscopic ultrasonography can avoid unnecessary laparotomies in patients with pancreatic adenocarcinoma and undetected peritoneal carcinomatosis. AB - BACKGROUND/OBJECTIVE: To assess the relationship between the presence of ascites detected by endoscopic ultrasonography (EUS) and peritoneal carcinomatosis (PC) in patients with pancreatic adenocarcinoma. METHODS: Consecutive patients who underwent a EUS for preoperative staging of a pancreatic adenocarcinoma between 1998 and 2014 were retrospectively reviewed. The diagnosis of PC was confirmed by histopathology or peritoneal fluid cytology. The main outcome of the study was the relationship of ascites at EUS and PC in patients with pancreatic cancer. Secondarily, to evaluate the relationship between this finding and survival as well as the development of PC during follow-up. RESULTS: A total of 136 patients were included: 30 patients with local unresectable tumor or metastatic disease and 106 potentially-resectable candidates based on CT staging. EUS showed ascites in 27 (20%) patients, of whom 8 (29.6%) had PC. The sensitivity, specificity, PPV, NPV and accuracy of ascites by EUS in the detection of PC in this group of patients were 67%, 85%, 30%, 96% and 83%, respectively. Ascites detected by EUS was the only independent predictive factor of PC with an OR of 11 (CI 95%: 3-40). The detection of ascites by EUS was associated with a shorter survival (median survival time 7,3 months; range 0-60 vs 14.2 months; range 0-140) (p = 0.018) and earlier development of PC during follow-up (median 3.2 months, range 1.4-18.1 vs 12.7 months, range 5.4-54.8; p = 0.003). CONCLUSION: The finding of ascites at EUS in patients with pancreatic adenocarcinoma is highly associated with PC and a poor outcome. PMID- 28844697 TI - Aggressive venous invasion in the area of carcinoma correlates with liver metastasis as an index of metastasis for invasive ductal carcinoma of the pancreas. AB - BACKGROUND: Invasive ductal carcinoma of the pancreas (IDCP) predominantly causes death through liver metastasis (LM) and peritoneal dissemination with local recurrence. However, whether its venous invasion is from the enlarged carcinoma accompanied by tumor growth, or from a distinct carcinoma group, for which venous invasion is facilitated by proximity to the origin, is unclear. We analyzed the correlation between LM and venous invasion in patients with small IDCP tumors. METHODS: Of 388 patients who were diagnosed with IDCP, 20 (5.2%) had tumors with diameters <2 cm. The follow-up period of the 20 patients with smaller tumors was 1-24 years. RESULTS: The small-tumor group (n = 20) included 11 men and 9 women, aged 51-80 years. Five died of liver metastasis (LM group, n = 5) and 15 patients (non-LM group, n = 15) were either alive without recurrence (n = 11) or died of peritonitis carcinomatosa following local recurrence, subarachnoid hemorrhage, primary lung cancer, or old age (n = 1 for each cause of death). The LM and non LM groups did not significantly differ in numbers of venous invasion by the carcinoma in IDCP and non-IDCP area of the pancreas. However, median numbers of invaded veins in the area of IDCP and percentage of invaded vein/total number of vein in IDCP area were significantly higher in the LM group. CONCLUSION: Among patients with small IDCP tumors, the LM group showed more aggressive venous invasion by IDPC. Patients in whom >=60% of veins were invaded by IDCP should be prepared for LM. PMID- 28844698 TI - Transposable Element Domestication As an Adaptation to Evolutionary Conflicts. AB - Transposable elements (TEs) are selfish genetic units that typically encode proteins that enable their proliferation in the genome and spread across individual hosts. Here we review a growing number of studies that suggest that TE proteins have often been co-opted or 'domesticated' by their host as adaptations to a variety of evolutionary conflicts. In particular, TE-derived proteins have been recurrently repurposed as part of defense systems that protect prokaryotes and eukaryotes against the proliferation of infectious or invasive agents, including viruses and TEs themselves. We argue that the domestication of TE proteins may often be the only evolutionary path toward the mitigation of the cost incurred by their own selfish activities. PMID- 28844700 TI - Attention-deficit/hyperactivity disorder during adulthood. AB - Attention-Deficit/Hyperactivity Disorder (ADHD), although considered a childhood onset neurodevelopmental condition, is nevertheless a frequent and disabling condition in adults. A proportion of such patients are not diagnosed during childhood or adolescence, as diagnosis of the syndrome is rather complex, especially when other psychiatric, neurological or other neurodevelopmental conditions are also associated, yet comorbidities and consequences of ADHD are frequently observed in adults and older populations. As ADHD patients present to memory clinics with attentional and executive disorders, neuropsychological examinations of undiagnosed ADHD patients may reveal atypical cognitive profiles that can complicate the usual diagnostic procedure and increase the risk of delayed diagnosis or misdiagnosis. Thus, explorations of cognitive and/or behavioral disorders in adult populations should systematically screen for this neurodevelopmental condition. Accurate diagnosis could lead to non-pharmaceutical and/or pharmaceutical treatments to improve symptoms and quality of life for adult ADHD patients. PMID- 28844699 TI - Circadian Clocks and Metabolism: Implications for Microbiome and Aging. AB - The circadian clock directs many aspects of metabolism, to separate in time opposing metabolic pathways and optimize metabolic efficiency. The master circadian clock of the suprachiasmatic nucleus synchronizes to light, while environmental cues such as temperature and feeding, out of phase with the light schedule, may synchronize peripheral clocks. This misalignment of central and peripheral clocks may be involved in the development of disease and the acceleration of aging, possibly in a gender-specific manner. Here we discuss the interplay between the circadian clock and metabolism, the importance of the microbiome, and how they relate to aging. PMID- 28844701 TI - Gestural apraxia. AB - Gestural apraxia was first described in 1905 by Hugo Karl Liepmann. While his description is still used, the actual terms are often confusing. The cognitive approach using models proposes thinking of the condition in terms of production and conceptual knowledge. The underlying cognitive processes are still being debated, as are also the optimal ways to assess them. Several neuroimaging studies have revealed the involvement of a left-lateralized frontoparietal network, with preferential activation of the superior parietal lobe, intraparietal sulcus and inferior parietal cortex. The presence of apraxia after a stroke is prevalent, and the incidence is sufficient to propose rehabilitation. PMID- 28844702 TI - Ficolin-2 triggers antitumor effect by activating macrophages and CD8+ T cells. AB - Ficolin-2 is an important serum complement lectin. Here, we describe novel findings indicating that serum ficolin-2 concentrations in multiple tumor patients are significantly lower than those in healthy donors. Administration of exogenous ficolin-2 or ficolin-A (a ficolin-2-like molecule in mouse), with only once, could remarkably inhibit the tumor cells growth in murine tumor models via early macrophages, dendritic cells (DCs) and CD8+ T cells, but not CD4+ T cells. Ficolin-A (FCN-A) knockout (KO) mice exhibits significantly increased tumor cell growth. Ficolin-2 induces macrophage activation, promotes M1 polarization and facilitates proliferation and antigen-specific cytotoxicity of CD8+ T cells. Ficolin-2 binds to Toll-like receptor 4 (TLR4) on macrophages and DCs and promotes their antigen-presenting abilities to CD8+ T cells. Our findings provide a new therapeutic strategy for tumors based on the triggering of immune-mediated antitumor effect by ficolin-2. PMID- 28844703 TI - [Influence of demographic changes on the number of visits to hospital emergency departments: 13 years experience]. AB - OBJECTIVE: The aim of the present study is to describe the trend in volume and age-specific rates in visits to the Paediatric Emergency Department of a university teaching hospital in Cantabria (Spain) from January 2001 to December 2013, and evaluate the influence of population growth on Emergency Department use. MATERIAL AND METHODS: A retrospective study was conducted in which an analysis was made on all Emergency Department visits over a 13 year period. Simple and polynomial linear regressions were used to assess the relationship between population size and Emergency Department attendance rates across 2 age groups (0-2 and 3-14 years). RESULTS: From 2001 to 2013, attendance in the Emergency Department increased by 14.1%, whereas the paediatric population rose by 26.3%. Rates of presentation per head of population were greatest among those aged<3 years: 1.48 (95% CI 1.40-1.56) vs. 0.46 (95% CI 0.44-0.48) for the older age group (P<.01). A significant regression equation was found (F[1, 11]=11.2, P<.05) with an R2=0.50, showing that population growth produces a continuous rise in the Emergency Department visits for those aged<3 years. However, ED presentations of patients aged 3-14 years fit a quadratic regression model (R2=0.48, F[2, 10]=4.6, P<.05) so increases in population increase ED presentations until an inflection point, after which increases in population will decrease ED visits. CONCLUSIONS: Those aged 0-2 years presented a steady increase in ED visits related to population growth, whereas children aged 3-14 years experienced a "saturation of the demand" and a reduction in ED presentations. PMID- 28844704 TI - Gallbladder adenomyomatosis: Diagnosis and management. AB - Gallbladder (GB) adenomyomatosis (ADM) is a benign, acquired anomaly, characterized by hypertrophy of the mucosal epithelium that invaginates into the interstices of a thickened muscularis forming so-called Rokitansky-Aschoff sinuses. There are three forms of ADM: segmental, fundal and more rarely, diffuse. Etiology and pathogenesis are not well understood but chronic inflammation of the GB is a necessary precursor. Prevalence of ADM in cholecystectomy specimens is estimated between 1% and 9% with a balanced sex ratio; the incidence increases after the age of 50. ADM, although usually asymptomatic, can manifest as abdominal pain or hepatic colic, even in the absence of associated gallstones (50% to 90% of cases). ADM can also be revealed by an attack of acalculous cholecystitis. Pre-operative diagnosis is based mainly on ultrasound (US), which identifies intra-parietal pseudo-cystic images and "comet tail" artifacts. MRI with MRI cholangiography sequences is the reference examination with characteristic "pearl necklace" images. Symptomatic ADM is an indication for cholecystectomy, which results in complete disappearance of symptoms. Asymptomatic ADM is not an indication for surgery, but the radiological diagnosis must be beyond any doubt. If there is any diagnostic doubt about the possibility of GB cancer, a cholecystectomy is justified. The discovery of ADM in a cholecystectomy specimen does not require special surveillance. PMID- 28844705 TI - Resectable pancreatic head adenocarcinoma: Is R0 resection an illusion? Genetic evaluation of venous resection margin affirmed unrecognized disease. AB - PURPOSE: To assess the K-ras gene mutation in the histologically negative venous margin of a pancreaticoduodenectomy (PD) specimen and its impact on survival. METHOD: From 2007 to 2010, 22 patients underwent R0 PD for resecable pancreatic adenocarcinoma. All specimens were stained and the portal vein (PV) bed was identified by blue ink; a 2mm3 sample (including the blue ink) was cut from a microscopic free-tumor block. DNA was extracted and assessed by quantitative real time polymerase chain reaction to detect the K-ras gene mutation. Twelve specimens (55%) (kras+ group) were identified with a K-ras mutation in the venous margin resection, and 10 specimens (kras- group) did not have K-ras mutation detected in the venous margin resection. RESULTS: The two groups were comparable. Overall 3years survival of patients of kras+ group versus patients of kras- group was 0 and 17% (P=0.03), respectively. Median survival time of patients of kras+ group versus patients of kras- group was 16months vs 25months (P=0.04; 95% confidence interval [1,11-1,88]), respectively. CONCLUSION: Genetic evaluation of venous resection margin affirmed unrecognized disease with strong impact on survival in more than 50% of patients with histologically R0 resection. PMID- 28844706 TI - Structural identification of N-linked carbohydrates using the GUcal application: A tutorial. AB - : In recent years, analytical glycomics gained a significant role due to the rapidly increasing number of glycoproteins introduced as biopharmaceuticals. One of the frequently used methods for the analysis of complex carbohydrates is capillary electrophoresis with laser induced fluorescent detection (CE-LIF). CE LIF is a high resolution separation technique with excellent sensitivity capable of discriminating between closely related positional and linkage carbohydrate isomers. Individual glycan structures corresponding to the separated peaks in an electropherogram are identified according to their glucose unit (GU) values by mining the built in database. This tutorial introduces the practical use of the GUcal application, a recently developed glycoinformatics tool, which automatically calculates GU values for all sample components of interest in an electropherogram using either the bracketing standard approach or the recently published triple internal standard method. Furthermore, a worked example demonstrates the way glycan structural elucidation of human immunoglobulin G is processed with the help of this simple and rapid GU value calculation application. SIGNIFICANCE: Biopharmaceuticals have seen something of tremendous development in recent years, which governs the parallel blooming of analytical glycomics. One of the frequently used methods for the analysis of complex carbohydrates is capillary electrophoresis with laser induced fluorescent detection (CE-LIF). CE-LIF is a high resolution separation technique with excellent sensitivity capable of discriminating between closely related positional and linkage carbohydrate isomers. While CE instrumentation is well developed, the related bioinformatics tools are lagging behind. According to our best knowledge, this is the first tutorial paper on the recently disseminated GUcal application, which automatically calculates GU values for all sample components of interest in an electropherogram using either the bracketing standard approach or the new triple internal standard method. On the top the step by-step instruction how to use the application, the paper includes a worked example demonstrates the way glycan structure elucidation of human immunoglobulin G is processed with the help of the simple and rapid GU value calculation of this new application. After very short training period, the software can be used readily for cutting-edge glycomics of exploratory research or high-throughput routine analysis. PMID- 28844707 TI - Are we reproducible in measurement of NET liver metastasis? AB - Accurate measurement of well-differentiated neuroendocrine tumours (NET) liver metastases is critical to determine tumour slope and to assess treatment efficacy. Our objectives were to determine which CT or MRI sequence is the most reproducible to measure NET liver metastases and to assess the percentage of variability of measurements. Intra and inter-observer variability were studied on triphasic abdominal CT or liver MRI in 22 and 32 NET patients respectively. Patients were treatment-naive or under somatostatin analogues. A maximum of 5 liver target lesions per patient was defined and three radiologists measured them on each sequence. Reproducibility were analysed by calculating the relative variation (RV) as defined by RECIST criteria. We analysed 1656 target measurements for CT and 3384 for MRI. Intra-observers RV were better than inter observers. T2 for MRI and portal-phase for CT were associated with the lowest measurement variability. The MRI sequence offering the best intra and inter observer reproducibility is the T2W-sequence. MRI allows more reproducible measurement than CT (inter-observer RV <20% in 96.8% for MRI and 81% for CT). Our study demonstrates intermediate to high imaging reproducibility of liver metastases measurements in NET patients. Non-enhanced MRI should be preferred to triphasic-CT for follow-up, assessment of treatment and trials. PMID- 28844708 TI - Osteopontin and their roles in hematological malignancies: Splice variants on the new avenues. AB - Osteopontin (OPN) is a protein expressed in several tissues, including bone marrow, in which it performs distinct roles, such as modulating hematopoietic stem cell niche and bone remodeling. Most data in hematological malignancies (HMs) refers to total OPN (tOPN), comprehending the sum of distinct OPN splicing isoforms (OPN-SI), while reports describing the expression and roles of each OPN SI are scarce. This review aims to summarize tOPN roles in HMs and provide evidence that OPN-SIs can also modulate specific functions in HMs biology. We summarize that upregulated tOPN can modulate HMs (leukemia, lymphoma and myeloma) progression, inducing cell adhesion, invasion, angiogenesis, cell differentiation and extramedullary and/or central nervous system infiltration. Based on this expression pattern, tOPN has been pointed out as a biomarker in those HMs, thus providing potential targets for therapeutic approaches. Our group found that OPN SIs are expressed in childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL) cell lines (unpublished data), providing early evidence that OPN-SIs are also expressed in BCP-ALL. Further studies should investigate whether these OPN SIs can differently modulate HMs biology and their putative application as auxiliary biomarkers for HMs. PMID- 28844709 TI - The miR-491-3p/Sp3/ABCB1 axis attenuates multidrug resistance of hepatocellular carcinoma. AB - As one of main obstacles in the treatment and prognosis of hepatocellular carcinoma (HCC), multidrug resistance (MDR) is usually associated with the overexpression of the drug efflux pump P-glycoprotein (P-gp/ABCB1) which is responsible for reducing the intracellular concentration of chemotherapeutic agents. In current work, we discovered the novel role of miR-491-3p in ABCB1 mediated multidrug resistance in HCC and revealed the underlying mechanism in which miR-491-3p downregulated the expression of ABCB1 and its transcription factor Sp3 by directly targeting their 3'-UTR. Moreover, overexpressing ABCB1 or Sp3 reversed the sensitivity to chemotherapeutics in Hep3B cells induced by miR 491-3p, confirming miR-491-3p/Sp3/ABCB1 regulatory loop plays an important role in enhancing the drugs sensitivity of HCC. Meanwhile, the discovery of that the expression level of miR-491-3p was inversely correlated with that of ABCB1 and Sp3 in HCC cell lines and clinical samples pointed out the possibility of miR-491 3p in clinical use. In summary, our results reveal a pivotal role of miR-491-3p in the regulation of MDR in HCC, and suggest the potential application of miR-491 3p as a therapeutic strategy for modulating MDR in cancer cells. PMID- 28844710 TI - Induction of Plac8 promotes pro-survival function of autophagy in cadmium-induced prostate carcinogenesis. AB - Chronic exposure to cadmium is known to be a risk factor for human prostate cancer. Despite over-whelming evidence of cadmium causing carcinogenicity in humans, the specific underlying molecular mechanisms that govern metal-induced cellular transformation remain unclear. Acute exposure (up to 72 h) to cadmium induces apoptosis in normal prostate epithelial cells (RWPE-1), while chronic exposure (>1 year) transforms these cells to a malignant phenotype (cadmium transformed prostate epithelial cells; CTPE). Increased expression of autophagy regulated genes; Plac8, LC3B and Lamp-1; in CTPE cells was associated with cadmium-induced transformation. Increased expression of Plac8, a regulator of autophagosome/autolysosome fusion, facilitates the pro-survival function of autophagy and upregulation of pAKT(ser473) and NF-kappabeta, to allow CTPE to proliferate. Likewise, inhibition of Plac8 suppresses CTPE cell growth. Additionally, overexpression of Plac8 in RWPE-1 cells induces resistance to cadmium toxicity. Pharmacological inhibitors and an inducer of autophagy failed to affect Plac8 expression and CTPE cell viability, suggesting a unique role for Plac8 in cadmium-induced prostate epithelial cell transformation. These results support a role for Plac8 as an essential component in the cadmium-induced transformation of normal prostate epithelial cells to a cancerous state. PMID- 28844711 TI - Novel flexible heteroarotinoid, SL-1-18, promotes ERalpha degradation to inhibit breast cancer cell growth. AB - SL-1-18 (1-(chrysen-6-yl)-3-(4-nitrophenyl)thiourea) is new flexible heteroarotinoid (Flex-Het) analog derived from the parent compound, SHetA2, and our previous study showed comparable activity to SHetA2 in terms of inhibiting ER+ breast cancer cell growth. This current study aims to determine the molecular mechanism underlying SL-1-18's effect on breast cancer cell growth. Our results indicate that SL-1-18 inhibits cell proliferation of ER+ breast cancer cells (MCF 7 and T-47D) by preventing cell cycle progression. SL-1-18 treatment correlated positively with decreased expression of key cell-cycle regulators, such as cyclin D1, as well as other ERalpha-target genes at both the transcript and protein levels. Interestingly, decreased expression of ERalpha was also observed, with a significant reduction at the protein level within 2 h of SL-1-18 treatment, while the decrease in mRNA occurred at a later time point. ERalpha degradation was shown to be mediated by the ubiquitination-proteasome pathway. In summary, this is the first study to show that a Flex-Het- SL-1-18- can promote the degradation of ERalpha via the ubiquitin-proteasome pathway and should be further developed as a therapeutic option for ER+ breast cancer. PMID- 28844712 TI - FOLFOXIRI in metastatic colorectal cancer: A criticism from its native land. PMID- 28844713 TI - PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling. AB - Peptidylargininedeiminase 1 (PAD1) catalyzes protein for citrullination, and this activity has been linked to the epidermal cornification. However, a role for PAD1 in tumorigenesis, including breast cancers has not been previously explored. Here we first showed that PAD1 is overexpressed in human triple negative breast cancer (TNBC). In cultured cells and xenograft mouse models, PAD1 depletion or inhibition reduced cell proliferation, suppressed epithelial-mesenchymal transition, and prevented metastasis of MDA-MB-231 cells. These changes were correlated with a dramatic decrease in MMP2/9 expression. Furthermore, ERK1/2 and P38 MAPK signaling pathways are activated upon PAD1 silencing. Treatment with MEK1/2 inhibitor in PAD1 knockdown cells significantly recovered MMP2 expression, while inhibiting P38 activation only slightly elevated MMP9 levels. We then showed that PAD1 interacts with and citrullinates MEK1 thereby disrupting MEK1 catalyzed ERK1/2 phosphorylation, thus leading to the MMP2 overexpression. Collectively, our data indicate that PAD1 appears to promote tumorigenesis by regulating MEK1-ERK1/2-MMP2 signaling in TNBC. These results also raise the possibility that PAD1 may function as an important new biomarker for TNBC tumors and suggest that PAD1-specific inhibitors could potentially be utilized to treat metastatic breast cancer. PMID- 28844714 TI - Up-regulation of OLR1 expression by TBC1D3 through activation of TNFalpha/NF kappaB pathway promotes the migration of human breast cancer cells. AB - Metastatic spread of cancer cells is the most life-threatening aspect of breast cancer and involves multiple steps including cell migration. We recently found that the TBC1D3 oncogene promotes the migration of breast cancer cells, and its interaction with CaM enhances the effects of TBC1D3. However, little is known regarding the mechanism by which TBC1D3 induces the migration of cancer cells. Here, we demonstrated that TBC1D3 stimulated the expression of oxidized low density lipoprotein receptor 1 (OLR1), a stimulator of cell migration, in breast cancer cells at the transcriptional level. Depletion of OLR1 by siRNAs or down regulation of OLR1 expression using pomalidomide, a TNFalpha inhibitor, significantly decreased TBC1D3-induced migration of these cells. Notably, TBC1D3 overexpression activated NF-kappaB, a major effector of TNFalpha signaling, while inhibition of TNFalpha signaling suppressed the effects of TBC1D3. Consistent with this, NF-kappaB inhibition using its specific inhibitor caffeic acid phenethyl ester decreased both TBC1D3-induced OLR1 expression and cell migration, suggesting a critical role for TNFalpha/NF-kappaB signaling in TBC1D3-induced migration of breast cancer cells. Mechanistically, TBC1D3 induced activation of this signaling pathway on multiple levels, including by increasing the release of TNFalpha, elevating the transcription of TNFR1, TRAF1, TRAF5 and TRAF6, and decreasing the degradation of TNFR1. In summary, these studies identify the TBC1D3 oncogene as a novel regulator of TNFalpha/NF-kappaB signaling that mediates this oncogene-induced migration of human breast cancer cells by up regulating OLR1. PMID- 28844716 TI - Oncogenic role of cytomegalovirus in medulloblastoma? AB - Medulloblastoma is the most common solid tumor among children. Current therapeutic strategies for this malignancy include surgical resection, radiation therapy and chemotherapy. However, these treatments are accompanied with serious side effects such as neurological complications and psychosocial problems, due to the severity of treatment on the developing nervous system. To solve this problem, novel therapeutic approaches are currently being investigated. One of them is targeting human cytomegalovirus in medulloblastoma cancer cells. However, this approach is still under debate, since the presence of cytomegalovirus in medulloblastomas remains controversial. In this review, we discuss the current controversies on the role of cytomegalovirus in medulloblastoma oncogenesis and the potential of cytomegalovirus as a novel (immuno)therapeutic target. PMID- 28844715 TI - Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells. AB - Emerging evidence links exosomes to cancer progression by the trafficking of oncogenic factors and neoplastic reprogramming of stem cells. This necessitates identification and integration of functionally validated exosome-targeting therapeutics into current cancer management regimens. We employed quantitative high throughput screen on two libraries to identify exosome-targeting drugs; a commercially available collection of 1280 pharmacologically active compounds and a collection of 3300 clinically approved compounds. Manumycin-A (MA), a natural microbial metabolite, was identified as an inhibitor of exosome biogenesis and secretion by castration-resistant prostate cancer (CRPC) C4-2B, but not the normal RWPE-1, cells. While no effect was observed on cell growth, MA attenuated ESCRT-0 proteins Hrs, ALIX and Rab27a and exosome biogenesis and secretion by CRPC cells. The MA inhibitory effect is primarily mediated via targeted inhibition of the Ras/Raf/ERK1/2 signaling. The Ras-dependent MA suppression of exosome biogenesis and secretion is partly mediated by ERK-dependent inhibition of the oncogenic splicing factor hnRNP H1. Our findings suggest that MA is a potential drug candidate to suppress exosome biogenesis and secretion by CRPC cells. PMID- 28844717 TI - Intranasal oxytocin reduces heart rate variability during a mental arithmetic task: A randomised, double-blind, placebo-controlled cross-over study. AB - Heart rate variability (HRV) refers to variation in the interval between successive heart beats. Low HRV is an indicator of potential autonomic nervous system dysfunction. People with chronic pain often display autonomic dysregulation, especially in the parasympathetic nervous system. The hormone oxytocin has been shown to increase HRV in non-clinical samples, but its potential impact on HRV in persons with chronic pain is unknown. This study investigated the impact of intranasal oxytocin on HRV in persons with chronic neck and shoulder pain. Participants included 24 individuals with chronic neck and shoulder pain lasting >12months and 24 age- and sex-matched pain-free controls. In a randomised double-blind, placebo-controlled, cross-over study, participants self-administered intranasal oxytocin (24IU) in one session, and placebo in another, before HRV was recorded at rest and during a mental arithmetic task. Intranasal oxytocin did not influence HRV at rest. However, compared to placebo, intranasal oxytocin elicited small decreases in low frequency and high-frequency HRV in both groups during the mental arithmetic task. These results suggest that intranasal oxytocin may enhance the salience of the mental arithmetic task, leading to reduced engagement of the parasympathetic nervous system when completing the task. Further investigation and replication of these findings are required to improve our understanding of the effects of intranasal oxytocin on autonomic functioning both at rest and under cognitive stress. PMID- 28844719 TI - Evaluation of a rapid immunochromatographic test for detection of distinct variants of Klebsiella pneumoniae carbapenemase (KPC) in Enterobacteriaceae. AB - The rapid detection of KPC-producing Enterobacteriaceae by microbiology laboratories has been required for infectious control programs. Herein we evaluated the performance of a novel immunochromatographic test for detecting KPC 2-, KPC-3-, KPC-4-, KPC-6-, KPC-7-, KPC-8-, and KPC-11-producing isolates and the influence of different growth media on the test performance. PMID- 28844720 TI - Development and standardization of an in-house indirect ELISA for detection of duck antibody to fowl cholera. AB - Serological tests, such as agglutination and indirect hemagglutination assay (IHA), have been used to identify antibodies against Pasteurella multocida in poultry sera, but none are highly sensitive. An enzyme-linked immunosorbent assays (ELISA) has been used with varying degrees of success in attempts to monitor seroconversion in vaccinated poultry, but are not suitable for diagnosis. Commercial ELISA kits are available for chickens and turkeys, but not for ducks. The present study reports development and standardization of an in-house indirect ELISA for detection of duck antibody to fowl cholera. The characteristics of ELISA and IHA were analyzed using a one population Bayesian model assuming conditional dependence between the two diagnostic tests. An in-house indirect ELISA was developed using a heat extract antigen of P. multocida strain X-73 as a coating antigen and horseradish peroxidase conjugated goat anti-duck IgG antibody (dIgG-HRP). The checkerboard titration method was done using sera from ducks immunized with P. multocida bacterin as positive sera and 1day old duckling sera as negative sera. The heat extract antigen at 1MUg/ml, sample serum at a dilution of 1:100, and dIgG-HRP 1:2000 were optimal concentrations for the assay. The cut off value was 0.200. Of the duck sera, 89.05% (244/274) were considered seropositive by ELISA. Estimates for sensitivity and specificity of ELISA were higher than prior values with medians of 94.7% [95% posterior probability interval (PPI)=89.6-98.2%] and 87.2% (PPI=68.2-98.3%). Estimates for sensitivity of IHA were lower than prior values (median=97.6, PPI=93.2-99.7%) while the specificity was close to the prior value (median=76.5, PPI=65.8-85.4%). This finding suggests that an in-house indirect ELISA can be used to detect duck antibody to fowl cholera. PMID- 28844721 TI - A multiplex real-time PCR for the direct, fast, economic and simultaneous detection of the carbapenemase genes blaKPC, blaNDM, blaVIM and blaOXA-48. AB - A novel multiplex real-time PCR was designed to detect the clinically most important carbapenemase genes, blaKPC, blaVIM, blaNDM and blaOXA-48. The multiplex assay was verified testing genomic DNA of 24 carbapenemase-producing strains. It was validated using a blinded panel of 82 carbapenemase-producing and 50 non-producing isolates by direct colony PCR. PMID- 28844718 TI - Nuclear DNA Replication in Trypanosomatids: There Are No Easy Methods for Solving Difficult Problems. AB - In trypanosomatids, etiological agents of devastating diseases, replication is robust and finely controlled to maintain genome stability and function in stressful environments. However, these parasites encode several replication protein components and complexes that show potentially variant composition compared with model eukaryotes. This review focuses on the advances made in recent years regarding the differences and peculiarities of the replication machinery in trypanosomatids, including how such divergence might affect DNA replication dynamics and the replication stress response. Comparing the DNA replication machinery and processes of parasites and their hosts may provide a foundation for the identification of targets that can be used in the development of chemotherapies to assist in the eradication of diseases caused by these pathogens. PMID- 28844722 TI - Chemotaxis detection towards chlorophenols using video processing analysis. AB - To our knowledge, this communication is the first report of chemotaxis towards chlorophenols by any bacteria. We used a recently published method based on the agarose in-plug assay combined with video processing analysis and we also present a new index of bacterial mean speed for these assays. PMID- 28844723 TI - Cocontraction measured with short-range stiffness was higher in obstetric brachial plexus lesions patients compared to healthy subjects. AB - We suggest short range stiffness (SRS) at the elbow joint as an alternative diagnostic for EMG to assess cocontraction. Elbow SRS is compared between obstetric brachial plexus lesion (OBPL) patients and healthy subjects (cross sectional study design). Seven controls (median 28years) and five patients (median 31years) isometrically flexed and extended the elbow at rest and three additional torques [2.1,4.3,6.4Nm] while a fast stretch stimulus was applied. SRS was estimated in silico using a neuromechanical elbow model simulating the torque response from the imposed elbow angle. SRS was higher in patients (250+/ 36Nm/rad) than in controls (150+/-21Nm/rad, p=0.014), except for the rest condition. Higher elbow SRS suggested greater cocontraction in patients compared to controls. SRS is a promising mechanical alternative to assess cocontraction, which is a frequently encountered clinical problem in OBPL due to axonal misrouting. PMID- 28844724 TI - Response to Letter to the Editor concerning "How symmetric are metal-on-metal hip resurfacing patients during gait? Insights for the rehabilitation". PMID- 28844725 TI - Sprint mechanics return to competition follow-up after hamstring injury on a professional soccer player: A case study with an inertial sensor unit based methodological approach. AB - BACKGROUND: The present research aimed to describe an inertial unit (IU)-based sprint mechanics evaluation model for assessing players' readiness to return to competition after suffering a grade I hamstring injury. METHODS: A professional male football player (age 19years; height 177cm; weight 70kg, midfielder, Spanish, 3 degrees Division) with a grade 1 biceps femoris injury was evaluated at pre-season, at return to play after injury and at the end of the competitive season. Sprint mechanics were analyzed via the use of an inertial orientation tracker (Xsens Technologies B.V. Enschede, Netherlands) attached over the L3-L4 region of the subject's lumbar spine. Sprint mechanics such as horizontal components of ground reaction force were assessed in both legs during sprinting actions. Findings and interpretation: Both the coefficient of the horizontal force application (SFV) and the ratio of forces (DRF) applied at increasing velocity were decreased in the injured limb compared with the contralateral healthy limb at the return to play evaluation (73% and 76% reductions, respectively) and returned to symmetrical levels at the end-season evaluation. PMID- 28844726 TI - Cycling and spinal trauma: A worrying trend in referrals to a national spine centre. AB - INTRODUCTION: Cycling has seen a large increase in popularity worldwide over the last number of years. This has been linked to an increase in the number of road traffic accidents involving cyclists. Participation in cycling as part of competitive sport and endurance events has seen particular growth. AIM: To examine patients referred with spinal trauma related to cycling and to assess whether the growing popularity of cycling and particularly competitive cycling is linked to an increase in spinal trauma. METHODS: A retrospective analysis was carried out of a prospectively maintained database of referrals to a national referral centre for spinal trauma over a 4-year period (2010-2013). Data were further analysed for years 2012-2013, as there were incomplete data for years 2010-2011. RESULTS: Spinal injuries involving cyclists increased by 200% from 2010 to 2013. In comparison those involving cars only increased by 29% and motorcycles reduced by 68%. From 2012 to 2013 there were 24 cyclist trauma referrals. The most common level injured was cervical spine (71%). Five patients (20.8%) had neurological deficit with 12.5% complete paralysis ASIA A disability score. The spinal fixation rate was 29.1%, 16.6% were managed with a HALO device. In total, 25% of patients were injured whilst training on a racer style bicycle, including all of the patients with complete spinal cord injury. CONCLUSION: There has been a significant increase in spinal trauma due to cycling accidents over this four year period. Competitive cycling has been a factor in the most severely injured patients. Increased public awareness campaigns for those participating in cycling for sport may be warranted. PMID- 28844727 TI - Does dispatcher-assisted CPR generate the same outcomes as spontaneously delivered bystander CPR in Japan? AB - AIM: We investigated whether DA-CPR would have the same effect as spontaneously delivered bystander CPR. METHODS: A total of 37,899 witnessed cardiogenic out of hospital cardiac arrest (OHCA) selected from a nationwide Utstein-Japanese database between 2008 and 2012. Patients were divided into four groups as follows: CPR initiated with dispatcher assistance (DA-CPR; n=10,424), no CPR provided with dispatcher assistance (DA-No CPR; n=4658), spontaneously-delivered bystander CPR provided without DA (BCPR; n=6630), and both BCPR and dispatcher assistance was not provided (No BCPR-No DA; n=16,187). The primary endpoint was rate of shockable rhythm on the initial ECG, return of spontaneous circulation (ROSC) on the field. A multivariable logistic regression analysis was used. Adjusted odds ratios (AOR) are presented as 95% confidence intervals (95% CIs) among the groups. RESULTS: The rate of DA-CPR implementation has gradually increased since 2005. In comparison with DA-No CPR, both spontaneously-delivered BCPR and DA-CPR were significantly associated with the following factors: increased rate of shockable rhythm on the initial ECG (AOR, 1.75 and 1.72; 95% CI, 1.67 to 1.85 and 1.63 to 1.83),improved field ROSC (AOR, 1.42 and 1.40; 95% CI, 1.33 to 1.52 and 1.30 to 1.51) and 1-month favorable neurological outcomes (AOR, 1.72 and 1.80; 95% CI, 1.59 to 1.88 and 1.64 to 1.97), respectively. CONCLUSIONS: We found that the spontaneously delivered BCPR group showed favorable results. In comparison to the DA-No BCPR group, DA-CPR group resulted in the nearly equivalent effect as spontaneously-delivered BCPR group. Further standard dispatcher education is indicated. PMID- 28844728 TI - Brain areas associated with numbers and calculations in children: Meta-analyses of fMRI studies. AB - Children use numbers every day and typically receive formal mathematical training from an early age, as it is a main subject in school curricula. Despite an increase in children neuroimaging studies, a comprehensive neuropsychological model of mathematical functions in children is lacking. Using quantitative meta analyses of functional magnetic resonance imaging (fMRI) studies, we identify concordant brain areas across articles that adhere to a set of selection criteria (e.g., whole-brain analysis, coordinate reports) and report brain activity to tasks that involve processing symbolic and non-symbolic numbers with and without formal mathematical operations, which we called respectively number tasks and calculation tasks. We present data on children 14 years and younger, who solved these tasks. Results show activity in parietal (e.g., inferior parietal lobule and precuneus) and frontal (e.g., superior and medial frontal gyri) cortices, core areas related to mental-arithmetic, as well as brain regions such as the insula and claustrum, which are not typically discussed as part of mathematical problem solving models. We propose a topographical atlas of mathematical processes in children, discuss findings within a developmental constructivist theoretical model, and suggest practical methodological considerations for future studies. PMID- 28844729 TI - Handling newborn monkeys alters later exploratory, cognitive, and social behaviors. AB - Touch is one of the first senses to develop and one of the earliest modalities for infant-caregiver communication. While studies have explored the benefits of infant touch in terms of physical health and growth, the effects of social touch on infant behavior are relatively unexplored. Here, we investigated the influence of neonatal handling on a variety of domains, including memory, novelty seeking, and social interest, in infant monkeys (Macaca mulatta; n=48) from 2 to 12 weeks of age. Neonates were randomly assigned to receive extra holding, with or without accompanying face-to-face interactions. Extra-handled infants, compared to standard-reared infants, exhibited less stress-related behavior and more locomotion around a novel environment, faster approach of novel objects, better working memory, and less fear towards a novel social partner. In sum, infants who received more tactile stimulation in the neonatal period subsequently demonstrated more advanced motor, social, and cognitive skills-particularly in contexts involving exploration of novelty-in the first three months of life. These data suggest that social touch may support behavioral development, offering promising possibilities for designing future early interventions, particularly for infants who are at heightened risk for social disorders. PMID- 28844730 TI - Association between SNCA rs2736990 polymorphism and Parkinson's disease: a meta analysis. AB - Emerging evidence suggests that the SNP rs2736990 of SNCA is a susceptibility factor for idiopathic Parkinson's disease (PD) in different populations, but the studies which examined the association have provided inconsistent results. Therefore, we performed a meta-analysis of some case-control studies to obtain a more exact estimation of there associations. All the relevant studies were extracted from PubMed, Embase, EBSCO, Chineses national knowledge infrastructure, Google Scholar and Wanfang databases (up to February 2017). A total of six studies with 2525 PD cases and 2165 controls were eventually enrolled in the present meta-analysis based on the strict inclusion and exclusion criteria. The pooled analysis showed that there is a significant association between rs2736990 polymorphism and PD susceptibility in all genetic models (T vs. C: OR=0.772, 95%CI: 0.709-0.840, P=0.001; TT vs. CC: OR=0.586, 95%CI: 0.490-0.701, P=0.001; TC vs. CC: OR=0.814, 95%CI: 0.716-0.925, P=0.002; TT+TC vs. CC: OR=0.752, 95%CI: 0.666-0.848, P=0.001; TT vs. TC+CC: OR=0.658, 95%CI: 0.561-0.772, P=0.001). Our meta-analysis provides evidence that the T allele, TT and TC genotype of rs2736990(C/T) polymorphism may decrease the risk of PD. PMID- 28844731 TI - Tumor necrosis factor alpha polymorphisms are associated with Parkinson's disease age at onset. AB - The role of neuroinflammation in Parkinson's disease (PD) has been demonstrated through several different approaches. It was suggested an inflammation-derived oxidative stress and cytokine-dependent toxicity role in the nigrostriatal pathway degeneration and hasten progression of disease. Tumor necrosis factor alpha (TNFA) gene promoter polymorphisms might alter the expression of this cytokine contributing to the pro- and anti-inflammatory polarization. An increased TNFA expression might lead to inflammatory profile predominance. The aim of study was to determine if TNFA haplotypes are associated with PD age at onset. Five polymorphisms in TNFA gene were investigated in 226 patients with idiopathic PD in relation to age at onset. Haplotype grouping was based on allele expression. Logistic binary regression analysis showed that the genetic background leading to higher TNF-alpha expression confers a higher risk to develop PD earlier. Gender and ancestry did not differ between groups. High TNFA expression may contribute for faster dopaminergic neuron degeneration. In this context, a higher genetic pro-inflammatory profile confers a higher risk to develop PD earlier. PMID- 28844732 TI - Evaluation of the Braak staging of brain pathology with 1H-MRS in patients with Parkinson's disease. AB - The Braak staging of Parkinson's disease (PD) pathology is usually based on the brain autopsy, which has not been confirmed in living patients of PD. In this study, we investigated the metabolites of medulla oblongata, substantia nigra (SN), putamen, and motor cortex by measuring N-acetylaspartate (NAA), choline containing compounds (Cho) and creatine (Cr) in 22 patients of PD and 15 age matched healthy controls, using single-voxel 1H-magnetic resonance spectroscopy (1H-MRS). The results showed that NAA/Cr in SN was lower in PD group than that in control group (p=0.006), however, there was no difference for NAA/Cr and Cho/Cr between PD group and control group in other regions. In SN, NAA/Cr was negatively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) (r=-0.743, p=0.002) and Hoehn-Yahr staging (r=-0.714, p=0.003), while Cho/Cr was positively correlated with UPDRS (r=0.850, p<0.001) and Hoehn-Yahr staging (r=0.647, p=0.009). In PD group, the variance of NAA/Cr in SN was significantly larger than that in other regions (p=0.005), but there was no difference for the variance of Cho/Cr among regions of interesting (ROIs) (p=0.267). These results indicate that SN is the most seriously injured region in PD, and the metabolites in SN measured by 1H-MRS is correlated with the severity of PD. However, the Braak staging of PD pathology is not validated by 1H-MRS. PMID- 28844733 TI - A pilot replication of QUIT, a randomized controlled trial of a brief intervention for reducing risky drug use, among Latino primary care patients. AB - BACKGROUND: QUIT is the only primary care-based brief intervention that has previously shown efficacy for reducing risky drug use in the United States (Gelberg et al., 2015). This pilot study replicated the QUIT protocol in one of the five original QUIT clinics primarily serving Latinos. DESIGN: Single-blind, two-arm, randomized controlled trial of patients enrolled from March-October 2013 with 3-month follow-up. SETTING: Primary care waiting room of a federally qualified health center (FQHC) in East Los Angeles. PARTICIPANTS: Adult patients with risky drug use (4-26 on the computerized WHO ASSIST): 65 patients (32 intervention, 33 control); 51 (78%) completed follow-up; mean age 30.8 years; 59% male; 94% Latino. INTERVENTIONS AND MEASURES: Intervention patients received: 1) brief (typically 3-4 minutes) clinician advice to quit/reduce their risky drug use, 2) video doctor message reinforcing the clinician's advice, 3) health education booklet, and 4) up to two 20-30 minute follow-up telephone drug use reduction coaching sessions. Control patients received usual care and cancer screening information. Primary outcome was reduction in number of days of drug use in past 30days of the highest scoring drug (HSD) on the baseline ASSIST, from baseline to 3-month follow-up. RESULTS: Controls reported unchanged HSD use between baseline and 3-month follow-up whereas Intervention patients reported reducing their use by 40% (p<0.001). In an intent-to-treat linear regression analysis, intervention patients reduced past month HSD use by 4.5 more days than controls (p<0.042, 95% CI: 0.2, 8.7). Similar significant results were found using a complete sample regression analysis: 5.2 days (p<0.03, 95% CI: 0.5, 9.9). Additionally, on logistic regression analysis of test results from 47 urine samples at follow-up, intervention patients were less likely than controls to test HSD positive (p<0.05; OR: 0.10, 95% CI: 0.01, 0.99). CONCLUSIONS: Findings support the efficacy of the QUIT brief intervention for reducing risky drug use. PMID- 28844734 TI - Employing proteomic analysis to compare Paracoccidioides lutzii yeast and mycelium cell wall proteins. AB - Paracoccidioidomycosis is an important systemic mycosis caused by thermodimorphic fungi of the Paracoccidioides genus. During the infective process, the cell wall acts at the interface between the fungus and the host. In this way, the cell wall has a key role in growth, environment sensing and interaction, as well as morphogenesis of the fungus. Since the cell wall is absent in mammals, it may present molecules that are described as target sites for new antifungal drugs. Despite its importance, up to now few studies have been conducted employing proteomics in for the identification of cell wall proteins in Paracoccidioides spp. Here, a detailed proteomic approach, including cell wall-fractionation coupled to NanoUPLC-MSE, was used to study and compare the cell wall fractions from Paracoccidioides lutzii mycelia and yeast cells. The analyzed samples consisted of cell wall proteins extracted by hot SDS followed by extraction by mild alkali. In summary, 512 proteins constituting different cell wall fractions were identified, including 7 predicted GPI-dependent cell wall proteins that are potentially involved in cell wall metabolism. Adhesins previously described in Paracoccidioides spp. such as enolase, glyceraldehyde-3-phosphate dehydrogenase were identified. Comparing the proteins in mycelium and yeast cells, we detected some that are common to both fungal phases, such as Ecm33, and some specific proteins, as glucanase Crf1. All of those proteins were described in the metabolism of cell wall. Our study provides an important elucidation of cell wall composition of fractions in Paracoccidioides, opening a way to understand the fungus cell wall architecture. PMID- 28844735 TI - Pseudo-peptide amyloid-beta blocking inhibitors: molecular dynamics and single molecule force spectroscopy study. AB - By combining MD simulations and AFS experimental technique, we demonstrated a powerful approach for rational design and single molecule testing of novel inhibitor molecules which can block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. We designed and tested novel pseudo-peptide amyloid-beta (Abeta) inhibitors that bind to the Abeta peptide and effectively prevent amyloid-amyloid binding. First, molecular dynamics (MD) simulations have provided information on the structures and binding characteristics of the designed pseudo-peptides targeting amyloid fragment Abeta (13-23). The binding affinities between the inhibitor and Abeta as well as the inhibitor to itself have been estimated using Umbrella Sampling calculations. Atomic Force Spectroscopy (AFS) was used to experimentally test several proposed inhibitors in their ability to block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. The experimental AFS data are in a good agreement with theoretical MD calculations and demonstrate that three proposed pseudo-peptides bind to amyloid fragment with different affinities and all effectively prevent Abeta-Abeta binding in similar way. We propose that the designed pseudo-peptides can be used as potential drug candidates to prevent Abeta toxicity in Alzheimer's disease. PMID- 28844736 TI - Structure and binding studies of proliferating cell nuclear antigen from Leishmania donovani. AB - Proliferating cell nuclear antigen (PCNA) acts as a sliding clamp to support DNA replication and repair. The structure of PCNA from Leishmania donovani (LdPCNA) has been determined at 2.73A resolution. Structure consists of six crystallographically independent molecules which form two trimeric rings. The pore diameter of the individual trimeric ring is of the order of 37A. The two rings are stacked through their front to front faces. In order to gain a stable packing, the rings are rotated by 42 degrees about the pore axis and shifted by 7A and tilted by 16 degrees along the perpendicular direction to pore axis. This form of stacking reduced the effective diameter of the pore to 32A. The sequence of LdPCNA consists of a long segment of 41 amino acid residues (186-Gly-Val-Ser Asp-Arg-Ser-Thr-Lys-Ser-Glu-Val-Lys-Ala-Glu-Val-Lys-Ala-Glu-Ala-Arg-Asp-Asp-Asp Glu-Glu-Pro-Leu-Ser-Arg-Lys-Tyr-Gly-Lys-Ala-Asp-Ser-Ser-Ala-Asn-Ala-Ile-226) whereas the corresponding segments in other PCNAs contain only eight residues corresponding to 186-Gly-Val-Ser-Asp-Arg------224-Asn-Ala-Ile-226. The enhanced length of this segment in LdPCNA may influence its mode of interaction with DNA and other proteins. The dissociation constants obtained using real time binding studies with surface plasmon resonance (SPR) for two peptides, Lys-Arg-Arg-Gln Thr-Ser-Met-Thr-Asp-Phe-Tyr-His (P1) from human cyclin-dependent kinase inhibitor 1(CKI-1) and Lys-Thr-Gln-Gly-Arg-Leu-Asp-Ser-Phe-Phe-Thr-Val (P2) from flap endonuclease 1 (Fen-1) as well as with two small molecule inhibitors, (S)-4-(4-(2 amino-3-hydroxypropyl)-2, 6-diiodophenoxy) phenol hydrochloride (ADPH) and N-(3 methylthiophene-2-carboxylicacid)-N'-((3-hydroxy-2-naphthalenyl) methylene) hydrazide (MCMH) are 0.29+/-0.09MUM, 0.37+/-0.08MUM, 0.35+/-0.09MUM and 1.20+/ 0.08MUM respectively. The corresponding values obtained using fluorescence spectroscopic methods were 0.22+/-0.06MUM, 0.68+/-0.07MUM, 0.44+/-0.07MUM and 0.75+/-0.05MUM respectively. PMID- 28844737 TI - Structural templating of J-aggregates: Visualizing bis(monoacylglycero)phosphate domains in live cells. AB - Identifying the key structural and dynamical determinants that drive the association of biomolecules, whether in solution, or perhaps more importantly in a membrane environment, has critical implications for our understanding of cellular dynamics, processes, and signaling. With recent advances in high resolution imaging techniques, from the development of new molecular labels to technical advances in imaging methodologies and platforms, researchers are now reaping the benefits of being able to directly characterize and quantify local dynamics, structures, and conformations in live cells and tissues. These capabilities are providing unique insights into association stoichiometries, interactions, and structures on sub-micron length scales. We previously examined the role of lipid headgroup chemistry and phase state in guiding the formation of pseudoisocyanine (PIC) dye J-aggregates on supported planar bilayers [Langmuir, 25, 10719]. We describe here how these same J-aggregates can report on the in situ formation of organellar membrane domains in live cells. Live cell hyperspectral confocal microscopy using GFP-conjugated GTPase markers of early (Rab5) and late (Rab7) endosomes revealed that the PIC J-aggregates were confined to domains on either the limiting membrane or intralumenal vesicles (ILV) of late endosomes, known to be enriched in the anionic lipid bis(monoacylglycero)phosphate (BMP). Correlated confocal fluorescence - atomic force microscopy performed on endosomal membrane-mimetic supported planar lipid bilayers confirmed BMP-specific templating of the PIC J-aggregates. These data provide strong evidence for the formation of BMP-rich lipid domains during multivesicular body formation and portend the application of structured dye aggregates as markers of cellular membrane domain structure, size, and formation. PMID- 28844738 TI - Thermal sensitivity and flexibility of the Cepsilon3 domains in immunoglobulin E. AB - Immunoglobulin E (IgE) is the antibody that plays a central role in the mechanisms of allergic diseases such as asthma. Interactions with its receptors, FcepsilonRI on mast cells and CD23 on B cells, are mediated by the Fc region, a dimer of the Cepsilon2, Cepsilon3 and Cepsilon4 domains. A sub-fragment lacking the Cepsilon2 domains, Fcepsilon3-4, also binds to both receptors, although receptor binding almost exclusively involves the Cepsilon3 domains. This domain also contains the N-linked glycosylation site conserved in other isotypes. We report here the crystal structures of IgE-Fc and Fcepsilon3-4 at the highest resolutions yet determined, 1.75A and 2.0A respectively, revealing unprecedented detail regarding the carbohydrate and its interactions with protein domains. Analysis of the crystallographic B-factors of these, together with all earlier IgE-Fc and Fcepsilon3-4 structures, shows that the Cepsilon3 domains exhibit the greatest intrinsic flexibility and quaternary structural variation within IgE-Fc. Intriguingly, both well-ordered carbohydrate and disordered polypeptide can be seen within the same Cepsilon3 domain. A simplified method for comparing the quaternary structures of the Cepsilon3 domains in free and receptor-bound IgE-Fc structures is presented, which clearly delineates the FcepsilonRI and CD23 bound states. Importantly, differential scanning fluorimetric analysis of IgE-Fc and Fcepsilon3-4 identifies Cepsilon3 as the domain most susceptible to thermally induced unfolding, and responsible for the characteristically low melting temperature of IgE. PMID- 28844739 TI - Recent progress on the application of 2H solid-state NMR to probe the interaction of antimicrobial peptides with intact bacteria. AB - Discoveries relating to innate immunity and antimicrobial peptides (AMPs) granted Bruce Beutler and Jules Hoffmann a Nobel prize in medicine in 2011, and opened up new avenues for the development of therapies against infections, and even cancers. The mechanisms by which AMPs interact with, and ultimately disrupt, bacterial cell membranes is still, to a large extent, incompletely understood. Up until recently, this mechanism was studied using model lipid membranes that failed to reproduce the complexity of molecular interactions present in real cells comprising lipids but also membrane proteins, a cell wall containing peptidoglycan or lipopolysaccharides, and other molecules. In this review, we focus on recent attempts to study, at the molecular level, the interaction between cationic AMPs and intact bacteria, by 2H solid-state NMR. Specifically labeled lipids allow us to focus on the interaction of AMPs with the heart of the bacterial membrane, and measure the lipid order and its variation upon interaction with various peptides. We will review the important parameters to consider in such a study, and summarize the results obtained in the past 5years on various peptides, in particular aurein 1.2, caerin 1.1, MSI-78 and CA(1-8)M(1 10). This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28844740 TI - Back to the future: Rational maps for exploring acetylcholine receptor space and time. AB - Global functions of nicotinic acetylcholine receptors, such as subunit cooperativity and compatibility, likely emerge from a network of amino acid residues distributed across the entire pentameric complex. Identification of such networks has stymied traditional approaches to acetylcholine receptor structure and function, likely due to the cryptic interdependency of their underlying amino acid residues. An emerging evolutionary biochemistry approach, which traces the evolutionary history of acetylcholine receptor subunits, allows for rational mapping of acetylcholine receptor sequence space, and offers new hope for uncovering the amino acid origins of these enigmatic properties. PMID- 28844741 TI - Direct kinetic comparison of the two cellobiohydrolases Cel6A and Cel7A from Hypocrea jecorina. AB - Cellulose degrading fungi such as Hypocrea jecorina secrete several cellulases including the two cellobiohydrolases (CBHs) Cel6A and Cel7A. The two CBHs differ in catalytic mechanism, attack different ends, belong to different families, but are both processive multi-domain enzymes that are essential in the hydrolysis of cellulose. Here we present a direct kinetic comparison of these two enzymes acting on insoluble cellulose. We used both continuous- and end-point assays under either enzyme- or substrate excess, and found distinct kinetic differences between the two CBHs. Cel6A was catalytically superior with a maximal rate over four times higher than Cel7A. Conversely, the ability of Cel6A to attack diverse structures on the cellulose surface was inferior to Cel7A. This latter difference was pronounced as the density of attack sites for Cel7A was almost an order of magnitude higher compared to Cel6A. We conclude that Cel6A is a fast but selective enzyme and that Cel7A is slower, but promiscuous. One consequence of this is that Cel6A is more effective when substrate is plentiful, while Cel7A excels when substrate is limiting. These diverse kinetic properties of Cel6A and Cel7A might elucidate why both cellobiohydrolases are prominent in cellulolytic degrading fungi. PMID- 28844742 TI - The oxygen-binding properties of hemocyanin from the mollusk Concholepas concholepas. AB - Hemocyanins have highly conserved copper-containing active sites that bind oxygen. However, structural differences among the hemocyanins of various mollusks may affect their physicochemical properties. Here, we studied the oxygen-binding cooperativity and affinity of Concholepas concholepas hemocyanin (CCH) and its two isolated subunits over a wide range of temperatures and pH values. Considering the differences in the quaternary structures of CCH and keyhole limpet hemocyanin (KLH), we hypothesized that the heterodidecameric CCH has different oxygen-binding parameters than the homodidecameric KLH. A novel modification of the polarographic method was applied in which rat liver submitochondrial particles containing cytochrome c oxidase were introduced to totally deplete oxygen of the test solution using ascorbate as the electron donor. This method was both sensitive and reproducible. The results showed that CCH, like other hemocyanins, exhibits cooperativity, showing an inverse relationship between the oxygen-binding parameters and temperature. According to their Hill coefficients, KLH has greater cooperativity than CCH at physiological pH; however, CCH is less sensitive to pH changes than KLH. Appreciable differences in binding behavior were found between the CCH subunits: the cooperativity of CCH-A was not only almost double that of CCH-B, but it was also slightly superior to that of CCH, thus suggesting that the oxygen-binding domains of the CCH subunits are different in their primary structure. Collectively, these data suggest that CCH-A is the main oxygen-binding domain in CCH; CCH-B may play a more structural role, perhaps utilizing its surprising predisposition to form tubular polymers, unlike CCH-A, as demonstrated here using electron microscopy. PMID- 28844743 TI - Recent advances in biophysical studies of rhodopsins - Oligomerization, folding, and structure. AB - Retinal-binding proteins, mainly known as rhodopsins, function as photosensors and ion transporters in a wide range of organisms. From halobacterial light driven proton pump, bacteriorhodopsin, to bovine photoreceptor, visual rhodopsin, they have served as prototypical alpha-helical membrane proteins in a large number of biophysical studies and aided in the development of many cutting-edge techniques of structural biology and biospectroscopy. In the last decade, microbial and animal rhodopsin families have expanded significantly, bringing into play a number of new interesting structures and functions. In this review, we will discuss recent advances in biophysical approaches to retinal-binding proteins, primarily microbial rhodopsins, including those in optical spectroscopy, X-ray crystallography, nuclear magnetic resonance, and electron paramagnetic resonance, as applied to such fundamental biological aspects as protein oligomerization, folding, and structure. PMID- 28844744 TI - On the quest for the elusive mechanism of action of daptomycin: Binding, fusion, and oligomerization. AB - Daptomycin, sold under the trade name CUBICIN, is the first lipopeptide antibiotic to be approved for use against Gram-positive organisms, including a number of highly resistant species. Over the last few decades, a number of studies have tried to pinpoint the mechanism of action of daptomycin. These proposed modes of action often have points in common (e.g. the requirement for Ca2+ and lipid membranes containing a high proportion of phosphatidylglycerol (PG) headgroups), but also points of divergence (e.g. oligomerization in solution and in membranes, membrane perturbation vs. inhibition of cell envelope synthesis). In this study, we investigate how concentration effects may have an impact on the interpretation of the biophysical data used to support a given mechanism of action. Results obtained from small angle neutron scattering (SANS) experiments and molecular dynamics (MD) simulations show that daptomycin oligomerizes at high concentrations (both with and without Ca2+) in solution, but that this oligomer readily falls apart. Photon correlation spectroscopy (PCS) experiments demonstrate that daptomycin causes fusion more readily in DMPC/PG membranes than in POPC/PG, suggesting that the latter may be a better model system. Finally, fluorescence and Forster resonance energy transfer (FRET) experiments reveal that daptomycin binds strongly to the lipid membrane and that oligomerization occurs in a concentration-dependent manner. The combined experiments provide an improved framework for more general and rigorous biophysical studies toward understanding the elusive mechanism of action of daptomycin. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28844746 TI - Anthranilate phosphoribosyltransferase: Binding determinants for 5'-phospho-alpha d-ribosyl-1'-pyrophosphate (PRPP) and the implications for inhibitor design. AB - Phosphoribosyltransferases (PRTs) bind 5'-phospho-alpha-d-ribosyl-1' pyrophosphate (PRPP) and transfer its phosphoribosyl group (PRib) to specific nucleophiles. Anthranilate PRT (AnPRT) is a promiscuous PRT that can phosphoribosylate both anthranilate and alternative substrates, and is the only example of a type III PRT. Comparison of the PRPP binding mode in type I, II and III PRTs indicates that AnPRT does not bind PRPP, or nearby metals, in the same conformation as other PRTs. A structure with a stereoisomer of PRPP bound to AnPRT from Mycobacterium tuberculosis (Mtb) suggests a catalytic or post catalytic state that links PRib movement to metal movement. Crystal structures of Mtb-AnPRT in complex with PRPP and with varying occupancies of the two metal binding sites, complemented by activity assay data, indicate that this type III PRT binds a single metal-coordinated species of PRPP, while an adjacent second metal site can be occupied due to a separate binding event. A series of compounds were synthesized that included a phosphonate group to probe PRPP binding site. Compounds containing a "bianthranilate"-like moiety are inhibitors with IC50 values of 10-60MUM, and Ki values of 1.3-15MUM. Structures of Mtb-AnPRT in complex with these compounds indicate that their phosphonate moieties are unable to mimic the binding modes of the PRib or pyrophosphate moieties of PRPP. The AnPRT structures presented herein indicated that PRPP binds a surface cleft and becomes enclosed due to re-positioning of two mobile loops. PMID- 28844745 TI - 'Something in the way she moves': The functional significance of flexibility in the multiple roles of protein disulfide isomerase (PDI). AB - Protein disulfide isomerase (PDI) has diverse functions in the endoplasmic reticulum as catalyst of redox transfer, disulfide isomerization and oxidative protein folding, as molecular chaperone and in multi-subunit complexes. It interacts with an extraordinarily wide range of substrate and partner proteins, but there is only limited structural information on these interactions. Extensive evidence on the flexibility of PDI in solution is not matched by any detailed picture of the scope of its motion. A new rapid method for simulating the motion of large proteins provides detailed molecular trajectories for PDI demonstrating extensive changes in the relative orientation of its four domains, great variation in the distances between key sites and internal motion within the core ligand-binding domain. The review shows that these simulations are consistent with experimental evidence and provide insight into the functional capabilities conferred by the extensive flexible motion of PDI. PMID- 28844747 TI - Glucose-1-phosphate uridylyltransferase from Erwinia amylovora: Activity, structure and substrate specificity. AB - Erwinia amylovora, a Gram-negative plant pathogen, is the causal agent of Fire Blight, a contagious necrotic disease affecting plants belonging to the Rosaceae family, including apple and pear. E. amylovora is highly virulent and capable of rapid dissemination in orchards; effective control methods are still lacking. One of its most important pathogenicity factors is the exopolysaccharide amylovoran. Amylovoran is a branched polymer made by the repetition of units mainly composed of galactose, with some residues of glucose, glucuronic acid and pyruvate. E. amylovora glucose-1-phosphate uridylyltransferase (UDP-glucose pyrophosphorylase, EC 2.7.7.9) has a key role in amylovoran biosynthesis. This enzyme catalyses the production of UDP-glucose from glucose-1-phosphate and UTP, which the epimerase GalE converts into UDP-galactose, the main building block of amylovoran. We determined EaGalU kinetic parameters and substrate specificity with a range of sugar 1-phosphates. At time point 120min the enzyme catalysed conversion of the sugar 1-phosphate into the corresponding UDP-sugar reached 74% for N-acetyl-alpha d-glucosamine 1-phosphate, 28% for alpha-d-galactose 1-phosphate, 0% for alpha-d galactosamine 1-phosphate, 100% for alpha-d-xylose 1-phosphate, 100% for alpha-d glucosamine 1-phosphate, 70% for alpha-d-mannose 1-phosphate, and 0% for alpha-d galacturonic acid 1-phosphate. To explain our results we obtained the crystal structure of EaGalU and augmented our study by docking the different sugar 1 phosphates into EaGalU active site, providing both reliable models for substrate binding and enzyme specificity, and a rationale that explains the different activity of EaGalU on the sugar 1-phosphates used. These data demonstrate EaGalU potential as a biocatalyst for biotechnological purposes, as an alternative to the enzyme from Escherichia coli, besides playing an important role in E. amylovora pathogenicity. PMID- 28844748 TI - Active site gate of M32 carboxypeptidases illuminated by crystal structure and molecular dynamics simulations. AB - Enzyme gates are important dynamic features that regulate function. Study of these features is critical for understanding of enzyme mechanism. In this study, the active-site gate of M32 carboxypeptidases (M32CP) is illuminated. Only a handful of members of this family have been structurally and functionally characterized and various aspects of their activity and mechanism are yet not clarified. Here, crystal structure of putative M32CP from Deinococcus radiodurans (M32dr) was solved to 2.4A resolution. Enzymatic assays confirmed its identity as a carboxypeptidase. Open and relatively closed conformations observed in the structure provided supporting evidence for previously hypothesized hinge motion in this family of enzymes. Molecular dynamics simulations of 1.5MUs displayed distinct open and closed conformations revealing amplitude of the motion to be beyond what was observed in the crystal structure. Hinge region and anchoring region of this shell-type gate were identified. A small displacement of 3A and a helical tilt of 9 degrees propagated by the hinge region translates into a 10A motion at the top of the gate. The dynamics of the gate was supported by our mutagenesis experiment involving formation of disulphide bond across helices of the gate. The nearly inactive mutant enzyme showed 65-fold increase in the enzymatic activity in presence of reducing agent. Further, while a previously proposed structural basis would have led to its classification in subfamily II, experimentally observed substrate length restriction places M32dr in subfamily I of M32CPs. PMID- 28844749 TI - Immune responses in DAA treated chronic hepatitis C patients with and without prior RG-101 dosing. AB - BACKGROUND&AIMS: With the introduction of DAA's, the majority of treated chronic hepatitis C patients (CHC) achieve a viral cure. The exact mechanisms by which the virus is cleared after successful therapy, is still unknown. The aim was to assess the role of the immune system and miRNA levels in acquiring a sustained virological response after DAA treatment in CHC patients with and without prior RG-101 (anti-miR-122) dosing. METHODS: In this multicenter, investigator initiated study, 29 patients with hepatitis C virus (HCV) genotype 1 (n = 11), 3 (n = 17), or 4 (n = 1) infection were treated with sofosbuvir and daclatasvir +/- ribavirin. 18 patients were previously treated with RG-101. IP-10 levels were measured by ELISA. Ex vivo HCV-specific T cell responses were quantified in IFN gamma-ELISpot assays. Plasma levels of miR-122 were measured by qPCR. RESULTS: All patients had an SVR12. IP-10 levels rapidly declined during treatment, but were still elevated 24 weeks after treatment as compared to healthy controls (median 53.82 and 39.4 pg/mL, p = 0.02). Functional IFN-gamma HCV-specific T cell responses did not change by week 12 of follow-up (77.5 versus 125 SFU/106 PBMC, p = 0.46). At follow-up week 12, there was no difference in plasma miR-122 levels between healthy controls and patients with and without prior RG-101 dosing. CONCLUSIONS: Our data shows that successful treatment of CHC patients with and without prior RG-101 dosing results in reduction of broad immune activation, and normalisation of miR-122 levels (EudraCT: 2014-002808-25). TRIAL REGISTRATION: EudraCT: 2014-002808-25. PMID- 28844750 TI - Integrating cancer diagnosis terminologies based on logical definitions of SNOMED CT concepts. AB - In oncology, the reuse of data is confronted with the heterogeneity of terminologies. It is necessary to semantically integrate these distinct terminologies. The semantic integration by using a third terminology as a support is a conventional approach for the integration of two terminologies that are not very structured. The aim of our study was to use SNOMED CT for integrating ICD-10 and ICD-O3. We used two complementary resources, mapping tables provided by SNOMED CT and the NCI Metathesaurus, in order to find mappings between ICD-10 or ICD-O3 concepts and SNOMED CT concepts. We used the SNOMED CT structure to filter inconsistent mappings, as well as to disambiguate multiple mappings. Based on the remaining mappings, we used semantic relations from SNOMED CT to establish links between ICD-10 and ICD-O3. Overall, the coverage of ICD-O3 and ICD10 codes was over 88%. Finally, we obtained an integration of 24% (203/852) of ICD-10 concepts with 86% (888/1032) of ICD-O3 morphology concepts combined to 39% (127/330) of ICD-O3 topography concepts. Comparing our results with the 23,684 ICD-O3 pairs mapped to ICD-10 concepts in the SEER conversion file, we found 17,447 pairs of ICD-O3 concepts in common among which 11,932 pairs were integrated with the same ICD-10 concept as the SEER conversion file. The automated process leverages logical definitions of SNOMED CT concepts. While the low quality of some of these definitions impacted negatively the integration process, the identification of such situations made it possible to indirectly audit the structure of SNOMED CT. PMID- 28844752 TI - Multifocal iris melanoma in a 2-year-old managed with I-125 plaque brachytherapy. AB - We report a 23-month-old patient presenting with multifocal iris melanoma who underwent plaque brachytherapy with full corneal coverage. The lesion demonstrated several high-risk clinical and histopathologic features associated with iris melanoma in adults, including growth and angle seeding. The patient has been subsequently followed for 3.5 years with no evidence of recurrence. This report demonstrates the importance of serial examination of suspected melanocytic iris lesions in very young children and the effective treatment option of globe sparing radiation therapy. PMID- 28844753 TI - Commentary to 'The role of pre operative intra muscular testosterone in improving functional and cosmetic outcomes following hypospadias repair: A prospective randomized study'. PMID- 28844751 TI - Idiopathic bilateral central artery occlusion in a young woman. AB - Central retinal artery occlusion (CRAO) is uncommon among children and young adults. Bilateral CRAO before the age of 18 years are extremely rare. We present a case of an idiopathic bilateral CRAO in a young healthy female. PMID- 28844754 TI - The role of preoperative intra muscular testosterone in improving functional and cosmetic outcomes following hypospadias repair: A prospective randomized study. AB - BACKGROUND: There are very few well-designed studies on the role of preoperative testosterone in hypospadias repair. The aims of the current study are to ascertain the efficacy of intramuscular testosterone in increasing the glans width, reducing the complications and improving the functional and cosmetic outcomes. MATERIALS AND METHODS: Between January 2013 and December 2016, a total of 200 patients with distal hypospadias were recruited to this prospective randomized study. Only patients with distal hypospadias eligible for a tubularized incised plate (TIP) repair were included. Group 1 did not receive any intervention, and group 2 received three doses of intramuscular testosterone enanthate 2 mg/kg at the age of 9, 10, and 11 months. Glans width was measured in millimeters in all patients using calipers at the time of recruitment and at the time of surgery. Within group 2, those who failed to have more than a 2 mm increase in size were considered non-responders (group 2a), and the remaining were taken to be responders (group 2b). TIP repair was performed by the same surgeon, and patients were followed up, looking for urethrocutaneous fistula, glans dehiscence, meatal stenosis, etc. Cosmetic evaluation was performed using the Parental Penile Perception Score (PPPS). RESULTS: A total of eight patients dropped out in group 1 (n = 92), while six dropped out in group 2 (n = 94). In group 2, 17% patients did not respond to testosterone (group 2a; n = 16), whereas 83% showed significant increase in glans width (group 2b; n = 78). The table compares the functional and cosmetic outcomes between groups. Total complications were significantly less in group 2b (17.9%) than in group 2a (50%). The reoperation rate was significantly less in group 2b (11.5%) than in group 1 (23.1%). A significantly higher number of parents (p = 0.03) were satisfied with cosmesis of the glans/meatus in group 2b (71/78; 91%) compared with group 2a (11/16; 69%) or group 1 (72/92; 78%). The overall PPPS was significantly higher (p = 0.003) in group 2b (8.88 +/- 2.20) than in group 1 (8.03 +/- 1.55). DISCUSSION: Two systematic reviews on the role of preoperative testosterone failed to reach any conclusion. One described a glans width <14 mm as a risk factor for urethral complications after hypospadias repair but another did not support this. Our findings reveal that preoperative testosterone significantly increases the glans width thereby reducing the complications and requirement for reoperation. It also improves the cosmetic outcomes and parental satisfaction. PMID- 28844756 TI - Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. AB - Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) comprise a category of versatile drug delivery systems that have been used in the biomedical field for >25years. SLNs and NLCs have been used for the treatment of various diseases including cardiovascular and cerebrovascular, and are considered a standard treatment for the latter, due to their inherent ability to cross the blood brain barrier (BBB). In this review, a presentation of the most important brain diseases (brain cancer, ischemic stroke, Alzheimer's disease, Parkinson's disease and multiple sclerosis) is approached, followed by the basic fabrication techniques of SLNs and NLCs. A detailed description of the reported studies of the last seven years, of active and passive targeting SLNs and NLCs for the treatment of glioblastoma multiforme and of other brain cancers, as well as for the treatment of neurodegenerative diseases is also carried out. Finally, a brief description of the advantages, the disadvantages, and the future perspectives in the use of these nanocarriers is reported, aiming at giving an insight of the limitations that have to be overcome in order to result in a delivery system with high therapeutic efficacy and without the limitations of the existing nano systems. PMID- 28844755 TI - Exploring intracellular fate of drug nanocrystals with crystal-integrated and environment-sensitive fluorophores. AB - Formulating a poorly water-soluble drug substance into nanocrystals offers many advantages. Understanding of the in vivo fate of drug nanocrystals is however very limited. In this study, we utilized the hybrid nanocrystal concept and studied the kinetic process of dissolution in cancer cells. By taking advantage of aggregation-induced emission (AIE), hybrid paclitaxel (PTX) nanocrystals integrated with tetraphenylethene (TPE) enabled a novel way for estimating the intracellular dissolution process of the nanocrystals. When TPE is entrapped in a nanocrystal, fluorescence is emitted when the nanocrystal is optically excited. When an entrapped TPE molecule is released to a liquid medium due to the dissolution of the nanocrystal, its fluorescence is quenched. By monitoring the change in fluorescence, it is possible to quantify the dissolution of nanocrystals in a biological environment. Cellular uptake studies of hybrid nanocrystals were conducted with KB and HT-29 cell lines and characterized by confocal microscopy, flow cytometry, and HPLC. The results suggest that drug nanocrystals were taken up directly by the cells, and subsequently dissolved in the cytoplasm. The extent to which the drug nanocrystal dissolved was estimated according to the fluorescence measurement. The cellular uptake and intracellular dissolution could be influenced by drug concentration, incubation time, and surface coating, as well as the type of cell line. PMID- 28844757 TI - Chemotherapy agent-unsaturated fatty acid prodrugs and prodrug-nanoplatforms for cancer chemotherapy. AB - Unsaturated fatty acids (UFAs), with the distinct advantages of good biocompatibility and innate tumor-targeting effect, have been widely investigated for the rational design of chemotherapy agent-unsaturated fatty acid (CA-UFA) prodrugs in cancer therapy. Among them, several CA-UFA prodrugs have successfully entered clinical trials and are promising prospects for potential clinical applications. In addition, CA-UFA prodrug-based nanoparticulate drug delivery systems (nano-DDS), which integrate the advantages of CA-UFA prodrugs and nano DDS, have been emerging as versatile nano-carriers for the efficient delivery of chemotherapeutics. In this paper, we review the advanced drug delivery strategies based on UFA conjugates and focus on the recent advances in CA-UFA prodrugs and the emerging CA-UFA prodrug-based nano-DDS. First, we discuss the rational design of CA-UFA prodrugs in response to the multiple obstacles in chemotherapy, with particular emphasis on the latest progress in both preclinical studies and clinical trials. Moreover, the emerging CA-UFA prodrug-based nano-DDS are also addressed. Finally, the prospects and potential challenges of CA-UFA prodrug based drug delivery strategies in chemotherapy are highlighted. PMID- 28844758 TI - Extensive preclinical investigation of polymersomal formulation of doxorubicin versus Doxil-mimic formulation. AB - Due to the severe cardiotoxicity of doxorubicin, its usage is limited. This shortcoming could be overcome by modifying pharmacokinetics of the drugs via preparation of various nanoplatforms. Doxil, a well-known FDA-approved nanoplatform of doxorubicin as antineoplastic agent, is frequently used in clinics in order to reduce cardiotoxicity of doxorubicin. Since Doxil shows some shortcomings in clinics including hand and food syndrome and very slow release pattern thus, there is a demand for the development and preparation of new doxorubicin nanoformulation with fewer side effects. The new formulation of the doxorubicin, synthesized previously by our group was extensively examined in the current study. This new formulation is doxorubicin encapsulated in PEG-PLGA polymersomes (PolyDOX). The main aim of the study was to compare the distribution and treatment efficacy of a new doxorubicin-polymersomal formulation (PolyDOX) with regular liposomal formulation (Doxil-mimic) in murine colon adenocarcinoma model. Additionally, the pathological, hematological changes, pharmacodynamics, biodistribution, tolerated dose and survival rate in vivo were evaluated and compared. Murine colon cancer model was induced by subcutaneous inoculation of BALB/c mice with C26 cells. Afterwards, either Doxil-mimic or PolyDOX was administered intravenously. The obtained results from biodistribution study showed a remarkable difference in the distribution of drugs in murine organs. In this regard, Doxil-mimic exhibited prolonged (48h) presence within liver tissues while PolyDOX preferentially accumulate in tumor and the presence in liver 48h post-treatment was significantly lower than that of Doxil-mimic. Obtained results demonstrated comparable final length of life for mice receiving either Doxil mimic or PolyDOX formulations whereas tolerated dose of mice receiving Doxil mimic was remarkably higher than those receiving PolyDOX. Therapeutic efficacy of formulation in term of tumor growth rate after one injection of formulations (5mg/kg, 10mg/kg or 15mg/kg) demonstrated better efficacy at lower dose for PolyDOX. Analysis of Kaplan Meier curve was in favor of both formulations in their treatment-dose. Pathological and hematological surveys of mice treated with both formulations did not show considerable difference except for a small atrophy in liver observed after successive administration of Doxil-mimic. It could be concluded that PolyDOX can potentially limit off-site effects of Doxil due to its biodegradability and sustained release properties while it exhibited favorable safety profile comparable to Doxil. PMID- 28844759 TI - A PEGylated hyaluronic acid conjugate for targeted cancer immunotherapy. AB - The cell-free approach to foreignizing tumor cells with non-self antigens has received increasing attention as a method to induce cytotoxic T lymphocyte (CTL) mediated immunological rejection of tumors, because the clinical translation of the conventional CTL-based cancer immunotherapies has been limited by a complicated manufacturing process and autotransplantation. In this study, we prepared matrix metalloproteinase 9 (MMP9)-responsive polymeric conjugates consisting of PEGylated hyaluronic acid (HA) as the targeting moiety and ovalbumin (OVA) as the model foreign antigen. The MMP9-cleavable linker was introduced between PEG and the HA backbone to facilitate the detachment of the PEG corona from the conjugate at the tumor site. From the in vitro cellular uptake study, it was revealed that the conjugate was effectively taken up by the CD44-expressing TC-1 cancer cells in the presence of MMP9 via receptor-mediated endocytosis. When the conjugate was systemically administered into the tumor bearing mice with endogenous OVA-specific CTLs, the tumor growth was markedly inhibited, which was attributed to the significant antigen presentation on the tumor cells. Overall, the MMP9-responsive conjugates bearing foreign antigens might have the potential as an alternative to CTL-based cancer immunotherapeutics. PMID- 28844760 TI - Template-operated MUP analysis is not accurate in the diagnosis of myopathic or neuropathic changes in the diaphragm. AB - OBJECTIVES: The aim of this study was to evaluate the quantitative motor unit potential (MUP) analysis in the diagnosis of myopathy and neuropathy of the diaphragm. METHODS: Diaphragm template-operated quantitative EMG were performed in 30 patients with myotonic dystrophy type 1 (DM1), 17 with myotonic dystrophy type 2 (DM2) and 40 with amyotrophic lateral sclerosis (ALS). RESULTS: Low MUP amplitude precluded MUP analysis in 21% of DM1 patients. Only a single DM1 patient had EMG findings consistent with myopathy. In this patient, and another 4 DM1 and 3 DM2 patients, findings were consistent with neuropathy. Neuropathic MUP changes were found in 92% of ALS patients, but due to motor neuron cell loss in only 60% MUPs analyses could be done. Phrenic nerve conduction studies correlated with respiratory function tests, whereas MUP parameters did not. CONCLUSION: Quantitative MUP analysis was not able to adequately sample diaphragm MUPs in patients with chronic myopathy or motor neuronopathy. PMID- 28844761 TI - The effect of pharmacological inactivation of the mammillary body and anterior thalamic nuclei on hippocampal theta rhythm in urethane-anesthetized rats. AB - The mammillary body (MB) and the anterior thalamic nuclei (ATN) are closely related structures, which take part in learning and memory processes. However, the exact role of these structures has remained unclear. In both structures neurons firing according to hippocampal theta rhythm have been found, mainly in the medial mammillary nucleus (MM) and anteroventral thalamic nucleus (AV). These neurons are driven by descending projections from the hippocampal formation and are thought to convey theta rhythm back to the hippocampus (HP). We argue that the MB-ATN axis not only relays theta signal, but may also modulate it. To examine it, we performed a pharmacological inactivation of the MM and AV by local infusion of procaine, and measured changes in theta activity in selected structures of the extended hippocampal system in urethane-anesthetized rats. The inactivation of the MM resulted in decrease in EEG power in the HP and AV, the most evidently in the lower theta frequency bands, i.e. 3-5Hz in the HP (down to 9.2% in 3- to 4-Hz band and 37.6% in 4- to 5-Hz band, in comparison to the power in the control conditions) and 3-4Hz in the AV (down to 24.9%). After the AV inactivation, hippocampal EEG power decreased in theta frequency bands of 3-8Hz (down to 61.6% in 6- to 7-Hz band and 69.4% in 7- to 8-Hz band). Our results suggest that the role of the MB-ATN axis in regulating theta rhythm signaling may be much more important than has been speculated so far. PMID- 28844762 TI - 2-Arachidonoylglycerol metabolism is differently modulated by oligomeric and fibrillar conformations of amyloid beta in synaptic terminals. AB - Alzheimer's disease (AD) is the most prevalent disorder of senile dementia mainly characterized by amyloid-beta peptide (Abeta) deposits in the brain. Cannabinoids are relevant to AD as they exert several beneficial effects in many models of this disease. Still, whether the endocannabinoid system is either up- or down regulated in AD has not yet been fully elucidated. Thus, the aim of the present paper was to analyze endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in cerebral cortex synaptosomes incubated with Abeta oligomers or fibrils. These Abeta conformations were obtained by "aging" the 1-40 fragment of the peptide under different agitation and time conditions. A diminished availability of 2-AG resulting from a significant decrease in diacylglycerol lipase (DAGL) activity was observed in the presence of large Abeta1-40 oligomers along with synaptosomal membrane damage, as judged by transmission electron microscopy and LDH release. Conversely, a high availability of 2-AG resulting from an increase in DAGL and lysophosphatidic acid phosphohydrolase activities occurred in the presence of Abeta1-40 fibrils although synaptosomal membrane disruption was also observed. Interestingly, neither synaptosomal mitochondrial viability assayed by MTT reduction nor membrane lipid peroxidation assayed by TBARS formation measurements were altered by Abeta1-40 oligomers or fibrils. These results show a differential effect of Abeta1-40 peptide on 2-AG metabolism depending on its conformation. PMID- 28844763 TI - Hyperexcitability in synaptic and firing activities of spinal motoneurons in an adult mouse model of amyotrophic lateral sclerosis. AB - Hyperexcitability is hypothesized to contribute to the degeneration of spinal motoneurons (MNs) in amyotrophic lateral sclerosis (ALS). Studies, thus far, have not linked hyperexcitability to the intrinsic properties of MNs in the adult ALS mouse model with the G93A-mutated SOD1 protein (mSOD1G93A). In this study, we obtained two types of measurements: ventral root recordings to assess motor output and intracellular recordings to assess synaptic properties of individual MNs. All studies were carried out in an in vitro preparation of the sacral spinal cords of mSOD1G93A mice and their non-transgenic (NT) littermates, both in the age range of 50-90days. Ventral root recordings revealed that maximum compound action potentials (coAPs) evoked by a short-train stimulation of corresponding dorsal roots were similar between the two types of mice. Although the progressive depression of coAPs was present during the train stimulation in all recordings, the coAP depression in mSOD1G93A mice was to a lesser extent, which suggests an increased firing tendency in mSOD1G93A MNs. Intracellular recordings showed no changes in fast excitatory postsynaptic potentials (EPSPs) in mSOD1G93A MNs. However, recording did show that oscillating EPSPs (oEPSPs) were induced by poly EPSPs at a higher frequency and by less-intense electrical stimulation in mSOD1G93A MNs. These oEPSPs were dependent upon the activities of spinal network and N-methyl-d-aspartate receptors (NMDARs), and were subjected to riluzole modulation. Taken together, these findings revealed abnormal electrophysiology in mSOD1G93A MNs that could underlie ALS excitotoxicity. PMID- 28844765 TI - Extremely Low Transfusion Rates: Contemporary Primary Total Hip and Knee Arthroplasties. AB - BACKGROUND: Considerable blood loss which requires transfusion is frequently reported after total hip and knee arthroplasties (THA and TKA). The purpose of this study is to review the transfusion rates in contemporary THA and TKA with optimized perioperative protocols including minimized surgical trauma and optimal perioperative patient care. METHODS: This retrospective study included 1442 consecutive patients receiving either a primary THA or a TKA from the same high volume surgeon between January 2008 and December 2015. Demographics and surgical data were collected from patients' journals. Estimated blood loss, decline in hemoglobin, and use of transfusion were registered. RESULTS: One (0.0013%) THA and 3 (0.0044%) TKAs required blood transfusion postoperatively. Average measured bleeding was 253 mL +/- 142 and 207 mL +/- 169 in THA and TKA, respectively. Average decline in hemoglobin was 23.5 g/L +/- 11.4 and 22.9 g/L +/- 11.6 for THA and TKA, respectively. CONCLUSION: In contemporary THA and TKA, perioperative protocols and patient optimization can decrease the rate of blood transfusion to near zero. PMID- 28844766 TI - Scanning Electron Microscopy and Energy-Dispersive X-Ray Spectroscopy as a Valuable Tool to Investigate the Ultra-High-Molecular-Weight Polyethylene Wear Mechanisms and Debris in Hip Implants. AB - BACKGROUND: The use of scanning electron microscopy (SEM) and energy-dispersive spectrometry (EDS) was investigated to understand the wear mechanisms from a metal-on-polyethylene bearing couple. Morphological features of femoral head acetabular liner, and isolated particles resulting from hip wear testing were evaluated. EDS was proposed to investigate the polymeric nature of the particles isolated from the wear testing. METHODS: In this work, 28-mm conventional ultra high-molecular-weight polyethylene acetabular liners paired with metallic heads were tested in a hip wear simulator over 2 million cycles. SEM-EDS was employed to investigate wear mechanisms on hip implant components and associated wear debris. RESULTS: SEM showed worn surfaces for both hip components, and a significant volume of ultra-high-molecular-weight polyethylene wear particles resulting from hip wear testing. Particles were classified into 3 groups, which were then correlated to wear mechanisms. Group I had particles with smooth surfaces, group II consisted of particles with rough surfaces, and group III comprised aggregate-like particles. Group I EDS revealed that particles from groups I and II had a high C/O ratio raising a concern about the particle source. On the other hand, particles from group III had a low C/O ratio, supporting the hypothesis that they resulted from the wear of acetabular liner. Most of particles identified in group III were in the biologically active size range (0.3 to 20 MUm). CONCLUSION: The use of optical and electron microscopy enabled the morphological characterization of worn surfaces and wear debris, while EDS was essential to elucidate the chemical composition of isolated debris. PMID- 28844764 TI - Hospital Strategies for Reducing Emergency Department Crowding: A Mixed-Methods Study. AB - STUDY OBJECTIVE: Emergency department (ED) crowding and patient boarding are associated with increased mortality and decreased patient satisfaction. This study uses a positive deviance methodology to identify strategies among high performing, low-performing, and high-performance improving hospitals to reduce ED crowding. METHODS: In this mixed-methods comparative case study, we purposively selected and recruited hospitals that were within the top and bottom 5% of Centers for Medicare & Medicaid Services case-mix-adjusted ED length of stay and boarding times for admitted patients for 2012. We also recruited hospitals that showed the highest performance improvement in metrics between 2012 and 2013. Interviews were conducted with 60 key leaders (physicians, nurses, quality improvement specialists, and administrators). RESULTS: We engaged 4 high performing, 4 low-performing, and 4 high-performing improving hospitals, matched on hospital characteristics including geographic designation (urban versus rural), region, hospital occupancy, and ED volume. Across all hospitals, ED crowding was recognized as a hospitalwide issue. The strategies for addressing ED crowding varied widely. No specific interventions were associated with performance in length-of-stay metrics. The presence of 4 organizational domains was associated with hospital performance: executive leadership involvement, hospitalwide coordinated strategies, data-driven management, and performance accountability. CONCLUSION: There are organizational characteristics associated with ED decreased length of stay. Specific interventions targeted to reduce ED crowding were more likely to be successfully executed at hospitals with these characteristics. These organizational domains represent identifiable and actionable changes that other hospitals may incorporate to build awareness of ED crowding. PMID- 28844767 TI - Comparison of High-Flexion Fixed-Bearing and High-Flexion Mobile-Bearing Total Knee Arthroplasties-A Prospective Randomized Study. AB - BACKGROUND: There is none, to our knowledge, about comparison of high-flexion fixed-bearing and high-flexion mobile-bearing total knee arthroplasties (TKAs) in the same patients. The purpose of this study was to determine whether clinical results; radiographic and computed tomographic scan results; and the survival rate of a high-flexion mobile-bearing TKA is better than that of a high-flexion fixed-bearing TKA. METHODS: The present study consisted of 92 patients (184 knees) who underwent same-day bilateral TKA. Of those, 17 were men and 75 were women. The mean age at the time of index arthroplasty was 61.5 +/- 8.3 years (range 52-65 years). The mean body mass index was 26.2 +/- 3.3 kg/m2 (range 23-34 kg/m2). The mean follow-up was 11.2 years (range 10-12 years). RESULTS: The Knee Society knee scores (93 vs 92 points; P = .531) and function scores (80 vs 80 points; P = 1.000), WOMAC scores (14 vs 15 points; P = .972), and UCLA activity scores (6 vs 6 points; P = 1.000) were not different between the 2 groups at 12 years follow-up. There were no differences in any radiographic and CT scan parameters between the 2 groups. Kaplan-Meier survivorship of the TKA component was 98% (95% confidence interval, 93-100) in the high-flexion fixed-bearing TKA group and 99% (95% confidence interval, 94-100) in the high-flexion mobile bearing TKA group 12 years after the operation. CONCLUSION: We found no benefit to mobile-bearing TKA in terms of pain, function, radiographic and CT scan results, and survivorship. Longer-term follow-up is necessary to prove the benefit of the high-flexion mobile-bearing TKA over the high-flexion fixed bearing TKA. PMID- 28844768 TI - Systemic Safety of Liposomal Bupivacaine in Simultaneous Bilateral Total Knee Arthroplasty. AB - BACKGROUND: Intraoperative periarticular injections (PAIs) with local anesthetic are an important component of multimodal pain control in total joint arthroplasty. Liposomal bupivacaine is an extended-release formulation of bupivacaine designed to provide extended pain relief, approved for use in a single surgical site. The systemic safety profile for use in simultaneous bilateral TKA (bTKA) with a full dose in each knee has not been evaluated. The purpose of this study was to determine the safety and pharmacokinetics of bilateral full-dose PAI liposomal bupivacaine in the blood collected in patients undergoing simultaneous bTKA. METHODS: In this prospective study, patients had an identical PAI consisting of 20 cc of liposomal bupivacaine (266 mg), 30 cc of 0.25% bupivacaine (75 mg) with epinephrine, and 10 cc of normal saline injected into each knee during bTKA. Blood samples were collected at predefined intervals until patient discharge. No exogenous bupivacaine was administered. Pharmacokinetic evaluations were subsequently performed and compared to bupivacaine toxicity levels. Patients were monitored for adverse events related to anesthetic toxicity (cardiac and neurologic). RESULTS: Fifteen patients (mean age, 60.7 years; range, 57-64 years) were enrolled in the study. The mean peak level (Cmax) was 0.8 MUg/mL (range, 0.4-1.2 MUg/mL). All patients were well below the reported systemic cardiac and toxicity levels reported as 2-4 MUg/mL. There were no reported cardiac and neurotoxic events in any patients. CONCLUSION: The use of full-dose PAI with liposomal bupivacaine placed into each knee during simultaneous bTKA is safe with systemic bupivacaine levels well below reported cardiac and neurotoxic levels. PMID- 28844769 TI - Perioperative Outcomes and Complications in Patients With Heart Failure Following Total Knee Arthroplasty. AB - BACKGROUND: Heart failure (HF) is a common comorbidity in the aging population and they will require major elective surgery. The purpose of this study is to determine if HF is a risk factor for adverse perioperative outcomes and short term complications following total knee arthroplasty. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was utilized to identify all patients who underwent total knee arthroplasty for osteoarthritis from 2008 to 2014. Any diagnosis other than osteoarthritis was excluded. A total of 111,634 patients were identified and 251 of these patients had a preoperative diagnosis of HF. The main outcomes included operative time, lengths-of-stay, discharge disposition, return to operating room, readmission, and short-term complications, including death. RESULTS: Patients with HF were found to have longer hospital stays (beta = 0.59, 95% confidence interval [CI] 0.12-1.06) following total knee arthroplasty, and were more likely to return to the operating room (odds ratio 2.00, 95% CI 1.01-3.94) and be readmitted (OR 1.88, 95% CI 1.21-2.94). In addition, HF was found to be a risk factor for 1 or more complications (OR 1.41, 95% CI 1.05-1.90), wound dehiscence (OR 4.86, 95% CI 1.68-14.03), and myocardial infarction (OR 4.81, 95% CI 1.90-12.16) postoperatively. CONCLUSION: Patients with HF are more likely to have a longer length-of-stay, return to the operating room, and be readmitted. Additionally, they have a higher risk for at least one postoperative complication, myocardial infarction, and wound dehiscence. PMID- 28844770 TI - Preoperative Chronic Opioid Users in Total Knee Arthroplasty-Which Patients Persistently Abuse Opiates Following Surgery? AB - BACKGROUND: Chronic opioid users pose a unique challenge for orthopedic surgeons, as they often report suboptimal outcomes following total knee arthroplasty (TKA). We aim at identifying risk factors associated with patients who were preoperative chronic opioid users and continued to use 6 months following TKA. METHODS: All preoperative chronic opioid users among 338 consecutive TKA cases performed at our institution between February and June 2016 were identified and divided into 2 cohorts: patients who (1) persistently used opioids and (2) discontinued use by the 6-month time point following surgery. Baseline characteristics were compared between cohorts in order to determine risk factors for persistent opioid use following TKA. RESULTS: Of the 338 patients, 53 (15.7%) were identified as preoperative chronic opioid users. Of these, 23 (43.4%) continued chronic opioid use 6 months following surgery, whereas 14 (4.9%) previously nonchronic users were identified as new chronic users at 6 months. Characteristics that were predictive of persistent opioid use included male gender, prior injury or surgery to the ipsilateral knee, current tobacco smoking status, and a history of psychiatric disorder. Opioid dose consumption of >=12 mg/d morphine-equivalents over the 3 months leading up to surgery had an increased risk of persistent chronic opioid use by a factor of 6. CONCLUSION: TKA candidates who have complicated medical, social, and surgical histories are at an increased risk of chronic opioid abuse postoperatively. By better understanding the risk factors associated with persistent chronic opioid use, targeted opioid reduction programs may be appropriately implemented to manage this high-risk population. PMID- 28844771 TI - Innate lymphoid cells and fibrotic regulation. AB - Innate lymphoid cells (ILCs) are innate immune cells that do not possess B or T cell receptors but belong to the lymphoid lineage. While these cells have not yet been extensively investigated since their classification as a homogenous group, emerging evidence suggests that they exert significant regulatory roles in both tissue remodelling and inflammation, and are therefore, also involved in fibrotic regulation. The following review will serve to outline the transcription factors, surface markers, and cytokines that define each subgroup, and the process by which these cells differentiate. Furthermore, the diverse functions of these cells in non-pathogenic states will be discussed, in addition to the interactions between ILCs and other cells of the immune system, both innate and adaptive, and how these pathways can elicit both pro- and anti-inflammatory and -fibrotic effects in varying tissues. PMID- 28844772 TI - Five- to 10-Year Prospective Follow-Up of Wrist Arthroplasty in 56 Nonrheumatoid Patients. AB - PURPOSE: The goal of the study was to evaluate the clinical and radiological outcomes of a cementless wrist arthroplasty with minimum 5-year follow-up in nonrheumatoid patients. METHODS: Fifty-seven (40 male) patients with end-stage arthritis changes received an uncemented ball-and-socket total wrist arthroplasty (Motec Wrist). Function was evaluated before surgery and at yearly follow-ups. Visual analog scale at rest and activity, quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), active range of motion (AROM), and grip-strength were recorded. Standardized radiographs were taken to assess osteolysis, loosening, and subsidence. RESULTS: Fifty-six patients were followed for a mean of 8 years (SD, 2 years). Eight wrists were reoperated with arthrodesis (4) or a new arthroplasty (4) owing to distal component loosening (3), infection (2), pain/fixed malposition (2), or proximal and distal component loosening (1). One radiocarpal dislocation was reduced closed and remained stable. Improved QuickDASH score and visual analog scale pain score both at rest and during activity were found at the last follow-up, as well as increased AROM (97 degrees vs 126 degrees ) and grip strength (21 kg vs 24 kg). The radiological follow-up demonstrated loosening in 2 wrists. Thirty-five patients were working at surgery (17 manual labor) and 27 (11 manual labor) at follow-up. The 10-year Kaplan-Meyer survival of the implants was 86% for revision for any cause; 2 additional arthroplasties are loose (but not revised), giving a survival rate of 82% if these are revised prior to 10 years of observation. CONCLUSIONS: An uncemented total wrist arthroplasty can provide long-lasting unrestricted hand function in young and active patients. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28844773 TI - Palmar Soft Tissue Infection From Shewanella putrefaciens. AB - Shewanella putrefaciens, a gram-negative bacillus, ubiquitous in marine environments, is an opportunistic agent reported to cause rare human infection, most commonly in patients who are immunocompromised or who have a preexisting soft tissue defect. We present an immunocompetent, 40-year-old woman with a soft tissue infection of the left palm caused by S. putrefaciens. The patient's infection was complicated by the presence of retained foreign bodies, seashell fragments, from a traumatic fall. Following appropriate evaluation and surgical treatment, our patient experienced a successful outcome with no recurrence of infection or deficit in the affected hand. This case report complements the growing literature regarding morbidity attributed to S. putrefaciens infection. PMID- 28844774 TI - Disseminated Cryptococcal Osteomyelitis to the Hand in an Immunosuppressed Lymphoma Patient. AB - Fungal osteomyelitis of the hand is rare with limited evidence-based literature to guide diagnosis and management. We report a case of disseminated cryptococcal osteomyelitis in the middle phalanx from a pulmonary fungal infection in a patient with a history of lymphoplasmacytic lymphoma. Although rare, cryptococcosis should be considered in the differential diagnosis of aggressive lytic lesions with bone pain and associated large soft tissue masses, especially in the immunosuppressed host. PMID- 28844775 TI - Treatment Trends in Older Adults With Midshaft Clavicle Fractures. AB - PURPOSE: We present a retrospective administrative claims database review examining the effect of recent literature supporting surgical clavicle fixation in a primarily young male population, on the treatment of midshaft clavicle fractures in patients older than 65 years. We tested the null hypothesis that there is no change in trends in surgical fixation of midshaft clavicle fractures in patients older than 65 years. Secondary analysis examined overall trends and trends based on sex. METHODS: Data from 2007 to 2012 were extracted using the Medicare Standard Analytic File and Humana administrative claim databases contained within the PearlDiver Patient Records Database. Patients with clavicle shaft fractures and their treatments were identified by International Classification of Disease, Ninth Revision, and Current Procedural Terminology codes. The primary response variable was the proportion of surgical to nonsurgical cases per year, and explanatory variables included age and sex. Data were analyzed using a trend in proportions test with significance set at P less than .05. RESULTS: A total of 32,929 patients with clavicle shaft fractures were identified. During the study period, the proportion of clavicle shaft fractures treated surgically in patients older than 65 years (2.4%-4.6%) and younger than 65 years (11.2%-16.4%) showed a significant increasing trend. When analyzed by both sex and age, there was also an increasing trend in the proportion of surgically treated males in the older than 65 years (3.3%-6.2%) and the younger than 65 years groups (10.9%-19.5%). Lastly, there was an increase in the proportion of surgically treated females older than 65 years (1.7%-3.4%) and younger than 65 years (12.1%-14.3%). CONCLUSIONS: Our analysis demonstrates an overall increase in the proportion of surgically treated clavicle shaft fractures, including in the male and female population older than 65 years. In the setting of an aging population, future research evaluating possible benefits of surgical intervention in this population is needed prior to adopting this practice pattern. TYPE OF STUDY/LEVEL OF EVIDENCE: II. PMID- 28844776 TI - Return to Play and Complications After Hook of the Hamate Fracture Surgery. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of hook of the hamate excision for fracture in a large cohort of patients to better understand recovery time and complications. METHODS: We retrospectively reviewed the medical records of patients treated with surgical excision for hook of the hamate fractures at 2 different centers. We collected information on demographics, clinical presentation, and postoperative complications. Continuous outcome variables included time to surgery, return to play, and return to activity. RESULTS: Our cohort of 81 patients had a median age of 22 years and was composed of 74 athletes including 57 baseball players and 8 golfers. The median time to return to play was 6 weeks (range, 1-36 weeks) after surgery; 11 patients (14%) had a return at 12 weeks or longer. Seventy-eight patients returned to preinjury activity levels. Twelve patients with a full recovery continued to experience some level of intermittent, nonspecific pain in the affected hand, although this was not severe enough to require additional treatment. We observed a 25% incidence of postoperative complications with the majority consisting of transient ulnar nerve dysfunction. Complications were more common among nonathletes, those presenting with nonunions, and those experiencing longer intervals between injury and surgery. CONCLUSIONS: In most cases, surgical excision as treatment for hook of the hamate fractures is safe and allows a relatively rapid return to play. However, we found a higher incidence of complications, including transient ulnar nerve dysfunction, than has been previously reported. In addition, there is a group of patients with delayed return to play and continued discomfort after surgery. These findings should inform the discussion with surgical candidates. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28844778 TI - Research misconduct and the INTERGROWTH-21st study. PMID- 28844777 TI - Multi-criteria decision-making on assessment of proposed tidal barrage schemes in terms of environmental impacts. AB - For tidal range power plants to be sustainable, the environmental impacts caused by the implement of various tidal barrage schemes must be assessed before construction. However, several problems exist in the current researches: firstly, evaluation criteria of the tidal barrage schemes environmental impact assessment (EIA) are not adequate; secondly, uncertainty of criteria information fails to be processed properly; thirdly, correlation among criteria is unreasonably measured. Hence the contributions of this paper are as follows: firstly, an evaluation criteria system is established from three dimensions of hydrodynamic, biological and morphological aspects. Secondly, cloud model is applied to describe the uncertainty of criteria information. Thirdly, Choquet integral with respect to lambda-fuzzy measure is introduced to measure the correlation among criteria. On the above bases, a multi-criteria decision-making decision framework for tidal barrage scheme EIA is established to select the optimal scheme. Finally, a case study demonstrates the effectiveness of the proposed framework. PMID- 28844779 TI - The Papworth donation-after-circulatory-death heart technique and its challenge to the permanence standard. PMID- 28844780 TI - 5-Aminolevulinic acid fluorescence guided resection of malignant glioma: Hong Kong experience. AB - BACKGROUND: 5-Aminolevulinic Acid (5-ALA) induced fluorescence is useful in guiding glioma resection. The extent of 5-ALA accumulation is beyond gadolinium contrast enhancement.1,2 Supratotal resection may be achieved, potentially granting patients with better survival. We present our experience on 5-ALA guided glioma resection in Chinese ethnics. METHOD: Sixteen Patients ingested 5-ALA (Gliolan, Medas Germany) 20 mg/kg.m2 4 h before surgery. The tumor resection was guided by fluorescence with neurosurgical microscope. Patient was monitored for general condition, especially for new neurological deficits. Postoperative MRI served as the assessment for extent of resection (EOR). RESULT: High grade glioma was confirmed in 12 cases, low grade glioma in three and one inflammation. 5-ALA was used in ten patients with known malignant glioma, and in six patients with presumed diagnosis of malignant glioma. Fifteen cases had positive fluorescence. The intensity was strong in eight and moderate in seven cases. MRI suggested total resection was achieved in 9 patients, near total resection in two and five had subtotal resection. EOR was associated with duration between ingestion of 5 ALA and timing when microscope was brought in for visualization of fluorescence (p = 0.038). Two patients suffered from temporary visual field defects. One patient developed hemiparesis after surgery. CONCLUSION: 5-ALA is a useful intra operative guidance for resection. It increases the percentage of total removal of the tumor. It should be used within the window period of the action (4-12 h). PMID- 28844781 TI - Comparison of efficacies of the self-expandable metallic stent versus transanal drainage tube and emergency surgery for malignant left-sided colon obstruction. AB - BACKGROUND/OBJECTIVE: Patients with left-sided malignant colorectal obstruction require emergency treatment. Emergency stoma surgery has traditionally been recommended, however many stomas became permanent, decreasing patient quality of life. Recently, self-expandable metallic stents (SEMS) and transanal decompression tubes (TDT) have become widely used decompression methods to avoid stoma surgery. In this study, we evaluated: 1) the efficacy of SEMS compared with TDT and emergency surgery (ES) to avoid permanent stomas; and 2) the safety and success rate of each treatment. METHODS: We retrospectively reviewed data from 56 patients who underwent SEMS, TDT, or emergency surgery for malignant left-sided colon obstruction. We compared the permanent stoma rate of each group, and assessed whether or not each treatment was an independent risk factor for permanent stomas. We compared morbidity and mortality for each treatment group (SEMS, TDT, ES), and the success rate of the decompression procedures (SEMS and TDT). RESULTS: The permanent stoma rates in the SEMS, TDT, and ES groups were 5.3%, 50.0%, and 56.0%, respectively. Emergency surgery (vs. SEMS) and TDT (vs. SEMS) were independent risk factors for permanent stomas, as was age >= 75 years. Operative morbidity, mortality, and hospital stay were not different between groups. The success rate of SEMS was significantly higher than TDT; however, two deaths, including one perforation, occurred in the former group. CONCLUSION: SEMS seems to be effective in avoiding permanent stomas, but caution should be taken to avoid complications. PMID- 28844782 TI - Methotrexate in the Treatment of Autoimmune Hepatitis. PMID- 28844783 TI - Doctors' opinions on clinical coordination between primary and secondary care in the Catalan healthcare system. AB - OBJECTIVE: To analyse doctors' opinions on clinical coordination between primary and secondary care in different healthcare networks and on the factors influencing it. METHODS: A qualitative descriptive-interpretative study was conducted, based on semi-structured interviews. A two-stage theoretical sample was designed: 1) healthcare networks with different management models; 2) primary care and secondary care doctors in each network. Final sample size (n = 50) was reached by saturation. A thematic content analysis was conducted. RESULTS: In all networks doctors perceived that primary and secondary care given to patients was coordinated in terms of information transfer, consistency and accessibility to SC following a referral. However, some problems emerged, related to difficulties in acceding non-urgent secondary care changes in prescriptions and the inadequacy of some referrals across care levels. Doctors identified the following factors: 1) organizational influencing factors: coordination is facilitated by mechanisms that facilitate information transfer, communication, rapid access and physical proximity that fosters positive attitudes towards collaboration; coordination is hindered by the insufficient time to use mechanisms, unshared incentives in prescription and, in two networks, the change in the organizational model; 2) professional factors: clinical skills and attitudes towards coordination. CONCLUSIONS: Although doctors perceive that primary and secondary care is coordinated, they also highlighted problems. Identified factors offer valuable insights on where to direct organizational efforts to improve coordination. PMID- 28844784 TI - Dieldrin-induced neurotoxicity involves impaired mitochondrial bioenergetics and an endoplasmic reticulum stress response in rat dopaminergic cells. AB - Mitochondria are sensitive targets of environmental chemicals. Dieldrin (DLD) is an organochlorine pesticide that remains a human health concern due to high lipid bioaccumulation, and it has been epidemiologically associated to an increased risk for Parkinson's disease (PD). As mitochondrial dysfunction is involved in the etiology of PD, this study aimed to determine whether DLD impaired mitochondrial bioenergetics in dopaminergic cells. Rat immortalized dopaminergic N27 cells were treated for 24 or 48h with one dose of either a solvent control, 2.5, 25, or 250MUM DLD. Dopaminergic cells treated with 250MUM DLD showed increased Casp3/7 activity at 24 and 48h. DLD also caused a dose dependent reduction in cell viability of ~25-30% over 24h. No significant effects on cell viability, apoptosis, nor cytotoxicity were detected at 24 or 48h with 2.5MUM DLD. Following a 24h exposure to 2.5 and 25MUM DLD, viable cells were subjected to a mitochondrial stress test using the Seahorse XFe24 Extracellular Flux Analyzer. Following three independent experiments conducted for rigor, dopaminergic cells that were treated with 2.5 and 25MUM DLD consistently showed a reduction in maximum respiration and spare capacity compared to the control group. Molecular responses were measured to determine mechanisms of DLD-induced mitochondrial dysfunction. There were no changes in transcripts associated with mitochondrial membrane potential and permeability (e.g. Ant, Hk1, Tspo, Vdac), nor PI3 K/Akt/mTor signaling or mitochondrial-associated apoptotic factors (Bax, Bcl2, Casp3). However, transcript levels for Chop/Gadd153 (DNA Damage Inducible Transcript 3), an apoptotic gene activated following endoplasmic reticulum (ER) stress, were 3-fold higher in N27 cells treated with DLD, suggesting that DLD induced mitochondrial dysfunction is related to ER stress. Dopamine cells were also assessed for changes in tyrosine hydroxylase (TH) protein, which did not differ among treatments. This study demonstrates that DLD impairs oxidative respiration in dopamine cells, and ER stress is hypothesized to be associated with the DLD-induced mitochondrial dysfunction. This is important as ER stress is also linked to PD. This study presents mechanistic insight into pesticide-induced mitochondrial dysfunction using a chemical that is reported to be associated to a higher risk for neurodegenerative disease. PMID- 28844786 TI - A randomized trial found online questionnaires supplemented by postal reminders generated a cost-effective and generalizable sample but don't forget the reminders. AB - OBJECTIVES: The objective of this study was to compare the response rates, data completeness, and representativeness of survey data produced by online and postal surveys. STUDY DESIGN AND SETTING: A randomized trial nested within a cohort study in Yorkshire, United Kingdom. Participants were randomized to receive either an electronic (online) survey questionnaire with paper reminder (N = 2,982) or paper questionnaire with electronic reminder (N = 2,855). RESULTS: Response rates were similar for electronic contact and postal contacts (50.9% vs. 49.7%, difference = 1.2%, 95% confidence interval: -1.3% to 3.8%). The characteristics of those responding to the two groups were similar. Participants nevertheless demonstrated an overwhelming preference for postal questionnaires, with the majority responding by post in both groups. CONCLUSION: Online survey questionnaire systems need to be supplemented with a postal reminder to achieve acceptable uptake, but doing so provides a similar response rate and case mix when compared to postal questionnaires alone. For large surveys, online survey systems may be cost saving. PMID- 28844785 TI - The new measuring multimorbidity index predicted mortality better than Charlson and Elixhauser indices among the general population. AB - OBJECTIVES: The aim of the study was to develop and validate an updated morbidity index for short-term mortality risk, using chronic conditions identified from routine hospital admission ICD-10 data. STUDY DESIGN AND SETTING: Retrospective cohort study of all adult New Zealand (NZ) residents at January 1, 2012. Adult NZ residents aged 18 years and over, defined by enrollment with a Primary Healthcare Organisation or accessing public health care in preceding year. Data were split into two data sets for index development (70%, n = 2,331,645) and validation (30%, n = 1,000,166). RESULTS: The M3 index was constructed using log hazard ratios for 1-year mortality modeled from presence of 61 chronic conditions. Validation results were improved for the M3 index for predicting 1-year mortality compared to Charlson and Elixhauser on the c-statistic (M3: 0.931, Charlson: 0.921, Elixhauser: 0.922; difference M3 vs. Charlson = 0.010, 95% confidence interval [CI]: 0.008, 0.012; M3 vs. Elixhauser = 0.009, 95% CI: 0.007, 0.012) and integrated discriminative improvement (M3 vs. Charlson = 0.024, 95% CI: 0.021, 0.026; M3 vs. Elixhauser = 0.024, 95% CI: 0.022, 0.027). CONCLUSION: The M3 index had improved predictive performance for 1-year mortality risk over Charlson and Elixhauser indices, allowing better adjustment for mortality risk from chronic conditions. This provides an important tool for population-level analyses of health outcomes. PMID- 28844787 TI - Are PROMs sufficient to record late outcome of breast cancer patients treated with radiotherapy? A comparison between patient and clinician reported outcome through an outpatient clinic after 10years of follow up. AB - AIM: To investigate whether breast cancer patients' visits to an outpatient clinic for late outcome (OCLO) can be replaced by patient reported outcome measures (PROMs), by comparing late toxicity scored at the OCLO with PROMs. METHODS: All breast cancer patients treated in our institute with adjuvant radiotherapy 10-11years ago were invited to visit the OCLO, and for filling out PROM-questionnaires. Concordance rate between PROMs and OCLO-reported outcome and the percentage of patients with >=2 degrees difference in toxicity level between patient and clinician was assessed. RESULTS: 686 of 1029 patients were still alive. 249 patients visited the OCLO, and 341 patients returned a questionnaire. At a group level, patients reported higher toxicity rates than clinicians. The mean concordance for individual patients was 58% between patient and clinician reported outcome. In 2.8%, the clinician reported >=2 degrees higher toxicity than the patients did, whereas in 6.8% patients reported >=2 degrees higher toxicity. CONCLUSION: PROMs do not underestimate late side-effects at a group level. In spite of the low concordance rate, PROMS can be used to identify patients who experience a heavy burden of side-effects, requiring specific attention. Therefore, patients can be spared a visit to the OCLO. PMID- 28844788 TI - Spatiotemporal resolution of spinal meningeal and parenchymal inflammation during experimental autoimmune encephalomyelitis. AB - Experimental autoimmune encephalomyelitis (EAE) induced by active immunization of C57BL/6 mice with peptide from myelin oligodendrocyte protein (MOG35-55), is a neuroinflammatory, demyelinating disease widely recognized as an animal model of multiple sclerosis (MS). Typically, EAE presents with an ascending course of paralysis, and inflammation that is predominantly localized to the spinal cord. Recent studies have further indicated that inflammation - in both MS and EAE - might initiate within the meninges and propagate from there to the underlying parenchyma. However, the patterns of inflammation within the respective meningeal and parenchymal compartments along the length of the spinal cord, and the progression with which these patterns develop during EAE, have yet to be detailed. Such analysis could hold key to identifying factors critical for spreading, as well as constraining, inflammation along the neuraxis. To address this issue, high-resolution 3-dimensional (3D) confocal microscopy was performed to visualize, in detail, the sequence of leukocyte infiltration at distinct regions of the spinal cord. High quality virtual slide scanning for imaging the entire spinal cord using epifluorescence was further conducted to highlight the directionality and relative degree of inflammation. Meningeal inflammation was found to precede parenchymal inflammation at all levels of the spinal cord, but did not develop equally or simultaneously throughout the subarachnoid space (SAS) of the meninges. Instead, meningeal inflammation was initially most obvious in the caudal SAS, from which it progressed to the immediate underlying parenchyma, paralleling the first signs of clinical disease in the tail and hind limbs. Meningeal inflammation could then be seen to extend in the caudal-to-rostral direction, followed by a similar, but delayed, trajectory of parenchymal inflammation. To additionally determine whether the course of ascending paralysis and leukocyte infiltration during EAE is reflected in differences in inflammatory gene expression by meningeal and parenchymal microvessels along the spinal cord, laser capture microdissection (LCM) coupled with gene expression profiling was performed. Expression profiles varied between these respective vessel populations at both the cervical and caudal levels of the spinal cord during disease progression, and within each vessel population at different levels of the cord at a given time during disease. These results reinforce a significant role for the meninges in the development and propagation of central nervous system inflammation associated with MS and EAE. PMID- 28844789 TI - Protocadherin 10 alters gamma oscillations, amino acid levels, and their coupling; baclofen partially restores these oscillatory deficits. AB - Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10+/-) has been investigated as a proxy for ASD. Male Pcdh10+/- mice have demonstrated sex specific deficits in social behavior, recapitulating the gender bias observed in ASD. Furthermore, in vitro slice preparations of these Pcdh10+/- mice demonstrate selective decreases to high frequency electrophysiological responses, mimicking clinical observations. The direct in vivo ramifications of such decreased in vitro high frequency responses are unclear. As such, Pcdh10+/- mice and their wild-type (WT) littermates underwent in vivo electrocorticography (ECoG), as well as ex vivo amino acid concentration quantification using High Performance Liquid Chromatography (HPLC). Similar to the previously observed reductions to in vitro high frequency electrophysiological responses in Pcdh10+/- mice, male Pcdh10+/- mice exhibited reduced gamma-band (30-80Hz), but not lower frequency (10 and 20Hz), auditory steady state responses (ASSR). In addition, male Pcdh10+/- mice exhibited decreased signal-to-noise-ratio (SNR) for high gamma-band (60-100Hz) activity. These gamma-band perturbations for both ASSR and SNR were not observed in females. Administration of a GABAB agonist remediated these electrophysiological alterations among male Pcdh10+/-mice. Pcdh10+/- mice demonstrated increased concentrations of GABA and glutamine. Of note, a correlation of auditory gamma-band responses with underlying GABA concentrations was observed in WT mice. This correlation was not present in Pcdh10+/- mice. This study demonstrates the role of Pcdh10 in the regulation of excitatory-inhibitory balance as a function of GABA in ASD. PMID- 28844790 TI - Multidimensional Performance of Farming Approaches: A Reply to Mehrabi et al. PMID- 28844791 TI - Climates Past, Present, and Yet-to-Come Shape Climate Change Vulnerabilities. AB - Climate change is altering life at multiple scales, from genes to ecosystems. Predicting the vulnerability of populations to climate change is crucial to mitigate negative impacts. We suggest that regional patterns of spatial and temporal climatic variation scaled to the traits of an organism can predict where and why populations are most vulnerable to climate change. Specifically, historical climatic variation affects the sensitivity and response capacity of populations to climate change by shaping traits and the genetic variation in those traits. Present and future climatic variation can affect both climate change exposure and population responses. We provide seven predictions for how climatic variation might affect the vulnerability of populations to climate change and suggest key directions for future research. PMID- 28844792 TI - Prognostic Index Model for Progression-Free Survival in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Treated With Abiraterone Acetate Plus Prednisone. AB - BACKGROUND: Radiographic progression-free survival (rPFS) is associated with overall survival (OS) in chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients. Using readily assessable baseline clinical and laboratory parameters, we developed a prognostic index model for rPFS in chemotherapy-naive mCRPC patients without visceral disease who were treated with abiraterone acetate plus prednisone. METHODS: Data from the abiraterone acetate plus prednisone arm of COU-AA-302 were used. rPFS was defined based on modified Prostate Cancer Working Group 2 criteria. Baseline variables were assessed for association with rPFS through univariate Cox modeling. The lower (LLN) and upper (ULN) limits of laboratory normal were used to dichotomize most laboratory parameters; baseline median was used to dichotomize prostate-specific antigen (PSA). Prognostic factors for rPFS were identified by multivariate Cox modeling. Model accuracy was estimated by the C-index. RESULTS: Presence of lymph node metastasis (hazard ratio [HR] = 1.76, P < .0001), lactate dehydrogenase > ULN (234 IU/L) (HR = 1.71, P = .0001), >= 10 bone metastases (HR = 1.71, P = .0015), hemoglobin <= LLN (12.7 g/dL) (HR = 1.47, P = .0030) and PSA > 39.5 ng/mL (HR = 1.42, P = .0078) were associated with poor outcome. Patients were categorized into 3 prognostic groups (good, n = 230; intermediate, n = 152; poor, n = 164) based on number of risk factors. Median rPFS was calculated (27.6, 16.6, and 8.3 months for good, intermediate, and poor, respectively). The C-index was 0.83 (95% confidence interval = 0.73-0.91). CONCLUSIONS: The prognostic index model for rPFS reveals differential outcomes based on factors readily available in clinical practice. If validated, this model can be integrated into clinical practice and design of risk-stratified trials. PMID- 28844793 TI - Utilization and Outcomes of Radical Cystectomy for High-grade Non-muscle-invasive Bladder Cancer in Elderly Patients. AB - BACKGROUND: Radical cystectomy (RC) represents a treatment option for patients with high-grade non-muscle-invasive bladder cancer (HG-NMIBC); however, perioperative morbidity is not insignificant, particularly in elderly patients. We sought to evaluate the associations of age with utilization and outcomes of RC for HG-NMIBC. PATIENTS AND METHODS: Patients with HG-NMIBC diagnosed between 2004 and 2013 were identified in the National Cancer Database and stratified by age: <= 60, 61-70, 71-80, and > 80 years. Association between age and treatment with RC was assessed by multivariable logistic regression. Associations between age and overall survival were assessed using the Kaplan-Meier method. A multi institutional analysis was performed to evaluate the associations of age with perioperative outcomes and survival among patients managed with RC for HG-NMIBC. RESULTS: On multivariable analysis, age was associated with RC utilization, with the lowest usage in patients > 80 years (2.1%; P < .01). Upstaging at RC occurred in 40% of patients with HG-NMIBC, and no association of age with upstaging risk was noted. Significantly inferior overall survival was observed in the patients who were upstaged across age strata (all P < .01). In the multi-institutional cohort, age was not associated with risks of upstaging, receipt of transfusion, 30-/90-day complications, or recurrence-free or cancer-specific survival (all P > .05), whereas upstaging was associated with inferior recurrence-free and cancer specific survival regardless of age. CONCLUSION: RC for HG-NMIBC is used less frequently in older adults, despite similar risks of pathologic upstaging. As upstaging is associated with inferior survival regardless of age, these data suggest that elderly patients with HG-NMIBC may be at risk for undertreatment. PMID- 28844794 TI - Probiotic species in the modulation of the anticancer immune response. AB - Mounting evidences are supporting a key role of distinct gut bacteria in the occurrence and progression of intestinal and extra-intestinal tumors. More importantly, it has been recently demonstrated that some gut bacteria strains synergize with largely-used anticancer drugs as alkylating or immune checkpoint blockade agents thus optimizing the immune response against multiple solid cancers. However, the exact role played by each gut bacterium in cancer occurrence and response to therapy is still in its infancy; and the current knowledge, although exciting, still needs to be transferred from mice models to human beings. Here, the advances in the understanding of how gut microbes and immune response shape each other in a cancer context are reviewed together with the implications of these finding for future antitumor therapy. Herein, the most important bacteria strains, able to boost the immune response triggered by anticancer drugs, together with their mechanism of action, whenever known, have been surveyed. It is reasonable to think that cocktails of beneficial bacteria together with an ad hoc diet or food supplements may be used as novel anticancer adjuvant agents in future therapeutic regimens. PMID- 28844795 TI - Author's Reply. PMID- 28844796 TI - Regarding "5-Millimeter Trocar Site Hernias after Laparoscopy Requiring Surgical Repair". PMID- 28844797 TI - Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue Resident Macrophages. AB - Mycobacterium tuberculosis (Mtb) enters the host in aerosol droplets deposited in lung alveoli, where the bacteria first encounter lung-resident alveolar macrophages. We studied the earliest mycobacterium-macrophage interactions in the optically transparent zebrafish. First-responding resident macrophages phagocytosed and eradicated infecting mycobacteria, suggesting that to establish a successful infection, mycobacteria must escape out of the initially infected resident macrophage into growth-permissive monocytes. We defined a critical role for mycobacterial membrane phenolic glycolipid (PGL) in engineering this transition. PGL activated the STING cytosolic sensing pathway in resident macrophages, inducing the production of the chemokine CCL2, which in turn recruited circulating CCR2+ monocytes toward infection. Transient fusion of infected macrophages with CCR2+ monocytes enabled bacterial transfer and subsequent dissemination, and interrupting this transfer so as to prolong mycobacterial sojourn in resident macrophages promoted clearing of infection. Human alveolar macrophages produced CCL2 in a PGL-dependent fashion following infection, arguing for the potential of PGL-blocking interventions or PGL targeting vaccine strategies in the prevention of tuberculosis. VIDEO ABSTRACT. PMID- 28844799 TI - Exposure to benzophenone-3 and reproductive toxicity: A systematic review of human and animal studies. AB - Hydroxy-4-methoxybenzophenone, also known as benzophenone-3 (BP-3), is a commonly used ultraviolet filter in skincare and as a food additive. Large concentrations of similar phenolic compounds have been detected in urine, amniotic fluid, and placental tissue, thereby raising questions about its impact on reproduction. The objective of this paper was to investigate the reproductive toxicity of BP-3 in humans and animals. In humans, studies showed that high levels of BP-3 exposure could be linked to an increase in male birth weight but a decline in female birth weight and male gestational age. In fish, BP-3 exposure resulted in a decline in egg production, hatching, and testosterone, along with a down-regulation of steroidogenic genes. In rats, a decrease in epididymal sperm density and a prolonged estrous cycle for females was observed. These positive associations may be attributed to an altered estrogen and testosterone balance as a result of endocrine disrupting effects of BP-3. However, the current body of literature is limited by non-uniform exposure and outcome measurements in studies both across and within species and future studies will need to be conducted in a standardized fashion to allow for a more significant contribution to the literature that allows for better comparison across studies. PMID- 28844798 TI - Utility of the Autism Observation Scale for Infants in Early Identification of Autism in Tuberous Sclerosis Complex. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder with high prevalence of associated autism spectrum disorder (ASD). Our primary objectives were to determine early predictors of autism risk to identify children with TSC in most need of early interventions. The Autism Observation Scale for Infants (AOSI) was evaluated as a measure of ASD-associated behaviors in infants with TSC at age 12 months and its ability to predict ASD at 24 months. METHODS: Children ages 0 to 36 months with TSC were enrolled in the TSC Autism Center of Excellence Research Network (TACERN), a multicenter, prospective observational study to identify biomarkers of ASD. The AOSI was administered at age 12 months and the Autism Diagnostic Observation Schedule-2 (ADOS-2) and Autism Diagnostic Interview Revised (ADI-R) at 24 months. Developmental functioning was assessed using the Mullen Scales of Early Learning. Children were classified as ASD or non-ASD according to the ADOS-2. RESULTS: Analysis included 79 children who had been administered the AOSI at 12 months and ADOS-2 and ADI-R at 24 months. The ASD group had a mean AOSI total score at 12 months significantly higher than the non ASD group (11.8 +/- 7.4 vs 6.3 +/- 4.7; P < 0.001). An AOSI total score cutoff of 13 provided a specificity of 0.89 to detect ASD with the ADOS-2. AOSI total score at 12 months was similarly associated with exceeding cutoff scores on the ADI-R. CONCLUSIONS: The AOSI is a useful clinical tool in determining which infants with TSC are at increased risk for developing ASD. PMID- 28844800 TI - Paternal use of azathioprine/6-mercaptopurine or methotrexate within 3 months before conception and long-term health outcomes in the offspring-A nationwide cohort study. AB - PURPOSE: We examined the effect of preconception paternal use of azathioprine (AZA)/6-mercaptopurine (6-MP) or methotrexate (MTX) and the risk of adverse long term outcomes in the offspring. METHODS: This study included all children born in Denmark from 1 January 1997 through 2013. Exposed cohort: children fathered by men who used AZA/6-MP (N=735) or MTX (N=209) within three months before conception; unexposed cohort: children fathered by men who did not use AZA/6 MP/MTX (N=1,056,524). OUTCOMES: malignancies, autism spectrum disorders (ASD)/schizophrenia/psychosis, and attention deficit hyperactivity disorder (ADHD). RESULTS: Outcomes: of children: AZA/6-MP exposure: one with leukemia (0.14%), one with ASD/schizophrenia (0.14%) and three with ADHD (0.41%); MTX exposure: three with ADHD (1.4%). Unexposed: 1710 with malignancies (0.16%), 2107 with ASD/schizophrenia (0.20%), 2799 with ADHD (0.26%). Median follow up times were 6.7 [IQR:3.6-11.3] and 9.9 [IQR:5.7-14.3] years respectively. CONCLUSIONS: There was no negative impact of paternal preconception use of AZA/6-MP/MTX on selected childhood health outcomes. PMID- 28844801 TI - Microbial, chemical, textural and sensory properties of coated rainbow trout by chitosan combined with pomegranate peel extract during frozen storage. AB - The current study was aimed to investigate the combined effects of chitosan (Ch) and pomegranate peel extract (PPE) on the overall quality of rainbow trout (Oncorhynchus mykiss) during the frozen storage. Fresh gutted fishes were dipped for 60s either in sterile distilled water (Control) or in chitosan combined with 0 (Ch), 1% (Ch+PPE1), 2% (Ch+PPE2), or 4% (Ch+PPE4) (w/v) PPE. Microbial, chemical, textural and sensory properties of the samples were intermittently checked during six months. At the end of storage, the highest and lowest values of psychrophilic, lactic acid bacteria and mold counts in the control and Ch+PPE4 groups were respectively, 5.14+/-0.19, 2.91+/-0.00; 3.11+/-0.03, 0.33+/-0.57 and 2.86+/-0.19, 2.24+/-0.13. Our results showed the best performance to prevent the oxidation of fats and protein was in the chitosan combined with 4% PPE, however, due to its undesirable color, the chitosan combined with 2% PPE was preferred. A considerable improvement in the chemical, microbial, sensory and textural properties was shown in the Ch+PPE2 groups. Therefore, this active coverage was suggested as safe to store rainbow trout up to 6 months frozen storage. PMID- 28844802 TI - Recent developments in small molecule therapies for renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and is known to be the 10th most common type of cancer in the world. Most of the currently available RCC drugs are tyrosine kinase inhibitors (TKIs). However, combination therapies of TKIs and immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand 1 (PD-L1) inhibitors are the focus of most of the final stage clinical trials. Meanwhile, other small molecule therapies for RCC that target indoleamine-2,3-dioxygenase (IDO1), glutaminase, C-X-C chemokine receptor 4 (CXCR4), and transglutaminase 2 (TG2) are emerging as the next generation of therapeutics. In this review, these three major streams for the development of small molecule drugs for RCC are described. PMID- 28844805 TI - The Voiced Oral High-frequency Oscillation Technique's Immediate Effect on Individuals With Dysphonic and Normal Voices. AB - OBJECTIVE: The aim of this study was to verify the effect of the voiced oral high frequency oscillation (VOHFO) on voice quality in acoustic voice symptoms and self-reported sensations in individuals with voice complaints and dysphonic voices, and in individuals with normal voices. METHODS: The participants, which included 60 individuals from 18 to 45 years of age, both genders, were divided into two groups: G1, 30 individuals without voice complaints and normal voices; and G2, 30 individuals with voice complaints and dysphonic voices. We used the following measures: acoustic analysis, voice and larynx symptom investigation, and phonation time before and after 3 minutes of performing the VOHFO technique. The sensations were reported only after the VOHFO technique. Data were analyzed using the Wilcoxon test (P <= 0.05), paired t test (P <= 0.05), and the Mann Whitney test (P <= 0.05). RESULTS: After the VOHFO, in G1, there was an increased fundamental frequency (both genders), a higher voice turbulence index, and a decrease in dryness symptoms (women); in G2, there was a decrease in the following symptoms: strong voice, dryness and lump in the throat, sensitive throat (women), and roughness and weak voice (men). The phonation measures and sensations did not present differences. The soft phonation index decreased in G1 and increased in G2 (women), in addition to a significant decrease in strong voice and sensitive throat (women) and roughness (men) in G2. CONCLUSIONS: The VOHFO technique improves the source-filter relationship and the severity of voice and larynx symptoms in dysphonic and normal individuals. Women improved more in terms of larynx symptoms, whereas men improved more in terms of voice symptoms. PMID- 28844804 TI - DAT SPECT may have diagnostic value in prodromal SCA2 patients with parkinsonism. AB - INTRODUCTION: Although spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia. METHODS: 123I-metaiodobenzyl guanidine (123I MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using 123I-ioflupane (123I-FP-CIT) were performed for the six patients from three SCA2 families. RESULTS: 123I-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested. DAT SPECT showed decreased uptake in the striatum in all four patients who were scanned, including one patient without parkinsonism. When patterns of uptake were compared to those with Parkinson's disease, most of the patients had minimal reduction of uptake in the putamen. CONCLUSION: DAT SPECT is expected to be useful in differentiating SCA2 from Parkinson's disease, making an early diagnosis, and allowing early therapeutic intervention. PMID- 28844803 TI - Picomolar inhibition of beta-galactosidase (bovine liver) attributed to loop closure. AB - In an effort to examine similarities in the active sites of glycosidases within the GH35 family, we performed a structure-activity-relationship study using our recently described library of galactonoamidines. The kinetic evaluation based on UV/Vis spectroscopy disclosed inhibition of beta-galactosidase (bovine liver) in the picomolar concentration range indicating significantly higher inhibitor affinity than previously determined for beta-galactosidase (A. oryzae). Possible alterations in the secondary protein structure or folding were excluded after further examination of the inhibitor binding using CD spectroscopy. Molecular dynamics studies suggested loop closing interactions as a rationale for the disparity of the active sites in the beta-galactosidases under investigation. PMID- 28844806 TI - Laryngeal Manual Therapies for Behavioral Dysphonia: A Systematic Review and Meta analysis. AB - OBJECTIVES: The aim of this study was to review systematically the literature and to analyze the effectiveness of laryngeal manual therapy in addressing the overall severity of vocal deviation, the intensity of vocal and laryngeal symptoms, and musculoskeletal pain in adults with behavioral dysphonia. STUDY DESIGN: This is a systematic review and meta-analysis. METHODS: Two independent authors selected clinical trials that analyzed the effectiveness of laryngeal manual therapy compared with other interventions in the treatment of adults with behavioral dysphonia from the Cochrane Library, PubMed, Web of Science, and LILACS. The analyzed outcomes were the overall severity of vocal deviation, the intensity of vocal and laryngeal symptoms, and musculoskeletal pain. Data analysis was conducted based on the following steps: the assessment of the risk of bias, the measures of treatment effect and descriptive data analysis, the assessment of heterogeneity, subgroup analysis, sensitivity analysis, and the assessment of reporting biases. RESULTS: A total of 2135 studies were identified, three of which met the selection criteria. Data analysis showed an unclear risk of 100% of performance bias and 66% of detection bias, in addition to a 33% high risk of selection bias. Low statistical and clinical heterogeneities were found. In addition, no significant difference was found in the relative risk of improvement with laryngeal manual therapy and with other interventions in the analyzed outcomes. CONCLUSIONS: Various types of laryngeal manual therapies are available with similar objectives and effects, but their effectiveness is equivalent to that of other interventions involving direct voice therapy in the rehabilitation of adults with behavioral dysphonia. PMID- 28844807 TI - [Hemophagocytic lymphohistiocytosis associated with Plasmodium falciparum]. PMID- 28844808 TI - The microbiota-gut-brain axis in obesity. AB - Changes in microbial diversity and composition are increasingly associated with several disease states including obesity and behavioural disorders. Obesity associated microbiota alter host energy harvesting, insulin resistance, inflammation, and fat deposition. Additionally, intestinal microbiota can regulate metabolism, adiposity, homoeostasis, and energy balance as well as central appetite and food reward signalling, which together have crucial roles in obesity. Moreover, some strains of bacteria and their metabolites might target the brain directly via vagal stimulation or indirectly through immune neuroendocrine mechanisms. Therefore, the gut microbiota is becoming a target for new anti-obesity therapies. Further investigations are needed to elucidate the intricate gut-microbiota-host relationship and the potential of gut-microbiota targeted strategies, such as dietary interventions and faecal microbiota transplantation, as promising metabolic therapies that help patients to maintain a healthy weight throughout life. PMID- 28844809 TI - [Pulmonary embolism as a presentation of nephrotic syndrome]. AB - BACKGROUND: Nephrotic syndrome (NS) in adults is defined by proteinuria>3g/24h or 50mg/kg/d, hypoproteinemia<60g/24h and hypoalbuminemia<30g/L. The final diagnosis is guided by the histopathology evidence when a renal biopsy is possible. The consequences of NS are multiple: high blood pressure, undernutrition, infections and a hypercoagulable state. OBSERVATION: We report the case of a patient presenting with thromboembolic disease, occurring in the absence of other thromboembolic risk factors, which revealed NS with spontaneously favorable evolution. CONCLUSION: Thromboembolic disease in NS is frequent but underestimated and may remain underdiagnosed. Thorough investigation - including serum protein levels and testing for proteinuria - are essential in thromboembolism, as is excluding cancer or another cause. The treatment of thromboembolic disease in NS is based on anticoagulation for as long as the NS persists. There is no consensus about primary prophylaxis but an albumin level below 20g/L should be considered as a risk factor of thrombosis and prophylactic anticoagulation should be started. PMID- 28844810 TI - [Respiratory diseases in black African carceral area]. AB - INTRODUCTION: The measures for people in specific situations such as prisoners are part of the Millennium Development Goals (MDGs). The objective of this study was to assess respiratory pathologies in a black African carceral center. METHODS: Retrospective study about the prevalence of respiratory pathologies in the arrest central house for men in Bamako (Mali), from May 2012 to April 2013. The admission records have served as data checking support on detainee's records. Statistical significance was investigated by the SAS 9.3 software with a threshold of 5%. RESULTS: Of 2740 admissions, 207 concerned respiratory pathologies (7.5%). All men, were of mean age 30+/-13 years (range 19-71). The respiratory diseases found were: pneumonia (33.8%), chronic bronchitis (26.6%), acute respiratory infection (14%), asthma (13.5%) and tuberculosis (5.3%). A definite diagnosis was made in 42% of cases. A tobacco intoxication was found in all age groups (CI 95%, R-square=0.01), without significant difference between the occurrence of cough in smoking and non-smoking men. CONCLUSION: According to their relative frequencies, the management of respiratory diseases requires collaboration between carceral health facilities and pneumological specialized services. PMID- 28844811 TI - The Multifaceted Personality of Intestinal CX3CR1+ Macrophages. AB - Intestinal macrophages expressing the fraktalkine receptor (CX3CR1+) represent a cell population that plays a variety of roles ranging from maintaining intestinal immune homeostasis at steady state to controlling antigen access by extending transepithelial dendrites (TEDs) to capture luminal microbes and shuttle them across the epithelium to initiate immune responses. However, recent evidence shows that very early during infection, pathogen-capturing CX3CR1+ macrophages migrate to the lumen of the small intestine, therefore preventing pathogens from traversing the epithelium. Here we discuss the complexity of the at-times seemingly opposing roles played by these cells and propose that CX3CR1-mediated pathogen exclusion is part of a defensive strategy against infections that includes multiple effector mechanisms acting synergistically at the intestinal mucosa. PMID- 28844812 TI - Antidepressant-like effects of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid receptor modulator, in a rat IFN-alpha-induced depression model. AB - Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-alpha) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro inflammatory cytokine, IFN-alpha, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-alpha, which may be reflective of mechanisms underlying inflammation associated depression. We also investigate the potential of 3-carboxamido seco-nalmefene (3CS-nalmefene), a novel opioid modulator (antagonist at mu and partial agonist at kappa and delta opioid receptors in vitro), to reverse IFN-alpha induced changes. In vitro radioligand receptor binding assays and the [35S] GTPgammaS were performed to determine the affinity of 3CS-nalmefene for the mu, kappa and delta opioid receptors. IFN-alpha treatment increased circulating and central markers of inflammation and hypothalamic-pituitaryadrenal (HPA) axis activity (IL-6, IL-1beta and corticosterone) while increasing immobility in the FST, impairing of object displacement learning in the object exploration task (OET), and decreasing neuronal proliferation and brain-derived neurotrophic factor (BDNF) in the hippocampus. Treatment with 3CS-nalmefene (0.3mg/kg/sc twice per day, 3 times per week for 4weeks) prevented IFN-alpha-induced immobility in the FST and impaired object displacement learning. In addition, 3CS-nalmefene prevented IFN-alpha induced increases in inflammation and hyperactivity of the HPA-axis, the IFN alpha-induced reduction in both neuronal proliferation and BDNF expression in the hippocampus. Overall, these preclinical data would support the hypothesis that opioid receptor modulation is a relevant target for treatment of depression. PMID- 28844813 TI - Measurement of O-GlcNAcylated endothelial nitric oxide synthase by using 2',5' ADP-Sepharose pull-down assay. AB - Endothelial nitric oxide synthase (eNOS) plays central roles in cardiovascular regulation and disease. eNOS function is critically affected by O-linked N acetylglucosamine (O-GlcNAc) modification. The present method for measuring O GlcNAcylated eNOS relies on immunoprecipitation. Such method exhibits low detection efficiency and is also costly. We here report a simplified assay by employing the high binding affinity of eNOS with the 2',5'-ADP-Sepharose resins. Together with the O-GlcNAc antibody, this assay readily allows the detection of O GlcNAcylated eNOS in both cultured endothelial cells and rat vascular tissues. By using this assay, we demonstrate that eNOS O-GlcNAcylation is markedly elevated in the vessels of diabetic rats. Thus, a 2',5'-ADP-Sepharose-based pull-down assay is developed to measure O-GlcNAcylated eNOS. This assay is simple and efficient in detecting O-GlcNAcylated eNOS in cultured cells and animal tissues under both normal and disease conditions. PMID- 28844814 TI - Imaged capillary isoelectric focusing in native condition: A novel and successful example. AB - Imaged capillary isoelectric focusing (icIEF) separates ampholytic components of biomolecules in an electric field according to their isoelectric points and has been used for protein charge variants quantification and characterization. Denaturants are ordinarily incorporated into icIEF to stabilize charge species in solution. In certain circumstances, however, denaturants are detrimental to stable isoelectric separation of proteins due to their unique structural and biophysical features, such as an aggregation-prone antibody we encountered recently. Here we report our novel matrix formula non-detergent sulfobetaine and taurine (NDSB-T). It is deprived of denaturants that notably ameliorates the assay robustness and peak resolution for this antibody. NDSB-T is a combination of non-detergent sulfobetaine (NDSB) and taurine possessing the stabilization and separation power while maintaining protein integrity. As a result, assay throughputs are tremendously increased for more than 10 folds along with extraordinarily improved assay accuracy. Furthermore, NDSB-T can separate and quantify protein charge species in native state and therefore avoid partial denaturation derived peaks which are often misleading and hard to characterize. NDSB-T may be a valuable tool for proteins incompatible with conventional icIEF matrices and potentially opens a new window for icIEF assay in native conditions. PMID- 28844815 TI - Pazopanib for advanced liposarcoma. PMID- 28844817 TI - Labetuzumab govitecan in metastatic colorectal cancer. PMID- 28844816 TI - Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. AB - BACKGROUND: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (>=65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. METHODS: We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32.8-74.4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38.8-77.6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35.8-64.2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). INTERPRETATION: More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. FUNDING: Astex Pharmaceuticals and Stand Up To Cancer. PMID- 28844818 TI - Guadecitabine: a new therapeutic option for acute myeloid leukaemia? PMID- 28844819 TI - In vitro studies on the tumorigenic potential of the halonitromethanes trichloronitromethane and bromonitromethane. AB - Epidemiological data indicate that chronic exposure to water disinfection by products (DBPs) may result in increased risk of cancer. However, the real carcinogenic potential of individual DBPs is not well known. In this study, we assessed the in vitro carcinogenic potential of trichloronitromethane (TCNM) and bromonitromethane (BNM), two halonitromethanes (HNMs) commonly found in DBPs' mixtures at comparably high concentrations. Human lung BEAS-2B cells were exposed for 8weeks to TCNM and BNM, and the acquisition of different in vitro cancer-like features was evaluated. The results indicate that long-term exposure to non cytotoxic doses of TCNM and BNM did not cause carcinogenic transformation as indicated by the absence of morphological changes, no effects on cell growth, no changes in the level of matrix metalloproteinases (MMPs) secretion, and no increased anchorage-independent cell growth capacity. Furthermore, TCNM- and BNM exposed BEAS-2B cells were unable to enhance tumour growth directly or by indirect influence of the surrounding stroma. Our results indicate that the carcinogenic effects of DBP mixtures cannot be attributed to the evaluated HNMs. This is the first study evaluating the cell transformation effects of TCNM and BNM under a long-term exposure scenario using suitable hallmarks of the cancer process. PMID- 28844820 TI - Clinical implementation of a novel Double-Balloon single-entry breast brachytherapy applicator. AB - PURPOSE: The purpose of the study was to describe the clinical utilization of a novel Double-Balloon applicator for accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: The Double-Balloon single-entry breast applicator contains a single central treatment catheter, as well as four peripheral catheters that can be differentially loaded to customize radiation dose coverage. An inner balloon is filled with up to 7-30 cm3 of saline to increase separation between the peripheral catheters, and an outer balloon is filled with up to 37 115 cm3 of saline to displace breast tissue from the peripheral catheters. Treatment planning objectives include coverage of the breast planning target volume to a minimum of V90 > 90%, limiting dose heterogeneity such that V200 < 10 cm3 and V150 < 50 cm3, and limiting maximum dose to skin (<100% of prescription dose) and ribs (<145% of prescription dose). RESULTS: High-dose-rate APBI was delivered to 11 women using this device (34 Gy in 10 twice daily fractions). The mean V90 was 98.2% (range 94.2-99.4%). The mean skin Dmax with the Double-Balloon applicator was 83.3% (range 75.6-99.5%). The mean breast V200 was 5.8 cm3 (range 2.3-10.2 cm3), and the mean breast V150 was 32.9 cm3 (range 25.0-41.7 cm3). Pretreatment quality assurance was performed using CT prior to each morning fraction and ultrasound prior to each afternoon fraction. CONCLUSIONS: The Double Balloon applicator can be easily introduced into a previously existing brachytherapy program. APBI plans created with this applicator achieve excellent planning target volume coverage, while limiting skin dose and maintaining breast V200 < 10 cm3. PMID- 28844821 TI - Low-dose-rate prostate brachytherapy: 4-8 week postimplant prostate-specific antigen a novel predictor of biochemical failure-free survival. AB - PURPOSE: The purpose of this study was to determine the relationship between patient, disease, and treatment variables and biochemical failure-free survival (bFFS) following low-dose-rate prostate brachytherapy (LDR-BT). METHODS AND MATERIALS: Data from 624 consecutive patients who received LDR-BT for localized prostate cancer between 2002 and 2012 at a single institution were collected for various patient, disease, and treatment characteristics including a 4-8 week postimplant PSA (4-8wkPSA). Subgroup analysis was stratified by risk category and treatment regimen. Analysis was performed using Kaplan-Meier survival curves, Cox proportional hazard ratios (HRs), and receiver-operator characteristic curves. RESULTS: A total of 624 consecutive patients were included with followup time of 4.0 +/- 3.1 years. Predictors of bFFS included PSA nadir and 4-8wkPSA (HR = 2.48, p = 0.000 and HR = 1.24, p = 0.000, respectively) for total population. Diabetes mellitus (p = 0.026), chronic obstructive pulmonary disease (p = 0.000), alcohol use (p = 0.024), and age (p = 0.002) were predictors for specific subgroups. Receiver-operator characteristic curves 4-8wkPSA were found to be significant (p = 0.036). CONCLUSION: 4-8wkPSA is a novel predictor of bFFS for patients receiving LDR-BT across several risk categories and treatment regimens with potential clinical utility as a prognostic indicator. Certain comorbidities and exposure histories also demonstrated significant relationships with bFFS including chronic obstructive pulmonary disease, diabetes mellitus, age, alcohol history, proton pump inhibitor use, PSA nadir, and PSA density. PMID- 28844823 TI - Addressing maternal deaths due to violence: the Illinois experience. AB - Homicide, suicide, and substance abuse accounted for nearly one fourth of all pregnancy-associated deaths in Illinois from 2002 through 2013. Maternal mortality review in Illinois has been primarily focused on obstetric and medical causes and little is known about the circumstances surrounding deaths due to homicide, suicide, and substance abuse, if they are pregnancy related, and if the deaths are potentially preventable. To address this issue, we implemented a process to form a second statewide maternal mortality review committee for deaths due to violence in late 2014. We convened a stakeholder group to accomplish 3 tasks: (1) identify appropriate committee members; (2) identify potential types and sources of information that would be required for a meaningful review of violent maternal deaths; and (3) revise the Maternal Mortality Review Form. Because homicide, suicide, and substance abuse are closely linked to the social determinants of health, the review committee needed to have a broad membership with expertise in areas not required for obstetric maternal mortality review, including social service and community organizations. Identifying additional sources of information is critical; the state Violent Death Reporting System, case management data, and police and autopsy reports provide contextual information that cannot be found in medical records. The stakeholder group revised the Maternal Mortality Review Form to collect information relevant to violent maternal deaths, including screening history and psychosocial history. The form guides the maternal mortality review committee for deaths due to violence to identify potentially preventable factors relating to the woman, her family, systems of care, the community, the legal system, and the institutional environment. The committee has identified potential opportunities to decrease preventable death requiring cooperation with social service agencies and the criminal justice system in addition to the physical and mental health care systems. Illinois has demonstrated that by engaging appropriate members and expanding the information used, it is possible to conduct meaningful reviews of these deaths and make recommendations to prevent future deaths. PMID- 28844822 TI - Diet and fertility: a review. AB - The literature on the relationship between diet and human fertility has greatly expanded over the last decade, resulting in the identification of a few clear patterns. Intake of supplemental folic acid, particularly at doses higher than those recommended for the prevention of neural tube defects, has been consistently related to lower frequency of infertility, lower risk of pregnancy loss, and greater success in infertility treatment. On the other hand and despite promising evidence from animal models, vitamin D does not appear to exert an important role in human fertility in the absence of deficiency. Antioxidant supplementation does not appear to offer any benefits to women undergoing infertility treatment, but it appears to be beneficial when it is the male partner who is supplemented. However, the available evidence does not allow discerning which specific antioxidants, or at which doses, are responsible for this benefit. Long-chain omega-3 fatty acids appear to improve female fertility, although it remains unclear to what extent contamination of shared food sources, such as fish with high levels of environmental toxicants, can dampen this benefit. Lastly, adherence to healthy diets favoring seafood, poultry, whole grains, fruits, and vegetables are related to better fertility in women and better semen quality in men. The cumulative evidence has also piled against popular hypotheses. Dairy and soy, once proposed as reproductive toxicants, have not been consistently related to poor fertility. In fact, soy and soy supplements appear to exert a beneficial effect among women undergoing infertility treatment. Similarly, because data from large, high-quality studies continue to accumulate, the evidence of a potentially deleterious effect of moderate alcohol and caffeine intake on the ability to become pregnant seems less solid than it once did. While a complete picture of the role of nutrition on fertility is far from complete, much progress has been made. The most salient gaps in the current evidence include jointly considering female and male diets and testing the most consistent findings in randomized trials. PMID- 28844824 TI - All-cause mortality in young women with endometrial cancer receiving progesterone therapy. AB - BACKGROUND: Uterine-preserving therapy with progesterone may be used in young women with endometrial cancer who desire fertility preservation. Such therapy delays definitive treatment with hysterectomy. OBJECTIVE: We examined the use and safety of progestational therapy in young women with endometrial cancer. The primary outcome of the analysis was overall survival. STUDY DESIGN: We identified women <=49 years of age with stage I endometrial cancer in the National Cancer Database from 2004 through 2014. Women treated with hormonal therapy with or without hysterectomy were compared to women treated with hysterectomy. After propensity score weighting, overall survival was examined using proportional hazards models. RESULTS: A total of 23,231 patients, including 872 (3.8%) women treated with hormonal therapy were identified. Use of hormonal therapy was 2.4% (95% confidence interval, 1.8-3.3%) in 2004 and increased over time to 5.9% (95% confidence interval, 5.0-6.9%) by 2014 (P < .0001). Use of hormonal therapy decreased with older age, higher substage, and increasing grade. Black women were more likely to receive hormonal therapy while Medicaid recipients were less likely to receive hormonal therapy. The 5-year survival for patients treated with hormonal therapy was 96.4% (95% confidence interval, 94.3-98.0%) compared to 97.2% (95% confidence interval, 96.9-97.4%) for hysterectomy. In a multivariable model, women treated with hormonal therapy were 92% (hazard ratio, 1.92; 95% confidence interval, 1.15-3.19) more likely to die compared to women who underwent primary hysterectomy. When stratified by stage, hormonal therapy was associated with increased mortality in women with stage IB and I-not otherwise specified tumors but not for stage IA neoplasms. CONCLUSION: Use of progestational therapy is increasing. Its use was associated with decreased survival, particularly in women with stage IB tumors. PMID- 28844825 TI - Patient navigation across the spectrum of women's health care in the United States. AB - Patient navigation is a patient-centered intervention that uses trained personnel to identify patient-level barriers, including financial, cultural, logistical, and educational obstacles to health care and then mitigate these barriers to facilitate complete and timely access to health services. For example, to assist a woman with Medicaid who is seeking postpartum care, a patient navigator could help her schedule an appointment before her insurance benefits change, coordinate transportation and child care, give her informational pamphlets on contraception options, and accompany her to the appointment to ensure her questions are answered. Existing studies examining the efficacy of patient navigation interventions show particularly striking benefits in the realm of cancer care, including gynecological oncology; patient navigation has been demonstrated to increase access to screening, shorten time to diagnostic resolution, and improve cancer outcomes, particularly in health disparity populations, such as women of color, rural populations, and poor women. Because of the successes in cancer care at reducing disparities in health care access and health outcomes, patient navigation has the potential to improve care and reduce disparities in obstetric and benign gynecological care. We review the concept of patient navigation, offer potential roles for patient navigation in obstetrics and gynecology, and discuss areas for further investigation. PMID- 28844826 TI - Pregnant trauma victims experience nearly 2-fold higher mortality compared to their nonpregnant counterparts. AB - BACKGROUND: Trauma is the leading nonobstetric cause of death in women of reproductive age, and pregnant women in particular may be at increased risk of violent trauma. Management of trauma in pregnancy is complicated by altered maternal physiology, provider expertise, potential disparate imaging, and distorted anatomy. Little is known about the impact of trauma on maternal mortality. OBJECTIVE: We sought to: (1) characterize nonviolent and violent trauma among pregnant women; (2) determine whether pregnancy is associated with increased mortality following traumatic injury; and (3) identify risk factors for trauma-related death in pregnant women. STUDY DESIGN: We studied 1148 trauma events among pregnant girls and women and 43,608 trauma events among nonpregnant girls and women of reproductive age (14-49 years) who presented to any accredited trauma center in Pennsylvania for treatment of trauma-related injuries from 2005 through 2015, as captured in the Pennsylvania Trauma Outcome Study. Traumas were categorized as violent (eg, homicide or assault) or nonviolent (eg, motor vehicle accident or accidental fall). We used modified Poisson regression to estimate relative rate of trauma-related death, adjusting for demographic characteristics and severity of trauma. RESULTS: Compared to nonpregnant women, pregnant women and girls had a lower injury severity score (8.9 vs 10.9, P < .001) and were significantly more likely to experience violent trauma (15.9% vs 9.8%, P < .001). Pregnant trauma victims had a 1.6-fold higher rate of mortality compared to their nonpregnant counterparts (P < .001), and were both more likely to be dead on arrival and to die during their hospital course (adjusted relative risk, 2.33, P < .001, and adjusted relative risk, 1.79, P = .004, respectively). Pregnancy was associated with increased mortality in both victims of nonviolent and violent trauma (adjusted relative risk, 1.69, P = .002, and adjusted relative risk, 1.60, P = .007, respectively). Pregnant trauma victims were less likely to undergo surgery (adjusted relative risk, 0.70, P = .001) and more likely to be transferred to another facility (adjusted relative risk, 1.72, P < .001). Even after adjusting for demographics and injury severity score, violent trauma was associated with 3.14-fold higher mortality in pregnant women and girls compared to nonviolent trauma (adjusted relative risk, 3.14, P = .003). CONCLUSION: Pregnant women and girls are nearly twice as likely to die after trauma and twice as likely to experience violent trauma. Universal screening for violence and trauma during pregnancy may provide an opportunity to identify women at risk for death during pregnancy. PMID- 28844828 TI - Port-site closure technique using a wound retractor after a transumbilical, single-incision laparoscopy for an adnexal mass: A retrospective wound review. PMID- 28844827 TI - Behcet Disease serum is immunoreactive to neurofilament medium which share common epitopes to bacterial HSP-65, a putative trigger. AB - Autoimmune and dysimmune inflammatory mechanisms on a genetically susceptible background are implicated in the etiology of Behcet's Disease (BD). Heat-shock protein-65 (HSP-65) derived from Streptococcus sanguinis was proposed as a triggering factor based on its homology with human HSP-60. However, none of the autoantigens identified so far in sera from BD share common epitopes with bacterial HSP-65 or has a high prevalence. Here, we report that sera from BD patients are immunoreactive against filamentous neuronal processes in the mouse brain, retina and scrotal skin in great majority of patients. By using matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and peptide mass fingerprinting, Western blotting and peptide blocking experiments, we have identified neurofilament medium (NF-M) as the probable antigen for the serologic response observed. Clustal Omega analyses detected significant structural homology between the human NF-M and bacterial HSP-65 corresponding to amino acids 111-126, 213-232 and 304-363 of mycobacterial HSP 65, which were previously identified to induce proliferation of lymphocytes obtained from BD patients. We also found that sera immunoreactive against NF-M cross-reacted with bacterial HSP-65. These findings suggest that NF-M may be involved in autoimmunity in BD due to its molecular mimicry with bacterial HSP 65. PMID- 28844829 TI - Late Thrombosis Associated With Left Atrial Appendage Closure Devices. Is It Rare or Is It Underdiagnosed? PMID- 28844830 TI - Healthcare resource use and associated costs of hypoglycemia in patients with type 2 diabetes prescribed sulfonylureas. AB - AIMS: The objective of this study was to evaluate diabetes-related healthcare resource use and associated costs in patients with type 2 diabetes (T2DM) treated with a sulfonylurea (SU), with and without hypoglycemia. METHODS: In this retrospective cohort study, patients 18years or older receiving SU monotherapy or as add-on to metformin were identified from a US healthcare claims database (MarketScan(r)). Of 113,743 patients (56.8% male, average age 62.6years), 61.6% were on SU/metformin dual therapy and 38.4% were on SU monotherapy, and 5% had one or more episodes of hypoglycemia during the 12-month follow-up period. RESULTS: Adjusted for baseline characteristics, patients with hypoglycemia were three times more likely than those without to use emergency room services (OR 3.04, 95% CI: 2.82, 3.25), almost four times more likely to have inpatient admissions (OR 3.84, 95% CI: 3.58, 4.12), and had more frequent physician office visits (4.3 vs 3.0 visits, p<0.01) in the 12-month follow-up period. The adjusted annual diabetes-related medical expenditure was three times higher in patients with hypoglycemia compared with those without ($6884 vs $2392, p<0.001). CONCLUSIONS: This study demonstrated the higher healthcare utilization and costs associated with hypoglycemia in patients with T2DM treated with an SU. PMID- 28844831 TI - Percutaneous Cryoablation of Renal Tumors: Is It Time for a New Paradigm Shift? AB - PURPOSE: To retrospectively assess long-term outcomes of percutaneous renal cryoablation, including factors affecting complications and local recurrence rates. MATERIALS AND METHODS: A total of 357 computed tomographic (CT) fluoroscopy-guided percutaneous cryoablation procedures were performed for 382 masses in 302 outpatients; 347 were biopsy-proven renal-cell carcinoma (RCC) or Bosniak category > III masses (n = 28). Benign pathologic conditions (n = 18) or metastatic non-RCC disease (n = 17) were included to analyze procedural complication rate, but recurrence rates, tumor staging, and nephrometry score were limited to RCCs. The average tumor diameter was 2.9 cm (range, 1-10.3 cm), and median nephrometry score for RCC was 8 (mean, 7.4). Protection of adjacent vital structures was performed in 34% of procedures (n = 121), and ureteral stent placement was performed for 9.2% (n = 33). All major complications were graded per surgical Clavien-Dindo criteria. RESULTS: The average CT-visible cryoablation zone diameter was 5 cm (range, 2.5-10.5 cm). Grade >= 3 complications occurred in 2.8% of procedures (n = 10), and appeared related to only high nephrometry scores (P = .0086) and larger tumors (P = .0034). No significant changes in renal function before and after the procedure were noted (P = .18). At a mean follow-up of 31.8 months, the local tumor recurrence rate was 3.2% (11 of 347) for RCC, and no significant difference was noted between tumors larger or smaller than 3 cm (P = .15). The difference reached significance only among the small number of stage >= T2 RCC tumors (P = .0039). CONCLUSIONS: Long-term follow-up of percutaneous renal cryoablation demonstrates low recurrence rates with preserved renal function, even for patients with high nephrometry scores and body mass index, assuming thorough cytotoxic technique and protection measures. PMID- 28844832 TI - Radiofrequency Ablation in the Treatment of Benign Thyroid Nodules: An Efficient and Safe Alternative to Surgery. AB - PURPOSE: To evaluate the efficacy and safety of radiofrequency (RF) ablation in the treatment of benign thyroid nodules (BTNs) by applying a modification of the moving-shot technique. MATERIALS AND METHODS: Fifty-one BTNs in 46 patients for whom surgery was contraindicated or who refused surgery were treated with RF ablation: 31 had lesion volumes < 20 cm3 (group A) and 20 had volumes >= 20 cm3 (group B). The solid component percentage of each lesion was assessed, and any present fluid component was aspirated. Symptomatic scores and cosmetic scores (CSs) were assessed. All RF ablations were performed under ultrasound (US) guidance with an 18-gauge electrode. Treatment response was evaluated by contrast enhanced US at 6-month intervals for 18 months in group A. In group B, after the 6- and 12-month follow-up assessments, a second treatment was performed in selected cases, and the 6-month contrast-enhanced US follow-up was started again. Volume reduction rate (VRR) was evaluated at each follow-up examination. RESULTS: No permanent paralysis of the laryngeal nerve was observed; 2 patients experienced transient hoarseness. In all nodules treated with a single RF ablation session, the VRRs at 6, 12, and 18 months were 69.4%, 78.7%, and 84% in group A, respectively, and 66.6%, 79.4%, and 81.5% in group B, respectively. The VRRs of group B nodules treated with a second RF ablation procedure (n = 6) were 86.4% and 88.2% at 6 and 12 mo after the second treatment, respectively. All patients reported symptom relief and CS improvement. CONCLUSIONS: RF ablation is a reliable alternative to surgery in patients affected by BTNs and can be safely repeated in selected cases. PMID- 28844833 TI - Theoretical frameworks informing family-based child and adolescent obesity interventions: A qualitative meta-synthesis. AB - BACKGROUND: Child and adolescent obesity trends are rising throughout the world, revealing treatment difficulties and a lack of consensus about treatment. The family system is broadly viewed as a potential setting for facilitation of behaviour change. Therefore, family-based interventions have come into focus. However, the use of theoretical frameworks to strengthen these interventions is rare and very uneven. OBJECTIVE AND METHOD: To conduct a qualitative meta synthesis of family-based interventions for child and adolescent obesity to identify the theoretical frameworks applied, thus understanding how theory is used in practice. A literature review was conducted between January and March 2016. A total of 35 family-based interventions were selected for analysis. RESULTS: Eleven interventions explicitly stated that theory guided the development and were classified as theory-inspired. The social cognitive, self efficacy and Family Systems Theory appeared most frequently. The remaining 24 were classified as theory-related as theoretical elements of self-monitoring; stimulus control, reinforcement and modelling were used. CONCLUSION: The designs of family-based interventions reveal numerous inconsistencies and a significant void between research results and health care practice. Based on the analysis, this article proposes three themes to be used as focus points when designing future interventions and when selecting theories for the development of solid, theory-based frameworks for application. The themes are: (1) age of target group, (2) intervention objective, and (3) self-efficacy and readiness for change. PMID- 28844835 TI - The skeletal vascular system - Breathing life into bone tissue. AB - During bone development, homeostasis and repair, a dense vascular system provides oxygen and nutrients to highly anabolic skeletal cells. Characteristic for the vascular system in bone is the serial organization of two capillary systems, each typified by specific morphological and physiological features. Especially the arterial capillaries mediate the growth of the bone vascular system, serve as a niche for skeletal and hematopoietic progenitors and couple angiogenesis to osteogenesis. Endothelial cells and osteoprogenitor cells interact not only physically, but also communicate to each other by secretion of growth factors. A vital angiogenic growth factor is vascular endothelial growth factor and its expression in skeletal cells is controlled by osteogenic transcription factors and hypoxia signaling, whereas the secretion of angiocrine factors by endothelial cells is regulated by Notch signaling, blood flow and possibly hypoxia. Bone loss and impaired fracture repair are often associated with reduced and disorganized blood vessel network and therapeutic targeting of the angiogenic response may contribute to enhanced bone regeneration. PMID- 28844834 TI - What Makes New Ischemic Lesions Symptomatic after Aortic Valve Replacement? AB - BACKGROUND: Acute cerebral infarctions on diffusion-weighted magnetic resonance imaging (MRI) are common after cardiothoracic surgery. However, most are asymptomatic and we aimed to identify features associated with clinical stroke symptoms. METHODS: Patients over 65 years of age undergoing surgical aortic valve replacement (AVR) for calcific stenosis were prospectively recruited (N = 196). All patients underwent neurological evaluation preoperatively and on postoperative days 1, 3, and 7, and MRI on planned postoperative day 5. Among those with new postoperative DWI lesions, we performed univariate and multivariable analyses to identify clinical, demographic, surgical, and imaging factors associated with clinical stroke symptoms. RESULTS: Of the 129 patients who completed a postsurgical MRI, 79 (61%) had DWI lesions and 17 (21.5%) of these had new stroke symptoms concordant with the infarct distribution. In an exploratory multivariable analysis, focal neurological symptoms were associated with increased age, a longer bypass duration, and a larger pre-existing lesion burden on fluid-attenuated inversion recovery. Limiting the analysis to the 61 patients with analyzable volume and location data, logistic regression failed to identify any location-related determinant of symptomatic lesions. CONCLUSIONS: New DWI lesions are common after AVR, but most are asymptomatic. Patients are more likely to have symptoms with longer bypass durations, increasing age, and larger pre-existing lesion burdens. PMID- 28844836 TI - The role of human phospholipid scramblases in apoptosis: An overview. AB - Human phospholipid scramblases (hPLSCRs) are a family of four homologous single pass transmembrane proteins (hPLSCR1-4) initially identified as the proteins responsible for Ca2+ mediated bidirectional phospholipid translocation in plasma membrane. Though in-vitro assays had provided evidence, the role of hPLSCRs in phospholipid translocation is still debated. Recent reports revealed a new class of proteins, TMEM16 and Xkr8 to exhibit scramblase activity challenging the function of hPLSCRs. Apart from phospholipid scrambling, numerous reports have emphasized the multifunctional roles of hPLSCRs in key cellular processes including tumorigenesis, antiviral defense, protein and DNA interactions, transcriptional regulation and apoptosis. In this review, the role of hPLSCRs in mediating cell death through phosphatidylserine exposure, interaction with death receptors, cardiolipin exposure, heavy metal and radiation induced apoptosis and pathological apoptosis followed by their involvement in cancer cells are discussed. This review aims to connect the multifunctional characteristics of hPLSCRs to their decisive involvement in apoptotic pathways. PMID- 28844838 TI - Complete oxidative conversion of lignocellulose derived non-glucose sugars to sugar acids by Gluconobacter oxydans. AB - Non-glucose sugars derived from lignocellulose cover approximately 40% of the total carbohydrates of lignocellulose biomass. The conversion of the non-glucose sugars to the target products is an important task of lignocellulose biorefining research. Here we report a fast and complete conversion of the total non-glucose sugars from corn stover into the corresponding sugar acids by whole cell catalysis and aerobic fermentation of Gluconobacter oxydans. The conversions include xylose to xylonate, arabinose to arabonate, mannose to mannonate, and galactose to galactonate, as well as with glucose into gluconate. These cellulosic non-glucose sugar acids showed the excellent cement retard setting property. The mixed cellulosic sugar acids could be used as cement retard additives without separation. The conversion of the non-glucose sugars not only makes full use of lignocellulose derived sugars, but also effectively reduces the wastewater treatment burden by removal of residual sugars. PMID- 28844837 TI - Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self Renewal via EP4 Receptor Activation and Repression of AP-1. AB - Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34+ stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a beta-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML. PMID- 28844839 TI - Microbial dynamics in petroleum oilfields and their relationship with physiological properties of petroleum oil reservoirs. AB - Petroleum is produced by thermal decay of buried organic material over millions of years. Petroleum oilfield ecosystems represent resource of reduced carbon which favours microbial growth. Therefore, it is obvious that many microorganisms have adapted to harsh environmental conditions of these ecosystems specifically temperature, oxygen availability and pressure. Knowledge of microorganisms present in ecosystems of petroleum oil reservoirs; their physiological and biological properties help in successful exploration of petroleum. Understanding microbiology of petroleum oilfield(s) can be used to enhance oil recovery, as microorganisms in oil reservoirs produce various metabolites viz. gases, acids, solvents, biopolymers and biosurfactants. The aim of this review is to discuss characteristics of petroleum oil reservoirs. This review also provides an updated literature on microbial ecology of these extreme ecosystems including microbial origin as well as various types of microorganisms such as methanogens; iron, nitrate and sulphate reducing bacteria, and fermentative microbes present in petroleum oilfield ecosystems. PMID- 28844840 TI - Forming Focus Groups for Pediatric Pain Research in Nursing: A Review of Methods. AB - BACKGROUND: Within current priorities for pain research set by the American Society for Pain Management Nursing, there is a paucity of pediatric pain research. Qualitative approaches are helpful when researching topics about which little is known. Focus groups are one method of qualitative data collection and have been successfully implemented with children and parents. AIMS: The purpose of this paper was to identify ideal conditions for nurse researchers to employ when using focus groups as a data collection method for studies aiming to investigate pain in children. The aims of this paper are to identify focus group conditions (1) facilitating adequate scientific rigor and trustworthiness and (2) eliciting the richest data from participants. METHODS: A critique of research studies that used focus groups with children, parents/caregivers, or nurses in hospital or community settings was performed to achieve the stated aims. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines directed the process of selecting studies for inclusion in this review. RESULTS: The final sample for critique included four studies. Methods such as transcription processes and approaches to analysis used in the four publications were appraised for scientific rigor and usefulness in pediatric pain research. CONCLUSIONS: Researchers investigating priority areas must consider trustworthiness and strategies to eliciting quality data when planning to employ focus groups as a data collection method. Nurses in the clinical setting can use findings of this report to strengthen pain assessment practices as well as evaluate qualitative work for inclusion in evidence-based policies. PMID- 28844841 TI - Effect of resveratrol on cognitive and memory performance and mood: A meta analysis of 225 patients. AB - Resveratrol is a natural dietary phenolic compound which is extensively present in many edible fruits, including grape, berries, pomegranates, and peanuts. Reseveratrol has a broad spectrum of biological activities including anti-aging, chemopreventive, anti-carcinogenic, anti-inflammatory and antioxidant effects and thus it is effective in related diseases. Particularly, the positive effects of resveratrol in neuropsychological diseases have been proven in in-vitro and in vivo studies. Some clinical trials have reported that resveratrol possesses preventive and therapeutic effects in cognitive disorders. Therefore, the current systematic review and meta-analysis aimed to assess the effects of resveratrol on cognition and memory performance as well as mood state. Electronic databases including Scopus, PubMed, Science Direct, and Cochrane library were searched with the keywords "Memory", "Cognitive", "Cognition" or "Mood" with "Resveratrol" until June 2017. Only clinical studies were included in this review. We have provided the most reliable evidence to date counting results obtained from 226 individuals from four randomized clinical trials evaluating the mentioned specific effects of resveratrol. The results of this meta-analysis showed that resveratrol has no significant effect on memory and cognitive performance assessed by auditory verbal learning tests. Two parameters of Profile of Mood States (POMS) including vigor and fatigue, decreased significantly by resveratrol. However, decrease in other parameters of POMS including tense/anxiety, depression, anger, and confusion by resveratrol was not significant. The key findings from this meta-analysis are that resveratrol has no significant impact on factors related to memory and cognitive performance, including learning ability, delayed recall, retention, and recognition with all effect sizes non-significant and effectively at zero. However, it has the potential to enhance mood. Further randomized, controlled trials are needed to achieve more conclusive results. PMID- 28844843 TI - The Sixth Stage: Mastery. PMID- 28844842 TI - Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura. AB - Dural cerebral veins (CV) are required for cerebrospinal fluid reabsorption and brain homeostasis, but mechanisms that regulate their growth and remodeling are unknown. We report molecular and cellular processes that regulate dural CV development in mammals and describe venous malformations in humans with craniosynostosis and TWIST1 mutations that are recapitulated in mouse models. Surprisingly, Twist1 is dispensable in endothelial cells but required for specification of osteoprogenitor cells that differentiate into preosteoblasts that produce bone morphogenetic proteins (BMPs). Inactivation of Bmp2 and Bmp4 in preosteoblasts and periosteal dura causes skull and CV malformations, similar to humans harboring TWIST1 mutations. Notably, arterial development appears normal, suggesting that morphogens from the skull and dura establish optimal venous networks independent from arterial influences. Collectively, our work establishes a paradigm whereby CV malformations result from primary or secondary loss of paracrine BMP signaling from preosteoblasts and dura, highlighting unique cellular interactions that influence tissue-specific angiogenesis in mammals. PMID- 28844844 TI - Promoting Collaborations Between Radiologists and Scientists. AB - Radiology as a discipline thrives on the dynamic interplay between technological and clinical advances. Progress in almost all facets of the imaging sciences is highly dependent on complex tools sourced from physics, engineering, biology, and the clinical sciences to obtain, process, and view imaging studies. The application of these tools, however, requires broad and deep medical knowledge about disease pathophysiology and its relationship with medical imaging. This relationship between clinical medicine and imaging technology, nurtured and fostered over the past 75 years, has cultivated extraordinarily rich collaborative opportunities between basic scientists, engineers, and physicians. In this review, we attempt to provide a framework to identify both currently successful collaborative ventures and future opportunities for scientific partnership. This invited review is a product of a special working group within the Association of University Radiologists-Radiology Research Alliance. PMID- 28844845 TI - Lepidic Predominant Pulmonary Lesions (LPL): CT-based Distinction From More Invasive Adenocarcinomas Using 3D Volumetric Density and First-order CT Texture Analysis. AB - RATIONALE AND OBJECTIVES: This study aimed to differentiate pathologically defined lepidic predominant lesions (LPL) from more invasive adenocarcinomas (INV) using three-dimensional (3D) volumetric density and first-order texture histogram analysis of surgically excised stage 1 lung adenocarcinomas. MATERIALS AND METHODS: This retrospective study was institutional review board approved and Health Insurance Portability and Accountability Act compliant. Sixty-four cases of pathologically proven stage 1 lung adenocarcinoma surgically resected between September 2006 and October 2015, including LPL (n = 43) and INV (n = 21), were evaluated using high-resolution computed tomography. Quantitative measurements included nodule volume, percent solid volume (% solid), and first-order texture histogram analysis including skewness, kurtosis, entropy, and mean nodule attenuation within each histogram quartile. Binomial logistic regression models were used to identify the best set of parameters distinguishing LPL from INV. RESULTS: Univariate analysis of 3D volumetric density and histogram features was statistically significant between LPL and INV groups (P < .05). Accuracy of a binomial logistic model to discriminate LPL from INV based on size and % solid was 85.9%. With optimized probability cutoff, the model achieves 81% sensitivity, 76.7% specificity, and area under the receiver operating characteristic curve of 0.897 (95% confidence interval, 0.821-0.973). An additional model based on size and mean nodule attenuation of the third quartile (Hu_Q3) of the histogram achieved similar accuracy of 81.3% and area under the receiver operating characteristic curve of 0.877 (95% confidence interval, 0.790-0.964). CONCLUSIONS: Both 3D volumetric density and first-order texture analysis of stage 1 lung adenocarcinoma allow differentiation of LPL from more invasive adenocarcinoma with overall accuracy of 85.9%-81.3%, based on multivariate analyses of either size and % solid or size and Hu_Q3, respectively. PMID- 28844846 TI - Analysis of polymorphic contamination in meloxicam raw materials and its effects on the physicochemical quality of drug product. AB - This work aims to evaluate the effect of polymorphism on the physicochemical properties of meloxicam, which is an antipyretic and non-steroidal anti inflammatory drug. Powder X-ray Diffraction, Infrared Spectroscopy with attenuated total reflectance, Thermogravimetric and Differential Scanning Calorimetry techniques were used for the polymorphic characterization. Comparative tests of solubility, intrinsic dissolution and dissolution profiles were performed on meloxicam active pharmaceutical ingredients (APIs) and formulated tablets. A polymorphic contamination (Forms I and III) was found in a studied meloxicam batch, which showed a higher solubility and greater intrinsic dissolution than those containing only the preconized form (Form I). Consequently, the dissolution profiles of the tablets that contained the polymorphic contamination showed higher drug release. Additionally, a thermal behavior study shows that MLX Form I and III are monotropy polymorphs being MLX Form III a metastable phase, which becomes MLX Form I at approximately 200 degrees C in solid state phase transition governed by kinetic variables. The kinetic of conversion of Form III to Form I in saturated solutions was also studied. These results illustrate the importance of the polymorphic characterization of meloxicam APIs and formulated tablets in order to avoid potential quality and efficacy problems of drug products. PMID- 28844847 TI - Strigolactones and Gibberellins: A New Couple in the Phytohormone World? AB - Strigolactones (SLs) and gibberellins (GAs) are plant hormones that share some unique aspects of their perception and signalling pathways. Recent discoveries indicate that these two phytohormones may act together in processes of plant development and that SL biosynthesis is regulated by GAs. PMID- 28844848 TI - Nano-sized titanium dioxide toxicity in rat prostate and testis: Possible ameliorative effect of morin. AB - This study investigated the effect of short-term oral exposure to nano-sized titanium dioxide (nTiO2) on Wistar rat prostate and testis, and the associating reproductive-related alterations. The study also evaluated the potential ameliorative effect of the natural flavonoid, morin, on nTiO2-induced aberrations. Intragastric administration of nTiO2 (50mg/kg/day for 1, 2 and 3weeks) increased testicular gamma-glutamyltransferase (gamma-GT) activity and decreased testicular steroidogenic acute regulatory protein (StAR) and c-kit gene expression, serum testosterone level and sperm count. nTiO2-treated rats also exhibited prostatic and testicular altered glutathione levels, elevated TNF-alpha levels, up-regulated Fas, Bax and caspase-3 gene expression, down-regulated Bcl-2 gene expression and enhanced prostatic lipid peroxidation. Sperm malformation and elevated testicular acid phosphatase (ACP) activity and malondialdehyde level, serum prostatic acid phosphatase activity, prostate specific antigen (PSA), gonadotrophin and estradiol levels occurred after the 2 and 3week regimens. Morin (30mg/kg/day administered intragastrically for 5weeks) mitigated nTiO2-induced prostatic and testicular injury as evidenced by lowering serum PSA level, testicular gamma-GT and ACP activities and TNF-alpha level, along with hampering both intrinsic and extrinsic apoptotic pathways. Moreover, morin alleviated prostatic lipid peroxidation, raised prostatic glutathione level, and relieved testicular reductive stress. Additionally, morin increased testicular StAR and c kit mRNA expression, raised the sperm count, reduced sperm deformities and modified the altered hormone profile. Histopathological evaluation supported the biochemical findings. In conclusion, morin could ameliorate nTiO2-induced prostatic and testicular injury and the corresponding reproductive-related aberrations via redox regulatory, anti-inflammatory and anti-apoptotic mechanisms, promoting steroidogenesis and spermatogenesis, and improving sperm count and morphology. PMID- 28844850 TI - Malnutrition in older patients with cancer: Appraisal of the Mini Nutritional Assessment, weight loss, and body mass index. PMID- 28844849 TI - Frailty and skeletal muscle in older adults with cancer. AB - OBJECTIVE: Computerized tomography (CT) imaging is routine in oncologic care and can be used to measure muscle quantity and composition that may improve prognostic assessment of older patients. This study examines the association of single-slice CT-assessed muscle measurements with a frailty index in older adults with cancer. MATERIALS AND METHODS: Using the Carolina Senior Registry, we identified patients with CT imaging within 60days +/- of geriatric assessment (GA). A 36-item Carolina Frailty Index was calculated. Cross-sectional skeletal muscle area (SMA) and Skeletal Muscle Density (SMD) were analyzed from CT scan L3 lumbar segments. SMA and patient height (m2) were used to calculate skeletal muscle index (SMI). Skeletal Muscle Gauge (SMG) was calculated by multiplying SMI*SMD. RESULTS: Of the 162 patients, mean age 73, 53% were robust, 27% pre frail, and 21% frail. Significant differences were found between robust and frail patients for SMD (29.4 vs 24.1 HU, p<0.001) and SMG (1188 vs 922AU, p=0.003), but not SMI (41.9 vs 39.5cm2/m2, p=0.29). After controlling for age and gender, for every 5 unit decrease in SMD, the prevalence ratio of frailty increased by 20% (PR=1.20 [1.09, 1.32]) while the prevalence of frailty did not differ based on SMI. CONCLUSIONS: Muscle mass (measured as SMI) was poorly associated with a GA based frailty index. Muscle density, which reflects muscle lipid content, was more associated with frailty. Although frailty and loss of muscle mass are both age-related conditions that are predictive of adverse outcomes, our results suggest they are separate entities. PMID- 28844851 TI - Synergistic interactions between mirtazapine and prazosin prevent the induction and expression of behavioral sensitization to cocaine in rats. AB - Cocaine abuse and dependence are a global public health problem. To date, no effective therapy has been established to treat cocaine dependence but mirtazapine-as well as prazosin used in preclinical and clinical trials-has been shown to decrease cocaine behavioral effects. Therefore, our hypothesis was that the effectiveness of mirtazapine might improve when used in combination with prazosin. This study investigated the combined effect of mirtazapine and prazosin on cocaine-induced locomotor activity impairment in rats subjected to locomotor sensitization testing. We found that chronic treatment with the mirtazapine prazosin combination significantly improved the effect of single mirtazapine dosing on cocaine-induced locomotor activity and on the induction and expression of cocaine sensitization. These results suggest that the combined use of mirtazapine and prazosin may be a potentially effective treatment to attenuate induction and expression of locomotor sensitization to cocaine. PMID- 28844852 TI - Temperament as a modulating factor of pain sensitivity in combat sport athletes. AB - The aim of this study was to characterise the temperament of combat athletes in comparison to that of individuals who do not practise any sports with regard to pain sensitivity measured with the cold pressor test (CPT) and pressure pain threshold (PPT). The study involved 284 healthy men, aged 18 to 43years. The first group consisted of 198 combat athletes, including boxing (n=19), mixed martial arts (MMA) (n=97) and karate (n=82), aged from 18 to 43years. The control group consisted of 86 subjects between the ages of 18 and 26years, academic students not practising any sport professionally. Pain threshold and pain tolerance were evaluated using the CPT and a pressure algometer. Temperament was measured with the Formal Characteristics of Behaviour - Temperament Inventory (FCB-TI). The contact athletes showed much higher tolerance to pain than the control group using both tools: CPT (p=0.007) and PPT (p<0.001). In athletes, but not in controls, relationships were noted between BMI and endurance (r=0.20; p=0.004), BMI and activity (r=-0.283; p<0.001), BMI and pain threshold (r=0.15; p<0.05), and BMI and pain tolerance (r=0.30; p<0.001), when measured by the algometer - this necessitating adjustment for further analysis. The athletes and students in the study groups differed significantly with regard to intensity of four temperamental traits, but after BMI adjustments only group differences in Preservation, Sensory sensitivity and Emotional reactivity remained significant'. These differences indicate individual differences in perception and reaction to external stimuli. Significantly higher pain tolerance (CPT and PPT) in the athletes studied was related to specific psychological features. The obtained results of temperamental characteristics may indicate higher resilience of the nervous system in combat athletes in comparison to non-athletes. PMID- 28844853 TI - Tolerance to rewarding brain electrical stimulation: Differential effects of contingent and non-contingent activation of parabrachial complex and lateral hypothalamus. AB - Electrical stimulation of the parabrachial complex and related insular cortex induces concurrent conditioned place preference (CPP) in a naloxone-dependent manner. Furthermore, repeated rewarding activation of these regions generates tolerance, i.e., a reduction of the reinforcing effect. This study examined the effects of contingent and non-contingent stimulation in a CPP task. In the former modality, the animals can voluntarily select areas of the maze and thereby determine whether or not they receive stimulation. In the non-contingent procedure, the animals passively receive the administration of the rewarding electrical current while confined in the preferred place. Tolerance to the rewarding stimulation was observed in the non-contingent procedure, in which the external lateral parabrachial subnucleus (LPBe) was stimulated in a behaviorally passive task, but not in the contingent procedure. In contrast, no tolerance was observed in the group receiving rewarding stimulation of the lateral hypothalamus after either contingent or non-contingent brain activation. These findings are discussed in terms of the rewarding effects induced after contingent or non contingent administration of electrical or chemical rewarding agents. PMID- 28844854 TI - Optimizing the Office Visit for Adolescents with Special Health Care Needs. AB - Youth with special health care needs (YSHCN) experience health care disparities and often need additional support to receive optimal medical care, particularly in adolescence as they prepare to transition to adult care. Many medical practices struggle to address their needs. Here, we discuss approaches to improve medical care in office-based settings for YSHCN. Office visits can be optimized by training staff in developmentally appropriate care and ensuring that the physical office space facilitates care. Participating in previsit preparation, including managing patient registries of YSHCN, engaging in regular team huddles, and incorporating previsit planning, can improve preparation and ensure that important needs are not overlooked. Additionally, approaches to improve patient and medical provider comfort with office visits with YSHCN, including approaches to measuring vital signs, examining patients, and communicating with patients with various disabilities, are reviewed. Finally, we discuss methods of supporting adolescents with special health care needs in developing self management skills that will allow them to be better prepared to enter adult health care settings when appropriate. Although YSHCN can present challenges to medical teams, their care can be improved by developing office-based changes and processes to support improved care for these patients. This may help overcome the health care disparities they experience and increase comfort for all members of the medical team. PMID- 28844855 TI - Pancreatic sphincter precutting using a dual knife to relieve acute pancreatic duct obstruction. PMID- 28844856 TI - RIP3 AND pMLKL promote necroptosis-induced inflammation and alter membrane permeability in intestinal epithelial cells. AB - BACKGROUND: Necroptosis is an inflammatory form of programmed cell death requiring receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). AIMS: The aim of this study is to examine in depth in vitro and ex vivo the contribution of necroptosis to intestinal inflammation. METHODS: In vitro: we used an intestinal cell line, HCT116RIP3, produced in our laboratory and overexpressing RIP3. Ex vivo: intestinal mucosal biopsies were taken from patients with inflammatory bowel disease (IBD) (20 with Crohn's disease; 20 with ulcerative colitis) and from 20 controls. RESULTS: RIP3-induced necroptosis triggers MLKL activation, increases cytokine/alarmin expression (IL 8, IL-1beta, IL-33, HMGB1), NF-kBp65 translocation and NALP3 inflammasome assembly. It also affects membrane permeability by altering cell-cell junctional proteins (E-cadherin, Occludin, Zonulin-1). Targeting necroptosis through Necrostatin-1 significantly reduces intestinal inflammation in vitro and in cultured intestinal explants from IBD. CONCLUSION: We show for the first time in vitro and ex vivo that RIP3-driven necroptosis seriously affects intestinal inflammation by increasing pMLKL, activating different cytokines and alarmins, and altering epithelial permeability. The inhibition of necroptosis causes a significant decrease of all these effects. These data strongly support the view that targeting necroptosis may represent a promising new option for the treatment of inflammatory enteropathies. PMID- 28844857 TI - Pathways from physical frailty to activity limitation in older people: Identifying moderators and mediators in the English Longitudinal Study of Ageing. AB - Physical frailty increases the risk of future activity limitation, which in turn, compromises independent living of older people and limits their healthspan. Thus, we seek to identify moderators and mediators of the effect of physical frailty on activity limitation change in older people, including gender- and age-specific effects. In a longitudinal study using data from waves 2, 4, and 6 of the English Longitudinal Study of Ageing, unique physical frailty factor scores of 4638 respondents aged 65 to 89years are obtained from confirmatory factor analysis of physical frailty, which is specified by three indicators, namely slowness, weakness, and exhaustion. Using a series of autoregressive cross-lagged models, we estimate the effect of physical frailty factor score on activity limitation change, including its moderation by social conditions, and indirect effects through physical and psychological conditions. We find that the effect of physical frailty on activity limitation change is significantly stronger with older age, while it has significant indirect effects through low physical activity, depressive symptoms, and cognitive impairment. In turn, indirect effects of physical frailty through low physical activity and cognitive impairment are stronger with older age. Sensitivity analyses suggest that these effects vary in their robustness to unmeasured confounding. We conclude that low physical activity, depressive symptoms, and cognitive impairment are potentially modifiable mediators on pathways from physical frailty to activity limitation in older people, including those who are very old. This evidence offers support for population-level interventions that target these conditions, to mitigate the effect of physical frailty on activity limitation, and thereby enhance healthspan. PMID- 28844858 TI - miR-221/222 promote cancer stem-like cell properties and tumor growth of breast cancer via targeting PTEN and sustained Akt/NF-kappaB/COX-2 activation. AB - MicroRNAs (miRNAs) play an important role in regulating cancer stem cell (CSC). Previous studies have shown that microRNA-221/222 (miR-221/222) cluster are involved in the propagation of breast cancer stem cell (BCSC), however, the underlying molecular mechanisms are still not fully understood. In this study, we found that miR-221/222 were overexpressed in highly aggressive breast cancer MDA MB-231 cells, that are enriched in markers for epithelial-mesenchymal transition (EMT) and BCSCs, than in MCF-7 cells. Phosphatase and tensin homolog (PTEN) was confirmed to be the target of miR-221/222 in breast cancer cells. MiR-221/222 enhanced breast cancer cell growth, migration and invasion by downregulating PTEN. Importantly, both ectopic expression of miR-221/222 and PTEN knockdown increased the mammosphere formation capacity and the expression of the stemness marker ALDH1. MiR-221/222 lentivirus vector infected MCF-7 cells produced larger subcutaneous tumors, while shRNA vector of PTEN showed similar trend. Along with the downregulation of PTEN caused by miR-221/222 in the breast cancer cells and the xenograft tumor tissues, Akt phosphorylation (p-Akt), NF-kappaB p65 and phosphorylated p65 (p-p65), and cyclooxygenase-2 (COX-2) were all overexpressed compared to the negative control. Taken together, our findings indicate that miR 221/222 play a critical role in the propagation of BCSCs and tumor growth possibly through targeting PTEN, which in turn activating the Akt/NF-kappaB/COX-2 pathway. MiR-221/222 might represent the potential target of breast cancer therapy. PMID- 28844859 TI - Endoplasmic reticulum stress restrains hepatocyte growth factor expression in hepatic stellate cells and rat acute liver failure model. AB - The aim of this study was to test whether endoplasmic reticulum (ER) stress suppresses hepatocyte growth factor (HGF) expression in hepatic stellate cells (HSCs) and whether ER stress plays a role in alleviating d-Galactosamine and Lipopolysaccharide (D-GalN/LPS)-induced acute liver failure (ALF) by regulating HGF expression. Rat HSCs line HSC-T6 were treated with the ER stress inducers tunicamycin or thapsigargin, and ER stress inhibitors sodium 4-phenylbutyrate (4 PBA) or salubrinal, respectively. Recombinant lentivirus containing eukaryotic translation initiation factor 2alpha (eIf2alpha), named LV-eIf2alpha-shRNA-GFP was produced to block eIf2alpha activated by ER stress. A rat ALF model was created by intraperitoneal injection of D-GalN/LPS, and 100 mg/kg 4-PBA was injected 6 h before injection as an inhibitor of ER stress. Levels of HGF, c-Met, vascular endothelial growth factor (VEGF), GRP78, eIf2alpha, phospho-eIF2alpha, ATF4 and CHOP in vitro and in vivo were measured. Our results demonstrated that ER stress stimulated VEGF but inhibited HGF expression in HSC-T6 cells. Both the stimulation of VEGF and the inhibition of HGF could be partly prevented by 4-PBA or Salubrinal. eIf2alpha expression was upregulated during ERS and interfering eIf2alpha expression proportionately down-regulated HGF expression. Inhibition of HGF and c-Met expression was also observed in the ALF rat. Treatment with 4-PBA prevented the reduction of HGF in ALF rats. ER stress regulates HGF expression in vitro and in vivo, which depends on eIf2alpha pathway. Reduction in liver damage of ALF by 4-PBA is associated with attenuation of ER stress and maintaining HGF production. PMID- 28844860 TI - An AAA Motor-Driven Mechanical Switch in Rpn11 Controls Deubiquitination at the 26S Proteasome. AB - Poly-ubiquitin chains direct protein substrates to the 26S proteasome, where they are removed by the deubiquitinase Rpn11 during ATP-dependent substrate degradation. Rapid deubiquitination is required for efficient degradation but must be restricted to committed substrates that are engaged with the ATPase motor to prevent premature ubiquitin chain removal and substrate escape. Here we reveal the ubiquitin-bound structure of Rpn11 from S. cerevisiae and the mechanisms for mechanochemical coupling of substrate degradation and deubiquitination. Ubiquitin binding induces a conformational switch of Rpn11's Insert-1 loop from an inactive closed state to an active beta hairpin. This switch is rate-limiting for deubiquitination and strongly accelerated by mechanical substrate translocation into the AAA+ motor. Deubiquitination by Rpn11 and ubiquitin unfolding by the ATPases are in direct competition. The AAA+ motor-driven acceleration of Rpn11 is therefore important to ensure that poly-ubiquitin chains are removed only from committed substrates and fast enough to prevent their co-degradation. PMID- 28844861 TI - The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure. AB - Pairing and synapsis of homologous chromosomes during meiosis is crucial for producing genetically normal gametes and is dependent upon repair of SPO11 induced double-strand breaks (DSBs) by homologous recombination. To prevent transmission of genetic defects, diverse organisms have evolved mechanisms to eliminate meiocytes containing unrepaired DSBs or unsynapsed chromosomes. Here we show that the CHK2 (CHEK2)-dependent DNA damage checkpoint culls not only recombination-defective mouse oocytes but also SPO11-deficient oocytes that are severely defective in homolog synapsis. The checkpoint is triggered in oocytes that accumulate a threshold level of spontaneous DSBs (~10) in late prophase I, the repair of which is inhibited by the presence of HORMAD1/2 on unsynapsed chromosome axes. Furthermore, Hormad2 deletion rescued the fertility of oocytes containing a synapsis-proficient, DSB repair-defective mutation in a gene (Trip13) required for removal of HORMADs from synapsed chromosomes, suggesting that many meiotic DSBs are normally repaired by intersister recombination in mice. PMID- 28844862 TI - VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy. AB - The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy. So far, we know little about the molecular mechanism of VPS34 activation besides its interaction with regulatory proteins to form complexes. Here, we report that VPS34 is specifically acetylated by the acetyltransferase p300, and p300-mediated acetylation represses VPS34 activity. Acetylation at K771 directly diminishes the affinity of VPS34 for its substrate PI, while acetylation at K29 hinders the VPS34-Beclin 1 core complex formation. Inactivation of p300 induces VPS34 deacetylation, PI3P production, and autophagy, even in AMPK-/-, TSC2-/-, or ULK1-/- cells. In fasting mice, liver autophagy correlates well with p300 inactivation/VPS34 deacetylation, which facilitates the clearance of lipid droplets in hepatocytes. Thus, p300-dependent VPS34 acetylation/deacetylation is the physiological key to VPS34 activation, which controls the initiation of canonical autophagy and of non-canonical autophagy in which the upstream kinases of VPS34 can be bypassed. PMID- 28844863 TI - Structural and Functional Impacts of ER Coactivator Sequential Recruitment. AB - Nuclear receptors recruit multiple coactivators sequentially to activate transcription. This "ordered" recruitment allows different coactivator activities to engage the nuclear receptor complex at different steps of transcription. Estrogen receptor (ER) recruits steroid receptor coactivator-3 (SRC-3) primary coactivator and secondary coactivators, p300/CBP and CARM1. CARM1 recruitment lags behind the binding of SRC-3 and p300 to ER. Combining cryo-electron microscopy (cryo-EM) structure analysis and biochemical approaches, we demonstrate that there is a close crosstalk between early- and late-recruited coactivators. The sequential recruitment of CARM1 not only adds a protein arginine methyltransferase activity to the ER-coactivator complex, it also alters the structural organization of the pre-existing ERE/ERalpha/SRC-3/p300 complex. It induces a p300 conformational change and significantly increases p300 HAT activity on histone H3K18 residues, which, in turn, promotes CARM1 methylation activity on H3R17 residues to enhance transcriptional activity. This study reveals a structural role for a coactivator sequential recruitment and biochemical process in ER-mediated transcription. PMID- 28844865 TI - Spiritual needs of mothers with sick new born or premature infants-A cross sectional survey among German mothers. AB - BACKGROUND: Spirituality is part of the basic needs of all humans, yet often undervalued by health professionals. Less is known about the spiritual needs of mothers of preterm or sick new born children. AIM: Identify unmet psychosocial and spiritual needs of these mothers, and to relate these needs to their perceived stress and impairments of life concerns. METHODS: Anonymous cross sectional survey with standardized instruments (e.g., Spiritual Needs Questionnaire) among 125 mothers of two paediatric departments in Germany. FINDINGS: Mothers felt supported by their partner and hospital staff, and hospital staff assured 82% of them that they must not worry about their child's prognosis. They nevertheless did have specific unmet spiritual needs. Religious Needs and Existentialistic Needs scored lowest, while Giving/Generativity Needs were of moderate and Inner Peace Needs of strongest relevance. With respect to the expected diagnosis and prognosis of their child, there were no significant differences for their secular spiritual needs scores, but significant differences for Religious Needs which scored highest in mothers with children having an unclear prognosis (F=8.6; p=.004). Particularly Inner Peace Needs correlated with their stress perception (r=.34), impairments of life concerns (r=.25) and grief (r=.23). DISCUSSION: Mothers of sick born/premature children felt supported by the hospital team and their partner, but nevertheless experienced stress and daily life impairments, and particularly have unmet Inner Peace Needs. CONCLUSIONS: Addressing mothers' specific needs may help support them in their struggle with their difficult situation avoiding fears and insecurity and thus facilitating positive bonding to their child. PMID- 28844864 TI - The Short Isoform of BRD4 Promotes HIV-1 Latency by Engaging Repressive SWI/SNF Chromatin-Remodeling Complexes. AB - BET proteins commonly activate cellular gene expression, yet inhibiting their recruitment paradoxically reactivates latent HIV-1 transcription. Here we identify the short isoform of BET family member BRD4 (BRD4S) as a corepressor of HIV-1 transcription. We found that BRD4S was enriched in chromatin fractions of latently infected T cells, and it was more rapidly displaced from chromatin upon BET inhibition than the long isoform. BET inhibition induced marked nucleosome remodeling at the latent HIV-1 promoter, which was dependent on the activity of BRG1-associated factors (BAF), an SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription. BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromodomain and extraterminal (ET) domain, and this isoform was necessary for BRG1 recruitment to latent HIV-1 chromatin. Using chromatin immunoprecipitation sequencing (ChIP-seq) combined with assay for transposase-accessible chromatin coupled to high-throughput sequencing (ATAC-seq) data, we found that the latent HIV-1 promoter phenotypically resembles endogenous long terminal repeat (LTR) sequences, pointing to a select role of BRD4S-BRG1 complexes in genomic silencing of invasive retroelements. PMID- 28844866 TI - Intimate partner violence during pregnancy and use of antenatal care among rural women in southern Terai of Nepal. AB - BACKGROUND: Underutilisation of antenatal care services due to intimate partner violence during pregnancy has been well documented elsewhere, but it is understudied in Nepal. Our study aimed at exploring the impact of intimate partner violence on antenatal care service utilisation in southern Terai of Nepal. METHOD: A community-based cross-sectional study was performed in 6 village development committees in Dhanusha district, Nepal. A total of 426 pregnant women in their second trimester were selected using a multistage cluster sampling method. Multivariable regression analyses were used to examine the association between exposure to intimate partner violence and selected antenatal care services, adjusting for covariates. RESULTS: Among 426 pregnant women, almost three out of ten women (28.9%) were exposed to intimate partner violence at some point during their pregnancy. Pregnant women who were exposed to intimate partner violence were less likely to: register for antenatal care (OR 0.31; 95% CI (0.08 0.50)), take iron and folic acid (OR 0.55; 95% CI (0.12-0.90)), report dietary diversity (middle vs low: OR 0.34; 95% CI (0.11-0.58) and high vs low: OR 0.18; 95% CI (0.08-0.37)), have rest and sleep during day time (OR 0.47; 95% CI (0.61 0.58)), and attend mother's group meetings (OR 0.29; 95% CI (0.10-0.83)). CONCLUSIONS: Intimate partner violence during pregnancy is associated with low utilisation of antenatal care services. Therefore, effective strategies to prevent or reduce intimate partner violence during pregnancy is needed, which may lead to improved antenatal care service utilization in Nepal with healthier mothers and children's outcome. PMID- 28844867 TI - Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity. AB - FGF21 is a multifunctional metabolic and stress hormone which is normally expressed in liver but cellular stress, e.g. mitochondrial or endoplasmic reticulum (ER) stress, can induce its expression and subsequent secretion from several mammalian tissues. The stress kinases of the integrated stress response (ISR) pathway stimulate the expression of FGF21 through the activation of ATF4 transcription factor, thus enhancing cellular stress resistance. The metabolic and stress-inducible transactivation mechanisms of FGF21 gene are mostly mediated through separate pathways. FGF21 is an interorgan regulator which can alleviate many age-related metabolic and stress disorders, e.g. through the activation of AMPK signaling. FGF21 signaling is also involved in circadian and torpor regulation. Given that circulating FGF21 can attenuate organelle stress, e.g. mitochondrial and ER stresses, it resembles a stress-induced cell non-autonomous regulation of proteostasis and longevity present in model organisms. The overexpression of FGF21 can even extend the lifespan of mice, probably by improving the healthspan. We will clarify the positive and negative signaling mechanisms which control the stress-related expression of FGF21 through the ISR pathway. Moreover, we will examine the role of FGF21 as an interorgan coordinator of survival functions in metabolic and stress disorders. We conclude that FGF21 can be viewed as a cell non-autonomous enhancer of longevity in mammals. PMID- 28844868 TI - Complexity of the Wnt/beta-catenin pathway: Searching for an activation model. AB - Wnt signaling refers to a conserved signaling pathway, widely studied due to its roles in cellular communication, cell fate decisions, development and cancer. However, the exact mechanism underlying inhibition of the GSK phosphorylation towards beta-catenin and activation of the pathway after biding of Wnt ligand to its cognate receptors at the plasma membrane remains unclear. Wnt target genes are widely spread over several animal phyla. They participate in a plethora of functions during the development of an organism, from axial specification, gastrulation and organogenesis all the way to regeneration and repair in adults. Temporal and spatial oncogenetic re-activation of Wnt signaling almost certainly leads to cancer. Wnt signaling components have been extensively studied as possible targets in anti-cancer therapies. In this review we will discuss one of the most intriguing questions in this field, that is how beta-catenin, a major component in this pathway, escapes the destruction complex, gets stabilized in the cytosol and it is translocated to the nucleus where it acts as a co transcription factor. Four major models have evolved during the past 20years. We dissected each of them along with current views and future perspectives on this pathway. This review will focus on the molecular mechanisms by which Wnt proteins modulate beta-catenin cytoplasmic levels and the relevance of this pathway for the development and cancer. PMID- 28844869 TI - What is the optimal anatomic location for coronary artery pressure measurement at CT-derived FFR? AB - BACKGROUND: CT-FFR is an area of growing interest in the field of cardiac imaging. However, the specific anatomic location distal to a lesion of interest where CT-FFR should be computed to yield the most valid results has not been examined. This study investigated the most appropriate anatomic location distal to a coronary artery stenosis for obtaining CT-FFR measurements. METHODS: 73 patients (60 +/- 9 years; 58% male) with at least one coronary lesion with 40-90% stenosis on coronary CTA (either a 2 * 128 slice or a 2 * 192 slice dual-source CT scanner) underwent stress cardiac magnetic resonance (CMR) perfusion imaging for inducible ischemia. 133 coronary arteries and corresponding myocardial territories were analyzed. The most appropriate anatomic location for predicting lesion-specific ischemia via CT-FFR (cFFR version 1.4, Siemens) was determined as either the distance from the lesion of interest or as a multiple of the reference vessel diameter distal to the minimum lumen area (MLA). RESULTS: Inducible myocardial ischemia was found on MRI in 24 (18.1%) vessels/corresponding myocardial territories. The area under the ROC curve was A) 0.866 for CT-FFR measurement locations distal to the MLA expressed as a multiple of the reference diameter, B) 0.854 when expressed as a distance (mm) distal to the MLA, C) 0.803 for CT-FFR values measured in the distal vessel, and D) 0.725 according to stenosis severity on coronary CTA (A vs B p = 0.093; A vs D p = 0.003; A vs C p = 0.019; B vs D p = 0.006; B vs C p = 0.061; C vs D p = 0.082). The most optimal thresholds for agreement of CT-FFR with the reference CMR perfusion were at 41 mm or 10.9 times the proximal reference diameter distal to the MLA. CONCLUSIONS: Our results suggest that the best agreement of CT-FFR with the reference CMR perfusion study is provided when CT-FFR values are computed at 41 mm or 10.9 times the proximal reference diameter distal to the MLA. PMID- 28844870 TI - Phoenixin-14 injected intracerebroventricularly but not intraperitoneally stimulates food intake in rats. AB - Phoenixin, a recently discovered 20-amino acid peptide was implicated in reproduction. However, the expression in food intake-regulatory nuclei such as the paraventricular nucleus, the arcuate nucleus and the nucleus of the solitary tract suggests an implication of phoenixin in food intake regulation. Therefore, we investigated the effects of phoenixin-14, the shorter form of phoenixin, on food intake following intracerebroventricular (icv) and intraperitoneal (ip) injection in ad libitum fed male Sprague-Dawley rats. Phoenixin-14 injected icv (0.2, 1.7 or 15nmol/rat) during the light phase induced a dose-dependent increase of light phase food intake reaching significance at a minimum dose of 1.7 nmol/rat (+72%, p<0.05 vs. vehicle) used for all further analyses. Assessment of the food intake microstructure showed an icv phoenixin-14-induced increase in meal size (+51%), meal duration (+157%), time spent in meals (+182%) and eating rate (+123%), while inter-meal intervals (-42%) and the satiety ratio (-64%) were decreased compared to vehicle (p<0.05). When injected icv during the dark phase, no modulation of food intake was observed (p>0.05). The light phase icv phoenixin 14-induced increase of water intake did not reach statistical significance compared to vehicle (+136%, p>0.05). The increase of food intake following icv phoenixin-14 was not associated with a significant alteration of grooming behavior (0.4-fold, p=0.377) or locomotion (6-fold, p=0.066) compared to vehicle. When injected ip at higher doses (0.6, 5nmol/kg or 45nmol/kg body weight) during the light phase, phoenixin-14 did not affect food intake (p>0.05). In summary, phoenixin-14 exerts a centrally-mediated orexigenic effect. PMID- 28844871 TI - Emerging role of amyloid beta in stress response: Implication for depression and diabetes. AB - Chronic stress is considered a widely accepted risk factor for the development of neuropsychiatric and neurological disorders. Indeed, high cortisol levels, and, thus, hypothalamic pituitary adrenal (HPA)-axis dysregulation, have been indicated as the most frequent alteration in patients affected by depression, as well as by Alzheimer's disease (AD). Furthermore, depressive state has been pointed as an early manifestation of AD, advocating an overlap between these neuropathological events. We have previously demonstrated that central soluble beta amyloid 1-42 (Abeta) administration peptide induces a depressive like behavior in rats, with altered HPA axis activation, reduced cortical serotonin and neurotrophin levels. The crucial role of Abeta in stress response is becoming more and more evident, indeed many reports indicate that its release is increased in stressful conditions and stress-based paradigm. Furthermore, it has been reported that stress controls Abeta production and/or clearance. Chronic stress is responsible of inducing neuroinflammation processes and reduced serotoninergic tone, both pathophysiological mechanisms proposed in the association of depression with another chronic disease, such as diabetes. Likewise, AD has also been indicated as type 3 diabetes, considering the large body of literature that suggests common biological bases. Thus, the main aim of the present review is to evaluate the most recent literature findings in humans and animal models in regard to the role of Abeta in stress response and in relation to the biological substrates and pathological pathways common to AD and comorbid diseases, such as depression and diabetes. PMID- 28844872 TI - Losartan protects against cerebral ischemia/reperfusion-induced apoptosis through beta-arrestin1-mediated phosphorylation of Akt. AB - Losartan, an angiotensin (Ang) II type 1 receptor blocker (ARB), has been revealed to protect against cerebral ischemia/reperfusion (I/R) injury. However, the mechanism by which losartan protect brain ischemia injury is still obscure. In this study, we investigated whether losartan protected against cerebral I/R injury by reducing apoptosis and the possible signaling pathways. Wistar rats were pretreated for 14 days with 5mg/kg losartan, and then subjected to middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion. Meanwhile, PC12 cells pretreated with losartan were exposed to oxygen-glucose deprivation reoxygenation (OGD/R), an in vitro model of cerebral ischemia. Our results showed that administration of losartan significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the protein level of cleaved caspase-3, cytochrom C and Bax, and increasing the level of Bcl-2 both in vivo and in vitro. Moreover, losartan treatment markedly enhanced the phosphorylation of Akt and blockade of PI3K activity by wortmannin dramatically inhibited Akt phosphorylation and attenuated the anti-apoptotic effect of losartan. Furthermore, pretreatment with losartan significantly increased the protein level of beta-arrestin1 and silence of beta-arrestin1 by siRNA partly attenuated losartan-induced anti-apoptotic effect and the phosphorylation of Akt. These results suggested that beta-arrestin1 modulated the activation of Akt in losartan induced anti-apoptotic effect in cerebral I/R. Our data would provide a new molecular basis for further understanding of protective effect of losartan in cerebral I/R injury and may provide benefits of using losartan in the treatment of cerebrovascular disease. PMID- 28844873 TI - Tobacco's minor alkaloids: Effects on place conditioning and nucleus accumbens dopamine release in adult and adolescent rats. AB - Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8mg/kg), cotinine (0.5-5.0mg/kg), anatabine (0.5 5.0mg/kg), and myosmine (5.0-20.0mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not adolescents. The dopamine release results were not related to place conditioning, as nicotine and cotinine had no effect on place conditioning, whereas anatabine and myosmine produced aversion in both ages. While the nucleus accumbens shell is hypothesized to play a role in strengthening drug-context associations following initiation of drug use, it may have little involvement in the motivational effects of tobacco constituents once these associations have been acquired. Effects of myosmine and anatabine on dopamine release may require a fully developed dopamine system, since no effects of these tobacco alkaloids were observed during adolescence. In summary, while anatabine and myosmine-induced dopamine release in nucleus accumbens may play a role in tobacco dependence in adults, the nature of that role remains to be elucidated. PMID- 28844875 TI - Challenging Patients: An International Perspective. PMID- 28844874 TI - Cannabinoid CB1 receptor inverse agonist MJ08 stimulates glucose production via hepatic sympathetic innervation in rats. AB - As a key insulin target tissue for maintaining systemic glucose homeostasis, the liver plays important roles in improving obesity-associated insulin intolerance via selective cannabinoid CB1 receptor antagonism/inverse agonism. However, it is unclear whether this receptor inverse agonism affects hepatic glucose metabolism. MJ08 is a novel cannabinoid CB1 receptor antagonist/inverse agonist that has superior inverse agonism over the well-known antagonist/inverse agonist, SR141716 (rimonabant). MJ08 remarkably elevates fasting blood glucose independent of inhibition of insulin release in mice. In the current study, MJ08 was used to investigate the mechanism by which liver cannabinoid CB1 receptor inverse activation regulates hepatic glucose metabolism. MJ08 stimulated hepatic glucose production (HGP) in a dose-dependent manner and promoted gluconeogenic gene expression in perfused rat liver. SR141716 exhibited similar but weaker effects. The cannabinoid CB1 receptor agonist (WIN 55,212-2), Gs protein-cyclic AMP (cAMP) dependent pathway inhibitors (NF449 and H89), beta-adrenoceptor antagonist (propranolol), and peripheral sympathetic inhibitor (reserpine) could antagonize MJ08-induced HGP. Furthermore, MJ08 and SR141716 induced monoamine neurotransmitter (noradrenaline) release and increased cAMP content significantly in perfused liver, although only a slight increase was observed in primary cultured hepatocytes. These results indicate that local liver cannabinoid CB1 receptor inverse agonism via hepatic sympathetic innervation is responsible for the HGP induced by MJ08. Thus, high inverse agonistic activity could increase fasting blood glucose levels and should be avoided in the development of peripheral cannabinoid CB1 receptor-targeted weight-loss drugs. PMID- 28844876 TI - "The stakes are so high": interviews with progressive journalists reporting on abortion. AB - OBJECTIVES: Because news frames can influence public and policy agendas, proponents of abortion access should be concerned with how this issue is covered in the news. While previous research has examined the content of news on abortion, this analysis explores the process of newsmaking on abortion, examining how journalists understand their role in and experience of covering abortion. STUDY DESIGN: We recruited journalists with experience reporting on abortion through listservs for progressive and feminist reporters. Thirty-one participants, with experiences at 75 diverse media outlets, completed in-depth, open-ended interviews. We used grounded theory to code interview transcripts in Dedoose to identity emergent themes. RESULTS: Journalists described many challenges that applied to reporting generally, but that they perceived to be more difficult around abortion: grappling with the meaning of "neutrality" on this issue, finding new angles for articles, and handling editors with varying knowledge of abortion. Over one-third (n=13) of participants mentioned feeling that the stakes were higher around abortion: this urgency and polarization left journalists frustrated by efforts to find new sources or angles on abortion stories. Finally, over 80% (n=28) of participants reported experiencing anti abortion harassment as a result of their abortion work. CONCLUSIONS: The difficulties journalists described when reporting on abortion were often rooted in abortion stigma and the political polarization around the issue. This pattern was true even for reporters who worked to counter abortion stigma through their reporting. IMPLICATIONS: Advocates interested in accurate, destigmatizing news frames might work pro-actively to educate editors and increase reporters' access to providers, patients, and advocates. PMID- 28844877 TI - Postpartum care and contraception provided to women with gestational and preconception diabetes in California's Medicaid program. AB - OBJECTIVES: To compare rates of postpartum care and contraception provided to women with gestational or preconception diabetes mellitus to women with no known diabetes mellitus. METHODS: A retrospective cohort study of 199,860 women aged 15 44 years who were continuously enrolled in California's Medicaid program, Medi Cal, from 43 days prior to 99 days after delivering in 2012. Claims for postpartum clinic visits and contraceptive supplies were compared for 11,494 mothers with preconception diabetes, 17,970 mothers with gestational diabetes, and 170,396 mothers without diabetes. Multivariable logistic regression was used to control for maternal age, race/ethnicity, primary language, residence in a primary care shortage area, state-funded healthcare program and Cesarean delivery, when examining the effects of diabetes on postpartum care and contraception. RESULTS: Although postpartum clinic visits were more common with diabetes (55% preconception, 55% gestational, 48% no diabetes, p=<.0001), almost half did not receive any postpartum care within 99 days of delivery. Women with pregnancies complicated by diabetes were more likely to receive permanent contraception than women without diabetes (preconception diabetes, aOR: 1.39, 95% CI: 1.31-1.47; gestational diabetes, aOR: 1.20, 95% CI: 1.14-1.27). However, among women without permanent contraception, less than half received any reversible contraception within 99 days of delivery (44% preconception, 43% gestational, 43% no diabetes) and less effective, barrier contraceptives were more commonly provided to women with preconception diabetes than women without diabetes (aOR: 1.24, 95% CI:1.16-1.33). CONCLUSIONS: Low-income Californian women with pregnancies complicated by diabetes do not consistently receive postpartum care or contraception that may prevent complication of future pregnancies. IMPLICATIONS: Efforts are needed to improve rates of provision of postpartum care and high quality contraceptive services to low income women in California, particularly following pregnancies complicated by diabetes. PMID- 28844878 TI - Overcoming barriers to levonorgestrel-releasing intrauterine system placement: an evaluation of placement of LNG-IUS 8 using the modified EvoInserter(r) in a majority nulliparous population. AB - OBJECTIVES: To report placement success rate, and ease and pain associated with placement, of the levonorgestrel-releasing intrauterine system (LNG-IUS) 8 using the modified EvoInserter(r) placement device. STUDY DESIGN: This was a pooled analysis using data from three previously reported Phase III studies in nulliparous (83.3%) or parous (16.7%) women aged 12-35 years (N=965). LNG-IUS 8 was placed using the modified Evolnserter(r). The main outcomes assessed were placement success, ease of placement as reported by healthcare professionals (HCPs), pain at placement as reported by participants, and assessment of the EvoInserter(r) placement device by HCPs. RESULTS: LNG-IUS 8 placement using the modified EvoInserter(r) with an insertion tube diameter of 3.8 mm was successful in 99.5% of subjects. HCPs rated the placement procedure as "easy" in 91.6% of cases. Placement pain was reported as absent by 19.1% of participants, as mild by 39.3%, as moderate by 31.6%, and as severe by 10.0%. Overall 89.2% of HCPs completely agreed that the device was easy to prepare and 85.7% completely agreed that placement of an LNG-IUS was easy/simple with the EvoInserter(r). Post hoc exploratory analyses indicated a significant association between ease/pain of placement and patient age and between pain of placement and parity. CONCLUSIONS: The modified Evolnserter(r) was associated with a high placement success rate, ease of placement, and manageable pain, and was assessed to have a user-friendly design. These findings suggest that the EvoInserter(r) may remove some concerns among HCPs about difficult placement of LNG-IUSs, thereby encouraging increased uptake of an effective contraceptive. IMPLICATIONS STATEMENT: Results reported in this study further strengthen evidence of the high placement success rate, ease of deployment, and manageable pain associated with the modified EvoInserter(r) placement device. These findings might reduce concerns among HCPs about placement of LNG-IUSs, meaning uptake of such contraceptives is increased. PMID- 28844879 TI - Creatine Fuels the Thermic Effect of Feeding. AB - The current obesity epidemic has focused a great deal of attention on cellular pathways of energy expenditure. While a crucial part of this process is diet induced thermogenesis, the underlying mechanisms have remained unexplained. In this issue of Cell Metabolism, Kazak et al. (2017) describe a new thermogenic pathway in adipocytes that responds to diet overload, involving creatine cycling. These data suggest that this pathway might limit weight gain during overnutrition. PMID- 28844880 TI - The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity. AB - Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor beta-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21 CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT. PMID- 28844881 TI - Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. AB - Diet-induced thermogenesis is an important homeostatic mechanism that limits weight gain in response to caloric excess and contributes to the relative stability of body weight in most individuals. We previously demonstrated that creatine enhances energy expenditure through stimulation of mitochondrial ATP turnover, but the physiological role and importance of creatine energetics in adipose tissue have not been explored. Here, we have inactivated the first and rate-limiting enzyme of creatine biosynthesis, glycine amidinotransferase (GATM), selectively in fat (Adipo-Gatm KO). Adipo-Gatm KO mice are prone to diet-induced obesity due to the suppression of elevated energy expenditure that occurs in response to high-calorie feeding. This is paralleled by a blunted capacity for beta3-adrenergic activation of metabolic rate, which is rescued by dietary creatine supplementation. These results provide strong in vivo genetic support for a role of GATM and creatine metabolism in energy expenditure, diet-induced thermogenesis, and defense against diet-induced obesity. PMID- 28844882 TI - The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity. AB - Obesity is a key risk factor for metabolic and cardiovascular diseases, and although we understand the mechanisms regulating weight and energy balance, the causes of some forms of obesity remain enigmatic. Despite the well-established connections between lymphatics and lipids, and the fact that intestinal lacteals play key roles in dietary fat absorption, the function of the lymphatic vasculature in adipose metabolism has only recently been recognized. It is well established that angiogenesis is tightly associated with the outgrowth of adipose tissue, as expanding adipose tissue requires increased nutrient supply from blood vessels. Results supporting a crosstalk between lymphatic vessels and adipose tissue, and linking lymphatic function with metabolic diseases, obesity, and adipose tissue, also started to accumulate in the last years. Here we review our current knowledge of the mechanisms by which defective lymphatics contribute to obesity and fat accumulation in mouse models, as well as our understanding of the lymphatic-adipose tissue relationship. PMID- 28844883 TI - Heavy metal tolerance traits of filamentous fungi isolated from gold and gemstone mining sites. AB - Increased environmental pollution has necessitated the need for eco-friendly clean-up strategies. Filamentous fungal species from gold and gemstone mine site soils were isolated, identified and assessed for their tolerance to varied heavy metal concentrations of cadmium (Cd), copper (Cu), lead (Pb), arsenic (As) and iron (Fe). The identities of the fungal strains were determined based on the internal transcribed spacer 1 and 2 (ITS 1 and ITS 2) regions. Mycelia growth of the fungal strains were subjected to a range of (0-100 Cd), (0-1000 Cu), (0-400 Pb), (0-500 As) and (0-800 Fe) concentrations (mgkg-1) incorporated into malt extract agar (MEA) in triplicates. Fungal radial growths were recorded every three days over a 13-days' incubation period. Fungal strains were identified as Fomitopsis meliae, Trichoderma ghanense and Rhizopus microsporus. All test fungal exhibited tolerance to Cu, Pb, and Fe at all test concentrations (400-1000mgkg 1), not differing significantly (p>0.05) from the controls and with tolerance index >1. T. ghanense and R. microsporus demonstrated exceptional capacity for Cd and As concentrations, while showing no significant (p>0.05) difference compared to the controls and with a tolerance index >1 at 25mgkg-1 Cd and 125mgkg-1 As. Remarkably, these fungal strains showed tolerance to metal concentrations exceeding globally permissible limits for contaminated soils. It is envisaged that this metal tolerance trait exhibited by these fungal strains may indicate their potentials as effective agents for bioremediative clean-up of heavy metal polluted environments. PMID- 28844884 TI - Effect of sulfonylurea tribenuron methyl herbicide on soil Actinobacteria growth and characterization of resistant strains. AB - Repeated application of pesticides disturbs microbial communities and cause dysfunctions on soil biological processes. Granstar(r) 75 DF is one of the most used sulfonylurea herbicides on cereal crops; it contains 75% of tribenuron methyl. Assessing the changes on soil microbiota, particularly on the most abundant bacterial groups, will be a useful approach to determine the impact of Granstar(r) herbicide. For this purpose, we analyzed Actinobacteria, which are known for their diversity, abundance, and aptitude to resist to xenobiotic substances. Using a selective medium for Actinobacteria, 42 strains were isolated from both untreated and Granstar(r) treated soils. The number of isolates recovered from the treated agricultural soil was fewer than that isolated from the corresponding untreated soil, suggesting a negative effect of Granstar(r) herbicide on Actinobacteria community. Even so, the number of strains isolated from untreated and treated forest soil was quite similar. Among the isolates, resistant strains, tolerating high doses of Granstar(r) ranging from 0.3 to 0.6% (v/v), were obtained. The two most resistant strains (SRK12 and SRK17) were isolated from treated soils showing the importance of prior exposure to herbicides for bacterial adaptation. SRK12 and SRK17 strains showed different morphological features. The phylogenetic analysis, based on 16S rRNA gene sequencing, clustered the SRK12 strain with four Streptomyces type strains (S. vinaceusdrappus, S. mutabilis, S. ghanaensis and S. enissocaesilis), while SRK17 strain was closely related to Streptomyces africanus. Both strains were unable to grow on tribenuron methyl as unique source of carbon, despite its advanced dissipation. On the other hand, when glucose was added to tribenuron methyl, the bacterial development was evident with even an improvement of the tribenuron methyl degradation. In all cases, as tribenuron methyl disappeared, two compounds were detected with increased concentrations. These by-products appeared to be persistent and were not degraded either chemically or by the studied strains. Based on these observations, we suggested that bacterial activity on carbon substrates could be directly involved in the partial breakdown of tribenuron methyl, by generating the required acidity for the first step of the hydrolysis. Such a process would be interesting to consider in bioremediation of neutral and alkaline tribenuron methyl-polluted soils. PMID- 28844885 TI - Glioma progression through the prism of heat shock protein mediated extracellular matrix remodeling and epithelial to mesenchymal transition. AB - Glial tumor is one of the intrinsic brain tumors with high migratory and infiltrative potential. This essentially contributes to the overall poor prognosis by circumvention of conventional treatment regimen in glioma. The underlying mechanism in gliomagenesis is bestowed by two processes- Extracellular matrix (ECM) Remodeling and Epithelial to mesenchymal transition (EMT). Heat Shock Family of proteins (HSPs), commonly known as "molecular chaperons" are documented to be upregulated in glioma. A positive correlation also exists between elevated expression of HSPs and invasive capacity of glial tumor. HSPs overexpression leads to mutational changes in glioma, which ultimately drive cells towards EMT, ECM modification, malignancy and invasion. Differential expression of HSPs - a factor providing cytoprotection to glioma cells, also contributes towards its radioresistance /chemoresistance. Various evidences also display upregulation of EMT and ECM markers by various heat shock inducing proteins e.g. HSF-1. The aim of this review is to study in detail the role of HSPs in EMT and ECM leading to radioresistance/chemoresistance of glioma cells. The existing treatment regimen for glioma could be enhanced by targeting HSPs through immunotherapy, miRNA and exosome mediated strategies. This could be envisaged by better understanding of molecular mechanisms underlying glial tumorigenesis in relation to EMT and ECM remodeling under HSPs influence. Our review might showcase fresh potential for the development of next generation therapeutics for effective glioma management. PMID- 28844886 TI - A Brucella Type IV Effector Targets the COG Tethering Complex to Remodel Host Secretory Traffic and Promote Intracellular Replication. AB - Many intracellular pathogens exploit host secretory trafficking to support their intracellular cycle, but knowledge of these pathogenic processes is limited. The bacterium Brucella abortus uses a type IV secretion system (VirB T4SS) to generate a replication-permissive Brucella-containing vacuole (rBCV) derived from the host ER, a process that requires host early secretory trafficking. Here we show that the VirB T4SS effector BspB contributes to rBCV biogenesis and Brucella replication by interacting with the conserved oligomeric Golgi (COG) tethering complex, a major coordinator of Golgi vesicular trafficking, thus remodeling Golgi membrane traffic and redirecting Golgi-derived vesicles to the BCV. Altogether, these findings demonstrate that Brucella modulates COG-dependent trafficking via delivery of a T4SS effector to promote rBCV biogenesis and intracellular proliferation, providing mechanistic insight into how bacterial exploitation of host secretory functions promotes pathogenesis. PMID- 28844887 TI - Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption. AB - Choline is an essential nutrient and methyl donor required for epigenetic regulation. Here, we assessed the impact of gut microbial choline metabolism on bacterial fitness and host biology by engineering a microbial community that lacks a single choline-utilizing enzyme. Our results indicate that choline utilizing bacteria compete with the host for this nutrient, significantly impacting plasma and hepatic levels of methyl-donor metabolites and recapitulating biochemical signatures of choline deficiency. Mice harboring high levels of choline-consuming bacteria showed increased susceptibility to metabolic disease in the context of a high-fat diet. Furthermore, bacterially induced reduction of methyl-donor availability influenced global DNA methylation patterns in both adult mice and their offspring and engendered behavioral alterations. Our results reveal an underappreciated effect of bacterial choline metabolism on host metabolism, epigenetics, and behavior. This work suggests that interpersonal differences in microbial metabolism should be considered when determining optimal nutrient intake requirements. PMID- 28844889 TI - Aiding sleep in type 2 diabetes: therapeutic considerations. AB - Insomnia and obstructive sleep apnoea (OSA) are more prevalent in patients with type 2 diabetes than in the general population. Both insomnia and OSA have been linked to cardiometabolic alterations (eg, hypertension, increased activity of the sympathetic nervous system, and systemic insulin resistance) that can exacerbate the pathophysiology of type 2 diabetes. Improvement of sleep in patients with diabetes could therefore aid the treatment of diabetes. To help health practitioners choose the best clinical tool to improve their patients' sleep without detrimentally affecting glucose regulation, this Review critically analyses the effects of common treatments for insomnia and OSA on both sleep and glucose metabolism in patients with type 2 diabetes. These treatments include pharmaceutical sleep aids (eg, benzodiazepine receptor agonists, melatonin) and cognitive behavioural therapy for insomnia, continuous positive airway pressure for OSA, and lifestyle interventions. PMID- 28844890 TI - Functional subdivisions of the hypothalamus using areal parcellation and their signal changes related to glucose metabolism. AB - The hypothalamus consists of numerous nuclei, and is regarded as the highest center for various autonomic functions. Although each hypothalamic nucleus implements a distinct function, it remains difficult to investigate the human hypothalamus at the nucleus level. In the present high-resolution functional MRI study, we utilized areal parcellation to discriminate individual nuclei in the human hypothalamus based on areal profiles of resting-state functional connectivity. The areal parcellation detected ten foci that were expected to represent hypothalamic nuclei, and the locations of the foci were consistent with those of the hypothalamic nuclei identified in previous histological studies. Regions of interest (ROI) analyses revealed contrasting brain activity changes following glucose ingestion: decrease in the ventromedial hypothalamic nucleus and increase in the lateral hypothalamic area in parallel with blood glucose increase. Moreover, decreased brain activity in the arcuate nucleus predicted future elevation of blood insulin during the first 10 min after glucose ingestion. These results suggest that the hypothalamic nuclei can putatively be determined using areal parcellation, and that the ROI analysis of the human hypothalamic nuclei is useful for future scientific and clinical investigations into the autonomic functions. PMID- 28844888 TI - An Oxidative Central Metabolism Enables Salmonella to Utilize Microbiota-Derived Succinate. AB - The mucosal inflammatory response induced by Salmonella serovar Typhimurium creates a favorable niche for this gut pathogen. Conventional wisdom holds that S. Typhimurium undergoes an incomplete tricarboxylic acid (TCA) cycle in the anaerobic mammalian gut. One change during S. Typhimurium-induced inflammation is the production of oxidized compounds by infiltrating neutrophils. We show that inflammation-derived electron acceptors induce a complete, oxidative TCA cycle in S. Typhimurium, allowing the bacteria to compete with the microbiota for colonization. A complete TCA cycle facilitates utilization of the microbiota derived fermentation product succinate as a carbon source. S. Typhimurium succinate utilization genes contribute to efficient colonization in conventionally raised mice, but provide no growth advantage in germ-free mice. Mono-association of gnotobiotic mice with Bacteroides, a major succinate producer, restores succinate utilization in S. Typhimurium. Thus, oxidative central metabolism enables S. Typhimurium to utilize a variety of carbon sources, including microbiota-derived succinate. PMID- 28844891 TI - Implementing the Academy of Nutrition and Dietetics Benchmarks for Nutrition Education for Children: Child-Care Providers' Perspectives. AB - BACKGROUND: National childhood obesity prevention policies recommend that child care providers educate young children about nutrition to improve their nutrition knowledge and eating habits. Yet, the provision of nutrition education (NE) to children in child-care settings is limited. OBJECTIVE: Using the 2011 Academy of Nutrition and Dietetics benchmarks for NE in child care as a guiding framework, researchers assessed child-care providers' perspectives regarding delivery of NE through books, posters, mealtime conversations, hands-on learning, and sensory exploration of foods to young children (aged 2 to 5 years). DESIGN: Using a qualitative design (realist method), individual, semistructured interviews were conducted until saturation was reached. PARTICIPANTS/SETTING: The study was conducted during 2012-2013 and used purposive sampling to select providers. Final sample included 18 providers employed full-time in Head Start or state-licensed center-based child-care programs in Central Illinois. MAIN OUTCOME MEASURE: Child care providers' perspectives regarding implementation of NE. STATISTICAL ANALYSES PERFORMED: Thematic analysis to derive themes using NVivo software. RESULTS: Three overarching themes emerged, including providers' motivators, barriers, and facilitators for delivering NE to children. Motivators for delivering NE included that NE encourages children to try new foods, NE improves children's knowledge of healthy and unhealthy foods, and NE is consistent with children's tendency for exploration. Barriers for delivering NE included that limited funding and resources for hands-on experiences and restrictive policies. Facilitators for delivering NE included providers obtain access to feasible, low-cost resources and community partners, providers work around restrictive policies to accommodate NE, and mealtime conversations are a feasible avenue to deliver NE. Providers integrated mealtime conversations with NE concepts such as food-based sensory exploration and health benefits of foods. CONCLUSIONS: Present study findings offer insights regarding providers' perspectives on implementing NE in child care. Drawing from these perspectives, registered dietitian nutritionists can train providers about the importance of NE for encouraging healthy eating in children, integrating NE with mealtime conversations, and practicing low-cost, hands-on NE activities that meet the food safety standards for state licensing. Such strategies may improve providers' ability to deliver NE in child-care settings. PMID- 28844892 TI - Susceptibility of contemporary single-bottle self-etch dentine adhesives to intrinsic water permeation. AB - OBJECTIVES: To evaluate the effect of intrinsic water permeation on the microtensile bond strengths of different adhesive systems to dentine and the quality of resin-dentine interfaces. METHODS: Ninety-six non-carious human third molars were divided into 4 groups: Clearfil S3 Bond Plus (CSBP; Kuraray); Clearfil S3 Bond (C3S; Kuraray); iBond Self-Etch (IB; Heraeus-Kulzer) and Prime&Bond NT (PB, control etch-and-rinse adhesive, Dentply-Sirona). For each adhesive, specimens from one subgroup (N=10) were bonded using zero pulpal pressure, while specimens from the other subgroup (N=10) were bonded using 15cm water pressure (PP). Each bonded tooth was sectioned into 1*1mm sticks and stressed to failure. Data were analysed using two-way ANOVA and Holm-Sidak pairwise comparisons to examine the effects of "adhesive", "pulpal pressure" and their interaction on bond strength (alpha=0.05). Representative fractured sticks were examined by SEM. The remaining tooth slabs in each subgroup were used for TEM and CLSM. RESULTS: Microtensile bond strengths (mean+/-SD; in MPa) were: 33.4+/-6.9 (CSBP), 33.2+/-4.7 (CSBP-PP), 35.0+/-8.6 (C3S), 25.5+/-7.3 (C3S-PP), 18.4+/-4.0 (IB), 16.5+/-6.9 (IB-PP), 28.2+/-5.5 (PB), 20.5+/-7.2 (PB-PP). "Adhesive-type" (P<0.001), "pulpal-pressure" (P<0.001) and their interactions (P<0.001) significantly affected bond strength results. No difference between no PP and PP subgroups was found for CSBP and IB (P>0.05). Water droplets were identified along the resin-dentine interface for IB, IB-PP and C3S-PP. CONCLUSION: IB exhibits water sensitivity when bonding is performed with/without pulpal pressure. C3S exhibits water sensitivity when bonding is performed with pulpal pressure. CSBP does not exhibit water sensitivity when bonding is performed with/without pulpal pressure. CLINICAL SIGNIFICANCE: Intrinsic water permeation during bonding procedures significantly affects bond strength results and the resin-dentine interface of contemporary single-bottle self-etch dentine adhesive systems. PMID- 28844893 TI - Tandem affinity purification of exosome and replication factor C complexes from the non-human infectious kinetoplastid parasite Crithidia fasciculata. AB - Kinetoplastid parasites are responsible for a range of diseases with significant global impact. Trypanosoma brucei and Trypanosoma cruzi cause human African trypanosomiasis and Chagas disease, respectively, while various Leishmania species are responsible for cutaneous, mucocutaneous and visceral leishmaniasis. Understanding the biology of these organisms is key for effective diagnosis, prophylaxis and treatment. The insect parasite Crithidia fasciculata offers a safe and low-cost alternative for studies of kinetoplastid biology. C. fasciculata does not infect humans, can be cultured to high yields in inexpensive serum-free medium in a standard laboratory, and has a completely sequenced publically available genome. Taking advantage of these features, however, requires the adaptation of existing methods of analysis to C. fasciculata. Tandem affinity purification is a widely used method that allows for the rapid purification of intact protein complexes under native conditions. Here we report the application of tandem affinity purification to C. fasciculata for the first time, demonstrating the effectiveness of the technique by purifying both the intact exosome and replication factor C complexes. Adding tandem affinity purification to the C. fasciculata toolbox significantly enhances the utility of this excellent model system. PMID- 28844894 TI - HLA gene and haplotype frequencies in a Nagaybaks population from the Chelyabinsk Region (Russian South Urals). AB - A total of 112 Nagaybaks, a Turkic ethnoconfessional group living mainly in the Nagaybak district of the Chelyabinsk Region of Russian South Urals, were genotyped for HLA-A, -B, -DRB1, -DQA1 and -DQB1 loci using PCR-SSP (low resolution) and HLA-A29 (high-resolution). All loci were in Hardy-Weinberg equilibrium (all p values >0.1 thus showing no locus-level deviations. The genotype data are available in the Allele Frequencies Net Database under the population name ''Russia, South Ural, Chelyabinsk Region, Nagaybaks" and the identifier AFND0003397. PMID- 28844895 TI - The suitability of common compressibility equations for characterizing plasticity of diverse powders. AB - The analysis of powder compressibility data yields useful information for characterizing compaction behavior and mechanical properties of powders, especially plasticity. Among the many compressibility equations proposed in powder compaction research, the Heckel equation and the Kawakita equation are the most commonly used, despite their known limitations. Systematic evaluation of the performance in analyzing compressibility data suggested the Kuentz-Leuenberger equation is superior to both the Heckel equation and the Kawakita equation for characterizing plasticity of powders exhibiting a wide range of mechanical properties. PMID- 28844896 TI - Expedited development of a high dose orally disintegrating metformin tablet enabled by sweet salt formation with acesulfame. AB - Salt formation has been extensively used to improve drug properties, including solubility, stability and mechanical properties. A sweet salt of metformin with acesulfame, prepared though an anion exchange reaction, showed superior properties over the commercial hydrochloride salt. These included both remarkable improvement of taste and significant enhancement in tabletability, which is explained by the different crystal structures and lower hardness as measured by nanoindentation. The relationship among crystal structure, mechanical properties and tabletability was rationalized through an energy framework analysis. This approach led to the successful development of an orally disintegrating tablet product containing 60% of metformin-acesulfame salt by direct compaction. PMID- 28844897 TI - Assessment of swallowability and palatability of oral dosage forms in children: Report from an M-CERSI pediatric formulation workshop. AB - The acceptability of pediatric pharmaceutical products to patients and their caregivers can have a profound impact on the resulting therapeutic outcome. However, existing methodology and approaches used for acceptability assessments for pediatric products is fragmented, making robust and consistent product evaluations difficult. A pediatric formulation development workshop took place in Washington, DC in June 2016 through the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI). A session at the workshop was dedicated to acceptability assessments and focused on two major elements that affect the overall acceptability of oral medicines, namely swallowability and palatability. The session started with presentations to provide an overview of literature, background and current state on swallowability and palatability assessments. Five parallel breakout discussions followed the presentations on each element, focusing on three overarching themes, risk-based approaches, methodology and product factors. This article reports the key outcomes of the workshop related to swallowability and palatability assessments. PMID- 28844898 TI - Scale-up of water-based spider silk film casting using a film applicator. AB - Spider silk proteins for applications in drug delivery have attracted an increased interest during the past years. Some possible future medical applications for this biocompatible and biodegradable material are scaffolds for tissue engineering, implantable drug delivery systems and coatings for implants. Recently, we reported on the preparation of water-based spider silk films for drug delivery applications. In the current study, we describe the development of a manufacturing technique for casting larger spider silk films from aqueous solution employing a film applicator. Films were characterized in terms of morphology, water solubility, protein secondary structure, thermal stability, and mechanical properties. Different post-treatments were evaluated (phosphate ions, ethanol, steam sterilization and water vapor) to increase the content of beta sheets thereby achieving water insolubility of the films. Finally, the mechanical properties of the spider silk films were improved by incorporating 2-pyrrolidone as plasticizer. PMID- 28844899 TI - Integrated hot-melt extrusion - injection molding continuous tablet manufacturing platform: Effects of critical process parameters and formulation attributes on product robustness and dimensional stability. AB - This study provides a framework for robust tablet development using an integrated hot-melt extrusion-injection molding (IM) continuous manufacturing platform. Griseofulvin, maltodextrin, xylitol and lactose were employed as drug, carrier, plasticizer and reinforcing agent respectively. A pre-blended drug-excipient mixture was fed from a loss-in-weight feeder to a twin-screw extruder. The extrudate was subsequently injected directly into the integrated IM unit and molded into tablets. Tablets were stored in different storage conditions up to 20 weeks to monitor physical stability and were evaluated by polarized light microscopy, DSC, SEM, XRD and dissolution analysis. Optimized injection pressure provided robust tablet formulations. Tablets manufactured at low and high injection pressures exhibited the flaws of sink marks and flashing respectively. Higher solidification temperature during IM process reduced the thermal induced residual stress and prevented chipping and cracking issues. Polarized light microscopy revealed a homogeneous dispersion of crystalline griseofulvin in an amorphous matrix. DSC underpinned the effect of high tablet residual moisture on maltodextrin-xylitol phase separation that resulted in dimensional instability. Tablets with low residual moisture demonstrated long term dimensional stability. This study serves as a model for IM tablet formulations for mechanistic understanding of critical process parameters and formulation attributes required for optimal product performance. PMID- 28844901 TI - Impact of Eudragit EPO and hydroxypropyl methylcellulose on drug release rate, supersaturation, precipitation outcome and redissolution rate of indomethacin amorphous solid dispersions. AB - The purpose of this work was to evaluate the impact of polymer(s) on the dissolution rate, supersaturation and precipitation of indomethacin amorphous solid dispersions (ASD), and to understand the link between precipitate characteristics and redissolution kinetics. The crystalline and amorphous solubilities of indomethacin were determined in the absence and presence of hydroxypropylmethyl cellulose (HPMC) and/or Eudragit (r) EPO to establish relevant phase boundaries. At acidic pH, HPMC could maintain supersaturation of the drug by effectively inhibiting solution crystallization while EPO increased both the crystalline and amorphous solubility of the drug, but did not inhibit crystallization. The HPMC dispersion dissolved relatively slowly without undergoing crystallization while the supersaturation generated by rapid dissolution of the EPO ASD was short-lived due to crystallization. The crystals thus generated underwent rapid redissolution upon pH increase, dissolving faster than the reference crystalline material, and at a comparable rate to the amorphous HPMC dispersion. A ternary dispersion containing both EPO and HPMC dissolved rapidly, generating an apparent drug concentration that exceeded the amorphous solubility of indomethacin, leading to the formation of a new nanosized droplet phase. These nanodroplets dissolved virtually immediately when the pH was increased. In conclusion, the concentration-time profiles achieved from indomethacin ASD dissolution are a complex interplay of drug release rate, precipitation kinetics and outcome, and precipitate redissolution rate, whereby each of these processes is highly dependent on the polymer(s) employed in the formulation. PMID- 28844900 TI - Targeting energy metabolism of cancer cells: Combined administration of NCL-240 and 2-DG. AB - Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2 deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL 240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive and resistant strains of A2780 cells treated with combinations of NCL-240/2-DG pointed to a G0/G1 phase arrest for 80-90% of the total, indicating an inability to grow and divide. Cytotoxicity studies with in vitro cancer cell monolayer models confirmed the results of cell cycle analysis. Significant improvements in cytotoxicity with combination treatments over control and individual treatments were seen in multiple cell lines. NCI/ADR-RES cancer cell spheroids further demonstrated the effectiveness of a NCL-240/2-DG combination. PMID- 28844902 TI - The in vivo transformation and pharmacokinetic properties of a liquid crystalline drug delivery system. AB - A liquid crystalline (LC) system, composed of phosphatidylcholine, sorbitan monoleate, and tocopherol acetate, was investigated to understand the in vivo transformation after subcutaneous injection, coupled with the physicochemical and pharmacokinetic properties of the formulation. The rat model was utilized to monitor a pseudo-time course transformation from a precursor LC formulation to the LC matrix, coupled with the blood concentration profiles of the formulations containing leuprolide acetate. Three formulations that result in the HII phase, demonstrating dissimilar in vitro release profiles, were used. The formulation showing the highest AUC, Cmax and Tmax, also displayed the greatest release rate in vitro, the lowest viscosity (LC matrix), and an earlier transformation (LC precursor to matrix) in vivo. A potential link between viscosity, phase transformation, and drug release properties of a liquid crystalline system is described. PMID- 28844903 TI - Increasing the affinity of cationized polyacrylamide-paclitaxel nanoparticles towards colon cancer cells by a surface recognition peptide. AB - Nanoparticles of cationized polyacrylamide (CPAA NP), decorated with the recognition peptide VRPMPLQ (to produce CPAA-Pep NP), were prepared, characterized and tested biologically. They were designed to target dysplasia regions in the colon, characterized by overexpressed sialic acid. This targetability was augmented by the addition of VRPMPLQ. Their mean hydrodynamic size was 137nm with narrow size distribution and positive zeta potential. When incubated with three types of colon cancer cells, a 10-fold increase in the cell's uptake was found for the CPAA-Pep NP compared with the CPAA NP. The use of a scrambled sequence of the VRPMPLQ peptide and competition studies, employing excess of the free peptide verified the specific nature of the NP cellular uptake. Nanoparticles loaded with paclitaxel with and without VRPMPLQ indicated an improved pro-apoptotic activity of the CPAA-Pep NP. It is speculated that both positive charge and the presence of VRPMPLQ could serve as an improved strategy to deliver nanoparticles loaded with cytotoxic drugs for the treatment of colon cancer. PMID- 28844904 TI - Germ cell cysts and simultaneous sperm and oocyte production in a hermaphroditic nematode. AB - Studies of gamete development in the self-fertile hermaphrodites of Caenorhabditis elegans have significantly contributed to our understanding of fundamental developmental mechanisms. However, evolutionary transitions from outcrossing males and females to self-fertile hermaphrodites have convergently evolved within multiple nematode sub-lineages, and whether the C. elegans pattern of self-fertile hermaphroditism and gamete development is representative remains largely unexplored. Here we describe a pattern of sperm production in the trioecious (male/female/hermaphrodite) nematode Rhabditis sp. SB347 (recently named Auanema rhodensis) that differs from C. elegans in two striking ways. First, while C. elegans hermaphrodites make a one-time switch from sperm to oocyte production, R. sp. SB347 hermaphrodites continuously produce both sperm and oocytes. Secondly, while C. elegans germ cell proliferation is limited to germline stem cells (GSCs), sperm production in R. sp. SB347 includes an additional population of mitotically dividing cells that are a developmental intermediate between GSCs and fully differentiated spermatocytes. These cells are present in males and hermaphrodites but not females, and exhibit key characteristics of spermatogonia - the mitotic progenitors of spermatocytes in flies and vertebrates. Specifically, they exist outside the stem cell niche, increase germ cell numbers by transit-amplifying divisions, and synchronously proliferate within germ cell cysts. We also discovered spermatogonia in other trioecious Rhabditis species, but not in the male/female species Rhabditis axei or the more distant hermaphroditic Oscheius tipulae. The discovery of simultaneous hermaphroditism and spermatogonia in a lab-cultivatable nematode suggests R. sp. SB347 as a richly informative species for comparative studies of gametogenesis. PMID- 28844905 TI - Arginyltransferase ATE1 is targeted to the neuronal growth cones and regulates neurite outgrowth during brain development. AB - Arginylation is an emerging protein modification mediated by arginyltransferase ATE1, shown to regulate embryogenesis and actin cytoskeleton, however its functions in different physiological systems are not well understood. Here we analyzed the role of ATE1 in brain development and neuronal growth by producing a conditional mouse knockout with Ate1 deletion in the nervous system driven by Nestin promoter (Nes-Ate1 mice). These mice were weaker than wild type, resulting in low postnatal survival rates, and had abnormalities in the brain that suggested defects in neuronal migration. Cultured Ate1 knockout neurons showed a reduction in the neurite outgrowth and the levels of doublecortin and F-actin in the growth cones. In wild type, ATE1 prominently localized to the growth cones, in addition to the cell bodies. Examination of the Ate1 mRNA sequence reveals the existence of putative zipcode-binding sequences involved in mRNA targeting to the cell periphery and local translation at the growth cones. Fluorescence in situ hybridization showed that Ate1 mRNA localized to the tips of the growth cones, likely due to zipcode-mediated targeting, and this localization coincided with spots of localization of arginylated beta-actin, which disappeared in the presence of protein synthesis inhibitors. We propose that zipcode-mediated co targeting of Ate1 and beta-actin mRNA leads to localized co-translational arginylation of beta-actin that drives the growth cone migration and neurite outgrowth. PMID- 28844906 TI - Selection originating from protein stability/foldability: Relationships between protein folding free energy, sequence ensemble, and fitness. AB - Assuming that mutation and fixation processes are reversible Markov processes, we prove that the equilibrium ensemble of sequences obeys a Boltzmann distribution with exp(4Nem(1-1/(2N))), where m is Malthusian fitness and Ne and N are effective and actual population sizes. On the other hand, the probability distribution of sequences with maximum entropy that satisfies a given amino acid composition at each site and a given pairwise amino acid frequency at each site pair is a Boltzmann distribution with exp(-psiN), where the evolutionary statistical energy psiN is represented as the sum of one body (h) (compositional) and pairwise (J) (covariational) interactions over all sites and site pairs. A protein folding theory based on the random energy model (REM) indicates that the equilibrium ensemble of natural protein sequences is well represented by a canonical ensemble characterized by exp(-DeltaGND/kBTs) or by exp(-GN/kBTs) if an amino acid composition is kept constant, where DeltaGND=GN-GD,GN and GD are the native and denatured free energies, and Ts is the effective temperature representing the strength of selection pressure. Thus, 4Nem(1-1/(2N)), DeltapsiND(=-psiN+psiD), and -DeltaGND/kBTs must be equivalent to each other. With h and J estimated by the DCA program, the changes (DeltapsiN) of psiN due to single nucleotide nonsynonymous substitutions are analyzed. The results indicate that the standard deviation of DeltaGN(=kBTsDeltapsiN) is approximately constant irrespective of protein families, and therefore can be used to estimate the relative value of Ts. Glass transition temperature Tg and DeltaGND are estimated from estimated Ts and experimental melting temperature (Tm) for 14 protein domains. The estimates of DeltaGND agree with their experimental values for 5 proteins, and those of Ts and Tg are all within a reasonable range. In addition, approximating the probability density function (PDF) of DeltapsiN by a log-normal distribution, PDFs of DeltapsiN and Ka/Ks, which is the ratio of nonsynonymous to synonymous substitution rate per site, in all and in fixed mutants are estimated. The equilibrium values of psiN, at which the average of Deltapsi in fixed mutants is equal to zero, well match psiN averaged over homologous sequences, confirming that the present methods for a fixation process of mutations and for the equilibrium ensemble of psiN give a consistent result with each other. The PDFs of Ka/Ks at equilibrium confirm that Ts negatively correlates with the amino acid substitution rate (the mean of Ka/Ks) of protein. Interestingly, stabilizing mutations are significantly fixed by positive selection, and balance with destabilizing mutations fixed by random drift, although most of them are removed from population. Supporting the nearly neutral theory, neutral selection is not significant even in fixed mutants. PMID- 28844907 TI - Effect of different stent configurations using Lattice Boltzmann method and particles image velocimetry on artery bifurcation aneurysm problem. AB - Proper design of stent for application at specific aneurysm effect arteries could help to reduce the issues with thrombosis and aneurysm. In this paper, four types of stent configuration namely half-Y (6 mm), half-Y (4 mm), cross-bar, and full-Y configuration will implanted on real 3D artery bifurcation aneurysm effected arteries. Comparisons were then conducted based on the flow patterns after stent placement using both LBM-based solver and PIV experimental findings. According to the data obtained from all 4 stent designs, the flow profiles and the computed velocity from both methods were in agreement with each other. Both methods found that half-Y (6 mm) stent configuration is by far the best configuration in reducing the blood velocity at the vicinity of the aneurysm sac. The analysis also show that the half-Y (6 mm) stent configuration recorded the highest percentage of velocity reduction and managed to substantially reduce the pressure at the bifurcation region. This high flow velocity reduction through the use of half-Y stent could consequently promote the formation of thrombus thereby reducing the risk of rupture in the aneurysm sac. PMID- 28844908 TI - Differential regulation of the duplicated fabp7, fabp10 and fabp11 genes of zebrafish by peroxisome proliferator activated receptors. AB - In the duplication-degeneration-complementation model, duplicated gene-pairs undergo nonfunctionalization (loss from the genome), subfunctionalization (the functions of the ancestral gene are sub-divided between duplicate genes), or neofunctionalization (one of the duplicate genes acquires a new function). These processes occur by loss or gain of regulatory elements in gene promoters. Fatty acid-binding proteins (Fabp) belong to a multigene family composed of orthologous proteins that are highly conserved in sequence and function, but differ in their gene regulation. We previously reported that the zebrafish fabp1a, fabp1b.1, and fabp1b.2 promoters underwent subfunctionalization of PPAR responsiveness. Here, we describe the regulation at the duplicated zebrafish fabp7a/fabp7b, fabp10a/fabp10b and fabp11a/fabp11b gene promoters. Differential control at the duplicated fabp promoters was assessed by DNA sequence analysis, responsiveness to PPAR-isoform specific agonists and NF-kappaB p50 antagonists in zebrafish liver and intestine explant tissue, and in HEK293A cells transfected with fabp promoter-reporter constructs. Each zebrafish fabp gene displayed unique transcriptional regulation compared to its paralogous duplicate. This work provides a framework to account for the evolutionary trajectories that led to the high retention (57%) of duplicated fabp genes in the zebrafish genome compared to only ~3% of all duplicated genes in the zebrafish genome. PMID- 28844909 TI - Regression of Pineal Lesions: Spontaneous or Iatrogenic? A Case Report and Systematic Literature Review. AB - BACKGROUND: Tumors arising from the pineal region account for approximately 1% of intracranial neoplasms. We present a case of a previously healthy 5-year-old boy with an acute onset of headache. A magnetic resonance imaging (MRI) scan showed a pineal mass with aqueduct compression. The patient was scheduled for tumor resection. An endoscopic third ventriculostomy was performed in advance for the treatment of hydrocephalus. Afterwards, MRI showed a relevant regression of the pineal mass without specific treatment. Consequently, surgery was cancelled and further MRI follow-up showed a regression of the mass and a constant tumor mass over a period of 30 months. Spontaneous regression of malignant tumors is a rare phenomenon with an incidence of 1 of 60,000-100,000 cases. Only a few cases with spontaneous regression of pineal tumors have been reported. METHODS: We performed a systematic literature review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines on spontaneously regressing pineal lesions and found 13 cases in the literature. RESULTS: Six hypotheses for explaining tumor regression were found, comprising treatment with steroids, effects of diagnostic irradiation, treatment of hydrocephalus, pineal apoplexy, surgical trauma, and immunologic mechanisms. None of these mechanisms was evidentiary. However, in all reported cases, some kind of treatment (e.g. treatment of hydrocephalus, application of steroids, and so on) has been performed before tumor regression. CONCLUSIONS: The clinician has to bear in mind that regression of pineal tumors might be triggered by use of steroids, for example, and in cases of improvement of the patient's presenting symptoms, new MRI scans should be performed. PMID- 28844910 TI - A Retrospective Study of Thoracolumbar Fractures Treated with Fixation and Nonfusion Surgery of Intravertebral Bone Graft Assisted with Balloon Kyphoplasty. AB - BACKGROUND: Posterior fixation and fusion is the primary treatment for thoracolumbar fractures, although this treatment may sacrifice range of motion (ROM) to achieve stability, rather than treating the fracture itself. Two issues addressed when treating thoracolumbar fractures are 1) replacing the fractured vertebrae, especially the upper end plate of the injured vertebrae and 2) providing strong fixation with biomechanical stability and flexibility. METHODS: This retrospective study included 61 consecutive patients with thoracic or lumbar fractures treated from October 2010 to May 2014. Patients were divided into 1 of 2 groups: group A, intravertebral bone graft with balloon kyphoplasty (nonfusion surgery), and group B, traditional posterior fixation and fusion surgery. The visual analog scale was used preoperatively and at 3 months, 1 year, and 2 years. Radiography, computed tomography, and magnetic resonance imaging were performed preoperatively. Radiography was performed postoperatively at 3 months and 2 years. At 3 months after surgery, computed tomography was used to confirm healing of the vertebral fracture. RESULTS: All fractures in both groups were reduced successfully, and deformities were improved. After the removal of hardware in group A, ROM at the injury level recovered, and at 2 years, there was no loss of vertebral height or recurrence of deformity. There was no hardware failure in group A, but there was evidence of screw loosening in 3 screws in group B. CONCLUSIONS: Nonfusion treatment of intravertebral bone graft assisted with balloon kyphoplasty showed good fracture reduction, deformity correction, fracture healing, and ROM maintenance. There were no complications associated with the implant. PMID- 28844911 TI - Endovascular Mechanical Thrombectomy for Acute Middle Cerebral Artery M2 Segment Occlusion: A Systematic Review. AB - INTRODUCTION: The benefit of endovascular mechanical thrombectomy (EMT) for acute distal occlusions of the middle cerebral artery M2 segment is incompletely defined. The aim of this systematic review is to analyze the recent literature regarding EMT for acute M2 occlusions. METHODS: We reviewed the literature to identify all studies of patients with acute M2 occlusions who underwent EMT that were published after January 1, 2015. Excellent and good outcomes were defined as modified Rankin Scale score of 0-1 and 0-2, respectively, at 3 months. Successful reperfusion was defined as modified Thrombolysis In Cerebral Infarction (mTICI) score of 2b-3. RESULTS: Eight studies, comprising 630 EMT-treated patients with acute M2 occlusions, were included in the analysis. The median National Institute of Health Stroke Scale score ranged from 10 to 16, and the median Alberta Stroke Program Computed Tomography Score ranged from 9 to 10. Excellent and good outcomes at 3-month follow-up were observed in 40% and 62%, respectively, of patients with acute M2 occlusion who underwent EMT, with a mortality of 11%. Successful reperfusion was achieved in 78% of cases. Postprocedural intracerebral hemorrhage (ICH) occurred in 14% of patients, including a symptomatic ICH rate of 5%. CONCLUSIONS: EMT for acute M2 occlusion affords functional independence to most patients, with a modest rate of symptomatic ICH. However, compared with the natural history of distal MCA occlusions, the benefit of M2 thrombectomy using stent retriever or direct aspiration techniques remains unclear. PMID- 28844912 TI - Relevance of Postoperative Magnetic Resonance Images in Evaluating Epidural Hematoma After Thoracic Fixation Surgery. AB - BACKGROUND: It is difficult to evaluate the significant findings of epidural hematoma in magnetic resonance images (MRIs) obtained immediately after thoracic posterior screw fixation (PSF). METHODS: Prospectively, immediate postoperative MRI was performed in 10 patients who underwent thoracic PSF from April to December 2013. Additionally, we retrospectively analyzed the MRIs from 3 patients before hematoma evacuation out of 260 patients who underwent thoracic PSF from January 2000 to March 2013. RESULTS: The MRI findings of 9 out of the 10 patients, consecutively collected after thoracic PSF, showed neurologic recovery with a well-preserved cerebrospinal fluid (CSF) space and no prominent hemorrhage. Even though there were metal artifacts at the level of the pedicle screws, the preserved CSF space was observed. In contrast, the MRI of 1 patient with poor neurologic outcome demonstrated a typical hematoma and slight spinal cord compression and reduced CSF space. In the retrospective analysis of the 3 patients who showed definite motor weakness in the lower extremities after their first thoracic fusion surgery and underwent hematoma evacuation, the magnetic resonance images before hematoma evacuation also revealed hematoma compressing the spinal cord and diminished CSF space. CONCLUSIONS: This study shows that epidural hematomas can be detected on MRI performed immediately after thoracic fixation surgery, despite metal artifacts and findings such as hematoma causing spinal cord compression. Loss of CSF space should be considered to be associated with neurologic deficit. PMID- 28844913 TI - Analysis of Predictors and Probability of Aneurysm Occlusion in the Internal Carotid Artery After Treatment with Pipeline Embolization Device. AB - BACKGROUND: Although the Pipeline Embolization Device (PED) has proved to be an excellent option for internal carotid artery (ICA) aneurysms, the rate of occlusion remains difficult to predict and factors associated with aneurysm occlusion are not well elucidated. This study aimed to investigate predictors and the rate of occlusion for aneurysms along the ICA. METHODS: A total of 117 saccular ICA aneurysms treated with the PED were studied. Occlusion rates were divided among 4 groups: group A [lesions >10 mm in the proximal ICA (petrous to the superior hypophyseal segments)]; group B (lesions <10 mm in the proximal ICA); group C [lesions >10mm in the distal ICA (posterior communicating segment to the ICA bifurcation)]; and group D (lesions <10 mm in the distal ICA). Predictors of aneurysm occlusion were entered into a multivariate Cox regression analysis. RESULTS: The median time to aneurysm occlusion was 8 months in group A (95% confidence interval [CI], 7.0-9.1), 5.2 months in group B (95% CI, 4.5-6.0), 6.9 months in group C (95% CI, 6.5-7.2), and 10.2 months in group D (95% CI, 6.9 13.6) (P = 0.045). There was a statistically significant difference between the probability of aneurysm occlusion in group B compared with distal ICA aneurysms (P = 0.02). Small proximal ICA aneurysms were more likely to occlude over time compared with other aneurysm groups (hazard ratio, 1.76; 95% CI, 1.07-2.9; P = 0.02). CONCLUSIONS: The rate of occlusion after PED is highest for small proximal ICA aneurysms and the probability of occlusion is lower for distal ICA aneurysms. PMID- 28844914 TI - Comparison of the Total and Hidden Blood Loss in Patients Undergoing Open and Minimally Invasive Transforaminal Lumbar Interbody Fusion. AB - PURPOSE: This study examined the volume of hidden blood loss (HBL) and compared perioperative blood loss between minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) and open transforaminal lumbar interbody fusion (O TLIF). METHODS: Forty-eight patients who were treated with MI-TLIF and 59 patients treated with O-TLIF were enrolled in this study. Patients' height, weight, and preoperative and postoperative hematocrit (Hct) were recorded and used to calculate total blood loss (TBL) according to the Gross formula. Each patient's HBL was calculated. The data were further analyzed by the Student t test and the chi2 test. RESULTS: The visible blood loss (VBL) was 186 +/- 95 mL in the MI-TLIF; however, the HBL (423 +/- 233 mL; 66.5 +/- 16.1% of TBL) was twice the VBL. The VBL in the O-TLIF group was 471 +/- 147 mL, and the HBL was 271 +/- 223 mL (31.3 +/- 23.9% of TBL). Although TBL in MI-TLIF (602 +/- 251 mL) was less than in O-TLIF (742 +/- 275 mL), the HBL was significantly higher (P < 0.01). No difference in postoperative blood loss was observed between the 2 groups. Seven and 10 patients had preoperative anemia in the MI-TLIF group and the O-TLIF group, respectively, and 32 and 45 postoperatively. CONCLUSION: HBL is seriously underestimated and accounts for a large percentage of TBL in both MI TLIF and O-TLIF. A correct understanding of HBL can ensure patient safety and improve postoperative rehabilitation. PMID- 28844915 TI - Moyamoya Disease in an 8-Year-Old Boy: Direct Bypass Surgery in a Province of Peru. AB - BACKGROUND: Pediatric moyamoya cases may be very arduous, even more so in a developing country, where access to specialized centers may be prevented by different factors. CASE DESCRIPTION: Herein we report a challenging case, which was managed in the new Neurosurgical Center of Trujillo, regarding the direct anastomosis between the left superficial temporal artery and a cortical branch of the left middle cerebral artery in a 8-year-old Peruvian boy with moyamoya disease. Postoperatively, the patient's motor deficits and aphasia improved. To the best of our knowledge, this is the first performance of a direct revascularization for a pediatric moyamoya case in Peru. CONCLUSIONS: The creation of highly specialized neurosurgical centers in the main strategic places of developing countries may allow optimal treatment of neurosurgical patients with complex diseases. PMID- 28844916 TI - Long-Term Outcomes of Surgical Treatment in 181 Patients with Supratentorial Cerebral Cavernous Malformation-Associated Epilepsy. AB - OBJECTIVE: To evaluate the efficacy of surgery as a treatment for supratentorial cerebral cavernous malformation-associated epilepsy (SCCMAE) and determine the factors that influence outcomes. METHODS: During the 5-year period from 2005 to 2009, this study included 181 consecutive patients who were diagnosed with SCCMAE and surgically treated in a single institution. Each patient was followed up for at least 5 years postoperatively. A time-to-event analysis was performed using Kaplan-Meier curves and Cox regression models to evaluate the associated risk factors. RESULTS: The age at seizure onset was 30.6 +/- 14.3 years, and the age at the time of surgery was 33.4 +/- 14.6 years. The female/male ratio was 0.81:1. The mean diameter of the cerebral cavernous malformations (CCMs) was 2.0 cm. For CCMs involving eloquent brain areas, the CCM was removed with (in 14 cases) or without (in 28 lesions) the peripheral hemosiderin. None of the patients had long term neurologic disabilities. An Engel class I outcome was achieved in 89.0%, 83.4%, 81.8%, and 80.1% of the patients after 6 months, 1 year, 2.5 years, and 5 years of follow-up, respectively. In patients who were class I after 1 year, the prevalence of seizure remission 5 years postoperatively was 96.0% (95% confidence interval, 94.4%-97.6%). CONCLUSIONS: This study supports the efficacy of using surgery to treat SCCMAE. A shorter duration of preoperative epilepsy was associated with better seizure control after surgery, and patient status at the 1 year follow-up was a reliable indicator of long-term Engel class I epilepsy control. PMID- 28844917 TI - Clinical Investigation of Refractory Chronic Subdural Hematoma: A Comparison of Clinical Factors Between Single and Repeated Recurrences. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is sometimes refractory, and this is troublesome for neurosurgeons. Although many studies have reported risk factors or treatments in efforts to prevent recurrence, those have focused on single recurrence, and few cumulative data are available to analyze refractory CSDH. METHODS: We defined refractory CSDH as >=2 recurrences, then analyzed and compared clinical factors between patients with single recurrence and those with refractory CSDH in a cohort study, to clarify whether patients with refractory CSDH experience different or more risk factors than patients with single recurrence, and whether burr-hole irrigation with closed-system drainage reduces refractory CSDH. RESULTS: Seventy-five patients had at least 1 recurrence, with single recurrence in 62 patients and >=2 recurrences in 13 patients. In comparing clinical characteristics, patients with refractory CSDH were significantly younger (P = 0.04) and showed shorter interval to first recurrence (P < 0.001). Organized CSDH was also significantly associated with refractory CSDH (P = 0.02). Multivariate logistic regression analysis identified first recurrence interval <1 month (odds ratio, 6.66, P < 0.001) and age <71 years (odds ratio, 4.16, P < 0.001) as independent risk factors for refractory CSDH. On the other hand, burr hole irrigation with closed-system drainage did not reduce refractory CSDH. CONCLUSIONS: When patients with risk factors for refractory CSDH experience recurrence, alternative surgical procedures may be considered as the second surgery, because burr-hole irrigation with closed-system drainage did not reduce refractory CSDH in our study. PMID- 28844918 TI - Risk Factors of Postoperative Low Back Pain for Low-Grade Degenerative Spondylolisthesis: An At Least 2-Year Follow-Up Retrospective Study. AB - OBJECTIVE: A retrospective study was conducted to clarify the risk factors of postoperative low back pain (LBP) for low-grade degenerative spondylolisthesis. PATIENTS AND METHODS: A total of 239 patients who underwent posterior lumbar fusion between January 2011 and January 2015 were included in this analysis. We investigated patient characteristics, surgical characteristics, and radiographic characteristics. RESULTS: The mean visual analog scale (VAS) score of LBP decreased dramatically after the operation. The mean preoperative VAS score was greater in patients with severe lumbar multifidus (LM) intramuscular adipose tissue (IMAT). The postoperative VAS score was dramatically lower in patients with shorter symptom duration. Postoperative LBP disappeared more often in patients with shorter symptom duration. LBP VAS changing showed significant differences in different symptom duration groups and LM IMAT groups. CONCLUSIONS: LM IMAT and symptom duration were risk factors for postoperative LBP. Patients with severe LM IMAT reported more severe LBP before the operation. Postoperative LBP disappeared more often in patients with shorter symptom duration. PMID- 28844919 TI - Guidewire Breakage During Cavernous Sinus Sampling: A Rare Complication and Its Treatment. AB - BACKGROUND: Venous sampling methods are valuable tools for the diagnosis of pituitary adenomas. However, these interventions also have complications, which may complicate the treatment process. CASE DESCRIPTION: A 49-year-old female pituitary adenoma patient with preliminary diagnosis of Cushing disease underwent cavernous sinus sampling (CSS) to delineate the adenoma. The microguidewire broke during the procedure, and the distal part of the microguidewire had to be left within the right cavernous sinus. Eventually, the broken part of the guidewire was removed after the removal of the tumor through an endoscopic endonasal approach. CONCLUSIONS: Current surgical experience on endoscopic skull base surgery allows management of diagnostic complications related to the cavernous sinus, such as safe access to materials which were inadvertently left during CSS, without the necessity for further interventions. PMID- 28844920 TI - Reappraisal of Pediatric Diastatic Skull Fractures in the 3-Dimensional CT Era: Clinical Characteristics and Comparison of Diagnostic Accuracy of Simple Skull X Ray, 2-Dimensional CT, and 3-Dimensional CT. AB - BACKGROUND: Diastatic skull fractures (DSFs) in children are difficult to detect in skull radiographs before they develop into growing skull fractures; therefore, little information is available on this topic. However, recent advances in 3 dimensional (3D) computed tomography (CT) imaging technology have enabled more accurate diagnoses of almost all forms of skull fracture. The present study was undertaken to document the clinical characteristics of DSFs in children and to determine whether 3D CT enhances diagnostic accuracy. METHODS: Two hundred and ninety-two children younger than 12 years with skull fractures underwent simple skull radiography, 2-dimensional (2D) CT, and 3DCT. Results were compared with respect to fracture type, location, associated lesions, and accuracy of diagnosis. RESULTS: DSFs were diagnosed in 44 (15.7%) of children with skull fractures. Twenty-two patients had DSFs only, and the other 22 had DSFs combined with compound or mixed skull fractures. The most common fracture locations were the occipitomastoid (25%) and lambdoid (15.9%). Accompanying lesions consisted of subgaleal hemorrhages (42/44), epidural hemorrhages (32/44), pneumocephalus (17/44), and subdural hemorrhages (3/44). A total of 17 surgical procedures were performed on 15 of the 44 patients. Fourteen and 19 patients were confirmed to have DSFs by skull radiography and 2D CT, respectively, but 3D CT detected DSFs in 43 of the 44 children (P < 0.001). CONCLUSION: 3D CT was found to be markedly superior to skull radiography or 2D CT for detecting DSFs. This finding indicates that 3D CT should be used routinely rather than 2D CT for the assessment of pediatric head trauma. PMID- 28844921 TI - Spinal Coccidioidomycosis: A Current Review of Diagnosis and Management. AB - OBJECTIVE: Coccidioidomycosis is an invasive fungal disease that may present with extrathoracic dissemination. Patients with spinal coccidioidomycosis require unique medical and surgical management. We review the risk factors and clinical presentations, discuss the indications for surgical intervention, and evaluate outcomes and complications after medical and surgical management. METHODS: A review of the English-language literature was performed. Eighteen articles included the management of 140 patients with spinal coccidioidomycosis. RESULTS: For the 140 patients, risk factors included male sex (95%), African American ethnicity (52%), and a recent visit to endemic areas (16%). The most frequent clinical presentation was pain (n = 80, 57%), followed by neurologic compression (52%). One-third of patients had concurrent pulmonary disease. The sensitivity of culture and histology for coccidioidomycosis was 80% and 90%, respectively. Complement fixation titers >1:128 suggest extensive or refractory vertebral infection. The most commonly affected spinal segments were the thoracic and lumbar spine (69%); an additional 40 patients (29%) had epidural and paravertebral abscesses. All patients received therapy with azoles (60%) and/or amphotericin B (43%). Surgical and medical management were used conjunctively to treat 110 patients (79%), with debridement (95% [105/110]) and fusion (64% [70/110]) being the most common surgical procedures. Clinical outcome improved/remained unchanged in 83 patients (59%) and worsened in 4 patients (3%). The mortality was 7%. Infection recurrence and disease progression were the most frequent complications. CONCLUSIONS: Emphasis should be placed on continuous and lifelong appropriate azole therapy. Spinal instability and neurologic compromise are surgical indications for decompression and fusion. PMID- 28844922 TI - Relationship Between Clot Quality and Microguidewire Configuration During Endovascular Thrombectomy for Acute Ischemic Stroke. AB - BACKGROUND: Although endovascular approaches for acute ischemic stroke have been developed, the appropriate selection and sequence of device application or other treatments is unclear. If information about the clot quality can be obtained before the selection of devices, fast recanalization with a suitable device and strategy can be achieved. We studied the relationship between clot quality and the configuration of a microguidewire during endovascular thrombectomy. METHODS: This prospective single-center study included all patients who were admitted for acute ischemic stroke between October 2015 and June 2017 and underwent emergency endovascular thrombectomy. We used a modified pigtail-shaped microguidewire to penetrate clots. The configurations under radiograph were distinguished into 2 types and assessed according to collected clot appearance and quality. RESULTS: A total of 54 patients underwent acute endovascular thrombectomy. When the tip of the microguidewire became stuck against a clot during penetration, the clot was solid and hard, with statistical significance (P = 0.013). CONCLUSIONS: Our results showed that we can select a suitable device and strategy for fast recanalization according to information about clot quality obtained using the modified pigtail-shaped microguidewire. PMID- 28844923 TI - Posttraumatic Uncal Herniation in a Conscious Patient. AB - The incidence of primary traumatic oculomotor nerve palsies in craniocerebral trauma is approximately 1.2% and is usually persistent and associated with loss of consciousness, other neurologic deficits, and skull base or orbital fractures. This case is a rare demonstration of complete left third nerve palsy from uncal herniation after trauma without any loss of consciousness. PMID- 28844924 TI - It Is Time to Reduce Free-Hand Manipulation: Case Report of Our Proposal for an Innovative 1-Step Cranioplasty. AB - BACKGROUND: Cranioplasty is a well-known procedure, and autologous graft bone is usually considered the best choice in this procedure, but it cannot be used in conditions such as bone-infiltrating tumors, spheno-orbital en plaque meningiomas, and bone infections. Polymethylmethacrylate (PMMA) offers great possibility of intraoperative adaption. We describe a case of 1-step cranioplasty performed in a patient with a meningeal fibrosarcoma using a custom-made silicon mold. CASE DESCRIPTION: A 48-year-old man was admitted to our department for a left temporo-parietal subcutaneous tumefaction that grew for a few months on the site of a previous osteodural decompression. After a biopsy that was diagnostic for meningeal fibrosarcoma, we planned tumor asportation, considering the bone infiltration of the tumor and the necessity of a cranioplasty. Before the intervention, we performed the craniotomy on a gypsum powder head phantom created based on a computed tomography scan. Then, using a computer-assisted design technique, a silicon mold was created and sterilized for the intervention. The edges of the preoperative simulated craniectomy were reproduced during the intervention using a rigid rail on the patient's scalp. The craniectomy was performed, and the tumor was removed. Then, a PMMA bone flap was made using a silicon mold and was fixed to the skull by miniscrews. Aesthetic results were considered excellent by the patient. CONCLUSIONS: We performed a 1-step cranioplasty after resection of a meningeal fibrosarcoma that infiltrated bone with a new technique to reproduce during intervention a preoperative simulated craniectomy and a computer-assisted design PMMA flap. PMID- 28844925 TI - Multimodal 18F-Fluciclovine PET/MRI and Ultrasound-Guided Neurosurgery of an Anaplastic Oligodendroglioma. AB - BACKGROUND: Structural magnetic resonance imaging (MRI) and histopathologic tissue sampling are routinely performed as part of the diagnostic workup for patients with glioma. Because of the heterogeneous nature of gliomas, there is a risk of undergrading caused by histopathologic sampling errors. MRI has limitations in identifying tumor grade and type, detecting diffuse invasive growth, and separating recurrences from treatment induced changes. Positron emission tomography (PET) can provide quantitative information of cellular activity and metabolism, and may therefore complement MRI. In this report, we present the first patient with brain glioma examined with simultaneous PET/MRI using the amino acid tracer 18F-fluciclovine (18F-FACBC) for intraoperative image guided surgery. CASE DESCRIPTION: A previously healthy 60-year old woman was admitted to the emergency care with speech difficulties and a mild left-sided hemiparesis. MRI revealed a tumor that was suggestive of glioma. Before surgery, the patient underwent a simultaneous PET/MRI examination. Fused PET/MRI, T1, FLAIR, and intraoperative three-dimensional ultrasound images were used to guide histopathologic tissue sampling and surgical resection. Navigated, image-guided histopathologic samples were compared with PET/MRI image data to assess the additional value of the PET acquisition. Histopathologic analysis showed anaplastic oligodendroglioma in the most malignant parts of the tumor, while several regions were World Health Organization (WHO) grade II. CONCLUSIONS: 18F Fluciclovine uptake was found in parts of the tumor where regional WHO grade, cell proliferation, and cell densities were highest. This finding suggests that PET/MRI with this tracer could be used to improve accuracy in histopathologic tissue sampling and grading, and possibly for guiding treatments targeting the most malignant part of extensive and eloquent gliomas. PMID- 28844926 TI - An Unusual Combination of Mirror-Image Dextrocardia with Familial Medulloblastoma: Is There a Histogenetic Relationship? AB - BACKGROUND: The occurrence of medulloblastoma in the absence of hereditary syndromes is rare. Dextrocardia with situs inversus is also called mirror-image dextrocardia. A combination of mirror-image dextrocardia with medulloblastoma has not been reported previously. To the best of our knowledge, this is the first report of this rare combination in a family with medulloblastoma. METHODS: The clinical manifestation, radiographic characteristics, treatment, and outcomes of 3 medulloblastoma cases in 2 cousins and their maternal uncle was described. Tumor samples of the 2 cousins were first examined for histologic subtypes. Total RNA of their tumors was extracted from formalin-fixed and paraffin-embedded samples. Then, expression of 22 subgroup-specific genes and 3 housekeeping genes was analyzed by the NanoString nCounter Analysis System. The posttest data were normalized by NanoStringNorm package for molecular subgroup prediction. RESULTS: The proband remains tumor free and alive up to the latest follow-up. His cousin, who had combined mirror-image dextrocardia with situs inversus, died of anoxia after surgery and his uncle died of tumor 2.5 years after surgery. Medulloblastoma of the 2 cousins was classified as classic and molecular group 4 subtype. CONCLUSIONS: The same classic and molecular group 4 subtype of the 2 cousins may suggest a similar genetic predisposition. Involvement of the Otx2 gene dysfunction in both group 4 subtype medulloblastoma and mirror-image dextrocardia with situs inversus points to a possible mechanism that dysfunction of a shared signaling pathway such as Otx2 might be the underlying cause of these 2 conditions in this family. PMID- 28844927 TI - Skull Metastasis from the Liver: Case Report and Literature Review. AB - BACKGROUND: Calvarial metastasis from liver cirrhosis in the absence of a primary focus is exceptionally rare. Few reports of metastases from hepatocellular carcinoma of an unknown primary focus have been published. CASE DESCRIPTION: A 66 year-old man with a history of Schistosoma japonicum infection presented to our hospital with a mass over the left occipital region associated with headache and dizziness. Imaging revealed a 6 * 5-cm lesion supplied principally by the left occipital artery. The metastatic tumor was removed via super-selective embolization and craniotomy. Pathology revealed that circulating tumor cells from the liver had metastasized to the calvaria. Postoperatively, no primary foci was found over 9 months of follow-up. CONCLUSIONS: A calvarial mass may be an initial manifestation of hepatocellular carcinoma. Early diagnosis is important. A calvarial metastasis from the liver, although very rare, should be included in the differential diagnosis of a patient with both cirrhosis and skull mass. PMID- 28844928 TI - Angiomatous Meningiomas Have a Very Benign Outcome Despite Frequent Peritumoral Edema at Onset. AB - OBJECTIVE: Angiomatous meningioma (AM) is a rare subtype of meningioma characterized by highly vascular tumor tissue comprising predominantly variable sized hyalinized blood vessels. The aim of this study is to evaluate the clinical radiologic features of AM and the long-term prognosis in a single neurosurgical center. METHODS: A total of 93 patients who underwent surgical resection of AMs between 2003 and 2008 were enrolled for analysis. Clinical information, treatment, and radiologic images were collected and analyzed; follow-up was carried out as well. Expression of estrogen receptor, progesterone receptor, and vascular endothelial growth factor was analyzed by immunohistochemistry. RESULTS: Forty-eight females and 45 males were identified. Forty-four patients (47.31%) manifested as hypersignal in T1-weighted imaging sequences and 68 (73.12%) as hypersignal in T2-weighted imaging, and a characteristic ringlike signal was observed in 28 patients (30.11%). Eighty-one cases (87.10%) showed different degrees of peritumor brain edema and it was significantly correlated with the vascular endothelial growth factor expression (P < 0.001). Simpson I resection was achieved in 63 patients (67.74%), grade II in 27 patients (29.03%), and grade III in 3 patients (3.23%). The extent of resection was not associated with the postoperative neurologic function (P = 0.546). Only 4 patients experienced recurrences during the follow-up and these 4 patients were stable until the last follow-up. CONCLUSIONS: AMs were a special subtype of meningioma with distinctive radiologic features. AMs manifest benign behavior with a satisfying outcome, which makes Simpson grade II resection an option. PMID- 28844929 TI - Distribution, properties, and inhibitor sensitivity of zebrafish catechol-O methyl transferases (COMT). AB - Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is an enzyme with multiple functions in vertebrates. COMT methylates and thus inactivates catecholamine neurotransmitters and metabolizes xenobiotic catechols. Gene polymorphism rs4680 that influences the enzymatic activity of COMT affects cognition and behavior in humans. The zebrafish is widely used as an experimental animal in many areas of biomedical research, but most aspects of COMT function in this species have remained uncharacterized. We hypothesized that both comt genes play essential roles in zebrafish. Both comt-a and comt-b were widely expressed in zebrafish tissues, but their relative abundance varied considerably. Homogenates of zebrafish organs, including the brain, showed enzymatic COMT activity that was the highest in the liver and kidney. Treatment of larval zebrafish with the COMT inhibitor Ro41-0960 shifted the balance of catecholamine metabolic pathways towards increased oxidative metabolism. Whole-body concentrations of dioxyphenylacetic acid (DOPAC), a product of dopamine oxidation, were increased in the inhibitor-treated larvae, although the dopamine levels were unchanged. Thus, COMT is likely to participate in the processing of catecholamine neurotransmitters in the zebrafish, but the inhibition of COMT in larval fish is compensated efficiently and does not have pronounced effects on dopamine levels. PMID- 28844930 TI - The antiadhesive activity of cranberry phytocomplex studied by metabolomics: Intestinal PAC-A metabolites but not intact PAC-A are identified as markers in active urines against uropathogenic Escherichia coli. AB - Cranberry procyanidins and quercetin derivatives are considered possible active compounds against urinary tract infections (UTIs). In this paper a small group (n=6) of healthy subjects consumed a product containing 360mg of cranberry extract (42.6% w/w of PAC-A and 14.6% w/w of PAC-B) and 200mg of quercetin. Urine samples were collected after 2,4,6,8, and 24h. The changes in antiadhesive properties against urophatogenic E. coli of the urinary output were determined in vitro and modification to urinary metabolome were studied by LC-MS. Significant antiadhesive properties of urine samples were observed, with the greatest effect 6-8h after oral administration, confirming the possible usefulness of cranberry containing products in urinary tract infections (UTI). Metabolomic analysis revealed that valeric acid and valerolactone derivatives that were detected in 6 and 8h sample, while 4-hydroxy-5-(phenyl)-valeric acid-O-glucuronide and 5-(3',4' dihydroxyphenyl)-gamma-valerolactone at 6h and 4-hydroxy-5-(phenyl)-valeric acid O-sulphate, 3-hydroxyphenyl-valeric acid, 5-(4'-hydroxyphenyl)-gamma valerolactone-4'-O-glucuronide and 4-hydroxy-5-(3'-hydroxyphenyl)-valeric acid-3' O-sulphate were the most abundant at 8h. The present study shows that the antiadhesive properties of urine sample after cranberry consumption are not ascribable to the direct effect of PAC-A, because their levels in urinary output are in the range of ng/mL. On the other hand, significant metabolites that were detected are mainly metabolites of intestinal action on polyphenols and PACs, as well as glucuronidated and sulphated quercetin, suggesting an important role of intestinal modification of phytoconstituents in the cranberry extract mechanism of action. PMID- 28844931 TI - Sesquiterpene amino ether and cytotoxic phenols from Dendrobium wardianum Warner. AB - A new bibenzyl derivative, dendrocandin V (1) and a new sesquiterpene amino ether, wardianumine A (2), together with eleven known compounds, including phenanthrenes (denbinobin (3), 9,10-dihydro-denbinobin (4), mostatin (5), loddigesiinols A (6)), bibenzyls (moscatilin (7), 5-hydroxy-3,4' dimethoxybibenzyl (8), 3,4-dihydroxy-5,4'-dimethoxy bibenzyl (9), dendrocandin A (10), gigantol (11), dendrocandin U (12)) and an alkaloids (dihydroshihunine, 13) were isolated from the EtOH extraction of stems of Dendrobium wardianum Warner. Isolation of the new compound 2 indicated that N,N-dimethylethanolamine as the key adduction in the synthesis of dendroxine and its analogs in Dendrobium species. The hypothetical biosynthetic pathway of 2 was then postulated. Inspired by literature and traditional usage of the herbal medicine, some compounds were sent for cytotoxic activity and the results indicated that compounds 1, 3, 4, 5 showed cytotoxic activities against five human cancer cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW-480) with IC50 from 2.33-38.48MUM. Among those compounds, 3 and 4 showed cell line selectivity with strong activity comparable to DDP. PMID- 28844932 TI - A quantitative-PCR based method to estimate ranavirus viral load following normalisation by reference to an ultraconserved vertebrate target. AB - Ranaviruses are important pathogens of amphibians, reptiles and fish. To meet the need for an analytical method for generating normalised and comparable infection data for these diverse host species, two standard-curve based quantitative-PCR (qPCR) assays were developed enabling viral load estimation across these host groups. A viral qPCR targeting the major capsid protein (MCP) gene was developed which was specific to amphibian-associated ranaviruses with high analytical sensitivity (lower limit of detection: 4.23 plasmid standard copies per reaction) and high reproducibility across a wide dynamic range (coefficient of variation below 3.82% from 3 to 3*108 standard copies per reaction). The comparative sensitivity of the viral qPCR was 100% (n=78) based on agreement with an established end-point PCR. Comparative specificity with the end-point PCR was also 100% (n=94) using samples from sites with no history of ranavirus infection. To normalise viral quantities, a host qPCR was developed which targeted a single copy, ultra-conserved non-coding element (UCNE) of vertebrates. Viral and host qPCRs were applied to track ranavirus growth in culture. The two assays offer a robust approach to viral load estimation and the host qPCR can be paired with assays targeting other pathogens to study infection burdens. PMID- 28844933 TI - Early detection of brain death using the Bispectral Index (BIS) in patients treated by extracorporeal cardiopulmonary resuscitation (E-CPR) for refractory cardiac arrest. AB - BACKGROUND: Despite increasing use of extracorporeal cardiopulmonary resuscitation (E-CPR) for treatment of refractory cardiac arrest patients, prognosis remains dismal, often resulting in brain-death. However, clinical assessment of brain-death occurence is difficult in post-cardiac arrest patients, sedated, paralyzed, under mild therapeutic hypothermia (MTH). Our objective was to assess the usefulness of Bispectral-Index (BIS) monitoring at bedside for an early detection of brain-death occurrence in refractory cardiac arrest patients treated by E-CPR. METHODS: This prospective study was performed in an intensive care unit of an university hospital. Forty-six patients suffering from refractory cardiac arrest treated by E-CPR were included. BIS was continuously recorded during ICU hospitalization. Clinical brain-death was confirmed when appropriate by EEG and/or cerebral CT angiography. RESULTS: Twenty-nine patients evolved into brain-death and had average BIS values under MTH and after rewarming (temperature >=35 degrees C) of 4 (0-47) and 0 (0-82), respectively. Among these, 11 (38%) entered into a procedure of organs donation. Among the 17 non-brain-dead patients, the average BIS values at admission and after rewarming were 39 (0-65) and 59 (22-82), respectively. Two patients had on admission a BIS value equal to zero and evolved to a poor prognostic (CPC 4) and died after care limitations. BIS values were significantly different between patients who developed brain death and those who did not. In both groups, no differences were observed between the AUCs of ROC curves for BIS values under MTH and after rewarming (respectively 0.86 vs 0.83, NS). CONCLUSIONS: Initial values of BIS could be used as an assessment tool for early detection of brain-death in refractory cardiac arrest patients treated by mild therapeutic hypothermia and E-CPR. PMID- 28844934 TI - Low cerebral blood flow after cardiac arrest is not associated with anaerobic cerebral metabolism. AB - AIM OF THE STUDY: Estimation of cerebral anaerobic metabolism in survivors and non-survivors after cardiac arrest. METHODS: We performed an observational study in twenty comatose patients after cardiac arrest and 19 healthy control subjects. We measured mean flow velocity in the middle cerebral artery (MFVMCA) by transcranial Doppler. Arterial and jugular blood samples were used for calculation of the jugular venous-to-arterial CO2/arterial to-jugular venous O2 content difference ratio. RESULTS: After cardiac arrest, MFVMCA increased from 26.0[18.6-40.4]cm/sec on admission to 63.9[48.3-73.1]cm/sec after 72h (p<0.0001), with no significant differences between survivors and non-survivors (p=0.4853). The MFVMCA in controls was 59.1[52.8-69.0]cm/sec. The oxygen extraction fraction (O2EF) was 38.9[24.4-47.7]% on admission and decreased significantly to 17.3[12.1 26.2]% at 72h (p<0.0001). The decrease in O2EF was more pronounced in non survivors (p=0.0173). O2EF in the control group was 35.4[32.4-38.7]%. The jugular bulb-arterial CO2 to arterial-jugular bulb O2 content difference ratio was >1 at all time points after cardiac arrest and did not change during admission, with no differences between survivors and non-survivors. Values in cardiac arrest patients were similar to those in normal subjects. CONCLUSIONS: In this study, low CBF after cardiac arrest is not associated with anaerobic metabolism. Hypoperfusion appears to be the consequence of a decrease of neuronal functioning and metabolic needs. Alternatively, hypoperfusion may decrease cerebral metabolism. Subsequently, metabolism increases in survivors, consistent with resumption of neuronal activity, whereas in non-survivors lasting low metabolism reflects irreversible neuronal damage. PMID- 28844935 TI - Predictive value of amplitude spectrum area of ventricular fibrillation waveform in patients with acute or previous myocardial infarction in out-of-hospital cardiac arrest. AB - BACKGROUND: Amplitude spectrum area (AMSA) of ventricular fibrillation (VF) has been associated with survival from out-of-hospital cardiac arrest (OHCA). Ischemic heart disease has been shown to change AMSA. We studied whether the association between AMSA and survival changes with acute ST-elevation myocardial infarction (STEMI) as cause of the OHCA and/or previous MI. METHODS: Multivariate logistic regression with log-transformed AMSA of first artifact-free VF segment was used to assess the association between AMSA and survival, according to presence of STEMI or previous MI, adjusting for resuscitation characteristics, medication use and comorbidities. RESULTS: Of 716 VF-patients included from an OHCA-registry in the Netherlands, 328 (46%) had STEMI as cause of OHCA. Previous MI was present in 186 (26%) patients. Survival was 66%; neither previous MI (P=0.11) nor STEMI (P=0.78) altered survival. AMSA was a predictor of survival (ORadj: 1.52, 95%-CI: 1.28-1.82). STEMI was associated with lower AMSA (8.4mV-Hz [3.7-16.5] vs. 12.3mV-Hz [5.6-23.0]; P<0.001), but previous MI was not (9.5mV-Hz [3.9-18.0] vs 10.6mV-Hz [4.6-19.3]; P=0.27). When predicting survival, there was no interaction between previous MI and AMSA (P=0.14). STEMI and AMSA had a significant interaction (P=0.002), whereby AMSA was no longer a predictor of survival (ORadj: 1.03, 95%-CI: 0.77-1.37) in STEMI-patients. In patients without STEMI, higher AMSA was associated with higher survival rates (ORadj: 1.80, 95% CI: 1.39-2.35). CONCLUSIONS: The prognostic value of AMSA is altered by the presence of STEMI: while AMSA has strong predictive value in patients without STEMI, AMSA is not a predictor of survival in STEMI-patients. PMID- 28844936 TI - Toronto HCC risk index: A validated scoring system to predict 10-year risk of HCC in patients with cirrhosis. AB - BACKGROUND & AIMS: Current guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in all patients with cirrhosis, regardless of etiology. However, HCC incidence is not well established for many causes of cirrhosis. We aimed to assess the disease-specific incidence of HCC in a large cohort of patients with cirrhosis and to develop a scoring system to predict HCC risk. METHODS: A derivation cohort of patients with cirrhosis diagnosed by biopsy or non-invasive measures was identified through retrospective chart review. The disease-specific incidence of HCC was calculated according to etiology of cirrhosis. Factors associated with HCC were identified through multivariable Cox regression and used to develop a scoring system to predict HCC risk. The scoring system was evaluated in an external cohort for validation. RESULTS: Of 2,079 patients with cirrhosis and >=6months follow-up, 226 (10.8%) developed HCC. The 10-year cumulative incidence of HCC varied by etiologic category from 22% in patients with viral hepatitis, to 16% in those with steatohepatitis and 5% in those with autoimmune liver disease (p<0.001). By multivariable Cox regression, age, sex, etiology and platelets were associated with HCC. Points were assigned in proportion to each hazard ratio to create the Toronto HCC Risk Index (THRI). The 10-year cumulative HCC incidence was 3%, 10% and 32% in the low-risk (<120points), medium-risk (120-240) and high-risk (>240) groups respectively, values that remained consistent after internal validation. External validation was performed on a cohort of patients with primary biliary cirrhosis, hepatitis B viral and hepatitis C viral cirrhosis (n=1,144), with similar predictive ability (Harrell's c statistic 0.77) in the validation and derivation cohorts. CONCLUSION: HCC incidence varies markedly by etiology of cirrhosis. The THRI, using readily available clinical and laboratory parameters, has good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis. LAY SUMMARY: HCC incidence varies markedly depending on the underlying cause of cirrhosis. Herein, using readily available clinical and laboratory parameters we describe a risk score, THRI, which has a good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis. PMID- 28844937 TI - Dimercapto-1-propanesulfonic acid (DMPS) induces metaphase II mouse oocyte deterioration. AB - In light of the recent lead contamination of the water in Flint, Michigan and its potential adverse outcomes, much research and media attention has turned towards the safety profile of commonly used chelators. Dimercapto-1-propanesulfonic acid (DMPS) typically used in the treatment of lead, mercury and arsenic poisoning also displays a high affinity towards transition metals such as zinc and copper, essential for biological functioning. It is given in series of dosages (0.2 0.4g/day) over a long period, and has the ability to enter cells. In this work, we investigated the mechanism through which increasing concentrations of DMPS alter oocyte quality as judged by changes in microtubule morphology (MT) and chromosomal alignment (CH) of metaphase II mice oocyte. The oocytes were directly exposed to increasing concentration of DMPS (10, 25, 50, 100 and 300MUM) for four hours (time of peak plasma concentration after administration) and reactive oxygen species (mainly hydroxyl radical and superoxide) and zinc content were measured. This data showed DMPS plays an important role in deterioration of oocyte quality through a mechanism involving zinc deficiency and enhancement of reactive oxygen species a major contributor to oocyte damage. Our current work, for the first time, demonstrates the possibility of DMPS to negatively impact fertility. This finding can not only help in counseling reproductive age patients undergoing such treatment but also in the development of potential therapies to alleviate oxidative damage and preserve fertility in people receiving heavy metal chelators. PMID- 28844938 TI - AMC-Bio-Artificial Liver culturing enhances mitochondrial biogenesis in human liver cell lines: The role of oxygen, medium perfusion and 3D configuration. AB - BACKGROUND: Human liver cell lines, like HepaRG and C3A, acquire higher functionality when cultured in the AMC-Bio-Artificial Liver (AMC-BAL). The three main differences between BAL and monolayer culture are the oxygenation (40% vs 20%O2), dynamic vs absent medium perfusion and 3D vs 2D configuration. Here, we investigated the background of the differences between BAL-cultures and monolayers. METHODS: We performed whole-genome microarray analysis on HepaRG monolayer and BAL-cultures. Next, mitochondrial biogenesis was studied in monolayer and BAL-cultures of HepaRG and C3A. The driving forces for mitochondrial biogenesis by BAL-culturing were investigated in representative culture models differing in oxygenation level, medium flow or 2D vs 3D configuration. RESULTS: Gene-sets related to mitochondrial energy metabolism were most prominently up-regulated in HepaRG-BAL vs monolayer cultures. This was confirmed by a 2.4-fold higher mitochondrial abundance with increased expression of mitochondrial OxPhos complexes. Moreover, the transcript levels of mitochondria-encoded genes were up to 3.6-fold induced and mitochondrial membrane potential activity was 8.3-fold increased in BAL vs monolayers. Culturing with 40% O2, dynamic medium flow and/or in 3D increased the mitochondrial abundance and expression of mitochondrial complexes vs standard monolayer culturing. The stimulatory effect of the BAL culture on mitochondrial biogenesis was confirmed in C3A cells in which mitochondrial abundance increased 2.2-fold with induction of mitochondria-encoded genes. CONCLUSIONS AND GENERAL SIGNIFICANCE: The increased functionality of liver cell lines upon AMC-BAL culturing is associated with increased mitochondrial biogenesis. High oxygenation, medium perfusion and 3D configuration contribute to the up-regulation of the mitochondrial biogenesis. PMID- 28844939 TI - Lack of Galanin Receptor 3 Alleviates Psoriasis by Altering Vascularization, Immune Cell Infiltration, and Cytokine Expression. AB - The neuropeptide galanin is distributed in the central and peripheral nervous systems and in non-neuronal peripheral organs, including the skin. Galanin acts via three G protein-coupled receptors which, except galanin receptor 1, are expressed in various skin structures. The galanin system has been associated with inflammatory processes of the skin and of several other organs. Psoriasis is an inflammatory skin disease with increased neovascularization, keratinocyte hyperproliferation, a proinflammatory cytokine milieu, and immune cell infiltration. In this study, we showed that galanin receptor 3 is present in endothelial cells in human and murine dermal vessels and is co-expressed with nestin in neo-vessels of psoriatic patients. Moreover, in a murine psoriasis model, we showed that C57/BL6 mice lacking galanin receptor 3 display a milder course of psoriasis upon imiquimod treatment, leading to decreased disease severity, delayed neo-vascularization, reduced infiltration of neutrophils, and significantly lower levels of proinflammatory cytokines compared with wild-type mice. In contrast, galanin receptor 2-knockout animals did not differ significantly from wild type mice at both the macroscopic and molecular levels in their inflammatory response to imiquimod treatment. Our data indicate that galanin receptor 3, but not galanin receptor 2, plays an important role in psoriasis-like skin inflammation. PMID- 28844940 TI - Subclonal Evolution of Cancer-Related Gene Mutations in p53 Immunopositive Patches in Human Skin. AB - Normal sun-exposed skin contains numerous epidermal patches that stain positive for p53 protein (p53 immunopositive patches, PIPs), which are considered potential early precursors of skin cancer. Although the TP53 gene is mutated in many PIPs, it is unclear whether PIPs contain any other cancer-related mutations. Here we report that PIPs, predominantly <3,000 p53 immunopositive cells in size, within normal chronically exposed skin contain mutations in multiple genes that are mutated in cutaneous squamous cell cancers. These mutations in the PIPs were not detected within the non-PIP epidermis of corresponding normal chronically exposed skin. Although some of these genetic alterations are clonal in the PIPs, many of the mutations are subclonal within these lesions. Similar mutations are seen in later precancers (actinic keratoses and Bowen's disease). Our results demonstrate that PIPs in chronically exposed skin contain multiple mutations in cancer-related genes. In addition, the results indicate that the clonal evolution of mutations that are seen within later precancerous lesions and in established malignancy can also occur in PIPs within normal human skin. PMID- 28844941 TI - Paracrine Activin-A Signaling Promotes Melanoma Growth and Metastasis through Immune Evasion. AB - The secreted growth factor Activin-A of the transforming growth factor beta family and its receptors can promote or inhibit several cancer hallmarks including tumor cell proliferation and differentiation, vascularization, lymphangiogenesis and inflammation. However, a role in immune evasion and its relationship with tumor-induced muscle wasting and tumor vascularization, and the relative contributions of autocrine versus paracrine Activin signaling remain to be evaluated. To address this, we compared the effects of truncated soluble Activin receptor IIB as a ligand trap, or constitutively active mutant type IB receptor versus secreted Activin-A or the related ligand Nodal in mouse and human melanoma cell lines and tumor grafts. We found that although cell-autonomous receptor activation arrested tumor cell proliferation, Activin-A secretion stimulated melanoma cell dedifferentiation and tumor vascularization by functional blood vessels, and it increased primary and metastatic tumor burden and muscle wasting. Importantly, in mice with impaired adaptive immunity, the tumor-promoting effect of Activin-A was lost despite sustained vascularization and cachexia, suggesting that Activin-A promotes melanoma progression by inhibiting antitumor immunity. Paracrine Activin-A signaling emerges as a potential target for personalized therapies, both to reduce cachexia and to enhance the efficacy of immunotherapies. PMID- 28844942 TI - Circadian Time Effects on NB-UVB-Induced Erythema in Human Skin In Vivo. PMID- 28844943 TI - The Unknown Aspect of BAFF: Inducing IL-35 Production by a CD5+CD1dhiFcgammaRIIbhi Regulatory B-Cell Subset in Lupus. AB - IL-35 is a critical immunosuppressive cytokine that plays an important role in various autoimmune diseases. The purpose of this study was to determine whether BAFF, a key pathogenic factor in systemic lupus erythematosus, also a dichotomous regulator for B-cell immune responses, has an effect on IL-35-producing regulatory B cells and their underlying mechanisms in lupus. We found that exogenous BAFF could induce IL-35 production by splenic B cells from MRL Faslpr/lpr mice. BAFF-induced IL-35-producing B cells were mainly from the marginal zone B-cell subset and exhibited a CD5+CD1dhiFcgammaRIIbhi phenotype. These IL-35-producing regulatory B-cell subsets exhibited regulatory effects on both CD4+CD25- T cells and CD4+CD25+ regulatory T cells. We further identified that BAFF-TACI interaction could induce the production of IL-35 through the classical NF-kappaB1 pathway. In vivo study also showed that BAFF could facilitate IL-35 secretion in marginal zone B cells, whereas anti-BAFF treatment could decrease the frequency of IL-35-producing CD5+CD1dhiFcgammaRIIbhi B cells in MRL-Faslpr/lpr mice. We showed that BAFF could induce IL-35 production by a unique CD5+CD1dhiFcgammaRIIbhi regulatory B-cell subset mainly through TACI activation in lupus, providing an advanced understanding of the regulatory effect of BAFF in autoimmune diseases. PMID- 28844944 TI - Anti-angiogenetic agents against tumor types and cardiovascular risk. PMID- 28844945 TI - Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells Correlate with Early Infections and Clinical Outcomes in Allogeneic Hematopoietic Stem Cell Transplantation. AB - The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9. PMID- 28844946 TI - Impact of Fluid Overload as New Toxicity Category on Hematopoietic Stem Cell Transplantation Outcomes. AB - Fluid overload (FO) commonly occurs during hospitalization for allogeneic hematopoietic stem cell transplantation. We hypothesized that FO is associated with transplantation outcomes and evaluated this complication in 2 cohorts of patients. FO was graded based on post-transplantation weight gain, symptoms, and need for treatment, scored in real time by an independent team. The first cohort (study cohort; n = 145) underwent haploidentical transplantation for hematologic malignancies following a melphalan-based conditioning regimen. In univariate analysis, factors associated with day +100 nonrelapse mortality (NRM) were FO grade >=2 (hazard ratio [HR], 15; 95% confidence interval [CI], 4.2 to 55; P < .001), creatinine >1 mg/dL (HR, 4.7; 95% CI, 1.6 to 14; P = .005), and age >55 years (HR, 4.5; 95% CI, 1.5 to 13; P = .008). In multivariate analysis, factors associated with day +100 NRM were FO grade >=2 (HR, 13.1; 95% CI, 3.4 to 50; P < .001) and serum creatinine level >1 mg/dL at transplantation admission (HR, 3.5; 95% CI, 1.1 to 11; P = .03). These findings were verified in a separate cohort (validation cohort) of patients with acute myelogenous leukemia/myelodysplastic syndrome who underwent HLA-matched transplantation with busulfan-based conditioning (n = 449). In multivariate analysis, factors associated with day +100 NRM were FO grade >=2 (HR, 34; 95% CI, 7.2 to 158; P < .001) and, in patients with FO grade <2, advanced disease status (HR, 5; 95% CI, 1.1 to 22; P = .03). A higher NRM translated to significantly poorer 1-year overall survival rates for patients with FO >=2 than for patients without FO (70% versus 42%, P < .001 in the study cohort and 64% versus 38%, P < .001 in the validation cohort). In conclusion, FO grade >=2 is strongly associated with higher NRM and shorter survival and should be considered an important prognostic factor in transplantation. PMID- 28844947 TI - Outcome of Second Transplantation Using Umbilical Cord Blood for Graft Failure after Allogeneic Hematopoietic Stem Cell Transplantation for Aplastic Anemia. AB - Graft failure (GF) is the most critical life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia, for which a second transplantation is the only effective treatment. Optimal procedures have not been established for the second transplantation in this setting, however. Here we retrospectively analyzed the outcomes of 22 patients with aplastic anemia, age >=16 years, who underwent umbilical cord blood transplantation for GF after the first HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median age of patients was 36 years (range, 16 to 72 years), and the median time from the first to the second transplant was 77 days (range, 29 to 1061 days). The cumulative incidence of neutrophil engraftment at day 60 post-transplantation was 45.5% (95% confidence interval [CI], 23.6% to 65.0%). With a median follow-up of 50 months, the 4-year overall survival (OS) was 38.5% (95% CI, 18.4% to 58.5%). Mycofenolate mofetil-based graft-versus-host disease prophylaxis demonstrated greater neutrophil recovery than prophylaxis with calcineurin inhibitor alone or methotrexate-based prophylaxis (66.7% versus 37.5%; P = .04). The use of such conditioning regimens as fludarabine + melphalan or cyclophosphamide + low-dose total body irradiation was associated with better engraftment (58.3% versus 30%; P = .05) and better 4-year OS (55.6% versus 20%; P = .05) than other regimens. Although further investigation is needed, umbilical cord blood could be an effective and promising option for stem cell source for urgent second transplantation in patients with aplastic anemia who develop GF after the first HSCT. PMID- 28844949 TI - Role of membrane GM1 on early neuronal membrane actions of Abeta during onset of Alzheimer's disease. AB - The ability of beta-amyloid peptide (Abeta) to disrupt the plasma membrane through formation of pores and membrane breakage has been previously described. However, the molecular determinants for these effects are largely unknown. In this study, we examined if the association and subsequent membrane perforation induced by Abeta was dependent on GM1 levels. Pretreatment of hippocampal neurons with D-PDMP decreased GM1 and Abeta clustering at the membrane (Abeta fluorescent punctas/20MUm, control=16.2+/-1.1 vs. D-PDMP=6.4+/-0.4, p<0.001). Interestingly, membrane perforation with Abeta occurred with a slower time course when the GM1 content was diminished (time to establish perforated configuration (TEPC) (min): control=7.8+/-2 vs. low GM1=12.1+/-0.5, p<0.01), suggesting that the presence of GM1 in the membrane can modulate the distribution and the membrane perforation by Abeta. On the other hand, increasing GM1 facilitated the membrane perforation (TEPC: control=7.8+/-2 vs. GM1=6.2+/-1min, p<0.05). Additionally, using Cholera Toxin Subunit-B (CTB) to block the interaction of Abeta with GM1 attenuated membrane perforation significantly. Furthermore, pretreatment with CTB decreased the membrane association of Abeta (fluorescent-punctas/20MUm, Abeta: control=14.8+/-2.5 vs. CTB=8+/-1.4, p<0.05), suggesting that GM1 also plays a role in both association of Abeta with the membrane and in perforation. In addition, blockade of the Abeta association with CTB inhibited synaptotoxicity. Taken together, our results strongly suggest that membrane lipid composition can affect the ability of Abeta to associate and subsequently perforate the plasma membrane thereby modulating its neurotoxicity in hippocampal neurons. PMID- 28844948 TI - Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3T3-L1 adipocytes. AB - Sortilin 1(Sort1) is a vesicle trafficking receptor that mediates protein sorting in the endocytic and exocytic pathways. Sort1 is a component of the GLUT4 storage vesicles in adipocytes and is also involved in the regulation of adipogenesis. Sort1 protein is reduced in adipose of obese mice and humans, but the underlying cause is not fully understood. Here we report that insulin/PI3K/AKT signaling cascade critically regulates adipose Sort1 protein abundance. Administration of a PI3K inhibitor rapidly decreased Sort1 protein but not mRNA in adipose of chow fed mice. In 3T3-L1 adipocytes, serum-starvation or inhibition of the PI3K/AKT signaling also decreased Sort1 protein without affecting Sort1 mRNA expression. Sort1 protein downregulation upon PI3K inhibition was blocked by pretreatment of MG132 but not Bafilomycin A1, suggesting that PI3K inhibition caused Sort1 degradation via the proteasome pathway. Using a phospho-specific Sort1 antibody, we showed that endogenous Sort1 was phosphorylated at S825 adjacent to the DXXLL sorting motif on the cytoplasmic tail. We demonstrated that mutagenesis that abolished Sort1 S825 phosphorylation decreased insulin-stimulated Sort1 localization on the plasma membrane and Sort1 protein stability in 3T3-L1 adipocytes. However, endogenous Sort1 phosphorylation at S825 was not affected by insulin stimulation or by inhibition of PI3K. In conclusion, this study revealed an important role of insulin signaling in regulating adipose Sort1 protein stability, and further suggests that impaired insulin signaling may underlie reduced adipose Sort1 in obesity. The cellular events downstream of insulin/PI3K/AKT signaling that mediates insulin regulation of Sort1 stability requires further investigation. PMID- 28844950 TI - miR-4516, a microRNA downregulated in psoriasis inhibits keratinocyte motility by targeting fibronectin/integrin alpha9 signaling. AB - Psoriasis is recognized as a T cell mediated inflammatory hyperproliferative skin disorder. Several microRNAs (miRNAs) have been implicated in the pathogenesis of psoriasis however, understanding of their mechanistic involvement remains unclear. Previously, we have shown that PUVA induced miR-4516 downregulates signal transducer and activator of transcription 3 (STAT3) by direct binding to its 3' untranslated region (3'UTR) and suppresses STAT3 downstream genes (Bcl xl, Cyclin D1). Here, we demonstrate for the first time that expression of miR-4516 is significantly downregulated in psoriatic skin. We additionally validated extracellular matrix protein fibronectin 1 (FN1) and integrin subunit alpha9 (ITGA9) as direct targets of miR-4516. Interestingly, ITGA9 expression was found to be increased in the suprabasal psoriatic epidermis. We further showed that ectopic expression of miR-4516 in human keratinocytes not only suppresses cell motility and proliferation via significant downregulation of genes orchestrating cytoskeletal reorganization (Rac1, RhoA, Cdc42), but also inhibits F-actin assembly and induces terminal differentiation. Collectively, our results provide evidence that loss of expression of miR-4516 in psoriatic skin might be contributing to accelerated migration, resistance to apoptosis and differentiation as seen in psoriasis lesional keratinocytes and also highlight its potential as a novel small molecule for therapeutic intervention in psoriasis. PMID- 28844951 TI - Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma. AB - Primary sclerosing cholangitis (PSC) is an idiopathic cholangiopathy strongly associated with inflammatory bowel disease (IBD) and characterized by cholestasis, chronic immune infiltration and progressive fibrosis of the intrahepatic and extrahepatic bile ducts. PSC confers a high risk of cholangiocarcinoma (CCA) with PSC-CCA representing the leading cause of PSC associated mortality. PSC-CCA is derived from cholangiocytes and associated progenitor cells - a heterogeneous group of dynamic epithelial cells lining the biliary tree that modulate the composition and volume of bile production by the liver. Infection, inflammation and cholestasis can trigger cholangiocyte activation leading to an increased expression of adhesion and antigen-presenting molecules as well as the release of various inflammatory and fibrogenic mediators. As a result, activated cholangiocytes engage in a myriad of cellular processes, including hepatocellular proliferation, apoptosis, angiogenesis and fibrosis. Cholangiocytes can also regulate the recruitment of immune cells, mesenchymal cells, and endothelial cells that participate in tissue repair and destruction in settings of persistent inflammation. In PSC, the role of cholangiocytes and the mechanisms governing their transformation to PSC-CCA are unclear however localization of disease suggests that cholangiocytes are a key target and potential regulator of hepatobiliary immunity, fibrogenesis and tumorigenesis. Herein, we summarize mechanisms of cholangiocyte activation in PSC and highlight new insights into disease pathways that may contribute to the development of PSC-CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28844953 TI - How the biliary tree maintains immune tolerance? AB - The liver is a vital organ with distinctive anatomy, histology and heterogeneous cell populations. These characteristics are of particular importance in maintaining immune homeostasis within the liver microenvironments, notably the biliary tree. Cholangiocytes are the first line of defense of the biliary tree against foreign substances, and are equipped to participate through various immunological pathways. Indeed, cholangiocytes protect against pathogens by TLRs related signaling; maintain tolerance by expression of IRAK-M and PPARgamma; limit immune response by inducing apoptosis of leukocytes; present antigen by expressing human leukocyte antigen molecules and costimulatory molecules; recruit leukocytes to the target site by expressing cytokines and chemokines. However, breach of tolerance in the biliary tree results in various cholangiopathies, exemplified by primary biliary cholangitis, primary sclerosing cholangitis and biliary atresia. Lessons learned from immune tolerance of the biliary tree will provide the basis for the development of effective therapeutic approaches against autoimmune biliary tract diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28844952 TI - Targeting cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA. Clinical trials targeting these specific driver mutations are in progress. However, The Tumor Genome Atlas (TCGA) marker analysis of CCA also highlights the tremendous molecular heterogeneity of this cancer rendering comprehensive employment of targeted therapies challenging. CCA also display a rich tumor microenvironment which may be easier to target. For example, targeting cancer associated fibroblasts for apoptosis with BH3-mimetics and/or and reversing T-cell exhaustion with immune check point inhibitors may help aid in the treatment of this otherwise devastating malignancy. Combinatorial therapy attacking the tumor microenvironment plus targeted therapy may help advance treatment for CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28844954 TI - Optimising the clinical strategy for autoimmune liver diseases: Principles of value-based medicine. AB - BACKGROUND: Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis represent the three major autoimmune liver diseases (AILDs). Their management is highly specialized, requires a multidisciplinary approach and often relies on expensive, orphan drugs. Unfortunately, their treatment is often unsatisfactory, and the care pathway heterogeneous across different centers. Disease-specific clinical outcome indicators (COIs) able to evaluate the whole cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. Aim of our study was to generate a set of COIs for the three AILDs. We then prospectively validated these indicators based on a series of consecutive patients recruited at three tertiary clinical centers in Lombardy, Italy. METHODS: In phase I using a Delphi method and a RAND 9-point appropriateness scale a set of COIs was generated. In phase II the indicators were applied in a real-life dataset. RESULTS: Two-hundred fourteen patients were enrolled and followed-up for a median time of 54months and the above COIs were recorded using a web-based electronic medical record program. The COIs were easy to collect in the clinical practice environment and their values compared well with the available natural history studies. CONCLUSIONS: We have generated a comprehensive set of COIs which sequentially capture different clinical outcome of the three AILDs explored. These indicators represent a critical tool to implement a value-based approach to patients with these conditions, to monitor, compare and improve quality through benchmarking of clinical performance and to assess the significance of novel drugs and technologies. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28844955 TI - BRD4 has dual effects on the HMGB1 and NF-kappaB signalling pathways and is a potential therapeutic target for osteoarthritis. AB - Osteoarthritis (OA) has traditionally been defined as a non-inflammatory disease. Recently, many studies have demonstrated that OA also has an inflammatory component. BRD4, a member of the Bromodomain and Extra-Terminal Domain family, has emerged as an important regulator of some chronic inflammatory diseases. JQ1, an antagonist of BRD4, modulates transcription of several genes. Our study demonstrated that BRD4 is up-regulated in articular cartilage of OA. BRD4 inhibition attenuated the inflammation and catabolism of chondrocytes and suppressed NF-kappaB signalling pathway activation. In addition, BRD4 inhibition abolished the transcriptional activity of High Mobility Group Protein B1 (HMGB1). We identified HMGB1 as a direct target of BRD4. Genetic and pharmacological inhibition of BRD4 suppressed IL-1beta-induced expression and translocation of HMGB1. Chromatin immunoprecipitation (ChIP) showed the enrichment of BRD4 around the HMGB1 upstream non-promoter region, which diminished with JQ1 treatment. Finally, haematoxylin & eosin and Safranin o/Fast Green staining demonstrated that JQ1 attenuates cartilage destruction in mice with anterior cruciate ligament transection without significant toxic effects. These studies highlighted the importance of BRD4 in the chronic inflammatory reactions of OA, which, as far as we know, was the first report of this finding, and suggested that BRD4 might be a novel potential therapeutic target for the treatment of OA. PMID- 28844956 TI - Interleukin-6 deficiency facilitates myocardial dysfunction during high fat diet induced obesity by promoting lipotoxicity and inflammation. AB - OBJECTIVE: Obesity is associated with metabolic disorder and chronic inflammation that plays a crucial role in cardiovascular diseases. IL-6 is involved in regulating obesity-related lipid metabolism and inflammation. In this study, we sought to determine the role of IL-6 in high-fat diet (HFD)-induced cardiomyopathy and explore the signaling pathway. METHODS: Female, 5-week-old IL 6 knockout (KO) and littermate mice were fed a normal diet (ND, 10% fat) or HFD (45% fat) for 14 weeks. At the end of treatment, cardiac function was assessed by echocardiography. Adipose tissues and plasma were collected for further measurement. Immunohistology of CD68 was performed to detect inflammation in the heart. Masson's trichrome staining and Oil Red O staining was applied to evaluated cardiac fibrosis and lipid accumulation. Real-time PCR and Western immunoblotting analyses on heart tissue were used to explore the underlying mechanism. RESULTS: IL-6 KO mice displayed increased insulin resistance compared to WT mice at baseline. When fed HFD, IL-6 KO mice showed decreased gains in body weight and fat mass, increased insulin resistance relative to IL-6 KO mice feed ND. Furthermore, IL-6 KO mice developed cardiac dysfunction during HFD-induced obesity. Histological analysis suggested increased lipid accumulation, fibrosis and inflammation without affecting cardiac morphology during HFD treatment in the heart of IL-6 KO mice. Finally, IL-6 deficiency increased the phosphorylation of AMPK and ACC in the heart during HFD-induced obesity. CONCLUSION: Our results suggest that IL-6 contributes to limit lipid metabolic disorder, cardiac hypertrophy, fibrosis, inflammation and myocardium lipotoxicity during HFD induced obesity. PMID- 28844957 TI - Adiponectin attenuates NADPH oxidase-mediated oxidative stress and neuronal damage induced by cerebral ischemia-reperfusion injury. AB - Adiponectin (APN), which is a major adipokine that regulated glucose and lipid metabolism, plays an important role in the protection of the cerebral nervous system. It also has been suggested to have anti-inflammatory effects and ameliorate oxidative stress. Stroke is a universal cause of death and permanent disability. Ischemic stroke accounts for most cases of stroke, and is characterized by cerebral ischemia and neurological deficits. We aimed to investigate the effects of APN-peptide (APN-P) in neurons following ischemia reperfusion (I/R) in C57BL/6J mice, and to study the potential mechanisms underlying its effects. Mice were treated with vehicle, 2.5, 5, or 10mg/kg of APN P and 2.5mg/kg of apocynin or vehicle before middle cerebral artery occlusion. Neurological deficits, infarct size, neuronal injury, and the ultrastructure of neurons were assessed. In addition, the levels of reactive oxygen species, superoxide dismutase, and malondialdehyde were measured. We assessed neuronal apoptosis using terminal deoxynucleotidyl transferase dUTP nick end labeling. The levels of oxidative stress- and apoptosis-related proteins were measured by western blot. Our results suggest that APN-P at 5mg/kg markedly improved neurological deficits, decreased infarct size, and attenuated neuronal injury after cerebral I/R injury. APN-P treatment also decreased neuronal apoptosis. Additionally, the increased levels of oxidative stress- and apoptosis-related proteins levels following I/R were alleviated by APN-P treatment. In conclusion, APN-P inhibits neuronal apoptosis and alleviates oxidative stress in neurons subjected to I/R, suggesting that it may be beneficial for the treatment of brain damage following ischemic stroke. PMID- 28844958 TI - Growth arrest and DNA damage-inducible 45alpha protects against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet. AB - Growth arrest and DNA damage-inducible 45 alpha (Gadd45alpha) is a stress inducible protein that plays an important role in cell survival/death and DNA repair, but its contribution to the development of nonalcoholic steatohepatitis (NASH) has not been investigated. C57BL/6 Gadd45a-null and wild-type (WT) mice were treated with a methionine and choline-deficient diet (MCD) for eight weeks and phenotypic changes examined. Gadd45a-null mice had more severe hepatic inflammation and fibrosis, higher levels of mRNAs encoding pro-inflammatory, pro fibrotic, and pro-apoptotic proteins, and greater oxidative and endoplasmic reticulum (ER) stress compared with WT mice. Indeed, Gadd45a mRNA was induced in response to ER stress in primary hepatocytes. Lipidomic analysis of NASH livers demonstrated decreased triacylglycerol (TG) in MCD-treated Gadd45a-null mice, which was associated with increased mRNAs encoding phospholipase D (Pld1/2), phosphatidic acid phosphatase type 2A, and choline/ethanolamine phosphotransferase 1 (Cept1), involved in the phosphatidylcholine-phosphatidic acid-diacylglycerol cycle, and decreased mRNAs encoding fatty acid (FA)-binding protein 1 (Fabp1) and FA transport protein 5. Treatment of cultured primary hepatocytes with tumor necrosis factor alpha, transforming growth factor beta, and hydrogen peroxide led to the corresponding induction of Fabp1, Pld1/2, and Cept1 mRNAs. Collectively, Gadd45alpha plays protective roles against MCD-induced NASH likely due to attenuating cellular stress and ensuing inflammatory signaling. These results also suggest an interconnection between hepatocyte injury, inflammation and disrupted glycerophospholipid/FA metabolism that yields a possible mechanism for decreased TG accumulation with NASH progression (i.e., "burned-out" NASH). PMID- 28844959 TI - Reversal of aberrant PI3K/Akt signaling by Salubrinal in a GalT-deficient mouse model. AB - Classic Galactosemia is an autosomal recessive disorder caused by deleterious mutations in the GALT gene, which encodes galactose-1 phosphate uridylyltransferase enzyme (GALT: EC 2.7.7.12). Recent studies of primary skin fibroblasts isolated from the GalT-deficient mice demonstrated a slower growth rate, a higher level of endoplasmic reticulum (ER) stress, and down-regulation of the Phosphoinositide 3 kinase/Protein kinase B (PI3K/Akt) signaling pathway. In this study, we compared the expression levels of the PI3K/Akt signaling pathway in normal and GalT-deficient mouse tissues. In mutant mouse ovaries, phospho-Akt [pAkt (Ser473)] and pGsk3beta were reduced by 62.5% and 93.5%, respectively (p<0.05 versus normal controls). In mutant cerebella, pAkt (Ser473) and pGsk3beta were reduced by 62%, 50%, respectively (p<0.05). To assess the role of ER stress in the down-regulation of PI3K/Akt signaling, we examined if administration of Salubrinal, a chemical compound that alleviates ER stress, to GalT-deficient fibroblasts and animals could normalize the pathway. Our results demonstrated that Salubrinal effectively reversed the down-regulated PI3K/Akt signaling pathway in the mutant cells and animals to levels close to those of their normal counterparts. Moreover, we revealed that Salubrinal can significantly slow down the loss of Purkinje cells in the cerebella, as well as the premature loss of primordial ovarian follicles in young mutant mice. These results open the door for a new therapeutic approach for the patients with Classic Galactosemia. PMID- 28844960 TI - Bile acid receptors in the biliary tree: TGR5 in physiology and disease. AB - Bile salts represent signalling molecules with a variety of endocrine functions. Bile salt effects are mediated by different receptor molecules, comprising ligand activated nuclear transcription factors as well as G protein-coupled membrane bound receptors. The farnesoid X receptor (FXR) and the plasma membrane-bound G protein-coupled receptor TGR5 (Gpbar-1) are prototypic bile salt receptors of both classes and are highly expressed in the liver including the biliary tree as well as in the intestine. In liver, TGR5 is localized in different non parenchymal cells such as sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells and small and large cholangiocytes. Through TGR5 bile salts can mediate choleretic, cell-protective as well as proliferative effects in cholangiocytes. A disturbance of these signalling mechanisms can contribute to the development of biliary diseases. In line with the important role of TGR5 for bile salt signalling, TGR5 knockout mice are more susceptible to cholestatic liver damage. Furthermore, in absence of TGR5 cholangiocyte proliferation in response to cholestasis is attenuated and intrahepatic and extrahepatic bile ducts show increased cell damage, underscoring the role of the receptor for biliary physiology. Decreased TGR5 expression may also contribute to the development or progression of cholangiopathies like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) since reduced TGR5-dependent cell protective mechanisms such as bicarbonate secretion renders cholangiocytes more vulnerable towards bile salt toxicity. Nevertheless, TGR5 overexpression or constant stimulation of the receptor can promote cholangiocyte proliferation leading to cyst growth in polycystic liver disease or even progression of cholangiocarcinoma. Not only the stimulation of TGR5-mediated pathways by suitable TGR5 agonists but also the inhibition of TGR5 signalling by the use of antagonists represent potential therapeutic approaches for different types of biliary diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28844961 TI - Mitochondrial dysfunction in rat splenocytes following hemorrhagic shock. AB - The regulation of mitochondrial function is critical in cellular homeostasis following hemorrhagic shock. Hemorrhagic shock results in fluid loss and reduced availability of oxygen and nutrients to tissues. The spleen is a secondary lymphoid organ playing a key role in 'filtering the blood' and in the innate and adaptive immune responses. To understand the molecular basis of hemorrhagic shock, we investigated the changes in splenocyte mitochondrial respiration, and concomitant immune and metabolic alterations. The hemorrhagic injury (HI) in our rat model was induced by bleeding 60% of the total blood volume followed by resuscitation with Ringers lactate. Another group of animals was subjected to hemorrhage, but did not receive fluid resuscitation. Oxygen consumption rate of splenocytes were determined using a Seahorse analyzer. We found a significantly reduced oxygen consumption rate in splenocytes following HI compared to sham operated rats. The mitochondrial stress test revealed a decreased basal oxygen consumption rate, ATP production, maximal respiration and spare respiratory capacity. The mitochondrial membrane potential, and citrate synthase activity, were also reduced in the splenocytes following HI. Hypoxic response in the splenocyte was confirmed by increased gene expression of Hif1alpha. Elevated level of mitochondrial stress protein, hsp60 and induction of high mobility group box1 protein (HMGB1) were observed in splenocytes following HI. An increased inflammatory response was demonstrated by significantly increased expression of IL-6, IFN-beta, Mip-1alpha, IL-10 and NFkappabp65. In summary, we conclude that splenocyte oxidative phosphorylation and metabolism were severely compromised following HI. PMID- 28844962 TI - Inhibitory effects of 3,3'-diindolylmethane on epithelial-mesenchymal transition induced by endocrine disrupting chemicals in cellular and xenograft mouse models of breast cancer. AB - As a phytoestrogen, 3,3'-diindolylmethane (DIM) plays a chemopreventive role by inhibiting cancer progression. In this study, we examined the effects of 17beta estradiol (E2), two endocrine disrupting chemicals (EDCs), triclosan (TCS) and bisphenol A (BPA), and DIM on epithelial-mesenchymal transition (EMT) and metastatic behaviors of estrogen receptor (ER)-positive MCF-7 breast cancer cells. An in vitro assay revealed that E2 (10-9 M), TCS (10-5-10-7 M), and BPA (10-5-10-7 M) induced MCF-7 cell proliferation compared to a control through the ER pathway. In addition, E2, TCS, and BPA changed the cell morphology from the epithelial to the mesenchymal phenotype and increased the migration and invasion capacity of MCF-7 cells via ER; however, co-treatment with DIM (20 MUM) effectively suppressed E2, TCS, and BPA-induced cell proliferation, EMT, migration, and invasion of MCF-7 cells. Western blot assay revealed that DIM regulated the protein expression of EMT- and metastasis-related genes toward the inhibition of these processes. Moreover, E2, TCS, and BPA increased the protein expression of CXCR4, which is a receptor of chemokine CXCL12 that is positively involved in breast cancer metastasis via an ER-dependent pathway. Conversely, DIM and a CXCR4 antagonist (AMD3100) decreased CXCR4 protein expression, which led to inhibition of the EMT process, indicating that DIM may suppress E2, TCS or BPA induced EMT, migration, and invasion of MCF-7 breast cancer cells by suppressing CXCR4 protein expression. These in vitro effects of E2, TCS, BPA, and DIM were also identified in a xenografted mouse model transplanted with MCF-7 breast cancer cells. Taken together, DIM is a potent chemopreventive compound for preventing metastatic behaviors of breast cancer cells induced by EDCs with cancer-related toxicity. PMID- 28844963 TI - Novel direct factor Xa inhibitory compounds from Tenebrio molitor with anti platelet aggregation activity. AB - Tenebrio molitor is an edible insect that has antimicrobial, anticancer, and antihypertensive effects. The aim of this study was to identify the unreported bioactive compounds from T. molitor larvae with inhibitory activities against factor Xa (FXa) and platelet aggregation. Isolated compounds were evaluated for their anti-FXa and anti-platelet aggregation properties by monitoring clotting time, platelet aggregation, FXa activity, and thrombus formation. A diketopiperazine (1, cyclo(L-Pro-L-Tyr)) and a phenylethanoid (2, N acetyltyramine) were isolated and inhibited the catalytic activity of FXa in a mixed inhibition model and inhibited platelet aggregation induced by adenosine diphosphate (ADP) and U46619. They inhibited ADP- and U46619-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) and the expression of P-selectin and PAC-1 in platelets. They also improved the production of nitric oxide and inhibited the oversecretion of endothelin-1 compared to that of the ADP- or U46619-treated group. In an animal model of arterial and pulmonary thrombosis, the isolated compounds showed enhanced antithrombotic effects. They also elicited anticoagulant effects in mice. Compounds 1-2 inhibited ADP-, collagen-, or U46619-induced platelet aggregation and showed similar anti-thrombotic efficacy to rivaroxaban, a positive control. Therefore, 1-2 could serve as candidates and provide scaffolds for the development of new anti-FXa and anti-platelet drugs. PMID- 28844964 TI - Regenerating bone with bioactive glass scaffolds: A review of in vivo studies in bone defect models. AB - : Large bone defects resulting from fractures and disease are a medical concern, being often unable to heal spontaneously by the body's repair mechanisms. Bone tissue engineering (BTE) is a promising approach for treating bone defects through providing a template to guide osseous regeneration. 3D scaffolds with microstructure mimicking host bone are necessary in common BTE strategies. Bioactive glasses (BGs) attract researchers' attention as BTE scaffolds as they are osteoconductive and osteoinductive in certain formulations. In vivo animal models allow understanding and evaluation of materials' performance in the complex physiological environment, being an inevitable step before clinical trials. The aim of this paper is to review for the first time published research investigating the in vivo osseous regenerative capacity of 3D BG scaffolds in bone defect animal models, to better understand and evaluate the progress and future outlook of the use of such scaffolds in BTE. The literature analysis reveals that the regenerative capacity of BG scaffolds depends on several factors; including BG composition, fabrication method, scaffold microstructure and pore characteristics, in addition to scaffold pretreatment and whether or not the scaffolds are loaded with growth factors. In addition, animal species selected, defect size and implantation time affect the scaffold in vivo behavior and outcomes. The review of the literature also makes clear the difficulty encountered to compare different types of bioactive glass scaffolds in their bone forming ability. Even considering such limitations of the current state-of-the art, results generated from animal bone defect models provide an essential source of information to guide the design of BG scaffolds in future. STATEMENT OF SIGNIFICANCE: Bioactive glasses are at the centre of increasing research efforts in bone tissue engineering as the number of research groups around the world carrying out research on this type of biomaterials continues to increase. However, there are no previous reviews in literature which specifically cover investigations of the performance of bioactive glass scaffolds in bone defect animal models. This is the topic of the present review, in which we have analysed comprehensively all available literature in the field. The review thus fills a gap in the biomaterials literature providing a broad platform of information for researchers interested in bioactive glasses in general and specifically in the outcomes of in vivo models. Bioactive glass scaffolds of different compositions tested in relevant bone defect models are covered. PMID- 28844965 TI - Osteosynthesis of a cranio-osteoplasty with a biodegradable magnesium plate system in miniature pigs. AB - : Biodegradable magnesium alloys are a new class of implant material suitable for bone surgery. The aim of this study was to investigate plates and screws made of magnesium for osteosynthesis in comparison to titanium in a cranial fracture model. Implants were used for internal fixation of a cranio-osteoplasty in nine minipigs. Computed tomography was conducted repeatedly after surgery. The implants and the adjacent tissues were harvested 10, 20 and 30weeks after surgery and investigated by micro-computed tomography and histological analysis. The surgical procedure and the inserted osteosynthesis material were well tolerated by the animals, and the bone healing of the osteoplasty was undisturbed at all times. The adjacent bone showed formation of lacunas in the magnesium group, resulting in a lower bone-to-implant contact ratio than that of titanium (72 vs. 94% at week 30), but this did not lead to clinical side effects. Radiological measurements showed no reduction in osteosynthesis material volume, but indicated signs of degradation: distinct volumes within the magnesium osteosynthesis group had lower density in micro-computed tomography, and these volumes increased up to 9% at week 30. The histological preparations showed areas of translucency and porosity inside the magnesium, but the outer shape of the osteosynthesis material remained unchanged. No fracture or loosening of the osteosynthesis devices appeared. Soft tissue probes confirmed sufficient biocompatibility. Given their biodegradable capacity, biocompatibility, mechanical strength and visibility on radiographs, osteosynthesis plates made of magnesium alloys are suitable for internal fixation procedures. STATEMENT OF SIGNIFICANCE: To the best of our knowledge this is the first study that used biodegradable magnesium implants for osteosynthesis in a cranial fracture model. The cranio-osteoplasty in miniature pigs allowed in vivo application of plate and screw osteosynthesis of standard sized implants and the implementation of surgical procedures similar to those conducted on human beings. The osteosynthesis configuration, size, and mechanical properties of the magnesium implants within this study were comparable to those of titanium-based osteosynthesis materials. The results clearly show that bone healing was undisturbed in all cases and that the biocompatibility to hard- and soft tissue was sufficient. Magnesium implants might help to avoid long-term complications and secondary removal procedures due to their biodegradable properties. PMID- 28844966 TI - Lipopolysaccharide-specific binding C-type lectin with one CRD domain from Fenneropenaeus merguiensis (FmLC4) functions as a pattern recognition receptor in shrimp innate immunity. AB - In crustaceans, an innate immune system is solely required because they lack an adaptive immunity. One kind of pattern recognition receptors (PRRs) that plays a particular role in the innate immunity of aquatic shrimp is lectin. A new diverse C-type lectin (FmLC4) was cloned from the hepatopancreas of Fenneropenaeus merguiensis by using RT-PCR and 5' and 3' rapid amplification of cDNA ends approaches. A full-length FmLC4 cDNA comprises 706 bp with an open reading frame of 552 bp, encoding a peptide of 184 amino acids. The predicted primary sequence of FmLC4 consists of a signal peptide of 19 amino acids, a molecular mass of 20.4 kDa, an isoelectric point of 5.13, one carbohydrate recognition domain with a QPD motif and a Ca2+ binding site as well as a double-loop characteristic supported by two conserved disulfide bonds. The FmLC4 mRNA expression was found only in the hepatopancreas of normal shrimp and significantly up-regulated upon challenge the shrimp with Vibrio harveyi or white spot syndrome virus (WSSV). Recombinant FmLC4 (rFmLC4) could agglutinate various bacterial strains with Ca2+-dependence. Lipopolysaccharide (LPS) could specifically inhibit the agglutinating activity and potently bind to rFmLC4, indicating that FmLC4 was LPS-specific binding C type lectin. Moreover, rFmLC4 itself displayed the in vivo effective clearance of the pathogenic bacterium V. harveyi. Altogether, FmLC4 may serve as LPS-specific PRR to recognize opportunistic bacterial and viral pathogens, and thus to play a role in the immune defense of aquatic shrimp via the binding and agglutination. PMID- 28844968 TI - Aging and immortality in unicellular species. AB - It has been historically thought that in conditions that permit growth, most unicellular species do not to age. This was particularly thought to be the case for symmetrically dividing species, as such species lack a clear distinction between the soma and the germline. Despite this, studies of the symmetrically dividing species Escherichia coli and Schizosaccharomyces pombe have recently started to challenge this notion. They indicate that E. coli and S. pombe do age, but only when subjected to environmental stress. If true, this suggests that aging may be widespread among microbial species in general, and that studying aging in microbes may inform other long-standing questions in aging. This review examines the recent evidence for and against replicative aging in symmetrically dividing unicellular organisms, the mechanisms that underlie aging, why aging evolved in these species, and how microbial aging fits into the context of other questions in aging. PMID- 28844967 TI - cDNA cloning, expression and immune function analysis of a novel Rac1 gene (AjRac1) in the sea cucumber Apostichopus japonicus. AB - The ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to Ras homolog (Rho) small GTPases subfamily. As an important molecular switch, Rac1 regulates various processes in the cell, especially in cellular immune response. With attempt to clarify characters and functions of Rac1 in sea cucumbers, full length cDNA of a Rac1 homolog in the sea cucumber Apostichopus japonicus (AjRac1) was cloned by transcriptome database mining and rapid amplification of cDNA ends (RACE) techniques. The open reading frame of AjRac1 is 579 bp encoding a protein with a length of 192 aa. Sequence analysis showed that AjRac1 is highly conserved as compared to those from other eukaryotic species. Phylogenetic analysis revealed that amino acid sequence of AjRac1 closely related to those from Strongylocentrotus purpuratus. Results of expression analysis showed that AjRac1 exhibited a relative high expression in blastula stage, adult coelomocytes and respiratory tree in A. japonicus. The transcription of AjRac1 in adult coelomocytes altered significantly at 4 h- and 12 h-after Vibrio splendidus infection, respectively, which indicated that AjRac1 involved in sea cucumber innate immunity. All data presented in this study will deepen our understanding of characterizations and immunological functions of Rac1 in sea cucumbers. PMID- 28844969 TI - Age related depth profiles of human Stratum Corneum barrier-related molecular parameters by confocal Raman microscopy in vivo. AB - In this study, stratum corneum (SC) depth profiles of hydrogen bound water molecule types, intercellular lipid (ICL) ordering, concentration of natural moisturizing factor (NMF) and keratin folding/unfolding properties are investigated in vivo for older (mean 50 years old) and younger (mean 29 years old) human skin using confocal Raman microscopy. The results show that the SC of the older group is modestly thicker (p<0.1), has more hydrogen bound water molecules at the depth 10-30% of the SC thickness (p<0.05), has a higher ordered organization of ICL (p<0.1) and higher concentration of NMF (p<0.05) at the depth 20-40% of the SC thickness compared to the younger group. This study also reveals, that the hydrogen bonding state of water highly correlates with NMF and the lateral structure of ICL but not with keratin's folding/unfolding properties. The presented results let suggest, that the decreased trans-epidermal water loss (TEWL) with increasing age cannot be sufficiently explained by only the increased SC thickness, but additionally by the increase of ICL ordering, higher NMF concentration and thus larger amount of hydrogen bound water molecules at the depth 20-40% of the SC thickness. PMID- 28844970 TI - Role of DNA methylation in human age prediction. AB - DNA methylation (DNAm) is a fundamental biochemical modification which occurs over the lifespan of an individual and it is a significant component in the aging process. Methylation level of CpG sites plays an important role in finding the age of a person. Different approaches were used to extract age-related CpG (AR CpG) sites for developing age-prediction models because the level of methylation is directly related to age for some CpG sites. Several age prediction models have been developed over the past few years and most of these models were based on regression techniques. This paper reviews and analyzes age-prediction models developed using methylated data. The first section introduces the problem of aging in humans. In the next section, the concept of DNA methylation is described in detail. Thereafter, DNA methylation based age-prediction methods are discussed. In addition to this, a summary of all these methods is also provided. Finally, some limitations of the current research along with future directions are given. PMID- 28844971 TI - Genetically driven antioxidant capacity in a Caucasian Southeastern European population. AB - Previous studies have underlined the function of specific xenobiotic metabolizing phase-I or phase-II enzymes and endogenous antioxidant-related enzymes in the reduction and/or progression of oxidative stress and consequently the incidence of several diseases. In the present study, 10 polymorphic variants (rs4880, rs1799895, rs660339, rs1050450, rs1001179, rs28665122, rs1695, rs1138272, rs1051740 and rs2234922) were investigated in 1132 individuals of a Caucasian Southeastern European population. The frequency distribution of alleles and genotypes was compared to data of European (Northern, Central, Northwestern and Southwestern) and Global populations, extracted from the ensembl genome browser. The allele frequencies in the case of rs1051740 were similar to the frequencies noted in the global population. The majority of the present study allelic polymorphisms showed similar frequency distribution to those of the European or the Global populations (0.88<=OR<=1.14). The rs1051740 polymorphism demonstrated similar to the Global population frequencies (OR=1.09). In conclusion, observed distributions of the polymorphisms studied in the Southeastern population demonstrate a positive impact (rs4880, rs1799895, rs660339, rs28665122) and a negative impact (rs1050450, rs1138272, rs109179, rs1695) against oxidative stress when compared to other population groups. PMID- 28844972 TI - Hypoxia acclimation increases novelty response strength during fast-starts in the African mormyrid, Marcusenius victoriae. AB - Many fishes perform quick and sudden swimming maneuvers known as fast-starts to escape when threatened. In pulse-type weakly electric fishes these responses are accompanied by transient increases in the rate of electric signal production known as novelty responses. While novelty responses may increase an individual's information about their surroundings, they are aerobically powered and may come at a high energetic cost when compared to fast-starts, which rely primarily on anaerobic muscle. The juxtaposition between two key aspects of fast-starts in these fishes - the aerobic novelty response and the anaerobic swimming performance - makes them an interesting model for studying effects of hypoxia on escape performance and sensory information acquisition. We acclimated the hypoxia tolerant African mormyrid Marcusenius victoriae to either high or low dissolved oxygen (DO) levels for 8weeks, after which fast-starts and novelty responses were quantified under both high (normoxic) and low-DO (hypoxic) test conditions. Hypoxia-acclimated fish exhibited higher maximum curvature than normoxia acclimated fish. Displacement of normoxia-acclimated fish was not reduced under acute hypoxic test conditions. Novelty responses were given upon each startle, whether or not the fish performed a fast-start; however, novelty responses associated with fast-starts were significantly stronger than those without, suggesting a functional link between fast-start initiation and the motor control of the novelty response. Overall, hypoxia-acclimated individuals produced significantly stronger novelty responses during fast-starts. We suggest that increased novelty response strength in hypoxia-acclimated fish corresponds to an increased rate of sensory sampling, which may compensate for potential negative effects of hypoxia on higher-level processing. PMID- 28844974 TI - Glabridin induces overexpression of two major apoptotic genes, MCA1 and NUC1, in Candida albicans. AB - OBJECTIVES: The growing trend in emergence of antifungal-resistant Candida strains has recently inspired researchers to design new antifungal agents with novel mechanisms of action. Glabridin is a natural substrate with multiple biological activities. In this study, the antifungal effects and possible mechanism of action of glabridin were investigated. METHODS: Minimum inhibitory concentrations (MICs) of glabridin against fluconazole (FLU)-resistant and FLU susceptible Candida albicans strains were investigated according to Clinical and Laboratory Standards Institute (CLSI) guidelines. To investigate the possible mechanism of action, expression of two critical genes involved in yeast apoptosis (MCA1 and NUC1) was assayed by real-time PCR. RESULTS: FLU-susceptible and FLU resistant C. albicans strains showed the same glabridin MICs (MIC50, 8MUg/mL). Therefore, a distinct azole-independent mechanism might be responsible for the inhibitory activity of glabridin. Overexpression of MCA1 and NUC1 was observed in C. albicans cells treated with glabridin, suggesting the involvement of apoptosis signalling in C. albicans strains exposed to glabridin. CONCLUSION: This study suggests that glabridin might be considered a safe agent to fight against C. albicans strains. PMID- 28844973 TI - In-vitro in-vivo correlation (IVIVC) in nanomedicine: Is protein corona the missing link? AB - One of the unmet challenges in nanotechnology is to understand and establish the relationship between physicochemical properties of nanoparticles (NPs) and its biological interactions (bio-nano interactions). However, we are still far from assessing the biofate of NPs in a clear and unquestionable manner. Recent developments in the area of bio-nano interface and the understanding of protein corona (PC) has brought new insight in predicting biological interactions of NPs. PC refers to the spontaneous formation of an adsorbed layer of biomolecules on the surface of NPs in a biological environment. PC formation involves the spatiotemporal interplay of an intricate network of biological, environmental and particle characteristics. NPs with its PC can be viewed as a biological entity, which interacts with cells and barriers in a biological system. Recent studies on the bio-nano interface have revealed biological signatures that participate in cellular and physiological bioprocesses and control the biofate and toxicity of NPs. The ability of in-vitro derived parameters to forecast in-vivo consequences by developing a mathematical model forms the basis of in-vitro in-vivo correlation (IVIVC). Understanding the effect of bio-nano interactions on the biological consequences of NPs at the cellular and physiological level can have a direct impact on the translation of future nanomedicines and can lead to the ultimate goal of developing a mathematical IVIVC model. The review summarizes the emerging paradigms in the field of bio-nano-interface which clearly suggests an urgent need to revisit existing protocols in nanotechnology for defining the physicochemical correlates of bio-nano interactions. PMID- 28844975 TI - Characterisation of two novel bacteriocin-like substances produced by Bacillus amyloliquefaciens ELI149 with broad-spectrum antimicrobial activity. AB - OBJECTIVES: The aim of this study was to isolate and characterise antifungal and bactericidal compounds from Bacillus amyloliquefaciens strain ELI149. METHODS: An absorbent resin (Amberlite(r) XAD-16) and silica gel column chromatography were used for isolation and purification purposes, respectively. Antibacterial and antifungal assays were performed by the well diffusion method to demonstrate the biological activity of each compound. Cell damage of the tested fungi was evaluated for fengycin under phase-contrast microscopy. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectroscopy techniques were performed to estimate the approximate molecular mass of each compound. RESULTS: Two bacteriocin-like substances (BLSs) with different physical properties and inhibitory activities were isolated along with two known antifungal compounds. The two BLSs were heat stable and were not sensitive to acid or alkaline conditions (pH 2-10), with broad-spectrum antimicrobial activity. The antifungal compounds were identified as surfactin and fengycin. Only fengycin showed marked antifungal properties against several phytopathogens. CONCLUSIONS: The two isolated BLSs were partially characterised and their bactericidal properties were analysed. The antifungals compounds were identified as surfactin and fengycin, this latter being mainly responsible for the antifungal activity. PMID- 28844976 TI - A calmodulin-like protein (LCALA) is a new Leishmania amazonensis candidate for telomere end-binding protein. AB - BACKGROUND: Leishmania spp. telomeres are composed of 5'-TTAGGG-3' repeats associated with proteins. We have previously identified LaRbp38 and LaRPA-1 as proteins that bind the G-rich telomeric strand. At that time, we had also partially characterized a protein: DNA complex, named LaGT1, but we could not identify its protein component. METHODS AND RESULTS: Using protein-DNA interaction and competition assays, we confirmed that LaGT1 is highly specific to the G-rich telomeric single-stranded DNA. Three protein bands, with LaGT1 activity, were isolated from affinity-purified protein extracts in-gel digested, and sequenced de novo using mass spectrometry analysis. In silico analysis of the digested peptide identified them as a putative calmodulin with sequences identical to the T. cruzi calmodulin. In the Leishmania genome, the calmodulin ortholog is present in three identical copies. We cloned and sequenced one of the gene copies, named it LCalA, and obtained the recombinant protein. Multiple sequence alignment and molecular modeling showed that LCalA shares homology to most eukaryotes calmodulin. In addition, we demonstrated that LCalA is nuclear, partially co-localizes with telomeres and binds in vivo the G-rich telomeric strand. Recombinant LCalA can bind specifically and with relative affinity to the G-rich telomeric single-strand and to a 3'G-overhang, and DNA binding is calcium dependent. CONCLUSIONS: We have described a novel candidate component of Leishmania telomeres, LCalA, a nuclear calmodulin that binds the G-rich telomeric strand with high specificity and relative affinity, in a calcium-dependent manner. GENERAL SIGNIFICANCE: LCalA is the first reported calmodulin that binds in vivo telomeric DNA. PMID- 28844977 TI - The reversible function switching of the circadian clock protein KaiA is encoded in its structure. AB - BACKGROUND: Circadian rhythms are important to the evolution of organisms and human health, and recent studies proved that post-translational circadian clocks widely exist in all phyla. The circadian clock of cyanobacteria is an important model system as the first verified circadian oscillator independent of transcriptional-/translational-level regulations. This circadian oscillator consists of three proteins, KaiA, KaiB, and KaiC, in which KaiA stimulates KaiC's phosphorylation but KaiB antagonizes KaiA. Despite of intense research on the molecular mechanism of this oscillator in the last decades, the regulation mechanism of KaiA's function remains unclear. METHODS: In this study, we combined computational tools and experimental assays to study the function switching of KaiA. We adopted different strategies to re-design KaiA protein to elucidate its function switch during the circadian oscillation. RESULTS: We showed that KaiA's function switch is determined by its structural dynamics, and KaiB antagonizes KaiA by switching it from an active state to an inactive state with the help of KaiC. CONCLUSIONS: The reversible function switching of KaiA is key to the KaiABC oscillator, and the switching could be regulated by the 3-D domain swapped homo dimer conformation of KaiA, which provides the necessary structural flexibility. GENERAL SIGNIFICANCE: Our finding updated the current knowledge on the regulation of KaiA's function. This work would deepen our understanding of the KaiABC oscillator, and should be conceptually useful in the design of artificial biological oscillators. PMID- 28844978 TI - Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter. AB - BACKGROUND: Trypanosoma cruzi, the etiological agent of Chagas disease, uses proline as its main carbon source, essential for parasite growth and stage differentiation in epimastigotes and amastigotes. Since proline is involved in many essential biological processes in T. cruzi, its transport and metabolism are interesting drug targets. METHODS: Four synthetic proline analogues (ITP 1B/1C/1D/1G) were evaluated as inhibitors of proline transport mediated through the T. cruzi proline permease TcAAAP069. The trypanocidal activity of the compounds was also assessed. RESULTS: The compounds ITP-1B and ITP-1G inhibited proline transport mediated through TcAAAP069 permease in a dose-dependent manner. The analogues ITP-1B, -1D and -1G had trypanocidal effect on T. cruzi epimastigotes with IC50 values between 30 and 40MUM. However, only ITP-1G trypanocidal activity was related with its inhibitory effect on TcAAAP069 proline transporter. Furthermore, this analogue strongly inhibited the parasite stage differentiation from epimastigote to metacyclic trypomastigote. Finally, compounds ITP-1B and ITP-1G were also able to inhibit the transport mediated by other permeases from the same amino acid permeases family, TcAAAP. CONCLUSIONS: It is possible to design synthetic amino acid analogues with trypanocidal activity. The compound ITP-1G is an interesting starting point for new trypanocidal drug design which is also an inhibitor of transport of amino acids and polyamines mediated by permeases from the TcAAAP family, such as proline transporter TcAAAP069 among others. GENERAL SIGNIFICANCE: The Trypanosoma cruzi amino acid transporter family TcAAAP constitutes a multiple and promising therapeutic target for the development of new treatments against Chagas disease. PMID- 28844979 TI - Tailoring naringenin conjugates with amplified and triple antiplatelet activity profile: Rational design, synthesis, human plasma stability and in vitro evaluation. AB - BACKGROUND: The current standard-of-care antiplatelet therapy in cardiovascular disease patients is consisted of cyclooxygenase-1 (COX-1) inhibitor aspirin, along with a platelet receptor P2Y12 antagonist. Recently, the triple antiplatelet therapy with aspirin, a P2Y12 receptor antagonist and a protease activated receptor-1 (PAR-1) antagonist, has been suggested for the secondary prevention of atherothrombotic events, however presented an increased risk of bleeding. Therefore, the quest for novel antiplatelet agents simultaneously targeting the three pathways with improved efficacy/safety profile is of immense importance. Flavonoids as pre-validated ligands for numerous targets could serve as scaffolds targeting the three platelet activation pathways. METHODS: Computational methods, Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) plasma stability and in vitro platelet aggregation experiments were used to establish the antiplatelet activity of the flavonoid naringenin and its conjugates. RESULTS: In silico studies indicated that naringenin could bear a potent triple antiplatelet activity by inhibiting different platelet aggregation mechanisms. However, we found that in human platelets naringenin has diminished activity. We rationally designed and synthesized different naringenin conjugates aiming to amplify the antiplatelet activity of the parent compound. UHPLC-MS/MS revealed a slow degradation rate for a docosahexaenoic acid (DHA) - naringenin conjugate in human plasma. The antiplatelet profile of the new analogues was evaluated against in vitro platelet aggregation induced by several platelet agonists. CONCLUSIONS: The DHA - naringenin hybrid presented triple antiplatelet activity simultaneously targeting PAR-1, P2Y12 and COX-1 platelet activation pathways. GENERAL SIGNIFICANCE: Natural products could offer a rich source for novel bioactives as a powerful alternative to the current combinatorial use of three different antiplatelet drugs. PMID- 28844980 TI - DCM associated LMNA mutations cause distortions in lamina structure and assembly. AB - BACKGROUND: A and B-type lamins are integral scaffolding components of the nuclear lamina which impart rigidity and shape to all metazoan nuclei. Over 450 mutations in A-type lamins are associated with 16 human diseases including dilated cardiomyopathy (DCM). Here, we show that DCM mutants perturb the self association of lamin A (LA) and it's binding with lamin B1 (LB1). METHODS: We used confocal and superresolution microscopy (NSIM) to study the effect of LA mutants on the nuclear lamina. We further used circular dichroism, fluorescence spectroscopy and isothermal titration calorimetry (ITC) to probe the structural modulations, self-association and heteropolymeric association of mutant LA. RESULTS: Transfection of mutants in cultured cell lines result in the formation of nuclear aggregates of varied size and distribution. Endogenous LB1 is sequestered into these aggregates. This is consistent with the ten-fold increase in association constant of the mutant proteins compared to the wild type. These mutants exhibit differential heterotypic interaction with LB1, along with significant secondary and tertiary structural alterations of the interacting proteins. Thermodynamic studies demonstrate that the mutants bind to LB1 with different stoichiometry, affinity and energetics. CONCLUSIONS: In this report we show that increased self-association propensity of mutant LA modulates the LA-LB1 interaction and precludes the formation of an otherwise uniform laminar network. GENERAL SIGNIFICANCE: Our results might highlight the role of homotypic and heterotypic interactions of LA in the pathogenesis of DCM and hence laminopathies in the broader sense. PMID- 28844982 TI - Mast cell degranulation via MRGPRX2 by isolated human albumin fragments. AB - BACKGROUND: Mast cells are important modulators of the human immune system via their release of several inflammatory mediators and proteases. The release can be activated by different pathways: the classical immunoglobulin E-dependent pathway and by the non-immunological immunoglobulin E-independent pathway. MAS-related G protein-coupled receptor X2 (MRGPRX2) is expressed in mast cells and it is one of the endogenous receptor responsible for the IgE-independent activation of human mast cell. The MRGPRX2 is classified as orphan receptor and unlike most GPCRs, the MRGPRX2 recognizes a wide range of basic molecules. Thus, there still might be several unknown ligands for the receptor. METHODS: MRGPRX2 activating peptides were isolated from human plasma using consecutive HPLC purification steps. The isolation process was monitored with MRGPRX2 transfected HEK 293 cells. The isolated peptides were sequenced by MS and synthetized. The synthetic peptides were used to determine degranulation of the human LAD 2 mast cell line by measuring beta-hexosaminidase release. RESULTS: Three endogenous MRGPRX2 activating peptides were isolated from human plasma. These peptides are identified as fragments of albumin. The isolated fragments activate MRGPRX2 and degranulate MRGPRX2 expressing LAD 2 cells in dose-dependent manner. CONCLUSIONS: The isolated basic peptides generated from human albumin are able to degranulate mast cells via the MRGPRX2. GENERAL SIGNIFICANCE: These endogenous albumin fragments, cleaved from albumin by mast cell secreted proteases, provide a possible pathway for self-perpetuating mast cell dependent inflammation. PMID- 28844983 TI - Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease. AB - DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, S-), oxidized (Cys106, SO2-), and over-oxidized (Cys106, SO3 ) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease. PMID- 28844984 TI - Epidermal growth factor and tumor necrosis factor alpha cooperatively promote the motility of hepatocellular carcinoma cell lines via synergistic induction of fibronectin by NF-kappaB/p65. AB - BACKGROUND: The interaction between hepatocellular carcinoma (HCC) cells and their microenvironment plays a fundamental role in tumor metastasis. The HCC microenvironment is rich in epidermal growth factor (EGF) and tumor necrosis factor alpha (TNFalpha), which may cooperatively, rather than individually, interact with tumor cells to influence their biological behavior. METHODS: Immunohistochemistry was performed to study the expression of EGF and TNFalpha in HCCs. Western blotting, immunofluorescence, qRT-PCR, wound healing scratch and invasion assay, and chromatin immunoprecipitation assays were used to study the combined roles of EGF and TNFalpha in the motility of HCC cells in vitro. RESULTS: We demonstrated that both EGF and TNFalpha were highly expressed in HCCs, and HCCs with higher expression of both EGF and TNFalpha were more frequently rated as high-grade tumors. In vitro, EGF and TNFalpha cooperatively promoted the motility of HCC cells mainly via synergistic induction of an extracellular matrix glycoprotein fibronectin (FN). Mechanistically, EGF and TNFalpha jointly increased the nuclear translocation and PKC mediated phosphorylation of NF-kappaB/p65 which could bind to the -356bp to -259bp fragment of the FN promoter, leading to a markedly increased activity of the FN promoter in HCC cells. CONCLUSIONS: HCCs with higher expression of both EGF and TNFalpha were more frequently rated as high-grade tumors. EGF and TNFalpha cooperatively promoted the motility of HCC cells mainly through NF-kappaB/p65 mediated synergistic induction of FN in vitro. GENERAL SIGNIFICANCE: These findings highlight the crosstalk between EGF and TNFalpha in promoting HCC, and provide potential targets for HCC prevention and treatment. PMID- 28844986 TI - Design and challenges for a randomized, multi-site clinical trial comparing the use of service dogs and emotional support dogs in Veterans with post-traumatic stress disorder (PTSD). AB - Posttraumatic stress disorder (PTSD) is a leading cause of impairments in quality of life and functioning among Veterans. Service dogs have been promoted as an effective adjunctive intervention for PTSD, however published research is limited and design and implementation flaws in published studies limit validated conclusions. This paper describes the rationale for the study design, a detailed methodological description, and implementation challenges of a multisite randomized clinical trial examining the impact of service dogs on the on the functioning and quality of life of Veterans with PTSD. Trial design considerations prioritized participant and intervention (dog) safety, selection of an intervention comparison group that would optimize enrollment in all treatment arms, pragmatic methods to ensure healthy well-trained dogs, and the selection of outcomes for achieving scientific and clinical validity in a Veteran PTSD population. Since there is no blueprint for conducting a randomized clinical trial examining the impact of dogs on PTSD of this size and scope, it is our primary intent that the successful completion of this trial will set a benchmark for future trial design and scientific rigor, as well as guiding researchers aiming to better understand the role that dogs can have in the management of Veterans experiencing mental health conditions such as PTSD. PMID- 28844985 TI - Pediatric advance care planning (pACP) for teens with cancer and their families: Design of a dyadic, longitudinal RCCT. AB - Cancer is the leading cause of disease-related death for adolescents and young adults (AYAs) in the United States. Parents of AYAs with life-threatening illnesses have expressed the desire to talk to their children about end of life (EOL) care, yet, like caregivers of adult patients, struggle to initiate this conversation. Building Evidence for Effective Palliative/End of Life Care for Teens with Cancer is a longitudinal, randomized, controlled, single-blinded clinical trial aimed at evaluating the efficacy of FAmily CEntered disease specific advance care planning (ACP) for teens with cancer (FACE-TC). A total of 130 dyads (260 subjects) composed of AYAs 14-20years old with cancer and their family decision maker (>=18years old) will be recruited from pediatric oncology programs at Akron Children's Hospital and St. Jude Children's Research Hospital. Dyads will be randomized to either the FACE-TC intervention or Treatment as Usual (TAU) control. FACE-TC intervention dyads will complete three 60-minute ACP sessions held at weekly intervals. Follow-up data will be collected at 3, 6, 12, and 18months post-intervention by a blinded research assistant (RA). The effects of FACE-TC on patient-family congruence in treatment preferences, quality of life (QOL), and advance directive completion will be analyzed. FACE-TC is an evidenced based and patient-centered intervention that considers QOL and EOL care according to the AYA's representation of illness. The family is involved in the ACP process to facilitate shared decision making, increase understanding of the AYA's preferences, and make a commitment to honor the AYA's wishes. PMID- 28844987 TI - Association between maternal vitamin D deficiency and small for gestational age: evidence from a meta-analysis of prospective cohort studies. AB - OBJECTIVE: To determine whether maternal vitamin D deficiency during pregnancy is associated with small for gestational age (SGA). METHODS: A comprehensive literature search of PubMed, the Cochrane Library, Embase, and the Elsevier ScienceDirect library was conducted to identify relevant articles reporting prospective cohort studies in English, with the last report included published in February 2017. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to evaluate the correlation in a random effects model. RESULTS: A total of 13 cohort studies were included in this meta-analysis with a sample of 28 285 individuals from seven countries. The pooled overall OR for babies born SGA was 1.588 (95% CI 1.138 to 2.216; p<0.01) for women with vitamin D deficiency. The prevalence of vitamin D deficiency during pregnancy varied from 13.2% to 77.3%. Subgroup analyses identified no significant differences in the association between vitamin D deficiency and SGA based on study quality, gestational week during which blood sampling was performed, cut-off vitamin D levels, sample size, adjustment for critical confounders and method for measuring vitamin D. CONCLUSION: This meta-analysis suggests that vitamin D deficiency is associated with an increased risk of SGA. PMID- 28844988 TI - Risk factors, demographics and clinical profile of Acanthamoeba keratitis in Melbourne: an 18-year retrospective study. AB - PURPOSE: To assess incidence, risk factors, presentation and final visual outcome of patients with Acanthamoebakeratitis (AK) treated at the Royal Victorian Eye and Ear Hospital (RVEEH), Melbourne, Australia, over an 18-year period. METHODS: A retrospective review of all cases of AK managed at RVEEH between January 1998 and May 2016 was performed. Data collected included age, gender, affected eye, signs and symptoms, time between symptoms and diagnosis, risk factors, presenting and final visual acuity (VA), investigations, medical treatment, surgical interventions and length of follow-up. RESULTS: A total of 36 eyes affected by AK in 34 patients were identified. There were 26 cases diagnosed early (<30 days) and 10 were diagnosed late (>=30 days). There were 31 (86.1%) cases associated with contact lens (CL). Signs associated with early AK included epithelial infiltrates, while signs of late AK included uveitis, ring infiltrate, endothelial plaque and corneal thinning (p<0.05). Surgical treatment was required in seven cases (19.4%). There were 29 (80.6%) cases that reported improved VA. Median best corrected final VA was worse in patients with late diagnosis (logarithm of minimal angle of resolution (logMAR) 0.5, IQR: 0.2-0.8), compared with patients with early diagnosis (logMAR 0.0, IQR: 0.0-0.3; p=0.01). Late diagnosis was associated with a prolonged disease period. CONCLUSION: AK was an uncommon cause of severe keratitis and was associated commonly with CL. Patients with late diagnosis had worse presenting and final VAs as well as a prolonged disease period, indicating need for early recognition and management. PMID- 28844981 TI - Marine natural product peptides with therapeutic potential: Chemistry, biosynthesis, and pharmacology. AB - The oceans are a uniquely rich source of bioactive metabolites, of which sponges have been shown to be among the most prolific producers of diverse bioactive secondary metabolites with valuable therapeutic potential. Much attention has been focused on marine bioactive peptides due to their novel chemistry and diverse biological properties. As summarized in this review, marine peptides are known to exhibit various biological activities such as antiviral, anti proliferative, antioxidant, anti-coagulant, anti-hypertensive, anti-cancer, antidiabetic, antiobesity, and calcium-binding activities. This review focuses on the chemistry and biology of peptides isolated from sponges, bacteria, cyanobacteria, fungi, ascidians, and other marine sources. The role of marine invertebrate microbiomes in natural products biosynthesis is discussed in this review along with the biosynthesis of modified peptides from different marine sources. The status of peptides in various phases of clinical trials is presented, as well as the development of modified peptides including optimization of PK and bioavailability. PMID- 28844989 TI - Acute Myocardial Infarction: Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-MI Program (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) 1995 to 2015. AB - BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) management has evolved considerably over the past 2 decades. Little information on mortality trends in the most recent years is available. We assessed trends in characteristics, treatments, and outcomes for acute myocardial infarction in France between 1995 and 2015. METHODS: We used data from 5 one-month registries, conducted 5 years apart, from 1995 to 2015, including 14 423 patients with acute myocardial infarction (59% STEMI) admitted to cardiac intensive care units in metropolitan France. RESULTS: From 1995 to 2015, mean age decreased from 66+/-14 to 63+/-14 years in patients with STEMI; it remained stable (68+/-14 years) in patients with NSTEMI, whereas diabetes mellitus, obesity, and hypertension increased. At the acute stage, intended primary percutaneous coronary intervention increased from 12% (1995) to 76% (2015) in patients with STEMI. In patients with NSTEMI, percutaneous coronary intervention <=72 hours from admission increased from 9% (1995) to 60% (2015). Six-month mortality consistently decreased in patients with STEMI from 17.2% in 1995 to 6.9% in 2010 and 5.3% in 2015; it decreased from 17.2% to 6.9% in 2010 and 6.3% in 2015 in patients with NSTEMI. Mortality still decreased after 2010 in patients with STEMI without reperfusion therapy, whereas no further mortality gain was found in patients with STEMI with reperfusion therapy or in patients with NSTEMI, whether or not they were treated with percutaneous coronary intervention. CONCLUSIONS: Over the past 20 years, 6-month mortality after acute myocardial infarction has decreased considerably for patients with STEMI and NSTEMI. Mortality figures continued to decline in patients with STEMI until 2015, whereas mortality in patients with NSTEMI appears stable since 2010. PMID- 28844991 TI - Recalibrating Reperfusion Waypoints. PMID- 28844990 TI - Efficacy and Safety of a Pharmaco-Invasive Strategy With Half-Dose Alteplase Versus Primary Angioplasty in ST-Segment-Elevation Myocardial Infarction: EARLY MYO Trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST-Segment-Elevation Myocardial Infarction). AB - BACKGROUND: Timely primary percutaneous coronary intervention (PPCI) cannot be offered to all patients with ST-segment-elevation myocardial infarction (STEMI). Pharmaco-invasive (PhI) strategy has been proposed as a valuable alternative for eligible patients with STEMI. We conducted a randomized study to compare the efficacy and safety of a PhI strategy with half-dose fibrinolytic regimen versus PPCI in patients with STEMI. METHODS: The EARLY-MYO trial (Early Routine Catheterization After Alteplase Fibrinolysis Versus Primary PCI in Acute ST Segment-Elevation Myocardial Infarction) was an investigator-initiated, prospective, multicenter, randomized, noninferiority trial comparing a PhI strategy with half-dose alteplase versus PPCI in patients with STEMI 18 to 75 years of age presenting <=6 hours after symptom onset but with an expected PCI related delay. The primary end point of the study was complete epicardial and myocardial reperfusion after PCI, defined as thrombolysis in myocardial infarction flow grade 3, thrombolysis in myocardial infarction myocardial perfusion grade 3, and ST-segment resolution >=70%. We also measured infarct size and left ventricular ejection fraction with cardiac magnetic resonance and recorded 30-day clinical and safety outcomes. RESULTS: A total of 344 patients from 7 centers were randomized to PhI (n=171) or PPCI (n=173). PhI was noninferior (and even superior) to PPCI for the primary end point (34.2% versus 22.8%, Pnoninferiority<0.05, Psuperiority=0.022), with no significant differences in the frequency of the individual components of the combined end point: thrombolysis in myocardial infarction flow 3 (91.3% versus 89.2%, P=0.580), thrombolysis in myocardial infarction myocardial perfusion grade 3 (65.8% versus 62.9%, P=0.730), and ST-segment resolution >=70% (50.9% versus 45.5%, P=0.377). Infarct size (23.3%+/-11.3% versus 25.8%+/-13.7%, P=0.101) and left ventricular ejection fraction (52.2%+/-11.0% versus 51.4%+/-12.0%, P=0.562) were similar in both groups. No significant differences occurred in 30-day rates of total death (0.6% versus 1.2%, P=1.0), reinfarction (0.6% versus 0.6%, P=1.0), heart failure (13.5% versus 16.2%, P=0.545), major bleeding events (0.6% versus 0%, P=0.497), or intracranial hemorrhage (0% versus 0%), but minor bleeding (26.9% versus 11.0%, P<0.001) was observed more often in the PhI group. CONCLUSIONS: For patients with STEMI presenting <=6 hours after symptom onset and with an expected PCI-related delay, a PhI strategy with half-dose alteplase and timely PCI offers more complete epicardial and myocardial reperfusion when compared with PPCI. Adequately powered trials with this reperfusion strategy to assess clinical and safety outcomes are warranted. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01930682. PMID- 28844993 TI - The 2016 National Institute for Health and Care Excellence guidelines for chest pain: better outcomes with cardiac CT. PMID- 28844994 TI - New Method for Assessing the Effect of Driving Distance to Hospital Care: Using OpenStreetMap Routing in Cardiovascular Research. PMID- 28844992 TI - Diagnostic and prognostic benefits of computed tomography coronary angiography using the 2016 National Institute for Health and Care Excellence guidance within a randomised trial. AB - OBJECTIVES: To evaluate the diagnostic and prognostic benefits of CT coronary angiography (CTCA) using the 2016 National Institute for Health and Care Excellence (NICE) guidelines for the assessment of suspected stable angina. METHODS: Post hoc analysis of the Scottish COmputed Tomography of the HEART (SCOT HEART) trial of 4146 participants with suspected angina randomised to CTCA. Patients were dichotomised into NICE guideline-defined possible angina and non anginal presentations. Primary (diagnostic) endpoint was diagnostic certainty of angina at 6 weeks and prognostic endpoint comprised fatal and non-fatal myocardial infarction (MI). RESULTS: In 3770 eligible participants, CTCA increased diagnostic certainty more in those with possible angina (relative risk (RR) 2.22 (95% CI 1.91 to 2.60), p<0.001) than those with non-anginal symptoms (RR 1.30 (1.11 to 1.53), p=0.002; pinteraction <0.001). In the possible angina cohort, CTCA did not change rates of invasive angiography (p=0.481) but markedly reduced rates of normal coronary angiography (HR 0.32 (0.19 to 0.52), p<0.001). In the non-anginal cohort, rates of invasive angiography increased (HR 1.82 (1.13 to 2.92), p=0.014) without reducing rates of normal coronary angiography (HR 0.78 (0.30 to 2.05), p=0.622). At 3.2 years of follow-up, fatal or non-fatal MI was reduced in patients with possible angina (3.2% to 1.9%%; HR 0.58 (0.34 to 0.99), p=0.045) but not in those with non-anginal symptoms (HR 0.65 (0.25 to 1.69), p=0.379). CONCLUSIONS: NICE-guided patient selection maximises the benefits of CTCA on diagnostic certainty, use of invasive coronary angiography and reductions in fatal and non-fatal myocardial infarction. Patients with non-anginal chest pain derive minimal benefit from CTCA and increase the rates of invasive investigation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01149590;post results. PMID- 28844995 TI - [Expression profile of long non-coding RNA in non-alcoholic fatty liver disease]. AB - OBJECTIVE: To analyze the characteristics of long non-coding RNA (lncRNA) expression in non-alcoholic fatty liver disease (NAFLD).? Methods: lncRNA-mRNA microarray was conducted on the liver tissue samples from 10 patients with simple gallbladder stone (5 NAFLD liver samples and 5 normal liver samples), and the differentially expressed lncRNA was analyzed by bioinformatics technology.? Results: Compared with the normal liver samples, there were abnormal expression of 1 735 lncRNAs and 1 485 mRNAs in NAFLD liver samples. Among them, 535 lncRNAs and 760 mRNAs were up-regulated, 1 200 lncRNAs and 725 mRNAs were down regulated.? Conclusion: Compared with normal liver, the expression of lncRNA in NAFLD tissues is obviously abnormal. These lncRNAs may play an important role in the occurrence and development of NAFLD. PMID- 28844996 TI - [Role of p38 mitogen activated protein kinase signaling pathway in lung ischemia reperfusion protection offered by HOE642]. AB - OBJECTIVE: To explore the protective effect of sodium channels antagonists HOE642 on lung ischemia reperfusion and the role of the p38 mitogen activated protein kinase (p38MAPK) signaling pathway in this process.? Methods: A total of 36 mice were randomly divided into a sham operation group (SHAM group), a lung ischemia reperfusion group (I/R group) and a lung ischemia reperfusion+HOE642 group (HOE group). The water content was detected by electronic scales, and the lung tissue pathological changes were observed under optical microscope. The inflammatory cytokines including IL-6 and TNF-alpha were examined by ELISA. The intracellular calcium fluorescence intensity was examined and observed under fluorescence microscope, and the protein expression of p38MAPK was detected by Western blot.? Results: Lung water content in the HOE group was lower than that in the I/R group, but higher than that in the SHAM group (both P<0.05). Lung interstitial edema, hemorrhage, lung tissue inflammatory cells infiltration were significantly alleviated in the HOE group than those in the I/R group, while the injury in the HOE group was aggravated than those in the SHAM group (both P<0.05). The IL-6 and TNF-alpha in lung tissues in the HOE group were lower than those in the I/R group, but higher than those in the SHAM group (both P<0.05). Intracellular calcium fluorescence intensity in the HOE group was lower than that in the I/R group, but higher than that in the SHAM group (both P<0.05). The protein expression of p38MAPK in lung tissues in the HOE group was lower than that in the I/R group, but higher than that in the SHAM group (both P<0.05).? Conclusion: HOE642 may exert protective effect on pulmonary I/R injury through regulation of the p38MAPK signaling pathway, resulting in reduction of intracellular calcium ion concentration and calcium overload, and decrease of inflammatory response. PMID- 28844997 TI - [MiR-26b regulates invasion and migration of lung cancer cells through targeting hENT1 depending on RhoA/ROCK-1 pathway]. AB - OBJECTIVE: To investigate the effect of miR-26b on the invasion and migration of lung cancer cell and to explore its mechanism.? Methods: qPCR was used to detect the expression of miR-26b in lung cancer. Luciferase reporter gene was used to detect interaction between miR-26b and hENT1. Transwell assay was used to detect invasion ability after treatment of miR-26b mimics. Scratch assay was used to detect migration ability after treatment of miR-26b mimics. The expressions of hENT1, ROCK-1 and RhoA were detected by Western blot. The changes of cytoskeleton after miR-26b mimics treatment with phalloidin were observed. The effect of miR 26b mimics on the tumor size and volume of lung cancer was determined by subcutaneous tumor formation in nude mice.? Results: MiR-26b expression was significantly reduced in lung cancer. With the progress of lung cancer, the expression of miR-26b was reduced. With the progress in differentiation of lung cancer, the expression of miR-26b was decreased. Decrease of miR-26b was associated with lung cancer lymph node metastasis. HENT1 was the direct target of miR-26b; miR-26b regulated the invasion and migration ability of human lung carcinoma A549 cells. MiR-26b regulated the expression of hENT1, ROCK-1 and RhoA. After the treatment with miR-26b mimics, the F-actin staining was significantly reduced, whereas the formation of wrinkles and the formation of pseudopodia were significantly reduced. Subcutaneous tumor formation in nude mice showed that miR 26b mimics treatment significantly reduced the tumor size and mass.? Conclusion: MiR-26b plays a role in tumor suppression in lung cancer. miR-26b can regulate the invasion and migration ability of lung carcinoma A549 cells by targeting hENT1 depending on the RhoA/ROCK-1 pathway. PMID- 28844998 TI - [Effects of bufalin combined with doxorubicin on the proliferation and apoptosis of human lung cancer cell line A549 in vitro]. AB - OBJECTIVE: To explore the effects of bufalin (BUF) combined with doxorubicin (DOX) on the proliferation and apoptosis in human lung cancer cell line A549 in vitro.? Methods: Methyl thiazolyl tetrazolium (MTT) assay was used to measure the inhibitory effects of BUF, DOX and their combination on the growth of A549 cells. Hoechst 33342 staining was used to observe the changes of nucleus. Flow cytometry was used to investigate the apoptosis and cell cycle distribution of A549 cells. Western blot was used to examine the expression of apoptotic protein.? Results: BUF and DOX showed inhibitory effect on the A549 cells in a dose and time dependent manner. Compared with BUF or DOX alone, combination of BUF (1, 20, 100 nmol/L) with DOX (1.0 MUg/mL) could significantly increase the growth inhibition rate of A549 cells at 24, 36, 72 h, respectively (all P<0.05). BUF and DOX alone could induce apoptosis, and their combination could significantly increase the apoptosis ratio. In addition, BUF combined with DOX could block the cell stage of A549 cells, keep the cell stage stay in S stage and up-regulate the expression of caspase-3.? Conclusion: BUF combined with DOX can significantly inhibit the proliferation of A549 cells, which might be related to the induction of apoptosis, cell cycle S phase arrest and caspase-3 up-regulation. PMID- 28844999 TI - [Over-expression and suppression of HMGB1 affect proliferation and invasion of endometrial carcinoma and underlying mechanisms]. AB - OBJECTIVE: To investigate effects of over-expression and suppression of HMGB1 on proliferation and invasion of endometrial carcinoma HEC-1A cell and underlying mechanisms.? Methods: Over-expression or silence of HMGB1 in HEC-1A cell lines were established by lentiviral vector containing HMGB1 recombinant plasmid or by HMGB1 shRNA, respectively. Cell counting kit-8, Transwell, and wound healing assay were used to analyze proliferation, invasion, and migration of HEC-1A cells, respectively. Western blot and reverse transcription-PCR (RT-PCR) were used to detect the expression of NF-kappaB, VEGF, and matrix metalloproteinase 2 (MMP2) in the cells.? Results: Over-expression of HMGB1 promoted the proliferation, invasion, and migration of HEC-1A cell, and up-regulated NF kappaB, VEGF, and MMP2 expressions, while suppression of HMGB1 inhibited the proliferation, invasion, and migration of HEC-1A cells and down-regulated NF kappaB, VEGF, and MMP2 expressions.? Conclusion: HMGB1 plays an important role in proliferation, invasion, and migration of HEC-1A cell via NF-kappaB/VEGF/MMP2 pathway. HMGB1 might be a potential target for endometrial carcinoma therapy. PMID- 28845000 TI - [Application of transcription mediated amplification and real-time reverse transcription polymerase chain reaction in detection of human immunodeficiency virus RNA]. AB - OBJECTIVE: To observe the sensitivity of transcription mediated amplification (TMA), and to compare its performance with real-time reverse transcription polymerase chain reaction (real-time RT-PCR) in detecting human immunodeficiency virus RNA (HIV RNA).? Methods: TMA system was established with TaqMan probes, specific primers, moloney murine leukemia virus (MMLV) reverse transcriptase, T7 RNA polymerase, and reaction substrates. The sensitivity of TMA was evaluated by amplifying a group of 10-fold diluted HIV RNA standards which were transcribed in vitro. A total of 60 plasma of HIV infected patients were measured by TMA and Cobas Amplicor HIV-1 Monitor test to observe the positive rate. The correlation and concordance of the above two technologies were investigated by linear regression and Bland-Altman analysis.? Results: TMA system was established successfully and HIV RNA transcribed standards at concentration of equal or more than 10 copies/mL could be detected by TMA technology. Among 60 samples of plasma from HIV infected patients, 46 were positively detected and 12 were negatively amplified by both TMA and Cobas reagents; 2 samples were positively tested by Cobas reagent but negatively tested by TMA system. The concordance rate of the two methods was 97.1% and the difference of positive detection rate between the two methods was not statistically significant (P>0.05). Linear regression was used for 46 samples which were positively detected by both TMA and Cobas reagents and showed an excellent correlation between the two reagents (r=0.997, P<0.001). Bland-Altma analysis revealed that the mean different value of HIV RNA levels for denary logarithm was 0.02. Forty-four samples were included in 95% of credibility interval of concordance.? Conclusion: TMA system has the potential of high sensitivity. TMA and real-time RT-PCR keep an excellent correlation and consistency in detecting HIV RNA. PMID- 28845001 TI - [Effect of M2 macrophage against rejection on islet allografts in diabetic mice]. AB - OBJECTIVE: To explore the possibility of using peritoneal alternatively activated M2 macrophages to prevent rejection after islet allotransplantation in a murine model.? Methods: Peritoneal monocytes from C57BL/6 mice were induced and modulated to M2 and M0 macrophages in vitro, then the phenotype of macrophage was assessed by flow cytometry. C57BL/6 mice were induced diabetic by streptozotocin (STZ) injection and transplanted with islets isolated from BALB/c mice under the left kidney capsule. The recipients were randomly divided to 3 groups (n=8). A total of 2.5*106 M2 macrophages were injected intravenously at 0, 3, 7 d after transplantation in islet+M2 group; 2.5*106 M0 macrophages were injected intravenously at 0, 3, 7 d after transplantation in islet+M0 group; the mice in islet+PBS group were injected with PBS. Blood glucose was monitored after transplantation. On day 10 after transplantation, 2 recipients in each group were randomly selected and sacrificed, and the left kidneys were resected for pathological examination.? Results: Achievement of euglycemia was significantly prolonged after islet transplantation in the islet+M2 group than that in the other two groups (P<0.01). The median survival time of islet allografts in the islet+PBS group, the islet+M0 group, and the islet+M2 group were 6.5 (4-10), 7.5 (4-10), and 24(>15) d, respectively. Pathological examination also showed that the grafts in islet+M2 group remained an intact structure with positive insulin stain and no apparent lymphocytes infiltration, while the graft was rejected in other 2 groups with negative insulin stain and massive lymphocytes infiltration.? Conclusion: Peritoneal alternatively activated M2 macrophages can prevent rejection after islet allotransplantation, prolong the survival time of islet allografts and enhance the tolerance of the recipient to blood glucose in mice. PMID- 28845002 TI - [Role of atorvastatin in improving the inflammation-induced adipokine imbalance in mice with acute myocardial infarction]. AB - OBJECTIVE: To investigate the effect of acute myocardial infarction (AMI) activated inflammation on adipokine imbalance and the therapeutic effects of statin.? Methods: A total of 32 C57BL/6 mice were divided into 4 groups: a sham group, an AMI group, a low-dose atorvastatin [2 mg/(kg.d)] group and a high-dose atorvastatin [20 mg/(kg.d)] group. AMI models were established by surgical coronary artery ligation. Plasma levels of high sensitive C reaction protein (hs CRP), adiponectin and resistin were measured. Adiponectin and resistin expressions were determined. In addition, mouse 3T3-L1 preadipocytes in vitro were differentiated and they were stimulated by oxidized low density lipoprotein (ox-LDL). The protein expressions of adiponectin and resistin in adipocytes were detected. The effects of atorvastatin on ox-LDL-induced adipokine imbalance in adipocytes were identified.? Results: The plasma levels of hs-CRP and resistin in AMI mice were significantly increased, whereas the plasma levels of adiponectin were remarkably decreased. However, atorvastatin treatment blocked the changes in the plasma levels of hs-CRP, resistin and adiponectin in AMI mice in a dose dependent manner. Consistent findings regarding the adipose expressions of the two adipokines were obtained. The plasma levels of hs-CRP were positively correlated with resistin but negatively with adiponectin. In vitro study, ox-LDL increased resistin protein and adiponectin expressions in adipocytes, which were dose-dependently reversed by atorvastatin.? Conclusion: Inflammation activation in AMI mice leads to adipokine imbalance. Atorvastatin ameliorates the AMI induced adipokine imbalance via anti-inflammation. PMID- 28845003 TI - [Diagnosis of right ventricular outflow tract and intraoperative lesion in patients with right coronary artery sinus rupture by transthoracic echocardiography]. AB - OBJECTIVE: To investigate the role of thoracic echocardiography in diagnosis and differential diagnosis of the right ventricular outflow tract into the right aorta with right ventricular aneurysm rupture. ? Methods: A total of 19 patients with sinus rupture caused by ventricular septal defect in the right ventricular outflow road were reviewed. These patients were diagnosed as aortic right coronary sinus by preoperative transthoracic echocardiography from February 2010 to September 2016 in Xiangya Second Hospital and Xiangya Medical College Affiliated Haikou Hospital. The clinical symptoms, echocardiography and intraoperative lesions were compared and analyzed among the patients.? Results: The intraoperative lesions were consistent with the preoperative echocardiographic diagnosis in 16 patients. Among them, 11 cases could be heard the continuous sound of the machine with systolic murmur and no tremor in left sternal rib 2-3 auscultation. The color Doppler imaging of right ventricular systolic indicated the based continuous Doppler spectrum. The preoperative echocardiography and intraoperative lesions testified the ventricular septal defect size and the right ventricular outflow tract into the right aorta with right ventricular aneurysm rupture. Among them, 3 cases were complicated with other heart diseases. Other 3 cases were not accorded with the preoperative diagnosis. There were auscultation smell and noise but no tremor. The preoperative echocardiography and lesions indicated the right ruptured aneurysm of the sinus of big and long mouth, 1 case with aortic valve stenosis and regurgitation, congenital aortic valve two valve malformation, 1 case with aortic valve-severe reflux, 1 case with pulmonary infection, and 3 cases with no intraoperative lesions in the ventricular septal defect.? Conclusion: Preoperative transthoracic echocardiography is the preferred preoperative, quick and noninvasive method for ruptured aneurysm. Each stage of observation procedure and method can observe the ruptured aneurysm of aortic sinus, the location, size and adjacent of ventricular septal defect. Meanwhile, the flow spectrum characteristics of the ventricular septal defect in the right outflow tract of the right sinus aneurysm can be found by Doppler ultrasound imaging. PMID- 28845004 TI - [Application of perimembranous ventricular septal defects closure solely by femoral vein approach under transesophageal echocardiography guidance]. AB - OBJECTIVE: To investigate the feasibility and safety of perimembranous ventricular septal defects (PmVSD) closure solely by femoral vein approach under transesophageal echocardiography (TEE) guidance.? Methods: From January 1, 2014 to May 31, 2016, 26 patients with PmVSD in Second Xiangya Hospital were selected, with age at 3.2-6.0 (4.3+/-0.7) years old and body weight at 15.0-19.5 (16.7+/ 1.4) kg. The diameter of VSD was 3.5-4.8 (4.1+/-0.3) mm. All patients were treated by percutaneous PmVSD closure solely by femoral vein approach under TEE guidance. The effect of the procedure was evaluated by TEE and transthoracic echocardiography (TTE). The clinical follow-up study was conducted by TTE at 1, 3, 6 and 12 month (s) after the procedure.? Results: Twenty cases were successfully treated with percutaneous PmVSD closure solely by femoral vein approach under TEE guidance, and the success rate was 76.9%. Six patients were converted to perventricular closure under TEE guidance because the guide wire in two cases or catheter in other cases could not pass through PmVSD. The diameter of symmetrical VSD occluder was 6.0-7.0 (6.2+/-0.4) mm. The procedural time was 12.0-64.0 (26.8+/-6.3) min. The residence time at ICU was 1.8-2.4 (26.8+/-6.3) h. The in-hospital time was 4.0-5.0 (4.4+/-0.5) d. There were 3 patients with immediate post-operative trivial residual shunt and incomplete right bundle branch block (IRBBB). All patients survived with no peripheral vascular injury or complications such as tricuspid regurgitation, pericardial tamponade and pulmonary infection. The residual shunt disappeared in 3 patients and IRBBB became normal rhythm in 3 patients at 1 month follow-up time point. No patients suffered from occluder malposition, residual shunt, pericardial effusion, arrhythmia (atrio-ventricular block), aortic valve regurgitation and tricuspid regurgitation.? Conclusion: TEE-guided percutaneous PmVSD closureby femoral vein approach is safe and effective. PMID- 28845005 TI - [Treatment of patellofemoral instability in adolescent by anatomical double bundle medial patellofemoral ligament reconstruction with double suture anchor technique]. AB - OBJECTIVE: To explore the clinical outcomes of anatomical double-bundle medial patellofemoral ligament (MPFL) reconstruction with double suture anchor technique in treating patellofemoral instability in adolescent.? Methods: Twenty-five young people with patellofemoral instability (25 knees) in our department from January 2013 to December 2014 were enrolled for this study. All patients were performed anatomical double-bundle MPFL reconstruction with arthroscopic-assisted suture anchors technique in the patella, and fixed in the femoral socket with absorbable interference screw. All patients are evaluated by different methods, including patient's satisfaction, patellar apprehension test, recurrent subluxation/dislocation, CT assessment of bone tunnel and patellar tilt angle. Lysholm scores, Tegner scores and Kujala scores were recorded at the final follow up.? Results: The mean follow-up was 24 (range 20-40) months. All cases were observed in negative patellar apprehension test. Infection, recurrent subluxation/dislocation and patellar fracture were not found at the last follow up. CT results demonstrated that the tunnel position were good. The patellar tilt angle was decreased from 21.6 degrees +/-2.3 degrees to 10.5 degrees +/-1.6 degrees (P<0.05); the Lysholm scores was increased from 51.7+/-5.3 to 93.8+/-6.5 (P<0.05). Tegner scores was increased from 4.1+/-1.1 to 5.5+/-0.6 (P<0.05). Kujala scores was increased from 53.5+/-6.4 to 94.6+/-4.3 (P<0.05).? Conclusion: Arthroscopic-assisted anatomical double-bundle MPFL reconstruction with the suture anchors technique is a safe, minimal invasive and effective surgical option for treating patellofemoral instability in adolescent. PMID- 28845006 TI - [Reasons for anastomotic leakage following the learning curve by laparoscopic anterior resection of rectal cancer]. AB - OBJECTIVE: To investigate the reasons of anastomotic leakage following learning curve by laparoscopic anterior resection of rectal cancer.? Methods: From December, 2011 to March, 2015, the clinical information of 179 patients in our hospital who underwent dixon of rectal cancer were collected. The patients were divided into a laparoscopic learning group, a laparotomy group and a laparoscopic group. The reasons of anastomotic leakage for each group were comparatively analyzed. Repeated cutting of anastomotic stoma was compared between the laparoscopic learning group and the laparoscopic group. The male, age, obesity, nutrition complications and the position of anastomotic stoma were compared among the 3 groups.? Results: The rate of anastomotic leakage in the laparoscopic learning group was significantly higher than that in the laparotomy group and the laparoscopic group (P<0.05). Repeated cutting was a significant risk factor in the laparoscopic learning group (P<0.05), but not in the laparoscopic group. Except obesity, the four factors were significant risk factors in the laparoscopic learning group (P<0.05). All of the five factors were not the significant risk factors in the laparotomy group and the laparoscopic group (P>0.05).? Conclusion: The operation technical shortcoming is the major factor in the learning of the laparoscopic anterior resection of rectal cancer. In order to reduce the rate of anastomotic leakage in the learning curve period, the selection of patients following the laparoscopic anterior resection of rectal cancer should avoid the following factors: male, older age, the low position of the tumor and the nutrition complications. PMID- 28845007 TI - [Advantages of foley catheter for nephrostomy tube after minimally invasive percutaneous nephrolithotomy]. AB - OBJECTIVE: To assess the advantages and nursing experience of foley catheter for nephrostomy tube after minimally invasive percutaneous nephrolithotomy (mPCNL).? Methods: From October 2015 to April 2016, the clinical data of 137 patients, who were diagnosed with upper urinary tract calculi and need to perform mPCNL, were collected and randomized into 2 groups: a foley catheter group (research group, n=69) and a normal nephrostomy tube group (control group, n=68). The patients in research group used foley catheter for nephrostomy tube, while those in the control group used normal nephrostomy tube. Bleeding volume, the days of bleeding, pipes shedding and pain degree were compared, and the experience of the nursing process was summarized.? Results: The bleeding volume, the days of bleeding in the research group were significantly lower than those in the control group (both P<0.01). The pipes shedding rate in the research group were lower than that in the control group (P<0.05). There was no significant difference in postoperative pain scores between the 2 groups (P>0.05). There was no other complications and discomfortable symptoms in the experimental group.? Conclusion: The use of foley catheter for nephrostomy tube after mPCNL is safe, and it can decrease the bleeding volume and pipes shedding rate. It doesn't increase the patient's postoperative pain and can reduce the difficulty and risk for postoperative nursing. PMID- 28845008 TI - [Therapeutic effect of Artemisia argyi on oral ulcer in rats]. AB - OBJECTIVE: To determine bacteriostatic abilities of Artemisia argyi extracts, and to explore the effect of Artemisia argyi extracts on oral ulcer in rats.? Methods: We extracted the mixture of Artemisia argyi volatile oils and water extraction by leaching method and evaluated the anti-microbial effect of Artemisia argyi extracts on common oral floras in vitro. The rat cheeks were burnt by NaOH to establish the models of oral ulcer. The curative effects of crude drug of Artemisia argyi extracts at 2.0, 1.0, 0.5 g/mL on oral ulcer in rats were evaluated by measuring the oral ulcer healing time. Serum TNF-alpha level and expression of proliferating cell nuclear antigen (PCNA) were analyzed by ELASA and immunohistochemical staining.? Results: Artemisia argyi extracts obviously inhibited the Staphylococcus aureus and Streptococcus. NaOH-made oral ulcer in rats were successfully established. The crude drug at 2.0 and 1.0 g/mL obviously reduced healing time, significantly inhibited the release of TNF-alpha, and improved the PCNA level in the ulcer tissues (All P<0.01). The extracts obviously reduced the local inflammatory reaction and promoted tissue repair of oral ulcer.? Conclusion: Artemisia argyi extracts promote tissue repair of oral ulcer via inhibiting bacterial growth, reducing the release of TNF-alpha and improving the PCNA level. PMID- 28845009 TI - [Establishment of medians for maternal serum markers in Down's syndrome screening during the second trimester of pregnancy in north-central region of Jiangxi Province]. AB - OBJECTIVE: To establish the median databases of serum markers for Down's syndrome screening during the second trimester of pregnancy women in the north-central area of Jiangxi Province.? Methods: Time-resolved fluorometry was used to detect the serum contents of AFP free beta-hCG and uE3 in 57 548 pregnant women during 15-20 gestational weeks. Risk evaluation was conducted by LifeCycle 4.0. SAS 9.2 software was used to establish a model of the median fitted equation. The newly constructed median system was used to reassess the risk of Down's syndrome development in pregnant women.? Results: The medianand built in medianof north central region in Jiangxi Province are significantly different (Z=2.201, P=0.028). The relationship between the median of the triple index and the gestational age was analyzed by the weight regression model. The relationship between the MoM value and the weight was used to calculate the reciprocal model. The median of the new system was more efficiency than the built in median. In the median of the new system than the reference, the detection rate improved from 62.75% to 72.55%, false positive rate reduced by 5.84% to 4.94%.? Conclusion: The newly constructed median system is suitable for Down's syndrome screening in the north-central region of Jiangxi Province. PMID- 28845010 TI - [Mediation role of self-efficacy between social support and depression of only child-lost people]. AB - OBJECTIVE: To investigate the relationship between social support and depression of only-child-lost (OCL) people, and the mediation role of self-efficacy in this relationship. ? Methods: By stratified cluster sampling, 214 OCL people were enrolled, with 80 males and 134 females, ages from 49 to 83 years old. They were assessed by General Self-Efficacy Scale, Social Support Rating Scale, and Self rating Depression Scale.? Results: Univariate analysis showed that there were significant differences in age groups (t=2.85, P<0.05), with or without spouse (t=5.62, P<0.05), family location (t=3.95, P<0.05), per capita monthly income (F=3.48, P<0.05) among the social support scores. There was significant difference between the per capita monthly income and self-efficacy scores in QCL people (F=5.46, P<0.05). Correlation analysis showed self-efficacy and social support were positively correlated (r=0.26, P<0.01). Self-efficacy (r=-0.59, P<0.01) and social support (r=-0.59, P<0.01) negatively correlated with depression in OCL people. Self-efficacy partially mediated the relationship between social support and depression.? Conclusion: The person who is <60 years old, with spouse and the high per capita monthly income, and lives the rural area, would have high social support levels among QCL people. The person who has high per capita monthly income would have high self-efficacy. Self-efficacy is one of the direct prediction for depression, and plays an indirect role between social support and depression. Intervention of depression among OCL people could be applied to change their cognition, and to enhance their self-efficacy. PMID- 28845011 TI - [Family function and its relationship with clinical prognosis in patients with major depressive disorder]. AB - OBJECTIVE: To explore characteristics of family function in patients with major depressive disorder (MDD), and to evaluate relationships between family function and prognosis of major depressive episode (MDE).? Methods: Forty-six patients with MDD were recruited in the outpatient or inpatient departments of Wuhan Mental Health Center from September 1, 2014 to August 31, 2015. At the baseline, the patients and their co-resident family members were interviewed for psychiatric screening and diagnosis, and the family function of each patient's family was assessed by Family Assessment Device (FAD). After clinic service or hospitalization, the patients were followed up by telephone until they recovered from the MDE (within 12 months since the follow-up) or for 12 months if they had not achieved remission. Forty-two mentally healthy subjects, with no family members diagnosis for psychiatric diseases, and matched with MDD patients for age, sex, number of children, family roleand socioeconomic status, were recruited from a community. The family function of the MDD families and the controls were compared by independent sample-T test, and the relationship between family function and duration of the MDE was analyzed by Pearson's correlation.? Results: MDD families exhibited higher FAD scores in 5 dimensions than control families except for affective involvement and behavior control (P<0.01). Patients with relatively good family function showed significantly shorter duration of MDE and higher proportion of remission within 6 months since the follow-up (P<0.01 and P<0.05). All the dimensions of FAD demonstrated significant positive correlation with the duration of MDE except for the behavior control.? Conclusion: Families with MDD patients show impairments in multiple dimensions of family function, and the family functions of MDD patients are correlated with the prognosis of MDE. Improvement of family function may contribute to better prognosis of MDD. PMID- 28845012 TI - [NOD-like receptor pyrin domain containing 3 inflammasome and myocardial ischemia reperfusion injury]. AB - Myocardial ischemia-reperfusion injury (MI/RI) is an inflammatory cascade process involving the interaction of multiple factors. In recent years, more and more evidence suggests that NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, an important component of the innate immune system, is closely associated with the inflammatory damage of MI/RI. Furthermore, blockage of NLRP3 inflammasome or the release of its downstream pro-inflammatory cytokines may provide new therapeutic targets for this disorder. PMID- 28845013 TI - [Progress in preoperative evaluation methods regarding cytoreduction in patients with advanced ovarian cancer]. AB - Primary cytoreductive surgery followed by platinum-based chemotherapy represents the standard treatment for patients with advanced ovarian cancer. But some patients with advanced ovarian cancer still have suboptimal residual disease after the primary debulking surgery. Neoadjuvant chemotherapy has been suggested as an alternative strategy to achieve no residual disease. It is important to find methods to estimate the likelihood that cytoreductive surgery will leave no residual disease. A number of studies have evaluated the use of serologic markers (such as CA-125), imaging modalities (such as CT, PETCT, MRI), and laparoscopic surgery to determine which patients are ideal predictors for neoadjuvant chemotherapy. As a new approach of assessment for preoperative evaluation regarding cytoreduction, laparoscopic surgery deserves further research. PMID- 28845014 TI - [A case of nasal NK/T-cell lymphoma]. AB - A 29-year-old male patient with extranodal NK/T-cell lymphoma, a nasal type lymphoma with involvement of skin as the first symptom, was reported. The patient presented with swelling in the left side of the nose and suffered intermittent fever for 1 month. The fester in the oral mucosa and skin under the left nostril and redness, and the swelling on the orbit of the left eye lasted for 1 week. Physical examination showed that the left side of nose was swelling, and the skin below the left nostril was anabrotic and crusted. There were different ulcers in his jaws and buccal mucosa. Bilateral eyelid was redness and swelling, especially in the left side. Binocular conjunctival was congestive. The diagnosis of extranodal NK/T-cell lymphoma (nasal type) was confirmed by biopsy and immunohistochemistry. PMID- 28845015 TI - [Application of carbon nanoparticles suspension injection in uremic patients with secondary hyperparathyroidism underwent total parathyroidectomy: 2 case report and literature review]. AB - Total parathyroidectomy (PTX) can be used to treat secondary hyperparathyroidism (SHPT) in uremic patients, relieving the patient's osteolytic destruction. Complete resection of bilateral parathyroid glands is key to successful operation. Recently, 2 patients successfully received surgical treatment, in which carbon nanoparticles suspension injection were used. With the help of carbon nanoparticles suspension injection, all of the 4 hyperplastic parathyroid glands were found successfully. The parathyroid hormone(PTH) was significantly decreased after operations and the clinical symptoms were relieved simultaneously. We conclude that the use of carbon nanoparticles suspension injection is helpful for total parathyroidectomy operation in uremic patients with SHPT, which can protect the normal thyroid and recurrent laryngeal nerve. PMID- 28845016 TI - A comparison of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) for the determination of the cyclosporin A concentration in whole blood from Chinese patients. AB - Cyclosporin A (CyA) is an immunosuppressive agent widely used in clinical therapy. In the therapeutic process, the blood concentration of CyA should be monitored to avoid or prevent rejection and toxicity. The objectives of this study were to compare the correlation of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) for the determination of the CyA concentration in human blood and to provide evidence for the rational usage of EMIT in clinical practice. Blood samples collected from 132 patients undergoing a liver or kidney transplant or patients with aplastic anemia at Qilu Hospital of Shandong University were tested using the two methods. The calibration curve was linear from 25-500 ng.mL-1 for LC-MS/MS and from 50-450 ng.mL-1 for EMIT. The inter- and intra-day RSDs were less than 15%. The CyA blood concentration according to EMIT was 3.5 ng.mL-1 more than that according to LC MS/MS. The 95% confidence interval was -10.0~16.9 ng.mL-1. The CyA blood concentration according to the two methods did not differ significantly (p > 0.05). LC-MS/MS and EMIT were suitable methods for determining the CyA blood concentration. The two methods were closely correlated (r2 = 0.969), but the CyA blood concentration according to EMIT was slightly higher than that according to LC-MS/MS. The clinical significance of this finding needs to be further evaluated. PMID- 28845017 TI - Organ-preserving surgery for locally advanced duodenal gastrointestinal stromal tumor after neoadjuvant treatment. AB - This report aims to investigate the feasibility and outcomes of neoadjuvant imatinib mesylate (IM) administration followed by organ-preserving surgery (OPS) for patients with locally advanced duodenal gastrointestinal stromal tumor (GIST). Between 2012 and 2015, 10 consecutive patients with locally advanced duodenal GISTs were treated in Peking University Cancer Hospital. Multidisciplinary assessment was implemented, and pancreaticoduodenectomy (PD) was initially indicated as the most probable surgical procedure for all 10 patients. To attempt to create opportunities of less-invasive OPS for patients, neoadjuvant IM was administered followed by radical resection. All data were prospectively collected, and the short- and long-term outcomes of the treatment strategy were analyzed. The median treatment duration of neoadjuvant IM administration was 5 mo (range 2-18 mo). Significant tumor shrinkage (from 9.2 to 5.9 cm on average) was observed in all patients, and partial response was achieved in eight patients (80.0%) according to the Response Evaluation Criteria in Solid Tumors 1.1. No tumor perforation occurred, and nine patients (90.0%) underwent successful OPS with four different operation types. Postoperative morbidity rate of OPS was 55.6% (5/9), and no mortality occurred. After a median follow-up of 36 mo, one patient developed multiple distant metastases, but no local recurrence was observed. For long-term follow-up, patients who underwent OPS did not show any degradation in quality of life, whereas the patient who underwent PD suffered weight loss of ~10 kg. In conclusion, in patients with locally advanced duodenal GISTs, neoadjuvant IM administration followed by OPS is a feasible treatment strategy which leads to favorable short- and long-term outcomes. PMID- 28845018 TI - Loss of angiotensin converting enzyme II (ACE2) accelerates the development of liver injury induced by thioacetamide. AB - Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue that displays antagonist effects on ACE/angiotensin II (Ang II) axis in renin-angiotensin system (RAS), could play a protective role against liver damages. The purpose of this study is to investigate whether inflammation mediated liver injury could be affected by ACE2 derived pathways in the RAS. Eight-weeks-old wild-type (WT; C57BL/6) and Ace2 KO (hemizygous Ace2-/y) male mice were used to induce liver fibrosis by thioacetamide (TAA) administration (0, 100, and 200 mg/kg BW). The mice administrated with TAA could be successfully induced liver fibrosis in a TAA-dose dependent manner. Compared to WT mice, the results show that Ace2 KO mice have high sensitive, and developed more serious reaction of hepatic inflammation and fibrosis by TAA administration. The physiological and pathological examinations demonstrated higher serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels, infiltration of white blood cells and fibrotic lesions within liver in the Ace2 KO mice. The severe liver damage of Ace2 KO mice were also confirmed by the evidence of higher expression of hepatic inflammation-related genes (IL-6 and Tnf) and fibrosis-related genes (Col1a1, Timp1 and Mmp9). Ace2 gene deficiency could lead to a severe inflammation and collagen remodeling in the liver administrated by TAA, and the responses lead the pathogenesis of liver fibrosis. Our studies provided the main messages and favorable study directions of relationship of Ace2 and liver disease. PMID- 28845019 TI - Progranulin haploinsufficiency reduces amyloid beta deposition in Alzheimer's disease model mice. AB - Granulin (Grn) mutations were identified in familial frontotemporal lobar degeneration (FTLD) patients with TAR DNA-binding protein of 43 kd (TDP-43) pathology. Grn transcript haploinsufficiency is proposed as a disease mechanism that leads to the loss of functional progranulin (PGRN) protein. Thus, these mutations are strongly involved in FTLD pathogenesis. Moreover, recent findings indicate that Grn mutations are associated with other neurodegenerative disorders with tau pathology, including Alzheimer's disease. To investigate the influence of PGRN on amyloid beta (Abeta) accumulation, amyloid precursor protein (APP) transgenic mice were interbred with Grn-deficient mice, producing APP transgenic mice harboring the Grn hemizygote (APP/Grn+/-). Brains were collected from 16-18 month-old APP and APP/Grn+/- mice and sequential extraction of proteins, immunoblotting and immunohistochemical analysis were performed. Immunohistochemical analysis showed that the number and area of Abeta plaque was significantly decreased in APP/Grn+/- mice as compared to APP mice. Immunoblotting analysis revealed that Abeta was reduced in the sarkosyl-insoluble fraction of 16-18-month-old APP/Grn+/- mice as compared with that of APP transgenic mice. Our data suggest that PGRN haploinsufficiency may decrease accumulation of Abeta. PMID- 28845020 TI - Is transcription in sperm stationary or dynamic? AB - Transcriptional activity is repressed due to the packaging of sperm chromatins during spermiogenesis. The detection of numerous transcripts in sperm, however, raises the question whether transcriptional events exist in sperm, which has been the central focus of the recent studies. To summarize the transcriptional activity during spermiogenesis and in sperm, we reviewed the documents on transcript differences during spermiogenesis, in sperm with differential motility, before and after capacitation and cryopreservation. This will lay a theoretical foundation for studying the mechanism(s) of gene expression in sperm, and would be invaluable in making better use of animal sires and developing reproductive control technologies. PMID- 28845021 TI - Diagnostic accuracy of electrocardiographic P wave related parameters in the assessment of left atrial size in dogs with degenerative mitral valve disease. AB - The purpose of this research was to compare the accuracy of newly described P wave-related parameters (P wave area, Macruz index and mean electrical axis) with classical P wave-related parameters (voltage and duration of P wave) for the assessment of left atrial (LA) size in dogs with degenerative mitral valve disease. One hundred forty-six dogs (37 healthy control dogs and 109 dogs with degenerative mitral valve disease) were prospectively studied. Two-dimensional echocardiography examinations and a 6-lead ECG were performed prospectively in all dogs. Echocardiography parameters, including determination of the ratios LA diameter/aortic root diameter and LA area/aortic root area, were compared to P wave-related parameters: P wave area, Macruz index, mean electrical axis voltage and duration of P wave. The results showed that P wave-related parameters (classical and newly described) had low sensitivity (range=52.3 to 77%; median=60%) and low to moderate specificity (range=47.2 to 82.5%; median 56.3%) for the prediction of left atrial enlargement. The areas under the curve of P wave-related parameters were moderate to low due to poor sensitivity. In conclusion, newly P wave-related parameters do not increase the diagnostic capacity of ECG as a predictor of left atrial enlargement in dogs with degenerative mitral valve disease. PMID- 28845022 TI - Discovery of fur seal feces-associated circular DNA virus in swine feces in Japan. AB - Fur seal feces-associated circular ssDNA virus (FSfaCV) was discovered in a pig for the first time in Japan using a next-generation sequencer with duplex specific nuclease. Full genome of the virus showed approximately 92% similarity to FSfaCVs from New Zealand fur seals. Furthermore, we investigated the prevalence of the ssDNA virus in 85 piglets in Japan, and 65 piglets were positive (76%) for the virus. PMID- 28845023 TI - Unilateral luteoma of the ovary in a pregnant Risso's dolphin (Grampus griseus). AB - A white, lobular mass was found in the right ovary of a pregnant Risso's dolphin (Grampus griseus) at necropsy. The mass was unilateral and occupied most of the pre-existing ovarian tissue. Histologically, the mass was composed of diffuse sheets of polyhedral cells with abundant eosinophilic cytoplasm and oval nuclei, separated by fibrous connective tissue. Only a few ovarian follicles were observed at the periphery of the mass. Immunohistochemically, the large eosinophilic cells were positive for vimentin and negative for pan-cytokeratins. Based on the histopathological features, the present case was diagnosed as luteoma. In human medicine, luteoma of pregnancy, a tumor-like proliferative lesion occurring in pregnant women, is well described. In veterinary medicine, luteoma associated with pregnancy has never been described. The present study would provide useful information for understanding the characteristics of luteoma in animals. PMID- 28845024 TI - Evaluation of mouse red blood cell and platelet counting with an automated hematology analyzer. AB - An evaluation of mouse red blood cell (RBC) and platelet (PLT) counting with an automated hematology analyzer was performed with three strains of mice, C57BL/6 (B6), BALB/c (BALB) and DBA/2 (D2). There were no significant differences in RBC and PLT counts between manual and automated optical methods in any of the samples, except for D2 mice. For D2, RBC counts obtained using the manual method were significantly lower than those obtained using the automated optical method (P<0.05), and PLT counts obtained using the manual method were higher than those obtained using the automated optical method (P<0.05). An automated hematology analyzer can be used for RBC and PLT counting; however, an appropriate method should be selected when D2 mice samples are used. PMID- 28845026 TI - Marked recovery from glucotoxicity of beta-cell function after medical nutrition therapy without pharmacotherapy in type 2 diabetic outpatients with extreme hyperglycemia: a pilot retrospective study. AB - We investigated whether glucotoxicity of beta-cell function could be eliminated after medical nutrition therapy (MNT) without forced correction of hyperglycemia by anti-diabetic medications including exogenous insulin administration. We analyzed newly diagnosed type 2 diabetic outpatients with hemoglobin A1c (HbA1c) of 10.1 +/- 1.5%, who were treated by MNT at least for three months, without any aid of anti-diabetic medications. The beta-cell function was calculated as the product of the DeltaIns0-120/DeltaGlu0-120 and the Matsuda index, where DeltaIns0 120/DeltaGlu0-120 represents the ratio of the incremental concentrations of insulin to those of glucose during the 0- to 120-min time periods under a 75-g oral glucose tolerance test. After MNT, HbA1c levels were reduced to 7.0 +/- 1.0% (p < 0.001). The beta-cell function was significantly improved (n = 13; p = 0.001; effect size d = 1.9). Fasting plasma glucose became below 7.0 mmol/l in 57% (8/13), and 120-minute plasma glucose became below 11.1 mmol/l in 43% (6/13). The beta-cell function after MNT was significantly correlated with HbA1c levels achieved after MNT (Pearson's correlation coefficient r = -0.62, p = 0.025). In conclusion, the beta-cell dysfunction was ameliorated after MNT without glucose lowering pharmacotherapy in newly diagnosed type 2 diabetic outpatients who presented extreme hyperglycemia. PMID- 28845025 TI - The polymorphisms in the thyroid peroxidase gene were associated with the development of autoimmune thyroid disease and the serum levels of anti-thyroid peroxidase antibody. AB - Graves' disease (GD) and Hashimoto's disease (HD) are well known autoimmune thyroid diseases (AITDs), and the severity and intractability of AITDs varies among patients. Thyroid peroxidase (TPO) is a thyroid-specific antigen. The levels of anti-thyroid peroxidase antibody (TPOAb) were higher in patients with HD and may be associated with thyroid destruction. In this study, we genotyped eight single nucleotide polymorphisms (SNPs) in the TPO gene to clarify the association of TPO gene polymorphisms with the development, severity and intractability of AITD. We genotyped TPO rs2071399G/A, rs2071400C/T, rs2071402A/G, rs2071403A/G, rs1126799C/T, rs1126797T/C, rs732609A/C, and rs2048722A/G polymorphisms in 145 patients with GD, 147 patients with HD and 92 healthy controls by PCR-RFLP method. TPO rs2071400 T carriers (CT + TT genotypes) were more frequent in AITD, GD, and HD patients (p=0.0079, 0.0041, and 0.0488, respectively). The TPO rs2071403 GG genotype was more frequent in AITD, GD, and HD patients (p=0.0227, 0.0465, and 0.0305, respectively). There was no significant association between the SNPs and the prognosis of AITD. Serum levels of TPOAb were significantly higher in AITD patients with TPO rs2071400 T carriers (CT + TT genotypes) than in those with the CC genotype (p=0.0295), and were also significantly higher in AITD patients with TPO rs2048722 T carriers (CT + TT genotypes) than in those with the CC genotype (p=0.0056). In conclusion, TPO rs2071400 and rs2071403 polymorphisms were associated with the development of HD and GD, but not with the prognosis. Moreover, TPO rs2071400 and rs2048722 polymorphisms were associated with the serum levels of TPOAb. PMID- 28845027 TI - Dibutyl Phthalate Rather than Monobutyl Phthalate Facilitates Contact Hypersensitivity to Fluorescein Isothiocyanate in a Mouse Model. AB - Dibutyl phthalate (DBP) is a plasticizer used for many consumer products including cosmetics. Potential health concerns regarding DBP include reproductive and developmental toxicity, endocrine disruption and neurotoxicity. DBP is a high priority chemical as to reduction of exposure of children to it. Through reproductive toxicity studies, monobutyl phthalate (MBP) has been proposed to be the active metabolite derived from DBP. We previously demonstrated that DBP activates transient receptor potential ankyrin 1 (TRPA1) cation channels expressed on sensory neurons. We have also shown that DBP enhanced skin sensitization in a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) mouse model. Through MBP formation by esterase in the skin, it is possible that MBP exerts a major effect on the biological activity we observed. To test this possibility, we directly compared DBP and MBP. A more than 40-fold higher concentration of MBP as compared with DBP was required for activation of TRPA1 in vitro. Unlike DBP, MBP did not enhance skin sensitization to FITC. These results demonstrated that DBP directly, i.e., not through its metabolite MBP, activates TRPA1 and enhances FITC-CHS. It is noteworthy that butyl benzoate, a related compound, activated TRPA1 and enhanced FITC-CHS. PMID- 28845030 TI - On What Day of Illness Does the Dilatation of Coronary Arteries in Patients With Kawasaki Disease Begin? AB - BACKGROUND: In the present study we used echocardiography to investigate coronary artery diameter at the time of diagnosis of Kawasaki disease (KD), before the start of treatment.Methods and Results:Diameters of the right, left main, left anterior descending, and left circumflex coronary arteries were determined in 410 patients before KD treatment commenced. The maximum Z-score was considered to be the pretreatment, maximum coronary artery Z-score (preZmax). The cumulative probability of coronary arterial dilatation was analyzed using the Kaplan-Meier method. In the present study, 31 patients (7.6%) had a preZmax >=3.0, 56 (13.7%) had a preZmax >=2.5, and 96 (23.4%) had a preZmax >=2.0. The cumulative probability of a preZmax >=2.0 was >20% on Day 5 of illness, 40% on Day 7, and 70% on Day 10. The positive predictive value (PPV) of a preZmax of 2.0 was approximately 0.9 on Day 5 of illness. CONCLUSIONS: The present study demonstrates that the coronary arteries may dilate before Day 5 of illness, and that the rate of dilatation increases gradually until Day 10. Because preZmax 2.0 has high PPV after Day 5 of illness, it is a useful marker of coronary artery dilatation in the early phase of KD. PMID- 28845031 TI - Morphological Changes and Device Migration After Stent Graft Insertion - Clinical Application of an Image-Based Modeling System and Analysis With Geometric Parameters. AB - BACKGROUND: Previously, we developed an image-based modeling system (V-Modeler) to investigate geometric changes in stent grafts (SGs) following their implantation for abdominal aortic aneurysms (AAAs). The aims of the present study were to improve this system for clinical use, to chronologically analyze postoperative morphological changes in SGs, and to demonstrate scenarios of SG migration.Methods and Results:Contrast-enhanced computed tomography data from 36 patients who underwent endovascular aneurysm repair (EVAR) for AAAs were used, with 72 centerline paths, in total, analyzed for bilateral SG legs. The existing V-modeler system was modified by introducing a penalty term, optimizing the number of control points using Akaike's information criterion, and changing the degree of the function from 3 to 5. Geometric parameters were then analyzed immediately, as well as >1 year after EVAR. Eight migrations were found and although overall SG curvature and curvature at the distal (leg) site did not change, curvature at the proximal (trunk) site of SGs decreased over time. Subanalysis revealed that SGs with severe curvature showed the same trend, whereas distal curvature increased in the non-severe curvature group. In addition, proximal curvature decreased more in Excluder than Zenith devices. CONCLUSIONS: The present study demonstrates SG behavior after implantation with numerical values for SG length and curvature. PMID- 28845032 TI - Streptococcus pyogenes translocates across an epithelial barrier. AB - Streptococcus pyogenes is a beta-hemolytic organism responsible for a wide variety of human diseases that commonly occur as self-limiting purulent diseases of the pharynx and skin. Although the occurrence of invasive infections by S. pyogenes is rare, mortality rates remain high even with progressive medical therapy. As a prerequisite for causing the severe invasive disease, S. pyogenes must invade underlying sterile tissues by translocating across the epithelial barrier. In this study, streptolysin S and SpeB were identified as the novel factors that facilitate bacterial translocation via degradation of intercellular junctions. Furthermore, we found that S. pyogenes exploits host plasminogen for acceleration of bacterial invasion into deeper tissues via tricellular tight junctions. Here, I would like to show our study on bacterial translocation across the epithelial barrier through paracellular route. PMID- 28845033 TI - Microleakage and penetration depth of different fissure sealant materials after cyclic thermo-mechanic and brushing simulation. AB - The aim of the study was to evaluate microleakage and the penetration-depths of different fissure-sealant materials applied with/without enameloplasty after cyclic aging. One-hundred-sixty mandibular molars were divided into non-invasive and enameloplasty preparation groups and eight material subgroups, including: flowable composites (microhyrid, nanohybrid, and nanofilled), three resin-based (unfilled, filled, and highly-filled), a giomer-based, and a glass-ionomer-based fissure sealant. Specimens were subjected to two-year cyclic chewing and brushing simulation. After 5% basic-fuchsin dye penetration, specimens were sectioned and scored under stereomicroscope. Kruskal-Wallis statistical data showed that preparation type significantly affected the penetration of all tested materials (p<0.05), but not significantly affected microleakage (p>0.05). Flowable composites showed the best and the glass-ionomer-based sealant showed the worst penetration and microleakage. Slight preparation of fissures is not important in microleakage. However, enameloplasty significantly enhanced the depth of penetration of the sealants. Flowable composites offer promising results at the fissure sealing. PMID- 28845034 TI - uCT-3D visualization analysis of resin composite polymerization and dye penetration test of composite adaptation. AB - This study evaluated the effects of the light curing methods and resin composite composition on composite polymerization contraction behavior and resin composite adaptation to the cavity wall using MUCT-3D visualization analysis and dye penetration test. Cylindrical cavities were restored using Clearfil tri-S Bond ND Quick adhesive and filled with Clearfil AP-X or Clearfil Photo Bright composite. The composites were cured using the conventional or the slow-start curing method. The light-cured resin composite, which had increased contrast ratio during polymerization, improved adaptation to the cavity wall using the slow-start curing method. In the MUCT-3D visualization method, the slow-start curing method reduced polymerization shrinkage volume of resin composite restoration to half of that produced by the conventional curing method in the cavity with adhesive for both composites. MUCT-3D visualization method can be used to detect and analyze resin composite polymerization contraction behavior and shrinkage volume as 3D image in the cavity. PMID- 28845035 TI - Comparative fracture behavior of monolithic and veneered zirconia posterior fixed dental prostheses. AB - The purpose of this study was to evaluate and to compare the fracture load and the fracture pattern of monolithic and veneered zirconia posterior fixed dental prostheses (FDPs). Twenty standardized steel dies were prepared to receive posterior 3-unit FDPs. Specimens were randomly divided into 2 groups (n=10): (1) Lava Zirconia, and (2) Lava Plus. All FDPs were cemented using glass ionomer cement and subjected to thermal and mechanical cycling at 5-55oC with a 30-s dwell time for 120,000 masticatory cycles. All specimens were subjected to a three-point bending test until fracture. Data were statistically analyzed using Student's t test, paired t-test and Weibull statistics (alpha=0.05). No differences were observed in fracture load between the groups. Veneering ceramic fractured before than framework in veneered zirconia group. The fracture pattern was different. The tested groups demonstrated clinically acceptable fracture load values. Monolithic zirconia solves the chipping problem. PMID- 28845036 TI - Interaction of backfilling techniques and MTA plugs with additives: Fracture strength and adaptation analyses. AB - The aims were to evaluate the effects of different additives on the adaptation of mineral trioxide aggregate (MTA) plugs before and after different backfilling techniques and analyze the interference of filling procedures on the fracture resistance of simulated immature teeth. The apical parts of 60 teeth were filled with MTA mixed with distilled water (DW), propylene glycol (PG) or calcium chloride (CaCl2) and backfilled with cold lateral condensation (CLC) or warm vertical compaction (WVC). The specimens were subjected to adaptation analysis and fracture testing. CaCl2 addition resulted in poor marginal adaptation, while PG addition significantly decreased the fracture values (p<0.05). WVC technique negatively affected the marginal adaptation of MTA-CaCl2 plugs and decreased the fracture values of teeth with MTA-PG plugs (p<0.05). Mixing MTA with DW can be recommended as apical plug when the remaining root canal space is going to be filled with either CLC or WVC techniques. PMID- 28845037 TI - Influence of water immersion on the transmitted load of home reliners. AB - This study aimed to clarify how composition and water immersion of home reliners affect the attenuation of the transmitted load. To conduct a transmitted load measurement, we used three different home reliners (Tafugurippu Pink A, Liodent Pink, and Cushion Correct), which were combined acrylic resin disks. They were immersed in distilled water and then placed on a silicone quasi-mucosa (phi20*1.5 mm), which was set on a pressure sensor (phi8*0.35 mm), followed by the application of static load. Subsequently, gel permeation chromatography (GPC) and gas chromatography (GC) were used to clarify the composition of each home reliner. The attenuation of the transmitted load began 3 h after immersion. Moreover, both GPC and GC revealed a difference in composition among the three products. Further, the difference in the vinyl acetate molecular weight distribution and ethyl alcohol content affected the attenuation of the transmitted load of home reliners after water absorption. PMID- 28845038 TI - Treatment Recommendations for Adult Patients with Diffuse Gliomas of Grades II and III According to the New WHO Classification in 2016. AB - With advanced understanding of molecular background and correlation with therapeutic outcomes, the revised 4th edition of World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular information into the definition of diffuse gliomas. Indeed, oligodendroglioma and astrocytoma are now defined by molecular signature, with diagnosis of glioblastoma being made by histology. In parallel, numerous clinical trials are underway all over the world, and important findings are being produced every year that have an impact on patient outcomes. Moreover, novel therapies/technologies are also being actively developed; however, there are still many CNS tumors for which no effective therapy has been established except radiotherapy. In this article, the authors review the recent results of major clinical trials and present their treatment recommendations for patients with adult, supratentorial diffuse gliomas of grades II and III stratified according to the new WHO classification. PMID- 28845039 TI - Preoperative and Postoperative Pituitary Function in Patients with Tuberculum Sellae Meningioma -Based on Pituitary Provocation Tests. AB - Given the anatomical proximity of tuberculum sellae meningioma (TSM) to the hypothalamo-pituitary system, pituitary function impairments are of great concern. We retrospectively investigated pituitary function changes following surgery in patients with TSM using pituitary provocation tests (PPTs). Thirty-one patients (27 females and 4 males) with TSM underwent initial transcranial surgery (29 patients) or transsphenoidal surgery (two patients); surgeries were performed carefully to avoid injuring the pituitary stalk. In 24 patients, the PPTs were performed via a triple bolus injection with regular insulin, thyrotropin releasing hormone (TRH), and luteinizing hormone releasing hormone (LH-RH). Seven patients underwent a quadruple test (growth-hormone-releasing factor, corticotrophin-releasing hormone, TRH, and LH-RH). The preoperative and postoperative target hormone levels of the anterior pituitary were normal in 93.5% and 96.8% of patients, respectively. At least one hormonal axis demonstrated impaired PPT responses in two patients (6.5%) preoperatively and in one patient (3.2%) postoperatively. The growth hormone (GH) response was also well preserved. A compromised GH peak level was only observed in one patient (3.2%) preoperatively. Postoperatively, transient diabetes insipidus and transient hyponatremia were observed in four (12.9%) and eight (25.8%) patients, respectively. No patients needed permanent postoperative hormone replacement. The preoperative pituitary function was well preserved in most patients, including those with large tumors pushing against the pituitary stalk considerably or embedded in it. After careful surgery to avoid damaging the pituitary stalk, pituitary function was preserved. However, transient postoperative hyponatremia occurred in 25.8% of patients; thus, surgeons should pay careful attention to this issue. PMID- 28845040 TI - Surgical Anatomy for the Endoscopic Endonasal Approach to the Ventrolateral Skull Base. AB - The authors describe the surgical anatomy for the endoscopic endonasal approach (EEA) to the ventrolateral skull base. The ventrolateral skull base can be divided into two segments: the upper lateral and lower lateral skull base. The upper lateral skull base includes the cavernous sinus and the orbit, while the lower lateral skull base includes the petrous apex, Meckel's cave, parapharyngeal space, infratemporal fossa, etc. To gain access to the upper lateral skull base, a simple opening of the ethmoid sinus provides sufficient exposure of this area. To reach the lower lateral skull base, a transpterygoid approach, following ethmoidectomy, is a key procedure providing wide exposure of this area. Understanding of surgical anatomy is mandatory for treating ventrolateral skull base lesions via EEA. An appropriate, less-invasive approach should be applied depending on the size, location, and type of lesion. PMID- 28845041 TI - Stress Induced Cardiomyopathy Triggered by Acute Myocardial Infarction: A Case Series Challenging the Mayo Clinic Definition. AB - BACKGROUND Various physical and emotional factors have been previously described as triggers for stress induced cardiomyopathy. However, acute myocardial infarction as a trigger has never been reported. CASE REPORT We describe four patients who presented with an acute myocardial infarction, in whom the initial echocardiography revealed wall motion abnormalities extending beyond the coronary distribution of the infarct artery. Of the four patients identified, the mean age was 59 years; three patients were women and two patients had underlying psychiatric history. Electrocardiogram revealed ST elevation in the anterior leads in three patients; QTc was prolonged in all cases. All patients had <= moderately elevated troponin. Single culprit lesion was found uniformly in the proximal or mid left anterior descending artery. Initial echocardiography revealed severely reduced ejection fraction with relative sparing of the basal segments, whereas early repeat echocardiography revealed significant improvement in the left ventricular function in all patients. CONCLUSIONS This is the first case series demonstrating that acute myocardial infarction can trigger stress induced cardiomyopathy. Extensive reversible wall motion abnormalities, beyond the ones expected from angiography, accompanied by modest elevation in troponin and marked QTc prolongation, suggest superimposed stress induced cardiomyopathy. PMID- 28845043 TI - Human regulatory gammadeltaT cells and their functional plasticity in the tumor microenvironment. PMID- 28845042 TI - Factors Determining Parents' Decisions to Bring Their Children to the Pediatric Emergency Department for a Minor Illness. AB - BACKGROUND The number of children visiting Emergency Departments (EDs) is increasing in Lithuania; therefore, the aim of this study was to determine the factors influencing the parental decision to bring their child to the ED for a minor illness that could be managed in a primary healthcare setting, and to compare parents' and medical professionals' attitudes toward a child's health status and need for urgent care. MATERIAL AND METHODS A prospective observational study was performed at the tertiary-level teaching Children's Hospital in Vilnius. A total of 381 patients' parents were interviewed using an original questionnaire based on Andersen's behavioral model of healthcare utilization; in addition, the medical records of patients were reviewed to identify factors that might have an impact on parental decisions to bring their child to the ED for a minor health problem. The study participants were enrolled from October 1, 2013 to August 31, 2014. The urgency of medical care needed to be provided to the patients was evaluated by a tertiary-level triage system. RESULTS Based on the assessment of the triage nurses, the need for emergency care to patients was distributed as follows: 298 patients (78.2%) needed non-urgent care and 83 patients (21.8%) needed urgent care. More than one-third (38.8%) of the parents reported that they came to the ED due to their child's urgent care need and worsened child's health; however, the opinion of ED professionals indicated only a fifth of patients required urgent care. Parents who brought their children to the ED without physician referral were five times more likely to visit the ED during evening hours and on weekends (OR=5.416; 95% CI, 3.259-8.99; p<0.001). The decision to come to the ED without visiting a primary care physician was made more often by parents with a higher income (OR=2.153; 95% CI, 1.167-3.97) and those who came due to children having rash (OR=4.303; 95% CI, 1.089-16.995) or fever (OR=3.463; 95% CI, 1.01-11.876). Older parents were 2.07 (95% CI, 1.1224 3.506) times more likely to evaluate their child's health unfavorably than younger parents. CONCLUSIONS We identified predisposing, enabling, and need factors that influenced the parents' decision to bring their child to the ED for minor health problems that could be managed by a primary care physician. Parents assessed their child's condition more critically and thought that their child required urgent medical aid more frequently than healthcare professionals. PMID- 28845044 TI - Flagellin: a unique microbe-associated molecular pattern and a multi-faceted immunomodulator. PMID- 28845045 TI - The niche for hematopoietic stem cell expansion: a collaboration network. PMID- 28845046 TI - Corrigendum: gamma-Ionylidene-type sesquiterpenoids possessing antimicrobial activity against Porphyromonas gingivalis from Phellinus linteus and their absolute structure determination. AB - This corrects the article DOI: 10.1038/ja.2017.35. PMID- 28845048 TI - The Kaplan-Meier Estimator as an Inverse-Probability-of-Censoring Weighted Average. AB - The Kaplan-Meier (product-limit) estimator of the survival function of randomly censored time-to-event data is a central quantity in survival analysis. It is usually introduced as a nonparametric maximum likelihood estimator, or else as the output of an imputation scheme for censored observations such as redistribute to-the-right or self-consistency. Following recent work by Robins and Rotnitzky, we show that the Kaplan-Meier estimator can also be represented as a weighted average of identically distributed terms, where the weights are related to the survival function of censoring times. We give two demonstrations of this representation; the first assumes a Kaplan-Meier form for the censoring time survival function, the second estimates the survival functions of failure and censoring times simultaneously and can be developed without prior introduction to the Kaplan-Meier estimator. PMID- 28845047 TI - Understanding Racial Differences in Exposure to Violent Areas: Integrating Survey, Smartphone, and Administrative Data Resources. AB - Emerging evidence indicates that exposure to violent areas may influence youth wellbeing. We employ smartphone GPS data on youth activity spaces to examine the extent of, and potential explanations for, racial disparities in these exposures. Multilevel models of data from the Adolescent Health and Development in Context study indicate that exposures to violent areas vary significantly across days of the week and between youth who reside in the same neighborhood. African American youth are exposed to areas with substantially higher levels of violence. Residing in a disadvantaged neighborhood is significantly associated with exposure to violent areas and explains a non-trivial proportion of the racial difference in this outcome. However, neighborhood factors are incomplete explanations of the racial disparity. Characteristics of the activity locations at which youth spend time explain the residual racial disparity in exposure to violent areas. These findings highlight the importance of youth activity spaces, above and beyond their neighborhood environments. PMID- 28845049 TI - Reactive molecular dynamics models from ab initio molecular dynamics data using relative entropy minimization. AB - We present two new multiscale molecular dynamics (MS-RMD) models for the hydrated excess proton in water developed directly from ab initio molecular dynamics (AIMD) simulation data of the same system. The potential of mean force along the proton transfer reaction coordinate and radial distribution functions for the MS RMD models are shown faithfully reproduce those of AIMD. The models are developed using an algorithm based on relative entropy minimization, thus demonstrating the ability of the method to rapidly generate accurate and highly efficient reactive MD force fields. PMID- 28845050 TI - Preservation of Fertility or Ovarian Function in Patients with Breast Cancer or Gynecologic and Internal Malignancies. AB - Because of the efficacy of systemic therapies, neoplasias which occur in pediatric and adolescent patients and in young adults have high cure rates. This means that fulfilling their wish to have children has become a more pressing concern, particularly among young women with malignant tumors. Premature ovarian failure is also a not insignificant problem as it has a lasting detrimental effect on quality of life. Every oncology patient who may potentially wish to have children should be informed about their options for preserving fertility prior to starting treatment. The rates of patient who received detailed briefing on this point remain low. This review presents the effects of different chemotherapeutic drugs on gonadal function together with an overview of currently valid recommendations on fertility preservation. Risk groups are defined and the specific approaches for malignancies of various organ systems are described. Cryopreservation of oocytes, fertilized embryos and ovarian tissue are fertility preserving options for girls/young women. The data on the benefits of administering GnRH analogs for ovarian protection prior to starting chemotherapy are not clear. In postpubertal boys or male cancer patients, the standard approach is to cryopreserve sperm before starting therapy. The cryopreservation of testicular tissue is possible for prepubertal boys, however in-vitro sperm maturation is still in its experimental stages. This review also presents existing drug options for the preservation of ovarian function in oncology patients prior to chemotherapy, particularly for patients with (hormone sensitive) breast cancer, and looks at the special issues of fertility-preserving surgery and radiation therapy in patients with gynecologic malignancies. PMID- 28845051 TI - Implementation and Feasibility of Electronic Patient-Reported Outcome (ePRO) Data Entry in the PRAEGNANT Real-Time Advanced and Metastatic Breast Cancer Registry. AB - PURPOSE: Patient-reported outcomes (PROs) have been incorporated into clinical trials for many symptoms and medical conditions. A transition from paper-based capture of PROs to electronic PROs (ePROs) has recently started. This study reports on the feasibility of ePRO assessment in a prospective registry including molecular data for patients with advanced breast cancer. METHODS: As part of the PRAEGNANT network, patients were invited by clinical trial staff, physicians, and nurses to complete three standardized Internet-based questionnaires (EQ 5D 5 L, CES-D and IPAQ). Feasibility was assessed by the staff members who assigned the user accounts by the patients. The completeness of the questionnaires was also assessed. RESULTS: Fifteen of 17 patients who were asked agreed to participate to complete the PRO questionnaires (EQ-5D-5L and CES-D). However, the IPAQ (physical activity) questionnaire was only validly completed by 9 patients. Feasibility was ranked better by the physicians and dedicated clinical trial staff than by the nursing staff. CONCLUSIONS: Incorporating ePRO questionnaires into an advanced breast cancer registry is feasible, and no major hurdles were reported. Involving stakeholders from the start, the application is tailored to the capacities and abilities of both patients and clinical staff. The patients' compliance was better with some questionnaires, but others may present difficulties. PMID- 28845052 TI - Should Breast Cancer Surgery Be Done in an Outpatient Setting?: Health Economics From the Perspective of Service Providers. AB - INTRODUCTION: The care of patients with breast cancer is extremely complex and requires interdisciplinary care in certified facilities. These specialized facilities provide numerous services without being correspondingly remunerated. The question whether breast cancer surgery should be performed in an outpatient setting to reduce costs is increasingly being debated. This study compares inpatient surgical treatment with a model of the same surgery performed on an outpatient basis to examine the potential financial impact. MATERIAL AND METHODS: A theoretical model was developed and the DRG fees for surgical interventions to treat primary breast cancer were calculated. A theoretical 1-day DRG was then calculated to permit comparisons with outpatient procedures. The costs of outpatient surgery were calculated based on the remuneration rates of the AOP (Outpatient Surgery) Contract and the EBM (Uniform Assessment Scale) and compared to the costs of the 1-day DRG. RESULTS: The DRG fee for both breast-conserving surgery and mastectomy is higher than the fee paid in the context of the EBM system, although the same procedures were carried out in both systems. If a hospital were to carry out breast-conserving surgery as an outpatient procedure, the fee would be ? 1313.81; depending on the type of surgery, the hospital would therefore only receive between 39.20% and 52.82% of the DRG fee. This was the case even for a 1-day treatment. Compared to the real DRG fees the difference would be even more striking. CONCLUSION: Carrying out breast cancer surgery as an outpatient procedure would result in a significant shortfall of revenues. Additional services from certified centers, such as the interdisciplinary planning of treatment, psycho-oncological and social-medical care with the involvement of relatives, detailed documentation, etc., which are currently provided without surcharge or adequate remuneration, could no longer be maintained. The quality of processes and excellent results which have been achieved and ultimately the care given by certified facilities would be significantly at risk. PMID- 28845053 TI - The Value of Partial HPV Genotyping After Conization of Cervical Dysplasias. AB - INTRODUCTION: In this retrospective study partial genotyping of human papilloma viruses (HPV) using the Abbott RealTime HighRisk HPV Test (RealTime) was compared with simple HPV detection (Qiagen Hybrid Capture 2 Test; hc2) for recurrence prediction at the first follow-up examination after conization of cervical intraepithelial neoplasia (CIN). METHODS: 144 women who had undergone conization for CIN between January 2007 and December 2013 were included. HPV status was determined preoperatively and at first follow-up using hc2 in 103 women and RealTime in 41 women. Recurrent or persistent CIN was assumed when CIN2+ was confirmed histologically or on comparable cytology findings. RESULTS: Of the 144 women with complete data 12 (8.3%) had a recurrence after conization. HPV persistence at follow-up correlated significantly with recurrence (hc2: p = 0.003; RealTime: p = 0.003) and both sensitivity and specificity were high (hc2 = 100 and 78.4% respectively; RealTime = 75.0 and 83.9%). Whereas isolated HPV testing had a relatively low positive predictive value for recurrence (hc2 16%; RealTime 54.5%), this rose to 80% with HPV 16 detection at follow-up. CONCLUSION: At follow-up after conization of CIN the combination of high risk HPV detection and partial genotyping of HPV 16 constitutes excellent diagnostic criteria for recurrence/persistence of CIN. PMID- 28845054 TI - Duty Rosters and Workloads of Obstetricians in Germany: Results of a Germany-wide Survey. AB - BACKGROUND: Compiling a daily hospital roster which complies with existing laws and tariff regulations and meets the requirements for ongoing professional training while also taking the legal regulations on the health of employees into account makes planning the duty roster a challenge. The aim of this study was to obtain a realistic picture of existing duty roster systems and of the current workloads of obstetricians in Germany. METHOD: This online survey was sent to 2770 physicians training to become obstetricians or specializing in specific areas of obstetric care. The survey consisted of an anonymized 95-item questionnaire which collected data on different types of duty roster systems and the workload of obstetricians in Germany for the period from 17.02.2015 to 16.05.2015. RESULTS: Out of a total of 2770 physicians who were contacted, 437 (16%) completed the questionnaire. Across all forms of care, the care provided outside normal working hours usually (75%) consisted of a combination of regular working times and on-call duty or even consisted entirely of standby duty. Level I perinatal centers were most likely 20% (n = 88) to have a shift system in place. Working a shift system was significantly more common in care facilities which had previously carried out a job analysis. The number of physicians in hospitals who are present during the night shift was higher in facilities with higher numbers of births and in facilities which offered higher levels of care. In addition to regularly working overtime and the fact that often not all the hours worked were recorded, it was notable that the systems used to compile duty rosters often did not comply with legal regulations or with collectively agreed working hours nor were they compatible with the staff planning requirements. OUTLOOK: The results of this study show that the conditions of work, the working times, and the organization of working times in obstetric departments are in need of improvement. Recording the actual times worked together with an analysis of the activities performed during working times and while on standby would increase the level of transparency for employers and employees. PMID- 28845055 TI - Recent Overdose Experiences in a Community Sample of Military Veterans Who Use Opioids. AB - Rising rates of overdose mortality underscore the importance of understanding and preventing overdose. We developed a seven-item scale for the assessment of nonfatal opioid-related overdose experiences, adding items on others' perceptions of whether the participant had overdosed and whether an intervention was attempted to frequently used criteria. We administered the scale to 240 primarily male and minority veterans, recruited using venue-based and chain-referral sampling, who separated from the military post-9/11 and reported current opioid use. The items were internally consistent, and correlated well with overdose risk behaviors (r = .13-.45). The new scale detected overdose events in a significantly higher proportion of participants (36.5%) than that using either self-report criterion (18.2%) or difficulty breathing and losing consciousness criteria (23.8%). These experiences or perceptions should be investigated to inform and better tailor the development of more effective overdose prevention and response programs. PMID- 28845056 TI - Why Do College Graduates Behave More Healthfully than Those Who Are Less Educated? AB - College graduates live much healthier lives than those with less education, but research has yet to document with certainty the sources of this disparity. This study examines why U.S. young adults who earn college degrees exhibit healthier behavior than those with less education. I use data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), which offers information on education and health behaviors across adolescence and young adulthood (N=14,265). Accounting for selection into college degree attainment substantially reduces the associations between college degree attainment and health behavior, but college degree attainment demonstrates a strong causal effect on young adult health. Financial, occupational, social, cognitive, and psychological resources explain less than half of the association between college degree attainment and health behavior. The healthier behaviors of college graduates are the result of sorting into educational attainment, embedding of human capital, and mechanisms other than socioeconomic and psychosocial resources. PMID- 28845057 TI - A water-stable lanthanide metal-organic framework for fluorimetric detection of ferric ions and tryptophan. AB - The preparation of a highly water stable and porous lanthanide metal-organic framework (MOF) nanoparticles (denoted SUMOF-7II; SU refers to Stockholm University) is described. SUMOF-7II was synthesized starting from the tritopic linker of 2,4,6-tri-p-carboxyphenyl pyridine (H3L2) and La(III) as metal clusters. SUMOF-7II forms a stable dispersion and displays high fluorescence emission with small variation over the pH range of 6 to 12. Its fluorescence is selectively quenched by Fe(III) ions compared to other metal ions. The intensity of the fluorescene emission drops drops linearly in 16.6-167 MUM Fe(III) concentration range, and Stern-Volmer plots are linear. The limit of detection (LOD) is 16.6 MUM (at an S/N ratio of >3). This indicator probe can also be used for selective detection of tryptophan among several amino acids. Compared to the free linker H3L2, SUMOF-7II offers improved sensitivity and selectivity of the investigated species. Graphical abstractA water-stable porous lanthanide metal organic framework SUMOF-7II (La) has shown to be an excellent probe for the detection of ferric ions among other metal ions, and tryptophan among other amino acids in aqueous solution. The new probe displays high and stable fluorescence signal in a wide pH range (6-12). PMID- 28845058 TI - Characterization of a mine fire using atmospheric monitoring system sensor data. AB - Atmospheric monitoring systems (AMS) have been widely used in underground coal mines in the United States for the detection of fire in the belt entry and the monitoring of other ventilation-related parameters such as airflow velocity and methane concentration in specific mine locations. In addition to an AMS being able to detect a mine fire, the AMS data have the potential to provide fire characteristic information such as fire growth - in terms of heat release rate - and exact fire location. Such information is critical in making decisions regarding fire-fighting strategies, underground personnel evacuation and optimal escape routes. In this study, a methodology was developed to calculate the fire heat release rate using AMS sensor data for carbon monoxide concentration, carbon dioxide concentration and airflow velocity based on the theory of heat and species transfer in ventilation airflow. Full-scale mine fire experiments were then conducted in the Pittsburgh Mining Research Division's Safety Research Coal Mine using an AMS with different fire sources. Sensor data collected from the experiments were used to calculate the heat release rates of the fires using this methodology. The calculated heat release rate was compared with the value determined from the mass loss rate of the combustible material using a digital load cell. The experimental results show that the heat release rate of a mine fire can be calculated using AMS sensor data with reasonable accuracy. PMID- 28845059 TI - Differential elemental uptake in three pseudo-metallophyte C4 grasses in situ in the eastern USA. AB - BACKGROUND AND AIMS: Elemental uptake in serpentine floras in eastern North America is largely unknown. The objective of this study was to determine major and trace element concentrations in soil and leaves of three native pseudo metallophyte C4 grasses in situ at five sites with three very different soil types, including three serpentine sites, in eastern USA. METHODS: Pseudo-total and extractible concentrations of 15 elements were measured and correlated from the soils and leaves of three species at the five sites. RESULTS: Element concentrations in soils of pseudo-metallophytes varied up to five orders of magnitude. Soils from metalliferous sites exhibited higher concentrations of their characteristic elements than non-metalliferous. In metallicolous populations, elemental concentrations depended on the element. Concentrations of major elements (Ca, Mg, K) in leaves were lower than typical toxicity thresholds, whereas concentrations of Zn were higher. CONCLUSIONS: In grasses, species can maintain relatively low metal concentrations in their leaves even when soil concentrations are richer. However, in highly Zn-contaminated soil, we found evidence of a threshold concentration above which Zn uptake increases drastically. Finally, absence of main characteristics of serpentine soil at one site indicated the importance of soil survey and restoration to maintain serpentinophytes communities and avoid soil encroachment. PMID- 28845060 TI - My Teaching Partner-Secondary: A video-based coaching model. AB - In the My Teaching Partner (MTP) program, coaches engage teachers in six to nine coaching cycles across a school year. Guided by the program's theory, coaches help teachers reflect on the emotional, organizational, and instructional features of classrooms. MTP was originally developed for Pre-K and early elementary classrooms (MTP Pre-K), but the current paper focuses on the secondary school version of this program, MTP-Secondary (MTP-S), given the need for coaching models with middle and high school teachers. The paper presents the guiding theory of MTP-S and how it relates to key components of the coaching cycle. We then offer a brief synthesis of research demonstrating its effectiveness in raising achievement, promoting positive peer interactions, and reducing racial disparities in teachers' discipline practices. We provide ideas for future research that would help advance theory on the essential components of effective coaching programs in secondary schools. PMID- 28845061 TI - A generalized multi-resolution expansion for uncertainty propagation with application to cardiovascular modeling. AB - Computational models are used in a variety of fields to improve our understanding of complex physical phenomena. Recently, the realism of model predictions has been greatly enhanced by transitioning from deterministic to stochastic frameworks, where the effects of the intrinsic variability in parameters, loads, constitutive properties, model geometry and other quantities can be more naturally included. A general stochastic system may be characterized by a large number of arbitrarily distributed and correlated random inputs, and a limited support response with sharp gradients or event discontinuities. This motivates continued research into novel adaptive algorithms for uncertainty propagation, particularly those handling high dimensional, arbitrarily distributed random inputs and non-smooth stochastic responses. In this work, we generalize a previously proposed multi-resolution approach to uncertainty propagation to develop a method that improves computational efficiency, can handle arbitrarily distributed random inputs and non-smooth stochastic responses, and naturally facilitates adaptivity, i.e., the expansion coefficients encode information on solution refinement. Our approach relies on partitioning the stochastic space into elements that are subdivided along a single dimension, or, in other words, progressive refinements exhibiting a binary tree representation. We also show how these binary refinements are particularly effective in avoiding the exponential increase in the multi-resolution basis cardinality and significantly reduce the regression complexity for moderate to high dimensional random inputs. The performance of the approach is demonstrated through previously proposed uncertainty propagation benchmarks and stochastic multi-scale finite element simulations in cardiovascular flow. PMID- 28845062 TI - Mathematical modeling and measurement of electric fields of electrode-based through-the-earth (TTE) communication. AB - There are two types of through-the-earth (TTE) wireless communication in the mining industry: magnetic loop TTE and electrode-based (or linear) TTE. While the magnetic loop systems send signal through magnetic fields, the transmitter of an electrode-based TTE system sends signal directly through the mine overburden by driving an extremely low frequency (ELF) or ultralow frequency (ULF) AC current into the earth. The receiver at the other end (underground or surface) detects the resultant current and receives it as a voltage. A wireless communication link between surface and underground is then established. For electrode-based TTE communications, the signal is transmitted through the established electric field and is received as a voltage detected at the receiver. It is important to understand the electric field distribution within the mine overburden for the purpose of designing and improving the performance of the electrode-based TTE systems. In this paper, a complete explicit solution for all three electric field components for the electrode-based TTE communication was developed. An experiment was conducted using a prototype electrode-based TTE system developed by National Institute for Occupational Safety and Health. The mathematical model was then compared and validated with test data. A reasonable agreement was found between them. PMID- 28845063 TI - Spread of Water-Borne Pollutants at Traffic Accidents on Roads. AB - Traffic accidents sometimes lead to the spread of hazardous compounds to the environment. Accidental spills of hazardous compounds on roads in the vicinity of vulnerable objects such as water supplies pose a serious threat to water quality and have to be assessed. This study compared three different assessment methods, electrical resistivity measurements, analytical flow calculations, and 1D and 2D dynamic flow modeling, to describe rapid transport processes in the road shoulder and roadside verge after a major spill. The infiltration and flow paths of water borne substances were described during simulated discharge of pollutants on different road types. Full-scale tracer tests using sodium chloride were carried out at nine different road locations in Sweden. Analysis of grain size distribution and infiltrometer tests were carried out at the road shoulder and verges. The pathways and travel times were traced using resistivity measurements and 3D inverse modeling. The resistivity measurements were compared to analytical flow calculations and 1D and 2D dynamic modeling. All measurement sites were highly heterogeneous, which caused preferential flow. Vertical flow velocities of 1.4-8.6 * 10-4 m/s were measured. The results of the analytical calculations and flow modeling were of the same order of magnitude. The measurements showed that almost all infiltration goes directly into the road embankment, hence the composition and structure of the built-up road must be considered. The non destructive resistivity measurements and 3D modeling provided useful information for clarifying the infiltration and flow pattern of water-borne compounds from road runoff. PMID- 28845064 TI - Progress in Social and Educational Inquiry Through Case Study: Generalization or Explanation? AB - Although much of the most productive research in applied social science is case based, there is still concern about the restricted utility of such research because of its limited power to offer generalizable findings. Such concern has contributed to a recent trend in policy-making circles-particularly those in education-to prefer experimentally orientated research for insights on policy. The argument is made here that concerns about generalization are exaggerated and that the focus upon them has allowed an evasion of issues about quality of explanation coming from different forms of social inquiry design. After discussing these generalization-based issues I proceed to define case study as an inquiry form, outlining its most significant ingredients and I offer a review of case study inquiries in education which exemplify its capacity for offering credible new insights on the questions being posed. PMID- 28845065 TI - Predicting What Will Happen When You Intervene. AB - This paper offers some rules of thumb that practicing social workers can use for case studies that aim to construct, albeit not fully and never entirely reliably, models designed to help predict what will happen if they intervene in specific ways to help this particular client, here and now. We call these 'ex ante case specific causal models'. 'Ex ante' because they are for before-the-fact prediction of what the likely effects of proposed actions are. 'Case-specific' because we are not concerned with studies that provide evidence for some general conclusion but rather with using what general and local knowledge one can get to predict what will happen to a specific client in the real settings in which they live. 'Causal' because this kind of case study aims to trace out as best possible the web of causal processes that will be responsible for what happens. In this sense our case studies resemble post facto realist evaluations. PMID- 28845066 TI - Marijuana policy opinions in Washington state since legalization: Would voters vote the same way? AB - BACKGROUND: In 2012, voters in Washington state approved Initiative 502 (I-502) which legalized recreational marijuana use at the state level. This study examines the relationship between demographics, marijuana and alcohol use, and voting outcomes, as well as how these variables relate to (i) whether voters would still vote the same way (a reflection of satisfaction with the new policy) and (ii) the likelihood of using marijuana purchased from legal retail stores. METHODS: The sample consists of 2,007 adult Washington state residents recruited through Random Digit Dial between January and October 2014. Bivariate tests and multivariable regressions were used for analyses. RESULTS: Less than five percent of those who voted for marijuana legalization would change their votes, whereas 14% of those who voted against legalization would change their votes. In multivariable models controlling for demographics, substance use, and marijuana related opinions, those who voted for legalization had half the odds of changing their votes than those who voted against it. Among past-year non-marijuana users, almost 10% were somewhat/very likely to use marijuana if they could buy it from a legal store. Past marijuana use, the belief that adults should be allowed to grow marijuana for personal use, and the belief that marijuana is not very risky for health were all related to increased likelihood of using marijuana purchased from legal stores. CONCLUSION: Since November 2012, support for marijuana legalization in Washington state has increased; accounting for the proportion of voters who would change their votes suggests that I-502 would pass today with even more votes in favor. PMID- 28845067 TI - Normal personality traits, rumination and stress generation among early adolescent girls. AB - This study examined associations between personality and stress generation. Expanding upon prior work, we examined (a) the role of Positive Emotionality (PE), Negative Emotionality (NE), and Constraint (CON), and their lower-order facets, as predictors of acute and chronic interpersonal stress generation; (b) whether personality moderated effects of rumination on stress generation; and (c) whether personality increased exposure to independent (uncontrollable) stress. These questions were examined in a one-year study of 126 adolescent girls (M age = 12.39 years) using contextual stress interviews. NE predicted increases in acute and chronic interpersonal stress generation, but not independent stress. NE, CON and affiliative PE each moderated the effect of rumination on chronic interpersonal stress generation. These effects were driven by particular lower order traits. PMID- 28845068 TI - Accelerating Innovation in the Creation of Biovalue: The Cell and Gene Therapy Catapult. AB - The field of regenerative medicine (RM) has considerable therapeutic promise that is proving difficult to realize. As a result, governments have supported the establishment of intermediary agencies to "accelerate" innovation. This article examines in detail one such agency, the United Kingdom's Cell and Gene Therapy Catapult (CGTC). We describe CGTC's role as an accelerator agency and its value narrative, which combines both "health and wealth." Drawing on the notion of sociotechnical imaginaries, we unpack the tensions within this narrative and its instantiation as the CGTC cell therapy infrastructure is built and engages with other agencies, some of which have different priorities and roles to play within the RM field. PMID- 28845069 TI - Highly Polymorphic Microsatellite Markers for the Assessment of Male Reproductive Skew and Genetic Variation in Critically Endangered Crested Macaques (Macaca nigra). AB - Genetic analyses based on noninvasively collected samples have become an important tool for evolutionary biology and conservation. Crested macaques (Macaca nigra), endemic to Sulawesi, Indonesia, are important for our understanding of primate evolution as Sulawesi macaques represent an exceptional example of primate adaptive radiation. Crested macaques are also Critically Endangered. However, to date we know very little about their genetics. The aim of our study was to find and validate microsatellite markers useful for evolutionary, conservation, and other genetic studies on wild crested macaques. Using fecal samples of 176 wild macaques living in the Tangkoko Reserve, Sulawesi, we identified 12 polymorphic microsatellite loci through cross-species polymerase chain reaction amplification with later modification of some of these primers. We tested their suitability by investigating and exploring patterns of paternity, observed heterozygosity, and evidence for inbreeding. We assigned paternity to 63 of 65 infants with high confidence. Among cases with solved paternity, we found no evidence of extragroup paternity and natal breeding. We found a relatively steep male reproductive skew B index of 0.330 +/- 0.267; mean +/- SD) and mean alpha paternity of 65% per year with large variation across groups and years (29-100%). Finally, we detected an excess in observed heterozygosity and no evidence of inbreeding across our three study groups, with an observed heterozygosity of 0.766 +/- 0.059 and expected heterozygosity of 0.708 +/- 0.059, and an inbreeding coefficient of -0.082 +/- 0.035. Our results indicate that the selected markers are useful for genetic studies on wild crested macaques, and possibly also on other Sulawesi and closely related macaques. They further suggest that the Tangkoko population of crested macaques is still genetically variable despite its small size, isolation, and the species' reproductive patterns. This gives us hope that other endangered primate species living in small, isolated populations may also retain a healthy gene pool, at least in the short term. PMID- 28845070 TI - The use of Vocalizations of the Sambirano Mouse Lemur (Microcebus sambiranensis) in an Acoustic Survey of Habitat Preference. AB - Primate vocalizations convey a variety of information to conspecifics. The acoustic traits of these vocalizations are an effective vocal fingerprint to discriminate between sibling species for taxonomic diagnosis. However, the vocal behavior of nocturnal primates has been poorly studied and there are few studies of their vocal repertoires. We compiled a vocal repertoire for the Endangered Sambirano mouse lemur, Microcebus sambiranensis, an unstudied nocturnal primate of northwestern Madagascar, and compared the acoustic properties of one of their call types to those of M. murinus and M. rufus. We recorded vocalizations from radio-collared individuals using handheld recorders over 3 months. We also conducted an acoustic survey to measure the vocal activity of M. sambiranensis in four forest habitat types at the study site. We identified and classified five vocalization types in M. sambiranensis. The vocal repertoires of the three Microcebus species contain very similar call types but have different acoustic properties, with one loud call type, the whistle, having significantly different acoustic properties between species. Our acoustic survey detected more calls of M. sambiranensis in secondary forest, riparian forest, and forest edge habitats, suggesting that individuals may prefer these habitat types over primary forest. Our results suggest interspecific differences in the vocal repertoire of mouse lemurs, and that these differences can be used to investigate habitat preference via acoustic surveys. PMID- 28845071 TI - Exploration of Factors Predictive of At-risk Fathers' Participation in a Pilot Study of an Augmented Evidence-Based Parent Training Program: A Mixed Methods Approach. AB - There has been burgeoning parenting intervention research specifically addressing fathers in recent decades. Corresponding research examining their participation and engagement in evidence-based parent training programs, which have almost exclusively targeted mothers, is just emerging. The current study used mixed methods to examine factors that influenced completion of an augmented version of an evidence-based child maltreatment prevention program developed for male caregivers called SafeCare Dad to Kids (Dad2K) in a pilot study. The current sample comprised 50 male caregivers (Mage = 29.42 years, SD = 8.18) of a child between the ages of 2 and 5 years. Fathers participated in a baseline assessment and were considered program completers (n = 27) if they participated in the program's six home visiting sessions. A subsample of completers (n = 11) was recruited to participate in qualitative interviews that provided in-depth information about fathers' experiences in Dad2K. Logistic regression indicated that, in the context of other demographic predictors, fathers with an education beyond high school were over 5 times more likely to complete Dad2K program compared to fathers with a high school education or less. Qualitative analyses revealed that interviewed father completers were motivated to enroll and participate in a fathering program because of an interest to learn and obtain skills to make them a better parent. Fathers with a high school education or less may require additional engagement strategies to help proactively encourage their enrollment and completion of parent training programs. PMID- 28845072 TI - SEARCHING FOR THE FAMILY LEGAL STATUS OF MEXICAN-ORIGIN CHILDREN: A PRIMER ON DIFFERENT MEASUREMENT STRATEGIES. AB - Interest in the consequences of family legal status for children has grown in response to immigration-related changes in the ethnic composition of American society. However, few population-based empirical studies devote attention to family legal status due to data limitations. Using restricted data from the California Health Interview Survey (2009), the primary objectives of this research are to identify and evaluate strategies for measuring this important determinant of life chances among Mexican-origin children. The results indicate that measurement strategies matter. Estimates of the size of status-specific segments of this population and their risks of living in poverty are sensitive to how family legal status is operationalized. These findings provide the foundation for a discussion of how various "combinatorial" measurement strategies may rely on untenable assumptions that can be avoided with less reductionist approaches. PMID- 28845073 TI - Serologic Testing for Syphilis: Benefits and Challenges of a Reverse Algorithm. AB - Syphilis is a human infection of global importance. Its diagnosis can be challenging, requiring construction of a serologic profile based on the results of at least two types of antibody tests: treponemal and nontreponemal. The traditional approach to the serodiagnosis of syphilis has been the use of a nontreponemal screening assay followed by the performance of a treponemal confirmatory test if the initial nontreponemal screening test was reactive. With the increasing availability of automated, easier-to-perform, and rapid treponemal assays, an increasing number of laboratory testing sites are adopting reverse sequence screening for the serodiagnosis of syphilis: screening with a treponemal assay first, then confirmation with a nontreponemal assay and, when necessary, discrepant resolution using another treponemal test. In addition to offering automation and increased throughput, a reverse algorithm can increase disease detection, especially in late latent and early primary stages of infection when the nontreponemal antibody test may be nonreactive. However, a disadvantage to this approach is that there can be an increase in false-positive test results. This article reviews the clinical and workflow benefits and limitations of a reverse testing algorithm and discusses current guidance available from the Centers for Disease Control and Prevention. PMID- 28845074 TI - Becoming Overweight Without Gaining a Pound: Weight Evaluations and the Social Integration of Mexicans in the United States. AB - Mexican women gain weight with increasing duration in the United States. In the United States, body dissatisfaction tends to be associated with depression, disordered eating, and incongruent weight evaluations, particularly among white women and women of higher socioeconomic status. However, it remains unclear how overweight and obesity is interpreted by Mexican women. Using comparable data of women ages 20-64 from both Mexico (the 2006 Encuesta Nacional de Salud y Nutricion; N=17,012) and the United States (the 1999-2009 National Health and Nutrition Examination Surveys; N=8,487), we compare weight status evaluations among Mexican nationals, Mexican immigrants, U.S.-born Mexicans, U.S.-born non Hispanic Whites, and U.S.-born non-Hispanic blacks. Logistic regression analyses, which control for demographic and social-economic variables and measured body mass index and adjust for the likelihood of migration for Mexican nationals, indicate that the tendency to self-evaluate as overweight among Mexicans converges with levels among non-Hispanic whites and diverges from blacks over time in the United States. Overall, the results suggest a U.S. integration process in which Mexican-American women's less critical self-evaluations originate in Mexico but fade with time in the United States as they gradually adopt U.S. white norms for thinner body sizes. These results are discussed in light of social comparison and negative health assimilation. PMID- 28845075 TI - Big Numbers about Small Children: Estimating the Economic Benefits of Addressing Undernutrition. AB - Different approaches have been used to estimate the economic benefits of reducing undernutrition and to estimate the costs of investing in such programs on a global scale. While many of these studies are ultimately based on evidence from well-designed efficacy trials, all require a number of assumptions to project the impact of such trials to larger populations and to translate the value of the expected improvement in nutritional status into economic terms. This paper provides a short critique of some approaches to estimating the benefits of investments in child nutrition and then presents an alternative set of estimates based on different core data. These new estimates reinforce the basic conclusions of the existing literature: the economic value from reducing undernutrition in undernourished populations is likely to be substantial. PMID- 28845076 TI - Effects of b-Value and Number of Gradient Directions on Diffusion MRI Measures Obtained with Q-ball Imaging. AB - High-angular-resolution diffusion-weighted imaging (HARDI) MRI acquisitions have become common for use with higher order models of diffusion. Despite successes in resolving complex fiber configurations and probing microstructural properties of brain tissue, there is no common consensus on the optimal b-value and number of diffusion directions to use for these HARDI methods. While this question has been addressed by analysis of the diffusion-weighted signal directly, it is unclear how this translates to the information and metrics derived from the HARDI models themselves. Using a high angular resolution data set acquired at a range of b values, and repeated 11 times on a single subject, we study how the b-value and number of diffusion directions impacts the reproducibility and precision of metrics derived from Q-ball imaging, a popular HARDI technique. We find that Q ball metrics associated with tissue microstructure and white matter fiber orientation are sensitive to both the number of diffusion directions and the spherical harmonic representation of the Q-ball, and often are biased when under sampled. These results can advise researchers on appropriate acquisition and processing schemes, particularly when it comes to optimizing the number of diffusion directions needed for metrics derived from Q-ball imaging. PMID- 28845077 TI - 3D Convolutional Neural Network for Automatic Detection of Lung Nodules in Chest CT. AB - Deep convolutional neural networks (CNNs) form the backbone of many state-of-the art computer vision systems for classification and segmentation of 2D images. The same principles and architectures can be extended to three dimensions to obtain 3D CNNs that are suitable for volumetric data such as CT scans. In this work, we train a 3D CNN for automatic detection of pulmonary nodules in chest CT images using volumes of interest extracted from the LIDC dataset. We then convert the 3D CNN which has a fixed field of view to a 3D fully convolutional network (FCN) which can generate the score map for the entire volume efficiently in a single pass. Compared to the sliding window approach for applying a CNN across the entire input volume, the FCN leads to a nearly 800-fold speed-up, and thereby fast generation of output scores for a single case. This screening FCN is used to generate difficult negative examples that are used to train a new discriminant CNN. The overall system consists of the screening FCN for fast generation of candidate regions of interest, followed by the discrimination CNN. PMID- 28845078 TI - Impact of Different Study Populations on Reader Behavior and Performance Metrics: Initial Results. AB - The FDA recently completed a study on design methodologies surrounding the Validation of Imaging Premarket Evaluation and Regulation called VIPER. VIPER consisted of five large reader sub-studies to compare the impact of different study populations on reader behavior as seen by sensitivity, specificity, and AUC, the area under the ROC curve (receiver operating characteristic curve). The study investigated different prevalence levels and two kinds of sampling of non cancer patients: a screening population and a challenge population. The VIPER study compared full-field digital mammography (FFDM) to screen-film mammography (SFM) for women with heterogeneously dense or extremely dense breasts. All cases and corresponding images were sampled from Digital Mammographic Imaging Screening Trial (DMIST) archives. There were 20 readers (American Board Certified radiologists) for each sub-study, and instead of every reader reading every case (fully-crossed study), readers and cases were split into groups to reduce reader workload and the total number of observations (split-plot study). For data collection, readers first decided whether or not they would recall a patient. Following that decision, they provided an ROC score for how close or far that patient was from the recall decision threshold. Performance results for FFDM show that as prevalence increases to 50%, there is a moderate increase in sensitivity and decrease in specificity, whereas AUC is mainly flat. Regarding precision, the statistical efficiency (ratio of variances) of sensitivity and specificity relative to AUC are 0.66 at best and decrease with prevalence. Analyses comparing modalities and the study populations (screening vs. challenge) are still ongoing. PMID- 28845079 TI - eeDAP: An Evaluation Environment for Digital and Analog Pathology. AB - PURPOSE: The purpose of this work is to present a platform for designing and executing studies that compare pathologists interpreting histopathology of whole slide images (WSI) on a computer display to pathologists interpreting glass slides on an optical microscope. METHODS: Here we present eeDAP, an evaluation environment for digital and analog pathology. The key element in eeDAP is the registration of the WSI to the glass slide. Registration is accomplished through computer control of the microscope stage and a camera mounted on the microscope that acquires images of the real time microscope view. Registration allows for the evaluation of the same regions of interest (ROIs) in both domains. This can reduce or eliminate disagreements that arise from pathologists interpreting different areas and focuses the comparison on image quality. RESULTS: We reduced the pathologist interpretation area from an entire glass slide (~10-30 mm)2 to small ROIs <(50 um)2. We also made possible the evaluation of individual cells. CONCLUSIONS: We summarize eeDAP's software and hardware and provide calculations and corresponding images of the microscope field of view and the ROIs extracted from the WSIs. These calculations help provide a sense of eeDAP's functionality and operating principles, while the images provide a sense of the look and feel of studies that can be conducted in the digital and analog domains. The eeDAP software can be downloaded from code.google.com (project: eeDAP) as Matlab source or as a precompiled stand-alone license-free application. PMID- 28845080 TI - Theoretical and Monte Carlo optimization of a stacked three-layer flat-panel x ray imager for applications in multi-spectral medical imaging. AB - We propose a new design of a stacked three-layer flat-panel x-ray detector for dual-energy (DE) imaging. Each layer consists of its own scintillator of individual thickness and an underlying thin-film-transistor-based flat-panel. Three images are obtained simultaneously in the detector during the same x-ray exposure, thereby eliminating any motion artifacts. The detector operation is two fold: a conventional radiography image can be obtained by combining all three layers' images, while a DE subtraction image can be obtained from the front and back layers' images, where the middle layer acts as a mid-filter that helps achieve spectral separation. We proceed to optimize the detector parameters for two sample imaging tasks that could particularly benefit from this new detector by obtaining the best possible signal to noise ratio per root entrance exposure using well-established theoretical models adapted to fit our new design. These results are compared to a conventional DE temporal subtraction detector and a single-shot DE subtraction detector with a copper mid-filter, both of which underwent the same theoretical optimization. The findings are then validated using advanced Monte Carlo simulations for all optimized detector setups. Given the performance expected from initial results and the recent decrease in price for digital x-ray detectors, the simplicity of the three-layer stacked imager approach appears promising to usher in a new generation of multi-spectral digital x-ray diagnostics. PMID- 28845082 TI - Gender Representation on Gender-Targeted Television Channels: A Comparison of Female- and Male-Targeted TV Channels in the Netherlands. AB - The current study investigated the differences in the representation of gender on male- and female-targeted channels with regard to recognition (i.e., the actual presence of men and women) and respect (i.e., the nature of that representation or portrayal). To this end, the presence of men and women on two female- and two male-targeted Dutch channels (N = 115 programs, N = 1091 persons) were compared via content analysis. The expectation that men's channels would portray a less equal and more traditional image of gender than women's channels was generally supported by the results. Regardless of genre as well as country of origin of the program, women were underrepresented on men's channels, while gender distribution on women's channels was more equal. The representation of women in terms of age and occupation was more stereotypical on men's channels than on women's channels, whereas men were represented in more contra-stereotypical ways (e.g., performing household tasks) on women's channels. Since television viewing contributes to the learning and maintenance of stereotyped perceptions, the results imply that it is important to strengthen viewers' defenses against the effects of gender stereotyping when watching gendered television channels, for instance through media literacy programs in schools. PMID- 28845081 TI - Soluble CD14 as a Diagnostic and Prognostic Biomarker in Hematological Patients with Febrile Neutropenia. AB - OBJECTIVE: Elevated levels of a cell surface glycoprotein, soluble cluster of differentiation 14 (sCD14), have been observed in patients with sepsis. Only scarce data are available on sCD14 in hematological patients with chemotherapy induced febrile neutropenia. The study aim was to investigate sCD14 as an early biomarker in febrile neutropenia after intensive chemotherapy to detect a rapidly deteriorating clinical course early enough to avoid serious infectious complications. PATIENTS AND METHODS: This prospective study included 87 adult hematological patients at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The study endpoints were septic shock, severe sepsis, and positive blood culture findings. sCD14 was analyzed from day 0 to day 2, and its prognostic capacity was compared to that of C-reactive protein and procalcitonin. RESULTS: Plasma level of sCD14 predicted the development of septic shock on day 1 (p = 0.001) and day 2 but not the development of severe sepsis or blood culture positivity in hematological patients with chemotherapy-induced febrile neutropenia. CONCLUSIONS: Soluble CD14 did not predict an overall complicated course at the early stages of febrile neutropenia. However, it was helpful in predicting the progression of the clinical course of neutropenic fever to septic shock. PMID- 28845083 TI - Bivariate Developmental Relations between Calculations and Word Problems: A Latent Change Approach. AB - The relation between 2 forms of mathematical cognition, calculations and word problems, was examined. Across grades 2-3, performance of 328 children (mean starting age 7.63 [SD=0.43]) was assessed 3 times. Comparison of a priori latent change score models indicated a dual change model, with consistently positive but slowing growth, described development in each domain better than a constant or proportional change model. The bivariate model including change models for both calculations and word problems indicated prior calculation performance and change were not predictors of subsequent word-problem change, and prior word-problem performance and change were not predictors of subsequent calculation change. Results were comparable for boys versus girls. The bivariate model, along with correlations among intercepts and slopes, suggest calculation and word-problem development are related, but through an external set of overlapping factors. Exploratory supplemental analyses corroborate findings and provide direction for future study. PMID- 28845084 TI - Part 1: Emerging Topics in Medical Displays. AB - New display applications for the interpretation of medical images include mobile image viewers, true-color modalities, and 3-D technologies for improved diagnostic performance. PMID- 28845085 TI - Part 2: Pre-Clinical Assessment of Medical Displays for Regulatory Evaluation. AB - Challenges are emerging with regard to the pre-clinical, regulatory assessment of display systems used for viewing and interpreting medical images. This article discusses those, and also the types of evidence that might be relevant to the evaluation of mobile image-viewing devices, true-color devices with applications in digital microscopy, and 3-D medical displays as discussed in Part 1. PMID- 28845086 TI - An exploratory comparison of name generator content: Data from rural India. AB - Since the 1970s sociologists have explored the best means for measuring social networks, although few name generator analyses have used sociocentric data or data from developing countries, partly because sociocentric studies in developing countries have been scant. Here, we analyze 12 different name generators used in a sociocentric network study conducted in 75 villages in rural Karnataka, India. Having unusual sociocentric data from a non-Western context allowed us to extend previous name generator research through the unique analyses of network structural measures, an extensive consideration of homophily, and investigation of status difference between egos and alters. We found that domestic interaction questions generated networks that were highly clustered and highly centralized. Similarity between respondents and their nominated contacts was strongest for gender, caste, and religion. We also found that domestic interaction name generators yielded the most homogeneous ties, while advice questions yielded the most heterogeneous. Participants were generally more likely to nominate those of higher social status, although certain questions, such as who participants talk to uncovered more egalitarian relationships, while other name generators elicited the names of social contacts distinctly higher or lower in status than the respondent. Some questions also seemed to uncover networks that were specific to the cultural context, suggesting that network researchers should balance local relevance with global generalizability when choosing name generators. PMID- 28845087 TI - Lives on hold: A qualitative study of young refugees' resilience strategies. AB - Although the literature on positive adjustment following traumatic events is growing, only a few studies have examined this phenomenon in young refugees. Using the social-ecological framework, the aim of this study was to identify factors and processes that according to young refugees promote their resilience. A total of 16 treatment-seeking refugees aged 13-21 years, living in the Netherlands, were interviewed. Data analysis revealed four resilience strategies: (1) acting autonomously, (2) performing at school, (3) perceiving support from peers and parents, and (4) participating in the new society. These strategies interacted with one another and demonstrated the interrelatedness between individuals and their social context. Having to wait long for a residence permit and being older appeared to negatively influence participants' resilience strategies. These findings suggest that resilience refers to a dynamic process that is context and time specific. PMID- 28845088 TI - Platelet-Rich Plasma as an Autologous and Proangiogenic Cell Delivery System. AB - Angiogenesis is a key factor in early stages of wound healing and is crucial for the repair of vascularized tissues such as the bone. However, supporting timely revascularization of the defect site still presents a clinical challenge. Tissue engineering approaches delivering endothelial cells or prevascularized constructs may overcome this problem. In the current study, we investigated platelet-rich plasma (PRP) gels as autologous, injectable cell delivery systems for prevascularized constructs. PRP was produced from human thrombocyte concentrates. GFP-expressing human umbilical vein endothelial cells (HUVECs) and human bone marrow-derived mesenchymal stem cells (MSCs) were encapsulated in PRP gels in different proportions. The formation of cellular networks was assessed over 14 days by time-lapse microscopy, gene expression analysis, and immunohistology. PRP gels presented a favorable environment for the formation of a three-dimensional (3D) cellular network. The formation of these networks was apparent as early as 3 days after seeding. Networks increased in complexity and branching over time but were only stable in HUVEC-MSC cocultures. The high cell viability together with the 3D capillary-like networks observed at early time points suggests that PRP can be used as an autologous and proangiogenic cell delivery system for the repair of vascularized tissues such as the bone. PMID- 28845089 TI - The Lymphotoxin beta Receptor Is Essential for Upregulation of IFN-Induced Guanylate-Binding Proteins and Survival after Toxoplasma gondii Infection. AB - Lymphotoxin beta receptor (LTbetaR) signaling plays an important role in efficient initiation of host responses to a variety of pathogens, encompassing viruses, bacteria, and protozoans via induction of the type I interferon response. The present study reveals that after Toxoplasma gondii infection, LTbetaR-/- mice show a substantially reduced survival rate when compared to wild type mice. LTbetaR-/- mice exhibit an increased parasite load and a more pronounced organ pathology. Also, a delayed increase of serum IL-12p40 and a failure of the protective IFNgamma response in LTbetaR-/- mice were observed. Serum NO levels in LTbetaR-/- animals rose later and were markedly decreased compared to wild-type animals. At the transcriptional level, LTbetaR-/- animals exhibited a deregulated expression profile of several cytokines known to play a role in activation of innate immunity in T. gondii infection. Importantly, expression of the IFNgamma-regulated murine guanylate-binding protein (mGBP) genes was virtually absent in the lungs of LTbetaR-/- mice. This demonstrates clearly that the LTbetaR is essential for the induction of a type II IFN-mediated immune response against T. gondii. The pronounced inability to effectively upregulate host defense effector molecules such as GBPs explains the high mortality rates of LTbetaR-/- animals after T. gondii infection. PMID- 28845091 TI - Tobacco-free economy: A SAM-based multiplier model to quantify the impact of changes in tobacco demand in Bangladesh. AB - In Bangladesh, where tobacco use is pervasive, reducing tobacco use is economically beneficial. This paper uses the latest Bangladesh social accounting matrix (SAM) multiplier model to quantify the economy-wide impact of demand driven changes in tobacco cultivation, bidi industries, and cigarette industries. First, we compute various income multiplier values (i.e. backward linkages) for all production activities in the economy to quantify the impact of changes in demand for the corresponding products on gross output for 86 activities, demand for 86 commodities, returns to four factors of production, and income for eight household groups. Next, we rank tobacco production activities by income multiplier values relative to other sectors. Finally, we present three hypothetical 'tobacco-free economy' scenarios by diverting demand from tobacco products into other sectors of the economy and quantifying the economy-wide impact. The simulation exercises with three different tobacco-free scenarios show that, compared to the baseline values, total sectoral output increases by 0.92%, 1.3%, and 0.75%. The corresponding increases in the total factor returns (i.e. GDP) are 1.57%, 1.75%, and 1.75%. Similarly, total household income increases by 1.40%, 1.58%, and 1.55%. PMID- 28845090 TI - The Correlation between FSTL1 Expression and Airway Remodeling in Asthmatics. AB - BACKGROUND: Asthma is characterized by airway remodeling. Follistatin-like protein 1 (FSTL1) is an extracellular glycoprotein. Recent studies suggest that FSTL1 may participate in the pathogenesis of asthma. OBJECTIVES: To analyze the association between FSTL1 and some parameters and inspect the role of FSTL1 in asthma. METHODS: We examined FSTL1 levels in 32 asthmatics and 25 controls. All subjects enrolled had routine blood tests, spirometry, and impulse oscillometry performed. Additionally, 15 of the 32 asthmatics underwent fibre optic bronchoscopy. Spearman rank analysis was performed to detect the correlation between FSTL1 and other parameters. RESULTS: Plasma FSTL1 levels were higher in asthmatics (130.762 +/- 46.029 ng/mL) than in controls (95.408 +/- 33.938 ng/mL) (p = 0.009). Plasma FSTL1 levels were associated with fibrosis levels around the airways (rs = 0.529, p = 0.043) and alpha-smooth muscle actin (alpha-SMA) (rs = 0.554, p = 0.032). FSTL1 levels in bronchoalveolar lavage fluid were associated with collagen I (rs = 0.536, p = 0.040), alpha-SMA (rs = 0.561, p = 0.029), fibrosis levels (rs = 0.779, p = 0.001), and the thickness of the airway reticular basement membrane (RBM) (rs = 0.660, p = 0.007). CONCLUSIONS: FSTL1 levels in asthmatics were linked with increased smooth muscle mass and thickened RBM. FSTL1 may contribute to airway remodeling in asthmatics. PMID- 28845092 TI - A modified nonmonotone BFGS algorithm for unconstrained optimization. AB - In this paper, a modified BFGS algorithm is proposed for unconstrained optimization. The proposed algorithm has the following properties: (i) a nonmonotone line search technique is used to obtain the step size [Formula: see text] to improve the effectiveness of the algorithm; (ii) the algorithm possesses not only global convergence but also superlinear convergence for generally convex functions; (iii) the algorithm produces better numerical results than those of the normal BFGS method. PMID- 28845093 TI - Vector critical points and generalized quasi-efficient solutions in nonsmooth multi-objective programming. AB - In this work, several extended approximately invex vector-valued functions of higher order involving a generalized Jacobian are introduced, and some examples are presented to illustrate their existences. The notions of higher-order (weak) quasi-efficiency with respect to a function are proposed for a multi-objective programming. Under the introduced generalization of higher-order approximate invexities assumptions, we prove that the solutions of generalized vector variational-like inequalities in terms of the generalized Jacobian are the generalized quasi-efficient solutions of nonsmooth multi-objective programming problems. Moreover, the equivalent conditions are presented, namely, a vector critical point is a weakly quasi-efficient solution of higher order with respect to a function. PMID- 28845094 TI - Strongly singular integrals along curves on alpha-modulation spaces. AB - In this paper, we study the strongly singular integrals [Formula: see text] along homogeneous curves [Formula: see text]. We prove that [Formula: see text] is bounded on the alpha-modulation spaces, including the inhomogeneous Besov spaces and the classical modulation spaces. PMID- 28845095 TI - School Aged Children's Experiences 7 and 13 Months Following a Sibling's Death. AB - This study described 6-year to 12-year-old children's responses 7 and 13 months after siblings' NICU/PICU/ED death. Using semi-structured interviews, at 7 months, children were asked about events around their sibling's death. At both 7 and 13 months, children were asked about their thoughts and feelings about the deceased, concerns or fears, and life changes since the death. Thirty one children (58% female), recruited from four South Florida hospitals and Florida obituaries, participated. Children's mean age was 8.4 years; 64.5% were Black, 22.5% Hispanic, 13% White. Interviews were analyzed using conventional content analysis. Resulting themes: circumstances of the death, burial events, thinking about and talking to the deceased sibling, fears, and life changes. Most children knew their sibling's cause of death, attended funeral/memorials, thought about and talked to their deceased sibling, reported changes in family and themselves over the 13 months. Fears (something happening to themselves, parents, other siblings-death, cancer, being snatched away) decreased from 7 to 13 months especially in 7-year to 9-year-olds. Seven-year to 9-year-olds reported the greatest change in themselves from 7 to 13 months. More Black children and girls thought about the deceased and reported more changes in themselves over the 13 months. School aged children thought about and talked with their deceased sibling, reported changes in themselves and their family and their fears decreased over the first 13 months after their sibling's death. PMID- 28845096 TI - Efficacy of the Young Women's CoOp: An HIV Risk-Reduction Intervention for Substance-Using African-American Female Adolescents in the South. AB - HIV/sexually transmitted infection (STI) risk-reduction interventions are needed to address the complex risk behaviors among African-American female adolescents in disadvantaged communities in North Carolina. In a two-group randomized trial, we reached 237 sexually active, substance-using African-American female adolescents, to test a risk-reduction intervention, the Young Women's CoOp (YWC), relative to a nutrition control. In efficacy analyses adjusting for baseline condom use, at three-month follow-up participants in the YWC were significantly less likely to report sex without a condom at last sex relative to control. There were mixed findings for within-group differences over follow-up, underscoring the challenges for intervening with substance-using female youths. PMID- 28845097 TI - Comparing models of change to estimate the mediated effect in the pretest posttest control group design. AB - Models to assess mediation in the pretest-posttest control group design are understudied in the behavioral sciences even though it is the design of choice for evaluating experimental manipulations. The paper provides analytical comparisons of the four most commonly used models used to estimate the mediated effect in this design: Analysis of Covariance (ANCOVA), difference score, residualized change score, and cross-sectional model. Each of these models are fitted using a Latent Change Score specification and a simulation study assessed bias, Type I error, power, and confidence interval coverage of the four models. All but the ANCOVA model make stringent assumptions about the stability and cross lagged relations of the mediator and outcome that may not be plausible in real world applications. When these assumptions do not hold, Type I error and statistical power results suggest that only the ANCOVA model has good performance. The four models are applied to an empirical example. PMID- 28845098 TI - Auto-Calibration for a Planar Epicardial Wire Robot. AB - Gene therapies have emerged as a promising treatment for congestive heart failure, yet they lack a method for minimally invasive, uniform delivery. To address this need we developed Cerberus, a minimally invasive parallel wire robot for cardiac interventions. Prior work on controlling the movement of Cerberus required accurate knowledge of device geometry. In order to determine the geometry of the device in vivo, this paper presents work on developing an auto calibration procedure to measure the geometry of the robot using force sensors to move injector. The presented auto-calibration routine is able to identify the shape of the device to within 0.5 mm and 0.9 degrees . PMID- 28845099 TI - An analysis of roof bolter fatalities and injuries in U.S. mining. AB - Roof bolting typically follows the extraction of a commodity to help keep the roof from collapsing. During 2004 to 2013, roof bolter operators had the highest number of machinery-related injuries, accounting for 64.7 percent, at underground coal mines. This paper analyzes U.S. roof bolter fatal and nonfatal lost-time injury data at underground work locations for all commodities from 2004 through 2013 and determines risk indices for six roof bolting tasks. For fatal and nonfatal incidences combined, the roof bolting tasks in order of the highest to lowest risk index were bolting, handling of materials, setting the temporary roof support (TRS), drilling, tramming, and traversing. For fatalities, the roof bolting tasks in order of the highest to lowest risk index were handling of materials, setting the TRS, bolting, drilling, traversing, and tramming. Age was found to be a significant factor. Severity of injury, indicated by days lost, was found to increase with increasing age as well as with increasing experience, largely due to the confounding of age and experience. The operation of the roof bolting machine used in underground mining should be a research priority given the high frequency and severity of incidents. The results also suggest that temporal factors may exist, so additional research is warranted to better understand these factors and potentially develop interventions. This research provides a data-driven foundation from which future research can be conducted for safety interventions to reduce the frequency and severity of incidences involving the roof bolter activities of bolting, handling of materials, and setting the TRS. PMID- 28845100 TI - Determination of the enantiomeric purity of epinephrine by HPLC with circular dichroism detection. AB - Several hundred drug substances approved by the U.S. Food and Drug Administration are chiral molecules. For the enantiomeric purity assessment, current practice is to develop separation techniques using chiral columns or mobile phase modifiers to separate enantiomers before detection. An alternative approach is to use currently accepted HPLC assay methods and use chiral-specific detectors to confirm whether the correct enantiomer is present. In this paper, adding a circular dichroism (CD) detector to an achiral HPLC method from the US Pharmacopeia (USP) is shown to be amenable for the determination of the enantiomeric purity of epinephrine, a substance used to treat anaphylaxis. This HPLC-UV-CD approach was able to detect the inactive D-(+) enantiomer at 1% of the total epinephrine composition. The linearity, accuracy, and precision of HPLC-UV CD were evaluated and compared to analyses using a chiral HPLC method. Additionally, an epinephrine drug product was analyzed for assay (concentration) and enantiomeric purity. The results from achiral and chiral methods were identical within the experimental error. Overall, achiral chromatography performed using a USP method with CD detection may serve as a general means of determining chiral drug enantiomer purity and avoids the need for the development of additional chiral-specific methods for each individual drug. PMID- 28845101 TI - Synthesis and Surface Activity of Cationic Amino Acid-Based Surfactants in Aqueous Solution. AB - I studied the possibility of using amino acid-based surfactants as emulsifiers at the same time as preservatives. Fourteen lipopeptides were synthesized employing a solid phase peptide synthesis procedure. All compounds were designed to be positively charged from +1 to +4 and acylated with fatty acid chain-palmitic and miristic. The surface activity of the obtained lipopeptides was tested using a semi-automatic tensiometer to calculate parameters describing the behavior of lipopeptides in the air/water interface. Such parameters as CMC, surface tension at the CMC point (sigmaCMC), effectiveness (piCMC), and efficiency (pC20) were measured. Emulsifying properties of all lipopeptides were also examined. The studies reveal that the surface active properties of synthesized compounds strongly depend on the length of alkyl chains as well as on the composition of amino acid polar heads. The critical micelle concentration decreases with increasing alkyl chain length of lipopeptides with the same polar head. The effectiveness and efficiency decrease when the number of amino acids in the polar head increases. All lipopeptides established a very weak emulsification power and created unstable water/Miglyol 812 and water/paraffin oil emulsions. Results suggest that lipopeptides cannot be used as emulsifiers; nonetheless, it is possible to use them as auxiliary surfactants with disinfectant properties in combination with more potent emulsifiers. PMID- 28845102 TI - Endoscopic electrocautery incision therapy for benign lower gastrointestinal tract anastomotic strictures. AB - Benign anastomotic strictures can occur in up to 22% of patients who undergo colonic or rectal resection. Traditionally, surgery was the preferred method of treatment, but, over time, endoscopic techniques, such as balloon dilation, have become the preferred modality. However, a high stricture recurrence rate of up to 18-20% and the increased risk of perforation due to uncontrolled stretching are its major drawbacks. Endoscopic electrocautery incision (EECI) allows for controlled mucosal incision in predetermined locations of stricture. In this meta analysis, we have summarized case reports, case series, retrospective studies and prospective studies describing the different endoscopic EECI techniques used for benign lower gastrointestinal tract anastomotic strictures. Our analysis showed that EECI, either alone or in combination with other modalities (e.g. balloon dilation, steroid injection or argon plasma coagulation) is an effective treatment option for both treatment-naive and refractory short non-inflammatory strictures. The overall success rate for EECI-based therapy for benign colorectal stricture was 98.4%, with a stricture recurrence rate of 6.0%. No major adverse event (bleeding, infection or perforation) was reported. Only minor adverse events (abdominal pain) were reported in 3.8% of the population. PMID- 28845104 TI - Gastrointestinal manifestations associated with systemic sclerosis: results from the nationwide inpatient sample. AB - BACKGROUND: Systemic sclerosis (SSc) is a multisystem disease associated with significant morbidity and increased mortality. The prevalence of different gastrointestinal (GI) manifestations has been investigated in multiple, but mainly small, retrospective studies. In this study, we investigated the prevalence and risk for a broad spectrum of GI disorders and malignancies in a large sample of inpatients with SSc in the United States. METHODS: We conducted a retrospective analysis using the 2010-2011 Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS). SSc patients were identified by ICD-9-CM code 710.1. Non-SSc patients ("controls") were matched to cases 4:1 by age and sex. We examined demographics, clinical characteristics, and a range of GI conditions. RESULTS: From 15,824,031 total patients, 13,633 cases of SSc were matched to 54,532 controls. The prevalence of GI manifestations among SSc patients was 59.24% compared to 29.96% for controls (P<0.0001). Significantly elevated GI manifestations in SSc patients included dysphagia (4.3% vs. 1.9%, P<0.0001), esophageal reflux (34.8% vs. 15.4%, P<0.0001), Barrett's esophagus (1.7% vs. 0.3%, P<0.0001), constipation (6% vs. 4.6%, P<0.0001), diarrhea (4.5% vs. 2.4%, P<0.0001), fecal incontinence (0.4% vs. 0.2%, P<0.0001), and celiac disease (0.2% vs. 0%, P<0.0001). Some GI disorders were significantly lower in SSc patients, including cholelithiasis (1.6% vs. 2.1%, P<0.0001) and GI malignancies (1% vs. 2.2%, P<0.0001). CONCLUSIONS: Our results emphasize the established association between SSc and esophageal disorders, such as dysphagia and reflux disease. Our analysis indicated a significant positive association between SSc and celiac disease, and a negative association between SSC and cholelithiasis. PMID- 28845103 TI - Bacterial translocation markers in liver cirrhosis. AB - Bacterial translocation (BT) is an important mechanism in the development of infection in liver cirrhosis. The migration and colonization of bacteria and/or bacterial products from the bowel to mesenteric lymph nodes is a controlled process in healthy persons. Increased intestinal permeability, bacterial overgrowth and defect of gut-associated lymphatic tissue promote impaired BT in cirrhotics. We reviewed the reports on markers used for the evaluation of BT published between 1987 and 2016. We focused on the clinical consequences of BT in cirrhosis, as indicated by the values of the BT markers. Patients with cirrhosis are reported to have elevated levels of surrogate markers associated with BT compared with controls. The most widely used BT parameters are C-reactive protein, procalcitonin, bacterial DNA, endotoxin or lipopolysaccharide, lipopolysaccharide binding protein, calprotectin, and bactericidal/permeability increasing protein. High levels of these factors in serum and/or ascitic fluid in humans may be associated with advanced liver disease, hemodynamic instability, high levels of proinflammatory cytokines, susceptibility to the development of severe or recurrent infections, acute-on-chronic liver failure, hepatic encephalopathy, hepatorenal syndrome and poor prognosis during follow up. In conclusion, high levels of BT markers are associated with a high inflammatory response, increased complications of liver cirrhosis and occasionally high fatality rates. PMID- 28845105 TI - Secondary systemic amyloidosis in inflammatory bowel disease: a nationwide analysis. AB - BACKGROUND: Secondary systemic amyloidosis (SSA) is a rare but severe complication of inflammatory bowel disease (IBD). We aimed to evaluate the clinical characteristics, predictors of complications, and in-hospital mortality of patients with Crohn's disease (CD) and Ulcerative colitis (UC) who develop SSA. METHODS: Using the National Inpatient Sample, we identified patients hospitalized for IBD and SSA between 2004 and 2012. Using multivariate logistic regression, patients with CD were compared with those with UC regarding the presence or absence of SSA. IBD patients without SSA were matched in a 2:1 ratio with those with SSA using propensity matching. We analyzed the hospitalization trends of SSA in CD and UC patients using Pearson's chi2 test. Analyses were performed using SAS version 9.3. RESULTS: Among the 302,548 patients with CD and 174,057 patients with UC hospitalized between 2004 and 2012, we identified 47 (0.02%) and 36 (0.02%) cases of SSA, respectively. We noted rising annual hospitalization trends for both CD and UC patients with or without SSA. In hospital mortality was significantly higher for both the UC+SSA group (16.7% vs. 2.1%, P<0.0001) and the CD+SSA group (6.4% vs. 1.0%, P=0.0001) before propensity matching. However, this difference was not seen for either UC+SSA (17.1% vs. 7.1%, P=0.11) or CD+SSA (6.8% vs. 2.3%, P=0.20) after matching. CONCLUSIONS: SSA rarely affects IBD patients, but when it does, it is associated with increased rates of infection, severe sepsis, and multi-organ system involvement. Despite this, SSA does not affect in-hospital mortality in IBD patients. Further studies are needed to explore this association. PMID- 28845106 TI - Impact of Full Spectrum Endoscopy(r) (Fuse(r), EndoChoice(r)) on adenoma detection: a prospective French pilot study. AB - BACKGROUND: Currently, colonoscopy and polypectomy are the gold standard methods for the prevention of incident cases of colorectal cancer. The use of a new colonoscope (Fuse(r), EndoChoice(r)) with a larger view of up to 330 degrees appears to improve the adenoma detection rate (ADR). We performed a prospective observational study concerning this scope. The primary endpoint was potentially omitted adenomas (POA), i.e. adenomas seen on the side screens that will not appear on the central display during colonoscopy withdrawal without oriented movements. Secondary endpoints included our ADR, Fuse(r) impact on ADR, time to cecal intubation and withdrawal time. METHODS: We performed a single-center prospective study in one French center. We enrolled patients over 18 years of age between January 2015 and March 2016. RESULTS: We included 141 patients; 3 were excluded because their colonoscopies were incomplete. Our study included 78 men and 60 women (sex ratio 1.3). The mean age was 60.4 years. A total of 130 polyps were resected. In all, 88/130 were adenomas (68%) and 34/88 adenomas (39%) were POA. The mean time to cecum was 10 min, and the mean withdrawal time was 12 min. ADR was 35% for men and 31% for women. The estimated ADR without POA was 29% for men and 19% for women. CONCLUSIONS: The Fuse(r) system appears to be safe and efficient. POA represented 39% of all adenomas. The impact of the panoramic view on the ADR was considered substantial. The main limitations are the lack of randomization and the absence of a control group. PMID- 28845107 TI - A decade of improved access to screening is associated with fewer colorectal cancer deaths in African Americans: a single-center retrospective study. AB - BACKGROUND: Controversy exists as to whether disparities in colorectal cancer (CRC) outcomes in African Americans (AAs) are best resolved by screening at age 45 or by proper use of existing guidelines. In 2004, an aggressive colonoscopy based CRC screening program was implemented throughout New York City. Our goal was to determine the effect of that program on CRC outcomes in our mostly AA population. METHODS: CRC cases entered into Harlem Hospital's tumor registry from January 1992 to December 2011 were divided into two cohorts: 1992-2003, the pre intensive screening era (PSE), and 2004-2011, the intensive screening era (ISE). Each cohort was reviewed for demographics, indication for colonoscopy, tumor location, tumor stage, and mortality. Multivariate analysis was applied to the pooled cohorts to determine factors associated with survival. RESULTS: Inclusion criteria were met by 379 patients: 207 PSE and 172 ISE. Racial distribution, gender, age at presentation, and tumor location were not different during the two eras. Over 75% of patients were AA. During the ISE, 84% were insured compared to 34% in the PSE (P<0.0001). Fewer patients died during the ISE (21%) than during the PSE (67%) (P<0.0001). The ISE patients were diagnosed with earlier stages of CRC compared to the PSE. Increased survival was associated with being insured (hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.30-2.81), distal tumors (HR 1.43, 95%CI 1.05-1.95), and being female (HR 1.36, 95%CI 1.01-1.850). CONCLUSIONS: A multifaceted program reduced CRC outcome disparities in a poor AA community. Aggressive implementation of current colonoscopy screening guidelines still has unrealized potential to reduce CRC mortality disparities in AAs. PMID- 28845108 TI - The role of endovascular therapy in acute mesenteric ischemia. AB - BACKGROUND: Endovascular therapy, including aspiration thrombectomy and local thrombolytic therapy, often associated with angioplasty and stent placement, has been described in the literature. The purpose of this study was to review case series of patients with acute mesenteric ischemia treated with endovascular therapy and evaluate their outcomes. METHODS: An online review using PubMed was carried out to identify all English articles about this topic in the time interval from 2005 to 2016. THE FOLLOWING VARIABLES WERE EXTRACTED: number of patients, cause of occlusion, symptoms, arteries involved, number of sessions of treatment, technical success, clinical success, recurrence rate, complications, mortality rate, number of patients who underwent diagnostic laparoscopy or surgical resection of ischemic bowel. RESULTS: Eighteen papers met the inclusion criteria and were included. Among the patients with arterial mesenteric ischemia treated with endovascular approach, the technical success rate was high (up to 100%) and data regarding clinical success are encouraging, even though they are few and heterogeneous. Technical success rate and clinical success of patients with acute venous mesenteric ischemia approached with endovascular treatment was 74-100% and 87.5-100% respectively. CONCLUSIONS: Current advances in endovascular therapies have made these treatments feasible for mesenteric ischemia. PMID- 28845109 TI - Liver stiffness is not associated with short- and long-term plasma HIV RNA replication in immunocompetent patients with HIV infection and with HIV/HCV coinfection. AB - BACKGROUND: Human immunodeficiency virus (HIV) may be directly responsible for liver damage but there are contrasting data regarding the influence of detectable plasma viremia. We analyzed the influence of plasma HIV RNA (pHIV) detectability and of other clinical and viro-immunological variables on liver stiffness (LS) measurement in adult immunocompetent HIV-monoinfected patients and in patients coinfected with hepatitis C virus (HCV). METHODS: Logistic regression analysis was performed using the value of LS>7.1 kPa as the dependent variable. A linear regression model was applied using LS measurement after log10 transformation (lkpa) as the dependent variable and we analyzed the predicted values versus the observed lkpa values; pHIV was classified as detectable or undetectable in the 12 and 36-month study periods before LS measurement. RESULTS: We studied 251 patients (178 with HIV monoinfection), most of whom were on antiviral treatment; 36-month study time was available for 154 subjects. The mean CD4+ cell count was 634 cells/mm3 in HIV-monoinfected patients and 606 cells/mm3 in coinfected patients. No difference in LS was found between patients with detectable or undetectable pHIV in either the 12- or the 36-month study period before transient elastography. The mean LS was higher in HIV/HCV coinfected patients (P<0.0001) than in the HIV-monoinfected subjects; lkpa was positively correlated with HCV coinfection (P<0.0001) and aspartate aminotransferase levels (P<0.0001). Detectable pHIV failed to reach significance. Eight HIV-monoinfected patients had a predicted LS measurement lower than the observed one, while eight patients had the opposite result. CONCLUSION: LS was not correlated with ongoing HIV replication during the 12- and 36-month study periods in immunocompetent HIV monoinfected and HIV/HCV-coinfected patients. PMID- 28845110 TI - Prioritization for interferon-free regimens and potential drug interactions of current direct-acting anti-hepatitis C agents in routine clinical practice. AB - BACKGROUND: We determined the proportions of patients with chronic hepatitis C (CHC) in association with possible prioritized indications for interferon-free regimens and the use of co-medications with potential drug-drug interactions (DDIs). METHODS: Five hundred consecutive mono-infected CHC patients seen in 2015 at 5 Greek centers were included. Priorities for interferon-free regimens were based on liver disease severity, contraindication(s) for interferon and prior interferon-treatment failure. All co-medications were classified into those with no DDIs/no clear data for DDIs, potential DDIs, and contraindication due to DDI for each agent, according to the HEP Drug Interaction Checker. RESULTS: Of the 500 patients, 1% had undergone liver transplantation, whereas 6.6% had decompensated cirrhosis, 21.8% F4, 17.1% F3, 10.4% F2, and 34.8% F0-1 fibrosis. Contraindications for interferon were present in 38.5% of non-transplant patients with compensated liver disease. The probability of contraindications/potential DDIs was greater for boceprevir/telaprevir and ombitasvir/paritaprevir/ritonavir+/-dasabuvir, compared to all other agents (P<0.001), and least for sofosbuvir (P<0.05). Contraindications/potential DDIs were more frequently present in patients >=50 than <50 years old (P<=0.034), and more common in F3-4 than F0-2, and F4 than F0-3 fibrosis (P<=0.019) for all direct-acting antivirals (DAAs). CONCLUSIONS: The expansion of the criteria for prioritization of interferon-free regimens from cirrhosis to F3 and perhaps F2 fibrosis will increase the proportion of patients with DAA access by only 10-15% and 10%, respectively. A potential for DDIs is frequently present with protease inhibitors, but also exists with other DAAs. The probability of DDIs is higher in patients with priority for DAAs, including those who have advanced liver disease and are usually of older age. PMID- 28845111 TI - The efficacy of endoscopic therapy for pancreas divisum: a meta-analysis. AB - BACKGROUND: The purpose of this study was to perform a meta-analysis assessing the efficacy and predictors of success of endoscopic therapy in the management of patients with pancreas divisum. METHODS: An electronic database search (PubMed and ScienceDirect) was performed for relevant studies. Studies were selected based on predefined criteria and data were extracted on patient population, follow up, endotherapy methods, success rates and complication rates. A random effect model was used to pool the effect size across studies. Heterogeneity testing and publication bias assessment were performed. Multivariate regression analysis was performed to identify predictors of successful endoscopic therapy. RESULTS: Of 381 articles reviewed, 23 studies with 874 patients met the inclusion criteria. All were case series with suboptimal quality. Endoscopic therapy included minor papilla sphincterotomy, minor papilla sphincteroplasty and dorsal duct stenting. Mean follow-up duration was 37 months. The rate of "improvement" as defined by authors after endoscopic therapy varied significantly across studies, ranging from 31-96%: 589/874 patients were reported to have improved, corresponding to a pooled efficacy rate of 67.5% (95% confidence interval [CI] 0.610-0.734; P=0.0001). The pooled rate of pancreatitis after endoscopic retrograde cholangiopancreatography was 10.1% (95%CI 0.084-0.124; 2-sided P=0.0001). On subgroup analysis, patients with recurrent acute pancreatitis had better endoscopic outcomes (pooled efficacy rate 76%, 95%CI 0.712-0.803, P=0.0001). Dorsal duct stenting and longer follow up were the only parameters predictive of successful endotherapy. Significant heterogeneity was observed within and across studies. CONCLUSIONS: Endoscopic efficacy in pancreas divisum is estimated at 67.5%. Available studies are of poor quality with significant heterogeneity. Comparative studies with rigorous methodology are needed. PMID- 28845112 TI - Safety and utility of endoscopic ultrasound-guided fine-needle aspiration of focal splenic lesions: a retrospective analysis. AB - BACKGROUND: Fine-needle aspiration (FNA) of focal splenic lesions (FSL) is usually done under ultrasound (US) or computed tomography guidance. Endoscopic US (EUS), because of its ability to provide high-resolution images, can be used for aspirating FSL. We studied the safety and efficacy of EUS-guided FNA of FSL. METHODS: We performed a retrospective analysis of patients with FSL undergoing EUS-guided FNA over the last six years. RESULTS: EUS-guided FNA was performed in 16 patients (age: 28-43 years; male: 11). A 22-G needle was used in 13 patients, a 25-G needle in 2 patients, and a 19-G needle in 1 patient. All patients had abdominal pain, with 6 patients also having fever. On EUS, 8 patients had focal hypoechoic lesion/lesions, whereas 8 patients had focal cystic lesion/lesions. The size of the focal lesions ranged from 0.8-10 cm. EUS-guided aspiration was performed successfully in all patients. The cytology was adequate in all patients and a diagnosis was established in 13 (81%) patients. The final diagnosis in patients with hypoechoic lesions was tuberculosis in 6 patients and sarcoidosis in 2 patients. The final diagnosis in patients with cystic lesions was pseudocyst in 5 patients and simple cyst in 3 patients. One patient with splenic pseudocyst had a massive hemorrhage from a splenic artery pseudoaneurysm 7 days after FNA. No other major complication was encountered. CONCLUSION: EUS-guided FNA of FSL is safe and provides adequate material for cytological examination, even in the case of small lesions. PMID- 28845113 TI - Impact of stepwise introduction of esophagojejunostomy during laparoscopic total gastrectomy: a single-center experience in Japan. AB - BACKGROUND: The number of laparoscopic gastrectomies performed in Japan is increasing with the development of laparoscopic and surgical instruments. However, laparoscopic total gastrectomy is developing relatively slowly because of technical difficulties, particularly in esophagojejunostomy. METHODS: We retrospectively reviewed 83 patients with early gastric cancer in the upper portion of the stomach who underwent laparoscopic total gastrectomy between April 2007 and March 2016. We classified the patients into three periods, mainly on the basis of the esophagojejunostomy procedures performed: first period, various conventional procedures based on the physicians' choice (n=14); second period, transoral method (n=51); and third period, fully intracorporeal technique (n=18). We evaluated the clinical impact of a stepwise introduction of unfamiliar new methods during laparoscopic total gastrectomy. RESULTS: Between the first and second periods, there were significant differences in the blood loss volume, number of harvested lymph nodes, frequency of conversion to open surgery, and postoperative hospital stay. The number of harvested lymph nodes was significantly higher in the third than in the second period, with no detriment to other intraoperative or postoperative factors. CONCLUSION: The use of a unified surgical method for esophagojejunostomy seems to be the key to a successful and advantageous laparoscopic total gastrectomy. Stepwise introduction of a well established technique of esophagojejunostomy during laparoscopic total gastrectomy will benefit patients, as shown, for example, by the higher number of dissected lymph nodes in the present study. However, a protracted learning curve is required. PMID- 28845115 TI - Endoscopic treatment of tracheoesophageal fistula using the over-the-scope-clip system. PMID- 28845114 TI - Outcome and evaluation of prognostic factors after pancreaticoduodenectomy for distal cholangiocarcinoma. AB - BACKGROUND: The aim of the present study was to examine the outcomes and prognostic factors after surgery with curative intent for distal cholangiocarcinoma during a modern timespan, in a Swedish tertiary referral center. METHODS: All patients who underwent pancreaticoduodenectomy for distal cholangiocarcinoma between April 2008 and December 2015 were identified. Survival was estimated using the Kaplan-Meier analysis. Demographic, clinical, laboratory and histopathological data were evaluated for prognostic factors relating to mortality, using univariable and multivariable statistical analysis. RESULTS: Fifty-four patients were included. The mean age was 68+/-8 years and 21 (39%) of the patients were female. Jaundice was present at diagnosis in 73% of the patients. There was no 90-day mortality. Complications graded as Clavien-Dindo >=3 occurred in 10 (19%) of the patients. Twenty-eight (52%) received adjuvant therapy. Overall survival rates at 1, 3, and 5 years were 80%, 21%, and 9.2%, respectively. Median survival was 22.2 months. The presence of lymph node metastases was found to be the only independent predictor of survival (hazard ratio 2.88, 95% confidence interval 1.22-6.84; P=0.016). The total number of lymph node metastases, lymph node ratio or total number of resected nodes did not improve the prediction. CONCLUSIONS: We found that the recurrence rate was higher and the survival poorer after surgery for distal cholangiocarcinoma than has previously been reported. Lymph node status at the time of resection was the most important prognostic factor for survival in the current material. PMID- 28845116 TI - Underwater polypectomy: successful endoscopic resection of a large gastric pedunculated polyp. PMID- 28845117 TI - Single tunneling technique for the resection of lateral spreading adenomas. PMID- 28845118 TI - Metastatic adnexal cancer in a man. AB - Primary cutaneous adnexal neoplasms are mostly benign in nature; however, there have been reports of malignant adnexal tumors with distant metastasis to lymph nodes. Adnexal cutaneous malignancy with metastasis to the gastrointestinal tract has never been reported. Here, we present a rare case of a man with primary adnexal cutaneous adenocarcinoma who presented with symptomatic anemia secondary to occult gastrointestinal bleeding, found to be from gastrointestinal metastasis of the adnexal malignancy. PMID- 28845119 TI - A novel minimally invasive treatment for anal fissure. PMID- 28845120 TI - Authors' reply. PMID- 28845121 TI - ELECTRONIC PLATFORM MEASURES OF BALANCE IMPAIRMENT IN PARKINSONIANS AND FIRST DEGREE RELATIVES. AB - Several measures of balance obtained from quiet stance on an electronic platform are described. These measures were found to discriminate patients with Parkinson disease (PD) from normal control subjects. First degree relatives of patients with PD show greater variability on these measures. A primary goal is to develop sensitive measures that would be capable of identifying impaired balance in early stages of non-clinical PD. PMID- 28845122 TI - TWO AUTOCOVARIANCE-BASED MEASURES OF BALANCE IN PARKINSONIANS AND NORMAL CONTROLS. AB - Center of pressure electronic platform testing is proposed as an affordable early diagnostic tool for persons at risk of Parkinson's disease. A stiffness measures and crossing time statistic are studied for possible use in such a diagnosis. PMID- 28845123 TI - A simple statistical approach to model the time-dependent response of polymers with reversible cross-links. AB - A new class of polymers characterized by dynamic cross-links is analyzed from a mechanical point of view. A thermodynamically consistent model is developed within the Lagrangian framework for polymers that can rearrange their internal cross-links. Such a class of polymers has the capability to reset their internal microstructure and the microscopic remodeling mechanism leads to a behavior similar to that of an elastic fluid. These materials can potentially be used in several fields, such as in biomechanics, smart materials, morphing materials to cite e few. However, a comprehensive understanding is necessary before we can predict their behavior and perform material design for advanced technologies. The proposed formulation-following a statistical approach adapted from classical rubber elasticitye is based on the evolution of the molecular chains' end-to-end distance distribution function. This distribution is allowed here to evolve with time, starting from an initial stress-free state and depending on the deformation history and the cross-link attachment/detachment kinetics. Some simple examples are finally presented and discussed to illustrate the capability and generality of the developed approach. PMID- 28845124 TI - Associations between CYP2C8 rs10509681 and rs11572080 gene polymorphisms and age related macular degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in industrialized countries. Early symptoms of AMD include drusen and changes in retinal pigment epithelium. However, the etiology of AMD and drusen formation is not fully understood. Recent studies suggest that CYP2C8-related metabolic processes might play an important role in the development of AMD. The aim of our study is to investigate CYP2C8 rs10509681 and CYP2C8 rs11572080 genotype frequencies in patients with early AMD and to compare them with healthy controls. MATERIALS AND METHODS: The study enrolled 305 patients with early AMD and 300 healthy controls. The genotyping of CYP2C8 rs10509681 and CYP2C8 rs11572080 was carried out using the real-time PCR method. RESULTS: The analysis of studied CYP2C8 polymorphisms did not reveal any statistically significant differences between the AMD and the control groups. For the CYP2C8 rs10509681 gene polymorphism the distribution of T/T, T/C, and C/C genotypes was 83.3%, 16.7%, and 0% vs. 83.7%, 15.7%, and 0.7%, p = 0.343. For the CYP2C8 rs11572080 gene polymorphism the distribution of C/C, T/C and T/T and genotypes was 84.9%, 15.1%, and 0% vs. 82.3%, 17.3%, and 0.3%, p = 0.447. CONCLUSION: The study revealed that there were no statistically significant differences in the distribution of CYP2C8 rs10509681 and CYP2C8 rs11572080 genotypes in patients with early AMD and in healthy controls. PMID- 28845125 TI - Refractive errors characteristic of the patients at the Children's Ophthalmology Outpatient Department of Kauno klinikos Hospital (Lithuanian University of Health Sciences) from 1 January 2012 to 31 December 2012. AB - BACKGROUND: The purpose of our study was to assess the distribution and patterns of refractive errors in children for the proper planning of paediatric eye care at the centre. MATERIAL AND METHODS: The study was conducted in the hospital of the Lithuanian University of Health Sciences in Kaunas, from 1 January 2012 to 31 December 2012. During this period, a total of 11,406 children, aged 0-18 years, were evaluated at the outpatient department of paediatric ophthalmology, Kauno klinikos, the Lithuanian University of Health Sciences. All the children underwent a complete ophthalmic examination with cycloplegic refraction. RESULTS: Myopia increased from 1.5% (95% CI:1.2, 1.8) in the age group of 0-1 to 44.7% (95% CI:43.46, 45.94) in the age group of 14-18 (p < 0.001). Myopia was associated with older age, female gender (20.3%; 95% CI:19.3, 21.3; p < 0.001). Hypermetropia decreased from 84.6% (95% CI:83.7, 85.5) in the cohort of 0-1 to 11.4% (95% CI: 10.61, 12.19) in the 14-18 age group (p < 0.001). Hypermetropia was associated with younger age, male gender (43.4%; 95% CI:42.16, 44.64; p < 0.001), preterm birth (56.1%; 95% CI:54.86, 57.34; 43.4%; p < 0.001), low birth weight (61.8%; 95% CI:60.59, 63.01; p < 0.001), and birth by Caesarean section (57.1%; 95% CI: 55.87; 58.33) (p < 0.001). The prevalence of astigmatism was 25.5% (95% CI: 24.41; 26.59) (p < 0.001). Astigmatism was associated with female gender (20.1%; 95%. CI: 19.1; 21.1) and too big pregnancy weight (22.1%.; 95%. CI: 21.06; 23.14) (p < 0.001). CONCLUSIONS: Of the 14-18 age group, 44.7% of the patients were myopic. Of the 0-1 age group, 84.6% were hypermetropic. Astigmatism was detected in about 25.5% of children. The prevalence of refractive errors was associated with age, gender, gestation age, gestation weight, and parental refractive error. PMID- 28845126 TI - Changes in macular thickness after trabeculectomy with or without adjunctive 5 fluorouracil. AB - CONFLICT OF INTEREST: None of the authors have any conflict of interest to declare, financial or otherwise. No financial or other support was received for the study. BACKGROUND: The aim of the study was to assess changes in macular thickness after trabeculectomy in respect to the use of 5-fluorouracil (5-FU) as well as to analyse possible associations between the postoperative changes in macular thickness and intraocular pressure (IOP). MATERIALS AND METHODS: The prospective observational study included 106 eyes (100 patients) with glaucoma who underwent trabeculectomy with or without 5-FU. Subsequently 5-FU needling was performed if failure of the filtrating bleb occurred. Macular thickness and the IOP were evaluated before, one week, and six months after the surgery. The mean and sectoral macular thickness was assessed using spectral domain optical coherence tomography. RESULTS: The mean (+/-SD) IOP reduced from 27.71 (+/-6.88) mmHg at baseline to 18.3 (+/-8.1) mmHg one week (p < 0.001) and 15.1 (+/-7.6) mmHg six months (p < 0.001) after trabeculectomy. One week postoperatively, the mean macular thickness increased from 285.19 (+/-15.98) MUm to 288.9 (+/-16.31) MUm (p < 0.001); macular thickening was significant in all subfields (p < 0.001) and correlated positively with IOP reduction (rho = 0.312, p = 0.001 for central subfield). After six months, macula remained thicker only at the central and inner nasal subfields (p < 0.05). The changes in macular thickness were not affected by the use of 5-fluorouracil. CONCLUSIONS: Trabeculectomy may induce a slight macular thickening which is more pronounced in the early postoperative period. The IOP reduction plays an important role in this process and is associated with thicker postoperative macula. However, the use of adjunctive 5-FU has no influence on macular thickness after glaucoma surgery despite its potential hypotonic, inflammatory and cytotoxic effects. PMID- 28845127 TI - Complications of orbital endoimplantation in the Eye Clinic of the Lithuanian University of Health Sciences. AB - The aim of the study was to analyse the rate of complications of orbital endoimplantation in patients operated from 2002 to 2014 at the Eye Clinic of the Lithuanian University of Health Sciences and to compare it with the results in the literature. Enucleation must be performed very carefully in order to prevent any additional trauma, infection, deformation, and to create an optimal conjunctival socket. However, complications occur despite efforts and qualified surgeons. The most common complications described in the literature are thinning and cysts of the conjunctiva, a foreign body reaction, secretion, symblepharons, fornix deficiency, ptosis, permanent pain, dislocation, migration and protrusion of the implant, a primary or secondary infection, and implant extrusion. From 2002 to 2014, 128 patients underwent orbital endoimplantation surgery at the Eye Clinic. The most common complications were conjunctival erosion (five patients, or 2.9%), cysts (nine patients, or 7%), and implant extrusion (five patients, or 2.9%). The type and rate of complications were very similar to the data in the literature. PMID- 28845128 TI - Clinical characteristics and long-term survival differences of the ANCA associated vasculitis group: a cross-sectional study of 27 patients. AB - OBJECTIVE: The goal of this study was to describe long-term patient survival and possible prognostic factors of a group of patients diagnosed with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) hospitalized at the tertiary Rheumatology Centre in Vilnius. MATERIAL AND METHODS: A cross-sectional study of 27 patients hospitalized at the Rheumatology Centre of Santaros klinikos of Vilnius University Hospital from 1 January 2001 to 31 December 2015 with diagnoses of GPA and MPA were carried out. Data on demographics, clinical characteristics, laboratory data, and the Birmingham Vasculitis Activity Score were collected. RESULTS: Seven (25.9%) patients during the onset of the disease received only oral glucocorticoids and 20 (74.1%) patients took additional medication. The BVAS median was 7 (minimum [min] - 2; maximum [max] - 23). The age median was 52 years (min - 12; max - 75). The overall mortality rate was 18.5%. Mean survival time was 126.6 months (95% confidence interval [CI] = 104.5 to 148.6) limited to 154.6 months for the longest-surviving patient. CONCLUSIONS: Life expectancy during past 15 years for AAV patients increased from 99.4 to 126.6 months. A high BVAS score at the onset of the disease is a bad prognostic factor related to shorter life expectancy. The growth of Staphylococcus aureus from nasopharynx might be associated with higher mortality rates and relapses in AAV patients. PMID- 28845129 TI - Sepsis epidemiology and outcome in the paediatric intensive care unit of Vilnius University Children's Hospital. AB - : Research was carried out at the paediatric intensive care unit (paediatric ICU) of the Children's Hospital, affiliate of Vilnius University Hospital Santariskiu klinikos. BACKGROUND: Being the most common cause of children's death, sepsis is a challenge for most physicians. In order to improve the outcomes, it is important to know the aetiology and peculiarities of sepsis in a particular region and hospital. The aim of this study was to analyse the outcomes of sepsis in a paediatric intensive care unit and their relation with patients' characteristics and causative microorganisms. MATERIALS AND METHODS: A retrospective analysis of the Sepsis Registration System in Vilnius University Children's hospital was started in 2012. From 2012 to 2015, we found 529 sepsis cases in our hospital, 203 of which were found to be fulfilling all of the inclusion criteria (patient's age >28 days on admission, taken blood culture/positive PCR test, need for paediatric ICU hospitalization) and were included in the final analysis. Abbreviations: ICD - international disease classification PCR - polymerase chain reaction. RESULTS: Sepsis made 4% of all patients of the paediatric ICU in the period from 2012 to 2015 and caused 32% of deaths in the unit. Paediatric mortality reached 14% of all sepsis cases in our analysis, the majority of them due to hospital-acquired sepsis that occurred in patients suffering from oncologic or hematologic diseases. Another significant part of the patients that did not survive were previously healthy with no co morbidities. The most common microorganism in lethal community-acquired cases was N. meningitidis and in hospital-acquired sepsis - Staphylococcus spp. Multi-drug resistance was observed, especially in the cases of hospital-acquired sepsis. CONCLUSIONS: A large percentage of lethal outcomes that occur in the paediatric ICU are due to sepsis. The majority of lethal cases of sepsis occur in patients suffering from chronic co-morbidities, such as oncologic, hematologic, neurologic, and others. PMID- 28845130 TI - Anaesthetic challenges in cancer patients: current therapies and pain management. AB - THE OBJECTIVE: The aim is to present the major effects of cancer treatment (chemotherapy, radiotherapy, surgery) that the anaesthesiologist should consider preoperatively, and to review techniques of the analgesic management of the disease. MATERIALS AND METHODS: To summarize the major challenges that cancer patients present for the anaesthesiologists, a literature review was conducted. Articles presenting evidence or reviewing the possible effects of anaesthetics on cancer cells were also included. Online databases of Science Direct, PubMed, and ELSEVIER, as well as reference lists of included studies were searched. Articles published from 2005 to 2016 were selected. RESULTS: Anaesthesiologists should pay attention to patients receiving chemotherapy and its side effects on organ systems. Bleomycin causes pulmonary damage, anthracyclines are cardiotoxic, and platinum-based chemotherapy agents are nephrotoxic. A lot of chemotherapy agents lead to abnormal liver function, vomiting, diarrhoea, etc. Surgery itself is suspected to be associated with an increased risk of metastasis and recurrence of cancer. Regional anaesthesia and general anaesthesia with propofol should be used and volatile agents should be avoided to prevent cancer patients from perioperative immunosuppression that leads to increased risk of cancer recurrence. Pain management for palliative patients remains a major problem. CONCLUSIONS: To provide the best treatment for cancer patients, cooperation of anaesthesiologists with oncologists and surgeons becomes imperative. It has been established that anaesthetic techniques and drugs could minimize the perioperative inflammation. However, further research of the perioperative "onco anaesthetic" is needed. PMID- 28845131 TI - Results of neuroblastoma treatment in Lithuania: a single centre experience. AB - BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumour in children. This is a very rare disease with heterogeneous biology varying from complete spontaneous regression to a highly aggressive tumour responsible for 15% of malignancy-related death in early childhood. Analyses of survival rates in Europe have shown a considerable difference between Northern/Western and Eastern European countries. Treatment results of NB in Lithuania have never been analyzed. AIM: To assess the survival rate of children with NB according to initial spread of the disease, age at diagnosis, the MYCN amplification, risk group, and treatment period. PATIENTS AND METHODS: A retrospective single-centre analysis of patients' records was performed. Children diagnosed and treated for NB between 2000 and 2015 at the Centre of Paediatric Oncology and Haematology of the Children's Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos were included. The patients were divided into three groups according to the spread of the disease: group 1 - patients with local NB older than 12 years of age; group 2 - stage IV patients, also called the M stage; group 3 - infants with stages 4S and MS. The patients were stratified into three risk groups - low, intermediate and high risk. Estimates of five-year overall survival (OS5y) were calculated using the Kaplan-Meier method comparing survival probability according to spread of the disease, age at diagnosis, the MYCN amplification, risk group and treatment period (2000-2007 vs 2008-2015). RESULTS: Overall 60 children (31 girls and 29 boys) with NB were included. The median age at diagnosis was 1.87 years (ranged from 4 days to 15 years). Seventy-eight percent of cases were found to be differentiated or undifferentiated NB, 22% - ganglioneuroblastoma. The local form of the disease was predominant: 57% (34/60) of patients were allocated to the group 1, 37% (22/60) with initial metastatic disease were assigned to group 2, and infants with 4S or MS stage comprising 7% (4/60) allocated to group 3, respectively. The probability of OS5y for the entire cohort was 71% with the median follow-up of 8.8 +/- 4.8 years. The probability of OS5y for local disease (group 1) was significantly higher compared to metastatic disease (group 2) (94% vs. 34%, p = 0.001, respectively) as well as for infants compared to children older than 12 months at the time of diagnosis (90% vs 60%, p = 0.009, respectively). The MYCN gene amplification had a negative influence on OS5y, with 78% of MYCN-negative patients surviving in comparison to 40% of MYCN-positive patients who did not survive (p = 0.153). The high-risk patients had significantly worse OS5y than children with intermediated or low risk (35% vs. 82% vs. 100%, respectively, p = 0.001). Comparison of OS5y between two treatment periods in the entire patient population revealed a non-significant increase in survival from 66% in the 2000-2007 period to 82% in the 2008-2015 period (p = 0.291), mostly due to a dramatic improvement achieved for high-risk patients whose survival rate increased from 9% in the 2000-2007 period to 70% in the 2008 2015 period (p = 0.009). CONCLUSIONS: There was a slight predominance of low-risk patients, probably due to a higher number of infants. A better probability of OS5y was confirmed in infants with local disease and in MYCN-negative patients. The OS5y for children treated for NB at our institution over 16 years increased from 66% in the 2000-2007 period to 82% in the 2008-2015 period with the most significant improvement achieved for high risk patients. The current survival rate of children treated for NB at our institution is in line with the reported numbers in Northern and Western European countries. PMID- 28845133 TI - Examination of space/volume requirements for US underground coal mine refuge alternatives. AB - The Mine Safety and Health Administration requires that 1.4 m2 (15 ft2) of floor space is to be provided for each person inside a refuge alternative (RA). However, the amount of floor space needed for a person to reside inside an RA and perform basic tasks is unknown. During testing, participants entered into an RA or a simulated RA of various space/volume configurations and performed several simulated tasks that are representative of the survivability tasks performed within an RA. The results indicate that the floor space requirements were generally adequate for the tasks studied. Certain tasks such as changing scrubber cartridges, using toilets, and moving about the RA were impacted by the minimum height tested (0.6 m). As such, RAs of this height will require critical design consideration as a whole and the supplies provided for use inside of the RA to ensure the ability to use an RA. PMID- 28845132 TI - Cell-free DNA in non-small cell lung cancer. AB - Lung cancer is the leading cause of cancer-associated deaths worldwide. Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC). Advances in the knowledge of the biology of non-small cell lung cancer have revealed molecular information used for systemic cancer therapy targeting metastatic disease, with an important impact on patients' overall survival (OS) and quality of life. However, a biopsy of overt metastases is an invasive procedure limited to certain locations and not easily acceptable in the clinic. The analysis of peripheral blood samples of cancer patients represents a new source of cancer-derived material, known as liquid biopsy, and its components (circulating tumour cells (CTCS), circulating free DNA (cfDNA), exosomes, and tumour-educated platelets (TEP)) can be obtained from almost any body fluids. These components have shown to reflect characteristics of the status of both the primary and metastatic diseases, helping the clinicians to move towards a personalized medicine (1). This review focuses on the liquid biopsy component - circulating free DNA, its benefit for non-invasive screening, early diagnosis, prognosis, response to treatment, and real time monitoring of the disease in non small cell lung cancer patients. PMID- 28845134 TI - Parkinson's Disease: What role do pedunculopontine nucleus cholinergic neurons play? PMID- 28845135 TI - Adolescents' Experiences 7 and 13 Months Following the Death of a Brother or Sister. AB - This qualitative study used semi-structured interviews to describe adolescents' responses at 7 and 13 months to siblings' NICU/PICU/ED death. At 7 months, adolescents were asked about events around the sibling's death; at 7 and 13 months, about concerns/fears, feelings, and life changes. Seventeen adolescents participated (13-18 years; M=15); 65% Black, 24% Hispanic, 11% White. Themes included death circumstances, burial events, thinking about the deceased sibling, fears, and life changes. Adolescents reported shock and disbelief that the sibling died; 80% knew the reason for the death; many had difficulty getting through burials; all thought about the sibling. From 7 - 13 months fears increased including losing someone and thoughts of dying. Adolescents reported more changes in family life and greater life changes in them (more considerate, mature) by 13 months; some felt friends abandoned them after the sibling's death. Girls had more fears and changes in family life and themselves. Adolescent's responses to sibling death may not be visually apparent. One recommendation from this study is to ask adolescents how they are doing separately from parents since adolescents may hide feelings to protect their parents, especially their mothers. Older adolescents (14-18 years) and girls may have more difficulty after sibling death. PMID- 28845136 TI - Evaluation of a Promotora-led Intervention on Colorectal Cancer among Hispanics: Findings related to Perceptions and Communications. AB - We implemented a home-based group educational intervention in the form of home health parties (HHPs) among Hispanic men and women in the Lower Yakima Valley of Washington State led by trained bilingual promotoras and compared participants' baseline and follow-up responses to questions related to communications about CRC screening. We also documented participants perceptions of the CRC related educational information presented as measures of effectiveness of the HHPs as well as possible indicators of their intentions to engage in timely CRC screenings. The group based educational sessions resulted in positive participants' perceptions about the benefits of the CRC related information and in improved communications about CRC screening. Results suggest the benefits of utilizing promotoras' cultural knowledge and awareness to present content about cancers such as CRC in ways that are easily understandable to Hispanic participants and that could result in improved communications and action about cancer screenings. PMID- 28845138 TI - LETTER FROM THE EDITOR. PMID- 28845137 TI - Encapsulation of Anticancer Drugs (5-Fluorouracil and Paclitaxel) into Polycaprolactone (PCL) Nanofibers and In Vitro Testing for Sustained and Targeted Therapy. AB - We report a continuous nanoscale encapsulation of cancer drugs 5-Fluorouracil (FU) and Paclitaxel into biocompatible polycaprolactone (PCL) nanofibers (NFs) using core-sheath electrospinning process. A high potential electric field of 19 23.2 kV was used to draw a compound solution jet from a specialized coaxial spinneret. Using of DMF in both core and Sheath resulted in NFs within 50-160 nm along with large beaded structures. Addition of Trichloromethane (TCM) or Trifluoroethanol (TFE) in sheath turned NFs in more uniform and thin fiber structure. The diameter range for paclitaxel encapsulated fibers was 22-90 nm with encapsulation efficiency of 77.5% and the amount of drug was only 4 to 5% of sheath polymer. Addition of PVA within core resulted drug nanocrystal formation outside of sheath and poor encapsulation efficiency (52%) with rapid initial release (52-53%) in first 3 days. Drug release test of NFs in different pH exhibited increase of release rate with the decrease of media pH. In-vitro cell viability test with FU encapsulated NFs in human prostatic cancer PC3 cells exhibited 38% alive cells at 5 MUM concentration while in pristine FU 43% cells were alive. Paclitaxel encapsulated NFs with breast cancer cells also exhibited increased efficacy in comparison to pristine anticancer drugs. Continuous decrease of cell density indicated the slow release of cancer drugs from the NFs. Both PCL+Paclitaxel and PCL+5FU treated conditions caused breast cancer cell death between 40% to 50%. PMID- 28845139 TI - Therapeutic Drug Monitoring of TNF Antagonists in Inflammatory Bowel Disease. AB - Although tumor necrosis factor (TNF)-alpha antagonists play a critical role in the treatment of moderate-to-severe inflammatory bowel disease (IBD), several factors can impact treatment response. The degree of systemic inflammation, serum albumin concentration, disease type, body mass index, gender, concomitant therapy with immunosuppressive agents, and especially development of antidrug antibodies (ADAs) are key determinants of TNF antagonist pharmacokinetics and clinical outcomes. Therefore, measurement of serum drug and antibody concentrations in patients with IBD who are on TNF antagonists has the potential to guide clinical decision-making, optimize treatment, improve outcomes, and reduce healthcare costs. Multiple strategies to prevent ADA formation exist, including multiple clinical algorithms that employ therapeutic drug monitoring to optimize treatment following a secondary loss of therapeutic response. An individualized approach is needed, however, to identify early predictors of ADA development and other confounders of TNF antagonist therapy. PMID- 28845140 TI - Endoscopic Management of Gastrointestinal Fistulae. AB - A gastrointestinal fistula is a common occurrence, especially after surgery. Patients who develop a fistula may have an infection, surgically altered anatomy, nutritional deficiency, or organ failure, making surgical revision more difficult. With advancements in flexible endoscopic devices and technology, new endoscopic options are available for the management of gastrointestinal fistulae. Endoscopically deployable stents, endoscopic suturing devices, through-the-scope and over-the-scope clips, sealants, and fistula plugs can be used to treat fistulae. These therapies are even more effective in combination. Despite the inherent challenges in patients with fistulae, endoscopic therapies for treatment of fistulae have demonstrated safety and efficacy, allowing many patients to avoid surgical fistula repair. In this paper, we review the emerging role of endoscopy in the management of gastrointestinal fistulae. PMID- 28845141 TI - A Health Survey of Gastroenterologist Prescribing Practices of Adalimumab for Treatment of Crohn's Disease: Final Results. AB - Adalimumab (Humira, AbbVie) has efficacy in treatment-naive and infliximab (Remicade, Janssen)-exposed patients with Crohn's disease (CD). An e-survey was sent to US gastroenterologists who were members of the American Gastroenterological Association. A total of 398 gastroenterologists (3%) completed the survey. Seventy-two percent prescribed adalimumab more than a few times yearly, 58% followed more than 50 patients with CD, and 15% followed 200 or more patients with CD. Ninety percent of gastroenterologists felt that adalimumab had a moderately significant positive impact on patient care. Eighty-two percent correctly identified the US Food and Drug Administration-approved adalimumab induction and maintenance regimens. These gastroenterologists were more likely to follow 200 or more patients with CD (P=.045) and prescribe adalimumab more than a few times per year (P=.037). Years in practice, practice setting, gender, and region did not impact prescribing. Correct dosing was associated with higher prescribing frequency (P=.014) and volume of patients with CD (P=.025). The frequency of adalimumab prescribing and volume of patients with CD were predictive of the total number of correct survey answers (P=.014 and P=.017, respectively). Only 50% of gastroenterologists always administered loading doses when switching to adalimumab from another anti-tumor necrosis factor (TNF) agent; 43.5% reported unclear loading efficacy and 24.3% reported infection concerns from excess anti-TNF as reasons. Eighteen percent of gastroenterologists reported that pharmacies had reduced their prescribed adalimumab doses. To our knowledge, this is the only study evaluating prescribing patterns of adalimumab in patients with CD in the United States. Our findings demonstrate that many gastroenterologists are not using optimal adalimumab dosing strategies, which may lead to a decreased rate of response in patients with CD. Further research is needed to confirm our findings and identify barriers to optimal adalimumab use by gastroenterologists for treatment of CD. PMID- 28845142 TI - Silent Crohn's Disease. PMID- 28845143 TI - Management of Esophageal Cancer. PMID- 28845144 TI - The Microbiome and the Liver. PMID- 28845145 TI - The Role of Endoscopy in the Diagnosis of Celiac Disease. PMID- 28845147 TI - Polyphenols of Carmenere Grapes. AB - Carmenere is the emblematic grape of Chile. Recent studies indicate that it has a different polyphenolic profile than other commercial varieties of grape among other factors, due to its long maturation period. The grape and wine of Carmenere stand out for having high concentrations of anthocyanins (malvidin), flavonols (quercetin and myricetin) and flavanols (catechin, epicatechin and epigallocatechin). These compounds are related to the distinctive characteristic of Carmenere wine regarding astringency and color. In vivo and in vitro models suggest some positive effects of these polyphenols in the treatment and prevention of chronic diseases, such as atherosclerosis and cancer. Therefore, there is a high level of interest to develop scalable industrial methods in order to obtain and purify Carmenere grape polyphenol extracts that could be used to improve the characteristics of wines from other varieties or produce nutraceuticals or functional foods for preventing and treating various chronic diseases. PMID- 28845148 TI - Eigenvector metabolite analysis reveals dietary effects on the association among metabolite correlation patterns, gene expression, and phenotypes. AB - INTRODUCTION: 'Multi-omics' datasets obtained from an organism of interest reared under different environmental treatments are increasingly common. Identifying the links among metabolites and transcripts can help to elucidate our understanding of the impact of environment at different levels within the organism. However, many methods for characterizing physiological connections cannot address unidentified metabolites. OBJECTIVES: Here, we use Eigenvector Metabolite Analysis (EvMA) to examine links between metabolomic, transcriptomic, and phenotypic variation data and to assess the impact of environmental factors on these associations. Unlike other methods, EvMA can be used to analyze datasets that include unidentified metabolites and unannotated transcripts. METHODS: To demonstrate the utility of EvMA, we analyzed metabolomic, transcriptomic, and phenotypic datasets produced from 20 Drosophila melanogaster genotypes reared on four dietary treatments. We used a hierarchical distance-based method to cluster the metabolites. The links between metabolite clusters, gene expression, and overt phenotypes were characterized using the eigenmetabolite (first principal component) of each cluster. RESULTS: EvMA recovered chemically related groups of metabolites within the clusters. Using the eigenmetabolite, we identified genes and phenotypes that significantly correlated with each cluster. EvMA identifies new connections between the phenotypes, metabolites, and gene transcripts. Conclusion EvMA provides a simple method to identify correlations between metabolites, gene expression, and phenotypes, which can allow us to partition multivariate datasets into meaningful biological modules and identify under studied metabolites and unannotated gene transcripts that may be central to important biological processes. This can be used to inform our understanding of the effect of environmental mechanisms underlying physiological states of interest. PMID- 28845149 TI - A Review on Medical Image Registration as an Optimization Problem. AB - OBJECTIVE: In the course of clinical treatment, several medical media are required by a phy-sician in order to provide accurate and complete information about a patient. Medical image registra-tion techniques can provide a richer diagnosis and treatment information to doctors and to provide a comprehensive reference source for the researchers involved in image registration as an optimization problem. METHODS: The essence of image registration is associating two or more different images spatial asso-ciation, and getting the translation of their spatial relationship. For medical image registration, its pro-cess is not absolute. Its core purpose is finding the conversion relationship between different images. RESULT: The major step of image registration includes the change of geometrical dimensions, and change of the image of the combination, image similarity measure, iterative optimization and interpo-lation process. CONCLUSION: The contribution of this review is sort of related image registration research methods, can provide a brief reference for researchers about image registration. PMID- 28845150 TI - An UPLC Method for Determination of Geraniin in Rat Plasma and its Application to Pharmacokinetic Studies. AB - INTRODUCTION: Geraniin has many biological activities including anti-osteoporotic and anti-hyperglycemic efficacies. MATERIALS AND METHODS: A rapid and simple method for the determination of geraniin in rat plasma using ultra performance liquid chromatography coupled to ultraviolet detector was developed. The plasma sample, spiked with epicatechin as an internal standard, was subjected to ethyl acetate extraction prior to analysis. Chromatographic separation was performed on the HSS T3 column and monitored at a wavelength of 280 nm. The limit of detection and lower limit of quantification was 0.07 MUg/mL and 0.2 MUg/mL in rat plasma, respectively. CONCLUSION: Good linearity was obtained in the range of 0.2 - 200 MUg/mL, and the correlation coefficient was better than 0.997. The intra-day and inter-day precisions decreased 9.8%. The accuracy of QC samples ranged from 84.4% to 87.1%. The extraction recovery ranged from 88.4% to 90.3% and the matrix effect ranged from 84.4% to 87.2%. The analyte was stable in rat plasma when stored at room temperature for 12 hours, 4 degrees C for 24 hours and -20 degrees C for 15 days. t1/2 and t1/2 for i.v. was 0.21 +/- 0.10 and 7.20 +/- 2.20 h, respectively. Plasma clearance (CL) was 0.03 +/- 0.02 L/h/kg and apparent volume of distribution (Vz) was 0.05 + 0.01 L/kg. The developed method was successfully applied to the pharmacokinetic study of geraniin in rats. PMID- 28845151 TI - Prevalence of Sarcocystis infection in processed meat products by using digestion and impression smear methods in Hamedan, Iran. AB - Sarcocystis is a common zoonotic parasite which can be transmitted through ingestion of contaminated, undercooked meat and is a major cause of economic loss in many countries. This study aimed to detect Sarcocystis parasite in processed meat products in Hamedan, Iran. A total of 20 samples of hamburger, sausage, and cocktail were collected from markets from three factories in Hamedan, Iran. The samples were examined by digestion and impression smear methods for detecting Sarcocystis parasite. The results showed that 80% of all tested samples were infected with Sarcocystis. The infection rate in hamburger, sausage, and cocktail were 87.5, 83.33, and 66.66%, respectively. The highest infestation rate was observed in hamburger. The present study shows that the rate of Sarcocystis contamination in meat products is very high. So, evaluation of raw meat quality in addition to applying hygienic programs at all stages of the production line is inevitable. Also, consumption of undercooked meat products or fast food should be avoided. PMID- 28845152 TI - Erratum: Exosomes: A Rising Star in Failing Hearts. AB - [This corrects the article on p. 494 in vol. 8, PMID: 28751864.]. PMID- 28845153 TI - Corrigendum: Psychopaths Show Enhanced Amygdala Activation during Fear Conditioning. AB - [This corrects the article on p. 348 in vol. 7, PMID: 27014154.]. PMID- 28845154 TI - Corrigendum: Age-Related Vestibular Loss: Current Understanding and Future Research Directions. AB - [This corrects the article on p. 231 in vol. 7, PMID: 28066316.]. PMID- 28845155 TI - Corrigendum: Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. AB - [This corrects the article on p. 73 in vol. 3, PMID: 22403576.]. PMID- 28845156 TI - Local Diversity and Biting Pattern of Anopheles Species in Southern Minahasa. AB - BACKGROUND: To optimize the preventive measures of malaria, it is important to synchronize the efforts with the behavior of local Anopheles species. However, the data of Anopheles species and their behavior in Indonesia is still lacking. METHOD: Explorative research was conducted from April to September 2016 in Southern Minahasa district. The Anopheles mosquito was baited by using animal and human (indoor or outdoor) from 18.00 to 06.00 hours. Then, the species were identified and Man Biting Rate (MBR) and Man/Animal Biting per Hour (MBPH) were calculated followed by statistical analysis by using SPSS 17. RESULT: The data showed that the dominant species in Southern Minahasa were An. barbirostris, An. kochi, and An. vagus. An. vagus was found to be zoophilic and An. barbirostris was showing strict anthropophilic characteristics. Meanwhile, An. kochi feeds on both human and animal. The MBR of An. kochi was found to be the highest (P < 0.005), but its MBPH only significantly exceeded that of An. vagus. All species tend to be more active during the early evening. CONCLUSION: An. barbirostris, An. kochi, and An. vagus were the dominant Anopheles species in Southern Minahasa. Further research is needed to determine the Plasmodium infestation rate of these species. PMID- 28845157 TI - Thickness of Extraocular Muscle and Orbital Fat in MRI Predicts Response to Glucocorticoid Therapy in Graves' Ophthalmopathy. AB - 33 patients with active, moderate-severe Graves' ophthalmopathy (GO) received 4.5 g methylprednisolone for 12 weeks and were divided by efficacy into two groups (responsive and unresponsive). All patients and 10 controls underwent orbital MRI examination at baseline. No significant difference was seen in baseline clinical characteristics between the two GO groups. The values of exophthalmos were higher in both GO groups than in the control and were higher in the responsive group versus the unresponsive group. Compared to the unresponsive group, the responsive group had a thicker inferior rectus as well as thinner orbital fat. The inferior rectus/fat ratio was significantly higher in the responsive group versus the unresponsive group. Multivariate logistic regression analysis showed that the exophthalmos value and inferior rectus/fat ratio were significantly associated with the response to glucocorticoid (GC). ROC analysis revealed that the cut-off points of the inferior rectus/fat ratio combined with the exophthalmos value to indicate efficacy were 1.42 and 20.78. For moderate-severe GO patients with CAS > 3, the combined inferior rectus/fat ratio and exophthalmos value in MRI may be a valuable indicator to predict the response to GC therapy. PMID- 28845158 TI - 2D-Shear Wave Elastography in the Evaluation of Parathyroid Lesions in Patients with Hyperparathyroidism. AB - BACKGROUND AND AIMS: 2D-shear wave elastography (2D-SWE) is a relatively new elastographic technique. The aim of the present study is to determine the values of the elasticity indexes (EI) measured by 2D-SWE in parathyroid benign lesions (adenomas or hyperplasia) and to establish if this investigation is helpful for the preoperative identification of the parathyroid adenoma. MATERIAL AND METHODS: The study groups were represented by 22 patients with primary or tertiary hyperparathyroidism, diagnosed by specific tests, and 43 healthy controls, in whom the thyroid parenchyma was evaluated, in order to compare the EI of the thyroid tissue with those of the parathyroid lesions. RESULTS: The mean EI measured by 2D-SWE in the parathyroid lesions was 10.2 +/- 4.9 kPa, significantly lower than that of the normal thyroid parenchyma (19.5 +/- 7.6 kPa; p = 0.007), indicating soft tissue. For a cutoff value of 12.5 kPa, the EI assessed by 2D-SWE had a sensitivity of 93% and a specificity of 86% (AUC = 0.949; p < 0.001) for predicting parathyroid lesions. CONCLUSION: A value lower than 12.5 kPa for the mean EI measured by 2D-SWE can be used to confirm that the lesion/nodule is a parathyroid adenoma. PMID- 28845159 TI - Analyzing Menton Deviation in Posteroanterior Cephalogram in Early Detection of Temporomandibular Disorder. AB - INTRODUCTION: Some clinicians believed that mandibular deviation leads to facial asymmetry and it also had a correlation with temporomandibular disorders (TMDs). Posteroanterior (PA) cephalogram was widely reported as a regular record in treating facial asymmetry and craniofacial anomalies. The objective of this study was to analyze the relationship of menton deviation in PA cephalogram with temporomandibular disorders (TMDs) symptoms. MATERIALS AND METHODS: TMJ function was initially screened based on TMD-DI questionnaire. PA cephalogram of volunteer subjects with TMDs (n = 37) and without TMDs (n = 33) with mean age of 21.61 +/- 2.08 years was taken. The menton deviation was measured by the distance (mm) from menton point to midsagittal reference (MSR) horizontally, using software digitized measurement, and categorized as asymmetric if the value is greater than 3 mm. The prevalence and difference of menton deviation in both groups were evaluated by unpaired t-test. RESULT: The prevalence of symmetry group showed that 65.9% had no TMDs with mean of 1,815 +/- 0,71 mm; in contrast, the prevalence of asymmetry group showed that 95.5% reported TMDs with mean of 3,159 +/- 1,053 mm. There was a significant difference of menton deviation to TMDs (p = 0.000) in subjects with and without TMDs. CONCLUSION: There was a significant relationship of menton deviation in PA cephalogram with TMDs based on TMD-DI index. PMID- 28845160 TI - Separation Process of Fine Coals by Ultrasonic Vibration Gas-Solid Fluidized Bed. AB - Ultrasonic vibration gas-solid fluidized bed was proposed and introduced to separate fine coals (0.5-0.125 mm fraction). Several technological methods such as XRF, XRD, XPS, and EPMA were used to study the composition of heavy products to evaluate the separation effect. Results show that the ultrasonic vibration force field strengthens the particle separation process based on density when the vibration frequency is 35 kHz and the fluidization number is 1.8. The ash difference between the light and heavy products and the recovery of combustible material obtain the maximum values of 47.30% and 89.59%, respectively. The sulfur content of the heavy product reaches the maximum value of 6.78%. Chemical state analysis of sulfur shows that organic sulfur (-C-S-), sulfate-sulfur (-SO4), and pyrite-sulfur (-S2) are confirmed in the original coal and heavy product. Organic sulfur (-C-S-) is mainly concentrated in the light product, and pyrite-sulfur ( S2) is significantly enriched in the heavy product. The element composition, phase composition, backscatter imagery, and surface distribution of elements for heavy product show concentration of high-density minerals including pyrite, quartz, and kaolinite. Some harmful elements such as F, Pb, and As are also concentrated in the heavy product. PMID- 28845161 TI - Targeting Cancer Stem Cells and Their Niche: Current Therapeutic Implications and Challenges in Pancreatic Cancer. AB - Cancer stem cells (CSCs) have been identified as a subpopulation of stem-like cancer cells with the ability of self-renewal and differentiation in hematological malignancies and solid tumors. Pancreatic cancer is one of the most lethal cancers worldwide. CSCs are thought to be responsible for cancer initiation, progression, metastasis, chemoresistance, and recurrence in pancreatic cancer. In this review, we summarize the characteristics of pancreatic CSCs and discuss the mechanisms involved in resistance to chemotherapy, the interactions with the niche, and the potential role in cancer immunoediting. We propose that immunotherapy targeting pancreatic CSCs, in combination with targeting the niche components, may provide a novel treatment strategy to eradicate pancreatic CSCs and hence improve outcomes in pancreatic cancer. PMID- 28845162 TI - Induced Pluripotent Stem Cells Reduce Progression of Experimental Chronic Kidney Disease but Develop Wilms' Tumors. AB - The therapeutic effect of induced pluripotent stem cells (iPSs) on the progression of chronic kidney disease (CKD) has not yet been demonstrated. In this study, we sought to assess whether treatment with iPSs retards progression of CKD when compared with bone marrow mesenchymal stem cells (BMSCs). Untreated 5/6 nephrectomized rats were compared with CKD animals receiving BMSCs or iPSs. Renal function, histology, immunohistochemistry, and gene expression were studied. Implanted iPSs were tracked by the SRY gene expression analysis. Both treatments minimized elevation in serum creatinine, significantly improved clearance, and slowed down progression of disease. The proteinuria was reduced only in the iPS group. Both treatments reduced glomerulosclerosis, iPSs decreased macrophage infiltration, and TGF-beta was reduced in kidneys from the BMSC group. Both types of treatments increased VEGF gene expression, TGF-beta was upregulated only in the iPS group, and IL-10 had low expression in both groups. The SRY gene was found in 5/8 rats treated with iPSs. These 5 animals presented tumors with histology and cells highly staining positive for PCNA and Wilms' tumor protein antibody characteristics of Wilms' tumor. These results suggest that iPSs may be efficient to retard progression of CKD but carry the risk of Wilms' tumor development. PMID- 28845164 TI - Posttraumatic Embitterment Disorder and Hwa-byung in the General Korean Population. AB - OBJECTIVE: Posttraumatic embitterment disorder (PTED) is characterized by states of "embitterment", characteristically similar to "Hwa-byung", which is a Korean culture-bound syndrome. The present study aimed to assess diagnostic relationships between PTED and Hwa-byung. METHODS: A total of 290 participants completed our survey. PTED and Hwa-byung were diagnosed using a diagnostic interview and scale. Scales for depression, suicide ideation, and anger were used for evaluation. Fisher's exact tests and Mann-Whitney U tests were performed to evaluate diagnostic overlap between PTED and Hwa-byung, and associations of scale scores for depression, suicide ideation, and anger between the PTED, Hwa-byung, and non-diagnosed groups. Associations of these scales between the depressive and non-depressive groups, and suicidal and non-suicidal groups were also evaluated. RESULTS: Among the participants, 1.7% of the sample fit the diagnostic criteria for PTED and 2.1% fit the criteria for Hwa-byung. No individual fit the criteria for both. Anger scores were significantly higher in the Hwa-byung group than in the non-diagnostic group. There were not any significant differences in anger scores between the PTED and non-diagnostic groups. Depression scores were significantly higher in the PTED than in the non-diagnostic groups. In contrast, no significant differences were observed between depression scores in the Hwa byung and non-diagnostic groups. CONCLUSION: These results suggest that PTED may be a disorder category that is distinct from Hwa-byung. PMID- 28845165 TI - Factors Associated with Insomnia among the Elderly in a Korean Rural Community. AB - OBJECTIVE: Sleep disturbance is common in the elderly, which is result from multi factorial causes encompassing socio-demographic, behavioral, and clinical factors. We aimed to identify factors associated with insomnia among the elderly in a rural community in South Korea, a country with a rapidly growing aged population. METHODS: This cross-sectional study used the data from the second wave of the Korean Social life, Health and Ageing Project, which is a cohort study of individuals living in a typical rural community in South Korea. Socio demographic, behavioral, and clinical characteristics were obtained through face to-face interviews. Various factors suspected to be associated with insomnia were compared between elderly participants with and without insomnia, and multiple logistic regression analyses were conducted to identify independent risk factors for insomnia. RESULTS: We found that 32.4% of 509 participants (72.8+/-7.7 years old) had insomnia. Female sex [odds ratio (OR)=2.19], low education level (OR=2.44), current smoking (OR=2.26), number of chronic diseases (OR=2.21 for 2-3 chronic diseases; OR=2.06 for 4 or more chronic diseases), and depression (OR=2.53) were independently associated with insomnia. CONCLUSION: We found that sex, education, chronic disease, and depression independently increase the risk of insomnia of the elderly in a Korean rural community. To overcome the elderly's insomnia, interventions should target modifiable factors such as depression. To promote active aging, longitudinal studies of factors associated with insomnia among the elderly should be performed in different regions and communities. PMID- 28845163 TI - Neuroprotection in Schizophrenia and Its Therapeutic Implications. AB - Schizophrenia is a chronic and debilitating mental disorder. The persisting negative and cognitive symptoms that are unresponsive to pharmacotherapy reveal the impairment of neuroprotective aspects of schizophrenia. In this review, of the several neuroprotective factors, we mainly focused on neuroinflammation, neurogenesis, and oxidative stress. We conducted a narrative and selective review. Neuroinflammation is mainly mediated by pro-inflammatory cytokines and microglia. Unlike peripheral inflammatory responses, neuroinflammation has a role in various neuronal activities such as neurotransmission neurogenesis. The cross talk between neuroinflammation and neurogenesis usually has beneficial effects in the CNS under physiological conditions. However, uncontrolled and chronic neuroinflammation exert detrimental effects such as neuronal loss, inhibited neurogenesis, and excessive oxidative stress. Neurogenesis is also a major component of neuroprotection. Adult neurogenesis mainly occurs in the hippocampal region, which has an important role in memory formation and processing. Impaired neurogenesis and an ineffective response to antipsychotics may be thought to indicate a deteriorating course of schizophrenia. Oxidative stress and excessive dopaminergic neurotransmission may create a vicious cycle and consequently disturb NMDA receptor-mediated glutamatergic neurotransmission. Based on the current evidences, several neuroprotective therapeutic approaches have been reported to be efficacious for improving psychopathology, but further longitudinal and large-sample based studies are needed. PMID- 28845166 TI - Somatic Symptoms as Mediating Factors between the Perceived Social Support and the Health-Related Quality of Life in North Korean Defectors. AB - OBJECTIVE: This study was conducted to examine the mediating effect of somatic symptoms between perceived social support and health-related quality of life among North Korean defectors living in South Korea. METHODS: A total of 200 North Korean defectors were assessed using the Multidimensional Scale of Perceived Social Support, the Short-Form 8-Item Health Survey, the Patient Health Questionnaire 15, the PTSD Checklist Civilian Version and the Patient Health Questionnaire 9. RESULTS: Somatic symptoms accounted for physical health-related quality of life after controlling for PTSD and depressive symptoms, but did not for mental health-related quality of life. Moreover, somatic symptoms mediated the relationship between perceived social support and physical and mental health related quality of life, indicating that perceived social support indirectly affects physical and mental health-related quality of life through somatic symptoms in North Korean defectors. CONCLUSION: The results of this study suggest that not only intervention for PTSD or depressive symptoms but also for somatic symptoms might be effective to improve physical and mental health-related quality of life for North Korean defectors, especially those who have a lack of perceived social support. PMID- 28845167 TI - Validation of the Korean Version of the Clinical Assessment Interview for Negative Symptoms. AB - OBJECTIVE: Clinical Assessment Interview for Negative Symptoms (CAINS) has recently been developed to improve measurement of negative symptoms in schizophrenia. We performed a multi-center study to validate the Korean version of the CAINS (CAINS-K) and explore potential cultural variation. METHODS: One hundred eighty schizophrenia patients diverse in demographic and illness profile were recruited from four centers in Korea. Along with the CAINS-K, the Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Calgary Depression Scale for Schizophrenia (CDSS), a self-report measure of behavioral inhibition and activation (BIS/BAS) and neurocognitive tasks were administered to verify external validities. RESULTS: The CAINS-K showed high internal-consistency (0.92) and inter-rater reliability (0.77). Exploratory Factor Analysis replicated a two-factor structure of the original scale including motivation/pleasure and expression deficits dimensions. Korean patients tended to report lower pleasure compared to American patients in the prior study. The CAINS K showed an adequate convergent validity with the SANS, negative symptoms of the BPRS, and BAS. A divergent validity was supported as the CAINS-K showed zero or only weak correlations with other symptoms of the BPRS, depression from the CDSS, and neurocognitive tasks. CONCLUSION: The CAINS-K demonstrated high internal consistency and adequate external validities, and is expected to promote studies on negative symptoms in Korean patients with schizophrenia. PMID- 28845169 TI - Psychometric Properties of the Coping Inventory for Stressful Situations in Korean Adults. AB - OBJECTIVE: The Coping Inventory for Stressful Situations (CISS) is a globally recognized measure of stress coping methods. However, research into the applicability of the CISS in a Korean context is still in its infancy. The aim of this study is to assess and report the validity of the CISS in Korean adults for the first time. METHODS: Three hundred and two Korean adults who currently have no distressing problems requiring psychiatric treatment completed the Korean version of the CISS. Principal component analysis was used to extract factors in the process of exploratory factor analysis. RESULTS: The result displayed a clear pattern matrix, and a high level of internal consistency was shown by Chronbach's alpha. The items classified under task-oriented and emotion-oriented coping presented adequate factorial validity, and only three items grouped under avoidance-oriented coping loaded poorly or loaded onto factors differing from the original. CONCLUSION: These results seem to indicate that the CISS may indeed be both applicable and useful in gauging the coping styles of Korean adults. However, the ambiguous meanings of certain items under avoidance-oriented coping would require adjustment for the purposes of future study. PMID- 28845168 TI - Clinical Dementia Rating Orientation Score as an Excellent Predictor of the Progression to Alzheimer's Disease in Mild Cognitive Impairment. AB - OBJECTIVE: This study aimed to examine the usefulness of each subscale score of the Clinical Dementia Rating (CDR) for predicting Alzheimer's disease (AD) dementia progression in amnestic mild cognitive impairment (MCI) elderly subjects. METHODS: Fifty-nine elderly MCI individuals were recruited from a university dementia and memory disorder clinic. Standardized clinical and neuropsychological tests were performed both at baseline and at the time of 2 years follow-up. Logistic regression analyses were conducted to examine the ability of various clinical measures or their combinations to predict progression to AD dementia in MCI individuals. RESULTS: MCIp individuals showed significantly higher CDR Orientation subscale and CDR sum-of-boxes (SOB) score than MCInp ones, while there were no significant differences in other CDR subscale scores between the two. MCIp individuals also showed marginally higher MMSE scores than MCInp ones. A series of logistic regression analyses demonstrated that the model including CDR Orientation subscale had better AD dementia prediction accuracy than either the model with either MMSE or CDR-SOB. CONCLUSION: Our findings suggest that CDR Orientation subscale score, a simple and easily available clinical measure, could provide very useful information to predict AD dementia progression in amnestic MCI individuals in real clinical settings. PMID- 28845170 TI - Psychological Factors Influence the Irritable Bowel Syndrome and Their Effect on Quality of Life among Firefighters in South Korea. AB - OBJECTIVE: The purpose of this study was to investigate the characteristics of psychological factors that are related to irritable bowel syndrome (IBS) and their effects on the quality of life (QOL) of firefighters in South Korea. METHODS: This study examined data collected from 1217 firefighters in South Korea. After identifying firefighters with IBS according to the Rome III diagnostic criteria for functional gastrointestinal disorders (FGIDs), we collected demographic data and psychological variables through self-administered questionnaires. In order to observe the distribution of the high-risk group in the Korean occupational stress scale (KOSS) subcategories, we conducted logistic multiple linear regression. The correlations between psychological factors and QOL were analyzed and we performed a stepwise regression analysis. RESULTS: The groups (firefighters with and without IBS) showed differences by sex, working period, task, working pattern, Patient Health Questionnaire-9, Generalized Anxiety Disorder Questionnaire-7, Korean Occupational Stress Scale, Rosenberg's Self-Esteem Scale, and the World Health Organization Quality of Life-BREF. IBS risk was higher in the following KOSS subcategories: job demand (OR 1.79, 95% CI: 1.11-2.89), interpersonal conflict (OR 2.21, 95% CI: 1.25-4.33), organizational system (OR 1.87, 95% CI: 0.58-3.30), and lack of reward (OR 2.39, 95% CI: 1.08 5.26). The final regression model explained 42.6% of the variance in overall quality of life. CONCLUSION: The findings of this study indicate that a number of psychological factors increase the likelihood of irritable bowel syndrome (IBS) and affect QOL. Therefore, when diagnosing IBS in the future, mental health aspects should be considered in addition to physical health. PMID- 28845172 TI - Balance Deficit and Brain Connectivity in Children with Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: We aimed to assess disturbances in postural and gait balance and functional connectivity within the brain regions controlling balance in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Thirteen children with ADHD and 13 age- and sex-matched controls were recruited. Gait balance was assessed by the difference in the center of pressure (COP) between the left and right foot, as well as the difference in plantar pressure between the left and right foot during gait. Neuroimaging data were acquired using a 3.0 Tesla MRI scanner. Functional connectivity between the vermis of the cerebellum and all other brain regionswas assessed. RESULTS: The difference in plantar pressure between the left foot and right foot in the ADHD group was greater than that observed in the control group. The average COP jerk score of the right foot in the ADHD group was higher than that observed in the control group. A higher functional connectivity between the cerebellum and the right middle frontal gyrus (premotor cortex) and medial frontal gyrus (cingulate gyrus) was observed in the control group relative to the ADHD group. In the ADHD group, the difference in plantar pressure between the left and right foot was also negatively correlated with the beta-value within the middle frontal gyrus. CONCLUSION: Children with ADHD had disturbance of balance as assessed by plantar pressure. Decreased brain connectivity from the cerebellum to the premotor cortex and anterior cingulate was associated with disturbances of posture and balance in children with ADHD. PMID- 28845171 TI - Altered Function of Ventrolateral Prefrontal Cortex in Adolescents with Peer Verbal Abuse History. AB - OBJECTIVE: Previous studies showing the association of exposure to peer (PeVA) and parental verbal abuse in childhood with structural alterations in the young adult brain suggest functional changes in adolescence. In this functional MRI study, we investigated the effects of exposure to PeVA, during elementary and middle school periods, on brain response to emotional words, in high school students. METHODS: An emotional Stroop task consisting of swear, negative, positive, and neutral words was performed during functional MRI scan for 23 subjects who were divided into low- and high exposure groups to PeVA. RESULTS: High-PeVA group had a higher depression score, greater left ventrolateral prefrontal cortex (VLPFC) activity, and higher left VLPFC-left hippocampus connectivity in swear word conditions. The VLPFC activity and left VLPFC-left hippocampus connectivity was negatively related to the severity of anxiety and depressive symptoms, respectively. CONCLUSION: These preliminary findings support the hypothesis that exposure to PeVA, during childhood, is an aversive stimulus associated with meaningful functional change in emotional regulation network, showing hypersensitivity to swear words, at middle adolescence. PMID- 28845173 TI - Dementia Care by Healthy Elderly Caregivers Is Associated with Improvement of Patients' Memory and the Caregivers' Quality of Life: A Before and After Study. AB - OBJECTIVE: The provision of care for elderly people with dementia by healthy elderly caregivers is one of the new health-care paradigms in South Korea. The aim of this study was to determine whether this type of care, which includes cognitive stimulation, would improve the cognitive function of dementia patients and the quality of life of the healthy elderly caregiver. METHODS: Totals of 132 dementia patients and 197 healthy elderly caregivers participated in this study. We evaluated the cognitive function of the dementia patients at baseline and after providing the program for 6 months using the Korean version of the Consortium to Establish a Registry for Alzheimer's disease, 1st Edition (CERAD K). We also evaluated the quality of life of the healthy elderly caregivers using the World Health Organization Quality of Life-Short Version (WHOQOL-BREF) at baseline and after 6 months. RESULTS: The word-list memory results of CERAD-K for the included dementia patients improved after 6 months (Z=-2.855, p=0.004). The WHOQOL-BREF score among the elderly caregiver also improved significantly (Z= 2.354, p=0.019). CONCLUSION: These data suggest that dementia care is associated with improvements in both the cognitive function of dementia patients and the quality of life of the healthy elderly caregivers. PMID- 28845174 TI - The Role of Conformity in Relation to Cohesiveness and Intimacy in Day-Hospital Groups of Patients with Schizophrenia. AB - OBJECTIVE: Conformity is defined as the act of adjusting one's behavior to match the social responses of others. Patients with schizophrenia often adjust their maladaptive behaviors by conforming in group treatment settings. This study aimed to examine whether the opinions of group members influence conformity of patients with schizophrenia who attend day-hospital programs. METHODS: Nineteen patients with schizophrenia from four different day-hospital programs and 23 healthy controls from four different social clubs completed the homographic meaning choice task under conditions of prior exposure to the pseudo-opinions of their group members, strangers, and unknown information sources. Group influences on conformity were observed when the level of group cohesiveness was high and the level of intimacy was low across participant groups. RESULTS: Controls did not exhibit a significant effect of group influence on conformity, whereas patients were significantly influenced by their group members when making conformity-based decisions despite significantly lower intimacy and cohesiveness levels. CONCLUSION: These findings suggest that unlike controls, patients with schizophrenia tend to respond with conformity when influenced by the opinions of their affiliated group. In patients with schizophrenia group conformity may be used to select a more accurate decision and to enhance feelings of affiliation among them. PMID- 28845175 TI - Microstructural Abnormalities of Basal Ganglia and Thalamus in Bipolar and Unipolar Disorders: A Diffusion Kurtosis and Perfusion Imaging Study. AB - OBJECTIVE: Bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatment and poor clinical outcomes. However, little is known about the similarities and differences in subcorticalgray matter regions between BD and UD. METHODS: Thirty-five BD patients, 30 UD patients and 40 healthy controls underwent diffusional kurtosis imaging (DKI) and three dimensional arterial spin labeling (3D ASL). The parameters including mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), radial diffusivity (Dr) and cerebral blood flow (CBF) were measured by using regions-of-interest analysis in the caudate, putamen and thalamus of the subcortical gray matter regions. RESULTS: UD exhibited differences from controls for DKI measures and CBF in the left putamen and caudate. BD showed differences from controls for DKI measures in the left caudate. Additionally, BD showed lower Ka in right putamen, higher MD in right caudate compared with UD. Receiver operating characteristic analysis revealed the Kr of left caudate had the highest predictive power for distinguishing UD from controls. CONCLUSION: The two disorders may have overlaps in microstructural abnormality in basal ganglia. The change of caudate may serve as a potential biomarker for UD. PMID- 28845176 TI - Effects of Mind-Body Training on Cytokines and Their Interactions with Catecholamines. AB - OBJECTIVE: Mind-body training (MBT) may control reactions to stress and regulate the nervous and immune systems. The present study was designed to assess the effects of MBT on plasma cytokines and their interactions with catecholamines. METHODS: The study group consisted of 80 subjects who practice MBT and a control group of 62 healthy subjects. Plasma catecholamine (norepinephrine, NE; epinephrine, E; and dopamine, DA) and cytokine (TNF-alpha, IL-6, IFN-gamma, and IL-10) levels were measured, and the differences between the MBT and control groups and the interactions of cytokines with catecholamines were investigated. RESULTS: A significant increase in IL-10+IFN-gamma was found in females of the MBT group compared with controls. Also, a significant increase of IL-10 (anti inflammatory cytokine) in the MBT group was shown in a specific condition in which TNF-alpha and IL-6 (pro-inflammatory cytokines) are almost absent (<=1 ng/L) compared with controls. In the MBT group, significant positive correlations were found between IL-10 and the NE/E ratio and between IL-10 and the DA/E ratio, whereas the control group did not show any such correlations. CONCLUSION: MBT may increase IL-10, under specific conditions such as a decrease of pro-inflammatory cytokines or E, which may regulate the stress response and possibly contribute to effective and beneficial interactions between the nervous and immune systems. PMID- 28845177 TI - Agoraphobia and Follicle-Stimulating Hormone Levels between Tamoxifen and Goserelin versus Tamoxifen Alone in Premenopausal Hormone Receptor-Positive Breast Cancer: A 12-Month Prospective Randomized Study. AB - OBJECTIVE: Tamoxifen is an estrogen receptor antagonist used to prevent recurrence of breast cancer, which may provoke depression and anxiety and increase follicle-stimulating hormone (FSH) to patients. We compared anxiety and depression symptoms and FSH levels who received conventional tamoxifen alone and combination treatment of goserelin, a gonadotropin-releasing hormone (GnRH) analogue, with tamoxifen. METHODS: Sixty-four premenopausal women with hormone receptor-positive early-stage breast cancer were included and were assigned randomly to receive either tamoxifen and goserelin combination or tamoxifen alone for 12 months. The participants were evaluated blindly using the Hamilton Depression and Anxiety Rating Scale, the Beck Depression Rating Scale, and the Albany Panic and Phobia Questionnaire (APPQ). Blood FSH levels were assessed at baseline, 6 and 12 months. RESULTS: A significant time*group difference was detected in the agoraphobia trends subscale of the APPQ and in FSH levels. The combination group showed significantly less increases in agoraphobia subscale of APPQ and greater decreases in FSH level than those in the tamoxifen-alone group from baseline to 12 months of treatment. No significant differences for age, tumor grade, body mass index, or family history were found at baseline between the two groups. CONCLUSION: Our results suggest that the combination treatment of tamoxifen and goserelin resulted in less agoraphobia than tamoxifen alone in premenopausal women with breast cancer, which may associated with FSH suppression of goserelin. PMID- 28845178 TI - Transdermal Nicotine Patch Effects on EEG Power Spectra and Heart Rate Variability During Sleep of Healthy Male Adults. AB - OBJECTIVE: The effect of transdermal nicotine patch on sleep physiology is not well established. The current study aimed to examine the influence of nicotine patch on homeostatic sleep propensity and autonomic nervous system. METHODS: We studied 16 non-smoking young healthy volunteers with nocturnal polysomnography in a double blind crossover design between sleep with and without nicotine patch. We compared the sleep variables, sleep EEG power spectra, and heart rate variability. RESULTS: The night with nicotine patch showed significant increase in sleep latency, wake after sleep onset, and stage 1 sleep; and decrease in total sleep time, sleep efficiency, and percentage of REM sleep. Also, spectral analysis of the sleep EEG in the night with nicotine patch revealed decreased slow wave activity in stage 2 and REM sleep and increased alpha activity in the first NREM-REM sleep cycle. Heart rate variability showed no differences between the 2 nights, but the low to high ratio (a parameter indicative of sympathetic nervous system activity) positively correlated with wake after sleep onset in night with nicotine patch. CONCLUSION: Transdermal nicotine patch significantly disrupts sleep continuity, sleep architecture, and homeostatic sleep propensity. The overactivation of the sympathetic nervous system may be responsible for these changes. PMID- 28845179 TI - Association of Serotonin 1A Receptor Polymorphism with Variation in Health Related Quality of Life in Korean Hemodialysis Patients. AB - OBJECTIVE: Hemodialysis patients may have psychological distress and reduced quality of life (QoL) related to chronic physical health problems. Genetic polymorphisms associated with reduced QoL in hemodialysis patients. The aim of this study was to investigate the relationship between genetic polymorphisms and variation in health-related QoL in Korean hemodialysis patients. METHODS: The 36 item Short-Form Health Survey and the Korean Hospital Anxiety and Depression Scale were used to assess health-related QoL and psychological distress, respectively. Twenty hundred and five clinically stable patients from 6 hemodialysis centers have participated with informed consents. Sociodemographic factors, clinical factors, and genotypes of serotonin 1A receptor, brain-derived neurotrophic factors, and glucocorticoid receptor were assessed. Independent t tests, correlation analyses, multiple regression analyses were performed for statistical analyses. RESULTS: The serotonin 1A receptor CC genotype group showed significantly higher physical and mental QoL levels than those with the GG/GC genotypes. In the final linear regression analysis, serotonin 1A receptor CC genotype was significantly associated with positive physical and mental QoL levels. CONCLUSION: ConclusionaaSerotonin 1A receptor polymorphism, as well as age and depression, were significantly associated with mental and physical QoL in hemodialysis patients. Functional activity in the serotonin receptor system may have a modulating effect on health-related QoL in hemodialysis patients. PMID- 28845180 TI - Development of a Biomarker-Based Diagnostic Algorithm for Posttraumatic Syndrome after Physical Injury: Design of the BioPTS Study. AB - Severe physical injury is a leading cause of posttraumatic syndrome (PTS). This is to develop a biomarker-based diagnostic algorithm for posttraumatic syndrome (BioPTS) study. This is a 2-year longitudinal cohort study assessing patients who were hospitalized beginning in 2015 at Chonnam National University Hospital in Gwangju, Korea, after experiencing severe physical injuries. Baseline evaluations were made during the acute phase (within 1 month) of the physical injury and included extensive information on sociodemographic and clinical variables as well as a list of biomarkers. All participants will be followed up for 2 years, and the diagnostic and predictive validities of various biomarkers for PTS will be estimated. The BioPTS study will develop the most accurate models for the diagnosis and prediction of PTS, and will contribute to existing research regarding the complex relationships between severe physical injury and psychological issues. PMID- 28845181 TI - Neosensitization to Multiple Drugs Following Valproate-Induced Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome. AB - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is associated with severe skin eruptions, fever, hematological abnormalities, and multi-organ involvement. Although aromatic anticonvulsant drugs have been frequently associated with the manifestation of DRESS syndrome, its induction following treatment with nonaromatic anticonvulsants, such as valproate, has rarely been reported. Moreover, there are limited data regarding the development of neosensitization related to chemically unrelated drugs following an episode of DRESS syndrome. Here, a case of neosensitization to multiple drugs is described. The present case report describes a female patient who experienced neosensitization to amoxicillin, olanzapine, and quetiapine following the manifestation of DRESS syndrome induced by valproate. PMID- 28845182 TI - A Case Report of a 37-Year-Old Alzheimer's Disease Patient with Prominent Striatum Amyloid Retention. AB - With recent advancement in amyloid imaging, diagnostic application of this new modality has become a great interest among researchers. New ligands, such as 18F- florbetaben, florbetapir and flutemetamol, have been discovered to overcome limitations of preexisting ligand Pittsburgh compound B. We report here a case of a 37-year-old male patient whose initial complaints comprised of gradual cognitive decline, apraxia, disorientation and sleep disturbances. 18F Florbetaben amyloid imaging of the patient showed diffuse amyloid retention with prominent striatal uptake. This finding supports the clinical utility of amyloid imaging in diagnostic process of early-onset AD. Moreover, striatal dominant uptake pattern demonstrated in this patient include some meaningful clinical implications that warrant special attention among clinicians. PMID- 28845183 TI - Efficacy of Topical Compound Danxiong Granules for Treatment of Dermatologic Toxicities Induced by Targeted Anticancer Therapy: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - Dermatologic toxicities resulting in dose reduction or discontinuation of treatment pose challenges for targeted anticancer therapies. We conducted this randomized, double-blind, placebo-controlled trial to investigate the efficacy of topical application of Compound Danxiong Granules (CDG) for treatment of dermatologic toxicities associated with targeted anticancer therapies. One hundred and ten patients with dermatologic toxicities induced by targeted anticancer therapies were randomly assigned to CDG or placebo group. Each crude herb (Rhizoma Chuanxiong, Paeonia suffruticosa Andr., Cortex Phellodendri, Geranium sibiricum L., and Flos Carthami) was prepared as an instant herbal powder. Application of the CDG via topical washes lasted 20 minutes, twice daily, for 10 days. The primary outcome was the total effective rate, defined as reduction in at least one grade of skin toxicity. The total effective rate was 77.61% (52/67) in the CDG group and 27.27% (9/33) in the placebo group (P < 0.0001). Compared to the placebo treatment, CDG treatment achieved a higher total effective rate for hand-foot skin reaction (95.45% versus 27.27%), acneiform eruption (69.23% versus 30.78%), and paronychia (68.42% versus 22.22%). Topical application of CDG can effectively attenuate dermatologic toxicities induced by targeted anticancer therapies. The effect of CDG was more pronounced in hand-foot skin reaction. PMID- 28845184 TI - The Anti-Inflammatory Effect of Guchangzhixie-Pill by Reducing Colonic EC Cell Hyperplasia and Serotonin Availability in an Ulcerative Colitis Rat Model. AB - Ulcerative colitis (UC) is one of the major types of inflammatory bowel diseases (IBD). Abnormal colonic enterochromaffin (EC) cell hyperplasia and serotonin availability have been described in UC. Guchangzhixie-pill (GCZX-pill), a Chinese herbal formula composed of six herbs, is modified based on a traditional formula (Jiechangyan-pill) for inflammatory and ulcerative gastrointestinal disorders. This study aims to investigate the anti-inflammatory effect and the underlying mechanisms of GCZX-pill on trinitrobenzene sulfonic acid- (TNBS-) induced UC in rats. After orally administrating a GCZX-pill to UC rats for 14 days, the results of the inflammation evaluation, such as disease activity index (DAI), macroscopic score (MS), myeloperoxidase (MPO) activity, and other methods, suggested that the GCZX-pill showed remarkable anti-inflammatory results in UC rats. In addition, the abnormal EC cell numbers, colonic tryptophan hydroxylase (TPH) expression, and serotonin (5-HT) contents in TNBS-induced UC rats were significantly reduced by the GCZX-pill. This data demonstrates that the GCZX-pill can attenuate the inflammation in UC rats and the anti-inflammatory effect of the GCZX-pill may be medicated by reducing colonic EC cell hyperplasia and 5-HT availability. PMID- 28845185 TI - Comparison of Deep Tissue Massage and Therapeutic Massage for Lower Back Pain, Disease Activity, and Functional Capacity of Ankylosing Spondylitis Patients: A Randomized Clinical Pilot Study. AB - OBJECTIVES: This study aims to compare the effectiveness of deep tissue massage (DTM) and therapeutic massage (TM) in the management of ankylosing spondylitis (AS) patients. MATERIALS AND METHODS: This was a small, randomized clinical pilot study. Subjects were 27 men with diagnosed AS, randomly assigned to DTM group or TM group. Subjects in each group had 10 sessions of massage. Outcomes included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), Modified Schober Test, Finger to Floor Test, chest expansion, and pain intensity of lower back. RESULTS: There are no statistical significant differences between groups, except for BASDAI and pain intensity of lower back. CONCLUSIONS: This study suggests that massage may have clinical benefits for treating ankylosing spondylitis patients. Additional scientific research in this area is warranted. PMID- 28845186 TI - What can photophobia tell us about dry eye? PMID- 28845187 TI - 1-Imidoalkylphosphonium salts with modulated Calpha-P+ bond strength: synthesis and application as new active alpha-imidoalkylating agents. AB - An effective synthesis of the hitherto unknown 1-imidoalkylphosphonium salts has been developed in the reported study. The crucial step in the method included the decarboxylative alpha-methoxylation of N-phthaloyl- or N-succinylamino acids to the corresponding N-(1-methoxyalkyl)imides, followed by the displacement of the methoxy group by the triarylphosphonium group through melting of the imide derivative with triarylphosphonium tetrafluoroborate. The imidoalkylating properties of the obtained 1-imidoalkylphosphonium salts were tested using the Tscherniac-Einhorn-type reaction with aromatic hydrocarbons as a model reaction. It was found that the Calpha-P+ bond strength can be considerably reduced and the imidoalkylation of arenes can be markedly facilitated using 1 imidoalkylphosphonium salts derived from triarylphosphines with electron withdrawing substituents such as tris(m-chorophenyl)phosphine, tris(p chlorophenyl)phosphine and tris[p-(trifluoromethyl)phenyl]phosphine. Microwave irradiation also considerably facilitates the cleavage of the highly polar Calpha P+ bond. PMID- 28845188 TI - Photocatalyzed synthesis of isochromanones and isobenzofuranones under batch and flow conditions. AB - Photocatalyzed reactions of 2-(alkoxycarbonyl)benzenediazonium tetrafluoroborates with various alkenes afforded isochromanones in good yields, according to a mechanism that was investigated. The advantage of using highly soluble esters rather than carboxylic acids as starting compounds became evident when the reactions were performed under flow conditions. On the other hand, when 2 vinylbenzoic acid derivatives were employed as reagents, isobenzofuranones were obtained together with unprecedented benzo[e][1,3]oxazepin-1(5H)-ones, with the latter derived from incorporation of the solvent (acetonitrile). PMID- 28845189 TI - Mechanochemical borylation of aryldiazonium salts; merging light and ball milling. AB - Merging of photo- and mechanochemical activation permitted studying the role of eosin Y in the borylation of aryldiazonium salts in a ball mill. Simultaneous neat grinding/irradiation of the reactants and the photocatalyst led to the formation of boronates in a molten state. On the other hand, the catalyst-free liquid-assisted grinding/irradiation reaction also led to product formation, featuring a direct photolysis pathway facilitated by substrate-solvent charge transfer complex formation. PMID- 28845190 TI - Syntheses of 3,4- and 1,4-dihydroquinazolines from 2-aminobenzylamine. AB - A straightforward strategy for the synthesis of dihydroquinazolines is presented, which allows for the preparation of 3,4- and 1,4-dihydroquinazolines with different substitution patterns from 2-aminobenzylamine (2-ABA) as common precursor. The required functionalization of both amino groups present in 2-ABA was achieved by different routes involving selective N-acylation and cesium carbonate-mediated N-alkylation reactions, avoiding protection/deprotection steps. The heterocycles were efficiently synthesized in short reaction times by microwave-assisted ring closure of the corresponding aminoamides promoted by ethyl polyphosphate (PPE). PMID- 28845191 TI - Development of a method for the synthesis of 2,4,5-trisubstituted oxazoles composed of carboxylic acid, amino acid, and boronic acid. AB - A novel method for the synthesis of trisubstituted oxazoles via a one-pot oxazole synthesis/Suzuki-Miyaura coupling sequence has been developed. One-pot formation of 5-(triazinyloxy)oxazoles using carboxylic acids, amino acids and a dehydrative condensing reagent, DMT-MM, followed by Ni-catalyzed Suzuki-Miyaura coupling with boronic acids provided the corresponding 2,4,5-trisubstituted oxazoles in good yields. PMID- 28845194 TI - Base-promoted isomerization of CF3-containing allylic alcohols to the corresponding saturated ketones under metal-free conditions. AB - Following to the computational expectation, our previously reported intriguing 1,3-proton shift of 4,4,4-trifluorobut-2-yn-1-ols was successfully extended to the 4,4,4-trifluorobut-2-en-1-ol system under metal-free conditions to afford the corresponding saturated ketones in high to excellent chemical yields using such a convenient and easy-to-handle base as DBU at the toluene refluxing temperature, and utilization of the corresponding optically active substrates unambiguously demonstrated that this transformation proceeded in a highly stereoselective fashion. PMID- 28845192 TI - Grip on complexity in chemical reaction networks. AB - A new discipline of "systems chemistry" is emerging, which aims to capture the complexity observed in natural systems within a synthetic chemical framework. Living systems rely on complex networks of chemical reactions to control the concentration of molecules in space and time. Despite the enormous complexity in biological networks, it is possible to identify network motifs that lead to functional outputs such as bistability or oscillations. To truly understand how living systems function, we need a complete understanding of how chemical reaction networks (CRNs) create function. We propose the development of a bottom up approach to design and construct CRNs where we can follow the influence of single chemical entities on the properties of the network as a whole. Ultimately, this approach should allow us to not only understand such complex networks but also to guide and control their behavior. PMID- 28845193 TI - 2-Methyl-2,4-pentanediol (MPD) boosts as detergent-substitute the performance of beta-barrel hybrid catalyst for phenylacetylene polymerization. AB - Covering hydrophobic regions with stabilization agents to solubilize purified transmembrane proteins is crucial for their application in aqueous media. The small molecule 2-methyl-2,4-pentanediol (MPD) was used to stabilize the transmembrane protein Ferric hydroxamate uptake protein component A (FhuA) utilized as host for the construction of a rhodium-based biohybrid catalyst. Unlike commonly used detergents such as sodium dodecyl sulfate or polyethylene polyethyleneglycol, MPD does not form micelles in solution. Molecular dynamics simulations revealed the effect and position of stabilizing MPD molecules. The advantage of the amphiphilic MPD over micelle-forming detergents is demonstrated in the polymerization of phenylacetylene, showing a ten-fold increase in yield and increased molecular weights. PMID- 28845195 TI - Phenylsilane as an effective desulfinylation reagent. AB - The reduction using phenylsilane in a KOH-catalyzed system was applied successfully to the conversion of sulfinyl-substituted cyclopropylcarboxylates into the corresponding alcohols. The presence of sulfinyl substituents in the alpha-position to the carboxylate group caused a desulfinylation product formation with full regio- and stereoselectivity, instead of a carbonyl group reduction. Investigations performed on different alpha-sulfinylcarbonyl compounds revealed that phenylsilane treatment constitutes a regiospecific method for the desulfinylation of a-sulfinylesters; for corresponding ketones the reaction course depends on the character of the carbonyl group. PMID- 28845196 TI - Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides. AB - Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantioselective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatility of bifunctional organocatalysts for the enantioselective construction of axially chiral compounds. Moderate to good enantioselectivities were afforded with a range of benzamide substrates. Mechanistic investigations were also carried out. PMID- 28845197 TI - Direct catalytic arylation of heteroarenes with meso-bromophenyl-substituted porphyrins. AB - The arylation of mono-, di- and tetra-meso-bromophenyl-substituted porphyrins with the heteroarenes containing "acidic" C-H bonds, such as benzoxazole, benzothiazole and N-methylimidazole was studied in the presence of three alternative catalytic systems: Pd(dba)2/DavePhos/Cs2CO3, Pd(PPh3)4/PivOH/K2CO3 and Pd(OAc)2/Cu(OAc)2/PPh3/K2CO3. The first catalytic system was found to be successful in the reaction with benzoxazole, the second one was less efficient for our purpose, while the third system proved to be most versatile and afforded corresponding mono-, di-, tri- and even tetraarylated derivatives of porphyrins. PMID- 28845198 TI - Effect of uridine protecting groups on the diastereoselectivity of uridine derived aldehyde 5'-alkynylation. AB - The 5'-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2',3'-di-O-protecting groups (R1): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5'R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5'S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported. PMID- 28845199 TI - Synthesis and metal binding properties of N-alkylcarboxyspiropyrans. AB - Spiropyrans bearing an N-alkylcarboxylate tether are a common structure in dynamic, photoactive materials and serve as colourimetric/fluorimetric cation receptors. In this study, we describe an efficient synthesis of spiropyrans with 2-12 carbon atom alkylcarboxylate substituents, and a systematic analysis of their interactions with metal cations using 1H NMR and UV-visible spectroscopy. All N-alkylcarboxyspiropyrans in this study displayed a strong preference for binding divalent metal cations and a modest increase in M2+ binding affinity correlated with increased alkycarboxylate tether length. PMID- 28845200 TI - Nature-Inspired Chemical Reaction Optimisation Algorithms. AB - Nature-inspired meta-heuristic algorithms have dominated the scientific literature in the areas of machine learning and cognitive computing paradigm in the last three decades. Chemical reaction optimisation (CRO) is a population based meta-heuristic algorithm based on the principles of chemical reaction. A chemical reaction is seen as a process of transforming the reactants (or molecules) through a sequence of reactions into products. This process of transformation is implemented in the CRO algorithm to solve optimisation problems. This article starts with an overview of the chemical reactions and how it is applied to the optimisation problem. A review of CRO and its variants is presented in the paper. Guidelines from the literature on the effective choice of CRO parameters for solution of optimisation problems are summarised. PMID- 28845201 TI - Advancements, measurement uncertainties, and recent comparisons of the NOAA frost point hygrometer. AB - The NOAA frost point hygrometer (FPH) is a balloon-borne instrument flown monthly at three sites to measure water vapor profiles up to 28 km. The FPH record from Boulder, Colorado, is the longest continuous stratospheric water vapor record. The instrument has an uncertainty in the stratosphere that is < 6 % and up to 12 % in the troposphere. A digital microcontroller version of the instrument improved upon the older versions in 2008 with sunlight filtering, better frost control, and resistance to radio frequency interference (RFI). A new thermistor calibration technique was implemented in 2014, decreasing the uncertainty in the thermistor calibration fit to less than 0.01 degrees C over the full range of frost - or dew point temperatures (-93 to +20 degrees C) measured during a profile. Results from multiple water vapor intercomparisons are presented, including the excellent agreement between the NOAA FPH and the direct tunable diode laser absorption spectrometer (dTDLAS) MC-PicT-1.4 during AquaVIT-2 chamber experiments over 6 days that provides confidence in the accuracy of the FPH measurements. Dual instrument flights with two FPHs or an FPH and a cryogenic frost point hygrometer (CFH) also show good agreement when launched on the same balloon. The results from these comparisons demonstrate the high level of accuracy of the NOAA FPH. PMID- 28845202 TI - Reflection as a Deliberative and Distributed Practice: Assessing Neuro Enhancement Technologies via Mutual Learning Exercises (MLEs). AB - In 1968, Jurgen Habermas claimed that, in an advanced technological society, the emancipatory force of knowledge can only be regained by actively recovering the 'forgotten experience of reflection'. In this article, we argue that, in the contemporary situation, critical reflection requires a deliberative ambiance, a process of mutual learning, a consciously organised process of deliberative and distributed reflection. And this especially applies, we argue, to critical reflection concerning a specific subset of technologies which are actually oriented towards optimising human cognition (neuro-enhancement). In order to create a deliberative ambiance, fostering critical upstream reflection on emerging technologies, we developed (in the context of a European 7th Framework Programme project on neuro-enhancement and responsible research and innovation, called NERRI) the concept of a mutual learning exercise (MLE). Building on a number of case studies, we analyse what an MLE involves, both practically and conceptually, focussing on key aspects such as ambiance and expertise, the role of 'genres of the imagination' and the profiles of various 'subcultures of debate'. Ideally, an MLE becomes a contemporary version of the Socratic agora, providing a stage where multiple and sometimes unexpected voices and perspectives mutually challenge each other, in order to strength-en the societal robustness and responsiveness of emerg-ing technologies. PMID- 28845203 TI - Nanoethics, Science Communication, and a Fourth Model for Public Engagement. AB - This paper develops a fourth model of public engagement with science, grounded in the principle of nurturing scientific agency through participatory bioethics. It argues that social media is an effective device through which to enable such engagement, as it has the capacity to empower users and transforms audiences into co-producers of knowledge, rather than consumers of content. Social media also fosters greater engagement with the political and legal implications of science, thus promoting the value of scientific citizenship. This argument is explored by considering the case of nanoscience and nanotechnology, as an exemplar for how emerging technologies may be handled by the scientific community and science policymakers. PMID- 28845204 TI - All-Hex Meshing of Multiple-Region Domains without Cleanup. AB - In this paper, we present a new algorithm for all-hex meshing of domains with multiple regions without post-processing cleanup. Our method starts with a strongly balanced octree. In contrast to snapping the grid points onto the geometric boundaries, we move points a slight distance away from the common boundaries. Then we intersect the moved grid with the geometry. This allows us to avoid creating any flat angles, and we are able to handle two-sided regions and more complex topologies than prior methods. The algorithm is robust and cleanup free; without the use of any pillowing, swapping, or smoothing. Thus, our simple algorithm is also more predictable than prior art. PMID- 28845205 TI - Medicolegal Death Scene Investigations After Natural Disaster- and Weather Related Events: A Review of the Literature. AB - BACKGROUND: The number of disaster-related deaths recorded by vital statistics departments often differs from that reported by other agencies, including the National Oceanic and Atmospheric Administration-National Weather Service storm database and the American Red Cross. The Centers for Disease Control and Prevention (CDC) has launched an effort to improve disaster-related death scene investigation reporting practices to make data more comparable across jurisdictions, improve accuracy of reporting disaster-related deaths, and enhance identification of risk and protective factors. We conducted a literature review to examine how death scene data are collected and how such data are used to determine disaster relatedness. METHODS: Two analysts conducted a parallel search using Google and Google Scholar. We reviewed published peer-reviewed articles and unpublished documents including relevant forms, protocols, and worksheets from coroners, medical examiners, and death scene investigators. RESULTS: We identified 177 documents: 32 published peer-reviewed articles and 145 other documents (grey literature). Published articles suggested no consistent approach for attributing deaths to a disaster. Researchers generally depended on death certificates to identify disaster-related deaths; several studies also drew on supplemental sources, including medical examiner, coroner, and active surveillance reports. CONCLUSIONS: These results highlight the critical importance of consistent, accurate data collection during a death investigation. Review of the grey literature found variation in use of death scene data collection tools, indicating the potential for widespread inconsistency in data captured for routine reporting and public health surveillance. Findings from this review will be used to develop guidelines and tools for capturing disaster related death investigation data. PMID- 28845206 TI - Influence of Meteorological Variables on Diversity and Abundance of Mosquito Vectors in Two Livestock Farms in Ibadan, Nigeria: Public Health Implications. AB - This study was undertaken to determine mosquito vector diversity and abundance in two livestock farms with previous history of arboviral activities in Ibadan, southwestern Nigeria. The influence of weather on mosquito populations was also studied. Adult mosquitoes were collected weekly in two proximate University of Ibadan livestock farms from March 2015 to February 2016 using CO2 baited CDC light trap and human landing collection methods. Mosquitoes were identified to species using morphological keys. Relationships and interaction of temperature, relative humidity, rainfall patterns and mosquito abundance were analysed using GENSTAT 4th edition. Among 6,195 adult mosquitoes collected, 16 species belonging to 5 genera were morphologically identified. Culex quinquefasciatus constituted the most abundant mosquito, representing 46.49% of all mosquitoes encountered. High abundance in mosquito population was noted in periods succeeding months with heavy rainfall, this is when arbovirus transmission risk is highest. A positive correlation was observed between relative humidity and abundance of Mansonia mosquitoes. This study shows the effect of weather on natural populations of mosquito vectors. The diverse mosquito species capable of transmitting arboviruses from animal reservoirs to human and animals in livestock farms and its environment in Ibadan, Nigeria was also revealed. There is need for intensive vector control strategies targeted at reducing mosquito populations and ultimately prevention of disease outbreaks. PMID- 28845207 TI - Electrochemical CO Oxidation at Platinum on Carbon Studied through Analysis of Anomalous in Situ IR Spectra. AB - The oxidation of adsorbed CO is a key reaction in electrocatalysis. It has been studied extensively on both extended model surfaces and on nanoparticles; however, correlation between the two is far from simple. Molecular insight into the reaction is often provided using in situ IR spectroscopy; however, practical challenges mean in situ studies on nanoparticles have yet to provide the same level of detail as those on model surfaces. Here we use a new approach to in situ IR spectroscopy to study the mechanism of CO adlayer oxidation on a commercial carbon-supported Pt catalyst. We observe bipolar IR absorption bands but develop a simple model to enable fitting. Quantitative analysis of band behavior during the oxidation prepeak using the model agrees well with previous analysis based on conventional absorption bands. A second linear CO band is observed during the main oxidation region and is assigned to the distinct contribution of CO on step as opposed to terrace sites. Analysis of the step and terrace CO bands during oxidation shows that oxidation begins on the terraces of the nanoparticles before CO on steps is removed. Further correlation of this behavior with the current shows that step CO is only lost in the first of the two main oxidation peaks. PMID- 28845208 TI - In-Situ 2p3d Resonant Inelastic X-ray Scattering Tracking Cobalt Nanoparticle Reduction. AB - In-situ carbon-thermal reduction of cobalt oxide nanoparticles supported on carbon nanotubes was studied by cobalt 2p3d resonant inelastic X-ray scattering (RIXS). The in-situ 2p X-ray absorption spectroscopy (XAS) and RIXS measurements were performed at 500, 600, and 700 degrees C, where four consistent excitation energies were used for RIXS acquisitions. After 700 degrees C reduction, the XAS spectrum shows a cobalt metal-like shape, while the RIXS spectra reveal the minority cobalt monoxide phase. The holistic fit on both XAS and RIXS data reveals the respective contributions from metal and monoxide. We show that the relative precision to determine the monoxide content changes from ~5.6% in XAS results to better than 0.8% in the RIXS analysis, suggesting that RIXS is a useful tool to track the oxidation state of nanoparticles under in situ conditions. We determined a relative radiative ratio (P) factor of approximately 5, where this factor gives the ratio between the relative strengths of the radiative decay channels compared to the nonradiative channels in CoO and Co metal. PMID- 28845209 TI - Nearly assumptionless screening for the mutually-exciting multivariate Hawkes process. AB - We consider the task of learning the structure of the graph underlying a mutually exciting multivariate Hawkes process in the high-dimensional setting. We propose a simple and computationally inexpensive edge screening approach. Under a subset of the assumptions required for penalized estimation approaches to recover the graph, this edge screening approach has the sure screening property: with high probability, the screened edge set is a superset of the true edge set. Furthermore, the screened edge set is relatively small. We illustrate the performance of this new edge screening approach in simulation studies. PMID- 28845210 TI - Impact of the home environment on the relationship between prenatal exposure to environmental tobacco smoke and child behavior. AB - The goal of this study was to ascertain whether the effect of prenatal ETS exposure on behavioral symptoms at age 7 years is modified by the quality of the home environment. In a cohort of 417 children enrolled in a longitudinal birth cohort in New York City, prenatal ETS exposure, child behavior and home environment were assessed. Prenatal ETS was measured by questionnaire and blood cotinine. Child Behavior Checklist (CBCL) and Early Childhood HOME Inventory Scale (HOME) were also used. We detected a significant interaction between prenatal ETS exposure and living in a "better" home environment on reported problems in the rule breaking and externalizing domains (p-value for interaction terms: 0.002 and 0.04, respectively), such that there was no significant adverse impact of ETS exposure on behavior among those who experienced a "better" environment. We also detected a significant interaction between prenatal ETS exposure and living in a "worse" home environment on reported problems in the aggressive and externalizing domains (p-value for interaction terms: 0.03 and 0.02, respectively), such that there was a significant adverse effect of ETS exposure on behavior among children who experienced a "worse" environment. Aspects of the HOME environment, both positive and negative, moderated the effects of prenatal ETS exposure on selected behaviors at 7 years of age. This finding suggests that some negative developmental behavioral effects associated with ETS exposure early in life may be modified by the provision of an enriched learning environment as measured by the HOME inventory. PMID- 28845211 TI - Oxidative Stress in Pancreatic Beta Cell Regeneration. AB - Pancreatic beta cell neogenesis and proliferation during the neonatal period are critical for the generation of sufficient pancreatic beta cell mass/reserve and have a profound impact on long-term protection against type 2 diabetes (T2D). Oxidative stress plays an important role in beta cell neogenesis, proliferation, and survival under both physiological and pathophysiological conditions. Pancreatic beta cells are extremely susceptible to oxidative stress due to a high endogenous production of reactive oxygen species (ROS) and a low expression of antioxidative enzymes. In this review, we summarize studies describing the critical roles and the mechanisms of how oxidative stress impacts beta cell neogenesis and proliferation. In addition, the effects of antioxidant supplements on reduction of oxidative stress and increase of beta cell proliferation are discussed. Exploring the roles and the potential therapeutic effects of antioxidants in the process of beta cell regeneration would provide novel perspectives to preserve and/or expand pancreatic beta cell mass for the treatment of T2D. PMID- 28845212 TI - Increased Circulating Levels of Interleukin-6 Induce Perturbation in Redox Regulated Signaling Cascades in Muscle of Dystrophic Mice. AB - Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy. PMID- 28845213 TI - Stress-Activated Degradation of Sphingolipids Regulates Mitochondrial Function and Cell Death in Yeast. AB - Sphingolipids are regulators of mitochondria-mediated cell death in higher eukaryotes. Here, we investigate how changes in sphingolipid metabolism and downstream intermediates of sphingosine impinge on mitochondrial function. We found in yeast that within the sphingolipid degradation pathway, the production via Dpl1p and degradation via Hfd1p of hexadecenal are critical for mitochondrial function and cell death. Genetic interventions, which favor hexadecenal accumulation, diminish oxygen consumption rates and increase reactive oxygen species production and mitochondrial fragmentation and vice versa. The location of the hexadecenal-degrading enzyme Hfd1p in punctuate structures all along the mitochondrial network depends on a functional ERMES (endoplasmic reticulum mitochondria encounter structure) complex, indicating that modulation of hexadecenal levels at specific ER-mitochondria contact sites might be an important trigger of cell death. This is further supported by the finding that externally added hexadecenal or the absence of Hfd1p enhances cell death caused by ectopic expression of the human Bax protein. Finally, the induction of the sphingolipid degradation pathway upon stress is controlled by the Hog1p MAP kinase. Therefore, the stress-regulated modulation of sphingolipid degradation might be a conserved way to induce cell death in eukaryotic organisms. PMID- 28845216 TI - Calcium Kinetic in a patient with acute renal failure due to Rhabdomyolysis. A Case Report and Review of Literature. AB - Hypercalcemia may follow hypocalcemia in the course of acute renal failure (also named now as acute kidney injury) secondary to rhabdomyolysis. The clinician should be aware of this calcium kinetics to avoid the complications of both hypocalcemia and hypercalcemia that may occur at few days interval during the recovery phase. We present herewith the case of a young gentleman who developed anuric ARF due to a strenuous exercise induced rhabdomyolysis. He was treated with supportive, corrective and dialysis measures. The progress was favourable with a diuretic phase. During the diuretic phase, he developed progressive hypercalcemia that reached up to 3.54 mEq/lwith constipation and drowsiness. Investigations showed besides stigmata of rhabdomyolysis and ARF, low initial levels of vitamin D metabolites. The calcemia eventually normalized with fluids, dialysis and a single dose of Pamidronate Sodium . The patient was discharged 3 weeks after admission with a recovered clinical condition, improved renal functions and normal calcemia. The biphasic kinetics of calcium in this setting is ocumented. We conclude that serum corrected calcium should be monitored in the context of ARF due to rhabdomyolysis. PMID- 28845214 TI - Elucidation of Molecular Mechanisms of Streptozotocin-Induced Oxidative Stress, Apoptosis, and Mitochondrial Dysfunction in Rin-5F Pancreatic beta-Cells. AB - Streptozotocin is a pancreatic beta-cell-specific cytotoxin and is widely used to induce experimental type 1 diabetes in rodent models. The precise molecular mechanism of STZ cytotoxicity is however not clear. Studies have suggested that STZ is preferably absorbed by insulin-secreting beta-cells and induces cytotoxicity by producing reactive oxygen species/reactive nitrogen species (ROS/RNS). In the present study, we have investigated the mechanism of cytotoxicity of STZ in insulin-secreting pancreatic cancer cells (Rin-5F) at different doses and time intervals. Cell viability, apoptosis, oxidative stress, and mitochondrial bioenergetics were studied. Our results showed that STZ induces alterations in glutathione homeostasis and inhibited the activities of the respiratory enzymes, resulting in inhibition of ATP synthesis. Apoptosis was observed in a dose- and time-dependent manner. Western blot analysis has also confirmed altered expression of oxidative stress markers (e.g., NOS and Nrf2), cell signaling kinases, apoptotic protein-like caspase-3, PARP, and mitochondrial specific proteins. These results suggest that STZ-induced cytotoxicity in pancreatic cells is mediated by an increase in oxidative stress, alterations in cellular metabolism, and mitochondrial dysfunction. This study may be significant in better understanding the mechanism of STZ-induced beta-cell toxicity/resistance and the etiology of type 1 diabetes induction. PMID- 28845217 TI - External Ophthalmomyiasis due to Oestrus Ovis: A Case Report from Oman. AB - Human myiasis has been reported from various regions in the world. We report a human case of external ophthalmomyiasis caused by the larvae of a sheep nasal botfly oestrus ovis from Wadi Alhawasna, North Batina, Oman. A 9-years-old boy presented with symptoms of acute conjunctivitis. Five larvae were removed from his eye and sent for identification. The patient recovered completely after removal of the larvae. PMID- 28845215 TI - PPAR-gamma Activation Prevents Septic Cardiac Dysfunction via Inhibition of Apoptosis and Necroptosis. AB - Sepsis-induced cardiac dysfunction remains one of the major causes of death in intensive care units. Overwhelmed inflammatory response and unrestrained cell death play critical roles in sepsis-induced cardiac dysfunction. Peroxisome proliferator-activated receptor- (PPAR-) gamma has been proven to be cardioprotective in sepsis. However, the mechanism of PPAR-gamma-mediated cardioprotection and its relationship with inflammation and cell death are unclear. We hypothesized that activation of PPAR-gamma by reducing cardiac inflammation, myocardial apoptosis, and necroptosis may prevent myocardial dysfunction in sepsis. Rats were subjected to cecal ligation and puncture (CLP) with or without PPAR-gamma agonist (rosiglitazone) or antagonist T0070907 (T007). After CLP, cardiac function was significantly depressed, which was associated with the destructed myocardium, upregulated proinflammatory cytokines, and increased apoptosis, necrosis, and necroptosis. This process is corresponded with decreased inhibitor kappaB (IkappaBalpha) and increased NF-kappaB, receptor interacting protein kinase-1 (RIP1), RIP3, and mixed lineage kinase-like (MLKL) protein. Activation of PPAR-gamma by rosiglitazone pretreatment enhanced PPAR gamma activity and prevented these changes, thereby improving the survival of septic rats. In contrast, inhibition of PPAR-gamma by T007 further exacerbated the condition, dropping the survival rate to nearly 0%. In conclusion, PPAR-gamma activation by reducing proinflammatory cytokines, apoptosis, and necroptosis in the myocardium prevents septic myocardial dysfunction. PMID- 28845218 TI - Segmental Infarction of Testis: A rare complication of acute epididymitis. AB - Doppler ultrasound of a thirty one year old patient presenting with acute scrotal pain showed features acute epididymitis. Follow up study done on third day showed total ischemia of the testis. Repeat scan on tenth day revealed partially regained flow in the testis with segmental infarction- an unusual complication of acute epididymitis. This was confirmed by orchidectomy and histopathological examination. PMID- 28845219 TI - Rapunzel Syndrome: A Case Report. AB - Rapunzel syndrome is a rare type of trichobezoar with extension of the hair into the small bowel. Clinical presentation can be deceptive ranging from upper abdominal mass to gastrointestinal obstructive symptoms. In majority of cases, the diagnosis is made very late in the history of the disease due to late patient presentation in lieu of his underlying mental disorder. Surgical removal is necessary. One such case is describe here stressing the importance of imaging in the diagnosis of this condition. PMID- 28845220 TI - Extradural Hemorrhage: A rare Complication and Manifestation of Stroke in Sickle Cell Disease. AB - We present a case of extradural hemorrhage, a rare and unusual complication associated with Sickle Cell Disease, from Nizwa, Oman. A 12-year old male child with Sickle cell disease (SD) was admitted to hospital with backache and pain in both lower Limbs. Clinical examination revealed an average built child with mild pallor, mild tenderness in the lower back and both legs. Rest of the examination was unremarkable including the Central Nervous System. The next day, the patient developed generalized convulsion and became unconscious with shallow breathing. CT of the brain revealed large extradural hemorrhage with shift of mid line structure. After prompt neurosurgical and a hematologic intervention, the child survived and is making progress in rehabilitation. Primary hemorrhagic stroke is a known but uncommon complication of sickle cell disease in childhood, but extradural hemorrhage is an even more rare complication. PMID- 28845221 TI - Peri-mortem Cesarean Delivery... A Reality not Fiction. AB - Antepartum hemorrhage is one of the leading causes of mortality around the world. It can result in hypovolemic shock leading to circulatory arrest during pregnancy. A well-planned strategy is required for its management in all hospitals. To deliver a woman in this situation is a dilemma, which needs very prompt decision and a swift speedy action. Not only the woman's life is in danger, the fetus is also at risk and urgent delivery may be life saving for both mother and the fetus. All obstetricians should be trained to deal with such situation with full understanding and awareness of the condition. PMID- 28845222 TI - Management of Pediatric Tracheo Bronchial Foreign Body Aspiration. AB - Foreign body aspiration is a relatively commonly encountered emergency in the pediatric age group. Foreign body can get lodge at any site from supraglottis to the terminal bronchioles. The removal of nasal foreign body in the pediatric age group particularly those lodged posteriorly should always be attempted under general anesthesia as it can dislodge down into the lower airway leading to fatal complications. Foreign body aspiration can result in a spectrum of presentations, from minimal symptoms, often unobserved, to respiratory compromise, failure, and even death. Children aged 1-3 years are particularly at risk because of their increasing independence, lessening of close parental supervision as they become older, increasing activity and curiosity. PMID- 28845223 TI - Prevalence of Depression in Karachi, Pakistan. PMID- 28845224 TI - Pseudo-obstruction of the Gastric Outlet Caused by Combined Hyperganglionosis and Ganglioneuromatosis in an adult: Case Report and Literature Review. AB - Gastrointestinal ganglioneuromatosis is a rare and benign proliferation of both ganglion and Schwann cells, which may present in a variety of clinicopathological characteristics including polypoid, localized and diffuse forms. It is characterized by the presence of a large number of dysplastic ganglion cells or hyperganglionosis. The affected patients are usually children and a number of them have intestinal neuronal dysplasia type B, which may overlap with ganglioneuromatosis. We report a very rare case of gastric ganglioneuromatosis with hyperganglionosis in a 34 year old male, who presented as a case of gastric outlet obstruction and marked gastric dilatation which was diagnosed both clinically and radiologically as a case of gastric obstruction due to gastric malignancy. Based on these findings and because of the patient's deteriorating clinical situation; the patient underwent distal gastrectomy and the final diagnosis was made following the histopathological examination of the resected specimen. The clinicopathological features and diagnostic criteria of this rare disorder are described together with a literature review of other similar cases affecting different parts of the gastrointestinal tract. PMID- 28845225 TI - Adult-Onset Still's Disease: A Case Report. AB - Adult-onset Still's disease (AOSD) is a rare clinical entity with unknown etiology, characterized by arthritis, fever, evanescent rash and other systemic presentations. This report described a 45-year-old male who presented with sore throat, fever, arthritis, evanescent rash, raised liver enzymes and hyperferritinemia. He was diagnosed to have AOSD based on Yamuguchi criteria after the exclusion of other potential diagnoses. The patient partially responded to combined celecoxib and prednisolone. He was also prescribed methotrexate and his symptoms improved. PMID- 28845226 TI - Dermatofibrosarcoma Protuberans Male Breast: A Case report. AB - Dermatofibrosarcoma protuberans is a relatively uncommon soft tissue tumor involving the dermal layer of skin with intermediate-to-low grade malignancy. Although metastasis rarely occurs, Dermatofibrosarcoma protuberans is a locally aggressive tumor with a high recurrence rate. We treated a 35-year-old male patient with Dermatofibrosarcoma protuberans left breast at Pakistan Air Force hospital Karachi. The reluctance on the patient's side unnecessarily delayed operative procedure. Allowing wide safety margins during resection, an extended resection was carried out. The patient was later subjected to radiotherapy. PMID- 28845227 TI - Solitary Rectal Ulcer Syndrome, a Pediatric Problem: Case Report. AB - Solitary rectal ulcer syndrome is common in adults; however, it is thought to be rare in children. The etiology and exact pathogenesis of this condition are poorly understood. The main presenting feature of solitary rectal ulcer syndrome is rectal bleeding, but the clinical diagnosis and treatment remain challenging, particularly in pediatric patients. We present two pediatric patients with solitary rectal ulcer syndrome, who were treated surgically, and remain asymptomatic after the procedures. Clinicians should be aware of this problem in order to avoid delayed diagnosis and management. PMID- 28845228 TI - Rupture of Splenic Artery Aneurysm during Pregnancy: A Report of two Cases. AB - Splenic artery aneurysm (SAA) is a rare clinical entity that carries the risk of rupture and fatal hemorrhage. Ruptured SAA, especially during pregnancy has fateful consequences for the mother, foetus or both. The role of the Radiologist is very important in preventing mortality. A diagnosis of ruptured SAA should be considered in any pregnant patient who complains of sudden epigastric or upper abdominal pain, with or without shock. This is a report of two cases where the mothers were saved but the foetuses were lost. PMID- 28845229 TI - Family-level stereoselective synthesis and biological evaluation of pyrrolomorpholine spiroketal natural product antioxidants. AB - The pyranose spiroketal natural products pollenopyrroside A and shensongine A (also known as xylapyrroside A, ent-capparisine B) have been synthesized by stereoselective spirocyclizations of a common C1-functionalized glycal precursor. In conjunction with our previously reported syntheses of the corresponding furanose isomers, this provides a versatile family-level synthesis of the pyrrolomorpholine spiroketal natural products and analogues. In rat mesangial cells, hyperglycemia-induced production of reactive oxygen species, which is implicated in diabetic nephropathy, was inhibited by pollenopyrroside A and shensongine A with mid-MUM IC50 values, while unnatural C2-hydroxy analogues exhibited more potent, sub-MUM activity. PMID- 28845230 TI - Screening for valve disease in patients with hyperprolactinaemia disorders prescribed cabergoline: a service evaluation and literature review. AB - OBJECTIVES: The indication for screening for valvular heart disease in patients taking cabergoline is based on evidence from patients with Parkinson's disease on high-dose medication. However, current patients take much lower doses for indications such as hyperprolactinaemia disorders. Contemporary guidelines for echocardiogram monitoring in patients taking cabergoline are conflicting. This study aimed to review current clinical practice in our area regarding echocardiographic screening and to review the literature examining the evidence of valvular heart disease in patients taking lower dose cabergoline. METHODS: This was a retrospective study of all patients with hyperprolactinaemia disorders prescribed cabergoline in a single UK NHS health board between January 2014 and July 2015. The proportion of patients receiving baseline and follow-up echocardiograms was recorded. A review of the published literature was carried out using the databases EMBASE and Medline to examine the current evidence for the effect cabergoline has on cardiac valves in patients treated for hyperprolactinaemia disorders. RESULTS: The mean age was 51.7 +/- 16.5 years with a 64.4% female predominance. The mean duration of therapy was 5.9 years +/- 4.1 years. Of the total cohort (n = 45), two (4.4%) patients had an initial baseline echocardiogram and five (13.2%) had follow-up echocardiograms every 24 months. Of the 25 articles identified, 12 showed no clinically significant evidence of valvular dysfunction in the cabergoline group groups. Of the remaining 13 articles, evidence for valvular changes was confined to high cumulative dose cabergoline patients and there was only one confirmed case of 'cabergoline associated valvulopathy' described. CONCLUSIONS: Clinically significant valvular dysfunction is uncommon and generally only reported in high cumulative dose treatment groups. We propose that clearer national guidelines are required and that echocardiogram screening be reserved for patients who are high risk, are taking a high weekly dose (>=2 mg cabergoline weekly) or high cumulative dose. PMID- 28845231 TI - A mathematical framework to quantify the masking effect associated with the confidence intervals of measures of disproportionality. AB - BACKGROUND: The lower bound of the 95% confidence interval of measures of disproportionality (Lower95CI) is widely used in signal detection. Masking is a statistical issue by which true signals of disproportionate reporting are hidden by the presence of other medicines. The primary objective of our study is to develop and validate a mathematical framework for assessing the masking effect of Lower95CI. METHODS: We have developed our new algorithm based on the masking ratio (MR) developed for the measures of disproportionality. A MR for the Lower95CI (MRCI) is proposed. A simulation study to validate this algorithm was also conducted. RESULTS: We have established the existence of a very close mathematical relation between MR and MRCI. For a given drug-event pair, the same product will be responsible for the highest masking effect with the measure of disproportionality and its Lower95CI. The extent of masking is likely to be very similar across the two methods. An important proportion of identical drug-event associations affected by the presence of an important masking effect is revealed by the unmasking exercise, whether the proportional reporting ratio (PRR) or its confidence interval are used. CONCLUSION: The detection of the masking effect of Lower95CI can be automated. The real benefits of this unmasking in terms of new true-positive signals (rate of true-positive/false-positive) or time gained by the revealing of signals using this method have not been fully assessed. These benefits should be demonstrated in the context of prospective studies. PMID- 28845232 TI - Solifenacin linked QT interval prolongation and torsades de pointes. PMID- 28845233 TI - Flexible functional regression methods for estimating individualized treatment regimes. AB - A major focus of personalized medicine is on the development of individualized treatment rules. Good decision rules have the potential to significantly advance patient care and reduce the burden of a host of diseases. Statistical methods for developing such rules are progressing rapidly, but few methods have considered the use of pre-treatment functional data to guide in decision-making. Furthermore, those methods that do allow for the incorporation of functional pre treatment covariates typically make strong assumptions about the relationships between the functional covariates and the response of interest. We propose two approaches for using functional data to select an optimal treatment that address some of the shortcomings of previously developed methods. Specifically, we combine the flexibility of functional additive regression models with Q-learning or A-learning in order to obtain treatment decision rules. Properties of the corresponding estimators are discussed. Our approaches are evaluated in several realistic settings using synthetic data and are applied to real data arising from a clinical trial comparing two treatments for major depressive disorder in which baseline imaging data are available for subjects who are subsequently treated. PMID- 28845235 TI - Cardiac Electrophysiology Under MRI Guidance: an Emerging Technology. AB - MR-guidance of electrophysiological (EP) procedures offers the potential for enhanced arrhythmia substrate assessment, improved procedural guidance and real time assessment of ablation lesion formation. Accurate device tracking techniques, using both active and passive methods, have been developed to offer an interface similar to electroanatomic mapping platforms, and MR-compatible EP equipment continues to be developed. Progress to clinical implementation of these technically complex fields has been relatively slow over the last 10 years, but recent developments have led to successful clinical experience. However, further advances, particularly in harnessing the full imaging potential of CMR, are required to realise the mainstream adoption of this powerful guidance modality. PMID- 28845234 TI - A Review of Image-guided Approaches for Cardiac Resynchronisation Therapy. AB - Cardiac resynchronisation therapy (CRT) is a standard treatment for patients with heart failure; however, the low response rate significantly reduces its cost effectiveness. A favourable CRT response primarily depends on whether implanters can identify the optimal left ventricular (LV) lead position and accurately place the lead at the recommended site. Myocardial imaging techniques, including echocardiography, cardiac magnetic resonance imaging and nuclear imaging, have been used to assess LV myocardial viability and mechanical dyssynchrony, and deduce the optimal LV lead position. The optimal position, presented as a segment of the myocardial wall, is then overlaid with images of the coronary veins from fluoroscopy to aid navigation of the LV lead to the target venous site. Once validated by large clinical trials, these image-guided techniques for CRT lead placement may have an impact on current clinical practice. PMID- 28845236 TI - Prostate adenocarcinoma metastases to the testis and brain: case report and review of the literature. AB - Prostate cancer is the second most common cancer in men worldwide. While clinicians commonly see metastases to the bones and lymph nodes, it may infrequently spread to more uncommon locations. We report an unusual case of an 83-year-old patient with previously treated prostate adenocarcinoma who presents with symptomatic metastases to the testis and brain in the absence of widely disseminated disease. This case report highlights the importance of including metastatic disease in the differential for patients with a history of prostate cancer and a newly discovered mass until an evaluation of the tissue can be performed. PMID- 28845237 TI - Topical 5-Fluorouracil associated skin reaction. AB - Topical 5- Fluorouracil (5-FU) is used more frequently to treat actinic keratosis. We are presenting a skin reaction as a side effect of this medication. Treatment for such cases of 5-FU-induced skin reactions is based on proper skin care and treatment of any superimposed infections. Medical providers should be aware of such side effects to provide their patients with proper instructions to avoid complications. PMID- 28845239 TI - Kinematic characteristics of infant leg movements produced across a full day. AB - INTRODUCTION: Our purpose is to directly measure variability in infant leg movement behavior in the natural environment across a full day. We recently we created an algorithm to identify an infant-produced leg movement from full-day wearable sensor data from infants with typical development between 1 and 12 months of age. Here we report the kinematic characteristics of their leg movements produced across a full day. METHODS: Wearable sensor data were collected from 12 infants with typical development for 8-13 hours per day. A wearable sensor was attached to each ankle, and recorded tri-axial accelerometer and gyroscope measurements at 20Hz. We determined the duration, average acceleration, and peak acceleration of each leg movement, and classified its type (unilateral, bilateral synchronous, bilateral asynchronous). RESULTS: There was a range of leg movement duration (0.23-0.33 s) and acceleration (average 1.59 to 3.88 m/s2, peak 3.10 to 8.83 m/s2) values produced by infants across visits. Infants predominantly produced unilateral and asynchronous bilateral movements. Our results collected across a full day are generally comparable to kinematic measures obtained by other measurement tools across short periods of time. CONCLUSION: Our results describe variable full-day kinematics of leg movements across infancy in a natural environment. These data create a reference standard for the future comparison of infants at risk for developmental delay. PMID- 28845238 TI - Trait aspects of auditory mismatch negativity predict response to auditory training in individuals with early illness schizophrenia. AB - BACKGROUND: Individuals with schizophrenia have heterogeneous impairments of the auditory processing system that likely mediate differences in the cognitive gains induced by auditory training (AT). Mismatch negativity (MMN) is an event-related potential component reflecting auditory echoic memory, and its amplitude reduction in schizophrenia has been linked to cognitive deficits. Therefore, MMN may predict response to AT and identify individuals with schizophrenia who have the most to gain from AT. Furthermore, to the extent that AT strengthens auditory deviance processing, MMN may also serve as a readout of the underlying changes in the auditory system induced by AT. METHODS: Fifty-six individuals early in the course of a schizophrenia-spectrum illness (ESZ) were randomly assigned to 40 h of AT or Computer Games (CG). Cognitive assessments and EEG recordings during a multi-deviant MMN paradigm were obtained before and after AT and CG. Changes in these measures were compared between the treatment groups. Baseline and trait like MMN data were evaluated as predictors of treatment response. MMN data collected with the same paradigm from a sample of Healthy Controls (HC; n = 105) were compared to baseline MMN data from the ESZ group. RESULTS: Compared to HC, ESZ individuals showed significant MMN reductions at baseline (p = .003). Reduced Double-Deviant MMN was associated with greater general cognitive impairment in ESZ individuals (p = .020). Neither ESZ intervention group showed significant change in MMN. We found high correlations in all MMN deviant types (rs = .59-.68, all ps < .001) between baseline and post-intervention amplitudes irrespective of treatment group, suggesting trait-like stability of the MMN signal. Greater deficits in trait-like Double-Deviant MMN predicted greater cognitive improvements in the AT group (p = .02), but not in the CG group. CONCLUSIONS: In this sample of ESZ individuals, AT had no effect on auditory deviance processing as assessed by MMN. In ESZ individuals, baseline MMN was significantly reduced relative to HCs, and associated with global cognitive impairment. MMN did not show changes after AT and exhibited trait-like stability. Greater deficits in the trait aspects of Double-Deviant MMN predicted greater gains in global cognition in response to AT, suggesting that MMN may identify individuals who stand to gain the most from AT. TRIAL REGISTRATION: NCT00694889. Registered 1 August 2007. PMID- 28845241 TI - A43 Modeling the ecology and evolution of H13 and H16 avian influenza A subtypes in black-headed gulls to understand influenza disease dynamics. PMID- 28845240 TI - Human protein secretory pathway genes are expressed in a tissue-specific pattern to match processing demands of the secretome. AB - Protein secretory pathway in eukaryal cells is responsible for delivering functional secretory proteins. The dysfunction of this pathway causes a range of important human diseases from congenital disorders to cancer. Despite the piled up knowledge on the molecular biology and biochemistry level, the tissue-specific expression of the secretory pathway genes has not been analyzed on the transcriptome level. Based on the recent RNA-sequencing studies, the largest fraction of tissue-specific transcriptome encodes for the secretome (secretory proteins). Here, the question arises that if the expression levels of the secretory pathway genes have a tissue-specific tuning. In this study, we tackled this question by performing a meta-analysis of the recently published transcriptome data on human tissues. As a result, we detected 68 as called "extreme genes" which show an unusual expression pattern in specific gene families of the secretory pathway. We also inspected the potential functional link between detected extreme genes and the corresponding tissues enriched secretome. As a result, the detected extreme genes showed correlation with the enrichment of the nature and number of specific post-translational modifications in each tissue's secretome. Our findings conciliate both the housekeeping and tissue-specific nature of the protein secretory pathway, which we attribute to a fine-tuned regulation of defined gene families to support the diversity of secreted proteins and their modifications. PMID- 28845242 TI - A46 MERS-CoV in Arabian camels in Africa and Central Asia. PMID- 28845243 TI - A13 HIV drug resistance over a decade of antiretroviral therapy scale-up for HIV/AIDS patients in Vietnam. PMID- 28845244 TI - A39 Human exome sequencing to evaluate the impact of rare coding variation on HIV 1 control. PMID- 28845245 TI - A44 Determination of highly conserved sites by deep sequencing in avian influenza A virus H5N1. PMID- 28845246 TI - A45 Family clusters of avian influenza A H7N9 infection in Guangdong Province, China. PMID- 28845247 TI - A52 Development and evaluation of a viral-specific random PCR and next-generation sequencing based assay for detection and sequencing of hand, foot, and mouth disease pathogens. PMID- 28845248 TI - A35 Viral evolution and innate immune responses during acute HIV-1 infection and their association with disease pathogenesis. PMID- 28845249 TI - A22 Increase in the numbers of HIV-1 non-B subtypes and potential recombinant forms circulating among Slovenian MSM in recent years. PMID- 28845250 TI - A12 Predictors of treatment failure among Irish individuals infected with hepatitis C virus. PMID- 28845251 TI - A5 Peripheral blood cells contribute to HIV-1 viremia induced by romidepsin. PMID- 28845252 TI - A30 Recombination & evolution in two viral families: effective steps or a random walk? PMID- 28845253 TI - A37 HIV drug resistance monitoring in children receiving first line antiretroviral therapy at two pediatric hospitals in Ho Chi Minh City. PMID- 28845254 TI - A14 Comprehensive characterisation and evolutionary analysis of endogenous retroviruses in the mouse genome. PMID- 28845255 TI - A29 Wolbachia for dengue control; will dengue viruses evolve resistance? PMID- 28845256 TI - A42 Evolution and spatial dissemination of the highly pathogenic Asian H5 avian influenza viruses. PMID- 28845257 TI - A16 A distributed pan-viral typing framework. PMID- 28845258 TI - A25 Phylogenetic analysis of the nucleocapsid and RNA-dependent RNA polymerase fragments of the first imported case of middle east respiratory syndrome coronavirus (MERS-CoV) infection in the Philippines from Saudi Arabia, February 2015. PMID- 28845259 TI - A10 The evolution and molecular epidemiology of epidemic GII.17 noroviruses. PMID- 28845260 TI - A20 The search for replication-competent HIV during effective therapy. PMID- 28845261 TI - A19 Genetic markers for protease inhibitor drug resistance in regions outside of the protease gene. PMID- 28845262 TI - A49 Molecular evolutionary dynamics of respiratory syncytial virus group A in recurrent epidemics in coastal Kenya. PMID- 28845263 TI - A40 Persistent circulation of highly divergent HIV-1M lineages in the Congo Basin Region. PMID- 28845264 TI - A34 Automated profiling of the human virome from raw metagenomic data. PMID- 28845265 TI - A11 Phylogenetic and phylogeographic analysis of viral surveillance data to inform rabies control programmes in Cambodia. PMID- 28845266 TI - A15 Rapid radiation of treponema pallidum pertenue in wild non-human primates. PMID- 28845267 TI - A8 The epidemiology and evolution of influenza A/H1N1 and A/H3N2 virus from 2010 to 2015, in Ho Chi Minh City, Vietnam. PMID- 28845268 TI - A2 HIV transmission networks among injection drug users in Pakistan. PMID- 28845269 TI - A50 The emergence of G8P[8] rotavirus group A across Vietnam. PMID- 28845270 TI - A26 Transmission patterns and evolution of RSV in a community outbreak identified by genomic analysis. PMID- 28845271 TI - A3 Genetic analysis and natural polymorphisms in HIV-1 gp41 isolates from Maputo, Mozambique. PMID- 28845272 TI - A23 Identification of HIV drug resistance mutation patterns using illumina MiSeq next generation sequencing in patients failing second-line boosted protease inhibitor therapy in Nigeria. PMID- 28845273 TI - A13 HIV drug resistance over a decade of antiretroviral therapy scale-up for HIV/AIDS patients in Vietnam. PMID- 28845275 TI - A33 The cervico-vaginale microbiota in chlamydia trachomtais notified women: a case-control study at the sexually transmitted infection outpatient clinic in Amsterdam. PMID- 28845274 TI - A21 HIV-1 sub-subtype F1 outbreak among MSM in Belgium. PMID- 28845276 TI - A36 Prevalence of HIV-1 subtypes in Slovenia with an emphasis on molecular and phylogenetic investigation of subtype A. PMID- 28845277 TI - A38 Diversity analyses of HIV-1 envelope glycoproteins in HIV-infected individuals with and without broadly neutralizing antibodies. PMID- 28845278 TI - A24 Application of large-scale sequencing and data analysis to research on emerging infectious diseases. PMID- 28845279 TI - A28 Frequent co-infection among human group a rotaviruses in Thailand. PMID- 28845280 TI - A48 Inference of biological functionality in individual genomic secondary structural elements found within capulavirus genomes. PMID- 28845281 TI - A7 Evolution of influenza A(H7N9) viruses from waves I to IV. PMID- 28845282 TI - A6 Persistence and transmission of H7N9 influenza virus in Guangdong, China 2013 2015: implications for live poultry market intervention. PMID- 28845283 TI - A32 Search for viral integration insertion sites into the human genome-strategy matters. PMID- 28845284 TI - A41 Diversity and evolution of avian influenza (AI) viruses in poultry and wild birds. PMID- 28845285 TI - A18 Random amplification with next-generation sequencing to cover HIV and HCV full-length genomes. PMID- 28845286 TI - A27 Using whole genome sequence data and minority variant profiles to elucidate transmission patterns during RSV household outbreaks. PMID- 28845287 TI - A51 Dengue virus multi-strain models as hypotheses for serotype interaction. PMID- 28845288 TI - A9 Deep sequencing analysis to investigate the importance of within host genetic diversity and evolution of influenza A viruses for the development of resistance against neuraminidase inhibitors. PMID- 28845289 TI - A4 The transmission dynamics over ten years of human immunodeficiency virus type 1 in Vietnam. PMID- 28845290 TI - A17 Molecular characteristics of hepatitis B virus (HBV) isolated from chronic hepatitis B patients in South Vietnam. PMID- 28845291 TI - A47 Origin and possible genetic recombination of the middle east respiratory syndrome coronavirus from the first imported case in china: phylogenetics and coalescence analysis. PMID- 28845292 TI - A1 Signature pattern and phylogenetic analysis of full-length env genes in 20 hemophiliacs infected with Korean subclade of HIV-1 subtype B. PMID- 28845293 TI - Erratum: iPS-derived MSCs from an expandable bank to deliver a prodrug-converting enzyme that limits growth and metastases of human breast cancers. AB - [This corrects the article DOI: 10.1038/cddiscovery.2016.64.]. PMID- 28845294 TI - Erratum: MicroRNA-122 ameliorates corneal allograft rejection through the downregulation of its target CPEB1. AB - [This corrects the article DOI: 10.1038/cddiscovery.2017.21.]. PMID- 28845295 TI - Apoptotic resistance of human skin mast cells is mediated by Mcl-1. AB - Mast cells (MCs) are major effector cells of allergic reactions and contribute to multiple other pathophysiological processes. MCs are long-lived in the tissue microenvironment, in which they matured, but it remains ill-defined how longevity is established by the natural habitat, as research on human MCs chiefly employs cells generated and expanded in culture. In this study, we report that naturally differentiated skin MCs exhibit substantial resilience to cell death with considerable portions surviving up to 3 days in the complete absence of growth factors (GF). This was evidenced by kinetic resolution of membrane alterations (Annexin-V, YoPro), DNA degradation (propidium iodide), mitochondrial membrane disruption (Depsipher), and Caspase-3 activity. Because of the high basal survival, further protection by SCF was modest. Conversely, survival was severely compromised by staurosporine, implying functional caspase machinery. Contrary to the resistance of freshly purified MCs, their culture-expanded counterpart readily underwent cell death upon GF deprivation. Searching for the molecular underpinnings explaining the difference, we identified Mcl-1 as a critical protector. In fact, silencing Mcl-1 by RNAi led to impaired survival in skin MCs ex vivo, but not their cultured equivalent. Therefore, MCs matured in the skin have not only higher expression of Mcl-1 than proliferating MCs, but also greater reliance on Mcl-1 for their survival. Collectively, we report that human skin MCs display low susceptibility to cell death through vast expression of Mcl-1, which protects from mortality and may contribute to MC longevity in the tissue. PMID- 28845296 TI - Tumor cell senescence response produces aggressive variants. AB - Tumors often respond favorably to initial chemotherapy but eventually relapse with drug resistance and increased metastatic potential. Cellular senescence is a major therapeutic outcome of cancer chemotherapy, which leads to tumor stasis or regression through immune clearance of senescent cells. However, senescent tumor cells have been shown to resume proliferation at low frequency. We found that subjecting arrested senescent tumor cells to cytotoxic treatments stimulates the clonogenic proliferation of remaining survivors. The senescence revertants showed a reduced rate of proliferation but increased migration and invasion potential in vitro, and increased tumorigenic potential in vivo. Gene expression profiling showed that the senescence revertants are distinct from both parental and senescent cells. A subset of senescence-activated genes remains active in the revertants. These genes are implicated in regulating cell motility, invasion, and metastasis, which may collectively contribute to the aggressiveness of the revertants. The findings suggest that although therapy-induced senescence has short-term benefits, the response also causes reprogramming of gene expression and activates invasion-related genes that accelerate tumor progression. PMID- 28845297 TI - Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin. AB - Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and no therapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for hemorrhagic stroke. ROCKs, which belong to the serine/threonine protein kinase family and participate in the organization of actin cytoskeleton, have become attractive targets for the treatment of strokes. In this study, in vitro enzyme-based assays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibit ROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1, and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions. Furthermore, FPND significantly prevented statin-induced cerebral hemorrhage in a zebrafish model. In addition, in vitro studies using the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented statin-induced cerebral hemorrhage by enhancing endothelial cell cell junctions through inhibiting the ROCK-mediated VE-cadherin signaling pathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrity loss-related diseases, such as hemorrhagic stroke. PMID- 28845298 TI - Amyloid single-cell cytotoxicity assays by nanomotion detection. AB - Cells are extremely complex systems able to actively modify their metabolism and behavior in response to environmental conditions and stimuli such as pathogenic agents or drugs. The comprehension of these responses is central to understand the molecular bases of human pathologies, including amyloid misfolding diseases. Conventional bulk biological assays are limited by intrinsic cellular heterogeneity in gene, protein and metabolite expression, and can investigate only indirectly cellular reactions in non-physiological conditions. Here we employ a label-free nanomotion sensor to study single neuroblastoma cells exposed to extracellular monomeric and amyloid alpha-synuclein species in real-time and in physiological conditions. Combining this technique with fluorescence microscopy, we demonstrate multispecies cooperative cytotoxic effect of amyloids and aggregate-induced loss of cellular membrane integrity. Notably, the method can study cellular reactions and cytotoxicity an order of magnitude faster, and using 100-fold smaller volume of reagents when compared to conventional bulk analyses. This rapidity and sensitivity will allow testing novel pharmacological approaches to stop or delay a wide range of human diseases. PMID- 28845299 TI - Enriched housing promotes post-stroke functional recovery through astrocytic HMGB1-IL-6-mediated angiogenesis. AB - Enriched environment (EE) is shown to promote angiogenesis, neurogenesis and functional recovery after ischemic stroke. However, the underlying mechanisms remain unclear. C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion, after which mice were housed in either standard environment (SE) or EE. Here we found that post-ischemic EE exhibited decreased depression and anxiety-like behavior, and promoted angiogenesis and functional recovery compared to SE mice. EE mice treated with high-mobility group box-1 (HMGB1) inhibitor glycyrrhizin had an increased post-stroke depression and anxiety-like behavior, and the angiogenesis and functional recovery were decreased. HMGB1 and interleukin-6 (IL-6) expression in astrocyte were increased in EE mice. EE mice treated with glycyrrhizin decreased, whereas EE mice treated with recombinant HMGB1 (rHMGB1) increased the levels of IL-6 and p-AKT. Blockade of IL-6 with anti-IL-6-neutralizing antibody in EE mice attenuated EE-mediated angiogenesis and functional recovery. Furthermore, our in vitro data revealed that in primary astrocyte cultures rHMGB1 promoted the expression of IL-6 in activated astrocytes. PI3K/AKT signaling pathway was involved in HMGB1-mediated expression of astrocytic IL-6. Thus, our results reveal a previously uncharacterized property of HMGB1/IL-6 signaling pathway in EE-mediated angiogenesis and functional recovery after ischemic stroke. PMID- 28845300 TI - Perceptions of women's HIV risk and partner HIV risk behaviors in substance using women with criminal justice involvement. AB - This article explores the perceptions of STI/HIV risk based on engagement in risk behaviors in a sample of women with substance use disorders and criminal justice involvement. We examined variables associated with higher risk of contracting STI/HIV: having more than one current sex partner, injecting drugs, and trading sex. We also examined risk variables associated with intimate relationships: whether a partner had ever been in prison, injected drugs, or shared needles. Findings reveal that certain high-risk behaviors influenced participant perceptions of HIV risk: having more than one current sex partner, having a partner who injected drugs, having a partner who had sex with a man, or having a partner who had been tested for HIV. Participants who were uncertain about whether a partner had engaged in risk behaviors had significantly higher worry and perceptions of HIV risk than participants who were certain of partners' risk behaviors. The implications of these findings for tailoring effective interventions for high-risk women are addressed. PMID- 28845301 TI - Limited evidence that the presence of a bone bruise alone affects the clinical outcome of surgically reconstructed anterior cruciate ligaments: a systematic review. AB - IMPORTANCE: Anterior cruciate ligament (ACL) injury can be a devastating injury that without surgery may lead to chronic instability. Although surgical reconstruction recreates the stabilising constraint of the native ACL, postoperative pain and subsequent arthrosis may follow. OBJECTIVES: The primary objective of this systematic review is to determine whether the presence of a bone bruise following ACL rupture adversely affects the clinical outcomes following surgical reconstruction. EVIDENCE REVIEW: A standardised research protocol was used as outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Studies included for review were those of high level of evidence (I or II) and had MRI data on the presence of bone bruise and clinical outcome measures in patients who underwent surgical reconstruction of the ACL after traumatic rupture. Articles were searched using PubMed/ Medline, Cochrane Library, CINAHL and EMBASE databases using a keyword search. Article references and conference proceedings were subsequently reviewed on identification of articles found via the keyword search. Non-English literature, animal and basic science studies, studies focused on the skeletally immature and low level of evidence (III, IV, V) were excluded. A quantitative analysis of the data retrieved was summarised. FINDINGS: Five studies met the inclusion criteria. Follow-up ranged from the time of surgical reconstruction to 165 months. Although a variety of clinical outcome measures were used across studies, bone bruise cohorts did not demonstrate clinically inferior outcome scores. CONCLUSIONS AND RELEVANCE: Although osteochondral injury is frequently identified following ACL injury, the presence of a bone bruise alone does not appear to significantly adversely affect the clinical outcome of surgically reconstructed ACLs. However, factors such as articular cartilage injury and alteration in joint loading may be important variables for further research. LEVEL OF EVIDENCE: IV. PMID- 28845302 TI - MDplot: Visualise Molecular Dynamics. AB - : The MDplot package provides plotting functions to allow for automated visualisation of molecular dynamics simulation output. It is especially useful in cases where the plot generation is rather tedious due to complex file formats or when a large number of plots are generated. The graphs that are supported range from those which are standard, such as RMsD/RMsF (root-mean-square deviation and root-mean-square fluctuation, respectively) to less standard, such as thermodynamic integration analysis and hydrogen bond monitoring over time. All told, they address many commonly used analyses. In this article, we set out the MDplot package's functions, give examples of the function calls, and show the associated plots. Plotting and data parsing is separated in all cases, i.e. the respective functions can be used independently. Thus, data manipulation and the integration of additional file formats is fairly easy. Currently, the loading functions support GROMOS, GROMACS, and AMBER file formats. Moreover, we also provide a Bash interface that allows simple embedding of MDplot into Bash scripts as the final analysis step. AVAILABILITY: The package can be obtained in the latest major version from CRAN (https://cran.r-project.org/package=MDplot) or in the most recent version from the project's GitHub page at https://github.com/MDplot/MDplot, where feedback is also most welcome. MDplot is published under the GPL-3 license. PMID- 28845303 TI - Use of 5-Fluorouracil-Soaked Bioamniotic Membranes in Trabeculectomy for Primary Open-Angle Glaucoma: A Retrospective Analysis. AB - The study is a retrospective analysis of 51 patients (76 eyes) with primary open angle glaucoma (POAG) who admitted to our hospital from 2008 to 2010 to analyze the efficacy of trabeculectomy in combination with 5-fluorouracil- (5-FU-) soaked amniotic membranes for the treatment of POAG patients. Among them, 30 patients (41 eyes) were treated with trabeculectomy in combination with 5-FU-soaked amniotic membrane and 21 patients (35 eyes) were treated with trabeculectomy in combination with MMC. Preoperative and postoperative intraocular pressures (IOP), cup/disc ratio, visual acuity and postoperative macular OCT, complications, treatment, and number of corneal endothelial cells were measured, recorded, and analyzed. At the end of 2 years of follow-up, IOP of 36 (87.8%) eyes of patients in the 5-FU group and IOP of 28 (80%) eyes of patients in the MMC group were <=21 mmHg and patients in the 5-FU group had more stable IOP than patients in the MMC group. During the two years of follow-up, the visual acuity of 22 (53.7%) eyes in the 5-FU group remained unchanged or even improved. Trabeculectomy in combination with 5-FU-soaked biological amniotic membranes can be a surgical option for POAG patients. PMID- 28845304 TI - Double Internal Limiting Membrane Insertion for Macular Hole-Associated Retinal Detachment. AB - PURPOSE: To describe a modified technique of internal limiting membrane (ILM) insertion for macular hole- (MH-) associated retinal detachment (RD) in highly myopic eyes. METHODS: Nine eyes underwent pars plana vitrectomy, cortical vitreous removal, and fovea-sparing ILM peeling. Double ILM insertion into the hole was performed with inverted perifoveal ILM and a free ILM flap followed by air-fluid exchange. RESULTS: Two of the 9 eyes had perifoveal ILM partially torn after cortical vitreous or epiretinal removal. All eyes had the ILM plug stabilized within the MH after double ILM insertion. Postoperatively, MH was sealed with the retina reattached in all the eyes. CONCLUSION: Double ILM insertion may further secure the ILM flap in place in the eyes with MH-associated RD, especially in cases in which insufficient perifoveal ILM was left. This trial is registered with the clinical registration number Clinicaltrials.gov NCT03174639. PMID- 28845305 TI - Optical Coherence Tomography Observation of Gonio Structures during Microhook Ab Interno Trabeculotomy. AB - INTRODUCTION: Intraoperative observation of ocular structures using microscope integrated optical coherence tomography (iOCT) has been adopted recently. I report my initial feasibility assessment of iOCT for the incised trabecular meshwork observation during microhook ab interno trabeculotomy. CASE SERIES: Both the nasal and temporal sides or either side of the trabecular meshwork/inner wall of Schlemm's canal was incised more than 3 clock hours. After then, under observation using a Swan-Jacob gonioprism lens with the real-time 5-line scan mode, OCT images of the area were successfully acquired in 10 (83%) of 12 sides in nine eyes. Based on the appearance of the acquired images of the 10 sides, the trabeculotomy cleft could be classified into three incisional patterns, that is, six (60%) anterior-opening patterns (posterior-based flap), three (30%) middle opening patterns (posterior- and anterior-based flaps), and one (10%) posterior opening pattern (anterior-based flap), according to the predominant locations of the trabecular meshwork flaps. CONCLUSION: Intraoperative observation of the gonio structures including the trabeculotomy cleft was feasible using the RESCAN 700 in combination with a gonioprism. PMID- 28845306 TI - TB Notification from Private Health Sector in Delhi, India: Challenges Encountered by Programme Personnel and Private Health Care Providers. AB - OBJECTIVE: To identify the challenges encountered by private health care providers (PHCP) to notify tuberculosis cases through a programme developed web based portal mechanism called "NIKSHAY." Study Design. It is a descriptive qualitative study conducted at two revised national tuberculosis control programme (RNTCP) districts of New Delhi. The study included in-depth interviews of PHCP registered with "NIKSHAY" and RNTCP programme personnel. Grounded theory was used to conceptualise the latent social patterns in implementation of tuberculosis case notification process and promptly identifying their challenges. RESULTS: The analysis resulted in identification of three broad themes: (a) system implementation by RNTCP: it emphasizes the TB notification process by the RNTCP programme personnel; (b) challenges faced by PHCP for TB notification with five different subthemes; and (c) perceived gaps and suggestions: to improvise the TB notification process for the private health sector. The challenges encountered by PHCP were mainly related to unsystematic planning and suboptimal implementation by programme personnel at the state and district level. The PHCP lacked clarity on the need for TB notification. CONCLUSION: Implementation of TB notification among private health care providers requires systematic planning by the programme personnel. The process should be user-friendly with additional benefits to the patients. PMID- 28845307 TI - A Hypothalamic Leptin-Glutamate Interaction in the Regulation of Sympathetic Nerve Activity. AB - Accumulated evidence indicates that obesity-induced type 2 diabetes (T2D) is associated with enhanced sympathetic activation. The present study was conducted to investigate the role for leptin-glutamate signaling within the hypothalamus in regulating sympathetic nerve activity. In anesthetized rats, microinjections of leptin (5 ng ~ 100 ng) into the arcuate nucleus (ARCN) and paraventricular nucleus (PVN) induced increases in renal sympathetic nerve activity (RSNA), blood pressure (BP), and heart rate (HR). Prior microinjections of NMDA receptor antagonist AP5 (16 pmol) into the ARCN or PVN reduced leptin-induced increases in RSNA, BP, and HR in both ARCN and PVN. Knockdown of a leptin receptor with siRNA inhibited NMDA-induced increases in RSNA, BP, and HR in the ARCN but not in the PVN. Confocal calcium imaging in the neuronal NG108 and astrocytic C6 cells demonstrated that preincubation with leptin induced an increase in intracellular calcium green fluorescence when the cells were challenged with glutamate. In high fat diet and low-dose streptozotocin-induced T2D rats, we found that leptin receptor and NMDA NR1 receptor expressions in the ARCN and PVN were significantly increased. In conclusion, these studies provide evidence that within the hypothalamic nuclei, leptin-glutamate signaling regulates the sympathetic activation. This may contribute to the sympathoexcitation commonly observed in obesity-related T2D. PMID- 28845308 TI - The Temporal Pattern of a Lesion Modulates the Functional Network Topology of Remote Brain Regions. AB - Focal brain lesions can alter the morphology and function of remote brain areas. When the damage is inflicted more slowly, the functional compensation by and structural reshaping of these areas seem to be more effective. It remains unclear, however, whether the momentum of lesion development also modulates the functional network topology of the remote brain areas. In this study, we compared resting-state functional connectivity data of patients with a slowly growing low grade glioma (LGG) with that of patients with a faster-growing high-grade glioma (HGG). Using graph theory, we examined whether the tumour growth velocity modulated the functional network topology of remote areas, more specifically of the hemisphere contralateral to the lesion. We observed that the contralesional network topology characteristics differed between patient groups. Based only on the connectivity of the hemisphere contralateral to the lesion, patients could be classified in the correct tumour-grade group with 70% accuracy. Additionally, LGG patients showed smaller contralesional intramodular connectivity, smaller contralesional ratio between intra- and intermodular connectivity, and larger contralesional intermodular connectivity than HGG patients. These results suggest that, in the hemisphere contralateral to the lesion, there is a lower capacity for local, specialized information processing coupled to a higher capacity for distributed information processing in LGG patients. These results underline the utility of a network perspective in evaluating effects of focal brain injury. PMID- 28845309 TI - White Matter Hyperintensity Load Modulates Brain Morphometry and Brain Connectivity in Healthy Adults: A Neuroplastic Mechanism? AB - White matter hyperintensities (WMHs) are acquired lesions that accumulate and disrupt neuron-to-neuron connectivity. We tested the associations between WMH load and (1) regional grey matter volumes and (2) functional connectivity of resting-state networks, in a sample of 51 healthy adults. Specifically, we focused on the positive associations (more damage, more volume/connectivity) to investigate a potential route of adaptive plasticity. WMHs were quantified with an automated procedure. Voxel-based morphometry was carried out to model grey matter. An independent component analysis was run to extract the anterior and posterior default-mode network, the salience network, the left and right frontoparietal networks, and the visual network. Each model was corrected for age, global levels of atrophy, and indices of brain and cognitive reserve. Positive associations were found with morphometry and functional connectivity of the anterior default-mode network and salience network. Within the anterior default-mode network, an association was found in the left mediotemporal-limbic complex. Within the salience network, an association was found in the right parietal cortex. The findings support the suggestion that, even in the absence of overt disease, the brain actuates a compensatory (neuroplastic) response to the accumulation of WMH, leading to increases in regional grey matter and modified functional connectivity. PMID- 28845310 TI - Developmental Changes in Sleep Oscillations during Early Childhood. AB - Although quantitative analysis of the sleep electroencephalogram (EEG) has uncovered important aspects of brain activity during sleep in adolescents and adults, similar findings from preschool-age children remain scarce. This study utilized our time-frequency method to examine sleep oscillations as characteristic features of human sleep EEG. Data were collected from a longitudinal sample of young children (n = 8; 3 males) at ages 2, 3, and 5 years. Following sleep stage scoring, we detected and characterized oscillatory events across age and examined how their features corresponded to spectral changes in the sleep EEG. Results indicated a developmental decrease in the incidence of delta and theta oscillations. Spindle oscillations, however, were almost absent at 2 years but pronounced at 5 years. All oscillatory event changes were stronger during light sleep than slow-wave sleep. Large interindividual differences in sleep oscillations and their characteristics (e.g., "ultrafast" spindle-like oscillations, theta oscillation incidence/frequency) also existed. Changes in delta and spindle oscillations across early childhood may indicate early maturation of the thalamocortical system. Our analytic approach holds promise for revealing novel types of sleep oscillatory events that are specific to periods of rapid normal development across the lifespan and during other times of aberrant changes in neurobehavioral function. PMID- 28845312 TI - Symptomatic Long Pauses and Bradycardia due to Massive Multinodular Goiter. AB - Sinus node dysfunction with symptomatic bradycardia or chronotropic incompetence is generally an indication for pacemaker implantation. However, in patients with symptomatic sinus bradycardia, the identification and treatment of underlying pathologies may avoid the need for permanent pacemaker implantation. We present a case of carotid sinus syndrome and severe obstructive sleep apnea due to a massive multinodular goiter in a patient who presented with recurrent sinus pauses and syncope. The patient was managed without pacemaker implantation but instead with thyroidectomy resulting in decompression of the carotid sinus and airway and resolution of bradycardic episodes. PMID- 28845313 TI - Cobalt Cardiomyopathy Secondary to Hip Arthroplasty: An Increasingly Prevalent Problem. AB - A forty-year-old man experienced worsening heart failure four years following bilateral complicated total hip replacement. His condition was extensively worked up but no underlying pathology was immediately evident. Given the cobalt-chromium alloy component present in the hip arthroplasties, the raised cobalt blood levels, and a fitting clinical picture coupled with radiological findings, the patient underwent right hip revision. Evidence of biotribocorrosion was present on direct visualisation intraoperatively. The patient subsequently experienced symptomatic improvement (NYHA class III to class I) and echocardiography showed recovery of ejection fraction. Cobalt exists as a bivalent and trivalent molecule in circulation and produces a cytotoxicity profile similar to nanoparticles, causing neurological, thyroid, and cardiological pathology. Blood levels are not entirely useful as there is no identifiable conversion factor for levels in whole blood, serum, and erythrocytes which seem to act independently of each other. Interestingly cobalt cardiomyopathy is frequently compounded by other possible causes of cardiomyopathy such as alcohol and a link has been postulated. Definitive treatment is revision of the arthroplasty as other treatments are unproven. PMID- 28845311 TI - Modulation of Central Synapses by Astrocyte-Released ATP and Postsynaptic P2X Receptors. AB - Communication between neuronal and glial cells is important for neural plasticity. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. Recent data show that postsynaptic P2X receptors underlie slow neuromodulatory actions rather than fast synaptic transmission at brain synapses. Here, we review these findings with a particular focus on the release of ATP by astrocytes and the diversity of postsynaptic P2X-mediated modulation of synaptic strength and plasticity in the CNS. PMID- 28845314 TI - Alveolar Soft Part Sarcoma with Unusual Cardiac Metastasis: A Case Report and Review of the Literature. AB - Alveolar soft part sarcoma is a very uncommon soft tissue malignancy which accounts for <1% of soft tissue sarcoma. It is a malignant and highly vascular tumor arising most commonly in the musculature of the lower extremities, with metastasis primarily to the lungs, bones, and brain. Cardiac metastasis is very rare and only 5 cases have been reported in the literature so far. We report a case of a young woman with a history of surgically resected alveolar soft part sarcoma of left thigh who presented with persistent dry cough and was found to have a cardiac mass, which on biopsy proved to be alveolar soft part sarcoma. PMID- 28845315 TI - Neuropsychological Outcome following Resuscitation after Out-of-Hospital Cardiac Arrest: A One-Year Follow-Up. AB - A 61-year-old woman survived resuscitation after out-of-hospital cardiac arrest. The heterogeneity of the resulting cognitive impairments and the recovery over a one-year period are presented, highlighting the need for standardized neuropsychological testing even after short cardiac arrests and for effective treatment both out of hospital and in hospital. PMID- 28845316 TI - Acute Heart Failure Exacerbation with Cardiogenic Shock and Elevated Systemic Vascular Resistance Treated with a Combination of Nicardipine and Dobutamine Therapy. AB - Acute heart failure is a common reason for hospital admission and is usually caused by decreased cardiac output either as a result of an intrinsic cardiac issue or as a result of severe hypertension with elevated afterload. We present a patient with a history of HFrEF who presented with acute heart failure, found to have hypotension requiring Dobutamine support and an elevated systemic vascular resistance requiring Nicardipine drip, with subsequent recovery of cardiac function. PMID- 28845317 TI - Arterial Thoracic Outlet Syndrome Treated Successfully with Totally Endoscopic First Rib Resection. AB - Thoracic outlet syndrome (TOS) is a constellation of signs and symptoms caused by compression of the neurovascular structures in the thoracic outlet. TOS may be classified as either neurogenic TOS (NTOS) or vascular TOS: venous TOS (VTOS) or arterial TOS (ATOS), depending on the specific structure being affected. The basis for the surgical treatment of TOS is resection of the first rib, and it may be combined with scalenectomy or cervical rib resection. Herein, we describe a case of arterial thoracic outlet syndrome which was successfully treated with totally endoscopic video-assisted thoracoscopic surgery (VATS) first rib resection. PMID- 28845318 TI - Angiosarcoma Developing in an Arteriovenous Fistula after Kidney Transplantation. AB - After transplantation, the main concerns involve immunosuppression, the prevention and treatment of infections and graft rejection, and tumor prevention. Sometimes the complications that may appear in the arteriovenous fistula are neglected following kidney transplantation. This is the reason why we are presenting the case of an angiosarcoma developing in an arteriovenous fistula after kidney transplantation. It is a very rare case and our goal is to create an alarm so that after kidney transplantation clinicians do not lose sight of the patients' previous history. PMID- 28845319 TI - Diagnostic Lessons from a Complex Case of Postintestinal Transplantation Enteropathy. AB - Recent advances in the field of intestinal transplantation have been mitigated by the incidence of allograft rejection. In such events, early identification and appropriate timing of antirejection therapy are crucial in retaining graft function. We present the case of a patient who suffered severe postintestinal transplantation allograft enteropathy, primarily characterized by extensive mucosal ulcerations, and was refractory to all conventional therapy. This progressed as chronic rejection; however crucially this was not definitively diagnosed until allograft function had irreversibly diminished. We argue that the difficulties encountered in this case can be attributed to the inability of our current array of investigative studies and diagnostic guidelines to provide adequate clinical guidance. This case illustrates the importance of developing reliable and specific markers for guiding the diagnosis of rejection and the use of antirejection therapeutics in this rapidly evolving field of transplant surgery. PMID- 28845320 TI - Transactional Sex between Men and Its Implications on HIV and Sexually Transmitted Infections in Nigeria. AB - INTRODUCTION: Men who have transactional sex with men (MTSM) are known to be at higher risk for HIV and sexually transmitted infections (STIs). This study explored the risk factors associated with STI symptoms and HIV prevalence among men who have transactional sex with men in Nigeria. METHODS: In 2014, a cross sectional study, using respondent driven sampling technique, was carried out to recruit 3,172 MSM across eight states in Nigeria. Relevant information on sociodemographic characteristics, sexual behaviors, and self-reported symptoms of STI was obtained. Bivariate and multivariate analysis was performed to identify risk factors for STI symptoms and HIV. RESULTS: 38.2% of the MSM were involved in transactional sex. Prevalence of self-reported STI symptoms was higher among MTSM than other MSM, while HIV prevalence was higher among other MSM than MTSM. Identified factors associated with STI symptoms and HIV among MSTM were being single, alcohol consumption, oral sex, and history of rape by a male partner. CONCLUSION: Sexually transmitted infections are a significant challenge to men who have transactional sex with men. Adolescents and single men are more at risk of these infections. Youth empowerment needs to be invested on to avoid increased risk among these groups of people. PMID- 28845321 TI - Evaluation of Anterior Segment Changes of Patients Taking Alpha1-Blockers by Ultrasound Biomicroscopy in the Drug-free Period. AB - OBJECTIVES: To evaluate and compare anterior segment changes in patients taking alpha-1 (alpha1) blockers (tamsulosin, terazosin, doxazosin, alfuzosin) for benign prostatic hypertrophy, during drug intake and drug-free period, using ultrasound biomicroscopy (UBM). MATERIALS AND METHODS: In this prospective study, UBM was done before and after pupil dilatation in 31 phakic eyes of 19 male patients taking alpha1-blockers. Undilated and dilated UBM was repeated before cataract extraction, after stopping the drug for 10 days. On ideal images, pupil diameter (PD), anterior chamber depth (ACD), anterior chamber angle (ACA), and angle opening distances at points 500 um and 250 um from the scleral spur (AOD500 and AOD250) values were noted and changes in parameters were evaluated to reveal any changes that occurred after discontinuing the drug. No patient in the study was previously or currently using any other alpha1-adrenergic antagonist medication. Exclusion criteria for all patients included a history of diabetes mellitus, systemic hypertension, glaucoma, pseudoexfoliation syndrome, chronic use of medicated eye drops, and previous ocular surgery. RESULTS: PD, ACD, ACA, AOD500 and AOD250 values measured before pupil dilatation in the drug-free period were not significantly different from those measured during alpha-blocker intake (p>0.05). In dilated eyes, the mean value of AOD500 was 0.35+/-0.08 mm during drug usage and 0.39+/-0.08 mm in the drug-free period. The mean value of AOD250 was 0.23+/-0.06 mm during drug usage and 0.26+/-0.07 mm after discontinuation. These increments were statistically significant (p<0.05, z=-3.699, z=-2.984). On the other hand, there were no significant differences in ACD, ACA, or PD values in dilated eyes after discontinuing alpha1-blockers (p>0.05). CONCLUSION: The interruption of taking alpha1-blockers in patients who have benign prostatic hypertrophy does not seem to influence anterior segment parameters generally. However, further investigation is needed. PMID- 28845322 TI - Intraocular Pressure and Retinal Nerve Fibre Layer Thickness Changes After Carotid Artery Stenting. AB - OBJECTIVES: The aim of this study was to evaluate intraocular pressure (IOP) and retinal nerve fiber layer (RNFL) changes in patients with carotid artery stenosis (CAS) after carotid artery stenting. MATERIALS AND METHODS: This study was conducted as a cross-sectional, non-randomised clinical case series. Fifteen male patients (mean age: 63.6+/-9.1) with CAS and more than 70% carotid artery narrowing were included. All of the patients were followed in the department of neurology and were operated in the interventional radiology division. Eighteen healthy male subjects (mean age: 63.7+/-5.3) were included in the control group. All of the healthy subjects had a detailed ophthalmological examination and subjects with any chronic eye disease were excluded from the study. All of the participants had a detailed ophthalmological examination including tonometry using Goldmann applanation tonometry and RNFL analysis using optical coherence tomography (RTVue-100 5.1). RESULTS: There were no ocular ischemic symptoms in any of the participants. The mean IOP value was 15.1+/-2.1 mmHg in the control group and 16.6+/-2.4 mmHg before stent implantation, 16.4+/-2.2 mmHg at 1 week after implantation, 16.6+/-2.5 mmHg at 1 month after implantation, and 16.7+/-2.9 mmHg at 3 months after implantation in the CAS group. Mean RNFL thickness was 105+/-6 um in the control group; in the CAS group, mean RNFL thickness values were 98+/-27 um before stent implantation and 103+/-11 um, 101+/-10 um, and 101+/ 11 um at 1 week, 1 month, and 3 months after stenting. There were no significant differences between the CAS group and control group regarding IOP and RNFL thickness values (p>0.05). IOP and RNFL thickness also did not show any statistically significant changes from preoperative measurements in 3 months postoperative follow-up in the CAS group (p>0.05). CONCLUSION: IOP and RNFL thickness remained unchanged after carotid stent implantation in carotid artery stenosis patients with no signs of ocular ischemic syndrome. PMID- 28845323 TI - Selective Laser Trabeculoplasty vs. Fixed Combinations with Timolol in Practice: A Replacement Study in Primary Open Angle Glaucoma. AB - OBJECTIVES: To evaluate the potential of selective laser trabeculoplasty (SLT) in two arms (360 vs. 180) as a replacement for fixed combinations (FCs) with timolol in primary open angle glaucoma over 6 months. MATERIALS AND METHODS: Of 40 patients in a prospective, comparative, interventional case series, 18 eyes and 22 eyes were randomized to SLT 180o and SLT 360o groups, respectively, along with 40 fellow-control eyes. FC with timolol was discontinued on the day of treatment for the eye to be operated on, while ongoing therapy was not interrupted for the contralateral eye. Eyes were examined for intraocular pressure (IOP) elevation 1 hour and 1 day after SLT. The follow-up visits were then scheduled for 1 week, 1 month, 3 months, and 6 months after, during the which the IOP of both eyes and any possible complications were evaluated. RESULTS: There were no statistically significant differences in mean IOPs through 6 months among the groups with exception of postlaser 1 hour and postlaser 1 day (p<0.001 and p=0.010, respectively). Multiple comparison analysis showed significantly higher IOP in both SLT 180o and SLT 360o subgroups compared to their controls at postlaser 1 hour (p=0.007, p<0.001) but significantly lower IOP only in SLT 360o subgroup compared to the controls at postlaser day 1 (p=0.013). CONCLUSION: SLT offers promising potential as a substitute equivalent to efficacy of FCs with timolol. However, SLT 360 may not achieve additional IOP reduction. PMID- 28845324 TI - Factors Affecting Compliance to Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in Patients with Age-Related Macular Degeneration. AB - OBJECTIVES: To determine factors influencing compliance in patients with neovascular age-related macular degeneration (n-AMD) undergoing intravitreal anti vascular endothelial growth factor (VEGF) therapy. MATERIALS AND METHODS: The files of n-AMD patients recommended treatment with ranibizumab were reviewed retrospectively. The treatment regimen was 3 consecutive monthly injections followed by monthly follow-up with intravitreal injections as needed (pro re nata, PRN). Demographic and ocular characteristics were recorded. The patients were categorized into 2 groups: full compliance to treatment, or incomplete loading schedule and/or irregular maintenance treatment. All patients were interviewed by phone about factors affecting continuation of treatment. RESULTS: Mean age of the 314 patients (160 female, 154 male) included in the study was 71.6+/-9.1 years. A total of 246 patients (78.3%) could complete 3 consecutive injections at 1-month intervals after the start of treatment; 57 patients (18.2%) did not attend monthly follow-up during the 1-year follow-up period following the 3 consecutive monthly injections. Overall, 39.8% of the patients were not able to fully comply with the ranibizumab treatment by PRN regimen for 1 year. Better visual acuity at baseline, smaller lesion size, living closer to the hospital, higher education and sociocultural level, and better financial status were determined as factors affecting patient compliance. The most frequent reasons to discontinue treatment were fear of injection, disbelief in the benefit of the treatment, financial limitations, continuation of treatment at another center, and comorbid systemic diseases. CONCLUSION: Patient compliance and success rates of anti-VEGF therapy may be increased by determining the factors affecting patient compliance and raising awareness about n-AMD among patients and their relatives. PMID- 28845325 TI - Ocular Causes of Abnormal Head Position: Strabismus Clinic Data. AB - OBJECTIVES: To determine the most common ocular causes and types of abnormal head position (AHP) and describe their clinical features. MATERIALS AND METHODS: Patients with AHP who had been followed in the strabismus unit were retrospectively reviewed. Demographic features and orthoptic characteristics were recorded. RESULTS: A total of 163 patients including 61 women (37.4%) and 102 men (62.6%), with a mean age of 19.9+/-18.3 were recruited. The most common causes of AHP were determined as fourth cranial nerve palsy (33.7%), Duane retraction syndrome (21.5%), sixth cranial nerve palsy (11%), nystagmus blockage syndrome (9.8%) and Brown syndrome (6.7%). Other less frequent causes were A-V pattern strabismus, comitant strabismus, thyroid orbitopathy and third cranial nerve palsy. The most common types of AHP were head tilt (45.4%) and face turn (36.8%). Out of 142 patients whose visual acuity could be evaluated, 28.2% had amblyopia. The frequency of amblyopia varied depending on the diagnosis (p<0.001), while there was no relation between amblyopia and different types of AHP (p=0.497). Stereopsis and fusion could be tested in 128 patients and 43.8% of them had stereopsis and fusion. The presence of stereopsis and fusion was found to be related with the diagnosis (p=0.001), whereas it was not related with the types of AHP (p=0.580). The presence of amblyopia was not significantly associated with fusion (p=1.000) or stereopsis (p=0.602). CONCLUSION: There are many ocular pathologies that cause AHP. Patients with similar diagnoses may have different types of AHP. Patients may have amblyopia and impaired binocularity despite AHP. Therefore, all patients with AHP should be examined in detail and these points should be considered in the treatment plan. PMID- 28845326 TI - Results of Screening in Schools for Visually Impaired Children. AB - OBJECTIVES: The aim of this study was to identify the causes of visual impairment in children attending schools for students with visual impairment and to identify children suitable for treatment and rehabilitation. MATERIALS AND METHODS: All students were examined in our department by a pediatric ophthalmologist and an ophthalmologist experienced in low vision and visual rehabilitation. The children's medical histories were recorded. All children underwent ophthalmological examination including visual acuity measurement, anterior segment and dilated fundus evaluation, retinoscopy with cycloplegia, and intraocular pressure measurement. The causes of visual impairment were grouped as avoidable and unavoidable. Children with residual visual acuity better than 20/1250 were included in the low vision rehabilitation programme. RESULTS: A total of 120 patients were evaluated and 79.2% were legally blind (visual acuity less than 0.05), 18.4% had low vision (visual acuity between 0.05 and 0.3), and 0.8% had normal vision (>0.3). The main causes of visual impairment were retinal dystrophies (24.2%) and retinopathy of prematurity (17.5%). Of all diseases related to visual impairment, 27.6% were avoidable. Improvement in visual acuity was achieved with low vision aids in 57.5% of all patients. CONCLUSION: The incidence of visual impairment due to avoidable causes can be decreased by ophthalmic screening. Treatment of these children in the early stages of visual development can improve visual acuity. Even in cases with delayed diagnosis, low vision aids are important for visual and neurobehavioral development, and these programmes may improve quality of life and education in these children. PMID- 28845328 TI - Eyelid Molluscum Contagiosum Lesions in Two Patients with Unilateral Chronic Conjunctivitis. AB - Molluscum contagiosum (MC) is a viral infection of the skin and mucosal tissues characterized by skin-colored or transparent round nodules with a dimple or pit in the center. The infection is caused by a DNA poxvirus called the MC virus. Although MC generally occurs in children, it has also been reported in immunocompromised and atopic patients. The virus is transmitted by skin contact or sexual intercourse. The lesions disappear spontaneously within several months in most cases. However, excision, cryotherapy, cauterization, topical chemical and antiviral agents, and/or oral cimetidine are used in refractory cases or to accelerate the healing process. Herein, we discussed the clinical findings and our treatment of two patients with unilateral chronic conjunctivitis associated with eyelid MC lesions in light of the literature. PMID- 28845327 TI - Biocompatibility of Intraocular Lenses. AB - The performance of an intraocular lens is determined by several factors such as the surgical technique, surgical complications, intraocular lens biomaterial and design, and host reaction to the lens. The factor indicating the biocompatibility of an intraocular lens is the behavior of inflammatory and lens epithelial cells. Hence, the biocompatibility of intraocular lens materials is assessed in terms of uveal biocompatibility, based on the inflammatory foreign-body reaction of the eye against the implant, and in terms of capsular biocompatibility, determined by the relationship of the intraocular lens with residual lens epithelial cells within the capsular bag. Insufficient biocompatibility of intraocular lens materials may result in different clinical entities such as anterior capsule opacification, posterior capsule opacification, and lens epithelial cell ongrowth. Intraocular lenses are increasingly implanted much earlier in life in cases such as refractive lens exchange or pediatric intraocular lens implantation after congenital cataract surgery, and these lenses are expected to exhibit maximum performance for many decades. The materials used in intraocular lens manufacture should, therefore, ensure long-term uveal and capsular biocompatibility. In this article, we review the currently available materials used in the manufacture of intraocular lenses, especially with regard to their uveal and capsular biocompatibility, and discuss efforts to improve the biocompatibility of intraocular lenses. PMID- 28845329 TI - Evaluation of Iris Melanoma with Anterior Segment Optical Coherence Tomography. AB - Anterior segment optical coherence tomography (AS-OCT) is a relatively new imaging modality that allows assessment of anterior segment structures. AS-OCT enables the differentiation of benign and malignant tumors through the evaluation of lesion size, internal structure, degree of vascularity, and anterior and posterior surfaces. Herein, we discuss the AS-OCT findings of a patient with spindle type iridociliary melanoma diagnosed in pathologic examination. PMID- 28845330 TI - Mantle Cell Lymphoma Presenting with Acute Bilateral Ophthalmoplegia. AB - A 72-year-old woman presented with acute onset of double vision, bilateral complete blepharoptosis, and nearly complete ophthalmoplegia. Orbital and brain magnetic resonance imaging were normal. Further investigation revealed bicytopenia with hepatosplenomegaly. Liver biopsy revealed mantle cell lymphoma. Cytology later showed the presence of mantle cells in cerebrospinal fluid analysis. Her ophthalmoplegia improved from her first cycle of systemic and intrathecal chemotherapy. To the best of our knowledge, this is the second case in the literature of mantle cell lymphoma with central nervous system involvement presenting with ophthalmoplegia. This symptom should be considered one of the initial signs of mantle cell lymphoma. PMID- 28845331 TI - Atypical Central Serous Chorioretinopathy. AB - Bullous central serous chorioretinopathy (CSCR) is a rare variant of CSCR characterized by severe serous retinal detachment which especially involves the inferior quadrants. Corticosteroid therapy administered for systemic or ocular misdiagnoses may induce and exacerbate CSCR. The purpose of this study was to report diagnosis and treatment results of an unusual case of bullous CSCR induced by systemic and periocular corticosteroid therapy received at another medical center due to a misdiagnosis of Vogt-Koyanagi-Harada disease. PMID- 28845332 TI - Choroidal Osteoma and Secondary Choroidal Neovascularization Treated with Ranibizumab. AB - A 47-year-old female patient presented with a complaint of decreased vision in the right eye. Her visual acuity was 0.16 in the right eye and 1.0 in the left eye. Fundus examination revealed a slightly elevated, yellowish-white lesion with regular borders at the macula of the right eye. Early and late hyperfluorescence related with choroidal neovascularization (CNV) was detected in the right eye on fundus fluorescein angiography. B-scan ultrasonography revealed a hyperechoic choroidal lesion with acoustic shadowing. The lesion was diagnosed as choroidal osteoma. The patient received 3 injections of intravitreal ranibizumab. After 4 months, the visual acuity of the right eye was 0.9 and the CNV had regressed. Follow-up at about 7 months revealed reduced visual acuity in the right eye with an increase in subretinal fluid. An additional ranibizumab injection was administered. In this case report, we discuss the findings and treatment of a rare case of choroidal osteoma with secondary CNV. PMID- 28845333 TI - Pediatric Patients and Tonometers. PMID- 28845334 TI - Air Pollution in Major Chinese Cities: Some Progress, But Much More to Do. AB - BACKGROUND: Ambient (outdoor) air pollution has been implicated as a major cause of acute cardiovascular and pulmonary illnesses and increased risk for acute and chronic effects after chronic exposures, including mortality and morbidity. In 2008, due to persistent health concerns about its workforce and their dependents, the US Mission in China began monitoring air quality at the US Embassy in Beijing. Subsequently, monitoring stations were also established at US consulates at Shanghai (2011), Guangzhou (2011), Chengdu (2012), and Shenyang (2013). OBJECTIVES: To determine whether there have been definable trends in air quality in these five Chinese cities. METHODS: Air monitoring results from each locale for accumulated PM2.5 particulate matter were calculated hourly. Accumulated data were organized, culled using a standardized set of heuristics, and analyzed for trends. RESULTS: China's capital city, Beijing, experienced decreased PM2.5 from 2013 through 2015, but no significant long-term downward trend from 2008 through 2015. Shanghai has not shown any definable air quality trend since 2012. Chengdu experienced some improvement in air quality since 2013, but none discernible from 2012 through 2015. Guangzhou had generally better air quality, and a downward trend since 2012. Shenyang experienced increasingly severe air pollution from 2013 through 2015. CONCLUSION: There appear to have been recent tangible, though modest, improvements in air quality in three large Chinese cities: Beijing, Chengdu, and Guangzhou, but no apparent progress in Shanghai, and a worrisome decline in air quality observed in Shenyang. Despite recent progress, there is a long way to go before even the cities which show improvement reach Chinese standards. PMID- 28845335 TI - Congenital Syphilis Masquerading as Leukemia. AB - As of late, the incidence of congenital syphilis in the United States is increasing. Each new case represents a failure of preventing, diagnosing, and treating syphilis in pregnant women. Pediatricians should confirm that all women have received adequate screening for and management of syphilis during pregnancy. Congenital syphilis is easily treatable but may be a diagnostic challenge with high morbidity and mortality. PMID- 28845336 TI - Elimination of Cancer Health Disparities through the Acceleration of HPV Vaccines and Vaccinations: A Simplified Version of the President's Cancer Panel Report on HPV Vaccinations. AB - The human papillomavirus (HPV) is a major public health concern affecting both females and males. HPV is associated with cervical, anal, head and neck cancers. About 99% of all cervical cancers are related to HPV. HPV vaccines, Gardasil, Cervarix, and Gardasil 9 are used in the primary prevention of HPV related cancers. Gardasil and Gardasil 9 are available for use in both females and males ages 9 to 26, while Cervarix is available for females ages 9 to 25. Gardasil 9 was approved by the FDA for prevention against additional HPV types. Despite the availability of this preventative measure against cervical cancer, the rate of HPV vaccination in the United States remains lower than that of other industrialized nations. The purpose of this study is to elucidate mechanisms to help increase the HPV vaccination rate by using education as a tool; by simplifying the president report so that lay person can understand the information presented in the report. Through the quantitative examination of the data from the states with the lowest and highest vaccination rates, using SPSS statistical analysis; we analyzed several factors involved with the low uptake of the vaccines. The results collected show that socioeconomic status, misconceptions about HPV, and misconceptions about the safety of the vaccines were identified as possible obstacles to the effective uptake of HPV vaccinations. The proposals made by the President's Cancer Panel to accelerate the uptake of vaccines include, increasing coverage of the vaccines through government-sponsored programs, and the Affordable Care Act; increasing accessibility to vaccines through pharmacies, schools, and clinics; and disseminating more information on HPV to healthcare providers, parents, caregivers, and patients. Allowing greater accessibility to the vaccines for all populations regardless of income, education, and eliminating misconceptions of the vaccines would play a significant role in eliminating cancer. PMID- 28845338 TI - Hierarchical Logic Models as a Tool to Evaluate Programmatic Initiatives: Practical Solutions to Identified Problems. AB - INTRODUCTION: Large programmatic grants advance the missions of funding agencies or organizations. This article describes the programmatic impact of using "hierarchical" logic models in two Centers funded by the National Institute of Occupational Safety and Health (NIOSH) that were designed to achieve NIOSH goals. Such models are supportive of priority setting, policy implementation, and effective evaluation. METHODS: Two NIOSH Centers, an Agricultural Center and an Occupational Safety and Health Education and Research Center, used the same hierarchical logic model process to support the NIOSH programmatic goal of improving worker health and safety in their respective occupational categories. The logic model development processes were led by the same evaluator. RESULTS: Case studies describe the utilization of "hierarchical" logic models: in each case, NIOSH was the "grandparent", the Center was its descendant (parent) and the cores were the children. This lineage was articulated through the Center-wide logic model and through the logic model of each of its core programmatic areas (core). The Center-wide logic model ensured that the Center's goals, and the intended outcomes and impact of its work were linked to the mission and goals of NIOSH. Each core's logic model articulated how its goals, activities, and outcomes were specifically linked to the Center-wide model. DISCUSSION: A hierarchical logic model process ensures that the objectives of the funding agency or organization are addressed, and enables stakeholders to articulate the linkages between each layer. This facilitates the process of developing, implementing and evaluating programmatic elements within the framework of strategic planning. PMID- 28845339 TI - Avoiding the Tragedy of the Commons in Health Care: Policy Options for Covering High-Cost Cures. AB - In this article, Mattke and his colleagues discuss the risk that strategic behavior by health insurers could unravel the market for curative therapies for chronic diseases. Because the cost of these cures is front-loaded but the benefits accrue over time, insurers might attempt to delay treatment or avoid patients who require it, in the hope that they might change insurers. The authors discuss policy options to remedy this potential free-rider problem through alignment of incentives at the patient level, coordination among payers, and government intervention. They present a framework to analyze policy options and real-world case studies. While implementing those policy options is far from easy, stakeholders need to collaborate in order to establish equitable mechanisms that fairly distribute the cost and benefits of high-cost cures. PMID- 28845340 TI - Private Health Insurance Exchanges: Early Evidence and Implications for the Future. AB - Private health insurance exchanges offer employer health insurance, combining online shopping, increased plan choice, benefit administration, and cost containment strategies. This article examines how private exchanges function, how they may affect employers and employees, and the possible implications for the Affordable Care Act's (ACA's) Small Business Health Options Program (SHOP) Marketplaces. The authors found that private exchanges could encourage employees to select less-generous plans. This could expose employees to higher out-of pocket costs, but premium contributions would drop substantially, so net spending would decrease. On the other hand, employee spending may increase if, in moving to private exchanges, employers decrease their health insurance contributions. Most employers can avoid the ACA's "Cadillac tax" by reducing the generosity of the plans they offer, regardless of whether they move to a private exchange. There is not yet enough evidence to determine whether the private exchanges will become prominent in the insurance market and how they will affect employers and their employees. PMID- 28845337 TI - A Carbon Nanotube Reporter of miRNA Hybridization Events In Vivo. AB - MicroRNAs and other small oligonucleotides in biofluids are promising disease biomarkers, yet conventional assays require complex processing steps that are unsuitable for point-of-care testing or for implantable or wearable sensors. Single-walled carbon nanotubes are an ideal material for implantable sensors, owing to their emission in the near-infrared spectral region, photostability and exquisite sensitivity. Here, we report an engineered carbon-nanotube-based sensor capable of real-time optical quantification of hybridization events of microRNA and other oligonucleotides. The mechanism of the sensor arises from competitive effects between displacement of both oligonucleotide charge groups and water from the nanotube surface, which result in a solvatochromism-like response. The sensor, which allows for detection via single-molecule sensor elements and for multiplexing by using multiple nanotube chiralities, can monitor toehold-based strand-displacement events, which reverse the sensor response and regenerate the sensor complex. We also show that the sensor functions in whole urine and serum, and can non-invasively measure DNA and microRNA after implantation in live mice. PMID- 28845341 TI - Building a National Culture of Health: Background, Action Framework, Measures, and Next Steps. AB - Because health is a function of more than medical care, solutions to U.S. health problems must encompass more than reforms to health care systems. But those working to improve health, well-being, and equity still too often find themselves traveling on parallel paths that rarely intersect. In 2013, the Robert Wood Johnson Foundation (RWJF) embarked on a pioneering effort to advance a Culture of Health initiative. A Culture of Health places well-being at the center of every aspect of life, with the goal of enabling everyone in our diverse society to lead healthier lives, now and for generations to come. To put this vision into action, RWJF worked with RAND to develop an action framework that identifies how the nation will work toward achieving these outcomes. This article provides background on the development of this action framework. The Culture of Health action framework is designed around four action areas and one outcome area. Action areas are the core areas in which investment and activity are needed: (1) making health a shared value; (2) fostering cross-sector collaboration to improve well-being; (3) creating healthier, more equitable communities; and (4) strengthening integration of health services and systems. Each action area contains a set of drivers indicating where the United States needs to accelerate change and a set of measures illustrating places for progress. Within the primary Culture of Health outcome---improved population health, well-being, and equity-- the authors identified three outcome areas: enhanced individual and community well-being, managed chronic disease and reduced toxic stress, and reduced health care costs. PMID- 28845342 TI - A Preliminary Evaluation of Interactive Video Simulation Training for Campus Law Enforcement in California. AB - This article evaluates the Interactive Video Simulation Training to help campus law enforcement professionals refer and intervene with college students experiencing psychological distress. PMID- 28845343 TI - Investment in Social Marketing Campaign to Reduce Stigma and Discrimination Associated with Mental Illness Yields Positive Economic Benefits to California. AB - This article examines the potential impact of the California Mental Health Services Authority's stigma and discrimination reduction social marketing campaign on the use of adult behavioral health services, and it estimates the benefit-cost ratios. PMID- 28845344 TI - Racial and Ethnic Differences in Mental Illness Stigma and Discrimination Among Californians Experiencing Mental Health Challenges. AB - Reports racial and ethnic differences on the California Well-Being Survey, a surveillance tool that tracks mental illness stigma and discrimination among a sample of California adults experiencing psychological distress. PMID- 28845345 TI - The Deployment Life Study: Longitudinal Analysis of Military Families Across the Deployment Cycle. AB - In 2009, RAND launched the Deployment Life Study, a longitudinal study of military families across a deployment cycle in order to assess family readiness. Family readiness refers to the state of being prepared to effectively navigate the challenges of daily living experienced in the unique context of military service. The study surveyed families at frequent intervals throughout a complete deployment cycle---before a service member deploys (sometimes months before), during the actual deployment, and after the service member returns (possibly a year or more after she or he redeployed). It assessed a number of outcomes over time, including: the quality of marital and parental relationshipsthe psychological, behavioral, and physical health of family memberschild and teen well-being (e.g., emotional, behavioral, social, and academic)military integration (e.g., attitudes toward military service, retention intentions).This culminating paper briefly reviews the study design and data collection procedures, presents results from analyses of the longitudinal data collected from some 2,700 military families, and offers recommendations for programs and future research related to military families. The research was jointly sponsored by the Office of the Surgeon General, U.S. Army, and by the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury. PMID- 28845346 TI - Enhancing Military-Civilian Medical Synergies: The Role of Army Medical Practice in Civilian Facilities. AB - Army medical professionals must maintain the high level of proficiency required to fulfill the Army's medical missions of supporting military operations and providing beneficiary care. Because beneficiary care demands in a U.S. medical treatment facility (MTF) do not mirror those in a combat setting and sometimes can exceed the MTF's capacity, some MTFs enter into agreements with local civilian facilities to meet shortfalls in beneficiary care or training. The study's objective was to assess Army medical practice in U.S. Department of Veterans Affairs and non--Veterans Affairs civilian facilities and suggest opportunities for improving military--civilian synergies. PMID- 28845347 TI - Introducing Value-Based Purchasing into TRICARE Reform. AB - TRICARE, the health benefits program created for beneficiaries of the U.S. Department of Defense, covers health care provided in military treatment facilities and by civilian providers. Congress is now considering how to update TRICARE, which was first developed in the 1980s drawing on managed care concepts from civilian health plans. This article places TRICARE's current managed care strategy in historical context and describes recent innovations by private insurers and Medicare intended to enhance the value---cost and quality---of the care they purchase for their members. With this movement toward value-based purchasing as background, the authors evaluate two existing proposals for reform and describe an alternative approach that blends the existing proposals. PMID- 28845348 TI - TRICARE Applied Behavior Analysis (ABA) Benefit: Comparison with Medicaid and Commercial Benefits. AB - This study compared the Applied Behavior Analysis (ABA) benefit provided by TRICARE as an early intervention for autism spectrum disorder with similar benefits in Medicaid and commercial health insurance plans. The sponsor, the Office of the Under Secretary of Defense for Personnel and Readiness, was particularly interested in how a proposed TRICARE reimbursement rate decrease from $125 per hour to $68 per hour for ABA services performed by a Board Certified Behavior Analyst compared with reimbursement rates (defined as third party payment to the service provider) in Medicaid and commercial health insurance plans. Information on ABA coverage in state Medicaid programs was collected from Medicaid state waiver databases; subsequently, Medicaid provider reimbursement data were collected from state Medicaid fee schedules. Applied Behavior Analysis provider reimbursement in the commercial health insurance system was estimated using Truven Health MarketScan(r) data. A weighted mean U.S. reimbursement rate was calculated for several services using cross-state information on the number of children diagnosed with autism spectrum disorder. Locations of potential provider shortages were also identified. Medicaid and commercial insurance reimbursement rates varied considerably across the United States. This project concluded that the proposed $68-per-hour reimbursement rate for services provided by a board certified analyst was more than 25 percent below the U.S. mean. PMID- 28845349 TI - Understanding Treatment of Mild Traumatic Brain Injury in the Military Health System. AB - Traumatic brain injury (TBI) is considered a signature injury of modern warfare, though TBIs can also result from training accidents, falls, sports, and motor vehicle accidents. Among service members diagnosed with a TBI, the majority of cases are mild TBIs (mTBIs), also known as concussions. Many of these service members receive care through the Military Health System, but the amount, type, and quality of care they receive has been largely unknown. A RAND study, the first to examine the mTBI care of a census of patients in the Military Health System, assessed the number and characteristics (including deployment history and history of TBI) of nondeployed, active-duty service members who received an mTBI diagnosis in 2012, the locations of their diagnoses and next health care visits, the types of care they received in the six months following their mTBI diagnosis, co-occurring conditions, and the duration of their treatment. While the majority of service members with mTBI recover quickly, the study further examined a subset of service members with mTBI who received care for longer than three months following their diagnosis. Diagnosing and treating mTBI can be especially challenging because of variations in symptoms and other factors. The research revealed inconsistencies in the diagnostic coding, as well as areas for improvement in coordinating care across providers and care settings. The results and recommendations provide a foundation to guide future clinical studies to improve the quality of care and subsequent outcomes for service members diagnosed with mTBI. PMID- 28845350 TI - Bibliometric Analysis of Mental Health Research: 1980--2008. AB - This article presents the findings of a bibliometric study of mental health research papers published from 1980 to 2008. The aim of this study was to map mental health research in the G20 and other leading countries in order to analyse i) the research productivity of nations; ii) the relative intensity of research; iii) the level of research (clinical or basic); iv) levels of scientific impact; and v) levels of collaboration. This work is the result of a collaboration between Observatoire des sciences et des technologies in Montreal and RAND Europe. PMID- 28845351 TI - The National Institute for Health Research at 10 Years: An Impact Synthesis: 100 Impact Case Studies. AB - The National Institute for Health Research (NIHR) funds and supports world leading clinical and applied health and social care research, as well as research infrastructure in the NHS. Providing L1 billion of funding each year, NIHR aims to: drive the faster translation of new treatments, technologies and diagnostics to improve outcomes for health and care services; promote the wealth of the nation, including via inward investment from the health research community; pull basic science discoveries through into tangible benefits for patients and the public; and provide research evidence to support more effective and cost effective NHS delivery. To mark its tenth anniversary, the Department of Health commissioned the Policy Research in Science and Medicine unit to consider the question: "What are the ways in which NIHR has benefited the health research landscape in the past ten years?" This study identifies and celebrates 100 examples of positive change resulting from NIHR's support of research. A synthesis of 100 case studies is provided, which highlights the benefits and wider impacts of research, capacity building, and other activities undertaken with NIHR's support since its creation in 2006. The study concludes with a reflection of how the NIHR has transformed R&D in and for the NHS and wider health service, and the people they serve. The study draws together---for the first time---examples of the breadth of NIHR's impacts in a single resource. It will be of interest to healthcare professionals involved in research, academics working in health and social care, and members of the public wishing to understand the value of research in the NHS and the wider health and care system. PMID- 28845352 TI - Letter from the Editor. PMID- 28845354 TI - Identifying and Coordinating Care for Complex Patients: Findings from the Leading Edge of Analytics and Health Information Technology. AB - In the United States, a relatively small proportion of complex patients---defined as having multiple comorbidities, high risk for poor outcomes, and high cost-- incur most of the nation's health care costs. Improved care coordination and management of complex patients could reduce costs while increasing quality of care. However, care coordination efforts face multiple challenges, such as segmenting populations of complex patients to better match their needs with the design of specific interventions, understanding how to reduce spending, and integrating care coordination programs into providers' care delivery processes. Innovative uses of analytics and health information technology (HIT) may address these challenges. Rudin and colleagues at RAND completed a literature review and held discussions with subject matter experts, reaching the conclusion that analytics and HIT are being used in innovative ways to coordinate care for complex patients but that the capabilities are limited, evidence of their effectiveness is lacking, and challenges are substantial, and important foundational work is still needed. PMID- 28845353 TI - Developing and Testing the Health Care Safety Hotline: A Prototype Consumer Reporting System for Patient Safety Events. AB - This article describes the design, development, and testing of the Health Care Safety Hotline, a prototype consumer reporting system for patient safety events. The prototype was designed and developed with ongoing review by a technical expert panel and feedback obtained during a public comment period. Two health care delivery organizations in one metropolitan area collaborated with the researchers to demonstrate and evaluate the system. The prototype was deployed and elicited information from patients, family members, and caregivers through a website or an 800 phone number. The reports were considered useful and had little overlap with information received by the health care organizations through their usual risk management, customer service, and patient safety monitoring systems. However, the frequency of reporting was lower than anticipated, suggesting that further refinements, including efforts to raise awareness by actively soliciting reports from subjects, might be necessary to substantially increase the volume of useful reports. It is possible that a single technology platform could be built to meet a variety of different patient safety objectives, but it may not be possible to achieve several objectives simultaneously through a single consumer reporting system while also establishing trust with patients, caregivers, and providers. PMID- 28845355 TI - Improving Population Health Through an Innovative Collaborative: The Be There San Diego Data for Quality Group. AB - In 2012, leaders from disparate health care organizations established a data group aligned around a regional goal of preventing heart attacks and strokes in San Diego. The group---now named the Be There San Diego Data for Quality (DFQ) Group---is a safe venue for medical directors and other quality-improvement leaders to share performance data on quality-of-care measures for diabetes, hypertension, and cardiovascular disease, as well as insights, lessons learned, and challenges faced by each organization in treating these conditions. The DFQ Group has focused its efforts on improving the quality of services provided by each participating health care organization, and has placed a strong emphasis on analyzing trends in combined quality data to better understand the health of the entire San Diego population. By fostering collaboration among organizations that collectively serve a large portion of the local population and other key community stakeholders, the DFQ Group has helped form the foundation of a unique, multifaceted, multi-stakeholder, regional effort that is gaining national attention and funding for its community-driven approach. PMID- 28845356 TI - Implementing a Drug Formulary for California's Workers' Compensation Program. AB - California Assembly Bill 1124 required the state's Division of Workers' Compensation in the Department of Industrial Relations to establish a drug formulary for all injured workers covered by the state's workers' compensation program. Such formularies serve to reinforce safe and effective prescribing patterns for practitioners and payers. In California, the formulary will need to be consistent with the Medical Treatment Utilization Schedule guidelines that define medically appropriate care for California's injured workers, create incentives to encourage prescribing of medically appropriate drugs, and reduce the administrative burdens associated with utilization review and medical necessity disputes. The objective of this study is to support the Division of Workers' Compensation in establishing the formulary. The authors compare and evaluate the strengths and weaknesses of four existing formularies and the formulary used by California's Medicaid program. The authors then analyze the issues involved in structuring the drug formulary for California to be consistent with the treatment guidelines, explore related policies that should be addressed in implementing the formulary, and offer recommendations. PMID- 28845357 TI - Identifying Future Disease Hot Spots: Infectious Disease Vulnerability Index. AB - Recent high-profile outbreaks, such as Ebola and Zika, have illustrated the transnational nature of infectious diseases. Countries that are most vulnerable to such outbreaks might be higher priorities for technical support. RAND created the Infectious Disease Vulnerability Index to help U.S. government and international agencies identify these countries and thereby inform programming to preemptively help mitigate the spread and effects of potential transnational outbreaks. The authors employed a rigorous methodology to identify the countries most vulnerable to disease outbreaks. They conducted a comprehensive review of relevant literature to identify factors influencing infectious disease vulnerability. Using widely available data, the authors created an index for identifying potentially vulnerable countries and then ranked countries by overall vulnerability score. Policymakers should focus on the 25 most-vulnerable countries with an eye toward a potential "disease belt" in the Sahel region of Africa. The infectious disease vulnerability scores for several countries were better than what would have been predicted on the basis of economic status alone. This suggests that low-income countries can overcome economic challenges and become more resilient to public health challenges, such as infectious disease outbreaks. PMID- 28845358 TI - Stakeholder Perspectives on a Culture of Health: Key Findings. AB - Since 2013, the Robert Wood Johnson Foundation (RWJF) has embarked on a pioneering effort to advance a Culture of Health. The Culture of Health action framework is founded on a vision in which "everyone in our diverse society leads healthier lives now and for generations to come." To put the Culture of Health vision into action, RWJF asked RAND Health to support the development of an action framework and measurement strategy. This article summarizes the stakeholder engagement efforts that RAND used to inform this work. It draws on a series of interviews and focus groups that RAND researchers conducted with stakeholders both within and outside the United States. It should be of interest to RWJF, as well as to those individuals and organizations interested in advancing the Culture of Health action framework. Given that RWJF is focused on using the Culture of Health action framework and measures to catalyze national dialogue about content and investments to improve population health and well being, the study should be beneficial to a range of national, state, and local leaders across a variety of sectors that contribute to health as described by the Culture of Health action framework. PMID- 28845359 TI - Evaluation Design Recommendations for the Certified Community Behavioral Health Clinic Demonstration Program. AB - This article provides information and recommendations regarding the evaluation design of the Certified Community Behavioral Health Clinic (CCBHC) demonstration. Mandated by Congress in Section 223 of the Protecting Access to Medicare Act of 2014, the CCBHC is a new model of specialty behavioral health clinic, designed to provide comprehensive and integrated care for adults with mental health or substance-use disorders and children with serious emotional distress. Certification criteria for the CCBHCs have been specified by Substance Abuse and Mental Health Services Administration covering six core areas: staffing; accessibility; care coordination; scope of services; quality and other reporting; and organizational authority, governance, and accreditation. In addition, services provided to Medicaid enrollees in CCBHCs will be reimbursed through one of two alternative prospective payment systems. At present, 24 states have been awarded grants to begin the planning process for implementing CCBHCs. Of these states, eight will be selected to participate in the demonstration project beginning in January 2017. Results from the evaluation will inform mandated reports to Congress over the two-year demonstration period and the three years following the end of the demonstration, providing information to policymakers on the program's impact and value. In addition, the results can inform the direction of future efforts at integration of behavioral health into the health care system at this critical time of transformation. PMID- 28845360 TI - Suicide Prevention Hotlines in California: Diversity in Services, Structure, and Organization and the Potential Challenges Ahead. AB - This article evaluates the landscape in which suicide prevention hotlines operate, focusing on California but with nationwide implications, and provides recommendations to ensure that callers at risk of suicide seek and receive the help they need. PMID- 28845361 TI - Letter from the Editor. PMID- 28845362 TI - Progress Towards Applications of Carbon Nanotube Photoluminescence. AB - In the fifteen years following the discovery of single-walled carbon nanotube (SWCNT) photoluminescence, investigators have made significant progress in their understanding of the phenomenon and towards the development of applications. The intrinsic potential of semiconducting carbon nanotubes - a family of bright, photostable near infrared (NIR) fluorophores (900-2100 nm) with tunable properties, has motivated their use as optical probes and sensors. In this perspective, we highlight the advances made in the synthesis, processing, modification, separation, and metrology of carbon nanotubes in the context of applications of their photoluminescence. PMID- 28845363 TI - New Methods for Quantification of Visual Photosensitivity Threshold and Symptoms. AB - PURPOSE: Visual photosensitivity is a common symptom difficult to measure and diagnose, and is found in many ocular and neurological disorders. We developed two novel reproducible quantitative assessments of visual photosensitivity. METHODS: We designed and built the ocular photosensitivity analyzer (OPA), an automated instrument to determine light intensity visual photosensitivity threshold (VPT), and developed the Visual Light Sensitivity Questionnaire-8 (VLSQ 8), an eight-question survey to assess the presence and severity of photosensitivity symptoms. We evaluated the test-retest variability and obtained normative values of these two approaches in 35 healthy normal subjects, distributed evenly over five age groups from eight to 60 years. Each subject underwent two test sessions, each with VLSQ-8, eye examination, and OPA, four weeks apart, between April 2015 and June 2016. RESULTS: Log-transformed VPTs (log10lux) and VLSQ-8 results were highly reproducible between the two sessions (VPT intraclass correlation coefficient [ICC] = 0.86; 95% confidence interval [CI] = 0.71-0.93; binocular testing, VLSQ-items ICC range = 0.53-0.87). No consistent significant differences in VPTs were found with monocular (P = 0.053, session 1) or binocular (P = 0.26) testing. Subjects in age group >30 to 40 years had significantly higher VPTs than those in other age groups (P <= 0.011) except the >40 to 50 years age group (P = 0.11). Photosensitivity symptoms assessed by the VLSQ-8 generally were low and highly reproducible with >=88% of responses between the 2 sessions being within one category of each other. CONCLUSIONS: Our results provide reliability data and normative results toward validation of two novel approaches to quantify visual photosensitivity and provide support for their potential use in ocular and neurologic conditions as well as in clinical trials. TRANSLATIONAL RELEVANCE: The new quantitative photosensitivity approaches are potential measures to characterize disease severity, monitor disease progression, and evaluate treatment efficacy. PMID- 28845364 TI - The Polaris Oncology Survivorship Transition (POST) System: A Patient- and Provider-Driven Cancer Survivorship Planning Program. AB - BACKGROUND: It is strongly recommended that individuals ending treatment for cancer have a "survivorship plan," and new standards require survivorship planning for accreditation, However, a comprehensive plan is often neglected. OBJECTIVE: To present the development and field test results of a web-based, breast cancer survivorship care planning system. METHODS: The Polaris Oncology Survivorship Transition (POST) blends input from the electronic health record (EHR), oncology care providers (OCPs), and patients to create a survivorship care plan (SCP). The content of the POST program was created with the assistance of end-user input (patients, oncologists, and primary care providers (PCPs)) and the full program was piloted on women ending treatment for breast cancer. This paper presents the pilot study that field-tested the POST In a clinical setting. Patients were recruited from outpatient care clinics and chemotherapy units in a comprehensive care center. The study included 25 women ending treatment for breast cancer in the past year, 4 OCPs, and PCPs. Patients received the POST computepized assessment and a tailored SCP. RESULTS: The POST assists providers in crafting efficient and comprehensive SCPs and was rated highly satisfactory by all end-users. DISCUSSION: The POST program can be used as a cancer survivorship planning program to assist OCPs in care planning for their patients ending treatment for breast cancer. CONCLUSION: This study provides support for Incorporating computerized SCP programs into clinical practice. Use of the POST in clinical practice has the potential to improve survivorship planning. PMID- 28845365 TI - HIV and STI Risk for Young Blacks in High Prevalence Areas: Implications for Health Equity in Communities Hosting Historically Black Colleges and Universities (HBCUs). AB - BACKGROUND: Every year, thousands of young black, high school graduates who are seeking higher education, attend one of the 105 historically black colleges and universities (HBCUs) located primarily in the south and east. The objective of the research was to examine the geographic proximity of HBCUs to areas of high HIV and STI disease burden among college age people to assess infectivity of potential sex partners in the areas surrounding HBCUs. METHODS: We examined the 14 states reporting the greatest HIV diagnoses burden among persons age 20-24 years old and STI burden among persons age 15 to 24 years old available for 2010. The Geographic Information System was used to create a spatially referenced data base of state level HIV and STI disease rates and HBCU zip codes to answer the question "How many HBCUs are in this location?" Maps were created to show HBCU locations in states along with the associated HIV and STI disease burden. FINDINGS: Results suggest high HIV and STI disease burden in the general population of persons ages 15-24 in 10 states with 4 or more Historically Black Colleges and Universities (HBCU) and an overall high rate of HIV and STI exposure in the pool of potential sex partners. Less risky behavior by minority young adults attending HBCUs could potentially translate to high risk for contracting the diseases because of high prevalence in surrounding communities. PUBLIC HEALTH MESSAGE: Public health agencies may want to consider prioritizing HBCUs for enhanced HIV and STI prevention collaborative efforts in those areas with a high burden of HIV and other STIs. PMID- 28845366 TI - Trends and Disparities in TB among U.S. Born Black and White Chicago Residents, 1998 - 2008. AB - OBJECTIVE: To describe the decline of tuberculosis (TB) cases among U.S.-born non Hispanic (NH) black and white Chicago residents. METHODS: Data from the National TB Surveillance System was used to analyze trends and characteristics of reported TB cases among U.S.-born NH black and U.S.-born NH white Chicago residents from 1998-2008. RESULTS: Chicago reported a total of 3,821 TB cases over the 11-year time period. Of these, 1,916 were U.S.-born NH black and 235 were U.S.-born NH white. The proportion of cases attributable to U.S.-born NH blacks was 63% (294/469) in 1998 and 34% in 2008 (72/213). Regression analysis for trends from 2000-2008 revealed a greater than predicted decrease in rates among U.S.-born NH blacks (p<0.05). U.S.-born NH blacks had greater odds than U.S.-born NH whites of HIV infection (OR 1.8), non-injecting drug use (OR 3.0), unemployment (OR 1.7), receiving care from the health department (OR 2.2) and receiving directly observed therapy (OR 3.0). CONCLUSION: Despite more TB risk factors in Chicago's U.S.-born black population, there was a narrowing of TB case disparity in Chicago from 1998-2008. Continued focused strategies aimed at controlling TB are needed. PMID- 28845367 TI - Tai Chi Improves Sleep Quality in Healthy Adults and Patients with Chronic Conditions: A Systematic Review and Meta-analysis. AB - BACKGROUND: Physical activity and exercise appear to improve sleep quality. However, the quantitative effects of Tai Chi on sleep quality in the adult population have rarely been examined. We conducted a systematic review and meta analysis evaluating the effects of Tai Chi on sleep quality in healthy adults and disease populations. METHODS: Medline, Cochrane Central databases, and review of references were searched through July 31, 2013. English-language studies of all designs evaluating Tai Chi's effect on sleep outcomes in adults were examined. Data were extracted and verified by 2 reviewers. Extracted information included study setting and design, population characteristics, type and duration of interventions, outcomes, risk of bias and main results. Random effect models meta analysis was used to assess the magnitude of treatment effect when at least 3 trials reported on the same sleep outcomes. RESULTS: Eleven studies (9 randomized and 2 non-randomized trials) totaling 994 subjects published between 2004 and 2012 were identified. All studies except one reported Pittsburg Sleep Quality Index. Nine randomized trials reported that 1.5 to 3 hour each week for a duration of 6 to 24 weeks of Tai Chi significantly improved sleep quality (Effect Size, 0.89; 95% confidence interval [CI], 0.28 to 1.50), in community-dwelling healthy participants and in patients with chronic conditions. Improvement in health outcomes including physical performance, pain reduction, and psychological well-being occurred in the Tai Chi group compared with various controls. LIMITATIONS: Studies were heterogeneous and some trials were lacking in methodological rigor. CONCLUSIONS: Tai Chi significantly improved sleep quality in both healthy adults and patients with chronic health conditions, which suggests that Tai Chi may be considered as an alternative behavioral therapy in the treatment of insomnia. High-quality, well-controlled randomized trials are needed to better inform clinical decisions. PMID- 28845368 TI - Effect of Maladaptive Beliefs and Attitudes about Sleep among Community-dwelling African American Men at Risk for Obstructive Sleep Apnea. AB - : This study compared differences in both maladaptive beliefs and attitudes about sleep between African American (heareafter referred to as black) men at risk for obstructive sleep apnea (OSA) and those without OSA risk. METHODS: A convenience sample of 120 community-dwelling men provided sociodemographic, health and sleep data. A validated questionnaire was used to identify men at high risk for OSA and the Dysfunctional Beliefs and Attitudes about Sleep (DBAS-16) scale was used to measure endorsed attitudes and beliefs about sleep. RESULTS: The mean age of the sample was 42 +/- 15 years. Men reported difficulty falling asleep (23%), difficulty maintaining sleep (23%), early morning awakening (35%), and use of sleep medicine (6%). 27% were at high risk for OSA. Men at high OSA risk had greater DBAS scores [F1, 92=13.68, p<0.001]; OSA risk was related to greater rate of sleep dissatisfaction overall [46% vs. 13%, Chi2=24.52, p<0.001]. CONCLUSION: The findings suggest that maladaptive beliefs and attitudes about sleep are important characteristics of black men at risk for OSA, and potential screenings around sleep difficulties should also consider these factors. PMID- 28845369 TI - Childcare in Infancy and Later Obesity: a Narrative Review of Longitudinal Studies. AB - PURPOSE OF REVIEW: The purpose of this review was to summarize the current literature on the longitudinal relationship between non-parental childcare during infancy and later obesity. RECENT FINDINGS: Eleven studies met the inclusion criteria, comprising 74 associations relevant to the review. Studies were highly heterogeneous in terms of defining childcare, categorizing different types of childcare, assessing obesity, and age at measurement of outcome and exposure. Most of the associations were either non-significant (42 associations, 57%) or showed a significant association between increased exposure to childcare and greater obesity (30 associations, 41%). There were very few examples of associations indicating that childcare was associated with lower obesity. SUMMARY: There is limited research on the longitudinal relationship between childcare in infancy and later obesity. Existing studies showed mixed results, similar to recent reviews reporting on cross-sectional studies and older ages. The different definitions of childcare and wide variety of measures of exposure make comparisons between studies challenging. PMID- 28845370 TI - Seismocardiography-Based Cardiac Computed Tomography Gating Using Patient Specific Template Identification and Detection. AB - To more accurately trigger cardiac computed tomography angiography (CTA) than electrocardiography (ECG) alone, a sub-system is proposed as an intermediate step toward fusing ECG with seismocardiography (SCG). Accurate prediction of quiescent phases is crucial to prospectively gating CTA, which is susceptible to cardiac motion and, thus, can affect the diagnostic quality of images. The key innovation of this sub-system is that it identifies the SCG waveform corresponding to heart sounds and determines their phases within the cardiac cycles. Furthermore, this relationship is modeled as a linear function with respect to heart rate. For this paper, B-mode echocardiography is used as the gold standard for identifying the quiescent phases. We analyzed synchronous ECG, SCG, and echocardiography data acquired from seven healthy subjects (mean age: 31; age range: 22-48; males: 4) and 11 cardiac patients (mean age: 56; age range: 31-78; males: 6). On average, the proposed algorithm was able to successfully identify 79% of the SCG waveforms in systole and 68% in diastole. The simulated results show that SCG-based prediction produced less average phase error than that of ECG. It was found that the accuracy of ECG-based gating is more susceptible to increases in heart rate variability, while SCG-based gating is susceptible to high cycle to cycle variability in morphology. This pilot work of prediction using SCG waveforms enriches the framework of a comprehensive system with multiple modalities that could potentially, in real time, improve the image quality of CTA. PMID- 28845371 TI - Predicting Drug Recalls From Internet Search Engine Queries. AB - Batches of pharmaceuticals are sometimes recalled from the market when a safety issue or a defect is detected in specific production runs of a drug. Such problems are usually detected when patients or healthcare providers report abnormalities to medical authorities. Here, we test the hypothesis that defective production lots can be detected earlier by monitoring queries to Internet search engines. We extracted queries from the USA to the Bing search engine, which mentioned one of the 5195 pharmaceutical drugs during 2015 and all recall notifications issued by the Food and Drug Administration (FDA) during that year. By using attributes that quantify the change in query volume at the state level, we attempted to predict if a recall of a specific drug will be ordered by FDA in a time horizon ranging from 1 to 40 days in future. Our results show that future drug recalls can indeed be identified with an AUC of 0.791 and a lift at 5% of approximately 6 when predicting a recall occurring one day ahead. This performance degrades as prediction is made for longer periods ahead. The most indicative attributes for prediction are sudden spikes in query volume about a specific medicine in each state. Recalls of prescription drugs and those estimated to be of medium-risk are more likely to be identified using search query data. These findings suggest that aggregated Internet search engine data can be used to facilitate in early warning of faulty batches of medicines. PMID- 28845372 TI - Guillain-Barre Syndrome After Revision Lumbar Surgery: A Case Report. AB - Guillain-Barre syndrome (GBS) is a term that is used to describe a group of immune-mediated peripheral neuropathies, with the most common feature being rapid polyradiculoneuropathy. The exact etiology of this syndrome is unknown. In the field of orthopedics, GBS has been reported to occur after total hip arthroplasty, orthopedic trauma, and spine surgery. We report a unique case of GBS after elective revision lumbar spine surgery. A 62-year-old female presented with persistent low back pain and radiculopathy and elected to have revision lumbar spine surgery. Approximately 24 to 36 hours after hospital discharge, she returned to the hospital with weakness in her legs. After an electromyography (EMG), the patient was diagnosed with GBS and placed on intravenous immunoglobulin (IVIG). She developed respiratory failure, which required intubation and eventually converted to a tracheostomy and was finally decannulated. Over the course of 12 months, she improved to her pre-surgical baseline, gaining 5/5 strength in her upper and lower extremities and was able to ambulate independently without any aids. This was a case of GBS that occurred in a patient approximately two weeks after revision lumbar surgery. GBS is a poorly understood and rare complication of lumbar spine surgery that needs to be recognized quickly to be effectively treated. PMID- 28845373 TI - First Case Report of Metastatic Squamous Cell Carcinoma of Lung Associated with Mounier-Kuhn Syndrome and Review of Literature. AB - Mounier-Kuhn syndrome is a relatively rare condition, mostly involving the trachea and main stem bronchi. It is caused either by the atrophy of elastic fibers or faulty fetal development of cartilage and smooth muscles, hence leading to an overall increase in the diameter of lower respiratory tract. No certain etiology was found in the majority of cases reported previously, however, several other connective tissue diseases have also been implicated with the congenital tracheobronchomegaly. One anecdotal case report mentioned the development of lung malignancy in a patient who had previously received external beam radiotherapy. Herein, we report the first case of Mounier-Kuhn syndrome in a 62-year-old male with a recent diagnosis of metastatic squamous cell carcinoma (SCC) of the lung. PMID- 28845374 TI - NOACs vs. Warfarin for Stroke Prevention in Nonvalvular Atrial Fibrillation. AB - Atrial fibrillation is a heart arrhythmia associated with increased risk for ischemic stroke. Vitamin K antagonists were developed to decrease a patient's clotting risk; however, these medications require therapeutic monitoring and have several drug interactions. Novel oral anticoagulants (NOACs) were developed as an alternative to vitamin K antagonists and several studies have evaluated the ability of NOAC to decrease clotting as well as the risk of major bleeding in comparison to vitamin K antagonists, such as warfarin. This study has found that NOACs are as effective as warfarin in reducing stroke and systemic embolism through anticoagulation. Notably, NOACs have a decreased risk of significant bleeding and other secondary adverse events. PMID- 28845375 TI - Correlation Between Ki-67 Index, World Health Organization Grade and Patient Survival in Glial Tumors With Astrocytic Differentiation. AB - Background Glioblastoma multiforme (GBM) is a class IV astrocytic tumor, the most malignant of the four groups of World Health Organization (WHO) tumors with astrocytic differentiation. Aim The aim of this study was to estab-lish whether a correlation exists between the Ki-67 index of tumors with astrocytic differentiation, WHO grade, and patient survival. Materials and methods A retrospective non-clinical approach to patient selection was chosen for the aim of the study. A total of 47 patients diagnosed and treated for CNS tumors with astrocytic differentiation in the St. Marina University Hospital, Varna, Bulgaria, from September 2012 to July 2016 were retrospectively included into the study cohort. The cases were tested for their immunohistochemistry (IHC) reaction with Ki-67 after their original Hematoxylin and Eosin and IHC slides were reviewed by a single author and blind coded. The Ki-67 positivity index of the nuclei was estimated after digitalization of the slides and calculated by the ImmunoRatio automated count-ing tool. The individual Ki-67 index and patient survival of each case were statistically compared. Results The histopathological groups, after the blind Ki-67 index automated calculation was carried out, revealed no WHO grade I, two WHO grade II samples, four WHO grade III samples and 41 WHO grade IV cases, and these were included in the analysis. The two samples of WHO grade II astrocytic tumors had a mean Ki-67 index of 25%; however, they comprised tumors with an individual index of 43% and 7%, both individual values with a highly unlikely index for this group. The four samples of WHO grade III had a mean Ki-67 index of 4%, standard deviation +/-2.16 (p>0.05), with the lowest index being 1% and the highest one being 6%. Both WHO grade II and III did not include enough samples to allow for a proper statistical analysis of patient survival. The 41 GBM cases had a mean Ki-67 index of 17.34%, standard deviation +/-10.79 (p>0.05). Statistical analysis of the Ki-67 index divid-ed dichotomously into two groups and patient survival revealed that cases with a high Ki-67 index had no significant difference in survival when compared to those with low expression. Conclusions Based on the reported results, the mean Ki-67 percentage of positive nuclei in GBM tumor sam-ples cannot be used to estimate the survival of patients. However, Ki-67 remains a valuable IHC pathological tool. PMID- 28845376 TI - Sirolimus-Associated Pruritus: Case Report and Review. AB - Sirolimus is an immunosuppressant drug used to prevent organ rejection in transplant patients. We describe a man with sirolimus-associated pruritus and review the features of this adverse event in other individuals receiving this drug. The patient was a 67-year-old heart transplant recipient receiving sirolimus as part of his immunosuppressive regimen. He developed severe pruritus over the distal extremities, face, and earlobes six months after starting the drug. The symptoms became progressively worse as he continued to receive this medication. Temporary elimination of the drug resulted in cessation of his itching. Subsequently, sirolimus was discontinued and everolimus was started; this provided temporary relief of his pruritus. PubMed was used to review the following terms: "sirolimus", "itch", and "pruritus." Relevant papers and their references were reviewed. We are aware of only one other patient in whom pruritus necessitated cessation of treatment with sirolimus. Systemic pruritus is a rare adverse event associated with sirolimus. It can occur in both heart and liver transplant patients, beginning several months after transplant, and typically persists. Dose reduction may improve symptoms. Discontinuation of the medication or use of alternative immunosuppressants may be necessary for complete symptom relief. PMID- 28845377 TI - An Extremely Rare Manifestation of Multiple Myeloma: An Immunoglobulin D Secreting Testicular Plasmacytoma. AB - Multiple myelomas (MM) of the immunoglobulin D (IgD) subtype is rare amongst plasma cell malignancies. It can present a diagnostic challenge because of the low amount of immunoglobulin in the serum. The amount of monoclonal (M)-protein is often undetectable on electrophoresis. Historically, survival in these patients was typically shorter compared to the immunoglobulin A (IgA) and immunoglobulin G (IgG) subtypes due to advanced disease upon presentation. With the advent of better diagnostic techniques, the prognosis of this disease is changing. We describe a case of an extramedullary testicular plasmacytoma (EMP) of the IgD subtype as the primary feature of MM, which responded well to novel therapy. A 72-year-old White male presented to the emergency room with a right testicular mass for three months. He subsequently underwent right radical orchiectomy. Pathology of the specimen revealed plasmacytoid cells positive for cluster of differentiation (CD79a), lambda free light chain, IgD, and BCL-1 (Cyclin D1) on immunochemical stains. Urine and serum immunofixation were positive for monoclonal IgD with lambda light chain specificity and Bence Jones proteinuria. Bone marrow biopsy showed large sheets of plasma cells with greater than 90% cellularity. Flow cytometry displayed atypical plasma cells expressing cluster of differentiation (CD38, CD20, and CD56) with cytoplasm and lambda light chain, approximately 20%, consistent with a plasma cell dyscrasia. Stage 3 IgD lambda multiple myeloma was diagnosed. He received novel treatment with Bortezomib and dexamethasone for three months, followed by Lenalidomide. His performance status and lab data improved significantly. He had progression-free survival (PFS) of approximately three years and remained in complete remission low-dose dose of Lenalidomide daily. IgD myeloma was considered a diagnostic challenge due to undetectable M-protein levels on serum protein electrophoresis (SPEP). With the advent of serum free light chain assay and serum and cytologic examinations, diagnostic accuracy has significantly improved. The IgD subtype is commonly associated with poor clinical outcomes. However, the use of novel agents and autologous transplant has changed the prognosis of this disease. PMID- 28845378 TI - Validation of Aura Microwave Limb Sounder stratospheric water vapor measurements by the NOAA frost point hygrometer. AB - Differences between stratospheric water vapor measurements by NOAA frost point hygrometers (FPHs) and the Aura Microwave Limb Sounder (MLS) are evaluated for the period August 2004 through December 2012 at Boulder, Colorado, Hilo, Hawaii, and Lauder, New Zealand. Two groups of MLS profiles coincident with the FPH soundings at each site are identified using unique sets of spatiotemporal criteria. Before evaluating the differences between coincident FPH and MLS profiles, each FPH profile is convolved with the MLS averaging kernels for eight pressure levels from 100 to 26 hPa (~16 to 25 km) to reduce its vertical resolution to that of the MLS water vapor retrievals. The mean FPH - MLS differences at every pressure level (100 to 26 hPa) are well within the combined measurement uncertainties of the two instruments. However, the mean differences at 100 and 83 hPa are statistically significant and negative, ranging from -0.46 +/- 0.22 ppmv (-10.3 +/- 4.8%) to -0.10 +/- 0.05 ppmv (-2.2 +/- 1.2%). Mean differences at the six pressure levels from 68 to 26 hPa are on average 0.8% (0.04 ppmv), and only a few are statistically significant. The FPH - MLS differences at each site are examined for temporal trends using weighted linear regression analyses. The vast majority of trends determined here are not statistically significant, and most are smaller than the minimum trends detectable in this analysis. Except at 100 and 83 hPa, the average agreement between MLS retrievals and FPH measurements of stratospheric water vapor is better than 1%. PMID- 28845379 TI - Evaluation of UT/LS hygrometer accuracy by intercomparison during the NASA MACPEX mission. AB - Acquiring accurate measurements of water vapor at the low mixing ratios (< 10 ppm) encountered in the upper troposphere and lower stratosphere (UT/LS) has proven to be a significant analytical challenge evidenced by persistent disagreements between high-precision hygrometers. These disagreements have caused uncertainties in the description of the physical processes controlling dehydration of air in the tropical tropopause layer and entry of water into the stratosphere and have hindered validation of satellite water vapor retrievals. A 2011 airborne intercomparison of a large group of in situ hygrometers onboard the NASA WB-57F high-altitude research aircraft and balloons has provided an excellent opportunity to evaluate progress in the scientific community toward improved measurement agreement. In this work we intercompare the measurements from the Midlatitude Airborne Cirrus Properties Experiment (MACPEX) and discuss the quality of agreement. Differences between values reported by the instruments were reduced in comparison to some prior campaigns but were nonnegligible and on the order of 20% (0.8 ppm). Our analysis suggests that unrecognized errors in the quantification of instrumental background for some or all of the hygrometers are a likely cause. Until these errors are understood, differences at this level will continue to somewhat limit our understanding of cirrus microphysical processes and dehydration in the tropical tropopause layer. PMID- 28845380 TI - Endovascular Extraction of a Needle from the Internal Carotid Artery: A Novel Approach to a Controversial Dental Misadventure. AB - Objective To review the literature concerning the management of dental needles broken off into the deep spaces of the neck, to report what we believe is the first case of a fractured dental needle migrating into the jugular foramen, and the unconventional use of endovascular intervention to retrieve the needle fragment. Design Case report with review of literature. Setting Academic tertiary care center. Participants Intervention was performed by the otolaryngology-head and neck surgery, vascular surgery, and neurovascular interventional radiology teams. Results Transoral exploration, including palatal split and exposure of the poststyloid parapharyngeal space with C-arm image guidance, was unable to retrieve the broken needle, which traversed the internal carotid lumen with the distal end entering the jugular foramen. Through endovascular intervention, the neurovascular interventional radiology team captured the proximal end of the needle and retrieved it through the femoral artery. The patient recovered uneventfully. Conclusion Fracture and loss of oral injection needles remain a persistent and preventable problem. This case demonstrates a novel, minimally invasive, well-tolerated, and successful method to extract a fractured needle that migrated into the lumen of the internal carotid artery at the level of the skull base. PMID- 28845381 TI - An Overview of Structural Characteristics in Problematic Video Game Playing. AB - PURPOSE OF REVIEW: There are many different factors involved in how and why people develop problems with video game playing. One such set of factors concerns the structural characteristics of video games (i.e., the structure, elements, and components of the video games themselves). Much of the research examining the structural characteristics of video games was initially based on research and theorizing from the gambling studies field. The present review briefly overviews the key papers in the field to date. RECENT FINDINGS: The paper examines a number of areas including (i) similarities in structural characteristics of gambling and video gaming, (ii) structural characteristics in video games, (iii) narrative and flow in video games, (iv) structural characteristic taxonomies for video games, and (v) video game structural characteristics and game design ethics. Many of the studies carried out to date are small-scale, and comprise self-selected convenience samples (typically using self-report surveys or non-ecologically valid laboratory experiments). SUMMARY: Based on the small amount of empirical data, it appears that structural features that take a long time to achieve in game are the ones most associated with problematic video game play (e.g., earning experience points, managing in-game resources, mastering the video game, getting 100% in-game). The study of video games from a structural characteristic perspective is of benefit to many different stakeholders including academic researchers, video game players, and video game designers, as well as those interested in prevention and policymaking by making the games more socially responsible. It is important that researchers understand and recognize the psycho social effects and impacts that the structural characteristics of video games can have on players, both positive and negative. PMID- 28845382 TI - Enhancing transglutaminase production of Streptomyces mobaraensis by iterative mutagenesis breeding with atmospheric and room-temperature plasma (ARTP). AB - OBJECTIVES: To improve the fermentation production of transglutaminase (TGase) from Streptomyces mobaraensis for applications in the food industry, the atmospheric and room-temperature plasma (ARTP) mutagenesis was applied to breed S. mobaraensis mutants with increased TGase production. RESULTS: After eight rounds of iterative ARTP mutagenesis, four genetically stable mutants, Sm5-V1, Sm6-V13, Sm2-V10, and Sm7-V12, were identified, which showed increased TGase production by 27, 24, 24, and 19%, respectively. The best mutant Sm5-V1 exhibited a maximum TGase activity of 5.85 U/mL during flask fermentation. Compared to the wild-type strain, the transcription levels of the zymogen TGase genes in the mutants increased significantly as indicated by quantitative real-time PCR, while the gene nucleotide sequences of the mutants did not change at all. It was shown that the overexpression of TGase zymogen gene in the mutants contributes to the increase in TGase production. CONCLUSIONS: ARTP is a potentially efficient tool for microbial mutation breeding to bring some significant changes required for the industrial applications. PMID- 28845383 TI - Older Adult Falls: Effective Approaches to Prevention. AB - PURPOSE: The issue of older adult falls combines a problem with high incidence and high injury susceptibility with an increasing population at risk. A firm understanding of both fall risk factors and effective strategies is required to reduce risk and prevent these injuries. RECENT FINDINGS: Each year, 28.7% of older adults aged >=65 sustain a fall. At the national level, this represents 29 million falls resulting in 27,000 deaths and 7 million injuries requiring medical treatment or restricted activity for at least 1 day. There are several strategies that have been shown to effectively reduce the risk or the incidence of falls. SUMMARY: More than 90% of older adults see a medical provider at least once a year providing an opportunity to identify and address fall risk factors. Comprehensive fall prevention in the primary care setting is both feasible and practical. PMID- 28845384 TI - Disruption of Circadian Rhythms by Light During Day and Night. AB - PURPOSE OF REVIEW: This study aims to discuss possible reasons why research to date has not forged direct links between light at night, acute melatonin suppression or circadian disruption, and risks for disease. RECENT FINDINGS: Data suggest that irregular light-dark patterns or light exposures at the wrong circadian time can lead to circadian disruption and disease risks. However, there remains an urgent need to: (1) specify light stimulus in terms of circadian rather than visual response; (2) when translating research from animals to humans, consider species-specific spectral and absolute sensitivities to light; (3) relate the characteristics of photometric measurement of light at night to the operational characteristics of the circadian system; and (4) examine how humans may be experiencing too little daytime light, not just too much light at night. SUMMARY: To understand the health effects of light-induced circadian disruption, we need to measure and control light stimulus during the day and at night. PMID- 28845385 TI - The Role of the Calcitonin Peptide Family in Prostate Cancer and Bone Metastasis. AB - PURPOSE OF REVIEW: This study is to highlight recent discoveries associated with the role of calcitonin peptide family and their receptors in prostate cancer progression and bone metastasis. RECENT FINDINGS: Studies have linked adrenomedullin (AM), calcitonin (CT) and calcitonin gene-related peptide (CGRP) to the spread of prostate tumours to the bone. AM can induce a metastatic phenotype in prostate cancer cells through its action on TRPV2 calcium channels and is also capable of influencing localised levels of RANKL in the bone to favour tumourigenesis. CT utilises A-kinase anchoring proteins to indirectly act on PKA and promote metastasis in prostate cancer. The receptor for CT contains a PDZ-binding domain, the deletion of which stops metastasis to the bone in orthotopic prostate models. SUMMARY: Recent findings show strong evidence for the role of calcitonin peptides and receptors in prostate cancer and bone metastasis. Further research could provide potential prognostic markers and therapeutic targets for prostate cancer patients. PMID- 28845386 TI - Innate Immunity and Mobilization of Hematopoietic Stem Cells. AB - PURPOSE OF REVIEW: Several mechanisms have been postulated to orchestrate mobilization of hematopoietic stem/progenitor cells (HSPCs), and still more work is needed to better understand this process and to gain better mechanistic insight. RECENT FINDINGS: Evidence accumulated that mobilization of HSPCs is a part of innate immunity response to tissue organ injury, stress, and infection. This evolutionary ancient process is orchestrated by granulocytes and monocytes that trigger activation of complement cascade and the coagulation cascade. SUMMARY: We will present data from our laboratory that initiation of complement cascade activation and subsequently activation of the coagulation cascade during mobilization process are dependent on mannan-binding lectin (MBL). The mannan binding pathway activates MBL-associated serine proteases (MASP-1 and MASP-2) that cleave the third complement component C3 and prothrombin. Cleavage of C3 leads to formation of classical C5 convertase and cleavage of prothrombin generates thrombin, which has "C5-like convertase" activity. Finally, both C5 convertase and thrombin cleave the fifth complement component C5, and activate distal part of the complement cascade that is crucial for egress of HSCPs from bone marrow niches into peripheral blood. PMID- 28845387 TI - Notch Signaling in the Regulation of Hematopoietic Stem Cell. AB - PURPOSE OF REVIEW: Understanding the signaling pathways that govern hematopoietic stem and progenitor cells (HSPCs) is fundamental to uncover their regulation and how this is skewed in hematological malignancies. Whether Notch is necessary for the regulation of mammalian HSPCs is still unclear. We therefore critically review the current literature on the role of Notch in HSPCs. RECENT FINDINGS: HSPCs have shown different requirements for Notch signals in vitro and in vivo and at different stages of differentiation. Additionally, bone marrow niche cells activate Notch signaling in HSPCs enhancing their regenerative and self-renewal capacity. SUMMARY: Despite the controversy, adequate levels of Notch signaling appear necessary to avoid the development of hematological malignancies. Contrary to early studies, recent research suggests that Notch signaling may play a role in homeostatic and regenerative hematopoiesis but further investigation is necessary to understand how it is regulated by the different ligand/receptor pairings and the molecular mechanisms that are triggered. PMID- 28845388 TI - Integrated Experimental and Theoretical Studies of Stem Cells. AB - PURPOSE OF REVIEW: Stem cells have to balance self-renewal and differentiation. The dynamic nature of these fate decisions has made stem cell study by traditional methods particularly challenging. Here we highlight recent advances in the field that draw on combining quantitative experiments and modeling to illuminate the biology of stem cells both in vitro and in vivo. RECENT FINDINGS: Recent studies have shown that seemingly complex processes such as the fate decision-making of stem cells or the self-organization of developing tissues obey remarkably simple mathematical models. Negative feedback loops appear to stabilize cellular states hereby ensuring robust fate decision-making and reproducible outcomes. Stochastic fate decisions can account for the great variability observed in biological systems. SUMMARY: The study of stem cells is hampered by the necessity to track the fate of a cell's progeny over time. Confronting experiments with simple predictive models has allowed to circumvent this problem and gain insights from stem cell heterogeneity in vitro to organ morphogenesis. PMID- 28845389 TI - EBV driven natural killer cell disease of the central nervous system presenting as subacute cognitive decline. AB - Brain biopsy in patients presenting with subacute encephalopathyis never straightforward and only undertaken when a 'treatable condition' is a realistic possibility. This 63 year old right handed, immunocompetent Caucasian woman presented with an 8 month history of rapidly progressive right-sided hearing impairment, a 4 month history of intermittent headaches, tinnitus, 'dizziness', dysphagia, nausea and vomiting, with the subsequent evolution of progressive gait ataxia and a subacute global encephalopathy. The possibility of CJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. She died 9 days later and autopsy brain examination confirmed widespread subacute infarction due to an EBV positive atypical NK/T-cell infiltrate with positivity for CD3, CD56, granzyme B, perforin and EBER with absence of CD4, CD5 and CD8 expression. Molecular studies for T-cell clonality were attempted but failed due to insufficient DNA quality. Serology was consistent with past EBV infection (EBV VCA and EBNA IgG Positive). There was no evidence of disease outside the CNS. Primary central nervous system NK/T-cell lymphoma is extremely rare. The rare reported cases all present with a discrete intracranial mass, unlike the diffuse infiltrative pattern in this case. Whilst the diffuse interstitial pattern is reminiscent of chronic active EBV infection (CAEBV) seen in other organ systems such as the liver and bone marrow, the clinical presentation and epidemiologic profile are not typical for CAEBV. PMID- 28845390 TI - Melatonin Modulates Prohibitin and Cytoskeleton in the Retinal Pigment Epithelium. AB - The retinal pigment epithelium (RPE) plays imperative roles in normal retinal function by photoreceptor protection from light and phagocytosis of rod and cone outer segments during disc shedding. Melatonin is the free radical scavenger and circadian determinant to protect the RPE and retina from oxidative stress and regulate the circadian clock. The current study tested the hypothesis whether melatonin could affect cytoskeletal structure within RPE. Our Western blot analysis demonstrated that melatonin treatment up-regulated prohibitin 3-fold compared to control. beta-tubulin levels were also up-regulated by melatonin but to a lesser extent. Initial cell shape of ARPE-19 is epitheloid, however, after 30-minute treatment with melatonin, RPE cells undergo a morphological change to a fusiform shape with spindle outgrowth. Cells return to epitheloid shape after 12 hours in untreated medium. Melatonin treated cells showed increased and dissimilar distribution of prohibitin and beta-tubulin compared to non-treated cells, thus altered cytoskeletal and mitochondrial structure in the RPE. Our data implies that melatonin may play a protective role under oxidative stress, which is shown by the marker prohibitin in terms of increased expression and nuclear distribution. During the protective process, cells change their morphology. Our results suggest that melatonin treatment could be beneficial to protect mitochondria under oxidative stress and treat certain ocular diseases, including age-related macular degeneration. PMID- 28845392 TI - What the young physician should know about May-Thurner syndrome. AB - May-Thurner syndrome (MTS) is an anatomically variable condition resulting in compression of the left common iliac vein between the right common iliac artery and the underlying spine with subsequent development of a left deep vein thrombosis (DVT). Although this syndrome is rare, its true prevalence is likely underestimated. Mainly, clinical symptoms and signs include, but are not limited to, pain, swelling, venous stasis ulcers, skin pigmentation changes and post thrombotic syndrome. Correct treatment is not well established and is based on clinical presentation. Staged thrombolysis with/without prophylactic retrievable inferior vena cava filter placement followed by angioplasty/stenting of the left iliac vein appears to be the best option in MTS patients with extensive DVT. The aim of this review is to present in a simple and didactic form all variable clinical presentations of MTS and to outline possible management within the current guidelines. PMID- 28845391 TI - Neuroprotective effects of estrogen in CNS injuries: insights from animal models. AB - Among the estrogens that are biosynthesized in the human body, 17beta-estradiol (estradiol or E2) is the most common and the best estrogen for neuroprotection in animal models of the central nervous system (CNS) injuries such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic brain injury (IBI). These CNS injuries are not only serious health problems, but also enormous economic burden on the patients, their families, and the society at large. Studies from animal models of these CNS injuries provide insights into the multiple neuroprotective mechanisms of E2 and also suggest the possibility of translating the therapeutic efficacy of E2 in the treatment SCI, TBI, and IBI in humans in the near future. The pathophysiology of these injuries includes loss of motor function in the limbs, arms and their extremities, cognitive deficit, and many other serious consequences including life-threatening paralysis, infection, and even death. The potential application of E2 therapy to treat the CNS injuries may become a trend as the results are showing significant therapeutic benefits of E2 for neuroprotection when administered into the animal models of SCI, TBI, and IBI. This article describes the plausible mechanisms how E2 works with or without the involvement of estrogen receptors and provides an overview of the known neuroprotective effects of E2 in these three CNS injuries in different animal models. Because activation of estrogen receptors has profound implications in maintaining and also affecting normal physiology, there are notable impediments in translating E2 therapy to the clinics for neuroprotection in CNS injuries in humans. While E2 may not yet be the sole molecule for the treatment of CNS injuries due to the controversies surrounding it, the neuroprotective effects of its metabolite and derivative or combination of E2 with another therapeutic agent are showing significant impacts in animal models that can potentially shape the new treatment strategies for these CNS injuries in humans. PMID- 28845393 TI - The Popliteal Vein Thrombosis in A Pediatric Patient: A Case Report. AB - INTRODUCTION: The incidence of deep vein thrombosis (DVT) in pediatric patients is significantly much lower than adults. Most of the pediatric in-patients with major trauma, sepsis do not undergo routine screening for DVT. CASE REPORT: We present a case of a 12-year-old boy presented to us with minor trauma to right ankle associated with swelling, pain and had associated cough, and fever. On investigation with plain X-ray of right ankle/chest, and blood parameters, patient was suspected of having cellulitis of right leg with chest infection. Patient was treated with IV Cloxacillin and ample of rest. During the course of treatment, patient's condition deteriorated with fever, tachycardia and a swollen leg without much pain. Duplex scan was performed where the right leg revealed thrombosis of popliteal vein, while CT scan of chest with angiogram ruled out possibility of pulmonary embolism. However, CT chest showed pneumonia with pulmonary effusion. Patient was treated with low molecular heparin and IV Cloxacillin for pneumonia. Patient recovered completely and there was no recurrence during follow up period of 6 months. CONCLUSION: The possibility of DVT in pediatric should be kept in mind and when suspected, should be properly investigated and treated. PMID- 28845394 TI - A very rare Presentation of Bifocal Non Union Radius with Ipsilateral Ulnar Shaft Non Union: Case Report. AB - INTRODUCTION: A bifocal non-union of shaft of radius associated with ipsilateral non-union shaft of ulna in an adult has not been reported in the literature till date to the best of our knowledge, though few similar cases of fresh fractures have been reported. The case being reported by us is the first of its kind. CASE PRESENTATION: We report a case of bifocal non-union of shaft radius with non union ipsilateral shaft of ulna in a 48-year-old right handed male along with discussion of alternative treatment options. CONCLUSION: We describe an extremely rare and complicated non-union in which our patient got excellent results along with satisfactory functional recovery as a result of appropriate surgical treatment. PMID- 28845395 TI - Acute Both Bone Fracture in a Chronic Contracted Forearm. AB - INTRODUCTION: There is a paucity of information on management of forearm fractures through pre-existing ischemic contractures. The prevention of a Volkmann's contracture in forearm compartment syndrome requires vigilant clinical evaluation and emergent fasciotomy, but many of the patients who develop these contractures often do so as a result of delayed presentation due to substance abuse and intoxication. This case describes the first report and management of a severely displaced both bone (BB) forearm fracture through a chronic forearm Volkmann's contracture. CASE REPORT: A 39 year old female presented with an acute both bone forearm fracture in the setting of a Volkmann's contracture. Although very limited in use, the arm was functional for holding objects and was determined to be important in her activities of daily living. The surgical management involved open reduction internal fixation with radial and ulnar shortening osteotomies to restore cortical alignment secondary to the extensive overlying soft tissue contractures. CONCLUSION: Restoration of the radial bow and other standard principles of open reduction and internal fixation of BB fractures may not be as important as obtaining fracture union in patients with these complicated injuries due to the pre-existing functional limitations of the limb. The soft tissue envelope in a contracted forearm is commonly fibrotic and provides an abnormal fracture healing environment. Careful attention to osseous and soft tissue healing in the postoperative period is recommended. This report details the first case, technical difficulties, and subsequent management of a BB fracture in the setting of subsequent management of a both bone fracture in the setting of a chronic Volkmann's contracture. PMID- 28845396 TI - Dietary Patterns and Overweight/Obesity: A Review Article. AB - BACKGROUND: Dietary patterns analysis may provide insights into the influence of overall diet on overweight/obesity. In the past two decades, the relation between dietary patterns and overweight/obesity has been a research focus and a number of results were reported in the research field. METHODS: An electronic literature search was conducted in PubMed and Web of Science, to identify human studies published by Mar 2015 and written in English. The following keywords or phrases were involved: dietary patterns, dietary pattern, factor analysis, principal component analysis, diet, obesity, adiposity, overweight and BMI. All the studies were retrieved and prudent/healthy (n=17) and western/unhealthy (n=18) dietary patterns were identified. RESULTS: When compared with the lowest categories of a prudent/healthy dietary pattern, a reduced overweight/obesity risk was shown in the highest (OR=0.64; 95% CI: 0.52, 0.78; P<0.0001). While there was an increased overweight/obesity risk in the highest when compared with the lowest categories of a western/unhealthy dietary pattern (OR=1.65; 95% CI: 1.45, 1.87; P<0.0001). CONCLUSION: A prudent/healthy dietary pattern and limit intake of western/unhealthy dietary pattern should be followed, which helps to keep a healthy body mass. PMID- 28845397 TI - Diagnosis Protocol of Stomach Distemperament for Clinical Practice in Iranian Traditional Medicine: A Narrative Review. AB - BACKGROUND: In Iranian traditional medicine (ITM) stomach is the important organ in the body. Its disorders can affect other organs such as liver, heart and also can cause depression. Stomach distemperaments can cause some disorders. The purpose of this study was to provide a diagnostic method of stomach distemperament for clinical practice. METHODS: In this study authoritative ITM books such as Canon of Avicenna, Zakhirah-E-Kharazm Shahi by Hakim Esmail Jorjani, Kamel al-Sina'ah al-Tibbiyah by Ali ibn al-'Abbas al-Majusi were assessed and symptoms and signs of stomach distemperament were collected. RESULTS: Stomach has some normal temperament. The imbalance in temperament and humor can cause distemperments. There are 12 types of stomach distemperament and based on symptoms and signs a primary protocol is designed for diagnosis of stomach distemperament. CONCLUSION: There is no available guideline for gastric distemperamet diagnosis protocol. As a result, the presented protocol should be considered for use in clinical practice. PMID- 28845398 TI - Prevalence of the Skipping Breakfast among the Iranian Students: A Review Article. AB - BACKGROUND: Adolescence is an important period since the establishment of dietary pattern can also affect the adulthood. This study aimed to estimate the overall prevalence of skipping breakfast among Iranian students. METHODS: The international and national databases, including Medline, Scopus, Science Direct, Embase, Web of sciences, Google Scholar, MagIran, and SID were searched 1945-2016 as per case. All studies addressing the prevalence of skipping breakfast among Iranian students were extracted. RESULTS: Out of 322 records, 24 articles remained for meta-analysis. The total pooled prevalence of skipping the breakfast was 0.216 (95% CI: 0.213-0.22), the girls had a higher percentage for skipping breakfast compared with boys (26% vs. 18%). CONCLUSION: Skipping breakfast is more prevalent in girls. Interventions are required to promote breakfast consumption in the targeted Iranian students, especially the girls. PMID- 28845399 TI - The Existing Approaches to Sexuality Education Targeting Children: A Review Article. AB - BACKGROUND: We aimed to assess what is already known about sexuality education (SE)-related policy or practical issues using review methods to search and critically appraise the existing SE approaches targeting children under age 12 yr. METHODS: We completed the data collection by an extensive search of the English and Persian published and unpublished literature, evidence from experts in the topic, and by searching citations. The MeSH-terms were sexuality and training, sexuality education and programs or approaches, sexuality and children, sexuality education and parents, sex or sexuality education, sex education and parents or caregivers. A systematic search of medical and health-related databases, the Cochrane Library and Web of Science was undertaken for the years 1970-2015 together with citation searching, reference list checking and recommendations from stakeholders to identify evidence for SE. RESULTS: According to the inclusion criteria, 20 documents were identified. They were synthesized into three main categories as sexuality-related knowledge, attitudes, and parents' skills to manage children's sexual behavior and related education. Employed approaches to children's sexuality were reported to be effective in developing healthy sexual behavior in children. Education was identified as the primary focus of the included packages and guidelines. Parents were recognized as first line educators in SE. However, interventions aiming to improve parents' skills in SE for children were limited. In other words, developing skills in parents, and their competency in children's sexual behavior management were not specified in the existing programs. CONCLUSION: Parents' skill-building must be the focus of SE programs in order to address children' sexual development goals. PMID- 28845400 TI - The Patterns of Graded Psychological Nursing Care for Patients after Cardiothoracic Surgeries. AB - BACKGROUND: To investigate the interventional efficacy and clinical significance of graded psychological nursing care for patients who have undergone cardiothoracic surgery by providing graded psychological nursing care for these patients according to the results of their psychological evaluation. METHODS: In this interventional study, 110 patients who had undergone cardiothoracic surgery between 2014 and 2015 in the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China, were enrolled. We divided them into two groups of 55 patients each, namely, a control group and a treatment group. For patients in the control group, we applied regular psychological nursing care; those in the treatment group were further divided into three different psychological grades after being assessed using Symptom Checklist 90 (SCL-90) and the Pittsburgh Sleep Quality Index (PSQI); patients at each grade were treated by graded psychological nursing care in addition to regular psychological nursing care. RESULTS: Significant decreases, with statistically significant differences (P<0.01), were observed in the SCL-90 and PSQI scores of patients in the treatment group as compared with the control group. Patients in the treatment group, who underwent graded psychological nursing care according to their varying psychological conditions, showed better improvement in their post surgery emotional state and sleep quality than those in the control group, thus indicating the great significance of graded psychological nursing care in clinical practices. CONCLUSION: Applying graded psychological nursing care in post-operation cardiothoracic patients improved nursing care efficiency and alleviated patients' negative feelings. Therefore, this type of nursing care should be further promoted and utilized in clinical practice for effective rehabilitation of patients. PMID- 28845401 TI - The Role of NT-proBNP in the Diagnosis of Ventricular Arrhythmias in Patients with Systemic Sclerosis. AB - BACKGROUND: In patients with systemic sclerosis, NT-proBNP is a useful diagnostic marker for pulmonary hypertension and ventricular dysfunction, with important prognostic significance. The aim of this study was to assess the relationship between the NT-proBNP levels and the presence and severity of ventricular arrhythmias in patients with scleroderma. METHODS: Forty consecutive patients with a diagnostic of systemic sclerosis according to the EULAR criteria admitted at the Rheumatology Clinic of Cluj-Napoca, Romania, from Jan 2014 to Apr 2014 were enrolled. Patients underwent a 12-lead ECG and a 24-hour Holter ECG monitoring for ventricular arrhythmias evaluation. Blood sample testing (including NT-proBNP level measurements), echocardiography, spirometry, chest X ray and, when considered appropriate, high-resolution chest CT were performed. RESULTS: Sixty percent of patients (n=24) had abnormal NT-proBNP serum levels (>125 pg/ml) and 10 patients had >100 PVC/24 h. There was a statistically significant correlation between the NT-proBNP levels and the total number of premature ventricular contractions (PVC) (r=0.445, P=0.006), total number of isolated PVC (r=0,493, P=0.002), total number of ventricular couplets (r=0.379, P=0.021) and the number of PVC morphologies (r=0.501, P=0.002). The presence of an NT-proBNP serum level >287 pg/ml had a sensitivity of 55% and a specificity of 93% in predicting the presence of complex ventricular arrhythmias on 24-hour Holter ECG monitoring. CONCLUSION: NT-proBNP levels could become a useful ventricular arrhythmia marker for assessing the arrhythmic risk in patients with systemic sclerosis. PMID- 28845402 TI - Population-based Prostate Cancer Screening in Kazakhstan. AB - BACKGROUND: Issues of mass screening for prostate cancer rather controversial since 2013 in 11 regions of Kazakhstan introduced a population-based screening for prostate cancer, so we need to evaluate its results. METHODS: In different regions of Kazakhstan during 2013-2015, a total of 321548 prostate-specific antigens (PSA) were determined in men aged 50-66 yr, under the Prostate Health Index (PHI) and transrectal ultrasonography (TRUS) guided prostate biopsy with histological examination. RESULTS: PSA level up to 4 ng/ml in 310870 (96.7%) men, PSA level between 4 and 10 ng/ml in 8 624 (2.7%) men, PSA level above 10 ng/ml in 2054 (0.6%) men. PHI was identified in 5716 (1.8%) men, of which 2867 cases were with PHI >= 25 (35.9%). Totally, 3680 biopsies (1.1%) of the prostate were performed. As part of the screening, 2870 cases (0.88%) of benign prostatic hyperplasia and prostatic intraepithelial neoplasia were found. Of 742 cases of prostate cancer (0.23%) were revealed. The stages of prostate cancer screening were as follows: stage I in 172 men (23.2%), stage II in 444 men (59.8%), stage III in 98 men (13.2%) and stage IV in 28 (3.8%) men. The indicators of prostate cancer early diagnosis in the I-II stages were bigger in the "screening regions" than in the "traditional diagnostics" regions: RR 1.35 95% CI (1.24 - 1.46), OR 1.84 95% CI (1.58-2.15). Prostate cancer was detected at I-II stages in the "screening" regions only by screening vs traditional diagnostics, with RR 1.64 95% CI (1.56 - 1.73), OR 4.77 95% CI (3.87-5.87). CONCLUSION: Implementation of screening can improve the diagnosis of prostate cancer in the early stages. PMID- 28845403 TI - The Effect of Comprehensive Care on the Patients Received Minimally Invasive Percutaneous Nephrolithotomy. AB - BACKGROUND: We analyzed the effect of comprehensive care on the patients who received minimally invasive percutaneous nephrolithotomy (MPCNL). METHODS: Patients hospitalized from 2013-2014 in Zhumadian Central Hospital (n=124) were enrolled and divided into two groups on random basis. The control group was treated with routine nursing model while the observation group was given comprehensive care additionally. The surgery time, degree of comfort, complications and successful cases, hospitalization time, sleep quality, nursing satisfaction and changes of systolic pressure, pulse and respiratory at different time were observed and analyzed. RESULTS: The surgery time of the control group was significantly longer than that of observation group (P<0.05). The observation group felt more comfortable and showed more significant successful cases than the control group. Moreover, the hospitalization time were significantly reduced in observation group when compared with control group (P<0.05). The sleep quality of the observation group was significantly better than that of the control group (P<0.05). Before anesthesia, diastolic blood pressure, systolic blood pressure, pulse and respiration were not significantly different between the two groups. The diastolic blood pressure, systolic blood pressure, pulse and respiration after anesthesia, intraoperative 30 min, postoperative 30 min and other moments were significantly different. The incidence of complications in the control group was significantly higher than that in the observation group. The nursing satisfaction of the observation group was significantly higher than that of the control group. CONCLUSION: The comprehensive care on the patients undergoing MPCNL was effective, and it can dramatically shorten surgery time, improve the success rate, improve the sleep quality of patients, keep life sign stable and minimize the complications. PMID- 28845404 TI - Barriers of Developing Medical Tourism in a Destination: A Case of South Korea. AB - BACKGROUND: This study aimed to determine the efficient factors that potentially lead to the barriers of developing medical tourism in South Korea. METHODS: To explore the current medical tourism trend, a qualitative procedure was adopted. Besides analyzing the current situation of medical tourism in Korea through a systematic searching on the available information and publications, in-depth interviews were conducted to collect data from relevant authorities and representatives of medical tourism associations in this country. RESULTS: The result revealed, although government have supported this industry, that lack of specialty and expertise among the health care practitioners in the scope of cross cultural communication, seems to be the core barrier to development of medical tourism in Korea. Demands for convenient promotional activities, policy making and action regulation are the other effective factors. DISCUSSION: Several strategies are required in order to address and combat these barriers, such as governmental support for cultural training, cooperative efforts to encourage health practitioners involved to enhance their cultural and linguistic competence in international scale. PMID- 28845405 TI - Essential Nutrition and Food Systems Components for School Curricula: Views from Experts in Iran. AB - BACKGROUND: This study aimed to investigate food experts' views on important nutrition and food systems knowledge issues for education purposes at schools in Iran. METHODS: In 2012, semi-structured, face-to-face or telephone interviews were conducted with twenty-eight acknowledged Iranian experts in food and nutrition fields. Participants were selected from four major provinces in Iran (Tehran, Isfahan, Fars and Gilan). Open-ended interview questions were used to identify nutrition and food systems knowledge issues, which experts considered as important to be included in school education programs. Qualitative interviews were analyzed thematically using NVivo. RESULTS: A framework of knowledge that would assist Iranian students and school-leavers to make informed decisions in food-related areas was developed, comprising five major clusters and several sub clusters. Major knowledge clusters included nutrition basics; food production; every day food-related practices; prevalent nutritional health problems in Iran and improvement of students' ethical attitudes in the food domain. CONCLUSION: These findings provide a guide to curriculum developers and policy makers to assess current education curricula in order to optimize students' knowledge of nutrition and food systems. PMID- 28845406 TI - In Vitro Hb Production in B-thalassemia Patients Is Not a Predictor of Clinical Responsiveness to Hydroxyurea. AB - BACKGROUND: The hematologic response to hydroxyurea (HU) is varied among beta thalassemia (BT) patients. The BCL11A and SOX6 genes are involved in response to HU. This study aimed to investigate the in-vitro responsiveness of HU among BT major patients homozygote for IVSII-1G>A mutation and XmnI single nucleotide polymorphism (SNP) in order to find whether the in-vitro Hb concentration is a predictor of clinical (HU) responsiveness. METHODS: In this case-control study, twenty BT patients homozygote for IVSII-1G>A mutation and XmnI SNP from Thalassemia Research Center, Sari, Iran in 2015 were selected and categorized into two groups of 10 Responder (R) and 10 Non-Responder (NR) according to their clinical HU response. Ten healthy individuals as a control group were also selected. Hematopoietic erythroid progenitors were expanded from peripheral blood. Hb concentration was measured using photometry method. The flow cytometry and real-time PCR methods were applied for the analysis of cell surface markers (CD71 and CD235a) and gene expression (BCL11A and SOX6), respectively. RESULTS: R and NR groups produced higher amount of Basic Hb than C group in cell culture medium at day 14 (P<0.05). After HU treatment, in R group, Hb levels was significantly elevated in comparison to NR and C group (P<0.05). BCL11A expression was decreased after exposure to HU in all groups while SOX6 expression was only down-regulated in C group, and its expression was increased in R and NR groups after HU treatment. CONCLUSION: Since different factors including wide networks of intracellular factors and individual differences between patients can affect response to HU in patients, the increasing Hemoglobin on culture medium alone cannot predict clinical responsiveness to that drug. PMID- 28845407 TI - The Prevalence of Psychiatric Distress and Associated Risk Factors among College Students Using GHQ-28 Questionnaire. AB - BACKGROUND: Adolescent and young adults are at increased risk of psychiatric distress and serious disability. We estimated the prevalence and associated risk factors of psychiatric distress among the college students of Hamadan University of Medical Sciences, Iran. METHODS: We performed this cross-sectional study, from Jan to May 2016 at Hamadan University of Medical Sciences, Hamadan, Iran. Students filled out voluntarily an anonymous self-administered questionnaire, including demographic characteristics, personal information, behavioral risk factors, and a validated Persian version of the GHQ-28 questionnaire, including somatic symptoms (items 1-7), anxiety/insomnia (items 8-14), social dysfunctions (items 15-21), and severe depression (items 22-28). RESULTS: Of 1259 participants, 518 (41.1%) had psychiatric distress, 166 (13.2%) had heterosexual intercourse, 100 (8.0%) had homosexual intercourse, 204 (16.2%) were smokers (31.6% in males and 6.3% in females), 124 (9.9%) reported a history of using opium/psychedelic substances, 204 (16.2%) reported suicide thought, and 103 (8.2%) had attempted suicide at least once in the past. After adjusting odds ratio (95% CI) for age and sex, psychiatric distress were significantly associated with emotional breakdown 2.67 (2.09, 3.40), heterosexual intercourse 2.56 (1.82, 3.62), homosexual intercourse 2.42 (1.57, 3.71), smoking 3.19 (2.29, 4.45), substance abuse 5.03 (3.26, 7.76), suicide thought 7.81 (5.42, 11.27), suicide attempt 5.64 (3.49, 9.12), uninterested in the discipline 2.29 (1.70, 3.07), and non-optimistic about future 2.16 (1.63, 2.86). CONCLUSION: A majority of college students had psychiatric distress and a substantial number of them reported one or more high-risk behaviors that if neglected, may severely impair the students' function and influence their subsequent development and productive lives. PMID- 28845408 TI - Pain in the Context of Family: A Study on Factors Contributing to Marital Satisfaction among Couples Suffering from Chronic Pain. AB - BACKGROUND: Chronic pain is associated with increased stress in families and has its own impact on the relationship between members of the family. Among couples, if one of them suffers from chronic pain, this may influence marital satisfaction in both of them and given the importance of marital satisfaction in the prediction of successful treatment outcome, it is important to investigate pain and personality-related factors contributing to inter-individuals variation in marital satisfaction. METHODS: Participants in this study were recruited from Atieh Hospital and Rasa Pain Clinic, Tehran, Iran in the year 2013. Chronic pain patients and their spouses were asked to complete a battery of questionnaires including measures on pain cognition and marital satisfaction. Using correlation and regression analysis factors with the highest level of contribution to marital satisfaction were investigated. RESULTS: Spouses' level of rumination about patients' pain has been found to be positively correlated with marital satisfaction in patients. In addition, patients' depression has been found to be the best predictor of level of marital satisfaction in patients. In addition, patients' level of depression, disability and perceived helplessness has been found to be the best predictors of marital satisfaction in their spouses. CONCLUSION: To improve marital satisfaction among chronic pain patients, their support-seeking needs should be satisfied through involvement of their spouses in the process of treatment. To improve marital satisfaction among patients' spouses, we should help patients regain their ability, improve their mood, and make patients believe that they have access to the support of their caregivers. PMID- 28845409 TI - Level and Factors Related to Unintended Pregnancy with a Brief Review of New Population Policies in Iran. AB - BACKGROUND: High rate of unintended pregnancies in Iran is one of problems in family planning. The main goal of this study was to determine the rate of unintended pregnancies and to examine factors among married women in Shiraz City, Iran. It also discusses the possible effects of new population policies on the rate of unintended pregnancy. METHODS: In this quantitative and survey study, data were collected by researcher-made questionnaire with interviewer from 400 pregnant women in Shiraz City referred to public and private health centers for prenatal care in 2013. Data were analyzed by SPSS both descriptively and analytically. RESULTS: Overall, 17% of total pregnancies were unintended. The highest rate occurred among couples whose level of education was under diploma. In addition, women above 39 yr old experienced a higher rate of unintended pregnancy. The most popular methods were pills, withdrawal, and condom. The highest rate of unintended pregnancy was related to withdrawal. Knowledge about modern contraceptives particularly emergency contraceptives was low. Age, residence place, use of traditional contraception methods, knowledge about contraceptives, fear of side effects and couple agreement on contraception method were the main predictors of unintended pregnancy. CONCLUSION: There is still unmet need in family planning. The main predictors of unintended pregnancies are high prevalence of traditional contraception methods and insufficient knowledge about modern contraception methods. Policymakers should pay more attention to these issues. Furthermore, although Iranian policy makers are worried about low fertility, they need to be aware that new population policy through restriction of access to family planning services is effective, but also may exacerbate the problem by leading to a higher chance of unintended pregnancy. PMID- 28845410 TI - Efficacy of Botox versus Placebo for Treatment of Patients with Major Depression. AB - BACKGROUND: Treatment of major depression is crucial to decrease the burden of disease. Hence, in this study, the efficacy of Botox was compared with placebo for treatment of patients with major depression. METHODS: In this randomized clinical trial, 28 consecutive patients with major depression were enrolled. The patients were randomly assigned to receive either Botox or placebo and the scores of Beck Depression Inventory were determined and compared at baseline and after two and six weeks in the groups and between the groups. In addition, the drug adverse effects were compared between groups. This study had been registered in TCTR with TCTR20170409001 code. RESULTS: There was a statistically significant difference two group for 6th week Beck Score (P=0.004), but at baseline and after two weeks, there was no significant difference (P>0.05). None of the patients experienced side effects. CONCLUSION: Finally, Botox is effective for treatment of patients with major depression and it has a high safety. PMID- 28845411 TI - Leech Therapy for Treating Priapism: Case Report. AB - Priapism is well-defined by persistent, painful penile erection which happens without sexual stimulation. Currently, the hirudotherapy is practiced to treat venous congestion and subsequent compartment syndrome. Here we will report a case of a male with priapism treated by leeches. The case was a 26 yr old young single male referred to the Razi Hospital Emergency Department, Guilan University of Medical Sciences, Rasht, Iran due to long-time spontaneous erections. The patient had no history of mental disorders, trauma or sickle cell anemia. we insert two leeches in each side of penile shaft for two hours, after a one hour break we insert do in same manner for another cycle. At follow-up two days later he had significantly decreased pain, though still had cavernosal swelling and tenderness to palpation. The patient was subsequently discharged after three days of admission. The pain and perineal swelling completely resolved over the course of one month. In this case, chronology indicates that leech therapy was possibly treatment option for priapism. This procedure seems to be non-invasive treatment strategy worth to discussing in such patients. PMID- 28845412 TI - Effects of Workout and Meditation Phenomenon Program on Body Composition, Flexibility, and Blood Pressure Data Analysis. PMID- 28845413 TI - Diet and Mental Health: What Should Be Done for Malaysian Adolescents. PMID- 28845414 TI - Consumption of Medicaments in the Slovak Republic. PMID- 28845415 TI - Understanding the Dynamics of Poliomyelitis Spread in Pakistan. PMID- 28845416 TI - Parents' Dental Knowledge and Oral Hygiene Habits in Slovak Children. PMID- 28845417 TI - Increasing Rate of Mortality Due to HIV/AIDS in Iranian Children: An Alarm for Health Policymakers. PMID- 28845418 TI - V64M Mutation in Leukemia Inhibitory Factor Gene in Women Infertility. PMID- 28845419 TI - Butterfly Patients in Iran Waiting to Specific Attention from Authorities. PMID- 28845420 TI - Task-Related Modulations of BOLD Low-Frequency Fluctuations within the Default Mode Network. AB - Spontaneous low-frequency Blood-Oxygenation Level-Dependent (BOLD) signals acquired during resting state are characterized by spatial patterns of synchronous fluctuations, ultimately leading to the identification of robust brain networks. The resting-state brain networks, including the Default Mode Network (DMN), are demonstrated to persist during sustained task execution, but the exact features of task-related changes of network properties are still not well characterized. In this work we sought to examine in a group of 20 healthy volunteers (age 33 +/- 6 years, 8 F/12 M) the relationship between changes of spectral and spatiotemporal features of one prominent resting-state network, namely the DMN, during the continuous execution of a working memory n-back task. We found that task execution impacted on both functional connectivity and amplitude of BOLD fluctuations within large parts of the DMN, but these changes correlated between each other only in a small area of the posterior cingulate. We conclude that combined analysis of multiple parameters related to connectivity, and their changes during the transition from resting state to continuous task execution, can contribute to a better understanding of how brain networks rearrange themselves in response to a task. PMID- 28845421 TI - The Yin & Yang of Mitochondrial Architecture - Interplay of MICOS and F1Fo-ATP synthase in cristae formation. AB - Oxidative phosphorylation takes place at specialized compartments of the inner mitochondrial membrane, the cristae. The elaborate ultrastructure of cristae membranes enables efficient chemi-osmotic coupling of respiratory chain and F1Fo ATP synthase. Dynamic membrane remodeling allows mitochondria to adapt to changing physiological requirements. The mitochondrial contact site and cristae organizing system (MICOS) and the oligomeric ATP synthase have been known to govern distinct features of cristae architecture. A new study 1 on the crosstalk between these two machineries now sheds light on the mechanisms of cristae formation and maintenance. PMID- 28845424 TI - Out with the old: Hsp90 finds amino acid residue more useful than co-chaperone protein. AB - Redundant functions maintained from single to multi-cellular organisms have made Saccharomyces cerevisiae an important model for the analysis of conserved com plex cellular processes. Yeast has been especially useful in understanding the regulation and function of the essential molecular chaperone, Heat Shock Protein 90 (Hsp90). Research focused on Hsp90 has determined that it is highly regulated by both co-chaperones and posttranslational modifications. A recent study per formed by (Zuehlke et al., 2017) demonstrates that the function of one co chaperone in yeast is replaced by posttranslational modification (PTM) of a single amino acid within Hsp90 in higher eukaryotes. PMID- 28845422 TI - Integrative metabolomics as emerging tool to study autophagy regulation. AB - Recent technological developments in metabolomics research have enabled in-depth characterization of complex metabolite mixtures in a wide range of biological, biomedical, environmental, agricultural, and nutritional research fields. Nuclear magnetic resonance spectroscopy and mass spectrometry are the two main platforms for performing metabolomics studies. Given their broad applicability and the systemic insight into metabolism that can be obtained it is not surprising that metabolomics becomes increasingly popular in basic biological research. In this review, we provide an overview on key metabolites, recent studies, and future opportunities for metabolomics in studying autophagy regulation. Metabolites play a pivotal role in autophagy regulation and are therefore key targets for autophagy research. Given the recent success of metabolomics, it can be expected that metabolomics approaches will contribute significantly to deciphering the complex regulatory mechanisms involved in autophagy in the near future and promote understanding of autophagy and autophagy-related diseases in living cells and organisms. PMID- 28845423 TI - Cristae architecture is determined by an interplay of the MICOS complex and the F1FO ATP synthase via Mic27 and Mic10. AB - The inner boundary and the cristae membrane are connected by pore-like structures termed crista junctions (CJs). The MICOS complex is required for CJ formation and enriched at CJs. Here, we address the roles of the MICOS subunits Mic27 and Mic10. We observe a positive genetic interaction between Mic27 and Mic60 and deletion of Mic27 results in impaired formation of CJs and altered cristae membrane curvature. Mic27 acts in an antagonistic manner to Mic60 as it promotes oligomerization of the F1FO-ATP synthase and partially restores CJ formation in cells lacking Mic60. Mic10 impairs oligomerization of the F1FO-ATP synthase similar to Mic60. Applying complexome profiling, we observed that deletion of Mic27 destabilizes the MICOS complex but does not impair formation of a high molecular weight Mic10 subcomplex. Moreover, this Mic10 subcomplex comigrates with the dimeric F1FO-ATP synthase in a Mic27-independent manner. Further, we observed a chemical crosslink of Mic10 to Mic27 and of Mic10 to the F1FO-ATP synthase subunit e. We corroborate the physical interaction of the MICOS complex and the F1FO-ATP synthase. We propose a model in which part of the F1FO-ATP synthase is linked to the MICOS complex via Mic10 and Mic27 and by that is regulating CJ formation. PMID- 28845425 TI - Having your cake and eating it - Staphylococcus aureus small colony variants can evolve faster growth rate without losing their antibiotic resistance. AB - Staphylococcus aureus can produce small colony variants (SCVs) during infections. These cause significant clinical problems because they are difficult to detect in standard microbiological screening and are associated with persistent infections. The major causes of the SCV phenotype are mutations that inhibit respiration by inactivation of genes of the menadione or hemin biosynthesis pathways. This reduces the production of ATP required to support fast growth. Importantly, it also decreases cross-membrane potential in SCVs, resulting in decreased uptake of cationic compounds, with reduced susceptibility to aminoglycoside antibiotics as a consequence. Because SCVs are slow-growing (mutations in men genes are associated with growth rates in rich medium ~30% of the wild-type growth rate) bacterial cultures are very susceptible to rapid takeover by faster-growing mutants (revertants or suppressors). In the case of reversion, the resulting fast growth is obviously associated with the loss of antibiotic resistance. However, direct reversion is relatively rare due to the very small genetic target size for such mutations. We explored the phenotypic consequences of SCVs evolving faster growth by routes other than direct reversion, and in particular whether any of those routes allowed for the maintenance of antibiotic resistance. In a recent paper (mBio 8: e00358-17) we demonstrated the existence of several different routes of SCV evolution to faster growth, one of which maintained the antibiotic resistance phenotype. This discovery suggests that SCVs might be more adaptable and problematic that previously thought. They are capable of surviving as a slow growing persistent form, before evolving into a significantly faster-growing form without sacrificing their antibiotic resistance phenotype. PMID- 28845426 TI - Lung function and disease severity in cystic fibrosis patients heterozygous for p.Arg117His. AB - Expression of p.Arg117His cystic fibrosis (CF) transmembrane conductance regulator is influenced by a polythymidine (poly-T) tract and a thymidine-guanine (TG) repeat on intron 9, which vary in length and affect exon 10 skipping. We compared clinical characteristics and the rate of progression of lung disease of CF patients carrying the p.Arg117His mutation with different intron 9 varying sequences (poly-T) and mutation classes in trans. Data were collected from patients in Northern Ireland, UK, including diagnostic features, sweat chloride, nutritional status, sputum microbiology, CF-related complications and lung function. Poly-T and TG repeats were determined by PCR. Forced expiratory volume in 1 s (FEV1) decline was determined from linear regression of FEV1 measurements of patients over time. We identified 62 patients with p.Arg117His, 55 with a class I/II mutation in trans and six with p.Arg117His/p.Gly551Asp. 42 patients had 5T and 13 had 7T. All patients had 12 TG repeats. Patients with p.Arg117His 5T had greater lung function decline, sweat chloride concentrations, pancreatic insufficiency and prevalence of Pseudomonas aeruginosa infection compared with patients with p.Arg117His-7T. Lung function decline and disease severity in p.Arg117His is determined by the poly-T tract length and identity of the mutation in trans. Patients with p.Arg117His-5T and a second class I/II mutation have a severity similar to p.Phe508del homozygous patients, although lung function decline is delayed to an older age. There may be linkage disequilibrium between p.Arg117His and 12 TG repeats. PMID- 28845427 TI - Pro-tumoural CXCL10/CXCR3-A autocrine loop in invasive mucinous lung adenocarcinoma. AB - Invasive mucinous adenocarcinoma (IMA) is a mucinous variant of lepidic predominant lung adenocarcinoma (LPA) and associated with a worse prognosis. We postulated that cytokine expression would enable us to differentiate IMA from LPA in terms of prognosis and acquisition of pro-tumoural capacities. A 30-cytokine panel was assessed in bronchoalveolar lavage fluids (BALF) from IMA (n=38), LPA (n=25) and control samples (n=7). We investigated the expression of differentially expressed cytokines and splice variants of their receptors in surgical samples. The presence of EGFR and KRAS mutations were determined. We also examined the expression of cytokines and splice variants of their receptors in different cell lines, exploring their functional impact on signalling pathways, proliferation and migration. Only C-X-C motif chemokine 10 (CXCL10) was differentially expressed, namely overexpressed in IMA BALF compared with LPA. CXCL10 overexpression in BALF was linked to a worse prognosis. In surgical samples, CXCL10 and its receptor C-X-C motif chemokine receptor 3 (CXCR3) were overexpressed in IMA compared to LPA. A pro-tumoural CXCR3-A splice variant was overexpressed in IMA, suggesting a CXCL10/CXCR3-A autocrine loop in IMA. CXCL10 and CXCR3 expression were not correlated with EGFR or KRAS status. CXCL10 up regulated CXCR3-A expression, Erk1/2 phosphorylation and enhanced migration in the mucinous H2228 cell line. CXCL10/CXCR3-A may play a pro-tumoural role in IMA via an autocrine mechanism. PMID- 28845428 TI - Variations in the prevalence of childhood asthma and wheeze in MeDALL cohorts in Europe. AB - While there is evidence for variations in prevalence rates of childhood wheeze and asthma between countries, longitudinal, individual-level data are needed to understand these differences. The aim of this study was to examine variations in prevalence rates of childhood asthma, wheeze and wheeze with asthma in Europe. We analysed datasets from 10 MeDALL (Mechanisms of the Development of ALLergy) cohorts in eight countries, representing 26 663 children, to calculate prevalence rates of wheeze and asthma by child age and wheeze with asthma at age 4 years. Harmonised variables included outcomes parent-reported wheeze and parent-reported doctor-diagnosed asthma, and covariates maternal education, parental smoking, pets, parental asthma, doctor-diagnosed allergic rhinitis, doctor-diagnosed eczema and wheeze severity. At age 4 years, asthma prevalence varied from 1.72% in Germany to 13.48% in England and the prevalence of wheeze varied from 9.82% in Greece to 55.37% in Spain. Adjusted estimates of the proportion of 4-year-old children with wheeze diagnosed with asthma remained highest in England (38.14%, 95% CI 31.38-44.90%) and lowest in Spain (15.94%, 95% CI 6.16-25.71%). The large differences in prevalence rates of asthma, wheeze and wheeze with asthma at age 4 years between European cohorts may indicate that childhood asthma is more readily diagnosed in some countries while going unrecognised elsewhere. PMID- 28845429 TI - Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis. AB - In chronic hypersensitivity pneumonitis (CHP), lack of improvement or declining lung function may prompt use of immunosuppressive therapy. We hypothesised that use of azathioprine or mycophenolate mofetil with prednisone reduces adverse events and lung function decline, and improves transplant-free survival. Patients with CHP were identified. Demographic features, pulmonary function tests, incidence of treatment-emergent adverse events (TEAEs) and transplant-free survival were characterised, compared and analysed between patients stratified by immunosuppressive therapy. A multicentre comparison was performed across four independent tertiary medical centres. Among 131 CHP patients at the University of Chicago medical centre (Chicago, IL, USA), 93 (71%) received immunosuppressive therapy, and had worse baseline forced vital capacity (FVC) and diffusing capacity, and increased mortality compared with those who did not. Compared to patients treated with prednisone alone, TEAEs were 54% less frequent with azathioprine therapy (p=0.04) and 66% less frequent with mycophenolate mofetil (p=0.002). FVC decline and survival were similar between treatment groups. Analyses of datasets from four external tertiary medical centres confirmed these findings. CHP patients who did not receive immunosuppressive therapy had better survival than those who did. Use of mycophenolate mofetil or azathioprine was associated with a decreased incidence of TEAEs, and no difference in lung function decline or survival when compared with prednisone alone. Early transition to mycophenolate mofetil or azathioprine may be an appropriate therapeutic approach in CHP, but more studies are needed. PMID- 28845430 TI - Stratification of eosinophilic asthma patients treated with reslizumab and GINA Step 4 or 5 therapy. AB - Reslizumab, an anti-interleukin-5 monoclonal antibody, significantly reduces exacerbation frequency and improves lung function, asthma control and quality of life in adults with severe eosinophilic asthma, as demonstrated in Phase III studies. This secondary analysis assessed reslizumab's efficacy in patients receiving baseline treatment per Global Initiative for Asthma (GINA) Step 4 and Step 5 guidelines. Pooled data from duplicate, Phase III, reslizumab versus placebo studies in patients with severe eosinophilic asthma (blood eosinophils >=400 cells.uL-1) were stratified by baseline therapy. Efficacy assessments were exacerbation rates and changes from baseline forced expiratory volume in 1 s (FEV1) and patient-reported outcomes. Of 953 patients, 69% (n=657) and 11% (n=106) were receiving Step 4 and Step 5 therapy, respectively. Compared with placebo, reslizumab reduced exacerbation rates by 53% (95% CI 0.36-0.62) and 72% (95% CI 0.15-0.52), in Step 4 and Step 5 groups respectively. By study end, reslizumab increased FEV1 in Step 4 and Step 5 groups by 103 mL (95% CI 52-154 mL) and 237 mL (95% CI 68-407 mL), respectively. Reslizumab also improved patient reported outcomes compared with placebo in both groups. Reslizumab reduces exacerbation rates and improves lung function and patient-reported outcomes in patients with eosinophilic asthma receiving therapy per Steps 4 and 5 of the GINA guidelines. PMID- 28845431 TI - Mapping QTL for Root and Shoot Morphological Traits in a Durum Wheat * T. dicoccum Segregating Population at Seedling Stage. AB - A segregating population of 136 recombinant inbred lines derived from a cross between the durum wheat cv. "Simeto" and the T. dicoccum accession "Molise Colli" was grown in soil and evaluated for a number of shoot and root morphological traits. A total of 17 quantitative trait loci (QTL) were identified for shoot dry weight, number of culms, and plant height and for root dry weight, volume, length, surface area, and number of forks and tips, on chromosomes 1B, 2A, 3A, 4B, 5B, 6A, 6B, and 7B. LODs were 2.1 to 21.6, with percent of explained phenotypic variability between 0.07 and 52. Three QTL were mapped to chromosome 4B, one of which corresponds to the Rht-B1 locus and has a large impact on both shoot and root traits (LOD 21.6). Other QTL that have specific effects on root morphological traits were also identified. Moreover, meta-QTL analysis was performed to compare the QTL identified in the "Simeto" * "Molise Colli" segregating population with those described in previous studies in wheat, with three novel QTL defined. Due to the complexity of phenotyping for root traits, further studies will be helpful to validate these regions as targets for breeding programs for optimization of root function for field performance. PMID- 28845432 TI - Interaction between Corneal and Internal Ocular Aberrations Induced by Orthokeratology and Its Influential Factors. AB - PURPOSE: To investigate the interaction between corneal, internal, and total wavefront aberrations (WAs) and their influential factors during orthokeratology (OK) treatment in Chinese adolescents. METHODS: Thirty teenagers (n = 30 eyes) were enrolled in the study; spherical equivalent refraction (SE), corneal curvature radius (CCR), central corneal thickness (CCT), WAs, and the difference in limbal transverse diameter and OK lens diameter (DeltaLLD) were detected before and after one-month OK treatment. Every component of WAs was measured simultaneously by iTrace aberrometer. The influential factors of OK-induced WAs were analyzed. RESULTS: SE and CCT decreased while CCR increased significantly (P < 0.01). Higher-order aberrations (HOAs), Spherical aberrations (SAs), and coma increased significantly (P < 0.01). Corneal horizontal coma (Z31-C) and corneal spherical aberrations (Z40-C) increased (P < 0.01). The HOAs, coma, SAs, Z31-C, Z31-T, Z40-C, and Z40-T were positively correlated with SE and CCR (P < 0.01). Z3 1-C showed negative correlations with (DeltaLLD) and positive correlations with SE (P < 0.05). CONCLUSIONS: The increase in OK-induced HOAs is mainly attributed to Z31 and Z40 of cornea. Z3-1 in the internal component showed a compensative effect on the corneal vertical coma. The degree of myopic correction and increase in CCR may be the essential influential factors of the increase in Z31 and Z40. The appropriate size of the OK lens may be helpful to decrease OK-induced vertical coma. PMID- 28845433 TI - Urinary Neutrophil Gelatinase-Associated Lipocalin Is Complementary to Albuminuria in Diagnosis of Early-Stage Diabetic Kidney Disease in Type 2 Diabetes. AB - BACKGROUND: Two clinical phenotypes of diabetic kidney disease (DKD) have been reported, that is, with or without increased albuminuria. The aim of study was to assess the usefulness of urinary neutrophil gelatinase-associated lipocalin (uNGAL) for the early diagnosis of DKD in the type 2 diabetes mellitus (T2DM). METHODS: The study group consisted of 123 patients with T2DM (mean age 62 +/- 14 years), with urine albumin/creatinine ratio (uACR) < 300 mg/g and eGFR >= 60 ml/min/1.73 m2. The control group included 22 nondiabetic patients with comparable age, sex, and comorbidities. uNGAL, albumin, and creatinine were measured in the first morning urine samples. uACR and uNGAL/creatinine ratios (uNCR) were calculated. RESULTS: In the control group, maximum uNCR was 39.64 ug/g. In T2DM group, 24 patients (20%) had higher results, with the maximum value of 378.6 ug/g. Among patients with uNCR > 39.64 ug/g, 13 (54%) did not have markedly increased albuminuria. Women with T2DM had higher uNCR than men (p < 0.001), without difference in uACR (p = 0.09). uNCR in T2DM patients correlated significantly with HbA1c. Sex, total cholesterol, and uACR were independent predictors of uNCR above 39.64 ug/g. CONCLUSIONS: Increased uNGAL and uNCR may indicate early tubular damage, associated with dyslipidemia and worse diabetes control, especially in females with T2DM. PMID- 28845435 TI - Histologic and Histomorphometric Comparison between Sintered Nanohydroxyapatite and Anorganic Bovine Xenograft in Maxillary Sinus Grafting: A Split-Mouth Randomized Controlled Clinical Trial. AB - The presence of vital bone after maxillary sinus augmentation is crucial to enhance the quality of bone-implant interface, ensuring predictable long-term results. The aims of this RCT with split-mouth design were the histologic and histomorphometric comparison of two different biomaterials in sinus elevation after 6 months of healing and the evaluation of the clinical outcomes of implants inserted in the augmented areas after 12 months of prosthetic loading. Twenty eight patients (10 females, 18 males) were treated with bilateral sinus floor elevation with lateral approach. Pure sintered nanohydroxyapatite (NHA) and anorganic bovine bone (ABB) were used as test and active control, respectively. After six months, 52 bone biopsies were harvested from 26 patients, and 107 implants were inserted in the augmented areas. Histomorphometry showed that, in the two groups, vital bone percentages were 34.9 +/- 15% (NHA) and 38.5 +/- 17% (ABB) (p = 0.428), marrow spaces percentages were 44.5 +/- 18% (NHA) and 43.5 +/- 23% (ABB) (p = 0.866), and residual graft percentages were 20.6 +/- 13% (NHA) and 22.3 +/- 12% (ABB) (p = 0.638). After 6 months of healing, no statistically significant difference was present in histomorphometric outcomes between NHA and ABB groups. Implant survival rate in NHA group after 12 months of loading was 96.4%, showing no statistically significant differences with ABB group. PMID- 28845436 TI - Overweight or Obesity, Gender, and Age Influence on High School Students of the City of Toluca's Physical Fitness. AB - MATERIAL AND METHOD: This is a prospective, cross-sectional, and correlational study with a probabilistic sampling in which 150 teenagers from three different high schools from the city of Toluca, Mexico, aged 15-17, were assessed. OBJECTIVE: To determine if weight, age, and gender have an influence on physical fitness evaluated with the EUROFIT and ALPHA-FITNESS batteries. RESULTS: Women have a higher overweight and obesity rate than men (3 : 1). Adolescents who have normal weight have regular physical fitness (74.9%). When comparing genders we found that men have a higher mean than women in the tests, except for skinfold thickness and waist circumference. Age was only correlated with the plate tapping test (p = 0.001). There are significant differences in the standing broad jump test and the Course-Navette of the EUROFIT and ALPHA-FITNESS batteries (p = 0.000). CONCLUSIONS: It is likely that regular physical activity, and not normal weight, helps generate healthy physical fitness. Male subjects had a higher mean than women, reporting a better physical fitness and more frequent physical activity. PMID- 28845437 TI - Examining Brain Networks in Prescription Opioid Users. PMID- 28845438 TI - Estimating the Proportion of Essential Tremor and Parkinson's Disease Patients Undergoing Deep Brain Stimulation Surgery: Five-Year Data From Columbia University Medical Center (2009-2014). AB - OBJECTIVE: The aim of this study was to estimate, at a tertiary referral center, the proportion of essential tremor (ET) and Parkinson's disease (PD) patients who underwent DBS surgery. BACKGROUND: DBS surgery is an important treatment for ET and PD. Surprisingly, there are no published data on the precise proportion of such patients who are referred for this procedure. METHODS: Using the computerized billing database at the Center for Parkinson's Disease and Other Movement Disorders, Columbia University Medical Center, we searched for patients who received the diagnostic codes 333.1 (tremor) and 332.0 (PD) and who were followed by a doctor at the center during the 5-year period from 2009 to 2014. The number of patients who underwent DBS surgery for these diagnoses during this time period was also determined. RESULTS: Seventy-seven patients with these diagnoses (52 PD, 14 ET, and 11 ET + PD) who were followed at the center underwent DBS surgery during this time period. The proportion of ET patients who underwent DBS surgery was 2.90% (95% confidence interval [CI]: 1.78-4.02), and for PD this was 1.38% (95% CI: 1.04-1.72). The difference was significant (P < 0.001). CONCLUSIONS: At a tertiary-referral center, 1 in 34 ET patients and 1 in 72 PD patients underwent DBS surgery. Similar studies from other major centers would be of additional value. These data are likely to have utility when planning health care services for patients with these diagnoses. PMID- 28845440 TI - Differential Salt Fractionation of Nuclei to Analyze Chromatin-associated Proteins from Cultured Mammalian Cells. AB - Nucleosomes are the core units of cellular chromatin and are comprised of 147 base pairs (bp) of DNA wrapped around an octamer of histone proteins. Proteins such as chromatin remodelers, transcription factors, and DNA repair proteins interact dynamically with chromatin to regulate access to DNA, control gene transcription, and maintain genome integrity. The extent of association with chromatin changes rapidly in response to stresses, such as immune activation, oxidative stress, or viral infection, resulting in downstream effects on chromatin conformation and transcription of target genes. To elucidate changes in the composition of proteins associated with chromatin under different conditions, we adapted existing protocols to isolate nuclei and fractionate cellular chromatin using a gradient of salt concentrations. The presence of specific proteins in different salt fractions can be assessed by Western blotting or mass spectrometry, providing insight into the degree to which they are associated with chromatin. PMID- 28845439 TI - Psychosocial Factors Associated with Substance Abuse and Anxiety on Immigrant and U.S. Born Latinos. AB - Latinos are exposed to adverse psychosocial factors that impact their health outcomes. Given the heterogeneity and rapid growth of this population, there is an urgent need to understand the mechanisms through which psychosocial factors impact substance abuse and anxiety between immigrant and U.S. born Latino adults. The present study employs a multi-group path analysis using Mplus 7.2 to examine generational differences in the paths between affiliation culture, years of formal education, contact with important people, and length of full-time employment to substance abuse and anxiety in immigrant and U.S. born Latino adults who completed substance abuse treatment. A total of 131 participants (Mage= 36.3, SD +/- 10.5, 86.3% males, 48.1% non-U.S. born with a mean length of stay of 19 years in the U.S. (SD +/- 13.71) in recovery from substance abuse completed self-report measures. Results from the multi-group path analysis suggest that being more affiliated to the U.S. culture is associated with substance abuse, whereas years of formal education and longer full-time employment is associated with reduced anxiety in the immigrant group. Conversely, frequent contact with important people and affiliation to the U.S. culture are associated with fewer years of substance abuse, whereas longer full-time employment is associated with substance abuse in the U.S. born group. Anxiety and substance abuse was correlated only in the U.S. born group. The implications of these findings are discussed. PMID- 28845434 TI - Phytotherapy and Nutritional Supplements on Breast Cancer. AB - Breast cancer is the most frequent type of nonskin malignancy among women worldwide. In general, conventional cancer treatment options (i.e., surgery, radiotherapy, chemotherapy, biological therapy, and hormone therapy) are not completely effective. Recurrence and other pathologic situations are still an issue in breast cancer patients due to side effects, toxicity of drugs in normal cells, and aggressive behaviour of the tumours. From this point of view, breast cancer therapy and adjuvant methods represent a promising and challenging field for researchers. In the last few years, the use of some types of complementary medicines by women with a history of breast cancer has significantly increased such as phytotherapeutic products and nutritional supplements. Despite this, the use of such approaches in oncologic processes may be problematic and patient's health risks can arise such as interference with the efficacy of standard cancer treatment. The present review gives an overview of the most usual phytotherapeutic products and nutritional supplements with application in breast cancer patients as adjuvant approach. Regardless of the contradictory results of scientific evidence, we demonstrated the need to perform additional investigation, mainly well-designed clinical trials in order to establish correlations and allow for further validated outcomes concerning the efficacy, safety, and clinical evidence-based recommendation of these products. PMID- 28845441 TI - Temporal and spatial context in the mind and brain. AB - Theories of episodic memory have long hypothesized that recollection of a specific instance from one's life is mediated by recovery of a neural state of spatiotemporal context. This paper reviews recent theoretical advances in formal models of spatiotemporal context and a growing body of neurophysiological evidence from human imaging studies and animal work that neural populations in the hippocampus and other brain regions support a representation of spatiotemporal context. PMID- 28845442 TI - Etherification of Glycerol with Propylene or 1-Butene for Fuel Additives. AB - The etherification of glycerol with propylene over acidic heterogeneous catalysts, Amberlyst-15, S100, and S200 resins, produced mono-propyl glycerol ethers (MPGEs), 1,3-di- and 1,2-di-propyl glycerol ethers (DPGEs), and tri-propyl glycerol ether (TPGE). The propylation of glycerol over Amberlyst-15 yielded only TPGE. The glycerol etherification with 1-butene over Amberlyst-15 and S200 resins produced 1-mono-, 2-mono-, 1,2-di-, and 1,3-di-butyl glycerol ethers (1-MBGE, 2 MBGE, 1,2-DBGE, and 1,3-DBGE). The use of Amberlyst-15 resulted in the propylation and butylation of glycerol with higher yields than those obtained from the S100 and S200 resins. The PGEs, TPGE, and BGEs were evaluated as cold flow improvers and octane boosters. These alkyl glycerol ethers can reduce the cloud point of blended palm biodiesels with diesel. They can increase the research octane number and the motor octane number of gasoline. PMID- 28845444 TI - Intranasal Oxytocin Failed to Affect Chimpanzee (Pan troglodytes) Social Behavior. AB - Oxytocin has been suggested as a treatment to promote positive social interactions in people with Autism Spectrum Disorders (ASD). However, it is difficult to test this effect outside of the laboratory in realistic social situations. One way to resolve this issue is to study behavioral changes in closely related species with complex social relationships, such as chimpanzees. Here, we use captive, socially housed chimpanzees to evaluate the effects of oxytocin in a socially complex environment. After administering intranasal oxytocin or a placebo to an individual chimpanzee (total n = 8), she was returned to her social group. An experimenter blind to the condition measured the subject's social behavior. We failed to find a behavioral difference between conditions. As one of the goals for oxytocin administration as a treatment for ASD is increasing prosocial behaviors during 'real world' encounters, it is problematic that we failed to detect behavioral changes in our closest living relatives. However, our null findings may be related to methodological challenges such as determining an effective dose of oxytocin for chimpanzees and how long oxytocin takes to cross the blood-brain barrier. Thus, more research on intranasal oxytocin dosing and uptake are needed to continue exploring whether oxytocin changes social behavior in naturalistic settings and as a treatment for ASD. PMID- 28845443 TI - In Vitro Antibacterial and Antibiofilm Activity of Lippia alba Essential Oil, Citral, and Carvone against Staphylococcus aureus. AB - In vitro antimicrobial and antibiofilm activities of the Lippia alba essential oil and its major components (citral and carvone) against Staphylococcus aureus were investigated. Essential oils (LA1EO, LA2EO, and LA3EO) were extracted from the aerial parts of three L. alba specimens by hydrodistillation and analyzed by gas chromatography coupled to a mass spectrometer. Minimum Inhibitory Concentrations (MIC) and Minimum Bacterial Concentration (MBC) were determined by the microdilution method. For the antibiofilm assays, the biomass formation in the biofilm was evaluated by the microtiter-plate technique with the crystal violet (CV) assay and the viability of the bacterial cells was analyzed. All oils and their major components presented antibacterial activity, and the lowest MIC and MBC values were 0.5 mg mL-1 when LA1EO and citral were used. Potential inhibition (100%) of S. aureus biofilm formation at the concentration of 0.5 mg mL-1 of all EOs was observed. However, the elimination of biofilm cells was confirmed at concentrations of 1 mg mL-1, 2 mg mL-1, 2 mg mL-1, and 0.5 mg mL-1 for LA1EO, LA2EO, LA3EO, and citral, respectively. The results obtained in the present research point to the promising antibacterial and antibiofilm potential of L. alba EOs against S. aureus, a species of recognized clinical interest. PMID- 28845445 TI - An Evaluation Framework for Lossy Compression of Genome Sequencing Quality Values. AB - This paper provides the specification and an initial validation of an evaluation framework for the comparison of lossy compressors of genome sequencing quality values. The goal is to define reference data, test sets, tools and metrics that shall be used to evaluate the impact of lossy compression of quality values on human genome variant calling. The functionality of the framework is validated referring to two state-of-the-art genomic compressors. This work has been spurred by the current activity within the ISO/IEC SC29/WG11 technical committee (a.k.a. MPEG), which is investigating the possibility of starting a standardization activity for genomic information representation. PMID- 28845446 TI - Polymer-modified halide perovskite films for efficient and stable planar heterojunction solar cells. AB - The solution processing of polycrystalline perovskite films introduces trap states that can adversely affect their optoelectronic properties. Motivated by the use of small-molecule surfactants to improve the optoelectronic performance of perovskites, we demonstrate the use of polymers with coordinating groups to improve the performance of solution-processed semiconductor films. The use of these polymer modifiers results in a marked change in the electronic properties of the films, as measured by both carrier dynamics and overall device performance. The devices grown with the polymer poly(4-vinylpyridine) (PVP) show significantly enhanced power conversion efficiency from 16.9 +/- 0.7% to 18.8 +/- 0.8% (champion efficiency, 20.2%) from a reverse scan and stabilized champion efficiency from 17.5 to 19.1% [under a bias of 0.94 V and AM (air mass) 1.5-G, 1 sun illumination over 30 min] compared to controls without any passivation. Treating the perovskite film with PVP enables a VOC of up to 1.16 V, which is among the best reported for a CH3NH3PbI3 perovskite solar cell and one of the lowest voltage deficits reported for any perovskite to date. In addition, perovskite solar cells treated with PVP show a long shelf lifetime of up to 90 days (retaining 85% of the initial efficiency) and increased by a factor of more than 20 compared to those without any polymer (degrading to 85% after ~4 days). Our work opens up a new class of chemical additives for improving perovskite performance and should pave the way toward improving perovskite solar cells for high efficiency and stability. PMID- 28845447 TI - When immiscible becomes miscible-Methane in water at high pressures. AB - At low pressures, the solubility of gases in liquids is governed by Henry's law, which states that the saturated solubility of a gas in a liquid is proportional to the partial pressure of the gas. As the pressure increases, most gases depart from this ideal behavior in a sublinear fashion, leveling off at pressures in the 1- to 5-kbar (0.1 to 0.5 GPa) range with solubilities of less than 1 mole percent (mol %). This contrasts strikingly with the well-known marked increase in solubility of simple gases in water at high temperature associated with the critical point (647 K and 212 bar). The solubility of the smallest hydrocarbon, the simple gas methane, in water under a range of pressure and temperature is of widespread importance, because it is a paradigmatic hydrophobe and occurs widely in terrestrial and extraterrestrial geology. We report measurements up to 3.5 GPa of the pressure dependence of the solubility of methane in water at 100 degrees C well below the latter's critical temperature. Our results reveal a marked increase in solubility between 1 and 2 GPa, leading to a state above 2 GPa where the maximum solubility of methane in water exceeds 35 mol %. PMID- 28845448 TI - Nucleation speed limit on remote fluid-induced earthquakes. AB - Earthquakes triggered by other remote seismic events are explained as a response to long-traveling seismic waves that temporarily stress the crust. However, delays of hours or days after seismic waves pass through are reported by several studies, which are difficult to reconcile with the transient stresses imparted by seismic waves. We show that these delays are proportional to magnitude and that nucleation times are best fit to a fluid diffusion process if the governing rupture process involves unlocking a magnitude-dependent critical nucleation zone. It is well established that distant earthquakes can strongly affect the pressure and distribution of crustal pore fluids. Earth's crust contains hydraulically isolated, pressurized compartments in which fluids are contained within low-permeability walls. We know that strong shaking induced by seismic waves from large earthquakes can change the permeability of rocks. Thus, the boundary of a pressurized compartment may see its permeability rise. Previously confined, overpressurized pore fluids may then diffuse away, infiltrate faults, decrease their strength, and induce earthquakes. Magnitude-dependent delays and critical nucleation zone conclusions can also be applied to human-induced earthquakes. PMID- 28845449 TI - Dynamic conservation for migratory species. AB - In an era of unprecedented and rapid global change, dynamic conservation strategies that tailor the delivery of habitat to when and where it is most needed can be critical for the persistence of species, especially those with diverse and dispersed habitat requirements. We demonstrate the effectiveness of such a strategy for migratory waterbirds. We analyzed citizen science and satellite data to develop predictive models of bird populations and the availability of wetlands, which we used to determine temporal and spatial gaps in habitat during a vital stage of the annual migration. We then filled those gaps using a reverse auction marketplace to incent qualifying landowners to create temporary wetlands on their properties. This approach is a cost-effective way of adaptively meeting habitat needs for migratory species, optimizes conservation outcomes relative to investment, and can be applied broadly to other conservation challenges. PMID- 28845450 TI - Oriented assembly of anisotropic nanoparticles into frame-like superstructures. AB - It is fascinating but challenging for nanoscientists to organize nanoparticles (NPs) into ordered architectures just as it is for chemists to manipulate atoms and molecules to form functional molecules and supramolecules. We explore a strategy to assemble anisotropic NPs into open frame-like superstructures via oriented attachment (OA), experimentally realizing a nanoscale analog to the bonding behavior in M8L12-type supramolecular cubes. We highlight the role of NP shape in the OA-involved assembly for constructing predictable superstructures. In addition, the frame-like superstructures can retain their basic structure when undergoing postcrystallization of the building blocks as well as annealing for conversion toward functional electrocatalytic materials. Our work enables fundamental insights into directional "bonding" among NPs and adds to the growing body of knowledge for bottom-up assembly of anisotropic NPs into sophisticated functional materials. PMID- 28845451 TI - Extensive arsenic contamination in high-pH unconfined aquifers in the Indus Valley. AB - Arsenic-contaminated aquifers are currently estimated to affect ~150 million people around the world. However, the full extent of the problem remains elusive. This is also the case in Pakistan, where previous studies focused on isolated areas. Using a new data set of nearly 1200 groundwater quality samples throughout Pakistan, we have created state-of-the-art hazard and risk maps of arsenic contaminated groundwater for thresholds of 10 and 50 MUg/liter. Logistic regression analysis was used with 1000 iterations, where surface slope, geology, and soil parameters were major predictor variables. The hazard model indicates that much of the Indus Plain is likely to have elevated arsenic concentrations, although the rest of the country is mostly safe. Unlike other arsenic contaminated areas of Asia, the arsenic release process in the arid Indus Plain appears to be dominated by elevated-pH dissolution, resulting from alkaline topsoil and extensive irrigation of unconfined aquifers, although pockets of reductive dissolution are also present. We estimate that approximately 50 million to 60 million people use groundwater within the area at risk, with hot spots around Lahore and Hyderabad. This number is alarmingly high and demonstrates the urgent need for verification and testing of all drinking water wells in the Indus Plain, followed by appropriate mitigation measures. PMID- 28845452 TI - Visualizing redox orbitals and their potentials in advanced lithium-ion battery materials using high-resolution x-ray Compton scattering. AB - Reduction-oxidation (redox) reactions are the key processes that underlie the batteries powering smartphones, laptops, and electric cars. A redox process involves transfer of electrons between two species. For example, in a lithium-ion battery, current is generated when conduction electrons from the lithium anode are transferred to the redox orbitals of the cathode material. The ability to visualize or image the redox orbitals and how these orbitals evolve under lithiation and delithiation processes is thus of great fundamental and practical interest for understanding the workings of battery materials. We show that inelastic scattering spectroscopy using high-energy x-ray photons (Compton scattering) can yield faithful momentum space images of the redox orbitals by considering lithium iron phosphate (LiFePO4 or LFP) as an exemplar cathode battery material. Our analysis reveals a new link between voltage and the localization of transition metal 3d orbitals and provides insight into the puzzling mechanism of potential shift and how it is connected to the modification of the bond between the transition metal and oxygen atoms. Our study thus opens a novel spectroscopic pathway for improving the performance of battery materials. PMID- 28845453 TI - Challenges For The Future Of Complementary And Integrative Care. PMID- 28845454 TI - Potential Co-Factor Role of Tobacco Specific Nitrosamine Exposures in the Pathogenesis of Fetal Alcohol Spectrum Disorder. AB - BACKGROUND: Cerebellar developmental abnormalities in Fetal Alcohol Spectrum Disorder (FASD) are linked to impairments in insulin signaling. However, co morbid alcohol and tobacco abuses during pregnancy are common. Since smoking leads to tobacco specific Nitrosamine (NNK) exposures which have been shown to cause brain insulin resistance, we hypothesized that neurodevelopmental abnormalities in FASD could be mediated by ethanol and/or NNK. METHODS: Long Evans rat pups were intraperitoneal (IP) administered ethanol (2 g/kg) on postnatal days (P) 2, 4, 6 and/or NNK (2 mg/kg) on P3, P5, and P7 to simulate third trimester human exposures. The Cerebellar function, histology, insulin and Insulin-like Growth Factor (IGF) signaling, and neuroglial protein expression were assessed. RESULTS: Ethanol, NNK and ethanol+NNK groups had significant impairments in motor function (rotarod tests), abnormalities in cerebellar structure (Purkinje cell loss, simplification and irregularity of folia, and altered white matter), signaling through the insulin and IGF-1 receptors, IRS-1, Akt and GSK-3beta, and reduced expression of several important neuroglial proteins. Despite similar functional effects, the mechanisms and severity of NNK and ethanol+NNK induced alterations in cerebellar protein expression differed from those of ethanol. CONCLUSIONS: Ethanol and NNK exert independent but overlapping adverse effects on cerebellar development, function, insulin signaling through cell survival, plasticity, metabolic pathways, and neuroglial protein expression. The results support the hypothesis that tobacco smoke exposure can serve as a co-factor mediating long-term effects on brain structure and function in FASD. PMID- 28845455 TI - Immigrant-based Disparities in Mental Health Care Utilization. AB - Studies of immigrant-based disparities in mental health care have been limited by small sample sizes and a lack of measures of different dimensions of acculturation. This study draws on the National Epidemiological Survey on Alcohol and Related Conditions to address these limitations. Results indicate first generation immigrants have lower rates of utilization for both mood and anxiety disorders. Nativity-based disparities in treatment are particularly notable among people from African and Hispanic origins, while there is little evidence of disparities among people from European origins. Of three dimensions of acculturation, only the identity dimension has a positive association with mental health care utilization. PMID- 28845456 TI - Outcome Analysis of Congenital Diaphragmatic Hernia Cohort before and after Implementation of Standardized Protocol in a Tertiary Neonatal Unit. AB - Despite evolving evidence and increased understanding, there is a strong argument that best outcomes in managing congenital diaphragmatic hernia (CDH) patients are achieved in centers which have a high admission rate of such patients and follow standardized operating protocols of management. Pneumothorax and air leak syndromes are one of the main causes of pre- and postoperative morbidity in these patients and experts believe that delivery room sedation and gentle ventilation strategies can minimize this. We observed a significant drop in incidence of pneumothorax and reduction of mortality following implementation of standardized guidelines at the neonatal unit at Southampton which is a tertiary-level neonatal care in the southern United Kingdom and a regional referral center for CDH patients. PMID- 28845457 TI - Near-Infrared Fluorescent Probes with Large Stokes Shifts for Sensing Zn(II) Ions in Living Cells. AB - We report two new near-infrared fluorescent probes based on Rhodol counterpart fluorophore platforms functionalized with dipicolylamine Zn(II)-binding groups. The combinations of the pendant amines and fluorophores provide the probes with an effective three-nitrogen-atom and one-oxygen-atom binding motif. The fluorescent probes with large Stokes shifts offer sensitive and selective florescent responses to Zn(II) ions over other metal ions, allowing a reversible monitoring of Zn(II) concentration changes in living cells, and detecting intracellular Zn(II) ions released from intracellular metalloproteins. PMID- 28845458 TI - PaperBLAST: Text Mining Papers for Information about Homologs. AB - Large-scale genome sequencing has identified millions of protein-coding genes whose function is unknown. Many of these proteins are similar to characterized proteins from other organisms, but much of this information is missing from annotation databases and is hidden in the scientific literature. To make this information accessible, PaperBLAST uses EuropePMC to search the full text of scientific articles for references to genes. PaperBLAST also takes advantage of curated resources (Swiss-Prot, GeneRIF, and EcoCyc) that link protein sequences to scientific articles. PaperBLAST's database includes over 700,000 scientific articles that mention over 400,000 different proteins. Given a protein of interest, PaperBLAST quickly finds similar proteins that are discussed in the literature and presents snippets of text from relevant articles or from the curators. PaperBLAST is available at http://papers.genomics.lbl.gov/. IMPORTANCE With the recent explosion of genome sequencing data, there are now millions of uncharacterized proteins. If a scientist becomes interested in one of these proteins, it can be very difficult to find information as to its likely function. Often a protein whose sequence is similar, and which is likely to have a similar function, has been studied already, but this information is not available in any database. To help find articles about similar proteins, PaperBLAST searches the full text of scientific articles for protein identifiers or gene identifiers, and it links these articles to protein sequences. Then, given a protein of interest, it can quickly find similar proteins in its database by using standard software (BLAST), and it can show snippets of text from relevant papers. We hope that PaperBLAST will make it easier for biologists to predict proteins' functions. PMID- 28845459 TI - Moderate Exercise Has Limited but Distinguishable Effects on the Mouse Microbiome. AB - The gut microbiome is known to have a complex yet vital relationship with host health. While both exercise and the gut microbiome have been shown to impact human health independently, the direct effects of moderate exercise on the intestinal microbiota remain unclear. In this study, we compared gut microbial diversity and changes in inflammatory markers associated with exercise over an 8 week period in mice that performed either voluntary exercise (VE) (n = 10) or moderate forced exercise (FE) (n = 11) and mice that did not perform any exercise (n = 21). VE mice, but not FE mice, had increased food intake and lean body mass compared to sedentary mice. The levels of inflammatory markers associated with exercise were similar for mice in all three groups. Traditional microbial profiles comparing operational taxonomic units (OTUs) in samples (P > 0.1) and multivariate analysis of beta diversity via Adonis testing (P > 0.1) did not identify significantly altered taxonomic profiles in the voluntary or forced exercise group compared to the sedentary controls. However, a random forests machine learning model, which takes into account the relationships between bacteria in a community, classified voluntary exercisers and nonexercisers with 97% accuracy at 8 weeks. The top bacteria used by the model allowed us to identify known taxa (Bacteroides, S24-7, and Lactobacillus) and novel taxa (Rikenellaceae and Lachnospiraceae) associated with exercise. Although aerobic exercise in mice did not result in significant changes of abundance in gut microbes or in host inflammatory response, more sophisticated computational methods could identify some microbial shifts. More study is needed on the effects of various exercise intensities and their impact on the gut microbiome. IMPORTANCE The bacteria that live in our gut have a complex yet vital relationship with our health. Environmental factors that influence the gut microbiome are of great interest, as recent research demonstrates that these microbes, mostly bacteria, are important for normal host physiology. Diseases such as obesity, diabetes, inflammatory bowel disease, and colon cancer have also been linked to shifts in the microbiome. Exercise is known to have beneficial effects on these diseases; however, much less is known about its direct impact on the gut microbiome. Our results illustrate that exercise has a moderate but measurable effect on gut microbial communities in mice. These methods can be used to provide important insight into other factors affecting the microbiome and our health. PMID- 28845460 TI - Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of Mycobacterium tuberculosis during Early Macrophage Infection. AB - Nutrient acquisition from the host environment is crucial for the survival of intracellular pathogens, but conceptual and technical challenges limit our knowledge of pathogen diets. To overcome some of these technical roadblocks, we exploited an experimentally accessible model for early infection of human macrophages by Mycobacterium tuberculosis, the etiological agent of tuberculosis, to study host-pathogen interactions with a multi-omics approach. We collected metabolomics and complete transcriptome RNA sequencing (dual RNA-seq) data of the infected macrophages, integrated them in a genome-wide reaction pair network, and identified metabolic subnetworks in host cells and M. tuberculosis that are modularly regulated during infection. Up- and downregulation of these metabolic subnetworks suggested that the pathogen utilizes a wide range of host-derived compounds, concomitant with the measured metabolic and transcriptional changes in both bacteria and host. To quantify metabolic interactions between the host and intracellular pathogen, we used a combined genome-scale model of macrophage and M. tuberculosis metabolism constrained by the dual RNA-seq data. Metabolic flux balance analysis predicted coutilization of a total of 33 different carbon sources and enabled us to distinguish between the pathogen's substrates directly used as biomass precursors and the ones further metabolized to gain energy or to synthesize building blocks. This multiple-substrate fueling confers high robustness to interventions with the pathogen's metabolism. The presented approach combining multi-omics data as a starting point to simulate system-wide host-pathogen metabolic interactions is a useful tool to better understand the intracellular lifestyle of pathogens and their metabolic robustness and resistance to metabolic interventions. IMPORTANCE The nutrients consumed by intracellular pathogens are mostly unknown. This is mainly due to the challenge of disentangling host and pathogen metabolism sharing the majority of metabolic pathways and hence metabolites. Here, we investigated the metabolic changes of Mycobacterium tuberculosis, the causative agent of tuberculosis, and its human host cell during early infection. To this aim, we combined gene expression data of both organisms and metabolite changes during the course of infection through integration into a genome-wide metabolic network. This led to the identification of infection-specific metabolic alterations, which we further exploited to model host-pathogen interactions quantitatively by flux balance analysis. These in silico data suggested that tubercle bacilli consume up to 33 different nutrients during early macrophage infection, which the bacteria utilize to generate energy and biomass to establish intracellular growth. Such multisubstrate fueling strategy renders the pathogen's metabolism robust toward perturbations, such as innate immune responses or antibiotic treatments. PMID- 28845461 TI - Large-Scale Phylogenomics of the Lactobacillus casei Group Highlights Taxonomic Inconsistencies and Reveals Novel Clade-Associated Features. AB - Although the genotypic and phenotypic properties of the Lactobacillus casei group have been studied extensively, the taxonomic structure has been the subject of debate for a long time. Here, we performed a large-scale comparative analysis by using 183 publicly available genomes supplemented with a Lactobacillus strain isolated from the human upper respiratory tract. On the basis of this analysis, we identified inconsistencies in the taxonomy and reclassified all of the genomes according to their most closely related type strains. This led to the identification of a catalase-encoding gene in all 10 L. casei sensu stricto strains, making it the first described catalase-positive species in the Lactobacillus genus. Moreover, we found that 6 of 10 L. casei genomes contained a SecA2/SecY2 gene cluster with two putative glycosylated surface adhesin proteins. Altogether, our results highlight current inconsistencies in the taxonomy of the L. casei group and reveal new clade-associated functional features. IMPORTANCE The closely related species of the Lactobacillus casei group are extensively studied because of their applications in food fermentations and as probiotics. Our results show that many strains in this group are incorrectly classified and that reclassifying them to their most closely related species type strain improves the functional predictive power of their taxonomy. In addition, our findings may spark increased interest in the L. casei species. We find that after reclassification, only 10 genomes remain classified as L. casei. These strains show some interesting properties. First, they all appear to be catalase positive. This suggests that they have increased oxidative stress resistance. Second, we isolated an L. casei strain from the human upper respiratory tract and discovered that it and multiple other L. casei strains harbor one or even two large, glycosylated putative surface adhesins. This might inspire further exploration of this species as a potential probiotic organism. PMID- 28845462 TI - Potential Cancer Prevention and Treatment by Silencing the Killer Cell Immunoglobulin-like Receptor Gene in Natural Killer Cells Derived from Induced Pluripotent Stem Cells. AB - Cancer immunosurveillance is an important host protection process, monitoring the presence of irregular cells that could potentially transform into tumor cells, effectively clearing the body of transformed tumor cells at their earliest stages, and thus maintaining regular cellular homeostasis. Natural killer (NK) cells are effector lymphocytes of the innate immune system, playing a critical role in surveillance for tumor cells, while also eliminating virally infected cells. The significance of the anti-tumor role of NK cells was recently further verified by findings that immunosuppression in most cancer patients is not perceptible until late stages. NK cells express the low-affinity Fc-activating receptor, CD16, and the inhibitory receptor, killer cell immunoglobulin-like receptor (KIR). Consequently, activation of NK cells is determined by the balance of inhibitory and activating receptor stimulation. Here, we propose establishing an induced pluripotent stem cell (iPSC)-derived NK cell line with KIR gene knockout or knockdown as a possible regimen to treat and prevent cancer. We further postulate that an optimal mixture of NK iPSCs with and without KIR gene knockout, would reach a maximum antitumor activity, with minimal side effects. We also discuss the possible advantages of KIR-knockout NK iPSCs for adoptive immunotherapy in patients with cancer. PMID- 28845463 TI - Contraceptive vaginal ring experiences among women and men in Kisumu, Kenya: A qualitative study. AB - BACKGROUND: Future HIV prevention options for women will likely include Antiretroviral (ARV)-based intravaginal rings. Valuable insights may be gained by examining user experiences with a similar licensed technology, a contraceptive ring, especially in settings where this technology may not be currently available. METHODS: In-depth interviews with 24 females enrolled in a trial assessing acceptability and use of a contraceptive ring, and 20 male sexual partners were conducted September 2014-April 2015. Elements of ethnography and phenomenological anthropology were used to collect, analyze, interpret, and describe ring users' experiences. Thematic analysis was completed in MaxQDA-10. RESULTS: Experiences with the contraceptive ring reflected a broader Family Planning (FP) paradigm that centered around three themes: latitudes and drawbacks of FP (being free); an FP method needs to be compatible with a woman's body (feeling normal); and dealing with fertility control uncertainties (how well does it really work). FP intentions and disclosure practices were influenced by partner support, socioeconomic factors, religion, cultural beliefs, and societal norms, including female sexuality. A user-friendly FP design was emphasized. Non suppression of menstruation was favored by most. Unease with vaginal insertion as well as ring placement issues (slippage, expulsion) created initial challenges requiring clinician assistance and practice for some participants. While minor side-effects were described, concerns centered on ring efficacy, negative effect on a woman's sexual desire, and future fertility issues. CONCLUSIONS: Awareness of the multiple contexts in ring users' experience may inform the development, education, and promotion approaches for future ARV rings. PMID- 28845465 TI - Comparison of a Micro-Neutralization Test with the Rapid Fluorescent Focus Inhibition Test for Measuring Rabies Virus Neutralizing Antibodies. AB - The rapid fluorescent focus inhibition test (RFFIT) is routinely used in the United States to measure rabies virus neutralizing antibodies (rVNA). RFFIT has a long history of reproducible and reliable results. The test has been modified over the years to use smaller volumes of reagents and samples, but requires a 50 MUL minimum volume of test serum. To conduct pathogenesis studies, small laboratory animals such as mice are regularly tested for rVNA, but the minimum volume for a standard RFFIT may be impossible to obtain, particularly in scenarios of repeated sampling. To address this problem, a micro-neutralization test was developed previously. In the current study, the micro-neutralization test was compared to the RFFIT using 129 mouse serum samples from rabies vaccine studies. Using a cut-off value of 0.1 IU/mL, the sensitivity, specificity, and concordance of the micro-neutralization test were 100%, 97.5%, and 98%, respectively. The geometric mean titer of all samples above the cut-off was 2.0 IU/mL using RFFIT and 3.4 IU/mL using the micro-neutralization test, indicating that titers determined using the micro-neutralization test are not equivalent to RFFIT titers. Based on four rVNA-positive hamster serum samples, the intra-assay coefficient of variability was 24% and inter-assay coefficient of variability was 30.4 %. These results support continued use of the micro-neutralization test to determine rabies virus neutralizing antibody titers for low-volume serum samples. PMID- 28845464 TI - Molecular signatures of differential responses to exercise trainings during rehabilitation. AB - : The loss and recovery of muscle mass and function following injury and during rehabilitation varies among individuals. While recent expression profiling studies have illustrated transcriptomic responses to muscle disuse and remodeling, how these changes contribute to the physiological responses are not clear. In this study, we quantified the effects of immobilization and subsequent rehabilitation training on muscle size and identified molecular pathways associated with muscle responsiveness in an orthopaedic patient cohort study. The injured leg of 16 individuals with ankle injury was immobilized for a minimum of 4 weeks, followed by a 6-week rehabilitation program. The maximal cross-sectional area (CSA) of the medial gastrocnemius muscle of the immobilized and control legs were determined by T1-weighted axial MRI images. Genome-wide mRNA profiling data were used to identify molecular signatures that distinguish the patients who responded to immobilization and rehabilitation and those who were considered minimal responders. RESULTS: Using 6% change as the threshold to define responsiveness, a greater degree of changes in muscle size was noted in high responders (-14.9 +/- 3.6%) compared to low responders (0.1 +/- 0.0%) during immobilization. In addition, a greater degree of changes in muscle size was observed in high responders (20.5 +/- 3.2%) compared to low responders (2.5 +/- 0.9%) at 6-week rehabilitation. Microarray analysis showed a higher number of genes differentially expressed in the responders compared to low responders in general; with more expression changes observed at the acute stage of rehabilitation in both groups. Pathways analysis revealed top molecular pathways differentially affected in the groups, including genes involved in mitochondrial function, protein turn over, integrin signaling and inflammation. This study confirmed the extent of muscle atrophy due to immobilization and recovery by exercise training is associated with distinct remodeling signature, which can potentially be used for evaluating and predicting clinical outcomes. PMID- 28845466 TI - The Formation of the Eastern Africa Rabies Network: A Sub-Regional Approach to Rabies Elimination. AB - International rabies networks have been formed in many of the canine-rabies endemic regions around the world to create unified and directed regional approaches towards elimination. The aim of the first sub-regional Eastern Africa rabies network meeting, which included Kenya, Ethiopia, Tanzania, Rwanda, and Uganda, was to discuss how individual country strategies could be coordinated to address the unique challenges that are faced within the network. The Stepwise Approach towards Rabies Elimination and the Global Dog Rabies Elimination Pathway tool were used to stimulate discussion and planning to achieve the elimination of canine-mediated human rabies by 2030. Our analysis estimated a total dog population of 18.3 million dogs in the Eastern Africa region. The current dog vaccination coverage was estimated to be approximately 5% (915,000 dogs), with an estimated 4910 vaccinators available. Assuming that every vaccinator performs rabies vaccination, this equated to each vaccinator currently vaccinating 186 dogs per year, whilst the target would be to vaccinate 2609 dogs every year for the community to reach 70% coverage. In order to achieve the World Health Organization-recommended 70% vaccination coverage, an additional 11 million dogs need to be vaccinated each year, pointing to an average annual shortfall of $ 23 million USD in current spending to achieve elimination by 2030 across the region. Improved vaccination efficiency within the region could be achieved by improving logistics and/or incorporating multiple vaccination methods to increase vaccinator efficiency, and could serve to reduce the financial burden associated with rabies elimination. Regional approaches to rabies control are of value, as neighboring countries can share their unique challenges while, at the same time, common approaches can be developed and resource-saving strategies can be implemented. PMID- 28845467 TI - Proton Pump Inhibitors and Kidney Disease - GI Upset for the Nephrologist? AB - Widely regarded as safe and effective, proton pump inhibitors (PPIs) are among the most commonly used medications in the world today. However, a spate of observational studies suggest an association between PPI use and adverse events, including infection, bone fracture, and dementia. This review details evidence linking the use of PPI therapy to the development of kidney disease, including early case reports of acute interstitial nephritis and subsequent large observational studies of acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD). The majority of studies showed higher risk of kidney outcomes among persons prescribed PPI medications, with effect sizes that were slightly higher for AKI (~2-3-fold) compared to CKD and ESRD (1.2-1.8-fold). Although observational pharmaco-epidemiology studies are limited by the possibility of residual confounding and confounding by indication, many of the described studies conducted rigorous sensitivity analyses aimed at minimizing these biases, including new-user design, comparison to similar agents (e.g., histamine2 receptor antagonists), and evaluation for a dose-response, with robust results. Given the widespread use of PPIs, even a small effect on kidney outcomes could result in large public health burden. Timely cessation of PPI therapy when there is no clear indication for use might reduce the population burden of kidney disease. PMID- 28845469 TI - The spectrum of hand dysfunction after hemodialysis fistula placement. AB - INTRODUCTION: Contemporary dogma has classically attributed hand dysfunction following hemodialysis arteriovenous fistula (AVF) placement to regional ischemia. We hypothesize that hemodynamic perturbations alone do not entirely explain the postoperative changes in hand function and, furthermore, that various elements of hand function are differentially affected following surgery. METHODS: Bilateral wrist and digital pressures and upper extremity nerve conduction tests were recorded preoperatively and at 6 weeks and 6 months following upper extremity AVF construction in 46 patients. Concurrently, biomechanical tests were administered to evaluate multiple limb functional domains including grip strength, dexterity, sensation and perception of hand function. RESULTS: Mean age was 59+/-14 years (75% male) and 48% were on hemodialysis at the time of access placement. 69% had a brachial-based AVF, and the remainder had radial-based accesses. Six weeks following AVF placement, a significant decrease in access side digital pressures was observed, with only partial recovery at 6 months (P<0.0001). Grip strength was significantly worse in the access side limb (P=0.0003), and Disability of Arm, Shoulder and Hand Questionnaire (DASH) score substantially worsened postoperatively (P=0.06). Digital sensation and limb dexterity did not differ between limb sides (P>0.1) or change significantly over time (P>0.1). Principal component analyses demonstrated that nerve conduction parameters tended to track the biomechanical parameters, yet both were relatively independent of the hemodynamic parameters. CONCLUSION: Our findings suggest that ischemia alone does not completely explain access-related hand dysfunction and that future study is needed to elucidate alternative mechanisms. PMID- 28845468 TI - Evolutionary Nephrology. AB - Progressive kidney disease follows nephron loss, hyperfiltration, and incomplete repair, a process described as "maladaptive." In the past 20 years, a new discipline has emerged that expands research horizons: evolutionary medicine. In contrast to physiologic (homeostatic) adaptation, evolutionary adaptation is the result of reproductive success that reflects natural selection. Evolutionary explanations for physiologically maladaptive responses can emerge from mismatch of the phenotype with environment or evolutionary tradeoffs. Evolutionary adaptation to a terrestrial environment resulted in a vulnerable energy-consuming renal tubule and a hypoxic, hyperosmolar microenvironment. Natural selection favors successful energy investment strategy: energy is allocated to maintenance of nephron integrity through reproductive years, but this declines with increasing senescence after ~40 years of age. Risk factors for chronic kidney disease include restricted fetal growth or preterm birth (life history tradeoff resulting in fewer nephrons), evolutionary selection for APOL1 mutations (that provide resistance to trypanosome infection, a tradeoff), and modern life experience (Western diet mismatch leading to diabetes and hypertension). Current advances in genomics, epigenetics, and developmental biology have revealed proximate causes of kidney disease, but attempts to slow kidney disease remain elusive. Evolutionary medicine provides a complementary approach by addressing ultimate causes of kidney disease. Marked variation in nephron number at birth, nephron heterogeneity, and changing susceptibility to kidney injury throughout life history are the result of evolutionary processes. Combined application of molecular genetics, evolutionary developmental biology (evo-devo), developmental programming and life history theory may yield new strategies for prevention and treatment of chronic kidney disease. PMID- 28845470 TI - The ASCENT (Allocation System Changes for Equity in Kidney Transplantation) Study: a Randomized Effectiveness-Implementation Study to Improve Kidney Transplant Waitlisting and Reduce Racial Disparity. AB - INTRODUCTION: The United Network for Organ Sharing (UNOS) implemented a new Kidney Allocation System (KAS) in December 2014 that is expected to substantially reduce racial disparities in kidney transplantation among waitlisted patients. However, not all dialysis facility clinical providers and end stage renal disease (ESRD) patients are aware of how the policy change could improve access to transplant. METHODS: We describe the ASCENT (Allocation System Changes for Equity in KidNey Transplantation) study, a randomized controlled effectiveness implementation study designed to test the effectiveness of a multicomponent intervention to improve access to the early steps of kidney transplantation among dialysis facilities across the United States. The multicomponent intervention consists of an educational webinar for dialysis medical directors, an educational video for patients and an educational video for dialysis staff, and a dialysis facility specific transplant performance feedback report. Materials will be developed by a multidisciplinary dissemination advisory board and will undergo formative testing in dialysis facilities across the United States. RESULTS: This study is estimated to enroll ~600 U.S. dialysis facilities with low waitlisting in all 18 ESRD Networks. The co-primary outcomes include change in waitlisting, and waitlist disparity at 1 year; secondary outcomes include changes in facility medical director knowledge about KAS, staff training regarding KAS, patient education regarding transplant, and a medical director's intent to refer patients for transplant evaluation. CONCLUSION: The results from the ASCENT study will demonstrate the feasibility and effectiveness of a multicomponent intervention designed to increase access to the deceased-donor kidney waitlist and reduce racial disparities in waitlisting. PMID- 28845471 TI - Acute Kidney Injury Risk Assessment: Differences and Similarities Between Resource-Limited and Resource-Rich Countries. AB - The incidence of acute kidney injury (AKI) among acutely ill patients is reportedly very high and has vexing consequences on patient outcomes and health care systems. The risks and impact of AKI differ between developed and developing countries. Among developing countries, AKI occurs in young individuals with no or limited comorbidities, and is usually due to environmental causes, including infectious diseases. Although several risk factors have been identified for AKI in different settings, there is limited information on how risk assessment can be used at population and patient levels to improve care in patients with AKI, particularly in developing countries where significant health disparities may exist. The Acute Disease Quality Initiative consensus conference work group addressed the issue of identifying risk factors for AKI and provided recommendations for developing individualized risk stratification strategies to improve care. We proposed a 5-dimension, evidence-based categorization of AKI risk that allows clinicians and investigators to study, define, and implement individualized risk assessment tools for the region or country where they practice. These dimensions include environmental, socioeconomic and cultural factors, processes of care, exposures, and the inherent risks of AKI. We provide examples of these risks and describe approaches for risk assessments in the developing world. We anticipate that these recommendations will be useful for health care providers to plan and execute interventions to limit the impact of AKI on society and each individual patient. Using a modified Delphi process, this group reached consensus regarding several aspects of AKI risk stratification. PMID- 28845472 TI - A Clinical Prediction Score to Guide Referral of Elderly Dialysis Patients for Kidney Transplant Evaluation. AB - INTRODUCTION: Dialysis patients aged >=70 years derive improved life expectancy through kidney transplantation compared to their waitlisted counterparts, but guidelines are not clear about how to identify appropriate transplantation candidates. We developed a clinical prediction score to identify elderly dialysis patients with expected 5-year survival appropriate for kidney transplantation (>5 years). METHODS: Incident dialysis patients in 2006-2009 aged >=70 were identified from the United States Renal Data System database and divided into derivation and validation cohorts. Using the derivation cohort, candidate variables with a significant crude association with 5-year all-cause mortality were included in a multivariable logistic regression model to generate a scoring system. The scoring system was tested in the validation cohort and a cohort of elderly transplant recipients. RESULTS: Characteristics most predictive of 5-year mortality included age >80, body mass index (BMI) <18, the presence of congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), immobility, and being institutionalized. Factors associated with increased 5-year survival were non-white race, a primary cause of end stage renal disease (ESRD) other than diabetes, employment within 6 months of dialysis initiation, and dialysis start via arteriovenous fistula (AVF). 5-year mortality was 47% for the lowest risk score group (3.6% of the validation cohort) and >90% for the highest risk cohort (42% of the validation cohort). CONCLUSION: This clinical prediction score could be useful for physicians to identify potentially suitable candidates for kidney transplantation. PMID- 28845473 TI - And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses. AB - Ligand-dependent activation of the Ah receptor (AhR) can result in an extremely diverse spectrum of biological and toxic effects that occur in a ligand-, species and tissue-specific manner. While the classical mechanism of AhR-dependent signal transduction is directly related to its ability to modulate gene expression, the dramatic diversity in responses observed following AhR activation or inhibition is inconsistent with a single molecular mechanism of AhR action. Recent studies have revealed that key molecular events underlying the AhR signaling pathway are significantly more varied and complex than previously established, and the specificity and diversity in AhR response can be selectively modulated by a variety of factors. Here we describe new insights into the mechanistic diversity in AhR signal transduction that can contribute to ligand-, species- and tissue-specific differences in AhR reponse. PMID- 28845474 TI - The Susceptibility of Bacterial Endophthalmitis Isolates to Vancomycin, Ceftazidime, and Amikacin: a 23 Year-Review. AB - PURPOSE: To investigate the in vitro susceptibility of Gram-positive and Gram negative endophthalmitis bacterial isolates to vancomycin, amikacin, and ceftazidime over a 23-year period. DESIGN: Retrospective non-comparative laboratory case series. SUBJECTS: Endophthalmitis patients that were culture positive for bacteria. METHODS: Laboratory records of bacteria isolated from endophthalmitis specimens collected from January 1st 1993 to December 31st 2015 were reviewed for incidence and standard susceptibility testing. MAIN OUTCOME MEASURES: The in vitro susceptibilities of bacteria cultured from endophthalmitis to vancomycin (VAN), amikacin (AMK), and ceftazidime (CEF). RESULTS: Patients with endophthalmitis were culture positive for bacteria in 665 cases.. Coagulase negative Staphylococci (CoNS) were the most common bacteria (54.6%), followed by Streptococci (Strep) species (20.8%), Staphylococcus aureus (SA) (10.2%), other Gram-positive (other-GP) bacteria (7.4%) and Gram-negative (GN) bacteria (7.1%). All Gram-positive organisms were susceptible to VAN, with the exception of 2 isolates. The in vitro susceptibilities of bacteria to AMK were: CoNS (95.3%), SA (75.0%), Strep (8.0%), GN (95.7%), and other-GP (81.1%). The in vitro susceptibilities of bacteria to CEF were: CoNS (58.5%), SA (54.4%), Strep (84.1%), GN (93.6.%), and other-GP (52.8%). There was no difference between AMK (95.7%) and CEF (93.6%) for GN coverage. AMK provided better coverage than CEF for CoNS, SA, and other-GP bacteria respectively (p<0.05, Fisher's exact), however, CEF appeared to provide better coverage (p<0.001, Fisher's exact) for Strep than AMK. CONCLUSIONS: Based on standard in vitro susceptibility testing, vancomycin remains an optimal antibiotic choice for the treatment of Gram positive endophthalmitis. AMK and CEF appear to provide equal GN coverage, but AMK appears to provide better coverage for CoNS, SA, and other-GP, but not Strep. PMID- 28845475 TI - Combat Exposure Severity is Associated with Reduced Cortical Thickness in Combat Veterans: A Preliminary Report. AB - BACKGROUND: Chronic stress and related physiological responses are known to have deleterious effects on neural integrity. Combat exposure is a notoriously pathogenic stressor and with over 2 million U.S. troops deployed to active combat zones since 2001, there is an urgent need to advance our understanding of its potential neural impact. Previous evidence suggests structural alterations in PTSD and more recent studies have explored cortical thinning specifically. This preliminary study investigates the impact of combat exposure on cortical thickness, controlling for history of early life stress and age. METHODS: Twenty one combat-exposed Veterans with PTSD and 20 non-PTSD combat-exposed controls (mean age 32.7) completed the Combat Exposure Scale, Childhood Trauma Questionnaire and structural magnetic resonance imaging in a Siemens 3T TIM trio system. GLM was used to examine the effect of combat exposure on cortical thickness, controlling for early life trauma exposure and age using cluster-wise correction (p<0.05). RESULTS: This preliminary study found a negative correlation between combat exposure severity (CES) and cortical thickness in the left superior temporal and left rostral middle frontal regions, as well as an interaction between PTSD diagnosis status and CES, in the superior temporal/insular region showing a stronger negative correlation between CES and cortical thickness in the non-PTSD group. CONCLUSIONS: Though caution should be taken with interpretation given the preliminary nature of the findings, the results indicate combat exposure may affect cortical structure beyond possible alterations due to early life stress exposure or PTSD psychopathology. Though replication in larger samples is required, these results provide useful information regarding possible neural biomarkers and treatment targets for combat related psychopathology as well as highlighting the pathogenic effects of combat. PMID- 28845476 TI - Opioid Prescription Drug Use and Expenditures in US Outpatient Physician Offices: Evidence from Two Nationally Representative Surveys. AB - BACKGROUND: Opioids are widely prescribed for their analgesic properties. Chronic opioid use is a persistent problem in the US. Nevertheless, little is known about its prescribing and utilization patterns and overall expenditures. OBJECTIVE: This study examined secular trends in opioid prescription drug utilization and expenditures, along with factors associated with opioid prescription drug use in US physician offices. METHODS: National Ambulatory Medical Care Survey (NAMCS) and Medical Expenditure Panel Survey (MEPS) data (2006-2010), both nationally representative surveys, were used to assess the trend, predictors of opioid prescription among US adults (more than 18 years) and the opioid-associated expenditures as a whole and borne by the patients in outpatient settings. RESULTS: Opioid prescription drugs use among US adults in outpatient settings, as a percentage of all prescription drugs, showed a gradual increase since 2006, leveling off in 2010. Opioid prescription drug expenditures showed an upward trend from 2009 after declining over three years. Mean out-of-pocket payments per prescription steadily declined over study period. LIMITATIONS: Cross-sectional nature and visit based information of NAMCS do not provide the actual prevalence and the reason for opioid prescription. CONCLUSIONS: Given the upward trend in opioid prescription drug utilization and associated expenditures, clinicians may benefit from evidence-based methods of monitoring prescription opioid use to prevent misuse, abuse, and other adverse patient outcomes. FUNDING: Drs. Qureshi, Haider, Ball, Horner and Bennett's efforts are partially supported by the University of South Carolina's ASPIRE I. Dr. Wooten's effort is funded by the National Institute on Drug Abuse (K01DA037412). PMID- 28845478 TI - Lung Ultrasound - A Novel Diagnostic Tool To Phenotype Chronic Lung Allograft Dysfunction? PMID- 28845477 TI - The Rotator Interval - A Link Between Anatomy and Ultrasound. AB - Shoulder pathologies of the rotator cuff of the shoulder are common in clinical practice. The focus of this pictorial essay is to discuss the anatomical details of the rotator interval of the shoulder, correlate the anatomy with normal ultrasound images and present selected pathologies. We focus on the imaging of the rotator interval that is actually the anterosuperior aspect of the glenohumeral joint capsule that is reinforced externally by the coracohumeral ligament, internally by the superior glenohumeral ligament and capsular fibers which blend together and insert medially and laterally to the bicipital groove. In this article we demonstrate the capability of high-resolution musculoskeletal ultrasound to visualize the detailed anatomy of the rotator interval. MSUS has a higher spatial resolution than other imaging techniques and the ability to examine these structures dynamically and to utilize the probe for precise anatomic localization of the patient's pain by sono-palpation. PMID- 28845479 TI - Incidental Diagnosis of a Carcinoid Tumor of the Ileum using Contrast-Enhanced Ultrasound (CEUS). PMID- 28845480 TI - IgG4-Related Sclerosing Mediastinitis: Report of a Case with Distinct Ultrasound Findings. PMID- 28845481 TI - H7N9 not only endanger human health but also hit stock marketing. AB - OBJECTIVE: This study aims to discuss the correlation between daily reported H7N9 cases and stock price indices in China. METHODS: Information on daily reported H7N9 cases and stock market sectors indices between February 19, 2013 and March 31, 2014 were collected. A distributed lag non-linear model was used to describe the variation trend for the stock indices. RESULTS: The daily reported number of H7N9 cases was associated with the closing price of the Avian Influenza Sector Index (P < 0.05) and the opening price of the Shanghai Composite Index (P = 0.029). The Avian Influenza Sector Index decreased with increasing of daily reported case number when daily reported cases <= 4. Case number was associated with the opening/closing price of the Chinese Traditional Medicine Sector Index, the Biological Product Sector Index, and the Biomedicine Sector Index (P < 0.05). CONCLUSION: New or reemerging infectious diseases epidemic cause economic loss which is reflected in movements in stock prices. PMID- 28845482 TI - Induced Abortion among Chinese Women with Living Child-A National Study. AB - OBJECTIVE: Induced abortion is widely practiced in China. However, the information on induced abortion is limited. A national cross-sectional survey was designed to determine the risk factors of induced abortion among Chinese women with one child. METHODS: We sampled 16,881 Chinese women with one living child for the study. A structured questionnaire was used to collect induced abortion and related health information. The National Research Institute for Family Planning of China conducted a cross-sectional study among women who had delivered a baby between 2006 and 2008. Information was collected in relation to demographic characteristics (age, ethnicity, region, area etc.), social economic status (education level and occupation), marriage, and the attitude towards potential child's gender. Multi-logistic regression was used to test potential predictors for conducting abortion stratified by consistency between gender preference and current infants' gender, and indicating adjusted estimation on selected models of risk factors for abortion. RESULTS: The mean age of participants was 27.96 +/- 4.10 years (median 27 years). Among those women, the prevalence of induced abortion was 8.13 %. In the final model, females living in rural areas (OR = 1.21, 95 %CI: 1.04-1.39), individuals ages 18-25 (OR = 0.84, 95% CI: 0.72-0.99), individuals ages 30 or older (OR = 1.63, 95% CI: 1.42-1.86), and single individuals (OR = 1.72, 95% CI: 1.05-2.83) were more likely to experience induced abortion. Wife gender preference (OR = 0.66, 95 %CI: 0.53 0.83), husband gender preference (Boy: OR = 1.33, 95 %CI: 1.10-1.63; Girl: OR = 1.5, 95% CI: 1.22-1.86), and the area where the individuals were located were significantly associated with the reporting of induced abortion. CONCLUSION: The prevalence of induced abortion is high among married women with child in China. There are also socio-demographic characteristics associated with induced abortion in China. PMID- 28845484 TI - Sparse Bayesian Inference of White Matter Fiber Orientations from Compressed Multi-resolution Diffusion MRI. AB - The RubiX [1] algorithm combines high SNR characteristics of low resolution data with high spacial specificity of high resolution data, to extract microstructural tissue parameters from diffusion MRI. In this paper we focus on estimating crossing fiber orientations and introduce sparsity to the RubiX algorithm, making it suitable for reconstruction from compressed (under-sampled) data. We propose a sparse Bayesian algorithm for estimation of fiber orientations and volume fractions from compressed diffusion MRI. The data at high resolution is modeled using a parametric spherical deconvolution approach and represented using a dictionary created with the exponential decay components along different possible directions. Volume fractions of fibers along these orientations define the dictionary weights. The data at low resolution is modeled using a spatial partial volume representation. The proposed dictionary representation and sparsity priors consider the dependence between fiber orientations and the spatial redundancy in data representation. Our method exploits the sparsity of fiber orientations, therefore facilitating inference from under-sampled data. Experimental results show improved accuracy and decreased uncertainty in fiber orientation estimates. For under-sampled data, the proposed method is also shown to produce more robust estimates of fiber orientations. PMID- 28845483 TI - Interaction of factor V B-domain acidic region with its basic region and with TFPI/TFPI2: Structural insights from molecular modeling studies. AB - BACKGROUND: Factor V (FV) B-domain contains an acidic region (FV-AR2) and a basic region (FV-BR), which interact with each other and maintain FV in a procofactor form; removal of either region via deletion/proteolysis results in an active FVa molecule. Tissue factor pathway inhibitor type-1 (TFPI) and type-2 (TFPI2) each contain a C-terminus basic segment homologous to FV-BR; this region in TFPI (and predicted in TFPI2) binds to FV-AR2 in platelet FVa (that lacks FV-BR) with high affinity and inhibits FVa function. OBJECTIVES: To understand molecular interactions between FV-AR2 with FV-BR, TFPI-BR and TFPI2-BR. METHODS: Circular dichroism (CD) and molecular modeling approaches. RESULTS AND CONCLUSIONS: CD experiments reveal the presence of ~20% helical content in both FV-AR2 and FV-BR but each lacks beta-sheet. Predicted structures of FV-AR2 and FV-BR, obtained using threading (I-TASSER), are consistent with the CD data and have compact folds with hydrophobic residues in the interior and charged residues on the surface. Scores from QMEAN and ModFOLD servers indicate a very high probability for each structure to be native. Predicted models of Kunitz domain-3 of TFPI and TFPI2 each with C-terminal basic tail are consistent with known homologous structures. Docking experiments using ClusPro indicate that the acidic groove of FV-AR2 has high shape complementarity to accommodate the conserved basic residues in FV-BR (1002-RKKKK-1006), TFPI-BR (256-RKRKK-260) or TFPI2-BR (191-KKKKK-195). Further, similar electrostatic interactions occur in each case. These models, in the absence of experimentally determined structures, provide a guiding point for proper mutagenesis studies in FV, TFPI and TFPI2. PMID- 28845485 TI - Emphysema Quantification on Cardiac CT Scans Using Hidden Markov Measure Field Model: The MESA Lung Study. AB - Cardiac computed tomography (CT) scans include approximately 2/3 of the lung and can be obtained with low radiation exposure. Large cohorts of population-based research studies reported high correlations of emphysema quantification between full-lung (FL) and cardiac CT scans, using thresholding-based measurements. This work extends a hidden Markov measure field (HMMF) model-based segmentation method for automated emphysema quantification on cardiac CT scans. We show that the HMMF based method, when compared with several types of thresholding, provides more reproducible emphysema segmentation on repeated cardiac scans, and more consistent measurements between longitudinal cardiac and FL scans from a diverse pool of scanner types and thousands of subjects with ten thousands of scans. PMID- 28845486 TI - The Effects of Chronic Medical Conditions and Obesity on Self-Reported Disability in Older Mexican Americans. AB - We investigated the effect of chronic medical conditions including obesity on self-reported disability and mobility in Mexican Americans aged 75 or over using data from the Hispanic Established Population for the Epidemiological Study of the Elderly (Hispanic EPESE) Wave 5 (2004-2005). Disability was assessed with a modified version of the Katz activities of daily living (ADL) scale and mobility was assessed with the Rosow Breslau scale of gross mobility function. The percentage of participants needing assistance with ADLs were as follows: 26.7% for transferring from a bed to chair, 26.6% for walking across a small room, 17.9% for dressing, 16.3% for using a toilet, 14.3% for grooming, and 8.2% for eating. Fifty percent reported limitation in the ability to walk 1/2 a mile and walking up and down stairs. Multivariate logistic regression analysis after controlling for all covariates showed that arthritis, diabetes, stroke, and obesity were significantly associated with any ADL limitation, walking up and down stairs, and walking 1/2 mile. Prevention of obesity and chronic medical conditions will help increase functional independence in this population. PMID- 28845487 TI - Ultrasound and liver elastography - tools for detection and quantification of severity in Nonalcoholic Fatty Liver Disease (NAFLD) in general population. PMID- 28845488 TI - Is Point of Care Ultrasound (PoCUS) integrated in clinical exam a key-tool for the future emergency physician? AB - . PMID- 28845489 TI - Is Contrast Enhanced Ultrasonography a useful tool in a beginner's hand? How much can a Computer Assisted Diagnosis prototype help in characterizing the malignancy of focal liver lesions? AB - AIM: Contrast enhanced ultrasound (CEUS) improved the characterization of focal liver lesions (FLLs), but is an operatordependent method. The goal of this paper was to test a computer assisted diagnosis (CAD) prototype and to see its benefit in assisting a beginner in the evaluation of FLLs. MATERIAL AND METHOD: Our cohort included 97 good quality CEUS videos[34% hepatocellular carcinomas (HCC), 12.3% hypervascular metastases (HiperM), 11.3% hypovascular metastases (HipoM), 24.7% hemangiomas (HMG), 17.5% focal nodular hyperplasia (FNH)] that were used to develop a CAD prototype based on an algorithm that tested a binary decision based classifier. Two young medical doctors (1 year CEUS experience), two experts and the CAD prototype, reevaluated 50 FLLs CEUS videos (diagnosis of benign vs. malignant) first blinded to clinical data, in order to evaluate the diagnostic gap beginner vs. expert. RESULTS: The CAD classifier managed a 75.2% overall (benign vs. malignant) correct classification rate. The overall classification rates for the evaluators, before and after clinical data were: first beginner 78%; 94%; second beginner-82%; 96%; first expert-94%; 100%; second expert-96%; 98%. For both beginners, the malignant vs. benign diagnosis significantly improved after knowing the clinical data (p=0.005; p=0,008). The expert was better than the beginner (p=0.04) and better than the CAD (p=0.001). CAD in addition to the beginner can reach the expert diagnosis. CONCLUSIONS: The most frequent lesions misdiagnosed at CEUS were FNH and HCC. The CAD prototype is a good comparing tool for a beginner operator that can be developed to assist the diagnosis. In order to increase the classification rate, the CAD system for FLL in CEUS must integrate the clinical data. PMID- 28845490 TI - Point shear wave speed measurement in differentiating benign and malignant focal liver lesions. AB - AIM: To investigate the value of ElastPQ measurement for differential diagnosis of benign and malignant focal liver lesions (FLLs) by using histologic results as a reference standard. MATERIAL AND METHODS: A total of 154 patients were included. ElastPQ measurement was performed for each lesion in which the shear wave speed (SWS) was measured. The difference in SWS and SWS ratio of FLL to surrounding liver were evaluated, and the cut off value was investigated. Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance. Histology as a gold standard was obtained by surgery in all patients. RESULTS: A total of 154 lesions including 129 (83.7 %) malignant FLLs and 25 (16.3 %) benign ones were analysed. The SWS of malignant and benign FLLs was significantly different, 2.77+/-0.68 m/s and 1.57+/-0.55 m/s (p<0.05). The SWS ratio of each FLL to surrounding liver parenchyma was 2.23+/-0.49 for malignant and 1.14+/-0.36 for benign FLLs (p<0.05). The cut off value for differential diagnosis was 2.06 m/s for SWS and 1.67 for SWS ratio. CONCLUSIONS: ElastPQ measurement provides reliable quantitative stiffness information of FLLs and may be helpful in the differential diagnosis between malignant and benign FLLs. PMID- 28845492 TI - Twinkle, twinkle little stone: an artifact improves the ultrasound performance! AB - AIMS: Ultrasound is a noninvasive method used for the diagnosis of urinary lithiasis. When the length of the stone is less than 5 mm, its detection may be difficult. The twinkling artifact (TwA) is an intense alternating color signal behind calcifications and stones in different organs. The aim of this paper was to evaluate the importance of the TwA in detecting kidney stones less than 5 mm in length. MATERIAL AND METHODS: We examined 230 patients with lumbar pain or a history of kidney stones. We excluded patients with stones larger than 5 mm. 174 patients corresponded to the inclusion criteria. We performed color Doppler ultrasound and we noticed the presence of the twinkling artifact. The gold standard for the diagnosis was either computed tomography (CT) scan, intravenous urography (IVU) or the spontaneous elimination of the stones. RESULTS: We found renal stones in 123 patients. The twinkling artifact was present in 113 cases and absent in the rest of 10 patients. In two patients the artifact was present but the stones were not confirmed by CT. The twinkling artifact had sensitivity, specificity, positive predictive value and negative predictive value of 99.12%, 90.91%, 99.12%, and 90.91% respectively. CONCLUSIONS: The twinkling artifact is a very useful color Doppler ultrasound tool for the detection of small urinary stones. We suggest the routine use of color Doppler in all suspicious cases in order to avoid unnecessary irradiating and expensive radiological methods. PMID- 28845491 TI - Non-alcoholic fatty liver disease, bulb carotid intima-media thickness and obesity phenotypes: results of a prospective observational study. AB - AIMS: The objective of this prospective study was to assess the correlation between carotid intima-media thickness at the common carotid (CIMTc) and carotid bifurcation (CIMTb) level, hepatic fat accumulation, and obesity phenotypes. MATERIAL AND METHODS: Two hundred obese adults, in which CIMTc and CIMTb thickness was determined, were included. According to body mass index (BMI) and presence of metabolic syndrome (MetS), patients were classified as metabolically healthy obese (MHO, obesity without MetS) and metabolically unhealthy obese (MUHO, obesity with MetS). MHO patients were further classified as MHO1 (obese with increased waist circumference) and MHO2 (obese with increased waist circumference plusone of the 4 criteria for MetS). Non-alcoholic fatty liver disease (NAFLD) presence was assessed by fatty liver index (FLI). RESULTS: CIMTc and CIMTb increased with obesity phenotypes from 0.74 mm and 1.04 mm in MHO1 to 0.84 mm and 1.23 mm in MHO2 and 0.88 mm and 1.74 mm in MUHO. Obesity phenotypes were significantly correlated with CIMTb. NAFLD frequency increased from 66.0% in the MHO1 to 73.0% in the MHO2 and 84.2% in the MUHO (p<0.05). Independent of age, BMI, total cholesterol, HbA1c, and HOMA-IR, the CIMTc was significantly associated with FLI in all obesity phenotypesand CIMTb only in MHO2 and MUHO. CONCLUSIONS: Our results suggest that subclinical atherosclerosis varies according to obesity phenotypes and is correlated with the hepatic fat accumulation. PMID- 28845493 TI - Performance of lung ultrasonography for the diagnosis of communityacquired pneumonia in hospitalized children. AB - AIMS: The objective of the study was to assess the performance of lung ultrasonography (LUS) as compared to chest radiography and the clinical criteria for the diagnosis of pneumonia in children. MATERIALS AND METHODS: This was a retrospective study in which data were collected from medical files of 81 children admitted with a clinical suspicion of pneumonia in which both an LUS and a chest radiograph during the hospitalization were performed. Reference standard used for the diagnosis of pneumonia were chest radiographs (consolidation, parenchymal infiltrates, and interstitial infiltrate) and clinical criteria. LUSfindings were reported as normal, parenchymal consolidations and pleural effusions. RESULTS: Radiological pneumonia was reported in 72 of the 81 patients (88.9%). LUS identified parenchymal consolidations in 62 cases. LUS correctly identified radiological pneumonia with a sensitivity of 79.2% and a specificity of 44.4%. The positive predictive value (PPV) was 91.9% and the negative predictive value (NPV) was 21.0%. When clinical criteria were used as reference standard, the sensitivity, specificity, PPV and NPV of correctly identifying clinical pneumonia cases by LUS (only consolidations) were 80.0%, 66.7%, 96.8% and 21.0%. When indicative for the presence of pneumonia either the ultrasound consolidation or the ultrasound detected pleural effusion were considered when the sensitivity, PPV and NPV increased to 96.0% (95%CI: 88.8-99.2), 97.3% (95%CI: 92.0-99.1), and 57.1% (95%CI: 27.7-82.2), respectively. CONCLUSIONS: In our opinion, our findings together withprevious ones available in the literature recommend LUS as a valuable investigation for the diagnosis of community acquiredpneumonia in children. PMID- 28845494 TI - Quantitative Doppler in musculoskeletal ultrasonography - suboptimal performance of both experienced and in-training sonographers in selection of the highest Doppler signal image from cine-loops. AB - AIMS: Doppler ultrasonography assessment is mandatory nowadays for the complete description of rheumatic disease activity. Initially it was performed in semi quantitative way but recently the (fully) quantitative assessment is gaining more interest. In quantitative assessment, the ratio between total colorized and total pixels (CTR) is computed for the whole image or just for the region of interest (ROI). The frame with the highest amount of Doppler signal (also called worst case scenario image - WCSI) is usually the only one analyzed. The technique requires a very precise identification of WCSI from a certain number of consecutive frames, captured from the same position of the US probe, (and in most cases this is done manually). Our study examined the ability of both experienced and in-training sonographers to identify WCSI using a computerized analytical system as the gold standard. MATERIALS AND METHODS: The study analyzed 480 frame selections done in two distinct exercises. The WCSI and other 3 images with a 5%, 10% and respectively 20% lower level of CTR compared with WCSI were packed in one selection. All frames emerging from the same video clip were randomly presented to six experienced and six in training sonographers; the request was to select the frame with the highest CTR (WCSI) from each package (twenty packages in total). A similar exercise was performed with CTRs decreasing in steps of 2%. RESULTS: In the first exercise the WCSI was correctly identified in 79.1% cases and in 67% of cases in the 2nd exercise. The interobserver agreement between experienced and in-trainer evaluators for the 1st exercise was 0.78 and 0.4 in the 2nd exercise. CONCLUSION: Using computerized analysis as the gold standard, we demonstrated a large heterogeneity across sonographers regarding their ability to identify the best Doppler image even from a small group of frames. PMID- 28845495 TI - A novel ultrasound-based technique to establish a correlation between disease activity and local carotid stiffness parameters in rheumatoid arthritis. AB - AIM: Cardiovascular (CV) disease is the reason for most mortality cases in RA and cannot be explained only by the presence of traditional CV risk factors. In this study, we aimed to investigate the relationship between local carotid stiffness (CS) parameters measured by a novel ultrasound method and inflammatory disease activity in rheumatoid arthritis (RA) patients. Material and methods: The study was conducted with 70 RA patients and 35 control subjects. According to their disease activity score (DAS-28), the RA patients were classified into active RA (n = 36; DAS-28 > 3.2) and inactive RA (n = 34; DAS-28 <= 3.2) groups. A novel non-invasive echo-tracking system was used to measure carotid intima-media thickness (C-IMT), diameter, pulsatile strain, distensibility, and carotid pulse wave velocity (PWV) on 128 sites of the common carotid artery. Erythrocytesedimentation rate (ESR) and C-reactive protein (CRP) levels were also determined. RESULTS: Carotid PWV and IMT were significantly higher in the active RA patients (8.20+/-1.47 m/s and 6.88+/-1.50 mm, respectively) compared to the inactive group (6.06+/-1.21 mm and 7.32+/-1.19 m/s, respectively) and the control subjects (0.68+/-0.12 mm and 6.41+/-0.98, respectively). In all RA patients, a statistically significant correlation was found between carotid PWV and age (r=0.435, p<0.001), ESR (r=0.257, p=0.033), and DAS-28 (r=0.314, p=0.009). According to the multivariate logistic regression analysis, age, DAS-28, and ESR were independent predictors of CS. CONCLUSION: A strong correlation was found between disease activity and local CS parameters in patients with RA. We also demonstrated that both active and inactive RA patients showed increased PWV values compared with the control subjects. This easily applicable and previously confirmed method can be used in future to assess cardiovascular risk in broad study populations from different risk groups. PMID- 28845496 TI - Can fetal adrenal artery Doppler velocimetry predict delivery date in pregnant women with spontaneous preterm birth? AB - AIM: To assess the accuracy of delivery date predictions made using fetal adrenal artery Doppler velocimetry in pregnant women with spontaneous preterm birth (PB) and to compare these predictions with cervical length (CL) measurements.Material and methods: A prospective study was performed with 51 pregnant women whose gestational lengths were between 24 and 36 weeks. The main outcome was the time between the Doppler velocimetry examination and delivery, categorized as delivery within 7 days or 7 days later after the examination. A receiver operating characteristics curve was performed to define the cutoffs among deliveries within 7 days for fetal adrenal artery Doppler velocimetry parameters and CL measurements. RESULTS: The incidence of delivery within 7 days was 37.3%, with a statistically significant difference for the pulsatility index (PI; p=0.045) and resistance index (RI; p=0.030) of the fetal adrenal artery. The best cutoff values of PI and RI for predicting deliveries within 7 days were 1.65 and 0.78, respectively. The sensitivity and specificity of PI, RI, and CL (20 mm) were 73.7% (95% CI: 51.9-95.5) and 56.3% (95% CI: 38.1-74.4); 68.4% (95% CI: 45.4 91.4) and 62.5% (95% CI: 44.8-80.2); and 76.5% (95% CI: 54.0-99.0) and 78.1% (95%: CI 71.1-97.7), respectively. CONCLUSION: Fetal adrenal artery Doppler velocimetry can predict delivery within 7 days among pregnant women in cases of spontaneous PB and this prediction is similar to the predictions made using CL measurements. PMID- 28845497 TI - Ultrasound-guided bone lesions biopsies - a systematic review. AB - AIMS: Ultrasound (US) is a highly valuable imagistic tool used to guide numerous interventional procedures. The US guided bone lesions biopsy has not yet received a consensus or a guideline. We aimed to evaluate the evidence to support the US role in guiding bone lesions biopsies. MATERIAL AND METHODS: A computer literature search of PubMed was conducted using the keywords "ultrasound" and "bone biopsy", in order to detect relevant studies regarding the aim of our analysis. Records were screened for eligible studies and data were extracted and analyzed. RESULTS: We included 23 studies (n=610 patients) in the final analysis. The specificity and diagnostic yield of US guided biopsy were very good (between 78-100%), depending on the type and dimensions of the bone lesions. The type of the biopsy - aspiration or cutting - influenced theresults. The studies which included larger groups showed a better performance for cutting needles (83.3 100% vs 50-80.5% for aspiration). The size of the bone lesion influences the diagnostic yield of the US guided bone biopsy. Most of the studies reported nil post-procedural complications. CONCLUSION: Core needle biopsy provided better diagnostic yield compared to fine needle aspiration. The number of the passages of the cutting needle biopsies in order to achieve the best diagnostic yield wasthree. Further studies are needed in order to standardize US-guided bone lesions biopsy and increase its role in the diagnosis algorithm of the bone lesions. PMID- 28845498 TI - Non-invasive diagnosis of portal hypertension in cirrhosis using ultrasound based elastography. AB - Liver stiffness measurement (LSM) by ultrasound-based elastography may be used to non-invasively discriminate between the stages of liver fibrosis, rule out cirrhosis and follow its evolution, including the prediction of the presence of oesophageal varices. The same is possible in order to diagnose clinically significant portal hypertension, referring primarilyto transient elastography and LSM values >=20-25 kPa. The same approach may be used to reliably rule out the presence ofoesophageal varices (LSM <20 kPa + platelets >150x109/L). These recommendations refer primarily to patients with viral aetiology of chronic liver disease (hepatitis C), while additional studies are required for other aetiologies. While spleen stiffness measurement (SSM) also poses a logical choice in this indication, controversial results have nevertheless been published on this issue. It should be emphasized, however, that more recent data indicate that this parameter should be included in the diagnostic algorithm for portal hypertension, if not as the sole then as a part of a sequential algorithm, combined with LSM. Until now, transient elastography has been most extensively studied and founded on scientific evidence, although the results of other ultrasound-based elastography techniques demonstrate the same trend for the non invasive assessment of portal hypertension. PMID- 28845499 TI - Adrenal glands transabdominal ultrasonography - pictorial essay. AB - Adrenal gland ultrasonography is one of the corner stones of the abdominal ultrasonography examination for many medical specialties. The adrenal areas can be easily overlooked though adrenal gland pathology is diverse. We present the normal aspects and various transabdominal ultrasonography findings of the adrenal glands, both common and rare. Even though ultrasound examination is operator and patient dependent, we consider the examination of the adrenal glands very important, due to relatively frequent incidental detection of an adrenal mass. PMID- 28845500 TI - Screw migration in a 14-year-old boy with hip osteotomy; a rare cause of upper thigh hematoma. AB - Soft tissue injury due to orthopedic hardware migration is an uncommon complication. However particularly patients who have routine physical therapy sessions for extremity contractures are at risk for vascular injury in the setting of migrated screws. Ultrasound is an efficient modality to evaluate migrated screws and adjacent soft tissue structures. As a consequence of repetitive trauma a migrated screw would eventually result in injury. Herein a case of upper thigh hematoma due to screw migration in a patient with hip osteotomy is reported. PMID- 28845501 TI - Imagistic and histopathological description of a cystic nephroma during early second trimester of gestation. Case report. AB - Cystic nephroma is a rare and benign renal tumour of unknown origin, usually diagnosed in the first years of childhood or during adult life. To our knowledge, there are no records in the literature of this particular tumour being descried prenatally. We present a case of a fetus diagnosed with cystic nephroma on 16 weeks of gestation. The renal tumour was evaluated by prenatal ultrasound, post mortem with 7T magnetic resonance imaging, and conventional autopsy. PMID- 28845502 TI - Transthoracic ultrasonography for the follow-up of a chronic lymphocytic leukemia patient with chemotherapy-induced immunosuppression prior to allogeneic stem cell transplantation. A case report. AB - In the last years, significant progress has been made in the clinical follow-up of leukemia patients who are especially prone to various infections because of the specific immunosuppressive state following chemotherapy. The follow-up of such patients is of special interest and is based on modern imaging protocols especially computer tomography (CT). Still, CT may not always be effective in the diagnosing of respiratory infections. We report a chronic lymphocytic leukemia patient in which the pleuro-pulmonary complications were successfully diagnosed and followed up using transthoracic ultrasonography. PMID- 28845503 TI - Tuberculous appendicitis. A case report. AB - Double localization of tuberculosis is a rare finding among immunocompetent patients. Intestinal tuberculosis is a rare condition and its diagnosis remains a challenge to the physician. We present the case of a 21 year old male patient with intestinal tuberculosis in which the first manifestation was an acute appendicitis. Ultrasound findings were an abscessed appendicular mass. The surgical intervention found a granulomatous aspect of the peritoneum and total necrosis of the appendix. Histopathological examination confirmed the diagnosis and the pulmonary radiography detected the concomitant pulmonary tuberculosis. PMID- 28845504 TI - Hepatic abscess as a complication of an abscessed gastric lipoma. AB - . PMID- 28845505 TI - Adductor Muscle Tear? Ultrasonographic Imaging of Avulsion Injury of the Iliopsoas Tendon. AB - . PMID- 28845506 TI - Ultrasonographic diagnosis of heterotopic ossification and secondary nerve entrapments in a patient with spinal cord injury. AB - . PMID- 28845507 TI - Toxicological interactions of pesticide mixtures: an update. AB - Pesticides can interact with each other in various ways according to the compound itself and its chemical family, the dose and the targeted organs, leading to various effects. The term interaction means situations where some or all individual components of a mixture influence each other's toxicity and the joint effects may deviate from the additive predictions. The various mixture effects can be greatly determined by toxicokinetic and toxicodynamic factors involving metabolic pathways and cellular or molecular targets of individual pesticides, respectively. However, the complexity of toxicological interactions can lead to unpredictable effects of pesticide mixtures. Interactions on metabolic processes affecting the biotransformation of pesticides seem to be by far the most common mechanism of synergism. Moreover, the identification of pesticides responsible for synergistic interactions is an important issue for cumulative risk assessment. Cholinesterase inhibiting insecticides (organophosphates and N methylcarbamates), triazole fungicides, triazine herbicides, and pyrethroid insecticides are overrepresented in the synergistic mixtures identified so far. Since the limited available empirical evidence suggests that synergisms at dietary exposure levels are rather rare, and experimentally occurred at unrealistic high concentrations, synergism cannot be predicted quantitatively on the basis of the toxicity of mixture components. The prediction of biological responses elicited by interaction of pesticides with each other (or with other chemicals) will benefit from using a systems toxicology approach. The identification of core features of pesticide mixtures at molecular level, such as gene expression profiles, could be helpful to assess or predict the occurrence of interactive effects giving rise to unpredicted responses. PMID- 28845508 TI - Impact of renal denervation on tissue Na+ content in treatment-resistant hypertension. AB - OBJECTIVES: Renal denervation (RDN) has been introduced for reducing blood pressure (BP) in treatment-resistant hypertension (TRH). The precise mechanism how RDN exerts its BP-lowering effects are not yet fully understood. It is widely accepted that sodium (Na+) plays a crucial role in the pathogenesis of hypertensive disease. However, there is increasing evidence of osmotically inactive Na+ storage. We investigated the impact of RDN on Na+ homeostasis using estimation of salt intake, and measurement of tissue Na+ content. METHODS: In a study 41 patients with TRH (office BP >=140/90 mmHg and diagnosis confirmed by 24 h ambulatory BP monitoring) underwent RDN. Tissue Na+ content was assessed non invasively with 3.0 T magnetic resonance imaging before and 6 months after RDN. In addition, 24-h urinary Na+ excretion as an estimate of salt intake and spot urine Na+/K+ excretion were assessed. The study was registered at http://www.clinicaltrials.gov (ID: NCT01687725). RESULTS: There was a significant fall in BP (office: -17 +/- 20/-10 +/- 12 mmHg; 24-h: -11 +/- 13/-6 +/- 9 mmHg, all p < 0.001) 6 months after RDN. In contrast, tissue Na+ content of the muscle (20.1 +/- 3.9 vs. 20.7 +/- 4.0 mmol/L, p = 0.229) and skin (24.4 +/- 6.5 vs. 24.8 +/- 6.6 mmol/L, p = 0.695) did not change after RDN. Moreover, there was also no change in salt intake after RDN, whereas Na+/K+ ratio only acutely increased. CONCLUSIONS: Although RDN resulted in a substantial reduction of BP, tissue Na+ content of the muscle and skin was not mobilized and reduced. These data indicate that the BP reduction after RDN is unrelated to Na+ homeostasis. PMID- 28845510 TI - Establishment of optimal barley straw biochar application conditions for rice cultivation in a paddy field. AB - This study was conducted to establish the optimal application conditions of barley straw biochar (BC) for rice cultivation and to determine the effects of combined application of BC and inorganic fertilizer (IF) on rice cultivation in a paddy field. Based on the characteristics of rice growth in pot-based experiments, the selected optimal application conditions of BC were application of 20 ton ha-1 at 14 days before rice transplanting. The effects of BC application on rice cultivation in a paddy field when using those conditions were then evaluated. Each treatment was separated by a control (Cn), IF, BC, and combined BC + IF treatments, respectively. The rice yields in the BC + IF treatment were 38.6, 21.7, and 24.5% greater than those in the Cn, IF, and BC treatments, respectively. In addition, yield components of rice were significantly improved in the BC + IF treatment relative to the other treatments. Following rice harvest, soil status was improved, showing greater soil aggregation stability, decreased bulk density, and increased porosity in the BC treated areas compared to those in the Cn- and IF-treated areas. At the time of rice harvesting, soil chemical properties such as pH, EC, SOC, TN, Avail. P2O5, and CEC in the BC-treated areas were improved over those in other areas. The results of this study indicate that using BC as a soil amendment is effective at improving rice cultivation and can benefit the soil environment. PMID- 28845509 TI - The role of TGF-beta signaling in dendritic cell tolerance. AB - Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine present in vertebrate and invertebrate organisms that functions in numerous physiological and pathological processes. TGF-beta impacts all the cells of the immune system, and of the three known TGF-beta isoforms, TGF-beta1 is the predominant isoform expressed in immune cells. TGF-beta1 is known to play a pivotal role in the function of all immune cells especially in the regulation of T cell development and in the induction of immunological tolerance in dendritic cells (DCs). Based on the importance of DCs in regulation of the innate and adaptive arms of the immune system, in this review we explore the regulatory functions of TGF-beta required for establishment and maintenance of DC-mediated immune tolerance. PMID- 28845511 TI - Removable thermoplastic appliances modified by incisal cuts show altered biomechanical properties during tipping of a maxillary central incisor. AB - BACKGROUND: The present study aimed to evaluate the force delivery of removable thermoplastic appliances (RTAs), modified by different sized incisal cuts, during tipping of a maxillary central incisor in palatal and vestibular direction. METHODS: Forty-five RTAs from three different materials (Biolon(r), Erkodur(r), Ideal Clear(r)) of the same thickness (1 mm) were used. Analysis was performed on a separated maxillary central incisor which was part of a resin model with a complete dentition. In 15 RTAs, of different material, a cut was inserted at the incisal edge of tooth 11. In 15 other appliances, the cut was extended to teeth 12 and 21. Fifteen aligners remained uncut. The experimental tooth was tipped starting from the zero position in 0.05 degrees steps to a maximal deflection of +/- 0.42 degrees of the incisal edge in vestibular and palatal direction, after positioning the RTA onto the model. RESULTS: The horizontal (Fx) and the vertical (Fz) force components were decreased by approximately half with increasing cut size. Fz values changed during palatal tipping from a weak intrusive force, for aligners without cut, to an extrusive force with increasing cut size. Compared to both other materials used (Erkodur(r) and Ideal Clear(r)), the Biolon(r) aligners showed significantly higher Fx and Fz values (p < 0.0001, respectively). CONCLUSIONS: RTAs modified by different sized incisal cuts show altered biomechanical properties and an inversion of the vertical force component, during tipping of a maxillary central incisor. PMID- 28845513 TI - Flanker task with equiprobable congruent and incongruent conditions does not elicit the conflict N2. AB - In many published studies, various modifications of the flanker task have been used. Regardless of the flanker task version, the conflict N2 component has been consistently reported and interpreted as evidence for the resolution of conflict introduced by incongruent flankers. However, ERP studies that used the most basic flanker task (i.e., a version with equiprobable congruent and incongruent conditions in which only congruency between the target and flankers is manipulated) have not provided compelling evidence for the conflict N2 component. We report the results of a large-sample ERP study employing a basic flanker task that allowed us to revisit the mechanism underlying the resolution of conflict introduced by incongruent flankers. In the behavioral data, we observed the classic effect of congruency. In the ERP data, we found three conflict-sensitive components: (a) an early frontal component, presumably corresponding to P2, (b) P300 for congruent trials, followed by (c) P300 for incongruent trials. We did not find evidence for the conflict N2 component. Based on a review of literature, we propose that the conflict N2 component observed in a basic flanker task might be a frontal aspect of the P300 component. Given previous attempts to attribute the functional role of the ERP components, the absence of the conflict N2 in the basic flanker task suggests that response inhibition may not be crucial for the resolution of conflict induced by incongruent flankers. Instead, the P2 component appears to indicate that selective attention might play an important role in resolving the flanker conflict. PMID- 28845512 TI - CTLA-4-expression on VZV-specific T cells in CSF and blood is specifically increased in patients with VZV related central nervous system infections. AB - VZV-reactivation may lead to symptomatic central nervous system (CNS) diseases, but identification of VZV as causative pathogen of CNS-diseases is challenging. This study was performed to characterize VZV-specific T cells from cerebrospinal fluid (CSF) and blood of patients with active CNS-disease and to determine whether this may improve differential diagnosis. 27 patients with pleocytosis in the CSF were recruited and classified into three groups (10 VZV-related, 10 non VZV-related, 7 unclear). VZV-specific CD4+ T cells were quantified in CSF and blood after simultaneous stimulation with a VZV-antigen lysate and detection of cytokines (IFN-gamma, IL-2, TNF-alpha) and CTLA-4. Polyclonal stimulation served as positive control. VZV-specific CD4+ T-cell frequencies were highest in both CSF (p = 0.0001) and blood (p = 0.011) of patients with VZV-infection, and were enriched at the site of infection (p = 0.002). While cytokine-expression profiles only showed minor differences between the groups, CTLA-4-expression levels on VZV specific T cells from CSF and blood were significantly increased in VZV-related CNS-infections (p = 0.0002 and p<0.0001) and clearly identified VZV-related CNS diseases (100% sensitivity and 100% specificity). Polyclonally stimulated T cells did not show any quantitative and phenotypical differences between the groups. Increased frequency and CTLA-4-expression of VZV-specific T cells from CSF or blood are specifically found in patients with VZV-related CNS-infection. PMID- 28845514 TI - Neoadjuvant hormonal therapy for low-risk prostate cancer induces biochemical recurrence after radical prostatectomy via increased lymphangiogenesis-related parameters. AB - BACKGROUND: The effects of neoadjuvant hormonal therapy (NHT) on pathological features and lymphangiogenesis in patients with prostate cancer (PCa) for each pre-operative risk classification are unclear. METHODS: To clarify the anti cancer effects of NHT, we investigated 153 patients (non-NHT group = 80 and NHT group = 73) who underwent radical prostatectomy (RP) in Nagasaki University Hospital. Lymph vessel density and area (evaluated by D2-40-positive vessels), vascular endothelial growth factor (VEGF)-C and VEGF-D expressions, and biochemical recurrence (BCR)-free survival were compared between these two groups for each D'Amico risk classification (low = 33, intermediate = 58, high = 62 patients). RESULTS: In low-risk PCa patients, the risks of lymph vessel invasion and BCR were significantly higher in the NHT group than in the non-NHT group (P = 0.040 and 0.022, respectively). Such significant difference was not seen in the intermediate- or high-risk PCa groups. Lymph vessel density of the peri-tumoral and intra-tumoral areas and the lymph vessel area were significantly higher (P < 0.001) in the NHT group than in the non-NHT group in low-risk PCa. In regard to the expression of VEGF-C or VEGF-D, significant difference was not detected in low-risk PCa. CONCLUSIONS: NHT stimulated cancer cell progression and BCR via up regulation of lymphangiogenesis-related parameters in patients with low-risk PCa. Although VEGF-C and VEGF-D expressions were not changed by NHT, lymph vessel density and area were increased in low-risk PCa patients. We suggest that NHT for patients with low-risk PCa may have a high risk for BCR after RP. PMID- 28845515 TI - A multi-sector assessment of community organizational capacity for promotion of Chinese immigrant worker health. AB - BACKGROUND: Community-based collaborative approaches have received increased attention as a means for addressing occupational health disparities. Organizational capacity, highly relevant to engaging and sustaining community partnerships, however, is rarely considered in occupational health research. METHODS: To characterize community organizational capacity specifically relevant to Chinese immigrant worker health, we used a cross-sectional, descriptive design with 36 agencies from six community sectors in King County, Washington. Joint interviews, conducted with two representatives from each agency, addressed three dimensions of organizational capacity: organizational commitment, resources, and flexibility. Descriptive statistics were used to capture the patterning of these dimensions by community sector. RESULTS: Organizational capacity varied widely across and within sectors. Chinese and Pan-Asian service sectors indicated higher capacity for Chinese immigrant worker health than did Chinese faith-based, labor union, public, and Pan-ethnic nonprofit sectors. CONCLUSIONS: Variation in organizational capacity in community sectors can inform selection of collaborators for community-based, immigrant worker health interventions. PMID- 28845517 TI - The grapes and wrath: using resveratrol to treat the pathophysiology of hemorrhagic shock. AB - Resveratrol, a naturally occurring polyphenol found in grapes, has been shown to reduce oxidative stress and inflammation in a variety of conditions. Recently, resveratrol has been investigated as a potential adjunct to resuscitation therapy for hemorrhagic shock-a condition characterized by tissue hypoxia, mitochondrial dysfunction, and inflammation. Although standard resuscitation restores tissue perfusion, it can exacerbate oxidative stress and organ damage. In rodent models of severe hemorrhagic shock, resveratrol mitigates reperfusion injury, preserves organ function, and improves survival. While many of these benefits can be attributed to its ability to activate sirtuin 1, resveratrol interacts with many targets that are relevant to ischemia-reperfusion. Here, we explore the probable mechanisms, potential benefits, and possible problems associated with administering resveratrol as an adjunct during resuscitation of hemorrhagic shock. PMID- 28845516 TI - Is ultraviolet exposure acquired at work the most important risk factor for cutaneous squamous cell carcinoma? Results of the population-based case-control study FB-181. AB - BACKGROUND: Squamous cell carcinoma (SCC) is one of the most frequent types of cancer constituting a significant public health burden. Prevention strategies focus on limiting ultraviolet (UV) exposure during leisure time. However, the relative impact of occupational and nonoccupational UV exposure for SCC occurrence is unclear. OBJECTIVES: To investigate the association between occupational and nonoccupational UV exposure for SCC in a multicentre population based case-control study hypothesizing that high occupational UV exposure increases the risk of SCC. METHODS: Consecutive patients with incident SCC (n = 632) were recruited from a German national dermatology network. Population-based controls (n = 996) without history of skin cancer were recruited from corresponding residents' registration offices and propensity score matched to cases. Lifetime UV exposure, sociodemographic and clinical characteristics were assessed by trained physicians. Occupational and nonoccupational UV exposure doses were estimated by masked investigators using established reference values. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were assessed using conditional logistic regression adjusting for relevant confounders. RESULTS: Total solar UV exposure was significantly associated with increased SCC. The OR for high (> 90th percentile) vs. low (< 40th percentile) and high vs, moderate (40-59th percentile) occupational UV exposure was 1.95 (95% CI 1.19 3.18) and 2.44 (95% CI 1.47-4.06) for SCC. Adjusting for occupational UV exposure, nonoccupational UV exposure was not significantly related to SCC incidence. Dose-response relationships were observed for occupational but not for nonoccupational solar UV exposure. CONCLUSIONS: Solar occupational UV exposure is a major determinant of incident SCC. Our findings indicate that prevention strategies should be further expanded to the occupational setting. PMID- 28845518 TI - Neurodevelopmental disorders in children with neurofibromatosis type 1. AB - Over the past several decades, neurofibromatosis type 1 (NF1) has become increasingly recognized as a neurodevelopmental disorder conferring increased risk for several important neurodevelopmental problems. In this review, we summarize the specific neurodevelopmental problems encountered in the context of NF1. These include impairments in general cognitive function, deficits in specific cognitive domains such as executive function and visuospatial processing and risk for specific learning disorders, impairments in attention and social skills and the overlap with attention-deficit-hyperactivity disorder and autism spectrum disorder, and the risk of developing other psychiatric conditions including anxiety and depression. Early recognition of these developmental impairments is important for the effective treatment of children with NF1, and further characterization is essential to improve our understanding of how mutations in the NF1 gene create the diversity of clinical neuropsychiatric symptomatology observed in this at-risk population. PMID- 28845519 TI - Parent-child coregulation of parasympathetic processes varies by social context and risk for psychopathology. AB - The parasympathetic nervous system supports social interaction and varies in relation to psychopathology. However, we know little about parasympathetic processes from a dyadic framework, nor in early childhood when parent-child social interactions become more complex and child psychopathology first emerges. We hypothesized that higher risk for psychopathology (maternal psychopathology symptoms and child problem behavior) would be related to weaker concordance of respiratory sinus arrhythmia (RSA) between mothers and children (M = 31/2 years old; N = 47) and that these relations could vary by social contextual demands, comparing unstructured free play, semistructured cleanup, and structured teaching tasks. Multilevel coupled autoregressive models of RSA during parent-child interactions showed overall dynamic, positive concordance in mother-child RSA over time, but this concordance was weaker during the more structured teaching task. In contrast, higher maternal psychological aggression and child externalizing and internalizing problems were associated with weaker dyadic RSA concordance, which was weakest during unstructured free play. Higher maternal depressive symptoms were related to disrupted individual mother and child RSA but not to RSA concordance. Thus, risk for psychopathology was generally related to weaker dyadic mother-child RSA concordance in contexts with less complex structure or demands (free play, cleanup), as compared to the structured teaching task that showed weaker RSA concordance for all dyads. Implications for the meaning and utility of the construct of parent-child physiological coregulation are discussed. PMID- 28845520 TI - PSCA regulates IL-6 expression through p38/NF-kappaB signaling in prostate cancer. AB - BACKGROUND: Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein. We previously reported that PSCA involved in proliferation and invasion of PCa cells, however, the underlying mechanisms are unknown. In this study, we aimed to explore the regulating role of PSCA gene expression in interleukin-6 (IL-6) autocrine of PCa cells. METHODS: The stable knockdown-PSCA and ectopically overexpressed-PSCA vector were constructed and transfected into human PCa DU145 and PC-3M cells. The effects of PSCA overexpression or knockdown were determined in proliferation, invasion, and metastasis assays. The effect of PSCA on the expression and secretion of IL-6 was evaluated by immunoblotting and ELISA. Subcellular localization and expression pattern of PSCA and IL-6 protein were examined by immunohistochemistry. Its clinical significance was statistically analyzed. RESULTS: The results showed that stable knockdown of PSCA delayed proliferation, migration, and invasion while overexpressing PSCA enhanced the proliferation, migration, and invasion in vitro and the lung metastasis in vivo of PCa cells. Importantly, the PSCA involved in the IL-6 secretion and positively regulated p38/NF-kappaB/IL-6 signaling, leading to enhanced PCa cell invasion and metastasis. Both the expression of PSCA and IL-6 were significantly associated with poor biochemical recurrence-free survival of patients with PCa. PSCA protein expression showed a prognostic value in overall survival as indicated by Kaplan-Meier analysis. CONCLUSIONS: These results indicate that PSCA regulates the expression and secretion of IL-6 in human PCa cells through p38/NF-kappaB signaling pathways. PSCA may be a potential diagnostic marker and therapeutic target for PSCA positive PCa. PMID- 28845521 TI - Recombinant Enaction: Manipulatives Generate New Procedures in the Imagination, by Extending and Recombining Action Spaces. AB - Manipulation of physical models such as tangrams and tiles is a popular approach to teaching early mathematics concepts. This pedagogical approach is extended by new computational media, where mathematical entities such as equations and vectors can be virtually manipulated. The cognitive and neural mechanisms supporting such manipulation-based learning-particularly how actions generate new internal structures that support problem-solving-are not understood. We develop a model of the way manipulations generate internal traces embedding actions, and how these action-traces recombine during problem-solving. This model is based on a study of two groups of sixth-grade students solving area problems. Before problem-solving, one group manipulated a tangram, the other group answered a descriptive test. Eye-movement trajectories during problem-solving were different between the groups. A second study showed that this difference required the tangram's geometrical structure, just manipulation was not enough. We propose a theoretical model accounting for these results, and discuss its implications. PMID- 28845522 TI - Adipochemokines induced by ultraviolet irradiation contribute to impaired fat metabolism in subcutaneous fat cells. AB - BACKGROUND: Adipose tissue is now appreciated as the pivotal regulator of metabolic and endocrine functions. Subcutaneous (SC) fat, in contrast to visceral fat, may protect against metabolic syndrome and systemic inflammation. We demonstrated that chronic as well as acute ultraviolet (UV) irradiation to the skin induces loss of underlying SC fat. UV-irradiated SC fat may produce chemokines or cytokines that modulate lipid homeostasis and secretion of adipokines. OBJECTIVES: To elucidate UV-induced specific adipochemokines implicated in UV-induced modulation of SC fat. METHODS: Primary cultured adipocytes were treated with conditioned medium from UV- or sham-irradiated skin cells. Young and older healthy participants provided SC fat from sun-exposed and sun-protected skin. Sun-protected skin from other participants was irradiated with UV. Differentially expressed adipochemokines were screened by cytokine array, and confirmed in vitro and in vivo. The functions of select adipochemokines involved in lipid metabolism were examined via short interfering RNA-mediated knockdown of cognate receptors. RESULTS: Specific adipochemokines, including C-X-C motif chemokine (CXCL) family members such as CXCL5/ENA-78, and C C motif chemokine (CCL) family members such as CCL20/MIP-3alpha and CCL5/RANTES, were greatly induced in SC fat by UV exposure. They could impair triglyceride synthesis via downregulation of lipogenic enzymes and sterol regulatory element binding protein-1 through their respective cognate receptors, CXC chemokine receptor type (CXC-R)2, C-C chemokine receptor type (CCR)-6, and CCR-5. In addition, UV irradiation induced infiltration of adipose tissue macrophages responsible for the secretion of several chemokines into SC fat. CONCLUSIONS: These UV-induced adipochemokines may be implicated in the reduction of lipogenesis in SC fat, leading to impairment of fat homeostasis and associated comorbidities such as obesity. PMID- 28845523 TI - Dupilumab treatment improves quality of life in adult patients with moderate-to severe atopic dermatitis: results from a randomized, placebo-controlled clinical trial. AB - BACKGROUND: Dupilumab, a human anti-interleukin-4 receptor alpha monoclonal antibody, significantly improved clinical signs and symptoms in adults with moderate-to-severe atopic dermatitis in a randomized, double-blind, placebo controlled, phase IIa trial. OBJECTIVES: We evaluate health-related quality of life (HRQoL) and correlation of HRQoL with secondary clinical and patient reported outcomes in a subset of patients from this trial of dupilumab. METHODS: Patients were randomized to 300 mg weekly subcutaneous dupilumab or placebo for 12 weeks (trial registration: NCT01548404). The Quality of Life Index of Atopic Dermatitis (QoLIAD) score (exploratory outcome) and its correlation with efficacy outcomes [Eczema Area and Severity Index (EASI); primary end point; SCORing Atopic Dermatitis (SCORAD), SCORAD visual analogue scale (VAS) scores for sleep and pruritus, pruritus numerical rating scale (NRS) and 5-dimensional pruritus] were assessed in 64 adults with moderate-to-severe atopic dermatitis. RESULTS: Mean QoLIAD scores at baseline +/- standard error (SE) were 13.3 +/- 1.34 and 11.3 +/- 1.09 for the placebo and dupilumab groups, respectively. Dupilumab significantly improved QoLIAD score after 12 weeks of treatment vs. placebo (mean % change from baseline in QoLIAD score +/- SE: -64.0 +/- 6.91 vs. -11.1 +/- 9.31). Least squares mean % difference from baseline vs. placebo in QoLIAD score +/-SE was -52.0 +/- 11.43, P < 0.001). QoLIAD scores significantly correlated with changes in efficacy outcomes, including EASI (r = 0.44), 5-dimensional pruritus (r = 0.49), pruritus NRS (r = 0.41), total SCORAD (r = 0.56) and SCORAD VAS scores for sleep (r = 0.47) and pruritus (r = 0.54); all P < 0.05. CONCLUSIONS: Dupilumab improved QoLIAD scores in adults with atopic dermatitis and was significantly associated with improvements in study outcomes. PMID- 28845524 TI - Fractalkine/CX3CR1 induces apoptosis resistance and proliferation through the activation of the AKT/NF-kappaB cascade in pancreatic cancer cells. AB - Fractalkine (FKN, CX3CL1) is highly expressed in a majority of malignant solid tumours. Fractalkine is the only known ligand for CX3CR1. In this study, we performed an analysis to determine the effects of fractalkine/CX3CR1 on modulating apoptosis and explored the related mechanisms. The expression of fractalkine/CX3CR1 was detected by immunohistochemistry and western blotting. The levels of AKT/p-AKT, BCL-xl, and BCL-2 were detected by western blotting. Then, the effects of exogenous and endogenous fractalkine on the regulation of tumour apoptosis and proliferation were investigated. The mechanism of fractalkine/CX3CR1 on modulating apoptosis in cancer cells through the activation of AKT/NF-kappaB/p65 signals was evaluated. The effect of fractalkine on regulating cell cycle distribution was also tested. Fractalkine, AKT/p-AKT, and apoptotic regulatory proteins BCL-xl and BCL-2 were highly expressed in human pancreatic cancer tissues. In vitro, fractalkine/CX3CR1 promoted proliferation and mediated resistance to apoptosis in pancreatic cancer cells. The antiapoptotic effect of fractalkine was induced by the activation of AKT/NF kappaB/p65 signalling in pancreatic cancer cells. The NF-kappaB/p65 contributes to promote the expressions of BCL-xl and BCL-2 and reduce caspase activity, thereby inhibiting apoptotic processes. Treatment with fractalkine resulted in the enrichment of pancreatic cancer cells in S phase with a concomitant decrease in the number of cells in G1 phase. The present study demonstrated the function of fractalkine in the activation of the AKT/NF-kappaB/p65 signalling cascade and mediation of apoptosis resistance in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as a diagnostic marker and as a potential target for chemotherapy in early stage pancreatic cancer. Pancreatic cancer is characterized by local recurrence, neural invasion, or distant metastasis. The present study demonstrated the overexpression of fractalkine/CX3CR1 in pancreatic cancer tissues, indicating its important role in the tumourigenesis of pancreatic cancer, and suggested that the overexpression of fractalkine/CX3CR1 could serve as a diagnostic marker for pancreatic cancer. Moreover, we reveal the mechanism that fractalkine functions on the activation of the AKT/NF-kappaB/p65 signalling cascade and regulation of the antiapoptosis process in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as an effective therapeutic target of chemotherapeutic and biologic agents in early stage pancreatic cancer. PMID- 28845525 TI - RGS3 inhibits TGF-beta1/Smad signalling in adventitial fibroblasts. AB - Recent evidence suggests that adventitial fibroblasts (AFs) are crucially implicated in atherosclerosis. However, the mechanisms by which AFs are dysfunctional and contribute to atherosclerosis remain unclear. This study aimed to investigate the role of regulator of G-protein signalling 3 (RGS3) in the regulation of AFs using apoE knockout mouse as the model. Pathological changes in aortic arteries of apoE knockout mice fed with hyperlipid diet were examined by Movat staining. The expression of RGS3, alpha-SMA, TGF-beta1, Smad2, and Smad3 in the adventitia was detected by immunohistochemistry. Adventitial fibroblasts were isolated from aortic arteries of apoE knockout mice and infected with RGS3 overexpression lentivirus or empty lentivirus. The expression of RGS3, alpha-SMA, TGF-beta1, Smad2, and Smad3 in AFs was detected by real-time polymerase chain reaction and Western blot analysis. We found that hyperlipidic diet caused significant aortic intima thickening and atherosclerotic plaques in 15-week-old apoE knockout mice. Compared to wild-type mice, RGS3 expression was lower while alpha-SMA, TGF-beta1, Smad2, and Smad3 expression was higher in the adventitia of apoE knockout mice. In addition, lentivirus mediated overexpression of RGS3 caused decreased expression of alpha-SMA, TGF-beta1, Smad2, and Smad3 in AFs derived from apoE(-/-) mice. In conclusion, these results suggest that RGS3 may provide protection against pathological changes of AFs and the development of atherosclerosis by inhibiting TGF-beta1/Smad signalling. RGS3 may be a potential therapeutic target for atherosclerosis. PMID- 28845527 TI - Extracellular NAMPT/visfatin causes p53 deacetylation via NAD production and SIRT1 activation in breast cancer cells. AB - Visfatin, which is secreted as an adipokine and cytokine, has been implicated in cancer development and progression. In this study, we investigated the NAD producing ability of visfatin and its relationship with SIRT1 (silent information regulator 2) and p53 to clarify the role of visfatin in breast cancer. MCF-7 breast cancer cells were cultured and treated with visfatin. SIRT1 activity was assessed by measuring fluorescence intensity from fluoro-substrate peptide. To investigate the effect of visfatin on p53 acetylation, SDS-PAGE followed by western blotting was performed using specific antibodies against p53 and its acetylated form. Total NAD was measured both in cell lysate and the extracellular medium by colorimetric method. Visfatin increased both extracellular and intracellular NAD concentrations. It also induced proliferation of breast cancer cells, an effect that was abolished by inhibition of its enzymatic activity. Visfatin significantly increased SIRT1 activity, accompanied by induction of p53 deacetylation. In conclusion, the results show that extracellular visfatin produces NAD that causes upregulation of SIRT1 activity and p53 deacetylation. These findings explain the relationship between visfatin and breast cancer progression. PMID- 28845526 TI - Serine peptidase inhibitor Kazal type I (SPINK1) promotes BRL-3A cell proliferation via p38, ERK, and JNK pathways. AB - Serine peptidase inhibitor Kazal type I (SPINK1) has the similar spatial structure as epidermal growth factor (EGF); EGF can interact with epidermal growth factor receptor (EGFR) to promote proliferation in different cell types. However, whether SPINK1 can interact with EGFR and further regulate the proliferation of hepatocytes in liver regeneration remains largely unknown. In this study, we investigated the role of SPINK1 in a rat liver hepatocyte line of BRL-3A in vitro. The results showed the upregulation of endogenous Spink1 (gene addition) significantly increased not only the cell viability, cell numbers in S and G2 /M phase, but also upregulated the genes/proteins expression related to cell proliferation and anti-apoptosis in BRL-3A. In contrast, the cell number in G1 phase and the expression of pro-apoptosis-related genes/proteins were significantly decreased. The similar results were observed when the cells were treated with exogenous rat recombinant SPINK1. Immunoblotting suggested SPINK1 can interact with EGFR. By Ingenuity Pathway Analysis software, the SPINK1 signalling pathway was built; the predicted read outs were validated by qRT-PCR and western blot; and the results showed that p38, ERK, and JNK pathways-related genes/proteins were involved in the cell proliferation upon the treatment of endogenous Spink1 and exogenous SPINK1. Collectively, SPINK1 can associate with EGFR to promote the expression of cell proliferation-related and anti-apoptosis related genes/proteins; inhibit the expression of pro-apoptosis-related genes/proteins via p38, ERK, and JNK pathways; and consequently promote the proliferation of BRL-3A cells. For the first time, we demonstrated that SPINK1 can associate with EGFR to promote the proliferation of BRL-3A cells via p38, ERK, and JNK pathways. This work has direct implications on the underlying mechanism of SPINK1 in regulating hepatocytes proliferation in vivo and liver regeneration after partial hepatectomy. PMID- 28845528 TI - Nutrient intake and urinary incontinence in Korean women: A propensity score matched analysis from the Korea National Health and Nutrition Examination Survey data. AB - OBJECTIVES: To evaluate the relationship between dietary nutrients and female urinary incontinence using nationally representative data from Korea. METHODS: We included 8090 women aged >20 years who had participated in the Korea National Health and Nutrition Examination Survey IV. We carried out a propensity-matched study by identifying women with urinary incontinence. Women without urinary incontinence, matched for age, body mass index, menopause, delivery history, hypertension, diabetes, hypercholesterolemia, stroke, asthma, chronic obstructive pulmonary disease and amount of total food intake, were included as a control group at a 2:1 ratio (661 women with urinary incontinence; 1322 women without urinary incontinence). Data were analyzed using the chi2 -test, Mann-Whitney test, Fisher's exact test and logistic regression. RESULTS: Following propensity score matching, 661 women with urinary incontinence and 1322 women without urinary incontinence were included; the confounders were evenly dispersed and did not differ significantly between the groups. There was no significant difference in the intake of water, fat, protein, calcium, phosphorus, iron, sodium, potassium, vitamin A, carotene, riboflavin, niacin and vitamin C. However, carbohydrate intake was significantly higher in the urinary incontinence group than in the control group (median [interquartile range]: 282.3 g/day [214.7; 352.0] vs 267.7 g/day [212.6; 339.1]; P = 0.041). CONCLUSION: High carbohydrate intake seems to be significantly related to female urinary incontinence in the Korean population. PMID- 28845529 TI - Map-based cloning of the pear gene MYB114 identifies an interaction with other transcription factors to coordinately regulate fruit anthocyanin biosynthesis. AB - Red fruits are popular and widely accepted by consumers because of an enhanced appearance and enriched anthocyanins. The molecular mechanism of anthocyanin regulation in red-skinned pear (Pyrus) has been studied, and the genes encoding the biosynthetic steps and several transcription factors (TFs) have been characterized. In this study, a candidate R2R3 MYB TF, PyMYB114, was identified by linkage to the quantitative trait loci (QTL) for red skin color on linkage group 5 in a population of Chinese pear (Pyrus bretschneideri). The function of PyMYB114 was verified by transient transformation in tobacco (Nicotinana tabacum) leaves and strawberry (Fragaria) and pear fruits, resulting in the biosynthesis of anthocyanin. Suppression of PyMYB114 could inhibit anthocyanin biosynthesis in red-skinned pears. The ERF/AP2 TF PyERF3 was found to interact with PyMYB114 and its partner PybHLH3 to co-regulate anthocyanin biosynthesis, as shown by a dual luciferase reporter system and a yeast two-hybrid assay. In addition, the transcript abundance of PyMYB114 and PyMYB10 were correlated, and co transformation of these two genes into tobacco and strawberry led to enhanced anthocyanin biosynthesis. This interaction network provides insight into the coloration of fruits and the interaction of different TFs to regulate anthocyanin biosynthesis. PMID- 28845530 TI - Association between the antioxidant uric acid and depression and antidepressant medication use in 96 989 individuals. AB - OBJECTIVE: In the last decade, several studies have suggested that depression is accompanied by increased oxidative stress and decreased antioxidant defenses. We tested the hypothesis that high levels of the antioxidant uric acid are associated with lower risk of hospitalization with depression and use of prescription antidepressant medication. METHOD: We examined plasma levels of the antioxidant uric acid in 96 989 individuals from two independent cohort studies. Logistic regression and Cox proportional hazards regression models were multivariable adjusted for age, gender, alcohol, smoking, income, body mass index, C-reactive protein, hemoglobin, triglycerides, cardiovascular disease, diabetes, and intake of meat and vegetables. Results were performed separately in each study and combined in a meta-analysis. RESULTS: In both studies, high uric acid was associated with lower risk of hospitalization as in-patient or out patient with depression and antidepressant medication use. A doubling in uric acid was associated with an effect estimate of 0.57 (95% CI 0.49-0.65) and 0.77 (0.73-0.81) for hospitalization with depression and antidepressant medication use. The association was consistent across strata of all covariates. Results were attenuated in Cox regression analyses with less statistical power. CONCLUSION: High plasma levels of uric acid were associated with low risk of depression hospitalization and antidepressant medication use. PMID- 28845531 TI - Radical chest wall resection and hyperfractionated accelerated radiotherapy for radiation-associated angiosarcoma of the breast: A safe and effective treatment strategy. AB - Radiation-associated angiosarcomas (RAS) of the breast are vascular tumors arising in a previous radiation field for primary breast cancer. They occur rarely but confer a high probability of local recurrence (LR) and poor prognosis. A wide range of treatment strategies exists due to limited evidence, and although resection is the definitive treatment, LR rates remain high. It has been suggested hyperfractionated accelerated radiotherapy (HART) has the potential to prevent LR. The sarcoma group at the Juravinski Cancer Centre (JCC) reports our experience of nine patients treated with radical resection and adjuvant HART. This is one of the largest reported cohorts we are aware of to receive this treatment. The JCC pathologic data base was reviewed between the year 2006-2015 for patients with RAS. Patients who received radical surgery and immediate HART were eligible. Patients underwent radical chest wall resection and en bloc mastectomy. Radiotherapy was then delivered to 4500 cGy in 45 fractions three times daily using parallel opposed photon beams and electron patching, or volumetric modulated arc therapy. Primary outcome was recurrence-free survival in months, and records were reviewed for descriptive reports of toxicity. We compared our results to other institutions experience with surgery alone or other adjuvant therapies. Median follow-up was 19 months (range 3-41 months). One of nine patients developed LR and developed metastasis, one died of other causes, and seven are alive with no recurrent disease. There were seven reports of mild skin toxicity during treatment. One patient developed chronic wound healing complications which eventually resolved and one patient developed asymptomatic radiation osteitis of a rib. On the basis of our experience at the JCC, we recommend treatment with radical chest wall resection and adjuvant HART to prevent recurrence in RAS patients. As demonstrated in our patients, the large normal tissue volume irradiated is tolerable with in combination with small fraction sizes, and no major toxicities were seen. Further investigation into adjuvant therapy regimens and prospective studies are required to reach consensus on optimal treatment for this disease. PMID- 28845532 TI - Mutational analysis using Sanger and next generation sequencing in sporadic spindle cell hemangiomas: A study of 19 cases. AB - Spindle cell hemangioma (SCH) is a distinct vascular soft-tissue lesion characterized by cavernous blood vessels and a spindle cell component mainly occurring in the distal extremities of young adults. The majority of cases harbor heterozygous mutations in IDH1/2 sporadically or rarely in association with Maffucci syndrome. However, based on mosaicism and accordingly a low percentage of lesional cells harboring a mutant allele, detection can be challenging. We tested 19 sporadic SCHs by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), conventional next generation sequencing (NGS), and NGS using a single molecule molecular inversion probes (smMIP)-based library preparation to compare their diagnostic value. Out of 10 cases tested by Sanger sequencing and 2 analyzed using MLPA, 4 and 1, respectively, revealed a mutation in IDH1 (p.R132C). The 7 remaining negative cases and additional 6 cases were investigated using smMIP/NGS, showing hot spot mutations in IDH1 (p.R132C) (8 cases) and IDH2 (3 cases; twice p.R172S and once p.R172G, respectively). One case was negative. Owing to insufficient DNA quality and insufficient coverage, 2 cases were excluded. In total, in 16 out of 17 cases successfully tested, an IDH1/2 mutation was found. Given that IDH1/2 mutations were absent in 161 other vascular lesions tested by smMIP/NGS, the mutation can be considered as highly specific for SCH. PMID- 28845533 TI - Scalable, "Dip-and-Dry" Fabrication of a Wide-Angle Plasmonic Selective Absorber for High-Efficiency Solar-Thermal Energy Conversion. AB - A galvanic-displacement-reaction-based, room-temperature "dip-and-dry" technique is demonstrated for fabricating selectively solar-absorbing plasmonic nanoparticle-coated foils (PNFs). The technique, which allows for facile tuning of the PNFs' spectral reflectance to suit different radiative and thermal environments, yields PNFs which exhibit excellent, wide-angle solar absorptance (0.96 at 15 degrees , to 0.97 at 35 degrees , to 0.79 at 80 degrees ), and low hemispherical thermal emittance (0.10) without the aid of antireflection coatings. The thermal emittance is on par with those of notable selective solar absorbers (SSAs) in the literature, while the wide-angle solar absorptance surpasses those of previously reported SSAs with comparable optical selectivities. In addition, the PNFs show promising mechanical and thermal stabilities at temperatures of up to 200 degrees C. Along with the performance of the PNFs, the simplicity, inexpensiveness, and environmental friendliness of the "dip-and-dry" technique makes it an appealing alternative to current methods for fabricating selective solar absorbers. PMID- 28845534 TI - Monomeric G-actin is uniformly distributed in pollen tubes and is rapidly redistributed via cytoplasmic streaming during pollen tube growth. AB - Dynamic assembly and disassembly of the actin cytoskeleton has been implicated in the regulation of pollen germination and subsequent tube growth. It is widely accepted that actin filaments are arrayed into distinct structures within different regions of the pollen tube. Maintenance of the equilibrium between monomeric globular actin (G-actin) and filamentous actin (F-actin) is crucial for actin assembly and array construction, and the local concentration of G-actin thus directly impacts actin assembly. The localization and dynamics of G-actin in the pollen tube, however, remain to be determined conclusively. To address this question, we created a series of fusion proteins between green fluorescent protein (GFP) and the Arabidopsis reproductive actin ACT11. Expression of a fusion protein with GFP inserted after methionine at position 49 within the DNase I-binding loop of ACT11 (GFPMet49 -ACT11) rescued the phenotypes in act11 mutants. Consistent with the notion that the majority of actin is in its monomeric form, GFPMet49 -ACT11 and GFP fusion proteins of four other reproductive actins generated with the same strategy do not obviously label filamentous structures. In further support of the functionality of these fusion proteins, we found that they can be incorporated into filamentous structures in jasplakinolide (Jasp)-treated pollen tubes. Careful observations showed that G actin is distributed uniformly in the pollen tube and is rapidly redistributed via cytoplasmic streaming during pollen tube growth. Our study suggests that G actin is readily available in the cytoplasm to support continuous actin polymerization during rapid pollen tube growth. PMID- 28845535 TI - Regulatory-associated protein of TOR (RAPTOR) alters the hormonal and metabolic composition of Arabidopsis seeds, controlling seed morphology, viability and germination potential. AB - Target of Rapamycin (TOR) is a positive regulator of growth and development in all eukaryotes, which positively regulates anabolic processes like protein synthesis, while repressing catabolic processes, including autophagy. To better understand TOR function we decided to analyze its role in seed development and germination. We therefore performed a detailed phenotypic analysis using mutants of the REGULATORY-ASSOCIATED PROTEIN OF TOR 1B (RAPTOR1B), a conserved TOR interactor, acting as a scaffold protein, which recruits substrates for the TOR kinase. Our results show that raptor1b plants produced seeds that were delayed in germination and less resistant to stresses, leading to decreased viability. These physiological phenotypes were accompanied by morphological changes including decreased seed-coat pigmentation and reduced production of seed-coat mucilage. A detailed molecular analysis revealed that many of these morphological changes were associated with significant changes of the metabolic content of raptor1b seeds, including elevated levels of free amino acids, as well as reduced levels of protective secondary metabolites and storage proteins. Most of these observed changes were accompanied by significantly altered phytohormone levels in the raptor1b seeds, with increases in abscisic acid, auxin and jasmonic acid, which are known to inhibit germination. Delayed germination and seedling growth, observed in the raptor1b seeds, could be partially restored by the exogenous supply of gibberellic acid, indicating that TOR is at the center of a regulatory hub controlling seed metabolism, maturation and germination. PMID- 28845536 TI - Prevalence and determinants of end-of-life chemotherapy use in patients with metastatic breast cancer. AB - Cessation of chemotherapy in the last few weeks of life could be an important quality-of-care benchmark. Proportion of metastatic breast cancer patients who receive end-of-life chemotherapy is not well described. We aimed to determine the prevalence and determinants of end-of-life chemotherapy use in patients with metastatic breast cancer. A retrospective cohort study using a prospectively collated database of patients with metastatic breast cancer who died between January 1, 2010, and September 30, 2014, was conducted. End-of-life chemotherapy (EOLC) use was defined as receipt of chemotherapy within 2 weeks of death (EOLC2) and receipt of chemotherapy within 4 weeks of death (EOLC4). Patients who did not receive any chemotherapy in the last 4 weeks before death were categorized as non EOLC. We identified 274 patients with metastatic breast cancer, of whom 28 received EOLC2 (10.2%) and 62 received EOLC4 (22.6%). In comparison with non EOLC, patients receiving EOLC4 were younger and had greater disease burden. Patients in EOLC4 group received more number of lines of chemotherapy. In a multivariable analysis, younger age at metastatic disease and greater number of metastatic organ systems involved were predictors of end-of-life chemotherapy use. Prevalence of the use of end-of-life chemotherapy in our cohort was higher than previously described. More end-of-life chemotherapy was used in younger women, and those with greater disease burden. Earlier initiation of end-of-life discussions may be targeted to such patients. PMID- 28845537 TI - Cerebral blood flow velocities and cerebrovascular resistance in normal-term neonates in the first 72 hours. AB - AIM: To determine the range of cerebral blood flow velocities (CBFVs) and Doppler indices of cerebrovascular resistance in normal-term neonates as a baseline for a study of hypoxic-ischaemic encephalopathy. METHODS: The CBFVs, resistive index (RI) and pulsatility index (PI) were measured in the anterior and middle cerebral arteries (ACA and MCA) of 38 normal neonates. RESULTS: The mean peak systolic, end diastolic and time-averaged velocities (PSV, EDV and TAV) were 36.3 +/- 6.6, 12.4 +/- 3.9 and 22.0 +/- 4.0 cm/s (ACA) and 41.4 +/- 13.2, 13.0 +/- 5.5 and 25.8 +/- 7.9 cm/s (MCA), respectively. All CBFVs in the ACA correlated with gestation; only EDV was correlated to post-natal age. The RI in the ACA (0.67 +/- 0.06) and MCA (0.68 +/- 0.07) were correlated (r = 0.72, P < 0.001); RI correlated to post natal age. Two infants with RI < 0.55 were both fed within 25 mins of the study; RI correlated with post-prandial time (dichotomous, pivot 25 min). The mean PI was 1.11 +/- 0.18 (ACA) and 1.17 +/- 0.23 (MCA). Correlations were observed with post-natal age and post-prandial time (dichotomous). The average angle of insonation was greater in the ACA than in the MCA (median of 5 degrees vs. 18 degrees ). CONCLUSIONS: Results corresponded with previous published studies. No correlation was observed between Doppler indices and gestation as component velocities all increase with advancing gestation. Less variation and smaller standard deviation of CBFV's was associated with a smaller angle of insonation. Low RIs (<0.55), without a pathological cause, warrants further study. PMID- 28845538 TI - Analysis of deep learning methods for blind protein contact prediction in CASP12. AB - Here we present the results of protein contact prediction achieved in CASP12 by our RaptorX-Contact server, which is an early implementation of our deep learning method for contact prediction. On a set of 38 free-modeling target domains with a median family size of around 58 effective sequences, our server obtained an average top L/5 long- and medium-range contact accuracy of 47% and 44%, respectively (L = length). A complete implementation has an average accuracy of 59% and 57%, respectively. Our deep learning method formulates contact prediction as a pixel-level image labeling problem and simultaneously predicts all residue pairs of a protein using a combination of two deep residual neural networks, taking as input the residue conservation information, predicted secondary structure and solvent accessibility, contact potential, and coevolution information. Our approach differs from existing methods mainly in (1) formulating contact prediction as a pixel-level image labeling problem instead of an image level classification problem; (2) simultaneously predicting all contacts of an individual protein to make effective use of contact occurrence patterns; and (3) integrating both one-dimensional and two-dimensional deep convolutional neural networks to effectively learn complex sequence-structure relationship including high-order residue correlation. This paper discusses the RaptorX-Contact pipeline, both contact prediction and contact-based folding results, and finally the strength and weakness of our method. PMID- 28845539 TI - Long-term outcomes of narrow diameter implants in posterior jaws: A retrospective study with at least 8-year follow-up. AB - OBJECTIVE: The aim of this study was to evaluate the long-term survival, complications, peri-implant conditions, marginal bone loss, and patient satisfaction of fixed dental prostheses supported by narrow diameter implants (NDIs) in the posterior jaws. MATERIALS AND METHODS: This study was designed as a retrospective cohort study with a mean follow-up time of 10.1 years (SD: 2.5 years). Patients receiving NDIs in posterior jaw were reviewed. Implant survival, hardware complication, modified plaque index (mPI), peri-implant probing depth (PPD), percentage of bleeding on probing (BOP%), marginal bone loss (MBL), and patient satisfaction were evaluated. Log-rank test and t test were used to detect the influence of implant location and restoration type. RESULTS: Sixty-seven patients with 98 NDIs (Premolar site: 81, Molar site: 17, Single crowns: 33, Splinted restorations: 65) were included. The overall implant survival rates were 96.9% at implant level and 97.0% at patient level. Veneer chipping was the most common hardware complication. The veneer chipping rates were 19.4% at patient level and 18.4% at implant level. All patients showed acceptable oral hygiene. Thus, the average MBL was 1.19 mm at implant level and 1.15 mm at patient level. Eight implants (8.5%) and six patients (9.2%) were diagnosed with peri implantitis. Fifty-eight patients (89.2%) were satisfied with the esthetics of the restorations, while 55 patients (84.6%) were satisfied with the function of the restorations. CONCLUSION: Narrow diameter implants could be a predictable treatment option in the long term. High survival rates, high patient satisfaction, acceptable complication rates and marginal bone loss could be achieved. Further long-term studies are needed to evaluate the predictability of NDIs in molar sites. PMID- 28845541 TI - Distribution of tachykinin-related peptides in the brain of the tobacco budworm Heliothis virescens. AB - Invertebrate tachykinin-related peptides (TKRPs) comprise a group of signaling molecules having sequence similarities to mammalian tachykinins. A growing body of evidence has demonstrated the presence of TKRPs in the central nervous system of insects. In this investigation, we used an antiserum against locustatachykinin II to reveal the distribution pattern of these peptides in the brain of the moth Heliothis virescens. Immunolabeling was found throughout the brain of the heliothine moth. Most of the roughly 500 locustatachykinin-II immunoreactive cell bodies, that is, ca. 400, were located in the protocerebrum, whereas the rest was distributed in the deutocerebrum, tritocerebrum, and the gnathal ganglion. Abundant immunoreactive processes were located in the same regions. Labeled processes in the protocerebrum were especially localized in optic lobe, central body, lateral accessory lobe, superior protocerebrum, and lateral protocerebrum, while those in the deutocerebrum were present exclusively in the antennal lobe. In addition to brain interneurons, four pairs of median neurosecretory cells in the pars intercerebralis with terminal processes in the corpora cardiaca and aorta wall were immunostained. No sexual dimorphism in immunoreactivity was found. Comparing the data obtained here with findings from other insect species reveals considerable differences, suggesting species-specific roles of tachykinin related peptides in insects. PMID- 28845540 TI - Building collagen IV smart scaffolds on the outside of cells. AB - Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After being secreted from cells, protomers are activated to initiate oligomerization, forming insoluble networks that are structurally reinforced with covalent crosslinks. Within these networks, embedded binding sites along the length of the protomer lead to the "decoration" of collagen IV triple helix with numerous functional molecules. We refer to these networks as "smart" scaffolds, which as a component of the basement membrane enable the development and function of multicellular tissues in all animal phyla. In this review, we present key molecular mechanisms that drive the assembly of collagen IV smart scaffolds. PMID- 28845542 TI - Cofactors associated with Sudden Acquired Retinal Degeneration Syndrome: 151 dogs within a reference population. AB - OBJECTIVE: To determine factors associated with sudden acquired retinal degeneration syndrome (SARDS) diagnosed within one referral population. ANIMALS STUDIED: 151 dogs diagnosed with SARDS. PROCEDURES: Breed, age, sex, and body weight were compared between dogs with electroretinogram-confirmed SARDS and dogs presented to the UC Davis Veterinary Medical Teaching Hospital (UCD-VMTH) from 1991 to 2014. RESULTS: SARDS was diagnosed in 151 dogs, representing 1.3% of dogs presented to the UCD-VMTH for ophthalmic disease. Although dogs of 36 breeds were affected, the Dachshund (n = 31, 21%), Schnauzer (16, 11%), Pug (11, 7%), and Brittany (5, 3%) were significantly overrepresented, and the Labrador Retriever (3, 2%) was significantly underrepresented vs. the reference population (P < 0.001). Median (range) age and body weight of affected vs. reference dogs were 8.9 (3-20) vs. 6.8 (0.1-26) years and 12.4 (2.8-52.7) vs. 22.3 (0.1-60) kg, respectively. Dogs 6-10 years of age and between 10-20 kg in body weight were significantly overrepresented in the SARDS population, while dogs <6 years of age were significantly underrepresented (P < 0.01). Spayed females (59% of affected dogs) were significantly overrepresented compared to the reference population, whereas intact females (1% of affected dogs) were significantly underrepresented. CONCLUSIONS: Consistent with previous studies, smaller, middle-aged, spayed female dogs may be at increased risk of developing SARDS. Unlike previous studies, this is the first study comparing a variety of SARDS-affected breeds to a reference population. Potentially increased risk of SARDS in several breeds, particularly Dachshunds, suggests a familial factor that warrants further investigation using genetic techniques. PMID- 28845543 TI - T cell replete-haploidentical second hematopoietic stem cell transplantation for primary graft failure in pediatric patients with hematologic malignancies. AB - GF is one of the fatal complications of allogeneic HSCT. To rescue patients with primary GF, a second HSCT should be conducted as soon as possible, but the optimal donor source and technique have yet to be established. In this study, we retrospectively analyzed six children with hematologic malignancies who received TCR-haploidentical second HSCT for primary GF. The median interval between the prior HSCT and the second HSCT was 37.5 days. All patients received fludarabine and ATG containing reduced-intensity re-conditioning before the second HSCT. All patients, except one who died early, achieved both neutrophil and Plt engraftment at a median time of 15 and 33 days, respectively. Chimerism analysis showed that all engrafted patients achieved complete donor chimerism within 3 weeks. Four patients developed acute GVHD, and three patients developed chronic GVHD. TRM occurred in two patients. Median follow-up of the four survivors was 6.8 years, and all remained in sustained remission until the last follow-up. These results suggested that a TCR-haploidentical second HSCT for pediatric patients is feasible, and this approach may provide a potent option for children with primary GF. PMID- 28845544 TI - Ventilatory choices for intubated patients during helicopter stretcher winching. AB - INTRODUCTION: The winching of intubated patients on a stretcher into a helicopter is a rare event. Intermittent positive pressure ventilation is mandatory, which can either be performed manually with a self-inflating bag, or automatically using a portable ventilator. Theoretically automatic ventilation would provide improved oxygenation, more stable arterial carbon dioxide levels and a reduced risk of airway disconnection. Furthermore, the stretcher attendant may better perform winching procedures with higher situational awareness, contributing to crew and patient safety. However ventilator failure, and the diagnosis and management of such, is of concern. OBJECTIVE: The aim of this study is to compare automatic against manual ventilation during intubated helicopter stretcher winching. METHOD: The trial had two phases. Initially a static winch on a hoist simulator was performed, followed by live winching into a helicopter. All stretcher attendants performed two winches with an intubated manikin. During one winch, the manikin was manually ventilated, and an automatic ventilator was used for the other. Airway pressures were measured. RESULTS: Automatic ventilation did not fail. Compared with automatic ventilation, manual ventilation displayed significant pauses, inconsistent rates and both high and low airway pressures. Automatic ventilation permitted better situational awareness and performance in winching manoeuvres. One airway disconnection occurred during manual ventilation. CONCLUSIONS: During helicopter winching, automatic ventilation is superior in providing controlled, consistent and reliable ventilation for intubated patients. The stretcher attendant is also able to provide more attention to the winching manoeuvres with subsequent safety gains. The risk of automatic ventilator failure is low. PMID- 28845545 TI - Can improving information to patients about emergency department processes reduce aggressive behaviour towards staff? PMID- 28845546 TI - Hitting the ground running: Returning to work after extended leave. PMID- 28845547 TI - Optimized inversion-time schedules for quantitative T1 measurements based on high resolution multi-inversion EPI. AB - PURPOSE: Demonstrate an optimized multi-inversion echo-planar imaging technique to accelerate quantitative T1 mapping by judicious selection of inversion times for each slice. METHODS: Slice ordering is optimized to maximize discrimination between tissues with different T1 values. The optimized slice orderings are tested in the International Society for Magnetic Resonance in Medicine/National Institute of Standards and Technology phantom and compared with an unoptimized 21 measurement acquisition. The utility of the method is demonstrated in a healthy subject in vivo at 3 T and validated with a gold-standard inversion-recovery sequence. The in vivo precision of our technique was tested by repeated scans of the same subject within a scan session and across scan sessions, occurring 28 days apart. RESULTS: Phantom measurements yielded good agreement (R2 = 0.99) between the T1 estimates from the proposed optimized protocol, reference values from the National Institute of Standards and Technology phantom and gold-standard inversion-recovery values, as well as a negligible estimation bias that was slightly lower than that from the unoptimized 21-measurement protocol (0.74 versus 19 ms). The range of values for the scan-rescan coefficient of variation was 0.86 to 0.93 (within session) and 0.83 to 0.92 (across sessions) across all scan durations tested. CONCLUSIONS: Optimized slice orderings allow faster quantitative T1 mapping. The optimized sequence yielded accurate and precise T1 maps. Magn Reson Med 79:2101-2112, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28845548 TI - Antiwrinkle effect of topical adhesive pads on crow's feet: How long does the effect last for? AB - BACKGROUND: Adhesive pads should reduce the action of the local muscle contraction on the skin leading to a decrease in the depth of existing wrinkles and the formation of new dynamic wrinkles. AIM OF THE WORK: This study aims at assessing the antiwrinkles action of adhesive pads during time, and the temporary improvement of facial skin appearance by reducing the vision of linear wrinkles and improving skin elasticity. PATIENTS AND METHODS: Thirty-nine subjects participated to a placebo-controlled study. In the short-term test, the measurements were taken 15, 30, and 60 minutes following 30 minutes application of the product; in the long-term test, the measurements were taken after wearing pads every night for 4 weeks. The roughness parameter of the skin surface was calculated by using a profilometry software 3D MEX(r) . RESULTS: In the short- and long-term tests, analyzing the average of the elastomeric measurements, no significant change was observed in any of the parameters analyzed after 15, 30, and 60 minutes. The adhesive pad decreased significantly all roughness skin parameters 15 minutes after short-term application and until 60 minutes after long-term application. These changes did not occur in the contralateral untreated zone. CONCLUSIONS: The use of topical adhesive pads improves wrinkles in the crow's feet area in the first hour after use. However, patient self-evaluation indicated that the use of topical adhesive pads for 3 weeks may offer subjective improvement in crow's feet zone over a 2 hour period. Topical adhesive pads are safe to use and tolerable for most users. PMID- 28845549 TI - pH-zone-refining elution-extrusion countercurrent chromatography: Separation of hydroxyanthraquinones from Cassiae semen. AB - Seven hydroxyanthraquinones were successfully separated from the traditional Chinese medicinal herb Cassiae semen by conventional and pH-zone-refining countercurrent chromatography with an environmentally friendly biphasic solvent system, in which elution-extrusion mode was investigated for pH-zone-refining countercurrent chromatography for the first time. A two-phase solvent system composed of n-hexane/ethyl acetate/ethanol/water (5:3:4:4, v/v/v/v) was used for the conventional countercurrent chromatography while the same system with a different volume ratio n-hexane/ethyl acetate/ethanol/water (3:5:2:6, v/v/v/v) was used for pH-zone-refining countercurrent chromatography, in which 20 mmol/L of trifluoroacetic acid was added in the organic phase as a retainer and 15 mmol/L of ammonia was added to the aqueous phase as an eluter. A 400 mg crude sample could be well separated by pH-zone-refining countercurrent chromatography, yielding 53 mg of aurantio-obtusin, 40 mg of chryso-obtusin, 18 mg of obtusin, 24 mg of obtusifolin, 10 mg of emodin, and 105 mg of the mixture of chrysophanol and physcion with a purity of over 95.8, 95.7, 96.9, 93.5, 97.4, 77.1, and 19.8%, as determined by high-performance liquid chromatography. Furthermore, the difference in elution sequence between conventional and pH-zone-refining mode was observed and discussed. PMID- 28845550 TI - Synthesis and in vitro investigation of halogenated 1,3-bis(4 nitrophenyl)triazenide salts as antitubercular compounds. AB - The diverse pharmacological properties of the diaryltriazenes have sparked the interest to investigate their potential to be repurposed as antitubercular drug candidates. In an attempt to improve the antitubercular activity of a previously constructed diaryltriazene library, eight new halogenated nitroaromatic triazenides were synthesized and underwent biological evaluation. The potency of the series was confirmed against the Mycobacterium tuberculosis lab strain H37Ra, and for the most potent derivative, we observed a minimal inhibitory concentration of 0.85 MUm. The potency of the triazenide derivatives against M. tuberculosis H37Ra was found to be highly dependent on the nature of the halogenated phenyl substituent and less dependent on cationic species used for the preparation of the salts. Although the inhibitory concentration against J774A.1 macrophages was observed at 3.08 MUm, the cellular toxicity was not mediated by the generation of nitroxide intermediate as confirmed by electron paramagnetic resonance spectroscopy, whereas no in vitro mutagenicity could be observed for the new halogenated nitroaromatic triazenides when a trifluoromethyl substituent was present on both the aryl moieties. PMID- 28845551 TI - Management of side effects during and post-treatment in breast cancer survivors. AB - Cancer-related fatigue, insomnia, and cancer-related cognitive impairment are commonly experienced symptoms that share psychological and physical manifestations. One or more of these symptoms will affect nearly all patients at some point during their course of treatment or survivorship. These side effects are burdensome and reduce patients' quality of life well beyond their cancer diagnosis and associated care treatments. Cancer-related fatigue, insomnia, and cancer-related cognitive impairment are likely to have multiple etiologies that make it difficult to identify the most effective method to manage them. In this review, we summarized the information on cancer-related fatigue, insomnia, and cancer-related cognitive impairment incidence and prevalence among breast cancer patients and survivors as well as recent research findings on pharmaceutical, psychological, and exercise interventions that have shown effectiveness in the treatment of these side effects. Our review revealed that most current pharmaceutical interventions tend to ameliorate symptoms only temporarily without addressing the underlying causes. Exercise and behavioral interventions are consistently more effective at managing chronic symptoms and possibly address an underlying etiology. Future research is needed to investigate effective interventions that can be delivered directly in clinic to a large portion of patients and survivors. PMID- 28845552 TI - Abstracts of the 18th Asia-Pacific Prostate Cancer Conference 2017, Australia, 30 August-02 September 2017. PMID- 28845553 TI - Survivin: A novel marker and potential therapeutic target for human angiosarcoma. AB - Human angiosarcoma is a rare malignant vascular tumor associated with extremely poor clinical outcome and generally arising in skin of the head and neck region. However, little is known about the molecular pathogeneses and useful immunohistochemical markers of angiosarcoma. To investigate the mechanisms of angiosarcoma progression, we collected 85 cases of human angiosarcoma specimens with clinical records and analyzed ISO-HAS-B patient-derived angiosarcoma cells. As control subjects, 54 cases of hemangioma and 34 of pyogenic granuloma were collected. Remarkably, consistent with our recent observations regarding the involvement of survivin expression following Hippo pathway inactivation in the neoplastic proliferation of murine hemangioendothelioma cells and human infantile hemangioma, nuclear survivin expression was observed in all cases of angiosarcoma but not in hemangiomas and pyogenic granulomas, and the Hippo pathway was inactivated in 90.3% of yes-associated protein (YAP) -positive angiosarcoma cases. However, survivin expression modes and YAP localization (Hippo pathway activation modes) were not correlated with survival. In addition, we confirmed that survivin small interference RNA (siRNA) transfection and YM155, an anti survivin drug, elicited decreased nuclear survivin expression and cell proliferation in ISO-HAS-B cells which expressed survivin consistently. Conclusively, these findings support the importance of survivin as a good marker and critical regulator of cellular proliferation for human angiosarcoma and YM155 as a potential therapeutic agent. PMID- 28845555 TI - Nurse practitioner-led transitional care interventions: An integrative review. AB - BACKGROUND AND PURPOSE: Chronically ill patients 65 and above have an increased risk of preventable readmission within 30 days of discharge from the hospital. The Transitional Care Model (TCM) introduced by Naylor and colleagues was implemented to improve the transition between hospital and home while decreasing readmissions. This article examines whether nurse practitioner (NP)- led TCM interventions as compared to standard care decrease hospital readmission rates in older adults. METHODS: A literature review was conducted from June 2016 to March 2017 using Cochrane Library, PubMed, Cumulative Index to Nursing and Health Literature (CINAHL) PLUS, Joanna Briggs Institute, and ProQuest Central to seek out the highest level of evidence. Search results were refined to focus on randomized control trials (RTCs) containing NP-led TCM interventions with older adults. CONCLUSIONS: Synthesis of three RTCs, one meta-analysis, and four nonrandomized studies reviewed TCM interventions that included these interventions: follow-up phone calls post discharge, home visits, and handoff of information to the patient's primary care provider. These interventions, although not exclusively led by NPs, decreased hospital readmission rates. IMPLICATIONS FOR PRACTICE: NP-led TCM interventions have the potential to decrease readmissions, but the level of evidence is insufficiently high to allow for generalizability, warranting further study. PMID- 28845554 TI - An X-linked Myh11-CreERT2 mouse line resulting from Y to X chromosome translocation of the Cre allele. AB - The Myh11-CreERT2 mouse line (Cre+ ) has gained increasing application because of its high lineage specificity relative to other Cre drivers targeting smooth muscle cells (SMCs). This Cre allele, however, was initially inserted into the Y chromosome (X/YCre+ ), which excluded its application in female mice. Our group established a Cre+ colony from male ancestors. Surprisingly, genotype screening identified female carriers that stably transmitted the Cre allele to the following generations. Crossbreeding experiments revealed a pattern of X-linked inheritance for the transgene (k > 1000), indicating that these female carries acquired the Cre allele through a mechanism of Y to X chromosome translocation. Further characterization demonstrated that in hemizygous X/XCre+ mice Cre activity was restricted to a subset arterial SMCs, with Cre expression in arteries decreased by 50% compared to X/YCre+ mice. This mosaicism, however, diminished in homozygous XCre+ /XCre+ mice. In a model of aortic aneurysm induced by a SMC-specific Tgfbr1 deletion, the homozygous XCre+ /XCre+ Cre driver unmasked the aortic phenotype that is otherwise subclinical when driven by the hemizygous X/XCre+ Cre line. In conclusion, the Cre allele carried by this female mouse line is located on the X chromosome and subjected to X-inactivation. The homozygous XCre+ /XCre+ mice produce uniform Cre activity in arterial SMCs. PMID- 28845556 TI - The association between sleep quality, low back pain and disability: A prospective study in routine practice. AB - BACKGROUND: The objective of this study was to estimate the association between sleep quality (SQ) and improvements in low back pain (LBP) and disability, among patients treated for LBP in routine practice. METHODS: This prospective cohort study included 461 subacute and chronic LBP patients treated in 11 specialized centres, 14 primary care centres and eight physical therapy practices across 12 Spanish regions. LBP, leg pain, disability, catastrophizing, depression and SQ were assessed through validated questionnaires upon recruitment and 3 months later. Logistic regression models were developed to assess: (1) the association between the baseline score for SQ and improvements in LBP and disability at 3 months, and (2) the association between improvement in SQ and improvements in LBP and disability during the follow-up period. RESULTS: Seventy-three per cent of patients were subacute. Median scores at baseline were four points for both pain and disability, as assessed with a visual analog scale and the Roland-Morris Questionnaire, respectively. Regression models showed (OR [95% CI]) that baseline SQ was not associated with improvements in LBP (0.99 [0.94; 1.06]) or in disability (0.99 [0.93; 1.05]), although associations existed between 'improvement in SQ' and 'improvement in LBP' (4.34 [2.21; 8.51]), and 'improvement in SQ' and 'improvement in disability' (4.60 [2.29; 9.27]). CONCLUSIONS: Improvement in SQ is associated with improvements in LBP and in disability at 3-month follow-up, suggesting that they may reflect or be influenced by common factors. However, baseline SQ does not predict improvements in pain or disability. SIGNIFICANCE: In clinical practice, sleep quality, low back pain and disability are associated. However, sleep quality at baseline does not predict improvement in pain and disability. PMID- 28845557 TI - Treatment of idiopathic pulmonary fibrosis in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand and the Lung Foundation Australia. AB - Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease (ILD) of unknown aetiology with a median survival of only 2-5 years. It is characterized by progressive dyspnoea and worsening lung function, ultimately resulting in death. Until recently, there were no effective therapies for IPF; however, with the publication of two landmark clinical trials in 2014, the anti fibrotic therapies, nintedanib and pirfenidone, have gained widespread approval. This position paper aims to highlight the current evidence for the treatment of IPF, with particular application to the Australian and New Zealand population. We also consider areas in which evidence is currently lacking, especially with regard to the broader IPF severity spectrum and treatment of co-morbid conditions. The utility of non-pharmacological therapies including pulmonary rehabilitation, oxygen as well as symptom management thought to be important in the holistic care of IPF patients are also discussed. PMID- 28845558 TI - History of pulmonary tuberculosis affects the severity and clinical outcomes of COPD. AB - BACKGROUND AND OBJECTIVE: Although an association between pulmonary tuberculosis (TB) and chronic obstructive pulmonary disease (COPD) has been suggested, studies on the effect of TB in COPD patients have not been conducted. We aimed to investigate the severity and clinical outcomes of COPD in patients with and without a history of TB. METHODS: We retrospectively reviewed the data of 1784 patients with COPD in the Korean COPD Subtype Study cohort collected from December 2011 to January 2017 and followed up for 3 years. RESULTS: Among the 1784 patients at baseline, the COPD assessment test (CAT) scores and total St George's Respiratory Questionnaire for COPD (SGRQc) scores were significantly higher in the prior TB group (n = 468) than in the non-TB group (n = 1316). Lung function and exacerbation prevalence were significantly poorer and higher, respectively, in the prior TB group than in the non-TB group. In a small-sized follow-up study, CAT scores (n = 318), SGRQc scores (n = 295) and lung function (n = 182) remained poorer, and exacerbation prevalence (n = 256) remained higher in the prior TB group over 3 years. The forced expiratory volume in 1 s in the prior TB group declined (-0.57%/year), whereas it improved (+0.93%/year) in the non-TB group (P for changes between the groups = 0.076). In the prior TB group, patients showed poorer lung function compared with the non-TB group regardless of having lung lesions visible or not on chest radiographs. CONCLUSION: TB history negatively affected the severity of COPD, and a small-sized follow-up study showed that the changes were sustained for several years. PMID- 28845560 TI - Dr Janan Iswaran 1936-2016. PMID- 28845559 TI - Use of cabergoline for oestrus induction in multiparous anoestrous Beagle bitches. AB - OBJECTIVE: The purpose of this study was to examine the efficacy of daily cabergoline administration on oestrus induction in bitches. METHODS AND RESULTS: Of 20 multiparous Beagle bitches, 15 were not mated with sires in their last oestrus and 5 bitches that had been mated whelped. All bitches were in early or mid-anoestrus and received 5 MUg/kg/day cabergoline PO. Oestrus was induced in the mid-anoestrus bitches at a higher rate than in the early anoestrus bitches. Comparing the different histories of previous pregnancy among the mid-anoestrus bitches, the rate of oestrus induction in the non-pregnant bitches was higher than in the bitches that whelped. CONCLUSION: Cabergoline is effective for oestrus induction in mid-anoestrus bitches. PMID- 28845561 TI - Effect of insemination site and diameter of the pre-ovulatory follicle on the odds of pregnancy in heifers using sexed or non-sexed semen. AB - OBJECTIVE: To determine if insemination site or pre-ovulatory follicle diameter at fixed-time artificial insemination (FTAI) affects the odds of pregnancy when heifers are inseminated with sexed semen. METHODS: The study was conducted in 422 Holstein heifers enrolled into 531 inseminations. Inseminations were randomly allocated to 1 of 16 treatment combinations involving three variables: semen type (sexed vs non-sexed), insemination site (uterine horn vs uterine body) and one of four sires. Ovaries were examined by transrectal ultrasound prior to FTAI to determine the follicle diameter and location. AI technician, times bred, age, weight and temperature-humidity index were also recorded. Pregnancy diagnosis was conducted 29 days post-insemination. Follicle diameter and body weight were categorised according to arbitrary cut-points. Each variable was analysed by logistic regression to determine the effect on pregnancy per AI and compare between sexed and non-sexed inseminations. RESULTS: Insemination site did not affect pregnancy per AI for either sexed (P = 0.528) or non-sexed (P = 0.886) inseminations. Heifers with an 18-22 mm follicle had better odds of pregnancy than heifers that did not (odds ratio (OR) 1.45, 95% confidence interval (CI) 1.004-2.09), although no effect was detected for only sexed or only non-sexed inseminations. Heifers weighing 310-370 kg had a higher pregnancy per AI than heifers weighing > 370 kg for non-sexed inseminations (P = 0.004) and sexed semen from sire 4 caused lower odds of pregnancy than semen from sire 1 (OR 0.40, 95% CI 0.18-0.89). CONCLUSION: Insemination site did not affect pregnancy per AI, but heifers with an 18-22 mm pre-ovulatory follicle at insemination had better odds of pregnancy for both sexed and non-sexed inseminations. PMID- 28845564 TI - Demographics, farm and reproductive management strategies used in Australian automatic milking systems compared with regionally proximal conventional milking systems. AB - OBJECTIVE: To determine the management practices utilised in automatic milking systems (AMS) that affect reproductive management and performance and how these compare with the management practices used in regionally proximal conventional milking systems (CMS). METHODS: This study examined demographic and management data from AMS and CMS dairy farms through a survey, with a specific focus on reproductive management procedures. RESULTS: Overall, responses from AMS and CMS dairy farms showed little difference in terms of respondent demographics, farm size, herd structure and most farm management strategies. AMS dairies were more likely to use activity meters or other electronic oestrus detection aids than CMS dairies (P < 0.001) and were also more likely to have changed to electronic recording systems (P = 0.007). Although many respondents indicated that they used key monitoring parameters to assess reproductive performance (e.g. days in milk, conception vs pregnancy rate etc.), the format of responses varied significantly, indicating a relatively widespread (among the respondents) lack of knowledge regarding the meaning and usage of some of these common parameters/terminology. CONCLUSIONS: Ultimately, reproductive management practices of AMS dairies were largely similar to those of CMS dairies, indicating that such practices can be implemented in a practical sense, even though the resultant reproductive performance is not yet understood. Understanding that the key reproductive management strategies do not need to change vastly is important to ensure that new adoptees are well informed. Further work is needed to objectively measure AMS performance to increase the knowledge base and generate the confidence that will facilitate further adoption of this innovation. PMID- 28845566 TI - Erratum. PMID- 28845565 TI - Overground endoscopy in 311 Thoroughbred racehorses: findings and correlation to resting laryngeal function. AB - OBJECTIVE: To review a large number of equine overground endoscopy (OGE) examinations to determine the incidence of dynamic upper airway obstructions (DUAO); correlations were explored with laryngeal endoscopy findings at rest and abnormal exercising respiratory noise. METHODS: Retrospective analysis of horses presenting for OGE because of perceived poor performance and/or history of abnormal exercising respiratory noise between 2010 and 2014. Signalment, history and examination findings during resting laryngeal endoscopy and OGE were reviewed. RESULTS: Of the total examinations, 311 were reviewed. One or more DUAO were found in 249/311 horses. From 210 males (colts and geldings), 121 had arytenoid cartilage collapse (ACC) and 111 had vocal fold collapse (VFC). From 101 females, 25 had intermittent dorsal displacement of the soft palate (DDSP). Resting laryngeal function grade 4 was found in 121/311 of the study population and 92/210 of males. An association was found between horses with lower resting arytenoid abduction ability to dynamic ACC and higher resting arytenoid abduction ability with DDSP. Abnormal exercising respiratory noise was positively associated with the presence of DUAO. CONCLUSIONS: Multiple DUAO in association with abnormal exercising respiratory noise was a common finding in horses examined for poor performance. This study highlights the importance of OGE in accurately diagnosing the nature of DUAO associated with poor performance. PMID- 28845567 TI - Assessment of florfenicol as a possible treatment for chlamydiosis in koalas (Phascolarctos cinereus). AB - OBJECTIVE: Because of limited availability of chloramphenicol to veterinary suppliers, a preliminary study was performed to predict whether an analogue, florfenicol, is an efficacious treatment for chlamydiosis in koalas. METHODS: Florfenicol was administered to koalas with naturally occurring chlamydiosis at 20 mg/kg SC (n = 3) and at 5 mg/kg (n = 3) and 10 mg/kg (n = 3) IV. The estimated areas under the plasma concentration versus time curves (AUC) were compared with the minimum inhibitory concentration to inhibit Chlamydia pecorum. Clinical data were also examined from field trials conducted on koalas (n = 19) with naturally occurring chlamydiosis and treated with florfenicol at a range of dosages (5-20 mg/kg SC and 6-15 mg/kg IV). Florfenicol binding to proteins in plasma was also determined. RESULTS: Florfenicol was not detectable in plasma 24 h post administration at 20 mg/kg SC. The estimated AUC0-24 h following administration at 10 mg/kg IV suggests florfenicol might be effective against Chlamydia spp. via this route. Florfenicol binding to plasma proteins was 13.0% (+/- 0.30 SEM). After treatment with florfenicol in field trials, 5 of 19 koalas (26%) were released without further treatment, 4 with no long-term follow-up; 6 (32%) required additional treatment with chloramphenicol to resolve chlamydiosis; 7 (36%) failed to clinically improve, of which 3 had clinical signs and/or necropsy findings suggestive of antibiotic-related gastrointestinal dysbiosis; another koala died within minutes of florfenicol administered IV at 7 mg/kg. CONCLUSION: When administered at dosages tolerable in the field, florfenicol is a problematic treatment for chlamydiosis based on equivocal outcomes and plasma concentrations below those that inhibit the pathogen. PMID- 28845568 TI - Poland's Syndrome: When there is no breast. AB - Poland's Syndrome is rare, therefore, clinicians may not be familiar with all that potentially defines this disorder. Much of the literature that exists regarding Poland's Syndrome focuses on the surgical correction of breast asymmetry for cosmesis. Inspired by a patient at our institution, this paper reviews this rare breast disorder and its associated findings within the context of the whole woman with special attention to breast cancer in this cohort. PMID- 28845569 TI - Papillary lesions of the breast: To excise or observe? AB - Papillary lesions of the breast range from benign to atypical to malignant. Although papillomas without frank cancer are benign, their management remains controversial. When a core needle biopsy of a lesion yields a diagnosis of intraductal papilloma with atypia, excision is generally recommended to rule out a concurrent malignant neoplasm. For intraductal papillomas without atypia, however, recommendations for excision versus observation are variable. The aims of this study are to evaluate the rate of concurrent malignancies for intraductal papilloma diagnosed on core needle biopsy and to assess the long-term risk of developing cancer after the diagnosis of a papillary lesion. This single institution retrospective study analyzed 259 patients that were diagnosed with intraductal papilloma (IDP) by core needle biopsy from 1995 to 2010. Patients were grouped by initial diagnosis into three groups (papilloma without atypia, papilloma with atypia, and papilloma with atypical duct hyperplasia or atypical lobular hyperplasia (ADH/ALH) and followed up for long-term outcomes. After a core needle biopsy showing IDP with atypia or IDP + ADH/ALH, surgical excision yielded a diagnosis of concomitant invasive or ductal in situ cancer in greater that 30% of cases. For intraductal papilloma without atypia, the likelihood of cancer was much lower. Moreover, even with excision, the finding of intraductal papilloma with atypia carries a significant risk of developing cancer long-term, and such patients should be followed carefully and perhaps should be considered for chemoprevention. PMID- 28845571 TI - Challenges faced by trainees returning to work after an extended period of leave: A Director of Emergency Medicine Training perspective. PMID- 28845570 TI - Peripheral blood monocyte count reflecting tumor-infiltrating macrophages is a predictive factor of adverse pathology in radical prostatectomy specimens. AB - BACKGROUND: Tumor-infiltrating macrophages, which are thought to be derived from blood monocytes, interact with tumor cells to promote cancer progression. The aim of this study was to assess the association of peripheral blood monocyte count with pathological findings and local tumor-infiltrating macrophages in prostatectomy specimens. METHODS: Preoperative peripheral blood monocyte counts were retrospectively assessed for their associations with pathological findings (pathological T stage, Gleason Score, extraprostatic extension, seminal vesicle invasion, and surgical margin) and biochemical recurrence of 248 patients who underwent radical prostatectomy. Local tumor-infiltrating macrophages were also evaluated immunohistochemically for their association with peripheral monocyte counts. RESULTS: The peripheral monocyte counts of the patients with extraprostatic extension, seminal vesicle invasion, or primary Gleason >=4 were significantly higher than those of the patients without each of these pathological findings (P < 0.001, P = 0.034, and P = 0.004, respectively). Peripheral monocyte count was a significant predictor of adverse pathology and postoperative biochemical recurrence in localized prostate cancer by multivariate analysis (P = 0.001 and P = 0.041, respectively). Both the density and the count of tumor-infiltrating macrophages correlated significantly with the peripheral blood monocyte count (Spearman rank correlation coefficients were 0.463 and 0.649, respectively, P < 0.001). CONCLUSIONS: Peripheral blood monocyte count reflecting local tumor-infiltrating macrophages was a predictive factor for tumor progression and prognosis in patients with localized prostate cancer. Elucidating the mechanism of the interaction of peripheral monocytes with tumor-infiltrating macrophages is necessary. PMID- 28845572 TI - Spontaneous nasal perforation in a bevacizumab-treated patient with metastatic breast cancer. AB - Nasal septum perforation in patients with cancer receiving systemic therapy is rare, and its association with bevacizumab use has described recently in the literature. Here, we report the case of a 34-year-old woman with hormone sensitive, HER-2/neu negative, metastatic breast cancer who develope a nasal septum perforation during the treatment with paclitaxel and bevacizumab. PMID- 28845573 TI - Editorial: Herpes Zoster: Fear the Infection, Value the Solution. PMID- 28845574 TI - Enucleation or exenteration in two dogs with previous parotid duct transposition: parotid duct ligation versus reverse parotid duct transposition. AB - Two dogs with previous parotid duct transpositions presented with unrelated ocular disease. In both cases, ophthalmic examination revealed the need for enucleation or exenteration. In case 1, systemic coccidioidomycosis was diagnosed with panuveitis and secondary glaucoma of the left eye. In this case, the parotid duct was ligated at the time of enucleation to stop salivary secretions. This dog encountered morbidity in the form of a sialocele that did not resolve for 11 months. In case 2, ultrasound and computed tomography revealed a discrete mass within the left medial orbit that was suspected to arise from the nictitating membrane. A combination of exenteration and parotid duct transposition reversal was performed to avoid morbidity associated with ligation of the parotid duct. The dog encountered no complications from this novel procedure. This case report represents the first report of re-routing a transposed parotid duct from the ventral conjunctival sac back to the mouth at the time of enucleation or exenteration in the dog. PMID- 28845575 TI - The common practice of "curbside consultation": A systematic review. AB - PURPOSE: Point-of-care information needs for nurse practitioners are tremendous. A phenomenon often referred to as curbside consultation (CC) with colleagues is an information source for point-of-care clinical decision making. This literature review was conducted to describe: (a) characteristics of CC, (b) consistency of CC definition, and (c) attitudes about CC among health professionals using this information source for point-of-care clinical decision making. METHODS: This literature review includes research conducted from 1980 to 2016 concerning CC among health professionals. Data bases including PubMed, CINAHL, Google Scholar, Web of Science, PsychInfo, Business Source, and Cochrane Library were searched resulting in 15 articles for inclusion in this review. Fink's recommendations were used to assess study bias risk. CONCLUSIONS: Only studies including physician samples met inclusion criteria. These studies, primarily from consultant perspectives, were conducted in varied settings and were considered highly valuable. CC s averaging 9.4 min were defined as informal advice and information-seeking without formal consultation. IMPLICATIONS FOR PRACTICE: A paucity of information exists concerning CC use among nurse practitioners. An assessment of CC processes among nurse practitioners is indicated to inform education and practice for research dissemination ultimately promoting patient care quality. PMID- 28845576 TI - SMU.940 regulates dextran-dependent aggregation and biofilm formation in Streptococcus mutans. AB - The oral bacterium Streptococcus mutans is the principal agent in the development of dental caries. Biofilm formation by S. mutans requires bacterial attachment, aggregation, and glucan formation on the tooth surface under sucrose supplementation conditions. Our previous microarray analysis of clinical strains identified 74 genes in S. mutans that were related to biofilm morphology; however, the roles of almost all of these genes in biofilm formation are poorly understood. We investigated the effects of 21 genes randomly selected from our previous study regarding S. mutans biofilm formation, regulation by the complement pathway, and responses to competence-stimulating peptide. Eight competence-stimulating peptide-dependent genes were identified, and their roles in biofilm formation and aggregation were examined by mutational analyses of the S. mutansUA159 strain. Of these eight genes, the inactivation of the putative hemolysin III family SMU.940 gene of S. mutansUA159 promoted rapid dextran dependent aggregation and biofilm formation in tryptic soy broth without dextrose (TSB) with 0.25% glucose and slightly reduced biofilm formation in TSB with 0.25% sucrose. The SMU.940 mutant showed higher expression of GbpC and gbpC gene than wild-type. GbpC is known to be involved in the dextran-dependent aggregation of S. mutans. An SMU.940-gbpC double mutant strain was constructed in the SMU.940 mutant background. The gbpC mutation completely abolished the dextran-dependent aggregation of the SMU.940 mutant. In addition, the aggregation of the mutant was abrogated by dextranase. These findings suggest that SMU.940 controls GbpC expression, and contributes to the regulation of dextran-dependent aggregation and biofilm formation. PMID- 28845577 TI - The Safety and Immunogenicity of Live Zoster Vaccination in Patients With Rheumatoid Arthritis Before Starting Tofacitinib: A Randomized Phase II Trial. AB - OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV). METHODS: In this phase II, 14-week, placebo-controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo 2-3 weeks postvaccination. We measured humoral responses (varicella zoster virus [VZV] specific IgG level as determined by glycoprotein enzyme-linked immunosorbent assay) and cell-mediated responses (VZV-specific T cell enumeration, as determined by enzyme-linked immunospot assay) at baseline and 2 weeks, 6 weeks, and 14 weeks postvaccination. End points included the geometric mean fold rise (GMFR) in VZV-specific IgG levels (primary end point) and T cells (number of spot forming cells/106 peripheral blood mononuclear cells) at 6 weeks postvaccination. RESULTS: One hundred twelve patients were randomized to receive tofacitinib (n = 55) or placebo (n = 57). Six weeks postvaccination, the GMFR in VZV-specific IgG levels was 2.11 in the tofacitinib group and 1.74 in the placebo group, and the VZV-specific T cell GMFR was similar in the tofacitinib group and the placebo group (1.50 and 1.29, respectively). Serious adverse events occurred in 3 patients in the tofacitinib group (5.5%) and 0 patients (0.0%) in the placebo group. One patient, who lacked preexisting VZV immunity, developed cutaneous vaccine dissemination 2 days after starting tofacitinib (16 days postvaccination). This resolved after tofacitinib was discontinued and the patient received antiviral treatment. CONCLUSION: Patients who began treatment with tofacitinib 2-3 weeks after receiving LZV had VZV-specific humoral and cell mediated immune responses to LZV similar to those in placebo-treated patients. Vaccination appeared to be safe in all of the patients except 1 patient who lacked preexisting VZV immunity. PMID- 28845578 TI - Patient harboring a novel PIK3CA point mutation after acquired resistance to crizotinib in an adenocarcinoma with ROS1 rearrangement: A case report and literature review. AB - ROS1 rearrangement occurs in 1-2% of non-small cell lung cancer (NSCLC) cases. These patients would benefit from treatment with the anaplastic lymphoma kinase inhibitor, crizotinib; however, resistance to crizotinib inevitably develops in such patients despite an initial response. The mechanism of acquired resistance to crizotinib in patients with NSCLC with ROS1 rearrangement has not yet been identified. Herein, we report a case of a 66-year-old woman diagnosed with adenocarcinoma. PCR revealed no EGFR or ALK mutations. After the patient underwent several rounds of chemotherapy, crizotinib was administered. The disease explosively progressed six months later. A novel PIK3CA gene point mutation (p.L531P) was detected by next generation sequencing. This case is the second report of bypass activation conferred crizotinib resistance in a patient with NSCLC with ROS1-rearrangement, but is the first to confirm that activation of the mTOR signaling pathway leads to acquired crizotinib resistance. PMID- 28845579 TI - Tear fluid collection in dogs and cats using ophthalmic sponges. AB - OBJECTIVE: To compare the use of two ophthalmic sponges for tear collection in dogs and cats. ANIMALS STUDIED: Ten healthy dogs and 10 healthy cats. PROCEDURES: A strip (4 * 10 mm) of either cellulose or polyvinyl acetal (PVA) sponge was inserted into the ventral fornix of each eye for either 15, 30, or 60 s. The wetted strip was placed into a 0.2-mL tube that was first punctured at its bottom. Tears were eluted through the drainage hole into a 1.5-mL tube via centrifugation. Tear volume absorbed (VA) and tear volume recovered (VR) were calculated as the difference of the post- and precollection weight of the 0.2-mL tube and 1.5-mL tube, respectively. Recovery ratio (RR) was determined as the ratio between VR and VA. RESULTS: Ophthalmic sponges were well tolerated by all subjects. In dogs and cats, median (95% range) VA, VR, and RR were as follows: 44 MUL (11-106 MUL) and 16 MUL (2-43 MUL); 27 MUL (1-84 MUL) and 6 MUL (0-29 MUL); 64% (7-91%) and 35% (0-86%), respectively. PVA sponges achieved significantly greater VR in cats and RR in both species. All parameters were significantly greater with a collection time of 60 vs. 30 and 15 s. Body weight was associated with VA and VR in dogs but not cats. CONCLUSIONS: Polyvinyl acetal is better than cellulose for tear collection given its superior recovery. Ophthalmic sponges could facilitate routine analysis of tear fluid in dogs and cats, although further studies are needed to evaluate the quality of tears obtained with this method. PMID- 28845580 TI - Comparison of extracardiac conduit and lateral tunnel for functional single ventricle patients: A meta-analysis. AB - OBJECTIVE: This study aims to assess and compare the early and long-term effects of extracardiac conduit (EC) and lateral tunnel (LT) in patients with a functional single ventricle through meta-analysis. DESIGN: A systematic search was performed in PubMed, Embase, Cochrane Library, CNKI, VIP, CBM, and WanFang databases for papers that were published until August 1, 2016. Cochrane systematic review method was used for paper screening and information retrieve, and RevMan 5.3 software was applied for the meta-analysis. RESULTS: Data for 10 studies with a total of 3814 patients were retrieved. The advantages of EC comparing to LT include: lower 30 day postsurgery supraventricular arrhythmia incidence (Relative Risk [RR] = 0.31 [0.17, 0.55], P < .001), lower protein loss enteropathy incidence (RR = 0.33 [0.11, 0.96], P = .04), and requiring no cardiopulmonary bypass. However, the chest drainage time was longer (mean difference [MD] = 1.99 [1.83, 2.15], P < .001) in EC. There were no significant differences in early postoperative mortality, long-term mortality, long-term arrhythmia, Fontan takedown, ventilator-assisted ventilation, ICU stay, thrombosis, pleural effusion, and pericardial effusion between EC and LT. CONCLUSIONS: EC had a lower incidence of supraventricular arrhythmia (30 days after operation) and the rate of protein losing enteropathy than LT, and requiring no cardiopulmonary bypass. These show that EC has an advantage over the LT in patients with a functional single ventricle. PMID- 28845581 TI - Primary atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) of the breast. PMID- 28845583 TI - Editorial Comment from Dr Sakakibara to Case of possible multiple system atrophy with a characteristic imaging finding of open bladder neck during storage phase as an initial sign. PMID- 28845582 TI - Pathophysiology of exercise intolerance in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a chronic disease with poor prognosis and important exercise limitation despite the proliferation of treatment options in the last decade. Chronically increased right ventricular (RV) afterload results in right heart failure and without treatment, rapid clinical deterioration is common. Exercise intolerance is the cardinal feature of the disease impacting upon quality of life and clinical outcome. The pathophysiological mechanisms that lead to reduced exercise capacity in this population are complex with ventriculoarterial uncoupling likely to be the predominant feature. The relative contributions of additional factors that contribute to exercise limitation beyond ventriculoarterial uncoupling have not been characterized. This review addresses these factors with a focus on recent developments and uncertainties. RV maladaptation and the intricate interplay between the heart, abnormal pulmonary vascular bed and peripheral factors such as dysfunction of the respiratory and peripheral muscles are discussed in detail. PMID- 28845584 TI - Enantioselective determination of 1-[4-(2-methoxyethyl)phenoxy]-3-[2-(2 methoxyphenoxy)ethylamino]-2-propanol hydrochloride, a novel antihypertensive agent, in rat plasma and tissues by liquid chromatography-tandem mass spectrometry. AB - Enantioselective biodistribution studies of 1-[4-(2-methoxyethyl)phenoxy]-3-[2-(2 methoxyphenoxy)ethylamino]-2-propanol hydrochloride (TJ0711), a novel antihypertensive agent, require the accurate and precise quantification of each TJ0711 enantiomer in biological fluids and tissues. Here we report a simple and sensitive liquid chromatography with tandem mass spectrometry method for simultaneous determination of (R)-TJ0711 and (S)-TJ0711 in rat plasma and tissue samples using protein precipitation. The influence of column type, temperature, mobile phase composition, and flow rate on the retention and enantioselectivity was evaluated. The separation of the TJ0711 enantiomers was ultimately achieved on a SUMICHIRAL OA-2500 column in 15 min using isocratic elution with ethanol/hexane (40:60) at a flow rate of 0.8 mL/min. Good linearities of spiked analyte concentration from 5 to 2000 ng/mL were achieved and the correlation coefficients (R) were greater than 0.99. The intra- and inter-day accuracy and precision for both analytes were <15% at all concentration levels, and the extraction recoveries were consistent among the five quality control concentrations. This assay was successfully applied to quantify plasma and tissue concentrations of TJ0711 enantiomers in a preclinical study. PMID- 28845585 TI - Intrafocal heterogeneity of ERG protein expression and gene fusion pattern in prostate cancer. AB - BACKGROUND: Prostate cancer is considered to be highly heterogeneous, with various morphologic features and biologic behaviors. The TMPRSS2-ERG gene fusion is the most frequently observed genetic aberration in prostate cancer. The aim of this study was to elucidate the intrafocal heterogeneity of ERG gene fusion status. METHODS: ERG immunohistochemistry (IHC) was performed in samples from 168 prostate cancer patients who had undergone radical prostatectomy, and 40 cases showing ERG-positive IHC staining were selected for tissue microarray (TMA) construction. Two to six representative cores were selected from each tumor focus. In the cases with heterogeneous ERG IHC staining intensity, the areas showing different intensities were separately selected. Using the TMA blocks, IHC and fluorescence in situ hybridization (FISH) were conducted to evaluate the heterogeneity of ERG protein expression and ERG fusion gene patterns, respectively, in a single tumor focus. Heterogeneity of ERG IHC staining was defined as the simultaneous presence of negative and positive cores in the same tumor focus. Heterogeneity of ERG FISH was defined by the presence of cores with positive and negative FISH signals or cores with break-apart and interstitial deletion FISH signals in the same tumor focus. RESULTS: A total of 202 TMA cores were isolated from 40 ERG-positive cases. Of the 202 total cores, 19 were negative for ERG IHC staining, and 46 showed 1+, 52 showed 2+, and 85 showed 3+ ERG staining intensity. Eleven cores were negative for ERG FISH signal, 119 cores showed ERG break-apart FISH signals, and the remaining 72 cores revealed interstitial deletion. Intrafocal heterogeneity of ERG IHC staining was found in 20% (8/40) of cases, and intrafocal heterogeneity of ERG gene fusion pattern was found in 32.5% (13/40) of cases. CONCLUSIONS: In summary, this study showed significantly frequent intrafocal heterogeneity of ERG protein expression, gene fusion status and fusion pattern. This heterogeneity can be caused by the development of subclones during cancer progression or the intermingling of different tumors. PMID- 28845586 TI - Hepatobiliary and Pancreatic: Development from gallbladder stone to gallstone ileus. PMID- 28845587 TI - Hepatobiliary and Pancreatic: Granulomatous hepatitis due to disseminated bacillus Calmette-Guerin disease. PMID- 28845588 TI - Gastrointestinal: Adenocarcinoma in ileal Crohn's disease: A devil in disguise. PMID- 28845589 TI - Gastrointestinal: Peroral endoscopic myotomy for distal esophageal spasm. PMID- 28845590 TI - Gastrointestinal: Gastric mucormycosis. PMID- 28845592 TI - Prevalence of beta-lactamase genes in domestic washing machines and dishwashers and the impact of laundering processes on antibiotic-resistant bacteria. AB - AIMS: To investigate the prevalence of beta-lactamase genes in domestic washing machines and dishwashers, and the decontamination efficacy of laundering. METHODS AND RESULTS: For the first investigation, swab samples from washing machines (n = 29) and dishwashers (n = 24) were analysed by real-time quantitative PCR to detect genes encoding beta-lactamases. To test the impact of laundering on resistant bacteria, cotton test swatches were artificially contaminated with susceptible and resistant strains of Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus within a second investigation. They were washed in a domestic washing machine with or without activated oxygen bleach (AOB)-containing detergent at 20-50 degrees C. beta-Lactamase genes (most commonly of the AmpC- and OXA-type) were detected in 79% of the washing machines and in 96% of the dishwashers and Pseudomonadaceae dominated the microbiota. The level of bacterial reduction after laundering was >=80% for all Ps. aeruginosa and Kl. pneumoniae strains, while it was only 37-61% for the methicillin resistant Staph. aureus outbreak strain. In general, the reduction was tendentially higher for susceptible bacteria than for the resistant outbreak strains, especially for Staph. aureus. CONCLUSIONS: beta-Lactamase genes seem to be frequently present in domestic appliances and may pose a potential risk for cross-contamination and horizontal transfer of genes encoding resistance against clinically important beta-lactams. In general, higher temperatures and the use of AOB can improve the reduction of antibiotic-resistant bacteria, including Staph. aureus which appears to be less susceptible to the decontamination effect of laundering. SIGNIFICANCE AND IMPACT OF THIS STUDY: Data on the presence of antibiotic-resistant bacteria in the domestic environment are limited. This study suggests that beta-lactamase genes in washing machines and dishwashers are frequent, and that antibiotic-resistant strains are generally more resistant to the used washing conditions. PMID- 28845591 TI - Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. AB - BACKGROUND: Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20-40% of cancer-related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer-induced muscle wasting in tumour-bearing mice. METHODS: First, weight-stable (MinStable) and cachectic (MinCC) ApcMin/+ mice were compared with C57Bl6/J controls for mRNA contents of mitochondrial quality regulators in quadriceps muscle. Next, Lewis lung carcinoma (LLC) cells or PBS (control) were injected into the hind flank of C57Bl6/J mice at 8 week age, and tumour allowed to develop for 1, 2, 3, or 4 weeks to examine time course of cachectic development. Succinate dehydrogenase stain was used to measure oxidative phenotype in tibialis anterior muscle. Mitochondrial quality and function were assessed using the reporter MitoTimer by transfection to flexor digitorum brevis and mitochondrial function/ROS emission in permeabilized adult myofibres from plantaris. RT-qPCR and immunoblot measured the expression of mitochondrial quality control and antioxidant proteins. Data were analysed by one-way ANOVA with Student-Newman-Kuels post hoc test. RESULTS: MinStable mice displayed ~50% lower Pgc-1alpha, Pparalpha, and Mfn2 compared with C57Bl6/J controls, whereas MinCC exhibited 10-fold greater Bnip3 content compared with C57Bl6/J controls. In LLC, cachectic muscle loss was evident only at 4 weeks post-tumour implantation. Oxidative capacity and mitochondrial content decreased by ~40% 4 weeks post-tumour implantation. Mitochondrial function decreased by ~25% by 3 weeks after tumour implantation. Mitochondrial degeneration was evident by 2 week LLC compared with PBS control, indicated by MitoTimer red/green ratio and number of pure red puncta. Mitochondrial ROS production was elevated by ~50 to ~100% when compared with PBS at 1-3 weeks post-tumour implantation. Mitochondrial quality control was dysregulated throughout the progression of cancer cachexia in tumour-bearing mice. In contrast, antioxidant proteins were not altered in cachectic muscle wasting. CONCLUSIONS: Functional mitochondrial degeneration is evident in LLC tumour-bearing mice prior to muscle atrophy. Contents of mitochondrial quality regulators across ApcMin/+ and LLC mice suggest impaired mitochondrial quality control as a commonality among pre-clinical models of cancer cachexia. Our data provide novel evidence for impaired mitochondrial health prior to cachectic muscle loss and provide a potential therapeutic target to prevent cancer cachexia. PMID- 28845593 TI - A historical perspective of nutrient change impact on an infectious disease in Daphnia. AB - Changes in food quality can play a substantial role in the vulnerability of hosts to infectious diseases. In this study, we focused on the genetic differentiation of the water flea Daphnia magna towards food of different quality (by manipulating C:N:P ratios) and its impact on the interaction with a virulent infectious disease, "White Fat Cell Disease (WFCD)". Via a resurrection ecology approach, we isolated two Daphnia subpopulations from different depths in a sediment core, which were exposed to parasites and a nutrient ratio gradient in a common garden experiment. Our results showed a genetic basis for sensitivity towards food deprivation. Both fecundity and host survival was differently affected when fed with low-quality food. This strongly impacted the way both subpopulations interacted with this parasite. A historical reconstruction of nutrient changes in a sediment core reflected an increase in organic material and phosphorus concentration (more eutrophic conditions) over time in the studied pond. These results enable us to relate patterns of genetic differentiation in sensitivity towards food deprivation to an increasing level of eutrophication of the subpopulations, which ultimately impacts parasite virulence effects. This finding was confirmed via a dynamic energy budgets (DEB), in which energy was partitioned for the host and the parasite. The model was tailored to our study by integrating (1) increased growth and a fecundity shift in the host upon parasitism and (2) differences of food assimilation in the subpopulations showing that a reduced nutrient assimilation resulted in increased parasite virulence. The combination of our experiment with the DEB model shows that it is important to consider genetic diversity when studying the impact of nutritional stress on species interactions, especially in the context of changing environments and emerging infectious diseases. PMID- 28845594 TI - Textural features of dynamic contrast-enhanced MRI derived model-free and model based parameter maps in glioma grading. AB - BACKGROUND: Presurgical glioma grading by dynamic contrast-enhanced MRI (DCE-MRI) has unresolved issues. PURPOSE: The aim of this study was to investigate the ability of textural features derived from pharmacokinetic model-based or model free parameter maps of DCE-MRI in discriminating between different grades of gliomas, and their correlation with pathological index. STUDY TYPE: Retrospective. SUBJECTS: Forty-two adults with brain gliomas. FIELD STRENGTH/SEQUENCE: 3.0T, including conventional anatomic sequences and DCE-MRI sequences (variable flip angle T1-weighted imaging and three-dimensional gradient echo volumetric imaging). ASSESSMENT: Regions of interest on the cross-sectional images with maximal tumor lesion. Five commonly used textural features, including Energy, Entropy, Inertia, Correlation, and Inverse Difference Moment (IDM), were generated. RESULTS: All textural features of model-free parameters (initial area under curve [IAUC], maximal signal intensity [Max SI], maximal up-slope [Max Slope]) could effectively differentiate between grade II (n = 15), grade III (n = 13), and grade IV (n = 14) gliomas (P < 0.05). Two textural features, Entropy and IDM, of four DCE-MRI parameters, including Max SI, Max Slope (model-free parameters), vp (Extended Tofts), and vp (Patlak) could differentiate grade III and IV gliomas (P < 0.01) in four measurements. Both Entropy and IDM of Patlak based Ktrans and vp could differentiate grade II (n = 15) from III (n = 13) gliomas (P < 0.01) in four measurements. No textural features of any DCE-MRI parameter maps could discriminate between subtypes of grade II and III gliomas (P < 0.05). Both Entropy and IDM of Extended Tofts- and Patlak-based vp showed highest area under curve in discriminating between grade III and IV gliomas. However, intraclass correlation coefficient (ICC) of these features revealed relatively lower inter-observer agreement. No significant correlation was found between microvascular density and textural features, compared with a moderate correlation found between cellular proliferation index and those features. DATA CONCLUSION: Textural features of DCE-MRI parameter maps displayed a good ability in glioma grading. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1099-1111. PMID- 28845595 TI - Idiopathic granulomatous mastitis associated with hyperprolactinemia: A nonoperative approach. AB - There is increasing evidence associating idiopathic granulomatous mastitis (IGM) with hyperprolactinemia. All documented cases have involved the patient having at least one operative procedure before the association has been made. We present a 55 year old female with IGM associated with risperidone induced hyperprolactinemia. She was successfully treated with a dopamine agonist, bromocriptine. We demonstrated that complete resolution can be achieved without surgical intervention, by targeting serum prolactin levels. We hope this will increase awareness of this rare clinically entity and avoid potentially unnecessary surgery. PMID- 28845596 TI - Improved performance in CAPRI round 37 using LZerD docking and template-based modeling with combined scoring functions. AB - We report our group's performance for protein-protein complex structure prediction and scoring in Round 37 of the Critical Assessment of PRediction of Interactions (CAPRI), an objective assessment of protein-protein complex modeling. We demonstrated noticeable improvement in both prediction and scoring compared to previous rounds of CAPRI, with our human predictor group near the top of the rankings and our server scorer group at the top. This is the first time in CAPRI that a server has been the top scorer group. To predict protein-protein complex structures, we used both multi-chain template-based modeling (TBM) and our protein-protein docking program, LZerD. LZerD represents protein surfaces using 3D Zernike descriptors (3DZD), which are based on a mathematical series expansion of a 3D function. Because 3DZD are a soft representation of the protein surface, LZerD is tolerant to small conformational changes, making it well suited to docking unbound and TBM structures. The key to our improved performance in CAPRI Round 37 was to combine multi-chain TBM and docking. As opposed to our previous strategy of performing docking for all target complexes, we used TBM when multi-chain templates were available and docking otherwise. We also describe the combination of multiple scoring functions used by our server scorer group, which achieved the top rank for the scorer phase. PMID- 28845598 TI - Altered pain sensitivity and axioscapular muscle activity in neck pain patients compared with healthy controls. AB - BACKGROUND: Previous studies have indicated that neck pain patients feel increased symptoms following upper limb activities, and altered axioscapular muscle function has been proposed as a contributing factor. METHODS: Pain sensitivity and muscle activity, during arm movements, were assessed in neck pain patients and controls. Patients with ongoing insidious-onset neck pain (IONP, N = 16) and whiplash-associated disorders (WAD, N = 9) were included along with sex- and age-matched controls (N = 25). Six series of repeated arm abductions were performed during electromyographic (EMG) recordings from eight bilateral muscles. The first and last three series were separated by 8 min and 42 s, respectively. Each series consisted of three slow and three fast movements. Pressure pain thresholds (PPTs) were recorded bilaterally from neck, head and arm at baseline, after the third and sixth movement series. Pain intensity was recorded on an electronic visual analogue scale (VAS). RESULTS: Larger pain areas and higher VAS scores were found in patients compared with controls (p < 0.001), and in patients, the VAS scores increased in the course of movements (p < 0.02). PPTs were lower in patients compared with controls at all sites (p < 0.03), and these decreased during arm movements in the IONP group (p < 0.03), while increasing at head and neck sites in controls (p < 0.04). During the slow movements, increasing serratus anterior EMG activity was found in the series with short breaks in between for the WAD group compared with IONP and controls (p < 0.001). CONCLUSION: Axioscapular movement caused different responses in pain sensitivity and muscle activity between neck pain patient groups compared with controls. SIGNIFICANCE: Neck pain patients report increased symptoms following upper limb activities. This study shows that repeated arm movements caused differentiated responses in pain sensitivity and muscle activity between subgroups of neck pain patient and asymptomatic controls. Such findings may be of great clinical significance when planning rehabilitation for this patient population. PMID- 28845597 TI - Pubertal growth and adult height in relation to breast cancer risk in African American women. AB - Adult height has been positively associated with breast cancer risk. The timing of pubertal growth-as measured by age at menarche and age at attained height-may also influence risk. We evaluated associations of adult height, age at attained height, and age at menarche with incidence of invasive breast cancer in 55,687 African American women in the prospective Black Women's Health Study. Over 20 years, 1,826 invasive breast cancers [1,015 estrogen receptor (ER) positive; 542 ER negative] accrued. We used multivariable Cox proportional hazards regression to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for associations with breast cancer overall and by ER status, mutually adjusted for the three factors of interest. Adult height was associated with increased risk of ER+ breast cancer (HR for >=70 inches vs <=63 inches: 1.44; 95% CI: 1.09, 1.89) but not ER- (corresponding HR: 1.16; 95% CI: 0.78, 1.71) (p heterogeneity = 0.34). HRs for attained height before age 13 versus age >17 were 1.30 (95% CI: 0.96, 1.76) for ER+ and 1.25 (95% CI: 0.80, 1.96) for ER- breast cancer. Results for age at menarche (<=11 vs >=14 years) were similar for ER+ and ER- breast cancer (HR for breast cancer overall: 1.30; 95% CI: 1.12, 1.50). We confirmed height as a strong risk factor for ER+ breast cancer in African American women and identified early age at attained height as a risk factor for both ER+ and ER- breast cancer, albeit without statistical significance of the latter associations. While adult height and timing of pubertal growth are inter-related, our findings suggest that they may be independent risk factors for breast cancer. PMID- 28845599 TI - Paediatric emergency medicine point-of-care ultrasound: Fundamental or fad? PMID- 28845600 TI - Implications of impaired zinc homeostasis in diabetic cardiomyopathy and nephropathy. AB - Impaired zinc homeostasis is observed in diabetes mellitus (DM2) and its complications. Zinc has a specific role in pancreatic beta-cells via insulin synthesis, storage, and secretion. Intracellular zinc homeostasis is tightly controlled by zinc transporters (ZnT and Zip families) and metallothioneins (MT) which modulate the uptake, storage, and distribution of zinc. Several investigations in animal models demonstrate the protective role of MT in DM2 and its cardiovascular or renal complications, while a copious literature shows that a common polymorphism (R325W) in ZnT8, which affects the protein's zinc transport activity, is associated with increased DM2 risk. Emerging studies highlight a role of other zinc transporters in beta-cell function, suggesting that targeting them could make a possible contribution in managing the hyperglycemia in diabetic patients. This article summarizes the current findings concerning the role of zinc homeostasis in DM2 pathogenesis and development of diabetic cardiomyopathy and nephropathy and suggests novel therapeutic targets. (c) 2017 BioFactors, 43(6):770-784, 2017. PMID- 28845601 TI - Asthma prescribing: Where are we headed? PMID- 28845603 TI - Comparison of anterior segment health in wild and captive common murres. AB - OBJECTIVE: To evaluate and compare the anterior segment health of wild and captive common murres. PROCEDURES: Thirty wild common murres (Uria aalge) were captured and housed in freshwater pools and had an adnexal and anterior segment exam performed prior to a subsequent wildlife health study. The examination included phenol red thread tear tests, fluorescein staining, slit-lamp biomicroscopy, rebound tonometry, and conjunctival culture sampling. Six captive common murres housed in natural seawater at the Monterey Bay Aquarium were examined in a similar manner. RESULTS: The most common ophthalmic lesion in the wild birds was corneal fibrosis with 55% prevalence, and over half of these were potentially vision threatening. Lenticular opacity (cataract or sclerosis or both) was the most common lesion in captive murres seen in 67% of the eyes. Mean phenol red tear test for all eyes without ulcers was 20 +/- 3.6 mm. Mean intraocular pressure for all eyes without ulcers or flare was 23 +/- 2.6 mmHg. The wild murres had a low percentage (17%) of positive conjunctival cultures. The captive murres had no growth on any culture. CONCLUSIONS: Wild murres are more likely to suffer corneal lesions, whereas captive murres are more likely to experience age-related lenticular diseases. Corneal scarring indicates that wild murres are frequently exposed to ocular trauma and the body condition scores indicate they appear to remain successful predators despite some vision compromise. PMID- 28845602 TI - The function of dendritic cells in modulating the host response. AB - Dendritic cells (DCs) are antigen-presenting cells that capture, process, and present antigens to lymphocytes to initiate and regulate the adaptive immune response. DCs detect bacteria in skin and mucosa and migrate into regional lymph nodes, where they stimulate antigen-specific T and B lymphocyte activation and proliferation. DCs direct CD4 T cells to differentiate to T-cell subsets such as T helper cells types 1, 2, and 17, and regulatory T cells. The periodontium is chronically exposed to oral bacteria that stimulate an inflammatory response to induce gingivitis or periodontitis. DCs play both protective and destructive roles through activation of the acquired immune response and are also reported to be a source of osteoclast precursors that promote bone resorption. FOXO1, a member of the forkhead box O family of transcription factors, plays a significant role in the activation of DCs. The function of DCs in periodontal inflammation has been investigated in a mouse model by lineage-specific deletion of FOXO1 in these cells. Deletion of FOXO1 reduces DC protective function and enhances susceptibility to periodontitis. The kinase Akt, phosphorylates FOXO1 to inhibit FOXO activity. Hence the Akt-FOXO1 axis may play a key role in regulating DCs to have a significant impact on periodontal disease. PMID- 28845605 TI - Use of the probably benign (BI-RADS category 3) assessment for masses on breast MRI: Is it transferable to general clinical practice? AB - The purpose of this study was to identify potential BI-RADS 3 mass descriptors on breast magnetic resonance imaging by systematically defining positive predictive values (PPV). In a blinded retrospective review of BI-RADS 4 masses, reader 1 identified 132 masses and reader 2 identified 76 masses. PPV for mass descriptors and for descriptor combinations was determined. No mass descriptor resulted in a PPV <=2% (BI-RADS 3 threshold). Descriptors with the lowest PPVs were circumscribed margin (8%), rim internal enhancement and persistent kinetics (13% each), and oval shape (15%). The results demonstrate the difficulty in transferring the theoretical concept of lesion surveillance to systematic clinical use. PMID- 28845604 TI - Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy. AB - OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib. METHODS: HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long-term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. RESULTS: Across all studies (6,192 patients; 16,839 patient-years), HZ was reported in 636 tofacitinib-treated patients (IR 4.0, 95% CI 3.7-4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0-2.9) in Eastern Europe to 8.0 (95% CI 6.6 9.6) in Japan and 8.4 (95% CI 6.4-10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07-2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72 7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. CONCLUSION: Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs. PMID- 28845606 TI - Returning to work after extended leave due to suspension: A director's perspective. PMID- 28845607 TI - Ventricular tachycardia with pseudo-2:1 right ventricular exit block. PMID- 28845608 TI - Variability in Weight Change Early in Behavioral Weight Loss Treatment: Theoretical and Clinical Implications. AB - OBJECTIVE: Response early in weight loss treatment predicts long-term weight change. Weight variability, independent of absolute early weight change, may also relate to long-term outcomes. This study examined whether weight variability early in treatment predicted later weight loss and maintenance. METHODS: Participants were 183 completers of a yearlong behavioral weight loss program (mean age = 51, 81% female, 69% white, mean BMI = 35 kg/m2 ). Weight variability was calculated using weights from the first 6 and 12 weekly treatment sessions. Multiple linear regressions examined whether weight variability predicted subsequent weight change 6, 12, and 24 months later. RESULTS: Weight variability over 6- and 12-week periods predicted less subsequent weight loss at 12 months (6 week: beta = 0.18, P = 0.02; 12-week: beta = 0.33, P < 0.01) and 24 months (6 week: beta = 0.17, P = 0.03; 12-week: beta = 0.15, P = 0.05). Relationships held when adjusting for covariates. Weight variability was more strongly associated with 6-month weight change in men than women (beta = 0.27, P = 0.01). CONCLUSIONS: Elevated weight variability early in a weight loss program predicted poor long-term outcomes, possibly reflecting inconsistent weight control behaviors. Tracking weight variability could prove useful for improving treatment outcomes. PMID- 28845609 TI - Erratum: Nonalcoholic Steatohepatitis is Associated with Cardiac Remodeling and Dysfunction. PMID- 28845610 TI - DC-Obesity: A New Model for Estimating Differential Lifetime Costs of Overweight and Obesity by Socioeconomic Status. AB - OBJECTIVE: The aim of this study was to quantify the magnitude of lifetime costs of overweight and obesity by socioeconomic status (SES). METHODS: Differential Costs (DC)-Obesity is a new model that uses time-to-event simulation and the Markov modeling approach to compare lifetime excess costs of overweight and obesity among individuals with low, middle, and high SES. SES was measured by a multidimensional aggregated index based on level of education, occupational class, and income by using longitudinal data of the German Socioeconomic Panel (SOEP). Random-effects meta-analysis was applied to combine estimates of (in)direct costs of overweight and obesity. RESULTS: DC-Obesity brings attention to opposite socioeconomic gradients in lifetime costs due to obesity compared to overweight. Compared to individuals with obesity and high SES, individuals with obesity and low SES had lifetime excess costs that were two times higher (?8,526). In contrast, these costs were 20% higher in groups with overweight and high SES than in groups with overweight and low SES (?2,711). CONCLUSIONS: The results of this study indicate that SES may play a pivotal role in designing cost effective and sustainable interventions to prevent and treat overweight and obesity. DC-Obesity may help public policy planners to make informed decisions about obesity programs targeted at vulnerable SES groups. PMID- 28845611 TI - Socioeconomic Status and Differential Lifetime Costs of Overweight and Obesity: An Application of Microsimulations. PMID- 28845612 TI - Gestational Weight Gain and its Association with Infant Birth Weight. PMID- 28845613 TI - The Epigenomic Analysis of Human Obesity. AB - OBJECTIVE: Analysis of the epigenome-the chemical modifications and packaging of the genome that can influence or indicate its activity-enables molecular insight into cell type-specific machinery. It can, therefore, reveal the pathophysiological mechanisms at work in disease. Detected changes can also represent physiological responses to adverse environmental exposures, thus enabling the epigenetic mark of DNA methylation to act as an epidemiological biomarker, even in surrogate tissue. This makes epigenomic analysis an attractive prospect to further understand the pathobiology and epidemiological aspects of obesity. Furthermore, integrating epigenomic data with known obesity-associated common genetic variation can aid in deciphering their molecular mechanisms. METHODS AND CONCLUSIONS: This review primarily examines epidemiological or population-based studies of epigenetic modifications in relation to adiposity traits, as opposed to animal or cell models. It discusses recent work exploring the epigenome with respect to human obesity, which to date has predominately consisted of array-based studies of DNA methylation in peripheral blood. It is of note that highly replicated BMI DNA methylation associations are not causal, but strongly driven by coassociations for more precisely measured intertwined outcomes and factors, such as hyperlipidemia, hyperglycemia, and inflammation. Finally, the potential for the future exploration of the epigenome in obesity and related disorders is considered. PMID- 28845615 TI - Acute alcoholic hepatitis and liver transplantation: Waiting for Godot. PMID- 28845614 TI - Early Pregnancy Weight Gain Exerts the Strongest Effect on Birth Weight, Posing a Critical Time to Prevent Childhood Obesity. AB - OBJECTIVE: Gestational weight gain (GWG) is associated with infant birth weight and childhood obesity; however, the patterns of GWG on infant birth weight are poorly understood. METHODS: This analysis in 16,218 mother-child dyads from Tianjin, China, determined the risk of infant size at birth according to GWG occurring throughout the first and second trimester (early GWG) or during the third trimester (late GWG), according to maternal prepregnancy BMI and the 2009 Institute of Medicine recommendations. RESULTS: Excessive GWG in early and late pregnancy had an increased risk for large-for-gestational-age (LGA) infants (odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.5-4.0, P < 0.001). Regardless of prepregnancy BMI, excessive GWG early in pregnancy (< 24 weeks) was associated with an increased risk of LGA infants (OR: 2.5; 95% CI: 2.1-3.1, P < 0.001), and inadequate early GWG was associated with a higher risk of small-for-gestational age (SGA) infants (OR: 1.4; 95% CI: 1.2-1.7, P < 0.001). CONCLUSIONS: The pattern of GWG early in pregnancy, regardless of GWG later in pregnancy, had the greatest impact on infant size at birth. Interventions initiated early in pregnancy may facilitate better adherence to the GWG guidelines and minimize the risk of LGA and SGA infants, a potential precursor for childhood obesity. PMID- 28845616 TI - UGT1As and predisposition to liver cancer: Still important, more elusive. PMID- 28845617 TI - Binge drinking as a risk factor for advanced alcoholic liver disease. PMID- 28845618 TI - Prediction of presence of oesophageal varices just by shear-wave elastography of the liver and spleen. PMID- 28845619 TI - Reply to the diagnostic conundrum of bacterial infections in cirrhotic patients. PMID- 28845620 TI - Response to Low L-Ficolin associated with disease severity during sepsis in adult ICU patients. PMID- 28845621 TI - In Memoriam: Ruth Illig, MD (1924-2017). PMID- 28845622 TI - For Debate: Does Cannabis Use by the Pregnant Mother Affect the Fetus and Newborn? AB - Cannabis, commonly called marijuana, is often used during pregnancy, likely due to the perception that it is a "safe" drug. Changes in legislation in many countries have lead to the increased availability of this drug and to its increasing use during pregnancy, often with other concomitant exposures such as alcohol, tobacco, and other drugs. Herein, we review the medical literature regarding effects of marijuana on the fetus and newborn. Possible effects of in utero exposure to marijuana focus on fetal growth, increase in the rates of stillbirth and preterm delivery, congenital malformations, and neurodevelopmental effects on the child. Published studies for all these outcomes are inconsistent. Fetal weight growth may be somewhat decreased, but the magnitude of this decrease is no greater than 100 g. There is insufficient evidence to conclude on any effect on the stillbirth rate. Although there are some reports of a slight increase in the rate of prematurity, most reports do not support this effect. Marijuana does not appear to be a major teratogen; however, a small increased risk for some congenital birth defects may be associated with early pregnancy use. Neurodevelopmental effects have been associated with marijuana use, but it is difficult to control for the effect of confounders. Despite the lack of conclusive evidence, it is important to remember that marijuana has not been shown to be a harmless drug during pregnancy and may affect the long-term neurodevelopment of the newborn infant. PMID- 28845623 TI - Human Sex Development: from Basic Science to Clinical Practice and Back. AB - The process of sexual differentiation is central for the reproduction of almost all metazoan, and therefore for the maintenance of multicellular organisms. In sex development, we can distinguish two different processes sex determination, the l decision directing the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development. The second process, sex differentiation, takes place once factors produced by the gonads determine the development of the phenotypic sex. Most of the knowledge on the factors involved in sexual development come from animal models and from studies of cases in which the genetic or the gonadal sex does not match the phenotypical sex, i.e. patients affected by disorders of sex development (DSD). This review focuses on the factors involved in gonadal determination and whenever possible, references on the 'prismatic' clinical cases are given. Furthermore, examples of diagnostic procedures for these complex diseases will be discussed. PMID- 28845624 TI - Prenatal Treatment with Dexamethasone in Suspected Congenital Adrenal Hyperplasia and Orofacial Cleft: a Case Report and Review of the Literature. AB - Congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency is a genetic disorder that leads to hypocortisolism, hyperandrogenism and, in the most severe forms, also to hypoaldosteronism. Girls with classic CAH are born with virilized external genitalia. Prenatal dexamethasone (DXM) treatment can reduce virilization but may have side effects for mother and fetus. We present the first case of a girl who was born with CAH and an orofacial cleft. She was treated with prenatal DXM to prevent virilization. Oral clefts have to be considered as a potential side effect of prenatal DXM treatment. PMID- 28845625 TI - Impact of Carbohydrate Restriction on Healthy Adolescent Development. AB - Carbohydrate-restricted diets are known for their impact on weight loss; however, research is still required to determine if low-carbohydrate diets are safe for adolescents. Carbohydrates directly stimulate an insulin response, and studies have recently shown that insulin and binding to respective insulin receptors (IRs) are critical in Kisspeptin (Kiss1) neuronal development. These neurons directly stimulate gonadotropin-releasing hormone, which activates the pituitary gonadal axis during puberty. This information suggests that carbohydrate restriction may delay pubertal development in adolescents due to the impact on insulin and Kiss1 transcription. Studies have observed disturbed insulin metabolism in Type I Diabetics leading to delayed puberty, along with overfeeding stimulating early pubertal onset. Additionally, recent clinical trials bred female mice with IR deletions on Kiss1 neurons and observed delayed vaginal opening and estrus. Current animal research suggests low carbohydrate intake may delay pubertal onset, however additional research is required to determine outcome in human subjects. PMID- 28845626 TI - Obesity in Survivors of Childhood Cancer: a Review. AB - Obesity is a late effect of antineoplastic treatment in childhood cancer survivors and this correlates with chronic complications. This review examines the data currently available to health professionals, for increasing awareness and identifying strategies to address the treatment and prevention of late effects. The mechanism involved in the pathophysiology of obesity remains unclear. However, damage to the hypothalamus and endocrine disorders (e.g. insulin and leptin resistance) and a positive energetic balance may play a role in increasing obesity rates. A patient's diet during, and after treatment may also influence the weight of survivors. Implementation of an effective educational program by professionals during all stages of treatment enables children to obtain basic knowledge regarding food and nutrition, thereby encouraging them to take responsibility for developing healthy eating behaviors. PMID- 28845627 TI - Meeting Reports: Endocrine Society (April 1-4, 2017) Selected Highlights. PMID- 28845628 TI - Meeting Reports: The 25th Anniversary of the Growth Hormone Research Society Lisbon, Portugal, May 20, 2017. PMID- 28845629 TI - Meeting Reports: Exercise is Medicine Israel 5th Annual Conference - Endocrine Aspects Tel Aviv, Israel, May 10th, 2017. PMID- 28845630 TI - [Chinese medicine industry 4.0:advancing digital pharmaceutical manufacture toward intelligent pharmaceutical manufacture]. AB - A perspective analysis on the technological innovation in pharmaceutical engineering of Chinese medicine unveils a vision on "Future Factory" of Chinese medicine industry in mind. The strategy as well as the technical roadmap of "Chinese medicine industry 4.0" is proposed, with the projection of related core technology system. It is clarified that the technical development path of Chinese medicine industry from digital manufacture to intelligent manufacture. On the basis of precisely defining technical terms such as process control, on-line detection and process quality monitoring for Chinese medicine manufacture, the technical concepts and characteristics of intelligent pharmaceutical manufacture as well as digital pharmaceutical manufacture are elaborated. Promoting wide applications of digital manufacturing technology of Chinese medicine is strongly recommended. Through completely informationized manufacturing processes and multi discipline cluster innovation, intelligent manufacturing technology of Chinese medicine should be developed, which would provide a new driving force for Chinese medicine industry in technology upgrade, product quality enhancement and efficiency improvement. PMID- 28845631 TI - [Progress of methodology for identifying target protein of natural active small molecules]. AB - Drug targets are special molecules that can interact with drugs and exert pharmacological functions in human body. The natural active small molecules are the bioactive basis of traditional Chinese medicine, and the mechanism study is a hot topic now, especially for the identification of their target proteins. However, little progress has been made in this field until now. Here, we summarized the recent technologies and methods for the identification of target proteins of natural bioactive small molecules, and introduced the main research methods, principles and successful cases in this field. We also explored the applicability and discussed the advantages and disadvantages among different methods. We hope this review can be used as a reference for the researchers who engaged in natural pharmaceutical chemistry, pharmacology and chemical biology. PMID- 28845632 TI - [Effect of endophytic fungi on modernization of traditional Chinese medicine]. AB - The modernization of traditional Chinese medicine (TCM) is a foundation of TCM to go abroad and get international recognition. It is the only way to revitalize the TCM industry. But in the process of it, we are facing various challenges: heavy metal contamination, low content of active ingredients, less innovation, the contradiction between resource utilization and protection, and so on. How to apply new technology and new theory of life science to solve these problems becomes an urgent matter. In recent years, the studies found that endophytic fungi played an irreplaceable positive role in the growth and development of herbal medicine, and had great impact on the quality of traditional Chinese medicine. Therefore this paper introduces the effect of endophytic fungi on genuine traditional Chinese medicines, cultivation of TCM, development and protection of TCM, et al, and explores its applicative prospect, providing new idea and new power for promoting the development of modernization of TCM. PMID- 28845633 TI - [Advance in studying early bolting of Umbelliferae medicinal plant]. AB - The early bolting has become one of the key issues affecting the Umbelliferae herbs production. The early bolting does not only reduce herbs production but also affect the active ingredients of plants. The concept of early bolting, physiological theory, induce factors of the quality of medicine and, control technology about the early bolting of Umbelliferae are integrative reviewed in the paper. Its occurrence mechanism include: genetic factors, environmental and ecological factors, endogenous hormones, sowing, fertilizer and other production management measures. For the above occurring mechanism, the proposed prevention measures are as follows: preferably germplasm, sowing, rational fertilization, exogenous hormones, shading, reed head cut off, cut fall the leaves, reasonable planting density and other agronomic measures can reduce its bolting rate. And the early bolting problem focused for future research are mentioned, including: development of authentic ingredients cultivation technical specifications, screened early bolting hormone inhibitor, in-depth study of the mechanism of early bolting, reveal its early bolting gene and key ecological factors. The research of vernalization gene, gene regulation of flowering early bolting will solve the problem of quality and production reducing fundamentally caused by the early bolting. PMID- 28845634 TI - [Development and innovation of traditional Chinese medicine processing discipline and Chinese herbal pieces industry]. AB - To elucidate the key issues in the development and innovation of traditional Chinese medicine processing discipline and Chinese herbal pieces industry Chinese herbal pieces industry. According to the author's accumulated experience over years and demand of the development of the Chinese herbal pieces industry, the key issues in the development and innovation on the Chinese herbal pieces industry were summarized. According to the author, the traditional Chinese medicine processing discipline shall focus on a application basis research. The development of this discipline should be closely related to the development of Chinese herbal pieces. The traditional Chinese medicine processing discipline can be improved and its results can be transformed only if this discipline were correlated with the Chinese herbal pieces industry, matched with the development of the Chinese herbal pieces industry, and solved the problems in the development on the Chinese herbal pieces industry. The development of traditional Chinese medicine processing discipline and the Chinese herbal pieces industry also requires scientific researchers to make constant innovations, realize the specialty of the researches, and innovate based on inheritance. PMID- 28845636 TI - [Effect of traditional Chinese medicine on coronary heart disease with phlegm and blood stasis syndrome]. AB - Coronary heart disease (CHD) with pathological characteristics of atherosclerotic coronary artery and myocardial ischemia is more likely to cause phlegm and blood stasis. The current study showed high morbidity and severity of phlegm and blood stasis syndrome in CHD, which has attracted increasing attention. This paper introduced the knowledge of traditional Chinese medicine (TCM) about the CHD with phlegm and blood stasis syndrome. On the basis of modern medical studies, we found a close relationship between phlegm and blood stasis syndrome and blood fat, hemorheology, oxygen free radical, blood coagulation function, inflammation, sugar metabolism and other related gene expression changes. We reviewed TCM therapies and prescriptions and found that TCM therapies achieved a good clinical effect through the understanding of etiology and pathogenesis and differentiation in organs. Besides, phlegm and blood stasis removing prescription relieved the objective indicators, which would have a good development prospects. PMID- 28845635 TI - [Study on essential oils of medicinal plants in insect repellent]. AB - Mosquitoes are seriously harmful to human health for transmitting some mortal diseases. Among the methods of mosquito control, synthetical insecticides are the most popular. However, as a result of longterm use of these insecticides, high resistant mosquitos and heavy environmental pollution appear. Thus, eco-friendly prevention measures are taken into the agenda. Essential oils extracted from medicinal plants have repellent and smoked killing effects on mosquitoes. With abundant medical plants resources and low toxicity, they have the potential of being developed as a new type of mosquito and insect repellent agent. The recent application advances of essential oils of medicinal plants in insect repellent and its application limitations are overviewed. This review will provide references for the future development and in-depth study of essential oils. PMID- 28845637 TI - [Advanced in studies on anxiolytic effects of natural flavonoids]. AB - Anxiety is one of the most common diseases endangering human health. Its pathogenesis is complex, the studies on the mechanisms of anxiety disorder are concentrated on neurotransmitter, neuroendocrine, immunologic system. Flavonoids are a kind of compounds which possess a variety of physiological activity, used in plenty of diseases. In recent years, researches of natural flavonoids on anti anxiety were increasing, but contents were incomplete. It was just involved several neurotransmitters in research area. This paper is based on different anxiolytic effect mechanisms and structure-activity relationships of natural flavonoids, summarizing the researches of domestic and foreign, which can serve as a reference for further studies on anxiolytic effects of natural flavonoids. PMID- 28845638 TI - [Isolation, identification and inhibition activity of endophytes in Fengdan]. AB - Endophytes were isolated and purified from the roots of medicinal plant Fengdan also known as Paeonia suffruticosa from Tongling region, Anhui province, China. Morphology and molecular biology methods were applied to indentify the endophyte strains. And methods of growth rate and filtering paper were also used for studying antibacterial/antifungal effects of the strains. As a result, 129 endophyte strains were isolated. Fifty-eight endophytic fungi strains were identified as 6 species in 4 genera and the dominant genus was Fusarium. Seventy one endophytic bacteria strains were identified as 9 species in 3 genera and the dominant genus was Bacillus. Inhibitory diameter with endophytic fermenting liquid of Pseudomonas chlororaphis, F. nematophilum and B. megaterium from P. suffruticosa against Staphyloccocus aureus, Escherichia coli and B. subtilis reached 25.0,20.2,24.0 mm respectively. The inhibition rate of endophytic fermenting liquid from F. nematophilum against Penicillium sp. and Colletotrichum dematium reached 90.6% and 83.3%, respectively. The inhibition effect of P. chlororaphis against F. oxysporum f. sp. niveum and Mucor sp. was good and the antifungal rate reached 80.0% and 84.9%, respectively. P. suffruticosa in Tongling region contains abundant endophytes. P. chlororaphis and F. nematophilum are valuable species as starting strain about microbicide. PMID- 28845639 TI - [Study on influence factors of seed germination and seeding growth of Lonicera macranthoides]. AB - In order to improve reproductive efficiency and quality standard, the influence factors of seed germination and seeding growth of Lonicera macranthoides werew studied. The fruit and seed morphological characteristics of L. macranthoides were observed, the seed water absorbing capacity was determined, and different wet sand stratification time, temperature and germination bed treatment were set up. The effects of the parameters on seed germination and seedling growth were analysed. There was no obstacles of water absorption on L. macranthoides seed, quantity for 22 h water absorption was close to saturation. In the first 80 d, with the increase of the stratification time, seed initial germination time was shortened, germination rate and germination potential was improved. Stratification for 100 d, germination rate decreased. At 15 C, seed germination and seedling growth indicators were the best. The seedling cotyledon width in light was significantly higher than that in dark. Seeds on the top of paper and top of sand germination rate, germination potential, and germination index was significantly higher than that of other germination bed and mildew rate is low. The optimal conditions of seeds germination test was stratified in 4 C wet sand for 80 d, 15 C illuminate culture on the top of paper or top of sand. The first seeding counting time was the 4th day after beginning the test, the final time was the 23th day. The germination potential statistical time was the 13th day after beginning the test. PMID- 28845640 TI - [Influence of different germination stage on plant biomass and active compounds of Scutellaria baicalensis germchit]. AB - This paper is aimed to study plant biomass and active compounds of Scutellaria baicalensis germchit in different five stages (from germination to transplant). The length of shoot and root, the diameter and the weight of root were determined. HPLC method was used to determine the content of active compounds (baicalin, scutellarin, wogonoside, baicalein, wogonin). According to the results, various biological indicators increased with the germination of seedling. However, the drying rate of the root declined to 27.96% from 32.90%. The contents of scutellarin and baicalein increased firstly, and then decreased. The maximums of them were 3.22,3.89 mg*g-1 while the data of shoot/root was 0.35. The maximums of the contents of baicalin and wogonoside were 107.39,16.11 mg*g-1 while the data of shoot/root was 0.23 and 0.06. The contents of wogonin gradually increased to the maximum of 0.88 mg*g-1 while the data of shoot/root was 0.50. In conclusion, the contents of baicalin, scutellarin, wogonoside, baicalein and wogonin reached or approached the maximum at germination stage while the data of shoot/root was 0.35. The rate of shoot and root can be used as a judging index of active compounds for S. baicalensis germchit. PMID- 28845641 TI - [Changes of specific chromatograms and contents of five components in Yinqiao powder decoctions during decocting process]. AB - To establish a method for the determination of chemical specific chromatograms and five components in Yinqiao powder decoction, and provide basis for elucidating the scientific connotation of "taking in when the fragrance volatilized fiercely". Yinqiao powder decoctions with different decocting times were prepared to study the changes of chemical components during decocting process. Specific chromatograms and contents of chlorogenic acid, phillyrin, arctiin, liquiritin and glycyrrhizin were determined by high performance liquid chromatography. According to the results, the similarities of Yinqiao powder decoctions with different decocting times were high, which indicated that their chemical compositions were similar. The dissolutions of the five components in Yinqiao powder reached more than 39.7% of 2 hour maximum dissolution amounts (MDA) after 20 minutes of soaking, more than 69.5% of MDA when boiling, more than 79.1% of MDA at the 5th minute after boiling, and more than 85.7% of MDA at the 10th minute after boiling. The concentrations of five components were not increasing obviously after 15 minutes of boiling (RSD<4.3%). The fragrance volatilized fiercely at about the 5th minute after boiling, which indicated that the contents of volatile components in Yinqiao powder decoctions were high, but it became weak after boiling for 15 minutes, which indicated that the contents of volatile components in Yinqiao powder decoctions were low. The results showed that the contents of five components in Yinqiao powder decoctions were heavily influenced by the decocting time. When boiling for about 5 minutes, the fragrance volatilized fiercely, both the contents of volatile components and non-volatile components were high. It is suggested that the traditional decocting method has a certain scientific basis. PMID- 28845642 TI - [Analysis on transfer rate change of heavy metal in decoction and precipitation of Curcuma phaeocaulis before and after processing with vinegar based on ICP-MS]. AB - Chinese herbs are mostly used to make decoction, which would form precipitation after standing for cooling and abandoned by patients. Processing with vinegar can change the property of the herbal pieces, such as the transfer rate of heavy metal into decoction. To analyze the transfer rate change of heavy metal in the decoction and precipitation of Curcuma phaeocaulis before and after processing with vinegar, inductively coupled plasma mass spectrometry (ICP-MS) was used to establish the determination method on five heavy metals in C. phaeocaulis, including Copper (Cu), arsenic (As), chromium (Cd), lead (Pb), mercury (Hg), using microwave to digest the samples, indium (In) as the internal standard, and national level standard material tea leaves GBW10016 (GSB-7 tea) as the quality control standard material. Then, the content of five heavy metals in the herbal pieces, decoction and five heavy metals of 6 representative batches of C. phaeocaulis and their vinegar-processing products was determinated. After computation, the transfer rates of heavy metals in the decoction and precipitation of C. phaeocaulis Val. before and after the processing with vinegar were obtained. The results showed that, after the processing with vinegar, total transfer rate of Pb and Hg was decreased significantly; total transfer rate of Cd and Cu was slightly decreased; total transfer rate of As was slightly increased, however heavy metals in all the precipitation were decreased. The results indicated that processing with vinegar had certain influence on heavy metal transfer rate, with certain synergistic and attenuated effect. PMID- 28845643 TI - [Multi-index integrated evaluation method optimizes water-extraction and ethanol precipitation of Xuanbi'antong formula (XBF)]. AB - To determine the process parameters of optimal water-extraction and ethanol precipitation method for Xuanbi'antong (XBF) extract, which is a clinically experience formula for coronary disease. Orthogonal test L9(34) was conducted for the study of XBF water-extraction and ethanol precipitation process. Extractum, salvianolic acid B, rhizoma coptidis alkaloid, paeoniflorin, puerarin, ginsenoside Rb1, ginsenosides and echinacoside were selected as marker components and multi-index comprehensive weighted score was used to select and verify optimal water-extraction and ethanol precipitation process. The optimal extraction process was as follows: XBF was added with 10 times distilled water, decocted for half an hour for 3 times. The best ethanol-precipitation process was established where the ethanol was added up to 70% and precipitated for 24 hours in 1.12 extract density (20 C). The optimized water-extraction and ethanol precipitation method is stable and reliable, and can provide reference for further development and utilization of the formula. PMID- 28845644 TI - [Optimization of one-step pelletization technology of Fuke IV granules with response surface methodology]. AB - To optimize the one-step pelletization technology of Fuke IV (FKIV) granules by response surface methodology. With the qualified rate of granules as evaluation indexes, 6 factors affecting one-step pelletization technology were investigated, significant levels of each factor were evaluated and the primal influential factors were determined by Plackett-Burman experimental design. According to the Plackett-Burman experimental design, the qualified rates of granules, moisture capacity and angle of repose as the evaluation indexes, Box-Behnken design with three levels and three factors was established for quadratic regression fitting of the models. Then the experimental results were optimized by Response Optimizer. The best process conditions were determined as follows: the extract relative density of 1.20, inlet air temperature of 88 C, and atomization pressure of 0.28 MPa. FKIV granules were prepared by the optimized experimental scheme. The determined qualified rate, moisture capacity and angle of response were 93.65%, 3.76% and 23.19 degrees respectively for the granules, basically similar to the predicted values, indicating that the optimal process conditions were in line with the manufacturing requirements. PMID- 28845645 TI - [Chemical constituents from Impatiens pritzllii var. hupehensis]. AB - Eight compounds were isolated from the 50% ethanol extract of Impatiens pritzllii var.hupehensis through various column chromatography methods including silica gel, Sephadex LH-20, and preparative HPLC. Their structures were elucidated as 2,6-dimethyl-2-vinyl-2,3,4,7-tetrahydrooxepine(1), 1,3,6-trihydroxy-7-methyl anthraquinone(2),4-hydroxybenzaldehyde(3),4-(3-methoxy-4-hydroxyphenyl)-2 butanone(4), podophyllotoxin(5),scopoletin(6), alpha-spinasterol(7) and 3-O-beta D-glucopyranosyl-alpha-spinasterol(8) based on the NMR and MS spectral data. Compound 1 is new compound and compounds 2-8 are isolated from this plant for the first time. PMID- 28845646 TI - [Flavonoid glycosides from callus cultures of Dysosma versipellis]. AB - Various chromatographic techniques, including silica gel column chromatography, Sephadex LH-20, preparative thin-layer chromatography, and preparative HPLC, were employed to isolate the chemical constituents from callus cultures of Dysosma versipellis. Structures of the compounds were elucidated based on UV, IR, MS and NMR spectroscopic data analysis. Totally, seven flavonoid glycosides were isolated from the 95% ethanol extract of the callus cultures and identified as kaempferol-3-O-[6"-(3"'-methoxy)-malonyl]-beta-D-glucopyranoside(1), kaempferol-3 O-(6"-O-acetyl)-beta-D-glucopyranoside(2), kaempferide-3-O-beta-D glucopyranoside(3), kaempferol-3-O-beta-D-glucopyranoside(4), isoquercitrin(5), quercetin-4'-O-beta-D-glucopyranoside(6) and kaempferol-3-(6"-malonyl)-beta-D glucopyranoside(7), respectively.All these compounds were isolated from callus cultures of D. versipellis for the first time.Compounds 1, 2, 3, 6 and 7 were firstly obtained from plant materials of D. versipellis, and compound 1 was a new compound. PMID- 28845647 TI - [A new cytotoxic isocoumarin from endophytic fungus Aspergillus versicolor]. AB - A new isocoumarin, along with five known ones,were isolated from the fermentation products of an endophytic fungus Aspergillus versicolorby using various chromatographic techniques.Their structures were elucidated on the basis of extensivespectroscopic analysis, including 1D-and 2D-NMR techniques. Compound 1 was evaluated for cytotoxicity against five human tumor cell lines. The results showed that 1 exhibited weak cytotoxicityagainst NB4, SHSY5Y and MCF7 cells with IC50 values of 6.8, 4.3,8.8 MUmol*L-1, respectively. PMID- 28845648 TI - [Studies on chemical constituents of rhizomes of Sophora tonkinensis]. AB - Thirteen compounds were isolated from the 95% aqueous EtOH extract of the rhizomes of Sophora tonkinensis by a combination of various chromatographic techniques including column chromatography over silica gel, Sphadex LH-20, MCI, ODS, and semi-preparative HPLC.Their structures were elucidated as 1-(6,7-dihydro 5H-pyrrolo[1,2-a]imidazol-3-yl)ethanone(1), cyclo(Pro-Pro)(2), nicotinic acid(3), p-hydroxybenzonic acid(4), p-methoxybenzonic acid(5), 4-hydroxymethyl-2,6 dimethoxyphenol-1-O-beta-D-glucopyranoside(6), coniferin(7), syringin(8),(-) secoisolariciresinol-4-O-beta-D-glucopyranoside(9),(-)-syringaresinol-4-O-beta-D glucopyranoside(10),(-)-syringaresinol-4,4'-di-O-beta-D-glucopyranoside(11),(-) pinoresinol-4,4'-di-O-beta-D-glucopyranoside(12), and(6S,9R)-roseoside(13) by their physicochemical properties and spectroscopic data.Compound 1 was a new naturalproduct, and compounds 2,5,6,9,10,12 and 13 were obtained from the Sophora genus for the first time.Compound 1 possessed moderate cytotoxic activity against A549 human tumor cell [IC50(23.05 +/- 0.46)MUmol*L-1]. PMID- 28845649 TI - [Chemical constituents of ethnic medicine Cynanchum otophyllum]. AB - In order to isolate and purify the reference compounds and improve the quality standard of ethnic medicine of Radix of Cynanchum otophyllum, the ethanol extracts were isolated by column chromatography onsilica gel, C18 reverse-phase silica gel, and semi-preparative HPLC. Twelve compounds were isolated and their structures were elucidated as 2,4-dihydroxy-6-methoxyphenylethanone(1), 4,6 dihydroxy-2-methoxyphenylethanone(2), p-hydroxyacetophenone(3), baishouwubenzophenone(4), 2,4-dihydroxyacetophenone(5), 2,5 dihydroxyacetophenone(6), otophylloside A(7),otophylloside B(8), caudatin-3-O beta-D-cymaropyranosyl-(1->4)-beta-D-digitoxopyranoside(9),caudatin-3-O-beta-D glucopyranosyl-(1->4)-beta-D-oleandropyranosyl-(1->4)-beta-D-cymaropyranosyl-(1 >4)-beta-D-digitoxopyranoside(10),qingyangshengenin-3-O-beta-D-oleandropyranosyl (1->4)-beta-D-cymaropyranoside(11),caudatin-3-O-beta-D-oleandropyranosyl-(1->4) beta-D-cymaropyranosyl-(1->4)-beta-D-cymaropyranoside(12) on the basis of spectral analysis. Compounds 1 and 2 were isolated from the genus Cynanchum for the first time, and compounds 3-4, 9-12 were obtained from this plant for the first time.These compounds are main active components of Radix of C.otophyllum and can be used as reference substances for the quality control of this ethnic medicine. PMID- 28845650 TI - [Chrysin inhibits adipogenic differentiation of mouse embryonic fibroblasts]. AB - Chrysin is an active flavonoid wildly presented in many herbs. It has the effect to reduce serum lipid. To investigate the effect of chrysin on the adipogenic differentiation of mouse embryonic fibroblasts, methyl thiazolyl tetrazolium (MTT) and crystal violet were used to detect the cytotoxic effect of chrysin on Immortalized mouse embryonic fibroblasts (iMEFs). Propidium iodide (PI) staining combined with flow cytometry (FCM) was employed to detect the effects of different concentrations of chrysin on iMEFs cell cycle. The effect of chrysin on adipogenic differentiation ability of iMEFs was determined by oil red O staining. Semi-quantitative PCR was employed to detect the effect of chrysin on mRNA transcriptional levels of adipogenic differentiation markers, including perilipin 2, adiponectin (adipoq), Fabp4, LPL, MCP-1 and adipogenic differentiation key transcription factor peroxisome proliferators-actiated receptor-gamma 2(PPAR gamma2). Results indicated that chrysin had certain cytotoxic effect for iMEFs in a dose-dependent manner, and the IC50 was identified nearly to 30 MUmol*L-1. FCM analysis showed that chrysin could affect the cell-cycle distribution of iMEFs, increasing the ratio of cells in G1 phase. Adipogenic differentiation inducing experiment showed that 30 MUmol*L-1 chrysin significantly reduced lipid drops accumulation induced by insulin and dexamethasone. In addition, the mRNA transcriptional levels of PPAR-gamma2 and LPL were significantly decreased and mRNA levels of fabp 4, MCP-1, adipoq were also affected after chrysin treatment. The experiment results suggest that chrysin attenuates the adipogenic differentiation capacity of mesenchymal stem cells. PMID- 28845651 TI - [Effect of Epimedii Herba alcohol extract on inhibition of lung tumor growth and immunomodulatory]. AB - To observe the effect of Epimedii Herba alcohol extract (HE) on tumor growth of lung cancer by establishing the model of Lewis tumor-bearing mice, ELISA method was used to detect the levels of TNF-alpha, IL-10, IL-17, IL-2 in serum. Ki67 and P53 protein expression was detected in lung cancer tissues by using Western blot assay method and immunohistochemical assay method. The experimental results showed that HE has certain inhibitory effect on Lewis lung cancer tumor growth, and it can reduce the levels of TNF-alpha, IL-10 and IL-17 in serum, improve the level of IL-2,significantly decrease the expression of Ki67, and significantly increase P53 expression. HE has obvious inhibitory effect against lung cancer, and has the ability to improve immune regulating effect. This study reveals the anti-lung cancer effect of HE may be related to its ability of improving immunity, thus provides the basis for further research on anti-lung cancer effect of HE. PMID- 28845652 TI - [Effects of Qizhi Jiangtang capsule on dermal ulcer in type 2 diabetic rats]. AB - The effect of Qizhi Jiangtang vapsule (QJC) on degree of dermal ulcer cicatrization in 2 type diabetic rats was studied. Except the rats for blank group, other male Wistar rats were used to establish type 2 diabetic model by feeding with high sugar and high fat diet for four weeks and intraperitonally injecting with 30 mg*kg-1 streptozotocin (STZ). After that, the rats were divided into balanced groups according to blood sugar, and received corresponding drugs for treatment for 8 weeks. At the end of week 8, 2 cm diameter circular incision was done on the back of rats. After that, the rats were administered continuously for10 days. Area of ulcer surface was detected every two days. After the last administration, wound granulation tissues were cut down to conduct pathological examination and detect the expression of VEGF, PI3K, p-ERK protein in wound tissues. The results showed that compared with the model group, after application of Qizhi Jiangtang capsule (2.24 g*kg-1), the wound was significantly reduced on day 6 and day 10 of wound formation; inflammation reaction on ulcer surface was significantly reduce; Qizhi Jiangtang capsule can increase VEGF expression in the wound tissues of diabetic rats, and inhibit ERK phosphorylation. It can be concluded that Qizhi Jiangtang capsule can promote skin ulcer healing for diabetes rats, and its mechanism may be related to regulating the expression of VEGA and p-ERK proteins. PMID- 28845653 TI - [Metabolic stability and metabolic enzyme phaenotypes of lanceolatin B in liver microsomes of different species by UPLC-MS/MS]. AB - To investigate the metabolic stability and parameters in vitro of lanceolatin B in liver microsomes of rats, human, Beagle dogs, and monkeys, and to identify the phaenotypes of CYP enzymes of lanceolatin B by using the liver microsome incubation system in vitro. After incubated with different species of liver microsomes, lanceolatin B was quantified by UPLC-MS/MS method to evaluate its metabolic stability and metabolic kinetic parameters in vitro. Lanceolatin B was incubated with specific inhibitors of CYP450 isoforms (CYP2E1, 2C19, 1A2, 2D6, 2C9, 3A4, and 2A1) to determine the phaenotypes of metabolic enzymes. The results showed that lanceolatin B was metabolized in the liver microsomes of rats and monkeys but not in the human and Beagle dogs. Their in vitro half-life T1/2 and intrinsic clearance rate CLint in rat and monkey liver microsomes were 11.57,8.07 min, and 0.12,0.17 mL*min-1*mg-1 without significant difference. The results of metabolic phenotyping indicated that CYP1A2 was mainly involved in the metabolism of lanceolatin B. There existed a difference in the metabolism of lanceolatin B in different types of liver microsomes. Several of CYP450 isoforms metabolized lanceolatin B together in liver microsomes of rats, in which CYP1A2 was the major enzyme mainly responsible for the metabolism of lanceolatin B. PMID- 28845654 TI - [Pharmacokinetics of epimedin A, B, C and icariin of Chuankezhi injection in rat]. AB - To study pharmacokinetic characteristics of epimedin A, B, C and icariin after intermuscular administration of Chuankezhi injection to rat. The established RRLC MS/MS method was applied for simultaneous determination of four analytes in rat plasma and calculating their pharmacokinetic parameters. As a result, each analyte showed a good linear relationship in the concentration range of 1-1 000 MUg*L-1.The intra-day precise was 96.9%-107.5% with RSD<5.99%, inter-day precise was 92.3%-105.0% with RSD<10.16%. The relative recovery of four analytes was 88.1%-101.1% with RSD<7.9% and their absolute recovery was 72.0%-86.6% with RSD<6.3%. After intermuscular administration of Chuankezhi injection, the plasma concentration of four flavonoid glycosides rapidly arose to peaks at about 10 min, and then quickly declined in rat. Tmax of epimedin A, B, C and icariin was 0.21, 0.19, 0.16 and 0.49 h, respectively, and their mean elimination half life(t1/2z) was 0.60, 0.62, 0.47 and 0.49 h. The established method was validated to be sensitive, rapid and specific for determination of the four analytes. Serum concentration of 4 species of epimedium flavonoids in Chuankezhi injection was low, and their absorption and elimination seem quickly, displaying similar pharmacokinetic characteristics in this study. PMID- 28845655 TI - [Quality control method of Tibetan medicine Saussureae obvalltae]. AB - To control the quality of Tibetan medicine Saussureae obvalltae, the quality control method and standard were established in this study. The water content, total ash, acid-insoluble ash and ethanol-soluble extractives of Saussureae obvalltae were determined according to the methods recorded in appendix of Chinese Pharmacopeia(2010 edition). Microscopical identification was performed for the plant and powder of the leaves. The TLC method was established, with chlorogenic acid and rutin as control substances, and a mixture of acetate btuanone-formic acid-water (10?6?1?2) as developing solvent and silica gel G as thin layer plate. Agilent ZORBAX Eclipse XDB-C18 (4.6 mm*250 mm, 5 MUm) column was adopted and eluted with the mobile phase of acetonitrile-0.1% phosphoric acid (17?83) in a gradient mode at a flow rate of 1.0 mL*min-1. The column temperature was 40 C and the detection wavelength was 350 nm. As a result, the plant and leaves of Saussureae obvalltae of different origins showed constent microscopic features. Chlorogenic acid, rutin and the other constituents were well separated on TLC detected under the sun light. According to the results of the methodological study, chlorogenic acid and rutin were in good linear correlation in the ranges of 0.119 2-0.715 4 MUg(r=0.999 9) and 0.160 7-0.964 4 MUg(r=1.000), and the average recoveries were 105.4% (RSD 1.4%) and 99.50% (RSD 0. 91%), respectively. The content of ethanol-soluble extractives, water content, total ash and acid-insoluble ash were 26.01%-31.59%, 7.16%-8.04%, 8.46%-11.14%,0.50% 1.87%, respectively. According to the study, the established method was specific and accurate, which could be used for the quality control of this drug. PMID- 28845656 TI - [Experimental verification and prospect on stress effect of Dao-di herbs Scutellaria baicalensis]. AB - The stress effect is a characteristic of Dao-di herbs caused by environmental gene expression of medical plants is influenced by environmental changes and finally affects the formation and accumulation of metabolites. Using Scutellaria baicalensis as material, active component of wild type of S. baicalensis from 19 production areas were analysed; It was found that climate change can influence the accumulation of active components. Then, S. baicalensis suspension cells was exposed to various environments, and enzyme activity and gene expression were measured, indicating the molecular mechanism of stress effect on S. baicalensis. Hence, we found the prerequisite and method to study the stress effect on Dao-di herbs, and we hope this research can provides some references for another studies of Dao-di herbs. PMID- 28845657 TI - [Scalability and extensionality of innovative Chinese medicine preparation under guidance of component structure theory]. AB - Chinese medicine preparation is a science to study how to make raw material into suitable dosage forms to be used in clinical operations. Its study scope is significantly different from traditional chemical drugs. As is known, the ingredients of Chinese medicine are complex and various, as a result, the composition of the ingredients is not clear and the property is not unified. The pre-treatment process is the key factor to affect the druggability, safety and efficacy of the Chinese medicine. The connotation of Chinese medicine is a huge systematic project, not only including the traditional dosage form design process but also including the components structure optimization process on material basis, components extraction, separation and purification process, components characterization process as well as the pharmacological and toxicological study processes which aim to select suitable dosage form to exert the maximum drug efficacy and evaluate the properties of preparations. Therefore, according to the requirement of modern innovative preparations and based on the integrity and systematicness of Chinese medicine, in this paper we will explore the scalability and extensionality of modern Chinese medicine, including the material basis of Chinese medicine based on component structure theory; separation, refining and purification of components; component structure optimization and network pharmacology and regulation, as well as biopharmaceutics properties of representative components, and we will construct the multi-unit drug delivery system and Chinese medicine multi-dimensional dynamic quality control system. This paper elaborates the scientific connotation and systematicness of modern Chinese preparation, and provides ideas and methods for the development of modern innovative Chinese preparations. PMID- 28845658 TI - [Safety grade of application of traditional Chinese medicines during pregnancy]. AB - The efficacy and safety of application of traditional Chinese medicines (TCMs) during the pregnancy is a hotspot among scholars. However, the traditional pregnancy contraindication content has certain historical limitations, and cannot meet the needs of the current pregnant women for rational drug use. We need to refine and interpret it with modern medical science. In this paper, we summarized the ancient and modern knowledge about pregnancy contradiction and tried to establish a grading safety system, based on the actual clinical practices and thte medication grading concept of western medicines. Specifically speaking, in this paper, we compared the connotations of forbidden/contradiction and cautious use, and focused on the safe herbs that included in the prescriptions for dietary therapy. Meanwhile, in this paper, we summarized the core content of the famous theories of "You Gu Wu Yun (pregnancy disease)" and "Shuai Qi Da Ban Er Zhi (therapy during pregnancy)", and studied the dangerous and unknown risk of TCMs during pregnancy. At last, a five-grade safety system of TCMs applied on the pregnant women was established, including forbidden, contraindicated, cautious, uncertain and available medicines. We classified medicines with the embryotoxicity (e.g. teratogenic, mutagenic, ageneisa), the traditional toxicity (e.g. abortion), the fierce herbal property (e.g. removing blood stasis, promoting Qi circulation) and reliable edible medicinal herbs. We also place an "uncertain" category based on objective reality. Meanwhile, 33 sample TCMs were preliminarily determined. This paper proposed the preference and ideas for the rational herbal use in pregnancy. PMID- 28845659 TI - Cholera vaccines: WHO position paper - August 2017. PMID- 28845661 TI - Insights into Geometric and Electronic Structures of VGe3-/0 Clusters from Anion Photoelectron Spectrum Assignment. AB - The global minima of both neutral and anionic clusters of VGe3-/0 were determined using different quantum chemical methods (DFT, RCCSD(T), CASSCF/CASPT2). On the basis of the ground states identified, most excited bands in the anion photoelectron spectrum of VGe3- were assigned. The tetrahedral isomers of both charged states are the most stable ones. A singlet state (Cs, 1A') of the tetrahedral isomer has the globally lowest energy on the potential hypersurface of VGe3-. Two states 12A' and 12A" of the neutral tetrahedral isomer are nearly degenerate and identified as the competing ground state of VGe3. From the anionic ground state, four of five bands in the anion photoelectron spectrum of VGe3- were determined to be the consequences of one-electron transitions starting from the anionic ground state 1A'. Both nearly degenerate neutral ground states are responsible for generation of the first band. Two different transitions from the anionic ground state 1A' to the first two nearly degenerate excited states (22A' and 22A") of the neutral underlie the second lowest ionization band. Two higher levels of ionization recorded in the spectrum were assigned to the two higher excited states 42A' and 52A' of the neutral. Franck-Condon factor simulations of the first band were performed to obtain more insights into the experimental bands of the spectrum. PMID- 28845660 TI - Medium-Throughput Screen of Microbially Produced Serotonin via a G-Protein Coupled Receptor-Based Sensor. AB - Chemical biosensors, for which chemical detection triggers a fluorescent signal, have the potential to accelerate the screening of noncolorimetric chemicals produced by microbes, enabling the high-throughput engineering of enzymes and metabolic pathways. Here, we engineer a G-protein-coupled receptor (GPCR)-based sensor to detect serotonin produced by a producer microbe in the producer microbe's supernatant. Detecting a chemical in the producer microbe's supernatant is nontrivial because of the number of other metabolites and proteins present that could interfere with sensor performance. We validate the two-cell screening system for medium-throughput applications, opening the door to the rapid engineering of microbes for the increased production of serotonin. We focus on serotonin detection as serotonin levels limit the microbial production of hydroxystrictosidine, a modified alkaloid that could accelerate the semisynthesis of camptothecin-derived anticancer pharmaceuticals. This work shows the ease of generating GPCR-based chemical sensors and their ability to detect specific chemicals in complex aqueous solutions, such as microbial spent medium. In addition, this work sets the stage for the rapid engineering of serotonin producing microbes. PMID- 28845662 TI - Adenosine-Phosphate-Fueled, Temporally Programmed Supramolecular Polymers with Multiple Transient States. AB - Natural systems have been an inspiration to synthetic supramolecular chemistry. Synthetic demonstrations of dissipative biological systems such as actin filaments are a formidable scientific challenge in attaining future life-like materials. Dynamic instability of such structures beckons control of self organization in the temporal regimes. In this study, we present a fuel-dependent helical assembly of a supramolecular polymer. We further attempt the synthetic manifestation of a temporally programmable self-assembly. Additionally, the fuel induced chiral (re)organization with the employment of various enzymes singularly and in tandem have resulted in designing a multistate transient self-assembly. These parameter modulations result in controllable lifetimes and rates. We thus report, for the first time, a temporally programmed multistate reorganization of self-assembly. PMID- 28845663 TI - PBr3-Mediated Cyclization of 1,7-Diyn-3,6-bis(propargyl carbonate)s: Synthesis of 5-Bromotetracenes. AB - A new and straightforward method for the synthesis of 5-bromotetracenes through PBr3-mediated cyclization of 1,7-diyn-3,6-bis(propargyl carbonate)s has been developed. This method offers several advantages such as easily accessible starting materials, high efficiency, and wide functional group compatibility. In addition, chloro- and iodo-substituted tetracenes were also synthesized using appropriate halogenating reagents. The utility of the 5-bromotetracene products has been illustrated by their efficient transformations through various palladium catalyzed cross-coupling reactions. PMID- 28845664 TI - Graphite-Based Nanocomposite Electrochemical Sensor for Multiplex Detection of Adenine, Guanine, Thymine, and Cytosine: A Biomedical Prospect for Studying DNA Damage. AB - Guanine (G), adenine (A), thymine (T), and cytosine (C) are the four basic constituents of DNA. Studies on DNA composition have focused especially on DNA damage and genotoxicity. However, the development of a rapid, simple, and multiplex method for the simultaneous measurement of the four DNA bases remains a challenge. In this study, we describe a graphite-based nanocomposite electrode (Au-rGO/MWCNT/graphite) that uses a simple electro-co-deposition approach. We successfully applied the developed sensor for multiplex detection of G, A, T, and C, using square-wave voltammetry. The sensor was tested using real animal and plant DNA samples in which the hydrolysis of T and C could be achieved with 8 mol L-1 of acid. The electrochemical sensor exhibited excellent sensitivity (G = 178.8 nA/MUg mL-1, A = 92.9 nA/MUg mL-1, T = 1.4 nA/MUg mL-1, and C = 15.1 9 nA/MUg mL-1), low limit of detection (G, A = 0.5 MUg mL-1; T, C = 1.0 MUg mL-1), and high selectivity in the presence of common interfering factors from biological matrixes. The reliability of the established method was assessed by method validation and comparison with the ultraperformance liquid chromatography technique, and a correlation of 103.7% was achieved. PMID- 28845665 TI - Cell-Permeant Large Stokes Shift Dyes for Transfection-Free Multicolor Nanoscopy. AB - We designed cell-permeant red-emitting fluorescent dye labels with >140 nm Stokes shifts based on 9-iminoanthrone, 9-imino-10-silaxanthone, and 9-imino-10 germaxanthone fluorophores. The corresponding probes selectively targeting mitochondria, lysosomes, and F-actin demonstrate low toxicity and enable stimulated emission depletion (STED) nanoscopy in neurons, human fibroblasts, U2OS, and HeLa cells. In combination with known small Stokes shift dyes, our probes allow live-cell three-color STED nanoscopy of endogenous targets on popular setups with 775 nm STED wavelength. PMID- 28845666 TI - Regeneration of NADPH Coupled with HMG-CoA Reductase Activity Increases Squalene Synthesis in Saccharomyces cerevisiae. AB - Although overexpression of the tHMG1 gene is a well-known strategy for terpene synthesis in Saccharomyces cerevisiae, the optimal level for tHMG1p has not been established. In the present study, it was observed that two copies of the tHMG1 gene on a dual gene expression cassette improved squalene synthesis in laboratory strain by 16.8-fold in comparison to single-copy expression. It was also observed that tHMG1p is limited by its cofactor (NADPH), as the overexpression of NADPH regenerating genes', viz., ZWF1 and POS5 (full length and without mitochondrial presequence), has led to its increased enzyme activity. Further, it was demonstrated that overexpression of full-length POS5 has improved squalene synthesis in cytosol. Finally, when tHMG1 and full-length POS5 were co overexpressed there was a net 27.5-fold increase in squalene when compared to control strain. These results suggest novel strategies to increase squalene accumulation in S. cerevisiae. PMID- 28845667 TI - Photoredox-Catalyzed Cascade Difluoroalkylation and Intramolecular Cyclization for Construction of Fluorinated gamma-Butyrolactones. AB - A cascade visible-light photocatalytic difluoroalkylation and intramolecular cyclization reaction has been developed for the synthesis of difluoroalkylated oxygen heterocycles. The reaction was carried out under very mild conditions, affording fluorinated isobenzofuran-1-ones, lactone, and cyclic ethers with up to 97% chemical yields. Furthermore, several types of bromofluoroalkane precursors bearing ester, keto, amido, and phosphate groups could all work very well in this reaction, which provides an easy method for the preparation of functionalized difluoroalkylated oxygen heterocycles. PMID- 28845668 TI - Toward Orthogonal Preparation of Sequence-Defined Monodisperse Heteromultivalent Glycomacromolecules on Solid Support Using Staudinger Ligation and Copper Catalyzed Click Reactions. AB - The investigation of heteromultivalent interactions of complex glycoligands and proteins is critical for understanding important biological processes and developing carbohydrate-based pharmaceutics. Synthetic glycomimetics, derived by mimicking complex glycoligands on a variety of scaffolds, have become important tools for studying the role of carbohydrates in chemistry and biology. In this paper, we report on a new synthetic strategy for the preparation of monodisperse, sequence-defined glycooligomers or so-called precision glycomacromolecules based on solid phase oligomer synthesis and the Staudinger ligation. This strategy employs a solid-supported synthetic approach using a novel carboxy-functionalized building block which bears a functional handle required for Staudinger ligation on solid support. Furthermore, we combined Staudinger ligation and copper catalyzed azide alkyne cycloaddition (CuAAC) reactions to synthesize heteromultivalent glycooligomers on solid support for the first time, demonstrating the utility of this approach for the synthesis of heterofunctional glycomacromolecules. PMID- 28845669 TI - Development of a Silicon-Rhodamine Based Near-Infrared Emissive Two-Photon Fluorescent Probe for Nitric Oxide. AB - Two-photon (TP) fluorescent probes are potential candidates for near-infrared (NIR) imaging which holds great promise in biological research. However, currently, most TP probes emit at wavelength <600 nm, which impedes their practical applications. In this work, we explored the TP properties of a silicon rhodamine (SiR) derivative and hence developed the first SiR scaffold based "NIR to-NIR" TP probe (SiRNO) for nitric oxide (NO). SiRNO exhibited high sensitivity and specificity, as well as fast response for NO detection. It was able to track the subtle variation of intracellular NO content in live cells. Owing to the NIR excitation and emission, SiRNO enabled the detection of NO in situ in the xenograft tumor mouse model, revealing the NO generation during the tumor progression. This work indicates that SiR can be an ideal platform for the development of NIR emissive TP probe and may thus promote the advancement of NIR imaging. PMID- 28845670 TI - Unveiling Structurally Engineered Carrier Dynamics in Hybrid Quasi-Two Dimensional Perovskite Thin Films toward Controllable Emission. AB - Quasi-two-dimensional Ruddlesden-Popper perovskites driving carrier self separation have rapidly advanced the development of high-performance optoelectronic devices. However, insightful understanding of carrier dynamics in the perovskites is still inadequate. The distribution of multiple perovskite phases, crucial for carrier separation, is controversial. Here we report a systematic study on carrier dynamics of spin-coated (C6H5CH2CH2NH3)2(CH3NH3)n 1PbnI3n+1 (n = 3 and 5) perovskite thin films. Efficient electrons transfer from small-n to large-n perovskite phases, and holes transfer reversely with time scales from ~0.3 to 30.0 ps. The multiple perovskite phases are arranged perpendicularly to substrate from small to large n and also coexist randomly in the same horizontal planes. Further, the carrier separation dynamics is tailored by engineering the crystalline structure of the perovskite film, which leads to controllable emission properties. These results have important significance for the design of optoelectronic devices from solar cells, light-emitting diodes, lasers, and so forth. PMID- 28845671 TI - Polyamide-Polyamine Cryptand as Dicarboxylate Receptor: Dianion Binding Studies in the Solid State, in Solution, and in the Gas Phase. AB - Polyamide-polyamine hybrid macrobicycle L is explored with respect to its ability to bind alpha,omega-dicarboxylate anions. Potentiometric studies of protonated L with the series of dianions from succinate (suc2-) through glutarate (glu2-), alpha-ketoglutarate (kglu2-), adipate (adi2-), pimelate (pim2-), suberate (sub2 ), to azelate (aze2-) have shown adipate preference with association constant value of K = 4900 M-1 in a H2O/DMSO (50:50 v/v) binary solvent mixture. The binding constant increases from glu2- to adi2- and then continuously decreases with the length of the anion chain. Further, potentiometric studies suggest that hydrogen bonding between the guest anions and the amide/ammonium protons of the receptor also contributes to the stability of the associations along with electrostatic interactions. Negative-mode electrospray ionization of aqueous solutions of host-guest complexes shows clear evidence for the selective formation of 1:1 complexes. Single-crystal X-ray structures of complexes of the receptor with glutaric acid, alpha-ketoglutaric acid, adipic acid, pimelic acid, suberic acid, and azelaic acid assist to understand the observed binding preferences. The solid-state structures reveal a size/shape complementarity between the host and the dicarboxylate anions, which is nicely reflected in the solution state binding studies. PMID- 28845672 TI - Proteome-Wide Analysis of N-Glycosylation Stoichiometry Using SWATH Technology. AB - N-glycosylation is a crucial post-translational modification (PTM) and plays essential roles in biological processes. Several methods have been developed for the relative quantification of N-glycosylation at the proteome scale. However, the proportion of N-glycosylated forms in a total protein population, or the "N glycosylation stoichiometry", varies greatly among proteins or cellular states and is frequently missing due to the lack of robust technologies. In the present study, we developed a data-independent acquisition (DIA)-based strategy that enabled the in-depth measurement of N-glycosylation stoichiometry. A spectral library containing 3,509 N-glycosylated peptides and 17,525 fragment ions from human embryonic kidney cells 293 (HEK-293) cells was established from which the stoichiometries of 1,186 N-glycosites were calculated. These stoichiometric values differ greatly among different glycosites, and many glycosites tend to occur with low stoichiometry. We then investigated the N-glycosylation changes induced by tunicamycin in HEK-293 cells and by a temperature shift in Chinese hamster ovary (CHO) cells. Quantifying the proteome, N-glycoproteome, and N glycosylation stoichiometry demonstrated that the regulation of N-glycosylation is primarily achieved by adjusting the N-glycosylation stoichiometry. In total, the stoichiometries of 2,274 glycosites were determined in the current study. Notably, our approach can be applied to other biological systems and other types of PTMs. PMID- 28845673 TI - Synthesis of Triarylamines via Sequential C-N Bond Formation. AB - A one-pot domino N-arylation protocol is described using diaryliodonium reagents under copper catalysis. The reaction uses both aryl groups of the diaryliodonium reagent to generate triarylamines starting from simple anilines, representing an atom-economical preparation of an important class of organic material building blocks. PMID- 28845674 TI - Mechanical Stretching of Fibronectin Fibers Upregulates Binding of Interleukin-7. AB - Since evidence is rising that extracellular matrix (ECM) fibers might serve as reservoirs for growth factors and cytokines, we investigated the interaction between fibronectin (FN) and interleukin-7 (IL-7), a cytokine of immunological significance and a target of several immunotherapies. By employing a FN fiber stretch assay and Forster resonance energy transfer (FRET) confocal microscopy, we found that stretching of FN fibers increased IL-7 binding. We localized the FN binding site on the CD loop of IL-7, since a synthetic CD loop peptide also bound stronger to stretched than to relaxed FN fibers. On the basis of a structural model, we propose that the CD loop can bind to FN, while IL-7 is bound to its cognate cell surface receptors. Sequence alignment with bacterial adhesins, which also bind the FN N-terminus, suggests that a conserved motif on the CD loop (110TKSLEEN116 and the truncated 112SLEE115 in human and mouse IL-7, respectively) might bind to the second FN type I module (FnI2) and that additional epitopes enhance the stretch-upregulated binding. FN fiber stretching might thus serve as a mechano-regulated mechanism to locally concentrate IL-7 in an ECM-bound state, thereby upregulating the potency of IL-7 signaling. A feedback model mechanism is proposed that could explain the well-known, but poorly understood, function of IL-7 in ECM homeostasis. Understanding how local IL-7 availability and signaling might be modulated by the tensional state of the ECM niche, which is adjusted by residing stroma cells, is highly relevant for basic science but also for advancing IL-7 based immunotherapies. PMID- 28845675 TI - Acute Hepatitis Caused by Empagliflozin in a Nonalcoholic Fatty Liver Disease Patient. PMID- 28845676 TI - Long-Term Impact of a Cell Phone-Enhanced Parenting Intervention. AB - Home visiting programs support positive parenting in populations at-risk of child maltreatment, but their impact is often limited by poor retention and engagement. The current study assessed whether a cellular phone-supported version (PCI-C) of the Parent-Child Interactions (PCI) intervention improved long-term parenting practices, maternal depression, and children's aggression. Low-income mothers ( n = 371) of preschool-aged children were assigned to one of the three groups: PCI C, PCI, and a wait-list control (WLC) group. Parenting improved in both intervention groups between baseline and 12-month follow-up compared to the WLC. Children in the PCI-C group were rated to be more cooperative and less aggressive than children in the WLC. The results offer evidence of the long-term effectiveness of PCI and the additional benefits of cellular phone supports for promoting intervention retention and improving children's behavior. PMID- 28845677 TI - Massage Therapy in Outpatient Cancer Care: A Metropolitan Area Analysis. AB - Massage offers cancer patients general quality of life benefits as well as alleviation of cancer-related symptoms/cancer-treatment-related symptoms including pain, anxiety, and fatigue. Little is known about whether massage is accessible to cancer patients who receive treatment in the outpatient setting and how massage is incorporated into the overall cancer treatment plan. Outpatient cancer centers (n = 78) in a single metropolitan area were included this mixed methods project that included a systematic analysis of website information and a telephone survey. Massage was offered at only 40 centers (51.3% of total). A range of massage modalities were represented, with energy-based therapies (Reiki and Therapeutic Touch) most frequently provided. Although massage therapists are licensed health care providers in the states included in this analysis, massage was also provided by nurses, physical therapists, and other health care professionals. PMID- 28845678 TI - A Preliminary Study Investigating the Association Between Hearing Acuity and a Screening Cognitive Tool. AB - OBJECTIVES: Studies in cognitive aging demonstrated inconsistent association between hearing and cognition in older adults. Furthermore, it is still unclear if hearing loss at high frequencies, which is the earliest to be affected, is associated with cognitive functioning. This study aimed to determine the association between global cognitive status and pure tone average (PTA) at 0.5, 1, and 2 kHz (PTA low) and PTA at 4 and 8 kHz (PTA high). METHODS: This study involved 307 adults aged 60 years and older. Participants had their hearing and cognition measured using pure tone audiometry and Mini Mental State Examination (MMSE), respectively. RESULTS: Pure tone average (low) accounted for significant but minimal amount of variance in measure of MMSE. Multiple regression analyses were also performed on normal and impaired hearing cohorts and cohorts with younger (60-69 years) and older (>=70 years) groups. The results revealed a significant relationship between PTA (low) and MMSE only in the younger age group. In contrast, no significant relationship was found between PTA (high) and cognition in any of the cohorts. CONCLUSION: Pure tone average (low) is significantly but minimally related to measure of general cognitive status. Similar relationship is not observed between high-frequency hearing and cognition. Further research using a more comprehensive cognitive test battery is needed to confirm the lack of association between high-frequency hearing and cognition. PMID- 28845680 TI - Effectiveness of the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders Among Veterans With Posttraumatic Stress Disorder: A Pilot Study. AB - Effective treatment options are needed for veterans who do not participate in trauma-focused psychotherapy. Research has yet to examine the effectiveness of transdiagnostic psychotherapy in veterans with posttraumatic stress disorder (PTSD) and co-occurring psychological disorders. This pilot study examined the effectiveness of the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) delivered in a 16-week group format. We examined treatment outcomes in male and female veterans ( n = 52) in an outpatient specialty PTSD clinic at a large Veterans Affairs (VA) medical center. We hypothesized significant decreases in emotion regulation difficulty (Difficulties in Emotion Regulation Scale), PTSD symptom severity (PTSD Checklist for DSM-5), and depressive symptom severity (Patient Health Questionnaire-9). In addition, we hypothesized that reductions in emotion regulation difficulty across treatment would negatively predict PTSD and depressive symptoms at posttreatment. PTSD symptoms, depressive symptoms, and emotion regulation difficulty all evidenced significant improvements at the end of treatment relative to baseline ( ps < .001). In addition, reductions in emotion regulation across treatment were associated with lower PTSD and depressive symptoms at posttreatment ( ps < .001). This pilot study provides preliminary evidence supporting use of UP among veterans with PTSD and co-occurring disorders. Well-designed clinical trials evaluating efficacy of UP among veterans are needed. PMID- 28845683 TI - Young Adults' Perspectives on Advance Care Planning. AB - OBJECTIVE: To describe the knowledge, attitudes, beliefs, and behaviors of young adults regarding advance care planning (ACP). METHODS: A cross-sectional sample of young adults (N = 310) from a single metropolitan university during September to November 2016 completed an online survey about their knowledge, attitudes, beliefs, and behaviors regarding ACP. Descriptive statistics and correlation tests were conducted. RESULTS: Young adults lacked familiarity and knowledge regarding ACP. Those who were most familiar with ACP terminology were more likely to be older, female, enrolled in a graduate program, and employed full time. Although the majority of respondents had positive attitudes and beliefs about ACP, only one-third had talked with their family/loved ones about their wishes for end-of-life care. DISCUSSION: Our study findings suggest a strong need to inform and engage young adults in ACP and end-of-life care discussions. As young adults are likely to become a caregiver for an aging family member, they can have an important role in initiating and facilitating conversations with loved ones and be instrumental in ACP for older adults. PMID- 28845684 TI - Additional Abstracts for the 20th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28845679 TI - Micro-CT and nano-CT analysis of filling quality of three different endodontic sealers. AB - OBJECTIVES: To investigate voids in different root canal sealers using micro-CT and nano-CT, and to explore the feasibility of using nano-CT for quantitative analysis of sealer filling quality. METHODS: 30 extracted mandibular central incisors were randomly assigned into three groups according to the applied root canal sealers (Total BC Sealer, Sure Seal Root, AH Plus) by the single cone technique. Subsequently, micro-CT and nano-CT were performed to analyse the incidence rate of voids, void fraction, void volume and their distribution in each sample. RESULTS: Micro-CT evaluation showed no significant difference among sealers for the incidence rate of voids or void fraction in the whole filling materials (p > 0.05), whereas a significant difference was found between AH Plus and the other two sealers using nano-CT (p < 0.05). All three sealers presented less void volume in the apical third; however, higher void volumes were observed in the apical and coronal thirds in AH Plus using micro-CT (p < 0.05), while nano CT results displayed higher void volume in AH Plus among all the sealers and regions (p < 0.05). CONCLUSIONS: Bioactive sealers showed higher root filling rate, lower incidence rate of voids, void fraction and void volume than AH Plus under nano-CT analysis, when round root canals were treated by the single cone technique. The disparate results suggest that the higher resolution of nano-CT have a greater ability of distinguishing internal porosity, and therefore suggesting the potential use of nano-CT in quantitative analysis of filling quality of sealers. PMID- 28845685 TI - Older New Zealanders in caregiving roles: Psychological functioning of caregivers of people living with dementia. AB - Research suggests that caregiving can have both positive and negative effects on psychological functioning. It is, however, less understood how these positive and negative effects interact within individuals. The present study aimed to identify different patterns of psychological functioning and their correlates among caregivers of dementia patients. The sample included 336 older caregivers. Latent profile analysis revealed three distinct profiles. The optimally functioning profile was characterized by high levels of positive outcomes and low levels of depression. Those with a suboptimally functioning profile reported low levels of positive outcomes and increased depression symptoms. The poorly functioning profile displayed extremely high levels of depression symptoms and extremely low levels of positive outcomes. Differentiation among groups was driven by differences in social support and to a lesser extent by socio-demographic factors and caregiving experience. Results suggest that caregiving is not necessarily a burdensome role and highlight the role of social relationships. PMID- 28845687 TI - Effect of semicrystalline polymers on self-emulsifying solid dispersions of nateglinide: in vitro and in vivo evaluation. AB - This study was undertaken to improve solubility and bioavailability of nateglinide by preparation of stable self-emulsifying solid dispersions (SESDs). The influence of semicrystalline polymers (poloxamer 407, gelucire 50/13) and method of preparation on dissolution behavior, in vivo performance and stability of nateglinide SESDs were investigated. After optimization, SESDs were prepared at 1:5 weight ratio of nateglinide and polymer individually. All the SESDs were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Aqueous solubility of nateglinide was enhanced by 91.82-fold. The SESDs (poloxamer 407 based solid dispersions) achieved rapid and complete drug release (~100% within 45 min) at pH 2. The improved dissolution appeared to be well correlated with the enhanced bioavailability of nateglinide in rabbits. After oral administration of SESDs (poloxamer 407-based solid dispersions), Cmax and AUC of nateglinide were increased by ~2.92 and 1.77-folds, respectively, signifying the effectiveness of solid dispersions to improve the bioavailability of nateglinide. Stability during storage was established to show prevention of recrystallization. In conclusion, SESDs with poloxamer 407 in solvent method appeared to be an economic and promising technique to improve the dissolution, bioavailability, and stability of nateglinide. PMID- 28845689 TI - Abstracts for the 20th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28845688 TI - Adopt a Care Home: An intergenerational initiative bringing children into care homes. AB - Dementia friendly communities, in which people living with dementia actively participate and those around them are educated about dementia, may improve the wellbeing of those living with dementia and reduce the associated stigma. The Adopt a Care Home scheme aims to contribute towards this by teaching schoolchildren about dementia and linking them with people living with dementia in a local care home. Forty-one children, 10 people living with dementia and 8 school/care home staff participated in a mixed methods (questionnaires, observations, interviews and focus groups) evaluation to assess the scheme's feasibility and impact. Data were analysed statistically and thematically. The scheme was successfully implemented, increased children's dementia awareness and appeared enjoyable for most participants. Findings, therefore, demonstrate the scheme's potential to contribute towards dementia friendly communities by increasing children's knowledge and understanding of dementia and engaging people living with dementia in an enjoyable activity, increasing their social inclusion. PMID- 28845686 TI - Mental Disorder Symptoms among Public Safety Personnel in Canada. AB - BACKGROUND: Canadian public safety personnel (PSP; e.g., correctional workers, dispatchers, firefighters, paramedics, police officers) are exposed to potentially traumatic events as a function of their work. Such exposures contribute to the risk of developing clinically significant symptoms related to mental disorders. The current study was designed to provide estimates of mental disorder symptom frequencies and severities for Canadian PSP. METHODS: An online survey was made available in English or French from September 2016 to January 2017. The survey assessed current symptoms, and participation was solicited from national PSP agencies and advocacy groups. Estimates were derived using well validated screening measures. RESULTS: There were 5813 participants (32.5% women) who were grouped into 6 categories (i.e., call center operators/dispatchers, correctional workers, firefighters, municipal/provincial police, paramedics, Royal Canadian Mounted Police). Substantial proportions of participants reported current symptoms consistent with 1 (i.e., 15.1%) or more (i.e., 26.7%) mental disorders based on the screening measures. There were significant differences across PSP categories with respect to proportions screening positive based on each measure. INTERPRETATION: The estimated proportion of PSP reporting current symptom clusters consistent with 1 or more mental disorders appears higher than previously published estimates for the general population; however, direct comparisons are impossible because of methodological differences. The available data suggest that Canadian PSP experience substantial and heterogeneous difficulties with mental health and underscore the need for a rigorous epidemiologic study and category-specific solutions. PMID- 28845691 TI - Four-dimensional CT angiography (4D-CTA) in the evaluation of juvenile nasopharyngeal angiofibromas: comparison with digital subtraction angiography (DSA) and surgical findings. AB - OBJECTIVES: To explore the value of four-dimensional CT angiography (4D-CTA) in the preoperative evaluation of juvenile nasopharyngeal angiofibromas (JNAs) using 320-row volume CT. METHODS: 4D-CTA and DSA data of 18 patients with histopathologically proven JNAs were retrospectively reviewed. The location, extent, feeding vessels and stage of JNAs were assessed by two radiologists independently and blindly. The agreements between both reviewers and between 4D CTA and surgical findings for assessing the above indicators were analysed, respectively. The radiation dose and the number of feeding arteries between 4D CTA and digital subtraction angiography (DSA) were also compared. RESULTS: 4D-CTA showed high diagnostic consistency with surgical pathology for JNAs with consistent rates of 96.2 and 100% in both reviewers, respectively. The effective dose of 4D-CTA was significantly less than that of DSA (p < 0.001). Good agreements between 4D-CTA and surgical findings and between the two reviewers were found in the assessment of the location, extent and stage of JNAs. 4D-CTA showed that 15 lesions were supplied strictly by the external carotid artery circulation and 3 by the external and internal carotid artery supply, which was in accordance with DSA. There were no significant differences in the main arterial feeder number obtained by 4D-CTA and DSA between different observers (all p > 0.05). CONCLUSIONS: 4D-CTA can provide a reliable preoperative diagnosis and assessment of JNAs, which is useful for determining the surgical strategy and management of this condition. PMID- 28845692 TI - Advancing Guideline Development in the United States: A Call to Action by the US GRADE Network. PMID- 28845694 TI - Self-Regulation of Weight After Sleeve Gastrectomy. AB - Bariatric surgery is recognized as the most effective method for achieving relevant weight loss in subjects with severe obesity. However, there is insufficient knowledge about weight self-regulation and quality of motivation in these patients. The main goal of this study was to characterize the association between the percentage of excess weight loss (%EWL) and the motivation to manage weight, at least 1 year after sleeve gastrectomy (SG). This is an observational longitudinal retrospective study. All patients corresponding to predefined inclusion criteria who underwent SG from January 2008 to July 2010 at a main general hospital were invited. A version of the Treatment Self-Regulation Questionnaire (TSRQ) was used to assess patients' quality of motivation: TSRQ concerning continuing the weight self-management program. Clinical data were collected from patients' records. Overall, 81 patients participated (16 men and 65 women, 25-64 years old). The average body mass index was significantly reduced from 45.3 +/- 7.0 kg/m2 preoperatively to 32.7 +/- 6.9 kg/m2 postoperatively. Autonomous self-regulation was higher than externally controlled self-regulation, regarding motives to keep managing weight after SG. Postoperatively, %EWL correlated negatively with external self-regulation. SG was found to be associated with the quality of motivation for losing weight. External motivations were associated with worse results. These findings support the importance of multiprofessional teams in the assessment and treatment of patients, aiming for the promotion of weight self-regulation after bariatric surgery. PMID- 28845693 TI - Automatic localization of three-dimensional cephalometric landmarks on CBCT images by extracting symmetry features of the skull. AB - To propose an algorithm for automatic localization of 3D cephalometric landmarks on CBCT data, those are useful for both cephalometric and upper airway volumetric analysis. 20 landmarks were targeted for automatic detection, of which 12 landmarks exist on the mid-sagittal plane. Automatic detection of mid-sagittal plane from the volume is a challenging task. Mid-sagittal plane is detected by extraction of statistical parameters of the symmetrical features of the skull. The mid-sagittal plane is partitioned into four quadrants based on the boundary definitions extracted from the human anatomy. Template matching algorithm is applied on the mid-sagittal plane to identify the region of interest ROI, further the edge features are extracted, to form contours in the individual regions. The landmarks are automatically localized by using the extracted knowledge of anatomical definitions of the landmarks. The overall mean error for detection of 20 landmarks was 1.88 mm with a standard deviation of 1.10 mm. The cephalometric land marks on CBCT data were detected automatically with in the mean error less than 2 mm. PMID- 28845695 TI - Effects of different periods of Tai Chi exercise on the kinesthesia of the lower limb joints of elderly women. AB - This study investigated the effects of different periods of Tai Chi exercise on knee and ankle joint kinesthesia. A total of 20 Tai Chi practitioners and 19 controls completed the final test. Customized devices were used to measure the kinesthesia of the knee and ankle joints at the start, after 24 weeks and after 48 weeks of the intervention. Results showed that the 24-week Tai Chi intervention considerably improved the kinesthesia of the knee flexion and extension and ankle dorsiflexion. The 48-week Tai Chi intervention improved the kinesthesia towards knee flexion and extension, ankle dorsiflexion and plantar flexion. Moreover, the 48-week Tai Chi intervention had better kinesthesia towards knee extension and ankle dorsiflexion compared with the 24-week Tai Chi intervention. Our results suggest that long-term (48 weeks versus 24 weeks) Tai Chi exercise benefits the knee and ankle kinesthesia of elderly women. PMID- 28845696 TI - Profiles of family routines during adolescence associated with profiles of health behaviors in young adulthood. AB - This study examined associations between profiles of family routines in early adolescence and profiles of health behaviors during young adulthood. In a sample of 4565 individuals, latent transition analysis indicated individuals in a family characterized by low involvement in adolescence were most likely, across classes, to demonstrate a profile characterized by substance use in young adulthood. The high-involvement class during adolescence was least likely to be a substance user but was relatively likely to be in the poor diet and exercise class during young adulthood. Results highlight the utility of examining complex family influences on health using person-centered methods. PMID- 28845697 TI - Development of phospholipid vesicle-based permeation assay models capable of evaluating percutaneous penetration enhancing effect. AB - OBJECTIVES: The phospholipid vesicle-based permeation assay (PVPA) model has recently been introduced as an in vitro model which can mimic stratum corneum (SC) barriers to estimate the skin permeability of drugs. The aim of this study was to evaluate whether the PVPA model was suitable for the evaluation of penetration enhancing effect of skin penetration enhancers (PE). METHODS: The PVPA model was optimized by changing the lipid composition of both small liposomes (SL), and large liposomes (LL). The barrier properties of the PVPA model were monitored by electrical resistance and permeability measurement of the fluorescent marker Rhodamine B (RB). Then the permeation studies of the five active compounds with different physicochemical properties, namely, ferulic acid, paeoniflorin, albiflorin, tetrahydrocolumbamine, and tetrahydropalmatine, were performed directly on PVPA model to evaluate the penetration enhancing effect of menthol. RESULTS AND DISCUSSIONS: The enhancement ratio (ER) ranking of the five active compounds observed using the optimized PVPA model was in accordance with what observed with Franz diffusion cell device using porcine ear skin. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) analysis of PVPA model and porcine ear skin after treatment with menthol has shown similar mechanism of menthol which perturbs the SC lipid arrangement and extracts the SC lipids. CONCLUSIONS: In summary, the optimized PVPA model was used for the first time for the evaluation of the permeation enhancing effect. The optimized PVPA model has shown potential to be applied in a more standardized, cheaper, and ethical way for the screening of PE. PMID- 28845698 TI - Novel CD123-aptamer-originated targeted drug trains for selectively delivering cytotoxic agent to tumor cells in acute myeloid leukemia theranostics. AB - Since conventional chemotherapy for acute myeloid leukemia (AML) has its limitations, a theranostic platform with targeted and efficient drug transport is in demand. In this study, we developed the first CD123 (AML tumor marker) aptamers and designed a novel CD123-aptamer-mediated targeted drug train (TDT) with effective, economical, biocompatible and high drug-loading capacity. These two CD123 aptamers (termed as ZW25 and CY30, respectively) can bind to a CD123 peptide epitope and CD123 + AML cells with high specificities and KD of 29.41 nM and 15.38 nM, respectively, while has minimal cross reactivities to albumin, IgG and trypsin. Further, TDT is self-assembled from two short primers by ligand modified ZW25 that acted as initiation position for elongation, while intercalated by doxorubicin (Dox). TDT is capable of transporting high capacity of Dox to CD123 + cells and retains the efficacy of Dox, while significantly reducing drug uptake and eased toxicity to CD123- cells in vitro (p < .01). Moreover, TDT can ease Dox cytoxicity to normal tissues, prolong survivals and inhibit tumor growth of mouse xenograft tumor model in vivo. These suggest that CD123 aptamer and CD123 aptamer-mediated targeted drug delivery system may have potential applications for selective delivery cytotoxic agents to CD123 expressing tumors in AML theranostics. PMID- 28845699 TI - Enhancement of oral bioavailability of anti-HIV drug rilpivirine HCl through nanosponge formulation. AB - OBJECTIVE: To synthesize beta cyclodextrin nanosponges using a novel and efficient microwave mediated method for enhancing bioavailability of Rilpivirine HCl (RLP). SIGNIFICANCE: Belonging to BCS class II RLP has pH dependent solubility and poor oral bioavailability. However, a fatty meal enhances its absorption hence the therapy indicates that the dosage form be consumed with a meal. But then it becomes tedious and inconvenient to continue the therapy for years with having to face the associated gastric side effects such as nausea. METHOD: Microwave synthesizer was used to mediate the poly-condensation reaction between beta-cyclodextrin and cross-linker diphenylcarbonate. Critical parameters selected were polymer to cross-linker ratio, Watt power, reaction time and solvent volume. Characterization studies were performed using FTIR, DSC, SEM, 1H NMR and PXRD. Molecular modeling was applied to confirm the possibility of drug entrapment. In vitro drug dissolution followed by oral bioavailability studies was performed in Sprawley rats. Samples were analyzed using HPLC. RESULTS: Microwave synthesis yields para-crystalline, porous nanosponges (~205 nm). Drug entrapment led to enhancement of solubility and a two-fold increase in drug dissolution (P < 0.001) following Higuchi release model. Enhanced oral bioavailability was observed in fasted Sprawley rats where Cmax and AUC0-infinity increases significantly (Cmax of NS~ 586 +/- 5.91 ng/mL; plain RLP ~310 +/- 5. 74 ng/mL). CONCLUSION: The approach offers a comfortable dosing zone for AIDs patients, negating the requirement of consuming the formulation in a fed state due to enhancement in drugs' oral bioavailability. PMID- 28845700 TI - Investigating the driving performance of drivers with and without autism spectrum disorders under complex driving conditions. AB - PURPOSE: The aim of this study was to investigate the driving performance of drivers with autism spectrum disorders under complex driving conditions. METHOD: Seventeen drivers with autism spectrum disorders and 18 typically developed drivers participated in a driving simulator trial. Prior to the assessment, participants completed the Driving Behaviour Questionnaire and measurements of cognitive and visual-motor ability. The driving simulation involved driving in an urban area with dense traffic and unpredictable events. RESULTS: In comparison with the typically developed group, drivers with autism spectrum disorders reported significantly more lapses in driving, committed more mistakes on the driving simulator, and were slower to react in challenging situations, such as driving through intersections with abrupt changes in traffic lights. However, they were also less likely to tailgate other vehicles, as measured by time-to collision between vehicles, on the driving simulator. CONCLUSIONS: The performances of licensed drivers with autism spectrum disorders appeared to be safer in respect to car-following distance but were poorer in their response to challenging traffic situations. Driver education for individuals with autism spectrum disorders should focus on quick identification of hazards, prompt execution of responses, and effective allocation of attention to reduce lapses in driving. Implications for rehabilitation Drivers with autism spectrum disorders reported significantly more lapses during driving. Drivers with autism spectrum disorders were observed to be poorer in traffic scenarios requiring critical response. Driver education for individuals with autism spectrum disorders should focus on managing anxiety and effective attention allocation while driving. Driving simulators can be used as a safe means for training critical response to challenging traffic scenarios. PMID- 28845701 TI - Article Commentary: Regenerative Medicine: An Analysis of Cell Transplantation's Impact. PMID- 28845703 TI - 16th Meeting of the Network of European CNS Transplantation and Restoration (NECTAR), Amsterdam, December 8-10, 2005. PMID- 28845704 TI - Online Manuscript Processing for Cell Transplantation. PMID- 28845710 TI - Combination therapy with the type II anti-CD20 antibody obinutuzumab. AB - INTRODUCTION: Obinutuzumab is a novel humanized type II glycoengineered anti-CD20 antibody approved for first-line treatment of chronic lymphocytic leukemia (CLL) in combination with chlorambucil and for treatment of rituximab-refractory follicular lymphoma (FL). Areas covered: We describe current preclinical and clinical evidence supporting the combination of obinutuzumab with not only chemotherapy but also novel targeted therapies for B-cell hematologic malignancies, and its application in chemoimmunotherapy. We also provide an overview of the current clinical trial landscape investigating novel combination therapies based on obinutuzumab. Expert opinion: Within the next 10 years the treatment of B-cell malignancies with obinutuzumab is expected to increasingly move towards chemotherapy-free regimens. Novel combinations of obinutuzumab will be explored with targeted therapies, antibody-drug conjugates, and/or other immunotherapeutic agents, with the aim to achieve clinically meaningful improvements in efficacy and patient safety. PMID- 28845712 TI - Correction to: Hammady A, et al., Laparoscopic repyeloplasty after failed open repair of ureteropelvic junction obstruction: a case-matched multi-institutional study. PMID- 28845711 TI - Does Anxiety Modify the Risk for, or Severity of, Conduct Problems Among Children With Co-Occurring ADHD: Categorical and Dimensional and Analyses. AB - OBJECTIVE: The goal was to examine whether anxiety modifies the risk for, or severity of, conduct problems in children with ADHD. METHOD: Assessment included both categorical and dimensional measures of ADHD, anxiety, and conduct problems. Analyses compared conduct problems between children with ADHD features alone versus children with co-occurring ADHD and anxiety features. RESULTS: When assessed by dimensional rating scales, results showed that compared with children with ADHD alone, those children with ADHD co-occurring with anxiety are at risk for more intense conduct problems. When assessment included a Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) diagnosis via the Schedule for Affective Disorders and Schizophrenia for School Age Children Epidemiologic Version (K-SADS), results showed that compared with children with ADHD alone, those children with ADHD co-occurring with anxiety neither had more intense conduct problems nor were they more likely to be diagnosed with oppositional defiant disorder or conduct disorder. CONCLUSION: Different methodological measures of ADHD, anxiety, and conduct problem features influenced the outcome of the analyses. PMID- 28845713 TI - Thrombopoietin-receptor agonists for children with immune thrombocytopenia: a systematic review. AB - OBJECTIVE: We conducted a systematic review to assess the efficacy and safety of Thrombopoietin-receptor agonists (TPOras) for pediatric immune thrombocytopenia (ITP). METHODS: We searched PubMed, Embase and Cochrane Library from their earliest records to January 2017. Randomized controlled trials (RCTs) were included. Primary outcomes were durable response and clinically significant bleeding. Secondary outcomes were overall response, overall bleeding events, the use of rescue medication and adverse events (AEs). RESULTS: Five randomized RCTs (261participants) were included. Compared with placebo group, the proportion of patients achieving durable platelet response was significantly higher in Eltrombopag (P = 0.0004) or Romiplostim (P = 0.002) group, so was the overall response in Eltrombopag [RR = 2.64, 95% CI (1.58, 4.44)] or Romiplostim [RR = 5.05, 95% CI (2.21, 11.53)] group. Both clinically significant bleeding (P = 0.04) and total bleeding (P = 0.01) in Eltrombopag group were significantly less frequent than those in placebo group, while no significant difference between Romiplostim and placebo group. The proportion of patients receiving rescue medication, the incidence of overall AEs and serious AEs between TPO-receptor agonists and placebo group were not significantly different. CONCLUSION: TPOras might improve both durable and overall platelet response in pediatric ITP, compared with placebo. PMID- 28845714 TI - The potential role of cannabinoids in epilepsy treatment. AB - INTRODUCTION: Epilepsy is one of the world's oldest recognized and prevalent neurological diseases. It has a great negative impact on patients' quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs' side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention. Areas covered: This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system. Expert commentary: Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy. On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy. PMID- 28845715 TI - How do line managers experience and handle the return to work of employees on sick leave due to work-related stress? A one-year follow-up study. AB - PURPOSE: To examine how line managers experience and manage the return to work process of employees on sick leave due to work-related stress and to identify supportive and inhibiting factors. MATERIALS AND METHODS: Semi-structured interviews with 15 line managers who have had employees on sick leave due to work related stress. The grounded theory approach was employed. RESULTS: Even though managers may accept the overall concept of work-related stress, they focus on personality and individual circumstances when an employee is sick-listed due to work-related stress. The lack of a common understanding of stress creates room for this focus. Line managers experience cross-pressure, discrepancies between strategic and human-relationship perspectives and a lack of organizational support in the return to work process. CONCLUSION: Organizations should aim to provide support for line managers. Research-based knowledge and guidelines on work-related stress and return to work process are essential, as is the involvement of coworkers. A commonly accepted definition of stress and a systematic risk assessment is also important. Cross-pressure on line managers should be minimized and room for adequate preventive actions should be provided as such an approach could support both the return to work process and the implementation of important interventions in the work environment. Implication for rehabilitation Organizations should aim to provide support for line managers handling the return to work process. Cross-pressure on line managers should be minimized and adequate preventive actions should be provided in relation to the return to work process. Research-based knowledge and guidelines on work-related stress and return to work are essential. A common and formal definition of stress should be emphasized in the workplace. PMID- 28845716 TI - Mediators of compassionate goal intervention effects on human neuroendocrine responses to the Trier Social Stress Test. AB - OBJECTIVES: The hypothalamic-pituitary-adrenal (HPA) axis is thought to mediate the effects of stress on illness. Research has identified a limited number of psychological variables that modulate human HPA responses to stressors (e.g. perceived control and social support). Prosocial goals can reduce subjective stress, but have not been carefully examined in experimental settings where pathways of impact on biological stress markers may be traced. Recent work demonstrated that coaching individuals to strive to help others reduced HPA responses to the Trier Social Stress Test (TSST) relative to other cognitive interventions. However, identification of mediational pathways, which were not examined in the original study, is necessary to determine whether the HPA buffering effects were due to helping motivations (compassionate goals; CGs) rather than via previously identified variables such as control or support. METHODS: In this new analysis, we combined the original cortisol data with novel observer ratings of interpersonal behavior and psychological variables during the stress task, and conducted new, theory-driven analyses to determine psychological mediators for the intervention's effect on cortisol responses (N = 54; 21 females, 33 males; 486 cortisol samples). RESULTS: Control, support, and task ego threat failed to account for the effects of the intervention. As hypothesized, self and observer-rated CGs, as well as observer-rated perceptions of participants' interpersonal behavior as morally desirable (but not as dominant or affiliative) were significant mediators of neuroendocrine responses. CONCLUSIONS: The findings suggest that stress-reduction interventions based on prosocial behavior should target particular motivational and interpersonal features. PMID- 28845717 TI - Characterization and minimization of the stress response to trapping in free ranging wolves (Canis lupus): insights from physiology and behavior. AB - OBJECTIVES: Wildlife capture is an essential management tool that induces a reactive homeostasis response in the captured animals. The aim of this study was to characterize the reactive homeostatic response to trapping in free-ranging wolves and assess the mitigation achieved by reducing the duration of restraint. MATERIALS AND METHODS: Making use of wolves captured for ecological research as a model for wildlife acute stress, we characterize 25 reactive homeostasis mediators and we assess the effect on these mediators of reducing the duration of restraint in trap by using remote trap activation alarms. RESULTS: Free-ranging wolves trapped by leg-hold snares (n = 15) showed higher stress leukogram, tissue injury and hematocrit; while lower glucose, ions and cardiac rate compared with captive wolves. They also showed higher leukocyte count and creatine kinase; but lower hematocrit, cardiac rate and rectal body temperature compared to wolves captured by darting from a helicopter. Daily distance travelled was significantly lower up to day 12 post-capture compared to the remainder of the telemetry follow up and this effect was more noticeable on the nocturnal distance travelled. Reducing the duration of restraint on trap significantly lowered the stress leukogram and dehydration. Daily distance travelled during the night by wolves captured using trap-alarms was significantly lower only up to day 4 post-capture compared to up to day 28 for wolves captured without trap-alarms. DISCUSSION: The capture method and duration of restraint influence the reactive homeostasis response of free-ranging wolves. Technological solutions that reduce the duration of restraint on trap significantly dampen this influence. CONCLUSIONS: Wildlife trapping actions should strive to minimize the delay from capture to manipulation. PMID- 28845718 TI - Nurses' Experiences of Grief Following Patient Death: A Qualitative Approach. AB - PURPOSE: To explore the lived experiences of nurses' feelings, emotions, grief reactions, and coping mechanisms following their patients' death. BACKGROUND: On a daily basis, nurses are experiencing patients' death, which exposes them to grief. Nurses' grief has not been sufficiently addressed in practice settings, although it has been a well-known threat to health and work performance. DESIGN: A qualitative design guided by a phenomenological approach was adopted. METHOD: Data were collected from a purposive sample of 21 Jordanian nurses by conducting three focus groups and analyzed using Colaizzi's framework. FINDINGS: Four themes were generated in which participants reported feelings of grief following their patients' death. Their grief emotions were reported as sadness, crying, anger, shock, denial, faith, fear, guilt, fear of the family's reaction, and powerlessness. CONCLUSIONS: The study provided evidence that nurses respond emotionally to patients' death and experience grief. Nurses are burdened by recurrent patients' deaths and try to cope and overcome their grief. This study emphasizes the importance of developing strategies to help nurses positively cope with their grief from a holistic perspective. This will reflect positively on the nurses' performance. PMID- 28845720 TI - Creativity in ADHD: Goal-Directed Motivation and Domain Specificity. AB - OBJECTIVE: This research aimed to provide explanations for the inconsistent findings regarding creativity in ADHD. METHOD: In Study 1, we assessed real-world creative achievements and intrinsic motivation during idea generation in adults with ADHD and compared these with controls. In Study 2, we manipulated competition during idea generation to investigate effects on idea originality in adults with ADHD versus controls, and assessed creativity in specific domains. RESULTS: Adults with ADHD reported more real-world creative achievements. We did not observe differences in intrinsic motivation during idea generation between groups, but adults with ADHD generated more original ideas when competing for a bonus. Moreover, adults with ADHD rated themselves as more creative in specific creative domains. CONCLUSION: Our findings suggest that goal-directed motivation may drive the enhanced real-world creative achievements of people with ADHD. Moreover, people with ADHD may selectively engage and excel in creative domains that fit their skills and preferences. PMID- 28845719 TI - Stress hormones at rest and following exercise testing predict coronary artery disease severity and outcome. AB - OBJECTIVES: Despite considerable knowledge regarding the importance of stress in coronary artery disease (CAD) pathogenesis, its underestimation persists in routine clinical practice, in part attributable to lack of a standardized, objective assessment. The current study examined the ability of stress hormones to predict CAD severity and prognosis at basal conditions as well as during and following an exertional stimulus. MATERIALS AND METHODS: Forty Caucasian subjects with significant coronary artery lesions (>=50%) were included. Within 2 months of coronary angiography, cardiopulmonary exercise testing (CPET) on a recumbent ergometer was performed in conjunction with stress echocardiography (SE). At rest, peak and after 3 min of recovery following CPET, plasma levels of cortisol, adrenocorticotropic hormone (ACTH) and NT-pro-brain natriuretic peptide (NT-pro BNP) were measured by immunoassay sandwich technique, radioimmunoassay, and radioimmunometric technique, respectively. Subjects were subsequently followed a mean of 32 +/- 10 months. RESULTS AND DISCUSSION: Mean ejection fraction was 56.7 +/- 9.6%. Subjects with 1-2 stenotic coronary arteries (SCA) demonstrated a significantly lower plasma cortisol levels during CPET compared to those with 3 SCA (p < .05), whereas ACTH and NT-pro-BNP were not significantly different (p > .05). Among CPET, SE, and hormonal parameters, cortisol at rest and during CPET recovery demonstrated the best predictive value in distinguishing between 1-, 2-, and 3-SCA [area under ROC curve 0.75 and 0.77 (SE = 0.11, 0.10; p = .043, .04) for rest and recovery, respectively]. DeltaCortisol peak/rest predicted cumulative cardiac events (area under ROC curve 0.75, SE = 0.10, p = .049). CONCLUSIONS: Cortisol at rest and following an exercise test holds predictive value for CAD severity and prognosis, further demonstrating a link between stress and unwanted cardiac events. PMID- 28845721 TI - Residential environment impact scale: Utilization of the Swedish version. AB - BACKGROUND: The Residential Environment Impact Scale (REIS) is an assessment and consulting instrument designed to examine the impact of the residential environment on its residents and to develop recommendations for adapting this environment. Since REIS is new for occupational therapists in Sweden it is important to evaluate its utilization potential. AIM: The aim was to examine the utility of the Swedish version of the Residential Environment Impact Scale (REIS S) for adults living in residential settings. MATERIAL AND METHODS: Twenty-two occupational therapists conducted 28 REIS-S assessments in residential settings including 92 older persons and persons with disabilities. In total, 44 questionnaires were answered before and after conduction of the assessment. The data was analyzed using qualitative methods of analysis. RESULTS: The REIS-S showed both positive and negative dimensions of utility among occupational therapists working in residential settings. It provided support for making recommendations and contributed to effective assessments but was found time consuming. The clinical relevance with REIS-S was positive since it met the needs expressed by the occupational therapists. CONCLUSIONS: REIS-S seems promising according to utility in Swedish residential settings for adults. However, psychometrically testing is required for further establishing the utilization of the instrument. PMID- 28845722 TI - The pillars of well-constructed simulated patient programs: A qualitative study with experienced educators. AB - INTRODUCTION: The inclusion of simulated patients (SPs) in health professional education is growing internationally. However, there is limited evidence for best practice in SP methodology. This study investigated how experienced SP educators support SPs in providing SP-based education for health professional students. METHODS: Experienced SP educators were identified via relevant professional associations, peer-reviewed publications, and peer referral. Semi-structured individual interviews were conducted via telephone. Data were analyzed independently by three researchers using principles of inductive thematic analysis. RESULTS: Four themes were identified that represent the key structural components of SP programs considered by educators seeking to optimize learning for health professional students in SP programs: managing SPs by operationalizing an effective program, selecting SPs by rigorously screening for suitability, preparing SPs by educating for a specific scenario, and directing SPs by leading safe and meaningful interactions. Within these components, subthemes were described, with considerable variation in approaches. CONCLUSIONS: Key structural components to SP programs were consistently described by experienced SP educators who operationalize them. A framework has been proposed to assist educators in designing high-quality SP programs that support SPs and learners. Future research is required to evaluate and refine this framework and other evidence-based resources for SP educators. PMID- 28845723 TI - Pelvic floor muscle function and urinary incontinence in the female athlete. AB - Urinary incontinence, defined as involuntary leakage of urine, is often considered a disorder of post-partum and post-menopausal women. However, this disorder is not exclusive to older women, as recent research has demonstrated a high prevalence of urinary incontinence among young, nulliparous female athletes. In fact, females participating in repetitive, high-impact sports are at the highest risk for urinary incontinence. In these athletes, the absence of sufficient pelvic floor strength and coordination to withstand sport related increases in intra-abdominal pressure results in physical activity related urinary incontinence, and may be a predictor of urinary incontinence in later adulthood. Pelvic floor dysfunction and urinary incontinence in this population is under-reported and consequently under-diagnosed and under-treated. Therefore, the prevalence is higher than one might expect, and the effects can include decreased performance, change in sport and avoidance of physical activity all together. This manuscript highlights the prevalence of pelvic floor dysfunction and outlines its pathophysiology, diagnosis, treatment, and rehabilitation. We discuss how greater recognition of this disorder by health care providers and routinely querying active females is a critical step in addressing this issue. Identification, education and appropriate rehabilitation can positively affect outcomes in regards to urinary incontinence symptoms and maintain physical activity participation in these athletes. PMID- 28845724 TI - Adding insult to brain injury: young adults' experiences of residing in nursing homes following acquired brain injury. AB - PURPOSE: There is general consensus that adults under age 65 with acquired brain injury residing in nursing homes is inappropriate, however there is a limited evidence base on the issue. Previous research has relied heavily on third-party informants and qualitative studies have been of questionable methodological quality, with no known study adopting a phenomenological approach. This study explored the lived experiences of young adults with brain injury residing in aged care facilities. METHODS: Interpretative phenomenological analysis was employed to collect and analyze data from six semi-structured interviews with participants regarding their experiences of living in nursing homes. RESULTS: Two themes were identified, including "Corporeal prison of acquired brain injury: broken selves" and "Existential prison of the nursing home: stagnated lives". Results illustrated that young adults with acquired brain injury can experience aged care as an existential prison in which their lives feel at a standstill. This experience was characterized by feelings of not belonging in a terminal environment, confinement, disempowerment, emptiness and hope for greater autonomy through rehabilitation. CONCLUSION: It is hoped that this study will provide relevant professionals, services and policy-makers with insight into the challenges and needs of young adults with brain injury facing these circumstances. Implications for rehabilitation This study supports the contention that more home-like and age-appropriate residential rehabilitation services for young adults with acquired brain injury are needed. As development of alternative accommodation is a lengthy process, the study findings suggest that the interim implementation of rehabilitative care in nursing homes should be considered. Taken together with existing research, it is proposed that nursing home staff may require training to deliver evidence-based rehabilitative interventions to those with brain injury. The present findings add support to the call for systemic change in Ireland, to clarify the acquired brain injury care pathway and establish integrated rehabilitation services. PMID- 28845726 TI - Twelve tips for the recruitment and retention of general practitioners as teachers of medical students. AB - BACKGROUND: Primary care physicians have become a fundamental aspect of teaching in modern medical school curricula worldwide with a significant proportion of undergraduate teaching taking place in primary care. There are calls for this to increase with more patient care occurring in the community but teaching capacity in primary care is a potential challenge. Medical schools, therefore, need strategies to be able to increase their primary care physician teaching workforce. METHODOLOGY: We asked all Heads of General Practice Teaching in UK medical schools to share their three top tips for recruiting and retaining GPs to teach undergraduate students. The majority (two-thirds) of medical schools responded and we have summarized the answers into the following twelve tips. RESULTS: Although the twelve tips are varied and comprehensive, including broad topics such as finances and training, one clear theme running through the majority of tips is good communication and relationships between education teams and GPs. CONCLUSIONS: The solutions to recruiting and retaining GPs to teach undergraduate medical students are clearly multifactorial and complex. We hope that by presenting suggestions from UK GP heads of teaching as these twelve tips provides some helpful, thought-provoking ideas and inspiration for both the UK and internationally. PMID- 28845725 TI - Characterizing the in vitro species differences in N-glucuronidation of a potent pan-PIM inhibitor GNE-924 containing a 3,5-substituted 6-azaindazole. AB - 1. Glucuronidation of amines has been shown to exhibit large species differences, where the activity is typically more pronounced in human than in many preclinical species such as rat, mouse, dog and monkey. The purpose of this work was to characterize the in vitro glucuronidation of GNE-924, a potent pan-PIM inhibitor, to form M1 using liver microsomes (LM) and intestinal microsomes (IM). 2. M1 formation kinetics varied highly across species and between liver and intestinal microsomes. In LM incubations, rat exhibited the highest rate of M1 formation (CLint,app) at 140 +/- 10 uL/min/mg protein, which was approximately 30-fold higher than human. In IM incubations, mouse exhibited the highest CLint,app at 484 +/- 40 uL/min/mg protein, which was >1000-fold higher than human. In addition, CLint,app in LM was markedly higher than IM in human and monkey. In contrast, CLint,app in IM was markedly higher than LM in dog and mouse. 3. Reaction phenotyping indicated that UGT1A1, UGT1A3, UGT1A9, UGT2B4 and the intestine-specific UGT1A10 contributed to the formation of M1. 4. This is one of the first reports showing that N-glucuronidation activity is significantly greater in multiple preclinical species than in humans, and suggests that extensive intestinal N-glucuronidation may limit the oral exposure of GNE-924. PMID- 28845727 TI - Will combination therapy with targeted drugs be better for achieving remission in chronic lymphocytic leukemia? PMID- 28845728 TI - Perceptions of the Meaningfulness of Work Among Older Social Purpose Workers: An Ecological Momentary Assessment Study. AB - The ecological momentary assessment (EMA) method was used to examine the antecedents and correlates of older adults' in-the-moment perceptions of meaning at work. Data were collected six times per day for 7 days from 30 older adults who were mostly social entrepreneurs and who were engaged in purpose work (i.e., work that addresses a social problem or issue). We found concurrent effects of two types of affective states (i.e., relaxed and energetic) and generative work behaviors (i.e., sharing information about one's work and encouraging/inviting others into one's work) on three measures of perceptions of meaningful work (i.e., high passion for one's work, high sense of engagement in one's work, and high connection to a sense of meaning in life). Feeling energetic had a lagged effect on meaningful work approximately 2.5 and 5 hr later in the day. We consider ways to foster engagement in meaningful work as a path toward healthy aging. PMID- 28845729 TI - Life Course Pathways From Adverse Childhood Experiences to Adult Physical Health: A Structural Equation Model. AB - OBJECTIVE: This study examines pathways from adverse childhood experiences (ACEs) to physical health, directly and indirectly through lower income, health risk behaviors, social support, and adult adversity within a theoretical framework postulating stress proliferative and biological trajectories of cumulative adversity. METHOD: Data were obtained from 12,549 adult respondents of a state Behavioral Risk Factor Surveillance System survey. Multigroup structural equation modeling elucidated pathways differentiated by sex and age (older/younger than 45). RESULTS: Good model fit was achieved in each test, indicating consistency with stress theorizing that ACEs significantly contribute to poorer physical health through direct and mediated paths. Younger adults evidenced direct ACE pathway to poor health suggesting early biological erosion, whereas paucity of social support among older adults was directly associated. DISCUSSION: Findings indicate that stress process roles in eroding physical health and experience of wellness. Addressing early adversity is an important strategy toward reducing preventable health problems. PMID- 28845730 TI - Organizational and Managerial Resources and Quality of Care in French Pediatric Oncology Nursing. AB - The purpose of this study was to examine the relationships between nurses' organizational and managerial resources (ie, perceived organizational support and transformational leadership) and their quality of patient care, and second, the mediating role of job satisfaction in these relationships. Participants were 510 nurses from 25 out of 29 French pediatric oncology units. Structural equation modeling results revealed that perceived organizational support and transformational leadership were related to nurses' perceived quality of care and that job satisfaction acted as a mediator between these 2 antecedents (ie, organizational and managerial determinants) and this outcome (ie, quality of care). Based on these findings, practical suggestions and directions for future research are discussed. PMID- 28845731 TI - Upregulation of P2Y1 in neonatal nociceptors regulates heat and mechanical sensitization during cutaneous inflammation. AB - Abstract: The upregulation of various channels and receptors classically linked to sensory transduction from the periphery tightly correspond with changes in the responsiveness of specific subpopulations of primary afferents to mechanical and heat stimulation of the skin at different ages. Previous reports in adults have suggested that the purinergic adenosine diphosphate receptor, P2Y1 can specifically regulate sensory neuron responsiveness to heat stimuli in addition to neurochemical alterations in primary afferents during cutaneous inflammation. To determine if the upregulation of P2Y1 found in the dorsal root ganglia of neonatal mice with cutaneous inflammation initiated at postnatal day 7 (P7) was responsible for the specific alteration in heat sensitivity found in faster conducting ("A"-fiber) nociceptors, we assessed the response properties of cutaneous afferents using an ex vivo hairy hindpaw skin-saphenous nerve-dorsal root ganglion-spinal cord preparation in conjunction with nerve-targeted knockdown of P2Y1. We found that P2Y1 knockdown during neonatal cutaneous inflammation was sufficient to reduce the sensitization of "A"-fiber nociceptors to heat stimuli. Surprisingly, we also found that nerve-specific downregulation of P2Y1 could reduce the observed sensitization of these afferent subtypes to mechanical deformation of the skin. Immunocytochemical analysis of dorsal root ganglia showed that P2Y1 may mediate its effects through modulation of the injury induced increase of transient receptor potential vanilloid type 1 receptor. This suggests that the upregulation of P2Y1 in cutaneous nociceptors during early life peripheral inflammation can regulate the sensitization of myelinated nociceptors to both mechanical and heat stimuli possibly through modulation of transient receptor potential vanilloid type 1 expression. PMID- 28845732 TI - Kindlin-1 is a key protein in hyperbaric oxygen therapy for the treatment of neuropathic pain. AB - Background: Hyperbaric oxygen therapy is increasingly used in adjuvant therapies to treat neuropathic pain. However, the specific targets of hyperbaric oxygen treatment in neuropathic pain remain unclear. Recently, we found that hyperbaric oxygen therapy produces an antinociceptive response via the kindlin-1/wnt-10a signaling pathway in a chronic pain injury model in rats. Methods: The rats received an intraperitoneal injection of AAV-FERMT1 or an adeno-associated virus control vector 20 days before the chronic constriction injury operation. During five consecutive days of hyperbaric oxygen treatment, mechanical withdrawal threshold and thermal withdrawal latency tests were performed. Then, kindlin-1 expression was examined by real-time polymerase chain reaction and Western blot analysis. Meanwhile, the activation of glial cells and the production of TNF alpha, IL-1beta, and fractalkine were also determined. Results: Our findings demonstrated that hyperbaric oxygen therapy inhibited the chronic constriction injury-induced increase in kindlin-1 expression. Furthermore, overexpression of kindlin-1 reversed the antinociceptive effects of hyperbaric oxygen therapy. The observed hyperbaric oxygen-induced reductions in glial cell activation and neuroinflammation, as indicated by the production of TNF-alpha, IL-1beta, and fractalkine, were also prominently diminished in the group with kindlin-1 overexpression. Conclusions: Our findings demonstrate that kindlin-1 is a key protein in the action of hyperbaric oxygen therapy in the treatment of neuropathic pain. Indeed, interference with kindlin-1 may be a drug target for reducing the neuroinflammatory responses of the glial population in neuropathic pain. PMID- 28845733 TI - The Chemokine Receptor CXCR2 Supports Nociceptive Sensitization after Traumatic Brain Injury. AB - Abstract: Chronic pain after traumatic brain injury (TBI) is very common, but the mechanisms linking TBI to pain and the pain-related interactions of TBI with peripheral injuries are poorly understood. Chemokine receptors play an important role in both pain and brain injury. In the current work, we pursued the hypothesis that the epigenetically regulated CXC chemokine receptor 2 (CXCR2) is a crucial modulator of nociceptive sensitization induced by TBI. For these studies, we used the rat lateral fluid percussion model of TBI. Histone actyltransferase activity was blocked using anacardic acid beginning immediately following injury, or delayed for seven days prior to administration. The selective CXCR2 antagonist SCH527123 administered systemically or intrathecally was used to probe the role of chemokine signaling on mechanical hindpaw sensitization after TBI. The expression of the CXCR2 receptor was accomplished using real-time PCR, immunohistochemistry, and Western blotting, while epigenetic regulation was assessed using chromatin immunoprecipitation assay. The spinal levels of several pain-related mediators including CXCL1, an endogenous ligand for CXCR2, as well as brain-derived neurotrophic factor and prodynorphin were measured by enzyme-linked immunosorbent assay. We observed that anacardic acid potently blocked and reversed mechanical hindpaw sensitization after TBI. The same drug was able to prevent the upregulation of CXCR2 after TBI, but did not affect the spinal expression of other pain mediators. On the other hand, both systemically and intrathecally administered SCH527123 reversed hindpaw allodynia after TBI. Most of the spinal CXCR2 appeared to be expressed by spinal cord neurons. Chromatin immunoprecipitation experiments demonstrated TBI-enhanced association of the CXCR2 promoter with acetylated-H3K9 histone protein that was also reversible using anacardic acid. Taken together, our findings suggested that TBI causes the upregulation of spinal CXCR2 through an epigenetic mechanism ultimately supporting nociceptive sensitization. The use of CXCR2 antagonists may, therefore, be useful in pain resulting from TBI. PMID- 28845734 TI - Local and Extensive Neuroplasticity in Carpal Tunnel Syndrome: A Resting-State fMRI Study. AB - Carpal tunnel syndrome (CTS) is a most common peripheral nerve entrapment neuropathy characterized by sensorimotor deficits in median nerve innervated digits. Block-design task-related functional magnetic resonance imaging (fMRI) studies have been used to investigate CTS-related neuroplasticity in the primary somatosensory cortices. However, considering the persistence of digital paresthesia syndrome caused by median nerve entrapment, spontaneous neuronal activity might provide a better understanding of CTS-related neuroplasticity, which remains unexplored. The present study aimed to investigate both local and extensive spontaneous neuronal activities with resting-state fMRI. A total of 28 bilateral CTS patients and 24 normal controls were recruited, and metrics, including amplitude of low-frequency fluctuation (ALFF) and voxel-wise functional connectivity (FC), were used to explore synaptic activity at different spatial scales. Correlations with clinical measures were further investigated by linear regression. Decreased amplitudes of low-frequency fluctuation were observed in the bilateral primary sensory cortex (SI) and secondary sensory cortex (SII) in CTS patients (AlphaSim corrected P < .05). This was found to be negatively related to the sensory thresholds of corresponding median nerve innervated fingers. In the voxel-wise FC analysis, with predefined seed regions of interest in the bilateral SI and primary motor cortex, we observed decreased interhemispheric and increased intrahemispheric FC. Additionally, both interhemispheric and intrahemispheric FC were found to be significantly correlated with the mean ALFF. PMID- 28845735 TI - Effect of diagnosis, body site and experience on text entry rate of individuals with physical disabilities: a systematic review. AB - OBJECTIVE: This study systematically reviewed the research on computer text entry by people with physical disabilities, and conducted a quantitative synthesis of text entry rates associated with individuals' diagnosis, body site used with the interface and their level of experience. METHOD: We searched 10 databases and included studies in which: typing speed was reported; the access interface was available for public use; and individuals with physical impairments were in the study population. For quantitative synthesis, we used only the text entry rates (TER) reported for individuals with physical impairments; studies also had to report the sample size, and the average and standard deviation for the text entry rates. RESULTS: Thirty-nine studies involving 248 subjects met the criteria for quantitative synthesis. Cerebral palsy was associated with significantly slower TER, at 5.5 wpm, than muscular dystrophy (12.5 wpm), spina bifida (10.4 wpm), SCI high cervical (10.1 wpm) and SCI low cervical (13.3 wpm). Among the 19 body sites represented, the Fingers bilateral category had the highest average, at 17.72 wpm. Head (2.92 wpm) and Hand (non-typing) (3.95 wpm) were each associated with significantly slower TER than Hands unspecified, Fingers bilateral, Hand with control enhancer, Voice and Mouth. The three levels of experience examined, LowPlus, Medium and High, provided very similar TER. CONCLUSION: This study contributes external evidence for service providers who provide computer access interventions for individuals with disabilities. The analyzed text entry performances serve as benchmarks to be used as guidelines during interface selection and training. Implications for Rehabilitation The median text entry rate (TER) across the literature for individuals with physical disabilities is 7.0 wpm. TER is affected by a user's diagnosis and the body site used for typing. These TER data can serve as diagnostic norms and benchmarks to be used as guidelines during interface selection and training. We recommend that practitioners measure text entry rate with clients, to place their performance in the context of these results and provide a baseline against which to measure effectiveness of an intervention. PMID- 28845737 TI - Biodistribution study of 99mTc-gemcitabine-loaded spherulites in Sprague-Dawley rats by gamma scintigraphy to investigate its lung targeting potential. AB - Gemcitabine hydrochloride (GCH) is drug of choice for treatment of non-small cell lung cancer. This project aims to formulate GCH-loaded spherulites for lung targeting using soyabean phosphatidylcholine, cholesterol (Chol) and 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]. Vesicles were characterised for size, entrapment efficiency, drug release and in vitro cytotoxicity. Radiolabelling of GCH was done using reduced technetium-99 m to study biodistribution in Sprague-Dawley rats. Discrete and spherical, PEGylated and non-PEGylated spherulites with an average size of 200 nm as seen in transmission electron microscopy had an entrapment efficiency of 76.28% and 77.42%, respectively. PEGylated spherulites showed sustained release followed by non-PEGylated and plain drug. GCH spherulites exhibited significantly higher cytotoxicity and apoptosis at reduced concentration than GCH solution. The radiolabelled complex showed high binding and radiolabelling efficiency. Gamma scintigraphy showed that GCH-loaded PEGylated spherulites were able to localise within lungs in higher concentration than non-PEGylated followed by plain drug. PMID- 28845738 TI - Numerical versus narrative: A comparison between methods to measure medical student performance during clinical clerkships. AB - BACKGROUND: Medical school evaluations typically rely on both language-based narrative descriptions and psychometrically converted numeric scores to convey performance to the grading committee. We evaluated inter-rater reliability and correlation of numeric versus narrative evaluations for students on their Neurology Clerkship. DESIGN/METHODS: 50 Neurology Clerkship in-training evaluation reports completed by their residents and faculty members at the University of Rochester School of Medicine were dissected into narrative and numeric components. 5 Clerkship grading committee members retrospectively gave new narrative scores (NNS) while blinded to original numeric scores (ONS). We calculated intra-class correlation coefficients (ICC) and their associated confidence intervals for the ONS and the NNS. In addition, we calculated the correlation between ONS and NNS. RESULTS: The ICC was greater for the NNS (ICC = .88 (95% CI = .70-.94)) than the ONS (ICC = .62 (95% CI = .40-.77)) Pearson correlation coefficient showed that the ONS and NNS were highly correlated (r = .81). CONCLUSIONS: Narrative evaluations converted by a small group of experienced graders are at least as reliable as numeric scoring by individual evaluators. We could allow evaluators to focus their efforts on creating richer narrative of greater value to trainees. PMID- 28845736 TI - The Life and Times of Parasites: Rhythms in Strategies for Within-host Survival and Between-host Transmission. AB - Biological rhythms are thought to have evolved to enable organisms to organize their activities according to the earth's predictable cycles, but quantifying the fitness advantages of rhythms is challenging and data revealing their costs and benefits are scarce. More difficult still is explaining why parasites that live exclusively within the bodies of other organisms have biological rhythms. Rhythms exist in the development and traits of parasites, in host immune responses, and in disease susceptibility. This raises the possibility that timing matters for how hosts and parasites interact and, consequently, for the severity and transmission of diseases. Here, we take an evolutionary ecological perspective to examine why parasites exhibit biological rhythms and how their rhythms are regulated. Specifically, we examine the adaptive significance (evolutionary costs and benefits) of rhythms for parasites and explore to what extent interactions between hosts and parasites can drive rhythms in infections. That parasites with altered rhythms can evade the effects of control interventions underscores the urgent need to understand how and why parasites exhibit biological rhythms. Thus, we contend that examining the roles of biological rhythms in disease offers innovative approaches to improve health and opens up a new arena for studying host-parasite (and host-parasite-vector) coevolution. PMID- 28845739 TI - Poor acute outcome in congestive heart failure is associated with increases in the plasma static oxidation-reduction potentials (sORP) in men but not in women. AB - OBJECTIVES: In congestive heart failure (CHF), men are younger, more likely to have reduced ejection fraction (HF-rEF), and to be diabetic compared to women. Despite this, sex differences in oxidative stress have yet to be explored in CHF. METHODS: Data from 67 males and 63 females hospitalized for CHF were collected. Static oxidation-reduction potential (sORP), a relative indicator of oxidative stress, and capacity ORP (icORP), a relative indicator of antioxidant capacity, were measured from plasma samples. We examined whether sex modified the relationship between ORP and hospital discharge disposition (poor outcome: death, hospice), along with other demographics, medications, and diagnostic parameters. RESULTS: Males with poor outcomes had higher sORP and icORP values than females (P < 0.05). For those with a good outcome, there were no differences between the sexes (P > 0.05). Males were younger and more likely to have HF-rEF and diabetes. Controlling for these variables did not account for the sex differences in ORP measures. Regardless of sex, higher creatinine was related to higher sORP and icORP, while lower magnesium and potassium were related to higher sORP and icORP, respectively. DISCUSSION: Increases in sORP during CHF are partially affected by sex and acute outcomes, but are also related to variables without sexual biases. PMID- 28845740 TI - Breaking Boundaries: Complementary and Alternative Medicine Provider Framing of Preventive Care. AB - This textual examination extends understandings of how complementary and alternative medicine (CAM) providers constitute preventive care in their discourse by identifying the frame of breaking boundaries referencing relational, structural, and philosophical orientations in their practice with their clients. Analysis of semistructured, in-depth interviews with CAM providers ( n = 17) reveals that the frame of breaking boundaries was comprised of three themes: finding one's own strength; I don't prescribe, so I'm exploring; and ground yourself, and have an escape route. The themes describe preventive care by identifying how CAM providers negotiate their relational positionality in connecting with clients, structural positionality within the field of health care, and philosophical positionality within the ontological understandings that guide how health is defined and conceptualized. The study contributes toward enhancing diverse understandings of constituting preventive care in practice and suggests pragmatic implications for addressing biomedical provider communication with their patients seeking CAM care alongside conventional treatments. PMID- 28845741 TI - How early does attention modulate visual information processing? The importance of experimental protocol and data analysis approach. AB - Whether attention can influence afferent information processing in primary visual cortex (V1) has long been topic of scientific debate. Findings from a recent study by Baumgarter et al. (this issue) add to this debate by providing a null replication of an influential study that reported that spatial attention can enhance feedforward information processing in human V1, as reflected in the amplitude of the C1 ERP component (Kelly, Gomez-Raminez, & Foxe, 2008). Here we discuss several factors, including analytic approach, experimental design, and motivational factors, that, once scientifically tested, may help resolve discrepancies in the current literature. PMID- 28845742 TI - Task dependence of early attention modulation: the plot thickens. AB - In Kelly, Gomez-Ramirez and Foxe (2008), we demonstrated strong spatial attentional modulation of initial afferent activity in human area V1 reflected in the C1 visual evoked potential (VEP) component. Using the same task and analysis strategy, Baumgartner and colleagues provide compelling evidence that there is no such modulation in their data. Here, we examine differences in task conditions between this new study and our original study, speculate on how they may account for the discrepant findings, and discuss the broader theoretical implications. PMID- 28845743 TI - The Influence of Physical and Psychosocial Factors on Disruptive Pain Among Seriously Ill Home Care Patients. AB - OBJECTIVES: To estimate the prevalence and correlates of disruptive pain in a sample of seriously ill home care patients in the Canadian province of Ontario. METHODS: The design was a cross-sectional analysis of secondary data from 2757 patients aged 65+. RESULTS: Overall, 69.0% (n = 1902) had any level of pain and 41.6% (n = 1146) indicated that their pain disrupted their usual activities. In the univariate analysis of demographics, the risk of disruptive pain decreased significantly with increasing age ( P < .0001) and was significantly less common among men ( P = .0015). Multivariate analysis showed that unsteady gait (relative risk [RR] = 1.37; 95% confidence interval [CI], 1.18-1.59), arthritis (RR = 1.35; 95% CI, 1.23-1.49), symptoms of depression (RR = 1.24; 95% CI, 1.13-1.37), and declines in social activity that the patient rated as distressing (RR = 1.19; 95% CI, 1.08-1.31) were independently associated with disruptive pain. CONCLUSION: Disruptive pain is highly prevalent in this group, and the key factors associated with this outcome represent physical as well as psychosocial domain areas. PMID- 28845744 TI - Item-specific proactive interference in olfactory working memory. AB - We examine item-specific olfactory proactive interference (PI) effects and undertake comparisons with verbal and non-verbal visual stimuli. Using a sequential recent-probes task, we show no evidence for PI with hard-to-name odours (Experiment 1). However, verbalisable odours do exhibit PI effects (Experiment 2). These findings occur despite above chance performance and similar serial position functions across both tasks. Experiments 3 and 4 apply words and faces, respectively, to our modified procedure, and show that methodological differences cannot explain the null finding in Experiment 1. The extent to which odours exhibit analogous PI effects to that of other modalities is, we argue, contingent on the characteristics of the odours employed. PMID- 28845745 TI - The Relationship of Welding Fume Exposure, Smoking, and Pulmonary Function in Welders. AB - The purpose of this study was to explore the relationship between occupational exposure to welding fumes and pulmonary function in an effort to add supportive evidence and clarity to the current body of research. This study utilized a retrospective chart review of pulmonary function testing and pulmonary questionnaires already available in charts from preplacement physicals to the most recent test. When comparing smokers to nonsmokers, utilizing multiple regression and controlling for age and percentage of time using a respirator, years welding was statistically significant at p = .04. Data support that smoking has a synergistic effect when combined with welding fume exposure on pulmonary decline. PMID- 28845746 TI - Diagnostic and prognostic role of resistin and copeptin in acute ischemic stroke. AB - OBJECTIVES: Our aim was to evaluate (i) whether there is a difference in the concentration of resistin and copeptin between acute ischemic stroke patients and stroke-free controls; and (ii) if there is any prognostic value of resistin and copeptin in predicting stroke infarct volume, stroke severity, and outcome. METHODS: Our case-control study has recruited 112 acute ischemic stroke patients admitted within 24 h after the stroke onset. We have also included 63 age and gender matched stroke-free controls. Resistin and copeptin levels were measured by a commercial ELISA kits. Stroke severity was assessed according to the modified National Institute of Health Stroke Scale (mNIHSS) and the degree of disability was assessed using Barthel index (BI). Stroke infarct volume was determined by the volumetric estimation. RESULTS: Resistin concentrations were significantly higher in patients (3.2 mg/L; IQR: 1.9-6.4) than in stroke-free controls (2.5 mg/L; IQR: 1.4-5.2; p = 0.024) whereas the concentration of copeptin did not differ between patients and controls. Copeptin concentrations were significantly higher in patients with poor functional outcome (Barthel index <60) (p = 0.021). There was a significant negative correlation between copeptin and BI score (rho = -0.309, p = 0.020). DISCUSSION: Resistin, but not copeptin levels are higher in acute ischemic stroke patients early after the stroke onset, than in age and gender matched stroke-free controls. Moreover, higher copeptin concentrations are predictive of poor short term functional outcome after ischemic stroke. If confirmed in larger prospective studies, resistin and copeptin could improve clinical diagnosis of stroke and effective management of patient recovery. PMID- 28845747 TI - The impact of different seats and whole-body vibration exposures on truck driver vigilance and discomfort. AB - Laboratory studies have shown that exposure to whole-body vibration (WBV) increases physical and mental fatigue, which are common issues professional drivers face. The objective of this study was to determine whether altering WBV exposures had any effect on driver vigilance and discomfort. A repeated measures crossover design of five truck drivers with regular 10-h routes was used. Active and passive suspension truck seats were evaluated. For each seat, WBV exposures were measured. Participants completed a discomfort questionnaire and a reaction time task before and after their shift for two weeks, one week per seat. Compared with the passive seat, the active seat significantly reduced WBV exposures, decrements in the optimal and mean reaction times (p = 0.02, 0.047, respectively), and discomfort in the lower back and wrist(s)/forearm(s) (p < 0.01, 0.01, respectively). Study results indicated that reducing WBV helps reduce discomfort and maintain vigilance, which may improve drivers' health and reduce the risk of truck collisions. Practitioner Summary: The active suspension seat used in this study reduced truck drivers' exposure to whole-body vibration (WBV) by over 33% in relation to their current industry standard passive suspension seat. This study demonstrated that reducing truck drivers' exposure to WBV reduced fatigue and discomfort development over a workday. PMID- 28845748 TI - Dopamine crosslinked graphene oxide membrane for simultaneous removal of organic pollutants and trace heavy metals from aqueous solution. AB - A graphene oxide-polydopamine-(beta-cyclodextrin) (GPC) ultrafiltration membrane was fabricated by using the method of drop-coating combined with vacuum filtration. The prepared GPC membrane was characterized with FTIR and XPS spectrophotometry and evaluated for its performances for the rejection of organic molecules (methylene blue) and adsorption of trace heavy metals (Pb2+) from aqueous solutions. The membrane exhibited an excellent rejection coefficient of 99.2% for methylene blue and the permeation flux was 12 L m-2 h-1 at 0.1 bar. The membrane also exhibited fast adsorption kinetics for Pb2+ and the adsorption capacity was 101.6 mg g-1 at a solution pH of 6. The performance of the membrane could almost be completely recovered after a simple clean and regeneration process. These results indicate that the GPC membrane has potential applications in treatment of complex industrial wastewater streams. PMID- 28845749 TI - Patterns of Acute Ischemic Strokes After Carotid Endarterectomy and Therapeutic Implications. AB - AIM: Acute ischemic strokes following surgical treatment of carotid stenosis lead to substantial disability and mortality, and vascular mechanisms underlying their development are not fully elucidated. The goal of this study was to analyze the topographic patterns of acute ischemic stroke following carotid endarterectomy (CEA) on diffusion-weighted and perfusion-weighted magnetic resonance imaging (MRI). MATERIAL AND METHODS: Data were retrospectively collected from consecutive patients who underwent CEA and developed postoperative acute ischemic stroke. Based on the MRI data sets, the lesion patterns of acute stoke were characterized. Morphology of the circle of Willis, the 3-D time-of-flight (3D TOF) of the cerebral arteries, and status of the carotid circulation were also analyzed in order to determine the vascular mechanisms involved in stroke development. RESULTS: Between January 2008 and May 2015, 821 patients were treated surgically for a symptomatic or asymptomatic carotid stenosis at the University Hospital of Nice. Nineteen (2.3%) patients had an acute ischemic stroke after surgery. Among them, 11 (57.9%) patients had a territorial infarction and 8 (42.1%) patients had an internal watershed infarction, cortical watershed infarction, or mixed border zone infarction. According to imaging data sets, embolic mechanism of stroke was reported for 12 (63.2%) patients, hemodynamic mechanism for 2 (10.5%) patients, and mixed mechanism for 5 (26.3%) patients. An asymmetry on 3D-TOF was observed in 60% and 50% of patients with hemodynamic and mixed stroke and in 25% of patients with embolic stroke. The latter 2 patients with embolic stroke underwent successful mechanical thrombectomy using stent-retriever devices. CONCLUSION: In this cohort, embolic mechanism leading to postoperative stroke was more frequently observed than hemodynamic mechanism. Immediate characterization of the cerebral lesion by postoperative brain MRI is of utmost importance because it may rapidly identify patients eligible for treatments such as mechanical thrombectomy. PMID- 28845750 TI - A Case Report of Reconstruction of the Left Superior Vena Cava Using the Right Superior Vena Cava Autograft at Bilateral Bidirectional Superior Cavopulmonary Anastomosis. AB - The choice of graft material for reconstruction of the vena cava in pediatric patients remains controversial. We successfully treated an eight-month-old female patient with single ventricle physiology and long segment obstruction of the left superior vena cava using the right superior vena cava autograft at the time of bilateral bidirectional superior cavopulmonary anastomosis. Postoperative computed tomography confirmed the patency of the reconstruction. PMID- 28845754 TI - Targeting NKG2D and NKp30 Ligands Shedding to Improve NK Cell-Based Immunotherapy. AB - Natural killer (NK) cells are critical immune effector cells capable of mediating antitumor responses. These cytotoxic lymphocytes recognize transformed cells through a mechanism mainly dependent on the engagement of several activating receptors. However, many tumors have developed strategies to evade immunosurveillance and detection by NK cells. A relevant immune escape mechanism is the down regulation of NK cell activating ligands on the surface of tumor cells by proteolytic shedding mediated by different members of metalloproteinase families. Here, we consider two important NK activating receptors, namely NKG2D and NKp30, the ligands (i.e., MICA/B, ULBPs, and B7-H6) of which can be released by cancer cells through proteolytic cleavage. Modulation of ligand shedding in response to cancer therapy is also examined, and we discuss how metalloproteinases implicated in the ligand cleavage could be targeted in novel therapeutic schemes to counteract tumor escape from stress-elicited immune responses. PMID- 28845752 TI - p38 Mitogen-Activated Protein Kinase is Involved in the Pathogenesis of Endometriosis by Modulating Inflammation, but not Cell Survival. AB - BACKGROUND: Local pro-inflammatory environment and enhanced cell survival contribute to the endometriosis development. A serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) mediates intracellular signaling of cytokine production, cell proliferation, and apoptosis in different cell types. The current study compares p38 MAPK activity in normal endometrium and endometriosis, and assesses role(s) of p38 MAPK on cytokine production and cell survival in endometriosis. METHODS: Immunohistochemical levels of total and phosphorylated (active) p38 MAPK as well as its correlation with interleukin 8 (IL-8) expression, and cell proliferation and apoptosis were compared in normal human endometrium and endometriosis. The action of p38 MAPK on pro-inflammatory cytokine-induced IL-8 and monocyte chemotactic protein (MCP)-1 expression in endometriotic cells were assessed by enzyme-linked immunosorbent assay. The 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell survival, 5-bromo 2'-deoxyuridine incorporation, and Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assays were used to determine the function of p38 MAPK in cultured human endometriotic stromal cell proliferation and apoptosis. RESULTS: p38 MAPK activity was significantly higher in both eutopic and ectopic endometria compared to normal endometria during late proliferative and early secretory phases ( P < .05). Increased p38 MAPK activity in endometriotic cells correlated with IL-8 expression (Pearson correlation coefficient r = 0.83, P < .01), but not with apoptosis in vivo. The pro inflammatory cytokines IL-1beta and tumor necrosis factor (TNF)-alpha induced activation of p38 MAPK. Inhibition of p38 MAPK activity blocked IL-1beta and TNF alpha-induced IL-8 and MCP-1 secretion in cultured endometriotic stromal cells ( P < .05), but did not impact on endometriotic cell survival. CONCLUSIONS: These results suggest that rather than modulating cell survival, increased p38 MAPK activity in endometriotic cells contributes to the pathogenesis of endometriosis by promoting the local inflammatory milieu. PMID- 28845753 TI - Follistatin Rescues Blastocyst Development of Poor Quality Porcine Cumulus-Oocyte Complexes by Delaying Meiotic Resumption With Decreased cGMP. AB - Mammalian oocytes resume maturation when removed from follicles and cultured in vitro. During folliculogenesis, oocytes are bathed in follicular fluid (FF), which provides an important and specialized microenvironment for oocyte competence. Follistatin (FST) is one component of FF that may play a role in oocyte maturation and embryo development. This study was conducted to examine possible effects of FST on porcine oocyte competence and embryo development. Exogenous FST in oocyte maturation medium for 22 or 44 hours did not improve nuclear maturation and had no effect on good quality cumulus-oocyte complexes (COCs). However, FST improved blastocyst rates in embryos derived from oocytes with less than 2 layers of cumulus. Follistatin treatment of the poor quality COC group increased transcript levels for genes indicative of oocyte quality. Transcript levels were also altered for cumulus expansion-related genes in response to FST when measured during the germinal vesicle breakdown stage. Interestingly, high-quality oocytes remained at germinal vesicle stage much longer than low-quality oocytes, FST treatment induced temporary blockage of spontaneous meiotic resumption when added during culture of both good and poor quality COCs, and levels of cyclic guanosine monophosphate (cGMP) were higher in FST-treated versus untreated groups for both good and poor quality oocytes. In conclusion, FST treatment of porcine oocytes during in vitro maturation can rescue competency of poor quality oocytes to develop to blastocyst stage following in vitro fertilization. Beneficial effects of addition of FST to culture medium may be mediated by inhibiting degradation of cGMP and temporarily delaying nuclear maturation. PMID- 28845755 TI - Emerging Roles of Granule Recycling in Mast Cell Plasticity and Homeostasis. AB - Secretory granules (SGs) of mast cells (MCs) release their contents to mediate many biological events and a variety of inflammatory diseases and have important protective roles in innate host defense and pathological functions in allergic reactions and anaphylaxis. There are two modes of MC degranulation during the release of granule contents to the extracellular environment. Anaphylactic degranulation (AND) after IgE-mediated activation is characterized by a rapid swelling and fusion of MC granules as well as abrupt mediators release. Piecemeal degranulation (PMD) is a slow and selective secretion of distinct granule mediators by vesicles shuttling from the granule compartment to the plasma membrane, and it is associated with several chronic diseases. Following degranulation, endocytosis is a fundamental biological event that is necessary to recycle granules and maintain the secretory response during repetitive stimulation. Rapid endocytosis through transient fusion (kiss-and-run, cavicapture and compound exo-endocytosis) has been described in MCs and can also result in the selective release of granule contents. In summary, several possible exo-endocytic mechanisms control the kinetics and magnitude of transmitter release, and each mechanism is associated with a different impact on granule replenishment, cell recovery, and consequently MC function under both normal and pathological conditions. PMID- 28845757 TI - Circulating Follicular Regulatory T Cells in Autoimmune Diseases and Their Waning in Multiple Sclerosis. AB - Follicular regulatory T cells (TFRs) are a subset of regulatory T cells that reside in the secondary lymphoid organs and participate in controlling the germinal center (GC) response. The GC response forms the basis of adaptive immunity to foreign protein antigens. In autoimmune diseases, hyperreactivity to self-antigens occurs that may result from an aberrant control of the GC response. TFR dysfunctionality may be one of the factors contributing to this breakdown of self-tolerance. In this review, we discuss how the investigation of circulating TFRs can help us understand their relative contribution to autoimmune-mediated disease processes. Multiple sclerosis is taken as a classical example of autoimmune disease. PMID- 28845756 TI - The Role of the Transcription Factor Ets1 in Lupus and Other Autoimmune Diseases. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by excess B- and T-cell activation, the development of autoantibodies against self-antigens including nuclear antigens, and immune complex deposition in target organs, which triggers an inflammatory response and tissue damage. The genetic and environmental factors that contribute to the development of SLE have been studied extensively in both humans and mouse models of the disease. One of the important genetic contributions to SLE development is an alteration in the expression of the transcription factor Ets1, which regulates the functional differentiation of lymphocytes. Here, we review the genetic, biochemical, and immunological studies that have linked low levels of Ets1 to aberrant lymphocyte differentiation and to the pathogenesis of SLE. PMID- 28845760 TI - Stimuli-Responsive Systems with Diverse Drug Delivery and Biomedical Applications: Recent Updates and Mechanistic Pathways. AB - With the advent of "intelligent" polymeric systems, the use of stimuli-responsive in situ gelling systems has been revolutionized. These interesting polymers exist as free-flowing aqueous solutions before administration and undergo a phase transition to form a viscoelastic gel in a physiological environ through various stimuli such as temperature, pH, solvent, biochemical, magnetic, electric, ultrasound, and photo-polymerization. These smart polymers are endowed with numerous merits such as ease of administration, sustained release, reduced frequent administration with improved patient compliance, and targeted and spatial delivery of a drug with reduced frequency of side effects. Concerted efforts are being made to modify these polymers synthetically because they hold immense potential in various fields such as polymer chemistry, materials science, pharmaceutics, bioengineering medicine, and chemical engineering. In addition to novel drug delivery, these smart polymeric systems have exhibited tremendous applications in tissue engineering, regenerative biomedicine, molecular imprinting, cancer therapy, gene delivery, theranostic and other applications. The current review mainly focuses on the fundamental principles involved during in situ gelling, use of various "smart" drug-delivery formulation systems through diverse routes for their administration, as well as their well-documented biomedical applications. The pertinent literature, marketed formulations, and recent advances on these stimuli-responsive sol-gel-transforming systems are also discussed. PMID- 28845759 TI - Three- and Four-Dimensional Spheroid and FiSS Tumoroid Cultures: Platforms for Drug Discovery and Development and Translational Research. AB - There have been remarkable improvements in our understanding of cancer biology. However, therapeutic improvements, with a few exceptions, have been minimal. Also, significant challenges remain in translating fundamental discoveries in cancer biology and genetics into effective drugs and cures. Traditional two dimensional monolayer cell cultures lack predictive value, resulting in a >90% failure rate of compounds in clinical trials. A developing cancer is a symbiotic tissue consisting of cancer cells, including cancer stem cells (CSCs), and cohabitating with the components of its environment to form a tumor microenvironment (TME) niche. Throughout the process of tumorigenesis, ubiquitous autocrine and paracrine signaling between the cellular and noncellular components of the TME dictates the milieu and structure of this niche. Arising out of such interactions are the cancer cell's phenotypic characteristics, such as stemness, epithelial mesenchymal transformation (EMT), and drug resistance which in turn greatly affect the response of these cells to drug therapy. For these reasons, in order to delineate the mechanism of tumorigenesis and in the process discover drugs that will have greatest impact on tumor growth, it becomes imperative to study the cancer cell in context of its microenvironment. In the present review, we enumerate the advantages of three- and four-dimensional (3D and 4D) cell cultures and describe the various cell culture platforms that are being used to study tumorigenesis in vitro. These culture systems will not only aid in the study of tumor progression complexities in a cost-effective and rapid manner; they also are expected to facilitate the discovery and delivery of therapeutic regimens that will have more success making it to the clinic. PMID- 28845758 TI - B Cell-Specific Biomarkers for Optimal Antibody Responses to Influenza Vaccination and Molecular Pathways That Reduce B Cell Function with Aging. AB - This review highlights recent findings on the effects of aging on influenza vaccine responses, with major emphasis on T and B cells, which are significantly impaired by aging. We discuss changes in T cell production and thymic output; T cell subsets; and TCR repertoire, function, and response to latent persistent infection. We also discuss changes in B cell subsets, repertoire, and function, and how function is impaired by increased intrinsic B cell inflammation and reduced signal transduction. This review presents age-related effects on antigen presenting cells, summarizes recent studies, including our own, aimed at the identification of biomarkers of protective vaccine responses, and provides examples of recent technical advances and insights into human vaccine responses that are helping to define the features associated with successful vaccination and that may enable a more predictive vaccinology in the future. PMID- 28845761 TI - Lipid Nanoparticles for Nasal/Intranasal Drug Delivery. AB - Studies on the development of drug delivery systems have increased because these systems have particular characteristics that allow them to improve therapeutics. Among these, lipid nanoparticles (solid lipid nanoparticles, SLNs; and nanostructured lipid carriers, NLCs) have demonstrated suitability for drug targeting. The nasal administration of drug-loaded lipid nanoparticles showed effectiveness in treating central nervous system (CNS) disorders, particularly neurodegenerative diseases, because the nasal route (also called intranasal route) allows direct nose-to-brain drug delivery by means of lipid nanoparticles. Nonetheless, the feasibility of this application remains an open field for researchers. Drawbacks must be overcome before reaching the clinic (e.g., drug absorption at subtherapeutic levels, rapid mucociliary clearance). The intranasal administration of drugs for systemic absorption is effective for treating other conditions, such as cardiovascular diseases, infections, severe pain, and menopausal syndrome. In the near future, it is expected that patients will benefit from the advantages of lipid nanoparticle-based formulations, via the nasal/intranasal route, which bypasses the blood-brain barrier (BBB), avoiding first-pass metabolism and gastrointestinal degradation. This review discusses the use of SLNs and NLCs for nasal drug administration. A brief description of the nasal route and the features of SLNs and NLCs is initially provided. PMID- 28845762 TI - Phytoestrogens and Related Food Components in the Prevention of Cancer. AB - Great progress has been made in the fight against disease in many different fields of medicine, especially in the field of natural medicine. Phytoestrogens and related compounds play a major role in the prevention and treatment of cancer. Chemoprevention, a narrative approach for controlling cancer, involves the use of specific natural products or synthetic chemical agents to overturn, repress, or prevent pre-malignancy before the development of invasive cancer. Several natural products confer protective effects against a wide range of cancers; examples include grains, nuts, cereals, spices, fruits, vegetables, beverages, medicinal plants, herbs, and their various phytochemical constituents including phenolics, flavonoids, carotenoids, and nitrogen-containing and organosulfur compounds. Phytoestrogens and related compounds act by different mechanisms that ultimately provide benefit with minimum or no side effects and protect and treat different types of cancer, including liver, lung, colon, breast, prostate, esophagus, oral, intestinal, and many other carcinomas. PMID- 28845763 TI - Ethnopharmacological Investigations of Phytochemical Constituents Isolated from the Genus Cuscuta. AB - The genus Cuscuta, of the family Cuscutaceae, is present in plants and has been traditionally used medicinally against many diseases and conditions, notably depression, mental illness, headache, spleen disease, jaundice, diabetes mellitus, and hypertension. Large numbers of phytochemical constituents such as alkaloids, flavonoids, lignins, oxygen heterocyclic compounds, steroids, fatty acids, phenolic acids, resin glycosides, and polysaccharides have been isolated from different species of Cuscuta. Ethnopharmacological studies conducted on such constituents have also been shown Cuscuta to possess anticancer, antiviral, antispasmodic, antihypertensive, anticonvulsant, antibacterial, antioxidant, diuretic, and hair-growth activity. Many tribes and traditional communities have long used the different forms of Cuscuta for treatment and prevention of many diseases. In this article, we comprehensively summarize relevant data regarding the phytochemical, ethnopharmacological, and traditional therapeutic uses of Cuscuta. In addition, we review the parts of the plants that are used as traditional therapeutic agents, their regions of existence, and their possible modes of action. To conclude, we provide evidence and new insights for further discovery and development of natural drugs from Cuscuta. We show that further studies are needed to investigate the mechanism of action and safety profile of phytochemical constituents isolated from Cuscuta. PMID- 28845764 TI - Mini-Review on Cachexia-Related miRNA. AB - Cachexia, or muscle wasting, is a complex metabolic syndrome associated with an underlying illness and characterized by loss of muscle mass. It is a rather prevalent condition, with impacts on patient survival, response to treatment, and quality of life. Treatment options are sparse because of cachexia's multifactorial pathogenesis. Recently, attention has focused on microRNAs (miRNAs) as potential therapeutic targets of several diseases. miRNAs are small, 18- to 25-base-long constructs that regulate gene expression on a post transcriptional level, selectively activating or repressing elements of specific signaling pathways. In this review, we investigated whether miRNAs play any role in cachexia's biochemical pathways and if miRNA targeting has any significant impact on preclinical models of cachexia. PMID- 28845765 TI - Role of Green Tea Flavonoids and Other Related Contents in Cancer Prevention. AB - Green tea is made from Camellia sinensis and leaves through the oxidation process. It mainly originates in China and has been used traditionally throughout Asia. In the West, black tea has been used mostly, but green tea has become the most popular beverage throughout the world. It is also used as a raw material in cosmetics, health foods, and as an added ingredient in various beverages. Different varieties of green tea are available. The main differences between the varieties are due to harvesting time, production procedures, and horticulture. Drinking green tea has many positive effects on the body. It helps to nourish our five vital organs, among which the most important is the heart. It also has many qualities to help improve our state of mind (thus possibly reducing the consumption of alcohol), it acts as a stimulant, cures blotchiness, fulfills thirst, eliminates indigestion, cures beriberi disease, prevents fatigue, and improves kidney and brain function. PMID- 28845766 TI - ABCB1 Polymorphisms and Childhood Acute Lymphoblastic Leukemia Risk: A Meta Analysis. AB - The association between ATP-binding cassette subfamily B member 1 (ABCB1) C3435T and C1236T polymorphisms and the risk for childhood acute lymphoblastic leukemia (ALL) is inconclusive. We conducted a meta-analysis of all published studies to determine the association of ABCB1 C3435T and C1236T polymorphisms and pediatric ALL risk. A systematic retrieval of relevant publications from the PubMed and Web of Science databases was performed. Data were calculated and statistical analysis was performed using STATA version 12.0 software. Metaanalysis results showed no significant association between C3435T polymorphism and pediatric ALL risk (TT vs. CC: odds ratio [OR] = 1.20, 95% confidence interval [CI] = 0.95-1.52; CT vs. CC: OR = 1.00, 95% CI = 0.82-1.23; the dominant model: OR = 1.07, 95% CI = 0.89 1.29; the recessive model: OR = 1.17, 95% CI = 0.84-1.62). Similarly, there was no association found for the C1236T polymorphism (TT vs. CC: OR = 1.18, 95% CI= 0.82-1.70; CT vs. CC: OR = 1.08, 95% CI = 0.80-1.45; the dominant model: OR = 1.10, 95% CI= 0.83-1.46; the recessive model: OR = 0.98, 95% CI = 0.61-1.58). Similar results were observed in the subgroup analyses on ethnicity and Hardy Weinberg equilibrium. The present meta-analysis found no evidence for ABCB1 C3435T and C1236T polymorphisms as risk factors for pediatric ALL. PMID- 28845767 TI - Role of lncRNAs as Novel Biomarkers and Therapeutic Targets in Ovarian Cancer. AB - Ovarian cancer (OC) is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. Compared with research on microRNAs, research on long non-coding RNAs (lncRNAs) is still in its infancy. Studies in recent years have demonstrated that lncRNAs exhibit multiple biological functions in various stages of OC development. In this review, we conclude that lncRNAs are closely involved in the pathogenesis of OC. The expression of lncRNAs indicates the early diagnosis, prognosis, and response to chemotherapy of OC. An attractive approach to treatment of OC is lncRNA small interfering RNA or acting as a plasmid targeting the expression of toxic genes, which is a novel step toward a major breakthrough in the treatment of human OC. E2-regulated lncRNA and its polymorphism, methylation, are also involved in OC. Further research efforts are needed before fully identifying, characterizing, and elucidating the actual functions of lncRNAs in OC at the molecular level and putting them into clinical practice. PMID- 28845768 TI - Investigation of Antimicrobial, Antioxidant, and Xanthine Oxidase--Inhibitory Activities of Phellinus (Agaricomycetes) Mushroom Species Native to Central Europe. AB - Ten representative Central European phellinoid Hymenochaetaceae species (Phellinus sensu lato) were selected to examine their potential pharmacological activity. In this study 40 organic (n-hexane, chloroform, 50% methanol) and aqueous extracts with different polarities were analyzed for their antimicrobial, antioxidant, and xanthine oxidase (XO)--inhibitory properties. Fomitiporia robusta, Fuscoporia torulosa, Phellopilus nigrolimitatus, and Porodaedalea chrysoloma showed moderate antibacterial activity; Bacillus subtilis ATCC 6633, methicillin-resistant Staphylococcus aureus ATCC 43300, and Moraxella catarrhalis ATCC 43617 were the strains most susceptible to the examined fungal species. The in vitro antioxidant and XO assays demonstrated that most of the selected species possess remarkable antioxidant and XO-inhibitory activities. The water extracts in general proved to be more active antioxidants than organic extracts. In the case of F. torulosa, Ph. Nigrolimitatus, and P. chrysoloma, the results of DPPH tests correlate well with those obtained by oxygen radical absorbance capacity tests; these mushrooms presented high antioxidant activities in both assays. Future studies involving phellinoid Hymenochaetaceae species are planned, which may furnish novel results in terms of the species' pharmacological activity and the specific compounds responsible for the observed activity. PMID- 28845769 TI - Characterization and Antiproliferative Effect of Novel Acid Polysaccharides from the Spent Substrate of Shiitake Culinary-Medicinal Mushroom Lentinus edodes (Agaricomycetes) Cultivation. AB - In this study, a high yield of crude polysaccharide (16.73 +/- 0.756%) was extracted from the spent mushroom substrate of Lentinus edodes using a hot alkali extraction method. Two groups of polysaccharides (designated as LSMS-1 and LSMS 2) were obtained from the crude extract by size exclusion chromatography (SEC), and their molecular characteristics were examined by a multiangle laser-light scattering (MALLS) and refractive index detector system. The weight-average molar masses of LSMS-1 and LSMS-2 were determined to be 6.842 * 106 and 2.154 * 106 g/mol, respectively. The SEC/MALLS analysis revealed that the molecular shapes of LSMS-1 and LSMS-2 were sphere-like forms in aqueous solution. Carbohydrate composition analysis using chromatography--mass spectrometry revealed that they were both acid heteropolysaccharides. LSMS-1 comprised mainly glucose and galacturonic acid, whereas LSMS-2 mainly consisted of xylose and glucuronic acid. Fourier transform infrared spectral analysis of the purified fractions revealed typical characteristic polysaccharide groups. In addition, MTT assays with refined polysaccharide doses of 25, 50, 100, 200, and 400 ug/mL suggested that both of the polysaccharide fractions exhibited antiproliferative activity against 6 tested human tumor cell lines in a concentration-dependent manner, and LSMS-2 had better anticancer capacity in vitro than LSMS-1. The inhibition ratio of LSMS 2 against A549 human lung cancer cells, the SGC7901 gastric cancer cell line, MCF 7 breast cancer cells, the U937 histiocytic lymphoma cell line, and the MG-63 human osteosarcoma cell line reached 43.55%, 29.97%, 19.63%, 18.24%, and 17.93%, respectively, at a concentration of 400 ug/mL. PMID- 28845770 TI - Tiger's Milk Medicinal Mushroom, Lignosus rhinocerotis (Agaricomycetes) Sclerotium Inhibits Nitric Oxide Production in LPS-Stimulated BV2 Microglia. AB - In Malaysia and China, the sclerotium of Lignosus rhinocerotis is used by local communities and traditional medicine practitioners as a general tonic and remedy to treat a variety of ailments, including inflammation-associated disorders. In this study, 10 samples from different preparations of L. rhinocerotis sclerotium, including a hot aqueous extract (HAE), an ethanol extract (EE), fractions from the HAE and EE, and crude polysaccharides, were tested for their in vitro cytotoxic and nitric oxide (NO) inhibitory activities in lipopolysaccharide (LPS) -stimulated BV2 microglia. Of the 10 samples tested, HAE was the least cytotoxic toward BV2 microglia, with a half-maximal inhibitory concentration of 176.23 +/- 2.64 mg/mL at 24 hours of incubation and 20.01 +/- 1.69 mg/ mL at 48 hours of incubation. The inhibition of NO production was explored by pretreatment of BV2 microglia with samples at 2 incubation time points (4 and 24 hours) before the stimulation by LPS for 24 hours. After 24 hours of pretreatment, 8 of the 10 samples inhibited NO production by 50% or more, and cytotoxic effects were not observed. Among the 8 active samples, 500 ug/mL of HAE, 250 ug/mL of an n-butanol fraction of the HAE, and 250 ug/mL of an ethyl acetate fraction of HAE showed maximum inhibition of NO production by 88.95%, 86.50%, and 85.93%, respectively. These results suggest that the L. rhinocerotis sclerotium may contain secondary metabolites that have the potential to inhibit NO production. PMID- 28845771 TI - Efficient Accumulation and In Vitro Antitumor Activities of Triterpene Acids from Submerged Batch--Cultured Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes). AB - Triterpene acids are among the major bioactive constituents of lucidum. However, submerged fermentation techniques for isolating triterpene acids from G. lucidum have not been optimized for commercial use, and the antitumor activity of the mycelial triterpene acids needs to be further proven. The aim of this work was to optimize the conditions for G. lucidum culture with respect to triterpene acid production, scaling up the process, and examining the in vitro antitumor activity of mycelial triterpene acids. The key conditions (i.e., initial pH, fermentation temperature, and rotation speed) were optimized using response surface methodology, and the in vitro antitumor activity was evaluated using the MTT method. The optimum key fermentation conditions for triterpene acid production were pH 6.0; rotation speed, 161.9 rpm; and temperature, 30.1 degrees C, resulting in a triterpene acid yield of 291.0 mg/L in the validation experiment in a 5-L stirred bioreactor; this yield represented a 70.8% increase in titer compared with the nonoptimized conditions. Furthermore, the optimized conditions were then successfully scaled up to a production scale of 200 L, and a triterpene productivity of 47.9 mg/L/day was achieved, which is, to our knowledge, the highest reported in the large-scale fermentation of G. lucidum. In addition, the mycelial triterpene acids were found to be cytotoxic to the SMMC-7721 and SW620 cell lines in vitro. Chemical analysis showed that the key active triterpene acid compounds, ganoderic acids T and Me, predominated in the extract, at 69.2 and 41.6 mg/g, respectively. Thus, this work develops a simple and feasible batch fermentation technique for the large-scale production of antitumor triterpene acids from G. lucidum. PMID- 28845772 TI - Volatile Composition of Some Cultivated and Wild Culinary-Medicinal Mushrooms from Hungary. AB - The volatile constituents of the fruiting bodies of 4 culinary-medicinal mushroom species (Agaricus bisporus, Boletus edulis, Cantharellus cibarius, and Hericium erinaceus) from Hungary were examined to review their aroma composition. Simultaneous distillation/extraction was applied to extract volatile compounds from fungi, and the values were measured with gas chromatography--mass spectrometry. Although the fragrances of fungi are not as characteristic as those of spices, several groups of volatile compounds have been found in mushrooms. The number of identified components ranged between 61 and 100, with a high ratio of 8 carbon volatiles generally occurring in fungi. Beyond common properties, individual attributes have been identified as well: an outstanding ratio of benzene compounds in champignons, numerous N-containing volatiles in boletes, carotenoid degradation products in chanterelles, and esters and fatty acids with a high carbon number in the lion's mane mushroom. The identification of these characteristic fragrance constituents can be very important in differentiating between species and confirming their presence in mushroom products. PMID- 28845773 TI - Colony Characteristics, Nucleoside Analog Profiles, and Genetic Variations of Medicinal Fungus Polycephalomyces nipponicus (Ascomycetes) Isolates from Northeast Thailand. AB - The entomopathogenic fungus Polycephalomyces nipponicus is known to have activity against human pathogenic bacteria and the malaria pathogen; however, information about its genetic variation is limited. In this study, cicada nymphs infected with entomopathogenic fungi were collected from various locations in the northeast of Thailand. Internal transcribed spacer sequencing was used to identify the fungal pathogen P. nipponicus. A total of 36 isolates of P. nipponicus from 6 provinces were investigated for variations in fungal morphology, nucleoside analog content, and genetics. The results showed that colony morphology varied depending on the strain of the tested fungi, without influence from its geographic origin. A similar finding was observed with regard to the production of nucleoside analog content. Interestingly, the important bioactive compound adenosine was detected in the mycelial extract of all 36 isolates. This indicates that P. nipponicus could possibly be used as a source of potential therapeutic bioactive compounds. In addition, random amplified polymorphic DNA analysis, as supported by the Nei Index and Shannon Index values, showed high genetic variation within and between the populations. These findings represent what is, to our knowledge, the first information on the colony morphology, adenosine analog profile, and genetic variation of P. nipponicus. PMID- 28845774 TI - A Validated Reverse-Phase HPLC Method for Quantitative Determination of Ganoderic Acids A and B in Cultivated Strains of Ganoderma spp. (Agaricomycetes) Indigenous to India. AB - Twenty isolates of Ganoderma spp. indigenous to India were used in this study. A reverse-phase high-performance liquid chromatography (HPLC) method was used to quantify 2 of the most bioactive triterpenes, ganoderic acid A (GAA) and ganoderic acid B (GAB), among the cultivated Ganoderma spp. The HPLC analysis was performed on an Agilent 1260 Infinity HPLC system with a Zorbax C18 column, using gradient elution of acetonitrile and 0.1% acetic acid. The detection wavelength was set at 254 nm, with a flow rate of 0.6 mL/min. The method was validated according to the guidelines of International Conference on Harmonisation and produced satisfactory results. The amount of GAA varied from 827.50 to 2010.36 ug/g, whereas GAB varied from 16.64 to 916.89 ug/g. The developed method is simple, specific, accurate, and precise, and can be useful for qualitative and quantitative evaluation of ganoderic acids. PMID- 28845775 TI - Preserving and Maintaining Culinary-Medicinal Royal Sun Mushroom, Agaricus brasiliensis (Agaricomycetes), in Sterile Distilled Water. AB - Strains of Agaricus brasiliensis require special procedures for conservation. Thus, the objective of this research was to establish conservation and maintenance procedures A. brasiliensis strain PSWC838 from the University of Pennsylvania (ABWC838) and an A. brasiliensis strain from the Fujian Agriculture and Forestry University (ABC). The medium in which mycelia grew the quickest for both strains was selected using a multifactorial design with 2 strains, 4 culture media, and incubation for 5 different times; the growth rate (mm/day) was the response variable. Analysis of variance showed that the potato dextrose agar (PDA) medium and potato extract did not display a significantly different growth rate, and PDA was selected for safety reasons. We also evaluated the viability of the strains grown on PDA and 0.2% activated carbon after 3 months of storage in sterile distilled water. A factorial design was applied with 2 factors, the strain and incubation for 10 different times. The Tukey post hoc test indicated that ABC showed quicker and more homogeneous growth than ABWC838. Finally, the results showed that pieces of mycelium of ABC and ABWC838 strains inoculated on the PDA medium with 0.2% activated carbon and preserved in sterile distilled water at 18 +/- 1 degrees C showed 100% viability after 3 months of storage. Moreover, the results of semiquantitative biochemical tests confirmed that the production of laccases and amylases was preserved in these strains after storage in sterile water, enhancing their ability to degrade substrates containing lignin and starchy waste. PMID- 28845777 TI - Department of error. PMID- 28845776 TI - Self-Heating Pasteurization of Substrates for Culinary-Medicinal Mushrooms Cultivation in Mexico. AB - The aim of this study was to evaluate a self-heating pasteurization technique in preparing substrates for mushroom production. Seven species were used: Agrocybe aegerita, Auricularia fuscosuccinea, Pleurotus djamor, P. eryngii, P. ostreatus, Lentinula edodes, and Ganoderma lucidum. They were cultivated on grass, corncob, wood shavings, and a mixture thereof. The self-heating technique allowed for pasteurization of 3 of the substrates (grass, corncob, and the mixture). The preheating chamber comprised a drawer placed under the pasteurization crate. With this chamber, it was possible to increase inlet air temperatures by 4--5 degrees C. The evaluated mushroom species responded in different ways to the pasteurization process. P. ostreatus (control) and P. djamor produced basidiomes when cultivated in all pasteurization substrates. A. aegerita and P. eryngii fruited only on corncob and the mixture, whereas A. fuscosuccinea fruited only on the pasteurized corncob. G. lucidum and L. edodes did not fructify on the pasteurized substrates. PMID- 28845778 TI - Department of Error. PMID- 28845780 TI - April 26-May 2, 2014. PMID- 28845779 TI - Department of Error. PMID- 28845781 TI - Corrections. PMID- 28845782 TI - Corrections. PMID- 28845783 TI - Corrections. PMID- 28845784 TI - Patrick Freund. PMID- 28845786 TI - Campylobacter jejuni vertebral osteomyelitis. PMID- 28845787 TI - A proper place for retraction. PMID- 28845788 TI - Dengue and stillbirth. PMID- 28845789 TI - International Surviving Sepsis Campaign guidelines 2016: the perspective from low income and middle-income countries. PMID- 28845790 TI - Successful cure of extensively drug-resistant pulmonary tuberculosis in a young child. PMID- 28845791 TI - Multidrug-resistant tuberculosis: pharmacokinetic and pharmacodynamic science. PMID- 28845792 TI - Combination therapy for carbapenemase-producing Entero-bacteriaceae: INCREMENT-al effect on resistance remains unclear. PMID- 28845793 TI - Divergent policy responses to increasing vaccine scepticism in southern Europe. PMID- 28845794 TI - Changing trends of neglected tropical diseases in China. PMID- 28845795 TI - Highlights from the 9th International AIDS Society meeting. PMID- 28845796 TI - No jab, no play: Australia and compulsory vaccination. PMID- 28845797 TI - Essential medicines for hepatitis C: at what price? PMID- 28845801 TI - Corrections. PMID- 28845802 TI - Corrections. PMID- 28845800 TI - Symptomatic dengue infection during pregnancy and the risk of stillbirth in Brazil, 2006-12: a matched case-control study. AB - BACKGROUND: Maternal infections during pregnancy can increase the risk of fetal death. Dengue infection is common, but little is known about its role in fetal mortality. We aimed to investigate the association between symptomatic dengue infection during pregnancy and fetal death. METHODS: We did a nested case-control study using obstetrician-collected data from the Brazilian livebirth information system (SINASC), the mortality information system (SIM), and the national reportable disease information system (SINAN). We identified all pregnancies ending in stillbirth and a random sample of livebirths between Jan 1, 2006, and Dec 31, 2012. We did linkage to determine which mothers were diagnosed with dengue infection during pregnancy. By use of stillbirths as cases and a sample of matched livebirths as a control, we calculated matched odds ratios (mORs) using conditional logistic regression adjusted for maternal age and education. FINDINGS: 275 (0.2%) of 162 188 women who had stillbirths and 1507 (0.1%) of 1 586 105 women who had livebirths were diagnosed with dengue infection during pregnancy. Symptomatic dengue infection during pregnancy almost doubled the odds of fetal death (mOR 1.9, 95% CI 1.6-2.2). The increase in risk was similar when analyses were restricted to laboratory-confirmed cases of dengue infection (1.8, 1.4-2.4). Severe dengue infection increased the risk of fetal death by about five times (4.9, 2.3-10.2). INTERPRETATION: Symptomatic dengue infection during pregnancy is associated with an increased risk of fetal death. We recommend further epidemiological and biological studies of the association between dengue and poor birth outcomes to measure the burden of subclinical infections and elucidate pathological mechanisms. FUNDING: Brazilian National Council for Scientific and Technological Development, Horizon 2020. PMID- 28845805 TI - Department of Error. PMID- 28845806 TI - Department of Error. PMID- 28845807 TI - Department of Error. PMID- 28845809 TI - Department of Error. PMID- 28845808 TI - Department of Error. PMID- 28845810 TI - Department of Error. PMID- 28845811 TI - August 3-9, 2013. PMID- 28845812 TI - Corrections. PMID- 28845813 TI - Corrections. PMID- 28845814 TI - Corrections. PMID- 28845815 TI - Dimethyl fumarate for relapsing-remitting multiple sclerosis. PMID- 28845816 TI - Sam Nightingale. PMID- 28845818 TI - Corrections. PMID- 28845819 TI - Corrections. PMID- 28845820 TI - Corrections. PMID- 28845821 TI - Corrections. PMID- 28845822 TI - The 2014 Longitude Prize. PMID- 28845825 TI - Editorial. AB - None. PMID- 28845826 TI - Diagnostic Imaging and workup of Malignant Pleural Mesothelioma. AB - Malignant pleural mesothelioma is the most frequent primary neoplasm of the pleura and its incidence is still increasing.This tumor has a strong association with exposure to occupational or environmental asbestos, often after a long latent period of 30-40 years.Plain chest radiography (CXR) is usually the first line radiologic examination, but the radiographic findings are nonspecific due to its limited contrast resolution and they need to be complemented by other imaging modalities such as computed tomography (CT), magnetic resonance Imaging (MRI), Positron emission tomography-computed tomography (PET-CT) and ultrasound (US).The aim of this paper is to describe the imaging features of this malignancy, underlining the peculiarity of CXR, CT, MRI, PET-CT and US and also focusing on diagnostic workup, based on the literature evidence and according to our experience. PMID- 28845827 TI - Non-conventional practice versus evidence-based medicine. A scientific and ethical analysis of the Italian regulation. AB - BACKGROUND: The current lack of scientific validation of non-conventional treatments in medicine, whose epistemological foundations lie in scientific evidence and experimentation, raises significant questions regarding the costs and benefits of alternative-treatment forms. Nonetheless, in the last few decades non-conventional treatments have been increasingly recognised by the Italian medical profession, with one regional healthcare administration adopting some non conventional practices as part of its conventional healthcare services. AIMS: The Authors aim to analyse non-conventional treatments in medicine from an epistemological, cultural, ethical, political and economic point of view, in order to highlight criticalities and incongruities, especially when these treatments are approved by a public healthcare system, which should be grounded on the "evidence-based medicine" principle. CONCLUSIONS: Non-conventional treatments in medicine are constituted by meta-theories, i.e. philosophical, religious and ideological concepts that conflict with contemporary rational, empirical medicine. In the interest of patients and society, the paper stresses the incongruity of a healthcare system which, despite being grounded on the "evidence-based medicine" principle, allows the development of non conventional treatments. Having said that, medical science should address not only the biological domain of illness but also its existential implications. Awareness and respect for the individual experience can undoubtedly lead to a new medical model that allows for a more effective therapeutic intervention. PMID- 28845828 TI - Spontaneous Dissemination in Neighboring Provinces of DKA Prevention Campaign Successfully Launched in Nineties in Parma's Province. AB - AIM: to investigate how much effectiveness of the historical campaign of DKA prevention at T1D diagnosis has survived in Parma's province where this was launched in Nineties, and how much it has spontaneously spread in the neighboring provinces. METHOD: children aged 6-14 years with newly diagnosed TID coming from province of Parma (Group 1) and from two other nearby provinces (Group 2) were investigated. Clinical and laboratory data were retrospectively collected from medical files of each patient and included age, gender, capillary pH, serum bicarbonate, 3-beta-hydroxybutyrate (3HB), glycated hemoglobin (HbA1c) at the time of admittance from 1st January 2012 and 31 December 2016. RESULTS: no DKA condition was globally found in 25/36 patients (69.4%): 16/17 and 9/19 patients belonged to Group 1 and 2 respectively (p=0.002). Mild or moderate DKA was reported in 5.9% patients of Group 1 and in 47.31% (p=0.005) patients from Group 2. Severe DKA was observed in only 1 child from Group 2. Normal 3-beta hydroxybutyrate (3HB) serum levels was reported in the 25 patients without DKA at diabetes diagnosis. Duration of hyperglycemia-related symptoms before overt T1D diagnosis was shorter (4.6+/-2.5 days) in patients with 3HB levels <1 mmol/dl than in those with 3HB levels exceeding 1 mmol/dl (9.6+/-4.2 days, p< 0.0001). HbA1c values were on overage lower in patients without DKA (9.9+/-1.2%) than in patients with DKA at diabetes diagnosis (13.60+/-1.3%; p< 0,001). CONCLUSION: 1) the campaign for DKA prevention, launched in Nineties and renewed at beginning of Twenties in Parma's province, continues to be effective in the same province after several years; 2) in the two control provinces despite no information campaign being officially promoted in loco, an unexpected decrease in severe DKA incidence as well a shorter latency before overt T1D diagnosis were observed in the same period. PMID- 28845829 TI - Reduction mammoplasty techniques in post-bariatric patients: our experience. AB - BACKGROUND AND AIM OF THE WORK: Excessive body weight represents a huge problem affecting a wide part of world population, causing significant physical and psychological consequences. To solve their obesity-related problems, patients should begin a bariatric treatment to lose an adequate percentage of their body mass and therefore, they should be subjected to body contouring surgery. In this article we describe our experience in applying breast remodeling techniques to post-bariatric patients. METHODS: We did a retrospective study on our post bariatric patients subjected to breast reduction and/or mastopexy during a five years period, considering breast features, kind of surgery performed, aesthetic and psychological outcomes and postoperative complications. RESULTS: Thirty-six post-bariatric patients underwent breast surgery in our unit between 2010 and 2015; their average age was 43 years. The follow up period ranged from 6 months to 4 years and an half. The most frequent surgical techniques performed were Thorek and inferior pedicle breast reduction. The prevalent complications observed were surgical wound delayed healing and nipple-areolar complex (NAC) partial or complete necrosis as immediate ones and unfavorable scarring as delayed ones. CONCLUSIONS: Breast reshaping after a massive loss of weight should be forerun by an accurate analysis of breast volume, shape and ptosis degree, in order to obtain optimal results both for the surgeon and the patient. PMID- 28845830 TI - The home management of Artificial Nutrition: a survey among doctors and nurses. AB - BACKGROUND AND AIM OF THE WORK: The management of Artificial Nutrition (NA), especially in the home environment (HAN) requires specific skills in order to ensure the correct therapeutic education, prevention of complications and the provision of appropriate treatment to the person. The aim of this survey was to identify the perceptions of nurses and doctors, as well as comparing to their perceived competence in NA and the gap between their perceived versus actual knowledge and management methods. METHODS: This observational study was conducted in a Tuscan health region of Italy, involving 50 Home Care Services nurses and 50 general practitioners. Participants were asked to complete an online questionnaire that was constructed for purpose. RESULTS: The results show that for the management of the person with NA, both for doctors and for nurses show great variability in responses. Less than half of those providing care make assessments of nutritional status and dysphagia as well as the possibility of re feeding by natural means in NA patients. Care providers expressed uncertainty as to which professional should carry out such assessments. A mismatch was also evident between the skills possessed and the self-assessments performed regarding their knowledge base of NA. Almost all of doctors of nurses indicated a desire to participate in training events relating to NA. CONCLUSIONS: The results highlight the need for caregivers to have specific operating protocols. The results also highlight the need to aim to work as a team, emphasizing the importance of basic communication as well as the need for clarity as to the responsibilities and roles of the professionals involved.Key words: Artificial Nutrition, Nurses, Doctors, home management, skills, training, team. PMID- 28845831 TI - Early rehabilitative treatment after infrainguinal lower limb bypass surgery. AB - BACKGROUND AND AIM OF THE WORK: Functional activity may remain limited in patients affected by critical limb ischemia, despite successful infrainguinal lower limb bypass surgery (ILLBS). The aim of the work was to evaluate the impact of a rehabilitative intervention on postoperative ambulatory status and pain. METHODS: In an observational study, data were collected on 34 patients undergoing ILLBS for critical limb ischemia or end-stage peripheral arterial disease. All patients underwent a postoperative rehabilitation program aimed at recovering gait autonomy. Information was collected on pre-operative comorbidities, ambulatory status (on admission to and discharge from hospital) and pain in the affected lower limb (on the first physiotherapy session and at discharge). RESULTS: Before ILLBS, 61.8% of the patients walked independently without aids or assistance. The rehabilitative program started on average 5.7 (SD: 2.1) days after surgery. At discharge, 50% of the patients walked independently, 41.2% walked with aids and/or assistance and 8.8% were not able to walk. Overall, 76.5% of the sample recovered their pre-operative ambulatory status. Although pain tended to decrease, the difference at the first (1.5; SD: 2.6) and at the last treatment session (0.8; SD= 1.3) was not statistically significant. CONCLUSION: Our exercise protocol resulted to be easy to perform during hospital stay, with an overall favourable outcome for ambulatory status. Our results are in line with those reported in literature about the rates of postoperative dependence in walking, but appear to be slightly better in regards to the percentage of patients who recovered pre-operative ambulatory status. PMID- 28845832 TI - Performance and antrhropometric characteristics of Elite Rugby Players. AB - BACKGROUND AND AIM OF THE STUDY: Physical performance is the result of a complex combination of several factors such as genetic and anthropometric aspects, nutrition and hormonal status. In the past few years many studies have considered the impact of vitamin D on muscular strength and athletic performance.The aim of the present study was to assess the anthropometric measures impacting on physical performance in a group of professional rugby athletes. As a secondary aim we investigated a possible relationship between baseline vitamin D status and athletic performance status in these subjects. METHODS: All rugby players completed a test-retest reliability study on performance measures, as 70kg jump squat and body weight (BW) jump squat to assess musculoskeletal performance. Additionally at the time point we collected a blood sample of every athletes for the assessment of serum vitamin D. RESULTS: We found that lean mass was an important independent predictor of performance score in 70kg jump squat (p=0.007, R2=0.74) and BW jump squat (p=0.010, R2=0.66) in these well trained athletes. No statistically significant association was present between performance score and serum vitamin D in this specific setting. CONCLUSIONS: We demonstrate a positive interaction between lower limb lean mass and performance score, but we have not been able to identify any statistically significant association between worsening in performance measures and decrease of serum 25 OH Vitamin D. PMID- 28845833 TI - Early-stage radiological critical analysis of unsuccessful cases following a four part fracture osteosynthesis of the proximal humerus: focus on the "P" sign. AB - Radiological evaluation of complex intra-articular fractures of the proximal humerus is still challenging. Here, we describe the post-operative "P" sign as a reproducible radiographical mark of a varus reduction, performed by assembling a head-shaft angulation of less than 130 degrees. Our retrospective study was conducted in a group of subjects who previously suffered from proximal humerus four-part fractures. We evaluated the post-operative evolution of specific radiographical parameters that are of crucial prognostic significance: Cervix diaphysis angle (HHSA), quality level of the orthopaedic reduction (insufficient, sufficient and good) based on a radiological generalized subjective overview, presence of calcar screws through the Philos plate. The final cohort included a group of 39 patients of 70.76 +/- 8.3 years of age and an average follow-up of 7.2 months. The post-operative mean HHSA was 131.5 +/- 9.4. Interestingly, a positive correlation was detected between presence of the radiographical "P" sign in the post-operative period and the number of surgical complications coming up in the post-operative period (OR: 3.68 - I.C. 95%: 0.7984255-19.2532430), although not statistically significant. In our study, the high number of complications corresponds to literature database. Presence of the "P" sign could be a useful tool for assessing the quality of reduction during intra and post operative radiological evaluation. We underline the importance of the "P" sign as a "quality of reduction" factor and strongly recommend its intra-operative monitoring as an additional tool together with a standard subjective evaluation of the reduction. PMID- 28845834 TI - Clinical stabilisation with lacosamide of mood disorder comorbid with PTSD and fronto-temporal epilepsy. AB - BACKGROUND AND AIM OF THE WORK: Mood disorders are often complicated by comorbidity with epilepsy. Anxiety and personality disorders may worsen prognosis and treatment outcome. Lacosamide has been recently introduced as adjunctive treatment for partial epilepsy. Its mechanism consists of selective slow inactivation of voltage-gated sodium channels, thus promoting an extended stabilisation of cell membranes. Antiepileptic drugs have been largely used since the 1950s in psychiatry as mood stabilisers due to their membrane stabilising and anti-kindling effects. Like lithium, antiepileptic drugs are first choice treatment for Bipolar and Cyclothymic Disorders. METHODS: We tested the efficacy of the most recent antiepileptic medication, lacosamide, in a patient with simultaneously occurring cyclothymic disorder, severe post-traumatic stress disorder, and fronto-temporal epilepsy. Lacosamide was titrated up to 200 mg/day, added on ongoing 750 mg/day lithium, 15 mg/day oral aripiprazole then switched to 400 mg/month long-acting aripiprazole, and 2 mg/day N-desmethyldiazepam. RESULTS: We observed EEG normalisation one month later, along with reduced anxiety and an additive effect to lithium-induced stabilisation of mood fluctuations since the second week of lacosamide addition. CONCLUSIONS: Further studies with this drug in the bipolar spectrum are warranted. PMID- 28845835 TI - Continuous dopaminergic stimulation in a patient treated with daytime Levodopa carbidopa intestinal gel and overnight Rotigotine: a case report. AB - Patients with Parkinson's disease (PD) receiving long-term L-Dopa therapy eventually develop motor complications with unpredictable "on-off" response fluctuations and involuntary movements, leading to progressive disability. Hence, the search for alternative therapeutic choices based on continuous dopaminergic stimulation (CDS) becomes crucial for the treatment of advanced PD. Here, we describe the case of a 70-year-old man with a 9-year history of PD, treated with daytime levodopa-carbidopa intestinal gel (LCIG) and overnight Rotigotine transdermal patch. LCIG monotherapy significantly reduced motor fluctuations and prevented the appearance of unpredictable off periods; concurrently, overnight Rotigotine improved his sleep quality and morning akinesia. Both LCIG and Rotigotine induce CDS, which conceptually mimics physiologic striatal dopamine receptor function. Hence, they both represent a good therapeutic option for the treatment of advanced PD. PMID- 28845836 TI - My best choice after a round trip from illness. AB - This article reports the experience of a 24-years-old Medical Student who was diagnosed a "Hodgkin Lymphoma" during her last year at the University Medical School of Parma (Italy) and her difficult choice to try to become an Oncologist. PMID- 28845837 TI - Mazabraud syndrome associated with McCune-Albright syndrome: a case report and review of the literature. AB - Mazabraud syndrome is a very rare benign disorder characterized by the association of monostotic or polyostotic fibrous dysplasia and one or multiple intramuscular myxomas. McCune -Albright syndrome is a rare benign disorder characterized by the association of polyostotic fibrous dysplasia, cafe-au-lait skin pigmentations and endocrine dysfunction, such as precocious puberty, diabetes mellitus, goiter and breast fibroadenomatosis. The association of Mazabraud syndrome and McCune-Albright in the same patient is an anecdotal event. We report the case of a 28-year-old girl with Mazabraud syndrome associated with McCune-Albright syndrome. Our literature review shows that in these patients there is a higher risk of malignant transformation of fibrous dysplasia into osteosarcoma, confirming previous reports. Conversely, no malignant transformation has been reported for myxomas in isolated Mazabraud syndrome or in the association with McCune-Albright syndrome. We conclude that these patients should be scheduled to a close and long-term follow-up. PMID- 28845838 TI - From informed consent to informed dissent in health care: historical evolution in the twentieth century. AB - Not available. PMID- 28845839 TI - Management of Adolescent Gynecomastia: An Update. AB - Gynecomastia refers to an enlargement of the male breast caused by benign proliferation of the glands ducts and stromal components including fat. It is the most common form of breast swelling seen in adolescent males. During pubertal development, gynecomastia can develop as a result of transient relative imbalances between androgens and estrogens. Pubertal gynecomastia is self-limited in 75 to 90% of adolescents and regresses over 1 to 3 years. However it may cause significant psychological stress and depression in adolescents. For boys with persistent gynecomastia that is causing substantial tenderness or embarrassment a tailored approach of close follow-up and use of anti-estrogen drugs may be recommended. These drugs block the effects of estrogens in the body and can reduce the size of the breasts somewhat. It appears that pharmacological therapy of persistent adolescent gynecomastia is reasonable effective if given early in the course of the disease and more successful in cases with small or moderate breast enlargement. However, neither of these drugs is universally approved for the treatment of gynecomastia because the risks and benefits have not been studied completely. Surgical approach may be needed under special conditions for cosmetic reasons. In this update, we review the different published trials for managing adolescent gynecomastia. PMID- 28845840 TI - A clinical approach to benign breast lesions in female adolescents. AB - The female breast undergoes two phases of growth and differentiation. The first occurs during fetal life and results in the formation of simple branched ducts, which are able to respond to the hormonal stimuli of maternal origin. The second period of growth occurs at puberty, when the ducts elongate, divide, and form terminal duct lobular units. Breast pathology during adolescence is usually benign and therefore management has to be mostly conservative. Familiarity with the spectrum of breast pathology in this age group is essential. Ultrasound is the imaging modality of choice. Open surgical biopsies can damage the developing breast and therefore availability and expertise with fine needle aspiration biopsy can circumvent this problem. PMID- 28845841 TI - Caffeinated energy drink consumption among adolescents and potential health consequences associated with their use: a significant public health hazard. AB - : Caffeinated energy drinks (EDs) are increasingly popular among adolescents despite growing evidence of their negative health effects. The consumption of EDs has seen a substantial increase during the past few decades, especially in the Western and Asian countries. EDs contain high levels of caffeine, sugar, and novel ingredients, and are often marketed through youth-oriented media and venues. The known and unknown pharmacology of the constituents of EDs poses a risk of caffeine toxicity and other ill effects when consumed by young people. Caffeine intoxication may result in tachycardia, vomiting, cardiac arrhythmias, seizures, and even death. Other health concerns related to consumption of EDs include obesity and dental enamel erosion resulting from the acidity of EDs. Coingestion of caffeine and ethanol has been associated with increased risk taking behaviors in adolescent users, impaired driving, and increased use of other illicit substances. Several researchers have demonstrated that consuming alcohol mixed with energy drinks leads to altered subjective states including decreased perceived intoxication, enhanced stimulation, and increased desire to drink/increased drinking compared to consuming alcohol alone. Caffeine's effect on intoxication may be most pronounced when mixers are artificially sweetened, that is, lack sucrose which slows the rate of gastric emptying of alcohol. IN CONCLUSION: 1) health care providers should educate youth and their parents about the risks of caffeinated drinks; 2) emergency department clinicians should consider asking patients about ED and traditional caffeine usage and substance use when assessing patient symptoms; 3) policy makers should increase their attention on introducing regulatory policies on television food advertising to which youth are exposed; 4) failure to comply with standards for efficacious product labelling, and absence of broader education regarding guidelines, need to be addressed and 5) further studies must be done to improve our understanding of potential negative consequences of caffeinated energy drinks on health. PMID- 28845842 TI - An adolescent with an asymptomatic adnexal cyst: To worry or not to worry? Medical versus surgical management options. AB - Paraovarian cysts or paratubal cysts (PTCs) arise from either the mesothelium or from paramesonephric remnants. These present as either adnexal mass or as an incidental finding. Diagnosis is usually established on ultrasound and it is important to differentiate these from ovarian cysts. Typically PCTs appear as simple cysts by ultrasound and are indistinguishable from ovarian cysts if one does not recognize the extraovarian location. Occasionally, PTCs have internal echoes due to hemorrhage. PTCs are usually asymptomatic and benign. The differential diagnosis includes a simple ovarian cyst, peritoneal inclusion cyst and hydrosalpinx. Malignant changes have been reported in about 2% to 3%, and it should be suspected if papillary projections are present. PTCs management depend upon the presence and severity of the symptoms, the cyst size and US characteristics, CA 125 results, age of the patient and the risk of malignancy. Simple PTCs can be expected to regress and may be managed expectantly. When surgery is indicated, a joint multidisciplinary management by the paediatric surgeons and trained paediatric gynaecologists should be the gold standard. PMID- 28845843 TI - Spinal cord compression secondary to extramedullary hematopoiesis: A rareness in a young adult with thalassemia major. AB - We report a case of a thalassemia major male patient with back pain associated to severe weakness in lower extremities resulting in the ability to ambulate only with assistance. An urgent magnetic resonance imaging (MRI) of thoracic and lumbosacral spine was requested. A posterior intraspinal extradural mass lesion compressing the spinal cord at the level of thoracic T5-8 was present, suggesting an extramedullary hematopoietic centre, compressing the spinal cord. He was treated successfully with thalassemia major alone. The patient was treated with blood transfusion, dexamethasone, morphine and paracetamol, followed by radiotherapy in 10 fractions to the spine (daily fraction of 2Gy from T3 to T9, total dose 20 Gy). His pain and neurologic examination quickly improved. A new MRI of the spine, one week after radiotherapy, showed an improvement of the extramedullary hematopoietic mass compression. In conclusion, EMH should be considered in every patient with ineffective erythropoiesis and spinal cord symptoms. MRI is the most effective method of demonstrating EMH. The rapid recognition and treatment can dramatically alleviate symptoms. There is still considerable controversy regarding indications, benefits, and risks of each of modality of treatment due to the infrequency of this disorder. PMID- 28845751 TI - Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. AB - BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1beta, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1beta innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .). PMID- 28845844 TI - Clinical audit in retina 2016: Chairman's introduction. PMID- 28845847 TI - Meeting Abstracts. PMID- 28845846 TI - Meeting Report. PMID- 28845845 TI - Lucentis(r) (ranibizumab) ABBREVIATED UK PRESCRIBING INFORMATION. PMID- 28845851 TI - [The health of foreign workers: an Italian and international priority.] AB - About 5 million migrants are resident in Italy. Migrant workers are mainly employed in manual, unqualified jobs that Italians tend not to perform anymore. Compared to Italians, they tend to be more hired by precarious contracts. Migrants present a higher risk of work injuries and occupational illnesses than natives. This excess risk is linked to the concentration of migrants in the most dangerous jobs, greater risk tolerance, language and cultural barriers that reduce the effectiveness of any training actions. With the economic crisis, there has been a further worsening of the conditions of workers. Despite the decline in work injury rates, which follow the trend of the economic cycle, the distance between Italians and migrants has remained largely unaltered. The worst health conditions of migrants are not related to individual intrinsic factors, but to the way the economy exploits the social weakness of the migrant to gain profits. Better surveillance data is needed to improve the description and understanding the mechanisms by which migrants are systematically in worse health and safety conditions and to provide direction to effective public health interventions. PMID- 28845852 TI - [Rare diseases in post-genomic era.] AB - The Human Genome Project and the "-omics" technologies will in future provide genetic maps and biosynthetic pathways permitting personalized medical interventions directed at maintaining or restoring wellbeing. This is reflected in the strategy aims of 4P medicine in being: predictive, preventive, personalized, and participatory. The results obtained in the field of cystic fibrosis, with the cloning of CFTR gene, and use of Kalydeco(r), have demonstrated how using the mentioned strategies could also have success in rare disease management. Kalydeco(r) is the emblematic example demonstrating the indispensable role of an active patient participation in fully achieving the P4 medicine goals. It is actually the patient involvement that will furnish the fundamental data necessary in defining molecular profiles specific to the health status of any patient. These molecular profiles will contribute in planning preventive, and/or therapeutic interventions aimed at maintaining, and/or restoring the health conditions. Hence, for a correct and effective implementation of P4 medicine, researchers and healthcare professionals should always consider the psychological experiences and characteristics of their patients and families; making them all participants in formulating an appropriate therapeutic path. In achieving this, it will not only be necessary to consider and use concepts of vulnerability and resilience, particularly in the rare disease field, where patient fragility is high, and caregivers are often faced with unique and difficult issues, never confronted before. PMID- 28845853 TI - [Resistant hypertension in the elderly.] AB - Actually, in literature there are no epidemiologic studies on the prevalence of resistant hypertension in the elderly; however the National Health and Nutrition Examination Survey observed in the adult population prevalence of 12.8% to clinical measurement. But, especially in elderly, it's necessary exclude pseudoresistance forms due to white coat hypertension, arterial stiffness, poor patient compliance to therapy, excessive salt intake, abuse of non-steroidal ant inflammatory drugs and the forms of secondary hypertension. Arterial hypertension, which is really resistant, it is a greater cardiovascular risk and thus the need to implement adherence to healthy lifestyle and therapy and to implement a pharmacological therapy to block the renin-angiotensin system or a dihydropyridine calcium channel, if they are not already present in the therapy and/or aldosterone antagonists. Currently experimental clinical therapeutic studies are examining such methods as renal denervation and the stimulation of the baroreflex. PMID- 28845854 TI - [A survey carried out among Italian physicians regarding non-required clinical examinations, treatments and procedures in the current clinical practice: results and considerations.] AB - A survey addressed to all Italian physicians regarding how they behave when a patient asks them to prescribe non-required clinical examinations, treatments and procedures has been carried out for the first time. The survey - realized during the last months of the year 2015 thanks to the collaboration between Slow Medicine and the National Federation of Associations of Doctors, Surgeons and Dentists - is based on a questionnaire given to the America physicians by the ABIM Foundation in 2014. The Italian survey results cannot be compared with the American ones because different approaches were used. 4,263 physicians started to fill in the questionnaire and 3,688 completed it. The results suggest that the physicians that answered the questions are highly aware of the over-usage of diagnostic tests and treatments, and among the main reasons they cite the need of safety and then the fear of legal consequences. Most of the physicians who answered the questions believe to be responsible for giving patients accurate information in order to avoid non-required practices, and that the physician is the right person with the most suitable role to face the problem. Among the most important and useful tools to reduce the prescription of non-required examinations and treatments, physicians indicate the possibility to have much more time available to discuss the different options with their patients, to arrange the evidence-based information material for the patients, and to explain the reform on the physician's responsibility (recently approved as law). Therefore, it stands out the opportunity to apply provisions aimed at providing the patients with more accurate information and at improving the relationship between the physician and the patient by ensuring on the one hand more availability of dedicated time and on the other hand the training of the physicians on scientific topics as well as on topics concerning communication and shared decisions. The communication can be strengthened by evidence-based information tools for patients and citizens to be used during the visits with the physician as well as in case of an institutional communication about the over usage of clinical examinations and treatments. PMID- 28845855 TI - [Role of combination NK/KIRs in the natural history of viral infections.] AB - Immunological mechanisms involved in the genesis of the immune response against viral infections take into account the activation of both innate adaptative response. Innate immune defenses trigger a rapid local response, which is often sufficient to control viral infection, and promotes the subsequent activation of specific immune defenses. Natural killer (NK) cells that constitute a subpopulation of lymphocyte-related cells are a key factor of innate immune response and play a role in defense against viral infections by killing infected cells or by producing cytokines and interacting with adaptative immune system's cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leukocyte antigens (HLA). KIRs and HLA loci are highly polymorphic and certain HLA-KIRs combinations have been found to protect against viral infections. In this study we review how the KIRs/HLA repertoire may influence the course of hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV) and Herpes Simplex Virus 1 (HSV-1) infection. Results of our study suggest that a combination of KIRs/HLA gene/alleles is able to predict the outcome of viral infection and allows to plan successful customized therapeutic strategies. PMID- 28845857 TI - [Fractional flow reserve: a practical guide for interventional cardiologists and the cardiologist's point of view]. AB - Fractional flow reserve (FFR) is considered the gold standard for functional assessment of coronary stenosis in stable coronary artery disease. The use of FFR enables an ischemia-guided revascularization with improvement of clinical outcomes in a cost-effective fashion. Both clinical and interventional cardiologists should be aware of the advantages and potential pitfalls of this technique. We focus on FFR with the aim to provide the clinical cardiologist with information on indications and technical aspects to confirm a correct execution of FFR in different coronary anatomical settings. PMID- 28845856 TI - [Web-based collection of educational needs in a medicine department. An intranet survey for planning CME corse.] AB - INTRODUCTION: Few evidences about methods to harvest educational needs by health care professionals in internal medicine have been published. In this project the following objectives have been pursued: to express preferences by each health care worker; to evaluate the efficacy of an intranet-based survey in order to structure continuing medical education (CME) planning. METHODS: We created a form based on 7 questions, exploring the following areas: knowledge, know-how, communication, transversal competencies. This survey, implemented on a google drive platform, was accessible through the Azienda Sanitaria Unica Regione (ASUR) Marche intranet. Each questionnaire was analyzed with Google drive and the results were discussed within Medicine Department Committee. RESULTS: 103/228 health care workers responded to the survey. On the basis of health care workers preferences, financial resources, relevance, untreated topics in the previous 5 years and congruence with ASUR targets, heart failure, malnutrition and non invasive mechanical ventilation were chosen as main topics for the year 2017 and practical training, internal courses and focus groups were planned. DISCUSSION AND CONCLUSIONS: A relevant percentage of health care workers (45%) responded to our online survey and the analysis of the results has been used for planning users-centered educational courses; this approach represents a sure novelty in failure of published experiences about the relationship between collection of needs and CME planning. PMID- 28845848 TI - Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure. AB - Cannabis use has become increasingly accepted socially and legally, for both recreational and medicinal purposes. Without reliable information about the effects of cannabis, people cannot make informed decisions regarding its use. Like alcohol and tobacco, cannabis can have serious adverse effects on health, and some people have difficulty discontinuing their use of the drug. Many cannabis users progress to using and becoming addicted to other drugs, but the reasons for this progression are unclear. The natural cannabinoid system of the brain is complex and involved in many functions, including brain development, reward, emotion, and cognition. Animal research provides an objective and controlled means of obtaining information about: (1) how cannabis affects the brain and behavior, (2) whether medications can be developed to treat cannabis use disorder, and (3) whether cannabis might produce lasting changes in the brain that increase the likelihood of becoming addicted to other drugs. This review explains the tactics used to address these issues, evaluates the progress that has been made, and offers some directions for future research. PMID- 28845858 TI - [Fractional flow reserve to establish the indication for and guide myocardial revascularization]. PMID- 28845859 TI - [The new frontiers of patent foramen ovale]. AB - Several evidences support the hypothesis that patent foramen ovale (PFO), especially when associated with specific anatomical features, relates to an increased incidence of paradoxical embolism including ischemic stroke. According to current guidelines, clinicians may offer percutaneous closure of PFO in rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified (American Academy of Neurology 2016) or deep venous thrombosis at high risk of recurrence (American Heart Association/American Stroke Association 2014).Recently, a device that allows percutaneous suturing of PFO with polypropylene stitches has been introduced. Preliminary data suggest that this new strategy is effective and safe because it could reduce the adverse events of the conventional approach. Moreover, it avoids to preclude any future percutaneous transeptal procedure. Larger and randomized controlled studies are warranted to validate the results obtained. PMID- 28845860 TI - [What future role for nurses and technicians working in a cath lab?] PMID- 28845861 TI - [Hybrid percutaneous coronary intervention with drug-eluting stent in combination with bioresorbable vascular scaffolds for complex coronary lesions]. AB - Drug-eluting stents (DES) have significantly improved the outcome of percutaneous coronary intervention (PCI); however, several concerns remain regarding late adverse events associated with the presence of a permanent rigid metallic cage that might impair the natural healing process of the coronary vessel wall. Recently, PCI with bioresorbable vascular scaffolds (BVS) has emerged as an interesting alternative with several potential advantages related to the complete resorption process that occurs within 3-5 years. As a consequence, it reduces the trigger for persistent inflammation, enables restoration of normal vessel reactivity and facilitates positive remodeling. However, current BVS have several limitations, including thicker and wider struts, less radial strength, and limited expansion. A hybrid strategy, combining the use of BVS and DES, is a novel approach that could be useful to avoid the limitations of currently available BVS, particularly in case of PCI for complex coronary lesions.We describe a case of hybrid percutaneous intervention with BVS in combination with DES for managing complex lesions unsuitable for pure scaffolding percutaneous coronary intervention. PMID- 28845863 TI - [Clinical interview in psychiatric difficult situations]. AB - There are here described a number of basic principles underlying an effective clinical interview in psychiatric difficult situations (violent or suicidal patients, victims of serious physical and psychological damages, authors of inadequate or anti-social requests to the therapist). The aim of the present study is to provide the psychiatric operator with useful skills for the optimal management of the interview in difficult situations both at diagnostically and therapeutically level. The methodology was based on examination of the literature and personal experience of the authors. The authors highlighted 18 working hypothesis that may represent beneficial instruments in situations of difficult psychiatric interview. Further studies will deepen under the clinical, actuarial and statistical validity the principles covered in various clinical and crisis situations with difficulty to the interview, in relation also to specific types of patients for a more updated training of the operators in the field of mental health. PMID- 28845862 TI - [The neural bases of social cognition in major depressive disorder: a review]. AB - INTRODUCTION: Major depressive disorder (MDD) is associated with a significant impairment of social and interpersonal functioning. Several neuroimaging studies have evaluated social cognition, i.e. how people with MDD process, store and analyze information about other people and social situations. METHODS: We conducted a focused review and selected manuscript published until August 2016 indexed on PubMed and PsycINFO, searching for the following keywords: "major depressive disorder", "major depression", "unipolar depression", "clinical depression", "fMRI", "emotion comprehension", "emotion perception", "affect comprehension", "affect perception", "facial expression", "prosody", "theory of mind", "mentalizing", "empathy". RESULTS: During depressive episodes, patients with MDD show a difference pattern of neural response during emotion processing, compared to healthy controls. Many studies show that those alterations disappear once the acute episodes remit. However, other studies show that the alterations may persist during remission periods. Limits. The studies evaluate only one component of social cognition and not all studies include a control group. CONCLUSIONS: Neurobiological research supports a role of social cognition deficits in MDD, especially for what pertains interpersonal functioning, this suggesting the need for further research and the possibility for treatment implications. PMID- 28845865 TI - Defence mechanisms and attachment styles in paranoid ideation evaluated in a sample of non-clinical young adults. AB - Objective: The aim of this investigation was to evaluate defence mechanisms and attachment styles in paranoid ideation through a cross-sectional design with sequential recruitment of subjects. Methods: Five hundred and fifty non-clinical subjects were recruited from university students. A psychometric protocol comprising paranoid ideation scale of Symptoms Check List (SCL-90-R-Par) to identify paranoid ideation, Defence Style Questionnaire (DSQ-40) to evaluate defence mechanisms, and Relationship Questionnaire (RQ) to measure attachment styles was then administered. Results: We found a significant predictive value of immature defence mechanisms (beta=0.48; p<0.0001)and preoccupied attachment style (beta=0.25; p<0.0001) in the paranoid ideation. Moreover, subjects reporting a preoccupied or fearful attachment style showed higher levels of paranoia. Conclusions: This study revealed that paranoid ideation is mainly characterised by immature defence mechanisms. A clear insecure attachment style associated with paranoia was also found. The assessment of paranoid ideation should therefore consider the role of attachment style and defence mechanisms as an integral part during the diagnostic and therapeutic processes. PMID- 28845864 TI - Attention to detail in Italian parents of women with anorexia nervosa: a comparative study. AB - Aim: Anorexia nervosa (AN) and autistic spectrum disorder (ASD) may share traits such as mental rigidity and attention to detail, some of which might be familial. We aimed to investigate the distribution of autistic traits among parents of daughters suffering from eating disorders (anorexia or bulimia nervosa), comparing them with control parents. Methods: As a whole, 40 parents of women with eating disorders (60% AN, 40% BN) and 33 control parents were recruited and accepted an examination through the administration of the autism spectrum quotient (AQ). The effects of eating disorders and other psychiatric traits were excluded by using EAT-26 and SCL-90-R respectively, while decision making skills were ruled out by using the cognitive estimation task (CET). Results: AQ scores revealed a between-groups difference for a specific trait, showing a reduction in attention to detail among ED family members, especially AN parents. Discussion: These findings suggest a preference for global processing in AN parents in contrast to what found in AN patients. Our findings support the role of a candidate trait in AN parents, supporting the need of further studies on the role of attention to detail as a family marker. Conclusion: This study identified a global processing preference in AN parents, suggesting a role of attention to detail as an ideal marker to be included in a wider clinical assessment for AN patients and their families. Considering some study limitations, further research is needed. PMID- 28845866 TI - Delusional sharing: a history focus-on and case report of folie a deux. AB - Folie a deux (FAD) is a clinical condition that was first described by Lasegue and Falret in 19th century. They reported a rarecondition where two or more people shared delusional ideas from a person to another. Nowadays a trace of this historical diagnosis and its theoretical framework, could be found on ICD-10 where FAD is translated in "Shared Psychotic Disorder". Given the lack of literature and a well-defined set of symptoms it is hard to detect the clinical limits of FAD. Furthermore, the complex of comorbidities could lead to a misdiagnosis. In this paper we report a peculiar case of FAD with an historical focus trying to give a wider point of view and tools to recognize this unconventional psychiatric diagnosis. PMID- 28845869 TI - ? PMID- 28845867 TI - Clozapine-related extrapyramidal side effects: a case report. AB - The present report describes extrapyramidal side effects (EPS) appearing after 32 months of exclusive treatment with clozapine at low dosages. This case evidences that long-term treatment with clozapine may be associated with EPS and suggests that, even if clozapine is considered the medication with the fewest EPS and it is often prescribed as an effective treatment for them, its use does not fully eliminate the risk of neurological side effects. PMID- 28845870 TI - [The EINSTEIN CHOICE study]. PMID- 28845871 TI - [The ROADMAP study]. PMID- 28845872 TI - [40 Years of coronary angioplasty: success comes from skills and determination!] PMID- 28845873 TI - [Late complications of Fontan operation]. AB - Complex univentricular heart defects are treated with the Fontan operation that consists in the diversion of the systemic venous return to the pulmonary arteries. Currently, the operation is achieved through a staged approach and with the use of prosthetic extracardiac conduits to connect the inferior vena cava to the pulmonary arteries. The improvement of early and late survival allowed these patients to reach adulthood, although long-term complications remain a relevant problem. Most of the complications are caused by chronic systemic venous hypertension due to the lack of a pumping sub-pulmonary ventricle. The most frequent complications are arrhythmias, thromboembolism, protein-losing enteropathy, heart failure and plastic bronchitis. The pathogenetic mechanisms are not completely understood but they are all connected to chronic systemic venous hypertension. Quality of life and life expectancy are deeply impaired by the onset of such complications and then a strict follow-up is required to recognize early sings of complications and to start early treatment. The creation of a highly specialized referral center network for the treatment of such complications and delicate patients is needed to improve the efficacy and the outcomes for the Fontan patients. PMID- 28845874 TI - [The frozen elephant trunk technique for the treatment of complex lesions of the thoracic aorta]. AB - The treatment of patients with extensive disease of the thoracic aorta represents a formidable challenge for the cardiovascular surgeon. The beginning of thoracic aortic endovascular aortic arch repair has promoted the development of different hybrid approaches as the frozen elephant trunk (FET) strategy, which includes classic arch replacement and antegrade stenting of the descending thoracic aorta. It represents an interesting approach for patients with extensive disease of the thoracic aorta, and its application has significantly increased over recent years. Our indications for this technique include degenerative aneurysms of the aortic arch and acute and chronic aortic dissections. For many years, the conventional surgical approach for the treatment of complex lesions of the thoracic aorta considered the two-stage elephant trunk technique. However, it is still associated with high mortality and morbidity with only half of the patients who underwent the second stage of the operation. These shortcomings can be attenuated by the FET technique which allows to replace in one stage-approach all the thoracic aorta. Anyway, the main problem of the FET remains the paraplegia. Key points during this surgery are represented by an accurate preoperative assessment of the aortic anatomy by angiography computed tomography scan, the employment of reliable methods of organ protection and of effective surgical techniques and strategies. Antegrade selective cerebral perfusion represents a fundamental tool for cerebral protection. In type A chronic aortic dissection utilizing FET technique, it is possible to use the stent-graft as landing-zone for secondary endovascular extension in order to cover the re-entry tears at the distal descending thoracic aorta. Despite the satisfactory short- and mid-term results, longer-term studies are needed to show the benefits of the FET technique versus other types of management. PMID- 28845876 TI - [Characteristics and outcomes of acute coronary syndrome in Italian-born patients and immigrants: a population-based observational study using health administrative data of the Emilia-Romagna Region]. AB - BACKGROUND: The aim of this study was to analyze the characteristics and outcomes of patients with acute coronary syndrome (ACS) in relation to country of origin. METHODS: The study population included patients living in the Emilia-Romagna Region and discharged from 2012 to 2014 with a diagnosis of acute myocardial infarction (with [STEMI] and without ST-elevation). The study outcomes were: percutaneous coronary intervention (PCI) within 48 hours of admission for STEMI, 30-day all-cause mortality, 1-year all-cause mortality, 1-year major adverse cardiac and cerebrovascular events (MACCE), and adherence to post-infarction medications. The relationship between outcomes and citizenship was investigated using multiple regression analysis. Potential confounders were identified among diagnoses recorded in the index hospitalization and in all hospitalizations occurring 2 years prior to the index hospitalization. RESULTS: Of the 23 884 study patients, 647 (2.7%) were non-Italians. The mean age of onset of ACS was lower among immigrants (56 years) than among Italians (73 years). Thirty-day mortality was 9.6% while 1-year mortality and MACCE were 19.8% and 20.8%, respectively. The proportion of PCI within 48 hours was 63.2%, while patients adherent to medications were 31.0%. Compared with Italians, patients from Africa and Asia had a reduced probability of undergoing PCI and were less adherent to medications. Adjusted mortality rates were similar between Italians and immigrants, while patients from Asia had a 62% increased probability of experiencing a MACCE during follow-up. CONCLUSIONS: Compared with Italians, immigrant citizens with ACS were younger, less likely to undergo PCI, and less adherent to drug treatment after discharge. Further studies are warranted to identify the determinants of these disparities and to develop organizational models tailored to the specific needs of immigrant patients. PMID- 28845877 TI - [Characteristics and outcomes of acute coronary syndrome in Italian-born patients and immigrants: an insight into the recent past]. PMID- 28845875 TI - [Cardiologists and mucopolysaccharidoses. Recommendations of GICEM (Cardiology Experts on Metabolic Disease Italian Group) for diagnosis, follow-up and cardiological management]. AB - Mucopolysaccharidoses (MPS) represent a group of rare lysosomal storage disorders, with a heterogeneous clinical presentation in terms of inheritance (autosomal and X-linked recessive), age of onset (infants, children, and adults), systemic and cardiac manifestations (mild to severe disease forms). Evidence based recommendations on the diagnosis and management of cardiovascular disease in MPS are scarce. GICEM (Gruppo Italiano Cardiologi Esperti Malattie Metaboliche) is a group of cardiologists, cardiac surgeons and pediatricians with a specific expertise in metabolic diseases including MPS. In this paper, we report our experience and recommendations on the diagnosis and management of cardiovascular aspects in MPS, with a tailored approach based on current evidence, and taking into account MPS phenotype (particularly, I, II, IVa, VI), age at presentation, and severity of systemic and cardiac manifestations. PMID- 28845878 TI - [Thrombotic storm in a teenager with previously diagnosed ulcerative colitis: a rare case of left ventricular thrombosis]. AB - Left ventricular thrombi usually occur in the setting of an acute myocardial infarction, left ventricular aneurysm, or dilated cardiomyopathy. In the absence of ventricular wall motion abnormalities, they are rare. We report the case of a patient with ulcerative colitis in whom two-dimensional echocardiography revealed a left intraventricular mass. Thrombosis in ulcerative colitis is a serious condition and can occur in a very young population. This case report also shows that left ventricular thrombi can occur in the active setting of ulcerative colitis. PMID- 28845879 TI - [A case of severe left main isolated stenosis in a young woman with previous history of non-Hodgkin lymphoma]. AB - We report the case of a 34-year-old female treated with radiotherapy and chemotherapy for non-Hodgkin lymphoma at the age of 16. The patient came to our attention because of progressive dyspnea on effort and a positive result on a pharmacologic stress echo test. Coronary angiography revealed focal critical ostial stenosis of the left main coronary artery. Considering the high surgical risk due to possible post-radiation thoracic adherence and the young patient age, she underwent successful stenting of the left main stenosis with drug-eluting stent, followed by an intravascular ultrasound-guided post-dilation and final kissing balloon inflation. The procedure was uncomplicated.Heart diseases are among the frequently seen long-term effects of chemo/radiotherapy used for lymphoma treatment. The pathogenesis of radiation-induced coronary artery disease is complex and not yet fully understood, the mechanism is multifactorial and likely involves direct damage from radiation exposure or mediated by inflammatory cytokine secretion. Surgery management is often challenging due to radiation sequences, and a percutaneous approach is therefore used. The risk of long-term radiotherapy damage depends on radiation dose and the field of exposure. Modern techniques with lower radiation exposure and smaller treatment volumes may reduce these risks in future. PMID- 28845880 TI - [Acute cardiac care in Europe: the ACCA White Book at a glance - waiting for the ACCA position statement on the organization of intensive care units]. PMID- 28845881 TI - [Letter to the Editor]. PMID- 28845882 TI - Rare clinically significant hepatic events and hepatitis B reactivation occur more frequently following rather than during direct-acting antiviral therapy for chronic hepatitis C: Data from a national US cohort. AB - Recently, cases of hepatitis B virus reactivation (HBVr) with direct-acting antiviral therapy (DAAs) for HCV have been reported. However, few data exist from large, Western cohorts. The study objectives were to evaluate the incidence of alanine aminotransferase (ALT) flares, clinically significant hepatic events, and HBVr among a national cohort of US veterans with prior exposure to HBV (anti HBc+) treated with DAAs. We used a national administrative database to identify patients treated with DAAs from January 2014 through November 2016 and obtained clinical and demographic as well as HBV and HCV treatment data. HBVr was defined as an at least 1-log increase in HBV DNA titre. Among 17 779 anti-HBc+ patients, 17 400 were HIV- and 379 were HIV+. Among the HIV- patients, 17 266 (99%) were HBsAg- prior to DAA therapy and 134 were HBsAg+. Among HIV-, HBsAg- patients, ALT elevations greater than 10 times the upper limit of normal (ULN; >=300 IU/mL) were rare and occurred more frequently after treatment completion: 31 cases (<0.1%) during vs 85 (0.6%) following treatment. Clinically significant hepatic events defined as ALT increases >100 IU/L with total bilirubin >2.5 mg/dL occurred in 39 cases (0.3%), most often following DAA completion (n = 35 cases, 3/35 in setting of HCV relapse). Among 31 patients with post-DAA hepatic events without HCV relapse, 10 (32%) were confirmed unrelated to HBVr by HBsAg and/or HBV DNA testing, 1 (3%) confirmed due to HBVr, and 20 (65%) did not have documented HBV-related testing. One additional case of HBsAg- to + seroreversion was identified. Among HBsAg+ DAA recipients, 2/97 (2%), both with cirrhosis, experienced ALT elevations >=300 IU/mL in the setting of HBVr. In conclusion, clinically significant hepatic events and HBVr were rare and much more likely among HBsAg-positive individuals. Anti-HBc + patients should be monitored for ALT flares and HBVr during and possibly for up to 6 months post-DAA therapy. PMID- 28845883 TI - Catalytic Asymmetric Formal [3+2] Cycloaddition of 2-Isocyanatomalonate Esters and Unsaturated Imines: Synthesis of Highly Substituted Chiral gamma-Lactams. AB - Unlike their isocyano and isothiocyanato analogues, isocyanato esters remain almost unexplored as formal 1,3-dipoles in asymmetric catalytic reactions. The first asymmetric formal [3+2] cycloaddition involving isocyanato esters and electrophilic alkenes is reported. Diisopropyl 2-isocyanatomalonate reacts with alpha,beta-unsaturated N-(o-anisidyl) imines in the presence of a Mg(OTf)2 -BOX complex to give highly substituted chiral pyrrolidinones featuring a conjugate exocyclic double bond with excellent yields and enantiomeric excesses up to 99 %. Several transformations of the resulting heterocycles, including the synthesis of a pyroglutamic acid derivative, have been carried out. PMID- 28845884 TI - Designed Synthesis of Au/Fe3 O4 @C Janus Nanoparticles for Dual-Modal Imaging and Actively Targeted Chemo-Photothermal Synergistic Therapy of Cancer Cells. AB - Elaborately designed novel multifunctional Janus nanoparticles (JNPs) have attracted considerable attention owing to their anisotropic surface properties and various functionalities that allow them to house several components for the detection and targeting of cancer cells. In this work, we report a novel and facile approach to synthesize Au/Fe3 O4 @C JNPs, which were further selectively functionalized with amino-poly(ethylene glycol)thiol (NH2 -PEG-SH) and folic acid (FA) on the exposed Au domains to achieve high contrast for X-ray computed tomography (CT) imaging, excellent stability, good biocompatibility, as well as cancer cell-specific targeting. Meanwhile, the other Fe3 O4 @C sides with mesoporous structure served as a drug delivery vehicle for doxorubicin (DOX), an efficient photothermal therapy (PTT) agent, and a magnetic resonance (MR) imaging contrast agent. Taking these features together, these unique multifunctional JNPs provide an intriguing nanoplatform for dual-modal CT and MR imaging-guided actively targeted chemo-photothermal synergistic cancer therapy. PMID- 28845885 TI - Analysis of vascular homogeneity and anisotropy on high-resolution primate brain imaging. AB - Using a systematic investigation of brain blood volume, in high-resolution synchrotron 3D images of microvascular structures within cortical regions of a primate brain, we challenge several basic questions regarding possible vascular bias in high-resolution functional neuroimaging. We present a bilateral comparison of cortical regions, where we analyze relative vascular volume in voxels from 150 to 1000 MUm side lengths in the white and grey matter. We show that, if voxel size reaches a scale smaller than 300 um, the vascular volume can no longer be considered homogeneous, either within one hemisphere or in bilateral comparison between samples. We demonstrate that voxel size influences the comparison between vessel-relative volume distributions depending on the scale considered (i.e., hemisphere, lobe, or sample). Furthermore, we also investigate how voxel anisotropy and orientation can affect the apparent vascular volume, in accordance with actual fMRI voxel sizes. These findings are discussed from the various perspectives of high-resolution brain functional imaging. Hum Brain Mapp 38:5756-5777, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28845886 TI - The Role of Water Distribution Controlled by Transmembrane Potentials in the Cytochrome c-Cardiolipin Interaction: Revealing from Surface-Enhanced Infrared Absorption Spectroscopy. AB - The interaction of cytochrome c (cyt c) with cardiolipin (CL) plays a crucial role in apoptotic functions, however, the changes of the transmembrane potential in governing the protein behavior at the membrane-water interface have not been studied due to the difficulties in simultaneously monitoring the interaction and regulating the electric field. Herein, surface-enhanced infrared absorption (SEIRA) spectroelectrochemistry is employed to study the mechanism of how the transmembrane potentials control the interaction of cyt c with CL membranes by regulating the electrode potentials of an Au film. When the transmembrane potential decreases, the water content at the interface of the membranes can be increased to slow down protein adsorption through decreasing the hydrogen-bond and hydrophobic interactions, but regulates the redox behavior of CL-bound cyt c through a possible water-facilitated proton-coupled electron transfer process. Our results suggest that the potential drop-induced restructure of the CL conformation and the hydration state could modify the structure and function of CL-bound cyt c on the lipid membrane. PMID- 28845887 TI - Syntheses of Exceptionally Stable Aluminum(III) Metal-Organic Frameworks: How to Grow High-Quality, Large, Single Crystals. AB - The difficulty of obtaining large single crystals of aluminum carboxylate metal organic frameworks (MOFs) for structure determinations has limited the development of these water and thermally stable MOFs. Herein, how large single crystals of known MIL-53(Al) and the first two tetrahedral ligand-based, visible light-absorbing 3D Al-MOFs, [Al3 (OH)3 (HTCS)2 ] (AlTCS-1) and [Al5 O2 (OH)3 (TCS)2 (H2 O)2 ] (AlTCS-2; TCS=tetrakis(4-oxycarbonylphenyl)silane), are obtained in the presence of hydrofluoric or formic acid for conventional single-crystal diffraction measurements is presented. The technique of obtaining those single crystals has potential to be a general method for obtaining large and good quality single crystals of Al-MOFs. AlTCS-1 and -2 are stable over a wide pH range (1-11), and AlTCS-1 is even stable in aqua regia solution for at least 24 h. The BET specific surface areas of AlTCS-1 and -2 are 11 and 1506 m2 g-1 , respectively. AlTCS-2 takes up 51 cm3 (STP) g-1 CO2 and 15 cm3 (STP) g-1 CH4 at 298 K and 1 bar, which is relatively high among MOF materials. AlTCS-1 takes up 30 cm3 g-1 CO2 and 4.2 cm3 g-1 CH4 at 298 K and 1 bar. The rapid and stable photocurrent responses of AlTCS-1 and -2 under UV and visible-light illumination are observed. Moreover, AlTCS-1 photocatalyzes the water-splitting reaction under visible light with an average hydrogen evolution efficiency of 50 MUmol g-1 h-1 for the first 10 h in a mixture of water and triethanolamine. PMID- 28845888 TI - Recent Progress in Bionic Condensate Microdrop Self-Propelling Surfaces. AB - Bionic condensate microdrop self-propelling (CMDSP) surfaces are attracting increased attention as novel, low-adhesivity superhydrophobic surfaces due to their value in fundamental research and technological innovation, e.g., for enhancing heat transfer, energy-effective antifreezing, and electrostatic energy harvesting. Here, the focus is on recent progress in bionic CMDSP surfaces. Metal based CMDSP surfaces, which are the most promising in their respective fields, are highlighted for use in future applications. The selected topics are divided into four sections: biological prototypes, mechanism and construction rules, fabrication, and applications of metal-based CMDSP surfaces. Finally, the challenges and future development trends in bionic CMDSP surfaces are envisioned, especially the utilization of potential bionic inspiration in the design of more advanced CMDSP surfaces. PMID- 28845890 TI - Long-term aspirin does not lower risk of stroke and increases bleeding risk in low-risk atrial fibrillation ablation patients. AB - BACKGROUND: Stroke risk is a significant concern in patients with atrial fibrillation (AF). Low stroke risk patients (CHADS2 VASc 0-2) are often treated long-term with aspirin after catheter ablation. Defining the long-term risks versus benefits of aspirin therapy, after an ablation, is essential to validate this common clinical approach. METHODS: A total of 4,124 AF ablation patients undergoing their index ablation were included in this retrospective observational study. We compared 1- and 3-year outcomes for cerebrovascular accident (CVA), transient ischemic attack (TIA), gastrointestinal (GI) bleeding, genitourinary (GU) bleeding, any bleeding, and AF recurrence among patients receiving: none, aspirin, or warfarin as long-term therapies. RESULTS: Patient distribution by CHADS2 VASc scores was as follows: 0: 1,143 (28%), 1: 1,588 (39%), and 2: 1,393 (34%). Significantly higher incidents of: female gender, hypertension, diabetes mellitus, heart failure, and vascular disease were seen with higher CHADS2 VASc scores (P < 0.0001 for all). At 3 years, 238 (5.9%) patients were on warfarin, 743 (18.6) on aspirin, and 3,013 (75.5%) on no therapy; with occurrences of CVA/TIA (1.4%, 3.0%, 3.9%, P < 0.0001, respectively), GI bleeding (0.8%, 1.9%, 1.1%, P = 0.06, respectively), and GU bleeding (1.7%, 2.8%, 2.1%, P = 0.008, respectively) that increased with advancing CHA2 DS2 VASc score. There was a significantly increased risk for both CVA/TIA with aspirin therapy, when compared to no therapy or warfarin therapy in general, and across all CHA2 DS2 VASc scores. CONCLUSIONS: After catheter ablation, low risk patients do not benefit from long-term aspirin therapy, but are at risk for higher rates of bleeding when compared to no therapy or warfarin. PMID- 28845889 TI - Heterovalent Glycodendrimers as Epitope Carriers for Antitumor Synthetic Vaccines. AB - The large majority of TACA-based (TACA=Tumor-Associated Carbohydrate Antigens) antitumor vaccines target only one carbohydrate antigen, thereby often resulting in the incomplete destruction of cancer cells. However, the morphological heterogeneity of the tumor glycocalix, which is in constant evolution during malignant transformation, is a crucial point to consider in the design of vaccine candidates. In this paper, an efficient synthetic strategy based on orthogonal chemoselective ligations to prepare fully synthetic glycosylated cyclopeptide scaffolds grafted with both Tn and TF antigen analogues is reported. To evaluate their ability to be recognized as tumor antigens, direct interaction ELISA assays have been performed with the anti-Tn monoclonal antibody 9A7. Although both heterovalent structures showed binding capacities with 9A7, the presence of the second TF epitope did not interfere with the recognition of Tn except in one epitope arrangement. This heterovalent glycosylated structure thus represents an attractive epitope carrier to be further functionalized with T-cell peptide epitopes. PMID- 28845891 TI - Ligand Noninnocence in Iron Corroles: Insights from Optical and X-ray Absorption Spectroscopies and Electrochemical Redox Potentials. AB - Two new series of iron meso-tris(para-X-phenyl)corrole (TpXPC) complexes, Fe[TpXPC]Ph and Fe[TpXPC]Tol, in which X=CF3 , H, Me, and OMe, and Tol=p methylphenyl (p-tolyl), have been synthesized, allowing a multitechnique electronic-structural comparison with the corresponding FeCl, FeNO, and Fe2 (MU O) TpXPC derivatives. Optical spectroscopy revealed that the Soret maxima of the FePh and FeTol series are insensitive to the phenyl para substituent, consistent with the presumed innocence of the corrole ligand in these compounds. Accordingly, we may be increasingly confident in the ability of the substituent effect criterion to serve as a probe of corrole noninnocence. Furthermore, four complexes-Fe[TPC]Cl, Fe[TPC](NO), {Fe[TPC]}2 O, and Fe[TPC]Ph-were selected for a detailed XANES investigation of the question of ligand noninnocence. The intensity-weighted average energy (IWAE) positions were found to exhibit rather modest variations (0.8 eV over the series of corroles). The integrated Fe-K pre edge intensities, on the other hand, vary considerably, with a 2.5 fold increase for Fe[TPC]Ph relative to Fe[TPC]Cl and Fe[TPC](NO). Given the approximately C4v local symmetry of the Fe in all the complexes, the large increase in intensity for Fe[TPC]Ph may be attributed to a higher number of 3d holes, consistent with an expected FeIV -like description, in contrast to Fe[TPC]Cl and Fe[TPC](NO), in which the Fe is thought to be FeIII -like. These results afford strong validation of XANES as a probe of ligand noninnocence in metallocorroles. Electrochemical redox potentials, on the other hand, were found not to afford a simple probe of ligand noninnocence in Fe corroles. PMID- 28845892 TI - Multiple functional networks modeling for autism spectrum disorder diagnosis. AB - Despite countless studies on autism spectrum disorder (ASD), diagnosis relies on specific behavioral criteria and neuroimaging biomarkers for the disorder are still relatively scarce and irrelevant for diagnostic workup. Many researchers have focused on functional networks of brain activities using resting-state functional magnetic resonance imaging (rsfMRI) to diagnose brain diseases, including ASD. Although some existing methods are able to reveal the abnormalities in functional networks, they are either highly dependent on prior assumptions for modeling these networks or do not focus on latent functional connectivities (FCs) by considering discriminative relations among FCs in a nonlinear way. In this article, we propose a novel framework to model multiple networks of rsfMRI with data-driven approaches. Specifically, we construct large scale functional networks with hierarchical clustering and find discriminative connectivity patterns between ASD and normal controls (NC). We then learn features and classifiers for each cluster through discriminative restricted Boltzmann machines (DRBMs). In the testing phase, each DRBM determines whether a test sample is ASD or NC, based on which we make a final decision with a majority voting strategy. We assess the diagnostic performance of the proposed method using public datasets and describe the effectiveness of our method by comparing it to competing methods. We also rigorously analyze FCs learned by DRBMs on each cluster and discover dominant FCs that play a major role in discriminating between ASD and NC. Hum Brain Mapp 38:5804-5821, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28845893 TI - Mixed Allyl Rare-Earth Borohydride Complexes: Synthesis, Structure, and Application in (Co-)Polymerization Catalysis of Cyclic Esters. AB - A series of new trivalent rare-earth allyl-borohydride complexes with the formula [RE(BH4 )2 (C3 H5 )(thf)x ] (RE=Sc (1), x=2; RE=Y (2) and La (3), x=3) were synthesized by reaction of the corresponding rare-earth trisborohydrides [RE(BH4 )3 (thf)x ] with half an equivalent of bis(allyl)magnesium. The complexes were fully characterized by determining their X-ray structure. Similar to their previously described Nd (4) and Sm (5) analogues, these complexes display a monomeric structure with two terminal trihapto BH4 groups, one pi-eta3 allyl ligand, three THF molecules for complexes 2 and 3, and two THF molecules for complex 1. The catalytic behavior of complexes 1-5 toward the ring-opening polymerization (ROP) of l-lactide (l-LA) and epsilon-caprolactone (epsilon-CL) was assessed. The Nd complex featured the best activity toward l-LA (turnover frequency (TOF)=1300 h-1 ) and the order was Nd>La>Sm>Y>Sc. Complexes 1-3 were found very active for the ROP of epsilon-CL (TOF=166 000 h-1 ), which is in line with the already established exceptionnally high performance of complexes 4 and 5. With both monomers, it was shown that the borohydride moiety was the preferentially initiating group, rather than the allyl one. The random copolymerization of l-LA and epsilon-CL was performed with complexes 1-5, in the absence or in the presence of benzyl alcohol as a chain-transfer agent, affording copolymers with epsilon-caprolactone up to 62 % inserted. The copolymers synthesized display a variety of microstructures, that is, blocky, random, or quasi-alternating. PMID- 28845894 TI - Presence of different hepatitis C virus genotypes in plasma and peripheral blood mononuclear cell samples of Iranian patients with HIV infection. AB - Due to the similar routes of transmission, individuals infected with the human immunodeficiency virus (HIV) may become infected with the hepatitis C virus (HCV) simultaneously. The aim of this study was to investigate the frequency of HCV co infection in Iranian individuals with HIV infection, and to genotype HCV in plasma and PBMC specimens of these patients. From September 2015 to October 2016, a total of 140 Iranian individuals with HIV infection were enrolled in this cross sectional study. The RNA from plasma and PBMC specimens was extracted, and genomic HCV-RNA was amplified using RT-nested PCR with primers that target 5' UTR. The HCV genotyping used the RFLP technique. To confirm HCV genotype, 10 randomly selected HCV-positive samples were also submitted for sequencing. The mean age of patients was 35.7 +/- 13.5 years (range: 1-66). Out of 140 patients, 62 (44.3 %) were positive for anti-HCV antibodies; among these, viral genomic RNA was detected in 34 (24.3%) and 39 (27.9%) of the plasma and PBMC specimens, respectively. The HCV genotyping showed a similar pattern of subtypes 1a (44% vs 46.2%), 3a (32.4% vs 33.3%), and 1b (17.6% vs 17.9%) in all sera and PBMC samples. It is noteworthy that the HCV genotypes in plasma and PBMC specimens of 6 HCV co-infected patients were not the same. This study reveals that HIV/HCV co infection is high in Iranian patients (44.3%), especially in people who have high risk factors (83.9%). Also, HIV/HCV co-infected individuals may have dissimilar HCV genotypes in their plasma and PBMC specimens. PMID- 28845895 TI - Bone markers in polycystic ovary syndrome: A multicentre study. AB - OBJECTIVE: Hyperandrogenism, hyperinsulinaemia and obesity, known characteristics of polycystic ovary syndrome (PCOS), may influence bone mineral density and biochemical markers of bone turnover (BTMs) can provide a noninvasive assessment of bone turnover. To this end, the serum concentrations of BTMs and 25 hydroxyvitamin D (25OHD) were analysed in women with PCOS, and their possible associations with metabolic parameters of PCOS were determined. SUBJECTS AND METHODS: Bone formation markers procollagen type I amino-terminal propeptide (PINP) and osteocalcin (OC), and bone resorption marker carboxy-terminal cross linking telopeptide of type I collagen (CTX), along with 25OHD, were measured in 298 women with PCOS and 194 healthy controls. RESULTS: Serum levels of PINP (47.0 +/- 20.2 vs 58.1 +/- 28.6 MUg/L, P < .001) and OC (18.2 +/- 7.5 vs 20.6 +/- 9.8 MUg/L, P < .001) were decreased in women with PCOS compared with controls, whereas no significant differences were found in CTX and 25OHD levels. Age stratified analyses suggested that PINP (50.5 +/- 21.7 vs 68.2 +/- 26.6 MUg/L, P < .001) and OC levels (20.4 +/- 7.6 vs 25.5 +/- 9.6 MUg/L, P < .001) were decreased only in the younger age group (<=30 years) women with PCOS compared with controls. The formation markers and resorption marker decreased with age in both study groups. CONCLUSIONS: Bone formation markers were decreased in younger women with PCOS when compared with healthy women, which may affect bone mass in these women. PMID- 28845896 TI - Development of a multiplex real-time PCR assay for detection of human enteric viruses other than norovirus using samples collected from gastroenteritis patients in Fukui Prefecture, Japan. AB - There are many varieties of gastroenteritis viruses, of which norovirus (NoV) accounts for over 90% of the viral food poisoning incidents in Japan. However, protocols for rapidly identifying other gastroenteritis viruses need to be established to investigate NoV-negative cases intensively. In this study, a multiplex real-time PCR assay targeting rotavirus A, rotavirus C, sapovirus, astrovirus, adenovirus, and enterovirus was developed using stool samples collected from gastroenteritis patients between 2010 and 2013 in Fukui Prefecture, Japan. Of the 126 samples collected sporadically from pediatric patients with suspected infectious gastroenteritis, 51 were positive for non-NoV target viruses, whereas 27 were positive for NoV, showing a high prevalence of non-NoV viruses in pediatric patients. In contrast, testing in 382 samples of 58 gastroenteritis outbreaks showed that non-NoV viruses were detected in 13 samples, with NoV in 267. Of the 267 NoV-positive patients, only two were co infected with non-NoV target viruses, suggesting that testing for non-NoV gastroenteritis viruses in NoV-positive samples was mostly unnecessary in outbreak investigations. Given these results, multiplex real-time PCR testing for non-NoV gastroenteritis viruses, conducted separately from NoV testing, may be helpful to deal with two types of epidemiological investigations, regular surveillance of infectious gastroenteritis and urgent testing when gastroenteritis outbreaks occur. PMID- 28845897 TI - High-Resolution Spin-on-Patterning of Perovskite Thin Films for a Multiplexed Image Sensor Array. AB - Inorganic-organic hybrid perovskite thin films have attracted significant attention as an alternative to silicon in photon-absorbing devices mainly because of their superb optoelectronic properties. However, high-definition patterning of perovskite thin films, which is important for fabrication of the image sensor array, is hardly accomplished owing to their extreme instability in general photolithographic solvents. Here, a novel patterning process for perovskite thin films is described: the high-resolution spin-on-patterning (SoP) process. This fast and facile process is compatible with a variety of spin-coated perovskite materials and perovskite deposition techniques. The SoP process is successfully applied to develop a high-performance, ultrathin, and deformable perovskite-on silicon multiplexed image sensor array, paving the road toward next-generation image sensor arrays. PMID- 28845899 TI - Pfeiffer syndrome: oral healthcare management and description of new dental findings in a craniosynostosis. AB - Pfeiffer syndrome is a rare fibroblast growth factor receptor-related craniosynostosis with variable clinical presentations. We describe new dental findings of hypodontia, microdontia, dilacerations, and radicular dentin dysplasia in a 19-year-old girl, and discuss the oral health management. PMID- 28845898 TI - Comparison of Bioavailability of Single-Dose Extended-Release Venlafaxine Capsules in Obese Patients Before and After Gastric Bypass Surgery. AB - STUDY OBJECTIVE: The extended-release (ER) form of venlafaxine is preferred because of improved patient adherence, but the immediate-release (IR) form is frequently used after Roux-en-Y gastric bypass (RYGB) surgery because of concerns for malabsorption. The objective of this study was to determine whether a statistically significant and predictable change in the bioavailability of venlafaxine ER capsules occurs after RYGB. DESIGN: Prospective nonblinded single dose pharmacokinetic study. SETTING: Clinical research unit at a large tertiary care medical practice. PATIENTS: Ten adult pre-bariatric surgery patients who met the criteria for noncomplicated RYGB were enrolled and served as their own controls. INTERVENTIONS: Patients were administered one venlafaxine ER 75-mg capsule at two visits-the first visit at least 1 week before undergoing RYGB and the second visit 3-4 months after RYGB. Blood samples were collected at predetermined intervals over 48 hours after each dose, and the pharmacokinetics of venlafaxine were measured. MEASUREMENTS AND MAIN RESULTS: Plasma levels of venlafaxine and its primary metabolite, O-desmethylvenlafaxine (ODV), were compared at baseline and 3-4 months after RYGB. The areas under the serum concentration-time curves from 0-24 hours (AUC0-24 ) for venlafaxine (mean +/- SD 734 +/- 602 vs 630 +/- 553 ng.hr/ml, p=0.22) and ODV (mean +/- SD 894 +/- 899 vs 1083 +/- 972 ng.hr/ml, p=0.07) were similar before and after RYGB. Using a bioequivalence approach, differences in pre-RYGB and post-RYGB values of AUC0-24 , peak serum concentration, and time to peak serum concentration were not statistically significant for either venlafaxine or ODV. CONCLUSION: This study suggests that RYGB does not significantly alter the amount of venlafaxine or its active metabolite, ODV, absorbed from a venlafaxine ER capsule or the time over which it is absorbed. PMID- 28845900 TI - Trends in hip replacements between 1999 and 2012 in Sweden. AB - National Registers document changes in the circumstance, practice, and outcome of surgery with the passage of time. In the context of total hip replacement (THR), registers can help elucidate the relevant factors that affect the clinical outcome. We evaluated the evolution of factors related to patient, surgical procedure, socio-economy, and various outcome parameters after merging databases of the Swedish Hip Arthroplasty Register, Statistics Sweden and the National Board of Health and Welfare. Data on 193,253 THRs (164,113 patients) operated between 1999 and 2012 were merged. We studied the evolution of surgical volume, patient demographics, socio-economic factors, surgical factors, length-of-stay, mortality rate, adverse events, re-operation and revision rates, and Patient Reported Outcome Measures (PROMs). Throughout this time period the majority of patients were operated on with a diagnosis of primary osteoarthritis. Comorbidity indices increased each year observed. The share of all-cemented implants has dropped from 92% to 68%. More than 88% of the bearings were metal-on polyethylene. Length-of-stay decreased by 50%. There was a reduction in 30- and 90-day mortality. Re-operation and revision rates at 2 years are decreasing. The post-operative PROMs improved despite the observation of worse pre-operative pain scores getting over time. The demographics of patients receiving a THR, their comorbidities, and their primary diagnosis are changing. Notwithstanding these changes, outcomes like mortality, re-operations, revisions, and PROMs have improved. The practice of hip arthroplasty has evolved, even in a country such as Sweden that is considered to be conservative with regard taking on new surgical practices. (c) 2017 The Authors. Journal of Orthopaedic Research(r) Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:432-442, 2018. PMID- 28845901 TI - Prospective mixture risk assessment and management prioritizations for river catchments with diverse land uses. AB - Ecological risk assessment increasingly focuses on risks from chemical mixtures and multiple stressors because ecosystems are commonly exposed to a plethora of contaminants and nonchemical stressors. To simplify the task of assessing potential mixture effects, we explored 3 land use-related chemical emission scenarios. We applied a tiered methodology to judge the implications of the emissions of chemicals from agricultural practices, domestic discharges, and urban runoff in a quantitative model. The results showed land use-dependent mixture exposures, clearly discriminating downstream effects of land uses, with unique chemical "signatures" regarding composition, concentration, and temporal patterns. Associated risks were characterized in relation to the land-use scenarios. Comparisons to measured environmental concentrations and predicted impacts showed relatively good similarity. The results suggest that the land uses imply exceedances of regulatory protective environmental quality standards, varying over time in relation to rain events and associated flow and dilution variation. Higher-tier analyses using ecotoxicological effect criteria confirmed that species assemblages may be affected by exposures exceeding no-effect levels and that mixture exposure could be associated with predicted species loss under certain situations. The model outcomes can inform various types of prioritization to support risk management, including a ranking across land uses as a whole, a ranking on characteristics of exposure times and frequencies, and various rankings of the relative role of individual chemicals. Though all results are based on in silico assessments, the prospective land use-based approach applied in the present study yields useful insights for simplifying and assessing potential ecological risks of chemical mixtures and can therefore be useful for catchment-management decisions. Environ Toxicol Chem 2018;37:715-728. (c) 2017 The Authors. Environmental Toxicology Chemistry Published by Wiley Periodicals, Inc. PMID- 28845902 TI - Persistence of Delirium after Cessation of Sedatives and Analgesics and Impact on Clinical Outcomes in Critically Ill Patients. AB - STUDY OBJECTIVE: As delirium is a common manifestation in critically ill patients and is associated with worse clinical outcomes, we sought to characterize the reversibility of delirium after discontinuation of sedation and to determine whether sedation-associated delirium that rapidly reverses impacts clinical outcomes. DESIGN: Post hoc subgroup analysis of prospectively collected data from a previously published study. PATIENTS: Seventy adults admitted to a medical intensive care unit (ICU) between March and July 2012 who required mechanical ventilation with continuous analgesia and/or sedation and underwent a spontaneous awakening trial (SAT). MEASUREMENTS AND MAIN RESULTS: Patients were grouped into four categories: delirium free, rapidly reversible delirium (RRD; defined as delirium always resolving within 4 hrs of stopping sedatives), persistent delirium (PD; defined as delirium always persisting for >= 4 hours after stopping sedatives), or mixed delirium (consisting of RRD and PD episodes). The incidence of the four delirium subtypes and their associations with clinical outcomes were evaluated. A validated, guideline-recommended, bedside delirium monitoring instrument-the Confusion Assessment Method for the ICU (CAM-ICU)-was used to assess for the presence or absence of delirium. Clinical outcomes included ventilator-free days at day 28, ICU and hospital length of stay, 28-day mortality, and patient disposition; time to first CAM-ICU becoming negative (delirium free) for a continuous 48-hour duration was also assessed. A total of 103 SATs were performed in the 70 patients. Of the 103 SATs, 28 (27.2%) were CAM ICU negative before the SAT. Of the remaining 75 SATs, PD was present for the majority of SATs (62 [82.7%]); RRD was present after 13 (17.3%) SATs. On a patient level, 17 patients (24.3%) were always delirium free before cessation of medications for continuous sedation. Of the 53 patients with delirium before undergoing an SAT, 11 (20.8%) had RRD, 2 (3.8%) had mixed delirium, and 40 (75.5%) had PD. Proportional odds logistic regression adjusting for age, Acute Physiology and Chronic Health Evaluation II score, sepsis, and preexisting hypertension showed that patients with PD had a higher probability of longer ICU length of stay (odds ratio 4.01 [95% confidence interval 1.36-11.77], p=0.011), but those with RRD did not. CONCLUSION: Despite the cessation of medications for continuous sedation, delirium persisted for the majority of patients and was associated with worse outcomes, which attests to the importance of strategies to minimize sedation. PMID- 28845903 TI - Carrier-Type Modulation and Mobility Improvement of Thin MoTe2. AB - A systematic modulation of the carrier type in molybdenum ditelluride (MoTe2 ) field-effect transistors (FETs) is described, through rapid thermal annealing (RTA) under a controlled O2 environment (p-type modulation) and benzyl viologen (BV) doping (n-type modulation). Al2 O3 capping is then introduced to improve the carrier mobilities and device stability. MoTe2 is found to be ultrasensitive to O2 at elevated temperatures (250 degrees C). Charge carriers of MoTe2 flakes annealed via RTA at various vacuum levels are tuned between predominantly pristine n-type ambipolar, symmetric ambipolar, unipolar p-type, and degenerate like p-type. Changes in the MoTe2 -transistor performance are confirmed to originate from the physical and chemical absorption and dissociation of O2 , especially at tellurium vacancy sites. The electron branch is modulated by varying the BV dopant concentrations and annealing conditions. Unipolar n-type MoTe2 FETs with a high on-off ratio exceeding 106 are achieved under optimized doping conditions. By introducing Al2 O3 capping, carrier field effect mobilities (41 for holes and 80 cm2 V-1 s-1 for electrons) and device stability are improved due to the reduced trap densities and isolation from ambient air. Lateral MoTe2 p n diodes with an ideality factor of 1.2 are fabricated using the p- and n-type doping technique to test the superb potential of the doping method in functional electronic device applications. PMID- 28845904 TI - Spreading the load: Antigen transfer between migratory and lymph node-resident dendritic cells promotes T-cell priming. AB - Dendritic cells (DC) are specialized in the processing and presentation of antigen for the activation of lymphocytes. Multiple subsets of DCs exist with distinct functions and roles in the initiation of immune responses. DCs found within tissues acquire antigens or become infected by pathogens and migrate to local draining lymph nodes (LN) where they can directly stimulate T cells. These migratory DCs can also transfer antigens to LN-resident DCs and may indirectly enhance T cell priming. In this issue of the European Journal of Immunology, Gurevich et al. [Eur. J. Immunol. 2017. 47: 1802-1818] elegantly demonstrate the influence of the transfer of antigen from migratory DCs to resident DCs on the dynamics of CD8 T-cell priming in mice. Using both in vitro imaging to visualise antigen dissemination and intravital 2-photon microscopy to track T cell clustering with migratory and resident DCs, antigen-donor DC were found to efficiently distribute antigen to recipient DC. This process, which involved LFA 1, enhanced the recruitment of CD8+ T cells into the response and rescued priming when DCs were impaired in presentation capacity. Together, these findings shed light on the dynamics of the transfer of antigens between DCs in vivo for the efficient priming of cytotoxic T cell responses. PMID- 28845905 TI - Delivery of Therapeutic Proteins Using Electrospun Fibers-Recent Developments and Current Challenges. AB - Proteins play a vital role within the human body by regulating various functions and even serving as structural constituent of many body parts. In this context, protein-based therapeutics have attracted a lot of attention in the last few decades as potential treatment of different diseases. Due to the steadily increasing interest in protein-based therapeutics, different dosage forms were investigated for delivering such complex macromolecules to the human body. Here, electrospun fibers hold a great potential for embedding proteins without structural damage and for controlled release of the protein for therapeutic applications. This review provides a comprehensive overview of the current state of protein-based carrier systems using electrospun fibers, with special emphasis on discussing their potential and key challenges in developing such therapeutic strategies, along with a prospective view of anticipated future directions. PMID- 28845906 TI - Injury risk factors to farm and ranch operators in the Central United States. AB - BACKGROUND: This study focused on risk factors for serious injuries in farm and ranch operators in the central United States. METHODS: The Central States Center for Agricultural Safety and Health, in collaboration with the National Agricultural Statistics Service, sent mail surveys to 6953, 6912, and 6912 farms/ranches in 2011-2013, respectively, covering seven Midwestern states. RESULTS: The average survey response rate was 35%. The average annual incidence rate (injuries/100 workers) was 6.91 for all injuries and 2.40 for serious injuries. Univariate analyses determined several demographic and farm production related risk factors for serious injury. Adjusted analysis showed a greater risk of serious injury for operators of age 45-54 years (vs. 65 and higher), those who worked 75-99% of their time (vs. less time), and those who operated larger land areas (vs. smaller). CONCLUSION: The identified risk factors should be considered when targeting injury prevention programs. PMID- 28845907 TI - Targeted axillary dissection after neoadjuvant therapy in breast cancer. PMID- 28845908 TI - Eplerenone might affect atrial fibrosis in patients with hypertension. AB - BACKGROUND: Eplerenone is reported to reduce the development of atrial fibrillation (AF). The aim of this study was to clarify the mechanism of eplerenone for AF prevention from the viewpoint of P wave morphology, which is reported to correlate with atrial fibrosis. METHODS: Thirty-five patients with hypertension, who were randomized to receive eplerenone (n = 16) or amlodipine (n = 19) for 1 year, were evaluated. P wave signal-averaged electrocardiography was recorded at baseline and 1 year after entry, and P wave duration (Ad) and P wave dispersion (P-disp) were obtained. Serum levels of intact procollagen type I N terminal propeptide (PINP) and N-terminal procollagen-III peptide (PIIIP) were also measured. RESULTS: There were no significant differences in baseline clinical characteristics including Ad, P-disp, and the decrease in blood pressure at 1-year follow-up between the two groups. Ad and P-disp (mean +/- standard deviation) significantly increased in patients on amlodipine after 1 year (140 +/ 21 ms to 139 +/- 19 ms vs 132 +/- 10 ms to 136 +/- 12 ms, P < 0.01 and 14 +/- 7 ms to 9 +/- 4 ms vs 12 +/- 5 to 16 +/- 8, P < 0.01, respectively). PINP was significantly more decreased in patients with eplerenone than amlodipine (56.6 +/ 30.4 MUg/mL to 46.6 +/- 19.4 MUg/mL vs 41.5 +/- 16.2 MUg/L to 48.7 +/- 21.3 MUg/L, P < 0.01). Percent changes of Ad, P-disp, PINP, and PIIIP were significantly smaller in patients with eplerenone than amlodipine (0.0 +/- 4.7% vs 3.2 +/- 4.4%, P < 0.05, - 28.6 +/- 31.0% vs 46.3 +/- 73.0%, P < 0.01, - 5.6 +/ 38.1% vs 22.7 +/- 42.7%, P < 0.05, and - 9.2 +/- 25.1% vs 7.4 +/- 19.0%, P < 0.05, respectively). CONCLUSIONS: Eplerenone reduced the increase of Ad and P disp with a decrease of PINP and PIIIP, which might translate into reduction of atrial fibrosis. This study showed that eplerenone may be useful as upstream therapy for AF in patients with hypertension. PMID- 28845909 TI - Nivolumab infusion reaction manifesting as plantar erythema and pulmonary infiltrate in a lung cancer patient. AB - Infusion reaction is an adverse event of therapeutic monoclonal antibodies. Nivolumab, an anti-programmed death-1 antibody, directly activates T cells, which could probably interact with endothelial cells. The etiology of infusion reaction induced by nivolumab may differ from that of other antibodies; however, the detailed clinical features are unknown. We report a case of lung cancer treated with nivolumab, in which the infusion reaction manifested as plantar erythema, followed by a transient local pulmonary infiltrate around the tumor. Physicians should be aware that an infusion reaction induced by anti-programmed death-1 antibodies could appear as local cutaneous and pulmonary adverse events. PMID- 28845910 TI - Successful eradication of Helicobacter pylori with a herbal medicine, goshuyuto (Wu Zhu Yu Tang), plus rabeprazole after failure of triplet therapy with vonoprazan: A report of three cases. PMID- 28845911 TI - The Forgotten Nitroaromatic Phosphines as Weakly Donating P-ligands: An N-Aryl benzimidazolyl Series in RhCl(CO) Complexes. AB - The coordination chemistry of a priori weakly sigma-donating nitroaromatic phosphines is addressed through a series of nitro-substituted (N-phenyl benzimidazol-1-yl)diphenylphosphines in RhI complexes. From a set of seven such phosphines L=Lxyz(') (x, y, z=0 or 1=number of NO2 substituents at the 5, 6 and N Ph para positions, respectively), including the non-nitrated parent L000 and its dicationic N-methyl counterpart L000 ', three LRhCl(COD) and seven L2 RhCl(CO) complexes have been obtained in 72-95 % yield. Despite of a cis orientation of the L and CO ligands, the C=O IR stretching frequency nuCO varies in the expected sense, from 1967+/-1 cm-1 for Lxy0 to 1978+/-1 cm-1 for Lxy1 , and 2005 cm-1 for L000 '. The 103 Rh NMR chemical shift deltaRh varies from -288 ppm for L000 to 316+/-1 ppm for L10z or L01z , and -436 ppm for L000 '. The nuCO and deltaRh probes thus reveal moderate but systematic variations, and act as "orthogonal" spectroscopic indicators of the presence of nitro groups on the N-Ph group and the benzimidazole core, respectively. For the dicationic ligand L000 ', a tight electrostatic sandwiching of the Rh-Cl bond by the benzimidazole moities is evidenced by X-ray crystallography (RhCldelta- ???CN2+ ~3.01 A). Along with the LRhCl(CO) complexes, dinuclear side-products (MU-CO)(RhClL)2 were also obtained in low spectroscopic yield: for the dinitro ligand L=L011 , a unique 1:6.7 clathrate structure, with dichloromethane as solvate, is also revealed by X-ray crystallography. PMID- 28845912 TI - Theoretical Study on the Conformational Bioeffect of the Fluorination of Acetylcholine. AB - There has been an increasing interest in the study of fluorinated derivatives of gamma-aminobutyric acid (GABA), an acetylcholine (AC) analog. This work reports a theoretical study on the effect of an alpha-carbonyl fluorination in AC, aiming at understanding the role of a distant fluorine relative to the positively charged nitrogen on the conformational folding of the resulting fluorinated AC. In addition, the chemical and structural changes were evaluated on the basis of ligand-enzyme (acetylcholinesterase) interactions. In an enzyme-free environment, the fluorination yields conformational changes relative to AC due to the appearance of some attractive interactions with fluorine and a weaker steric repulsion between the fluorine substituent and the carboxyl group, rather than to a possible electrostatic interaction F???N+ . Moreover, the gauche orientation in the N-C-C-O fragment of AC owing to the electrostatic gauche effect is reinforced after fluorination. For instance, the conformational equilibrium in AC is described by a competition between gauche and anti conformers (accounting for the N-C-C-O dihedral angle) in DMSO, while the population for a gauche conformer in the fluorinated AC is almost 100 % in both gas phase and DMSO. However, this arrangement is disrupted in the biological environment even in the fluorinated derivative (whose bioconformation-like geometry shows a ligand-protein interaction of -84.1 kcal mol-1 against -79.5 kcal mol-1 for the most stable enzyme-free conformation), which shows an anti N-C-C-O orientation, because the enzyme induced-fit takes place. Nevertheless, the most likely bioconformation for the fluorinated AC does not match the bioactive AC backbone nor the most stable enzyme-free conformation, thus revealing the role of fluorination on the bioconformational control of AC. PMID- 28845913 TI - Alcohol-related presentations to the Royal Perth Hospital Emergency Department: A prospective study. AB - OBJECTIVE: To quantify and describe alcohol-related presentations to our ED, as part of the binational Alcohol Harm in Emergency Departments study. METHODS: A prospective observational study at Royal Perth Hospital of every patient attending ED for the 168-h period commencing 08.00 hours Monday 1 December 2014. Patient presentations were classified as alcohol-related (alcohol-positive) using predefined criteria. These patients were compared to alcohol-negative patients on a range of demographic and clinical descriptors. RESULTS: Two hundred and thirteen (15.2%) of 1403 patients screened were alcohol-positive. Compared with alcohol-negative patients, alcohol-positive patients were more likely to be male (148/213, 69.5% vs 636/1190, 53.4%, P < 0.001) and younger (mean 38 years vs 48 years, P < 0.001). They were more likely to arrive in police custody (OR 3.7, 95% CI 1.3-9.5, P = 0.005), and be admitted to the State Adult Major Trauma Unit (OR 4.2, 95% CI 2.1-8.3, P < 0.001). Forty-two (19.7%) of 213 patients had injuries suspected to be caused by an alcohol-affected third party. The ED length of stay and admission rate were not significantly different between the groups. CONCLUSIONS: 15.2% of patient presentations over the study week were alcohol related. These patients were more likely to present with injury; one in five having injuries suspected to be caused by a third party affected by alcohol. This is a significant public health problem. PMID- 28845914 TI - Efficient Aryl Migration from an Aryl Ether to a Carboxylic Acid Group To Form an Ester by Visible-Light Photoredox Catalysis. AB - We have developed a highly efficient aryl migration from an aryl ether to a carboxylic acid group through retro-Smiles rearrangement by visible-light photoredox catalysis at ambient temperature. Transition metals and a stoichiometric oxidant and base are avoided in the transformation. Inspired by the high efficiency of this transformation and the fundamental importance of C-O bond cleavage, we developed a novel approach to the C-O cleavage of a biaryl ether to form two phenolic compounds, as demonstrated by a one-pot, two-step gram scale reaction under mild conditions. The aryl migration exhibits broad scope and can be applied to the synthesis of pharmaceutical compounds, such as guacetisal. Primary mechanistic studies indicate that the catalytic cycle occurs by a reductive quenching pathway. PMID- 28845915 TI - Sorbus aucuparia and Sorbus aria as a Source of Antioxidant Phenolics, Tocopherols, and Pigments. AB - Due to its nutritive and medicinal properties, berries of some Sorbus species are used for the preparation of jams and jelly as well as in traditional medicine. On the other hand, their chemical composition is not much studied especially of those grown in Balkan Peninsula. We have analyzed individual phenolics, tocopherols, carotenoids and chlorophylls using HPLC in berries from Sorbus aucuparia and Sorbus aria collected in different localities in Serbia and Montenegro together with the amounts of total phenolics and proanthocyanidins as well as their radical scavenging activity against DPPH radical. Berries of S. aucuparia were richer source of polyphenolics in comparision with S. aria and, regardless the species and locality, caffeoylquinic acids such as neochlorogenic and chlorogenic acid were the most abundant compounds. Among analyzed tocopherols the most abundant in all samples was alpha-tocopherol (0.48 - 19.85 MUg/g dw) as it was beta-carotene among carotenoids (mean concentration of 0.98 MUg/g dw in S. aucuparia and 0.40 MUg/g dw in S. aria, respectively). Correlation between total phenolics and DPPH radical scavenging activity was noticed. Our study represents comprehensive report on chemical composition of S. aucuparia and S. aria which could contribute to a better understanding of their quality. PMID- 28845916 TI - Pressure-Induced Phase Transition in Weyl Semimetallic WTe2. AB - Tungsten ditelluride (WTe2 ) is a semimetal with orthorhombic Td phase that possesses some unique properties such as Weyl semimetal states, pressure-induced superconductivity, and giant magnetoresistance. Here, the high-pressure properties of WTe2 single crystals are investigated by Raman microspectroscopy and ab initio calculations. WTe2 shows strong plane-parallel/plane-vertical vibrational anisotropy, stemming from its intrinsic Raman tensor. Under pressure, the Raman peaks at ~120 cm-1 exhibit redshift, indicating structural instability of the orthorhombic Td phase. WTe2 undergoes a phase transition to a monoclinic T' phase at 8 GPa, where the Weyl states vanish in the new T' phase due to the presence of inversion symmetry. Such Td to T' phase transition provides a feasible method to achieve Weyl state switching in a single material without doping. The new T' phase also coincides with the appearance of superconductivity reported in the literature. PMID- 28845917 TI - Polypyrrole Whelk-Like Arrays toward Robust Controlling Manipulation of Organic Droplets Underwater. AB - Whelk-like polypyrrole (PPy) arrays film is successfully prepared by electropolymerization of pyrrole in the presence of low-surface-energy tetraethylammonium perfluorooctanesulfonate (TEAPFOS) as dopant. The underwater wettability of PPy whelk-like arrays can be successfully tuned by electrical doping/dedoping of PFOS ions. Interestingly, CCl4 droplets with microliter-size as a representative sample are gathered together to form a larger droplet underwater at the potential of +0.8 V (vs Ag/AgCl), because PPy is in its PFOS doped states. Note that CCl4 droplet can climb uphill successfully on the inclined whelk-like arrays PPy film under the applied potential of -1.0 V (vs Ag/AgCl), which may be attributed to wettability gradient derived from different oxidation states of PPy induced by electrochemical potential. These results may provide a simple strategy for on-demand manipulation of organic droplets underwater at low voltage. PMID- 28845918 TI - HKOH-1: A Highly Sensitive and Selective Fluorescent Probe for Detecting Endogenous Hydroxyl Radicals in Living Cells. AB - The hydroxyl radical (. OH), one of the most reactive and deleterious reactive oxygen species (ROS), has been suggested to play an essential role in many physiological and pathological scenarios. However, a reliable and robust method to detect endogenous . OH is currently lacking owing to its extremely high reactivity and short lifetime. Herein we report a fluorescent probe HKOH-1 with superior in vitro selectivity and sensitivity towards . OH. With this probe, we have calibrated and quantified the scavenging capacities of a wide range of reported . OH scavengers. Furthermore, HKOH-1r, which was designed for better cellular uptake and retention, has performed robustly in detection of endogenous . OH generation by both confocal imaging and flow cytometry. Furthermore, this probe has been applied to monitor . OH generation in HeLa cells in response to UV light irradiation. Therefore, HKOH-1 could be used for elucidating . OH related biological functions. PMID- 28845919 TI - Optimizing Optical Absorption, Exciton Dissociation, and Charge Transfer of a Polymeric Carbon Nitride with Ultrahigh Solar Hydrogen Production Activity. AB - Polymeric or organic semiconductors are promising candidates for photocatalysis but mostly only show moderate activity owing to strongly bound excitons and insufficient optical absorption. Herein, we report a facile bottom-up strategy to improve the activity of a carbon nitride to a level in which a majority of photons are really used to drive photoredox chemistry. Co-condensation of urea and oxamide followed by post-calcination in molten salt is shown to result in highly crystalline species with a maximum pi-pi layer stacking distance of heptazine units of 0.292 nm, which improves lateral charge transport and interlayer exciton dissociation. The addition of oxamide decreases the optical band gap from 2.74 to 2.56 eV, which enables efficient photochemistry also with green light. The apparent quantum yield (AQY) for H2 evolution of optimal samples reaches 57 % and 10 % at 420 nm and 525 nm, respectively, which is significantly higher than in most previous experiments. PMID- 28845920 TI - Ethical issues in pediatric face transplantation. AB - Facial transplantation has become a reality in adult medicine. Children are subject to congenital craniofacial differences, disease-related, traumatic, or thermochemical craniofacial changes and might be suitable for face transplantation. This manuscript addresses unique ethical issues in considering potential pediatric face transplant. These challenges are operant at the individual, technologic, and psychosocial level for clinicians, investigators, and society. PMID- 28845921 TI - Safety of hematopoietic cell infusion in children with malignant and non malignant diseases. AB - HPC infusions have been associated with a variety of adverse events related to either patient or HPC product-related factors. Studies documenting infusion related AEs in children are limited. We reviewed HPC infusion records in 354 children. Infusion-related adverse events were classified as follows: grade 0 absent, grade I-mild, grade II-moderate, grade III-severe, grade IV-life threatening, and grade V-death. The percentage of patients with grade 0, I, and II-IV AEs was as follows: 0 = 67%, I = 23.4%, and II-V = 9.6% (one patient had fatal anaphylactic reaction to dimethyl sulfoxide). The incidence of grade II-IV hypertension was 7.1%. There was a higher incidence of AEs with infusion of allogeneic bone marrow versus allogeneic PBSCs (47.4% vs 25.3%, P = .001). Cryopreserved products had a lower incidence of infusion-associated AEs compared with fresh HPC products (24% vs 39.4%, P = .003). Allogeneic HPC infusion volume (>100 mL) was a significant risk factor for infusion-associated AEs (P < .001). Patients >10 years who received autologous HPC infusions had higher risk of AEs when compared to patients <10 years (P = .01). Our study demonstrated that despite a high incidence of infusion-associated hypertension, HPC infusion is relatively safe in children. Investigating strategies to optimize management of hypertension in the setting of HPC infusion is warranted. PMID- 28845925 TI - [Female urinary incontinence]. PMID- 28845924 TI - [Lower urinary tract symptoms and benign prostatic hyperplasia]. PMID- 28845926 TI - [Lower urinary tract symptoms secondary to benign prostatic hyperplasia in 2017: update from the 32nd annual congress of European association of urology]. AB - This review article summarizes new data on mono- and combination therapy for male urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). A special attention is paid to the reports made at the 32nd Annual EAU Congress and published in the congress proceedings. The article outlines new data on the epidemiology of LUTS secondary to BPH, recent changes in the pathogenesis of LUTS, provides a critical analysis of the latest publications on -blockers, 5 reductase inhibitors, antimuscarinics and phosphodiesterase type 5 inhibitors in pharmacological management of LUTS. The authors analyze recent data on the effectiveness of surgical methods for treating BPH. PMID- 28845923 TI - Clinical rating scale for pantothenate kinase-associated neurodegeneration: A pilot study. AB - BACKGROUND: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration. METHODS: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs. RESULTS: Forty-seven genetically confirmed patients (30 +/- 17 years; range, 6-77 years) were examined with the scale (mean score, 62 +/- 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's alpha = 0.87). On interrater analysis, weighted kappa values (0.30 0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale. CONCLUSIONS: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28845927 TI - [Conservative management of benign prostatic hyperplasia: are urologists satisfied?] AB - The author presents his point of view on the conservative management of benign prostatic hyperplasia and the role of combination therapy (co-administration of blockers and 5-reductase inhibitors) in the treatment of voiding symptoms. The latest evidence for combination therapy of prostatic hyperplasia published in 2017 is also presented. PMID- 28845922 TI - Three-Dimensional Models of the Human Brain Development and Diseases. AB - Deciphering the human brain pathophysiology remains one of the greatest challenges of the 21st century. Neurological disorders represent a significant proportion of diseases burden; however, the complexity of the brain physiology makes it challenging to model its diseases. Simple in vitro models have been very useful for precise measurements in controled conditions. However, existing models are limited in their ability to replicate complex interactions between various cells in the brain. Studying human brain requires sophisticated models to reconstitute the tangled architecture and functions of brain cells. Recently, advances in the development of three-dimensional (3D) brain cell culture models have begun to recapitulate various aspects of the human brain physiology in vitro and replicate basic disease processes of Alzheimer's disease, amyotrophic lateral sclerosis, and microcephaly. In this review, we discuss the progress, advantages, limitations, and future directions of 3D cell culture systems for modeling the human brain development and diseases. PMID- 28845928 TI - [Male infertility]. PMID- 28845929 TI - [Erectile dysfunction]. PMID- 28845930 TI - [Urolythiasis]. PMID- 28845931 TI - [Adjuvant antioxidant therapy in varicocele infertility]. AB - INTRODUCTION: Infertility affects an estimated 15% of couples globally. Male factor infertility accounts for about a half of infertility cases. About 40% of infertile men have varicocele. The aim of this study was to investigate the efficacy and safety of a complex of acetyl-L-carnitine, L-carnitine fumarate and alpha-lipoic acid (SpermActin-forte) (SA) for adjuvant antioxidant therapy after microsurgical varicocelectomy (MVE) in men with varicocele and assess its impact on the level of DNA fragmentation in sperm cells. MATERIALS AND METHODS: This is an open, prospective, randomized trial comprising 114 men aged 25-45 (mean 34.1+/ 12.1) years who underwent MVE. The patients were allocated to receive either adjuvant SA (n=38), SA in combination with a vitamin complex (VC) (n=38) or no adjuvant therapy (n=38). The efficacy was assessed at 3 months by testing standard semen parameters and the level of sperm DNA fragmentation. RESULTS: MVE led to a 21.7% increase in the progressive sperm motility compared to the baseline level. In patients receiving SA, this was by 76.7% due to active sperm motility (category A) at 3 months. MVE with concurrent supplementation of SA resulted in a 22.3% decrease in the level of sperm DNA fragmentation at 3 months. When used in the postoperative period after MVE, SA and VC resulted in a 27% increase in the sperm concentration at 3 months. There were no side effects of pharmacotherapy. The statistical significance of the change in variables was calculated using the Wilcoxon test. Critical level =0.05 was established for all criteria. CONCLUSION: Using nutraceuticals (SA) after MVE is an effective and safe adjuvant antioxidant therapy of male infertility in patients with varicocele which leads to an improvement in the basic sperm parameters (sperm concentration and motility) and a decrease in the level of sperm DNA fragmentation in the short term. Adjuvant antioxidant therapy of varicocele infertility potentiates the effects of monotherapy (both medical and surgical), leads to an increase in its effectiveness and shortens the time to pregnancy. Further studies in this field are needed to assess long-term outcomes of the treatment. PMID- 28845932 TI - [Early diagnosis of risk for developing calcium oxalate urolithiasis]. AB - AIM: To identify risk groups for calcium oxalate urolithiasis among healthy individuals and patients with urolithiasis in the Russian population using molecular genetics. MATERIALS AND METHODS: The study comprised 72 patients with calcium oxalate urolithiasis (study group) and 189 healthy adults from the general Russian population (control group). The study group consisted of 39 (54.2%) men and 33 (45.8%) women. The mean age of urolithiasis patients was 41.5+/-12.4 years. Analysis of polymorphic variants of 8 candidate urolithiasis genes: tumor necrosis factor 11B (TNFRSF11B, rs3134057), -subunit of the nuclear estrogen receptor (ESR1, rs851982), Cloto gene (KL, rs526906), vitamin D receptor (VDR, rs1540339 ), an extracellular calcium-sensing receptor (CASR, rs2202127), membrane anion transporter family 26 (SLC26A6, rs2310996), tumor necrosis factor 11 (TNFSF11, rs9525641), the calcium release-activated calcium modulator 1 (ORAI1, rs7135617) in two groups was performed by real-time PCR using Applied Biosystems test. Statistical analysis was performed using Fishers angular transformation and 2. RESULTS: In the polymorphism of the ORAI1 gene (rs7135617), the differences in the frequencies of the GG genotype and the G allele in the control sample and in the sample of patients with calcium oxalate urolithiasis were significant: p=0.0004 and p=0.001, respectively. No statistically significant differences in the genotype and allele frequencies were found in the remaining seven gene polymorphisms. CONCLUSIONS: Healthy individuals and patients with urolithiasis in the Russian population who have the GG genotype and/or the G allele of the polymorphism of the ORAI1 gene (rs7135617) represent risk groups for the formation of calcium oxalate stones. PMID- 28845933 TI - [Is bacteriological testing of bladder urine informative in acute obstructive pyelo- nephritis?] AB - : The problem of the etiology and pathogenesis of acute obstructive pyelonephritis (OOP) remains one of the challenging issues of modern urology. Etiological agents of pyelonephritis can be both gram-negative and gram-positive opportunistic bacteria mostly belonging to the normal flora in humans. The generally accepted diagnostic work-up involves a bacteriological testing of not pelvic urine, but of bladder urine collected by a transurethral catheter or midstream specimens of urine collected from the patients. The aim of our study was to compare the microbiota of bladder and pelvic urine in patients with OOP. MATERIALS AND METHODS: The study comprised 72 sequentially selected patients (12 men and 60 women) with OOP associated with ureteral stones. Mean age of patients was 53.7+/-0.5 years. All patients underwent bacteriological examination of the bladder urine collected by a transurethral catheter and pelvic urine obtained after relieving stone-related ureteral obstruction. Urinary diversion was performed using j-j stent and PCN in 64 and 8 patients, respectively. Preoperative prophylactic antibiotics were administered routinely. Bacteriological testing of urine was carried out using an extended set (9-10) of culture media. Empirical antibiotic therapy was initiated only after the restoration of urine outflow from the kidney and continued for 5-6 days until the availability of bacteriological testing results. RESULTS: Levels of bacteriuria with Enterobacteria, gram-positive pathogens and NAB in two urine samples did not differ significantly (p>0.05). There was a wide range of bacteriuria from 101 to 106 CFU/ml of most microorganisms except @Proteus spp., S. aureus. In bladder urine, the rates of bacteriuria of more or equal 104 CFU/ml for E. coli, Klebsiella spp. and Proteus spp. were 90.9%, 72.7% and 100.0%, respectively. For the remaining microorganisms, predominant bacteriuria was less or equal 103 CFU/ml. In pelvic urine, the rates of bacteriuria of more or equal 104 CFU/ml for E. coli, Klebsiella spp. and Proteus spp. was 71.8%, 40.0% and 66.7%, respectively. Other uropathogens in the pelvic urine mainly had a bacterial count of less or equal 103 CFU/ml. Only the concentration of Corynebacterium spp. in the pelvic urine significantly (p=0.023) differed from that of the bladder urine. There were no significant differences between microbiota of bladder and pelvic urine depending on duration of OOP except higher rates of Corynebacterium spp. in the bladder urine. PMID- 28845934 TI - [Troyakov. Experience in using hytolysin in the integrated management of urinary tract infections and methapylactics of nephrolithiasis]. AB - RELEVANCE: Urinary tract infection (UTI) are a risk factor for diseases leading to impairment of renal function and kidney stone disease (KSD). Growing resistance of uropathogens to antibacterial agents is a challenging issue in most countries of the world. Urolithiasis is the second most prevalent urologic condition following urinary tract infections and has a pronounced tendency to recur. Rational stone metaphylaxis leads to a significant reduction in the incidence of recurrent stones. In recent decades, there has been a markedly increasing interest in plant-based therapies in managing urologic diseases. AIM: To evaluate the effectiveness of phytotherapeutic medication Phytolysin in the integrated management of UTI and metaphylaxis of urolithiasis. MATERIALS AND METHODS: Comprehensive evaluation of the effectiveness of Phytolysin was conducted at the Department of Urology, I.M. Sechenov First MSMU and Department of Urology, Andrology and Sexology, Voino-Yasenetsky Krasnoyarsk SMU in 40 women with episodes of exacerbation of chronic cystitis and 30 patients of both sexes during the postoperative metaphylaxis of the KSD. The age of the patients ranged from 20 to 68 years (mean age 40+/-2,8 years). RESULTS: Adding Phytolysin to the integrated management results in the improvement in general clinical signs and laboratory parameters of blood and urine, leads to a decrease in the level of leukocyturia, bacteriuria and an increase in diuresis and urinary alkalinization, reduces the number relapses of UTI and stone formation. CONCLUSION: Phytolysin is an effective and safe medication. PMID- 28845935 TI - [Using L- and acetyl-L-carnintines in combination with clomiphene citrate and antioxidant complex for treating idiopathic male infertility: a prospective randomized trial]. AB - : The most common cause of male infertility is idiopathic oligo-, and or astheno , and /or teratozoospermia. In such cases, anti-estrogens, antioxidants (vitamins and trace elements) or carnitines are used, but the evidence on their effectiveness is inconsistent; there are currently no published studies exploring their concurrent use. AIM: To investigate the efficacy and safety of the L- and acetyl-L-carnitine complex, vitamins A, E, C, selenium, zinc and other antioxidants ("SpermActin" + "More than vitamins") in combination with clomiphene citrate (CC) in managing male idiopathic infertility in the form of oligo, and/or astheno-, and/or teratozoospermia. MATERIALS AND METHODS: The study comprised 173 men from infertile couples aged 25-45 years who were divided into two groups - the study group (n=88) and control group (n=85). All the patients were examined according to the WHO recommendations. Patients of the study group received L carnitine fumarate (1 g), acetyl-L-carnitine (0.5 g) twice daily, a complex of vitamins and microelements and CC 25 mg twice daily orally. Patients of the control group were administered the same dosages of CC and a complex of vitamins. Ejaculate was evaluated before and after 3-4 months of treatment. Six months after the start of treatment, information about the onset or absence of pregnancy over the last six months was collected via telephone or online survey. RESULTS: Co-administration of L- and acetyl-L-carnitines concurrently with CC and antioxidant complex (vitamins and minerals) in patients with idiopathic oligo- and/or asteno- and/or teratozoospermia provides some additional positive effect on the concentration of spermatozoa, more pronounced in patients with multiple impaired semen parameters - oligoasthenoteratozoospermia, but does not improve the morphology, progressive sperm motility and pregnancy rates compared to patients receiving basic treatment. PMID- 28845936 TI - [Systematic approach in performing isolated and simultaneous operations in elderly patients with prostate adenoma]. AB - AIM: To develop a scientifically based system for treating elderly patient with prostate adenoma (AP), aimed at reducing the incidence and severity of complications and mortality after isolated and simultaneous operations. MATERIALS AND METHODS: Between 1995 and 2015, 1170 elderly and older patients with prostate adenoma (PA) underwent isolated adenomectomy (AE) or transurethral resection of the prostate (TURP) or simultaneous operations (SO). Simultaneous interventions were performed in 335 (28.6%) patients. RESULTS: Immediate treatment results were significantly better in patients who underwent isolated TURP or TURP as a part of SO than that of those who had isolated AE or AE as a part of SO. SO was not associated with greater incidence of local or general postoperative complications and mortality compared with isolated AE or TURP. CONCLUSION: Continuous advancements in diagnostic and treatment methods contributed to a significant reduction in the incidence of postoperative complications and deaths in geriatric patients with PA. The study findings confirm the superiority of TURP over AE, as previously reported by other authors. PMID- 28845937 TI - [Laparoscopic pyelolithotomy for staghorn kidney stones. multi-center study]. AB - AIM: To analyze the effectiveness and safety of laparoscopic pyelolithotomy (LP) in treating staghorn stones. MATERIALS AND METHODS: A multicentre retrospective analysis of the results of LP performed from January 2004 to December 2016 was conducted. INCLUSION CRITERIA: patients with staghorn calculi K3-K4, who underwent LP as an alternative to percutaneous nephrolithotripsy. The analysis included the incidence and structure of intra- and postoperative complications, the causes of access conversion, operating time, duration of postoperative hospital stay and stone clearance. RESULTS: A total of 137 patients met the inclusion criteria, including 78 (56.93%) men. There was no mortality and access conversion. Intraoperative complications occurred in 2 (1.46%) patients. Operating time was 130 [100; 150] min, blood loss was 150 [100; 200] ml. No need for blood transfusion was observed. The cumulative rate of postoperative complications was 5.11%, stone clearance was achieved in 86.13% of observations, the duration of postoperative hospital stay was 7 [7; 11] days. CONCLUSION: In cases of dense staghorn calculi located in a large "extra-renal" pelvis and have calyceal branches equal to the diameter of their necks, laparoscopic pyelolithotomy is an alternative not only to open, but also to percutaneous surgery. PMID- 28845938 TI - [Questions of terminology, systematization and grading of complications of contact ureteral lithotripsy]. AB - AIM: To investigate the advantages and disadvantages of the current variants of systematization and grading of complications of contact ureteral lithotripsy (CULT) and develop a working classification of CULT complications. MATERIALS AND METHODS: The study analyzed results of 545 fluoroscopy-guided endoscopic procedures performed at the MRRCI Clinic of Urology from 2008 to 2015 in 506 patients with ureterolithiasis. RESULTS: The proposed and implemented classification and terminology of CULT complications unifies the diagnostic and management algorithm. This tool is more systematic and structured than the classical classification and universal methods of systematization and grading of CULT complications (classifying CULT complications in "major" and "minor", PULS scale, Satava and Clavien-Dindo grading systems). Given the lack of clear grading of ureteral rupture, it was divided into amputation (two-level rupture) and avulsion (one-level rupture). Using such term as extravasation of the contrast media and/or migration of the stone outside of the ureter is groundless because these complications occur only after the perforation of the ureteral wall. Therefore, these conditions are complications not of CULT, but of the ureteral wall perforation. The ureteral perforation was classified into macro- and micro perforation. CONCLUSION: The existing terminology, classification and grading of the CULT complications should undergo a more detailed analysis. None of the existing classifications of CULT complications afford them to be fully staged and systematized. The working classification of complications of CULT developed at the M.F. Vladimirsky MRRCI Clinic of Urology warrants a multi-center prospective study to validate it and investigate its effectiveness. PMID- 28845939 TI - [Experience in ureteroscopy for managing urolithiasis in one clinic. when does quantity transform into quality?] AB - INTRODUCTION: In recent years, there has been an increasing role of ureteroscopy in managing urinary tract calculi of various locations. Several studies have reported the relationship between the efficacy and safety of ureteroscopic interventions and surgeons skills and hospital caseload volume. The aim of our study was to assess the effectiveness of urethroscopic stone removal, the changes in treatment effectiveness, frequency and types of complications along with gaining experience in these interventions. MATERIALS AND METHODS: We analyzed 4031 urolithiasis patients who were admitted to our urological department and underwent ureteroscopy from 2001 to 2013. To determine the effectiveness and safety of the method, as the experience gained, the time of observation was divided into three periods: from 2000 to 2004, from 2004 to 2009, from 2009 to 2013. The parameters were evaluated for the entire observation time and for each period. RESULTS: Complete fragmentation of the stones was observed in 3628 (90%) patients, partial - in 219 (5.4%). No treatment effect was observed in 138 (3.4%) patients. The greatest effectiveness (96.94%) was seen in stones in the lower third of the ureter. The proportion of unsuccessful ureteroscopies was 5.7%, 4.5% and 3.5% for the periods 2000 -2004, 2005-2009 and 2009-2013, respectively (p=0.027). The incidence of acute postoperative pyelonephritis in the corresponding periods was 15.4%, 3.3% and 2.9% (p<0.001). CONCLUSION: Ureteroscopy is an effective and safe treatment modality for managing upper urinary tract calculi. It is most effective in treating distal ureteral stones. The increase in the treatment effectiveness and the reduction in the incidence of complications along with gaining experience, suggests that these interventions should be practiced mainly in urology centers specializing in the care of patients with urolithiasis. PMID- 28845940 TI - [High oncogenic risk human papillomavirus and urinary bladder cancer]. AB - AIM: To determine the role of human papillomavirus (HPV) of high oncogenic risk in the development of urinary bladder cancer. MATERIALS AND METHODS: 100 patients (72 men and 28 women) aged 38 to 90 years (mean age 65+/-10 years) diagnosed with bladder cancer were examined and underwent treatment. Clinical assessment was complemented by enzyme-linked immunosorbent assays for the presence of antiviral antibodies to herpes simplex virus (HSV) type 1 and type 2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), urethra scraping for detecting high oncogenic risk HPV. Tumor tissue was sampled for PCR virus detection. Semi-quantitative analysis was used to evaluate the components of lymphocyte-plasmocyte and leukocyte infiltrates and cytopathic changes in tumor tissue. RESULTS: There were positive correlations between cytopathic cell changes (koylocytosis and intranuclear inclusions, as manifestations of HPV) and the level of antiviral antibodies, the presence of viruses in the tumor, as well as with the components of the lymphoid-plasmocyte infiltrate. Negative correlations were found between the presence of papillomatosis and the above changes. CONCLUSION: Human papillomavirus is believed to be a trigger for the initiation of a tumor in young patients with a latent infection (CMV and EBV, HSV, HPV). Cytopathic changes (kylocytosis and intranuclear inclusions) were associated with the activity and morphological features of herpes-viral infections. Their degree varied depending on the stage of the process, but not on the anaplasia degree. Papillomatosis is associated with a more favorable course of the tumor process. PMID- 28845941 TI - [Ultrasound-guided percutaneous cryoablation of renal tumors]. AB - INTRODUCTION: Surgery remains the gold-standard curative treatment for localized (T1) renal carcinoma. However, recent medical-technological advances have led to the development of new minimally invasive treatment options, one of which is percutaneous cryoablation. AIM: To assess the effectiveness and safety of ultrasound-guided percutaneous cryoablation of renal tumors. MATERIALS AND METHODS: The study comprised 12 patients aged 52 to 76 years who underwent ultrasound-guided percutaneous cryoablation of renal tumors from 2015 to 2017. In 11 patients, the size of the renal mass was 3.0 cm (T1a), in 1 patient 4.5 cm (T1b). A Doppler ultrasound, contrast-enhanced MSCT and computer 3D modeling were performed in all patients pre-operatively and 6 months after surgery to assess the tumors size and extent and the spatial location of the tumor internal surface to the pelvicalyceal system. In all patients, the tumors were located along the posterior or lateral surface of the kidney, in the lower or middle segment and without sinus invasion. We used a 3rd generation Galil Medicals SeedNet Gold Cryotherapy System and IceSeed and IceRod cryoprobes. Intraoperatively, immediately before cryoablation, the tumor was biopsied. In all patients the diagnosis of renal cell carcinoma was confirmed morphologically. RESULTS: Mean duration of cryoablation was 60 minutes. Endotracheal, spinal, local and intravenous anesthesia was used in 1, 6, 5 and 1 patients, respectively. Doppler ultrasound at 6 months after surgery showed that in 11 patients (T1a) the tumor size decreased on average by 8 mm, with no blood flow in the tumors. MSCT with 3D modeling also revealed a decrease in tumor size and total absence of contrast agent accumulation, or accumulation gradient not exceeding 10 HU (initially it was about 200 HU). In the patient with T1b stage renal carcinoma, MSCT showed a decrease in tumor size from 4.5 to 3.7 cm, however, there was a mass up to 1.5 cm with a high gradient of contrast agent accumulation. The patient underwent kidney resection. No intra- and postoperative complications were observed. CONCLUSION: The accumulated experience allows to confirm the effectiveness and safety of ultrasound-guided percutaneous cryoablation and to consider it a method of choice for patients with stage T1a renal carcinoma located along the posterior or lateral surface of the kidney in the lower or middle segment, without sinus invasion. PMID- 28845942 TI - [An injury of major vessels during laparoscopic procedure in urology. Surgical management by analyzing of clinical cases]. AB - An injury of major vessels is a life - threating complication in laparoscopic urology. Review of the literature and analysis of own cases have been performed. The authors offer original surgical management with using hand-assistant technic. It has advantages of open and laparoscopic approach. PMID- 28845943 TI - [Laparoscopic cystoprostatvesiculeectomy with orthotopic excentric ileal bladder substitution]. AB - There are numerous options for forming an orthotopic bladder by the source tissue and the shape of the urinary reservoir. In our practice, we use the technique reported by Karolinska Institute (Sweden). This technique allows us to form a neobladder most resembling the natural urinary bladder in the shape and volume. The article presents a clinical observation describing this technique in a 63 year old patient who was initially diagnosed with bladder cancer pT2N0M0G3 and underwent transurethral resection of the bladder wall with the tumor. Thereafter, the patient underwent laparoscopic cystoprostatvesicleectomy with extended pelvic lymph node dissection and orthotopic ileal bladder substitution. His upper urinary tract on both sides was drained by ureteral stents with external diversion. The eccentric suturing technique makes it possible to form an oval shaped urinary reservoir that is anatomically and functionally most comparable to a healthy man's bladder. PMID- 28845944 TI - [Penile revascularization using laparoscopic mobilization of the inferior epigastric artery]. AB - The article presents a case of successful penile revascularization using laparoscopic mobilization of the inferior epigastric artery in a 35 y. o. patient with penile arteriovenous insufficiency. PMID- 28845945 TI - [Laparoscopic antevasal uretero-ureteral anastomosis for treating retrocaval ureter]. AB - The article presents a case of laparoscopic antevasal correction of the retrocaval ureter in a 16 year old patient, who was admitted to the hospital with complaints of aching pain in the right lower back. His history was noteworthy of early age onset of intermittent fever accompanied by abdominal and lumbar pain. Blood count and urinalysis were within normal limits, and he was treated symptomatically. However, no renal ultrasound scan was done. Intravenous urography and MSCT showed a retrocaval ureter. The diagnosis was confirmed by retrograde ureteropyelography. With the patient placed in the lateral position, the right ureter was mobilized by transperitoneal access, transected and mobilized from under the inferior vena cava. Anterior uretero-ureteral anastomosis on the stent was performed, drainage was established. The operating time was 90 minutes, blood loss was 60 ml. There were no postoperative complications. Drainage was removed 2 days after surgery and the patient was discharged for outpatient treatment. The stent was removed 6 weeks postoperatively. Control urography showed normal function of both kidneys, no urodynamic abnormality of the upper urinary tract was identified. PMID- 28845946 TI - [Nephrolithiasis coexisting with type 2 diabetes: current concept of the features of stone formation and the effects of hypoglycemic therapy on lithogenesis]. AB - The article analyzes Russian and international literature examining specific features of the pathogenesis of renal stones in the setting of carbohydrate metabolism disorders. The authors outline the renal effects of the main pharmacological groups of oral hypoglycemic drugs regarding metaphylaxis of nephrolithiasis. An increased risk of nephrolithiasis in type 2 diabetes mellitus is realized through hyperuricemia with concurrent urine acidification. Current literature is lacking studies on the effects of oral hypoglycemic drugs on urine properties. There are reports about the tendency of biguanides (metformin) to shift the urine reaction to the acid side. Derivatives of sulfonylureas, incretins and inhibitors of dipeptidyl peptidase-4, do not significantly affect the urinary acidity and urinary salt excretion. Inhibitors of sodium-glucose cotransporter type 2 (gliflozins) tend to reduce the blood level of urate, but the mechanism of this effect and the safety of these drugs in the setting of urolithiasis have not yet been investigated. PMID- 28845947 TI - [Dual energy computed tomography in diagnosis of urolithiasis: a new method for determining the chemical composition of urinary stones]. AB - The "gold standard" for the diagnosis and evaluation of urinary stones is native computed tomography, which allows determining stone localization and size of with high accuracy. However, this imaging technique has limited diagnostic usefulness in determining the stone chemical composition. The newly introduced method of dual-energy computed tomography, based on obtaining images at two different energy levels is highly effective in determining the composition of urinary stones. The review outlines the principles and methods of performing dual-energy computed tomography using various scanners. The authors analyze the results of using this method for diagnosing urolithiasis, determining the stone chemical composition and point out the limitations and difficulties encountered in its application. PMID- 28845948 TI - [Resistance of urinary tract pathogens and the choice of antimicrobial therapy: deceptive simplicity]. AB - Urinary tract infection (UTI) is one of the most common reasons for prescribing antibiotics in outpatient and inpatient settings. One of the main criteria for selecting antimicrobial drugs for treating UTI is data on the antibiotic resistance of uropathogens. The article discusses the difficulties in interpreting the results of antimicrobial sensitivity testing of uropathogens and the impact of antibiotic resistance of uropathogens on the clinical effectiveness of managing UTI. PMID- 28845949 TI - [The role of mycoplasma infection (M. hominis and U. urealyticum) in inflammatory diseases of the genitourinary system the debate continues]. AB - The article presents current views on urogenital diseases caused by M. hominis and U. urealyticum. Particular attention is paid to concurrent (co-occurring) urogenital infections. The review reports the data from epidemiological studies and outlines recent Russian and international guidelines and consensuses on managing patients with urogenital inflammatory diseases. The importance of adequate diagnosis and rational therapy of urogenital infections is discussed. PMID- 28845950 TI - [PDE-5 inhibitors: patients preferences]. AB - To date, multidisciplinary approach is commonly used to treat erectile dysfunction (ED), and the first line of ED pharmacotherapy, despite its multiple causes, is phosphodiesterase inhibitors of type 5 (PDE-5). They are considered an effective and well tolerated treatment option [1-4]. Concurrently, sildenafil has the largest evidence base for efficacy and safety [5]. The satisfaction of patients with ED therapy is a complex and personal matter, and there are no clearly established and reliable criteria for showing preferences when choosing a PDE-5. Adherence of patients to the PDE-5 therapy is determined not only by the erectile response and side effects, but also by how well the treatment meets the needs and expectations of patients and how it affects the relationship between the partners. This review examines the tolerability and efficacy of the various types of PDE-5 available for treating ED, with a special emphasis on the patient's preferences, and in particular on the new sildenafil orodispersible films. As an alternative route of drug administration, films quickly dissolve in the mouth [6] and have several advantages, improve sexual health and the sense of psychological well-being of patients and their partners. PMID- 28845951 TI - [American urological association guideline for diagnosis and management of male urethral stricture 2016]. AB - The article provides coverage of the main features of the American Urological Association (AUA) Guideline for the diagnosis and management of male urethral stricture published in 2016. Clinical guideline on this medical condition is published for the first time and is unique in the world of urology. The authors present their comments based on the accumulated experience of diagnosis and treatment of this urological condition. PMID- 28845952 TI - [Russian experience with Vitaprost Forte suppositories in patients with lower urinary tract symptoms and benign prostatic hyperplasia: comparative analysis of studies]. AB - The article reviews the domestic studies showing the efficacy and safety of suppositories containing prostate extract (Samprost substance) Vitaprost Forte in treating men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. The data obtained by Russian specialists confirm the effectiveness of Vitaprost Forte suppositories in managing patients with moderate LUTS and infravesical obstruction caused by BPH to reduce dysuria, improve the quality of life and normalize urodynamic parameters. PMID- 28845953 TI - Vasculopathies, cutaneous necrosis and emergency in dermatology. AB - Most emergencies in dermatology comprise a variety of entities with a usually benign course. However, vasculopathies and vasculitis are not common, but they could represent respectively 1.9% and 4.4% of these entities according to some studies of Emergency Dermatology Department. They become an important disease which has to be identified early to establish appropriate management and treatment. Some of them are well known, such as the leukocitoclastic vasculitis, Scholein-Henoch, panarteritis nodosa, antineutrophil cytoplasmic antibody associated vasculitis, giant cell arteritis, cryoglobulinemic vasculitis and antiphospholipid syndrome. More frequent vasculopathies are livedoid vasculopathy, pigmented purpuric dermatosis and calciphylaxis. Less common ones are caused by interferon and cholesterol crystal embolization. Others are very infrequent as Degos disease and Sneddon Syndrome. Among the more recently described ones there are deficiency of adenosine deaminase type 2 and crystalglobulinemia. The other group is composed of vasculopathies associated to microorganism as infective endocarditis, septic vasculopathy, aspergillosis, fusariosis, strongiloidosis, ecthyma gangrenosum, lucio phenomenon of leprosy and necrotic arachnidism. Finally, among these entities we can also find diseases associated with proinflammatory stages as disseminated intravascular coagulation, myeloproliferative disorders, intravascular lymphoma, metastasis intravascular. When we face cutaneous lesions characterized by reticulated violaceous lesions, palpable purpura or cutaneous necrosis, a careful clinico-pathological correlation as well as some laboratory or radiological tests are mandatory to further delineate a diagnosis and a proper first line empirical treatment. PMID- 28845954 TI - Phototherapy of mycosis fungoides. AB - Mycosis fungoides (MF), the most common variant among cutaneous T cell lymphomas (CTCL), is characterized in its early stages by clonal proliferation of malignant T-cells in the skin manifesting as erythematous patches and plaques with a chronic course and progression to cutaneous tumors and extracutaneous organs in some patients. Skin directed therapies (SDT) are primarily used for effective palliation in early stage disease. Phototherapy with ultraviolet A radiation combined with 8-methoxypsoralen (PUVA) and with ultraviolet B radiation (UVB) has a longstanding history in the treatment of MF and are highly effective in inducing remissions. Patients with erythroderma and blood involvement benefit from treatment with extracorporeal photochemotherapy (ECP) where peripheral blood is exposed to PUVA. Phototherapy can be safely combined with systemic agents, most notably interferon-alpha and retinoids. Recently updated treatment guidelines have been published to provide evidence based algorithms for the stage oriented treatment of MF. PUVA and narrow-band UVB (NB-UVB) are recommended as first line treatment for early stages with combination modalities reserved for refractory and more advanced cases and ECP is among the standard treatments for MF erythroderma. Areas of uncertainty relate to optimized treatment dose and schedules, the use of phototherapy for maintenance, and the role of newer phototherapeutic modalities (e.g. ultraviolet A1 radiation, excimer sources, photodynamic therapy) in the treatment of MF. PMID- 28845955 TI - Hepatosplenic T-cell lymphoma: an acute leukemia presentation PMID- 28845956 TI - Sleep Disorders: Foreword. PMID- 28845957 TI - Sleep Disorders: Sleep-Related Breathing Disorders. AB - Sleep-related breathing disorders or sleep-disordered breathing are characterized by abnormal respiration during sleep. They are grouped into obstructive sleep apnea (OSA), central sleep apnea, sleep-related hypoventilation, and sleep related hypoxemia disorder. OSA is a common disorder encountered in the family medicine setting that is increasingly being recognized because of the obesity epidemic and greater public and physician awareness. OSA is characterized by recurrent episodes of partial or complete closure of the upper airway resulting in disturbed breathing during sleep. It is associated with decreased quality of life and significant medical comorbidities. Untreated OSA can lead to a host of cardiovascular diseases including coronary artery disease, stroke, and atrial fibrillation. Patients who report symptoms of snoring, witnessed apneas, or daytime sleepiness should be screened for sleep apnea. In-laboratory attended diagnostic polysomnography or portable home sleep testing can be used to diagnose sleep apnea. Continuous positive airway pressure (CPAP) therapy is the first-line treatment for OSA in adults. Other modalities include mandibular advancement devices, surgery, or upper airway stimulation therapy. Adjunctive therapy should include weight loss in overweight patients, avoidance of sedatives and alcohol before sleep, and possibly positional therapy. PMID- 28845958 TI - Sleep Disorders: Insomnia. AB - Insomnia is the most common type of sleep disorder in the family medicine population. It is defined as a persistent difficulty initiating or maintaining sleep, or a report of nonrestorative sleep, accompanied by related daytime impairment. Insomnia is a significant public health problem because of its high prevalence and management challenges. There is increasing evidence of a strong association between insomnia and various medical and psychiatric comorbidities. Diagnosis of insomnia and treatment planning rely on a thorough sleep history to address contributing and precipitating factors as well as maladaptive behaviors resulting in poor sleep. Using a sleep diary or sleep log is more accurate than patient recall to determine sleep patterns. A sleep study is not routinely indicated for evaluation of insomnia. Cognitive behavioral therapy for insomnia (CBT-I) is the mainstay of treatment and is a safe and effective approach. The key challenge of CBT-I is the lack of clinicians to implement it. The newer generation nonbenzodiazepines (eg, zolpidem, zaleplon) are used as first-line pharmacotherapy for chronic insomnia. Newer drugs active on targets other than the gamma-aminobutyric acid receptor are now available, but clear treatment guidelines are needed. PMID- 28845959 TI - Sleep Disorders: Restless Legs Syndrome. AB - Restless legs syndrome (RLS) is a common disorder that often is underdiagnosed and undertreated. Patients with RLS describe an urge to move their legs, especially in the evenings and during periods of inactivity. The prevalence of clinically significant RLS is approximately 2% to 3% in adults in Europe and North America. RLS can be an independent disorder or may occur in conjunction with other conditions (eg, iron deficiency, pregnancy, chronic renal failure). Diagnosis is based on clinical history. Routine polysomnography typically is not recommended unless there is suspicion of other sleep disorders (eg, obstructive sleep apnea). Management includes a combination of supportive measures, dopaminergic drugs, gabapentinoids, opioids, or benzodiazepines. Good sleep hygiene can help prevent development of insomnia related to RLS. Avoiding alcohol and reducing caffeine intake is recommended. If iron stores are low, iron supplementation may improve symptoms. The main pharmacologic options for RLS management are dopaminergic agonists (eg, pramipexole and ropinirole); gabapentinoids also are good options. Patients may experience augmentation, an increase in RLS symptom severity with increasing drug dosage, which is the main complication of dopaminergic drugs. There is no evidence to support use of vibratory devices that provide stimulation to the lower extremities. PMID- 28845960 TI - Sleep Disorders: Circadian Rhythm Sleep-Wake Disorders. AB - Shift work sleep disorder is a common problem in industrialized countries because of the need for occupations and services to continue to function 24 hours/day. Approximately 20% of employed adults in the United States are engaged in shift work. Shift work sleep disorder is diagnosed if there is a report of insomnia or excessive sleepiness for at least 3 months associated with a recurring work schedule that overlaps the usual time for sleep. Shift work is associated with an increased occurrence of metabolic disorders, such as insulin resistance, diabetes, dyslipidemia, and metabolic syndrome, and it has been implicated in weight gain and cognitive impairment. There is evidence of increased absenteeism in night workers compared with day workers. A planned sleep schedule, timed bright light exposure, timed melatonin administration, and stimulants or drugs promoting alertness can be used to manage shift work sleep disorder. Jet lag is characterized by a misalignment between internal circadian rhythms and local time caused by rapid travel across at least two time zones. Not all travelers experience jet lag; risk factors include age, number of time zones crossed, and circadian preference. Management includes timed melatonin along with optional timed and dosed bright light exposure. PMID- 28845961 TI - CuFeS2 Quantum Dots Anchored in Carbon Frame: Superior Lithium Storage Performance and the Study of Electrochemical Mechanism. AB - Herein, we report a simple and quick synthetic route to prepare the pure CuFeS2 quantum dots (QDs) @C composites with the unique structure of CuFeS2 QDs encapsulated in the carbon frame. When tested as anode materials for the lithium ion battery, the CuFeS2 QDs @C composites based electrodes exhibit excellent electrochemical performances. When charge-discharge occurred with a current density of 0.5 A g-1, the electrodes exhibit a high reversible capacity (760 mA h g-1) for as long as 700 cycles, which indicates the superior cycling life. Detailed investigations of the morphological and structural changes of CuFeS2 QDs by ex situ XRD, ex situ Raman, and ex situ TEM reveal an interesting electrochemical reaction mechanism, a hybrid of a lithium-copper iron sulfide battery and lithium-sulfur battery. The direct observation of orthorhombic FeS2 by HRTEM and the existence of Li2FeS2 detected by Raman support our assertion. We believe such an electrochemical mechanism would attract more attention to the CuFeS2 nanomaterials as lithium ion battery anode materials. The excellent electrochemical properties would be derived from the unique structure, which include CuFeS2 QDs encapsulated in the carbon frame. PMID- 28845962 TI - Integration of a Genetically Encoded Calcium Molecular Sensor into Photopolymerizable Hydrogels for Micro-Optrode-Based Sensing. AB - Genetically encoded molecular-protein sensors (GEMS) are engineered to sense and quantify a wide range of biological substances and events in cells, in vitro and even in vivo with high spatial and temporal resolution. Here, we aim to stably incorporate these proteins into a photopatternable matrix, while preserving their functionality, to extend the application of these proteins as spatially addressable optical biosensors. For this reason, we examined the fabrication of 3D hydrogel microtips doped with a genetically encoded fluorescent biosensor, GCaMP3, at the end of an optical fiber. Stable incorporation parameters of GCaMP3 into a photo-cross-linkable monomer matrix were investigated through a series of characterization and optimization experiments. Different precursor-solution formulations and irradiation parameters of in situ photopolymerization were tested to determine the factors affecting protein stability and sensor reproducibility during photoencapsulation. The microstructure and performance of hydrogel microtips were controlled by varying UV irradiation intensity as well as the molecular weight and concentration of the photocurable monomer, PEGDA (polyethylene glycol diacrylate), in precursor solution. Protein-doped hydrogel micro-optrodes (microtip sensors) were fabricated successfully and reproducibly at the distal end of optical fiber. Under optimized conditions, the bioactivity of GCaMP3 within a hydrogel matrix of micro-optrodes remained similar to that of the protein-free matrix in buffer. The limit of detection of protein optrodes for free calcium was also determined to be 4.3 nM. The hydrogel formulation and fabrication process demonstrated here using microtip optrodes can be easily adapted to other conformation-dependent protein biosensors and can be used in sensing applications. PMID- 28845964 TI - Array-Based Rational Design of Short Peptide Probe-Derived from an Anti-TNT Monoclonal Antibody. AB - Complementarity-determining regions (CDRs) are sites on the variable chains of antibodies responsible for binding to specific antigens. In this study, a short peptide probe for recognition of 2,4,6-trinitrotoluene (TNT), was identified by testing sequences derived from the CDRs of an anti-TNT monoclonal antibody. The major TNT-binding site in this antibody was identified in the heavy chain CDR3 by antigen docking simulation and confirmed by an immunoassay using a spot-synthesis based peptide array comprising amino acid sequences of six CDRs in the variable region. A peptide derived from heavy chain CDR3 (RGYSSFIYWF) bound to TNT with a dissociation constant of 1.3 MUM measured by surface plasmon resonance. Substitution of selected amino acids with basic residues increased TNT binding while substitution with acidic amino acids decreased affinity, an isoleucine to arginine change showed the greatest improvement of 1.8-fold. The ability to create simple peptide binders of volatile organic compounds from sequence information provided by the immune system in the creation of an immune response will be beneficial for sensor developments in the future. PMID- 28845963 TI - Quantum-Dot-Based Theranostic Micelles Conjugated with an Anti-EGFR Nanobody for Triple-Negative Breast Cancer Therapy. AB - A quantum-dot (QD)-based micelle conjugated with an anti-epidermal growth factor receptor (EGFR) nanobody (Nb) and loaded with an anticancer drug, aminoflavone (AF), has been engineered for EGFR-overexpressing cancer theranostics. The near infrared (NIR) fluorescence of the indium phosphate core/zinc sulfide shell QDs (InP/ZnS QDs) allowed for in vivo nanoparticle biodistribution studies. The anti EGFR nanobody 7D12 conjugation improved the cellular uptake and cytotoxicity of the QD-based micelles in EGFR-overexpressing MDA-MB-468 triple-negative breast cancer (TNBC) cells. In comparison with the AF-encapsulated nontargeted (i.e., without Nb conjugation) micelles, the AF-encapsulated Nb-conjugated (i.e., targeted) micelles accumulated in tumors at higher concentrations, leading to more effective tumor regression in an orthotopic triple-negative breast cancer xenograft mouse model. Furthermore, there was no systemic toxicity observed with the treatments. Thus, this QD-based Nb-conjugated micelle may serve as an effective theranostic nanoplatform for EGFR-overexpressing cancers such as TNBCs. PMID- 28845965 TI - Property Enhancement Effects of Side-Chain-Type Naphthalene-Based Sulfonated Poly(arylene ether ketone) on Nafion Composite Membranes for Direct Methanol Fuel Cells. AB - Nafion/SNPAEK-x composite membranes were prepared by blending raw Nafion and synthesized side-chain-type naphthalene-based sulfonated poly(arylene ether ketone) with a sulfonation degree of 1.35 (SNPAEK-1.35). The incorporation of SNPAEK-1.35 polymer with ion exchange capacity (IEC) of 2.01 mequiv.g-1 into a Nafion matrix has the property enhancement effects, such as increasing IECs, improving proton conductivity, enhancing mechanical properties, reducing methanol crossover, and improving single cell performance of Nafion. Morphology studies show that Nafion/SNPAEK-x composite membranes exhibit a well-defined microphase separation structure depending on the contents of SNPAEK-1.35 polymer. Among them, Nafion/SNPAEK-7.5% with a bicontinuous morphology exhibits the best comprehensive properties. For example, it shows the highest proton conductivities of 0.092 S cm-1 at 25 degrees C and 0.163 S cm-1 at 80 degrees C, which are higher than those of recast Nafion with 0.073 S cm-1 at 25 degrees C and 0.133 S cm-1 at 80 degrees C, respectively. Nafion/SNPAEK-5.0% and Nafion/SNPAEK-7.5% membranes display an open circuit voltage of 0.77 V and a maximum power density of 47 mW cm-2 at 80 degrees C, which are much higher than those of recast Nafion of 0.63 V and 24 mW cm-2 under the same conditions. Nafion/SNPAEK-5.0% membrane also has comparable tensile strength (12.7 MPa) to recast Nafion (13.7 MPa), and higher Young's modulus (330 MPa) than that of recast Nafion (240 MPa). By combining their high proton conductivities, comparable mechanical properties, and good single cell performance, Nafion/SNPAEK-x composite membranes have the potential to be polymer electrolyte materials for direct methanol fuel cell applications. PMID- 28845966 TI - Metal-Organic Framework-Derived Reduced Graphene Oxide-Supported ZnO/ZnCo2O4/C Hollow Nanocages as Cathode Catalysts for Aluminum-O2 Batteries. AB - Aluminum-air battery is a promising candidate for large-scale energy applications because of its low cost and high energy density. Remarkably, tremendous efforts have been concentrated on developing efficient and stable cathode electrocatalysts toward the oxygen reduction reaction. In this work, a hydrothermal-calcination approach was utilized to prepare novel reduced graphene oxide (rGO)-supported hollow ZnO/ZnCo2O4 nanoparticle-embedded carbon nanocages (ZnO/ZnCo2O4/C@rGO) using a zeolitic imidazolate framework (ZIF-67)/graphene oxide/zinc nitrate composite as the precursor. The ZnO/ZnCo2O4/C@rGO hybrid exhibits remarkable electrocatalytic performance for oxygen reduction reaction under alkaline conditions and superior stability and methanol tolerance to those of the commercial Pt/C catalyst. Furthermore, novel and simple Al-air coin cells were first fabricated using the hybrid materials as cathode catalysts under ambient air conditions to further investigate their catalytic performance. The coin cell with the ZnO/ZnCo2O4/C@rGO cathode catalyst displays a higher open circuit voltage and discharge voltage and more sluggish potential drop than those of the cell with the ZnO/ZnCo2O4/C cathode catalyst, which confirms that rGO can enhance the electrocatalytic activity and stability of the catalyst system. The excellent electrocatalytic performance of the ZnO/ZnCo2O4/C@rGO hybrid is attributed to the prominent conductivity and high specific surface area resulting from rGO, the more accessible catalytic active sites induced by the unique porous hollow nanocage structure, and synergic covalent coupling between rGO sheets and ZnO/ZnCo2O4/C nanocages. PMID- 28845967 TI - Luminescent Iridium(III) Pyridinium-Derived N-Heterocyclic Carbene Complexes as Versatile Photoredox Catalysts. AB - The development of novel luminescent iridium(III) complexes with highly tunable emission energy and versatile applications is of particular importance. In this Communication, a series of luminescent iridium(III) complexes supported by chromophoric pyridinium-derived N-heterocyclic carbene (NHC) ligands that display tunable emission from 516 to 682 nm were prepared. These complexes can be used as photocatalysts in photooxidation and photoreduction reactions and could have potential applications in pH sensing. PMID- 28845968 TI - High-Rate Partial Nitritation of Municipal Wastewater after Psychrophilic Anaerobic Pretreatment. AB - Partial nitritation/anammox can provide energy-efficient nitrogen removal from the main stream of municipal wastewater. The main bottleneck is the growth of nitrite oxidizing bacteria (NOB) at low temperatures (<15 degrees C). To produce effluent suitable for anammox, real municipal wastewater after anaerobic pretreatment was treated by enriched ammonium oxidizing bacteria (AOB) in suspended sludge SBR at 12 degrees C. NOB were continually washed out using aerobic duration control strategy (ADCS). Solids retention time was set to 9-16 days. Using this approach, average ammonia conversion higher than 57% at high oxidation rate of 0.4 +/- 0.1 kg-N kg-VSS-1 d-1 was achieved for more than 100 days. Nitrite accumulation (N-NO2-/N-NOX) of 92% was maintained. Thus, consistently small amounts of present NOB were efficiently suppressed. Our mathematical model explained how ADCS enhanced the inhibition of NOB growth via NH3 and HNO2. This approach will produce effluent suitable for anammox even under winter conditions in mild climates. PMID- 28845970 TI - Resolution Ladder for High-Resolution Mass Spectrometry. AB - High-resolution mass spectrometry has become a key technology in life sciences. Since it is often unfeasible to find pairs of analytes with an appropriate mass difference to actually quantify the resolution experimentally, resolution is usually calculated from the shape of a single mass peak. In this study we show that the commonly employed strategy yields a poor measure of true resolution since it does not account for interactions that take place between ions of very similar mass and might be further distorted by signal processing effects. We present a straightforward and easily adaptable method to create a ladder of mass pairs to experimentally quantify actual mass resolution over a wide m/z range, compare the experimental resolution to the single peak based calculated resolution, and demonstrate the applicability of mass resolution ladders to study interactions of similar ions in various types of widely used mass spectrometers. PMID- 28845969 TI - Calcium Sulfate Hemihydrate Nanowires: One Robust Material in Separation of Water from Water-in-Oil Emulsion. AB - Here we report a facile and cost-effective wet-chemical approach to the synthesis of calcium sulfate hemihydrate nanowires (HH NWs, CaSO4.0.5H2O), and their robust performance in immobilizing water molecules to the crystal lattice of CaSO4 and then separating them from a surfactant-stabilized water-in-oil emulsion (mean droplet size of around 1.2 MUm). Every gram of HH NWs are capable of treating 20 mL emulsion (water content: 10.00 mg mL-1) with a separation efficiency of 99.23% at room temperature, and this efficiency can be further improved by tuning the surface charge density of HH. Along with the water immobilization, HH NWs are converted to large cubic-like calcium sulfate dihydrate microparticles (DH, CaSO4.2H2O, mean size: 50 MUm), and the accompanied size increment enables efficient collection of the solid phase from oil. DH microparticles can be regenerated into HH NWs, which retain the high performance of the original NWs. Such a unique renewable feature improves the economics of our method and simultaneously prevents the secondary pollution. Further economic evaluation finds that purification of every cubic meters of emulsion (water content: 10.00 mg mL-1) will cost about $34.18 for HH NWs, much lower than the $490.78 for the previously reported HH NPs, and $11 052.05-$23 420.32 Fe3O4 NP-based adsorbents, respectively. With the high efficiency, easy collection, low cost, and renewable feature, HH NWs show highly promising applications in the field of oil purification and recycle. PMID- 28845971 TI - Antibacterial Electrospun Poly(vinyl alcohol)/Enzymatic Synthesized Poly(catechol) Nanofibrous Midlayer Membrane for Ultrafiltration. AB - Two different nanofibrous antibacterial membranes containing enzymatically synthesized poly(catechol) (PC) or silver nitrate (AgNO3, positive control) blended with poly(vinyl alcohol) (PVA) and electrospun onto a poly(vinylidene fluoride) (PVDF) basal disc to generate thin-film composite midlayers were produced for water ultrafiltration applications. The developed membranes were thoroughly characterized in terms of morphology, chemical composition, and general mechanical and thermal features, antimicrobial activity, and ultrafiltration capabilities. The electrospun blends were recognized as homogeneous. Data revealed relevant conformational changes in the PVA side groups, attributed to hydrogen bonding, high thermal stability, and residual mass. PVDF+PVA/AgNO3 membrane displayed 100% growth inhibition of both Gram positive and Gram-negative bacteria strains, despite the wide range of fiber diameters generated, from 24 to 125 nm, formation of numerous beads, and irregular morphology. The PVDF+PVA/PC membrane showed a good growth inhibition of Staphylococcus aureus (92%) and revealed a smooth morphology with no relevant bead formations and diameters ranging from 68 to 131 nm. The ultrafiltration abilities of the membrane containing PVA/PC were tested in a dead-end high pressure cell (4 bar) using a reactive dye in distilled water and seawater. After 5 cycles, a maximum rejection of ~85% with an average flux rate of 70 L m-2 h-1 for distilled water and ~64% with an average flux rate of 62 L m-2 h-1 for seawater were determined with an overall salt rejection of ~5%. PMID- 28845972 TI - Biocompatible Periodic Mesoporous Ionosilica Nanoparticles with Ammonium Walls: Application to Drug Delivery. AB - Periodic mesoporous ionosilica nanoparticles with ammonium walls were synthesized exclusively from a trisilylated ammonium precursor. The nanoparticles display a uniform particle size, together with a high specific surface area and an ordered hexagonal pore architecture. Completely biocompatible in vitro and in vivo, the nanoparticles are efficiently endocytosed by RAW 264.7 macrophages and used as carrier vehicles for anionic drugs. Diclofenac-loaded ionosilica nanoparticles are very efficient in inhibiting lipopolysaccharides-induced inflammation. PMID- 28845973 TI - Human Microbiome Inspired Antibiotics with Improved beta-Lactam Synergy against MDR Staphylococcus aureus. AB - The flippase MurJ is responsible for transporting the cell wall intermediate lipid II from the cytoplasm to the outside of the cell. While essential for the survival of bacteria, it remains an underexploited target for antibacterial therapy. The humimycin antibiotics are lipid II flippase (MurJ) inhibitors that were synthesized on the basis of bioinformatic predictions derived from secondary metabolite gene clusters found in the human microbiome. Here, we describe an SAR campaign around humimycin A that produced humimycin 17S. Compared to humimycin A, 17S is a more potent beta-lactam potentiator, has a broader spectrum of activity, which now includes both methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE), and did not lead to any detectable resistance when used in combination with a beta-lactam. Combinations of beta-lactam and humimycin 17S provide a potentially useful long-term MRSA regimen. PMID- 28845974 TI - Polydopamine Modified TiO2 Nanotube Arrays for Long-Term Controlled Elution of Bivalirudin and Improved Hemocompatibility. AB - Sustained and controllable release characteristics are pivotal factors for novel drug delivery technologies. TiO2 nanotube arrays prepared by self-ordering electrochemical anodization are attractive for the development of biomedical devices for local drug delivery applications. In this work, several layers of polydopamine (PDA) were deposited to functionalize TiO2 nanotube arrays. The anticoagulant drug bivalirudin (BVLD) was used as a model drug. PDA extended the release period of BVLD and maintained a sustained release kinetic. Depending on the number of PDA layers, the release characteristics of BVLD improved, as there was a reduced burst release (from 45% to 11%) and extended overall release period from 40 days to more than 300 days in the case of 5 layers. Besides, the BVLD loaded 5-layer PDA coating maintained the high bioactivity of BVLD and effectively reduced the thrombosis formation by inhibition of the adhesion and denaturation of fibrinogen, platelets, and other blood components. Both in vitro and ex vivo blood evaluation results demonstrated that this coating significantly improved the hemocompatibility. These results confirmed the capability of PDA fitted TiO2 nanotube systems to be applied for local drug delivery over an extended period with well retained bioactivity and predictable release kinetics. PMID- 28845975 TI - Structural, Spectroscopic, and Theoretical Investigation of a T-Shaped [Fe3(MU3 O)] Cluster. AB - The synthesis, X-ray crystal and electronic structures of [Fe3(MU3 O)(mpmae)2(OAc)2 Cl3], 1, where mpmae-H = 2-(N-methyl-N-((pyridine-2 yl)methyl)amino)ethanol, are described. This cluster comprises three high-spin ferric ions and exhibits a T-shaped site topology. Variable-frequency electron paramagnetic resonance measurements performed on single crystals of 1 demonstrate a total spin ST = 5/2 ground state, characterized by a small, negative, and nearly axial zero-field splitting tensor D = -0.49 cm-1, E/D ~ 0.055. Analysis of magnetic susceptibility, magnetization, and magneto-structural correlations further corroborate the presence of a sextet ground-spin state. The observed ground state originates from the strong anti-ferromagnetic interaction of two iron(III) spins, with J = 115(5) cm-1, that, in turn, are only weakly coupled to the spin of the third site, with j = 7(1) cm-1. These exchange interactions lead to a ground state with magnetic properties that are essentially entirely determined by the weakly coupled site. The contributions of the individual spins to the total ground state of the cluster were monitored using variable-field 57Fe Mossbauer spectroscopy. Field-dependent spectra reveal that, while one of the iron sites exhibits a large negative internal field, typical of ferric ions, the other two sites exhibit small, but not null, negative and positive internal fields. A theoretical analysis reveals that these small internal fields originate from the mixing of the lowest ST = 5/2 excited state into the ground state which, in turn, is induced by a minute structural distortion. PMID- 28845976 TI - From Chlorella to Nestlike Framework Constructed with Doped Carbon Nanotubes: A Biomass-Derived, High-Performance, Bifunctional Oxygen Reduction/Evolution Catalyst. AB - The development of effective bifunctional catalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is significant for energy conversion systems, such as Li-air batteries, fuel cells, and water splitting technologies. Herein, a Chlorella-derived catalyst with a nestlike framework, composed of bamboolike nanotubes that encapsulate cobalt nanoparticles, has been prepared through a facile pyrolysis process. It achieves perfect bifunctional catalysis both in ORR and OER on a single catalyst. For our optimal catalyst Co/M Chlorella-900, its ORR half-wave potential is positively shifted by 40 mV compared to that of a commercial Pt/C catalyst, and the overpotential at 10 mA cm 2 for the OER is 23 mV lower than that of a commercial IrO2/C catalyst in an alkaline medium. This superior bifunctional catalytic performance is benefited from the simultaneous increase of pyridinic N sites for ORR and graphitic N sites for OER. In addition, N-doped carbon-encapsulated Co nanoparticles improve both ORR and OER performance by forming new active centers. The unique nestlike carbon nanotube framework not only afforded highly dense ORR and OER active sites but also promoted the electron and mass transfer. Our catalyst also displays notable durability during the ORR and OER, making it promising for use in ORR/OER-related energy conversion systems. PMID- 28845977 TI - A Highly Symmetric Ionic Crystal Constructed by Polyoxoniobates and Cobalt Complexes for Preferential Water Uptake over Alcohols. AB - An ionic crystal assembled by PNb12O40(VO)6 and tris(1,2-diaminopropane)cobalt complexes was hydrothermally isolated and structurally characterized by routine methods. The compound exhibits three-dimensional channels with a pore size of 3.68 A * 2.30 A and composed of hydrophilic oxygen atoms of polyanions and hydrophobic -CH3 groups of 1,2-diaminopropane ligands. With increasing vapor pressure, the compound shows preferable adsorption toward water over alcohols, and a gate-opening behavior was deduced from the water adsorption isotherm. PMID- 28845979 TI - Sensitive Detection of Transcription Factor in Nuclear Extracts by Target Actuated Isothermal Amplification-Mediated Fluorescence Enhancement. AB - Transcription factors (TFs) modulate the process of gene transcription by binding to specific DNA sequences, and their alteration may cause a variety of diseases. Here, we develop a simple and sensitive method to directly detect TF in crude nuclear extracts using target-actuated isothermal amplification-mediated fluorescence enhancement with fluorescent base 2-aminopurine (2-AP) as the fluorophore. In the presence of TF, its specific binding to the probe prevents the digestion of the probe by exonuclease III (Exo III), initiating the extension reaction to produce DNA duplexes which may be subsequently digested by lambda exonuclease to release single-stranded DNAs (ssDNAs) and free 2-AP molecules. Although some excess probes may be partially digested by Exo III, the phosphorothioate modification between two binding sites of the probe may generate a hindrance to preserve the rest of TF-binding probes which may hybridize with the released ssDNAs to initiate new cycles of nicking-digestion-hybridization, generating abundant free 2-AP molecules for significant fluorescence enhancement. Different from the reported amplification strategies, all the TF-binding probes take part in the amplification reaction no matter if they bind with TF or not, greatly improving the detection signal. This method can be used for sensitive detection of NF-kappaBp50 with a detection limit of 4.11 * 10-4 mg/mL and the screening of potential TF inhibitors as well. Importantly, this method is very simple without the involvement of any external quenchers, extra primers, and templates, and it may be extended to selectively detect various DNA-binding proteins by simply changing the binding-site sequences of the probes. PMID- 28845978 TI - Reverse Transcription Past Products of Guanine Oxidation in RNA Leads to Insertion of A and C opposite 8-Oxo-7,8-dihydroguanine and A and G opposite 5 Guanidinohydantoin and Spiroiminodihydantoin Diastereomers. AB - Reactive oxygen species, both endogenous and exogenous, can damage nucleobases of RNA and DNA. Among the nucleobases, guanine has the lowest redox potential, making it a major target of oxidation. Although RNA is more prone to oxidation than DNA is, oxidation of guanine in RNA has been studied to a significantly lesser extent. One of the reasons for this is that many tools that were previously developed to study oxidation of DNA cannot be used on RNA. In the study presented here, the lack of a method for seeking sites of modification in RNA where oxidation occurs is addressed. For this purpose, reverse transcription of RNA containing major products of guanine oxidation was used. Extension of a DNA primer annealed to an RNA template containing 8-oxo-7,8-dihydroguanine (OG), 5-guanidinohydantoin (Gh), or the R and S diastereomers of spiroiminodihydantoin (Sp) was studied under standing start conditions. SuperScript III reverse transcriptase is capable of bypassing these lesions in RNA inserting predominantly A opposite OG, predominantly G opposite Gh, and almost an equal mixture of A and G opposite the Sp diastereomers. These data should allow RNA sequencing of guanine oxidation products by following characteristic mutation signatures formed by the reverse transcriptase during primer elongation past G oxidation sites in the template RNA strand. PMID- 28845980 TI - Synthesis and Spectroscopic and Cellular Properties of Near-IR [a]Phenanthrene Fused 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes. AB - A new synthetic method to build aryl-fused 4,4-difluoro-4-bora-3a,4a-diaza-s indacenes (BODIPYs) is reported. The intramolecular cyclization step was completed in a short time (1-2 h) and in high yields (>90%), due to the intrinsic rigid structural conformation of the precursor BODIPY and the high reactivity of its 1,7-bromo groups. The [a]phenanthrene-fused BODIPYs 4a-c were characterized by NMR spectroscopy, HRMS, DFT calculations, and, in the case of 4a, by X-ray crystallography. Spectroscopic studies show that 4a-c strongly absorb and emit in the NIR spectral region, in the range 642-701 nm. In addition, BODIPYs 4b and 4c exhibit no toxicity in the light or dark in HEp2 cells and accumulate intracellularly in a time-dependent manner, mainly in the cell endoplasmic reticulum. These results suggest the potential use of [a]phenanthrene-fused BODIPYs as NIR bioimaging probes. PMID- 28845981 TI - Direct Electrochemical Measurements of Reactive Oxygen and Nitrogen Species in Nontransformed and Metastatic Human Breast Cells. AB - The production of reactive oxygen and nitrogen species (ROS and RNS) in human cells is implicated in various diseases, including cancer. Micrometer-sized electrodes coated with Pt black and platinized Pt nanoelectrodes have previously been used for the detection of primary ROS and RNS in biological systems. In this Article, we report the development of platinized carbon nanoelectrodes with well characterized geometry and use them as scanning electrochemical microscopy (SECM) tips to measure ROS and RNS inside noncancerous and metastatic human breast cells. By performing time-dependent quantitative amperometric measurements at different potentials, the relative concentrations of four key ROS/RNS in the cell cytoplasm and their dynamics were determined and used to elucidate the chemical origins and production rates of ROS/RNS in nontransformed and metastatic human breast cells. PMID- 28845982 TI - Gordonic Acid, a Polyketide Glycoside Derived from Bacterial Coculture of Streptomyces and Gordonia Species. AB - Despite numerous efforts to discover novel bioactive products from microorganisms, previously reported compounds are repetitively reisolated. A new polyketide glycoside, gordonic acid (1), isolated from the mixed culture of two Gram-positive bacteria, Gordonia sp. KMC005 and Streptomyces tendae KMC006, is reported. The structure of 1 was characterized as an acyclic polyene polyketide substituted with a beta-d-digitoxopyranose through NMR, HR-ESI-QTOF-MS, IR, and UV spectral data. The stereochemistry for 1 was determined by Mosher's method followed by 2D NOESY analysis and by NMR chemical shift calculations supported by DP4 analysis. Gordonic acid (1) showed weak activity against Micrococcus luteus and Enterococcus hirae. PMID- 28845983 TI - A Dual Modulator of Farnesoid X Receptor and Soluble Epoxide Hydrolase To Counter Nonalcoholic Steatohepatitis. AB - Nonalcoholic steatohepatitis arising from Western diet and lifestyle is characterized by accumulation of fat in liver causing inflammation and fibrosis. It evolves as serious health burden with alarming incidence, but there is no satisfying pharmacological therapy to date. Considering the disease's multifactorial nature, modulation of multiple targets might provide superior therapeutic efficacy. In particular, farnesoid X receptor (FXR) activation that revealed antisteatotic and antifibrotic effects in clinical trials combined with inhibition of soluble epoxide hydrolase (sEH) as anti-inflammatory strategy promises synergies. To exploit this dual concept, we developed agents exerting partial FXR agonism and sEH inhibitory activity. Merging known pharmacophores and systematic exploration of the structure-activity relationship on both targets produced dual modulators with low nanomolar potency. Extensive in vitro characterization confirmed high dual efficacy in cellular context combined with low toxicity, and pilot in vivo data revealed favorable pharmacokinetics as well as engagement on both targets in vivo. PMID- 28845984 TI - Relation Between Ring Currents and Hydrogenation Enthalpies for Assessing the Degree of Aromaticity. AB - Magnetically induced ring-current strength susceptibilities and nucleus independent chemical shifts (NICS) have been studied for 15 single-ring aromatic, antiaromatic, and nonaromatic molecules. The current densities have been calculated at the density functional theory (DFT), Hartree-Fock (HF) theory, and second-order Moller-Plesset perturbation theory (MP2) levels using the gauge including magnetically induced current method (GIMIC). The ring-current strength susceptibilities have been obtained by numerical integration of the current density flowing around the molecular ring. The calculated ring-current strength susceptibilities are almost independent of the level of theory. The relative degree of aromaticity deduced from the magnetic properties has been compared with the ones deduced from hydrogenation enthalpies that are considered to be proportional to aromatic stabilization energies (ASE). For the studied single ring molecules, GIMIC, NICS, and ASE calculations yield similar trends. The study shows that there is a linear correlation between the magnetic and energetic criteria of aromaticity. The largest uncertainty originates from the accuracy of the energy data, because they are much more dependent on the employed computational level than the calculated magnetic properties. Thus, ring-current strength susceptibilities can be used for assessing the degree of aromaticity. PMID- 28845985 TI - Hairy Uniform Permanently Ligated Hollow Nanoparticles with Precise Dimension Control and Tunable Optical Properties. AB - The ability to tailor the size and shape of nanoparticles (NPs) enables the investigation into the correlation between these parameters and optical, optoelectronic, electrical, magnetic, and catalytic properties. Despite several effective approaches available to synthesize NPs with a hollow interior, it remains challenging to have a general strategy for creating a wide diversity of high-quality hollow NPs with different dimensions and compositions on demand. Herein, we report on a general and robust strategy to in situ crafting of monodisperse hairy hollow noble metal NPs by capitalizing on rationally designed amphiphilic star-like triblock copolymers as nanoreactors. The intermediate blocks of star-like triblock copolymers can associate with metal precursors via strong interaction (i.e., direct coordination or electrostatic interaction), followed by reduction to yield hollow noble metal NPs. Notably, the outer blocks of star-like triblock copolymers function as ligands that intimately and permanently passivate the surface of hollow noble metal NPs (i.e., forming hairy permanently ligated hollow NPs with superior solubility in nonpolar solvents). More importantly, the diameter of the hollow interior and the thickness of the shell of NPs can be readily controlled. As such, the dimension-dependent optical properties of hollow NPs are scrutinized by combining experimental studies and theoretical modeling. The dye encapsulation/release studies indicated that hollow NPs may be utilized as attractive guest molecule nanocarriers. As the diversity of precursors are amenable to this star-like triblock copolymer nanoreactor strategy, it can conceptually be extended to produce a rich variety of hairy hollow NPs with different dimensions and functionalities for applications in catalysis, water purification, optical devices, lightweight fillers, and energy conversion and storage. PMID- 28845986 TI - Correction to "Effect of Anodic Alumina Oxide Pore Diameter on the Crystallization of Poly(butylene adipate)". PMID- 28845987 TI - Diversification of Quinazolinones by Pd-Catalyzed C(sp3)-Acetoxylation. AB - The quinazolinone ring has been exploited as a directing group for C(sp3)-H functionalization for the first time. The proximal C-gamma(sp3)-H bonds have been oxidized by palladium-catalyzed acetoxylation reaction. Various functional groups on the quinazolinone scaffold were tolerated to provide novel quinazolinone derivatives. The use of base was found to be crucial for the monoselective acetoxylations. PMID- 28845988 TI - A Synthetic Route for Crystals of Woven Structures, Uniform Nanocrystals, and Thin Films of Imine Covalent Organic Frameworks. AB - Developing synthetic methodology to crystallize extended covalent structures has been an important pursuit of reticular chemistry. Here, we report a homogeneous synthetic route for imine covalent organic frameworks (COFs) where crystallites emerge from clear solutions without forming amorphous polyimine precipitates. The key feature of this route is the utilization of tert-butyloxycarbonyl group protected amine building blocks, which are deprotected in situ and gradually nucleate the crystalline framework. We demonstrate the utility of this approach by crystallizing a woven covalent organic framework (COF-112), in which covalent organic threads are interlaced to form a three-dimensional woven framework. The homogeneous imine COF synthesis also enabled the control of nucleation and crystal growth leading to uniform nanocrystals, through microwave-assisted reactions, and facile preparation of oriented thin films. PMID- 28845989 TI - Comment on "Solid-Liquid Work of Adhesion". AB - In a recent article, Tadmor and co-workers (Tadmor, R., et al. Langmuir 2017, 33, 3594-3600) used a centrifugal adhesion balance (CAB) to detach liquid drops from solid surfaces. By orienting solid surfaces in their CAB such that normal and lateral surfaces were balanced, the debonding force acted perpendicularly to the surface and drops detached by the axisymmetric retraction of their contact line. The detachment force was used to estimate the work of adhesion. To match the work of adhesion values from CAB to those calculated from the Young-Dupre equation, relatively large contact angles were required. Here, an alternative interpretation of their results is offered. Receding contact angles were estimated from their data and then used to predict the work of adhesion. These alternative predictions of the work of adhesion agreed with their estimates from the CAB. PMID- 28845990 TI - Normalizing Tumor Vessels To Increase the Enzyme-Induced Retention and Targeting of Gold Nanoparticle for Breast Cancer Imaging and Treatment. AB - Abnormal tumor vessels impede the transport and distribution of chemotherapeutics, resulting in low drug concentration at tumor sites and compromised drug efficacy. Normalizing tumor vessels can modulate tumor vascular permeability, alleviate tumor hypoxia, increase blood perfusion, attenuate interstitial fluid pressure, and improve drug delivery. Herein, a novel strategy combining cediranib, a tumor vessel normalizing agent, with an enzyme responsive size-changeable gold nanoparticle (AuNPs-A&C) was developed. In vivo photoacoustic and fluorescence imaging showed that oral pretreatment with 6 mg/kg/day of cediranib for two consecutive days significantly enhanced the retention of AuNPs-A&C in 4T1 tumor. In vivo photoacoustic imaging for hemoglobin (Hb) and oxyhemoglobin (HbO2), Evans blue assay, and immunofluorescence assay showed that cediranib pretreatment markedly increased tumor vascular permeability and tumor oxygenation, while distinctly decreased the tumor microvessel density, demonstrating normalized tumor vessels and favorably altered microenvironment. Additionally, the combination strategy considerably elevated the tumor targeting capacity of different nanoparticle formulations (AuNPs-PEG, AuNPs-A&C), while coadministration of cediranib and AuNPs-A&C achieved prevailing tumor targeting and antitumor efficacy in 4T1 tumor bearing mouse model. In conclusion, we report a novel combined administration strategy to further improve tumor diagnosis and treatment. PMID- 28845991 TI - Analysis of the Efficiency of Surfactant-Mediated Stabilization Reactions of EGaIn Nanodroplets. AB - A methodology based on light scattering and spectrophotometry was developed to evaluate the effect of organic surfactants on the size and yield of eutectic gallium/indium (EGaIn) nanodroplets formed in organic solvents by ultrasonication. The process was subsequently applied to systematically evaluate the role of headgroup chemistry as well as polar/apolar interactions of aliphatic surfactant systems on the efficiency of nanodroplet formation. Ethanol was found to be the most effective solvent medium in promoting the formation and stabilization of EGaIn nanodroplets. For the case of thiol-based surfactants in ethanol, the yield of nanodroplet formation increased with the number of carbon atoms in the aliphatic part. In the case of the most effective surfactant system octadecanethiol-the nanodroplet yield increased by about 370% as compared to pristine ethanol. The rather low overall efficiency of the reaction process along with the incompatibility of surfactant-stabilized EGaIn nanodroplets in nonpolar organic solvents suggests that the stabilization mechanism differs from the established self-assembled monolayer formation process that has been widely observed in nanoparticle formation. PMID- 28845992 TI - Self-Rearrangement of Silicon Nanoparticles Embedded in Micro-Carbon Sphere Framework for High-Energy and Long-Life Lithium-Ion Batteries. AB - Despite its highest theoretical capacity, the practical applications of the silicon anode are still limited by severe capacity fading, which is due to pulverization of the Si particles through volume change during charge and discharge. In this study, silicon nanoparticles are embedded in micron-sized porous carbon spheres (Si-MCS) via a facile hydrothermal process in order to provide a stiff carbon framework that functions as a cage to hold the pulverized silicon pieces. The carbon framework subsequently allows these silicon pieces to rearrange themselves in restricted domains within the sphere. Unlike current carbon coating methods, the Si-MCS electrode is immune to delamination. Hence, it demonstrates unprecedented excellent cyclability (capacity retention: 93.5% after 500 cycles at 0.8 A g-1), high rate capability (with a specific capacity of 880 mAh g-1 at the high discharge current density of 40 A g-1), and high volumetric capacity (814.8 mAh cm-3) on account of increased tap density. The lithium-ion battery using the new Si-MCS anode and commercial LiNi0.6Co0.2Mn0.2O2 cathode shows a high specific energy density above 300 Wh kg-1, which is considerably higher than that of commercial graphite anodes. PMID- 28845993 TI - Enhanced Dispersibility of Graphitic Carbon Nitride Particles in Aqueous and Organic Media via a One-Pot Grafting Approach. AB - A facile route to synthesize hydrophilically or hydrophobically grafted graphitic carbon nitride (g-CN) is reported. For this purpose, functionalized olefinic molecules with a low polymerization tendency are utilized for grafting onto the surface to preserve the features of g-CN while improving its dispersibility. One pot, visible light-induced grafting yields highly dispersible g-CNs either in aqueous or organic media. Moreover, functional groups such as amines can be introduced, which yields pH-dependent dispersibility in aqueous media. Compared with unfunctionalized g-CN, low sonication times are sufficient to redisperse g CN. In addition, because of increased dispersion stability, higher amounts of functionalized g-CN can be dispersed (up to 10% in aqueous dispersion and 2% in organic dispersion) when compared to unfunctionalized g-CN. PMID- 28845994 TI - Discrete Fractional Component Monte Carlo Simulation Study of Dilute Nonionic Surfactants at the Air-Water Interface. AB - We present a newly developed Monte Carlo scheme to predict bulk surfactant concentrations and surface tensions at the air-water interface for various surfactant interfacial coverages. Since the concentration regimes of these systems of interest are typically very dilute (?10-5 mol. frac.), Monte Carlo simulations with the use of insertion/deletion moves can provide the ability to overcome finite system size limitations that often prohibit the use of modern molecular simulation techniques. In performing these simulations, we use the discrete fractional component Monte Carlo (DFCMC) method in the Gibbs ensemble framework, which allows us to separate the bulk and air-water interface into two separate boxes and efficiently swap tetraethylene glycol surfactants C10E4 between boxes. Combining this move with preferential translations, volume biased insertions, and Wang-Landau biasing vastly enhances sampling and helps overcome the classical "insertion problem", often encountered in non-lattice Monte Carlo simulations. We demonstrate that this methodology is both consistent with the original molecular thermodynamic theory (MTT) of Blankschtein and co-workers, as well as their recently modified theory (MD/MTT), which incorporates the results of surfactant infinite dilution transfer free energies and surface tension calculations obtained from molecular dynamics simulations. PMID- 28845995 TI - Functional Characterization of Cell-Free Expressed OprF Porin from Pseudomonas aeruginosa Stably Incorporated in Tethered Lipid Bilayers. AB - OprF has a central role in Pseudomonas aeruginosa virulence and thus provides a putative target for either vaccines or antibiotic cofactors that could overcome the bacterium's natural resistance to antibiotics. Here we describe a procedure to optimize the production of highly pure and functional OprF porins that are then incorporated into a tethered lipid bilayer. This is a stable biomimetic system that provides the capability to investigate structural aspects and function of OprF using and neutron reflectometry and electrical impedance spectroscopy. The recombinant OprF produced using the optimized cell-free procedure yielded a quantity of between 0.5 to 1.0 mg/mL with a purity ranging from 85 to 91% in the proteoliposomes. The recombinant OprF is capable of binding IFN-gamma and is correctly folded in the proteoliposomes. Because OprF proteins form pores the biomimetic system allowed the measurement of OprF conductance using impedance spectroscopy. The neutron reflectometry measurements showed that the OprF protein is incorporated into the lipid bilayer but with parts of the protein in both the regions above and below the lipid bilayer. Those structural aspects are coherent with the current assumed structure of a transmembrane N terminal domain composed by eight stranded beta-barrels and a globular C-terminal domain located in the periplasm. Currently there are no crystal structures available for OprF. The experimental model system that we describe provides a basis for further fundamental studies of OprF and particularly for the ongoing biotechnological development of OprF as a target for antibacterial drugs. PMID- 28845996 TI - Wrinkling and Periodic Folding of Graphene Oxide Monolayers by Langmuir-Blodgett Compression. AB - Crumples, wrinkles, and other three-dimensional topographical features in graphene oxide (GO) have been of recent interest as these features have improved material performance for a variety of applications. However, wrinkling of monolayer GO films has yet to be reported. Herein, we demonstrate wrinkling and folding of monolayer GO using the Langmuir-Blodgett technique for the first time. First, cetyltrimethylammonium bromide (CTAB) and GO are deposited on the air water interface and uniaxially compressed to form a monolayer. CTAB enhances in plane rigidity of the monolayer through hydrophobic tail aggregation, preventing GO-GO in-plane sliding behavior. Overcompression of the GO monolayer results in the out-of-plane periodic nanoscale wrinkling and in turn generates folds that are stable during deposition onto a substrate and GO chemical reduction. Furthermore, we investigate one potential application of this material by constructing a 3D electrode of the stacked nanofolded GO-CTAB layers that exhibits superior volumetric capacitance compared to commercial devices and comparable volumetric capacitance compared to high-performing recently reported devices. The high volumetric capacitance is attributed to the electrolyte accessible channels generated by the nanofolds which are similar in size to the hydrated ions. PMID- 28845997 TI - Ask versus tell: Potential confusion when child witnesses are questioned about conversations. AB - Children's potential confusion between "ask" and "tell" can lead to misunderstandings when child witnesses are asked to report prior conversations. The verbs distinguish both between interrogating and informing, and between requesting and commanding. Children's understanding was examined using both field (Study 1) and laboratory methods (Studies 2-4). Study 1 examined 100 5- to 12 year-olds' trial testimony in child sexual abuse cases, and found that potentially ambiguous use of ask and tell was common, typically found in yes-no questions that elicited unelaborated answers, and virtually never clarified by attorneys or child witnesses. Studies 2 to 4 examined 345 maltreated 6- to 11 year-olds' understanding of ask and tell. The results suggest that children initially comprehend telling as saying, and thus believed that asking is a form of telling. As such, they often endorsed asking as telling when asked yes-no questions, but distinguished between asking and telling when explicitly asked to choose. Their performance was impaired by movement between different use of the words. Child witnesses' characterization of their conversations can easily be misconstrued by the way in which they are questioned, leading questioners to misinterpret whether they were coached by disclosure recipients or coerced by abuse suspects. (PsycINFO Database Record PMID- 28845998 TI - The role of sense of belonging in self-stigma among people with serious mental illnesses. AB - OBJECTIVE: Self-stigma significantly impacts people with serious mental illnesses. Evidence from other marginalized groups has indicated that sense of belonging may buffer these impacts. The purpose of this study was to assess the buffering of self-stigma by sense of belonging among this population, including the relationship between these effects and self-identification in other marginalized groups. METHOD: In the study, 267 adults with serious mental illnesses completed demographic, self-stigma, exposure to stigma, and sense of belonging measures. Regression analyses were conducted to determine whether sense of belonging buffered self-stigma and, if so, whether those effects vary by race and gender identification. RESULTS: Sense of belonging buffered self-stigma. Self identification with other marginalized groups did not impact the buffering effect. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Sense of belonging can protect against self-stigma. Self-stigma interventions should integrate components that improve sense of belonging, including community integration. These components should be flexible to meet the cultural context of individual consumers. (PsycINFO Database Record PMID- 28845999 TI - Predictors of urge to smoke under stressful conditions: An experimental investigation utilizing the PASAT-C task to induce negative affect in smokers. AB - Experimental evidence has demonstrated that the presence of cues previously associated with smoking behavior can increase urges to smoke in abstinent smokers. This study examined the effect of a laboratory-induced negative affective task (paced auditory serial addition task) on smoking urges among a sample of 35 abstinent college smokers (Mage = 20.83 years, SD = 1.71). Emotional states and physiological reactions experienced during the experiment, as well as individual differences in stress intolerance (anxiety sensitivity and experiential avoidance) were examined as predictors of the association between stressful states and smoking cravings. Smoking urges (smoking desire and negative affect relief) and negative emotions (frustration, irritability, stress) significantly increased, whereas positive emotions decreased from pre- to posttask. No significant interactions between individual differences and changes in urge were found. Results suggest that changes in negative affect may in part explain the association between induced stress and smoking cravings. (PsycINFO Database Record PMID- 28846000 TI - Emotion regulation and coping motives serially affect cannabis cessation problems among dually diagnosed outpatients. AB - Little empirical work has evaluated why anxious cannabis users are especially vulnerable to poorer cannabis cessation outcomes. Presumably, these individuals rely on cannabis because they have difficulties with emotion regulation and they therefore use cannabis to manage their negative emotions. The current study examined the direct and indirect effects of anxiety severity on a range of cannabis cessation variables among 79 (63.3% non-Hispanic White; 43.0% female) adults with anxiety disorders seeking outpatient treatment for cannabis use disorder. The independent and serial indirect effects of difficulties with emotion regulation and coping motives were examined in relation to the anxiety cannabis variables. Anxiety severity was directly and robustly related to greater cannabis withdrawal symptom severity, less self-efficacy to refrain from using cannabis in emotionally distressing situations, and more reasons for quitting. Anxiety was indirectly related to cannabis outcomes via the serial effects of emotion regulation and coping motives. These findings document the important role of emotion regulation and coping motives in the relations of anxiety with cannabis cessation variables among dually diagnosed outpatients. (PsycINFO Database Record PMID- 28846001 TI - Slope-based and geometric encoding of a goal location by the terrestrial toad (Rhinella arenarum). AB - The current study was designed to test for the ability of terrestrial toads, Rhinella arenarum, to use slope as source of spatial information to locate a goal, and investigate the relative importance of slope and geometric information for goal localization. Toads were trained to locate a single, water-reward goal location in a corner of a rectangular arena placed on an incline. Once the toads learned the task, 3 types of probe trials were carried out to determine the relative use of slope and geometric information for goal localization. The probe trials revealed that the toads were able to independently use slope, and as previously reported, geometry to locate the goal. However, the boundary geometry of the experimental arena was found to be preferentially used by the toads when geometric and slope information were set in conflict. (PsycINFO Database Record PMID- 28846002 TI - Stressful family environments and children's behavioral control: A multimethod test and replication study with twins. AB - Young children's behavioral control predicts a broad range of developmental outcomes in child- and adulthood. It is therefore important to study how individual differences in behavioral control arise. Previous studies suggest that there are both genetic and environmental influences, which were estimated in the current study using a sample of mono- and dizygotic same-sex twins. Furthermore, we examined the associations between indicators of a stressful family environment like household chaos, parenting daily hassles, and parental depressive symptoms and children's behavioral control in 2 samples. Children of the same twin pair were randomly divided over 2 samples; a test (N = 201, 48.3% boys, M age 46.53 months) and replication sample (N = 201, 49.8% boys, M age 46.06 months). Both parents reported on their children's effortful control via the Child Behavior Questionnaire and children's cheating behavior was observed during a throwing game. We found that AE models fitted the data for effortful control (A = 31%, E = 69%) and cheating (A = 16%, E = 84%) best. Path analyses revealed that children of parents experiencing more parenting daily hassles and depressive symptoms had lower levels of effortful control in the test sample. Furthermore, we found that children growing up in more chaotic households (parent report) had an increased risk of being in the cheating group versus the possible intention to cheat group in the test sample. These results were partially replicated. We suggest that the role of stressful family environments in the development of behavioral control should be considered when setting up prevention and intervention programs targeting children's behavioral control. (PsycINFO Database Record PMID- 28846003 TI - Facing humanness: Facial width-to-height ratio predicts ascriptions of humanity. AB - [Correction Notice: An Erratum for this article was reported in Vol 114(1) of Journal of Personality and Social Psychology (see record 2017-57724-002). In the article, there is a data error in the Results section of Study 1c. The fourth sentence of the fourth paragraph should read as follows: High fWHR targets (M= 74.39, SD=18.25) were rated as equivalently evolved as their low fWHR counterparts (M=79.39, SD=15.91).] The ascription of mind to others is central to social cognition. Most research on the ascription of mind has focused on motivated, top-down processes. The current work provides novel evidence that facial width-to-height ratio (fWHR) serves as a bottom-up perceptual signal of humanness. Using a range of well-validated operational definitions of humanness, we provide evidence across 5 studies that target faces with relatively greater fWHR are seen as less than fully human compared with their relatively lower fWHR counterparts. We then present 2 ancillary studies exploring whether the fWHR-to humanness link is mediated by previously established fWHR-trait links in the literature. Finally, 3 additional studies extend this fWHR-humanness link beyond measurements of humanness, demonstrating that the fWHR-humanness link has consequences for downstream social judgments including the sorts of crimes people are perceived to be guilty of and the social tasks for which they seem helpful. In short, we provide evidence for the hypothesis that individuals with relatively greater facial width-to-height ratio are routinely denied sophisticated, humanlike minds. (PsycINFO Database Record PMID- 28846004 TI - Bayesian mixture modeling of significant p values: A meta-analytic method to estimate the degree of contamination from H0. AB - Publication bias and questionable research practices have long been known to corrupt the published record. One method to assess the extent of this corruption is to examine the meta-analytic collection of significant p values, the so-called p-curve (Simonsohn, Nelson, & Simmons, 2014a). Inspired by statistical research on false-discovery rates, we propose a Bayesian mixture model analysis of the p curve. Our mixture model assumes that significant p values arise either from the null-hypothesis H0 (when their distribution is uniform) or from the alternative hypothesis H1 (when their distribution is accounted for by a simple parametric model). The mixture model estimates the proportion of significant results that originate from H0, but it also estimates the probability that each specific p value originates from H0. We apply our model to 2 examples. The first concerns the set of 587 significant p values for all t tests published in the 2007 volumes of Psychonomic Bulletin & Review and the Journal of Experimental Psychology: Learning, Memory, and Cognition; the mixture model reveals that p values higher than about .005 are more likely to stem from H0 than from H1. The second example concerns 159 significant p values from studies on social priming and 130 from yoked control studies. The results from the yoked controls confirm the findings from the first example, whereas the results from the social priming studies are difficult to interpret because they are sensitive to the prior specification. To maximize accessibility, we provide a web application that allows researchers to apply the mixture model to any set of significant p values. (PsycINFO Database Record PMID- 28846005 TI - Choice as an engine of analytic thought. AB - Choice is a behavioral act that has a variety of well-documented motivational consequences-it fosters independence by allowing people to simultaneously express themselves and influence the environment. Given the link between independence and analytic thinking, the current research tested whether choice also leads people to think in a more analytic rather than holistic manner. Four experiments demonstrate that making choices, recalling choices, and viewing others make choices leads people to think more analytically, as indicated by their attitudes, perceptual judgments, categorization, and patterns of attention allocation. People who made choices scored higher on a subjective self-report measure of analytic cognition compared to whose did not make a choice (pilot study). Using an objective task-based measure, people who recalled choices rather than actions were less influenced by changes in the background when making judgments about focal objects (Experiment 1). People who thought of others' behaviors as choices rather than actions were more likely to group objects based on categories rather than relationships (Experiment 2). People who recalled choices rather than actions subsequently allocated more visual attention to focal objects in a scene (Experiment 3). Together, these experiments demonstrate that choice has important yet previously unexamined consequences for basic psychological processes such as attention and cognition. (PsycINFO Database Record PMID- 28846006 TI - Blame it on the bossa nova: Transfer of perceived sexiness from music to touch. AB - Emotion elicited through music transfers to subsequent processing of facial expressions. Music may accordingly function as a social technology by promoting social bonding. Here, we investigated whether music would cross-modally influence the perception of sensual touch, a behavior related to mating. A robot applied precisely controlled gentle touch to a group of healthy participants while they listened to music that varied with respect to its perceived sexiness. As the perceived sexiness of the music increased, so did the subjective sexiness of the touch stimulations. In short, the perception of sexiness transferred from music to touch. Because sensual touch is key to mating behavior and relates to procreation, this association has implications for the universality and evolutionary significance of music. (PsycINFO Database Record PMID- 28846007 TI - Emodiversity: Robust predictor of outcomes or statistical artifact? AB - This article examines the concept of emodiversity, put forward by Quoidbach et al. (2014) as a novel source of information about "the health of the human emotional ecosystem" (p. 2057). Quoidbach et al. drew an analogy between emodiversity as a desirable property of a person's emotional make-up and biological diversity as a desirable property of an ecosystem. They claimed that emodiversity was an independent predictor of better mental and physical health outcomes in two large-scale studies. Here, we show that Quoidbach et al.'s construct of emodiversity suffers from several theoretical and practical deficiencies, which make these authors' use of Shannon's (1948) entropy formula to measure emodiversity highly questionable. Our reanalysis of Quoidbach et al.'s two studies shows that the apparently substantial effects that these authors reported are likely due to a failure to conduct appropriate hierarchical regression in one case and to suppression effects in the other. It appears that Quoidbach et al.'s claims about emodiversity may reduce to little more than a set of computational and statistical artifacts. (PsycINFO Database Record PMID- 28846008 TI - Real-time sun protection decisions in first-degree relatives of melanoma patients. AB - OBJECTIVE: Melanoma is the most serious skin cancer, and consistent use of sun protection is recommended to reduce risk. Yet sun protection use is generally inconsistent. Understanding the decisional factors driving sun protection choices could aid in intervention development to promote sun protection maintenance. METHOD: In 59 first-degree relatives of melanoma patients, an interactive voice response system (IVRS) on participants' cell phones was used to assess twice daily (morning, afternoon) real-time sun protection usage (sunscreen, shade, hats, protective clothing) and decision factors (weather, type of activity, convenience, social support) over a 14-day summer interval where morning and afternoon outdoor exposures were anticipated. Generalized estimating equations and hierarchical linear models were used to examine the effect of demographics and decisional factors on sun protection choices over time. RESULTS: Sun protection use was inconsistent (e.g., 61% used sunscreen inconsistently). Most strategies were used independently, with the exception of moderate overlap of sunscreen and hat usage. Decision factors were highly relevant for sun protection. For instance, sunscreen use was related to the perception of having adequate time to apply it, whereas shade and hat usage were each related to convenience. Few findings emerged by gender, age, time of day, or year. Significant within-subject variation remained, however. CONCLUSIONS: The findings support continued examination of decision factors in understanding sun protection consistency in real time. Interventions where cues to action and environmental supports work together in varied settings can be developed to improve sun protection maintenance in populations at risk for this common disease. (PsycINFO Database Record PMID- 28846009 TI - Metabolic Response to Omega-3 Fatty Acids and Vitamin E Co-Supplementation in Patients with Fibrocystic Breast Disease: A Randomized, Double-Blind, Placebo Controlled Trial. AB - BACKGROUND: There is scarce data on the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with fibrocystic breast disease (FBD). The current study was carried out to determine the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with FBD. METHODS: A randomized clinical trial was conducted on 56 patients with FBD. Participants were randomly divided into two groups to receive either 1000 mg omega-3 fatty acids plus 400 mg vitamin E (n = 28) or placebo (n = 28) for 12 weeks. Fasting blood samples were taken at the beginning of the study and after 12 weeks of intervention to determine inflammatory factors, biomarkers of oxidative stress, and metabolic profiles. RESULTS: After 12 weeks of intervention, changes in serum high-sensitivity C-reactive protein (-2171.4 +/- 3189.1 vs. +696.9 +/- 2774.8 ng/mL, P = 0.001) and plasma nitric oxide (+1.8 +/- 4.0 vs. -0.1 +/- 2.4 umol/L, P = 0.04) in supplemented women were significantly different from those in the placebo group. In addition, compared to the placebo group, subjects who consumed omega-3 fatty acids plus vitamin E supplements had significantly decreased serum insulin concentrations (-3.2 +/- 6.5 vs. -0.2 +/- 1.7 uIU/mL, P = 0.01), the homeostasis model of assessment-estimated insulin resistance (-0.8 +/- 1.7 vs. -0.02 +/- 0.4, P = 0.03), serum triglycerides levels (-11.5 +/- 47.3 vs. +10.6 +/- 24.3 mg/dL, P = 0.03) and VLDL-cholesterol (-2.3 +/ 9.5 vs. +2.1 +/- 4.9 mg/dL, P = 0.03), as well as increased quantitative insulin sensitivity check index (+0.01 +/- 0.01 vs. +0.001 +/- 0.007, P = 0.001) and HDL cholesterol (+3.4 +/- 6.0 vs. -1.3 +/- 4.3 mg/dL, P = 0.001). CONCLUSION: Overall, omega-3 fatty acids and vitamin E co-supplementation for 12 weeks had beneficial effects on inflammatory markers and metabolic profiles in patients with FBD. PMID- 28846010 TI - Comparison of Three Diet Quality Indices for Patients with Chronic Kidney Disease. AB - BACKGROUND: Patients with chronic kidney disease (CKD) have specific dietary needs due to recommended dietary restrictions. However, there is no specific index for evaluating the quality of diet in patients with CKD. OBJECTIVE: To define and compare three specific diet quality indices in patients with CKD. METHODS: Two hundred twenty-one subjects with CKD were selected for this cross sectional study. The patients' Dietary intake was assessed with a validated food frequency questionnaire. Total protein intake per body weight (TP/BW), animal protein intake per body weight (AP/BW) and animal protein to vegetable protein ratio (AP/VP) were defined as diet quality indices. Renal function was measured by blood urea nitrogen (BUN) and serum creatinine (Cr). RESULTS: Patients in the highest tertile of TP/BW and tertile of AP/BW consumed more amounts of nutrients which should be limited in CKD (i.e., sodium, potassium and phosphorus). Subjects in the last tertile of AP/BW had higher BUN and Cr. A marginally significant increased risk of higher stage of CKD across the tertiles of AP/BW was observed after adjusting for potential confounders (OR = 2.20, 95% CI: 1.06, 4.56; P = 0.08). CONCLUSION: The results showed that AP/BW is a good diet quality index and is marginally associated with being in higher stages of CKD. PMID- 28846011 TI - How to Overcome the Challenges of Non-Detachable Connector Tubes in Submental Intubation for Panfacial Fractures. AB - INTRODUCTION: Armored removable connector tubes are not always available in operating rooms for routine Altemir submental intubation (SMI) technique. The present study addresses a fiber-optic glidoscopy assisted 2-tubes modification of Green & Moore sequence for submandibular intubation. METHODS: The sample was composed of 11 patients (8 males and 3 females) with panfacial fractures where neither the oral and nasal intubation techniques nor tracheostomy were feasible. The inter-operative procedure duration was recorded and a comparison was made between the present results with those obtained in similar studies. Moreover, postoperative complications were assessed over a duration of 6 months. RESULTS: The average duration of this modified procedure was 8-13 min. (Mean, 10.54 +/- 1.75 min). No perioperative or postoperative complications were observed. Based on the findings in this study, it is suggested that this new technique is safe, quick and reliable for submandibular intubation. CONCLUSION: This modification establishes a secure airway for treatment of maxillofacial panfacial fractures, where traditional methods are impossible due to non-detachable connector tubes. No perioperative or postoperative complications were observed. This study suggests that this new technique is safe, quick and reliable for submandibular intubation. PMID- 28846012 TI - Management of Laparoscopic Cholecystectomy-Related Bile Duct Injuries: A Tertiary Center Experience. AB - BACKGROUND: Laparoscopic cholecystectomy (LC)-related bile duct injuries remains a challenging issue with major implications for patient's outcome. METHODS: Between January 2008 and December 2012, we retrospectively analyzed the management and treatment outcomes of 90 patients with bile duct injury following LC. RESULTS: Forty-seven patients (52.2%) were treated surgically while the remaining 43 patients (47.8%) underwent non-surgical intervention. Injuries of Strasberg Type A and C were significantly more frequent in the non-surgical intervention group (P = 0.016, P = 0.044) whereas Type E2 was more frequent in the definitive surgery group (P < 0.001). The success rate of non-surgical intervention decreased as the waiting time increased whereas the success of definitive surgery was not time-dependent (P = 0.048). Initial jaundice (direct biluribin >1.3 gr/dL) significantly reduced the success rate of non-surgical interventions (P = 0.017). Presence of intraabdominal abscess significantly increased the complication rate after both definitive surgery and non-surgical interventions (P = 0.04, P = 0.023). Treatment success rates were similar in both surgery and non-surgical intervention groups according to the distribution of Strasberg injury types. CONCLUSION: A multimodality approach is recommended in planning for patient-based treatment. Delayed referral reduces the success of nonsurgical interventions while it does not seem to significantly affect the success of surgical interventions when intraabdominal sepsis is under control. PMID- 28846014 TI - A New Approach to Survival Analysis of Head and Neck Squamous Cell Carcinoma. AB - BACKGROUND: Squamous cell carcinoma is the most common histological subtype of head and neck cancers. METHODS: In a retrospective longitudinal study, we assessed the risk of local or metastatic recurrence and death in 140 patients with head and neck squamous cell carcinoma (HNSCC). Multivariate and shared frailty models were used for survival analysis with sex, primary tumor site, grade and stage of the tumor, and treatment modalities as contributing factors. RESULTS: The most frequent site for HNSCC was the oral cavity (30%), followed by the tongue (26.4%). For most primary sites, men were at nearly 2-fold higher risk of local recurrence than women, but there was no difference by sex in the risk of metastatic recurrence. Undifferentiated HNSCC was associated with a higher risk of local recurrence (nearly 4-fold) and metastasis (6-15-fold based on the primary site) than well-differentiated tumors. In early months after surgical resection alone, the risk of local recurrence was higher compared to other treatment modalities. There was a strong dependency between the risk of local and metastatic recurrence. CONCLUSION: In conclusion, men diagnosed with HNSCC, those with higher grade or advanced state tumor, and those treated by surgery alone are at higher risk of unfavorable outcomes than others and may need more frequent follow-up visits. PMID- 28846013 TI - Feasibility and Data Quality of the National Spinal Cord Injury Registry of Iran (NSCIR-IR): A Pilot Study. AB - BACKGROUND: Spinal cord injury (SCI) is one of the most disabling consequences of trauma with unparalleled economic, social, and personal burden. Any attempt aimed at improving quality of care should be based on comprehensive and reliable data. This pilot investigation studied the feasibility of implementing the National Spinal Cord and Column Injury Registry of Iran (NSCIR-IR) and scrutinized the quality of the registered data. METHODS: From October 2015 to May 2016, over an 8 month period, 65 eligible trauma patients who were admitted to hospitals in three academic centers in mainland Iran were included in this pilot study. Certified registered nurses and neurosurgeons were in charge of data collection, quality verification, and registration. RESULTS: Sixty-five patients with vertebral column fracture dislocations were registered in the study, of whom 14 (21.5%) patients had evidence of SCI. Mechanisms of injury included mechanical falls in 30 patients (46.2%) and motor vehicle accidents in 29 (44.6%). The case identification rate i.e. clinical and radiographic confirmation of spine and SCI, ranged from 10.0% to 88.9% in different registry centers. The completion rate of all data items was 100%, except for five data elements in patients who could not provide clinical information because of their medical status. Consistency i.e. identification of the same elements by all the registrars, was 100% and accuracy of identification of the same pathology ranged from 66.6% to 100%. CONCLUSIONS: Our pilot study showed both the feasibility and acceptable data quality of the NSCIR-IR. However, effective and successful implementation of NSCIR-IR data use requires some modifications such as presence of a dedicated registrar in each center, verification of data by a neurosurgeon, and continuous assessment of patients' neurological status and complications. PMID- 28846015 TI - Evaluation of a Web-based Error Reporting Surveillance System in a Large Iranian Hospital. AB - BACKGROUND: Proper reporting of medical errors helps healthcare providers learn from adverse incidents and improve patient safety. A well-designed and functioning confidential reporting system is an essential component to this process. There are many error reporting methods; however, web-based systems are often preferred because they can provide; comprehensive and more easily analyzed information. This study addresses the use of a web-based error reporting system. METHODS: This interventional study involved the application of an in-house designed "voluntary web-based medical error reporting system." The system has been used since July 2014 in Nemazee Hospital, Shiraz University of Medical Sciences. The rate and severity of errors reported during the year prior and a year after system launch were compared. RESULTS: The slope of the error report trend line was steep during the first 12 months (B = 105.727, P = 0.00). However, it slowed following launch of the web-based reporting system and was no longer statistically significant (B = 15.27, P = 0.81) by the end of the second year. Most recorded errors were no-harm laboratory types and were due to inattention. Usually, they were reported by nurses and other permanent employees. Most reported errors occurred during morning shifts. DISCUSSION: Using a standardized web-based error reporting system can be beneficial. This study reports on the performance of an in-house designed reporting system, which appeared to properly detect and analyze medical errors. The system also generated follow-up reports in a timely and accurate manner. Detection of near-miss errors could play a significant role in identifying areas of system defects. PMID- 28846016 TI - Impact of Merger and Acquisition on University Performance. AB - PURPOSE: Merger and acquisitions (M&A) widen access to higher education, improve quality of teaching and research, and increase efficiency of higher education institutions. Three big medical universities in Iran merged in 2010. The purpose of this study was to highlight the impact of this acquisition on the performance of Tehran University of Medical Sciences. METHODS: This qualitative study was conducted using semi-structured in-depth interviews with 60 participants from April 2015 to November 2015. Purposeful sampling was used to recruit participants. Data analysis was performed using MAXQDA software (V. 10). FINDINGS: The reasons for acquisition of IUMS by TUMS were to enhance the position of TUMS worldwide, and to increase its efficiency. The acquisition improved the organization and management of the newly formed TUMS, enhanced its academic position and market recognition. However, the achieved benefits did not come without shortcomings and unanticipated consequences. CONCLUSION: The merger and acquisition in higher education has some advantages and disadvantages. A well planned and carefully implemented M&A gives cutting edge to the higher education institutes. PMID- 28846017 TI - Pharmacologic Treatment of Wet Type Age-related Macular Degeneration; Current and Evolving Therapies. AB - Age-related macular degeneration as the major cause of blindness in the elderly population has remained at the epicenter of clinical research in ophthalmology. This retinal disorder is characterized by the photoreceptor and retinal pigment epithelial cells loss, occurring within the macula. The disease represents a spectrum of clinical manifestations. It is a multifactorial disease resulting from a combination of genetic predispositions and environmental risk factors. AMD is classified into two different types, dry and wet. Wet AMD is in close relation with angiogenesis and inflammatory processes.A variety of anti-angiogenesis and anti-inflammatory drugs have been proposed for the treatment of the disease. The purpose of this paper is to briefly review the pharmacological therapies of the wet form of AMD and focus on new drugs that are currently in different stages of research and development. PMID- 28846018 TI - Investigating the Effect of Syrian Refugees on the Pharmaceutical Sector in Jordan. AB - The aim of this study was to investigate the effect of Syrian refugees on the pharmaceutical sector in Jordan. Based on a standardized methodology developed by the WHO, Level II Facility (2009) structured questionnaires (including: medicine access [availability, affordability and geographical accessibility], quality, and rational use of medicines) were used to investigate the effect of Syrian refugees influx on the pharmaceutical sector in Jordan. Lists of essential medicines (N = 50) were included in the survey forms. The results showed more progress in all indicators for the public sector compared with the previous results in the 2009 survey and in comparison to the private sector. For example, access to medicines improved in the public sector while it decreased (if it did not remain the same) in the private sector. Also, average stock out duration time decreased dramatically in both public and private sectors. As indicated by the median price ratio (MPR), brand prices increased much in the public health facilities while they decreased by 23%-30% in the private sector. In northern areas where most Syrian refugees stay, a significant decrease in availability was noticed, in addition to the dramatic decrease in days of average stock out and adequate inventory record percentage of those medicines. In conclusion, despite the international help received to support health care provision and medications procurement for the refugees, more support is needed immediately. PMID- 28846019 TI - Draft of Iranian National Guideline for Cell Therapy Manufacturing. AB - Cell therapy, a promising method for treatment of incurable diseases, has been moving fast from basic research laboratories to clinical practice in recent years. Defining clear and strict regulations for manufacturing of cell therapy products in clinical applications is the best way to give assurance to the public sector for safe usage, harmonizing research projects, and placing barriers for unqualified products from entering this market. To achieve this goal, the Iranian Council for Stem cell Science and Technologies sponsored a project in 2013 to develop a national cell therapy guideline for research and clinical trials. To prepare the preliminary guideline, a comprehensive literature and document review was performed by an expert team. The draft was subsequently revised and approved in May 2014 by a large group of experts who were practically involved in basic and clinical fields of regenerative medicine. The final guideline covered all aspects of cell manufacturing, including ethical issues, manufacturing process, quality controls, transportation, harvesting, storage, and release of cell-based products. The optimal infrastructure of the cell manufacturing facility as well as the eligibilities of man-power working in the facility were also described. After adoption in the Council, the guideline was sent to the Ministry of Health and Medical Education for confirmation and final approval. In this report, we introduce the main topics and mention some of the important items of this guideline. The complete draft of the guideline is available as a supplement in this issue. PMID- 28846020 TI - A Girl with Abdominal Pain. PMID- 28846021 TI - Remembering Marcel Baltazard, Great Researcher and the French President of Pasteur Institute of Iran. AB - Dr. Marcel Baltazard (1908-1971), French scientist and former director of Pasteur Institute of Iran, is known in the international arena due to his research on the control of infectious diseases such as plague, rabies, relapsing fever, leprosy, smallpox and tuberculosis. Dr. Baltazard also played a significant role in the launch of vaccination against tuberculosis, cholera and smallpox. Dr. Baltazard's spent the first 13 years of academic life at Pasteur Institute of Casablanca, Morocco, and then 20 years at Pasteur Institute of Iran and over the last five years at Pasteur Institute of Paris. In this paper, the activities of this important and influential researcher in the field of health and medicine are addressed. PMID- 28846022 TI - Buspirone in Children and Adolescents with Anxiety: A Review and Bayesian Analysis of Abandoned Randomized Controlled Trials. AB - OBJECTIVES: An increasing number of abandoned clinical trials have forestalled efforts to advance the evidence base for the treatment of mood and anxiety disorders in children and adolescents. With this in mind, we sought to present and validate a Bayesian approach for the reanalysis of summary data in abandoned clinical trials and to review and re-evaluate available pharmacokinetic, tolerability, and efficacy data from two large, randomized controlled trials of buspirone in pediatric patients with generalized anxiety disorder (GAD). METHODS: Prospective, randomized, parallel-group controlled trials of buspirone in pediatric patients with GAD as well as associated pharmacokinetic studies were identified and data were extracted. In addition to descriptive statistics, marginal posterior densities for each variable of interest were determined and a Monte Carlo pseudosample was generated with random draws obtained from the Student's t-distribution to assess, with inferential statistics, differences in variables of interest. RESULTS: Buspirone was evaluated in one flexibly dosed (N = 227) and one fixed-dose (N = 341) trial in children and adolescents aged 6-17 years with a primary diagnosis of GAD. With regard to improvement in the sum of the Columbia Schedule for Affective Disorders and Schizophrenia GAD items, buspirone did not separate from placebo in the fixed-dose trial at low (95% CI: 0.78 to 2.39, p = 0.32) or high dose (95% CI: -0.87 to 1.87, p = 0.47) nor did it separate from placebo in the flexibly dosed study (95% CI: -0.3 to 1.9, p = 0.15). Drop out as a result of a treatment-emergent adverse event was significantly greater in buspirone-treated patients compared to placebo (p = 0.011). Side effects were consistent with the known profile of buspirone with lightheadedness occurring more frequently in buspirone-treated patients (p < 0.001). CONCLUSIONS: Buspirone is well tolerated in pediatric patients with GAD, although two randomized controlled trials were underpowered to detect small effect sizes (Cohen's d < 0.15). Finally, Bayesian approaches may facilitate re examination of data from abandoned clinical trials. PMID- 28846023 TI - Quality indicators of psychotropic prescribing to people with dementia in aged psychiatry inpatient units. AB - OBJECTIVES: To develop indicators of safe psychotropic prescribing practices for people with dementia and to test them in a convenience sample of six aged mental health services in Victoria, Australia. METHOD: The clinical records of 115 acute inpatients were checked by four trained auditors against indicators derived from three Australian health care quality and safety standards or guidelines. Indicators addressed psychotropic medication history taking; the prescribing of regular and 'as needed' psychotropics; the documentation of psychotropic adverse reactions, and discharge medication plans. RESULTS: The most problematic areas concerned the gathering of information about patients' psychotropic prescribing histories at the point of entry to the ward and, later, the handing over on discharge of information concerning newly prescribed treatments and the reasons for ceasing medications, including adverse reactions. There were wide variations between services. CONCLUSION: The indicators, while drawn from current Australian guidelines, were entirely consistent with current prescribing frameworks and provide useful measures of prescribing practice for use in benchmarking and other quality improvement activities. PMID- 28846024 TI - An Online Life Like Any Other: Identity, Self-Determination, and Social Networking Among Adults with Intellectual Disabilities. AB - Research focusing on online identity and the personal experiences of adults with intellectual disabilities (ID) is currently limited. Eleven adults with ID were interviewed regarding personal experiences of being online and using social media. Data were analyzed qualitatively using thematic network analysis. Two global themes, online relatedness and sharing and online agency and support, highlighted the positive potential of social media in enabling the development and maintenance of social bonds, valued social roles, and feelings of enjoyment, competence, autonomy, and self-worth. Participants reported sharing various expressed online identities that did not focus on or hide impairment, challenging notions of dependency, with participants both providing support and being supported online. PMID- 28846025 TI - Indicators to estimate the appropriateness of activating interventions for people living with dementia and for their informal caregivers. AB - OBJECTIVES: Dyadic activating interventions support both people with dementia and their informal caregivers to maintain activities. For a person-centered approach referrers need insight in how specific interventions might meet individual needs, characteristics, and preferences of a dyad. This study aimed to develop a set of indicators for three psychosocial dyadic, activating interventions. METHOD: We used the 'RAND Appropriateness Method' directed at agreement on indicators within a panel of experts. Qualitative research had identified 31 relevant conceptual indicators. A panel of 12 experts in dementia care rated the extent to which these indicators are recognizable in their clinical practice. Indicators with median ratings in the top third segment of the nine-point-scale were considered recognizable. RESULTS: 18/31 conceptual indicators (58%) were found recognizable in 75%-90% of the panelists' clients. Although consensus on the recognizability of some indicators about the need or preference for physical and social activities was lacking, the respondents nevertheless recommended including these in regular assessments. Other indicators were judged too difficult to recognize in clinical practice. CONCLUSION: The selected indicators offer guidance to referrers on what intervention(s) to choose, and discuss the appropriateness in a shared decision-making process, thus contributing to a person-centered approach. PMID- 28846026 TI - Lactoferricin/verbascoside topical emulsion: a possible alternative treatment for atopic dermatitis in dogs. AB - Atopic dermatitis affects 3-15% of the general dog population and it has been diagnosed by veterinarians up to 58% of dogs affected with skin disease. It is usually a life-long pathology which can be controlled, but it can be seldom cured. The present investigation describes a case study in which lactoferricin and verbascoside are part of a formulation to obtain a dermatological lotion for canine dermatitis treatment. The study was an open-label trial design of two-week treatment. Thirty-eight dogs (23 females and 15 males), with atopic dermatitis and secondary bacterial or yeast overgrowth have been included. During treatment period the total clinical score progressively decreased associated with an improvement in clinical signs. No adverse effects were reported in any of the treated dogs. The present research suggests that daily applications of tested emulsion are effective in reducing bacterial overgrowth and clinical signs in skin folds and atopic dermatitis. PMID- 28846027 TI - Perceptions of Social Responsibility of Prominent Animal Welfare Groups. AB - Nonhuman animal welfare is an increasingly important component of consumer expectations of corporate social responsibility (CSR). The extent to which prominent animal welfare or protection organizations may influence people's perceptions of food industry CSR may be related to an organization's perceived social responsibility. Data from an online survey of 300 U.S. residents were used to explore relationships between demographics/lifestyle choices and perceptions of prominent animal welfare organizations (using best-worst scaling methodology). Overall, the American Society for the Prevention of Cruelty to Animals was perceived to be the most socially responsible organization analyzed, followed by the Humane Society of the United States and the American Humane Association (AHA). Results suggest that the perceived social responsibility of animal protection organizations in this study was not strongly linked to personally (financially) supporting them, with 2 exceptions: the perceptions of People for the Ethical Treatment of Animals and AHA. Improved understanding of the perception of animal welfare or protection organizations can inform decision making by organizations interested in furthering animal welfare causes. PMID- 28846029 TI - Ayurvedic preparation of Zingiber officinale Roscoe: effects on cardiac and on smooth muscle parameters. AB - The rhizome of the Zingiber officinale Roscoe, a biennial herb growing in South Asia, is commonly known as ginger. Ginger is used in clinical disorders, such as constipation, dyspepsia, diarrhoea, nausea and vomiting and its use is also recommended by the traditional medicine for cardiopathy, high blood pressure, palpitations and as a vasodilator to improve the circulation. The decoction of ginger rhizome is widely used in Ayurvedic medicine. In this papery by high performance liquid chromatography, we have seen that its main phytomarkers were 6 gingerol, 8-gingerol and 6-shogaol and we report the effects of the decoction of ginger rhizome on cardiovascular parameters and on vascular and intestinal smooth muscle. In our experimental models, the decoction of ginger shows weak negative inotropic and chronotropic intrinsic activities but a significant intrinsic activity on smooth muscle with a potency on ileum is greater than on aorta: EC50 = 0.66 mg/mL versus EC50 = 1.45 mg/mL. PMID- 28846030 TI - Suicidal ideation and hopelessness in PTSD: spiritual well-being mediates outcomes over time. AB - Background There is an increased interest in understanding the mechanisms through which post-traumatic stress disorder (PTSD) relates with hopelessness and suicidal ideation. Spiritual well-being could help explain the link between PTSD and both hopelessness and suicidal ideation in African Americans. However, no study has examined the mediational role of existential and religious well-being among these variables. Objectives To examine if initial levels of existential and religious well-being mediated the relation between levels of PTSD symptoms and prospective levels of hopelessness and suicidal ideation in a sample of African American females. Design The study used a longitudinal design with a 10-week time interval. Methods The sample comprised of 113 disadvantaged African American women survivors of a recent suicide attempt recruited from a southern hospital. Self-report measures of PTSD symptoms, hopelessness, suicidal ideation, and spiritual well-being were administered to examine the variables of interest. Bootstrapping techniques were used to test the mediational models. Results Existential, but not religious well-being, mediated the relationship between levels of PTSD symptoms severity and both levels of hopelessness and suicidal ideation over time. Conclusions Existential well-being appears to play a promising protective role against the negative effects of PTSD on both hopelessness and suicidal ideation. PMID- 28846031 TI - Parity Influences the Demeanor of Sows in Group Housing. AB - Across the globe, producers are moving from individual housing to group housing for sows during gestation. Producers typically group sows of a range of parities together, although the impacts are largely unknown. This study examined the behavioral expression at mixing for young, midparity, and older sows. Ten mixed parity groups were filmed at mixing on a commercial piggery. One-minute clips were edited from continuous footage where focal sows of known parity could be identified, and scored for qualitative behavioral expression. Parity 2 and 6 sows were more calm/tired than Parity 4 sows, who were more active/energetic. Parity 2 sows were more curious/inquisitive than Parity 4 and 6 sows, who were more anxious/frustrated. Correlations between qualitative behavioral expression and activity indicated sows scored as more calm/tired spent a greater proportion of time standing, while sows scored as more active/energetic spent more time performing avoidance behavior. Different body language is likely to reflect physical or affective differences in how sows cope with mixing. PMID- 28846032 TI - The Graded Response Differential Discrimination Model Accounting for Extreme Response Style. AB - Extreme response style or, more generally, individual differences in response spacing have been shown to be an influential bias when analyzing questionnaire data. Recently a promising model adjusting for this bias - the differential discrimination model - has been proposed. An advantage to other related approaches is that the model can be fitted using standard structural equation modeling software. However, the model is designed for analyzing continuous item responses, whereas graded response formats are certainly more prominent in behavioral sciences. To resolve this limitation, the present article extends the differential discrimination model to analyzing graded responses. Empirical examples as well as a small simulation study are presented. PMID- 28846033 TI - Metabolic Alterations of Qinghai-Tibet Plateau Pikas in Adaptation to High Altitude. AB - Cao, Xue-Feng, Zhen-Zhong Bai, Lan Ma, Shuang Ma, and Ri-Li Ge. Metabolic alterations of Qinghai-Tibet plateau pikas in adaptation to high altitude. High Alt Med Biol. 18:219-225, 2017.-To determine specific metabolic alterations in the myocardium of plateau pikas (Ochotona curzoniae) and potential metabolic biomarkers involved in their adaptation to the high-altitude environment of the Qinghai-Tibet Plateau. Ten pikas were captured by traps in the Kekexili Reserve (4630 m a.s.l; n = 5) and at the foot of the Laji Mountain (2600 m a.s.l; n = 5) on the Qinghai-Tibet Plateau, Qinghai Province, China. Metabolite levels were determined by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) metabolomics, and multivariate statistical analysis was performed. Several metabolites involved in carbohydrate, fat, energy, and redox homeostasis pathways were significantly altered in pikas living at 4630 m. In addition, those pikas showed increased levels of lactic acid, sarcosine, 4-hydroxybutyrate, methionine, tartaric acid, ribose, tyrosine, pentadecanoic acid, 2-monoolein, 3,5 dihydroxyphenylglycine, trehalose-6-phosphate, succinic acid, myoinositol, fumaric acid, taurine, 2-hydroxybutanoic acid, gluconic acid, citrulline, and glutathione, but decreased levels of oleic acid and 2'-deoxyadenosine 5' monophosphate. Metabolic activity is significantly altered in the myocardium of pikas in the high-altitude areas of the Qinghai-Tibet Plateau. This study provides important insights into metabolic biomarkers related to the adaptation of pikas to high-altitude hypoxia. PMID- 28846034 TI - Advances in the use of Xenopus for successful drug screening. AB - INTRODUCTION: Understanding embryogenesis currently relies largely on the control of gene expression via several signaling pathways. Many of the embryonic signaling pathways guiding embryological events are implicated in diseases that lack effective cure or treatment. Because of the large number and size of the eggs, the rapid development of the embryos and the fact they are amenable to pharmacological, surgical and genetic techniques, Xenopus laevis has been successfully used in searching for compounds that target embryonic signaling pathways. Areas covered: Here, the authors address the use of amphibian eggs/embryos in successful chemical screenings; egg extracts as well as embryo phenotypes have been assayed to reveal drug toxicology effects and novel compounds acting in the Wnt/beta-catenin signaling pathway. They do not discuss the use of Xenopus oocyte two-electrode voltage clamps or genome editing tools as approaches for drug discovery because they have been discussed elsewhere. Expert opinion: While high-throughput screening is commonly performed in egg extracts, the embryo axes perturbation system is more suited to the refinement and/or the validation of drug discovery targeting embryonic signaling (particularly the Wnt/beta-catenin pathway). In addition, Xenopus has also been used in FETAX (frog embryo teratogenesis assay: Xenopus) to address chemical toxic/teratogenic effects. However, further studies are necessary. PMID- 28846035 TI - High-Altitude Pulmonary Edema in Mountain Community Residents. AB - Ebert-Santos, Christine. High-altitude pulmonary edema in mountain community residents. High Alt Med Biol. 18:278-284, 2017.-High-altitude pulmonary edema (HAPE) affects lowlanders ascending quickly to elevations above 2440 m. Mountain resident children with no travel can sometimes develop HAPE as was observed over 30 years ago (Fasules et al., 1985). This is not well known and children instead are diagnosed as having pneumonia or asthma. In our clinic at 2800 m, we see children presenting with severe hypoxemia, clinical, and radiographic findings consistent with HAPE despite no recent travel. We call this mountain resident HAPE. We reviewed records of 48 patients with pulmonary symptoms. Analysis included vital signs, pulse oximetry, laboratories, physical findings, and clinical course. We identified 33 residents with HAPE and no travel, five with reentry HAPE, two visitors with classic HAPE, six residents with pneumonia, and two with asthma. Also, 48 X-rays on hypoxemic children seen between 2006 and 2017 were reviewed. Five showed definite HAPE with follow-up X-rays within 48 hours confirming rapid clearing on oxygen, 27 showed findings consistent with HAPE or viral pneumonia and no repeat study. Children living at elevation presenting with hypoxemia are commonly misdiagnosed. Rapid improvement with oxygen and little to no improvement with bronchodilators are more consistent with HAPE, and thus, antibiotics and other treatments can be avoided. PMID- 28846036 TI - Differential Relationships of Anxiety and Autism Symptoms on Social Skills in Young Boys With Fragile X Syndrome. AB - Social skills are critical for academic, social, and psychological success of children with both typical and atypical development. Boys with fragile X syndrome (FXS) are at high risk for social skill impairments, given intellectual impairments and secondary conditions. The present study examines the impact of adaptive behavior, autism symptoms, and anxiety symptoms to social skills at the composite and subdomain level in boys with FXS across age. This cross-sectional study included boys with FXS (3-14 years) contrasted to age-matched typical control boys. Results revealed that social skills are generally within developmental expectations, with adaptive behavior as the primary predictor. Anxiety and autism symptoms emerged as additive risk factors, particularly in the areas of responsibility and self-control. PMID- 28846037 TI - Narrative Language and Reading Comprehension in Students With Mild Intellectual Disabilities. AB - Past research shows positive correlations between oral narrative skill and reading comprehension in typically developing students. This study examined the relationship between reading comprehension and narrative language ability of 102 elementary students with mild levels of intellectual disability. Results describe the students' narrative language microstructure and relative strengths and weaknesses in narrative macrostructure. Students' narrative macrostructure accounted for significant variance in reading comprehension beyond what was accounted for by narrative microstructure (i.e., mean length of utterance in morphemes, number of different words, total utterances). This study provides considerations for measuring narrative quality when characterizing the functional language skills of students with mild levels of intellectual disability. Measurement tools that quantify the quality of language provide important information regarding targets of intervention beyond grammar and vocabulary. PMID- 28846038 TI - A Case-Controlled Investigation of Tactile Reactivity in Young Children With and Without Global Developmental Delay. AB - Assessing tactile function among children with intellectual, motor, and communication impairments remains a clinical challenge. A case control design was used to test whether children with global developmental delays (GDD; n = 20) would be more/less reactive to a modified quantitative sensory test (mQST) compared to controls (n = 20). Reactivity was indexed by blinded behavioral coding across vocal, facial, and gross motor responses during the mQST. On average the children with GDD were significantly more reactive than controls to most tactile sensory modalities including light touch (p = .034), pin prick (p = .008), cool (p = .039), pressure (p = .037), and repeated von Frey (p = .003). The results suggest the mQST approach was feasible and highlights the GDD sample was more reactive than controls to a range of stimuli. PMID- 28846039 TI - Psychometric Properties of the Beach Center Family Quality of Life in French Speaking Families With a Preschool-Aged Child Diagnosed With Autism Spectrum Disorder. AB - The Beach Center Family Quality of Life Scale (Beach Center FQOL) is used to evaluate and develop family-centered intervention services. However, its use with families of children with autism spectrum disorder (ASD) and in non-English speaking populations requires further investigation. The present study sought to assess the psychometric properties of a French translation of this scale on 452 parents of children aged 5 and under who were recently diagnosed with ASD. The resulting Satisfaction and Importance scales presented excellent internal consistency at the scale level and acceptable internal consistency at the subscale level. Theoretical model positing 5 dimensions of FQOL generally fit the data acceptably. Satisfaction ratings were found to be sensitive to changes and were negatively correlated with parenting stress. PMID- 28846041 TI - Resumenes al Espanol. PMID- 28846040 TI - Longitudinal Correlates of Maternal Depression Among Mothers of Children With or Without Intellectual Disability. AB - This study identified trajectories of depressive symptoms among mothers of children with or without intellectual disability longitudinally across eight time points. Results of fitting a linear growth model to the data from child ages 3-9 indicated that child behavior problems, negative financial impact, and low dispositional optimism all significantly related to initial maternal depressive symptoms. Child behavior problems were significantly associated with changes in depressive symptoms over time, relating above and beyond child disability status. When looking from late childhood into early adolescence, hierarchical linear regression analysis revealed that maternal depressive symptoms at child age 9 and perceived financial impact significantly related to maternal depressive symptoms at child age 13. Implications for practice and future research directions are discussed. PMID- 28846042 TI - Feasibility and Reliability of Tests Measuring Health-Related Physical Fitness in Children With Moderate to Severe Levels of Intellectual Disability. AB - Physical fitness is an important marker for health. In this study we investigated the feasibility and reliability of health-related physical fitness tests in children with moderate to severe levels of intellectual disability. Thirty-nine children (2-18 yrs) performed tests for muscular strength and endurance, the modified 6-minute walk test (6mwt) for cardiorespiratory fitness, and body composition tests, and 30-97% of the tests were successfully completed. Short term test-retest reliability of all tests was good (Intraclass Correlation Coefficient [ICC] > .8), long-term test-retest reliability was good for most tests (ICC > .7), but low ICCs were found for most strength tests. Measuring body composition and cardiorespiratory fitness is feasible and reliable. Measuring muscle endurance is fairly feasible and reliable. PMID- 28846043 TI - Resumes en Francais. PMID- 28846044 TI - Red Maca (Lepidium meyenii), a Plant from the Peruvian Highlands, Promotes Skin Wound Healing at Sea Level and at High Altitude in Adult Male Mice. AB - Nunez, Denisse, Paola Olavegoya, Gustavo F. Gonzales, and Cynthia Gonzales Castaneda. Red maca (Lepidium meyenii), a plant from the Peruvian highlands, promotes skin wound healing at sea level and at high altitude in adult male mice. High Alt Med Biol 18:373-383, 2017.-Wound healing consists of three simultaneous phases: inflammation, proliferation, and remodeling. Previous studies suggest that there is a delay in the healing process in high altitude, mainly due to alterations in the inflammatory phase. Maca (Lepidium meyenii) is a Peruvian plant with diverse biological properties, such as the ability to protect the skin from inflammatory lesions caused by ultraviolet radiation, as well as its antioxidant and immunomodulatory properties. The aim of this study was to determine the effect of high altitude on tissue repair and the effect of the topical administration of the spray-dried extract of red maca (RM) in tissue repair. Studies were conducted in male Balb/c mice at sea level and high altitude. Lesions were inflicted through a 10 mm-diameter excisional wound in the skin dorsal surface. Treatments consisted of either (1) spray-dried RM extract or (2) vehicle (VH). Animals wounded at high altitude had a delayed healing rate and an increased wound width compared with those at sea level. Moreover, wounding at high altitude was associated with an increase in inflammatory cells. Treatment with RM accelerated wound closure, decreased the level of epidermal hyperplasia, and decreased the number of inflammatory cells at the wound site. In conclusion, RM at high altitude generate a positive effect on wound healing, decreasing the number of neutrophils and increasing the number of macrophages in the wound healing at day 7 postwounding. This phenomenon is not observed at sea level. PMID- 28846045 TI - Aldoxorubicin for the treatment of soft tissue sarcoma. AB - Intoduction: Soft tissue sarcomas (STS) encompass a group of rare tumors arising from mesenchymal tissue. Traditionally, anthracycline-based chemotherapy, with doxorubicin, is the main treatment for advanced STS. Areas covered: Aldoxorubicin is a doxorubicin derivative containing a carboxylic hydrazone and serves as a prodrug of doxorubicin. It covalently binds to albumin in the blood until reaching the acidic tumor environment, which dissolves the hydrazone linker, thus releasing doxorubicin into the tissue. In this review paper, we analyze the pharmacokinetics, current phase I, phase II, and phase III trials, as well as adverse effect profile of aldoxorubicin in patients with advanced STS. Expert opinion: Aldoxorubicin represents a promising drug for treatment of sarcomas. The drug has minimal cardiac toxicity, which represents a significant advantage to doxorubicin. Preliminary phase 3 study results demonstrate PFS advantage in patients with leiomyosarcoma and liposarcoma. However, more studies are needed to establish the role of aldoxorubicin in sarcoma treatment. PMID- 28846046 TI - The Use of Simulated Altitude Techniques for Beneficial Cardiovascular Health Outcomes in Nonathletic, Sedentary, and Clinical Populations: A Literature Review. AB - : Lizamore, Catherine A., and Michael J. Hamlin. The use of simulated altitude techniques for beneficial cardiovascular health outcomes in nonathletic, sedentary, and clinical populations: A literature review. High Alt Med Biol 18:305-321, 2017. BACKGROUND: The reportedly beneficial improvements in an athlete's physical performance following altitude training may have merit for individuals struggling to meet physical activity guidelines. AIM: To review the effectiveness of simulated altitude training methodologies at improving cardiovascular health in sedentary and clinical cohorts. METHODS: Articles were selected from Science Direct, PubMed, and Google Scholar databases using a combination of the following search terms anywhere in the article: "intermittent hypoxia," "intermittent hypoxic," "normobaric hypoxia," or "altitude," and a participant descriptor including the following: "sedentary," "untrained," or "inactive." RESULTS: 1015 articles were returned, of which 26 studies were accepted (4 clinical cohorts, 22 studies used sedentary participants). Simulated altitude methodologies included prolonged hypoxic exposure (PHE: continuous hypoxic interval), intermittent hypoxic exposure (IHE: 5-10 minutes hypoxic:normoxic intervals), and intermittent hypoxic training (IHT: exercising in hypoxia). CONCLUSIONS: In a clinical cohort, PHE for 3-4 hours at 2700-4200 m for 2-3 weeks may improve blood lipid profile, myocardial perfusion, and exercise capacity, while 3 weeks of IHE treatment may improve baroreflex sensitivity and heart rate variability. In the sedentary population, IHE was most likely to improve submaximal exercise tolerance, time to exhaustion, and heart rate variability. Hematological adaptations were unclear. Typically, a 4-week intervention of 1-hour-long PHE intervals 5 days a week, at a fraction of inspired oxygen (FIO2) of 0.15, was beneficial for pulmonary ventilation, submaximal exercise, and maximum oxygen consumption ([Formula: see text]O2max), but an FIO2 of 0.12 reduced hyperemic response and antioxidative capacity. While IHT may be beneficial for increased lipid metabolism in the short term, it is unlikely to confer any additional advantage over normoxic exercise over the long term. IHT may improve vascular health and autonomic balance. PMID- 28846047 TI - Launching a new initiative. PMID- 28846048 TI - Communicated Sense-making After Miscarriage: A Dyadic Analysis of Spousal Communicated Perspective-Taking, Well-being, and Parenting Role Salience. AB - Grounded in communicated sense-making (CSM) theorizing, we investigated communicated perspective-taking (CPT; i.e., conversational partners' attendance to and confirmation of each other's views) in association with individual and relational well-being in married couples who had miscarried (n = 183; N = 366). Actor-partner interdependence modeling revealed husbands' perceptions of wives' CPT were positively related to husbands' positive affect about the miscarriage and both spouses' relational satisfaction, as well as negatively associated with wives' positive affect. Wives' perceptions of husbands' CPT related positively to their own relational satisfaction and negatively to husbands' negative affect. Analyses revealed identification as a parent to the miscarried child (i.e., "parenting role salience") positively moderated the relationship between CPT and relational satisfaction. Implications for advancing CSM theorizing in health contexts and practical applications are explored. PMID- 28846049 TI - The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis. AB - INTRODUCTION: Lumacaftor-ivacaftor is indicated for treatment of cystic fibrosis (CF) in patients homozygous for the Phe-508del cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. In clinical trials, treated patients showed improved pulmonary function, reduced pulmonary exacerbations, and other benefits. This article reviews safety of this therapy. Areas covered: Safety findings in ivacaftor, lumacaftor and combined therapy trials, and reported subsequently through post-approval evaluation, were accessed by PubMed and Google searches using key words 'VX-770', 'ivacaftor', 'VX-809', and 'lumacaftor'. Transaminitis was seen in ivacaftor and combination trials. Non-congenital cataracts were seen in pre-clinical animal studies and in children taking ivacaftor and combined therapy. Dyspnea occurs in some patients taking lumacaftor and combined therapy and usually resolves without stopping treatment. Lumacaftor is a strong inducer of CYP3A while ivacaftor is a CYP3A sensitive substrate. Combination therapy can decrease systemic exposure of medications that are substrates of CYP3A, decreasing therapeutic effect. Co-administration of lumacaftor-ivacaftor with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index is not recommended. Expert opinion: Lumacaftor-ivacaftor therapy may be associated with ocular and hepatic side effects. Specific recommendations for monitoring are available. Dyspnea occurs, especially during initiation of treatment. Potential drug interactions should be evaluated in patients taking combination therapy. The risk benefit ratio of lumacaftor ivacaftor favors therapy. PMID- 28846050 TI - A Hierarchical Rater Model for Longitudinal Data. AB - Research studies in psychology and education often seek to detect changes or growth in an outcome over a duration of time. This research provides a solution to those interested in estimating latent traits from psychological measures that rely on human raters. Rater effects potentially degrade the quality of scores in constructed response and performance assessments. We develop an extension of the hierarchical rater model (HRM), which yields estimates of latent traits that have been corrected for individual rater bias and variability, for ratings that come from longitudinal designs. The parameterization, called the longitudinal HRM (L HRM), includes an autoregressive time series process to permit serial dependence between latent traits at adjacent timepoints, as well as a parameter for overall growth. We evaluate and demonstrate the feasibility and performance of the L-HRM using simulation studies. Parameter recovery results reveal predictable amounts and patterns of bias and error for most parameters across conditions. An application to ratings from a study of character strength demonstrates the model. We discuss limitations and future research directions to improve the L-HRM. PMID- 28846051 TI - In-vivo or ex-vivo T cell depletion or both to prevent graft-versus-host disease after hematopoietic stem cell transplantation. AB - INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) represents a widely accepted therapeutic strategy for the treatment of hematologic disorders which are otherwise considered incurable. Alloreactive T cells infused with the stem cell inoculum may generate graft-versus-host disease (GVHD) representing one the most relevant obstacles to the successful outcome of patients receiving allogeneic HSCT. Areas covered: In this review, the authors provide an overview of the most recent approaches of T-cell depletion (TCD) including ex-vivo alphabeta+ TCD and in-vivo TCD with anti-thymocyte globulin (ATG). Expert opinion: Ex vivo depletion of donor T-cells prevents both acute and chronic GVHD without the need for any additional posttransplant immunological prophylaxis either in haploidentical HSCT and HLA matched transplants. Three prospective trials evaluating the efficacy of ATG in matched unrelated donor transplant recipients demonstrated that ATG reduces the incidence of both acute and chronic GVHD without a significant increase of relapse rate, and similar results have been reported in the setting of blood stem cell grafts from matched sibling donors. PMID- 28846052 TI - Association of HTRA1 rs11200638 with age-related macular degeneration (AMD) in Brazilian patients. AB - Age-related macular degeneration is a multifactorial disease that can lead to vision impairment in older individuals. Although the etiology of age-related macular degeneration remains unknown, risk factors include age, ethnicity, smoking, hypertension, obesity, and genetic factors. Two main loci have been identified through genome-wide association studies, on chromosomes 1 and 10. Among the variants located at the 10q26 region, rs11200638, located at the HTRA1 gene promoter, has been associated with age-related macular degeneration in several populations and is considered the main polymorphism. We conducted a replication case-control study to analyze the frequency and participation of rs11200638 in the etiology of age-related macular degeneration in a sample of patients and controls from the State of Sao Paulo, Brazil, through polymerase chain reaction and enzymatic digestion. The frequency of the A allele was 57.60% in patients with age-related macular degeneration and 36.45% in controls (p value < 1e-07), representing a 2.369-fold higher risk factor for the disease. Both the AA and AG genotypes were observed more frequently in the age-related macular degeneration group compared to the control group (p = 1.21e-07 and 0.0357, respectively). No statistically significant results were observed after stratification in dry versus wet types or advanced versus non-advanced forms. To our knowledge, this is the first time the association between rs11200638 and overall age-related macular degeneration has been reported in South America. PMID- 28846053 TI - Letter to the Editor regarding the article "Association of elevated interleukin 17 and angiopoietin-2 with prostate size in benign prostatic hyperplasia". PMID- 28846054 TI - Severe clinical events in 100 patients with schizophrenia: a retrospective clinical description using a system-specific psychopathological approach. AB - Catatonic states and numerous other severe clinical events can complicate the course of schizophrenia. Whether these severe courses are associated with particular system-specific symptom dimensions remain unclear. Aim is to assess the frequency of severe clinical events in a clinical population and to investigate the association of these events with sociodemographic data and system specific psychopathology, combining qualitative and quantitative data. We performed a comprehensive retrospective description of a well-described and geographically stable sample of 100 patients with schizophrenia or schizoaffective disorder and linked severe clinical events with sociodemographic data at inclusion into the study (as indicators of social functioning) and symptoms at first admission, classified with the Bern Psychopathology Scale (BPS). We found 12 mentions of catatonic stupor or excitement, 45 of suicide attempts, 26 of suicidality, 18 of deliberate self-harm, 18 of self-threatening behaviour other than deliberate self-harm, 34 of violence against other persons, 18 of violence against objects and six of sexual harassment. Disinhibited language on first admission seemed to be a protective factor against suicidality and disinhibited motor behaviour seemed to predict self-threatening and violent behaviour. Catatonia and violence in particular seemed to be socially disabling. This exploratory study showed that the BPS is a promising instrument and might represent a system-specific approach in identifying patients at risk for severe sequelae of schizophrenia. This will have to be tested in future prospective studies. PMID- 28846055 TI - Homeostatic model assessment of beta cell function predicting abnormal oral glucose tolerance testing in pregnancy: a systematic review and meta-analysis. AB - BACKGROUND: Gestational diabetes mellitus (GDM) complicates 1-14% of pregnancies and relates to increased risk of adverse obstetric outcomes. Currently GDM is diagnosed using an oral glucose tolerance test (OGTT), which is burdensome and time intensive. OBJECTIVE: To compare current literature on whether the homeostatic model assessment beta cell function (HOMA-beta) is an accurate predictor of an abnormal OGTT in pregnant women. METHODS: Pubmed, Cochrane and Embase were searched. Included studies evaluated pregnant women at risk for GDM using the homeostatic model assessment of beta cell function (HOMA-beta) for the assessment of beta cell function and the OGTT. Studies with animals, non-pregnant women, women with type 2 diabetes and post-partum diabetes were excluded. The QUADAS-2 criteria were used to assess the methodological quality of studies. RESULTS: A total of 12 studies were included, reporting on 7292 women. Seven studies showed a difference in beta cell function between women with impaired glucose tolerance compared to healthy pregnant women. HOMA-beta is significantly lower in impaired glucose tolerance (p < 0.001). CONCLUSIONS: Although HOMA-beta is lower in women with abnormal OGTT in pregnancy, given the high degree of heterogeneity of studies, we do not propagate HOMA-beta as a sole diagnostic tool replacing OGTT to diagnose GDM. PMID- 28846056 TI - Identification and Pathogenicity of Bacteria Associated with Etiolation and Decline of Creeping Bentgrass Golf Course Putting Greens. AB - Bacterial etiolation and decline has developed into a widespread issue with creeping bentgrass (CBG) (Agrostis stolonifera) putting green turf. The condition is characterized by an abnormal elongation of turfgrass stems and leaves that in rare cases progresses into a rapid and widespread necrosis and decline. Recent reports have cited bacteria, Acidovorax avenae and Xanthomonas translucens, as causal agents; however, few cases exist where either bacterium were isolated in conjunction with turf exhibiting bacterial disease symptoms. From 2010 to 2014, turfgrass from 62 locations submitted to the NC State Turf Diagnostic Clinic exhibiting bacterial etiolation and/or decline symptoms were sampled for the presence of bacterial pathogens. Isolated bacteria were identified using rRNA sequencing of the 16S subunit and internal transcribed spacer region (16S-23S or ITS). Results showed diverse bacteria isolated from symptomatic turf and A. avenae and X. translucens were only isolated in 26% of samples. Frequently isolated bacterial species were examined for pathogenicity to 4-week-old 'G2' CBG seedlings and 8-week-old 'A-1' CBG turfgrass stands in the greenhouse. While results confirmed pathogenicity of A. avenae and X. translucens, Pantoea ananatis was also shown to infect CBG turf; although pathogenicity varied among isolated strains. These results illustrate that multiple bacteria are associated with bacterial disease and shed new light on culturable bacteria living in CBG turfgrass putting greens. Future research to evaluate additional microorganisms (i.e., bacteria and fungi) could provide new information on host-microbe interactions and possibly develop ideas for management tactics to reduce turfgrass pests. PMID- 28846057 TI - Examining marianismo gender role attitudes, ethnic identity, mental health, and substance use in Mexican American early adolescent girls. AB - Given the increased trend in substance use patterns among Latina adolescents in recent years, the need for research that identifies gender-specific and culturally relevant protective factors is essential in tailoring interventions. The current study examined the links between marianismo gender role attitudes, ethnic identity, and substance use abstinence among 277 low-income Mexican American early adolescent girls. Mental health was also examined as a potential moderator in these links. Results of linear regression analysis revealed that familismo, virtuous/chaste, and spiritual marianismo gender role attitudes were predictive of stronger ethnic identity; conversely, self-silencing marianismo attitudes were predictive of weaker ethnic identity. Second, results of hierarchical logistic regressions revealed that both virtuous/chaste marianismo gender role attitudes and mental health (low rates of psychological distress) were inversely linked with substance use; furthermore, they had a combined link that was related to even lower rates of substance use among participants. However, ethnic identity did not have a direct or moderating effect on substance use. Findings suggest that the promotion of positive components of marianismo and mental health may have a protective effect against early substance use in Mexican American early adolescent girls. PMID- 28846058 TI - Intercorrelation of Alcohol and Other Drug Use Disorders among a National Sample of Drivers. AB - This study examined the relationship between alcohol, marijuana, cocaine, and painkiller use disorders in a sample of drivers. We studied nighttime drivers aged 16 to 87 (n = 4,277) from the 2007 National Roadside Survey who reported substance use behaviors and provided breath tests for alcohol. Logistic regression analyses assessed the relationships between (1) substance (i.e., alcohol/marijuana/cocaine/pain killer) use disorders; (2) demographic characteristics; and (3) BAC levels. Overall, 13.2% of participants met criteria for marijuana use disorder, 7% met criteria for cocaine use disorder, and 15.4% met criteria for extra-medicinal painkiller use disorder. When self-report data were analyzed, three reciprocal associations emerged: (1) marijuana use disorders and alcohol use disorders were correlated; (2) marijuana use disorders and cocaine use disorders were correlated; and (3) cocaine use disorders and painkiller use disorders were correlated. BAC data revealed that marijuana and cocaine use disorders were both associated with positive BAC levels, but only cocaine use disorders were associated with BAC levels over the legal limit. Results suggest significant poly-substance use disorders in a sample of nighttime drivers, with variations by demographic characteristics. The individual and public health consequences of multiple substance use disorders among drivers are significant. PMID- 28846059 TI - Mortality Trends among Cocaine Users Treated between 1989 and 2013 in Northern Italy: Results of a Longitudinal Study. AB - A total of 852 participants attending 11 centers for addiction treatment in north Italy following problems due to cocaine abuse between 1989 and 2013 were recruited. Two typologies were created: cocaine users (never heroin) (CU) and heroin and cocaine users (HCU). During the 38-year follow-up period, 4.8% of the whole cohort died. Over the whole period, tumors were the main causes of death; starting in 2010, suicide deaths became the first cause of death. Among CUs, most deaths were due to road accidents and suicide; among HCUs, most of the deaths were from opiate overdose and from cardio-circulatory system diseases. The excess mortality observed for all causes in either sex was 6.24; higher in females (15.03) as compared in males (6.23), higher in HCUs (9.06) as compared in CUs (5.21). The directly age-sex standardized mortality rates were 5.31 per 100, higher for females, declining after 2009 for all patients and after 2004 for HCUs. Multivariate analysis confirms the decreasing trend in the risk of death and shows a higher mortality risk for participants in the under-25 age group. Among cocaine users, special attention should be paid to the prevention of suicide deaths. PMID- 28846060 TI - In vivo visualization of lipid coronary atheroma with intravascular near-infrared spectroscopy. AB - INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) has become a major health burden and is expected to further increase in the future. Better predictive approaches for ASCVD and more efficacious therapies are required to further improve cardiovascular outcomes. Intravascular imaging has contributed to the elucidation of atherosclerotic mechanisms and evaluation of novel therapies. Near-infrared spectroscopy has enabled the visualization of the lipid extent of atherosclerotic plaques in vivo. Given that lipid accumulation is considered to promote the formation and progression of atherosclerosis, this technology may harbor the potential to identify subjects with high cardiovascular risks and thus adopt more optimized therapeutic approaches. Areas covered: This review will outline the characteristics of NIRS, its validation data and in vivo findings of NIRS imaging in patients with coronary artery disease. The comparisons of NIRS with other imaging modalities will reveal the distinct capability of NIRS imaging to monitor high-risk atheroma harboring lipidic composition. Furthermore, the predictive ability of NIRS-derived measures in the occurrence of ASCVD will be summarized. Expert commentary: Ex vivo and in vivo findings suggest NIRS imaging as a potential tool for cardiovascular risk assessment and monitoring the benefit of pharmacological approaches. PMID- 28846061 TI - Obstetric Outcomes in Women with Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the Western world and yet there is little research into its impact on pregnancy. METHODS: A literature review was conducted in the database PubMed, with articles published between 1990 and 2017. The selected studies addressed features specifically attributed to NAFLD and associated obstetric and neonatal outcomes. Nine studies met criteria. Our aim was to consolidate the limited literature and identify trends. RESULTS: There was considerable heterogeneity in the diagnostic approach to NAFLD. Data are conflicting as to whether NAFLD increases the risk of gestational diabetes independent of obesity. NAFLD is associated with an elevated risk of extremes of birth weight, both small and large for gestational age. Several studies found a greater impact of NAFLD on maternal morbidity including preeclampsia in women with a body mass index <30kg/m2. CONCLUSIONS: NAFLD appears to be associated with increased obstetric morbidity, particularly among non-obese women. More research is needed to clarify the pathophysiology and optimize safe treatment. PMID- 28846062 TI - Association of the Salivary Triggering Receptor Expressed on Myeloid Cells/ its Ligand Peptidoglycan Recognition Protein 1 Axis With Oral Inflammation in Kidney Disease. AB - BACKGROUND: Triggering Receptor Expressed on Myeloid Cells (TREM-1) is a cell surface receptor involved in amplification of inflammatory response to bacterial infections, along with its ligand peptidoglycan recognition protein 1 (PGLYRP1). TREM-1 is shed by matrix metalloproteinases (MMPs) to its soluble (s) form. The aim of the study was to investigate association of sTREM-1 and PGLYRP1 with oral inflammatory burden among chronic kidney disease (CKD) patients at predialysis and post-transplantation stages. METHODS: 144 CKD patients were examined at predialysis and oral infection foci were treated prior to kidney transplantation. 53 patients of them were available for follow-up after transplantation. Oral inflammatory burden was assessed by Periodontal Inflammatory Burden Index (PIBI) and Total Dental Index (TDI). sTREM-1, PGLYRP1, IL-1beta were measured in saliva by ELISA, and MMP-8 by IFMA. RESULTS: In the predialysis stage, sTREM-1 and PGLYRP1 were positively associated with IL-1beta, MMP-8 and PIBI. More specifically, patients with deeper PPD (>= 2 sites with >= 6mm) had higher concentrations of salivary sTREM-1 and PGLYRP1 compared to those with shallower PPD. PGLYRP1 and IL-1beta associated with a higher number of teeth (> 25). On the follow-up, higher PGLYRP1 and sTREM-1 were associated with one or more sites with >= 4mm PPD. CONCLUSION: sTREM-1 and PGLYRP1 are elevated in CKD patients with poor oral health and positively correlate with the number of active periodontal pockets, following oral infection therapy. Moreover, they positively correlate with MMP-8 and IL-1beta. Hence, salivary TREM-1- PGLYRP1 axis could be useful as diagnostic marker for oral infection within CKD patients. PMID- 28846063 TI - How predictions of economic behavior are affected by the socio-economic status of the target person. AB - We investigate how the stereotype of the poor (vs. middle class) influences behavioral predictions. In Study 1, participants made predictions regarding another person's economic behavior in scenarios pertaining to rate of time preferences (loss, gain of smaller and larger amount). We find that participants, across scenarios, expect individuals with low SES to show more short-sightedness i.e., steeper temporal discounting. This pattern persisted until strong diagnostic information about previous economic behavior was provided. These results are novel but consistent with previous work on stereotype application. Study 2 probed stereotype accuracy. Participants with lower vs. higher SES reported how they would act in scenarios matching those of Study 1. We find that they respond very similarly, which is in contrast to the stereotype that poor people are more short-sighted and may possibly be taken to suggest that the association between low SES and short-sightedness is biased. PMID- 28846064 TI - Challenges in the management of sickle cell disease during pregnancy in Senegal, West Africa. AB - OBJECTIVES: The aim of this study was to evaluate the maternal and fetal complications in pregnant patients with sickle cell disease (SCD) and find risk factors of stillbirth. METHOD: We conducted a prospective study in pregnant women with SCD. Demographic characteristics, maternal and fetal morbi-mortality, and outcome of pregnancies were described. Risk factors of fetal loss were evaluated by comparing the parameters of the pregnancies that led to a live birth with those interrupted. RESULTS: We included 70 pregnancies in 58 women with SCD. The average age was 29.3 years. The average gestational age at the start of follow-up was 13 weeks. The occurrence of acute complications was significantly higher during pregnancy compared to the year before (p < 0.05). Maternal mortality was 0%. Live birth rate was 80%. Fetal loss rate was 3.9 times higher in previous pregnancies that had not been monitored in hematology (71.8 versus 18.6%). Stillbirth was associated with nulliparity, high leukocytes or platelet counts (p < 0.05). CONCLUSION: Pregnancy in SCD was associated with a high maternal morbidity and stillbirth. Nulliparity, high leucokocytes or platelet count were identified as risk factors of fetal loss. PMID- 28846065 TI - Race and socioeconomic status in substance use progression and treatment entry. AB - This study examined trajectories of progression from early substance use to treatment entry as a function of race, among inpatient treatment seekers (N = 945). Following primary race-contingent analyses of use progression, secondary analyses were conducted to investigate the effects of socioeconomic status (SES) on the observed differences. African Americans reported significant delays in treatment entry relative to Caucasians. Racial differences in alcohol, marijuana, and cocaine use trajectories were observed. Accounting for SES rendered observations of accelerated use among African Americans nonsignificant. However, inclusion of SES failed to mitigate the marked racial disparity in treatment entry. PMID- 28846066 TI - Force and Directional Force Modulation Effects on Accuracy and Variability in Low Level Pinch Force Tracking. AB - The authors investigated how varying the required low-level forces and the direction of force change affect accuracy and variability of force production in a cyclic isometric pinch force tracking task. Eighteen healthy right-handed adult volunteers performed the tracking task over 3 different force ranges. Root mean square error and coefficient of variation were higher at lower force levels and during minimum reversals compared with maximum reversals. Overall, the thumb showed greater root mean square error and coefficient of variation scores than did the index finger during maximum reversals, but not during minimum reversals. The observed impaired performance during minimum reversals might originate from history-dependent mechanisms of force production and highly coupled 2-digit performance. PMID- 28846067 TI - Compression therapy for deep vein thrombosis - why, yes! PMID- 28846068 TI - Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents. AB - Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein alpha (FAPalpha) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPalpha expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPalpha-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments. PMID- 28846069 TI - Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche. AB - Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady state and stressful conditions, such as hematopoietic cell transplantation and G CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by beta3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis. PMID- 28846070 TI - Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification. AB - During an immune response, CD8+ T lymphocytes can undergo asymmetric division, giving rise to daughter cells that exhibit distinct tendencies to adopt terminal effector and memory cell fates. Here we show that "pre-effector" and "pre-memory" cells resulting from the first CD8+ T cell division in vivo exhibited low and high rates of endogenous proteasome activity, respectively. Pharmacologic reduction of proteasome activity in CD8+ T cells early during differentiation resulted in acquisition of terminal effector cell characteristics, whereas enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulating proteasome activity in CD8+ T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Taken together, these results demonstrate that proteasome activity is an important regulator of CD8+ T cell fate and raise the possibility that increasing proteasome activity may be a useful therapeutic strategy to enhance the generation of memory lymphocytes. PMID- 28846071 TI - ER phospholipid composition modulates lipogenesis during feeding and in obesity. AB - Sterol regulatory element-binding protein 1c (SREBP-1c) is a central regulator of lipogenesis whose activity is controlled by proteolytic cleavage. The metabolic factors that affect its processing are incompletely understood. Here, we show that dynamic changes in the acyl chain composition of ER phospholipids affect SREBP-1c maturation in physiology and disease. The abundance of polyunsaturated phosphatidylcholine in liver ER is selectively increased in response to feeding and in the setting of obesity-linked insulin resistance. Exogenous delivery of polyunsaturated phosphatidylcholine to ER accelerated SREBP-1c processing through a mechanism that required an intact SREBP cleavage-activating protein (SCAP) pathway. Furthermore, induction of the phospholipid-remodeling enzyme LPCAT3 in response to liver X receptor (LXR) activation promoted SREBP-1c processing by driving the incorporation of polyunsaturated fatty acids into ER. Conversely, LPCAT3 deficiency increased membrane saturation, reduced nuclear SREBP-1c abundance, and blunted the lipogenic response to feeding, LXR agonist treatment, or obesity-linked insulin resistance. Desaturation of the ER membrane may serve as an auxiliary signal of the fed state that promotes lipid synthesis in response to nutrient availability. PMID- 28846072 TI - Mice expressing KrasG12D in hematopoietic multipotent progenitor cells develop neonatal myeloid leukemia. AB - Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that bears distinct characteristics associated with abnormal fetal development. JMML has been extensively modeled in mice expressing the oncogenic KrasG12D mutation. However, these models have struggled to recapitulate the defining features of JMML due to in utero lethality, nonhematopoietic expression, and the pervasive emergence of T cell acute lymphoblastic leukemia. Here, we have developed a model of JMML using mice that express KrasG12D in multipotent progenitor cells (Flt3Cre+ KrasG12D mice). These mice express KrasG12D in utero, are born at normal Mendelian ratios, develop hepatosplenomegaly, anemia, and thrombocytopenia, and succumb to a rapidly progressing and fully penetrant neonatal myeloid disease. Mutant mice have altered hematopoietic stem and progenitor cell populations in the BM and spleen that are hypersensitive to granulocyte macrophage-CSF due to hyperactive RAS/ERK signaling. Biased differentiation in these progenitors results in an expansion of neutrophils and DCs and a concomitant decrease in T lymphocytes. Flt3Cre+ KrasG12D fetal liver hematopoietic progenitors give rise to a myeloid disease upon transplantation. In summary, we describe a KrasG12D mouse model that reproducibly develops JMML-like disease. This model will prove useful for preclinical drug studies and for elucidating the developmental origins of pediatric neoplasms. PMID- 28846073 TI - Genome editing of human embryos: to edit or not to edit, that is the question. PMID- 28846074 TI - CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis. PMID- 28846076 TI - A new combination therapy for asthma using dual-function dexamethasone-conjugated polyethylenimine and vitamin D binding protein siRNA. AB - Asthma is a multifactorial disease that is influenced by the interaction of genetic and environmental factors. Because of its complex nature, there is no cure for asthma currently. Instead, reliever and controller medications are used to treat asthma. Unfortunately, conventional treatments do not work in some severe cases of asthma. In addition, there may be adverse, systemic effects of long-term treatment with high-dose inhaled corticosteroids (ICSs) as a controller medication. Therefore, we attempted to develop a novel combination therapy for asthma. Our regimen included dexamethasone as a controller medication and vitamin D binding protein (VDBP) small interfering RNA (siRNA) as a novel target therapeutic. The dexamethasone moiety of DEXA-PEI (dexamethasone-conjugated polyethylenimine) was used as an ICS, combined with anti-VDBP treatment via delivery of VDBP siRNA, using DEXA-PEI as a siRNA carrier molecule. Treatment with DEXA-PEI/VDBP siRNA effectively reduced the ovalbumin sensitization/challenge-induced enhancement of airway inflammation, goblet cell hyperplasia and expression of interleukin (IL)-4, IL-13 and CCL11. These findings suggest that the DEXA-PEI/VDBP siRNA can be developed as a potent asthma therapeutic by dose-reducing ICSs and using a multitarget therapeutic method. PMID- 28846075 TI - Dysfunction of the MDM2/p53 axis is linked to premature aging. AB - The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient's primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation's aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria. PMID- 28846077 TI - Metabolic cooperation between co-cultured lung cancer cells and lung fibroblasts. AB - Cooperation of cancer cells with stromal cells, such as cancer-associated fibroblasts (CAFs), has been revealed as a mechanism sustaining cancer cell survival and growth. In the current study, we focus on the metabolic interactions of MRC5 lung fibroblasts with lung cancer cells (A549 and H1299) using co-culture experiments and studying changes of the metabolic protein expression profile and of their growth and migration abilities. Using western blotting, confocal microscopy and RT-PCR, we observed that in co-cultures MRC5 respond by upregulating pyruvate dehydrogenase (PDH) and the monocarboxylate transporter MCT1. In contrast, cancer cells increase the expression of glucose transporters (GLUT1), LDH5, PDH kinase and the levels of phosphorylated/inactivated pPDH. H1299 cells growing in the same culture medium with fibroblasts exhibit a 'metastasis-like' phenomenon by forming nests within the fibroblast area. LDH5 and pPDH were drastically upregulated in these nests. The growth rate of both MRC5 and cancer cells increased in co-cultures. Suppression of LDHA or PDK1 in cancer cells abrogates the stimulatory signal from cancer cells to fibroblasts. Incubation of MRC5 fibroblasts with lactate resulted in an increase of LDHB and of PDH expression. Silencing of PDH gene in fibroblasts, or silencing of PDK1 or LDHA gene in tumor cells, impedes cancer cell's migration ability. Overall, a metabolic cooperation between lung cancer cells and fibroblasts has been confirmed in the context of direct Warburg effect, thus the fibroblasts reinforce aerobic metabolism to support the intensified anaerobic glycolytic pathways exploited by cancer cells. PMID- 28846079 TI - E6/E7 oncogenes in epithelial suprabasal layers and estradiol promote cervical growth and ear regeneration. AB - Tissue growth is a common characteristic of carcinogenesis and regeneration. Here we show that suprabasal expression of human papillomavirus (HPV)16 E6/E7 oncogenes in Tg(K6b-E6/E7) mice, similar to that observed in HPV-infected human tissue, and estradiol increased cervical epithelium growth and ear-hole closure efficiency. Oncogenes in combination with estradiol had a significant contribution to the proliferation of suprabasal cells of cervical epithelium that correlated with an increased expression of keratin genes. Remarkably, long-term treatments with estradiol resulted in evident cellular and tissue abnormalities indicative of a precancerous phenotype. Regenerating ear epithelium of transgenic mice also showed increased suprabasal cell proliferation and expression of keratin genes. Unexpectedly, we observed higher ear regeneration efficiency in adult than in young female mice, which was further increased by E6/E7 oncogenes. Supporting a role of estradiol in this phenomenon, ovariectomy and treatment with an estrogen receptor inhibitor caused a significant reduction in regenerative capacity. Our data suggest that Tg(K6b-E6/E7) mice are unique to mimic the initial stages of HPV-mediated cervical carcinogenesis, and ear regeneration could facilitate the elucidation of mechanisms involved. PMID- 28846080 TI - Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3beta/beta-catenin signaling pathway. AB - Stromal cell populations in the tumor microenvironment (TME) play a critical role in the oncogenesis and metastasis of renal cell carcinoma. In this study, we found that there are alpha-smooth muscle actin positive (alpha-SMA (+)) cells in the stroma of clear cell renal cell carcinoma (ccRCC) tissues, and their numbers are significantly associated with poor survival in ccRCC patients. Interleukin 6 (IL-6) is a critical diver that induces alpha-SMA (+) cells in ccRCC tissues via promotion of epithelial to mesenchymal transition (EMT) and stimulates migration and invasion in ccRCC. Peritumoral CD4+ T cells are the main source of IL-6 in ccRCC tissues. In addition to biochemical factors, mechanical compression within tumors affects tumor cell behavior. Tumors grown in a confined space exhibit intratumoral compressive stress and, with sufficient pressure, stress-stimulated migration of cancer cells. Moreover, a combination of IL-6 secreted by CD4+ T cells and growth-induced solid stress further contributes to the regulation of cancer cell morphogenesis, EMT and acquisition of a stemness phenotype. The effects in the combination group were driven by the Akt/GSK-3beta/beta-catenin signaling pathway, and deregulation of beta-catenin expression was predictive of poor outcome in ccRCC patients. Notably, the expression of a cancer stem cell marker, CD44, was correlated with T stage, high Fuhrman grade and metastasis in ccRCC. These data provide evidence for new stress-reducing and IL-6 targeting strategies in cancer therapy. PMID- 28846078 TI - Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. AB - The unfolded protein response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress. During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply) challenges, with which they must cope to survive. Moreover, chemotherapy represents an additional extrinsic challenge that cancer cells are facing and to which they adapt in the case of resistance. As of today, resistance to chemotherapy and targeted therapies is one of the important issues that oncologists have to deal with for treating cancer patients. In this review, we first describe the key molecular mechanisms controlling the UPR and their implication in solid cancers. Then, we review the literature that connects cancer chemotherapy resistance mechanisms and activation of the UPR. Finally, we discuss the possible applications of targeting the UPR to bypass drug resistance. PMID- 28846081 TI - Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging. AB - To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living mice and then used multiphoton microscopy to monitor these cells over time. Under homeostatic conditions, we found that neocortical resident microglia were long-lived, with a median lifetime of well over 15 months; thus, approximately half of these cells survive the entire mouse lifespan. While proliferation of resident neocortical microglia under homeostatic conditions was low, microglial proliferation in a mouse model of Alzheimer's beta amyloidosis was increased threefold. The persistence of individual microglia throughout the mouse lifespan provides an explanation for how microglial priming early in life can induce lasting functional changes and how microglial senescence may contribute to age-related neurodegenerative diseases. PMID- 28846082 TI - Memory reactivation improves visual perception. AB - Human perception thresholds can improve through learning. Here we report findings challenging the fundamental 'practice makes perfect' basis of procedural learning theory, showing that brief reactivations of encoded visual memories are sufficient to improve perceptual discrimination thresholds. Learning was comparable to standard practice-induced learning and was not due to short training per se, nor to an epiphenomenon of primed retrieval enhancement. The results demonstrate that basic perceptual functions can be substantially improved by memory reactivation, supporting a new account of perceptual learning dynamics. PMID- 28846083 TI - Glia initiate brain assembly through noncanonical Chimaerin-Furin axon guidance in C. elegans. AB - Brain assembly is hypothesized to begin when pioneer axons extend over non neuronal cells, forming tracts guiding follower axons. Yet pioneer-neuron identities, their guidance substrates, and their interactions are not well understood. Here, using time-lapse embryonic imaging, genetics, protein interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans glia are key for assembly initiation, guiding pioneer and follower axons using distinct signals. Pioneer sublateral neurons, with unique growth properties, anatomy, and innervation, cooperate with glia to mediate follower-axon guidance. We further identify a Chimaerin (CHIN-1)- Furin (KPC-1) double-mutant that severely disrupts assembly. CHIN-1 and KPC-1 function noncanonically, in glia and pioneer neurons, for guidance-cue trafficking. We exploit this bottleneck to define roles for glial Netrin and Semaphorin in pioneer- and follower-axon guidance, respectively, and for glial and pioneer-neuron Flamingo (CELSR) in follower-axon navigation. Taken together, our studies reveal previously undescribed glial roles in pioneer-axon guidance, suggesting conserved principles of brain assembly. PMID- 28846084 TI - IFN-lambda suppresses intestinal inflammation by non-translational regulation of neutrophil function. AB - Interferon-lambda (IFN-lambda) is a central regulator of mucosal immunity; however, its signaling specificity relative to that of type I interferons is poorly defined. IFN-lambda can induce antiviral interferon-stimulated genes (ISGs) in epithelia, while the effect of IFN-lambda in non-epithelial cells remains unclear. Here we report that neutrophils responded to IFN-lambda. We found that in addition to inducing ISG transcription, IFN-lambda (but not IFN beta) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils. In mice, IFN-lambda was elicited by enteric viruses and acted on neutrophils to decrease oxidative stress and intestinal damage. Thus, IFN-lambda acted as a unique immunomodulatory agent by modifying transcriptional and non translational neutrophil responses, which might permit a controlled development of the inflammatory process. PMID- 28846085 TI - A two-amino-acid substitution in the transcription factor RORgammat disrupts its function in TH17 differentiation but not in thymocyte development. AB - The transcription factor RORgammat regulates differentiation of the TH17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORgammat prevents TH17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORgammat (RORgammatM) that 'preferentially' disrupted TH17 differentiation but not thymocyte development. Mice expressing RORgammatM were resistant to EAE associated with defective TH17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. RORgammatM showed less ubiquitination at Lys69 that was selectively required for TH17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH17 cell-mediated autoimmunity but do not affect thymocyte development or induce lymphoma. PMID- 28846086 TI - The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus. AB - DEAD-box (DDX) helicases are vital for the recognition of RNA and metabolism and are critical for the initiation of antiviral innate immunity. Modification of RNA is involved in many biological processes; however, its role in antiviral innate immunity has remained unclear. Here we found that nuclear DDX member DDX46 inhibited the production of type I interferons after viral infection. DDX46 bound Mavs, Traf3 and Traf6 transcripts (which encode signaling molecules involved in antiviral responses) via their conserved CCGGUU element. After viral infection, DDX46 recruited ALKBH5, an 'eraser' of the RNA modification N6-methyladenosine (m6A), via DDX46's DEAD helicase domain to demethylate those m6A-modified antiviral transcripts. It consequently enforced their retention in the nucleus and therefore prevented their translation and inhibited interferon production. DDX46 also suppressed antiviral innate immunity in vivo. Thus, DDX46 inhibits antiviral innate responses by entrapping selected antiviral transcripts in the nucleus by erasing their m6A modification, a modification normally required for export from the nucleus and translation. PMID- 28846087 TI - Convolutional neural networks for automated annotation of cellular cryo-electron tomograms. AB - Cellular electron cryotomography offers researchers the ability to observe macromolecules frozen in action in situ, but a primary challenge with this technique is identifying molecular components within the crowded cellular environment. We introduce a method that uses neural networks to dramatically reduce the time and human effort required for subcellular annotation and feature extraction. Subsequent subtomogram classification and averaging yield in situ structures of molecular components of interest. The method is available in the EMAN2.2 software package. PMID- 28846088 TI - Massively parallel single-nucleus RNA-seq with DroNc-seq. AB - Single-nucleus RNA sequencing (sNuc-seq) profiles RNA from tissues that are preserved or cannot be dissociated, but it does not provide high throughput. Here, we develop DroNc-seq: massively parallel sNuc-seq with droplet technology. We profile 39,111 nuclei from mouse and human archived brain samples to demonstrate sensitive, efficient, and unbiased classification of cell types, paving the way for systematic charting of cell atlases. PMID- 28846089 TI - Oscillatory stimuli differentiate adapting circuit topologies. AB - Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems. PMID- 28846090 TI - An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. AB - We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-to-background ratio and information content. The Omni-ATAC protocol generates chromatin accessibility profiles from archival frozen tissue samples and 50-MUm sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies. PMID- 28846092 TI - Crystal structure of an inactivated mutant mammalian voltage-gated K+ channel. AB - C-type inactivation underlies important roles played by voltage-gated K+ (Kv) channels. Functional studies have provided strong evidence that a common underlying cause of this type of inactivation is an alteration near the extracellular end of the channel's ion-selectivity filter. Unlike N-type inactivation, which is known to reflect occlusion of the channel's intracellular end, the structural mechanism of C-type inactivation remains controversial and may have many detailed variations. Here we report that in voltage-gated Shaker K+ channels lacking N-type inactivation, a mutation enhancing inactivation disrupts the outermost K+ site in the selectivity filter. Furthermore, in a crystal structure of the Kv1.2-2.1 chimeric channel bearing the same mutation, the outermost K+ site, which is formed by eight carbonyl-oxygen atoms, appears to be slightly too small to readily accommodate a K+ ion and in fact exhibits little ion density; this structural finding is consistent with the functional hallmark of C-type inactivation. PMID- 28846091 TI - NEAT1 scaffolds RNA-binding proteins and the Microprocessor to globally enhance pri-miRNA processing. AB - MicroRNA (miRNA) biogenesis is known to be modulated by a variety of RNA-binding proteins (RBPs), but in most cases, individual RBPs appear to influence the processing of a small subset of target miRNAs. Here, we report that the RNA binding NONO-PSF heterodimer binds a large number of expressed pri-miRNAs in HeLa cells to globally enhance pri-miRNA processing by the Drosha-DGCR8 Microprocessor. NONO and PSF are key components of paraspeckles organized by the long noncoding RNA (lncRNA) NEAT1. We further demonstrate that NEAT1 also has a profound effect on global pri-miRNA processing. Mechanistic dissection reveals that NEAT1 broadly interacts with the NONO-PSF heterodimer as well as many other RBPs and that multiple RNA segments in NEAT1, including a 'pseudo pri-miRNA' near its 3' end, help attract the Microprocessor. These findings suggest a 'bird nest' model in which an lncRNA orchestrates efficient processing of potentially an entire class of small noncoding RNAs in the nucleus. PMID- 28846094 TI - Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress. AB - Protein aggregation is mostly viewed as deleterious and irreversible causing several pathologies. However, reversible protein aggregation has recently emerged as a novel concept for cellular regulation. Here, we characterize stress-induced, reversible aggregation of yeast pyruvate kinase, Cdc19. Aggregation of Cdc19 is regulated by oligomerization and binding to allosteric regulators. We identify a region of low compositional complexity (LCR) within Cdc19 as necessary and sufficient for reversible aggregation. During exponential growth, shielding the LCR within tetrameric Cdc19 or phosphorylation of the LCR prevents unscheduled aggregation, while its dephosphorylation is necessary for reversible aggregation during stress. Cdc19 aggregation triggers its localization to stress granules and modulates their formation and dissolution. Reversible aggregation protects Cdc19 from stress-induced degradation, thereby allowing cell cycle restart after stress. Several other enzymes necessary for G1 progression also contain LCRs and aggregate reversibly during stress, implying that reversible aggregation represents a conserved mechanism regulating cell growth and survival. PMID- 28846093 TI - Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome. AB - Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS. PMID- 28846095 TI - ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors. AB - Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS-glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients' own cells that are safe for transplantation. PMID- 28846096 TI - Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. AB - Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-kappaB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-kappaB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies. PMID- 28846097 TI - GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. AB - Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-beta family, is a secreted protein that circulates as a 25 kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor alpha-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-beta superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity. PMID- 28846098 TI - The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. AB - Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-beta (TGF-beta) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor alpha-like (GFRAL), an orphan member of the GFR-alpha family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral-/- mice were refractory to the effects of recombinant human GDF15 on body weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15. PMID- 28846099 TI - GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. AB - Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-beta superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor alpha-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake. PMID- 28846100 TI - Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). AB - Copy number variations (CNVs) often include noncoding sequences and putative enhancers, but how these rearrangements induce disease is poorly understood. Here we investigate CNVs involving the regulatory landscape of IHH (encoding Indian hedgehog), which cause multiple, highly localized phenotypes including craniosynostosis and synpolydactyly. We show through transgenic reporter and genome-editing studies in mice that Ihh is regulated by a constellation of at least nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips. Consecutive deletions, resulting in growth defects of the skull and long bones, showed that these enhancers function in an additive manner. Duplications, in contrast, caused not only dose-dependent upregulation but also misexpression of Ihh, leading to abnormal phalanges, fusion of sutures and syndactyly. Thus, precise spatiotemporal control of developmental gene expression is achieved by complex multipartite enhancer ensembles. Alterations in the composition of such clusters can result in gene misexpression and disease. PMID- 28846101 TI - LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. AB - After fertilization, to initiate development, gametes are reprogramed to become totipotent. Approximately half of the mammalian genome consists of repetitive elements, including retrotransposons, some of which are transcribed after fertilization. Retrotransposon activation is generally assumed to be a side effect of the extensive chromatin remodeling underlying the epigenetic reprogramming of gametes. Here, we used a targeted epigenomic approach to address whether specific retrotransposon families play a direct role in chromatin organization and developmental progression. We demonstrate that premature silencing of LINE-1 elements decreases chromatin accessibility, whereas prolonged activation prevents the gradual chromatin compaction that occurs naturally in developmental progression. Preventing LINE-1 activation and interfering with its silencing decreases developmental rates independently of the coding nature of the LINE-1 transcript, thus suggesting that LINE-1 functions primarily at the chromatin level. Our data suggest that activation of LINE-1 regulates global chromatin accessibility at the beginning of development and indicate that retrotransposon activation is integral to the developmental program. PMID- 28846102 TI - Effective NaCl and dye rejection of hybrid graphene oxide/graphene layered membranes. AB - Carbon nanomaterials are robust and possess fascinating properties useful for separation technology applications, but their scalability and high salt rejection when in a strong cross flow for long periods of time remain challenging. Here, we present a graphene-based membrane that is prepared using a simple and environmentally friendly method by spray coating an aqueous dispersion of graphene oxide/few-layered graphene/deoxycholate. The membranes were robust enough to withstand strong cross-flow shear for a prolonged period (120 h) while maintaining NaCl rejection near 85% and 96% for an anionic dye. Experimental results and molecular dynamic simulations revealed that the presence of deoxycholate enhances NaCl rejection in these graphene-based membranes. In addition, these novel hybrid-layered membranes exhibit better chlorine resistance than pure graphene oxide membranes. The desalination performance and aggressive shear and chlorine resistance of these scalable graphene-based membranes are promising for use in practical water separation applications. PMID- 28846103 TI - Water treatment: A scalable graphene-based membrane. PMID- 28846104 TI - Berberine binds RXRalpha to suppress beta-catenin signaling in colon cancer cells. AB - Berberine, an isoquinoline alkaloid, is a traditional oriental medicine used to treat diarrhea and gastroenteritis. Recently, we reported that it could inhibit the growth of intestinal polyp in animals and in patients with the familial adenomatous polyposis by downregulating beta-catenin signaling. However, the intracellular target mediating the effects of berberine remains elusive. Here, we provide evidence that berberine inhibits beta-catenin function via directly binding to a unique region comprising residues Gln275, Arg316 and Arg371 in nuclear receptor retinoid X receptor alpha (RXRalpha), where berberine concomitantly binding to and synergistically activating RXRalpha with 9-cis retinoic acid (9-cis-RA), a natural ligand binding to the classical ligand binding pocket of RXRalpha. Berberine binding promotes RXRalpha interaction with nuclear beta-catenin, leading to c-Cbl mediated degradation of beta-catenin, and consequently inhibits the proliferation of colon cancer cells. Furthermore, berberine suppresses the growth of human colon carcinoma xenograft in nude mice in an RXRalpha-dependent manner. Together, our study not only identifies RXRalpha as a direct protein target for berberine but also dissects their binding mode and validates that berberine indeed suppresses beta-catenin signaling and cell growth in colon cancer via binding RXRalpha, which provide new strategies for the design of new RXRalpha-based antitumor agents and drug combinations. PMID- 28846106 TI - Brg-1 targeting of novel miR550a-5p/RNF43/Wnt signaling axis regulates colorectal cancer metastasis. AB - This corrects the article DOI: 10.1038/onc.2015.124. PMID- 28846105 TI - C-reactive protein binds to integrin alpha2 and Fcgamma receptor I, leading to breast cell adhesion and breast cancer progression. AB - C-reactive protein (CRP) is an acute phase protein synthesized upon the inflammatory responses, associated with breast cancer. The process of tumor cell invasion and metastasis involves the adherence of cells to the extracellular matrix via integrin as a receptor for matrix molecules. The present study investigated the role of CRP in the adhesive phenotype of breast cells and the underlying mechanisms. Here, we first showed that CRP induces adhesion of MCF10A human breast epithelial cells through the activation of integrin alpha2 signaling. Expression of integrin alpha2 was induced by CRP in which transcription factors c-fos and SP1 may be involved. Binding of CRP with integrin alpha2 leads to the activation of focal adhesion kinase (FAK), paxillin and ERKs. CRP also binds to an Fcgamma receptor Fcgamma receptor I (FcgammaRI), and induces activation of paxillin, FAK and ERKs. Integrin alpha2 and FAK have crucial roles in the adhesive and invasive phenotypes as well as MMP-9 upregulation induced by CRP in MCF10A cells. Treatment with an inflammatory lipid sphingosine-1-phosphate induced CRP, which may be secreted and exert an autocrine effect by binding to FcgammaRI and integrin alpha2. Involvement of CRP in adhesion, invasion, anchorage-independent growth and upregulation of integrin alpha2, paxillin and FAK was observed in MDA-MB-231 triple-negative human breast cancer (TNBC) cells. Using an in vivo invasion model and an orthotopic mouse tumor model with MDA-MB 231 cells, we showed that CRP has an important role in intravasation and tumor growth in vivo, demonstrating the in vivo relevance of our in vitro results. The present study elucidates a critical molecular basis between CRP, integrin alpha2 and FcgammaRI pathways in MCF10A breast cells and MDA-MB-231 TNBC cells, thereby providing useful information on CRP-induced aggressiveness of breast cells in the inflammatory microenvironment. PMID- 28846107 TI - Nuclear factor E2-related factor-2 has a differential impact on MCT1 and MCT4 lactate carrier expression in colonic epithelial cells: a condition favoring metabolic symbiosis between colorectal cancer and stromal cells. AB - Malignant tumors, such as colorectal cancer (CRC), are heterogeneous diseases characterized by distinct metabolic phenotypes. These include Warburg- and reverse Warburg phenotypes depending on differential distribution of the lactate carrier proteins monocarboxylate transporter-4 and -1 (MCT4 and MCT1). Here, we elucidated the role of the antioxidant transcription factor nuclear factor E2 related factor-2 (Nrf2) as the key regulator of cellular adaptation to inflammatory/environmental stress in shaping the metabolism toward a reverse Warburg phenotype in malignant and premalignant colonic epithelial cells. Immunohistochemistry of human CRC tissues revealed reciprocal expression of MCT1 and MCT4 in carcinoma and stroma cells, respectively, accompanied by strong epithelial Nrf2 activation. In colorectal tissue from inflammatory bowel disease patients, MCT1 and Nrf2 were coexpressed as well, relating to CD68+inflammatory infiltrates. Indirect coculture of human NCM460 colonocytes with M1- but not M2 macrophages induces MCT1 as well as G6PD, LDHB and TALDO expression, whereas MCT4 expression was decreased. Nrf2 knockdown or reactive oxygen species (ROS) scavenging blocked these coculture effects in NCM460 cells. Likewise, Nrf2 knockdown inhibited similar effects of tBHQ-mediated Nrf2 activation on NCM460 and HCT15 CRC cells. M1 coculture or Nrf2 activation/overexpression greatly altered the lactate uptake but not glucose uptake and mitochondrial activities in these cells, reflecting the reverse Warburg phenotype. Depending on MCT1-mediated lactate uptake, Nrf2 conferred protection from TRAIL-induced apoptosis in NCM460 and HCT15 cells. Moreover, metabolism-dependent clonal growth of HCT15 cells was induced by Nrf2-dependent activation of MCT1-driven lactate exchange. These findings indicate that Nrf2 has an impact on the metabolism already in premalignant colonic epithelial cells exposed to inflammatory M1 macrophages, an effect accompanied by growth and survival alterations. Favoring the reverse Warburg effect, these Nrf2-dependent alterations add to malignant transformation of the colonic epithelium. PMID- 28846108 TI - Runx3 plays a critical role in restriction-point and defense against cellular transformation. AB - The restriction (R)-point decision is fundamental to normal differentiation and the G1-S transition, and the decision-making machinery is perturbed in nearly all cancer cells. The mechanisms underlying the cellular context-dependent R-point decision remain poorly understood. We found that the R-point was dysregulated in Runx3-/-mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenicity of Runx3-/-MEFs and K-Ras-activated Runx3-/-MEFs (Runx3-/-;K-RasG12D/+). During the R-point, Runx3 transiently formed a complex with pRb and Brd2 and induced Cdkn1a (p21Waf1/Cip1/Sdi1; p21), a key regulator of the R-point transition. Cyclin D-CDK4/6 promoted dissociation of the pRb-Runx3-Brd2 complex, thus turning off p21 expression. However, cells harboring oncogenic K-Ras maintained the pRb Runx3-Brd2 complex and p21 expression even after introduction of Cyclin D1. Thus, Runx3 plays a critical role in R-point regulation and defense against cellular transformation. PMID- 28846109 TI - Merkel cell polyomavirus small T antigen induces genome instability by E3 ubiquitin ligase targeting. AB - The formation of a bipolar mitotic spindle is an essential process for the equal segregation of duplicated DNA into two daughter cells during mitosis. As a result of deregulated cellular signaling pathways, cancer cells often suffer a loss of genome integrity that might etiologically contribute to carcinogenesis. Merkel cell polyomavirus (MCV) small T (sT) oncoprotein induces centrosome overduplication, aneuploidy, chromosome breakage and the formation of micronuclei by targeting cellular ligases through a sT domain that also inhibits MCV large T oncoprotein turnover. These results provide important insight as to how centrosome number and chromosomal stability can be affected by the E3 ligase targeting capacity of viral oncoproteins such as MCV sT, which may contribute to Merkel cell carcinogenesis. PMID- 28846111 TI - Acetylation is essential for nuclear heme oxygenase-1-enhanced tumor growth and invasiveness. AB - Overexpression of heme oxygenase-1 (HO-1), an endoplasmic reticulum-anchored enzyme, is observed in many cancers. HO-1 nuclear translocation has been shown to correlate with progression of several cancers. We recently reported that HO-1 is susceptible to intramembrane proteolysis and translocates to the nucleus to promote cancer growth and invasiveness without depending on its enzymatic activity. In the present study, we show that the HO-1 lacking C-terminal transmembrane segment (t-HO-1) was susceptible to acetylation by p300 and CREB binding protein (CBP) histone acetyltransferase in the nucleus. Mass spectrometry analysis of HO-1 isolated from human embryonic kidney cells 293T (HEK293T) cells overexpressing CBP and t-HO-1 revealed two acetylation sites located at K243 and K256. Mutation of both lysine residues to arginine (R) abolished t-HO-1-enhanced tumor cell growth, migration and invasion. However, mutation of the lysine residues to glutamine (Q), a mimic of acetylated lysine, had no significant effect on t-HO-1-mediated tumorigenicity. Mechanistic studies demonstrated that transcriptional factor JunD interacted with wild-type (WT) t-HO-1 and mutant carrying K243/256Q but not K243/256 R mutation. Moreover, JunD-induced AP-1 transcriptional activity was significantly enhanced by coexpression with WT and acetylation-mimic but not acetylation-defective t-HO-1. Consistent with the in vitro observations, the implication of K243/256 acetylation in t-HO-1-enhanced tumorigenicity was also demonstrated in xenograft models. Immunohistochemistry performed with a specific antibody against acetyl-HO-1 showed the positive acetyl HO-1 nuclear staining in human lung cancer tissues but not in the corresponding non-tumor tissues, supporting its clinical significance. Collectively, our findings highlight the importance of nuclear HO-1 post-translational modification in the induction of cancer progression. PMID- 28846110 TI - Hepatitis B virus X protein promotes the development of liver fibrosis and hepatoma through downregulation of miR-30e targeting P4HA2 mRNA. AB - Hepatitis B virus (HBV)-induced liver necrosis takes great part in liver cirrhosis progression. However, less is known about whether hepatitis B virus X protein (HBx) has effect on liver fibrosis. Here, we report that HBV leads to liver fibrosis and hepatocarcinogenesis through miR-30e targeting P4HA2. HBV transgenic mouse was treated by CCl4 to generate a model of liver fibrosis. A crucial enzyme catalyzing collagen formation, prolyl 4-hydroxylase subunit alpha2 (P4HA2) was evaluated by immunohistochemistry, western blotting or quantitative reverse transcription-PCR analysis. The function of HBV-modulated P4HA2 in hepatoma cell growth in vitro and in vivo was analyzed by EdU, MTT, colony forming assay and animal transplantation assay. HBV transgenic mice exhibited more collagen deposition in liver after intraperitoneal injection of CCl4. P4HA2 was dramatically augmented in liver samples of HBV transgenic mice, clinical liver cirrhosis and liver cancer patients. Mechanistically, HBx was capable of inducing P4HA2 through suppressing miR-30e, in which miR-30e could target P4HA2 mRNA 3' untranslated region in liver cancer cells. HBx inhibited the miR-30e expression through increasing methylation of CpG islands in its promoter mediated by EZH2-formed complexes. Functionally, HBx-elevated P4HA2 enhanced the collagen deposition in the liver in vivo and in vitro, leading to liver fibrosis and liver cancer progression. In conclusion, HBx promotes the development of liver fibrosis and hepatocellular carcinoma through miR-30e targeting P4HA2 mRNA. We provide novel perspective on how HBx induces liver fibrosis. PMID- 28846112 TI - Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis. AB - RNA polymerase III (Pol III) transcribes medium-sized non-coding RNAs (collectively termed Pol III genes). Emerging diverse roles of Pol III genes suggest that individual Pol III genes are exquisitely regulated by transcription and epigenetic factors. Here we report global Pol III expression/methylation profiles and molecular mechanisms of Pol III regulation that have not been as extensively studied, using nc886 as a representative Pol III gene. In a human mammary epithelial cell system that recapitulates early breast tumorigenesis, the fraction of actively transcribed Pol III genes increases reaching a plateau during immortalization. Hyper-methylation of Pol III genes inhibits Pol III binding to DNA via inducing repressed chromatin and is a determinant for the Pol III repertoire. When Pol III genes are hypo-methylated, MYC amplifies their transcription, regardless of its recognition DNA motif. Thus, Pol III expression during tumorigenesis is delineated by methylation and magnified by MYC. PMID- 28846113 TI - VPS34 stimulation of p62 phosphorylation for cancer progression. AB - Vps34, a class III PtdIns3 lipid kinase involved in the control of both autophagic and endocytic systems, has been studied extensively in numerous fundamental cellular processes. Accumulating evidence indicates that Vps34 may also contribute to the development and progression of human cancers. However, the mechanism of Vps34 in tumorigenesis remains elusive. Here, we report an unanticipated role of Vps34 in the activation of p62 for cancer development. We identified that Vps34 is a transcriptional activator of p62 through competition of Nrf2 (nuclear factor erythroid 2-related factor 2) for Keap1 binding. Vps34 augments the association of PKC-delta with p62 for its phosphorylation at Serine 349, which leads to positive feedback on the Nrf2-dependent transcription of oncogenes. Additionally, we found that the expression of Vps34 is correlated with the tumorigenic activity of human breast cancer cells. Normally inactive in breast cancer, caspase 8 can cleave Vps34 at residue D285, which directly abolished its lipid kinase activity and dramatically altered cell invasion potential, colony formation, as well as tumorigenesis in orthotopic engraftments in mice. The cleavage at D285 blocks expression of LC3-II, Nrf2 and subsequently, p62, in addition to blocking tumor growth, indicating that the intact structure of Vps34 is essential for its activity. Moreover, either knockout of PKC-delta or knockdown of p62 by small interfering RNA in MCF-7 cells abrogates Vps34 dependent tumor growth. Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-delta- activation of p62. PMID- 28846114 TI - Identification of translationally controlled tumor protein in promotion of DNA homologous recombination repair in cancer cells by affinity proteomics. AB - Translationally controlled tumor protein(TCTP) has been implicated in the regulation of apoptosis, DNA repair and drug resistance. However, the underlying molecular mechanisms are poorly defined. To better understand the molecular mechanisms underlying TCTP involved in cellular processes, we performed an affinity purification-based proteomic profiling to identify proteins interacting with TCTP in human cervical cancer HeLa cells. We found that a group of proteins involved in DNA repair are enriched in the potential TCTP interactome. Silencing TCTP by short hairpin RNA in breast carcinoma MCF-7 cells leads to the declined repair efficiency for DNA double-strand breaks on the GFP-Pem1 reporter gene by homologous recombination, the persistent activation and the prolonged retention of gammaH2AX and Rad51 foci following ionizing radiation. Reciprocal immunoprecipitations indicated that TCTP forms complexes with Rad51 in vivo, and the stability maintenance of Rad51 requires TCTP in MCF-7 cells under normal cell culture conditions. Moreover, inactivation of TCTP by sertraline treatment enhances UVC irradiation-induced apoptosis in MCF-7 cells, and causes sensitization to DNA-damaging drug etoposide and DNA repair inhibitor olaparib. Thus, we have identified an important role of TCTP in promoting DNA double-stand break repair via facilitating DNA homologous recombination processes and highlighted the great potential of TCTP as a drug target to enhance conventional chemotherapy for cancer patients with high levels of TCTP expression. PMID- 28846116 TI - Targeting prohibitins with chemical ligands inhibits KRAS-mediated lung tumours. AB - This corrects the article DOI: 10.1038/onc.2017.93. PMID- 28846115 TI - CUT-PCR: CRISPR-mediated, ultrasensitive detection of target DNA using PCR. AB - Circulating tumor DNA (ctDNA) has emerged as a tumor-specific biomarker for the early detection of various cancers. To date, several techniques have been devised to enrich the extremely small amounts of ctDNA present in plasma, but they are still insufficient for cancer diagnosis, especially at the early stage. Here, we developed a novel method, CUT (CRISPR-mediated, Ultrasensitive detection of Target DNA)-PCR, which uses CRISPR endonucleases to enrich and detect the extremely small amounts of tumor DNA fragments among the much more abundant wild type DNA fragments by specifically eliminating the wild-type sequences. We computed that by using various orthologonal CRISPR endonucleases such as SpCas9 and FnCpf1, the CUT-PCR method would be applicable to 80% of known cancer-linked substitution mutations registered in the COSMIC database. We further verified that CUT-PCR together with targeted deep sequencing enables detection of a broad range of oncogenes with high sensitivity (<0.01%) and accuracy, which is superior to conventional targeted deep sequencing. In the end, we successfully applied CUT PCR to detect sequences with oncogenic mutations in the ctDNA of colorectal cancer patients' blood, suggesting that our technique could be adopted for diagnosing various types of cancer at early stages. PMID- 28846117 TI - Genetic Studies Help Clarify the Complexities of Lipid Biology and Treatment. PMID- 28846119 TI - Detection of Early Loss of Color Vision in Age-Related Macular Degeneration - With Emphasis on Drusen and Reticular Pseudodrusen. AB - Purpose: To evaluate chromatic sensitivity in patients with age-related macular degeneration (AMD) characterized by drusen and reticular pseudodrusen. To investigate whether the severity of color vision loss can distinguish between various stages of AMD and hence be used as an index of progression toward advanced AMD. Methods: Chromatic sensitivity was measured by using the Color Assessment and Diagnosis (CAD) test in asymptomatic individuals with early and intermediate AMD and compared to normative data. All study participants had logMAR visual acuity of 0.3 or better. The CAD thresholds measured in eyes with and without reticular pseudodrusen were also compared and related to central macular thickness (CMT). Student's t-test P values < 0.05 were considered significant. Results: All early- and intermediate-AMD eyes (n = 90) had chromatic sensitivity loss in either RG (red/green) or YB (yellow/blue), or both (P < 0.0001) as compared to age-matched normal subjects. The eyes exhibited a range of CAD thresholds affecting both color mechanisms, but YB color thresholds were in general higher than RG thresholds (P < 0.001). Intermediate-AMD patients exhibited large intersubject variability. In general, eyes with reticular pseudodrusen and eyes with CMT < 200 MUm had significantly higher CAD thresholds. Conclusions: The anatomic integrity of cone photoreceptors remains relatively unaffected in early and intermediate stages of AMD. The processing of cone signals in the retina can, however, be heavily disrupted with subsequent loss of both YB and RG chromatic sensitivity. The greatest losses were observed in eyes with reticular pseudodrusen. PMID- 28846118 TI - Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk. AB - Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures: Differences in mean high-density lipoprotein cholesterol (HDL C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events. Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955 1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles. PMID- 28846120 TI - Mother Still. PMID- 28846121 TI - Pennsylvania Otolaryngologists as a Model for the Implications of Practice Location of Osteopathic vs Allopathic Surgical Subspecialists. AB - Background: Evidenced-based models should be used to predict future implications of the single accreditation system for graduate medical education. Compared with other states, Pennsylvania has a relatively high number of osteopathic physicians (ie, DOs) and may be used as a model for a health care system with an increased DO presence. Objective: To compare the geographic distribution of otolaryngologist DOs with otolaryngologist allopathic physicians (ie, MDs) in Pennsylvania and identify differences in community size (urban, urbanized, and rural) in which these physicians practice. Methods: A list of otolaryngologist practice locations in Pennsylvania was developed using Centers for Medicare and Medicaid Services data, the American Osteopathic Colleges of Ophthalmology and Otolaryngology-Head and Neck Surgery Masterfile, and the American Medical Association Physician Masterfile. The United States Census data were used to document the general population of those locations. The samples of individual otolaryngologist DOs and MDs were then analyzed by determining where each otolaryngologist practiced, identifying the type of community in which they practiced, and then comparing the percentage of otolaryngologist DOs and MDs who practiced in each community type (urbanized area, urban cluster, and rural). A chi2 analysis was used to determine whether a difference existed in practice location between otolaryngologist DOs and MDs. Results: Of the 47 otolaryngologist DOs, 32 (70%) practiced in cities with a population of 49,999 or less. More than half (120 of 238) of the otolaryngologist MDs practiced in cities larger than 50,000, and 96 of 238 (40%) practiced in cities with a population of at least 200,000. chi2 analysis showed a significant difference in the geographic distribution of otolaryngologist DOs and MDs (P=.012). Conclusion: A correlation exists between the practice location of otolaryngologists in Pennsylvania and the medical degree they hold. PMID- 28846122 TI - Single Osteopathic Manipulative Therapy Session Dampens Acute Autonomic and Neuroendocrine Responses to Mental Stress in Healthy Male Participants. AB - Context: The efficacy of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) is supported by observational data and patient feedback, but there is still a need for objective, quantitative biomarkers that allow measurement of the underlying mechanisms. No study exploring the protective potential of OMTh for mental stress has been published, to the authors' knowledge. Objectives: To explore the modulating effect of OMTh on autonomic neural regulation of the heart and verifiy its ability to influence the activity of the hypothalmic-pituitary-adrenocortical axis. Methods: Healthy young adult men who had never received OMTh were exposed to either a brief protocol using craniosacral techniques or sham therapy (control) involving the same anatomical areas. A laboratory stress episode consisting of a 5-minute arithmetic task participants were required to perform in front of a committee preceded the therapy sessions. Continuous electrocardiograph recordings were done before, during, and after the stress episode. Heart rate and frequency-domain parameters of heart rate variability (specifically, high-frequency component power in normalized units and the ratio of low-frequency to high-frequency power) were measured to quantify the activity of the parasympathetic nervous system and the state of sympathovagal balance at the level of the heart, respectively. Saliva samples were also collected at points throughout the study to determine cortisol levels. Results: Osteopathic manipulative therapy reduced the overall chronotropic effect of the stressor (t=-2.9, P<.05) and counteracted the vagal withdrawal and the shift of autonomic balance toward sympathetic prevalence (t= 2.8, P<.05) that were observed in control participants. Moreover, OMTh participants had a much lower overall cortisol level during the mental stressor compared with control participants (t=-2.3, P<.05). Participants in the OMTh group did not show the statistically significant reduction in the amplitude of the cortisol awakening response observed in their control counterparts after the stress episode (control: t=2.7, P<.05; OMT: P=.83). Conclusion: The application of a single OMTh session to healthy participants induced a faster recovery of heart rate and sympathovagal balance after an acute mental stressor by substantially dampening parasympathetic withdrawal and sympathetic prevalence. The OMTh session also prevented the typical increase in cortisol levels observed immediately after a brief mental challenge. PMID- 28846123 TI - Osteopathic Manipulative Treatment to Manage Ophthalmic Conditions. AB - Although there is little evidence-based literature regarding osteopathic manipulative treatment for ophthalmic conditions, the general principles and techniques of osteopathic manipulative medicine can be used to manage various ophthalmic pathologic conditions. Additional research to support these treatment options and evaluate the role of OMT as a potential conservative treatment option used by ophthalmologists is needed. PMID- 28846124 TI - Self-efficacy of Osteopathic Medical Students in a Rural-Urban Underserved Pathway Program. AB - Context: Self-efficacy has been shown to play a role in medical students' choice of practice location. More physicians are needed in rural and urban underserved communities. Ohio University Heritage College of Osteopathic Medicine has a co curricular training program in rural and urban underserved practice to address this shortage. Objective: To assess whether participation in the co-curricular program in rural and urban underserved practice affects self-efficacy related to rural and underserved urban practice. Methods: This cross-sectional study explored self-efficacy using Bandura's 5 sources of self-efficacy (vicarious learning, verbal persuasion, positive emotional arousal, negative emotional arousal, and performance accomplishments). A validated scale on self-efficacy for rural practice was expanded to include self-efficacy for urban underserved practice and e-mailed to all 707 medical students across 4 years of medical school. Composite rural and urban underserved self-efficacy scores were calculated. Scores from participants in the rural and urban underserved training program were compared with those who were not in the program. Results: Data were obtained from 277 students. In the overall sample, students who indicated that they grew up in a rural community reported significantly higher rural self efficacy scores than those who did not grow up in a rural community (F1,250=27.56, P<.001). Conversely, students who indicated that they grew up in a nonrural community reported significantly higher urban underserved self-efficacy scores than those who grew up in a rural community (F1,237=7.50, P=.007). The participants who stated primary care as their career interest (n=122) had higher rural self-efficacy scores than the participants who reported a preference for generalist specialties (general surgery, general psychiatry, and general obstetrics and gynecology) or other specialties (n=155) (F2,249=7.16, P=.001). Students who participated in the rural and urban underserved training program (n=49) reported higher rural self-efficacy scores (mean [SD], 21.06 [5.06]) than those who were not in the program (19.22 [4.22]) (t65=2.36; P=.022; equal variances not assumed). The weakest source of self-efficacy for rural practice in participants was vicarious experience. The weakest source of urban underserved self-efficacy was verbal persuasion. Conclusion: Opportunities exist for strengthening weaker sources of self-efficacy for rural practice, including vicarious experience and verbal persuasion. The findings suggest a need for longitudinal research into self-efficacy and practice type interest in osteopathic medical students. PMID- 28846125 TI - Intuitive Judgement in the Context of Osteopathic Clinical Reasoning. AB - Previous research into osteopathic clinical and diagnostic decision making suggests that reasoning is commonly based on highly analytical as well as intuitive processes. According to the dual-process theory, the intuitive and analytical processing that leads to decision making is equally important in diagnostic reasoning. This article aims to explore the underlying and influencing factors that may lead to the development and reliability of intuition in clinical decision making generally and in osteopathic clinical reasoning specifically. Practical suggestions are given on how to encourage the development of intuition within the context of osteopathic teaching and practice. PMID- 28846126 TI - Progressive Infantile Scoliosis Managed With Osteopathic Manipulative Treatment. AB - Infantile idiopathic scoliosis is a compensatory result of cranial and sacral intraosseous dysfunction associated with asymmetric developmental deformation of the occiput, leading to dysfunction of the sphenobasilar synchondrosis. A female infant with progressive infantile idiopathic scoliosis diagnosed at age 12 months (46.9 degrees left scoliotic curve) initially received standard orthopedic care, including casting. The patient presented for osteopathic evaluation at age 14 months, at which time her scoliotic curve was 52 degrees . The patient wore a Risser cast extending from T1-L5 at her first osteopathic manipulative treatment (OMT) visit, which included osteopathic cranial manipulative medicine. Her parents chose to have the cast removed at age 17 months, with a 23 degrees curve remaining. For approximately 12 months, OMT was the only continued, consistent treatment, which occurred once per month. By 28 months of age, radiographs measured 0 degrees of scoliosis. This case demonstrates that OMT can dramatically improve infantile idiopathic scoliosis and prevent its progression. PMID- 28846127 TI - Loffler Endocarditis and Endomyocardial Fibrosis. PMID- 28846128 TI - What Osteopathic Physicians Do. PMID- 28846129 TI - Do Safety Culture Scores in Nursing Homes Depend on Job Role and Ownership? Results from a National Survey. AB - OBJECTIVES: To identify facility- and individual-level predictors of nursing home safety culture. DESIGN: Cross-sectional survey of individuals within facilities. SETTING: Nursing homes participating in the national Agency for Healthcare Research and Quality Safety Program for Long-Term Care: Healthcare-Associated Infections/Catheter-Associated Urinary Tract Infections Project. PARTICIPANTS: Responding nursing home staff (N = 14,177) from 170 (81%) of 210 participating facilities. MEASUREMENTS: Staff responses to the Nursing Home Survey on Patient Safety Culture (NHSOPS), focused on five domains (teamwork, training and skills, communication openness, supervisor expectations, organizational learning) and individual respondent characteristics (occupation, tenure, hours worked), were merged with data on facility characteristics (from the Certification and Survey Provider Enhanced Reporting): ownership, chain membership, percentage residents on Medicare, bed size. Data were analyzed using multivariate hierarchical models. RESULTS: Nursing assistants rated all domains worse than administrators did (P < .001), with the largest differences for communication openness (24.3 points), teamwork (17.4 points), and supervisor expectations (16.1 points). Clinical staff rated all domains worse than administrators. Nonprofit ownership was associated with worse training and skills (by 6.0 points, P =.04) and communication openness (7.3 points, P =.004), and nonprofit and chain ownership were associated with worse supervisor expectations (5.2 points, P =.001 and 3.2 points, P =.03, respectively) and organizational learning (5.6 points, P =.009 and 4.2 points, P = .03). The percentage of variation in safety culture attributable to facility characteristics was less than 22%, with ownership having the strongest effect. CONCLUSION: Perceptions of safety culture vary widely among nursing home staff, with administrators consistently perceiving better safety culture than clinical staff who spend more time with residents. Reporting safety culture scores according to occupation may be more important than facility-level scores alone to describe and assess barriers, facilitators, and changes in safety culture. PMID- 28846130 TI - Identification and characterisation of the proteins bound by specific phage displayed recombinant antibodies (scFv) obtained against Brazil nut and almond extracts. AB - BACKGROUND: Almonds and Brazil nuts are widely consumed allergenic nuts whose presence must be declared according to food labelling regulations. Their detection in food products has been recently achieved by ELISA methods with recombinant antibodies (scFv) isolated against complete Brazil nut and almond protein extracts. The screening of phage-scFv libraries against complete protein extracts confers a series of advantages over the use of purified proteins, as recombinant proteins might alter their native folding. However, using this strategy, the nature of the target detected by phage-displayed antibodies remains unknown, and requires further research to identify whether they are nut allergens or other molecules present in the extract, but not related to their allergenic potential. RESULTS: Electrophoretic, chromatographic, immunological and spectrometric techniques revealed that the Brazil nut (BE95) and almond (PD1F6 and PD2C9) specific phage-scFvs detected conformational epitopes of the Brazil nut and almond 11S globulins, recognised by WHO/IUIS as Ber e 2 and Pru du 6 major allergens. Circular dichroism data indicated that severe heat treatment would entail loss of epitope structure, disabling scFv for target detection. CONCLUSIONS: The presence of important Brazil nut and almond allergens (Ber e 2 and Pru du 6) in foodstuffs can be determined by using phage-display antibodies BE95, PD1F6 and PD2C9 as affinity probes in ELISA. (c) 2017 Society of Chemical Industry. PMID- 28846131 TI - Development and Validation of a Geriatrics Knowledge Test to Evaluate Geriatrics Fellowship Programs. AB - BACKGROUND/OBJECTIVES: Although the Accreditation Council for Graduate Medical Education requires that geriatrics fellowship programs be evaluated, evaluation is challenging because of lack of appropriate instruments. The purpose of this study was to develop and validate a geriatrics knowledge test appropriate for evaluation of geriatrics fellowship programs. DESIGN: Initial and replication cross-sectional validation studies. SETTING: Academic medical center. PARTICIPANTS: Initial study: 11 postgraduate year (PGY)-2 and five PGY-3 internal medicine residents, eight incoming and eight graduating geriatrics fellows, and 11 geriatrics faculty (N = 43). Replication study: nine graduating fellows and three mid-year fellow cohorts (n = 11, 8, and 9) (N = 37). MEASUREMENTS: A geriatrics knowledge test was developed consisting of 31 multiple-choice questions (MCQs) selected from a 54-item pool of MCQs that the authors created. Selection criteria included content appropriateness, item correlation with total score, item discriminatory power, and item difficulty. RESULTS: The instrument demonstrated high reliability (Cronbach alpha = 0.83) and known group validity. The mean percentage correct scores on the knowledge test were progressively higher with more geriatrics training (P < .001). The replication study continued to show patterns of progressive increases in score with additional training. There were no floor or ceiling effects. CONCLUSION: A 31-item geriatrics knowledge test demonstrates sound reliability and validity. The findings support that it is appropriate as a tool for evaluation of geriatrics fellowship programs. PMID- 28846132 TI - Age-related histologic and biochemical changes in auricular and septal cartilage. AB - OBJECTIVES/HYPOTHESIS: To characterize the histologic and biochemical properties of auricular and septal cartilage and analyze age-related changes in middle-aged to older adults. STUDY DESIGN: Cross-sectional study of auricular and septal cartilage from 33 fresh cadavers. METHODS: Auricular and septal cartilage specimens were stained using Safranin O for glycosaminoglycans, Verhoeff's stain for elastin, and Masson's trichrome for collagen. Percentage of tissue stained, cell density and size were quantified. Relationships between donor characteristics and histologic properties were evaluated using mixed model analyses. RESULTS: The average donor age was 75 years (standard deviation = 11 years; range, 55-93 years). In auricular cartilage, each 1-year increase in age was associated with a 0.97% decrease in glycosaminoglycans (P < .001) and a 0.98% decrease in elastin (P < .001). In septal cartilage, glycosaminoglycans decreased 2.4% per year (P < .001). Age did not affect collagen content significantly in auricular (P = .417) or septal cartilage (P = .284). Cell density and cell size declined with age in auricular (both P < .001) and septal cartilage (P = .044, P = .032, respectively). Compared to septal cartilage in patients of all ages, auricular cartilage had more glycosaminoglycans, less collagen, higher cell density, and smaller cells. CONCLUSIONS: In auricular and septal cartilage, glycosaminoglycans, elastin, cell density, and cell size decrease significantly with age in patients over 55 years of age. Glycosaminoglycan content declines faster with age in septal cartilage than auricular cartilage. These age-related changes may affect biomechanical properties and tissue viability, and thereby have implications for graft choice in functional, aesthetic, and reconstructive nasal surgery. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:E399-E407, 2017. PMID- 28846133 TI - Is Alzheimer's Prevention Possible Today? PMID- 28846134 TI - Mineral trioxide aggregate and other bioactive endodontic cements: an updated overview - part II: other clinical applications and complications. AB - Mineral trioxide aggregate (MTA) is a dental material used extensively for vital pulp therapies (VPT), protecting scaffolds during regenerative endodontic procedures, apical barriers in teeth with necrotic pulps and open apices, perforation repairs as well as root canal filling and root-end filling during surgical endodontics. A number of bioactive endodontic cements (BECs) have recently been introduced to the market. Most of these materials have calcium and silicate in their compositions; however, bioactivity is a common property of these cements. These materials include the following: BioAggregate, Biodentine, BioRoot RCS, calcium-enriched mixture cement, Endo-CPM, Endocem, EndoSequence, EndoBinder, EndoSeal MTA, iRoot, MicroMega MTA, MTA Bio, MTA Fillapex, MTA Plus, Neo MTA Plus, Ortho MTA, Quick-Set, Retro MTA, Tech Biosealer, and TheraCal LC. It has been claimed that these materials have properties similar to those of MTA but without the drawbacks. In Part I of this review, the available information on the chemical composition of the materials listed above was reviewed and their applications for VPT was discussed. In this article, the clinical applications of MTA and other BECs will be reviewed for apexification, regenerative endodontics, perforation repair, root canal filling, root-end filling, restorative procedures, periodontal defects and treatment of vertical and horizontal root fractures. In addition, the literature regarding the possible drawbacks of these materials following their clinical applications is reviewed. These drawbacks include their discolouration potential, systemic effects and retreatability following use as a root filling material. Based on selected keywords, all publications were searched regarding the use of MTA as well as BECs for the relevant clinical applications. Numerous publications were found regarding the use of BECs for various endodontic applications. The majority of these investigations compared BECs with MTA. Despite promising results for some materials, the number of publications using BECs for various clinical applications was limited. Furthermore, most studies had several methodological shortcomings and low levels of evidence. PMID- 28846135 TI - Group Membership Influences More Social Identification Than Social Learning or Overimitation in Children. AB - Group membership is a strong driver of everyday life in humans, influencing similarity judgments, trust choices, and learning processes. However, its ontogenetic development remains to be understood. This study investigated how group membership, age, sex, and identification with a team influenced 39- to 60 month-old children (N = 94) in a series of similarity, trust, and learning tasks. Group membership had the most influence on similarity and trust tasks, strongly biasing choices toward in-groups. In contrast, prior experience and identification with the team were the most important factors in the learning tasks. Finally, overimitation occurred most when the children's team, but not the opposite, displayed meaningless actions. Future work must investigate how these cognitive abilities combine during development to facilitate cultural processes. PMID- 28846136 TI - A micro-computed tomographic study of band-shaped root canal isthmuses, having their floor in the apical third of mesial roots of mandibular first molars. AB - AIM: To conduct a quantitative and qualitative analysis of the band-shaped isthmus area, the floor of which was in the apical third in the mesial roots of mandibular first molars using micro-computed tomography (micro-CT). METHODOLOGY: Micro-CT images of 269 mesial roots of mandibular first molars were evaluated, and 40 specimens with a band-shaped isthmus, with a floor in the apical third, were selected. The major diameter, minor diameter, roundness, area and perimeter values for the most coronal and apical slices where the isthmus was visible were measured. The distances between these slices were measured as the isthmus length, and the total volume, structure model index and surface area of the isthmus were measured. The distances between the isthmus floor and two apical foramina and the number of root canal orifices were calculated. The dimensions of the isthmus roof and the floor were compared, and the data were analysed using descriptive statistics and Student's t-tests with a significance threshold set at 5%. RESULTS: A total of 15% of the specimens had band-shaped isthmuses with a floor in the apical third. The isthmus roof exhibited significantly greater major and minor diameter values compared to the isthmus floor (P < 0.05). No significant difference was detected between the isthmus roof and the floor with regard to roundness (P > 0.05). CONCLUSION: Three- and two-dimensional analyses of the mesial roots of mandibular molars revealed that band-shaped isthmuses had complex shapes. PMID- 28846137 TI - Enhanced recovery after surgery-Preoperative fasting and glucose loading-A review. AB - In this review, we explore the rationale and history behind the practice of preoperative fasting in elective surgery including the gradual move toward longer fasting and the more recent change in direction of practice. Gastric emptying physiology and the metabolic effects of prolonged fasting and carbohydrate loading are examined. Most recent guidelines related to these topics are discussed and practical recommendations for implementing these guidelines are suggested. PMID- 28846138 TI - ERAS: Safety checklists, antibiotics, and VTE prophylaxis. AB - The concept rested on several components that many of us have now tried to adopt or improve on, inclusive of a multidisciplinary team, a multimodal approach to anesthesia and preoperative preparedness, evidence-based approach to care protocols; and a change in management using interactive and continuous audit prior to and post-procedure. This article describes the development of ERAS protocols relative to checklist implementation, antibiotic use, and venous thromboembolism (VTE) prevention, how these ideas are developed and operationalized as well as how they are evolving and spreading across the care continuum to achieve sustained outcome improvements. PMID- 28846139 TI - Pooled analysis of 1-year recall data from three root canal treatment outcome studies undertaken using cone beam computed tomography. AB - AIM: To provide an estimate of the proportion of successful outcomes of primary and secondary root canal treatments (retreatments) determined by periapical radiographs and cone beam computed tomography (CBCT), a pooled analysis of the data collected from three previous prospective clinical outcome studies was undertaken. METHODOLOGY: The analysis pooled the 1-year results for 354 teeth, including 123 primary treatments and 231 retreatments. All root canals were instrumented with ProTaper Universal and filled using a warm vertical condensation technique. Comparisons of favourable results between root canal treatments and retreatments and between different tooth types were made using chi square/Fisher's exact test. RESULTS: The overall percentage of favourable results was 91% using periapical radiographs and 80% for CBCT (P < 0.001). With CBCT, the percentage of favourable results for primary treatments (84.7%) was not significantly different (P = 0.316) from that of retreatments (77.9%). When assessed by tooth group, the overall percentage of favourable results with CBCT was 75.5%, 90.6% and 91.1% for molar, premolar and anterior teeth, respectively. When CBCT is used to assess the outcome, the proportion of favourable outcomes in molars was significantly lower than that of premolars and anterior teeth (P < 0.05). Teeth with root fillings terminating more than 2 mm short of the radiographic apex had less favourable outcomes (73%) compared to long (83%) and adequate root filling length (84%). CONCLUSIONS: The proportions of favourable outcomes of primary root canal treatments and retreatments assessed with CBCT were lower when compared to periapical radiographs, and also lower than those historically reported by periapical radiograph-based outcome studies. Considering the very high favourable outcome of anterior teeth and premolars compared to molar teeth, future studies assessing the effect of new materials and techniques on the outcome of root canal treatments should be based on preoperative and postoperative CBCT images, and focus on molar teeth. PMID- 28846140 TI - An examination of surface epithelium structures of the embryo across the genus Poeciliopsis (Poeciliidae). AB - In viviparous, teleost fish, with postfertilization maternal nutrient provisioning, embryonic structures that facilitate maternal-fetal nutrient transfer are predicted to be present. For the family Poeciliidae, only a handful of morphological studies have explored these embryonic specializations. Here, we present a comparative morphological study in the viviparous poeciliid genus, Poeciliopsis. Using microscopy techniques, we examine the embryonic surface epidermis of Poeciliopsis species that vary in their level of postfertilization maternal nutrient provisioning and placentation across two phylogenetic clades and three independent evolutionary origins of placentation. We focus on surface features of the embryo that may facilitate maternal-fetal nutrient transfer. Specifically, we studied cell apical-surface morphology associated with the superficial epithelium that covers the body and sac (yolk and pericardial) of embryos at different developmental stages. Scanning electron microscopy revealed common surface epithelial cells across species, including pavement cells with apical-surface microridges or microvilli and presumed ionocytes and/or mucus secreting cells. For three species, in the mid-stage embryos, the surface of the body and sac were covered in microvillus epithelium. The remaining species did not display microvillus epithelium at any of the stages examined. Instead, their epithelium of the body and sac were composed of cells with apical-surface microridges. For all species, in the late stage embryos, the surface of the body proper was composed of apical-surface microridges in a "fingerprint-like arrangement." Despite the differences in the surface epithelium of embryos across Poeciliopsis species and embryonic developmental stages, this variation was not associated with the level of postfertilization maternal nutrient provisioning. We discuss these results in light of previous morphological studies of matrotrophic, teleost fish, phylogenetic relationships of Poeciliopsis species, and our earlier comparative microscopy work on the maternal tissue of the Poeciliopsis placenta. PMID- 28846141 TI - The Effect of Carboxamide/Sulfonamide Replacement in Arylpiperazinylalkyl Derivatives on Activity to Serotonin and Dopamine Receptors. AB - A series of carboxamide and sulfonamide alkyl (p-xylyl and benzyl) 1-(2 methoxyphenyl)piperazine (o-OMe-PhP) and 1-(2,3-dichlorophenyl)piperazine (2,3 DCPP) analogs were prepared and tested for their affinity to bind to serotonin 5 HT1A /5-HT6 /5-HT7 and dopamine D2 receptors. This chemical modification let us explore the impact of the replacement of the carboxamide by the sulfonamide group on the affinity changes. In both the o-OMe-PhP and 2,3-DCPP series, the relative activities of the carboxamides versus sulfonamides toward the 5-HT1A /5-HT6 /5 HT7 and D2 receptors show similar trends. Varied or similar activities for particular receptors were found for the carboxamides/sulfonamides with p-xylyl spacer, while of the two classes of carboxamides and sulfonamides examined, benzyl derivatives of the sulfonamides displayed the highest serotoninergic affinity, in particular to the 5-HT7 receptors (Ki 8-85 nM). The Ki values revealed that, irrespective of the carboxamide/sulfonamide zone, both p-xylyl and benzyl derivatives had the highest affinity for the dopamine D2 receptor (i.e., 16 out of 24 compounds investigated have an affinity below 100 nM). A molecular modeling study of carboxamide 9a and sulfonamide 9b showed that their binding effects to each of 5-HT1A R and D2 R created binding modes interaction with different conserved receptors residues. Structural similarities of carboxamide 9a in complexes with a 5-HT1A R (9aI) and D2 R (9aII) are over 83%, while the respective similarities of sulfonamide 9b structures (9bI/9bII) are only about 40%. PMID- 28846142 TI - First case of dermatosis papulosa nigra in a white child. PMID- 28846143 TI - Characterization of a stepwise approach in cavotricuspid isthmus ablation for typical atrial flutter: A randomized study comparing three catheters. AB - INTRODUCTION: Our aim was to characterize a stepwise approach in cavotricuspid isthmus ablation for typical atrial flutter in a prospective, noncrossover randomized study. METHODS: One hundred and fifty patients referred for cavotricuspid isthmus (CTI)-dependent atrial flutter ablation were randomized to undergo an ablation with an 8-mm-tip catheter (group 1), a 3.5-mm open irrigation tip catheter (group 2), and a 3.5-mm open irrigation porous-tip catheter (group 3). A stepwise approach was performed, changing the ablation site from medial to septal aspects of the CTI, in case it was not effective without crossover between catheters. RESULTS: CTI block was achieved in all the patients using only one catheter. There was a 68% efficacy in group 1, 40% in group 2, and 28% in group 3 to achieve CTI block within 10 minutes (P = 0.001) and 96%, 70%, and 70% in groups 1, 2, and 3, respectively, within 20 minutes (P = 0.002) of radiofrequency ablation. The 8-mm catheter was also faster in fluoroscopy time and CTI block time. There were no differences in efficiency in the both irrigated catheters. There were no significant differences in complications among three catheters. CONCLUSIONS: With this stepwise approach, it is possible to achieve CTI block in all cases, using a single catheter without crossover, with good times of procedure and with a low complication rate. The 8-mm solid catheter is faster than the other irrigated-tip catheters. The 3.5-mm open irrigation porous tip catheter is as effective and safe as the conventional irrigated-tip catheter. PMID- 28846144 TI - Impact of ICD lead on the system durability, predictors of long-term survival following ICD system extraction. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy defibrillator (CRT-D) systems are considered as having higher risk of complication and shorter durability but reasons of this multifactorial phenomenon remain unclear. We aimed to analyze this problem in population of patients with ICD leads referred for lead extraction (TLE). METHODS: We have compared TLE indications, procedural results, and defined the long-term outcomes of TLE in patients with ICD/CRT-D devices (n = 482, ICD (+)) with lead extractions in patients with standard pacemakers (n = 1,402, ICD ( )). Demographic, clinical characteristics, and procedural outcomes were ascertained from single, primary operator registry. Long-term survival data were provided by the National Health Fund. RESULTS: The ICD (+) subgroup had a significantly higher incidence rate of either infective or noninfective indications for TLE. The clinical success rate of extraction was 99.2% in ICD (+) versus 97.4% in ICD (-) (P = 0.05) at a complication rate of 1.04% versus 2.14% (NS), respectively. In the median follow-up of 3.39 years, 142 patients from the ICD (+) subgroup and 303 from the ICD (-) subgroup died. The highest mortality rate of 41.1% was observed in the ICD (+) subgroup with infective indications. Infection, renal failure, diabetes, and age were the multivariate factors associated with increased mortality in the ICD (+) subgroup. CONCLUSION: ICD leads remain more vulnerable, with respect to mechanical failure and their propensity to infection, in comparison to pacing leads. Their TLE is very effective at least complication rate, when performed by a highly skilled and experienced operator. However, long-term mortality after their TLE is high and is affected mostly by infections or patient-related factors. PMID- 28846145 TI - Development of a genetic sexing strain of Anopheles arabiensis for KwaZulu-Natal, South Africa. AB - An efficient sexing system is important for the release of sterile males for any control programme using the sterile insect technique. This study describes the development and characterization of a new genetic sexing strain from South Africa (GMK), needed for the planned implementation of such a programme in northern KwaZulu-Natal Province. The base colony used was a locally modified laboratory strain of Anopheles arabiensis containing a sex-linked gene conferring dieldrin resistance to male mosquitoes. Female A. arabiensis mosquitoes from northern KwaZulu-Natal were mated with these males and backcrossed to introduce the dieldrin resistance gene to the Y chromosome. The resulting strain therefore had an overall genotype representing the local population but with the Y chromosome containing the dieldrin resistance gene. Life-history characteristics, stability of the sex-linked resistance marker, and reduction in dieldrin waste were investigated. The strain showed semi-sterility exhibited by low egg hatch rates, faster development in the immature stages and longer adult survivorship compared with the parental strains. While the GMK strain carrying the dieldrin-resistant gene was successfully established, the stability of the gene is limited, requiring periodic purification. Dieldrin waste can be limited by treating many more eggs than currently recommended. PMID- 28846146 TI - Paroxysmal atrioventricular block: Electrophysiological mechanism of phase 4 conduction block in the His-Purkinje system: A comparison with phase 3 block. AB - BACKGROUND: Paroxysmal atrioventricular (A-V) block is relatively rare, and due to its transient nature, it is often under recognized. It is often triggered by atrial, junctional, or ventricular premature beats, and occurs in the presence of a diseased His-Purkinje system (HPS). Here, we present a 45-year-old white male who was admitted for observation due to recurrent syncope and near-syncope, who had paroxysmal A-V block. The likely cellular electrophysiological mechanisms(s) of paroxysmal A-V block and its differential diagnosis and management are discussed. METHODS: Continuous electrocardiographic monitoring was done while the patient was in the cardiac unit. RESULTS: Multiple episodes of paroxysmal A-V block were documented in this case. All episodes were initiated and terminated with atrial/junctional premature beats. The patient underwent permanent pacemaker implantation and has remained asymptomatic since then. CONCLUSIONS: Paroxysmal A V block is rare and often causes syncope or near-syncope. Permanent pacemaker implantation is indicated according to the current guidelines. Paroxysmal A-V block occurs in the setting of diseased HPS and is bradycardia-dependent. The detailed electrophysiological mechanisms, which involve phase 4 diastolic depolarization, and differential diagnosis are discussed. PMID- 28846147 TI - Cardiac mapping and pulmonary vein isolation using a novel ablation catheter with tip minielectrodes. AB - BACKGROUND: Pulmonary vein isolation (PVI) is a standard treatment for atrial fibrillation (AF). Identification of gaps in the ablation line is difficult. Tip ring electrograms from ablation catheters represent relative large areas of myocardial tissue. Recently, an ablation catheter with three minielectrodes (ME) on the catheter tip with closer interelectrode spacing was introduced. The aim of our study was to evaluate the novel electrodes during PVI. METHODS: PVI was performed with an irrigated ablation catheter equipped with conventional electrodes and three additional radial tip electrodes. Detection of pulmonary vein potentials (PVPs), local signal amplitude, amplitude reduction during ablation, and loss of capture after ablation were compared between the ME and the conventional tip-ring electrodes. RESULTS: Thirty-one patients (mean age 67.8 +/- 10.3 years, 45.2 % men) were included. A total of 306 mapping/lesion points were analyzed. A PVP was significantly more often obtained with the ME compared to the conventional tip-ring electrodes (99.2% vs 83.5%, P < 0.001). Local amplitude was significantly higher on the ME (0.8 +/- 0.6 mV vs 0.67 +/- 0.46 mV, P = 0.003). Amplitude reduction during 1 RF pulse was significantly greater on the ME (82.9 +/- 19.5% vs. 61.8 +/- 26.9%, P < 0.001). During pace mapping, loss of capture after 1 RF pulse was observed significantly more often on ME (98.3% vs 63.3%, P < 0.001). CONCLUSION: Signal amplitude is higher and sensitivity during PVP mapping and ablation is increased when ME are used. ME may facilitate catheter ablation of AF in the future. PMID- 28846148 TI - Prevalence and distribution of Borrelia and Babesia species in ticks feeding on dogs in the U.K. AB - Ticks were collected during March-July 2015 from dogs by veterinarians throughout the U.K. and used to estimate current prevalences and distributions of pathogens. DNA was extracted from 4750 ticks and subjected to polymerase chain reaction and sequence analysis to identify Borrelia burgdorferi sensu lato (Spirochaetales: Spirochaetaceae) and Babesia (Piroplasmida: Babesiidae) species. Of 4737 ticks [predominantly Ixodes ricinus Linneaus (Ixodida: Ixodidae)], B. burgdorferi s.l. was detected in 94 (2.0%). Four Borrelia genospecies were identified: Borrelia garinii (41.5%); Borrelia afzelli (31.9%); Borrelia burgdorferi sensu stricto (25.5%), and Borrelia spielmanii (1.1%). One Rhipicephalus sanguineus Latreille (Ixodida: Ixodidae), collected from a dog with a history of travel outside the U.K., was positive for B. garinii. Seventy ticks (1.5%) were positive for Babesia spp. Of these, 84.3% were positive for Babesia venatorum, 10.0% for Babesia vulpes sp. nov., 2.9% for Babesia divergens/Babesia capreoli and 1.4% for Babesia microti. One isolate of Babesia canis was detected in a Dermacentor reticulatus (Ixodida: Ixodidae) tick collected from a dog that had recently travelled to France. Prevalences of B. burgdorferi s.l. and Babesia spp. did not differ significantly between different regions of the U.K. The results map the widespread distribution of B. burgdorferi s.l. and Babesia spp. in ticks in the U.K. and highlight the potential for the introduction and establishment of exotic ticks and tick-borne pathogens. PMID- 28846149 TI - Using video and theater to increase knowledge and change attitudes-Why are gorillas important to the world and to Congo? AB - Applying environmental education in primate range countries is an important long term activity to stimulate pro-conservation behavior. Within captive settings, mega-charismatic species, such as great apes are often used to increase knowledge and positively influence attitudes of visitors. Here, we evaluate the effectiveness of a short-term video and theater program developed for a Western audience and adapted to rural people living in two villages around Nouabale-Ndoki National Park, Republic of Congo. We assessed the knowledge gain and attitude change using oral evaluation in the local language (N = 111). Overall pre-program knowledge about Western gorillas (Gorilla gorilla) was high. Detailed multivariate analysis of pre-program knowledge revealed differences in knowledge between two villages and people with different jobs while attitudes largely were similar between groups. The short-term education program was successful in raising knowledge, particularly of those people with less pre-program knowledge. We also noted an overall significant attitude improvement. Our data indicate short-term education programs are useful in quickly raising knowledge as well improving attitudes. Furthermore, education messages need to be clearly adapted to the daily livelihood realities of the audience, and multi-variate analysis can help to identify potential target groups for education programs. PMID- 28846150 TI - Venipuncture procedure affects heart rate variability and chronotropic response. AB - BACKGROUND: Heart rate variability (HRV) has been shown to be influenced by several factors such as noise, sleep status, light, and emotional arousal; however, little evidence is available concerning autonomic responses to a venipuncture. The purpose of this study was to investigate changes of HRV indexes and heart rate (HR) during and following a venipuncture procedure among healthy individuals. METHODS: 33 healthy individuals (22.8 +/- 0.56 years, 167 +/- 1.56 cm, 69.5 +/- 2.61 kg) participated. Testing included 10-minute HRV analysis prior to the venipuncture, a 1-minute venipuncture procedure followed by a 10-minute analysis of HRV, and a total recording of 21 minutes. The first 5 minutes of the 21-minute recordings were discarded, and the remaining 5 minutes of the resting segment was analyzed (PRE), and the last 5 minutes of the 21-minute recording (POST). The log transformation of the time domain root mean squared of successive differences (lnRMSSD) and the frequency domains of high frequency (lnHF) and low frequency (lnLF) and LF/HF ratio (lnLF/HF) were used to quantify autonomic activity. HR was measured in 1-minute segments at 2 minutes prior (PRE), venipuncture (STICK), and post (P1-5). RESULTS: HR significantly increased at STICK (P = 0.002), and fell below resting at P-5 (P < 0.001). lnRMSSD and lnHF increased significantly by POST (P < 0.001, P = 0.005). lnLF/HF ratio significantly decreased at POST (P = 0.047), while no significant changes occurred for lnLF (P = 0.590). CONCLUSIONS: HRV and HR are influenced for 10 minutes following the venipuncture procedure. Practitioners and researchers who are interested in collecting blood and measuring HRV need to account for the influence of the venipuncture. PMID- 28846151 TI - Ivabradine in the treatment of postural tachycardia syndrome (POTS), a single center experience. AB - BACKGROUND: Ivabradine is a selective If channel blocker that reduces heart rate without affecting other cardiovascular functions. In case reports and case series, it was shown to improve symptoms in patients with postural tachycardia syndrome (POTS). METHODOLOGY AND RESULTS: This retrospective study examined patients who were diagnosed with POTS and received ivabradine as part of their treatment. Forty-nine patients (47 females, 95.9%) received ivabradine. The average age was 35.1 +/- 10.35 years. The most common symptoms were palpitations and lightheadedness and both improved significantly, 88.4% and 76.1% response rate, respectively. A total of 38 patients reported improvement in their symptoms. In addition, ivabradine resulted in an objective decrease in sitting and standing heart rate (78.1 +/- 10.7 vs 72.5 +/- 7.6, P-value: 0.01) and (107.4 +/- 14.1 vs 95.1 +/- 13.7, P-value: < 0.001), respectively, with no significant change in blood pressure. The most common reported side effect was luminous phenomena/visual brightness occurring in nine patients. However, none of the patients stopped ivabradine due to side effects. CONCLUSION: Our study shows that ivabradine is likely to be effective in treating patients with POTS. Nearly 78% of our cohort reported a significant improvement in symptoms with no major adverse effects reported. A future randomized, placebo-controlled trial is warranted. PMID- 28846152 TI - Ablation of the vanishing PVC, facilitated by quantitative morphology-matching software. AB - BACKGROUND: Ablation of cardiac arrhythmias in children and teenagers often necessitates the use of anesthesia, which can suppress ventricular arrhythmias (VAs), making it difficult to map the site of origin using activation time (AT). Pace mapping, a technique employed to assist with VA origin localization, depends on subjective comparison of paced and targeted QRS morphology. We assessed the utility of a quantitative approach to paced QRS to VA morphology matching using the PaSo software (Carto 3, Biosense Webster), to localize the VA site of origin. METHODS: Twenty-four patients underwent 26 procedures for frequent VAs, 29 for targeted VA. If AT mapping was precluded due to infrequent VA, pace mapping was executed using the PaSo software, after regionalization based on targeted VA QRS morphology. RESULTS: Subjects were aged 1-32 (mean 14 +/- 6) years; 10 were male. Heart disease was present in six patients. PVC frequency prior to onset of anesthesia was 15 +/- 16/min, decreasing to 0-1 PVC/min in 17 cases prior to ablation. Arrhythmia localization was performed by AT mapping + PaSo (12) or PaSo only (17). Pace mapping exhibited an intraventricular gradient of percent QRS morphology match. Highest achieved QRS match averaged 96 +/- 2%. Successful ablation (> 1-month follow-up) was achieved in 24/29 targeted VAs, 11/12 ablated using AT and pace mapping, and 13/17 VA ablated using pace mapping only, P = 0.29. CONCLUSIONS: (1) Spontaneous VA frequency was markedly reduced following anesthesia, despite catecholamine administration. (2) Notwithstanding the ability to perform AT mapping, successful ablation can still be performed using pace mapping only, facilitated by the PaSo software. PMID- 28846153 TI - International survey of knowledge, attitudes, and practices of cardiologists regarding prevention and management of cardiac implantable electronic device infections. AB - BACKGROUND: Cardiovascular implantable electronic devices (CIEDs) can be life saving. However, complications from CIED infection can be life-threatening, often requiring device removal. Despite publication of CIED infection management guidelines, there remains marked variation in clinical practice. OBJECTIVE: To better understand and quantify these differences, we conducted a multinational survey of practitioners of CIED management. METHODS: An electronic survey was sent to Heart Rhythm Society members, spanning 70 countries across six continents. All responses were collected anonymously. RESULTS: 227 out of 3,600 (6.3%) responded to the survey. The majority of surveys were completed by practitioners from the United States (168; 68.3%) and 53.8% of these practiced in academic medical centers. The large majority (92.7%) of sites had protocols to ensure appropriate timing of prophylactic antibiotics. Superficial (incisional) site infections were treated with antibiotics alone 52.5% of the time (consistent with guidelines); in contrast, deep pocket infections were treated with antibiotics (with device removal) in accordance to guidelines only 37.4% of the time. Almost all providers (98.7%) were inclined to perform complete hardware removal in cases of CIED-related endocarditis. In contrast, 82.2% of survey participants suggested complete CIED system removal in patients with an occult Gram-positive bacteremia, 65.5% with occult Gram-negative bacteremia, and 59.3% with prolonged bacteremia due to a source other than CIED. CONCLUSIONS: These data suggest wide variability in clinical practice in managing CIED infection with significant deviations from published guidelines. There is critical need to increase awareness and develop institutional protocols to ensure adherence with evidence-based guidelines to optimize outcomes. PMID- 28846154 TI - Biopsy forceps fixation: Novel trick of the trade for duodenal guidewire unlooping. PMID- 28846155 TI - Dermoscope-guided lesional biopsy to diagnose EMA+ CK7+ CK20+ extramammary Paget's disease with an extensive lesion. PMID- 28846156 TI - A pediatric case of selective fixed drug eruption to amoxicillin. PMID- 28846157 TI - Allergy-like immediate reactions with herbal medicines in children: A retrospective study using data from VigiBase(r). AB - BACKGROUND: The use of herbal medicines in children and the general population is continually on the rise with an overall herbal lifetime and current use ranging between 0.8%-85.5% and 2.2%-8.9%, respectively. Although acute hypersensitivity reactions are generally considered to be rare, little knowledge exists on the frequency and type of these reactions especially in specific populations like children. OBJECTIVES: To assess the patterns of acute hypersensitivity reactions to herbal medicines reported to the WHO global individual case safety report (ICSR) database VigiBase(r) in children. STUDY DESIGN: From the original VigiBase(r) extract for the time between 1968 and 2014, we included all reports with adverse drug reactions (ADR) associated with herbal medicines in children where WHO-ART reaction terms were indicative of acute hypersensitivity reactions. RESULTS: VigiBase(r) contained 2646 ICSRs with 14 860 distinct adverse reactions reported in association with herbal medicine in children. Among those, 79 cases with 107 allergy-like reactions met our inclusion criteria. The most commonly reported WHO-ART terms were urticaria or rash/rash erythematous (59.8%), and allergic reaction (8.4%). The most frequently reported suspected herbal medicines were mixed herbal products (51.4%), Hedera helix (15.0%), and Echinacea purpurea (5.6%). Most frequent routes of administration were oral (75.9%), topical (8.9%), and rectal (3.8%). Over 30% of cases were reported in the age group from 7 to 12 years. The majority of reports were received from Germany (29.1%), Thailand (21.5%), and Australia (11.4%). CONCLUSION: VigiBase(r) contains a considerable number of acute hypersensitivity reactions in children associated with herbal medicines, including life-threatening reactions such as anaphylactic shock. PMID- 28846158 TI - Different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines correlate with serum autoreactivity and allergen sensitivity in chronic spontaneous urticaria. AB - BACKGROUND: Clinical features and basophil activation levels correlate with serum autoreactivity and allergen sensitivity in patients with chronic spontaneous urticaria (CSU). OBJECTIVES: To explore the relationship of the expression patterns of plasma T-helper cell (Th) 1-, Th2-, Th17- and Th22-related cytokines with the serum autoreactivity and the allergen sensitivity in CSU. METHOD: Twenty related cytokines were measured and analysed in 60 patients with CSU, 15 patients with acute urticaria, 10 patients with atopic dermatitis (AD) and 15 healthy persons, respectively. Autologous serum skin testing (ASST) and skin prick testing (SPT) were performed to detect autoreactivity and allergy sensitivity, respectively. The protein-protein interaction of cytokines and the molecular pathways were analysed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and KyotoEncyclopedia of Genes and Genomes (KEGG database), respectively. RESULTS: Th1-/Th2- and Th17-related cytokines were significantly elevated and correlated with disease activity in CSU than in healthy controls. Interleukin (IL)-6, IL-10 and IL-13 were significantly higher in acute urticaria than in patients with CSU. Granulocyte/macrophage colony stimulating factor (GM-CSF), IL-10 and IL-17 were significantly higher in ASST+ than in ASST- CSU patients. IFN-gamma, IL-2, IL-12p70 and IL-21 were significantly higher in SPT+ than in SPT- CSU patients. The plasma levels of interferon-gamma, IL-2 and IL-21 varied among ASST+/SPT+, ASST+/SPT-, ASST-/SPT+ and ASST-/SPT- CSU subgroups, which appeared to involve the positive regulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. CONCLUSION: This study indicates acute urticaria elicits a more prominent Th2 immune response than CSU. There was association between different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines and serum autoreactivity or allergen sensitivity in CSU. Further studies on the JAK-STAT pathway in the pathogenesis of CSU are warranted. PMID- 28846159 TI - Immune deficiency and rosacea. PMID- 28846160 TI - Efficacy of different irrigant protocols and application systems on sealer penetration using a stepwise CLSM analysis. AB - This study compared several irrigation protocols and application systems for sealer penetration into dentinal tubules. Single-rooted-human teeth were divided into 5 experimental groups (n = 15) and a control group (n = 5), according to final irrigation protocols: standard needle irrigation (SNI); Vibringe; Vibringe + NaviTip FX (Vibringe NFX); Endo Spray (ES); and passive-ultrasonic-irrigation (PUI). Following obturation of the root canals, the percentage of the sealer penetration was measured at different depths using stepwise CLSM analysis. The sealer penetration in the experimental groups was significantly higher than the control group at all levels (p < .05). No significant differences were observed between Vibringe and SNI or Vibringe NFX, ES, and PUI at all depths (p > .05). The Vibringe NFX, ES, and PUI groups allowed deeper sealer penetration than SNI at 100, 250, and 500 MUm levels (p < .05). The irrigant activation, the needle design, and the application form (syringe or spray) may impact the quality of the seal that is achieved with root canal filling. PMID- 28846161 TI - Different properties of skin of different body sites: The root of keloid formation? AB - The purpose of this study was to examine extracellular matrix composition, vascularization, and immune cell population of skin sites prone to keloid formation. Keloids remain a complex problem, posing esthetical as well as functional difficulties for those affected. These scars tend to develop at anatomic sites of preference. Mechanical properties of skin vary with anatomic location and depend largely on extracellular matrix composition. These differences in extracellular matrix composition, but also vascularization and resident immune cell populations might play a role in the mechanism of keloid formation. To examine this hypothesis, skin samples of several anatomic locations were taken from 24 human donors within zero to 36 hours after they had deceased. Collagen content and cross-links were determined through high-performance liquid chromatography. The expression of several genes, involved in extracellular matrix production and degradation, was measured by means of real-time PCR. (Immuno)histochemistry was performed to detect fibroblasts, collagen, elastin, blood vessels, Langerhans cells, and macrophages. Properties of skin of keloid predilections sites were compared to properties of skin from other locations (nonpredilection sites [NPS]). The results indicated that there are site specific variations in extracellular matrix properties (collagen and cross-links) as well as macrophage numbers. Moreover, predilection sites (PS) for keloid formation contain larger amounts of collagen compared to NPS, but decreased numbers of macrophages, in particular classically activated CD40 positive macrophages. In conclusion, the altered (histological, protein, and genetic) properties of skin of keloid PS may cause a predisposition for and contribute to keloid formation. PMID- 28846162 TI - Wound healing outcomes: Using big data and a modified intent-to-treat method as a metric for reporting healing rates. AB - Chronic wounds are increasing in prevalence and are a costly problem for the US healthcare system and throughout the world. Typically outcomes studies in the field of wound care have been limited to small clinical trials, comparative effectiveness cohorts and attempts to extrapolate results from claims databases. As a result, outcomes in real world clinical settings may differ from these published studies. This study presents a modified intent-to-treat framework for measuring wound outcomes and measures the consistency of population based outcomes across two distinct settings. In this retrospective observational analysis, we describe the largest to date, cohort of patient wound outcomes derived from 626 hospital based clinics and one academic tertiary care clinic. We present the results of a modified intent-to-treat analysis of wound outcomes as well as demographic and descriptive data. After applying the exclusion criteria, the final analytic sample includes the outcomes from 667,291 wounds in the national sample and 1,788 wounds in the academic sample. We found a consistent modified intent to treat healing rate of 74.6% from the 626 clinics and 77.6% in the academic center. We recommend that a standard modified intent to treat healing rate be used to report wound outcomes to allow for consistency and comparability in measurement across providers, payers and healthcare systems. PMID- 28846164 TI - Cutaneous sporotrichosis treated with methylene blue-daylight photodynamic therapy. PMID- 28846163 TI - Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. AB - BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI treatment-naive patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. RESULTS: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). CONCLUSION: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines. PMID- 28846165 TI - A Trishistidine Pseudopeptide with Ability to Remove Both CuIota and CuIotaIota from the Amyloid-beta Peptide and to Stop the Associated ROS Formation. AB - The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Abeta). Its synthesis and coordination properties for CuIota and CuIotaIota are described. L efficiently complex CuIotaIota in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond. By contrast, CuIota is coordinated in a tetrahedral environment. The redox behavior is irreversible and follows an ECEC mechanism in accordance with the very different environments of the two redox states of the Cu center. This is in line with the observed resistance of the CuIota complex to oxidation by oxygen and the CuIotaIota complex reduction by ascorbate. The affinities of L for CuIotaIota and CuIota at physiological pH are larger than that reported for the Abeta peptide. Therefore, due to its peculiar Cu coordination properties, the ligand L is able to target both redox states of Cu, redox silence them and prevent reactive oxygen species production by the CuAbeta complex. Because reactive oxygen species contribute to the oxidative stress, a key issue in Alzheimer's disease, this ligand thus represents a new strategy in the long route of finding molecular concepts for fighting Alzheimer's disease. PMID- 28846166 TI - Cortisol inhibits CSF2 and CSF3 via DNA methylation and inhibits invasion in first-trimester trophoblast cells. AB - PROBLEM: Heightened maternal stress affects trophoblast function and increases risk for adverse pregnancy outcomes. METHODS OF STUDY: Studies were performed using the first-trimester trophoblast cell line, Sw.71. Cytokines were quantified using qPCR and ELISA. Epigenetic regulation of cytokines was characterized by inhibiting histone deacetylation (1 MUmol/L suberoylanilide hydroxamic acid [SAHA]) or methylation (5 MUmol/L 5-azacytidine), or with chromatin immunoprecipitation (ChIP) with a pan-acetyl histone-3 antibody. Invasion assays used Matrigel chambers. RESULTS: Cortisol inhibited expression of CSF2 (GM-CSF) and CSF3 (G-CSF) in trophoblast cells. Cortisol-associated inhibition was dependent on DNA methylation and was not affected by acetylation. There was also a modest decrease in trophoblast invasion, not dependent on loss of CSFs. CONCLUSION: In first-trimester trophoblast cells, the physiological glucocorticoid, cortisol, inhibited two cytokines with roles in placental development and decreased trophoblast invasion. Cortisol-associated changes in trophoblast function could increase the risk for immune-mediated abortion or other adverse pregnancy outcomes. PMID- 28846167 TI - Chronic urticaria and the metabolic syndrome: a cross-sectional community-based study of 11 261 patients. AB - BACKGROUND: Emerging evidence suggests that chronic urticaria (CU) is associated with chronic, low-grade, inflammatory process. OBJECTIVE: To evaluate the association between CU and metabolic syndrome and its components in a large community-based medical database. METHODS: A cross-sectional study of CU patients and matched controls was performed. CU was defined as eight urticaria diagnoses (with each two diagnoses registered within a period of 6 weeks) from 2002 to 2012. Data regarding the prevalence of metabolic syndrome, its components and possible complications were collected. RESULTS: The study included 11 261 patients with CU and 67 216 controls. In a univariate analysis, CU was significantly associated with higher body mass index (BMI) and a higher prevalence of obesity, diabetes, hyperlipidaemia, hypertension, metabolic syndrome, chronic renal failure and gout. Multivariate analysis demonstrated a significant association between CU and metabolic syndrome (OR = 1.12, 95% CI 1.1 1.2, P < 0.001) and its components - obesity (OR = 1.2, 95% CI 1.1-1.3, P < 0.001), diabetes (OR = 1.08, 95% CI 1.01-1.15, P = 0.001), hyperlipidaemia (OR = 1.2, 95% CI 1.1-1.2, P < 0.001) and hypertension (OR = 1.1, 95% CI 1.1-1.2, P < 0.001). CONCLUSIONS: CU patients may have one or more undiagnosed components of metabolic syndrome despite their young age. Thus, appropriate targeted screening is advised. PMID- 28846168 TI - Water-Enabled Healing of Conducting Polymer Films. AB - The conducting polymer polyethylenedioxythiophene doped with polystyrene sulfonate (PEDOT:PSS) has become one of the most successful organic conductive materials due to its high air stability, high electrical conductivity, and biocompatibility. In recent years, a great deal of attention has been paid to its fundamental physicochemical properties, but its healability has not been explored in depth. This communication reports the first observation of mechanical and electrical healability of PEDOT:PSS thin films. Upon reaching a certain thickness (about 1 um), PEDOT:PSS thin films damaged with a sharp blade can be electrically healed by simply wetting the damaged area with water. The process is rapid, with a response time on the order of 150 ms. Significantly, after being wetted the films are transformed into autonomic self-healing materials without the need of external stimulation. This work reveals a new property of PEDOT:PSS and enables its immediate use in flexible and biocompatible electronics, such as electronic skin and bioimplanted electronics, placing conducting polymers on the front line for healing applications in electronics. PMID- 28846169 TI - Exploring the Charge Transport in Conjugated Polymers. AB - Conjugated polymers came to an unprecedented epoch that the charge transport is limited only by small disorder within aggregated domains. Accurate evaluation of transport performance is thus vital to optimizing further molecule design. Yet, the routine method by means of the conventional field-effect transistors may not satisfy such a requirement. Here, it is shown that the extrinsic effects of Schottky barrier, access transport through semiconductor bulk, and concurrent ambipolar conduction seriously influence transport analysis. The planar transistors incorporating ohmic contacts free of access and ambipolar conduction afford an ideal access to charge transport. It is found, however, that only the planar transistors operating in low-field regime are reliable to explore the inherent transport properties due to the energetic disorder lowering by the lateral field induced by high drain voltage. This work opens up a robust approach to comprehend the delicate charge transport in conjugated polymers so as to develop high-performance semiconducting polymers for promising plastic electronics. PMID- 28846170 TI - Stalk size and altruism investment within and among populations of the social amoeba. AB - Reproductive division of labour is common in many societies, including those of eusocial insects, cooperatively breeding vertebrates, and most forms of multicellularity. However, conflict over what is best for the individual vs. the group can prevent an optimal division of labour from being achieved. In the social amoeba Dictyostelium discoideum, cells aggregate to become multicellular and a fraction behaves altruistically, forming a dead stalk that supports the rest. Theory suggests that intra-organismal conflict over spore-stalk cell fate can drive rapid evolutionary change in allocation traits, leading to polymorphisms within populations or rapid divergence between them. Here, we assess several proxies for stalk size and spore-stalk allocation as metrics of altruism investment among strains and across geographic regions. We observe geographic divergence in stalk height that can be partly explained by differences in multicellular size, as well as variation among strains in clonal spore-stalk allocation, suggesting within-population variation in altruism investment. Analyses of chimeras comprised of strains from the same vs. different populations indicated genotype-by-genotype epistasis, where the morphology of the chimeras deviated significantly from the average morphology of the strains developed clonally. The significantly negative epistasis observed for allopatric pairings suggests that populations are diverging in their spore-stalk allocation behaviours, generating incompatibilities when they encounter one another. Our results demonstrate divergence in microbial social traits across geographically separated populations and demonstrate how quantification of genotype-by-genotype interactions can elucidate the trajectory of social trait evolution in nature. PMID- 28846171 TI - Dermoscopy and the diagnosis of primary cutaneous B-cell lymphoma. AB - BACKGROUND: Primary cutaneous B-cell lymphomas (PCBCLs) are frequently misdiagnosed, and a biopsy is needed to attain the correct diagnosis. OBJECTIVE: To characterize the dermoscopic features of PCBCL. METHODS: In this retrospective observational study, we analysed the pathology reports of 172 newly diagnosed PCBCL for the initial clinical differential diagnosis. The dermoscopic images of 58 PCBCL were evaluated for dermoscopic features. Two dermoscopy experts, who were blinded to the diagnosis and the study objective, evaluated images from 17 cases for a dermoscopic differential diagnosis. RESULTS: Of 172 biopsy-proven PCBCL lesions, cutaneous lymphoma was suspected by the clinician in 16.3%; the leading diagnosis was basal cell carcinoma in 17.4%, and other skin neoplasms in 21%. Studying 58 PCBCL dermoscopic images, we most frequently identified salmon coloured background/area (79.3%) and prominent blood vessels (77.6%), mostly of serpentine (linear-irregular) morphology (67.2%). Dermoscopic features did not differ significantly by subtype or location. Blinded evaluation by dermoscopy experts raised a wide differential diagnosis including PCBCL, arthropod bite, basal cell carcinoma, amelanotic melanoma and scar/keloid. CONCLUSIONS: Two dermoscopic features, salmon-coloured area/background and serpentine vessels, are frequently seen in PCBCL lesions. These characteristic dermoscopic features, although not specific, can suggest a possible diagnosis of PCBCL. PMID- 28846172 TI - Titanocene Silylpropyne Complexes: Promising Intermediates en route to a Four Membered 1-Metallacyclobuta-2,3-diene? AB - Coordination of the alkyl-substituted alkynes Me3 SiC2 CH2 R (1: R=SiMe3 ; 2: R=N(SiMe3 )2 ) to titanocene centres [Cp'2 Ti] (Cp'=Cp, Cp*) yields stable alkyne complexes of the type Cp'2 Ti(eta2 -Me3 SiC2 CH2 R) (3: Cp'=Cp, R=SiMe3 ; 5: Cp'=Cp, R=N(SiMe3 )2 ; 6: Cp'=Cp*, R=SiMe3 ) that are not prone to alkyne/allene isomerisation. When reacting alkyne 2 with Cp*2 TiCl2 and Mg formation of the complex Cp*2 Ti(III)(eta3 -Me3 SiC2 CH2 ) (7) which displays a propargylic unit coordinated to the TiIII centre takes place. All complexes were fully characterised, the molecular structures for 5, 6, and 7 are discussed. PMID- 28846173 TI - Benzodisilacyclobutadienes: 8pi-Electron Systems with an Antiaromatic Silicon Ring. AB - Benzodisilacyclobutadienes 2 a-c were isolated as blue to green crystalline solids from the reaction of stable disilyne 1 and 1,2-dibromobenzenes in the presence of potassium graphite. In the solid state, substantial bond alternation was observed within the benzene rings of 2 a-c. In hexane, 2 a-c showed remarkable bathochromic shifts of the pi->pi* (HOMO->LUMO) absorption bands at 625-670 nm. NMR spectra and theoretical calculations indicated that the diamagnetic ring currents of the benzene rings of 2 a-c are considerably reduced by contributions from the antiaromatic 1,2-disilacyclobutadienes. In their entirety, the obtained results indicate that 2 a-c represent 8pi-electron systems that contain an antiaromatic 1,2-disilacyclobutadiene. PMID- 28846174 TI - Palladium-Catalyzed [3+3] Annulation of Vinyl Chromium(0) Carbene Complexes through Carbene Migratory Insertion/Tsuji-Trost Reaction. AB - Vinyl chromium(0) Fischer carbene complexes were employed as the source of pi allylic palladium species for catalytic [3+3] annulation under palladium catalysis. Mechanistically, this transformation is proposed to involve carbene migratory insertion and intramolecular Tsuji-Trost reaction as the key steps. Substituted six-membered heterocyclic flavonones and quinolines are obtained, depending on the nucleophilic functional group on the coupling partners. PMID- 28846175 TI - Mannequin-based Telesimulation: Increasing Access to Simulation-based Education. AB - A telesimulation platform utilizes communications technology to provide mannequin based simulation education between learners and instructors located remotely from one another. Specifically, the instructor controls the mannequin and moderates the debriefing remotely. During these sessions, the instructor observes the learners in real time and provides immediate feedback during the debriefing. This platform obviates the need to have instructors, learners, and mannequins in the same place at the same time, potentially allowing simulation-based educational sessions to occur with greater frequency for institutions not located proximate to formal simulation centers. Additionally, the telesimulation platform enables an experienced simulation instructor to observe and directly help new simulation instructors at remote simulation locations. Readily available Web-conferencing, screen-sharing software, microphones, and webcams makes telesimulation possible. Mannequin-based telesimulation is relatively new and not well represented in the literature, but could facilitate systems changes, providing educational experiences to health care professionals in locations not currently benefiting from mannequin-based simulation opportunities. Several research questions need to be addressed in future studies to better develop this educational approach, including technical feasibility, logistic issues, a comparison of telesimulation to other simulation approaches, and assessing limitations of the telesimulation platform. PMID- 28846176 TI - The role of ultrasound in appropriate endotracheal tube size selection in pediatric patients. AB - BACKGROUND: The aim of this prospective study was to investigate the success of ultrasound in pediatric patients in determining the appropriate sized cuffed endotracheal tube and to compare the results with conventional height-based (Broselow) tape and age-based formula tube size. METHODS: One hundred and fifty two children of 1-10 years of age, who received general anesthesia for adenotonsillectomy were enrolled to the study. In all participants, the transverse diameter of the subglottis was measured with ultrasound during apnea. An endotracheal tube was chosen with the outer diameter matched to the measured subglottic airway diameter. An age-based (Motoyama-Khine) and height-based (Broselow) endotracheal tube size was calculated. If there was resistance to passage of the tube into the trachea or an airway pressure >25 cmH2 0 was required to detect an audible leak, the endotracheal tube was replaced with internal diameter of 0.5 mm smaller. If there was an audible leak at airway pressure <10 cmH2 O, or peak pressure >25 cmH2 0 or a cuff pressure > 25 cmH2 O was required to seal, the tube was changed to the 0.5 mm larger internal diameter. Best-fit tube internal diameter was the resultant tube internal diameter that met the previously stated conditions. The need for endotracheal tube replacement and peak airway pressure were recorded. RESULTS: The internal diameter of ultrasound determined tube was the same as best-fit tube in 88% of children. Endotracheal tube was replaced in 15 patients with a one size larger, and in three patients with one size smaller tube. Using Bland-Altman analysis, a better agreement was observed with ultrasound measurement rather than height based estimation and age-based formulas. CONCLUSION: Our findings show that subglottic diameter measured by ultrasound appears to be a reliable predictor for the assessment of the subglottic diameter of the airway in estimating appropriate size pediatric endotracheal tube. PMID- 28846177 TI - Malonic Acid Diazoesters for C-H Insertion Crosslinking (CHic) Reactions: A Versatile Method for the Generation of Tailor-Made Surfaces. AB - A simple and versatile method for the modification of a broad spectrum of surfaces with thin polymer films through the thermally or photochemically induced generation of surface-attached polymer networks is reported. The system is based on copolymers containing diazomalonate groups, which can be activated by heat or light. To this end, the copolymers are deposited from solution onto solid substrates by standard techniques of thin-film deposition (spin coating, dip coating). Upon activation the diazomalonate group decomposes and forms a carbene, which induces C-H insertion crosslinking (CHic) reactions. In the course of this process network formation and covalent surface attachment occur at the same time. The crosslinking process proceeds very rapidly, especially when the carbenes generated in the activation process cannot undergo Wolff-rearrangement. The presented system can be used for the generation of a wide range of polymer layers and microstructures on a broad spectrum of surfaces. PMID- 28846178 TI - Lower airway dimensions in pediatric patients-A computed tomography study. AB - BACKGROUND: The aim of this study was to obtain lower airway dimensions in children by means of computed tomography (CT). METHODS: Chest CT scans from 195 pediatric patients (118 boys/77 girls) aged 0.04-15.99 years were analyzed. Tracheal and bronchial lengths, anterior-posterior and lateral diameters, as well as cross-sectional area were assessed at the following levels: mid trachea, right proximal and distal bronchus, proximal bronchus intermedius, and left proximal and distal bronchus. Mediastinal angles of tracheal bifurcation were measured. Data were analyzed by means of linear and polynomial regression plots. RESULTS: The strongest correlations were found between tracheal and bronchial diameters and age as well as between tracheal and bronchial lengths and body length. All measured airway parameters correlated poorly to body weight. Bronchial angles revealed no association with patient's age, body length, or weight. CONCLUSION: This comprehensive anatomical database of lower airway dimensions demonstrates that tracheal and bronchial diameters correlate better to age, and that tracheal and bronchial length correlate better to body length. All measured airway parameters correlated poorly to body weight. PMID- 28846179 TI - "What Do People Do If They Don't Have Insurance?": ED-to-ED Referrals. AB - OBJECTIVE: Up to 20% of patients seen in public emergency departments (EDs) have already been seen for the same complaint at another ED, but little is known about the origin or impact of these duplicate ED visits. The goals of this investigation were to explore 1) whether patients making a repeat ED visit are self-referred or indirectly referred from the other ED and 2) gather the perspective of affected patients on the health, social, and financial consequences of these duplicate ED visits. METHODS: This mixed-methods study conducted over a 10-week period during 2016 in a large public hospital ED in Texas prospectively surveyed patients seen in another ED for the same chief complaint. Selected patients presenting with fractures were then enrolled for semistructured qualitative interviews, which were audiotaped, transcribed, and independently coded by two team members until thematic saturation was reached. RESULTS: A total of 143 patients were identified as being recently seen at another local ED for the same chief complaint prior to presenting to the public hospital; 94% were uninsured and 61% presented with fractures. A total of 27% required admission at the public ED and 95% of those discharged required further outpatient follow-up. Fifty-one percent of patients completed a survey and qualitative interviews were conducted with 23 fracture patients. Fifty-three percent of patients reported that staff at the first hospital told them to go the public hospital ED, and 23% reported referral from a follow-up physician associated with the first hospital. Seventy-three percent reported receiving the same tests at both EDs. Interview themes identified multiple health care visits for the same injury, concern about complications, disrespectful treatment at the first ED, delayed care, problems accessing needed follow-up care without insurance, loss of work, and financial strain. CONCLUSIONS: The majority of patients presenting to a public hospital ED after treatment for the same complaint in another local ED were indirectly referred to the public ED without transferring paperwork or records, incurring duplicate testing and patient anxiety. PMID- 28846181 TI - Impact of behaviors (smoking, treatment adherence, exercise, alcohol) on allograft function and outcomes. PMID- 28846180 TI - Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non-small cell lung cancer cells. AB - The highly selective multi-targeted agent sorafenib is an inhibitor of a number of intracellular signaling kinases with anti-proliferative, anti-angiogenic and pro-apoptotic effects in various types of tumors, including human non-small cell lung cancer (NSCLC). Betulin displays a broad spectrum of biological and pharmacological properties, including anticancer and chemopreventive activity. Combination of drugs with different targets is a logical approach to overcome multilevel cross-stimulation among key signaling pathways in NSCLC progression. NSCLC cell lines, A549, H358 and A427, with different KRAS mutations, and normal human peripheral blood lymphocyte cells, were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of different combined treatments on viability (MTS test), proliferation and apoptotic susceptibility based on flow cytometry, alterations in signaling pathways by western blotting and colony-forming ability. The combination of sorafenib with betulinic acid had a strong effect on the induction of apoptosis of different NSCLC cell lines. In addition, this combination was not toxic for human peripheral blood lymphocytes. Combination treatment changed the expression of proteins involved in the mitochondrial apoptosis pathway and induced apoptotic death by caspase activation. Importantly, combination treatment with low drug concentrations tremendously reduced the colony-forming ability of A549, H358 and A427 cells, as compared to both compounds alone. In this study, we showed that combination therapy with low concentrations of sorafenib and betulinic acid had the capacity to induce high levels of cell death and abolish clonogenic activity in some NSCLC cell lines regardless of KRAS mutations. PMID- 28846182 TI - Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials. AB - The aim of this study was to describe the effects of sodium-glucose co transporter 2 (SGLT2) inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). PubMed, CENTRAL, EMBASE and ClinicalTrials.gov were searched for randomized controlled trials of SGLT2 inhibitors in patients with T2DM up to May 20, 2017. A total of 62 studies, comprising 34 941 patients, were included. Any of the SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, tofogliflozin, luseogliflozin or ipragliflozin) significantly decreased SUA levels compared with control (total weighted mean difference [WMD] 37.73 MUmol/L, 95% CI [-40.51, -34.95]). Treatment with empagliflozin resulted in a superior reduction in SUA (WMD -45.83 MUmol/L, 95% CI [-53.03, -38.63]). The effect persisted during long-term treatment. Dapagliflozin decreased SUA in a dose-dependent manner (from 5 to 50 mg, P = .014). In subgroup analyses, greater reductions could be observed during the course of early diabetes and the SUA lowering effect was abolished in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2 ). The effect of SGLT2 inhibitors on SUA reduction suggests that this class of drugs might be beneficial for diabetic patients with hyperuricaemia. PMID- 28846183 TI - Maximizing donors with viral hepatitis in the current era. PMID- 28846184 TI - Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease. AB - Human Vps13 proteins are associated with several diseases, including the neurodegenerative disorder Chorea-acanthocytosis (ChAc), yet the biology of these proteins is still poorly understood. Studies in Saccharomyces cerevisiae, Dictyostelium discoideum, Tetrahymena thermophila and Drosophila melanogaster point to the involvement of Vps13 in cytoskeleton organization, vesicular trafficking, autophagy, phagocytosis, endocytosis, proteostasis, sporulation and mitochondrial functioning. Recent findings show that yeast Vps13 binds to phosphatidylinositol lipids via 4 different regions and functions at membrane contact sites, enlarging the list of Vps13 functions. This review describes the great potential of simple eukaryotes to decipher disease mechanisms in higher organisms and highlights novel insights into the pathological role of Vps13 towards ChAc. PMID- 28846185 TI - Outcomes and readmissions after transcatheter and surgical aortic valve replacement in patients with cirrhosis: A propensity matched analysis. AB - BACKGROUND: The data on the comparative outcomes and readmissions after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in patients with cirrhosis are limited. We compared mortality, complications, discharge disposition, 30-day readmission rates, length of stay, and cost of hospitalization in cirrhotic patients undergoing TAVR and SAVR. METHODS: The National Inpatient Sample (NIS) and the National Readmission Database (NRD) were used for the study. The International Classification of Diseases-9th version was used to define cohorts of patients undergoing TAVR and SAVR. Patients undergoing concomitant other valve or coronary bypass surgery were excluded. Propensity-score matching was used to compare the outcomes between the groups. RESULTS: From 2012 to 2014, a total of 126 and 157 patients with cirrhosis underwent TAVR and SAVR, respectively. Of the 283 patients, 16 (5.7%) died during the same hospitalization. We found 345 patients with cirrhosis who had undergone an aortic valve replacement (156 with TAVR, and 189 with SAVR) in the 2013 and 2014 NRD. On propensity matching, there were no significant differences between the in-hospital mortality, readmissions, hospitalization costs, and discharges to home within the TAVR and SAVR groups. However, post procedure length of stay (6.3 vs. 10.2 days; P < 0.001) and blood transfusion rates (22% vs. 58%; P < 0.001) were significantly lower in TAVR patients. CONCLUSIONS: Cirrhotic patients undergoing TAVR has high, but similar mortality and 30-day readmission rates when compared to SAVR; however, has shorter length of stay and lower blood transfusion rates. PMID- 28846186 TI - Puccinia coronata f. sp. avenae: a threat to global oat production. AB - : Puccinia coronata f. sp. avenae (Pca) causes crown rust disease in cultivated and wild oat (Avena spp.). The significant yield losses inflicted by this pathogen make crown rust the most devastating disease in the oat industry. Pca is a basidiomycete fungus with an obligate biotrophic lifestyle, and is classified as a typical macrocyclic and heteroecious fungus. The asexual phase in the life cycle of Pca occurs in oat, whereas the sexual phase takes place primarily in Rhamnus species as the alternative host. Epidemics of crown rust happens in areas with warm temperatures (20-25 degrees C) and high humidity. Infection by the pathogen leads to plant lodging and shrivelled grain of poor quality. Disease symptoms: Infection of susceptible oat varieties gives rise to orange-yellow round to oblong uredinia (pustules) containing newly formed urediniospores. Pustules vary in size and can be larger than 5 mm in length. Infection occurs primarily on the surfaces of leaves, although occasional symptoms develop in the oat leaf sheaths and/or floral structures, such as awns. Symptoms in resistant oat varieties vary from flecks to small pustules, typically accompanied by chlorotic halos and/or necrosis. The pycnial and aecial stages are mostly present in the leaves of Rhamnus species, but occasionally symptoms can also be observed in petioles, young stems and floral structures. Aecial structures display a characteristic hypertrophy and can differ in size, occasionally reaching more than 5 mm in diameter. Taxonomy: Pca belongs to the kingdom Fungi, phylum Basidiomycota, class Pucciniomycetes, order Pucciniales and family Pucciniaceae. Host range: Puccinia coronata sensu lato can infect 290 species of grass hosts. Pca is prevalent in all oat-growing regions and, compared with other cereal rusts, displays a broad telial host range. The most common grass hosts of Pca include cultivated hexaploid oat (Avena sativa) and wild relatives, such as bluejoint grass, perennial ryegrass and fescue. Alternative hosts include several species of Rhamnus, with R. cathartica (common buckthorn) as the most important alternative host in Europe and North America. CONTROL: Most crown rust management strategies involve the use of rust-resistant crop varieties and the application of fungicides. The attainment of the durability of resistance against Pca is difficult as it is a highly variable pathogen with a great propensity to overcome the genetic resistance of varieties. Thus, adult plant resistance is often exploited in oat breeding programmes to develop new crown rust-resistant varieties. Useful website: https://www.ars.usda.gov/midwest-area/st-paul mn/cereal-disease-lab/docs/cereal-rusts/race-surveys/. PMID- 28846187 TI - Increased fear learning, spatial learning as well as neophobia in Rgs2-/- mice. AB - Anxiety disorders result from a complex interplay of genetic and environmental factors such as stress. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety. However, there is limited knowledge about the role of Rgs2 in fear learning and reactivity to stress. In this study, Rgs2-/- mice showed increased fear learning, male mice displayed increased contextual and cued fear learning, while females showed selectively enhanced cued fear learning. Male Rgs2-/- mice displayed increased long-term-contextual fear memory, but increased cued fear extinction. Learning in spatial non-aversive paradigms was also increased in Rgs2-/- mice. Female, but not male mice show increased spatial learning in the Barnes maze, while male mice showed enhanced place preference in the IntelliCage, rendering enhanced cognitive function non-specific for aversive stimuli. Consistent with the previous results, Rgs2 deletion resulted in increased innate anxiety, including neophobic behavior expressed as hypolocomotion, in three different tests based on the approach-avoidance conflict. Acute electric foot shock stress provoked hypolocomotion in several exploration-based tests, suggesting fear generalization in both genotypes. Rgs2 deletion was associated with reduced monoaminergic neurotransmitter levels in the hippocampus and prefrontal cortex and disturbed corresponding GPCR expression of the adrenergic, serotonergic, dopaminergic and neuropeptide Y system. Taken together, Rgs2 deletion promotes improved cognitive function as well as increased anxiety-like behavior, but has no effect on acute stress reactivity. These effects may be related to the observed disruption of the monoaminergic systems. PMID- 28846188 TI - Controversies in liver transplantation: A new series for the journal. PMID- 28846189 TI - The mechanisms for lung cancer risk of PM2.5 : Induction of epithelial mesenchymal transition and cancer stem cell properties in human non-small cell lung cancer cells. AB - Fine particulate matter (PM2.5 ) is a major component of air pollutions that are closely associated with increased risk of lung cancer. However, the role of PM2.5 in the etiology of lung cancer is largely unknown. In this study, we performed acute (24 hours) and chronic (five passages) exposure models to investigate the carcinogenetic mechanisms of PM2.5 by targeting the induction of epithelial mesenchymal transition (EMT) and cancer stem cells (CSC) properties in human non small cell lung cancer cell line A549. We found that both acute and chronic PM2.5 exposure enhanced cell migration and invasion, decreased mRNA expression of epithelial markers and increased mRNA expression of mesenchymal markers. Chronic PM2.5 exposure further induced notable EMT morphology and CSC properties, indicating the developing process of cell malignant behaviors from acute to chronic PM2.5 exposure. CSC properties induced by chronic PM2.5 exposure characterized with increased cell-surface markers (CD44, ABCG2), self-renewal genes (SOX2 and OCT4), side population cells and neoplastic capacity. Furthermore, the levels of three stemness-associated microRNAs, Let-7a, miR-16 and miR-34a, were found to be significantly downregulated by chronic PM2.5 exposure, with microarray data analysis from TCGA database showing their lower expression in human lung adenocarcinoma tissues than that in the adjacent normal lung tissues. These data revealed that the induction of EMT and CSC properties were involved in the lung cancer risk of PM2.5 , and implicated CSC properties and related microRNAs as possible biomarkers for carcinogenicity prediction of PM2.5 . PMID- 28846190 TI - Therapeutic effect of cisplatin given with a lymphatic drug delivery system on false-negative metastatic lymph nodes. AB - Systemic administration of drugs into the blood circulation is standard treatment for prevention of metastasis. However, systemic delivery cannot maintain sufficiently high concentrations of anticancer drugs in lymph nodes (LN). Here, we show that giving cisplatin (CDDP) using a lymphatic drug delivery system (LDDS) has the potential to treat false-negative metastatic LN. We found that in MXH10/Mo-lpr/lpr mice, which develop systemic swelling of LN up to 10 mm in diameter, accumulation of indocyanine green (ICG), which has a similar molecular weight to CDDP, in a target LN was greater for lymphatic delivery of ICG than for systemic (i.v.) administration. Furthermore, CDDP administration with a LDDS inhibited tumor growth in false-negative metastatic LN and produced fewer adverse effects than systemically given CDDP. We anticipate that drug delivery using a LDDS will, in time, replace systemic chemotherapy for the treatment of false negative metastatic LN. PMID- 28846191 TI - Rmg8 and Rmg7, wheat genes for resistance to the wheat blast fungus, recognize the same avirulence gene AVR-Rmg8. AB - Rmg8 and Rmg7 are genes for resistance to the wheat blast fungus (Pyricularia oryzae), located on chromosome 2B in hexaploid wheat and chromosome 2A in tetraploid wheat, respectively. AVR-Rmg8, an avirulence gene corresponding to Rmg8, was isolated from a wheat blast isolate through a map-based strategy. The cloned fragment encoded a small protein containing a putative signal peptide. AVR Rmg8 was recognized not only by Rmg8, but also by Rmg7, suggesting that these two resistance genes are equivalent to a single gene from the viewpoint of resistance breeding. PMID- 28846192 TI - Oncoidal granular iron formation in the Mesoarchaean Pongola Supergroup, southern Africa: Textural and geochemical evidence for biological activity during iron deposition. AB - We document the discovery of the first granular iron formation (GIF) of Archaean age and present textural and geochemical results that suggest these formed through microbial iron oxidation. The GIF occurs in the Nconga Formation of the ca. 3.0-2.8 Ga Pongola Supergroup in South Africa and Swaziland. It is interbedded with oxide and silicate facies micritic iron formation (MIF). There is a strong textural control on iron mineralization in the GIF not observed in the associated MIF. The GIF is marked by oncoids with chert cores surrounded by magnetite and calcite rims. These rims show laminated domal textures, similar in appearance to microstromatolites. The GIF is enriched in silica and depleted in Fe relative to the interbedded MIF. Very low Al and trace element contents in the GIF indicate that chemically precipitated chert was reworked above wave base into granules in an environment devoid of siliciclastic input. Microbially mediated iron precipitation resulted in the formation of irregular, domal rims around the chert granules. During storm surges, oncoids were transported and deposited in deeper water environments. Textural features, along with positive delta56 Fe values in magnetite, suggest that iron precipitation occurred through incomplete oxidation of hydrothermal Fe2+ by iron-oxidizing bacteria. The initial Fe3+ oxyhydroxide precipitates were then post-depositionally transformed to magnetite. Comparison of the Fe isotope compositions of the oncoidal GIF with those reported for the interbedded deeper water iron formation (IF) illustrates that the Fe2+ pathways and sources for these units were distinct. It is suggested that the deeper water IF was deposited from the evolved margin of a buoyant Fe2+aq -rich hydrothermal plume distal to its source. In contrast, oncolitic magnetite rims of chert granules were sourced from ambient Fe2+aq -depleted shallow ocean water beyond the plume. PMID- 28846193 TI - Endothelial glycocalyx in health and kidney disease: Rising star or false Dawn? AB - The endothelial glycocalyx is a layer comprised of proteins and carbohydrates on the luminal surface of vascular endothelial cells, thought to have an important role in the health and function of the endothelium. Disrupted by various pathophysiological conditions and linked with clinical outcomes, it is increasingly recognized as an early indicator of endothelial injury and a potential marker of vascular injury. In this review, we discuss current methods of assessment (including novel optical approaches), evidence for its use as a marker of vascular disease and its potential role in relation to microalbuminuria and glomerular endothelial dysfunction. Therapeutic strategies for restoration of the glycocalyx following injury are also explored. PMID- 28846194 TI - Spectrum of biopsy proven renal disease in South Asian children: Two decades at a tropical tertiary care centre. AB - AIM: We report findings from a large single centre paediatric renal biopsy cohort in South Asia. METHODS: We analyzed all renal biopsies performed on children aged <=18 years between 1996 and 2015 at our centre. The clinical characteristics and histological diagnosis pertaining to each case, distribution of renal diseases in children with various clinical presentations, and changes in the pattern of kidney disease during the study period were analyzed. RESULTS: A total of 1740 paediatric kidney biopsies were performed during the study period. The mean age was 12.8 +/- 4.9 years (8 months to 18 years) and the male: female ratio was 1.5:1. The most common indication for renal biopsy was nephrotic syndrome (63.2%) followed by acute nephritic syndrome (13%). Minimal change disease was the most common cause of nephrotic syndrome while endocapillary proliferative glomerulonephritis (65.7% infection related), remained the commonest cause of acute nephritic syndrome. IgA nephropathy was the commonest cause of chronic kidney disease. Contrary to trends in European paediatric cohorts, the frequency of lupus nephritis increased over the two decades of the study, while that of endocapillary proliferative glomerulonephritis did not show any appreciable decline. CONCLUSION: This study provides the largest data on biopsy proven renal disease in children from South Asia published till date and highlights important differences in the spectrum and trends of kidney disease compared to data from other regions. PMID- 28846195 TI - Environmental fate and behaviour of the biocontrol agent Bacillus amyloliquefaciens CPA-8 after preharvest application to stone fruit. AB - BACKGROUND: Bacillus amyloliquefaciens strain CPA-8 has been described as an effective biocontrol agent to control brown rot in stone fruit for both preharvest and postharvest applications. However, no information about the environmental fate and behaviour of this strain under field conditions is available. RESULTS: The dispersion of the CPA-8 application was evaluated using water-sensitive papers, and complete coverage was observed on the leaves of treated trees, while <1% of non-treated tree leaves had CPA-8. CPA-8 persisted on the fruit of treated trees during preharvest and postharvest conditions, while a significant decrease on leaves and weeds was observed 21 days after treatment. On non-treated trees, CPA-8 was detected on leaves until 180 days after treatment, and on weeds, the CPA-8 population was dependent on the distance from the treated trees. A high persistence of CPA-8 was detected on inert materials, such as clothes and gloves worn by handlers and plastic harvesting boxes. More than 99% of the samples with a CPA-8 phenotype were confirmed as CPA-8 using polymerase chain reaction (PCR). CONCLUSION: This work demonstrated a good distribution, persistence and adaptation of the CPA-8 strain to field and postharvest conditions. Monitoring of dispersion and persistence is an excellent tool to determine the time of application and provides valuable information for registering issues. (c) 2017 Society of Chemical Industry. PMID- 28846196 TI - Development of a measure for the assessment of peer-related positive emotional memories. AB - OBJECTIVES: Previous research has demonstrated a link between early experiences of warmth, safeness, and soothing, and positive feelings, health, and well-being outcomes. Although the impact of positive parent-related early relationships and its posterior recall is well documented, research on the recall of warmth and safeness experiences within early peer relationships remains scarce. In fact, it is considered that the protective role of early positive peer relationships deserves intensive research; however, a specific measure that assesses this construct is still to be created. This study describes the development and validation of a new measure designed to assess the recall of early experiences of warmth, safeness, and affection in relation to peers (EMWSS-peers). DESIGN AND METHODS: Distinct samples, comprising individuals of both genders aged between 18 and 68 years old, were used to test the EMWSS-peers factorial structure through principal axis factoring (PAF) and confirmatory factor analysis (CFA), and to examine its psychometric properties. RESULTS: Principal axis factoring's results indicated that the 12-item scale presents a one-factor structure explaining a total of 71.50% of the variance. The CFA confirmed the plausibility of this structure. The EMWSS-peers also presented excellent internal consistency and construct, concurrent, and divergent validities. CONCLUSIONS: The EMWSS-peers seems to be a new avenue for the study of memories of early experiences with friends and colleagues and may entail a relevant contribution to clinical and research fields, particularly for upcoming investigations on the relationship of peer-related affiliative memories with well-being and mental health. PRACTITIONER POINTS: The EMWSS-peers is a specific measure to assess the recall of warmth and safeness in early peer relationships. The EMWSS-peers is a brief, robust, and reliable self-report instrument. The EMWSS-peers presented excellent internal consistency and construct, concurrent, and divergent validities. The EMWSS-peers may open a new avenue for the study of memories of early peer-related experiences, with potential clinical and research implications. PMID- 28846197 TI - Reply. PMID- 28846198 TI - Cysticercosis: Reiterating the role of cytodiagnosis. AB - BACKGROUND: Cysticercosis is a common parasitic infection in many Asian countries. The histopathological features of this parasitic infection are well established, however, the subtle cytological features and their importance in diagnosing this condition need more elaboration. In this case series we have reiterated the role of fine-needle aspiration cytology (FNAC) in the diagnosis of cysticercosis in clinically unsuspected cases, thereby obviating the need for a biopsy. METHODS: Sixteen patients presented with palpable subcutaneous swellings. The clinical diagnosis varied from tubercular/reactive lymphadenitis, lipoma to neurofibromatosis. These patients were subjected to FNAC of the swellings. RESULT: In all 16 cases, a definitive diagnosis of cysticercosis was made on FNAC on the basis of characteristic features like parasite tegument/bladder wall and occasional hooklets. Features suggestive of host reaction were also observed, which included multinucleated giant cells, mixed inflammatory infiltrate with conspicuous eosinophils, histiocytes, and palisading granulomas. These findings were correlated with histopathology and patients were followed up. We noticed spontaneous resolution of the nodules after the FNAC in six patients. CONCLUSION: The cytological diagnosis of cysticercosis is quite straightforward in cases where the actual parasitic structures are identified in the smears. However, in the absence of parasitic fragments, features suggestive of host reaction should alert the cytologist to search for the evidence of cysticercosis in the smear, which can help in early and timely diagnosis and treatment of the disease. We also postulate that injury to certain parts of the larval form during FNAC procedure would result in degeneration of the parasite. PMID- 28846199 TI - Bio-Based Production of Dimethyl Itaconate From Rice Wine Waste-Derived Itaconic Acid. AB - Dimethyl itaconate is an important raw material for copolymerization, but it is not synthesized from itaconic acid by organisms. Moreover, Corynebacterium glutamicum is used as an important industrial host for the production of organic acids, but it does not metabolize itaconic acid. Therefore, the biosynthetic route toward dimethyl itaconate from itaconic acid is highly needed. In this study, a biological procedure for dimethyl itaconate production is developed from rice wine waste-derived itaconic acid using the engineered C. glutamicum strain. The first step is to investigate the effect of the co-overexpression of the codon optimized cis-aconitic acid decarboxylase (CadA*) and a transcriptional regulator of genes involved in acetic acid metabolism (RamA) on itaconic acid production. The second step is to convert itaconic acid into dimethyl itaconate by lipase catalyzed esterification. The CadA* and RamA-overexpressing CG4 strain increases the itaconic acid concentration under N-starvation with glucose and acetic acid compared with the concentration produced in the base mCGXII medium with glucose. Furthermore, the rice wine waste-derived itaconic acid is successfully converted into dimethyl itaconate using lipase from Rhizomucor miehei and a methanol substrate. This study is the first trial for bio-based production of dimethyl itaconate from rice wine waste-derived itaconic acid. PMID- 28846200 TI - Efficiency of the Lung Flute for sputum induction in patients with presumed pulmonary tuberculosis. AB - INTRODUCTION: High quality sputum helps increase the sensitivity of the diagnosis of pulmonary tuberculosis. OBJECTIVES: To evaluate the efficiency of the acoustic device (Lung Flute; LF) in sputum induction compared with the conventional method, hypertonic saline inhalation (HSI). METHODS: In this crossover study, patients with presumed pulmonary tuberculosis submitted 3 consecutive sputa: the first sputum without induction and the second and third ones using LF and HSI. We compared the efficiency of the 2 induction methods. RESULTS: Sixty-four participants were eligible. Thirty-five (54.6%) patients had negative smears on the first sputum without induction. Among those patients, 25.7% and 22.9% patients were smear-positive after using LF and HSI, respectively (P = .001). The positive conversion rate was not significantly different between the methods. The first samples without induction yielded 65.7% positive cultures, whereas 71.4% and 77.1% of the samples from LF and HSI were positive, respectively (P = .284). Similar results were observed in the nucleic acid amplification test [no induction (60.0%), LF (72.0%) and HSI (60.0%); P = .341]. In 29 smear-positive patients on the first sputum without induction, we observed no significant increase in smear grade, culture yield and nucleic acid amplification test positivity with either method. LF tended to induce fewer adverse events; desaturation (3.1% vs 11.1%; P = .082) and throat pain (1.5% vs 9.5%; P = .057). LF showed significantly fewer total adverse events (15.8% vs 34.9%; P = .023). CONCLUSIONS: Our study showed LF had similar sputum induction efficiency to HSI with relatively fewer complications. PMID- 28846201 TI - Identification of a new HLA-B*51:226 allele in a Chinese bone marrow-related donor. AB - HLA-B*51:226 was initially identified in a Chinese-related donor for stem cell transplantation. PMID- 28846202 TI - HLA-A*33:74N, a novel HLA-A*33 variant, identified by sequence-based typing in a Taiwanese individual. AB - A one nucleotide replacement in codon 803 of HLA-A*33:03:01 results in a novel allele, HLA-A*33:74N. PMID- 28846203 TI - Anilines as C-Nucleophiles in Ir-Catalyzed Intramolecular Asymmetric Allylic Substitution Reactions. AB - Anilines generally act as N-nucleophiles in transition-metal-catalyzed allylic substitution reactions. In this paper, a highly enantioselective intramolecular Friedel-Crafts-type allylic alkylation of aniline derivatives was realized by using an iridium catalyst derived from [Ir(cod)Cl]2 and (Ra )-BHPphos. Various tetrahydroisoquinilin-5-amines were obtained in moderate to good yields, excellent enantioselectivity and regioselectivity under mild reaction conditions. BHPphos=N-benzhydryl-N-phenyldinaphthophosphoramidite. PMID- 28846204 TI - Predicting the ability of elderly diabetes patients to acquire the insulin self injection technique based on the number of animal names recalled. AB - AIMS/INTRODUCTION: To our knowledge, no studies have reported that cognitive tests can be used to evaluate whether or not patients can acquire the insulin self-injection technique. We investigated whether or not the number of animal names recalled in 1 min by elderly diabetes patients could be used as a predictor of the patients' ability to acquire the insulin self-injection technique within 1 week. MATERIALS AND METHODS: We enrolled 57 inpatients with type 2 diabetes aged >60 years who were starting insulin therapy. We carried out the Mini-Mental State Examination and verbal fluency tests, which included recalling animal names and common nouns starting with the letters 'a,' 'ka' and 'shi' (Japanese letters). We used 12 checkpoints for insulin self-injection to judge the patients' levels of acquisition of the technique. The most predictive cognitive test was determined by multivariate logistic regression analysis. RESULTS: In the present study, multivariate logistic analysis showed that the number of animal names recalled was the most reliable predictor of the ability to acquire the insulin self injection technique within 1 week. A figure of 11 animal names predicted a successful acquisition, with a sensitivity of 73% and a specificity of 91% being observed (area under the curve 0.87, 95% confidence interval 0.76-0.97, P < 0.01). CONCLUSIONS: The number of animal names recalled in 1 min was the most useful indicator of the ability of elderly diabetes patients to learn to manage insulin self-injection therapy within 1 week. The cut-off value was 11 animal names. PMID- 28846205 TI - Electrolyte Engineering towards Efficient Water Splitting at Mild pH. AB - The development of processes for the conversion of H2 O and CO2 driven by electricity generated by renewable means is essential to achieving sustainable energy and chemical cycles, in which the electrocatalytic oxygen evolution reaction (OER) is one of the bottlenecks. In this study, the influences of the electrolyte molarity and identity on the OER at alkaline to neutral pH were investigated at an appreciable current density of around 10 mA cm-2 , revealing both the clear boundary of reactant switching between H2 O/OH- , owing to the diffusion limitation of OH- , and the substantial contribution of the mass transport of the buffered species in buffered mild-pH conditions. These findings suggest a strategy of electrolyte engineering: tuning the electrolyte properties to maximize the mass-transport flux. The concept is successfully demonstrated for the OER, as well as overall water electrolysis in buffered mild-pH conditions, shedding light on the development of practical solar fuel production systems. PMID- 28846206 TI - Recombinant Domain V of Human Perlecan Is a Bioactive Vascular Proteoglycan. AB - The C-terminal domain V of the extracellular matrix proteoglycan perlecan plays unique and often divergent roles in a number of biological processes, including angiogenesis, vascular cell interactions, wound healing, and autophagy. Recombinant forms of domain V have been proposed as therapeutic agents for the treatment of cancer, stroke, and the development of cardiovascular devices and bioartificial tissues. However, the effect of domain V appears to be related to the differences in domain V structure and function observed in different expression systems and environments and exactly how this occurs is not well understood. In this study, the sequence from amino acid 3626 to 4391 of the perlecan protein core, which includes domain V, is expressed in HEK-293 cells and purified as a secreted product from conditioned media. This recombinant domain V (rDV) is expressed as a proteoglycan decorated with heparan sulfate and chondroitin sulfate chains and supports endothelial cell interactions to the same extent as full-length perlecan. This expression system serves as an important model of recombinant proteoglycan expression, as well as a source of biologically active rDV for therapeutic applications. PMID- 28846208 TI - Issue Information - Editorial Board. PMID- 28846209 TI - Issue Information - ToC. PMID- 28846207 TI - Facile Spray-Pyrolysis Synthesis of Yolk-Shell Earth-Abundant Elemental Nickel Iron-Based Nanohybrid Electrocatalysts for Full Water Splitting. AB - The development of high-activity electrocatalysts for water splitting that comprise only inexpensive, earth-abundant elements is critical but remains a daunting challenge. In this work, yolk-shell Ni3 Fe/Ni3 FeN was prepared by a spray-pyrolysis technique, which could be scaleable. The yolk-shell Ni3 Fe/Ni3 FeN presents excellent catalytic activity for the oxygen evolution reaction (OER) and the hydrogen evolution reaction (HER) with overpotentials of 268 and 166 mV at 10 mA cm-2 , respectively, and bears a prominent electrochemical durability. Overall water splitting with an electrolyzer containing the yolk-shell Ni3 Fe/Ni3 FeN as the cathode and anode only requires a cell voltage of 1.62 V to reach a current density of 10 mA cm-2 . The present research not only introduces a new route for the synthesis of advanced functional electrocatalysts for overall water splitting but also sheds light on their potential commercial applications. PMID- 28846210 TI - Two-Dimensional Calix[4]arene-based Metal-Organic Coordination Networks of Tunable Crystallinity. AB - A flexible and versatile method to fabricate two-dimensional metal-organic coordination networks (MOCNs) by bottom-up self-assembly is described. 2D crystalline layers were formed at the air-water interface, coordinated by ions from the liquid phase, and transferred onto a solid substrate with their crystallinity preserved. By using an inherently three-dimensional amphiphile, namely 25,26,27,28-tetrapropoxycalix[4]arene-5,11,17,23-tetracarboxylic acid, and a copper metal node, large and monocrystalline dendritic MOCN domains were formed. The method described allows for the fabrication of monolayers of tunable crystallinity on liquid and solid substrates. It can be applied to a large range of differently functionalized organic building blocks, also beyond macrocycles, which can be interconnected by diverse metal nodes. PMID- 28846211 TI - Valence Interconversion of Octahedral Nickel(II/III/IV) Centers. AB - Three oxidation states (+2, +3, +4) of an octahedral nickel center were stabilized in a newly prepared RhNiRh trinuclear complex, [Ni{Rh(apt)3 }2 ]n+ (apt=3- aminopropanethiolate), in which the nickel center was bound by six thiolato donors sourced from two redox-inert fac-[RhIII (apt)3 ] octahedral units. The three oxidation states of the octahedral nickel center were fully characterized by single-crystal X-ray crystallography, as well as spectroscopic, electrochemical, and magnetic measurements; all three were interconvertible, and the conversion was accompanied by changes in color, magnetism, and Jahn-Teller distortion. PMID- 28846212 TI - Donation after cardiac death in the hepatocellular carcinoma patient: Same indication? PMID- 28846213 TI - Proteome Dynamics in Biobanked Horse Peripheral Blood Derived Lymphocytes (PBL) with Induced Autoimmune Uveitis. AB - Equine recurrent uveitis is the only spontaneous model for recurrent autoimmune uveitis in humans, where T cells target retinal proteins. Differences between normal and autoaggressive lymphocytes were identified in this study by analyzing peripheral blood derived lymphocytes (PBL) proteomes from the same case with interphotoreceptor retinoid binding protein induced uveitis sampled before (Day 0), during (Day 15), and after uveitic attack (Day 23). Relative protein abundances of PBL were investigated in a quantitative, label-free differential proteome analysis in cells that were kept frozen for 14 years since the initial experiment. Quantitative data could be acquired for 2632 proteins at all three time points. Profound changes (>=2-fold change) in PBL protein abundance were observed when comparing Day 0 with 15, representing acute inflammation (1070 regulated proteins) and Day 0 with 23 (cessation; 1571 regulated). Significant differences applied to proteins with functions in integrin signaling during active uveitis, involving "Erk and pi-3 kinase are necessary for collagen binding in corneal epithelia," "integrins in angiogenesis," and "integrin-linked kinase signaling" pathways. In contrast, at cessation of uveitic attack, significantly changed proteins belonged to pathways of "nongenotropic androgen signaling," "classical complement pathway," and "Amb2 integrin signaling." Several members of respective pathways were earlier shown to be changed in naturally occurring uveitis, underscoring the significance of these findings here and proofing the value of the induced model in mimicking spontaneous autoimmune uveitis. All MS data have been deposited to the ProteomeXchange consortium via the PRIDE partner repository (dataset identifier PXD005580). PMID- 28846214 TI - Identification of a novel allele, HLA-A*02:01:131, by full-length genomic sequencing. AB - The HLA-A*02:01:131 allele differs by a single nucleotide at codon 236 compared with HLA-A*02:01:01:01. PMID- 28846366 TI - Structure, Biosynthesis, and Biological Activity of the Cyclic Lipopeptide Anikasin. AB - The class of cyclic lipopeptide natural products consists of compounds with a diverse range of bioactivities. In this study, we elucidated the structure of the cyclic lipopeptide anikasin using X-ray crystallography, analyzed its biosynthetic gene cluster, and investigated its natural role in the interaction between the producer strain Pseudomonas fluorescens HKI0770 and protozoal predators. These results led to the conclusion that anikasin has dual functionality enabling swarming motility and acting as a niche amoebicide, which effectively inhibits the social amoeba Polysphondylium violaceum and protects the producer strain from protozoal grazing. PMID- 28846368 TI - Novel Approach to the Fabrication of an Alumina-MoS2 Self-Lubricating Composite via the In Situ Synthesis of Nanosized MoS2. AB - The fabrication of a self-lubricating ceramic composite with MoS2 as the solid lubricant is extremely difficult given the high temperature sensitivity of MoS2. In this study, a hydrothermal method was utilized for the in situ synthesis of nanosized-MoS2 in Al2O3 ceramic to fabricate an Al2O3-MoS2 self-lubricating composite. The composite exhibited excellent self-lubricating properties with low friction coefficient and wear rate in a high-vacuum environment because of the efficient formation of self-lubricating films from the finely structured MoS2 in the Al2O3 matrix. The results of this study establish a new approach to the fabrication of self-lubricating ceramic composites with temperature-sensitive solid lubricants. PMID- 28846367 TI - Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway. AB - Colibactin is a genotoxic hybrid nonribosomal peptide/polyketide secondary metabolite produced by various pathogenic and probiotic bacteria residing in the human gut. The presence of colibactin metabolites has been correlated to colorectal cancer formation in several studies. The specific function of many gene products in the colibactin gene cluster can be predicted. However, the role of ClbQ, a type II editing thioesterase, has not been established. The importance of ClbQ has been demonstrated by genetic deletions that abolish colibactin cytotoxic activity, and recent studies suggest an atypical role in releasing pathway intermediates from the assembly line. Here we report the 2.0 A crystal structure and biochemical characterization of ClbQ. Our data reveal that ClbQ exhibits greater catalytic efficiency toward acyl-thioester substrates as compared to precolibactin intermediates and does not discriminate among carrier proteins. Cyclized pyridone-containing colibactins, which are off-pathway derivatives, are not viable substrates for ClbQ, while linear precursors are, supporting a role of ClbQ in facilitating the promiscuous off-loading of premature precolibactin metabolites and novel insights into colibactin biosynthesis. PMID- 28846369 TI - Silk-Silk Interactions between Silkworm Fibroin and Recombinant Spider Silk Fusion Proteins Enable the Construction of Bioactive Materials. AB - Natural silk is easily accessible from silkworms and can be processed into different formats suitable as biomaterials and cell culture matrixes. Recombinant DNA technology enables chemical-free functionalization of partial silk proteins through fusion with peptide motifs and protein domains, but this constitutes a less cost-effective production process. Herein, we show that natural silk fibroin (SF) can be used as a bulk material that can be top-coated with a thin layer of the recombinant spider silk protein 4RepCT in fusion with various bioactive motifs and domains. The coating process is based on a silk assembly to achieve stable interactions between the silk types under mild buffer conditions. The assembly process was studied in real time by quartz crystal microbalance with dissipation. Coatings, electrospun mats, and microporous scaffolds were constructed from Antheraea assama and Bombyx mori SFs. The morphology of the fibroin materials before and after coating with recombinant silk proteins was analyzed by scanning electron microscopy and atomic force microscopy. SF materials coated with various bioactive 4RepCT fusion proteins resulted in directed antibody capture, enzymatic activity, and improved cell attachment and spreading, respectively, compared to pristine SF materials. The herein-described procedure allows a fast and easy route for the construction of bioactive materials. PMID- 28846370 TI - Hydrothermal Synthesis of Highly Dispersed Co3O4 Nanoparticles on Biomass-Derived Nitrogen-Doped Hierarchically Porous Carbon Networks as an Efficient Bifunctional Electrocatalyst for Oxygen Reduction and Evolution Reactions. AB - Developing high-performance bifunctional electrocatalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is of vital importance in energy storage and conversion systems. Herein, we demonstrate a facile hydrothermal synthesis of highly dispersed Co3O4 nanoparticles (NPs) anchored on cattle-bone-derived nitrogen-doped hierarchically porous carbon (NHPC) networks as an efficient ORR/OER bifunctional electrocatalyst. The as-prepared Co3O4/NHPC exhibits a remarkable catalytic activity toward both ORR (outperforming the commercial Pt/C) and OER (comparable with the commercial RuO2 catalyst) in alkaline electrolyte. The superior bifunctional catalytic activity can be ascribed to the large specific surface area (1070 m2 g-1), the well-defined hierarchically porous structure, and the high content of nitrogen doping (4.93 wt %), which synergistically contribute to the homogeneous dispersion of Co3O4 NPs and the enhanced mass transport capability. Moreover, the primary Zn-air battery using the Co3O4/NHPC cathode demonstrates a superior performance with an open circuit potential of 1.39 V, a specific capacity of 795 mA h gZn-1 (at 2 mA cm 2), and a peak power density of 80 mW cm-2. This work delivers a new insight into the design and synthesis of high-performance bifunctional nonprecious metal electrocatalysts for Zn-air battery and other electrochemical devices. PMID- 28846371 TI - Controlled Synthesis of CuInS2/ZnS Nanocubes and Their Sensitive Photoluminescence Response toward Hydrogen Peroxide. AB - We synthesized uniform CuInS2/ZnS nanocubes by adjusting reaction parameters at the ZnS growth stage. Higher temperature and zinc concentration were shown to drive resultant crystals to have cubic morphology, which could be ascribed to the facet-dependent ligand dynamics on the crystal surface and concomitantly preferred directions of crystal growth. It was found that these nanocubes exhibit sensitive responses, as of photoluminescence quenching, toward hydrogen peroxide, compared to pyramid-shaped nanocrystals. The origin of quenching was further analyzed to be the oxidation of thiolate ligands that leaves the quenching center on the surface. It was noted that the quenched photoluminescence could be fully recovered by introducing additional ligand molecules into the system. Being adopted in the shape-controlled crystal growth, the ligand-to-crystal interaction was shown to still govern the interfacial reaction, the oxidation by hydrogen peroxide, of faceted crystals in our system. It turns out that the reactivity at the crystal surface depends on the exposed facets, especially induced by shape control, and the weak ligand-binding nature of the nanocube renders it vulnerable to the surface reaction. PMID- 28846372 TI - AC Measurements Using Organic Electrochemical Transistors for Accurate Sensing. AB - Organic electrochemical transistors (OECTs) have been successfully employed for a variety of applications , especially chemical and biological sensing. Although the device response to analytes can be directly monitored by measuring steady state channel currents of the devices, it is challenging to obtain stable signals with high signal-to-noise ratios. In this work, we developed a novel method for electrochemical sensing by measuring both the transconductance and the phase of the AC channel current for the first time. Then we successfully realized highly sensitive ion strength sensors and dopamine sensors based on the AC method. Our results indicate that the AC method is more sensitive than typical DC methods and can provide more stable data in sensing applications. Considering that the sensors can be conveniently integrated with AC circuits, this technology is expected to find broad applications in the future. PMID- 28846373 TI - Superhelicity Constrains a Localized and R-Loop-Dependent Formation of G Quadruplexes at the Upstream Region of Transcription. AB - Transcription induces formation of intramolecular G-quadruplex structures at the upstream region of a DNA duplex by an upward transmission of negative supercoiling through the DNA. Currently the regulation of such G-quadruplex formation remains unclear. Using plasmid as a model, we demonstrate that while it is the dynamic negative supercoiling generated by a moving RNA polymerase that triggers a formation of a G-quadruplex, the constitutional superhelicity determines the potential and range of the formation of a G-quadruplex by constraining the propagation of the negative supercoiling. G-quadruplex formation is maximal in negatively supercoiled and nearly abolished in relaxed plasmids while being moderate in nicked and linear ones. The formation of a G-quadruplex strongly correlates with the presence of an R-loop. Preventing R-loop formation virtually abolished G-quadruplex formation even in the negatively supercoiled plasmid. Enzymatic action and protein binding that manipulate supercoiling or its propagation all impact the formation of G-quadruplexes. Because chromosomes and plasmids in cells in their natural form are maintained in a supercoiled state, our findings reveal a physical basis that justifies the formation and regulation of G-quadruplexes in vivo. The structural features involved in G-quadruplex formation may all serve as potential targets in clinical and therapeutic applications. PMID- 28846374 TI - Turning Waste Chemicals into Wealth-A New Approach To Synthesize Efficient Cathode Material for an Li-O2 Battery. AB - An Li-O2 battery requires the oxygen-breathing cathode to be highly electronically conductive, rapidly oxygen diffusive, structurally stable, and often times electrocatalytically active. Catalyst-decorated porous carbonaceous materials are the chosen air cathode in this regard. Alternatively, biomass derived carbonaceous materials possess great ability to remove heavy and toxic metal ions from waste, forming a metal-adsorbed porous carbonaceous material. The similar structure between the air cathode and the metal-adsorbed biomass-derived carbon nicely bridges these two irrelevant areas. In this study, we investigated the electrochemical activity of a biochar material Ag-ESB directly synthesized from ethanol sludge residue in a rechargeable aprotic Li-O2 battery. Ag ions were adsorbed from sewage and became Ag nanoparticles with uniform coverage on the biochar surface. The as-prepared material exhibits good electrochemical behavior in battery testing, especially toward the battery efficiency and cyclability. This study provides the possibility of synthetically efficient cathode material by reusing "waste" such as biofuel sludge residue. It is an economically and environmentally friendly approach both for an energy-storage system and for waste recycling. PMID- 28846376 TI - Ultralight and Flexible Polyurethane/Silver Nanowire Nanocomposites with Unidirectional Pores for Highly Effective Electromagnetic Shielding. AB - Flexible waterborne polyurethane (WPU)/silver nanowire (AgNW) nanocomposites with unidirectionally aligned micrometer-sized pores are fabricated using a facile freeze-drying process, and their dimensions, densities, and AgNW contents are easily controllable. The high-aspect-ratio AgNWs are well-dispersed in the nanocomposite cell walls, giving the nanocomposites good compression strength and excellent electrical conductivity even at very low densities. The large conductivity mismatch between the AgNWs and WPU also induces substantial interfacial polarization that benefits the absorption of electromagnetic (EM) waves, whereas the aligned cell walls promote multireflections of the waves in the porous architectures, further facilitating the absorption. The synergistic actions of the AgNWs, WPU, and unidirectionally aligned pores lead to ultrahigh EM shielding performance. The X-band shielding effectiveness (SE) of the nanocomposites is 64 and 20 dB at the densities of merely 45 and 8 mg/cm3, respectively, and ultrahigh surface specific SE of ~1087 dB cm3/(g mm) is achieved with only 0.027 vol % AgNWs, demonstrating that they are promising ultralight, flexible, mechanically robust, high-performance EM shielding materials. PMID- 28846375 TI - Binding of the Microbial Cyclic Tetrapeptide Trapoxin A to the Class I Histone Deacetylase HDAC8. AB - Trapoxin A is a microbial cyclic tetrapeptide that is an essentially irreversible inhibitor of class I histone deacetylases (HDACs). The inhibitory warhead is the alpha,beta-epoxyketone side-chain of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (l-Aoe), which mimics the side-chain of the HDAC substrate acetyl-l-lysine. We now report the crystal structure of the HDAC8-trapoxin A complex at 1.24 A resolution, revealing that the ketone moiety of l-Aoe undergoes nucleophilic attack to form a zinc-bound tetrahedral gem-diolate that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Mass spectrometry, activity measurements, and isothermal titration calorimetry confirm that trapoxin A binds tightly (Kd = 3 +/- 1 nM) and does not covalently modify the enzyme, so the epoxide moiety of l-Aoe remains intact. Comparison of the HDAC8-trapoxin A complex with the HDAC6-HC toxin complex provides new insight regarding the inhibitory potency of l-Aoe-containing natural products against class I and class II HDACs. PMID- 28846377 TI - In Situ XPS Investigation of Transformations at Crystallographically Oriented MoS2 Interfaces. AB - Nanoscale transition-metal dichalcogenide (TMDC) materials, such as MoS2, exhibit promising behavior in next-generation electronics and energy-storage devices. TMDCs have a highly anisotropic crystal structure, with edge sites and basal planes exhibiting different structural, chemical, and electronic properties. In virtually all applications, two-dimensional or bulk TMDCs must be interfaced with other materials (such as electrical contacts in a transistor). The presence of edge sites vs basal planes (i.e., the crystallographic orientation of the TMDC) could influence the chemical and electronic properties of these solid-state interfaces, but such effects are not well understood. Here, we use in situ X-ray photoelectron spectroscopy (XPS) to investigate how the crystallography and structure of MoS2 influence chemical transformations at solid-state interfaces with various other materials. MoS2 materials with controllably aligned crystal structures (horizontal vs vertical orientation of basal planes) were fabricated, and in situ XPS was carried out by sputter-depositing three different materials (Li, Ge, and Ag) onto MoS2 within an XPS instrument while periodically collecting photoelectron spectra; these deposited materials are of interest due to their application in electronic devices or energy storage. The results showed that Li reacts readily with both crystallographic orientations of MoS2 to form metallic Mo and Li2S, while Ag showed very little chemical or electronic interaction with either type of MoS2. In contrast, Ge showed significant chemical interactions with MoS2 basal planes, but only minor chemical changes were observed when Ge contacted MoS2 edge sites. These findings have implications for electronic transport and band alignment at these interfaces, which is of significant interest for a variety of applications. PMID- 28846378 TI - Printable Heterostructured Bioelectronic Interfaces with Enhanced Electrode Reaction Kinetics by Intermicroparticle Network. AB - Printable organic bioelectronics provide a fast and cost-effective approach for the fabrication of novel biodevices, while the general challenge is to achieve optimized reaction kinetics at multiphase boundaries between biomolecules and electrodes. Here, we present an entirely new concept based on a modular approach for the construction of heterostructured bioelectronic interfaces by using tailored functional "biological microparticles" combined with "transducer microparticles" as modular building blocks. This approach offers high versatility for the design and fabrication of bioelectrodes with a variety of forms of interparticle spatial organization, from layered-structures to more advance bulk heterostructured architectures. The heterostructured biocatalytic electrodes delivered twice the reaction rate and a six-fold increase in the effective diffusion kinetics in response to a catalytic model using glucose as the substrate, together with the advantage of shortened diffusion paths for reactants between multiple interparticle junctions and large active particle surface. The consequent benefits of this improved performance combined with the simple means of mass production are of major significance for the emerging printed electronics industry. PMID- 28846379 TI - Chitin Liquid-Crystal-Templated Oxide Semiconductor Aerogels. AB - Chitin nanocrystals have been used as a liquid crystalline template to fabricate layered oxide semiconductor aerogels. Anisotropic chitin liquid crystals are transformed to sponge-like aerogels by hydrothermally cross-linked gelation and lyophilization-induced solidification. The hydrothermal gelation of chitin aqueous suspensions then proceeds with peroxotitanate to form hydrogel composites that recover to form aerogels after freeze-drying. The homogeneous peroxotitanate/chitin composites are calcined to generate freestanding titania aerogels that exhibit the nanostructural integrity of layered chitin template. Our extended investigations show that coassembling chitin nanocrystals with other metal-based precursors also yielded semiconductor aerogels of perovskite BaTiO3 and CuOx nanocrystals. The potential of these materials is great to investigate these chitin sponges for biomedicine and these semiconductor aerogels for photocatalysis, gas sensing, and other applications. Our results present a new aerogel templating method of highly porous, ultralight materials with chitin liquid crystals. PMID- 28846381 TI - Optimization and Changes in the Mode of Proteolytic Turnover of Quantum Dot Peptide Substrate Conjugates through Moderation of Interfacial Adsorption. AB - Enzymes have many important roles in biology and industry, and proteases are one of the most important classes of enzymes. Semiconductor quantum dots (QDs) are attractive materials for developing protease activity probes because of their advantageous physical and optical properties; however, interactions between a protease and a QD conjugated with its substrate can affect the turnover of that substrate. Here, we study the turnover of multivalent QD-peptide substrate conjugates as a function of multiple parameters: (i) the ligand coating on the QD, including dihydrolipoic acid (DHLA), glutathione (GSH), DHLA-poly(ethylene glycol) (DHLA-PEG), and DHLA-zwitterionic sulfobetaine (DHLA-SB); (ii) the identity of the protease, including trypsin, thrombin, and plasmin; and (iii) the number of substrate and nonsubstrate biomacromolecules conjugated per QD. We show that limiting protease adsorption on QDs is critical for optimizing the turnover of conjugated peptide substrates. Protease adsorption is inhibitory, and very strong adsorption leads to an apparent "scooting" mode of activity with limited turnover. In contrast, with weaker adsorption, enhancements in the turnover rate likely result from a "hopping" mode of activity. The putative hopping mode is thought to feature processive turnover of all substrates in multivalent conjugates with a rate-limiting step of diffusion between individual conjugates, and the magnitude of such enhancements increases with decreases in adsorption. Although it was possible to passivate DHLA- and GSH-coated QDs with high densities of conjugated biomacromolecules, the most effective strategy for reducing adsorption was the substitution of these ligands. Whereas passivation incrementally increased turnover, DHLA-PEG and DHLA-SB ligands converted the mode of turnover with plasmin from scooting to hopping and the DHLA-SB enhanced the turnover rates with thrombin and trypsin by approximately an order of magnitude relative to GSH ligands. The new insights from the broad scope of this study provide an important framework for designing optimized QD conjugates as probes and sensors for enzyme activity. PMID- 28846380 TI - Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library. AB - Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D2R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D2R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and beta arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated beta-arrestin recruitment (EC50 = 320 nM, Emax = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed. PMID- 28846382 TI - Rates of CO2 Mineralization in Geological Carbon Storage. AB - Geologic carbon storage (GCS) involves capture and purification of CO2 at industrial emission sources, compression into a supercritical state, and subsequent injection into geologic formations. This process reverses the flow of carbon to the atmosphere with the intention of returning the carbon to long-term geologic storage. Models suggest that most of the injected CO2 will be "trapped" in the subsurface by physical means, but the most risk-free and permanent form of carbon storage is as carbonate minerals (Ca,Mg,Fe)CO3. The transformation of CO2 to carbonate minerals requires supply of the necessary divalent cations by dissolution of silicate minerals. Available data suggest that rates of transformation are highly uncertain and difficult to predict by standard approaches. Here we show that the chemical kinetic observations and experimental results, when they can be reduced to a single cation-release time scale that describes the fractional rate at which cations are released to solution by mineral dissolution, show sufficiently systematic behavior as a function of pH, fluid flow rate, and time that the rates of mineralization can be estimated with reasonable certainty. The rate of mineralization depends on both the abundance (determined by the reservoir rock mineralogy) and the rate at which cations are released from silicate minerals by dissolution into pore fluid that has been acidified with dissolved CO2. Laboratory-measured rates and field observations give values spanning 8 to 10 orders of magnitude, but when they are evaluated in the context of a reservoir-scale reactive transport simulation, this range becomes much smaller. The reservoir scale simulations provide limits on the applicable conditions under which silicate mineral dissolution and subsequent carbonate mineral precipitation are likely to occur (pH 4.5 to 6, fluid flow velocity less than 5 m/year, and 50-100 years or more after the start of injection). These constraints lead to estimates of 200 to 2000 years for conversion of 60-90% of injected CO2 when the reservoir rock has a sufficient volume fraction of divalent cation-bearing silicate minerals and confirms that when reservoir rock mineralogy is not favorable the fraction of CO2 converted to carbonate minerals is minimal over 104 years. A sufficient amount of reactive minerals is typically about 20% by volume. Our approach may allow for rapid evaluation of mineralization potential of subsurface storage reservoirs and illustrates how reservoir scale modeling can be integrated with other observations to address key issues relating to engineering of geologic systems. PMID- 28846383 TI - Mannobiose Binding Induces Changes in Hydrogen Bonding and Protonation States of Acidic Residues in Concanavalin A As Revealed by Neutron Crystallography. AB - Plant lectins are carbohydrate-binding proteins with various biomedical applications. Concanavalin A (Con A) holds promise in treating cancerous tumors. To better understand the Con A carbohydrate binding specificity, we obtained a room-temperature neutron structure of this legume lectin in complex with a disaccharide Manalpha1-2Man, mannobiose. The neutron structure afforded direct visualization of the hydrogen bonding between the protein and ligand, showing that the ligand is able to alter both protonation states and interactions for residues located close to and distant from the binding site. An unprecedented low barrier hydrogen bond was observed forming between the carboxylic side chains of Asp28 and Glu8, with the D atom positioned equidistant from the oxygen atoms having an O...D...O angle of 101.5 degrees . PMID- 28846384 TI - Unraveling the Molecular Requirements for Macroscopic Silk Supercontraction. AB - Spider dragline silk is a protein material that has evolved over millions of years to achieve finely tuned mechanical properties. A less known feature of some dragline silk fibers is that they shrink along the main axis by up to 50% when exposed to high humidity, a phenomenon called supercontraction. This contrasts the typical behavior of many other materials that swell when exposed to humidity. Molecular level details and mechanisms of the supercontraction effect are heavily debated. Here we report a molecular dynamics analysis of supercontraction in Nephila clavipes silk combined with in situ mechanical testing and Raman spectroscopy linking the reorganization of the nanostructure to the polar and charged amino acids in the sequence. We further show in our in silico approach that point mutations of these groups not only suppress the supercontraction effect, but even reverse it, while maintaining the exceptional mechanical properties of the silk material. This work has imminent impact on the design of biomimetic equivalents and recombinant silks for which supercontraction may or may not be a desirable feature. The approach applied is appropriate to explore the effect of point mutations on the overall physical properties of protein based materials. PMID- 28846385 TI - Diels-Alder "Clickable" Biodegradable Nanofibers: Benign Tailoring of Scaffolds for Biomolecular Immobilization and Cell Growth. AB - Biodegradable polymeric nanofibers have emerged as promising candidates for several biomedical applications such as tissue engineering and regenerative medicine. Many of these applications require modification of these nanofibers with small ligands or biomolecules such as peptides and other growth factors, which necessitates functionalization of these materials in mild and benign fashion. This study reports the design, synthesis, and functionalization of such nanofibers and evaluates their application as a cell culture scaffold. Polylactide based copolymers containing furan groups and triethylene glycol (TEG) units as side chains were synthesized using organocatalyzed ring opening polymerization. The furan moiety, an electron rich diene, provides "clickable" handles required for modification of nanofibers since they undergo facile cycloaddition reactions with maleimide-containing small molecules and ligands. The TEG units provide these fibers with hydrophilicity, enhanced biodegradability, and antibiofouling characteristics to minimize nonspecific adsorption. A series of copolymers with varying amounts of TEG units in their side chains were evaluated for fiber formation and antibiofouling characteristics to reveal that an incorporation of 7.5 mol % TEG-based monomer was optimal for nanofibers containing 20 mol % furan units. Facile functionalization of these nanofibers in a selective manner was demonstrated through attachment of a dienophile containing fluorophore, namely, fluorescein maleimide. To show efficient ligand-mediated bioconjugation, nanofibers were functionalized with a maleimide appended biotin, which enabled efficient attachment of the protein, Streptavidin. Importantly, the crucial role played by the TEG-based side chains was evident due to lack of any nonspecific attachment of protein to these nanofibers in the absence of biotin ligand. Furthermore, these nanofibers were conjugated with a cell adhesive cyclic peptide, cRGDfK-maleimide, at room temperature without the need of any additional catalyst. Importantly, comparison of the cell attachment onto nanofibers with and without the peptide demonstrated that fibers appended with the peptides promoted cells to spread nicely and protrude actin filaments for enhanced attachment to the support, whereas the cells on nonfunctionalized nanofibers showed a rounded up morphology with limited cellular spreading. PMID- 28846386 TI - Pressure-Responsive, Surfactant-Free CO2-Based Nanostructured Fluids. AB - Microemulsions are extensively used in advanced material and chemical processing. However, considerable amounts of surfactant are needed for their formulation, which is a drawback due to both economic and ecological reasons. Here, we describe the nanostructuration of recently discovered surfactant-free, carbon dioxide (CO2)-based microemulsion-like systems in a water/organic-solvent/CO2 pressurized ternary mixture. "Water-rich" nanodomains embedded into a "water depleted" matrix have been observed and characterized by the combination of Raman spectroscopy, molecular dynamics simulations, and small-angle neutron scattering. These single-phase fluids show a reversible, pressure-responsive nanostructuration; the "water-rich" nanodomains at a given pressure can be instantaneously degraded/expanded by increasing/decreasing the pressure, resulting in a reversible, rapid, and homogeneous mixing/demixing of their content. This pressure-triggered responsiveness, together with other inherent features of these fluids, such as the absence of any contaminant in the ternary mixture (e.g., surfactant), their spontaneous formation, and their solvation capability (enabling the dissolution of both hydrophobic and hydrophilic molecules), make them appealing complex fluid systems to be used in molecular material processing and in chemical engineering. PMID- 28846387 TI - Correction to Probing Evolution of Twist-Angle-Dependent Interlayer Excitons in MoSe2/WSe2 van der Waals Heterostructures. PMID- 28846388 TI - Affinity-Based Purification of Polyisocyanopeptide Bioconjugates. AB - Water-soluble polyisocyanopeptides (PICs) are a new class of synthetic polymers that mimic natural protein-based filaments. Their unique semiflexible properties combined with a length of several hundred nanometers have recently enabled a number of biomedical applications ranging from tissue engineering to cancer immunotherapy. One crucial step toward the further development of PICs for these applications is the efficient and controlled synthesis and purification of PIC biomolecule conjugates. Considering the large size of PICs and the biomolecules to be conjugated, conjugation reactions do usually not proceed to completion due to steric effects. As a consequence, purification of the reaction mixture is necessary to separate the obtained bioconjugates from unreacted biomolecules. As a direct result of the semiflexible nature of PICs, standard polymer and protein purification methods based on molecular weight have not been successful. Here, we introduce a new affinity-based purification method utilizing biotin as an affinity tag. PICs decorated with a controlled and tunable density of biotin molecules (biotinPICs) were efficiently bound to and eluted from a monoavidin resin in buffered aqueous solution. Using these biotinPICs, two different protein conjugates were synthesized, one carrying the enzyme alkaline phosphatase (PhoA) and the other T-cell activating anti-CD3 antibodies. The resulting biotinPIC protein conjugates were successfully obtained in high purity (>90%) and without any loss of protein activity. The high purity greatly simplifies the analysis of biotinPIC bioconjugates, such as the determination of the average number of biomolecules conjugated per biotinPIC chain. Most importantly, it allows for the direct and straightforward application of the obtained bioconjugates in the desired applications. The new method developed may further be adapted for the purification of other advanced bioconjugates that are difficult to obtain in high purity with the available standard methods. PMID- 28846390 TI - Reversible Regulation of Enzyme Activity by pH-Responsive Encapsulation in DNA Nanocages. AB - Reversible regulation of enzyme activity by chemical and physical stimuli is often achieved by incorporating stimuli-responsive domains in the enzyme of interest. However, this method is suitable for a limited number of enzymes with well-defined structural and conformational changes. In this study, we present a method to encapsulate enzymes in a DNA cage that could transform its conformation depending on the pH, allowing reversible control of the accessibility of the enzyme to the surrounding environment. This enabled us to regulate various properties of the enzyme, such as its resistance to protease-dependent degradation, binding affinity to the corresponding antibody, and most importantly, enzyme activity. Considering that the size and pH responsiveness of the DNA cage can be easily adjusted by the DNA length and sequence, our method provides a broad-impact platform for controlling enzyme functions without modifying the enzyme of interest. PMID- 28846389 TI - Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers. AB - We report herein the first-time exploration of the attachment of well-defined saccharide units onto a synthetic polymer backbone for the inhibition of a glycosidase. More specifically, glycopolymers endowed with heparan sulfate (HS) disaccharides were established to inhibit the glycosidase, heparanase, with an IC50 value in the low nanomolar range (1.05 +/- 0.02 nm), a thousand-fold amplification over its monovalent counterpart. The monomeric moieties of these glycopolymers were designed in silico to manipulate the well-established glycotope of heparanase into an inhitope. Studies concluded that (1) the glycopolymers are hydrolytic stable toward heparanase, (2) longer polymer length provides greater inhibition, and (3) increased local saccharide density (monoantennary vs diantennary) is negligible due to hindered active site of heparanase. Furthermore, HS oligosaccharide and polysaccharide controls illustrate the enhanced potency of a multivalent scaffold. Overall, the results on these studies of the multivalent presentation of saccharides on bottlebrush polymers serve as the platform for the design of potent glycosidase inhibitors and have potential to be applied to other HS-degrading proteins. PMID- 28846391 TI - Quantification of Active Apohemoglobin Heme-Binding Sites via Dicyanohemin Incorporation. AB - Apohemoglobin (apoHb) is produced by removing heme from hemoglobin (Hb). However, preparations of apoHb may contain damaged globins, which render total protein assays inaccurate for active apoHb quantification. Fortunately, apoHb heme binding sites react with heme via the proximal histidine-F8 (His-F8) residue, which can be monitored spectrophotometrically. The bond between the His-F8 residue of apoHb and heme is vital for maintenance of fully functional and cooperative Hb. Additionally, most apoHb drug delivery applications facilitate hydrophobic drug incorporation inside the apoHb hydrophobic heme-binding pocket in which the His-F8 residue resides. This makes the His-F8 residue a proper target for apoHb activity quantification. In this work, dicyanohemin (DCNh), a stable monomeric porphyrin species, was used as a probe molecule to quantify active apoHb through monocyanohemin-His-F8 bond formation. ApoHb activity was quantified via the analysis of the 420 nm equilibrium absorbance of DCNh and apoHb mixtures. His-F8 saturation was determined by the presence of an inflection point from a plot of the 420 nm absorbance of a fixed concentration of apoHb against an increasing DCNh concentration. Various concentrations of a stock apoHb solution were tested to demonstrate the precision of the assay. The accuracy of the assay was assessed via spectral deconvolution, confirming His-F8 saturation at the inflection point. The effect of the heme-binding protein bovine serum albumin and precipitated apoHb on assay sensitivity was not significant. An analysis of the biophysical properties of reconstituted Hb confirmed heme-binding pocket activity. Taken together, this assay provides a simple and reliable method for determination of apoHb activity. PMID- 28846392 TI - London Dispersion Directs On-Surface Self-Assembly of [121]Tetramantane Molecules. AB - London dispersion (LD) acts between all atoms and molecules in nature, but the role of LD interactions in the self-assembly of molecular layers is still poorly understood. In this study, direct visualization of single molecules using atomic force microscopy with CO-functionalized tips revealed the exact adsorption structures of bulky and highly polarizable [121]tetramantane molecules on Au(111) and Cu(111) surfaces. We determined the absolute molecular orientations of the completely sp3-hybridized tetramantanes on metal surfaces. Moreover, we demonstrate how LD drives this on-surface self-assembly of [121]tetramantane hydrocarbons, resulting in the formation of a highly ordered 2D lattice. Our experimental findings were underpinned by a systematic computational study, which allowed us to quantify the energies associated with LD interactions and to analyze intermolecular close contacts and attractions in detail. PMID- 28846394 TI - Two-Dimensional Titanium Nitride (Ti2N) MXene: Synthesis, Characterization, and Potential Application as Surface-Enhanced Raman Scattering Substrate. AB - We report on the synthesis, characterization, and application of Ti2N (MXene), a two-dimensional transition metal nitride of M2X type. Synthesis of nitride-based MXenes (Mn+1Nn) is difficult due to their higher formation energy from Mn+1ANn and poor stability of Mn+1Nn layers in the etchant employed, typically HF. Herein, the selective etching of Al from ternary layered transition metal nitride Ti2AlN (MAX) and intercalation were achieved by immersing the powder in a mixture of potassium fluoride and hydrochloric acid. The multilayered Ti2NTx (T is the surface termination) obtained was sonicated in DMSO and centrifuged to obtain few layered Ti2NTx. MXene formation was verified, and the material was completely characterized by Raman spectroscopy, XRD, XPS, FESEM-EDS, TEM, STM, and AFM techniques. Surface-enhanced Raman scattering (SERS) activity of the synthesized Ti2NTx was investigated by fabricating paper, silicon, and glass-based SERS substrates. A Raman enhancement factor of 1012 was demonstrated using rhodamine 6G as the model compound with 532 nm excitation wavelength. Detection of trace level explosives with a simple paper-based SERS substrate with Ti2N (MXene) as active material was also illustrated. PMID- 28846393 TI - Dual Function Injectable Hydrogel for Controlled Release of Antibiotic and Local Antibacterial Therapy. AB - We present vancomycin-loaded dual-function injectable hydrogel that delivers antibiotic locally suitable for treatment of infections in avascular or necrotic tissues. The syringe-deliverable gels were developed using polydextran aldehyde and an inherently antibacterial polymer N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride along with vancomycin. The antibiotic was primarily encapsulated via reversible imine bonds formed between vancomycin and polydextran aldehyde in the hydrogel which allowed sustained release of vancomycin over an extended period of time in a pH-dependent manner. Being inherently antibacterial, the gels displayed excellent efficacy against bacteria due to dual mode of action (killing bacteria upon contact as well as by releasing antibiotics into surroundings). Upon subcutaneous implantation, the gel was shown to kill methicillin-resistant Staphylococcus aureus (>99.999%) when bacteria were introduced directly into the gel as well as at distal site from the gel in a mice model. These materials thus represent as novel noninvasive drug-delivery device suitable for local antibiotic therapy. PMID- 28846395 TI - Comparative Transcriptomic Analysis in Paddy Rice under Storage and Identification of Differentially Regulated Genes in Response to High Temperature and Humidity. AB - The transcriptomes of paddy rice in response to high temperature and humidity were studied using a high-throughput RNA sequencing approach. Effects of high temperature and humidity on the sucrose and starch contents and alpha/beta amylase activity were also investigated. Results showed that 6876 differentially expressed genes (DEGs) were identified in paddy rice under high temperature and humidity storage. Importantly, 12 DEGs that were downregulated fell into the "starch and sucrose pathway". The quantitative real-time polymerase chain reaction assays indicated that expression of these 12 DEGs was significantly decreased, which was in parallel with the reduced level of enzyme activities and the contents of sucrose and starch in paddy rice stored at high temperature and humidity conditions compared to the control group. Taken together, high temperature and humidity influence the quality of paddy rice at least partially by downregulating the expression of genes encoding sucrose transferases and hydrolases, which might result in the decrease of starch and sucrose contents. PMID- 28846396 TI - Correction to Luminescent Zn(II) Coordination Polymers for Highly Selective Sensing of Cr(III) and Cr(VI) in Water. PMID- 28846397 TI - Gadolinium Doping in Zirconia-Toughened Alumina Systems and Their Structural, Mechanical, and Aging Behavior Repercussions. AB - A series of Gd3+ dopings in zirconia-toughened alumina (ZTA) systems were undertaken to explore the resultant structural, morphological, hydrothermal aging, and mechanical behavior and imaging contrast abilities. The results from the characterization techniques demonstrate the significance of Gd3+ in preserving the structural stability of ZTA systems. ZTA undergoes phase degradation with 10 wt % Gd3+ at 1400 degrees C, while the 100 wt % Gd3+ yields GdAlO3 even at 1200 degrees C. Gd3+ doping at the intermediate level preserves the structural stability of ZTA systems until 1400 degrees C. Gd3+ occupies the ZrO2 lattice, and its gradual accumulation induces tetragonal ZrO2 (t-ZrO2) to cubic ZrO2 (c-ZrO2) phase transition. alpha-Al2O3 crystallizes at 1200 degrees C and remains unperturbed except for its reaction with the free Gd3+ ions to yield GdAlO3. Aging studies and mechanical tests signify the impeccable role of Gd3+ in ZTA systems to resist phase degradation. Further, the imaging contrast ability of ZTA systems due to Gd3+ doping is verified from the in vitro magnetic resonance imaging (MRI) tests. PMID- 28846398 TI - Forgotten and Resurrected Chernovite-(Y): YAsO4 Doped with Eu3+ Ions as a Potential Nanosized Luminophore. AB - In the present work, a precipitation method was employed to prepare nanosized YAsO4 doped with Eu3+ ions. The raw nanomaterials have been thermally treated in a temperature range between 500 and 900 degrees C for 3 h. The XRD analysis demonstrated that the powders were single-phase nanopowders with high crystallite dispersion. Our studies were focused on relating the luminescence properties of the Eu3+ dopant to the nanocrystallite (NC) size. The average NC size varied accordingly between 15 and 45 nm. We have found that the size effect is manifested mainly in the expansion of the cell volume and broadening of XRD peaks, as indicated by Rietveld analysis. Moreover, the emission and excitation spectra, although typical for Eu3+ ions, demonstrated some degree of variability with calcination temperatures and doping concentration. To explain these differences, a detailed analysis of luminescence spectra by the Judd-Ofelt theory has been performed. PMID- 28846399 TI - Synthesis of Azobenzenes Using N-Chlorosuccinimide and 1,8 Diazabicyclo[5.4.0]undec-7-ene (DBU). AB - A convenient method for the synthesis of symmetrical azobenzenes is reported. This one-step procedure involves treatment of anilines with N-chlorosuccinimide (NCS) and organic base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). A wide range of commercially available substituted anilines readily participate in this reaction to produce the corresponding azobenzenes in moderate-to-excellent yields in minutes. PMID- 28846400 TI - A Dense I1O3 Hybrid Superhydrophobic Network, Pb(H-BTMB), Exhibits Selectivity toward CO2 Gas Sorption. AB - We achieved a dense I1O3 hybrid superhydrophobic porous coordination polymer (PCP), [Pb(H-BTMB)(DMF)] (1), by solvothermal methods. The single-crystal XRD structure of 1 indicated that it has a three-dimensional M-L-M framework with one dimensional M-O-M connectivity leading to an I1O3 network. The new PCP obtained exhibited open metal sites (OMSs) by losing a coordinated DMF molecule. The degassed phase displayed selective adsorption of CO2 gas over N2, C2H6, and C2H4 gases. Additionally, it has a superhydrophobic surface with a contact angle of 156.4 degrees at room temperature and it is stable even at 90 degrees C, displaying a contact angle of 135.3 degrees . PMID- 28846401 TI - Novel Three-Dimensional Semiconducting Materials Based on Hybrid d10 Transition Metal Halogenides as Visible Light-Driven Photocatalysts. AB - The development of new visible light-driven photocatalysts based on semiconducting materials remains a greatly interesting and challenging task for the purpose of solving the energy crisis and environmental issues. By using photosensitive [(Me)2-2,2'-bipy]2+ (1,1'-dimethyl-2,2'-bipyridinium) cation as template, we synthesized one new type of inorganic-organic hybrid cuprous and silver halogenides of [(Me)2-2,2'-bipy]M8X10 (M = Cu, Ag, X = Br, I). The compounds feature a three-dimensional anionic [M8X10]2- network composed of a one dimensional [M8X12] chain based on MX4 tetrahedral units. The photosensitization of organic cationic templates results in narrow band gaps of hybrid compounds (1.66-2.06 eV), which feature stable visible light-driven photodegradation activities for organic pollutants. A detailed study of the photocatalytic mechanism, including the photoelectric response, photoluminescence spectra, and theoretical calculations, shows that the organic cationic template effectively inhibits the recombination of photoinduced electron-hole pairs leading to excellent photocatalytic activities and photochemical stabilities. PMID- 28846402 TI - Revisiting the Si-Te System: SiTe2 Finally Found by Means of Experimental and Quantum-Chemical Techniques. AB - Through explorations of the silicon-tellurium system we identified the extremely air-sensitive, red Si1.67(4)Te3=Si1.11(3)Te2 that is a silicon-deficient relative of the previously reported Si2Te3. The crystal structure features hexagonal closest packed layers of tellurium atoms with disordered [Si2] dumbbells residing in about 50% of the octahedra of every second layer enclosed by the tellurium atoms. In addition to the determination of the crystal structure for this silicon telluride, we probed the opportunity of the existence of a SiTe2 adopting the Si2Te3-structure by means of quantum chemical techniques. The investigations of the electronic structures and a subsequent chemical bonding analysis based on the projected Crystal Orbital Hamilton Population (pCOHP) technique for two "SiTe2" models revealed a tendency to align the [Si2] dumbbells parallel to the c axis to maximize Si-Te bonding. However, the disorder of the [Si2] dumbbells appears to be a consequence of non-equilibrium condensation into the solid state. PMID- 28846403 TI - A Robust Pentacoordinated Iron(II) Proton Reduction Catalyst Stabilized by a Tripodal Phosphine. AB - A pentacoordinated triphosphine benzenedithiolatoiron(II) complex containing a vacant site for binding has been prepared and characterized. The complex is found to be a robust proton reduction catalyst with an overpotential of 0.56 V and a turnover frequency of 2900 s-1 with respect to 0.28 M acetic acid as the proton source. A mechanism describing the electroproton reduction process has been proposed. PMID- 28846404 TI - Synthesis, Crystal Structure, and Luminescence Properties of Tunable Red-Emitting Nitride Solid Solutions (Ca1-xSrx)16Si17N34:Eu2+ for White LEDs. AB - A series of nitride solid solutions (Ca1-xSrx)16Si17N34:0.03Eu2+ were successfully synthesized through the conventional solid-state method. The electronic crystal structure and photoluminescence characteristics were studied in detail. The excitation in the near-ultraviolet and blue regions of the samples shows a broad band in the 250-550 nm range, which can match well with the n-UV and blue lighting-emitting diode chips. Partial substitution of Ca2+ by Sr2+ results in a redshift emission, and the impacts of Sr content on the luminescence were researched in detail. Under 410 nm excitation, the phosphor exhibited tunable red emission from 616 to 653 nm by changing the concentration of Sr2+. Based on the crystal data, the emission can be fitted into three distinguished Gaussian components, which are attributed to the different Eu2+ luminescence centers occupied in three disparate Ca2+ (Sr2+) lattice sites. The temperature quenching property of the phosphor was also investigated, and the good thermal stability of the phosphors was analyzed through the activation energy for thermal quenching. And the obtained CCT values from 2642 to 2817 K are suitable for a warm white light region. All the results indicated that the phosphors have possible application in the warm white light-emitting diodes. PMID- 28846405 TI - Mechanisms for Increasing the pH Buffering Capacity of an Acidic Ultisol by Crop Residue-Derived Biochars. AB - The effects and underlying mechanisms of crop residue-derived biochars on the pH buffering capacity (pHbuff) of an acidic Ultisol, with low pHbuff, were investigated through indoor incubation and simulated acidification experiments. The incorporation of biochars significantly increased soil pHbuff with the magnitude of the increase dependent on acid buffering capacity of the biochar incorporated to the soil. Cation release, resulting from the protonation of carboxyl groups on biochar surfaces and the dissolution of carbonates, was the predominant mechanism responsible for the increase in soil pHbuff at pH 4.0-7.0 and accounted for >67% of the increased pHbuff. The reaction of protons with soluble silica (Si) in biochars derived from rice straw and corn stover also accounted for ~20% of the pHbuff increase due to H3SiO4- precipitation. In conclusion, the incorporation of crop residue-derived biochars into acidic soils increased soil pHbuff with peanut stover biochar being the most effective biochar tested. PMID- 28846406 TI - Ball and Socket Assembly of Binary Superatomic Solids Containing Trinuclear Nickel Cluster Cations and Fulleride Anions. AB - The superlattice structures of hierarchical cluster solids are dictated by short range interactions between constituent building blocks. Here we show that shape complementary sites, as well as halogen and chalcogen bonding between exposed capping ligands and fullerides, govern the packing arrangement of the resulting binary solids. Four new superatomic solids, [Ni3(MU3-I)2(MU2-dppm)3+](C60*-) (1.C60), [Ni3(MU3-I)2(MU2-dppm)3+](C70-)2 (1.C70), [Ni3(MU3-Te)2(MU2 dppm)3+](C60*-) (2.C60), and [Ni3(MU3-Te)2(MU2-dppm)3](C70-)2 (2.C70), (dppm = Ph2PCH2PPh2) were prepared and crystallized from solution. All four compounds were characterized by single crystal X-ray diffraction, IR spectroscopy, and SQUID magnetometry. Charge transfer between the molecular clusters is confirmed via optical spectroscopy and structural data. Compounds 1.C60 and 2.C60 are paramagnetic and 100 times more conductive than the constituent cluster precursors. The obtained solids exhibit close contacts, indicative of halogen/chalcogen bonds, between the fulleride anions and the nickel cluster capping ligands (I/Te) in the solid-state. PMID- 28846408 TI - Michael Additions Involving Amino Acid Esters with Alkenyl N-Heterocycles. AB - Michael addition has been achieved with a variety of amino acid esters and 2- or 4-vinylpyridine. Similar reactions were accomplished with an alkenyl-substituted pyrimidine, pyrazine, thiazole, quinoxaline, benzoxazole, and quinolone. In reactions at a prochiral center, modest diastereoselectivities were observed with the formation of the new stereogenic carbon. NMR experiments indicate that the addition reaction is reversible under acidic conditions. PMID- 28846407 TI - Monofunctional BODIPY-Appended Imidazoplatin for Cellular Imaging and Mitochondria-Targeted Photocytotoxicity. AB - Monofunctional platinum(II) complexes of formulation cis-[Pt(NH3)2(L)Cl](NO3), where L is an imidazole base conjugated to 4,4-difluoro-4-bora-3a,4a-diaza-s indacene (BODIPY) with emissive (L1 in 1) and nonemissive (L2 in 2) moieties were prepared and characterized, and their singlet oxygen-mediated photoinduced cytotoxicity was studied. The 1-methylimidazole (1-MeIm) complex 3 was prepared as a control and for structural characterization by X-ray crystallography. Complexes 1 and 2 showed strong visible absorption bands at 500 nm (epsilon = 2.7 * 104 M-1 cm-1) and 540 nm (1.4 * 104 M-1 cm-1). Complex 1 is emissive with a band at 510 nm (PhiF = 0.09) in 1% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (pH 7.2). Singlet oxygen generation upon photoirradiation with visible light (400-700 nm) was evidenced from 1,3-diphenylisobenzofuran titration experiments showing significant photosensitizing ability of the BODIPY complexes. Both 1 and 2 were remarkably photocytotoxic in visible light (400-700 nm, 10 J cm 2) in skin keratinocyte HaCaT and breast cancer MCF-7 cells giving IC50 values in nanomolar concentration. The complexes were, however, essentially nontoxic to the cells in the dark (IC50 > 80 MUM). Complex 2 having a diiodo-BODIPY unit is nonemissive but an efficient photosensitizer with high singlet oxygen generation ability in visible light (400-700 nm). Confocal microscopy using the emissive complex 1 showed significant mitochondrial localization of the complex. Cell death via apoptotic pathway was observed from the Annexin-V-FITC/PI assay. The formation of Pt-DNA adducts was evidenced from the binding experiments of the complexes 1 and 2 with 9-ethylguanine as a model nucleobase from 1H NMR and mass spectral studies. PMID- 28846409 TI - Nitazoxanide Analogs Require Nitroreduction for Antimicrobial Activity in Mycobacterium smegmatis. AB - In this study, we aimed to decipher the natural resistance mechanisms of mycobacteria against novel compounds isolated by whole-cell-based high-throughput screening (HTS). We identified active compounds using Mycobacterium aurum. Further analyses were performed to determine the resistance mechanism of M. smegmatis against one hit, 3-bromo-N-(5-nitrothiazol-2-yl)-4-propoxybenzamide (3), which turned out to be an analog of the drug nitazoxanide (1). We found that the repression of the gene nfnB coding for the nitroreductase NfnB was responsible for the natural resistance of M. smegmatis against 3. The overexpression of nfnB resulted in sensitivity of M. smegmatis to 3. This compound must be metabolized into hydroxylamine intermediate for exhibiting antibacterial activity. Thus, we describe, for the first time, the activity of a mycobacterial nitroreductase against 1 analogs, highlighting the differences in the metabolism of nitro compounds among mycobacterial species and emphasizing the potential of nitro drugs as antibacterials in various bacterial species. PMID- 28846411 TI - Rationalization of Benzazole-2-carboxylate versus Benzazine-3-one/Benzazine-2,3 dione Selectivity Switch during Cyclocondensation of 2 Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium. AB - The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. On the other hand, the reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chemical calculations (density functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates versus benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier. PMID- 28846410 TI - Prion Peptides Are Extremely Sensitive to Copper Induced Oxidative Stress. AB - Copper(II) binding to prion peptides does not prevent Cu redox cycling and formation of reactive oxygen species (ROS) in the presence of reducing agents. The toxic effects of these species are exacerbated in the presence of catecholamines, indicating that dysfunction of catecholamine vesicular sequestration or recovery after synaptic release is a dangerous amplifier of Cu induced oxidative stress. Cu bound to prion peptides including the high affinity site involving histidines adjacent to the octarepeats exhibits marked catalytic activity toward dopamine and 4-methylcatechol. The resulting quinone oxidation products undergo parallel oligomerization and endogenous peptide modification yielding catechol adducts at the histidine binding ligands. These modifications add to the more common oxidation of Met and His residues produced by ROS. Derivatization of Cu-prion peptides is much faster than that undergone by Cu-beta amyloid and Cu-alpha-synuclein complexes in the same conditions. PMID- 28846412 TI - Biotransformation of the Flame Retardant 1,2-Dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH) in Vitro by Human Liver Microsomes. AB - The technical mixture of 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH or DBE-DBCH) and the pure beta-TBECH isomer were subjected to in vitro biotransformation by human liver microsomes (HLM). After 60 min of incubation, 5 potential metabolites of TBECH were identified in microsomal assays of both the TBECH mixture and beta-TBECH using ultraperformance liquid chromatography-Q Exactive Orbitrap mass spectrometry. These include mono- and dihydroxylated TBECH and mono- and dihydroxylated TriBECH as well as an alpha-oxidation metabolite bromo-(1,2-dibromocyclohexyl)-acetic acid. Our results indicate potential hepatic biotransformation of TBECH via cyctochrome P450-catalyzed hydroxylation, debromination, and alpha-oxidation. Kinetic studies revealed that the formation of monohydroxy-TBECH, dihydroxy-TBECH, and monohydroxy-TriBECH were best fitted to a Michaelis-Menten enzyme kinetic model. Respective estimated Vmax values (maximum metabolic rate) for these metabolites were 11.8 +/- 4, 0.6 +/- 0.1, and 10.1 +/- 0.8 pmol min-1 mg protein-1 in TBECH mixture and 4992 +/- 1340, 14.1 +/- 4.9, and 66.1 +/- 7.3 pmol min-1 mg protein-1 in beta-TBECH. This indicates monohydroxy-TBECH as the major metabolite of TBECH by in vitro HLM-based assay. The estimated in vitro intrinsic clearance (Clint) of TBECH mixture was slower (P < 0.05) than that of pure beta-TBECH. While the formation of monohydroxy-TBECH may reduce the bioaccumulation potential and provide a useful biomarker for monitoring TBECH exposure, further studies are required to fully understand the levels and toxicological implications of the identified metabolites. PMID- 28846413 TI - Conformational Control of Ultrafast Molecular Rotor Property: Tuning Viscosity Sensing Efficiency by Twist Angle Variation. AB - Fluorescent molecular rotors find widespread application in sensing and imaging of microscopic viscosity in complex chemical and biological media. Development of viscosity-sensitive ultrafast molecular rotor (UMR) relies upon the understanding of the excited-state dynamics and their implications for viscosity-dependent fluorescence signaling. Unraveling the structure-property relationship of UMR behavior is of significance toward development of an ultrasensitive fluorescence microviscosity sensor. Herein we show that the ground-state equilibrium conformation has an important role in the ultrafast twisting dynamics of UMRs and consequent viscosity sensing efficiency. Synthesis, photophysics, and ultrafast spectroscopic experiments in conjunction with quantum chemical calculation of a series of UMRs based on dimethylaniline donor and benzimidazolium acceptor with predefined ground-state torsion angle led us to unravel that the ultrafast torsional dynamics around the bond connecting donor and acceptor groups profoundly influences the molecular rotor efficiency. This is the first experimental demonstration of conformational control of small-molecule-based UMR efficiencies which can have wider implication toward development of fluorescence sensors based on the UMR principle. Conformation-controlled UMR efficiency has been shown to exhibit commensurate fluorescence enhancement upon DNA binding. PMID- 28846414 TI - Zero-Magnetic-Field Splitting in the Excited Triplet States of Octahedral Hexanuclear Molybdenum(II) Clusters: [{Mo6X8}(n-C3F7COO)6]2- (X = Cl, Br, or I). AB - Temperature (T)-dependent emission from [{Mo6X8}(n-C3F7COO)6]2- (X = Cl (1), Br (2), and I (3)) in optically transparent polyethylene glycol dimethacrylate matrices were studied in 3 K < T < 300 K to elucidate the spectroscopic and photophysical properties of the clusters, in special reference to zero-magnetic field splitting (zfs) in the lowest-energy excited triplet states (T1) of the clusters. The cluster complexes 1 and 2 showed the T-dependent emission characteristics similar to those of [{Mo6Cl8}Cl6]2-, while 3 exhibited emission properties different completely from those of 1 and 2. Such T-dependent emission characteristics of 1, 2, and 3 were explained successfully by the excited triplet state spin-sublevel (Phin, n = 1-4) model. The zfs energies between the lowest energy (Phi1) and highest-energy (Phi4) spin sublevels, DeltaE14, resulted by the first-order spin-orbit coupling, were evaluated to be 650, 720, and 1000 cm-1 for 1, 2, and 3, respectively. The emission spectra of 1, 2, and 3 in CH3CN at 298 K were reproduced very well by the DeltaE14 values and the population percentages of Phin at 300 K. We also report that the DeltaE14 values of the clusters correlate linearly with the fourth power of the atomic number (Z) of X: DeltaE14 ? {Z(X)}4. PMID- 28846415 TI - Hydration Control Through Intramolecular Degrees of Freedom: Molecular Dynamics of [Cu(II)(Imidazole)4]. AB - Structural characterization of the copper-coordination shell is important in catalysis and biology. Cu-containing domains are prevalent in biological systems and play important roles in oxidation and electron transport process. Here, the solution structure, solvent organization, and dynamics around aqueous [Cu(II)(Imidazole)4] were characterized using atomistic simulations. Asymmetric axial water coordination around the metal atom was found which agrees with results from Minuit X-ray absorption near-edge structure (MXAN) experiments. The simulations reveal that exchange of the axial water occurs on the 25 to 50 ps time scale and is facilitated by and coupled to the flexibility of the copper-out of plane motion relative to the nitrogen atoms. Both concerted and stepwise water exchange of the two axially coordinated water molecules with first-shell water molecules are observed. The results suggest that axial access of a copper center can be fine-tuned by the degree of flexibility of its first coordination sphere. PMID- 28846416 TI - Observing the Electrochemical Oxidation of Co Metal at the Solid/Liquid Interface Using Ambient Pressure X-ray Photoelectron Spectroscopy. AB - Recent advances of ambient pressure X-ray photoelectron spectroscopy (AP-XPS) have enabled the chemical composition and the electrical potential profile at a liquid/electrode interface under electrochemical reaction conditions to be directly probed. In this work, we apply this operando technique to study the surface chemical composition evolution on a Co metal electrode in 0.1 M KOH aqueous solution under various electrical biases. It is found that an ~12.2 nm thick layer of Co(OH)2 forms at a potential of about -0.4 VAg/AgCl, and upon increasing the anodic potential to about +0.4 VAg/AgCl, this layer is partially oxidized into cobalt oxyhydroxide (CoOOH). A CoOOH/Co(OH)2 mixture layer is formed on the top of the electrode surface. Finally, the oxidized surface layer can be reduced to Co0 at a cathodic potential of -1.35 VAg/Cl. These observations indicate that the ultrathin layer containing cobalt oxyhydroxide is the active phase for oxygen evolution reaction (OER) on a Co electrode in an alkaline electrolyte, consistent with previous studies. PMID- 28846417 TI - Interaction between Charged Cylinders in Electrolyte Solution; Excluded Volume Effect. AB - Electrostatic interactions govern the physical properties of charged cylindrical structures in electrolyte solutions. Besides the surface charge on the cylinders, another factor influencing the electrostatic interactions are the mobile ions. The finite size of the mobile ions is included by the excluded volume effect within the lattice statistics, while the electrostatic interactions are considered by means of the mean electrostatic field. In this article we consider charged parallel cylinders embedded into an electrolyte solution of mobile monovalent ions. A modified nonlinear Poisson-Boltzmann equation is proposed via variational procedure, and we implement the finite element method to solve it numerically. Excluded volume effect of the system containing two and multiple charged parallel cylinders are taken into account. Numerical results show that the excluded volume effect decreases the concentration of counterion and increases the electrostatic potential near the charged cylinders. The angular distribution of counterion around the particular cylinder is asymmetric. The study of the electrostatic interaction between two parallel equally charged cylinders reveals that an increase in the free energy is seen when the ionic strength is decreased. The free energy decreases as a function of the cylinders separation distance. On the contrary for two oppositely charged cylinders, the free energy increases with increasing cylinder separation distance, while for two cylinders with different charged density it shows nonmonotonic variation with the increasing cylinders separation distance. PMID- 28846418 TI - Observation of Morphology and Structure Evolution during Gelation of a Bis(Anhydrazide) Derivative. AB - A new bis(anhydrazide) derivative containing cyclohexyl terminal groups (compound 1) was synthesized, and its gelation process was investigated. Compound 1 showed both thermal-induced gelation (T-gel) and sonication-induced gelation (S-gel) in alcohols. We investigated the gelation process of compound 1 in ethanol by different techniques. It was demonstrated that gelator 1 in ethanol underwent a transition from a clear solution through a turbid suspension to an opaque gel. Scanning electron microscopy (SEM) observations indicated that the turbid suspension consisted of separated clew-like spheres, connected spheres, and short nanorods, whereas the opaque gel consisted of fibers or bundles of fiber networks. Molecules packed loosely into an unknown phase in the spheres, whereas they packed tightly into a hexagonal columnar phase with a = 1.62 nm in the fibers. Intermolecular H-bonding between -C?O and -N-H was revealed to be the driving force for gelation, and the strength of the H-bonding became stronger in the fibers than in the spheres. We propose that the gel of compound 1 in ethanol consisting of fibers is a stable phase compared to the turbid suspension consisting of spheres or short nanorods, which is considered to be metastable. The kinetics of gelation of gelator 1 in ethanol under sonication suggest that the gelation process is a two-stage kinetic pathway with fractal values of 1.27 and 0.84. Our study hence provides new insights into the formation of fibers and the structural evolution of the gelation process and can be exploited to achieve a detailed understanding of gels. PMID- 28846419 TI - Asymmetric Synthesis of Glutamic Acid Derivatives by Silver-Catalyzed Conjugate Addition-Elimination Reactions. AB - The enantioselective construction of a family of chiral glycine-derived aldimino esters is described. The asymmetric tandem conjugate addition-elimination procedure is characterized by its exceptional mild reaction conditions and features with an exquisite enantioselectivity profile using commercially available silver/DTBM-SegPhos catalyst, allowing for the facile preparation of a variety of substituted and chiral glutamic acid derivatives (up to 99% ee) bearing Schiff base in a straightforward manner. PMID- 28846420 TI - Rh(II)-Catalyzed Cyclopropanation of Furans and Its Application to the Total Synthesis of Natural Product Derivatives. AB - Rh(II)-catalyzed enantioselective cyclopropanations of furans, providing access to synthetically useful building blocks, are reported. After screening of 10 Rh(II) catalysts, Rh2(S-TCPTTL)4 was identified as a highly efficient and selective catalyst (up to 98% ee, TON 88000, and TOF 24/s) for the cyclopropanation of furans. These cyclopropanes were successfully applied to the enantioselective synthesis of novel paraconic acid derivatives. PMID- 28846421 TI - Operando Spectroscopic Analysis of CoP Films Electrocatalyzing the Hydrogen Evolution Reaction. AB - Transition metal phosphides exhibit high catalytic activity toward the electrochemical hydrogen-evolution reaction (HER) and resist chemical corrosion in acidic solutions. For example, an electrodeposited CoP catalyst exhibited an overpotential, eta, of -eta < 100 mV at a current density of -10 mA cm-2 in 0.500 M H2SO4(aq). To obtain a chemical description of the material as-prepared and also while effecting the HER in acidic media, such electrocatalyst films were investigated using Raman spectroscopy and X-ray absorption spectroscopy both ex situ as well as under in situ and operando conditions in 0.500 M H2SO4(aq). Ex situ analysis using the tandem spectroscopies indicated the presence of multiple ordered and disordered phases that contained both near-zerovalent and oxidized Co species, in addition to reduced and oxygenated P species. Operando analysis indicated that the active electrocatalyst was primarily amorphous and predominantly consisted of near-zerovalent Co as well as reduced P. PMID- 28846422 TI - Formation of Phenalenone Skeleton by an Unusual Rearrangement Reaction. AB - The frame rearrangement reaction of dinaphthyl ketones, possessing hydroxy groups at appropriate positions, into phenalenone derivatives under acidic conditions was discovered serendipitously. Although this rearrangement had limited scope, its mechanism was unusual, involving the division of naphthalene rings into one phenalenone ring and one benzene ring. The reaction mechanism was elucidated by direct determination of intermediate structures using 1H NMR measurements. The generated phenalenones are expected to be key intermediates toward natural products and functional materials. PMID- 28846423 TI - Oxidation Mechanism and Protection Strategy of Ultrathin Indium Selenide: Insight from Theory. AB - Ultrathin indium selenide (InSe), as a newly emerging two-dimensional material with high carrier mobility and a broad absorption spectrum, has been the focus of current research. However, the long-term environmental instability of atomically thin InSe seriously limits its practical applications. To develop an effective strategy to protect InSe, it is crucial to reveal the degradation mechanism at the atomic level. By employing density functional theory and ab initio molecular dynamics simulations, we provide an in-depth understanding of the oxidation mechanism of InSe. The defect-free InSe presents excellent stability against oxidation. Nevertheless, the Se vacancies on the surface can react with water and oxygen in air directly and activate the neighboring In-Se bonds on the basal plane for further oxidation, leading to complete degradation of InSe into oxidation products of In2O3 and elemental Se. Furthermore, we propose an efficient strategy to repair the Se vacancies by thiol chemistry. In this way, the repaired surface can resist oxidation from oxygen and retain the original high electron mobility of pristine InSe simultaneously. PMID- 28846425 TI - Contributions of Nanoscale Roughness to Anomalous Colloid Retention and Stability Behavior. AB - All natural surfaces exhibit nanoscale roughness (NR) and chemical heterogeneity (CH) to some extent. Expressions were developed to determine the mean interaction energy between a colloid and a solid-water interface, as well as for colloid colloid interactions, when both surfaces contain binary NR and CH. The influence of heterogeneity type, roughness parameters, solution ionic strength (IS), mean zeta potential, and colloid size on predicted interaction energy profiles was then investigated. The role of CH was enhanced on smooth surfaces with larger amounts of CH, especially for smaller colloids and higher IS. However, predicted interaction energy profiles were mainly dominated by NR, which tended to lower the energy barrier height and the magnitudes of both the secondary and primary minima, especially when the roughness fraction was small. This dramatically increased the relative importance of primary to secondary minima interactions on net electrostatically unfavorable surfaces, especially when roughness occurred on both surfaces and for conditions that produced small energy barriers (e.g., higher IS, lower pH, lower magnitudes in the zeta potential, and for smaller colloid sizes) on smooth surfaces. The combined influence of roughness and Born repulsion frequently produced a shallow primary minimum that was susceptible to diffusive removal by random variations in kinetic energy, even under electrostatically favorable conditions. Calculations using measured zeta potentials and hypothetical roughness properties demonstrated that roughness provided a viable alternative explanation for many experimental deviations that have previously been attributed to electrosteric repulsion (e.g., a decrease in colloid retention with an increase in solution IS; reversible colloid retention under favorable conditions; and diminished colloid retention and enhanced colloid stability due to adsorbed surfactants, polymers, and/or humic materials). PMID- 28846424 TI - Examining the Scope and Thermodynamics of Assembly in Nesting Complexes Comprising Molecular Baskets and TPA Ligands. AB - Molecular baskets capture various tris(2-pyridylmethyl)amine ligands, with and without zinc(II) cation, to form nesting complexes. The results of our computational (MD) and experimental (1H NMR/ITC) studies suggest that the assembly is driven by the hydrophobic effect with the charge of complementary molecular components playing an important role in the formation of nesting complexes. In brief, the complexation only takes place when the basket and the ligand carry either oppositely charged or noncharged groups. PMID- 28846426 TI - A Unified Modular Synthetic Strategy for Dictyodendrins F, H, I, and G. AB - A unified modular synthetic strategy has been developed for the first total synthesis of dictyodendrins G and synthesis of dictyodendrin F, H and I in 11 steps. The synthesis features consecutive functionalization of the core aminoquinone by palladium-mediated Suzuki-Miyaura coupling reaction, 1,4 addition, acylation and base mediated formation of a pyrrolinone, and the formation of carbazolequinone moiety through a formal [3 + 2] cycloaddition using arynes generated in situ. Several dictyodendrin analogues were also synthesized using this strategy. PMID- 28846427 TI - Cobalt Catalyzed, Regioselective C(sp2)-H Activation of Amides with 1,3-Diynes. AB - The development of a first row transition metal (cobalt)-based catalyst for the as yet unexplored C-H activation-driven reaction of 1,3-diynes, themselves a functional class of interest in a range of application areas, to form isoquinolinones-an important structural motif in a number of biologically active substances-is presented. This versatile and inexpensive catalyst employs a covalently attached bidendate-directing group, 8-aminoquinoline. The template directs the C-H activation and facilitates the synthesis of a wide range of alkynylated heterocycles under mild conditions and with excellent regioselectivity. This strategy provides a novel and efficient route to diverse heterocyclic frameworks as demonstrated by its late stage application in bisheterocycle syntheses. PMID- 28846428 TI - Theoretical Insights into Proton-Coupled Electron Transfer from a Photoreduced ZnO Nanocrystal to an Organic Radical. AB - Proton-coupled electron transfer (PCET) at metal-oxide nanoparticle interfaces plays a critical role in many photocatalytic reactions and energy conversion processes. Recent experimental studies have shown that photoreduced ZnO nanocrystals react by PCET with organic hydrogen atom acceptors such as the nitroxyl radical TEMPO. Herein, the interfacial PCET rate constant is calculated in the framework of vibronically nonadiabatic PCET theory, which treats the electrons and transferring proton quantum mechanically. The input quantities to the PCET rate constant, including the electronic couplings, are calculated with density functional theory. The computed interfacial PCET rate constant is consistent with the experimentally measured value for this system, providing validation for this PCET theory. In this model, the electron transfers from the conduction band of the ZnO nanocrystal to TEMPO concertedly with proton transfer from a surface oxygen of the ZnO nanocrystal to the oxygen of TEMPO. Moreover, the proton tunneling at the interface is gated by the relatively low-frequency proton donor-acceptor motion between the TEMPO radical and the ZnO nanocrystal. The ZnO nanocrystal and TEMPO are found to contribute similar amounts to the inner-sphere reorganization energy, implicating structural reorganization at the nanocrystal surface. These fundamental mechanistic insights may guide the design of metal-oxide nanocatalysts for a wide range of energy conversion processes. PMID- 28846429 TI - Droplet Bouncing and Breakup during Impact on a Microgrooved Surface. AB - We experimentally investigate the impact dynamics of a microliter water droplet on a hydrophobic microgrooved surface. The surface is fabricated using photolithography, and high-speed visualization is employed to record the time varying droplet shapes in the transverse and longitudinal directions. The effect of the pitch of the grooved surface and Weber number on the droplet dynamics and impact outcome are studied. At low pitch and Weber number, the maximum droplet spreading is found to be greater in the longitudinal direction than the transverse direction to the grooves. The preferential spreading inversely scales with the pitch at a given Weber number. In this case, the outcome is no bouncing (NB); however, this changes at larger pitch or Weber number. Under these conditions, the following outcomes are obtained as a function of the pitch and Weber number: droplet completely bounces off the surface (CB), bouncing occurs with droplet breakup (BDB), or no bouncing because of a Cassie to Wenzel wetting transition (NBW). In BDB and NBW, the liquid partially or completely penetrates the grooves beneath the droplet as a result of the wetting transition. The former results in droplet breakup alongside bouncing, while the latter suppresses the bouncing. These outcomes are demarcated on the Weber number-dimensionless pitch plane, and the proposed regime map suggests the existence of a critical Weber number or pitch for the transition from one regime to the other. CB and BDB are quantified by plotting the coefficient of restitution of the bouncing droplet and the volume of the daughter droplet left on the surface, respectively. The critical Weber number needed for the transition from CB to BDB is estimated using an existing mathematical model and is compared with the measurements. The comparison is good and provides insights into the mechanism of liquid penetration into the grooves. The present results on microgrooved surfaces are compared with published results on micropillared surfaces in order to assess the water repelling properties of the two surfaces. PMID- 28846430 TI - Ramifications of Water-in-Salt Interfacial Structure at Charged Electrodes for Electrolyte Electrochemical Stability. AB - Development of safe aqueous batteries and supercapacitors critically relies on expanding the electrolyte electrochemical stability window. A novel mechanism responsible for widening the electrochemical stability window of water-in-salt electrolytes (WiSEs) compared to conventional salt-in-water electrolytes is suggested based on molecular dynamics (MD) simulations of the electrolyte electrode interface. Water exclusion from the interfacial layer at the positive electrode provided additional kinetic protection that delayed the onset of the oxygen evolution reactions. The interfacial structure of a WiSE at negative electrodes near the potential of zero charge clarified why the recently discovered passivation layers formed in WiSEs are robust. The onset of water accumulation at potentials below 1.5 V vs Li/Li+ leads to formation of water-rich nanodomains at the negative electrode, limiting the robustness of the WiSE. Unexpectedly, the bis(trifluoromethanesulfonyl)imide anion adsorbed and trifluoromethanesulfonate desorbed with positive electrode polarization, demonstrating selective anion partitioning in the double layer. PMID- 28846431 TI - Self-Regulated Ion Permeation through Extraction Membranes. AB - Separation of rare earth compounds from water into an organic phase in practical cases requires the use of specific ion binding ligands in high concentrations. These tend to form complex liquid crystalline phases preferentially at ion-rich locations inside a pertraction membrane. They form a blocking layer above an ion concentration threshold, which is experimentally characterized. It is shown to limit the flux through the membrane, which is studied for the application of rare earth recycling, an example being the phase transfer of Nd from water into organic phase. This feedback leads to a stationary membrane permeation rate that can be modeled without any free parameters in very good agreement with experiment. The ion-specific formation and dissolution of the blocking layer, a feature found also in nature, and its control suggest further studies to enhance permeation as well as its selectivity control. PMID- 28846432 TI - Organocatalytic Enantioselective [1 + 4] Annulation of Morita-Baylis-Hillman Carbonates with Electron-Deficient Olefins: Access to Chiral 2,3-Dihydrofuran Derivatives. AB - A reaction has been developed for the chiral phosphine-catalyzed enantioselective [1 + 4] annulation of Morita-Baylis-Hillman carbonates with electron-deficient olefins via a Michael alkylation process. Morita-Baylis-Hillman carbonates reacted smoothly with beta,gamma-unsaturated alpha-keto ester and alpha,beta unsaturated ketone substrates under 1,2-bis[(2R,5R)-2,5 dimethylphospholano]benzene monoxide catalysis to furnish a wide range of optically active 2,3-dihydrofurans in high yields (up to 95%) with excellent asymmetric induction (up to >99% ee, >20:1 dr). This protocol represents an efficient strategy for the synthesis of optically active multifunctional 2,3 dihydrofurans via an asymmetric Michael alkylation domino reaction. PMID- 28846433 TI - Theoretical Understanding of Mechanisms of Proton Exchange Membranes Made of 2D Crystals with Ultrahigh Selectivity. AB - Recent reports on proton conduction across pristine graphene and hexagonal boron nitride (h-BN) provide a new avenue for the design of proton exchange membranes. The uniform pores formed by the electron clouds of two-dimensional (2D) crystals can effectively block the undesired transportation of other species thus ultrahigh selectivity can be achieved. With the aid of first-principles calculations, we investigate the proton conduction process across six kinds of intact 2D crystals, namely graphene, h-BN, beta12 boron sheet, chi3 boron sheet, phosphorene, and silicene. To clarify the proton conduction mechanism, three proton penetration modes are proposed: dissociation-penetration, adsorption penetration, and direct penetration. Based on our calculation results, for graphene and h-BN without atomic defects, they are unlikely to provide sufficient proton conductivity at room temperature when no bias potential is applied. By contrast, the beta12 boron sheet, chi3 boron sheets, and silicene exhibit relatively lower proton penetration energy barriers, making them prospective candidates for future proton exchange membrane applications. PMID- 28846434 TI - Highly Regioselective Carbamoylation of Electron-Deficient Nitrogen Heteroarenes with Hydrazinecarboxamides. AB - The use of hydrazinecarboxamides as a new class of carbamoylating agents has been established through the dehydrazinative Minisci reaction of electron-deficient nitrogen heteroarenes. A wide range of electron-deficient nitrogen heteroarenes, including isoquinoline, quinoline, pyridine, phenanthridine, quinoxaline, and phthalazine, underwent copper/acid-catalyzed oxidative carbamoylation with hydrazinecarboxamide hydrochlorides to afford structurally diverse nitrogen heteroaryl carboxamides as single regioisomers in moderate to excellent yields. The functional group tolerance was substantially demonstrated in the direct carbamoylation of quinine obviating multistep sequences involving protecting groups and prefunctionalization of the heterocycle. PMID- 28846435 TI - Structure of Ralsolamycin, the Interkingdom Morphogen from the Crop Plant Pathogen Ralstonia solanacearum. AB - Ralsolamycin, an inducer of chlamydospore formation in fungi, was recently reported from the plant pathogenic bacterium Ralstonia solanacearum. Although interpretation of tandem mass data and bioinformatics enabled a preliminary chemical characterization, the full structure of ralsolamycin was not resolved. We now report the recovery of this secondary metabolite from an engineered R. solanacearum strain. The structure of ralsolamycin was elucidated by extensive spectroscopic analyses. Chemical derivatization as well as bioinformatics were used to assign the absolute stereochemistry. Our results identified an erroneous genome sequence, thereby emphasizing the value of chemical methods to complement bioinformatics-based procedures in natural product research. PMID- 28846436 TI - The Multistep Tuberculosis Diagnostic Cascade. More Than Meets the Eye. PMID- 28846438 TI - My Secret Life. AB - In my early childhood, my parents gave me to my maternal grandparents for a "visit" that extended over a period of nine years. I seemed to be a fairly ordinary student in primary grades, and had to take a remedial general science class upon entering high school, my first exposure to science. It was the teacher of that class, Mr. Auer, who told me that I had scored amazingly high on a science aptitude test given to all freshmen. The people who administered the testing were convinced that I must have cheated somehow. Mr. Auer suggested that I might want to consider a career in science if I liked it. I loved it, and I did. This autobiographical article recounts my changing interests as I became aware of new fields of science during my education and the start of my career. Out of basic studies of a microbe that causes plant cancer, we developed a method to engineer new and useful genes into crop plants. PMID- 28846437 TI - Oxygen Administration Improves Survival but Worsens Cardiopulmonary Functions in Chlorine-exposed Rats. AB - Chlorine is a highly reactive gas that can cause significant injury when inhaled. Unfortunately, its use as a chemical weapon has increased in recent years. Massive chlorine inhalation can cause death within 4 hours of exposure. Survivors usually require hospitalization after massive exposure. No countermeasures are available for massive chlorine exposure and supportive-care measures lack controlled trials. In this work, adult rats were exposed to chlorine gas (LD58 67) in a whole-body exposure chamber, and given oxygen (0.8 FiO2) or air (0.21 FiO2) for 6 hours after baseline measurements were obtained. Oxygen saturation, vital signs, respiratory distress and neuromuscular scores, arterial blood gases, and hemodynamic measurements were obtained hourly. Massive chlorine inhalation caused severe acute respiratory failure, hypoxemia, decreased cardiac output, neuromuscular abnormalities (ataxia and hypotonia), and seizures resulting in early death. Oxygen improved survival to 6 hours (87% versus 42%) and prevented observed seizure-related deaths. However, oxygen administration worsened the severity of acute respiratory failure in chlorine-exposed rats compared with controls, with increased respiratory acidosis (pH 6.91 +/- 0.04 versus 7.06 +/- 0.01 at 2 h) and increased hypercapnia (180.0 +/- 19.8 versus 103.2 +/- 3.9 mm Hg at 2 h). In addition, oxygen did not improve neuromuscular abnormalities, cardiac output, or respiratory distress associated with chlorine exposure. Massive chlorine inhalation causes severe acute respiratory failure and multiorgan damage. Oxygen administration can improve short-term survival but appears to worsen respiratory failure, with no improvement in cardiac output or neuromuscular dysfunction. Oxygen should be used with caution after massive chlorine inhalation, and the need for early assisted ventilation should be assessed in victims. PMID- 28846440 TI - Low Tidal Volume versus Non-Volume-Limited Strategies for Patients with Acute Respiratory Distress Syndrome. A Systematic Review and Meta-Analysis. AB - RATIONALE: Trials investigating use of lower tidal volumes and inspiratory pressures for patients with acute respiratory distress syndrome (ARDS) have shown mixed results. OBJECTIVES: To compare clinical outcomes of mechanical ventilation strategies that limit tidal volumes and inspiratory pressures (LTV) to strategies with tidal volumes of 10 to 15 ml/kg among patients with ARDS. METHODS: This is a systematic review and meta-analysis of clinical trials investigating LTV mechanical ventilation strategies. We used random effects models to evaluate the effect of LTV on 28-day mortality, organ failure, ventilator-free days, barotrauma, oxygenation, and ventilation. Our primary analysis excluded trials for which the LTV strategy was combined with the additional strategy of higher positive end-expiratory pressure (PEEP), but these trials were included in a stratified sensitivity analysis. We performed metaregression of tidal volume gradient achieved between intervention and control groups on mortality effect estimates. We used Grading of Recommendations Assessment, Development, and Evaluation methodology to determine the quality of evidence. RESULTS: Seven randomized trials involving 1,481 patients met eligibility criteria for this review. Mortality was not significantly lower for patients receiving an LTV strategy (33.6%) as compared with control strategies (40.4%) (relative risk [RR], 0.87; 95% confidence interval [CI], 0.70-1.08; heterogeneity statistic I2 = 46%), nor did an LTV strategy significantly decrease barotrauma or ventilator-free days when compared with a lower PEEP strategy. Quality of evidence for clinical outcomes was downgraded for imprecision. Metaregression showed a significant inverse association between larger tidal volume gradient between LTV and control groups and log odds ratios for mortality (beta, -0.1587; P = 0.0022). Sensitivity analysis including trials that protocolized an LTV/high PEEP cointervention showed lower mortality associated with LTV (nine trials and 1,629 patients; RR, 0.80; 95% CI, 0.66-0.98; I2 = 46%). Compared with trials not using a high PEEP cointervention, trials using a strategy of LTV combined with high PEEP showed a greater mortality benefit (RR, 0.58; 95% CI, 0.41-0.82; P for interaction = 0.05). CONCLUSIONS: The trend toward lower mortality with LTV ventilation in the primary analysis and the significant relationship between the degree of tidal volume reduction and the mortality effect together suggest, but do not prove, that LTV ventilation improves mortality among critically ill adults with ARDS. PMID- 28846441 TI - Recent developments and applications of hyperspectral imaging for rapid detection of mycotoxins and mycotoxigenic fungi in food products. AB - Mycotoxins are the foremost naturally occurring contaminants of food products such as corn, peanuts, tree nuts, and wheat. As the secondary metabolites, mycotoxins are mainly synthesized by many species of the genera Aspergillus, Fusarium and Penicillium, and are considered highly toxic and carcinogenic to humans and animals. Most mycotoxins are detected and quantified by analytical chemistry-based methods. While mycotoxigenic fungi are usually identified and quantified by biological methods. However, these methods are time-consuming, laborious, costly, and inconsistent because of the variability of the grain sampling process. It is desirable to develop rapid, non-destructive and efficient methods that objectively measure and evaluate mycotoxins and mycotoxigenic fungi in food. In recent years, some spectroscopy-based technologies such as hyperspectral imaging (HSI), Raman spectroscopy, and Fourier transform infrared spectroscopy have been extensively investigated for their potential use as tools for the detection, classification, and sorting of mycotoxins and toxigenic fungal contaminants in food. HSI integrates both spatial and spectral information for every pixel in an image, making it suitable for rapid detection of large quantities of samples and more heterogeneous samples and for in-line sorting in the food industry. In order to track the latest research developments in HSI, this paper gives a brief overview of the theories and fundamentals behind the technology and discusses its applications in the field of rapid detection and sorting of mycotoxins and toxigenic fungi in food products. Additionally, advantages and disadvantages of HSI are compared, and its potential use in commercial applications is reported. PMID- 28846439 TI - Microbial Lineages in Sarcoidosis. A Metagenomic Analysis Tailored for Low Microbial Content Samples. AB - RATIONALE: The etiology of sarcoidosis is unknown, but microbial agents are suspected as triggers. OBJECTIVES: We sought to identify bacterial, fungal, or viral lineages in specimens from patients with sarcoidosis enriched relative to control subjects using metagenomic DNA sequencing. Because DNA from environmental contamination contributes disproportionately to samples with low authentic microbial content, we developed improved methods for filtering environmental contamination. METHODS: We analyzed specimens from subjects with sarcoidosis (n = 93), control subjects without sarcoidosis (n = 72), and various environmental controls (n = 150). Sarcoidosis specimens consisted of two independent sets of formalin-fixed, paraffin-embedded lymph node biopsies, BAL, Kveim reagent, and fresh granulomatous spleen from a patient with sarcoidosis. All specimens were analyzed by bacterial 16S and fungal internal transcribed spacer ribosomal RNA gene sequencing. In addition, BAL was analyzed by shotgun sequencing of fractions enriched for viral particles, and Kveim and spleen were subjected to whole-genome shotgun sequencing. MEASUREMENTS AND MAIN RESULTS: In one tissue set, fungi in the Cladosporiaceae family were enriched in sarcoidosis compared with nonsarcoidosis tissues; in the other tissue set, we detected enrichment of several bacterial lineages in sarcoidosis but not Cladosporiaceae. BAL showed limited enrichment of Aspergillus fungi. Several microbial lineages were detected in Kveim and spleen, including Cladosporium. No microbial lineage was enriched in more than one sample type after correction for multiple comparisons. CONCLUSIONS: Metagenomic sequencing revealed enrichment of microbes in single types of sarcoidosis samples but limited concordance across sample types. Statistical analysis accounting for environmental contamination was essential to avoiding false positives. PMID- 28846442 TI - The Incidence of Subsequent Meniscal Surgery Is Higher in the Anterior Cruciate Ligament-Reconstructed Knee Than in the Contralateral Knee. AB - BACKGROUND: A goal of anterior cruciate ligament (ACL) reconstruction is to provide a meniscal protective effect for the knee. PURPOSE: (1) To evaluate whether there was a different likelihood of subsequent meniscal surgery in the ACL-reconstructed knee or in the normal contralateral knee and (2) to compare the risk factors associated with subsequent meniscal surgery in the ACL-reconstructed knee and contralateral knee. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Using an integrated health care system's ACL reconstruction registry, patients undergoing primary ACL reconstruction, with no meniscal injury at the time of index surgery and a normal contralateral knee, were evaluated. Subsequent meniscal tears associated with ACL graft revision were excluded. Subsequent meniscal surgery in either knee was the outcome of interest. Sex, age, and graft type were assessed as potential risk factors. Survival analysis was used to compare meniscal surgery-free survival rates and to assess risk factors of subsequent meniscal surgery. RESULTS: Of 4087 patients, there were 32 (0.78%) patients who underwent subsequent meniscal surgery in the index knee and 9 (0.22%) in the contralateral knee. The meniscal surgery-free survival rate at 4 years was 99.08% (95% CI, 98.64%-99.37%) in the index knee and 99.65% (95% CI, 99.31%-99.82%) in the contralateral knee. There was a 3.73 (95% CI, 1.73-8.04; P < .001) higher risk of subsequent meniscal surgery in the index knee compared with the contralateral knee, or a 0.57% absolute risk difference. After adjustments, allografts (hazard ratio [HR], 5.06; 95% CI, 1.80-14.23; P = .002) and hamstring autografts (HR, 3.11; 95% CI, 1.06-9.10; P = .038) were risk factors for subsequent meniscal surgery in the index knee compared with bone patellar tendon-bone (BPTB) autografts. CONCLUSION: After ACL reconstruction, the overall risk of subsequent meniscal surgery was low. However, the relative risk of subsequent meniscal surgery in the ACL-reconstructed knee was higher compared with the contralateral knee. Only graft type was found to be a risk factor for subsequent meniscal surgery in the ACL-reconstructed knee, with a higher risk for allografts and hamstring autografts compared with BPTB autografts. PMID- 28846443 TI - Effect of high pressure treatment on the color of fresh and processed meats: A review. AB - High pressure (HP) treatment often results in discoloration of beef, lamb, pork, and poultry. The degree of color changes depends on the physical and chemical state of the meat, especially myoglobin, and the atmospheric conditions during and after pressurization. A decreased redness is attributed to a large degree to the oxidation of the bright red oxymyoglobin or the purplish deoxymyoglobin into the brownish metmyoglobin, as well as to the denaturation of myoglobin. Surely, the high myoglobin content makes beef more exposed to this discoloration compared to the white chicken meat. In addition, HP treatment causes denaturation of myofibrillar proteins followed by aggregation, consequently, changing the surface reflectance and increasing lightness. Other intrinsic and extrinsic factors may affect the pressure-induced color changes positively or negatively. In this review, the pressure-induced color changes in meat are discussed in relation to modification of the myoglobin molecule, changes in the meat microstructure, and the impact of the presence of different chemical compounds and physical conditions during processing. PMID- 28846444 TI - Validity of fractional exhaled nitric oxide and small airway function indices in diagnosis of cough-variant asthma. AB - OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is a non-invasive method used to reveal the eosinophilic inflammation of airway and to diagnose and manage asthma. The use of FeNO measurement or its combination with the small airway function in differentiating CVA patients from chronic cough patients is unexplored. METHODS: From December 2012 to June 2016, patients with chronic non productive cough for more than 8 weeks based on physician's opinion were subjected to FeNO, pulmonary function, and bronchial hyperresponsiveness (BHR) tests. Receiver operating characteristic (ROC) curves were obtained to evaluate the clinical value of FeNO and small airways indices in CVA diagnosis. The optimal cutoff point for the level of FeNO was also determined. RESULTS: The FeNO value in the CVA group was significantly higher than that in the non-cough variant asthma (NCVA) group [42(41) parts per billion (ppb) vs. (16(11) ppb), P < 0.05]. The area under the ROC curve was estimated to be 0.874 for FeNO. An optimal cutoff point of 25 ppb had respective sensitivity and specificity values of 81.3% and 84.0% in differentiating CVA patients from NCVA patients. The CVA group showed small airway dysfunction, and the small airway resistance was significantly higher than in the NCVA group. The area under the ROC curve of FeNO combined with maximal midexpiratory flow (MEF) (% predicted) was 0.883, and that combined with MEF50 (% predicted) was 0.886. CONCLUSIONS: The measurement of FeNO is a non-invasive, reproducible, and sensitive method of differentiating CVA patients from NCVA patients. A combination of the level of FeNO (25 ppb) and the abnormal small airway function suggested higher CVA possibility, thereby resulting in a rapid diagnosis. Unnecessary treatments are avoided. This finding provides a new perspective for the management of patients with CVA. PMID- 28846445 TI - Utilization of just-in-time training for nursing education using the LA Phonospirometry asthma tool. AB - OBJECTIVE: Just-in-time training (JITT) has been used to teach and re-teach known medical techniques, but has not been used to teach novel techniques. We aimed to assess the performance retention of JITT on a novel asthma exacerbation severity assessment technique known as Los Angeles (LA) Phonospirometry. METHODS: This was a prospective cohort study using a convenience sample of pediatric emergency department registered nurses (RNs) who were asked to watch a brief instructional digital video on LA Phonospirometry, and then asked to practice the technique on a research assistant (RA). A checklist was used to evaluate proficiency with the primary outcome being the number correct on the checklist. The secondary outcome included whether or not they could identify a common error demonstrated by the RA. RNs were re-tested after 4-6 months to assess skill retention. RESULTS: Forty RNs were enrolled in the study and six were lost to follow-up. The mean time from the first to second testing was 5.4 months +/- 0.5 months. The mean score of the first part of the checklist on the initial testing was 4.6 +/- 0.7 and on second testing was 3.8 +/- 1.5 (p = 0.008). This represented a drop in scores and thus minimal knowledge decay of 18% (from 91% to 73%). The mean values for number of errors picked up for the first test and second test were 1.3 and 1.5, respectively (p = 0.2). CONCLUSIONS: JITT demonstrated feasibility as a rapid instructional tool for RNs, with a limited decay in cognitive knowledge surrounding the LA Phonospirometry technique. PMID- 28846446 TI - Sodium status and the metabolic syndrome: A systematic review and meta-analysis of observational studies. AB - The prevalence of metabolic syndrome (MetS) has been greatly increased, worldwide. In recent years, investigators have proposed that sodium might contribute to the development of metabolic syndrome; however, the published data were conflicting. The present systematic review aimed to summarize the evidence from observational studies in this regard. We conducted a systematic search for relevant observational studies investigating the association between sodium status and MetS, published until June 2017 in electronic databases including PubMed, EMBASE, Scopus and Google Scholar. Summary effects were derived using random effects model. After screening the records, seventeen publications with 66,274 participants were eligible to be included in the systematic review and meta-analysis. The analysis revealed that subjects with MetS have significantly higher levels of sodium compared to healthy controls (Hedges' g = 0.21, 95% CI: 0.12, 0.29, I2 = 68.6). Subgroup analyses revealed that the difference was significant when the sodium status was assessed using urinary sodium levels. The random effects meta-regression analysis also revealed that body sodium level increases with the number of MetS components. Furthermore, participants with highest dietary/urinary or serum sodium levels had 37% higher chance of developing MetS when compared with participants with the lowest sodium levels (OR = 1.37 95%CI: 1.31, 1.42, I2 = 86.9). The current meta-analysis revealed that higher sodium input into the body is directly associated with the likelihood of MetS. Prospective cohort studies and well-designed randomized clinical trials considering the effect of sodium restricted diets on the risk of MetS as an outcome are necessary to represent the causal association. PMID- 28846447 TI - Stability of Commercially Available Glucagon Formulation for Dual-Hormone Artificial Pancreas Clinical Use. AB - BACKGROUND: Available glucagon formulations are approved for immediate use after reconstitution for severe hypoglycemia emergency treatment. However, they are used in dual-hormone artificial pancreas (insulin and glucagon) studies through subcutaneous infusion pumps over 24 h. Chemical and physical stability of such glucagon use have not been reported in a comprehensive manner. MATERIALS AND METHODS: Recombinant Glucagon DNA (Eli Lilly) was used. Compatibility and sterility of glucagon delivery through subcutaneous pump systems were verified. Glucagon degradation through liquid chromatography with tandem mass spectrometry (LC-MS/MS), fibrillation using intrinsic tryptophan fluorescence shift, and bioactivity through a cell-protein kinase A-based fluorescent bioassay were assessed over a range of different physical conditions (temperature, movement, and air bubbles). RESULTS: Subcutaneous infusion pump systems administered glucagon in sterile conditions and with comparable accuracy to insulin delivery; mean absolute relative difference of actual versus expected weights were 1.2% +/- 1.1% for glucagon and 1.1% +/- 0.5% for insulin (P = 0.9). In comparison to freshly reconstituted samples, glucagon analyzed through LC-MS/MS was intact at 93.0% +/- 7.0% after 24 h (P = 0.42) and 83.04% +/- 6.0% after 48 h (P = 0.02) of incubation in pumps at 32 degrees C. Peak wavelengths for Trp fluorescence did not differ from samples exposed to air bubbles or movement whether incubated (in infusion sets for 24 h at 32 degrees ) immediately or 24- and 48-h poststorage at 4 degrees C (P = 0.10, 0.70 and 0.80, respectively) and no significant differences in bioactivity (shifts in EC50) were found for the same conditions (P = 0.13, 0.83, and 0.63). CONCLUSION: Available glucagon formulations are chemically and physically stable, as well as compatible with delivery through subcutaneous infusion pumps over 24 h and can be used in long-term clinical trials. PMID- 28846448 TI - In vitro effects of melatonin on colonization of neonate mouse spermatogonial stem cells. AB - We have recently reported that antioxidant supplements enhance the efficacy of cryopreserved spermatogonial stem cells. Melatonin is considered a free radical scavenger which has direct and indirect antioxidant effects in in vitro and in vivo microenvironments. Due to the anti-apoptotic properties of melatonin, researchers have proposed that melatonin may improve the efficiency of spermatogonial stem cell (SSC) transplantation. However, the appropriate methodology which facilitates SSC proliferation remains to be determined. Identification of a proper propagation system is essential for the future application of SSCs in the field of infertility. The aim of the present study was to investigate the effects of melatonin on the colonization of SSCs. SSCs were isolated from the testes of three to six day old mice, and their purities were assessed by cytometry using Plzf antibody. Isolated testicular cells were cultured in the absence or presence of melatonin extract for two weeks. Suppression of differentiation and maintenance of spermatogonial stem cells was confirmed by alkaline phosphatase staining and immunocytochemistry using Plzf antibody. The number and diameter of the colonies of SSCs were assessed during the 7th and 14th days of culture, and the expression of Id4, Plzf, and C-kit were evaluated using real-time PCR at the end of the culture period. The survival rate of the cultured cells in the presence of melatonin was significantly higher than the control group. The number and diameter of colonies also increased in the cells treated with melatonin. The results of our study suggest that culture of SSCs with 100 MUM melatonin supplementation can increase SSCs proliferation significantly. PMID- 28846449 TI - Academy of Breastfeeding Medicine 2017 Summit Summary. PMID- 28846450 TI - Targeting the gut microbiota by dietary nutrients: A new avenue for human health. AB - The gut microbiota is a complex ecosystem consisted of trillions of microbes that have co-evolved with their host for hundreds of millions of years. During the last decade, a growing body of knowledge has suggested that there is a compelling set of connections among diet, gut microbiota and human health. Various physiological functions of the host, ranging from metabolic and immune regulation to nerve and endocrine development, are possibly mediated by the structural components of microbial cell or the products of microbial metabolism, which are greatly influenced by dietary macronutrients and micronutrients. Thus, governing the production and activity of these microbial-associated small molecules and metabolites through dietary intervention may provide promising strategies for the improvement of human health and disease. In this review article, we first provide an overview of current findings about the intimate interrelationships between diet and gut microbiota. We also introduce the physiological effects of some microbial-associated small molecules and metabolites on the host as well as the detailed signaling mechanisms. PMID- 28846451 TI - Differential effects of obesity on eosinophilic vs. non-eosinophilic asthma subtypes. AB - OBJECTIVE: Asthma is a heterogeneous disease composed of multiple disease subtypes. Obesity may worsen asthma, although the mechanism is poorly understood and its effects on different subtypes are not well characterized. We sought to determine whether obesity affects eosinophilic asthma differently from non eosinophilic asthma. METHODS: Charts of 196 persistent asthmatics were reviewed. Subjects were categorized according to BMI (obese >= 30 kg/m2) and blood eosinophilia based on two different cutoffs (>=200 or >=400 cells/ul): eosinophilic, non-obese (E-NO), eosinophilic, obese (E-O), non-eosinophilic, non obese (NE-NO), and non-eosinophilic, obese (NE-O). We analyzed clinical parameters across these groups to determine associations with obesity and/or eosinophilia. RESULTS: Obesity was highly prevalent in our population (50.5%, 99/196). The majority of asthmatics were female (75.5%), though the ratio was lower in the E-NO group (56%). The NE-NO group was associated with lowest asthma severity, lower atopy, and less medication use. Regardless of eosinophilia, obesity was associated with higher inhaled corticosteroid doses and lower FVC% predicted than their non-obese counterparts. Obesity was associated with reduced FEV1% only in the non-eosinophilic group. Eosinophilia was also associated with reduced FEV1% in the non-obese subjects, but FEV1% was not further reduced in the E-O group compared to the E-NO and NE-O groups. Similar findings were observed regardless of whether the blood eosinophil cutoff was 200 or 400 cells/ ul. CONCLUSION: Multiple clinical features of asthma are adversely affected by obesity, which may affect eosinophilic and non-eosinophilic subtypes differently. PMID- 28846452 TI - Concise Review: LIN28/let-7 Signaling, a Critical Double-Negative Feedback Loop During Pluripotency, Reprogramming, and Tumorigenicity. AB - MicroRNAs (miRNAs) with 20-30 nucleotides have recently emerged as the multidimensional regulators of cell fate decisions. Recent improvement in high throughput sequencing has highlighted the potential role of LIN28/let-7 regulatory network in several developmental events. It was proposed that this pathway might represent a functional signature in cell proliferation, transition between commitment and pluripotency, and regulation of cancer and tumorigenicity. LIN28/let-7 regulatory pathway is one of the excellent examples of the relationship between an miRNA and mRNAs. This review article highlights the potentials of LIN28/let-7 signaling in gene regulatory pathways during pluripotency, reprogramming, and tumorigenicity. PMID- 28846453 TI - 2017 AAHA Canine Vaccination Guidelines. PMID- 28846454 TI - GLIS3 and TYK2 Single Nucleotide Polymorphisms Are Not Associated with Dermatomyositis/Polymyositis in Chinese Han Population. AB - AIM: Racial differences and genetic overlap have been shown to be responsible for the difference in susceptibility to dermatomyositis (DM)/polymyositis (PM) in a variety of populations. Single nucleotide polymorphisms (SNPs) in the GLI-similar 3 (GLIS3) and tyrosine kinase 2 (TYK2) genes have been associated with various autoimmune diseases. The aim of this study was to investigate whether SNPs in GLIS3 (rs7020673, rs10758593, and rs10814916) and TYK2 (rs280519, rs2304256, rs17000730, and rs280501) were associated with an increase in susceptibility to DM/PM in a Chinese Han population. MATERIALS AND METHODS: SNPs in GLIS3 and TYK2 were analyzed in a cohort of 1017 patients with DM/PM and 1280 healthy controls using a Sequenom MassArray system. Association analyses were performed using the PLINK v1.07 software. RESULTS: In our study, the GLIS3 polymorphisms rs7020673 and rs10758593 were initially found to be predisposing risk factors for PM and PM with interstitial lung disease (p < 0.05). Both rs7020673 and rs10758593 were associated with PM in both additive and dominant models (p < 0.05); however, these observed associations were not apparent after Bonferroni correction. Other SNPs examined in our study were not associated with susceptibility to DM/PM. CONCLUSION: GLIS3 and TYK2 polymorphisms are not associated with DM/PM in the Chinese Han population. As associations of SNPs in these genes in patients with DM/PM have been previously reported in other populations, we may conclude that the lack of association in our study may be the result of differences in genetic background. Further studies in other populations are needed to confirm our findings. PMID- 28846455 TI - Witnessing Genome Evolution: Experimental Reconstruction of Endosymbiotic and Horizontal Gene Transfer. AB - Present day mitochondria and plastids (chloroplasts) evolved from formerly free living bacteria that were acquired through endosymbiosis more than a billion years ago. Conversion of the bacterial endosymbionts into cell organelles involved the massive translocation of genetic material from the organellar genomes to the nucleus. The development of transformation technologies for organellar genomes has made it possible to reconstruct this endosymbiotic gene transfer in laboratory experiments and study the mechanisms involved. Recently, the horizontal transfer of genetic information between organisms has also become amenable to experimental investigation. It led to the discovery of horizontal genome transfer as an asexual process generating new species and new combinations of nuclear and organellar genomes. This review describes experimental approaches towards studying endosymbiotic and horizontal gene transfer processes, discusses the new knowledge gained from these approaches about both the evolutionary significance of gene transfer and the underlying molecular mechanisms, and highlights exciting possibilities to exploit gene and genome transfer in biotechnology and synthetic biology. PMID- 28846456 TI - Technologies for enhancement of bioactive components and potential health benefits of cereal and cereal-based foods: Research advances and application challenges. AB - Cereal grains are a major source of human food and their production has steadily been increased during the last several decades to meet the demand of our increasing world population. The modernized society and the expansion of the cereal food industry created a need for highly efficient processing technologies, especially flour production. Earlier scientific research efforts have led to the invention of the modern steel roller mill, and the refined flour of wheat has become a basic component in most of cereal-based foods such as breads and pastries because of the unique functionality of wheat protein. On the other hand, epidemiological studies have found that consumption of whole cereal grains was health beneficial. The health benefit of whole cereal grain is attributed to the combined effects of micronutrients, phytochemicals, and dietary fibre, which are mainly located in the outer bran layer and the germ. However, the removal of bran and germ from cereal grains during polishing and milling results in refined flour and food products with lower bioactive compounds and dietary fibre contents than those from whole grain. Also, the level of bioactive compounds in cereal food is influenced by other food preparation procedures such as baking, cooking, extrusion, and puffing. Therefore, food scientists and nutritionists are searching for strategies and processing technologies to enhance the content and bioavailability of nutrients, bioactive compounds, and dietary fibre of cereal foods. The objective of this article was to review the research advances on technologies for the enhancement of bioactive compounds and dietary fibre contents of cereal and cereal-based foods. Bioactivities or biological effects of enhanced cereal and cereal-based foods are presented. Challenges facing the application of the proposed technologies in the food industry are also discussed. PMID- 28846457 TI - Beacon Editor: Capturing Signal Transduction Pathways Using the Systems Biology Graphical Notation Activity Flow Language. AB - The Beacon Editor is a cross-platform desktop application for the creation and modification of signal transduction pathways using the Systems Biology Graphical Notation Activity Flow (SBGN-AF) language. Prompted by biologists' requests for enhancements, the Beacon Editor includes numerous powerful features for the benefit of creation and presentation. PMID- 28846458 TI - Effects of regular exercise on asthma control in young adults. AB - BACKGROUND: According to our systematic literature review, no previous study has assessed potential effects of regular exercise on asthma control among young adults. We hypothesized that regular exercise improves asthma control among young adults. METHODS: We studied 162 subjects with current asthma recruited from a population-based cohort study of 1,623 young adults 20-27 years of age. Asthma control was assessed by the occurrence of asthma-related symptoms, including wheezing, shortness of breath, cough, and phlegm production, during the past 12 months. Asthma symptom score was calculated based on reported frequencies of these symptoms (range: 0-12). Exercise was assessed as hours/week. RESULTS: In Poisson regression, adjusting for gender, age, smoking, environmental tobacco smoke exposure, and education, the asthma symptom score reduced by 0.09 points per 1 hour of exercise/week (95% CI: 0.00 to 0.17). Applying the "Low exercise" quartile as the reference, "Medium exercise" reduced the asthma symptom score by 0.66 (-0.39 to 1.72), and "High exercise" reduced it significantly by 1.13 (0.03 to 2.22). The effect was strongest among overweight subjects. CONCLUSIONS: Our results provide new evidence that regular exercising among young adults improves their asthma control. Thus, advising about exercise should be included as an important part of asthma self-management in clinical practice. PMID- 28846459 TI - Calcifediol to treat secondary hyperparathyroidism in patients with chronic kidney disease. AB - INTRODUCTION: Deranged vitamin D metabolism represents an active trigger of secondary hyperparathyroidism (SHPT) in CKD. Correction of 25(OH)D deficiency by nutritional Vitamin D administration is suggested by KDIGO guidelines, to prevent and treat SHPT in CKD stage G3-G5 and G1T-G5T patients, although with a still inconsistent background. Nutritional vitamin D is available as cholecalciferol, ergocalciferol, or calcifediol. Superiority of calcifediol in increasing 25(OH)D levels has been suggested due to its better bioavailability. The safer pharmacokinetic of the recent modified-release (MR) formulation of calcifediol was effective in replenishing 25(OH)D levels with minimal impact on vitamin D catabolism and fibroblast-growth factor-23 (FGF-23) activation. Areas covered: the review discusses utility of calcifediol for treating SHPT in different CKD stages under physiology driven approach, focusing on vitamin D metabolism, guidelines suggestions and comparison between clinical effects on SHPT elicited by calcifediol, cholecalciferol and ergocalciferol. Expert commentary: although optimal targets of 25(OH)D and parathormone remain uncertain, calcifediol, especially in its newer MR formulation, may represent an intriguing option to combine an efficacious correction of 25(OH)D deficit and SHPT, with a limited impact on vitamin D catabolism and FGF-23 activation. Newer data are required to better explore the role of MR calcifediol in treating SHPT. PMID- 28846460 TI - Evaluation of Commercial beta-Agonists, Dietary Protein, and Shade on Fecal Shedding of Escherichia coli O157:H7 from Feedlot Cattle. AB - Escherichia coli O157:H7 is a foodborne pathogen commonly associated with cattle feces. Diet, including dietary supplements such as beta-agonists, may impact fecal shedding of this pathogen. A series of three experiments were conducted to determine if the beta-agonists ractopamine hydrochloride (RAC) or zilpaterol hydrochloride (ZH) would impact the level or prevalence of fecal E. coli O157:H7 shedding. In Experiment 1, dietary RAC did not impact fecal shedding of E. coli O157:H7 based on the level or prevalence, but the addition of dietary soybean meal (SBM) in the study did reduce E. coli O157:H7 shedding. In Experiments 2 and 3, dietary ZH did not affect fecal E. coli O157:H7 shedding as determined by enumeration or prevalence, but in Experiment 2 the addition of 30% (dry matter basis) wet distillers grains with solubles (WDGS) in the diet tended to increase E. coli O157:H7 shedding. Shade is a potential management tool to reduce heat stress in cattle, and in Experiment 3 the presence of shade over the feedlot pens did not affect E. coli O157:H7 shedding. The use of beta-agonists in cattle diets did not significantly affect fecal shedding of E. coli O157:H7, and in particular the percentage of animals shedding enumerable levels of the pathogen did not change, indicating that there was not a change in colonization. As has been reported previously and indicated again in this study, the use of WDGS in the diet may increase E. coli O157:H7 shedding. In contrast, the addition of SBM to cattle diets, to increase the dietary crude protein, appeared to reduce E. coli O157:H7 shedding, but this potential dietary intervention needs to be confirmed with additional research. PMID- 28846461 TI - Deficits in comprehending wh-questions in children with hearing loss - the contribution of phonological short-term memory and syntactic complexity. AB - The aim of the study is to investigate if German children with hearing loss (HL) display persisting problems in comprehending complex sentences and to find out whether these problems can be linked to limitations in phonological short-term memory (PSTM). A who-question comprehension test (picture pointing) and a nonword repetition (NWR) task were conducted with 21 German children with bilateral sensorineural HL (ages 3-4) and with age-matched 19 normal hearing (NH) children. Follow-up data (ages 6-8) are reported for 10 of the children with HL. The data reveal that the comprehension of who-questions as well as PSTM was significantly more impaired in children with HL than in children with NH. For both groups of participants, there were no correlations between question comprehension scores and performance in the NWR test. Syntactic complexity (subject vs. object question) affected question comprehension in children with HL, however, these problems were overcome at school age. In conclusion, the data indicate that a hearing loss affects the comprehension of complex sentences. The observed problems did, however, not persist and were, therefore, unlikely to be caused by a genuine syntactic deficit. For the tested wh-questions, there is no indication that syntactic comprehension problems of children with HL are due to limitations in PSTM. PMID- 28846463 TI - Determination of Follicular Localization in Human Ovarian Cortex for Vitrification. AB - PURPOSE: To determine the optimal follicle localization for ovarian vitrification in adolescent and young adult (AYA)-aged (between 15 and 39 years of age) patients with cancer or primary ovarian insufficiency (POI). METHODS: In total, ovaries from 24 women were included in our study. These include women who received ovariectomy for fertility preservation before gonadotoxic treatments for cancer (n = 4), or for the treatment of POI by the in vitro activation method (n = 8), and other women and infants (0-3 years of age) whose ovaries were autopsied (n = 12). Before cryopreservation, a portion of the ovary sampled from cancer and POI patients was used for histological analysis. Depths of follicles from the surface of ovarian cortices were then measured by using digital imaging software. The locations of the follicles at different developmental stages in the ovarian cortex were noted. RESULTS: The mean depth at which the primordial and primary follicles were located was 271 MUm in infants. This was deeper in women in their twenties, thirties, and forties (501, 462, and 493 MUm, respectively). The majority of secondary follicles were located <1000 MUm from the ovarian surface (mean depth, 639 MUm). In regard to patients with POI, the mean depth of primordial and primary follicles was 566 MUm, whereas 70% of secondary follicles were located >1000 MUm deep. CONCLUSION(S): These findings suggest that <1 mm is a potential optimum thickness of normal ovarian tissue for vitrification and a requirement that thicker ovarian cortices include secondary follicles in POI patients. PMID- 28846462 TI - Immunohistochemical Markers for Prospective Studies in Neurofibromatosis-1 Porcine Models. AB - Neurofibromatosis type 1 (NF1) is a common, cancer-predisposing disease caused by mutations in the NF1 tumor gene. Patients with NF1 have an increased risk for benign and malignant tumors of the nervous system (e.g., neurofibromas, malignant peripheral nerve sheath tumors, gliomas) and other tissues (e.g., leukemias, rhabdomyosarcoma, etc.) as well as increased susceptibility to learning disabilities, chronic pain/migraines, hypertension, pigmentary changes, and developmental lesions (e.g., tibial pseudoarthrosis). Pigs are an attractive and upcoming animal model for future NF1 studies, but a potential limitation to porcine model research has been the lack of validated reagents for direct translational study to humans. To address that issue, we used formalin-fixed tissues (human and pigs) to evaluate select immunohistochemical markers (activated caspase-3, allograft inflammatory factor-1, beta-tubulin III, calbindin D, CD13, CD20, desmin, epithelial membrane antigen, glial fibrillary acidic protein, glucose transporter-1, laminin, myelin basic protein, myoglobin, proliferating cell nuclear antigen, S100, vimentin, and von Willebrand factor). The markers were validated by comparing known expression and localization in human and pig tissues. Validation of these markers on fixed tissues will facilitate prospective immunohistochemical studies of NF1 pigs, as well as other pig models, in a more efficient, reproducible, and translationally relevant manner. PMID- 28846464 TI - The Presence of MMP-20 Reinforces Biomimetic Enamel Regrowth. AB - Biomimetic synthesis of artificial enamel is a promising strategy for the prevention and restoration of defective enamel. We have recently reported that a hydrogel system composed of chitosan-amelogenin (CS-AMEL) and calcium phosphate is effective in forming an enamel-like layer that has a seamless interface with natural tooth surfaces. Here, to improve the mechanical system function and to facilitate the biomimetic enamel regrowth, matrix metalloproteinase-20 (MMP-20) was introduced into the CS-AMEL hydrogel. Inspired by our recent finding that MMP 20 prevents protein occlusion inside enamel crystals, we hypothesized that addition of MMP-20 to CS-AMEL hydrogel could reinforce the newly grown layer. Recombinant human MMP-20 was added to the CS-AMEL hydrogel to cleave full-length amelogenin during the growth of enamel-like crystals on an etched enamel surface. The MMP-20 proteolysis of amelogenin was studied, and the morphology, composition, and mechanical properties of the newly grown layer were characterized. We found that amelogenin was gradually degraded by MMP-20 in the presence of chitosan. The newly grown crystals in the sample treated with MMP-20 CS-AMEL hydrogel showed more uniform orientation and greater crystallinity than the samples treated with CS-AMEL hydrogel without MMP-20. Stepwise processing of amelogenin by MMP-20 in the CS-AMEL hydrogel prevented undesirable protein occlusion within the newly formed crystals. As a result, both the modulus and hardness of the repaired enamel were significantly increased (1.8- and 2.4-fold, respectively) by the MMP-20-CS-AMEL hydrogel. Although future work is needed to further incorporate other enamel matrix proteins into the system, this study brings us one step closer to biomimetic enamel regrowth. PMID- 28846465 TI - Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation as Alternative to Matched Sibling or Unrelated Donor Transplantation for Hodgkin Lymphoma: A Registry Study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation. AB - Purpose To compare the outcome of patients with Hodgkin lymphoma who received post-transplantation cyclophosphamide-based haploidentical (HAPLO) allogeneic hematopoietic cell transplantation with the outcome of patients who received conventional HLA-matched sibling donor (SIB) and HLA-matched unrelated donor (MUD). Patients and Methods We retrospectively evaluated 709 adult patients with Hodgkin lymphoma who were registered in the European Society for Blood and Marrow Transplantation database who received HAPLO (n = 98), SIB (n = 338), or MUD (n = 273) transplantation. Results Median follow-up of survivors was 29 months. No differences were observed between groups in the incidence of acute graft-versus host disease (GVHD). HAPLO was associated with a lower risk of chronic GVHD (26%) compared with MUD (41%; P = .04). Cumulative incidence of nonrelapse mortality at 1 year was 17%, 13%, and 21% in HAPLO, SIB, and MUD, respectively, and corresponding 2-year cumulative incidence of relapse or progression was 39%, 49%, and 32%, respectively. On multivariable analysis, relative to SIB, nonrelapse mortality was similar in HAPLO ( P = .26) and higher in MUD ( P = .003), and risk of relapse was lower in both HAPLO ( P = .047) and MUD ( P < .001). Two-year overall survival and progression-free survival were 67% and 43% for HAPLO, 71% and 38% for SIB, and 62% and 45% for MUD, respectively. There were no significant differences in overall survival or progression-free survival between HAPLO and SIB or MUD. The rate of the composite end point of extensive chronic GVHD and relapse-free survival was significantly better for HAPLO (40%) compared with SIB (28%; P = .049) and similar to MUD (38%; P = .59). Conclusion Post transplantation cyclophosphamide-based HAPLO transplantation results in similar survival outcomes compared with SIB and MUD, which confirms its suitability when no conventional donor is available. Our results also suggest that HAPLO results in a lower risk of chronic GVHD than MUD transplantation. PMID- 28846466 TI - Identification and Characterization of a New Series of Ghrelin O-Acyl Transferase Inhibitors. AB - Ghrelin O-acyl transferase (GOAT; MBOAT4) catalyzes O-acylation at serine-3 of des-acyl ghrelin. Acyl ghrelin is secreted by stomach X/A-like cells and plays a role in appetite and metabolism. Therefore, GOAT has been expected to be a novel antiobesity target because it is responsible for acyl ghrelin production. Here, we report homogeneous time-resolved fluorescence (HTRF) and enzyme-linked immunosorbent assay (ELISA) methods utilizing human GOAT-expressing microsomes as a novel high-throughput assay system for the discovery of hit compounds and optimization of lead compounds. Hit compounds exemplified by compound A (2-[(2,4 dichlorobenzyl)sulfanyl]-1,3-benzoxazole-5-carboxylic acid) were identified by high-throughput screening using the HTRF assay and confirmed to have GOAT inhibitory activity using the ELISA. Based on the hit compound information, the novel lead compound (compound B, (4-chloro-6-{[2-methyl-6 (trifluoromethyl)pyridin-3-yl]methoxy}-1-benzothiophen-3-yl)acetic acid) was synthesized and exhibited potent GOAT inhibition with oral bioavailability. Both the hit compound and lead compound showed octanoyl-CoA competitive inhibitory activity. Moreover, these two compounds decreased acyl ghrelin production in the stomach of mice after their oral administration. These novel findings demonstrate that GOAT is a druggable target, and its inhibitors are promising antiobesity drugs. PMID- 28846467 TI - Advanced Care Planning: Pearls, Perils, Pitfalls, and Promises. PMID- 28846468 TI - The newly filed patent applications for vaccines against staphylococcus aureus. AB - Staphylococcus aureus (S. aureus) frequently causes life threatening disease. To release the threat, vaccine has been proposed as a preventive intervention against the cause. However, the development of the vaccines is still in early stages. Thus, highlighting the related newly filed patent applications would stimulate further developments. PMID- 28846469 TI - Randomized Clinical Trial of 12% and 38% Silver Diamine Fluoride Treatment. AB - This 30-mo randomized clinical trial compared the effectiveness of 2 concentrations (12% or 38%) of silver diamine fluoride (SDF) and 2 periodicity of application (once or twice a year) in arresting cavitated dentin caries in primary teeth. Children aged 3 to 4 y who had at least 1 active cavitated caries lesion were enrolled and randomly allocated into 4 groups for intervention. Group 1 had 12% SDF applied annually (every 12 mo), group 2 had 12% SDF applied semiannually (every 6 mo), group 3 had 38% SDF applied annually, and group 4 had 38% SDF applied semiannually. Clinical examinations were performed semiannually in kindergarten by a single examiner to investigate whether the SDF-treated caries became arrested. A total of 888 children with 4,220 decayed tooth surfaces received SDF application at baseline, and 799 (90.0%) children with 3,790 surfaces (89.8%) were evaluated at the 30-mo examination. The caries arrest rates were 55.2%, 58.6%, 66.9%, and 75.7% for groups 1, 2, 3, and 4, respectively ( P < 0.001). Caries treated with 38% SDF had a higher chance of becoming arrested than those treated with 12% SDF (odds ratio [OR], 1.98; 95% confidence interval [CI], 1.51-2.60, P < 0.001). The interaction between frequency of SDF application and visible plaque index (VPI) score was significant ( P = 0.017). Among those children who received annual SDF application, children with a higher VPI score had a lower chance to have their caries become arrested (OR, 0.59, 95% CI, 0.49 0.72). In conclusion, SDF at a concentration of 38% is more effective than that of 12% in arresting active caries in primary teeth. For children with poor oral hygiene, caries arrest rate of SDF treatment can be increased by increasing the frequency of application from annually to semiannually ( ClinicalTrials.gov NCT02385474). PMID- 28846470 TI - Open Spaces and Running into Clarity. PMID- 28846471 TI - CIMT 2017: Anniversary symposium - Report on the 15th CIMT Annual Meeting of the Association for Cancer Immunotherapy. PMID- 28846472 TI - The current state of food allergy therapeutics. AB - The prevalence of IgE mediated food allergy is an increasing public health concern. The current standard of treatment is strict avoidance of the offending food(s). There are no FDA approved treatments for food allergy. This review will provide an overview of strategies currently under investigation for the treatment of food allergy. The main focus of research has been directed at various forms of immunotherapy, including oral, sublingual and epicutaneous delivery routes. While oral immunotherapy (OIT) has shown the greatest promise for efficacy in terms of amount of protein that can be ingested, it has also demonstrated less tolerability and a less favorable safety profile as compared to sublingual immunotherapy (SLIT) and epicutaneous immunotherapy (EPIT), which offers the least protection but has the best safety and tolerability profile. Investigation is also underway for modified antigens that may be used for immunotherapy and for adjuncts that may help facilitate immunotherapy, including biologics such as anti IgE therapy, and also probiotics. There are also a number of preclinical concepts that are being evaluated to manipulate the antigens and/or the immune system that may one day be translatable to patients. PMID- 28846475 TI - The "Surprise Question" Asked of Emergency Physicians May Predict 12-Month Mortality among Older Emergency Department Patients. AB - BACKGROUND: Identification of older adults with serious illness (life expectancy less than one year) who may benefit from serious illness conversations or other palliative care interventions in the emergency department (ED) is difficult. OBJECTIVES: To assess the performance of the "surprise question (SQ)" asked of emergency physicians to predict 12-month mortality. DESIGN: We asked attending emergency physician "Would you be surprised whether this patient died in the next 12 months?" regarding patients >=65 years old that they had cared for that shift. We prospectively obtained death records from Massachusetts Department of Health Vital Records. SETTING: An urban, university-affiliated ED. MEASUREMENT: Twelve month mortality. RESULTS: We approached 38 physicians to answer the SQ, and 86% participated. The mean age of our cohort was 76 years, 51% were male, and 45% had at least one serious illness. Out of 207 patients, the physicians stated that they "would not be surprised" if the patient died in the next 12 months for 102 of the patients (49%); 44 of the 207 patients (21%) died within 12 months. The SQ demonstrated sensitivity of 77%, specificity of 56%, positive predictive value of 32%, and negative predictive value of 90%. When combined with other predictors, the model sorted the patient who lived from the patient who died correctly 72% of the time (c-statistic = 0.72). CONCLUSION: Use of the SQ by emergency physicians may predict 12-month mortality in older ED patients and may help emergency physicians identify older adults in need of palliative care interventions. PMID- 28846473 TI - Methods for ascertaining norovirus disease burdens. AB - Norovirus is the commonest cause of gastrointestinal disease worldwide in. Infections with norovirus occur in all age groups, however, the highest incidence is in children aged less than five years. Surveillance of norovirus is complicated because most people do not contact medical services when they are ill. Nevertheless, Public health laboratory surveillance worldwide has demonstrated the dominance of GII.4 viruses in the population. Better epidemiological surveillance and outbreak investigations, coupled with wider implementation of molecular-based laboratory diagnostics are leading to better estimates of the burden of norovirus infections as well as improved outbreak control. Recent advances in cell culture systems for norovirus and current research investigating the distribution of norovirus-associated disease in the population, for whom the disease burden is greatest, understanding host susceptibility factors, and methodologies for ascertaining cases, are important in increasing our understanding of norovirus. The key to surveillance of norovirus is allying the epidemiology with surveillance of virology. With recent advances in laboratory culture systems for norovirus, next generation sequencing technologies, improved diagnostics and measuring phenotypic characteristics of noroviruses, there are new opportunities to advance understanding of this common and important human pathogen that will help design strategies for vaccine and antiviral development, and how these might be best deployed to control norovirus infection. PMID- 28846474 TI - Extracellular Distribution of Collagen II and Perifibrillar Adapter Proteins in Healthy and Osteoarthritic Human Knee Joint Cartilage. AB - Perifibrillar adapter proteins, interconnecting collagen fibrils, and linking the collagen network with the aggrecan matrix seem to play a crucial role in the pathogenesis of osteoarthritis (OA). Therefore, we examined immunohistochemically the extracellular distribution of collagen II and the main perifibrillar adapter proteins-collagen IX, decorin, cartilage oligomeric matrix protein (COMP), and matrilin-3-in human samples of healthy (n=4) and OA (n=42) knee joint cartilage. Histopathology assessment was performed using an OA score. Staining patterns were evaluated in relation to the disease stage. The perifibrillar adapter proteins were uniformly distributed in the upper zones of healthy cartilage. In moderate OA (n=8; score 14.3 +/- 4.7), all proteins analyzed were locally absent in the fibrillated area or the superficial and upper mid zone. In advanced OA (n=20; score 18.9 +/- 5.3), they were uniformly distributed in these zones and accumulated pericellularly. Perifibrillar adapter proteins are important for the stabilization of the collagen network in the upper zones of healthy cartilage. Their degradation might be a critical event in early OA. In advanced OA, there are indications for an increased synthesis in an attempt to regenerate the lost tissue and to protect the remaining cartilage from further destruction. PMID- 28846476 TI - Identification of multiple serine to asparagine sequence variation sites in an intended copy product of LUCENTIS(r) by mass spectrometry. AB - Patent expiration of first-generation biologics and the high cost of innovative biologics are 2 drivers for the development of biosimilar products. There are, however, technical challenges to the production of exact copies of such large molecules. In this study, we performed a head-to-head comparison between the originator anti-VEGF-A Fab product LUCENTIS(r) (ranibizumab) and an intended copy product using an integrated analytical approach. While no differences could be observed using size-exclusion chromatography, capillary electrophoresis-sodium dodecyl sulfate and potency assays, different acidic peaks were identified with cation ion exchange chromatography and capillary zone electrophoresis. Further investigation of the intact Fab, subunits and primary sequence with mass spectrometry demonstrated the presence of a modified light chain variant in the intended copy product batches. This variant was characterized with a mass increase of 27.01 Da compared to the originator sequence and its abundance was estimated in the range of 6-9% of the intended copy product light chain. MS/MS spectra interrogation confirmed that this modification relates to a serine to asparagine sequence variant found in the intended copy product light chain. We demonstrated that the integration of high-resolution and sensitive orthogonal technologies was beneficial to assess the similarity of an originator and an intended copy product. PMID- 28846477 TI - Modified Vaccinia virus Ankara-based vaccines in the era of personalized immunotherapy of cancer. AB - While interest in immunotherapies is renewed by the successful introduction of immune checkpoint blocking agent in the clinic, advances in genome sequencing are opening new possibilities in the design of increasingly personalized vaccines. Personalization of medicine can now be realistically contemplated at the single patient level. Unlike the previous generation of cancer vaccines, neoantigen directed vaccines would target truly specific tumor antigens resulting from acquired tumor genome mutations. Immune response induced by this next generation vaccine would not be subject to self-tolerance and will likely result to enhanced efficacy. Nevertheless, this new technologies can hold to their promises only if sponsors manage to meet several scientific, technical, logistical and regulatory challenges. In particular manufacturers will have to design, manufacture, and deliver to the patient a new pharmaceutical grade in a matters of weeks. In this paper, we briefly review current technologies currently tried at the translation of personalized vaccines and explore the possibilities offered by the Modified Vaccinia virus Ankara in this next wave of cancer vaccines. PMID- 28846479 TI - An Elegy for Miss Beverly. PMID- 28846480 TI - Influenza vaccine effectiveness against medically attended influenza illness in Beijing, China, 2014/15 season. AB - Influenza vaccination is the most effective way of preventing influenza infections but its coverage is extremely low in China. Poor influenza vaccine effectiveness (VE) was reported in the 2014/15 season in some Northern Hemisphere countries with a predominance of H3N2 viruses belonging to the 3C.2a clade. However, there is limited information regarding the preventive effect of influenza vaccination for the same season in China, in which H3N2 viruses belonging to the 3C.3a clade predominated. Through influenza virological surveillance in Beijing, China during the 2014/15 season, we estimated the influenza VE against medically attended influenza-like illness (ILI) associated with laboratory-confirmed influenza virus infection using a test-negative design, and the effect of prior vaccination on current vaccination was examined. In total, 9297 patients with ILI were enrolled in this study. Among them, 3434 (36.9%) tested positive for influenza viruses: 2167 (63.1%) for A(H3N2), 1261 (36.7%) for influenza B, and 3 (0.1%) for A(H1N1)pdm09. The adjusted VE was estimated as -25% (95% CI: -70%, 8%) against A(H3N2) and -8% (95% CI: -50%, 23%) against B, with an overall VE of -18% (95% CI: -49%, 6%). The overall VE estimate for patients who received 2014/15 vaccination only was -12% (-57%, 20%), while VE for patients who received both 2013/14 and 2014/15 vaccinations was -27% (-72%, 7%). There was no evidence that the influenza vaccine protected vaccinees against medically attended influenza in Beijing, China during the 2014/15 season. PMID- 28846481 TI - Effectiveness of Combined Tear Film Therapy in Patients with Evaporative Dry Eye with Short Tear Film Breakup Time. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of combined tear film therapy targeted to aqueous, mucin, and lipid layers in patients with refractory evaporative dry eye (EDE) with short tear film breakup time (TBUT). METHODS: The patients who had EDE with short TBUT and severe symptoms refractory to artificial tears were treated with hyaluronic acid (HA) 0.15% and diquafosol tetrasodium (DQS) 3% (Group 1), HA and carbomer-based lipid-containing eyedrops (Liposic EDO Gel, LPO) (Group 2), or HA, DQS, and LPO (Group 3). Ocular Surface Disease Index (OSDI) score, visual analog scale (VAS) symptom score, TBUT, Schirmer score, and corneal and conjunctival staining scores were evaluated, and noninvasive tear film breakup time (NIBUT) and tear meniscus height were measured using Keratograph(r) 5 M before and 1 and 3 months after treatment. RESULTS: OSDI scores, VAS scores, TBUT, and NIBUT were improved at 1 and 3 months after treatment in all groups (all P < 0.05). At each follow-up visit, the total OSDI, OSDI symptom, and all VAS scores were significantly lower in group 3 compared with groups 1 and 2 (all P < 0.05). In addition, TBUT and NIBUT were significantly higher in group 3 compared with groups 1 and 2 (all P < 0.05). No significant adverse effects were noted in the groups during treatment. CONCLUSIONS: Mucin or lipid-targeting agents combined with aqueous supplements in patients with refractory EDE with short TBUT might improve subjective symptoms and TBUT. Of this, targeting whole tear film layers was most effective in improving ocular symptoms and tear film quality. PMID- 28846482 TI - Valved Holding Chambers and In Vitro Metered Dose Inhaler Performance: Effects of Flow Rate and Inhalation Delay. AB - BACKGROUND: Multiple factors may influence the performance of a metered dose inhaler (MDI) when used with a valved holding chamber (VHC or "spacer"). METHODS: Andersen Cascade Impactor measurements were conducted for three MDI products and two different VHCs using a specially designed system that accommodated variable delay times between MDI actuation and introduction of the aerosol into the impactor, and allowed reduced flow through the VHC while the impactor was operated at 28.3 L/min. Deposited drug mass and aerodynamic particle size distribution were determined using validated high-performance liquid chromatography (HPLC) methods. A two-level, three-factor full-factorial design of experiments (DOE) design was applied to assess the influences of VHC type, flow rate, and inhalation delay on a total of seven performance characteristics for each MDI product. An experiment without a VHC was added to assess the influence of VHC presence. RESULTS: DOE study shows the presence and type of VHC are the major influences on emitted dose and respirable fraction. Following the VHC effect, the inhalation delay has the most significant influence on most MDI performance metrics-emitted dose, respirable particle dose and fraction (aerosols between 1.1 and 4.7 MUm), and fine particle dose and fraction (aerosols under 4.7 MUm). CONCLUSION: This study illustrates the use of DOE analysis to effectively assess the effects of patient handling parameters (flow rate and inhalation delay) on the performance of MDI drugs when used with a VHC. The results of this study will inform Food and Drug Administration reviewers, the pharmaceutical industry, and healthcare practitioners as to safe and effective use of MDI products when used in conjunction with spacer devices. PMID- 28846478 TI - New roles for Dicer in the nucleolus and its relevance to cancer. AB - The nucleolus is a distinct compartment of the nucleus responsible for ribosome biogenesis. Mis-regulation of nucleolar functions and of the cellular translation machinery has been associated with disease, in particular with many types of cancer. Indeed, many tumor suppressors (p53, Rb, PTEN, PICT1, BRCA1) and proto oncogenes (MYC, NPM) play a direct role in the nucleolus, and interact with the RNA polymerase I transcription machinery and the nucleolar stress response. We have identified Dicer and the RNA interference pathway as having an essential role in the nucleolus of quiescent Schizosaccharomyces pombe cells, distinct from pericentromeric silencing, by controlling RNA polymerase I release. We propose that this novel function is evolutionarily conserved and may contribute to the tumorigenic pre-disposition of DICER1 mutations in mammals. PMID- 28846483 TI - Palliative Care Needs in an Acute Internal Medicine Ward in Mexico. AB - BACKGROUND: Palliative care is an evolving but underdeveloped practice in Mexico. OBJECTIVE: The primary end point of this prospective observational study was to identify internal medicine inpatients fulfilling advanced criteria within a second-level hospital. Secondary end points were symptom burden, treatment, resource utilization, and one-year survival. DESIGN AND MEASUREMENTS: The 390 sample size calculation was based on previous studies where 15% of inpatients fulfilled palliative care needs. Consecutive admissions were assessed to identify patients with any of the following: cancer, cardiac, renal, hepatic insufficiency, COPD, AIDS, stroke, or fragility until sample size was completed. After obtaining informed consent, interview to patient, attending physician, and chart review was completed to identify any of the following advanced disease criteria in each patient: (1) Surprise question to attending physician of the possibility of the patient dying in the following year, (2) Palliative Performance Scale (PPS) <50, and (3) Advanced disease specific criteria. Interview also included presence of symptoms, functional capacity, and previous resource utilization. Treatment offered was analyzed only on day of admission. One-year follow-up to assess survival was done through the state death certificates. RESULTS: Out of 390 patients, 131 (34%) had any of the diseases studied. Out of 131 patients, 86 (66%) had at least one of the three inclusion criteria for advanced disease. Out of 86 patients, 70 (81%) advanced disease patients died after one-year follow-up. Comparison between patients with no advanced disease (no criteria) versus advanced disease (at least one criteria) showed a significant difference in mean PPS, nutrition status, survival days, inhospital death, weight loss, dependency on activities of daily living, and previous multiple emergency room visits. Advanced disease patients with no death at one year follow-up had significantly more new admissions to that hospital. CONCLUSIONS: The number of patients requiring palliative care in internal medicine wards may be excessive to the current palliative care structures available. PMID- 28846485 TI - Plant-made vaccines and reagents for the One Health initiative. AB - The One Health initiative is increasingly becoming a prominent discussion topic in animal and human health, with its focus on prevention of spread of zoonotic diseases, both in animals, and from animals to humans. An important part of One Health is that diagnostics and vaccines for diseases may be the same thing - and be used for both humans and animals. One potential problem standing in the way of wider adoption of One Health principles, though, is that use of conventional cell fermentation systems for production of the recombinant proteins that could be used as diagnostics or vaccines is often expensive and is not easily scalable. A solution to this may be the use of plants or plant cells as bioreactors: molecular farming, or the production of biologics in plants, is now a well established science with many proofs of principle and important proofs of efficacy for especially animal vaccines. This review discusses how molecular farming could enable important advances in One Health, using as examples plant made vacccines, reagents and therapeutics for influenza viruses, ebolaviruses, rabies virus, bunyaviruses and flaviviruses. PMID- 28846486 TI - Flexible Automation System for Determination of Elemental Composition of Incrustations in Clogged Biliary Endoprostheses Using ICP-MS. AB - Automation systems are well established in industries and life science laboratories, especially in bioscreening and high-throughput applications. An increasing demand of automation solutions can be seen in the field of analytical measurement in chemical synthesis, quality control, and medical and pharmaceutical fields, as well as research and development. In this study, an automation solution was developed and optimized for the investigation of new biliary endoprostheses (stents), which should reduce clogging after implantation in the human body. The material inside the stents (incrustations) has to be controlled regularly and under identical conditions. The elemental composition is one criterion to be monitored in stent development. The manual procedure was transferred to an automated process including sample preparation, elemental analysis using inductively coupled plasma mass spectrometry (ICP-MS), and data evaluation. Due to safety issues, microwave-assisted acid digestion was executed outside of the automation system. The performance of the automated process was determined and validated. The measurement results and the processing times were compared for both the manual and the automated procedure. Finally, real samples of stent incrustations and pig bile were analyzed using the automation system. PMID- 28846484 TI - Vaccines for emerging infectious diseases: Lessons from MERS coronavirus and Zika virus. AB - The past decade and a half has been characterized by numerous emerging infectious diseases. With each new threat, there has been a call for rapid vaccine development. Pathogens such as the Middle East Respiratory Syndrome coronavirus (MERS-CoV) and the Zika virus represent either new viral entities or viruses emergent in new geographic locales and characterized by novel complications. Both serve as paradigms for the global spread that can accompany new pathogens. In this paper, we review the epidemiology and pathogenesis of MERS-CoV and Zika virus with respect to vaccine development. The challenges in vaccine development and the approach to clinical trial design to test vaccine candidates for disease entities with a changing epidemiology are discussed. PMID- 28846487 TI - Development of an Intelligent Spacer Data Logger System. AB - BACKGROUND: Although delivery of drugs from pressurized metered dose inhalers (pMDIs) via spacer devices is widespread it cannot be assumed that patients take their medication as prescribed or use their spacer appropriately. We developed a Spacer Data Logger device to record patient adherence and whether patients had shaken the pMDI, actuated it soon after shaking, and inhaled a sufficient volume from it. METHODS: We report an assessment of the Spacer Data Logger to measure and record that the pMDI was adequately shaken, the time to actuation, and the volume "inhaled" from the spacer up to 26 seconds after actuation. The effect of a delay in actuation following shaking on the dose available for inhalation from the spacer and the effect of a delay in extraction of aerosol from the spacer were assessed using different strengths of beclomethasone dipropionate (50 and 100 MUg) and fluticasone propionate (50, 125 and 250 MUg). RESULTS: The volumes measured by the Spacer Data Logger were in close agreement with the reference volumes of four simulated breathing patterns. A delay between shaking and actuating the pMDI resulted in a significant increase in the dose available for inhalation after only 4 seconds for the 50 and 250 MUg strengths of fluticasone propionate pMDIs (p = 0.004 and p < 0.001, respectively). A delay between actuation of the drug into the spacer and "inhalation" of aerosol from the spacer also resulted in a steady decline in the dose available from the spacer (p < 0.0001). CONCLUSIONS: These results confirmed the importance of using the pMDI spacer correctly by actuating directly after shaking and inhaling the aerosol from the spacer as soon after actuation as possible to optimize the dose available for inhalation. The Spacer Data Logger should be a useful tool to determine adherence to and "optimum" use of pMDI spacers in patients with asthma and chronic obstructive pulmonary disease (COPD). PMID- 28846488 TI - Circulating Tumor DNA: Measurement and Clinical Utility. AB - Circulating tumor DNA (ctDNA) is a component of the "naked" DNA found in blood. It can be isolated from plasma and represents combined genetic material from the primary tumor and metastases. Quantitative and qualitative information about a cancer, including mutations, can be derived using digital polymerase chain reaction and other technologies. This "liquid biopsy" is quicker and more easily repeated than tissue biopsy, yields real-time information about the cancer, and may suggest therapeutic options. All stages of cancer therapy have the ability to benefit from ctDNA, starting with screening for cancer before it is clinically apparent. During treatment of metastatic disease, it is useful to predict response and monitor disease progression. Currently, ctDNA is used in the clinic to select patients who may benefit from epidermal growth factor receptor-targeted therapy in non-small cell lung cancer. In the future, ctDNA technology promises useful applications in every part of clinical oncology care. PMID- 28846489 TI - Zika, Chikungunya, and Other Emerging Vector-Borne Viral Diseases. AB - Arthropod-borne viruses (arboviruses) have a long history of emerging to infect humans, but during recent decades, they have been spreading more widely and affecting larger populations. This is due to several factors, including increased air travel and uncontrolled mosquito vector populations. Emergence can involve simple spillover from enzootic (wildlife) cycles, as in the case of West Nile virus accompanying geographic expansion into the Americas; secondary amplification in domesticated animals, as seen with Japanese encephalitis, Venezuelan equine encephalitis, and Rift Valley fever viruses; and urbanization, in which humans become the amplification hosts and peridomestic mosquitoes, mainly Aedes aegypti, mediate human-to-human transmission. Dengue, yellow fever, chikungunya, and Zika viruses have undergone such urban emergence. We focus mainly on the latter two, which are recent arrivals in the Western Hemisphere. We also discuss a few other viruses with the potential to emerge through all of these mechanisms. PMID- 28846490 TI - Post-marketing surveillance study to assess the safety and tolerability of an Inactivated Poliomyelitis Vaccine in Indian children. AB - OBJECTIVE: To evaluate the incidence of adverse events following administration of an Inactivated poliomyelitis vaccine (IPV) manufactured by Serum Institute of India Pvt. Ltd., Pune, India. METHODS: A single 0.5 ml dose of the IPV was administered intramuscularly to children attending private clinics or out-patient department of hospitals for routine immunization across different cities in India. They were observed over a period of 30 d for local or systemic adverse events and rare case of anaphylaxis, if any. RESULTS: A total of 2210 children were enrolled of which 2120 children received the vaccine within primary immunization series and 90 children received booster dose. The common adverse events reported were pain, erythema, swelling and fever. No serious adverse event was reported during the study period. CONCLUSIONS: Poliomyelitis vaccine (Inactivated) manufactured by Serum Institute of India Pvt. Ltd., Pune can be safely administered to children following the Expanded Programme on Immunization or World Health Organization recommended immunization schedule. PMID- 28846491 TI - Human papilloma virus vaccine for low and middle income countries: A step too soon? AB - Cervical Cancer is the most common genital cancer in women in India. Human papilloma virus (HPV) causes precancerous lesions that often develop into cervical cancer suggesting that cervical cancer has an infective etiology and is potentially preventable by preventing HPV infection through the use of HPV vaccines. The incidence in developing nations is largely under-reported due to large population size, poor and incomplete database. HPV vaccine is being considered for inclusion in the immunization schedule of developing countries. An effective surveillance system for a vaccine requires that the baseline incidence, prevalence, and mortality rates of cervical cancer are established for a given population. The lessons learnt from the polio vaccine must be applied to every vaccine being introduced for its optimal utilization. HPV vaccines might be used as a cost-effective scientific intervention to prevent cervical cancer but need to be combined with good screening methods in developing countries for a paradigm shift in the management of cervical cancer. PMID- 28846492 TI - Planktonic Subsidies to Surf-Zone and Intertidal Communities. AB - Plankton are transported onshore, providing subsidies of food and new recruits to surf-zone and intertidal communities. The transport of plankton to the surf zone is influenced by wind, wave, and tidal forcing, and whether they enter the surf zone depends on alongshore variation in surf-zone hydrodynamics caused by the interaction of breaking waves with coastal morphology. Areas with gently sloping shores and wide surf zones typically have orders-of-magnitude-higher concentrations of plankton in the surf zone and dense larval settlement in intertidal communities because of the presence of bathymetric rip currents, which are absent in areas with steep shores and narrow surf zones. These striking differences in subsidies have profound consequences; areas with greater subsidies support more productive surf-zone communities and possibly more productive rocky intertidal communities. Recognition of the importance of spatial subsidies for rocky community dynamics has recently advanced ecological theory, and incorporating surf-zone hydrodynamics would be an especially fruitful line of investigation. PMID- 28846493 TI - LncRNAs in Secondary Hair Follicle of Cashmere Goat: Identification, Expression, and Their Regulatory Network in Wnt Signaling Pathway. AB - Long noncoding RNAs (lncRNAs) are a novel class of eukaryotic transcripts. They are thought to act as a critical regulator of protein-coding gene expression. Herein, we identified and characterized 13 putative lncRNAs from the expressed sequence tags from secondary hair follicle of Cashmere goat. Furthermore, we investigated their transcriptional pattern in secondary hair follicle of Liaoning Cashmere goat during telogen and anagen phases. Also, we generated intracellular regulatory networks of upregulated lncRNAs at anagen in Wnt signaling pathway based on bioinformatics analysis. The relative expression of six putative lncRNAs (lncRNA-599618, -599556, -599554, -599547, -599531, and -599509) at the anagen phase is significantly higher than that at telogen. Compared with anagen, the relative expression of four putative lncRNAs (lncRNA-599528, -599518, -599511, and -599497) was found to be significantly upregulated at telogen phase. The network generated showed that a rich and complex regulatory relationship of the putative lncRNAs and related miRNAs with their target genes in Wnt signaling pathway. Our results from the present study provided a foundation for further elucidating the functional and regulatory mechanisms of these putative lncRNAs in the development of secondary hair follicle and cashmere fiber growth of Cashmere goat. PMID- 28846494 TI - Dietary Sodium Butyrate Supplementation Promotes Oxidative Fiber Formation in Mice. AB - Sodium butyrate (SB), a sodium salt of butyric acid, has been shown to improve the animal production performance. The aim of this work was to test the effect of feeding mice with diets containing different dose of SB (1, 3, and 5%) on oxidative fiber formation. Dietary SB supplementation had no effect on body weights and food intakes. Dietary SB supplementation upregulated the expressions of oxidative fiber-related protein including MyHC I, MyHC IIa, myoglobin, and troponin-I-slow. Dietary SB supplementation also upregulated the expressions of phospho-FoxO1 and MEF2C protein, but did not affect total FoxO1 protein expression. Taken together, these results indicate that dietary SB supplementation promotes oxidative fiber formation in mice, which might be through inactivation of FoxO1 and upregulation of MEF2C expression. PMID- 28846495 TI - Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. AB - Purpose To perform a systematic review and meta-analysis to determine if there are differences in rates of immediate allergic events between classes of gadolinium-based contrast agents (GBCAs). Materials and Methods PubMed and Google Scholar databases were searched for studies in which rates of immediate adverse events to GBCAs were reported. The American College of Radiology classification system was used to characterize allergic-like events as mild, moderate, or severe, and the total number of administrations of each GBCA was recorded. Where necessary, authors of studies were contacted to clarify data and eliminate physiologic reactions. Relative risks of GBCA types were estimated by using the Mantel-Haenszel type method. Results Nine studies in which immediate reactions to GBCA were recorded from a total of 716 978 administrations of GBCA met the criteria for inclusion and exclusion. The overall rate of patients who had immediate allergic-like reactions was 9.2 per 10 000 administrations and the overall rate of severe immediate allergic-like reactions was 0.52 per 10 000 administrations.. The nonionic linear chelate gadodiamide had the lowest rate of reactions, at 1.5 (95% confidence interval [CI]: 0.74, 2.4) per 10 000 administrations, which was significantly less than that of linear ionic GBCAs at 8.3 (95% CI: 7.5, 9.2) per 10 000 administrations (relative risk, 0.19 [95% CI: 0.099, 0.36]; P < .00001) and less than that for nonionic macrocyclic GBCAs at 16 (95% CI: 14, 19) per 10 000 administrations (relative risk, 0.12 [95% CI: 0.05, 0.31]; P < .001). GBCAs known to be associated with protein binding had a higher rate of reactions, at 17 (95% CI: 15, 20) per 10 000 administrations compared with the same chelate classification without protein binding, at 5.2 (95% CI: 4.5, 6.0) per 10 000 administrations (relative risk, 3.1 [95% CI: 2.4, 3.8]; P < .0001). Conclusion These data show the lowest rate of immediate allergic adverse events with use of the nonionic linear GBCA gadodiamide in comparison with those of ionic linear or nonionic macrocyclic GBCAs. A higher rate of immediate allergic adverse events was associated with ionicity, protein binding, and macrocyclic structure. (c) RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on August 31, 2017. PMID- 28846496 TI - Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study. AB - Purpose To develop, evaluate, and demonstrate the feasibility of a whole-body protocol for simultaneous assessment of tissue-specific insulin-mediated fluorine 18 (18F) fluorodeoxyglucose (FDG) influx rates, tissue depots, and whole-body insulin sensitivity (referred to as the M value). Materials and Methods An integrated positron emission tomography (PET)/magnetic resonance (MR) imaging system combined with hyperinsulinemic euglycemic clamp (HEC) was used. Dynamic whole-body PET imaging was used to determine the insulin-mediated 18F-FDG tissue influx rate (Ki) in the whole-body region by using the Patlak method. M value was determined with the HEC method at PET imaging. Tissue depots were quantified by using water-fat separated MR imaging and manual segmentations. Feasibility of the imaging protocol was demonstrated by using five healthy control participants and five patients with type 2 diabetes. Associations between M value and Ki were studied in multiple tissues by using the Pearson correlation. Results Positive correlations were found between M value and Ki in multiple tissues: the gluteus muscle (r = 0.875; P = .001), thigh muscle (r = 0.903; P , .001), calf muscle (r = 0.825; P = .003), and abdominal visceral adipose tissue (r = 0.820; P = .004). A negative correlation was found in the brain (r = 20.798; P = .006). The MR imaging-based method for quantification of tissue depots was feasible for determining adipose tissue volumes and fat fractions. Conclusion This PET/MR imaging protocol may be feasible for simultaneous assessment of tissue-specific insulin-mediated 18F-FDG influx rates, tissue depots, and M value. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28846497 TI - The Efficacy of a Novel Surgical Device in Preventing Intraoperative Wound Contamination in an In Vivo Porcine Model. AB - BACKGROUND: Surgical site infections (SSIs) remain a morbid and costly complication in abdominal surgery. Topical antibiotic delivery via intraoperative irrigation and barrier wound protection are strategies for preventing SSI. We tested the safety and efficacy of a novel wound protector device with an integrated fluid irrigation platform in a porcine model. METHODS: A simulated colorectal resection model was designed and performed on adult female pigs with a standardized concentration of 109 colony-forming units (CFU) of Escherichia coli administered to the wound site in 10 mL of normal saline (n = 7). The device was tested intraoperatively with and without irrigation with gentamicin-containing irrigant solution. Swab and tissue samples were obtained in addition to peripheral blood samples. Quantitative culture analysis was performed in addition to histological and immunohistochemical analysis and gentamicin concentration measurements. RESULTS: There were no adverse events observed in the animals. Tissue protected by the device yielded exponentially lower levels of E. coli growth compared to exposed tissue, with a mean 1 * 102 CFU/swab. Use of the device, both with and without irrigation, was associated with an exponential reduction in quantitative bacterial load compared to the control wounds with no device, with limited growth after wound closure in the pigs receiving irrigation. Histology and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining analysis revealed no significant damage to tissue. Serum gentamicin levels remained below the clinical threshold and decreased over time. CONCLUSIONS: This in vivo study suggests safety and efficacy of a novel device for the prevention of intraoperative wound contamination. PMID- 28846499 TI - Letter to the editor: Attention restoration in natural environments: Mixed mythical metaphors for meta-analysis. PMID- 28846498 TI - Benefits of incorporating the adaptive dynamic range optimization amplification scheme into an assistive listening device for people with mild or moderate hearing loss. AB - This study investigated whether a self-designed assistive listening device (ALD) that incorporates an adaptive dynamic range optimization (ADRO) amplification strategy can surpass a commercially available monaurally worn linear ALD, SM100. Both subjective and objective measurements were implemented. Mandarin Hearing-In Noise Test (MHINT) scores were the objective measurement, whereas participant satisfaction was the subjective measurement. The comparison was performed in a mixed design (i.e., subjects' hearing status being mild or moderate, quiet versus noisy, and linear versus ADRO scheme). The participants were two groups of hearing-impaired subjects, nine mild and eight moderate, respectively. The results of the ADRO system revealed a significant difference in the MHINT sentence reception threshold (SRT) in noisy environments between monaurally aided and unaided conditions, whereas the linear system did not. The benchmark results showed that the ADRO scheme is effectively beneficial to people who experience mild or moderate hearing loss in noisy environments. The satisfaction rating regarding overall speech quality indicated that the participants were satisfied with the speech quality of both ADRO and linear schemes in quiet environments, and they were more satisfied with ADRO than they with the linear scheme in noisy environments. PMID- 28846500 TI - Neuro-, Cardio-, and Immunoplasticity: Effects of Early Adversity. AB - The relationship between early adversity and outcomes across the lifespan is apparent in a striking range of measures. Evidence suggests that many of these outcomes can be traced to the impacts of early adversity on multiple and integrated biological systems mediated by the brain. In this review, we integrate empirical and theoretical advances in the understanding of relationships among the brain and the functions of the endocrine, autonomic, and immune systems. We emphasize the effects of environmental experiences related to caregiver relationships because it is these experiences, in particular, that shape regulatory and threat response systems in ways that increase vulnerability and may underlie the wide range of poor outcomes associated with early adversity. Thus, we metaphorically extend the concept of plasticity to highlight our goal of a broader consideration of these interconnected mechanisms. We conclude by discussing implications for neurobiologically informed interventions that can potentially ameliorate the broad and costly effects of early adversity. PMID- 28846501 TI - Rapid Source-Control Laparotomy: Is There a Mortality Benefit? AB - BACKGROUND: The purpose of this study was to determine the influence rapid source control laparotomy (RSCL) has on the mortality rate in non-trauma patients with intra-abdominal infection. The hypothesis was that RSCL reduces deaths and hospital lengths of stay (LOS) in patients compared with definitive repair and primary fascial closure (PFC). METHODS: The International Classification of Diseases-10 codes for sepsis, gastric and duodenal ulcer perforation or hemorrhage, incisional or ventral hernia with obstruction, intestinal volvulus, ileus with obstruction, diverticulitis with perforation or abscess, vascular disorder of intestine, non-traumatic intestinal perforation, peritoneal abscess, and unspecified peritonitis were used to query the 2015 National Surgical Quality Improvement Project (NSQIP) database for all patients treated with either RSCL or PFC. The two groups of patients were compared on the basis of LOS and deaths. Collected data included age, gender, body mass index (BMI), site classification, American Society of Anesthesiologists (ASA) class, operative time, number of risk factors, and pre-operative septic state. RESULTS: After adjusting for the aforementioned variables, propensity score-matched cohorts (n = 210 in each cohort) were used to evaluate the influence of incision closure type on LOS and mortality rate. The odds of death (31.4% vs. 21.4%) with RSCL was 1.78 (95% confidence interval 1.08-2.95; p = 0.02) times that of PFC. Closure type was not significantly associated with an increased LOS (median 14 vs. 11 days; p = 0.35). CONCLUSIONS: This retrospective cohort analysis demonstrated that RSCL is associated with higher odds of death in general surgical patients with intra abdominal infection. There is a need for further studies to delineate what, if any, physiologic parameters indicate a need for RSCL. PMID- 28846503 TI - Does Self-Control Training Improve Self-Control? A Meta-Analysis. AB - Self-control is positively associated with a host of beneficial outcomes. Therefore, psychological interventions that reliably improve self-control are of great societal value. A prominent idea suggests that training self-control by repeatedly overriding dominant responses should lead to broad improvements in self-control over time. Here, we conducted a random-effects meta-analysis based on robust variance estimation of the published and unpublished literature on self control training effects. Results based on 33 studies and 158 effect sizes revealed a small-to-medium effect of g = 0.30, confidence interval (CI95) [0.17, 0.42]. Moderator analyses found that training effects tended to be larger for (a) self-control stamina rather than strength, (b) studies with inactive compared to active control groups, (c) males than females, and (d) when proponents of the strength model of self-control were (co)authors of a study. Bias-correction techniques suggested the presence of small-study effects and/or publication bias and arrived at smaller effect size estimates (range: gcorrected = .13 to .24). The mechanisms underlying the effect are poorly understood. There is not enough evidence to conclude that the repeated control of dominant responses is the critical element driving training effects. PMID- 28846504 TI - A Mobile Health Data Collection System for Remote Areas to Monitor Women Participating in a Cervical Cancer Screening Campaign. AB - BACKGROUND: Barriers to efficient cervical cancer screening in low- and medium income countries include the lack of systematic monitoring of the participants' data. The aim of this study was to assess the feasibility of a mobile health (m Health) data collection system to facilitate monitoring of women participating to cervical cancer screening campaign. METHODS: Women aged 30-65 years, participating in a cervical cancer screening campaign in Ambanja, Madagascar, were invited to participate in the study. Cervical Cancer Prevention System, an m Health application, allows the registration of clinical data, while women are undergoing cervical cancer screening. All data registered in the smartphone were transmitted onto a secure, Web-based platform through the use of an Internet connection. Healthcare providers had access to the central database and could use it for the follow-up visits. Quality of data was assessed by computing the percentage of key data missing. RESULTS: A total of 151 women were recruited in the study. Mean age of participants was 41.8 years. The percentage of missing data for the key variables was less than 0.02%, corresponding to one woman's medical history data, which was not sent to the central database. Technical problems, including transmission of photos, human papillomavirus test results, and pelvic examination data, have subsequently been solved through a system update. CONCLUSION: The quality of the data was satisfactory and allowed monitoring of cervical cancer screening data of participants. Larger studies evaluating the efficacy of the system for the women's follow-up are needed in order to confirm its efficiency on a long-term scale. PMID- 28846502 TI - Rare, high-affinity anti-pathogen antibodies from human repertoires, discovered using microfluidics and molecular genomics. AB - Affinity-matured, functional anti-pathogen antibodies are present at low frequencies in natural human repertoires. These antibodies are often excellent candidates for therapeutic monoclonal antibodies. However, mining natural human antibody repertoires is a challenge. In this study, we demonstrate a new method that uses microfluidics, yeast display, and deep sequencing to identify 247 natively paired anti-pathogen single-chain variable fragments (scFvs), which were initially as rare as 1 in 100,000 in the human repertoires. Influenza A vaccination increased the frequency of influenza A antigen-binding scFv within the peripheral B cell repertoire from <0.1% in non-vaccinated donors to 0.3-0.4% in vaccinated donors, whereas pneumococcus vaccination did not increase the frequency of antigen-binding scFv. However, the pneumococcus scFv binders from the vaccinated library had higher heavy and light chain Replacement/Silent mutation (R/S) ratios, a measure of affinity maturation, than the pneumococcus binders from the corresponding non-vaccinated library. Thus, pneumococcus vaccination may increase the frequency of affinity-matured antibodies in human repertoires. We synthesized 10 anti-influenza A and nine anti-pneumococcus full length antibodies that were highly abundant among antigen-binding scFv. All 10 anti-influenza A antibodies bound the appropriate antigen at KD<10 nM and neutralized virus in cellular assays. All nine anti-pneumococcus full-length antibodies bound at least one polysaccharide serotype, and 71% of the anti pneumococcus antibodies that we tested were functional in cell killing assays. Our approach has future application in a variety of fields, including the development of therapeutic antibodies for emerging viral diseases, autoimmune disorders, and cancer. PMID- 28846505 TI - Development and Validation of a Portable and Inexpensive Tool to Measure the Drop Vertical Jump Using the Microsoft Kinect V2. AB - BACKGROUND: Noncontact anterior cruciate ligament (ACL) injury in adolescent female athletes is an increasing problem. The knee-ankle separation ratio (KASR), calculated at initial contact (IC) and peak flexion (PF) during the drop vertical jump (DVJ), is a measure of dynamic knee valgus. The Microsoft Kinect V2 has shown promise as a reliable and valid marker-less motion capture device. HYPOTHESIS: The Kinect V2 will demonstrate good to excellent correlation between KASR results at IC and PF during the DVJ, as compared with a "gold standard" Vicon motion analysis system. STUDY DESIGN: Descriptive laboratory study. LEVEL OF EVIDENCE: Level 2. METHODS: Thirty-eight healthy volunteer subjects (20 male, 18 female) performed 5 DVJ trials, simultaneously measured by a Vicon MX-T40S system, 2 AMTI force platforms, and a Kinect V2 with customized software. A total of 190 jumps were completed. The KASR was calculated at IC and PF during the DVJ. The intraclass correlation coefficient (ICC) assessed the degree of KASR agreement between the Kinect and Vicon systems. RESULTS: The ICCs of the Kinect V2 and Vicon KASR at IC and PF were 0.84 and 0.95, respectively, showing excellent agreement between the 2 measures. The Kinect V2 successfully identified the KASR at PF and IC frames in 182 of 190 trials, demonstrating 95.8% reliability. CONCLUSION: The Kinect V2 demonstrated excellent ICC of the KASR at IC and PF during the DVJ when compared with the Vicon system. A customized Kinect V2 software program demonstrated good reliability in identifying the KASR at IC and PF during the DVJ. CLINICAL RELEVANCE: Reliable, valid, inexpensive, and efficient screening tools may improve the accessibility of motion analysis assessment of adolescent female athletes. PMID- 28846507 TI - Assessing Distance Training: How Well Does It Produce Psychoanalytic Psychotherapists? AB - How effective is psychoanalytic/psychodynamic distance training over the Internet? To assess this, we surveyed graduates of the 2-year and 4-year programs of the China America Psychoanalytic Alliance (CAPA). The main results of the 90 graduates' surveys showed that 77% of their work involves a psychoanalytic formulation of their cases as compared to other theoretical orientations. Graduates highly rated the effectiveness of their own psychoanalytic therapy over videoconferencing (VCON). Graduates' ratings of treatment with their patients over VCON positively correlated with years of psychoanalytic education, number of days a week in own treatment, years doing psychoanalytic treatment, and degree working with a psychoanalytic orientation. Graduates thought that therapist variables (skillfulness, warmth, empathy, and wisdom) were much more important in the effectiveness of their treatment than whether the treatment was in-person or with VCON, or the presence of cultural differences with their therapist. The graduates' ratings of how they are practicing psychoanalytic treatment were highly correlated with how their own therapists practiced psychoanalytic psychotherapy, as measured by the psychodynamic/interpersonal process items on the Comparative Psychotherapy Process Scale (CPPS). PMID- 28846508 TI - Editorial. PMID- 28846506 TI - Rare, high-affinity mouse anti-PD-1 antibodies that function in checkpoint blockade, discovered using microfluidics and molecular genomics. AB - Conventionally, mouse hybridomas or well-plate screening are used to identify therapeutic monoclonal antibody candidates. In this study, we present an alternative to hybridoma-based discovery that combines microfluidics, yeast single-chain variable fragment (scFv) display, and deep sequencing to rapidly interrogate and screen mouse antibody repertoires. We used our approach on six wild-type mice to identify 269 molecules that bind to programmed cell death protein 1 (PD-1), which were present at an average of 1 in 2,000 in the pre-sort scFv libraries. Two rounds of fluorescence-activated cell sorting (FACS) produced populations of PD-1-binding scFv with a mean enrichment of 800-fold, whereas most scFv present in the pre-sort mouse repertoires were de-enriched. Therefore, our work suggests that most of the antibodies present in the repertoires of immunized mice are not strong binders to PD-1. We observed clusters of related antibody sequences in each mouse following FACS, suggesting evolution of clonal lineages. In the pre-sort repertoires, these putative clonal lineages varied in both the complementary-determining region (CDR)3K and CDR3H, while the FACS-selected PD-1 binding subsets varied primarily in the CDR3H. PD-1 binders were generally not highly diverged from germline, showing 98% identity on average with germline V genes. Some CDR3 sequences were discovered in more than one animal, even across different mouse strains, suggesting convergent evolution. We synthesized 17 of the anti-PD-1 binders as full-length monoclonal antibodies. All 17 full-length antibodies bound recombinant PD-1 with KD < 500 nM (average = 62 nM). Fifteen of the 17 full-length antibodies specifically bound surface-expressed PD-1 in a FACS assay, and nine of the antibodies functioned as checkpoint inhibitors in a cellular assay. We conclude that our method is a viable alternative to hybridomas, with key advantages in comprehensiveness and turnaround time. PMID- 28846509 TI - Reliability and Validity of the Interpersonal Guilt Rating Scale-15: A New Clinician-Reporting Tool for Assessing Interpersonal Guilt According to Control Mastery Theory. AB - This article introduces the Interpersonal Guilt Rating Scale-15 (IGRS-15), a brief clinician-rated tool for the clinical assessment of interpersonal guilt as conceived in Control-Mastery Theory (CMT; Silberschatz, 2015; Weiss, 1993), and its psychometric proprieties. The items of the IGRS-15 were derived from the CMT clinical and empirical literature about guilt, and from the authors' clinical experiences. Twenty-eight clinicians assessed 154 patients with the IGRS-15, the patient self-reported Interpersonal Guilt Questionnaire-67 (IGQ-67; O'Connor, Berry, Weiss, Bush, & Sampson, 1997), and the Clinical Data Form (CDF; Westen & Shedler, 1999). A semi-exploratory factor analysis pointed to a four-factor solution in line with the kinds of guilt described in CMT: Survivor guilt, Separation/disloyalty guilt, Omnipotent responsibility guilt, and Self-hate. The test-retest reliability of the IGRS-15 was good. Moreover, the IGRS-15 showed good concurrent and discriminant validity with the IGQ-67. IGRS-15 represents a first step in the direction of supporting the clinical judgment about interpersonal guilt with an empirically sound and easy-to-use tool. PMID- 28846510 TI - Psychological Mindedness and Psychotherapy Process in Short-Term Group Therapy. AB - Psychological mindedness is regarded as an important patient characteristic that can influence the course of psychotherapy. The purpose of this study was to investigate the relationship between patients' capacity for psychological mindedness and aspects of the group psychotherapy process as experienced and rated by therapists and other group members. Participants were 110 patients who completed two forms of short-term group therapy for the treatment of complicated grief. Psychological mindedness was assessed at pretreatment by external raters using a video-interview procedure. Group therapists assessed patients' therapeutic work and therapeutic alliance following each group therapy session. Therapists and other group members rated each patient's expression of emotion and provided appraisals of their cohesion to each patient throughout the course of therapy. Psychological mindedness was found to be positively associated with several group process variables as rated by the therapist and other group members. PMID- 28846511 TI - Personality and Affect When the Central Nervous System is Sensitized: An Analysis of Central Sensitization Syndromes in a Substance Use Disorder Population. AB - Functional somatic syndromes, or more recently termed central sensitivity syndromes (CSS), comprise a significant portion of the chronic pain population. Although it is evident that personality is intricately related to the pain experience, it has not been widely studied. This article examines the impact of CSS on the clinical presentation of individuals presenting to treatment for a substance use disorder (SUD), with an emphasis on personality and emotional functioning. We examined personality profiles of individuals presenting to treatment with SUD between three groups: those with a CSS (n = 30), non-CSS chronic pain (n = 79), and no pain (n = 232). Based on previous research and a psychodynamic conceptualization of CSS, we hypothesized that predictors of the presence of a CSS in this sample would be higher rates of overall anxiety, traumatic stress, perfectionistic traits, and a need for interpersonal closeness. Logistic regression analyses did not support our hypothesis. Exploratory analyses indicated which personality traits most strongly predicted the presence of CSS. We discuss these findings using descriptive psychopathology literature, with recommendations for future research. PMID- 28846513 TI - Low-Volume High-Intensity Interval Training Is Sufficient to Ameliorate the Severity of Metabolic Syndrome. AB - BACKGROUND: High-intensity interval training (HIIT) is superior to moderate intensity continuous training (MICT) at improving cardiometabolic risk. However, the optimal volume of HIIT to reduce the severity of the metabolic syndrome (MetS) has yet to be investigated. The aim of this study was to examine the impact of different volumes of HIIT and MICT on MetS severity (MetS z-score). METHODS: This was a substudy of the "Exercise in prevention of Metabolic Syndrome" (EX-MET) multicenter trial, reporting data collected at the Brisbane site. Ninety-nine adults diagnosed with MetS were randomized to one of the following 16-week interventions: (1) MICT [n = 34, 30 min at 60%-70% heart rate (HR) peak/session, 150 min/week]; (2) 4HIIT (n = 34, 4 * 4 min bouts at 85%-95% HR peak, interspersed with 3 min active recovery at 50%-70% HR peak, 114 min/week); or (3) 1HIIT (n = 31, 1 * 4 min bout at 85%-95% HR peak, 51 min/week). Z-scores were derived from levels of MetS risk factors before and after the intervention. RESULTS: Eighty-one participants completed post-testing (MICT, n = 26; 4HIIT, n = 28, 1HIIT, n = 27). After excluding 16 participants who had a change in medication dosage or type during the intervention, a total of 65 participants were included in the analysis [MICT, n = 22, age 55 +/- 10 years, body mass index (BMI) 32 +/- 6 kg/m; 4HIIT, n = 22, 56 +/- 10 years, 35 +/- 9 kg/m2; 1HIIT, n = 21, 57 +/- 8 years, 32 +/- 5 kg/m). MetS severity reduced following all interventions (pre- to post-MetS z-score: MICT, 1.80 +/- 1.93 to 0.90 +/- 1.93; 4HIIT, 2.75 +/- 2.56 to 2.17 +/- 2.71; 1HIIT, 2.48 +/- 3.38 to 0.84 +/- 2.98), with no significant differences between groups. There were no reported adverse events that were directly related to the exercise interventions. CONCLUSIONS: Low-volume HIIT (51 min/week) was as effective as high-volume HIIT (114 min/week) and MICT (150 min/week) in ameliorating MetS severity. PMID- 28846514 TI - Should Long-Term Consequences of NICU Care Be Discussed in Terms of Prognostic Uncertainty or Possible Harm? AB - We will examine several ethical considerations in the resuscitation of infants born at the margin of gestational viability in analyzing a case of preterm labor. More specifically, we will discuss the obligations of physicians in characterizing expected outcomes, both mortality and long-term morbidity, for extremely premature infants and how potential adverse outcomes should be framed as complications of prematurity itself or as iatrogenic complications of care. We will also explore how the concept of a "trial of therapy" can support parents and neonatologists in decision making concerning withholding or withdrawing care for periviable infants. PMID- 28846515 TI - Should Clinicians Medicate against Structural Violence? Potential Iatrogenic Risks and the Need for Social Interventions. AB - This paper examines how a child psychiatrist might approach treatment of aggression in foster care youth. We argue that a multimodal approach is best. Physicians should weigh not only the iatrogenic risks of off-label antipsychotic medications but also the possible consequences of failing to treat complicating social factors at hand. Advocates must address structural violence and failures of imagination in their efforts to improve mental health equity among vulnerable youth. PMID- 28846516 TI - How Should Physicians Help Gender-Transitioning Adolescents Consider Potential Iatrogenic Harms of Hormone Therapy? AB - Counseling and treatment of transgender youth can be challenging for mental health practitioners, as increased availability of gender-affirming treatments in recent years raises ethical and clinical questions. Is a gender identity diagnosis helpful? What is the right time to treat, and should the adolescent's age matter in decision making? In this article, we discuss these questions in light of a case in which an adolescent wishes to pursue hormone therapy. Our analysis focuses on the importance of balanced decision making when counseling and treating adolescents with nonconforming gender identities. We argue that clinicians' communicating appropriate expectations about the effectiveness and limitations of hormone therapy and the risks of psychological and physical iatrogenic effects is critical. PMID- 28846517 TI - Clowning as a Complementary Approach for Reducing Iatrogenic Effects in Pediatrics. AB - Hospitalized children who undergo painful procedures are more susceptible than others to experiencing iatrogenic effects, such as anxiety, pain, and severe stress. Clowns in clinical setting have been found to be effective in reducing children's experiences of these effects during hospitalization and before procedures. This article provides an overview of clowning in health care settings; reviews major studies conducted on clowning for hospitalized children, discussing evidence that clown interventions decrease pain and distress in pediatric patients; and concludes with a discussion of health care clowning as a profession. PMID- 28846518 TI - Etiology and Manifestations of Iatrogenesis in Pediatrics. AB - There is general agreement in the literature of what ought to occur following iatrogenic harm. Senior members of the team should disclose what occurred and how the problem will be remedied. Those involved should express heartfelt regrets and apologize sincerely. But in the pediatric setting, parents, as surrogates, can sometimes place clinicians on the horns of a dilemma: respect parental autonomy, which may involve continuing nonadvised therapy, or uphold the patient's best interests, which may indicate another course of care. In other cases, clinicians themselves may initiate or continue care without real benefit. The young patients who may be harmed as a result often cannot understand an explanation, an apology, or, when warranted, receive reparation; what duties are owed them? In this paper, we first discuss iatrogenesis writ large and then propose the formulation of this concept in this latter context, where harm occurs as a result of counterpoise between two or more ethical obligations, which we term counterpoise iatrogenesis. We then articulate its etiology and manifestation through two true cases. We conclude with a re-examination of the meaning and function of autonomy in pediatrics and the designation of secondary victims. PMID- 28846519 TI - What Do Clinicians Caring for Children Need to Know about Pediatric Medical Traumatic Stress and the Ethics of Trauma-Informed Approaches? AB - Medical experiences can be frightening and traumatic for children. Ill and injured children can experience pediatric medical traumatic stress-psychological and physiological distress responses related to their medical event and subsequent medical treatment experiences-which can lead to symptoms of posttraumatic stress disorder (PTSD) and suboptimal health outcomes. Trauma informed care provides a framework for acknowledging, addressing, and mitigating the risks of psychological trauma associated with medical treatment experiences and is congruent with the ethical principles of respect for autonomy, beneficence, nonmaleficence, and justice. Health care systems and professionals are encouraged to apply the principles of trauma-informed care to address the effects of pediatric medical traumatic stress. PMID- 28846520 TI - Should Euthanasia Be Considered Iatrogenic? AB - As more countries adopt laws and regulations concerning euthanasia, pediatric euthanasia has become an important topic of discussion. Conceptions of what constitutes harm to patients are fluid and highly dependent on a myriad of factors including, but not limited to, health care ethics, family values, and cultural context. Euthanasia could be viewed as iatrogenic insofar as it results in an outcome (death) that some might consider inherently negative. However, this perspective fails to acknowledge that death, the outcome of euthanasia, is not an inadvertent or preventable complication but rather the goal of the medical intervention. Conversely, the refusal to engage in the practice of euthanasia might be conceived as iatrogenic insofar as it might inadvertently prolong patient suffering. This article will explore cultural and social factors informing families', health care professionals', and society's views on pediatric euthanasia in selected countries. PMID- 28846521 TI - Nontherapeutic Circumcision of Minors as an Ethically Problematic Form of Iatrogenic Injury. AB - Nontherapeutic circumcision (NTC) of male infants and boys is a common but misunderstood form of iatrogenic injury that causes harm by removing functional tissue that has known erogenous, protective, and immunological properties, regardless of whether the surgery generates complications. I argue that the loss of the foreskin itself should be counted, clinically and morally, as a harm in evaluating NTC; that a comparison of benefits and risks is not ethically sufficient in an analysis of a nontherapeutic procedure performed on patients unable to provide informed consent; and that circumcision violates clinicians' imperatives to respect patients' autonomy, to do good, to do no harm, and to be just. When due consideration is given to these values, the balance of factors suggests that NTC should be deferred until the affected person can perform his own cost-benefit analysis, applying his mature, informed preferences and values. PMID- 28846522 TI - Are Physicians Blameworthy for Iatrogenic Harm Resulting from Unnecessary Genital Surgeries? AB - We argue that physicians should, in certain cases, be held accountable by patients and their families for harm caused by "successful" genital surgeries performed for social and aesthetic reasons. We explore the question of physicians' blameworthiness for three types of genital surgeries common in the United States. First, we consider surgeries performed on newborns and toddlers with atypical sex development, or intersex. Second, we discuss routine neonatal male circumcision. Finally, we consider cosmetic vaginal surgery. It is important for physicians not just to know when and why to perform genital surgery, but also to understand how their patients might react to wrongful performance of these procedures. Equally, physicians should know how to respond to their own blameworthiness in socially productive and morally restorative ways. PMID- 28846523 TI - Performing Pain and Inflammation: Rendering the Invisible Visible. AB - These drawings represent everyday experiences of an artist who has been living with rheumatoid arthritis since her teenage years. Over the course of 20 years, the disease has damaged a series of joints in her body. Pain and inflammation accompany the most mundane of her movements and gestures. Fatigue and side effects of medications are routine parts of life. None of her impairments are publicly recognized and duly accommodated, as she is not (yet) visibly disabled. Asking for a seat on the bus, for instance, turns into a thorough social negotiation, as does having to constantly remind people that she actually is disabled. Lacking visual signs of disability, she is often accosted for "evidence"-an authentication, a reminder of "her" disability. With these drawings, each of which describes the artist's daily negotiations with pain, inflammation, and fatigue, she seeks to render visible what remains locked up within the boundaries of her skin. PMID- 28846524 TI - Outcome of Patients with Low-Flow/Low-Gradient Severe Aortic Stenosis Who Underwent Aortic Valve Replacement. AB - BACKGROUND: It is well-documented that stroke volume and gradient are indexed to classify patients with aortic stenosis into several phenotypes. The purpose of the present study was to estimate the impact of stroke volume and gradient on the clinical outcome of patients with AS who have undergone aortic valve replacement. Methods: A total of 154 consecutive patients were studied. They all had severe aortic stenosis (aortic valve area [AVA] <= 1 cm2, left ventricular ejection fraction [LVEF] >= 50%) and underwent aortic valve replacement (AVR) from January 1, 2004 to December 31, 2010. Clinical and echocardiography data was collected. According to stroke volume index (SVi), low flow (LF, SVi < 35 mL/m2) and normal flow (NF, SVi >= 35 mL/m2) were defined, and according to transvalvular pressure gradient, low gradient (LG, gradient < 40 mmHg) and high gradient (HG, gradient >= 40 mmHg) were also defined. Based on the above classification, patients were separated into four groups: NF/HG (59 patients), NF/LG (30 patients), LF/HG (40 patients) and LF/LG (25 patients). To estimate the discrepancy between patients with bicuspid aortic valve (BAV) and normal 3-leaflets aortic valve, 154 cases were divided into 2 groups: BAV group and 3-leaflets group. In-hospital mortality and overall survival were followed up. The risk factors of in-hospital mortality and overall survival were estimated by logistic regression analysis and Cox regression analysis. Results: The mean follow-up time was 59 +/- 32 months of 154 patients among whom the in-hospital mortality of NF/HG was 1.7% compared with NF/LG (6.7%), LF/HG (12.5%) and LF/LG (10.5%). The overall survival rates among the four groups were NF/HG (72%), NF/LG (92%), LF/HG (55%) and LF/LG (84%). The 5 year survival rate was lower in the BAV group than in the 3-leaflets group (78% and 93%; P < .05). The independent value for the in-hospital mortality included atrial fibrillation, concomitant coronary artery bypass graft, cardiac index, and bicuspid aortic valve. The independent factors for the overall survival included valvulo-arterial impedance, time of cardiopulmonary bypass, atrial fibrillation, bicuspid aortic valve, and concomitant coronary artery bypass graft. Conclusion: The in-hospital outcome of LF/LG is worse than NF/HG and NF/LG, but similar to LF/HG. For the overall outcome, LF/LG is better than NF/HG and LF/HG, but worse than NF/LG. Patients with BAV exhibit worse survival compared to 3-leaflets aortic valve. PMID- 28846525 TI - Timing of Surgery for Fungal Infective Endocarditis. AB - Fungal endocarditis rarely occurs and is difficult to treat. Taguchi et al described that a 55-year-old man, who developed severe mitral regurgitation with persistent fungal infective endocarditis (IE) 8 months after coronary artery bypass grafting, was cured with mitral valve replacement via the anterolateral right thoracotomy without cross-clamping method [Taguchi 2016]. PMID- 28846526 TI - Clinical and Angiographic Outcomes in Coronary Artery Bypass Surgery with Multiple versus Single Distal Target Grafts. AB - BACKGROUND: Coronary artery bypass grafting (CABG) with multiple distal target (MDT) grafts requires less graft material and reduces cardiopulmonary bypass time; however, there may be a higher incidence of graft failure. A real-world analysis reporting long-term outcomes associated with MDT grafts is lacking. MATERIAL AND METHODS: In 6262 consecutive patients who underwent an isolated first CABG from 2004-2012, patients with MDTs were propensity matched to those with single distal target (SDT) grafts. Logistic regression adjusted for traditional, anatomical, and functional definitions of complete revascularization (CR). Outcomes included 30-day, 1-year, and long-term mortality (median 6.29 years). Results: A total of 549 (8.8%) CABG patients had a MDT graft. CR defined using traditional (96.1% versus 92.0%, P = .005), anatomical (89.0% versus 80.20%, P < .001), and functional (90.7% versus 82.6, P < .001) definitions was more frequent in MDT patients. No significant differences in mortality were observed at 30 days (2% versus 3.3%, P = .18), 1-year (3.8% versus 4.9%, P = .37), or through end of follow-up (18.0% versus 16.6% P = .52) between the MDT and SDT groups, respectively. Similarly, no differences were observed after adjustment for all definitions of CR. Graft failure in MDT and SDT patients was 37.8% and 27.6%, respectively (P = .18). CONCLUSION: In a contemporary population based cohort, no differences in mortality were observed between CABG patients with MDT and SDT grafts. Our findings support the safety of MDT grafts to facilitate CR in patients and when graft material is limited. PMID- 28846527 TI - Kinking of the Outflow Graft, Consequent Ventricular Tachycardia, and the Need for Reoperation in a Patient with Left Ventricular Assist Device. AB - BACKGROUND: Left ventricular assist devices (LVAD) have become a lifesaving solution for patients awaiting heart transplantation as well as an option to support the failing hearts of non-transplant candidates as a lifelong, or destination therapy (DT). Improvements in LVAD design have enabled greater durability and broader patient applicability, but not without complications. Ventricular arrhythmias in LVAD patients were considered benign in the early days of LVADs, but today are increasingly recognized for their harmful impact on morbidity and quality of life. CASE PRESENTATION: We describe a 53-year-old male who underwent HeartWare left ventricular assist device (HVAD) implantation. During the postoperative period, the patient experienced ventricular tachycardia (VT) during a coughing episode, later found on CT to be due to significant angulation of the outflow graft. Following reoperation to shorten the outflow graft, the patient returned to hemodynamic stability, without VT or other arrhythmias. CONCLUSIONS: Innovative strategies in VT prevention and improved clinical outcomes in LVAD patients may be the result of better understanding of characteristics that predispose these patients to VT. This case report showed that an excessively long outflow graft with considerable kinking created significant VT, but reoperation to correct the length of the graft mitigated further VT complications. PMID- 28846528 TI - Effects of Preoperative Tricuspid Valve Diameters on Early Postoperative Surgical Outcomes in Patients Undergoing Tricuspid Valve Surgery. AB - BACKGROUND: Many of the previous studies on tricuspid valve surgery were on the materials that were used and the advantages and disadvantages of them. In this study, effects of preoperative tricuspid valve diameter on early postoperative outcomes were investigated. Methods: A total of 43 patients who underwent tricuspid valve repair surgery with the ring between the years 2012-2014 were included in this study. Tricuspid valve diameters and other cardiac functions of patients undergoing tricuspid intervention were evaluated with transthoracic echocardiography.Patients included in this study were divided into 2 groups: those with minimal, minimal-to-1st degree and 1st-degree tricuspid valve regurgitation found on thoracic echocardiography in the early postoperative period were considered as having a successful tricuspid repair (Group 1). Those with 1st-2nd degree and higher degrees of tricuspid regurgitation were considered as having an unsuccessful tricuspid repair (Group 2).The relationship between tricuspid valve dimensions and early tricuspid valve regurgitation was assessed with the help of preoperative, intraoperative, and postoperative data. RESULTS: Thirty patients (Group 1) were found to have a successful tricuspid valve repair in the postoperative period. The mean annulus diameter of the tricuspid valve at end-diastole in patients from Group 1 was similar to Group 2 (4.24 +/- 0.44 cm versus 3.99 +/- 0.40; P = .080). Also, tricuspid valve end-systolic diameter in Group 1 was similar to patients in Group 2 (3.59 +/- 0.38 cm versus 3.42 +/- 0.33 cm; P = .151). Conclusion: A direct relationship was not found between tricuspid valve diameter and post-operative development of moderate to severe regurgitation in tricuspid valve surgery in this study. PMID- 28846529 TI - Association between Preoperative Cardiac Left Ventricular Dysfunction and Perioperative Intraaortic Balloon Pump in Patients Undergoing Off-Pump Coronary Artery Bypass Surgery. AB - BACKGROUND: Prophylactic use of intraaortic balloon pump (IABP) reduces hospital mortality in patients with left ventricular (LV) systolic dysfunction undergoing coronary artery bypass surgery (CABG); however, its association in patients with LV diastolic dysfunction is unclear. This retrospective study investigated the association between preoperative LV function and perioperative use of IABP in patients undergoing off-pump CABG (OPCAB) at a university hospital. METHODS: 100 consecutive patients who underwent OPCAB between January 1, 2011 and August 31, 2014 were studied. Preoperative LV function was categorized into four groups based on LV systolic and diastolic function determined with preoperative transthoracic echocardiography. The use of IABP was reviewed from medical records. The Mann-Whitney test, Pearson chi-square test, or Fisher exact test were used. RESULTS: Patients were categorized into the following groups: normal LV function (n = 43), isolated LV systolic dysfunction (n = 13), isolated LV diastolic dysfunction (n = 21), and combined LV systolic and diastolic dysfunction (n = 14). Intraoperative IABP use was significantly more frequent in patients with isolated LV systolic dysfunction, isolated LV diastolic dysfunction, and combined LV systolic and diastolic dysfunction than in those with normal LV function (P < .05). Furthermore, IABP was used more frequently in patients who developed combined LV systolic and diastolic dysfunction postoperatively (P < .05). Conclusion: Not only the presence of preoperative systolic dysfunction but also LV diastolic dysfunction in the presence of normal LV systolic function were associated with increased use of IABP during and after OPCAB. PMID- 28846530 TI - Diazoxide Attenuates Ischemic Myocardial Injury in a Porcine Model. AB - BACKGROUND: We hypothesized that diazoxide, a mitochondrial ATP-sensitive potassium channel opener, has cardioprotective effects during acute myocardial ischemia. Diazoxide is suggested to act through protein kinase Cepsilon (PKCepsilon) activation. METHODS: Twelve piglets were randomly assigned to receive intravenous infusion of diazoxide (3.5 mg/kg) with solvent or only solvent (6 animals per group) before cardiac ischemia. Myocardial ischemia was induced by occluding the left circumflex artery (LCX) for 40 minutes. The reperfusion and follow-up period lasted for three hours. Throughout the experiment hemodynamic measurements and blood samples were collected, and after the follow-up period the hearts were harvested for transmission electron microscopy (TEM) as well as histopathological and immunohistochemical analyses. RESULTS: TEM showed less ischemic damage on a cellular level in the diazoxide group (P = .004) than in the control group. Creatinine kinase MB levels (Pt*g = .030) were lower, and oxygen consumption (Pt*g = .037) and delivery (Pg = .038) were higher in the diazoxide group compared to the controls. CONCLUSION: Diazoxide preserves myocardial cellular structure and cellular function, and thus it may have benefits in treating ischemic myocardial injury. PMID- 28846531 TI - Post-Myocardial Infarction Ventricular Septal Defect Six Months following Coronary Artery Bypass Grafting. AB - Mechanical complications following acute myocardial infarction are associated with high mortality. We present the first reported case of a new post myocardial infarction ventricular septal defect (VSD) within six months of coronary artery bypass grafting. The patient underwent successful surgical correction of the VSD with the assistance of mechanical circulatory support (MCS). This case highlights the importance of mechanical circulatory support in the management of cardiogenic shock associated with rare complications of myocardial infarction, even after surgical revascularization. PMID- 28846532 TI - Randomized Trial of Sternal Closure for Low Risk Patients: Rigid Fixation versus Wire Closure. AB - BACKGROUND: A previous retrospective analysis of our cardiac surgery patients showed shortened ventilation time and hospital stay among patients receiving rigid sternal fixation compared to sternal wire fixation. We performed a prospective randomized study to further investigate these outcomes and determine if rigid closure can provide reduced pain after cardiac surgery. METHODS: Patients undergoing cardiac surgery between July 2011 and May 2014 were prospectively randomized into wire closure (Group C) or rigid fixation using sternal plates (Group R) groups. Age above 80, emergency surgery, redo sternotomy, and immunosuppression were among major exclusion criteria precluding randomization. Intubation time was recorded for all patients. Pain scores were determined daily from postoperative day 1 until day 5 at 6 a.m. using a numeric rating scale. Narcotic pain medication requirements from day 1 to 5 were collected and converted into intravenous morphine equivalents. RESULTS: Of 80 patients, 39 patients were in Group R (average age 65 +/- 8; 31 male and 8 female) and 41 patients were in Group C (average age 66 +/- 9; 34 male and 7 female). Group R patients had a higher body mass index than patients in Group C (Group R: 31 +/- 5; Group C: 29 +/- 5; P = .04). No significant differences in the end points of intubation time and postoperative pain were observed. Conclusion: This randomized study of cardiac surgery patients showed no significant benefits of rigid fixation over conventional sternal wire closure with regard to intubation time, postoperative pain, or length of hospital stay. PMID- 28846533 TI - The Prognostic Risk Factors of ECMO in Patients with Cardiogenic Shock: A Retrospective Cohort Analysis. AB - BACKGROUND: Advances in ECMO have rapidly progressed in recent years; however, the clinical mortality rate remains high. This study aimed to identify the risk factors of ECMO in patients with cardiogenic shock. METHODS: Data of patients with cardiogenic shock who received ECMO from January 2006 to August 2013 at the Affiliated Hospital of Sun Yat-Sen University were retrospectively analyzed. All patients with cardiogenic shock were divided into two groups according to whether death occurred in the hospital. The possible prognostic risk factors of ECMO were first obtained in a univariate analysis of the two groups, and the risk factors that affected the prognosis of patients who underwent ECMO were determined using a logistic regression analysis. RESULTS: This study included 94 cardiogenic shock patients who were treated with ECMO. Overall, 59 patients were successfully weaned from ECMO, which accounted for 62.7% of all patients. The multivariate analysis indicated that the independent risk factors associated with prognosis included ECMO timing (OR = 7.68; 95% CI 1.60-37.01), the occurrence of postoperative MOF (OR = 2,823.09; 95% CI 14.75-540,171.06), and the lactate level at weaning (OR = 493.17; 95% CI: 1.55-156,653.27). CONCLUSION: For patients with refractory cardiogenic shock, the early establishment of ECMO, improvement in perfusion, and the prevention of complications may improve the prognosis. PMID- 28846534 TI - The Skeleton in the Closet: Harvesting a Skeletonized IMA. AB - There is a considerable amount of data that using more than one arterial graft provides a survival advantage for patients undergoing coronary bypass operations. The Society of Thoracic Surgeons has a set of official guidelines for the use of arterial grafts which include the following recommendations:Internal mammary arteries (IMA's) should be used to bypass the left anterior descending (LAD) artery when bypass of the LAD is indicated.As an adjunct to left internal mammary artery (LIMA), a second arterial graft (right IMA or radial artery [RA]) should be considered in appropriate patients.Use of bilateral IMA's (BIMA's) should be considered in patients who do not have an excessive risk of sternal complications.To reduce the risk of sternal infection with bilateral IMA's, skeletonized grafts should be considered, smoking cessation is recommended, glycemic control should be considered, and enhanced sternal stabilization may be considered.Use of arterial grafts should be a part of the discussion of the heart team in determining the optimal approach for each patient. [Ann Thorac Surg 2016; 101: 801-9]. PMID- 28846535 TI - The (New York) Times, They are a-Changin': The Asian Journal of Anesthesiology confronts change in medical publishing. PMID- 28846536 TI - Effect of blood pressure elevation on cerebral oxygen desaturation in the beach chair position. AB - OBJECTIVE: The beach chair position (BCP) during shoulder arthroscopy is a known risk factor for cerebral ischemia. We retrospectively investigated whether maintaining the arterial blood pressure (ABP) prevented the decrease in the regional cerebral tissue oxygen saturation (rSO2). METHODS: We analyzed 20 consecutive patients who underwent elective shoulder surgery in the BCP under general anesthesia. The bilateral rSO2 was monitored continuously throughout the procedure with the help of near-infrared spectroscopy (INVOS 5100 Cerebral Oximeter, Somanetics Corporation, Troy, MI, USA). Anesthesiologists maintained patient blood pressure while they were in the BCP, which was measured using an ABP transducer placed at the level of the external auditory meatus. We compared rSO2 measured in the supine position and in the BCP. RESULTS: Measurement of cortex level mean ABP (mABP) values in the BCP were >50 mmHg and over 60% higher than those noted for the supine position in most patients. Although all bilateral rSO2 values in the BCP were significantly lower than those in the supine position, the reductions was <20%. Further, 35% (7 of 20) patients that were part of the study experienced cerebral desaturation events at any given point during the procedure. None of the patients experienced clinical postoperative neurological complications. CONCLUSIONS: Although cortex level mABP in the BCP was >50 mmHg, a decrease was recorded in the rSO2 values. This rSO2 decrease was proportional to the reduction in the cortex level mABP induced by a postural change to the BCP. Therefore, despite appropriate blood pressure management, shoulder surgery in the BCP might involve certain risks for patients with cerebrovascular diseases. PMID- 28846538 TI - Proteus syndrome: Unveiling the anesthetic myths. PMID- 28846537 TI - A comparison of the video laryngoscopes with Macintosh laryngoscope for nasotracheal intubation. AB - : Nasotracheal intubation (NTI) is usually required in patients undergoing maxillofacial surgery. Though video-scopes have been demonstrated to perform well in oral endotracheal intubation, limited information is available concerning NTI. The aim of the study is to compare the efficiency of video-scopes and the traditional direct laryngoscopy in NTI. One hundred and eight patients scheduled for elective oro-maxillofacial surgery under nasotracheal intubation general anesthesia were randomly allocated into one of 3 groups of GlideScope, Pentax AirWay Scope, or Macintosh laryngoscope respectively. The primary outcome measures were total intubation time and each separate time interval (time A: for placement for the nasotracheal tube from selected nostril to oropharynx; time B: for use of devices to view the glottic opening; time C: for advancing nasotracheal tube from oropharynx into trachea and removing the scope from the oral cavity). The secondary outcomes were measurement of scores of modified naso intubation difficulty scale (MNIDS) and attempts at intubation. RESULTS: Mean total intubation time and time C interval were taken with GlideScope (33.1 s and 9.7 s), Pentax (38.4 s and 12.9 s), and Macintosh (42.2 s and 14.9 s) respectively. There was a significant difference among the groups (total time, P = 0.03; time C, P = 0.02). The median score of MNIDS was significantly lower using GlideScope or Pentax compared with using Macintosh in NTI (P = 0.037) and difficult intubation grading by MNIDS presented as easier in the GlideScope group than in the Macintosh group (0.016). Using GlideScope, intubation was successful at the first attempt in 80% patients whereas only 65% and 72.5% with the Pentax and Macintosh (P = 0.02). CONCLUSION: As compared with the Macintosh laryngoscope, the GlideScope video laryngoscope facilitated nasotracheal intubations with shortened intubation time and reduced intubation difficulty in patients undergoing oromaxillofacial surgery. PMID- 28846539 TI - Catheterization in an ultrasound-guided thoracic paravertebral block using thoracoscopy. AB - Thoracic paravertebral block (TPVB) is an efficient alternative to epidural anesthesia. The location of a catheter within the thoracic paravertebral space (TPVS) has been examined in the human cadaver studies, but it is unclear how it goes into the TPVS during catheterization. In this report, thoracoscopy was used to observe the thoracic cavity in real-time during a parasagittal in-plane approach of ultrasound-guided TPVB. During thoracoscopy, we observed whether a paravertebral catheter could be advanced caudally beyond the ribs into the neighboring TPVS. Our result demonstrated that the catheter was difficult to be advanced beyond the ribs and confined within the same level of TPVS as where it was inserted. In the previous thoracoscopic observation of the paravertebral spread, we assumed that the local anesthetic acts most strongly at the intercostal level of the injection. Therefore, we recommend to insert the catheter for TPVB at the level corresponding to the incision site of thoracotomy. PMID- 28846540 TI - Determinants of long-term outcome in patients after percutaneous stent-assisted management of symptomatic subclavian or innominate artery stenosis or occlusion. AB - AIMS: Incidence and determinants of restenosis and adverse events after endovascular management (PTA+/-stent) of the subclavian/innominate artery (SA/IA) stenosis/occlusion remain unclear due to the relatively short-term follow-up or limited size of prior studies. This large-scale, long-term prospective study investigated safety, efficacy, and prognosis after SA/IA PTA+/-stent. METHODS AND RESULTS: The study involved 411 consecutive patients with symptomatic SA/IA stenosis/ occlusion; 393 were followed annually after successful PTA+/-stent for up to 16 (minimum one) years. Primary outcomes were freedom from restenosis and MACCE (cardiovascular death, myocardial infarction, stroke). Angiographic success rate was 99.7% in stenoses and 76.1% in occlusions. The incidence of any periprocedural complication was 4.4% (serious - 1.2%). Symptoms of limb ischaemia, vertebrobasilar insufficiency or angina resolved in 79.1%, decreased in 19.6%. Freedom from restenosis was 82.6% and 77.9% whereas freedom from MACCE was 86.6% and 78.3% at five and 10 years, respectively. MACCE determinants (HR; 95% CI) were previous myocardial infarction (5.36; 2.9-9.91), ischaemic stroke (2.03; 1.12-3.66), hs-CRP (1.04; 1.02-1.07), concurrent atherosclerosis (1.35; 1.00-1.82). Restenosis determinants were implantation of >=2 stents (2.65; 1.23 5.72), stent diameter (0.45; 0.34-0.59), hs-CRP (1.06; 1.02-1.1), WBC (1.2; 1.07 1.35), age (0.97; 0.94-0.99), concurrent carotid or vertebral disease (1.85; 1.07 3.18), IA intervention (2.28; 1.08-4.84). CONCLUSIONS: This study established long-term durability of stent-assisted PTA of symptomatic SA/IA disease and identified risk factors for restenosis and long-term MACCE. Patients at increased risk might benefit from targeted, intensified prevention measures. PMID- 28846541 TI - A randomised comparison of incidence of radial artery occlusion and symptomatic radial artery spasm associated with elective transradial coronary intervention using 6.5 Fr SheathLess Eaucath Guiding Catheter vs. 6.0 Fr Glidesheath Slender. AB - AIMS: The aim of this study was to compare incidences of radial artery occlusion (RAO) and spasm (RAS) associated with transradial coronary intervention (TRI) using a 6.5 Fr SheathLess hydrophilic-coated guide catheter (SH-GC) vs. a 6.0 Fr Glidesheath Slender (GSS). METHODS AND RESULTS: We conducted an open-label, single-centre, randomised study to compare radial complications in 600 consecutive patients undergoing elective TRI using 6.5 Fr SH-GC (n=300) or 6.0 Fr GSS (n=300) between 2015 and 2016. The primary endpoint was a composite of RAO evaluated by sonography and symptomatic RAS. The mean diameter of radial arteries was 2.20 mm in both groups; however, the sheath/radial artery diameter (S/RA) ratio was significantly smaller in the SH-GC group (1.03 vs. 1.17, p<0.001). SH GC was associated with a higher rate of system crossover (1.7% vs. 0.7%, p=0.450) and coronary ostial dissection (1.0% vs. 0.3%, p=0.624), although there were no statistically significant differences. The incidence of major adverse cardiac events was comparable. A lower incidence of RAO and access-site crossover owing to RAS was significantly associated with SH-GC (0.0% vs. 2.0%, p=0.031). Multivariate analysis revealed that a larger S/RA ratio predicted RAO and RAS independently (p=0.007). CONCLUSIONS: The 6.5 Fr SH-GC offers a promising alternative to conventional TRI and is associated with fewer radial complications than the 6.0 Fr GSS. PMID- 28846542 TI - Impact of bioresorbable versus permanent polymer on longterm vessel wall inflammation and healing: a comparative drug-eluting stent experimental study. AB - AIMS: Drug-eluting stents (DES) have evolved to using bioresorbable polymers as a method of drug delivery. The impact of bioresorbable polymer on long-term neointimal formation, inflammation, and healing has not been fully characterised. This study aimed to evaluate the biological effect of polymer resorption on vascular healing and inflammation. METHODS AND RESULTS: A comparative DES study was performed in the familial hypercholesterolaemic swine model of coronary stenosis. Permanent polymer DES (zotarolimus-eluting [ZES] or everolimus-eluting [EES]) were compared to bioresorbable polymer everolimus-eluting stents (BP-EES) and BMS. Post implantation in 29 swine, stents were explanted and analysed up to 180 days. Area stenosis was reduced in all DES compared to BMS at 30 days. At 180 days, BP-EES had significantly lower area stenosis than EES or ZES. Severe inflammatory activity persisted in permanent polymer DES at 180 days compared to BP-EES or BMS. Qualitative para-strut inflammation areas (graded as none to severe) were elevated but similar in all groups at 30 days, peaked at 90 days in DES compared to BMS (p<0.05) and, at 180 days, were similar between BMS and BP EES but were significantly greater in DES. CONCLUSIONS: BP-EES resulted in a lower net long-term reduction in neointimal formation and inflammation compared to permanent polymer DES in an animal model. Further study of the long-term neointima formation deserves study in human clinical trials. PMID- 28846543 TI - Final five-year outcomes after implantation of biodegradable polymer-coated biolimus-eluting stents versus durable polymer-coated sirolimus-eluting stents. AB - AIMS: Our aim was to report the long-term safety and efficacy of the biodegradable polymer-coated biolimus- eluting Nobori stent compared to the durable polymer-coated sirolimus-eluting CYPHER stent. METHODS AND RESULTS: SORT OUT V randomised 2,468 patients 1:1 to the Nobori (n=1,229) versus the CYPHER stent (n=1,239). Clinically driven event detection based on Danish registries was used. The primary endpoint was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularisation). Individual components of the primary endpoint comprise the secondary endpoints. At five-year follow-up, the composite endpoint rate was found to be similar in patients treated with the two study stents (Nobori 182/1,229 [14.8%] vs. CYPHER 197/1,239 [15.8%]; odds ratio [OR] 0.93, 95% CI: 0.75-1.16; p=0.53). The rates of definite stent thrombosis were also found to be similar in patients treated with the two study stents (Nobori 23/1,229 [1.9%] vs. CYPHER 18/1,239 [1.5%]; OR 1.31, 95% CI: 0.70-2.47; p=0.40), as were the other secondary endpoints. CONCLUSIONS: At five-year follow-up, the Nobori stent with a biodegradable polymer coating provided a similar safety and efficacy profile when compared to the durable polymer first-generation CYPHER stent. PMID- 28846544 TI - First-in-human implantation of a novel transfemoral selfexpanding transcatheter heart valve to treat pure aortic regurgitation. AB - Here we will describe the first case of a novel JenaValve design (JenaValve Technology, Irvine, CA, USA) using the transfemoral approach in a 78-year-old female patient with pure aortic regurgitation. The implantation was successfully performed with good haemodynamics and good clinical outcome at six-month follow- up. The technology is especially appealing in non-calcified anatomies due to the clipping mechanism which was previously utilised in the transapical design. PMID- 28846545 TI - Physiologic evaluation of coronary lesions using instantaneous wave-free ratio (iFR) in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. AB - AIMS: We sought to assess eventual changes in iFR measurements in patients with aortic stenosis (AS) before and after TAVI in coronary lesions with different degrees of angiographic severity. METHODS AND RESULTS: The functional relevance of 145 coronary lesions was assessed by online iFR and FFR measurement in 66 patients with severe AS before and after TAVI, during the same procedure. The iFR FFR classification agreement was calculated for pre-TAVI and post-TAVI measurements. Mean iFR values remained identical before and after TAVI, irrespective of the angiographic severity of the coronary stenosis (0.89+/-0.12 vs. 0.89+/-0.12, p=0.66). However, individual iFR values varied widely after TAVI and the 0.89 iFR threshold was crossed by 15% of the investigated coronary lesions. Higher iFR variation was related to a higher transaortic gradient drop after valve intervention. The diagnostic accuracy of iFR in predicting an FFR <=0.8 was poor (65%) in lesions with severe obstructions, and tended to increase post TAVI. CONCLUSIONS: Although overall values did not change after TAVI, iFR presented significant and mostly erratic individual variations after valve replacement. Delta iFR was influenced by the extent of the transaortic gradient drop induced by TAVI. Therefore, caution is advisable in the interpretation of iFR in the presence of AS. PMID- 28846546 TI - Combined jugular and femoral approach for treating severe tricuspid valve regurgitation. PMID- 28846547 TI - Basil A. Pruitt Jr. MD and the US Army Institute for Surgical Research: Five Decades of Science, Clinical Care, Mentorship, and Leadership. AB - Over the past half century Dr. Basil A. Pruitt, Jr., a great citizen, surgeon, innovator, mentor and leader, transformed our world through his dogged commitment to science and service to humanity. Dr. Pruitt's contribution lives on in the work of the US Army Institute of Surgical Research and the surgeons, physicians and scientists he shaped and inspired. PMID- 28846548 TI - Congenital Infiltrating Lipomatosis of the Face: Case Report and Literature Review. AB - RATIONALE: Congenital infiltrating lipomatosis of the face (CILF) is a rare disorder characterized by collections of nonencapsulated mature lipocytes that infiltrate surrounding tissues. In this article, we would report a new case of CILF, which may be one of the first few cases reported in China. PATIENT CONCERNS: An 8-year-old boy presented with a hyperplasia of subcutaneous tissue of his left face, which had been gradually progressing since birth, resulting in a marked facial asymmetry. Then he underwent an operation of resection of the subcutaneous mass, and the postoperative pathological analysis reported a mature adipose tissue. DIAGNOSES AND OUTCOMES: The diagnosis of CILF was finally made according to a comprehensive consideration of the patient's situation. We then searched different databases for studies that had investigated CILF, reviewed those literatures, and gave our summaries for such a rare disease. LESSONS: Congenital infiltrating lipomatosis of the face is an extremely rare disease. There is so much unknown about it, and the gradual progress and recurrence make it even harder to cure. Besides, the psychological impact on such patients must be considered. Thus, a proper collection and analysis of the reports of such a disease are very important. PMID- 28846549 TI - Re: "Localizing the Lost Rectus Muscle Using the Connective Tissue Framework: Revisiting the Tunnel Technique". PMID- 28846551 TI - Highlighting a Common Quality of Care Delivery Problem: Overuse of Low-value Healthcare Services. AB - BACKGROUND: Low-value healthcare services (LVHS) are defined as procedures delivered that provide little or no clinical benefit. Overuse of LVHS, or delivery when the risks exceed the benefits, contributes to excessive spending without improved outcomes. Furthermore, overuse contributes to healthcare waste. PURPOSE: The primary purpose of this commentary is to (1) examine the problem of LVHS overuse and its impacts on quality care delivery and (2) propose factors to consider in developing quality measures to help reduce overuse and waste and thus improve patient outcomes. METHODS: To inform and support this commentary, we conducted a limited review of the literature related to LVHS overuse, its consequences, and suggested solutions. Online search engines were used to identify research related to our primary areas of interest. RESULTS: This commentary demonstrates that overuse and associated healthcare waste is growing among selected LVHS. The factors of overuse are multidimensional and poorly understood. Meanwhile, overuse of LVHS has financial consequences and impacts quality of care and outcomes. CONCLUSIONS: Overuse of LVHS is common in the United States, leading to waste and suboptimal patient outcomes. Thus a need exists to address overuse and develop measures to capture a larger scope of services. PMID- 28846550 TI - Localizing the Lost Rectus Muscle Using the Connective Tissue Framework: Revisiting the Tunnel Technique. AB - PURPOSE: To describe a technique for localizing a lost rectus muscle during strabismus or retinal surgery or following trauma. METHODS: In this single center, retrospective chart review, 5 patients were identified between January 2012 and June 2016 with a lost rectus muscle; 3 during strabismus surgery and 2 post trauma. The inclusion criteria included a lost rectus muscle during strabismus surgery, or a disinserted/lacerated rectus muscle following ocular/orbital trauma. The primary outcome measure was successful reattachment of the rectus muscle. RESULTS: The lost rectus muscle was identified in each patient and reattached to the globe by gently applying traction anteriorly at the conjunctiva/Tenon edge using double-pronged skin hooks and following the path of the rectus muscle through its Tenon capsule tunnel where it remained attached by suspensory ligaments. There was no instance where orbital fat was obscuring or blocking the view of the lost rectus muscles. There were no other complications associated with the procedure. CONCLUSIONS: The authors describe a simple and effective method in 5 patients to localize a lost rectus muscle based on knowledge of the orbital connective tissue framework. PMID- 28846552 TI - Qualitative and Quantitative Evaluation of Structural Myocardial Alterations by Grating-Based Phase-Contrast Computed Tomography. AB - OBJECTIVES: Grating-based phase-contrast computed tomography (gb-PCCT) relies on x-ray refraction instead of absorption to generate high-contrast images in biological soft tissue. The aim of this study was to evaluate the potential of gb PCCT for the depiction of structural changes in heart disease. MATERIALS AND METHODS: Four human heart specimens from patients with hypertensive disease, ischemic disease, dilated heart disease, and cardiac lipomatosis were examined. The gb-PCCT setup consisted of an x-ray tube (40 kV, 70 mA), grating interferometer, and detector, and allowed simultaneous acquisition of phase- and absorption-contrast data. With histopathology as the standard of reference, myocardium (MC), fibrotic scar (FS), interstitial fibrosis (IF), and fatty tissue (FT) were visually and quantitatively evaluated. Systematic differences in absorption- and phase-contrast Hounsfield units (HUabs and HUp) were assessed. RESULTS: Thirteen corresponding cross-sections were included, and MC, FS, IF, and FT were found in 13 (100%), 4 (30.8%), 7 (53.8%), and 13 (100%) cross-sections, respectively. Mean HUp/HUabs were 52.5/54.1, 86.6/69.7, 62.4/62.3, and -38.6/ 258.9 for MC, FS, IF, and FT, respectively. An overlap in HUabs was observed for MC and IF (P = 0.84) but not for HUp (P < 0.01). Contrast-to-noise ratios were significantly higher in phase- than in absorption-contrast for MC/FT (35.4 vs 7.8; P < 0.01) and for MC/FS (12.3 vs 0.2; P < 0.01). CONCLUSIONS: Given its superior soft tissue contrast, gb-PCCT is able to depict structural changes in different cardiomyopathies, which can currently not be obtained by x-ray absorption-based imaging methods. If current technical limitations can be overcome, gb-PCCT may evolve as a powerful tool for the anatomical assessment of cardiomyopathy. PMID- 28846553 TI - Improved Outcomes When Surgical Postoperative Complications Are Managed According to the Principles of Continuity of Care and Specificity of Expertise. PMID- 28846554 TI - American Urogynecologic Society Best Practice Statement: Evaluation and Counseling of Patients With Pelvic Organ Prolapse. AB - Women with prolapse should have an examination to quantify the loss of anatomic support and should be evaluated for associated bladder, bowel, and prolapse symptoms as well as associated bother. Treatment options should be tailored to meet the patient's medical health and personal functional goals. In most cases, women should be informed of the range of treatment options including observation as well as nonsurgical and surgical management. PMID- 28846555 TI - Swine Leukocyte Antigen Class II Is a Xenoantigen. AB - BACKGROUND: Over 130 000 patients in the United States alone need a lifesaving organ transplant. Genetically modified porcine organs could resolve the donor organ shortage, but human xenoreactive antibodies destroy pig cells and are the major barrier to clinical application of xenotransplantation. The objective of this study was to determine whether waitlisted patients possess preformed antibodies to swine leukocyte antigen (SLA) class II, homologs of the class II HLA. METHODS: Sera from people currently awaiting solid organ transplant were tested for IgG binding to class II SLA proteins when expressed on mammalian cells. Pig fibroblasts were made positive by transfection with the class II transactivator. As a second expression system, transgenes encoding the alpha and beta chains of class II SLA were transfected into human embryonic kidney cells. RESULTS: Human sera containing IgG specific for class II HLA molecules exhibited greater binding to class II SLA positive cells than to SLA negative cells. Sera lacking antibodies against class II HLA showed no change in binding regardless of the presence of class II SLA. These antibodies could recognize either SLA-DR or SLA-DQ complexes. CONCLUSIONS: Class II SLA proteins may behave as xenoantigens for people with humoral immunity toward class II HLA molecules. PMID- 28846556 TI - Direct-Acting Antiviral Therapy and Improvement in Graft Survival of Hepatitis C Liver Transplant Recipients. PMID- 28846557 TI - Cytomegalovirus Viral Load in Bronchoalveolar Lavage to Diagnose Lung Transplant Associated CMV Pneumonia. AB - BACKGROUND: The diagnostic yield for cytomegalovirus (CMV) polymerase chain reaction (PCR) viral load in bronchoalveolar lavage (BAL) or in plasma to diagnose CMV pneumonia in lung transplant recipients remains uncertain and was investigated in a large cohort of consecutive lung transplant recipients. METHODS: Bronchoscopies within the first year of lung transplantation with CMV detectable in BAL by PCR (ie, viral load, >=273 IU/mL) were included (66 recipients; 145 bronchoscopies); at each bronchoscopy episode, 2 independent experts reviewed clinical and laboratory information to determine whether the patient at that time fulfilled the criteria for CMV pneumonia per current international recommendations. Corresponding plasma CMV PCR viral load determined at time of the bronchoscopy (n = 126) was also studied. Optimal CMV PCR viral load cutoff for CMV pneumonia diagnosis was determined using receiver operating characteristics. RESULTS: CMV was detected in BAL with CMV PCR in 145 episodes, and 34 (23%) of these episodes fulfilled the criteria for CMV pneumonia. The area under the curve-receiver operating characteristics for CMV in BAL was 90% at the optimum cutoff (4545 IU/mL) with a corresponding sensitivity of 91% and specificity of 77% (in plasma the corresponding values were 274 IU/mL, 63% and 76%, respectively). CONCLUSIONS: CMV PCR viral load in BAL had a high performance to diagnose CMV pneumonia in lung transplant recipients; plasma CMV viral load did not reliably aid as a diagnostic tool. PMID- 28846558 TI - Improved Outcomes of Kidney Transplantation in Infants (Age < 2 years): A Single Center Experience. AB - BACKGROUND: Infants (age, < 2 years) with end-stage renal disease (ESRD) have increased morbidity and mortality. We evaluated our long-term outcomes of kidney transplants (KTx) in infants. METHODS: Between 1984 and 2014, 136 infants underwent KTx. We examined trends in survival rates and complications by era (1984-1993 [era 1], 1994-2003 [era 2], 2004-2014 [era 3]). RESULTS: Patients were 92.6% white and 70.6% males. Posttransplant (Tx) initial length of hospital stay declined 37% over the 30-year period (P <0.01). Ten-year death-censored graft survival improved from 60% (era 1) to 80% (era 2) (P = 0.04). The incidence of acute rejection, graft thrombosis, cytomegalovirus, and urine leaks did not significantly change across eras. Frequency of Epstein-Barr virus diagnosis (era 2 vs era 3, P < 0.01) increased. Post-Tx lymphoproliferative disorder incidence was increased in era 2 compared with eras 1 and 3 (P = 0.03). CONCLUSIONS: Infants deserve earlier consideration for KTx. Length of initial hospital stay and patient and graft survival rates after KTx have improved in infants since 1984. PMID- 28846560 TI - Comparative Study on Osseointegration of Implants After Flap and Flapless Surgery in the Mandible of Dogs. AB - PURPOSE: The objective of this study was to compare the implant stability and osseointegration of implants using a flap or flapless technique. MATERIAL AND METHODS: Mandibular premolars and molars were extracted from both sides in 6 dogs. After 8 weeks, 4 fixtures were implanted using either a flap or flapless technique. Implant stability quotient was measured on insertion and at 2, 4, and 8 weeks later. The animals were killed while the tissues were histologically analyzed. RESULTS: Implant stability increased for 8 weeks, and no statistically significant differences were observed between the surgical protocols. Bone implant contact showed 60.27% +/- 30.99% for flapless surgery and 59.73% +/- 17.12% for flap surgery. And the results of new bone formation area from total area showed 56.07% +/- 27.78% for flapless surgery and 57.00% +/- 14.66% for flap surgery. There were no statistically significant differences. CONCLUSION: This study showed no significant difference in implant stability as well as osseointegration regardless of flap or flapless technique. PMID- 28846559 TI - Sofosbuvir-Based Regimens in HIV/HCV Coinfected Patients After Liver Transplantation: Results From the ANRS CO23 CUPILT Study. AB - BACKGROUND: A recurrence of hepatitis C virus (HCV) after liver transplantation affects survival in human immunodeficiency virus (HIV)/HCV coinfected patients. This study assessed the efficacy and safety of sofosbuvir (SOF)-based regimens in HIV/HCV coinfected patients after liver transplantation. METHODS: Twenty-nine HIV/HCV coinfected transplanted patients receiving tacrolimus-, cyclosporine-, or everolimus-based immunosuppressive therapy were enrolled in the Compassionate Use of Protease Inhibitors in Viral C Liver Transplantation cohort. Their antiviral treatment combined SOF, daclatasvir with or without ribavirin (n = 10/n = 6), or SOF, ledipasvir with or without ribavirin (n = 2/n = 11). RESULTS: The median delay between liver transplantation and treatment initiation was 37.5 months (interquartile range [IQR], 14.4-99.2). The breakdown of HCV genotypes was G1, 22 patients (75.9%); G3, 3 patients (10.3%); and G4, 4 patients (13.8%). The treatment indications were HCV recurrence (>= F1 n = 23) or fibrosing cholestatic hepatitis (n = 6). Before starting SOF, the HCV viral load and CD4 count were 6.7 log10 IU/mL (IQR, 5.9-7.2) and 342 cells/mm (IQR, 172-483), respectively. At week 4, the HCV viral load was less than 15 IU/mL in 12 (42.9%) patients. The overall sustained virological response 12 was 96.6%. No significant drug-drug interactions were observed. CONCLUSIONS: SOF-based treatment regimens produced excellent results in HIV/HCV coinfected patients after liver transplantation, suggesting an important change in their prognosis. PMID- 28846561 TI - Incidence and Management of Fractured Dental Implants: Case Reports. AB - The fracture of dental implants is a rare occurrence in clinical settings. Possible causes of implant fracture include design or production flaws, overloaded occlusion force, implant location, metal fatigue, and bone resorption around the implant. This study reports on the successful removal and reimplantation of fractured implants. PMID- 28846562 TI - Feedback Leads to Better Exercise Quality in Adolescents with Patellofemoral Pain. AB - PURPOSE: Adolescents with patellofemoral pain (PFP) do not comply with their exercise prescription, performing too few and too fast repetitions, compromising recovery. We investigated if real-time feedback on contraction time would improve the ability of adolescents with PFP to perform exercises as prescribed. METHODS: A randomized, controlled, participant-blinded, superiority trial with a 6-wk intervention of three weekly sessions of three elastic band exercises was undertaken. Forty 15- to 19-yr-old adolescents with PFP were randomized to real time BandCizerTM-iPad feedback on contraction time or not by a physiotherapist. The primary outcome was the mean deviation from the prescribed contraction time of 8 s per repetition. Secondary outcomes included isometric hip and knee strength, Kujala Patellofemoral Scale, and Global Rating of Change. RESULTS: The mean deviation from prescribed 8 s per repetition contraction time was 1.5 +/- 0.5 s for the feedback group, compared with 4.3 +/- 1.0 s for the control group (mean difference: 2.7 s (95% confidence interval = 2.2-3.2, P < 0.001). On the basis of total contraction time during the intervention, the feedback group received 35.4% of the prescribed exercise dose whereas the control group received 20.3%. Isometric hip and knee strength increased significantly more in the feedback group compared with controls (mean difference = 1.35 N.kg, 95% confidence interval = 0.02-2.68, P = 0.047). There were no significant differences in Kujala Patellofemoral Scale and Global Rating of Change between groups, but the study was not powered for this. CONCLUSION: Real-time feedback on contraction time resulted in the ability to perform exercises closer to the prescribed dose and also induced larger strength gains. PMID- 28846563 TI - Temporal Response of Angiogenesis and Hypertrophy to Resistance Training in Young Men. AB - : Although endurance exercise training promotes angiogenesis and improves metabolic health, the effect of resistance training on this process is less well defined. We hypothesized that capillarization would increase proportionally, and concurrently, with muscle fiber hypertrophy in response to resistance training in young men. METHODS: In this double-blind, randomized control trial, 36 men (22 +/ 1 yr) were randomized to placebo or protein supplementation, and participated in 12 wk of resistance training. Skeletal muscle biopsies were collected before and after 2, 4, 8, and 12 wk of training. Immunohistochemistry assessed fiber type specific size and capillarization. Western blot and reverse transcription polymerase chain reaction assessed proteins involved in the molecular regulation of angiogenesis. RESULTS: Resistance training effectively increased Type I (15% +/- 4%; P < 0.01) and Type II fiber cross-sectional area (28% +/- 5%; P < 0.0001), an effect that tended to be further enhanced with protein supplementation in Type II fibers (P = 0.078). Capillary-to-fiber ratio significantly increased in Type I (P = 0.001) and II (P = 0.015) fibers after 12 wk of resistance exercise training and was evident after only 2 wk. Capillary-to fiber perimeter exchange index increased in the Type I fibers only (P = 0.054) after 12 wk of training. Training resulted in a reduction in vascular endothelial growth factor mRNA. A (P = 0.008), while vascular endothelial growth factor receptor 2 (P = 0.016), hypoxia-inducible factor 1alpha (P = 0.016), and endothelial nitric oxide synthase (P = 0.01) increased in both groups. Hypoxia inducible factor 1alpha protein content was higher in the protein group (main group effect, P = 0.02), and endothelial nitric oxide synthase content demonstrated a divergent relationship (time-group interaction, P = 0.049). CONCLUSIONS: This study presents novel evidence that microvascular adaptations and the molecular pathways involved are elevated after 2 wk of a 12-wk resistance training program. Increases in muscle fiber cross-sectional area are effectively matched by the changes in the microvasculature, providing further support for resistance training programs to optimize metabolic health. PMID- 28846564 TI - Implementing Resistance Training in Secondary Schools: A Cluster RCT. AB - PURPOSE: Guidelines recommend that young people engage in muscle-strengthening activities on at least three days per week. The purpose of this study was to examine the impact of a school-based intervention focused on resistance training (RT) for adolescents. METHODS: The 'Resistance Training for Teens' intervention was evaluated using a cluster randomized controlled trial with 607 adolescents (50.1% female; 14.1+/-0.5 years) from 16 secondary schools. Teachers were trained to deliver the intervention, which included: (i) an interactive student seminar; (ii) a structured physical activity program, focused on RT; (iii) lunchtime fitness sessions; and, (iv) web-based smartphone apps. The primary outcome was muscular fitness (MF) and secondary outcomes included body mass index (BMI), RT skill competency, flexibility, physical activity, self-efficacy and motivation. Assessments were conducted at baseline, 6- (post-program; primary end-point) and 12-months (follow-up). Outcomes were assessed using linear mixed models, with three potential moderators tested using interaction terms (and sub-group analyses where appropriate). RESULTS: For the primary outcome (MF), a group-by-time effect was observed at 6-months for upper body (2.0 repetitions, 95% confidence interval [CI]: 0.8 to 3.2), but not lower body (-1.4cm, 95% CI: -4.7 to 1.9). At 6-months, there were intervention effects for RT skill competency and self-efficacy, but no other secondary outcomes. Effects for upper body MF and RT skill competency were sustained at 12-months. Despite overall no effect for BMI, there was a group-by time effect at 12-months among students who were overweight/obese at baseline ( 0.55 kg/m, 95% CI: -1.01 to -0.08). CONCLUSIONS: The school-based RT intervention resulted in immediate and sustained improvements in upper body MF and RT skill competency, demonstrating an effective and scalable approach to delivering RT within secondary schools. PMID- 28846565 TI - Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins. AB - INTRODUCTION: Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. METHODS: We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. RESULTS: TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. CONCLUSIONS: Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT. PMID- 28846566 TI - Activation of Pyruvate Dehydrogenase Activity by Dichloroacetate Improves Survival and Neurologic Outcomes After Cardiac Arrest in Rats. AB - No pharmacological interventions are currently available to provide neuroprotection for patients suffering from cardiac arrest. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase inhibitor, which activates pyruvate dehydrogenase (PDH), and increases cell adenosine triphosphate (ATP) production by promoting influx of pyruvate into the Krebs cycle. In this study, we investigated the effects of DCA on post-resuscitation neurological injury in an asphyxial cardiac arrest rat model. Asphyxial cardiac arrest was established by endotracheal tube clamping. A total of 111 rats were randomized into three groups: Sham group, Control group, and DCA intervention group. Animals in DCA intervention group were intraperitoneally administered DCA with a loading dose of 80 mg/kg at 15 min after return of spontaneous circulation (ROSC), whereas rats in the Control group received equivalent volume of saline. DCA treatment increased 3-day survival time, and reduced neurologic deficit scores at 24, 48, and 72 h after ROSC. It also attenuated cellular apoptosis and neuronal damage in the hippocampal cornuammonis one region by hematoxylin-eosin staining and TdT mediated dUTP nick-end labeling assay. In addition, DCA reduced the messenger RNA expression of tumor necrosis factor alpha and interleukin 1beta in brain hippocampus and cortex after ROSC. Furthermore, DCA treatment significantly increased ATP production, PDH activity, and decreased blood glucose, lactate, and brain pyruvate levels after ROSC. Our results suggested that DCA has neuroprotective effects on brain injury after cardiac arrest, and its salutary effects were associated with an increase of mitochondrial energy metabolism in the brain through activation of PDH activity. PMID- 28846567 TI - Chronic Kidney Disease Exacerbates Myocardial Ischemia Reperfusion Injury: Role of Endoplasmic Reticulum Stress-Mediated Apoptosis. AB - Chronic kidney disease (CKD) is known to exacerbate myocardial ischemia reperfusion (IR) injury. However, the underlying mechanisms are still not well understood. Despite various strategies for cardioprotection, limited studies have been focused on the prevention of CKD-induced myocardial susceptibility to IR injury. Here, we hypothesized that excessive endoplasmic reticulum (ER) stress mediated apoptosis involved in myocardial IR injury in CKD mice and pretreatment with chemical ER chaperone rendered the heart resistant to myocardial IR injury in the setting of CKD. CKD was induced by 5/6 subtotal nephrectomy (SN) in mice, whereas sham-operated mice served as control (Sham). CKD significantly aggravated the cardiac injury after IR in SN group than Sham group as reflected by more severe cardiac dysfunction, increased myocardial infarct size and the ratio of myocardial apoptosis. The expression of ER stress-mediated apoptotic proteins (Bcl-2 associated X protein (Bax), glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12) was markedly upregulated after IR injury in SN group than Sham group, whereas the expression of anti-apoptotic protein, Bcl-2, was obviously downregulated. In addition, the chemical ER chaperone sodium 4-phenylbutyrate (4PBA) pretreatment ameliorated cardiac dysfunction and lessened the infarct size and myocardial apoptosis after IR injury in mice with CKD. Taken together, these findings demonstrated that excessive activation of ER stress-mediated apoptosis pathway involved in the CKD-induced myocardial susceptibility to IR injury, and chemical ER chaperone 4PBA alleviated myocardial IR injury in mice with CKD. PMID- 28846568 TI - Impact of Blood Mixing and ABO Compatibility on Platelet-Leukocyte Aggregations and Platelet P-Selectin Expression: An in Vitro Study. AB - Effects of blood transfusions on platelet- and leukocyte-related inflammation are unclear. We simulated transfusion using in vitro blood mixing to evaluate platelet-leukocyte aggregations (PLA) and platelet P-selectin expression, and the mechanism of PLA. Donor packed red blood cells (pRBCs) were obtained from a blood bank. Recipient whole blood samples were obtained from patients undergoing cardiac surgery. Blood sample mixtures were divided into four groups: group M, cross-matched blood type mixing; group O, donor type O with other blood type mixing (A, B, or AB); group S, ABO type-specific uncross-matched blood mixing; and group I, ABO incompatibility mixing. Donor pRBCs were added to recipient blood to reach 1%, 5%, and 10% (vol/vol) concentrations. Blood sample mixtures were analyzed to determine the PLA; P-selectin expression; and leukocyte CD11a, CD11b, and CD18 subunits of integrin expression. Analysis of variance tests were used to analyze differences. PLA significantly increased only in groups O and I (P = 0.003 and P < 0.001). Subpopulations of leukocytes significantly increased in all groups. There were no significant differences among the four groups (P = 0.578) in PLA increase. Although there was no significant effect on P-selectin expression (P = 1.000) and leukocyte CD11a and CD18 expression (P = 0.999, P = 0.422) within and between the groups, there was an increase in CD11b expression (P = 0.018). Blood mixing can increase PLA, especially in platelet-neutrophil and platelet-monocyte aggregations, possibly through nonhemolytic reactions. The CD11b integrin with CD18 may play a role in the formation of PLA. PMID- 28846569 TI - Effects of Prior Psychosocial Trauma on Subsequent Immune Response After Experimental Thorax Trauma. AB - Overshooting inflammation during the early phase after blunt thorax trauma promotes the development of acute respiratory distress syndrome, multiple organ failure, and subsequent mortality. Given that individuals diagnosed with stress related disorders are characterized by chronic low-grade inflammation, we hypothesize that "psychosocial traumatic preload" poses a risk factor for the abovementioned complications after thorax trauma.Here, we used the chronic subordinate colony housing (CSC) paradigm to induce "psychosocial traumatic preload" and systemic low-grade immune activation in male mice, indicated by elevated plasma concentrations of different inflammatory mediators. Subsequent thorax trauma was induced in anaesthetized mice by a single blast wave centered on the thorax; SHAM animals were exposed to anesthesia only. Mice were killed 2, 6, and 24 h after thorax trauma or SHAM treatment.Independent of thorax trauma, CSC caused an increase in adrenal weight, and a decrease in thymus weight, indicating that the stress paradigm worked reliably. Moreover, although lung histology was not affected by prior stress, CSC exposure aggravated the early immune response after thorax trauma, indicated by elevated myeloperoxidase lung concentrations in thorax trauma-exposed CSC versus respective single-housed control (SHC) mice (2 h). Furthermore, thorax trauma caused an increase in total bronchoalveolar lavage fluid (BAL) protein (24 h), BAL C5a (2 h), BAL cell counts (24 h), and BAL keratinocyte chemoattractant (6 h and 24 h) in CSC but not SHC mice.Our data indicate that repeated psychosocial traumatization during adulthood moderately aggravates the local immune response toward thorax trauma, but overall may be considered as a rather minor risk factor in terms of thorax trauma associated complications. PMID- 28846570 TI - Macrophage Migration Inhibitory Factor-Induced Autophagy Contributes to Thrombin Triggered Endothelial Hyperpermeability in Sepsis. AB - Vascular leakage contributes to the high morbidity and mortality associated with sepsis. Exposure of the endothelium to inflammatory mediators, such as thrombin and cytokines, during sepsis leads to hyperpermeability. We recently observed that autophagy, a cellular process for protein turnover, is involved in macrophage migration inhibitory factor (MIF)-induced endothelial hyperpermeability. Even though it is known that thrombin induces endothelial cells to secrete MIF and to increase vascular permeability, the possible role of autophagy in this process is unknown. In this study, we proposed and tested the hypothesis that MIF-induced autophagy plays an important role in thrombin-induced endothelial hyperpermeability. We evaluated the effects of thrombin on endothelial permeability, autophagy induction, and MIF secretion in vitro using the human microvascular endothelial cell line-1 and human umbilical vein endothelial cells. Several mechanisms/read outs of endothelial permeability and autophagy formation were examined. We observed that blocking autophagy attenuated thrombin-induced endothelial hyperpermeability. Furthermore, thrombin-induced MIF secretion was involved in this process because MIF inhibition reduced thrombin induced autophagy and hyperpermeability. Finally, we showed that blocking MIF or autophagy effectively alleviated vascular leakage and mortality in endotoxemic mice. Thus, MIF-induced autophagy may represent a common mechanism causing vascular leakage in sepsis. PMID- 28846571 TI - Pulmonary Mechanics and Mortality in Mechanically Ventilated Patients Without Acute Respiratory Distress Syndrome: A Cohort Study. AB - BACKGROUND: Driving pressure has been proposed as a major determinant of outcome in patients with acute respiratory distress syndrome (ARDS), but there is little data examining the association between pulmonary mechanics, including driving pressure, and outcomes in mechanically ventilated patients without ARDS. METHODS: Secondary analysis from 1,705 mechanically ventilated patients enrolled in a clinical study that examined outcomes associated with the use of early lung protective mechanical ventilation. The primary outcome was mortality and the secondary outcome was the incidence of ARDS. Multivariable models were constructed to: define the association between pulmonary mechanics (driving pressure, plateau pressure, and compliance) and mortality; and evaluate if driving pressure contributed information beyond that provided by other pulmonary mechanics. RESULTS: The mortality rate for the entire cohort was 26.0%. Compared with survivors, non-survivors had significantly higher driving pressure [15.9 (5.4) vs. 14.9 (4.4), P = 0.005] and plateau pressure [21.4 (5.7) vs. 20.4 (4.6), P = 0.001]. Driving pressure was independently associated with mortality [adjusted OR, 1.04 (1.01-1.07)]. Models related to plateau pressure also revealed an independent association with mortality, with similar effect size and interval estimates as driving pressure. There were 152 patients who progressed to ARDS (8.9%). Along with driving pressure and plateau pressure, mechanical power [adjusted OR, 1.03 (1.00-1.06)] was also independently associated with ARDS development. CONCLUSIONS: In mechanically ventilated patients, driving pressure and plateau pressure are risk factors for mortality and ARDS, and provide similar information. Mechanical power is also a risk factor for ARDS. PMID- 28846572 TI - Sleep Disorders Among Holocaust Survivors: A Review of Selected Publications. AB - After World War II, traumatic after effects often caused persistent sleep disorders for Holocaust survivors (HSs). This is a review of studies reporting on sleep disturbances and nightmares (as primary or secondary outcomes) among HSs between 1939 and 2015, conducted in various countries and contexts (clinical settings, pension claims, community surveys, sleep laboratories). Most studies revealed various sleep disturbances among HSs. Some studies found those disturbances in the absence of clinical disorders. Both men and women reported similar frequencies of sleep disturbances, although posttraumatic stress disorder and depression were more frequent in women. Sleep laboratory studies provided the single most direct and detailed sources of information. Findings included a) long standing changes in sleep architecture, for example, decreased rapid eye movement (REM) sleep, and b) contrasting patterns of dreaming and recall among better versus poorly adjusted survivors. These results are of importance to both HSs and their families and for medical and mental health professionals. PMID- 28846573 TI - Pharmacotherapy of Attention Deficit Hyperactivity Disorder Symptom Profile in ASD. PMID- 28846574 TI - Personality Disorders in College Students With Internet Addiction. PMID- 28846575 TI - Personality Disorders in Female and Male College Students With Internet Addiction. PMID- 28846576 TI - Blood and Tissue Silver Levels Following Application of Silver-Based Dressings to Sulfur Mustard Chemical Burns. AB - Silver-based dressings are commonly used in burn care. Silver sulfadiazine use is associated with elevated blood, urine, and tissue levels of silver ion. We examined wound and tissue levels of silver ion in a two-species model of sulfur mustard chemical burn injury treated with two different silver-based dressings. Superficial dermal and moderate thickness dermal chemical burns were induced in 16 hairless guinea pigs and in 16 Gottingen minipigs by exposure to sulfur mustard vapor. After debridement, silver-nylon burn dressings or silver-calcium alginate dressings were applied and changed every 7 days until wound healing or a maximum of 60 days post exposure. At autopsy, liver, spleen, and wound samples were harvested. Silver ion was measured using inductively coupled plasma-mass spectrography with a lower level of detection of 0.02 parts per billion. Negligible silver ion levels were found in the liver (mean < 0.003 MUg/g of tissue) and spleen (mean < 0.05 MUg/g) of all 32 animals. Wound biopsies showed silver ion levels ranging from 0.07 to 19.5 MUg/g of tissue. Wound levels were higher in minipigs than in hairless guinea pigs and were higher in animals treated with silver-nylon burn wound dressings than with silver-calcium alginate dressings. Silver ion could be detected in some wounds 40 days after dressings were removed. In a chemical burn model, application of silver-nylon or silver calcium alginate dressings is associated with elevated wound levels but negligible tissue levels of silver ion. PMID- 28846577 TI - Rotational thromboelastometry significantly optimizes transfusion practices for damage control resuscitation in combat casualties. AB - BACKGROUND: Up to 40% of combat casualties with a truncal injury die of massive hemorrhage before reaching a surgeon. This hemorrhage can be prevented with damage control resuscitation (DCR) methods, which are focused on replacing shed whole blood by empirically transfusing blood components in a 1:1:1:1 ratio of platelets:fresh frozen plasma:erythrocytes:cryoprecipitate (PLT:FFP:RBC:CRYO). Measurement of hemostatic function with rotational thromboelastometry (ROTEM) may allow optimization of the type and quantity of blood products transfused. Our hypothesis was that incorporating ROTEM measurements into DCR methods at the US Role 3 hospital at Bagram Airfield, Afghanistan would change the standard transfusion ratios of 1:1:1:1 to a product mix tailored specifically for the combat causality. METHODS: This retrospective study collected data from the Department of Defense Trauma Registry to compare transfusion practices and outcomes before and after ROTEM deployment to Bagram Airfield. Over the course of six months, 134 trauma patients received a transfusion (pre-ROTEM) and 85 received a transfusion and underwent ROTEM testing (post-ROTEM). Trauma teams received instruction on ROTEM use and interpretation, with no provision of a specific transfusion protocol, to supplement their clinical judgment and practice. RESULTS: The pre and post groups were not significantly different in terms of mortality, massive transfusion protocol activation, mean injury severity score, or coagulation measurements. Despite the difference in size, each group received an equal total number of transfusions. However, the post-ROTEM group received a significant increase in PLT and CRYO transfusions ratios, 4* and 2*, respectively. CONCLUSION: The introduction of ROTEM significantly improved adherence to DCR practices. The transfusion differences suggest that aggressive DCR without thromboelastometry data may result in reduced hemostatic support and underestimate the need for PLT and CRYO. Thus, future controlled trials should include ROTEM-guided coagulation management in trauma resuscitation. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 28846578 TI - The lung rescue unit-Does a dedicated intensive care unit for venovenous extracorporeal membrane oxygenation improve survival to discharge? AB - BACKGROUND: The use of venovenous extra corporeal membrane oxygenation (VV ECMO) for acute respiratory failure (ARF)/acute respiratory (ARDS) has increased since 2009. Specialized units for patients requiring VV ECMO are not standard and patients are often cohorted with other critically ill patients. The purpose of this study was to report the outcome of adult patients admitted in 2015 to the lung rescue unit, which, to our knowledge, is the first intensive care unit in the United States that has been specifically created to provide care for patients requiring VV ECMO. METHODS: Data were collected on all patients admitted to the lung rescue unit on VV ECMO between January 1, 2015, and December 31, 2015. Demographics, medical history, pre-ECMO data, indication for VV ECMO as well as duration of ECMO and survival to decannulation and discharge were recorded. Means (+/- standard deviation) and medians (interquartile range [IQR]) were reported when appropriate. RESULTS: Forty-nine patients were enrolled. Median age was 48 years (IQR, 32-57). Median PaO2/FIO2 ratio before cannulation was 66 (IQR, 53 86). Median ventilator days before cannulation was 2 (IQR, 1-4). Median time on VV ECMO for all patients was 311 hours (IQR, 203-461). Thirty-eight (78%) patients were successfully decannulated with 35 (71%) patients surviving to hospital discharge. CONCLUSION: The use of VV ECMO for ARF/ARDS is increasing. We have demonstrated that a dedicated multidisciplinary intensive care unit for the purpose of providing standardized care with specialized trained providers can improve survival to discharge for patients that require VV ECMO for ARF/ARDS. LEVEL OF EVIDENCE: Therapeutic, level V. PMID- 28846580 TI - Postintubation hypotension in the critically ill: An (un)necessary evil? PMID- 28846581 TI - Featured Articles for CME Credit September 2017. PMID- 28846579 TI - Comparison of direct site endovascular repair utilizing expandable polytetrafluoroethylene stent grafts versus standard vascular shunts in a porcine (Sus scrofa) model. AB - INTRODUCTION: The small diameter of temporary vascular shunts for vascular trauma management may restrict flow and result in ischemia or early thrombosis. We have previously reported a clinical experience with direct, open surgical reconstruction using expandable polytetrafluoroethylene stent grafts to create a "sutureless" anastomosis as an alternative to standard temporary vascular shunts. We sought to characterize patency and flow characteristics of these grafts compared with standard shunts in a survival model of porcine vascular injury. METHODS: Twelve Yorkshire-cross swine received a 2-cm-long near-circumferential defect in the bilateral iliac arteries. A 14 Fr Argyle shunt was inserted into one randomly assigned artery, with a self-expanding expandable polytetrafluoroethylene stent deployed in the other. At 72 hours, conduit patency was evaluated by angiography. Arterial flow measurements were obtained at baseline, immediately after intervention, and after 72 hours via direct measurement with perivascular flow meters. Blood pressure proximal and distal to the conduits and arterial samples for histopathology were obtained during the terminal procedure. RESULTS: Angiography revealed no difference in patency at 72 hours (p = 1.0). While there was no difference in baseline arterial flow between arteries (p = 0.63), the stent grafts demonstrated significantly improved blood flow compared with shunts both immediately after intervention (390 +/- 36 mL/min vs. 265 +/- 25 mL/min, p = 0.002) and at 72 hours (261 +/- 29 mL/min vs. 170 +/- 36 mL/min, p = 0.005). The pressure gradient across the shunts was greater than that of the stent grafts (11.5 mm Hg [interquartile range, 3-19 mm Hg] vs. 3 mm Hg [interquartile range, 3-5 mm Hg], p = 0.013). The speed of deployment was similar between the two devices. CONCLUSIONS: Open "sutureless" direct site repair using commercially available stent grafts to treat vascular injury is a technically feasible strategy for damage control management of peripheral vascular injury and offers increased blood flow when compared with temporary shunts. Furthermore, stent grafts may offer improved durability to extend the window until definitive vascular repair. The combination of these traits may improve outcomes after vascular injury. LEVEL OF EVIDENCE: Epidemiologic/Prognostic, level III. PMID- 28846583 TI - Article Summaries for September 2017 Psychosomatic Medicine, Volume 79, Issue 7. PMID- 28846584 TI - Effects of Preoperative Psychological Interventions on Catecholamine and Cortisol Levels After Surgery in Coronary Artery Bypass Graft Patients: The Randomized Controlled PSY-HEART Trial. AB - OBJECTIVE: The aim of the study was to examine whether preoperative psychological interventions targeting patients' expectations are capable of influencing the biological stress response after coronary artery bypass graft (CABG) surgery and could thus improve recovery after heart surgery. METHODS: Randomized controlled trial with assessments 10 days before surgery, after psychological intervention (day of hospital admission, but before surgery), postoperative (6-8 days later), and at follow-up (6 months after surgery). Eligible patients (N = 124) scheduled for elective on-pump CABG or CABG with valve replacement surgery were approached before hospital admission. Standard medical care (SMC) was compared with two additional preoperative psychological interventions: (a) an expectation manipulation intervention to optimize patients' expectations about course and outcomes or (b) supportive therapy, containing the same amount of therapeutic attention, but without specifically focusing on expectations. Postoperative plasma adrenaline, noradrenaline, and cortisol levels were a secondary outcome of our study (primary outcome patients' disability 6 months after surgery and other secondary patient-reported or clinical outcomes were reported elsewhere). RESULTS: Expectation manipulation intervention (3.68 ln pg/mL, 95% confidence interval = 3.38-3.98, p = .015) and supportive therapy (3.70 ln pg/mL, 95% confidence interval = 3.38-4.01, p = .026) led to significantly lower postoperative adrenaline levels compared with SMC (4.26 ln pg/mL, 95% confidence interval = 3.99-4.53) only. There were no treatment effects of the preoperative intervention for noradrenaline (p = .90) or cortisol (p = .30). Higher postoperative adrenaline levels predicted disability 6 months after surgery (r = .258, p = .018). CONCLUSIONS: In addition to SMC, preoperative psychological interventions seem to buffer psychobiological stress responses and could thus facilitate recovery from CABG surgery. Patients' postoperative stress responses could be an important factor for explaining trajectories of long-term outcomes. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov(NCT01407055). PMID- 28846585 TI - Plutonium Bioassay Testing of United States Atmospheric Nuclear Test Participants and Occupation Forces of Hiroshima and Nagasaki, Japan. AB - The pilot urine plutonium bioassay testing program engaged 100 atomic veterans and 58 persons representative of the United States general population using the fission track analysis technique, developed by Brookhaven National Laboratory. The methodology, collected data, scientific challenges, and test results are presented herein. The Defense Threat Reduction Agency and its predecessor agencies conducted this program in the late 1990s to the mid-2000s to determine the feasibility of bioassay testing to supplement dose reconstruction to estimate atomic veterans' doses under the agency's Nuclear Test Personnel Review Program. In summary, Pu urine bioassay using fission track analysis showed inconsistencies in sample measurement repeatability. To use the analysis as a tool to enhance current processes to perform accurate dose reconstructions requires extensive understanding and resolution of the measurement inconsistencies well beyond the scope of this pilot study. Therefore, fission track analysis (FTA) was found not feasible for implementation on a wide scale basis for atomic veterans. PMID- 28846586 TI - Performance Testing Of Selected Types of Electronic Personal Dosimeters in X- and Gamma Radiation Fields. AB - Electronic personal dosimeters (EPDs) are increasingly being used alongside conventional thermoluminescent dosimeters to measure the dose of legal record in terms of personal dose equivalent. Therefore, it is of great importance to execute performance tests of these dosimeters in photon fields of various energies and at various angles of incidence. This testing is done in order to simulate the behavior of these dosimeters in realistic multidirectional polyenergetic ionizing radiation fields. Tests of accuracy, linearity, energy response, and angular response have been performed on 10 EPDs from multiple manufacturers. Various radiation qualities have been used in the energy range from 33 keV to 1.33 MeV and for angles of incidence 0 degrees to 80 degrees . This research proves that many of the EPDs tested performed according to the manufacturer's specifications and the requirements of the international standards regarding personal dosimetry. PMID- 28846587 TI - A History of the International Commission on Non-Ionizing Radiation Protection. AB - Concern about health risks from exposure to non-ionizing radiation (NIR) commenced in the 1950s after tracking radars were first introduced during the Second World War. Soon after, research on possible biological effects of microwave radiation in the former Soviet Union and the U.S. led to public and worker exposure limits being much lower in Eastern European than in Western countries, mainly because of different protection philosophies. As public concern increased, national authorities began introducing legislation to limit NIR exposures from domestic microwave ovens and workplace devices such as visual display units. The International Radiation Protection Association (IRPA) was formed in 1966 to represent national radiation protection societies. To address NIR protection issues, IRPA established a Working Group in 1974, then a Study Group in 1975, and finally the International NIR Committee (INIRC) in 1977. INIRC's publications quickly became accepted worldwide, and it was logical that it should become an independent commission. IRPA finally established the International Commission on Non-Ionizing Radiation Protection (ICNIRP), chartering its remit in 1992, and defining NIR as electromagnetic radiation (ultraviolet, visible, infrared), electromagnetic waves and fields, and infra- and ultrasound. ICNIRP's guidelines have been incorporated into legislation or adopted as standards in many countries. While ICNIRP has been subjected to criticism and close scrutiny by the public, media, and activists, it has continued to issue well-received, independent, science-based protection advice. This paper summarizes events leading to the formation of ICNIRP, its key activities up to 2017, ICNIRP's 25th anniversary year, and its future challenges. PMID- 28846588 TI - Considerations for Bioassay Monitoring of Mixtures of Radionuclides. AB - Complying with regulations for bioassay monitoring of radionuclide intakes is significantly more complex for mixtures than it is for pure radionuclides. Different constituents will naturally have different dose coefficients, be detectable at significantly different levels, and may require very different amounts of effort to bioassay. The ability to use certain constituents as surrogates for others will depend on how well characterized the mixture is, as well as whether the employee is also working with other radionuclides. This is further compounded by the fact that the composition of a mixture (or even of a pure radionuclide) is likely to change over time. Internal dosimetrists must decide how best to monitor employees who work with radionuclide mixtures. In particular, they must decide which constituents should be monitored routinely, which constituents only need to be monitored in the case of an intake, and how to estimate doses based on intakes of monitored and unmonitored constituents. PMID- 28846591 TI - Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT2C Modulators. AB - A series of pyrimidine derivatives 4a-i were synthesized and evaluated for their binding affinities towards 5-HT2C receptors. With regard to designed molecules 4a i, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT2C binding affinity and selectivity was studied. The most promising diasteromeric mixtures 4d and 4e were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols 5d and 5e, prepared by an enzymatic kinetic resolution. Pyrimidine analogue (R,R)-4e displayed an excellent 5-HT2C binding affinity with good selectivity values against a broad range of other 5-HT receptor subtypes. PMID- 28846592 TI - Improved Housing Accessibility for Older People in Sweden and Germany: Short Term Costs and Long-Term Gains. AB - The physical housing environment is important to facilitate activities of daily living (ADL) for older people. A hindering environment may lead to ADL dependence and thus increase the need for home services, which is individually restricting and a growing societal burden. This study presents simulations of policy changes with regard to housing accessibility that estimates the potential impact specifically on instrumental activities of daily living (I-ADL), usage of home services, and related costs. The models integrate empirical data to test the hypothesis that a policy providing funding to remove the five most severe environmental barriers in the homes of older people who are at risk of developing dependence in I-ADL, can maintain independence and reduce the need for home services. In addition to official statistics from state agencies in Sweden and Germany, we utilized published results from the ENABLE-AGE and other scientific studies to generate the simulations. The simulations predicted that new policies that remove potentially hindering housing features would improve I-ADL performance among older people and reduce the need for home services. Our findings suggest that a policy change can contribute to positive effects with regard to I-ADL independence among older people and to a reduction of societal burden. PMID- 28846593 TI - Optimization of the Fano Resonance Lineshape Based on Graphene Plasmonic Hexamer in Mid-Infrared Frequencies. AB - In this article, the lineshape of Fano-like resonance of graphene plasmonic oligomers is investigated as a function of the parameters of the nanostructures, such as disk size, chemical potential and electron momentum relaxation time in mid-infrared frequencies. Also, the mechanism of the optimization is discussed. Furthermore, the environmental index sensing effect of the proposed structure is revealed, and a figure of merit of 25.58 is achieved with the optimized graphene oligomer. The proposed nanostructure could find applications in the fields of chemical or biochemical sensing. PMID- 28846594 TI - Low-FODMAP Diet Improves Irritable Bowel Syndrome Symptoms: A Meta-Analysis. AB - Irritable bowel syndrome (IBS) affects 7-15% of the general population. A recently devised dietary approach consists of restricting foods with highly fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs), which can trigger and/or exacerbate IBS symptoms. The aim of this study is to use meta analysis to provide an update on the randomised control trials (RCTs) and cohort studies, and examine them separately in relation to diet type. Papers were selected using the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) flowchart. Cohen's d and odds ratios were used as a measure of effect size for RCTs. A random effects model was used to account for different sources of variation among studies. Heterogeneity was assessed using Q statistics, I2, Tau, and Tau2. Publication bias was analysed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger's test. The results showed that in the RCTs, the patients receiving a low-FODMAP diet experienced a statistically significant pain and bloating reduction compared with those receiving a traditional diet; as regards to stool consistency, there was no significant difference between treatments. A significant reduction in abdominal pain and bloating were described by patients receiving a low-FODMAP diet compared with those receiving a high-FODMAP diet. In cohort studies, pain and bloating were significantly reduced after treatment compared with the baseline diet. We conclude that there is evidence that a low-FODMAP diet could have a favourable impact on IBS symptoms, especially abdominal pain and bloating. However, it remains to be demonstrated whether a low-FODMAP diet is superior to conventional IBS diets, especially in the long term. PMID- 28846595 TI - Maternal Prenatal Folic Acid Supplementation Programs Offspring Lipid Metabolism by Aberrant DNA Methylation in Hepatic ATGL and Adipose LPL in Rats. AB - The effects of maternal prenatal folic acid supplementation (FAS) on offspring lipid metabolism in adulthood remains unclear, although prenatal FAS is compulsively suggested in many countries. Female Sprague-Dawley rats were fed with control (CON) or FAS diets before and during pregnancy. Male offspring of CON and FAS dams were further divided into two groups at seven weeks for CON and high-fat (HF) diet interventions for eight weeks in adulthood (n = 10). The interactive effects of maternal prenatal FAS and offspring HF in adulthood on lipid metabolism and DNA methylation of genes involved in lipids metabolism were assessed. The male offspring of FAS dams had elevated serum and liver triglyceride level when fed with HF compared to the male offspring of CON dams. The mRNA and protein expression levels of hepatic ATGL and adipose LPL were significantly decreased in offspring of FAS dams than in offspring of CON dams. Furthermore, maternal prenatal FAS resulted in elevated DNA methylation levels in the promoter and first exon region of hepatic ATGL and adipose LPL in offspring. Maternal FAS exacerbated the adverse effects of HF on lipid metabolism in offspring through inducing aberrant DNA methylation levels of hepatic ATGL and adipose LPL. PMID- 28846596 TI - Increase of Elderly Population in the Rainstorm Hazard Areas of China. AB - In light of global warming, increased extreme precipitation events have enlarged the population exposed to floods to some extent. Extreme precipitation risk assessments are of great significance in China and allow for the response to climate change and mitigation of risks to the population. China is one of the countries most influenced by climate change and has unique national population conditions. The influence of extreme precipitation depends on the degree of exposure and vulnerability of the population. Accurate assessments of the population exposed to rising rainstorm trends are crucial to mapping extreme precipitation risks. Studying the population exposed to rainstorm hazard areas (RSHA) at the microscale is extremely urgent, due to the local characteristics of extreme precipitation events and regional diversity of the population. The spatial distribution of population density was mapped based on the national population census data from China in 1990, 2000 and 2010. RSHA were also identified using precipitation data from 1975-2015 in China, and the rainstorm tendency values were mapped using GIS in this paper. The spatial characteristics of the rainstorm tendencies were then analyzed. Finally, changes in the population in the RSHA are discussed. The results show that the extreme precipitation trends are increasing in southeastern China. From 1990 to 2010, the population in RSHA increased by 110 million, at a rate of 14.6%. The elderly in the region increased by 38 million at a rate of 86.4%. Studying the size of the population exposed to rainstorm hazards at the county scale can provide scientific evidence for developing disaster prevention and mitigation strategies from the bottom up. PMID- 28846597 TI - Neighbourhood Environmental Attributes Associated with Walking in South Australian Adults: Differences between Urban and Rural Areas. AB - Although the health benefits of walking are well established, participation is lower in rural areas compared to urban areas. Most studies on walkability and walking have been conducted in urban areas, thus little is known about the relevance of walkability to rural areas. A computer-assisted telephone survey of 2402 adults (aged >=18 years) was conducted to determine walking behaviour and perceptions of neighbourhood walkability. Data were stratified by urban (n = 1738) and rural (n = 664). A greater proportion of respondents reported no walking in rural (25.8%) compared to urban areas (18.5%). Compared to urban areas, rural areas had lower walkability scores and urban residents reported higher frequency of walking. The association of perceived walkability with walking was significant only in urban areas. These results suggest that environmental factors associated with walking in urban areas may not be relevant in rural areas. Appropriate walkability measures specific to rural areas should be further researched. PMID- 28846598 TI - Synthesis of Au-Pd Bimetallic Nanoflowers for Catalytic Reduction of 4 Nitrophenol. AB - Due to the great potential to improve catalytic performance, gold (Au) and palladium (Pd) bimetallic catalysts have prompted structure-controlled synthesis of Au-Pd nanoalloys bounded by high-index facets. In this work, we prepared Au-Pd bimetallic nanoflowers (NFs) with a uniform size, well-defined dendritic morphology, and homogeneous alloy structure in an aqueous solution by seed mediated synthesis. The prepared bimetallic NFs were fully characterized using a combination of transmission electron microscopy, Ultraviolet-Visible (UV-vis) spectroscopy, inductively coupled plasma optical emission spectroscopy, and cyclic voltammetry measurements. The catalytic activities of the prepared Au-Pd nanoparticles for 4-nitrophenol reduction were also investigated, and the activities are in the order of Au@Pd NFs > Au-Pd NFs (Au1Pd1 core) > Au-Pd NFs (Au core), which could be related to the content and exposed different reactive surfaces of Pd in alloys. This result clearly demonstrates that the superior activities of Au-Pd alloy nanodendrites could be attributed to the synergy between Au and Pd in catalysts. PMID- 28846599 TI - Application and Optimization of Stiffness Abruption Structures for Pressure Sensors with High Sensitivity and Anti-Overload Ability. AB - The influence of diaphragm bending stiffness distribution on the stress concentration characteristics of a pressure sensing chip had been analyzed and discussed systematically. According to the analysis, a novel peninsula-island based diaphragm structure was presented and applied to two differenet diaphragm shapes as sensing chips for pressure sensors. By well-designed bending stiffness distribution of the diaphragm, the elastic potential energy induced by diaphragm deformation was concentrated above the gap position, which remarkably increased the sensitivity of the sensing chip. An optimization method and the distribution pattern of the peninsula-island based diaphragm structure were also discussed. Two kinds of sensing chips combined with the peninsula-island structures distributing along the side edge and diagonal directions of rectangular diaphragm were fabricated and analyzed. By bonding the sensing chips with anti-overload glass bases, these two sensing chips were demonstrated by testing to achieve not only high sensitivity, but also good anti-overload ability. The experimental results showed that the proposed structures had the potential to measure ultra low absolute pressures with high sensitivity and good anti-overload ability in an atmospheric environment. PMID- 28846601 TI - Synergetic Use of Sentinel-1 and Sentinel-2 Data for Soil Moisture Mapping at 100 m Resolution. AB - The recent deployment of ESA's Sentinel operational satellites has established a new paradigm for remote sensing applications. In this context, Sentinel-1 radar images have made it possible to retrieve surface soil moisture with a high spatial and temporal resolution. This paper presents two methodologies for the retrieval of soil moisture from remotely-sensed SAR images, with a spatial resolution of 100 m. These algorithms are based on the interpretation of Sentinel 1 data recorded in the VV polarization, which is combined with Sentinel-2 optical data for the analysis of vegetation effects over a site in Urgell (Catalunya, Spain). The first algorithm has already been applied to observations in West Africa by Zribi et al., 2008, using low spatial resolution ERS scatterometer data, and is based on change detection approach. In the present study, this approach is applied to Sentinel-1 data and optimizes the inversion process by taking advantage of the high repeat frequency of the Sentinel observations. The second algorithm relies on a new method, based on the difference between backscattered Sentinel-1 radar signals observed on two consecutive days, expressed as a function of NDVI optical index. Both methods are applied to almost 1.5 years of satellite data (July 2015-November 2016), and are validated using field data acquired at a study site. This leads to an RMS error in volumetric moisture of approximately 0.087 m3/m3 and 0.059 m3/m3 for the first and second methods, respectively. No site calibrations are needed with these techniques, and they can be applied to any vegetation-covered area for which time series of SAR data have been recorded. PMID- 28846600 TI - The Satiating Properties of Pork are not Affected by Cooking Methods, Sousvide Holding Time or Mincing in Healthy Men-A Randomized Cross-Over Meal Test Study. AB - Low temperature long time (LTLT) sous-vide cooking may modify meat proteins in a way that could promote satiety. We investigated the effects of (1) cooking method (LTLT 58 degrees C vs. oven 160 degrees C), (2) LTLT holding time (17 h vs. 72 min), and (3) pork structure, LTLT 58 degrees C for 17 h (minced vs. roast) on appetite regulation and in vitro protein digestibility. In a cross-over study, 37 healthy men consumed four meals containing pork: LTLT-cooked roast, 58 degrees C, 72 min; LTLT-cooked roast, 58 degrees C, 17 h; and, oven-cooked roast, 160 degrees C to a core temperature of 58 degrees C and LTLT-cooked minced patties, 58 degrees C, 17 h. Ad libitum energy intake (EI) after three hours was the primary endpoint. Moreover, subjective appetite sensations were assessed. Protein digestibility was determined in an in vitro simulated digestion model. Ad libitum EI did not differ between the meals. Furthermore, appetite ratings were not clearly affected. LTLT cooking for 72 min increased the proteolytic rate in the early gastric phase during digestion as compared to LTLT cooking for 17 h or oven cooking. In conclusion, LTLT cooking, LTLT holding time, and pork structure did not affect ad libitum EI. However, LTLT cooking at 58 degrees C for 72 min seemed to enhance in vitro protein digestibility. PMID- 28846602 TI - Selecting Lentil Accessions for Global Selenium Biofortification. AB - : The biofortification of lentil (Lens culinaris Medikus.) has the potential to provide adequate daily selenium (Se) to human diets. The objectives of this study were to (1) determine how low-dose Se fertilizer application at germination affects seedling biomass, antioxidant activity, and Se uptake of 26 cultivated lentil genotypes; and (2) quantify the seed Se concentration of 191 lentil wild accessions grown in Terbol, Lebanon. A germination study was conducted with two Se treatments [0 (control) and 30 kg of Se/ha] with three replicates. A separate field study was conducted in Lebanon for wild accessions without Se fertilizer. Among cultivated lentil accessions, PI533690 and PI533693 showed >100% biomass increase vs. CONTROLS: Se addition significantly increased seedling Se uptake, with the greatest uptake (6.2 ug g-1) by PI320937 and the least uptake (1.1 ug g 1) by W627780. Seed Se concentrations of wild accessions ranged from 0 to 2.5 ug g-1; accessions originating from Syria (0-2.5 ug g-1) and Turkey (0-2.4 ug g-1) had the highest seed Se. Frequency distribution analysis revealed that seed Se for 63% of accessions was between 0.25 and 0.75 ug g-1, and thus a single 50 g serving of lentil has the potential to provide adequate dietary Se (20-60% of daily recommended daily allowance). As such, Se application during plant growth for certain lentil genotypes grown in low Se soils may be a sustainable Se biofortification solution to increase seed Se concentration. Incorporating a diverse panel of lentil wild germplasm into Se biofortification programs will increase genetic diversity for effective genetic mapping for increased lentil seed Se nutrition and plant productivity. PMID- 28846603 TI - Transformation from a Single Antenna to a Series Array Using Push/Pull Origami. AB - We propose a push/pull origami antenna, transformable between a single antenna element and a three-element array. In limited space, the proposed origami antenna can work as a single antenna. When the space is not limited and a higher gain is required, the proposed origami antenna can be transformed to a series antenna array by pulling the frame. In order to push the antenna array back to a single antenna, the frame for each antenna element size must be different. The frame and supporting dielectric materials are built using a three-dimensional (3D) printer. The conductive patterns are inkjet-printed on paper. Thus, the proposed origami antenna is built using hybrid printing technology. The 10-dB impedance bandwidth is 2.5-2.65 GHz and 2.48-2.62 GHz for the single-antenna and array mode, respectively, and the peak gains in the single-antenna and array mode are 5.8 dBi and 7.6 dBi, respectively. The proposed antenna can be used for wireless remote sensing applications. PMID- 28846604 TI - Preparation of Desirable Porous Cell Structure Polylactide/Wood Flour Composite Foams Assisted by Chain Extender. AB - Polylactide (PLA)/wood flour composite foam were prepared through a batch foaming process. The effect of the chain extender on the crystallization behavior and dynamic rheological properties of the PLA/wood flour composites were investigated as well as the crystal structure and cell morphology of the composite foams. The incorporation of the chain extender enhanced the complex viscosity and storage modulus of PLA/wood flour composites, indicating the improved melt elasticity. The chain extender also led to a decreased crystallization rate and final crystallinity of PLA/wood flour composites. With an increasing chain extender content, a finer and more uniform cell structure was formed, and the expansion ratio of PLA/wood flour composite foams was much higher than without the chain extender. Compared to the unfoamed composites, the crystallinity of the foamed PLA/wood flour composites was improved and the crystal was loosely packed. However, the new crystalline form was not evident. PMID- 28846605 TI - Food Consumption Patterns among U.S. Children from Birth to 23 Months of Age, 2009-2014. AB - Early dietary patterns can have long-term health consequences. This study describes food consumption patterns among US children <=23 months. We used one 24 h dietary recall from the National Health and Nutrition Examination Survey 2009 2014 to estimate the percentage of children <=23 months who consumed selected food/beverage categories on any given day by age and race/Hispanic origin. Among 0 to 5 month olds, 42.9% (95% Confidence Interval (CI): 37.0%, 49.1%) consumed breast milk, with non-Hispanic blacks less likely (21.2%, 95% CI: 13.2%, 32.2%) compared with non-Hispanic whites (49.0%, 95% CI: 39.0%, 59.1%) (p < 0.001). The percentage of children consuming vegetables was 57.4%, 48.2%, and 45.1% for ages 6 to 11, 12 to 18 and 19 to 23 months, respectively (p < 0.01 for trend). The percentage of children consuming sugar-sweetened beverages was 6.6%, 31.8% and 38.3% for ages 6 to 11, 12 to 18 and 19 to 23 months, respectively (p < 0.01 for trend). Among children aged >=6 months, lower percentages of non-Hispanic black and Hispanic children consumed vegetables, and higher percentages consumed sugar sweetened beverages and 100% juice compared with non-Hispanic white children, although differences were not always statistically significant. Compared with children in the second year of life, a higher percentage of children 6 to 11 months of age consumed vegetables and a lower percentage consumed 100% juice, sugar-sweetened beverages, snacks, or sweets; with differences by race/Hispanic origin. These data may be relevant to the upcoming 2020-2025 federal dietary guidelines. PMID- 28846607 TI - Green Composites Based on Blends of Polypropylene with Liquid Wood Reinforced with Hemp Fibers: Thermomechanical Properties and the Effect of Recycling Cycles. AB - Green composites from polypropylene and lignin-based natural material were manufactured using a melt extrusion process. The lignin-based material used was the so called "liquid wood". The PP/"Liquid Wood" blends were extruded with "liquid wood" content varying from 20 wt % to 80 wt %. The blends were thoroughly characterized by flexural, impact, and dynamic mechanical testing. The addition of the Liquid Wood resulted in a great improvement in terms of both the flexural modulus and strength but, on the other hand, a reduction of the impact strength was observed. For one blend composition, the composites reinforced with hemp fibers were also studied. The addition of hemp allowed us to further improve the mechanical properties. The composite with 20 wt % of hemp, subjected to up to three recycling cycles, showed good mechanical property retention and thermal stability after recycling. PMID- 28846608 TI - Conditional Variational Autoencoder for Prediction and Feature Recovery Applied to Intrusion Detection in IoT. AB - The purpose of a Network Intrusion Detection System is to detect intrusive, malicious activities or policy violations in a host or host's network. In current networks, such systems are becoming more important as the number and variety of attacks increase along with the volume and sensitiveness of the information exchanged. This is of particular interest to Internet of Things networks, where an intrusion detection system will be critical as its economic importance continues to grow, making it the focus of future intrusion attacks. In this work, we propose a new network intrusion detection method that is appropriate for an Internet of Things network. The proposed method is based on a conditional variational autoencoder with a specific architecture that integrates the intrusion labels inside the decoder layers. The proposed method is less complex than other unsupervised methods based on a variational autoencoder and it provides better classification results than other familiar classifiers. More important, the method can perform feature reconstruction, that is, it is able to recover missing features from incomplete training datasets. We demonstrate that the reconstruction accuracy is very high, even for categorical features with a high number of distinct values. This work is unique in the network intrusion detection field, presenting the first application of a conditional variational autoencoder and providing the first algorithm to perform feature recovery. PMID- 28846606 TI - The Emerging Role of GLP-1 Receptors in DNA Repair: Implications in Neurological Disorders. AB - Glucagon-like peptide-1 (GLP-1) is originally found as a metabolic hormone (incretin) that is able to regulate blood-glucose levels via promoting synthesis and secretion of insulin. GLP-1 and many analogues are approved for treatment of type II diabetes. Accumulating results imply that GLP-1 performs multiple functions in various tissues and organs beyond regulation of blood-glucose. The neuroprotective function of GLP-1 has been extensively explored during the past two decades. Three of our previous studies have shown that apurinic/apyrimidinic endonuclease 1 (APE1) is the only protein of the base excision repair (BER) pathway able to be regulated by oxidative stress or exogenous stimulations in rat primary cortical neurons. In this article, we review the role of APE1 in neurodegenerative diseases and its relationship to neuroprotective mechanisms of the activated GLP-1 receptor (GLP-1R) in neurodegenerative disorders. The purpose of this article is to provide new insight, from the aspect of DNA damage and repair, for studying potential treatments in neurodegenerative diseases. PMID- 28846609 TI - The Effect of Heat Treatment on the Emission Color of P-Doped Ca2SiO4 Phosphor. AB - In a series of (Ca2-x/2-yEuy?x/2)(Si1-xPx)O4 (x = 0.06, 0.02 <= y <=0.5), various color-emitting phosphors were successfully synthesized by a solid-state reaction. These phosphors were characterized by photoluminescence (PL) spectroscopy, X-ray powder diffractometry, transmission electron microscopy, and X-ray absorption fine structure spectroscopy. We evaluated the effect of heat treatment on PL properties with various annealing temperatures at 1373-1773 K for 4 h before/after reduction treatment from Eu3+ to Eu2+. In the red-emitting (Ca1.95Eu3+0.02?0.03)(Si0.94P0.06)O4+delta phosphor, the highest PL intensity exhibited when it was annealed at 1773 K. On the other hand, in the green emitting (Ca1.95Eu2+0.02?0.03)(Si0.94P0.06)O4 phosphor, the highest PL intensity was realized when it was annealed at 1473 K and consequently treated under a reductive atmosphere. With increasing annealing temperature, the emission peak wavelength steadily decreased. Furthermore, with increasing Eu2+ content, the emission peak wavelength increased, with the color of emitting light becoming yellowish. Thus, the PL properties of the phosphors were affected by both the structural change from beta to alpha'L, which occurred by heat treatment, and the amount of doped Eu ions. PMID- 28846610 TI - A QRS Detection and R Point Recognition Method for Wearable Single-Lead ECG Devices. AB - In the new-generation wearable Electrocardiogram (ECG) system, signal processing with low power consumption is required to transmit data when detecting dangerous rhythms and to record signals when detecting abnormal rhythms. The QRS complex is a combination of three of the graphic deflection seen on a typical ECG. This study proposes a real-time QRS detection and R point recognition method with low computational complexity while maintaining a high accuracy. The enhancement of QRS segments and restraining of P and T waves are carried out by the proposed ECG signal transformation, which also leads to the elimination of baseline wandering. In this study, the QRS fiducial point is determined based on the detected crests and troughs of the transformed signal. Subsequently, the R point can be recognized based on four QRS waveform templates and preliminary heart rhythm classification can be also achieved at the same time. The performance of the proposed approach is demonstrated using the benchmark of the MIT-BIH Arrhythmia Database, where the QRS detected sensitivity (Se) and positive prediction (+P) are 99.82% and 99.81%, respectively. The result reveals the approach's advantage of low computational complexity, as well as the feasibility of the real-time application on a mobile phone and an embedded system. PMID- 28846611 TI - High Intensity Exercise: Can It Protect You from A Fast Food Diet? AB - The purpose of this study was to assess the ability of high intensity exercise to counteract the deleterious effects of a fast food diet on the cardiometabolic profile of young healthy men. Fifteen men were subjected to an exclusive fast food diet from a popular fast food restaurant chain (three extra value meals/day + optional snack) for 14 consecutive days. Simultaneously, participants were asked to perform each day high intensity interval training (HIIT) (15 * 60 sec sprint intervals (~90% of maximal heart rate)) on a treadmill. Fast food diet and energy expenditure profiles of the participants during the intervention were assessed as well as body composition (DXA), cardiometabolic profile (lipid, hepatic enzymes, glycated hemoglobin, glucose, insulin, hsC-reactive protein (hsCRP) and blood pressure) and estimated maximal oxygen consumption (VO2 max) pre- and post-experiment. We found significant improvements for fat mass, lean body mass, estimated VO2 max, fasting glucose, serum lipoprotein(a) and hsCRP after the intervention (p < 0.05). HDL-cholesterol significantly decreased (p < 0.002), but the triglycerides/HDL-cholesterol ratio did not change. All other cardiometabolic variables measured remained stable, which includes the primary outcome: the HOMA index (pre: 1.83 +/- 1.2 vs. post: 1.54 +/- 0.7 values; p = 0.35). In conclusion, in large part, insulin resistance and the cardiometabolic profile of young healthy individuals seems to be protected by HIIT from a fast food diet. PMID- 28846612 TI - Genome-Wide Transcriptome Analysis Reveals Conserved and Distinct Molecular Mechanisms of Al Resistance in Buckwheat (Fagopyrum esculentum Moench) Leaves. AB - Being an Al-accumulating crop, buckwheat detoxifies and tolerates Al not only in roots but also in leaves. While much progress has recently been made toward Al toxicity and resistance mechanisms in roots, little is known about the molecular basis responsible for detoxification and tolerance processes in leaves. Here, we carried out transcriptome analysis of buckwheat leaves in response to Al stress (20 uM, 24 h). We obtained 33,931 unigenes with 26,300 unigenes annotated in the NCBI database, and identified 1063 upregulated and 944 downregulated genes under Al stress. Functional category analysis revealed that genes related to protein translation, processing, degradation and metabolism comprised the biological processes most affected by Al, suggesting that buckwheat leaves maintain flexibility under Al stress by rapidly reprogramming their physiology and metabolism. Analysis of genes related to transcription regulation revealed that a large proportion of chromatin-regulation genes are specifically downregulated by Al stress, whereas transcription factor genes are overwhelmingly upregulated. Furthermore, we identified 78 upregulated and 22 downregulated genes that encode transporters. Intriguingly, only a few genes were overlapped with root Al regulated transporter genes, which include homologs of AtMATE, ALS1, STAR1, ALS3 and a divalent ion symporter. In addition, we identified a subset of genes involved in development, in which genes associated with flowering regulation were important. Based on these data, it is proposed that buckwheat leaves develop conserved and distinct mechanisms to cope with Al toxicity. PMID- 28846613 TI - Method for Estimating Three-Dimensional Knee Rotations Using Two Inertial Measurement Units: Validation with a Coordinate Measurement Machine. AB - Three-dimensional rotations across the human knee serve as important markers of knee health and performance in multiple contexts including human mobility, worker safety and health, athletic performance, and warfighter performance. While knee rotations can be estimated using optical motion capture, that method is largely limited to the laboratory and small capture volumes. These limitations may be overcome by deploying wearable inertial measurement units (IMUs). The objective of this study is to present a new IMU-based method for estimating 3D knee rotations and to benchmark the accuracy of the results using an instrumented mechanical linkage. The method employs data from shank- and thigh-mounted IMUs and a vector constraint for the medial-lateral axis of the knee during periods when the knee joint functions predominantly as a hinge. The method is carefully validated using data from high precision optical encoders in a mechanism that replicates 3D knee rotations spanning (1) pure flexion/extension, (2) pure internal/external rotation, (3) pure abduction/adduction, and (4) combinations of all three rotations. Regardless of the movement type, the IMU-derived estimates of 3D knee rotations replicate the truth data with high confidence (RMS error < 4 degrees and correlation coefficient r >= 0.94 ). PMID- 28846614 TI - Antimicrobial Properties of Silver Cations Substituted to Faujasite Mineral. AB - A goal of our study was to find an alternative to nano-silver-based antimicrobial materials which would contain active silver immobilized in a solid matrix that prevents its migration into the surrounding environment. In this study, we investigated whether silver cations dispersed in an atomic form and trapped in an ion-exchanged zeolite show comparable antimicrobial activity to silver nanoparticles (NPs). The biocidal active material was prepared from the sodium form of faujasite type zeolite in two steps: (1) exchange with silver cations, (2) removal of the external silver oxide NPs by elution with Na2EDTA solution. The modified biocidal zeolite was then added to paper pulp to obtain sheets. The zeolite paper samples and reference samples containing silver NPs were tested in terms of biocidal activity against an array of fungi and bacteria strains, including Escherichia coli, Serratia marcescens, Bacillus subtilis, Bacillus megaterium, Trichoderma viride, Chaetomium globosum, Aspergillus niger, Cladosporium cladosporioides, and Mortierella alpina. The paper with the modified faujasite additive showed higher or similar antibacterial and antifungal activities towards the majority of tested microbes in comparison with the silver NP-filled paper. A reverse effect was observed for the Mortierella alpina strain. PMID- 28846615 TI - Responses of Biogeochemical Characteristics and Enzyme Activities in Sediment to Climate Warming under a Simulation Experiment in Geographically Isolated Wetlands of the Hulunbuir Grassland, China. AB - Climate warming generates a tremendous threat to the stability of geographically isolated wetland (GIW) ecosystems and changes the type of evaporation and atmospheric precipitation in a region. The intrinsic balance of biogeochemical processes and enzyme activity in GIWs may be altered as well. In this paper, we sampled three types of GIWs exhibiting different kinds of flooding periods. With the participation of real-time temperature regulation measures, we assembled a computer-mediated wetland warming micro-system in June 2016 to simulate climate situation of ambient temperature (control group) and two experimental temperature differences (+2.5 degrees C and +5.0 degrees C) following a scientific climate change circumstance based on daily and monthly temperature monitoring at a two minutes scale. Our results demonstrate that the contents of the total organic carbon (TOC), total nitrogen (TN), and total phosphorus (TP) in the warmed showed, roughly, a balance or a slight decrease than the control treatment. Warming obstructed the natural subsidence of sediment, but reinforced the character of the ecological source, and reduced the activity of urease (URE), but promoted the activity of alkaline phosphatase (AKP) and sucrase (SUC). Redundancy analysis showed that sucrase, urease, available phosphorus (AP), and pH were the major correlating factors under warming conditions in our research scope. Total organic carbon, total nitrogen, sucrase, catalase (CAT), and alkaline phosphatase were the principal reference factors to reflect the ambient temperature variations. Nutrient compositions and enzyme activities in GIW ecosystems could be reconstructed under the warming influence. PMID- 28846616 TI - Assessing Knowledge and Attitudes towards Cervical Cancer Screening among Rural Women in Eastern China. AB - There is a heavy burden of cervical cancer in China. Although the Chinese government provides free cervical cancer screening for rural women aged 35 to 59 years, the screening rate remains low even in the more developed regions of eastern China. This study aimed to assess knowledge and attitudes about cervical cancer and its screening among rural women aged 30 to 65 years in eastern China. A cross-sectional study was conducted in four counties of Jining Prefecture in Shandong Province during August 2015. In total, 420 rural women were randomly recruited. Each woman participated in a face-to-face interview in which a questionnaire was administered by a trained interviewer. A total of 405 rural women (mean age 49 years old) were included in the final study. Among them, 210 (51.9%) participants had high knowledge levels. An overwhelming majority, 389 (96.0%) expressed positive attitudes, whilst only 258 (63.7%) had undergone screening for cervical cancer. Related knowledge was higher amongst the screened group relative to the unscreened group. Age, education and income were significantly associated with a higher knowledge level. Education was the only significant factor associated with a positive attitude. In addition, women who were older, or who had received a formal education were more likely to participate in cervical cancer screening. The knowledge of cervical cancer among rural women in eastern China was found to be poor, and the screening uptake was not high albeit a free cervical cancer screening program was provided. Government led initiatives to improve public awareness, knowledge, and participation in cervical cancer screening programs would likely be highly beneficial in reducing cervical cancer incidence and mortality for rural women. PMID- 28846618 TI - The Collaborative Payer Provider Model Enhances Primary Care, Producing Triple Aim Plus One Outcomes: A Cohort Study. AB - Rising health care costs are threatening the fiscal solvency of patients, employers, payers, and governments. The Collaborative Payer Provider Model (CPPM) addresses this challenge by reinventing the role of the payer into a full-service collaborative ally of the physician. From 2010 through 2014, a Medicare Advantage plan prospectively deployed the CPPM, averaging 30,561 members with costs that were 73.6% of fee-for-service (FFS) Medicare (p < 0.001). The health plan was not part of an integrated delivery system. After allocating $80 per member per month (PMPM) for primary care costs, the health plan had medical cost ratios averaging 75.1% before surplus distribution. Member benefits were the best in the market. The health plan was rated 4.5 Stars by the Centers for Medicare and Medicaid Services for years 1-4, and 5 Stars in study year 5 for quality, patient experience, access to care, and care process metrics. Primary care and specialist satisfaction were significantly better than national benchmarks. Savings resulted from shifts in spending from inpatient to outpatient settings, and from specialists to primary care physicians when appropriate. The CPPM is a scalable model that enables a win-win-win system for patients, providers, and payers. PMID- 28846619 TI - Acetylation of Microcrystalline Cellulose by Transesterification in AmimCl/DMSO Cosolvent System. AB - Recently, IL/cosolvent systems have generated a lot of interest as cellulose dissolving solvents and reaction media for various kinds of cellulose modification. In the present study, both 1-allyl-3-methylimidazolium chloride (AmimCl)/dimethyl sulfoxide (DMSO) and AmimCl/N,N-dimethylformamide (DMF) systems were employed to synthesize cellulose acetate by transesterification. Microcrystalline cellulose, 1,8-diazabicyclo[5.4.0]undec-7-ene and isopropenyl acetate were chosen as the raw material, catalyst and acetylation reagent, respectively. The results revealed that DMSO was a suitable cosolvent for the transesterification in the homogeneous solution. Moreover, DMSO had a positive effect on the reaction as the cosolvent under the given conditions and the degree of the substitution of cellulose acetate could be significantly enhanced through increasing the molar ratio of DMSO. The synthesized products were characterized by Fourier transform infrared (FT-IR) spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy (1H-NMR and 13C-NMR), correlation spectroscopy (COSY), heteronuclear single quantum correlation (HSQC) spectroscopy, and X-ray diffraction (XRD) to confirm the chemical and physical structure of the cellulose acetate generated. The thermal properties were also evaluated using thermogravimetric analysis (TGA)/derivative thermogravimetry (DTG). PMID- 28846620 TI - An Overview of LEDs' Effects on the Production of Bioactive Compounds and Crop Quality. AB - Light-emitting diodes (LEDs) are characterized by their narrow-spectrum, non thermal photon emission, greater longevity, and energy-saving characteristics, which are better than traditional light sources. LEDs thus hold the potential to revolutionize horticulture lighting technology for crop production, protection, and preservation. Exposure to different LED wavelengths can induce the synthesis of bioactive compounds and antioxidants, which in turn can improve the nutritional quality of horticultural crops. Similarly, LEDs increase the nutrient contents, reduce microbial contamination, and alter the ripening of postharvest fruits and vegetables. LED-treated agronomic products can be beneficial for human health due to their good nutrient value and high antioxidant properties. Besides that, the non-thermal properties of LEDs make them easy to use in closed-canopy or within-canopy lighting systems. Such configurations minimize electricity consumption by maintaining optimal incident photon fluxes. Interestingly, red, blue, and green LEDs can induce systemic acquired resistance in various plant species against fungal pathogens. Hence, when seasonal clouds restrict sunlight, LEDs can provide a controllable, alternative source of selected single or mixed wavelength photon source in greenhouse conditions. PMID- 28846617 TI - In Vitro Innervation as an Experimental Model to Study the Expression and Functions of Acetylcholinesterase and Agrin in Human Skeletal Muscle. AB - Acetylcholinesterase (AChE) and agrin, a heparan-sulfate proteoglycan, reside in the basal lamina of the neuromuscular junction (NMJ) and play key roles in cholinergic transmission and synaptogenesis. Unlike most NMJ components, AChE and agrin are expressed in skeletal muscle and alpha-motor neurons. AChE and agrin are also expressed in various other types of cells, where they have important alternative functions that are not related to their classical roles in NMJ. In this review, we first focus on co-cultures of embryonic rat spinal cord explants with human skeletal muscle cells as an experimental model to study functional innervation in vitro. We describe how this heterologous rat-human model, which enables experimentation on highly developed contracting human myotubes, offers unique opportunities for AChE and agrin research. We then highlight innovative approaches that were used to address salient questions regarding expression and alternative functions of AChE and agrin in developing human skeletal muscle. Results obtained in co-cultures are compared with those obtained in other models in the context of general advances in the field of AChE and agrin neurobiology. PMID- 28846622 TI - Enhanced Azo-Dyes Degradation Performance of Fe-Si-B-P Nanoporous Architecture. AB - Nanoporous structures were fabricated from Fe76Si9B10P5 amorphous alloy annealed at 773 K by dealloying in 0.05 M H2SO4 solution, as a result of preferential dissolution of alpha-Fe grains in form of the micro-coupling cells between alpha Fe and cathodic residual phases. Nanoporous Fe-Si-B-P powders exhibit much better degradation performance to methyl orange and direct blue azo dyes compared with gas-atomized Fe76Si9B10P5 amorphous powders and commercial Fe powders. The degradation reaction rate constants of nanoporous powders are almost one order higher than those of the amorphous counterpart powders and Fe powders, accompanying with lower activation energies of 19.5 and 26.8 kJ mol-1 for the degradation reactions of methyl orange and direct blue azo dyes, respectively. The large surface area of the nanoporous structure, and the existence of metalloids as well as residual amorphous phase with high catalytic activity are responsible for the enhanced azo-dyes degradation performance of the nanoporous Fe-Si-B-P powders. PMID- 28846621 TI - TiO2-Based Nanoheterostructures for Promoting Gas Sensitivity Performance: Designs, Developments, and Prospects. AB - Gas sensors based on titanium dioxide (TiO2) have attracted much public attention during the past decades due to their excellent potential for applications in environmental pollution remediation, transportation industries, personal safety, biology, and medicine. Numerous efforts have therefore been devoted to improving the sensing performance of TiO2. In those effects, the construct of nanoheterostructures is a promising tactic in gas sensing modification, which shows superior sensing performance to that of the single component-based sensors. In this review, we briefly summarize and highlight the development of TiO2-based heterostructure gas sensing materials with diverse models, including semiconductor/semiconductor nanoheterostructures, noble metal/semiconductor nanoheterostructures, carbon-group-materials/semiconductor nano- heterostructures, and organic/inorganic nanoheterostructures, which have been investigated for effective enhancement of gas sensing properties through the increase of sensitivity, selectivity, and stability, decrease of optimal work temperature and response/recovery time, and minimization of detectable levels. PMID- 28846623 TI - Antifouling Compounds from Marine Invertebrates. AB - In this review, a comprehensive overview about the antifouling compounds from marine invertebrates is described. In total, more than 198 antifouling compounds have been obtained from marine invertebrates, specifically, sponges, gorgonian and soft corals. PMID- 28846624 TI - Review on Molecular Mechanisms of Antifouling Compounds: An Update since 2012. AB - Better understanding of the mechanisms of antifouling compounds is recognized to be of high value in establishing sensitive biomarkers, allowing the targeted optimization of antifouling compounds and guaranteeing environmental safety. Despite vigorous efforts to find new antifouling compounds, information about the mechanisms of antifouling is still scarce. This review summarizes the progress into understanding the molecular mechanisms underlying antifouling activity since 2012. Non-toxic mechanisms aimed at specific targets, including inhibitors of transmembrane transport, quorum sensing inhibitors, neurotransmission blockers, adhesive production/release inhibitors and enzyme/protein inhibitors, are put forward for natural antifouling products or shelf-stable chemicals. Several molecular targets show good potential for use as biomarkers in future mechanistic screening, such as acetylcholine esterase for neurotransmission, phenoloxidase/tyrosinase for the formation of adhesive plaques, N-acyl homoserine lactone for quorum sensing and intracellular Ca2+ levels as second messenger. The studies on overall responses to challenges by antifoulants can be categorized as general targets, including protein expression/metabolic activity regulators, oxidative stress inducers, neurotransmission blockers, surface modifiers, biofilm inhibitors, adhesive production/release inhibitors and toxic killing. Given the current situation and the knowledge gaps regarding the development of alternative antifoulants, a basic workflow is proposed that covers the indispensable steps, including preliminary mechanism- or bioassay-guided screening, evaluation of environmental risks, field antifouling performance, clarification of antifouling mechanisms and the establishment of sensitive biomarkers, which are combined to construct a positive feedback loop. PMID- 28846625 TI - Antifouling Compounds from Marine Macroalgae. AB - Marine macroalgae produce a wide variety of biologically-active metabolites that have been developed into commercial products, such as antibiotics, immunosuppressive, anti-inflammatory, cytotoxic agents, and cosmetic products. Many marine algae remain clean over longer periods of time, suggesting their strong antifouling potential. Isolation of biogenic compounds and the determination of their structure could provide leads for the development of environmentally-friendly antifouling paints. Isolated substances with potent antifouling activity belong to fatty acids, lipopeptides, amides, alkaloids, lactones, steroids, terpenoids, and pyrroles. It is unclear as yet to what extent symbiotic microorganisms are involved in the synthesis of these compounds. Algal secondary metabolites have the potential to be produced commercially using genetic and metabolic engineering techniques. This review provides an overview of publications from 2010 to February 2017 about antifouling activity of green, brown, and red algae. Some researchers were focusing on antifouling compounds of brown macroalgae, while metabolites of green algae received less attention. Several studies tested antifouling activity against bacteria, microalgae and invertebrates, but in only a few studies was the quorum sensing inhibitory activity of marine macroalgae tested. Rarely, antifouling compounds from macroalgae were isolated and tested in an ecologically-relevant way. PMID- 28846626 TI - Mini-Review: Antifouling Natural Products from Marine Microorganisms and Their Synthetic Analogs. AB - Biofouling causes huge economic loss and generates serious ecological issues worldwide. Marine coatings incorporated with antifouling (AF) compounds are the most common practices to prevent biofouling. With a ban of organotins and an increase in the restrictions regarding the use of other AF alternatives, exploring effective and environmentally friendly AF compounds has become an urgent demand for marine coating industries. Marine microorganisms, which have the largest biodiversity, represent a rich and important source of bioactive compounds and have many medical and industrial applications. This review summarizes 89 natural products from marine microorganisms and 13 of their synthetic analogs with AF EC50 values <= 25 MUg/mL from 1995 (the first report about marine microorganism-derived AF compounds) to April 2017. Some compounds with the EC50 values < 5 MUg/mL and LC50/EC50 ratios > 50 are highlighted as potential AF compounds, and the preliminary analysis of structure-relationship (SAR) of these compounds is also discussed briefly. In the last part, current challenges and future research perspectives are proposed based on opinions from many previous reviews. To provide clear guidance for the readers, the AF compounds from microorganisms and their synthetic analogs in this review are categorized into ten types, including fatty acids, lactones, terpenes, steroids, benzenoids, phenyl ethers, polyketides, alkaloids, nucleosides and peptides. In addition to the major AF compounds which targets macro-foulers, this review also includes compounds with antibiofilm activity since micro-foulers also contribute significantly to the biofouling communities. PMID- 28846627 TI - Paulomycin G, a New Natural Product with Cytotoxic Activity against Tumor Cell Lines Produced by Deep-Sea Sediment Derived Micromonospora matsumotoense M-412 from the Aviles Canyon in the Cantabrian Sea. AB - The present article describes a structurally novel natural product of the paulomycin family, designated as paulomycin G (1), obtained from the marine strain Micromonospora matsumotoense M-412, isolated from Cantabrian Sea sediments collected at 2000 m depth during an oceanographic expedition to the submarine Aviles Canyon. Paulomycin G is structurally unique since-to our knowledge-it is the first member of the paulomycin family of antibiotics lacking the paulomycose moiety. It is also the smallest bioactive paulomycin reported. Its structure was determined using HRMS and 1D and 2D NMR spectroscopy. This novel natural product displays strong cytotoxic activities against different human tumour cell lines, such as pancreatic adenocarcinoma (MiaPaca_2), breast adenocarcinoma (MCF-7), and hepatocellular carcinoma (HepG2). The compound did not show any significant bioactivity when tested against a panel of bacterial and fungal pathogens. PMID- 28846628 TI - Cytotoxicity of the Essential Oil of Fennel (Foeniculum vulgare) from Tajikistan. AB - The essential oil of fennel (Foeniculum vulgare) is rich in lipophilic secondary metabolites, which can easily cross cell membranes by free diffusion. Several constituents of the oil carry reactive carbonyl groups in their ring structures. Carbonyl groups can react with amino groups of amino acid residues in proteins or in nucleotides of DNA to form Schiff's bases. Fennel essential oil is rich in anise aldehyde, which should interfere with molecular targets in cells. The aim of the present study was to investigate the chemical composition of the essential oil of fennel growing in Tajikistan. Gas chromatographic-mass spectrometric analysis revealed that the main components of F. vulgare oil were trans-anethole (36.8%); alpha-ethyl-p-methoxy-benzyl alcohol (9.1%); p-anisaldehyde (7.7%); carvone (4.9%); 1-phenyl-penta-2,4-diyne (4.8%) and fenchyl butanoate (4.2%). The oil exhibited moderate antioxidant activities. The potential cytotoxic activity was studied against HeLa (human cervical cancer), Caco-2 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma), CCRF-CEM (human T lymphoblast leukaemia) and CEM/ADR5000 (adriamycin resistant leukaemia) cancer cell lines; IC50 values were between 30-210 mg L-1 and thus exhibited low cytotoxicity as compared to cytotoxic reference compounds. PMID- 28846629 TI - A Time-Space Domain Information Fusion Method for Specific Emitter Identification Based on Dempster-Shafer Evidence Theory. AB - Specific emitter identification plays an important role in contemporary military affairs. However, most of the existing specific emitter identification methods haven't taken into account the processing of uncertain information. Therefore, this paper proposes a time-space domain information fusion method based on Dempster-Shafer evidence theory, which has the ability to deal with uncertain information in the process of specific emitter identification. In this paper, radars will generate a group of evidence respectively based on the information they obtained, and our main task is to fuse the multiple groups of evidence to get a reasonable result. Within the framework of recursive centralized fusion model, the proposed method incorporates a correlation coefficient, which measures the relevance between evidence and a quantum mechanical approach, which is based on the parameters of radar itself. The simulation results of an illustrative example demonstrate that the proposed method can effectively deal with uncertain information and get a reasonable recognition result. PMID- 28846631 TI - A T-Type Capacitive Sensor Capable of Measuring5-DOF Error Motions of Precision Spindles. AB - The precision spindle is a core component of high-precision machine tools, and the accurate measurement of its error motions is important for improving its rotation accuracy as well as the work performance of the machine. This paper presents a T-type capacitive sensor (T-type CS) with an integrated structure. The proposed sensor can measure the 5-degree-of-freedom (5-DOF) error motions of a spindle in-situ and simultaneously by integrating electrode groups in the cylindrical bore of the stator and the outer end face of its flange, respectively. Simulation analysis and experimental results show that the sensing electrode groups with differential measurement configuration have near-linear output for the different types of rotor displacements. What's more, the additional capacitance generated by fringe effects has been reduced about 90% with the sensing electrode groups fabricated based on flexible printed circuit board (FPCB) and related processing technologies. The improved signal processing circuit has also been increased one times in the measuring performance and makes the measured differential output capacitance up to 93% of the theoretical values. PMID- 28846630 TI - Sequence Analysis, Kinetic Constants, and Anion Inhibition Profile of the Nacrein Like Protein (CgiNAP2X1) from the Pacific Oyster Magallana gigas (Ex-Crassostrea gigas). AB - The carbonic anhydrase (CA, EC 4.2.1.1) superfamily of metalloenzymes catalyzes the hydration of carbon dioxide to bicarbonate and protons. The catalytically active form of these enzymes incorporates a metal hydroxide derivative, the formation of which is the rate-determining step of catalytic reaction, being affected by the transfer of a proton from a metal-coordinated water molecule to the environment. Here, we report the cloning, expression, and purification of a particular CA, i.e., nacrein-like protein encoded in the genome of the Pacific oyster Magallana gigas (previously known as Crassostrea gigas). Furthermore, the amino acid sequence, kinetic constants, and anion inhibition profile of the recombinant enzyme were investigated for the first time. The new protein, CgiNAP2X1, is highly effective as catalyst for the CO2 hydration reaction, based on the measured kinetic parameters, i.e., kcat = 1.0 * 106 s-1 and kcat/KM = 1.2 * 108 M-1.s-1. CgiNAP2X1 has a putative signal peptide, which probably allows an extracellular localization of the protein. The inhibition data demonstrated that the best anion inhibitors of CgiNAP2X1 were diethyldithiocarbamate, sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid, which showed a micromolar affinity for this enzyme, with KIs in the range of 76-87 MUM. These studies may add new information on the physiological role of the molluskan CAs in the biocalcification processes. PMID- 28846632 TI - Monitoring and Measuring Autophagy. AB - Autophagy is a cytoplasmic degradation system, which is important for starvation adaptation and cellular quality control. Recent advances in understanding autophagy highlight its importance under physiological and pathological conditions. However, methods for monitoring autophagic activity are complicated and the results are sometimes misinterpreted. Here, we review the methods used to identify autophagic structures, and to measure autophagic flux in cultured cells and animals. We will also describe the existing autophagy reporter mice that are useful for autophagy studies and drug testing. Lastly, we will consider the attempts to monitor autophagy in samples derived from humans. PMID- 28846633 TI - Strawberries Improve Pain and Inflammation in Obese Adults with Radiographic Evidence of Knee Osteoarthritis. AB - Osteoarthritis (OA), the most common form of arthritis, is a significant public health burden in U.S. adults. Among its many risk factors, obesity is a key player, causing inflammation, pain, impaired joint function, and reduced quality of life. Dietary polyphenols and other bioactive compounds in berries, curcumin, and tea have shown effects in ameliorating pain and inflammation in OA, but few clinical studies have been reported. The purpose of the present study was to examine the effects of dietary strawberries on pain, markers of inflammation, and quality of life indicators in obese adults with OA of the knee. In a randomized, double-blind cross-over trial, adults with radiographic evidence of knee OA (n = 17; body mass index (BMI): (mean +/- SD) 39.1 +/- 1.5; age (years): 57 +/- 7) were randomized to a reconstituted freeze-dried strawberry beverage (50 g/day) or control beverage daily, each for 12 weeks, separated by a 2-week washout phase (total duration, 26 weeks). Blood draws and assessments of pain and quality of life indicators were conducted using the Visual Analog Scale for Pain (VAS Pain), Measures of Intermittent and Constant Osteoarthritis Pain (ICOAP), and Health Assessment Questionnaire-Disability Index (HAQ-DI) questionnaires, which were completed at baseline and at weeks 12, 14, and 26 of the study. Among the serum biomarkers of inflammation and cartilage degradation, interleukin (IL)-6, IL 1beta, and matrix metalloproteinase (MMP)-3 were significantly decreased after strawberry vs. control treatment (all p < 0.05). Strawberry supplementation also significantly reduced constant, intermittent, and total pain as evaluated by the ICOAP questionnaire as well as the HAQ-DI scores (all p < 0.05). No effects of treatment were noted on serum C-reactive protein (CRP), nitrite, glucose, and lipid profiles. Dietary strawberries may have significant analgesic and anti inflammatory effects in obese adults with established knee OA. PMID- 28846634 TI - Determination of Selected Chemical Levels in Room Air and on Surfaces after the Use of Cartridge- and Tank-Based E-Vapor Products or Conventional Cigarettes. AB - There is an ongoing debate regarding the potential of secondhand exposure of non users to various chemicals from use of e-vapor products (EVPs). Room air levels of 34 chemicals (nicotine, propylene glycol (PG), glycerol, 15 carbonyl chemicals, 12 volatile organic chemicals (VOCs), and four selected trace elements) were measured where EVPs and cigarettes were used by n = 37 healthy adult tobacco users in an exposure chamber. The products used were MarkTen(r) 2.5% Classic (Group I), a Prototype GreenSmoke(r) 2.4% (Group II), Ego-T(r) Tank with subjects' own e-liquids (Group III) and subjects' own conventional cigarettes (Group IV). Products were used under controlled conditions and 4-h ad libitum use. Background (without subjects) and baseline levels (with subjects) were measured. Cumulative 4-h. levels of nicotine, PG and glycerol measured were several-fold below the time-weighted average limits used in workplace exposure evaluation. Most the other chemicals (>75%) were at or below the limit of quantification during EVP use. Significant levels of chemicals (17 out of 34) were observed in Group IV. Overall, our results indicate that under the study conditions with the products tested, cumulative room air levels of the selected chemicals measured over 4-h were relatively small and were several-fold below the current occupational regulatory and consensus limits. PMID- 28846637 TI - The Preparation of Ag Nanoparticle and Ink Used for Inkjet Printing of Paper Based Conductive Patterns. AB - Ag nanoparticles were successfully prepared using a liquid reduction method with a suitable mixture reductant of polyethylene glycol (PEG) and ethylene glycol (EG). OP-10 as a dispersing agent, was used to prepare the conductive Ag ink. Ag nanoparticles with an average particle size of 40 nm were prepared while the ratio of PEG to EG was 1:2. Meanwhile, the Ag particles had a narrow size distribution and great dispersion performance. The effects of paper substrates, sintering temperature, and sintering time on the conductivity of the printed Ag ink pattern were also studied. It was found that Lucky porous high glossy photo paper was a good candidate as the printing substrate. The resistivity of the printed pattern could reach 5.1 * 10-3 Omega.cm after heated at 100 degrees C for 2 h. Hence, the printed pattern showed good conductivity which led to the LED light being on. Furthermore, the Ag nanoparticle ink could be printed to form any pattern as required that still showed good electrical conductivity after being sintered under low-temperature. This could provide new possibilities for the preparation of flexible electrodes. PMID- 28846636 TI - Occurrence, Distribution, and Risk Assessment of Perfluoroalkyl Acids (PFAAs) in Muscle and Liver of Cattle in Xinjiang, China. AB - Despite risks associated with perfluoroalkyl acids (PFAAs) in many regions, little is known about their prevalence in Xinjiang. We determined the presence of 13 PFAAs in 293 beef muscle and liver samples collected in 22 cities covering northern, southern, and eastern Xinjiang using liquid chromatography, coupled with tandem mass spectrometry. Overall, the average values for PFAAs were relatively low compared with previous studies. Liver presented higher mean levels of total PFAAs at 1.632 ng/g, which was over 60-fold higher than in muscle (0.026 ng/g). Among the PFAAs analyzed, medium-chain compounds were dominant, accounting for more than 70% of the total. Perfluorooctane sulfonate (PFOS) was highly prevalent in the liver with the highest mean concentration (0.617 ng/g) and detection frequency (80%). When comparing the three regions of Xinjiang, we found differences in PFAA profiles, with the northern region showing the highest levels. Furthermore, the average daily intake and hazard ratios of PFOS and perfluorooctanoic acid varied by region, urban/rural environment, gender, ethnicity, and age. The highest risk value of 13 PFAAs was estimated to be 0.837 * 10-3, which is far below 1, indicating that there is no health risk posed by eating beef muscle and liver in Xinjiang. PMID- 28846635 TI - Regulation of Apoptosis during Flavivirus Infection. AB - Apoptosis is a type of programmed cell death that regulates cellular homeostasis by removing damaged or unnecessary cells. Its importance in host defenses is highlighted by the observation that many viruses evade, obstruct, or subvert apoptosis, thereby blunting the host immune response. Infection with Flaviviruses such as Japanese encephalitis virus (JEV), Dengue virus (DENV) and West Nile virus (WNV) has been shown to activate several signaling pathways such as endoplasmic reticulum (ER)-stress and AKT/PI3K pathway, resulting in activation or suppression of apoptosis in virus-infected cells. On the other hands, expression of some viral proteins induces or protects apoptosis. There is a discrepancy between induction and suppression of apoptosis during flavivirus infection because the experimental situation may be different, and strong links between apoptosis and other types of cell death such as necrosis may make it more difficult. In this paper, we review the effects of apoptosis on viral propagation and pathogenesis during infection with flaviviruses. PMID- 28846638 TI - REP1 Modulates Autophagy and Macropinocytosis to Enhance Cancer Cell Survival. AB - Rab escort protein 1 (REP1), a component of the Rab geranyl-geranyltransferase 2 complex, plays a role in Rab protein recruitment in proper vesicles during vesicle trafficking. In addition to having well-known tissue degenerative phenotypes in the REP1 mutant, REP1 is tightly associated with cancer development and contributes to cell growth and survival. However, the functional mechanism of REP1 in cancer progression is largely uninvestigated. Here, we show that REP1 plays a crucial role in regulating mammalian target of rapamycin (mTOR) signaling and its downstream pathways, as well as autophagy and macropinocytosis, which are essential for cancer cell survival during metabolic stresses including starvation. REP1 small interfering RNA (siRNA) treatment downregulates mTORC1 activity in growing media, but blocks autophagosome formation under nutrient depleted conditions. In contrast to the mild decrease of lysosomal enzyme activity seen in REP1 depletion, in REP1 knockdown the subcellular localization of lysosomes is altered, and localization of REP1 itself is modulated by intracellular nutrient levels and mTOR activity. Furthermore, REP1 depletion increases macro pinocytosis which may be a feedback mechanism to compensate autophagy inhibition. Concomitant treatment with macropinocytosis inhibitor and REP1siRNAresults in more significant cell death than autophagy blockade with REP1 knockdown. Therefore, REP1-mediated autophagy and lysosomal degradation processes act as novel regulatory mechanisms to support cancer cell survival, which can be further investigated as a potential cancer-targeting pathway. PMID- 28846639 TI - Interactions Controlling the Slow Dynamic Conformational Motions of Ubiquitin. AB - Rational mutation of proteins based on their structural and dynamic characteristics is a useful strategy for amplifying specific fluctuations in proteins. Here, we show the effects of mutation on the conformational fluctuations and thermodynamic stability of ubiquitin. In particular, we focus on the salt bridge between K11 and E34 and the hydrogen bond between I36 and Q41, which are predicted to control the fluctuation between the basic folded state, N1, and the alternatively folded state, N2, of the protein, using high-pressure NMR spectroscopy. The E34A mutation, which disrupts the salt bridge, did not alter picosecond-to-nanosecond, microsecond-to-millisecond dynamic motions, and stability of the protein, while the Q41N mutation, which destabilizes the hydrogen bond, specifically amplified the N1-N2 conformational fluctuation and decreased stability. Based on the observed thermodynamic stabilities of the various conformational states, we showed that in the Q41N mutant, the N1 state is more significantly destabilized than the N2 state, resulting in an increase in the relative population of N2. Identifying the interactions controlling specific motions of a protein will facilitate molecular design to achieve functional dynamics beyond native state dynamics. PMID- 28846640 TI - Coffee Consumption and Risk of Biliary Tract Cancers and Liver Cancer: A Dose Response Meta-Analysis of Prospective Cohort Studies. AB - BACKGROUND: A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. METHODS: Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. RESULTS: We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose-response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). CONCLUSIONS: The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC. PMID- 28846641 TI - Salt Use Behaviours of Ghanaians and South Africans: A Comparative Study of Knowledge, Attitudes and Practices. AB - Salt consumption is high in Africa and the continent also shares the greatest burden of hypertension. This study examines salt-related knowledge, attitude and self-reported behaviours (KAB) amongst adults from two African countries-Ghana and South Africa-which have distributed different public health messages related to salt. KAB was assessed in the multinational longitudinal World Health Organisation (WHO) study on global AGEing and adult health (WHO-SAGE) Wave 2 (2014-2015). Respondents were randomly selected across both countries-Ghana (n = 6746; mean age 58 years old; SD 17; 41% men; 31% hypertensive) and South Africa (n = 3776, mean age 54 years old; SD 17; 32% men; 45% hypertensive). South Africans were more likely than Ghanaians to add salt to food at the table (OR 4.80, CI 4.071-5.611, p < 0.001) but less likely to add salt to food during cooking (OR 0.16, CI 0.130-0.197, p < 0.001). South Africans were also less likely to take action to control their salt intake (OR 0.436, CI 0.379-0.488, p < 0.001). Considering the various salt reduction initiatives of South Africa that have been largely absent in Ghana, this study supports additional efforts to raise consumer awareness on discretionary salt use and behaviour change in both countries. PMID- 28846642 TI - Increases in Alcohol Intakes Are Concurrent with Higher Energy Intakes: Trends in Alcohol Consumption in Australian National Surveys from 1983, 1995 and 2012. AB - This research aimed to provide the first assessment of the contribution of alcohol to Australian adults' diets over time and determine if people reporting alcohol had higher total dietary energy intakes. Secondary analyses of cross sectional national nutrition surveys from 1983, 1995, and 2011/12 for adults 18 years (n = 26,675) and over were conducted. Alcoholic beverage intake and diet were assessed using 24-h recalls. The proportion of participants reporting alcohol consumption declined over time and in 1983, 1995, and 2011/12 was 52.0%, 44.2%, and 39.8%, respectively, for men (p < 0.001) and 31.6%, 25.7%, and 25.7%, respectively, for women (p < 0.001). A decline in alcohol intake was seen between 1983 and 2012 for all subpopulations, except for women aged over 45 years, for whom alcohol intake increased. Energy intake was higher for participants reporting alcohol intake and the mean difference (SD) in energy intake for those reporting alcohol versus non-consumers was +1514 kJ (462) for men and +1227 kJ (424) for women. Consistent with apparent consumption data, reported alcohol intake for the total population decreased over time. As those reporting alcohol had much higher energy intakes than non-consumers, promoting alcohol intakes consistent with national recommendations may have important implications for the prevention of obesity, particularly for middle-aged women. PMID- 28846643 TI - A Portable Impedance Immunosensing System for Rapid Detection of Salmonella Typhimurium. AB - SalmonellaTyphimurium is one of the most dangerous foodborne pathogens and poses a significant threat to human health. The objective of this study was to develop a portable impedance immunosensing system for rapid and sensitive detection of S. Typhimurium in poultry. The developed portable impedance immunosensing system consisted of a gold interdigitated array microelectrode (IDAM), a signal acquisitive interface and a laptop computer with LabVIEW software. The IDAM was first functionalized with 16-Mercaptohexadecanoic acid, and streptavidin was immobilized onto the electrode surface through covalent bonding. Then, biotin labelled S. Typhimurium-antibody was immobilized onto the IDAM surface. Samples were dropped on the surface of the IDAM and the S. Typhimurium cells in the samples were captured by the antibody on the IDAM. This resulted in impedance changes that were measured and displayed with the LabVIEW software. An equivalent circuit of the immunosensor demonstrated that the largest change in impedance was due to the electron-transfer resistance. The equivalent circuit showed an increase of 35% for the electron-transfer resistance value compared to the negative control. The calibration result indicated that the portable impedance immunosensing system could be used to measure the standard impedance elements, and it had a maximum error of measurement of approximately 13%. For pure culture detection, the system had a linear relationship between the impedance change and the logarithmic value of S. Typhimurium cells ranging from 76 to 7.6 * 106 CFU (colony-forming unit) (50 MUL)-1. The immunosensor also had a correlation coefficient of 0.98, and a high specificity for detection of S. Typhimurium cells with a limit of detection (LOD) of 102 CFU (50 MUL)-1. The detection time from the moment a sample was introduced to the display of the results was 1 h. To conclude, the portable impedance immunosensing system for detection of S. Typhimurium achieved an LOD that is comparable with commercial electrochemical impedance instruments. The developed impedance immunosensor has advantages in portability, low cost, rapid detection and label-free features showing a great potential for in-field detection of foodborne pathogens. PMID- 28846644 TI - The Mediating Role of Psychological Capital on the Association between Occupational Stress and Job Satisfaction among Township Cadres in a Specific Province of China: A Cross-Sectional Study. AB - Background: Township cadres, considered as basic executors of state policy, play an important role in Chinese society. Their job satisfaction is a vital issue for township management, but there are few studies on this topic in China. The goal of this study is to analyze the relationship between occupational stress and job satisfaction, and to further examine whether psychological capital (PsyCap) can serve as a mediator between stress and job satisfaction in Chinese township cadres. Methods: A cross-sectional survey was carried out during the period of from October 2015 to January 2016 in Liaoning Province of China. The questionnaires, which consisted of an effort-reward imbalance scale, Minnesota Satisfaction Questionnaire (MSQ) for job satisfaction, and the psychological capital questionnaire (PCQ-24), as well as questions about demographic characteristics, were distributed to 1800 township cadres and complete responses were received from 1525 participants. Structural equation modeling was used to examine the role that psychological capital played in mediating between occupational stress and job satisfaction. Results: In the present study, effort reward ratio (ERR= 11 * effort/6 * reward) was negatively associated with job satisfaction (r = -0.372, p < 0.001), whereas psychological capital was positively associated with job satisfaction in township cadres (r = 0.587, p < 0.001) from a specific province in China. Psychological capital is a mediator between the association of job stress and job satisfaction. Conclusions: Psychological capital partially mediated the relationship between job stress and job satisfaction among Chinese township cadres. Interventions to improve Chinese township cadres' job satisfaction should be developed in the future, especially the enhancement of PsyCap. Interventions need to be verified in further cohort studies. At present, we are only proposing a theoretical model. Intervention effects need to be validated in further cohort studies. PMID- 28846645 TI - Vitamin D Sufficiency of Canadian Children Did Not Improve Following the 2010 Revision of the Dietary Guidelines That Recommend Higher Intake of Vitamin D: An Analysis of the Canadian Health Measures Survey. AB - In 2010, the dietary guidelines for vitamin D for Canadians and Americans aged 1 70 years were revised upward. It is unknown whether the vitamin D status of Canadian children improved after 2010. We compared the prevalence of vitamin D sufficiency (25-hydroxy vitamin D (25(OH)D) concentration of >=50 nmol/L), 25(OH)D concentration and the frequency of consuming vitamin D-rich foods among children aged 6-18 years-old using data from the nationally representative 2007/2009 and 2012/2013 Canadian Health Measures Surveys. Associations of sociodemographic, anthropometric, seasonal, and regional variables with achieving vitamin D sufficiency, 25(OH)D concentration, and consumption of vitamin D-rich foods were assessed using multiple logistic and linear regression models. 79% and 68% of children in 2007/2009 and 2012/2013 respectively, were vitamin D sufficient. The main dietary source of vitamin D was milk. Between 2007/2009 and 2012/2013, the frequency of milk and fish consumption declined, but egg and red meat consumption was unchanged. Age, income, weight status, season and ethnicity were associated with 25(OH)D concentration and vitamin D sufficiency. Vitamin D status declined after the upward revision of dietary guidelines for vitamin D, consequently, dietary intake was inadequate to meet sufficiency. Public health initiatives to promote vitamin D-rich foods and supplementation for Canadian children are needed. PMID- 28846646 TI - Impact of Age and Race on Outcomes of a Program to Prevent Excess Weight Gain and Disordered Eating in Adolescent Girls. AB - Interpersonal psychotherapy (IPT) prevents weight gain and reduces loss-of control (LOC)-eating in adults. However, IPT was not superior to health-education (HE) for preventing excess weight gain and reducing LOC-eating over 1-year in adolescent girls at risk for excess weight gain and eating disorders. Limited data suggest that older and non-White youth may be especially responsive to IPT. In secondary analyses, we examined if age or race moderated weight and LOC-eating outcomes. The 113 participants (12-17 years; 56.6% White) from the original trial were re-contacted 3 years later for assessment. At baseline and follow-up visits through 3 years, we assessed BMI, adiposity by dual energy X-ray absorptiometry, and LOC-eating presence. In linear mixed models, baseline age moderated 3-year BMI outcome; older girls in IPT had the lowest 3-year BMI gain compared to younger girls in IPT and all girls in HE, p = 0.04. A similar pattern was observed for adiposity. Race moderated 3-year LOC-eating; non-White girls in IPT were most likely to abstain from LOC-eating at 3 years compared to all other girls, p = 0.04. This hypothesis-generating analysis suggests future studies should determine if IPT is especially efficacious at reducing LOC-eating in older, non-White adolescents. PMID- 28846647 TI - Sinapic Acid Affects Phenolic and Trichothecene Profiles of F. culmorum and F. graminearum Sensu Stricto. AB - Plant-derived compounds for reducing the mycotoxin load in food and feed have become a rapidly developing research field of importance for plant breeding efforts and in the search for natural fungicides. In this study, toxigenic strains of Fusarium culmorum and F. graminearum sensu stricto were exposed to sinapic acid on solid YES media at levels close to those reported in wheat bran. Fusaria produced phenolic acids, whose accumulation was decreased by exogenous sinapic acid. Strains exposed to the lowest doses of sinapic acid showed more efficient reduction of phenolic acid production than fungi kept at higher concentrations of this compound. Fungi reduced exogenous sinapic acid, leading to the formation of syringic aldehyde. Treatment with sinapic acid led to a dramatic accumulation of its parent compound ferulic acid, presumably due to inhibition of the further conversion of this phenolic compound. Exogenous sinapic acid decreased the production of trichothecenes by fungi. Higher doses of sinapic acid resulted in more efficient reduction of mycotoxin accumulation in the media. Gene expression studies of Tri genes responsible for trichothecene biosynthesis (Tri4, Tri5 and Tri10) proved that the inhibition of mycotoxin production by sinapic acid occurred at the transcriptional level. Fusaria respond to sinapic acid by stimulation of ergosterol biosynthesis. PMID- 28846648 TI - Sensitive and Selective Detection of Oxo-Form Organophosphorus Pesticides Based on CdSe/ZnS Quantum Dots. AB - A rapid, sensitive and enzyme-based optical biosensor was applied for the determination of seven organophosphorus pesticides (OPPs), including the oxo forms (malaoxon, paraoxon, dibrom, and dichlorvos), the thio forms (malathion and parathion) and the mixed form (demeton) in Panax ginseng. The principal of the proposed method is that the fluorescence quenching effect of quantum dots (QDs) can be observed by enzyme-generated H2O2. The active centers of acetylcholinesterase (AChE) could be inhibited in the presence of pesticides, which caused decrease of the generated H2O2. Then, the inhibition efficiency of pesticide to AChE activity could be evaluated by measuring the fluorescence changes. Different from biosensors based on immobilized enzyme or self-assembling technique, the proposed biosensor demonstrated a good selectivity for the detection of oxo forms of OPPs. In the present study, the important experimental conditions of the proposed biosensor were investigated. Under the optimized conditions (incubation temperature, 35 degrees C; incubation time, 20 min; pH value, 8.0; detection time, 30 min; AChE concentration, 40.9 U/L; and choline oxidase (ChOx) concentration, 637.5 U/L), the limit of detection for the investigated oxo-form OPPs was no more than 0.05 MUM, which suggested that the proposed method could be used for sensitive and selective determination of trace amounts of OPPs residues in real samples with complex matrices. PMID- 28846649 TI - Enhancement of Glucose Uptake by Meso-Dihydroguaiaretic Acid through GLUT4 Up Regulation in 3T3-L1 Adipocytes. AB - Type 2 diabetes is characterized by insulin resistance, which leads to increased blood glucose levels. Adipocytes are involved in the development of insulin resistance, resulting from the dysfunction of the insulin signaling pathway. In this study, we investigated whether meso-dihydroguaiaretic acid (MDGA) may modulate glucose uptake in adipocytes, and examined its mechanism of action. MDGA enhanced adipogenesis through up-regulation of peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding protein alpha in 3T3-L1 adipocytes partially differentiated with sub-optimal concentrations of insulin. MDGA also increased glucose uptake by stimulating expression and translocation of glucose transporter 4 (GLUT4) in adipocytes. These results suggest that MDGA may increase GLUT4 expression and its translocation by promoting insulin sensitivity, leading to enhanced glucose uptake. PMID- 28846650 TI - Rapid Removal of Zinc(II) from Aqueous Solutions Using a Mesoporous Activated Carbon Prepared from Agricultural Waste. AB - A low-cost activated carbon (XSBLAC) prepared from XanthocerasSorbifoliaBungehull via chemical activation was investigated to determine its adsorption and desorption properties for zinc(II) ions from aqueous solutions. XSBLAC was characterized based on its N2-adsorption/desorption isotherm, EDX, XRD, SEM and FTIR results. An adsorption study was conducted in a series of experiments to optimize the process variables for zinc(II) removal using XSBLAC. Modeling the adsorption kinetics indicated good agreement between the experimental data and the pseudo-second-order kinetic model. The Langmuir equilibrium isotherm fit the experimental data reasonably well. The calculated enthalpy (DeltaH0), entropy (DeltaS0) and Gibbs free energy (DeltaG0) values revealed the endothermic and spontaneous nature of the adsorption process. HNO3 displayed the best desorption performance. The adsorption mechanism was investigated in detail through FTIR and SEM/EDX spectroscopic analyses. The results suggested that XSBLAC is a potential biosorbent for removing zinc(II) from aqueous solutions. PMID- 28846651 TI - Analytical Model of Nonlinear Stress-Strain Relation for a Strand Made of Two Materials. AB - Unlike conventional steel strands, the smart strand supports strain-measuring function and adopts different materials for its core wire and helical wires. This study intends to analytically derive the nonlinear stress-strain model of this strand made of two materials. The effect of the bending moment and torsional moment of the helical wires on the overall load within the range of geometric shapes shown by actually used strands is verified to be negligible and is thus ignored in order to simplify the analytical model. Moreover, the slight difference between the actual and analytic behaviors, which only appears in the slope varying part in the case of bilinear behavior, such as that of steel, is also ignored. The proposed constitutive model of the smart strand obtained by introducing the experimental stress-strain relation between the carbon fiber reinforced polymer core wire and the helical steel wires is in good agreement with the experimental data. The previous analytical models are applicable only to strands made of a unique linear material, whereas the model proposed in this study is also applicable to strands in which the core wire and the helical wires are made of two different materials, exhibiting nonlinear behavior. PMID- 28846652 TI - One-Pot Green Regioselesctive Synthesis of gamma-Lactones from Epoxides and Ketene Silyl Acetals Using 1,3-Dimethylimidazolium Fluoride as a Recoverable Metal-Free Catalyst. AB - In a straightforward and fast protocol, a mixture of 1,3-dimethylimidazolium fluoride ([DMIM]F) and 1-butylimidazolium tetrafluoroborate ([Hbim]BF4) efficiently catalyzed the reaction of epoxides with ketene silyl acetals (KSA) to give various gamma-lactones under metal-free conditions. Diverse kinds of the desired gamma-lactones were directly prepared with high regioselectivities and yields in a simple one-pot procedure using [DMIM]F as Si-O bond activator and [Hbim]BF4 as solvent and acidic ionic liquid catalyst. The ionic liquid mixture was recovered and reused three times and no loss in its activity was observed. PMID- 28846653 TI - New Marine Antifouling Compounds from the Red Alga Laurencia sp. AB - Six new compounds, omaezol, intricatriol, hachijojimallenes A and B, debromoaplysinal, and 11,12-dihydro-3-hydroxyretinol have been isolated from four collections of Laurencia sp. These structures were determined by MS and NMR analyses. Their antifouling activities were evaluated together with eight previously known compounds isolated from the same samples. In particular, omaezol and hachijojimallene A showed potent activities (EC50 = 0.15-0.23 ug/mL) against larvae of the barnacle Amphibalanus amphitrite. PMID- 28846654 TI - Can Magnesium Enhance Exercise Performance? AB - Magnesium (Mg) is an essential mineral that plays a critical role in the human body. It takes part in the process of energy metabolism and assists the maintenance of normal muscle function. A number of studies evaluated the association between Mg status/supplementation and exercise performance and found that the need for Mg increased as individuals' physical activity level went up. Animal studies indicated that Mg might improve exercise performance via enhancing glucose availability in the brain, muscle and blood; and reducing/delaying lactate accumulation in the muscle. The majority of human studies focused on physiological effects in blood pressure, heart rate and maximal oxygen uptake (VO2 max), rather than direct functional performances. Some cross-sectional surveys demonstrated a positive association between Mg status and muscle performance, including grip strength, lower-leg power, knee extension torque, ankle extension strength, maximal isometric trunk flexion, rotation, and jumping performance. Additionally, findings from intervention studies showed that Mg supplementation might lead to improvements in functional indices such as quadriceps torque. Moreover, Mg supplementation could improve gait speed and chair stand time in elderly women. This comprehensive review summarized the literature from both animal and human studies and aimed to evaluate scientific evidence on Mg status/supplementation in relation to exercise performance. PMID- 28846655 TI - Numerical Simulation of Droplets Behavior of Cu-Pb Immiscible Alloys Solidifying under Magnetic Field. AB - A model has been presented for the coarsening of the dispersed phase of liquid liquid two-phase mixtures in Cu-Pb alloys under the effect of a high magnetic field (HMF). The numerical results show that the evolution of size distribution is the result of several factors and the diffusional growth, the collision coagulation of the Cu-rich droplets (gravity sedimentation and Marangoni migration), and melt flow also have obvious effects on the movement of droplets and coarsening process. The effect of the HMF in the coarsening process of Cu-Pb alloy is studied in this work both by simulation and experiment. The analysis shows that the HMF leads to a decrease in the melt flow velocity, and can also lead to a decrease in the moving velocity of Cu-rich droplets. The HMF significantly reduces the coarsening rate of droplets as compared by the distribution evolutions. Finally, it is shown that droplet collision and coagulation can be dramatically retarded by the HMF. The results of the simulation are compared with the experiments performed with immiscible Cu-Pb alloys, and the discrepancy between theory and experiment is discussed. PMID- 28846656 TI - The Sea as a Rich Source of Structurally Unique Glycosaminoglycans and Mimetics. AB - Glycosaminoglycans (GAGs) are sulfated glycans capable of regulating various biological and medical functions. Heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate and hyaluronan are the principal classes of GAGs found in animals. Although GAGs are all composed of disaccharide repeating building blocks, the sulfation patterns and the composing alternating monosaccharides vary among classes. Interestingly, GAGs from marine organisms can present structures clearly distinct from terrestrial animals even considering the same class of GAG. The holothurian fucosylated chondroitin sulfate, the dermatan sulfates with distinct sulfation patterns extracted from ascidian species, the sulfated glucuronic acid-containing heparan sulfate isolated from the gastropode Nodipecten nodosum, and the hybrid heparin/heparan sulfate molecule obtained from the shrimp Litopenaeus vannamei are some typical examples. Besides being a rich source of structurally unique GAGs, the sea is also a wealthy environment of GAG resembling sulfated glycans. Examples of these mimetics are the sulfated fucans and sulfated galactans found in brown, red and green algae, sea urchins and sea cucumbers. For adequate visualization, representations of all discussed molecules are given in both Haworth projections and 3D models. PMID- 28846657 TI - Surveillance Bias in Child Maltreatment: A Tempest in a Teapot. AB - Background: Children are believed to be more likely to be reported for maltreatment while they are working with mental health or social service professionals. This "surveillance bias" has been claimed to inflate reporting by fifty percent or more, and has been used to explain why interventions such as home visiting fail to reduce official maltreatment reporting rates. Methods: We use national child abuse reporting data (n = 825,763), supplemented by more detailed regional data from a multi-agency administrative data study (n = 7185). We determine the percentage of all re-reports made uniquely by mental health and social service providers within and across generations, the report sources which could be subject to surveillance bias. Results: At three years after the initial Child protective services (CPS) report, the total percentage of national reports uniquely made by mental health or social service providers is less than 10%, making it impossible that surveillance bias could massively inflate CPS reporting in this sample. Analysis of national data find evidence of a very small (+4.54%) initial surveillance bias "bump" among served cases which decays to +1.84% within three years. Our analysis of regional data showed similar or weaker effects. Conclusions: Surveillance bias effects appear to exist, but are very small. PMID- 28846658 TI - The Improvement of Skin Whitening of Phenylethyl Resorcinol by Nanostructured Lipid Carriers. AB - Phenylethyl resorcinol (4-(1-phenylethyl)1,3-benzenediol) (PR) is a new whitening agent that has been found to have the ability to inhibit tyrosinase activity. However, the application of PR is limited by photo instability and poor solubility. PR-loaded nanostructured lipid carriers (PR-NLCs) were prepared by the hot-melted ultrasonic method. Glycerol monostearate and olive oil were selected as the solid lipid and liquid lipid for considering the solubility of PR in liquid lipid and partition coefficient of PR in solid lipid, respectively. The particle size and polydispersity index of PR-NLCs were 57.9 +/- 1.3 nm and 0.24 +/- 0.01, respectively. The encapsulation efficiency and loading capacity of PR NLCs were 93.1 +/- 4.2% and 8.5 +/- 0.4%, respectively. The stability test demonstrated that the incorporation of PR into NLCs conferred excellent physicochemical stability and photo stability for at least three months at 4 degrees C in the dark and 25 degrees C under daylight. In vitro release of PR NLCs revealed a sustained release pattern. Cellular tyrosinase assay showed that PR-NLCs could significantly inhibit tyrosinase activity in melanoma cells, suggesting that NLCs can be used as a biocompatible nanocarrier for the effective delivery of skin whitening agents. PMID- 28846660 TI - Human Meibum Age, Lipid-Lipid Interactions and Lipid Saturation in Meibum from Infants. AB - Tear stability decreases with increasing age and the same signs of instability are exacerbated with dry eye. Meibum lipid compositional changes with age provide insights into the biomolecules responsible for tear film instability. Meibum was collected from 69 normal donors ranging in age from 0.6 to 68 years of age. Infrared spectroscopy was used to measure meibum lipid phase transition parameters. Nuclear magnetic resonance spectroscopy was used to measure lipid saturation. Increasing human meibum lipid hydrocarbon chain unsaturation with age was related to a decrease in hydrocarbon chain order, cooperativity, and in the phase transition temperature. The change in these parameters was most dramatic between 1 and 20 years of age. Meibum was catalytically saturated to determine the effect of saturation on meibum lipid phase transition parameters. Hydrocarbon chain saturation was directly related to lipid order, phase transition temperature, cooperativity, changes in enthalpy and entropy, and could account for the changes in the lipid phase transition parameters observed with age. Unsaturation could contribute to decreased tear film stability with age. PMID- 28846659 TI - Current Status and Future Prospects of Marine Natural Products (MNPs) as Antimicrobials. AB - The marine environment is a rich source of chemically diverse, biologically active natural products, and serves as an invaluable resource in the ongoing search for novel antimicrobial compounds. Recent advances in extraction and isolation techniques, and in state-of-the-art technologies involved in organic synthesis and chemical structure elucidation, have accelerated the numbers of antimicrobial molecules originating from the ocean moving into clinical trials. The chemical diversity associated with these marine-derived molecules is immense, varying from simple linear peptides and fatty acids to complex alkaloids, terpenes and polyketides, etc. Such an array of structurally distinct molecules performs functionally diverse biological activities against many pathogenic bacteria and fungi, making marine-derived natural products valuable commodities, particularly in the current age of antimicrobial resistance. In this review, we have highlighted several marine-derived natural products (and their synthetic derivatives), which have gained recognition as effective antimicrobial agents over the past five years (2012-2017). These natural products have been categorized based on their chemical structures and the structure-activity mediated relationships of some of these bioactive molecules have been discussed. Finally, we have provided an insight into how genome mining efforts are likely to expedite the discovery of novel antimicrobial compounds. PMID- 28846661 TI - Multimodality Imaging in Tumor Angiogenesis: Present Status and Perspectives. AB - Angiogenesis is a complex biological process that plays a central role in progression of tumor growth and metastasis. It led to a search for antiangiogenic molecules, and to design antiangiogenic strategies for cancer treatment. Noninvasive molecular imaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), could be useful for lesion detection, to select patients likely to respond to antiangiogenic therapies, to confirm successful targeting, and dose optimization. Additionally, nuclear imaging techniques could also aid in the development of new angiogenesis-targeted drugs and their validation. Angiogenesis imaging can be categorized as targeted at three major cell types: (I) non-endothelial cell targets, (II) endothelial cell targets, and (III) extracellular matrix proteins and matrix proteases. Even if radiopharmaceuticals studying the metabolism and hypoxia can be also used for the study of angiogenesis, many of the agents used in nuclear imaging for this purpose are yet to be investigated. The purpose of this review is to describe the role of molecular imaging in tumor angiogenesis, highlighting the advances in this field. PMID- 28846662 TI - Vitamin D Deficiency: A Potential Modifiable Risk Factor for Cardiovascular Disease in Children with Severe Obesity. AB - Severe obesity is associated with abnormal lipids and increased risk for cardiovascular disease. Obesity is a risk factor for vitamin D deficiency. We examined relationship between 25-hydroxy vitamin D (25(OH)D) concentrations and lipids in children with severe obesity. Medical records of 376 children were reviewed. Linear regression models and logistic regression were used to examine the relationship between 25(OH)D and lipids after adjustment for age, gender, season of blood draw, body mass index (BMI) z-score, and BMI % of 95th percentile. Two-hundred sixty-three out of 376 children (70%) had 25(OH)D concentrations < 30 ng/mL. Concentrations of 25(OH)D were positively correlated with those of high-density lipoprotein cholesterol (HDL-C) (r2 = 0.08, r = 0.22, beta = 0.16, 95% CI = 0.05-0.27, p = 0.004). HDL-C was lower in children with 25(OH)D < 30 ng/mL (n = 263) compared to those with 25(OH)D >= 30 ng/mL (n = 113) (41.3 +/- 10.2 vs. 46.4 +/- 12 mg/dL, p < 0.0001). Children with 25(OH)D concentrations < 30 ng/mL had greater adjusted odds of low HDL-C (<40 mg/dL) compared with those with 25(OH)D >= 30 ng/mL (47.9% vs. 29.2%, OR 2.15 (1.33 3.51), p = 0.0019). Total cholesterol and non-HDL-C were not correlated with 25(OH)D concentrations. Vitamin D deficiency is highly prevalent in children with severe obesity. Prospective clinical trials are warranted to determine if vitamin D supplementation can improve HDL-C and potentially decrease risk for cardiovascular disease in children with obesity. PMID- 28846664 TI - Multienzyme Biosynthesis of Dihydroartemisinic Acid. AB - One-pot multienzyme biosynthesis is an attractive method for producing complex, chiral bioactive compounds. It is advantageous over step-by-step synthesis, as it simplifies the process, reduces costs and often leads to higher yield due to the synergistic effects of enzymatic reactions. In this study, dihydroartemisinic acid (DHAA) pathway enzymes were overexpressed in Saccharomyces cerevisiae, and whole-cell biotransformation of amorpha-4,11-diene (AD) to DHAA was demonstrated. The first oxidation step by cytochrome P450 (CYP71AV1) is the main rate-limiting step, and a series of N-terminal truncation and transcriptional tuning improved the enzymatic activity. With the co-expression of artemisinic aldehyde dehydrogenase (ALDH1), which recycles NADPH, a significant 8-fold enhancement of DHAA production was observed. Subsequently, abiotic conditions were optimized to further enhance the productivity of the whole-cell biocatalysts. Collectively, approximately 230 mg/L DHAA was produced by the multi-step whole-cell reaction, a ~50% conversion from AD. This study illustrates the feasibility of producing bioactive compounds by in vitro one-pot multienzyme reactions. PMID- 28846663 TI - Chemopreventive Potential of Ethanolic Extracts of Luobuma Leaves (Apocynum venetum L.) in Androgen Insensitive Prostate Cancer. AB - Luobuma (Apocynum venetum L. (AVL)) is a popular beverage in Asia and has been reportedly to be associated with the bioactivities such as cardiotonic, diuretic, antioxidative, and antihypertensive. However, its biofunction as chemoprevention activity is seldom addressed. Herein, we aimed to characterize the anti-androgen insensitive-prostate-cancer (anti-AIPC) bioactive compounds of Luobuma, and to investigate the associated molecular mechanisms. Activity-guided-fractionation (antioxidative activity and cell survivability) of Luobuma ethanolic extracts was performed to isolate and characterize the major bioactive compounds using Ultra Performance Liquid Chromatography (UPLC), Liquid Chromatography-Mass Spectrometry (LC-MS), and Nuclear Magnetic Resonance (NMR). Plant sterols (lupeol, stigamasterol and beta-sitosterol) and polyphenolics (isorhamnetin, kaempferol, and quercetin) were identified. Lupeol, a triterpene found in the fraction (F8) eluted by 10% ethyl acetate/90% hexane and accounted for 19.3% (w/w) of F8, inhibited the proliferation of PC3 cells. Both lupeol and F8 induced G2/M arrest, inhibition of beta-catenin signaling, regulation of apoptotic signal molecules (cytochrome c, Bcl-2, P53, and caspase 3 and 8), and suppression DNA repair enzyme expression (Uracil-DNA glycosylase (UNG)). To our knowledge, our study is the first report that lupeol inhibited the expression of UNG to elicit the cytotoxicity against androgen-insensitive-prostate-cancer cells. Collectively, Luobuma, which contains several antitumor bioactive compounds, holds the potential to be a dietary chemopreventive agent for prostate cancer. PMID- 28846665 TI - Assessment of Initial Vancomycin Dosing in Pediatric Oncology Patients. AB - This was a retrospective audit assessing vancomycin dosing of 60 mg/kg/day in the attainment of therapeutic concentrations between 10-20 mcg/mL among 56 pediatric oncology patients. Twelve patients (21%) achieved therapeutic concentrations of 10-20 mcg/mL, while 44 patients (79%) obtained trough levels below 10 mcg/mL despite the addition of nephrotoxic agents. PMID- 28846666 TI - Interleukin 6 (IL-6) and Tumor Necrosis Factor alpha (TNF-alpha) Single Nucleotide Polymorphisms (SNPs), Inflammation and Metabolism in Gestational Diabetes Mellitus in Inner Mongolia. AB - BACKGROUND Gestational diabetes mellitus (GDM) is common all over the world. GDM women are with inflammatory and metabolisms abnormalities. However, few studies have focused on the association of IL-65-72C/G and TNF-alpha -857C/T single nucleotide polymorphisms (SNPs), inflammatory biomarkers, and metabolic indexes in women with GDM, especially in the Inner Mongolia population. The aim of this study was to investigate the associations of IL-65-72C/G and TNF-alpha -857C/T SNPs, and inflammation and metabolic biomarkers in women with GDM pregnancies. MATERIAL AND METHODS Blood samples and placentas from 140 women with GDM and 140 women with healthy pregnancies were collected. Matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) and MassARRAY-IPLEX were performed to analyze IL-65-72C/G and TNF-alpha -857C/T SNPs. Enzyme linked immunosorbent assay (ELISA) was performed to analyze inflammatory biomarkers and adipokines. RESULTS Distribution frequency of TNF-alpha -857CT (OR=3.316, 95% CI=1.092-8.304, p=0.025) in women with GDM pregnancies were obviously higher than that in women with healthy pregnancies. Women with GDM were of older maternal age, had higher BMI, were more nulliparous, and had T2DM and GDM history, compared to women with healthy pregnancies (p<0.05). Inflammatory biomarkers in serum (hs-CRP, IL-6, IL-8, IL-6/IL-10 ratio) and placental (NF-kappaB, IL-6, IL 8, IL-6/IL-10 ratio, IL-1b, TNF-alpha) were significantly different (p<0.05) between women with GDM and women with healthy pregnancies. Differences were found for serum FBG, FINS, HOMA-IR, and HOMA-beta, and placental IRS-1, IRS-2, leptin, adiponectin, visfatin, RBP-4, chemerin, nesfatin-1, FATP-4, EL, LPL, FABP-1, FABP 3, FABP-4, and FABP-5. CONCLUSIONS TNF-alpha -857C/T SNP, hs-CRP, IL-6, IL-8, and IL-6/IL-10 were associated with GDM in women from Inner Mongolia, as was serious inflammation and disordered lipid and glucose metabolisms. PMID- 28846667 TI - Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel. AB - Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity. Biochemical in vitro studies indicate that KLB inhibits ribosomes by interfering with translation elongation. Structural analysis of the ribosome-KLB complex showed that the compound binds in the peptide exit tunnel overlapping with the binding sites of macrolides or streptogramin-B. KLB adopts a compact conformation and largely obstructs the tunnel. Engineered KLB fragments were observed to retain in vitro activity, and thus have the potential to serve as a starting point for the development of new bioactive compounds. PMID- 28846668 TI - Oxidative cleavage of polysaccharides by monocopper enzymes depends on H2O2. AB - Enzymes currently known as lytic polysaccharide monooxygenases (LPMOs) play an important role in the conversion of recalcitrant polysaccharides, but their mode of action has remained largely enigmatic. It is generally believed that catalysis by LPMOs requires molecular oxygen and a reductant that delivers two electrons per catalytic cycle. Using enzyme assays, mass spectrometry and experiments with labeled oxygen atoms, we show here that H2O2, rather than O2, is the preferred co substrate of LPMOs. By controlling H2O2 supply, stable reaction kinetics are achieved, the LPMOs work in the absence of O2, and the reductant is consumed in priming rather than in stoichiometric amounts. The use of H2O2 by a monocopper enzyme that is otherwise cofactor-free offers new perspectives regarding the mode of action of copper enzymes. Furthermore, these findings have implications for the enzymatic conversion of biomass in Nature and in industrial biorefining. PMID- 28846669 TI - Creatine supplementation to total parenteral nutrition improves creatine status and supports greater liver and kidney protein synthesis in neonatal piglets. AB - BackgroundCreatine is not included in commercial pediatric parenteral products; the entire creatine requirement must be met by de novo synthesis from arginine during parenteral nutrition (PN). Poor arginine status is common during PN in neonates, which may compromise creatine accretion. We hypothesized that creatine supplementation will improve creatine status and spare arginine in PN-fed piglets.MethodsPiglets (3-5-day (d) old) were provided PN with or without creatine for 14 d. Tissue concentrations of creatine metabolites and activities of creatine-synthesizing enzymes, as well as tissue protein synthesis rates and liver lipid parameters, were measured.ResultsCreatine provision lowered kidney and pancreas L-arginine:glycine amidinotransferase (AGAT, EC number 2.1.4.1) activities and plasma guanidinoacetic acid (GAA) concentration, suggesting the downregulation of de novo creatine synthesis. Creatine increased plasma creatine concentrations to sow-fed reference levels and increased the creatine concentrations in most tissues, but not in the brain. PN creatine resulted in greater protein synthesis in the liver and the kidney, but not in the pancreas, skeletal muscle, or gut. Creatine supplementation also reduced liver cholesterol concentrations, but not triglyceride or total fat.ConclusionThe addition of creatine to PN may optimize the accretion of creatine and reduce the metabolic burden of creatine synthesis in rapidly growing neonates. PMID- 28846670 TI - Single-Immunoglobulin Interleukin-1-Related Receptor regulates vulnerability to TLR4-mediated necrotizing enterocolitis in a mouse model. AB - BackgroundThe mechanisms underlying aberrant activation of intestinal Toll-like receptor 4 (TLR4) signaling in necrotizing enterocolitis (NEC) remain unclear. In this study, we examined the role of single-immunoglobulin interleukin-1 receptor related molecule (SIGIRR), an inhibitor of TLR signaling, in modulating experimental NEC vulnerability in mice.MethodsExperimental NEC was induced in neonatal wild-type and SIGIRR-/- mice using hypoxia, formula-feeding, and lipopolysaccharide administration. Intestinal TLR canonical signaling, inflammation, apoptosis, and severity of experimental NEC were examined at baseline and after NEC induction in mice.ResultsSIGIRR is developmentally regulated in the neonatal intestine with a restricted expression after birth and a gradual increase by day 8. At baseline, breast-fed SIGIRR-/- mouse pups exhibited low-grade inflammation and TLR pathway activation compared with SIGIRR+/+ pups. With experimental NEC, SIGIRR-/- mice had significantly more intestinal interleukin (IL)-1beta, KC (mouse homolog to IL-8), intercellular adhesion molecule-1 (ICAM-1), and interferon-beta (IFN-beta) expression in association with the amplified TLR pathway activation. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, cleaved caspase 3, and severity of intestinal injury with NEC were worse in SIGIRR-/- mice in comparison with SIGIRR+/+ mice.ConclusionSIGIRR is a negative regulator of TLR4 signaling in the developing intestine, and its insufficiency results in native intestinal TLR hyper-responsiveness conducive to the development of severe experimental NEC in mice. PMID- 28846671 TI - Effects of postnatal overfeeding and fish oil diet on energy expenditure in rats. AB - BackgroudEarly life nutrition may have a role in the regulation of metabolism in adulthood. The present study aimed to evaluate the effects of postnatal overfeeding and a postweaning fish oil diet on energy expenditure.MethodsOn postnatal day 3, rat litters were adjusted to a litter size of three (small litters, SLs) or ten (normal litters, NLs). After weaning, SLs were fed the standard diet or a fish oil diet enriched with polyunsaturated fatty acids (SL FOs) for 10 weeks. The metabolic parameters of rats were monitored using the TSE LabMaster at postnatal week 3 (W3) and postnatal week 13 (W13).ResultsAt W3, the O2 consumption and heat production in SLs were lower than those in NLs, while the respiratory exchange ratio (RER) was higher than NLs. SLs showed obesity, dyslipidemia, and impaired glucose tolerance at W13. The postweaning fish oil diet in SLs not only increased O2 consumption, CO2 production, heat production, and reduced the RER but it also reduced weight gain, serum triglycerides, and improved glucose tolerance at W13.ConclusionPostnatal overfeeding can decrease the level of body energy expenditure and induce obesity, but a fish oil diet can increase the energy expenditure and prevent the development of metabolic dysregulation in adults. PMID- 28846672 TI - Validation of serum creatinine-based formulae in pediatric renal transplant recipients. AB - BackgroundAccurate monitoring of kidney function is important post-renal transplant; however, the routine use of measured glomerular filtration rate (GFR) or addition of newer serum markers is prohibitively expensive for routine clinical use, especially in children. We validated the modified Schwartz formula in pediatric renal transplant recipients across a range of demographic and clinical characteristics.MethodsIn a retrospective cohort study with nested cross sectional analysis, we compared 505 measurements of estimated GFR using serum creatinine to simultaneous diethylenetriaminepentaacetic acid (DTPA) nuclear GFR (nGFR) measurements from 173 pediatric kidney transplant recipients who were < 18 years of age from 1 January 2001 to 31 December 2012 accounting for repeated measures.ResultsAmong 173 children, 62% were males, 85% with nGFR of >=60 ml/min/1.73 m2, and the median age at transplant was 13.6 years (interquartile range 8.3-16 years). Overall, the modified Schwartz and Pottel formulae had better bias (0.07 and -0.03 ml/min/1.73 m2, respectively) and accuracy within 30% (both 84.4%) in comparison to Lyon and Zappitelli formulae. The 30% accuracy varied for girls and children <5 and >15 years.ConclusionModified Schwartz is a practical, non-invasive, and a valid bedside tool that provides a valid measurement of GFR in pediatric kidney transplant recipients. PMID- 28846673 TI - Skeletal evolution in Marfan syndrome: growth curves from a French national cohort. AB - BackgroundTo describe the growth patterns of children affected by Marfan syndrome (MFS) compared with those of unaffected children and to create growth charts.MethodsAn observational study of children referred to the French National MFS Reference Centre. A total of 259 children carrying an FBN1 gene mutation and fulfilling Ghent 1 criteria (MFS group) and 474 mutation-negative sibling controls (non-MFS group) were evaluated. Both groups were compared with French accepted reference nomograms (Reference group).ResultsBoys and girls from the MFS group were significantly taller than those in the non-MFS group and in the reference group at all ages (P<0.0001). But, MFS children's overgrowth reduced with age. At 17 years of age, the mean height (MFS vs. non-MFS) was 191.2+/-8.4 cm (+2.9 SD) vs. 182.9+/-8.1 (+1.6 SD) for boys and 178.3+/-7.6 cm (+2.7 SD) vs. 169.5+/-6.8 (+1.2 SD) for girls, respectively. By contrast, the mean BMI of children in the MFS group was similar to those in the non-MFS group and inferior to the values of French general population, evolving around -1 SD.ConclusionGrowth patterns differ in patients with an FBN1 mutation. Knowing the growth parameters should allow physicians to better counsel patients and detect the associated diseases. The provided curves could also help to predict the final height. PMID- 28846674 TI - Alcohol use in early adolescence: findings from a survey among middle school students in Italy. AB - BackgroundThe aims of this study were to measure the extent of alcohol use among a sample of early adolescents and to provide information on the factors influencing the consumption.MethodsData were collected via self-administered anonymous questionnaires from 1,520 middle school students (mean age of 13.1 years (range 12-15 years)), who were recruited from a random sample of public schools in Calabria Region, Italy.ResultsA total of 1,032 participants completed the survey for a response rate of 68%. Nearly 70% of the respondents had drunk at least once during their lifetime, and 16.7% reported consuming alcohol during 30 days before the survey. Multivariate analysis showed that the factors associated with the consumption of alcohol were being male (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.41-0.80), being older (OR 1.88, 95% CI 1.37-2.56), living in an urban area (OR 0.29, 95% CI 0.21-0.40), reporting a sad self perceived mood (OR 2.76, 95% CI 1.87-4.48), reporting parental drinking habits (OR 7.11, 95% CI 5.02-10.08), and not considering alcohol use as an unhealthy behavior (OR 2.43, 95% CI 1.11-5.31).ConclusionAlcohol use among early adolescents is widespread. Multicomponent interventions are required in order to reduce the average levels of alcohol drinking among early adolescents. PMID- 28846675 TI - HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes. AB - The major histocompatibility complex (MHC) contains the most polymorphic genetic system in humans, the human leukocyte antigen (HLA) genes of the adaptive immune system. High allelic diversity in HLA is argued to be maintained by balancing selection, such as negative frequency-dependent selection or heterozygote advantage. Selective pressure against immune escape by pathogens can maintain appreciable frequencies of many different HLA alleles. The selection pressures operating on combinations of HLA alleles across loci, or haplotypes, have not been extensively evaluated since the high HLA polymorphism necessitates very large sample sizes, which have not been available until recently. We aimed to evaluate the effect of selection operating at the HLA haplotype level by analyzing HLA A~C~B~DRB1~DQB1 haplotype frequencies derived from over six million individuals genotyped by the National Marrow Donor Program registry. In contrast with alleles, HLA haplotype diversity patterns suggest purifying selection, as certain HLA allele combinations co-occur in high linkage disequilibrium. Linkage disequilibrium is positive (Dij'>0) among frequent haplotypes and negative (Dij'<0) among rare haplotypes. Fitting the haplotype frequency distribution to several population dynamics models, we found that the best fit was obtained when significant positive frequency-dependent selection (FDS) was incorporated. Finally, the Ewens-Watterson test of homozygosity showed excess homozygosity for 5-locus haplotypes within 23 US populations studied, with an average Fnd of 28.43. Haplotype diversity is most consistent with purifying selection for HLA Class I haplotypes (HLA-A, -B, -C), and was not inferred for HLA Class II haplotypes (-DRB1 and-DQB1). We discuss our empirical results in the context of evolutionary theory, exploring potential mechanisms of selection that maintain high linkage disequilibrium in MHC haplotype blocks. PMID- 28846676 TI - A method of determining where to target surveillance efforts in heterogeneous epidemiological systems. AB - The spread of pathogens into new environments poses a considerable threat to human, animal, and plant health, and by extension, human and animal wellbeing, ecosystem function, and agricultural productivity, worldwide. Early detection through effective surveillance is a key strategy to reduce the risk of their establishment. Whilst it is well established that statistical and economic considerations are of vital importance when planning surveillance efforts, it is also important to consider epidemiological characteristics of the pathogen in question-including heterogeneities within the epidemiological system itself. One of the most pronounced realisations of this heterogeneity is seen in the case of vector-borne pathogens, which spread between 'hosts' and 'vectors'-with each group possessing distinct epidemiological characteristics. As a result, an important question when planning surveillance for emerging vector-borne pathogens is where to place sampling resources in order to detect the pathogen as early as possible. We answer this question by developing a statistical function which describes the probability distributions of the prevalences of infection at first detection in both hosts and vectors. We also show how this method can be adapted in order to maximise the probability of early detection of an emerging pathogen within imposed sample size and/or cost constraints, and demonstrate its application using two simple models of vector-borne citrus pathogens. Under the assumption of a linear cost function, we find that sampling costs are generally minimised when either hosts or vectors, but not both, are sampled. PMID- 28846677 TI - Small airway dysfunction in smokers with stable ischemic heart disease. AB - BACKGROUND: A higher prevalence of airflow limitation (AL) has been described in patients with ischemic heart disease (IHD). Although small airway dysfunction (SAD) is an early feature of AL, there is little information about its occurrence in IHD patients. Our objective was to describe the prevalence of SAD in IHD patients, while comparing patient-related outcomes and future health risk among IHD patients with AL, SAD and normal lung function. METHODS: In 118 consecutive smoking patients with stable IHD, comorbidities, utilization of healthcare resources, current treatment, blood biochemistry and health status were recorded. SAD was evaluated by impulse oscillometry, and pre- and post-bronchodilator spirometry was performed. RESULTS: The prevalence of AL and SAD were 20.3 (95% CI, 13.1-27.6%) and 26.3% (95% CI, 18.3-34.2%), respectively. Compared to the normal lung function group, patients with SAD and without AL had lower spirometric values, poorer quality of life and higher levels of C-reactive protein (CRP), as well as increased cardiovascular risk and more vascular age. In patients with normal spirometry, the presence of SAD was independently associated with pack-years, HDL-cholesterol and CRP levels. CONCLUSION: In patients with IHD, the presence of SAD is common and that it is associated with reduced health status and increased future cardiac risk. PMID- 28846678 TI - Human leptospirosis in Seychelles: A prospective study confirms the heavy burden of the disease but suggests that rats are not the main reservoir. AB - BACKGROUND: Leptospirosis is a bacterial zoonosis caused by pathogenic Leptospira for which rats are considered as the main reservoir. Disease incidence is higher in tropical countries, especially in insular ecosystems. Our objectives were to determine the current burden of leptospirosis in Seychelles, a country ranking first worldwide according to historical data, to establish epidemiological links between animal reservoirs and human disease, and to identify drivers of transmission. METHODS: A total of 223 patients with acute febrile symptoms of unknown origin were enrolled in a 12-months prospective study and tested for leptospirosis through real-time PCR, IgM ELISA and MAT. In addition, 739 rats trapped throughout the main island were investigated for Leptospira renal carriage. All molecularly confirmed positive samples were further genotyped. RESULTS: A total of 51 patients fulfilled the biological criteria of acute leptospirosis, corresponding to an annual incidence of 54.6 (95% CI 40.7-71.8) per 100,000 inhabitants. Leptospira carriage in Rattus spp. was overall low (7.7%) but dramatically higher in Rattus norvegicus (52.9%) than in Rattus rattus (4.4%). Leptospira interrogans was the only detected species in both humans and rats, and was represented by three distinct Sequence Types (STs). Two were novel STs identified in two thirds of acute human cases while noteworthily absent from rats. CONCLUSIONS: This study shows that human leptospirosis still represents a heavy disease burden in Seychelles. Genotype data suggests that rats are actually not the main reservoir for human disease. We highlight a rather limited efficacy of preventive measures so far implemented in Seychelles. This could result from ineffective control measures of excreting animal populations, possibly due to a misidentification of the main contaminating reservoir(s). Altogether, presented data stimulate the exploration of alternative reservoir animal hosts. PMID- 28846679 TI - Microgrooved-surface topography enhances cellular division and proliferation of mouse bone marrow-derived mesenchymal stem cells. AB - Mesenchymal stem cells' (MSCs) fate is largely determined by the various topographical features and a range of extracellular matrix (ECM) components present in their niches. Apart from maintaining structural stability, they regulate cell morphology, division, proliferation, migration and differentiation among others. Traditional MSC cultures, which are mainly based on two-dimensional smooth surfaces of culture dishes and plates, do not provide topographical cues similar to in vivo three-dimensional niches, impacting various cellular processes. Therefore, we culture the mouse bone marrow-derived MSCs on microgrooved bearing surface, partially mimicking in vivo reticulated niche, to study its effect on morphology, pluripotency factor-associated stemness, cell division and rate of proliferation. Following culture, morphological features, and MSC-specific marker gene expression, such as CD29, CD44, Sca-1 along with HSC (Haematopoietic stem cell)-specific markers like CD34, CD45, CD11b were evaluated by microscopy and immunophenotyping, respectively. HSC is another type of bone marrow stem cell population, which concertedly interacts with MSC during various functions, including haematopoiesis. In addition, mesenchymal stem cells were further analyzed for gene expression of pluripotency-associated transcription factors such as Oct3/4, Sox-2, Nanog and Myc, as well as differentiated into adipocytes, osteocytes and chondrocytes. Our results show that microgrooved surface-cultured mesenchymal stem cells (MMSCs) expressed higher levels of expected cell surface and pluripotency-associated markers and proliferated more rapidly (2-3*fold) with higher percentage of cells in S/G2-M-phase, consequently giving rise to higher cell yield compared to standard culture flask-grown cells (MSCs), taken as control. Furthermore, both MSCs and MMSCs showed considerable accumulation of intracellular lipid-droplets, higher alkaline phosphatase activity and secretion of extracellular matrix that are characteristics of adipogenesis, osteogenesis and chondrogenesis, respectively. PMID- 28846680 TI - A curated catalog of canine and equine keratin genes. AB - Keratins represent a large protein family with essential structural and functional roles in epithelial cells of skin, hair follicles, and other organs. During evolution the genes encoding keratins have undergone multiple rounds of duplication and humans have two clusters with a total of 55 functional keratin genes in their genomes. Due to the high similarity between different keratin paralogs and species-specific differences in gene content, the currently available keratin gene annotation in species with draft genome assemblies such as dog and horse is still imperfect. We compared the National Center for Biotechnology Information (NCBI) (dog annotation release 103, horse annotation release 101) and Ensembl (release 87) gene predictions for the canine and equine keratin gene clusters to RNA-seq data that were generated from adult skin of five dogs and two horses and from adult hair follicle tissue of one dog. Taking into consideration the knowledge on the conserved exon/intron structure of keratin genes, we annotated 61 putatively functional keratin genes in both the dog and horse, respectively. Subsequently, curators in the RefSeq group at NCBI reviewed their annotation of keratin genes in the dog and horse genomes (Annotation Release 104 and Annotation Release 102, respectively) and updated annotation and gene nomenclature of several keratin genes. The updates are now available in the NCBI Gene database (https://www.ncbi.nlm.nih.gov/gene). PMID- 28846681 TI - Genome-wide analysis of DUF221 domain-containing gene family in Oryza species and identification of its salinity stress-responsive members in rice. AB - DUF221 domain-containing genes (DDP genes) play important roles in developmental biology, hormone signalling transduction, and responses to abiotic stress. Therefore to understand their structural and evolutionary relationship, we did a genome-wide analysis of this important gene family in rice. Further, through comparative genomics, DDP genes from Oryza sativa subsp. (indica), nine different wild species of rice and Arabidopsis were also identified. We also found an expansion of the DDP gene families in rice and Arabidopsis which is due to the segmental duplication events in some of the gene family members. In general, a highly purifying selection was found acting on all the deduced paralogous and orthologous DDP gene pairs. The data from microarray and subsequent qRT-PCR analysis revealed that although several OsDDPs were differentially regulated under salinity stress, yet OsDDP6 was upregulated at all the developmental stages in salt tolerant rice genotype, FL478. Interestingly, OsDDP6 was found to be involved in proline metabolism pathway as indicated by protein network analysis. The diverse gene structures, varied transmembrane topologies and the differential expression patterns implied the functional diversity in DDP genes. Therefore, the comprehensive evolutionary analysis of DDP genes from different Oryza species and Arabidopsis performed in this study will provide the basis for further functional validation studies vis-a-vis DDP genes of rice and other plant species. PMID- 28846682 TI - The elimination of the dengue vector, Aedes aegypti, from Brisbane, Australia: The role of surveillance, larval habitat removal and policy. AB - Aedes aegypti (L.) (Diptera: Culicidae) is a highly invasive mosquito whose global distribution has fluctuated dramatically over the last 100 years. In Australia the distribution of Ae. aegypti once spanned the eastern seaboard, for 3,000 km north to south. However, during the 1900s this distribution markedly reduced and the mosquito disappeared from its southern range. Numerous hypotheses have been proffered for this retraction, however quantitative evidence of the mechanisms driving the disappearance are lacking. We examine historical records during the period when Ae. aegypti disappeared from Brisbane, the largest population centre in Queensland, Australia. In particular, we focus on the targeted management of Ae. aegypti by government authorities, that led to local elimination, something rarely observed in large cities. Numerous factors are likely to be responsible including the removal of larval habitat, especially domestic rainwater tanks, in combination with increased mosquito surveillance and regulatory enforcement. This account of historical events as they pertain to the elimination of Ae. aegypti from Brisbane, will inform assessments of the risks posed by recent human responses to climate change and the reintroduction of 300,000 rainwater tanks into the State over the past decade. PMID- 28846683 TI - Acylcarnitines profile best predicts survival in horses with atypical myopathy. AB - Equine atypical myopathy (AM) is caused by hypoglycin A intoxication and is characterized by a high fatality rate. Predictive estimation of survival in AM horses is necessary to prevent unnecessary suffering of animals that are unlikely to survive and to focus supportive therapy on horses with a possible favourable prognosis of survival. We hypothesized that outcome may be predicted early in the course of disease based on the assumption that the acylcarnitine profile reflects the derangement of muscle energetics. We developed a statistical model to prognosticate the risk of death of diseased animals and found that estimation of outcome may be drawn from three acylcarnitines (C2, C10:2 and C18 -carnitines) with a high sensitivity and specificity. The calculation of the prognosis of survival makes it possible to distinguish the horses that will survive from those that will die despite severe signs of acute rhabdomyolysis in both groups. PMID- 28846684 TI - Outer membrane proteins analysis of Shigella sonnei and evaluation of their antigenicity in Shigella infected individuals. AB - Bacillary dysentery caused by infection with Shigella spp. remains as serious and common health problem throughout the world. It is a highly multi drug resistant organism and rarely identified from the patient at the early stage of infection. S. sonnei is the most frequently isolated species causing shigellosis in industrialized countries. The antigenicity of outer membrane protein of this pathogen expressed during human infection has not been identified to date. We have studied the antigenic outer membrane proteins expressed by S. sonnei, with the aim of identifying presence of specific IgA and IgG in human serum against the candidate protein biomarkers. Three antigenic OMPs sized 33.3, 43.8 and 100.3 kDa were uniquely recognized by IgA and IgG from patients with S. sonnei infection, and did not cross-react with sera from patients with other types of infection. The antigenic proteome data generated in this study are a first for OMPs of S. sonnei, and they provide important insights of human immune responses. Furthermore, numerous prime candidate proteins were identified which will aid the development of new diagnostic tools for the detection of S. sonnei. PMID- 28846685 TI - Myeloid Wnt ligands are required for normal development of dermal lymphatic vasculature. AB - Resident tissue myeloid cells play a role in many aspects of physiology including development of the vascular systems. In the blood vasculature, myeloid cells use VEGFC to promote angiogenesis and can use Wnt ligands to control vascular branching and to promote vascular regression. Here we show that myeloid cells also regulate development of the dermal lymphatic vasculature using Wnt ligands. Using myeloid-specific deletion of the WNT transporter Wntless we show that myeloid Wnt ligands are active at two distinct stages of development of the dermal lymphatics. As lymphatic progenitors are emigrating from the cardinal vein and intersomitic vessels, myeloid Wnt ligands regulate both their numbers and migration distance. Later in lymphatic development, myeloid Wnt ligands regulate proliferation of lymphatic endothelial cells (LEC) and thus control lymphatic vessel caliber. Myeloid-specific deletion of WNT co-receptor Lrp5 or Wnt5a gain of-function also produce elevated caliber in dermal lymphatic capillaries. These data thus suggest that myeloid cells produce Wnt ligands to regulate lymphatic development and use Wnt pathway co-receptors to regulate the balance of Wnt ligand activity during the macrophage-LEC interaction. PMID- 28846686 TI - The successive projection algorithm as an initialization method for brain tumor segmentation using non-negative matrix factorization. AB - Non-negative matrix factorization (NMF) has become a widely used tool for additive parts-based analysis in a wide range of applications. As NMF is a non convex problem, the quality of the solution will depend on the initialization of the factor matrices. In this study, the successive projection algorithm (SPA) is proposed as an initialization method for NMF. SPA builds on convex geometry and allocates endmembers based on successive orthogonal subspace projections of the input data. SPA is a fast and reproducible method, and it aligns well with the assumptions made in near-separable NMF analyses. SPA was applied to multi parametric magnetic resonance imaging (MRI) datasets for brain tumor segmentation using different NMF algorithms. Comparison with common initialization methods shows that SPA achieves similar segmentation quality and it is competitive in terms of convergence rate. Whereas SPA was previously applied as a direct endmember extraction tool, we have shown improved segmentation results when using SPA as an initialization method, as it allows further enhancement of the sources during the NMF iterative procedure. PMID- 28846688 TI - Effects of lay support for pregnant women with social risk factors on infant development and maternal psychological health at 12 months postpartum. AB - BACKGROUND: The ELSIPS (Evaluation of Lay Support in Pregnant Women with Social Risk) RCT showed that lay support for women with social risk had a positive effect on maternal mental health and mother-infant bonding. This exploratory study examined whether these observed benefits would impact infant development at 1 year. METHODS: A sub-sample of women whose infants were under one year who had participated in the ELSIPS RCT which randomised women to receive either standard care or the services of a Pregnancy Outreach Worker (POW), and who were contactable, were eligible to participate in the follow up. At home visits, the Bayley Scales of Infant Development (3rd Edition) and standardised measures of depression, self efficacy, mind-mindedness and bonding were completed. RESULTS: 486 women were eligible for follow up, of whom 154 agreed to participate. 61/273 were successfully followed up in the standard maternity care arm and 51/213 in the POW arm. Women who completed follow up were less depressed and had higher selfefficacy scores at 8-12 weeks postpartum than those who did not complete follow up. There were no significant differences in maternal outcomes, infant cognitive development, receptive communication, expressive communication, fine motor development or social/emotional functioning between groups at 12 month follow up. Infants of mothers who received the POW intervention had significantly better gross motor development than infants whose mothers received standard care (p<0.03). CONCLUSIONS: The provision of lay support to women with social risk may facilitate infant gross motor skill development at one year but there were no other demonstrable benefits. The effects of the intervention may be underestimated given that those women who completed follow up had better mental health than the original study sample. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN35027323. PMID- 28846687 TI - beta-catenin is required for taste bud cell renewal and behavioral taste perception in adult mice. AB - Taste stimuli are transduced by taste buds and transmitted to the brain via afferent gustatory fibers. Renewal of taste receptor cells from actively dividing progenitors is finely tuned to maintain taste sensitivity throughout life. We show that conditional beta-catenin deletion in mouse taste progenitors leads to rapid depletion of progenitors and Shh+ precursors, which in turn causes taste bud loss, followed by loss of gustatory nerve fibers. In addition, our data suggest LEF1, TCF7 and Wnt3 are involved in a Wnt pathway regulatory feedback loop that controls taste cell renewal in the circumvallate papilla epithelium. Unexpectedly, taste bud decline is greater in the anterior tongue and palate than in the posterior tongue. Mutant mice with this regional pattern of taste bud loss were unable to discern sweet at any concentration, but could distinguish bitter stimuli, albeit with reduced sensitivity. Our findings are consistent with published reports wherein anterior taste buds have higher sweet sensitivity while posterior taste buds are better tuned to bitter, and suggest beta-catenin plays a greater role in renewal of anterior versus posterior taste buds. PMID- 28846689 TI - Domain-based prediction of the human isoform interactome provides insights into the functional impact of alternative splicing. AB - Alternative splicing is known to remodel protein-protein interaction networks ("interactomes"), yet large-scale determination of isoform-specific interactions remains challenging. We present a domain-based method to predict the isoform interactome from the reference interactome. First, we construct the domain resolved reference interactome by mapping known domain-domain interactions onto experimentally-determined interactions between reference proteins. Then, we construct the isoform interactome by predicting that an isoform loses an interaction if it loses the domain mediating the interaction. Our prediction framework is of high-quality when assessed by experimental data. The predicted human isoform interactome reveals extensive network remodeling by alternative splicing. Protein pairs interacting with different isoforms of the same gene tend to be more divergent in biological function, tissue expression, and disease phenotype than protein pairs interacting with the same isoforms. Our prediction method complements experimental efforts, and demonstrates that integrating structural domain information with interactomes provides insights into the functional impact of alternative splicing. PMID- 28846690 TI - Incidence of lower extremity amputations in the diabetic compared with the non diabetic population: A systematic review. AB - SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD4201501780. PMID- 28846691 TI - Hair cortisol levels, psychological stress and psychopathological symptoms as predictors of postpartum depression. AB - Postpartum depression affects a huge number of women and has detrimental consequences. Knowing the factors associated with postpartum depression during pregnancy can help its prevention. Although there is evidence surrounding behavioral or psychological predictors of postpartum depression, there is a lack of evidence of biological forecasters. The aim of this study was to analyze the sociodemographic, obstetric, and psychological variables along with hair cortisol levels during the first, second, and third trimesters of pregnancy that could predict postpartum depression symptoms. A sample of 44 pregnant women was assessed during 3 trimesters of pregnancy and the postpartum period using psychological questionnaires and hair cortisol levels. Participants were divided into 2 groups: a group with postpartum depression symptoms and a group with no postpartum depression symptoms. Results showed significant positive differences between groups in the first trimester regarding the Somatization subscale of the SCL-90-R (p < .05). In the second trimester, significant differences were found in the Somatization, Depression, Anxiety, and GSI subscales (p < .05). In the third trimester significant differences between both groups were found regarding pregnancy-specific stress. We found significant positive differences between groups regarding hair cortisol levels in the first and the third trimester. Hair cortisol levels could predict 21.7% of the variance of postpartum depression symptoms. In conclusion, our study provided evidence that psychopathological symptoms, pregnancy-specific stress, and hair cortisol levels can predict postpartum depression symptoms at different time-points during pregnancy. These findings can be applied in future studies and improve maternal care in clinical settings. PMID- 28846692 TI - Gyri of the human parietal lobe: Volumes, spatial extents, automatic labelling, and probabilistic atlases. AB - Accurately describing the anatomy of individual brains enables interlaboratory communication of functional and developmental studies and is crucial for possible surgical interventions. The human parietal lobe participates in multimodal sensory integration including language processing and also contains the primary somatosensory area. We describe detailed protocols to subdivide the parietal lobe, analyze morphological and volumetric characteristics, and create probabilistic atlases in MNI152 stereotaxic space. The parietal lobe was manually delineated on 3D T1 MR images of 30 healthy subjects and divided into four regions: supramarginal gyrus (SMG), angular gyrus (AG), superior parietal lobe (supPL) and postcentral gyrus (postCG). There was the expected correlation of male gender with larger brain and intracranial volume. We examined a wide range of anatomical features of the gyri and the sulci separating them. At least a rudimentary primary intermediate sulcus of Jensen (PISJ) separating SMG and AG was identified in nearly all (59/60) hemispheres. Presence of additional gyri in SMG and AG was related to sulcal features and volumetric characteristics. The parietal lobe was slightly (2%) larger on the left, driven by leftward asymmetries of the postCG and SMG. Intersubject variability was highest for SMG and AG, and lowest for postCG. Overall the morphological characteristics tended to be symmetrical, and volumes also tended to covary between hemispheres. This may reflect developmental as well as maturation factors. To assess the accuracy with which the labels can be used to segment newly acquired (unlabelled) T1 weighted brain images, we applied multi-atlas label propagation software (MAPER) in a leave-one-out experiment and compared the resulting automatic labels with the manually prepared ones. The results showed strong agreement (mean Jaccard index 0.69, corresponding to a mean Dice index of 0.82, average mean volume error of 0.6%). Stereotaxic probabilistic atlases of each subregion were obtained. They illustrate the physiological brain torque, with structures in the right hemisphere positioned more anteriorly than in the left, and right/left positional differences of up to 10 mm. They also allow an assessment of sulcal variability, e.g. low variability for parietooccipital fissure and cingulate sulcus. Illustrated protocols, individual label sets, probabilistic atlases, and a maximum-probability atlas which takes into account surrounding structures are available for free download under academic licences. PMID- 28846693 TI - PBRM1 regulates proliferation and the cell cycle in renal cell carcinoma through a chemokine/chemokine receptor interaction pathway. AB - PBRM1 is a novel tumor suppressor gene that can inhibit cancer cell proliferation and predict the outcome of renal cell carcinoma (RCC), but its biological role needs further elucidation. We examined expression of the PBRM1 gene in RCC cell lines and the effect of PBRM1 on cell proliferation and cell cycle in RCC ACHN cells. Microarray processing and analysis was used to explore novel pathways involved in tumorigenesis related to PBRM1 knockdown. PBRM1 was expressed at high levels in RCC ACHN cells and lentivirus-mediated PBRM1 knockdown in these cells caused an increase in the proportion of cells in S phase of the cell cycle and promoted in vitro proliferation and migration. In vivo experiments showed that downregulation of PBRM1 promoted tumorigenesis in nude mice. In pathway gene chip analysis, the chemokine/chemokine receptor interaction pathway showed the greatest difference in gene expression upon PBRM1 knockdown. Protein levels of IL6ST and CCL2 were increased, whereas levels of interleukin (IL)-8, IL-6, and CXCL2 were decreased, in knockdown cells. Re-expression of IL-8 in PBRM1 knockdown ACHN cells could significantly decrease cell proliferation/migration and induced cell arrest in the G2/M phase. These findings indicate that PBRM1 alters cell cycle progression and inhibits proliferation and migration of ACHN cells through the chemokine/chemokine receptor pathway. PMID- 28846694 TI - Analysis of 62 hybrid assembled human Y chromosomes exposes rapid structural changes and high rates of gene conversion. AB - The human Y-chromosome does not recombine across its male-specific part and is therefore an excellent marker of human migrations. It also plays an important role in male fertility. However, its evolution is difficult to fully understand because of repetitive sequences, inverted repeats and the potentially large role of gene conversion. Here we perform an evolutionary analysis of 62 Y-chromosomes of Danish descent sequenced using a wide range of library insert sizes and high coverage, thus allowing large regions of these chromosomes to be well assembled. These include 17 father-son pairs, which we use to validate variation calling. Using a recent method that can integrate variants based on both mapping and de novo assembly, we genotype 10898 SNVs and 2903 indels (max length of 27241 bp) in our sample and show by father-son concordance and experimental validation that the non-recurrent SNP and indel variation on the Y chromosome tree is called very accurately. This includes variation called in a 0.9 Mb centromeric heterochromatic region, which is by far the most variable in the Y chromosome. Among the variation is also longer sequence-stretches not present in the reference genome but shared with the chimpanzee Y chromosome. We analyzed 2.7 Mb of large inverted repeats (palindromes) for variation patterns among the two palindrome arms and identified 603 mutation and 416 gene conversions events. We find clear evidence for GC-biased gene conversion in the palindromes (and a balancing AT mutation bias), but irrespective of this, also a strong bias towards gene conversion towards the ancestral state, suggesting that palindromic gene conversion may alleviate Muller's ratchet. Finally, we also find a large number of large-scale gene duplications and deletions in the palindromic regions (at least 24) and find that such events can consist of complex combinations of simultaneous insertions and deletions of long stretches of the Y chromosome. PMID- 28846695 TI - Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors. AB - OBJECTIVE: Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown. METHODS: To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating. RESULTS: An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin 4 significantly reduced food intake in a mouse model of 'binge-like' eating. CONCLUSIONS: These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating. PMID- 28846696 TI - The "hypnotic state" and eye movements: Less there than meets the eye? AB - Responsiveness to hypnotic procedures has been related to unusual eye behaviors for centuries. Kallio and collaborators claimed recently that they had found a reliable index for "the hypnotic state" through eye-tracking methods. Whether or not hypnotic responding involves a special state of consciousness has been part of a contentious debate in the field, so the potential validity of their claim would constitute a landmark. However, their conclusion was based on 1 highly hypnotizable individual compared with 14 controls who were not measured on hypnotizability. We sought to replicate their results with a sample screened for High (n = 16) or Low (n = 13) hypnotizability. We used a factorial 2 (high vs. low hypnotizability) x 2 (hypnosis vs. resting conditions) counterbalanced order design with these eye-tracking tasks: Fixation, Saccade, Optokinetic nystagmus (OKN), Smooth pursuit, and Antisaccade (the first three tasks has been used in Kallio et al.'s experiment). Highs reported being more deeply in hypnosis than Lows but only in the hypnotic condition, as expected. There were no significant main or interaction effects for the Fixation, OKN, or Smooth pursuit tasks. For the Saccade task both Highs and Lows had smaller saccades during hypnosis, and in the Antisaccade task both groups had slower Antisaccades during hypnosis. Although a couple of results suggest that a hypnotic condition may produce reduced eye motility, the lack of significant interactions (e.g., showing only Highs expressing a particular eye behavior during hypnosis) does not support the claim that eye behaviors (at least as measured with the techniques used) are an indicator of a "hypnotic state." Our results do not preclude the possibility that in a more spontaneous or different setting the experience of being hypnotized might relate to specific eye behaviors. PMID- 28846697 TI - Prognostic relevance of a T-type calcium channels gene signature in solid tumours: A correlation ready for clinical validation. AB - BACKGROUND: T-type calcium channels (TTCCs) mediate calcium influx across the cell membrane. TTCCs regulate numerous physiological processes including cardiac pacemaking and neuronal activity. In addition, they have been implicated in the proliferation, migration and differentiation of tumour tissues. Although the signalling events downstream of TTCC-mediated calcium influx are not fully elucidated, it is clear that variations in the expression of TTCCs promote tumour formation and hinder response to treatment. METHODS: We examined the expression of TTCC genes (all three subtypes; CACNA-1G, CACNA-1H and CACNA-1I) and their prognostic value in three major solid tumours (i.e. gastric, lung and ovarian cancers) via a publicly accessible database. RESULTS: In gastric cancer, expression of all the CACNA genes was associated with overall survival (OS) among stage I-IV patients (all p<0.05). By combining the three potential biomarkers, a TTCC signature was developed, which retained a significant association with OS both in stage IV and stage I-III patients. In lung and ovarian cancer, association with OS was also significant when all tumour stages were considered, but was partly lost or inconclusive after splitting cases into localized and metastatic subsets. CONCLUSIONS: Alterations in CACNA gene expression are linked to tumour prognosis. Gastric cancer represents the most promising setting for further evaluation. PMID- 28846698 TI - Association between mitochondrial DNA variations and schizophrenia in the northern Chinese Han population. AB - To determine whether mitochondrial DNA (mtDNA) variations are associated with schizophrenia, 313 patients with schizophrenia and 326 unaffected participants of the northern Chinese Han population were included in a prospective study. Single nucleotide polymorphisms (SNPs) including C5178A, A10398G, G13708A, and C13928G were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Hypervariable regions I and II (HVSI and HVSII) were analyzed by sequencing. The results showed that the 4 SNPs and 11 haplotypes, composed of the 4 SNPs, did not differ significantly between patient and control groups. No significant association between haplogroups and the risk of schizophrenia was ascertained after Bonferroni correction. Drawing a conclusion, there was no evidence of an association between mtDNA (the 4 SNPs and the control region) and schizophrenia in the northern Chinese Han population. PMID- 28846699 TI - Response surface methodology based extraction of Tribulus terrestris leads to an upsurge of antilithiatic potential by inhibition of calcium oxalate crystallization processes. AB - Tribulus terrestris has significant antilithiatic efficacy established via both in vitro as well as in vivo studies and is used in numerous anti-urolithiatic herbal formulations viz. Cystone, Uriflow, Uritone and Neeri. However, to fully utilize its antilithiatic potential, the influence of different extraction parameters on antilithiatic ability of T. terrestris aqueous extract needs elucidation. Thus, the current study was undertaken using statistically optimized extraction conditions for aqueous extract preparation. Response surface methodology was employed to observe the influence of three variables i.e. temperature ( degrees C), time (h) and solid: liquid ratio (S: L) on the extraction yield (%) and protein content (mg/g) of T. terrestris aqueous extract. RSM results revealed that the high S:L ratio, low temperature and reduced incubation time were optimal conditions for aqueous extraction. Under such extraction conditions the protein content reached the value of 26.6+/-1.22 mg/g and the obtained extraction yield was 27.32+/-1.62%. The assessment of antilithiatic activity of 4 selected extracts (AE1-4), revealed enhanced nucleation and aggregation inhibition of calcium oxalate crystals with AE1 and AE2, which in addition significantly altered the size and morphology of calcium oxalate monohydrate (COM) crystals compared to AE3 and AE4. In vitro cell culture based studies on renal epithelial cells (MDCK, NRK-52E and PK 15) proved that the AE1 showed higher cytoprotective potency by increasing cell viability as compared to the oxalate treated group. The free radical scavenging activity of aqueous extract lowered the reactive oxygen specie's induced damage and potentially reduced the signals of programmed cell death due to oxalate injury. In addition, modulation of the COM crystal morphology was enhanced by AE1 as compared to AE2. The FTIR and GC-MS analysis of AE1, showed the presence of biomolecules which could aid in the attenuation of lithiatic process. In the light of these results the utility of the RSM approach to fully optimize the antilithiatic potential of T. terrestris cannot be undermined. PMID- 28846700 TI - pFAK-Y397 overexpression as both a prognostic and a predictive biomarker for patients with metastatic osteosarcoma. AB - Focal adhesion kinase (FAK) is important for tumor cell survival and metastasis in various cancers. However, its expression and prognostic value in patients with metastatic osteosarcoma remain unknown. We investigated the expression of FAK and its phosphorylated form (pFAK-Y397) in osteosarcoma tissues from 53 patients by immunohistochemistry and evaluated their correlations with clinicopathologic characteristics and outcomes. The prognostic values were assessed using Kaplan Meier survival and Cox regression analyses. Total FAK and pFAK-Y397 were overexpressed in 48 (90.6%) and 33 (62.3%) cases, respectively. pFAK-Y397 overexpression was correlated with poor histologic response after neoadjuvant chemotherapy in patients with osteosarcoma regardless of the presence of metastasis or not. Kaplan-Meier curve showed that patients with metastatic osteosarcoma with pFAK-Y397 overexpression had significantly worse overall survival (OS) than those with non-overexpression (P = 0.044). Multivariate Cox regression analysis confirmed pFAK-Y397 overexpression as an independent prognostic predictor for OS and post metastases OS (PMOS) (P = 0.017, P = 0.006, respectively). Age at diagnosis was also an independent indicator for PMOS (P = 0.003). However, total FAK expression was not correlated with any clinicopathologic characteristics or OS in patients with metastatic osteosarcoma. In conclusion, our findings identified FAK as a common aberrant protein overexpression in various subtypes of osteosarcoma. pFAK-Y397 overexpression can be used as a prognostic biomarker predicting poor OS for patients with metastatic osteosarcoma, and the expression of pFAK-Y397 differentiated good and poor responders to neoadjuvant chemotherapy. PMID- 28846701 TI - A comparison of visual outcome and rotational stability of two types of toric implantable collamer lenses (TICL) : V4 versus V4c. AB - PURPOSE: To compare the efficacy and rotational stability after implantation of two types of toric implantable collamer lenses (Toric ICLTM(TICL);V4 and V4c, STAAR Surgical Co.). STUDY DESIGN: Retrospective case series. METHODS: This retrospective study evaluated total 48 eyes of 48 patients who underwent the implantation with V4 and V4c TICL with a central hole; A twenty-four eyes of 24 patients with V4 TICL and 24 eyes of 24 patients with V4c TICL with a central hole. Visual acuity, manifest refraction, and intraocular pressure were evaluated before and after surgery. Rotational stability (disparity between the intended axis and achieved axis) was assessed in both groups using digital anterior segment photographs, and vector analysis was also performed. RESULTS: Uncorrected visual acuity improved in both groups without significant difference (P = .111). There were no statistical differences between two groups in postoperative SE and cylindrical errors (P = .067 and .384, respectively). The mean value of rotation was 4.17+/-3.31 degrees and 3.39+/-2.36 degrees in the V4 and V4c TICL groups, respectively without significant difference (P = .364). Vector analysis of astigmatic correction showed no significant diffrence between two groups. CONCLUSION: V4 and V4c TICL have similar efficacy with regard to visual acuity and refractive outcomes and rotational stability. PMID- 28846702 TI - Association between statin use, the vaginal microbiome, and Gardnerella vaginalis vaginolysin-mediated cytotoxicity. AB - BACKGROUND: Bacterial vaginosis (BV) is the leading dysbiosis of the vaginal microbiome. The pathways leading towards the development of BV are not well understood. Gardnerella vaginalis is frequently associated with BV. G. vaginalis produces the cholesterol-dependent cytolysin (CDC), vaginolysin, which can lyse a variety of human cells and is thought to play a role in pathogenesis. Because membrane cholesterol is required for vaginolysin to function, and because HMG-CoA reductase inhibitors (statins) affect not only serum levels of cholesterol but membrane levels as well, we hypothesized that statins might affect the vaginal microbiome. METHODS: To investigate the relationship between use of the statins and the vaginal microbiome, we analyzed 16S rRNA gene taxonomic surveys performed on vaginal samples from 133 women who participated in the Vaginal Human Microbiome Project and who were taking statins at the time of sampling, 152 women who reported high cholesterol levels but were not taking statins, and 316 women who did not report high cholesterol. To examine the effect of statins on the cytolytic effect of vaginolysin, the cholesterol-dependent cytolysin (CDC) produced by Gardnerella vaginalis, we assessed the effect of simvastatin pretreatment of VK2E6/E7 vaginal epithelial cells on vaginolysin-mediated cytotoxicity. RESULTS: The mean proportion of G. vaginalis among women taking statins was significantly lower relative to women not using statins. Women using statins had higher mean proportions of Lactobacillus crispatus relative to women with normal cholesterol levels, and higher levels of Lactobacillus jensenii relative to women with high cholesterol but not taking statins. In vitro, vaginal epithelial cells pretreated with simvastatin were relatively resistant to vaginolysin and this effect was inhibited by cholesterol. CONCLUSIONS: In this cross-sectional study, statin use was associated with reduced proportions of G. vaginalis and greater proportions of beneficial lactobacilli within the vaginal microbiome. The negative association between statin use and G. vaginalis may be related to inhibition of vaginolysin function. PMID- 28846703 TI - Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity. AB - Cystic Fibrosis (CF) is the most common monogenic disease among people of Western European descent and caused by mutations in the CFTR gene. However, the disease severity is immensely variable even among patients with similar CFTR mutations due to the possible effect of 'modifier genes'. To identify genetic modifiers, we applied RNA-seq based transcriptomic analyses in CF patients with a mild and severe lung phenotype. Global gene expression and enrichment analyses revealed that genes of the type I interferon response and ribosomal stalk proteins are potential modifiers of CF related lung dysfunction. The results provide a new set of CF modifier genes with possible implications as new therapeutic targets for the treatment of CF. PMID- 28846704 TI - Is crossed laterality associated with academic achievement and intelligence? A systematic review and meta-analysis. AB - Over the last century, sporadic research has suggested that people whose hand, eye, foot, or ear dominances are not consistently right- or left-sided are at special risk of suffering academic difficulties. This phenomenon is known as crossed laterality. Although the bulk of this research dates from 1960's and 1970's, crossed laterality is becoming increasingly popular in the area of school education, driving the creation of several interventions aimed at restoring or consolidating lateral dominance. However, the available evidence is fragmentary. To determine the impact of crossed laterality on academic achievement and intelligence, we conducted a systematic review and meta-analysis of articles published since 1900. The inclusion criteria for the review required that studies used one or more lateral preference tasks for at least two specific parts of the body; they included a valid measure of crossed laterality; they measured the impact of crossed laterality on academic achievement or intelligence; and they included participants between 3 and 17 years old. The final sample included 26 articles that covered a total population of 3578 children aged 5 to 12. Taken collectively, the results of these studies do not support the claim that there is a reliable association between crossed laterality and either academic achievement or intelligence. Along with this, we detected important shortcomings in the literature, such as considerable heterogeneity among the variables used to measure laterality and among the tasks utilized to measure the outcomes. The educational implications of these results are discussed. PMID- 28846705 TI - Insulin modulates the frequency of Ca2+ oscillations in mouse pancreatic islets. AB - Pancreatic islets can adapt to oscillatory glucose to produce synchronous insulin pulses. Can islets adapt to other oscillatory stimuli, specifically insulin? To answer this question, we stimulated islets with pulses of exogenous insulin and measured their Ca2+ oscillations. We observed that sufficiently high insulin (> 500 nM) with an optimal pulse period (~ 4 min) could make islets to produce synchronous Ca2+ oscillations. Glucose and insulin, which are key stimulatory factors of islets, modulate islet Ca2+ oscillations differently. Glucose increases the active-to-silent ratio of phases, whereas insulin increases the period of the oscillation. To examine the dual modulation, we adopted a phase oscillator model that incorporated the phase and frequency modulations. This mathematical model showed that out-of-phase oscillations of glucose and insulin were more effective at synchronizing islet Ca2+ oscillations than in-phase stimuli. This finding suggests that a phase shift in glucose and insulin oscillations can enhance inter-islet synchronization. PMID- 28846706 TI - Experience of, awareness of and help-seeking for potential cancer symptoms in smokers and non-smokers: A cross-sectional study. AB - BACKGROUND: Presenting to primary care with potential cancer symptoms is contingent on one's ability to recognize potentially serious symptoms. We investigated differences between smokers and non-smokers in symptoms experienced, awareness and consulting of potential respiratory, head and neck cancer symptoms. METHODS: Smokers and non-smokers aged over 50 from Yorkshire general practice lists were sent a postal questionnaire asking about symptoms, consulting and awareness of cancer symptoms. Data were analysed using STATA14. RESULTS: Response rate after one reminder was 30.5% (1205/3954). Smoking status was associated with experience of cough (p<0.001), breathlessness (p = 0.002) and tiredness (p = 0.004) with smokers (25.8% of population) more likely than never-smokers (53.6% of population) to experience all three symptoms (cough OR = 2.56;95%CI[1.75 3.75], breathlessness OR = 2.39;95%CI[1.43-4.00], tiredness OR = 1.57;95%CI[1.12 2.19]). Smoking status was associated with awareness of breathlessness as a potential cancer symptom (p = 0.035) and consulting for cough (p = 0.011) with smokers less likely to consult than never-smokers (OR = 0.37;95% CI[0.17-0.80]). CONCLUSION: Our findings suggest that current smokers are more likely to experience cough, breathlessness and tiredness, but are less likely to consult for cough than never-smokers. To increase cancer awareness and promote consulting among smokers, innovative interventions improving symptom recognition and empowering smokers to seek help are required. PMID- 28846708 TI - RNA sequencing demonstrates large-scale temporal dysregulation of gene expression in stimulated macrophages derived from MHC-defined chicken haplotypes. AB - Discovering genetic biomarkers associated with disease resistance and enhanced immunity is critical to developing advanced strategies for controlling viral and bacterial infections in different species. Macrophages, important cells of innate immunity, are directly involved in cellular interactions with pathogens, the release of cytokines activating other immune cells and antigen presentation to cells of the adaptive immune response. IFNgamma is a potent activator of macrophages and increased production has been associated with disease resistance in several species. This study characterizes the molecular basis for dramatically different nitric oxide production and immune function between the B2 and the B19 haplotype chicken macrophages.A large-scale RNA sequencing approach was employed to sequence the RNA of purified macrophages from each haplotype group (B2 vs. B19) during differentiation and after stimulation. Our results demonstrate that a large number of genes exhibit divergent expression between B2 and B19 haplotype cells both prior and after stimulation. These differences in gene expression appear to be regulated by complex epigenetic mechanisms that need further investigation. PMID- 28846707 TI - Kek-6: A truncated-Trk-like receptor for Drosophila neurotrophin 2 regulates structural synaptic plasticity. AB - Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK) signaling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek) genes, suggesting that evolutionarily conserved functions for this receptor class may exist. Here, we asked whether Keks function together with Drosophila neurotrophins (DNTs) at the larval glutamatergic neuromuscular junction (NMJ). We tested the eleven LRR and Ig-containing (LIG) proteins encoded in the Drosophila genome for expression in the central nervous system (CNS) and potential interaction with DNTs. Kek-6 is expressed in the CNS, interacts genetically with DNTs and can bind DNT2 in signaling assays and co-immunoprecipitations. Ligand binding is promiscuous, as Kek-6 can also bind DNT1, and Kek-2 and Kek-5 can also bind DNT2. In vivo, Kek-6 is found presynaptically in motoneurons, and DNT2 is produced by the muscle to function as a retrograde factor at the NMJ. Kek-6 and DNT2 regulate NMJ growth and synaptic structure. Evidence indicates that Kek-6 does not antagonise the alternative DNT2 receptor Toll-6. Instead, Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. Using pull down assays, we identified and validated CaMKII and VAP33A as intracellular partners of Kek-6, and show that they regulate NMJ growth and active zone formation downstream of DNT2 and Kek-6. The synaptic functions of Kek-6 could be evolutionarily conserved. This raises the intriguing possibility that a novel mechanism of structural synaptic plasticity involving truncated Trk-family receptors independently of TyrK signaling may also operate in the human brain. PMID- 28846709 TI - Infection of Ixodes ricinus by Borrelia burgdorferi sensu lato in peri-urban forests of France. AB - Lyme borreliosis is the most common tick-borne disease in the northern hemisphere. In Europe, it is transmitted by Ixodes ticks that carry bacteria belonging to the Borrelia burgdorferi sensu lato complex. The objective of this work was to explore eco-epidemiological factors of Lyme borreliosis in peri-urban forests of France (Senart, Notre-Dame and Rambouillet). We investigated whether the introduction of Tamias sibiricus in Senart could alter the density of infected ticks. Moreover, the density and tick infection were investigated according to the tree species found in various patches of Senart forest. For this purpose, ticks were sampled during 3 years. In the Senart forest, the density of nymph and adult ticks showed no significant difference between 2008, 2009 and 2011. The nymph density varied significantly as a function of the month of collection. Regarding the nymphs, a higher rate of infection and infected density were found in 2009. Plots with chipmunks (C) presented a lower density of both nymphs and adult ticks than plots without chipmunks (NC) did. A higher rate of infection of nymphs with Borrelia was seen in C plots. The prevalence of the various species of Borrelia was also found to vary between C and NC plots with the year of the collect. The presence of chestnut trees positively influenced the density of both nymphs and adults. The infected nymph density showed a significant difference depending on the peri-urban forest studied, Senart being higher than Rambouillet. The prevalence of Borrelia species also differed between the various forests studied. Concerning the putative role that Tamias sibiricus may play in the transmission of Borrelia, our results suggest that its presence is correlated with a higher rate of infection of questing ticks by Borrelia genospecies and if its population increases, it could play a significant role in the risk of transmission of Lyme borreliosis. PMID- 28846710 TI - Apparent diffusion coefficient maps in the assessment of surgical patients with lumbar spine degeneration. AB - PURPOSE: To assess the utility of apparent diffusion coefficient (ADC) maps for the assessment of patients with advanced degenerative lumbar spine disease and describe characteristic features of ADC maps in various degenerative lumbar spinal conditions. METHODS: T1-weighted, T2-weighted and diffusion weighted (DWI) MR images of 100 consecutive patients admitted to the spinal surgery service were assessed. ADC maps were generated from DWI images using Osyrix software. The ADC values and characteristic ADC maps were assessed in the regions of interest over the different pathological entities of the lumbar spine. RESULTS: The study included 452 lumbar vertebral segments available for analysis of ADCs. Characteristic ADC map features were identified for protrusion, extrusion and sequester types of lumbar disk herniations, spondylolisthesis, reactive Modic endplate changes, Pfirrmann grades of IVD degeneration, and compromised spinal nerves. Compromised nerve roots had significantly higher mean ADC values than adjacent (p < 0.001), contralateral (p < 0.001) or adjacent contralateral (p < 0.001) nerve roots. Compared to the normal bone marrow, Modic I changes showed higher ADC values (p = 0.01) and Modic 2 changes showed lower ADC values (p = 0.02) respectively. ADC values correlated with the Pfirrmann grading, however differed from herniated and non-herniated disks of the matched Pfirrmann 3 and 4 grades. CONCLUSION: Quantitative and qualitative evaluation of ADC mapping may provide additional useful information regarding the fluid dynamics of the degenerated spine and may complement standard MRI imaging protocol for the comprehensive assessment of surgical patients with lumbar spine pathology. ADC maps were advantageous in differentiating reactive bone marrow changes, and more precise assessment of the disk degeneration state. ADC mapping of compressed nerve roots showed promise but requires further investigation on a larger cohort of patients. PMID- 28846711 TI - Identification of novel biomarkers to monitor beta-cell function and enable early detection of type 2 diabetes risk. AB - A decline in beta-cell function is a prerequisite for the development of type 2 diabetes, yet the level of beta-cell function in individuals at risk of the condition is rarely measured. This is due, in part, to the fact that current methods for assessing beta-cell function are inaccurate, prone to error, labor intensive, or affected by glucose-lowering therapy. The aim of the current study was to identify novel circulating biomarkers to monitor beta-cell function and to identify individuals at high risk of developing beta-cell dysfunction. In a nested case-control study from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort (n = 1157), proteomics and miRNA profiling were performed on fasting plasma samples from 43 individuals who progressed to impaired glucose tolerance (IGT) and 43 controls who maintained normal glucose tolerance (NGT) over three years. Groups were matched at baseline for age, gender, body mass index (BMI), insulin sensitivity (euglycemic clamp) and beta cell glucose sensitivity (mathematical modeling). Proteomic profiling was performed using the SomaLogic platform (Colorado, USA); miRNA expression was performed using a modified RT-PCR protocol (Regulus Therapeutics, California, USA). Results showed differentially expressed proteins and miRNAs including some with known links to type 2 diabetes, such as adiponectin, but also novel biomarkers and pathways. In cross sectional analysis at year 3, the top differentially expressed biomarkers in people with IGT/ reduced beta-cell glucose sensitivity were adiponectin, alpha1-antitrypsin (known to regulate adiponectin levels), endocan, miR-181a, miR-342, and miR-323. At baseline, adiponectin, cathepsin D and NCAM.L1 (proteins expressed by pancreatic beta-cells) were significantly lower in those that progressed to IGT. Many of the novel prognostic biomarker candidates were within the epithelial-mesenchymal transition (EMT) pathway: for example, Noggin, DLL4 and miR-181a. Further validation studies are required in additional clinical cohorts and in patients with type 2 diabetes, but these results identify novel pathways and biomarkers that may have utility in monitoring beta-cell function and/ or predicting future decline, allowing more targeted efforts to prevent and intercept type 2 diabetes. PMID- 28846712 TI - Hybrid multiscale modeling and prediction of cancer cell behavior. AB - BACKGROUND: Understanding cancer development crossing several spatial-temporal scales is of great practical significance to better understand and treat cancers. It is difficult to tackle this challenge with pure biological means. Moreover, hybrid modeling techniques have been proposed that combine the advantages of the continuum and the discrete methods to model multiscale problems. METHODS: In light of these problems, we have proposed a new hybrid vascular model to facilitate the multiscale modeling and simulation of cancer development with respect to the agent-based, cellular automata and machine learning methods. The purpose of this simulation is to create a dataset that can be used for prediction of cell phenotypes. By using a proposed Q-learning based on SVR-NSGA-II method, the cells have the capability to predict their phenotypes autonomously that is, to act on its own without external direction in response to situations it encounters. RESULTS: Computational simulations of the model were performed in order to analyze its performance. The most striking feature of our results is that each cell can select its phenotype at each time step according to its condition. We provide evidence that the prediction of cell phenotypes is reliable. CONCLUSION: Our proposed model, which we term a hybrid multiscale modeling of cancer cell behavior, has the potential to combine the best features of both continuum and discrete models. The in silico results indicate that the 3D model can represent key features of cancer growth, angiogenesis, and its related micro-environment and show that the findings are in good agreement with biological tumor behavior. To the best of our knowledge, this paper is the first hybrid vascular multiscale modeling of cancer cell behavior that has the capability to predict cell phenotypes individually by a self-generated dataset. PMID- 28846713 TI - Plasmid stability analysis based on a new theoretical model employing stochastic simulations. AB - Here, we present a simple theoretical model to study plasmid stability, based on one input parameter which is the copy number of plasmids present in a host cell. The Monte Carlo approach was used to analyze random fluctuations affecting plasmid replication and segregation leading to gradual reduction in the plasmid population within the host cell. This model was employed to investigate maintenance of pEC156 derivatives, a high-copy number ColE1-type Escherichia coli plasmid that carries an EcoVIII restriction-modification system. Plasmid stability was examined in selected Escherichia coli strains (MG1655, wild-type; MG1655 pcnB, and hyper-recombinogenic JC8679 sbcA). We have compared the experimental data concerning plasmid maintenance with the simulations and found that the theoretical stability patterns exhibited an excellent agreement with those empirically tested. In our simulations, we have investigated the influence of replication fails (alpha parameter) and uneven partition as a consequence of multimer resolution fails (delta parameter), and the post-segregation killing factor (beta parameter). All of these factors act at the same time and affect plasmid inheritance at different levels. In case of pEC156-derivatives we concluded that multimerization is a major determinant of plasmid stability. Our data indicate that even small changes in the fidelity of segregation can have serious effects on plasmid stability. Use of the proposed mathematical model can provide a valuable description of plasmid maintenance, as well as enable prediction of the probability of the plasmid loss. PMID- 28846715 TI - Needs and concerns of transgender individuals regarding interdisciplinary transgender healthcare: A non-clinical online survey. AB - This study investigates the needs and concerns transgender (short: trans) individuals have concerning trans healthcare (THC) in interdisciplinary THC centres. Trans individuals' gender does not (fully/constantly) match their sex assigned at birth. To be able to live in their gender role and to prevent or minimise gender dysphoria, they might require a multidisciplinary set of transition related healthcare services. The current shift from the traditionally highly regulated, hierarchical and pathologising approach to THC towards a more patient-centred approach has highlighted the importance of trans patients' satisfaction with treatment processes and results. As the still influential regulations have a negative effect on patient satisfaction, and might also keep trans individuals from seeking transition related treatment, it is crucial to investigate what trans individuals, whether patients or not, need and fear regarding transition related healthcare. Against the backdrop of mixed reactions received from the local trans community regarding the foundation of the Interdisciplinary Transgender Healthcare Centre Hamburg (ITHCCH), Germany, this study seeks to determine what trans individuals need with respect to THC in order to guarantee for high quality service provision at the ITHCCH. To this end, an online questionnaire was developed. The researchers employed a participatory approach to questionnaire development by involving a working group consisting of local trans support group representatives and (THC) specialists (N = 4). The sample consisted of N = 415 trans-identified individuals aged between 16 and 76. Most of them were based in Germany. 85.2% (n = 382) reported experience with transition related healthcare and 72.5% (n = 301) had (additional) treatments planned. Analysis revealed a need for communication and feedback opportunities. Furthermore, during the treatment process, addressing individual needs was considered crucial by participants. They agreed moderately with concerns towards THC centres. 96.5% of participants would like high decision-making power concerning treatment-associated decisions. The results demonstrate the importance of patient-centred THC that takes patients' individual needs and realities into consideration and involves patients in decision-making processes. PMID- 28846714 TI - Genome sequencing and comparative genomics reveal a repertoire of putative pathogenicity genes in chilli anthracnose fungus Colletotrichum truncatum. AB - Colletotrichum truncatum, a major fungal phytopathogen, causes the anthracnose disease on an economically important spice crop chilli (Capsicum annuum), resulting in huge economic losses in tropical and sub-tropical countries. It follows a subcuticular intramural infection strategy on chilli with a short, asymptomatic, endophytic phase, which contrasts with the intracellular hemibiotrophic lifestyle adopted by most of the Colletotrichum species. However, little is known about the molecular determinants and the mechanism of pathogenicity in this fungus. A high quality whole genome sequence and gene annotation based on transcriptome data of an Indian isolate of C. truncatum from chilli has been obtained. Analysis of the genome sequence revealed a rich repertoire of pathogenicity genes in C. truncatum encoding secreted proteins, effectors, plant cell wall degrading enzymes, secondary metabolism associated proteins, with potential roles in the host-specific infection strategy, placing it next only to the Fusarium species. The size of genome assembly, number of predicted genes and some of the functional categories were similar to other sequenced Colletotrichum species. The comparative genomic analyses with other species and related fungi identified some unique genes and certain highly expanded gene families of CAZymes, proteases and secondary metabolism associated genes in the genome of C. truncatum. The draft genome assembly and functional annotation of potential pathogenicity genes of C. truncatum provide an important genomic resource for understanding the biology and lifestyle of this important phytopathogen and will pave the way for designing efficient disease control regimens. PMID- 28846717 TI - Robust Adaptive Lasso method for parameter's estimation and variable selection in high-dimensional sparse models. AB - High dimensional data are commonly encountered in various scientific fields and pose great challenges to modern statistical analysis. To address this issue different penalized regression procedures have been introduced in the litrature, but these methods cannot cope with the problem of outliers and leverage points in the heavy tailed high dimensional data. For this purppose, a new Robust Adaptive Lasso (RAL) method is proposed which is based on pearson residuals weighting scheme. The weight function determines the compatibility of each observations and downweight it if they are inconsistent with the assumed model. It is observed that RAL estimator can correctly select the covariates with non-zero coefficients and can estimate parameters, simultaneously, not only in the presence of influential observations, but also in the presence of high multicolliearity. We also discuss the model selection oracle property and the asymptotic normality of the RAL. Simulations findings and real data examples also demonstrate the better performance of the proposed penalized regression approach. PMID- 28846716 TI - Association between local inflammation and breast tissue age-related lobular involution among premenopausal and postmenopausal breast cancer patients. AB - Increased levels of pro-inflammatory markers and decreased levels of anti inflammatory markers in the breast tissue can result in local inflammation. We aimed to investigate whether local inflammation in the breast tissue is associated with age-related lobular involution, a process inversely related to breast cancer risk. Levels of eleven pro- and anti-inflammatory markers were assessed by immunohistochemistry in normal breast tissue obtained from 164 pre- and postmenopausal breast cancer patients. Involution status of the breast (degree of lobular involution and the predominant lobule type) was microscopically assessed in normal breast tissue on hematoxylin-eosin stained mastectomy slides. Multivariate generalized linear models were used to assess the associations. In age-adjusted analyses, higher levels of pro-inflammatory markers IL-6, TNF-alpha, CRP, COX-2, leptin, SAA1 and IL-8; and anti-inflammatory marker IL-10, were inversely associated with the prevalence of complete lobular involution (all P<=0.04). Higher levels of the pro-inflammatory marker COX-2 were also associated with lower prevalence of predominant type 1/no type 3 lobules in the breast, an indicator of complete involution, in age-adjusted analysis (P = 0.017). Higher tissue levels of inflammatory markers, mainly the pro-inflammatory ones, are associated with less involuted breasts and may consequently be associated with an increased risk of developing breast cancer. PMID- 28846718 TI - Intensity-modulated radiotherapy reduces gastrointestinal toxicity in pelvic radiation therapy with moderate dose. AB - This retrospective study was performed to evaluate and compare gastrointestinal (GI) toxicities caused by conventional radiotherapy (cRT) and intensity modulated radiotherapy (IMRT) in 136 cancer patients treated with pelvic radiotherapy (RT) with moderate radiation dose in a single institution. A matched-pair analysis of the two groups was performed; each group included 68 patients. Conventional RT was delivered using the four-field box technique and IMRT was delivered with helical tomotherapy. The median daily dose was 1.8 Gy and the median total dose was 50.4 Gy (range 25.2-56 Gy). Primary end point was GI toxicity during and after RT. Secondary end point was factors that affect toxicity. Patients treated with IMRT had lower incidence of grade >= 2 acute GI toxicity compared to the patients treated with cRT (p = 0.003). The difference remained significant in multivariate analysis (p = 0.01). The incidence of chronic GI toxicity was not statistically different between the two groups, but the cRT group had higher incidence of grade 3 chronic GI toxicity. Based on our results, IMRT can reduce GI toxicity compared to cRT in the treatment of pelvic radiotherapy even with moderate radiation dose and this will enhance patients' quality of life and treatment compliance. PMID- 28846719 TI - Aging effects on airflow dynamics and lung function in human bronchioles. AB - BACKGROUND AND OBJECTIVE: The mortality rate for patients requiring mechanical ventilation is about 35% and this rate increases to about 53% for the elderly. In general, with increasing age, the dynamic lung function and respiratory mechanics are compromised, and several experiments are being conducted to estimate these changes and understand the underlying mechanisms to better treat elderly patients. MATERIALS AND METHODS: Human tracheobronchial (G1 ~ G9), bronchioles (G10 ~ G22) and alveolar sacs (G23) geometric models were developed based on reported anatomical dimensions for a 50 and an 80-year-old subject. The aged model was developed by altering the geometry and material properties of the model developed for the 50-year-old. Computational simulations using coupled fluid solid analysis were performed for geometric models of bronchioles and alveolar sacs under mechanical ventilation to estimate the airflow and lung function characteristics. FINDINGS: The airway mechanical characteristics decreased with aging, specifically a 38% pressure drop was observed for the 80-year-old as compared to the 50-year-old. The shear stress on airway walls increased with aging and the highest shear stress was observed in the 80-year-old during inhalation. A 50% increase in peak strain was observed for the 80-year-old as compared to the 50-year-old during exhalation. The simulation results indicate that there is a 41% increase in lung compliance and a 35%-50% change in airway mechanical characteristics for the 80-year-old in comparison to the 50-year-old. Overall, the airway mechanical characteristics as well as lung function are compromised due to aging. CONCLUSION: Our study demonstrates and quantifies the effects of aging on the airflow dynamics and lung capacity. These changes in the aging lung are important considerations for mechanical ventilation parameters in elderly patients. Realistic geometry and material properties need to be included in the computational models in future studies. PMID- 28846720 TI - The association of long-term glycaemic variability versus sustained chronic hyperglycaemia with heart rate-corrected QT interval in patients with type 2 diabetes. AB - OBJECTIVES: Prolonged heart rate-corrected QT(QTc) interval is related to ventricular arrhythmia and cardiovascular mortality, with considerably high prevalence of type 2 diabetes. Additionally, long-term glycaemic variability could be a significant risk factor for diabetic complications in addition to chronic hyperglycaemia. We compared the associations of long-term glycaemic variability versus sustained chronic hyperglycaemia with the QTc interval among type 2 diabetes patients. METHODS: In this cross-sectional study, 2904 type 2 diabetes patients were recruited who had undergone at least four fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPG) measurements (at least once for every 3 months, respectively) during the preceding year. Long-term glycaemic variabilities of FPG and 2-hour PPG were assessed by their standard deviations (SD-FPG and SD-PPG, respectively), and chronic fasting and postprandial hyperglycaemia were assessed by their means (M-FPG and M-PPG, respectively). HbA1c was also determined upon enrolment to assess current overall glycaemic control. QTc interval was estimated from resting 12-lead electrocardiograms, and more than 440 ms was considered abnormally prolonged. RESULTS: Patients with prolonged QTc interval (>=440 ms) had greater M-FPG, M PPG, SD-PPG and HbA1c than those with normal QTc interval but comparable SD-FPG. QTc interval was correlated with M-FPG, M-PPG, SD-PPG and HbA1c (r = 0.133, 0.153, 0.245 and 0.207, respectively, p = 0.000) but not with SD-FPG (r = 0.024, p = 0.189). After adjusting for metabolic risk factors via multiple linear regression analysis, SD-PPG, M-PPG and HbA1c (t = 12.16, 2.69 and 10.16, respectively, p = 0.000) were the major independent contributors to the increased QTc interval. The proportion of prolonged QTc interval increased significantly from 10.9% to 14.2% to 26.6% for the first (T1) to second (T2) to third (T3) tertiles of SD-PPG. After adjusting via multiple logistic regression analysis, the odd ratios of prolonged QTc interval of the T2 and T3 versus the T1 of SD-PPG were 1.15 (95% CI, 0.82-1.60) and 2.62 (1.92-3.57), respectively. CONCLUSIONS: Increased long-term variability of PPG is a strong independent risk factor for prolonged QTc interval in type 2 diabetes patients, in addition to long-term postprandial hyperglycaemia and current HbA1c. PMID- 28846721 TI - Heritable heading time variation in wheat lines with the same number of Ppd-B1 gene copies. AB - The ability of plants to identify an optimal flowering time is critical for ensuring the production of viable seeds. The main environmental factors that influence the flowering time include the ambient temperature and day length. In wheat, the ability to assess the day length is controlled by photoperiod (Ppd) genes. Due to its allohexaploid nature, bread wheat carries the following three Ppd-1 genes: Ppd-A1, Ppd-B1 and Ppd-D1. While photoperiod (in)sensitivity controlled by Ppd-A1 and Ppd-D1 is mainly determined by sequence changes in the promoter region, the impact of the Ppd-B1 alleles on the heading time has been linked to changes in the copy numbers (and possibly their methylation status) and sequence changes in the promoter region. Here, we report that plants with the same number of Ppd-B1 copies may have different heading times. Differences were observed among F7 lines derived from crossing two spring hexaploid wheat varieties. Several lines carrying three copies of Ppd-B1 headed 16 days later than other plants in the population with the same number of gene copies. This effect was associated with changes in the gene expression level and methylation of the Ppd-B1 gene. PMID- 28846722 TI - Proteome dynamics and physiological responses to short-term salt stress in Leymus chinensis leaves. AB - Salt stress is becoming an increasing threat to global agriculture. In this study, physiological and proteomics analysis were performed using a salt-tolerant grass species, Leymus chinensis (L. chinensis). The aim of this study is to understand the potential mechanism of salt tolerance in L. chinensis that used for crop molecular breeding. A series of short-term (<48 h) NaCl treatments (0 ~ 700 mM) were conducted. Physiological data indicated that the root and leaves growth were inhibited, chlorophyll contents decreased, while hydraulic conductivity, proline, sugar and sucrose were accumulated under salt stress. For proteomic analysis, we obtained 274 differentially expressed proteins in response to NaCl treatments. GO analysis revealed that 44 out of 274 proteins are involved in the biosynthesis of amino acids and carbon metabolism. Our findings suggested that L. chinensis copes with salt stress by stimulating the activities of POD, SOD and CAT enzymes, speeding up the reactions of later steps of citrate cycle, and synthesis of proline and sugar. In agreement with our physiological data, proteomic analysis also showed that salt stress depress the expression of photosystem relevant proteins, Calvin cycle, and chloroplast biosynthesis. PMID- 28846723 TI - Habitat quality affects the incidence of morphological abnormalities in the endangered salamander Ambystoma ordinarium. AB - Identification of early warning signals previous to the occurrence of population decline or extinction is a major challenge for the conservation of animal species. Prevalence of morphological abnormalities in a population can be one of these signals. We registered morphological abnormalities in the salamander Ambystoma ordinarium. We also evaluated the relation between habitat quality and the prevalence of abnormalities in this species. We used scores from rapid bioassessment protocols (RBPs) to assess the habitat quality of streams inhabited by A. ordinarium. A preliminary survey indicated that of 29 streams where this species has been historically registered, 13 might have few or no A. ordinarium. The association between habitat quality and the incidence of morphological abnormalities was evaluated in these 16 streams. Of 502 sampled individuals, 224 (44.62%) had at least one body abnormality. Of the 224 individuals with body abnormalities, 84 (37.5%) presented more than one abnormality. Of a total of 5,522 evaluated morphological characters, 344 (6.74%) were abnormal. Partial loss of gills and missing digits were the most frequent abnormalities. Results of a binomial logistic regression indicated that the probability of a character of an individual to be abnormal was significantly associated with habitat quality; as the levels of the quality of the habitat increased, the prevalence of morphological abnormalities decreased. These results suggest that RBPs are a quick and useful method for assessing the habitat quality of streams inhabited by A. ordinarium. Given that RBPs provide rapid and cost-effective assessments of the ecological health of aquatic ecosystems, it will be important to test if the RBPs protocols can be used to rapidly assess habitat quality for other species of stream amphibians. The negative association between habitat quality and the prevalence of morpohological abnormalities that we found indicates that habitat condition plays an important role in the high number of abnormalities registered in A. ordinarium. Therefore, our results suggest that one of the several negative effects of habitat degradation on amphibians is an increase in the frequency of morphological abnormalities with marked consequences for the survival and general fitness of aquatic amphibians. PMID- 28846725 TI - Elevated plasma homocysteine upon ischemic stroke is associated with increased long-term mortality in women. AB - BACKGROUND: Ischemic stroke is a leading cause of death worldwide, despite preventive and therapeutic advances during the last twenty years. Blood-borne biomarkers have been studied in association to short- and long-term outcome, in order to investigate possible modifiable predictors of disability and death. Increased homocysteine has been associated with increased vascular risk and unfavorable outcome, but homocysteine lowering treatment has not consistently been successful in risk reduction. The aim of this study was to investigate homocysteine levels upon acute ischemic stroke in association to long-term mortality. METHODS: Of 622 patients included in our hospital-based registry, 331 survived the first month after admission, and had a diagnosis of ischemic stroke and available homocysteine values. All-cause and vascular mortality were investigated based on the national patient- and cause of death-registries. Survival analysis and Cox proportional hazard models were used to investigate time to death and predictors of outcome. RESULTS: Of 331 patients, 148 (45%) had low homocysteine (<13 micromol/L) and 183 (55%) had high homocysteine (> = 13 micromol/L). During 10 years of follow-up (median 5.5 years), 47 patients (32%) with low homocysteine and 94 (51%) with high homocysteine died (p<0.0001). Estimated median survival was not reached for the low homocysteine group, and was 80 months in the high homocysteine group (p with log-rank test 0.002). High homocysteine was not independently associated with increased risk for death after adjustment for age, sex, comorbidities, and eGFR (HR 1.29, 95% CI 0.86-1.93; p = 0.2). Subgroup analysis by sex showed that high homocysteine was an independent predictor of mortality in women after adjustment for age and vascular comorbidities (HR 1.85; 95% CI 1.03-3.31; p = 0.04), but not in men (HR 0.87; 95% CI 0.52-1.43; p = 0.6). CONCLUSION: Increased plasma homocysteine (> = 13 micromol/L) upon acute ischemic stroke was not independently associated with mortality in our study. In the subgroup of women, high homocysteine was associated with increased five-year risk of death. Our study's retrospective design and the exploratory nature of subgroup analysis, prevent robust conclusions based on that observation. Future studies on homocysteine levels before as well as upon stroke will shed further light on a possible causal association. PMID- 28846724 TI - Constraint-induced aphasia therapy in post-stroke aphasia rehabilitation: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Constraint-induced aphasia therapy (CIAT) has been widely used in post-stroke aphasia rehabilitation. An increasing number of clinical controlled trials have investigated the efficacy of the CIAT for the post-stroke aphasia. PURPOSE: To systematically review the randomized controlled trials (RCTs) concerning the effect of the CIAT in post-stroke patients with aphasia, and to identify the useful components of CIAT in post-stroke aphasia rehabilitation. METHODS: A computerized database search was performed through five databases (Pubmed, EMbase, Medline, ScienceDirect and Cochrane library). Cochrane handbook domains were used to evaluate the methodological quality of the included RCTs. RESULTS: Eight RCTs qualified in the inclusion criteria. Inconsistent results were found in comparing the CIAT with conventional therapies without any component from the CIAT based on the results of three RCTs. Five RCTs showed that the CIAT performed equally well as other intensive aphasia therapies, in terms of improving language performance. One RCT showed that therapies embedded with social interaction were likely to enhance the efficacy of the CIAT. CONCLUSION: CIAT may be useful for improving chronic post-stroke aphasia, however, limited evidence to support its superiority to other aphasia therapies. Massed practice is likely to be a useful component of CIAT, while the role of "constraint" is needed to be further explored. CIAT embedded with social interaction may gain more benefits. PMID- 28846726 TI - Statistical physics of balance theory. AB - Triadic relationships are accepted to play a key role in the dynamics of social and political networks. Building on insights gleaned from balance theory in social network studies and from Boltzmann-Gibbs statistical physics, we propose a model to quantitatively capture the dynamics of the four types of triadic relationships in a network. Central to our model are the triads' incidence rates and the idea that those can be modeled by assigning a specific triadic energy to each type of triadic relation. We emphasize the role of the degeneracy of the different triads and how it impacts the degree of frustration in the political network. In order to account for a persistent form of disorder in the formation of the triadic relationships, we introduce the systemic variable temperature. In order to learn about the dynamics and motives, we propose a generic Hamiltonian with three terms to model the triadic energies. One term is connected with a three-body interaction that captures balance theory. The other terms take into account the impact of heterogeneity and of negative edges in the triads. The validity of our model is tested on four datasets including the time series of triadic relationships for the standings between two classes of alliances in a massively multiplayer online game (MMOG). We also analyze real-world data for the relationships between the "agents" involved in the Syrian civil war, and in the relations between countries during the Cold War era. We find emerging properties in the triadic relationships in a political network, for example reflecting itself in a persistent hierarchy between the four triadic energies, and in the consistency of the extracted parameters from comparing the model Hamiltonian to the data. PMID- 28846727 TI - Latching dynamics in neural networks with synaptic depression. AB - Prediction is the ability of the brain to quickly activate a target concept in response to a related stimulus (prime). Experiments point to the existence of an overlap between the populations of the neurons coding for different stimuli, and other experiments show that prime-target relations arise in the process of long term memory formation. The classical modelling paradigm is that long term memories correspond to stable steady states of a Hopfield network with Hebbian connectivity. Experiments show that short term synaptic depression plays an important role in the processing of memories. This leads naturally to a computational model of priming, called latching dynamics; a stable state (prime) can become unstable and the system may converge to another transiently stable steady state (target). Hopfield network models of latching dynamics have been studied by means of numerical simulation, however the conditions for the existence of this dynamics have not been elucidated. In this work we use a combination of analytic and numerical approaches to confirm that latching dynamics can exist in the context of a symmetric Hebbian learning rule, however lacks robustness and imposes a number of biologically unrealistic restrictions on the model. In particular our work shows that the symmetry of the Hebbian rule is not an obstruction to the existence of latching dynamics, however fine tuning of the parameters of the model is needed. PMID- 28846728 TI - Carbon nanotubes exhibit fibrillar pharmacology in primates. AB - Nanomedicine rests at the nexus of medicine, bioengineering, and biology with great potential for improving health through innovation and development of new drugs and devices. Carbon nanotubes are an example of a fibrillar nanomaterial poised to translate into medical practice. The leading candidate material in this class is ammonium-functionalized carbon nanotubes (fCNT) that exhibits unexpected pharmacological behavior in vivo with important biotechnology applications. Here, we provide a multi-organ evaluation of the distribution, uptake and processing of fCNT in nonhuman primates using quantitative whole body positron emission tomography (PET), compartmental modeling of pharmacokinetic data, serum biomarkers and ex vivo pathology investigation. Kidney and liver are the two major organ systems that accumulate and excrete [86Y]fCNT in nonhuman primates and accumulation is cell specific as described by compartmental modeling analyses of the quantitative PET data. A serial two-compartment model explains renal processing of tracer-labeled fCNT; hepatic data fits a parallel two-compartment model. These modeling data also reveal significant elimination of the injected activity (>99.8%) from the primate within 3 days (t1/2 = 11.9 hours). These favorable results in nonhuman primates provide important insight to the fate of fCNT in vivo and pave the way to further engineering design considerations for sophisticated nanomedicines to aid late stage development and clinical use in man. PMID- 28846729 TI - Histones bundle F-actin filaments and affect actin structure. AB - Histones are small polycationic proteins complexed with DNA located in the cell nucleus. Upon apoptosis they are secreted from the cells and react with extracellular polyanionic compounds. Actin which is a polyanionic protein, is also secreted from necrotic cells and interacts with histones. We showed that both histone mixture (histone type III) and the recombinant H2A histone bundles F actin, increases the viscosity of the F-actin containing solution and polymerizes G-actin. The histone-actin bundles are relatively insensitive to increase of ionic strength, unlike other polycation, histatin, lysozyme, spermine and LL-37 induced F-actin bundles. The histone-actin bundles dissociate completely only in the presence of 300-400 mM NaCl. DNA, which competes with F-actin for histones, disassembles histone induced actin bundles. DNase1, which depolymerizes F- to G actin, actively unbundles the H2A histone induced but slightly affects the histone mixture induced actin bundles. Cofilin decreases the amount of F-actin sedimented by low speed centrifugation, increases light scattering and viscosity of F-actin-histone mixture containing solutions and forms star like superstructures by copolymerizing G-actin with H2A histone. The results indicate that histones are tightly attached to F-actin by strong electrostatic and hydrophobic forces. Since both histones and F-actin are present in the sputum of patients with cystic fibrosis, therefore, the formation of the stable histone actin bundles can contribute to the pathology of this disease by increasing the viscosity of the sputum. The actin-histone interaction in the nucleus might affect gene expression. PMID- 28846731 TI - Involvement of Arabidopsis thaliana endoplasmic reticulum KDEL-tailed cysteine endopeptidase 1 (AtCEP1) in powdery mildew-induced and AtCPR5-controlled cell death. AB - Programmed cell death (PCD) is a prerequisite for successful development and it limits the spread of biotrophic pathogens in a rapid hypersensitive response at the site of infection. KDEL-tailed cysteine endopeptidases (KDEL CysEP) are a subgroup of papain-type cysteine endopeptidases expressed in tissues undergoing PCD. In Arabidopsis, three KDEL CysEPs (AtCEP1, AtCEP2, and AtCEP3) are expressed. We have previously shown that AtCEP1 is a factor of basal resistance to powdery mildew caused by the biotrophic ascomycete Erysiphe cruciferarum, and is expressed in spatiotemporal association with the late fungal development on Arabidopsis leaves. The endoplasmic reticulum-localized proenzyme of AtCEP1 was further visualized at the haustorial complex encased with callose. The AtCPR5 gene (CONSTITUTIVE EXPRESSION OF PR GENES 5) is a regulator of expression of pathogenesis related genes. Loss of AtCPR5 leads to spontaneous expression of chlorotic lesions which was associated with enhanced expression of AtCEP1. We used the atcpr5-2 mutant plants and the atcep1 atcpr5-2 double mutants harboring a non-functional reporter (PCEP1::pre-pro-3xHA-EGFP-KDEL) for visualization of AtCEP1 promoter activity. We found the specific up-regulation of AtCEP1 in direct neighborhood of spreading leaf lesions thus likely representing cells undergoing PCD. Furthermore, we found a strong resistance of atcpr5 mutant plants against infection with E. cruciferarum. Loss of AtCEP1 had no obvious influence on the strong resistance of atcpr5-2 mutant plants against infection with E. cruciferarum. However, the area of necrotic leaf lesions associated with E. cruciferarum colonies was significantly larger in atcpr5-2 as compared to atcep1 atcpr5-2 double mutant plants. The presence of AtCEP1 thus contributes to AtCPR5 controlled PCD at the sites of powdery mildew infection. PMID- 28846730 TI - Role of amygdala kisspeptin in pubertal timing in female rats. AB - To investigate the mechanism by which maternal obesity disrupts reproductive function in offspring, we examined Kiss1 expression in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV) nuclei, and posterodorsal medial amygdala (MePD) of pre-pubertal and young adult offspring. Sprague-Dawley rats were fed either a standard or energy-dense diet for six weeks prior to mating and throughout pregnancy and lactation. Male and female offspring were weaned onto normal diet on postnatal day (pnd) 21. Brains were collected on pnd 30 or 100 for qRT-PCR to determine Kiss1 mRNA levels. Maternal obesity increased Kiss1 mRNA expression in the MePD of pre-pubertal male and female offspring, whereas Kiss1 expression was not affected in the ARC or AVPV at this age. Maternal obesity reduced Kiss1 expression in all three brain regions of 3 month old female offspring, but only in MePD of males. The role of MePD kisspeptin on puberty, estrous cyclicity and preovulatory LH surges was assessed directly in a separate group of post-weanling and young adult female rats exposed to a normal diet throughout their life course. Bilateral intra-MePD cannulae connected to osmotic mini-pumps for delivery of kisspeptin receptor antagonist (Peptide 234 for 14 days) were chronically implanted on pnd 21 or 100. Antagonism of MePD kisspeptin delayed puberty onset, disrupted estrous cyclicity and reduced the incidence of LH surges. These data show that the MePD plays a key role in pubertal timing and ovulation and that maternal obesity may act via amygdala kisspeptin signaling to influence reproductive function in the offspring. PMID- 28846732 TI - The effect of training methodology on knowledge representation in categorization. AB - Category representations can be broadly classified as containing within-category information or between-category information. Although such representational differences can have a profound impact on decision-making, relatively little is known about the factors contributing to the development and generalizability of different types of category representations. These issues are addressed by investigating the impact of training methodology and category structures using a traditional empirical approach as well as the novel adaptation of computational modeling techniques from the machine learning literature. Experiment 1 focused on rule-based (RB) category structures thought to promote between-category representations. Participants learned two sets of two categories during training and were subsequently tested on a novel categorization problem using the training categories. Classification training resulted in a bias toward between-category representations whereas concept training resulted in a bias toward within category representations. Experiment 2 focused on information-integration (II) category structures thought to promote within-category representations. With II structures, there was a bias toward within-category representations regardless of training methodology. Furthermore, in both experiments, computational modeling suggests that only within-category representations could support generalization during the test phase. These data suggest that within-category representations may be dominant and more robust for supporting the reconfiguration of current knowledge to support generalization. PMID- 28846734 TI - Identifying species at coextinction risk when detection is imperfect: Model evaluation and case study. AB - Losing a species from a community can cause further extinctions, a process also known as coextinction. The risk of being extirpated with an interaction partner is commonly inferred from a species' host-breadth, derived from observing interactions between species. But observational data suffers from imperfect detection, making coextinction estimates highly unreliable. To address this issue and to account for data uncertainty, we fit a hierarchical N-mixture model to individual-level interaction data from a mutualistic network. We predict (1) with how many interaction partners each species interacts (to indicate their coextinction risk) and (2) how completely the community was sampled. We fit the model to simulated interactions to investigate how variation in sampling effort, interaction probability, and animal abundances influence model accuracy and apply it to an empirical dataset of flowering plants and their insect visitors. The model performed well in predicting the number of interaction partners for scenarios with high abundances, but indicated high parameter uncertainty for networks with many rare species. Yet, model predictions were generally closer to the true value than the observations. Our mutualistic plant-insect community most closely resembled the scenario of high interaction rates with low abundances. Median estimates of interaction partners were frequently much higher than the empirical data indicate, but uncertainty was high. Our analysis suggested that we only detected 14-59% of the flower-visiting insect species, indicating that our study design, which is common for pollinator studies, was inadequate to detect many species. Imperfect detection strongly affects the inferences from observed interaction networks and hence, host specificity, specialisation estimates and network metrics from observational data may be highly misleading for assessing a species' coextinction risks. Our study shows how models can help to estimate coextinction risk, but also indicates the need for better data (i.e., intensified sampling and individual-level observations) to reduce uncertainty. PMID- 28846733 TI - Paracoccin distribution supports its role in Paracoccidioides brasiliensis growth and dimorphic transformation. AB - Paracoccidioides brasiliensis yeast was reported to express paracoccin, a GlcNAc binding protein that displays N-acetyl-beta-d-glucosaminidase (NAGase) activity. Highly specific anti-paracoccin antibodies have been previously used to examine the localization of paracoccin in yeast and inhibit its growth in vitro. In the present study, anti-paracoccin antibodies were used to characterize, by scanning confocal microscopy, the distribution of paracoccin in P. brasiliensis hyphae, transition forms from hyphae to yeast, and mature yeast. In the mycelial phase, paracoccin was detected mainly in the hyphae tips, where it demonstrated a punctate distribution, and was associated with the cell wall. During the first 48 hours after a temperature shift from 26 degrees C to 37 degrees C, paracoccin expression in the differentiating hyphae was mainly detected in the budding regions, i.e. lateral protrusions, and inside the new daughter cells. There was an increased number of chlamydoconidia that expressed a high concentration of paracoccin on their surfaces and/or in their interiors 72-96 hours after the temperature shift. After 120 hours, yeast cells were the predominant form and their cytoplasm stained extensively for paracoccin, whereas Wheat Germ Agglutinin (WGA) staining was predominant on their exterior walls. After 10 days at 37 degrees C, the interior of both mother and daughter yeast cells, as well as the budding regions, stained intensely for paracoccin. The comparison of mRNA expression in the different fungal forms showed that PCN transcripts, although detected in all evaluated morphological forms, were higher in hypha and yeast-to hypha transition forms. In conclusion, the pattern of paracoccin distribution in all P. brasiliensis morphotypes supports prevalent beliefs that it plays important roles in fungal growth and dimorphic transformation. PMID- 28846735 TI - Circulating interleukin-8 and tumor necrosis factor-alpha are associated with hot flashes in healthy postmenopausal women. AB - INTRODUCTION: Hot flashes have been postulated to be linked to systemic inflammation. This study aimed to investigate the relationship between hot flashes, pro-inflammatory factors, and leukocytes in healthy, non-obese postmenopausal women. PARTICIPANTS AND DESIGN: In this cross-sectional study, a total of 202 women aged 45-60 years were stratified into one of four groups according to their hot-flash status: never experienced hot flashes (Group N), mild hot flashes (Group m), moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, leukocytes, and fasting plasma levels of nine circulating cytokines/chemokines measured by using multiplex assays. Multiple linear regression analysis was used to evaluate the associations of hot flashes with these pro-inflammatory factors. SETTINGS: The study was performed in a hospital medical center. RESULTS: The mean values of leukocyte number were not different between these four groups. The hot flash status had a positive tendency toward increased levels of circulating IL-6 (P-trend = 0.049), IL-8 (P-trend < 0.001), TNF-alpha (P-trend = 0.008), and MIP1beta (P-trend = 0.04). Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with IL-8 (P-trend < 0.001) and TNFalpha (P-trend = 0.007) among these nine cytokines/chemokines after adjustment for age, menopausal duration, BMI and FSH. Multivariate analysis further revealed that severe hot flashes were strongly associated with a higher IL-8 (% difference, 37.19%; 95% confidence interval, 14.98,63.69; P < 0.001) and TNFalpha (51.27%; 6.64,114.57; P < 0.05). CONCLUSION: The present study provides evidence that hot flashes are associated with circulating IL-8 and TNF-alpha in healthy postmenopausal women. It suggests that hot flashes might be related to low-grade systemic inflammation. PMID- 28846736 TI - Molecular cloning and characterization of pirarucu (Arapaima gigas) follicle stimulating hormone and luteinizing hormone beta-subunit cDNAs. AB - The common gonadotrophic hormone alpha-subunit (GTHalpha) has been previously isolated by our research group from A. gigas pituitaries; in the present work the cDNA sequences encoding FSHbeta and LHbeta subunits have also been isolated from the same species of fish. The FSH beta-subunit consists of 126 amino acids with a putative 18 amino acid signal peptide and a 108 amino acid mature peptide, while the LH beta-subunit consists of 141 amino acids with a putative 24 amino acid amino acid signal peptide and a 117 amino acid mature peptide. The highest identity, based on the amino acid sequences, was found with the order of Anguilliformes (61%) for FSHbeta and of Cypriniformes (76%) for LHbeta, followed by Siluriformes, 53% for FSHbeta and 75% for LHbeta. Interestingly, the identity with the corresponding human amino acid sequences was still remarkable: 45.1% for FSHbeta and 51.4% for LHbeta. Three dimensional models of ag-FSH and ag-LH, generated by using the crystal structures of h-FSH and h-LH as the respective templates and carried out via comparative modeling and molecular dynamics simulations, suggested the presence of the so-called "seat-belt", favored by a disulfide bond formed between the 3rd and 12th cysteine in both beta-subunits. The sequences found will be used for the biotechnological synthesis of A. gigas gonadotrophic hormones (ag-FSH and ag-LH). In a first approach, to ascertain that the cloned transcripts allow the expression of the heterodimeric hormones, ag-FSH has been synthesized in human embryonic kidney 293 (HEK293) cells, preliminarily purified and characterized. PMID- 28846737 TI - Immunosuppressant prescription pattern and trend in kidney transplantation: A multicenter study in Korea. AB - BACKGROUND: The actual prescription pattern of immunosuppressive agents in kidney transplantation is unclear. METHODS: We investigated the pattern and trend of immunosuppressive treatment for kidney transplant patients in South Korea. A total of 636 patients at nine transplant centers were enrolled and followed for one year. We reviewed medical records and evaluated induction therapy, as well as the changing pattern and cause of maintenance therapy. RESULTS: Most patients (n = 621, 97.6%) received induction therapy often comprising basiliximab (n = 542, 85.2%). The triple therapy including calcineurin inhibitor, mycophenolic acid, and steroids was the major initial maintenance immunosuppression (n = 518, 81.4%), but its proportion decreased by 14% (81.4% to 67.5%) after 1 year. Almost 40% of patients changed immunosuppressive regimen during the 1-year follow-up, most often at an early period (60.2% within the first 4 months). The primary reason for the change was gastrointestinal discomfort (n = 113, 29.8%), followed by infection (112, 29.6%). The most common changing pattern was mycophenolic acid withdrawal (n = 155, 39.1%). CONCLUSION: The initial immunosuppressive regimen is prone to change within the first year of kidney transplantation. Further studies are needed to evaluate the benefits and risks in patients who changed immunosuppressants. PMID- 28846738 TI - "It doesn't seem to make sense for a company that sells cigarettes to help smokers stop using them": A case study of Philip Morris's involvement in smoking cessation. AB - BACKGROUND: In the late 1990s, American tobacco companies began offering limited cessation assistance to smokers by posting links on their company websites to government-sponsored smoking cessation resources. Philip Morris USA (PM) went further, funding youth cessation programs and creating its own online cessation program, QuitAssist. We explore why PM entered the cessation arena, and describe the variety of options considered and how PM-supported cessation programs were evaluated and promoted. METHODS: We retrieved and analyzed archival PM documents from 1998-2005. We supplemented information from the documents with scholarly articles assessing QuitAssist and archived versions of the PM and QuitAssist websites. RESULTS: PM's Youth Smoking Prevention department began funding youth cessation projects and programs soon after its creation in 1998, motivated by the same issue that drove its interest in youth smoking prevention: regulatory threats posed by public and policymaker concern about youth smoking. The department took a similar approach to youth smoking cessation as it did with prevention, rejecting curricula with "anti-industry" themes. In 2002, a "cessation exploration team" examined a variety of rationales for and approaches to company support for adult smoking cessation. Ultimately, PM chose QuitAssist, a limited and less expensive option that nonetheless provided opportunities for engagement with a variety of public health and government officials. Independent research indicates that QuitAssist is not an effective cessation tool. CONCLUSIONS: While the transformation of ambitious plans into a mundane final product is a recurring theme with PM's corporate responsibility efforts, it would be inappropriate to dismiss PM's smoking cessation endeavors as half-hearted attempts to appear responsible. Such endeavors have the potential to inflict real harm by competing with more effective programs and by helping to maintain a tobacco-favorable policy environment. If PM truly wanted to support cessation, it could drop legal and other challenges to public policies that discourage smoking. PMID- 28846739 TI - ?Sorbinicharax verraesi: An unexpected case of a benthic fish outside Acanthomorpha in the Upper Cretaceous of the Tethyan Sea. AB - ?Sorbinicharax verraesi is a marine teleostean fish from the Upper Cretaceous of Nardo (Italy). It was first attributed to the otophysan order Characiformes, which represents potential evidence for the controversial marine origin of the clade. Through a review of all the available material, we demonstrate that this species is not an otophysan since it lacks key structures that would allow for its inclusion in this group. ?Sorbinicharax has a body shape that recalls ground fishes classically assigned to Acanthomorpha. However, no unambiguous feature allows us to relate it to this clade. In fact, the presence of cellular bony tissue supports its exclusion from Eurypterygii. Since no feature permits the definitive attribution of ?Sorbinicharax to any teleost group, it remains as Teleostei incertae sedis. We infer that the morphology of ?Sorbinicharax indicates a benthic ecology. It displays: an anteriorly wide body with enlarged ribs; large pectoral fins, while anal and dorsal fins are reduced; a large head measuring 1/4 of the total body length; and a mouth opening dorsally in a high position. Such morphology was so far undescribed in Nardo. It is surprisingly displayed by a non-eurypterygian teleost fish which means by a fish which does not belong to the clades that diversify since the upper Cretaceous and include the extant families that show ground ecomorphologies. PMID- 28846740 TI - Bioactive properties of faveleira (Cnidoscolus quercifolius) seeds, oil and press cake obtained during oilseed processing. AB - To the best of our knowledge, this is the first report in the literature concerning the bioactive properties of faveleira products. This work focuses on the physicochemical evaluation of faveleira oil, as well as it investigates the bioactive properties of faveleira seeds, faveleira oil and the press cake obtained during the oilseed processing. The seeds were cold pressed and the following tests were performed: physicochemical characteristics (acidity, peroxide values, moisture and volatile matter, density and viscosity) and fatty acid profile of faveleira oil; total phenolic and flavonoid content of faveleira seed and press cake; antibacterial activity of seed, oil and press cake; and antioxidant activity (DPPH radical scavenging activity, reducing power assay, total antioxidant capacity, superoxide radical scavenging assay and oxygen radical absorbance capacity) of seed, oil and press cake. Our work demonstrated that the faveleira seed oil has low acidity (0.78 +/- 0.03% oleic acid) and peroxide value (1.13 +/- 0.12 mEq/1000g), associated with the relevant concentration of linoleic acid (53.56%). It was observed that important phenolics (398.89 +/- 6.34 mg EAG/100 g), especially flavonoids (29.81 +/- 0.71 mg RE/g) remain in the press cake, which indicates that the by-product of the faveleira oilseed production constitutes a rich residual source of bioactive compounds. No bacterial growth inhibition was detected, but all samples including faveleira seeds, press cake, oil and its fractions have potent antioxidant activities, mainly the press cake, with oxygen radical absorbance capacity of 28.39 +/- 4.36 MUM TE/g. Our results also show that faveleira oil has potential to be used as edible oil and the press cake should be used to contain the most antioxidants from seed. PMID- 28846742 TI - Body mass index and self-rated health in East Asian countries: Comparison among South Korea, China, Japan, and Taiwan. AB - There have been conflicting findings regarding the relationship between body mass index (BMI) and self-rated health (SRH) worldwide. The purpose of this study was to examine the association between BMI and SRH by comparing its relationship in four East Asian countries: South Korea, China, Japan, and Taiwan. Using data from the East Asian Social Survey, the relationship between weight status and SRH status was investigated and compared between four countries, China, Japan, South Korea, and Taiwan. An ordinal logit regression model was estimated for each country, and the results were compared. We found that the relationship between weight status and SRH status differed across the four countries. In China, people who were overweight reported better SRH scores than those of normal weight, whereas in Japan, obese and severely obese people reported poor scores. In contrast, South Koreans who were underweight, obese, or severely obese reported poor ratings of health status than those of normal weight. In Taiwan, however, no differences in respondents' weight status were found across SRH scores. There were notable differences in the relationship between BMI and SRH status in four East Asian countries. Individual countries should consider these relationships when designing and implementing obesity intervention programs. PMID- 28846741 TI - Decoding social intentions in human prehensile actions: Insights from a combined kinematics-fMRI study. AB - Consistent evidence suggests that the way we reach and grasp an object is modulated not only by object properties (e.g., size, shape, texture, fragility and weight), but also by the types of intention driving the action, among which the intention to interact with another agent (i.e., social intention). Action observation studies ascribe the neural substrate of this 'intentional' component to the putative mirror neuron (pMNS) and the mentalizing (MS) systems. How social intentions are translated into executed actions, however, has yet to be addressed. We conducted a kinematic and a functional Magnetic Resonance Imaging (fMRI) study considering a reach-to-grasp movement performed towards the same object positioned at the same location but with different intentions: passing it to another person (social condition) or putting it on a concave base (individual condition). Kinematics showed that individual and social intentions are characterized by different profiles, with a slower movement at the level of both the reaching (i.e., arm movement) and the grasping (i.e., hand aperture) components. fMRI results showed that: (i) distinct voxel pattern activity for the social and the individual condition are present within the pMNS and the MS during action execution; (ii) decoding accuracies of regions belonging to the pMNS and the MS are correlated, suggesting that these two systems could interact for the generation of appropriate motor commands. Results are discussed in terms of motor simulation and inferential processes as part of a hierarchical generative model for action intention understanding and generation of appropriate motor commands. PMID- 28846743 TI - Evaluation of two 4th generation point-of-care assays for the detection of Human Immunodeficiency Virus infection. AB - BACKGROUND: Fourth generation assays detect simultaneously antibodies for HIV and the p24 antigen, identifying HIV infection earlier than previous generation tests. Previous studies have shown that the Alere Determine HIV-1/2 Combo has lower than anticipated performance in detecting antibodies for HIV and the p24 antigen. Furthermore, there are currently very few studies evaluating the performance of Standard Diagnostics BIOLINE HIV Ag/Ab Combo. OBJECTIVE: To evaluate the performance of the Alere Determine HIV-1/2 Combo and the Standard Diagnostics BIOLINE HIV Ag/Ab Combo in a panel of frozen serum samples. STUDY DESIGN: The testing panel included 133 previously frozen serum specimens from the UCLA Clinical Microbiology & Immunoserology laboratory. Reference testing included testing for HIV antibodies by a 3rd generation enzyme immunoassay followed by HIV RNA detection. Antibody negative and RNA positive sera were also tested by a laboratory 4th generation HIV Ab/Ag enzyme immunoassay. RESULTS: Reference testing yielded 97 positives for HIV infection and 36 negative samples. Sensitivity of the Alere test was 95% (88-98%), while the SD Bioline sensitivity was 91% (83-96%). Both assays showed 100% (90-100%) specificity. No indeterminate or invalid results were recorded. Among 13 samples with acute infection (HIV RNA positive, HIV antibody negative), 12 were found positive by the first assay and 8 by the second. The antigen component of the Alere assay detected 10 acute samples, while the SD Bioline assay detected only one. CONCLUSIONS: Both rapid assays showed very good overall performance in detecting HIV infection in frozen serum samples, but further improvements are required to improve the performance in acute infection. PMID- 28846744 TI - Individual and institutional factors associated with functional disability in nursing home residents: An observational study with multilevel analysis. AB - BACKGROUND: High prevalence of functional limitations has been previously observed in nursing homes. Disability may depend not only on the characteristics of the residents but also on the facility characteristics. The aims of this study were: 1, to describe the prevalence of functional disability in older people living in Spanish nursing homes; and 2, to analyze the relationships between individual and nursing home characteristics and residents' functional disability. METHODS: A cross-sectional study with data collected from 895 residents in 34 nursing homes in the province of Albacete (Spain) was conducted. Functional status was assessed by the Barthel Index. Taking into account both levels of data (individual and institutional characteristics) we resorted to a multilevel analysis in order to take different sources of variability in the data. RESULTS: The prevalence of functional disability of the total sample was 79.8%. The best fitting multilevel model showed that female gender, older age, negative self perception of health, and living in private nursing homes were factors significantly associated with functional disability. After separating individual and institutional effects, the institutions showed significant differences. CONCLUSIONS: In line with previous findings, our study found high levels of functional dependence among institutionalized elders. Gender, age, self perception of health, and institution ownership were associated with functional status. Disentangling individual and institutional effects by means of multilevel models can help evaluate the quality of the residences. PMID- 28846745 TI - Comparison of cognitive and brain grey matter volume profiles between multiple sclerosis and neuromyelitis optica spectrum disorder. AB - OBJECTIVE: Brain regions responsible for cognitive dysfunction in MS and neuromyelitis optica spectrum disorder (NMOSD) are not known. Our aim of this study was to investigate whether cognitive function and brain volume differed between MS and NMOSD in Japanese patients. METHODS: Brain MRI and neuropsychological tests including the Wechsler Adult Intelligence Scale-III (WAIS-III), Wechsler Memory Scale-Revised (WMS-R), Trail Making Test (TMT) and Clinical Assessment for Attention (CAT) were performed. Parametric grey matter (GM) and white matter (WM) volumes determined from lesion-filled T1-weighted images using whole-brain voxel-based morphometry (VBM) were compared by two tailed t test. RESULTS: Twenty relapsing-remitting MS and sixteen NMOSD patients were included. MS patients were younger than NMOSD patients. Processing speed intelligence quotient (IQ), general memory, verbal memory and delayed recall were significantly worse in MS patients than in NMOSD patients. Furthermore, left superior temporal gyrus (STG) GM volume was smaller in MS patients than in NMOSD patients (P < 0.05, family-wise error [FWE] corrected, Zmax = 4.97, 62 voxel). The left STG GM volume tended to be positively correlated with delayed recall in MS patients. CONCLUSIONS: Despite being younger, MS patients demonstrated worse performance in certain cognitive variables than NMOSD patients, which might be associated with left STG GM volume loss. PMID- 28846746 TI - CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart. AB - Cardiac progenitors are specified early in development and progressively differentiate and mature into fully functional cardiomyocytes. This process is controlled by an extensively studied transcriptional program. However, the regulatory events coordinating the progression of such program from development to maturation are largely unknown. Here, we show that the genome organizer CTCF is essential for cardiogenesis and that it mediates genomic interactions to coordinate cardiomyocyte differentiation and maturation in the developing heart. Inactivation of Ctcf in cardiac progenitor cells and their derivatives in vivo during development caused severe cardiac defects and death at embryonic day 12.5. Genome wide expression analysis in Ctcf mutant hearts revealed that genes controlling mitochondrial function and protein production, required for cardiomyocyte maturation, were upregulated. However, mitochondria from mutant cardiomyocytes do not mature properly. In contrast, multiple development regulatory genes near predicted heart enhancers, including genes in the IrxA cluster, were downregulated in Ctcf mutants, suggesting that CTCF promotes cardiomyocyte differentiation by facilitating enhancer-promoter interactions. Accordingly, loss of CTCF disrupts gene expression and chromatin interactions as shown by chromatin conformation capture followed by deep sequencing. Furthermore, CRISPR-mediated deletion of an intergenic CTCF site within the IrxA cluster alters gene expression in the developing heart. Thus, CTCF mediates local regulatory interactions to coordinate transcriptional programs controlling transitions in morphology and function during heart development. PMID- 28846747 TI - Distinctive behaviour of live biopsy-derived carcinoma cells unveiled using coherence-controlled holographic microscopy. AB - Head and neck squamous cell carcinoma is one of the most aggressive tumours and is typically diagnosed too late. Late diagnosis requires an urgent decision on an effective therapy. An individualized test of chemosensitivity should quickly indicate the suitability of chemotherapy and radiotherapy. No ex vivo chemosensitivity assessment developed thus far has become a part of general clinical practice. Therefore, we attempted to explore the new technique of coherence-controlled holographic microscopy to investigate the motility and growth of live cells from a head and neck squamous cell carcinoma biopsy. We expected to reveal behavioural patterns characteristic for malignant cells that can be used to imrove future predictive evaluation of chemotherapy. We managed to cultivate primary SACR2 carcinoma cells from head and neck squamous cell carcinoma biopsy verified through histopathology. The cells grew as a cohesive sheet of suspected carcinoma origin, and western blots showed positivity for the tumour marker p63 confirming cancerous origin. Unlike the roundish colonies of the established FaDu carcinoma cell line, the SACR2 cells formed irregularly shaped colonies, eliciting the impression of the collective invasion of carcinoma cells. Time-lapse recordings of the cohesive sheet activity revealed the rapid migration and high plasticity of these epithelial-like cells. Individual cells frequently abandoned the swiftly migrating crowd by moving aside and crawling faster. The increasing mass of fast migrating epithelial-like cells before and after mitosis confirmed the continuation of the cell cycle. In immunofluorescence, analogously shaped cells expressed the p63 tumour marker, considered proof of their origin from a carcinoma. These behavioural traits indicate the feasible identification of carcinoma cells in culture according to the proposed concept of the carcinoma cell dynamic phenotype. If further developed, this approach could later serve in a new functional online analysis of reactions of carcinoma cells to therapy. Such efforts conform to current trends in precision medicine. PMID- 28846749 TI - Toward Improving Patient Safety: Systems-Based Approaches Are Our Best Way Forward. PMID- 28846748 TI - Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype. AB - BACKGROUND: Hyperactive B cells and a continuous interferon (IFN)-alpha production by plasmacytoid dendritic cells (pDCs) play a key role in systemic lupus erythematosus (SLE). We asked whether the interaction between B cells and pDCs stimulated with RNA-containing immune complexes affects peripheral B cell subsets. METHODS: B cells and pDCs were isolated from blood of healthy individuals and stimulated with immune complexes consisting of SLE-IgG and U1snRNP (RNA-IC). Expression of cell surface molecules as well as IL-6 and IL-10 production were determined by flow cytometry and immunoassays. Gene expression profiles were determined by a NanoString nCounter expression array. RESULTS: We found a remarkable increase of double negative CD27-IgD- B cells, from 7% within fresh CD19+ B cells to 37% in the RNA-IC-stimulated co-cultures of B cells and pDCs, comparable to the frequency of double negative B cells in SLE patients. Gene expression analysis of the double negative CD27-IgD- and the CD27+IgD- memory B cells revealed that twenty-one genes were differentially expressed between the two B cell subsets (>= 2-fold, p<0.001). The, IL21R, IL4R, CCL4, CCL3, CD83 and the IKAROS Family Zinc Finger 2 (IKZ2) showed higher expression in the double negative CD27-IgD- B cells. CONCLUSION: The interactions between B cells and pDCs together with RNA-containing IC led to an expansion of B cells with similar phenotype as seen in SLE, suggesting that the pDC-B cell crosstalk contributes to the autoimmune feed-forward loop in SLE. PMID- 28846750 TI - Big Data Not Yet Big Enough to Determine the Influence of Intracranial Pressure Monitoring on Outcome in Children With Severe Traumatic Brain Injury. PMID- 28846751 TI - Multiple Intracranial Parenchymal Lesions Evolving Over a Decade. PMID- 28846752 TI - Brief Therapy for Anxiety and Depression in the Pediatric Primary Care Setting: Implications and Next Steps. PMID- 28846753 TI - Neurodevelopmental Outcome in Relation to Treatment of Patent Ductus Arteriosus Reply. PMID- 28846754 TI - Lessons From an Educational Never Event. PMID- 28846755 TI - Neurodevelopmental Outcome in Relation to Treatment of Patent Ductus Arteriosus. PMID- 28846756 TI - Prevalence of Pathogenic Copy Number Variation in Adults With Pediatric-Onset Epilepsy and Intellectual Disability. AB - Importance: Copy number variation (CNV) is an important cause of neuropsychiatric disorders. Little is known about the role of CNV in adults with epilepsy and intellectual disability. Objectives: To evaluate the prevalence of pathogenic CNVs and identify possible candidate CNVs and genes in patients with epilepsy and intellectual disability. Design, Setting, and Participants: In this cross sectional study, genome-wide microarray was used to evaluate a cohort of 143 adults with unexplained childhood-onset epilepsy and intellectual disability who were recruited from the Toronto Western Hospital epilepsy outpatient clinic from January 1, 2012, through December 31, 2014. The inclusion criteria were (1) pediatric seizure onset with ongoing seizure activity in adulthood, (2) intellectual disability of any degree, and (3) no structural brain abnormalities or metabolic conditions that could explain the seizures. Main Outcomes and Measures: DNA screening was performed using genome-wide microarray platforms. Pathogenicity of CNVs was assessed based on the American College of Medical Genetics guidelines. The Residual Variation Intolerance Score was used to evaluate genes within the identified CNVs that could play a role in each patient's phenotype. Results: Of the 2335 patients, 143 probands were investigated (mean [SD] age, 24.6 [10.8] years; 69 male and 74 female). Twenty three probands (16.1%) and 4 affected relatives (2.8%) (mean [SD] age, 24.1 [6.1] years; 11 male and 16 female) presented with pathogenic or likely pathogenic CNVs (0.08-18.9 Mb). Five of the 23 probands with positive results (21.7%) had more than 1 CNV reported. Parental testing revealed de novo CNVs in 11 (47.8%), with CNVs inherited from a parent in 4 probands (17.4%). Sixteen of 23 probands (69.6%) presented with previously cataloged human genetic disorders and/or defined CNV hot spots in epilepsy. Eight nonrecurrent rare CNVs that overlapped 1 or more genes associated with intellectual disability, autism, and/or epilepsy were identified: 2p16.1-p15 duplication, 6p25.3-p25.1 duplication, 8p23.3p23.1 deletion, 9p24.3-p23 deletion, 10q11.22-q11.23 duplication, 12p13.33-13.2 duplication, 13q34 deletion, and 16p13.2 duplication. Five genes are of particular interest given their potential pathogenicity in the corresponding phenotypes and least tolerability to variation: ABAT, KIAA2022, COL4A1, CACNA1C, and SMARCA2. ABAT duplication was associated with Lennox-Gastaut syndrome and KIAA2022 deletion with Jeavons syndrome. Conclusions and Relevance: The high prevalence of pathogenic CNVs in this study highlights the importance of microarray analysis in adults with unexplained childhood-onset epilepsy and intellectual disability. Additional studies and comparison with similar cases are required to evaluate the effects of deletions and duplications that overlap specific genes. PMID- 28846758 TI - Noninvasive Vagus Nerve Stimulation for Treatment of Indomethacin-Sensitive Headaches. PMID- 28846759 TI - Neurodevelopmental Outcome in Relation to Treatment of Patent Ductus Arteriosus. PMID- 28846760 TI - The Role of Environmental Factors in the Pathogenesis of Inflammatory Bowel Diseases: A Review. AB - Importance: Inflammatory bowel diseases (IBD), such as Crohn disease and ulcerative colitis, are chronic relapsing conditions that affect a growing number of children worldwide. The pathogenesis of these disorders is complex and thought to be mediated by the interplay between genetic susceptibility, microbial dysbiosis, and environmental factors that result in a dysregulated immune system. This dysregulation ultimately mediates intestinal inflammation and clinical symptoms typically observed in patients with IBD including abdominal pain, diarrhea, and poor growth. A dramatic increase in the incidence of IBD has been observed in the past 2 decades, mainly in developed countries but also in developing regions. This increased incidence has paralleled changes in diet, sanitation conditions, and lifestyle habits. Observations: The increased incidence of IBD can likely be attributed to more than evolving genetic diversity alone and strongly suggests that environmental factors are playing an increasingly critical role in the development of these disorders and in the modulation of IBD clinical phenotypes over time. Here, we review the data suggesting how different environmental factors may modulate the risk of developing IBD including diets, smoking, lifestyle choices, enteric infections, appendectomy, air pollution, and the use of medications, with an emphasis on antibiotics. We will also discuss how early-life events can influence the subsequent likelihood of developing one of these diseases and suggest directions that can help decrease the risk of IBD in particularly high-risk populations. Conclusions and Relevance: Dramatic lifestyle changes in the last century have substantially improved the quality of life but are also associated with increased risk of various diseases. Pediatricians should be aware of the changing epidemiology of IBD and environmental factors that modulate the risk of developing these conditions. PMID- 28846761 TI - Apolipoprotein E epsilon4 and Risk Factors for Alzheimer Disease-Let's Talk About Sex. PMID- 28846762 TI - Making All Lives Matter in Medicine From the Inside Out. PMID- 28846757 TI - Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta analysis. AB - Importance: It is unclear whether female carriers of the apolipoprotein E (APOE) epsilon4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective: To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data Sources: Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants. Study Selection: Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data Extraction and Synthesis: Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main Outcomes and Measures: Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results: Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE epsilon3/epsilon4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE epsilon3/epsilon4 had an increased risk of AD compared with men with APOE epsilon3/epsilon3. The APOE epsilon2/epsilon3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60 0.85). There was no difference between men with APOE epsilon3/epsilon4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE epsilon4/epsilon4 showed increased risks vs individuals with epsilon3/epsilon4, but no significant differences between men and women with epsilon4/epsilon4 were seen. Conclusions and Relevance: Contrary to long-standing views, men and women with the APOE epsilon3/epsilon4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages. PMID- 28846763 TI - Functional Outcome After Intracranial Pressure Monitoring for Children With Severe Traumatic Brain Injury. AB - Importance: Intracranial pressure (ICP) monitoring is a mainstay of therapy for children with traumatic brain injury (TBI), but its overall association with patient outcome is unclear. Objective: To test the hypothesis that ICP monitoring is associated with improved functional survival of children with severe TBI. Design, Setting, and Participants: A propensity-weighted effectiveness analysis was conducted using 2 linked national databases with data from 30 US children's hospitals from January 1, 2007, to December 31, 2012, on 3084 children with severe TBI. Clinical events including neurosurgical procedures were identified using validated computable phenotypes. Data analysis was conducted from September 1, 2016, to March 1, 2017. Exposure: Placement of an ICP monitor. Main Outcomes and Measures: A composite of hospital mortality, discharge to hospice, or survival with placement of new tracheostomy and gastrostomy tubes. Results: Of the 3084 children in the study (1128 girls and 1956 boys; mean [SD] age, 7.03 [5.44] years), 1002 (32.4%) underwent ICP monitoring, with substantial hospital variation (6% to 50% by hospital). Overall, 484 children (15.7%) experienced the primary composite outcome. A propensity approach using matching weights generated good covariate balance between those who did and those who did not undergo ICP monitoring. Using a propensity-weighted logistic regression model clustered by hospital, no statistically significant difference was found in functional survival between monitored and unmonitored patients (odds ratio of poor outcome among those who underwent ICP monitoring, 1.31; 95% CI, 0.99-1.74). In a prespecified secondary analysis, no difference in mortality was found (odds ratio, 1.16; 95% CI, 0.89-1.50). Prespecified subgroup analyses of children younger and older than 2 years of age and among those with unintentional and inflicted (intentional) injuries also showed no difference in outcome with ICP monitoring. Conclusions and Relevance: With the use of linked national data and validated computable phenotypes, no evidence was found of a benefit from ICP monitoring on functional survival of children with severe TBI. Intracranial pressure monitoring is a widely but inconsistently used technology with incompletely demonstrated effectiveness. A large prospective cohort study or randomized trial is needed. PMID- 28846765 TI - Building Stronger Online Communities Through the Creation of Facebook-Integrated Health Applications. PMID- 28846764 TI - Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis. AB - Importance: Growing evidence suggests an association between sleep-disordered breathing (SDB) and cognitive decline in elderly persons. However, results from population-based studies have been conflicting, possibly owing to different methods to assess SDB or cognitive domains, making it difficult to draw conclusions on this association. Objective: To provide a quantitative synthesis of population-based studies on the relationship between SDB and risk of cognitive impairment. Data Sources: PubMed, EMBASE, and PsychINFO were systematically searched to identify peer-reviewed articles published in English before January 2017 that reported on the association between SDB and cognitive function. Study Selection: We included cross-sectional and prospective studies with at least 200 participants with a mean participant age of 40 years or older. Data Extraction and Synthesis: Data were extracted independently by 2 investigators. We extracted and pooled adjusted risk ratios from prospective studies and standard mean differences from cross-sectional studies, using random-effect models. This meta analysis followed the PRISMA guidelines and also adhered to the MOOSE guidelines. Main Outcomes and Measures: Cognitive outcomes were based on standard tests or diagnosis of cognitive impairment. Sleep-disordered breathing was ascertained by apnea-hypopnea index or clinical diagnosis. Results: We included 14 studies, 6 of which were prospective, covering a total of 4 288 419 men and women. Pooled analysis of the 6 prospective studies indicated that those with SDB were 26% (risk ratio, 1.26; 95% CI, 1.05-1.50) more likely to develop cognitive impairment, with no evidence of publication bias but significant heterogeneity between studies. After removing 1 study that introduced significant heterogeneity, the pooled risk ratio was 1.35 (95% CI, 1.11-1.65). Pooled analysis of the 7 cross-sectional studies suggested that those with SDB had slightly worse executive function (standard mean difference, -0.05; 95% CI, -0.09 to 0.00), with no evidence of heterogeneity or publication bias. Sleep-disordered breathing was not associated with global cognition or memory. Conclusions and Relevance: Sleep-disordered breathing is associated with an increased risk of cognitive impairment and a small worsening in executive function. Further studies are required to determine the mechanisms linking these common conditions and whether treatment of SDB might reduce risk of cognitive impairment. PMID- 28846766 TI - The Trump Administration and the Abandonment of Teen Pregnancy Prevention Programs. PMID- 28846768 TI - Association of Frequency of Lipid Testing With Changes in Lipid-Lowering Therapy. PMID- 28846767 TI - Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS). AB - Importance: Sexual dysfunction, an important determinant of women's health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition. Objective: To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women. Design, Setting, and Participants: Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017. Interventions: Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 ug/d transdermal 17beta-estradiol (t-E2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E2) or placebo (if randomized to placebo estrogens) for 12 days each month. Main Outcomes and Measures: Aspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated. Results: The 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, -0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E2 and o-CEE groups on average across 48 months (adjusted P = .22). In the individual domains of sexual function, t-E2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF. Conclusions and Relevance: Treatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known. Trial Registration: clinicaltrials.gov Identifier: NCT00154180. PMID- 28846770 TI - Cardiac Resynchronization Therapy-Does One Size Fit All?: A Teachable Moment. PMID- 28846771 TI - Association of a PDCD1 Polymorphism With Sympathetic Ophthalmia in Han Chinese. AB - Purpose: Several studies have shown that sympathetic ophthalmia (SO) and Vogt Koyanagi-Harada (VKH) disease possess many similarities concerning their clinical manifestations. The aim of this study was to investigate whether single nucleotide polymorphisms that have been shown to be associated with VKH disease in earlier studies may also be associated with SO. Methods: There were 114 SO patients and 1230 healthy controls included in a case-control study, whereby 24 VKH-related single nucleotide polymorphisms (SNPs) were tested. Genotyping was performed using the MassARRAY platform and iPLEX Gold Assay. Results: The results showed a significantly lower frequency of the PDCD1/rs2227981 GG genotype in SO (Pc =7.85 * 10-3, OR = 0.471). However, no apparent increase in the GA and AA genotype frequency was detected. Moreover, a significant decrease in the G allele frequency of PDCD1/rs2227981 was detected in SO (Pc = 5.08 * 10-3, OR = 0.56). Conclusions: This study shows that only PDCD1/rs2227981 contributes to the genetic susceptibility of SO, and that the other 23 susceptibility loci of VKH disease are probably not involved in the pathogenesis of this disease. PMID- 28846769 TI - Collaborative Care for Opioid and Alcohol Use Disorders in Primary Care: The SUMMIT Randomized Clinical Trial. AB - Importance: Primary care offers an important and underutilized setting to deliver treatment for opioid and/or alcohol use disorders (OAUD). Collaborative care (CC) is effective but has not been tested for OAUD. Objective: To determine whether CC for OAUD improves delivery of evidence-based treatments for OAUD and increases self-reported abstinence compared with usual primary care. Design, Setting, and Participants: A randomized clinical trial of 377 primary care patients with OAUD was conducted in 2 clinics in a federally qualified health center. Participants were recruited from June 3, 2014, to January 15, 2016, and followed for 6 months. Interventions: Of the 377 participants, 187 were randomized to CC and 190 were randomized to usual care; 77 (20.4%) of the participants were female, of whom 39 (20.9%) were randomized to CC and 38 (20.0%) were randomized to UC. The mean (SD) age of all respondents at baseline was 42 (12.0) years, 41(11.7) years for the CC group, and 43 (12.2) yearsfor the UC group. Collaborative care was a system-level intervention, designed to increase the delivery of either a 6-session brief psychotherapy treatment and/or medication-assisted treatment with either sublingual buprenorphine/naloxone for opioid use disorders or long-acting injectable naltrexone for alcohol use disorders. Usual care participants were told that the clinic provided OAUD treatment and given a number for appointment scheduling and list of community referrals. Main Outcomes and Measures: The primary outcomes were use of any evidence-based treatment for OAUD and self reported abstinence from opioids or alcohol at 6 months. The secondary outcomes included the Healthcare Effectiveness Data and Information Set (HEDIS) initiation and engagement measures, abstinence from other substances, heavy drinking, health related quality of life, and consequences from OAUD. Results: At 6 months, the proportion of participants who received any OAUD treatment was higher in the CC group compared with usual care (73 [39.0%] vs 32 [16.8%]; logistic model adjusted OR, 3.97; 95% CI, 2.32-6.79; P < .001). A higher proportion of CC participants reported abstinence from opioids or alcohol at 6 months (32.8% vs 22.3%); after linear probability model adjustment for covariates (beta = 0.12; 95% CI, 0.01 0.23; P = .03). In secondary analyses, the proportion meeting the HEDIS initiation and engagement measures was also higher among CC participants (initiation, 31.6% vs 13.7%; adjusted OR, 3.54; 95% CI, 2.02-6.20; P < .001; engagement, 15.5% vs 4.2%; adjusted OR, 5.89; 95% CI, 2.43-14.32; P < .001) as was abstinence from opioids, cocaine, methamphetamines, marijuana, and any alcohol (26.3% vs 15.6%; effect estimate, beta = 0.13; 95% CI, 0.03-0.23; P = .01). Conclusions and Relevance: Among adults with OAUD in primary care, the SUMMIT collaborative care intervention resulted in significantly more access to treatment and abstinence from alcohol and drugs at 6 months, than usual care. Trial Registration: clinicaltrials.gov Identifier: NCT01810159. PMID- 28846772 TI - Conditional Muller Cell Ablation Leads to Retinal Iron Accumulation. AB - Purpose: Retinal iron accumulation is observed in a wide range of retinal degenerative diseases, including AMD. Previous work suggests that Muller glial cells may be important mediators of retinal iron transport, distribution, and regulation. A transgenic model of Muller cell loss recently demonstrated that primary Muller cell ablation leads to blood-retinal barrier leakage and photoreceptor degeneration, and it recapitulates clinical features observed in macular telangiectasia type 2 (MacTel2), a rare human disease that features Muller cell loss. We used this mouse model to determine the effect of Muller cell loss on retinal iron homeostasis. Methods: Changes in total retinal iron levels after Muller cell ablation were measured using inductively coupled plasma mass spectrometry. Corresponding changes in the expression of iron flux and iron storage proteins were determined using quantitative PCR, Western analysis, and immunohistochemistry. Results: Muller cell loss led to blood-retinal barrier breakdown and increased iron levels throughout the neurosensory retina. There were corresponding changes in mRNA and/or protein levels of ferritin, transferrin receptor, ferroportin, Zip8, and Zip14. There were also increased iron levels within the RPE of retinal sections from a patient with MacTel2 and both RPE and neurosensory retina of a patient with diabetic retinopathy, which, like MacTel2, causes retinal vascular leakage. Conclusion: This study shows that Muller cells and the blood-retinal barrier play pivotal roles in the regulation of retinal iron homeostasis. The retinal iron accumulation resulting from blood-retinal barrier dysfunction may contribute to retinal degeneration in this model and in diseases such as MacTel2 and diabetic retinopathy. PMID- 28846774 TI - Erratum. PMID- 28846775 TI - Erratum. PMID- 28846773 TI - Racioethnic Differences in Human Posterior Scleral and Optic Nerve Stump Deformation. AB - Purpose: The purpose of this study was to quantify the biomechanical response of human posterior ocular tissues from donors of various racioethnic groups to better understand how differences in these properties may play a role in the racioethnic health disparities known to exist in glaucoma. Methods: Sequential digital image correlation (S-DIC) was used to measure the pressure-induced surface deformations of 23 normal human posterior poles from three racioethnic groups: African descent (AD), European descent (ED), and Hispanic ethnicity (HIS). Regional in-plane principal strains were compared across three zones: the optic nerve stump (ONS), the peripapillary (PP) sclera, and non-PP sclera. Results: The PP scleral tensile strains were found to be lower for ED eyes compared with AD and HIS eyes at 15 mm Hg (P = 0.024 and 0.039, respectively). The mean compressive strains were significantly higher for AD eyes compared with ED eyes at 15 mm Hg (P = 0.018). We also found that the relationship between tensile strain and pressure was significant for those of ED and HIS eyes (P < 0.001 and P = 0.004, respectively), whereas it was not significant for those of AD (P = 0.392). Conclusions: Our results suggest that, assuming glaucomatous nerve loss is caused by mechanical strains in the vicinity of the optic nerve head, the mechanism of increased glaucoma prevalence may be different in those of AD versus HIS. Our ONS strain analysis also suggested that it may be important to account for ONS geometry and material properties in future scleral biomechanical analysis. PMID- 28846776 TI - Nonarteritic Anterior Ischemic Optic Neuropathy Induced Retinal Folds and Deformations. AB - Purpose: We hypothesized that the edema/swelling in the retina due to acute nonarteritic anterior ischemic optic neuropathy (NAION) can induce retinal folds (RF). We determined the pattern and frequency of folds in NAION at presentation and in follow-up, and the relationship between folds and a number of functional and structural parameters over time. Methods: We prospectively studied eyes with acute NAION by spectral-domain optic coherence tomography (SD-OCT). We used transaxial and en face views to evaluate the presence of peripapillary fluid (PPF), peripapillary wrinkles (PPW), RF, choroidal folds (CF), creases, macular edema, and vitreous traction on the optic disc. Retinal deformations were correlated with the retinal nerve fiber layer (RNFL) thickness, logMAR visual acuity (VA) and mean deviation (MD). Results: At presentation, 60 eyes had mean RNFL = 224 +/- 75 MUm, no vitreous traction, and similar VA and MD regardless of the retinal deformation or macular edema. There was PPF in 73%, PPW in 57%, RF in 38%, creases in 20%, and macular edema in 18% of eyes, and no CF. Eyes with retinal deformations had significantly greater RNFL thickness (P< 0.026). At 1 to 2 months, 49 eyes had reduction of the RNFL (112 +/- 40 MUm, P = 0.001) and unchanged VA and MD that did not correlate with fewer eyes having PPF (15%, P = 0.001), PPW (10%, P = 0.001), RF (10%, P = 0.001), creases (17%), and macular edema (0%, P = 0.007). Conclusions: RF in NAION reflect stresses and strains due to extracellular fluid without increased pressure in the retrolaminar tissue and subarachnoid space, seen with papilledema. In NAION, the deformations and their resolution do not correlate with vision loss. PMID- 28846777 TI - Efficacy of a Fixed Combination of Tetracycline, Chloramphenicol, and Colistimethate Sodium for Treatment of Candida albicans Keratitis. AB - Purpose: To evaluate the antifungal activity of a fixed antibiotic combination (AC) containing tetracycline (TET), chloramphenicol (CAF), and colistimethate sodium (CS). Methods: In vitro: Candida ATCC and clinical strains were used. The minimum inhibitory concentrations (MICs) of AC and of each antibiotic were determined. Fluconazole (FLC) was tested for comparison. Time-killing curves of selected strains were performed. Ex vivo keratitis: corneas were injected intrastromally with the selected strains. After the injection, corneas were divided into groups of treatments: AC, FLC, or saline. Then, the tissues were analyzed for colony-forming units per gram (CFU/g). Propidium iodide (PI) and MitoTracker (MTR) staining were used to investigate the mode of action. Results: Values of MIC required to inhibit the growth of 90% of organisms for the antibiotics alone were higher than FLC. However, their activity was enhanced when used in combination against Candida yeasts. Time-killing curves showed that at 24 hours, AC reduced the load of both strains of approximately 1 Log10 CFU/g compared with the initial inoculum (P < 0.0001). This effect was also significant versus FLC. In ex vivo, AC was effective in decreasing the loads of both strains by 4 Log10 CFU/g with respect to the control. Moreover, it showed higher activity than FLC against Candida albicans ATCC 10231 (1 Log10 CFU/g, P < 0.01 versus control). PI staining demonstrated that CS changed the membrane's permeability, whereas MTR staining demonstrated that TET or CAF altered mitochondrial function. The cells treated with AC and stained showed both effects. Conclusions: In this study, AC showed antifungal efficacy versus Candida spp.; this activity can be due to the synergistic effects of antibiotics in it. PMID- 28846778 TI - Variations and Trends in Health Burden of Visual Impairment Due to Cataract: A Global Analysis. AB - Purpose: To evaluate the global trends in health burden of people visually impaired from cataract in terms of disability-adjusted life years (DALY) and its correlations with national levels of socioeconomic development. Methods: Global, regional, and national DALY numbers, crude rate, and age-standardized rate of cataract vision loss by age and sex were obtained from the database of the Global Burden of Disease Study 2015. The human development index, per capita gross domestic product, and other country-level data were derived from international open databases. Regression analysis was used to assess the correlations between age-standardized DALY rate and socioeconomic variables. Results: The global DALY numbers of cataract vision loss increased by 89.42%, from 2048.18 (95%CI [confidence interval]: 1457.60-2761.80) thousands in 1990 to 3879.74 (95% CI: 2766.07-5232.43) thousands in 2015 (P < 0.001). Females had higher DALY number 315.83 (95%CI: 237.17-394.4) and crude rate 38.29 (95%CI: 35.35-41.23) after adjusting for age and country (all P < 0.001). The age-standardized DALY rate was higher in countries with low human development index (HDI), with 91.03 (95%CI: 73.04-108.75) for low HDI, 81.67 (95%CI: 53.24-108.82) for medium HDI, 55.89 (95%CI: 36.87-69.63) for high HDI, and 17.10 (95%CI: 13.91-26.84) for very high HDI countries (P < 0.01), respectively. The national age-standardized DALY rates in 2015 were negatively associated with both HDI (R2 = 0.489, P < 0.001) and per capita gross domestic product (R2 = 0.331, P < 0.001). Stepwise multiple regression showed that HDI was significantly correlated with national age standardized DALY rates in 2015 after adjusting for other confounding factors (P < 0.001). Conclusions: The global health burden of vision loss due to cataract increased between 1990 and 2015 despite considerable efforts from the World Health Organization and VISION 2020 initiatives. PMID- 28846779 TI - Centralized Otolaryngology Research Efforts (CORE) grants [Editorial]. PMID- 28846780 TI - 25 years of powered endoscopic transnasal sphenoidotomy. PMID- 28846781 TI - Paresis podule on a paralyzed vocal fold. PMID- 28846782 TI - Nasal cavity tumefactive fibroinflammatory lesion mimicking recurrent mucoepidermoid carcinoma. PMID- 28846783 TI - An incidental thyroid nodule. PMID- 28846784 TI - Assessment of discrimination ability in ipsilateral and contralateral ears with a unilateral bone-anchored hearing system. AB - This study aimed to determine the speech discriminatory ability of the contralateral ear of users of a unilateral bone-anchored hearing system (BAHS). The Oticon Medical Ponto Pro/Ponto Pro Power device brand was used for all patients. Five BAHS users (3 men, 2 women) participated in the study. Pure-tone air-conduction thresholds at 250 to 6,000 Hz, masked and unmasked bone-conduction thresholds at 250 to 4,000 Hz, and participants' speech discrimination scores in both ears were determined. Speech discrimination tests were carried out in a silent environment with monosyllabic and trisyllabic word lists. After this, the ipsilateral ear (the BAHS side) was masked with wide-band noise using an insert earphone, and the word tests were repeated. A mild decrease was observed in monosyllabic words in ipsilateral masking; however, this was not found to be statistically significant. Conversely, a decrease was not observed in the repetition of trisyllabic words in any participants, even under high-level ipsilateral masking. These results suggested that unilateral BAHS application could prevent or reduce the neural deprivation of the contralateral ear. PMID- 28846785 TI - Cerebrospinal fluid leak during stapes surgery: Gushing leaks and oozing leaks, two different phenomena. AB - Cerebrospinal fluid (CSF) leak is an uncommon event that can occur during stapes surgery. Such leaks can be classified as gushing leaks (stapes gushers) and oozing leaks. A stapes gusher is a massive flow of CSF through the perforated footplate that fills the middle ear suddenly, while an oozing leak is a slower and less profuse flow. We conducted a retrospective, observational, multicenter study of 38 patients-23 men and 15 women, aged 23 to 71 years (mean: 47)-who had experienced a CSF leak during stapes surgery. Patients were divided into various groups according to the type of surgical procedure performed and the type of postoperative complications they experienced. Audiometric and clinical evaluations were carried out pre- and postoperatively. Correlations among surgical variations (total or partial stapedectomy, placement of a prosthesis), hearing outcomes, and the incidence of postoperative complications (postoperative CSF leak and vertigo) were studied. Our statistical analysis revealed that gushing leaks and oozing leaks result in different degrees of hearing impairment and different rates of complications. We recommend that an individual approach be used to manage these complications. PMID- 28846786 TI - Platelet-rich plasma myringoplasty: A new office procedure for the repair of small tympanic membrane perforations. AB - We conducted a prospective study to assess the effectiveness of a platelet-rich plasma hourglass graft in the repair of small tympanic membrane perforations as an office-based procedure. Our study population was made up of 25 patients-10 men and 15 women, aged 19 to 45 years (mean: 30.4 +/- 7.2)-who each underwent repair of one eardrum. After administration of topical anesthesia, a single piece of platelet-rich plasma approximately double the size of the perforation was obtained from each patient's intravenous blood sample. After the margin of the perforation was freshened, the platelet-rich plasma was placed in an hourglass configuration, with equal portions lying medial and lateral to the perforation. Successful perforation repair was achieved in 21 of the 25 ears (84%). No patient developed an infection, hearing impairment, tinnitus, vertigo, bleeding, taste disturbance, or hyperkeratosis. We conclude that office-based platelet-rich plasma myringoplasty is a safe and effective minimally invasive procedure that is suitable for repairing small tympanic membrane perforations. PMID- 28846787 TI - Comparison of clinical outcomes using a Piezosurgery device vs. a conventional osteotome for lateral osteotomy in rhinoplasty. AB - Our aim for this study was to evaluate and compare the clinical outcomes in patients who underwent lateral osteotomy with a Piezosurgery device or a conventional osteotome in open-technique rhinoplasty. This cohort trial involved 65 patients (36 women and 29 men; average age: 23.6 +/- 5.71 yr) who underwent surgery between May 2015 and January 2016. Piezosurgery was used for lateral osteotomy in 32 patients, whereas 33 patients underwent conventional external osteotomy. These 2 groups were compared for duration of surgery, perioperative bleeding, postoperative edema, ecchymosis, pain, and patient satisfaction on the first and seventh postoperative days. The Piezosurgery group revealed significantly more favorable outcomes in terms of edema, ecchymosis, and hemorrhage on the first day postoperatively (p < 0.001 for all). Similarly, edema (p = 0.005) and ecchymosis (p < 0.001) on the seventh postoperative day also were better in the Piezosurgery group. Hemorrhage was similar in both groups on the seventh postoperative day (p = 0.67). The Piezosurgery group not only experienced less pain on the first postoperative day (p < 0.001), but these patients also were more satisfied with their results on both the first and seventh postoperative days. Results of the present study imply that Piezosurgery may be a promising, safe, and effective method for lateral osteotomy, a critical step in rhinoplasty. The time interval necessary for the learning curve is counteracted by the comfort and satisfaction of both patients and surgeons. PMID- 28846788 TI - Sudden sensorineural hearing loss in human monocytic ehrlichiosis. AB - The hallmarks of symptomatic human monocytic ehrlichiosis (HME) include fever, headache, myalgia, nausea, malaise, transaminitis, and blood cell abnormalities. Previous case reports have described isolated cranial nerve palsies in infected patients but not hearing loss. We describe the onset of sudden sensorineural hearing loss in 2 patients with HME-a 31-year-old woman and an 82-year-old woman. The older patient experienced objective and subjective improvement in her hearing after treatment with an antibiotic and steroid taper; the younger patient was lost to audiologic follow-up. Additionally, we discuss the possible mechanisms of the hearing loss in these patients. PMID- 28846789 TI - Multinodular goiter: A study of malignancy risk in nondominant nodules. AB - The long-standing belief that multinodular goiters are associated with a lower risk of developing into carcinoma has been challenged by the results of some recent studies. In addition, we have noticed in our practice that a sizable proportion of cancers have been arising from nondominant nodules. We performed a retrospective study of 223 cases to determine (1) the incidence of carcinoma in multinodular goiters that required surgical management in our local, predominantly Asian population and (2) the incidence of carcinoma arising from nondominant nodules. We reviewed the records of all patients with a multinodular goiter who had undergone a thyroidectomy over a period of more than 10 years in our Department of Otolaryngology-Head and Neck Surgery. We examined the histopathology reports for (1) the presence of carcinoma, (2) whether the carcinoma was isolated/unifocal or multifocal, (3) the histologic type of cancer, and (4) whether the isolated/unifocal cancers arose from the dominant or nondominant nodule. Our study population was made up of 47 males and 176 females, aged 15 to 90 years (mean: 53). We found that the incidence of malignancy in surgically treated multinodular goiters was 14.3% (32 of 223 patients). Of the 32 malignancies, 18 (56.3%) were isolated/unifocal and 14 (43.8%) were multifocal. In the isolated/unifocal group, 9 malignancies (50.0%) arose from nondominant nodules and 8 (44.4%) from dominant nodules; in the remaining case, the nodule of origin could not be determined. Our findings corroborate those in the recent literature in that the risk of malignancy associated with multinodular goiters is comparable to that of single thyroid nodules. We recommend that physicians be equally vigilant when monitoring dominant and nondominant nodules. PMID- 28846790 TI - Can lateral nasopharyngeal radiographs be used to predict eustachian tube dysfunction? AB - The objective of our case-control study was to determine whether craniofacial features on lateral nasopharyngeal radiographs (LNPRs) can predict eustachian tube dysfunction (ETD). The study included patients seen in the otolaryngology clinic from 2005 to 2011. Patients 0 to 10 years old with pressure equalization tube (PET) placement and LNPR within 6 months were included. Measurements were compared with age-matched controls selected at random to identify craniofacial features associated with ETD. Using receiver operating curve methodology, selected measurements were used to correlate age, craniofacial features, and ETD. The study population consisted of 32 patients and 34 controls. No significant differences were found between groups on any individual measurement: cranial base angle; lengths of anterior, middle, and total skull base; mandible; hard and soft palates; sella-soft-palate tip; sella-posterior nasal spine; and nasopharyngeal and palatal airway. Further statistical analysis demonstrated that patients who required PETs were more likely to have shortened anterior cranial base and maxilla relative to mandibular length. Contrary to the findings of previous studies, no single measurement was found to identify craniofacial features that may select for children with ETD requiring PETs. However, younger patients with a smaller cranial base and/or maxilla relative to mandibular length are more likely to require PETs, implying persistent ETD. PMID- 28846791 TI - Cornelia de Lange syndrome: What every otolaryngologist should know. AB - Cornelia de Lange Syndrome (CdLS) can be expressed in multiple organ systems requiring a variety of specialists, including pediatric otolaryngology. We present the case of a 20-month-old boy with CdLS actively managed by an aerodigestive team consisting of pediatric otolaryngology, pediatric pulmonology, pediatric gastroenterology, with support staff from audiology, speech, and nutrition. His presentation included mixed hearing loss, dysphagia, microaspiration, gastroesophageal reflux, and failure to thrive. We submit this challenging case of CdLS with a review of the literature to focus specific attention on the otolaryngic manifestations of the syndrome and to discuss the benefits of a multidisciplinary approach to these unique patients. PMID- 28846792 TI - Computerized dynamic posturography for evaluating dizziness in patients with scarred orbital content. AB - Our objective was to assess the capability of computerized dynamic posturography (CDP) to evaluate dizziness in blind patients who lack corneoretinal potential. We performed a retrospective analysis of 2 young blind subjects with intraorbital scarring who complained of dizziness and underwent CDP. Tests were carried out at our center for balance disorders using the NeuroCom's EquiTest System version 4.0. CDP demonstrated vestibular dysfunction and revealed it to be severe. We conclude that CDP can serve as a potentially reliable tool for assessing dizziness in blind patients who have no corneoretinal potential. PMID- 28846793 TI - A clinicopathologic and epidemiologic study of chronic white lesions in the oral mucosa. AB - Invasive oral squamous cell carcinoma is often preceded by the presence of clinically identifiable premalignant changes of the oral mucosa, including white lesions. We conducted a cross-sectional, observational study to assess the clinicopathologic and epidemiologic aspects of chronic oral mucosal white lesions to determine the necessity of early biopsy in these cases. Our study population was made up of 77 patients-50 males and 27 females, aged 15 to 70 years (mean: 42.9)-who presented with white lesions persisting for at least 4 weeks. All but 3 patients underwent a biopsy; the 3 exceptions were diagnosed with smear-proven candidiasis. Patients with moderate or severe dysplasia underwent an excision biopsy. The buccal mucosa was the single most common site of white lesions, occurring in 15 patients (19.5%), although 21 patients (27.3%) exhibited a diffuse involvement of the oral mucosa. Of the 77 patients, 59 (76.6%) had concerning findings: premalignant lesions in 45 patients (58.4%) and malignant lesions in 14 (18.2%). Also, dysplasia was seen in 8 patients (10.4%), all of whom had premalignant lesions. Tobacco chewing (p = 0.008) and betel quid chewing (p = 0.029) were significantly associated with the development of premalignant and malignant lesions; a longer duration of tobacco chewing (>=10 yr) was significantly associated with a higher risk of malignant but not premalignant lesions (p = 0.031). Finally, illiteracy was a significant risk factor for premalignant and malignant lesions (p = 0.03). Our findings support the necessity of biopsy in every case. Early detection of oral carcinoma by biopsy of all oral white lesions would not only prevent patients from undergoing disfiguring surgery and chemoradiation, but it also would increase the 5-year survival rate. PMID- 28846794 TI - Use of sialendoscopy as an aid to identify a large retained foreign body. AB - We describe the novel use of sialendoscopy in a 51-year-old man to identify a large and long-standing foreign body (wood) within the facial soft tissues that had eluded detection on previous imaging and surgical exploration. The identification of this foreign body was elusive on both computed tomography and magnetic resonance imaging, illustrating the limitations of imaging in identifying vegetable matter within soft tissues. PMID- 28846795 TI - Neonatal nasal septal deviation: Two cases of successful early surgical intervention. AB - Neonatal nasal septal deviations can occur as a result of trauma in utero or during birth. They are associated with significant clinical implications, including respiratory distress and failure to thrive. The incidence and classification of these deformities are varied in the otolaryngology literature. Some authors advocate conservative observation, but no consensus on management has been reached. We present 2 cases of neonatal septal deviation that occurred during difficult deliveries. We repaired the defects with closed reduction in the operating room within the first 2 weeks of life to good effect. PMID- 28846796 TI - Modified two-handed transnasal endoscopic surgery: Innovative instrument design and an experimental canine study. AB - This study was conducted to design new instruments to solve the current issues of one-hand control and the obscuring of the endoscope by blood during transnasal endoscopic surgery. An endoscope holder and an electronically controlled irrigation-suction system were designed and manufactured. The feasibility and effectiveness of the designed instruments and operation models were verified in a model transnasal endoscopic surgery procedure performed on a mongrel dog. During the operation, one hand was used to perform the operation and move the endoscope, and the other hand was used for irrigation and suction to keep the surgical field and the endoscope clear. The combined use of an endoscope holder and an electronically controlled irrigation-suction system facilitates single-surgeon bimanual transnasal endoscopic surgery in a model surgical procedure. The clinical value of this technique warrants further research. PMID- 28846797 TI - Otolaryngic manifestations of Cushing disease. AB - Cushing disease is a relatively rare cause of Cushing syndrome secondary to a hyperfunctioning pituitary adenoma. In addition to signs and symptoms of hypercortisolism, Cushing disease may present with diverse otolaryngic manifestations, which may guide diagnosis and management. We performed a retrospective chart review of patients who were found to have Cushing disease and who underwent transnasal transsphenoidal surgery for pituitary adenomas between January 1, 2007, and July 1, 2014, at a tertiary academic medical center. There were 37 consecutive patients in this series with Cushing disease caused by a pituitary adenoma. Fifteen (41%) patients complained of visual changes. Five (14%) patients suffered from obstructive sleep apnea. Four (11%) patients had thyroid disease. Other symptoms included hearing loss, vertigo, tinnitus, epistaxis, dysphagia, and salivary gland swelling. Although Cushing disease traditionally presents with classic "Cushingoid" systemic features, it also may present with various otolaryngic manifestations. A thorough workup by otolaryngologists is critical in the comprehensive management of these patients. PMID- 28846798 TI - Recognizing malleus fracture in a woman with a head injury after a fall. PMID- 28846799 TI - The southernmost parakeet might be enhancing pollination of a dioecious conifer. PMID- 28846800 TI - Trajectories of posttraumatic growth among US military veterans: a 4-year nationally representative, prospective cohort study. AB - OBJECTIVE: This study examined the nature and determinants of predominant trajectories of posttraumatic growth (PTG) over time. METHOD: Using data from a prospective, nationally representative survey of 2718 US veterans assessed in 2011, 2013, and 2015, we used latent growth mixture modeling to identify PTG trajectories, and to examine key determinants of PTG trajectories from a comprehensive set of sociodemographic, military, health, and psychosocial variables. RESULTS: Three PTG trajectories were identified, labeled as Low and Decreasing PTG (74.0%), Consistently Moderate PTG (12.0%), and High and Increasing PTG (14.0%). Greater severity of posttraumatic stress disorder symptoms, specifically re-experiencing and avoidance symptoms, at baseline predicted Consistently Moderate and High and Increasing PTG trajectories. Compared to the Low and Decreasing PTG trajectory, the High and Increasing PTG trajectory scored higher on baseline measures of gratitude, purpose in life, Spirituality, and social support. CONCLUSION: Posttraumatic growth is a dynamic process with divergent trajectories. Developing interventions that target certain psychosocial factors may help trauma survivors maintain PTG over time. PMID- 28846801 TI - Increased illness burden in women with comorbid bipolar and premenstrual dysphoric disorder: data from 1 099 women from STEP-BD study. AB - BACKGROUND: The impact of comorbid premenstrual dysphoric disorder (PMDD) in women with bipolar disorder (BD) is largely unknown. AIMS: We compared illness characteristics and female-specific mental health problems between women with BD with and without PMDD. MATERIALS & METHODS: A total of 1 099 women with BD who participated in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were studied. Psychiatric diagnoses and illness characteristics were assessed using the Mini International Neuropsychiatric Interview. Female-specific mental health was assessed using a self-report questionnaire developed for STEP BD. PMDD diagnosis was based on DSM-5 criteria. RESULTS: Women with comorbid BD and PMDD had an earlier onset of bipolar illness (P < 0.001) and higher rates of rapid cycling (P = 0.039), and increased number of past-year hypo/manic (P = 0.003), and lifetime/past-year depressive episodes (P < 0.05). Comorbid PMDD was also associated with higher proportion of panic disorder, post-traumatic stress disorder, generalized anxiety disorder, bulimia nervosa, substance abuse, and adult attention deficit disorder (all P < 0.05). There was a closer gap between BD onset and age of menarche in women with comorbid PMDD (P = 0.003). Women with comorbid PMDD reported more severe mood symptoms during the perinatal period and while taking oral contraceptives (P < 0.001). DISCUSSION: The results from this study is consistent with research suggesting that sensitivity to endogenous hormones may impact the onset and the clinical course of BD. CONCLUSIONS: The comorbidity between PMDD and BD is associated with worse clinical outcomes and increased illness burden. PMID- 28846802 TI - Deceleration capacity of heart rate predicts 1-year mortality of patients undergoing transcatheter aortic valve implantation. AB - BACKGROUND: Risk prediction in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) is challenging. Development of novel markers for patient risk assessment is of great clinical value. Deceleration capacity (DC) of heart rate is a strong risk predictor in post-infarction patients. HYPOTHESIS: DC provides prognostic information in patients undergoing TAVI. METHODS: We enrolled 374 consecutive patients with severe AS undergoing TAVI. All patients received 24-hour Holter recording or continuous heart-rate monitoring to assess DC before intervention. Primary endpoint was all-cause mortality after 1 year. RESULTS: Forty-nine patients (13.1%) died within 1 year. DC was significantly lower in nonsurvivors than in survivors (1.2 +/- 4.8 ms vs 3.3 +/- 2.9 ms; P < 0.001), whereas the logistic EuroSCORE and EuroSCORE II were comparable between groups (logistic EuroSCORE: 27.3% +/- 17.0% vs 22.9% +/- 14.2%; P = 0.122; EuroSCORE II: 8.0% +/- 6.9% vs 6.7% +/- 4.8%, P = 0.673). One-year mortality in the 116 patients with impaired DC (<2.5 ms) was significantly higher than in patients with normal DC (23.3% vs 8.5%; P < 0.001). In multivariate Cox regression analysis that included DC, sex, paroxysmal atrial fibrillation, hemoglobin level before TAVI, and logistic EuroSCORE, DC was the strongest predictor of 1-year mortality (hazard ratio: 0.88, 95% confidence interval: 0.85-0.94, P < 0.001). DC yielded an AUC in the ROC analysis of 0.645. CONCLUSIONS: DC of heart rate is a strong and independent predictor of 1-year mortality in patients with severe AS undergoing TAVI. PMID- 28846803 TI - Comprehensive primary prevention of cardiovascular disease in women. AB - Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality in women. Historically, medical research has focused on male patients, and subsequently, there has been decreased awareness of the burden of ASCVD in females until recent years. The biological differences between sexes and differences in societal expectations defined by gender roles contribute to gender differences in ASCVD risk factors. With these differing risk profiles, risk assessment, risk stratification, and primary preventive measures of ASCVD are different in women and men. In this review article, clinicians will understand the risk factors unique to women, such as preeclampsia, gestational diabetes, and those that disproportionately affect them such as autoimmune disorders. With these conditions in mind, the approach to ASCVD risk assessment and stratification in women will be discussed. Furthermore, the literature behind the effects of primary preventive measures in women, including lifestyle modifications, aspirin, statins, and anticoagulation, will be reviewed. The aim of this review article was to ultimately improve ASCVD primary prevention by reducing gender disparities through education of physicians. PMID- 28846805 TI - An exploration of the association between ischemic etiology and the likelihood of heart failure hospitalization following cardiac resynchronization therapy. AB - BACKGROUND: Myocardial scarring resulting from cardiomyopathy with ischemic etiology may interfere with effective lead placement during implantation of multi lead cardioverter-defibrillators for cardiac resynchronization therapy (CRT-D). Extensive scarring is known to be associated with poorer physiological and survival outcomes in patients who undergo CRT-D. HYPOTHESIS: Ischemic CRT-D recipients respond as well as nonischemic recipients, using hospital admission for heart failure (HF) as a measure of response. METHODS: Patients who underwent CRT-D between February 1, 2013, and February 1, 2014, were identified in an insurer's claims. Inclusion required 1 year of enrollment pre- and post-CRT-D. The sample was divided into nonischemic and ischemic groups, and a subset of the ischemic group with a history of ST-segment elevation myocardial infarction (STEMI) was identified. The likelihood of HF hospital admissions in the year before and after CRT-D was computed for each group, as well as for the subset of patients with HF admissions prior to CRT-D. RESULTS: A significant (P = 0.02) association was found between ischemic etiology and the post-CRT-D HF admission likelihood. No association was found between history of STEMI vs nonischemic status and likelihood of post-CRT-D HF admission. All groups had significantly lower risk of HF admissions after CRT-D. None of the comparisons involving only patients with a HF hospitalization in the year prior to CRT-D were significant. CONCLUSIONS: Patients with nonischemic etiology were significantly less likely to experience a HF admission after CRT-D, but the risk of HF admission improved significantly in all groups after CRT-D. PMID- 28846804 TI - Overexpression of MiR-335-5p Promotes Bone Formation and Regeneration in Mice. AB - MicroRNAs (miRNAs) and the Wnt signaling pathway play critical roles in regulating bone development and homeostasis. Our previous study revealed high expression of miR-335-5p in osteoblasts and hypertrophic chondrocytes in mouse embryos and the ability of miR-335-5p to promote osteogenic differentiation by downregulating Wnt antagonist Dickkopf-1 (DKK1). The purpose of this study was to investigate the effects of miR-335-5p constitutive overexpression on bone formation and regeneration in vivo. To that end, we generated a transgenic mouse line specifically overexpressing miR-335-5p in osteoblasts lineage by the osterix promoter and characterized its bone phenotype. Bone histomorphometry and MUCT analysis revealed higher bone mass and increased parameters of bone formation in transgenic mice than in wild-type littermates. Increased bone mass in transgenic mice bones also correlated with enhanced expression of osteogenic differentiation markers. Upon osteogenic induction, bone marrow stromal cells (BMSCs) isolated from transgenic mice displayed higher mRNA expression of osteogenic markers than wild-type mice BMSCs cultures. Protein expression of Runx2 and Osx was also upregulated in BMSC cultures of transgenic mice upon osteogenic induction, whereas that of DKK1 was downregulated. Most important, BMSCs from transgenic mice were able to repair craniofacial bone defects as shown by MUCT analysis, H&E staining, and osteocalcin (OCN) immunohistochemistry of newly formed bone in defects treated with BMSCs. Taken together, our results demonstrate constitutive overexpression of miR-335-5p driven by an osterix promoter in the osteoblast lineage induces osteogenic differentiation and bone formation in mice and support the potential application of miR-335-5p-modified BMSCs in craniofacial bone regeneration. (c) 2017 American Society for Bone and Mineral Research. PMID- 28846806 TI - Apixaban, rivaroxaban, and dabigatran use in patients undergoing catheter ablation for atrial fibrillation using the second-generation cryoballoon. AB - BACKGROUND: Data are limited on the safety of periprocedural anticoagulation with novel oral anticoagulants (NOACs) in patients undergoing pulmonary vein isolation (PVI) using the second-generation cryoballoon (CB) for the treatment of atrial fibrillation. HYPOTHESIS: We hypothesized that the incidence of acute periprocedural complications in patients undergoing PVI do not differ between patients treated with VKA compared to NOACs. METHODS: In 200 consecutive patients (mean age, 64.3 _ 10.6 years; female, n = 83) with symptomatic atrial fibrillation, PVI using the second-generation 28-mm CB was performed. In patients treated with NOACs, the medication was stopped the day of the procedure and continued the evening after the procedure with a reduced dosage. Patients treated with phenprocoumon were continued on uninterrupted phenprocoumon with a target INR of 2 to 3. If INR was <2, bridging with low-molecular-weight heparin was performed. RESULTS: Forty-seven of 200 patients (23.5%) were treated with a vitamin K antagonist (VKA) and 55 (27.5%) were treated with apixaban, 67 (33.5%) with rivaroxaban, and 31 (15.5%) with dabigatran. Seven (3.5%) major complications occurred in the overall population. Major bleeding complications did not differ significantly between the 2 groups (P = 0.23). One patient taking VKA had a pericardial tamponade at the end of the procedure; 2 patients treated with apixaban developed a groin hematoma requiring surgical intervention. Transient ischemic attack occurred in 1 patient of the apixaban and rivaroxaban group. CONCLUSIONS: Apixaban, rivaroxaban, and dabigatran, compared with uninterrupted VKA, did not show a higher risk for major bleeding or ischemic complications in patients undergoing PVI using the second-generation CB. PMID- 28846807 TI - Two penetrating vessels as a novel indicator of the appropriate distal end of peroral endoscopic myotomy. AB - BACKGROUND AND AIM: One of the challenges during peroral endoscopic myotomy (POEM) is ensuring the appropriate length of myotomy on the gastric side. To determine the appropriate distal end of the gastric myotomy, we focused on the two penetrating vessels (TPVs) found in the gastric cardia during POEM. In the present study, we evaluated whether the TPVs could serve as an accurate indicator of the appropriate distal end of the gastric myotomy. METHODS: All patients who underwent POEM between March and August 2016 were included for this study. When making the submucosal tunnel in the 5 o'clock direction into the stomach, two vessels penetrating through the circular muscle along the edge of oblique muscle in the cardia can be exposed. We designated these two vessels as TPVs. The myotomy was extended until the second TPVs was exposed. The anal end of the submucosal tunnel was confirmed by the double-scope POEM technique, and the length from the gastroesophageal junction to the anal side end of the myotomy was measured by the scale on the endoscope. RESULTS: Among 37 patients who underwent myotomy in the 5 o'clock position, TPVs were found in 34 patients (91.2%). Sufficient submucosal tunneling on the gastric side was confirmed by the double scope POEM technique in these 34 patients. Median length of the gastric myotomy was 3.0 cm (range 2-4 cm). CONCLUSION: TPVs appears to be a simple and reliable indicator to determine the appropriate distal end of myotomy. PMID- 28846808 TI - DNA methylation dysregulations in valvular atrial fibrillation. AB - BACKGROUND: The epigenetic changes underlying the development of atrial fibrillation (AF) remain incompletely understood. Limited evidence suggests that abnormal DNA methylation might be involved in the pathogenesis of AF. In the present study, we evaluated the methylation status of genomic DNA from myocardial tissue in AF patients and sinus rhythm (SR) patients systematically. HYPOTHESIS: DNA methylation dysregulations will be associated with valvular AF. METHODS: Right atrial myocardial tissue was obtained from rheumatic valvular patients who had undergone valve replacement surgery (SR group, n = 10; AF group, n = 10). The global DNA methylation level, the promoter methylation level of the natriuretic peptide receptor-A gene (NPRA), and its correlation with the mRNA expression level of DNA methyltransferase genes were detected. RESULTS: The global DNA methylation level was significantly higher in the AF group than in the SR group (P < 0.05). The NPRA mRNA expression was decreased and the NPRA gene was hypermethylated in the AF group (P < 0.05). Meanwhile, the NPRA mRNA expression level has a negative correlation with the mean methylation level in the promoter region of the NPRA gene. CONCLUSIONS: DNA methylation dysregulations may be relevant in the pathogenesis of AF. DNA methyltransferase 3B likely plays an essential role in the DNA methylation dysregulations in AF. PMID- 28846809 TI - Relation of premature atrial complexes with stroke and death: Systematic review and meta-analysis. AB - Frequent premature atrial complexes (PACs) are universal in the general population; however, their clinical significance is unclear. We hypothesize that frequent PACs are associated with increased risk of stroke and death. The PubMed (from 1966 to April 2017) and Embase (from 1974 to April 2017) databases were searched for longitudinal studies that reported the relation of PACs with incidence of stroke and death with various etiologies. Study quality was evaluated, and the relative risks (RR) of unfavorable outcomes in subjects with frequent PACs vs those without were calculated. Eleven studies with overall high quality were eligible according to inclusion criteria. The meta-analysis demonstrated that frequent PACs were associated with an increased risk of stroke (unadjusted RR: 2.20, 95% confidence interval [CI]: 1.79-2.70; adjusted RR: 1.41, 95% CI: 1.25-1.60) and death from all causes (unadjusted RR: 2.17, 95% CI: 1.80 2.63; adjusted RR: 1.26, 95% CI: 1.13-1.41), cardiovascular diseases (unadjusted RR: 2.89, 95% CI: 2.20-3.79; adjusted RR: 1.38, 95% CI: 1.24-1.54), and coronary artery disease (unadjusted RR: 2.74, 95% CI: 1.64-4.58; adjusted RR: 1.74, 95% CI: 1.27-2.37). No significant publication bias was detected. The association was robust in sensitivity analysis, subgroup analysis, and pooled analysis of estimates adjusting for confounding factors. Frequent PACs are not benign phenomena; they are associated with higher risk of unfavorable outcomes. Further research on the optimal management of subjects with frequent PACs is urgently required. PMID- 28846810 TI - Impact of Cooking Procedures and Storage Practices at Home on Consumer Exposure to Listeria Monocytogenes and Salmonella Due to the Consumption of Pork Meat. AB - The objective of this research was to analyze the impact of different cooking procedures (i.e., gas hob and traditional static oven) and levels of cooking (i.e., rare, medium, and well-done) on inactivation of Listeria monocytogenes and Salmonella in pork loin chops. Moreover, the consumer's exposure to both microorganisms after simulation of meat leftover storage at home was assessed. The results showed that well-done cooking in a static oven was the only treatment able to inactivate the tested pathogens. The other cooking combinations allowed to reach in the product temperatures always >=73.6 degrees C, decreasing both pathogens between 6 log10 cfu/g and 7 log10 cfu/g. However, according to simulation results, the few cells surviving cooking treatments can multiply during storage by consumers up to 1 log10 cfu/g, with probabilities of 0.059 (gas hob) and 0.035 (static oven) for L. monocytogenes and 0.049 (gas hob) and 0.031 (static oven) for Salmonella. The key factors affecting consumer exposure in relation to storage practices were probability of pathogen occurrence after cooking, doneness degree, time of storage, and time of storage at room temperature. The results of this study can be combined with prevalence data and dose-response models in risk assessment models and included in guidelines for consumers on practices to be followed to manage cooking of pork meat at home. PMID- 28846812 TI - Optimal Inspection of Imports to Prevent Invasive Pest Introduction. AB - The United States imports more than 1 billion live plants annually-an important and growing pathway for introduction of damaging nonnative invertebrates and pathogens. Inspection of imports is one safeguard for reducing pest introductions, but capacity constraints limit inspection effort. We develop an optimal sampling strategy to minimize the costs of pest introductions from trade by posing inspection as an acceptance sampling problem that incorporates key features of the decision context, including (i) simultaneous inspection of many heterogeneous lots, (ii) a lot-specific sampling effort, (iii) a budget constraint that limits total inspection effort, (iv) inspection error, and (v) an objective of minimizing cost from accepted defective units. We derive a formula for expected number of accepted infested units (expected slippage) given lot size, sample size, infestation rate, and detection rate, and we formulate and analyze the inspector's optimization problem of allocating a sampling budget among incoming lots to minimize the cost of slippage. We conduct an empirical analysis of live plant inspection, including estimation of plant infestation rates from historical data, and find that inspections optimally target the largest lots with the highest plant infestation rates, leaving some lots unsampled. We also consider that USDA-APHIS, which administers inspections, may want to continue inspecting all lots at a baseline level; we find that allocating any additional capacity, beyond a comprehensive baseline inspection, to the largest lots with the highest infestation rates allows inspectors to meet the dual goals of minimizing the costs of slippage and maintaining baseline sampling without substantial compromise. PMID- 28846811 TI - Locking and Unlocking the Molecular Spin Crossover Transition. AB - The Fe(II) spin crossover complex [Fe{H2 B(pz)2 }2 (bipy)] (pz = pyrazol-1-yl, bipy = 2,2'-bipyridine) can be locked in a largely low-spin-state configuration over a temperature range that includes temperatures well above the thermal spin crossover temperature of 160 K. This locking of the spin state is achieved for nanometer thin films of this complex in two distinct ways: through substrate interactions with dielectric substrates such as SiO2 and Al2 O3 , or in powder samples by mixing with the strongly dipolar zwitterionic p-benzoquinonemonoimine C6 H2 (-? NH2 )2 (-? O)2 . Remarkably, it is found in both cases that incident X ray fluences then restore the [Fe{H2 B(pz)2 }2 (bipy)] moiety to an electronic state characteristic of the high spin state at temperatures of 200 K to above room temperature; that is, well above the spin crossover transition temperature for the pristine powder, and well above the temperatures characteristic of light- or X-ray-induced excited-spin-state trapping. Heating slightly above room temperature allows the initial locked state to be restored. These findings, supported by theory, show how the spin crossover transition can be manipulated reversibly around room temperature by appropriate design of the electrostatic and chemical environment. PMID- 28846813 TI - Nonsuicidal Self-Injury: Increased Prevalence in Engagement. AB - While some suggest nonsuicidal self-injury (NSSI) is increasing, very little has been done systematically to explore this possibility. The current study employed three cohorts of freshman (total N = 949) from the same university across a period of 7 years to explore engagement in NSSI. Related intrapersonal factors were also examined. NSSI lifetime and current engagement use drastically increased across the three cohorts. Anxiety followed a similar trajectory as NSSI behaviors as increasing in reported levels, while depression and coping behaviors did not. Implications of these trends are discussed. PMID- 28846814 TI - Light-Patterned Crystallographic Direction of a Self-Organized 3D Soft Photonic Crystal. AB - Uniform and patterned orientation of a crystallographic direction of ordered materials is of fundamental significance and of great interest for electronic and photonic applications. However, such orientation control is generally complicated and challenging with regard to inorganic and organic crystalline materials due to the occurrence of uncontrollable dislocations or defects. Achieving uniform lattice orientation in frustrated liquid-crystalline phases, like cubic blue phases, is a formidable task. Taming and tailoring the ordering of such soft, cubic lattices along predetermined or desired directions, and even imparting a prescribed pattern on lattice orientation, are more challenging, due to the entropy-domination attribute of soft matter. Herein, we disclose a facile way to realize designed micropatterning of a crystallographic direction of a soft, cubic liquid-crystal superstructure, exhibiting an alternate uniform and random orientation of the lattice crystallographic direction enabled by a photoalignment technique. Because of the rewritable trait of the photoalignment film, the pattern can be erased and rewritten on-demand by light. Such an oriented soft lattice sensitively responds to various external stimuli such as temperature, electric field, and light irradiation. Furthermore, advanced reflective photonic applications are achieved based on the patterned crystallographic orientation of the cubic blue phase, soft lattice. PMID- 28846815 TI - Reply. PMID- 28846816 TI - Granulomatous skin reactions after tumour vaccine in two patients. PMID- 28846817 TI - The usefulness of investigating the possible underlying conditions in rosacea. PMID- 28846818 TI - Low-Noise and Large-Linear-Dynamic-Range Photodetectors Based on Hybrid Perovskite Thin-Single-Crystals. AB - Organic-inorganic halide perovskites are promising photodetector materials due to their strong absorption, large carrier mobility, and easily tunable bandgap. Up to now, perovskite photodetectors are mainly based on polycrystalline thin films, which have some undesired properties such as large defective grain boundaries hindering the further improvement of the detector performance. Here, perovskite thin-single-crystal (TSC) photodetectors are fabricated with a vertical p-i-n structure. Due to the absence of grain-boundaries, the trap densities of TSCs are 10-100 folds lower than that of polycrystalline thin films. The photodetectors based on CH3 NH3 PbBr3 and CH3 NH3 PbI3 TSCs show low noise of 1-2 fA Hz-1/2 , yielding a high specific detectivity of 1.5 * 1013 cm Hz1/2 W-1 . The absence of grain boundaries reduces charge recombination and enables a linear response under strong light, superior to polycrystalline photodetectors. The CH3 NH3 PbBr3 photodetectors show a linear response to green light from 0.35 pW cm-2 to 2.1 W cm-2 , corresponding to a linear dynamic range of 256 dB. PMID- 28846819 TI - Graded Heterojunction Engineering for Hole-Conductor-Free Perovskite Solar Cells with High Hole Extraction Efficiency and Conductivity. AB - Despite great progress in the photovoltaic conversion efficiency (PCE) of inorganic-organic hybrid perovskite solar cells (PSCs), the large-scale application of PSCs still faces serious challenges due to the poor-stability and high-cost of the spiro-OMeTAD hole transport layer (HTL). It is of great fundamental importance to rationally address the issues of hole extraction and transfer arising from HTL-free PSCs. Herein, a brand-new PSC architecture is designed by introducing multigraded-heterojunction (GHJ) inorganic perovskite CsPbBrx I3-x layers as an efficient HTL. The grade adjustment can be achieved by precisely tuning the halide proportion and distribution in the CsPbBrx I3-x film to reach an optimal energy alignment of the valance and conduction band between MAPbI3 and CsPbBrx I3-x . The CsPbBrx I3-x GHJ as an efficient HTL can induce an electric field where a valance/conduction band edge is leveraged to bend at the heterojunction interface, boosting the interfacial electron-hole splitting and photoelectron extraction. The GHJ architecture enhances the hole extraction and conduction efficiency from the MAPbI3 to the counter electrode, decreases the recombination loss during the hole transfer, and benefits in increasing the open circuit voltage. The optimized HTL-free PCS based on the GHJ architecture demonstrates an outstanding thermal stability and a significantly improved PCE of 11.33%, nearly 40% increase compared with 8.16% for pure HTL-free devices. PMID- 28846820 TI - 'No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic treated, obese patients with schizophrenia': authors' response. PMID- 28846821 TI - Polymer-Based Surfaces Designed to Reduce Biofilm Formation: From Antimicrobial Polymers to Strategies for Long-Term Applications. AB - Contact-active antimicrobial polymer surfaces bear cationic charges and kill or deactivate bacteria by interaction with the negatively charged parts of their cell envelope (lipopolysaccharides, peptidoglycan, and membrane lipids). The exact mechanism of this interaction is still under debate. While cationic antimicrobial polymer surfaces can be very useful for short-term applications, they lose their activity once they are contaminated by a sufficiently thick layer of adhering biomolecules or bacterial cell debris. This layer shields incoming bacteria from the antimicrobially active cationic surface moieties. Besides discussing antimicrobial surfaces, this feature article focuses on recent strategies that were developed to overcome the contamination problem. This includes bifunctional materials with simultaneously presented antimicrobial and protein-repellent moieties; polymer surfaces that can be switched from an antimicrobial, cell-attractive to a cell-repellent state; polymer surfaces that can be regenerated by enzyme action; degradable antimicrobial polymers; and antimicrobial polymer surfaces with removable top layers. PMID- 28846823 TI - Synergistic Effects in PtII -Porphyrinoid Dyes as Candidates for a Dual-Action Anticancer Therapy: A Theoretical Exploration. AB - The combination of a photosensitizer (PS) with a cisplatin-like unit represents a challenging strategy to increase the effectiveness of photodynamic therapy and to afford a dual-action anticancer treatment. Recently, new tetra-PtII -porphyrin conjugates have been proposed as promising multitarget agents. To reveal the effect of the PtII center on the chemical and physical properties of the PS and to explore the effect of the PS on the activation mechanism of PtII ligand before reaching its biological target, we carried out a first-principle investigation on these tetra-PtII -porphyrin conjugates. To propose a further advance in this novel field and to gain useful insights for the design of new, more efficient PtII -PS conjugates, we introduced structural modifications into the porphyrin dye, which involved the synthesis of the tetra-PtII -chlorin and tetra-PtII bacteriochlorin derivatives. Results showed that the designed dyes better met the criteria to be successful in a dual-action therapy, as they displayed improved optical properties and reduced the hydrolysis rate of the PtII moiety, the latter being a desirable feature to avoid many side reactions of the conjugate during their transport to the biological target. PMID- 28846822 TI - Extended pharmacologic thromboprophylaxis in oncologic liver surgery is safe and effective. AB - : Essentials The risk for venous thromboembolism after liver surgery remains high in the modern era. We evaluated the safety/efficacy of extended anticoagulation in liver surgery. This protocol reports zero venous thromboembolism events in 124 liver surgery patients. Extended anticoagulation after oncologic liver surgery is safe and effective. SUMMARY: Background The incidence of venous thromboembolism (VTE) after liver surgery remains high. Objective To evaluate the safety and efficacy of extended pharmacologic thromboprophylaxis after liver surgery for the prevention of VTE. Patient/Methods From August 2013 to April 2015, 124 patients who underwent liver resection for malignancy were placed on an extended pharmacologic thromboprophylaxis protocol. Intraoperative VTE prophylaxis included thromboembolic deterrent hoses and sequential compression devices. Once hemostasis had been ensured following hepatectomy, daily anticoagulant VTE prophylaxis was initiated for the duration of hospitalization. After hospital discharge, the large majority of patients (114, 91.9%) continued to receive anticoagulant thromboprophylaxis (enoxaparin) to complete a total course of 14 days after minor/minimally invasive hepatectomy or 28 days after major hepatectomy or a history of VTE. Results The cohort included 39 (31.2%) major hepatectomies and 38 (31.5%) minor/minimally invasive approaches. The intraoperative, postoperative and overall transfusion rates were 5.6%, 8.1%, and 10.5%, respectively. Pharmacologic thromboprophylaxis was started on postoperative day (POD) 0 for 40 (32.3%) patients and on POD 1 for 84 (67.7%) patients. During 90 days of follow-up, no postoperative symptomatic deep vein thrombosis or pulmonary embolic events were diagnosed. Standard-protocol computed tomography scans of the chest, abdomen and pelvis that were obtained for 112 (90.3%) study patients showed no pulmonary emboli, or other thoracic, splanchnic or ileofemoral vein thromboses. Two (1.6%) patients had minor bleeding events that resolved after discontinuation of enoxaparin, requiring neither blood transfusion nor reoperation. The severe complication rate was 5.6%, with no 90 day mortalities. Conclusions These preliminary data suggest that extended pharmacologic thromboprophylaxis for liver surgery patients is safe and effective. PMID- 28846824 TI - Rationalizing the 2.25 A Resolution Crystal Structure of the Water Oxidising Complex of Photosystem II in the S3 State. AB - Quantum chemical calculations are described which rationalize the recent X-ray diffraction (XRD) structure at 2.25 A of the Mn4 Ca water oxidising complex (WOC) of photosystem II (PSII) in the S3 intermediate state. The new S3 XRD structure shows remarkable similarity to earlier atomic resolution (1.9, 1.95 A) WOC structures in the dark stable S1 state and is inconsistent with most current proposals, from computational chemistry and other sources, regarding the Mn oxidation state levels in the WOC cluster and the nature of water substrate binding, particularly in S3 . This mirrors earlier failures to rationalise the WOC geometry in the 1.9 and 1.95 A S1 XRD structures, assuming "high" paradigm Mn oxidation models. However, we recently showed that a lower Mn oxidation assumption closely reproduces the S1 XRD structures, computationally. This same "low" Mn oxidation model, now computationally applied in S3 , not only reproduces the latest 2.25 A XRD structure but also rationalises a number of other important, experimental features of the WOC, including the metal-metal distances inferred from EXAFS studies as well as earlier S3 state XRD structures of lower resolution (4-5 A). As found previously for S1 , the WOC in the S3 state is computationally revealed to be structurally variable, consistent with some EXAFS and lower-resolution XRD data. This is a direct consequence of at least two MnIII ions being present in all metastable S states. PMID- 28846825 TI - Fluorine Pseudocontact Shifts Used for Characterizing the Protein-Ligand Interaction Mode in the Limit of NMR Intermediate Exchange. AB - The characterization of protein-ligand interaction modes becomes recalcitrant in the NMR intermediate exchange regime as the interface resonances are broadened beyond detection. Here, we determined the 19 F low-populated bound-state pseudocontact shifts (PCSs) of mono- and di-fluorinated inhibitors of the BRM bromodomain using a highly skewed protein/ligand ratio. The bound-state 19 F PCSs were retrieved from 19 F chemical exchange saturation transfer (CEST) in the presence of the lanthanide-labeled protein, which was termed the 19 F PCS-CEST approach. These PCSs enriched in spatial information enabled the identification of best-fitting poses, which agree well with the crystal structure of a more soluble analog in complex with the BRM bromodomain. This approach fills the gap of the NMR structural characterization of lead-like inhibitors with moderate affinities to target proteins, which are essential for structure-guided hit-to lead evolution. PMID- 28846827 TI - Royal Society of Chemistry Prizes and Awards 2017. PMID- 28846826 TI - Autoimmune heparin-induced thrombocytopenia. AB - Autoimmune heparin-induced thrombocytopenia (aHIT) indicates the presence in patients of anti-platelet factor 4 (PF4)-polyanion antibodies that are able to activate platelets strongly even in the absence of heparin (heparin-independent platelet activation). Nevertheless, as seen with serum obtained from patients with otherwise typical heparin-induced thrombocytopenia (HIT), serum-induced platelet activation is inhibited at high heparin concentrations (10-100 IU mL-1 heparin). Furthermore, upon serial dilution, aHIT serum will usually show heparin dependent platelet activation. Clinical syndromes associated with aHIT include: delayed-onset HIT, persisting HIT, spontaneous HIT syndrome, fondaparinux associated HIT, heparin 'flush'-induced HIT, and severe HIT (platelet count of < 20 * 109 L-1 ) with associated disseminated intravascular coagulation (DIC). Recent studies have implicated anti-PF4 antibodies that are able to bridge two PF4 tetramers even in the absence of heparin, probably facilitated by non-heparin platelet-associated polyanions (chondroitin sulfate and polyphosphates); nascent PF4-aHIT-IgG complexes recruit additional heparin-dependent HIT antibodies, leading to the formation of large multimolecular immune complexes and marked platelet activation. aHIT can persist for several weeks, and serial fibrin, D dimer, and fibrinogen levels, rather than the platelet count, may be helpful for monitoring treatment response. Although standard anticoagulant therapy for HIT ought to be effective, published experience indicates frequent failure of activated partial thromboplastin time (APTT)-adjusted anticoagulants (argatroban, bivalirudin), probably because of underdosing in the setting of HIT-associated DIC, known as 'APTT confounding'. Thus, non-APTT-adjusted therapies with drugs such as danaparoid and fondaparinux, or even direct oral anticoagulants, such as rivaroxaban or apixaban, are suggested therapies, especially for long-term management of persisting HIT. In addition, emerging data indicate that high-dose intravenous immunoglobulin can interrupt HIT antibody-induced platelet activation, leading to rapid platelet count recovery. PMID- 28846828 TI - Loss of Fbxw7 expression is a predictor of recurrence in colorectal liver metastasis. AB - BACKGROUND: Fbxw7 is a tumor suppressor through ubiquitination and degradation of multiple oncoproteins. Loss of Fbxw7 is frequently observed in various human cancers. In this study, we examined the role of Fbxw7 expression in colorectal liver metastasis (CRLM) and its mechanism. METHODS: Fifty-six patients with CRLM who undergo curative resection were enrolled. Fbxw7 in tumor tissue was determined by immunohistochemistry. Patients were divided into two groups, the Fbxw7 high and low groups. Clinicopathological factors including miR-223 expression were compared between the high (n = 32) and low Fbxw7 groups (n = 24). RESULTS: Fbxw7 expression in tumor tissues was significantly lower than that in normal tissues. The disease-free survival in the low Fbxw7 group was significantly worse than that in the high Fbxw7 group, and 3 years disease-free survival of the low and high Fbxw7 groups were 12.5% and 47.0%, respectively (P = 0.023). On multivariate analysis, loss of Fbxw7 was detected as one of the independent risk factors for recurrence of CRLM (hazard ratio: 2.390, P = 0.017). Likewise, Fbxw7 expression inversely correlated to miR-223 expression (P = 0.017). CONCLUSION: Loss of Fbxw7 in tumor tissues could be a reliable predictor of recurrence after hepatectomy in patients with CRLM, and miR-223 might be a possible regulator of Fbxw7. PMID- 28846830 TI - Iron-Catalyzed anti-Selective Carbosilylation of Internal Alkynes. AB - Reported is the anti-selective carbosilylation of internal alkynes with silylborane and alkyl halides using a FeBr2 /DPPE catalyst system. The iron catalyst allows simultaneous introduction of a carbon electrophile and a silicon nucleophile to simple internal alkynes, including diaryl-, dialkyl-, and aryl/alkyl-substituted alkynes, in a highly stereoselective manner. Alkyl halides are applicable as the electrophiles, thereby enabling the synthesis of a variety of tetrasubstituted alkenylsilanes. In addition, syn-selective carbosilylation was achieved through stereoswitching, by using a silylborane having oxygen functionality on the silyl group. This novel iron-catalyzed carbosilylation is a useful tool for expedient synthesis of stereodefined multisubstituted olefins, a fundamental structural motif in organic chemistry. PMID- 28846829 TI - RhoGDIbeta promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation. AB - Our most recent studies demonstrate that RhoGDIbeta is able to promote human bladder cancer (BC) invasion and metastasis in an X-link inhibitor of apoptosis protein-dependent fashion accompanied by increased levels of matrix metalloproteinase (MMP)-2 protein expression. We also found that RhoGDIbeta and MMP-2 protein expressions are consistently upregulated in both invasive BC tissues and cell lines. In the present study, we show that knockdown of RhoGDIbeta inhibited MMP-2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of RhoGDIbeta upregulated MMP-2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP-2 was upregulated by RhoGDIbeta at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp-2 promoter region. Further investigation revealed that RhoGDIbeta overexpression led to downregulation of miR-200c, whereas miR-200c was able directly to target 3'-UTR of jnk2mRNA and attenuated JNK2 protein translation, which resulted in attenuation of Sp1mRNA and protein expression in turn, inhibiting Sp1-dependent mmp-2 transcription. Collectively, our studies demonstrate that RhoGDIbeta overexpression inhibits miR-200c abundance, which consequently results in increases of JNK2 protein translation, Sp1 expression, mmp-2 transcription, and BC invasion. These findings, together with our previous results showing X-link inhibitor of apoptosis protein mediating mRNA stabilization of both RhoGDIbeta and mmp-2, reveal the nature of the MMP-2 regulatory network, which leads to MMP 2 overexpression and BC invasion. PMID- 28846831 TI - Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study. AB - : Essentials Prothrombin complex concentrates (PCCs) may reverse the effect of factor Xa (FXa) inhibitors. We conducted an open-label, randomized, placebo controlled, three-period crossover study in 15 subjects. Both PCCs rapidly reversed apixaban-mediated decreases in mean endogenous thrombin potential. Four factor PCC administration had no effect on apixaban pharmacokinetics or anti-FXa activity. SUMMARY: Background Currently, there is no approved reversal agent for direct activated factor Xa (FXa) inhibitors; however, several agents are under investigation, including prothrombin complex concentrates (PCCs). Objective This open-label, randomized, placebo-controlled, three-period crossover study assessed the effect of two four-factor PCCs on apixaban pharmacodynamics and pharmacokinetics in 15 healthy subjects. Methods Subjects received apixaban 10 mg twice daily for 3 days. On day 4, 3 h after apixaban, subjects received a 30-min infusion of 50 IU kg-1 Cofact, Beriplex P/N (Beriplex), or saline. Change in endogenous thrombin potential (ETP), measured with a thrombin generation assay (TGA), was the primary endpoint. Secondary endpoints included changes in other TGA parameters, prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time, anti-FXa activity, apixaban pharmacokinetics, and safety. Results Apixaban-related changes in ETP and several other pharmacodynamic measures occurred following apixaban administration. Both PCCs reversed apixaban's effect on ETP; the differences in adjusted mean change from pre-PCC baseline to end of infusion were 425 nm min (95% confidence interval [CI] 219.8-630.7 nm min; P < 0.001) for Cofact, and 91 nm min (95% CI - 31.3 to 212.4 nm min; P > 0.05) for Beriplex. Both PCCs returned ETP to pre-apixaban baseline levels 4 h after PCC infusion, versus 45 h for placebo. For both PCCs, mean ETP peaked 21 h after PCC initiation, and then slowly decreased over the following 48 h. Both PCCs reversed apixaban's effect on TGA peak height, PT, and INR. Apixaban pharmacokinetic and anti-FXa profiles were consistent across treatments. Conclusions Cofact and Beriplex reversed apixaban's steady-state effects on several coagulation assessments. PMID- 28846833 TI - Loss of Surfacten(r) during bolus administration with a feeding catheter. AB - BACKGROUND: Surfactant replacement therapy is widely used for treating neonatal respiratory distress syndrome, but insufficient evidence is available on the use of Surfacten(r) (S-TA). This study investigated the inadvertent loss of S-TA during instillation via feeding catheters with different bore sizes. METHODS: In this bench-based study, we measured the weight of syringes and tubes before and after surfactant treatment using a high-accuracy balance, and determined the amount of S-TA lost in tubes. We injected 120 mg of S-TA suspended in 4 or 3 mL into tubes followed with or without air boluses. Experiments were performed in triplicate. Percent weight loss of S-TA in each tube was calculated with or without air boluses. RESULTS: Percent weight loss of S-TA was significantly higher in larger-bore tubes (P < 0.01, overall ANOVA), and was significantly lower after air bolus flushing in 3 Fr, 4 Fr, and 5 Fr tubes (P < 0.005, respectively). The 3 mL S-TA suspensions had a significantly higher percent loss than the 4 mL S-TA suspensions when using 4 Fr and 5 Fr tubes, and the 5 Fr closed system (P < 0.05, respectively). CONCLUSIONS: Routine air bolus flushing effectively reduces S-TA loss in tubes. The 3 mL S-TA suspensions appear to be more susceptible to inadvertent S-TA loss during instillation. Therefore, caution is warranted for this procedure. PMID- 28846832 TI - Induction of a novel isoform of the lncRNA HOTAIR in Claudin-low breast cancer cells attached to extracellular matrix. AB - Elevated overexpression of the lncRNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin-low MDA-MB-231 and Hs578T cells in two-dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin-rich extracellular matrix-based three-dimensional organotypic culture (lrECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin alpha2 and SRC kinase activity. Moreover, invasive growth was suppressed by HOTAIR-specific siRNA. Induction of HOTAIR in lrECM 3D culture resulted from the activation of a novel isoform of HOTAIR (HOTAIR-N) whose transcription is started from the first intron of the HOXC11 gene. The HOTAIR-N promoter exhibited increased trimethylation of histone H3 lysine 4, a histone marker of active transcription, and binding of BRD4, a reader of transcriptionally active histone markers. Inhibition of BRD4 substantially reduced the expression of HOTAIR in lrECM 3D culture. In summary, our results indicate that HOTAIR expression is activated by BRD4 binding to a novel HOTAIR-N promoter in Claudin-low breast cancer cells that are attached to ECM. Induction of HOTAIR is required for invasive growth of Claudin-low breast cancer cells in lrECM 3D culture. PMID- 28846834 TI - Microanatomical profiles on the lymphatic system in the human ampulla of Vater (immunohistochemistry and scanning electron microscopy). AB - BACKGROUND: Little information is available regarding microanatomy of lymphatic system in the ampulla of Vater, though it is of critical importance for an understanding of tumor progression via the lymphatics and determination of surgical strategy. The present study, therefore, aimed to demonstrate the distribution and microanatomical profiles on the lymphatic system in the ampulla. METHODS: The fine distribution and structure of the lymphatic vessels were investigated in the ampulla and the stomach by immunohistochemistry for lymphatic (D2-40) and blood vascular- (CD31) specific markers and scanning electron microscopy. The densities of lymphatic and blood vessels were also compared. RESULTS: The duodenal papilla densely developed the lymphatics with distinct aspects of lymphatic capillaries, together with blood vessels. The density of lymphatic capillaries in the extramuscular layer in the ampulla was higher than those of both the other ampullary layers and the gastric extramuscular (subserosal) layer. CONCLUSIONS: The ampulla of Vater showed widespread lymphatic capillaries throughout the entire wall. The specific vascular system is suited to produce lymph everywhere and drain without via such a large vessel as lymphatic collector. This suggests that tumor cells invade the lymphatics and metastasize more easily in the ampulla than in the other gastrointestinal regions. PMID- 28846835 TI - Impact of neutrophil to lymphocyte ratio on survival for hepatocellular carcinoma after curative resection. AB - BACKGROUND: Neutrophil-lymphocyte ratio (NLR) represents a pro-tumor inflammatory environment and host immunity. The aim of this study was to examine the effect of subsequent NLR for hepatocellular carcinoma (HCC) after liver resection. METHODS: A total of 672 patients had liver resection for HCC were included in this study. NLR at diagnosis of HCC and HCC recurrence were collected. NLR at 2.5 was used as cut-off value to calculate its prognostic effect. RESULTS: According to NLR cut off value, the patients with NLR >2.5 had larger tumor size, higher histology grade, and higher rates of tumor multiplicity and vascular invasion. After a median follow-up of 76.3 months, 437 (65.0%) patients had tumor recurrence. The 1 , 3- and 5-year recurrence-free survival were 77.4%, 55.2% and 44.8% in NLR <=2.5 group, compared to 64.1%, 45.2% and 35.5% in NLR >2.5 group (P = 0.016). When patients had tumor recurrence, 5-year post-recurrent survival was best in the patients staying with NLR <=2.5 all the time and decreased from 45.9% to 24.6% if NLR was <=2.5 at resection and became >2.5 at recurrence (P = 0.013). CONCLUSION: High NLR was an independent unfavorable prognostic factor. Subsequent change of NLR between liver resection and HCC recurrence could predict post-recurrent survival. PMID- 28846836 TI - High Risk for Invasive Meningococcal Disease Among Patients Receiving Eculizumab (Soliris) Despite Receipt of Meningococcal Vaccine. PMID- 28846837 TI - Elevated Parenchymal Arterial Resistive Indices After Renal Transplantation. PMID- 28846838 TI - The Unbearable Lightness of Breathing. PMID- 28846839 TI - The Opioid Epidemic Weaves Its Way Through the Transplant Community. PMID- 28846840 TI - Au/TiO2 Hollow Spheres with Synergistic Effect of Plasmonic Enhancement and Light Scattering for Improved Dye-Sensitized Solar Cells. AB - Au-decorated TiO2 hollow spheres (Au-THS) have been successfully synthesized via a facile one-pot solvothermal method. The Au-THS hybrid features unique hollow structure with a large specific surface area of 120 m2 g-1 and homogeneous decoration of Au nanoparticles, giving rise to enhanced light harvesting and charge generation/separation efficiency. When incorporated into the active layer of dye-sensitized solar cells (DSSCs), an improved power conversion efficiency of 7.3% is obtained, which is increased by 37.7% compared with the controlled P25 DSSC. The underlying mechanism to rationalize the efficiency enhancement can be mainly attributed to the strong synergistic effect of superior light scattering ability of the THS and the plasmonic-enhanced effect rendered by the Au nanoparticles. PMID- 28846841 TI - Charge Carriers Modulate the Bonding of Semiconductor Nanoparticle Dopants As Revealed by Time-Resolved X-ray Spectroscopy. AB - Understanding the electronic structure of doped semiconductors is essential to realize advancements in electronics and in the rational design of nanoscale devices. Reported here are the results of time-resolved X-ray absorption studies on copper-doped cadmium sulfide nanoparticles that provide an explicit description of the electronic dynamics of the dopants. The interaction of a dopant ion and an excess charge carrier is unambiguously observed via monitoring the oxidation state. The experimental data combined with DFT calculations demonstrate that dopant bonding to the host matrix is modulated by its interaction with charge carriers. Furthermore, the transient photoluminescence and the kinetics of dopant oxidation reveal the presence of two types of surface bound ions that create midgap states. PMID- 28846842 TI - Circularly Polarized Light with Sense and Wavelengths To Regulate Azobenzene Supramolecular Chirality in Optofluidic Medium. AB - Circularly polarized light (CPL) as a massless physical force causes absolute asymmetric photosynthesis, photodestruction, and photoresolution. CPL handedness has long been believed to be the determining factor in the resulting product's chirality. However, product chirality as a function of the CPL handedness, irradiation wavelength, and irradiation time has not yet been studied systematically. Herein, we investigate this topic using achiral polymethacrylate carrying achiral azobenzene as micrometer-size aggregates in an optofluidic medium with a tuned refractive index. Azobenzene chirality with a high degree of dissymmetry ratio (+/-1.3 * 10-2 at 313 nm) was generated, inverted, and switched in multiple cycles by irradiation with monochromatic incoherent CPL (313, 365, 405, and 436 nm) for 20 s using a weak incoherent light source (~ 30 MUW.cm-2). Moreover, the optical activity was retained for over 1 week in the dark. Photoinduced chirality was swapped by the irradiating wavelength, regardless of whether the CPL sense was the same. This scenario is similar to the so-called Cotton effect, which was first described in 1895. The tandem choice of both CPL sense and its wavelength was crucial for azobenzene chirality. Our experimental proof and theoretical simulation should provide new insight into the chirality of CPL-controlled molecules, supramolecules, and polymers. PMID- 28846843 TI - Multisubunit RNA Polymerase Cleavage Factors Modulate the Kinetics and Energetics of Nucleotide Incorporation: An RNA Polymerase I Case Study. AB - All cellular RNA polymerases are influenced by protein factors that stimulate RNA polymerase-catalyzed cleavage of the nascent RNA. Despite divergence in amino acid sequence, these so-called "cleavage factors" appear to share a common mechanism of action. Cleavage factors associate with the polymerase through a conserved structural element of the polymerase known as the secondary channel or pore. This mode of association enables the cleavage factor to reach through the secondary channel into the polymerase active site to reorient the active site divalent metal ions. This reorientation converts the polymerase active site into a nuclease active site. Interestingly, eukaryotic RNA polymerases I and III (Pols I and III, respectively) have incorporated their cleavage factors as bona fide subunits known as A12.2 and C11, respectively. Although it is clear that A12.2 and C11 dramatically stimulate the polymerase's cleavage activity, it is not known if or how these subunits affect the polymerization mechanism. In this work we have used transient-state kinetic techniques to characterize a Pol I isoform lacking A12.2. Our data clearly demonstrate that the A12.2 subunit profoundly affects the kinetics and energetics of the elementary steps of Pol I-catalyzed nucleotide incorporation. Given the high degree of conservation between polymerase-cleavage factor interactions, these data indicate that cleavage factor modulated nucleotide incorporation mechanisms may be common to all cellular RNA polymerases. PMID- 28846844 TI - Microwave-Assisted Synthesis of Graphene-SnO2 Nanocomposites and Their Applications in Gas Sensors. AB - We obtained extremely high and selective sensitivity to NO2 gas by fabricating graphene-SnO2 nanocomposites using a commercial microwave oven. Structural characterization revealed that the products corresponded to agglomerated structures of graphene and SnO2 particles, with small secondary SnOx (x <= 2) nanoparticles deposited on the surfaces. The overall oxygen atomic ratio was decreased with the appearance of an SnOx (x < 2) phase. By the microwave treatment of graphene-SnO2 nanocomposites, with the graphene promoting efficient transport of the microwave energy, evaporation and redeposition of SnOx nanoparticles were facilitated. The graphene-SnO2 nanocomposites exhibited a high sensor response of 24.7 for 1 ppm of NO2 gas, at an optimized temperature of 150 degrees C. The graphene-SnO2 nanocomposites were selectively sensitive to NO2 gas, in comparison with SO2, NH3, and ethanol gases. We suggest that the generation of SnOx nanoparticles and the SnOx phase in the matrix results in the formation of SnO2/SnO2 homojunctions, SnO2/SnOx (x < 2) heterojunctions, and SnO2/graphene heterojunctions, which are responsible for the excellent sensitivity of the graphene-SnO2 nanocomposites to NO2 gas. In addition, the generation of surface Sn interstitial defects is also partly responsible for the excellent NO2 sensing performance observed in this study. PMID- 28846845 TI - Expanding Single Particle Mass Spectrometer Analyses for the Identification of Microbe Signatures in Sea Spray Aerosol. AB - Ocean-derived microbes in sea spray aersosol (SSA) have the potential to influence climate and weather by acting as ice nucleating particles in clouds. Single particle mass spectrometers (SPMSs), which generate in situ single particle composition data, are excellent tools for characterizing aerosols under changing environmental conditions as they can provide high temporal resolution and require no sample preparation. While SPMSs have proven capable of detecting microbes, these instruments have never been utilized to definitively identify aerosolized microbes in ambient sea spray aersosol. In this study, an aerosol time-of-flight mass spectrometer was used to analyze laboratory generated SSA produced from natural seawater in a marine aerosol reference tank. We present the first description of a population of biological SSA mass spectra (BioSS), which closely match the ion signatures observed in previous terrestrial microbe studies. The fraction of BioSS dramatically increased in the largest supermicron particles, consistent with field and laboratory measurements of microbes ejected by bubble bursting, further supporting the assignment of BioSS mass spectra as microbes. Finally, as supported by analysis of inorganic ion signals, we propose that dry BioSS particles have heterogeneous structures, with microbes adhered to sodium chloride nodules surrounded by magnesium-enriched coatings. Consistent with this structure, chlorine-containing ion markers were ubiquitous in BioSS spectra and identified as possible tracers for distinguishing recently aerosolized marine from terrestrial microbes. PMID- 28846846 TI - Excess Electron and Hole in 1-Benzylpyridinium-Based Ionic Liquids. AB - The study of ionic liquids that may be compatible with the type of radiation chemistry events occurring in nuclear separation processes is a topic of high current interest. In this article, we focus on two ionic liquids based on the benzylpyridinium cation. This cation has been proposed to be able to capture either an excess electron or hole without undergoing fast dissociation. Shkrob, Wishart, and collaborators ( J. Phys. Chem. B 2013 , 117 ( 46 ), 14385 - -14399 ) have indicated that the stabilization is likely in the form of dimers in solution with the excess electron localized on adjacent pyridinium rings and the excess hole localized on phenyl rings. Our first-principles dynamical studies support these ideas but present a more nuanced view of the time-dependent behavior that is likely to occur at short time for systems at room temperature. PMID- 28846847 TI - Yttrium-Catalyzed Tandem Intermolecular Hydroalkoxylation/Claisen Rearrangement. AB - An efficient yttrium-catalyzed tandem intermolecular hydroalkoxylation/Claisen rearrangement has been developed, providing various gamma,delta-unsaturated amides in generally good to excellent yields. Importantly, high Z/E selectivity and diastereoselectivity were achieved. Other notable features of this method include widespread availability of the substrates, compatibility with a broad range of functional groups, and mild reaction conditions. PMID- 28846848 TI - Divergent Approach to Thiazolylidene Derivatives: A Perspective on the Synthesis of a Heterocyclic Skeleton from beta-Amidothioamides Reactivity. AB - Herein we report a domino protocol able to reach regioselectively thiazolylidene systems by combining the reactive peculiarities of both beta-amidothioamides (ATAs) and 1,2-diaza-1,3-dienes (DDs). Depending on the reaction conditions and/or the nature of the residue at C4 of the heterodiene system, ATAs can act as hetero-mononucleophiles or hetero-dinucleophiles in the diversified thiazolylidene ring assembly. PMID- 28846849 TI - Cyclic Hexapeptide Dimers, Antatollamides A and B, from the Ascidian Didemnum molle. A Tryptophan-Derived Auxiliary for l- and d-Amino Acid Assignments. AB - Two dimerized cyclic hexapeptides, antatollamides A (1) and B (2), were isolated from the colonial ascidian Didemnum molle collected in Pohnpei. The amino acid compositions and sequences were determined by interpretation of MS and 1D and 2D NMR data. Raney Ni reduction of antatollamide A cleaved the dimer to the corresponding monomeric cyclic hexapeptide with replacement of Cys by Ala. The amino acid configuration of 1 was established, after total hydrolysis, by derivatization with a new chiral reagent, (5-fluoro-2,4-dinitrophenyl)-Nalpha-l tryptophanamide (FDTA), prepared from l-Trp, followed by LCMS analysis; all amino acids were found to be l-configured except for d-Ala. PMID- 28846850 TI - Building a local medical workforce in Tasmania: where are international fee paying medical graduates likely to work? AB - INTRODUCTION: Much of regional Australia continues to face challenges in recruitment and retention of medical practitioners, despite the apparently successful rural medical education initiatives funded by the Commonwealth Government. International fee-paying (IFP) medical students are a significant component of Australian medical education, contributing additional income and more diverse learning environments for universities. Their contribution to the Australian medical workforce is harder to determine. After obtaining registration, IFP graduates may apply to remain in Australia as skilled migrants. Since 1999 there has been a 325% increase in the number of international medical students in Australia, with approximately 73% of IFP graduates remaining in Australia for at least some postgraduate training. Recognising the potential contribution of IFP students to the Tasmanian medical workforce, the authors sought better understanding of the career intentions and work locations of IFP graduates from the medical program in Tasmania, Australia, through two studies. Firstly, a quantitative study was conducted of the locations of all IFP graduates from the Tasmanian medical program, and then a qualitative study exploring graduating students' intentions and factors that contribute to their decisions about work location choices. METHODS: This was a cohort study of IFP students who graduated from the University of Tasmania School of Medicine over the period 2000 2015. Work locations for 2016 were mapped to a Modified Monash rurality classification. Semi-structured interviews were held with 15 final year IFP medical students, exploring career intentions and location preferences. RESULTS: There were 261 IFP graduates, 54.4% male. The most common country of origin was Malaysia (55.2%). In 2016, 189 (72.4 %) were working in Australia, 42 (16.1%) in Tasmania and 126 (66.7%) in areas categorised as Modified Monash 1. Recent graduates in postgraduate year 1/2 (71.3%) were more likely to be working in Tasmania but most left for specialty training. All 15 interview participants intended to remain in Australia for at least their intern year, although at enrolment only six had planned to remain. Factors influencing workplace location decisions were (1) 'professional': greater appeal of Australian medical workplaces, intention to pursue a speciality, and to complete this at an Australian metropolitan hospital; (2) 'social': proximity to family/partner or opportunity to meet a prospective partner, family obligations, positive rural experiences; and (3) 'location': direct travel access to family. CONCLUSIONS: IFP graduates from the Tasmanian medical program make an important contribution to the Australian mainland metropolitan medical workforce, but play only a small role in workforce development for both Tasmania and the broader Australian rural and remote context. Most IFPs do not choose to work rurally. Rurally focused medical programs need to consider how they place IFP students to meet both the learning and career needs of IFP students and the goal of the rural medical programs in developing a rural workforce. PMID- 28846851 TI - The regulation of pituitary-thyroid abnormalities by peripheral administration of levothyroxine increased brain-derived neurotrophic factor and reelin protein expression in an animal model of Alzheimer's disease. AB - Alzheimer's disease (AD) is associated with decreased serum levels of thyroid hormones (THs), increased levels of thyroid-stimulating hormone (TSH), and decreased protein expression of brain-derived neurotrophic factor (BDNF) and reelin in the hippocampus. In this study, we have evaluated the effect of subcutaneous administration of levothyroxine (L-T4) on levels of THs and TSH as well as protein expression of BDNF and reelin in AD rats. To make an animal model of AD, amyloid-beta peptide (Abeta) plus ibotenic acid were infused intrahippocampally, and rats were treated with L-T4 and (or) saline for 10 days. The levels of THs and TSH were measured by ELISA kits. Protein synthesis was detected by Western blotting method. Results have been shown that serum level of THs, BDNF, and reelin protein expression in the hippocampus were significantly decreased (P < 0.001) in AD animals and elevated significantly in AD rats treated with L-T4 (P < 0.01). Data showed that TSH level significantly decreased in AD rats treated with L-T4 (P < 0.05). These findings indicated that L-T4 increased BDNF and reelin protein expression by regulation of serum THs and TSH level in Abeta-induced AD rats. PMID- 28846852 TI - Adaptation of mitochondrial expression and ATP production in dedifferentiating vascular smooth muscle cells. AB - Atherosclerosis is one of the leading causes of morbidity and mortality in the Western world. Although the clinical manifestations of this disease are well documented, the etiology and progression remain to be fully understood. Recently, the mitochondria have been implicated in important cellular processes involved in development of atherosclerosis. Despite the link between mitochondria and atherosclerosis, early-phase mechanisms of the disease have yet to be elucidated. The aim of this project was to explore the role of mitochondria in vascular smooth muscle (VSMC) dedifferentiation. A murine in vitro model, involving organ culture of aortic tissue in serum-free media, was used. Mitochondrial function was measured by high-resolution respirometry. Proteins associated with the VSMC phenotype switch, as well as mitochondrial density, were assessed by immunoblotting. The findings show that intrinsic mitochondrial Complex I activity is significantly upregulated during VSMC dedifferentiation. Diminished coupling between phosphorylation and oxidation was also found, indicating a greater ADP:ATP ratio. This data suggests increased leak in the electron transport chain and altered mitochondrial function specifically at Complex I. This project provides important information regarding the role of mitochondria in the early atherosclerotic process and that detectable changes in mitochondrial function and expression are related to VSMC dedifferentiation. PMID- 28846853 TI - Is this child sick? Usefulness of the Pediatric Assessment Triangle in emergency settings. AB - OBJECTIVE: The Pediatric Assessment Triangle is a rapid assessment tool that uses only visual and auditory clues, requires no equipment, and takes 30-60s to perform. It's being used internationally in different emergency settings, but few studies have assessed its performance. The aim of this narrative biomedical review is to summarize the literature available regarding the usefulness of the Pediatric Assessment Triangle in clinical practice. SOURCES: The authors carried out a non-systematic review in the PubMed(r), MEDLINE(r), and EMBASE(r) databases, searching for articles published between 1999-2016 using the keywords "pediatric assessment triangle," "pediatric triage," "pediatric assessment tools," and "pediatric emergency department." SUMMARY OF THE FINDINGS: The Pediatric Assessment Triangle has demonstrated itself to be useful to assess sick children in the prehospital setting and make transport decisions. It has been incorporated, as an essential instrument for assessing sick children, into different life support courses, although little has been written about the effectiveness of teaching it. Little has been published about the performance of this tool in the initial evaluation in the emergency department. In the emergency department, the Pediatric Assessment Triangle is useful to identify the children at triage who require more urgent care. Recent studies have assessed and proved its efficacy to also identify those patients having more serious health conditions who are eventually admitted to the hospital. CONCLUSIONS: The Pediatric Assessment Triangle is quickly spreading internationally and its clinical applicability is very promising. Nevertheless, it is imperative to promote research for clinical validation, especially for clinical use by emergency pediatricians and physicians. PMID- 28846854 TI - Conformations of the HIV-1 protease: A crystal structure data set analysis. AB - The HIV protease is an important drug target for HIV/AIDS therapy, and its structure and function have been extensively investigated. This enzyme performs an essential role in viral maturation by processing specific cleavage sites in the Gag and Gag-Pol precursor polyproteins so as to release their mature forms. This 99 amino acid aspartic protease works as a homodimer, with the active site localized in a central cavity capped by two flexible flap regions. The dimer presents closed or open conformations, which are involved in the substrate binding and release. Here the results of the analysis of a HIV-1 protease data set containing 552 dimer structures are reported. Different dimensionality reduction methods have been used in order to get information from this multidimensional database. Most of the structures in the data set belong to two conformational clusters. An interesting observation that comes from the analysis of these data is that some protease sequences are localized preferentially in specific areas of the conformational landscape of this protein. PMID- 28846855 TI - Expert - Non-expert differences in visual behaviour during alpine slalom skiing. AB - The aim of this study was to investigate visual behaviour of expert and non expert ski athletes during an alpine slalom. Fourteen non-experts and five expert slalom skiers completed an alpine slalom course in an indoor ski slope while wearing a head-mounted eye tracking device. Experts completed the slalom clearly faster than non-experts, but no significant difference was found in timing and position of the turn initiation. Although both groups already looked at future obstacles approximately 0,5s before passing the upcoming pole, the higher speed of experts implied that they shifted gaze spatially earlier in the bend than non experts. Furthermore, experts focussed more on the second next pole while non expert slalom skiers looked more to the snow surface immediately in front of their body. No difference was found in the fixation frequency, average fixation duration, and quiet eye duration between both groups. These results suggest that experts focus on the timing of their actions while non-experts still need to pay attention to the execution of these actions. These results also might suggest that ski trainers should instruct non-experts and experts to focus on the next pole and, shift their gaze to the second next pole shortly before reaching it. Based on the current study it seems unadvisable to instruct slalom skiers to look several poles ahead during the actual slalom. However, future research should test if these results still hold on a real outdoor slope, including multiple vertical gates. PMID- 28846856 TI - Perception and action in swimming: Effects of aquatic environment on upper limb inter-segmental coordination. AB - This study assessed perception-action coupling in expert swimmers by focusing on their upper limb inter-segmental coordination in front crawl. To characterize this coupling, we manipulated the fluid flow and compared trials performed in a swimming pool and a swimming flume, both at a speed of 1.35ms-1. The temporal structure of the stroke cycle and the spatial coordination and its variability for both hand/lower arm and lower arm/upper arm couplings of the right body side were analyzed as a function of fluid flow using inertial sensors positioned on the corresponding segments. Swimmers' perceptions in both environments were assessed using the Borg rating of perceived exertion scale. Results showed that manipulating the swimming environment impacts low-order (e.g., temporal, position, velocity or acceleration parameters) and high-order (i.e., spatial temporal coordination) variables. The average stroke cycle duration and the relative duration of the catch and glide phases were reduced in the flume trial, which was perceived as very intense, whereas the pull and push phases were longer. Of the four coordination patterns (in-phase, anti-phase, proximal and distal: when the appropriate segment is leading the coordination of the other), flume swimming demonstrated more in-phase coordination for the catch and glide (between hand and lower arm) and recovery (hand/lower arm and lower arm/upper arm couplings). Conversely, the variability of the spatial coordination was not significantly different between the two environments, implying that expert swimmers maintain consistent and stable coordination despite constraints and whatever the swimming resistances. Investigations over a wider range of velocities are needed to better understand coordination dynamics when the aquatic environment is modified by a swimming flume. Since the design of flumes impacts significantly the hydrodynamics and turbulences of the fluid flow, previous results are mainly related to the characteristics of the flume used in the present study (or a similar one), and generalization is subject to additional investigations. PMID- 28846857 TI - Assessment of specific muscle tension in dogs through functional electrical stimulation of the gastrocnemius muscle. PMID- 28846859 TI - Diosmin ameliorates the effects of oxidative stress in lenses of streptozotocin induced type 1 diabetic rats. AB - BACKGROUND: Diabetic cataractogenesis is a complex process connected with hyperglycemia and oxidative stress. Free radicals induce many unfavorable changes in the activity of the antioxidative enzymes and may also lead to oxidative damage. Since diosmin, a plant-derived flavonoid, reveals antioxidative activity, the aim of the study was to investigate if this substance may counteract the oxidative stress in the lenses of diabetic rats. METHODS: The study was conducted on the male Wistar rats with streptozotocin-induced type 1 diabetes. After the administration of diosmin at the doses of 50 and 100mg/kg for 4 weeks the oxidative stress markers in the lenses of these rats were evaluated. Tested markers included: activity of superoxide dismutase, catalase and glutathione peroxidase, as well as levels of total and soluble protein, level of glutathione, vitamin C, advanced oxidation protein products and malonyldialdehyde. RESULTS: The obtained results indicate that the administration of diosmin to the diabetic rats counteracted the unfavorable changes induced by diabetes in the lenses. CONCLUSION: It can be assumed that diosmin may be a promising compound in prevention or delaying the cataract formation during diabetes. PMID- 28846858 TI - Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo31P MRS study. AB - Evidence from 31P magnetic resonance spectroscopy (31P MRS) studies suggest that different psychiatric disorders, which typically emerge during adolescence and young adulthood, are associated with abnormalities in mitochondrial bioenergetics and membrane phospholipid metabolism. These disorders are also associated with deficits in omega-3 polyunsaturated fatty acids (n-3 PUFA), including docosahexaenoic acid (DHA) which accumulates in mitochondrial and synaptic membranes. The present study investigated the effects of dietary-induced alterations in brain DHA accrual during adolescence on phospholipid metabolism and bioenergetics in the adult rat brain using 31P MRS. During the peri adolescent period (P21-P90), male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (18:3n-3, n = 20). On P90, 31P MRS was performed under isoflurane anesthetic using a 7 T Bruker Biospec system. Compared with controls, brain DHA levels were significantly lower in adult rats fed the DEF diet (-17%, p <= 0.0001) and significantly higher in rats fed the FO diet (+14%, p <= 0.0001). There were no significant group differences for indices of bioenergetics, including adenosine triphosphate and phosphocreatine levels, or indices of membrane phospholipid metabolism including phosphomonoesters and phosphodiesters. Therefore, the present 31P MRS data suggest that rat brain DHA levels are not a significant predictor of mitochondrial bioenergetics or membrane phospholipid metabolism. PMID- 28846860 TI - Biometric and physiological responses of Egeria densa Planch. cultivated with toxic and non-toxic strains of Microcystis. AB - Cyanobacterial blooms are becoming increasingly common in aquatic environments around the world, mainly due to eutrophication and climate change. Cyanotoxin producing strains (e.g., microcystins (MC) producers) may be present in these blooms, affecting the growth of other aquatic organisms, such as aquatic macrophytes. In this study, we evaluated the morphometric and physiological responses of the aquatic macrophyte Egeria densa to the exposure to a toxic strain of Microcystis aeruginosa (MCs producer) and a non-toxic Microcystis panniformis (non-MC producer). The effects of Microcystis strains on E. densa growth and biomass were verified for five weeks (Experiment 1) and physiological responses were evaluated for 14days (Experiment 2). Prolonged exposure of E. densa to the MC producing strain reduced growth, accompanied by the inhibition of shoot and root emission. Both Microcystis strains caused a decrease in the content of photosynthetic pigments, like total chlorophyll and chlorophyll a and b, accompanied by an increase of carotenoids. At the beginning of the MC producing strain exposure, E. densa showed an increase in the activity of the anti-oxidative enzymes superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), accompanied by an increase in the levels of malondialdehyde, indicating lipid peroxidation. During the 14th day of exposure, the activity of antioxidant enzymes remained similar to the control, suggesting that E. densa has an efficient anti-oxidative system to control the reactive oxygen species produced in response to the stress caused by microcystins. However, when prolonged exposure occurred, possible damage to proteins may have affected the growth and development of E. densa. No changes were observed in the enzymatic activity of the plants exposed to the non-MC producing strain, suggesting that this cyanobacterial strain do not cause significant damage to the development of E. densa. These results are important for understanding the anti-oxidative defense mechanisms of aquatic macrophytes when coexisting with an MC producing strain. PMID- 28846861 TI - Wildfire effects on lipid composition and hydrophobicity of bulk soil and soil size fractions under Quercus suber cover (SW-Spain). AB - Soil water repellency (hydrophobicity) prevents water from wetting or infiltrating soils, triggering changes in the ecosystems. Fire may develop, enhance or destroy hydrophobicity in previously wettable or water-repellent soils. Soil water repellency is mostly influenced by the quality and quantity of soil organic matter, particularly the lipid fraction. Here we report the results of a study on the effect of fire on the distribution of soil lipids and their role in the hydrophobicity grade of six particle size fractions (2-1, 1-0.5, 0.5 0.25, 0.25-0.1, 0.1-0.05 and <0.05mm) of an Arenosol under Quercus suber canopy at the Donana National Park (SW-Spain). Hydrophobicity was determined using water drop penetration time test. Field emission scanning electron microscopy (FESEM) was used to assess the presence and morphology of the inorganic and organic soil components in the particle size fractions. Soil lipids were Soxhlet extracted with a dichloromethane-methanol mixture. Fatty acids (FAs) and neutral lipids were separated, derivatized, identified and quantified by gas chromatography/mass spectrometry and gas chromatography/flame ionization detection. The hydrophobicity values of soil samples and fractions were statistically different (P < 0.05), for both, the unburnt and burnt soils, and particle size fractions. All samples displayed a similar distribution of FAs, straight-chain saturated acids in the C14-C32 range, and neutral lipids (n-alkan-1-ols, n-alkanes), only differing in their relative abundances. Among possible biogeochemical mechanisms responsible for the changes in soil lipids, the observed depletion of long chain FAs (C>=24) in the coarse fraction is best explained by thermal cracking caused by the heat of the fire. The enrichment of long chain FAs observed in other fractions suggests possible exogenous additions of charred, lipid-rich, material, like cork suberin or other plant-derived macromolecules (cutins). Principal component analysis was used to study the relationships between hydrophobicity with soil organic matter and its different components. Extractable organic matter (EOM) and specifically long chain FAs content were positively correlated to soil hydrophobicity. Therefore, the latter could be used as biomarkers surrogated to hydrophobicity in sandy soils. PMID- 28846862 TI - The impact of adjustments to the diagnostic criteria for biochemical remission in surgically treated patients with acromegaly. AB - BACKGROUND: The suggested criteria for biochemical remission in patients treated for acromegaly were recently modified. The aim of this project was to study to what extent this modification influences remission rates. DESIGN, PATIENTS AND METHODS: This was a retrospective study of 55 consecutive patients [29 men; median age 47years (interquartile range 38-68)] diagnosed with acromegaly between 2003 and 2014. After treatment serum IGF-I and/or GH was measured according to a standardized protocol. The biochemical remission status was defined according to the clinical guidelines from 2010 and2014. RESULTS: Out of 55 patients, 44 patients were primarily operated. Of these, 33 (75%) were evaluated 3-12months postoperatively by measuring serum IGF-I and GH during an oral glucose tolerance test. According to the 2010 guidelines, 11 patients (33%) were in biochemical remission, 15 patients (46%) were not and 7 patients (21%) had discordant results (normal IGF-I and high GH or vice versa). Applying the 2014 guidelines in the same group, 16 patients (49%) were in biochemical remission, 7 patients (21%) were not and 10 patients (30%) had discordant results. Thus, by using the most recent criteria for biochemical control, more patients were considered to be in remission, or with discordant results, and fewer patients not in remission (P<0.05). CONCLUSION: An apparently minor adjustment of the criteria for biochemical control has a significant impact on remission status in patients treated for acromegaly, eventually affecting follow-up and treatment strategies. PMID- 28846863 TI - Extra pelvic endometriosis: Retrospective analysis on 200 cases in two different countries. AB - OBJECTIVE(S): The purpose of the study was to review patients' characteristics and the location of extrapelvic endometriosis. STUDY DESIGN: Out of 1000 women with endometriosis during a 20year period, we found 200 cases with extra pelvic endometriosis. Medical reports were evaluated and the diagnosis was confirmed on the pathological specimen. This study involved cases from two different geographical areas, New Haven and Crete. The age, parity, symptoms, previous surgeries, diagnostic modalities, histopathological evaluation and location of endometriotic implants found in other areas were recorded and analyzed from the patient's charts. MAIN OUTCOME MEASURE(S): Statistical methods included x2 and Mann-Whitney U test s measuring incidence of right-VS left sided endometriosis. RESULTS: 200 patients with extrapelvic endometriosis and 800 patients with pelvic endometriosis were included in the study. The gastrointestinal tract represents the most common location of extrapelvic endometriosis with 104/200(52%) cases (p<0, 01), followed by the urinary system with70/200(35%) cases. We observed the Left-sided ureter being involved in 49/200(24, 5%) cases, significantly higher compare with the right-sided ureter 21/100(10, 5%) (p <0, 01). All women had similar characteristics involving age, weight, main complaints, age of menarche, endometriosis stages, gravid and family history of endometriosis. CONCLUSION(S): The gastrointestinal tract and the urinary system are the most common sites of the extrapelvic endometriosis, which was obvious in both countries. Moreover, we observed that there are no significant differences in demographic variants, menstrual and reproductive characteristics in women with extrapelvic and pelvic endometriosis. PMID- 28846864 TI - Anti-Mullerian hormone levels and fecundability in women with a natural conception. AB - OBJECTIVES: To investigate the association between anti-Mullerian hormone (AMH), a well-established marker of the ovarian reserve, and time-to-pregnancy (TTP) in natural conceptions, and to assess changes in serum-AMH in early pregnancy. STUDY DESIGN: A cross sectional study comprising 279 women aged 21-42 years with a natural conception recruited during 2012-2014. AMH was measured in gestational week 10-19. AMH z-scores (z-AMH) adjusted for gestational week at blood sampling were categorised in the 1st, 2nd-4th (reference), and 5th quintile. Data were analysed by discrete-time survival-analysis and results presented as odds ratios (OR), 95% confidence interval (CI); OR <1 indicating a longer TTP and OR >1 indicating a shorter TTP. RESULTS: The median AMH-level was 23.0 (range:<3.0;144.0)pmol/l, and serum-AMH decreased by 7.5% (95% CI:-12.0%;-2.8%) per gestational week. Mean+/-SD female age was 30.9+/-3.6years. The median TTP was 2 (range: 1-32) months. After adjustment for possible confounders including total sperm count, TTP was unrelated to female age (aOR:1.0, 95% CI:0.9;1.0) and continuous z-AMH (aOR:0.8, 95% CI:0.7;1.0), but women in the low z-AMH group had a shorter TTP than the reference group (aOR:1.7, 95% CI:1.1;2.7). TTP was prolonged in preconception oral contraceptive (OC) users (aOR:0.7, 95% CI:0.5;1.0, p=0.04). Compared with women having used OC <2 years, TTP was significantly longer in women having used OC for 2-12 years (aOR:0.5, 95% CI:0.2;1.0, p=0.048) and >12 years (aOR:0.4, 95% CI:0.2;0.9, p=0.022) after age adjustment. CONCLUSIONS: TTP was unrelated with z-AMH when modelled as a continuous covariate. Unexpectedly, TTP was shorter in the low z-AMH group. Natural conception was observed in women with a wide range of AMH-levels including women with undetectable serum-AMH. A continuous decrease in serum-AMH was observed during first and second trimester. Preconception OC-use was identified as an independent predictor of a prolonged TTP, and the duration of OC use appeared to influence the delay in conception. Although this is presently one of the largest studies investigating the association between AMH and fecundability in fertile women, the study has some limitation including a relatively low participation rate and a risk of selection bias in addition to AMH assessment in pregnancy and a retrospective collection of TTP and OC-use associated with a risk of recall bias. These limitations may explain the unexpected finding of a shorter TTP in the low z-AMH group. PMID- 28846865 TI - Insulin glargine and its two active metabolites: A sensitive (16pM) and robust simultaneous hybrid assay coupling immunoaffinity purification with LC-MS/MS to support biosimilar clinical studies. AB - MK-1293 is a newly approved follow-on/biosimilar insulin glargine for the treatment of Type 1 and Type 2 diabetics. To support pivotal clinical studies during biosimilar evaluation, a sensitive, specific and robust liquid chromatography and tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantification of glargine and its two active metabolites, M1 and M2 were developed. Strategies to overcome analytical challenges, so as to optimize assay sensitivity and improve ruggedness, were evolved, resulting in a fully validated LC-MS/MS method with a lower limit of quantification (LLOQ) at 0.1ng/mL (~16pM, equivalent to ~2.8MUU/mL) for glargine, M1 and M2, respectively, using 0.5mL of human plasma. The assay employed hybrid methodology that combined immunoaffinity purification and reversed-phase chromatography followed by electrospray-MS/MS detection operated under positive ionization mode. Stable-isotope labeled 6[D10]Leu-glargine and 4[D10]Leu-M1 were used as internal standards. With a calibration range from 0.1 to 10ng/mL, the intra-run precision (n=5) and accuracy were <6.21%, and 96.9-102.1%, while the inter-run (n=5/run for 7days) precision and accuracy were <9.55% and 96.5-105.1%, respectively, for all 3 analytes. Matrix effect, recovery, analyte stability, and interferences from control matrix, potential concomitant medications and anti-drug antibody were assessed. The assay was fully automated and has been successfully used in support of biosimilar clinical studies. Greater than 94.3% of incurred sample reanalysis (ISR) results met acceptance criteria, demonstrating the robustness of the assay. The strategic considerations during method development and validation are discussed, and can be applied to quantification of other peptides, especially insulin analogs, in the future. PMID- 28846866 TI - The effect of deep eutectic solvent on the pharmacokinetics of salvianolic acid B in rats and its acute toxicity test. AB - Deep eutectic solvent (DES), the benign green solvent with uniquely physical properties, has been widely applied in various fields. Our previous study indicated that DES could improve the stability and extraction efficiency of salvianolic acid B (SAB). In this work, with SAB as a model drug, the feasibility of DES as a drug carrier for oral preparation was investigated by evaluating the influence of DES on the pharmacokinetics of SAB and the toxicity of DES. Acute oral toxicity test illustrated that choline chloride-glycerol (ChCl-GL, molar ratio 1:2) was non-toxic with the median lethal dose of 7733mg/kg. To comparison the difference of pharmacokinetics between SAB dissolved in ChCl-GL (1:2) and in water, a rapid and sensitive ultra-performance liquid chromatography coupled with mass spectrum was established to determine SAB and its metabolites in rat plasma. The method validation was also tested for the specificity, linearity (r2>0.9980 over two orders of magnitude), precision (intra-day relative standard deviation (RSD)<2.73% and inter-day RSD<7.72%), extraction recovery (70.96-80.78%) and stability under three different situations. Compared to water, the pharmacokinetic parameters clarified that ChCl-GL (1:2) could promote the absorption of SAB, the peak concentration (Cmax) of 0.308+/-0.020mg/L was slightly higher than 0.277+/-0.024mg/L (SAB dissolved in water), and the peak time (Tmax) was significantly decreased from 30min (SAB dissolved in water) to 20min. There was no significant difference on the metabolites between SAB dissolved in ChCl-GL (1:2) and in water. This is the first report on the pharmacokinetic study of DES as a candidate of drug carrier, and the results provide a meaningful basis for the application of DES in pharmaceutical preparation. PMID- 28846868 TI - Transcription coupled repair deficiency protects against human mutagenesis and carcinogenesis: Personal Reflections on the 50th anniversary of the discovery of xeroderma pigmentosum. AB - Xeroderma pigmentosum (XP) patients who lack the main damage recognition protein for global genome repair (GGR), XPC, have greatly increased skin cancer rates and elevated mutation frequencies originating from unrepaired ultraviolet photoproducts in the nontranscribed regions of the genome and in nontranscribed strands of expressed genes. But they show no increased mutations in transcribed strands. In contrast, cancer is absent from Cockayne syndrome (CS) patients that have defective transcription coupled repair (TCR) despite severe photosensitivity, CS patients remarkably show no elevation of UV induced mutagenesis implying that defective TCR may be protective against mutagenesis and carcinogenesis. Mutation avoidance in CS is postulated to occur through arrested transcription that generates a tripled stranded R loop consisting of DNA double strands and a nascent mRNA strand. R loops result in S phase apoptosis or activation of ATM kinase that causes a delay in DNA replication until TCR, or transcript cleavage by TFIIS or RNAaseH, relieves the transcription block. Resumption of replication then occurs on repaired DNA without concomitant mutagenesis. PMID- 28846867 TI - Simultaneous measurement of whole blood vitamin B1 and vitamin B6 using LC-ESI MS/MS. AB - Vitamin B1 and B6 have recently been included in the Dutch clinical guidelines for the general practitioner in the differential diagnosis of dementia. To keep up with the sharp rise in the number of requests, an LC-MS/MS method using stable isotopes as internal standards was developed. The active vitamers thiamine pyrophosphate (TPP) and pyridoxal-5'-phosphate (PLP) in whole blood are simultaneously measured with a short run time of 2min. Whole blood is mixed with internal standard solution containing both TPP-d3 and PLP-d3, followed by deproteinization with a trichloroacetic acid (TCA) solution. A UPLC-MS/MS system from WatersTM was used for chromatographic separation and subsequent detection by electrospray ionization in the positive mode with mass transitions of 425.1>121.85 for TPP and 247.9>149.9 for PLP. The method is linear across the range of 12-4870 nmol/L for TPP and 6-4850 nmol/L for PLP. The mean intra-assay and inter-assay precision are 3.5% and 7.6% respectively for TPP and 3.4% and 6.1% for PLP. The relative matrix effect (TPP 97%, PLP 93%), recovery (TPP 99%, PLP 94%) and lower limit of quantification (TPP 12 nmol/L, PLP 6 nmol/L) meet the applied acceptance criteria. The comparison of the new LC-ESI-MS/MS method for TPP with our current HPLC-Fluorescence method for total thiamine yields the following equation: TPP LC-MS/MS=0.97*total thiamine HPLC - 10.61 (r2=0.94). The comparison of the new LC-ESI-MS/MS method for PLP with our current LC-ESI-MS/MS method results in PLP LC-MS/MS new=1.01*PLP LC-MS/MS old - 1.58 (r2=0.99). In conclusion, this LC-MS/MS based assay is characterized by simple sample processing with a short run time and comparison with the current methods is excellent. The new LC-MS/MS method is a convenient method to determine TPP and PLP in whole blood for both clinical routine and research applications. PMID- 28846869 TI - XLF/Cernunnos: An important but puzzling participant in the nonhomologous end joining DNA repair pathway. AB - DNA double strand breaks (DSBs) are one of the most deleterious DNA lesions that promote cell death, genomic instability and carcinogenesis. The two major cellular mechanisms that repair DSBs are Nonhomologous End-Joining (NHEJ) and Homologous Recombination Repair (HRR). NHEJ is the predominant pathway, in which XLF (also called Cernunnos) is a key player. Patients with XLF mutation exhibit microcephaly, lymphopenia, and growth retardation, and are immunodeficient and radiosensitive. During NHEJ, XLF interacts with XRCC4-Ligase IV, stimulates its ligase activity, and forms DNA-binding filaments of alternating XLF and XRCC4 dimers that may serve to align broken DNA and promote ligation of noncomplementary ends. Despite its central role in NHEJ, the effects of XLF deficiency are surprisingly variable in different biological contexts, and different individual cell lines. This review summarizes the role of XLF in NHEJ, and the unexpected complexity of its interplay with other repair factors in supporting radiosurvival and V(D)J recombination. PMID- 28846870 TI - Sphingosine kinase AtSPHK1 functions in fumonisin B1-triggered cell death in Arabidopsis. AB - The fungal toxin Fumonisin B1 (FB1) is a strong inducer to trigger plant hypersensitive responses (HR) along with increased long chain bases (LCB) and long chain base phosphates (LCBP) contents, though the regulatory mechanism of FB1 action and how the LCB/LCBP signalling cassette functions during the process is still not fully understood. Here, we report sphingosine kinase 1 (SPHK1) as a key factor in FB1-induced HR by modulating the salicylic acid (SA) pathway and reactive oxygen species (ROS) accumulation in Arabidopsis thaliana. Overexpression of SPHK1 increases the FB1-induced accumulations of ROS and SA. The double mutant that simultaneously overexpresses SPHK1 and suppresses the SPPASE or DPL1, two enzymes are mainly responsible for Phyto-sphingosine-1 phosphate (Phyto-S1P) removal, showed enhanced susceptibility to FB1 killing and FB1-induced SA activation than the plants overexpress SPHK1 alone. Exogenous sphingosine-1-phosphate (S1P) can modulate the transcription of the SA-responsive marker gene PR1 in a concentration-dependent biphasic manner. Suppression of SPHK1 decreases SA production whereas promotes jasmonic acid (JA) biosynthesis in response to FB1 applications. Our findings indicate a role of SPHK1 in modulating FB1-triggered cell death via SA and JA pathway interactions. PMID- 28846871 TI - Pediatric reference data on activity of urinary N-acetyl-beta-D-hexosaminidase and its isoenzymes. AB - PURPOSE: The objective of the study was to establish age - dependent values of the urinary lysosomal exoglycosidases activities: N-acetyl-beta-D-hexosaminidase (HEX) and its isoenzyme A (HEX A) as well as isoenzyme B (HEX B) in healthy children and adolescents. MATERIAL AND METHODS: The study was performed using a random sample of 203 healthy children and adolescents (girls=99, boys=104), aged six months to 17.9 years. The activities of HEX, HEX A and HEX B were determined by a colorimetric method. The activities of the urinary HEX and its isoenzymes were expressed in pKat/MUg of creatinine (pKat/MUg Cr). RESULTS: Median concentrations of urinary HEX, and its HEX A, HEX B isoenzymes in particular age groups were analyzed using ANOVA. Urinary HEX, HEX A and HEX B activities (pKat/MUg Cr) were the highest in children below 3 years, in comparison to remaining age groups. There were statistically significant negative correlations between urinary HEX, HEX A as well as HEX B and age (r=-0.24, p<0.001 (HEX); r= 0.20, p<0.01 (HEX A); r=-0.26, p<0.001 (HEX B), respectively. We constructed the reference values for urinary activity of HEX, HEX A and HEX B (pKat/MUg Cr) in centiles according to age, in three-year intervals. CONCLUSIONS: Reported data present, for the first time, reference values for urinary activities of HEX and its isoenzymes HEX A and HEX B in children and adolescent. PMID- 28846872 TI - The signatures of conscious access and its phenomenology are consistent with large-scale brain communication at criticality. AB - Conscious awareness refers to information processing in the brain that is accompanied by subjective, reportable experiences. Current models of conscious access propose that sufficiently strong sensory stimuli ignite a global network of regions allowing further processing. The immense number of possible experiences indicates that activity associated with conscious awareness must be highly differentiated. However, information must also be integrated to account for the unitary nature of consciousness. We present a computational model that identifies conscious access with self-sustained percolation in an anatomical network. We show that the amount of integrated information (Phi) is maximal at the critical threshold. To the extent that self-sustained percolation relates to conscious access, the model supports a link between information integration and conscious access. We also identify a posterior "hotspot" of regions presenting high levels of information sharing. Finally, competitive activity spreading qualitatively describes the results of paradigms such as backward masking and binocular rivalry. PMID- 28846873 TI - What role do nightmares play in suicide? A brief exploration. AB - The suicide rate in the United States has climbed each year for more than a decade, highlighting the need for greater understanding of, and prevention strategies for suicidal behavior. Nightmares have been shown to be associated with suicidal behavior independent of several psychiatric risk factors for suicide, such as symptoms of depression, anxiety, and posttraumatic stress disorder (PTSD). The specific role of nightmares in contributing to suicide remains unclear due to the difficulty in delineating causal factors. However, the reporting, screening and treatment of nightmares continues to remain rare making progress difficult. Research is beginning to make some progress in uncovering the mechanisms by which nightmares increase suicide risk providing opportunities for intervention and prediction of suicidal behaviors. PMID- 28846874 TI - Eating disorders and suicidality: what we know, what we don't know, and suggestions for future research. AB - Suicide is the second leading cause of death among individuals with anorexia nervosa (AN), and suicidal behavior is elevated in bulimia nervosa (BN) and binge eating disorder (BED) relative to the general population. This paper reviews the suicidality literature within each ED, as well as theoretical explanations for the elevated risk for suicidality among those with EDs. Approximately one-quarter to one-third of people with AN, BN, or BED have thought about suicide, and one quarter to one-third of people with AN and BN have attempted suicide. Relative to gender and aged matched comparison groups, individuals with AN are 18 times more likely to die by suicide, and individuals with BN are seven times more likely to die by suicide. However, the majority of the research in this area is cross sectional or retrospective, which leaves the timing of the mortality risk unclear. Longitudinal work that is designed to examine dynamic and acute fluctuations in suicidality among ED samples is needed in order to determine meaningful risk factors. PMID- 28846875 TI - Comparison of MRI segmentation techniques for measuring liver cyst volumes in autosomal dominant polycystic kidney disease. AB - PURPOSE: To compare MRI segmentation methods for measuring liver cyst volumes in autosomal dominant polycystic kidney disease (ADPKD). METHODS: Liver cyst volumes in 42 ADPKD patients were measured using region growing, thresholding and cyst diameter techniques. Manual segmentation was the reference standard. RESULTS: Root mean square deviation was 113, 155, and 500 for cyst diameter, thresholding and region growing respectively. Thresholding error for cyst volumes below 500ml was 550% vs 17% for cyst volumes above 500ml (p<0.001). CONCLUSION: For measuring volume of a small number of cysts, cyst diameter and manual segmentation methods are recommended. For severe disease with numerous, large hepatic cysts, thresholding is an acceptable alternative. PMID- 28846876 TI - Inhalation delivery of complex drugs-the next steps. AB - Oral inhalation offers the opportunity of targeting drugs locally to different regions of the respiratory tract or alternatively, using the high surface area of the alveoli for systemic delivery. Pulmozyme and the inhaled insulins (i.e. Exubera and Afrezza) are examples of the scope of pulmonary drug delivery of biopharmaceuticals-albeit with strikingly different commercial success. Particularly, the failure of Exubera and the subsequent overreactions (e.g. the unsubstantiated lung cancer fear), lastingly stunned the field of systemically inhaled protein and peptide drugs. Building on the lessons learned from these early products, a new wave of inhaled biomolecules has recently entered clinical trials. Moreover, oral inhalation has become an attractive alternative for the delivery of small molecules with difficult oral pharmacokinetics and/or extensive liver first-pass metabolism. Advances in inhaler design and our increased understanding of lung physiology continue to make oral inhalation of complex drugs an attractive therapeutic option. PMID- 28846877 TI - Plasma anti-FXa concentration after continuous intravenous infusion and subcutaneous dosing of enoxaparin for thromboprophylaxis in critically ill patients. A randomized clinical trial. AB - INTRODUCTION: In intensive care unit (ICU) patients, subcutaneous low-molecular weight heparin thromboprophylaxis results in lower plasma anti-factor Xa (anti FXa) levels compared to general ward patients. The aim of this study was to examine whether enoxaparin thromboprophylaxis given as a continuous intravenous infusion (CII) results in more constant and predictable anti-FXa concentration than standard subcutaneous bolus (SCB) administration. MATERIALS AND METHODS: This was a prospective, single-blind, multicenter, randomized controlled trial where ICU patients requiring thromboprophylaxis received enoxaparin either 40mg as a SCB once daily or 40mg as a CII over 24h for three consecutive days. The primary outcome was maximum serum anti-FXa concentration (Cmax24h) within the first 24h; the secondary outcome was anti-FXa area under the curve (AUC)(0-24h). Trough level was measured at 72h. RESULTS: Thirty-nine patients were included in the intention to treat analysis. The median anti-FXa Cmax24h was 0.05 (interquartile range, IQR, 0.05-0.18) IU/ml in the CII group and 0.18 (IQR, 0.12 0.33) IU/ml in the SCB group (p=0.05). Median anti-FXa AUC(0-24h) was 1.20 (IQR, 0.98-2.88) in the CII and 1.54 (IQR, 1.22-4.12) in the SCB group (p=0.095). After 72h, 66.7% of patients in the CII group had a detectable anti-FXa concentration of >0.1IU/ml, compared with 16.7% in the SCB group (p=0.019). CONCLUSIONS: Continuous infusion of enoxaparin led to lower anti-FXa Cmax24h than standard SCB administration. No difference in anti-FXa AUC0-24h was detected. PMID- 28846878 TI - Study on a novel polymorphism in the VKORC1 promoter region using bioinformatic tools and warfarin dosing data. PMID- 28846879 TI - Insufficient sleep is associated with impaired nitric oxide-mediated endothelium dependent vasodilation. AB - BACKGROUND AND AIMS: Habitual short nightly sleep duration is associated with increased atherosclerotic cardiovascular disease risk and morbidity. Vascular endothelial dysfunction represents an important mechanism that may underlie this heightened cardiovascular risk. Impaired endothelium-dependent vasodilation, particularly NO-mediated vasodilation, contributes to the development and progression of atherosclerotic vascular disease and acute vascular events. We tested the hypothesis that chronic insufficient sleep is associated with impaired NO-mediated endothelium-dependent vasodilation in middle-aged adults. METHODS: Thirty adult men were studied: 15 with normal nightly sleep duration (age: 58 +/- 2 y; sleep duration: 7.7 +/- 0.2 h/night) and 15 with short nightly sleep duration (55 +/- 2 y; 6.1 +/- 0.2 h/night). Forearm blood flow (FBF) responses to intra-arterial infusion of acetylcholine, in the absence and presence of the endothelial NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), as well as responses to sodium nitroprusside, were determined by strain-gauge venous occlusion plethysmography. RESULTS: The FBF response to acetylcholine was lower (~20%; p<0.05) in the short sleep duration group (from 4.6 +/- 0.3 to 11.7 +/- 1.0 ml/100 ml tissue/min) compared with normal sleep duration group (from 4.4 +/- 0.3 to 14.5 +/- 0.5 ml/100 ml tissue/min). L-NMMA significantly reduced the FBF response to acetylcholine in the normal sleep duration group (~40%), but not the short sleep duration group. There were no group differences in the vasodilator response to sodium nitroprusside. CONCLUSIONS: These data indicate that short nightly sleep duration is associated with endothelial-dependent vasodilator dysfunction due, in part, to diminished NO bioavailability. Impaired NO-mediated endothelium-dependent vasodilation may contribute to the increased cardiovascular risk with insufficient sleep. PMID- 28846880 TI - Analyzing driver-pedestrian interaction in a mixed-street environment using a driving simulator. AB - This paper presents the design, analysis and results of a driving simulator experiment conducted to study the interaction between drivers and pedestrians in a mixed-street environment. Ninety-six students of the American University of Beirut (AUB) participated in the experiment that took place in the Transportation and Infrastructure Laboratory of AUB. The study looked at the driver-pedestrian interaction from the driver's perspective, by quantifying the effects of different scenario variables on the driving behavior of the participants. Kruskall-Wallis test shows that drivers' behavior in proximity of pedestrians tends to be statistically significantly less aggressive when their approach velocity is lower, curb-side parking is not allowed, a crosswalk exists, and the number of pedestrians crossing the street is higher. A discrete choice model for the yielding behavior of the drivers was also developed as a function of different predictor variables. Five out of the six predictors considered (except for gender) had a statistically significant effect on the yielding behavior, particularly the effects of curb-side parking, number of pedestrians crossing, and approach velocity. The model was then used to evaluate the effect of policy variables on the yielding probabilities of the drivers. The results of this study enrich current knowledge and understanding of drivers' behavior and their interaction with pedestrians, especially with studying the effects of scenario variables that were not addressed before; this would help planners propose and evaluate safety measures and traffic calming techniques to reduce the risks on pedestrians. The study also confirms the effectiveness of driving simulators in studying driver-pedestrian interactions. PMID- 28846881 TI - Cultural models of self and social class disparities at organizational gateways and pathways. AB - Attaining a college degree has traditionally been assumed to be key to upward social and professional mobility. However, college graduates from working-class backgrounds achieve less career success in professional, white-collar workplaces compared to those from middle-class backgrounds. Using a cultural models approach, we examine how the independent cultural beliefs and practices promoted by professional organizations disadvantage people from working-class backgrounds, who espouse interdependent beliefs and practices. Our review illustrates how this disadvantage can manifest in two ways. First, despite relative equality in objective qualifications, it can occur at organizational gateways (e.g., interview and hiring decisions). Second, even after people from working-class backgrounds gain access to an organization, it can occur along organizational pathways (e.g., performance evaluations and assignment to high-profile tasks). PMID- 28846883 TI - Socio-demographic and reproductive health profile of women who experienced signs of obstetric fistula: Results from Pakistan Demographic and Health Survey (PDHS) 2006-2007. AB - OBJECTIVE: to examine the socio-demographic profile of women experiencing signs of obstetric fistula and factors contributing to the development of this condition in Pakistan. METHODS: secondary data analysis of Pakistan Demographic and Health Survey 2006-07, which for the first time measured signs of obstetric fistula, using a questionnaire at a population level. For the present study, questions directly related to obstetric fistula signs were used to construct a dependent variable. Data were analysed by descriptive and logistic regression analysis, to examine factors associated with development of fistula. FINDINGS: among women of reproductive age (n = 9134, aged 15-49 years), some 277 (3.0%, 30 per 1000 women who ever gave birth) experienced obstetric fistula signs, whereas 103 (1.1% of all women) were still experiencing the condition at the time of survey. In a logistic regression model, women from the Punjab region (OR = 5.67, 95%CI = 2.10-15.31), women who delivered by caesarean section (OR = 1.91, 95% CI = 1.06-3.42) and reported having complications during pregnancy were more likely to develop obstetric fistula (OR = 1.96, 95%CI = 1.19-3.16). CONCLUSIONS: Obstetric fistula is one of the neglected public and reproductive health concerns in Pakistan. To eliminate this preventable tragedy, there is a need for better emergency obstetric care facilities and the availability of a fistula repair service throughout the country. PMID- 28846882 TI - Alzheimer's-related cortical atrophy is associated with postoperative delirium severity in persons without dementia. AB - Patients with dementia due to Alzheimer's disease (AD) have increased risk of developing delirium. This study investigated the relationship between a magnetic resonance imaging (MRI)-derived biomarker associated with preclinical AD and postoperative delirium. Participants were older adults (>=70 years) without dementia who underwent preoperative MRI and elective surgery. Delirium incidence and severity were evaluated daily during hospitalization. Cortical thickness was averaged across a published set of a priori brain regions to derive a measure known as the "AD signature." Logistic and linear regression was used, respectively, to test whether the AD signature was associated with delirium incidence in the entire sample (N = 145) or with the severity of delirium among those who developed delirium (N = 32). Thinner cortex in the AD signature did not predict incidence of delirium (odds ratio = 1.15, p = 0.38) but was associated with greater delirium severity among those who developed delirium (b = -1.2, p = 0.014). These results suggest that thinner cortices, perhaps reflecting underlying neurodegeneration due to preclinical AD, may serve as a vulnerability factor that increases severity once delirium occurs. PMID- 28846884 TI - Clozapine withdrawal catatonia, psychosis and associated neuroleptic malignant syndrome. PMID- 28846885 TI - Lorazepam precipitated alcohol withdrawal delirium - Two case report. PMID- 28846886 TI - Immunomodulatory effects induced by intramuscular administration of autologous total immunoglobulin G in patients with atopic dermatitis. AB - BACKGROUND: Polyvalent human immunoglobulin G (IgG) preparations produced from the plasma pools of healthy blood donors have been used for the treatment of various autoimmune diseases and allergic diseases because of their anti inflammatory and immunomodulatory effects. We hypothesized that intramuscular administration of autologous total IgG would induce immunomodulatory effects in patients with allergic diseases, based on the clinical efficacy of autologous blood therapy in patients with atopic dermatitis (AD). METHODS: Sixteen adult AD patients with IgE-mediated sensitization to the house dust mite (Dermatophagoides farinae) received intramuscular injections of 50 mg autologous total IgG twice a week for 4 weeks. The serum levels of IgE, IgG, and IgG4 antibodies to the recombinant group 2 major allergen of Dermatophagoides farinae (Der f 2) and serum levels of interleukin (IL)-10, IL-4, IL-12, and interferon gamma (IFN gamma) were measured by enzyme-linked immunosorbent assay at baseline and at weeks 4, 8, and 12. RESULTS: The serum level of IgE antibodies to Der f 2 was significantly decreased at 12 weeks compared with baseline (p<0.005). The serum levels of IgG and IgG4 antibodies to Der f 2 were significantly increased at 4, 8, and 12 weeks compared with baseline (p<0.05). The serum levels of IL-10 and IFN-gamma were significantly increased at 4, 8, and 12 weeks compared with baseline (p<0.05). There were no significant differences in the serum levels of IL-4 or IL-12 before and after intramuscular administrations of autologous total IgG (p>0.05). CONCLUSION: Intramuscular administration of autologous total IgG induced anti-allergic immunomodulatory effects in AD patients. Further studies are required to evaluate the detailed immunological mechanism underlying these effects. PMID- 28846887 TI - Attenuation of cyclosporine A induced nephrotoxicity by schisandrin B through suppression of oxidative stress, apoptosis and autophagy. AB - Cyclosporine A (CsA) is a potent immunosuppressive agent whose clinical usage is limited by nephrotoxicity. Schisandrin B (SchB), isolated from the fruit of Schisandra chinensis, is a natural compound with multiple pharmacological activities that has been shown to attenuate organ injury caused by CsA. Hence, the primary objective of the current study was to evaluate whether SchB has a cytoprotective effect on CsA-induced nephrotoxicity in human proximal tubular epithelial cell line (HK-2). This study demonstrated that pre-incubation of HK-2 cells with 2.5-10.0MUM SchB ameliorated CsA induced cytotoxicity caused by oxidative stress as evidenced by reduced levels of intracellular reactive oxygen species (ROS) and LDH release along with increased levels of mitochondrial membrane potential (DeltaPsim) and glutathione (GSH). Also, it was demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) activation was involved in modulating cellular oxidative stress, where SchB promoted Nrf2 translocation into the nucleus and downstream target gene expression of heme oxygenase-1 (HO 1), NAD(P)H:quinone oxidoreductase 1 (NQO1) and Glutamate-cysteine ligase modifier subunit (GCLM). Additionally, SchB was found to enhance cell survival via reducing apoptosis rate as well as recover the CsA induced blockade of autophagic flux. Collectively, these findings demonstrated that SchB mediated alleviation of CsA induced nephrotoxicity by preventing the accumulation of ROS by way of suppressing oxidative stress, apoptosis and autophagy. PMID- 28846888 TI - Prognostic value of tumor PD-L1 expression combined with CD8+ tumor infiltrating lymphocytes in high grade serous ovarian cancer. AB - Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but the relationship between tumor PD-L1 expression and tumor-infiltrating lymphocytes (TILs), and their association with clinical outcomes in patients with high grade serous ovarian cancer (HGSOC) remain ambiguous. We detected the expression of PD-L1 and CD3+, CD4+, CD8+ TILs in 107 patients with HGSOC by immunohistochemical analysis. Using a 5% threshold, 24.30% and 15.89% cases were found with positive expression of PD-L1 in the membrane of tumor cells and TILs respectively. Carcinoma PD-L1 expression mainly localized to the tumor invasive front and was associated with advanced FIGO stage (p=0.023) and abundant stromal CD8+ TILs infiltration (p=0.020). Tumors containing PD-L1+ TILs were more likely to have PD-L1 expression by the carcinoma cells (p<0.001). Univariate and multivariate analyses demonstrated that a higher number of intraepithelial CD3+ or CD8+ TILs was an independent prognostic factor for longer overall survival (OS), whereas tumor PD-L1 expression was a predictive factor for poorer OS only in univariate analysis. PD-L1 expression in TILs was not a prognostic factor in univariate analysis. The Kaplan-Meier curves of the four sub-groups and log-rank test showed that patients with negative tumor PD-L1 expression/higher numbers of intraepithelial CD8+ TILs had the longest median OS, while those with positive tumor PD-L1 expression/lower numbers of intraepithelial CD8+ TILs had the shortest median OS (p<0.001). Our results indicate that tumor PD-L1 expression in combination with intraepithelial CD8+ TILs infiltration has prognostic impact in patients with HGSOC. These biomarkers may be useful for the stratification of patients. Further evaluation of PD-1/PD-L1 as therapeutic targets for HGSOC is warranted. PMID- 28846889 TI - Integrating within-catchment and interbasin connectivity in riverine and nonriverine freshwater conservation planning in the North China Plain. AB - Freshwater ecosystems encompass all inland water bodies, in which riverine and nonriverine freshwaters are linked through hydrological connectivity within a catchment. However, riverine and nonriverine freshwaters have often been assessed separately and their interdependence and connection has not been considered appropriately in prevailing freshwater conservation planning. To address the representation and persistence of freshwater ecosystems in conservation assessment, we integrated riverine and nonriverine freshwater wetlands as broad scale conservation surrogates and incorporated longitudinal, lateral and vertical connectivity rules in a conservation planning for the freshwater wetlands in the North China Plain (NCP). We also considered interbasin connectivity by incorporating conservation features of key transferring nodes of the South-to North Water Diversion Project (SNWD) in the NCP to safeguard their unique ecosystem services of regulating interbasin freshwater. Three scenarios (i.e., 2D, 3D and interbasin scenario) were developed by incorporating different multiple conservation targets, and their spatial priorities and cost-efficiency in freshwater conservation were compared. We applied systematic conservation framework and modified Marxan to accommodate these multidirectional and interbasin connectivity targets in our freshwater conservation assessment. The results indicated that the existing conservation system covered approximately 20% of the freshwater wetlands in the NCP, and there were still considerable conservation gaps that need to be filled. The optimal scenarios could substantially improve the representation, complementarity and persistence for the conservation of freshwater ecosystems, but would not significantly increased overall costs. The framework developed by our research has the potential to facilitate further application of systematic methods in freshwater conservation and rehabilitation planning at multiple scales. PMID- 28846890 TI - Innovative encapsulated oxygen-releasing beads for bioremediation of BTEX at high concentration in groundwater. AB - Both a low concentration of dissolved oxygen and the toxicity of a high concentration of BTEX inhibit the bioremediation of BTEX in groundwater. A novel method of preparing encapsulated oxygen-releasing beads (encap-ORBs) for the biodegradation of BTEX in groundwater was developed. Experimental results show that the integrality and oxygen-releasing capacity of encap-ORBs exceeded those of ORBs. The use of polyvinyl alcohol (PVA) with high M.W. to prepare encap-ORBs improved their integrality. The encap-ORBs effectively released oxygen for 128 days. High concentration of BTEX (480 mg L-1) inhibited the biodegradation by the free cells. Immobilization of degraders in the encap-ORB alleviated the inhibition. Scanning electron microscope analysis reveals that the BTEX degraders grew on the surface of encap-ORB after bioremediation. The above results indicate that the encap-ORBs were effective in the bioremediation of BTEX at high concentration in groundwater. PMID- 28846891 TI - A multi-technique phytoremediation approach to purify metals contaminated soil from e-waste recycling site. AB - Multiple techniques for soil decontamination were combined to enhance the phytoremediation efficiency of Eucalyptus globulese and alleviate the corresponding environmental risks. The approach constituted of chelating agent using, electrokinetic remediation, plant hormone foliar application and phytoremediation was designed to remediate multi-metal contaminated soils from a notorious e-waste recycling town. The decontamination ability of E. globulese increased from 1.35, 58.47 and 119.18 mg per plant for Cd, Pb and Cu in planting controls to 7.57, 198.68 and 174.34 mg per plant in individual EDTA treatments, respectively, but simultaneously, 0.9-11.5 times more metals leached from chelator treatments relative to controls. Low (2 V) and moderate (4 V) voltage electric fields provoked the growth of the species while high voltage (10 V) had an opposite effect and metal concentrations of the plants elevated with the increment of voltage. Volumes of the leachate decreased from 1224 to 134 mL with voltage increasing from 0 to 10 V due to electroosmosis and electrolysis. Comparing with individual phytoremediation, foliar cytokinin treatments produced 56% more biomass and intercepted 2.5 times more leachate attributed to the enhanced transpiration rate. The synergistic combination of the individuals resulted in the most biomass production and metal accumulation of the species under the stress condition relative to other methods. Time required for the multi technique approach to decontaminate Cd, Pb and Cu from soil was 2.1-10.4 times less than individual chelator addition, electric field application or plant hormone utilization. It's especially important that nearly no leachate (60 mL in total) was collected from the multi-technique system. This approach is a suitable method to remediate metal polluted site considering its decontamination efficiency and associated environmental negligible risk. PMID- 28846892 TI - Wood (Bagassa guianensis Aubl) and green coconut mesocarp (cocos nucifera) residues as textile dye removers (Remazol Red and Remazol Brilliant Violet). AB - In this work the efficiency of two lignocellulosic waste materials, wood residues and coconut mesocarp, were investigated as adsorbents towards two representative textile dyes (Remazol Red, RR and Remazol Brilliant Violet, RBV). The moisture, carbohydrate, protein, lipid, ash and fiber contents of both natural matrices were characterized. The materials were also characterized by infrared spectroscopy, X-ray diffractometry, scanning electron microscopy, specific surface area analysis and thermogravimetry. The adsorption of dyes was monitored by using UV-Vis spectrophotometry. It was verified that both, coconut mesocarp (CM) and wood residues can act as effective adsorbents towards the investigated dyes. It is verified that the maximum adsorption capacity GammaM (mg g-1) for RBV and RR are 7.28 and 3.97 towards CM and 0.64 and 0.71 towrads SD. Furthermore, it was verified that the adsorption is strongly pH dependent and, as a general behavior, an increase in the pH value is associated with a decrease of the total amount of adsorbed dye. The adsorption of violet dye onto coconut mesocarp is well described by the Langmuir model, while all the remazol red fitted better with the Freundlich equation. PMID- 28846893 TI - Optimization of storage tank locations in an urban stormwater drainage system using a two-stage approach. AB - Storage is important for flood mitigation and non-point source pollution control. However, to seek a cost-effective design scheme for storage tanks is very complex. This paper presents a two-stage optimization framework to find an optimal scheme for storage tanks using storm water management model (SWMM). The objectives are to minimize flooding, total suspended solids (TSS) load and storage cost. The framework includes two modules: (i) the analytical module, which evaluates and ranks the flooding nodes with the analytic hierarchy process (AHP) using two indicators (flood depth and flood duration), and then obtains the preliminary scheme by calculating two efficiency indicators (flood reduction efficiency and TSS reduction efficiency); (ii) the iteration module, which obtains an optimal scheme using a generalized pattern search (GPS) method based on the preliminary scheme generated by the analytical module. The proposed approach was applied to a catchment in CZ city, China, to test its capability in choosing design alternatives. Different rainfall scenarios are considered to test its robustness. The results demonstrate that the optimal framework is feasible, and the optimization is fast based on the preliminary scheme. The optimized scheme is better than the preliminary scheme for reducing runoff and pollutant loads under a given storage cost. The multi-objective optimization framework presented in this paper may be useful in finding the best scheme of storage tanks or low impact development (LID) controls. PMID- 28846894 TI - Synthetic endeavors on cadmium species bearing glycolate and aromatic chelators with structure-specific biotoxic correlations in vitro. AB - Cadmium is a well-known metallotoxin widespread in the environment and easily reaching cellular targets in lower and higher organisms, including humans. The form(s) of that metal ion through which it interacts with biomolecular targets in a cellular milieu are critical in cell survival. Poised to investigate the structure-specific activity of Cd(II) in a cellular environment and delve into the associated biotoxic processes, binary and ternary systems of that metal ion in the presence of the physiological alpha-hydroxycarboxylic acid glycolic acid and aromatic (N,N')-binders 2,2'-bipyridine (2,2'-bipy) and 4,4'-bipyridine (4,4' bipy) were examined synthetically in aqueous media and a pH-specific fashion. The arising new materials [Cd(C2H3O3)2]n (1), [Cd(C2H3O3)(C10H8N2)(NO3)]n.nH2O (2), and {[Cd(C2H3O3)(C10H8N2)(H2O)](NO3)}n.2nH2O (3) project coordination polymers, which were physicochemically characterized through elemental analysis, FT-IR, NMR, luminescence and X-ray crystallography. The distinct spectroscopic features of 1-3, with luminescence exemplifying distinct behavior (2,3), further corroborated by crystallographic analysis, lend credence to a structure-specific selection of species employed in ensuing in vitro biological studies. The emerging results in two different cell lines (3T3-L1, Saos-2) reveal a concentration-dependent, structure-specific and cell line-specific toxicity profile of Cd(II), reflecting its coordination composition and formulation, rendering it soluble and bioavailable (1,2). Mechanistic information riding on caspase-dependent investigation unravels that metal ion's specific behavior compromising cell survival and integrity. Employment of ethylenediamine tetraacetic acid (EDTA) a) shows efficient sequestration of Cd(II) away from its toxic reactivity denoting the strength of interactions involved, and b) lends credence to further development of appropriately configured organic binders, selectively providing molecular protection from Cd(II) toxicity. PMID- 28846895 TI - Massive transfusion practice in non-trauma related hemorrhagic shock. AB - PURPOSE: Evidence suggests that trauma patients with hemorrhagic shock requiring massive transfusion have improved outcomes if resuscitated with a prescribed massive transfusion protocol (MTP). However, there is limited data regarding the efficacy of MTP in non-trauma patients. METHODS: This was a retrospective observational study of all patients who received a massive transfusion protocol for non-traumatic hemorrhagic shock over a four-year period. The primary outcome was in-patient hospital survival. We dichotomized recipients of MTP into survivors versus non-survivors, comparing outcomes of interest within the categories by nonparametric testing. Summary statistics expressed as median (interquartile range). RESULTS: Fifty-nine patients were reviewed, with the median age of 59.0 (35.0-71.0) years old. Thirty-three (56%) patients survived. Survivors were younger, 57.0 (30.0-67.0) versus 64.0 (53.5-71.5) years old (p=0.047), and had lower Sequential Organ Failure Assessment scores (6.0 (3.0 8.0) versus11.5 (9.5-13.0); p=0.008). Patients on the medical service receiving MTP had an increased risk of mortality (odds ratio 4.26; p=0.02). CONCLUSION: Over half of the patients receiving massive transfusion protocols for their non trauma related hemorrhagic shock survived. Survivors were younger, were less acutely ill, and on non-medical services. Further research is needed to investigate best practice for transfusion in non-trauma related hemorrhagic shock. PMID- 28846896 TI - End-of-life discussions: Who's doing the talking? AB - PURPOSE: To determine, in a tertiary academic medical center, the reported frequency of end-of-life discussions among nurses and the influence of demographic factors on these discussions. METHODS: Survey of nurses on frequency of end-of-life discussions in two urban academic medical centers. Chi-square tests were used to separately assess the relationship between age, gender, specialty, and experience with responses to the question, "Do you regularly talk with your patients about end-of-life wishes?" RESULTS: Overall, more than one third of respondents reported rarely or never discussing end-of-life wishes with their patients. Only specialty expertise (p<0.001) was statistically significantly associated with discussing end-of-life issues with patients. Over half of nurses specializing in critical care responded that they have these discussion "always" or "most of the time." However, for the specialties of surgery (59%) and anesthesiology (56%), the majority of respondents reported rarely or never having end-of-life discussions with patients. CONCLUSIONS: In a survey conducted in two tertiary care institutions, more than one-third of nurses from all disciplines responded that they never or almost never discuss end-of life issues with their patients. Specialty influenced the likelihood of discussing end-of-life issues with patients. PMID- 28846897 TI - Muscle synergies underlying sit-to-stand tasks in elderly people and their relationship with kinetic characteristics. AB - BACKGROUND: Physiological evidence suggests that the nervous system controls motion by using a low-dimensional synergy organization for muscle activation. Because the muscle activation produces joint torques, kinetic changes accompanying aging can be related to changes in muscle synergies. OBJECTIVES: We explored the effects of aging on muscle synergies underlying sit-to-stand tasks, and examined their relationships with kinetic characteristics. METHODS: Four younger and three older adults performed the sit-to-stand task at two speeds. Subsequently, we extracted the muscle synergies used to perform these tasks. Hierarchical cluster analysis was used to classify these synergies. We also calculated kinetic variables to compare the groups. RESULTS: Three independent muscle synergies generally appeared in each subject. The spatial structure of these synergies was similar across age groups. The change in motion speed affected only the temporal structure of these synergies. However, subject specific muscle synergies and kinetic variables existed. CONCLUSIONS: Our results suggest common muscle synergies underlying the sit-to-stand task in both young and elderly adults. People may actively change only the temporal structure of each muscle synergy. The precise subject-specific structuring of each muscle synergy may incorporate knowledge of the musculoskeletal kinetics. PMID- 28846898 TI - Pathogenicity testing of influenza candidate vaccine viruses in the ferret model. AB - The development of influenza candidate vaccine viruses (CVVs) for pre-pandemic vaccine production represents a critical step in pandemic preparedness. The multiple subtypes and clades of avian or swine origin influenza viruses circulating world-wide at any one time necessitates the continuous generation of CVVs to provide an advanced starting point should a novel zoonotic virus cross the species barrier and cause a pandemic. Furthermore, the evolution and diversity of novel influenza viruses that cause zoonotic infections requires ongoing monitoring and surveillance, and, when a lack of antigenic match between circulating viruses and available CVVs is identified, the production of new CVVs. Pandemic guidelines developed by the WHO Global Influenza Program govern the design and preparation of reverse genetics-derived CVVs, which must undergo numerous safety and quality tests prior to human use. Confirmation of reassortant CVV attenuation of virulence in ferrets relative to wild-type virus represents one of these critical steps, yet there is a paucity of information available regarding the relative degree of attenuation achieved by WHO-recommended CVVs developed against novel viruses with pandemic potential. To better understand the degree of CVV attenuation in the ferret model, we examined the relative virulence of six A/Puerto Rico/8/1934-based CVVs encompassing five different influenza A subtypes (H2N3, H5N1, H5N2, H5N8, and H7N9) compared with the respective wild type virus in ferrets. Despite varied virulence of wild-type viruses in the ferret, all CVVs examined showed reductions in morbidity and viral shedding in upper respiratory tract tissues. Furthermore, unlike the wild-type counterparts, none of the CVVs spread to extrapulmonary tissues during the acute phase of infection. While the magnitude of virus attenuation varied between virus subtypes, collectively we show the reliable and reproducible attenuation of CVVs that have the A/Puerto Rico/9/1934 backbone in a mammalian model. PMID- 28846899 TI - Virus-like particle vaccine primes immune responses preventing inactivated-virus vaccine-enhanced disease against respiratory syncytial virus. AB - Formalin inactivated respiratory syncytial virus (FI-RSV) vaccination caused vaccine-enhanced respiratory disease (ERD) upon exposure to RSV in children. Virus-like particles presenting RSV F fusion protein (F VLP) are known to increase T helper type-1 (Th1) immune responses and avoid ERD in animal models. We hypothesized that F VLP would prime immune responses preventing ERD upon subsequent exposure to ERD-prone FI-RSV. Here, we demonstrated that heterologous F VLP priming and FI-RSV boosting of mice prevented FI-RSV vaccine-enhanced lung inflammation and eosinophilia upon RSV challenge. F VLP priming redirected pulmonary T cells toward effector CD8 T cells producing Th1 cytokines and significantly suppressed pulmonary Th2 cytokines. This study suggests that RSV F VLP priming would modulate and shift immune responses to subsequent exposure to ERD-prone FI-RSV vaccine and RSV infection, suppressing Th2 immune-mediated pulmonary histopathology and eosinophilia. PMID- 28846900 TI - Antibiotic resistome promotion in drinking water during biological activated carbon treatment: Is it influenced by quorum sensing? AB - The contamination of antibiotic resistance genes (ARGs) in drinking water may pose a direct threat to human health. This study applied high-throughput qPCR and sequencing to investigate the dynamics of ARGs and bacterial communities during the advanced treatment of drinking water using biological activated carbon. The promotion of ARGs was observed, and the normalized copy number of ARGs increased significantly after BAC treatment, raising the number of detected ARGs from 84 to 159. Twenty-nine ARGs were identified as biofilm-influencing sources in the BAC, and they persisted after chlorination. The shift of bacterial communities primarily had effects on the changes in resistome. Firmicutes, Cyanobacteria were related to persistent ARGs mostly in the BAC biofilm. Meanwhile, the Acyl Homoserine Lactones (AHLs), quorum sensing molecules, and bacteria that produced AHLs were identified to understand the promotion of ARGs. The isolated AHL producing bacteria belonged to the Proteobacteria, Firmicutes and Bacteroidetes phyla. Six detectable AHLs had an influence on plasmid-based horizontal gene transfer in the intragenus mating systems, indicating that the dynamics of ARGs were strongly affected by quorum sensing between specific bacteria in the biofilm. These results provide new insight into the mechanism of antibiotic resistome promotion in BAC biofilms. PMID- 28846901 TI - Synthesis of cobalt-impregnated carbon composite derived from a renewable resource: Characterization and catalytic performance evaluation. AB - A novel nitrogen-doped biochar embedded with cobalt (Co-NB) was fabricated via pyrolysis of glucose pretreated with melamine (N donor) and Co(II). The Co-NB showed high catalytic capability by converting p-nitrophenol (PNP) into p aminophenol (PAP) by NaBH4. The analyses of FE-SEM, TEM, BET, XRD, Raman, and X ray photoelectron spectroscopy XPS of the Co-NB showed hierarchical porous structure (BET 326.5m2g-1 and pore volume: 0.2403cm3g-1) with well-dispersed Co nanoparticles (20-60nm) on the N-doped graphitic biochar surface. The Co-NB showed higher PNP reduction capability compared to the Co-biochar without N doping, achieving 94.3% removal within 4min at 0.24gL-1 catalyst dose and initial concentration of 0.35mM PNP. Further conversion experiments under varying environmental conditions (e.g., NaBH4 concentration (7.5-30mM), biochar dosage (0.12-1.0gL-1), initial PNP concentration (0.08-0.17mM)) were conducted in batch mode. The reusability of Co-NB was validated by the repetitive conversion experiments (5cycles). The overall results demonstrated biochar potential as catalysts for environmental applications if properly designed. PMID- 28846902 TI - Emergency multiple sclerosis hospital admissions attributable to chemical and acoustic pollution: Madrid (Spain), 2001-2009. AB - INTRODUCTION: Multiple sclerosis (MS) is the most prevalent neurological disease among young adults in Spain. A number of recent studies have linked traffic related pollution, both chemical and acoustic, to the aetiology and exacerbation of neurodegenerative diseases. OBJECTIVE: To analyse the existence of a significant short-term association between daily emergency MS hospital admissions and chemical and acoustic pollution caused by traffic in Madrid. METHODOLOGY: We conducted a longitudinal ecological time series study, in which the dependent variable was the number of daily emergency MS hospital admissions (ICD-9: 340) registered in Madrid from 1 January 2001 to 31 December 2009. The independent variables were daily mean concentrations (MUg/m3) of PM2.5, PM10, O3 and NO2. Equivalent diurnal (Leqd), nocturnal (Leqn) and daily equivalent noise levels (Leq24) were also considered. In addition, we controlled for linear trends, seasonality and the autoregressive nature of the series itself. Day of the week was also added as a covariate. Significant environmental variables were determined using Poisson GLM models. Relative risk (RR) and attributable risk (AR) values were calculated for increases of 10MUg/m3 in the case of chemical pollutants and 1dB(A) in noise levels. RESULTS: While there was no association between chemical pollutants caused by traffic and MS admissions, such an association was in evidence for Leqd at lag zero. This association is linear without a threshold, with there being a level above 67dB(A) from which this effect is more pronounced. The RRs were as follows: for all Leqd values, 1.21 (95% CI: 1.16, 1.26); and for Leqd >67dB(A), 1.62 (95% CI: 1.24, 2.13). CONCLUSION: The above results indicate that traffic noise can exacerbate MS symptoms, leading to hospital admissions due to this cause. PMID- 28846903 TI - Riverine inputs and source tracing of perfluoroalkyl substances (PFASs) in Taihu Lake, China. AB - The occurrence, riverine inputs and sources of perfluoroalkyl substances (PFASs) in Taihu Lake, one of the largest lakes in China, were investigated by measuring PFASs including the isomers of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA) and perfluorohexanesulfonate (PFHxS) in the Lake and its main flow-in rivers. It was found that PFHxS, instead of PFOS or PFOA, was predominant both in the Lake and rivers (45.9-351ng/L), reflecting increasing demand of PFHxS in recent years. The riverine flux of PFASs into the Lake was estimated to be 1255kg/year. The percentage of linear (n-) PFOS and the ratio of 3+5m-/1m-PFOS were combined to indicate indirect source due to biodegradation of PFOS-precursors. The percentage order of n-PFOS was: the Lake (48.7%)the rivers (8.99)>ECF (electrochemical fluorination) product (6.76). These suggested that degradation of PFOS-precursors made distinct contribution to PFOS load in the waters, particularly in the Lake. The Lake and river waters had a consistent proportion of n-PFHxS (89.0%), which was slightly lower than the ECF product (96.0%), indicating it was mainly due to the release from production and application of PFHxS as an active ingredient. PMID- 28846904 TI - Driver detection of water quality trends in three large European river basins. AB - This study analyses how indicators of water quality (thirteen physico-chemical variables) and drivers of change (i.e., monthly aggregated air temperature and streamflow, population density, and percentage of agricultural land use) coevolve in three large European river basins (i.e., Adige, Ebro, Sava) with different climatic, soil and water use conditions. Spearman rank correlation, Principal Component Analysis, and Mann-Kendall trend tests were applied to long-term time series of water quality data during the period 1990-2015 in order to investigate the relationships between water quality parameters and the main factors controlling them. Results show that air temperature, considered as a proxy of climatic change, has a significant impact, in particular in the Adige and Ebro: positive trends of water temperature and negative of dissolved oxygen are correlated with upward trends of air temperatures. The aquatic ecosystems of these rivers are, therefore, experiencing a reduction in oxygen, which may exacerbate in the future given the projected further increase in temperature. Furthermore, monthly streamflow has been shown to reduce in the Ebro, thereby reducing the beneficial effect of dilution, which appears evident from the observed upward patterns of chloride concentrations and electrical conductivity. Upward trends of chloride and biological oxygen demand in the Adige and Sava, and of phosphate in the Adige appears to be related to increasing human population density, whereas phosphates in the Sava and biological oxygen demand in the Ebro are highly correlated with agricultural land use, considered as a proxy of the impact of agricultural practises. The present study shows the complex relationships between drivers and observed changes in water quality parameters. Such analysis can represent, complementary to a deep knowledge of the investigated systems, a reliable tool for decision makers in river basin planning by providing an overview of the potential impacts on the aquatic ecosystem of the three basins. PMID- 28846905 TI - Prescribed fire experiences on crop residue removal for biomass exploitations. Application to the maritime pine forests in the Mediterranean Basin. AB - Socioeconomic changes, climate change, rural migration and fire exclusion have led to a high woody biomass accumulation increasing potential wildfire severity. Mechanical thinning and prescribed burning practices are commonly used to prevent large fires. The purpose of this study was to assess burning treatment effectiveness following mechanical thinning from biomass harvesting. Prescribed burning to reduce residue removal could help mitigate fire behavior, mainly in strategic management or critical focal points. Field samplings were conducted before and immediately after burnings on different environmental scenarios where fuel load was classified by categories. Prescribed fires reduced available fuel in all fuel categories, mainly in surface litter layer. Total fuel load reduction ranged from 59.07% to 86.18%. In this sense, fuel reduction effects were more pronounced when burns were conducted fewer than 10% on surface litter moisture. The difference in fuel consumption among scenarios was higher for most all woody fuel components and decomposition litter layer than for surface litter layer. Managers can use this information to design technical prescription to achieve the targets while decomposed litter retention maintaining the soil properties and biodiversity. Understanding the most effective "burn window" should help better plan prescribed burning, both in term of fire behavior and fuel consumption, without altering ecosystem properties. PMID- 28846906 TI - Spatiotemporal dynamics of Phormidium cover and anatoxin concentrations in eight New Zealand rivers with contrasting nutrient and flow regimes. AB - Toxic benthic cyanobacterial proliferations, particularly of the genus Phormidium, are a major concern in many countries due to their increasing extent and severity. The aim of this study was to improve the current understanding of the dominant physicochemical variables associated with high Phormidium cover and toxin concentrations. Phormidium cover and anatoxin concentrations were assessed weekly for 30weeks in eight predominately cobble-bed rivers in the South Island of New Zealand. Phormidium cover was highly variable both spatially (among and within sites) and temporally. Generalized additive mixed models (GAMMs) identified site, month of the year, conductivity and nutrient concentrations over the accrual period as significant variables associated with Phormidium cover. Cover was greatest under low to intermediate accrual dissolved inorganic nitrogen (DIN) and dissolved reactive phosphorus (DRP) concentrations. Accrual nutrients had a strong, negative effect on cover at concentrations>0.2mgL-1 DIN and 0.014mgL-1 DRP. The effect of flow was generally consistent across rivers, with cover accruing with time since the last flushing flow. Total anatoxins were detected at all eight study sites, at concentrations ranging from 0.008 to 662.5mgkg-1 dried weight. GAMMs predicted higher total anatoxin concentrations between November and February and during periods of accrual DRP<0.02mgL-1. This study suggests that multiple physicochemical variables may influence Phormidium proliferations and also evidenced large site-to-site variability. This result highlights a challenge from a management perspective, as it suggests that mitigation options are likely to be site-specific. PMID- 28846907 TI - Marking petroglyphs with calcite and gypsum-based chalks: Interaction with granite under different simulated conditions and the effectiveness and harmfulness of cleaning methods. AB - Marking petroglyphs with chalk is a common practice to enhance them for documentation and reproduction. Although this procedure has started to be less frequently used, there is no knowledge about the interaction between the rock engravings nor about the effectiveness achieved by the common cleaning procedures of such markers considering the chalk extraction and the induced damage to the rock. This study evaluates the interaction between two chalks of different composition (calcite and gypsum) and a granite on which the majority of NW Iberian Peninsula-petroglyphs are carved. Granitic samples marked with these chalks were subjected to artificial rain events and high temperatures (700 degrees C) related to fires. After each aging test, chemical and physical modifications on the rock were analysed by means of stereomicroscopy, x-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy and colour spectrophotometry. Moreover, the evaluation of the effectiveness and harmfulness of several mechanical and chemical cleaning procedures commonly used in the field of cultural heritage conservation was carried out. Both chalks remained at different extent on the surface after the artificial rain events. Water would promote a different penetration-depth of the chalks into the stone, depending on their solubility. High temperatures led to mineral phase transformations of the chalks influencing the interaction with the rock. Regarding cleaning effectiveness, despite a few chalk remains were found in all the cleanings, chemical methods showed higher effectiveness than mechanical procedures even though some of them leave chemical contamination. Benzalkonium chloride can be considered as the cleaner with the best results to extract both types of chalk on granite. PMID- 28846908 TI - Gravel pit lakes in Denmark: Chemical and biological state. AB - Mining of gravel and sand for construction purposes is big business and gravel pit lakes have become increasingly common all over the world. In Denmark, hundreds of gravel pit lakes have been created during the past decades. We investigated the chemical and biological status of 33-52 gravel pit lakes and compared the results with data from similar-sized natural Danish lakes. The area of the lakes ranged from 0.2 to 13ha and their age from 0.5 to 26years. Generally, the gravel pit lakes were clear with low nutrient concentrations, the median concentrations of total phosphorus and total nitrogen being 0.023mg/l and 0.30mg/l compared with 0.115mg/l and 1.29mg/l, respectively, in natural lakes. Correspondingly, median chlorophyll a was 5MUg/l in the gravel pit lakes and 36MUg/l in the natural lakes. Submerged macrophytes were found in all gravel pit lakes, with particularly high cover in the shallow ones. Most gravel pit lakes were deeper than the natural lakes, which may restrict the area potentially to be covered by submerged macrophytes, with implications also for the biological quality of the lakes. Fish were found in most of the gravel pit lakes, roach (Rutilus rutilus), perch (Perca fluviatilis) and rudd (Scardinius erythrophalmus) being the most frequently observed species. Fish stocking was common and included also non-native species such as carp (Cyprinus carpio) and rainbow trout (Oncorchynchus mykiss). Compared with the natural lakes, fish species richness and catch per gillnet were overall lower in the gravel pit lakes. Groundwater-fed gravel pit lakes add importantly to the number of high-quality lakes in Denmark and with an optimised design and by avoiding negative side effects, they can be positive for both nature and society. PMID- 28846909 TI - Uptake of silver by brown rice and wheat in soils repeatedly amended with biosolids. AB - There have been numerous studies simulating the behaviour and fate of silver (Ag) applied to soils in biosolids in recent decades but the results remain to be verified under actual farming conditions. Here, we report a study of the transfer of Ag along the biosolids-soil-crop pathway with repeated biosolid applications over a four-year period to three contrasting soil types under rice-wheat rotation cultivation. A systematic investigation of Ag concentrations in biosolids throughout China shows Ag concentrations ranging from 0.64 to 7.47mgkg-1 with a mean value of 3.58mgkg-1 and a median of 3.02mgkg-1 on a dry weight basis. Silver concentrations were significantly higher in industrial biosolids than in domestic or mixed flow biosolids. Biosolids application enhanced Ag accumulation in whole wheat. Silver concentrations in whole wheat increased to 20.8, 20.5 and 4.87MUgkg 1 after four years of high-metal industrial biosolids application to an acid Typic Ali-Perudic Aragsol, a neutral Typic Hapli-Stagnic Anthrosol, and a calcareous Typic Carbonati-Perudic Ferrosol, respectively. Moreover, the Ag translocation factor also increased in wheat following biosolids application with values of 5.6, 3.1 and 1.4, respectively. However, Ag accumulation in rice was found only in the acid soil with no discernible increase (p>0.05) in the translocation factor. The seasonal redox cycle may contribute to this phenomenon. A seedling incubation experiment confirms the influence of soil water regime on Ag bioavailability with a higher Ag translocation factor during the wheat growing season than the rice growth period. Incorporating a fallow period during the wheat (winter crop) season might be a suitable strategy for repeated biosolids application. PMID- 28846910 TI - Fate of organic microcontaminants in wastewater treatment and river systems: An uncertainty assessment in view of sampling strategy, and compound consumption rate and degradability. AB - The growing awareness of the relevance of organic microcontaminants on the environment has led to a growing number of studies on attenuation of these compounds in wastewater treatment plants (WWTP) and rivers. However, the effects of the sampling strategies (frequency and duration of composite samples) on the attenuation estimates are largely unknown. Our goal was to assess how frequency and duration of composite samples influence uncertainty of the attenuation estimates in WWTPs and rivers. Furthermore, we also assessed how compound consumption rate and degradability influence uncertainty. The assessment was conducted through simulating the integrated wastewater system of Puigcerda (NE Iberian Peninsula) using a sewer pattern generator and a coupled model of WWTP and river. Results showed that the sampling strategy is especially critical at the influent of WWTP, particularly when the number of toilet flushes containing the compound of interest is small (<=100 toilet flushes with compound day-1), and less critical at the effluent of the WWTP and in the river due to the mixing effects of the WWTP. For example, at the WWTP, when evaluating a compound that is present in 50 pulses.d-1 using a sampling frequency of 15-min to collect a 24-h composite sample, the attenuation uncertainty can range from 94% (0% degradability) to 9% (90% degradability). The estimation of attenuation in rivers is less critical than in WWTPs, as the attenuation uncertainty was lower than 10% for all evaluated scenarios. Interestingly, the errors in the estimates of attenuation are usually lower than those of loads for most sampling strategies and compound characteristics (e.g. consumption and degradability), although the opposite occurs for compounds with low consumption and inappropriate sampling strategies at the WWTP. Hence, when designing a sampling campaign, one should consider the influence of compounds' consumption and degradability as well as the desired level of accuracy in attenuation estimations. PMID- 28846911 TI - Testicular volumetry and prediction of daily sperm output in stallions by orchidometry and two- and three-dimensional sonography. AB - Accurate determination of the testes volume and prediction of the daily sperm output (DSO) is valuable information for reproductive management of a stallion. The aim of this study was to compare different methods for measuring the testes volume, including caliper, 2D and 3D ultrasound. Special emphasis was on feasibility of 3D volume analysis. First, 22 castrated testes were measured and derived volumes were compared with volumes determined via volume displacement in a graded cylinder with saline solution. Then, during the breeding season, testes sizes of 52 stallions were measured in vivo and analyzed. With the derived volumes, predicted DSO (pDSO) values were calculated which were compared with actual values (aDSO) determined from semen evaluation. Analyses of castrated testes revealed a discrepancy between volume assessments via the caliper and ultrasound methods and actual volumes as found via volume displacement. The smallest difference was found for 3D volume analysis, followed by caliper and 2D ultrasound. Testicular volumes of breeding stallions were highest if determined via 3D ultrasound, followed by measurements using 2D ultrasound and caliper. Correlation between the total testicular volume (TTV) and aDSO was high with volume assessment via ultrasound (2D: r = 0.639, p < 0.001, and 3D: r = 0.604, p < 0.001), and moderate for using caliper (r = 0.46, p < 0.01). Linear regression analyses of TTV and aDSO values revealed that changes in aDSO in part could be explained by differences in testes volume: 32% and 27% in case of 3D and 2D ultrasound, and 12% with caliper. pDSO values that were predicted from testicular measurements correlated best with aDSO values from semen collection protocols in case of using 3D ultrasound (r = 0.56, p < 0.001), followed by 2D ultrasound (r = 0.52; p < 0.001) and caliper (r = 0.34, p = 0.01). In conclusion, 3D ultrasound can be performed on equine testes for more accurate volume predictions, which in turn may increase precision when determining the breeding potential of a stallion. PMID- 28846912 TI - Impact of estradiol cypionate prior to TAI and progesterone supplementation at initial diestrus on ovarian and fertility responses in beef cows. AB - In cattle, early diestrus progesterone (P4) supplementation modulates endometrial function to exert pro- and anti-pregnancy establishment effects; specifically, P4 stimulates conceptus growth, but also induces early onset of luteolysis. This paradoxical effect is frequently related to the inconsistent fertility outcomes that result from P4 supplementation experiments. Aim was to investigate the impact of exogenous estradiol (E2) treatment at the end of timed fixed AI (TAI) on frequency of early luteolysis and pregnancy of beef cows supplemented with P4. Ovulations (D0 of study) of suckled multiparous (n = 643) and primiparous (n = 193) Nelore cows (Bos indicus) were synchronized with an E2/P4-based protocol for TAI and assigned to receive 1.0 mg of estradiol cypionate (CP) or nothing (NoCP) on D-2 and 150 mg of injectable long-acting P4 (iP4) or Placebo (NoiP4) on D4 on a 2 * 2 factorial arrangement. On D15, the iP4 supplementation increased (P < 0.05) the frequency of early luteolysis (NoCP + iP4: 26.0%; [13/50] vs. NoCP: 8.0% [4/50]), but CP prevented this effect (CP + iP4: 8.3% [4/48] and CP: 6.4% [3/47]). The CP improved pregnancy/AI (P/AI) of multiparous (CP: 51.6% [165/320] and NoCP: 35.0% [113/323]; P < 0.001) and primiparous cows (CP: 40.4% [40/99] and NoCP: 24.5% [23/94], P < 0.05), regardless of iP4 treatment. The iP4 supplementation affected P/AI of CP and NoCP treated cows according to follicle size at TAI. For the CP treated cows, the iP4 supplementation improved P/AI of sub-populations of cows with follicles <12.35 mm (42.0% [34/81] vs. 53.1% [34/64]), while for NoCP treated cows, the improvements occurred in subpopulations of cows with follicles >=12.35 mm (46.1% [35/76] vs. 58.7% [37/63]). In conclusion, strategies associating E2 and P4 supplementation decrease the incidence of early onset of luteolysis and improve P/AI of suckled beef cows with smaller follicles. PMID- 28846913 TI - Differentiation and identification of 5F-PB-22 and its isomers. AB - Quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5-Fluoro-PB-22 or 5F-PB 22; QUPIC N-(5-fluoropentyl) analog), is a synthetic cannabinoid which mimics the effects of cannabis. Several countries have reported numerous detections of this compound and its abuse has led to adverse effects including death. The aim of this study was to separate and identify the fluoropentyl positional isomers of fluoro-PB-22 using gas chromatography-mass spectrometry, solid deposition gas chromatography-infrared detection spectroscopy and 1H and 13C nuclear magnetic resonance spectroscopy. Data acquired from these multiple techniques can assist forensic laboratories lacking the reference drug standard(s) to identify the specific isomer of fluoro-PB-22 in seized material. PMID- 28846914 TI - Two halves make a whole: Both first responders and experts are needed for the management and identification of the dead in large disasters. AB - Catastrophic natural disasters are a regular global issue claiming thousands of lives and having severe and long lasting consequences for communities. Along with the rescue and care of survivors and the provision of basic services, managing the dead in a proper and dignified manner is one of the three pillars of disaster response. Since the 2004 Indian Ocean Tsunami, progress to facilitate better coordination in the management of the dead has been made. Two guidelines contributing to this positive trend are the Interpol DVI Guide, and the "Management of the Dead after Disasters - A Field Manual for First Responders". The former is aimed at forensic specialists and emergency services, the latter at untrained first responders confronted with the management of the dead when specialist forensic services are not available. This paper sets out the complementarity of the two publications, illustrating that ideally, both first responders and experts are needed to properly manage and identify the dead following large disasters. PMID- 28846915 TI - Humanitarian forensic action - Its origins and future. AB - Humanitarian forensic action is the application of the knowledge and skills of forensic medicine and science to humanitarian action, especially following conflicts or disasters. It has its early roots in the experience of the Argentine Forensic Anthropology Team and that of the Grandmothers of Plaza de Mayo in Argentina, is moulded by International Humanitarian and Human Rights Law and was developed by the International Committee of the Red Cross. Having demonstrated its worth, this new field of application of forensic medicine and science needs further development, integration and research. PMID- 28846916 TI - Electric arc furnace dust as an alternative low-cost oxygen carrier for chemical looping combustion. AB - The relative abundance and low cost of electric arc furnace dust (EAFD) make it a viable oxygen carrier for chemical looping combustion (CLC) system. Under a reducing agent, zinc ferrite (ZnFe2O4) phase in EAFD releases zinc vapor in a complex gas-solid reaction. In an effort to suppress the emission of zinc vapor, the reaction mechanism of ZnFe2O4 prepared as an oxygen carrier in a redox cycling test is primarily discussed, as well as the issue of coupling with an inert Al2O3 support. The study focused the investigation on redox cycling behavior and CO2 conversion in ZnFe2O4/Al2O3 and EAFD/Al2O3 systems using a thermogravimetric analyzer (TGA) and fixed-bed reactor (FxBR). In a lab-scaled semi-fluidized bed reactor (semi-FzBR) of EAFD/Al2O3 as an oxygen carrier system, a high CO gas yield approximately 0.98 after fifty redox cycles is also experimentally obtained. It can be anticipated that the use of EAFD/Al2O3 system as an oxygen carrier in a reversible CLC process could be economical and environmentally beneficial. PMID- 28846917 TI - Fire behavior of halogen-free flame retardant electrical cables with the cone calorimeter. AB - Fires involving electrical cables are one of the main hazards in Nuclear Power Plants (NPPs). Cables are complex assemblies including several polymeric parts (insulation, bedding, sheath) constituting fuel sources. This study provides an in-depth characterization of the fire behavior of two halogen-free flame retardant cables used in NPPs using the cone calorimeter. The influence of two key parameters, namely the external heat flux and the spacing between cables, on the cable fire characteristics is especially investigated. The prominent role of the outer sheath material on the ignition and the burning at early times was highlighted. A parameter of utmost importance called transition heat flux, was identified and depends on the composition and the structure of the cable. Below this heat flux, the decomposition is limited and concerns only the sheath. Above it, fire hazard is greatly enhanced because most often non-flame retarded insulation part contributes to heat release. The influence of spacing appears complex, and depends on the considered fire property. PMID- 28846918 TI - A new 3DOM Ce-Fe-Ti material for simultaneously catalytic removal of PM and NOx from diesel engines. AB - A new 3DOM material was designed and synthesized for the simultaneous removal of PM (soot particulates) and NOx from diesel engine exhausts. The catalytic purification taking place over the material with double efficacy is cost efficient. The contact between solid PM and catalyst active site has been process intensified by 3DOM unique structure. 3DOM Ce0.7Fe0.2Ti0.1O2 catalyst possess a high SCR activity and an excellent selectivity to N2, giving a maximum concentration of CO2 at 385 degrees C for PM combustion and 100% NO conversion in the temperature range of 281-425 degrees C. The dual redox cycles (Fe3++Ce3+< >Fe2++Ce4+,Fe3++Ti3+<->Fe2++Ti4+) and the excellent reducibility and sufficient acid sites of catalysts play key roles for the highly catalytic performance. PMID- 28846919 TI - Simultaneous absorption of SO2 and NO from flue gas using ultrasound/Fe2+/heat coactivated persulfate system. AB - A novel process on simultaneous absorption of SO2 and NO from flue gas using ultrasound (US)/Fe2+/heat coactivated persulfate system was proposed. The influencing factors, active species, products and mechanism of SO2 and NO removal were investigated. The results indicate that US enhances NO removal due to enhancement of mass transfer and chemical reaction. US of 28kHz is more effective than that of 40kHz. NO removal efficiency increases with increasing persulfate concentration, ultrasonic power density and Fe2+ concentration (at high persulfate concentration). Solution pH, solution temperature and Fe2+ concentration (at low persulfate concentration) have double effect on NO removal. SO2 is completely removed in most of tested removal systems, except for using water absorption. US, Fe2+ and heat have a synergistic effect for activating persulfate to produce free radicals, and US/Fe2+/heat coactivated persulfate system achieves the highest NO removal efficiency. .OH and SO4-. play a leading role for NO oxidation, and persulfate only plays a complementary role for NO oxidation. PMID- 28846920 TI - Protective effect of naringin on pentylenetetrazole (PTZ)-induced kindling; possible mechanisms of antikindling, memory improvement, and neuroprotection. AB - The present study investigated the effects of Naringin on seizure severity, progress of kindling, memory impairment, oxidative stress, neurochemicals, and neural damage in Pentylenetetrazole (PTZ)-induced kindling. Alternate intra peritoneal injections of PTZ induced kindling at 22 injections of PTZ. In comparison with the PTZ group, pretreatment with Naringin 30 min prior to PTZ administration and on a PTZ-free day was found to lead to a decreased seizure score, a mitigated progress of kindling, decreased transfer latency, and increased total number of arm entries, % alternation behavior in Y maze, and % conditioned avoidance response in a pole climbing apparatus. Biochemical analysis of the frontal and temporal cortexes and the hippocampus of the brain showed that Naringin attenuated the level of lipid peroxidation (MDA) and augmented the reduced glutathione, superoxide dismutase, catalase, and total thiol results in decreased oxidative stress compared with the PTZ group and control group. Investigation of neurochemicals revealed a minute change in gamma amino butyric acid (GABA), glutamate and dopamine, and decreased AChE in the three regions. Increased CA1 neuronal density in the hippocampus and increased cell density in the frontal and temporal regions indicate the potential of naringin to act against PTZ-induced kindling, memory impairment, oxidative stress, neurochemical changes, and histological aberrations. PMID- 28846921 TI - Distinct effects of estrogen receptor antagonism on object recognition and spatial memory consolidation in ovariectomized mice. AB - Exogenous treatment with the potent estrogen 17beta-estradiol (E2) or selective estrogen receptor alpha/beta (ERalpha/beta) agonists enhances the consolidation of hippocampal-dependent object recognition (OR) and object placement (OP) memories in ovariectomized rodents. Although such data suggest that individual ERs are sufficient for memory consolidation, the necessity of a given ER for memory consolidation can only be demonstrated by blocking receptor function, for example with an ER antagonist. However, the effects on memory of antagonizing ERalpha or ERbeta function are not well understood. Moreover, ER antagonism in ovariectomized subjects also provides indirect information about the role of individual ERs in the memory-enhancing effects of local hippocampal E2 synthesis. Therefore, this study used pharmacological inhibition of ERalpha and ERbeta to elucidate the importance of each ER to memory consolidation. Specifically, we examined effects on OR and OP memory consolidation of immediate post-training dorsal hippocampal (DH) infusion of MPP and PHTPP, selective antagonists for ERalpha and ERbeta, respectively. Each drug exhibited a distinct effect on OR and OP. DH infusion of MPP (0.28 or 2.78ng/hemisphere) impaired memory in OP, but not OR. However, DH infusion of PHTPP (0.21 or 2.12ng/hemisphere) impaired memory in both OR and OP. Neither drug affected the elapsed time to accumulate object exploration in either task, suggesting a specific effect on memory. These results indicate that activation of either classical ER within the dorsal hippocampus is important for hippocampal memory consolidation in ovariectomized mice, but suggest that specific ER involvement is memory- or task-specific. The findings also indirectly support a role for ERalpha and ERbeta in mediating the memory enhancing effects of hippocampally-synthesized E2. PMID- 28846922 TI - Interaction of Zap70 and CXCR4 receptor at lamellipodia that determines the directionality during Jurkat T cells chemotaxis. AB - Directional migration of T-lymphocytes is a key process during immune activation and is tightly regulated both temporally and spatially. The initial cell membrane protrusion at a particular site is critical for determining the direction of cell migration. In this study, we found that ZAP-70 protein appeared not only at the margin of the spreading areas of polarized Jurkat T cells but also formed clusters near the center of the cell body on a fibronectin plate. Specifically, some pZAP-70 was located at the lamellipodia/filopodia and was closely associated with the most extended membrane contact. To visualize the dynamic distribution of ZAP-70 on migrating Jurkat T cells, we generated a fluorescent ZAP-70-EGFP fusion protein (hZAP70G). Expression of the hZAP70G in P116 cells, a ZAP-70 defective Jurkat derivative, restored its chemotactic migration toward SDF-1, adhesion to fibronectin matrix, and integrin activation. In addition, the distribution of hZAP70G protein is associated with changes in cell shape, specifically the membrane protrusion step, forming filopodia/lamellipodia and a retracting uropod. Furthermore, SDF-1 stimulated the formation of ZAP-70 and CXCR4 complex. CXCR4 was observed mainly at the leading edge of migrating cell. The localization of ZAP-70 at the very front edge of protruding lamellipodia was close to CXCR4 and a part of them were overlapped. Collectively, our data describe the critical early step of directional cell movement toward SDF-1 that ZAP-70 is recruited to the CXCR4 at the leading edge of membrane and consequently modulates lamellipodia/filopodia formation and integrin activation. PMID- 28846923 TI - Elevated intrathymic sphingosine-1-phosphate promotes thymus involution during sepsis. AB - Sepsis mouse models revealed thymus atrophy, characterised by decreased thymus weight and loss of thymocytes due to apoptosis. Mice suffered from lymphopenia, a lack of T cells in the periphery, which attenuates their ability to fight against recurring and secondary infections during sepsis progression. Key players in thymus atrophy are IL-6, which is directly involved in thymus involution, and the sphingosine-1-phosphate - sphingosine-1-phosphate receptor 1 signaling, influencing thymocytes emigration. In healthy individuals a sphingosine-1 phosphate (S1P) gradient from lymphoid organs to the circulatory system serves as signal for mature T cell egress. In the present study we investigated, whether inhibition of S1P generation improves thymus involution. In sepsis, induced by cecal ligation and puncture (CLP), S1P in the thymus increased, while it decreased in serum, thus disrupting the naturally occurring S1P gradient. As a potential source of S1P we identified increased numbers of apoptotic cells in the thymic cortex of septic mice. Pharmacological inhibition of the S1P generating sphingosine kinases, by 4- [[4-(4-Chlorophenyl)-2-thiazolyl]amino]phenol (SK I II), administered directly following CLP, prevented thymus atrophy. This was reflected by lymphocytosis, diminished apoptosis, decreased IL-6 expression, and an unaltered thymus weight. In addition SK I-II-treatment preserved the S1P balance and prevented S1P-dependent internalization of the sphingosine-1 phosphate receptor 1. Our data suggest that inhibition of sphingosine kinase and thus, S1P generation during sepsis restores thymic T cell egress, which might improve septic outcome. PMID- 28846924 TI - The circular RNA of peripheral blood mononuclear cells: Hsa_circ_0005836 as a new diagnostic biomarker and therapeutic target of active pulmonary tuberculosis. AB - It has been reported that circular RNA (circRNA) is associated with human cancer. However, few studies have been reported in active pulmonary tuberculosis (APTB). The global circRNA expression was detected in the peripheral blood mononuclear cells (PBMCs) of APTB patients (n=5) and health controls (HC) (n=5) by using high throughput sequencing. According to the systematical bioinformatics analysis, the basic content of circRNAs and their fold changes in the two groups were calculated. We selected 6 significant differentially expressed circRNAs, hsa_circ_0005836, hsa_circ_0009128, hsa_circ_0003519, hsa_circ_0023956, hsa_circ_0078768, and hsa_circ_0088452 and validated the expression in PBMCs from APTB (n=10) and HC (n=10) by real-time quantitative reverse transcription polymerase chain reactions (qRT-PCRs). Further, the verification of these specific circRNAs (hsa_circ_0005836 and hsa_circ_0009128) between APTB (n=34) and HC (n=30) in PBMCs was also conducted by qRT-PCRs. The RNA-seq data showed the significant differential expression of the 523 circRNAs between the APTB and HC groups (199 circRNAs were significantly up-regulated and 324 circRNAs were down regulated). Hsa_circ_0005836 and hsa_circ_0009128 expression was significantly down-regulated in the PBMCs of APTB (P<0.05) in the samples of APTB compared to HC in our study. The gene ontology based enrichment analysis of the circRNA-miRNA mRNAs network showed that cellular catabolic process (P=7.10E-08), regulation of metabolic process (P=2.10E-06), catalytic activity (P=3.67E-08), protein binding (P=1.71E-07), cell part (P=3.46E-06), intracellular part (P=1.71E-07), and intracellular (P=3.67E-08) were recognized in the comparisons between APTB and HC. Based on KEGG analysis, HTLV-I infection, regulation of actin cytoskeleton, neurotrophin signaling pathway and mTOR signaling pathway were relevant during tuberculosis bacillus infection. We found for the first time that hsa_circ_0005836 and hsa_circ_0009128 were significantly down-regulated in the PBMCs of APTB compared with HC. Our findings indicate hsa_circ_0005836 might serve as a novel potential biomarker for TB infection. PMID- 28846925 TI - Interaction of extremophilic archaeal viruses with human and mouse complement system and viral biodistribution in mice. AB - Archaeal viruses offer exceptional biophysical properties for modification and exploration of their potential in bionanotechnology, bioengineering and nanotherapeutic developments. However, the interaction of archaeal viruses with elements of the innate immune system has not been explored, which is a necessary prerequisite if their potential for biomedical applications to be realized. Here we show complement activation through lectin (via direct binding of MBL/MASPs) and alternative pathways by two extremophilic archaeal viruses (Sulfolobus monocaudavirus 1 and Sulfolobus spindle-shaped virus 2) in human serum. We further show some differences in initiation of complement activation pathways between these viruses. Since, Sulfolobus monocaudavirus 1 was capable of directly triggering the alternative pathway, we also demonstrate that the complement regulator factor H has no affinity for the viral surface, but factor H deposition is purely C3-dependent. This suggests that unlike some virulent pathogens Sulfolobus monocaudavirus 1 does not acquire factor H for protection. Complement activation with Sulfolobus monocaudavirus 1 also proceeds in murine sera through MBL-A/C as well as factor D-dependent manner, but C3 deficiency has no overall effect on viral clearance by organs of the reticuloendothelial system on intravenous injection. However, splenic deposition was significantly higher in C3 knockout animals compared with the corresponding wild type mice. We discuss the potential application of these viruses in biomedicine in relation to their complement activating properties. PMID- 28846926 TI - Cirtical role for Salmonella effector SopB in regulating inflammasome activation. AB - OBJECTIVE: Salmonella is known to evolve many mechanisms to avoid or delay inflammasome activation which remain largely unknown. In this study, we investigated whether the SopB protein critical to bacteria virulence capacity was an effector that involved in the regulation of inflammasome activation. METHODS: BMDMs from NLRC4-, NLRP3-, caspase-1/-11-, IFI16- and AIM2-deficient mice were pretreated with LPS, and subsequently stimulated with a series of SopB-related strains of Salmonella, inflammasome induced cell death, IL-1beta secretion, cleaved caspase-1 production and ASC speckle formation were detected. RESULTS: We found that SopB could inhibit host IL-1beta secretion, caspase-1 activation and inflammasome induced cell death using a series of SopB-related strains of Salmonella; however the reduction of IL-1beta secretion was not dependent on sensor that contain PYD domain, such as NLRP3, AIM2 or IFI16, but dependent on NLRC4. Notably, SopB specifically prevented ASC oligomerization and the enzymatic activity of SopB was responsible for the inflammasome inhibition. Furthermore, inhibition of Akt signaling induced enhanced inflammasome activation. CONCLUSIONS: These results revealed a novel role in inhibition of NLRC4 inflammasome for Salmonella effector SopB. PMID- 28846927 TI - Arsenic distribution in a pasture area impacted by past mining activities. AB - Former mine exploitations entail a serious threat to surrounding ecosystems as after closure of mining activities their unmanaged wastes can be a continuous source of toxic trace elements. Quite often these mine sites are found within agricultural farming areas, involving serious hazards as regards product (feed/food) quality. In this work a grazing land impacted by the abandoned mine exploitation of an arsenical deposit was studied so as to evaluate the fate of arsenic (As) and other trace elements and the potential risks involved. With this aim, profile soil samples (0-50cm) and pasture plant species (Agrostis truncatula, Holcus annus and Leontodon longirostris) were collected at different distances (0-100m) from the mine waste dump and analyzed for their trace element content and distribution. Likewise, plant trace element accumulation from impacted grazing soils and plant trace element translocation were assessed. The exposure of livestock grazing animals to As was also evaluated, establishing its acceptability regarding food safety and animal health. International soil guideline values for As in grazing land soils (50mgkg-1) resulted greatly exceeded (up to about 20-fold) in the studied mining-affected soils. Moreover, As showed a high mobilization potential under circumstances such as phosphate application or establishment of reducing conditions. Arsenic exhibited relatively high translocation factor (TF) values (up to 0.32-0.89) in pasture plant species, reaching unsafe concentrations in their above-ground tissues (up to 32.9, 16.9 and 9.0mgkg-1 in Agrostis truncatula, Leontodon longirostris and Holcus annus, respectively). Such concentrations represent an elevated risk of As transfer to the high trophic-chain levels as established by international legislation. The limited fraction of arsenite found in plant roots should play an important role in the relatively high As root-to-shoot translocation shown by these plant species. Both soil ingestion and pasture intake resulted important entrance pathways of As into livestock animals, showing quite close contribution levels. The cow acceptable daily intake (ADI) of As regarding food safety was surpassed in some locations of the study area when the species Agrostis truncatula was considered as the only pasture feed. Restrictions in the grazing use of lands with considerable As contents where this plant was the predominant pasture species should be established in order to preserve food quality. Therefore, the exposure of livestock animals to As via both soil ingestion and pasture consumption should be taken into account to establish the suitability of mining impacted areas for gazing. PMID- 28846928 TI - PAEs occurrence and sources in road dust and soil in/around parks in May in Tianjin, China. AB - This is the first study reporting the presence of six phthalic acid esters (PAEs) in 45 composite soil and road dust samples collected in the urban zone of Tianjin, China. Three sample types (one soil and two road dust) were collected from the city parks. Soil samples (SI) were obtained from inside the park, road dust samples (RDI) were gathered from inside the park roads and the others (RDA) from roads surrounding parks. The range of concentrations of ?6PAEs in SI, RDI and RDA were 0.07-0.92MUgg-1, 0.42-6.32MUgg-1 and 0.40-7.54MUgg-1, respectively. The highest SI ?6PAEs concentration (0.92MUgg-1 in The People's Park) was 13 times higher than that of the lowest content (0.07MUgg-1 in XiLiu Park). Furthermore, the spatial distribution of PAEs in RDI showed higher contents in the Nankai and Hexi districts. PAEs concentrations in different types of roads displayed significant differences (P < 0.05). The RDA PAEs distribution expressed decreasing order for different types of roads such as arterial road > sub arterial road > branch road. The results of nonparametric tests on ?6PAEs revealed significant differences between every two different sample types (P < 0.05). The analysis of the six PAEs types indicated DnBP and DEHP were the primary contaminating compounds in all sample types. The PCA results showed cosmetics and personal care products were important sources of PAEs in SI, and plasticizers were the key sources of PAEs in RDI and RDA. PMID- 28846929 TI - Glyphosate-based herbicides toxicity on life history parameters of zoophytophagous Podisus nigrispinus (Heteroptera: Pentatomidae). AB - The increase of agricultural areas with glyphosate-resistant (GR) crops, and use of this herbicide in Brazil, makes necessary to assess its impacts on non-target organisms. The objective was to evaluate the development, reproduction and life table parameters of Podisus nigrispinus (Heteroptera: Pentatomidae) reared on GR soybean plants treated with glyphosate formulations (Zapp-Qi, Roundup-Transorb-R and Roundup-Original) at the recommended field dose (720g acid equivalent ha-1). Glyphosate formulations had no affect on nymph and adult weight of this predator. Fourth instar stage was shortest with Zapp Qi. Egg-adult period was similar between treatments (26 days) with a survival over 90%. Zapp-Qi and Roundup Transorb-R (potassium-salt: K-salt) reduced the egg, posture and nymph number per female, and the longevity and oviposition periods of this predator. Podisus nigrispinus net reproductive rate was highest in GR-soybean plants treated with Roundup-Original (isopropylamine-salt: IPA-salt). However, the duration of one generation, intrinsic and finite increase rates, and time to duplicate the population, were similar between treatments. Glyphosate toxicity on P. nigrispinus depends of the glyphosate salt type. IPA-salt was least harmless to this predator. Formulations based on K-salt altered its reproductive parameters, however, the development and population dynamic were not affect. Therefore, these glyphosate formulations are compatible with the predator P. nigrispinus with GR soybean crop. PMID- 28846930 TI - Combined effects of arsenic, salinity and temperature on Crassostrea gigas embryotoxicity. AB - The combined effects of different salinity and temperature levels on the toxicity of Arsenic (As) were studied on the embryonic development of the oyster Crassostrea gigas. A standardized embryotoxicity test was performed to assess the interactive effects of these stressors, in a full factorial design experiment including a range of salinities (15, 19, 24, 28 and 32), temperatures (16, 20, 24, 28 and 32 degrees C) and As concentrations (100, 300, 600, 1200, 2400ugL-1). The embryotoxicity endpoint was about the determination of normal larvae development rates at various conditions, and median effect concentration (EC50) determination for each As exposure condition. Results showed that toxicity induced by As was characterized by retardation of embryonic development observing toxic effects at lower concentrations than previously reported studies. The presence of As in seawater resulted in a narrower range of tolerance to both salinity and temperature. These findings bring new insights on the impacts of a common contaminant on an important shellfish species having a planktonic early life stage development, with potential implications for population survival and ecosystem functioning in a changing environment. PMID- 28846931 TI - Stimulation of morphofunctional repair of the facial nerve with photobiomodulation, using the end-to-side technique or a new heterologous fibrin sealant. AB - This research evaluated the influence of Photobiomodulation Therapy (PBMT) on lesions of the facial nerve repaired with the end-to-side technique or coaptation with a new heterologous fibrin sealant. Thirty-two Wistar rats were separated into 5 groups: Control group (CG), where the buccal branch of the facial nerve was collected; Experimental Suture Group (ESG) and Experimental Fibrin Group (EFG), in which the buccal branch was end-to-side sutured to the zygomatic branch on the right side of the face or coaptated with fibrin sealant on the left side; Experimental Suture Laser Group (ESLG) and Experimental Fibrin Laser Group (EFLG), in which the same procedures were performed as the ESG and EFG, associated with PBMT (wavelength of 830nm, energy density 6.2J/cm2, power output 30mW, beam area of 0.116cm2, power density 0.26W/cm2, total energy per session 2.16J, cumulative dose of 34.56J). The laser was applied for 24s/site at 3 points on the skin's surface, for a total application time of 72s, performed immediately after surgery and 3 times a week for 5weeks. A statistically significant difference was observed in the fiber nerve area between the EFG and EFLG (57.49+/ 3.13 and 62.52+/-3.56MUm2, respectively). For the area of the axon, fiber diameter, axon diameter, myelin sheath area and myelin sheath thickness no statistically significant differences were found (p<0.05). The functional recovery of whisker movement occurred faster in the ESLG and EFLG, which were associated with PBMT, with results closer to the CG. Therefore, PBMT accelerated morphological and functional nerve repair in both techniques. PMID- 28846932 TI - Effect of in vivo low-level laser therapy on bone marrow-derived mesenchymal stem cells in ovariectomy-induced osteoporosis of rats. AB - : Postmenopausal osteoporosis (PMOP) is considered by decreased bone strength that escalates the threat of fractures. Positive effects of photobiomodulation (PBM) with pulse wave have been demonstrated in cell culture and animal models. The aim of this study was to assess the in vivo effects of PBM on viability and calcium ion release of ovariectomy induced osteoporosis (OVX) - bone marrow derived mesenchymal stem cells (BMMSCs). MATERIAL AND METHODS: 18 female rats were distributed into the following groups: 1) control healthy, 2) LASER-healthy (890nm, 80Hz, 1.5J/cm2, three days weekly, 60days), 3) control OVX, 4) LASER-OVX, 5) Alendronate (Alen.)-OVX [0.5mg/kg, 5days per week, 60days], and 6) Alen.+LASER OVX. Ovariectomy was done on rats of groups 3, 4, 5 and 6. After that all rats were euthanized and their MSC harvested and cultured in complete osteogenic medium. In all groups, BMMSC viability, and calcium colorimetric assay were performed. RESULTS: We observed a significant increase in optical density (OD) of BMMSCs viability in LASER healthy group compared to control-OVX, Alen.-OVX, LASER OVX, LASER+Alen.-OVX, groups. LASER+Alen.-OVX group displayed a significant escalation in OD of BMMSCs viability compared to LASER-OVX, Alen.-OVX, and control-OVX groups. There were a significant increase in calcium ion release of LASER-healthy group compared to control healthy, control-OVX, Alen.-OVX, LASER OVX, and LASER+Alen.-OVX groups. LASER+Alen.-OVX group displayed a significant escalation in calcium ion release compared to LASER-OVX, Alen.-OVX, and control OVX groups. CONCLUSION: Pulse wave (PW) PBM significantly stimulated viability and cell proliferation of healthy BMMSCs compared to those of control-OVX, OVX alendronate, OVX-LASER, and LASER+alendronate-OVX. In addition stimulatory effect of LASER+alendronate on viability and cell proliferation of OVX-BMMSCs compared to those of control-OVX, alendronate-OVX, and LASER-OVX groups were found. PMID- 28846933 TI - Low temperature one-pot synthesis of Cu-doped ZnO/Al2O3 composite by a facile rout for rapid methyl orange degradation. AB - ZnO/Al2O3 composite modified by 2.5-10wt% Cu were prepared using a set of wet chemical techniques (solvothermal, co-precipitation, ultrasonic and reflux) and characterized. All processes were done under the atmospheric condition and without any calcination step. The product was characterized by PXRD, FE-SEM, FT IR and UV-Vis spectroscopy. The microscopy images clearly showed lamellar particles morphology in nano regime. X-ray diffraction studies revealed the wurtzite-type ZnO and gamma-Al2O3 crystallinity. The Band gap varied from 3.20eV for the un-doped Al2O3/ZnO sample to 2.18eV for the Al2O3/ZnO:Cu with Cu content of 10%. Formed Al2O3/ZnO:Cu composite exhibited a supreme photocatalytic performance upon the degradation of methyl orange (MO) under visible-light irradiation. The optimum catalyst indicated completely remove of MO dye with the 15mgL-1 concentration from the water after 50min photocatalytic reaction time, where for the optimum sample the removal efficiency was 77% after only 10min reaction. Results showed that the inserting of Cu in composite improves the photocatalytic activity of ZnO under visible light. The degradation rate of MO for optimum Cu-doped sample was almost 20 times the un-doped sample. PMID- 28846934 TI - LED antimicrobial photodynamic therapy with phenothiazinium dye against Staphylococcus aureus: An in vitro study. AB - The objective of this study was to evaluate, in vitro, the bactericidal effect of AmPDT on Staphylococcus aureus (ATCC 25923) using different concentrations (100, 50, 25, 12.5 and 6.25MUg/mL) of phenothiazine compound combined with LED light (lambda632+/-2nm) using varied energy densities (12, 9.6, 7.2, 4.8 and 2.4J/cm2). The experiments were carried out in triplicate and the samples were divided into groups: Control, Irradiated (treated only with light at different energy densities), Photosensitizer (treated only in the presence of the dye), AmPDT (treatment with light associated with dye). Counts of the colony forming units and the data obtained were statistically analyzed (ANOVA, Tukey's test, p<0.05). The results showed no difference between irradiated and Control groups. However, using the photosensitizer alone caused significant increased cytotoxicity and consequent reduction on the CFU counts (12.5MUg/mL (p<0.001), 25MUg/mL, 50MUg/mL and 100MUg/mL (p<0.0001). When AmPDT was used significant inhibition above 70% were detected for all concentrations of the photosensitize (p<0.0001) except for 6.25MUg/mL. The results indicate a dose-response dependent when the photosensitizer is used alone but not for the sole use of the light is used. It is concluded that, a single application of AmPDT, using energy density of 12J/cm2 associated either to 12.5 (81.52%) or 25MUg/mL (91.57%) resulted in higher in vitro inhibition of S. aureus. PMID- 28846935 TI - The disulfide-rich Metridia luciferase refolded from E. coli inclusion bodies reveals the properties of a native folded enzyme produced in insect cells. AB - The bioluminescence of a marine copepod Metridia longa is determined by a small secreted coelenterazine-dependent luciferase that uses coelenterazine as a substrate of enzymatic reaction to generate light (lambdamax=480nm). To date, four different isoforms of the luciferase differing in size, sequences, and properties have been cloned by functional screening. All of them contain ten conserved Cys residues that suggests up to five SS intramolecular bonds per luciferase molecule. Whereas the use of copepod luciferases as bioluminescent reporters in biomedical research in vivo is growing from year to year, their application for in vitro assays is still limited by the difficulty in obtaining significant amounts of luciferase. The most cost-effective host for producing recombinant proteins is Escherichia coli. However, prokaryotic and eukaryotic cells maintain the reductive environment in cytoplasm that hinders the disulfide bond formation and consequently the proper folding of luciferase. Here we report the expression of the MLuc7 isoform of M. longa luciferase in E. coli cells and the efficient procedure for refolding from inclusion bodies yielding a high active monomeric protein. Furthermore, in a set of identical experiments we demonstrate that bioluminescent and structural features of MLuc7 produced in bacterial cells are identical to those of MLuc7 isoform produced from culture medium of insect cells. Although the yield of high-purity protein is only 6mg/L, the application of E. coli cells to produce the luciferase is simpler and more cost-effective than the use of insect cells. We expect that the suggested technology of Metridia luciferase production allows obtaining of sufficient amounts of protein both for the development of novel in vitro analytical assays with the use of MLuc7 as a label and for structural studies. PMID- 28846936 TI - A new in vitro assay to test UVR protection of dermal extracellular matrix components by a flat spectrum sunscreen. AB - The efficacy of topical sunscreens is currently assessed by crude, costly and time consuming in vivo assays. We have previously demonstrated that components of the dermal extracellular matrix (ECM), rich in UV-absorbing amino acids, are susceptible to damage by solar simulated radiation (SSR) in vitro. Here we developed an in vitro method to test the ability of sunscreens to protect fibrillin-rich microfibrils (FRM) and fibronectin, key components of the dermal ECM from UV-induced damage. Solutions of FRM or fibronectin were irradiated without protection, in the presence of a vehicle or a commercially-available flat spectrum sunscreen. The effect of SSR on molecular structure was determined by atomic force microscopy (FRM) and SDS-PAGE (fibronectin). Following irradiation, FRM periodicity became bi-modally distributed (peaks: 40nm & 59nm) compared to the unimodal distribution in unexposed controls (peak: 50nm). Irradiation in the presence of flat-spectrum sunscreen protected against this change, maintaining the unimodal distribution. SSR induced significant aggregation of fibronectin (p=0.005), which was abrogated by sunscreen. These results demonstrate that this in vitro assay system is sufficiently sensitive to act as an initial/additional screen of sunscreen efficacy. We conclude that sunscreen can reduce UV-mediated damage of key dermal ECM in vitro and thereby prevent remodelling associated with photoageing. PMID- 28846937 TI - A Novel IMP1 Inhibitor, BTYNB, Targets c-Myc and Inhibits Melanoma and Ovarian Cancer Cell Proliferation. AB - The oncofetal mRNA-binding protein, IMP1 or insulin-like growth factor-2 mRNA binding protein 2 (IGF2BP1), binds to and stabilizes c-Myc, beta-TrCP1, and other oncogenic mRNAs, leading to increased expression of the proteins encoded by its target mRNAs. IMP1 is frequently overexpressed in cancer and is strongly correlated with a poor prognosis and reduced survival in melanoma, ovarian, breast, colon, and lung cancer. While IMP1 is an attractive anticancer drug target, there are no small molecule inhibitors of IMP1. A fluorescence anisotropy based assay was used to screen 160,000 small molecules for their ability to inhibit IMP1 binding to fluorescein-labeled c-Myc mRNA. The small molecule, BTYNB, was identified as a potent and selective inhibitor of IMP1 binding to c Myc mRNA. In cells, BTYNB downregulates several mRNA transcripts regulated by IMP1. BTYNB destabilizes c-Myc mRNA, resulting in downregulation of c-Myc mRNA and protein. BTYNB downregulates beta-TrCP1 mRNA and reduces activation of nuclear transcriptional factors-kappa B (NF-kappaB). The oncogenic translation regulator, eEF2, emerged as a new IMP1 target mRNA, enabling BTYNB to inhibit tumor cell protein synthesis. BTYNB potently inhibited proliferation of IMP1 containing ovarian cancer and melanoma cells with no effect in IMP1-negative cells. Overexpression of IMP1 reversed BTYNB inhibition of cell proliferation. BTYNB completely blocked anchorage-independent growth of melanoma and ovarian cancer cells in colony formation assays. With its ability to target c-Myc and to inhibit proliferation of difficult-to-target melanomas and ovarian cancer cells, and with its unique mode of action, BTYNB is a promising small molecule for further therapeutic evaluation and mechanistic studies. PMID- 28846938 TI - Drinking to cope with depression mediates the relationship between social avoidance and alcohol problems: A 3-wave, 18-month longitudinal study. AB - Undergraduates with high social anxiety have increased alcohol problems, despite lower or equivalent alcohol use levels. Drinking motives mediate the cross sectional relationship between social anxiety and alcohol problems, with coping and conformity motives being the most commonly observed mediators. Our study extended prior research by using a longitudinal design, examining coping with anxiety motives (CAM) and coping with depression motives (CDM) separately using path analysis, simultaneously considering a variety of drinking motives in the model, and focusing on a particularly severe form of social anxiety - namely, social avoidance. We collected data from 219 undergraduates (72.6% women, mean age of 20.59years) over three waves spaced six months apart. Results indicated CDM mediated the prospective relationship between social avoidance and alcohol problems. Findings suggest socially avoidant students' escalations in CDM explain their increased alcohol problems over time. Future research should examine involvement of depression and social isolation in contributing to this pathway to alcohol problems. PMID- 28846939 TI - PTSD symptom presentation among people with alcohol and drug use disorders: Comparisons by substance of abuse. AB - Posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) commonly co-occur, and there is some evidence to suggest that PTSD symptom clusters are differentially related to various substances of abuse. However, few studies to date have compared PTSD symptom patterns across people with different types of SUDs, and fewer still have accounted for the presence of comorbidity across types of SUDs in understanding symptom patterns. Thus, in the current study, we use a treatment-seeking sample of people with elevated symptoms of PTSD and problem alcohol use to explore differential associations between past-year SUDs with active use and PTSD symptoms, while accounting for the presence of multiple SUDs. When comparing alcohol and drug use disorders, avoidance symptoms were elevated in those with alcohol use disorder, and hyperarousal symptoms were elevated in those who had a drug use disorder. In the subsample with alcohol use disorder, hyperarousal symptoms were elevated in people with co-occurring cocaine use disorders and numbing symptoms were elevated in people with co-occurring sedative/hypnotic/anxiolytic use disorder. These findings provide evidence for different symptom cluster patterns between PTSD and various types of SUDs and highlight the importance of examining the functional relationship between specific substances of abuse when understanding the interplay between PTSD and SUDs. PMID- 28846940 TI - Perception of intoxication in a field study of the night-time economy: Blood alcohol concentration, patron characteristics, and event-level predictors. AB - OBJECTIVE: Determine the relationship of subjective intoxication to blood alcohol concentration (BAC) and examine whether patron and event-level characteristics modify the relationship of BAC to subjective intoxication. METHODS: An in-situ systematic random sample of alcohol consumers attending night-time entertainment districts between 10pm and 3am on Friday and Saturday nights in five Australian cities completed a brief interview (n=4628). Participants reported age, sex, and pre-drinking, energy drink, tobacco, illicit stimulant and other illicit drug use that night, and their subjective intoxication and BAC were assessed. RESULTS: Male and female drinkers displayed equally low sensitivity to the impact of alcohol consumption when self-assessing their intoxication (BAC only explained 19% of variance). The marginal effect of BAC was not constant. At low BAC, participants were somewhat sensitive to increases in alcohol consumption, but at higher BAC levels that modest sensitivity dissipated (actual BAC had less impact on self-assessed intoxication). The slope ultimately leveled out to be non responsive to additional alcohol intake. Staying out late, pre-drinking, and being young introduced biases resulting in higher self-assessed intoxication regardless of actual BAC. Further, both energy drinks and stimulant use modified the association between BAC and perceived intoxication, resulting in more compressed changes in self-assessment as BAC varies up or down, indicating less ability to perceive differences in BAC level. CONCLUSIONS: The ability of intoxicated patrons to detect further intoxication is impaired. Co-consumption of energy drinks and/or stimulant drugs is associated with impaired intoxication judgment, creating an additional challenge for the responsible service and consumption of alcohol. PMID- 28846941 TI - Incremental predictive validity of the Addiction Severity Index psychiatric composite score in a consecutive cohort of patients in residential treatment for drug use disorders. AB - BACKGROUND: The Addiction Severity Index (ASI) is a widely used assessment instrument for substance abuse treatment that includes scales reflecting current status in seven potential problem areas, including psychiatric severity. The aim of this study was to assess the ability of the psychiatric composite score to predict suicide and psychiatric care after residential treatment for drug use disorders after adjusting for history of psychiatric care. METHODS: All patients treated for drug use disorders in residential treatment centers in Denmark during the years 2000-2010 with complete ASI data were followed through national registers of psychiatric care and causes of death (N=5825). Competing risks regression analyses were used to assess the incremental predictive validity of the psychiatric composite score, controlling for previous psychiatric care, length of intake, and other ASI composite scores, up to 12years after discharge. RESULTS: A total of 1769 patients received psychiatric care after being discharged from residential treatment (30.3%), and 27 (0.5%) committed suicide. After adjusting for all covariates, psychiatric composite score was associated with a higher risk of receiving psychiatric care after residential treatment (subhazard ratio [SHR]=3.44, p<0.001), and of committing suicide (SHR=11.45, p<0.001). CONCLUSIONS: The ASI psychiatric composite score has significant predictive validity and promises to be useful in identifying patients with drug use disorders who could benefit from additional mental health treatment. PMID- 28846942 TI - Co-occurrence of tobacco product use, substance use, and mental health problems among youth: Findings from wave 1 (2013-2014) of the population assessment of tobacco and health (PATH) study. AB - INTRODUCTION: Cigarette use is associated with substance use and mental health problems among youth, but associations are unknown for non-cigarette tobacco product use, as well as the increasingly common poly-tobacco use. METHODS: The current study examined co-occurrence of substance use and mental health problems across tobacco products among 13,617 youth aged 12-17years from Wave 1 (2013 2014) of the nationally representative Population Assessment of Tobacco and Health (PATH) Study. Participants self-reported ever cigarette, e-cigarette, smokeless tobacco, traditional cigar, cigarillo, filtered cigar, hookah, and other tobacco product use; alcohol, marijuana, and other drugs; and lifetime substance use, internalizing and externalizing problems. RESULTS: In multivariable regression analyses, use of each tobacco product was associated with substance use, particularly cigarillos and marijuana (AOR=18.9, 95% CI: 15.3 23.4). Cigarette (AOR=14.7, 95% CI: 11.8-18.2) and cigarillo (AOR=8.1, 95% CI: 6.3-10.3) use were strongly associated with substance use problems and tobacco users were more likely to report internalizing (AOR=1.6, 95% CI: 1.4-1.8) and externalizing (AOR=1.4, 95% CI: 1.3-1.6) problems. Female tobacco users were more likely to have internalizing problems than male tobacco users. Poly-tobacco users were more likely than exclusive users to use substances (AOR=3.4, 95% CI: 2.7 4.3) and have mental health (AOR=1.2, 95% CI: 1.0-1.5) and substance use (AOR=4.7, 95% CI: 3.4-6.6) problems. CONCLUSIONS: Regardless of the tobacco product used, findings reveal high co-occurrence of substance use and mental health problems among youth tobacco users, especially poly-tobacco users. These findings suggest the need to address comorbidities among high risk youth in prevention and treatment settings. PMID- 28846943 TI - Breast metastasis nine years after nephrectomy for renal cell carcinoma: A case report. AB - INTRODUCTION: The breast is a rare site for metastatic disease. We report a rare case of breast metastasis 9 years after nephrectomy for renal cell carcinoma (RCC) and include a review of the relevant literature. PRESENTATION OF CASE: An 82-year-old woman who developed an RCC underwent left nephrectomy in 2005. In October 2014, computed tomography (CT) revealed a mass of approximately 1cm in the lateral portion of the right breast. Breast ultrasonography (US) revealed a well-circumscribed, hypoechoic mass at the same site. Fine needle aspiration (FNA) was performed, but the sample was inadequate because it did not capture breast duct epithelial cells. In June 2015, follow-up US revealed enlargement of the mass, and core needle biopsy (CNB) was performed to confirm the diagnosis. Histological examination resulted in the diagnosis of breast metastasis from an RCC. The patient underwent surgery for partial mastectomy in November 2015. The patient was asymptomatic and free of detectable disease at 18-month follow-up. DISCUSSION: The diagnosis of breast metastasis by imaging examination is difficult, and the results of FNA examination are often inconclusive because of the absence of breast duct epithelial cells. Only 22 cases of breast metastasis from RCC have been described in the literature. In almost all the reported cases, lumpectomy or partial mastectomy was performed. CONCLUSION: It is important that histological diagnosis be determined by CNB and by other methods if the patient has a history of malignancy, and minimally invasive therapy should be performed in accordance with the prognosis. PMID- 28846944 TI - Antegrade jejunogastric intussusception and common bile duct stones at 14 months after gastrectomy and cholecystectomy: A case report. AB - INTRODUCTION: Intussusception after gastrectomy is a minor complication after gastrectomy, while common bile duct stone (CBD) is also a rare complication post cholecystectomy. We report a case that simultaneously caused both intussusception and CBD stone following gastrectomy with prophylactic cholecystectomy. CASE PRESENTATION: A 74-year-old woman underwent distal gastrectomy with Roux-en-Y reconstruction and prophylactic cholecystectomy for gastric cancer. After 14 months, the patient reported nausea and vomiting. Abdominal computed tomography scanning showed antegrade intussusception of the Roux limb of the gastrojejunostomy and calculi in the common bile duct, with a diagnosis of jejunogastric intussusception and common bile duct stones. The patient was hospitalized and endoscopic examination was performed on day 3. Endoscopic treatment did not resolve the intussusception, which also obstructed the bile duct stones. Elective surgery was performed on day 10, in which the invaginated Roux limb of the gastrojejunostomy was resected after manual reinstatement to its original position. This was followed by open exploration of the common bile duct and T-tube drainage. The patient was discharged 25days post- surgery. DISCUSSION: Jejunogastric intussusception and CBD stone may require operative management, although the operation could be elective after sufficient examination and preparation. CONCLUSION: Jejunogastric intussusception and bile duct stones are rare after distal gastrectomy, physicians should be alerted to the possibility of these complications. PMID- 28846945 TI - Colonic mesenteric lymphatic malformation presenting as an intraabdominal abscess in an infant: A case report. AB - INTRODUCTION: Lymphatic malformations are low-flow vascular malformations most commonly located in the head and neck; isolated intraabdominal involvement is rare. PRESENTATION OF CASE: An 8-month-old previously healthy male presented with a 9-day history of fevers. On examination, right-sided abdominal tenderness was noted. Ultrasound revealed a large heterogeneous mass, and CT scan revealed a rim enhancing cystic mass adjacent to the right colon. Laboratory investigation including blood cultures was normal. His fever resolved with broad-spectrum antibiotics. Diagnostic laparoscopy revealed a large, firm mass arising from the mesentery of the right colon. An open right hemicolectomy with ileocolonic anastomosis was performed. The infant tolerated the procedure well, and he was discharged home on postoperative day four, pathologic examination identified a mesenteric lymphatic malformation with secondary abscess formation. CONCLUSION: This atypical presentation of an uncommon entity was instructive in several ways, particularly illustrating the diagnostic pitfalls that can be introduced by superinfection. PMID- 28846946 TI - Surgical treatment for the excluded bile leakage from Spiegel lobe after right hemihepatectomy: A case report. AB - INRODUCTION: The treatments of excluded bile duct leakage after hepatectomy are not easy and various strategies have been reported, such as surgery, ethanol or fibrin glue injection, and portal vein embolization. PRESENTATION OF CASE: A 72 year-old man with a surgical history of laparoscopic ileocecal resection for diverticular bleeding was diagnosed as having hepatocellular carcinoma. Right hemihepatectomy was performed, and computed tomography examination on postoperative day 9 showed abdominal fluid collection in the right subphrenic space. Percutaneous intra-abdominal fluid drainage was performed and it was diagnosed as bile leakage. After that it was diagnosed as excluded bile leakage from the Spiegel lobe by drip infusion cholangiographic-computed tomography and endoscopic retrograde cholangiography. To improve this clinical condition, we performed the Spiegel lobe excision on postoperative day 48. The postoperative course was uneventful and the patient was discharged. DISCUSSION: According to the postoperative examination, it appeared that the bile duct from the Spiegel lobe joined to the right main bile duct or the bile duct of the right posterior section. This bile duct anomaly was not detected preoperatively on imaging examination. It is most likely that the bile duct from the Spiegel lobe was cut when the hepatoduodenal ligament in the hepatic hilum was peeled. To prevent excluded bile leakage, the hepatoduodenal ligament should be carefully peeled and ligated instead of using energy devices. CONCLUSION: We consider that surgical treatment for postoperative excluded bile leakage is both a quick and reliable procedure in patients with acceptable liver function and anatomical subject. PMID- 28846947 TI - Transanal total mesorectal excision as a surgical procedure for diffuse cavernous hemangioma of the rectum: A case report. AB - BACKGROUND: The safety and feasibility of transanal total mesorectal excision (TaTME) were demonstrated in the management of rectal cancer. However, its role in the management of patients with diffuse cavernous hemangioma of the rectum (DCHR) has not been evaluated. METHODS: A female patient with DCHR was admitted to our hospital. Colonoscopy, magnetic resonance imaging (MRI), abdominal computed tomography (CT) and arteriography were performed. Lesions were detected in mesorectum and rectal wall extending from the dentate line to 5cm proximally. TaTME with a protecting loop ileostomy were performed. The research work has been reported in line with the SCARE criteria Agha et al., 2016 [1]. RESULTS: TaTME and a protecting loop ileostomy were safely performed, with an intact mesorectal specimen being harvested. The entire procedure took 348min. The estimated blood loss was 100ml. The patient recovered uneventfully. Her symptom of painless rectal bleeding was resolved satisfactorily following the surgery. The histopathological evaluation confirmed the diagnosis of DCHR. CONCLUSIONS: TaTME appears to be a safe and feasible procedure for patients with DCHR in experienced hands. PMID- 28846948 TI - Biopsy-proven progressive fatty liver disease nine months post mini-gastric bypass surgery: A case study. AB - INTRODUCTION: Mini-gastric bypass (MGB) is a popular bariatric procedure. Its effect on non-alcoholic fatty liver disease (NAFLD), however, has not yet been comprehensively studied. PRESENTATION OF CASE: A 57 year-old non-alcoholic female with a body mass index of 42.8kg/m2 underwent MGB without any incident. A concurrent liver biopsy showed an NAFLD activity score (NAS) of 2/8 without fibrosis. She presented at postoperative month eight with edema, vague abdominal pain, nausea, and vomiting and was hospitalized. Her BMI had dropped to 25.7kg/m2. Her blood workup revealed mild anemia, mildly elevated liver enzymes, and hypoalbuminemia (2.5g/dL). Liver ultrasound revealed grade-2 fatty liver. She received parenteral nutrition and intensive nutrient supplementation. Nevertheless, with regard to unsuccessful supportive measures and rising liver enzymes, revisional surgery -gastrogastrostomy- was performed. Her liver biopsy demonstrated a NAS of 7/8 at the time of revisional surgery. Her postoperative course was uneventful and she was discharged after one week. DISCUSSION: Bariatric surgery has shown favorable results regarding improvement of NAFLD in morbid obesity. This beneficial effect has been linked to the amount of weight loss. However, case reports have shown deteriorating liver function and NAFLD even after significant weight loss. They all have in common significant weight loss in a relatively short period of time. There may also be a connection between specific bariatric surgery procedures and this phenomenon. CONCLUSION: Future studies comparing the effect of various bariatric procedures, including MGB, are necessary to help clinicians decide the optimal procedure for patients with this liver condition. PMID- 28846949 TI - Splenic hamartoma associated with thrombocytopenia: A case report. AB - INTRODUCTION: Hamartomas are rare, benign tumors of the spleen. Few cases of splenic hamartomas associated with thrombocytopenia have been reported. PRESENTATION OF CASE: An asymptomatic 64-year-old man with myelodysplastic syndrome was found to have a splenic tumor. Laboratory tests were significant for thrombocytopenia, with a platelet count of 7.8*104/MUL. Ultrasonography showed splenomegaly (10.8*6.6cm), and a hypoechoic splenic mass (8.0*7.0cm). Color doppler ultrasound revealed blood flow within the mass, and the mass density was homogeneous on abdominal computed tomography (CT). Contrast-enhanced CT showed heterogeneous enhancement of the splenic mass during the arterial phase. Positron emission tomography (PET)-CT showed no significant fludeoxyglucose (FDG) accumulation within the mass. The differential diagnosis included splenic hamartoma, splenic hemangioma, splenomegaly associated with extramedullary hematopoiesis, and malignant tumor, including solitary splenic metastasis. A laparoscopic splenectomy was performed due to the possibility of malignancy, the presence of thrombocytopenia, and the risk of splenic rupture. The resected specimen showed a localized, well-demarcated, 8.0*7.0cm splenic mass. Histological examination revealed abnormal red pulp proliferation and the absence of normal splenic structures. The patient's post-operative course was uneventful. His platelet count improved on post-operative day 1 and he was discharged on post operative day 9. He remained in good health with a normal platelet count one month after surgery. DISCUSSION: Making definitive preoperative diagnosis is difficult in splenic hamartomas. Surgery is necessary for diagnosis when malignancy cannot be ruled out. CONCLUSIONS: Surgery may also improve symptoms of hypersplenism, including thrombocytopenia. PMID- 28846950 TI - Osteochondrosis of the medial malleolar epiphysis: A case report and review of the literature. AB - INTRODUCTION: Osteochondrosis is characterized by a disturbance of enchondral ossification in skeletally immature patients and should be investigated in children having a history of persistent foot and ankle pain. Involvement of the medial malleolar epiphysis is rarely reported. PRESENTATION OF CASE: We describe the case of a sporty 12-year-old male with osteochondrosis of the left medial malleolar epiphysis treated with a conservative management. DISCUSSION: Calcanear, navicular and metatarsal apophysis are the most common locations for osteochondrosis in ankle and foot. Anyway other osteochondrosis should be excluded. Medial malleolar osteochondrosis is occasionally described. We performed a review of the relevant literature and we summarized clinical aspects, radiological characteristics and reported management of this painful and probably underestimated condition. CONCLUSION: Medial malleolar osteochondrosis is a rare but well recognized condition. Only seven cases are described in literature. PMID- 28846951 TI - Unstable thoracic spine fracture with aortic encroachment: A potentially fatal association and a suggested treatment. AB - BACKGROUND: The coexistence of an unstable spinal fracture with a pending aortic lesion is potentially catastrophic and a therapeutic challenge as to timing of treatment, assigning priorities and selecting the best approach. CASE REPORT: A 41 year-old healthy male victim of bike accident. Imaging revealed a fracture of 6th and 7th thoracic vertebrae with a bone fragment in close proximity to the descending thoracic aorta. After consultation with spine/vascular surgeons and interventional radiologists it was decided to secure the potential aortic injury with an endovascular stent-graft followed by posterior vertebral instrumentation for fracture's reduction. DISCUSSION/CONCLUSION: A multi-specialists teamwork approach is mandatory. Vascular lesion is priority, followed by vertebral surgery. As to the treatment options, we suggest a "best but still safest" philosophy: endovascular repair and posterior spinal instrumentation should be considered first in the acute stage. PMID- 28846952 TI - Mesh erosion to urinary bladder causing fistulation to abdominal wall resulting in necrotizing fasciitis: A case report of late complication of incisional hernia. AB - INTRODUCTION: Incisional hernia is not an uncommon complication after abdominal operation, and laparoscopic ventral hernia repair with mesh is commonly performed nowadays. It is thought to have less complication compare to the traditional open repair, yet late complication is still observed occasionally and can be disastrous. CASE REPORT: We hereby report a case of abdominal wall necrotizing fasciitis 21 months after laparoscopic incisional hernia repair in lower midline with dual mesh, due to mesh migration and erosion into urinary bladder, resulting in fistulation between bladder and abdominal wall. Repeated debridement and removal of mesh was required for sepsis control and the patient required intensive care support due to multi-organ failure. Subsequent repair of urinary bladder and abdominoplasty was performed after condition stabilized. CONCLUSION: This case was the first reported incident with bladder erosion by dual mesh causing vesico-cutaneous fistula complicated with necrotizing fasciitis. Although dual mesh theoretically reduces the risk of mesh erosion, mesh erosion to viscera can still happen and cause severe complication. Its risk should be balanced and discussed with patient with full consent. PMID- 28846953 TI - Post-remissional and pre-transplant role of minimal residual disease detected by WT1 in acute myeloid leukemia: A retrospective cohort study. AB - In acute myeloid leukemia (AML), the detection of minimal residual disease (MRD) is still under investigation. The aim of the present retrospective study was to assess the role of Wilms tumor gene 1 (WT1) overexpression in a large monocentric cohort of AML patients. Among 255 enrolled patients, MRD was investigated in those in complete remission (CR) with an available WT1 at baseline (>250 copies) and at two further time-points: after induction (n=117) and prior allogeneic hematopoietic cell transplantation (allo-HCT), n=65. Baseline BM WT1 overexpression was not associated with response to induction (p=0.244). Median overall survival (OS) and disease-free survival (DFS) were significantly shorter in patients with >350 WT1 copies after induction compared to those with <=350 (HR for mortality 2.13; 95% CI 1.14-3.97, p=0.018 and HR for relapse 2.81; 95% CI 1.14-6.93, p=0.025). Patients with WT1>150 copies pre allo-HCT had a significantly higher 2-year cumulative incidence of relapse (CIR) compared to those with WT1<=150 (HR 4.61; 95% CI 1.72-12.31, p=0.002). The prognostic role of WT1 overexpression resulted independent from other well-established risk factors. According to these results, WT1 overexpression might represent an additional MRD tool for risk stratification in patients classified nowadays in CR. PMID- 28846954 TI - Race/ethnicity and marijuana use in the United States: Diminishing differences in the prevalence of use, 2006-2015. AB - BACKGROUND: Marijuana use has been decreasing in the past several years among adolescents, though variation in the extent and rate of decrease across racial/ethnic groups is inadequately understood. METHODS: The present study utilized nationally-representative data in Monitoring the Future from 2006 to 2015 to examine trends over time in past 30-day marijuana use. We examine whether differences in trends over time by race and ethnicity also differ by individual level, school-level, and state-level factors. Sample included 131,351 8th grade students, 137,249 10th grade students, and 123,293 12th grade students; multi level models and difference-in-differences tests were used. RESULTS: In 10th grade, Black students had a positive linear increase in marijuana use (est=0.04, SE=0.01, p<0.001), and the magnitude of the increase was significantly greater than among non-Hispanic White students (est=0.38, SE=0.009, p<0.001). The increase trend among Black students was greater among those in large class sizes. In 12th grade, all racial ethnic groups except non-Hispanic Whites demonstrated a linear increase in prevalence across time. The magnitude of the increase among Hispanic students was greater among those in urban areas and large class sizes. The magnitude of the increase among Black students was greater in states with a medical marijuana law before 2006 (est=0.06, SE=0.03, p=0.02), among other state level covariates. CONCLUSION: Together these results suggest that the next stage of public health approaches to reducing the harms associated with adolescent drug use should attend to shifting demographic patterns of use among adolescents and ensure that services and programmatic approaches to adolescent prevention are applied equitably. PMID- 28846955 TI - Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. AB - BACKGROUND: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Delta9-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. METHODS: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. RESULTS: THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the alpha1 adrenergic antagonist prazosin. CONCLUSIONS: Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow. PMID- 28846956 TI - Hypermutated tumours in the era of immunotherapy: The paradigm of personalised medicine. AB - Immune checkpoint inhibitors have demonstrated unprecedented clinical activity in a wide range of cancers. Significant therapeutic responses have recently been observed in patients presenting mismatch repair-deficient (MMRD) tumours. MMRD cancers exhibit a remarkably high rate of mutations, which can result in the formation of neoantigens, hypothesised to enhance the antitumour immune response. In addition to MMRD tumours, cancers mutated in the exonuclease domain of the catalytic subunit of the DNA polymerase epsilon (POLE) also exhibit an ultramutated genome and are thus likely to benefit from immunotherapy. In this review, we provide an overview of recent data on hypermutated tumours, including MMRD and POLE-mutated cancers, with a focus on their distinctive clinicopathological and molecular characteristics as well as their immune environment. We also discuss the emergence of immune therapy to treat these hypermutated cancers, and we comment on the recent Food and Drug Administration approval of an immune checkpoint inhibitor, the programmed cell death 1 antibody (pembrolizumab, Keytruda), for the treatment of patients with metastatic MMRD cancers regardless of the tumour type. This breakthrough represents a turning point in the management of these hypermutated tumours and paves the way for broader strategies in immunoprecision medicine. PMID- 28846957 TI - ERP investigation of attentional disengagement from suicide-relevant information in patients with major depressive disorder. AB - BACKGROUND: Previous studies suggest the presence of attentional bias towards suicide-relevant information in suicidal individuals. However, the findings are limited by their reliance on behavioral measures. This study investigates the role of difficulty in disengaging attention from suicide-relevant stimuli using the P300 component of event-related potentials (ERPs). METHODS: Forty-four adults with Major Depressive Disorder (MDD) were administered the spatial cueing task using suicide-relevant and negatively-valenced words as cue stimuli. Disengagement difficulty was measured using reaction time and P300 during invalid trials. RESULTS: P300 amplitudes at Pz were higher in suicide-relevant compared to negatively-valenced word condition on invalid trials for participants with low rates of suicidal behavior. However, no such difference was found among participants with high rates of suicidal behavior. P300 amplitudes for suicide relevant word condition were negatively correlated with "lifetime suicide ideation and attempt" at Pz. No significant results were found for the reaction time data, indicating that the ERP may be more sensitive in capturing the attentional disengagement effect. LIMITATIONS: The groups were divided according to Suicidal Behaviors Questionnaire-Revised (SBQ-R) total score. Neutral stimulus was not included as cue stimuli. Most participants were under medication during the experiment. CONCLUSIONS: Our results indicate that patients with MDD and low rates of suicidal behavior show difficulty in disengaging attention from suicide relevant stimuli. We suggest that suicide-specific disengagement difficulties may be related to recentness of suicide attempt and that acquired capability for suicide may contribute to reduced disengagement difficulties. PMID- 28846958 TI - Substance use disorders and self- and other-directed violence among adults: Results from the National Survey on Drug Use And Health. AB - BACKGROUND: Previous studies have identified a violence typology of self- and other-directed violence. This study examines the extent to which substance use disorders (SUDs) as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), independent of serious psychological distress, major depressive episodes, assault arrest, and criminal justice involvement, are associated with these violence categories. METHOD: Data were obtained from the National Survey on Drug Use and Health (NSDUH) pooled across survey years 2008-2015, with a combined sample of 314,881 adult respondents. According to self-report data on suicide attempt (self-directed) and attacking someone with the intent for serious injury (other-directed), violence was categorized in four categories: none, self-directed only, other-directed only, and combined self-/other-directed. Multinomial logistic regression was used to estimate the adjusted odds ratios associated with the risk factors for different forms of violence. RESULTS: Nicotine dependence and the number of DSM-IV SUDs criteria (except the criterion of legal problems) for alcohol, marijuana, and pain reliever use disorders are significantly associated with the self-/other directed violence categories. LIMITATIONS: Cross-sectional data do not allow assessment of directionality of important factors. CONCLUSIONS: The identification of the combined self- and other-directed violence among adults in the general population extends studies in the adolescent population, and significant correlation between self- and other-directed violence provides additional support for clinical studies that established this association. Findings expand the associated risk factors identified in previous studies for the adult population. Prevention and treatment programs need to address both forms of violence and suicidality. PMID- 28846959 TI - Association of genetic variations in the serotonin and dopamine systems with aggressive behavior in the Chinese adolescent population: Single- and multiple risk genetic variants. AB - BACKGROUND: Genetic predisposition is an important factor leading to aggressive behavior. However, the relationship between genetic polymorphisms and aggressive behavior has not been elucidated. METHODS: We identified candidate genes located in the dopaminergic and serotonin system (DRD3, DRD4, and FEV) that had been previously reported to be associated with aggressive behavior. We investigated 14 tag single-nucleotide polymorphisms (SNPs) using a multi-analytic strategy combining logistic regression (LR) and classification and regression tree (CART) to explore higher-order interactions between these SNPs and aggressive behavior in 318 patients and 558 controls. RESULTS: Both LR and CART analyses suggested that the rs16859448 polymorphism is the strongest individual factor associated with aggressive behavior risk. In CART analysis, individuals carrying the combined genotypes of rs16859448TT/GT-rs11246228CT/TT-rs3773679TT had the highest risk, while rs16859448GG-rs2134655CT had the lowest risk (OR = 5.25, 95% CI: 2.53 10.86). CONCLUSION: This study adds to the growing evidence on the association of single- and multiple-risk variants in DRD3, DRD4, and FEV with aggressive behavior in Chinese adolescents. However, the aggressive behavior scale used to diagnose aggression in this study did not account for comorbid conditions; therefore, further studies are needed to confirm our observations. PMID- 28846960 TI - Impact of obesity and mood disorders on physical comorbidities, psychological well-being, health behaviours and use of health services. AB - BACKGROUND: Albeit obesity and mood disorders frequently co-occur, few studies examined the impacts of this co-occurrence. The aim was to compare individuals with obesity and mood disorders (ObMD) to those with obesity without mood disorder in terms of physical comorbidities, psychological well-being, health behaviours and use of health services. METHODS: Cross-sectional study using the Canadian Community Health Survey including a weighted sample of individuals with obesity (n = 1298) representing inhabitants from the province of Quebec (Canada). RESULTS: Adjusted multivariate logistic regressions indicated that ObMD reported more physical conditions with odds ratio (OR) ranging from 1.8 [95%CI: 1.1 - 2.8] (hypertension) to 2.8 [95%CI: 1.3 - 6.0] (stomach ulcer). Also, ObMD reported poorer psychological well-being with OR ranging from 2.1 [95%CI: 1.4 - 3.3] (stress) to 25.6 [95%CI: 14.7 - 45.0] (poor perceived mental health). ObMD also reported more consultations with health professionals with OR ranging from 1.9 [95%CI: 1.0 - 3.5] (physicians) to 7.7 [95%CI: 4.2 - 14.3] (psychologists), and less healthy behaviours with OR ranging from 1.7 [95%CI: 1.1 - 2.6] (fruits and vegetables intake) to 2.1 [95%CI: 1.3 - 3.3] (tobacco). LIMITATIONS: Self reported data so we cannot discard the possibility of a bias in reporting. Also, given the cross-sectional design, no directional conclusion or causality about our results is possible. DISCUSSION: The co-occurrence of mood disorder and obesity seems to be an aggravating factor of obesity-related factors because it is associated with poorer health in several areas. Interventions to prevent or manage obesity in mood disorders are necessary. PMID- 28846961 TI - Prevalence trends of pre- and postnatal depression in Japanese women: A population-based longitudinal study. AB - BACKGROUND: This study aimed to describe the prevalence trends of pre- and postnatal depression, via measures of the Edinburgh Postnatal Depression Scale (EPDS) total and factor scores, from 20 weeks' gestation to 3 months postpartum, stratified by parity, in a Japanese female population. METHODS: A longitudinal, population-based study was conducted among perinatal women giving birth at maternity facilities in Setagaya area of Tokyo, Japan. Of the 1775 women who participated, 1311 women met the inclusion criteria of this analysis. All data, including EPDS, were collected via self-administrated questionnaires at 20 weeks' gestation and at 5 time points postpartum, from the first few days to 3 months postpartum. We divided EPDS items into three factors: "anxiety," "anhedonia," and "depression," according to factor analysis. RESULTS: The prevalence of individuals exhibiting depressive symptoms, EPDS total score, and each factor score peaked at two weeks postpartum in primiparas (EPDS total = 5.58, anhedonia = 0.47, anxiety = 2.64, and depression = 1.23). In contrast, the EPDS total score and factor scores for "anxiety" and "depression" gradually decreased for multiparas, from the prenatal to postpartum period (EPDS total 3.33, 3.03, 3.03, 2.72, 2.76, and 2.37). LIMITATIONS: Each factor score was not weighted; instead, we simply added up the item scores ranging from 0 to 3 for each question. Additionally, the population representativeness of Japanese women was not high, although the sample was population-based and had a high follow-up rate. CONCLUSIONS: This study shows that the trends of EPDS total and factor scores differ by parity throughout the pre- and postnatal periods among a Japanese female population. PMID- 28846962 TI - Effects of polymer topology on biointeractions of polymer brushes: Comparison of cyclic and linear polymers. AB - Cyclic polymers, having no chain ends, are in contrast to their linear counterparts with respect to topology and related properties. While the behavior of cyclic polymers in solution is well investigated, there is little information on the effects of cyclic chain topology on surfaces grafted with these polymers. In particular, the effects of topology on the interactions of such surfaces with biological systems are unknown. In this work, we prepared gold surfaces modified with either cyclic or linear polystyrene (CPS, LPS) using a grafting-to strategy, and used these surfaces to investigate the effects of chain topology on their biointerfacial interactions. It was shown that compared to LPS with similar molecular weight, the smaller hydrodynamic radius of CPS leads to brushes of higher chain density, and that the higher chain density facilitates the adsorption of larger proteins but suppresses the adsorption of smaller ones. However, no significant differences in bacterial attachment or mammalian cell proliferation between CPS and LPS brushes were found, indicating that topological effects are absent for the larger entities. PMID- 28846963 TI - Catalase-modified gold nanoparticles: Determination of the degree of protein adsorption by gel electrophoresis. AB - In this study we present a method to determine the degree to which catalase (CAT) is adsorbed onto gold nanoparticles (AuNPs) using polyacrylamide gel electrophoresis (PAGE) with silver staining. AuNPs (13nm) were synthesized in water by the chemical reduction method and modified with CAT (AuNPs-CAT). The colloidal stability and NP size before and after the modification were investigated by dynamic light scattering and scanning transmission electron microscopy. Electrophoresis was performed under different conditions (native, with and without SDS, and with and without beta-mercaptoethanol) to find the optimal conditions for determining the surface coverage of AuNPs with CAT protein. The results clearly indicate that PAGE can be used to determine the amount of protein adsorbed on the NP surface and the use of native PAGE does not alter the colloidal stability of the NPs. These features allowed us to monitor the state of NPs and protein-NP interactions during the electrophoretic process. PMID- 28846964 TI - Graphene oxide-iron oxide nanocomposite as an inhibitor of Abeta 42 amyloid peptide aggregation. AB - Inhibiting amyloid beta (Abeta) aggregation has drawn much attention because it is one of the main reasons for the cause of Alzheimer's disease (AD). Here we have synthesized a nanocomposite of graphene oxide-iron oxide (GOIO) and demonstrated its ability of modulating Abeta aggregation. The inhibition effects of the GOIO nanocomposite on Abeta aggregates was studied by Thioflavin T fluorescence assay, circular dichroism and transmission electron microscopy, respectively. Furthermore, the cell viability study revealed that the GOIO nanocomposite can reduce the toxicity of Abeta fibrils to neuroblastoma cells. Our results demonstrated that the combination of GO and IO as a nanocomposite material has a potential use for the design new therapeutic agents for the treatment of Alzheimer's disease. PMID- 28846965 TI - Striving for balance - A qualitative study to explore the experiences of nurses new to the ambulance service in Sweden. AB - New nurses and nurses new to a professional practice go through a transition where they adopt a new professional identity. This has been described as a challenging time where peer support and limited responsibility are considered necessary. Little is known about the experience of nurses being new to the ambulance service where support is limited and the nurse holds full responsibility of patient care. The aim of this study has therefore been to explore nurses' experiences during their first year of employment in the Swedish ambulance service. Data was generated from semi-structured interviews with 13 nurses having less than 12 months of experience of work in the ambulance service. The nurses represented nine different districts in Sweden. Analysis was a latent inductive qualitative content analysis. The analysis resulted in the main category, "Striving for balance during the transition process in the ambulance context". Transition in the ambulance service was experienced as a balance act between emotions, expectations and a strive for professional development. The balance was negatively affected by harsh, condescending attitudes among colleagues and the lack of structured support and feedback. In striving for balance in their new professional practice, the nurses described personal, unsupervised strategies for professional development. PMID- 28846966 TI - Novel rhynchophylline analogues as microvascular relaxation agents for the treatment of microvascular dysfunction caused by diabetes. AB - Dysfunction in vascular reactivity in the micro- and macrocirculation is well established in cardiovascular disease. However, little is known about methods that may improve vascular reactivity in patients likely to develop microvascular dysfunction. One of the racemic analogues of rhynchophylline (G2) and its stereoisomers (G2-a and G2-b) were synthesized to address this knowledge gap. The preliminary pharmaceutical studies on the relaxation of the rat thoracic aorta showed that G2 and its stereoisomers are more potent (at least 30-fold) than the natural product rhynchophylline, which encouraged us to further investigate their functions and mechanisms as treatments for microvascular dysfunction caused by diabetes. G2-a displayed the best microvascular relaxation activity on rat mesenteric arteries among the three compounds, and G2 or G2-a caused relaxation in an endothelium-dependent manner. In ex vivo tests, G2 and G2-a exhibited a weaker potency in inducing microvascular relaxation in mesenteric arteries from diabetic rats than from normal rats, most likely, due to microvascular endothelium damage caused by diabetes. However, based on the animal studies, G2 ameliorated diabetes-induced endothelial dysfunction in rat mesenteric arteries in vivo. Further investigations of the mechanism showed that G2 mainly induced the recovery of endothelial function by upregulating endothelial nitric oxide synthase (eNOS) expression and further increasing the concentration of nitric oxide (NO), which is required for vascular relaxation. PMID- 28846968 TI - Phosphate enhanced abiotic and biotic arsenic mobilization in the wetland rhizosphere. AB - Although abiotic process of competitive sorption between phosphate (P) and arsenate (As(V)), especially onto iron oxides, are well understood, P-mediated biotic processes of Fe and As redox transformation contributing to As mobilization and speciation in wetlands remain poorly defined. To gain new insights into the effects of P on As mobility, speciation, and bioavailability in wetlands, well-controlled greenhouse experiments were conducted. As expected, increased P levels contributed to more As desorption, but more interestingly the interactions between P and wetland plants played a synergistic role in the microbially-mediated As mobilization and enhanced As uptake by plants. High levels of P promoted plant growth and the exudation of labile organic carbon from roots, enhancing the growth of heterotrophic bacteria, including As and Fe reducers. This in turn resulted in both, more As desorption into solution due to reductive iron dissolution, and a higher fraction of the dissolved As in the form of As(III) due to the higher number of As(V) reducers. Consistent with the dissolved As results, arsenic-XANES spectra from solid medium samples demonstrated that more As was sequestered in the rhizosphere as As(III) in the presence of high P levels than for low P levels. Hence, increased P loading to wetlands stimulates both abiotic and biotic processes in the wetland rhizosphere, resulting in more As mobilization, more As reduction, as well as more As uptake by plants. These interactions are important to be taken into account in As fate and transport models in wetlands and management of wetlands containing As. PMID- 28846967 TI - Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis. AB - The promising antibacterial potency of arylthiazole antibiotics is offset by their limited activity against intracellular bacteria (namely methicillin resistant Staphylococcus aureus (MRSA)), similar to many clinically-approved antibiotics. The failure to target these hidden pathogens is due to the compounds' lack of proper characteristics to accumulate intracellularly. Fine tuning of the size and polar-surface-area of the linking heteroaromatic ring provided a new series of 5-thiazolylarylthiazoles with balanced properties that allow them to sufficiently cross and accumulate inside macrophages infected with MRSA. The most promising compound 4i exhibited rapid bactericidal activity, good metabolic stability and produced over 80% reduction of intracellular MRSA in infected macrophages. PMID- 28846969 TI - Effects of maternal exposure to bisphenol AF on emotional behaviors in adolescent mice offspring. AB - Exposure to bisphenol A (BPA), one kind of environmental endocrine disruptors (EEDs), exerted significantly detrimental effects on neuro-endocrinological system and related disorders, such as memory dysfunction and depression. Bisphenol AF (BPAF),a newly introduced chemical structurally related to BPA, is used extensively. BPAF has stronger estrogenic activities than BPA. However, the potential neurotoxicological effects of BPAF are still elusive. The present study aimed to investigate the potential effects of maternal BPAF exposure during pregnancy on emotional behaviors of adolescent mice offspring. In male adolescent offspring, maternal exposure to BPAF (0.4, 4.0 mg kg-1, intragastrically administration) induced significant anxiety- and depressive-like behaviors, assessed by open field test (OFT), novelty-suppressed feeding test (NSF), sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST). In female adolescent offspring, BPAF exposure at 0.4 mg kg-1 dose reduced the latency to feeding in the NSF test, while increased the floating time in the FST. Maternal BPAF exposure decreased the recognition index in the long term memory (LTM) test in both sexes, while only decreased the freezing time of male offspring in the contextual fear conditioning (CFC) task. These results indicate that maternal exposure to BPAF significantly affect emotion-related behaviors in adolescent mice offspring, and the male offspring with a higher probability to develop symptoms of anxiety and depression and to suffer memory impairment after maternal exposure to BPAF. PMID- 28846970 TI - Entrapped cells-based-anaerobic membrane bioreactor treating domestic wastewater: Performances, fouling, and bacterial community structure. AB - A laboratory scale study on treatment performances and fouling of entrapped cells based-anaerobic membrane bioreactor (E-AnMBR) in comparison with suspended cells based-bioreactor (S-AnMBR) treating domestic wastewater was conducted. The difference between E-AnMBR and S-AnMBR was the uses of cells entrapped in phosphorylated polyvinyl alcohol versus planktonic cells. Bulk organic removal efficiencies by the two AnMBRs were comparable. Lower concentrations of suspended biomass, bound extracellular polymeric substances and soluble microbial products in E-AnMBR resulted in less fouling compared to S-AnMBR. S-AnMBR provided 7 days of operation time versus 11 days for E-AnMBR before chemical cleaning was required. The less frequent chemical cleaning potentially leads to a longer membrane life-span for E-AnMBR compared to S-AnMBR. Phyla Proteobacteria, Chloroflexi, Bacteroidetes and Acidobacteria were dominant in cake sludge from both AnMBRs but their abundances were different between the two AnMBRs, suggesting influence of cell entrapment on the bacteria community. PMID- 28846971 TI - UV characterization and photodegradation mechanism of the fungicide chlorothalonil in the presence and absence of oxygen. AB - An experimental and theoretical study of the UV spectrum of chlorothalonil (CT) was carried out and the vibrationally resolved HOMO->LUMO transition is presented for the first time. The fluorescence spectrum has also been recorded. Furthermore, preparative photolysis allowed a detailed study of the photoproducts formed with recognition of different isomers. In the presence of oxygen only the first reductive dechlorination-decyanation occurred, while in its absence a successive dechlorination-decyanation takes place. PMID- 28846972 TI - Mutagenic, recombinogenic and carcinogenic potential of thiamethoxam insecticide and formulated product in somatic cells of Drosophila melanogaster. AB - Thiamethoxam (TMX) belongs to a class of neuro-active insecticides referred as neonicotinoids, while actara(r) (AC) is one of the most popular TMX-based products in Brazil. The aim of this study was to evaluate the mutagenic, recombinogenic and carcinogenic potential of TMX and AC insecticides. The mutagenic and recombinogenic effect of TMX and AC were evaluated in vivo by the Somatic Mutation and Recombination Test (SMART) while carcinogenic effects were evaluated through the Test for Detection of Epithelial Tumor Clones (wts test), both in somatic cells of Drosophila melanogaster. In the SMART, third instar larvae from standard (ST) and high bioactivation (HB) crosses were treated with different concentrations of TMX and AC (2.4; 4.8; 9.7 * 10-4 mM and 1.9 * 10-3 mM). The results revealed mutagenic effects at the highest concentrations tested in the HB cross. In the test for the detection of epithelial tumor, third instar larvae resulting from the cross between wts/TM3, Sb1 virgin females and mwh/mwh males were treated with the same concentrations of TMX and AC used in the SMART. No carcinogenic effect was observed at any of the concentrations tested. In this work, the inhibition of the mechanism of repair by homologous recombination was observed in flies exposed to 9.7 * 10-4 and 1.9 * 10-3 mM of AC. In conclusion, TMX and AC demonstrated to be a promutagen in the highest concentrations tested. PMID- 28846973 TI - Developmental fluoride exposure influenced rat's splenic development and cell cycle via disruption of the ERK signal pathway. AB - Excessive fluoride exposure has been reported to cause damage to spleen. Neonatal period is characterized by rapid proliferation and differentiation of lymphocyte in the spleen. Children may be more sensitive to the toxicity of fluoride compared to the adults. The aim of this study was to investigate the effects of postnatal exposure (from neonatal period to early adulthood) to fluoride on the development of spleen on a regular basis and the underlying signal pathway. Results showed a marked decrease in spleen weight index and altered morphology in the spleen of fluoride-treated group on PND-84, which reflected fluoride inhibition of the development of spleen. Fluoride exposure induced cell cycle arrest of splenocytes and decreased the mRNA expression of IL-2, which indicated compromised baseline lymphocyte proliferation in the spleen. Time course research from 3-wk-of-age until 12-wk-of-age showed an adverse and cumulative impact of fluoride on the development of spleen. In view of the key role of MAPK/ERK pathway in lymphocyte development, Raf-1/MEK-1/ERK-2/c-fos mRNA expression and ERK/p-ERK protein expression were detected. Results showed despite a transitory increase in mRNA expression from PND-42 to PND-63 in fluoride-treated group, the expression of these genes on PND-84 decreased significantly compared with PND-42 or PND-63. NaF significantly inhibited the phosphorylation of ERK protein on PND 84. Taken together, these results emphasized the vital role of ERK pathway in the interfered development of spleen induced by a high dose of fluoride exposure in rats. PMID- 28846974 TI - Prediction of mercury bioavailability to common carp (Cyprinus carpio L.) using the diffusive gradient in thin film technique. AB - The mercury bioaccumulation by common carp (Cyprinus carpio L.) tissues (gills, skin, eyes, scales, muscle, brain, kidneys, liver, and spleen) and the capability of the diffusive gradient in thin film (DGT) technique to predict bioavailability of mercury for individual carp's tissues were evaluated. Carp and DGT units were exposed to increasing concentrations of mercury (Hg2+: 0 MUg L-1, 0.5 MUg L-1, 1.5 MUg L-1 and 3.0 MUg L-1) in fish tanks for 14 days. In the uncontaminated fish group, the highest mercury concentration was determined in the muscle tissues and, in fish groups exposed to mercury, the highest mercury concentration was determined in the detoxification (kidneys) and input (gills) organs. A strong and positive correlation between the rate of mercury uptake by the DGT technique and the rate of mercury accumulation by fish tissues (gills, skin, scales, and eyes) was observed. PMID- 28846975 TI - Stabilization of cesium in alkali-activated municipal solid waste incineration fly ash and a pyrophyllite-based system. AB - Environmentally sound treatments are required to dispose of municipal solid waste incineration fly ash (MSWIFA) contaminated with radioactive cesium (Cs) from the Fukushima Daiichi nuclear power plant accident in Japan. This study focuses on the stabilization of Cs using an alkali-activated MSWIFA and pyophyllite-based system. Three composite solid products were synthesized after mixtures of raw materials (dehydrated pyrophyllite, MSWIFA, 14 mol/L aqueous sodium hydroxide, and sodium silicate solution) were cured at 105 degrees C for 24 h. Three types of MSWIFAs were prepared as raw fly ash, raw fly ash with 0.1% CsCl, and raw fly ash with 40% CsCl to understand the stabilization mechanism of Cs. Cs stabilization in two solid products was successful, with less than 6.9% leaching observed from two types tests, and was partly successful for the solid product with the highest concentration of Cs. X-ray diffraction showed that all of the solid products produced several crystalline phases, and that pollucite was formed in the highest Cs concentration product. The X-ray absorption fine structure and scanning electron microscopy with X-ray analysis suggested that most Cs species formed pollucite in the two solid products from MSWIFA with added CsCl. This system provides a technique for the direct stabilization of Cs in MSWIFA. PMID- 28846976 TI - Behavior and mechanisms for sorptive removal of perfluorooctane sulfonate by layered double hydroxides. AB - Perfluorooctane sulfonate (PFOS) is known to be extremely persistent and is toxic to wildlife and humans. In this study, we evaluated the sorptive removal behavior of PFOS from aqueous solution using three forms of layered double hydroxides (LDHs), namely, nitrate-, carbonate- and chloride-intercalated LDHs. Batch experiments showed that the sorption process was very fast with an equilibrium time of 10-60 min. The nitrate-LDH had the greatest ability to remove PFOS with a removal rate of 99.7% at an initial concentration of 100 mg/L and the maximum uptake capacity reached 865 mg/g. The sorption kinetic and equilibrium data could be fitted well with the pseudo-second-order model and Langmuir model, respectively. The intraparticle diffusion model suggests that both external diffusion and intraparticle diffusion are the rate-limiting processes for PFOS sorption onto the LDHs. The initial pH, background electrolyte concentration and coexisting ions influenced the sorption of PFOS by the LDHs. It was concluded that both surface adsorption and anion exchange were involved in the PFOS sorption onto the LDHs. PMID- 28846977 TI - Structural and vibrational study of a neurotransmitter molecule: Dopamine [4-(2 aminoethyl) benzene-1,2-diol]. AB - Structural and vibrational studies for the most stable conformer of dopamine {4 (2-Aminoethyl) benzene-1, 2-diol} have been carried out at the DFT/B3LYP/6 311++G** level using the Gaussian 09 software. The IR and Raman spectra have been recorded and analyzed in light of the computed vibrational parameters using the DFT and the PEDs computed with the help of the GAR2PED software. Some of the fundamentals have considerably changed frequencies in going from benzene to dopamine. Except the rocking and wagging modes of the NH2 group the other four modes are pure group modes. The rocking and wagging modes of the NH2 group show mixing with the other modes. The two OH stretching vibrations are highly localized modes. The Kekule phenyl ring stretching mode is found to remain almost unchanged. The HOMO-LUMO study suggests the existence of charge transfer within the molecule and the energy gap supports the pharmacological active property of the dopamine molecule. The NBO analysis has been carried out to understand the proper and improper hydrogen bonding. PMID- 28846978 TI - Ultrasensitive and highly selective detection of Cu2+ ions based on a new carbazole-Schiff. AB - A new chemosensor for Cu2+ based on Schiff base with high sensitivity and selectivity was designed and synthesized. The fluorescence intensity of the chemosensor in CH3CN solution was enhanced 160-fold after the addition of 10 equiv. Cu2+ over other metal ions. In addition, it also facilitates colorimetric detection for Cu2+ in CH3CN solution. The chemosensor displayed low detection limit and fast response time to Cu2+. PMID- 28846979 TI - Neural networks and determination of diatomic molecule interatomic potential of cadmium dimer. AB - A new method for obtaining a pointwise potential energy curve of diatomic molecule using Neural Network is reported. The method is employed to generate new characteristics of the B11u(51P1) electronic state of Cd2 based on LIF excitation spectrum previously recorded using the B11u<-X10g+ (51S0) transition. The obtained potential provides better simulation-to-experiment agreement than those obtained using other methods. Correctness of the method is additionally tested on artificially generated LIF excitation spectra based on well characterized b30u+(53P1)<-X10g+ transition in Cd2. A method for obtaining parameters of an analytical form of the potential using Neural Network applied on artificially generated Cd2 spectra is also presented. PMID- 28846980 TI - Colorimetric detection of glucose based on ficin with peroxidase-like activity. AB - In this work, we developed a colorimetric biosensing system for glucose detection by coupling the peroxidase-like of ficin and the glucose oxidase (GOx). GOx can catalyze the oxidation of glucose to produce H2O2, then, ficin catalyzes the oxidation of peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 to produce a blue color reaction. The present sensing system showed a linear response toward glucose detection over range of 2.0-100MUM with a detection limit of 0.5MUM. This system is simple, low cost, highly sensitive and selective for glucose detection, and was also applied to measuring glucose in human serum. Furthermore, in order to expand the application of ficin in biological sensing, we immobilized ficin onto the SiO2@Fe3O4 NPs, which exhibited the merits of recycling as well as allowing the repeated detection of glucose. Thus it may provide great potential applications in biomedicine, biotechnology and environmental chemistry. PMID- 28846981 TI - 3D-printing zirconia implants; a dream or a reality? An in-vitro study evaluating the dimensional accuracy, surface topography and mechanical properties of printed zirconia implant and discs. AB - PURPOSE: The aim of this study was to evaluate the dimensional accuracy, surface topography of a custom designed, 3D-printed zirconia dental implant and the mechanical properties of printed zirconia discs. MATERIALS AND METHODS: A custom designed implant was 3D-printed in zirconia using digital light processing technique (DLP). The dimensional accuracy was assessed using the digital subtraction technique. The mechanical properties were evaluated using biaxial flexure strength test. Three different build angles were adopted to print the specimens for the mechanical test; 0 degrees (Vertical), 45 degrees (Oblique) and 90 degrees (Horizontal) angles. The surface topography, crystallographic phase structure and surface roughness were evaluated using scanning electron microscopy analysis (SEM), X-ray diffractometer and confocal microscopy respectively. RESULTS: The printed implant was dimensionally accurate with a root mean square (RMSE) value of 0.1mm. The Weibull analysis revealed a statistically significant higher characteristic strength (1006.6MPa) of 0 degrees printed specimens compared to the other two groups and no significant difference between 45 degrees (892.2MPa) and 90 degrees (866.7MPa) build angles. SEM analysis revealed cracks, micro-porosities and interconnected pores ranging in size from 196nm to 3.3um. The mean Ra (arithmetic mean roughness) value of 1.59um (+/-0.41) and Rq (root mean squared roughness) value of 1.94um (+/-0.47) was found. A crystallographic phase of primarily tetragonal zirconia typical of sintered Yttria tetragonal stabilized zirconia (Y-TZP) was detected. CONCLUSIONS: DLP prove to be efficient for printing customized zirconia dental implants with sufficient dimensional accuracy. The mechanical properties showed flexure strength close to those of conventionally produced ceramics. Optimization of the 3D-printing process parameters is still needed to improve the microstructure of the printed objects. PMID- 28846982 TI - MiR-200a modulates TGF-beta1-induced endothelial-to-mesenchymal shift via suppression of GRB2 in HAECs. AB - Endothelial-mesenchymal transition (EndMT) is closely associated with embryogenesis, injury restitution, tissue neogenesis, tumor progressions and viscera fibrosis. EndMT may occur in the proximal tubular endothelial cells, inducing fibroblasts to produce matrix and then accelerating the process of cardiac fibrosis. Transforming growth factor-beta1 (TGF-beta1), a profibrotic cytokine, was recently shown to be a crucial trigger of EndMT in tubular endothelial cells. Increasing evidence suggests that growth factor receptor-bound 2 (GRB2) dysfunction affects fibrocytes; thus, GRB2 may be a novel target for treating fibrosis. The miR-200 miRNA cluster (miR-429, miR-141, miR-200c, miR 200b and miR-200a) was reported to inhibit EndMT. However, the underlying mechanisms, specifically that of miR-200a, are unclear. To elucidate the vital role of miR-200a in EndMT, we established a cardiac interstitial fibrosis model with a widely used EndMT assay, TGF-beta1-induced EndMT in human aortic endothelial cells (HAECs). We found that overexpression of miR-200a blocked EndMT in HAECs by inhibiting fibroblast-specific protein-1 (FSP-1) and alpha-smooth muscle actin (alpha-SMA) expression and increasing platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial cadherin (VE-cadherin) expression, regardless of the presence of TGF-beta1. MiR-200a expression was suppressed during the EndMT process, in both time- and dose-dependent manners, following GRB2 upregulation. EndMT was promoted by ectopic expression of GRB2 via decreased CD31 and VE-cadherin. Furthermore, EndMT was partially inhibited by co transfection of miR-200a with GRB2 ORF, likely by restoring CD31 and VE-cadherin expression. MiR-200a negatively regulated GRB2 protein levels via direct binding to the GRB2 3'UTR. Finally, these discoveries may provide novel insights into the functional mechanism of miR-200a in regulating fibrosis via the TGFbeta1/miR 200a/GRB2/EndMT pathway, and miR-200a may serve as a new target for treating fibrosis in the future. PMID- 28846983 TI - Indian propolis ameliorates the mitomycin C-induced testicular toxicity by reducing DNA damage and elevating the antioxidant activity. AB - Development of excellent curative therapy for most of the malignancies has resulted in a growing population of cancer survivors who are at increased risk for a variety of health problems including infertility. Therefore, fertility preservation has become an important issue during cancer treatment in recent years. Combination therapy with natural agents such as vitamins, antioxidants, dietary supplements, and plant products are considered as an attractive option to mitigate normal tissue toxicity imparted by chemotherapy. The aim of the present study was to explore the beneficial effect of hydroethanolic extract of Indian propolis (HEIP) on mitigating mitomycin C (MMC)-induced testicular damage and its mechanism of action. Healthy adult male mice were injected intraperitoneally with saline, MMC, HEIP and HEIP followed by MMC after 1h. The animals were dissected at 35days after various treatments to analyze testicular function. MMC administration resulted in significant reduction in testicular function in a dose dependent manner at 35days after treatment which significantly improved by HEIP pre-treatment. At 24h after treatment, MMC induced significant increase in oxidative stress, gamma-H2AX foci and expression of RAD51 and KU80 in testicular cells. Prior treatment with HEIP decreased the oxidative stress, reduced DNA damage and restored the testicular testosterone and inhibin B level. In conclusion, co-administration of Indian propolis extract may play a promising beneficial role in fertility preservation of males undergoing chemotherapy. PMID- 28846984 TI - Household air pollution and personal inhalation exposure to particles (TSP/PM2.5/PM1.0/PM0.25) in rural Shanxi, North China. AB - Personal exposure to size-segregated particles among rural residents in Shanxi, China in summer, 2011 were investigated using portable carried samplers (N = 84). Household air pollution was simultaneously studied using stationary samplers in nine homes. Information on household fuel types, cooking activity, smoking behavior, kitchen ventilation conditions etc., were also collected and discussed. The study found that even in the summer period, the daily average concentrations of PM2.5 and PM1.0 in the kitchen were as high as 376 +/- 573 and 288 +/- 397 MUg/m3 (N = 6), that were nearly 3 times of 114 +/- 81 and 97 +/- 77 MUg/m3 in the bedroom (N = 8), and significantly higher than those of 64 +/- 28 and 47 +/- 21 MUg/m3 in the outdoor air (N = 6). The personal daily exposure to PM2.5 and PM1.0 were 98 +/- 52 and 77 +/- 47 MUg/m3, respectively, that were lower than the concentrations in the kitchen but higher than the outdoor levels. The mass fractions of PM2.5 in TSP were 90%, 72%, 65% and 68% on average in the kitchen, bedroom, outdoor air and personal inhalation exposure, respectively, and moreover, a majority of particles in PM2.5 had diameters less than 1.0 MUm. Calculated time-weighted average exposure based on indoor and outdoor air concentrations and time spent indoor and outdoor were positively correlated but, was ~33% lower than the directly measured exposure. The daily exposure among those burning traditional solid fuels could be lower by ~41% if the kitchen was equipped with an outdoor chimney, but was still 8-14% higher than those household using cleaning energies, like electricity and gas. With a ventilator in the kitchen, the exposure among the population using clean energies could be further reduced by 10-24%. PMID- 28846985 TI - Lake-sediment record of PAH, mercury, and fly-ash particle deposition near coal fired power plants in Central Alberta, Canada. AB - We report a historical record of atmospheric deposition in dated sediment cores from Hasse Lake, ideally located near both currently and previously operational coal-fired power plants in Central Alberta, Canada. Accumulation rates of spheroidal carbonaceous particles (SCPs), an unambiguous marker of high temperature fossil-fuel combustion, in the early part of the sediment record (pre 1955) compared well with historical emissions from one of North America's earliest coal-fired power plants (Rossdale) located ~43 km to the east in the city of Edmonton. Accumulation rates in the latter part of the record (post-1955) suggested inputs from the Wabamun region's plants situated ~17-25 km to the west. Increasing accumulation rates of SCPs, polycyclic aromatic hydrocarbons (PAHs) and Hg coincided with the previously documented period of peak pollution in the Wabamun region during the late 1960s to early 1970s, although Hg deposition trends were also similar to those found in western North American lakes not directly affected by point sources. A noticeable reduction in contaminant inputs during the 1970s is attributed in part to technological improvements and stricter emission controls. The over one hundred-year historical record of coal-fired power plant emissions documented in Hasse Lake sediments has provided insight into the impact that both environmental regulations and changes in electricity output have had over time. This information is crucial to assessing the current and future role of coal in the world's energy supply. PMID- 28846986 TI - Chemical characteristics of dicarboxylic acids and related organic compounds in PM2.5 during biomass-burning and non-biomass-burning seasons at a rural site of Northeast China. AB - Fine particulate matter (PM2.5) samples were collected using a high-volume air sampler and pre-combusted quartz filters during May 2013 to January 2014 at a background rural site (47?35 N, 133?31 E) in Sanjiang Plain, Northeast China. A homologous series of dicarboxylic acids (C2-C11) and related compounds (oxoacids, alpha-dicarbonyls and fatty acids) were analyzed by using a gas chromatography (GC) and GC-MS method employing a dibutyl ester derivatization technique. Intensively open biomass-burning (BB) episodes during the harvest season in fall were characterized by high mass concentrations of PM2.5, dicarboxylic acids and levoglucosan. During the BB period, mass concentrations of dicarboxylic acids and related compounds were increased by up to >20 times with different factors for different organic compounds (i.e., succinic (C4) acid > oxalic (C2) acid > malonic (C3) acid). High concentrations were also found for their possible precursors such as glyoxylic acid (omegaC2), 4-oxobutanoic acid, pyruvic acid, glyoxal, and methylglyoxal as well as fatty acids. Levoglucosan showed strong correlations with carbonaceous aerosols (OC, EC, WSOC) and dicarboxylic acids although such good correlations were not observed during non-biomass-burning seasons. Our results clearly demonstrate biomass burning emissions are very important contributors to dicarboxylic acids and related compounds. The selected ratios (e.g., C3/C4, maleic acid/fumaric acid, C2/omegaC2, and C2/levoglucosan) were used as tracers for secondary formation of organic aerosols and their aging process. Our results indicate that organic aerosols from biomass burning in this study are fresh without substantial aging or secondary production. The present chemical characteristics of organic compounds in biomass-burning emissions are very important for better understanding the impacts of biomass burning on the atmosphere aerosols. PMID- 28846987 TI - Estimation of inhaled airborne particle number concentration by subway users in Seoul, Korea. AB - Exposure to airborne particulate matter (PM) causes several diseases in the human body. The smaller particles, which have relatively large surface areas, are actually more harmful to the human body since they can penetrate deeper parts of the lungs or become secondary pollutants by bonding with other atmospheric pollutants, such as nitrogen oxides. The purpose of this study is to present the number of PM inhaled by subway users as a possible reference material for any analysis of the hazards to the human body arising from the inhalation of such PM. Two transfer stations in Seoul, Korea, which have the greatest number of users, were selected for this study. For 0.3-0.422 MUm PM, particle number concentration (PNC) was highest outdoors but decreased as the tester moved deeper underground. On the other hand, the PNC between 1 and 10 MUm increased as the tester moved deeper underground and showed a high number concentration inside the subway train as well. An analysis of the particles to which subway users are actually exposed to (inhaled particle number), using particle concentration at each measurement location, the average inhalation rate of an adult, and the average stay time at each location, all showed that particles sized 0.01-0.422 MUm are mostly inhaled from the outdoor air whereas particles sized 1-10 MUm are inhaled as the passengers move deeper underground. Based on these findings, we expect that the inhaled particle number of subway users can be used as reference data for an evaluation of the hazards to health caused by PM inhalation. PMID- 28846988 TI - Emotional reactivity in a clinical sample of patients with eating disorders and nonsuicidal self-injury. AB - Emotional reactivity is theorized to contribute to both eating disorders (ED) and nonsuicidal self-injury (NSSI). Although EDs and NSSI frequently co-occur, no study has examined emotional reactivity in individuals with both conditions. This study examined the following hypotheses in a large clinical sample (N = 648): (1) patients with co-occurring ED and NSSI would report higher emotional reactivity and more severe clinical characteristics; (2) among those with EDs, patients with bulimia nervosa (BN) would be more likely to report NSSI and evidence higher emotional reactivity compared to those with anorexia nervosa (AN); and (3) higher emotional reactivity would be associated with worse treatment outcomes. Data were collected at admission and discharge from inpatient, partial hospitalization, and intensive outpatient treatment programs for EDs or NSSI. The NSSI-only and co occurring groups reported significantly higher emotional reactivity than the ED only group. Among those with EDs, individuals with BN reported higher emotional reactivity and were more likely to engage in NSSI compared to those with AN. Emotional reactivity was inconsistently related to treatment outcomes among the co-occurring and ED-only groups. In sum, results highlight the importance of emotional reactivity in clinical presentations, particularly when NSSI is present. PMID- 28846989 TI - Social disorganization and homicide mortality rate trajectories in Brazil between 1991 and 2010. AB - Since the 1990s, researchers have noted declining trends in crime and violence, particularly homicide, in Western countries. Studies have explored national and sub-national trends using latent trajectory analysis techniques and identified several factors associated with declining and/or increasing trajectories. Social disorganization (SD) has been consistently linked to increases in homicide rates over time, explaining at least some of the spatial and temporal heterogeneity of homicide. Similar studies have not yet been carried out in Latin America's cities. In this paper we use Group Based Trajectory models to study homicide mortality rate [HMR] trajectories in Brazilian municipalities between 1991 and 2010. Then, through binary and multinomial logistic regression we investigated the association between SD in 1991, and the likelihood of an increasing HMR trajectory. We carried out an ecological time series study using all Brazilian municipalities in the period between 1991 and 2010 (n = 4491). Data on homicide deaths were collected from the Mortality Information System of the Ministry of Health and standardized by age to calculate HMR per 100,000 population. Socioeconomic and demographic data for 1991 were used to compose the composite measure of SD. Our results highlight the spatial and temporal heterogeneity of homicide mortality in Brazilian municipalities. While national trends are steadily increasing, disaggregating municipal trajectories shows that this is driven by a small proportion of municipalities in the country. We found that SD is associated with an ascending homicide trajectory. This result generally supports the notion that poor social structural conditions can create 'space' for criminal behavior and groups and, consequently, violent death. PMID- 28846990 TI - Bisphenol A affects cell viability involved in autophagy and apoptosis in goat testis sertoli cell. AB - Bisphenol A (BPA) is shown to be the endocrine disruptor that induces reproductive dysfunction in male animals. In this study, we aim to probe the effects of BPA exposure on induction of autophagy in goat Sertoli Cells (gSCs), as well as the relationship between autophagy and apoptosis. Results indicated that exposure to BPA (100, 200, 300, 400, 500 and 600MUM) decreased the cell viability in a concentration-dependent manner. Exposure of gSCs to 500MUM BPA for 12h resulted in in vitro triggered loss of mitochondrial membrane potential (DeltaPsim) and increased reactive oxygen species (ROS) production. Apoptosis with an increase in Bax:Bcl-2 ratio and higher rates of autophagy, such as autophagosome formation and increased expression of autophagy-related markers were also induced in gSCs exposed to 500MUM BPA. Furthermore, treatment with 350nM Rapamycin (Rap, autophagy activator) alleviated a decrease in cell viability, intracellular ROS production, and reduction of DeltaPsim, as well as decreasing apoptosis. Collectively, our results indicated that gSCs viability was disrupted after BPA treatment through affecting ROS production, mitochondrial membrane potential and inducing autophagy/apoptosis. PMID- 28846991 TI - Effects of glyphosate exposure on sperm concentration in rodents: A systematic review and meta-analysis. AB - BACKGROUND: Correlation between exposure to glyphosate and sperm concentrations is important in reproductive toxicity risk assessment for male reproductive functions. Many studies have focused on reproductive toxicity on glyphosate, however, results are still controversial. We conducted a systematic review of epidemiological studies on the association between glyphosate exposure and sperm concentrations of rodents. The aim of this study is to explore the potential adverse effects of glyphosate on reproductive function of male rodents. METHODS: Systematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Embase, WANFANG and CNKI databases with different combinations of glyphosate exposure and sperm concentration. 8 studies were eventually identified and random effect model was conducted. Heterogeneity among study results was calculated via chi-square tests. Ten independent experimental datasets from these eight studies were acquired to synthesize the random-effect model. RESULTS: A decrease in sperm concentrations was found with mean difference of sperm concentrations(MDsperm)= 2.774*106/sperm/g/testis(95%CI=-0.969 to -4.579) in random-effect model after glyphosate exposure. There was also a significant decrease after fitting the random-effect model: MDsperm=-1.632*106/sperm/g/testis (95%CI=-0.662 to -2.601). CONCLUSIONS: The results of meta-analysis support the hypothesis that glyphosate exposure decreased sperm concentration in rodents. Therefore, we conclude that glyphosate is toxic to male rodent's reproductive system. PMID- 28846992 TI - Improving Research Enrollment of Severe Burn Patients. AB - Enrolling severely burn injured patients into prospective research studies poses specific challenges to investigators. The authors describe their experience of recruiting adults with >=20% TBSA burns or inhalation injury admitted to a single academic burn unit into observational research with minimally invasive specimen collection. The authors outline iterative changes that they made to their recruitment processes in response to perceived weaknesses leading to delays in enrollment. The primary outcome was the change in days to consent for enrolled patients or cessation of recruitment for nonenrolled patients before and after the interventional modifications. The authors assessed change in overall enrollment as a secondary outcome. Study enrollment was approximately 70% in both 4-month study periods before and after the intervention. Following the intervention, time to consent by surrogate decision maker decreased from a median of 26.5 days (interquartile range [IQR] 14-41) to 3 days (IQR 3-6) (P = .004). Time to initial consent by patient changed from a median of 15 days (IQR 2-30) to 3 days (IQR 2-6) (P = .27). Time to decline for nonenrolled patients decreased from a median of 12 days (IQR 6.5-27) to 1.5 days (IQR 1-3.5) (P = .026). Both the findings of the study and a brief literature review suggest that careful design of the recruitment protocol, increased experience of the study team, and broad time windows for both approach and enrollment improve the efficiency of recruiting critically injured burn patients into research. PMID- 28846994 TI - Vital Exhaustion, Burnout, and Other Avatars of Depression. PMID- 28846993 TI - Objectively Measured Daily Physical Activity and Postural Changes as Related to Positive and Negative Affect Using Ambulatory Monitoring Assessments. AB - OBJECTIVE: The aim of the study was to determine whether objectively measured daily physical activity and posture of sitting, standing, and sit-to-stand transitions are associated with daily assessments of affect. METHODS: Participants (N = 51, 49% female) wore ActivPal accelerometers for 24 h/d for seven consecutive days. Time spent sitting, standing, and being physically active and sit-to-stand transitions were derived for each day. Participants also completed a mood inventory each evening. Multilevel models examined within- and between-person associations of daily physical activity with positive and negative affect, adjusting for age, sex, body mass index, education, and sleep duration. RESULTS: Within-person associations showed that a 1-hour increase in daily physical activity was associated with a decrease in negative affect over the same day (B = -0.11, 95% confidence interval [CI], -0.21 to -0.01). Between-person associations indicated a borderline significant association between higher average daily physical activity levels and higher positive affect (B = 1.85, 95% CI = -0.25 to 3.94). There were no between- or within-person associations between sitting, standing, and sit-to-stand transitions with affect. CONCLUSIONS: Promoting physical activity may be a potential intervention strategy to acutely suppress negative affective states. PMID- 28846995 TI - Vital Exhaustion and Depression: A Reply to Bianchi and Colleagues. PMID- 28846996 TI - Transcranial Magnetic Stimulation and the Urge to Eat: A Comment on Lowe, Vincent, and Hall (2017). PMID- 28846997 TI - Brain Stimulation Effects on Food Cravings and Consumption: An Update on Lowe et al. (2017) and a Response to Generoso et al. (2017). PMID- 28846998 TI - Plant science: Sexual attraction channelled in moss. PMID- 28846999 TI - Magnetic antiskyrmions above room temperature in tetragonal Heusler materials. AB - Magnetic skyrmions are topologically stable, vortex-like objects surrounded by chiral boundaries that separate a region of reversed magnetization from the surrounding magnetized material. They are closely related to nanoscopic chiral magnetic domain walls, which could be used as memory and logic elements for conventional and neuromorphic computing applications that go beyond Moore's law. Of particular interest is 'racetrack memory', which is composed of vertical magnetic nanowires, each accommodating of the order of 100 domain walls, and that shows promise as a solid state, non-volatile memory with exceptional capacity and performance. Its performance is derived from the very high speeds (up to one kilometre per second) at which chiral domain walls can be moved with nanosecond current pulses in synthetic antiferromagnet racetracks. Because skyrmions are essentially composed of a pair of chiral domain walls closed in on themselves, but are, in principle, more stable to perturbations than the component domain walls themselves, they are attractive for use in spintronic applications, notably racetrack memory. Stabilization of skyrmions has generally been achieved in systems with broken inversion symmetry, in which the asymmetric Dzyaloshinskii Moriya interaction modifies the uniform magnetic state to a swirling state. Depending on the crystal symmetry, two distinct types of skyrmions have been observed experimentally, namely, Bloch and Neel skyrmions. Here we present the experimental manifestation of another type of skyrmion-the magnetic antiskyrmion in acentric tetragonal Heusler compounds with D2d crystal symmetry. Antiskyrmions are characterized by boundary walls that have alternating Bloch and Neel type as one traces around the boundary. A spiral magnetic ground-state, which propagates in the tetragonal basal plane, is transformed into an antiskyrmion lattice state under magnetic fields applied along the tetragonal axis over a wide range of temperatures. Direct imaging by Lorentz transmission electron microscopy shows field-stabilized antiskyrmion lattices and isolated antiskyrmions from 100 kelvin to well beyond room temperature, and zero-field metastable antiskyrmions at low temperatures. These results enlarge the family of magnetic skyrmions and pave the way to the engineering of complex bespoke designed skyrmionic structures. PMID- 28847000 TI - Feedback regulation of steady-state epithelial turnover and organ size. AB - Epithelial organs undergo steady-state turnover throughout adult life, with old cells being continually replaced by the progeny of stem cell divisions. To avoid hyperplasia or atrophy, organ turnover demands strict equilibration of cell production and loss. However, the mechanistic basis of this equilibrium is unknown. Here we show that robustly precise turnover of the adult Drosophila intestine arises through a coupling mechanism in which enterocyte apoptosis breaks feedback inhibition of stem cell division. Healthy enterocytes inhibit stem cell division through E-cadherin, which prevents secretion of mitogenic epidermal growth factors (EGFs) by repressing transcription of the EGF maturation factor rhomboid. Individual apoptotic enterocytes promote divisions by loss of E cadherin, which releases cadherin-associated beta-catenin (Armadillo in Drosophila) and p120-catenin to induce rhomboid. Induction of rhomboid in the dying enterocyte triggers activation of the EGF receptor (Egfr) in stem cells within a discrete radius. When we blocked apoptosis, E-cadherin-controlled feedback suppressed divisions, and the organ retained the same number of cells. When we disrupted feedback, apoptosis and divisions were uncoupled, and the organ developed either hyperplasia or atrophy. Together, our results show that robust cellular balance hinges on the obligate coupling of divisions to apoptosis, which limits the proliferative potential of a stem cell to the precise time and place at which a replacement cell is needed. In this way, localized cell-cell communication gives rise to tissue-level homeostatic equilibrium and constant organ size. PMID- 28847001 TI - Kinetic analysis of a complete nitrifier reveals an oligotrophic lifestyle. AB - Nitrification, the oxidation of ammonia (NH3) via nitrite (NO2-) to nitrate (NO3 ), is a key process of the biogeochemical nitrogen cycle. For decades, ammonia and nitrite oxidation were thought to be separately catalysed by ammonia oxidizing bacteria (AOB) and archaea (AOA), and by nitrite-oxidizing bacteria (NOB). The recent discovery of complete ammonia oxidizers (comammox) in the NOB genus Nitrospira, which alone convert ammonia to nitrate, raised questions about the ecological niches in which comammox Nitrospira successfully compete with canonical nitrifiers. Here we isolate a pure culture of a comammox bacterium, Nitrospira inopinata, and show that it is adapted to slow growth in oligotrophic and dynamic habitats on the basis of a high affinity for ammonia, low maximum rate of ammonia oxidation, high growth yield compared to canonical nitrifiers, and genomic potential for alternative metabolisms. The nitrification kinetics of four AOA from soil and hot springs were determined for comparison. Their surprisingly poor substrate affinities and lower growth yields reveal that, in contrast to earlier assumptions, AOA are not necessarily the most competitive ammonia oxidizers present in strongly oligotrophic environments and that N. inopinata has the highest substrate affinity of all analysed ammonia oxidizer isolates except the marine AOA Nitrosopumilus maritimus SCM1 (ref. 3). These results suggest a role for comammox organisms in nitrification under oligotrophic and dynamic conditions. PMID- 28847003 TI - Heart disease: Putative medicines that mimic mutations. PMID- 28847002 TI - Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep. AB - Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified. Wake-promoting cell types include hypocretin and GABA (gamma-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep-wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep. PMID- 28847004 TI - A heterochromatin-dependent transcription machinery drives piRNA expression. AB - Nuclear small RNA pathways safeguard genome integrity by establishing transcription-repressing heterochromatin at transposable elements. This inevitably also targets the transposon-rich source loci of the small RNAs themselves. How small RNA source loci are efficiently transcribed while transposon promoters are potently silenced is not understood. Here we show that, in Drosophila, transcription of PIWI-interacting RNA (piRNA) clusters-small RNA source loci in animal gonads-is enforced through RNA polymerase II pre-initiation complex formation within repressive heterochromatin. This is accomplished through Moonshiner, a paralogue of a basal transcription factor IIA (TFIIA) subunit, which is recruited to piRNA clusters via the heterochromatin protein-1 variant Rhino. Moonshiner triggers transcription initiation within piRNA clusters by recruiting the TATA-box binding protein (TBP)-related factor TRF2, an animal TFIID core variant. Thus, transcription of heterochromatic small RNA source loci relies on direct recruitment of the core transcriptional machinery to DNA via histone marks rather than sequence motifs, a concept that we argue is a recurring theme in evolution. PMID- 28847005 TI - Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. AB - In two previously described donors, the extracellular domain of LAIR1, a collagen binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5-10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1 containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering. PMID- 28847006 TI - A series of energetic metal pentazolate hydrates. AB - Singly or doubly bonded polynitrogen compounds can decompose to dinitrogen (N2) with an extremely large energy release. This makes them attractive as potential explosives or propellants, but also challenging to produce in a stable form. Polynitrogen materials containing nitrogen as the only element exist in the form of high-pressure polymeric phases, but under ambient conditions even metastability is realized only in the presence of other elements that provide stabilization. An early example is the molecule phenylpentazole, with a five membered all-nitrogen ring, which was first reported in the 1900s and characterized in the 1950s. Salts containing the azide anion (N3-) or pentazenium cation (N5+) are also known, with compounds containing the pentazole anion, cyclo N5-, a more recent addition. Very recently, a bulk material containing this species was reported and then used to prepare the first example of a solid-state metal-N5 complex. Here we report the synthesis and characterization of five metal pentazolate hydrate complexes [Na(H2O)(N5)].2H2O, [M(H2O)4(N5)2].4H2O (M = Mn, Fe and Co) and [Mg(H2O)6(N5)2].4H2O that, with the exception of the Co complex, exhibit good thermal stability with onset decomposition temperatures greater than 100 degrees C. For this series we find that the N5- ion can coordinate to the metal cation through either ionic or covalent interactions, and is stabilized through hydrogen-bonding interactions with water. Given their energetic properties and stability, pentazole-metal complexes might potentially serve as a new class of high-energy density materials or enable the development of such materials containing only nitrogen. We also anticipate that the adaptability of the N5- ion in terms of its bonding interactions will enable the exploration of inorganic nitrogen analogues of metallocenes and other unusual polynitrogen complexes. PMID- 28847007 TI - Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. AB - Regulatory T cells (Treg cells) have a pivotal role in the establishment and maintenance of immunological self-tolerance and homeostasis. Transcriptional programming of regulatory mechanisms facilitates the functional activation of Treg cells in the prevention of diverse types of inflammatory responses. It remains unclear how Treg cells orchestrate their homeostasis and interplay with environmental signals. Here we show that liver kinase B1 (LKB1) programs the metabolic and functional fitness of Treg cells in the control of immune tolerance and homeostasis. Mice with a Treg-specific deletion of LKB1 developed a fatal inflammatory disease characterized by excessive TH2-type-dominant responses. LKB1 deficiency disrupted Treg cell survival and mitochondrial fitness and metabolism, but also induced aberrant expression of immune regulatory molecules including the negative co-receptor PD-1 and the TNF receptor superfamily proteins GITR and OX40. Unexpectedly, LKB1 function in Treg cells was independent of conventional AMPK signalling or the mTORC1-HIF-1alpha axis, but contributed to the activation of beta-catenin signalling for the control of PD-1 and TNF receptor proteins. Blockade of PD-1 activity reinvigorated the ability of LKB1-deficient Treg cells to suppress TH2 responses and the interplay with dendritic cells primed by thymic stromal lymphopoietin. Thus, Treg cells use LKB1 signalling to coordinate their metabolic and immunological homeostasis and to prevent apoptotic and functional exhaustion, thereby orchestrating the balance between immunity and tolerance. PMID- 28847009 TI - Raising the Bar in Attribution. PMID- 28847010 TI - A Misleading Pattern of Serologic Findings During Hepatitis B Virus Infection. PMID- 28847008 TI - Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. AB - AIM: To evaluate the effects of metformin (Met) on inflammation, oxidative stress, and bone loss in a rat model of ligature-induced periodontitis. MATERIALS & METHODS: Male albino Wistar rats were divided randomly into five groups of twenty-one rats each, and given the following treatments for 10 days: (1) no ligature + water, (2) ligature + water, (3) ligature + 50 mg/kg Met, (4) ligature + 100 mg/kg Met, and (5) ligature + 200 mg/kg Met. Water or Met was administered orally. Maxillae were fixed and scanned using Micro-computed Tomography (MUCT) to quantitate linear and bone volume/tissue volume (BV/TV) volumetric bone loss. Histopathological characteristics were assessed through immunohistochemical staining for MMP-9, COX-2, the RANKL/RANK/OPG pathway, SOD-1, and GPx-1. Additionally, confocal microscopy was used to analyze osteocalcin fluorescence. UV-VIS analysis was used to examine the levels of malondialdehyde, glutathione, IL-1beta and TNF-alpha from gingival tissues. Quantitative RT-PCR reaction was used to gene expression of AMPK, NF-kappaB (p65), and Hmgb1 from gingival tissues. Significance among groups were analysed using a one-way ANOVA. A p-value of p<0.05 indicated a significant difference. RESULTS: Treatment with 50 mg/kg Met significantly reduced concentrations of malondialdehyde, IL-1beta, and TNF alpha (p < 0.05). Additionally, weak staining was observed for COX-2, MMP-9, RANK, RANKL, SOD-1, and GPx-1 after 50 mg/kg Met. OPG and Osteocalcin showed strong staining in the same group. Radiographically, linear measurements showed a statistically significant reduction in bone loss after 50 mg/kg Met compared to the ligature and Met 200 mg/kg groups. The same pattern was observed volumetrically in BV/TV and decreased osteoclast number (p<0.05). RT-PCR showed increased AMPK expression and decreased expression of NF-kappaB (p65) and HMGB1 after 50 mg/kg Met. CONCLUSIONS: Metformin, at a concentration of 50 mg/kg, decreases the inflammatory response, oxidative stress and bone loss in ligature induced periodontitis in rats. PMID- 28847011 TI - Population Health Science and the Challenges of Prediction. PMID- 28847012 TI - Accuracy of Cardiovascular Risk Prediction Varies by Neighborhood Socioeconomic Position: A Retrospective Cohort Study. AB - Background: Inequality in health outcomes in relation to Americans' socioeconomic position is rising. Objective: First, to evaluate the spatial relationship between neighborhood disadvantage and major atherosclerotic cardiovascular disease (ASCVD)-related events; second, to evaluate the relative extent to which neighborhood disadvantage and physiologic risk account for neighborhood-level variation in ASCVD event rates. Design: Observational cohort analysis of geocoded longitudinal electronic health records. Setting: A single academic health center and surrounding neighborhoods in northeastern Ohio. Patients: 109 793 patients from the Cleveland Clinic Health System (CCHS) who had an outpatient lipid panel drawn between 2007 and 2010. The date of the first qualifying lipid panel served as the study baseline. Measurements: Time from baseline to the first occurrence of a major ASCVD event (myocardial infarction, stroke, or cardiovascular death) within 5 years, modeled as a function of a locally derived neighborhood disadvantage index (NDI) and the predicted 5-year ASCVD event rate from the Pooled Cohort Equations Risk Model (PCERM) of the American College of Cardiology and American Heart Association. Outcome data were censored if no CCHS encounters occurred for 2 consecutive years or when state death data were no longer available (that is, from 2014 onward). Results: The PCERM systematically underpredicted ASCVD event risk among patients from disadvantaged communities. Model discrimination was poorer among these patients (concordance index [C], 0.70 [95% CI, 0.67 to 0.74]) than those from the most affluent communities (C, 0.80 [CI, 0.78 to 0.81]). The NDI alone accounted for 32.0% of census tract-level variation in ASCVD event rates, compared with 10.0% accounted for by the PCERM. Limitations: Patients from affluent communities were overrepresented. Outcomes of patients who received treatment for cardiovascular disease at Cleveland Clinic were assumed to be independent of whether the patients came from a disadvantaged or an affluent neighborhood. Conclusion: Neighborhood disadvantage may be a powerful regulator of ASCVD event risk. In addition to supplemental risk models and clinical screening criteria, population-based solutions are needed to ameliorate the deleterious effects of neighborhood disadvantage on health outcomes. Primary Funding Source: The Clinical and Translational Science Collaborative of Cleveland and National Institutes of Health. PMID- 28847014 TI - A Call for Open-Source Cost-Effectiveness Analysis. PMID- 28847015 TI - [Fracture dislocations of the first through fifth carpometacarpal joints]. PMID- 28847013 TI - Do Less Harm: Evaluating HIV Programmatic Alternatives in Response to Cutbacks in Foreign Aid. AB - Background: Resource-limited nations must consider their response to potential contractions in international support for HIV programs. Objective: To evaluate the clinical, epidemiologic, and budgetary consequences of alternative HIV program scale-back strategies in 2 recipient nations, the Republic of South Africa (RSA) and Cote d'Ivoire (CI). Design: Model-based comparison between current standard (CD4 count at presentation of 0.260 * 109 cells/L, universal antiretroviral therapy [ART] eligibility, and 5-year retention rate of 84%) and scale-back alternatives, including reduced HIV detection, no ART or delayed initiation (when CD4 count is <0.350 * 109 cells/L), reduced investment in retention, and no viral load monitoring or second-line ART. Data Sources: Published RSA- and CI-specific estimates of the HIV care continuum, ART efficacy, and HIV-related costs. Target Population: HIV-infected persons, including future incident cases. Time Horizon: 5 and 10 years. Perspective: Modified societal perspective, excluding time and productivity costs. Outcome Measures: HIV transmissions and deaths, years of life, and budgetary outlays (2015 U.S. dollars). Results of Base-Case Analysis: At 10 years, scale-back strategies increase projected HIV transmissions by 0.5% to 19.4% and deaths by 0.6% to 39.1%. Strategies can produce budgetary savings of up to 30% but no more. Compared with the current standard, nearly every scale-back strategy produces proportionally more HIV deaths (and transmissions, in RSA) than savings. When the least harmful and most efficient alternatives for achieving budget cuts of 10% to 20% are applied, every year of life lost will save roughly $900 in HIV-related outlays in RSA and $600 to $900 in CI. Results of Sensitivity Analysis: Scale back programs, when combined, may result in clinical and budgetary synergies and offsets. Limitation: The magnitude and details of budget cuts are not yet known, nor is the degree to which other international partners might step in to restore budget shortfalls. Conclusion: Scaling back international aid to HIV programs will have severe adverse clinical consequences; for similar economic savings, certain programmatic scale-back choices result in less harm than others. Primary Funding Source: National Institutes of Health and Steve and Deborah Gorlin MGH Research Scholars Award. PMID- 28847016 TI - [Calcinosis of the wrist after trauma: case report of a rare entity]. PMID- 28847017 TI - [Transtrapezoid carpal dislocation: a case report]. AB - Fracture dislocations of the STT joint are extremely rare. We present the case of a 50-year-old worker, who sustained a crush injury of his left hand with a dorsal fracture dislocation of the trapezoid bone and the associated second metacarpal bone at the STT, and a concomitant compartment syndrome of the hand. The fracture was reduced immediately and compartment release was performed, followed by percutaneous stabilisation using three K-wires. Material removal after six weeks was followed by intensive physical therapy. At the final follow-up examination after three months, we observed a good recovery of hand function compared to the unaffected right side with 75 % grip strength, 90 % ROM in extension/flexion and full thumb opposition (Kapandji score 9/10). Immediate surgical treatment of this rare injury can lead to a good functional result of the hand. PMID- 28847018 TI - Erratum: Terpenoids from the Oleo-Gum-Resin of Boswellia serrata and Their Antiplasmodial Effects In Vitro. PMID- 28847019 TI - Metabolomic-Guided Isolation of Bioactive Natural Products from Curvularia sp., an Endophytic Fungus of Terminalia laxiflora. AB - Endophytic fungi associated with medicinal plants are a potential source of novel chemistry and biology. Metabolomic tools were successfully employed to compare the metabolite fingerprints of solid and liquid culture extracts of endophyte Curvularia sp. isolated from the leaves of Terminalia laxiflora. Natural product databases were used to dereplicate metabolites in order to determine known compounds and the presence of new natural products. Multivariate analysis highlighted the putative metabolites responsible for the bioactivity of the fungal extract and its fractions on NF-kappaB and the myelogenous leukemia cell line K562. Metabolomic tools and dereplication studies using high-resolution electrospray ionization mass spectrometry directed the fractionation and isolation of the bioactive components from the fungal extracts. This resulted in the isolation of N-acetylphenylalanine (1: ) and two linear peptide congeners of 1: : dipeptide N-acetylphenylalanyl-L-phenylalanine (2: ) and tripeptide N acetylphenylalanyl-L-phenylalanyl-L-leucine (3: ). PMID- 28847020 TI - Effect of Encapsulated Artemisia aucheri. L Magnetic Nanogel Extract on Shoulder Block in Rat. AB - INTRODUCTION: Due to the severe pain generated after shoulder surgery, we aim to formulate and intravenously (IV) inject magnetic nanogel encapsulated Artemisia aucheri. L extract for inducing shoulder block in the rat. METHODS: Artemisia aucheri. L extract encapsulated magnetic nanoparticles (MNPs) was fabricated and tested in rat using paw withdrawal latencies (PWL) from thermal stimuli on the forepaw. The animals were divided into two groups; the untreated left forepaw (control group), and the test group with treated right forepaw. Sixteen (16) lab animals were used in this study, of which 3 in each of the two groups of the cumulative drug release experiments at 37 degrees C and 43 degrees C, and 5 in each of the two groups of PWL experiments. RESULTS: UV spectroscopy data shows that decreasing the pH of the fabricated nanocomposite has an influence on the extract release rate than increasing its temperature. CONCLUSIONS: The present study gave a proof of inducing a shoulder block in rat by IV injection administration of NIPAAM-MAA/Arthemisia aucheri. L extract complexes and magnet application to the shoulder. This will be a prospective formulation if a lower pH and temperature is considered for optimum release of this nanoanesthetics, thus, this can be translated into clinical practice for future applications. PMID- 28847021 TI - Characterisation and Safety of Intraperitoneal Perioperative Administration of Antibacterial Agents: A Systematic Review. AB - Background Intraperitoneal drug administration applies treatment at the site of diseases with gynaecological, urological, or gastrointestinal origin. The objective of this systematic review was to investigate perioperative intraperitoneal administration of antibacterial agents to characterise the drugs used and their safety profile. Methods A protocol was registered at PROSPERO (CRD42016038956). A systematic review was conducted and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A search was performed in PubMed and EMBASE on the 22nd of April 2016. The inclusion criteria were original articles involving at least 5 patients where antibacterial agents were administered intraperitoneally during or after abdominal surgery as prophylaxis or treatment of infection. Languages were limited to English, German, Danish, Norwegian, or Swedish articles. Results 79 studies were included which used a total of 12 different antibacterial classes. Aminoglycosides, 1st and 2nd generation cephalosporins, tetracyclines, and penicillins were most commonly administered intraperitoneally during or after surgery. The antibacterial agent was usually administered intraperitoneally as monotherapy. However, some studies administered combination regimens with heparin or with another antibacterial agent. The most frequent combination was aminoglycosides and lincosamides. In total, 43% of studies lacked information regarding adverse events. The most frequently reported adverse event was discomfort or pain during administration, especially with use of oxytetracycline. Conclusion At least 12 different classes of antibacterial agents have been administered intraperitoneally during or after surgery as prophylaxis or treatment of intraabdominal infections. Intraperitoneal administration seems safe although use of oxytetracycline may cause discomfort or pain. PMID- 28847022 TI - Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats. AB - BACKGROUND: Dependence and tolerance to morphine are major problems which limit its chronic clinical application. PURPOSE: This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. METHODS: Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5-25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. RESULTS: Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62+/-2, 77+/-4 and 85+/-6%, respectively). CONCLUSION: In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence. PMID- 28847023 TI - Saliva versus Plasma Bioequivalence of Valsartan/Hydrochlorothiazide in Humans: Validation of Classes II and IV Drugs of the Salivary Excretion Classification System. AB - AIM: The aim of this study is to investigate the robustness of using non-invasive saliva instead of plasma for bioequivalence of valsartan and hydrochlorothiazide (HCT) in humans based on Salivary Excretion Classification System (SECS). METHODS: Plasma and resting saliva samples were collected over 24 h after oral administration of single dose 160 mg valsartan and 12.5 mg HCT to 12 healthy male volunteers after 10 h overnight fasting. Plasma and saliva concentrations were determined by validated liquid chromatography-mass spectrometry. WinNonlin program V5.2 was used to determine pharmacokinetic parameters and bioequivalence metrics. Moreover, optimized effective intestinal permeability was estimated using PK-Sim/Mobi program V5.6. RESULTS AND DISCUSSION: Valsartan is SECS class IV drug due of low permeability and high protein binding and hence didn't appear in saliva. However, HCT is SECS class II drug due to low permeability and low protein binding. No significant differences were observed in the pharmacokinetic parameters in both plasma matrix and saliva matrix (P?0.05). The 90% confidence intervals did not pass in all parameters due to the high intra-subject variability and small sample size used in this study. Saliva to plasma ratios of HCT were low, yet with high correlation coefficient of 0.96-0.98. So saliva can be used as alternative to plasma sample in pharmacokinetic studies and in bioequivalence when adequate sample size is used. PMID- 28847024 TI - Incorporation of Fluorinated Pyridine in the Side Chain of 4-Aminoquinolines: Synthesis, Characterization and Antibacterial Activity. AB - A series of hybrid of 4-aminoquinoline and fluorinated pyridine derivatives were synthesized and their chemical structure were confirmed by 19F-NMR, 1H-NMR, 13C NMR and FT-IR. All compounds were tested against one Gram-positive and one Gram negative bacteria to assess their in vitro antibacterial activity. Compounds 10A: , 10B: , 11A: and 12B: showed moderate antibacterial activity against Gram positive bacterium, Staphylococcus aureus. PMID- 28847025 TI - What are the Possibilities of Uterine Transplantation in Transgender Patients? PMID- 28847026 TI - Relationship between Anxiety and Interleukin 10 in Female Soccer Players with and Without Premenstrual Syndrome (PMS). AB - Objective To investigate the level of anxiety and its relationship with interleukin (IL)-10 (anti inflammatory cytokine that modulates mood swings) in a group of female soccer players. Methods Fifty-two eumenorrheic soccer players were evaluated (age 19.8 +/- 4.7 years). The presence of premenstrual syndrome (PMS) and phases of the menstrual cycle were determined by a daily symptom report (DSR) kept for 3 consecutive months. The concentration of cytokine IL-10 was determined from urine samples collected at four moments: at the follicular and luteal phases of the menstrual cycle, and before (pre) and after (post) the simulated game, and it was quantified by flow cytometry (Luminex xMAP - EMD Millipore, Billerica, MA, USA). The level of anxiety was determined through the BAI anxiety questionnaire answered by all athletes at the same time of the urine collection. The Student t-test, analysis of variance (ANOVA) and Pearson correlation with significance level at 5% were used for data analysis. Results We showed that the prevalence of PMS among female soccer players is similar to that reported in the literature. In addition, we showed that the group with PMS has a higher level of anxiety compared with group without PMS (p = 0.002). Interleukin 10 analysis in players without PMS revealed that there was a significant decrease in the level of this cytokine before the game during the luteal phase when compared with the follicular phase (p < 0.05). The correlation analysis between IL-10 and anxiety showed a negative correlation post-game in the luteal phase in the group without PMS (p = 0.02; r = -0.50) and a positive correlation post-game in the luteal phase in PMS group (p = 0.04; r = 0.36). Conclusion Our results suggest that IL-10 may contribute to reduce anxiety in the group without PMS. This could be attributed to the fact that no IL-10 variation was observed in the group with PMS, which presented higher anxiety symptoms when compared with the group without PMS. PMID- 28847027 TI - Applying the Newman-Peacock Prognostic System to a Portuguese Obstetrical Population - A Useful Tool? AB - BACKGROUND: External cephalic version (ECV) is a maneuver that enables the rotation of the non-cephalic fetus to a cephalic presentation. The Newman-Peacock (NP) index, which was proposed by Newman et al. in a study published in 1993, was described as a prediction tool of the success of this procedure; it was validated in a North-American population, and three prognostic groups were identified. PURPOSE: To evaluate the value of the NP score for the prediction of a successful ECV in a Portuguese obstetrical population, and to evaluate maternal and fetal safety. METHODS: We present an observational study conducted from 1997 2016 with pregnant women at 36-38 weeks of pregnancy who were candidates for external cephalic version in our department. Demographic and obstetrical data were collected, including the parameters included in the NP index (parity, cervical dilatation, estimated fetal weight, placental location and fetal station). The calculation of the NP score was performed, and the percentages of success were compared among the three prognostic groups and with the original study by Newman et al. The performance of the score was determined using the Student t-test, the Chi-squared test, and a receiver operating characteristic (ROC) curve. RESULTS: In total, 337 women were included. The overall success rate was of 43.6%. The univariate analysis revealed that multiparity, posterior placentation and a less engaged fetus were factors that favored a successful maneuver (p < 0.05). Moreover, a higher amniotic fluid index was also a relevant predictive factor (p < 0.05). The Newman-Peacock score had a poorer performance in our population compared with that of the sample of the original study, but we still found a positive relationship between higher scores and higher prediction of success (p < 0.001). No fetal or maternal morbidities were registered. CONCLUSIONS: The Newman-Peacock score had a poorer performance among our population compared to its performance in the original study, but the results suggest that this score is still a useful tool to guide our clinical practice and counsel the candidate regarding ECV. PMID- 28847028 TI - Pelvic Floor 3D Ultrasound of Women with a TVT, TVT-O, or TVT-S for Stress Urinary Incontinence at the Three-year Follow-up. AB - Objective Using three-dimensional ultrasound (3D-US), we aimed to compare the tape position and the angle formed by the sling arms in different techniques of mid-urethral sling insertion for the surgical treatment of stress urinary incontinence, three years after surgery. In addition, we examined the correlations between the US findings and the clinical late postoperative results. Methods A prospective cross-sectional cohort study of 170 patients who underwent a sling procedure between May 2009 and December 2011 was performed. The final sample, with US images of sufficient quality, included 26 retropubic slings (tension-free vaginal tape, TVT), 42 transobturator slings (tension-free vaginal tape-obturator, TVT-O), and 37 single-incision slings (tension-free vaginal tape Secur, TVT-S). The images (at rest, during the Valsalva maneuver, and during pelvic floor contraction) were analyzed offline by 2 different observers blinded against the surgical and urinary continence status. Group comparisons were performed using the Student t-test, the chi-squared and the Kruskal-Wallis tests, and analyses of variance with Tukey multiple comparisons. Results Differences among the groups were found in the mean angle of the tape arms (TVT = 119.94 degrees , TVT-O = 141.93 degrees , TVT-S = 121.06 degrees ; p < 0.001) and in the distance between the bladder neck and the tape at rest (TVT = 1.65 cm, TVT-O = 1.93 cm, TVT-S = 1.95 cm; p = 0.010). The global objective cure rate was of 87.8% (TVT = 88.5%, TVT-O = 90.5%, TVT-S = 83.8%; p = 0.701). The overall subjective cure rate was of 83.8% (TVT = 88.5%, TVT-O = 88.5% and TVT-S = 78.4%; p = 0.514). The slings were located in the mid-urethra in 85.7% of the patients (TVT = 100%, TVT-O = 73.8%, TVT-S = 89.2%; p = 0.001), with a more distal location associated with obesity (distal: 66.7% obese; mid-urethra: 34% obese; p = 0.003). Urgency related symptoms were observed in 23.8% of the patients (TVT = 30.8%, TVT-O = 21.4%, TVT-S = 21.6%; p = 0.630). Conclusions The angle formed by the arms of the sling tape was more obtuse for the transobturator slings compared with the angles for the retropubic or single-incision slings. Retropubic slings were more frequently located in the mid-urethra compared with the other slings, regardless of obesity. However, the analyzed sonographic measures did not correlate with the urinary symptoms three years after the surgery. PMID- 28847029 TI - Prevalence of the MTHFR C677T Mutation in Fertile and Infertile Women. AB - Introduction The importance of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in infertile women remains controversial. Objective To evaluate if the MTHFR C677T mutations are more frequent in infertile women, and if they can be associated with the occurrence of infertility in the Brazilian population. Methods This case-control study included 130 infertile women consulting at a private clinic between March 2003 and March 2005 (data previously published), and 260 fertile women attending the family planning outpatient clinic of our institution between April 2012 and March 2013. Data analysis The Chi-squared and Fisher Exact tests were used to evaluate the association between the presence of the MTHFR C677T mutation and a history of infertility. Results The frequency of the mutation was of 58.5% for the case group (n = 76) and of 49.2% for the fertile controls (n = 128). The mutation was homozygous in 13 women in the case group (10%) and in 23 of the fertile women in the control group (8.8%). These differences were not statistically significant. Conclusions These results suggest that the presence of the MTHFR C677T mutation does not constitute a risk factor for infertility, even when the mutation is homozygous. Further studies are needed to confirm whether research on this mutation should be considered unnecessary in women with infertility. PMID- 28847030 TI - Macrophages in Nonalcoholic Fatty Liver Disease: A Role Model of Pathogenic Immunometabolism. PMID- 28847031 TI - Natural Killer Cells in Liver Disease. PMID- 28847032 TI - Learning the Roles of the Hepatic Adaptive Immune System in Hepatocellular Carcinoma-Nature's Guide for Successful Cancer Immunotherapy. PMID- 28847033 TI - Epigenetics in Liver Fibrosis. PMID- 28847034 TI - Challenges to a Cure for HBV Infection. PMID- 28847035 TI - Quantitative Imaging in Diffuse Liver Diseases. PMID- 28847036 TI - Functional Imaging and Assessment of Antitumor Activity in Systemic Therapy for Hepatocellular Carcinoma. PMID- 28847037 TI - Is Propensity Score Analysis a Valid Surrogate of Randomization for the Avoidance of Allocation Bias? PMID- 28847038 TI - Predicting Postpartum Hemorrhage (PPH) during Cesarean Delivery Using the Leicester PPH Predict Tool: A Retrospective Cohort Study. AB - OBJECTIVE: The aim of the present study was to develop a toolkit combining various risk factors to predict the risk of developing a postpartum hemorrhage (PPH) during a cesarean delivery. STUDY DESIGN: A retrospective cohort study of 24,230 women who had cesarean delivery between January 2003 and December 2013 at a tertiary care teaching hospital within the United Kingdom serving a multiethnic population. Data were extracted from hospital databases, and risk factors for PPH were identified. Hothorn et al recursive partitioning algorithm was used to infer a conditional decision tree. For each of the identified combinations of risk factors, two probabilities were calculated: the probability of a patient producing >=1,000 and >= 2,000 mL blood loss. RESULTS: The Leicester PPH predict score was then tested on the randomly selected remaining 25% (n = 6,095) of the data for internal validity. Reliability testing showed an intraclass correlation of 0.98 and mean absolute error of 239.8 mL with the actual outcome. CONCLUSION: The proposed toolkit enables clinicians to predict the risk of postpartum hemorrhage. As a result, preventative measures for postpartum hemorrhage could be undertaken. Further external validation of the current toolkit is required. PMID- 28847039 TI - Neurodevelopment and Growth of a Cohort of Very Low Birth Weight Preterm Infants Compared to Full-Term Infants in Brazil. AB - OBJECTIVE: The objective of this study was to investigate the neurodevelopment and growth of very low birth weight (BW) preterm infants, at 8 and 18 months corrected age (CA), compared with full term in Brazil. METHODS: Prospective cohort study including 83 preterm infants with BW <= 1,500 g and gestational age <= 32 weeks, and 52 full-term control infants. Preterm infants free from significant sensory and motor disability, and from congenital anomalies were included. Alberta infant motor scale (AIMS) and Brunet-Lezini scale (BLS) were used to evaluate the neurodevelopment at 8 and 18 months. Anthropometric measurements were collected to evaluate the growth in both age groups. RESULTS: At 8 months CA, preterm infants scored significantly lower in total AIMS score (p = 0.001). At 18 months, they scored significantly lower on the stand subscale from AIMS (p = 0.040) and exhibited poor psychomotor development in the BLS (p = 0.006). The nutritional status showed significant differences between the groups, in both age groups (p < 0.001). There were positive correlations between nutritional status and AIMS (r = 0.420; p < 0.001) and BLS (r = 0.456; p < 0.001) at 8 months, and between head circumference and BLS (r = 0.235; p < 0.05) at 8 months and AIMS (r = 0.258; p < 0.05) at 18 months. CONCLUSION: Very low BW preterm infants at 8 and 18 months CA showed significant differences in the neurodevelopment and growth pattern when compared with their full-term peers. PMID- 28847040 TI - Metabolic effects of Hedyotis diffusa on rats bearing Walker 256 tumor revealed by NMR-based metabolomics. AB - Hedyotis diffusa, a traditional Chinese herbal medicine, is widely used for oncotherapy and shows a positive effect in the clinical treatment. But its mechanism of anticancer activities is complicated and unclear. This study was undertaken to assess the therapeutic effects and reveal detailed mechanisms of H. diffusa for oncotherapy. A Walker 256 tumor-bearing rat model was established, and metabolomic profiles of plasma and urine were obtained from 1 H NMR technique. Multivariate statistical analysis methods were used to characterize the discriminating metabolites between control (C), Walker 256 tumor-bearing rats model (M), and H. diffusa treatment (H) groups. Finally, 13 and 10 metabolomic biomarkers in urine and plasma samples were further identified as characteristic metabolites in M group, whereas H group showed a partial metabolic balance recovered, such as ornithine, N-acetyl-l-aspartate, l-aspartate, and creatinine in urine samples, and acetate, lactate, choline, l-glutamine, and 3 hydroxybutyrate in plasma samples. On the basis of the methods above, we hypothesized H. diffusa treatment reduced the injury caused by Walker 256 tumor and maintained a metabolic balance. Our study demonstrated that this method provided new insights into metabolic alterations in tumor-bearing biosystems and researching on the effects of H. diffusa on the endogenous metabolism in tumor bearing rats. PMID- 28847041 TI - Age of Drinking Initiation as a Risk Factor for Alcohol Use Disorder Symptoms is Moderated by ALDH2*2 and Ethnicity. AB - BACKGROUND: An early age of drinking initiation (ADI) has been associated with increased risk for alcohol use disorders (AUDs), but the consistency of this risk across diverse samples has not been well studied. The purpose of this study was to examine whether the pathway from ADI to AUD symptoms by early adulthood is moderated by ethnicity and possessing an alcohol-metabolizing gene ALDH2*2 variant allele. METHODS: We used multigroup structural equation modeling, including 5 groups split by ethnicity and ALDH2*2, to examine the consistency of the path from ADI to AUD symptoms in 604 Chinese-, Korean-, and White-American college students. We further examined the effects of ALDH2*2, ethnicity, and their interaction in Asians to better understand their unique contributions to the moderation. RESULTS: The association between ADI and AUD symptoms was moderated, with ADI negatively associated with AUD symptoms among Koreans without ALDH2*2 and Whites, but not among Koreans with ALDH2*2 or Chinese regardless of ALDH2*2. Both ALDH2*2 and ethnicity within Asians contributed unique variability in the effect. CONCLUSIONS: Ethnicity and ALDH2*2 altered the relationship of ADI as a risk factor for AUD symptoms. Being Chinese and possessing an ALDH2*2 allele within Koreans both buffered against the risk for AUD symptoms associated with earlier ADI, indicating that this relationship can be attenuated by protective factors. PMID- 28847042 TI - Fatty acid derivatives from the halotolerant fungus Cladosporium cladosporioides. AB - Halotolerant fungus Cladosporium cladosporioides OUCMDZ-187 was isolated from the mangrove plant Rhizophora stylosa collected in Shankou, Guangxi Province of China. Three new fatty acid esters cladosporesters A-C (1-3) and 5 new fatty acids cladosporacids A-E (4-8) were isolated from the ethyl acetate extract of the fermentation broth of OUCMDZ-187 in a hypersaline (10% salt) medium. Their structures were elucidated by UV, IR, MS, specific rotation, and 1D and 2D NMR data. PMID- 28847043 TI - [Life expectancy and influence on disease in China, 2013]. AB - Objective: To analyze the characteristics of life expectancy and influencing factors in Chinese population in different areas and provide scientific evidence for policy-making on disease managements, medical care and risk factor intervention. Methods: Based on the national census data from National Bureau of Statistics and the death registration data from the National Health and Family Planning Commission, we used exponential model, under-report adjustment model and abbreviated life tables to estimate the life expectancy and influence on disease in Chinese population in 2013. Results: The Chinese life expectancy was 75.8 years in 2013, 1 year higher than that in 2010. The life expectancy in urban area was 77.4 years, while it was 75.1 years that in rural area with the gap between the rural area and urban area was 2.3 years. The life expectancy was 77.2 years in the eastern area, 75.8 years in middle area and 73.5 years in western area, the gap between the east and west was 3.6 years. In 2013, the first 10 leading diseases causing the life expectancy lost were cerebrovascular disease, ischemic heart disease, chronic obstructive pulmonary disease, lung cancer, road injury, liver cancer, stomach cancer, hypertensive heart disease, lower respiratory infection, esophagus cancer, resulting in 7.97 years of life expectancy lost. Conclusion: The life expectancy in Chinese has already reached a relative high level, while the gap between different areas still exists. Different policies on disease management, medical care and risk factor interventions targeting different areas are needed to increase the life expectancy and improve the quality of life. PMID- 28847044 TI - [Death and impact of life expectancy attributable to smoking in China, 2013]. AB - Objective: To analyze the death attributable to smoking and impact of life expectancy in China in 2013. Methods: According to the characteristics of different diseases, we calculated the population attributable fractions of different diseases, death and impact of life expectancy which caused by smoking, using direct method (current smoking rate as exposure levels) and indirect method (smoking impact ratio as exposure levels), based on data from both programs of death surveillance and Chinese chronic disease risk factor surveillance of 2013. Results: In 2013, smoking caused around 1.59 million deaths which accounted for 17.38% of all deaths in China. Constituent ratio of death caused by smoking in males (23.66%) was much higher than that in females (8.30%). However, in urban areas (17.24%), it was slightly lower than that in rural areas (17.51%). Constituent ratio of death caused by smoking in the eastern regions appeared the lowest (16.81%), with western regions the highest (17.91%). In 2013, lung cancer, COPD and ischemia heart disease were the top three diseases causing deaths that related to smoking, but the top three population attributable fractions were lung cancer, COPD and nasopharyngeal carcinoma in China. In 2013, smoking caused a reduction of 2.04 years of life expectancy loss in China, with males in the western regions the highest (3.05 years). Conclusion: Smoking is still an important public health problem in China. Tobacco-control-targeted programs in the heavily involved areas could reduce the number of deaths from related diseases that caused by smoking. PMID- 28847045 TI - [Mortality and life expectancy that attributable to high blood pressure in Chinese people in 2013]. AB - Objective: To estimate the deaths (mortality) and life expectancy that attributable to high blood pressure in people from different regions and gender, in China in 2013. Methods: Data was from the 'China Chronic Disease Risk Factor Surveillance 2013' and the 'China National Mortality Surveillance 2013'. According to the comparative risk assessment theory, population attributable fraction (PAF) of high blood pressure by gender, urban-rural, east-central-west regions was calculated before the estimations on deaths (mortality) and life expectancy attributable to high blood pressure was made. Results: In 2013, among the Chinese people aged 25 years old and above, the mean SBP was (129.48+/-20.27) mmHg. High blood pressure[SBP>(115+/-6) mmHg]caused 20.879 million deaths and accounted for 22.78% of the total deaths. SBP, deaths, mortality rate and standardized mortality rate that attributable to high blood pressure all appeared higher in men [(131.15+/-18.73) mmHg, 11.517 million, 165.56/100 000 and 106.97/100 000, respectively]than in women[(127.79+/-21.60) mmHg, 9.362 million, 141.99/100 000 and 68.93/100 000, respectively]. SBP, deaths, mortality rate and PAF were all seen higher in rural[(130.25+/-20.66) mmHg, 11.234 million, 178.58/100 000 and 23.59%, respectively]than in urban[(128.58+/-19.77) mmHg, 9.645 million, 132.87/100 000 and 21.54%, respectively]areas. However, levels of SBP were similar in the east, central or west regions, with attributable deaths, attributable mortality rate and PAF the highest as 7.658 million 179.93/100 000, and 26.72% respectively. In 2013, among the Chinese people aged 25 years old and above, deaths caused by cardiovascular disease and chronic kidney disease attributable to high blood pressure were 19.912 million and 0.966 million, accounting for 52.31% of the total deaths due to cardiovascular diseases and 62.11% to the total chronic kidney diseases. The top three deaths attributable to high blood pressure were ischemic heart disease (6.656 million), hemorrhagic stroke (5.331 million) and ischemic stroke (3.593 million). When the effect of high blood pressure had been eliminated, the life expectancy per capita would have increased by 2.86 years old, with higher in women than in men (3.07 and 2.64 years old, respectively), higher in central than in east and west (3.48, 2.56 and 2.58 years, respectively) areas, in rural than in urban (2.97 and 2.59 years, respectively) areas. Conclusions: In 2013, the number of deaths attributable to high blood pressure was around 20.9 million, accounting for 22.78% of the total deaths, and appeared higher in men than in women, in rural than in urban, in central than in east and west areas. The mortality burden induced by ischemic heart disease, hemorrhagic stroke and ischemic stroke was most serious since the high blood pressure brought about 2.86 years of lost in life expectancy. PMID- 28847046 TI - [The effect of high total cholesterol on life expectancy in 2013 in China]. AB - Objective: To estimate the effect of high total cholesterol (TC) on life expectancy in China. Methods: Population attributable fractions (PAF) of high TC were calculated in both urban, rural areas and regions, using data related to TC levels from the chronic disease risk factor surveillance in China, 2013. Together with PAFs, data related to death registry, demographics, attributable deaths from high TC and its effect on life expectancy, were estimated. Results: In 2013, the TC level in Chinese population aged 25 and above appeared as (4.8+/-1.0) mmol/L, higher in urban areas[(4.8+/-1.0) mmol/L]than that in rural areas[(4.7+/-1.0) mmol/L)], with the highest in eastern regions[(4.9+/-1.0) mmol/L] and lowest in the central regions [(4.6+/-1.0) mmol/L]. TC level appeared as (4.8+/-1.0) mmol/L in both sexes. A total of 2.9% of all the deaths were attributed to high TC (264 998 deaths), among which 89.3% were caused by ischemic heart disease (236 540 deaths). PAF was seen higher in females (3.7%) than that in males (2.3%), higher in urban (3.4%) than that in rural areas (2.4%), with the highest in eastern (3.7%) and lowest in western regions (2.1%). Mortality that attributed to high TC was 19.6/100 000, higher in females (21.2/100 000) than that in males (18.0/100 000), higher in urban(20.8/100 000) than that in rural areas (18.2/100 000), with the highest in eastern (23.2/100 000) and lowest in western regions (15.6/100 000). In 2013, the loss of life expectancy that caused by high TC was 0.30 year, higher in females (0.35 year) than in males (0.26 year), higher in urban (0.34 year) than that in rural areas (0.28 year), with the highest seen in the eastern (0.36 year) and lowest (0.23 year) in the western regions. Conclusion: In 2013, the effect of high TC on life expectancy appeared different between genders, urban and rural areas or regions, with greater impact on females, urban and eastern areas of the country. PMID- 28847047 TI - [Deaths and life expectancy losses attributable to diet high in sodium in China]. AB - Objective: To quantitatively estimate the deaths and life expectancy losses attributable to diet high in sodium in China, and examine the gains and shifts under different control scenarios of sodium consumption. Methods: Based on data from the cause-of-death through the National Mortality Surveillance System, and 24 hours urinary sodium values from Global Burden of Disease study on Chinese's estimates, population attributable fractions with the framework of comparative risk assessment were used to analyze the deaths and life expectancy losses due to diet high in sodium. The same methods were followed to examine the gains and shifts under different control scenarios of sodium consumption. Results: In 2013, 1 430 (940 for men and 490 for women) thousand deaths were attributable to diet high in sodium, accounting for 15.6% (17.4% for men and 13.0% for women) of all cause deaths in China, which causing 2.17 (2.49 for men and 1.71 for women) years of life expectancy loss. Diet with high sodium in 2013 caused 1 200, 50 and 180 thousand deaths from cardiovascular disease, chronic kidney disease and stomach cancer respectively, accounting for 31.5%, 30.8% and 64.8% of those specific causes. Comparing to the baseline in 2013, if the targets of 10% decrease of sodium consumption by 2020 and 15% by 2030 for Chinese chronic disease prevention and treatment planning, and 30% decrease by 2030 for WHO non-communicable disease monitoring framework are achieved, 220, 340 and 730 thousand deaths will be averted, which may gain 0.30, 0.45 and 0.95 years of life expectancy, respectively. Conclusions: As one of the leading risk factors, diet high in sodium had caused heavy burden of disease from cardiovascular disease, chronic kidney disease and stomach cancer on Chinese residents. Intervention programs on sodium-reduction are urgently needed in China and related cost-effectiveness is highly expected. PMID- 28847048 TI - [Number of deaths that attributable to high fasting plasma glucose among population aged 25 and above and its impact on life expectancy in China, 2013]. AB - Objective: To analyze deaths that attributable to high fasting plasma glucose and its impact on life expectancy among Chinese residents in 2013. Methods: Data from the Mortality Surveillance Programs in National Disease Surveillance Points System and the China Chronic Disease Surveillance (2013) were used. Death attributed to high fasting plasma glucose and its impact on the life expectancy of Chinese residents were estimated, based on the principle of population attributable fraction. Results: In 2013, the total number of deaths attributed to high fasting plasma glucose among aged >=25 years old was 621 thousand, with 333 thousand males and 288 thousand females. Diseases related to the number of deaths caused by high fasting plasma glucose would include ischemic heart disease (212 thousand) as the most important one. Cerebrovascular disease appeared the 2(nd) place, with around 181 thousand cases and then followed by diabetes (145 thousand), chronic kidney disease (52 thousand) and tuberculosis (31 thousand). After removal of the effects on high blood glucose exposure, the life expectancy of Chinese residents in 2013 would have reached 76.5 years old, an average increase of 0.7 years, compared to the average life expectancy of all deaths, with men having an increase of 0.7 years and women of 0.8 years, respectively. Conclusions: High fasting plasma glucose appeared an important risk factor for mortality and life expectancy on the Chinese residents. Programs related to prevention and control of high fasting plasma glucose and related diseases should be strengthened. PMID- 28847049 TI - [Effects of insufficient physical activity on motality and life expectancy in adult aged 25 and above among Chinese population]. AB - Objective: To analyze the attribution of mortality and impact on life expectancy caused by insufficient physical activity in different gender and areas in adults aged >=25 years among Chinese people. Methods: Data from the programs related to Chinese death surveillence, risk factors of chronic survey, health outcomes of physical activity as well as relative risk (RR) on Global Burden of Disease (GBD) study were used. Population attributable fraction (PAF) of different health outcomes attributable to deaths that caused physical activity and the influence of life expectancy in adults aged >=25 years in Chinese people were calculated. Results: The overall PAF for all cause of death due to physical activity in adults aged >=25 years was 4.24%, with 4.86% in females and 3.82% in males. The health outcomes of inadequate physical activity would include breast cancer, colorectal cancer, ischemic heart disease, ischemic stroke and diabetes with relative PAFs as 9.04%, 13.96%, 14.96%, 17.80% and 16.92%, respectively. The attribution of death on Physical activity was 388 954. The most attributed death was ischemic heart disease, followed by ischemic stroke. With the elimination of physical inactivity, the total life expectancy was expected to lose by 0.43 years, with 0.47 years in women, and 0.39 years in men. Conclusion: The increase of physical activity may benefit on health condition so to reduce the burden of chronic diseases and increase the life expectancy. PMID- 28847050 TI - [Mortality attributable to inadequate intake of fruits among population aged 25 and above in China, 2013]. AB - Objective: To assess the mortality attributable to low fruit intake among people over 25 years old in China, 2013, and its effect on life expectancy. Methods: Based on data collected from China Chronic Disease and Risk Factor Surveillance in 2013, the average fruit intake in different genders and areas were calculated. Potential impact fraction (PIF) was used to examine the impact on deaths, mortality and life expectancy. Results: The average daily fruit intake was (113.3+/-168.9) g among people over 25 years old, with (103.6+/-160.1) g for men and (122.7+/-176.6) g for women, in China in 2013. Fruit intake for urban residents was significantly higher than that in rural residents and higher in eastern regions than that in central or western regions. Scores that attributable to low fruit intake accounted for 15.21% of the total deaths and the population attributable fraction of inadequate intake of fruits to associated diseases was 35.00%. PIF for all the deaths in rural residents (16.50%) appeared higher than that of the urban residents (13.88%), and higher in the residents living in the eastern region (15.48%) than that in the central (16.27%) or western (13.75%) regions. Number of deaths that attributable to low fruit intake was 1.348 4 million. Deaths caused by related diseases appeared as: ischemic heart disease (472.5 thousands), hemorrhagic stroke (338.8 thousands), ischemic stroke (259.0 thousands), lung cancer (208.4 thousands), esophageal cancer (60.7 thousands), laryngeal cancer (5.4 thousands) and oral cancer (3.6 thousands). Numbers of all deaths and related diseases for urban residents were lower than that of the rural residents, with central regions (452.7 thousands) higher than that in the eastern (531.1 thousands) or western (364.6 thousands) regions. The average life expectancy loss caused by low fruit intake was 1.73 years, 1.80 years for men and 1.58 years for women, in this country. Loss of life expectancy in the rural residents was higher than that of the urban residents, and higher in central regions than that in the eastern or western regions. Conclusions: The intake of fruit was far lower than the recommended standard set for the Chinese people. Population attributable fraction was related to the associated diseases caused by inadequate intake of fruits which also made serious impact on life expectancy. PMID- 28847051 TI - [Association between birth cohort and the heritability of body mass index]. AB - Objective: To investigate the varying variances of the genetic components in birth cohorts. Methods: Twin samples used in the current study were collected from the Chinese National Twin Registry and a two-wave study was conducted, in Qingdao and Lishui regions. Samples were broken down by birth cohort to create four subgroups: -1958, 1959-1961, 1962-1970 and 1970-. Structural equation models were fitted in each subgroup to estimate the genetic and environmental variances. Results: From each birth cohort, weight and body mass index in 2012 appeared higher than those in 2001. Twins of 1971- cohort subgroup showed lower weight than in the other cohort subgroups. Except for the 1959-1961 cohort subgroup, the later birth cohorts were inversely related to the body mass indexes. Genetic factors might explain 54%-76% of the total variations on the body mass index. Heritability of body mass index of twins born during 1959-1961 was increasing along with age. Conclusion: Genetic factors might explain the main portion which related to the phenotypic variance of body mass index. Effects of genetic factors on body mass index of twins born during 1959-1961 might have increased along with age. PMID- 28847052 TI - [Association between family history and the risk of hypertension in rural districts of Hanzhong in Shaanxi province]. AB - Objective: To understand the prevalence of hypertension and quantitative relationship between family history and the risk of hypertension among rural residents living in Hanzhong District, Shaanxi province. Methods: A multistage random sampling survey was conducted. Data on the characteristics related to hypertension were collected and physical examination was conducted. Logistic regression was used to analyze the relationship between family history and hypertension. Results: A total number of 2 817 rural residents aged 18-80 with complete information were recruited. The crude prevalence of hypertension was 33.7%. Results from the logistic regression analysis showed that the OR was 2.06 (95% CI: 1.70-2.50) between family histories with or without hypertension. When the first-degree relatives were with the degrees of family history of hypertention as I, II or III, the OR values of hypertension appeared as 1.83 (95% CI: 1.47-2.27), 2.94 (95% CI: 2.09-4.13) and 4.48 (95% CI: 2.17-9.27) respectively. Either father or mother having the positive family history of hypertension, the corresponding OR values appeared as 2.50 (95% CI: 1.84-3.40), 1.61(95% CI: 1.22-2.12) seen in mothers. However, when both father and mother having the family history of hypertention, the OR value was seen 2.82 (95%CI: 1.76-4.51) in the mothers. Conclusion: Family history appeared as a risk factor for hypertension. The number of first-degree relatives with positive family history showed a dose-response relationship to the occurrence of hypertension. Family history in both father or mother might further affect the incidence of hypertension. PMID- 28847053 TI - [Association between the change of daily living activities and symptoms of depression in Chinese middle-aged and elderly people]. AB - Objective: To explore the association between the change of daily living activities and the suymtoms of depression in Chinese middle-age and elderly people. Methods: People without symptoms on depression, emotional or spiritual diseases or memories related diseases in baseline survey (2011), those who were aged >=45 years in the China Health and Retirement Longitudinal Survey (CHARLS) with two waves from 2011 to 2013 were invited to participate in this CHARLS study. Information related to demographic characteristics and health status of the subjects were collected through household-interview. Depression symptom was assessed with the Center for Epidemiological Studies of Depression (CES-D10) scale. Activities of daily living function was assessed by both Basic Activities of Daily Living (BADL) and Instrument Activities of Daily Living (IADL) scales. Symptoms of depression was compared and the differences in various BADL/IADL changing groups were analyzed with Log-rank test. Association between the changes of daily living activities and depression symptom was analyzed by Cox regression model. Results: Results from the log-rank test showed that the differences of depression symptom hazard ratio were statistically significant in different BADL/IADL changing groups. Results from the Cox regression analysis showed that the BADL/IADL in the deteriorating groups was associated with the higher hazard ratio of depression symptom (P<0.01), with the HR value (95%CI) for BADL and IADL deteriorate groups as 1.45 (1.20-1.76) and 1.64 (1.36-1.98), respectively, when comparing to the 'stablized' group. This phenomenon appeared an urban-rural difference. Statistical significances on IADL also happened in both urban and rural areas while BADL only occurred in rurals. Conclusion: There appeared an association between the change of daily living activities and depression symptom in Chinese middle-age and elderly people. Difference between IADL and BADL was also noticed between urban and rural areas. PMID- 28847054 TI - [Dietary patterns among preschoolers and its association with education level of the parents]. AB - Objective: To identify the dietary patterns among preschoolers in Ma'anshan, and to investigate its association with the education levels of the parents. Methods: A total of 16 439 children aged 3-6 were recruited from 91 kindergartens in Ma'anshan city to participate in the study. Food frequency and socio-demographic information were collected through questionnaire survey. Dietary data was collected using a food frequency questionnaire (FFQ), and principal-components analysis was used to derive the dietary patterns. Ordinal multinomial logistic regression was employed to explore the association between the education level of parents and the dietary patterns. Results: Five dietary patterns- "processed" , "beverage" , "snack" , "protein" and "vegetarian" were identified. Data showed that the total variance was 48.02% and the cumulative proportion of processed reached 24.78%. Low educational level of the father was positively associated with both "beverage" (OR=1.36, 95%CI: 1.15-1.63) and "snack" dietary pattern (OR=1.21, 95%CI: 1.01-1.43). Low educational level of mother was positively associated with the "processed" (OR=1.31, 95%CI: 1.09-1.57) and "beverage" dietary pattern (OR=1.48, 95%CI: 1.23-1.77), and showed a negative correlation with "protein" (OR=0.62, 95%CI: 0.52-0.74) and "vegetarian" dietary pattern (OR=0.72, 95%CI: 0.60-0.86). Conclusion: Findings from this study showed that preschoolers in Ma'anshan tend to choose unhealthy dietary pattern. Dietary pattern was directly influenced by the parents, and especially the education level of the mothers. PMID- 28847055 TI - [Reliability and validity of the Chinese version on Alcohol Use Disorders Identification Test]. AB - Objective: To assess the reliability and validity of the Chinese version on Alcohol Use Disorders Identification Test (AUDIT) among medical students in China and to provide correct way of application on the recommended scales. Methods: An E-questionnaire was developed and sent to medical students in five different colleges. Students were all active volunteers to accept the testings. Cronbach's alpha and split-half reliability were calculated to evaluate the reliability of AUDIT while content, contract, discriminant and convergent validity were performed to measure the validity of the scales. Results: The overall Cronbach's alpha of AUDIT was 0.782 and the split-half reliability was 0.711. Data showed that the domain Cronbach's alpha and split-half reliability were 0.796 and 0.794 for hazardous alcohol use, 0.561 and 0.623 for dependence symptoms, and 0.647 and 0.640 for harmful alcohol use. Results also showed that the content validity index on the levels of items I-CVI) were from 0.83 to 1.00, the content validity index of scale level (S-CVI/UA) was 0.90, content validity index of average scale level (S-CVI/Ave) was 0.99 and the content validity ratios (CVR) were from 0.80 to 1.00. The simplified version of AUDIT supported a presupposed three-factor structure which could explain 61.175% of the total variance revealed through exploratory factor analysis. AUDIT semed to have good convergent and discriminant validity, with the success rate of calibration experiment as 100%. Conclusion: AUDIT showed good reliability and validity among medical students in China thus worth for promotion on its use. PMID- 28847056 TI - [Characteristics of HIV seropositive cases and related high risk behaviors in a community in Yunnan province, 2012-2015]. AB - Objective: To understand the characteristics of newly detected HIV infection cases and related high risk behaviors in the areas with high HIIV infection prevalence in Yunnan province. Methods: A questionnaire survey was conducted with census method during January to March 2016 among newly detected HIV infected persons in Dehong, Honghe, Lincang and Dali prefectures in Yunnan during 2012 2015. Results: Among 451 HIV seropositive cases, the major transmission route of HIV was heterosexual contact, accounting for 92.5% (417/451). The total awareness rate of AIDS related knowledge was 73.0% (329/451). The rates of condom use at sex with regular sexual partners, occasional sexual partners, commercial sexual partners and men who have sex with men within 1 year before knowing their infection status were 48.7% (167/343), 4.2% (7/165), 9.9% (15/151) and 0.0% (0/3), respectively. The risk factors for using no condom at sex with regular sexual partners included living at Dali, being farmer, unmarried, cohabitation, divorced and widowed, monthly income under 1 000 yuan (RMB), living in urban area before infection, knowing no AIDS related knowledge etc. The risk factors for using no condom at sex with occasional sexual partners included living in Dehong, Honghe and Lincang, aged <=30 years and being farmer. The injecting drug users accounted for 8.2% (37/450) and 75.5% of these cases had received AIDS related intervention (340/450). Conclusion: High prevalence of heterosexual transmission of HIV, poor AIDS related knowledge on awareness, high risk behavior and poor condom use and poor intervention service utilization were found among newly detected HIV infected persons in areas with high HIV infection prevalence in Yunnan. PMID- 28847057 TI - [Three-level logistic analysis related to influencing factors on condom use among female sex workers aged 35 years and above in Qingdao]. AB - Objective: To analyze the influencing factors on condom use among 35-years-or older female sex workers (OFSWs) in Qingdao by using the three-level logistic model. Methods: From March to June 2014, OFSWs were recruited in Qingdao, using respondent-driven sampling. Related information on OFSWs and their recent five sexual partners (not including husband) were obtained by conducting a questionnaire survey on OFSWs. A Three-level logistic regression model was conducted to analyze the influencing factors of condom use between OFSWs and their sexual partners. Results: A total of 420 OFSWs participated the survey as well as information on 2 100 sexual partners. Results from the empty model showed that the use of condoms among OFSWs having an aggregation that related to the levels of working sites and their own behaviors. Results from the three-levels of logistic model analysis showed that, OFSWs that having had junior middle school education (OR=1.450, 95%CI: 1.054-1.994)/high school education or above (OR=2.264, 95%CI: 1.215-4.222), knowing the function of condom use (OR=2.004, 95%CI: 1.273-3.154) would have higher rates of condom use. OFSWs with higher score of attitude on condom use (OR=0.796, 95%CI: 0.745-0.849), having had syphilis infections in the past (OR=0.657, 95%CI: 0.478-0.902) would have lower rate of condom use. For the sexual partners, the rate of condom use among OFSWs' regular partners were higher than that of OFSWs' boyfriends (OR=15.291, 95%CI: 8.441-27.700; OR=29.032, 95%CI: 15.413-54.682). Conclusion: Condom use of OFSWs was affected by behaviors of both OFSWs themselves and their sexual partners. Prevention and control programs should focus on OFSWs and their sexual partners at the same time. The key intervention contents should include target populations as: OFSWs with low level of education, having had infections of syphilis, those who do not use condoms with their trusted partners. PMID- 28847058 TI - [Factors related to antiretroviral therapy among HIV/AIDS positive students aged 15-30, in a hospital of Shenyang city]. AB - Objective: To investigate the risk factors on antiretroviral therapy (ART) among HIV/AIDS positive students in Shenyang. Methods: A cross-sectional study was conducted among HIV/AIDS positive students aged between 15 and 30, in an HIV treatment-designated hospital in Shenyang city, during 2007-2015. Data were analyzed by multivariate logistic regression mode to identify the risk factors related to ART. Results: A total of 2 379 HIV/AIDS patients attended the hospital and 6.1% (146/2 379) of them were students, during 2007-2015. All of the HIV/AIDS positive students were males, with homosexual transmission accounted for 93.2% (136/146). The overall rate on delayed diagnosis was 52.7% (77/146), when at diagnosis of CD(4)(+)T lymphocyte counts <=350 cells/MUl. The proportion of ART was 67.1% (98/146). Factors as: year that the HIV diagnosis was made (aOR=1.21, 95%CI: 1.02-1.44), age between 24-30 (compared with age below 18-year-old, aOR=8.15, 95%CI: 1.46-45.52), and delayed diagnosis (aOR=2.22, 95%CI: 1.05-4.71), appeared independently related to ART among HIV/AIDS positive students. Conclusions: Factors as the year that HIV diagnosis was made, age and delayed diagnosis of the patients seemed to be at higher risk for ART among HIV/AIDS positive students. PMID- 28847059 TI - [Acceptability of pre-exposure HIV prophylaxis clinical trial among MSM in Shenyang city]. AB - Objective: To investigate the acceptability and related factors of an "on-demand" pre-exposure prophylaxis (PrEP) to prevent HIV transmission among MSM in Shenyang. Methods: MSM recruited by non-probability sampling method and questionnaire survey conducted by investigators to collect information on social and behavioral characteristics, awareness of PrEP, Truvada and the acceptability of two different PrEP-based trials. Multivariate logistic regression was employed for statistical analysis. Results: Among the 292 respondents, 34.2% had heard of PrEP and 58.2% (170/292) reported were interested in participating a PrEP trial- "on-demand" use or 48.3% (141/292) interested on "daily" use (chi(2)=5.785, P=0.02). Factors independently associated with those "on-demand" would include: having more than 2 male sexual partners during the past 6 month (aOR=1.7, 95%CI: 1.1-2.7), concerning on the positive effect of PrEP (vs. side effects) (aOR=6.4, 95%CI:2.2-18.9), having an HIV-infected sexual partners (aOR=8.1, 95%CI: 1.0 63.3) and self-reported high risk for HIV (aOR=2.6, 95%CI: 1.2-6.0). The last two factors were only associated with the "on-demand" group. Conclusions: "On-demand" PrEP (as opposed to daily) seemed a more feasible prevention strategy on HIV and particularly in those having high risk behavior of HIV. For those who could not follow the daily medication or having HIV risk perception, "On-demand" basis PrEP trial should be recommended for them to follow. PMID- 28847060 TI - [Factors that related to the depressive symptoms among elderly in urban and rural areas of China]. AB - Objective: The aim of this research was to study the prevalence and differences of depressive symptoms and related factors in elderly in both urban and rural areas so as to develop relative strategies on this issue. Methods: Ten-question version of the Center Epidemiologic Studies-Depression scale (CES-D) was applied to score the depressive status. Data used in this research was from the 2013 China Health and Retirement Longitudinal Study (CHARLS). Binary logistic regressions method was applied to examine the influential factors related to depression symptoms. Results: In the elderly population, the mean score on depressive symptoms was 8.3+/-5.9, with a prevalence as 26.8%. The incidence rates on 'Elderly depression' in urban and rural areas were 16.4% and 30.0% respectively. The prevalence of depressive symptoms was relatively low (P<0.05) with protective factors including: being male, status related to self-rated health, without chronic diseases, active participation in social activities etc. noticed, among elderly in both urban and rural areas. Age and alcohol consumption appeared factors that influencing the depressive symptoms of the elderly in rural areas, while the average income was an influencing factor on the elderly in urban areas. Incidence of depression was relatively low in age >=75 years group in rural areas. However, elderly in the rural areas with abstinence of alcohol intake showed higher incidence of depressive symptoms (P<0.05). Incidence of depression was reltively low (P<0.05) among elderly with high income in the urban areas. Conclusions: Incidence of depression appeared high among the elderly and even higher in the rural areas. Strategies would include the following points: to strengthen the construction of urban-rural integration, improving and strengthening the rural pension insurance system, upgrading the urban social assistance for low-income elderly, strengthening the psychological consultation service of primary medical institutions and actively developing the three-tier levels related to the prevention of chronic diseases. PMID- 28847061 TI - [Study on the classification of dominant pathogens related to febrile respiratory syndrome, based on the method of Bayes discriminant analysis]. AB - Objective: To understand the dominant pathogens of febrile respiratory syndrome (FRS) patients in Gansu province and to establish the Bayes discriminant function in order to identify the patients infected with the dominant pathogens. Methods: FRS patients were collected in various sentinel hospitals of Gansu province from 2009 to 2015 and the dominant pathogens were determined by describing the composition of pathogenic profile. Significant clinical variables were selected by stepwise discriminant analysis to establish the Bayes discriminant function. Results: In the detection of pathogens for FRS, both influenza virus and rhinovirus showed higher positive rates than those caused by other viruses (13.79%, 8.63%), that accounting for 54.38%, 13.73% of total viral positive patients. Most frequently detected bacteria would include Streptococcus pneumoniae, and haemophilus influenza (44.41%, 18.07%) that accounting for 66.21% and 24.55% among the bacterial positive patients. The original-validated rate of discriminant function, established by 11 clinical variables, was 73.1%, with the cross-validated rate as 70.6%. Conclusion: Influenza virus, Rhinovirus, Streptococcus pneumoniae and Haemophilus influenzae were the dominant pathogens of FRS in Gansu province. Results from the Bayes discriminant analysis showed both higher accuracy in the classification of dominant pathogens, and applicative value for FRS. PMID- 28847062 TI - [Temperature that modifies the effect of air pollution on emergency room visits for circulatory and respiratory diseases in Beijing, China]. AB - Objective: To analyze the temperature modification effect on emergency room visits for circulatory and respiratory diseases caused by air pollution, in Beijing. Methods: Data on both circulatory and respiratory diseases in 2010 and 2011 were collected, Both meteorological and air pollutants related data were obtained from the National Scientific Data Sharing Platform for Population and Health. By using the stratified time-series models, we analyzed the effects of air pollution on emergency room visits for circulatory and respiratory diseases under different temperature zones, from 2010 to 2011, in Beijing. Results: Low temperature (daily average temperature<-4.9 C) seemed to have obviously enhanced the effect of air pollution index (API) on emergency room visits for circulatory diseases, Under 10 units of API, the relative risks and confidence interval appeared as 1.067 (1.054-1.080). However, high (daily average temperature between 24.4 C and 28.5 C) and extra-high temperature (daily average temperature >28.5 C) could enhance the effect of API on emergency room visits for respiratory diseases, Under 10 units of API, the relative risks and confidence interval were 1.021 (1.015-1.028) and 1.006 (1.003-1.008), respectively. Conclusion: Temperature seemed to have modified the association between air pollution and both circulatory and respiratory diseases. PMID- 28847063 TI - [Data analysis on HIV/AIDS sentinel surveillance programs targeting community population in Liangshan Yi Autonomous Prefecture, 2010-2015]. AB - Objective: To investigate the epidemiologic and behavioral characteristics of HIV among community population in Liangshan prefecture. Methods: We collected social demographic, behavioral and serological information by means of the monitoring questionnaire and serological tests. Data was analyzed by using the chi-square test and logistic regression. Results: From April to June of 2010 to 2015, 14 092 cases of community population were selected as the study objects, with 267 cases diagnosed as HIV positive patients. The HIV positive rates were 3.24%, 3.07%, 1.17%, 1.38%,1.42% and 1.25%, respectively. We observed that when community population having the following characteristics as: living in Butuo country (OR=3.83), being males (OR=1.77), being Yi nationality (OR=4.40) being widowed (OR=28.57), with history of drug abuse (OR=3.71) or injecting drug use (PWID) (OR=4.92), or history of needle sharing among PWID (OR=8.53), were under higher risks for HIV infection. With histories as: having had secondary or above levels of schooling (OR=0.59), having protected sex with regular partners (OR=0.21) and with non-regular partners (OR=0.46), they seemed to be somehow protected for getting HIV infection. Conclusion: The positive HIV rates of HIV among community population in Dechang, Ningnan and Butuo varied from 0.10% to 8.77% while the HIV transmission among general population remained challenging. PMID- 28847064 TI - [HIV subtype in newly reported HIV infected cases in Dehong prefecture of Yunnan province, 2015]. AB - Objective: To explore the distribution of HIV subtype in newly detected people living with HIV from January to November, 2015 in Dehong Dai and Jingpo Autonomous Prefecture, Yunnan province. Methods: DNA extraction, reverse transcription polymerase chain reaction (RT-PCR) for gag, env, and pol amplification and amplification product sequencing were conducted by using plasmas of newly detected HIV-infected persons. The subtypes were confirmed by analyzing the sequences of 3 genes. Results: A total of 963 HIV infection cases were reported during this period, the HIV subtype was confirmed in 499 cases. Unique recombinant form (URF) was the most common subtype (27.1%, 135/499), followed by C (26.7%, 133/499), CRF01_AE (19.2%, 96/499) and others. URF included 4 kinds of combination, of which combination of subtype B and C was most common. HIV subtype distribution differed between the Chinese HIV infection cases and the Burmese HIV infection cases, the proportion of B and C combination was higher in the Chinese cases. Transmission route was the only factor influencing HIV subtype distribution. Conclusions: HIV subtype distribution in Dehong was complex. URF was predominant. The HIV subtype distribution differed between Chinese and Burmese under different transmission route. PMID- 28847065 TI - [Interaction between polycyclic aromatic hydrocarbons and p16, FHIT gene CpG island methylation in patients with cervical intraepithelial neoplasias]. AB - Objective: To explore the effect of polycyclic aromatic hydrocarbons (PAHs) and p16, FHIT gene CpG island methylation, as well as their interaction in cervical intraepithelial neoplasias. Methods: Objects of this study were from a cohort of cervical lesions study in Yangqu county of Shanxi province. All the patients were diagnosed pathologically, that including 83 patients with high-grade cervical intraepithelial neoplasia (CINII/III), 86 patients with low-grade cervical intraepithelial neoplasia (CINI) and another 91 women under normal cervical (NC) condition. 1-hydroxy pyrene in the urine was detected by high performance liquid chromatography (HPLC) while CpG island methylation status of tumor suppressor gene p16 and FHIT were measured by methylation-specifc polymerase chain reaction (MSP). Data were analyzed with Kruskal-Wallis H test, chi-square test and trend of chi-square test. Logistic regression models were used to estimate the odds ratio (OR) and corresponding 95% confidence intervals (95%CI) between influencing factors and the cervical disease by using the SPSS statistical software (version 20.0). The interaction under study was evaluated by using the generalized multifactor dimensionality reduction (GMDR) model. Results: Level of 1-hydroxy pyrene (H=50.743, P<0.001) and the high exposure rate of 1-hydroxy pyrene (trend chi(2)=20.146, P<0.001) were gradually increasing along with the severity of cervical intraepithelial neoplasia. The CpG island methylation rates of p16, FHIT in CINIand CINII/III group were higher than that in NC group, and gradually increasing along with the severity of cervical intraepithelial neoplasia (trend chi(2)=9.75, P=0.002; trend chi(2)=10.39, P=0.001). Results from the GMDR model showed that interaction existed among the high exposure of 1-hydroxy pyrene and the CpG island methylation of p16, FHIT in CINI and CINII/III group. Conclusion: Under the high exposure of 1-hydroxy pyrene and the CpG island methylation of p16, FHIT appeared to have increased the risk of cervical intraepithelial neoplasia and causing synergistic effect in cervical intraepithelial neoplasia. PMID- 28847066 TI - [Reliability and validity of the Chinese version on Comprehensive Scores for Financial Toxicity based on the patient-reported outcome measures]. AB - Objective: To evaluate the reliability and validity of the Chinese version on comprehensive scores for financial toxicity (COST), based on the patient-reported outcome measures. Methods: A total of 118 cancer patients were face-to-face interviewed by well-trained investigators. Cronbach's alpha and Pearson correlation coefficient were used to evaluate reliability. Content validity index (CVI) and exploratory factor analysis (EFA) were used to evaluate the content validity and construct validity, respectively. Results: The Cronbach's alpha coefficient appeared as 0.889 for the whole questionnaire, with the results of test-retest were between 0.77 and 0.98. Scale-content validity index (S-CVI) appeared as 0.82, with item-content validity index (I-CVI) between 0.83 and 1.00. Two components were extracted from the Exploratory factor analysis, with cumulative rate as 68.04% and loading>0.60 on every item. Conclusion: The Chinese version of COST scale showed high reliability and good validity, thus can be applied to assess the financial situation in cancer patients. PMID- 28847067 TI - [Prenatal exposure to ambient air pollution and congenital heart disease: a Meta analysis]. AB - Objective: To explore the association between exposure to ambient air pollution during pregnancy and congenital heart disease so as to provide evidence for primary prevention of congenital heart disease. Methods: Epidemiologic studies on ambient air pollution and congenital heart diseases were reviewed. Summary risk estimates were calculated at high versus low exposure levels and risk per-unit increase in continuous pollutant concentration. Meta-analysis was conducted with Stata 12.0 software. Results: A total of 20 articles in English were qualified for inclusion. Results from Meta-analysis showed that CO exposures were related to the increase on the risk of tetralogy of fallot (high versus low exposure level OR=1.22, 95%CI: 1.03-1.44), while the exposures to NO(2) were related to the increase on risk of coarctation of aorta (per 10 mm(3)/m(3) OR=1.01, 95%CI: 1.01-1.20). Exposures to O(3) were related to the increase on risk of atrial septal defect (per 10 mm(3)/m(3) OR=1.14, 95%CI: 1.03-1.26), and PM(10) exposures were related to the increase on risk of atrial septal defect (per 10 MUg/m(3) OR=1.10, 95%CI: 1.03-1.19). In addition, there were inverse associations between CO and atrial septal defect and between PM(10) and ventricular septal defect. Conclusion: Exposures to CO, NO(2), O(3), PM(10) during pregnancy seemed to be associated with congenital heart diseases. PMID- 28847068 TI - [A new perspective of survival data on clinical epidemiology: introduction of competitive risk model]. AB - Competing risks occur frequently in the analysis of survival data that should be dealt with competing risk models. Competing risk is an event whose occurrence precludes the occurrence of the primary event of interest. Previous commonly used Kaplan-Meier method tends to overestimate the cumulative survival functions, while the traditional Cox proportional hazards model falsely evaluates the effects of covariates on the hazard related to the occurrence of the event. There are few domestic reports mentioning the concept, application and methodology of competing risk model as well as the implementation procedures or resolution of model conditions and parameters. The current work aims to explain the core concept and methodology of the competing risk model and to illustrate the process of analysis on cumulative incidence rate, using both the cause-specific hazard function model and the sub-distribution hazard function model. Software macro code in SAS 9.4 is also provided to assist clinical researchers to further understand the application of the model so to properly analyze the survival data. PMID- 28847069 TI - [The latent variable growth curve model of longitudinal data and its implementation in Mplus]. AB - To discuss the latent variable growth curve model of longitudinal data and give its implementation method in Mplus. The application of Mplus software has been used to deal with the longitudinal data of mental health status of college students in an university. Results show that the model can process the longitudinal data with latent variables, which can compare the differences of the overall development trend and individual development, also taking a covariate into the model to improve the effect of model fitting. Using Mplus software to process the longitudinal data with latent variables, the program is simple and easy to operate. This study provides the latent variable growth curve model of longitudinal data and its procedure of implementation in Mplus, and the statistical methodology guidance and reference for practical applications of epidemiological cohort study. PMID- 28847070 TI - [Study on the 19(th) century puerperal fever epidemic: Semmelweis-an often neglected pioneer epidemiologist]. AB - Puerperal fever was a major cause of maternal death in Europe in the 19(th) century. Many efforts were made to investigate the cause of the epidemic but failed. In 1846, Semmelweis, a young obstetrician in Vienna General Hospital, started his historical investigation. His breakthrough was largely due to his doctor friend's accidental injury during autopsy and his consequential death. Semmelweis found the pathological findings in his friend's post mortem examination were very similar to puerperal fever. He postulated his friend's death might be caused by "cadaverous particles" from cadavers and further inferred that puerperal fever might also be caused by the cadaverous particles that doctors brought to the delivering women after autopsy classes. He advocated hand-washing with chlorinated lime solution to wash off those particles, which rapidly reduced the maternal mortality in his department by 80% (from 10.65% to 1.98%). However, what his unprecedented work brought him was only denial, mockery and career setback rather than support, honor and compliments. Under substantial psychological pressure, he had a mental breakdown and died in a psychiatry asylum at the age of 47. He was a pioneer in epidemiological investigations before John Snow and in aseptic techniques before Joseph Lister, but his work is still often neglected. PMID- 28847071 TI - [Directed acyclic graphs: languages, rules and applications]. AB - Nearly all scientific studies explore causality, which will be met by directed acyclic graphs (DAGs). This paper systematically introduces graphic language, basic and interference rules of DAGs, and their applications into identifying research questions, understanding and undertaking research designs, guiding data analysis, classifying biases, etc. DAGs play key roles in causality studies. PMID- 28847072 TI - [Intestinal microbiota and progression of AIDS]. AB - Antiretroviral treatment has significantly reduced the mortality and morbidity of AIDS. However, recent studies have shown that when HIV viremia is successfully inhibited by antiretroviral treatment, intestinal immune disorders and secondary structural damage can still bring out microbial translocation which give rise to immune activation and the related inflammation will later lead to the progression of AIDS disease. Since intestinal microbiota is important for maintaining the function of the intestinal mucosal barrier, regulating innate immunity/acquired immunity and maintaining intestinal balance, studies on the relationship between changes in intestinal microbiota and the progression AIDS disease are of significantly theoretical value and practical meaning. This review focuses on the relationship between intestinal microbiota and the progressive AIDS, as well as the potential of application in treatment. PMID- 28847073 TI - Efficacy of the Over-the-Scope Clip System for Treatment of Gastrointestinal Fistulas, Leaks, and Perforations: A Korean Multi-Center Study. AB - BACKGROUND/AIMS: Currently, a new over-the-scope clip (OTSC) system has been introduced. This system has been used for gastrointestinal perforations and fistulas in other countries. The aim of our study is to examine the therapeutic success rate of endoscopic treatment using the OTSC system in Korea. METHODS: This was a multicenter prospective study. A total of seven endoscopists at seven centers performed this procedure. RESULTS: A total of 19 patients were included, with gastrointestinal leakages from anastomosis sites, fistulas, or esophageal perforations due to Boerhaave's syndrome. Among these, there were three gastrojejunostomy sites, three esophagojejunostomy sites, four esophagogastrostomy sites, one esophagocolonostomy site, one jejuno-jejunal site, two endoscopic full thickness resection site closures, one Boerhaave's syndrome, two esophago-bronchial fistulas, one gastrocolonic fistula, and one colonopseudocyst fistula. The size of the leakage ranged from 5 to 30 mm. The median procedure time was 16 min. All cases were technically successful. Complete closure of the leak was achieved in 14 of 19 patients using OTSC alone. CONCLUSIONS: The OTSC system is a safe and effective method for the management of gastrointestinal leakage, especially in cases of anastomotic leakage after surgery. PMID- 28847074 TI - Different organic loading rates on the biogas production during the anaerobic digestion of rice straw: A pilot study. AB - The aim of this work was to investigate the mesophilic methane fermentation of rice straw at different organic loading rates (OLRs) in a 300m3 bioreactor. It was found that biogas production increased when the OLR was below 2.00kg VSsubstrate/(m3.d). The average volumetric biogas production reached 0.86m3/(m3.d) at an OLR of 2.00kg VSsubstrate/(m3.d). Biogas production rate was 323m3/t dry rice straw over the whole process. The pH, chemical oxygen demand, volatile fatty acid, and NH4+-N concentrations were all in optimal range at different OLRs. High-throughput sequencing analysis indicated that Firmicutes, Fibrobacteres, and Spirochaetes predominated in straw samples. Chloroflexi, Proteobacteria, and Planctomycetes were more abundant in the slurry. The hydrogenotrophic pathway was the main biochemical pathway of methanogenesis in the reactor. This study provides new information regarding the OLR and the differences in the spatial distribution of specific microbiota in a rice straw biogas plant. PMID- 28847075 TI - The performance and evolution of bacterial community of activated sludge exposed to trimethoprim in a sequencing batch reactor. AB - The performance and microbial community changes of an activated sludge sequencing batch reactor were evaluated after exposure to trimethoprim for 51days. The average chemical oxygen demand, ammonia nitrogen, phosphorus efficiencies were 88.6%+/-0.56%, 90.47%+/-0.29% and 64.25%+/-1.12%, respectively. The protein and polysaccharide contents increased with increasing trimethoprim concentration to protect the cells from the unfavorable conditions. The chemical composition of extracellular polymeric substances increased. For denitrifying bacteria, the read numbers of Pseudomonas, Flavobacterium and Bacillus were both significantly increased from Day 1 to 25 and sharply decreased by Day 50 (p<0.05), which is consistent with the tendency of Planctomyces (Anammox). The read number of Paracoccus displayed an increasing trend, whereas Nitrospirales, Nitrospira (nitrite oxidizer) and Nitrosomonadaceae (ammonia oxidizer) were significantly decreased (p<0.05). The read number of Rhodocyclaceae (phosphorus oxidizer) was significantly decreased from Day 1 to 25 and sharply increased by Day 50 (p<0.05). PMID- 28847076 TI - In-depth characterization of valuable char obtained from hydrothermal conversion of hazelnut shells to levulinic acid. AB - For the first time, the exploitation of hazelnut shells for the combined production of levulinic acid (LA) and hydrochar was investigated. The optimization of the catalytic hydrothermal treatment was performed both in autoclave and microwave reactor, approaching a maximum LA yield of ~9-12wt%. Hydrochars recovered with high yield (~43-47wt%) were characterized by different techniques, including elemental and proximate analysis, heating value, FT-IR, XPS, XRD, SEM-EDX, and SAA. Their "lignite-like" energetic properties make them suitable for the energy recovery within the same biorefinery plant for LA production, thus partially offsetting the cost of the entire process. Alternatively, since the synthesized hydrochars maintain high levels of oxygenated groups, they could be smartly exploited as natural sorbents for environmental applications. The proposed integrated approach makes possible to fully exploit this waste, smartly closing its biorefinery cycle in a sustainable development perspective. PMID- 28847077 TI - OrganoCat pretreatment of perennial plants: Synergies between a biogenic fractionation and valuable feedstocks. AB - A successful biorefinery needs to align suitable pretreatment with sustainable production of biomasses. Herein, four perennial plants, (Sida, Silphium, Miscanthus and Szarvasi) regarded as promising feedstocks for biorefineries were subjected to the OrganoCat pretreatment. The technology was successfully applied to the different perennial plants revealing that pretreatment of grasses was more efficient than of non-grasses. Thorough analyses of the lignocellulose - before and after fractionation - enabled a detailed description of the fate of cellulosic, non-cellulosic polysaccharides and lignin during the pretreatment. Especially Szarvasi pulp displayed outstanding results in terms of fractionation efficiency and enzymatic digestibility, though in all cases successful lignocellulose fractionation was observed. These insights into the structural composition of different perennial plant species and the impact of the OrganoCat pretreatment on the plant material leads to useful information to strategically adapt such processes to the individual lignocellulosic material aiming for a full valorisation. PMID- 28847078 TI - Enhanced nitrogen removal with spent mushroom compost in a sequencing batch reactor. AB - In order to remove nitrogen effectively from the wastewater with a low C/N ratio, the feasibility of using spent mushroom compost (SMC) hydrolysates as carbon sources for denitrification was investigated in a sequencing batch reactor (SBR). With SMCs supplement, the SBR performance was improved obviously within the 180days of operation. The total nitrogen removal was promoted from 46.9% to 81 89.4%, and no negative impact induced by different SMCs on the SBR system was observed. The abundance of functional genes including amoA, nirS/K, norB and nosZ in the active sludge was quantified by qPCR, and most of them elevated after SMC was fed. 16S rRNA gene high-throughput sequencing showed that the significant change in microbial community not only promoted pollutants removal but also benefited the stability of the reactor. Therefore, SMC could be an extremely promising carbon source used for nitrogen removal due to its cost-effective and efficient characteristics. PMID- 28847079 TI - Gentamicin degradation and changes in fungal diversity and physicochemical properties during composting of gentamicin production residue. AB - An indoor co-composting of gentamicin fermentation residues (GFR) and lovastatin fermentation residues (LFR) inoculated with gentamicin-degrading Aspergillus terreus FZC3 was conducted to remove gentamicin residues. The results showed that treatment MFZC3, consisting of a 10:1 blend of GFR and LFR (w/w), had the longest thermophilic phase (7days), quickest gentamicin degradation (t1/2=4.4days), and relatively higher gentamicin degradation percentage (96.7%) at the end of composting. Addition of Aspergillus terreus FZC3 affected fungal diversity of the compost and improved the removal of gentamicin during composting of the 15:1 GFR:LFR blend. By analyzing the variations of gentamicin and fungal community dynamics, it was speculated that Aspergillus terreus could accelerate gentamicin degradation. The microbial community and dynamic during composting were deeply affected by the physicochemical properties, and vice versa. In conclusion, co composting of GFR with LFR could be a promising technology to solve the problem of gentamicin residue in GFR waste. PMID- 28847080 TI - Improved performance of the microbial electrolysis desalination and chemical production cell with enlarged anode and high applied voltages. AB - The aim of this study was to improve performance of the microbial electrolysis desalination and chemical-production cell (MEDCC) using enlarged anode and high applied voltages. MEDCCs with anode lengths of 9 and 48cm (i.e., the 9cm-anode MEDCC and 48cm-anode MEDCC, respectively) were tested under different voltages (1.2-3.0V). Our results demonstrated for the first time that the MEDCC could maintain high performance even under the applied voltage higher than that for water dissociation (i.e., 1.8V). Under the applied voltage of 2.5V, the maximum current density in the 48cm-anode MEDCC reached 32.8+/-2.6A/m2, which is one of the highest current densities reported so far in the bioelectrochemical system (BES). The relative abundance of Geobacter was changed along the anode length. Our results show the great potential of the BES with enlarged anode and high applied voltages. PMID- 28847081 TI - Free nitrous acid-based nitrifying sludge treatment in a two-sludge system enhances nutrient removal from low-carbon wastewater. AB - A new method to enhance nutrient removal from low carbon-wastewater was developed. The method consists of a two-sludge system (i.e., an anaerobic-anoxic oxic reactor coupled to a nitrifying reactor (N-SBR)) and a nitrifying-sludge treatment unit using free nitrous acid (FNA). Initially, 65.1+/-2.9% in total nitrogen removal and 69.6+/-3.4% in phosphate removal were obtained without nitrite accumulation. When 1/16 of the nitrifying sludge was daily treated with FNA at 1.1mgN/L for 24h, ~28.5% of nitrite was accumulated in the N-SBR, and total nitrogen and phosphate removal increased to 72.4+/-3.2% and 76.7+/-2.9%, respectively. About 67.8% of nitrite was accumulated at 1.9mgN/L FNA, resulting in 82.9+/-3.8% in total nitrogen removal and 87.9+/-3.5% in phosphate removal. Fluorescence in-situ hybridization analysis showed that FNA treatment reduced the abundance of nitrite oxidizing bacteria (NOB), especially that of Nitrospira sp. PMID- 28847082 TI - Production of fumaric acid by immobilized Rhizopus arrhizus RH 7-13-9# on loofah fiber in a stirred-tank reactor. AB - Fumaric acid is an important building-block chemical. The production of fumaric acid by fermentation is possible. Loofah fiber is a natural, biodegradable, renewable polymer material with highly sophisticated and pore structure. This work investigated a new immobilization method using loofah fiber as carrier to produce fumaric acid in a stirred-tank reactor. Compared with other carriers, loofah fiber was proven to be efficiently and successfully used in the reactor. After the optimization process, 20g addition of loofah fiber and 400rpm agitation speed were chosen as the most suitable process conditions. 30.3g/L fumaric acid in the broth as well as 19.16g fumaric acid in the precipitation of solid was achieved, while the yield from glucose reached 0.211g/g. Three batches of fermentation using the same loofah fiber carrier were conducted successfully, which meant it provided a new method to produce fumaric acid in a stirred-tank reactor. PMID- 28847083 TI - New insights into comparison between synthetic and practical municipal wastewater in cake layer characteristic analysis of membrane bioreactor. AB - In previous studies, cake layer analysis in membrane bioreactor (MBR) was both carried out with synthetic and practical municipal wastewater (SMW and PMW), leading to different results. This study aimed to identify the comparison between SMW and PMW in cake layer characteristic analysis of MBR. Two laboratory-scale anoxic/oxic MBRs were operated for over 90days with SMW and PMW, respectively. Results showed that PMW led to rough cake layer surface with particles, and the aggravation of cake layer formation with thinner and denser cake layer. Additionally, inorganic components, especially Si and Al, in PMW accumulated into cake layer and strengthened the cake layer structure, inducing severer biofouling. However, SMW promoted bacterial metabolism during cake layer formation, thus aggravated the accumulation of organic components into cake layer. Therefore, SMW highlighted the organic components in cake layer, but weakened the inorganic functions in practical MBR operation. PMID- 28847084 TI - Choline chloride (ChCl) and monosodium glutamate (MSG)-based green solvents from optimized cactus malic acid for biomass delignification. AB - This work aimed to develop an efficient microwave-hydrothermal (MH) extraction of malic acid from abundant natural cactus as hydrogen bond donor (HBD) whereby the concentration was optimized using response surface methodology. The ideal process conditions were found to be at a solvent-to-feed ratio of 0.008, 120 degrees C and 20min with 1.0g of oxidant, H2O2. Next generation environment-friendly solvents, low transition temperature mixtures (LTTMs) were synthesized from cactus malic acid with choline chloride (ChCl) and monosodium glutamate (MSG) as hydrogen bond acceptors (HBAs). The hydrogen-bonding interactions between the starting materials were determined. The efficiency of the LTTMs in removing lignin from oil palm biomass residues, empty fruit bunch (EFB) was also evaluated. The removal of amorphous hemicellulose and lignin after the pretreatment process resulted in an enhanced digestibility and thermal degradability of biomass. PMID- 28847085 TI - Corn stover for biogas production: Effect of steam explosion pretreatment on the gas yields and on the biodegradation kinetics of the primary structural compounds. AB - This study evaluated the effect of steam explosion on the chemical composition and biomethane potential of corn stover using temperatures ranging between 140 and 220 degrees C and pretreatment times ranging between 2 and 15min. Biodegradation kinetics during the anaerobic digestion of untreated and corn stover, pretreated at two different intensities, 140 degrees C for 5min and 180 degrees C for 5min, were studied in tandem. Results showed that pretreatment at 160 degrees C for 2min improved the methane yield by 22%. Harsher pretreatment conditions led to lower hemicellulose contents and methane yields, as well as higher lignin contents, which may be due to the formation of pseudo-lignin. The biodegradation kinetics trial demonstrated that steam explosion enhances the degradation of structural carbohydrates and acid insoluble lignin. PMID- 28847086 TI - Adsorption of cellobiohydrolases I onto lignin fractions from dilute acid pretreated Broussonetia papyrifera. AB - Broussonetia papyrifera, known as paper mulberry, is a potential feed stock for bioethanol production because of its cellulose-rich composition. Lignin in dilute acid pretreated Broussonetia papyrifera was fractionated to three different fractions, and their physiochemical properties were determined by FT-IR, GPC and NMR analyses. Different structural characteristics were observed from each lignin fraction. Cellobiohydrolases I (CBH) adsorption to each lignin was understood by the lignin properties. The results showed that aliphatic hydroxyl groups in lignin showed positive correlations with the maximum binding ability of CBH onto lignin samples. Also, the contents of phenolic compounds such as p-hydroxyphenyl benzoate (PB), syringyl (S) and guaiacyl (G) units in the lignin influenced their CBH binding. PMID- 28847087 TI - Studies on influence of process parameters on hydrothermal catalytic liquefaction of microalgae (Chlorella vulgaris) biomass grown in wastewater. AB - In this study, liquefaction of Chlorella vulgaris biomass grown in photo bioreactor using wastewater as source of nutrition was studied and influence of process parameters on the yield of bio-oil was analysed. Different biomass to water ratio (5g/200ml, 10g/200ml, 15g/200ml, and 20g/200ml) was taken and bio-oil yield at various temperatures ranging from 220 to 340 degrees C was studied. Catalyst loading of the range 2.5-8%wt of NaOH was also studied to analyse the influence of catalyst concentration on bio-oil yield. Obtained bio-oil was characterized using Gas Chromatography Mass Spectroscopy (GC-MS) and Fourier Transform Infrared Spectroscopy (FTIR). Results showed that maximum bio-oil yield of 26.67%wt was observed at operating conditions of 300 degrees C, 15g/200ml biomass load and 2.5%wt of NaOH at 60min holding time. Fatty acids and other high carbon compounds were detected in the bio-oil obtained through liquefaction process. PMID- 28847088 TI - Degradation of lignin in birch sawdust treated by a novel Myrothecium verrucaria coupled with ultrasound assistance. AB - Combined treatment of a novel fungal endophyte Myrothecium verrucaria coupled with ultrasound assistance was conducted to enhance lignin degradation in birch sawdust. The optimum treatment conditions were confirmed as the materials to liquid ratio 1:20, temperature 30 degrees C, time 4days and pH 7, respectively. The results showed that the combined treatment led to the lignin degradation reaching 67.95+/-2.14%, while the lignin degradation were 45.50+/-2.12% and 13.75+/-0.66% with separate fungal treatment and ultrasound treatment, respectively. Moreover, SEM and FTIR analysis indicated that combined treatment significantly altered surface morphology and chemical structure of birch sawdust. The combined treatment greatly increased lignin removal during short time in mild environment. Therefore, these results demonstrated that the combined treatment of fungal endophyte coupled with ultrasound assistance has the high potential for the removal lignin in lignocellulose. PMID- 28847089 TI - A mathematical model to describe the fungal assisted algal flocculation process. AB - Fungal assisted algal harvesting is an attractive option for separating algae from bulk media. Although numerous studies have been reported in the recent time, no workable mathematical model has been developed for the same. In the present study, a mathematical model has been developed for fungal-assisted algal harvesting which shows that the process is not a second order process unlike other flocculation models. The process is also dependent on the radius of the algal cells and fungal pellets. Moreover, the flocculation process is affected by the velocity gradient of the system. The model was validated using different experiments viz. different fungal-algal ratio, variation in rpm, different algal strains, algae grown in different wastewaters and finally in a 10L photobioreactor. The proposed model is found to be in agreement with the experimental results along with r2>0.90 in most of the cases. PMID- 28847090 TI - Nitrate accumulation and leaching potential reduced by coupled water and nitrogen management in the Huang-Huai-Hai Plain. AB - Irrigation and nitrogen (N) fertilization in excess of crop requirements are responsible for substantial nitrate accumulation in the soil profile and contamination of groundwater by nitrate leaching during intensive agricultural production. In this on-farm field trial, we compared 16 different water and N treatments on nitrate accumulation and its distribution in the soil profile (0 180cm), nitrate leaching potential, and groundwater nitrate concentration within a summer-maize (Zea mays L.) and winter-wheat (Triticum aestivum L.) rotation system in the Huang-Huai-Hai Plain over five cropping cycles (2006-2010). The results indicated that nitrate remaining in the soil profile after crop harvest and nitrate concentration of soil solutions at two depths (80cm and 180cm) declined with increasing irrigation amounts and increased greatly with increasing N application rates, especially for seasonal N application rates higher than 190kgNha-1. During the experimental period, continuous torrential rainfall was the main cause for nitrate leaching beyond the root zone (180cm), which could pose potential risks for contamination of groundwater. Nitrate concentration of groundwater varied from 0.2 to 2.9mgL-1, which was lower than the limit of 10mgL 1 as the maximum safe level for drinking water. In view of the balance between grain production and environmental consequences, seasonal N application rates of 190kgNha-1 and 150kgNha-1 were recommended for winter wheat and summer maize, respectively. Irrigation to the field capacity of 0-40cm and 0-60cm soil depth could be appropriate for maize and wheat, respectively. Therefore, taking grain yields, mineral N accumulation in the soil profile, nitrate leaching potential, and groundwater quality into account, coupled water and N management could provide an opportunity to promote grain production while reducing negative environmental impacts in this region. PMID- 28847091 TI - Combined electrochemical, sunlight-induced oxidation and biological process for the treatment of chloride containing textile effluent. AB - This study presents a combined electrochemical, sunlight-induced oxidation and biological process for the treatment of textile effluent. In the first step, RuO2 TiO2/Ti and Titanium were used as the electrodes in EO process and color removal was achieved in 40 min at an applied current density of 20 mA cm-2. The EO process generated about 250 mg L-1 of active chlorine which hampered the subsequent biological treatment process. Thus, in the second step, sun light induced photolysis (SLIP) is explored to remove hypochlorite present in the EO treated effluent. In the third step, the SLIP treated effluent was fed to laccase positive bacterial consortium for biological process. To assess the effect of SLIP in the overall process, experiments were carried out with and without SLIP process. In experiments without SLIP, sodium thiosulfate was used to remove active chlorine. HPLC analysis showed that SLIP integrated experiments achieved an overall dye component degradation of 71%, where as only 22% degradation was achieved in the absence of SLIP process. The improvement in degradation with SLIP process is attributed to the presence of ClO radicals which detected by EPR analysis. The oxidation of organic molecules during process was confirmed by FT IR and GC-MS analysis. PMID- 28847092 TI - Development of a novel biochar/PSF mixed matrix membrane and study of key parameters in treatment of copper and lead contaminated water. AB - Mixed matrix membrane (MMM) has attracted increasing attentions in various applications, such as water treatment. In this study, an innovative biochar/polysulfone (PSF) mixed matrix hollow fiber membrane was fabricated by incorporating micro-sized biochar particles in the PSF matrix. It was demonstrated that the membrane was more hydrophilic than the pure PSF membrane. Higher water flux was obtained. The adsorption of copper and lead on the MMM increased as the pH was increased with the maximum adsorption capacity observed at pH > 4.5. The adsorption equilibrium was established in 7 and 12 h for lead and copper, respectively. The adsorption kinetics and isotherm followed the intraparticle surface diffusion model and Freundlich isotherm, respectively. The presence of humic acid (HA) had a little effect on the adsorption, while the ionic strength showed an adverse effect on the removal. In addition, the feed concentration and cross flow rate significantly affected the removal efficiency in a continuous filtration mode. The increase in feed concentration and cross flow rate resulted in a reduction in the volume of treated permeate that had the copper/lead concentrations below the regulated levels for drinking water. The MMM exhibited an excellent regeneration-reuse performance in the removal of both copper and lead. Finally, our mechanism studies indicated that the uptake of heavy metals was controlled by a combination of key reactions of complexation, ion-exchange and precipitation. This study indicated that the MMM can be applied as an effective and eco-friendly material for the treatment of heavy metals contaminated water. PMID- 28847093 TI - Effects of carbon source on methanogenic activities and pathways incorporating metagenomic analysis of microbial community. AB - In this study, the effects of four types of organic compounds (tryptone, acetate/propionate, glucose and ethanol) on methanogenesis, electron transfer processes and microbial community structure were examined. When tryptone and acetate/propionate were used, the dominant methanogenic pathway was aceticlastic methanogenesis and Methanosarcina was the most abundant methanogen. When glucose or ethanol were provided as the external carbon source, the aceticlastic and hydrogenotrophic pathways were utilised simultaneously, and Methanosarcina and Methanobacterium were enriched. However, the reactor fed with glucose was prone to acidification because volatile fatty acids accumulated in the medium, which inhibited methane synthesis. Geobacter was dominant in the reactor fed with ethanol and 45% of genes encoding pili synthesis were attributable to Geobacter, indicating that direct interspecies electron transfer may be a possible mechanism during syntrophic methanogenesis. PMID- 28847094 TI - Biological hydrolysis pretreatment on secondary sludge: Enhancement of anaerobic digestion and mechanism study. AB - The performance of biological hydrolysis (BH) pretreatment on municipal secondary sludge was evaluated in this study. During 6-day BH at 42 degrees C (BH42), soluble chemical oxygen demand (sCOD) increased from 175.2+/-38.2mg/L to 3314.5+/ 683.4mg/L; the dominant volatile fatty acid (VFA) was acetic acid, and its concentration increased from 41.5+/-2.1mg/L to 786.0+/-133.2mg/L. The extracted extracellular polymeric substances (EPS) from untreated secondary sludge contained three main fractions, and Fraction I gradually decreased from 133.9kDa to 24.9kDa during 6-day BH42. The BH pre-treatment at 42 degrees C and 55 degrees C both achieved more than 4-log reduction of total coliforms and 3-log reduction of E. coli. The BH pretreated secondary sludge at 15-day biochemical methane potential (BMP) test was comparable with the untreated secondary sludge after 30 day BMP, showing a significant enhancement on the acceleration of biogas production by BH pretreatment. PMID- 28847095 TI - Oil pollution in soils and sediments from the Northern Peruvian Amazon. AB - Oil has been extracted from the Northern Peruvian Amazon for over four decades. However, few scientific studies have assessed the impacts of such activities in the environment and health of indigenous communities in the region. We have investigated the occurrence of petrogenic hydrocarbon pollution in soils and sediments from areas favoured as hunting or fishing grounds by local indigenous inhabitants. The study was conducted in one of the most productive oil blocks in Peru, located in the headwaters of the Amazon river. Soils and river sediments, in the vicinity of oil extraction and processing infrastructure, contained an oil pollution signature as attested by the occurrence of hopanes and steranes. Given the lack of any other significant source of oil pollution in the region, the sources of hydrocarbons are likely to be the activities of the oil industry in the oil block, from voluntary discharges or accidental spills. Spillage of produced water was commonplace until 2009. Moreover, petrogenic compounds were absent in control samples in sites far removed from any oil infrastructure in the oil block. Our findings suggest that wildlife and indigenous populations in this region of the Amazon are exposed to the ingestion of oil polluted soils and sediments. The data obtained supports previous claims that the local spillage of oil and produced waters in the water courses in the Corrientes and Pastaza basins could have eventually reached the main water course of the Amazon. PMID- 28847096 TI - Evaluation of water quality during successive severe drought years within Microcystis blooms using fish embryo toxicity tests for the San Francisco Estuary, California. AB - In the San Francisco Estuary, California, the largest estuary on the Pacific Coast of North America, the frequency and intensity of drought and associated cyanobacteria blooms are predicted to increase with climate change. To assess the impact of water quality conditions on estuarine fish health during successive severe drought years with Microcystis blooms, we performed fish embryo toxicity testing with Delta Smelt and Medaka. Fish embryos were exposed to filtered ambient water collected from the San Francisco Estuary during the Microcystis bloom season in 2014 and 2015, the third and fourth most severe recorded drought years in California. Medaka embryos incubated in filtered ambient waters exhibited high mortality rates (>77%), which was mainly due to bacterial growth. Medaka mortality data was negatively correlated with chloride, and positively correlated with water temperature, total and dissolved organic carbon, and ambient and net chlorophyll a concentration. Delta Smelt embryo mortality rates were lower (<42%) and no prominent seasonal or geographic trend was observed. There was no significant correlation between the Delta Smelt mortality data and water quality parameters. Aeromonas was the dominant bacteria that adversely affected Medaka. The growth of Aeromonas was suppressed when salinity was greater than or equal to 1psu and resulted in a significant reduction in mortality rate. Bacterial growth test demonstrated that the lysate of Microcystis cells enhanced the growth of Aeromonas. Toxin production by Microcystis is a major environmental concern, however, we conclude that dissolved substances released from Microcystis blooms could result in water quality deterioration by promoting growth of bacteria. Furthermore, a distinctive developmental deformity was observed in Medaka during the toxicity tests; somite formation was inhibited at the same time that cardiogenesis occurred and the functional heart was observed to be beating. The exact cause of the embryonic developmental deformity is still unknown. PMID- 28847097 TI - A linear and non-linear polynomial neural network modeling of dissolved oxygen content in surface water: Inter- and extrapolation performance with inputs' significance analysis. AB - Accurate prediction of water quality parameters (WQPs) is an important task in the management of water resources. Artificial neural networks (ANNs) are frequently applied for dissolved oxygen (DO) prediction, but often only their interpolation performance is checked. The aims of this research, beside interpolation, were the determination of extrapolation performance of ANN model, which was developed for the prediction of DO content in the Danube River, and the assessment of relationship between the significance of inputs and prediction error in the presence of values which were of out of the range of training. The applied ANN is a polynomial neural network (PNN) which performs embedded selection of most important inputs during learning, and provides a model in the form of linear and non-linear polynomial functions, which can then be used for a detailed analysis of the significance of inputs. Available dataset that contained 1912 monitoring records for 17 water quality parameters was split into a "regular" subset that contains normally distributed and low variability data, and an "extreme" subset that contains monitoring records with outlier values. The results revealed that the non-linear PNN model has good interpolation performance (R2=0.82), but it was not robust in extrapolation (R2=0.63). The analysis of extrapolation results has shown that the prediction errors are correlated with the significance of inputs. Namely, the out-of-training range values of the inputs with low importance do not affect significantly the PNN model performance, but their influence can be biased by the presence of multi-outlier monitoring records. Subsequently, linear PNN models were successfully applied to study the effect of water quality parameters on DO content. It was observed that DO level is mostly affected by temperature, pH, biological oxygen demand (BOD) and phosphorus concentration, while in extreme conditions the importance of alkalinity and bicarbonates rises over pH and BOD. PMID- 28847098 TI - Life expectancy impacts due to heating energy utilization in China: Distribution, relations, and policy implications. AB - The relation between life expectancy and energy utilization is of particular concern. Different viewpoints concerned the health impacts of heating policy in China. However, it is still obscure that what kind of heating energy or what pattern of heating methods is the most related with the difference of life expectancies in China. The aim of this paper is to comprehensively investigate the spatial relations between life expectancy at birth (LEB) and different heating energy utilization in China by using spatial autocorrelation models including global spatial autocorrelation, local spatial autocorrelation and hot spot analysis. The results showed that: (1) Most of heating energy exhibit a distinct north-south difference, such as central heating supply, stalks and domestic coal. Whereas spatial distribution of domestic natural gas and electricity exhibited west-east differences. (2) Consumption of central heating, stalks and domestic coal show obvious spatial dependence. Whereas firewood, natural gas and electricity did not show significant spatial autocorrelation. It exhibited an extinct south-north difference of heat supply, stalks and domestic coal which were identified to show significant positive spatial autocorrelation. (3) Central heating, residential boilers and natural gas did not show any significant correlations with LEB. While, the utilization of domestic coal and biomass showed significant negative correlations with LEB, and household electricity shows positive correlations. The utilization of domestic coal in China showed a negative effect on LEB, rather than central heating. To improve the solid fuel stoves and control consumption of domestic coal consumption and other low quality solid fuel is imperative to improve the public health level in China in the future. PMID- 28847099 TI - Effect of ozonation on the characteristics of effluent organic matter fractions and subsequent associations with disinfection by-products formation. AB - Ozonation could be used in advanced wastewater treatment plants to reduce the precursors of disinfection by-products (DBPs), or for disinfection and oxidation of trace organic compounds. Detailed analysis of effluent organic matter (EfOM) is intrinsic to the understanding of impact of ozonation on the characterization variation of EfOM, which is closely related with DBPs formation during subsequent chlorination. In this study, the raw as well as oxidized EfOM with ozone were fractionated into hydrophobic acids, neutrals and bases, and hydrophilic acids, neutrals and bases. Results indicated that ozonation increased the proportion of hydrophilic fractions in EfOM, especially of hydrophilic acids, which resulted in increased specific haloacetic acids formation potential (HAAFP) in the subsequent chlorination. Although ozonation decreased the total organic carbon and SUVA254 of EfOM and most isolated fractions, further ozonation increased the SUVA of hydrophilic acids after the initial decrease. This was in accordance with the chemical structures analysis with FTIR, which showed the relative abundance of unsaturated structures such as CO bonds in hydrophilic fractions increased with further ozonation. Furthermore, specific trihalomethanes formation potential (THMFP) of each fraction decreased after initial pre-ozonation but increased with different extent with further ozonation. While for HAAs, pre-ozonation of hydrophilic acids significantly increased the dichloroacetic acid (DCAA) formation potential. In brief, EfOM containing a relatively high content of aromatic structures i.e. SUVA254 and aliphatic structures yielded a remarkably high specific DBPFP. Further mineralization of organic fractions and specific increased formation of aliphatic CH structures by further ozonation caused the increased DBPFPs especially DCAAFP during subsequent chlorination. PMID- 28847100 TI - Optimal siting of solid waste-to-value-added facilities through a GIS-based assessment. AB - Siting a solid waste conversion facility requires an assessment of solid waste availability as well as ensuring compliance with environmental, social, and economic factors. The main idea behind this study was to develop a methodology to locate suitable locations for waste conversion facilities considering waste availability as well as environmental and social constraints. A geographic information system (GIS) spatial analysis was used to identify the most suitable areas and to screen out unsuitable lands. The analytic hierarchy process (AHP) was used for a multi-criteria evaluation of relative preferences of different environmental and social factors. A case study was conducted for Alberta, a western province in Canada, by performing a province-wide waste availability assessment. The total available waste considered in this study was 4,077,514tonnes/year for 19 census divisions collected from 79 landfills. Finally, a location-allocation analysis was performed to determine suitable locations for 10 waste conversion facilities across the province. PMID- 28847101 TI - Effect of public transport strikes on air pollution levels in Barcelona (Spain). AB - Public transport strikes can lead to an increase of the number of private vehicle trips, which in turn can increase air pollution levels. We aimed to estimate the change in air pollution concentrations during public transport strikes in the city of Barcelona (Spain). Data on strikes of the metro, train or bus systems were collected from government records (2005-2016). We collected daily concentrations of NOx; particulate matter with an aerodynamic diameter smaller than 10MUm (PM10), 2.5MUm (PM2.5), and 1MUm (PM1); particle number concentration (N); black carbon (BC) and CO from research and official monitoring stations. We fitted linear regression models for each pollutant with the strike indicator as an independent variable, and models were adjusted for day of the week, month, year, and holiday periods. During the study period, there were 208days affected by a strike of the metro (28), train (106) or bus (91) systems. Half of the strikes were partial, most of them were single-day strikes, there was little overlap between strikes of the different transport systems, and all strikes had to comply with mandatory minimal services. When pooling all types of strikes, NOx and BC showed higher levels during strike days in comparison with non-strike days (increase between 4.1% and 7.7%, with higher increases for NO). The increases in these concentrations were more evident during full day and multiday metro strikes. In conclusion, alterations in public transport have consequences on air quality. This highlights the importance of public transport in reducing air pollution concentrations in cities. PMID- 28847102 TI - The effect of nanoparticles and humic acid on technology critical element concentrations in aqueous solutions with soil and sand. AB - As a consequence of their growing use in electronic and industrial products, increasing amounts of technology critical elements (TCEs) are being released to the environment. Currently little is known about the fate of many of these elements. Initial research on their potential environmental impact identifies TCEs as emerging contaminants. TCE movement in the environment is often governed by water systems. Research on "natural" waters so far demonstrates that TCEs tend to be associated with suspended particulate matter (SPM), which influences TCE aqueous concentrations (here: concentration of TCEs in dissolved form and attached to SPM) and transport. However, the relative potential of different types of SPM to interact with TCEs is unknown. Here we examine the potential of various types of particulate matter, namely different nanoparticles (NPs; Al2O3, SiO2, CeO2, ZnO, montmorillonite, Ag, Au and carbon dots) and humic acid (HA), to impact TCE aqueous concentrations in aqueous solutions with soil and sand, and thus influence TCE transport in soil-water environments. We show that a combination of NPs and HA, and not NPs or HA individually, increases the aqueous concentrations of TCEs in soil solutions, for all tested NPs regardless of their type. TCEs retained on SPM, however, settle with time. In solutions with sand, HA alone is as influential as NPs+HA in keeping TCEs in the aqueous phase. Among NPs, Ag-NPs and Au-NPs demonstrate the highest potential for TCE transport. These results suggest that in natural soil-water environments, once TCEs are retained by soil, their partitioning to the aqueous phase by through-flowing water is unlikely. However, if TCEs are introduced to soil-water environments as part of solutions rich in NPs and HA, it is likely that NP and HA combinations can increase TCE stability in the aqueous phase and prevent their retention on soil and sand, thus facilitating TCE transport. PMID- 28847103 TI - Assessing summertime urban warming and the cooling efficacy of adaptation strategy in the Chengdu-Chongqing metropolitan region of China. AB - Western China has experienced rapid urbanization since the Chinese reform process began in the late 1970s. It is essential to study the spatiotemporal patterns of warming induced by historical and future urban expansion and to evaluate adaptation strategies for the Chengdu-Chongqing metropolitan region (CCMR) in western China. The observed urban heat island intensity was ~1.5K in July 2009 2011. We employed the weather research and forecasting (WRF) model using real and projected urban land-use data to simulate near-surface air temperatures for a crop, urban in 2010 and urban in 2030 scenarios in summer over the CCMR. The difference between urban 2010 and cropland scenarios is 0.93K. Warming induced by urban development in 2010-2030 is in the range of 1-1.5K, but warming induced by future urban development will be less intense than historical warming over eastern China. We increased roof albedo to 0.8 to assess the difference in near surface air temperature between cool roofs (CR) and urban 2030 scenarios, which represents the maximum potential impact of CR; we also assessed the cooling caused by green roofs (GR) (i.e., the difference between the GR and urban 2030 scenarios). Greater cooling occurs during the day due to reflection of solar radiation by CR and additional water evaporation by GR. We provided an evaluation criterion, cooling efficiency (CE), to measure the local performances of CR and GR. CE represents the local cooling capability based on urban warming rather than absolute cooling over a larger spatial scale. CE reveals a lower nocturnal cooling capability, which poses a significant challenge to the applications of CR and GR at night. CR has a better cooling capability across CCMR than GR, only when roof albedo of CR exceeds 0.68. Measures enacted should be appropriately adjusted to optimize for cost, technology and energy savings. PMID- 28847104 TI - Multi-year prediction of estrogenicity in municipal wastewater effluents. AB - In this study, the estrogenicity of two major wastewater treatment plant (WWTP) effluents located in the central reaches of the Grand River watershed in southern Ontario was estimated using population demographics, excretion rates, and treatment plant-specific removals. Due to the lack of data on estrogen concentrations from direct measurements at WWTPs, the treatment efficiencies through the plants were estimated using the information obtained from an effects directed analysis. The results show that this approach could effectively estimate the estrogenicity of WWTP effluents, both before and after major infrastructure upgrades were made at the Kitchener WWTP. The model was then applied to several possible future scenarios including population growth and river low flow conditions. The scenario analyses showed that post-upgrade operation of the Kitchener WWTP will not release highly estrogenic effluent under the 2041 projected population increase (36%) or summer low flows. Similarly, the Waterloo WWTP treatment operation is also expected to improve once the upgrades have been fully implemented and is expected to effectively treat estrogens even under extreme scenarios of population growth and river flows. The developed model may be employed to support decision making on wastewater management strategies designed for environmental protection, especially on reducing the endocrine effects in fish exposed to WWTP effluents. PMID- 28847105 TI - Fire intensity drives post-fire temporal pattern of soil carbon accumulation in Australian fire-prone forests. AB - The impact of fire on global C cycles is considerable but complex. Nevertheless, studies on patterns of soil C accumulation following fires of differing intensity over time are lacking. Our study utilised 15 locations last burnt by prescribed fire (inferred low intensity) and 18 locations last burnt by wildfire (inferred high intensity), with time since fire (TSF) up to 43years, in a homogenous forest type in south eastern Australia. Following a stratified approach to mineral soil sampling, the soil % total C (% CTot) and % recalcitrant pyrogenic C (% RPC), were estimated. Generalised additive models indicated increases in % CTot at TSF >30years in sites last burnt by wildfire. Estimates in sites last subjected to prescribed fire however, remained constant across the TSF chronosequence. There was no significant difference in % CTot between the different fire types for the first 20years after fire. In the first 10years after wildfires, % RPC was elevated, declining to a minimum at ca. TSF 25years. After prescribed fires, % RPC was unaffected by TSF. Differences in response of % CTot and % RPC to fire type may reflect the strength of stimulation of early successional processes and extent of charring. The divergent response to fire type in % CTot was apparent at TSF longer than the landscape average fire return interval (i.e., 15 to 20years). Thus, any attempt to increase C sequestration in soils would require long-term exclusion of fire. Conversely, increased fire frequency is likely to have negligible impact on soil C stocks in these forests. Further investigation of the effects of fire frequency, fire intensity combinations and interaction of fire with other disturbances will enhance prediction of the likely impact of imposed or climatically induced changes to fire regimes on soil C. PMID- 28847106 TI - Bio-electrochemical reactors using AMI-7001S and CMI-7000S membranes as separators for silver recovery and power generation. AB - Bioelectrochemical reactors using AMI-7001S and CMI-7000S membranes were investigated for silver recovery and power generation. High silver removal (83.73 92.50%) and columbic efficiency (11.50-19.89%) were obtained in CMI-based reactor after 24h, although, some diffusion of Ag+ ions was observed. In contrast, substrate loss was found in AMI-based reactor, which caused low overall performance. At an initial Ag+ concentration 2000mg/L, a maximum power density of 5396mW/m3 and 3385mW/m3 were obtained in CMI and AMI-based reactor, respectively. Under SEM analysis, different morphologies of metallic silver deposits were detected on the cathode surfaces, and was confirmed by EDX and XRD technique. High diversity of anodic microbial communities were also found, in which Firmulates, Proteobacteria, and Bateroidetes were dominant phyla. Geobacter sp. and other exoelectrogens could be detected while no Shewanella-like sequences were retrieved. The study suggests that CMI-7000S showed better performance when compared to AMI-7001S at the same operational conditions. PMID- 28847107 TI - Polycyclic aromatic hydrocarbons on particulate matter emitted during the co generation of bioenergy and biochar from rice husk. AB - The aim of this study was to evaluate the emissions of polycyclic aromatic hydrocarbons (PAHs) bound to the particulate matter (PM) during the combustion of raw pyrolysis volatiles (bio-oil and pyrogas mixture) generated from the pyrolysis of rice husk. Five different raw pyrolysis volatiles were produced at varying pyrolysis temperatures (400-800 degrees C) and subsequently combusted in a laboratory-scale, continuous pyrolysis-combustion facility at 850 degrees C. 15 priority pollutant PAH levels in the resulting biochar, bio-oil, and PM were evaluated. Results showed that combustion of the raw pyrolysis volatiles produced at elevated pyrolysis temperatures resulted in greater concentrations of PM-bound PAHs (119% increase between 400 and 800 degrees C) due to the increased PAH and oxy-aromatic content of the bio-oil fraction. Significantly increased benzo(a)pyrene (BaP) - equivalent toxicity of the biochar and PM was observed at elevated pyrolysis temperatures. PMID- 28847108 TI - The volatilization of heavy metals during co-combustion of food waste and polyvinyl chloride in air and carbon dioxide/oxygen atmosphere. AB - The volatilization of three heavy metals (Cd, Cr and Zn) during food waste and PVC and their blending combustion in N2/O2 or CO2/O2 atmosphere in a lab-scale tubular furnace was investigated. The concentration of heavy metals in combustion ash was decreased with the increment of furnace temperature in most cases. The replacement of 80N2/20O2 by 80CO2/20O2 decreased the volatilization rate of Cd and Cr, but increased Zn. The increased amount of PVC added into food waste led to less content of Zn in combustion ash, 5% PVC added into food waste decreased the volatilization rate of Cr but 15% PVC added led to the higher volatilization. The volatilization rate of Zn in 70CO2/30O2 was significantly lower than in 85CO2/15O2 or 80CO2/20O2. The result contributes to the understanding of heavy metal volatilization during incineration and emission control of MSW oxy-fuel combustion. PMID- 28847109 TI - Microalgal-biochar immobilized complex: A novel efficient biosorbent for cadmium removal from aqueous solution. AB - The feasibility of the bioremediation of cadmium (Cd) using microalgal-biochar immobilized complex (MBIC) was investigated. Major operating parameters (e.g., pH, biosorbent dosage, initial Cd(II) concentration and microalgal-biochar ratio) were varied to compare the treatability of viable algae (Chlorella sp.), biochar and MBIC. The biosorption isotherms obtained by using algae or biochar were found to have satisfactory Langmuir predictions, while the best fitting adsorption isotherm model for MBIC was the Sips model. The maximum Cd(II) adsorption capacity of MBIC with a Chlorella sp.: biochar ratio of 2:3 (217.41mgg-1) was higher than that of Chlorella sp. (169.92mgg-1) or biochar (95.82mgg-1) alone. The pseudo-second-order model fitted the biosorption process of MBIC well (R2>0.999). Moreover, zeta potential, SEM and FTIR studies revealed that electrostatic attraction, ion exchange and surface complexation were the main mechanisms responsible for Cd removal when using MBIC. PMID- 28847110 TI - Improving methane production and anaerobic digestion stability of food waste by extracting lipids and mixing it with sewage sludge. AB - Anaerobic digestion (AD) of FW shows instability due to both the presence of high lipids and accumulation of volatile fatty acids. In this study, AD of food waste (FW) was optimized by removing lipids (LRFW) and by co-digestion with sewage sludge (1:1w/w on dry matter). The results obtained showed that lipids extraction increased FW methane yield from 400 to 418mL-gVSadded-1 under mesophilic conditions (35 degrees C) and from 426 to 531mL-gVSadded-1 in thermophilic conditions (55 degrees C). Two degradation phases (k1 and k2) described FW and LRFW degradation. In the thermophilic, LRFW-k1 (0.1591d-1) was slightly higher than that of FW (k1 of 0.1543d-1) and in the second stage FW-k2 of 0.0552d-1 was higher than that of LRFW (k2 of 0.0117d-1). The majority of LRFW was degraded in the first stage. FW and sewage sludge co-digestion reduced VFA accumulation, preventing media acidification and improving process stability. PMID- 28847111 TI - Rosette-Forming Glioneuronal Tumor Arising from the Spinal Cord. PMID- 28847112 TI - Predicting Shape, Location, and Course of Facial Nerve in Relation to Large Vestibular Schwannoma on Diffusion Tensor Imaging with Intraoperative Correlation: Important Surgical Adjunct. PMID- 28847113 TI - In Reply to "Predicting Shape, Location, and Course of Facial Nerve in Relation to Large Vestibular Schwannoma on Diffusion Tensor Imaging with Intraoperative Correlation: Important Surgical Adjunct". PMID- 28847114 TI - Single Stage Surgery Avoiding Cranioplasty at a Later Date Following Decompressive Hemicraniectomy. PMID- 28847115 TI - In Reply to "Intraocular Silicone Oil Migration into the Ventricles Resembling Intraventricular Hemorrhage: Case Report and Review of the Literature". PMID- 28847116 TI - Does Spinal Cord Line Influence Choice of Surgical Approach in Multilevel Cervical Spondylotic Myelopathy? PMID- 28847117 TI - In Reply to "Does Spinal Cord Line Influence Choice of Surgical Approach in Multilevel Cervical Spondylotic Myelopathy?" PMID- 28847118 TI - Small Stories: In Defense of the Humble Case Report. PMID- 28847119 TI - In Reply to "Small Stories: In Defense of the Humble Case Report". PMID- 28847120 TI - A Neurosurgical Stratagem: Doing the Same with Less? PMID- 28847121 TI - In Reply to "A Neurosurgical Stratagem: Doing the Same with Less?" PMID- 28847122 TI - Letter to the Editor Regarding "Prophylactic Antiepileptic Drug Use in Patients with Brain Tumors Undergoing Craniotomy". PMID- 28847123 TI - In Reply to the Letter to the Editor Regarding "Prophylactic Antiepileptic Drug Use in Patients with Brain Tumors Undergoing Craniotomy". PMID- 28847124 TI - Letter to the Editor Regarding "Effects of Oral Glibenclamide on Brain Contusion Volume and Functional Outcome of Patients with Moderate and Severe Traumatic Brain Injuries: A Randomized Double-Blind Placebo-Controlled Clinical Trial". PMID- 28847125 TI - In Reply to the Letter to the Editor Regarding "Effects of Oral Glibenclamide on Brain Contusion Volume and Functional Outcome of Patients with Moderate and Severe Traumatic Brain Injuries: A Randomized Double-Blind Placebo-Controlled Clinical Trial". PMID- 28847126 TI - Letter to the Editor Regarding "Safety and Efficacy of Noncompliant Balloon Angioplasty for the Treatment of Subarachnoid Hemorrhage-Induced Vasospasm: A Multicenter Study". PMID- 28847127 TI - In Reply to the Letter to the Editor Regarding "Safety and Efficacy of Noncompliant Balloon Angioplasty for the Treatment of Subarachnoid Hemorrhage Induced Vasospasm: A Multicenter Study". PMID- 28847128 TI - In Reply to "Indication of Surgical Management of Vestibular Schwannoma in the Older Age Group: Mysteries Still Unsolved". PMID- 28847129 TI - Postoperative Depression Following Spinal Fusion Surgery; Is There a Role for Elevated Serum Levels of Cobalt and Chromium? PMID- 28847130 TI - In Reply to "Postoperative Depression Following Spinal Fusion Surgery; Is There a Role for Elevated Serum Levels of Cobalt and Chromium?" PMID- 28847132 TI - Residential radon and cancer mortality in Galicia, Spain. AB - Residential radon exposure is a serious public health concern, and as such appears in the recommendations of European Code Against Cancer. The objective of this study was to assess the association between residential radon levels and mortality due to different types of cancer, using misaligned data analysis techniques. Mortality data (observed cases) for each of the 313 Galician municipalities were drawn from the records of the National Statistics Institute for the study period (1999-2008). Expected cases were computed using Galician mortality rates for 14 types of malignant tumors as reference, with a total of 56,385 deaths due to the tumors analyzed. The effect estimates of indoor radon (3371 sampling points) were adjusted for sociodemographic variables, altitude, and arsenic topsoil levels (1069 sampling points), using spatial/geostatistical models fitted with stochastic partial differential equations and integrated nested Laplace approximations. These models are capable of processing misaligned data. The results showed a statistical association between indoor radon and lung, stomach and brain cancer in women in Galicia. Apart from lung cancer (relative risk (RR)=1.09), in which a twofold increase in radon exposure led to a 9% rise in mortality, the association was particularly relevant in stomach (RR=1.17) and brain cancer (RR=1.28). Further analytical epidemiologic studies are needed to confirm these results, and an assessment should be made of the advisability of implementing interventions targeting such exposure in higher-risk areas. PMID- 28847133 TI - Physical properties of botanical surfactants. AB - Some vegetal species have saponins in their composition with great potential to be used as natural surfactants in organic crops. This work aims to evaluate some surfactants physical properties of Quillaja brasiliensis and Agave angustifolia, based on different methods of preparation and concentration. The vegetal samples were prepared by drying and grinding, frozen and after chopped or used fresh and chopped. The neutral bar soap was used as a positive control. The drying and grinding of samples were the preparation method that resulted in higher foam column height in both species but Q. brasiliensis was superior to A. angustifolia in all comparisons and foam index was 2756 and 1017 respectively. Critical micelle concentration of Q. brasiliensis was 0.39% with the superficial tension of 54.40mNm-1 while neutral bar soap was 0.15% with 34.96mNm-1. Aspects such as genetic characteristics of the species, environmental conditions, and analytical methods make it difficult to compare the results with other studies, but Q. brasiliensis powder has potential to be explored as a natural surfactant in organic farming. Not only the surfactants physical properties of botanical saponins should be taken into account but also its effect on insects and diseases control when decided using them. PMID- 28847134 TI - Brominated flame retardants in black plastic kitchen utensils: Concentrations and human exposure implications. AB - Concerns exist that restricted brominated flame retardants (BFRs) present in waste polymers may have, as a result of recycling, inadvertently contaminated items not required to meet flame retardancy regulations (e.g. plastic kitchen utensils). To investigate the extent to which kitchen utensils are contaminated with BFRs and the potential for resultant human exposure, we collected 96 plastic kitchen utensils and screened for Br content using a hand-held X-ray fluorescence (XRF) spectrometer. Only 3 out of 27 utensils purchased after 2011 contained detectable concentrations of Br (>=3MUg/g). In contrast, Br was detected in 31 out of the 69 utensils purchased before 2011. Eighteen utensils with Br content higher than 100MUg/g, and 12 new utensils were selected for GC-MS analysis of BFRs. BFRs targeted were polybrominated diphenyl ethers (PBDEs) BDE-28, 47, 99, 100, 153, 154, 183 and 209, and novel BFRs (NBFRs) pentabromoethylbenzene (PBEB), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB), 1,2-bis(2,4,6 tribromophenoxy)ethane (BTBPE), bis(2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate (BEH-TEBP) and decabromodiphenyl ethane (DBDPE). The ability of XRF to act as a surrogate metric of BFR concentration was indicated by a significant (Spearman coefficient=0.493; p=0.006) positive relationship between Br and SigmaBFR concentration. Measurements of SigmaBFRs were always exceeded by those of Br. This may be due partly to the presence of BFRs not targeted in our study and also to reduced extraction efficiency of BFRs from utensils. Of our target BFRs, BDE 209 was the most abundant one in most samples, but an extremely high concentration (1000MUg/g) of BTBPE was found in one utensil. Simulated cooking experiments were conducted to investigate BFR transfer from selected utensils (n=10) to hot cooking oil, with considerable transfer (20% on average) observed. Estimated median exposure via cooking with BFR contaminated utensils was 60ng/day for total BFRs. In contrast, estimated exposure via dermal contact with BFR containing kitchen utensils was minimal. PMID- 28847135 TI - The role of sorption processes in the removal of pharmaceuticals by fungal treatment of wastewater. AB - The contribution of the sorption processes in the elimination of pharmaceuticals (PhACs) during the fungal treatment of wastewater has been evaluated in this work. The sorption of four PhACs (carbamazepine, diclofenac, iopromide and venlafaxine) by 6 different fungi was first evaluated in batch experiments. Concentrations of PhACs in both liquid and solid (biomass) matrices from the fungal treatment were measured. Contribution of the sorption to the total removal of pollutants ranged between 3% and 13% in relation to the initial amount. The sorption of 47 PhACs in fungi was also evaluated in a fungal treatment performed in 26days in a continuous bioreactor treating wastewater from a veterinary hospital. PhACs levels measured in the fungal biomass were similar to those detected in conventional wastewater treatment (WWTP) sludge. This may suggest the necessity of manage fungal biomass as waste in the same manner that the WWTP sludge is managed. PMID- 28847136 TI - Sorption, transport and biodegradation - An insight into bioavailability of persistent organic pollutants in soil. AB - Contamination of soils with persistent organic pollutants (POPs), such as organochlorine pesticide, polybrominated diphenyl ethers, halohydrocarbon, polycyclic aromatic hydrocarbons (PAHs) is of increasing concern. Microbial degradation is potential mechanism for the removal of POPs, but it is often restricted by low bioavailability of POPs. Thus, it is important to enhance bioavailability of POPs in soil bioremediation. A series of reviews on bioavailability of POPs has been published in the past few years. However, bioavailability of POPs in relation to soil organic matter, minerals and soil microbes has been little studied. To fully understand POPs bioavailability in soil, research on interactions of POPs with soil components and microbial responses in bioavailability limitation conditions are needed. This review focuses on bioavailability mechanisms of POPs in terms of sorption, transport and microbial adaptation, which is particularly novel. In consideration of the significance of bioavailability, further studies should investigate the influence of various bioremediation strategies on POPs bioavailability. PMID- 28847137 TI - Determination of two progestin metabolites (17alpha-hydroxypregnanolone and pregnanediol) and different classes of steroids (androgens, estrogens, corticosteroids, progestins) in rivers and wastewaters by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). AB - A highly sensitive and robust method was developed for routine analysis of two progestin metabolites, 17alpha-hydroxypregnanolone (17OH-Delta5P) and pregnanediol (PD), and 31 other natural and synthetic steroids and related metabolites (estrogens, androgens, corticosteroids, progestins) in river water, as well as influents and effluents of municipal wastewater treatment plants (WWTP) using HPLC-MS/MS combined with solid-phase extraction. For the various matrixes considered, the optimized method showed satisfactory performance with recoveries of 70-120% for most of target steroids. The method detection limits (MDLs) ranged from 0.01 to 3ng/L for river water, 0.02 to 10ng/L for WWTP effluents, and 0.1 to 40ng/L for influents with good linearity and reproducibility. The developed method was successfully applied for the analysis of steroids in rivers and WWTP influent and effluents. WWTP influents concentrations of 17OH-Delta5P and PD were 51-256ng/L and up to 400ng/L, respectively, along with androstenedione (concentration range: 38-220ng/L), testosterone (11-26ng/L), estrone (2.3-37ng/L), 17beta-estradiol (N.D.-8.7ng/L), 17alpha-hydroxyprogesterone (N.D.-66ng/L), medroxyprogesterone acetate (N.D. 5.3ng/L), and progesterone (2.0-22ng/L), while only androstenedione (ADD), estrone (E1), and estriol (E3) were detected in effluent with concentrations ranging up to 1.7ng/L, 0.90ng/L and 0.8ng/L, respectively. In river water samples, only ADD and E1 were detected with concentrations up to 1.0ng/L and 0.91ng/L. Our procedure represents the first method for analyzing 17OH-Delta5P and PD in environmental samples along with a large series of steroids. PMID- 28847138 TI - Seasonal variation of macrolide resistance gene abundances in the South Fork Iowa River Watershed. AB - The Midwestern United States is dominated by agricultural production with high concentrations of swine, leading to application of swine manure onto lands with artificial subsurface drainage. Previous reports have indicated elevated levels of antibiotic resistance genes (ARGs) in surface water and groundwater around confined animal feeding operations which administer antimicrobials. While previous studies have examined the occurrence of ARGs around confined swine feeding operations, little information is known how their transport from tile drained fields receiving swine manure application impacts downstream environments. To further our knowledge in this area, water samples were collected from five locations in the agriculturally dominated South Fork Iowa River Watershed with approximately 840,000 swine present in the 76,000ha basin. Samples were collected monthly from three stream sites and two main artificial subsurface drainage outlets. Samples were analyzed for macrolide resistance genes ermB, ermF and 16S rRNAgene abundance using qPCR. Abundance of erm genes ranged from below limits of quantification to >107 copies 100mL-1 water. Eighty-nine percent of stream water samples contained one of these two ARGs. Results indicate significantly more ermB and ermF in main drainage outlets than stream samples when normalized by 16S rRNA abundance (p<0.0001). Both artificial drainage locations revealed temporal trends for ermB and ermF abundance when normalized to 16S rRNA abundance. The higher resistance gene concentrations identified in artificial drainage samples occurring mid-Spring and late-Fall are likely due to manure application. PMID- 28847139 TI - Swimming Three Ice Miles within Fifteen Hours. AB - Ice Mile swimming (1608 m in water of below 5 degrees Celsius) is becoming increasingly popular. Thiscase study aimed to identify body core temperature and selected haematological and biochemical parametersbefore and after repeated Ice Miles. An experienced ice swimmer completed three consecutive Ice Mileswithin 15 h. Swim times, body core temperatures, and selected urinary and haematological parameterswere recorded. Body core temperature reached its maximum between 5, 8 and 15 min after immersion(37.7 degrees C, 38.1 degrees C, and 38.0 degrees C, respectively). The swimmer suffered hypothermia during the first IceMile (35.4 degrees C) and body core temperature dropped furthermore to 34.5 degrees C during recovery after thefirst Ice Mile. He developed a metabolic acidosis in both the first and the last Ice Mile (pH 7.31 andpH 7.34, respectively). We observed hyperkalaemia ([K+] > 5.5 mM) after the second Ice Mile (6.9 mM).This was followed by a drop in [K+] to3.7 mM after the third Ice Mile. Anticipatory thermogenesis(i.e. an initial increase of body core temperature after immersion in ice cold water) seems to be aphysiological response in a trained athlete. The results suggest that swimming in ice-cold water leadsto a metabolic acidosis, which the swimmer compensates with hyperventilation (i.e. leading to respiratoryalkalosis). The shift of serum [K+] could increase the risk of a cardiac arrhythmia. Further studiesaddressing the physiology and potential risks of Ice Mile swimming are required to substantiate thisfinding. PMID- 28847140 TI - Effects of B Vitamins Overload on Plasma Insulin Level and Hydrogen Peroxide Generation in Rats. AB - It has been reported that nicotinamide-overload induces oxidative stress associated with insulinresistance, the key feature of type 2 diabetes mellitus (T2DM). This study aimed to investigate the effectsof B vitamins in T2DM. Glucose tolerance tests were carried out in adult Sprague-Dawley rats treatedwith or without cumulative doses of B vitamins. More specifically, insulin tolerance tests were alsocarried out in adult Sprague-Dawley rats treated with or without cumulative doses of Vitamin B3. Wefound that cumulative Vitamin B1 and Vitamin B3 administration significantly increased the plasmaH2O2 levels associated with high insulin levels. Only Vitamin B3 reduced muscular and hepatic glycogencontents. Cumulative administration of nicotinic acid, another form of Vitamin B3, also significantlyincreased plasma insulin level and H2O2 generation. Moreover, cumulative administration of nicotinicacid or nicotinamide impaired glucose metabolism. This study suggested that excess Vitamin B1 andVitamin B3 caused oxidative stress and insulin resistance. PMID- 28847141 TI - Na+/Ca2+ Exchanger 2 (NCX2) in the Circadian Clock of the Rat Suprachiasmatic Nucleus: Colocalization with Neuropeptides and Daily Profiles of Gene Expression and Protein Levels. AB - The plasmalemmal Na+/Ca2+ changer (NCX) regulates intracellular Ca2+ by exchanging 3 Na+ for1 Ca2+ in either the Ca2+ exit or Ca2+ entry mode. All three NCX isoforms NCX1, NCX2, and NCX3are expressed in the rat brain, with isoform specific differential distribution. In the central clock ofsuprachiasmatic nucleus (SCN), intracellular Ca2+ controls the circadian release of major neuropeptides,which are the arginine vasopressin (AVP), vasoactive intestinal peptide (VIP) and gastrin releasingpeptide (GRP), and the NCX, most likely NCX1, rapidly clears depolarization-induced somatic Ca2+influx. However, the role of NCX2 in the SCN remains unknown. This study aimed to investigate thecolocalization of NCX2 with neuropeptides and daily expression profiles of NCX2 in mRNA and proteinlevels. Consistent with the restricted distribution of NCX2 in the retinorecipient ventral SCN, theimmunostaining results showed colocalization of NCX2 with VIP, GRP and VIP/GRP in the ventralSCN, but not with AVP in the dorsal SCN, or markers for astrocyte and major input pathways.Importantly, the presynaptic marker Bassoon was found to colocalize with NCX2/GRP and NCX2/VIP, indicating localization of both VIP/NCX2 and GRP/NCX2 at the presynaptic sites. Furthermore,real-time PCR and western blotting revealed no day-night difference in NCX2 mRNA and protein levels,in contrast to a robust circadian rhythm in the expression of clock genes Per1 and Per2. Together theresults suggest a role of NCX2 in the regulation of the release of VIP and GRP. PMID- 28847142 TI - Stress as a Cause of Recurrent Aphthous Stomatitis and Its Correlation with Salivary Stress Markers. AB - Stress causes an increase in cortisol and amylase. Recurrent aphthous stomatitis (RAS) resultsdue to a multitude of causes, amongst which stress is one of the most important. Aim of the study wasto estimate the level of stress, serum cortisol, salivary cortisol, amylase and electrolytes in subjectswith RAS. 34 subjects with RAS (cases) were compared with 34 controls. Stress was measuredusing state trait anxiety inventory (STAI). Serum cortisol (Radioimmunoassay), Salivary cortisol,amylase (ELISA) and electrolytes (Flame photometry) were measured. Statistical analysis was doneusing SPSS 18.0 version software. The mean STAI scores were 48.71 +/- 4.6 in cases and 46.74 +/- 6.4 incontrols (P = 0.13). The mean salivary cortisol concentration was 3.35 +/- 1.8 ng/dl in cases and 3.65 +/- 2.5ng/dl in controls (P = 0.78). The mean salivary amylase was 155.09 +/- 116.1 U/ml in cases and 128.74+/- 86.3 U/ml in controls (P = 0.49). The salivary sodium (0.24 +/- 0.4 in both groups) and potassium (0.65+/- 0.5 in cases and 0.82 +/- 0.4 in controls; P = 0.07) was not different in the two groups (electrolytesin mEq/dl). No correlation was seen between the salivary stress markers and STAI scores. Thoughstress was higher in RAS group none of the measured parameters were different from the controlgroup. Stress may cause RAS but, in this study, there was no change in the salivary homeostasis. PMID- 28847143 TI - Description of Three Female 24-h Ultra-Endurance Race Winners in Various Weather Conditions and Disciplines. AB - A The incidence of exercise-associated hyponatremia (EAH) is higher in women than in men.We present three cases of a very mild post-race EAH in female winners of three 24-h ultra races invarious weather conditions and disciplines with post race plasma sodium [Na+] levels of 134 mM (Case1), 133 mM (Case 2) and 134 mM (Case 3). Moreover, Case 1 and Case 2 showed elevated creatinekinase concentrations of >10,000 U/l with an absence of renal function abnormality. The commoncharacteristics were female sex, veteran recreational category, long race experience in the particularsports discipline, excellent race performance, similar total weekly training hours and the presenceof luteal phase of the menstrual cycle during the race. Hematocrit and hemoglobin decreased andpost-race K+/Na+ ratio in urine increased in all three cases. In addition, an increased body mass anda decreased urine specific gravity and urine osmolality suggested over-drinking in Case 1. A decrease inthe glomerular filtration rate and creatine clearance accompanied by an increase in urine [Na+] maycontribute to fluid overload in Cases 2 and 3. Furthermore, urine osmolality reached a level indicatingantidiuretic hormone secretion in all the present cases. Therefore, we recommend that race medicalpersonnel should not forget to look for EAH even in fast and experienced female athletes and duringraces in different environmental conditions. PMID- 28847144 TI - Association of Activation of Induced COX-2, iNOS and Cytokines with NF-kappa B Depression by Taiwan Wild Grape Ethanolic Extract in Mice. AB - Taiwan wild grape (Vitis thunbergii var. taiwaniana; VTT) is an important traditional herbalmedicine used to treat muscle injuries and acute and chronic pain of the ligaments. Information onits bioactivity and the underlying mechanisms, which have not been elucidated thus far, is neededto demonstrate its value for pharmacological and clinical use. This study presents evidence to clarifythe antinociceptive and anti-inflammatory activities of an ethanolic extract of VTT stem (VTTEtOH)and the possible molecular mechanisms involved in such biactivities. In the mice, VTTEtOHsignificantly reduced the acetic acid induced writhing response (P < 0.01), formalin-induced lickingtime (P < 0.01), and edema paw volume at 4 and 5 h after lambda-carrageenan injection. VTTEtOH obviouslydecreased the levels of tumor necrosis factor alpha (P < 0.01), interleukin (IL)-1beta (P < 0.05),interleukin (IL)-6 (P < 0.001), nuclear factor kappa B (P < 0.001), iNOS (P < 0.001), cyclooxygenase-2 (P< 0.001) and Nitric oxide (P < 0.001) in edema-paw tissue. The molecular mechanisms underlying theseeffects might involve significant inhibition of the activity of cyclooxygenase-2 through suppression ofnuclear factor-kappa B and inducible nitric oxide synthase expression and reduction of the levels ofvarious inflammatory mediators, including tumor necrosis factor alpha, interleukin (IL) 1beta, IL-6,and nitric oxide. Our findings provided pharmacological and histopathological evidences that VTTEtOHalleviates inflammatory pain-related diseases. PMID- 28847145 TI - Magnetic resonance imaging of the intraluminal thrombus in abdominal aortic aneurysms. A quantitative and qualitative evaluation and correlation with growth rate. AB - BACKGROUND: The role of the intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) growth remains incompletely understood. MRI is superior to other methods in depicting the morphology of the ILT. This study brings preliminary, but novel information on the presence and morphological characteristics of the ILT and AAA growth rates in a screening cohort. METHODS: Cohort study with 46 patients from the Viborg Vascular trial(1). All underwent one non- contrast enhanced magnetic resonance imaging (MRI) at the end of follow-up. ILT presence was noted and, if present, it was allocated to one of four morphological categories based on visual appearance and signal intensity on T2 weighted images. RESULTS: The mean growth rate was 1.95 mm/year +/- 0.87 (SD). The observation time was 5.59 +/- 0.63 (SD) years. ILT was present in AAA size groups as follows: 30-34.9 mm 20.00%, 35-39.9 mm 88.89%, 40-44.9 mm 81.25%, 45-49.9 mm 100% and 50 54.9 mm 100%. Out of 46, 8 had no ILT at the time of MRI. The presence of any sort of ILT yielded a significantly increased unadjusted and an adjusted growth rate of 1.09 mm/year (95%CI: 0.48; 1.70) and 1.24 mm/year (95%CI: 0.64; 1.83), respectively. All four thrombus types were retrospectively associated with an increased recorded growth rate compared with "no thrombus". Presence of a thin circumferential thrombus was retrospectively associated with the highest increase in growth rate, viz. 2.09 mm/year (95%CI: 1.23; 2.95). CONCLUSIONS: We observed faster growth rate in those AAA that had developed an ILT. Even faster growth was observed amongst those AAA containing a thin ILT located along the inner circumference. PMID- 28847146 TI - On-X versus St Jude Medical Mechanical Prosthesis in mitral position: are we moving forward in design technology? AB - BACKGROUND: Continuous effort is still provided in designing optimal artificial heart valves with better hemodynamic function and reduced thromboembolic potential. The question is do we have moved forward toward this goal or not. METHODS: A prospective, randomized comparative study was done on 360 patients scheduled for elective mitral valve replacement. Patients were grouped into an On X group (N.=180), who received On-X mechanical valve, and a SJM group (N.=180), who received St Jude mechanical valve. Echocardiographic and clinical assessments were performed for all patients at 6 and 12 months follow-up period. RESULTS: Rheumatic heart disease was the most common cause of valve affection (94.2%). Early mortality was 6.4%. The mean follow-up time was 3.11+/-2.44 years. No structural or non-structural valvular dysfunction and no thromboembolism cases were encountered. Late valve thrombosis was1.9%/patient-year in On-X group and 2.1%/patient-year in SJM group. The mean EOA was higher in On-X group (2.0+/-0.3 cm2) than in SJM group (1.9+/-0.2 cm2), (P>=0.05). The mean EOAI was higher in On X group (1.1+/-0.1 cm2/m2) than in SJM group (1.0+/-0.1 cm2/m2), (P=0.034), especially significant in small valve size (25 mm) where it was 1.09+/-021 cm2/m2 in On-X group and 0.93+/-0.12 cm2/m2 in SJM group (P=0.02). CONCLUSIONS: On-X and St Jude prosthetic valves have a comparable hemodynamic performance in mitral position. However, On-X prosthesis might have a forward step on the way of design technology that may allow better function in terms of EOA and EOAI especially in smaller valve size. PMID- 28847148 TI - Rapid and Green Separation of Mono- and Diesters of Monochloropropanediols by Ultrahigh Performance Supercritical Fluid Chromatography-Mass Spectrometry Using Neat Carbon Dioxide as a Mobile Phase. AB - This study demonstrates the effect of column selectivity and density of supercritical carbon dioxide (SC-CO2) on the separation of monochloropropanediol (MCPD) esters, known as food toxicants, using SC-CO2 without addition of cosolvent in ultrahigh performance supercritical fluid chromatography-mass spectrometry (UHPSFC-MS). This study shows that over 20 2-monochloropropanediol (2-MCPD) and 3-monochloropropanediol (3-MCPD) mono- and diesters are separated on a 2-picolylamine column in less than 12 min. The presence and position of a hydroxyl group in the structure, the number of unsaturated bonds, and the acyl chain length play a significant role in the separation of MCPD esters. The flow rate, backpressure, and column oven temperature, which affect the density of the mobile phase, were shown to have a substantial impact on retention, efficiency, and selectivity. The developed method was successfully applied for the determination of MCPD esters in refined oils and showed a close to excellent green analysis score using the Analytical Eco-Scale. PMID- 28847149 TI - Surfactant-free Colloidal Particles with Specific Binding Affinity. AB - Colloidal particles with specific binding affinity are essential for in vivo and in vitro biosensing, targeted drug delivery, and micrometer-scale self-assembly. Key to these techniques are surface functionalizations that provide high affinities to specific target molecules. For stabilization in physiological environments, current particle coating methods rely on adsorbed surfactants. However, spontaneous desorption of these surfactants typically has an undesirable influence on lipid membranes. To address this issue and create particles for targeting molecules in lipid membranes, we present here a surfactant-free coating method that combines high binding affinity with stability at physiological conditions. After activating charge-stabilized polystyrene microparticles with EDC/Sulfo-NHS, we first coat the particles with a specific protein and subsequently covalently attach a dense layer of poly(ethyelene) glycol. This polymer layer provides colloidal stability at physiological conditions as well as antiadhesive properties, while the protein coating provides the specific affinity to the targeted molecule. We show that NeutrAvidin-functionalized particles bind specifically to biotinylated membranes and that Concanavalin A-functionalized particles bind specifically to the glycocortex of Dictyostelium discoideum cells. The affinity of the particles changes with protein density, which can be tuned during the coating procedure. The generic and surfactant-free coating method reported here transfers the high affinity and specificity of a protein onto colloidal polystyrene microparticles. PMID- 28847150 TI - Copper/Bisphosphine Catalysts in the Internally Borylative Aminoboration of Unactivated Terminal Alkenes with Bis(pinacolato)diboron. AB - Cu(I)/modified dppbz catalyst systems for the regioselective aminoboration of unactivated terminal alkenes have been developed. The bisphosphine-based Cu catalysis enables the introduction of the readily transformable Bpin group at the more congested internal position and shows better regioselectivity for broader terminal alkenes involving sterically demanding allylbenzenes, which are relatively challenging substrates in the previous IPrCuBr catalysis. Additionally, the second-generation catalyst systems accommodate the exo methylene-type disubstituted alkenes to deliver the corresponding aminoborated products in good yields with a high regioselectivity. PMID- 28847151 TI - Self-Organization Ability of Chiral Nalpha-Substituted, Nbeta-Boc Protected alpha Hydrazinoacetamides in the Crystal and Solution States. AB - The limitations of peptides have severely hampered their use in pharmacology, thus prompting the design of new peptidomimetic foldamers. This requires precise knowledge of the secondary structure of new compounds and the ability to predict their folding. Conformational studies of the basic units of these foldamers can be of invaluable assistance in designing new bioactive compounds. To this end, we investigated the conformation of three chiral Nalpha-substituted, Nbeta-Boc protected alpha-hydrazinoacetamide model compounds containing various side chains both on the Nalpha- and Calpha-atoms in both the crystal and solution states. On the basis of IR absorption spectroscopy, NMR, molecular dynamics calculations and X-ray diffraction experiments, we demonstrated that these three models adopt conformational preferences, relying on eight-, six- or five-membered H-bonded pseudocycles (C8, C6 or C5), depending on the steric bulk of both Nalpha- or Calpha-side chains. This study sheds light onto the versatile folding ability of the specific class of alpha-Nalpha-hydrazinopeptides and emphasizes the key role of the Calpha-side chain on the conformational preference of the folding. PMID- 28847152 TI - Renal function after off-pump versus on-pump coronary artery bypass grafting. AB - Background Renal dysfunction is a well-recognized major complication after coronary artery bypass grafting. Off-pump coronary artery bypass theoretically appears to have less impact on renal function. We estimated preoperative and postoperative creatinine clearance as a marker of renal dysfunction in patients undergoing off-pump and on-pump coronary artery bypass. Methods Thirty patients undergoing coronary artery bypass were randomly allocated to undergo either on pump ( n = 15) or off-pump surgery ( n = 15). The two groups had similar preoperative demographic characteristics. Serum creatinine and creatinine clearance were measured for 4 days postoperatively and the results were compared with preoperative levels. Results The rise in serum creatinine on postoperative day 1 was 0.28 mgcdL-1 in the on-pump group and 0.22 mgcdL-1 in the off-pump group ( p = 0.27); on postoperative day 4 it was 0.15 mgcdL-1 and 0.10 mgcdL-1, respectively, ( p = 0.28). Similarly, the fall in creatinine clearance was 17.34 mLcmin-1 in the on-pump group and 19.62 mLcmin-1 in the off-pump group on postoperative day 1 ( p = 0.42), and 10.9 and 10.94 mLcmin-1, respectively, on postoperative day 4 ( p = 0.64). Conclusion Renal function is not affected by the technique of coronary artery bypass surgery, whether with or without cardiopulmonary bypass, in spite of the theoretical advantage of off-pump surgery. Our study suggests that off-pump coronary artery bypass surgery does not confer significant protection from postoperative renal dysfunction in low-risk patients, when compared with on-pump surgery. PMID- 28847153 TI - FABP4 and Cardiovascular Events in Peripheral Arterial Disease. AB - Fatty acid-binding protein 4 (FABP4) is a possible biomarker of atherosclerosis. We evaluated FABP4 levels, for the first time, in patients with peripheral artery disease (PAD) and the possible association between baseline FABP4 levels and cardiovascular events over time. Patients (n = 327; mean age 69 +/- 10 years) with stable PAD were enrolled in this study. Serum FABP4 was measured by bead based multiplex assay. Cardiovascular events were analyzed by FABP4 tertiles using Kaplan-Meier and Cox regression analyses after 5 years. Serum FABP4 levels showed a significant association with the classical 3-point major adverse cardiovascular event (MACE) end point (including death, nonlethal myocardial infarction, or nonfatal stroke) in patients with PAD ( P = .038). A standard deviation increase of FABP4 resulted in a hazard ratio (HR) of 1.33 (95% confidence interval [95% CI]: 1.03-1.71) for MACE. This association increased (HR: 1.47, 95% CI: 1.03-1.71) after multivariable adjustment ( P = .020). Additionally, in multivariable linear regression analysis, FABP4 was linked to estimated glomerular filtration rate ( P < .001), gender ( P = .005), fasting triglycerides ( P = .048), and body mass index ( P < .001). Circulating FABP4 may be a useful additional biomarker to evaluate patients with stable PAD at risk of major cardiovascular complications. PMID- 28847154 TI - Sexual risk during initial months in US among Latina young adults. AB - Latina young adults are disproportionately at risk for sexually transmitted infections (e.g., HIV). However, little is known about social and cultural factors contributing to sexual health disparities among young adult Latina recent immigrants. The present study examined social and cultural factors contributing to sexual risk behaviors among 530 Latina women (ages 18-23) who immigrated to Miami-Dade County, Florida, approximately 12 months before assessment. At the cultural/macrosystemic level, participants who reported more sexual risk behaviors tended to (a) be less acculturated; (b) use less positive religious coping; (c) endorse to a greater extent the marianismo belief that Latinas should be the pillar of the family; and (d) endorse less of the marianismo belief that Latinas should be virtuous and chaste (i.e., abstain from premarital sex). As for individual-level factors, participants who reported more sexual risk behaviors also indicated (e) older age, (f) being married/partnered, (g) being employed, (h) living in the US longer, and (i) drinking more alcohol. Findings indicate areas for HIV/STI prevention for this underserved population. PMID- 28847155 TI - Clinical description of attack-related cognitive symptoms in migraine: A systematic review. AB - Introduction Cognitive symptoms have been described during migraine attacks since the Roman era; while being neglected throughout the centuries, they are relevant contributors to migraine-related disability. Objective To determine whether cognitive symptoms are included in clinical series describing migraine attack phenomenology, and which symptoms occur in each attack phase. Method Systematic review of existing data on clinical descriptions of migraine attacks, focusing on cognitive symptomatology. Data were organized and analyzed qualitatively, due to methodological differences between studies. Results Twenty-four articles were reviewed, with a total sample of 7007 patients, including 82.9% females with an average age of 39.2 years. Twenty one (75%) studies analyzed one phase of the attack (eight prodromes, five auras, one between aura and pain, three headaches and three postdromes), the remaining studied more than one phase. Cognitive complaints were the most frequent symptom of the prodromic (30%) and headache (38%) phases, while fatigue (70%) dominated the resolution phase. Not enough data is available to estimate the frequency of cognitive symptoms during the aura. Discussion Cognitive symptoms are described in all phases of the migraine attack phenomenology in published clinical series of migraine. Their characteristics appear to be different in each attack phase, although methodological limitations prevent generalization of this finding. PMID- 28847156 TI - HIV testing preferences among long distance truck drivers in Kenya: a discrete choice experiment. AB - Providing HIV testing services to truck drivers in Africa is crucial but has proven challenging. The introduction of HIV self-testing promises to provide expanded service delivery options for clients, potentially increasing demand for services and expanding coverage - especially important for high-risk and difficult-to-reach populations. This study examines the preferences regarding HIV testing service delivery models, among long distance truck drivers to identify testing services that would appeal to this population. Using a discrete choice experiment, this study examines the drivers of choice regarding HIV counselling and testing among 305 truck drivers recruited from two roadside wellness clinics along major trucking routes in Kenya. Participants made trade-offs between characteristics of HIV testing service delivery models by making hypothetical choices in a series of paired HIV testing scenarios. Conditional logit models were used to identify the HIV testing characteristics driving the selection of preferred scenarios, as well as determine whether preferences interact with individual characteristics - especially HIV testing history. Participants preferred free, provider-administered HIV testing at a roadside clinic, using a finger-prick test, with in-person counselling, undertaken in the shortest possible time. The strongest driver of choice was the cost of the test. Those who had never tested previously preferred oral testing and telephonic counselling, while those who were not regular testers favoured clinic based - over self testing. The results of this study indicate that for the majority of participants - most of whom had tested before - the existing services offered at roadside clinics were the preferred service delivery model. The introduction of oral self testing increases the options available to truck drivers and may even improve testing uptake for some, especially among those who have never tested before. However, these findings suggest the impact on HIV testing uptake of introducing oral self-testing may be limited in this population. PMID- 28847158 TI - Baseline fatty acids, food groups, a diet score and 50-year all-cause mortality rates. An ecological analysis of the Seven Countries Study. AB - OBJECTIVES: This analysis deals with the ecologic relationships of dietary fatty acids, food groups and the Mediterranean Adequacy Index (MAI, derived from 15 food groups) with 50-year all-cause mortality rates in 16 cohorts of the Seven Countries Study. MATERIAL AND METHODS: A dietary survey was conducted at baseline in cohorts subsamples including chemical analysis of food samples representing average consumptions. Ecologic correlations of dietary variables were computed across cohorts with 50-year all-cause mortality rates, where 97% of men had died. RESULTS: There was a 12-year average age at death population difference between extreme cohorts. In the 1960s the average population intake of saturated (S) and trans (T) fatty acids and hard fats was high in the northern European cohorts while monounsaturated (M), polyunsaturated (P) fatty acids and vegetable oils were high in the Mediterranean areas and total fat was low in Japan. The 50-year all-cause mortality rates correlated (r= -0.51 to -0.64) ecologically inversely with the ratios M/S, (M + P)/(S + T) and vegetable foods and the ratio hard fats/vegetable oils. Adjustment for high socio-economic status strengthened (r= 0.62 to -0.77) these associations including MAI diet score. CONCLUSION: The protective fatty acids and vegetable oils are indicators of the low risk traditional Mediterranean style diets. KEY MESSAGES We aimed at studying the ecologic relationships of dietary fatty acids, food groups and the Mediterranean Adequacy Index (MAI, derived from 15 food groups) with 50-year all-cause mortality rates in the Seven Countries Study. The 50-year all-cause mortality rates correlated (r = -0.51 to -0.64) ecologically inversely with the ratios M/S [monounsaturated (M) + polyunsaturated (P)]/[saturated (S) + trans (T)] fatty acids and vegetable foods and the ratio hard fats/vegetable oils. After adjustment for high socio-economic status, associations with the ratios strengthened (r = -0.62 to -0.77) including also the MAI diet score. The protective fatty acids and vegetable oils are indicators of the low risk traditional Mediterranean style diets. PMID- 28847157 TI - Bacterial Heme-Based Sensors of Nitric Oxide. AB - SIGNIFICANCE: The molecule nitric oxide (NO) has been shown to regulate behaviors in bacteria, including biofilm formation. NO detection and signaling in bacteria is typically mediated by hemoproteins such as the bis-(3',5')-cyclic dimeric adenosine monophosphate-specific phosphodiesterase YybT, the transcriptional regulator dissimilative nitrate respiration regulator, or heme-NO/oxygen binding (H-NOX) domains. H-NOX domains are well-characterized primary NO sensors that are capable of detecting nanomolar NO and influencing downstream signal transduction in many bacterial species. However, many bacteria, including the human pathogen Pseudomonas aeruginosa, respond to nanomolar concentrations of NO but do not contain an annotated H-NOX domain, indicating the existence of an additional nanomolar NO-sensing protein (NosP). Recent Advances: A newly discovered bacterial hemoprotein called NosP may also act as a primary NO sensor in bacteria, in addition to, or in place of, H-NOX. NosP was first described as a regulator of a histidine kinase signal transduction pathway that is involved in biofilm formation in P. aeruginosa. CRITICAL ISSUES: The molecular details of NO signaling in bacteria are still poorly understood. There are still many bacteria that are NO responsive but do encode either H-NOX or NosP domains in their genomes. Even among bacteria that encode H-NOX or NosP, many questions remain. FUTURE DIRECTIONS: The molecular mechanisms of NO regulation in many bacteria remain to be established. Future studies are required to gain knowledge about the mechanism of NosP signaling. Advancements on structural and molecular understanding of heme-based sensors in bacteria could lead to strategies to alleviate or control bacterial biofilm formation or persistent biofilm-related infections. PMID- 28847159 TI - Twenty-Five Years of Gene Therapy for ADA-SCID: From Bubble Babies to an Approved Drug. AB - Twenty-five years have passed since first attempts of gene therapy (GT) in children affected by severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) defect, also known by the general public as bubble babies. ADA SCID is fatal early in life if untreated. Unconditioned hematopoietic stem cell (HSC) transplant from matched sibling donor represents a curative treatment but is available for few patients. Enzyme replacement therapy can be life-saving, but its chronic use has many drawbacks. This review summarizes the history of ADA SCID GT over the last 25 years, starting from first pioneering studies in the early 1990s using gamma-retroviral vectors, based on multiple infusions of genetically corrected autologous peripheral blood lymphocytes. HSC represented the ideal target for gene correction to guarantee production of engineered multi lineage progeny, but it required a decade to achieve therapeutic benefit with this approach. Introduction of low-intensity conditioning represented a crucial step in achieving stable gene-corrected HSC engraftment and therapeutic levels of ADA-expressing cells. Recent clinical trials demonstrated that gamma-retroviral GT for ADA-SCID has a favorable safety profile and is effective in restoring normal purine metabolism and immune functions in patients >13 years after treatment. No abnormal clonal proliferation or leukemia development have been observed in >40 patients treated experimentally in five different centers worldwide. In 2016, the medicinal product StrimvelisTM received marketing approval in Europe for patients affected by ADA-SCID without a suitable human leukocyte antigen-matched related donor. Positive safety and efficacy results have been obtained in GT clinical trials using lentiviral vectors encoding ADA. The results obtained in last 25 years in ADA-SCID GT development fundamentally contributed to improve patients' prognosis, together with earlier diagnosis thanks to newborn screening. These advances open the way to further clinical development of GT as treatment for broader applications, from inherited diseases to cancer. PMID- 28847160 TI - Beyond drug-drug interactions: effects of transporter inhibition on endobiotics, nutrients and toxins. AB - INTRODUCTION: Membrane transport proteins play a central role in regulating the disposition of endobiotics, dietary nutrients and environmental toxins. The inhibition of transporters by drugs has potential physiologic consequences. The full extent of the effect of drugs on the function of transporters is poorly understood because only a small subset of the hundreds of transporters expressed in humans - primarily those mediating the rate-determining step in the elimination of specific drugs - are assessed during clinical development. Areas covered: We provide a comprehensive overview of literature reports implicating the inhibition of transporters as the mechanism for off-target effects of drugs. Expert opinion: Transporter inhibition, the mechanism of action of many marketed drugs, appears to play an underappreciated role in a number of side effects including vitamin deficiency, edema, dyslipidemia, cholestasis and gout. Cell systems more broadly expressing transporter networks and methods like unbiased metabolomics should be incorporated into the screening paradigm to expand our understanding of the impact of drugs on the physiologic function of transporters and to allow for these effects to be taken into account in drug discovery and clinical practice. PMID- 28847163 TI - Relamorelin for the treatment of gastrointestinal motility disorders. AB - INTRODUCTION: Current treatments for gastroparesis are limited. Chronic idiopathic constipation (CIC) has more treatment options, but none are efficacious for severe cases. Areas covered: Molecular targets to accelerate GI motility are being identified, and relamorelin, a synthetic ghrelin analog, has been promising. In humans, relamorelin increases growth hormone levels and accelerates gastric emptying. Relamorelin was superior to placebo for symptom relief in phase IIA studies for diabetic gastroparesis (DG) and CIC. In phase IIB studies in DG, relamorelin did not significantly reduce vomiting frequency when compared to placebo, but it reduced four symptoms of DG (nausea, fullness, bloating and abdominal pain) and accelerated gastric emptying. To date, relamorelin has been well tolerated and safe in humans without cardiac or neurologic adverse effects. It is still in clinical trial stages and not yet approved by the Food and Drug Administration. Phase III studies are underway. Expert opinion: Relamorelin shows promise in treating DG, with a reduction in core symptoms. Relative to available treatments, it appears to be efficacious and well tolerated. The absence of neurological or cardiovascular adverse effects places it at an advantage over other available therapies. Once approved, it will likely become the drug of first choice for DG. PMID- 28847164 TI - Histological effects of fibrin glue and synthetic tissue glues on the spinal cord: are they safe to use? AB - INTRODUCTION: Fibrin glues such as Tisseel(r) have been established in neurosurgery for over thirty years. They are recommended for extradural use but have intradural applications. Brachial plexus reimplantation after trauma requires intradural fibrin glue because reimplanted nerves cannot be sutured to the spinal cord. Recently synthetic glues have become popular in spinal surgery but there is limited information about their safety. Our study compared the histological effects of Tisseel(r), Adherus(r) and BioGlue(r) on spinal cord using our rat brachial plexus repair model. MATERIALS & METHODS: Randomised observational animal study. Forty-one Sprague-Dawley rats divided in to control (n = 9), Tisseel(r) (n = 8), BioGlue(r) (n = 10) and Adherus(r) (n = 14) groups. Under general anaesthesia a posterior midline cervical incision was made and hemi laminectomies performed at C7 and T1. Dura was opened and T1 dorsal root transected and repositioned on the spinal cord. Two drops of Tisseel(r), BioGlue(r), Adherus(r) or no glue (control) were applied over the cut nerve and cord. At days 7, 14 and 28 rats were euthanized, processed and sections stained with Haematoxylin & Eosin and evaluated blind by a neuropathologist. RESULTS: Control and Tisseel(r) groups showed only mild focal inflammation in the cord. Adherus(r) and Bioglue(r) groups showed evidence of spinal cord inflammation and degeneration. All BioGlue(r) and Adherus(r) rats had evidence of distortion of the cord from the glue mass at all time points. Two BioGlue(r)-treated and one Adherus(r)-treated rat developed a hemiparesis. One BioGlue(r) rat developed hind limb paralysis. One BioGlue(r) rat failed to wake up at the end of the procedure. There were no complications in control and Tisseel(r) groups. CONCLUSION: Tisseel(r) caused a similar inflammatory response to control and may be used on spinal cord. BioGlue(r) and Adherus(r) should be applied thinly for a watertight dural closure but intradural use and contact with spinal tissue must be avoided. PMID- 28847161 TI - Short and Long Noncoding RNAs Regulate the Epigenetic Status of Cells. AB - SIGNIFICANCE: The concepts of junk DNA and transcriptional noise are long gone as the existence of noncoding RNAs (ncRNAs) has been tested extensively in recent years. Given that the epigenetic status of cells affects many biological processes, how ncRNAs mechanistically contribute to these processes is of great interest. Recent Advances: Recent studies show that various ncRNAs interact with epigenetic and/or transcription factors to modulate the epigenetic status of cells directly and/or indirectly. There exists growing interest in the field of cardiovascular research to understand the roles of ncRNAs. Due to the large number of ncRNAs in the mammalian genome, only a handful of ncRNAs have been functionally elucidated, which makes it difficult to understand how ncRNAs interact with protein-coding genes and their encoded proteins. CRITICAL ISSUES: Although the canonical function of microRNAs (miRNAs) to inhibit the translation of protein-coding genes is well established, the number of functionally annotated long noncoding RNAs (lncRNAs) is still small, which is especially true in the heart. FUTURE DIRECTIONS: Future studies must connect the epigenetic controls of various cellular phenomena by incorporating both miRNAs and lncRNAs. Antioxid. Redox Signal. 29, 832-845. PMID- 28847165 TI - Advanced nanomedicine for rheumatoid arthritis treatment: focus on active targeting. PMID- 28847166 TI - Myalgic encephalomyelitis/chronic fatigue syndrome patients' reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys. AB - Cognitive behavioural therapy and graded exercise therapy are promoted as evidence-based treatments for myalgic encephalomyelitis/chronic fatigue syndrome. This article explores patients' symptom responses following these treatments versus pacing therapy, an approach favoured by many sufferers. We analyse data from a large cross-sectional patient survey ( n = 1428) and compare our findings with those from comparable patient surveys ( n = 16,665), using a mix of descriptive statistics and regression analysis modelling. Findings from analysis of primary and secondary surveys suggest that cognitive behavioural therapy is of benefit to a small percentage of patients (8%-35%), graded exercise therapy brings about large negative responses in patients (54%-74%), while pacing is the most favoured treatment with the lowest negative response rate and the highest reported benefit (44%-82%). PMID- 28847167 TI - Automated Manufacturing of Potent CD20-Directed Chimeric Antigen Receptor T Cells for Clinical Use. AB - The clinical success of gene-engineered T cells expressing a chimeric antigen receptor (CAR), as manifested in several clinical trials for the treatment of B cell malignancies, warrants the development of a simple and robust manufacturing procedure capable of reducing to a minimum the challenges associated with its complexity. Conventional protocols comprise many open handling steps, are labor intensive, and are difficult to upscale for large numbers of patients. Furthermore, extensive training of personnel is required to avoid operator variations. An automated current Good Manufacturing Practice-compliant process has therefore been developed for the generation of gene-engineered T cells. Upon installation of the closed, single-use tubing set on the CliniMACS ProdigyTM, sterile welding of the starting cell product, and sterile connection of the required reagents, T cells are magnetically enriched, stimulated, transduced using lentiviral vectors, expanded, and formulated. Starting from healthy donor (HD) or lymphoma or melanoma patient material (PM), the robustness and reproducibility of the manufacturing of anti-CD20 specific CAR T cells were verified. Independent of the starting material, operator, or device, the process consistently yielded a therapeutic dose of highly viable CAR T cells. Interestingly, the formulated product obtained with PM was comparable to that of HD with respect to cell composition, phenotype, and function, even though the starting material differed significantly. Potent antitumor reactivity of the produced anti-CD20 CAR T cells was shown in vitro as well as in vivo. In summary, the automated T cell transduction process meets the requirements for clinical manufacturing that the authors intend to use in two separate clinical trials for the treatment of melanoma and B cell lymphoma. PMID- 28847168 TI - Medical management of chronic rhinosinusitis - a review of traditional and novel medical therapies. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is a commonly seen persistent inflammatory disease process affecting the paranasal sinuses with extensively reported economic implications. Despite an elusive pathophysiologic mechanism underlying this disease process, treatment outcomes are encouraging with the employment of an array of medical and surgical therapies. Areas covered: The goal of this paper is to provide a comprehensive, up to date analysis of the literature concerning the medical management of CRS by summarizing the evidence in support of traditional medical therapies for the management of CRS in addition to highlighting novel medical therapies currently under investigation. Expert opinion: The current staples of medical therapy for CRS based on the strength of available evidence include topical and oral corticosteroids, oral antibiotics and topical saline. The introduction of immunomodulatory therapies ('Biologics') for the treatment of CRS shows promise but have yet to be employed in a widespread fashion due to the need for additional research to better elucidate their role. PMID- 28847169 TI - Genetic Barcodes Facilitate Competitive Clonal Analyses In Vivo. AB - Monitoring the fate of individual cell clones is an important task to better understand normal tissue regeneration, for example after hematopoietic stem cell (HSC) transplantation, but also cancerogenesis. Based on their integration into the host cell's genome, retroviral vectors are commonly used to stably mark target cells and their progeny. The development of genetic barcoding techniques has opened new possibilities to determine clonal composition and dynamics in great detail. A modular genetic barcode was recently introduced consisting of 32 variable positions (BC32) with a customized backbone, and its advantages were demonstrated with regard to barcode calling and quantification. The study presented applied the BC32 system in a complex in vivo situation, namely to analyze clonal reconstitution dynamics for HSC grafts consisting of up to three cell populations with distinguishable barcodes using different alpha- and lentiviral vectors. In a competitive transplantation setup, it was possible to follow the differently marked cell populations within individual animals. This enabled the clonal contribution of the different BC32 constructs during reconstitution and long-term hematopoiesis in the peripheral blood and the spatial distribution in bone marrow and spleen to be identified. Thus, it was demonstrated that the system allows the output of individually marked cells to be tracked in vivo and their influence on clonal dynamics to be analyzed. Successful application of the BC32 system in a complex, competitive in vivo situation provided proof-of-principle that its high complexity and the large Hamming distance between individual barcodes, combined with the easy customization, facilitate efficient and precise quantification, even without prior knowledge of individual barcode sequences. Importantly, simultaneous high-sensitivity analyses of different cell populations in single animals may significantly reduce numbers of animals required to investigate specific scientific questions in accordance with RRR principles. It is concluded that this BC32 system will be excellently suited for various research applications in regenerative medicine and cancer biology. PMID- 28847170 TI - Becoming a health literate organization: Formative research results from healthcare organizations providing care for undeserved communities. AB - Background Integrating health literacy into primary care institutional policy and practice is critical to effective, patient centered health care. While attributes of health literate organizations have been proposed, approaches for strengthening them in healthcare systems with limited resources have not been fully detailed. Methods We conducted key informant interviews with individuals from 11 low resourced health care organizations serving uninsured, underinsured, and government-insured patients across Missouri. The qualitative inquiry explored concepts of impetus to transform, leadership commitment, engaging staff, alignment to organization wide goals, and integration of health literacy with current practices. Findings Several health care organizations reported carrying out health literacy related activities including implementing patient portals, selecting easy to read patient materials, offering community education and outreach programs, and improving discharge and medication distribution processes. The need for change presented itself through data or anecdotal staff experience. For any change to be undertaken, administrators and medical directors had to be supportive; most often a champion facilitated these changes in the organization. Staff and providers were often resistant to change and worried they would be saddled with additional work. Lack of time and funding were the most common barriers reported for integration and sustainability. To overcome these barriers, managers supported changes by working one on one with staff, seeking external funding, utilizing existing resources, planning for stepwise implementation, including members from all staff levels and clear communication. Conclusion Even though barriers exist, resource scarce clinical settings can successfully plan, implement, and sustain organizational changes to support health literacy. PMID- 28847171 TI - Quantification of Renal Stone Contrast with Ultrasound in Human Subjects. AB - PURPOSE: Greater visual contrast between calculi and tissue would improve ultrasound (US) imaging of urolithiasis and potentially expand clinical use. The color Doppler twinkling artifact has been suggested to provide enhanced contrast of stones compared with brightness mode (B-mode) imaging, but results are variable. This work provides the first quantitative measure of stone contrast in humans for B-mode and color Doppler mode, forming the basis to improve US for the detection of stones. MATERIALS AND METHODS: Using a research ultrasound system, B mode imaging was tuned for detecting stones by applying a single transmit angle and reduced signal compression. Stone twinkling with color Doppler was tuned by using low-frequency transmit pulses, longer pulse durations, and a high-pulse repetition frequency. Data were captured from 32 subjects, with 297 B-mode and Doppler images analyzed from 21 subjects exhibiting twinkling signals. The signal to clutter ratio (i.e., stone to background tissue) (SCR) was used to compare the contrast of a stone on B-mode with color Doppler, and the contrast between stone twinkling and blood-flow signals within the kidney. RESULTS: The stone was the brightest object in only 54% of B-mode images and 100% of Doppler images containing stone twinkling. On average, stones were isoechoic with the tissue clutter on B-mode (SCR = 0 dB). Stone twinkling averaged 37 times greater contrast than B-mode (16 dB, p < 0.0001) and 3.5 times greater contrast than blood-flow signals (5.5 dB, p = 0.088). CONCLUSIONS: This study provides the first quantitative measure of US stone to tissue contrast in humans. Stone twinkling contrast is significantly greater than the contrast of a stone on B mode. There was also a trend of stone twinkling signals having greater contrast than blood-flow signals in the kidney. Dedicated optimization of B-mode and color Doppler stone imaging could improve US detection of stones. PMID- 28847172 TI - The care of pregestational and gestational diabetes and drug metabolism considerations. AB - INTRODUCTION: Normal pregnancy development involves gradual decline in insulin sensitivity, which sometimes requires pharmacotherapy. Insulin is the drug of choice for gestational and pregestational diabetes. Metabolism of traditional insulins results in inadequate onset and duration of action and marked peak activity. These properties increase risk of excessive glucose excursions, which are especially undesirable during pregnancy. Insulin analogs have been emerging as a safer and more effective treatment of diabetes during pregnancy. Areas covered: This manuscript reviews currently used antihyperglycemic agents: fast and long-acting insulins, metformin and glyburide. Trials demonstrating their efficacy and safety during pregnancy are described. Certain drug metabolism considerations (e.g. affinity to IGF-1) are emphasized. Expert opinion: The theories that insulin analogs bind to immunoglobulin and cross placenta have been disproved. Lispro, aspart, glargine and detemir do not transfer across the placenta and do not result in adverse maternal and neonatal outcomes. In addition, favorable pharmacokinetic profiles (rapid onset and 24-hour near peakless activity) substantially reduce blood glucose variability including hypoglycemia. We believe that insulin analogs should be given strong consideration for the treatment of diabetes during pregnancy. Metformin has also proven to be safe and may be considered as an initial single agent for milder gestational diabetes. PMID- 28847173 TI - Ultrasound-guided microwave ablation in the treatment of benign thyroid nodules in 435 patients. AB - The objective of the present study was to investigate the effectiveness and safety of ultrasound-guided microwave ablation in the treatment of benign thyroid nodules. A total of 474 benign thyroid nodules in 435 patients who underwent ultrasound-guided microwave ablation from September 2012 to August 2015 were included. Nodule volume and thyroid function were measured before treatment and at 1, 3, 6, and 12 months and subsequently after every 6 months. The nodule volume reduction rate and changes of thyroid function were evaluated. The volume of all thyroid nodules significantly decreased after ultrasound-guided microwave ablation. The average volume was 13.07 +/- 0.95 ml before treatment, and 1.14 +/- 0.26 ml at 12-months follow-up. The mean volume reduction rate was 90% and the final volume reduction rate was 94%. The volume reduction rate of mainly cystic nodules was significantly higher than that of simple solid and mainly solid nodules (all P < 0.05). The pretreatment volume of nodules was positively correlated with the final volume reduction rate at final follow-up ( P = 0.004). No serious complications were observed after treatment. In conclusion, ultrasound guided microwave ablation is an effective and safe technique for treatment of benign thyroid nodules, and has the potential for clinical applications. Impact statement Ultrasound-guided MWA is an effective and safe technique for the treatment of benign thyroid nodules. It can significantly reduce the nodule volume, improve the patients' clinical symptoms, has less complication, guarantees quick recovery, meets patients' aesthetic needs, and shows less interference on the physiological and psychological aspects of the body. MWA should be a good complement to traditional open surgery and has potentials in clinical applications. PMID- 28847174 TI - [Measurement and health economic evaluation of informal care]. AB - Informal care is non-financed care outside the realm of formal healthcare, which represents an increasing challenge for aging societies. Informal care has frequently been neglected in health economic analyses, while in recent years its coverage has increased considerably in the international scientific literature. This review summarizes the methodology of the health-economic assessment of informal care, including the objective and subjective metrics of caregiver burden, its financial and non-financial valuation and practical applications, with special emphasis on the introduction of care-related quality of life instruments (e.g. Care Related Quality of Life - CarerQoL instrument). Care related quality of life is a different entity from health-related quality of life, the two cannot be combined, so their joint evaluation requires multi criteria decision analysis methods. Therefore, it is important to determine the societal preferences of care-related quality of life versus health-related quality of life, and map the relationship of care-related quality of life with time. The local validation of tools measuring care-related quality of life, its more widespread practical application and the analysis of its effect on decision making are also important part of the future research agenda. Orv Hetil. 2017; 158(35): 1363-1372. PMID- 28847176 TI - [Clinical features and therapeutic response of our anti-SRP positive patients with myositis]. AB - INTRODUCTION: Idiopathic inflammatory myopathies are a group of clinically heterogeneous diseases, which have been classified by myositis specific antibodies recently. The anti-SRP positive subset of this group is characterized by more severe clinical prognosis than other myositis specific antibody positive types. AIM: Our goal was to compare 16 anti-SRP positive patients in the Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen with 16 antibody negative ones. METHOD: Muscle strength validated in both groups by the manual muscle test proved to be significantly decreased both before and after therapy (chi2 = 0.006 and 0.019) in the anti-SRP positive group. RESULTS: Muscle-specific inflammatory laboratory parameters showed significant difference only in case of LDH-levels after therapy. Both groups showed good clinical response to first line steroid treatment, yet the significantly higher rate of second line administration suggests worse therapeutic response of the antibody positive group. CONCLUSION: Based on these facts we determined poor clinical prognosis and therapeutic response of the anti-SRP positive group. Orv Hetil. 2017; 158(35): 1382-1389. PMID- 28847177 TI - [Evaluation of anatomic and prognostic stages of breast cancer according to the 8th edition of the TNM staging system - Retrospective analysis based on data from deceased patients once diagnosed with breast cancer]. AB - INTRODUCTION: The 8th edition of the Tumor-Node-Metastasis (TNM) based staging of breast cancer introduces a prognostic stage influenced by biomarkers along the traditional T, N and M categories. AIM: To retrospectively assess stage influencing prognostic variables; and the anatomic and prognostic stages on the basis of the overall survival (OS) of a cohort of deceased patients once diagnosed with breast cancer. METHOD: We included patients with known causes of death certified at the Bacs-Kiskun County Teaching Hospital and having a history of breast cancer diagnosed on a resection specimen at the same institution. Prognostic factors were obtained from the histopathological reports. Statistics included one-way ANOVA, Dunn's post hoc test and Kaplan-Meier curve analyses. RESULTS: The 303 patients grouped as breast cancer related death (n = 168) or unrelated (n = 135) showed significant differences in most stage defining prognostic factors and the anatomic and prognostic stages. Significant differences in 5-year OS were observed between pT and pN categories, histological grades and estrogen receptor statuses. Except for stages I and II, significant differences were found between both different anatomic and prognostic stages (p<0.001). Stage IV is by definition uniform, but we identified survival differences between biomarker based subgroups: triple negative carcinomas had worse OS than estrogen receptor positive and HER2 negative carcinomas. CONCLUSIONS: Our analysis based on real survival data suggests that the prognostic stages separate patients according to OS similarly to the anatomic stages. The results validate the prognostic stages, but also suggest that separating stage IV disease according to biomarkers makes sense. Orv Hetil. 2017; 158(35): 1373-1381. PMID- 28847178 TI - [Analysis of telemetry, on-line and non-telemetry data for characterization of the physical activity of patients with heart failure]. AB - INTRODUCTION: Several studies have demonstrated that the prevalence of heart disease can be accounted for between 0.4 and 2% in developed countries. AIM: The present study aimed to use the PA% of the telemetry data to estimate the 6-minute walk test result. METHOD: A total of seventeen patients with heart disease; 3 females and 14 males; age: 57.35 yrs +/- 9.54; body mass 98.71 +/- 9.89 kg; average BMI 36.69 +/- 3.67 were recruited into the study. Using the two sets of values describing physical performance, linear regression was calculated providing a mathematical equation, thus, the Physical Activity % value is used to estimate the distance traveled over a 6-minute walk test. RESULTS: On further data analysis, we have come to the conclusion that the distance walked during the six-minute-long test may be measured by PA% from the data of CRT device. CONCLUSIONS: With our method, based on the values received from the physical activity sensor implanted into the resynchronisation devices, changes in patients' health status could be monitored telemetrically with the assistance from the implanted electronic device. Orv Hetil. 2017; 158(35): 1390-1395. PMID- 28847179 TI - Preclinical evaluation and molecular docking of 1,3-benzodioxole propargyl ether derivatives as novel inhibitor for combating the histone deacetylase enzyme in cancer. AB - Even after huge strides in medicine, cancer continues to be a formidable disease, which is slated to become the leading cause of death worldwide. The present study investigates the 1,3-benzodioxole and its propargyl ether derivatives as a novel histone deacetylase enzyme inhibitor in order to cure cancer, as aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Bioinformatics approaches were employed to carry out preclinical and pharmacological evaluations of designed benzodioxole derivatives. Furthermore, their interaction with HDAC-1 enzyme was studied through computational methods for their specific inhibitory effects and evaluated for their LD50 (oral rat acute toxicity) value. In addition to this work, three-dimensional (3D) structure of HDAC-1 enzyme was extracted and evaluated using various parameters including Ramachandran plot and molecular docking stimulation. In our study, we found that compound 7 and compound 9 have higher binding score than approved drugs (SAHA, TSA and VPA). Importantly, these compounds were found to possess good pharmacological and pharmacokinetic properties and can be considered as potent novel compound to combat the HDAC-1 enzyme to cure cancer. Compounds were also analyzed and validated with parameters like absorption, metabolism, excretion, toxicity and synthetic accessibility during the preclinical evaluation. This study paves way to search for novel and potent small chemical compounds for inhibiting HDAC-1 enzyme and in particular to combat the cancer progression by interrupting the cell cycle. PMID- 28847180 TI - Medical management for neurosurgical related seizures. AB - INTRODUCTION: Seizures or chronic epilepsy are a relatively common occurrence in a neurosurgical setting. However, seizure treatment after neurosurgery has received less attention compared with other causes and only few data are availaible in the literature on management in neurosurgical patients. Areas covered: This paper reviews the availaible data on the risk of seizures in patients undergoing neurosurgery and discusses the role of antiseizure therapy in the management of the postoperative period. Finally, some controversial issues on this topic are addressed. Expert opinion: Despite the studies so far published on this topic, there are still no guidelines for the clinical practice. International recommendations do not generally support the use of antiseizure drugs in postsurgical patients. Nevertheless, their use still remains wide in the routine practice. Initiation of a treatment should be considered when the risk for prolonged seizures or chronic epilepsy is high and the risk of toxicity is acceptable. First generation antiseizures drugs seem to be quite effective although new drugs are associated with lower adverse effects risk and better tolerability. PMID- 28847181 TI - Current and investigational non-dopaminergic agents for management of motor symptoms (including motor complications) in Parkinson's disease. AB - INTRODUCTION: Parkinson's disease is characterized by a heterogeneous combination of motor and non motor symptoms. The nigrostriatal dopamine deficit is one of its essential pathophysiologic features. Areas covered: This invited narrative review provides an overlook over current available and future promising non dopaminergic therapeutics to modulate altered dopaminergic neurotransmission in Parkinson's disease. Current research strategies aim to proof clinical efficacy by amelioration of motor symptoms and preponderant levodopa related movement fluctuations. These so-called motor complications are characterized by involuntary movements as a result of an overstimulation of the nigrostriatal dopaminergic system or by temporary recurrence of motor symptoms, when beneficial effects of dopamine substituting drugs vane. Expert opinion: Non dopaminergic modulation of dopamine replacement is currently mostly investigated in well defined and selected patients with motor complications to get approval. However, the world of daily maintenance of patients with its individually adapted, so called personalised, therapy will determine the real value of these therapeutics. Here the clinical experience of the treating neurologists and the courage to use unconventional drug combinations are essential preconditions for successful treatments of motor and associated non motor complications in cooperation with the patients and their care giving surroundings. PMID- 28847182 TI - Efficacy of antipsychotics for irritability and aggression in children: a meta analysis. AB - BACKGROUND: Aggression and irritability in children occur across a range of diagnoses, and are associated with both economic cost and negative psychosocial outcomes. Antipsychotics are frequently prescribed in these cases. METHODS: A random effects meta-analysis of 14 random controlled trials was conducted. Overall effect sizes for antipsychotics for irritability and aggression were extracted. Subgroup analyses were conducted according to diagnostic indication, specific medication and degree of sedation. Meta-regression examined effects of antipsychotic dose. RESULTS: Overall, antipsychotics were effective in reducing aggression and irritability (SMD = 0.74, 95% confidence interval [CI] 0.57-0.92, z = 8.4, p < 0.0001). In stratified subgroup analysis, individual antipsychotic agents did not differ in efficacy (chi2 = 1.1, df = 3, p = 0.78). However, aripiprazole and risperidone demonstrated significant benefit over placebo. Antipsychotic efficacy did not differ significantly based on diagnostic indication (chi2 = 4.2, df = 4, p = 0.39). Meta-regression showed no overall dose effect. CONCLUSIONS: Clinical data supports the efficacy of risperidone and aripiprazole for aggression and irritability across diagnoses, with insufficient data available for other agents. Available data does not support a difference in efficacy based on underlying diagnosis, choice of agent, or its degree of sedation. PMID- 28847183 TI - The impact of pain frequency, pain localization and perceived cause of pain on quality of life after cholecystectomy. AB - OBJECTIVE: Further research is needed to understand how pain frequency, localization of pain and the patient's conviction of the cause of pain effects long-term outcome after gallstone surgery. MATERIALS AND METHODS: A cohort study was conducted based on patients evaluated with SF-36 along with three single items focusing on gallstone specific symptoms. The physical component summary (PCS) and bodily pain (BP) of SF-36 were used as main outcome measures. To assess the improvement from the procedure, the differences between the preoperative and postoperative ratings were tested with univariate and multivariate logistic regression analysis. The ratings on the single-items regarding pain frequency, pain localization and patient's conviction of the cause of pain were used as predictors. In the multivariate analysis, adjustment was made for age, gender and approach. The study was approved by the Swedish Ethics Committee, Dnr 2015/115. RESULTS: The study group was based on 4021 patients who responded to the questionnaire SF-36 and the three gallstone specific items preoperatively. A total of 2216 (55.1%) patients also responded postoperatively. In multivariate logistic regression analysis the frequency of the pain attacks and the patient's conviction of the origin of pain significantly predicted postoperative pain as well as PCS of SF-36 (all p < .05). CONCLUSIONS: The preoperative frequency of pain attacks and the patient's conviction of the cause of pain can predict the outcome regarding PCS and the subscale BP of SF-36 with significantly better ratings in patients with a pain frequency exceeding once per month and in patients convinced of having pain related to gallstones. PMID- 28847184 TI - Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis. AB - BACKGROUND: Sorafenib remains the only standard first-line drug for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a very common side-effect in patients treated with sorafenib, and also affects the treatment schedule and quality of life. However, the association of HFSR and response of HCC to sorafenib remain unclear. METHODS: Databases including PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched up to May 7th, 2017. Review Manager 5.3 software was adopted for performing meta analyses, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofler software for further assessing outcomes obtained from meta-analyses. RESULTS: 1478 articles were reviewed, and 12 cohort studies with 1017 participants were included in the analyses. The pooled hazard ratio (HR) of overall survival is 0.45 (95% confidence interval (CI) 0.36, 0.55; P < 0.00001; I2 = 35%). The pooled HR of time to progression is 0.41 (95% CI 0.28, 0.60; P < 0.00001; I2 = 0%). Patients suffering HFSR had significantly better outcomes from sorafenib therapy than those without HFSR. CONCLUSIONS: The results indicate that HFSR is a beneficial indicator for HCC patients receiving sorafenib therapy. However, molecular mechanisms accounting for sorafenib-induced HFSR in HCC patients remain. PMID- 28847185 TI - Graduate medical education competencies for international health electives: A qualitative study. AB - BACKGROUND: Residency programs offer international health electives (IHEs), providing multiple educational benefits. This study aimed to identify how IHEs fulfill the Accreditation Council for Graduate Medical Education (ACGME) core competencies. METHODS: We conducted a thematic analysis of post-rotation reflective reports from residents who participated in IHEs through the Mayo International Health Program. We coded reports using a codebook created from the ACGME competencies. Using a constant comparative method, we identified significant themes within each competency. RESULTS: Residents from 40 specialties participated in 377 IHEs in 56 countries from 2001 to 2014. Multiple themes were identified within each of the six ACGME core competencies: Patient Care and Procedural Skills (4), Medical Knowledge (5), Practice-Based Learning and Improvement (3), Interpersonal and Communication Skills (5), Professionalism (4), and Systems-Based Practice and Improvement (3). Themes included improving physical exam and procedural skills, providing care in resource-limited setting, gaining knowledge of tropical and non-tropical diseases, identifying socioeconomic determinants of health, engaging in the education of others, and increasing communication across cultures and multidisciplinary teams. CONCLUSIONS: Through IHEs, residents advanced their knowledge, skills, and attitudes in each of the six ACGME competencies. These data can be used for development of IHE competencies and milestones for resident assessment. PMID- 28847186 TI - An update on medications and noninvasive brain stimulation to augment language rehabilitation in post-stroke aphasia. AB - INTRODUCTION: Aphasia is among the most debilitating outcomes of stroke. Aphasia is a language disorder occurring in 10-30% of stroke survivors. Speech and Language Therapy (SLT) is the gold standard, mainstay treatment for aphasia, but gains from SLT may be incomplete. Pharmaceutical and noninvasive brain stimulation (NIBS) techniques may augment the effectiveness of SLT. Areas covered: Herein reviewed are studies of the safety and efficacy of these adjunctive interventions for aphasia, including randomized placebo-controlled and open-label trials, as well as case series from Pubmed, using search terms 'pharmacological,' 'tDCS' or 'TMS' combined with 'aphasia' and 'stroke.' Expert commentary: Relatively small studies have included participants with a range of aphasia types and severities, using inconsistent interventions and outcome measures. Results to-date have provided promising, but weak to moderate evidence that medications and/or NIBS can augment the effects of SLT for improving language outcomes. We end with recommendations for future approaches to studying these interventions, with multicenter, double-blind, randomized controlled trials. PMID- 28847187 TI - Retrograde portal vein flow and transarterial chemoembolization in patients with hepatocellular carcinoma - a case-control study. AB - BACKGROUND AND AIMS: Transarterial chemoembolization (TACE) is the most common treatment for hepatocellular carcinoma (HCC). In case of portal vein (PV) flow diversion, outcome may be compromised due to a decompensation of hepatic perfusion following arterial embolization. The aim of this study was to determine whether TACE in patients with retrograde PV flow results in a stronger deterioration of liver function and a poorer survival compared to patients with orthograde PV flow. METHODS: A database of 606 patients treated with TACE between 2000 and 2015 at Hannover Medical School was screened for Doppler ultrasound (US) findings on PV flow prior to TACE. A total of 407 patients were identified, among which 32 patients had retrograde PV flow. RESULTS: Patients with retrograde PV flow had significantly more often liver cirrhosis with advanced hepatic dysfunction (93.5% vs. 72.7%, p < .05). Median overall survival (OS) was 12 and 19 months in patients with retro- and orthograde PV flow, respectively (HR 1.27, p > .05). Patients with retrograde PV flow showed a trend for a shorter OS when matched for cirrhosis (12 vs. 21months, HR 1.51), Child-Pugh score/albumin bilirubin grade (12 vs. 15 months). There was no difference in the deterioration of liver function after repeated treatments between both groups as assessed by increase of CP points and ALBI grade. CONCLUSIONS: Retrograde PV flow alone was not a significant prognostic marker, but patients with retrograde PV flow and advanced liver cirrhosis treated with TACE had a very short survival. Assessment of PV flow prior TACE may be helpful in borderline cases considered for TACE. PMID- 28847188 TI - Immediate evaluation and guidance of liver cancer thermal ablation by three dimensional ultrasound/contrast-enhanced ultrasound fusion imaging. AB - PURPOSE: To investigate the feasibility and value of three-dimensional ultrasound/contrast-enhanced ultrasound (3D US-CEUS) fusion imaging for the immediate evaluation of technical success and the guidance of supplementary ablation during the liver cancer thermal ablation procedure. MATERIALS AND METHODS: Patients diagnosed with malignant liver cancer intending to receive thermal ablation including radiofrequency ablation (RFA) or microwave ablation (MWA) were enrolled. 3D US-CEUS fusion imaging was used to immediately assess the technical success and guide supplementary ablation. Contrast-enhanced computed tomography/magnetic resonance imaging (CECT/CEMRI) was performed one month after ablation to assess the technique effectiveness of the ablation. The registration success rate, duration time of 3D US-CEUS fusion imaging, technique effectiveness rate and major complications were recorded. RESULTS: In total, 76 patients with 95 tumours who underwent RFA or MWA and assessed by 3D US-CEUS fusion imaging were enrolled. The registration success rate of 3D US-CEUS fusion imaging was 93.7% (89/95), and the duration time was 4.0 +/- 1.1 min. Thirty lesions received supplementary ablation immediately during the procedure. The technique effectiveness rate of the ablation was 98.8% (81/82). There were no major complications related to ablation. CONCLUSIONS: 3D US-CEUS fusion imaging is a feasible and valuable technique for the immediate evaluation and guidance of supplementary ablation during the liver cancer thermal ablation procedure. PMID- 28847189 TI - Does HERV-K represent a potential therapeutic target for prostate cancer? PMID- 28847190 TI - Low-dose CT protocols for guiding radiofrequency ablation for the treatment of small renal cell carcinomas. AB - OBJECTIVE: Computed tomography (CT)-guided radiofrequency ablation (RFA) results in a high radiation dose. This study aimed to assess low-dose CT protocols for guiding RFA and oncologic outcomes for the treatment of small renal cell carcinoma (RCC). MATERIALS AND METHODS: Between December 2011 and December 2014, CT-guided RFA was performed in 31 patients with 31 biopsy-proven RCCs (median, 2.1 cm). RFA included planning, targeting, monitoring and survey phases. The dose length product (DLP), CT dose index volume (CTDIvol), effective dose, number of scans, scan range, tube current and exposure time of RFA phases were compared. The 3-year recurrence-free survival rate was recorded. Nonparametric or parametric repeated-measures ANOVA with Dunn's or Tukey-Kramer multiple comparisons and Kaplan-Meier analysis were used for statistical analysis. RESULTS: The median total DLP, CTDIvol and effective dose of CT-guided RFA procedures per session were 1238.8 mGy (range 517.4-3391.7 mGy), 259.7 mGy (10.7 67.9 mGy) and 18.6 mSv (7.8-50.9 mSv), respectively. The median DLP, CTDIvol, effective dose, number of scans, tube current and exposure time during the targeting phase were higher than those during the other phases (p < 0.001). The scan range in the targeting phase was the same as that in the monitoring phase (p > 0.05) but smaller than those in the planning and survey phases (p < 0.001). The 3-year recurrence-free survival rate was 96.7%. CONCLUSIONS: Low-dose CT protocols for guiding RFA may reduce radiation dose without compromising oncologic outcomes. Reducing the number of scans during the targeting phase contributes to dose reduction. PMID- 28847191 TI - Managing multiple myeloma in elderly patients. AB - Multiple myeloma (MM) is a plasma cell neoplasm that affects elderly individuals with two-thirds of patients over 65 years at diagnosis. However, data available are derived from clinical trials conducted in younger patients. Fewer studies investigated treatment options in the elderly. This review summarizes the clinical outcomes and toxicities associated with therapeutic regimens in older patients including doublet, triplet and high dose therapyin newly diagnosed patients and relapsed patients with MM. We highlight the importance of an approach tailored to individuals, incorporates the geriatric frailty assessment, considers comorbiditiess and commits to early recognition and management of toxicities ranging from myelosuppression to polypharmacy. To date, no trial has prospectively investigated a tailored treatment paradigm in older patients based on frailty and/or comorbidities. As the population ages, the proportion of MM patients with advanced age will grow. Studies are indicated to determine optimal treatment approaches in this increasingly heterogeneous geriatric population. PMID- 28847192 TI - Maternal asthma: pregnancy course and outcome. AB - OBJECTIVE: To evaluate the association between maternal asthma and perinatal outcome. STUDY DESIGN: In this retrospective population-based cohort study, all pregnancies between 1991 and 2014 in a tertiary medical center, were included. Multiple pregnancies and congenital malformations were excluded. Pregnancy course and outcomes were compared between women with and without asthma, and multivariable generalized estimating equations were used to control for confounders. RESULTS: During the study period, 243,363 deliveries met the inclusion criteria, 1.35% of which (n = 3283) occurred in women diagnosed with asthma. Multiple perinatal complications were found to be associated with maternal asthma, including hypertensive disorders, preterm delivery, and cesarean delivery. However, no significant differences between the groups were noted in neonatal outcomes, including perinatal mortality rates and low Apgar scores. In the regression model, maternal asthma was noted as an independent risk factor for preterm delivery, hypertensive disorders of pregnancy, and cesarean delivery (aOR = 1.21, 95%CI 1.1-1.4, p = .007; aOR = 1.35, 95%CI 1.2-1.6, p < .001; and aOR = 1.27, 95%CI 1.2-1.4, p < .001, respectively) while controlling for multiple confounders. CONCLUSIONS: Maternal asthma is associated with an increased risk for adverse pregnancy outcome. This association remains significant while controlling for variables considered to coexist with maternal asthma. Nevertheless, perinatal outcome is generally favorable. PMID- 28847193 TI - Maternal exercise during pregnancy reduces the risk of preterm birth through the mediating role of placenta. AB - OBJECTIVE: The extent of research on maternal exercise during pregnancy and the risk of preterm birth (PTB) have grown substantially, but conclusions still remained controversial. Thus, this study aims to examine the relationship of maternal exercise during pregnancy and PTB and explore whether placenta mediates their relationship. STUDY DESIGN: We investigated 849 pregnant women delivering PTB newborns (cases) and 1306 delivering full-term appropriate for gestational age newborns (controls) in this case-control study. Information concerning maternal exercise during pregnancy, sociodemographics and obstetric characteristics were collected at Women and Children's Hospitals of Shenzhen and Foshan in Guangdong, China. A series of logistic and linear regressions were used to examine the relationships of maternal exercise during pregnancy, placenta, and PTB. RESULTS: After adjusting for the potential confounders, maternal exercise frequency and duration during pregnancy were negatively associated with PTB. Moreover, compared with mother taking no exercise during pregnancy, those taking exercise lowered the risk of PTB except those taking low/medium frequency and short duration exercise, and their adjusted ORs ranged from 0.43 to 0.65. Furthermore, mediation analysis illustrated that placental weight partially mediated 65.20% of the effects of maternal exercise frequency on PTB, as well as 41.98% of the association between maternal exercise duration and PTB. CONCLUSIONS: Maternal exercise during pregnancy is beneficial for lowering the risk of PTB, especially when taking appropriate and enough exercise. Placenta weight may partially mediate the association between maternal exercise during pregnancy and PTB. PMID- 28847194 TI - The safety and efficacy of microwave ablation for the treatment of CRC pulmonary metastases. AB - PURPOSE: Microwave ablation (MWA) is a recently developed thermal ablation technique that has been used for the treatment of different types of tumours. In the present study, we retrospectively evaluated the safety and efficacy of CT guided percutaneous MWA for the treatment of colorectal cancer (CRC) pulmonary metastases. MATERIALS AND METHODS: From June 2010 to June 2015, 48 unresectable lesions in 32 patients with CRC pulmonary metastases were subjected to CT-guided MWA. Imaging follow-up was with contrast-enhanced CT and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. RESULTS: Oncologic imaging showed that 42 (87.5%) of the 48 lesions in the 32 patients were completely ablated. Needle track metastatic seeding was not found, and no patient deaths occurred within 30 d after ablation. The mean hospital stay was 3 d (range, 2-7 d). Pneumothorax was the most frequent complication and occurred in 6 (12.5%) of the 48 lesions. The median survival time was 31 months (95% CI: 15.4-46.6). The 1-, 2 and 3-year survival rates were 79.5%, 63.1% and 44.4%, respectively. Univariate Cox regression analysis showed that tumour size, disease-free interval (DFI) and number of tumours were significantly related to the overall survival time (p = .007, p = .022 and p = .030, respectively). Multivariate analysis showed that tumour size was an independent prognostic factor for survival (p = .017). CONCLUSION: CT-guided percutaneous MWA is a safe and effective minimally invasive method for treating CRC pulmonary metastases. PMID- 28847195 TI - Chitosan microencapsulation of the dispersed phase of an O/W nanoemulsion to hydrochlorothiazide delivery. AB - In view of biopharmaceutical limitations of hydrochlorothiazide (HCTZ), Trojan type mucoadhesive systems were proposed, aiming to improve HCTZ pharmacological properties by modulating its release. Nanoemulsions were formed spontaneously by combining medium-chain triglycerides (Lipoid(r) S75 and Pluronic(r) F68) and high encapsulation efficiency was obtained. The mucoadhesive properties were provided by chitosan and microencapsulation of nanoemulsions in spray-dryer was successfully achieved by using Aerosil(r) as wall material. The rapid redispersion of nanoemulsion in simulated fluids led to a fast and complete release of HCTZ in gastric medium. The pharmacodynamics of HCTZ was improved, extending the diuretic activity. Once a simple and low-energy method contributed to obtain stable mucoadhesive nanoemulsions, advantages in terms of production could also be achieved, allowing easy scaling up. This novel mucoadhesive Trojan particulate system of HCTZ showed to be a promising approach to overcome limitations in terms of absorption and consequently improve the therapeutic efficacy. PMID- 28847196 TI - Consumption of fruits, vegetables, and risk of hematological malignancies: a systematic review and meta-analysis of prospective studies. AB - We examined the association between fruit/vegetable consumption and the risk of hematological malignancies in cohort studies (end of search: August 31, 2016). Total fruit consumption was not associated with the risk of non-Hodgkin lymphoma (NHL) (RR = 1.03, 95% CI: 0.92-1.16, I2 = 12.1%, n = 7), acute myeloid leukemia (RR = 1.23, 95% CI: 0.94-1.61, I2 = 0%, n = 3), multiple myeloma (MM; RR = 1.05, 95% CI: 0.72-1.55, I2 = 60.0%, n = 4), and Hodgkin lymphoma. However, citrus fruit consumption was associated with reduced NHL risk (RR = 0.85, 95% CI: 0.73 1.00, p = .044, I2 = 0%, n = 6). Vegetable intake was marginally associated with reduced NHL risk (RR = 0.89, 95% CI: 0.79-1.00, p = .056, I2 = 16.2%, n = 7), but not with acute myeloid leukemia, multiple myeloma, and Hodgkin lymphoma risk. Nevertheless, NHL risk was inversely associated with cruciferous vegetable consumption (RR = 0.84, 95% CI: 0.71-1.00, p = .047, I2 = 0%, n = 3). Notably, combined fruit/vegetable consumption was associated with decreased NHL risk (RR = 0.79, 95% CI: 0.65-0.96, I2 = 11.2%, n = 3). This meta-analysis reveals possible protective effects; however, confounding and reporting bias could have affected the results. PMID- 28847197 TI - Subcutaneous and intravenous belimumab in the treatment of systemic lupus erythematosus: a review of data on subcutaneous and intravenous administration. AB - INTRODUCTION: Loss of B cell tolerance is a hallmark feature of the pathogenesis of Systemic Lupus Erythematosus (SLE). Recent advances in B cell therapy have focused on targeted therapy aimed at inhibiting B cell activation and reducing B cell survival. Belimumab, a human monoclonal antibody against B cell activating factor (BAFF) was licensed in 2011 for the treatment of SLE. Areas covered: We review the data on the intravenous and subcutaneous formulations of belimumab in the management of patients with SLE. BLISS-52 and BLISS-76 demonstrated the efficacy of intravenous belimumab (10mg/kg) as an add-on therapy in SLE patients with active disease. A recent phase III trial of intravenous belimumab reported similar results in North East Asian patients. Subcutaneous belimumab (200mg/weekly) has demonstrated similar efficacy, safety and tolerability and was approved by the FDA in 2017 for the treatment of active autoantibody positive SLE patients receiving standard therapy. Expert commentary: Belimumab is generally safe and well tolerated. The most common clinical manifestations of SLE in the clinical trials were arthritis, mucocutaneous disease and serositis. Patients with severe lupus nephritis and central nervous system disease were excluded from these clinical trials. PMID- 28847198 TI - The effects of vitamin E supplementation on endometrial thickness, and gene expression of vascular endothelial growth factor and inflammatory cytokines among women with implantation failure. AB - OBJECTIVE: Data on the effects of vitamin E supplementation on endometrial thickness, and gene expression of vascular endothelial growth factor (VEGF) and inflammatory cytokines among women with implantation failure are limited. This research was performed to determine the effects of vitamin E supplementation on endometrial thickness, and gene expression of VEGF and inflammatory cytokines among women with implantation failure. METHODS: A randomized clinical trial was done among 40 women with implantation failure aged 18-37 years old. Participants were randomly divided into two groups: group A (n = 20) received 400-IU vitamin E supplements and group B (n = 20) received placebo for 12 weeks. Fasting blood samples were taken at baseline and after the 12-week treatment to determine biomarkers of oxidative stress, and gene expression of VEGF and inflammatory cytokines. RESULTS: After the 12-week intervention, compared with the placebo, women with implantation failure who consumed vitamin E supplements had significantly increased serum vitamin E levels (+18.6 +/- 15.0 versus -1.5 +/- 1.0 nmol/mL, p < .001) and endometrial thickness (+1.1 +/- 0.9 versus -0.5 +/- 0.3 mm, p = .01), and significantly decreased plasma malondialdehyde (MDA) concentrations (-0.4 +/- 0.3 versus +0.4 +/- 0.3 umol/L, p < .004). In addition, results of RT-PCR demonstrated that compared with the placebo, vitamin E intake downregulated gene expression of low-density lipoprotein receptor (LDLR) (p = .008), interleukin-1 (IL-1) (p = .02), and tumor necrosis factor alpha (TNF alpha) (p = .007) in peripheral blood mononuclear cells of women with implantation failure. CONCLUSIONS: Overall, vitamin E supplementation for 12 weeks among women with implantation failure had beneficial effects on endometrial thickness, MDA values, and gene expression of LDLR, IL-1, and TNF-alpha. PMID- 28847199 TI - The burden of familial chylomicronemia syndrome from the patients' perspective. AB - BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by high levels of plasma triglycerides and chylomicrons, which may cause life-threatening acute pancreatitis. Currently no FDA-approved treatment exists. Management is low-fat diet (<20g fat/day), which is difficult to maintain. With the restricted diet, triglycerides may remain elevated. We conducted discussions with patients and caregivers to better understand the burden of FCS from their perspectives. METHODS: A panel of FCS patients and caregivers was assembled to discuss and assess the clinical and psychosocial burden of FCS. RESULTS: Ten adults with FCS (median age 48 yr) and their spouses/caregivers were asked specific questions about their experiences living with FCS. Patients with FCS stated their symptoms were abdominal pain, nausea, diarrhea, constipation, bloating, and fatigue. Patients reported a median of 34 episodes of acute pancreatitis over their lifetimes; half of these led to hospitalizations, each with an average stay of 6.5 days. The psychosocial burden of FCS was primarily associated with the restricted diet, anxiety and stress of FCS. CONCLUSIONS: Living with FCS imposes a significant clinical and psychosocial burden on patients and caregivers, who reported reduced quality of life, limited employment opportunities, socialization and increased burden on family. PMID- 28847200 TI - Utility of selection methods for specialist medical training: A BEME (best evidence medical education) systematic review: BEME guide no. 45. AB - BACKGROUND: Selection into specialty training is a high-stakes and resource intensive process. While substantial literature exists on selection into medical schools, and there are individual studies in postgraduate settings, there seems to be paucity of evidence concerning selection systems and the utility of selection tools in postgraduate training environments. AIM: To explore, analyze and synthesize the evidence related to selection into postgraduate medical specialty training. METHOD: Core bibliographic databases including PubMed; Ovid Medline; Embase, CINAHL; ERIC and PsycINFO were searched, and a total of 2640 abstracts were retrieved. After removing duplicates and screening against the inclusion criteria, 202 full papers were coded, of which 116 were included. RESULTS: Gaps in underlying selection frameworks were illuminated. Frameworks defined by locally derived selection criteria, and heavily weighed on academic parameters seem to be giving way to the evidencing of competency-based selection approaches in some settings. Regarding selection tools, we found favorable psychometric evidence for multiple mini-interviews, situational judgment tests and clinical problem-solving tests, although the bulk of evidence was mostly limited to the United Kingdom. The evidence around the robustness of curriculum vitae, letters of recommendation and personal statements was equivocal. The findings on the predictors of past performance were limited to academic criteria with paucity of long-term evaluations. The evidence around nonacademic criteria was inadequate to make an informed judgment. CONCLUSIONS: While much has been gained in understanding the utility of individual selection methods, though the evidence around many of them is equivocal, the underlying theoretical and conceptual frameworks for designing holistic and equitable selection systems are yet to be developed. PMID- 28847201 TI - Pubertal Communication Between School Nurses and Adolescent Girls in Ile-Ife, Nigeria. AB - We examined information on pubertal changes provided by school nurses to adolescent girls, the methods, and media of communication. We also examined the challenges faced by the nurses in the course of communication. The study setting was five private high schools located in Ile-Ife, Nigeria. Participants were 10 school nurses and 420 school adolescent girls. Cross-sectional descriptive design was employed using quantitative and qualitative data collection methods. Results showed school nurses paid more attention to physical body changes, menarche, and menstrual hygiene as contents of pubertal communication rather than contraception, prevention of sexually transmitted infection, and teenage pregnancy prevention. Materials for communication were reportedly lacking in many of the schools while the school management censors pubertal information. Efforts should be tailored at equipping the school clinic with audiovisual aids and school nurses should be encouraged to give comprehensive pubertal education irrespective of their values and beliefs. PMID- 28847202 TI - Evidence-Based Practice and School Nurse Practice: A Review of Literature. AB - School nurses report that evidence-based practice (EBP) is not a part of their daily practice, and most have had no formal education regarding EBP or its implementation. The purpose of this review is to identify what strategies might be effective to educate school nurses about EBP as a first step toward establishing EBP in school nurse practice. Three scientific databases were searched, and eight pertinent manuscripts were identified. A review of the manuscripts indicates that EBP learners should be addressed in terms of the level of education needed (EBP "user" vs. "practitioner") and that a multifaceted approach to learning that addresses EBP knowledge, skill, and attitude is most effective. School nurse leaders and educators should work to provide learning opportunities to develop school nurses knowledge and skill using various learning modalities and delivery methods. EBP mentor relationships should be developed to bridge knowledge into practice. PMID- 28847203 TI - INTRODUCTORY NOTE FOR BGRS-2012 SPECIAL ISSUE. PMID- 28847204 TI - The Future of Tissue Engineering and Regenerative Medicine in Africa. PMID- 28847205 TI - Moderate, but not vigorous, intensity exercise training reduces C-reactive protein. AB - BACKGROUND: Sprint interval cycle training is a contemporary popular mode of training but its relative efficacy, under conditions of matched energy expenditure, to reduce risk factors for cardiometabolic disease is incompletely characterised, especially in young women. The purpose of this investigation was to determine the relative efficacy of six weeks of moderate-intensity cycling (MOD-C) and vigorous sprint-interval cycling (VIG-SIC) on lipid profile, insulin (INS) and insulin resistance using the homeostatic model assessment (HOMA-IR) and C-reactive protein (CRP) in inactive, overweight/obese (OW/OB) young women. METHODS: Participants (BMI >=25 kg/m2, waist circumference >=88 cm) were randomly assigned to MOD-C (20-30 min at 60-70% of heart rate reserve(HRR)) or VIG-SIC (5 7 repeated bouts 30-second maximal effort sprints, followed by four minutes of active recovery) supervised training three days/week for six weeks, with each group matched on energy expenditure. Adiposity (%Fat) was measured using dual x ray absorptiometry. RESULTS: Forty-four participants (20.4 +/- 1.6 years, 65.9% Caucasian, 29.8 +/- 4.1 kg/m2) were included in the analysis. The improvement in CRP observed in the MOD-C group was larger than the VIG-C group (p = .034). Overall, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) levels improved following training (p < .05); however, total cholesterol, triglyceride, INS and HOMA-IR did not improve (p > .05). CONCLUSION: These results indicate MOD-C training may be more effective in reducing CRP than VIG SIC. PMID- 28847208 TI - Gap analysis of service needs for adults with neurodevelopmental disorders. AB - In Florida, the Agency for Persons with Disabilities provides waivers for adults with the following types of disabilities: intellectual disability, autism spectrum disorder, cerebral palsy, spina bifida, Down syndrome, and Prader-Willi syndrome. This review examined the peer-reviewed literature to indicate and assess the common needs for individuals with intellectual and developmental disabilities. Current models of service delivery, the efficacy of these services, and remaining gaps in the need fulfillment of individuals within the six diagnostic categorizations of interest were examined. Severity level within each diagnostic category was plotted on a matrix according to whether the needs of individuals were minimal, moderate, severe, or universal. The study found that sexual health education, socialization, and adult-focused medical care are universal needs among the six conditions. The study indicates that health-care professionals must work toward addressing the many unmet needs in comprehensive life span care services for adult individuals with neurodevelopmental disorders. PMID- 28847207 TI - Employment effects of a multidisciplinary health assessment for mentally ill persons - A quasi-randomised controlled trial. AB - AIM: Relatively little is known about the effectiveness of return-to-work interventions for employees sick-listed with mental disorders, and the results of the literature are contradictory. This study evaluated the return-to-work effect of a multidisciplinary health assessment for persons sick-listed with mental disorders. METHODS: The study population consisted of 244 persons who were allocated to the treatment and control groups based on their birth year. In addition to the usual case management, the treatment group ( n = 83) was assessed by a team consisting of a case manager, a psychiatrist, and a job coach. The control group ( n = 99) received the usual case management. We used unique register data to code outcome variables (sick-leave duration and return-to-work duration). RESULTS: The multidisciplinary treatment had no statistically significant effect on the sick-leave duration (HR = 1.05; 95% CI 0.74-1.43) or the return-to-work duration (HR = 0.94; 95% CI 0.65-1.35). Subgroup analyses showed that the treatment effect did not systematically depend on age, education or severity of the mental disorder. We found no signs of systematic dropout from the study population or of imbalanced data. We found an insignificant tendency indicating that control-group case managers may have learned about the intervention from treatment case managers ( p = 0.31). CONCLUSIONS: This study showed no return-to-work effect of a multidisciplinary assessment of sick-listed individuals with mental disorders. Together with the sparse and inconclusive findings of the literature, this finding suggests that further research is needed for disentangling the elements that constitute an effective intervention. PMID- 28847209 TI - Corrigendum. PMID- 28847210 TI - Flexible Bayesian P-splines for smoothing age-specific spatio-temporal mortality patterns. AB - In this paper age-space-time models based on one and two-dimensional P-splines with B-spline bases are proposed for smoothing mortality rates, where both fixed relative scale and scale invariant two-dimensional penalties are examined. Model fitting and inference are carried out using integrated nested Laplace approximations, a recent Bayesian technique that speeds up computations compared to McMC methods. The models will be illustrated with Spanish breast cancer mortality data during the period 1985-2010, where a general decline in breast cancer mortality has been observed in Spanish provinces in the last decades. The results reveal that mortality rates for the oldest age groups do not decrease in all provinces. PMID- 28847211 TI - Medical manslaughter - time for a rethink? PMID- 28847212 TI - Developmental tasks and well-being in adolescent elite athletes in comparison with recreational/non-athletes. AB - Young elite athletes (EA) have to solve the same developmental tasks (DTs) as non athletes, even though they spend a lot of time with their sports and have to solve certain sports-related DTs in addition [Ohlert & Kleinert (2014). Entwicklungsaufgaben jugendlicher Elite-Handballerinnen und -Handballer [Developmental tasks in adolescent elite handball players]. Zeitschrift fur Sportpsychologie, 21(4), 161-172. doi: 10.1026/1612-5010/a000129 ]. The aim of this study was to find out if this situation leads to a shortfall in certain DTs and, furthermore, to a reduced well-being in adolescent EA. In total, 185 EA participated in the survey together with 166 recreational/non-athletes (RA). Participants were between 16 and 19 years old (69% female) and answered questions regarding the relevance of different DTs, their actual progression, satisfaction with their actual progression, and the WHO-5 measure for well-being. Compared to the RA group, the EA group reported a different relevance for some DTs. No significant differences were found between the two groups in progression or satisfaction with progression. The stepwise multiple regression resulted in two significant predictors for well-being in EA: satisfaction with progression in the DTs "to find oneself" and "circle of friends". For RA, the analysis revealed only satisfaction with progression in "circle of friends" as a significant predictor. Implications are that, at least for this age group, problems with DTs were not detected for the adolescent EA. However, if satisfaction with the own progression in certain DTs is low, well-being will also be reduced. PMID- 28847214 TI - Role of Social Detachment in Coping With Death Anxiety: A Case of Elderly Hindu Pilgrims. AB - The present research examines the strength of terror management theory in an indigenous Indian context of religious fair called Magh Mela. It explores how elderly Hindu people deal with death anxiety through practicing Kalpvas in Magh Mela. The research explores the role of social detachment and self-esteem in coping with terror of death. Study 1, a field experiment on 150 Kalpvasis (practitioners of Kalpvas) confirms the significant role of social detachment as an adaptive strategy for coping with death terror. The role of self-esteem did not emerge in the study. Study 2, another field experiment on 62 Kalpvasis confirms results of study 1. Significant role of years of Kalpvas on fear of death shows importance of the religious practices in managing terror related to death. The relation of terror management theory and death anxiety thus follows a different explanation for more indigenous contexts. PMID- 28847213 TI - Immunohistochemical Staining for Uroguanylin, a Satiety Hormone, is Decreased in Intestinal Tissue Specimens From Female Adolescents With Obesity. AB - Gastrointestinal tract-secreted satiety hormones play a significant role in one of the largest health-care challenges for children and adults, obesity. Recent studies in mice identified a novel role for uroguanylin, the endogenous intestinal hormone that binds guanylyl cyclase C (GUCY2C), in regulating satiety via a gut-brain signaling pathway. Mice bred without GUCY2C receptors over-ate and developed obesity. We hypothesized that intestinal uroguanylin expression in pediatric patients with obesity would be lower than patients without obesity, and we attempted to examine the difference with immunohistochemistry. Retrospective chart review of gastrointestinal endoscopic procedures at an academic children's hospital identified patients with normal pathology findings on biopsy. Children aged 8-17 were included in the review; we analyzed biopsy samples from 20 matched pairs that differed only by body mass index (BMI)-for-age (average: 25%-75% vs. high: >95%). Biopsies of the duodenum, terminal ileum, ascending colon, and descending colon were subjected to immunohistochemistry for GUCY2C, uroguanylin, and the endogenous colonic hormone, guanylin. Intensity staining of all specimens was scored by a blinded pathologist. The overall staining intensity for females with high BMI-for-age was less for uroguanylin and guanylin as compared to average BMI-for-age females while GUCY2C staining was equal. Males did not exhibit different staining intensities for uroguanylin or guanylin. More matched female pairs had greater uroguanylin and guanylin staining in the average BMI-for age cohort. The intestinal expression of uroguanylin, a key satiety hormone, appears to be diminished in female pediatric patients in the setting of obesity. PMID- 28847216 TI - Corrigendum. AB - May CD and Fletcher R. The development and application of a protocol for the writing, assessing, and validating of a corpus of relationship-focused text messages for new and expecting fathers. Health Informatics Journal 2017; DOI: 10.1177/1460458217704249 The funding statement of this article was not wholly correct. The correct funding statement is given below. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The research reported in this paper was funded by beyondblue with donations from the Movember Foundation. The subsequent versions of the article have been corrected. PMID- 28847215 TI - Prefrontal Cortical Thickening after Mild Traumatic Brain Injury: A One-Year Magnetic Resonance Imaging Study. AB - The objective of this study was to evaluate group-by-time interactions between gray matter morphology of healthy controls and that of patients with mild traumatic brain injury (mTBI) as they transitioned from acute to chronic stages, and to relate these findings to long-term cognitive alterations to identify distinct recovery trajectories between good outcome (GO) and poor outcome (PO). High-resolution T1-weighted magnetic resonance images were acquired in 49 mTBI patients within 7 days and 1 year post-injury and at equivalent times in 49 healthy controls. Using linear mixed-effects models, we performed mass-univariate analyses and associated the results of the interaction with changes in cognitive performance. Morphological alterations indexed by increased or decreased cortical thickness have been expected mainly in frontal, parietal, and temporal brain regions. A significant interaction was found in cortical thickness, spatially restricted to bilateral structures of the prefrontal cortex, showing thickening in mTBI and normal developmental thinning in controls. A discrete thickness increase that can interpreted as the absence of cortical thinning typically seen in the healthy population was associated with cognitive recovery in the GO subgroup, while the exaggerated cortical thickening in the PO patients was linked to worsening cognitive performance. Thickness of the prefrontal cortex is subject to structural alterations during the first year after mTBI. Beside beneficial neuroplasticity, a prolonged state of neuroinflammation for symptomatic patients (maladaptive neuroplasticity) cannot be excluded. If the underlying cellular processes responsible for cortical thickening following mTBI have been determined, brain stimulation or even pharmacological intervention targeting the prefrontal cortex might promote endogenous neural restoration. PMID- 28847217 TI - Subliminal gaze cues increase preference levels for items in the gaze direction. AB - Another individual's gaze automatically shifts an observer's attention to a location. This reflexive response occurs even when the gaze is presented subliminally over a short period. Another's gaze also increases the preference level for items in the gaze direction; however, it was previously unclear if this effect occurs when the gaze is presented subliminally. This study showed that the preference levels for nonsense figures looked at by a subliminal gaze were significantly greater than those for items that were subliminally looked away from (Task 1). Targets that were looked at by a subliminal gaze were detected faster (Task 2); however, the participants were unable to detect the gaze direction (Task 3). These results indicate that another individual's gaze automatically increases the preference levels for items in the gaze direction without conscious awareness. PMID- 28847218 TI - Left ventricular assist device: exercise capacity evolution and rehabilitation added value. AB - BACKGROUND: With more than 15,000 implanted patients worldwide and a survival rate of 80% at 1-year and 59% at 5-years, left ventricular assist device (LVAD) implantation has become an interesting strategy in the management of heart failure patients who are resistant to other kinds of treatment. There are limited data in the literature on the change over time of exercise capacity in LVAD patients, as well as limited knowledge about the beneficial effects that rehabilitation might have on these patients. Therefore, the aim of our study was to evaluate the evolution of exercise capacity on a cohort of patients implanted with the same device (HeartWare(c)) and to analyse the potential impact of rehabilitation. METHODS: Sixty-two patients implanted with a LVAD between June 2011 and June 2015 were screened. Exercise capacity was evaluated by cardiopulmonary exercise testing at 6 weeks, 6 and 12 months after implantation. RESULTS: We have observed significant differences in the exercise capacity and evolution between the trained and non-trained patients. Some of the trained patients nearly normalised their exercise capacity at the end of the rehabilitation programme. CONCLUSIONS: Exercise capacity of patient implanted with a HeartWare(c) LVAD increased in the early period after implantation. Rehabilitation allowed implanted patients to have a significantly better evolution compared to non-rehabilitated patients. PMID- 28847220 TI - Vaccine hesitancy and trust. Ethical aspects of risk communication. AB - AIM: This paper analyses vaccination policy from an ethical perspective, against the background of the growing hesitancy towards e.g. the measles vaccine. METHODS: The paper is normative and analyses ethical aspects of risk communication in the context of vaccination. It is argued that ethical analysis of risk communication should be done at the level of the message, the procedure and the effects. The paper takes examples from the Swedish context, linking the current lack of trust in experts to the 2009 vaccination policy and communication promoting the H1N1 vaccine Pandemrix. RESULTS: During the Swedish H1N1 vaccination policy in 2009, the message was that the vaccine is safe. However, a group of adolescents developed narcolepsy as a side effect of the vaccine. Taking this into account, it becomes clear that the government should communicate risks and benefits responsibly and take responsibility for individuals affected negatively by populational health interventions. CONCLUSION: To communicate respectfully entails not treating vaccine sceptics as ill-informed or less educated, but instead taking the concerns of the vaccine hesitant, who potentially could change their minds, as a starting-point of a respectful discussion. There will inevitably be individuals who suffer from side effects of justifiable population-based health promotion activities. However, the public should be able to trust the message and count on the government to take responsibility for individuals affected by side effects. This is important for normative reasons, but is additionally likely to contribute to restored and maintained trust. PMID- 28847219 TI - SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts. AB - BACKGROUND: There is a pressing need for robust longitudinal cohort studies in the modern treatment era of multiple sclerosis. OBJECTIVE: Build a multiple sclerosis (MS) cohort repository to capture the variability of disability accumulation, as well as provide the depth of characterization (clinical, radiologic, genetic, biospecimens) required to adequately model and ultimately predict a patient's course. METHODS: Serially Unified Multicenter Multiple Sclerosis Investigation (SUMMIT) is an international multi-center, prospectively enrolled cohort with over a decade of comprehensive follow-up on more than 1000 patients from two large North American academic MS Centers (Brigham and Women's Hospital (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB; BWH)) and University of California, San Francisco (Expression/genomics, Proteomics, Imaging, and Clinical (EPIC))). It is bringing online more than 2500 patients from additional international MS Centers (Basel (Universitatsspital Basel (UHB)), VU University Medical Center MS Center Amsterdam (MSCA), Multiple Sclerosis Center of Catalonia-Vall d'Hebron Hospital (Barcelona clinically isolated syndrome (CIS) cohort), and American University of Beirut Medical Center (AUBMC-Multiple Sclerosis Interdisciplinary Research (AMIR)). RESULTS AND CONCLUSION: We provide evidence for harmonization of two of the initial cohorts in terms of the characterization of demographics, disease, and treatment-related variables; demonstrate several proof-of-principle analyses examining genetic and radiologic predictors of disease progression; and discuss the steps involved in expanding SUMMIT into a repository accessible to the broader scientific community. PMID- 28847221 TI - Classification of Uterine Anomalies by 3-Dimensional Ultrasonography Using ESHRE/ESGE Criteria: Interobserver Variability. AB - OBJECTIVE: To evaluate the interobserver repeatability of the coronal view measurements and classification of the uterine malformations (UM) according to the ESHRE/ESGE consensus by transvaginal three-dimensional ultrasound (3D-US). METHODS: 89 transvaginal 3D-US volumes acquired during the last two years at Delta Ecografia in Madrid, Spain, were selected from our archive by convenience sampling. Two expert operators blinded from each other, performed post-hoc analysis using render mode and multiplanar-Volume Contrast Imaging (VCI) navigation. Uterine wall thickness at the fundus, indentation of the cavity and indentation of the fundus were measured, classified and sub-classified following the recommendations of the ESHRE/ESGE consensus. The reproducibility of interobserver measurements and classification was examined by calculating intraclass correlation coefficients (ICC) and their 95% confidence intervals (CI) and kappa statistic (k). RESULTS: Repeatability in the measurements: uterine wall thickness: ICC = 0.93 (95% CI, 0.90-0.96), P < 0.0001; indentation of the cavity: ICC = 0.93 (95% CI, 0.86-0.96), P < 0.0001; indentation of the fundus: ICC = 0.93 (95% CI, 0.90-0.96), P < 0.0001. Level of agreement in the classification: overall (U0, U1, U2, U3, U4, U5): k = 0.73 (95% CI, 0.61-0.84), P > 0.0001; U2 (U2a, U2b): k = 0.56 (95% CI, 0.31-0.80), P < 0.001 (0.78 observed agreement compared to 0.49 expected); U3 (U3a, U3b, U3c): k = 0.69 (95% CI, 0.16-1.00), P < 0.05 (0.85 observed agreement compared to 0.53 expected); U4 (U4a, U4b): k = 1.00 (95% CI, 1.00-1.00), P < 0.0001. CONCLUSIONS: Transvaginal 3D-US examination of the uterus allows assessment and classification of the UM by the ESHRE/ESGE criteria showing a good interobserver repeatability and reproducibility in most cases. PMID- 28847222 TI - Anti-JCV serology during natalizumab treatment: Review and meta-analysis of 17 independent patient cohorts analyzing anti-John Cunningham polyoma virus sero conversion rates under natalizumab treatment and differences between technical and biological sero-converters. AB - BACKGROUND: Anti-John Cunningham virus (JCV) serology has been studied with varying results concerning longitudinal changes. OBJECTIVES AND METHODS: Results from 17 published natalizumab-treated multiple sclerosis (MS) patient cohorts were analyzed with common parameters and subsequently verified in two large independent cohorts with 722 and 499 patients from Germany and the United States. RESULTS: Published studies and the verification showed (1) a mean of 10.80% sero negative patients presented with sero-status change to positivity per year; (2) patients, who sero-convert to index values <0.9, convert from near the threshold and have a high probability of reverting with time; (3) patients, who convert to index values >0.9, start with low index values; (4) while JCV sero-positive patients with low index values sometimes revert to sero-negativity, patients with high index values almost never revert; and (5) the conversion rate of natalizumab treated patients is three to four times higher than the biological conversion by age. CONCLUSION: JCV sero-conversion was comparable using standardized parameters and indicates influence of natalizumab on JCV immune control. Converters to low index values are probably consistently infected with JCV with varying low levels of activity, in line with their low risk to develop progressive multifocal leukoencephalopathy (PML). Patients with high index values rarely revert back to sero-negativity. PMID- 28847223 TI - Compulsory school achievement and gambling among men and women aged 18-29 in Finland. AB - AIMS: This study aims to explore the associations between final compulsory school grades and gambling and their relation to substance use and perceived mental health among people aged 18-29 in Finland (N = 831). METHODS: Cross-sectional random sample data, weighted on the basis of age, gender and region of residence, were collected in 2015. The data were analysed using logistic regression models adjusted for sociodemographic variables, risky alcohol use, daily smoking, and perceived mental health. RESULTS: Weekly gambling and at-risk and problem gambling (ARPG) were more common among men. Weekly gambling was linked to smoking and risky alcohol use among men and smoking among women. Additionally, ARPG was linked to risky alcohol use among men. ARPG was associated with moderate/poor mental health among men and women, but this was not the case with weekly gambling. Among men, low and average final school grades at age 16 were associated with weekly gambling later in life, even when adjusting for other variables. Among women, low and average final school grades were not associated with weekly gambling when adjusting for substance use. Lower final school grades were associated with ARPG among women but not among men when all potential confounders were adjusted for. CONCLUSIONS: Adolescents with lower final school grades are more likely to gamble weekly later in life. Lower final school grades are also linked with ARPG among women. It is important therefore for schools to have clear policies on gambling and to implement early prevention programmes. PMID- 28847224 TI - Response to Krieger et al. re: "TSHR/IGF-1R Cross-Talk, Not IGF-1R Stimulating Antibodies, Mediates Graves' Ophthalmopathy Pathogenesis" (Thyroid 2017;27:746 747). PMID- 28847225 TI - Downregulation of inflammatory markers by conjugated linoleic acid isomers in human cultured astrocytes. AB - OBJECTIVES: Conjugated linoleic acid (CLA) isomers have been shown to possess anti-inflammatory activity in the central nervous system. In this study, we aimed to evaluate whether modulation of the fatty acid profile by the CLA isomers c9,t11 or t10,c12CLA was associated with changes in the expression of pro inflammatory molecules in human astrocytes. METHODS: Cultured astrocytes were treated for 6 days with 100 uM fatty acids (c9,t11CLA or t10,c12CLA or oleic acid). Following the treatment, the fatty acid profile of the cell and pro inflammatory molecule expression were assessed. RESULTS: Only the t10,c12CLA isomer induced a significant decrease in arachidonic acid and increased the ratio of docosahexaenoic acid/eicosapentaenoic acid, which constitutes indirect evidence of peroxisome proliferator-activated receptor alpha activation. Inhibition of tumour necrosis factor-alpha, interleukin-1beta, and RANTES expression was observed in astrocytes treated with c9,t11CLA and t10,c12CLA. DISCUSSION: Current data demonstrate that CLA isomers, particularly t10,c12, may affect neuroinflammation by reducing the pro-inflammatory molecules in cultured astrocytes, suggesting a potential nutritional role of CLA isomers in modulating the astrocyte inflammatory response. PMID- 28847226 TI - Dynamic Risk Stratification in Stage I Papillary Thyroid Cancer Patients Younger Than 45 Years of Age. AB - BACKGROUND: This study validated the dynamic risk stratification (DRS) system with regard to its association with structural recurrence and risk factors associated with non-excellent responses in patients <45 years with stage I classical papillary thyroid cancer (PTC). METHODS: This historical cohort study included 598 patients with stage I classical PTC <45 years of age treated with total thyroidectomy followed by radioactive iodine remnant ablation (n = 440), total thyroidectomy without radioactive iodine remnant ablation (n = 23), and thyroid lobectomy alone (n = 135). RESULTS: The median follow-up period was 123 months. Structural recurrence occurred in 4.2% (n = 18/432) of the patients with an excellent response, 17.1% (18/105) of patients with an indeterminate response, 44.7% (17/38) of patients with a biochemically incomplete response, and 82.6% (19/23) of patients with a structurally incomplete response (p < 0.001) during the follow-up. The disease-free survival curves of each response showed significant differences (p < 0.001). Extensive extrathyroidal extension and extranodal extension were the independent risk factors associated with non excellent response (p < 0.05). CONCLUSIONS: DRS may reduce unnecessary additional treatments by reclassifying initial risk estimates of structural recurrence. Furthermore, applying the risk factors associated with non-excellent response to initial therapy may be a more useful and viable surrogate of the risk for structural recurrence in stage I PTC patients <45 years of age. PMID- 28847227 TI - "Our lifestyle is a mix-match": Traditional healers talk about suicide and suicide prevention in South Africa. AB - Practitioners of traditional African medicine (traditional healers) are an important part of the health care system in South Africa, yet their voices are often absent from discussions about public health. In this context, we set out to investigate how a group of traditional healers in South Africa understand suicide and suicide prevention. In-depth, semistructured interviews were conducted with 6 traditional healers and analysed using thematic content analysis. The traditional healers report they are frequently consulted by suicidal individuals and they are confident about their ability to help people in a suicidal crisis. Findings suggest that traditional healers understand suicidal behaviour as a symptom of social disconnection and cultural discontinuity. Traditional healers report that suicidal individuals can be helped by reestablishing interpersonal connections, reconnecting to family and ancestors, and renewing their cultural identities through rituals. These findings suggest that there is some congruence between the way traditional healers understand suicide and the Western scientific and biomedical literature. Our findings raise important questions about cultural approaches to suicide research which are commonly premised on dualistic thinking that constructs culture as something distinct from Western biomedicine. PMID- 28847228 TI - Current therapies for the treatment of multidrug-resistant tuberculosis in children in India. AB - INTRODUCTION: Multidrug-resistant tuberculosis (MDR-TB) is a serious life threatening condition affecting children as well as adults worldwide. Timely diagnosis and effective treatment, both of which are complex in children, are the prerogatives for a favorable outcome. Areas covered: This review covers epidemiology, treatment regimen and duration, newer drugs and adverse events in children with MDR-TB. Special note has been made of epidemiology and principles of treatment followed in Indian children. Expert opinion: High index of suspicion is essential for diagnosing childhood MDR-TB. If there is high probability, a child can be diagnosed as presumptive MDR-TB and started on empiric treatment in consultation with experts. However, every effort should be made to confirm the diagnosis. Backbone of an effective MDR-TB regimen consists of four 2nd line anti TB drugs plus pyrazinamide; duration being 18-24 months. The newer drugs delamanid and bedaquiline can be used in younger children if no other alternatives are available after consultation with experts. Wider availability of these drugs should be ensured for benefit to all concerned. More research is required for development of new and repurposed drugs to combat MDR-TB. Children need to be included in clinical trials for such life-saving drugs, so that nobody is denied the benefits. PMID- 28847229 TI - Building a primary care research network - lessons to learn. PMID- 28847231 TI - Road Map for Research Training in the Residency Learning Experience. AB - The American Society of Health-System Pharmacists residency accreditation standards require all postgraduate residency training programs to teach and evaluate a resident's ability to advance practice through project development and presentation, underscoring the importance of conducting research in today's professional climate. Although many residents express strong interest in research participation and contributing to the medical literature, many obstacles to publication have been identified. We aim to illustrate a deliberate approach to teaching this material and structuring the longitudinal experience in a way that maximizes resources to overcome these barriers. Such efforts should aid residents, advisors, and program directors in establishing curriculum which leads to successful completion and publication of pharmacy resident's research projects. PMID- 28847230 TI - Development of Glatopa(r) (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis. AB - The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa(r) 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone(r)) dosage form. Despite glatiramer acetate's complex nature-being a chemically synthesized (ie, nonbiologic) mixture of peptides-the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS. PMID- 28847232 TI - Significant Publications on Infectious Diseases Pharmacotherapy in 2016. AB - PURPOSE: This is a summary of the most important articles on infectious diseases (ID) pharmacotherapy published in peer-reviewed literature in 2016 as selected by clinical pharmacists with ID expertise. SUMMARY: The Houston Infectious Diseases Network (HIDN) was asked to identify articles published in peer-reviewed literature in 2016 that were believed to contribute significantly to ID pharmacotherapy, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 46 articles on general ID pharmacotherapy and 8 articles on HIV/AIDS were nominated. Members of the Society of Infectious Diseases Pharmacists (SIDP) were surveyed to select 10 general ID articles believed to have made a significant impact on general ID pharmacotherapy and 1 article most significant to HIV/AIDS pharmacotherapy. Of 445 SIDP members surveyed, 212 (47.6%) and 95 (21.3%) members voted for general ID pharmacotherapy and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles and 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the large number of ID-related articles published each year, it can be challenging to stay current with the most relevant ID publications. This review of significant publications in 2016 may provide a starting point for that process. PMID- 28847233 TI - Sex difference in the association of serum uric acid with metabolic syndrome and its components: a cross-sectional study in a Chinese Yi population. AB - OBJECTIVES: Since the association between serum uric acid (SUA) and metabolic syndrome (MetS) has been reported extensively, it remains unclear whether SUA is associated with MetS and its components in a Chinese Yi population. METHODS: This study recruited 1,903 people (912 men, 991 women) older than 18 years old from the Liangshan region in Sichuan province. Anthropometric measurements and biochemical indexes were measured by a standard protocol. SUA levels were divided into four quartiles by sex. RESULTS: The prevalence of hyperuricemia and MetS is 21.0% and 17.1%, respectively. The levels of SUA were positively correlated with waist circumference, body mass index and triglycerides while negatively correlated with high-density lipoprotein cholesterol in both sexes. Increased SUA levels were accompanied with prevalence of MetS and several components in both sexes (P < 0.05). Men with the highest SUA quartile had an increased risk of MetS [OR (95% CI): 3.101 (1.281-7.504)], and men with higher SUA levels had an increased risk of central obesity, high blood pressure and hypertriglyceridemia compared to the lowest SUA quartile. Women with higher SUA levels had an increased risk of MetS, central obesity, hypertriglyceridemia and a lower risk of high blood pressure compared to the lowest SUA quartile. CONCLUSIONS: SUA levels were closely associated with MetS and several components by sex in Chinese Yi population. PMID- 28847234 TI - Initial training with difficult items does not facilitate category learning. AB - In the phenomenon of transfer along a continuum (TAC), initial training on easy items facilitates later learning of a harder discrimination. TAC is a widely replicated cross-species phenomenon that is well predicted by certain kinds of associative theory (e.g., Sutherland & Mackintosh, 1971). A recent report of an approximately-opposite phenomenon (i.e. facilitation by initial training on hard items, Spiering & Ashby, 2008) poses a puzzle for such theories, but is predicted by a dual-system model (COVIS; Ashby et al., 1998). However, across four experiments we present substantial evidence that Spiering and Ashby's conclusions were in error. Their result appears to be a false positive and, as such, should not form part of the evidence base for COVIS, nor be considered as a counter example to the pervasive TAC phenomenon. PMID- 28847235 TI - Competing Forces of Socioeconomic Development and Environmental Degradation on Health and Happiness for Different Income Groups in China. AB - China's rapid socioeconomic growth in recent years and the simultaneous increase in many forms of pollution are generating contradictory pictures of residents' well-being. This paper applies multilevel analysis to the 2013 China General Social Survey data on social development and health to understand this twofold phenomenon. Multilevel models are developed to investigate the impact of socioeconomic development and environmental degradation on self-reported health (SRH) and self-reported happiness (SRHP), differentiating among lower, middle, and higher income groups. The results of the logit multilevel analysis demonstrate that income, jobs, and education increased the likelihood of rating SRH and SRHP positively for the lower and middle groups but had little or no effect on the higher income group. Having basic health insurance had an insignificant effect on health but increased the likelihood of happiness among the lower income group. Provincial-level pollutants were associated with a higher likelihood of good health for all income groups, and community-level industrial pollutants increased the likelihood of good health for the lower and middle income groups. Measures of community-level pollution were robust predictors of the likelihood of unhappiness among the lower and middle income groups. Environmental hazards had a mediating effect on the relationship between socioeconomic development and health, and socioeconomic development strengthened the association between environmental hazards and happiness. These outcomes indicate that the complex interconnections among socioeconomic development and environmental degradation have differential effects on well-being among different income groups in China. PMID- 28847236 TI - Spectrum of Off-Label Nitric Oxide Utilization After Pediatric Cardiac Surgery Among Centers of Varying Surgical Volume. AB - OBJECTIVE: Nitric oxide is utilized after pediatric cardiac surgery as an off label medication without much evidence, is expensive, and varies among centers of varying surgical volume. The objective of our study was to describe the spectrum of nitric oxide utilization and to evaluate the effect of nitric oxide utilization on outcomes among patients cared for in centers of varying surgical volume using Pediatric Health Information system. METHODS: Patients aged <=18 years undergoing heart surgery were included (2004-2015). Multivariable mixed effects logistic regression models were fitted to evaluate association of center volume with odds of nitric oxide utilization among patients undergoing heart operations. Centers were classified into 3 volume categories based on tertiles of number of cardiopulmonary bypass cases performed (low volume: 34 792 patients, 21 centers; medium volume: 38 362 patients, 13 centers; high volume: 30 560 patients, 7 centers). RESULTS: A total of 103 714 patients from 41 hospitals were included. Of these, 15 708 (15.1%) patients received nitric oxide after cardiac surgery. Of the patients receiving nitric oxide, only 3936 (25.1%) patients were associated with a diagnosis of pulmonary hypertension. In adjusted models, low- and medium-volume centers were associated with higher nitric oxide utilization after heart operations as compared to high-volume centers (low vs high, odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.38-1.60; medium vs high, OR: 1.33, 95% CI: 1.26-1.41). Despite higher nitric oxide utilization, the mortality was worse among patients treated in low- and medium-volume centers, as compared to high-volume centers (low vs high, OR: 1.42, 95% CI: 1.26-1.60; medium vs high, OR: 1.14, 95% CI: 1.04-1.25). CONCLUSIONS: This study demonstrates variation in nitric oxide utilization after heart operations among centers of varying surgical volume. Further, it raises questions on the benefit of nitric oxide administration after pediatric cardiac surgery. PMID- 28847237 TI - Clinical Outcomes and Prognostic Factors for Spontaneous Intracerebral Hemorrhage in Pediatric ICU: A 12-Year Experience. AB - BACKGROUND: In the pediatric population, spontaneous intracerebral hemorrhage (sICH) is as common as ischemic stroke and accounts for significant mortality and morbidity. Differently from the ischemic stroke, there are few guidelines for directing management of sICH. This article aims to analyze both clinical outcomes and prognostic factors in order to produce tools for the design of prospective randomized studies addressed to implement treatment of pediatric sICH. METHODS: Twelve-year retrospective review of a single-center consecutivesICH pediatric cases admitted to the pediatric intensive care unit (PICU). Selected end points were survival, PICU stay, and dichotomized Glasgow Outcome Score (GOS), with recovery and moderate disability (GOS 4-5) classified as favorable outcome and vegetative state or severe disability (GOS 2-3) classified as unfavorable. RESULTS: Data of 107 children younger than 14 years admitted to our PICU due to sICH were analyzed. Overall PICU mortality was 24.2%. On multivariate analysis, the single factor markedly influencing survival was the presence of midline shift ( P = .002). In PICU survivors, there were 42 GOS 2-3 and 39 GOS 4-5. A low Glasgow Coma Scale (GCS) on PICU admission was predictive of severe neurological impairment in survivors ( P = .003). Intraventricular hemorrhage and infratentorial origin did not influence outcome in this series. CONCLUSION: The severity of presentation of sICH expressed by the midline shift and the GCS at PICU admission are significant prognostic factors for survival and neurological outcome. Some prognostic factors of the adult population have not been confirmed. PMID- 28847238 TI - Mobilization of Mechanically Ventilated Patients in Switzerland. AB - PURPOSE: Growing evidence suggests that early mobilization benefits intensive care unit (ICU) patients. However, national practices and the culture of individual ICUs influence mobilization activities. MATERIALS AND METHODS: In a 1 day, Swiss point prevalence study conducted in 35 ICUs (representing 45% of all ICUs), the highest level of mobilization for mechanically ventilated patients was characterized using the validated ICU Mobility Scale, along with data collection for potential safety events and mobilization barriers. RESULTS: Among 161 mechanically ventilated patients, a total of 33% (n = 53) had active mobilization, with walking achieved by only 2% (n = 4). More severe organ failure was associated with lower mobilization (respiratory Sequential Organ Failure Assessment score: P = .037, cardiac: P = .008, neurology: P < .001). Barriers to mobilization were reported in 71% (n = 115), with deep sedation significantly higher among patients receiving passive versus active mobilization (14% vs 0%, P = .005). Potential safety events occurred in 20% (n = 33) of patients without significant differences between passive and active mobilization. Availability of physiotherapists and appropriate equipment were not reported barriers. CONCLUSION: Mobilization during mechanical ventilation occurred infrequently with greater organ failure associated with lower mobilization. Addressing the identified modifiable barriers via structured efforts to achieve multidisciplinary culture change is essential to decrease the common use of bed rest in Swiss ICUs. PMID- 28847239 TI - Thyroid Hormone Receptor Alpha is Essential to Maintain the Satellite Cell Niche During Skeletal Muscle Injury and Sarcopenia of Aging. AB - BACKGROUND: Myopathic changes are commonly described in hypothyroid and hyperthyroid patients, including muscular atrophy and weakness. Satellite cells (SCs) play a major role in skeletal muscle maintenance and regeneration after injury. A mouse model of resistance to thyroid hormone-TRalpha1PV demonstrated impaired skeletal muscle regeneration after injury with significant reduction of SCs, suggesting that exhaustion of the SC pool contributes to the impaired regeneration. To test this hypothesis, SC activation and proliferation were analyzed in vivo in response to skeletal muscle injury and during aging. METHODS: SCs of TRalpha1PV male mice were analyzed four days after cardiotoxin-induced muscle injury, and they were compared to wild-type (WT) male animals. TRalpha knockdown C2C12 myoblasts were injected into injured skeletal muscle, and four days after transplantation, the in vivo behavior was compared to control C2C12 myoblasts. Skeletal muscle regeneration was compared in younger and older TRalpha1PV and WT animals. RESULTS: The total number of SCs in skeletal muscle of TRalpha1PV mice was significantly lower than control, both before and shortly after muscle injury, with significant impairment of SC activation, consistent with SC pool exhaustion. TRalpha-knockdown myoblasts showed impaired in vivo proliferation and migration. TRalpha1PV mice had skeletal muscle loss and significant impairment in skeletal muscle regeneration with aging. This translated to a significant reduction of the SC pool with aging compared to WT mice. CONCLUSION: TRalpha plays an important role in the maintenance of the SC pool. Impaired skeletal muscle regeneration in TRalpha1PV mice is associated with insufficient SC activation and proliferation, as well as the progressive loss of the SC pool with aging. Regulation of the SC pool and SC proliferation provides a therapeutic target to enhance skeletal muscle regeneration and possibly slow age associated sarcopenia. PMID- 28847240 TI - Humerus shaft fracture associated with traumatic radial nerve palsy: An international survey among orthopedic trauma surgeons from Latin America and Asia/Pacific. AB - PURPOSE: The purpose of this article is to explore the real-life practice of clinical management of humeral shaft fracture associated with traumatic radial nerve palsy among orthopedic trauma surgeons. METHODS: Two hundred seventy-nine orthopedic surgeons worldwide reviewed 10 real cases of a humeral shaft fracture associated with traumatic radial nerve palsy answering two questions: (1) What treatment would you choose/recommend: nonoperative or operative? (2) What are the reasons for your decision-making? The survey was developed in an online survey tool. All participants were active members from AOTrauma International. RESULTS: Two hundred sixty-six (95.3%) participants were from Latin America and Asia/Pacific. One hundred sixty-two participants (58.1%) had more than 10 years in practice and 178 (63.8%) of them did trauma as the main area of interest. One hundred fifty-one (54.1%) participants treated less than three humeral shaft fractures a month. Traumatic radial nerve palsy was the main reason (88.4%) for surgeons to recommend surgical treatment. Open reduction and internal fixation (ORIF) or percutaneous fixation of the fracture associated with acutely explore of radial nerve was the first option in 62.0% of the cases. A combination of morphology and level of the fracture and the presence of the radial nerve palsy was the most suggested reason to surgically treat the humerus fracture. The main isolated factor was the morphology of the fracture. CONCLUSION: Our survey highlight the tendency for a more aggressive management of any humeral shaft fracture associated with a traumatic radial nerve palsy, with surgeons preferring to use ORIF with acute exploration of the radial nerve. Nonsurgical management was the less chosen option among the 279 respondents. Fracture morphology, level of the fracture, and the presence of the radial nerve palsy were most influential for guiding their treatment. PMID- 28847241 TI - A new technique of arthroscopic subscapularis repair with 2-year clinical outcomes in an Asian population. AB - BACKGROUND: Tears of the subscapularis are not as common as the other rotator cuff muscles and hence not as many arthroscopic repair techniques have been previously described in the literature. The purpose of this study is to evaluate the clinical outcomes in patients undergoing arthroscopic subscapularis repairs (with and without repairs of the other cuff muscles) using a technique devised by the senior author of this study. METHODS: A retrospective study of 40 consecutive patients who underwent arthroscopic subscapularis repair at a single centre, by a single surgeon from 2009 to 2014. All patients were assessed preoperatively and post-operatively at 3, 6, 12 and 24 months. The Visual Analogue Scale (VAS), Constant-Murley Shoulder Score (CMSS), University of California at Los Angeles (UCLA) Shoulder Score and Oxford Shoulder Score (OSS) were recorded and used. RESULTS: At 24 months follow-up, the VAS for pain improved from 6 (+/-2) points preoperation to 0 (+/-1) points. The CMSS improved from 41 (+/-18) points preoperation to 71 (+/-15). The relative CMSS improved from 55 (+/-24%) preoperation to 96 (+/-22%; % of the uninjured side). The ULCA Shoulder Score improved from 15 (+/-5) points preoperation to 30 (+/-4). The OSS improved from 28 (+/-12) points preoperation to 45 (+/-5). p < 0.001 for all outcomes measured. CONCLUSION: Overall clinical outcomes are favourable at 2 years post-operatively. The described technique is an effective method for arthroscopic subscapularis repair in the Asian population. PMID- 28847242 TI - Localized pigmented villonodular synovitis of posterior compartment of the knee. AB - Pigmented villonodular synovitis (PVNS) is an uncommon entity involving articular or extra-articular tissues and maybe localized or diffuse in extent. The knee is by far the commonest joint to get involved. Localized PVNS of the knee can occur in any location but its confinement to the posterior compartment is infrequent. We present our experience of managing localized posterior compartment PVNS of the knee. There were 10 patients (7 males and 3 females) with average age of 33 years. These patients had symptoms of pain, locking, or swelling for a mean of 13.9 years before diagnosis. All the patients underwent arthroscopic synovectomy without adjuvant therapy, and PVNS was proven on histopathology. At an average follow-up of 23 months, no patient had recurrence of symptoms. The average International Knee Documentation Committee (IKDC) score at last follow-up was 85.21. Magnetic resonance imaging evaluation at final follow-up did not reveal any residual disease or recurrence in any patient. PMID- 28847243 TI - Is calcar referenced tip-apex distance a better predicting factor for cutting out in biaxial cephalomedullary nails than tip-apex distance? AB - PURPOSE: To test the significance of calcar referenced tip-apex distance (CalTAD) and the length of anti-rotation screw (AR screw) as predictors for failure after biaxial cephalomedullary (CM) nailing of intertrochanteric fractures. METHODS: We retrospectively reviewed 190 consecutive fractures that had undergone biaxial CM nailing. Of these, 67 met the inclusion criteria of a non-pathological fracture with a minimum of 90 days radiological follow-up (mean 458 days; 91 days to 4.9 years). RESULTS: The overall failure rate was 15% (10 of 67). Failure was associated with a higher CalTAD in most of the patients (13%, p < 0.001). A higher tip-apex distance (TAD) was not significantly associated with failure ( p = 0.132), when the CalTAD was less than 25 mm. When the AR screw length exceeded a line connecting the tip of the nail and the lag screw, screw cutout occurred only in one patient ( p = 0.095). CONCLUSION: Our data provide the first reported clinical evidence that the CalTAD is a better predictor of cutout in biaxial CM nailing than TAD measurement. However, the length of anti-rotational element does not seem to be an independent predictor of CM nailing failure. PMID- 28847244 TI - The Myth of Fibroid Degeneration in the Canine Intervertebral Disc: A Histopathological Comparison of Intervertebral Disc Degeneration in Chondrodystrophic and Nonchondrodystrophic Dogs. AB - Since the seminal work by Hans-Jorgen Hansen in 1952, it has been assumed that intervertebral disc (IVD) degeneration in chondrodystrophic (CD) dogs involves chondroid metaplasia of the nucleus pulposus, whereas in nonchondrodystrophic (NCD) dogs, fibrous metaplasia occurs. However, more recent studies suggest that IVD degeneration in NCD and CD dogs is more similar than originally thought. Therefore, the aim of this study was to compare the histopathology of IVD degeneration in CD and NCD dogs. IVDs with various grades of degeneration (Thompson grade I-III, n = 7 per grade) from both CD and NCD dogs were used (14 CD and 18 NCD dogs, 42 IVDs in total). Sections were scored according to a histological scoring scheme for canine IVD degeneration, including evaluation of the presence of fibrocyte-like cells in the nucleus pulposus. In CD dogs, the macroscopically non-degenerated nucleus pulposus contained mainly chondrocyte like cells, whereas the non-degenerated nucleus pulposus of NCD dogs mainly contained notochordal cells. The histopathological changes in degenerated discs were similar in CD and NCD dogs and resembled chondroid metaplasia. Fibrocytes were not seen in the nucleus pulposus, indicating that fibrous degeneration of the IVD was not present in any of the evaluated grades of degeneration. In conclusion, intervertebral disc degeneration was characterized by chondroid metaplasia of the nucleus pulposus in both NCD and CD dogs. These results revoke the generally accepted concept that NCD and CD dogs suffer from a different type of IVD degeneration, in veterinary literature often referred to as chondroid or fibroid degeneration, and we suggest that chondroid metaplasia should be used to describe the tissue changes in the IVD in both breed types. PMID- 28847245 TI - [A new HIV prevention strategy: we are ready]. PMID- 28847246 TI - Cost-effectiveness study of closed system transfer devices for the preparation of antineoplastic agents. AB - Most cytostatic drugs cannot be administered directly to patients in their marketed presentation, but require previous reconstitution conducted in the Pharmacy Unit areas for cytostatic preparation. There are systems that allow drug reconstitution and transfer once it has been diluted, in order to protect staff from any potential contamination during handling. These are commonly known as Closed Systems, and generally have a piece for vial attachment and a syringe adapter with a built-in filter, that replace the traditional needles. Closed systems feature different characteristics and costs which is necessary to analyze in order to determine the most efficient one. PMID- 28847247 TI - Adequancy of treatment with canaglifozin alter alerts pharmacovigilance in the health management area. AB - OBJECTIVE: To analyze the impact of a strategy on the suitability of canaglizozin, and its level of acceptance, after issuing recommendations based on drug surveillance alerts issued by the Spanish Medicines and Medical Devices Agency (AEMPS). DESIGN: A prospective intervention from may 2016 to october 2016. Location: South Seville Health Management Area. Participants: Patients with active canagliflozin prescription. Interventions: The study was conducted in three phases, the first one linked to the issuance of the safety information note on the canaglifozin by the AEMPS, the obtaining of the patient lists and the recommendations of the adequacy in the sending of letters. A second phase where the medical professional performed the actions and a final phase in which the degree of acceptance of the recommendations made by the Pharmacy Service is evaluated. MAIN MEASUREMENTS: Suitability of canaglizozin treatment and the level of acceptance by physicians. RESULTS: A total of 61 patients at baseline were included in treatment canagliflozin. Of the total number of patients referred to, some type of intervention was performed by the family and community medicine doctor after the pharmaceutical intervention (PI), by means of letters (n = 30), 56.7% were monitored, 33.3% were discontinued and 10.0% were closely monitoredConclusions: Interventions aimed at reviewing patients on canagliptin, based on pharmacovigilance alerts, have been effective, with a high degree of acceptance by the family and community medicine practitioner. PMID- 28847248 TI - Complementary medicine use in cancer patients receiving intravenous antineoplastic treatment. AB - OBJECTIVE: Complementary and alternative medicine (CAM) use has grown considerably, although there is little research on the topic in Spain. The aim of this study was to determine the prevalence of complementary medicine use in adult cancer patients at the same time as they were receiving conventional treatment in a Spanish referral cancer centre. METHOD: An observational, descriptive, cross sectional study was conducted in the Ambulatory Treatment Unit during 2 consecutive weeks in March 2015. Adult patients who were receiving intravenous chemotherapy were included. Study variables were obtained from a questionnaire and medical records. RESULTS: 316 patients were included. 32.3% of the patients reported complementary medicine use during this period and 89% were ingesting products by mouth, herbs and natural products being the most commonly used. 81% of patients started to use complementary medicine after diagnosis, and family/friends were the main source of information. 65% of the patients reported improvements, especially in their physical and psychological well-being. Significant predictors of CAM use were female gender (P=0.028), younger age (P<0.001), and secondary education (P=0.009). CONCLUSIONS: A large proportion of cancer patients receiving intravenous chemotherapy also use complementary medicine, which they mainly take by mouth. Due to the risk of chemotherapy-CAM interactions, it is important for health-professionals to keep abreast of research on this issue, in order to provide advice on its potential benefit and risks. PMID- 28847249 TI - Cost-utility analysis of the fixed-dose combination of dolutegravir/abacavir/lamivudine as initial treatment of HIV+ patients in Spain. AB - OBJECTIVE: Fixed-dose combinations of antiretroviral drugs have meant an important step forward in simplifying treatment and improving compliance and has led to an increased effectiveness of therapy, a viral load decrease and improving the quality of life of patients. The single-table formulation of dolutegravir with abacavir and lamivudine (DTG/ABC/3TC) is a highly efficacious and well tolerated once-daily regimen for HIV-infected patients. The objective of the study was to assess the incremental cost-utility ratio of the fixed-dose combination of (DTG/ABC/3TC) versus the combinations emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and darunavir/r (DRV/r) or raltegravir (RAL) with emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) as initial antiretroviral therapy in patients infected with HIV-1 from the perspective of the Spanish National Health System. METHOD: The ARAMIS model, which uses a microsimulation approach to simulate the individual changes in each patient from the start of treatment to death through a Markov chain of descriptive health states of the disease, was adapted to Spain. The alternatives used for comparison were the fixed-dose combination of emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and the fixed- dose combinations of emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) with darunavir/r (DRV/r) or raltegravir (RAL). The probability of achieving virological suppression by the treatments included in the model was obtained from clinical trials SINGLE, SPRING-2 and FLAMINGO and the costs were expressed in ? (2015). The model use the perspective of the Spanish National Health System, with a lifetime horizon and a discount rate of 3% was applied to cost and effectiveness. RESULTS: Treatment initiation with DTG/ABC/3TC was dominant when it was compared with treatment initiation with all the comparators: vs. FTC/TDF/EFV (-67 210.71?/QALY), vs. DRV/r + FTC/TDF or ABC/3TC (-1 787 341.44?/QALY), and vs. RAL + FTC/TDF or ABC/3TC (-1 005 117.13?/QALY). All the sensitivity analyses performed showed the consistency of these findings. CONCLUSIONS: With the premises considered, treatment initiation with DTG/ABC/3TC STR appears to be the most cost-effective option in ARTnaive HIV infected patients from the Spanish Health System perspective. PMID- 28847250 TI - Evaluation of standardized triple intrathecal therapy toxicity in oncohematological adult patients. AB - OBJECTIVE: To assess the toxicity of a standardized triple intrathecal chemotherapy in onco- hematological adult patients and to establish risk factors of toxicity. METHOD: Observational and prospective study of standardized triple intrathecal chemotherapy administrations in onco-hematologic adult patients for 18 months. RESULTS: There were some adverse events in 39.3% of the 56 administrations registered. 96.7% of the events were grade 1-2 and only 1 event was grade 3. The lower age of the patient and the greater difference between the administered drug volume and cerebrospinal fluid removed volume were shown as risk factors for toxicity. CONCLUSIONS: The administration of standardized triple intrathecal chemotherapy was related to a low frequency of toxicity and most of adverse events were mild-moderate. The detection of adverse effects was significantly greater in young adults and in those administrations where the difference between cerebrospinal fluid remove volume and the administered drug was greater. PMID- 28847251 TI - Polypharmacy and potential drug-drug interactions in an HIV-infected elderly population. AB - OBJECTIVE: Comorbidities associated with the ageing of the HIV+ population may require chronic treatment. Our aim is to determine the degree of polypharmacy and the number of potential drug-drug interactions, as well as the relationship between both variables in a HIV-infected population over the age of 65. METHODS: Descriptive transversal study targeting HIV+ patients aged >=65, attended in a Spanish hospital in 2014. The prevalence of polypharmacy (>=5 drugs) and potential drug-drug interactions were assessed, and also risk factors associated with such. RESULTS: 265 subjects aged >=65 years were identified, 197 of whom were on antiretroviral treatment and had data about their electronic prescription. 93% were polymedicated. The patients whose antiretroviral treatment included a non-nucleoside reverse transcriptase inhibitor (NNRTI) demonstrated a fourfold probability of being polymedicated. 65% of the patients showed at least one potential drug-drug interaction and 6.6% a severe potential drug-drug interaction. The risk of interaction was significantly associated with the number of prescribed drugs (incidence rate ratio per prescribed drug, CI 95%: 1.18 (1.14;1.22; p<0.0001) and with the use of protease inhibitors (PI) (incidence rate ratio, CI 95%: 1.65 (1.28;2.11; p=0.0001)). CONCLUSION: Polypharmacy has a high prevalence and is more common in patients treated with NNRTI. The number of potential drug-drug interactions increase with the number of prescribed drugs and is higher in those patients on PI. PMID- 28847252 TI - Chemical stability of ondansetron hydrochloride with other drugs in admixtures via parenteral; a review. AB - OBJECTIVE: This review was prepared to offer the most complete information about the use of ondansetron in parenteral admixtures with other drugs. METHOD: The search was done from September 2016 to April 2017 by using electronic databases Stabilis(r) and Micromedex(r) solutions, Medline/PubMed and Scholar Google searching publications about ondansetron stability in parenteral infusion when is administered by itself or with other medication. RESULTS: 49 studies are included with a total of 53 drugs. 15 drugs were found compatible administered with ondansetron in a clinical routine concentration range in intravenous administration. Also, four ternary blends were found compatible and another one was incompatible. Otherwise, 38 drugs were found incompatible. DISCUSSION: Compatibility of ondansetron offers a broad number of options to be used to avoid nausea and vomiting symptoms in patients with other concomitant medication. PMID- 28847253 TI - Pre-exposure prophylaxis (PrEP) against HIV: efficacy, safety and uncertainties. AB - Despite the global stabilization of the number of new HIV infections in recent years, there has been an increase in new infections among men who have sex with men. This fact indicates the lack of effectiveness of the measures and prevention campaigns established so far for this group. It is therefore necessary to implement alternative preventive measures for them. Pre-exposure pharmacological prophylaxis (PrEP) is one of the best evaluated options and has had high protection rates in both clinical and real-life trials. The strategy has also shown an adequate profile in terms of safety, tolerance, adverse effects and cost effectiveness in the studies carried out to assess this important topic. PMID- 28847254 TI - [Sodium thiosulfate in the treatment of calcific uremic arteriolopathy (calciphylaxis)]. PMID- 28847255 TI - [Young patient diagnosed with severe poisoning caused by yew leaves]. PMID- 28847256 TI - [Dalbavancin in the treatment of skin and soft tissues infection]. PMID- 28847257 TI - [Severe trombopenia induced by imipenem: a low frecuent association]. PMID- 28847259 TI - Development of the Anticholinergic Burden Calculator Web Tool. PMID- 28847258 TI - [Formulation of neomycin and streptomycin for the digestive decontamination of carbapenemases producing klebsiella pneumoniae]. PMID- 28847260 TI - [Traceability of oncohematological drugs through data capture codes]. PMID- 28847261 TI - [61 SEFH Congress; Outstanding Clinical Cases (second part)]. PMID- 28847262 TI - Effect of Over 10-Year Cryopreserved Encapsulated Pancreatic Islets Of Langerhans. AB - OBJECTIVES: Immunoisolation of pancreatic islets of Langerhans performed by the encapsulation process may be a method to avoid immunosuppressive therapy after transplant. The main problem related to islet transplant is shortage of human pancreata. Resolution of this obstacle may be cryopreservation of encapsulated islets, which enables collection of sufficient numbers of isolated islets required for transplant and long-term storage. Here, we assessed the ability of encapsulated islets to function after long-term banking at low temperature. MATERIALS AND METHODS: Islets of Langerhans isolated from rat, pig, and human pancreata were encapsulated within alginate-poly-L-lysine-alginate microcapsules. Cryopreservation was carried out using a controlled method of freezing (Kriomedpol freezer; Kriomedpol, Warsaw, Poland), and samples were stored in liquid nitrogen. After 10 years, the samples were thawed with the rapid method (with 0.75 M of sucrose) and then cultured. RESULTS: We observed that microcapsules containing islets maintained their shape and integrity after thawing. During culture, free islets were defragmented into single cells, whereas encapsulated islets were still round in shape and compact. After 1, 4, and 7 days of culture of encapsulated islets, the use of 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide tests showed increased mitochondrial activity. After they were thawed, the insulin secretion capacity was comparable with that obtained with fresh islets. CONCLUSIONS: Cryopreservation and storage of free and microencapsulated islets were possible for about 10 years, although only encapsulated islets retained viability and secretory properties. PMID- 28847263 TI - Immunosuppression Practices in Liver Transplantation: A Survey of North American Centers. AB - OBJECTIVES: There is a clear lack of clinical evidence guiding immunosuppressive management in long-term stable liver transplant recipients. As a result, anecdotal experience suggests wide variability across transplant centers. We aimed to identify patterns of immunosuppression practices in liver transplant centers across Canada and the United States. MATERIALS AND METHODS: From February 9 to May 31, 2015, we invited clinicians from all liver transplant centers in Canada and the United States to answer a 6-question survey generated using SurveyMonkey. RESULTS: Seventeen respondents from 15 liver transplant centers completed the survey. Although immun-suppressive practices are relatively uniform for induction and early maintenance therapy, significant variations exist in the management of long-term immunosuppression in stable transplant recipients with a relative lack of minimization protocols. CONCLUSIONS: Our survey confirms a wide variability in immunosuppression practices across Canadian and US liver transplant centers. Research and practice priorities include design of pragmatic randomized controlled trials and development of clinical practice guidelines to standardize immunosuppressive management of long-term stable liver transplant recipients with a focus on immunosuppression minimization. PMID- 28847264 TI - Pre- and Posttransplant Refractory Idiopathic Membranous Glomerulonephritis: The Forgotten Potential Culprit. AB - Idiopathic membranous nephropathy has been recently recognized as an autoimmune disease that may recur or develop de novo posttransplant, whereby specific auto- or alloantibodies are directed against recently recognized podocyte structures such as the phospholipase receptor PLAR2 and the thrombospondin receptor THSD7A. The observed inconsistencies in therapeutic responses with all presently recognized therapies irrespective of immunosuppressive regimen used and the superiority of complete and sustained remission rates in recurrent disease after kidney transplant compared with native disease imply the existence of different immunopathogenic signatures that may be operational, either isolated or combined, in the pathogenesis of membranous nephropathy. These pathogenic mechanisms involve primarily B-cell-mediated pathways with a T-cell help component and distinct auto- and alloantibody-secreting mechanisms involving different B cells. These pathways are present in separate compartments such as in CD20+-activated B cells found in spleen and lymph nodes, CD19+/CD20- plasmablasts and short-lived plasma cells in the blood, and CD19-/CD20-/CD38+/CD138+ long-lived memory plasma cells niched naturally in the bone marrow and ectopically in the native or grafted inflamed kidney. These latter nonproliferating plasma cells lacking CD19 and CD20 markers would be resistant to in vivo B-cell depletion by anti-CD20 monoclonal therapies. They produce considerable amounts of immunoglobulin G (IgG) autoantibodies and alloantibodies and provide the basis for humoral memory and refractory autoimmune diseases. This may explain the limited rate of sustained complete remission, which, as observed in most studies, does not exceed a rate of 20% in all rituximab-treated patients despite total B-cell eradication. There is an important need for the development of new biomarkers to help identify and predict therapeutic responses. Potential new therapeutic targets against plasma cells such as proteasome inhibitors, anti-CD38 monoclonal antibodies, and autoreactive pathogenic B-cell-specific depleting regimens, as well as new anti CD20 monoclonal antibodies, may help tailor therapy to the individual need for optimal outcome. PMID- 28847265 TI - In Silico Modeling of Crabtree Effect. AB - BACKGROUND AND OBJECTIVE: Glycolytic activity during Crabtree effect is similar to that in tumor cells. Research regarding Crabtree effect is very much crucial. METHODS: The mechanism of metabolic activities in glycolysis pathway and oxidative phosphorylation pathway in regards to Crabtree effect in Saccharomyces cerevisiae was studied in this paper. We also explored the effects of hexose phosphates in the activities of respiratory chain complexes (III and IV) in inhibition of respiration. Besides, the enhancement of fermentation in response to excess glucose concentration was studied. We discussed the significance of Crabtree effect in mammalian cancer in terms of Crabtree effect in a Crabtree positive organism, as it is similar to cancer metabolism in mammalian cells. We developed an in silico model of Crabtree effect. RESULTS: A comparative study was performed with laboratory experiments regarding inhibitory role of fructose 1,6 bisphosphate on metabolic respiration. The model was simulated for different concentration levels of glucose and hexose phosphates using COPASI and SNOOPY tools. CONCLUSION: We have shown that a hike in glucose concentration increases ethanol concentration and leads glycolytic activity towards fermentation. This phenomenon occurs during Crabtree effect. PMID- 28847267 TI - TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis. AB - Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The health and economic burden of skin cancer treatment is substantial, creating an increasingly urgent need for the development of improved molecular strategies for photoprotection and photochemoprevention. The role of Toll-like receptor 4 (TLR4) as a key regulator of skin anti-microbial defense, wound healing, and cutaneous tumorigenic inflammation has now been recognized, and recently published evidence suggests that TLR4 represents a novel molecular target for skin photoprotection and cancer photochemoprevention. Specifically, it has been shown that pharmacological and genetic antagonism of TLR4 suppresses UV-induced inflammatory signaling involving the attenuation of cutaneous NF-kappaB and AP-1 stress signaling observable in vitro and in vivo. A number of TLR4-directed small molecule pharmacological antagonists [including eritoran, (+)-naloxone, ST2825, and resatorvid] have now been identified and are at various stages of preclinical and clinical development for the modulation of dysregulated TLR4-dependent inflammatory signaling. PMID- 28847266 TI - Independent Relationship between Serum Osteocalcin and Uric Acid in a Cohort of Apparently Healthy Obese Subjects. AB - BACKGROUND: It is generally accepted that serum osteocalcin (OC) is a reliable marker of bone formation, while the role of serum uric acid (UA) in bone metabolism is still debated. However, recent studies have shown that endogenous UA within the normal range may exert a positive effect in bone formation by means of its antioxidant role in both sexes. To date, no studies have been carried out in obese subjects aiming to study the relationship between serum OC and UA, given that obesity is considered as a risk factor for osteoporosis and fracture and, at the same time, for cardiovascular events. OBJECTIVES: Our search purpose was to verify the relationship between endogenous levels of OC and serum UA in a cohort of obese subjects without any metabolic or chronic diseases (i.e. hypertension, renal failure, diabetes mellitus, etc.). MATERIALS AND METHODS: One hundred and twenty one obese subjects (93 women and 28 men) were enrolled for this study. Serum OC and UA were assessed and compared with demographic characteristics, clinical and biochemical parameters (age, body mass index (BMI), blood pressure, waist circumference, serum lipids and glycaemia). RESULTS: Serum OC was directly and independently correlated with circulating UA in our population of obese subjects, while neither BMI, age, serum lipids, fasting glycaemia nor gender showed a statistically significant correlation with endogenous plasma levels of OC. CONCLUSION: The positive effect determined by serum OC in bone metabolism of our obese subjects might be partly due to the antioxidant properties that normal plasma UA levels exert at bone tissue level. PMID- 28847268 TI - Design, Synthesis and Biological Evaluation of Spiro Cyclohexane-1,2-Quinazoline Derivatives as Potent Dipeptidyl Peptidase IV Inhibitors. AB - Inhibition of dipeptidyl peptidase IV (DPP-4) is currently one of the most valuable and potential chemotherapeutic regime for the medication of type 2 diabetes mellitus (T2DM). Based on linagliptin, this study discusses the design, synthesis and biological evaluation of spiro cyclohexane-1,2'-quinazoline scaffold hybridized with various heterocyclic ring systems through different atomic spacers as a highly potent DPP-4 inhibitors. DPP-4 enzyme assay represented that most of the target compounds are 102-103 folds more active than the reference drug linagliptin (IC50: 0.0005-0.0089 nM vs 0.77 nM; respectively). Moreover, in vivo oral hypoglycemic activity assay revealed that most of the tested candidates were more potent than the reference drug sitagliptin producing rapid onset with long duration of activity that extends to 24 h. Interestingly, the derivatives 11, 16, 18a and 23 showed evidence of mild cytochrome P450 3A4 (CYP3A4) inhibition (IC50; > 210 uM) and their acute toxicity (LD50) were more than 1.9 gm/kg. Molecular simulation study of the new quinazoline derivatives explained the obtained biological results. Finally, we conclude that our target compounds could be highly beneficial for diabetic patients in the clinic. PMID- 28847269 TI - T-shaped Peptide Amphiphiles Self Assemble into Nanofiber Networks. AB - BACKGROUND: Conventional nanofiber forming peptide amphiphiles comprise a beta sheet forming, short peptide sequence with an alkyl chain attached at one terminus. We report the selfassembly of a peptide amphiphile possessing a mid chain located alkyl substituent (a T-shaped peptide amphiphile) into nanofiber networks. METHOD: Peptide synthesis was carried out using standard 9 fluorenylmethoxycarbonyl solid phase peptide synthesis protocols, followed by covalent attachment of the alkyl chains to yield target peptide amphiphiles. Self assembly was then studied using electron microscopy and coarse-grained molecular dynamics simulations. RESULTS: T-shaped peptide amphiphiles self-assembled into nanofibers just like linear peptide amphiphiles, but then unlike linear peptide amphiphiles, T-shaped peptide amphiphiles formed inter-fiber associations and ultimately nanofiber networks. CONCLUSION: Changing the position of the alkyl chain in a peptide amphiphile from the terminal end of the peptide to the middle part of the peptide, to form a T-shaped peptide amphiphile, does not disrupt the molecular interactions required for the self-assembly of the peptide amphiphiles into nanofibers. PMID- 28847270 TI - Development of Timolol Maleate Loaded Chitosan Nanoparticles For Improved Ocular Delivery. AB - BACKGROUND: The poor retention and penetration are the major issues in the bioavailability of drugs through ocular route. Recently, the natural polymers have been exploited for the development of nanoparticles to improve the ocular performance of various drugs. In the present investigation, nanoparticles of timolol maleate (TM) were developed by using chitosan polymer to improve its release through ocular delivery. METHOD: Ionic gelation method was used for the development of timolol loaded chitosan nanoparticles by using a cross linking agent, sodium tripolyphosphate (NaTPP). The Box- Behnken design was used for the optimization of various parameters for the development of nanoparticles. OBJECTIVE: The objective behind the study was to study the effect of three critical parameters; concentration of chitosan (X1), the concentration of NaTPP (X2), and the volume of NaTPP (X3) on the drug release from the prepared nanoparticles. RESULTS: The results obtained showed that high level of the chitosan concentration and low level of the NaTPP concentration and the mid levels of the NaTPP volume resulted in high levels of encapsulation efficiency. The loading capacity was found maximum at a low level of chitosan and mid level of volume of the NaTPP with a low level of NaTPP concentration. The optimized batch (NP-2) showed that the entrapment efficiency was 75.34+/-0.17%, the particle size of 190.9 nm and in vitro cumulative percentage of drug release was 49.11+/-0.49% in 12 h. CONCLUSION: The study concluded that chitosan nanoparticles loaded with timolol maleate resulted in improved drug release for ocular treatment. PMID- 28847271 TI - Influence of Divalent Cation on Morphology and Drug Delivery Efficiency of Mixed Polymer Nanoparticles. AB - BACKGROUND: Biopolymeric nanoparticles comprising chitosan-alginate have attracted interest in drug delivery due to their protective nature, biocompatibility, biodegradability and hydrophilicity. OBJECTIVE: The present study was designed to encapsulate levofloxacin in chitosan-alginate hybrid gel for controlled release and to evaluate the effect of divalent alkaline earth metal ions (Mg2+, Ca2+, Sr2+, Ba2+) on encapsulation efficiency and drug release kinetics considering their role in polyelectrolyte gelation method. METHOD: Divalent metal ions control the rigidity and elasticity of the hydrogels and have the ability to change the shape and size of nanostructure formed by chitosan alginate. The particle size increases and encapsulation efficiency decreases with the size of the divalent ions. Spherical shaped particles were formed by Mg2+ and Ca2+, whereas Sr2+ and Ba2+ produced non-spherical particles. RESULTS: SEM image clearly shows transformation of sphere to truncated tetrahedron by Sr2+ and clear rod shape by Ba2+. CONCLUSION: Therefore, it is concluded that metal ions have significant influence on the morphology and drug encapsulation and release profile of the chitosan-alginate hybrid polymer nanoparticles. PMID- 28847272 TI - Oral Vaccination Through Peyer's Patches: Update on Particle Uptake. AB - BACKGROUND: Oral immunization has numerous advantages over parenteral administrations. In addition to ease administration, more effective pathogen elimination on the mucosa before spreading into the blood circulation, constitutes the main benefit. This is particularly true for pathogens that enter the body through the oral route. On the other hand, it is the most challenging administration route for peptides, proteins and recombinant antigens due to gastrointestinal (GI) tract, numerous barriers including the harsh environment and the inherent weak immunogenicity. In addition to the adjuvant properties, polymeric particles arise as the most promising strategy to overcome poor antigen bioavailability/ stability upon oral administration. The Peyer's patches have been considered an important structure of the gut associate lymphoid tissue (GALT) for the initiation of the immune response towards particulate oral antigens. OBJECTIVE: The transport mechanism of both, nano and microparticles across intestinal mucosa, particularly throughout Peyer's patches, is discussed in this review. CONCLUSION: We provide a short and concise update (last decade) focused on the importance of particle physicochemical properties, M-cell ligands and size-dependent transport and intracellular fate concerning Peyer's patches targeted oral vaccination. PMID- 28847273 TI - Copaiba Oil: Chemical Composition and Influence on In-vitro Cutaneous Permeability of Celecoxib. AB - BACKGROUND: Use of topical or transdermal administration of Celecoxib (Cxb) is an interesting strategy in cutaneous treatments since it reduces or avoids side effects of the oral route. However, Cxb's high lipophilicity and the stratum corneum (SC) barrier impair cutaneous penetration. OBJECTIVE: Evaluation of copaiba oil (C.O) as a potential skin penetration enhancer (P.E) for Cxb. METHODS: The chemical composition of C.O was evaluated by GC-MS. Both in-vitro release and permeability assay of Cxb in Polyethylene glycol 400/ propylene glycol (PEG 400/PG) vehicle associated to C.O (1-50% w/w) were determined in a modified diffusion cell fitted with a synthetic hydrophobic membrane and pig ear skin as model, respectively. RESULTS: GC-MS analysis of C.O showed that it is composed of sesquiterpenes (68.65%) and diterpenes (22.26%). Formulations containing 25% C.O (F4) and 50% C.O (F5) have shown in-vitro burst release in the first 2 h, but only F4 released 100% of drug after 24 h. The highest Cxb permeation across skin was obtained from F4 and the highest skin retentions for F4 and F5 in the stratum corneum and epidermis plus dermis. CONCLUSION: The increased Cxb permeability through skin and its retention for an extended time (24h) at 25% C.O suggest that it could be a promising adjuvant for the development of transdermal formulations of Cxb. PMID- 28847274 TI - Nano Era of Dentistry-An Update. AB - BACKGROUND: Management of the health of oral tissues is a prime requirement in dentistry. The prevention of tooth decay and the treatment of lesions and cavities are ongoing challenges. The limitations in dental materials, medications, instruments, procedures put off the accomplishment of this goal. Rationalization of science and technology has made possible to work out these limitations. Nanotechnology which is the outcome of this rationalization has become one of the most favored technologies in medical and dental application. The substantial contribution of nano dental materials is the identification of oral health related problems by better diagnosis and management of dental disorders by bionanomaterials. CONCLUSION: Application of nanodentistry holds promise for comprehensive dental care by utilizing nanomaterials and ultimately by nanorobots. This review discusses the rationale of nanodentistry, nanocarriers researched in treatment of different dental diseases, the latest innovations in nanomaterials in various disciplines of dentistry; patent literature and related marketed products. Advances in nanotechnology have placed plenty of hopes in terms of improving the oral health care of dental patients. PMID- 28847275 TI - Pharmacologic Considerations during the Preoperative Evaluation of Neurologic Patients. AB - BACKGROUND: Optimizing a patient for surgery is a central goal during the preoperative period. Patients with common neurologic disorders, such as Alzheimer's disease, epilepsy, Parkinson's disease, and multiple sclerosis may require special attention in the perioperative management of their neurologic medications. OBJECTIVE: This review aims to organize the most current recommendations for neurologic medication management during the perioperative period to minimize the risk of postoperative neurologic decline. METHODS: A review of current literature present on PubMed and Medline of peer-reviewed research papers was conducted. The quality of the papers was assessed according to their research methodology and many of their sources were further analyzed in the same manner. A focused review question for each disease type was used, and, at times, inclusion and exclusion criteria were applied. RESULTS: Manuscripts covered a wide range of medical subspecialties with the most common sources being anesthetic, neurologic, and pharmacologic journals. CONCLUSION: The systemic inflammation that occurs in the perioperative period is detrimental to a patient's neurologic status. It is important to recognize that the proper management of neurologic medications can limit the negative effects of these stresses on a patient. Most medications appear safe to continue until the morning of surgery. Consultation with a neurologist regarding continuation of specific medications may be necessary to further ensure patient safety. PMID- 28847276 TI - Perioperative Management of Beta Blockers and Other Antiarrhythmic Medications. AB - BACKGROUND: Antiarrhythmic medications are an important tool in preventing recurrence of intraoperative and postoperative arrhythmias. OBJECTIVE: To review current literature and recommendations for perioperative management of antiarrhythmic medications. METHODS: Literature review is presented along with the pharmacology of antiarrhythmics. RESULTS: Antiarrhythmic medications should be continued perioperatively for the prevention of arrhythmias intra- and postoperatively. However, beta blockers have had controversies regarding their perioperative safety profile. CONCLUSION: Continuation of antiarrhythmic medications is safe perioperatively. However, initiation of beta blockers should be patient-tailored and titrated to a target heart rate in advance surgery. PMID- 28847277 TI - Evaluating Scientific Research Knowledge and Attitude Among Medical Representatives in Jordan: A Cross-sectional Survey. AB - BACKGROUND: Pharmaceutical companies provide a broad range of different mandatory trainings to their medical representatives to keep the business running; however research related training has often been neglected by these companies. Thus, this study was developed to assess the amount of scientific research knowledge and interest among pharmacy medical representatives in Jordan. METHOD: A cross sectional study was conducted in Jordan in 2016. During the study period, a questionnaire was administered to 250 medical representatives working in pharmaceutical companies to evaluate their scientific research knowledge and attitudes. RESULTS: The majority of medical representatives had positive attitudes towards clinical trials and research communication and believe that it will increase the value of their work, but a considerable number of medical representatives did not detail clinical trials on every visit and found difficulty in answering clinical trials and research related questions asked by health care professionals. Most of the medical representatives did not have a complete understanding of some basic research terminologies. Medical representatives working in multinational companies seemed to have a significantly better understanding of research and terminologies compared to local companies (P value= 0.000). Also Medical representatives with higher educational degrees seemed to have significantly better understanding of basic research terminologies (P-value= 0.023). CONCLUSION: The majority of medical representatives had positive attitudes towards clinical trials and research communication and found that it will increase the value of their work, but still there is a gap in their frequency of detailing. Thus, local pharmaceutical companies need to invest more in research and clinical trials knowledge kind of training. Also, universities need to include research related courses and subject in their bachelors' program curriculum in order to make pharmacists equipped in terms of research knowledge, regardless of the career path they choose. PMID- 28847278 TI - The Phosphoinositide Signal Transduction Pathway in the Pathogenesis of Alzheimer's Disease. AB - BACKGROUND: During aging and in age-associated disorders, such as Alzheimer's Disease (AD), learning abilities decline. Probably, disturbances in signal transduction in brain cells underlie the cognitive decline. The phosphorylation/dephosphorylation imbalance occurring in degenerating neurons was recently related to abnormal activity of one or more signal transduction pathways. AD is known to be associated with altered neuronal Ca2+ homeostasis, as Ca2+ accumulates in affected neurons leading to functional impairment. It is becoming more and more evident the involvement of signal transduction pathways acting upon Ca2+ metabolism and phosphorylation regulation of proteins. A growing interest raised around the role of signal transduction systems in a number of human diseases including neurodegenerative diseases, with special regard to the systems related to the phosphoinositide (PI) pathway and AD. The PI signal transduction pathway plays a crucial role, being involved in a variety of cell functions, such as hormone secretion, neurotransmitter signal transduction, cell growth, membrane trafficking, ion channel activity, cytoskeleton regulation, cell cycle control, apoptosis, cell and tissue polarity, and contributes to regulate the Ca2+ levels in the nervous tissue. CONCLUSION: A number of observations indicated that PI-specific phospholipase C (PLC) enzymes might be involved in the alteration of neurotransmission. To understand the role and the timing of action of the signalling pathways recruited during the brain morphology changes during the AD progression might help to elucidate the aetiopathogenesis of the disease, paving the way to prognosis refinement and/or novel molecular therapeutic strategies. PMID- 28847279 TI - Use of Speech Analyses within a Mobile Application for the Assessment of Cognitive Impairment in Elderly People. AB - BACKGROUND: Various types of dementia and Mild Cognitive Impairment (MCI) are manifested as irregularities in human speech and language, which have proven to be strong predictors for the disease presence and progress ion. Therefore, automatic speech analytics provided by a mobile application may be a useful tool in providing additional indicators for assessment and detection of early stage dementia and MCI. METHOD: 165 participants (subjects with subjective cognitive impairment (SCI), MCI patients, Alzheimer's disease (AD) and mixed dementia (MD) patients) were recorded with a mobile application while performing several short vocal cognitive tasks during a regular consultation. These tasks included verbal fluency, picture description, counting down and a free speech task. The voice recordings were processed in two steps: in the first step, vocal markers were extracted using speech signal processing techniques; in the second, the vocal markers were tested to assess their 'power' to distinguish between SCI, MCI, AD and MD. The second step included training automatic classifiers for detecting MCI and AD, based on machine learning methods, and testing the detection accuracy. RESULTS: The fluency and free speech tasks obtain the highest accuracy rates of classifying AD vs. MD vs. MCI vs. SCI. Using the data, we demonstrated classification accuracy as follows: SCI vs. AD = 92% accuracy; SCI vs. MD = 92% accuracy; SCI vs. MCI = 86% accuracy and MCI vs. AD = 86%. CONCLUSIONS: Our results indicate the potential value of vocal analytics and the use of a mobile application for accurate automatic differentiation between SCI, MCI and AD. This tool can provide the clinician with meaningful information for assessment and monitoring of people with MCI and AD based on a non-invasive, simple and low-cost method. PMID- 28847280 TI - Voice Markers of Lexical Access in Mild Cognitive Impairment and Alzheimer's Disease. AB - BACKGROUND: Recent studies have identified the correlation between dementia and certain vocal features, such as voice and speech changes. Vocal features may act as early markers of Alzheimer's disease (AD). Despite being present in non pathological senescence and Mild Cognitive Impairment, especially in its amnesic subtype (aMCI), these voice- and speech-related symptoms are the first signs of AD. The purpose of this study is to verify whether these signs are related to deficits in lexical access, which appear early in AD. METHOD: Anomic deficits in persons with MCI and AD are assessed through tests on verbal memory, denomination by confrontation, and verbal fluency. In addition, an acoustic analysis of speech is conducted in a reading task to identify the acoustic parameters associated with the groups analyzed, and their relation to the degree of anomic impairment observed in each one of them. RESULTS AND CONCLUSIONS: The results show a direct relationship between the different acoustic parameters present in AD and the verbal fluency tests results. PMID- 28847282 TI - Ginkgo biloba Extract EGb761 Attenuates Hyperhomocysteinemia-induced AD Like Tau Hyperphosphorylation and Cognitive Impairment in Rats. AB - BACKGROUND: Ginkgo biloba extract EGb761 has shown the neuroprotective effects on Alzheimer's disease (AD) through the protection against the Abeta-induced neurotoxicity. However, it is not completedly clear whether EGb761 attenuates tau hyperphosphorylation, another of the most prominent mechanisms underlying the pathology of AD. METHODS: we employed hyperhomocysteinemia (HHcy) to mimic AD like pathological alterations and memory deficits in rats as model, and injected EGb761 with or after HHcy injection as prevention and treatment, injected saline as control. We measured the status of oxidative damage and spatial and learning memory in rats. Then we detected the level of memory-related proteins, tau phosphorylation and the level and activity of tau kinase (GSK-3beta) and phosphatase (PP2A) by Western blotting and Immunohistochemistry. RESULTS: We found that EGb761 could significantly antagonize HHcy-induced oxidative damage, recover PP2Ac and GSK3beta activities deregulated by HHcy. Furthermore, tau was hyperphosphorylated at Thr231, Ser262, Ser396, and Ser404, most common PP2Ac and GSK3beta targeted sites in the hippocampus and prefrontal cortex of HHcy rats, whereas EGb761 recovered the tau phosphorylation at those sites. Behavioral tests revealed that EGb761 rescued HHcy-induced spatial reference memory deficit and upregulated the expression of synapse-associated protein PSD95 and synapsin-1. CONCLUSION: EGb761 might be a promising drug to treat AD through its anti oxidative activity and decreasing tau hyperphosphorylation besides the protection against the Abeta-induced neurotoxicity. PMID- 28847281 TI - Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease. AB - BACKGROUND: Psychosis is a common phenomenon in Alzheimer's disease (AD). The APOE epsilon4 allele is the strongest genetic risk factor for the development of AD, but its association with psychosis remains unclear. OBJECTIVE: We investigated the associations between psychosis, subdivided into delusions and hallucinations, as well as APOE epsilon4 allele on cognitive and functional outcomes. Secondarily, we investigated the associations between APOE epsilon4, Lewy bodies, and psychosis. METHODS: Data from the National Alzheimer's Coordinating Center (NACC) were used. Nine hundred patients with a confirmed diagnosis of AD based on the NIA-AA Reagan were included in the analysis. Global cognition was assessed using the Mini-Mental State Exam (MMSE) and functional status was assessed using the Functional Activities Questionnaire (FAQ). Psychosis status was determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Factorial design was used to assess the effects of psychosis and APOE epsilon4, as well as their interaction. RESULTS: Psychosis and the presence of APOE epsilon4 were both associated with lower MMSE scores, while only psychosis was associated with higher FAQ scores. Furthermore, patients with hallucinations had lower MMSE and higher FAQ scores than patients with only delusions. There was a significant interaction effect between psychosis and APOE epsilon4 on MMSE scores, with APOE epsilon4 negatively affecting patients with hallucinations-only psychosis. APOE epsilon4 was positively associated with the presence of Lewy body pathology, and both were found to be more prevalent in psychotic patients, with a stronger association with hallucinations. CONCLUSION: Psychosis in AD was associated with greater cognitive and functional impairments. Patients with hallucinations-with or without delusions-conferred even greater deficits compared to patients with only delusions. The APOE epsilon4 allele was associated with worse cognition, especially for patients with hallucination-only psychosis. APOE epsilon4 may mediate cognitive impairment in the hallucinations phenotype through the development of Lewy bodies. Our findings support that subtypes of psychosis should be evaluated separately. PMID- 28847283 TI - miRNAs in Alzheimer Disease - A Therapeutic Perspective. AB - BACKGROUND: Alzheimer's disease is a neurodegenerative disorder which generally affects people who are more than 60 years of age. The disease is clinically characterised by dementia, loss of cognitive functions and massive neurodegeneration. The presence of neurofibrilary tangles and amyloid plaques in the hippocampal region of the brain are the hallmarks of the disease. Current therapeutic approaches for the treatment of Alzheimer's disease are symptomatic and disease modifying, none of which provide any permanent solution or cure for the disease. Dysregulation of miRNAs is one of the major causes of neurodegeneration. CONCLUSION: In the present review, the roles of different miRNAs such as miR-9, miR-107, miR-29, miR-34, miR-181, miR-106, miR-146a, miR132, miR124a, miR153 has been discussed in detail in the pathogenesis of various neurodegenerative diseases with special focus on AD. The probability of miRNAs as an alternative and more sensitive approach for detection and management of the AD has also been discussed. PMID- 28847284 TI - Modulation of Inflammation as a Way of Delaying Alzheimer's Disease Progression: The Diet's Role. AB - BACKGROUND: Most of the recent reports suggest that inflammatory mediators play a central role in the etiopathogenesis of Alzheimer's disease (AD) and that the conditions leading to a chronic low-grade inflammation, such as stress, depression, obesity and metabolic syndrome, increase the odds of developing Mild Cognitive Impairment (MCI) and AD. Microglia cells are the main actors in the AD process: stimuli from the microenvironment may induce microglia cells to switch to a classically activated inflammatory phenotype M1, or, on the contrary to an alternatively activated M2 phenotype characterized by the secretion of different types of cytokines. Many attempts are currently being made in order to delay the progression of AD by reducing inflammatory mechanisms underlying the disease. Several studies support a relationship among neuroinflammation and nutrients, foods or dietary patterns, taking into account the synergistic or antagonistic biochemical interactions among nutrients as well as the different food sources of the same nutrient. Natural antioxidant and anti-inflammatory compounds found in plant foods, such as fruits, particularly berries (such as strawberry, blueberry, blackcurrant, blackberry, blueberry and mulberry) have been shown to exert neuroprotective activity. It is still unclear whether the dietary bioactive compounds enter the Blood Brain Barrier (BBB) playing a direct antiinflammatory or pro-inflammatory effect on microglia and/or other Central Nervous System (CNS) cells. Another hypothesis is that they may trigger a peripheral reaction that induce indirectly a CNS' response. The subsequent synthesis of cytokines may drive microglia polarization by different ways. So, via an indirect route microglia detects and responds to immune-to-brain signaling. CONCLUSION: This review summarizes current evidence about the potential mechanisms of the interaction among diet, neuroinflammation and AD. PMID- 28847285 TI - Relations between Sensorimotor Integration and Speech Disorders in Parkinson's Disease. AB - BACKGROUND: Sensorimotor integration mechanisms can be affected by many factors, among which are those involving neuromuscular disorders. Parkinson's disease (PD) is characterized by well-known motor symptoms, among which lately have been included motor speech deficits. Measurement of the acoustic startle reflex (ASR) and its modulations (prepulse inhibition and prepulse facilitation, PPI and PPF respectively) represent a simple and quantifiable tool to assess sensorimotor function. However, it remains unknown whether measures of the PPI and PPF are associated with motor speech deficits in PD. METHODS: A total of 88 subjects participated in this study, 52 diagnosed with PD and 36 control subjects. After obtaining written informed consent, participants were assessed with PPI at several interstimulus intervals, and PPF at 1000 ms using the SRH-Lab system (San Diego, CA). Percentage of change in the amplitude and latency of the ASR was analyzed between groups. Voice recordings were register of a specific text given to the subjects with a professional recorder and temporal patterns of speech were analyzed. RESULTS: Statistical analysis conducted in this study showed differences in PPI and PPF in subjects with PD compared to controls. In addition, discriminative parameters of voice abnormalities were observed in PD subjects related to control subjects showing a reduction in phonation time, vowel pulses, breaks, breakage and voice speech periods. CONCLUSIONS: PD presents a disruption in sensorimotor filter mechanisms and speech disorders, and there is a relationship between these alterations. The correlation between the PPI and PPF with an alteration of the voice in PD subjects contributes toward understanding mechanism underlying the neurophysiological alterations in both processes. Overall, easy and non-invasive tests such as PPI, PPF together with voice analysis may be useful to identify early stages of PD. PMID- 28847286 TI - Review of Pediatric Osteoarticular Infections. AB - BACKGROUND: Pediatric osteoarticular infections are relatively rare but important diseases to identify early and treat appropriately in order to avoid associated acute complications or long-term morbidity. OBJECTIVE: To review the current epidemiology and etiology of pediatric osteoarticular infections as well as recent advances in the diagnosis and treatment of these infections. METHODS: We searched PubMed (MEDLINE) and Scopus databases for potentially relevant publications in the past 5 years. RESULTS: Bacterial epidemiology and antimicrobial resistance profiles vary greatly worldwide, although Staphylococcus aureus, streptococci and Kingella kingae are the predominant pathogens. There is emerging evidence supporting the role of PCR assays for pathogen detection. CONCLUSION: Current data suggest that most children with osteoarticular infections can be successfully transitioned to oral antibiotics after having received at least several days of intravenous therapy, undergone removal of significant infectious foci and having demonstrated clinical improvement with down trending inflammatory markers. The optimal length and route of antimicrobial therapy have not been fully elucidated and should depend on individual patient factors, the virulence of the pathogen and the monitored clinical and laboratory response to therapy. PMID- 28847287 TI - Analgesia for Children in Acute Pain in the Post-codeine Era. AB - BACKGROUND: Acute pain is one of the most common presenting complaints in pediatric patients presenting to the emergency department. Recently, concern about the safety of narcotics such as codeine has sparked a renewed interest in opioids such as morphine and intranasal fentanyl. OBJECTIVES: Consequently, opioids are being increasingly used in the clinical setting. Despite this, there is ample evidence that clinicians are less willing to offer opioids to children compared to adults. METHODS: The reasons for this are multifactorial but nevertheless, the provision of adequate analgesia in children is echoed by a several academic societies as a priority for comprehensive care. To address this mandate, evidence for therapies such as oral morphine, topical analgesia, and intranasal fentanyl is now mounting. RESULT AND CONCLUSIONS: This review will discuss the evidence and effectiveness of analgesia for children with acutely painful conditions in the post-codeine era. PMID- 28847288 TI - Maternal Empowerment - An Underutilized Strategy to Prevent Kernicterus? AB - BACKGROUND: Kernicterus is a common cause of death and morbidity in many Low- Middle-income Countries (LMICs) and still occurs in affluent nations. In either case, the immediate cause is delayed treatment of severe hyperbilirubinemia. In the West, a provider driven "systems approach" has been widely adopted to identify babies at risk prior to discharge from birthing centers with follow up monitoring based on the serum bilirubin level at time of discharge. The situation is more complicated in regions of the world where kernicterus is endemic, especially in LMICs where Glucose-6-phosphate Dehydrogenase Deficiency (G6PDd) is common and the system of jaundice management is often fragmented. OBJECTIVE: To examine reasons for errors in jaundice management leading to kernicterus and the potential beneficial role of enlisting more parental participation in management decisions. METHOD: We searched world literature related to pitfalls in jaundice management including deficiencies in providers' and parents' knowledge and behavior. Perspectives from mothers of children with kernicterus supplemented the literature review. RESULT: System failures contributing to kernicterus in affluent countries include a lack of follow up planning, bad advice by providers, and a delay in care seeking by parents. In many LMICs, the majority of births occur at home with unskilled attendants. Traditional practices potentiate hemolysis in G6PDd babies. The danger of severe jaundice is frequently underestimated both by parents and care providers, and cultural and economic barriers as well as ineffective therapies delay care seeking. The failure to provide parents information about identifying severe jaundice and knowledge about the risks and treatment of hyperbilirubinemia has contributed to delayed treatment in both affluent and low-middle-income countries. A recent non randomized clinical trial, supports teaching all parents skills to monitor jaundice, signs of early neurotoxicity, the importance of breast feeding, avoidance of ineffective or dangerous practices, and when/where to seek help. CONCLUSION: Empowering parents allow them to participate more fully in care decisions and to confront obstacles to care when provider services fail. PMID- 28847289 TI - Fate of T Cells and their Secretory Proteins During the Progression of Leprosy. AB - Leprosy is an infectious disease caused by non-cultivable bacteria Mycobacterium leprae. Ridley and Jopling classified the disease into five polar forms, Tuberculoid (TT) and Lepromatous (LL), in between two forms of the disease Borderline tuberculoid (BT), Borderline (BB) and Borderline lepromatous (BL) are laid. The tuberculoid type (BT/TT) leprosy patients show good recall of cellmediated immune (CMI) response and Th1 type of immune response, while lepromatous leprosy (LL) patients show defect in cell-mediated immunity to the causative agent and Th2 type of immune response. Due to distinct clinical and immunological spectra of the disease, leprosy attracted immunologists to consider an ideal model for the study of deregulations of various immune reactions. Recent studies show that Tregs, Th3 (TGF-beta, IL-10), IL-35 producing Treg immune response associated with the immune suppressive environment, survival of bugs. IL 17 producing Th17 immune response associated with tuberculoid leprosy and play protective role. gammadelta T cells also increased from tuberculoid to lepromatous pole of leprosy. In this review, we will discuss the role of various subtypes of T-cell and their cytokines in the pathogenesis of leprosy. PMID- 28847290 TI - Protein-protein Interactions and their Role in Various Diseases and their Prediction Techniques. AB - Protein-protein interaction (PPI) is necessary for most of the biological processes and requisite for host-pathogen communication. Most of the threatening human diseases are caused by different types of interactions of proteins with their prior infected proteins or with pathogen's proteins. Understanding of involved mechanisms of interacting pairs, functional domains and characterizing specific molecular interaction of host and pathogen is critical. In this era of advanced research in medical and pharmaceutical sciences, the treatment of severe diseases is being tackled at genetic and PPI level. In this review, a brief introduction and application of PPI is described. Moreover, the classifications of PPI and their application in diseases are highlighted. Furthermore, methods for prediction of PPI are also discussed including brief introduction and update on detection techniques. We hope this review will prove to be very helpful for researchers to get better understanding and update on PPI. PMID- 28847291 TI - Immunogenicity in Protein and Peptide Based-Therapeutics: An Overview. AB - Currently it is well known that all biological drugs, including those with a fully human structure, are capable of inducing a host immune response known as immunogenicity [1]. The presence of ADAs can condition the drug's level and action, thus modifying the therapeutic effect and even the safety profile by its mechanism of action - neutralizing or non-neutralizing - and / or an increase in its clearance. Immunogenicity is a dynamic factor to be taken into account in biological therapy, especially in long-term treatments, and as a relevant aspect in the assessment of secondary response loss [2]. With the above, not only the knowledge but also the management of the immunogenicity of the different biological treatments, represent a useful instrument for optimization of the strategies of use for each drug, and in the design of predictive models of response, which finally permits a significant improvement in the efficacy and safety profile, aiming to a personalization of the therapies, especially in patients with autoimmune diseases, genetic disorders and cancer [3]. This review summarizes the events of immunogenicity that produce the biological drug, the factor that influence to immunogenicity and the assessment of immunogenicity. PMID- 28847292 TI - Therapeutic Targeting of Amyloid Precursor Protein and its Processing Enzymes for Breast Cancer Treatment. AB - Breast cancer cases in women are increasing at an alarming rate globally and extensive research is being conducted to identify a breakthrough medicine against this dreadful disease. In fact, researchers are looking for fresh targets to develop novel treatment strategies for cancer of the breasts. In this article, 'amyloid precursor protein' or (APP) and its processing enzymes are deeply studied so as to explore the same as prospective targets for breast cancer treatment. Even though most of the studies on APP and its processing enzymes have been performed on neuronal cells owing to their linkage with Alzheimer's disease, they are omnipresent on various non-neuronal cells also. Interestingly, APP and its processing enzymes have a role in the proliferation of cancer cells as well as in their growth, adherence and movement. Over-synthesis of APP and its processing enzymes are emerging as important hallmark features in breast cancer. It has been found that APP and its processing enzymes, i.e., gamma-secretase and alpha- secretase are strongly linked with breast cancer via Akt phosporylation and Notch signaling pathways. Thus, targeting APP or gamma-secretase or alpha secretase could be considered as an effective strategy to treat breast cancer and even metastasis. There are various clinical trials which are in progress to explore the potential of gamma-secretase inhibitor against breast cancer. Hence, the present review is composed of two sections, one section deals with all the possible linkages of APP and APP processing enzymes (alpha- secretase, beta secretase and gamma-secretase) with breast cancer. However, the other section provides recent information on breast cancer treatment strategy using APP and APP processing enzymes as targets. We strongly believe that compilation of these studies would be beneficial to the scientist working in the field of 'breast cancer-treatment'. PMID- 28847293 TI - Correlation between Blood and Oral Fluid Psychoactive Drug Concentrations and Cognitive Impairment in Driving under the Influence of Drugs. AB - BACKGROUND: The effects of drugs on driving performance should be checked with drug concentration in the brain and at the same time with the evaluation of both the behavioural and neurophysiological effects. The best accessible indicator of this information is the concentration of the drug and/or metabolites in blood and, to a certain extent, oral fluid. We sought to review international studies on correlation between blood and oral fluid drug concentrations, neurological correlates and cognitive impairment in driving under the influence of drugs. METHODS: Relevant scientific articles were identified from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE up to April 2017. RESULTS: Up to 2010, no epidemiological studies were available on this matter and International scientists suggested that even minimal amounts of parent drugs in blood and oral fluid could affect driving impairment. More recently, epidemiological data, systematic reviews and meta-analysis on drugged drivers allowed the suggestion of impairment concentration limits for the most common illicit drugs. These values were obtained comparing driving disability induced by psychotropic drugs with that of established blood alcohol limits. Differently from ethyl alcohol where both detection methods and concentration limits have been well established even with inhomogeneity of ranges within different countries, in case of drugs of abuse no official cut-offs have yet been established, nor any standardized analytical protocols. CONCLUSION: Multiple aspects of driving performance can be differently affected by illicit drugs, and even if for few of them some dose/concentration dependent impairment has been reported, a wider knowledge on concentration/impairment relationship is still missing. PMID- 28847206 TI - Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. AB - BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .). PMID- 28847297 TI - NGF and BDNF Alterations by Prenatal Alcohol Exposure. AB - BACKGROUND: It is now widely established the devastating effects of prenatal alcohol exposure on the embryo and fetus development causing marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention. OBJECTIVE: Both paternal and maternal alcohol exposure have been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure. METHODS: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways. RESULTS: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns. CONCLUSIONS: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce a potential prevention of the harmful effects of the paternal and/or maternal alcohol exposure. PMID- 28847294 TI - Therapeutic Strategies for Treatment of Inflammation-related Depression. AB - BACKGROUND: Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation- withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation. METHODS: In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies. RESULTS: Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression. CONCLUSION: The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of antiinflammatory co-treatments, is required. PMID- 28847296 TI - Neuron-glia Interaction as a Possible Pathophysiological Mechanism of Bipolar Disorder. AB - Accumulating evidence has shown the importance of glial cells in the neurobiology of bipolar disorder. Activated microglia and inflammatory cytokines have been pointed out as potential biomarkers of bipolar disorder. Indeed, recent studies have shown that bipolar disorder involves microglial activation in the hippocampus and alterations in peripheral cytokines, suggesting a potential link between neuroinflammation and peripheral toxicity. These abnormalities may also be the biological underpinnings of outcomes related to neuroprogression, such as cognitive impairment and brain changes. Additionally, astrocytes may have a role in the progression of bipolar disorder, as these cells amplify inflammatory response and maintain glutamate homeostasis, preventing excitotoxicity. The present review aims to discuss neuron-glia interactions and their role in the pathophysiology and treatment of bipolar disorder. PMID- 28847295 TI - Combination Therapy for Multi-Target Manipulation of Secondary Brain Injury Mechanisms. AB - Traumatic brain injury (TBI) is a major healthcare problem that affects millions of people worldwide. Despite advances in understanding and developing preventative and treatment strategies using preclinical animal models, clinical trials to date have failed, and a 'magic bullet' for effectively treating TBI induced damage does not exist. Thus, novel pharmacological strategies to effectively manipulate the complex and heterogeneous pathophysiology of secondary injury mechanisms are needed. Given that goal, this paper discusses the relevance and advantages of combination therapies (COMTs) for 'multi-target manipulation' of the secondary injury cascade by administering multiple drugs to achieve an optimal therapeutic window of opportunity (e.g., temporally broad window) and compares these regimens to monotherapies that manipulate a single target with a single drug at a given time. Furthermore, we posit that integrated mechanistic multiscale models that combine primary injury biomechanics, secondary injury mechanobiology/neurobiology, physiology, pharmacology and mathematical programming techniques could account for vast differences in the biological space and time scales and help to accelerate drug development, to optimize pharmacological COMT protocols and to improve treatment outcomes. PMID- 28847298 TI - Genetic Aspects of Glial Cells Regarding Neurodegenerative Diseases. AB - Glial cells (also known as glia or neuroglia) are structures which are found in large numbers throughout the nervous system, fulfilling multiple functions, such as regulating the synapses, providing structure, support and nutrition, contributing towards the immune response and tissue oxygenation. Knowledge regarding glial cells has increased during the last few years, since Virchow defined them as supporting connective tissue, followed by Ramon y Cajal who described them as tissue in themselves, until today when a first order physiological role has been recognised for them and a leading role in the appearance and progression of various pathological processes, primarily in the group of Neurodegenerative Diseases (ND). The ND represents a group of pathologies which gradually cause the degeneration of nervous tissue, have a broad spectrum regarding their appearance and, in some cases, are the direct consequence of genetic alterations leading to physiological changes in the nervous system. The present article has thus been aimed at describing glial cells' genetic interaction with ND through a systemic review of the pertinent literature. The mechanisms through which the different classes of glial cells become involved in the appearance of ND are poorly understood; however, evidence indicates that their role could be a critical factor in these pathologies' appearance, regulation and chronicity, these being largely determined by different types of cellular interactions and interaction with the microenvironment. This review shows that ND genetics regarding glial cells' cellular, molecular and genetic functioning represents a complex and understudied process; studying these factors could be a key step for ascertaining the origin of these pathologies, thereby leading to more effective therapies being developed. PMID- 28847299 TI - The Effect of Physical Exercise on Neurogenesis Factor Production in Glial Cells. AB - The effects of physical exercise on cerebral function have been reported in various research studies, thereby leading to better understanding of the brain's cellular mechanisms related to adaptations concerning physical exercise and the different cell responses which become compromised regarding chronic mechanisms. Relearning patterns of movement may thus be an alternative clinical approach affecting cognition and brain plasticity. Recent evidence has shown that neurogenesis can become increased by exercise; nevertheless, moderation mechanisms and the times involved in this process are not at all clear. This review thus provides an update for understanding physical exercise-induced neurogenesis, covering mediating mechanisms and maturation. This is important as glial cell mechanisms are signals activating the neurons and synaptically influencing them, as well as their development, transmission and plasticity via a series of secreted signals depending on contact in human beings. Neurogenesis thus represents a natural model for understanding how new neurons become regenerated and incorporated into brain circuits, thus representing therapeutic potential regarding delay or repair of brain damage caused by injury or disease. PMID- 28847300 TI - Analgesics in Pregnancy: An Update on Use, Safety and Pharmacokinetic Changes in Drug Disposition. AB - BACKGROUND: Although medications should only be prescribed in pregnancy if benefits to the mother outweigh the risk to the fetus, drug use in pregnancy especially prescribed and over-the-counter analgesics, is very common. OBJECTIVE: The objective of this review is to present an update on known changes in analgesic disposition in pregnancy caused by pharmacokinetic mechanisms. METHOD: Herein, we discuss a wide range of medical, biomedical and scientific literature that includes reports from the fields of dentistry, general medicine, obstetrics and gynecology, pharmacology and toxicology to provide an update on the use (including indications, contraindications and concerns) of major classes of analgesics during human pregnancy. RESULTS: Over 50% of analgesics are in pregnancy category C, and even more category D specifically in the third trimester. Changes in renal filtration, cardiac output, plasma protein concentration and plasma volume particularly affect analgesics and dose adjustments may be necessary to maintain therapeutic concentrations in pregnant woman, and/or to protect the developing fetus. CONCLUSION: Analgesics are one of the most frequently used drug classes in pregnancy. More than 60% of women self report using analgesics while pregnant, both prescribed and by self-medication. For the majority of analgesics available (excepting acetaminophen and the NSAIDs, and to a lesser extent certain opioids), good prospective clinical trials documenting pharmacokinetic changes do not exist. More research is needed in both the scientific and clinical community to understand the risks and benefits of analgesic use in pregnancy, particularly as prevalence is rising. PMID- 28847301 TI - Nasal Delivery of Antioxidants by Cholesterol-incorporated Liposomes Extends the Neuroprotective Time Window in Cerebral Ischemia. AB - Antioxidants have the potential to prevent cerebral ischemia-reperfusion (IR) associated secondary damage induced by reactive oxygen species (ROS); however, the short therapeutic time window of IR is a considerable obstacle. Nano-sized nasal delivery systems provide an effective means of delivering drugs through the BBB, but few such systems have been developed to extend the treatment time window in IR. In this work, a nanosized nasal delivery system for antioxidants was found to have the potential to extend the neuroprotective time window. The authors chose to use the antioxidant C-phycocyanin (C-Pc) to design a neuroprotective liposome with a long life, controllable release, and high neuronal uptake rate. Liposomes formulated with various cholesterol to phospholipid ratios were assessed thermodynamically, kinetically, and biologically. Thermodynamically stable, monodispersive, and release-controllable C-Pc liposomes were more effectively taken up by Neuro2a cells than free C-Pc and were biocompatible, maintaining the anti-oxidative properties of C-Pc. When optimal C-Pc liposomes were administered to middle cerebral artery occlusion (MCAO) rats 2 h after onset, infarct sizes were smaller and behavioral activities improved compared with the same metrics in free C-Pc-treated rats. Liposomal delivery still reduced infarct sizes and improved behavioral activity 6 h after onset, whereas free C-Pc did not. PMID- 28847302 TI - An Overview of Cardenolides in Digitalis - More Than a Cardiotonic Compound. AB - The genus Digitalis L. containing species, commonly known as the "foxglove", is the main source of cardenolides, which have various pharmacological properties effective against certain pathological conditions including myocardial infarction, arterial hypertension, cardiac dysfunction, angina, and hypertrophy. Togehter with a prime effect of controlling the heart rhythm, many workers demonstrated that lanatoside C and some other cardiac glycosides are effective in several cancer treatments such as prostate and breast cancers. Due to digoxigenin derivatives of cardenolides, which are mainly used for medicinal purposes, such as digoxigenin, D. lanata as a main source is of great interest for commercial scale production of cardenolides in Europe. Phytochemical studies on cardenolides, naturally occurring plant secondary metabolites, have mainly focused on the species of the genus Digitalis L., as the members of this family have a high level and diverse content of cardenolides. During the last few decades, plant tissue culture techniques have been optimised for many plant species including Digitalis, however, the production capacity of cardenolides somehow failed to reach a commercially desired extent. In this review paper, the genus Digitalis is evaluated in terms of its main botanical and physiological features, traditional uses, molecular genetics and metabolomics, cellular mechanism of action, medicinal uses, clinical pharmacology, drug interactions, therapy in the management of cardiovascular disorders, potential utility of therapy in extracardiac conditions, and toxicity. PMID- 28847303 TI - Instrumenting a Fetal Membrane on a Chip as Emerging Technology for Preterm Birth Research. AB - Preterm birth (PTB) is clinically defined as process of giving birth before 37 weeks of gestation and is a leading cause of death among neonates and children under the age of five. Prematurity remains a critical issue in developed countries, yet our understanding of the pathophysiology of PTB remains largely unknown. Among pregnancy complications, subclinical infections such as chorioamnionitis (CAM) are implicated in up to 70% of PTB cases. Specifically, CAM is characterized by the infection of the fetal membranes that surround the developing fetus and extend from the placenta, and is often associated with preterm, premature rupture of the fetal membranes (PPROM). The fetal membrane plays a key structural role in maintaining the fetal and maternal compartments of the gravid uterus. However, our understanding of the mechanisms of PPROM and the spatio-temporal progress of CAM remains vastly unknown. A lack of human-derived models have hindered our understanding of the mechanism that govern spontaneous PTB. Thus, in this short review, we discuss the emerging microfabrication technologies, specifically, organ-on-chip (OoCs) models, that seek to recapitulate the cellular and molecular context of the gestational membranes in vitro. These models show promise to facilitate the investigation of pathologic mechanisms that drive these disease conditions by mimicking the interactive contribution of the major cell types that make up the microenvironment of the fetal membrane and enable high throughput screening. Herein, we histologically characterize the microenvironment of the fetal membrane as a metric for scaling to recapitulate the functional components of the human fetal membrane. We review the current OoC models of the gravid uterus and conceptualize an "Instrumented Fetal Membrane on a Chip" (IFMOC) design as a prototype for PPROM and CAM research. Lastly, we discuss further applications of these OoC models for toxicological or pharmacological screening and personalized medicine. Fetal membrane OoCs offer an innovative and valuable platform to explore complex interactions between multiple drug types, toxic substances, and/or pathogenic microbes and their potential impacts on pregnancy outcomes. Further work will be required by integrating technological and analytical capabilities in order to characterize the fetal membrane microenvironment for preterm birth research. PMID- 28847304 TI - Preterm Birth and Neonatal Injuries: Importance of Interleukin-1 and Potential of Interleukin-1 Receptor Antagonists. AB - Preterm birth (PTB) is a leading cause of neonatal mortality and morbidity worldwide, and surviving infants are at increased risks of lifelong complications. PTB has been firmly linked to inflammation regardless of infection, specific aetiology or timing of birth. Deleterious inflammation is observed in maternal and fetal tissue, and correlates with the severity of perinatal complications. At present, PTB is treated with tocolytics as though it is exclusively a myometrial contractile disorder. These agents do not address underlying inflammatory processes and are thus vastly ineffective at improving neonatal outcomes. Of all inflammatory mediators, IL-1 is central to the pathophysiology of PTB and most adverse neonatal outcomes. We thus present herein a review of the various effects of IL-1 in utero, with a brief overview of its mechanism of action. We then discuss the potential of different IL-1-targeting agents based on pre-clinical testing in relevant models of PTB and neonatal inflammatory injuries. PMID- 28847305 TI - Graphene-Based Nanomaterials: Potential Tools for Neurorepair. AB - Graphene, with its outstanding electrical properties, large surface area, and excellent mechanical properties, is found in a wide variety of applications in biomimetic substrates and biomedicine, with the result that there is growing interest in the effect of graphene-based nanomaterials on neural cells. This review sums up current research on the effectiveness of graphene and its derivatives on neural cells. We emphasize the biocompatibility of graphene and its derivatives, and how they affect the behavior of neural cells, including adhesion, proliferation, neurite outgrowth and differentiation. In addition, we discuss at great length the literature on graphenebased nanomaterials for drug delivery applications. While their in vivo effects on the nervous system remain to be explored, encouraging findings indicate that graphene-based nanomaterials have significant potential as novel therapies for neurodegenerative disease. PMID- 28847306 TI - Statins in Stable Angina Pectoris. AB - BACKGROUND: Stable angina is a debilitating and progressive disease caused by narrowing of the coronary arteries, which in turn affects cardiac perfusion. Statins have a well-established role, modifying symptoms and progression of the disease not only through lipid lowering, but also through pleiotropic effects. OBJECTIVE: We sought to evaluate the effect of statins in stable angina pectoris Method: We performed a systematic review of the literature searching MEDLINE via Pubmed for all studies which examine the possible effects of statins in stable angina pectoris. RESULTS: Statins have demonstrated favourable modification of both biochemical markers (oxidative stress, inflammatory and coagulation markers/factors) and clinical symptoms (anginal and ischemic) of the disease. These effects have been demonstrated in vitro, ex vivo and in vivo in animals and humans, independently of the lipid lowering effects. CONCLUSION: With an excellent safety profile and evidence of efficacy in managing patients with stable angina, statins appear an essential part of the therapeutic armoury against atherosclerotic disease. PMID- 28847307 TI - Alzheimer's Disease and Parkinson's Disease: A Review of Current Treatment Adopting a Nanotechnology Approach. AB - Neurodegenerative disorders (NDDs) are characterized by the progressive loss of structure or neuron function, often associated with neuronal death. Treatments for neurodegenerative diseases only address symptoms without having any disease modifying effect but serious side effects. Currently, there is no effective treatment for NDDs. This is due to the poor flow of drugs to the blood-barrier brain (BBB) which does not allow macromolecules like proteins and peptides to pass through it. Targeted drug delivery to the central nervous system (CNS) for the diagnosis and treatment of NDDs, such as Alzheimer's disease (AD), is restricted due to the limitations posed by the BBB as well as opsonization by plasma proteins in the systemic circulation and peripheral side-effects. Nanotechnology thereby presents a broad approach for transporting molecules through the BBB, thus allowing the entry of substances acting directly on the site affected by the disease. The aim of this review is to outline current strategies in nanotechnology for treating Alzheimer's and Parkinson's diseases. PMID- 28847308 TI - Editorial:Cannabis: Neurological Correlates in Abuse and Medical Use. PMID- 28847309 TI - Ganglioneuroblastoma in a newborn with multiple metastases: a case report. AB - BACKGROUND: Ganglioneuroblastoma is a tumor of peripheral neuroblastic tissue which occurs predominantly in the pediatric age group; it is a rare occurrence in the newborn period with only one case reported at birth to date. CASE PRESENTATION: We report the case of a newborn male baby of Brahmin ethnicity from Nepal who presented with respiratory distress and blueberry muffin skin lesions after birth. A computed tomography scan showed a mass lesion in the posterior mediastinum, which was diagnosed as ganglioneuroblastoma on fine-needle aspiration cytology. He also had metastases to multiple sites including heart, lungs, skin and brain. CONCLUSIONS: Ganglioneuroblastoma is a rare tumor in newborns. Any newborn presenting with respiratory distress associated with blueberry muffin skin lesions should be evaluated for neuroblastic tumor. PMID- 28847310 TI - A study on satisfaction with publicly financed health services in China. AB - BACKGROUND: With implementation of Chinese universal healthcare, the performance of urban and rural residents' healthcare and the degree of satisfaction with publicly financed health services have become a hot issue in assessing health reforms in China. An evaluation model of health services in community and evaluation indexes of health-system performance have been put forward in related researches. This study examines variation in satisfaction with publicly financed health services among urban and rural residents in five Chinese cities and assesses their determinants. METHODS: The data are derived from a survey of 1198 urban and rural residents from five nationally representative regions concerning their perceptions of satisfaction with China's publicly financed health services. The respondents assessed their degree of satisfaction with publicly financed health services on a 5-point Likert scale. It is a kind of questionaire scale that features the answers for 1-5 points labeled very unsatisfied, unsatisfied, neither unsatisfied nor satisfied, satisfied and very satisfied linking to each factor or variable, where a score of 1 reflects the lowest degree of satisfaction and a score of 5 represents the highest degree. The logistic regression methods are used to identify the variables into its determining components. RESULTS: The overall satisfaction degree representing satisfaction of all factors (variables) is 3.02, which is at the middle level of a 1-5 Likert scale, inferring respondents' neutral attitude to publicly financed health services. According to the correlation test, the factors with characteristic root greater than 0.5 are chosen to take the factor analysis and 12 extracted factors can explain 77.97% of original 18 variables' total variance. Regression analysis based on the survey data finds that health records, vaccinations, pediatric care, elder care, and mental health management are the main factors accounting for degree of satisfaction with publicly financed health services for both urban and rural residents. CONCLUSIONS: What can be done to increase the degree of satisfaction with health services needs to be considered based on our findings. Regression analysis based on the survey data finds that health records, vaccinations, pediatric care, elder care, and mental health management are the main factors accounting for degree of satisfaction with publicly financed health services for both urban and rural residents. Therefore, with improvements in health records, timely vaccination, elder care for women or elder, pediatric care and major psychosis management, degree of satisfaction with publicly financed health services are likely to grow. PMID- 28847311 TI - The 150 most important questions in cancer research and clinical oncology series: questions 50-56. AB - Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, seven more questions are presented as followed. Question 50. When tumor cells spread from primary site to distant sites, are they required to be "trained" or "armed" in the bone marrow niche prior to colonizing soft tissues? Question 51. Are there tipping points during cancer progression which can be identified for manipulation? Question 52. Can we replace molecular biomarkers by network biomarkers? Question 53. Are conventional inhibitors of key cellular processes such as cell proliferation and differentiation more effective than targeted chemotherapeutics that antagonize the downstream cell signaling network via cell-surface receptors such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and c-Met, or intracellular receptors such as androgen receptor (AR) and estrogen receptor (ER), by drugs like erlotinib, sunitinib and cabozantinib, or enzalutamide and tomoxifen? Question 54. How can we robustly identify the candidate causal event of somatic genome alteration (SGA) by using computational approach? Question 55. How can we systematically reveal the immune evasion mechanism exploited by each tumor and utilize such information to guide targeted therapy to restore immune sensitivity? Question 56. Can the nasopharyngeal carcinoma (NPC) patients with sarcomatoid carcinoma (SC) subtype benefit from more specific targeted therapy? PMID- 28847312 TI - Associations between bride price stress and intimate partner violence amongst pregnant women in Timor-Leste. AB - BACKGROUND: Reducing violence against women is a global public health priority, particularly in low-income and conflict-affected societies. However, more needs to be known about the causes of intimate partner violence (IPV) in these settings, including the stress of bride price obligations. METHODS: The representative study of women attending ante-natal clinics in Dili, Timor-Leste was conducted between June, 2013 and September, 2014 with 1672 pregnant women, a response rate of 96%. We applied contextually developed measures for the stress of bride price and poverty, and the World Health Organisation measure for intimate partner violence. RESULTS: Compared to those with no problems with bride price, women with moderate or serious problems with that custom reported higher rates of IPV (18.0% vs. 43.6%). Adjusting for socio-demographic factors, multivariate analysis revealed that ongoing poverty (OR = 1.75, 95% CI: 1.20 2.56) was significantly associated with IPV. Importantly, the strongest association with IPV was problems with bride price (OR = 2.73, 95% CI: 1.86 4.01). CONCLUSIONS: This is the first large consecutively sampled study to demonstrate a strong association between the stressors of bride price and poverty with IPV. Notably, bride price stress had the strongest association with IPV. Revealing this hitherto unrecognized factor of bride price stress may prove pivotal in guiding policy and interventions aimed at reducing IPV, and thereby improve the health and psychosocial status of women in low income and conflict affected settings. PMID- 28847313 TI - Female hormones: do they influence muscle and tendon protein metabolism? AB - Due to increased longevity, women can expect to live more than one-third of their lives in a post-menopausal state, which is characterised by low circulating levels of oestrogen and progesterone. The aim of this review is to provide insights into current knowledge of the effect of female hormones (or lack of female hormones) on skeletal muscle protein turnover at rest and in response to exercise. This review is primarily based on data from human trials. Many elderly post-menopausal women experience physical disabilities and loss of independence related to sarcopenia, which reduces life quality and is associated with substantial financial costs. Resistance training and dietary optimisation can counteract or at least decelerate the degenerative ageing process, but lack of oestrogen in post-menopausal women may reduce their sensitivity to these anabolic stimuli and accelerate muscle loss. Tendons and ligaments are also affected by sex hormones, but the effect seems to differ between endogenous and exogenous female hormones. Furthermore, the effect seems to depend on the age, and as a result influence the biomechanical properties of the ligaments and tendons differentially. Based on the present knowledge oestrogen seems to play a significant role with regard to skeletal muscle protein turnover. Therefore, oestrogen/hormonal replacement therapy may counteract the degenerative changes in skeletal muscle. Nevertheless, there is a need for greater insight into the direct and indirect mechanistic effects of female hormones before any evidence based recommendations regarding type, dose, duration and timing of hormone replacement therapy can be provided. PMID- 28847314 TI - Characterising the muscle anabolic potential of dairy, meat and plant-based protein sources in older adults. AB - The age-related loss of skeletal muscle mass and function is caused, at least in part, by a reduced muscle protein synthetic response to protein ingestion. The magnitude and duration of the postprandial muscle protein synthetic response to ingested protein is dependent on the quantity and quality of the protein consumed. This review characterises the anabolic properties of animal-derived and plant-based dietary protein sources in older adults. While approximately 60 % of dietary protein consumed worldwide is derived from plant sources, plant-based proteins generally exhibit lower digestibility, lower leucine content and deficiencies in certain essential amino acids such as lysine and methionine, which compromise the availability of a complete amino acid profile required for muscle protein synthesis. Based on currently available scientific evidence, animal-derived proteins may be considered more anabolic than plant-based protein sources. However, the production and consumption of animal-derived protein sources is associated with higher greenhouse gas emissions, while plant-based protein sources may be considered more environmentally sustainable. Theoretically, the lower anabolic capacity of plant-based proteins can be compensated for by ingesting a greater dose of protein or by combining various plant-based proteins to provide a more favourable amino acid profile. In addition, leucine co-ingestion can further augment the postprandial muscle protein synthetic response. Finally, prior exercise or n-3 fatty acid supplementation have been shown to sensitise skeletal muscle to the anabolic properties of dietary protein. Applying one or more of these strategies may support the maintenance of muscle mass with ageing when diets rich in plant-based protein are consumed. PMID- 28847315 TI - Letter to the Editor: The half-alive concept of schizophrenia is still better than the spectrum of everything. PMID- 28847316 TI - Children with hypoplastic left heart syndrome have lower quality of life than healthy controls and children with other illnesses. AB - OBJECTIVE: Previous studies suggest that children with congenital cardiac diagnoses report lower quality of life when compared with healthy norms. A few studies have evaluated quality of life specifically in children born with hypoplastic left heart syndrome, a condition requiring several surgeries before age three. The aim of this study was to use an empirically validated and standardised measure - the Pediatric Quality of Life Inventory - to evaluate quality of life in children with hypoplastic left heart syndrome and compare the findings with similar, medically complicated samples. METHODS: The parent-report Pediatric Quality of Life Inventory was administered, and demographic information was collected through an internet portal. A total of 121 caregivers of children with hypoplastic left heart syndrome responded. The sample included children aged 2-18 years (M=10.81 years). Independent sample t-tests were used to compare our sample with published norms of healthy children and children with acute or chronic illnesses. RESULTS: Children with hypoplastic left heart syndrome were rated as having significantly lower overall quality-of-life scores (M=59.69) compared with published norms of children without medical diagnoses (M=83.00) and those with acute (M=78.70) or chronic (M=77.19) illnesses (p<0.001). Children with hypoplastic left heart syndrome complicated by a stroke or seizure (15%) reported the lowest quality of life. The results held for all subscales (p<0.001). CONCLUSIONS: Children with hypoplastic left heart syndrome appear to be a significantly vulnerable population with difficulties in functioning across psychosocial domains and across the age span. Further research is required to facilitate early identification of the need for resources for these children and families, especially for children who experience additional medical complications. PMID- 28847318 TI - Sunspot activity and influenza pandemics: a statistical assessment of the purported association. AB - Since 1978, a series of papers in the literature have claimed to find a significant association between sunspot activity and the timing of influenza pandemics. This paper examines these analyses, and attempts to recreate the three most recent statistical analyses by Ertel (1994), Tapping et al. (2001), and Yeung (2006), which all have purported to find a significant relationship between sunspot numbers and pandemic influenza. As will be discussed, each analysis had errors in the data. In addition, in each analysis arbitrary selections or assumptions were also made, and the authors did not assess the robustness of their analyses to changes in those arbitrary assumptions. Varying the arbitrary assumptions to other, equally valid, assumptions negates the claims of significance. Indeed, an arbitrary selection made in one of the analyses appears to have resulted in almost maximal apparent significance; changing it only slightly yields a null result. This analysis applies statistically rigorous methodology to examine the purported sunspot/pandemic link, using more statistically powerful un-binned analysis methods, rather than relying on arbitrarily binned data. The analyses are repeated using both the Wolf and Group sunspot numbers. In all cases, no statistically significant evidence of any association was found. However, while the focus in this particular analysis was on the purported relationship of influenza pandemics to sunspot activity, the faults found in the past analyses are common pitfalls; inattention to analysis reproducibility and robustness assessment are common problems in the sciences, that are unfortunately not noted often enough in review. PMID- 28847317 TI - Identifying transmission routes of Streptococcus pneumoniae and sources of acquisitions in high transmission communities. AB - Identifying the transmission sources and reservoirs of Streptococcus pneumoniae (SP) is a long-standing question for pneumococcal epidemiology, transmission dynamics, and vaccine policy. Here we use serotype to identify SP transmission and examine acquisitions (in the same household, local community, and county, or of unidentified origin) in a longitudinal cohort of children and adults from the Navajo Nation and the White Mountain Apache American Indian Tribes. We found that adults acquire SP relatively more in the household than other age groups, and children 2-8 years old typically acquire in their own or surrounding communities. Age-specific transmission probability matrices show that transmissions within household were mostly seen from older to younger siblings. Outside the household, children most often transmit to other children in the same age group, showing age assortative mixing behavior. We find toddlers and older children to be most involved in SP transmission and acquisition, indicating their role as key drivers of SP epidemiology. Although infants have high carriage prevalence, they do not play a central role in transmission of SP compared with toddlers and older children. Our results are relevant to inform alternative pneumococcal conjugate vaccine dosing strategies and analytic efforts to inform optimization of vaccine programs, as well as assessing the transmission dynamics of pathogens transmitted by close contact in general. PMID- 28847319 TI - Premature ventricular contractions as a side effect of filgrastim in a child with B-thalassaemia. AB - Premature ventricular contractions are a rare side effect of filgrastim, reported mainly in elderly men. Here we report the case of a 9-year-old child with thalassaemia who developed frequent premature ventricular contractions after three doses of filgrastim were given for deferiprone-induced agranulocytosis. The arrhythmia resolved 3 weeks after discontinuation of filgrastim. Children treated with filgrastim should be carefully monitored for potentially serious arrhythmia. PMID- 28847321 TI - Population-attributable risk estimates for factors associated with inappropriate complementary feeding practices in The Gambia. AB - OBJECTIVE: The present cross-sectional study aimed to determine population attributable risk (PAR) estimates for factors associated with inappropriate complementary feeding practices in The Gambia. DESIGN: The study examined the first and most recent Demographic and Health Survey of The Gambia (GDHS 2013). The four complementary feeding indicators recommended by the WHO were examined against a set of individual-, household- and community-level factors, using multilevel logistic analysis. PAR estimates were obtained for each factor associated with inappropriate complementary feeding practices in the final multivariate logistic regression model. SETTING: The Gambia. SUBJECTS: Last-born children (n 2362) aged 6-23 months. RESULTS: Inadequate meal frequency was attributed to 20 % (95 % CI 15.5 %, 24.2 %) of children belonging to the youngest age group (6-11 months) and 9 % (95 % CI 3.2 %, 12.5 %) of children whose mothers were aged less than 20 years at the time of their birth. Inadequate dietary diversity was attributed to 26 % (95 % CI 1.9 %, 37.8 %) of children who were born at home and 20 % (95 % CI 8.3, 29.5 %) of children whose mothers had no access to the radio. Inadequate introduction of solid, semi-solid or soft foods was attributed to 30 % (95 % CI 7.2 %, 38.9 %) of children from poor households. CONCLUSIONS: Findings of the study suggest the need for community-based public health nutrition interventions to improve the nutritional status of Gambian children, which should focus on sociocultural and economic factors that negatively impact on complementary feeding practices early in infancy (6-11 months). PMID- 28847320 TI - Cardiac surgery in adults with high-surgical complexity CHD: results of a network collaborative programme. AB - BACKGROUND: Adults with CHD often exhibit complex cardiac abnormalities, whose management requires specific clinical and surgical expertise. To enable easier access of these patients to highly specialised care, we implemented a collaborative programme that incorporates medical and surgical specialists belonging to both paediatric and adult cardiovascular institutions. OBJECTIVES: The objective of this study was to review the experience gained and to analyse the surgical outcome of major cardiac surgery. METHODS: We retrospectively reviewed all consecutive patients admitted for major cardiac surgery using our network between January, 2010 and December, 2013. Analysis of surgical outcome was performed in patients selected for major cardiac surgery with cardiopulmonary bypass. Early and late outcomes were evaluated. RESULTS: Out of a total of 433 inward patients, 86 were selected for surgery. The median age was 25.5 years, -64 patients (74.4%) had previously undergone heart surgery, and -55 patients (64%) had been subjected to at least one sternotomy. Abnormalities of the left ventricular and right ventricular outflow tract were the most frequent (37.2% and 30.2%, respectively), and despite high-surgical complexity only one death occurred (in-hospital mortality 1.1%). On a median follow-up time of 4 years no deaths and no heart-failure events have occurred; one patient underwent further cardiac surgery programmed at the time of discharge. CONCLUSIONS: Low mortality and morbidity rates can be obtained in high-surgical complexity adults with CHD populations when paediatric and adult cardiac specialists operate in the same multidisciplinary environment. PMID- 28847322 TI - Feasibility of a healthcare system-based tetralogy of Fallot patient registry. AB - BACKGROUND: Patient-reported outcomes and epidemiological studies in adults with tetralogy of Fallot are lacking. Recruitment and longitudinal follow-up investigation across institutions is particularly challenging. Objectives of this study were to assess the feasibility of recruiting adult patients with tetralogy of Fallot for a patient-reported outcomes study, describe challenges for recruitment, and create an interactive, online tetralogy of Fallot registry. METHODS: Adult patients living with tetralogy of Fallot, aged 18-58 years, at the University of North Carolina were identified using diagnosis code query. A survey was designed to collect demographics, symptoms, history, and birth mother information. Recruitment was attempted by phone (Part I, n=20) or by email (Part II, n=20). Data analysis included thematic grouping of recruitment challenges and descriptive statistics. Feasibility threshold was 75% for recruitment and for data fields completed per patient. RESULTS: In Part I, 60% (12/20) were successfully contacted and eight (40%) were enrolled. Demographics and birth mother information were obtained for all enrolled patients. In Part II, 70% (14/20) were successfully contacted; 30% (6/20) enrolled and completed all data fields linked to REDCap database; the median time for survey completion was 8 minutes. Half of the patients had cardiac operations/procedures performed at more than one hospital. Automatic electronic data entry from the online survey was uncomplicated. CONCLUSIONS: Although recruitment (54%) fell below our feasibility threshold, enrolled individuals were willing to complete phone or online surveys. Incorrect contact information, privacy concerns, and patient-reported time constraints were challenges for recruitment. Creating an online survey and linked database is technically feasible and efficient for patient-reported outcomes research. PMID- 28847323 TI - Developing multidimensional measures of healthy food access among low-income adults in Cleveland, Ohio, USA. AB - OBJECTIVE: Access to nutritious foods is key to achieving health promotion goals. While there is evidence that nutritious food access is complex, measures assessing multiple domains of access, including spatial-temporal, economic, social, service delivery and personal, are lacking. The current study evaluates psychometric properties of scales designed to measure perceptions of multiple domains of nutritious food access among low-income populations. DESIGN: A cross sectional survey was conducted in 2015. Eighty-one items were selected or developed to represent five domains of nutritious food access for food shopping overall and specific to shopping at farmers' markets. Evaluation of the items included exploratory factor analysis within each domain and internal consistency reliability for each of the sub-scales. SETTING: Data were collected in seventeen urban neighbourhoods in Greater Cleveland, Ohio, USA that have high levels of poverty. All participants had access to at least one farmers' market within 1.6 km (1 mile) of their home to standardize spatial access to nutritious foods. SUBJECTS: Adults (n 304) receiving Supplemental Nutrition Assistance Program benefits. RESULTS: Each domain included multiple sub-domains: spatial-temporal (four), service delivery (two), economic (two), social (three) and personal (three), for a total of fourteen subdomains. The internal consistency reliability for one of the sub-domains was outstanding (>0.90), seven were excellent (0.80 0.89), five were very good (0.70-0.79) and one scale had poor reliability (0.58). CONCLUSIONS: Multiple sub-domains of nutritious food access can be assessed using short measures that have been tested for internal consistency. These measures are suitable for assessing the complex phenomena of nutritious food access among low income populations. PMID- 28847324 TI - Are Big Food's corporate social responsibility strategies valuable to communities? A qualitative study with parents and children. AB - OBJECTIVE: Recent studies have identified parents and children as two target groups whom Big Food hopes to positively influence through its corporate social responsibility (CSR) strategies. The current preliminary study aimed to gain an in-depth understanding of parents and children's awareness and interpretation of Big Food's CSR strategies to understand how CSR shapes their beliefs about companies. DESIGN: Community-based qualitative semi-structured interviews. SETTING: New South Wales, Australia. SUBJECTS: Parents (n 15) and children aged 8 12 years (n 15). RESULTS: Parents and children showed unprompted recognition of CSR activities when shown McDonald's and Coca-Cola brand logos, indicating a strong level of association between the brands and activities that target the settings of children. When discussing CSR strategies some parents and most children saw value in the activities, viewing them as acts of merit or worth. For some parents and children, the companies' CSR activities were seen as a reflection of the company's moral attributes, which resonated with their own values of charity and health. For others, CSR strategies were in conflict with companies' core business. Finally, some also viewed the activities as harmful, representing a deceit of the public and a smokescreen for the companies' ultimately unethical behaviour. CONCLUSIONS: A large proportion of participants valued the CSR activities, signalling that denormalising CSR to sever the strong ties between the community and Big Food will be a difficult process for the public health community. Efforts to gain public acceptance for action on CSR may need greater levels of persuasion to gain public support of a comprehensive and restrictive approach. PMID- 28847325 TI - Letter to the Editor: Schizophrenia does not represent the extreme of a normally distributed trait. PMID- 28847327 TI - Punch-out lesion following regression of a large left ventricular outflow rhabdomyoma. AB - Abstracts We report the case of a patient with rhabdomyoma of the left ventricular outflow tract, causing severe obstruction at birth. The tumour regressed completely by 6 years of age, leaving a punch-out lesion. The potential for spontaneous regression of these tumours and the formation of a myocardial lesion following rhabdomyoma regression are discussed. PMID- 28847326 TI - The Antimicrobial Scrub Contamination and Transmission (ASCOT) Trial: A Three Arm, Blinded, Randomized Controlled Trial With Crossover Design to Determine the Efficacy of Antimicrobial-Impregnated Scrubs in Preventing Healthcare Provider Contamination. AB - OBJECTIVE To determine whether antimicrobial-impregnated textiles decrease the acquisition of pathogens by healthcare provider (HCP) clothing. DESIGN We completed a 3-arm randomized controlled trial to test the efficacy of 2 types of antimicrobial-impregnated clothing compared to standard HCP clothing. Cultures were obtained from each nurse participant, the healthcare environment, and patients during each shift. The primary outcome was the change in total contamination on nurse scrubs, measured as the sum of colony-forming units (CFU) of bacteria. PARTICIPANTS AND SETTING Nurses working in medical and surgical ICUs in a 936-bed tertiary-care hospital. INTERVENTION Nurse subjects wore standard cotton-polyester surgical scrubs (control), scrubs that contained a complex element compound with a silver-alloy embedded in its fibers (Scrub 1), or scrubs impregnated with an organosilane-based quaternary ammonium and a hydrophobic fluoroacrylate copolymer emulsion (Scrub 2). Nurse participants were blinded to scrub type and randomly participated in all 3 arms during 3 consecutive 12-hour shifts in the intensive care unit. RESULTS In total, 40 nurses were enrolled and completed 3 shifts. Analyses of 2,919 cultures from the environment and 2,185 from HCP clothing showed that scrub type was not associated with a change in HCP clothing contamination (P=.70). Mean difference estimates were 0.118 for the Scrub 1 arm (95% confidence interval [CI], -0.206 to 0.441; P=.48) and 0.009 for the Scrub 2 rm (95% CI, -0.323 to 0.342; P=.96) compared to the control. HCP became newly contaminated with important pathogens during 19 of the 120 shifts (16%). CONCLUSIONS Antimicrobial-impregnated scrubs were not effective at reducing HCP contamination. However, the environment is an important source of HCP clothing contamination. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT 02645214 Infect Control Hosp Epidemiol 2017;38:1147-1154. PMID- 28847328 TI - Characterisation of three-dimensional mapping in Wolff-Parkinson-White syndrome with septal aneurysmal dyskinesis. AB - A 21-year-old man with Wolff-Parkinson-White syndrome and aneurysmal septal dyskinesis underwent radiofrequency catheter ablation of the accessory pathways. Before radiofrequency catheter ablation, the activation wavefront arose from the aneurysmal septum, whereas the propagation of the left ventricle was normalised after radiofrequency catheter ablation. These findings demonstrate the importance of the electro-mechanical interaction in patients with Wolff-Parkinson-White syndrome and ventricular dysfunction. PMID- 28847330 TI - Impaired cortisol awakening response in eating disorder women with childhood trauma exposure: evidence for a dose-dependent effect of the traumatic load. AB - BACKGROUND: Childhood trauma is a non specific risk factor for adult eating disorders (ED), and the hypothalamic-pituitary-adrenal (HPA) axis seems to mediate such a risk. Here we explored the impact of different types of childhood trauma and of traumatic load on the cortisol awakening response (CAR) of women with anorexia nervosa (AN) or bulimia nervosa (BN). METHODS: Saliva samples were collected at awakening and after 15, 30, 60 min to measure cortisol levels by 121 women (44 AN patients, 36 BN patients and 41 healthy women). Participants filled in the Childhood Trauma Questionnaire. RESULTS: AN and BN patients with childhood maltreatment exhibited an attenuated CAR compared with non-maltreated ones. In the whole ED patient group, the CAR showed a progressive impairment with the increasing number of reported trauma types. Although significant negative correlations emerged between the type or the number of traumas and the CAR, only the number of traumas remained significantly associated with the CAR in a stepwise multiple regression analysis. CONCLUSIONS: Present findings confirm that childhood trauma is associated with an impaired CAR in adult AN and BN patients and demonstrate for the first time a negative dose-dependent effect of the traumatic load on HPA axis activity. PMID- 28847329 TI - Utilisation of early intervention services in young children with hypoplastic left heart syndrome. AB - OBJECTIVE: Children with hypoplastic left heart syndrome are at a risk for neurodevelopmental delays. Current guidelines recommend systematic evaluation and management of neurodevelopmental outcomes with referral for early intervention services. The Single Ventricle Reconstruction Trial represents the largest cohort of children with hypoplastic left heart syndrome ever assembled. Data on life events and resource utilisation have been collected annually. We sought to determine the type and prevalence of early intervention services used from age 1 to 4 years and factors associated with utilisation of services. METHODS: Data from 14-month neurodevelopmental assessment and annual medical history forms were used. We assessed the impact of social risk and geographic differences. Fisher exact tests and logistic regression were used to evaluate associations. RESULTS: Annual medical history forms were available for 302 of 314 children. Greater than half of the children (52-69%) were not receiving services at any age assessed, whereas 20-32% were receiving two or more therapies each year. Utilisation was significantly lower in year 4 (31%) compared with years 1-3 (with a range from 40 to 48%) (p<0.001). Social risk factors were not associated with the use of services at any age but there were significant geographic differences. Significant delay was reported by parents in 18-43% of children at ages 3 and 4. CONCLUSION: Despite significant neurodevelopmental delays, early intervention service utilisation was low in this cohort. As survival has improved for children with hypoplastic left heart syndrome, attention must shift to strategies to optimise developmental outcomes, including enrolment in early intervention when merited. PMID- 28847331 TI - Consequences of organ choice in describing bacterial pathogen assemblages in a rodent population. AB - High-throughput sequencing technologies now allow for rapid cost-effective surveys of multiple pathogens in many host species including rodents, but it is currently unclear if the organ chosen for screening influences the number and identity of bacteria detected. We used 16S rRNA amplicon sequencing to identify bacterial pathogens in the heart, liver, lungs, kidneys and spleen of 13 water voles (Arvicola terrestris) collected in Franche-Comte, France. We asked if bacterial pathogen assemblages within organs are similar and if all five organs are necessary to detect all of the bacteria present in an individual animal. We identified 24 bacteria representing 17 genera; average bacterial richness for each organ ranged from 1.5 +/- 0.4 (mean +/- standard error) to 2.5 +/- 0.4 bacteria/organ and did not differ significantly between organs. The average bacterial richness when organ assemblages were pooled within animals was 4.7 +/- 0.6 bacteria/animal; Operational Taxonomic Unit accumulation analysis indicates that all five organs are required to obtain this. Organ type influences bacterial assemblage composition in a systematic way (PERMANOVA, 999 permutations, pseudo-F 4,51 = 1.37, P = 0.001). Our results demonstrate that the number of organs sampled influences the ability to detect bacterial pathogens, which can inform sampling decisions in public health and wildlife ecology. PMID- 28847333 TI - Group independent component analysis reveals alternation of right executive control network in Internet gaming disorder. AB - OBJECTIVE: Previous studies have demonstrated that individuals with Internet gaming disorder (IGD) showed attentional bias toward gaming-related cues and exhibited impaired executive functions. The purpose of this study was to explore the alternations in related functional brain networks underlying attentional bias in IGD subjects. METHODS: Eighteen IGD subjects and 19 healthy controls (HC) were scanned with functional magnetic resonance imaging while they were performing an addiction Stroop task. Networks of functional connectivity were identified using group independent component analysis (ICA). RESULTS: ICA identified 4 functional networks that showed differences between the 2 groups, which were related to the right executive control network and visual related networks in our study. Within the right executive control network, in contrast to controls, IGD subjects showed increased functional connectivity in the temporal gyrus and frontal gyrus, and reduced functional connectivity in the posterior cingulate cortex, temporal gyrus, and frontal gyrus. CONCLUSION: These findings suggest that IGD is related to abnormal functional connectivity of the right executive control network, and may be described as addiction-related abnormally increased cognitive control processing and diminished response inhibition during an addiction Stroop task. The results suggest that IGD subjects show increased susceptibility towards gaming-related cues but weakened strength of inhibitory control. PMID- 28847332 TI - Asymptomatic atresia of the anomalous pulmonary vein in a patient with scimitar syndrome presenting in childhood. AB - An asymptomatic 6-year-old boy with a history of right lung hypoplasia was referred for cardiology evaluation. Echocardiography demonstrated right pulmonary artery hypoplasia with flow reversal in that vessel. The right pulmonary veins were not visualised in the echocardiogram. Cardiac catheterisation confirmed the diagnosis of scimitar syndrome with a characteristic large vertical vein; however, the right pulmonary veins were found to be atretic with no connection to the heart with decompression through the azygos vein. In all, four systemic to pulmonary arterial collaterals were identified, supplying the right lung, which were occluded using embolization coils. This case demonstrates the potential for progressive stenosis and atresia of the so-called "scimitar vein" without previous surgical instrumentation, and that this can occur without haemodynamic embarrassment or development of pulmonary vascular disease. PMID- 28847334 TI - Food appearances in children's television programmes in Iceland. AB - OBJECTIVE: Exposure to advertisements cannot fully explain the associations between young children's dietary intake and the time they spend in front of the television. It is therefore of importance to study television content other than advertisements in this aspect. The present study aimed to examine the nature and extent of verbal and visual appearances of foods and beverages in children's television programmes on Icelandic public service television. DESIGN: A total of 27 h of children's programmes (domestic and internationally produced) were watched. All verbal and visual appearances of foods and beverages were coded, as well as the context in which the foods/beverages were discussed or appeared. SETTING: Children's programmes on Icelandic public service television. SUBJECTS: Two food groups were of special interest for their importance from a public health perspective: high-calorie and low-nutrient (HCLN) foods and fruits and vegetables (F&V). The chi 2 test and logistic regression were performed to analyse if the occurrence of the two groups was associated with the context where foods/beverages appeared. RESULTS: Of the 125 different programmes, a food or beverage appeared in 86 %. Of the total food appearances (n 599), HCLN foods accounted for 26 % and F&V for 23 %. HCLN foods were presented as desirable by appearing more frequently with child characters (P<0.01) than F&V. CONCLUSIONS: Public service television has the potential to improve the way food and eating is presented in children's programmes, as young childhood is a critical period for founding healthy habits for later life. PMID- 28847335 TI - Applying a food processing-based classification system to a food guide: a qualitative analysis of the Brazilian experience. AB - OBJECTIVE: The present paper aimed to identify the stakeholders, as well as their arguments and recommendations, in the debate on the application of a food processing-based classification system to the new Brazilian Food Guide. DESIGN: Qualitative approach; an analysis was made of documents resulting from the consultation conducted for the development of the new Brazilian Food Guide, which uses the NOVA classification for its dietary recommendations. A thematic matrix was constructed and the resulting themes represented the main points for discussion raised during the consultation. SETTING: Brazil. SUBJECTS: Actors from academia, government and associations/unions/professional bodies/organizations related to the area of nutrition and food security; non-profit institutions linked to consumer interests and civil society organizations; organizations, associations and food unions linked to the food industry; and individuals. RESULTS: Four themes were identified: (i) conflicting paradigms; (ii) different perceptions about the role and need of individuals; (iii) we want more from the new food guide; and (iv) a sustainable guide. CONCLUSIONS: There was extensive participation from different sectors of society. The debate generated by the consultation revealed two main conflicting opinions: a view aligned with the interests of the food industry and a view of healthy eating which serves the interests of the population. The first group was against the adoption of a food processing-based classification system in a public policy such as the new Brazilian Food Guide. The second group, although mostly agreeing with the new food guide, argued that it failed to address some important issues related to the food and nutrition agenda in Brazil. PMID- 28847337 TI - Femoral vein homograft as Sano shunt results in improved pulmonary artery growth after Norwood operation. AB - OBJECTIVE: To evaluate differences in interstage growth of pulmonary arteries between use of polytetrafluoroethylene and femoral vein homograft as Sano shunt during stage-I Norwood palliation. METHODS: A retrospective review of all patients who survived to the second stage following Norwood-Sano operation at two institutions was performed. Either polytetrafluoroethylene or the valved segment of femoral vein homograft was used for construction of the Sano shunt. The size of pulmonary arteries was compared at pre-Glenn catheterisation. RESULTS: A total of 48 neonates with the diagnosis of hypoplastic left heart syndrome or its variants comprised the study population. Femoral vein homograft of 5-6 mm diameter was used in 14 and polytetrafluoroethylene graft of 5 mm was used in 34 patients. The two groups were comparable in terms of preoperative demographics and age at time of pre-Glenn catheterisation (3.9+/-0.7 versus 3.4+/-0.8 months, p=0.06). Patients who received femoral vein homograft demonstrated a significantly higher pre-Glenn Nakata index [264 (130-460) versus 165 (108-234) mm2/m2, p=0.004]. The individual branch pulmonary arteries were significantly larger in the femoral vein group (right, 7.8+/-3.6 versus 5.0+/-1.2, p=0.014; left, 7.2+/-2.1 versus 5.6+/-1.9, p=0.02). There were no differences in cardiac index, Qp:Qs, ventricular end-diastolic pressure or systemic oxygen saturations. CONCLUSIONS: Utilisation of a valved segment of femoral vein homograft as right ventricle to pulmonary artery conduit during Norwood-Sano operation confers better interstage growth of the pulmonary arteries. Further studies are needed to evaluate the impact of femoral vein homograft on single ventricle function. PMID- 28847336 TI - Embracing polygenicity: a review of methods and tools for psychiatric genetics research. AB - The availability of genome-wide genetic data on hundreds of thousands of people has led to an equally rapid growth in methodologies available to analyse these data. While the motivation for undertaking genome-wide association studies (GWAS) is identification of genetic markers associated with complex traits, once generated these data can be used for many other analyses. GWAS have demonstrated that complex traits exhibit a highly polygenic genetic architecture, often with shared genetic risk factors across traits. New methods to analyse data from GWAS are increasingly being used to address a diverse set of questions about the aetiology of complex traits and diseases, including psychiatric disorders. Here, we give an overview of some of these methods and present examples of how they have contributed to our understanding of psychiatric disorders. We consider: (i) estimation of the extent of genetic influence on traits, (ii) uncovering of shared genetic control between traits, (iii) predictions of genetic risk for individuals, (iv) uncovering of causal relationships between traits, (v) identifying causal single-nucleotide polymorphisms and genes or (vi) the detection of genetic heterogeneity. This classification helps organise the large number of recently developed methods, although some could be placed in more than one category. While some methods require GWAS data on individual people, others simply use GWAS summary statistics data, allowing novel well-powered analyses to be conducted at a low computational burden. PMID- 28847338 TI - Association of eating out with bone density in Taiwan. AB - OBJECTIVE: The present study analysed data derived from the 2004-2008 Nutrition and Health Survey in Taiwan, conducted by the Ministry of Health and Welfare, to understand the relationship among eating-out behaviour, related non-nutritional factors and osteopenia in the Taiwanese population. Design/Setting/Subjects Data of 1140 adults who had been evaluated with dual-energy X-ray absorptiometry in June 2007 were included. The data were analysed through descriptive and inferential statistics to determine the association of osteopenia with the frequency of eating out, demographic variables (i.e. age, sex, level of education, marital status and place of birth), BMI, waist circumference and food consumption. RESULTS: Gender, age, education level, personal income and waist circumference were all factors found to be significantly associated with eating out frequency and the incidence of osteopenia. Eating-out frequency was negatively associated with the incidence of osteopenia. Individuals with BMI>27 kg/m2 had a lower frequency of eating out and a lower incidence of osteopenia. Individuals with a lower monthly income had a significantly greater chance of developing osteopenia. Men living without spouses had significantly higher chances of osteopenia. Ca intake was negatively associated with breakfast eating out frequency. CONCLUSIONS: Eating-out frequency was not associated with an increasing incidence of osteopenia, but affected the Ca intake in the Taiwanese population. Having a balanced selection of food is crucial to reduce the incidence of osteopenia. Improving nutritional knowledge for those under higher risk of osteopenia is necessary to prevent osteopenia and Ca deficiency. PMID- 28847339 TI - Sleep patterning changes in a prenatal stress model of depression. AB - Clinical depression is accompanied by changes in sleep patterning, which is controlled in a circadian fashion. It is thus desirable that animal models of depression mirror such diurnally-specific state alterations, along with other behavioral and physiological changes. We previously found several changes in behavior indicative of a depression-like phenotype in offspring of rats subjected to repeated, variable prenatal stress (PNS), including increased locomotor activity during specific periods of the circadian cycle. We, therefore, investigated whether PNS rats also exhibit alterations in sleep/wakefulness behavior around the change from light-to-dark phase. Control and PNS Sprague Dawley rats were implanted with electrodes for continuous monitoring of electroencephalic activity used to determine behavioral state. The distribution of slow-wave sleep (SWS), rapid eye movement sleep (REMS) and wakefulness was compared for periods before and after lights were turned off, between baseline conditions and after exposure to an acute stressor. Both REMS and SWS amounts were increased in PNS rats relative to control animals in the beginning of the dark phase. REMS changes were due to an increase in REMS bout number, rather than in bout duration. During this circadian time period, we did not find any sex differences in the state changes. These results indicate that PNS affects baseline sleep patterning in both male and female rats around active-phase onset. PMID- 28847340 TI - Genome organization: connecting the developmental origins of disease and genetic variation. AB - An adverse early life environment can increase the risk of metabolic and other disorders later in life. Genetic variation can modify an individual's susceptibility to these environmental challenges. These gene by environment interactions are important, but difficult, to dissect. The nucleus is the primary organelle where environmental responses impact directly on the genetic variants within the genome, resulting in changes to the biology of the genome and ultimately the phenotype. Understanding genome biology requires the integration of the linear DNA sequence, epigenetic modifications and nuclear proteins that are present within the nucleus. The interactions between these layers of information may be captured in the emergent spatial genome organization. As such genome organization represents a key research area for decoding the role of genetic variation in the Developmental Origins of Health and Disease. PMID- 28847342 TI - Availability of dopamine transporters and auditory P300 abnormalities in adults with attention-deficit hyperactivity disorder: preliminary results. AB - OBJECTIVE: Previous studies have indicated that there is dopamine transporter (DAT) dysregulation and P300 abnormality in adults with attention-deficit hyperactivity disorder (ADHD); however, the correlations among the three have not been fully explored. METHODS: A total of 11 adults (9 males and 2 females) with ADHD and 11 age-, sex-, and education-level-matched controls were recruited. We explored differences in DAT availability using single-photon emission computed tomography and P300 wave of event-related potentials between the two groups. The correlation between DAT availability and P300 performance was also examined. RESULTS: DAT availability in the basal ganglia, caudate nucleus, and putamen was significantly lower in the ADHD group. Adults with ADHD had lower auditory P300 amplitudes at the Pz and Cz sites, as well as longer Fz latency than controls. DAT availability was negatively correlated to P300 latency at Pz and Fz. CONCLUSIONS: Adults with ADHD had both abnormal DAT availability and P300 amplitude, suggesting that ADHD is linked to dysfunction of the central dopaminergic system and poor cognitive processes related to response selection and execution. PMID- 28847341 TI - Giant coronary artery aneurysms complicating Kawasaki disease in Mexican children. AB - BACKGROUND: One of the most important complications of Kawasaki disease is the development of giant coronary aneurysms. Risk factors for their development are still not clear. METHODS: A retrospective analysis was conducted at the National Institute of Paediatrics in Mexico City, Mexico. It included all patients with a diagnosis of acute Kawasaki disease between August, 1995 and August, 2015. Clinical and laboratory findings, as well as echocardiographic measurements, were recorded. Patients with giant coronary aneurysms (z-score?10) were compared with the rest of the patients. A value of p<0.05 was considered statistically significant. Odds ratios and their 95% confidence intervals were calculated to define risk factors. RESULTS: During the study period, 416 patients were diagnosed with Kawasaki disease. Of them, 34 developed giant coronary aneurysms during the acute stage of the disease. In the multivariate analysis, patients younger than 1 year, those with a higher duration of illness at the time of diagnosis, and those who received additional intravenous immunoglobulin showed a significantly higher frequency of giant coronary aneurysms. CONCLUSIONS: One of the main factors associated with the development of giant coronary aneurysms was the delay in the diagnosis of Kawasaki disease. This finding highlights the importance of maintaining a high suspicion of the disease, which would enable an early diagnosis and prompt treatment and decrease the risk for developing giant coronary aneurysms. PMID- 28847343 TI - The Great East Japan Earthquake: Analyses of Disaster Impacts on Health Care Clinics. AB - OBJECTIVE: Local health facilities play a critical role in mitigating the deterioration of health after catastrophic disasters. However, limited information is available on clinic damage. Therefore, the National Institute of Public Health conducted surveillance on clinic damage after the 2011 Great East Japan Earthquake (GEJE) to identify risk factors. METHODS: A cross-sectional study using a paper-based questionnaire was conducted that targeted 728 clinics located in coastal areas in the 3 prefectures most affected by the GEJE. RESULTS: The risk of building damage was inversely correlated with distance from the coast, whereas the risk of ceasing operations was significantly correlated with building damage and some specialties of clinics, namely, internal medicine and pediatrics.DiscussionIn mountainous countries like Japan, clinics often need to be built in coastal areas, where the majority of residents live. This surveillance revealed that clinics built in readily accessible locations and that provide care with high needs are more likely to get damaged by tsunamis. As clinics are often the frontline health facilities in disaster settings, local disaster plans need to include plans to reinforce disaster preparedness among clinics. For effective planning and resource allocation, nationwide hazard vulnerability analysis using a global standard will be helpful. (Disaster Med Public Health Preparedness. 2018; 12: 291-295). PMID- 28847344 TI - Reference Materials: Critical Importance to the Infant Formula Industry. AB - Infant formula is one of the most regulated foods in the world. It has advanced in complexity over the years as a result of numerous research innovations. To ensure product safety and quality, analytical technologies have also had to advance to keep pace. Given the rigorous performance demands expected of these methods and the ever-growing array of complex matrixes, there is the potential for gaps to exist in current Official MethodsSM and other recognized international methods for infant formula and adult nutritionals. Food safety concerns, particularly for infants, drive the need for extensive testing by manufacturers and regulators. The net effect is the potential for an increase in time- and resource-consuming regulatory disputes. In an effort to mitigate such costly activities, AOAC INTERNATIONAL, under the direction of the Infant Formula Council of America-a trade association of manufacturers and marketers of formulated nutritional products-agreed to establish voluntary consensus Standard Method Performance Requirements, and, ultimately, to identify and publish globally recognized, fit-for-purpose standard methods. To accomplish this task, nutritional reference materials (RMs), representing all major commercially available nutritional formulations, were (and continue to be) a critical necessity. In this paper, various types of RMs will be defined, followed by review and discussion of their importance to the infant formula industry. PMID- 28847345 TI - Highly Sensitive GMO Detection Using Real-Time PCR with a Large Amount of DNA Template: Single-Laboratory Validation. AB - Current genetically modified organism (GMO) detection methods allow for sensitive detection. However, a further increase in sensitivity will enable more efficient testing for large grain samples and reliable testing for processed foods. In this study, we investigated real-time PCR-based GMO detection methods using a large amount of DNA template. We selected target sequences that are commonly introduced into many kinds of GM crops, i.e., 35S promoter and nopaline synthase (NOS) terminator. This makes the newly developed method applicable to a wide range of GMOs, including some unauthorized ones. The estimated LOD of the new method was 0.005% of GM maize events; to the best of our knowledge, this method is the most sensitive among the GM maize detection methods for which the LOD was evaluated in terms of GMO content. A 10-fold increase in the DNA amount as compared with the amount used under common testing conditions gave an approximately 10-fold reduction in the LOD without PCR inhibition. Our method is applicable to various analytical samples, including processed foods. The use of other primers and fluorescence probes would permit highly sensitive detection of various recombinant DNA sequences besides the 35S promoter and NOS terminator. PMID- 28847346 TI - Establishing an Accuracy Basis for the Vitamin D External Quality Assessment Scheme (DEQAS). AB - Until recently, the Vitamin D External Quality Assessment Scheme (DEQAS) assessed the performance of various assays for the determination of serum total 25 hydroxyvitamin D [25(OH)D] by using a consensus mean based on the all-laboratory trimmed mean (ALTM) of the approximately 1000 participants' results. Since October 2012, the National Institute of Standards and Technology (NIST), as part of the Vitamin D Standardization Program, has participated in DEQAS by analyzing the quarterly serum sample sets using an isotope dilution LC-tandem MS (ID LC MS/MS) reference measurement procedure to assign an accuracy-based target value for serum total 25(OH)D. NIST has analyzed 90 DEQAS samples (18 exercises * 5 samples/exercise) to assign target values. The NIST-assigned values are compared with the ALTM and the biases assessed for various assays used by the participants, e.g., LC-MS/MS, HPLC, and several ligand-binding assays. The NIST value assignment process and the results of the analyses of the 90 DEQAS samples are summarized. The absolute mean bias between the NIST-assigned values and the ALTM was 5.6%, with 10% of the samples having biases >10%. Benefits of the accuracy-based target values are presented, including for sample sets with high concentrations of 25(OH)D2 and 3-epi-25(OH)D3. PMID- 28847348 TI - The Grand Challenge: Creating a Healthier Nation. PMID- 28847347 TI - Composition, Distribution, and Antioxidant Activity of Phenolic Compounds in 18 Soybean Cultivars. AB - Natural phenols are an important functional compound widely distributed in plants with benefits that promote human health. The content of total phenols, flavonoids, and anthocyanins and their composition distribution in 18 soybean cultivars was investigated. There are four phenolic acid distribution forms in these soybean cultivars, namely free, esterified, glycosided, and insoluble bound. Total phenols, flavonoids, and anthocyanins from 6 black soybean cultivars were found in higher numbers than those from 12 other yellow soybean cultivars. Free and esterified phenolic acids were the main phenolic acid form in all 18 soybean samples. Chlorogenic acid and caffeic acid were the dominant phenolic acids in eight detected phenolic acids, and daidzin and genistin were the abundant isoflavones in five detected isoflavones. Furthermore, the antioxidant activities of total phenols from the 6 black soybean cultivars were greater than those from the 12 yellow soybean cultivars, and there was a significant positive correlation between antioxidant activity and total phenolic content. Black soybeans could be a potential resource for developing natural antioxidants that may play a crucial role in human health protection. PMID- 28847349 TI - Patent Ductus Arteriosus in Preterm Infants, Part 1: Understanding the Pathophysiologic Link Between the Patent Ductus Arteriosus and Clinical Complications. AB - The clinical guidelines for treating patent ductus arteriosus (PDA) have significantly evolved over the last decades from treating any ductal shunt to more conservative management where only the hemodynamically significant patent ductus arteriosus (HSPDA) is treated. This shift has resulted largely from a lack of evidence from randomized controlled trials supporting a relationship between treating a PDA and improving long-term neonatal outcomes. However, there are many unresolved issues. There is no consensus on the precise definition of HSPDA requiring treatment or a clear understanding of when to treat HSPDA. Moreover, the current evidence shows worsening of the long-term neurodevelopmental outcome for infants undergoing surgical PDA ligation.
The presence of physiologic variability among preterm infants, and the presence of different compensatory mechanisms may make it difficult to establish a link between pathophysiology and long-term outcomes. That is, the physiologic variability cannot be simply assessed by randomly assigning infants into two arms of a study. Relying on research from animal and human studies, this article explains the link between the pathophysiology of a PDA and neonatal outcomes. PMID- 28847350 TI - The Use of Whole Body Cooling in the Treatment of Hypoxic-Ischemic Encephalopathy. AB - Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in neonates. Hypoxic-ischemic encephalopathy occurs as a result of a perinatal hypoxic-ischemic event just prior to or during delivery. Therapeutic hypothermia using whole body cooling is the current treatment of choice to reduce brain injury and improve long-term neurodevelopmental outcomes for neonates with HIE. All English language articles published since 2005 in PubMed and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were analyzed for existing evidence-based methods for whole body cooling. Whole body cooling is effective in the treatment of HIE in term and near-term neonates. Further research is needed to investigate the use of adjunctive therapies in conjunction with whole body cooling for improved neuroprotection. PMID- 28847351 TI - Hereditary Spherocytosis in the Neonatal Period: A Case Report. AB - Hereditary spherocytosis (HS) is the third most common yet most frequently underrecognized, congenitally acquired hemolytic disease of the neonate. Hereditary spherocytosis is caused by a defect of one or more erythrocyte membrane proteins, which leads to an increased rate of destruction of circulating red blood cells. The HS spectrum of symptoms is varied from asymptomatic to intrauterine hydrops. Diagnostic tests range from a complete blood count (CBC) analysis to deoxyribonucleic acid (DNA) sequencing. Management in the neonatal period focuses primarily on associated comorbidities, including the prevention of severe hyperbilirubinemia and anemia. Life span implications of HS include hemolysis, jaundice, anemia, splenomegaly, and periodic gallstones. Early identification and diagnosis of HS is essential to ensure proper monitoring and medical management throughout infancy, childhood, and adulthood. PMID- 28847352 TI - Fatigue: Has It Affected Your Compassion? AB - Compassion fatigue is a concept used to describe how various stressors affect individuals who work in health care and other caregiving professions. The results of compassion fatigue may include decreased work productivity, poor quality of care, safety concerns, job dissatisfaction, and job turnover. The NICU professionals are at an increased risk for experiencing compassion fatigue because of the nature of working with critically ill infants, their families, and the additional stress of the workplace. The purpose of this article is for the NICU professional to understand compassion fatigue, identify the risk factors, recognize the signs and symptoms, and offer strategies to implement within the NICU environment. PMID- 28847354 TI - Development and Evaluation of a Radiation Safety Program in the NICU. AB - PURPOSE: To develop and evaluate a radiation safety program used to educate NICU staff regarding safety procedures to minimize the effects of radiation on the newborn.
Background: Advancements in medical care have resulted in infants born at lower gestational ages and higher acuity. With increased acuity comes an increase in diagnostic testing, including radiologic imaging. Although x-rays are necessary, they do not come without risk, including the future development of cancers.
Methods: The number of x-rays completed in the NICU over a one-year period, was evaluated prior to the radiation safety program, directly after implementation, and five years postintervention.
Results: Prior to the radiation safety program, the mean number of x-rays was 4.2 per patient per NICU admission. Immediately after implementation, the mean decreased to 3.8 per patient, and five years postintervention, the mean significantly decreased to 1.9 x-rays per patient per NICU stay. PMID- 28847353 TI - The Effect of Education on Chlorhexidine Use in the NICU. AB - BACKGROUND: Neonates are at greater risk for central line-associated bloodstream infection (CLABSI) because of prolonged vascular access for nutrition and medications. Skin antisepsis using chlorhexidine gluconate (CHG), particularly the formulation with alcohol (CHG/alcohol), during central line insertion and maintenance activities is a key clinical care process associated with CLABSI reduction. One area of ongoing confusion for many clinicians is whether to adhere to the manufacturer's recommendations that CHG remain on the skin following the procedure to promote persistent microbicidal effects or to foster product removal in hopes of preventing skin-related complications. PURPOSE: Determine the effect of a targeted education program on the knowledge and attitudes of nurses who place peripherally inserted central catheters in the NICU regarding the use and removal of CHG antiseptic. METHODS: A quasi-experimental presurvey/postsurvey quality improvement project (QI project) recruited participants from the electronic mailing list of a national neonatal nursing organization. RESULTS: There was a statistically significant deficiency in knowledge or misinformation related to the use of CHG/alcohol on the presurvey assessment. Eight questions reflecting knowledge consistent with most recent evidence were answered correctly only 11.4-25.7 percent of the time, all of which were considered statistically significant. Following completion of the education program, a nearly 100 percent correct response rate on all but three postsurvey questions resulted. CONCLUSIONS: This quality improvement project demonstrated success in the ability to change knowledge surrounding the removal of CHG/alcohol from the skin of babies in the NICU following completion of a targeted education program and the effectiveness of targeted web-based educational programs. PMID- 28847356 TI - Atrial Flutter in the Neonate: A Case Study. AB - Atrial flutter (AF) is an uncommon neonatal tachyarrhythmia that can present during the first few days after birth. The infant with AF may demonstrate an abrupt increase in heart rate greater than 220 bpm that is sustained despite vagal maneuvers. The diagnosis is made by electrocardiogram (ECG), and the treatments may include medication management and cardioversion. We present a case review of an infant diagnosed with AF and describe the incidence, pathophysiology, diagnosis, and management. PMID- 28847358 TI - Understanding the NICU: What Parents of Preemies and Other Hospitalized Newborns Need to Know. PMID- 28847357 TI - "Mental Health" in the NICU: Time to Catch Up and Provide Trauma-Informed Care for Families and Pros. AB - Mental health in the NICU has often been on the outer edge of neonatal care because of the focus being on the baby's health. Yet, with postpartum depression and posttraumatic stress disorder (PTSD) skyrocketing in the NICU and being proven to affect developmental outcomes, it is time to change that. Evidence is provided in this interview with Cheryl Milford, EdS, a NICU psychologist. PMID- 28847359 TI - Continuing Education Course. PMID- 28847360 TI - News of the Academy of Neonatal Nursing. PMID- 28847361 TI - Chondroitin Sulfate: A Critical Review of Generic and Specific Problems in Its Characterization and Determination-An Exemplar of a Material with an Unknown or Variable Composition (UVCB). AB - This review discusses the criteria for the selection of appropriate reference samples of chondroitin sulfate (CS) and the properties and specific problems of analytical methods for CS, namely titration with cetylpyridinium chloride; various separations; and UV-Vis, NMR, MS, and IR spectroscopies. Suggestions are put forward with regard to acceptable protocols for manufactures' and for official/referee analysts for the analysis of CS in products. PMID- 28847362 TI - MicroRNA expression in bovine preimplantation embryos. AB - We profiled 98 mature microRNAs (miRNAs) using a stem-loop reverse transcription polymerase chain reaction assay array based on human miRNAs. We demonstrated that one, but not two, base-pair changes in the miRNA recognition sequence at the 3' end only marginally affected copy number estimates. Absolute levels of miRNAs were measured in matured cattle oocytes, eight-cell embryos and normal and parthenogenetic blastocysts and Day-14 trophoblast. Most miRNA concentrations were below the expected functional threshold required for effective repression of moderately to highly abundant target RNA. In oocytes and peri-embryonic genome activation embryos, miRNA 320, a member of the Dgcr8/Drosha-independent class of miRNAs, was expressed at greater than 1000 copies per embryo. miRNAs were more abundant at the eight-cell than the oocyte stage. miRNA concentrations per cell increased from the eight-cell to the blastocyst stage. Both the number of miRNA species and their expression levels were reduced in trophoblast tissue at Day 14. The parthenogenetic samples were more related in their miRNA expression profiles to each other than to their wild-type (in vitro-produced cultured) counterparts. miRNAs 299 and 323, which have been shown to be maternally expressed in other species, were also more than 4-fold overexpressed in the cattle parthenogenetic samples. PMID- 28847363 TI - Mouse double minute homologue 2 (MDM2) downregulation by miR-661 impairs human endometrial epithelial cell adhesive capacity. AB - Human blastocysts that fail to implant following IVF secrete elevated levels of miR-661, which is taken up by primary human endometrial epithelial cells (HEECs) and impairs their adhesive capability. MicroRNA miR-661 downregulates mouse double minute homologue 2 (MDM2) and MDM4 in other epithelial cell types to activate p53; however, this has not been examined in the endometrium. In this study MDM2 protein was detected in the luminal epithelium of the endometrium, the site of blastocyst attachment, during the mid secretory receptive phase of the menstrual cycle. The effects of miR-661 on gene expression in and adhesion of endometrial cells was also examined. MiR-661 overexpression consistently downregulated MDM2 but not MDM4 or p53 gene expression in the Ishikawa endometrial epithelial cell line and primary HEEC. Adhesion assays were performed on the real-time monitoring xCELLigence system and by co-culture using Ishikawa cells and HEECs with HTR8/SVneo trophoblast spheroids. Targeted siRNA-mediated knockdown of MDM2 in endometrial epithelial cells reduced Ishikawa cell adhesion (P<0.001) and also reduced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.05) and HEECs (P<0.05). MDM2 overexpression using recombinant protein treatment resulted in enhanced HTR8/SVneo trophoblast spheroid adhesion to Ishikawa cells (P<0.01) and HEECs (P<0.05). This study highlights a potential new mechanism by which human blastocyst-secreted miR-661 reduces endometrial epithelial cell adhesion; via downregulation of MDM2. These findings suggest that MDM2 contributes to endometrial-blastocyst adhesion, implantation and infertility in women. PMID- 28847364 TI - Spermatogenic phenotype of testis-specific protein, Y-encoded, 1 (TSPY1) dosage deficiency is independent of variations in TSPY-like 1 (TSPYL1) and TSPY-like 5 (TSPYL5): a case-control study in a Han Chinese population. AB - Testis-specific protein, Y-encoded, 1 (TSPY1) is involved in the regulation of spermatogenic efficiency via highly variable copy dosage, with dosage deficiency of the multicopy gene conferring an increased risk of spermatogenic failure. TSPY like 1 (TSPYL1) and TSPY-like 5 (TSPYL5), two autosomal homologous genes originating from TSPY1, share a core sequence that encodes a functional nucleosome assembly protein (NAP) domain with TSPY1. To explore the potential effects of TSPYL1 and TSPYL5 on the TSPY1-related spermatogenic phenotype, we investigated the expression of these genes in 15 healthy and nonpathological human tissues (brain, kidney, liver, pancreas, thymus, prostate, spleen, muscle, leucocytes, placenta, intestine, ovary, lung, colon and testis) and explored associations between their variations and spermatogenic failure in 1558 Han Chinese men with different spermatogenic conditions, including 304 men with TSPY1 dosage deficiency. TSPYL1 and TSPYL5 were expressed in many different tissues, including the testis. An unreported rare variant that is likely pathogenic (c.1057A>G, p.Thr353Ala) and another of uncertain significance (c.1258C>T, p.Arg420Cys) in the NAP-coding sequence of TSPYL1 were observed in three spermatogenesis-impaired patients with heterozygous status. The distribution differences in the alleles, genotypes and haplotypes of eight TSPYL1- and TSPYL5 linked common variants did not reach statistical significance in comparisons of patients with spermatogenic failure and controls with normozoospermia. No difference in sperm production was observed among men with different genotypes of the variants. Similar results were obtained in men with TSPY1 dosage deficiencies. Although the distribution of missense variants of TSPYL1 found in the present and other studies suggests that patients with spermatogenic failure may have a statistically significant greater burden of rare variations in TSPYL1 relative to normozoospermic controls, the functional evidence suggests that TSPYL1 contributes to impaired spermatogenesis. Moreover, the present study suggests that the effects of TSPYL1 and TSPYL5 on the spermatogenic phenotype of TSPY1 dosage deficiency are limited, which may be due to the stability of their function resulting from high sequence conservation. PMID- 28847368 TI - Making the shift to population health. PMID- 28847365 TI - Luqin-like RYamide peptides regulate food-evoked responses in C. elegans. AB - Peptide signaling controls many processes involving coordinated actions of multiple organs, such as hormone-mediated appetite regulation. However, the extent to which the mode of action of peptide signaling is conserved in different animals is largely unknown, because many peptides and receptors remain orphan and many undiscovered peptides still exist. Here, we identify two novel Caenorhabditis elegans neuropeptides, LURY-1-1 and LURY-1-2, as endogenous ligands for the neuropeptide receptor-22 (NPR-22). Both peptides derive from the same precursor that is orthologous to invertebrate luqin/arginine-tyrosine-NH2 (RYamide) proneuropeptides. LURY-1 peptides are secreted from two classes of pharyngeal neurons and control food-related processes: feeding, lifespan, egg laying, and locomotory behavior. We propose that LURY-1 peptides transmit food signals to NPR-22 expressed in feeding pacemaker neurons and a serotonergic neuron. Our results identified a critical role for luqin-like RYamides in feeding related processes and suggested that peptide-mediated negative feedback is important for satiety regulation in C. elegans. PMID- 28847369 TI - Gender Wage Gap. PMID- 28847367 TI - Positioning statement of the Spanish Association of Urology on the document published by the Spanish Society of Medical Oncology about the use of medical treatments in oncological patients. PMID- 28847366 TI - Regulation of rice root development by a retrotransposon acting as a microRNA sponge. AB - It is well documented that transposable elements (TEs) can regulate the expression of neighbouring genes. However, their ability to act in trans and influence ectopic loci has been reported rarely. We searched in rice transcriptomes for tissue-specific expression of TEs and found them to be regulated developmentally. They often shared sequence homology with co-expressed genes and contained potential microRNA-binding sites, which suggested possible contributions to gene regulation. In fact, we have identified a retrotransposon that is highly transcribed in roots and whose spliced transcript constitutes a target mimic for miR171. miR171 destabilizes mRNAs encoding the root-specific family of SCARECROW-Like transcription factors. We demonstrate that retrotransposon-derived transcripts act as decoys for miR171, triggering its degradation and thus results in the root-specific accumulation of SCARECROW-Like mRNAs. Such transposon-mediated post-transcriptional control of miR171 levels is conserved in diverse rice species. PMID- 28847370 TI - Authors' response. PMID- 28847371 TI - Ethics and Third-Party Payers. PMID- 28847372 TI - Author's response. PMID- 28847373 TI - Corrections. PMID- 28847374 TI - Destructive and painful ulcer in the posterior oral cavity and oropharynx. PMID- 28847375 TI - The appreciative leader. PMID- 28847376 TI - Patient care and responsibilities of the itinerant provider. PMID- 28847377 TI - A GABRA2 polymorphism improves a model for prediction of drinking initiation. AB - BACKGROUND: Survival analysis was used to explore the addition of a single nucleotide polymorphism (SNP) and covariates (sex, interview age, and ancestry) on a previously published model's ability to predict onset of drinking. A SNP variant of rs279871, in the chromosome 4 gene encoding gamma-aminobutyric acid receptor (GABRA2), was selected due to its associations with alcoholism in young adults and with behaviors that increased risk for early drinking. METHODS: A subsample of 674 adolescents (ages 14-17) participating in the Collaborative Study on the Genetics of Alcoholism (COGA) was examined using a previously derived Cox proportional hazards model containing: 1) number of non-drinking related conduct disorder (CD) symptoms, 2) membership in a high-risk alcohol dependent (AD) family, 3) most best friends drank (MBFD), 4) Achenbach Youth Self Report (YSR) externalizing score, and 5) YSR social problems score. The above covariates along with the SNP variant of GABRA2, rs279871, were added to this model. Five new prototype models were examined. The most parsimonious model was chosen based on likelihood ratio tests and model fit statistics. RESULTS: The final model contained four of the five original predictors (YSR social problems score was no longer significant and hence dropped from subsequent models), the three covariates, and a recessive GABRA2 rs279871 TT genotype (two copies of the high-risk allele containing thymine). The model indicated that adolescents with the high-risk TT genotype were more likely to begin drinking than those without this genotype. CONCLUSIONS: The joint effect of the gene (rs279871 TT genotype) and environment (MBFD) on adolescent alcohol initiation is additive, but not interactive, after controlling for behavior problems (CD and YSR externalizing score). This suggests that the impact of the high-risk TT genotype on the onset of drinking is affected by controlling for peer drinking and does not include genotype-by-environment interactions. PMID- 28847378 TI - Persistent negative effects of alcohol drinking on aspects of novelty-directed behavior in male rhesus macaques. AB - Humans with histories of prolonged heavy alcohol use exhibit poorer performance on cognitive tasks associated with problem solving, short-term memory, and visuospatial reasoning, even following the cessation of drinking, when compared with healthy controls. It is unclear, however, whether the cognitive problems are a consequence of alcohol exposure or a contributing factor to alcohol-use disorders. Here, we examined the relationship between performance on a novel object recognition (NOR) task and total alcohol consumption (TAC) in adult male rhesus macaques (n = 12; ETH group; trained to self-administer alcohol). NOR performance in this group was assessed prior to induction of alcohol drinking ("pre") and, again, after a 1-year abstinence period ("post") and was compared to the performance of a second group (n = 6; Control group), which was alcohol naive. In the NOR task, difficulty was manipulated across three phases by varying specific object features and/or by varying duration of access to objects. For each monkey, we measured aspects of novelty-related behavior including novelty detection, novelty reactivity, and perseverative behavior. TAC during induction and a "free" access period in which the monkey could choose between water and a 4% w/v ethanol solution also was determined. We found that performance deficits in the NOR task were a consequence of high total alcohol intake instead of a predictor of subsequent high intake. Poor NOR performance in drinkers with the highest intakes was characterized by increased perseverative behavior rather than an inability to detect or react to novelty. Finally, the observed deficits are long-lasting - persisting even after a year of abstinence. Given the prevalent and persistent nature of alcohol-induced cognitive deficits in patients in treatment settings, understanding the nature of the deficit and its neural basis could ultimately offer novel treatment approaches based on the reversal of alcohol-induced impairment. PMID- 28847379 TI - Binge drinking and anxiety at the end of the nocturnal period in alcohol preferring sP rats. AB - Previous studies suggested that exposure of Sardinian alcohol-preferring (sP) rats to daily drinking sessions of 1 h, during the dark phase of the light/dark cycle, with multiple alcohol concentrations, and unpredictable access to alcohol, resulted in exceptionally high intakes of alcohol when the drinking session occurred over the last hours of the dark phase. Additionally, higher levels of anxiety-related behaviors were observed at the 12th, rather than 1st, hour of the dark phase, suggesting that uncertainty of time of alcohol access and expectation of alcohol availability produced an emotional "distress". The present study was designed to provide pharmacological support to the hypothesis that high alcohol intake under this drinking procedure is secondary to exacerbation of the anxiety like state of sP rats. To this end, sP rats were initially exposed to daily 1-h drinking sessions during the dark phase and with multiple alcohol concentrations (0%, 10%, 20%, and 30%; v/v); time of alcohol exposure was changed each day and was unpredictable to rats. Rats were then treated acutely with non-sedative doses of diazepam (0, 1, 2, and 3 mg/kg; intraperitoneally [i.p.]) before two drinking sessions occurring at the 1st and 12th hour of the dark phase, respectively. Treatment with diazepam was ineffective at the 1st hour; conversely, it selectively reduced alcohol intake (up to 50% at the dose of 3 mg/kg) at the 12th hour. The preferential effectiveness of diazepam in reducing alcohol intake when the drinking session occurred at the 12th hour of the dark phase is consistent with the hypothesis that uncertainty of time of alcohol access and expectation of alcohol availability generated an emotional "distress" that rats counterbalanced with high alcohol drinking; the results of the present study are interpreted as the anxiolytic effects of diazepam substituting for those of alcohol, resulting in the observed reduction in alcohol intake. PMID- 28847380 TI - P3b amplitude is not reduced in abstinent alcoholics with a current MDD. AB - BACKGROUND AND AIMS: In two studies of long-term abstinent alcoholics (LTAAs), we found that about 17% had a current major depressive disorder (MDD). We tested the hypothesis that LTAAs with a current MDD diagnosis do not exhibit the reduced P3b event-related potential amplitude endophenotype for alcoholism. This is consistent with the majority of LTAAs with a current MDD having developed alcohol dependence via self-medication of their MDD rather than their alcohol dependence arising from the alcoholism endophenotype. We revisited the P3b data from the two LTAAs studies, comparing LTAAs with a current MDD vs. LTAAs without a current MDD to each other and to non-substance abusing controls (NSACs). In northern California, 48 LTAAs and 48 non-substance abusing controls were studied, while in Honolulu, 105 LTAAs and 77 NSACs were studied. A total of 26 LTAAs had a current MDD (10 in California and 16 in Honolulu). The difference in P3b amplitude and latency (measured in targets-standards) in a 3-condition visual oddball paradigm was compared to MDD diagnoses gathered using the computerized Diagnostic Interview Schedule. Across both study sites, LTAAs without a current MDD (either with no lifetime MDD or a lifetime, but not current MDD) had lower P3b amplitudes than NSACs. In contrast, P3b amplitudes in LTAAs with a current MDD did not differ from controls. We conclude that alcohol dependence in LTAAs with a current MDD did not derive from the alcoholism endophenotype. This group may not exhibit the externalizing diathesis characterized by impulsive, disinhibited behavior and may have developed alcohol dependence via excessive drinking in an attempt to self-medicate their MDD. These results have major implications for targeted treatments of alcoholism and comorbid MDD. PMID- 28847381 TI - Isolation stress and chronic mild stress induced immobility in the defensive burying behavior and a transient increased ethanol intake in Wistar rats. AB - Stress can be experienced with or without adverse effects, of which anxiety and depression are two of the most important due to the frequent comorbidity with alcohol abuse in humans. Historically, stress has been considered a cause of drug use, particularly alcohol abuse due to its anxiolytic effects. In the present work we exposed male Wistar rats to two different stress conditions: single housing (social isolation, SI), and chronic mild stress (CMS). We compared both stressed groups to group-housed rats and rats without CMS (GH) to allow the determination of a clear behavioral response profile related to their respective endocrine stress response and alcohol intake pattern. We found that SI and CMS, to a greater extent, induced short-lasting increased sucrose consumption, a transient increase in serum corticosterone level, high latency/immobility, and low burying behavior in the defensive burying behavior (DBB) test, and a transient increase in alcohol intake. Thus, the main conclusion was that stress caused by both SI and CMS induced immobility in the DBB test and, subsequently, induced a transient increased voluntary ethanol intake in Wistar rats with a free choice home-cage drinking paradigm. PMID- 28847382 TI - Ethanol suppresses carbamylcholine-induced intracellular calcium oscillation in mouse pancreatic acinar cells. AB - Oscillation of intracellular calcium levels is closely linked to initiating secretion of digestive enzymes from pancreatic acinar cells. Excessive alcohol consumption is known to relate to a variety of disorders in the digestive system, including the exocrine pancreas. In this study, we have investigated the role and mechanism of ethanol on carbamylcholine (CCh)-induced intracellular calcium oscillation in murine pancreatic acinar cells. Ethanol at concentrations of 30 and 100 mM reversibly suppressed CCh-induced Ca2+ oscillation in a dose-dependent manner. Pretreatment of ethanol has no effect on the store-operated calcium entry induced by 10 MUM of CCh. Ethanol significantly reduced the initial calcium peak induced by low concentrations of CCh and therefore, the CCh-induced dose-response curve of the initial calcium peak was shifted to the right by ethanol pretreatment. Furthermore, ethanol significantly dose-dependently reduced inositol 1,4,5-trisphosphate-induced calcium release from the internal stores in permeabilized acinar cells. These results provide evidence that excessive alcohol intake could impair cytosolic calcium oscillation through inhibiting calcium release from intracellular stores in mouse pancreatic acinar cells. PMID- 28847383 TI - Is catalase involved in the effects of systemic and pVTA administration of 4 methylpyrazole on ethanol self-administration? AB - The oxidative metabolism of ethanol into acetaldehyde involves several enzymes, including alcohol dehydrogenase (ADH) and catalase-hydrogen peroxide (H2O2). In this regard, while it is well known that 4-methylpyrazole (4-MP) acts by inhibiting ADH in the liver, little attention has been placed on its ability to interfere with fatty acid oxidation-mediated generation of H2O2, a mechanism that may indirectly affect catalase whose enzymatic activity requires H2O2. The aim of our investigation was twofold: 1) to evaluate the effect of systemic (i.p. [intraperitoneal]) and local (into the posterior ventral tegmental area, pVTA) administration of 4-MP on oral ethanol self-administration, and 2) to assess ex vivo whether or not systemic 4-MP affects liver and brain H2O2 availability. The results show that systemic 4-MP reduced ethanol but not acetaldehyde or saccharin self-administration, and decreased the ethanol deprivation effect. Moreover, local intra-pVTA administration of 4-MP reduced ethanol but not saccharin self administration. In addition, although unable to affect basal catalase activity, systemic administration of 4-MP decreased H2O2 availability both in liver and in brain. Overall, these results indicate that 4-MP interferes with ethanol self administration and suggest that its behavioral effects could be due to a decline in catalase-H2O2 system activity as a result of a reduction of H2O2 availability, thus highlighting the role of central catalase-mediated metabolism of ethanol and further supporting the key role of acetaldehyde in the reinforcing properties of ethanol. PMID- 28847384 TI - Binge alcohol consumption 18 h after induction of sepsis in a mouse model causes rapid overgrowth of bacteria, a cytokine storm, and decreased survival. AB - Alcohol abuse increases vulnerability to infections and infection-related mortality. In previous studies, we found that acute alcohol abuse in a binge drinking model in mice decreased resistance to bacterial sepsis when alcohol was administered near the time of bacterial challenge. In the present study, we investigated the effects of alcohol administered later in the course of sepsis (18 h after injection of Escherichia coli). Our working hypothesis was that decreased production of cytokines caused by alcohol at this time would actually improve survival, because overproduction of pro-inflammatory mediators is thought to be the proximate cause of mortality in sepsis. Unexpectedly, administration of alcohol late in the course of sepsis led to a rapid increase in the number of viable bacteria in the peritoneal cavity. Significant increases in the concentrations of several cytokines and chemokines coincided with the increased number of bacteria in alcohol-treated mice and decreased survival time. These results demonstrated our working hypothesis to be incorrect, and reiterated the complexity of sepsis. Hypothermia is a consistent feature in this model of sepsis. In control mice (E. coli only), body temperature was near normal by 18 h or 21 h after administration of E. coli, but in mice treated with alcohol 18 h after E. coli, hypothermia was significant 3 h later and ultimately mortality was significantly increased. However, counteracting the hypothermic effect of alcohol by external warming of mice led to earlier mortality, demonstrating that hypothermia was not the major cause of mortality. These results, along with previous results from studies in which alcohol was given before initiation of sepsis, suggest that decreased cytokine and chemokine production may not be the key effect of alcohol that decreases resistance to sepsis. It seems more likely that suppression of mechanisms by which macrophages and neutrophils kill bacteria is critical, and this can occur even in the presence of high levels of cytokines and chemokines. PMID- 28847385 TI - Corrigendum to "Selective improvement of anosognosia for hemiplegia during transcranial direct current stimulation: A case report" [Cortex 61 (2014) 107 119]. PMID- 28847386 TI - The Pediatric Neurology Trainee Publication Award for 2015. PMID- 28847387 TI - Delivery of Functionality in Complex Food Systems: Physically inspired approaches from nanoscale to microscale, Paris 14 to 17 July, 2015. AB - The 6th international symposium in the series "Delivery of Functionality in Complex Food Systems: Physically inspired approaches from nanoscale to microscal" was held in the heart of Paris from 14 to 17 July, 2015. It brought together PhD students, academic food researchers and industrials from diversified food sectors. The scientific sessions of this meeting were constructed around important topics dealing with 1) Engineering of tailored-made structures in bio based systems; 2) Complexity and emergent phenomena in the integrative food science; 3) Investigation of nano and microstructures in the bulk and at interfaces; 4) Modeling approaches from bio-molecules and matrix structures to functionality; 5) Tuning binding & release of bioactive compounds by matrix modulation, and finally; 6) Tuning the delivery of functionality to the body. These topics were selected to cover different scientific fields and to show the contribution of food physical structures to development of health- and plaisure supporting food functions. The oral communications were all introduced by key note speakers and they were all illustrated by outstanding high quality short communications. One of the most original features of this symposium was the increasing number of presentations using multiscale and modeling approaches illustrating the concept of complexity and emergent phenomena integrative food science. These highlighted the importance of studies on interactions between structure properties of engineered delivery systems and human body (sensory properties, digestion, release, bioavailability and bioaccessibility). PMID- 28847388 TI - Salt reduction in sheeted dough: A successful technological approach. AB - The challenge of reducing the salt content while maintaining shelf life, stability and acceptability of the products is major for the food industry. In the present study, we implemented processing adjustments to reduce salt content while maintaining the machinability and the saltiness perception of sheeted dough: the homogeneous distribution of a layer of encapsulated salt grains on the dough during the laminating process. During sheeting, for an imposed deformation of 0.67, the final strain remained unchanged around 0.50 for salt reduction below 50%, and then, increased significantly up to 0.53 for a dough without salt. This increase is, in fine, positive regarding the rolling process since the decrease of salt content induces less shrinkage of dough downstream, which is the main feature to be controlled in the process. Moreover, the final strain was negatively correlated to the resistance to extension measured with a texture analyzer, therefore providing a method to evaluate the machinability of the dough. From these results, a salt reduction of 25% was achieved by holding 50% of the salt in the dough recipe to maintain the dough properties and saving 25% as salt grains to create high-salted areas that would enhance the saltiness perception of the dough. The distributor mounted above the rollers of the mill proved to be able to distribute evenly salt grains at a calculated step of the rolling out process. An innovative method based on RX micro-tomography allowed to follow the salt dissolving and to demonstrate the capability of the coatings to delay the salt dissolving and consequently the diffusion of salt within the dough piece. Finally, a ranking test on the salted perception of different samples having either an even distribution of encapsulated salt grains, a single layer of salt grains or a homogeneous distribution of salt, demonstrated that increasing the saltiness perception in salt-reduced food product could be achieved by a technological approach. PMID- 28847389 TI - In vitro release of grape-seed polyphenols encapsulated from uncoated and chitosan-coated liposomes. AB - Grape-seed extract (GSE), a rich source for polyphenols, was incorporated into liposomes (1.1% w/w soy lecithin) using high-pressure homogenization (22,500psi). A chitosan coating (1% w/w) was used to obtain more stable liposomes. Physiochemical properties (zeta-potential, mean particle size) of all liposomes were analyzed. In vitro release of GSE-polyphenols from various liposomes was investigated by measuring the total phenolic content of the dialysate (acetate buffer, pH3.8+/-0.1, 25mM) over time. Diverse kinetic models were used to describe the release of the polyphenols incorporated from liposomes. Z-average particle diameters increased with the incorporation of GSE and chitosan coating. Chitosan-coated liposomes containing GSE had larger particle sizes than coated liposomes without GSE. The zeta-potential changed from -38mV in uncoated liposomes to +65mV in coated liposomes. Entrapment efficiency for uncoated and coated liposomes was 88.2+/-4.7% and 99.5+/-2.3%, respectively. The release rate increased gradually by increasing time. In vitro release of GSE polyphenols from both uncoated and coated liposomes followed an exponential equation (first order Q(t)=a.(1-exp(-k.t))). The release from coated liposomes was much lower than uncoated liposomes. The release rate after 24h from uncoated liposomes was 0.55 and from coated liposomes was 0.24. This study indicates that the release of bioactive compounds from liposomes can be reduced by coating with chitosan, allowing an application of coated liposomes with a controlled release of GSE polyphenols in water-based foods. PMID- 28847390 TI - Protection of echium oil by microencapsulation with phenolic compounds. AB - The consumption of omega-3 enables the reduction of cardiovascular disease risk; however they are unstable. The aim of this work was to encapsulate echium oil (Echium plantagineum L.), a rich source of omega-3 fatty acids, with phenolic compounds (sinapic acid and rutin) by double emulsion followed by complex coacervation or by complex coacervation with sinapic acid in the capsule wall. Analyses of morphology, particle size, circularity, water activity, moisture, Fourier transform infrared spectroscopy, thermogravimetry, process yield, accelerated oxidation and identification and quantification of fatty acids present in the encapsulated oil were performed. Samples presented values of encapsulation process yield of phenolics and oil in the range of 39-80% and 73 99%, respectively. Moreover, all samples protected the oil against oxidation, obtaining induction time (accelerated oxidation) of 5h for pure oil and values in the range from 10 to 18h for samples. Thus, better protection to the oil was possible with sinapic acid applied in the capsule wall, which enhances its protection against lipid oxidation. PMID- 28847391 TI - Strategies to limit colour changes when fortifying food products with iron. AB - Iron, vitamin A, zinc and iodine have been recognized to be the micronutrients with the largest deficiencies worldwide. Among these, iron is highly reactive and may lead to negatively perceived organoleptic changes in products such as dull colour and off-taste. The colour change originated in fortified fruit-containing food products was confirmed to be the result of the complexation of iron and polyphenols. Phenolic compounds with two or more vicinal hydroxy benzyl moieties in their structure, such as catechols and pyrogallols were investigated for their ability to give bathochromic shift phenomena when mixed with iron salts. Furthermore, strategies for limiting colour development were based on: 1) pH adjustment; 2) saturation of polyphenols with unreactive divalent metal ions; 3) suppression of iron reactivity through complexation. Some of these strategies showed a significant improvement in colour stability, with the best results achieved by the latter. The findings in model systems gave a good insight of the mechanisms involved in colour changes, and results were transferable to iron fortified banana puree. PMID- 28847392 TI - Dissolution kinetics of pH responsive alginate-pectin hydrogel particles. AB - Encapsulation is used for protection of bioactive compounds during processing, storage, and passage through the upper gastrointestinal (GI) tract and delivery to the small intestine. A number of pH responsive synthetic polymers are approved for drug delivery but are not allowed for food applications. We developed a biopolymer mixture composed of alginate and pectin that can form hydrogel when the pH is below 3.0. We also produced novel disc shaped particles which can potentially enhance the particle adhesion in intestines. As the pH increases, Al P hydrogels go through a gel-sol transition and the dissolution kinetics of the hydrogel dominates the bioactive compound release. The goals of this study are to investigate the relative effects of factors contributing to the dissolution kinetics of Al-P hydrogel and to develop mathematical models characterizing the degradation behavior of the hydrogels under product storage and lower GI tract conditions. The volume change of spherical and disc shaped particles at pH3.0 showed that the hydrogel particles would be stable in low pH beverages during storage. At pH5.0 and 7.0, hydrogel particle dissolution followed a zero-order kinetic model. The 2.8% TGC 43:57wt% Al-P disc particles had the fastest and the 2.2% TGC 82:18wt% Al-P spherical particles had the slowest volume dissolution rate at pH7.0 and 37 degrees C. Activation energies of hydrogel particles were significantly affected by pH, particle shape and Al to P ratio. Such a biopolymer system which responds to pH provides an opportunity to use food as a vehicle for targeted delivery of bioactive compounds. PMID- 28847393 TI - Boosting the bioavailability of hydrophobic nutrients, vitamins, and nutraceuticals in natural products using excipient emulsions. AB - Many highly hydrophobic bioactives, such as non-polar nutrients, nutraceuticals, and vitamins, have a relatively low or variable oral bioavailability. The poor bioavailability profile of these bioactives may be due to limited bioaccessibility, poor absorption, and/or chemical transformation within the gastrointestinal tract (GIT). The bioavailability of hydrophobic bioactives can be improved using specially designed oil-in-water emulsions consisting of lipid droplets dispersed within an aqueous phase. The bioactives may be isolated from their natural environment and then incorporated into the lipid phase of emulsion based delivery systems. Alternatively, the bioactives may be left in their natural environment (e.g., fruits or vegetables), and then ingested with emulsion based excipient systems. An excipient emulsion may have no inherent health benefits itself, but it boosts the biological activity of bioactive ingredients co-ingested with it by altering their bioaccessibility, absorption, and/or chemical transformation. This review discusses the design and fabrication of excipient emulsions, and gives some examples of recent research that demonstrates their potential efficacy for improving the bioavailability of hydrophobic bioactives. The concept of excipient emulsions could be used to formulate emulsion-based food products (such as excipient sauces, dressings, dips, creams, or yogurts) specifically designed to increase the bioavailability of bioactive agents in natural foods, such as fruits and vegetables. PMID- 28847394 TI - Improving the performance of transglutaminase-crosslinked microparticles for enteric delivery. AB - Various agents for cross-linking have been investigated for stabilizing and controlling the barrier properties of microparticles for enteric applications. Transglutaminase, in addition to being commercially available for human consumption, presents inferior cross-linking action compared to glutaraldehyde. In this study, the intensity of this enzymatic cross-linking was investigated in microparticles obtained by complex coacervation between gelatin and gum Arabic. The effectiveness of cross-linking in these microparticles was evaluated based on swelling, release of a model substance (parika oleoresin: colored and hydrophobic) and gastrointestinal assays. The cross-linked microparticles remained intact under gastric conditions, whereas the uncross-linked microparticles have been dissolved. However, all of the microparticles have been dissolved under intestinal conditions. The amount of oily core that was released decreased as the amount of transglutaminase increased. For the most efficient microparticles (50U/g of protein), the performance was improved by increasing the pH of cross-linking from 4.0 to 6.0, resulting in a release of 17.1% rather than 32.3% of the core material. These results were considerably closer to the 10.3% of core material released by glutaraldehyde-cross-linked microparticles (1mM/g of protein). PMID- 28847395 TI - Bioavailability of quercetin in humans and the influence of food matrix comparing quercetin capsules and different apple sources. AB - The objective of the four-way cross-over pilot study was the investigation of quercetin bioavailability after ingestion of apple quercetin incorporated in different matrices and quercetin dihydrate capsule. Six healthy volunteers were given a standard diet supplemented with 71MUmol quercetin equivalents from vacuum impregnated apple chips, apple peel extract capsules and apple peel. Quercetin dihydrate capsules were used as control. The vacuum impregnated apple chips were enriched with a quercetin rich apple peel extract. The ingestion of vacuum impregnated apple chips, apple peel extract capsules and apple peel resulted in similar plasma quercetin and plasma total flavonol concentrations compared to the quercetin dihydrate capsule. With regard to the bioavailabilities of all quercetin treatments, a reduced release from vacuum impregnated apple chips can be excluded. The apple peel matrix which is rich in indigestible dietary fibers impacted the profile of the plasma flavonol time curve similar to poor soluble quercetin dihydrate. Finally, the quercetin bioavailability of vacuum impregnated apple chips (AUC0-1440min: 104+/-24MUmol.min?L-1) as functional food was similar to the supplementation with apple peel extract capsules (AUC0-1440min: 87+/ 27MUmol?min?L-1). PMID- 28847396 TI - Influence of heat on miscibility of Quillaja saponins in mixtures with a co surfactant. AB - Thermal treatment of mixed surfactant systems can have a major impact on their phase behavior through modified interactions between the surfactants. In this study, we investigated the miscibility behavior of aqueous binary surfactant systems composed of Quillaja saponin extract and sodium caseinate, pea protein, rapeseed lecithin, or egg lecithin at different concentration ratios (0-5% w/v) at pH3, 5, and 7 upon heat treatment (25-75 degrees C). The results revealed that the heat-treated Quillaja saponin-sodium caseinate mixtures at pH7 remained miscible when the ratio of Quillaja saponins was equal or higher to the ratio of caseinate, otherwise the mixtures flocculated due to increased hydrophobic interactions. At pH3, the aggregation of Quillaja saponin-sodium caseinate structures was intensified by heating mainly through self-association of casein molecules. In Quillaja saponin-pea protein mixtures as well as in pure pea protein samples heating led to weakening of the gel structures at all tested pH values. In contrast, heating did not affect Quillaja saponin-rapeseed lecithin mixtures, which stayed miscible independent of pH due to electrostatic repulsive forces. Furthermore, the flocculated (pH5, 7) or aggregated (pH3) Quillaja saponin-egg lecithin mixtures were only slightly affected by heating. These results are important for understanding the interactions of binary surfactant systems when subjected to heating, which is a common processing step in many food applications. PMID- 28847397 TI - Development of polyphenol-enriched vacuum and atmospheric fried matrices: Evaluation of quality parameters and in vitro bioavailability of polyphenols. AB - Polyphenols are very unstable and may be degraded when exposed to harsh conditions, such as those found in frying. The inclusion of vacuum seems to be a reasonable solution to avoid these adverse effects. Accordingly, the purpose of this study was to analyze the effect of olive-leaf polyphenol extract on quality parameters of vacuum and atmospheric fried gluten-starch matrices. Matrices were prepared using 12% (d.b.) gluten and 88% (d.b.) starch, using either native or a mixture of native (90%) and pre-gelatinized starch (10%). Polyphenols were added as a freeze-dried powder. Atmospheric and vacuum (91.4kPa, Twater boiling point=46 degrees C) frying were compared using an equivalent thermal driving force, which is defined as the difference between oil temperature and water boiling point at the working pressure. Bioavailability of polyphenols was evaluated using simulated digestion and caco-2 cells absorption. The addition of pre-gelatinized starch significantly decreased oil absorption in vacuum fried matrices, however, no significant differences were noted when added into atmospheric fried ones. Polyphenols retention was higher than 70% in vacuum fried matrices. Their bioavailability was ~15%, much higher than in atmospheric fried ones (~8%), and that the one reported in other studies. Interestingly, polyphenol addition reduced the oil content of vacuum fried snacks by 20%. This could be attributed to the hydrating effect of polyphenols, which may facilitate starch gelatinization, improving structure formation during vacuum frying, which will be the focus of future research. PMID- 28847398 TI - Sequential transformation of the structural and thermodynamic parameters of the complex particles, combining covalent conjugate (sodium caseinate + maltodextrin) with polyunsaturated lipids stabilized by a plant antioxidant, in the simulated gastro-intestinal conditions in vitro. AB - The present work is focused on the structural transformation of the complexes, formed between covalent conjugate (sodium caseinate + maltodextrin) and an equimass mixture of the polyunsaturated lipids (PULs): (soy phosphatidylcholine + triglycerides of flaxseed oil) stabilized by a plant antioxidant (an essential oil of clove buds), in the simulated conditions of the gastrointestinal tract. The conjugate was used here as a food-grade delivery vehicle for the PULs. The release of these PULs at each stage of the simulated digestion was estimated. PMID- 28847399 TI - Extraction and physicochemical characterization of Tenebrio molitor proteins. AB - This study focused on the extraction and physicochemical characterization of proteins from larvae and larvae meal of Tenebrio molitor. The larvae were subjected to a protein extraction process which involved a thermo-mechanical pre treatment to produce the larvae meal. Soluble proteins from larvae and from larvae meal were subsequently extracted by solubilisation at an alkaline pH. The products obtained were then characterized and compared. The larvae and larvae meal were rich in protein (65.6% and 71.6% respectively) and displayed good essential amino acid (EAA) profiles. They contained all EAA and in sufficient quantities to meet the dietary requirements of both humans and salmon, except for a deficiency in methionine. The EAA profile of the larvae meal was also comparable to those of fish and soya meals used for feed. At pH10 and 45 degrees C, the protein extraction yield of larvae (59.9%) was two-fold that of larvae meal (26.4%). The soluble proteins had protein contents on dry matter of 84% and 80% from larvae and larvae meal respectively. Molecular weights ranged from <=14 to 100kDa but the two soluble proteins differed. The soluble proteins had a solubility which was highly pH-dependent, with a low solubility at pH3 to 5. Their surface charge depended on both the pH (in particular) and the NaCl concentration. The surface hydrophobicity at pH7 of soluble proteins from larvae (670.3) was higher than that of soluble proteins from larvae meal (102.5). These soluble proteins lowered the water surface tension to 42mN/m and 32mN/m for the soluble proteins from larvae and from larvae meal respectively. Chemical compounds used in this work. Glycine (PubChem CID: 750); Glycerol (PubChem CID: 753); Tris-(hydroxymethyl)aminomethane (PubChem CID: 4468930); Sodium chloride (PubChem CID: 5234); Ethanol (PubChem CID: 702); Monosodium phosphate (PubChem CID: 23672064); Disodium hydrogen phosphate (PubChem CID: 24203); 2 mercaptoethanol (PubChem CID: 1567); Hydrochloric acid (PubChem CID: 313); Bromophenol blue (PubChem CID: 8272); Sodium hydroxide (PubChem CID: 14798); Sodium dodecyl sulphate (PubChem CID: 3423265). PMID- 28847400 TI - Vitamin A degradation in triglycerides varying by their saturation levels. AB - Vitamin A deficiency has a widespread occurrence globally and is considered as one of the world's most serious health risk factors. Potential solutions to address this deficiency include dietary diversification or supplementation, but food fortification is generally accepted as the most cost-effective solution. The main issue with food fortification of this vitamin is related to its high instability in food matrices. Dilution of vitamin A in triglycerides is a natural and appropriate way to stabilize this compound. We show here that vitamin A palmitate stability increases with increasing concentration of triglycerides. Moreover, we found that vitamin A palmitate displays improved stability in more saturated oils. Using various temperatures, and Arrhenius plots of experiments performed at storage temperatures between 30 degrees C and 60 degrees C for oils varying by their saturation and crystallinity, we demonstrate that crystallization is not responsible for this phenomenon. Additionally, we show by centrifugation that vitamin A is preferably solubilized in the liquid phase compared to the crystalline phase, explaining that triglyceride crystallization does not stabilize vitamin A palmitate. It is proposed that unsaturated fats generate more oxidation products such as radicals and peroxides, leading to a quicker degradation of vitamin A. PMID- 28847401 TI - Effect of alpha-tocopherol on oxidative stability of oil during spray drying and storage of dried emulsions. AB - Lipophilic compounds such as polyunsaturated fatty acids (PUFAs) and antioxidants can be encapsulated by spray drying in order to protect and prolong their functionalities and get new handling properties. The aim of this work was to study the effect of both the spray drying stage and storage (60 degrees C - 50% RH) on the oxidation of lipophilic compounds encapsulated in spray dried oil-in water emulsions (10% w/w oil in dry matter) using maltodextrin as matrix and Tween(r) 20 as emulsifier. Emulsions were prepared with oil containing or not containing alpha-tocopherol (482ppm in oil) in order to also demonstrate the influence of the antioxidant. Results showed that there is a beginning of oxidation during spray drying, evidenced by a slight increase of markers of rancidity, i.e. conjugated dienes and volatile organic compounds. During storage, the oxidative degradation of PUFAs and alpha-tocopherol started quickly under the conditions of aging. This was shown to be due to the negative effect of the process and to the porosity of the solid matrix to oxygen, associated with the hollow structure of the particles. An inhibitory action of maltodextrin on alpha tocopherol was also hypothesized, but it has to be confirmed. PMID- 28847402 TI - Improving thermal stability of hydrolysed whey protein-based infant formula emulsions by protein-carbohydrate conjugation. AB - Whey protein hydrolysate (WPH) ingredients are commonly used in the manufacture of partially-hydrolysed infant formulae. The heat stability of these emulsion based formulae is often poor, compared with those made using intact whey protein. The objective of this study was to improve the heat stability of WPH-based emulsions by conjugation of WPH with maltodextrin (MD) through wet heating. Emulsions stabilised by different protein ingredients, whey protein isolate (WPIE), whey protein hydrolysate (WPHE), heated WPH (WPH-HE), and WPH conjugated with MD (WPH-CE) were prepared and heat treated at 75 degrees C, 95 degrees C or 100 degrees C for 15min. Changes in viscosity, fat globule size distribution (FGSD) and microstructure, evaluated using confocal laser scanning microscopy (CLSM), were used to monitor the effects of hydrolysis, pre-heating and conjugation on the heat stability of the emulsions. Heat stability increased in the order WPHE95%) of encapsulation of these all combinations of lipids by the conjugate was found along with both the high protection of the lipids against oxidation and their high solubility in an aqueous medium. To gain a better insight into such functionality of the complex particles a number of their structural (the weight-averaged molar weight, Mw; the radius of gyration, RG; the hydrodynamic radius, Rh; the architecture; the volume; the density; the zeta potential; the microviscosity of both the bilayers of PC liposomes and LPC micelles), and thermodynamic (the osmotic second virial coefficient, A2, reflecting the nature and intensity of both the complex-complex and complex solvent pair interactions) parameters were measured by a combination of such basic physico-chemical methods as static and dynamic multiangle laser light scattering, particle electrophoresis, atomic-force microscopy and electron spin resonance spectroscopy. PMID- 28847406 TI - Simulation of oleuropein structural conformation in vacuum, water and triolein water systems using molecular dynamics. AB - Oleuropein, the main phenolic compound of olive leaves, exhibits a unique blend of biological activities and has been shown to locate itself at the oil-water (O/W) interface. This behavior could influence the physico-chemical properties of dispersed systems such as emulsions. In this work, we study the effect of the microenvironment (vacuum, water, and triolein-water) on the conformational preferences of oleuropein using molecular dynamics (MD) simulations at 300K for at least 30ns. The seven torsions that describe the flexible skeleton of oleuropein were monitored together with the distance between the glucose (Glu) and hydroxytyrosol (Hyd) moieties (dglu-hyd) of the molecule. The obtained trajectories demonstrated that oleuropein adopts different conformations that depend on the environment. The preferential conformers in each system were analyzed for their molecular geometry and internal energy. In vacuum, the oleuropein preferential conformation is tight with the glucose moiety in close proximity with the hydroxytyrosol moiety. In water, oleuropein preferential conformers presented large differences in their structural properties, varying from a close like U form, and a semi-opened form, to an opened form characterized by high fluctuations in dglu-hyd values. In a triolein-water system, oleuropein tends to adopt a more open form where the glucose moiety could be approximately aligned with the hydroxytyrosol and elenolic acid moieties. Based on a calculation at the HF/6-31G* level, these flexibilities of oleuropein required energy of 19.14kcal/mol in order to adopt the conformation between water and triolein-water system. A radial distribution function (RDF) analysis showed that specific hydroxyl groups of Hyd and Glu interact with water molecules, enabling us to understand the amphiphilic character of oleuropein at the triolein-water interface. MD calculations together with interfacial tension measurements revealed that the oleuropein binding at O/W interface is an enthalpy driven mechanism. PMID- 28847407 TI - Molecular thermodynamics for food science and engineering. AB - We argue that thanks to molecular modeling approaches, many thermodynamic properties required in Food Science and Food Engineering will be calculable within a few hours from first principles in a near future. These new possibilities will enable to bridge via multiscale modeling composition, process and storage effects to reach global optimization, innovative concepts for food or its packaging. An outlook of techniques and a series of examples are given in this perspective. We emphasize solute chemical potentials in polymers, liquids and their mixtures as they cannot be understood and estimated without theory. The presented atomistic and coarse-grained methods offer a natural framework to their conceptualization in polynary systems, entangled or crosslinked homo- or heteropolymers. PMID- 28847408 TI - Critical evaluation of dipolar, acid-base and charge interactions II. Charge exchange within electrolytes and electron exchange with semiconductors. AB - Electron displacements may be considered as a general measure of semiconductor activity as well as of dipolar, acid-base and charge interactions. Electron transfers during reduction and oxidation reactions between dissolved cations and anions correspond to an extreme Lewis acid-base electron displacement. Brphinsted proton release (protolysis) represents an extremely weakened hydrogen bond. The most common electrostatic (Born, PCM) and chemical (pKa matching) models for electron and proton exchange between dissolved species are reviewed using aluminium species as examples. Dissolution of ions from solids (salts) may be considered as a reversed precipitation reaction. For partly covalent solids dissociation is dependent on electron or vacancy (hole) transfers to the solid which connects oxidation and reduction reactions to electron displacements in semiconductors. The electron exchange is characterized by Femi energy of semiconductors and of electrolytes. The standard reduction potential may thus be converted to Fermi energy of connected electrochemical cells. In disconnected particle suspensions (sols) the electron activity is a more appropriate parameter which may be converted both to standard reduction potential of ions and to Fermi energy of semiconductors. Dissolution of potential determining cations and anions and hydrolysis of surface sites determines the charging (electron transfer to/from surface) of solids. Both electrostatic (MUSIC) and chemical equilibrium constant models are available for Brphinsted equilibrium of surface hydroxyls. Point of zero charge is a result of positive and negative charge matching and it represents the optimal condition for condensation of polynuclear species by olation and oxolation. The capability of partial charge (PCM) model to predict condensation is evaluated. Acidity (pH), composition and temperature dependence of aluminium species is illustrated by solubility limits of contributing species and by phase diagrams. Influence of ions on macroscopic suspension properties, such as wetting and electrophoretic mobility is evaluated with reference to point of zero charge and to isoelectric point. Restrictions to the use of zeta potentials are related to the surface potential and particle size - Debye length ratios. Macroscopic settling (particle precipitation) and viscosity of suspensions (sols) are discussed with reference to Deryagin-Landau-Verwey Overbeek (DLVO) model. The primary dependence on counterion valence is evaluated according to Schulz-Hardy approach. The secondary dependence on counterion hydration (Hofmeister or lyotropic effect) and ion association (Debye-Huckel limiting model) are discussed. PMID- 28847409 TI - Investigating the underreporting of pedestrian and bicycle crashes in and around university campuses - a crowdsourcing approach. AB - In this paper, the non-motorized traffic safety concerns in and around three university campuses are evaluated by comparing police-reported crash data with traffic safety information sourced from the campus communities themselves. The crowdsourced traffic safety data comprise of both self-reported crashes as well as perceived hazardous locations. The results of the crash data analysis reveal that police-reported crashes underrepresent non-motorized safety concerns in and around the campus regions. The spatial distribution of police-reported crashes shows that police-reported crashes are predominantly unavailable inside the main campus areas, and the off-campus crashes over-represent automobile involvement. In comparison, the self-reported crash results report a wide variety of off campus collisions not involving automobiles, while also highlighting the issue of high crash concentrations along campus boundaries. An assessment of the perceived hazardous locations (PHLs) reveals that high concentrations of such observations at/near a given location have statistically significant association with both survey-reported crashes as well as future police-reported crashes. Moreover, the results indicate the presence of a saturation point in the relationship between crashes and PHLs wherein beyond a certain limit, an increasing number of traffic safety concerns may not necessarily correlate with a proportional increase in the number of crashes. These findings suggests that augmenting our existing knowledge of traffic safety through crowdsourcing techniques can potentially help in better estimating both existing as well as emerging traffic safety concerns. PMID- 28847410 TI - Assessing acute kidney injury following pancreatic surgery. PMID- 28847411 TI - Intensive Care Unit Outcomes Among Patients With Cancer After Palliative Radiation Therapy. AB - PURPOSE: To inform goals of care discussions at the time of palliative radiation therapy (RT) consultation, we sought to characterize intensive care unit (ICU) outcomes for patients treated with palliative RT compared to all other patients with metastatic cancer admitted to the ICU. METHODS AND MATERIALS: We conducted a retrospective cohort study of patients with metastatic cancer admitted to an ICU in a tertiary medical center from January 2010 to September 2015. We compared in hospital mortality between patients who received palliative RT in the 12 months before admission and all other patients with metastatic cancer. We used multivariable logistic regression to evaluate the association between receipt of palliative RT and in-hospital mortality, adjusting for patient characteristics and acute illness severity. RESULTS: Among 1424 patients with metastatic cancer, 11.3% (n=161) received palliative RT before ICU admission. In-hospital mortality was 36.7% for palliative RT patients, compared with 16.6% for other patients with metastatic cancer (P<.001). Receipt of palliative RT was associated with increased in-hospital mortality (odds ratio 2.08, 95% confidence interval 1.34 3.21, P=.001), after adjusting for patient characteristics and severity of critical illness. Only 34 patients (21.1%) treated with palliative RT received additional cancer-directed treatment after ICU admission. CONCLUSIONS: For patients with metastatic cancer, prior treatment with palliative RT is associated with increased in-hospital mortality after ICU admission. Nearly half of patients previously treated with palliative RT either died during hospitalization or were discharged with hospice care, and few received further cancer-directed therapy. Palliative RT referral may represent an opportunity to discuss end-of-life treatment preferences with patients and families. PMID- 28847413 TI - Impact of Zn excess on biomineralization processes in Juncus acutus grown in mine polluted sites. AB - Juncus acutus, an halophite plant pioneer in extremely polluted mine areas, was harvested in three different locations of Sardinia (Italy), having Zn soil concentration up to 80g/kg, and Zn water concentration ranging between 10-3g/L and 10-1g/L. Rhizosphere and plant samples were investigated combining X-ray microscopy (XM)/spectroscopy (XAFS) and infrared microspectroscopy (FTIR) to elucidate the chemical composition, (bio)mineralogy and Zn coordinative environment. The multi-technique approach allowed recognizing different biomineralization processes, and Zn complexes in the plant tissues. The Zn chemical environment in root biominerals is multi-phase and, depending on the sampling site, can comprise amorphous Zn silicate, Zn apatite, hydrozincite, and Zn sulphate. Zn cysteine and Zn histidine, complexes quoted as part of a detoxification strategy, were found mainly in plants from the site where the Zn water concentration has the highest values. This different site-specific mode of Zn biomineralization has relevant implications for phytoremediation techniques and for further biotechnology development, which can be better designed and developed after knowledge of site-specific-molecular processes ruling mineral evolution and biomineralization. Carboxylic groups and organic compounds (lignin, cellulose, hemicellulose, pectin and esters) were identified by FTIR analysis, thought the Zn speciation is not apparently linked to these carboxylic group rich biopolymers. PMID- 28847412 TI - Relapse Rates With Surgery Alone in Human Papillomavirus-Related Intermediate- and High-Risk Group Oropharynx Squamous Cell Cancer: A Multi-Institutional Review. AB - PURPOSE: To evaluate whether historic risk categories and indications for adjuvant therapy in the pre-human papillomavirus (HPV) and pre-transoral surgery (TOS) era were associated with clinically significant relapse rates in HPV+ oropharyngeal squamous cell cancer patients undergoing TOS. METHODS AND MATERIALS: A multi-institutional retrospective review of intermediate- and high risk HPV+ oropharyngeal squamous cell cancer patients not receiving adjuvant therapy after TOS was performed. Perineural invasion, lymphovascular invasion, T3 T4, or >=N2 disease were considered to be intermediate-risk factors, and extracapsular extension or positive margins were considered to be high-risk features, according to established risk categories. RESULTS: Median follow-up was 42.9 months. Among all 53 patients, the 3-year cumulative incidence of relapse was 26.0%. The 3-year cumulative incidence was 11.8% in the 37 intermediate-risk patients and 52.4% in the 16 high-risk patients. On univariate analysis only high risk status was significantly associated with an increased risk of relapse (hazard ratio 3.9; P=.018). The salvage rate for relapse was 77%, with 10 of 13 patients undergoing salvage therapy. CONCLUSIONS: Risk category was associated with clinically significant relapse rates after TOS alone in HPV+ oropharyngeal cancer, comparable to historical data and traditional indications for adjuvant therapy for all oropharyngeal cancer. PMID- 28847414 TI - The regulation of autophagy by calcium signals: Do we have a consensus? AB - Macroautophagy (hereafter called 'autophagy') is a cellular process for degrading and recycling cellular constituents, and for maintenance of cell function. Autophagy initiates via vesicular engulfment of cellular materials and culminates in their degradation via lysosomal hydrolases, with the whole process often being termed 'autophagic flux'. Autophagy is a multi-step pathway requiring the interplay of numerous scaffolding and signalling molecules. In particular, orthologs of the family of ~30 autophagy-regulating (Atg) proteins that were first characterised in yeast play essential roles in the initiation and processing of autophagic vesicles in mammalian cells. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a master regulator of the canonical autophagic response of cells to nutrient starvation. In addition, AMP-activated protein kinase (AMPK), which is a key sensor of cellular energy status, can trigger autophagy by inhibiting mTOR, or by phosphorylating other downstream targets. Calcium (Ca2+) has been implicated in autophagic signalling pathways encompassing both mTOR and AMPK, as well as in autophagy seemingly not involving these kinases. Numerous studies have shown that cytosolic Ca2+ signals can trigger autophagy. Moreover, introduction of an exogenous chelator to prevent cytosolic Ca2+ signals inhibits autophagy in response to many different stimuli, with suggestions that buffering Ca2+ affects not only the triggering of autophagy, but also proximal and distal steps during autophagic flux. Observations such as these indicate that Ca2+ plays an essential role as a pro autophagic signal. However, cellular Ca2+ signals can exert anti-autophagic actions too. For example, Ca2+ channel blockers induce autophagy due to the loss of autophagy-suppressing Ca2+ signals. In addition, the sequestration of Ca2+ by mitochondria during physiological signalling appears necessary to maintain cellular bio-energetics, thereby suppressing AMPK-dependent autophagy. This article attempts to provide an integrated overview of the evidence for the proposed roles of various Ca2+ signals, Ca2+ channels and Ca2+ sources in controlling autophagic flux. PMID- 28847415 TI - Importance of resilience research and multi-level interventions. PMID- 28847416 TI - Hydroxyurea: Analytical techniques and quantitative analysis. AB - Hydroxyurea is a potent disease-modifying therapeutic agent with efficacy for the treatment of sickle cell anemia. When administered at once-daily oral doses that lead to mild marrow suppression, hydroxyurea leads to substantial and sustained fetal hemoglobin induction, which effectively inhibits erythrocyte sickling. When escalated to maximum tolerated dose, hydroxyurea has proven laboratory and clinical effects for both children and adults with sickle cell anemia. However, there is substantial inter-patient variability with regard to the optimal dosing regimen, as well as differences in treatment-related toxicities and responses that may be explained by hydroxyurea pharmacokinetics and pharmacogenetics. Addressing the safety and efficacy of hydroxyurea treatment requires quantitative and accurate drug analysis, and various laboratory techniques have been established. We review the historical and current analytical techniques for measuring hydroxyurea concentrations accurately, and discuss clinical settings where quantitative analysis can increase understanding and safety of this important therapeutic agent, and ultimately improve patient outcomes. PMID- 28847417 TI - Diagnosis and Management of Subacute Ruminal Acidosis in Dairy Herds. AB - Subacute ruminal acidosis (SARA) is a common problem in lactating dairy cows that causes chronic health problems, impairs feed efficiency, and increases the environmental impact of milk production. Low ruminal pH appears to be the main instigator of the pathophysiology of SARA, although other metabolites produced in the rumen may be involved. Inflammatory responses to SARA are variable but important determinants of a cow's response to SARA. SARA can be diagnosed at the herd level by integrating information about clinical signs and on-farm measures of ruminal pH. Prevention of SARA requires excellent feeding management and proper diet formulation. PMID- 28847418 TI - Disorders of Rumen Distension and Dysmotility. AB - Rumen distension and hypomotility are common clinical findings in ruminants. A thorough physical examination to assess the rumen shape and consistency of rumen contents are critical to determining the underlying pathology. Most cases can be classified into 1 of the 4 types of vagal indigestion. Type 1 is characterized by gas distension of the rumen dorsally on the left side. Types 2, 3, and 4 will often appear similar on physical examination with fluid distension of the rumen on the left and ventrally on the right. Serum chloride and bicarbonate measurement and assessment of rumen chloride allow for differentiation of type 2 versus types 3 and 4 vagal indigestion. This is critical, as type 2 vagal indigestion will commonly require a rumenotomy, whereas types 3 and 4 typically are addressed through a right flank exploratory. PMID- 28847420 TI - Preface. PMID- 28847419 TI - Chromoblastomycosis and sporotrichosis, two endemic but neglected fungal infections in Madagascar. AB - Chromoblastomycosis and sporotrichosis are endemic fungal infections of tropical and subtropical regions, including Madagascar. The causal fungi develop in the soil or on plants and infect humans through wounds, either directly (wounding by the plant, through thorns, for example), or through the contact of an existing wound with contaminated soil. For this reason, the lesions predominantly occur on the limbs, and these fungi principally infect people working outside with bare hands and/or feet. The subcutaneous lesions of chromoblastomycosis are initially nodular, subsequently becoming warty, tumoral, cauliflower-like and pruriginous, which promotes dissemination. The chronic nature of the infection and its progression over long periods lead to highly disabling lesions in essentially rural and agricultural populations. The lesions of sporotrichosis are also nodular, but more ulcerous, and they form an extended chain following the route of the lymph vessels. Pus, squamous or skin biopsy specimens are used for the mycological examination of these mycoses. Treatment depends on the severity and form of the lesions and is based on antifungal drugs sometimes combined with physical methods. There has been no study of these infections for more than two decades in Madagascar, despite the large numbers of cases seen by doctors in all parts of the island. The nature, diversity and distribution of the plants responsible for contamination have not been described in Madagascar. In this review, we described these two endemic mycoses in terms of their epidemiological, mycological, clinical and therapeutic characteristics, focusing particularly on Madagascar, which is one of the leading foci of these two infections worldwide. PMID- 28847421 TI - Carotenoid esters in foods - A review and practical directions on analysis and occurrence. AB - Carotenoids are naturally found in both free form and esterified with fatty acids in most fruits and some vegetables; however, up to now the great majority of studies presents data on carotenoid composition only after saponification. The reasons for this approach are that a single xanthophyll can be esterified with several different fatty acids, generating a great number of different compounds with similar chemical and structural characteristics, thus, increasing the complexity of analysis compared to the respective saponified extract. This means that since UV/Vis spectrum does not change due to esterification, differentiation between free and acylated xanthophylls is dependent at least on elution order and mass spectrometry (MS) features. The presence of interfering compounds, especially triacylglycerides (TAGs), in the non-saponified extract of carotenoids can also impair carotenoid ester analyses by MS due to high background noise and ionization suppression since TAGs can be present in much higher concentrations than the carotenoid esters. This leads to the need of development of new and effective clean-up procedures to remove the potential interferents. In addition, only few standards of xanthophyll esters are commercially available, making identification and quantification of such compounds even more difficult. Xanthophyll esterification may also alter some properties of these compounds, including solubility, thermostability and bioavailability. Considering that commonly consumed foods are dietary sources of xanthophyll esters and that it is the actual form of ingestion of such compounds, an increasing interest on the native carotenoid composition of foods is observed nowadays. This review presents a compilation of the current available information about xanthophyll ester analyses and occurrence and a practical guide for extraction, pre-chromatographic procedures, separation and identification by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PMID- 28847422 TI - Home cooking and ingredient synergism improve lycopene isomer production in Sofrito. AB - There has been increasing interest in tomato products rich in lycopene Z-isomers since these carotenoids present greater bioavailability and antioxidant capacity than the all-E lycopene form. Intrinsic food properties as well as processing and the interaction between dietary components can all influence the content, type and bioavailability of carotenoids. The aim of this study was to evaluate whether carotenoid content and isomerization in tomato-based Mediterranean sofrito is affected by the process of home cooking and the presence of other ingredients such as extra virgin olive oil, onion and garlic. We used a full factorial design to clarify the contribution of each ingredient to the carotenoid composition of sofrito and to determine whether this can be improved by the cooking time and ingredient synergism. Cooking time and onion content were associated with a higher production of 5-Z-lycopene, 9-Z-lycopene and 13-Z-lycopene in sofrito. Onion proved to be the most interesting ingredient in the sofrito formulation due to their enhancing effect on lycopene isomerization. The use of onion combined with an adequate processing time may improve the bioavailability of lycopene in tomato products. PMID- 28847423 TI - Kinetics of carotenoids degradation and furosine formation in dried apricots (Prunus armeniaca L.). AB - The kinetics of carotenoid and color degradation, as well as furosine formation, were investigated in apricot fruits during convective heating at 50, 60 and 70 degrees C. Degradation of carotenoids and color, expressed as total color difference (TCD), followed a first and zero order kinetic, respectively. The activation energy (Ea) for carotenoids degradation ranged from 73.7kJ/mol for 13 cis-beta-carotene to 120.7kJ/mol for lutein, being about 91kJ/mol for all-trans beta-carotene. Violaxanthin and anteraxanthin were the most susceptible to thermal treatment. The furosine evolution was fitted at zero order kinetic model. The Ea for furosine formation was found to be 83.3kJ/mol and the Q10 (temperature coefficient) varied from 1.59 to 4.14 at the temperature ranges 50-60 degrees C and 60-70 degrees C, respectively. PMID- 28847424 TI - S-layer proteins as a source of carotenoids: Isolation of the carotenoid cofactor deinoxanthin from its S-layer protein DR_2577. AB - S-layers are regular paracrystalline arrays of proteins or glycoproteins that characterize the outer envelope of several bacteria and archaea. The auto assembling properties of these proteins make them suitable for application in nanotechnologies. However, the bacterial cell wall and its S-layer are also an important binding sites for carotenoids and they may represent a potential source of these precious molecules for industrial purposes. The S-layer structure and its components were extensively studied in the radio-resistant bacterium Deinococcus radiodurans, which for long time represented one of the model organisms in this respect. The protein DR_2577 has been shown to be one of the naturally over-expressed S-layer components in this bacterium. The present report describes a high scale purification procedure of this protein in solution. The purity of the samples, assayed by native and denaturing electrophoresis, showed how this method leads to a selective and high efficient recovery of the pure DR_2577. Recently, we have found that the deinoxanthin, a carotenoid typical of D. radiodurans, is a cofactor non covalently bound to the protein DR_2577. The pure DR_2577 samples may be precipitated or lyophilized and used as a source of the carotenoid cofactor deinoxanthin by an efficient extraction using organic solvents. The procedure described in this work may represent a general approach for the isolation of S-layer proteins and their carotenoids with potentials for industrial applications. PMID- 28847425 TI - Effect of long-term storage on the free and esterified carotenoids in durum wheat (Triticum turgidum conv. durum) and tritordeum (*Tritordeum Ascherson et Graebner) grains. AB - The effect of long-term storage on the carotenoid composition in durum wheat and tritordeum grains was studied. Total carotenoid (mainly lutein) content decreased according to a temperature dependent first-order degradative kinetic model. The carotenoid retention was similar in both genotypes at the lower temperatures (71 73% at -32 degrees C, 70% at 6 degrees C and 55-56% at 20 degrees C), whereas at the higher temperatures the pigment retention was higher in tritordeum (42% at 37 degrees C; 10% at 50 degrees C) than durum wheat (23% at 37 degrees C; 1% at 50 degrees C), probably due to the greater proportion of esterified xanthophylls. A clear difference between free and esterified pigments was observed, with smaller losses and slower degradation (higher stability) observed for the latter. The xanthophyll esterification process was highly specific and had a significant effect on the carotenoid stability according to the fatty acids involved in the esterification and their position on the lutein molecule. The results were consistent with a degradation process in which the carotenoid behavior is influenced by the chemical structure. Xanthophyll esterification can be promoted by environmental conditions, regardless of the cereal genotype, and is a powerful tool to modulate the carotenoid profile in cereals. PMID- 28847426 TI - Carotenoids microencapsulation by spray drying method and supercritical micronization. AB - Carotenoids are used as natural food colourants in the food industry. As unstable natural pigments they need protection. This protection can involve the microencapsulation process. There are numerous techniques that can be used for carotenoid protection, but two of them -spray drying and supercritical micronization - are currently the most commonly used. The objective of this paper is to describe these two techniques for carotenoid microencapsulation. In this review information from articles from the last five years was taken into consideration. Pigments described in the review are all carotenoids. Short summary of carotenoids sources was presented. For the spray drying technique, a review of carrier material and process conditions was made. Moreover, a short description of some of the most suitable processes involving supercritical fluids for carotenoids (astaxanthin, beta-carotene, lutein and lycopene) encapsulation was given. These include the Supercritical Antisolvent process (SAS), Particles from Gas-Saturated Solutions (PGSS), Supercritical Fluid Extraction From an Emulsion (SFEE) and Solution Enhanced Dispersion by Supercritical fluids (SEDS). In most cases the studies, independently of the described method, were conducted on the laboratory scale. In some a scale-up was also tested. In the review a critical assessment of the used methods was made. PMID- 28847427 TI - Biomarkers of carotenoid bioavailability. AB - The use of biomarkers constitutes an essential tool to assess the bioavailability of carotenoids in humans. The present article aims to review several methodological, host-related and modulating factors relevant on assessing and interpreting carotenoid bioavailability. Markers for carotenoid bioavailability can be broadly divided into direct, biochemical or "analytical" markers and indirect, physiological or "functional" indicators. Analytical markers usually refer to biochemical indicators of intake and/or status (short and long term exposure) while functional measures may be interpreted in terms of cumulative exposure, biological effect (bioactivity) or modification of risk factors. Both types of markers display advantages and limitations but, in general, a relationship exists among the type of marker, the biological specimen needed and the time required for a change. Humans may absorb a wide range of carotenes and xanthophylls and many of them may be found in serum and tissues. However, under physiological conditions, the several classes of dietary carotenoids may behave unequally leading to a different systemic profile and, moreover, they can be selectively accumulated at target tissues. In addition, some carotenoids may be chemically and enzymatically modified generating different oxidative metabolites and apocarotenoids. Quantitatively, the biological response upon carotenoid intervention (assessed by analytical and functional markers) is highly variable but the use of large doses and long-term protocols may lead to saturation effects and the loss of linearity in the response. Also, despite carotenoid exposition is considered to be safe, markers of overexposure include clinical signs (i.e. carotenodermia, corneal rings and retinopathy) and biochemical indicators (hypercarotenemia, xanthophyll esters). Overall, both host-related and methodological factors may influence analytical and functional markers to assess carotenoid bioavailability although the different subclasses of carotenoids may not be equally affected. PMID- 28847428 TI - Effects of pectin on lipid digestion and possible implications for carotenoid bioavailability during pre-absorptive stages: A review. AB - Pectin, an abundant polysaccharide in the human diet, has structural characteristics and functional properties that are strongly dependent on the food matrix (e.g., origin, type, cultivar/variety, ripening stage, style and intensity of processing). These polysaccharides have a strong effect on lipid digestion, which is required for the liberation of carotenoids from emulsified lipid droplets in the gastrointestinal content and for the formation of micelles, in which the carotenoids must be incorporated before absorption. Only micellarized carotenoids can be absorbed and subsequently exert protective effects on human health. The alteration of lipolysis by pectin can occur through several mechanisms; however, they have not been linked directly to carotenoid micellarization. This paper provides an overview of the effects of the properties of pectin on the ion concentration in the digestive content, the viscosity of the digestive medium, the properties of the lipid droplet surfaces and lipase activity and analyzes the impact of these events on lipid digestion and subsequent carotenoid micellarization. PMID- 28847429 TI - Carotenoids from gac fruit aril (Momordica cochinchinensis [Lour.] Spreng.) are more bioaccessible than those from carrot root and tomato fruit. AB - Using a simulated digestion procedure in vitro, liberation and bioaccessibility of beta-carotene (29.5+/-1.7% and 22.6+/-0.9%, respectively) and lycopene (51.3+/ 2.6% and 33.2+/-3.1%, respectively) from gac fruit aril were found to be significantly higher than from carrot root (beta-carotene, 5.2+/-0.5% and 0.5+/ 0.2%, respectively) and tomato fruit (lycopene, 15.9+/-2.8% and 1.8+/-0.5%, respectively). Gac fruit aril naturally contained significantly more lipids (11% on fresh weight base) than carrot root and tomato fruit (<1%). However, when test meals were supplemented with an O/W emulsion to match the content of gac fruit aril, carotenoid bioaccessibility was still considerably lower than that from genuine gac fruit aril. Carotenoids in gac fruit aril were found to be stored in small, round-shaped chromoplasts. Despite the high lipid content, these carotenoids are unlikely to occur in a lipid-dissolved state according to simple solubility estimations, instead being possibly deposited as submicroscopic crystallites. In contrast, carotenoids of carrot root and tomato fruit were stored in large, needle-like crystallous chromoplasts. Consequently, we hypothesized the natural deposition form to be majorly responsible for the observed differences in bioaccessibility. A favorable surface-to-volume ratio of the deposition form in gac fruit aril might have allowed a more rapid micellization during digestion, and thus, an enhanced bioaccessibility. Irrespective of the ultimate reason, gac fruit aril provided a highly bioaccessible form of both lycopene and provitamin A (beta-carotene), thus offering a most valuable dietary source of both carotenoids. Currently, gac is majorly grown in Southeast Asia, where its consumption might help to diminish the 'hidden hunger' namely the insufficient supply with vitamin A. Ultimately, gac fruit might thus contribute to alleviating most severe health implications of vitamin A deficiency, such as anaemia and xerophthalmia, the prevailing cause of preventable childhood blindness, as well as mortality from infectious diseases. PMID- 28847430 TI - Bioaccessibility and intestinal cell uptake of astaxanthin from salmon and commercial supplements. AB - Although the keto-carotenoid astaxanthin (Ast) is not typically present in human plasma due to its relative scarcity in the typical diet, global consumption of salmon, the primary source of Ast in food, and Ast supplements continues to increase. The first objective of the present study was to investigate the bioaccessibility of Ast from uncooked and cooked fillets of wild and aquacultured salmon, Ast-supplements and krill oil, during simulated gastric and small intestinal digestion. Uptake of E-Ast from micelles generated during digestion of wild salmon by monolayers of Caco-2 was also monitored. Both wild and aquacultured salmon flesh contained E-Ast and Z-isomers of unesterified Ast, whereas Ast esters were the predominant form of the carotenoid in commercial supplements and krill oil. Flesh from wild salmon contained approximately 10 times more Ast than aquacultured salmon. Common styles of cooking flesh from wild and aquacultured salmon decreased Ast content by 48-57% and 35-47%, respectively. Ast in salmon flesh, supplements and krill oil was relatively stable (>80% recovery) during in vitro digestion. The efficiency of transfer of Ast into mixed micelles during digestion of uncooked wild salmon was 43%, but only 12% for uncooked acquacultured salmon. Cooking wild salmon significantly decreased Ast bioaccessibility. The relative bioaccessibility of Ast (41-67%) after digestion of oil vehicle in commercial supplements was inversely proportional to carotenoid content (3-10mg/capsule), whereas bioaccessibility of endogenous Ast in phospholipid-rich krill oil supplement was 68%. >95% of Ast in mixed micelles generated during digestion of supplements and krill oil was unesterified. Caco-2 intestinal cells accumulated 11-14% of E-Ast delivered in mixed micelles generated from digested wild salmon. Apical uptake and basolateral secretion of E Ast by Caco-2 cells grown on inserts were greater after digestion of Ast-enriched krill oil compared to uncooked wild salmon. These data suggest that the bioacessibility of Ast in wild salmon and soft-gel capsules is greater than that in aquacultured salmon, and that uptake and basolateral secretion of the carotenoid by enterocyte-like cells is enhanced by the digestion products of phospholipid-rich krill oil. PMID- 28847431 TI - Additional consumption of one egg per day increases serum lutein plus zeaxanthin concentration and lowers oxidized low-density lipoprotein in moderately hypercholesterolemic males. AB - The egg is a nutrient-dense food and contains antioxidative carotenoids, lutein and zeaxanthin, but its impact on serum cholesterol levels has been a matter of concern, especially for individuals who have high serum cholesterol levels. We conducted this study to determine whether and how the daily additional consumption of one egg affects serum lipid profiles and parameters of LDL oxidation in moderately hypercholesterolemic males. Nineteen male Japanese adults (total cholesterol [TC]>5.2mmol/L) participated, consuming one soft boiled egg per day for 4weeks in addition to their habitual diet. Despite the significant increase in their intake of dietary cholesterol during the intervention period, the subjects' serum concentrations of TC and low-density lipoprotein cholesterol (LDL-C) did not increase. Their serum malondialdehyde modified low-density lipoprotein (MDA-LDL) concentrations were significantly decreased and their LDL oxidation lag times, reflecting the resistance of free-radical-induced LDL lipid peroxidation (ex vivo), was prolonged after 2 and 4weeks. At weeks 2 and 4, the subjects' serum lutein+zeaxanthin concentrations were significantly higher than their baseline values and showed both an inverse relation with MDA-LDL and a positive relationship with the LDL oxidation lag time. These data showed that in moderately hypercholesterolemic males, the additional consumption of one egg per day for 4weeks did not have adverse effects on serum TC or LDL-C, and it might reduce the susceptibility of LDL to oxidation through an increase in the serum lutein and zeaxanthin concentrations. PMID- 28847432 TI - Malaysian brown seaweeds Sargassum siliquosum and Sargassum polycystum: Low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), alpha amylase, and alpha-glucosidase inhibition activities. AB - Two Malaysian brown seaweeds, Sargassum siliquosum and Sargassum polycystum were first extracted using methanol to get the crude extract (CE) and further fractionated to obtain fucoxanthin-rich fraction (FRF). Samples were evaluated for their phenolic, flavonoid, and fucoxanthin contents, as well as their inhibitory activities towards low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), alpha-amylase, and alpha-glucosidase. In LDL oxidation assay, an increasing trend in antioxidant activity was observed as the concentration of FRF (0.04-0.2mg/mL) and CE (0.2-1.0mg/mL) increased, though not statistically significant. As for serum oxidation assay, significant decrease in antioxidant activity was observed as concentration of FRF increased, while CE showed no significant difference in inhibitory activity across the concentrations used. The IC50 values for ACE inhibitory activity of CE (0.03-0.42mg/mL) were lower than that of FRF (0.94-1.53mg/mL). When compared to reference drug Voglibose (IC50 value of 0.61mg/mL) in the effectiveness in inhibiting alpha amylase, CE (0.58mg/mL) gave significantly lower IC50 values while FRF (0.68 0.71mg/mL) had significantly higher IC50 values. The alpha-glucosidase inhibitory activity of CE (IC50 value of 0.57-0.69mg/mL) and FRF (IC50 value of 0.50 0.53mg/mL) were comparable to that of reference drug (IC50 value of 0.54mg/mL). Results had shown the potential of S. siliquosum and S. polycystum in reducing cardiovascular diseases related risk factors following their inhibitory activities on ACE, alpha-amylase and alpha-glucosidase. In addition, it is likelihood that FRF possessed antioxidant activity at low concentration level. PMID- 28847433 TI - Lycopene rich extract from red guava (Psidium guajava L.) displays anti inflammatory and antioxidant profile by reducing suggestive hallmarks of acute inflammatory response in mice. AB - This study investigated the anti-inflammatory activity of the extract (LEG) and purified (LPG) lycopene from guava (Psidium guajava L.), as well as some mechanisms possibly involved in this effect. The anti-inflammatory activity was initially assessed using paw edema induced by Carrageenan, Dextran, Compound 48/80, Histamine and Prostaglandin E2 in Swiss mice. A peritonitis model was used to evaluate neutrophil migration, the activity of myeloperoxidase (MPO) and reduced glutathione (GSH) concentration; while the effect on the expression of iNOS, COX-2 and NF-kappaB, was assessed by immunohistochemistry analysis. Results showed that oral and intraperitoneal administration of LEG and LPG inhibited inflammation caused by carrageenan. LPG (12.5mg/kg p.o.) significantly inhibited the edema formation induced by different phlogistic agents and immunostaining for iNOS, COX-2 and NF-kappaB. Leukocytes migration in paw tissue and peritoneal cavity was reduced, as well as MPO concentration, whereas GSH levels increased. Thus, lycopene-rich extract from red guava has beneficial effect on acute inflammation, offering protection against the consequences of oxidative stress by downregulating inflammatory mediators and inhibiting gene expression involved in inflammation. PMID- 28847435 TI - In response to the letter to the editor regarding: Serious assessment of mtDNA variants is a prerequisite to confirm pathogenicity. PMID- 28847434 TI - Kinematics of collagen fibers in carotid arteries under tension-inflation loading. AB - Biomechanics of the extracellular matrix in arteries determines their macroscopic mechanical behavior. In particular, the distribution of collagen fibers and bundles plays a significant role. Experimental data showed that, in most arterial walls, there are preferred fiber directions. However, the realignment of collagen fibers during tissue deformation is still controversial: whilst authors claim that fibers should undergo affine deformations, others showed the contrary. In order to have an insight about this important question of affine deformations at the microscopic scale, we measured the realignment of collagen fibers in the adventitia layer of carotid arteries using multiphoton microscopy combined with an unprecedented Fourier based method. We compared the realignment for two types of macroscopic loading applied on arterial segments: axial tension under constant pressure (scenario 1) and inflation under constant axial length (scenario 2). Results showed that, although the tissue underwent macroscopic stretches beyond 1.5 in the circumferential direction, fiber directions remained unchanged during scenario 2 loading. Conversely, fibers strongly realigned along the axis direction for scenario 1 loading. In both cases, the motion of collagen fibers did not satisfy affine deformations, with a significant difference between both cases: affine predictions strongly under-estimated fiber reorientations in uniaxial tension and over-estimated fiber reorientations during inflation at constant length. Finally, we explained this specific kinematics of collagen fibers by the complex tension-compression interactions between very stiff collagen fibers and compliant surrounding proteins. A tensegrity representation of the extracellular matrix in the adventitia taking into account these interactions was proposed to model the motion of collagen fibers during tissue deformation. PMID- 28847436 TI - Serious assessment of mtDNA variants is a prerequisite to confirm pathogenicity. PMID- 28847438 TI - Training physiotherapy students to educate patients: A randomised controlled trial. AB - OBJECTIVE: To determine the effect of a training intervention on physiotherapy students' self-efficacy and skills in the area of patient education. METHODS: Final year physiotherapy students were randomised to an intervention group or a wait-list control group. The intervention group participated in a 3.5h training intervention about patient education that included video observation, simulated patient practice and structured feedback. The control group did not receive any training. Self-efficacy was assessed at baseline (T1) and after the intervention (or no intervention for the control group) (T2). Patient education performance was assessed by a blinded rater from a video-recorded standardised clinical examination. RESULTS: 83 students were randomised to the intervention group and 81 students to the control group. There were no differences in demographic variables or self-efficacy between groups at baseline. There was significant improvement in self-efficacy for the intervention group, but no change for the control group. The intervention group performed significantly better than the control group for nine of the eleven performance items, with significantly higher scores overall. CONCLUSION: A training intervention enhances physiotherapy student self-efficacy and performance in patient education. PRACTICE IMPLICATION: Use of patient education training is recommended to enhance student self-efficacy and performance. PMID- 28847439 TI - The MATRIX, a novel tool exploring dynamic psychotherapy: Preliminary psychometric properties. AB - Most measures in the field of psychodynamic psychotherapy are bound to a specific theory, and usually focus only on patient processes or therapist interventions. The MATRIX is a newly developed research tool that focuses on events within both the patient and the therapist individually, as well as on dyadic events, and provides the simple and meaningful coding of content for therapy session transcripts in psychotherapy. The present study describes the inter-rater reliability and construct validity of the MATRIX. Reliability of the MATRIX was assessed by applying it to 805 fragments of psychodynamic-oriented psychotherapy sessions. Three independent experts coded fragments, and the tool was examined for reliability. Validity in identifying the theoretical inclinations was assessed by applying the MATRIX to 30 segments (containing 1309 fragments) of sessions that reflect different theoretical orientations. Findings evinced high inter-rater reliability for all dimensions. The MATRIX was found to have high degree of validity for differentiating the theoretical inclinations of segments of sessions. The MATRIX is a reliable and valid measure that may enable moment-to moment, quantitative, analysis of psychodynamic psychotherapy. PMID- 28847440 TI - Multicenter evaluation of quality of life and patient satisfaction after breast reconstruction, a long-term retrospective study. AB - INTRODUCTION: Breast reconstruction techniques are multiple and they should be chosen in order to improve women's satisfaction and well-being, thus obtaining a personalized treatment. This report's major purpose was to study, through the Breast-Q questionnaire, how the functional and aesthetic outcomes, as well as the complications, of the main autologous breast reconstruction techniques, can affect patients quality of life and well-being at long-term. The secondary purpose was to analyse, thus to identify, the independent factors characterizing the different reconstructive techniques, which may affect patients' satisfaction. METHODS: Women who underwent autologous breast reconstruction through deep inferior epigastric artery perforator or Latissimus dorsi muscle flap from May 2006 to May 2013 were included. The assessment was based on the Breast-Q reconstruction questionnaire. All times of post-mastectomy reconstruction were concerned: immediate, delayed, after previous procedure failure or conversion to another reconstructive technique due to the patient's dissatisfaction. RESULTS: A total of 98 patients were included. Concerning patients satisfaction, the breast Q score is highest in patients who underwent immediate breast reconstruction, while scores after delayed breast reconstruction, previous surgery failure or conversion to another technique are generally equivalent. Higher scores have been observed in patients who underwent reconstruction through autologous Latissimus dorsi compared to Latissimus dorsi with prosthetic implant reconstruction. CONCLUSION: The authors identified factors of higher patients' satisfaction, like absence of major complication and advanced patient's age, in order to personalize the surgical planning according to the patient's priorities. PMID- 28847437 TI - Preterm labor in the absence of acute histologic chorioamnionitis is characterized by cellular senescence of the chorioamniotic membranes. AB - BACKGROUND: Decidual senescence has been considered a mechanism of disease for spontaneous preterm labor in the absence of severe acute inflammation. Yet, signs of cellular senescence have also been observed in the chorioamniotic membranes from women who underwent the physiological process of labor at term. OBJECTIVE: We aimed to investigate whether, in the absence of acute histologic chorioamnionitis, the chorioamniotic membranes from women who underwent spontaneous preterm labor or labor at term exhibit signs of cellular senescence. STUDY DESIGN: Chorioamniotic membrane samples were collected from women who underwent spontaneous preterm labor or labor at term. Gestational age-matched nonlabor controls were also included. Senescence-associated genes/proteins were determined using reverse transcription quantitative polymerase chain reaction analysis (n = 7-9 each for array; n = 26-28 each for validation), enzyme-linked immunosorbent assays (n = 7-9 each), immunoblotting (n = 6-7 each), and immunohistochemistry (n = 7-8 each). Senescence-associated beta-galactosidase activity (n = 7-11 each) and telomere length (n = 15-22 each) were also evaluated. RESULTS: In the chorioamniotic membranes without acute histologic chorioamnionitis: (1) the expression profile of senescence-associated genes was different between the labor groups (term in labor and preterm in labor) and the nonlabor groups (term no labor and preterm no labor), yet there were differences between the term in labor and preterm in labor groups; (2) most of the differentially expressed genes among the groups were closely related to the tumor suppressor protein (TP53) pathway; (3) the expression of TP53 was down-regulated in the term in labor and preterm in labor groups compared to their nonlabor counterparts; (4) the expression of CDKN1A (gene coding for p21) was up-regulated in the term in labor and preterm in labor groups compared to their nonlabor counterparts; (5) the expression of the cyclin kinase CDK2 and cyclins CCNA2, CCNB1, and CCNE1 was down-regulated in the preterm in labor group compared to the preterm no labor group; (6) the concentration of TP53 was lower in the preterm in labor group than in the preterm no labor and term in labor groups; (7) the senescence-associated beta-galactosidase activity was greater in the preterm in labor group than in the preterm no labor and term in labor groups; (8) the concentration of phospho-S6 ribosomal protein was reduced in the term in labor group compared to its nonlabor counterpart, but no differences were observed between the preterm in labor and preterm no labor groups; and (9) no significant differences were observed in relative telomere length among the study groups (term no labor, term in labor, preterm no labor, and preterm in labor). CONCLUSION: In the absence of acute histologic chorioamnionitis, signs of cellular senescence are present in the chorioamniotic membranes from women who underwent spontaneous preterm labor compared to those who delivered preterm in the absence of labor. However, the chorioamniotic membranes from women who underwent spontaneous labor at term did not show consistent signs of cellular senescence in the absence of histologic chorioamnionitis. These results suggest that different pathways are implicated in the pathological and physiological processes of labor. PMID- 28847441 TI - [Face rejuvenation with tensor threads]. AB - The last decades has seen new priorities in treatment of a flabby, ageing face towards minimally invasive aesthetic surgery, to be accompanied and followed by the requirements to perform such interventions with the maximally reduced health hazards, with inconsiderable injury, without cuts and, respectively, to be followed by no resulting scars, as well as a short postoperative period. We propose a new reviewing presentation of the tensor threads. After having explained the technology of the threads, we will discuss the good patient indication, the criteria which determine the choice of the threads and methods for each type of patient. There are many techniques, which we will present. Then, we will discuss the results, unsatisfactory outcomes obtained and complications encountered, as well as how to improve the cosmetic outcomes to be obtained. To conclude, we will propose a strategy for the long-term treatment of the neck and the face, preventing surgical management of the aging process. PMID- 28847442 TI - [Face-lift surgery in ambulatory]. AB - OBJECTIVE: The proposal is to demonstrate that facelift surgery is particularly suitable for the care in ambulatory. METHODS: Between 2010 and 2016, 246 patients were operated for a facelift in ambulatory. RESULTS: No major complication arose in this series (241). Among the patients, 98% expressed their satisfaction and would accept again this intervention in ambulatory. CONCLUSION: The facelift can be realized in ambulatory with complete safety. The rate of satisfaction shows a very strong support of the patients for the ambulatory care. PMID- 28847443 TI - Botulinum neurotoxin injection for the treatment of epiphora in nasolacrimal duct obstruction. AB - PURPOSE: Retrospective long-term study to evaluate the efficacy of botulinum neurotoxin A (BoNT/A) therapy for epiphora due to non-surgical nasolacrimal duct obstruction. INTRODUCTION: BoNT/A has been used successfully since 2000 in axillary hyperhidrosis to reduce secretory disorders. Some isolated cases of hyperlacrimation or crocodile tear syndrome have been treated on this basis. We used BoNT/A to decrease lacrimal secretion in cases of epiphora. METHODS: We reviewed the qualitative and quantitative degree of improvement of epiphora after botulinum neurotoxin injections in the palpebral lobe of the lacrimal gland, carried out in an ophthalmic centre between 2009 and 2016. Epiphora was graded using a questionnaire, Munk scores and Schirmer tests before and after injections. Severity of side effects was recorded. RESULTS: Twenty-seven palpebral lacrimal glands of twenty patients with epiphora, mean age 65+/-13, were treated with BoNT/A (Botox(r) or Xeomin(r)) from April 2009 to April 2016. The epiphora was induced by persistent nasolacrimal duct stenosis after surgical treatment. No conventional medical nor surgical treatment was effective at this time. The technique of injection, dilution and dosage were specific. We re injected 14/27 cases on an as-needed basis, 7/27 cases three times, 3/27 cases four times, and 2/27 cases (same patient both glands) five times. The Schirmer test measured a decrease of lacrimal secretion in 24/27 (89%) lacrimal glands after neurotoxin injection. Side effects were ptosis in 4 cases and transient esotropia in 2 cases. The authors describe the injection techniques, the dosage, the volume and concentration of BoNT/A. CONCLUSION: Patients with epiphora can be treated effectively with BoNT/A to reduce lacrimal secretion of the principal lacrimal gland in its palpebral portion. Ninety percent of the patients were very satisfied, with few side effects (ptosis or mild diplopia lasting from 3 days to 3 weeks). More studies are needed to delineate which types of epiphora can be treated with BoNT/A. PMID- 28847444 TI - Sex effects on spatial learning but not on spatial memory retrieval in healthy young adults. AB - OBJECTIVES: Sex differences have been found in spatial learning and spatial memory, with several studies indicating that males outperform females. We tested in the virtual Morris Water Maze (vMWM) task, whether sex differences in spatial cognitive processes are attributable to differences in spatial learning or spatial memory retrieval in a large student sample. METHODS: We tested 90 healthy students (45 women and 45 men) with a mean age of 23.5 years (SD=3.5). Spatial learning and spatial memory retrieval were measured by using the vMWM task, during which participants had to search a virtual pool for a hidden platform, facilitated by visual cues surrounding the pool. Several learning trials assessed spatial learning, while a separate probe trial assessed spatial memory retrieval. RESULTS: We found a significant sex effect during spatial learning, with males showing shorter latency and shorter path length, as compared to females (all p<0.001). Yet, there was no significant sex effect in spatial memory retrieval (p=0.615). Furthermore, post-hoc analyses revealed significant sex differences in spatial search strategies (p<0.05), but no difference in the number of platform crossings (p=0.375). CONCLUSION: Our results indicate that in healthy young adults, males show faster spatial learning in a virtual environment, as compared to females. Interestingly, we found no significant sex differences during spatial memory retrieval. Our study raises the question, whether men and women use different learning strategies, which nevertheless result in equal performances of spatial memory retrieval. PMID- 28847445 TI - A motorized pellet dispenser to deliver high intensity training of the single pellet reaching and grasping task in rats. AB - The single pellet reaching and grasping (SPG) task is widely used to study forelimb motor performance in rodents and to provide rehabilitation after neurological disorders. Nonetheless, the time necessary to train animals precludes its use in settings where high-intensity training is required. In the current study, we developed a novel high-intensity training protocol for the SPG task based on a motorized pellet dispenser and a dual-window enclosure. We tested the protocol in naive adult rats and found 1) an increase in the intensity of training without increasing the task time and without affecting the overall performance of the animals, 2) a reduction in the variability within and between experiments in comparison to manual SPG training, and 3) a reduction in the time required to conduct experiments. In summary, we developed and tested a novel protocol for SPG training that provides higher-intensity training while reducing the variability of results observed with other protocols. PMID- 28847446 TI - Sequential treatment with ProACTTM device implantation after male sling failure for male urinary incontinence. AB - OBJECTIVES: There is no strong evidence for second line therapy after male sling failure for post-prostatectomy urinary incontinence (PPUI). We report the outcomes after periurethral balloons implantation for persistence or recurrence of mild PPI symptoms after male sling implantation. METHODS: All patients implanted of a ProACTTM device (Uromedica, Inc., MN, USA) following I-STOP transobturator male sling (TOMS) failure, in a tertiary reference center between 2009 and 2016, were included. Patients were evaluated by 24-hour pad-test before and after implantation, and after each balloon repressurizing procedure. PGI-I and Likert scale patient satisfaction were estimated during a telephone interview conducted in 2016. Objective and subjective cure of urinary incontinence were defined by a 24-hour pad-test<8g and the use of zero or one pad per day, respectively. RESULTS: Fourteen patients were included. Median follow-up was 34months [4-89]. Objective and subjective cure were 29% (n=4) and 57% (n=8), respectively. Median pad-test decreased from 95g [IQR: 130] to 34g [IQR: 83] (P=0.022). ProACTTM significantly decreased median pad-test by a factor 2.73 [1.19-6.29]. Eighty-eight percent patients were feeling a little better, much better or very much better and 77% were satisfied or very satisfied at the end of follow-up. Reoperation rate was 28% (n=4): 3 balloons were changed for caudally migration (n=2) or deflation (n=1) and 1 had a urinary sphincter implanted for severe UI. CONCLUSIONS: ProACTTM is a safe and efficient treatment that can be used in second line therapy after TOMS failure for PPUI. LEVEL OF EVIDENCE: 4. PMID- 28847447 TI - Calcium dobesilate prevents the oxidative stress and inflammation induced by diabetes in the retina of db/db mice. AB - AIM: Calcium dobesilate (CaD) is beneficial in early stages of diabetic retinopathy (DR), but its mechanisms of action remains to be elucidated. The aim was to investigate the effect of CaD on proinflammatory cytokines and oxidative stress. METHODS: db/db mice were randomly assigned to daily oral treatment with CaD (200mg/kg/day) or vehicle for 15days. Biomarkers of oxidative stress (dihydroethidium, malondialdehyde), NF-kappaB, and proinflammatory cytokines (IL 1beta, IL-6, IL-8, TNF-alpha, MCP-1) were examined in the retina by immunohistochemical analysis. Cultures of human retinal endothelial cells (HRECs) were used for complementary experiments. RESULTS: CaD significantly reduced the biomarkers of oxidative stress in the retina of db/db mice. In addition, CaD prevented the increase of NF-kappaB, IL-6, IL-8, TNF-alpha and MCP-1 induced by diabetes. CaD inhibited the activation of NF-kbeta induced by IL-1beta by preventing IKKB-alpha phosphorylation in HRECs and reduced the upregulation of IL 6 and IL-18 induced by TNF-alpha in a dose-dependent manner. CONCLUSION: Our results suggest that antioxidant and antiinflammatory effects are crucial in accounting for the effectiveness of CaD for treating DR. PMID- 28847448 TI - A novel mutation in FGD4 causes Charcot-Marie-Tooth disease type 4H with cranial nerve involvement. AB - Charcot-Marie-Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H. PMID- 28847449 TI - Polypharmacy and risk of non-fatal overdose for patients with HIV infection and substance dependence. AB - INTRODUCTION: People living with HIV (PLWH) are at risk of both polypharmacy and unintentional overdose yet there are few data on whether polypharmacy increases risk of overdose. The study objective was to determine if the number and type of medication (e.g., sedating) were associated with non-fatal overdose (OD) among PLWH with past-year substance dependence or a lifetime history of injection drug use. MATERIALS AND METHODS: This was a longitudinal study of adults recruited from two urban, safety-net HIV clinics. Outcomes were i) lifetime and ii) past year non-fatal OD assessed at baseline and a 12-month follow-up. We used logistic regression to examine the association between each outcome and the number of medications (identified from the electronic medical record) in the following categories: i) overall medications, ii) non-antiretroviral (non-ARV), iii) sedating, iv) non-sedating, as well as any vs no opioid medication and any vs no non-opioid sedating medication. Covariates included demographics, medical comorbidities, depressive and anxiety symptoms, and substance use. RESULTS: Among 250 participants, 80% were prescribed a sedating medication, 50% were prescribed an opioid; 51% exceeded risky drinking limits. In the past month, 23% reported illicit opioid use and 9% illicit opioid sedative use; 37% reported lifetime non fatal OD and 7% past-year non-fatal OD. The median number (interquartile range) of total medications was 10 (7, 14) and 2 (1, 3) sedating. The odds of lifetime non-fatal OD were significantly higher with each additional sedating medication (OR 1.26, 95% CI 1.08, 1.46) and any opioid medication (OR 2.31; 95% CI 1.37, 3.90), but not with each overall, non-ARV, or non-sedating medication. The odds of past year non-fatal OD were greater with each additional sedating medication (OR 1.18; 95% CI 1.00, 1.39, p=0.049), each additional non-ARV medication (OR 1.07; 95% CI 1.00, 1.15, p=0.048), and non-significantly for any opioid medication (OR 2.23; 95% CI 0.93, 5.35). CONCLUSIONS: In this sample of PLWH with substance dependence and/or injection drug use, number of sedating medications and any opioid were associated with non-fatal overdose; sedating medications were prescribed to the majority of patients. Polypharmacy among PLWH and substance dependence warrants further research to determine whether reducing sedating medications, including opioids, lowers overdose risk. PMID- 28847450 TI - Influence of a targeted performance measure for brief intervention on gender differences in receipt of brief intervention among patients with unhealthy alcohol use in the Veterans Health Administration. AB - AIMS: Women are less likely than men to receive brief intervention (BI) for unhealthy alcohol use. In 2007, the U.S. Veterans Health Administration (VA) used a national performance measure to implement BI. Although AUDIT-C scores >=3 for women and >=4 for men optimize sensitivity and specificity for identifying unhealthy alcohol use, VA's performance measure required BI only among a targeted subgroup defined by a non-gender-specific score threshold (AUDIT-C >=5). This may have influenced gender differences in receipt of BI among those optimally eligible for BI. Therefore, we evaluate differences in proportions of women and men offered BI before and after BI implementation. METHODS: National secondary chart review data (7/06-6/10) identified all outpatients with unhealthy alcohol use for whom BI would be indicated (AUDIT-C >=3 women, >=4 men). Logistic regression, including a time-by-gender interaction, estimated the prevalence and 95% confidence interval (CI) of BI for women and men pre- and post implementation. FINDINGS: Among patients optimally eligible for BI (n=51,272, 8206 women and 43,066 men), the prevalence of BI increased more steeply for men than women after implementation (interaction p-value <0.0001). Pre-implementation rates of BI were 21% (95% CI, 18-24) for women and 26% (95% CI, 24-29) for men, and post-implementation rates were 32% (95% CI, 30-34) for women and 47% (95% CI, 45-49) for men. CONCLUSIONS: Healthcare systems implementing BI with performance measures may wish to consider that specifying a single alcohol screening threshold for men and women may increase gender differences in receipt of BI among patients likely to benefit. PMID- 28847451 TI - Interpersonal styles, peer relationships, and outcomes in residential substance use treatment. AB - Interpersonal relationships play a key role in recovery from substance use disorders (SUDs). We examined the associations between problematic interpersonal styles, peer relationships, and treatment outcomes in a sample of U.S. military veterans in residential SUD treatment. Participants were 189 veterans enrolled in a residential SUD treatment program at a Department of Veterans Affairs medical center. Participants were interviewed at the time of treatment entry (baseline), one month into treatment, and 12months following discharge from treatment. More problematic interpersonal styles at treatment entry, measured by the Inventory of Interpersonal Problems-Circumplex (IIP-C), predicted more SUD symptoms 12months post-discharge (r=0.29, P<0.01). Results of a principal components analysis of the IIP-C subscales revealed three main factors of interpersonal styles: Passive, Cruel/Aloof, and Controlling. With the exception of the Passive factor, the relationship between these interpersonal styles and SUD symptoms 12months after discharge was mediated by relationship quality with peers one month in treatment: i.e., more problematic interpersonal styles at baseline predicted poorer relationship quality with peers at 1month, which in turn predicted more SUD symptoms at 12months. Results demonstrate the importance of assessing interpersonal styles among patients in residential SUD treatment, as well as potentially augmenting existing evidence-based psychosocial treatments with a focus on interpersonal styles. PMID- 28847453 TI - Integrating intimate partner violence and parenting intervention into residential substance use disorder treatment for fathers. AB - Despite positive outcomes for the incorporation of gender- and motherhood-focused programing within substance use disorder treatment programs for women, a focus on gender and fatherhood has not been the focus of intervention or evaluation research for men in substance use disorder treatment. This was a mixed method study to examine the initial feasibility of incorporating a fatherhood-focused intervention within a substance use disorder treatment program for men. Forty four fathers enrolled in a coordinated intervention for intimate partner violence and parenting. Interviews were conducted at baseline and follow-up to assess the impact of the intervention on anger, hostile thinking and emotion regulation problems. Focus groups were also conducted with the participants to gain further insight into their needs as fathers and their recommendations for interventions that they would find helpful. Results indicated a high prevalence of anger related thoughts at baseline that significantly decreased at follow up; there were also significant reductions in affect regulation problems. Importantly, 84.1% of participants completed the program in its entirety and were highly satisfied with the content. These findings suggest that Fathers for Change can be implemented, successfully, in a men's residential treatment program. PMID- 28847452 TI - Monetary conversion factors for economic evaluations of substance use disorders. AB - AIMS: Estimating the economic consequences of substance use disorders (SUDs) is important for evaluating existing programs and new interventions. Policy makers in particular must weigh program effectiveness with scalability and sustainability considerations in deciding which programs to fund with limited resources. This study provides a comprehensive list of monetary conversion factors for a broad range of consequences, services, and outcomes, which can be used in economic evaluations of SUD interventions (primarily in the United States), including common co-occurring conditions such as HCV and HIV. METHODS: Economic measures were selected from standardized clinical assessment instruments that are used in randomized clinical trials and other research studies (e.g., quasi-experimental community-based projects) to evaluate the impact of SUD interventions. National datasets were also reviewed for additional SUD-related consequences, services, and outcomes. Monetary conversion factors were identified through a comprehensive literature review of published articles as well as targeted searches of other sources such as government reports. RESULTS: Eight service/consequence/outcome domains were identified containing more than sixty monetizable measures of medical and behavioral health services, laboratory services, SUD treatment, social services, productivity outcomes, disability outcomes, criminal activity and criminal justice services, and infectious diseases consequences. Unit-specific monetary conversion factors are reported, along with upper and lower bound estimates, whenever possible. CONCLUSIONS: Having an updated and standardized source of monetary conversion factors will facilitate and improve future economic evaluations of interventions targeting SUDs and other risky behaviors. This exercise should be repeated periodically as new sources of data become available to maintain the timeliness, comprehensiveness, and quality of these estimates. PMID- 28847454 TI - Building capacity for continuous quality improvement (CQI): A pilot study. AB - BACKGROUND AND OBJECTIVE: Little is known about the feasibility, effectiveness, and sustainability of CQI approaches in substance use disorder treatment settings. METHODS: In the initial phase of this study, eight programs were randomly assigned to receive a CQI intervention or to a waitlist control condition to obtain preliminary information about potential effectiveness. In the second phase, the initially assigned control programs received the CQI intervention to gain additional information about intervention feasibility while sustainability was explored among the initially assigned intervention programs. RESULTS AND CONCLUSIONS: Although CQI was feasible and sustainable, demonstrating its effectiveness using administrative data was challenging suggesting the need to better align performance measurement systems with CQI efforts. Further, although the majority of staff were enthusiastic about utilizing this approach and reported provider and patient benefits, many noted that dedicated time was needed in order to implement and sustain it. PMID- 28847456 TI - The response of substance use disorder treatment providers to changes in macroeconomic conditions. AB - OBJECTIVE: To study how substance use disorder (SUD) treatment providers respond to changes in economic conditions. DATA SOURCES: 2000-2012 National Survey of Substance Abuse Treatment Services (N-SSATS) which contains detailed information on specialty SUD facilities in the United States. STUDY DESIGN: We use fixed effects regression to study how changes in economic conditions, proxied by state unemployment rates, impact treatment setting, accepted payment forms, charity care, offered services, special programs, and use of pharmacotherapies by specialty SUD treatment providers. DATA COLLECTION: Secondary data analysis in the N-SSATS. PRINCIPAL FINDINGS: Our findings suggest a one percentage point increase in the state unemployment rate is associated with a 2.5% reduction in outpatient clients by non-profit providers and a 1.8% increase in the acceptance of private insurance as a form of payment overall. We find no evidence that inpatient treatment, the provision of charity care, offered services, or special programs are impacted by changes in the state unemployment rate. However, a one percentage point increase in the state unemployment rate leads to a 2.5% increase in the probability that a provider uses pharmacotherapies to treat addiction. CONCLUSIONS: Deteriorating economic conditions may increase financial pressures on treatment providers, prompting them to seek new sources of revenue or to change their care delivery models. PMID- 28847455 TI - Reductions in cannabis use are associated with improvements in anxiety, depression, and sleep quality, but not quality of life. AB - AIMS: This study examined the longitudinal association between reductions in cannabis use and changes in anxiety, depression, sleep quality, and quality of life. METHODS: Secondary analyses were conducted based on data from a cannabis use disorder medication trial in 302 adults (ages 18-50). Changes in symptoms of anxiety and depression, sleep quality, and quality of life were assessed in relation to changes in cannabis use during the 12-week trial of treatment. RESULTS: Based on the slope of individual cannabis use trajectory, the sample was classified into two groups (Cannabis Use Reduction, n=152 vs. Cannabis Use Increase, n=150) which was included as a binary covariate in subsequent modeling. Controlling for demographics (age, gender, race/ethnicity), treatment condition, and time-varying tobacco and alcohol use, separate latent growth curve models showed a significant association between the Cannabis Use Reduction group and improvement (i.e., lower values in slope) in anxiety (beta=-0.09, SE=0.04; p<0.05), depression (beta=-0.11, SE=0.04; p<0.01), and sleep quality (beta=-0.07, SE=0.03; p<0.05) over the observation period, but not in quality of life. CONCLUSIONS: These results indicate a longitudinal relationship between reductions in cannabis use and improvements in anxiety, depression, and sleep quality. Clinicians treating patients with co-occurring cannabis use and problems with anxiety, depression, or sleep quality should attend to cannabis use reduction as a component of treatment. PMID- 28847458 TI - Attention and memory deficits in crack-cocaine users persist over four weeks of abstinence. AB - BACKGROUND: Crack-cocaine addiction is an important public health problem worldwide. Although there is not a consensus, preliminary evidence has suggested that cognitive impairments in patients with crack-cocaine dependence persist during abstinence, affecting different neuropsychological domains. However, few studies have prospectively evaluated those deficits in different phases of abstinence. OBJECTIVES: The main aim of present study was to examine neuropsychological performance of patients with crack-cocaine dependence during early abstinence and after four weeks, comparing with matched controls. METHODS: Thirty-five males with crack-cocaine dependence, aged 18 to 50years, who met DSM IV criteria for cocaine dependence and a control group of 33 healthy men were enrolled. They were assessed through Block Design, Digit Span and Vocabulary of Wechsler Adult Intelligence Scale (WAIS-III), the Rey Auditory Learning Test (RAVLT) and the Verbal Fluency (FAS) between 3 and 10days (mean of 6.1+/-2.0days) and after 4weeks of abstinence. RESULTS: Compared to controls, the crack-cocaine dependent group exhibited deficits in cognitive performance affecting attention, verbal memory and learning tasks in early withdrawal. Most of the cognitive deficits persisted after four weeks of abstinence. CONCLUSION: Present results observed that the group of patients with crack-cocaine dependence presented persistent deficits affecting memory and attention even after four weeks of abstinence, confirming previous studies that had disclosed such cognitive impairments. PMID- 28847457 TI - Assessing informed consent in an opioid relapse prevention study with adults under current or recent criminal justice supervision. AB - Concerns persist that individuals with substance use disorders who are under community criminal justice supervision experience circumstances that might compromise their provision of valid, informed consent for research participation. These concerns include the possibilities that desire to obtain access to treatment might lead individuals to ignore important information about research participation, including information about risks, or that cognitive impairment associated with substance use might interfere with attending to important information. We report results from a consent quiz (CQ) administered in a multisite randomized clinical trial of long-acting naltrexone to prevent relapse to opioid use disorder among adults under community criminal justice supervision a treatment option difficult to access by this population of individuals. Participants were required to answer all 11 items correctly before randomization. On average, participants answered 9.8 items correctly (89%) at baseline first attempt (n=306). At week 21 (n=212), participants scored 87% (9.5 items correct) without review. Performance was equivalent to, or better than, published results from other populations on a basic consent quiz instrument across multiple content domains. The consent quiz is an efficient method to screen for adequate knowledge of consent information as part of the informed consent process. Clinical researchers who are concerned about these issues should consider using a consent quiz with corrected feedback to enhance the informed consent process. Overall, while primarily useful as an educational tool, employing a CQ as part of the gateway to participation in research may be particularly important as the field continues to advance and tests novel experimental treatments with significant risks and uncertain potential for benefit. PMID- 28847459 TI - Tumour-derived plasma cell-free DNA in patients with head and neck cancer: A short review. AB - Head and neck squamous cell carcinoma is one of the leading causes of cancer mortality worldwide. The prognosis for patients with head and neck squamous cell carcinoma has not substantially improved during the last decades, despite numerous advancements in treatment options. Reliable markers for early tumour detection and treatment response, which complement clinical examinations, imaging techniques, and biopsies would be extremely useful. One fairly new and promising method is the analysis of tumour-derived cell-free DNA (ctDNA) in the plasma of cancer patients. First data indicate that this method may assist, in the future, in the early detection of head and neck squamous cell carcinoma, the real-time monitoring of the disease course, the therapy response, and the prediction of prognosis with direct therapeutic implications by determining the best therapeutic modality for patient care. PMID- 28847460 TI - Brachytherapy for prostate cancer: Present and future. AB - Based on recent, important publications on the impact of brachytherapy in the management of prostate cancer, we analysed already validated indications and the "under investigations" use of brachytherapy. Published studies (MEDLINE), randomized trials and recommendations were reviewed, as well as Delphi consensus when available. While low-dose rate brachytherapy remains a standard of care for low-risk eligible patients, three randomized trials are now available to consider that combination of external beam radiation therapy with brachytherapy boost (low or high-dose rate) appears as a recommended treatment for intermediate and high risk patients. Other indications of prostate brachytherapy (monotherapy and salvage) remain under evaluation. For low-risk patients with good urinary status, low-dose rate brachytherapy alone should be offered. For low-intermediate risk prostate cancer, low-dose rate brachytherapy alone may be offered as monotherapy, while for high-intermediate risk prostate cancer, a combination of external beam radiation therapy (with or without androgen deprivation therapy) plus brachytherapy boost (low- or high-dose rate) should be offered to eligible patients. For patients with high-risk prostate cancer receiving external beam radiation therapy and androgen deprivation therapy, brachytherapy boost (low- or high-dose rate) should be offered to eligible patients. High-dose rate brachytherapy as monotherapy (single dose for low-risk/multifractionated for intermediate and high-risk) must be explored under clinical investigations, as well as salvage brachytherapy for local recurrence. PMID- 28847461 TI - [Active surveillance of prostate cancer]. AB - Several prospective studies have demonstrated the safety of active surveillance as a first treatment of prostate cancer. It spares many patients of a useless treatment, with its potential sequelae. Patients with a low-risk cancer are all candidates for this approach, as recommended by the American Society of Clinical Oncology (ASCO). Some patients with an intermediate risk could be also concerned by active surveillance, but this is still being discussed. Currently, the presence of grade 4 lesions on biopsy is a contra-indication. Modalities included a repeated prostate specific antigen test and systematic rebiopsy during the first year after diagnosis. MRI is now proposed to better select patients at inclusion and also during surveillance. No life style changes or drugs are significantly associated with a longer duration of surveillance. PMID- 28847462 TI - [Radiotherapy of oligometastatic pelvic node relapses in patients with prostate cancer]. AB - The Oligopelvis 2 studies is based on the assumption that salvage pelvic radiotherapy may prolong the interval between the first and the second intermittent hormone therapy sequence in pelvic lymph node oligometastatic prostate cancer. This phase 3 study will compare intermittent hormone therapy (standard arm) alone or combined with salvage pelvic radiotherapy (experimental arm). PMID- 28847463 TI - [What does the radiation oncologist expect from the physicist and inversely]. AB - The cooperation between radiation oncologists and physicists is essential to guarantee the quality and safety of the irradiation of our patients. It would be wrong to consider that the intervention of physicists in the patient management process is limited to the provision of calibrated and controlled equipment and to guarantee the validity of the dose distribution and the treatment time, while the radiation oncologist has the complete control of all clinical activities related to irradiation. The intervention of physicists at the stage of acquisition of anatomical data and throughout the phase of optimization of the treatment is already a reality. The recognition of the profession of medical physicist as a health profession comes to legitimize this intervention. Should physician physicist cooperation be limited to these common tasks and participation in continuing care? Can we consider a true synergy of action that goes beyond the field of care? The answer to the question: "what does the radiation oncologist expect from the physicist and inversely?" may bring elements to reinforce tomorrow's cooperation. PMID- 28847464 TI - [Hypofractionated irradiation of prostate cancer: What is the radiobiological understanding in 2017?] AB - For prostate cancer, hypofractionation has been based since 1999 on radiobiological data, which calculated a very low alpha/beta ratio (1.2 to 1.5Gy). This suggested that a better local control could be obtained, without any toxicity increase. Consequently, two types of hypofractionated schemes were proposed: "moderate" hypofractionation, with fractions of 2.5 to 4Gy, and "extreme" hypofractionation, utilizing stereotactic techniques, with fractions of 7 to 10Gy. For moderate hypofractionation, the linear-quadratic (LQ) model has been used to calculate the equivalent doses of the new protocols. The available trials have often shown a "non-inferiority", but no advantage, while the equivalent doses calculated for the hypofractionated arms were sometimes very superior to the doses of the conventional arms. This finding could suggest either an alpha/beta ratio lower than previously calculated, or a negative impact of other radiobiological parameters, which had not been taken into account. For "extreme" hypofractionation, the use of the LQ model is discussed for high dose fractions. Moreover, a number of radiobiological questions are still pending. The reduced overall irradiation time could be either a positive point (better local control) or a negative one (reduced reoxygenation). The prolonged duration of the fractions could lead to a decrease of efficacy (because allowing for reparation of sublethal lesions). Finally, the impact of the large fractions on the microenvironment and/or immunity remains discussed. The reported series appear to show encouraging short to mid-term results, but the results of randomized trials are still awaited. Today, it seems reasonable to only propose those extreme hypofractionated schemes to well-selected patients, treating small volumes with high-level stereotactic techniques. PMID- 28847465 TI - Evaluating tear clearance rate with optical coherence tomography. AB - PURPOSE: To assess the early-phase of tear clearance rate (TCR) with anterior segment optical coherence tomography (OCT) and to determine the association between TCR and other clinical measures of the tear film in a group of young subjects with different levels of tear film quality. METHODS: TCR was classified as the percentage decrease of subject's inferior tear meniscus height 30s after instillation of 5MUl 0.9% saline solution. Fifty subjects (32F and 18M) aged (mean+/-standard deviation) 25.5+/-4.3 years volunteered for the study. It consisted of a review of medical history, Ocular Surface Disease Index (OSDI) questionnaire, tear film osmolarity measurements, slit lamp examination and TCR estimation based on dynamic measurements of the lower tear meniscus with OCT. Estimates of TCR were contrasted against subject age and tear film measures commonly used for dry eye diagnosis, which includes OSDI score, fluorescein tear film break-up time (FBUT), tear meniscus height (TMH), blinking frequency, tear film osmolarity and corneal staining. RESULTS: The group mean TCR was 29+/-13% and 36+/-19% respectively after 30 and 60s margin after saline solution instillation. Statistically significant correlations were found between TCR and FBUT (r2=0.319, p<0.001), blinking frequency (r2=0.138, p<0.01), tear film osmolarity (r2=0.133, p<0.01) and subject's age (r2=0.095, p<0.05). CONCLUSIONS: Anterior segment optical coherence tomography allows following changes of tear meniscus morphology post saline solution instillation and evaluating the TCR. OCT based TCR might be used as additional measure of the lacrimal functional unit. PMID- 28847466 TI - A novel in-vitro method for assessing contact lens surface dewetting: Non invasive keratograph dry-up time (NIK-DUT). AB - PURPOSE: This study was designed to develop a novel technique called non-invasive keratograph dry-up time (NIK-DUT), which used an adapted corneal topographer, to analyse in-vitro contact lens surface dewetting and the effects of combinations of lenses and lens care solutions on dewetting. METHODS: Variables were assessed to optimise sensitivity and reproducibility. To validate the method, in-vitro dewetting of silicone hydrogel contact lenses (balafilcon A, comfilcon A, lotrafilcon A, lotrafilcon B and senofilcon A) was tested. All lens types were soaked in OPTI-FREE(r) PureMoist(r) Multipurpose Disinfecting Solution (OFPM) and Sensitive Eyes(r) Saline Solution. The mean NIK-DUT, defined as drying of 25% of the placido ring measurement segments (NIK-DUT_S25), was calculated for each lens/lens solution combination and a visual map constructed representing the time and location of the dry-up event. RESULTS: Optimal conditions for NIK-DUT measurement included mounting onto a glass stage with a surface geometry of r=8.5mm, e=0, and measuring with high intensity red or white illumination. This method detected significant differences in contact lens dewetting with different lens soaking solutions. NIK-DUT_S25 for all lenses was longer when pre-soaked in OFPM versus saline. Visual analysis showed that dewetting of contact lenses was not uniform across surfaces and differed between test solutions. CONCLUSIONS: NIK DUT is suitable for detecting differences in dewetting among various contact lenses and lens-care combinations. NIK-DUT can quantify the dewetting of large areas of lens surfaces with little subjective influence. Lens care solutions containing surface-active wetting agents were found to delay surface dewetting of silicone hydrogel lenses. PMID- 28847467 TI - Injured Children Receive Twice the Radiation Dose at Nonpediatric Trauma Centers Compared With Pediatric Trauma Centers. AB - BACKGROUND: Use of cranial CT scans in children has been increasing, in part due to increased awareness of sports-related concussions. CT is the largest contributor to medical radiation exposure, a risk factor for cancer. Long-term cancer risks of CT scans can be two to three times higher for children than for adults because children are more radiosensitive and have a longer lifetime in which to accumulate exposure from multiple scans. STUDY AIM: To compare the radiation exposure injured children receive when imaged at nonpediatric hospitals (NPHs) versus pediatric hospitals. METHODS: Injured children younger than 18 years who received a CT scan at a referring hospital during calendar years (CYs) 2010 and 2013 were included. Patient-level factors included demographics, mode of transportation, and Injury Severity Score, and hospital-level factors included region of state, radiology services, and hospital type and size. Our primary outcome of interest was the effective radiation dose. RESULTS: Four hundred eighty-seven children were transferred to the pediatric trauma center during CYs 2010 and 2013, with a median age of 7.2 years (interquartile range 5-13). The median effective radiation dose received at NPHs was twice that received at the pediatric trauma center (3.8 versus 1.6 mSv, P < .001). Results were confirmed in independent and paired analyses, after controlling for mode of transportation, emergency department disposition, level of injury severity, and at the NPH trauma center level, hospital type, size, region, and radiology services location. CONCLUSION: NPHs have the potential to substantially reduce the medical radiation received by injured children. Pediatric CT protocols should be considered. PMID- 28847468 TI - Effect of melatonin in reducing second-generation antipsychotic metabolic effects: A double blind controlled clinical trial. AB - INTRODUCTION: The use of second-generation atypical antipsychotics has an increasing role in the development of metabolic syndrome. However, these medications due to metabolic disorders can lead to an increased risk of cardiovascular disease and subsequently mortality as well as reduced adherence to treatment. The main objective of current study was to determine the ability of melatonin to reduce the metabolic effects of second-generation antipsychotics. METHODS: This double blind controlled clinical trial was conducted on 100 patients aged 18-64 years old were treated with the second-generation antipsychotics for the first time. The patients were divided randomly into two groups of 50. The case group received slow-release melatonin at a dose of 3mg and the control group was given oral placebo at 8 p.m. RESULTS: The findings in melatonin group indicated significantly increase of HDL and decreased fasting blood sugar and systolic blood pressure, as well as had statistically significant increase in waist circumference, weight and BMI compared with placebo group. CONCLUSION: According to the findings, it can be claimed that the addition of melatonin to atypical antipsychotics has led to a reduction in some of the metabolic effects of these drugs. In this study, HDL level was increased, and the mean systolic blood pressure and FBS were decreased in the melatonin group. Considering that these factors are contributing to cardiovascular disease as a leading cause of mortality in psychiatric patients, so the use of melatonin can reduce some of the medical effects of long-term treatment of atypical antipsychotics. PMID- 28847469 TI - T-cell therapy for chronic viral hepatitis. AB - Although therapy for chronic hepatitis C virus infection has delivered remarkable cure rates, curative therapies for hepatitis B virus (HBV) may only be available in the distant future. The possibility to eliminate or at least stably maintain low levels of HBV replication under the control of a functional anti-host response has stimulated the development of specific immunotherapies for HBV infection. We reviewed the development of T-cell therapy for HBV, highlighting its potential antiviral efficiency but also its potential toxicities in different groups of chronic HBV patients. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the only two communicable diseases in which there have been increases in related morbidity and mortality over the past 20 years [1]. Both viruses are chronically infecting about 500 million people (HBV ~350 million, HCV ~150 million) and represent the seventh most frequent cause of death worldwide [1]. HBV and HCV are hepatotropic, non-cytopathic viruses able to establish persistent infections that cause different degrees of hepatic inflammation (chronic hepatitis), leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). The two viruses are unrelated and virologically different. HCV remains prevalent in North America and Europe, whereas chronic hepatitis B is prevalent in Asia and sub-Saharan Africa [1,2]. HCV is an RNA virus belonging to the Flaviviridae family, and HBV is a DNA virus of the Hepadnaviridae family and uses reverse transcriptase to synthesize its DNA from a pre-genomic RNA form [3]. HCV is able to activate in the infected host a classical type I interferon (IFN)-mediated innate response [3], whereas HBV generally escapes innate immune recognition and does not activate type I IFN mediated immunity. Chronic HBV and HCV infections are both characterized by quantitative and functional defects of virus-specific T-cell response [4,5]. The frequency of virus-specific T cells is extremely low, and virus-specific T cells show features of exhaustion in both chronic HBV and HCV patients [6]. However, the quantitative and functional defects are more pronounced in HBV infections, with T cells virtually undetectable in the blood of many chronic HBV patients by ex vivo analysis [7-9]. In addition, while frequency and impact of viral mutations in T cell epitopes are frequently detectable in HCV infections [10], viral mutations affecting CD8 T-cell epitopes are scarcer in chronic HBV patients [6,11,12]. Of extreme practical importance in relation to the potential impact of T-cell therapy for HBV and HCV are the efficacies of currently available treatments. New therapies for HCV have delivered remarkable cure rates, with more than 90% of patients achieving viral clearance with all oral direct-acting antivirals [13]. In contrast, curative therapies for HBV will not be available until the distant future (14). Thus, although it is difficult to see a possible therapeutic advantage of a new T-cell-based therapy in chronic HCV patients, the fact that current therapies for HBV only partially suppress but do not eliminate HBV from the infected host has encouraged research for new and more radical therapies designed to eliminate or at least stably maintain low levels of HBV replication under the control of a functional anti-host response. For these reasons, in this review, we concentrate on the development of T-cell therapy for HBV. T-cell therapy for HCV chronic infection is certainly important for understanding the mechanisms of T-cell antiviral control [15,16], but their use for therapy appears unlikely. PMID- 28847470 TI - Anal ulcerations in Crohn's disease: Natural history in the era of biological therapy. AB - BACKGROUND: The natural history of anal ulcerations in Crohn's disease remains unknown. AIMS: To assess the long-term outcomes of anorectal ulcerations. METHODS: Data from consecutive patients with perineal Crohn's disease were prospectively recorded. The data of patients with anal ulceration were extracted. RESULTS: Anal ulcerations were observed in 154 of 282 patients (54.6%), and 77 cases involved cavitating ulcerations. The cumulative healing rates were 47%, 70% and 82% at 1, 2 and 3 years, respectively. Patients with a primary fistula phenotype had a shorter median time to healing of their anal ulceration (28 [13 83] weeks) than those with a stricture (81 [28-135] weeks) or those with isolated ulceration (74 [31-181] weeks) (p=0.004). Among patients with ulcerations but no fistula at referral (n=67), only 4 (6%) developed de novo abscesses and/or fistula during follow-up. There was no benefit associated with introducing or optimising biologics, nor with combining immunosuppressants and biologics. CONCLUSION: Anal ulceration in Crohn's disease usually requires a long time to achieve sustained healing. Determining the impact of biologics on healing rates will require dedicated randomised trials although it does not show a significant healing benefit in the present study. PMID- 28847471 TI - Endoscopic findings and colonic perforation in microscopic colitis: A systematic review. AB - INTRODUCTION: Microscopic colitis (MC) is a clinical syndrome of severe watery diarrhea with few or no endoscopic abnormalities. The incidence of MC is reported similar to that of other inflammatory bowel diseases. The need for histological confirmation of MC frequently guides reimbursement health policies. With the advent of high-definition (HD) coloscopes, the incidence of reporting distinct endoscopic findings in MC has risen. This has the potential to improve timely diagnosis and cost-effective MC management and diminish the workload and costs of busy modern endoscopy units. METHODS: Publications on distinct endoscopic findings in MC available until March 31st, 2017 were searched systematically (electronic and manual) in PubMed database. The following search terms/descriptors were used: collagenous colitis (CC) OR lymphocytic colitis (LC) AND endoscopy, colonoscopy, findings, macroscopic, erythema, mucosa, vasculature, scars, lacerations, fractures. An additional search for MC AND perforation was made. RESULTS: Eighty (n=80) articles, predominantly single case reports (n=49), were found. Overall, 1582 (1159F; 61.6+/-14.1 years) patients (pts) with MC and endoscopic findings were reported. The majority of articles (n=62) were on CC (pts 756; 77.5% females). We identified 16 papers comprising 779 pts (69.2% females) with LC and 7 articles describing 47 pts (72.3% females) diagnosed as MC. The youngest patient was 10 and the oldest a 97-year-old. Aside diarrhea, symptoms included abdominal pain, weight loss, bloating, flatulence, edema and others. In the study group we found 615 (38.8%) persons with macroscopic lesions in gut. Isolated linear ulcerations were identified in 7 pts (1.1%) while non ulcerous lesions i.e. pseudomembranes, a variable degree of vasculature pruning & dwindling, mucosal lacerations and abnormalities such as erythema/edema/nodularity, or surface textural alteration in 608 pts (98.1%). The location of endoscopic findings was not reported in 27 articles. The distinct endoscopic findings were described in the left (descending, sigmoid, rectum - 10/21/11 studies), right (cecum, ascending - 7/7 studies), transverse colon (n=12), as well as duodenum (n=4), and terminal ileum (n=2). In 17 (1.1%) pts colonic perforation occurred. CONCLUSION: Endoscopic findings are recognized with increased frequency in pts with MC. This could improve MC diagnosis by prompting a more extensive biopsy protocol in such cases and an earlier initiation of treatment. Procedure-related perforation has been reported in this group; therefore, cautious air insufflation is advisable when endoscopic findings are recognised. PMID- 28847472 TI - The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer. AB - Gastric cancer is a leading cause of cancer-related mortality worldwide, and options to treat gastric cancer are limited. Fluorouracil (5Fu)-based chemotherapy is frequently used as a neoadjuvant or an adjuvant agent for gastric cancer therapy. Most patients with advanced gastric cancer eventually succumb to the disease despite the fact that some patients respond initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat gastric cancer. In this study, we discovered that residual cancer cells following 5Fu treatment have elevated expression of hedgehog (Hg) target genes GLI1 and GLI2, suggestive of Hh signaling activation. Hh signaling, a pathway essential for embryonic development, is an important regulator for putative cancer stem cells/residual cancer cells. We found that high GLI1/GLI2 expression is associated with some features of putative cancer stem cells, such as increased side population. We demonstrated that GLI2 knockdown sensitized gastric cancer cells to 5Fu treatment, decreased ABCG2 expression, and reduced side population. Elevated GLI2 expression is also associated with an increase in tumor sphere size, another marker for putative cancer stem cells. We believe that GLI2 regulates putative cancer stem cells through direct regulation of ABCG2. ABCG2 can rescue the GLI2 shRNA effects in 5Fu response, tumor sphere formation and side population changes, suggesting that ABCG2 is an important mediator for GLI2-associated 5Fu resistance. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high GLI1/GLI2/ABCG2 expression is associated with a high incidence of cancer relapse in two cohorts of gastric cancer patients who underwent chemotherapy (containing 5Fu). Taken together, we have identified a molecular mechanism by which gastric cancer cells gain 5Fu resistance. PMID- 28847473 TI - Mitochondrial replacement techniques or therapies (MRTs) to improve embryo development and to prevent mitochondrial disease transmission. PMID- 28847474 TI - Neuropsychology of traumatic brain injury: An expert overview. AB - Traumatic brain injury (TBI) is a serious healthcare problem, and this report is a selective review of recent findings on the epidemiology, pathophysiology and neuropsychological impairments following TBI. Patients who survive moderate-to severe TBI frequently suffer from a wide range of cognitive deficits and behavioral changes due to diffuse axonal injury. These deficits include slowed information-processing and impaired long-term memory, attention, working memory, executive function, social cognition and self-awareness. Mental fatigue is frequently also associated and can exacerbate the consequences of neuropsychological deficits. Personality and behavioral changes can include combinations of impulsivity and apathy. Even mild TBI raises specific problems: while most patients recover within a few weeks or months, a minority of patients may suffer from long-lasting symptoms (post-concussion syndrome). The pathophysiology of such persistent problems remains a subject of debate, but seems to be due to both injury-related and non-injury-related factors. PMID- 28847476 TI - Physiologically Based Oral Absorption Modelling to Study Gut-Level Drug Interactions. AB - Physiologically based oral absorption models are in silico tools primarily used to guide formulation development and project the clinical performance of formulation variants. This commentary briefly discusses additional oral absorption model applications, focusing on gut-level drug interactions. Gut-level drug interactions can involve drug degradation, metabolic enzymes, transporters, gastrointestinal motility modulators, acid-reducing agents, and food. The growth in publications reporting physiologically based oral absorption model utilization and successful pharmacokinetic prediction (e.g., after acid-reducing agents or food coadministration) indicate that oral absorption models have achieved a level of maturity within the industry particularly over the past 15 years. Provided appropriate data and model validation, oral absorption modeling/simulation may serve as a surrogate for clinical studies by providing both mechanistic and quantitative understanding of oral delivery considerations on pharmacokinetics. PMID- 28847475 TI - Outcomes of Chronic Myeloid Leukemia Patients With Early Molecular Response at 3 and 6 Months: A Comparative Analysis of Generic Imatinib and Glivec. AB - BACKGROUND: The molecular response at 3 months of the original imatinib (OI) in patients with chronic myeloid leukemia has prognostic significance; however, this has never been tested for generic imatinib (GI). PATIENTS AND METHODS: We evaluated the BCR-ABL1 [international reporting scale (IS)] transcript levels at 3 and 6 months to determine whether an early molecular response (EMR) had a prognostic effect on the outcome among chronic myeloid leukemia patients receiving GI. Ninety patients were divided into 2 groups, according to the imatinib they received, as OI (group A) and GI (group B). RESULTS: Two groups were equally balanced for age, gender, Sokal risk score, and optimal response. The 2 groups did not differ in achieving an EMR at 3 months, and patients with EMR at 3 months had significantly superior complete cytogenetic response and major molecular response rates compared with patients who did not achieve an EMR in both groups. The percentage of an optimal response [BCR-ABL1 (IS), < 1%] and a warning response [BCR-ABL1 (IS), 1%-10%] at 6 months was 93% and 95% for groups A and B, respectively (P = .553). Patients with an optimal response (OR) at both 3 and 6 months had significantly superior event-free survival rates compared with patients without an OR in groups A and B. CONCLUSION: The results of the present study have demonstrated most probably for the first time that an OR at 3 and 6 months in patients receiving either first-line GI and OI is clearly associated with greater response and event-free survival rates. Prospective randomized trials with larger numbers of patients and longer follow-up periods are needed to address the effect of EMR in patients receiving GI. PMID- 28847478 TI - Pharmacologically Safe Nanomicelles of Amphotericin B With Lipids: Nuclear Magnetic Resonance and Molecular Docking Approach. AB - This study presents the mode of interaction, structural features, and micellization of amphotericin B (AmB) with sodium deoxycholate sulfate (SDCS) as small lipid molecule at different ratios, as revealed by molecular docking simulations and nuclear magnetic resonance (NMR). AmB-SDCS micelles were synthesized by single pot rinsing method. Solid-state 13C NMR revealed hydrogen (H)-bonding as the main interaction, occurring at different positions between AmB and SDCS at various ratios. Molecular docking elucidated that AmB-SDCS complex was stabilized by multiple H-bonds and van der Waals forces between SDCS and AmB. SDCS molecules wrap around the AmB in a head-to-tail fashion into a nanomicellar structure. AmB-SDCS micelles were stable after freeze-drying and presented zeta potential values between -27.5 and -42.6 mV and particle size in the range of 63.9 to 203.1 nm, upon rehydration in water. Hematological toxicity of AmB was controlled by exposure versus release of drug from SDCS micelles and concentration of SDCS to envelop the drug. Hemolysis of human erythrocytes was significantly reduced as compared to market formulation Fungizone(r) and pure AmB. This study explained the chemical interaction of micellization of AmB in lipids, which can have greater implications in designing toxicologically safe formulations of hydrophobic drugs. PMID- 28847477 TI - Hot Melt Extrudates Formulated Using Design Space: One Simple Process for Both Palatability and Dissolution Rate Improvement. AB - This work aimed at obtaining an optimized itraconazole (ITZ) solid oral formulation in terms of palatability and dissolution rate by combining different polymers using hot melt extrusion (HME), according to a simplex centroid mixture design. For this, the polymers Plasdone(r) (poly(1-vinylpyrrolidone-co-vinyl acetate) [PVP/VA]), Klucel(r) ELF (2-hydroxypropyl ether cellulose [HPC]), and Soluplus(r) (SOL, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol) were processed using a laboratory HME equipment operating without recirculation at constant temperature. Samples were characterized by physicochemical assays, as well as dissolution rate and palatability using an e-tongue. All materials became homogeneous and dense after HME processing. Thermal and structural analyses demonstrated drug amorphization, whereas IR spectroscopy evidenced drug stability and drug-excipient interactions in HME systems. Extrudates presented a significant increase in dissolution rate compared to ITZ raw material, mainly with formulations containing PVP/VA and HPC. A pronounced improvement in taste masking was also identified for HME systems, especially in those containing higher amounts of SOL and HPC. Data showed polymers act synergistically favoring formulation functional properties. Predicted best formulation should contain ITZ 25.0%, SOL 33.2%, HPC 28.9%, and PVP/VA 12.9% (w/w). Optimized response considering dissolution rate and palatability reinforces the benefit of polymer combinations. PMID- 28847480 TI - The Association of Serum Testosterone Levels and Urinary Incontinence in Women. AB - PURPOSE: Pelvic floor integrity is an important predictor of stress urinary incontinence. Androgen receptors have been found in the pelvic floor musculature and fascia, and testosterone administration has been shown to increase levator ani hypertrophy and improve stress incontinence in a rodent model. We examined the relationship between serum total testosterone levels and self-reported urinary incontinence in women. MATERIALS AND METHODS: We included women older than 20 years in the 2012 NHANES (National Health and Nutrition Examination Survey) cycle who underwent serum total testosterone measurement and answered self-reported urinary incontinence questions. A weighted, multivariate logistic regression model was used to determine the association between incontinence and serum testosterone levels after adjusting for age, body mass index, diabetes, race, parity, menopause and time of venipuncture. RESULTS: A total of 2,321 women were included in analysis, of whom 37.5% had stress incontinence, 29.8% had urge incontinence and 16.4% had mixed incontinence. Women in the lowest quartile of serum testosterone were more likely to complain of stress and mixed incontinence (OR 1.45, 95% CI 1.03-2.12 and OR 1.68, 95% CI 1.23-2.22, respectively). No association was noted between serum testosterone levels and urge incontinence. CONCLUSIONS: Low serum testosterone is associated with an increased likelihood of stress and mixed incontinence in women. Given the role of pelvic musculature in maintaining urethral support and the anabolic effect of androgens on skeletal muscle, a physiological mechanism for this relationship can be proposed and further evaluated in prospective and translational studies. PMID- 28847479 TI - Type 2 diabetes in adolescents and young adults. AB - The prevalence of type 2 diabetes in adolescents and young adults is dramatically increasing. Similar to older-onset type 2 diabetes, the major predisposing risk factors are obesity, family history, and sedentary lifestyle. Onset of diabetes at a younger age (defined here as up to age 40 years) is associated with longer disease exposure and increased risk for chronic complications. Young-onset type 2 diabetes also affects more individuals of working age, accentuating the adverse societal effects of the disease. Furthermore, evidence is accumulating that young onset type 2 diabetes has a more aggressive disease phenotype, leading to premature development of complications, with adverse effects on quality of life and unfavourable effects on long-term outcomes, raising the possibility of a future public health catastrophe. In this Review, we describe the epidemiology and existing knowledge regarding pathophysiology, risk factors, complications, and management of type 2 diabetes in adolescents and young adults. PMID- 28847482 TI - Esculetin exerts antitumor effect on human gastric cancer cells through IGF 1/PI3K/Akt signaling pathway. AB - : In this study, we aimed to investigate the antitumor effect of esculetin, a coumarin derivative extracted from natural plants, on human gastric cancer cells, and to illustrate the potential mechanisms. The results showed that esculetin exhibited anti-proliferative effects against gastric cancer cells and induced their apoptosis in a dose dependent manner with lower toxicity against normal gastric epithelial cells. Mechanism study indicated that esculetin induced gastric cancer MGC-803 cells apoptosis by triggering the activation of mitochondrial apoptotic pathway through reducing the mitochondrial membrane potential (MMP), increasing Bax/Bcl-2 ratio, activating caspase-3 and caspase-9 activity, and increasing cytochrome c release from mitochondria. Further study showed that the pro-apoptotic effects of esculetin were associated with down regulation of insulin-like growth factor-1/ phosphatidylinositide 3 kinase/protein kinase B (IGF-1/PI3K/Akt) signaling pathway. Activation of IGF 1/PI3K/Akt pathway by IGF-1 abrogated the pro-apoptotic effects of esculetin, while inhibition of IGF-1/PI3K/Akt pathway by triciribine or LY294002 enhanced the pro-apoptotic effects of esculetin. In addition, esculetin inhibited in vivo tumor growth with no obvious toxicity following subcutaneous inoculation of MGC 803 cells in nude mice, and inhibited activation of IGF-1/PI3K/Akt pathway in tumor tissue. CONCLUSION: These results indicate that esculetin could inhibit cell proliferation and induce apoptosis of gastric cancer cells through IGF 1/PI3K/Akt mediated mitochondrial apoptosis pathway, and may be a novel effective chemotherapeutic agent against gastric cancer. PMID- 28847481 TI - Active Surveillance for Low Risk Nonmuscle Invasive Bladder Cancer: A Confirmatory and Resource Consumption Study from the BIAS Project. AB - PURPOSE: We investigated predictive factors of failure and performed a resource consumption analysis in patients who underwent active surveillance for nonmuscle invasive bladder cancer. MATERIALS AND METHODS: This prospective observational study monitored patients with a history of pathologically confirmed stage pTa (grade 1-2) or pT1a (grade 2) nonmuscle invasive bladder cancer, and recurrent small size and number of tumors without hematuria and positive urine cytology. The primary end point was the failure rate of active surveillance. Assessment of failure predictive variables and per year direct hospital resource consumption analysis were secondary outcomes. Descriptive statistical analysis and Cox regression with univariable and multivariable analysis were done. RESULTS: Of 625 patients with nonmuscle invasive bladder cancer 122 with a total of 146 active surveillance events were included in the protocol. Of the events 59 (40.4%) were deemed to require treatment after entering active surveillance. Median time on active surveillance was 11 months (IQR 5-26). Currently 76 patients (62.3%) remain under observation. On univariable analysis only time from the first transurethral resection to the start of active surveillance seemed to be inversely associated with recurrence-free survival (HR 0.99, 95% CI 0.98-1.00, p = 0.027). Multivariable analysis also revealed an association with age at active surveillance start (HR 0.97, 95% CI 0.94-1.00, p = 0.031) and the size of the lesion at the first transurethral resection (HR 1.55, 95% CI 1.06-2.27, p = 0.025). The average specific annual resource consumption savings for each avoided transurethral bladder tumor resection was ?1,378 for each intervention avoided. CONCLUSIONS: Active surveillance might be a reasonable clinical and cost effective strategy in patients who present with small, low grade pTa/pT1a recurrent papillary bladder tumors. PMID- 28847483 TI - Discriminative control by deprivation states and external cues in male and female rats. AB - Previous research indicates that decisions about when to eat in response to food cues in the environment are based on interoceptive energy states (i.e., hunger and fullness) and learning about and remembering prior eating experiences. However, this animal model has exclusively been tested on male rodents. Despite evidence that women are more susceptible to obesity and cognitive disorders associated with excess weight (e.g., Alzheimer's disease) than men, the generality of these findings with males to females remains unknown. To address this gap, the current research investigated associative learning mechanisms involved in food intake control in females by training both males and females in a Pavlovian deprivation discrimination in which varying levels of food deprivation are trained with competitive external cues to signal reward. In Experiment 1, male and female rats showed similar performance in discriminating between 0 and 24h deprivation state/external cue compounds and in subsequent tests, confirming stimulus control by deprivation states. Experiment 2 assessed learning about more ecologically valid 0 and 4h deprivation states in competition with external cues in both males and females. With the low-level deprivation state parameters, females outperformed males in discriminative control by deprivation states, particularly on the contingency rewarded under satiation and not deprivation. While females showed an enhanced degree of energy state processing under some deprivation conditions, overall, these findings suggest similar mechanisms of learned appetitive control in both sexes. PMID- 28847485 TI - Mechanisms of fetal epigenetics that determine telomere dynamics and health span in adulthood. AB - Advances in epigenetics now enable us to better understand environmental influences on the genetic background of human diseases. This refers especially to fetal development where an adverse intrauterine environment impacts oxygen and nutrient supply to the fetus. Recently, differences in telomere length and telomere loss dynamics among individuals born with intrauterine growth restriction compared to normal controls have been described. In this paper we propose possible molecular mechanisms that (pre)program telomere epigenetics during pregnancy. This programming sets differences in telomere lengths and dynamics of telomere shortening in adulthood and therefore dictates the dynamics of aging and morbidity in later life. PMID- 28847484 TI - The Rho-specific guanine nucleotide exchange factor Plekhg5 modulates cell polarity, adhesion, migration, and podosome organization in macrophages and osteoclasts. AB - Osteoclasts are multinucleated bone-resorbing cells that are formed by fusion of monocyte/macrophage lineage. Osteoclasts and macrophages generate podosomes that are actin-based dynamic organelles implicated in cell adhesion, spreading, migration, and degradation. However, the detailed mechanisms of podosome organization remain unknown. Here, we identified the Rho-specific guanine nucleotide exchange factor (Rho-GEF) Plekhg5 as an up-regulated gene during differentiation of osteoclasts from macrophages. Knockdown of Plekhg5 with small interfering RNA in both macrophages and osteoclasts induced larger cell formation with impaired cell polarity and resulted in an elongated and flattened shape. In macrophages, Plekhg5 depletion enhanced random migration, but impaired directional migration, adhesion, and matrix degradation. Plekhg5 in osteoclasts affected random migration, podosome organization, and bone resorption. Plekhg5 depletion affected signaling and localization of several Rho downstream effectors. In fact, end-binding protein 1 (EB1), cofilin and vinculin were abnormally localized in Plekhg5-depleted cells, and mDia1 and LIM kinase (LIMK)1 were upregulated in Plekhg5-depleted cells compared with control cells. However, overexpression of Plekhg5 in macrophages induced an increase in its mRNA level, but failed to increase the protein level, indicating that overexpressed Plekhg5 was degraded in macrophages but not HEK293T cells. Thus, Plekhg5 affects cell polarity, migration, adhesion, degradation, and podosome organization in macrophages and osteoclasts. PMID- 28847486 TI - miRNAs in stem cell aging and age-related disease. AB - MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of mRNA targets and play a part in the post-transcriptional silencing. To date, the prominent roles of miRNAs in stem cells have been investigated in a wide range of biological processes, including self-renewal, differentiation and proliferation. In this commentary, we first demonstrate the causes and mechanisms of somatic stem cell aging in a new aspect of miRNAs. The functions of stem cells decline with age in diverse tissues due to cellular damages and congenital disorders. The somatic stem cells exhibit type-specific phenotypes with cellular senescence during the aging process. We explore the specific miRNAs regulating stem cell aging and age-related diseases. The functional investigations of the miRNAs in somatic stem cells and degenerative diseases might facilitate the translation of knowledge into clinical practice for the regulation of stem cell aging and aging related diseases. PMID- 28847487 TI - Magnetoencephalography Reveals Mismatch Field Enhancement from Unexpected Syntactic Category Errors in English Sentences. AB - The type of syntactic operations that increase neuronal activation in humans as a result of syntactically erroneous, unexpected lexical items in hearing sentences has remained unclear. In the present study, we used recordings of magnetoencephalographic (MEG) activity to compare bare infinitive and full infinitive constructions in English. This research aims to identify the type of syntactic deviance that may trigger an early syntax-related mismatch field (MMF) component when unexpected words appear in sentences. Six speakers of English as a first language were presented with auditory stimuli of sentences or words in a passive odd-ball paradigm while watching a silent movie. The experimental protocol included four sessions, specifically investigating the sentential (structural) versions of full (with the 'to' infinitival particle) and bare infinitival structures (without the particle) and the lexical (non-structure) versions of the verb either with or without the particle to determine whether the structure processing of sentences was a more crucial factor in the detection of the MMF than the simple processing of lexical items in verb-only conditions. The amplitude analysis of the resulting evoked fields showed that the presence of the syntactic category error of bare infinitival structures against syntactic predictions evoked a significantly larger MMF activation with a peak latency of approximately 200ms in the anterior superior temporal sulci in the left hemisphere, compared with the lexical items that did not have any syntactic status. These results clearly demonstrate that syntactically unexpected, illegal input in the bare infinitival structure is likely to be noticed more robustly in the brain while processing the structural information of the entire sentence than the corresponding verb-only items. PMID- 28847488 TI - Impact of 3.5% O2 culture on embryo development and clinical outcomes: a comparative study. AB - OBJECTIVE: To evaluate the effect of culturing human embryos in vitro in 3.5% oxygen (O2) concentration. DESIGN: Comparative study. SETTING: Private IVF center. PATIENT(S): The study included 558 women in two groups. INTERVENTION(S): After intracytoplasmic sperm injection (ICSI), women's oocytes were assigned to undergo cultivation in either 3.5% O2 concentration (intervention) or 5% O2 level (control group), continuously, from day 0 through day 5 or 6. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR) after ET. RESULT(S): There were significantly higher fertilization and cleavage rates in the 3.5% O2 group (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.53-1.93) and (OR 3.74, 95% CI 2.30-6.07) than in the 5% O2 group. The compaction rate on day 3, and the number of formed, high-quality and cryopreserved blastocysts on day 5 were significantly lower in 3.5% O2 than in 5% O2 concentration ([OR 0.81, 95% CI 0.69-0.91], [OR 0.40, 95% CI 0.36-0.46], [OR 0.32, 95% CI 0.28-0.37] and [OR 0.47, 95% CI 0.40 0.54]), respectively. Culturing embryos in 3.5% O2 concentration led to significantly lower rates of biochemical pregnancy, clinical PR, and implantation ([OR 0.66, 95% CI 0.47-0.92], [OR 0.60, 95% CI 0.43-0.84] and [OR 0.61, 95% CI 0.46-0.81]), respectively. CONCLUSION(S): Culturing human embryos, continuously from day 0 to 5 or 6, in 3.5% O2 concentration is associated with significantly lower blastocyst formation rate and clinical outcomes parameters, but rather with significantly higher rates of fertilization and cleavage. Whether these findings hold true for other patient populations and culture media brands remain unknown. PMID- 28847489 TI - Maternal substance use during pregnancy and offspring conduct problems: A meta analysis. AB - We conducted meta-analyses of relationships between highly prevalent substance use during pregnancy and offspring conduct disorder problems. In total 36 studies were included. Odds ratios (ORs) were 2.06 (1.67-2.54, 25 studies) for maternal smoking, 2.11 (1.42-3.15, 9 studies) for alcohol use, and 1.29 (0.93-1.81, 3 studies) for cannabis use, while a single study of caffeine use reported no effects. Our meta-analyses support an association between smoking and alcohol use during pregnancy, and offspring conduct problems, yet do not resolve causality issues given potential confounding by genetic factors, gene-environment interactions, and comorbidity such as with attention deficit hyperactivity disorders. Future studies should use genetically sensitive designs to investigate the role of pregnancy substance use in offspring conduct problems and may consider more broadly defined behavioral problems. PMID- 28847490 TI - Apelin attenuates TGF-beta1-induced epithelial to mesenchymal transition via activation of PKC-epsilon in human renal tubular epithelial cells. AB - Epithelial to mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of renal fibrosis. Apelin, a bioactive peptide, has recently been recognized to protect against renal profibrotic activity, but the underlying mechanism has not yet been elucidated. In this study, we investigated the regulation of EMT in the presence of apelin-13 in vitro. Expression of the mesenchymal marker alpha-smooth muscle actin (alpha-SMA) and the epithelial marker E-cadherin was examined by immunofluorescence and western blotting in transforming growth factor beta 1 (TGF-beta1)-stimulated human proximal tubular epithelial cells. Expression of extracellular matrix, fibronectin and collagen-I was examined by quantitative real-time PCR and ELISA. F13A, an antagonist of the apelin receptor APJ, and small interfering RNA targeting protein kinase C epsilon (PKC-epsilon) were used to explore the relevant signaling pathways. Apelin attenuated TGF-beta1-induced EMT, and inhibited the EMT-associated increase in alpha-SMA, loss of E-cadherin, and secretion of extracellular matrix. Moreover, apelin activated PKC-epsilon in tubular epithelial cells, which in turn decreased phospho-Smad2/3 levels and increased Smad-7 levels. APJ inhibition or PKC-epsilon deletion diminished apelin induced modulation of Smad signaling and suppression of tubular EMT. Our findings identify a novel PKC-epsilon-dependent mechanism in which apelin suppresses TGF beta1-mediated activation of Smad signaling pathways and thereby inhibits tubular EMT. These results suggest that apelin may be a new agent that can suppress renal fibrosis and retard chronic kidney disease progression. PMID- 28847491 TI - On the contribution of motor planning to the retroactive cuing benefit in working memory: Evidence by mu and beta oscillatory activity in the EEG. AB - Attention can be allocated toward mental representations in working memory also after the initial encoding of information has been completed. It was shown that focusing on only one item within working memory transfers this representation into a protected state, reducing its susceptibility to interference by incoming signals. The present study investigated the nature of this retroactive cue (retro cue) benefit by means of oscillatory activity in the EEG. In a working memory task with a retro-cue indicating one, two or three memory representations as relevant and a block-wise distractor display presented after the retro-cue, participants had to remember the orientation of a colored bar. On behavioral level, we found that the interfering effect of the distractor display on memory performance could be prevented when a retro-cue reduced the number of attended representations in working memory. However, only the one-item retro-cue led to an overall increase in task performance compared to a condition without a retro-cue. The neural basis of this special representational status was investigated by means of oscillatory parameters in the EEG and a clustering approach on level of the independent components (ICs) in the signal. The retroactive reduction of attended working memory representations was reflected in a suppression of alpha power over right parietal and parieto-occipital sites. In addition, we found that an IC cluster representing oscillatory activity in the mu/beta range (10-12 Hz and 20-24 Hz) with a source in sensorimotor cortex revealed a power suppression already prior to the memory probe following the one-item retro-cue. This suggests that the retro-cue benefit results in large parts from the possibility to focus attention on one particular item in working memory and initiate motor planning processes already ahead of the probe stimulus indicating the respective response. PMID- 28847492 TI - Decoding of auditory and tactile perceptual decisions in parietal cortex. AB - Perceptual decision making is the process in which stimuli of a rich environment are reduced to a single choice. Parietal cortex is involved in many tasks that require perceptual decisions such as attentional focusing, categorization, and eventually response selection. While much work in both the human and monkey domains has investigated processes related to visual decision making, relatively little research has explored auditory and tactile perceptual decisions. As such, we wanted to know whether these regions also play a role in auditory and tactile decision making. Using functional magnetic resonance imaging on humans and a paradigm specifically designed to avoid motor confounds, we found that one area in the right intraparietal sulcus, contained high-level abstract representations of auditory and tactile category-specific information. Our findings advance the idea that parietal cortex represents information that abstracts away from both the input and output domains. PMID- 28847493 TI - The EEG microstate topography is predominantly determined by intracortical sources in the alpha band. AB - Human brain electric activity can be measured at high temporal and fairly good spatial resolution via electroencephalography (EEG). The EEG microstate analysis is an increasingly popular method used to investigate this activity at a millisecond resolution by segmenting it into quasi-stable states of approximately 100 ms duration. These so-called EEG microstates were postulated to represent atoms of thoughts and emotions and can be classified into four classes of topographies A through D, which explain up to 90% of the variance of continuous EEG. The present study investigated whether these topographies are primarily driven by alpha activity originating from the posterior cingulate cortex (all topographies), left and right posterior cortices, and the anterior cingulate cortex (topographies A, B, and C, respectively). We analyzed two 64-channel resting state EEG datasets (N = 61 and N = 78) of healthy participants. Sources of head-surface signals were determined via exact low resolution electromagnetic tomography (eLORETA). The Hilbert transformation was applied to identify instantaneous source strength of four EEG frequency bands (delta through beta). These source strength values were averaged for each participant across time periods belonging to a particular microstate. For each dataset, these averages of the different microstate classes were compared for each voxel. Consistent differences across datasets were identified via a conjunction analysis. The intracortical strength and spatial distribution of alpha band activity mainly determined whether a head-surface topography of EEG microstate class A, B, C, or D was induced. EEG microstate class C was characterized by stronger alpha activity compared to all other classes in large portions of the cortex. Class A was associated with stronger left posterior alpha activity than classes B and D, and class B was associated with stronger right posterior alpha activity than A and D. Previous results indicated that EEG microstate dynamics reflect a fundamental mechanism of the human brain that is altered in different mental states in health and disease. They are characterized by systematic transitions between four head-surface topographies, the EEG microstate classes. Our results show that intra-cortical alpha oscillations, which likely reflect decreased cortical excitability, primarily account for the emergence of these classes. We suggest that microstate class dynamics reflect transitions between four global attractor states that are characterized by selective inhibition of specific intra cortical regions. PMID- 28847494 TI - Isolated Pseudomonas aeruginosa strain VIH2 and antagonistic properties against Ralstonia solanacearum. AB - The aim of this study was to isolates with antagonist activity against R. solanacearum. Thirty-two bacterial isolates were obtained from samples, and they were screened for potential antagonistic activity against R. Solanacearum. Using the agar spot method, ten out of the 21 tested bacteria showed antilisterial activity. VIH2 had the highest inhibitory effect on the growth of R. Solanacearum. Based on 16S rDNA and Biolog test analysis, the strain VIH2 was identified as Pseudomonas aeruginosa. Single-factor and Response Surface Methodology experiments were used to optimize the culture medium and conditions. This study was to explore whether the hemolysin-co-regulated protein secretion island I (HSI-I)-encoded type VI secretion system (T6SS) in Pseudomonas can be used as a biological control approach against Ralstonia solanacearum under field conditions. Bacterial competition assay showed that the HSI-I type T6SS of strain VIH2 exhibited dramatic antibacterial killing activity against R. solanacearum. The HSI-I T6SS of P. aeruginosa was regulated by the ppKA gene. We disrupted the gene ppKA in VIH2 by a single crossover to yield the VIH2 (DeltappKA) mutant. The antagonism of VIH2 was significantly decreased by ppKA gene disruption. In conclusion, our data supported the idea that HSI-I T6SS plays a crucial role in the antagonistic action of strain VIH2 against R. solanacearum. This alternative approach for antagonism against R. solanacearum might help develop attenuated strains of engineered bacteria for biological control. PMID- 28847495 TI - Communicable and non-communicable disease risks at the Grand Magal of Touba: The largest mass gathering in Senegal. AB - BACKGROUND: An estimated 4-5 million individuals gather each year in the holy city of Touba, Senegal during the Grand Magal religious pilgrimage. Pilgrims come from across Senegal and the surrounding countries, as well as from countries outside Africa. It is the largest mass gathering (MG) of the Mouride community and the largest Muslim religious MG in West Africa. METHOD: A cross-sectional study was conducted on all patients who attended a public healthcare structure during the November 2015 Grand Magal. RESULT: Data were collected on a total of 32,229 healthcare contacts. The most frequent reasons for consultation were trauma, followed by fatigue and heatstroke. Infectious diseases were also prevalent with, notably, a high rate of febrile systemic illnesses and malaria, diarrheal diseases, and respiratory tract infections. Such results are likely to be linked to overcrowding and climatic conditions, the relative lack of sanitary facilities, and limited medical resources available during the event. CONCLUSION: The context of the Grand Magal MG is unique, given its location in a tropical developing country and its international component which may favor the globalization of locally endemic diseases. As such, it warrants investment in modern methods for public health surveillance and planning of the event. PMID- 28847496 TI - Female Genital Mutilation, "vacation cutting" and the travel medicine consultation. PMID- 28847497 TI - Efficacy testing of novel chemical disinfectants on clinically relevant microbial pathogens. AB - BACKGROUND: There has been a dramatic increase in the number of hospital-acquired infections, which is linked to the pandemic of multidrug resistance. Clinical environments provide an ideal reservoir for the growth, proliferation, and transmission of pathogenic organisms, including bacterial and yeast species. Consequently, the need for improved, effective disinfectants is of paramount importance. METHODS: Studies were conducted to assess the efficacy of chemical disinfectants-peracetic acid and triameen-on microbial strains. Testing included the assessment of antimicrobial and antisporicidal activity of disinfection solutions performed on a range of clinical isolates that pose a high risk for patient morbidity in clinical settings. RESULTS: Both chemical disinfectants successfully inactivated all test strains, with peracetic acid showing a greater level of antimicrobial activity. Escherichia coli proved most susceptible when assessed by the Kirby disk diffusion, suspension, and medical suspension assays with the greatest reduction in cell viability achieved. Antibiotic-resistant Enterococcus and Staphylococcus aureus strains showed greatest resistance to both disinfectants. DISCUSSION AND CONCLUSIONS: Test chemicals show potential to act as intermediate-level disinfectants inactivating vegetative microorganisms and bacterial spores on clinically relevant strains where they show potential as a preventative measure in relation to nosocomial infections. PMID- 28847498 TI - Imaging Features on Contrast-Enhanced Ultrasound and Clinical Characteristics of Hepatitis B Virus-Related Combined Hepatocellular-Cholangiocarcinoma: Comparison with Hepatitis B Virus-Related Hepatocellular Carcinoma. AB - The objective of this study was to compare the clinical characteristics and imaging features on contrast-enhanced ultrasound (CEUS) of hepatitis B virus (HBV)-related combined hepatocellular-cholangiocarcinoma (CHC) and hepatocellular carcinoma (HCC). Thirty-one pathologically proven CHCs were included and 31 HCCs were randomly selected as controls. Elevated carbohydrate antigen (CA) 19-9 alone and simultaneous elevation of alpha-fetoprotein and CA19-9 were more frequent in CHC than in HCC patients (p = 0.004 and 0.029, respectively). On CEUS, homogeneous, heterogeneous and peripheral irregular rim-like enhancement was illustrated in 8 (25.8%), 12 (38.7%) and 11 (35.5%) CHCs and in 6 (19.4%), 23 (74.1%) and 2 (6.5%) HCCs, respectively (p = 0.007). Multivariate logistic regression analysis revealed CA19-9 elevation (p = 0.011, odds ratio [OR] = 6.545) and peripheral irregular rim-like enhancement on CEUS (p = 0.017, OR = 7.718) were independent variables. A receiver operating characteristic curve was plotted and the area under the curve was 0.740. CHC should be watched for in HBV infected patients with liver tumor manifesting peripheral irregular rim-like enhancement on CEUS, accompanied by CA19-9 elevation. PMID- 28847499 TI - Combining Subharmonic and Ultraharmonic Modes for Intravascular Ultrasound Imaging: A Preliminary Evaluation. AB - Contrast-enhanced intra-vascular ultrasound (CE-IVUS) imaging could provide clinicians a valuable tool to assess cardiovascular risk and guide the choice of therapeutic strategies. In this technical note, we evaluated the feasibility of combining subharmonic and ultraharmonic imaging to improve the performance of CE IVUS. Vessel phantoms perfused with phospholipid-shelled ultrasound contrast agents were visualized using subharmonic, ultraharmonic and combined CE-IVUS modes with commercial peripheral and coronary imaging catheters. Flow channels as small as 0.8 mm and 0.5 mm were imaged at 12-MHz and 30-MHz transmit frequencies, respectively. Subharmonic and ultraharmonic imaging modes achieved a contrast-to tissue ratio (CTR) up to 18.1 +/- 1.8 dB and 19.6 +/- 1.9 dB at 12-MHz, and 8.8 +/- 1.8 and 12.5 +/- 1.1 dB at 30-MHz transmit frequencies, respectively. Combining these modes improved the CTR to 32.5 +/- 3.0 dB and 25.0 +/- 1.6 dB at 12-MHz and 30-MHz transmit frequencies. These results underscore the potential of combined-mode CE-IVUS imaging. Furthermore, the demonstration of this approach with commercial catheters may serve as a first step toward the clinical translation of CE-IVUS. PMID- 28847501 TI - Solubilization of human cells by the styrene-maleic acid copolymer: Insights from fluorescence microscopy. AB - Extracting membrane proteins from biological membranes by styrene-maleic acid copolymers (SMAs) in the form of nanodiscs has developed into a powerful tool in membrane research. However, the mode of action of membrane (protein) solubilization in a cellular context is still poorly understood and potential specificity for cellular compartments has not been investigated. Here, we use fluorescence microscopy to visualize the process of SMA solubilization of human cells, exemplified by the immortalized human HeLa cell line. Using fluorescent protein fusion constructs that mark distinct subcellular compartments, we found that SMA solubilizes membranes in a concentration-dependent multi-stage process. While all major intracellular compartments were affected without a strong preference, plasma membrane solubilization was found to be generally slower than the solubilization of organelle membranes. Interestingly, some plasma membrane localized proteins were more resistant against solubilization than others, which might be explained by their presence in specific membrane domains with differing properties. Our results support the general applicability of SMA for the isolation of membrane proteins from different types of (sub)cellular membranes. PMID- 28847500 TI - Mechanistic Insight into Sonoporation with Ultrasound-Stimulated Polymer Microbubbles. AB - Sonoporation is emerging as a feasible, non-viral gene delivery platform for the treatment of cardiovascular disease and cancer. Despite promising results, this approach remains less efficient than viral methods. The objective of this work is to help substantiate the merit of polymeric microbubble sonoporation as a non viral, localized cell permeation and payload delivery strategy by taking a ground up approach to elucidating the fundamental mechanisms at play. In this study, we apply simultaneous microscopy of polymeric microbubble sonoporation over its intrinsic biophysical timescales-with sub-microsecond resolution to examine microbubble cavitation and millisecond resolution over several minutes to examine local macromolecule uptake through enhanced endothelial cell membrane permeability-bridging over six orders of magnitude in time. We quantified microbubble behavior and resulting sonoporation thresholds at transmit frequencies of 0.5, 1 and 2 MHz, and determined that sonic cracking is a necessary but insufficient condition to induce sonoporation. Further, sonoporation propensity increases with the extent of sonic cracking, namely, from partial to complete gas escape from the polymeric encapsulation. For the subset that exhibited complete gas escape from sonic cracking, a proportional relationship between the maximum projected gas area and resulting macromolecule uptake was observed. These results have revealed one aspect of polymeric bubble activity on the microsecond time scale that is associated with eliciting sonoporation in adjacent endothelial cells, and contributes toward an understanding of the physical rationale for sonoporation with polymer encapsulated microbubble contrast agents. PMID- 28847502 TI - How kanamycin A interacts with bacterial and mammalian mimetic membranes. AB - Biological membranes are natural barriers to the transport of molecules and drugs within human bodies. Many antibacterial agents need to cross these membranes to reach their target and elicit specific effects. Kanamycin A belongs to the family of aminoglycoside antibiotics that target cellular RNA to inhibit bacterial and viral replication. Previous studies have shown that aminoglycosides bind to mammalian but disrupt bacterial membranes. In this study, molecular dynamics (MD) simulations and infrared (IR) spectroscopy were applied to investigate the initial, first key interactions of kanamycin A, as a representative aminoglycoside, with both bacterial and mammalian lipid bilayers at the molecular level. Computational studies revealed strong hydrogen bonding interactions between the hydroxyl and amino groups of the aminoglycoside with the ester carbonyl and phosphate groups of the lipids. IR spectroscopy provided experimental verification of the important role of the lipid's ester carbonyl, phosphate and hydroxyl groups for aminoglycoside binding. The bacterial membrane became disordered upon aminoglycoside addition, whereas the mammalian membrane became stiffer and more ordered. This indicates the bacterial membrane disruption observed by previous studies. PMID- 28847503 TI - Interaction of lysozyme with a tear film lipid layer model: A molecular dynamics simulation study. AB - The tear film is a thin multilayered structure covering the cornea. Its outermost layer is a lipid film underneath of which resides on an aqueous layer. This tear film lipid layer (TFLL) is itself a complex structure, formed by both polar and nonpolar lipids. It was recently suggested that due to tear film dynamics, TFLL contains inhomogeneities in the form of polar lipid aggregates. The aqueous phase of tear film contains lachrymal-origin proteins, whereby lysozyme is the most abundant. These proteins can alter TFLL properties, mainly by reducing its surface tension. However, a detailed nature of protein-lipid interactions in tear film is not known. We investigate the interactions of lysozyme with TFLL in molecular details by employing coarse-grained molecular dynamics simulations. We demonstrate that lysozyme, due to lateral restructuring of TFLL, is able to penetrate the tear lipid film embedded in inverse micellar aggregates. PMID- 28847504 TI - ALS-causing profilin-1-mutant forms a non-native helical structure in membrane environments. AB - Despite having physiological functions completely different from superoxide dismutase 1 (SOD1), profilin 1 (PFN1) also carries mutations causing amyotrophic lateral sclerosis (ALS) with a striking similarity to that triggered by SOD1 mutants. Very recently, the C71G-PFN1 has been demonstrated to cause ALS by a gain of toxicity and the acceleration of motor neuron degeneration preceded the accumulation of its aggregates. Here by atomic-resolution NMR determination of conformations and dynamics of WT-PFN1 and C71G-PFN1 in aqueous buffers and in membrane mimetics DMPC/DHPC bicelle and DPC micelle, we deciphered that: 1) the thermodynamic destabilization by C71G transforms PFN1 into coexistence with the unfolded state, which is lacking of any stable tertiary/secondary structures as well as restricted ps-ns backbone motions, thus fundamentally indistinguishable from ALS-causing SOD1 mutants. 2) Most strikingly, while WT-PFN1 only weakly interacts with DMPC/DHPC bicelle without altering the native structure, C71G-PFN1 acquires abnormal capacity in strongly interacting with DMPC/DHPC bicelle and DPC micelle, energetically driven by transforming the highly disordered unfolded state into a non-native helical structure, similar to what has been previously observed on ALS-causing SOD1 mutants. Our results imply that one potential mechanism for C71G-PFN1 to initiate ALS might be the abnormal interaction with membranes as recently established for SOD1 mutants. PMID- 28847506 TI - Cooperative interactions between VEGFR2 extracellular Ig-like subdomains ensure VEGFR2 dimerization. AB - BACKGROUND: Prior studies have suggested that the interactions occurring between VEGFR2 extracellular domains in the absence of ligand are complex. Here we seek novel insights into these interactions, and into the role of the different Ig like domains (D1 through D7) in VEGFR2 dimerization. METHODS: We study the dimerization of a single amino acid mutant and of three deletion mutants in the plasma membrane using two photon microscopy and fully quantified spectral imaging. RESULTS: We demonstrate that a set of cooperative interactions between the different Ig-like domains ensure that VEGFR2 dimerizes with a specific affinity instead of forming oligomers. CONCLUSIONS: The contributions of subunits D7 and D4 seem to be the most critical, as they appear essential for strong lateral interactions and for the formation of dimers, respectively. GENERAL SIGNIFICANCE: This study provides new insights into the mechanism of VEGFR2 dimerization and activation. PMID- 28847505 TI - Selective substrate uptake: The role of ATP-binding cassette (ABC) importers in pathogenesis. AB - The uptake of nutrients, including metals, amino acids and peptides are required for many biological processes. Pathogenic bacteria scavenge these essential nutrients from microenvironments to survive within the host. Pathogens must utilize a myriad of mechanisms to acquire these essential nutrients from the host while mediating the effects of toxicity. Bacteria utilize several transport proteins, including ATP-binding cassette (ABC) transporters to import and expel substrates. ABC transporters, conserved across all organisms, are powered by the energy from ATP to move substrates across cellular membranes. In this review, we will focus on nutrient uptake, the role of ABC importers at the host-pathogen interface, and explore emerging therapies to combat pathogenesis. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain. PMID- 28847507 TI - Solution NMR views of dynamical ordering of biomacromolecules. AB - BACKGROUND: To understand the mechanisms related to the 'dynamical ordering' of macromolecules and biological systems, it is crucial to monitor, in detail, molecular interactions and their dynamics across multiple timescales. Solution nuclear magnetic resonance (NMR) spectroscopy is an ideal tool that can investigate biophysical events at the atomic level, in near-physiological buffer solutions, or even inside cells. SCOPE OF REVIEW: In the past several decades, progress in solution NMR has significantly contributed to the elucidation of three-dimensional structures, the understanding of conformational motions, and the underlying thermodynamic and kinetic properties of biomacromolecules. This review discusses recent methodological development of NMR, their applications and some of the remaining challenges. MAJOR CONCLUSIONS: Although a major drawback of NMR is its difficulty in studying the dynamical ordering of larger biomolecular systems, current technologies have achieved considerable success in the structural analysis of substantially large proteins and biomolecular complexes over 1MDa and have characterised a wide range of timescales across which biomolecular motion exists. While NMR is well suited to obtain local structure information in detail, it contributes valuable and unique information within hybrid approaches that combine complementary methodologies, including solution scattering and microscopic techniques. GENERAL SIGNIFICANCE: For living systems, the dynamic assembly and disassembly of macromolecular complexes is of utmost importance for cellular homeostasis and, if dysregulated, implied in human disease. It is thus instructive for the advancement of the study of the dynamical ordering to discuss the potential possibilities of solution NMR spectroscopy and its applications. This article is part of a Special Issue entitled "Biophysical Exploration of Dynamical Ordering of Biomolecular Systems" edited by Dr. Koichi Kato. PMID- 28847508 TI - Large-scale examination of functional and sequence diversity of 2 oxoglutarate/Fe(II)-dependent oxygenases in Metazoa. AB - BACKGROUND: The 2-oxoglutarate/Fe(II)-dependent oxygenase (2OG oxygenase) superfamily in Metazoa is responsible for protein modification, nucleic acid repair and/or modification, and fatty acid metabolism. METHODS: Phylogenetic analysis, protein sequence similarity network (SSN) and other bioinformatics tools were used to analyze the evolutionary relationship and make functional inferences of Metazoa 2OG oxygenases. RESULTS: Sixty-four 2OG oxygenases have been previously found in Homo sapiens; they catalyze two reactions: hydroxylation and demethylation. Phylogenetic analyses indicated that enzymes with similar domain architecture are always clustered together, and the redox function can be performed by the 2OG oxygenase domain or Jumonji C (JmjC) domain, where the JmjC domain is always fused to other functional domains. We used the SSN to make functional inferences and to conduct distribution analysis of Metazoa 2OG oxygenases. >11,000 putative 2OG oxygenases across Metazoa could be assigned potential functions based on the SSN. The multiple sequence alignments showed that the residues binding iron are most highly conserved in both the 2OG oxygenase domain and JmjC domain. In contrast, the residues binding oxoglutarate are quite different in the two domains: the 2OG oxygenase domain tends to have an Arg/Lys at the C terminus, whereas the JmjC domain, an Asn/Lys residue in the middle region. CONCLUSIONS: The results indicated that gene duplication and vertical gene transfer have played important roles in 2OG oxygenase evolution in Metazoa and clarified the difference between the 2OG oxygenase domain and JmjC domain. GENERAL SIGNIFICANCE: These findings expand the understanding of the diversity, evolution, and functions of 2OG oxygenases. PMID- 28847509 TI - Funnel-like Intima After Blunt Aortic Injury. PMID- 28847511 TI - The HRH4 rs11662595 mutation is associated with histamine H4 receptor dysfunction and with increased epithelial-to-mesenchymal transition progress in non-small cell lung cancer. AB - We previously demonstrated that histamine H4 receptor (HRH4) played important roles to suppress epithelial-to-mesenchymal transition (EMT) progress in non small cell lung cancer (NSCLC). Furthermore, recent investigations suggested that genetic variations in HRH4 gene affected HRH4 function and eventually contributed to certain HRH4-related diseases. However, the relations between polymorphisms in HRH4 gene and NSCLC as well as their underlying mechanisms remain largely uninvestigated. This study aims to investigate the genetic effect of a nonsynonymous HRH4 polymorphism (rs11662595) on HRH4 function and its association with NSCLC both basically and clinically. For basic experiments, A549 cells were transfected with either wild type or rs11662595 mutated HRH4 clone and subjected to both in vitro and in vivo experiments. We showed that rs11662595 significantly decreased the ability of HRH4 to activate Gi protein, which resulted in facilitation of EMT progress, cell proliferation, and invasion behavior in vitro. Moreover, in vivo experiments also showed that rs11662595 attenuated the anti-EMT effects of HRH4 agonist in inoculated nu/nu mice. For clinical experiments, we performed a prospective cohort study among 624 NSCLC patients and further proved that rs11662595 was responsible for the prognosis, degree of malignancy and metastasis of NSCLC. In conclusion, these findings reveal that rs11662595 is a loss-of-function polymorphism that results in dysfunction of HRH4 and attenuates the anti-EMT function of HRH4 in NSCLC, which provides a promising biomarker for prognosis and therapy of NSCLC. PMID- 28847510 TI - AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation. AB - Activin A receptor type I or activin receptor-like kinase 2 (ACVRI/ALK2) belongs to type I TGF-beta family and plays an important role in bone development. Activating mutations of ALK2 containing the R206 to H mutation, are present in 95% in the rare autosomal genetic disease fibrodysplasia ossificans progressiva (FOP), which leads to the development of ectopic bone formation in muscle. The effect of AMP-activated protein kinase (AMPK) activation on ALK2R206H-mediated signaling in fibroblasts obtained from a FOP patient was assessed in the present study. The activity of the mutated ALK2 was suppressed by pharmacological AMPK activators such as metformin and aspirin, while their actions were blocked by the dominant negative mutant of AMPK and mimicked by the constitutively active mutant of AMPK. Furthermore, activation of AMPK upregulated Smad6 and Smurf1 and thereby enhanced their interactions, resulting in its proteosome-dependent degradation of ALK2. In contrast, knockdown of Smad6 or Smurf1 prevented metformin-induced reduction of ALK2. To evaluate the biological relevance of AMPK action on ALK2 activity, we induced FOP fibroblasts into iPS cells and found that their osteogenic differentiation in vitro was inhibited by metformin. Our studies provide novel insight into potential approaches to treatment of FOP, since several AMPK activators (e.g. metformin, berberine, and aspirin) are already in clinical use for the treatment of diabetes and metabolic syndromes. PMID- 28847512 TI - Insulin-like growth factor-1 signaling in cardiac aging. AB - Cardiovascular disease (CVD) is the leading cause of death in most developed countries. Aging is associated with enhanced risk of CVD. Insulin-like growth factor-1 (IGF-1) binds to its cognate receptor, IGF-1 receptor (IGF-1R), and exerts pleiotropic effects on cell growth, differentiation, development, and tissue repair. Importantly, IGF-1/IGF-1R signaling is implicated in cardiac aging and longevity. Cardiac aging is an intrinsic process that results in cardiac dysfunction, accompanied by molecular and cellular changes. In this review, we summarize the current state of knowledge regarding the link between the IGF-1/IGF 1R system and cardiac aging. The biological effects of IGF-1R and insulin receptor will be discussed and compared. Furthermore, we describe data regarding how deletion of IGF-1R in cardiomyocytes of aged knockout mice may delay the development of senescence-associated myocardial pathologies. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. PMID- 28847513 TI - Endpoints in the design of clinical trials for primary sclerosing cholangitis. AB - Primary sclerosing cholangitis is an enigmatic disease affecting the bile ducts, eventually leading to liver failure necessitating liver transplantation in many cases. There is currently no therapy that has proven to halt disease progression. One of the reasons for this is the lack of proper endpoints to measure the effect of medical intervention on the course of the disease. Relevant clinical endpoints such as death or liver transplantation occur too infrequently in this orphan disease to be used as endpoints in phase 2 or 3 trials. It is therefore of utmost importance to identify appropriate surrogate endpoints that are reasonably likely to measure true clinical benefit. This article will discuss a number of surrogate endpoints that are likely candidates to serve this role. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28847514 TI - Omega-3 polyunsaturated fatty acids ameliorate ethanol-induced adipose hyperlipolysis: A mechanism for hepatoprotective effect against alcoholic liver disease. AB - Alcohol exposure induces adipose hyperlipolysis and causes excess fatty acid influx into the liver, leading to alcoholic steatosis. The impacts of omega-3 polyunsaturated fatty acids (n-3 PUFA) on ethanol-induced fatty liver are well documented. However, the role of n-3 PUFA in ethanol-induced adipose lipolysis has not been sufficiently addressed. In this study, the fat-1 transgenic mice that synthesizes endogenous n-3 from n-6 PUFA and their wild type littermates with an exogenous n-3 PUFA enriched diet were subjected to a chronic ethanol feeding plus a single binge as model to induce liver injury with adipose lipolysis. Additionally, the differentiated adipocytes from 3T3-L1 cells were treated with docosahexaenoic acid or eicosapentaenoic acid for mechanism studies. Our results demonstrated that endogenous and exogenous n-3 PUFA enrichment ameliorates ethanol-stimulated adipose lipolysis by increasing PDE3B activity and reducing cAMP accumulation in adipocyte, which was associated with activation of GPR120 and regulation of Ca2+/CaMKKbeta/AMPK signaling, resultantly blocking fatty acid trafficking from adipose tissue to the liver, which contributing to ameliorating ethanol-induced adipose dysfunction and liver injury. Our findings identify that endogenous and exogenous n-3 PUFA enrichment ameliorated alcoholic liver injury by activation of GPR120 to suppress ethanol-stimulated adipose lipolysis, which provides the new insight to the hepatoprotective effect of n-3 PUFA against alcoholic liver disease. PMID- 28847515 TI - Mechanisms of endothelial cell dysfunction in cystic fibrosis. AB - Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans-endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a beta2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF. PMID- 28847517 TI - Association of exposure to manganese and iron with relaxation rates R1 and R2*- magnetic resonance imaging results from the WELDOX II study. AB - OBJECTIVE: Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. MATERIAL AND METHODS: We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. RESULTS: MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn>100MUg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. CONCLUSIONS: MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB. PMID- 28847516 TI - Role of S100A9 in the development of neutrophilic inflammation in asthmatics and in a murine model. AB - S100A9 is an endogenous danger signal that promotes and exacerbates the neutrophilic inflammatory response. To investigate the role of S100A9 in neutrophilic asthma, S100A9 levels were measured in sputum from 101 steroid-naive asthmatics using an ELISA kit and the levels were significantly correlated with percentages of neutrophils in sputum. Intranasal administration of recombinant S100A9 markedly increased neutrophil numbers at 8h and 24h later with concomitant elevation of IL-1beta, IL-17, and IFN-gamma levels. Treatment with an anti-S100A9 antibody restored the increased numbers of neutrophils and the increased airway resistance in OVA/CFA mice toward the levels of sham-treated mice. Concomitantly, the S100A9 and neutrophil elastase double positive cells were markedly reduced with attenuation of IL-1beta, IL-17, and IFN-gamma levels by the treatment with the anti-S100A9 antibody. Our data support a role of S100A9 to initiate and amplify the neutrophilic inflammation in asthma, possibly via inducing IL-1beta, IL-17 and IFN-gamma. PMID- 28847518 TI - Hippocampal-dependent memory deficit induced by perinatal exposure to polutted eels in middle-aged offspring mice: Sex differential effects. AB - The effects of perinatal exposure to low, intermediate, or highly polluted eels on neonatal, postnatal, adult and middle-aged brain inflammation, and on cognitive performances of middle-aged offspring mice were compared to those of offspring controls. Inflammatory markers in microglia were assessed in offspring on the postnatal days-PNDs 1, 21, 100 and 330. Activated p38MAPK, ERK-1/2 and p65, and acetylcholine levels were assessed in the middle-aged hippocampus. Plasma myeloperoxidase and corticosterone levels were evaluated at PND 330. Learning and its retention, and working memory in middle-aged offspring were assessed using the Morris water maze, and Y-maze. Our results showed enhanced microglia production of inflammatory markers across the lifespan of male as well as female exposed offspring. Inflammation and increased p38 MAPK activation were detected in the exposed middle-aged hippocampus of both exposed sexes. Significant levels of MPO, but not corticosterone, were found in middle-aged males and females perinatally exposed to eels. However, decreases in ERK1/2 and p65 activation, and acetylcholine levels were only detected in female hippocampus exposed to either intermediately or highly polluted eels. Sex selective effects were also detected with regard to memory, the only altered cognitive function. Thus, middle-aged females, but not males, perinatally exposed to either intermediately or highly polluted eels take longer to locate the escape platform, spend considerably less time in the platform and perform less visit to the platform in the retention test. Our results suggest perinatal programming of hippocampal-dependent memory deficit by inflammation in middle-aged offspring, in sex and dose dependent manner. PMID- 28847520 TI - Do we understage SABR candidates? PMID- 28847519 TI - Differential procoagulant effects of saw-scaled viper (Serpentes: Viperidae: Echis) snake venoms on human plasma and the narrow taxonomic ranges of antivenom efficacies. AB - Saw-scaled vipers (genus Echis) are one of the leading causes of snakebite morbidity and mortality in parts of Sub-Saharan Africa, the Middle East, and vast regions of Asia, constituting a public health burden exceeding that of almost any other snake genus globally. Venom-induced consumption coagulopathy, owing to the action of potent procoagulant toxins, is one of the most relevant clinical manifestations of envenomings by Echis spp. Clinical experience and prior studies examining a limited range of venoms and restricted antivenoms have demonstrated for some antivenoms an extreme lack of antivenom cross-reactivity between different species of this genus, sometimes resulting in catastrophic treatment failure. This study undertook the most comprehensive testing of Echis venom effects upon the coagulation of human plasma, and also the broadest examination of antivenom potency and cross-reactivity, to-date. 10 Echis species/populations and four antivenoms (two African, two Asian) were studied. The results indicate that the venoms are, in general, potently procoagulant but that the relative dependence on calcium or phospholipid cofactors is highly variable. Additionally, three out of the four antivenoms tested demonstrated only a very narrow taxonomic range of effectiveness in preventing coagulopathy, with only the SAIMR antivenom displaying significant levels of cross-reactivity. These results were in conflict with previous studies using prolonged preincubation of antivenom with venom to suggest effective cross-reactivity levels for the ICP Echi-Tab antivenom. These findings both inform upon potential clinical effects of envenomation in humans and highlight the extreme limitations of available treatment. It is hoped that this will spur efforts into the development of antivenoms with more comprehensive coverage for bites not only from wild snakes but also from specimens widely kept in zoological collections. PMID- 28847521 TI - An Innovative Approach to Increasing Donor Heart Supply: Will It Work? PMID- 28847522 TI - Universal Coverage for Heart Failure Diagnosis and Treatment: Looking from Sub Saharan Africa to Central Australia. PMID- 28847525 TI - Chronic pain and suicide risk: A comprehensive review. AB - Death by suicide is one of the leading causes of mortality worldwide. Because individuals with chronic pain are at least twice as likely to report suicidal behaviors or to complete suicide, it is of utmost importance to target which risk factors contribute the most to increasing suicidality. This comprehensive review aims to provide an update on research advancements relating to the identification of potential risk factors for suicidality in individuals with chronic pain. Supporting the results of prior reviews, we found robust evidence that chronic pain itself, regardless of type, was an important independent risk factor for suicidality. The only sociodemographic factor found to be associated with suicidality in individuals with chronic pain was being unemployed/disabled. Depressive symptoms, anger problems, harmful habits (e.g. smoking, alcohol misuse, illicit drugs), childhood or adulthood adversities, and family history of depression/suicide were all also identified as general risk factors. Regarding pain-related factors, sleep problems, poorer perceived mental health, concurrent chronic pain conditions, and more frequent episodes of intermittent pain, were all found to be predictors of suicidality. Unexpectedly, pain characteristics (e.g. type, duration, and intensity/severity) and physical status (e.g. pain interference or disability) were not related to suicide risk. We also identified promising new psychosocial factors (e.g. mental defeat, pain catastrophizing, hopelessness, perceived burdensomeness and thwarted belongingness) associated with suicidality outcomes. A large number of these factors are amenable to change through targeted intervention, highlighting the importance of comprehensively assessing chronic pain patients at risk for suicide, while also incorporating a suicide prevention component into chronic pain management programs. PMID- 28847524 TI - Understanding the response of Desulfovibrio desulfuricans ATCC 27774 to the electron acceptors nitrate and sulfate - biosynthetic costs modulate substrate selection. AB - Sulfate-reducing bacteria (SRB) are a diverse group of anaerobic microorganisms that obtain their energy from dissimilatory sulfate reduction. Some SRB species have high respiratory versatility due to the possible use of alternative electron acceptors. A good example is Desulfovibrio desulfuricans ATCC 27774, which grows in the presence of nitrate (end product: ammonium) with higher rates and yields to those observed in sulfate containing medium (end product: sulfide). In this work, the mechanisms supporting the respiratory versatility of D. desulfuricans were unraveled through the analysis of the proteome of the bacterium under different experimental conditions. The most remarkable difference in the two dimensional gel electrophoresis maps is the high number of spots exclusively represented in the nitrate medium. Most of the proteins with increase abundance are involved in the energy metabolism and the biosynthesis of amino acids (or proteins), especially those participating in ammonium assimilation processes. qPCR analysis performed during different stages of the bacterium's growth showed that the genes involved in nitrate and nitrite reduction (napA and nrfA, respectively) have different expressions profiles: while napA did not vary significantly, nrfA was highly expressed at a 6h time point. Nitrite levels measured along the growth curve revealed a peak at 3h. Thus, the initial consumption of nitrate and concomitant production of nitrite must induce nrfA expression. The activation of alternative mechanisms for energy production, aside several N-assimilation metabolisms and detoxification processes, solves potential survival problems in adapting to different environments and contributes to higher bacterial growth rates. PMID- 28847523 TI - Computational membrane biophysics: From ion channel interactions with drugs to cellular function. AB - The rapid development of experimental and computational techniques has changed fundamentally our understanding of cellular-membrane transport. The advent of powerful computers and refined force-fields for proteins, ions, and lipids has expanded the applicability of Molecular Dynamics (MD) simulations. A myriad of cellular responses is modulated through the binding of endogenous and exogenous ligands (e.g. neurotransmitters and drugs, respectively) to ion channels. Deciphering the thermodynamics and kinetics of the ligand binding processes to these membrane proteins is at the heart of modern drug development. The ever increasing computational power has already provided insightful data on the thermodynamics and kinetics of drug-target interactions, free energies of solvation, and partitioning into lipid bilayers for drugs. This review aims to provide a brief summary about modeling approaches to map out crucial binding pathways with intermediate conformations and free-energy surfaces for drug-ion channel binding mechanisms that are responsible for multiple effects on cellular functions. We will discuss post-processing analysis of simulation-generated data, which are then transformed to kinetic models to better understand the molecular underpinning of the experimental observables under the influence of drugs or mutations in ion channels. This review highlights crucial mathematical frameworks and perspectives on bridging different well-established computational techniques to connect the dynamics and timescales from all-atom MD and free energy simulations of ion channels to the physiology of action potentials in cellular models. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28847526 TI - Modeling consequences of prolonged strong unpredictable stress in zebrafish: Complex effects on behavior and physiology. AB - Chronic stress is the major pathogenetic factor of human anxiety and depression. Zebrafish (Danio rerio) have become a novel popular model species for neuroscience research and CNS drug discovery. The utility of zebrafish for mimicking human affective disorders is also rapidly growing. Here, we present a new zebrafish model of clinically relevant, prolonged unpredictable strong chronic stress (PUCS). The 5-week PUCS induced overt anxiety-like and motor retardation-like behaviors in adult zebrafish, also elevating whole-body cortisol and proinflammatory cytokines - interleukins IL-1beta and IL-6. PUCS also elevated whole-body levels of the anti-inflammatory cytokine IL-10 and increased the density of dendritic spines in zebrafish telencephalic neurons. Chronic treatment of fish with an antidepressant fluoxetine (0.1mg/L for 8days) normalized their behavioral and endocrine phenotypes, as well as corrected stress elevated IL-1beta and IL-6 levels, similar to clinical and rodent data. The CNS expression of the bdnf gene, the two genes of its receptors (trkB, p75), and the gfap gene of glia biomarker, the glial fibrillary acidic protein, was unaltered in all three groups. However, PUCS elevated whole-body BDNF levels and the telencephalic dendritic spine density (which were corrected by fluoxetine), thereby somewhat differing from the effects of chronic stress in rodents. Together, these findings support zebrafish as a useful in-vivo model of chronic stress, also calling for further cross-species studies of both shared/overlapping and distinct neurobiological responses to chronic stress. PMID- 28847527 TI - The safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with stage III-IV non small cell lung cancer. AB - Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. We carried out a clinical trial to evaluate the safety and pharmacokinetics of those methods in patients with stage III-IV non-small cell lung cancer (NSCLC). Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I study. They were randomized allocated into 3 groups, and received doses 1.0, 1.2, 1.5g/kg AA infusions. Participants in the first group received intravenous AA (IVAA) when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. Pharmacokinetic profiles were obtained when they received solely IVAA and when IVAA in combination with mEHT. The process was applied 3 times a week (every other day, weekend days off) for 4weeks. We found that fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA was significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAA-managed groups. IVAA synergy with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients. PMID- 28847528 TI - Cervical tumor unusual etiology. PMID- 28847529 TI - Exposure to atrazine alters behaviour and disrupts the dopaminergic system in Drosophila melanogaster. AB - Atrazine is an extensively used herbicide, and has become a common environmental contaminant. Effects on dopaminergic neurotransmission in mammals following exposure to atrazine have been previously demonstrated. Here, the effects of atrazine regarding behavioural and dopaminergic neurotransmission parameters were assessed in the fruit fly D. melanogaster, exposed during embryonic and larval development. Embryos (newly fertilized eggs) were exposed to two atrazine concentrations (10MUM and 100MUM) in the diet until the adult fly emerged. Negative geotaxis assay, as well as exploratory behaviour, immobility time and number of grooming episodes in an open field system were assessed. Tyrosine hydroxylase (TH) activity and gene expression of the dopaminergic system were also evaluated in newly emerged male and female flies. All analyzed parameters in male flies were not significantly affected by atrazine exposure. However female flies exposed to atrazine at 10MUM presented an increase in immobility time and a reduction in exploratory activity in the open field test, which was offset by an increase in the number of grooming episodes. Also, female flies exposed to 100MUM of atrazine presented an increase in immobility time. Gene expression of DOPA decarboxylase and dopamine (DA) receptors were also increased only in females. The behavioural effects of atrazine exposure observed in female flies were due to a disturbance in the dopaminergic system. PMID- 28847530 TI - Lymphocyte-to-Monocyte Ratio: A Novel Predictor of the Prognosis of Acute Ischemic Stroke. AB - BACKGROUND: Lymphocyte-to-monocyte ratio (LMR) is associated with diverse malignancies and cardiovascular diseases. However, it has not yet been identified whether LMR is correlated with stroke severity and prognosis. We aimed to explore the relationship between LMR and stroke severity, prognosis, and the predictive value of LMR on a 3-month functional outcome in patients with acute ischemic stroke (AIS). MATERIALS AND METHODS: A total of 512 patients were enrolled in this study. Baseline demographic and clinical data of all patients were collected. Based on the LMR value on admission (>4.83, 2.97-4.83, <2.97), patients were divided into 3 groups. Moderate to severe stroke was defined as a National Institutes of Health Stroke Scale score of 6 or higher. Poor outcome was defined as a modified Rankin Scale score of 3 or higher. We used the Spearman rank correlation to evaluate the relationship between LMR and stroke severity. Binary logistic regression analysis was used to assess risk factors of stroke severity and prognosis. The receiver operating characteristic (ROC) curve was used to estimate the predictive value of LMR on prognosis. RESULTS: LMR was inversely correlated with stroke severity (r = -.014, P = .019). Moreover, LMR was an independent protective factor of stroke severity (odds ratio [OR] .891, 95% confidence interval [CI] .815-.973, P = .010) and prognosis (OR .507, 95% CI .437-.590, P < .001). ROC indicated that an LMR lower than 2.99 predicted a poor outcome, with a sensitivity of 69.3% and a specificity of 86.6%. CONCLUSION: A lower LMR on admission was independently associated with severe stroke and 3 month poor outcome in patients with AIS. PMID- 28847531 TI - A storm in the niche: Iron, oxidative stress and haemopoiesis. AB - Iron, although essential, is harmful in high amounts. Oxidative stress as a result of excess reactive oxygen species (ROS) and a prooxidative/antioxidative imbalance between ROS production and elimination, play a key role in cellular damage. There is evidence to support the role of ROS in the pathogenesis of a range of diseases including the myelodysplastic syndromes (MDS) and leukaemia. Oxidative stress seems to affect the self-renewal, proliferation and differentiation of haematopoietic stem cells and impair cell growth. Three aspects of these defective haemopoietic mechanisms may be associated with the activities of ROS: clonal evolution, haematological improvement and recovery of haemopoiesis after haematopoietic stem cell transplantation (HSCT). This review aims to provide haematologists with an overview of results from in vitro and murine models and preliminary clinical evidence on the diagnostic, prognostic and therapeutic implications of the complex interactions between the haemopoietic niche, iron, oxidative stress and inadequate haemopoiesis. PMID- 28847532 TI - Effects of reduced energy availability on bone metabolism in women and men. AB - BACKGROUND: The short-term effects of low energy availability (EA) on bone metabolism in physically active women and men are currently unknown. PURPOSE: We evaluated the effects of low EA on bone turnover markers (BTMs) in a cohort of women and a cohort of men, and compared effects between sexes. METHODS: These studies were performed using a randomised, counterbalanced, crossover design. Eleven eumenorrheic women and eleven men completed two 5-day protocols of controlled (CON; 45kcal.kgLBM-1.d-1) and restricted (RES; 15kcal.kgLBM-1.d-1) EAs. Participants ran daily on a treadmill at 70% of their peak aerobic capacity (VO2 peak) resulting in an exercise energy expenditure of 15kcal.kgLBM-1.d-1 and consumed diets providing 60 and 30kcal.kgLBM-1.d-1. Blood was analysed for BTMs [beta-carboxyl-terminal cross-linked telopeptide of type I collagen (beta-CTX) and amino-terminal propeptide of type 1 procollagen (P1NP)], markers of calcium metabolism [parathyroid hormone (PTH), albumin-adjusted calcium (ACa), magnesium (Mg) and phosphate (PO4)] and regulatory hormones [sclerostin, insulin-like growth factor 1 (IGF-1), triiodothyronine (T3), insulin, leptin, glucagon-like peptide-2 (GLP-2)]. RESULTS: In women, beta-CTX AUC was significantly higher (P=0.03) and P1NP AUC was significantly lower (P=0.01) in RES compared to CON. In men, neither beta-CTX (P=0.46) nor P1NP (P=0.12) AUCs were significantly different between CON and RES. There were no significant differences between sexes for any BTM AUCs (all P values>0.05). Insulin and leptin AUCs were significantly lower following RES in women only (for both P=0.01). There were no differences in any AUCs of regulatory hormones or markers of calcium metabolism between men and women following RES (all P values>0.05). CONCLUSIONS: When comparing within groups, five days of low EA (15kcal.kgLBM-1.d-1) decreased bone formation and increased bone resorption in women, but not in men, and no sex specific differences were detected. PMID- 28847533 TI - High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations. AB - INTRODUCTION: Controversy exists about the pathogenesis of idiopathic pulmonary fibrosis acute exacerbations (IPF-AEs). According to one hypothesis IPF-AEs represent the development of any etiology diffuse alveolar damage (DAD) upon usual interstitial pneumonia (UIP), whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated IPF patients. METHODS: Consecutive IPF patients referred to our department were included. Diagnoses of IPF and IPF AE were based on international guidelines and consensus criteria. The interleukins (IL)-4, IL-6, IL-8, IL-10, and IL-13 as well asactive transforming growth factor-beta (TGF-beta) were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The IL-6 and IL-8 levels were significantly higher in exacerbated patients (p=0.002 and p=0.046, respectively). An increase in either IL-6 or IL-8 by 1pg/ml increases the odds of death by 5.6% (p=0.021) and 6.7% (p=0.013), respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of IL-6 and IL-8 characterize early-on IPF-AEs and an increase in the levels of IL-6 and IL-8 associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-beta, IL-10, IL-4 and IL 13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of IL-6 further studies are necessary to clarify the enigma of IPF AEs etiopathogenesis. PMID- 28847534 TI - Increased BAFF and APRIL levels in the cerebrospinal fluid of patients with anti neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis. AB - Hypertrophic pachymeningitis (HP) is an inflammatory disorder involving intracranial or spinal thickened dura mater. It has been recognized that anti neutrophil cytoplasmic antibody (ANCA)-associated vasculitis may lead to HP; however, the immune-mediated pathogenesis of ANCA-related HP (ANCA-HP) remains elusive. In the present study, we analyzed B-cell activation factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) expression in the cerebrospinal fluid (CSF) and serum of patients with ANCA-HP, multiple sclerosis (MS), and non-inflammatory neurological disorders (NIND). BAFF and APRIL levels in the CSF were significantly higher in patients with ANCA-HP than in those with MS and NIND. In addition, a positive correlation between BAFF levels in the CSF and IgG-index was found in patients with ANCA-HP. On the other hand, no correlation was detected between CSF and serum levels of BAFF or APRIL. The results suggest that increased levels of BAFF and APRIL produced in the central nervous system may influence the development of ANCA-HP. PMID- 28847535 TI - Trends in employer postings for epidemiology jobs: an analysis of PublicHealthJobs.net data from 2003 to 2016. AB - PURPOSE: To analyze public health job posting data to help objectively inform epidemiology faculty and students about skills sought by employers. METHODS: Raw data from PublicHealthJobs.net database (January 2003-October 2016) was data mined and analyzed (n = 25,308 job postings). There were 3985 jobs that were classified with an epidemiology designation, either as the only designation or co occurring with another designation. Frequencies and percentages were calculated for job type, industry, location, degree requirements, CPH credential, and specialized skills. RESULTS: The majority of recent postings (January 2014 October 2016) were for full-time positions (60.8%). The highest proportion of recent job industries was education/academic/research (44.3%), state government (17.5%), and nonprofit/NGO (16.3%). A masters-level degree was listed in 71.4% of postings, frequently co-occurring with other degree levels. Epidemiology as the only job class was listed in 1765 postings (45.3%). Most characteristics of epidemiology job postings did not appreciably change over the time period, but there were some specialized skill differences. CONCLUSIONS: This analysis illustrates how employment sites can be used to identify employer preferences in epidemiology hires. There may be some skills that are beneficial additions to public health curricula or that job-seeking future epidemiologists may wish to enhance during their training. PMID- 28847536 TI - Long-Term Transplant-Free Survival After Repair of Total Anomalous Pulmonary Venous Connection. AB - BACKGROUND: Long-term survival, risk of transplantation, and causes of death after repair of total anomalous pulmonary venous connection (TAPVC) remain unknown. By linking the Pediatric Cardiac Care Consortium with the National Death Index and the United Network for Organ Sharing, we evaluated long-term transplant free survival in children undergoing repair of TAPVC. METHODS: We identified 777 infants within the Pediatric Cardiac Care Consortium who underwent TAPVC repair (median 21 days; interquartile range, 5 to 80) and had sufficient personal identifiers for linkage with the National Death Index and United Network for Organ Sharing. Sixty-six deaths, ten cardiac transplantations, and one bilateral lung transplantation had occurred by the end of 2014. Data collected included age and weight at time of procedure, TAPVC type, associated cardiac lesions, and postoperative length of stay. The study cohort was divided into simple and complex TAPVC based on the presence of an associated cardiac lesion. Parametric survival plots were constructed, and risk factor analyses were performed to identify demographic and clinical characteristics associated with long-term outcomes. RESULTS: Mortality or need for transplantation was 9.7% with a median follow-up of 18.4 years and a median age of death or transplant of 0.74 years. The risk of mortality and transplant after TAPVC repair was highest during the first 18 months after hospital discharge. Cardiac causes accounted for the majority of deaths. Multivariate regression models for transplant-free survival demonstrated that complex TAPVC, mixed TAPVC, and postoperative length of stay were associated with increased risk of death/transplant. CONCLUSIONS: Transplant free survival after TAPVC repair is excellent, with most deaths or transplant events occurring early. Factors associated with the worst long-term outcomes included complex TAPVC, mixed TAPVC, and prolonged postoperative length of stay. PMID- 28847537 TI - The Optimal Timing of Stage-2-Palliation After the Norwood Operation. AB - BACKGROUND: The effect of the timing of stage-2-palliation (S2P) on survival through single ventricle palliation remains unknown. This study investigated the optimal timing of S2P that minimizes pre-S2P attrition and maximizes post-S2P survival. METHODS: The Congenital Heart Surgeons' Society's critical left ventricular outflow tract obstruction cohort was used. Survival analysis was performed using multiphase parametric hazard analysis. Separate risk factors for death after the Norwood and after S2P were identified. Based on the multivariable models, infants were stratified as low, intermediate, or high risk. Cumulative 2 year, post-Norwood survival was predicted. Optimal timing was determined using conditional survival analysis and plotted as 2-year, post-Norwood survival versus age at S2P. RESULTS: A Norwood operation was performed in 534 neonates from 21 institutions. The S2P was performed in 71%, at a median age of 5.1 months (IQR: 4.3 to 6.0), and 22% died after Norwood. By 5 years after S2P, 10% of infants had died. For low- and intermediate-risk infants, performing S2P after age 3 months was associated with 89% +/- 3% and 82% +/- 3% 2-year survival, respectively. Undergoing an interval cardiac reoperation or moderate-severe right ventricular dysfunction before S2P were high-risk features. Among high-risk infants, 2-year survival was 63% +/- 5%, and even lower when S2P was performed before age 6 months. CONCLUSIONS: Performing S2P after age 3 months may optimize survival of low- and intermediate-risk infants. High-risk infants are unlikely to complete three-stage palliation, and early S2P may increase their risk of mortality. We infer that early referral for cardiac transplantation may increase their chance of survival. PMID- 28847538 TI - Novel Debate-Style Cardiothoracic Surgery Journal Club: Results of a Pilot Curriculum. AB - BACKGROUND: Traditional journal clubs addressing single articles are limited by the lack of a standardized process for conduct and evaluation. We developed a novel, debate-style journal club for trainees to use best available evidence to address controversial topics in cardiothoracic surgery through discussion of realistic patient scenarios. METHODS: After implementation of our new curriculum, trainee knowledge acquisition and retention were assessed by a summative test of published literature and standardized debate scoring. Feedback was additionally obtained by trainee and faculty surveys. RESULTS: Cardiothoracic surgery trainees (n = 4) participated in five debates each over 10 monthly sessions. Written examination results after debate revealed a nonsignificant improvement in scores on topics that were debated compared with topics that were not (+9.8% versus 4.2%, p = 0.105). Trainee ability to sway the debate position supported by the attendee strongly correlated with trainee use of supporting literature (r = 0.853), moderately correlated with persuasiveness (r = 0.465), and overall effect of the debate (r = 0.625). Surveys completed by trainees and faculty unanimously favored the debate-style journal club as compared to the traditional journal club in gaining familiarity and applying published literature to questions encountered clinically. CONCLUSIONS: Our novel debate-style cardiothoracic surgery journal club is an effective educational intervention for cardiothoracic surgery trainees to acquire, retain, and gain practice in applying specialty-specific literature based evidence to controversial case-based issues. Evaluation by multi institutional expansion is needed to validate our preliminary findings in this initial trainee cohort. PMID- 28847539 TI - Surgical Management of Esophageal Epiphrenic Diverticula: A Transthoracic Approach Over Four Decades. AB - BACKGROUND: Epiphrenic esophageal diverticula are infrequent. Although surgical treatment is generally recommended, technique varies widely and optimal management remains controversial. This study evaluated a single-institution experience for surgical treatment of epiphrenic diverticula. METHODS: A retrospective review was made of medical records of 31 patients undergoing surgical treatment for epiphrenic diverticula from 1974 to 2016. RESULTS: There were 17 men (55%); median age was 65 years. Dysphagia (87%) and regurgitation (71%) were the most common symptoms. Three patients (10%) presented acutely: 2 with ruptured diverticula and 1 with hematemesis. All patients underwent an open transthoracic approach. Diverticulectomy was performed in 28 patients (90%), myotomy in 28 (90%), and a concomitant antireflux procedure in 6 (19%). A total of 22 patients (71%) underwent diverticulectomy and myotomy, 4 (13%) underwent diverticulectomy with myotomy and antireflux procedure, 2 (6%) had myotomy and antireflux, 2 had diverticulectomy alone, and 1 patient had imbrication of the diverticulum after myotomy. Overall, morbidity occurred in 11 patients (35.5%), with major morbidity in 6 (19.4%). There was one postoperative esophageal leak (3%). Ninety-day mortality was zero. Mean follow-up was 30 +/- 43 months in 28 patients. Additional procedures (ie, reoperation, balloon dilation) were needed in 7 patients (25%). An excellent outcome (ie, absence of symptoms) was accomplished in 21 patients (75%). Acute presentation was associated with need for further procedures (p = 0.011) and symptoms at follow-up (p = 0.011). CONCLUSIONS: A tailored transthoracic approach to the surgical management of epiphrenic diverticula can provide excellent results. The need for a concomitant antireflux procedure remains controversial and may not be routinely necessary. Acute presentation is associated with poor functional outcome. PMID- 28847540 TI - A Challenging Treatment for Aortic Arch Aneurysm With Fenestrated Stent Graft. AB - BACKGROUND: The endovascular stent graft is a novel therapeutic technique that is used in the treatment of aortic aneurysms. However, the aortic arch is a still an area that requires endovascular repair. Since 2008, the authors have treated aortic arch aneurysms (AAA) in patients without an extraanatomical bypass using a fenestrated stent graft (FSG). This study aimed to evaluate the early outcomes of FSG treatment. METHODS: The authors retrospectively investigated the early outcomes of 54 AAA cases that were performed in their department from January 2008 to May 2016. The early results were analyzed retrospectively. RESULTS: The primary technical success rate was 100%. There were 2 operative deaths due to shower embolism and respiratory failure (2 of 54, 3.7%). Two patients suffered central nervous system injury (2 of 54, 3.7%) without remaining sequelae. At a mean follow-up period of 41.4 months, the survival rate was 75.0% and there were no aortic-related deaths. On follow-up, secondary intervention was necessary in 3 cases. The rate of freedom from secondary reintervention was 92.5%. CONCLUSIONS: Although further observation and prospective studies involving larger numbers of patients will be needed to validate this process, the outcomes of FSG treatment and our procedures were acceptable. This procedure has the potential to expand the indications for treatment in patients with AAA that are deemed to be suitable for this treatment. PMID- 28847542 TI - [Sexual activity in implantable cardioverter defibrillator patients included in cardiac rehabilitation]. AB - OBJECTIVES: To analyse the effects of a Cardiac Rehabilitation Program (CRP) on quality of life and sexual activity levels in patients with implantable cardioverter defibrillators (ICD). METHOD: A total of 25 patients (22 men and 3 women) were included in a study that consisted of the analysis of any defibrillator discharges, their repercussion on the couple, and the effects of CRP on physical and psychological aspects, and on sexual activity (SA). RESULTS: The mean age of the patients was 55years (22 to 79). Initially, fear for device discharges was present in all patients. On arrival, 14 patients (56%) did not have any SA: 2 with ages of 69 and 79years; one woman due to severe anxiety; an alcoholic man, and 10 because the ICD had been implanted less than 1 month before. Nine men and two women had restarted SA: 5 of them 5-52months after the implantation, and the other 6, 30days after implantation of the ICD while attending the CRP. At the end of the study, 21 patients had regained SA. Two men had clinical signs of depression and anxiety, with one requiring specialised treatment. Functional capacity improved significantly, 6.5+/-3.0METs at the beginning of the program and 9.2+/-3.3METs at the end, with a P<.005. There was only one inappropriate discharge. CONCLUSIONS: Discharges caused by newest devices have dropped significantly. This fact, together with the action of CRP at physical, psychological, and informative levels, makes it possible to control the dysfunctions in the quality of life and sexuality in patients. PMID- 28847543 TI - Homocysteine Biochemistry and Cognitive Decline in the Elderly. PMID- 28847541 TI - Inactivation of MarR gene homologs increases susceptibility to antimicrobials in Bacteroides fragilis. AB - Bacteroides fragilis is the strict anaerobic bacteria most commonly found in human infections, and has a high mortality rate. Among other virulence factors, the remarkable ability to acquire resistance to a variety of antimicrobial agents and to tolerate nanomolar concentrations of oxygen explains in part their success in causing infection and colonizing the mucosa. Much attention has been given to genes related to multiple drug resistance derived from plasmids, integrons or transposon, but such genes are also detected in chromosomal systems, like the mar (multiple antibiotic resistance) locus, that confer resistance to a range of drugs. Regulators like MarR, that control expression of the locus mar, also regulate resistance to organic solvents, disinfectants and oxygen reactive species are important players in these events. Strains derived from the parental strain 638R, with mutations in the genes hereby known as marRI (BF638R_3159) and marRII (BF638R_3706) were constructed by gene disruption using a suicide plasmid. Phenotypic response of the mutant strains to hydrogen peroxide, cell survival assay against exposure to oxygen, biofilm formation, resistance to bile salts and resistance to antibiotics was evaluated. The results showed that the mutant strains exhibit statistically significant differences in their response to oxygen stress, but no changes were observed in survival when exposed to bile salts. Biofilm formation was not affected by either gene disruption. Both mutant strains however, became more sensitive to multiple antimicrobial drugs tested. This indicates that as observed in other bacterial species, MarR are an important resistance mechanism in B. fragilis. PMID- 28847544 TI - Anatomical plaque and vessel characteristics are associated with hemodynamic indices including fractional flow reserve and coronary flow reserve: A prospective exploratory intravascular ultrasound analysis. AB - OBJECTIVES: To assess the relationship between anatomical form and physiological function in atherosclerotic coronary arteries. BACKGROUND: Although adverse cardiovascular events are predicted by plaque morphology or invasively-derived hemodynamic indices, the link between these important prognostic measures remains unexplored. METHODS: Patients with stable angina underwent fractional flow reserve (FFR), coronary flow reserve (CFR), pressure-derived collateral flow index (CFIp), trans-myocardial biomarker sampling and radiofrequency intravascular ultrasound (IVUS) imaging prior to intervention. Physiological ischemia was defined as either FFR<=0.8 or CFR<2.0. RESULTS: Mean FFR was 0.70+/ 0.15 and CFR was 2.1+/-1.3, with 68/92 lesions having FFR<=0.8 and 61/92 having CFR<2.0. On IVUS, FFR<=0.8 lesions had reduced minimal luminal area (MLA, p=0.03), increased plaque burden (PB, p=0.04) and volume (p=0.01). There was no relationship between FFR and IVUS-defined plaque composition. FFR<=0.8 was observed in 75.3%, 72.4% and 70.4% of lesions with MLA<=4mm2, PB>=70% and thin cap fibroatheroma, respectively. Multivariate regression demonstrated FFR<=0.8 was independently predicted by MLA (odds ratio (OR) 0.53, 95% CI 0.29-0.97, p=0.04) and PB (OR 1.10, 95% CI 1.01-1.21, p=0.03). There were no identifiable relationships between plaque structure and CFR or CFIp. CFR<2.0 was associated with whole vessel necrotic core increases (p=0.047), fibrofatty tissue reduction (p=0.004) and elevated baseline transmyocardial high-sensitivity C-reactive protein (hsCRP) gradients (p=0.02). CONCLUSIONS: Measures of plaque structure including PB and MLA are independently associated with FFR, but not with CFR or CFIp. Instead, vessels with low CFR have increased lipid accumulation and a higher transmyocardial hsCRP gradient. These results may explain similarities in clinical outcomes between physiologically and anatomically orientated trials. PMID- 28847545 TI - Cardiac 123I-mIBG scintigraphy is associated with freedom of appropriate ICD therapy in stable chronic heart failure patients. AB - AIM: Chronic heart failure (CHF) is a life-threatening clinical syndrome, partly due to sudden cardiac death (SCD). Implantable cardioverter defibrillators (ICD) for primary prevention of SCD have improved overall survival of CHF patients. However, a high percentage of patients never receives appropriate ICD therapy. This prospective multicentre study evaluated whether cardiac sympathetic activity assessed by 123I-mIBG scintigraphy could be helpful in selecting patients for ICD implantation. MATERIALS AND METHODS: 135 stable CHF subjects (age 64.5+/ 9.3years, 79% male, LVEF 25+/-6%) referred for prophylactic ICD implantation were enrolled in 13 institutions. All subjects underwent planar and SPECT 123I-mIBG scintigraphy. Early and late heart-to-mediastinum (H/M) ratio, 123I-mIBG washout (WO) and late summed scores were calculated. The primary endpoint was appropriate ICD therapy. The secondary endpoint was defined as the combined endpoint of all first cardiac events: appropriate ICD therapy, progression of heart failure (HF) and cardiac death. RESULTS: During a median follow-up of 30months (6-68months), 24 subjects (17.8%) experienced a first cardiac event (appropriate ICD therapy [12], HF progression [6], cardiac death [6]). Late H/M ratio and defect size of 123I-mIBG SPECT were not associated with appropriate ICD therapy. However, late H/M ratio was independently associated with the combined endpoint (HR 0.135 [0.035-0.517], p=0.001). Post-hoc analysis showed that the combination of late H/M ratio (HR 0.461 [0.281-0.757]) and LVEF (HR 1.052 [1.021-1.084]) was significantly associated with freedom of appropriate ICD therapy (p<0.001). CONCLUSION: 123I-mIBG scintigraphy seems to be helpful in selecting CHF subjects who might not benefit from ICD implantation. PMID- 28847546 TI - Mobile Health Technology for Atrial Fibrillation Management Integrating Decision Support, Education, and Patient Involvement: mAF App Trial. AB - BACKGROUND: Mobile Health technology for the management of patients with atrial fibrillation is unknown. METHODS: The simple mobile AF (mAF) App was designed to incorporate clinical decision-support tools (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age >=75 years, Diabetes Mellitus, Prior Stroke or TIA, Vascular disease, Age 65-74 years, Sex category], HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly], SAMe-TT2R2 [Sex, Age <60 years, Medical history, Treatment, Tobacco use, Race] scores), educational materials, and patient involvement strategies with self-care protocols and structured follow up. Patients with atrial fibrillation were randomized into 2 groups (mAF App vs usual care) in a cluster randomized design pilot study. Patients' knowledge, quality of life, drug adherence, and anticoagulation satisfaction were evaluated at baseline, 1 month, and 3 months. Usability, feasibility, and acceptability of the mAF App were assessed at 1 month. RESULTS: A total of 113 patients were randomized to mAF App intervention (mean age, 67.4 years; 57.5% were male; mean follow-up, 69 days), and 96 patients were randomized to usual care (mean age, 70.9 years; 55.2% were male; mean follow-up, 95 days). More than 90% of patients reported that the mAF App was easy, user-friendly, helpful, and associated with significant improvements in knowledge compared with the usual care arm (P values for trend <.05). Drug adherence and anticoagulant satisfaction were significantly better with the mAF App versus usual care (all P < .05). Quality of life scores were significantly increased in the mAF App arm versus usual care, with anxiety and depression reduced (all P < .05). CONCLUSIONS: The pilot mAFA Trial is the first prospective randomized trial of Mobile Health technology in patients with atrial fibrillation, demonstrating that the mAF App, integrating clinical decision support, education, and patient-involvement strategies, significantly improved knowledge, drug adherence, quality of life, and anticoagulation satisfaction. PMID- 28847547 TI - Assessment of Per-Endoscopic Placement of Fiducial Gold Markers for Small Peripheral Lung Nodules < 20 mm Before Stereotactic Radiation Therapy. AB - BACKGROUND: Stereotactic radiotherapy is used to treat peripheral lung cancer in inoperable patients. Placement of fiducial gold markers (FMs) is crucial for tracking small lesions that are not visible on chest radiographs. Our objective was to assess endoscopic FM placement in small peripheral lung nodules (PLNs) that are not trackable using automated tracking software. METHODS: All patients benefiting from virtual bronchoscopy and radial endobronchial ultrasonography (R EBUS)-guided placement of FMs for PLNs < 20 mm were included. After confirmation by biopsy sampling, a gold-seed FM was inserted into the nodule using a bronchial brush, without the use of fluoroscopy. The performance and complications of the procedure were recorded. RESULTS: From May 2010 to June 2015, FMs were placed in the PLNs of 54 consecutive patients, 34 of whom presented with a nodule < 20 mm. Seventy-six percent of the procedures were performed using local anesthesia on an outpatient basis. The median long- and short-axis diameters of nodules were 15 mm (9-20 mm) and 11 mm (6-20 mm), respectively, with 31 of 34 nodules exhibiting a short axis of < 15 mm. In 23 cases (79%), histologic samples were obtained during the procedure that allowed FM placement. Migration occurred in six cases, including two in the hours following the procedure. FMs were in place and visible on CT imaging performed 3 months after radiation therapy in 80% of cases. No complications were reported. CONCLUSIONS: Diagnosis of peripheral nodules < 20 mm and FM placement using R-EBUS are efficient and safe in a single procedure. PMID- 28847548 TI - Cholestatic Alterations in the Critically Ill: Some New Light on an Old Problem. AB - Liver dysfunction and jaundice are traditionally viewed as late features of sepsis and other critical illnesses and are associated with a complicated ICU stay. However, study results suggest that cholestatic alterations occur early in the course of critical illnesses, perceived only as minor abnormalities in routinely used biochemical liver tests. Inflammation-induced alterations in the transport of bile acids (BAs) appear to drive BAs and bilirubin toward the systemic circulation. Ongoing BA synthesis with an, at least partial, loss of feedback inhibition further contributes to elevated circulating BAs and bilirubin. To what extent these changes reflect a biochemical epiphenomenon, true illness-induced liver dysfunction, or a beneficial and adaptive response to illness should be investigated further. Because of the lack of specificity of standard laboratory tests, especially in the context of a complex systemic condition such as critical illness, identifying true cholestatic liver dysfunction remains a great challenge. However, high levels of cholestatic markers that are sustained in patients with prolonged critical illness almost always indicate a complicated illness course and should be monitored closely. Preventing cholestatic liver dysfunction comprises minimizing inflammation and hypoxia in the liver and preventing hyperglycemia, avoiding early use of parenteral nutrition, and reducing the administration of avoidable drugs. Future research on the effects of BAs and on modulating underlying drivers of cholestasis induced by critical illness is warranted as this could open perspectives for a targeted diagnostic approach and ultimately for novel therapies to improve outcome. PMID- 28847549 TI - Determinants of Unintentional Leaks During CPAP Treatment in OSA. AB - BACKGROUND: Unintentional leakage from the mouth or around the mask may lead to cessation of CPAP treatment; however, the causes of unintentional leaks are poorly understood. The objectives of this study were (1) to identify determining factors of unintentional leakage and (2) to determine the effect of the type of mask (nasal/oronasal) used on unintentional leakage. METHODS: Seventy-four polysomnograms from patients with OSA syndrome treated with auto-CPAP were analyzed (23 women; 56 +/- 13 years; BMI, 32.9 kg/m2 (range, 29.0-38.0 kg/m2). Polysomnographic recordings were obtained under auto-CPAP, and mandibular behavior was measured with a magnetic sensor. After sleep and respiratory scoring, polysomnographic signals were computed as mean values over nonoverlapping 10-s intervals. The presence/absence of unintentional leakage was dichotomized for each 10-s interval (yes/no). Univariate and multivariate conditional regression models estimated the risk of unintentional leaks during an interval "T" based on the explanatory variables from the previous interval "T-1." A sensitivity analysis for the type of mask was then conducted. RESULTS: The univariate analysis showed that mandibular lowering (mouth opening), a high level of CPAP, body position (other than supine), and rapid eye movement (REM) sleep increased the risk of unintentional leaks and microarousal decreased it. In the multivariate analysis, the same variables remained independently associated with an increased risk of unintentional leakage. The sensitivity analysis showed that oronasal masks reduced the risk of unintentional leaks in cases of mouth opening and REM sleep. CONCLUSIONS: Mouth opening, CPAP level, sleep position, and REM sleep independently contribute to unintentional leakage. These results provide a strong rationale for the definition of phenotypes and the individual management of leaks during CPAP treatment. PMID- 28847550 TI - Effect of Statins on COPD: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Much controversy persists regarding the place of statin drugs in the treatment of patients with COPD. This systematic review and meta-analysis sought to determine the clinical efficacy of statin therapy in COPD. METHODS: We searched MEDLINE, EMBASE, the Cochrane Database, and PubMed for relevant clinical studies. Randomized controlled trials (RCTs) comparing the effects of statin drugs with placebo in COPD populations were included. Pooled estimates were calculated using a random-effects model. Heterogeneity was determined using the I2 statistic. RESULTS: Ten trials with a total of 1,471 patients were included. Statin treatment was associated with a larger improvement in exercise capacity, lung function, and St. George's Respiratory Questionnaire score compared with placebo, but there were no statistically significant differences in inflammatory markers, all-cause mortality, and safety outcomes; however, subgroup analysis indicated that statin drugs improved clinical outcomes in the subjects from trials enrolling patients with overt cardiovascular disease (CVD), elevated baseline C-reactive protein levels, or a high cholesterol level. CONCLUSIONS: The findings from this systematic review suggest a role for statin drugs in patients with COPD and coexisting CVD, evidence of increased systemic inflammation, or hyperlipidemia with respect to improving exercise tolerance and pulmonary function. These findings need to be confirmed by RCTs specifically designed to test this hypothesis and identify appropriate patients for statin use. TRIAL REGISTRY: PROSPERO: CRD42017060594; https://www.crd.york.ac.uk/PROSPERO/. PMID- 28847551 TI - Multilevel Posterior Column Osteotomies Are Not Inferior For the Correction of Rigid Adult Spinal Deformity Compared with Pedicle Subtraction Osteotomy. AB - BACKGROUND: Posterior column osteotomy (PCO) has been used for the correction of various spinal deformities. However, little evidence is available regarding the effects of multilevel PCO in adult spinal deformity (ASD) surgery. This study aimed to show the usefulness of PCO in rigid ASD surgery by assessing radiographic and clinical outcomes. We also aimed to assess the corrective potential of multilevel PCOs compared with a single-level pedicle subtraction osteotomy (PSO). METHODS: Between 2012 and 2016, the medical records of 70 consecutive patients who underwent a multilevel PCO (35 patients) or a single level PSO (35 patients) for ASD in a single institute were reviewed. Baseline data, radiographic measurements, and clinical outcomes using the Scoliosis Research Society-22 (SRS-22) questionnaire were compared between groups. RESULTS: The following variables were no different between the groups: age at surgery, sex, level fused, preoperative and postoperative radiologic parameters, and bone mineral density T score. However, operation time (380.0 vs. 483.6 minutes), estimated blood loss (1175.7 vs. 1362.6 mL), and the number of complications (8 vs. 20) were significantly reduced in the PCO group compared with the PSO group. A significant improvement in the SRS-22 score was seen in both groups after surgery, although no difference was observed between the groups postoperatively. CONCLUSIONS: Multilevel PCOs for the correction of rigid ASD were slightly superior to PSO, regarding clinical outcomes. Radiographic outcomes were similar between groups. Thus, multilevel PCOs may be a viable option for the treatment of rigid ASD with a mobile segment. PMID- 28847552 TI - Prognostic Impact of Health Care-Associated Meningitis in Adults with Intracranial Hemorrhage. AB - BACKGROUND: Health care-associated meningitis and ventriculitis (HCAMV) occurs in adults with intracranial hemorrhage (ICH) and is associated with high rates of morbidity and mortality, but the prognostic impact of this infectious complication in a controlled matched study of ICH is unknown. METHODS: We conducted a case-control study of adult patients with ICH and HCAMV at a large tertiary care hospital in Houston, Texas, from 2003 to 2016. Cases were defined as patients with ICH and HCAMV as documented by a positive cerebrospinal fluid culture. Controls were defined as patients with ICH without evidence of HCAMV. An adverse clinical outcome was defined as a Glasgow Outcome Scale score of <=4. RESULTS: This study included 120 patients with ICH; 40 patients also had HCAMV, whereas 80 patients had ICH with no evidence of HCAMV. Cases and controls were appropriately matched by age, Glasgow Coma Scale score, and Acute Physiology and Chronic Health Evaluation II score (P > 0.05). Patients with ICH and meningitis had more comorbidities, higher rates of abnormal neurologic examination, hypoglycorrhachia, and elevated cerebrospinal fluid lactate levels (P < 0.05). Adverse clinical outcomes were greater in patients with HCAMV and ICH than in patients with ICH alone (83% vs. 30%; P < 0.001). On logistic regression analysis, independent risk factors associated with an adverse outcome were HCAMV and mechanical ventilation (P < 0.05). CONCLUSIONS: HCAMV has a significant prognostic impact in adults with ICH. PMID- 28847553 TI - Delayed Catheter-Related Intracranial Hemorrhage After a Ventriculoperitoneal or Ventriculoatrial Shunt in Hydrocephalus. AB - OBJECTIVE: Delayed catheter-related intracranial hemorrhage is not rare after a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt for the treatment of hydrocephalus. Immediate postoperative catheter-related intracranial hemorrhage is possibly due to the procedure itself; however, delayed intracranial hemorrhage may have other underlying mechanisms. This study aimed to investigate the clinical characteristics and reveal the risk factors of delayed catheter-related intracranial hemorrhage after a VP or VA shunt. METHODS: We did a retrospective study to review patients with hydrocephalus and underwent VP or VA shunt in our department from September 2011 to December 2015. We reviewed the clinical characteristics of the patients with delayed catheter-related intracranial hemorrhage, and its risk factors were analyzed with SPSS 16.0. RESULTS: Of the 218 patients enrolled in the study (145 male, 73 female), 17 (7.8%) patients experienced delayed catheter-related intracranial hemorrhage, including 11 of 151 (7.3%) patients with a VP shunt and 6 of 67 (9.0%) patients with a VA shunt. Additionally, 4 of the 16 patients with postoperative low-molecular-weight heparin (LMWH) therapy and 13 of the 202 patients without LMWH experienced bleeding, showing a significant difference (25% vs. 6.4%, P = 0.026). The relative risk was 4.8 (95% confidence interval: 1.4-17.1). CONCLUSION: Delayed catheter-related intracranial hemorrhage is not rare after a VP or VA shunt. However, most patients can be cured after appropriate treatment. Postoperative anticoagulation therapy with enoxaparin may be associated with an increased risk of bleeding. PMID- 28847554 TI - Candida Meningitis After Transsphenoidal Surgery: A Single-Institution Case Series and Literature Review. AB - Candida meningitis after neurosurgical procedures is a rare but potentially devastating complication. The presentation of meningitis can be insidious in immunosuppressed patients and thus can be easily overlooked. Cerebrospinal fluid studies often resemble bacterial profiles, and cultures can be falsely negative. Candida albicans is the most common species identified in postsurgical Candida meningitis, and delay in diagnosis and treatment can be devastating. The standard induction therapy for Candida meningitis has been amphotericin B combined with flucytosine. A high index of suspicion is needed in any patient with risk factors such as abdominal surgery, bowel perforation, recent broad spectrum antibiotic therapy, intravenous drug use, extremes of age, indwelling catheters, and immunosuppression such as AIDS, malignancy, antineoplastic therapy, and steroid use. Here, we describe 3 case presentations of patients with giant skull base tumors who developed postsurgical Candida meningitis, each with vastly different clinical courses and outcomes, ranging from benign to catastrophic. We performed a literature review with special focus on common risk factors, Candida species, diagnostic criteria, and treatment. PMID- 28847555 TI - Mechanisms, Treatment, and Patient Outcome of Iatrogenic Injury to the Brachial Plexus-A Retrospective Single-Center Study. AB - BACKGROUND: Injury to the brachial plexus is a devastating condition, with severe impairment of upper extremity function resulting in distinct disability. There are no systematic reports on epidemiology, causative mechanisms, treatment strategies. or outcomes of iatrogenic brachial plexus injury (iBPI). METHODS: We screened all cases of iatrogenic nerve injuries recorded between 2007 and 2017 at a single specialized institution. Mechanism of iBPI, type of previous causative intervention, location and type of the lesion as well as the type of revision surgery and functional patient outcome were analyzed. RESULTS: We identified 14 cases of iBPI, which all presented with significant impairment of upper extremity motor function (at least 1 muscle Medical Research Council grade 0). Neuropathic pain was present in most patients (11/14). Orthopedic shoulder procedures such as rotator cuff fixation, arthroplasty, and repositioning of a clavicle fracture accounted for iBPI in 7 of 14 patients. Other reasons for iBPI were resection or biopsy of a peripheral nerve sheath tumor in 3 patients or lymph node situated at the cervicomediastinal area in 2 patients. Mechanisms also included transaxillary rib resection in one and sternotomy in another patient. The treatment of iBPI was conducted according to each individual's needs and included neurolysis in 4, nerve grafting in 9, and nerve transfers in 1 patient. We found improved symptoms after treatment in most patients (11/14). CONCLUSIONS: Most common causes for iBPI were shoulder surgery and resection or biopsy of peripheral nerve sheath tumor and lymph nodes. Early referral to specialized peripheral nerve centers may help to improve functional patient outcome. PMID- 28847556 TI - Surgical Treatment of Cavernous Malformations Involving the Midbrain: A Single Center Case Series of 34 Patients. AB - BACKGROUND: Cavernous malformations (CMs) involving the midbrain are more challenging for surgical treatment than are CMs at other sites because of the surrounding critical structures and deep location. However, specific features and treatment strategies have not been well illustrated. OBJECTIVE: To evaluate the long-term durability of surgical treatment of midbrain CMs (MBCMs) as well as surgical outcomes and complications. METHODS: A retrospective study was conducted in 34 patients who underwent microsurgical resection of MBCMs between 1995 and 2015. Demographics, lesion characteristics, surgical approaches, surgical outcomes, and complications were analyzed. RESULTS: A total of 34 adult patients with a mean age of 38.6 years were assessed. All patients presented with a history of hemorrhage. Lesion locations included the midbrain (n = 27), midbrain and thalamus (n = 2), and pontomesencephalic junction (n = 5). Mean lesion size was 1.7 cm; average clinical follow-up was 5.6 years. Mean modified Rankin Scale (mRS) scores on admission, at discharge, and at last follow-up were 2.0, 2.7, and 1.7, respectively. Postoperatively, 19 patients (55.9%) showed new or worsened neurologic deficits. Multivariate analysis showed that admission mRS score (>=3) was an independent predictor of poor functional outcome (odds ratio, 50.832; 95% confidence interval, 2.967-901.283; P = 0.007). No rehemorrhage or recurrence case was found during the follow-up period. CONCLUSIONS: Although surgery for MBCMs is associated with significant perioperative morbidity and mortality, most patients show favorable outcomes. Higher preoperative mRS score is an independent predictor of poor functional outcome. PMID- 28847557 TI - Hybrid Bone SPECT/CT Imaging in Evaluation of Chronic Low Back Pain: Correlation with Facet Joint Arthropathy. AB - BACKGROUND: Evidence to support the use of bone hydroxydiphosphonate (HDP) single photon emission computed tomography (SPECT/CT) in patients with facetogenic low back pain (LBP) is still limited. In this study we compared the scintigraphic patterns on bone SPECT/CT with the degree of structural facet joint (FJ) degeneration on CT in patients with LBP. METHODS: Ninety-nine consecutive patients with LBP were prospectively evaluated. Patients with known or suspected malignancy, trauma, infectious processes, chronic inflammatory diseases, and previous surgery were excluded. The effect of LBP on the daily quality of life was assessed with the Oswestry disability index (ODI). The Pathria grading system was used to score FJ degeneration on CT scans. The correlation between the degree of FJ degeneration and osteoblastic activity on SPECT/CT was analyzed with Kappa statistics. RESULTS: Ninety-nine patients were included (59 female, mean age 56.2 years). The mean ODI score was 38.5% (range, 8% to 72%). In all, 792 FJ (L2-3 to L5-S1) were examined. Of the FJs, 49.6% were Pathria grade 0-1 (normal to mild degeneration) on CT, 35% were grade 2 (moderate degeneration), and 16% were grade 3 (severe degeneration). Sixty-seven percent of the patients had scintigraphically active FJs on SPECT/CT. Sixty-nine percent of Pathria grade 3 FJs were scintigraphically active; 5.5% and 16.8% of Pathria grade 0-1 and Pathria grade 2, respectively, were active. Of the metabolically active FJs, 71.4% were at the L4-5/L5-S1 levels. CONCLUSIONS: The ability of SPECT/CT to precisely localize scintigraphically active FJs may provide significant improvement in the diagnosis and treatment of patients with LBP. In this study we demonstrate that in >40% of FJs, the scintigraphic patterns on SPECT/CT did not correlate with the degree of degeneration on CT. PMID- 28847558 TI - Strain Rate and Its Positive Force-Frequency Relationship: Further Evidence from a Premature Infant Cohort. PMID- 28847559 TI - Authors' Reply. PMID- 28847560 TI - Author's Reply. PMID- 28847561 TI - Non-canonical function of Tat in regulating host microtubule dynamics: Implications for the pathogenesis of lentiviral infections. AB - Lentiviruses are a class of genetically unique retroviruses that share similar features, despite their wide variety of host species. Transactivator of transcription (Tat) proteins of lentiviruses are critical for the regulation of viral transcription and replication. Recent studies demonstrate that in addition to mediating transactivation, Tat binds to the microtubule cytoskeleton of the host cell and interferes with microtubule dynamics, ultimately triggering apoptosis. This non-canonical function of Tat appears to be critical for the pathogenesis of lentiviral diseases, such as acquired immunodeficiency syndrome. Here, we compare the structure and activity of Tat proteins from three different types of lentiviruses, focusing on the roles of these proteins in the alteration of host microtubule dynamics and induction of apoptosis. We propose that further investigation of the Tat-microtubule interaction will provide important insight into the process of lentiviral pathogenesis and elucidate new avenues for the development of antiviral therapies. PMID- 28847563 TI - Simultaneous detection of three lily viruses using Triplex IC-RT-PCR. AB - Viruses commonly infecting lily (Lilium spp.) include: Lily symptomless virus (LSV), Cucumber mosaic virus (CMV) and Lily mottle virus (LMoV). These viruses usually co-infect lilies causing severe economic losses in terms of quantity and quality of flower and bulb production around the world. Reliable and precise detection systems need to be developed for virus identification. We describe the development of a triplex immunocapture (IC) reverse transcription (RT) polymerase chain reaction (PCR) assay for the simultaneous detection of LSV, CMV and LMoV. The triplex IC-RT-PCR was compared with a quadruplex RT-PCR assay. Relative to the quadruplex RT-PCR, the specificity of the triplex IC-RT-PCR system for LSV, CMV and LMoV was 100% for field samples. The sensitivity of the triplex IC-RT-PCR system was 99.4%, 81.4% and 98.7% for LSV, CMV and LMoV, respectively. Agreement (kappa) between the results obtained from the two tests was 0.968, 0.844 and 0.984 for LSV, CMV and LMoV, respectively. This is the first report of the simultaneous detection of LSV, CMV and LMoV in a triplex IC-RT-PCR assay. In particular we believe this convenient and reliable triplex IC-RT-PCR method could be used routinely for large-scale field surveys or crop health monitoring of lily. PMID- 28847564 TI - Binary components of food reinforcement: Amplitude and persistence. AB - BACKGROUND: Demand curves provide an index of how reinforcing a food is. Research examining the latent structure of alcohol and tobacco reinforcement identified two underlying components of reinforcement, amplitude and persistence. No research has assessed latent structure of food reinforcement and how these factors are related to BMI. SUBJECTS AND METHODS: Participants were 297 adults from two studies that completed food purchasing tasks to assess the following measures of relative reinforcing efficacy (RRE) of food: intensity (Q0): purchases made when the food was free or of very minimal price, Omax: maximum expenditure (purchases*price), Pmax: price point where maximum expenditure was observed, breakpoint: first price where 0 purchases are made, and demand elasticity (alpha): quantitative non-linear relationship between purchasing and price. Principal components analysis was used to examine the factor structure of RRE for food across samples and types of food. RESULTS: Both studies revealed two factor solutions, with Pmax, Omax, breakpoint and alpha loading on factor 1 (persistence) and intensity (Q0) loading on factor 2 (amplitude) across both high and low energy dense foods. Persistence reflects an aggregate measure of price sensitivity and amplitude reflects the preferred volume of consumption (how long vs. how much). The two factors accounted for between 91.7 and 95.4% of the variance in food reinforcement. Intensity for high energy dense foods predicted BMI for both studies (r = 0.18 and r = 0.22, p's < 0.05). CONCLUSIONS: The latent factor structure was similar across two significantly different independent samples and across low and high energy dense snack foods. In addition, the amplitude of the demand curve, but not persistence, was related to BMI. These results suggest specific aspects of food reinforcement that can be targeted to alter food intake. PMID- 28847562 TI - Cannabis use during pregnancy: Pharmacokinetics and effects on child development. AB - The broad-based legalization of cannabis use has created a strong need to understand its impact on human health and behavior. The risks that may be associated with cannabis use, particularly for sensitive subgroups such as pregnant women, are difficult to define because of a paucity of dose-response data and the recent increase in cannabis potency. Although there is a large body of evidence detailing the mode of action of Delta9-tetrahydrocannabinol (THC) in adults, little work has focused on understanding how cannabis use during pregnancy may impact the development of the fetal nervous system and whether additional plant-derived cannabinoids might participate. This manuscript presents an overview of the historical and contemporary literature focused on the mode of action of THC in the developing brain, comparative pharmacokinetics in both pregnant and nonpregnant model systems and neurodevelopmental outcomes in exposed offspring. Despite growing public health significance, pharmacokinetic studies of THC have focused on nonpregnant adult subjects and there are few published reports on disposition parameters during pregnancy. Data from preclinical species show that THC readily crosses the placenta although fetal exposures appear lower than maternal exposures. The neurodevelopmental data in humans and animals suggest that prenatal exposure to THC may lead to subtle, persistent changes in targeted aspects of higher-level cognition and psychological well-being. There is an urgent need for well-controlled studies in humans and preclinical models on THC as a developmental neurotoxicant. Until more information is available, pregnant women should not assume that using cannabis during pregnancy is safe. PMID- 28847565 TI - What does a person's eating identity add to environmental influences on fruit and vegetable intake? AB - OBJECTIVE: To evaluate whether knowledge of a person's eating identity (EI) can explain any additional variation in fruit and vegetable intake above and beyond that explained by food environment characteristics, perceptions of the food environment, and shopping behaviors. DESIGN: Cross-sectional study. SETTING: A total of 968 adults were recruited for a telephone survey by the Survey Research Laboratory in an eight-county region in South Carolina. SUBJECTS: The survey queried information on shopping behaviors, perceptions of the food environment, demographic and address information, fruit and vegetable intake, and EI. EI was assessed using the Eating Identity Type Inventory, a 12-item instrument that differentiates four eating identity types: healthy, emotional, meat, and picky. Statistical analyses were restricted to 819 participants with complete data. RESULTS: Healthy EI and picky EI were significantly and directly related to fruit and vegetable intake, with coefficients of 0.31 (p-value<0.001) for healthy EI and -0.16 (p-value<0.001) for picky EI, whereas emotional EI (beta = 0.00, p value = 0.905) and meat EI (beta = -0.04, p-value = 0.258) showed no association. Shopping frequency also directly and significantly influenced fruit and vegetable intake (beta = 0.13, p-value = 0.033). With the inclusion of EI, 16.3% of the variation in fruit and vegetable intake was explained. CONCLUSIONS: Perceptions and GIS-based measures of environmental factors alone do not explain a substantial amount of variation in fruit and vegetable intake. EI, especially healthy EI and picky EI, is an important, independent predictor of fruit and vegetable intake and contributes significantly to explaining the variation in fruit and vegetable intake. PMID- 28847567 TI - Continues administration of Nano-PSO significantly increased survival of genetic CJD mice. AB - We have shown previously that Nano-PSO, a nanodroplet formulation of pomegranate seed oil, delayed progression of neurodegeneration signs when administered for a designated period of time to TgMHu2ME199K mice, modeling for genetic prion disease. In the present work, we treated these mice with a self-emulsion formulation of Nano-PSO or a parallel Soybean oil formulation from their day of birth until a terminal disease stage. We found that long term Nano-PSO administration resulted in increased survival of TgMHu2ME199K lines by several months. Interestingly, initiation of treatment at day 1 had no clinical advantage over initiation at day 70, however cessation of treatment at 9months of age resulted in the rapid loss of the beneficial clinical effect. Pathological studies revealed that treatment with Nano-PSO resulted in the reduction of GAG accumulation and lipid oxidation, indicating a strong neuroprotective effect. Contrarily, the clinical effect of Nano-PSO did not correlate with reduction in the levels of disease related PrP, the main prion marker. We conclude that long term administration of Nano-PSO is safe and may be effective in the prevention/delay of onset of neurodegenerative conditions such as genetic CJD. PMID- 28847568 TI - MicroRNA-124 alleviates chronic skin inflammation in atopic eczema via suppressing innate immune responses in keratinocytes. AB - Chronic skin inflammation in atopic eczema is associated with elevated expression of proinflammatory genes and activation of innate immune responses in keratinocytes. MicroRNAs (miRNAs) are short, single-stranded RNA molecules that silence genes via the degradation of target mRNAs or inhibition of translation. Recent studies have demonstrated that miR-124 is associated with regulation of inflammation factors in several diseases. The aim of this study was to investigate the role of miR-124 in skin inflammation of atopic eczema. We showed that miR-124 expression is decreased in chronic lesional skin of patients with atopic eczema, and could be strongly inhibited by IFN-gamma and TNF-alpha. Through Western blot, real-time PCR and luciferase assays, we revealed that miR 124 inhibited the expression of p65, a member of NF-kappaB family which can regulate many factors involved in the immune response and inflammatory reactions, through direct targeting. Further, upon IFN-gamma or TNF-alpha stimulation, IL8, CCL5 and CCL8 showed to be significantly upregulated by IFN-gamma or TNF-alpha, downregulated by miR-124; the promotive effect of IFN-gamma and TNF-alpha could be partially reversed by miR-124. The levels of IL8, CCL5 and CCL8 could be significantly downregulated by p65 knockdown, upregulated by miR-124 inhibition; the suppressive effect of p65 knockdown could be partially reversed by miR-124. Moreover, contrary to miR-124, p65, IL8, CCL5 and CCL8 mRNA expression was upregulated in chronic lesional skin of patients with atopic eczema, and all inversely correlated with miR-124. Taken together, our data demonstrate that miR 124 controls NF-kappaB-dependent inflammatory responses in keratinocytes and chronic skin inflammation in atopic eczema; rescuing miR-124 expression presents a promising strategy for atopic eczema treatment. PMID- 28847569 TI - NeuronRead, an open source semi-automated tool for morphometric analysis of phase contrast and fluorescence neuronal images. AB - Neurons are specialized cells of the Central Nervous System whose function is intricately related to the neuritic network they develop to transmit information. Morphological evaluation of this network and other neuronal structures is required to establish relationships between neuronal morphology and function, and may allow monitoring physiological and pathophysiologic alterations. Fluorescence based microphotographs are the most widely used in cellular bioimaging, but phase contrast (PhC) microphotographs are easier to obtain, more affordable, and do not require invasive, complicated and disruptive techniques. Despite the various freeware tools available for fluorescence-based images analysis, few exist that can tackle the more elusive and harder-to-analyze PhC images. To surpass this, an interactive semi-automated image processing workflow was developed to easily extract relevant information (e.g. total neuritic length, average cell body area) from both PhC and fluorescence neuronal images. This workflow, named 'NeuronRead', was developed in the form of an ImageJ macro. Its robustness and adaptability were tested and validated on rat cortical primary neurons under control and differentiation inhibitory conditions. Validation included a comparison to manual determinations and to a golden standard freeware tool for fluorescence image analysis. NeuronRead was subsequently applied to PhC images of neurons at distinct differentiation days and exposed or not to DAPT, a pharmacological inhibitor of the gamma-secretase enzyme, which cleaves the well known Alzheimer's amyloid precursor protein (APP) and the Notch receptor. Data obtained confirms a neuritogenic regulatory role for gamma-secretase products and validates NeuronRead as a time- and cost-effective useful monitoring tool. PMID- 28847566 TI - Modulation of mitochondrial dysfunction and endoplasmic reticulum stress are key mechanisms for the wide-ranging actions of epoxy fatty acids and soluble epoxide hydrolase inhibitors. AB - The arachidonic acid cascade is arguably the most widely known biologic regulatory pathway. Decades after the seminal discoveries involving its cyclooxygenase and lipoxygenase branches, studies of this cascade remain an active area of research. The third and less widely known branch, the cytochrome P450 pathway leads to highly active oxygenated lipid mediators, epoxy fatty acids (EpFAs) and hydroxyeicosatetraenoic acids (HETEs), which are of similar potency to prostanoids and leukotrienes. Unlike the COX and LOX branches, no pharmaceuticals currently are marketed targeting the P450 branch. However, data support therapeutic benefits from modulating these regulatory lipid mediators. This is being approached by stabilizing or mimicking the EpFAs or even by altering the diet. These approaches lead to predominantly beneficial effects on a wide range of apparently unrelated states resulting in an enigma of how this small group of natural chemical mediators can have such diverse effects. EpFAs are degraded by soluble epoxide hydrolase (sEH) and stabilized by inhibiting this enzyme. In this review, we focus on interconnected aspects of reported mechanisms of action of EpFAs and inhibitors of soluble epoxide hydrolase (sEHI). The sEHI and EpFAs are commonly reported to maintain homeostasis under pathological conditions while remaining neutral under normal physiological conditions. Here we provide a conceptual framework for the unique and broad range of biological activities ascribed to epoxy fatty acids. We argue that their mechanism of action pivots on their ability to prevent mitochondrial dysfunction, to reduce subsequent ROS formation and to block resulting cellular signaling cascades, primarily the endoplasmic reticulum stress. By stabilizing the mitochondrial - ROS - ER stress axis, the range of activity of EpFAs and sEHI display an overlap with the disease conditions including diabetes, fibrosis, chronic pain, cardiovascular and neurodegenerative diseases, for which the above outlined mechanisms play key roles. PMID- 28847570 TI - The interaction of l-cysteine/H2S pathway and muscarinic acetylcholine receptors (mAChRs) in mouse corpus cavernosum. AB - The aim of this study was to investigate the possible interaction of l cysteine/H2S pathway and muscarinic acetylcholine receptors (mAChRs) in the mouse corpus cavernosum (CC). l-cysteine (endogenous H2S substrate; 10-6-10-3 M), sodium hydrogen sulfide (NaHS; exogenous H2S; 10-6-10-3 M) and acetylcholine (10 9-10-4 M) produced concentration-dependent relaxation in isolated mouse CC tissues. Relaxations to endogenous and exogenous H2S were reduced by non selective mAChR antagonist atropine (5 * 10-5 M), selective M1 mAChR antagonist pirenzepine (5 * 10-5 M) and selective M3 mAChR antagonist 4-DAMP (10-7 M) but not by selective M2 mAChR antagonist AF-DX 116 (10-6 M). Also, acetylcholine induced relaxations were reduced by atropine, pirenzepine, 4-DAMP and AF-DX 116, confirming the selective effects of mAChR antagonists. Furthermore, acetylcholine induced relaxations were attenuated by cystathionine-gamma-lyase (CSE) inhibitor d,l-propargylglycine (PAG, 10-2 M) and cystathionine-beta-synthase inhibitor (CBS) aminooxyacetic acid (AOAA, 10-3 M). l-nitroarginine, nitric oxide synthase inhibitor, augmented the inhibitory effects of mAChR antagonists and H2S enzyme inhibitors on acetylcholine-induced relaxations. In addition, the existence and localization of CSE, CBS and 3-MST were demonstrated in mouse CC. Furthermore, tissue acetylcholine release was significantly increased by l-cysteine but not by exogenous H2S. The increase in acetylcholine level was completely inhibited by AOAA and PAG. These results suggest that M1 and M3 mAChRs contributes to relaxant effect mediated by endogenous H2S but at same time l-cysteine triggers acetylcholine release from cavernosal tissue. Also, the role of NO in the interaction of l-cysteine/H2S pathway and muscarinic acetylcholine receptors (mAChRs) could not be excluded. PMID- 28847571 TI - The impact of tailored intervention services on charges and mortality for adult super-utilizers. AB - BACKGROUND: Interventions designed to improve care and reduce costs for patients with the highest rates of hospital utilization (super-utilizers) continue to proliferate, despite conflicting evidence of cost savings. METHODS: We evaluated a practice transformation intervention that implemented team-based care and risk stratification to match specific primary care resources based on need. This included an intensive outpatient clinic for super-utilizers. We used multivariate regression and a difference-in-differences approach to compare changes in mortality, utilization, and charges between the intervention group and a historical control. Sensitivity analyses tested the robustness of findings and revealed the inherent challenges associated with quasi-experimental designs. RESULTS: Observed charges for the intervention group were significantly lower than expected charges as derived by the trend of the historical control (p<0.04) resulting in total charge avoidance of approximately $26 million. While inpatient admissions were significantly higher (p<0.01), charges associated with total inpatient (p=0.01), intensive-care unit (p<0.05, not robust to sensitivity analyses), and surgery (p<0.01) were significantly lower than expected in the intervention group. One year mortality was significantly less in the intervention group (12.6% vs 11.5%, p<0.01). CONCLUSIONS: The use of tailored services, including a dedicated intensive outpatient clinic, for super-utilizers within a larger primary care practice transformation reduced mortality and provided significant savings, even while total hospitalizations increased. These savings were achieved through a reduction in the intensity of inpatient services. The unexpected finding of a reduction in ICU charges deserves further exploration. IMPLICATIONS: These findings suggest that intensity of inpatient service, and not merely volume of services, should be considered a focus for future intervention design and evaluated as an outcome. LEVEL OF EVIDENCE: Level III (Quasi Experimental Design). PMID- 28847573 TI - Long Head of Biceps Tendon Pathology and Results of Tenotomy in Full-Thickness Reparable Rotator Cuff Tear. AB - PURPOSE: To document the incidence of long head of the biceps tendon (LHBT) pathology in full-thickness reparable rotator cuff tears and report the clinical results of arthroscopic LHBT tenotomy combined with rotator cuff repair. METHODS: Between January 2012 and January 2014, 141 shoulders with full-thickness rotator cuff tears that had undergone arthroscopic repair were included for the analysis. The LHBT was thoroughly examined during arthroscopy, and tenotomy was performed in all patients with a pathologic LHBT. Shoulder range of movement and the Constant score were recorded at an average follow-up of 2.2 years (range, 24-40 months). RESULTS: The overall incidence of LHBT pathology was 36.1% (51 of 141 shoulders). The increase in LHBT pathology with the increase in the size of the rotator cuff tear was statistically significant (P = .001). Tears involving the subscapularis had a statistically significantly higher incidence of LHBT pathology (P = .001). The duration of the rotator cuff tear showed no statistical significance regarding the incidence of LHBT pathology (P = .598). Of 141 patients with full-thickness rotator cuff tears, 89 had tears due to trauma and 52 had atraumatic tears. The difference in the incidence of LHBT pathology between the traumatic and atraumatic groups was not statistically significant (P = .412). The average Constant score in the patients who had undergone LHBT tenotomy was 82 (range, 70-90), and in those with normal tendons, it was 84 (range, 72-92). The difference was not statistically significant (P = .423). CONCLUSIONS: About one-third of patients with full-thickness reparable rotator cuff tears are likely to have LHBT pathology. Large and massive rotator cuff tears and tears involving the subscapularis are more likely to have LHBT pathology. Tenotomy of the pathologic LHBT as an adjunct to rotator cuff repair produces satisfactory results. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28847574 TI - The Tibial Tubercle-to-Trochlear Groove Distance Is Reliable in the Setting of Trochlear Dysplasia, and Superior to the Tibial Tubercle-to-Posterior Cruciate Ligament Distance When Evaluating Coronal Malalignment in Patellofemoral Instability. AB - PURPOSE: To determine best practices for consistent and accurate evaluation of coronal alignment in patients with patellofemoral (PF) instability. METHODS: Six reviewers examined 239 knee magnetic resonance images (MRIs) in patients with PF instability and anterior cruciate ligament (ACL) rupture. Measurements included tibial tubercle-to-trochlear groove (TT-TG) distance measured at the most proximal and distal portions of the trochlea, tibial tubercle-to-PCL (TT-PCL) distance, and Dejour classification of trochlear dysplasia. RESULTS: Interrater reliability was low for Dejour classification (k = 0.289), but improved to moderate (k = 0.448) when patients were separated into normal/Dejour A and Dejour B/C/D. Interrater reliability was high for proximal and distal TT-TG measurements (interclass correlation coefficients [ICCs] = 0.807 and 0.936, respectively). TT PCL was moderately reliable (ICC = 0.625), and correlated with TT-TG (r = 0.457, P < .001 proximal and r = 0.451, P < .001 distal). No significant difference was found between the proximal and distal measurements of TT-TG in each patient, though the PF group exhibited higher values than the ACL group (P < .001 for both). TT-PCL was significantly higher for the PF group than the ACL group (P = .015), but this difference lost significance when the group was divided by the TT PCL cutoff of 24 mm (P = .371). CONCLUSIONS: The proximal and distal techniques for measuring the TT-TG distance are similar to each other, and reliable despite level of reviewer training or presence of dysplasia. The TT-TG distance was predictive of patellofemoral instability. The TT-PCL distance was found to be less reliable than either method of measuring the TT-TG distance. Thus, this study demonstrated TT-TG to be superior to TT-PCL as a measurement of coronal malalignment. Given the variability in Dejour classification in this and other studies, a more reliable classification system for trochlear dysplasia as defined on cross-sectional imaging is warranted. LEVEL OF EVIDENCE: Level III, retrospective clinical trial. PMID- 28847572 TI - Change in Anterior Cruciate Ligament Graft Choice and Outcomes Over Time. AB - PURPOSE: To analyze failure rate in 2-year increments to determine if graft choice changed over time and graft failure rate. METHODS: A prospective 2002-2008 database was used to identify risk factors for anterior cruciate ligament (ACL) retear. Subjects who had primary ACL retear with no history of contralateral surgery and 2-year follow-up were included. Subjects who underwent a multiligament reconstruction were excluded. Graft type, age, sex, smoking status, body mass index, Marx activity level at index surgery, medial and lateral meniscus status at time of ACL retear, sport played after ACL reconstruction, and clinical site were evaluated. Analysis was repeated using 2002-2003 (early) and 2007-2008 (late) 2-year databases. Analysis of variance with post hoc analysis was performed to detect significant differences in age and Marx score by graft type over time. RESULTS: Two-year follow-up for graft failure was obtained on 2,497 of 2,692 (93%) subjects. There were 112 of 2,497 (4.5%) ACL retears identified at 2-year follow-up. The only predictor that changed between early/late periods was allograft use. Allograft odds ratio decreased from 13.1 to 9.5 (P < .01). Allografts were used in older patients (31-40 years) and with lower Marx scores (10-8) from early to late periods. The mean age of subjects who received bone-patellar tendon-bone autografts did not significantly change over time (22.8-23.5). The mean age of subjects who received hamstring autografts fell (27.9-25.5). The mean age of subjects who received allografts rose significantly (31.3-39.8, P < .01). The mean Marx score of subjects who received bone-patellar tendon-bone and hamstring autografts did not significantly change over time. The mean Marx score of subjects who received allografts decreased significantly (P < .01). CONCLUSIONS: After early recognition, allograft use in young active patients was a risk factor for retear; graft choice by surgeons changed in the late period to use of allografts in older and less-active patients, which correlated with a significant decrease in retear risk. LEVEL OF EVIDENCE: Level III, case control study. PMID- 28847575 TI - Arthroscopic Sternoclavicular Joint Diskectomy for Acute and Chronic Tears. AB - PURPOSE: To describe the results and functional scores in a group of patients who underwent arthroscopic excision of a symptomatic sternoclavicular joint (SCJ) disk tear with a minimum follow-up period of 2 years. METHODS: Between April 2010 and December 2014, 14 patients underwent arthroscopic excision of a torn SCJ disk. Patients whose intended surgery was an isolated diskectomy and underwent that surgery only, with no additional procedure, were included. The minimum follow-up period was 24 months. All patients underwent an arthroscopic SCJ diskectomy. Postoperatively, no immobilization was required, and the patients were encouraged to mobilize as pain permitted. The patients were assessed preoperatively and at final follow-up with the visual analog scale score for pain, Rockwood score, and QuickDASH (short version of the Disabilities of the Arm, Shoulder and Hand questionnaire) score. RESULTS: The average age at surgery was 29.4 years (range, 19-39 years). Ten of the patients had been symptom free before a specific incident, after which SCJ symptoms developed. The other 4 patients reported a gradual onset of symptoms and were considered to have chronic tears. The average duration of symptoms was 22.8 months (range, 6-48 months). At a mean follow-up of 33.4 months (range, 24-59 months), a significant improvement in the Rockwood score was noted, from 7 (range, 5-9; standard deviation [SD], 1.4) to 13.6 (range, 9-15; SD, 1.9) (P = .001) (minimal clinically important difference not described). The mean QuickDASH score improved from 23.7 points (range, 6.8-40.9 points; SD, 11.8 points) to 8 points (range, 0-29.5 points; SD, 9 points) (P = .0024) (minimal clinically important difference, 13.4 points). There were no reported complications and specifically no instability. CONCLUSIONS: The results of this series suggest that arthroscopic SCJ diskectomy is a safe and reproducible procedure for the treatment of patients with symptomatic SCJ disk tears. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28847576 TI - Selective production of deacetylated mannosylerythritol lipid, MEL-D, by acetyltransferase disruption mutant of Pseudozyma hubeiensis. AB - Mannosylerythritol lipids (MELs) are produced by several smut fungi of the Ustilaginaceae family; they are promising microbial biosurfactants and have excellent surface-active and self-assembling properties. Pseudozyma hubeiensis is a candidate for abundant MEL production and produces large amounts of 4-O-[(4' mono-O-acetyl-2',3'-di-O-alkanoyl)-beta-d-mannopyranosyl]-meso-erythritol (MEL C). An acetyltransferase disruption mutant of P. hubeiensis, SY62-MM36, was obtained to selectively produce deacetylated 4-O-[(2',3'-di-O-alkanoyl)-beta-d mannopyranosyl]-meso-erythritol (MEL-D), and the structures of the products were determined. Lower mobility of major spots of the mutant on silica gel thin-layer chromatography verified its more hydrophilic nature than that of wild-type MEL-A, B, and C. Structural analyses confirmed the product to be MEL-D, which comprises acyl chains of caproic acid (C6:0), capric acid (C10:0), and lauric acid (C12:0). The critical micelle concentration (CMC) and the surface tension (gammaCMC) of the MEL-D were 2.0 * 10-5 M and 29.7 mN/m, respectively. SY62-MM36 also produced a minor product that was estimated as triacylated MEL-D. The triacylated MEL-D had a CMC of 3.5 * 10-5 M and a gammaCMC of 29.6 mN/m. In water, MEL-D formed a lamella liquid crystal phase over a broad range of concentrations. By fed-batch cultivation, the mutant produced 91.6 +/- 6.3 g/L of MEL-D for 7 days. PMID- 28847577 TI - Characterization of a thermostable mutant of Agaricus brasiliensis laccase created by phylogeny-based design. AB - Laccases are enzymes that oxidize various aromatic compounds, and therefore they have attracted much attention from the standpoints of medical and industrial applications. We previously isolated the cDNA that codes for a laccase isozyme (Lac2a) from the medicinal mushroom Agaricus brasiliensis (Matsumoto-Akanuma et al., Int. J. Med. Mushrooms, 16, 375-393, 2014). In this study, we first attempted heterologous expression of the wild-type laccase using a Pichia pastoris secretory expression system. However, the trial was unsuccessful most likely because the enzyme was too unstable and degraded immediately after production. Therefore, we improved the stability of the laccase by using a phylogeny-based design method. We created a mutant laccase in which sixteen original residues were replaced with those found in the phylogenetically inferred ancestral sequence. The resulting mutant protein was successfully produced using the P. pastoris secretory expression system and then purified. The designed laccase showed catalytic properties similar to those of other fungal laccases. Moreover, the laccase is highly thermally stable at acidic and neutral pH and is also stable at alkaline pH at moderate temperatures. We expect that the laccase will serve as a useful tool for enzymatic polymerization of di-phenolic compounds. PMID- 28847578 TI - Characterization of genetically engineered mouse hepatoma cells with inducible liver functions by overexpression of liver-enriched transcription factors. AB - New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver enriched transcription factors that could be inducibly overexpressed-hepatocyte nuclear factor (HNF)1alpha, HNF1beta, HNF3beta [FOXA2], HNF4alpha, HNF6, CCAAT/enhancer binding protein (C/EBP)alpha, C/EBPbeta and C/EBPgamma-we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research. PMID- 28847579 TI - Mathematical determination of kinetic parameters for assessing the effect of the organic solvent on the selectivity of peptide synthesis with immobilized alpha chymotrypsin. AB - The synthesis of the dipeptide N-benzoyl-l-tyrosine-l-argininamide (BTAA) was conducted under kinetic control with N-benzoyl-l-tyrosine ethyl ester as acyl donor and argininamide as nucleophile using immobilized alpha-chymotrypsin as catalyst. Using a mathematical procedure, the kinetic constants corresponding to the proposed mechanism of peptide synthesis were determined in three different cosolvent media, namely, ethanol, diglyme and acetonitrile. These constants were used for evaluating the selectivity of glyoxyl-agarose immobilized alpha chymotrypsin in the synthesis of BTAA by determining the ratios of synthesis to hydrolysis rates. PMID- 28847580 TI - Simultaneous liquid chromatography/mass spectrometry determination of both polar and "multiresidue" pesticides in food using parallel hydrophilic interaction/reversed-phase liquid chromatography and a hybrid sample preparation approach. AB - Pesticide testing of foodstuffs is usually accomplished with generic wide-scope multi-residue methods based on liquid chromatography tandem mass spectrometry (LC MS/MS). However, this approach does not cover some special pesticides, the so called "single-residue method" compounds, that are hardly compatible with standard reversed-phase (RP) separations due to their specific properties. In this article, we propose a comprehensive strategy for the integration of single residue method compounds and standard multiresidue pesticides within a single run. It is based on the use of a parallel LC column assembly with two different LC gradients performing orthogonal hydrophilic interaction chromatography (HILIC) and reversed-phase (RPLC) chromatography within one analytical run. Two sample aliquots were simultaneously injected on each column, using different gradients, being the eluents merged post-column prior to mass spectrometry detection. The approach was tested with 41 multiclass pesticides covering a wide range of physicochemical properties across several orders of log Kow (from -4 to +5.5). With this assembly, distinct separation from the void was attained for all the pesticides studied, keeping similar performance in terms of sensitivity, peak area reproducibility (<6 RSD% in most cases) and retention time stability of standard single column approaches (better than+/-0.1min). The application of the proposed approach using parallel HILIC/RPLC and RPLC/aqueous normal phase (Obelisc) were assessed in leek using LC-MS/MS. For this purpose, a hybrid QuEChERS (Quick, easy, cheap, effective, rugged and safe)/QuPPe (quick method for polar pesticides) method was evaluated based on solvent extraction with MeOH and acetonitrile followed by dispersive solid-phase extraction, delivering appropriate recoveries for most of the pesticides included in the study within the log Kow in the range from -4 to +5.5. The proposed strategy may be extended to other fields such as sport drug testing or environmental analysis, where the same type of variety of analytes featuring poor retention within a single chromatographic separation occurs. PMID- 28847581 TI - Pyrolytic in situ magnetization of metal-organic framework MIL-100 for magnetic solid-phase extraction. AB - In this study, we report a facile, environmental friendly fabrication of a type of magnetic metal-organic framework (MOF) MIL-100 that can be used for magnetic solid-phase extraction (MSPE). The magnetic MOF composites were fabricated using in situ calcination method. The as-synthesized materials exhibited both high porosity and magnetic characteristics. They used for the MSPE of polycyclic aromatic hydrocarbons (PAHs) from water samples. Such MOF-based magnetic solid phase extraction in combination with gas chromatography equipped with a flame ionization detector (GC-FID), exhibited wide linearity (0.02-250MUgL-1), low detection limits (4.6-8.9ngL-1), and high enrichment factors (452-907) for PAHs. The relative standard deviations (RSDs) for intra- and inter-day extractions of PAHs were ranging from 1.7% to 9.8% and 3.8% to 9.2%, respectively. The recoveries for spiked PAHs (1MUgL-1) in water samples were in the range of 88.5% to 106.6%. The results showed that the special anion-pi orbital (electron donor acceptor) interaction and pi-pi stacking between magnetic MIL-100 and PAHs play an important role in the adsorption of PAHs. PMID- 28847582 TI - Consequences of transition from liquid chromatography to supercritical fluid chromatography on the overall performance of a chiral zwitterionic ion-exchanger. AB - Major differences in the chromatographic performance of a zwitterion ion-exchange type (ZWIX) chiral stationary phase (CSP) in supercritical fluid chromatography (SFC) and high-performance liquid chromatography (HPLC) have been observed. To explain these differences, transition from HPLC to SFC conditions has been performed. The amount of a protic organic modifier in supercritical carbon dioxide (scCO2) was stepwise increased and the effect of this change studied using acidic, basic and ampholytic analytes. At the same time, the effect of various basic additives to the mobile phase and transient acidic buffer species, formed by the reaction of scCO2 with the organic modifier and additives, was assessed. Evidence is provided that a transient acid together with the intrinsic counter-ions present in the ZWIX selector structure drive the elution of analytes even when no buffer is employed. We show that the tested analytes can be enantioseparated under both SFC and HPLC conditions; the best conditions for the resolution of ampholytes are in the so-called enhanced-fluidity mobile phase region. As a consequence, subcritical fluid and enhanced-fluidity mobile phase regions seem to be chromatographic modes with a high potential for operating ZWIX CSPs. PMID- 28847583 TI - Interconversion and chromatographic separation of carbohydrate stereoisomers on polystyrene-divinylbenzene resins. AB - Mutarotation of sugars causes distorted and splitted peaks in liquid chromatography. The shape of the elution profile is affected by the different anomeric and isomeric forms in solution. The rate of interconversion between the different forms relative to the propagation velocity in the column determines the extent of the distortion. This interplay of interconversion reaction and chromatographic separation was examined both experimentally and theoretically. Elution profiles resulting from pulse injections of glucose and fructose solutions at different flow rates and temperatures were analyzed both qualitatively and quantitatively. Adsorption equilibrium and reaction kinetic parameters were estimated by a simple fitting procedure, based on peak elution times and area ratios obtained from the analysis of the experimental profiles. To enhance the accuracy of the model parameters further, estimated reaction kinetic parameters were provided as an initial guess for inverse fitting to elution profiles, using a numeric mass balance model. Simulations with the numeric model, based on the enhanced parameters, allowed a very precise description of the experimental profiles. Accuracy of the fitted parameters was further confirmed through comparison with literature values. Reaction rate constants for the adsorbed phase were calculated and interpreted based on apparent rate constant values determined in this work, and on literature data for aqueous solutions. PMID- 28847584 TI - Chiral separation and chemical profile of Dengzhan Shengmai by integrating comprehensive with multiple heart-cutting two-dimensional liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - Chemical profile for Chinese medicine formulas composed of several herbs is always a challenge due to a big array of small molecules with high chemical diversity so much as isomers. The present paper develops a feasible strategy to characterize and identify complex chemical constituents of a four-herb traditional Chinese medicine formula, Denzhan Shenmai (DZSM) by integrating comprehensive two-dimensional liquid chromatography coupled with quadrupole time of-flight mass spectrometry (LC*LC-qTOF-MS) with multiple heart-cutting two dimensional liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (MHC-qTOF-MS). DZSM was separated by C8*C18 HPLC column system for comprehensive two-dimensional liquid chromatography system and 283 compounds most of which belonged to phenolic acid, flavonoid, saponin and lignan families were characterized and identified within 75min. Some isomers and compounds at low level were analyzed on C8*Chiral HPLC column system for multiple heart-cutting two-dimensional liquid chromatography system with 1D and 2D optimized gradient elution program. These 1D cutting fractions were successively separated on 2D chiral chromatographic column under extended the 2D gradient elution time from 30s to 5.0min. 12 pairs of isomer compounds were separated with good resolution. The combination of LC*LC and MHC system provides a powerful technique for global chemical profiling of DZSM and provided feasible strategy for other complex systems. PMID- 28847585 TI - Optimization and application of octadecyl-modified monolithic silica for solid phase extraction of drugs in whole blood samples. AB - Monolithic silica in MonoSpin for solid-phase extraction of drugs from whole blood samples was developed to facilitate high-throughput analysis. Monolithic silica of various pore sizes and octadecyl contents were synthesized, and their effects on recovery rates were evaluated. The silica monolith M18-200 (20MUm through-pore size, 10.4nm mesopore size, and 17.3% carbon content) achieved the best recovery of the target analytes in whole blood samples. The extraction proceeded with centrifugal force at 1000rpm for 2min, and the eluate was directly injected into the liquid chromatography-mass spectrometry system without any tedious steps such as evaporation of extraction solvents. Under the optimized condition, low detection limits of 0.5-2.0ngmL-1 and calibration ranges up to 1000ngmL-1 were obtained. The recoveries of the target drugs in the whole blood were 76-108% with relative standard deviation of less than 14.3%. These results indicate that the developed method based on monolithic silica is convenient, highly efficient, and applicable for detecting drugs in whole blood samples. PMID- 28847587 TI - The role of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of lymphoproliferative disorders. PMID- 28847586 TI - Assessment of mortality by qSOFA in patients with sepsis outside ICU: A post hoc subgroup analysis by the Japanese Association for Acute Medicine Sepsis Registry Study Group. AB - Quick sequential organ failure assessment (qSOFA) was proposed in the new sepsis definition (Sepsis-3). Although qSOFA was created to identify patients with suspected infection and likely to have poor outcomes, the clinical utility of qSOFA to screen sepsis has not been fully evaluated. We investigated the number of patients diagnosed as having severe sepsis who could not be identified by the qSOFA criteria and what clinical signs could complement the qSOFA score. This retrospective analysis of a multicenter prospective registry included adult patients with severe sepsis diagnosed outside the intensive care unit (ICU) by conventional criteria proposed in 2003. We conducted receiver operating characteristic (ROC) analyses to assess the predictive value for in-hospital mortality and compared clinical characteristics between survivors and non survivors with qSOFA score <= 1 point (qSOFA-negative). Among 387 eligible patients, 63 (16.3%) patients were categorized as qSOFA-negative, and 10 (15.9%) of these patients died. The area under the ROC curve for the qSOFA score was 0.615, which was superior to that for the systemic inflammatory response syndrome score (0.531, P = 0.019) but inferior to that for the SOFA score (0.702, P = 0.005). Multivariate logistic regression analysis showed that hypothermia might be associated with poor outcome independently of qSOFA criteria. Our findings suggested that qSOFA had a suboptimal level of predictive value outside the ICU and could not identify 16.3% of patients who were once actually diagnosed with sepsis. Hypothermia might be associated with an increased risk of death that cannot be identified by qSOFA. PMID- 28847588 TI - Cellular distribution of invadopodia is regulated by nanometer scale surface protein patterns. AB - Invadopodia are proteolytic structures formed by cancer cells. It is not known whether their cellular distribution can be regulated by the organization of the extracellular matrix or the organization of the golgi complex or whether they have an adhesion requirement. Here, we used electron beam lithography to fabricate fibronectin (FN) nanodots with isotropic and gradient micrometer scale spacings on K-casein and laminin backgrounds. Investigating cancer cells cultured on protein nanopatterns, we showed that (i) presence of FN nanodots on a K-casein background decreased percent of cells with neutral invadopodia polarization compared to FN control surfaces; (ii) presence of a gradient of FN nanodots on a K-casein background increased percent of cells with negative invadopodia polarization compared to FN control surfaces; (iii) polarization of the golgi complex was similar to that of invadopodia in agreement with a spatial link; (iv) local adhesion did not necessarily appear to be a prerequisite for invadopodia formation. PMID- 28847589 TI - Prone positioning for intramedullary nailing of subtrochanteric fractrures, the techniques of intraoperative fluoroscopy and reduction: A technique note. AB - The treatment of subtrochanteric fractures is a challenge for orthopaedic trauma surgeons. Three positions have been described previously: supine on a fracture table, supine on a flat radiolucent table, and the lateral decubitus position on a flat radiolucent table. Each one has its advantages and limitations. In this article we describe a prone position for intramedullary nailing of subtrochanteric femoral fractures. This position has the advantages including: 1) an easy approach to reduce and maintain the reduction of fracture by adjusting only the leg plate on injured side, 2) perfect intraoperation fluoroscopic imaging on both anteroposterior view and lateral view, and 3) an easy approach to establish an appropriate entry point even in obese patients. PMID- 28847590 TI - Comparative study between biologic plating and intramedullary nailing for the treatment of subtrochanteric fractures: Is biologic plating using LCP-DF superior to intramedullary nailing? AB - BACKGROUND: The objective of this study is to evaluate the outcome measures of subtrochanteric fractures between biologic plating and intramedullary nailing and determine if biologic plating is superior to intramedullary nailing. METHODS: Between March 2009 and December 2015, 81 patients with subtrochanteric fractures were enrolled (52 males and 29 females; 31 treated with biologic plating and 50 with intramedullary nailing). Biologic plating was conducted consecutively between May 2011 and March 2013 and intramedullary nailing was performed for the rest of period. Perioperative outcomes including operation time and blood loss during the operation; postoperative radiologic outcomes including union, time to union, coronal alignment, and shortening of the femur; and clinical outcomes including walking ability and pain were evaluated. The biologic plating group was compared with the intramedullary nailing group as a historical control. RESULTS: No significant differences were identified for bony union and time to union between the two different fixation methods Coronal alignment was significantly better in the biologic plating group than in the intramedullary nailing group (p<0.016). Postoperative coronal alignment was the only risk factor associated with the nonunion of subtrochanteric fractures (unadjusted OR: 1.915, 95% CI: 0.190 - 19.273; adjusted OR: 0.042, 95% CI: 0.000 - 21.517; p=0.320). CONCLUSION: Surgical outcomes using LCP-DF are comparable to those using intramedullary nailing. Further clinical studies with a larger sample size are required to show the advantage of biologic plating for the treatment of subtrochanteric fractures. PMID- 28847591 TI - A fluorescence method for determination of glucose transport by intestinal BBMV of common carp. AB - Epithelial brush-border membrane vesicles (BBMVs) were isolated from the intestine of common carp and studied systematically by enzyme activity, transmission electron microscopy and immunoblotting. The uptake time course and the substrate concentration effect were assessed, and then, the ability of phlorizin and cytochalasin B to inhibit uptake was analyzed. The results show that sucrase, alkaline phosphatase and Na+-K+-ATPase activities in these vesicles were enriched 7.94-, 6.74- and 0.42-fold, respectively, indicating a relatively pure preparation of apical membrane with little basolateral contamination. The vesicular structure was in complete closure, as confirmed by electron microscopy. The presence of SGLT1 on the BBMVs was confirmed by Western blot analysis. In the time course experiment, the glucose uptake by BBMVs in Na+ medium displayed an initial accumulation (overshoot) at 5 min followed by a rapid return to equilibrium values at 60 min. Over the 2-NBDG concentration range selected, the external 2-NBDG concentration in NaSCN medium graphed as a curved line. Phlorizin and cytochalasin B had an obvious inhibitory effect on 2-NBDG transport in carp BBMVs, and the detected fluorescence intensity decreased. The inhibition rate in the 1000 MUM group was the strongest at 64.18% and 63.61% of phlorizin and cytochalasin B, respectively, indicating the presence of carriers other than SGLT1. This study is the first to demonstrate that 2-NBDG can be used as a convenient and sensitive probe to detect glucose uptake in fish BBMVs. This technology will provide a convenient method to discover new effects and factors in glucose metabolism. PMID- 28847592 TI - Capillary electrophoresis - Mass spectrometry metabolomics analysis revealed enrichment of hypotaurine in rat glioma tissues. AB - Glioma is one of the most lethal brain malignancies with unknown etiologies. Many metabolomics analysis aiming at diverse kinds of samples had been performed. Due to the varied adopted analytical platforms, the reported disease-related metabolites were not consistent across different studies. Comparable metabolomics results are more likely to be acquired by analyzing the same sample types with identical analytical platform. For tumor researches, tissue samples metabolomics analysis own the unique advantage that it can gain more direct insight into disease-specific pathological molecules. In this light, a previous reported capillary electrophoresis - mass spectrometry human tissues metabolomics analysis method was employed to profile the metabolome of rat C6 cell implantation gliomas and the corresponding precancerous tissues. It was found that 9 metabolites increased in the glioma tissues. Of them, hypotaurine was the only metabolite that enriched in the malignant tissues as what had been reported in the relevant human tissues metabolomics analysis. Furthermore, hypotaurine was also proved to inhibit alpha-ketoglutarate-dependent dioxygenases (2-KDDs) through immunocytochemistry staining and in vitro enzymatic activity assays by using C6 cell cultures. This study reinforced the previous conclusion that hypotaurine acted as a competitive inhibitor of 2-KDDs and proved the value of metabolomics in oncology studies. PMID- 28847593 TI - Evidence of Dietary Improvement and Preventable Costs of Cardiovascular Disease. AB - We conducted a review to summarize preventable medical costs of cardiovascular disease (CVD) associated with improved diet, as defined by the 2020 Strategic Impact Goal of the American Heart Association. We searched databases of PubMed, Embase, CINAHL and ABI/INFORM to identify population-based studies published from January 1995 to December 2015 on CVD medical costs related to excess intake of salt/sodium or sugar-sweetened beverages, and inadequate intake of fruits and vegetables, fish/fish oils/omega-3 fatty acids, or whole grains/fiber/dietary fiber. Based on the American Heart Association's secondary dietary metrics, we also searched the literature on inadequate intake of nuts and excess intake of processed meat and saturated fat. For each component, we evaluated the CVD cost savings if consumption levels were changed. The cost savings were adjusted into 2013 US dollars. Among 330 studies focusing on diet and economic consequences, 16 studies evaluated CVD costs associated with 1 or more dietary components: salt/sodium (n = 13), fruits and vegetables (n = 1), meat (n = 1), and saturated fat (n = 3). In the United States, reducing individual sodium intake to 2,300 mg/day from the current level could potentially save $1,990.9/person per year for hypertension treatment, based on a simulation study. Increasing consumption of fruits and vegetables from <0.5 cup/day to >1.5 cups/day could save $1,568.0/person per year in treatment costs for CVD, based on a cohort study. Potential CVD cost savings associated with diet improvement are substantial. Interventions for reducing sodium intake and increasing fruit and vegetable consumption could be viable means to alleviate the increasing national medical expenditures. PMID- 28847594 TI - Usefulness of Released Cardiac Myosin Binding Protein-C as a Predictor of Cardiovascular Events. AB - Cardiac myosin binding protein-C (cMyBP-C) is a heart muscle-specific thick filament protein. Elevated level of serum cMyBP-C is an indicator of early myocardial infarction (MI), but its value as a predictor of future cardiovascular disease is unknown. Based on the presence of significant amount of cMyBP-C in the serum of previous study subjects independent of MI, we hypothesized that circulating cMyBP-C is a sensitive indicator of ongoing cardiovascular stress and disease. To test this hypothesis, 75 men and 83 women of similar ages were recruited for a prospective study. They underwent exercise stress echocardiography to provide pre- and poststress blood samples for subsequent determination of serum cMyBP-C levels. The subjects were followed for 1 to 1.5 years. Exercise stress increased serum cMyBP-C in all subjects. Twenty-seven primary events (such as death, MI, revascularization, invasive cardiovascular procedure, or cardiovascular-related hospitalization) and 7 critical events (CE; such as death, MI, stroke, or pulmonary embolism) occurred. After adjusting for sex and cardiovascular risk factors with multivariate Cox regression, a 96% sensitive prestress cMyBP-C threshold carried a hazard ratio of 8.1 with p = 0.041 for primary events. Most subjects (6 of 7) who had CE showed normal ejection fraction on echocardiography. Prestress cMyBP-C demonstrated area under receiver operating curve of 0.91 and multivariate Cox regression hazard ratio of 13.8 (p = 0.000472) for CE. Thus, basal cMyBP-C levels reflected susceptibility for a variety of cardiovascular diseases. Together with its high sensitivity, cMyBP-C holds potential as a screening biomarker for the existence of severe cardiovascular diseases. PMID- 28847595 TI - Meta-Analysis of Efficacy and Safety of Low-Intensity Warfarin Therapy for East Asian Patients With Nonvalvular Atrial Fibrillation. AB - For patients with nonvalvular atrial fibrillation (NVAF) receiving warfarin therapy, the target international normalized ratio range of 2.0 to 3.0 is recommended by Western countries. However, this treatment carries a higher risk of bleeding which suggests more researches on whether low-intensity warfarin therapy (range <2.0 to 3.0) is suitable for East Asian patients. Three databases were searched from inception to April 21, 2016. Studies that reported thromboembolic and hemorrhagic events in low- and standard-intensity warfarin groups were included. Finally, seven studies were included in the analysis. There was a significantly decreased risk of hemorrhagic events (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.43 to 0.82, p = 0.002) with no statistically increased risk of thromboembolic events (OR 1.14, 95% CI 0.80 to 1.62, p = 0.47) in the 1.5 to 2.0 group compared with that of the 2.0 to 3.0 group. Meanwhile, there was no significant difference of cardiovascular mortality (OR 1.58, 95% CI 0.89 to 2.83, p = 0.12) between the 2 groups. Further analysis showed there was no significance in thromboembolic events (OR 1.15, 95% CI 0.83 to 1.60, p = 0.40), major bleeding events (OR 0.74, 95% CI 0.50 to 1.09, p = 0.13), and cardiovascular mortality (OR 1.45, 95% CI 0.79 to 2.65, p = 0.23) between 1.5 to 2.5 and 2.0 to 3.0 groups. Although no significant difference was found in hemorrhagic events (OR 0.76, 95% CI 0.57 to 1.01, p = 0.06), there was a decreased trend in it. In conclusion, low-intensity warfarin therapy can achieve reduced hemorrhage without increasing thromboembolism for East Asian patients with NVAF receiving warfarin therapy. PMID- 28847596 TI - Meta-Analysis of Circadian Variation in the Onset of Acute Aortic Dissection. AB - Circadian variation in the onset of acute aortic dissection (AAD) has been less investigated than other cardiovascular diseases. We performed a meta-analysis to assess the presence of an circadian rhythmic variability of AAD onset. Eligible studies were observational studies enrolling patients with AAD and reporting a circadian variation in AAD. Study-specific estimates, that is, 2-hour incidence of AAD, were combined using the random-effects model. Chronobiological analysis (analysis of circadian rhythmicity) was performed by applying a partial Fourier series to the pooled 2-hour incidence using the weighted least-squares method. We identified 7 eligible studies enrolling a total of 1,827 patients with AAD. Pooled 2-hour period incidence of AAD was 3.4% in 0:00 to 2:00, 4.8% in 2:00 to 4:00, 5.4% in 4:00 to 6:00, 9.6% in 6:00 to 8:00, 13.8% in 8:00 to 10:00, 11.1% in 10:00 to 12:00, 8.1% in 12:00 to 14:00, 8.9% in 14:00 to 16:00, 8.8% in 16:00 to 18:00, 7.0% in 18:00 to 20:00, 8.1% in 20:00 to 22:00), and 5.5% in 22:00 to 24:00. Chronobiological analysis (nonlinear Fourier rhythm analysis) identified a significant (p = 0.0082) circadian pattern in the occurrence of AAD with a peak in 8:00 to 10:00 and a nadir in 0:00 to 2:00. Pooled analysis demonstrated significantly more incidence in 8:00 to 10:00 than in 0:00 to 2:00 (risk ratio 3.59, 95% confidence interval 2.19 to 5.90, p<0.00001). The incidence of AAD was 8.8%, 15.5%, 25.0%, 17.7%, 16.1%, and 13.8% in 0:00 to 4:00, 4:00 to 8:00, 8:00 to 12:00, 12:00 to 16:00, 16:00 to 20:00, and 20:00 to 24:00, respectively. A significant circadian pattern was found in the occurrence of AAD with a peak in 8:00 to 10:00 and a nadir in 0:00 to 2:00. PMID- 28847597 TI - Cholesterol is the Cause of Atherosclerosis. PMID- 28847599 TI - Preeclampsia: The Vasculature Never Forgets, Neither Should We. PMID- 28847598 TI - Nutrients recovery from anaerobic digestate of agro-waste: Techno-economic assessment of full scale applications. AB - The sustainable production of fertilizers, especially those based on phosphorus, will be one of the challenges of this century. Organic wastes produced by the agriculture, urban and industrial sectors are rich in nutrients which can be conveniently recovered and used as fertilizers. In this study five full scale systems for the recovery of nutrients from anaerobic digestate produced in farm scale plants were studied. Monitored technologies were: drying with acidic recovery, stripping with acidic recovery and membrane separation. Results showed good performances in terms of nutrients recovery with average yields always over 50% for both nitrogen and phosphorus. The techno-economic assessment showed how the specificity of the monitored systems played a major role: in particular, membranes were able to produce a stream of virtually pure water (up to 50% of the treated digestate) reducing the digestate volume, while drying, because of the limitation on recoverable heat, could treat only a limited portion (lower than 50%) of produced digestate while stripping suffered some problems because of the presence of suspended solids in the liquid fraction treated. Specific capital and operational costs for the three systems were comparable ranging between 5.40 and 6.97 ? per m3 of digestate treated and followed the order stripping > drying > membranes. Costs determined in this study were similar to those observed in other European experiences reported in literature. PMID- 28847600 TI - Carotid Artery Intima-Media Thickness and Subclinical Atherosclerosis in Women With Remote Histories of Preeclampsia: Results From a Rochester Epidemiology Project-Based Study and Meta-analysis. AB - OBJECTIVE: To measure carotid artery intima-media thickness (CIMT), a marker of subclinical atherosclerosis, in postmenopausal women with and without histories of preeclampsia and to synthesize these results with those from prior studies of CIMT performed 10 or more years after preeclamptic pregnancies. PATIENTS AND METHODS: Forty women (median age, 59 years) with histories of preeclampsia and 40 with histories of normotensive pregnancy (confirmed by medical record review) were selected from women who resided and gave birth in Olmsted County, Minnesota, between January 1, 1976, and December 31, 1982. The participants were identified and recruited in 2014-2015, and CIMT was measured by B-mode ultrasonography. Meta analysis included CIMT studies that were performed 10 or more years after preeclamptic pregnancies and which were identified through PubMed, EMBASE, and Web of Science. Heterogeneity was assessed using the I2 statistic. Standardized mean difference was used as a measure of effect size. RESULTS: Carotid artery intima-media thickness, expressed as a median (interquartile range), was greater in the preeclamptic than in the normotensive group (0.80 mm [0.75-0.85 mm] vs 0.73 mm [0.70-0.78]; P=.004); the odds of having CIMT higher than threshold (0.77 mm) was statistically significant after adjusting for confounding factors (odds ratio, 3.17; 95% CI, 1.10-9.14). A meta-analysis of 10 studies conducted 10 or more years post partum included 813 women with and 2874 without histories of preeclampsia. Carotid artery intima-media thickness was greater among women with histories of preeclampsia, with a standardized mean difference of 0.18 and 95% CI of 0.05 to 0.30 mm (P=.004). CONCLUSION: Among women with histories of preeclampsia, CIMT may identify those with subclinical atherosclerosis, thus offering an opportunity for early intervention. PMID- 28847601 TI - Mesenchymal cells are required for epithelial duct cell-to-beta cell maturation and function in an injured adult pancreas in the rat. AB - The islet, the endocrine portion of the pancreas - develops from an invagination of the pancreatic duct epithelial cells (PDECs) into the surrounding tissue. The contact of the PDECs with mesenchymal cells (MSCs) may be an essential drive for endocrine cell fate. During pancreatic development, cells that express Neurogenin 3 (Ngn3) biomarker are precursors of insulin- producing beta cells. These precursors have been reported in the neogenesis of islets from adult tissues following the surgical ligation of the main pancreatic duct (PDL). But the capacity of these precursors to induce the appropriate signals to complete the entire neogenesis program has been questioned. We studied the fate of co-culture of PDECs and MSCs from the ligated adult pancreas and established the exact location of adult stem- or progenitor-like cells that give rise to beta cells. PDECs were cultured in direct contact with or without MSCs in serum-containing culture media. The cytomorphology of the cells in co-cultures was determined and the immunocytochemical study of the cells was carried out using anti-Ngn3, anti insulin and anti-cytokeratin-7 (CK7) antibodies. Both the PDEC/MSC- and PDEC/MSC+ cultures showed out- pocketing from duct epithelium by the end of the second week, which are distinct as cell clusters only in PDEC/MSC+ cells later in week four, exhibiting numerous branching ducts. Co-expression of Ngn3 with insulin was observed in both cultures from the second week. However, characterizations of these Ngn3+ cells in the PDEC/MSC+ culture revealed that these cells also co expressed a CK7 biomarker. This study provides new evidence of the ductal epithelial nature of beta cells in injured adult pancreata; and that the mesenchymal stromal cells are required to sustain Ngn3 expression for beta cell maturation and function. PMID- 28847602 TI - Application of nanocompostie chitosan and carboxymethyl cellulose films containing natural preservative compounds in minced camel's meat. AB - In the present study, novel films based on nanomontmorillonite-chitosan (MMT-Ch) and nanomontmorillonite-carboxymethyl cellulose (MMT-CMC) incorporated with different concentrations of Ziziphora clinopodioides essential oil (ZEO; 0.5, 1 and 2%) alone and in combination with Ficus carica extract (FCH; 1%) were investigated as active packaging materials for minced camel's meat to increase the shelf life (microbial, chemical and sensory properties) and inhibit the growth of Listeria monocytogenes and Escherichia coli O157:H7 during storage at refrigerated condition. Final microbial populations of meat samples packed in CMC MMT+ZEO 2%+FCH 1% and Ch-MMT+ZEO 2%+FCH 1% were decreased approximately 1-4 log CFU/g compared to control (P<0.05). Packed meats with nanocomposite films tended to retard the increases in total volatile base nitrogen (TVB-N), pH, peroxide value (PV), protein carbonyl content and thiobarbituric acid reactive substances (TBARS). Sensory attributes (odor, color and overall acceptability) were significantly enhanced in treated meat samples (P<0.05). The results indicated that CMC-MMT+ZEO 2%+FCH 1% and Ch-MMT+ZEO 2%+FCH 1% films could be considered as promising packaging materials for minced camel's meat. PMID- 28847603 TI - Isolation and characterization of three novel catechol 2,3-dioxygenase from three novel haloalkaliphilic BTEX-degrading Pseudomonas strains. AB - Benzene, toluene, ethylbenzene, and xylene (BTEX) are highly water soluble, hence can contaminate a large volume of groundwater and soil, exhibiting a serious negative impact on human health. To get efficient biodegradation and bioremediation of BTEX in the highly salt and pH contaminated sites, this study captured, investigated and identified three novel haloalkaliphilic bacterial strains HA10, HA12 and HA14 belong to genus Pseudomonas that have strong capability to degrade BTEX at 7% NaCl (w/v) and pH 9. Study of enzymes in halophiles will help understanding the mechanism of BTEX degradation in saline and alkaline environments. Three novel catechol 2,3-dioxygenase genes C23O10, C23O12 and C23O14 were amplified, cloned and overexpressed from the three obtained haloalkaliphilic strains HA10, HA12 and HA14 respectively. Phylogenetic tree analysis for the three novel C23Os and their relatives formed a new branch. C23O12 and C23O14 showed activity with only catechol, while the activity was observed in C23O10 on catechol and 2,3-dihydroxybiphenyl. Kinetic properties analysis for C23O10 indicated that its preferred substrates were catechol and 2,3 Dihydroxybiphenyl. C23O10 activity severely affected and rapidly inactivated by 3 Chlorocatechol. This finding may be necessary for developing in-site bioremediation of BTEX contaminated sites in both highly saline and alkaline environments. PMID- 28847604 TI - Preparation of the Auricularia auricular polysaccharides simulated hydrolysates and their hypoglycaemic effect. AB - The anti-diabetic effect of the Auricularia auricular polysaccharides simulated hydrolysates (APSHs) obtained from the dried fruiting body of Auricularia auricular was studied in this paper. The APSHs were administered intragastrically (i.g.) at the dose of 0.15g/kg b.w. to the streptozotocin (STZ) -induced diabetic male SD rats for 7 weeks. The results showed that fasting blood glucose level was significantly reduced (p<0.05), whereas the glucose tolerance was remarkable improvement in STZ-induced diabetic rats through APSHs administration, and loss in body weight was also prevented in diabetic mice (p<0.05). Moreover, APSHs could increase hepatic glycogen and pancreatic insulin level (p<0.01), as well as decrease the levels of serum TG and LDL-C compared to the diabetic control group (p<0.05). APSHs had no significant effects on the total cholesterol and HDL-C levels. APSHs were composed of arabinose, xylose, mannose, glucose, galactose and glucosamine with the molar ratio of 1.91:0.52:2.89:1.00:0.67:0.23. These studies suggest that APSHs exerts marked antidiabetic effect in experimental diabetes mellitus, thus justifying the potential treatment for diabetic mellitus. PMID- 28847605 TI - Self-structure assembly in single stranded polyriboadenylic acid by benzophenanthridine alkaloid: Spectroscopic and calorimetric exploration. AB - Present study allows us a better understanding of the interaction of nitidine, a benzophenanthridine alkaloid with single stranded polyriboadenylic acid [ss-poly (rA)]. The interaction leads to self-structure induction in ss-poly (rA) under the experimental condition of pH 7.0. Interaction of nitidine with ss-poly (rA) was ascertained by monitoring the change in absorbance, fluorescence intensity and circular dichroism values. Binding mode of nitidine with ss-poly (rA) was observed to be intercalation as confirmed from the quenching and viscometric studies. The association was characterized by both negative enthalpy and entropy changes accompanying with a moderately high binding constant of 5.10*105M-1. Nitidine induced double helical organization in single stranded poly (rA) under the experimental pH. PMID- 28847606 TI - Spatially controlled rhBMP-2 mediated calvarial bone formation in a transgenic mouse model. AB - The study aimed to investigate the localized osteogenic activity of recombinant human bone morphogenetic protein (rhBMP-2), when delivered using enzymatically crosslinkable injectable glycol chitosan hydrogel. A critical sized bilateral calvarial defect model was used wherein one defect was implanted with rhBMP-2 loaded hydrogel (HPP-GC+BMP). The neighboring defect was implanted with an osteoconductive, collagen hydroxyapatite matrix "Healos(r)". The implantation of HPP-GC+BMP led to complete closure of the critical sized defect at 4 weeks post implantation. The neighboring site implanted with Healos(r) however, did not show any bone formation. The spatial control of rhBMP-2 bioactivity at the cellular level was confirmed by histological and histomorphometric analysis of the calvaria isolated from Col3.6 transgenic animals which can express fluorescence in osteoblast and pre-osteoblast cells. The retained rhBMP-2 in HPPGC+BMP implant was able to localize osteoprogenitor recruitment and osteogenesis, at the implantation site. The results demonstrate the efficacy of HPP-GC hydrogel in minimizing the diffusive loss of rhBMP-2 from the implantation site, compared to the collagen hydroxyapatite scaffold. PMID- 28847608 TI - Prediction of body composition in anorexia nervosa: Results from a retrospective study. AB - BACKGROUND & AIMS: The assessment of body composition is crucial in evaluating nutritional status in female subjects with anorexia nervosa (AN) and improving their clinical management. The aim of this retrospective study was to assess the accuracy of selected BIA (bioimpedance analysis) equations for fat-free mass (FFM) in female AN subjects and to formulate a specific equation for these subjects. METHODS: Eighty-two restrictive female AN subjects (age 20.5 +/- 3.7 yrs, BMI 15.7 +/- 1.7 kg/m2) were studied. Body composition was determined with dual-energy X-ray absorptiometry (DXA) and estimated by BIA using five different equations. Linear correlation analysis was carried out to evaluate the association of FFM with selected variables. Multiple regression analysis was used to formulate specific equations to predict FFM in AN. RESULTS: All predictive equations underestimated FFM at the population level with a bias from -5.6 to 11.7%, while the percentage of accurate predictions varied from 12.2% to 35.4%. More interestingly, multiple regression analysis clearly indicates that, in addition to weight, ZI100 or RI also emerged as independent predictors of DXA derived FFM, increasing the prediction power of the equation well above that observed with anthropometric characteristics only. CONCLUSIONS: This study shows that the selected predictive BIA equations considered exhibit an insufficient accuracy at the population and the individual level. Predictive formulas based on body weight plus BIA parameters such as RI and ZI100 offer a rather accurate prediction of FFM (with high R squared). PMID- 28847607 TI - Effect of molecular weight on electro-spinning performance of regenerated silk. AB - Owing to the excellent biocompatibility of silk fibroins (SFs) and ease of fabrication of nano-fibrous webs by the electro-spinning technique, electro-spun SF webs have attracted the attention of researchers for various biomedical applications, including their use as tissue engineering scaffolds and membranes for guided bone regeneration. In this work, the effect of the molecular weight (MW) and concentration of SFs on the structure and properties of the electro-spun SF webs was examined. The fiber morphology and porosity of these SF webs were strongly affected by the viscosity of the SF dope solution. It was found that the electro-spinning rate of the SF solution could be increased significantly (7.5 fold) by controlling the MW and concentration of the SF. Interestingly, as the SF MW and concentration (i.e., solution viscosity) increased, the extent of beta sheet crystallization of the SF decreased, leading to a decrease in the overall crystallinity. The strength and elongation of the electro-spun SF web decreased with an increase in the web porosity (i.e., increasing SF concentration) and a decrease in the MW of the SF. PMID- 28847610 TI - How Peircean semiotic philosophy connects Western science with Eastern emptiness ontology. AB - In recent articles in this journal I have discussed why a traditional physicalist and mechanist, as well as an info-computationalist, view of science cannot fulfil the goal of building a transdisciplinary science across Snow's two cultures. There seems to be no path proceeding from mechanistic physicalism to views that encompass phenomenological theories of experiential consciousness and meaning based cognition and communication. I have suggested, as an alternative, the Cybersemiotic framework's integration of Peirce's semiotics and Luhmann's autopoietic system theory. The present article considers in greater depth the ontological developments necessary to make this possible. It shows how Peirce avoids materialism and German idealism through his building on a concept of emptiness similar to modern quantum field theory, positing an indeterminist objective chance feeding into an evolutionary philosophy of knowing based on pure mathematics and phenomenology that is itself combined with empirically executed fallibilism. Furthermore, he created a new metaphysics in the form of a philosophical synechist triadic process philosophy. This was integrated into the transcendentalist view of process view of science and spirituality developed from Western Unitarianism by Emerson (agapism), and featuring a metaphysics of emptiness and spontaneity (tychism) that are also essential for the Eastern philosophies of Buddhism and Vedanta. PMID- 28847611 TI - Cellular intelligence: Microphenomenology and the realities of being. AB - Traditions of Eastern thought conceptualised life in a holistic sense, emphasising the processes of maintaining health and conquering sickness as manifestations of an essentially spiritual principle that was of overriding importance in the conduct of living. Western science, which drove the overriding and partial eclipse of Eastern traditions, became founded on a reductionist quest for ultimate realities which, in the modern scientific world, has embraced the notion that every living process can be successfully modelled by a digital computer system. It is argued here that the essential processes of cognition, response and decision-making inherent in living cells transcend conventional modelling, and microscopic studies of organisms like the shell-building amoebae and the rhodophyte alga Antithamnion reveal a level of cellular intelligence that is unrecognized by science and is not amenable to computer analysis. PMID- 28847609 TI - Structural and evolutionary analysis of Leishmania Alba proteins. AB - The Alba superfamily proteins share a common RNA-binding domain. These proteins participate in a variety of regulatory pathways by controlling developmental gene expression. They also interact with ribosomal subunits, translation factors, and other RNA-binding proteins. The Leishmania infantum genome encodes two Alba domain proteins, LiAlba1 and LiAlba3. In this work, we used homology modeling, protein-protein docking, and molecular dynamics (MD) simulations to explore the details of the Alba1-Alba3-RNA complex from Leishmania infantum at the molecular level. In addition, we compared the structure of LiAlba3 with the human ribonuclease P component, Rpp20. We also mapped the ligand-binding residues on the Alba3 surface to analyze its druggability and performed mutational analyses in Alba3 using alanine scanning to identify residues involved in its function and structural stability. These results suggest that the RGG-box motif of LiAlba1 is important for protein function and stability. Finally, we discuss the function of Alba proteins in the context of pathogen adaptation to host cells. The data provided herein will facilitate further translational research regarding Alba structure and function. PMID- 28847612 TI - President of Zambia declares HIV testing mandatory. PMID- 28847613 TI - Concerns about the design, analyses, and findings of the trial of dopamine serotonin stabilizer RP5063 by Cantillon and colleagues. PMID- 28847614 TI - Delayed massive cerebral fat embolism secondary to severe polytrauma. PMID- 28847615 TI - Severe vitamin D deficiency upon admission in critically ill patients is related to acute kidney injury and a poor prognosis. AB - OBJECTIVES: To evaluate the prevalence of vitamin D deficiency in critically ill patients upon admission to an Intensive Care Unit (ICU) and its prognostic implications. DESIGN: A single-center, prospective observational study was carried out from January to November 2015. Patients were followed-up on until death or hospital discharge. SETTING: The department of Critical Care Medicine of a university hospital. PATIENTS: All adults admitted to the ICU during the study period, without known factors capable of altering serum 25(OH)D concentration. INTERVENTIONS: Determination of serum 25(OH)D levels within the first 24h following admission to the ICU. MAIN VARIABLES OF INTEREST: Prevalence and mortality at 28 days. RESULTS: The study included 135 patients, of which 74% presented deficient serum 25(OH)D levels upon admission to the ICU. Non-survivors showed significantly lower levels than survivors (8.14ng/ml [6.17-11.53] vs. 12ng/ml [7.1-20.30]; P=.04], and the serum 25(OH)D levels were independently associated to mortality (OR 2.86; 95% CI 1.05-7.86; P=.04]. The area under the ROC curve was 0.61 (95% CI 0.51-0.75), and the best cut-off point for predicting mortality was 10.9ng/ml. Patients with serum 25(OH)D<10.9ng/ml also showed higher acute kidney injury rates (13 vs. 29%; P=.02). CONCLUSION: Vitamin D deficiency is highly prevalent upon admission to the ICU. Severe Vitamin D deficiency (25[OH]D<10.9ng/ml) upon admission to the ICU is associated to acute kidney injury and mortality. PMID- 28847616 TI - In vivo assessment of hair cell damage and developmental toxicity caused by gestational caffeine exposure using zebrafish (Danio rerio) models. AB - The aim of the present study was to evaluate hair cell damage and associated developmental toxicity caused by gestational caffeine exposure. We exposed embryos to various caffeine concentrations (25MUM, 125MUM, 250MUM, and 500MUM) and evaluated developmental toxicity of the embryos at 72 and 120h and hair cell damage at 120h after fertilization. The average number of total hair cells within four neuromasts exposed to various concentrations of caffeine was compared with that of the control group. To seek the underlying mechanisms, TUNEL and DASPEI assay were carried out to evaluate hair cell apoptosis and mitochondrial damage, respectively. Morphologic abnormality, mortality, hatching rate, and heart rate were also evaluated. Caffeine induced significant hair cell damage compared with control group (p<0.01, control; 35.64+/-10.48 cells, 500MUM caffeine; 23.32+/ 12.14 cells, n=25-30). Significant increase in the hair cell apoptosis was confirmed in a dose-dependent manner (p<0.01, TUNEL assay) and the mitochondrial damage in high caffeine concentrations (250, 500MUM) (p<0.01, DASPEI assay).Morphologic abnormalities were significantly increased in high caffeine concentrations (250 or 500MUM) for body shape, notochord, and heart at both 3-, and 5-dpf. The control group exhibited 3.3% mortality which increased up to 11.6% at 500MUM caffeine. Rapid hatching was present at 48h (control; 46.6%, 500MUM caffeine; 100%). In conclusion, gestational caffeine exposure caused significant hair cell damage and developmental toxicities in zebrafish at early developmental stages. PMID- 28847617 TI - Effect of expertise on pacing strategies and sprint performance in batsmen. AB - OBJECTIVES: To assess whether the absence of a known endpoint, at the beginning of repeated-sprint bouts between the wickets, affects how skilled compared to less skilled batsmen pace themselves. DESIGN: Repeated measures. METHODS: Twelve skilled and 12 less skilled batsmen completed three trials. All trials required the same number of sprints (14 shuttles, 28 runs), while only the information before each trial differed. CT: batsmen were aware of the endpoint (28 runs). UT: not informed of the exercise endpoint and were required to run on command for an indefinite period (28 runs). DT: told they were only doing 14 runs when they actually did 28 runs. Sprint times, electrical muscle activity, and ratings of perceived effort were recorded. RESULTS: Skilled batsmen were significantly faster than less skilled across all trials. Hamstring muscles activity decreased significantly over time in the skilled players during the UT, and during the CT and DT for the less skilled players. There were significant reductions in quadriceps muscles activation for the less skilled over time in all trials and in the skilled batsmen in the vastus medialis during the UT only. Perceived effort increased significantly in both groups in all trials. Skilled batsmen were fastest in the UT and less skilled fastest in the CT. CONCLUSIONS: Better batting skill facilitated improved sprint times, especially when the exact endpoint was unknown. These results suggest that less skilled players should be given more central wicket practice with uncertainty to better develop their ability to maintain their sprint performance. PMID- 28847618 TI - Systematic review of the relationship between 20m shuttle run performance and health indicators among children and youth. AB - OBJECTIVE: This systematic review aimed to summarize research that assessed the associations between 20m shuttle run test (20mSRT) performance and indicators of physiological, psychosocial and cognitive health among school-aged children and youth. DESIGN: Systematic review. METHODS: Five online databases were used to identify peer-reviewed studies published from 1980 to 2016. Studies were included if they matched these criteria: population (children and youth with a mean age of 5-17 years and/or in Grades 1-12), intervention/exposure (performance on the 20mSRT), and outcomes (health indicators: adiposity, cardiometabolic biomarkers, cognition, mental health, psychosocial health, self-esteem and physical self perception, quality of life and wellbeing, bone health, musculoskeletal fitness, motor skill development, and injuries and/or harm). Narrative syntheses were applied to describe the results. A lack of homogeneity precluded a meta-analysis approach. RESULTS: Overall, 142 studies that determined an association between 20mSRT performance and a health indicator were identified, representing 319,311 children and youth from 32 countries. 20mSRT performance was favourably associated with indicators of adiposity, and some indicators of cardiometabolic, cognitive, and psychosocial health in boys and girls. Fewer studies examined the relationship between 20mSRT performance and measures of quality of life/wellbeing, mental health and motor skill development, and associations were generally inconsistent. The quality of the evidence ranged from very low to moderate across health indicators. CONCLUSION AND IMPLICATIONS: These findings support the use of the 20mSRT as a holistic indicator of population health in children and youth. PMID- 28847620 TI - Measurement is always better than self-report: is it that easy? PMID- 28847619 TI - Pharmacologic Therapy for Heart Failure With Reduced Ejection Fraction: Closing the Gap Between Clinical Guidelines and Practice. AB - Despite the great progress made in the management of heart failure (HF) with reduced ejection fraction (HFrEF), its prevalence continues to rise owing to an aging population and an epidemic of hypertension, obesity and coronary artery disease. For decades, angiotensin converting enzyme inhibitors and beta blockers have been the mainstay of HFrEF therapy. The recent addition of sacubitril/valsartan and ivabradine to the HF armamentarium has the potential to transform our therapeutic approach to HFrEF, while simultaneously raising some questions and uncertainties on their applicability. In this paper, we review the pathophysiology of HFrEF, discuss already established and novel evidenced-based pharmacologic therapies available for these patients. We also share some therapeutic strategies aimed to optimize HF therapy in specific undertreated patient populations including the elderly and patients with chronic kidney disease, while offering insight on how to tailor therapy in the "real-world." PMID- 28847621 TI - Persistent testicular structural and functional alterations after exposure of adult rats to atrazine. AB - Atrazine is an endocrine disruptor affecting testicular steroidogenesis, and promoting testicular atrophy and 3beta-HSD reduction. However, it remains unknown whether these effects are reversible or permanent. To address this issue was the aim of this study. Exposition of rats to 200mg/kg of atrazine resulted in transient increase in testicular weight, seminiferous tubules dilation and atrophy, and reduction in Leydig cell 3beta-HSD. Testicular atrophy and 3beta-HSD reduction were more pronounced after the recovery period of 75days. There was increase in aromatase expression after long-term exposure but it returned to control level after recovery. Moreover, there was increase in ED1-/ED2+, ED1+/ED2+ and ED1+/ED2- macrophages, in the recovery group. These macrophages were positive for 3beta-HSD, thereby raising possibility of their involvement in steroidogenesis. These findings further emphasize the adverse effects of atrazine on male reproduction, highlighting that testicular damages may be irreversible even after a recovery period longer than the spermatogenic cycle. PMID- 28847622 TI - Lateral tarsoligamentous sling: A successful treatment for involutional entropion in Asians as a modified lateral tarsal strip. AB - OBJECTIVE: To compare the effectiveness of the Quickert suture (Q-suture) with that of the lateral tarsoligamentous sling in treating lower eyelid involutional entropion in Asians. METHOD: We reviewed the charts of all patients who underwent repair of an involutional lower eyelid entropion in Hangil Eye Hospital between September 2011 and March 2016. A single surgeon (S. C. Kim) performed the procedure in every case. Patients underwent either Q-suturing or lateral tarsoligamentous sling. We analyzed the results using Mann-Whitney and Chi-square tests, as well as Kaplan-Meier survival analysis. A p-value of <0.05 was considered to indicate significance. RESULTS: A total of 50 patients (61 eyes) were included in the study. Of the 50 patients, 24 (30 eyelids) received Q-suture and 26 patients (31 eyelids) underwent lateral tarsoligamentous sling. In all patients who underwent lateral tarsoligamentous sling, the entropion was successfully corrected and did not recur. Furthermore, none of the patients experienced any significant postoperative complications. In contrast, entropion recurred in 16 (36.67%) of the patients who underwent Q-suture (mean of 10.88 +/- 9.02 months after surgery). The recurrence rate was not significantly correlated with age (p = 0.093); it was higher in men than in women, although this was not a significant difference (46.67% vs 26.6.7%; p = 0.175 by Chi-squared test). Kaplan Meier survival analysis showed that the recurrence rate after Q-suture differed significantly from that after lateral tarsoligamentous sling (36.67% vs 0%, respectively; p = 0.007). CONCLUSION: This study suggests that lateral tarsoligamentous sling is an effective surgical method for correcting lower eyelid involutional entropion; the technique is not associated with recurrence or significant complications in Asians. PMID- 28847623 TI - Accuracy and reproducibility of the DAVID SLS-2 scanner in three-dimensional facial imaging. AB - PURPOSE: A prospective study was performed to test the accuracy and reproducibility of the DAVID-SLS-2 scanner (SLS-2) [DAVID Vision Systems GmbH], compared to the validated 3dMDtrio scanner (3dMD) [3dMD, LLC, Atlanta, GA, USA]. MATERIALS AND METHODS: The accuracy of the SLS-2 was determined through multiple scans of a mannequin face model using both scanners. The reproducibility of a protocol for achieving consistent three-dimensional (3D) face scans in live subjects was carried out using the SLS-2. A precision of <=1 mm was considered clinically significant. RESULTS: The mannequin face model was reproduced with no significant errors in the SLS-2 compared to the 3dMDtrio, with normally distributed data (mean = 0.002 mm; SD = 0.01 mm). In live subjects, the forehead, midface, chin and general face region showed mean errors and SD <0.24 mm and <1 mm, respectively. In the neck area, the data were not found to be normally distributed (mean = -1.6 mm; SD = 2.1 mm). CONCLUSION: Structured light scanning may be used for acquiring 3D face scans in live subjects in a radiation-free and reproducible manner, provided that the head of the subject is positioned in the same posture for each scan. Special care is recommended in positioning the head in the sagittal plane during scanning. PMID- 28847624 TI - Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. AB - OBJECTIVE: To systematically review the literature for studies investigating knee osteoarthritis (OA) phenotypes to examine what OA characteristics are relevant for phenotyping. METHODS: A comprehensive search was performed in Medline, EMBASE, Web of Sciences, CINAHL, and Scopus databases from inception to September 2016. Inclusion was limited to observational studies of individuals with symptomatic knee OA that identified phenotypes based on any OA characteristics and assessed their association with clinically important outcomes. A descriptive synthesis of the data was performed. RESULTS: Of the 2777 citations retrieved, 34 studies were included. Clinical phenotypes were investigated most frequently, followed by laboratory, imaging and aetiologic phenotypes. Eight studies defined subgroups based on outcome trajectories (pain, function and radiographic progression trajectories). Most studies used a single patient or disease characteristic to identify patients subgroups while five included characteristics from multiple domains. We found evidence from multiple studies suggesting that pain sensitization, psychological distress, radiographic severity, body mass index (BMI), muscle strength, inflammation and comorbidities are associated with clinically distinct phenotypes. Gender, obesity and other metabolic abnormalities, the pattern of cartilage damage, and inflammation may be implicated in delineating distinct structural phenotypes. Only a few studies investigated the external validity of the phenotypes or their prospective validity using longitudinal outcomes. CONCLUSIONS: There is marked heterogeneity in the data selected by the studies investigating knee OA phenotypes. We identified the phenotypic characteristics that can be considered for a comprehensive phenotype classification in future studies. A framework for the investigation of phenotypes could be useful for future studies. PROTOCOL REGISTRATION: PROSPERO CRD42016036220. PMID- 28847625 TI - Clinical Presentation and Outcome of Patients With Optic Pathway Glioma. AB - BACKGROUND: Optic pathway gliomas (OPGs) occur sporadically or in patients with neurofibromatosis type 1 (NF1). The purpose of this study was to evaluate the clinical presentation at diagnosis and at progression of patients with OPGs. METHODS: We conducted a chart review of patients with OPGs diagnosed in a single center over a period of 15 years. Demographic data including age, sex, NF1 status, clinical presentation, and outcome were collected. RESULTS: Of the 40 patients who were identified, 23 had sporadic tumors (57.5%) and 17 had NF1 related tumors (42.5%). Among the children with NF1, there was a significant overrepresentation of girls (82.3%) (P = 0.02), while among the children without NF1, there were slightly more boys (56.5%) than girls (43.5%). The presence of nystagmus was strongly associated with sporadic optic pathway gliomas. Poor visual outcome was related to tumor affecting both optic pathways, hydrocephalus at diagnosis, and optic nerve atrophy. Of the 40 patients, five died of OPG complications (12.5%) and all had sporadic tumors. CONCLUSIONS: Our cohort is one of the largest with OPGs and a detailed description of the clinical presentation both at diagnosis and at progression. We observed a significant difference between sporadic and NF1 optic pathway gliomas in terms of demographics, clinical presentation, and outcome. PMID- 28847626 TI - Cerebral oximetry versus end tidal CO2 in predicting ROSC after cardiac arrest. AB - STUDY OBJECTIVE: Both end tidal CO2 (ETCO2) and cerebral oxygen saturations (rSO2) have been studied to determine their ability to monitor the effectiveness of CPR and predict return of spontaneous circulation (ROSC). We compared the accuracy of ETCO2 and rSO2 at predicting ROSC in ED patients with out-of-hospital cardiac arrest (OHCA). METHODS: We performed a prospective, observational study of adult ED patients presenting in cardiac arrest. We collected demographic and clinical data including age, gender, presenting rhythm, rSO2, and ETCO2. We used receiver operating characteristic curves to compare how well rSO2 and ETCO2 predicted ROSC. RESULTS: 225 patients presented to the ED with cardiac arrest between 10/11 and 10/14 of which 100 had both rSO2 and ETCO2 measurements. Thirty three patients (33%) had sustained ROSC, only 2 survived to discharge. The AUCs for rSO2 and ETCO2 were similar (0.69 [95% CI, 0.59-0.80] and 0.77 [95% CI, 0.68 0.86], respectively), however, rSO2 and ETCO2 were poorly correlated (0.12, 95% CI, -0.08-0.31). The optimal cutoffs for rSO2 and ETCO2 were 50% and 20mm Hg respectively. At these cutoffs, ETCO2 was more sensitive (100%, 95% CI 87-100 vs. 48%, 31-66) but rSO2 was more specific (85%, 95% CI, 74-92 vs. 45%, 33-57). CONCLUSIONS: While poorly correlated, rSO2 and ETCO2 have similar diagnostic characteristics. ETCO2 is more sensitive and rSO2 is more specific at predicting ROSC in OHCA. PMID- 28847627 TI - Emergency department patient experience and waiting time. PMID- 28847628 TI - Disco spotlight sign: A sign that may be useful for diagnosis of pneumomediastinum. AB - The use of ultrasonography for the investigation of pneumomediastinum is limited by the presence of air artifacts. Air accumulation in the mediastinum obscures the heart, sometimes leading to misinterpretation as lung tissue. We found that cardiac apical swinging during the heart cycle, however, can create a uniquely characteristic squeezing of mediastinal free air, producing a sonographic B-line that flashes in and out. We named this dynamic finding, the "disco spotlight" sign. This finding may be useful to confirm the diagnosis of pneumomediastinum. PMID- 28847629 TI - Analysis of the correlation between dental arch and articular eminence morphology: a cone beam computed tomography study. AB - OBJECTIVE: The aim of the study was to assess the correlation between the morphology of the dental arches (DAs) of patients with normal occlusion and of the articular eminence (AE) by using cone beam computed tomography (CBCT). STUDY DESIGN: CBCT scans of 60 patients were evaluated in terms of height and inclinations (angles alpha, beta, and delta) of the AE. DAs were classified according to their shapes (tapered, square, ovoid), and their perimeters, widths, and depths were measured. One-way analysis of variance, Pearson's correlation coefficients, and simple and multivariate linear regression models were used for the calculations. RESULTS: The ovoid arch was the most predominant shape (n = 66/120). Inclination of the AE (angle beta) had the greatest difference between DA shapes, with this angle usually being greater in the ovoid arch and smaller in the square arch (P < .05). The height of the AE presented greater correlation with DA measurements, with tapered arches having the most significant correlations (P < .05). DA depth had no influence on AE measurements (P > .05). The perimeter and width of the DAs had some influence (P < .05). CONCLUSIONS: Correlations were found between the DA and AE morphologies. The correlations should be taken into consideration, although the results do not prove absolute association between the variables. Whenever possible, the morphologic features of DAs should be preserved to avoid possible changes in AE. PMID- 28847630 TI - Finding some seagrass optimism in Wales, the case of Zostera noltii. AB - There exists limited understanding of the long-term dynamics of the seagrass Zostera noltii and how this is influenced by anthropogenic pressures. Milford Haven is a heavily industrialised estuary and also one of the important sites for Zostera sp. in the UK. In this study we examine all available long-term spatial variability and abundance data of Zostera noltii within Milford Haven using historic datasets. Results show that Z. noltii in all sites have shown meadow expansion when compared to the first obtainable records. Little change in abundance over the past 10-15years for the two sites confirms certain seagrass populations to be robust and thriving. We hypothesise that these populations are showing a level of resilience to the high nutrient levels, disturbance and high turbidity present within the water column of the Haven. PMID- 28847631 TI - Ecological quality status of the Adriatic coastal waters evaluated by the organotin pollution biomonitoring. AB - The aim of this study was to evaluate the post-legislation change in tributyltin (TBT) pollution at Croatian Adriatic coast. Gastropod Hexaplex trunculus and sediments were collected, nearly 10years after TBT based antifouling paints were banned, at 12 locations along the coast where a previous study was conducted in 2005. The study showed a decline of TBT levels over the investigated period, although all gastropods populations were highly affected by imposex meaning that prohibition did not result in the recovery of populations. The further aim was to propose the Ecological Quality Ratio (EQR) boundaries for potential use of H. trunculus as a principal bioindicator in the assessment of the ecological status of the Mediterranean regarding TBT pollution, under the Water Framework Directive (WFD). According to the proposed EQR classes, the WFD target for achieving the Good ecological status of the marine environment by 2015 was not reached. PMID- 28847632 TI - A tropical bay as a reference area defined by multiple lines of evidences. AB - References areas are sites that have undergone little or no anthropogenic impact and therefore represent the natural state of an environment. The objective of this study was to test if the Camamu Bay (CB), Bahia, can be used as a reference area for tropical coastal environments. Trace and major elements, polycyclic aromatic hydrocarbons (PAH), and the structure of the benthic macrofauna were determined. To compare the studied sites and identify the possible occurrence of anomalous concentrations, trace elements were normalized by Al and linear regressions were also performed. For all trace elements (except Cu), regressions showed a significant correlation (p<0.05) and few outliers (<3% of cases), showing that the concentrations found represent natural values for this bay. In the case of Cu, the highest concentrations were found near small municipalities, which may be associated with domestic sewage. About 60% of the organic compounds occurred at levels below the limit of quantification (<0.26ngg-1). The sum of PAHs was low for all stations, ranging from 1.17 to 313ngg-1. The benthic assemblages also indicated that the CB is a healthy, well-preserved ecosystem that deserves conservation efforts. The integrated use of geochemical and biotic data supported the use of CB as a reference area. Capsule: Organic and inorganic contaminants together with macrobenthic assemblages indicated that Camamu Bay is a pristine, tropical reference area. PMID- 28847633 TI - Sediments indicate the continued use of banned antifouling compounds. AB - Antifouling paints are widely used to avoid organisms settling on boat hulls. The active ingredients in the paints have differed over the years where lead, TBT, irgarol and diuron have been deemed too harmful to non-target organisms and subsequently been banned within the EU. Most of these compounds however are persistent in the environment and can cause problems long after they are deposited. We have examined if present-day and banned substances used in antifouling paints can be found in sediments in a national park on the Swedish west coast. Sampled locations include waterways, natural harbours and small marinas for leisure crafts to investigate if number of visiting boats affect the concentration of antifouling compounds in sediments. Few significant differences were found when comparing the different locations types, suggesting that overall boat presence is more important than specific mooring sites, however, several banned antifouling compounds were found in the surface sediments. PMID- 28847634 TI - Distribution and source of organic matter in surface sediment from the muddy deposit along the Zhejiang coast, East China Sea. AB - To constrain organic matter compositions and origins, elemental (TOC, TN, C/N) and stable carbon (delta13C) and nitrogen isotope (delta15N) compositions are measured for surface sediments collected from muddy deposit along the Zhejiang coast, East China Sea. The results showed that the TOC, TN, C/N, delta13C, and delta15N were 0.19-0.67%, 0.03-0.09%, 6.76-9.22, -23.43 to -20.260/00, and 3.93 5.270/00, respectively. The delta13C values showed that the mixing inputs of terrigenous and marine organic matter generally dominated sedimentary organic matter in the west part, and the sedimentary organic matters were mainly influenced by the marine organic matter in the east part of the study area. A stable carbon isotope two end member mixing model estimates ~38% terrestrial derived and ~62% marine-derived inputs to sedimentary organic matter. Microbial mineralization strongly controls delta15N values, and therefore cannot be used to identify the provenance of organic matter for the Zhenjiang coast. PMID- 28847635 TI - Method for reduction of the NOX emissions in marine auxiliary diesel engine using the fuel mixtures containing biodiesel using HCCI combustion. AB - The marine auxiliary diesel engines installed in the large transoceanic ships are used in order to generate the electricity but at the same time these engines are able to produce a significant amount of the harmful exhaust gas emissions. Therefore the International Maritime Organisation (IMO) concluded an agreement, which has to control generating of gaseous emissions in maritime transport. From this reason started to be used some of the alternative fuels in this branch. There was performed a study, which investigated emissions of the auxiliary marine diesel engine during application of the experimental fuels. The different testing fuels were created using the ratios 0%, 50%, 80% and 100% between the biodiesel and the ULSDF (Ultra Low Sulphur Diesel Fuel). The experimental measurements were performed at the different engine loading levels and various engine speeds in order to investigate an influence of the mixed fuels on the engine operational characteristics. PMID- 28847637 TI - CRP: tell-tale biomarker or common denominator? PMID- 28847636 TI - Point-of-care C-reactive protein-based tuberculosis screening for people living with HIV: a diagnostic accuracy study. AB - BACKGROUND: Symptom-based screening for tuberculosis is recommended for all people living with HIV. This recommendation results in unnecessary Xpert MTB/RIF testing in many individuals living in tuberculosis-endemic areas and thus poor implementation of intensified case finding and tuberculosis preventive therapy. Novel approaches to tuberculosis screening are needed to help achieve global targets for tuberculosis elimination. We assessed the performance of C-reactive protein (CRP) measured with a point-of-care assay as a screening tool for active pulmonary tuberculosis. METHODS: For this prospective study, we enrolled adults (aged >=18 years) living with HIV with CD4 cell count less than or equal to 350 cells per MUL who were initiating antiretroviral therapy (ART) from two HIV/AIDS clinics in Uganda. CRP concentrations were measured at study entry with a point of-care assay using whole blood obtained by fingerprick (concentration >=10 mg/L defined as screen positive for tuberculosis). Sputum samples were collected for Xpert MTB/RIF testing and culture. We calculated the sensitivity and specificity of point-of-care CRP and WHO symptom-based screening in reference to culture results. We repeated the sensitivity analysis with Xpert MTB/RIF as the reference standard. FINDINGS: Between July 8, 2013, and Dec 15, 2015, 1237 HIV-infected adults were enrolled and underwent point-of-care CRP testing. 60 (5%) patients with incomplete or contaminated cultures were excluded from the analysis. Of the remaining 1177 patients (median CD4 count 165 cells per MUL [IQR 75-271]), 163 (14%) had culture-confirmed tuberculosis. Point-of-care CRP testing had 89% sensitivity (145 of 163, 95% CI 83-93) and 72% specificity (731 of 1014, 95% CI 69-75) for culture-confirmed tuberculosis. Compared with WHO symptom-based screening, point-of-care CRP testing had lower sensitivity (difference -7%, 95% CI -12 to -2; p=0.002) but substantially higher specificity (difference 58%, 95% CI 55 to 61; p<0.0001). When Xpert MTB/RIF results were used as the reference standard, sensitivity of point-of-care CRP and WHO symptom-based screening were similar (94% [79 of 84] vs 99% [83 of 84], respectively; difference -5%, 95% CI 12 to 2; p=0.10). INTERPRETATION: The performance characteristics of CRP support its use as a tuberculosis screening test for people living with HIV with CD4 count less than or equal to 350 cells per MUL who are initiating ART. HIV/AIDS programmes should consider point-of-care CRP-based tuberculosis screening to improve the efficiency of intensified case finding and increase uptake of tuberculosis preventive therapy. FUNDING: National Institutes of Health; President's Emergency Plan for AIDS Relief; University of California, San Francisco, Nina Ireland Program for Lung Health. PMID- 28847638 TI - Osmotic tolerance of feline epididymal spermatozoa. AB - During the cryopreservation process, spermatozoa are exposed to hypertonic solutions contributed by the high concentration of cryoprotectant. During addition and removal of cryoprotectant the spermatozoa are subjected to a substantial osmotic stress. Spermatozoa of different species and different stages of maturation may have different susceptibility to osmotic stress depending on the biology of the cell membrane and this will affect their tolerance to the freezing-thawing stress. The aims of this study were to determine the osmotic tolerance limits for motility, membrane integrity and mitochondrial membrane potential of feline epididymal spermatozoa and to study the effect of osmotic stress on the feline spermatozoa of different epididymal regions. Epididymal spermatozoa from three regions (caput, corpus and cauda) were pre-exposed to various osmolalities (75, 300, 600, 900, 1200 mOsm) in a single step for 10min and returned to 300 mOsm afterward. Percentage of motile spermatozoa was measured subjectively and membrane integrity (SYBR-14 positive cells) was evaluated prior to and after exposure to different osmolalities. The mitochondrial membrane potential (JC1) of spermatozoa were evaluated using flow cytometer and compared between epididymal regions (caput, corpus and cauda). All the parameters were compared using a mixed procedure. The percentage of motile epididymal spermatozoa decreased significantly when spermatozoa were exposed to 75 mOsm and 600 mOsm. Epididymal spermatozoa showed signs of damage when pre-exposed to 900 and 1200 mOsm and returned to isotonic condition as significant reduction of membrane integrity and mitochondrial membrane potential were observed (P<0.05). The plasma membrane of spermatozoa from the cauda epididymal region showed higher susceptibility to osmotic stress than the other regions as demonstrated by a significant difference between regions after return to isotonicity from 900 mOsm (P>0.01) and a difference between caput and corpus after return from 1200 mOsm (P<0.05). The corpus and cauda epididymal spermatozoa had higher percentage of spermatozoa with high mitochondrial membrane potential than those from caput when exposed to 75, 300 and 600 mOsm (P<0.05). In conclusion, a single step exposure to hypertonic solution of greater than 600 mOsm prior to return to isotonic condition can cause severe damage to sperm membrane and mitochondrial membrane potential compared to non-returning (exposure to various osmolality but not returned to isotonic condition). Changes in osmolality impacted mostly on sperm motility. Spermatozoa from cauda epididymis were more susceptible to osmotic stress compared to those from corpus and caput indicating that the maturation changes in the sperm membrane during passage through the epididymis increase susceptibility to the osmotic changes that may occur during sperm cryopreservation. PMID- 28847639 TI - Gonadorelin increases semen production and does not affect its quality in Leporinus obtusidens. AB - Use of carp pituitary extract (CPE) as a hormone inducer for Leporinus obtusidens is cost-prohibitive; moreover, CPE contains unknown concentrations of gonadotropins. We evaluated the efficacy of gonadorelin as a substitute by analyzing its effect on sperm characteristics of L. obtusidens and cost effectiveness (20, 40, 60, 80, and 100MUgkg-1). Untreated and CPE-treated (4mgkg 1) fish were used as negative and positive controls, respectively. Following a single intramuscular dose of hormones, semen was collected at 200 degrees -h. At doses from 60MUgkg-1, all fish produced higher milt volume (P<0.05) than the negative control (0.2-0.8mLkg-1), equal (P>0.05) to the positive control (3.52+/ 0.97mLkg-1). Gonadorelin did not affect sperm concentration (P>0.05). The percentage of morphologically normal spermatozoa was >64% in all treatments. The number of spermatozoa with intact membrane (70%-85%) was equal (P>0.05) to that in the controls. Relative to the negative control, gonadorelin did not affect the motility rate (P>0.05). Curvilinear velocity was equal (P>0.05) to that in both controls. The sperm swimming path was linear (0.9) 10s after activation and was not (P>0.05) dose-dependent. Considering the response rate of gonadorelin-induced fish and the similarity of semen quality compared to controls, the lowest effective dose to produce a higher volume of semen in L. obtusidens is 60MUgkg-1, and the cost to induce 1kg of L. obtusidens is 14.0% lower than that with CPE. PMID- 28847640 TI - Increased Epicardial Fat Volume Is Independently Associated with the Presence and Severity of Systemic Sclerosis. AB - RATIONALE AND OBJECTIVES: The study aimed to determine if intrathoracic fat volumes are associated with the presence and severity of systemic sclerosis (SSc), defined by the presence of pulmonary arterial hypertension (PAH). MATERIALS AND METHODS: A total of 265 patients were included in the study, 202 of whom had SSc (134 had SSc with no PAH and 68 had SSc-associated PAH) and who underwent high-resolution computed tomography, and 63 controls who underwent coronary computed tomography angiography with calcium scoring. Intrathoracic and epicardial (EFV) fat volumes were quantified by manual tracing of the mediastinum and the pericardium, the difference of which represents the extrapericardial fat volume. Associations between these three fat volumes and the presence and severity of SSc, adjusted for cardiovascular risk factors and interstitial lung disease, were evaluated by logistic regression analysis. RESULTS: Of the 202 patients with SSc, the mean age was 55 years (ranged from 20 to 86), and 79% (159 of 202) were women. Adjusted EFV (odds ratio [OR]: 1.065; 95% confidence interval [CI]: 1.046-1.084, P = < 0.0001), extrapericardial fat volume (OR: 1.028, 95% CI: 1.017-1.038, P = < 0.0001), and intrathoracic fat volume (OR: 1.033, 95% CI: 1.023-1.043, P = 0.001) were associated with the presence of SSc. Only EFV was associated with SSc severity (adjusted OR: 1.010, 95% CI: 1.003-1.018, P = 0.007). CONCLUSION: Increased epicardial fat volume is associated with the presence and severity of SSc, independent of cardiovascular risk factors and interstitial lung disease. PMID- 28847642 TI - Clinical characteristics of Lynch-like cases collaterally classified by Lynch syndrome identification strategy using universal screening in endometrial cancer. AB - OBJECTIVE: Lynch syndrome (LS), an autosomal-dominant inherited disorder, increases the risk for LS-associated cancers (LS-AC). Molecular LS assessment for all cases is referred to as universal screening (U/S) and is recommended for endometrial cancer (EC) and colorectal cancer. Lynch-like cases (LL) lack LS pathogenic mutations despite being suspected as LS by U/S, but have been poorly investigated in EC. The aim of this study was to capture the features of LL in EC and to devise LL management in EC. METHODS: U/S, consisting of immunohistochemistry and reflex methylation analysis, was applied to 348 Asian ECs, and sporadic cancer (SC) cases were screened out. Genetic testing was offered to "suspected-LS" cases selected by U/S. The features of the LS, LL, and SC groups were recorded and compared. RESULTS: U/S screened 306 ECs as SC. The recurrence rates of suspected-LS and SC cases were 14.3% (6/42) and 26.5% (81/306), respectively. Of the 42 suspected-LS cases, 10 were identified as LS, 17 were classified as LL, and 15 did not undergo genetic testing. In the LS group, the frequency of personal history (50%) and family history (100%) of LS-AC were prominent. Of note, the prevalence of family history of LS-AC and gastric cancer was significantly higher in the LL group than in the SC group (76.5% vs. 38.6% and 47.1% vs. 25.2%, respectively). CONCLUSIONS: Herein, we report the features of LL classified by LS identification via U/S in Asian EC. LL should be candidates for tailored surveillance based on regionality and family history. PMID- 28847641 TI - Optical Coherence Tomography Predictors of Risk for Progression to Non Neovascular Atrophic Age-Related Macular Degeneration. AB - PURPOSE: Appearance of geographic atrophy (GA) on color photography (CP) is preceded by specific features on spectral-domain optical coherence tomography (SD OCT). We aimed to build SD OCT-based risk assessment models for 5-year new onset of GA and central GA on CP. DESIGN: Prospective, longitudinal study. PARTICIPANTS: Age-Related Eye Disease Study 2 Ancillary SD OCT study participants with age-related macular degeneration (AMD) with bilateral large drusen or noncentral GA and at least 1 eye without advanced disease (n = 317). METHODS: For 1 eye per participant, qualitative and quantitative SD OCT variables were derived from standardized grading and semiautomated segmentation, respectively, at baseline. Up to 7 years later, annual outcomes were extracted and analyzed to fit multivariate logistic regression models and build a risk calculator. MAIN OUTCOME MEASURES: New onset of CP-visible GA and central GA. RESULTS: Over a follow-up median of 4.0 years and among 292 AMD eyes (without advanced disease at baseline) with complete outcome data, 46 (15.8%) developed central GA. Among 265 eyes without any GA on baseline CP, 70 (26.4%) developed CP-visible GA. Final multivariate models were adjusted for age. In the model for GA, the independent predicting SD OCT factors (P < 0.001-0.03) were: hyperreflective foci and retinal pigment epithelium (RPE) layer atrophy or absence, followed by choroid thickness in absence of subretinal drusenoid deposits, photoreceptor outer segment loss, RPE drusen complex volume, and RPE drusen complex abnormal thinning volume. For central GA, the factors (P < 0.001) were RPE drusen complex abnormal thinning volume, intraretinal fluid or cystoid spaces, hyperreflective foci, and RPE layer atrophy or absence. The models yielded a calculator that computes the probabilities of CP-visible, new-onset GA and central GA after 1 to 5 years. CONCLUSIONS: For AMD eyes with large drusen and no advanced disease, we built a novel risk assessment model-based on age and SD OCT segmentation, drusen characteristics, and retinal pathology-for progression to CP-visible GA over up to 5 years. This calculator may simplify SD OCT grading and with future validation has a promising role as a clinical prognostic tool. PMID- 28847643 TI - Posterior Tibial Nerve Lymphoma Presenting as Tarsal Tunnel Syndrome: A Case Report. AB - We report a case of isolated posterior tibial B-cell lymphoma of the posterior tibial nerve presenting as tarsal tunnel syndrome. This diagnosis was considered because of the clinical presentation and electrophysiologic abnormalities. It was further confirmed by the magnetic resonance imaging findings of the ankle and tissue pathologic findings. Whole body positron emission tomography confirmed this to be a localized lymphoma involving the peripheral nerve. The patient underwent chemotherapy with complete tumor resolution. She had had no relapse after 8 months of follow-up. Isolated peripheral nerve lymphomas are very rare, and involvement of the posterior tibial nerve has not been previously reported. Furthermore, the present case report highlights the importance of the clinical examination in the diagnosis of tarsal tunnel syndrome before performing surgical decompression. PMID- 28847644 TI - Reversed First Dorsal Metatarsal Artery Island Flap for First Ray Defects. AB - Reconstruction of the first ray is challenging because of poor skin laxity, bone and tendon exposure, and limited local flap options. Repair using full- or split thickness skin grafts is generally not an option because of the bone and tendon exposure. Reconstructive options using local flaps from the distal foot area are restricted owing to insufficient soft tissue. Many reconstructive options have been described to overcome these difficult situations. We present 2 cases in which the great toe and first ray defect were repaired using a reversed first dorsal metatarsal artery island flap. The findings from these clinical cases and anatomic studies have shown that the reversed first dorsal metatarsal artery island flap is an alternative and suitable option for reconstruction of soft tissue defect of the distal foot, especially first and second ray defects, because it is thin and simple, has anatomic characteristics similar to those at the recipient site, and results in minimal donor site morbidity. PMID- 28847645 TI - European interpretation of North American post mastectomy radiotherapy guideline update. PMID- 28847646 TI - ? PMID- 28847647 TI - Effects of Fe and Mn deficiencies on the protein profiles of tomato (Solanum lycopersicum) xylem sap as revealed by shotgun analyses. AB - The aim of this work was to study the effects of Fe and Mn deficiencies on the xylem sap proteome of tomato using a shotgun proteomic approach, with the final goal of elucidating plant response mechanisms to these stresses. This approach yielded 643 proteins reliably identified and quantified with 70% of them predicted as secretory. Iron and Mn deficiencies caused statistically significant and biologically relevant abundance changes in 119 and 118 xylem sap proteins, respectively. In both deficiencies, metabolic pathways most affected were protein metabolism, stress/oxidoreductases and cell wall modifications. First, results suggest that Fe deficiency elicited more stress responses than Mn deficiency, based on the changes in oxidative and proteolytic enzymes. Second, both nutrient deficiencies affect the secondary cell wall metabolism, with changes in Fe deficiency occurring via peroxidase activity, and in Mn deficiency involving peroxidase, Cu-oxidase and fasciclin-like arabinogalactan proteins. Third, the primary cell wall metabolism was affected by both nutrient deficiencies, with changes following opposite directions as judged from the abundances of several glycoside-hydrolases with endo-glycolytic activities and pectin esterases. Fourth, signaling pathways via xylem involving CLE and/or lipids as well as changes in phosphorylation and N-glycosylation also play a role in the responses to these stresses. Biological significance In spite of being essential for the delivery of nutrients to the shoots, our knowledge of xylem responses to nutrient deficiencies is very limited. The present work applies a shotgun proteomic approach to unravel the effects of Fe and Mn deficiencies on the xylem sap proteome. Overall, Fe deficiency seems to elicit more stress in the xylem sap proteome than Mn deficiency, based on the changes measured in proteolytic and oxido-reductase proteins, whereas both nutrients exert modifications in the composition of the primary and secondary cell wall. Cell wall modifications could affect the mechanical and permeability properties of the xylem sap vessels, and therefore ultimately affect solute transport and distribution to the leaves. Results also suggest that signaling cascades involving lipid and peptides might play a role in nutrient stress signaling and pinpoint interesting candidates for future studies. Finally, both nutrient deficiencies seem to affect phosphorylation and glycosylation processes, again following an opposite pattern. PMID- 28847648 TI - Changes in protein abundance and activity involved in freezing tolerance acquisition in winter barley (Hordeum vulgare L.). AB - : The changes in protein abundance induced by cold hardening were analysed by 2 DE in ten doubled haploid (DH) lines of winter barley, highly differentiated with respect to freezing tolerance level. Among 45 differential proteins identified by MALDI-TOF/TOF, the majority was classified as related to photosynthesis, carbohydrate metabolism, oxidation-reduction reactions and stress response. Among the detected proteins, higher abundance of RuBisCO large and small subunits, RuBisCO activase, two Oxygen-evolving enhancer proteins, Ferredoxin-NADP reductase, Cytochrome P450-dependent fatty acid hydroxylase and 14-3-3 protein was associated with higher freezing tolerance level. Lower relative level of hypothetical ATP synthase beta subunit, uncharacterized mitochondrial protein AtMg00810 and ribosomal RNA small subunit methyltransferase G also seems to be important. The results of proteomic studies were complemented by the evaluation of photosynthetic apparatus acclimation, showing distinctive differences between the studied genotypes in the number of active PSII reaction centres (RC/CSm). Additionally, the analysis of antioxidative enzyme activities suggests the importance of H2O2 as a signalling molecule possibly involved in the initiation of cold-induced plant acclimation. However, in DH lines with high freezing tolerance, H2O2 generation during cold hardening treatment was accompanied by more stable activity of catalase, H2O2-decomposing enzyme. SIGNIFICANCE: In the study, the changes in protein abundance induced by cold hardening treatment were analysed by two-dimensional gel electrophoresis in ten doubled haploid (DH) lines of winter barley. Harnessing DH technology resulted in distinctive widening of genetic variation with respect to freezing tolerance level. Both the cold hardening effect on the protein pattern in an individual winter barley DH line as well as the variation among the selected DH lines were investigated, which resulted in the identification of 45 differentiated proteins classified as involved in 14 metabolic pathways and cellular processes. Among them, eight proteins: (1) the precursor of RuBisCO large subunit, (2) RuBisCO small subunit (partial), (3) RuBisCO activase small isoform, (4) the precursor of Oxygen evolving enhancer protein 1-like (predicted protein), (5) Oxygen-evolving enhancer protein 2, (6) the leaf isozyme of Ferredoxin-NADP reductase, (7) hypothetical protein M569_12509 Cytochrome P450-dependent fatty acid hydroxylase like and (8) hypothetical protein BRADI_1g11290 (14-3-3 protein A-like) were accumulated to a higher level in leaves of cold-hardened seedlings of freezing tolerant winter barley DH lines in comparison with susceptible ones. Three others: (9) hypothetical protein BRADI_5g05668 F1 ATP synthase beta subunit-like, (10) predicted protein uncharacterized mitochondrial protein AtMg00810-like and (11) BnaA02g08010D Ribosomal RNA small subunit methyltransferase G-like were detected at lower level in freezing tolerant seedlings in comparison with susceptible genotypes. The last two were for the first time linked to cold acclimation. The results of complementary analyses indicate that PSII activity and stability of antioxidative enzymes under low temperature are also very important for freezing tolerance acquisition. PMID- 28847649 TI - Proteomic analysis reveals strong mitochondrial involvement in cytoplasmic male sterility of pepper (Capsicum annuum L.). AB - : Although cytoplasmic male sterility (CMS) is widely used for developing pepper hybrids, its molecular mechanism remains unclear. In this study, we used a high throughput proteomics method called label-free to compare protein abundance across a pepper CMS line (A-line) and its isogenic maintainer line (B-line). Data are available via ProteomeXchange with identifier PXD006104. Approximately 324 differentially abundant protein species were identified and quantified; among which, 47 were up-accumulated and 140 were down-accumulated in the A-line; additionally, 75 and 62 protein species were specifically accumulated in the A line and B-line, respectively. Protein species involved in pollen exine formation, pyruvate metabolic processes, the tricarboxylic acid cycle, the mitochondrial electron transport chain, and oxidative stress response were observed to be differentially accumulated between A-line and B-line, suggesting their potential roles in the regulation of pepper pollen abortion. Based on our data, we proposed a potential regulatory network for pepper CMS that unifies these processes. BIOLOGICAL SIGNIFICANCE: Artificial emasculation is a major obstacle in pepper hybrid breeding for its high labor cost and poor seed purity. While the use of cytoplasmic male sterility (CMS) in hybrid system is seriously frustrated because a long time is needed to cultivate male sterility line and its isogenic restore line. Transgenic technology is an effective and rapid method to obtain male sterility lines and its widely application has very important significance in speeding up breeding process in pepper. Although numerous studies have been conducted to select the genes related to male sterility, the molecular mechanism of cytoplasmic male sterility in pepper remains unknown. In this study, we used the high-throughput proteomic method called "label-free", coupled with liquid chromatography-quadrupole mass spectrometry (LC-MS/MS), to perform a novel comparison of expression profiles in a CMS pepper line and its maintainer line. Based on our results, we proposed a potential regulated protein network involved in pollen development as a novel mechanism of pepper CMS. PMID- 28847652 TI - Eosinophilic granulomatosis with polyangiitis (Churg-Strauss vasculitis) presenting as Samter's triad. PMID- 28847651 TI - Vitamin D insufficiency, plasma cytokines, and severe asthma exacerbations in school-aged children. PMID- 28847653 TI - A three-level stepwise oral food challenge for egg, milk, and wheat allergy. PMID- 28847650 TI - Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development. AB - Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation. PMID- 28847654 TI - A case of lichenoid and pigmented drug eruption to acetazolamide confirmed by a lichenoid patch test. PMID- 28847655 TI - Long-Acting beta2-Agonists and Risk of Hypertensive Disorders of Pregnancy: A Cohort Study. AB - BACKGROUND: Maternal asthma has been found to be associated with an increased risk of hypertensive disorders of pregnancy (HDP), that is, gestational hypertension, preeclampsia, and eclampsia. There is limited data, however, regarding the relationship between the use of long-acting beta-agonists (LABAs) during pregnancy and these outcomes. OBJECTIVE: To investigate whether exposure to a LABA in addition to an inhaled corticosteroid increases the risk of HDP or preeclampsia/eclampsia, as compared with nonexposure to LABAs, in pregnant women with asthma. METHODS: A cohort of 8,936 pregnancies in women with asthma who delivered between 1998 and 2010 was reconstructed using Quebec (Canada) health administrative databases. Cox proportional hazard regression models, adjusted for potential confounders, were used for statistical analyses. The primary exposure was LABA use (yes/no) measured on the first day of the 20th week of pregnancy. HDP were identified on the basis of recorded diagnoses and on prescriptions of antihypertensive drugs filled on or after the first day of week 20 of gestation. RESULTS: There were 567 (6.3%) cases of HDP and 256 (2.9%) cases of preeclampsia/eclampsia in the cohort, and the rates of both disorders were similar in women exposed or not exposed to LABAs. LABA use was not associated with increased risks of HDP (adjusted hazard ratio, 0.96; 95% CI, 0.69-1.33) or preeclampsia/eclampsia (adjusted hazard ratio, 0.89; 95% CI, 0.53-1.50). CONCLUSIONS: The results of this study provide evidence suggesting the safety of LABAs for the treatment of asthma in pregnancy, in terms of the risks of HDP and preeclampsia/eclampsia. PMID- 28847656 TI - National Prevalence of Poor Asthma Control and Associated Outcomes Among School Aged Children in the United States. AB - BACKGROUND: The degree of asthma control among school-aged children (SAC) nationally is not well understood. OBJECTIVE: The objective of this study was to characterize poor control among SAC (aged 6-17 years) in the United States. METHODS: This was a retrospective analysis of the 2007-2013 Medical Expenditure Panel Survey. Indicators of poor control included exacerbation in previous year; use of >3 canisters of short-acting beta-agonist (SABA) in 3 months; and asthma specific (AS) emergency department (ED) or inpatient (IP) visits. Treatment indicators included daily controller medication and peak flow meter use. Negative binomial regression was used for health resource utilization (HRU); generalized linear models with log-link were used for health care expenditures. RESULTS: There were 44,320 SAC, of whom 5,890 had asthma. The prevalence of poor control and treatment among SAC with asthma were as follows: exacerbation (59%), >3 canisters of SABA (4%), ED/IP visit (3%), daily controller (19%), peak flow (12%). In 2013, 3.4 million SAC had an asthma exacerbation and 200,000 had an AS ED/IP visit. SAC with asthma and an exacerbation had 18.9 times more annual AS ED visits (and 43.3 times more AS hospitalizations) than SAC with asthma but no exacerbation. SAC with asthma and an indicator of poor control incurred greater annual all-cause expenditures than SAC without asthma ($US 2015): $1,144 (exacerbation), $1,859 (>=3 canisters of SABA), and $3,063 (ED/IP visit). Use of daily controller medication was low even among SAC with poor control (27% to 61%). CONCLUSION: Renewed and vigilant asthma management and treatment is necessary to mitigate the current and long-term public health effects and expenditures associated with poor asthma control. PMID- 28847657 TI - Long-term results of endovascular repair for descending thoracic aortic aneurysms. AB - OBJECTIVE: Since thoracic endovascular aortic repair (TEVAR) received U.S. Food and Drug Administration approval for the treatment of descending thoracic aneurysms in March 2005, excellent 30-day and midterm outcomes have been described. However, data on long-term outcomes are lacking with Medicare data suggesting that TEVAR has worse late survival compared with open descending repair. As such, the purpose of this study was to examine the long-term outcomes for on-label use of TEVAR for repair of descending thoracic aneurysms. METHODS: Of 579 patients undergoing TEVAR between March 2005 and April 2016 at a single referral center for aortic surgery, 192 (33.2%) were performed for a descending thoracic aneurysm indication in accordance with the device instructions for use, including 106 fusiform (55.2%), 80 saccular (41.7%), and 6 with both saccular and fusiform (3.1%) aneurysms. All aneurysms were located distal to the left subclavian artery and proximal to the celiac axis, and hybrid procedures including arch or visceral debranching were excluded with the exception of left carotid-subclavian artery bypass. Aortic dissection and intramural hematoma as indications for TEVAR were also excluded. Primary 30-day and in-hospital outcomes included mortality, stroke, need for new permanent dialysis, and permanent paraparesis or paraplegia. Primary long-term outcomes included survival and rate of reintervention secondary to endoleak. The Kaplan-Meier method was used to estimate long-term overall and aorta-specific survivals. RESULTS: The mean age was 71.1 +/- 10.4 years. All aneurysms in this series were degenerative in nature and no patients with a connective tissue disorder were included. The mean aortic diameter was 5.9 +/- 1.5 cm at time of intervention. Rates of 30-day and in hospital mortality, stroke, permanent dialysis, and permanent paraparesis and paraplegia were 4.7%, 2.1%, 0.5%, and 0.5%, respectively. At a mean follow-up of 69 +/- 44 months (range, 3-141 months), there were 68 late deaths (35.4%), two of which were due to aortic rupture. Overall and aorta-specific survivals at 141 months (11.8 years) were 45.7% and 96.2%, respectively. Endovascular reintervention was required in 14 patients (7.3%) owing to type I (n = 10), type II (n = 2), and type III (n = 2) endoleak, all of which subsequently resolved. No patient required open reintervention for any cause. CONCLUSIONS: Long-term (12 year) aorta-specific survival after on-label endovascular repair of degenerative descending thoracic aneurysms in nonsyndromic patients is excellent (96%) with sustained protection from rupture, and a low rate of reintervention owing to endoleak (7%). Endovascular repair should be considered the treatment of choice for this pathology. PMID- 28847658 TI - Perioperative psoas to lumbar vertebral index does not successfully predict amputation-free survival after lower extremity revascularization. AB - BACKGROUND: Accurate and convenient methods for assessing a patient's risk of postoperative morbidity and mortality comprise important tools in clinical decision-making. Whereas some aspects of the patient's fitness for surgery can be easily quantified, measurement of the patient's frailty is often difficult or time-consuming. Previous research in the context of multiple types of major surgical procedures has reported psoas-L4 vertebral index (PLVI) to be a useful predictor of postoperative morbidity and mortality. METHODS: This retrospective cohort study assessed the hypothesis that PLVI can predict amputation-free survival (AFS) in patients undergoing open or endovascular lower extremity revascularization. The records of all lower extremity revascularization patients with preoperative computed tomography arteriography before revascularization during a recent 6-year period were reviewed for demographic information and outcomes. With use of embedded computed tomography software, the cross-sectional area of the bilateral psoas muscles and vertebral body at the L4 level were measured and used to calculate the PLVI. Univariate, multivariate logistic regression, and Cox proportional hazards analyses were performed for the primary outcome of AFS. RESULTS: During a 6-year period, 188 patents had preoperative scanning, qualifying for inclusion in the study; 52% received open surgical bypass and 48% received a percutaneous endovascular procedure, with a median duration of follow-up of 12 months (interquartile range [IQR], 3-24 months). Median bilateral psoas cross-sectional area was 24.9 cm2 (IQR, 20.5-29.7 cm2), and mean PLVI was 1.74 (IQR, 1.39-2.05). Cox proportional hazards analysis identified age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.01-1.14; P = .026), congestive heart failure (HR, 4.7; 95% CI, 1.29-16.9; P = .019), and dyslipidemia (HR, 0.34; 95% CI, 0.12-0.99; P = .049) as independent predictors of AFS loss, whereas PLVI was not (HR, 2.6; 95% CI, 0.83-8.39; P = .099). Kaplan Meier life-table analysis demonstrated no significant differences in survival between the highest and lowest PLVI cohorts of patients. Hazard analysis showed concomitant congestive heart failure (HR, 15; 95% CI, 1.1-210; P = .042) and serum albumin concentration (HR, 0.16; 95% CI, 0.05-0.52; P = .0026) to be independent predictors of limb loss, whereas advanced age (HR, 1.20; 95% CI, 1.07 1.35; P = .0026), bypass procedure (HR, 4.6; 95% CI, 1.04-21; P = .045), non African American race (HR, 9.09; 95% CI, 1.02-100; P = .048), and higher PLVI (HR, 10.9; 95% CI, 1.7-72; P = .013) predicted increased risk of mortality. CONCLUSIONS: PLVI did not predict AFS after intervention for peripheral arterial occlusive disease. This is contrary to the ability of PLVI to predict perioperative and midterm survival after abdominal aortic aneurysm repair and other major abdominal surgery. PMID- 28847659 TI - Discussion. PMID- 28847660 TI - Estimated annual health care expenditures in individuals with peripheral arterial disease. AB - OBJECTIVE: The clinical impact of peripheral arterial disease (PAD) is well characterized and is associated with significant morbidity and mortality. Health care-related expenditures among individuals with PAD, particularly for patients, are not well described. METHODS: Health care-related expenditure data from the 2011 to 2014 Agency for Healthcare Research and Quality Medical Expenditure Panel Surveys were analyzed for individuals with a diagnosis of PAD compared with U.S. adults 40 years of age and older. Weighted average annual expenditures were estimated using a multivariable generalized linear model. Subanalyses were also performed for out-of-pocket (OOP) expenditures by insurance type. RESULTS: Adjusted for age, gender, and race, individuals with a diagnosis of PAD (weighted n = 640,098) had significantly higher average annual health care-related expenditures compared with the U.S. adult population as a whole (weighted n = 148,387,362). Average annual expenditures per individual for patients with PAD were $11,553 (95% confidence interval [CI], $8137-$14,968) compared with only $4219 (95% CI, $4064-$4375; P < .001) for those without. Expenditures were driven by increased prescription medication expenditures as well as by expenditures for inpatient care, outpatient hospital-based care, and outpatient office-based care. Individuals with PAD had significantly higher OOP prescription medication expenditures ($386 [95% CI, $258-$515] vs $192 [95% CI, $183-$202]; P = .003), which varied by insurance type, ranging from $179 (95% CI, $70-$288) for those with Medicare to $1196 (95% CI, $106-$2244) for those without insurance, although this difference did not reach significance. CONCLUSIONS: Individuals with a diagnosis of PAD have higher health care-related expenditures and OOP expenses compared with other US adults. These expenditures compound lost wages, care by family members, and lost opportunity costs, increasing the burden carried by patients with PAD. PMID- 28847661 TI - Role of TGFBR1 and TGFBR2 genetic variants in Marfan syndrome. AB - OBJECTIVE: Genetic variants in transforming growth factor beta (TGF-beta) receptors type 1 (TGFBR1) and type 2 (TGFBR2) genes have been associated with different hereditary connective tissue disorders sharing thoracic aortic aneurysm and dissection (TAA/D). Mutations in both TGFBR1/2 genes have been described in patients with TAA/D and Marfan syndrome (MFS), and they are associated consistently with Loeys-Dietz syndrome. The existing literature shows discordant data resulting from mutational screening of TGFBR1/2 genes in patients with MFS. The aim of the study was to investigate the role of TGFBR1/2 genetic variants in determining and/or modulating MFS clinical phenotype. METHODS: We investigated 75 unrelated patients with MFS referred to the Center for Marfan Syndrome and Related Disorders (Careggi University Hospital, Florence) who were subjected to FBN1 and TGFBR1/2 Sanger mutational screening. RESULTS: Forty-seven patients with MFS (63%) carried a pathogenetic FBN1 mutation. No pathogenetic mutations were detected in TGFBR1/2 genes. Ten common polymorphisms were identified in TGFBR2 and 6 in TGFBR1. Their association with cardiovascular manifestations was evaluated. Carriers of the A allele of rs11466512, delA allele of c.383delA or delT allele of c.1256-15del1T polymorphisms had a trend toward or significantly reduced z-scores (median [interquartile range (IQR)], 2.2 [1.13-4.77]; 2.1 [1.72 3.48]; 2.5 [1.85-3.86]) with respect to homozygous patients with wild-type MFS (median [IQR], 4.20 [2.39-7.25]; 3.9 [2.19-7.00]; 3.9 [2.14-6.93]). Carriers of the A allele of the rs2276767 polymorphism showed a trend toward increased z score (median [IQR], 4.9 [2.14-7.16]) with respect to patients with wild-type MFS (median [IQR], 3.3 [1.75-5.45]). The protective effect of TGFBR1/2 genetic score including all the 4 variants was also evaluated. Patients with MFS with two or more protective alleles included in the score had statistically significant reduced aortic z-scores (median [IQR], 2.20 [1.48-3.37]) with respect to patients with 1 or no protective alleles (median [IQR], 4.20 [2.48-7.12]; P = .007). Patients with severe aortic manifestations (aortic z-score >= 2 or aortic surgery) showed a significantly lower prevalence of subjects with two or more protective alleles included in the genetic score (29.7%) than patients with no or milder cardiovascular involvement (63.6%; P = .029). The genetic score protective effect on global aortic manifestations severity (aortic z-score >= 2 or aortic surgery) was also observed at the logistic regression analysis adjusted for the presence of FBN1 gene mutations (odds ratio, 0.21; 95% CI, 0.05-0.84; P = .028). CONCLUSIONS: In conclusion, our data reappraise the role of TGFBR1 and TGFBR2 as major genes in patients with MFS, and suggest that TGFBR1/2 genetic variants (in particular when evaluated as a burden by score) might play a role in modulating the severity of cardiovascular manifestation in MFS. PMID- 28847662 TI - Sarcopenia predicts poor long-term survival in patients undergoing endovascular aortic aneurysm repair. AB - OBJECTIVE: Sarcopenia measured by decreased psoas muscle size has been used as a surrogate for frailty and correlates with adverse outcomes in both the short and long term after many major operations. Our aim was to evaluate this measure as a predictor of outcomes in patients undergoing endovascular aortic aneurysm repair (EVAR). METHODS: Once Institutional Review Board approval was obtained, all patients who underwent EVAR from December 2010 to March 2016 at a Veterans Affairs hospital were assessed for sarcopenia by total psoas muscle area (TPA) measured on axial computed tomography scan immediately inferior to the fourth lumbar (L4) superior end plate. Outcomes including length of stay and mortality were collected from the medical record. RESULTS: There were 135 patients who underwent EVAR at a median age of 70 years. Median aneurysm size was 5.5 cm. Length of stay was >2 days in 25% of patients (n = 33), with the most common reasons for delayed discharge including respiratory complications (8.9% [n = 12]) and urinary retention (4.0% [n = 9]). Low TPA was not associated with extended length of stay (P = .40). Patients with lowest tertile TPA had 42% 5-year survival compared with 93% survival observed for the remaining two-thirds of patients (P = .01). Multivariate analysis revealed increased likelihood of mortality at 5 years for patients in the lowest tertile for TPA (odds ratio, 3.9; 95% confidence interval, 1.2-12.9) as well as for patients with chronic kidney disease (odds ratio, 5.2; 95% confidence interval, 1.5-18.0). CONCLUSIONS: Preoperative sarcopenia does not appear to affect length of stay but does portend worse long-term survival. This simple preoperative measurement may help vascular surgeons tailor repair thresholds and avoid nonbeneficial procedures. PMID- 28847663 TI - A current systematic evaluation and meta-analysis of chimney graft technology in aortic arch diseases. AB - OBJECTIVE: The aim of this study was to provide a review of the literature on the use of chimney graft (CG) technique in treating arterial diseases of the aortic arch and to extrapolate conclusions by summarizing the reported outcomes in a meta-analysis. METHODS: An extensive electronic search was made using PubMed/MEDLINE, Science Direct Databases, and the Cochrane Library. Included in this meta-analysis were all papers published up to February 2016 on endovascular chimney technique in the arch vessels with or without adjunct extra-anatomic debranching, in any language, providing data about at least one of the essential outcomes: early and late type I endoleak, 30-day mortality rate, development of perioperative stroke, patency, and retrograde aortic dissection. RESULTS: Of the 478 reports yielded by the electronic search, a total of 11 publications (on 373 patients and 387 CGs) fulfilled the inclusion criteria and were included in this study. The overall estimated proportion of technical success was 91.3% (95% confidence interval [CI], 87.4%-94.0%). Of the 373 patients, 26 (7%) experienced a type Ia endoleak in the perioperative period. The overall estimated proportion of early type Ia endoleak was 9.4% (95% CI, 6.5%-13.4%). Among the 10 studies that provided data, a retrograde type A dissection was observed in 2 of 351 patients, resulting in an overall estimated proportion of 1.8% (95% CI, 0.8% 4.0%). The pooled 30-day mortality rate was 7.9% (95% CI, 4.6%-13.2%). The pooled estimation for reintervention was 10.6% (95% CI, 5%-21%); for major stroke, 2.6% (95% CI, 1.3%-5.0%); for early patency, 97.9% (95% CI, 95.8%-99%); and for late patency, 92.9% (95% CI, 87.3%-96%). CONCLUSIONS: Treatment of aortic diseases involving the aortic arch poses a great challenge. The CG technique has been applied as an alternative treatment option. This meta-analysis shows that endovascular repair of aortic arch disease using a CG technique in the aortic arch vessels is technically feasible and effective but not without major risk of complications. PMID- 28847664 TI - Bacterial signatures in thrombus aspirates of patients with lower limb arterial and venous thrombosis. AB - OBJECTIVE: Increasing data supports the role of bacterial inflammation in adverse events of cardiovascular and cerebrovascular diseases. In our previous research, DNA of bacterial species found in coronary artery thrombus aspirates and ruptured cerebral aneurysms were mostly of endodontic and periodontal origin, where Streptococcus mitis group DNA was the most common. We hypothesized that the genomes of S mitis group could be identified in thrombus aspirates of patients with lower limb arterial and deep venous thrombosis. METHODS: Thrombus aspirates and control blood samples taken from 42 patients with acute or acute-on-chronic lower limb ischemia (Rutherford I-IIb) owing to arterial or graft thrombosis (n = 31) or lower limb deep venous thrombosis (n = 11) were examined using a quantitative real-time polymerase chain reaction to detect all possible bacterial DNA and DNA of S mitis group in particular. The samples were considered positive, if the amount of bacterial DNA in the thrombus aspirates was 2-fold or greater in comparison with control blood samples. RESULTS: In the positive samples the mean difference for the total bacterial DNA was 12.1-fold (median, 7.1), whereas the differences for S mitis group DNA were a mean of 29.1 and a median of 5.2-fold. Of the arterial thrombus aspirates, 57.9% were positive for bacterial DNA, whereas bacterial genomes were found in 75% of bypass graft thrombosis with 77.8% of the prosthetic grafts being positive. Of the deep vein thrombus aspirates, 45.5% contained bacterial genomes. Most (80%) of bacterial DNA-positive cases contained DNA from the S mitis group. Previous arterial interventions were significantly associated with the occurrence of S mitis group DNA (P = .049, Fisher's exact test). CONCLUSIONS: This is the first study to report the presence of bacterial DNA, predominantly of S mitis group origin, in the thrombus aspirates of surgical patients with lower limb arterial and deep venous thrombosis, suggesting their possible role in the pathogenesis of thrombotic events. Additional studies will, however, be needed to reach a final conclusion. PMID- 28847665 TI - Short-Term Results of Ultra-Short Anatomic vs Ultra-Short Non-Anatomic Proximal Loading Uncemented Femoral Stems. AB - BACKGROUND: Question arises as to whether rigid fixation of ultra-short anatomic or ultra-short non-anatomic proximal loading uncemented femoral stem can be obtained without diaphyseal stem fixation. The purpose of this study is to compare the short-term clinical results, radiographic results, revision and survival rates, and complication rates of ultra-short anatomic versus ultra-short non-anatomic uncemented femoral stems. METHODS: This study consisted of 50 patients (56 hips) in the ultra-short anatomic uncemented stem group (mean age 61.4 +/- 14.7 years) and 50 patients (56 hips) in the ultra-short non-anatomic uncemented stem group (mean age 59.5 +/- 15.2 years). The mean follow-up was 3.4 years (range 3-4) in the ultra-short anatomic stem group and 3.5 years (range 3 4) in the ultra-short non-anatomic stem group. RESULTS: At the final follow-up, the mean Harris hip scores (92 vs 93 points), Western Ontario and McMaster Universities Osteoarthritis scores (16 vs 15 points), University of California at Los Angeles activity scores (6.5 vs 6.8 points), the incidence of thigh pain (0% vs 4%), revision rates (0% vs 4%), aseptic loosening rate (0% vs 2%), and complication rates (2% vs 4%) were not significantly different between 2 groups. CONCLUSION: Both ultra-short anatomic and ultra-short non-anatomic proximal loading uncemented femoral stems obtained rigid fixation without diaphyseal stem fixation in the short-term follow-up. This finding suggests that an ultra-short anatomic uncemented femoral stem can be replaced with an ultra-short non-anatomic uncemented stem to reduce inventory of the femoral stems, and consequently reduce manufacturing and delivery cost of these femoral stems. PMID- 28847666 TI - Nanosuspensions of a new compound, ER-beta005, for enhanced oral bioavailability and improved analgesic efficacy. AB - Estrogen receptor-beta005 (ER-beta005) is a novel compound developed by our group; however, its application has been greatly hindered due to its low solubility. A nanosuspension of insoluble drugs is a nanoscale colloidal dispersion that has extremely higher drug-loading compared with other nanomedicines. In this study, nanosuspensions of ER-beta005 (Nano-ER-beta005) stabilized by a food protein, beta-casein (beta-CN), were prepared via an antisolvent-precipitation method to improve oral absorption and thus promote therapeutic efficacy. Nano-ER-beta005, which has a diameter of 110nm and drug loading of 50%, was developed. Analyses of fluorescence and circular dichroism (CD) spectra demonstrated a strong interaction between beta-CN and drug particles in Nano-ER-beta005, indicating that beta-CN is a potent nanosuspension stabilizer. The oral bioavailability of Nano-ER-beta005 was 1.6-fold greater than that of raw drug particles. Additionally, ER-beta005 was confirmed to have a strong therapeutic effect against pain reactions in animal models, and inhibition of this effect was significantly increased with Nano-ER-beta005 treatment. In conclusion, by using beta-CN as a stabilizer, nanosuspensions of ER-beta005 were developed and oral absorption was enhanced. Moreover, ER-beta005 is a powerful drug that inhibits pain reactions, and its therapeutic efficacy was markedly increased in the Nano-ER-beta005. PMID- 28847667 TI - Engineering of budesonide-loaded lipid-polymer hybrid nanoparticles using a quality-by-design approach. AB - Chronic obstructive pulmonary disease (COPD) is a complex disease, characterized by persistent airflow limitation and chronic inflammation. The purpose of this study was to design lipid-polymer hybrid nanoparticles (LPNs) loaded with the corticosteroid, budesonide, which could potentially be combined with small interfering RNA (siRNA) for COPD management. Here, we prepared LPNs based on the biodegradable polymer poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid dioleyltrimethylammonium propane (DOTAP) using a double emulsion solvent evaporation method. A quality-by-design (QbD) approach was adopted to define the optimal formulation parameters. The quality target product profile (QTPP) of the LPNs was identified based on risk assessment. Two critical formulation parameters (CFPs) were identified, including the theoretical budesonide loading and the theoretical DOTAP loading. The CFPs were linked to critical quality attributes (CQAs), which included the intensity-based hydrodynamic particle diameter (z average), the polydispersity index (PDI), the zeta-potential, the budesonide encapsulation efficiency, the actual budesonide loading and the DOTAP encapsulation efficiency. A response surface methodology (RSM) was applied for the experimental design to evaluate the influence of the CFPs on the CQAs, and to identify the optimal operation space (OOS). All nanoparticle dispersions displayed monodisperse size distributions (PDI<0.2) with z-averages of approximately 150nm, suggesting that the size is not dependent on the investigated CFPs. In contrast, the zeta-potential was highly dependent on the theoretical DOTAP loading. Upon increased DOTAP loading, the zeta-potential reached a maximal point, after which it remained stable at the maximum value. This suggests that the LPN surface is covered by DOTAP, and that the DOTAP loading is saturable. The actual budesonide loading of the LPNs was mainly dependent on the initial amount of budesonide, and a clear positive effect was observed, which shows that the interaction between drug and PLGA increases when increasing the initial amount of budesonide. The OOS was modeled by applying the QTPP. The OOS had a budesonide encapsulation efficiency higher than 30%, a budesonide loading above 15MUg budesonide/mg PLGA, a zeta-potential higher than 35mV and a DOTAP encapsulation efficiency above 50%. This study shows the importance of systematic formulation design for understanding the effect of formulation parameters on the characteristics of LPNs, eventually resulting in the identification of an OOS. PMID- 28847668 TI - The discovery and investigation of a crystalline solid solution of an active pharmaceutical ingredient. AB - Understanding the phase behavior of crystal forms is essential in drug formulation development, as physical stability of the active pharmaceutical ingredient (API) is critical to achieving the desired bioavailability. Solvents greatly impact the physical stability of crystalline solids, resulting in a variety of well-known phase transitions, such as hydrate/solvate formation. However, solvent incorporation may also result in the formation of a less-known crystalline solid solutions (CSSs). The identification and characterization of CSSs and their effect on API physicochemical properties have not been investigated. This is the first reported instance of a CSS for an API. An exhaustive study of the phase behavior of the enantiotropically related polymorphs, I and II, of Benzocaine in water and ethanol revealed that Form I formed a CSS with water below 294.5K. Construction of the phase diagrams of Forms I and II in water and ethanol revealed that CSS formation significantly decreased the phase transition temperature between Forms I and II in water. This change resulted from the increased disorder in the lattice of Form I due to the presence of water. This work demonstrates the importance of understanding the formation of CSSs on the thermodynamic behavior of crystalline pharmaceutical solids. PMID- 28847669 TI - Exploration of melanoma metastases in mice brains using endogenous contrast photoacoustic imaging. AB - Photoacoustic imaging (PAI) provides real time non-invasive and contrast agent free monitoring of some endogenous compounds concentrations that provides improved insights into tissue vascularization and oxygenation which are particularly important during tumor progression. This study assessed the input of PAI for examination of melanoma brain metastases in an orthotopic mouse model and further focused on spatial analyses within the tumor tissue. Hemoglobin content appeared to be higher in tumors than in healthy brains. Spatial analyses further showed that angiogenesis was mainly at the tumor periphery. Concomitantly, while healthy brains were highly oxygenated, the tumors were hypoxic and subjected to a gradient of hypoxia from the periphery to the core. In tumor-bearing brains, spectroscopic PAI clearly revealed the presence of melanin, generating a signal 3 times higher than the background signal in healthy brains. When inserted into tissue mimicking phantoms, the photoacoustic signal of B16F10 melanin-containing cells was linearly correlated to their concentration and the detection limit was 625 cells. In vivo biological characterization of tumor models by non-invasive imaging of vasculature and tissue hypoxia represents an interesting opportunity for better understanding cancer progression; it is opening new research prospects to improve diagnostic, therapy, and early assessment of tumor treatment efficacy. PMID- 28847670 TI - In vitro and in vivo release of dinalbuphine sebacate extended release formulation: Effect of the oil ratio on drug release. AB - Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Dinalbuphine sebacate (DNS) is a prodrug of nalbuphine for which we have developed long-acting lipophilic formulations in a benzyl benzoate/sesame oil mixture for intramuscular (IM) injection. In this study, we found that the in vitro release profile of DNS could be affected by adjusting the weight ratio of benzyl benzoate to sesame oil (the solvent/oil ratio). A longer release period could be attained by increasing the solvent/oil ratio in the formulation. A pharmacokinetic study was conducted in beagle dogs to verify the relationship between the in vitro release and the drug release from the formulations in vivo. The pharmacokinetic study confirmed that the formulation with a higher benzyl benzoate to oil ratio exhibits a longer drug release profile with a lower maximum concentration (Cmax) and a longer time to peak blood concentration level (Tmax) than the formulation with a lower benzyl benzoate to oil ratio. PMID- 28847671 TI - Erlotinib-loaded albumin nanoparticles: A novel injectable form of erlotinib and its in vivo efficacy against pancreatic adenocarcinoma ASPC-1 and PANC-1 cell lines. AB - Erlotinib was loaded on albumin nanoparticles for the first time and the cytotoxic effect of the resulting nanoparticles against ASPC-1 and PANC-1 pancreatic adenocarcinoma cell lines was evaluated. The carrier (albumin nanoparticles, ANPs) was synthesized by desolvation method using a mixed solvent followed by thermal crosslinking for stabilization. ANPs and the drug-loaded ANPs were characterized by field emission scanning and transmission electron microscopies, particle size analysis and Fourier transform infrared spectroscopy. The nanoformulation had a size of <14nm with a good monodispersity. Drug loading and encapsulation efficiencies were evaluated as 27 and 44%. Cytotoxicity assays after 72h revealed the potential of ANPs to improve erlotinib toxicity (54% against 34% of free drug toward ASPC-1 cell line, and 52% against 30% toward PANC 1 cell line). Values of IC50 were obtained for both cell lines and indicated significant reduction in the erlotinib dose necessary for killing the cells, while, ANPs were completely safe. The results demonstrated that erlotinib-loaded ANPs had a remarkable potential for pancreatic cancer drug delivery. PMID- 28847672 TI - Intestinal parasitic infections: Current prevalence and risk factors among schoolchildren in capital area of the Republic of Marshall Islands. AB - Intestinal parasitic infections (IPIs) among schoolchildren in Republic of Marshall Islands (RMI) largely remains unknown, thus investigation on IPIs status to establish the baseline data is urgently needed. This cross-sectional study intended to investigate the current IPIs status and associated risk factors among schoolchildren at capital of RMI. Single stool sample from 400 schoolchildren (207 boys and 193 girls) aged 9.73+/-2.50 yrs old was examined by employing merthiolate-iodine-formaldehyde concentration method. Demographic characteristics, uncomfortable symptoms and risk factors were obtained by questionnaires investigation. The overall prevalence of IPIs in schoolchildren was 22.8% (91/400), of them 24.2% harbored at least 2 different parasites. Notably, the majority was infected by waterborne protozoan parasites (82.4%, 75/91). Nine different intestinal parasites have been identified, of which six were pathogenic including Hook worm, Trichuris trichiura, Enterobius vermicularis, Entamoeba histolytica/dispar, Giardia intestinalis and Blastocystis hominis. Schoolchildren who ever complained dizziness or headache showed a significant higher prevalence of pathogenic IPIs than those who did not (p<0.05). Schoolchildren who lived in urban area than rural area had higher chance to acquire pathogenic IPIs (p=0.03). However, none of risk factors were identified to be associated with pathogenic IPIs. PMID- 28847673 TI - Determination of multiple-clone infection at allelic dimorphism site of Plasmodium vivax merozoite surface protein-1 in the Republic of Korea by pyrosequencing assay. AB - Allelic diversity leading to multiple gene polymorphisms of vivax malaria parasites has been shown to greatly contribute to antigenic variation and drug resistance, increasing the potential for multiple-clone infections within the host. Therefore, to identify multiple-clone infections and the predominant haplotype of Plasmodium vivax in a South Korean population, P. vivax merozoite surface protein-1 (PvMSP-1) was analyzed by pyrosequencing. Pyrosequencing of 156 vivax malaria-infected samples yielded 97 (62.18%) output pyrograms showing two main types of peak patterns of the dimorphic allele for threonine and alanine (T1476A). Most of the samples evaluated (88.66%) carried multiple-clone infections (wild- and mutant-types), whereas 11.34% of the same population carried only the mutant-type (1476A). In addition, each allele showed a high frequency of guanine (G) base substitution at both the first and third positions (86.07% and 81.13%, respectively) of the nucleotide combinations. Pyrosequencing of the PvMSP-1 42-kDa fragment revealed a heterogeneous parasite population, with the mutant-type dominant compared to the wild-type. Understanding the genetic diversity and multiple-clone infection rates may lead to improvements in vivax malaria prevention and strategic control plans. Further studies are needed to improve the efficacy of the pyrosequencing assay with large sample sizes and additional nucleotide positions. PMID- 28847674 TI - New Trypanosoma species, Trypanosoma gennarii sp. nov., from South American marsupial in Brazilian Cerrado. AB - Hundreds of trypanosome species have been described in all mammalian orders, on every continent, including with mixed infections. Trypanosomes circulate in the form of sylvatic enzootic infections transmitted by blood-sucking insects that are associated with the host mammals. Small wild mammals were caught in a fragment of Cerrado terrain on an island in the hydroelectric reservoir of Tres Marias, in the central region of the state of Minas Gerais, using pitfall and Sherman traps with different means of attraction. DNA samples from these mammals were subjected to the conventional polymerase chain reaction (PCR) for the full length genes SSU rDNA and gGAPDH. A total of 232 animals of the orders Didelphimorphia, Rodentia, Chiroptera and Cingulata were caught (total of 17 species). There were also four species of marsupials: Monodelphis domestica, Didelphis albiventris, Gralicinanus agilis and Micoureus paraguaianus. Among these, there were eight positive individuals of Monodelphis domestica. However, nine cultures were established, because one of them was parasitized by two species of trypanosomes: Trypanosoma cruzi and a new trypanosome species. The new species have a large epimastigote forms, and with a well-developed undulating membrane in trypomastigote forms. The new species Trypanosoma gennarii was described in Monodelphis domestica. PMID- 28847675 TI - A simple method for quantification of plasma globotriaosylsphingosine: Utility for Fabry disease. AB - Fabry disease (FD) results from impaired globotriaosylceramide (Gb3) catabolism, due to a deficiency of the lysosomal hydrolase, alpha-galactosidase A (alpha GalA). As a direct consequence, the deacetylated derivative, globotriaosylsphingosine (lyso-Gb3), is produced and contemporary evidence exemplifies its use as a biomarker. Here we developed a simple method to enable quantification of lyso-Gb3 in just 0.01mL of plasma and explored its concentration in a cohort of 73 Australian FD patients, as well as in individuals with other sphingolipidoses. In 2000 patients without FD, but with related metabolic conditions, lyso-Gb3 returned concentrations of <5pmol/mL. In the FD cohort, 53/60 patients with classical mutations returned lyso-Gb3 concentrations>=5pmol/mL whereas only 4/13 patients with "late-onset" mutations had lyso-Gb3>=5pmol/mL. Five females with normal alpha-GalA activity and genetically confirmed FD returned lyso-Gb3>=5pmol/mL. The prevalence of clinically significant disease including cardiomyopathy, nephropathy and cerebrovascular disease was congruent with higher lyso-Gb3 concentrations. Repeat testing was available for 51 patients-26 undergoing enzyme replacement therapy and concentrations of lyso-Gb3 remained unaltered throughout 6-18 months independent of sex, mutation or treatment status. Our data suggest that the optimum use of lyso-Gb3 resides in laboratory confirmation of classical FD and for monitoring at least the initial response to therapeutic intervention. There is no evidence that lyso-Gb3 can inform on clinical events. PMID- 28847676 TI - Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians. AB - Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme beta-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD. PMID- 28847677 TI - Laceration Management. AB - BACKGROUND: Traumatic lacerations to the skin represent a fairly common reason for seeking emergency department care. Although the incidence of lacerations has decreased over the past decades, traumatic cutaneous lacerations remain a common reason for patients to seek emergency department care. OBJECTIVE: Innovations in laceration management have the potential to improve patient experience with this common presentation. DISCUSSION: Studies have confirmed that delays in wound closure rarely confer increased rates of infection, although comorbidities such as diabetes, chronic renal failure, obesity, human immunodeficiency virus, smoking, and cancer should be considered. Antibiotics should be reserved for high risk wounds, such as those with comorbidities, gross contamination, involvement of deeper structures, stellate wounds, and selected bite wounds. Topical anesthetics, which are painless to apply, have a role in select populations. In most studies, absorbable sutures perform similarly to nonabsorbable sutures and do not require revisit for removal. Novel atraumatic closure devices and expanded use of tissue adhesives for wounds under tension further erode the primacy of regular sutures in wound closure. Maintaining a moist wound environment with occlusive dressings is more important than previously thought. Most topical wound agents are of limited benefit. CONCLUSIONS: Recent innovations in wound closure are allowing emergency physicians to shift toward painless, atraumatic, and rapid closure of lacerations. PMID- 28847678 TI - [Perinatal health and medical administrative data: What uses, which stakeholders, what the issues for birth data? - Special REDSIAM]. AB - BACKGROUND: The uses of medical administrative data (MAD/BDMA) emerged in perinatal health following the work on regionalization of very pre-term birth. They have become more numerous since the late 2000s. The objective of this article is to take stock of the existing work carried out within the REDSIAM perinatality group, on MAD/BDMA and their uses for the period of "birth". METHODS: The studied MADs are the Hospital Discharge Data (PMSI) and the French national health database (SNIIRAM). The material includes knowledge shared by the members of the REDSIAM-perinatality group, scientific references and gray literature. RESULTS: Our exploratory study shows that the uses of MAD in perinatal health are diversified at the local, regional and national levels. The works and publications, increasing, take the form of public access of processed data. Collective thinking makes it possible to move from a localized use to an institution, a network or several, to a national use and an inscription in public authorities' responses. In 2015/2016, two institutional sites provide access to data on maternal and child health: Data.Drees and ATIH ScanSante. MAD/BDMA uses are multiple: epidemiological use (count of births by gestational age, weight in particular; perinatal indicators), quality of care, planning (maternity activities, regionalization of care). There is an increasing interest among stakeholders, producers and/or operators of MAD/BDMA (decision-makers, professionals or researchers). CONCLUSION: The BDMA, including the PMSI and the SNIIRAM, are used and relevant in Perinatal health with the rise of health networks, the territorialisation of health, in an increased demand for quality of care. Their use will increase the reliability of the data collected and an inscription in the validation studies, more and more numerous in the field of BDMA. The algorithms need to be more finely compiled, validated and enhanced. PMID- 28847679 TI - Sockeye salmon immunoglobulin VH usage and pathogen loads differ between spawning sites. AB - The Immunological Imprinting Hypothesis proposes that juvenile anadromous fish respond to the pathogen fingerprint specific to their natal site by producing protective long lived plasma cells (LLPCs) that constitutively produce antibodies against those pathogens. Hence, fish returning to their natal streams have immunological protection from pathogens at that specific location. Here, we tested the hypothesis through analysis of antibody composition and usage in sockeye salmon populations in Alaska. Spleen and anterior kidney were sampled from salmon from six sites, and relative usage levels of six different Immunoglobulin VH gene families determined using RT-qPCR. Additionally, prevalence and pathogen loads were measured in each fish for Renibacterium salmoninarum, Flavobacterium psychrophilum, and Infectious Hematopoietic Necrosis Virus. Results revealed differences in VH usage, pathogen loads, and infection rates between spawning sites, while probability of infection was dependent on location for each pathogen analyzed. Further, several negative correlations between specific VH usage patterns and pathogen loads were uncovered. Greater understanding of site-dependent VH usage in spawning fish potentially suggests a method of natural immunization against common fish pathogens and thus protection of both farmed and wild populations. PMID- 28847680 TI - The association between handgrip strength and sleep duration in Japanese patients with type 2 diabetes. PMID- 28847681 TI - Pilot cohort study of endoscopic botulinum neurotoxin injection in Parkinson's disease. AB - BACKGROUND: Gastrointestinal symptoms, such as dysphagia, postprandial bloating, and defecatory straining are common in Parkinson's Disease (PD) and they impact quality of life. Endoscopic botulinum neurotoxin (BoNT) injection has been used in the treatment of dysphagia, gastroparesis and chronic anismus. AIMS: To examine the feasibility, safety and efficacy of endoscopically delivered BoNT injection to distal esophagus, pylorus or anal canal aiming at relieving regional gastrointestinal symptoms in patients with PD. METHODS: This is a retrospective open cohort pilot study to assess the clinical response to endoscopic BoNT injection on selected PD patients with symptoms and identifiable abnormalities on high-resolution manometry and wireless motility capsule, to generate early uncontrolled data on feasibility, tolerability, safety and efficacy. Baseline symptoms and response to therapy were assessed by questionnaires. RESULTS: Fourteen PD patients (10 M:4 F), mean age 73 (range: 62-93) were treated. Three patients had esophageal Botox for ineffective esophageal motility (IEM) (n = 1), esophago-gastric junction outlet obstruction (EGJOO) & IEM (n = 1), and diffuse esophageal spasm (DES) (n = 1). Nine patients were treated with pyloric BoNT injection for gastroparesis with mean gastric transit time of 21.2 h; range 5.2 44.2 h. Two patients received anal Botox for defecatory dyssynergia ((Type I) (n = 1) and overlap (slow-transit and dyssynergic) constipation (n = 1). Endoscopic BoNT injection (100-200 units) was well tolerated and there were no significant adverse events. CONCLUSIONS: Endoscopic BoNT injection to esophagus, pylorus or anal canal is safe, well-tolerated and leads to symptomatic improvement that lasts up to several months. The procedure can be repeated as needed and combined with other therapies. PMID- 28847682 TI - Improved tumor accumulation and therapeutic efficacy of CTLA-4-blocking antibody using liposome-encapsulated antibody: In vitro and in vivo studies. AB - Cancer immunotherapies using monoclonal antibodies including cytotoxic T lymphocyte-associated protein-4 (CTLA-4) blocking monoclonal antibody have several drawbacks including lack of appropriate penetration to the tumors, and organ toxicity. To address these obstacles, PEGylated and non-PEGylated liposomes containing CTLA-4 was prepared and characterized and the anti-tumor therapeutic responses were studied on the mice bearing C26 colon cancer tumors. The biodistribution study showed that the PEGylated liposomes had prolonged blood half-lives and accumulated remarkably more than non-PEGylated liposomes and free CTLA-4 antibody in tumor area. The lowest tumor volumes, highest time to reach end points (TTE: 34.29+/-3.09 days) and tumor growth delay percent (TGD: 29.37%) were seen in mice that received PEGylated liposomes than free CTLA-4 blocking antibody treatment (TTE: 31.16+/-4.13 days, TGD: 17.57%). In conclusion, PEGylated liposomes containing anti CTLA-4 antibody are delivered to tumor sites more efficiently and have a greater effect on anti-tumor immune responses than free antibodies and merits further investigation. PMID- 28847683 TI - Is antimicrobial photodynamic therapy a useful therapeutic protocol for oral decontamination? A systematic review and meta-analysis. AB - BACKGROUND: The aim of the present systematic review and meta-analysis was to assess the efficacy of antimicrobial photodynamic therapy (aPDT) as a therapeutic protocol for oral decontamination. METHODS: In order to address the focused question: Is aPDT a useful therapeutic protocol for oral decontamination?, an electronic search without time or language restrictions was conducted up to July 2017 in indexed databases using the combination of different key words including photochemotherapy, lasers, photodynamic therapy, disinfection, mouth, saliva and oral. The exclusion criteria included reviews, case-reports, case-series, commentaries, letters to the editor, interviews, and updates. Four randomized control trials were included and processed for data extraction. RESULTS: All studies reported that aPDT was effective in reducing the overall oral microbial load in saliva. Considering the effects of aPDT+photosensitizer (PS) compared with PS alone, there was no heterogeneity noticed for aPDT+PS (Q value=0.15, P=0.69, I2=0%). The overall mean difference for bacterial count in CFU/ml between aPDT+PS and PS alone was also not significant (weighted mean difference=-0.41, 95% CI=-1.12 to 0.29, p=0.24) at follow-up. CONCLUSION: The efficacy of aPDT for oral decontamination remains unclear. Further well-designed randomized clinical trials assessing the efficacy of aPDT reducing the oral microbial load are need. PMID- 28847684 TI - Do not forget about pre-analytics in faecal calprotectin measurement! PMID- 28847685 TI - Neonatal screening parameters in infants with congenital Cytomegalovirus infection. AB - Congenital Cytomegalovirus infection (cCMV) is the most common cause of congenital infections worldwide that can cause long-term impairment (LTI). The metabolic alterations due to cCMV are largely unknown. This study aims to assess the metabolites included in the neonatal screening in relation to cCMV and cCMV outcome, allowing the identification of prognostic markers for clinical outcome. Essential amino acids, hormones, carnitines and enzymes from Dried Blood Spots (DBS) were analyzed of 102 children with cCMV and 179 children without cCMV, and they were related to symptoms at birth and LTI at 6years of age. In this cohort, the neonatal screening parameters did not change in relation to cCMV, nor to symptoms at birth or LTI. However, metabolic changes were observed in children born preterm, with lower concentrations of essential amino acids in premature infants with cCMV compared to premature controls. Finally, a higher concentration of palmytoilcarnitine (C16) in the group with higher viral load was observed. Though these data demonstrate limitations in the use of neonatal screening data as predictors for long-term cCMV outcome, the metabolism of preterm neonates with cCMV merits further evaluation. PMID- 28847686 TI - Obstacles in Renal Regenerative Medicine: Metabolic and Epigenetic Parallels Between Cellular Reprogramming and Kidney Cancer Oncogenesis. AB - CONTEXT: Regenerative medicine has recently presented a revolutionary solution to end-stage kidney disease. Reprogramming patients' own cells generates induced pluripotent stem cells that are subsequently differentiated to "kidney organoid," a structure that is anatomically and functionally similar to the kidney. This approach holds the promise of a transplantable, immunocompetent, and functional kidney that could be produced in vitro. However, caution must be taken due to the molecular-level similarities between induced pluripotent stem cells and renal cell carcinomas. As such, if cell reprogramming is not tightly controlled, it can lead to carcinogenic changes. OBJECTIVE: Based on recent next-generation sequencing results and other supporting data, we identified three major molecular attributes of renal cell carcinoma: metabolic alterations, epigenetic changes, and miRNA-based alterations. Strikingly, these variations are mirrored in induced pluripotent stem cells, which are the main cell source of renal regenerative medicine. Our objective was to discuss the shared metabolic, epigenetic and miRNA regulated characteristics and to abridge their significance in renal regenerative medicine. EVIDENCE ACQUISITION: English-language literature was retrieved through PubMed. EVIDENCE SYNTHESIS: Authors collected the published evidence and evaluated the content based on independent literature findings. Articles were filtered to include only highly relevant, recent publications that presented reproducible results by authorities of the field. CONCLUSIONS: The kidney represents a unique metabolic environment that could be hijacked by induced pluripotent stem cells or by partially differentiated cells for oncogenic transformation. Future differentiation protocols must produce kidney organoids that are fully engaged in filtration function. PATIENT SUMMARY: A new technology can produce mini-kidneys or kidney organoids. This review discusses some of the challenges this technology has to face, including its high oncogenic potential. Understanding these similarities will lead to the safe creation of new functional kidney units in patients with kidney failure. PMID- 28847687 TI - A Preliminary Evaluation of Ovine Bladder Mucosal Damage Associated With 2 Different Indwelling Urinary Catheters. AB - OBJECTIVE: To determine whether a new catheter design with a low-profile, open ended rounded rather than pointed Foley catheter tip can reduce mucosal damage to the bladder of ewes. METHODS AND MATERIALS: Six ewes were randomly assigned to 1 of 2 indwelling urinary catheters-a 16 Fr Foley catheter or a 16 Fr open-tip CystoSure catheter. After 96 hours, all the animals were sacrificed and their bladder and urethra harvested for analysis. RESULTS: Image analysis of the bladder surfaces demonstrated a significant decrease in the percentage of bladder area covered by ulceration and inflammation in sheep with CystoSure catheters compared with Foley catheters (P < .002) as well as a trend toward less edema (P = .17). Macro-morphologic evaluations were confirmed with immunohistochemical markers of cell proliferation and inflammation. CONCLUSION: In this pilot study, we were able to demonstrate that a new catheter design with an open-ended rounded rather than pointed tip and a reduced balloon base-to-tip profile may reduce mucosal damage to the bladder of ewes. Based on the findings from this trial, we believe this new catheter design with its low-profile, rounded tip may reduce bladder mucosal injury, which is a risk factor for catheter-associated urinary tract infections. PMID- 28847688 TI - Cancer and All-cause Mortality in Bladder Cancer Patients Undergoing Radical Cystectomy: Development and Validation of a Nomogram for Treatment Decision making. AB - OBJECTIVE: To develop and validate a nomogram assessing cancer and all-cause mortality following radical cystectomy. Given concerns regarding the morbidity associated with surgery, there is a need for incorporation of cancer-specific and competing risks into patient counseling and recommendations. MATERIALS AND METHODS: A total of 5325 and 1257 diagnosed with clinical stage T2-T4a muscle invasive bladder cancer from January 1, 2006 to December 31, 2011 from Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry Medicare linked data, respectively. Cox proportional hazards models were used and a nomogram was developed to predict 3- and 5-year overall and cancer-specific survival with external validation. RESULTS: Patients who underwent radical cystectomy were mostly younger, male, married, non-Hispanic white and had fewer comorbidities than those who did not undergo radical cystectomy (P < .001). Married patients, in comparison with their unmarried counterparts, had both improved overall (hazard ratio 0.76; 95% confidence interval 0.70-0.83, P < .001) and cancer-specific (hazard ratio 0.76; 95% confidence interval 0.68-0.85, P < .001) survival. A nomogram developed using Surveillance, Epidemiology, and End Results-Medicare data, predicted 3- and 5-year overall and cancer-specific survival rates with concordance indices of 0.65 and 0.66 in the validated Texas Cancer Registry-Medicare cohort, respectively. CONCLUSION: Older, unmarried patients with increased comorbidities are less likely to undergo radical cystectomy. We developed and validated a generalizable instrument that has been converted into an online tool (Radical Cystectomy Survival Calculator), to provide a benefit-risk assessment for patients considering radical cystectomy. PMID- 28847689 TI - Nature and Architecture of the Puboprostatic Ligament: A Macro- and Microscopic Cadaveric Study Using Epoxy Sheet Plastination. AB - OBJECTIVE: To investigate the nature and the architecture of the puboprostatic ligament (PPL) and its relationship with surroundings. MATERIALS AND METHODS: Six adult male cadaveric pelvises (age range, 46-87 years) were prepared as serial transverse (2 sets), coronal (1 set), or sagittal (3 sets) plastinated sections, and were examined under a stereoscope and a confocal microscope. The thickness of the section was 2.5 mm, the interval between 2 adjacent sections was about 0.9 mm, and a total of about 70 serial sections per set were collected. RESULTS: First, the musculotendinous sheet of the pubococcygeus contributed to the visceral endopelvic fascia, decussated in front of the detrusor apron, and fixed to the pubis. Second, anteriorly to the prostate, the detrusor apron split up into anterior, middle, and posterior layers, which contributed to the PPL, the fascial sheaths of the dorsal vascular complex, and the anterior fibromuscular stroma of the prostate, respectively. Third, the PPL originated from both the detrusor apron and the decussated and undecussated fibers of the pubococcygeus, and inserted onto the pubis. CONCLUSION: This study revealed the nature and the architecture of the PPL and its relationship with surroundings. These findings provide new insights in the "suspensory system" involving the urinary continence and may incite for future surgical techniques that aim to preserve the decussated pubococcygeus and the intactness of a pubococcygeus-detrusor apron complex during radical retropubic prostatectomy. PMID- 28847690 TI - Understanding Simple Cystectomy for Benign Disease: A Unique Patient Cohort With Significant Risks. AB - OBJECTIVE: To explore patient characteristics and complications of simple cystectomy for benign disease. A secondary objective was to compare these parameters to those in radical cystectomy. METHODS: Current Procedural Terminology codes were used to identify patients within the National Surgical Quality Improvement Program who underwent cystectomy (2005-2014). International Classification of Disease, Ninth Revision, codes were used to classify patients with benign or malignant diagnoses. Perioperative complications (30 days) were identified and logistic regression analysis was used to identify factors associated with morbidity. RESULTS: We identified 389 patients who had a cystectomy for benign diagnosis. A total of 235 patients (60.4%) had complications. The most frequently reported complication was bleeding (requiring a transfusion within 72 hours) in 150 patients (38.6%). Other complications were wound infection (63, 16.2%), respiratory complication (29, 7.5%), wound dehiscence (8, 2.1%), renal complication (9, 2.3%), cardiovascular complication (6, 1.5%), and postoperative deep vein thrombosis (8; 2.1). On multivariate analysis, diabetes (odds ratio 1.9, P = .04) and smoking (odds ratio 1.8, P = .03) were associated with increased odds of any complication. Compared with those with cystectomy for malignancy, this cohort was younger, with higher American Society of Anesthesiologists scores, and chronic kidney disease stages, and the complication risk was similar (60.4% vs 57.7%, P = .3). CONCLUSION: Our data suggest that the benign and radical cystectomy patients are different patient populations, with benign patients being younger with a higher American Society of Anesthesiologists class. Even in benign disease, cystectomy is not without risk, and patients should be counseled accordingly. PMID- 28847691 TI - Reply by the Authors. PMID- 28847692 TI - Racial and Socioeconomic Disparities in Short-term Urethral Sling Surgical Outcomes. AB - OBJECTIVE: To evaluate the association of racial and socioeconomic factors with the risk of adverse events in the first 30 days following urethral sling placement. METHODS: We accessed nonpublic data from the Office of Statewide Health Planning and Development in California from 2005 to 2011. All female patients who underwent an ambulatory urethral sling procedure in the entire state of California over the study period were identified (Current Procedural Terminology 57288). Our main outcome was any unplanned hospital visits within 30 days of the patient's surgery in the form of an inpatient admission, revision surgery, or emergency department visit. RESULTS: A total of 28,635 women who underwent outpatient urethral sling placement were identified. Within 30 days, 1628 women (5.7%) had at least 1 unplanned hospital visit. In the adjusted multivariate model, black race and Medicaid insurance status were both independently associated with increased odds of having an unplanned hospital visit (odds ratio 1.80, P < .01 and odds ratio 1.53, P < .01, respectively). This significance persisted even when controlling for patient comorbidities, demographics, and facility characteristics. CONCLUSION: We found that, similar to what has been reported in other fields, disparities in outcomes exist between socioeconomic and racial groups in the field of urogynecology. PMID- 28847693 TI - Re: Oberlin et al.: Diagnostic Value of Guided Biopsies: Fusion and Cognitive registration Magnetic Resonance Imaging Versus Conventional Ultrasound Biopsy of the Prostate (Urology 2016;92:75-79). PMID- 28847694 TI - Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis. AB - An increased incidence of narcolepsy was seen in many countries after the pandemic H1N1 influenza vaccination campaign in 2009-2010. The H1N1 vaccine - narcolepsy connection is based on observational studies that are prone to various biases, e.g., confounding by H1N1 infection, and ascertainment, recall and selection biases. A direct pathogenic link has, however, remained elusive. We conducted a systematic review and meta-analysis to analyze the magnitude of H1N1 vaccination related risk and to examine if there was any association with H1N1 infection itself. We searched all articles from PubMed, Web of Science and Scopus, and other relevant sources reporting the incidence and risk of post vaccine narcolepsy. In our paper, we show that the risk appears to be limited to only one vaccine (Pandemrix(r)). During the first year after vaccination, the relative risk of narcolepsy was increased 5 to 14-fold in children and adolescents and 2 to 7-fold in adults. The vaccine attributable risk in children and adolescents was around 1 per 18,400 vaccine doses. Studies from Finland and Sweden also appear to demonstrate an extended risk of narcolepsy into the second year following vaccination, but such conclusions should be interpreted with a word of caution due to possible biases. Benefits of immunization outweigh the risk of vaccination-associated narcolepsy, which remains a rare disease. PMID- 28847695 TI - 1977-2017: Nursing research in Spain after 40 years in the University. AB - Nursing research in Spain cannot be understood without analyzing the development of this profession over the last 40 years. The social, political and economic context has determined the evolution of nursing research, and an analysis of the current situation is necessary to confront the immediate challenges the nursing profession has to handle. To offer a global perspective of care research in Spain as a framework for reflection and discussion on possible short and medium-term strategies that guide the planning and decision making of the different stakeholders involved in nursing research in Spain. A multi-method study combining documentary analysis with bibliometric methods was carried out. Some isolated policies to promote nursing research have been identified, a significant increase in doctoral training (49 doctoral programs) and 89 nurse research groups (1.92 groups per million inhabitants) responsible for a scientific production that puts Spain in seventh place in the world ranking of scientific production in the area of nursing. The increase in public expenditure on R & D &I and the growth in bibliometric impact are associated with a higher density of nursing research groups. Nursing research in Spain is sensitive to research promotion policies and resources, although there is no consolidated and uniform strategy that overcomes current barriers. The impact of the academic development of Spanish nNursing in scientific production is still unknown. PMID- 28847696 TI - Neurological adverse events associated with metronidazole. PMID- 28847697 TI - Proximity as a predictor of social behavior in rats. AB - BACKGROUND: In studies that measure social behavior of a freely interacting pair rats social behavior of one rat is strongly influenced by the behavior of the other. This prevents evaluating social behavior of one single rat. NEW METHOD: We assessed the motivation to interact socially in a modified open-field, by measuring the time a rat attempted to interact with a co-specific separated by a grid in a birdcage outside of the apparatus. We propose time in front of the birdcage is an indicator of social behavior. RESULTS: We showed that the focal rat allocates more time in front of the birdcage, interacting with another rat through the grid. Also, that the presence of the other rat that attracts the focal rat. Habituation to the apparatus, repeated testing and illumination condition did not alter the proximity measures of rats. Finally, treatment with chlordiazepoxide (3.0mg/kg) either increased the time spent in front of the cage by males and females or (5.6mg/kg) increased the proximity measure of females. COMPARING WITH EXISTING METHOD: Our method prevents partners from influencing the target rat's social behavior; existing methods do not. Also, it is more sensitive to the effect of chlordiazepoxide than the broadly used method proposed by File and Hyde (1978). CONCLUSIONS: Proximity is an advantageous measure: it allows the assessment of only one focal animal without the interference of a partner; it is simple to take; it requires little interpretation skills or training from the experimenter, no special equipment or conditions. PMID- 28847698 TI - Borrelia burgdorferi sensu lato in Ixodes longiscutatus ticks from Brazilian Pampa. AB - Borrelia burgdorferi sensu lato (s.l.) complex includes the agents of Lyme disease/borreliosis in North America, Europe, and Asia, such Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borrelia garinii, Borrelia bavariensis, Borrelia spielmanii, Borrelia bissettiae, and Borrelia mayonii. In 2013 B. burgdorferi s.l. was reported for the first time in the Neotropical region, from Ixodes aragaoi ticks in Uruguayan Pampa. In addition, from 2011 to 2016, 17 suspected human cases of borreliosis-like syndrome were reported in Rio Grande do Sul (RS) state, Brazil, which contains only part of country in the Pampa biome. The goal of this work is to report the results of a state surveillance program conducted in order to investigate the presence of B. burgdorferi s.l. in its classic vector, Ixodes spp. ticks, from the Brazilian Pampa. For this, we searched for Ixodes spp. ticks in 307 rodents from 11 municipalities of RS state. We then tested the ticks for the presence of B. burgdorferi s.l. DNA using PCR analysis. Of 35 Ixodes spp. ticks tested, one larva and one nymph of Ixodes longiscutatus ticks tested positive for Borrelia sp. DNA. The phylogenetic analysis of the flaB fragment grouped our samples (referred as Borrelia sp. haplotype Pampa) into B. burgdorferi s.l. group in a particular branch with other South American haplotypes, and this group was close to Borrelia carolinensis, B. bissettiae, and Borrelia californiensis. This is the first evidence of B. burgdorferi s.l. circulation in ticks of the genus Ixodes in Brazil. These results highlight the need for the implementation of public health policies for the diagnosis and prevention of potential cases of human borreliosis in Brazil. Further studies are needed to fill the gaps in our knowledge of the distribution, pathogenicity, reservoirs, and vectors of these emerging South American B. burgdorferi s.l. haplotypes. PMID- 28847699 TI - Molecular characterization of canine parvovirus and canine enteric coronavirus in diarrheic dogs on the island of St. Kitts: First report from the Caribbean region. AB - Although canine parvovirus (CPV) and canine enteric coronavirus (CCoV) are important enteric pathogens of dogs and have been studied extensively in different parts of the world, there are no reports on these viruses from the Caribbean region. During 2015-2016, a total of 104 diarrheic fecal samples were collected from puppies and adult dogs, with or without hemorrhagic gastroenteritis, on the Caribbean island of St. Kitts (KNA). By PCR, 25 (24%, n=104) samples tested positive for CPV. Based on analysis of the complete deduced VP2 amino acid sequences, 20 of the KNA CPV strains were assigned to new CPV-2a (also designated as CPV-2a-297A). On the other hand, the VP2 genes of the remaining 5 strains were partially characterized, or could not be sequenced. New CPV-2a was the predominant CPV variant in St. Kitts, contrasting the molecular epidemiology of CPV variants reported in most studies from nearby North and South American countries. By RT-PCR, CCoVs were detected in 5 samples (4.8%, n=104). Based on analysis of partial M-protein gene, the KNA CCoV strains were assigned to CCoV-I genotype, and were closely related to CCoV-I strains from Brazil. To our knowledge, this is the first report on detection and genetic diversity of CPV and CCoV in dogs from the Caribbean region, and underscores the importance of similar studies in the other Caribbean islands. PMID- 28847700 TI - The HBx gene of hepatitis B virus can influence hepatic microenvironment via exosomes by transferring its mRNA and protein. AB - The cellular secretory vesicles known as 'exosomes' have emerged as key player in intercellular transport and communication between different eukaryotic in order to maintain body homeostasis. Many pathogenic viruses utilize exosome pathway to efficiently transfer bioactive components from infected cells to naive cells. Here, we show that HBx can tweak the exosome biogenesis machinery both by enhancing neutral sphingomyelinase2 activity as well as by interacting with exosomal biomarkers such as neutral sphingomyelinase2, CD9 and CD81. The nano particle tracking analysis revealed enhanced secretion of exosomes by the HBx expressing cells while confocal studies confirmed the co-localization of HBx with CD9 and CD63. Importantly, we observed the encapsulation of HBx mRNA and protein in these exosomes besides some other qualitative changes. The exosomal cargo secreted by HBx-expressing cells had a profound effect on the recipient hepatic cells including creation of a milieu conducive for cellular-transformation. Thus, the present study unfolds a novel role of HBx in intercellular communication by facilitating horizontal transfer of viral gene products and other host factors via exosomes in order to support viral spread and pathogenesis. PMID- 28847701 TI - Invasive meningococcal disease: Impact of short course therapy. A DOOR/RADAR study. AB - BACKGROUND: Invasive meningococcal disease is a severe infection. The appropriate duration of antibiotic therapy is not well established. METHODS: Two hundred and sixty-three consecutive patients with invasive meningococcal disease treated with 4 days' antibiotic therapy were compared with 264 consecutive patients treated previously at the same center with 7 days' antibiotic therapy. A Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) study was also performed. RESULTS: No relapses were recorded in any patient. Patients on the 4-day course were 63% female, with a median age of 23 years old (IQR 16-54) and patients on the 7-day course were 61% female, with a median age of 17 years old (IQR 12-43). Case fatality rate was 7% in the 4-d patients and 6% in the 7-d patients (p = 0.582). Neurological sequelae were recorded in 6% of the 4-d group and in 7% of the 7-d group ((p = 0.509) and cutaneous sequelae in 3% in both groups. There were no statistical significant differences between the groups in terms of clinical characteristics, laboratory findings or complications. The probability that a patient had a randomly chosen DOOR better with the 4-day regimen than with the 7-day regimen was 80.4% [95% CI 80.1-80.7%]. CONCLUSION: Invasive meningococcal disease may be successfully treated with a four-day course of antibiotic therapy without relapses. PMID- 28847702 TI - Putting the heart into microvascular training: The micropump, a practical "heart like" device to enhance vascular anastomosis non-living simulation. PMID- 28847703 TI - Protective effect of alpha-lipoic acid against alpha-cypermethrin-induced changes in rat cerebellum. AB - Alfa cypermethrin is a pyrethroids extensively used as ectoparasiticide in domestic animals, insecticidal spray on cotton, vegetables and other crops and to kill cockroaches, fleas and termites in house and other buildings. Previous studies have shown the adverse effect of alpha -cypermethrin on brain. This study was planned to evaluate the possible role of alpha-lipoic acid in alpha cypermethrin induced toxicity in brain of male albino rats. Rats were divided into four groups. The control, alpha-cypermethrin, alpha-lipoic acid and alpha cypermethrin plus alpha-lipoic acid treated groups. The duration of the experiment was four weeks. Our results showed that the administration of alpha cypermethrin caused a significant decreased in gamma- aminobutyric acid level, acetylcholinesterase, catalase, superoxide dismutase activities and increase in lipid peroxidation in cerebellum. Furthermore, the co-administration of alpha lipoic acid mitigates the toxicity of alpha-cypermethrin by partially normalizing the biochemical parameters. The biochemical observations were supported by histopathological examinations. The findings of this investigation suggest that alpha-lipoic acid may play a protective role against alpha-cypermethrin induced toxicity in cerebellum of treated rats. PMID- 28847705 TI - An effective model of cerebrovascular pressure reactivity and blood flow autoregulation. AB - Understanding cerebral blood flow dynamics is crucial for the care of patients at risk of poor cerebral perfusion. We describe an effective model of cerebral hemodynamics designed to reveal important macroscopic features of cerebral blood flow without having to resolve the detailed microvasculature of the brain. Based on principles of fluid and elastic dynamics and vascular pressure-reactivity, the model quantifies the physical means by which the vasculature executes autoregulatory reflexes. We demonstrate that the frequency response of the proposed model matches experimental measurements and explains the influence of mechanical factors on the autoregulatory performance. Analysis of the model indicates the existence of an optimal mean arterial pressure which minimizes the sensitivity of the flow to changes in perfusion pressure across the frequency spectrum of physiological oscillations. We highlight the simplicity of the model and its potential to improve monitoring of brain perfusion via real-time computational simulations of cerebro- and cardio-vascular interventions. PMID- 28847704 TI - Longitudinal Patterns of Occurrence and Remission of Erectile Dysfunction in Men With Type 1 Diabetes. AB - BACKGROUND: Men with diabetes are at greater risk of erectile dysfunction (ED). AIM: To describe the natural history of ED in men with type 1 diabetes. METHODS: We examined up to 30 years of prospectively collected annual ED status and demographic and clinical variables from 600 male participants in the Diabetes Control and Complications Trial (DCCT; 1983-1993) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (1994-present; data in this study are through 2012). OUTCOMES: Yes vs no response to whether the participant had experienced impotence in the past year and whether he had used ED medication. RESULTS: Sixty-one percent of men reported ED at least once during the study. For some men, the initial report of ED was permanent. For others, potency returned and was lost multiple times. Visual display of the data showed four longitudinal ED phenotypes: never (38.7%), isolated (6.7%), intermittent (41.8%), and persistent (12.8%). Men who never reported ED or in only 1 isolated year were younger, had lower body mass index, and better glycemic control than men in the intermittent and persistent groups at DCCT baseline. In a multivariable logistic model comparing men at their first year reporting ED, men who were older had lower odds of remission and men who were in the conventional DCCT treatment group had higher odds of remission. CLINICAL TRANSLATION: If validated in other cohorts, such findings could be used to guide individualized interventions for patients with ED. STRENGTHS AND LIMITATIONS: This is the first examination of ED with repeated measures at an annual resolution, with up to 30 years of responses for each participant. However, the yes vs no response is a limitation because the real phenotype is not binary and the question can be interpreted differently depending on the participant. CONCLUSIONS: Age, glycemic control, and BMI were important longitudinal predictors of ED. We have described a more complex ED phenotype, with variation in remission patterns, which could offer insight into different mechanisms or opportunities for intervention. If validated in other cohorts, such findings could be used to establish more accurate prognostication of outcomes for patients with ED to guide individualized interventions. Palmer MR, Holt SK, Sarma AV, et al. Longitudinal Patterns of Occurrence and Remission of Erectile Dysfunction in Men With Type 1 Diabetes. J Sex Med 2017;14:1187-1194. PMID- 28847706 TI - Botulinum toxin to treat pelvic pain. AB - Botulinum toxin's (BoNT) success in treating several pain disorders has triggered interest in its application for pelvic pain disorders. This article summarizes results presented at the recent Neurotoxins Meeting in Madrid, Spain, in January 2017. It does not include BoNT use for Interstitial Cystitis/Bladder Pain Syndrome, which was the topic of a separate lecture. It includes studies documenting the beneficial effects of OnaBoNTA for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men using both transrectal and transurethral injection techniques. It also focuses on research using OnaBoNTA to treat levator spasms in women with chronic pelvic pain. Finally, it presents a novel approach using high density quantitative surface EMG to map out innervation zones and allow for more precise targeting of hypertonic pelvic floor muscles. PMID- 28847707 TI - Updating knowledge on new medically important scorpion species in Mexico. AB - The increment in the number of scorpion envenoming cases in Mexico is mainly associated to the rapid growth of the urban areas, and consequently, to the invasion of natural habitats of these arachnids. On the other hand, there is a great diversity of scorpion species, so it is indispensable to identify those of medical importance, which we now know are many more than the 7-8 previously reported as dangerous to humans. Because different LD50 values have been reported for the venom of the same species, probably due to variations in the experimental conditions used, in this work we determined the LD50 values for the venoms of 13 different species of scorpions using simple but systematic procedures. This information constitutes a referent on the level of toxicity of medically important scorpion species from Mexico and establishes the bases for a more comprehensive assessment of the neutralizing capacity of current and developing antivenoms. PMID- 28847708 TI - Effects of coenzyme Q10 supplementation on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. AB - The aim of this systematic review and meta-analysis of prospective interventional studies was to investigate the effects of coenzyme Q10 (CQ10) on plasma C reactive protein (CRP) levels. PubMed/Medline, Web of Science (WoS), Cochrane Database and Google Scholar databases were searched (up to December 2016) to identify prospective studies evaluating the impact of CQ10 supplementation on CRP. Random effects models meta-analysis was used for quantitative data synthesis. Sensitivity analysis used the leave-one-out method, and heterogeneity was quantitatively assessed using the I2 index. Systematic review PROSPERO database registration: CRD42016038155. From a total of 119 entries identified via searches, 7 studies were finally included to the analysis. The results of the meta-analysis indicated a non-significant reduction in CRP concentrations following supplementation with CQ10 with a weighted mean difference [WMD] of 0.25mg/l (95% confidence intervals [CI] -0.56 to 0.06, I2=42.0%). The WMD for the effects on interleukin 6 (IL6) was -0.72pg/dl, (95% CI -1.24 to -0.24, I2=51.8%). These findings were robust in sensitivity analyses. Random-effects meta regression revealed that changes in plasma CRP levels were independent of the dosage of CQ10 (slope: -0.0005; 95% CI: -0.005, 0.004; p=0.832) while duration of supplementation was the dependent mediator (slope: slope: -0.111; 95% CI: -0.21, 0.004; p=0.042). In conclusion, CQ10 supplementation has a borderline favourable effect on CRP levels, and a significant effect on IL-6 level. This suggests that CQ10 supplementation likely attenuates subclinical inflammation. PMID- 28847709 TI - Targeting NAD+ degradation: The therapeutic potential of flavonoids for Alzheimer's disease and cognitive frailty. AB - Flavonoids are efficacious candidates as pharmaceuticals or nutraceuticals in the treatment of Alzheimer's disease (AD), aging and other age-related chronic inflammatory diseases. Natural flavonoids reduce pathological hallmarks, extracellular amyloid deposits and neurofibrillary tangles by mediating amyloid precursor protein (APP) processing, Abeta accumulation and tau pathology. The antioxidant and anti-inflammatory actions as well as modulation of sirtuins and telomeres are also involved in the amelioration of aging, neurodegeneration and other age-related diseases. Recently, some flavonoids were shown to inhibit poly (ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose (cADP) synthases (CD38 and CD157), elevate intracellular nicotinamide adenine dinucleotide+ (NAD+) levels and activate NAD+ dependent sirtuin -mediated signaling pathways. We summarized how flavonoids reduce the degradation of NAD+ with an emphasis on the mechanisms through which flavonoids affect the NAD+-sirtuin axis to protect against AD. Aging and age-related diseases as well as a decline in the physiological reserve are the risk factors for cognitive frailty. Flavonoids with multiple therapeutic targets may also be potential candidates for the prevention and treatment of cognitive frailty. PMID- 28847711 TI - Johannes Joseph van Rood, Transplantation Pioneer (April 7, 1926, to July 21, 2017). PMID- 28847710 TI - Lack of a Prognostic Impact of the MyD88 L265P Mutation for Diffuse Large B Cell Lymphoma Patients Undergoing Autologous Stem Cell Transplantation. AB - Cell-of-origin determination has emerged as an important prognostic factor for patients initially diagnosed with diffuse large B cell lymphoma (DLBCL). Specifically, the nongerminal center B cell-like (non-GCB) subtype, composed predominantly of the activated B cell-like (ABC) molecular subtype, has been shown to portend poor prognosis because of its more aggressive nature and resistance to standard cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP)-like chemotherapy compared with the GCB subtype. The recurrent MyD88 L265P mutation, present in 29% of ABC DLBCL, was reported as an independent poor prognostic factor for patients with newly diagnosed DLBCL. For patients whose disease relapses or is refractory to first-line chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) is frequently offered as salvage therapy. However, the impact of MyD88 mutation status on post ASCT outcome has not been reported. Here, we retrospectively analyzed, with up to 20 years of follow-up, 165 patients who underwent ASCT for relapsed/refractory DLBCL at our institution. We found that MyD88 mutation status did not correlate with overall survival (OS), post-ASCT OS, or progression-free survival (PFS). Patients with non-GCB subtype had significantly worse OS from initial diagnosis and after ASCT. Notably, high International Prognostic Index score was predictive of poor pre- and post-transplant PFS and post-transplant OS. PMID- 28847712 TI - Corrections for multiple comparisons in voxel-based lesion-symptom mapping. AB - Voxel-based lesion-symptom mapping (VLSM) is an important method for basic and translational human neuroscience research. VLSM leverages modern neuroimaging analysis techniques to build on the classic approach of examining the relationship between location of brain damage and cognitive deficits. Testing an association between deficit severity and lesion status in each voxel involves very many individual tests and requires statistical correction for multiple comparisons. Several strategies have been adapted from analysis of functional neuroimaging data, though VLSM faces a more difficult trade-off between avoiding false positives and statistical power (missing true effects). We used simulated and real deficit scores from a sample of approximately 100 individuals with left hemisphere stroke to evaluate two such permutation-based approaches. Using permutation to set a minimum cluster size identified a region that systematically extended well beyond the true region, making it ill-suited to identifying brain behavior relationships. In contrast, generalizing the standard permutation-based family-wise error correction approach provided a principled way to balance false positives and false negatives. Comparison with the widely-used parametric false discovery rate (FDR) correction showed that FDR produces anti-conservative results at smaller sample sizes (N = 30-60). An implementation of the continuous permutation-based FWER correction method described here is included in the lesymap package for lesion-symptom mapping (https://dorianps.github.io/LESYMAP/). PMID- 28847713 TI - Clinical characteristics, treatments, and outcomes of hematogenous pyogenic vertebral osteomyelitis, 12-year experience from a tertiary hospital in central Taiwan. AB - BACKGROUND: In Taiwan, studies about hematogenous pyogenic vertebral osteomyelitis (HPVO) are limited. We conducted a retrospective study to evaluate the clinical presentations, treatment, and outcomes of patients with the diagnosis of HPVO. METHOD: This 12.5-year retrospective study included patients with a diagnosis of HPVO. Medical records of all HPVO patients were thoroughly reviewed and their clinical data were analyzed by the SPSS software. RESULT: 414 HPVO cases were included and the mean age was 61.6 +/- 13.4 years. The mean duration of symptoms was 29 +/- 35.3 days and pain over the affected site was reported by most patients (86.0%). Gram-positive bacteria, especially Staphylococcus aureus (162/399 = 40.6%), were the main HPVO pathogens. Escherichia coli (42/399 = 10.5%) was the most common gram-negative isolate. Surgery was performed in 68.8% of cases and the mean duration of total antibiotic treatment was 104.7 +/- 77.7 days. All-cause mortality and recurrence rates were 6.3% and 18.8%, respectively. In multivariate analysis, polymicrobial infection (OR: 4.154, 95% CI: 1.039-16.604, p = 0.044), multiple vertebral body involvement (OR: 2.202, 95% CI: 1.088-4.457, p = 0.028), abscess formation treated with antibiotics alone (OR: 2.912, 95% CI: 1.064-7.966, p = 0.037), and the duration of antimicrobial treatment less than 4 weeks (OR: 3.737, 95% CI: 1.195-11.683, p = 0.023) were associated with HPVO recurrence. CONCLUSION: In Taiwan, HPVO mainly affected the elderly and S. aureus remained the most common HPVO pathogen. In patients with risk factors associated with HPVO recurrence, a longer duration (>=6 weeks) of antimicrobial therapy is suggested. PMID- 28847714 TI - Molecular methods as tools to control plant diseases caused by Dickeya and Pectobacterium spp: A minireview. AB - Dickeya spp. and Pectobacterium spp. are etiological agents of soft rot on crops, vegetables, and ornamentals. They also cause blackleg on potato. These pectinolytic phytopathogens are responsible for significant economic losses, mostly within the potato production sector. Importantly, there are no methods to eradicate these microorganisms once they have infected plant material. Solely preventive measures remain, including early detection and identification of the pathogens, monitoring of their spread in addition to planting certified seed material tested for latent infections. As proper identification of the causative agent allows for efficient limitation of disease spread, numerous detection and differentiation methods have been developed. Most commonly followed procedures involve: isolation of viable bacterial cells (alternatively post-enrichment) on semi-selective media, identification to species level by PCR (single, multiplex, Real time), serology or fatty acids profiling. Differentiation of the isolates is often accomplished by sequencing the housekeeping genes or molecular fingerprinting. In view of lowering total costs of next-generation sequencing (NGS), a huge amount of generated data reveals subtle differences between strains that have proven to be potentially useful for the establishment of specific novel detection pipelines. Successful implementation of molecular diagnostic methods is exemplified by 20-year studies on the populations of pectinolytic bacteria on potatoes in Poland. The presented work aims to gather the characteristics of Dickeya spp. and Pectobacterium spp. important for the identification process in addition to providing an overview of modern and newly developed specific, rapid, high-throughput and cost-effective screening methods for the detection and identification of these phytopathogens. PMID- 28847716 TI - Public data mining plus domestic experimental study defined involvement of the old-yet-uncharacterized gene matrix-remodeling associated 7 (MXRA7) in physiopathology of the eye. AB - Matrix-remodeling associated 7 (MXRA7) gene was first reported in 2002 and named so for its co-expression with several genes known to relate with matrix remodeling. However, not any studies had been intentionally performed to characterize this gene. We started defining the functions of MXRA7 by integrating bioinformatics analysis and experimental study. Data mining of MXRA7 expression in BioGPS, Gene Expression Omnibus and EurExpress platforms highlighted high level expression of Mxra7 in murine ocular tissues. Real-time PCR was employed to measure Mxra7 mRNA in tissues of adult C57BL/6 mice and demonstrated that Mxra7 was preferentially expressed at higher level in retina, corneas and lens than in other tissues. Then the inflammatory corneal neovascularization (CorNV) model and fungal corneal infections were induced in Balb/c mice, and mRNA levels of Mxra7 as well as several matrix-remodeling related genes (Mmp3, Mmp13, Ecm1, Timp1) were monitored with RT-PCR. The results demonstrated a time-dependent Mxra7 under expression pattern (U-shape curve along timeline), while all other matrix remodeling related genes manifested an opposite changes pattern (dome-shape curve). When limited data from BioGPS concerning human MXRA7 gene expression in human tissues were looked at, it was found that ocular tissue was also the one expressing highest level of MXRA7. To conclude, integrative assay of MXRA7 gene expression in public databank as well as domestic animal models revealed a selective high expression MXRA7 in murine and human ocular tissues, and its change patterns in two corneal disease models implied that MXRA7 might play a role in pathological processes or diseases involving injury, neovascularization and would healing. PMID- 28847715 TI - The role of enteric neurons in the development and progression of colorectal cancer. AB - The enteric nervous system (ENS) is the intrinsic neural network of the gastrointestinal tract, which is essential for regulating gut functions and intestinal homeostasis. The importance of the ENS is underscored by the existence of severe gastrointestinal diseases, such as Hirschsprung's disease and intestinal pseudo-obstruction, which arise when the ENS fails to develop normally or becomes dysregulated. Moreover, it is known that enteric neurons are involved in intestinal inflammation. However, the role of the ENS in colorectal cancer (CRC) carcinogenesis remains poorly understood, even though processes like perineural invasion and neoneurogenesis are important factors in CRC. Here we summarize how enteric neurons are affected during CRC and discuss the influence of enteric neurons, either direct or indirect, on the development and/or progression of CRC. Finally, we illustrate how the ENS could be targeted as a potential anti-cancer therapy, establishing the ENS as an integral part of the tumor microenvironment. PMID- 28847717 TI - A novel G to A transition at initiation codon and exon-intron boundary of PAX9 identified in association with familial isolated oligodontia. AB - Several studies on experimental animals indicate that the process of organogenesis crucially depends upon the spatiotemporal dose of certain critical bio-molecules. Tooth development is also not an exception. While most of the knowledge regarding the molecular mechanism of tooth development comes from the studies on mouse model, pathogenic variations identified in human tooth agenesis also provide valuable information on mammalian tooth development. Until now five major candidate genes have been identified for tooth agenesis in human. Among them, PAX9 plays the crucial role in tooth development and in non-syndromic congenital tooth agenesis. In this study, microsatellite and SNP based genotyping identifies a disease specific haplotype block, which includes PAX9 gene, segregates with autosomal dominant tooth agenesis phenotype. Direct sequencing of PAX9 identifies a novel heterozygous G to A transition at the third base (c.3G>A) of initiation codon leading to ATG to ATA shift in all affected individuals which is absent in all unaffected relatives and 200 control chromosomes. Further, in vitro functional analysis creating PAX9 minigene construct did apparently show no effect on the splice-site migration. It is therefore proposed that haploinsufficiency of PAX9 is the causal factor for tooth agenesis in this family. PMID- 28847718 TI - The investigation of interferences in immunoassay. AB - Immunoassay procedures have a wide application in clinical medicine and as such are used throughout clinical biochemistry laboratories both for urgent and routine testing. Clinicians and laboratory personnel are often presented with immunoassay results which are inconsistent with clinical findings. Without a high index of suspicion interferences will often not be suspected. Artifactual results can be due to a range of interferences in immunoassays which can include cross reacting substances, heterophile antibodies, autoantibodies and the high dose hook effect. Further, pre-analytical aspects and certain disease states can influence the potential for interference in immunoassays. Practical solutions for investigation of artifactual results in the setting of the routine clinical laboratory are provided. PMID- 28847719 TI - Rofa Nadofederal-The greatest tennis player that ever lived: A science fiction story depicting a future where biotechnology is unchecked. PMID- 28847721 TI - Erratum to "Erratum to "The SCARE guidelines: Consensus-based surgical case report guidelines" [Int. J. Surg. 34 (2016) 180-186]" [Int. J. Surg. 36 (2016) 396]. PMID- 28847720 TI - LC3-Associated Phagocytosis and Inflammation. AB - LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B-light chain 3) is conjugated to phagosome membranes using a portion of the canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an "immunologically silent" clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages. PMID- 28847722 TI - The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway. AB - Sarcopenia is an age-related syndrome characterized by progressive loss of muscle mass and function. Exercise is an important strategy to prolong life and increase muscle mass, and resveratrol has been shown a variety beneficial effects on skeletal muscle. In the present study, we investigated the potential efficacy of using short-term exercise (six weeks), resveratrol (150mg/kg/day), or combined exercise+resveratrol (150mg/kg/day) on gastrocnemius muscle mass, grip strength, cross-sectional area and microscopic morphology in aged rats, and explored the potential mechanism at the apoptosis level. Six months old SD rats were used as young control group and 24months old SD rats were adopted as aged group. After six weeks intervention, the data provide evidence that exercise, resveratrol or their combination significantly increase the relative grip strength and muscle mass in aged rats (P<0.05). Electron microscopy discovered a significant increase in sarcomere length, I-band and H-zone in aged rats (P<0.05), and exercise, resveratrol or their combination significantly reduced the increasement (P<0.05). Moreover, light microscopy revealed a significant increase on Feret's diameter and cross-sectional area (CSA) in aged rats (P<0.05), but exercise and resveratrol did not show significant effects on them (P>0.05). Furthermore, exercise, resveratrol or their combination significantly increased the expression of p-AMPK and SIRT1, decreased the expression of acetyl P53 and Bax/Bcl-2 ratio in aged rats (P<0.05). These findings show that aged rats show significant changes in gastrocnemius muscle morphology and ultrastructure, and the protective effects of exercise, resveratrol and their combination are probably associated with anti-apoptotic signaling pathways through activation of AMPK/Sirt1. PMID- 28847723 TI - Unifying aging and frailty through complex dynamical networks. AB - To explore the mechanistic relationships between aging, frailty and mortality, we developed a computational model in which possible health attributes are represented by the nodes of a complex network, with the connections showing a scale-free distribution. Each node can be either damaged (i.e. a deficit) or undamaged. Damage of connected nodes facilitates local damage and makes local recovery more difficult. Our model demonstrates the known patterns of frailty and mortality without any assumption of programmed aging. It helps us to understand how the observed maximum of the frailty index (FI) might arise. The model facilitates an initial understanding of how local damage caused by random perturbations propagates through a dynamic network of interconnected nodes. Very large model populations (here, 10 million individuals followed continuously) allow us to exploit new analytic tools, including information theory, showing, for example that highly connected nodes are more informative than less connected nodes. This model permits a better understanding of factors that influence the health trajectories of individuals. PMID- 28847724 TI - Age verification of the longest lived man in the world. AB - Identifying the correct length of life for long-lived individuals is highly important for the social and natural sciences, as well as for policymaking. The purposes of this paper are to propose a standardized age verification procedure and to report on the age verification case of Jiroemon Kimura (J.K.), who is assumed to be the longest lived man in the world. We propose two verification processes that we have named face validity and concurrent validity of age verification. We collected official documents, and non-official records to check face validity. We also gathered life episodes told by J.K. and historical records to evaluate concurrent validity. Although we found several date inconsistencies among documents and mismatches between told episodes and actual dates of events, no critical discordances were discovered. In conclusion, we could verify that J.K. was born on April 19, 1897 and passed away on June 12, 2013 at the age of 116years and 54days. PMID- 28847726 TI - Effects of curcumin and ursolic acid on the mitochondrial coupling efficiency and hydrogen peroxide emission of intact skeletal myoblasts. AB - Curcumin may improve blood glucose management, but the mechanism is not fully established. We demonstrated that curcumin (40 MUM) reduced the mitochondrial coupling efficiency (percentage of oxygen consumption coupled to ATP synthesis) of intact skeletal muscle cells. A 30-minute pretreatment with curcumin reduced mitochondrial coupling efficiency by 17.0 +/- 0.4% relative to vehicle (p < 0.008). Curcumin pretreatment also decreased the rate of hydrogen peroxide emission by 43 +/- 13% compared to vehicle (p < 0.05). Analysis of cell respiration in the presence of curcumin revealed a 40 +/- 4% increase in the rate of oxygen consumption upon curcumin administration (p < 0.05 compared to vehicle). No difference in mitochondrial coupling efficiency was observed between vehicle- and curcumin-pretreated cells after permeabilization of cell membranes (p > 0.7). The interaction between curcumin and ursolic acid, another natural compound that may improve blood glucose management, was also examined. Pretreatment with ursolic acid (0.12 MUM) increased the mitochondrial coupling efficiency of intact cells by 4.1 +/- 1.1% relative to vehicle (p < 0.008) and attenuated the effect of curcumin when the two compounds were used in combination. The observed changes to mitochondrial coupling efficiency and hydrogen peroxide emission were consistent with the established effects of curcumin on blood glucose control. Our findings also show that changes to mitochondrial coupling efficiency after curcumin pretreatment may go undetected unless cells are assessed in the intact condition. PMID- 28847725 TI - Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. AB - Renal cell carcinoma (RCC) is the most aggressive type of genitourinary cancer and highly resistant to current available therapies. In this work, we investigated the effects and mechanism of anti-parasitic agent ivermectin in RCC. We show that ivermectin significantly inhibits proliferation and induces apoptosis in multiple RCC cell lines that represent different histological subtypes and various mutation status. Importantly, ivermectin is significantly less or ineffective in normal kidney cells compared with RCC cells, demonstrating the preferential toxicity of ivermectin to RCC. Ivermectin also significantly inhibits RCC tumor growth in vivo. Mechanistically, ivermectin induces mitochondrial dysfunction via decreasing mitochondrial membrane potential, mitochondrial respiration and ATP production. As a consequence of mitochondrial dysfunction, oxidative stress and damage is detected in ivermectin treated RCC cells and xenograft mouse model. The rescue of ivermectin's effect by acetyl-l Carnitine (ALCAR, a mitochondrial fuel) or antioxidant N-acetyl-l-cysteine (NAC) confirms mitochondria as the target of ivermectin in RCC cells. Compared to normal kidney cells, RCC cells have higher mitochondrial mass and respiration, and ATP production, which might explain the preferential toxicity of ivermectin to RCC. Our work suggest that ivermectin is a promising candidate for RCC treatment and targeting mitochondrial metabolism is an alternative therapeutic strategy for RCC. PMID- 28847727 TI - Studies on anti-angiogenesis of ginsenoside structure modification HRG in vitro. AB - This study investigates the anti-angiogenic effect of 3beta, 12beta, 20(S) trihydroxy dammarane-3-O-beta-d-glucopyranosyl(1-2)-beta-d-glucopyranoside(HRG), a new chemical compound obtained by structure modification on Ginseng saponins Rg3, associated with the regulation of matrix metalloproteinases(MMPs) and its upstream signal-regulated molecule of vascular endothelial growth factor(VEGF) and basic fibroblast growth factor(b-FGF) in vitro, which plays an critical role in angiogenesis during the process of carcinoma. In our study, to investigate the anti-angiogenesis effect of HRG in HUVECs, we utilized cell proliferation assay, tube formation assay, wound-healing assay, Semi-quantitative reverse transcription PCR, and Western blot assay. Our results demonstrated that HRG plays a major role in the regulation of proliferation, migration and tube formation of HUVECs by suppressing the expression of VEGF and b-FGF in both transcriptional and post-transcriptional levels. In addition, the expression of MMP-2 and MMP-9, which were related to the ECM degradation, were down-regulated after administration of HRG as well. Overall, our results revealed that HRG strongly inhibited the process of angiogenesis and shows better effectiveness than Rg3. PMID- 28847728 TI - The effect of brassinolide, a plant steroid hormone, on drug resistant small-cell lung carcinoma cells. AB - Small-cell lung carcinoma (SCLC) has a dismal prognosis in part because of multidrug resistance (MDR). Epibrassinolide (EB) is a steroid hormone in plants, with many physiological effects. It acts via a membrane receptor and GSK3 pathway, resulting in stabilization of a transcription factor. The parallels to the Wnt signaling pathway, which is activated in SCLC and results in increased beta-catenin, prompted investigations of the effects of EB on drug-resistant (VPA17) and drug-sensitive (H69) SCLC cells. EB was cytotoxic to both cell lines (IC50 = 2 MUM), indicating a lack of cross-resistance in the VPA17 cell line. EB was pro-apoptotic after 24 h as measured by ELISA of BUdR-labeled DNA fragments and caspase-3 specific activity (2.5 enzyme units/mg protein vs. 0.01 units/mg protein for untreated controls). Matrigel assays showed that EB reduced the SCLC cell invasion phenotype by 80%. Pre-incubation of VPA17 cells in 1 MUM EB for 96 h reversed resistance to etoposide (IC50 = 6.0 MUM, reduced to 1.8 MUM with EB) and doxorubicin (IC50 = 0.37 MUM, reduced to 0.09 MUM). Synergism between EB and chemotherapy drugs was investigated by exposure of VPA17 cells to 1:1 ratios at the respective IC50 values, with serial dilutions at 0.25 to 2.0 * IC50 and determination of the combination index (CI). EB and etoposide showed synergism (CI = 0.80 at ED50); EB and doxorubicin also showed synergism (CI = 0.65 at ED50). Incubation of SCLC cells in EB led to a time- and dose dependent reduction of beta-catenin (maximum 80% reduction). Gene expression analyses of SCLC cells showed EB incubation resulted in significant reduction in expression of beta catenin-dependent genes that are anti-apoptotic (e.g., c-Jun, survivin), cell division-related (e.g., CCND1 cyclin, sox9), and metastasis-related (e.g., MMP7, uPAR). WIKI4, a known inhibitor of Wnt signaling, was cytotoxic to SCLC cells (IC50 = 0.02 MUM). Synergism between EB and WIKI4 was determined by the CI method and showed antagonism (CI = 1.09 at ED50), suggesting that EB and WIKI4 act on the same pathway. Taken together, these data indicate that EB, a natural product with widespread occurrence in plants, is pharmacologically active in both drug sensitive and drug-resistant SCLC cells and acts through the Wnt signaling pathway. PMID- 28847729 TI - Hepatic GDF15 is regulated by CHOP of the unfolded protein response and alleviates NAFLD progression in obese mice. AB - The adaptive unfolded protein responses (UPR) initiated by ER stress have been implicated in metabolic dysfunctions and liver diseases. Growth differentiation factor 15 (GDF15) shows a broad range of effects on lipid homeostasis. The functional interconnections between ER stress and GDF15 are still unclear, however. Here we present that hepatic excess lipid accumulation along with ER stress could exacerbate GDF15 expression in mouse liver. Administration of chemical ER stressor tunicamycin to activate the UPR pathway resulted in robust increase of hepatic and circulating GDF15 levels. Further studies revealed that C/EBP-homologous protein (CHOP) of the UPR pathway could directly bind to the promoter of GDF15 and activate its transcription under ER stress conditions both ex vivo and in vivo. Ectopic expression of hepatic GDF15 reduced lipid accumulation in liver and alleviated non-alcoholic fatty liver disease (NAFLD) progression via enhancing hepatic fatty acid beta-oxidation in HFD-feeding mice. Together, our results demonstrate that hepatic GDF15 acts as a downstream component of the UPR program and exerts beneficial functions in regulating lipid metabolism of liver. PMID- 28847730 TI - The L530R variation associated with recurrent kidney stones impairs the structure and function of TRPV5. AB - TRPV5 is a Ca2+-selective channel that plays a key role in the reabsorption of Ca2+ ions in the kidney. Recently, a rare L530R variation (rs757494578) of TRPV5 was found to be associated with recurrent kidney stones in a founder population. However, it was unclear to what extent this variation alters the structure and function of TRPV5. To evaluate the function and expression of the TRPV5 variant, Ca2+ uptake in Xenopus oocytes and western blot analysis were performed. The L530R variation abolished the Ca2+ uptake activity of TRPV5 in Xenopus oocytes. The variant protein was expressed with drastic reduction in complex glycosylation. To assess the structural effects of this L530R variation, TRPV5 was modeled based on the crystal structure of TRPV6 and molecular dynamics simulations were carried out. Simulation results showed that the L530R variation disrupts the hydrophobic interaction between L530 and L502, damaging the secondary structure of transmembrane domain 5. The variation also alters its interaction with membrane lipid molecules. Compared to the electroneutral L530, the positively charged R530 residue shifts the surface electrostatic potential towards positive. R530 is attracted to the negatively charged phosphate group rather than the hydrophobic carbon atoms of membrane lipids. This shifts the pore helix where R530 is located and the D542 residue in the Ca2+-selective filter towards the surface of the membrane. These alterations may lead to misfolding of TRPV5, reduction in translocation of the channel to the plasma membrane and/or impaired Ca2+ transport function of the channel, and ultimately disrupt TRPV5 mediated Ca2+ reabsorption. PMID- 28847731 TI - KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer. AB - KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3'UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3'UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes. PMID- 28847732 TI - Variable cardiac alpha-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation. AB - Different genes encode the alpha-actin isoforms that are predominantly expressed in heart and skeletal muscle. Mutations in the skeletal muscle alpha-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac alpha-actin (ACTC1). ACTC1 is the predominant striated alpha-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actc1 in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actc1 expression in early adult skeletal muscles. PMID- 28847733 TI - DNA methyltransferase homologue TRDMT1 in Plasmodium falciparum specifically methylates endogenous aspartic acid tRNA. AB - In eukaryotes, cytosine methylation regulates diverse biological processes such as gene expression, development and maintenance of genomic integrity. However, cytosine methylation and its functions in pathogenic apicomplexan protozoans remain enigmatic. To address this, here we investigated the presence of cytosine methylation in the nucleic acids of the protozoan Plasmodium falciparum. Interestingly, P. falciparum has TRDMT1, a conserved homologue of DNA methyltransferase DNMT2. However, we found that TRDMT1 did not methylate DNA, in vitro. We demonstrate that TRDMT1 methylates cytosine in the endogenous aspartic acid tRNA of P. falciparum. Through RNA bisulfite sequencing, we mapped the position of 5-methyl cytosine in aspartic acid tRNA and found methylation only at C38 position. P. falciparum proteome has significantly higher aspartic acid content and a higher proportion of proteins with poly aspartic acid repeats than other apicomplexan pathogenic protozoans. Proteins with such repeats are functionally important, with significant roles in host-pathogen interactions. Therefore, TRDMT1 mediated C38 methylation of aspartic acid tRNA might play a critical role by translational regulation of important proteins and modulate the pathogenicity of the malarial parasite. PMID- 28847734 TI - Improvement in the Spatial Distribution of Pain, Somatic Symptoms, and Depression After a Weight Loss Intervention. AB - : Weight loss is known to improve pain localized to weight-bearing joints but it is not known how weight loss affects the spatial distribution of pain and associated somatic symptoms like fatigue. We sought to determine if weight loss using a low-calorie diet improves pain, affect, and somatic symptoms commonly associated with chronic pain conditions in an observational study. We also documented changes in inflammatory markers in serum before and after weight loss. Participants were 123 obese individuals undergoing a 12- to 16-week calorie restriction weight loss intervention. The spatial distribution of pain, symptom severity (eg, fatigue, sleep difficulties), depression, and total fibromyalgia scale scores were measured before and after weight loss. Pain (P = . 022), symptom severity (P = .004), depression (P < .001), and fibromyalgia scores (P = .004) improved after weight loss; men showed greater improvement than women on somatic symptoms and fibromyalgia scores (both P < .01). Those who lost at least 10% of body weight showed greater improvement than those who lost <10%. Levels of the regulatory cytokine interleukin-10 increased after the intervention (P = .002). Weight loss may improve diffuse pain and comorbid symptoms commonly seen in chronic pain participants. PERSPECTIVE: This article presents the effect of a weight loss intervention on characteristics of chronic pain, including the spatial distribution of pain and comorbid somatic symptoms. Weight loss appeared to produce larger improvements in somatic symptoms for men. PMID- 28847735 TI - Loss of Temporal Inhibition of Nociceptive Information Is Associated With Aging and Bodily Pain. AB - : An age-related decline in endogenous pain inhibitory processes likely places older adults at an increased risk for chronic pain. Limited research indicates that older adults may be characterized by deficient offset analgesia, an inhibitory temporal sharpening mechanism that increases the detectability of minor decreases in noxious stimulus intensity. The primary purpose of the study was to examine age differences in offset analgesia in community-dwelling younger, middle-aged, and older adults. An additional aim of the study was to determine whether the magnitude of offset analgesia predicted self-reported bodily pain. Eighty-seven younger adults, 42 middle-aged adults, and 60 older adults completed 4 offset analgesia trials and 3 constant temperature trials in which a noxious heat stimulus was applied to the volar forearm for 40 seconds. The offset trials consisted of 3 continuous phases: an initial 10-second painful stimulus, either a 1.0 degrees C or .4 degrees C increase in temperature from the initial 10-second painful stimulus for 10 seconds, and either a 1.0 degrees C or .4 degrees C decrease back to the initial testing temperature for 20 seconds. During each trial, subjects rated pain intensity continuously using an electronic visual analog scale (0-100). All subjects also completed the Short-Form Health Survey-36 including the Bodily Pain subscale. The results indicated that older and middle aged adults showed reduced offset analgesia compared with younger adults in the 1.0 degrees C and .4 degrees C offset trials. Furthermore, the magnitude of offset analgesia predicted self-reported bodily pain, with those exhibiting reduced offset analgesia reporting greater bodily pain. Dysfunction of this endogenous inhibitory system could increase the risk of developing chronic pain for middle-aged and older adults. PERSPECTIVE: Older and middle-aged adults showed reduced offset analgesia compared with younger adults. The significant association between reduced offset analgesia and pain in daily life supports the notion that pain modulatory deficits are associated with not just a chronic pain condition but with the experience of pain in general. PMID- 28847736 TI - Development of a luciferase reporter Jurkat cell line under the control of endogenous interleukin-2 promoter. AB - During new drug development, it is critical to have a cell-based reporter bioassay to measure drug-mediated physiological changes. In a conventional reporter cell line, a reporter expression construct is randomly inserted into the host cell genome with the reporter gene under control of an engineered promoter. This design ensures high signal output but may not represent the true physiological cell signaling. Here we used the CRISPR/Cas9 technology to engineer a Jurkat cell line by replacing one interleukin 2 (IL2) allele with firefly luciferase gene while keeping the other IL2 allele intact. The expression of luciferase is thus under control of endogenous IL2 promoter. We demonstrated that, in this engineered cell line, the IL-2 secretion pathway remained intact and luciferase activity significantly increased upon stimulation with phorbol ester or CD3/CD28 antibodies. We next expressed glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in this cell line and observed dose-dependent IL-2 and luciferase responses to GITR agonist antibody. Thus we have successfully constructed a reporter cell line by engineering a reporter gene under control of an endogenous target gene promoter. This novel strategy may provide a more physiologically relevant alternative to the traditional method of reporter cell line construction. PMID- 28847737 TI - Human papillomavirus type 16 lineage analysis based on E6 region in cervical samples of Iranian women. AB - It is suggested that distinct HPV 16 variants differ in oncogenic potential and geographic distribution. As such, understanding the regional variants of HPV 16 would be of great importance for evolutionary, epidemiological and biological analysis. In this regard, the sequence variations of E6 gene were investigated to characterize more common variants of HPV 16 in normal cells, premalignant and malignant lesions of the cervix. In total, 106 isolates of HPV 16 were analyzed by PCR and sequencing. Overall, two different lineages (A and D) were identified. Lineage D comprised 70.7% of samples and the remaining 29.3% belonged to lineage A. Regarding to cytology/histology, lineage D was dominant in both normal+CIN I II and CIN III+ICC groups as it was detected in 80% and 66.2% of cases, respectively. The comparison of the lineages between different groups (35 normal+CIN I-II samples and 71 CIN III+ICC samples) revealed that lineage A is more prevalent in cervical cancer cases (7 (20%) vs. 24 (33.8%)) although the difference observed did not reach statistical significance (p=0.07). In conclusion, our findings confirm that HPV lineages A and D are more prevalent in Iran, with the lineage D as the most dominant in all studied groups. PMID- 28847738 TI - Sorsby fundus dystrophy - A review of pathology and disease mechanisms. AB - Sorsby fundus dystrophy (SFD) is an autosomal dominant macular dystrophy with an estimated prevalence of 1 in 220,000 and an onset of disease around the 4th to 6th decade of life. Similar to age-related macular degeneration (AMD), ophthalmoscopy reveals accumulation of protein/lipid deposits under the retinal pigment epithelium (RPE), referred to as drusen, in the eyes of patients with SFD. SFD is caused by variants in the gene for tissue inhibitor of metalloproteinases-3 (TIMP3), which has been found in drusen-like deposits of SFD patients. TIMP3 is constitutively expressed by RPE cells and, in healthy eyes, resides in Bruch's membrane. Most SFD-associated TIMP3 variants involve the gain or loss of a cysteine residue. This suggests the protein aberrantly forms intermolecular disulphide bonds, resulting in the formation of TIMP3 dimers. It has been demonstrated that SFD-associated TIMP3 variants are more resistant to turnover, which is thought to be a result of dimerisation and thought to explain the accumulation of TIMP3 in drusen-like deposits at the level of Bruch's membrane. An important function of TIMP3 within the outer retina is to regulate the thickness of Bruch's membrane. TIMP3 performs this function by inhibiting the activity of matrix metalloproteinases (MMPs), which have the function of catalysing breakdown of the extracellular matrix. TIMP3 has an additional function to inhibit vascular endothelial growth factor (VEGF) signalling and thereby to inhibit angiogenesis. However, it is unclear whether SFD-associated TIMP3 variant proteins retain these functions. In this review, we discuss the current understanding of the potential mechanisms underlying development of SFD and summarise all known SFD-associated TIMP3 variants. Cell culture models provide an invaluable way to study disease and identify potential treatments. These allow a greater understanding of RPE physiology and pathophysiology, including the ability to study the blood-retinal barrier as well as other RPE functions such as phagocytosis of photoreceptor outer segments. This review describes some examples of such recent in vitro studies and how they might provide new insights into degenerative diseases like SFD. Thus far, most studies on SFD have been performed using ARPE-19 cells or other, less suitable, cell types. Now, induced pluripotent stem cell (iPSC) technologies allow the possibility to non-invasively collect somatic cells, such as dermal fibroblast cells and reprogram those to produce iPSCs. Subsequent differentiation of iPSCs can generate patient-derived RPE cells that carry the same disease-associated variant as RPE cells in the eyes of the patient. Use of these patient-derived RPE cells in novel cell culture systems should increase our understanding of how SFD and similar macular dystrophies develop. PMID- 28847741 TI - The molecular mechanisms of sexual orientation and gender identity. AB - Differences between males and females are widely represented in nature. There are gender differences in phenotypes, personality traits, behaviors and interests, cognitive performance, and proneness to specific diseases. The most marked difference in humans is represented by sexual orientation and core gender identity, the origins of which are still controversial and far from being understood. Debates continue on whether sexual behavior and gender identity are a result of biological (nature) or cultural (nurture) factors, with biology possibly playing a major role. The main goal of this review is to summarize the studies available to date on the biological factors involved in the development of both sexual orientation and gender identity. A systematic search of published evidence was performed using Medline (from January 1948 to June 2017). Review of the relevant literature was based on authors' expertise. Indeed, different studies have documented the possible role and interaction of neuroanatomic, hormonal and genetic factors. The sexual dimorphic brain is considered the anatomical substrate of psychosexual development, on which genes and gonadal hormones may have a shaping effect. In particular, growing evidence shows that prenatal and pubertal sex hormones permanently affect human behavior. In addition, heritability studies have demonstrated a role of genetic components. However, a convincing candidate gene has not been identified. Future studies (e.i. genome wide studies) are needed to better clarify the complex interaction between genes, anatomy and hormonal influences on psychosexual development. PMID- 28847740 TI - Understanding the value of minimally invasive procedures for the treatment of lumbar spinal stenosis: the case of interspinous spacer devices. AB - BACKGROUND CONTEXT: Minimally invasive lumbar spinal stenosis procedures have uncertain long-term value. PURPOSE: This study sought to characterize factors affecting the long-term cost-effectiveness of such procedures using interspinous spacer devices ("spacers") relative to decompression surgery as a case study. STUDY DESIGN: Model-based cost-effectiveness analysis. PATIENT SAMPLE: The Medicare Provider Analysis and Review database for the years 2005-2009 was used to model a group of 65-year-old patients with spinal stenosis who had no previous spine surgery and no contraindications to decompression surgery. OUTCOME MEASURES: Costs, quality-adjusted life years (QALYs), and cost per QALY gained were the outcome measures. METHODS: A Markov model tracked health utility and costs over 10 years for a 65-year-old cohort under three care strategies: conservative care, spacer surgery, and decompression surgery. Incremental cost effectiveness ratios (ICER) reported as cost per QALY gained included direct medical costsfor surgery. Medicare claims data were used to estimate complication rates, reoperation, and related costs within 3 years. Utilities and long-term reoperation rates for decompression were derived frompublished studies. Spacer failure requiring reoperation beyond 3 years and post-spacer health utilities are uncertain and were evaluated through sensitivity analyses. In the base-case, the spacer failure rate was held constant for years 4-10 (cumulative failure: 47%). In a "worst-case" analysis, the 10-year cumulative reoperation rate was increased steeply (to 90%). Threshold analyses were performed to determine the impact of failure and post-spacer health utility on the cost-effectiveness of spacer surgery. RESULTS: The spacer strategy had an ICER of $89,500/QALY gained under base-case assumptions, and remained under $100,000 as long as the 10-year cumulative probability of reoperation did not exceed 54%. Under worst-case assumptions, the spacer ICER was $482,000/QALY and fell below $100,000 only if post-spacer utility was 0.01 greater than post-decompression utility or the cost of spacer surgery was $1,600 less than the cost of decompression surgery. CONCLUSIONS: Spacers may provide a reasonably cost-effective initial treatment option for patients with lumbar spinal stenosis. Their value is expected to improve if procedure costs are lower in outpatient settings where these procedures are increasingly being performed. Decision analysis is useful for characterizing the long-term cost-effectiveness potential for minimally invasive spinal stenosis treatments and highlights the importance of complication rates and prospective health utility assessment. PMID- 28847742 TI - A global optimization algorithm inspired in the behavior of selfish herds. AB - In this paper, a novel swarm optimization algorithm called the Selfish Herd Optimizer (SHO) is proposed for solving global optimization problems. SHO is based on the simulation of the widely observed selfish herd behavior manifested by individuals within a herd of animals subjected to some form of predation risk. In SHO, individuals emulate the predatory interactions between groups of prey and predators by two types of search agents: the members of a selfish herd (the prey) and a pack of hungry predators. Depending on their classification as either a prey or a predator, each individual is conducted by a set of unique evolutionary operators inspired by such prey-predator relationship. These unique traits allow SHO to improve the balance between exploration and exploitation without altering the population size. To illustrate the proficiency and robustness of the proposed method, it is compared to other well-known evolutionary optimization approaches such as Particle Swarm Optimization (PSO), Artificial Bee Colony (ABC), Firefly Algorithm (FA), Differential Evolution (DE), Genetic Algorithms (GA), Crow Search Algorithm (CSA), Dragonfly Algorithm (DA), Moth-flame Optimization Algorithm (MOA) and Sine Cosine Algorithm (SCA). The comparison examines several standard benchmark functions, commonly considered within the literature of evolutionary algorithms. The experimental results show the remarkable performance of our proposed approach against those of the other compared methods, and as such SHO is proven to be an excellent alternative to solve global optimization problems. PMID- 28847739 TI - Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer. AB - Mortality rates for ovarian cancer have declined only slightly in the past forty years since the "War on Cancer" was declared. The current standard care of ovarian cancer is still cytoredutive surgery followed by several cycles of chemotherapy. The severe adverse effect from chemotherapy drug is a leading cause for the patients to fail in long term therapy post-surgery. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. Here we reported a unique type of extremely long tumor retention, multi-responsive boronate crosslinked micelles (BCM) for ovarian cancer therapy. We systemically investigated the stability of BCM in serum and plasma, and their responsiveness to acidic pH and cis-diols (such as mannitol, a safe FDA approved drug for diuresis) through particle size measurement and forster resonance energy transfer (FRET) approach. Paclitaxel (PTX) loaded BCM (BCM-PTX) exhibited higher stability than non crosslinked micelles (NCM) in the presence of plasma or serum. BCMs possessed a longer in vivo blood circulation time when compared to NCM. Furthermore, BCM could be disassembled in an acidic pH environment or by administrating mannitol, facilitating drug release in an acidic tumor environment and triggered by exogenous stimuli after drug enrichment in tumor mass. Near infra-red fluorescence (NIRF) imaging on SKOV-3 ovarian cancer mouse model demonstrated that the NIR dye DiD encapsulated BCM could preferentially accumulate in tumor site and their tumor retention was very long with still 66% remained on 12th day post injection. DiD-NCM had similar high-level uptake in tumor with DiD-BCM within the first 3days, its accumulation, however, decreased obviously on 4th day and only 15% dye was left 12days later. In both formulations, the dye uptake in normal organs was mostly washed away within the first 24-48h. In in vivo tumor treatment study, PTX loaded BCM showed superior therapeutic efficacy than that of NCM and Taxol. The mice could tolerate 20mg/kg PTX formulated in nano formulations, which doubled the maximum tolerated dose (MTD) of Taxol. The administration of mannitol 24h after BCM-PTX injection further improved the tumor therapeutic effect and elongated the survival time of the mice. The novel boronate-catechol crosslinked nanocarrier platform demonstrated its superior capability in targeted drug delivery, which is not only useful for ovarian cancer treatment but will also be beneficial for the therapy of many other solid tumors. PMID- 28847743 TI - Endogenous spatial attention directed to intracutaneous electrical stimuli on the forearms involves an external reference frame. AB - In the present study, we examined whether the direction of attention while anticipating intracutaneous electrical stimuli on the left or right forearm occurs within an internal somatotopic or an external body-based reference frame. Participants placed their hands on a table in front of them in a normal position or in a crossed-hands position. A symbolic cue with a validity of 80% instructed participants to attend to either the left or the right side, which varied from trial to trial. Crossing the hands induces a conflict of internal and external reference frames which allows to determine the dominating reference frame(s). Analyses of the electroencephalogram (EEG) during the orienting phase revealed that crossing the arms did not induce a reversal of neural activity over central sites as a late direction attention-related positivity and increased ipsilateral alpha power over occipital and central sites was observed in both conditions. Hand position influenced the processing of the electrical stimuli as no effect of cue validity was observed on the P3a component in the crossed-hands position. Our results indicate that endogenous spatial attention to intracutaneous electrical stimuli primarily occurs within an external reference frame. PMID- 28847744 TI - Low genetic diversity in Ozobranchus jantseanus (Hirudinida: Ozobranchidae) in Japan: Possibility of introduction with their host turtles. AB - Leeches belonging to the genus Ozobranchus are ectoparasitic on sea and freshwater turtles. The freshwater species O. jantseanus has been recorded from China and Japan. Ozobranchus jantseanus inhabiting Japan is considered to be a non-indigenous species, because their primary host, the Reeves' pond turtle, Mauremys reevesii, is thought to have been introduced in the last few centuries from adjacent Asian countries. To assess whether the Japanese populations of O. jantseanus were likely to have been introduced, their genetic diversity was investigated using mitochondrial cytochrome c oxidase subunit I sequences. The very low sequence diversity as well as the historical record of this species from Japan suggest that Japanese populations of O. jantseanus may have been artificially introduced along with their host turtles. Molecular phylogenies of COI showed that two marine Ozobranchus species formed a clade together with the freshwater O. jantseanus. PMID- 28847745 TI - ESCRT genes and regulation of developmental signaling. AB - ESCRT (Endosomal Sorting Complex Required for Transport) proteins have been shown to control an increasing number of membrane-associated processes. Some of these, and prominently regulation of receptor trafficking, profoundly shape signal transduction. Evidence in fungi, plants and multiple animal models support the emerging concept that ESCRTs are main actors in coordination of signaling with the changes in cells and tissues occurring during development and homeostasis. Consistent with their pleiotropic function, ESCRTs are regulated in multiple ways to tailor signaling to developmental and homeostatic needs. ESCRT activity is crucial to correct execution of developmental programs, especially at key transitions, allowing eukaryotes to thrive and preventing appearance of congenital defects. PMID- 28847746 TI - 17beta-Hydroxysteroid dehydrogenase 3 deficiency: Three case reports and a systematic review. AB - 17beta-Hydroxysteroid dehydrogenase 3 deficiency is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, however, no case has been reported in East Asia. The aim of this study was to report three Chinese 46, XY females with 17beta-HSD3 deficiency in a single center and perform a systematic review of the literature. Clinical examination, endocrine evaluation and HSD17B3 gene sequencing were performed in the three Chinese phenotypically females (two sisters and one unrelated patient). Relevant articles were searched by using the term "HSD17B3" OR "17beta-HSD3 gene" with restrictions on language (English) and species (human) in Pubmed and Embase. All the three phenotypically female subjects showed 46, XY karyotype, inguinal masses, decreased testosterone and increased androstenedione. Two novel homozygous mutations (W284X and c.124_127delTCTT) in HSD17B3 gene were identified. A systematic review found a total of 121 pedigrees/158 patients, with 78.5% (124/158) of patients assigned as females, 15.2% (24/158) from females to males, and 5.1% (8/158) raised as males. The most common mutation was c.277+4C>T (allele frequency: 25/72) for patients from Europe, and R80Q (allele frequency: 21/54) for patients from West Asia. The testicular histology showed normal infantile testicular tissue in 100% (9/9) infantile patients, normal quantity germ cells in 44.4% (8/18) prepubertal patients and 19.0% (4/21) pubertal and adult patients. We reported the first East Asian 17beta-hydroxysteroid dehydrogenase 3 deficiency cases. Additional literature reviews found founder effects among patients with different ethnic background and early orchiopexy may benefit fertility in patients assigned as males. These findings may significantly expand the clinical, ethnic and genetic spectrum of 17beta-hydroxysteroid dehydrogenase 3 deficiency. PMID- 28847747 TI - Hypoxia induced phosphorylation of estrogen receptor at serine 118 in the absence of ligand. AB - The estrogen receptor (ER) plays an important role in breast cancer development and progression. Hypoxia modulates the level of ERalpha expression and induces ligand-independent transcriptional activation of ERalpha, which is closely related with the biology of breast carcinomas. Since phosphorylation itself affects the transcriptional activity and stabilization of ERalpha, we examined changes in ERalpha phosphorylation under hypoxic conditions. Hypoxia induced phosphorylation of ERalpha at serine residue 118 (S118) in the absence of estrogen through the mitogen-activated protein kinase (MAPK)/ERK1/2 pathway. Cell proliferation was significantly decreased under normoxia or hypoxia when ERalpha harboring the S118A mutation was overexpressed. Our previous studies showed that ER degradation is the most prominent phenomenon under hypoxia. E2-induced ER protein downregulation is dependent on phosphorylation of S118. However, hypoxia induced ERalpha degradation did not involve S118 phosphorylation. Our study implies the existence of a differential mechanism between E2 and hypoxia-mediated ERalpha protein degradation. Understanding the mechanistic behavior of ER under hypoxia will likely facilitate understanding of endocrine therapy resistance and development of treatment strategies for breast cancer. PMID- 28847748 TI - Estradiol (E2)- and tamoxifen (Tmx)-bound ER-alpha (ERalpha) interact differentially with histone deacetylases 1 and 3 (HDACs 1 and 3). AB - Although ERalpha activation properties have been intensively studied, this is not the case for their repressive properties. In this report, the ERalpha ligand binding domain (LBD) is shown to interact both with a deacetylase function and with HDAC1 and HDAC3. Ligands do not affect binding to the deacetylase activity or to HDAC1. In distinction, E2 reduced LBD binding to HDAC3, whereas Tmx had no effect. Knock-down of either HDAC1 or 3 led to increased transcriptional activity by both HDACs, presumably by decreased repression. In distinction, only HDAC3 knock-down led to increased activity in the presence of Tmx. In summary, ERalpha differentially interacts with HDACs 1 and 3 to regulate transcriptional activity. PMID- 28847749 TI - Efficacy of hybrid vitamin D receptor agonist/histone deacetylase inhibitors in vitamin D-resistant triple-negative 4T1 breast cancer. AB - Hormonal 1,25-dihydroxyvitamin D (1,25D) and its analogues have shown efficacy in some preclinical models of cancer. However, many models are resistant to the antiproliferative effects of 1,25D or its analogues in vitro or in vivo, and such compounds have failed in the clinic as monotherapies because of tumor resistance. Given the observed synergism between 1,25D analogues and histone deacetylase inhibitors (HDACi) in 1,25D-resistant cells, we previously developed a series of hybrid secosteroidal and easily assembled non-secosteroidal analogues that combined agonism for the vitamin D receptor and HDACi in a single backbone. These compounds displayed enhanced efficacy against 1,25D-resistant malignant cells in vitro. Structure/function studies led to synthesis of several non-secosteroidal variants in which HDACi potency was optimized without substantially sacrificing VDR agonism. Here, we present the first studies of efficacy in vivo of two of these compounds, DK-366 and DK-406, in the aggressive mouse 4T1 model of triple negative breast cancer, a form of the disease for which treatment options are limited. 4T1 cells are resistant in vitro to the cytostatic and cytotoxic effects of 1,25D and the potent HDACi SAHA individually up to concentrations of 1MUM and 50MUM, respectively, whereas combinations of the two are efficacious. In vitro, DK-366 or -406 induced dose-dependent arrest of cell proliferation and cytotoxicity at 10-20MUM. In vivo, the maximum tolerated dose (MTD) of DK-366 and DK-406 were 2.5 and 5.0mg/kg, respectively. Although the compounds induced hypercalcemia at elevated doses, consistent with VDR agonism in vivo, they both reduced tumor burden at doses below their MTD's. Moreover, in a separate experiment, DK-406 at 5mg/kg reduced 4T1 lung metastases by at least 50%. Under the same conditions, 1,25D (0.25MUg/kg) and SAHA (25mg/kg) combined had no effect on tumor burden or on lung metastases. These experiments show that hybrid compounds are bioavailable and efficacious against a particularly aggressive model of metastatic breast cancer, providing strong support for the therapeutic potential of the hybrid concept. PMID- 28847751 TI - Effects of Mongersen (GED-0301) on Endoscopic and Clinical Outcomes in Patients With Active Crohn's Disease. AB - GED-0301 is an antisense oligodeoxynucleotide with a sequence complementary to the Smad7 mRNA transcript. Smad7 is a negative regulator of transforming growth factor-beta, which is increased in the intestinal mucosa of patients with active Crohn's disease (CD). We randomly assigned 63 CD patients to 4-, 8-, or 12-week treatment groups receiving oral GED-0301 (160 mg/day). The primary objective was to determine GED-0301's effect on endoscopic CD measures; secondary objectives included effects on clinical activity. Endoscopic improvement was observed in 37% of participants with evaluable endoscopy results at week 12. At week 12, 32% (4 weeks), 35% (8 weeks), and 48% (12 weeks) of patients receiving GED-0301 were in remission (CD activity index score <150); corresponding reductions from baseline in mean CD activity index scores were -124, -112, and -133 points. No new safety signals were observed. These findings support a GED-0301 benefit in active CD. ClinicalTrials.gov no: NCT02367183. PMID- 28847750 TI - A Panel of Methylated MicroRNA Biomarkers for Identifying High-Risk Patients With Ulcerative Colitis-Associated Colorectal Cancer. AB - BACKGROUND & AIMS: Methylation of specific microRNAs (miRNAs) often occurs in an age-dependent manner, as a field defect in some instances, and may be an early event in colitis-associated carcinogenesis. We aimed to determine whether specific mRNA signature patterns (MIR1, MIR9, MIR124, MIR137, MIR34B/C) could be used to identify patients with ulcerative colitis (UC) who are at increased risk for colorectal neoplasia. METHODS: We obtained 387 colorectal tissue specimens collected from 238 patients with UC (152 without neoplasia, 17 with dysplasia, and 69 with UC-associated colorectal cancer [UC-CRC]), from 2 independent cohorts in Japan between 2005 and 2015. We quantified methylation of miRNAs by bisulfite pyrosequencing analysis. We analyzed clinical data to determine whether miRNA methylation patterns were associated with age, location, or segment of the colorectum (cecum, transverse colon, and rectum). Differences in tissue miRNA methylation and expression levels were compared among samples and associated with cancer risk using the Wilcoxon, Mann-Whitney, and Kruskal-Wallis tests as appropriate. We performed a validation study of samples from 90 patients without UC and 61 patients with UC-associated dysplasia or cancer to confirm the association between specific methylation patterns of miRNAs in non-tumor rectal mucosa from patients with UC at risk of UC-CRC. RESULTS: Among patients with UC without neoplasia, rectal tissues had significantly higher levels of methylation levels of MIR1, MIR9, MIR124, and MIR137 than in proximal mucosa; levels of methylation were associated with age and duration of UC in rectal mucosa. Methylation of all miRNAs was significantly higher in samples from patients with dysplasia or CRC compared with samples from patients without neoplasia. Receiver operating characteristic analysis revealed that methylation levels of miRNAs in rectal mucosa accurately differentiated patients with CRC from those without. Methylation of MIR137 in rectal mucosa was an independent risk factor for UC-CRC. Methylation patterns of a set of miRNAs (panel) could discriminate discriminate UC patients with or without dysplasia or CRC in the evaluation cohort (area under the curve, 0.81) and the validation cohort (area under the curve, 0.78). CONCLUSIONS: In evaluation and validation cohorts, we found specific miRNAs to be methylated in rectal mucosal samples from patients with UC with dysplasia or CRC compared with patients without neoplasms. This pattern also associated with patient age and might be used to identify patients with UC at greatest risk for developing UC-CRC. Our findings provide evidence for a field defect in rectal mucosa from patients with UC-CRC. PMID- 28847753 TI - Sub-chronic toxicity study of arecae semen aqueous extract in Wistar rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Arecae semen, the ripe seed of Areca catechu L., has been used as vermifuge and digestant in traditional Chinese medicine (TCM). However, the potential toxicity effect of arecae semen has not been completely investigated. THE AIM OF THE STUDY: The present study was aimed at evaluating the sub-chronic toxicity of arecae semen by oral administration in Wistar rats. MATERIALS AND METHODS: A total of 120 Wistar rats were randomly divided into 4 groups (15 males and 15 females per group). The treated groups were given arecae semen aqueous extract (ASAE) at the dose of 750, 1500 and 4500mg/kg/day by oral administration respectively, and the control group was received distilled water only. The rats and their consumed feed were weighted every 3 days. The clinical changes and mortality were observed and recorded daily. Hematological parameters, biochemical parameters, organ weights, urinalysis and histopathological examination of all rats were tested at the end of the 30-day treatment period and another 10-day recovery period. RESULTS: Deaths, weight loss, diarrhea, sluggish action, tremors and body curl up were observed in the 1500 and 4500mg/kg groups during the study. The relative organ weights of liver and testis in male rats of 4500mg/kg group were significantly different compared with the control group at the end of the treatment period. As for laboratory parameters, there were no significant differences at the dose of 1500 and 4500mg/kg groups compared with the control group in the study, except the white blood cell count (WBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), blood urea nitrogen (BUN), creatinine (Cr), glucose (GLU) and total cholesterol (CHOL). In addition, the results of histopathological examination and feed intake showed no significant difference compared with the control group. CONCLUSIONS: The results showed that ASAE at the dose of 750mg/kg/day was safe, but long-term oral administration of ASAE with high dosage was toxic. Moreover, the toxic ingredients of ASAE including arecoline, and also some other compounds should be researched. PMID- 28847752 TI - The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells. AB - BACKGROUND & AIMS: Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces up-regulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. METHODS: We studied the combined effects of ethanol (EtOH) and cigarette smoke extract (CSE) on ER stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with EtOH (50 mmol/L), CSE (20-40 MUg/mL), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse-transcription polymerase chain reaction, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an EtOH containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per week) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. RESULTS: In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased adenosine triphosphate levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP, and induced cell death. In rats fed an EtOH diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. CONCLUSIONS: Cigarette smoke promotes cell death and features of pancreatitis in EtOH-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death. PMID- 28847754 TI - Anti-inflammatory sesquiterpenoids from the Traditional Chinese Medicine Salvia plebeia: Regulates pro-inflammatory mediators through inhibition of NF-kappaB and Erk1/2 signaling pathways in LPS-induced Raw264.7 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Salvia plebeia R. Brown, a traditional Chinese medicinal herb, has been used to treat inflammatory diseases such as cough, hepatitis, and diarrhea for a long history. AIM OF THE STUDY: The aim of the present study was to isolate and identify potential anti-inflammatory agents from the herb of S. plebeia, which may have contributed to its folk pharmacological use in the treatment of inflammatory diseases. MATERIAL AND METHODS: The aerial parts of S. plebeia were extracted with 95% ethanol and separated by silica gel, RP-C18, Sephadex LH-20, and HPLC. The structures of the isolated compounds were elucidated by extensive spectroscopic analysis (MS, NMR, and X-ray). Anti inflammatory activities of all compounds were evaluated by the model of LPS induced up-regulated of NO in Raw264.7 macrophages. The expression levels of cytokine (TNF-alpha) and proteins (iNOS and COX-2) were assessed by ELISA kit and Western blotting analysis, respectively. Furthermore, the influences of salviplenoid A (1) on NF-kappaB and MAPK signaling pathways were determined by Western blotting analysis and immunofluorescence assay. RESULTS: Six new (1-6, salviplenoids A-F) and ten known (7-16) sesquiterpenoids were isolated from the herb of S. plebeia. The absolute configurations of compounds 1, 2, and 7 were determined by X-ray diffraction. The new eudesmane-type sesquiterpenoid, salviplenoid A (1), significantly decreased the release of NO and TNF-alpha and the expression of proteins iNOS and COX-2. In addition, the biochemical mechanistic study indicated that 1 regulated the NF-kappaB dependent transcriptional activity through inhibiting the nuclear translocation of p50/p65 dimer and decreasing the phosphorylation of IkappaB and Erk1/2. CONCLUSIONS: Among all sesquiterpenoids isolated from S. plebeian, the new salviplenoid A (1) exhibited the most potent anti-inflammatory activity in LPS-induced Raw264.7 cells via inhibition of NF-kappaB and Erk1/2 signaling pathways. PMID- 28847755 TI - Modeling a novel hypothetical use of postal collection boxes as automated external defibrillator access points. AB - INTRODUCTION: Optimizing placement of Automated External Defibrillators (AED) can increase survival after an out-of-hospital cardiac arrest (OHCA). Using postal collection boxes (PCB) as locations for AEDs could potentially enhance accessibility and streamline maintenance. In this study, we modeled the hypothetical effects of deploying AEDs at PCB locations. HYPOTHESIS: We hypothesized that PCB-AEDs would increase AED coverage overall and in residential areas, and reduce the distance from OHCA to an AED. METHODS: AEDs in Pittsburgh, PA were identified by the University of Pittsburgh Resuscitation Logistics and Informatics Venture (n=747). PCB locations were obtained from the United States Postal Service (n=479). OHCA locations from 2009 to 2014 were obtained from the Pittsburgh site of the Resuscitation Outcomes Consortium. AED coverage assuming a 1/4 mile radius around each AED was estimated for known AEDs, PCB-AEDs (hypothetical AED locations), and known AEDs augmented by PCB-AEDs, both overall and for residential and non-residential zones. Linear distance from each OHCA to the nearest AED was calculated and compared between the sets. RESULTS: The set of known AEDs augmented with PCB-AEDs covered more of the city overall (55% vs 30%), as well as greater proportions of residential (62% vs 27%) and non-residential areas (45% vs 30%). The median distance from OHCA to AED was significantly shorter when known AEDs were augmented with PCB-AEDs (0.12mi vs 0.32mi; p=0.001). CONCLUSION: Augmenting existing publicly accessible AEDs with AEDs deployed at PCBs can increase AED spatial coverage in both residential and non-residential areas, and reduce the distance from AED to OHCA. PMID- 28847756 TI - Pediatric Foley Catheter Placement After Operative Hysteroscopy Does Not Cause Ascending Infection. AB - STUDY OBJECTIVE: To determine the incidence of postoperative ascending infection without antibiotics with the use of a pediatric Foley catheter (PFC) after operative hysteroscopy for intrauterine pathology. DESIGN: Retrospective case series (Canadian Task Force classification III). SETTING: University-affiliated outpatient medical center. PATIENTS: Patients who underwent operative hysteroscopy for uterine septum, arcuate uterine anomaly, or multiple submucosal myomas between 1992 and 2015. INTERVENTIONS: In all patients, a PFC was placed in the endometrial cavity at the conclusion of operative hysteroscopy and left in place for 7 days to reduce intrauterine adhesion formation. MEASUREMENTS AND MAIN RESULTS: A total of 1010 patients who underwent operative hysteroscopy for uterine septum (n = 479), arcuate uterine anomaly (n = 483), or multiple submucosal myomas (n = 48) were studied. All patients presented with infertility, recurrent pregnancy loss, or excessive uterine bleeding (in patients with submucous myomas). In all patients, a PFC was placed at the conclusion of the procedure and left in place for 7 days. An 8Fr PFC was used after hysteroscopic division of uterine septum or arcuate uterine anomaly, and a 10Fr PFC was used after hysteroscopic myomectomy. Patients with a history of pelvic inflammatory disease were excluded. Following PFC placement, patients were prescribed estrogen for 6 weeks and progestogen for the last 10 days of the estrogen course. No prophylactic antibiotic therapy was provided. All patients were discharged to home on the same day. Postoperative pain was well controlled with oral pain medication in 98.5% of the patients. There were no reported postoperative infections, and all patients had an uneventful recovery. CONCLUSION: In 1010 consecutive operative hysteroscopies followed by temporary (7-day) PFC placement, no clinically significant uterine infection was observed. PMID- 28847757 TI - Creation of a Composite Score to Predict Adnexal Torsion in Children and Adolescents. AB - STUDY OBJECTIVE: To create a composite score to predict adnexal torsion in children and adolescents. DESIGN: A prospective cross-sectional study. SETTING: Emergency department of a tertiary care children's hospital. PARTICIPANTS: Three hundred twenty-four female participants aged 6-21 years who presented to the emergency department with lower abdominal pain and underwent ultrasound or computed tomography imaging. INTERVENTIONS: Collection of possible clinical and radiologic predictors of torsion. MAIN OUTCOME MEASURES: The primary outcome was a composite score to predict adnexal torsion. We used chi2 analyses to identify possible risk factors. The classification and regression tree decision method was used to identify risk factor cutoff points. Independent risk factors were combined into a composite score. Receiver operating characteristic curve analyses were used to assessed score performance. RESULTS: Of 324 participants with abdominal pain, 241 underwent imaging, and 6.6% (16 of 241) had torsion. Duration of pain, intermittent pain, nausea, and absence of arterial or venous flow were not associated with torsion. Vomiting (P = .05 in premenarchal subjects; P < .001 in menarchal subjects), adnexal volume (P = .008 in premenarchal subjects; P < .001 in menarchal subjects), and adnexal volume ratio (P = .04 in premenarchal subjects; P < .001 in menarchal subjects) were independent predictors of torsion. These predictors were incorporated into a composite score. No torsions were identified with a score of less than 2. There was an increasing risk of torsion for each 1-point score increase. CONCLUSION: Independent predictors of torsion can reliably be combined into a composite score to identify children and adolescents at risk for adnexal torsion. This score might aid in improving triage and management of these challenging patients. PMID- 28847758 TI - Zinc oxide nanoparticles: a promising nanomaterial for biomedical applications. AB - Zinc oxide (ZnO) nanoparticles (NPs) are a promising platform for use in biomedical research, especially given their anticancer and antimicrobial activities. These activities are associated with the ability of ZnO NPs to generate reactive oxygen species (ROS) and induce apoptosis. In addition, ZnO NPs have been successfully exploited as drug carriers for loading and transporting drugs to target sites, thereby reducing unwanted toxicity and off-target effects, and resulting in amplified synergistic effects. Here, we discuss the synthesis and biomedical applications of ZnO NPs. PMID- 28847759 TI - RanBPM: a potential therapeutic target for modulating diverse physiological disorders. AB - The Ran-binding protein microtubule-organizing center (RanBPM) is a highly conserved nucleocytoplasmic protein involved in a variety of intracellular signaling pathways that control diverse cellular functions. RanBPM interacts with proteins that are linked to various diseases, including Alzheimer's disease (AD), schizophrenia (SCZ), and cancer. In this article, we define the characteristics of the scaffolding protein RanBPM and focus on its interaction partners in diverse physiological disorders, such as neurological diseases, fertility disorders, and cancer. PMID- 28847760 TI - Hepatitis E virus infection as a promoting factor for hepatocellular carcinoma in Cameroon: Preliminary Observations. AB - OBJECTIVES: To determine the seroprevalence of hepatitis E virus (HEV) infection in patients with chronic hepatitis and/or hepatocellular carcinoma (HCC) and to assess its potential consequences for disease progression. METHODS: We conducted a prospective case-control study on patients with HCC hepatitis B or C related and non-HCC patients including patients with CLD and patients without clinical evidence of liver disease. Anti-HEV IgG and IgM were tested by ELISA using commercially available kits. Liver damage was assessed by alanine aminotransferase, aspartate aminotransferase, platelets and prothrombin measurements. RESULTS: We observed a significant anti-HEV IgG carriage in HCC patients compared to non-HCC subjects with CLD (41.8% vs 12.6%; P=9.1 E-6; OR=4.8, 95%CI: 2.3-10.6). HCC patients with HEV infection display more profound alterations of circulating liver enzymes, platelets count and prothrombin time than HCC patients without sero-reactivity to HEV. CONCLUSION: Overall, this study indicates a high prevalence of HEV infection in Cameroonian patients with CLD and HCC. These data suggest either that patients with liver tumors are more susceptible to hepeviral infection or that, in a tropical context, HEV might promote the progression of liver diseases towards tumor. PMID- 28847761 TI - Protective effect and mechanism of action of diallyl disulfide against acetaminophen-induced acute hepatotoxicity. AB - The aim of this study was to investigate the potential protective effects of diallyl disulfide (DADS) against acetaminophen (AAP)-induced acute hepatotoxicity and elucidate the molecular mechanisms underlying these protective effects in rats. Treatment with AAP caused acute hepatotoxicity manifested by elevated levels of aspartate aminotransferase and alanine aminotransferase with corresponding histopathological changes and high levels of oxidative stress in the livers. AAP treatment also caused hepatocellular apoptosis with phosphorylation of c-Jun-N-terminal protein kinase (JNK). In addition, AAP caused activation of nuclear factor kappaB (NF-kappaB) concurrent with induction of inflammatory mediators. In contrast, pretreatment with DADS effectively attenuated acute liver injury and oxidative stress caused by AAP. DADS pretreatment suppressed cytochrome P450 2E1 (CYP2E1) levels in a dose-dependent manner and inhibited elevation of CYP2E1 activity induced by AAP. DADS pretreatment suppressed the phosphorylation of JNK and attenuated hepatocellular apoptotic changes. In addition, DADS inhibited the nuclear translocation of NF kappaB and subsequent induction of inflammatory mediators. Overall, these results indicate that DADS confers a protective effect against oxidative stress-mediated JNK activation and apoptotic changes caused by AAP in the rat livers. This may be due to its ability to inhibit CYP2E1, enhance antioxidant enzymes activities, and suppress NF-kappaB activation. PMID- 28847762 TI - Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing? AB - The unique properties of nanomaterials (NMs) are beneficial in numerous industrial and medical applications. However, they could also induce unintended effects. Thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. Toxicity can be tested in vivo and in vitro; in compliance with the 3Rs, alternative strategies for in vitro testing should be further developed for NMs. Robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. Oxidative stress has been shown to be an underlying mechanism of possible toxicity of NMs, causing both immunotoxicity and genotoxicity. For testing NMs in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. Novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. However, to initiate epigenetic toxicity screens for NM exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity. PMID- 28847763 TI - Epigenomics in toxicology and medicine. PMID- 28847764 TI - Exposure of livestock to GM feeds: Detectability and measurement. AB - This review explores the possibilities to determine livestock consumption of genetically modified (GM) feeds/ingredients including detection of genetically modified organism (GMO)-related DNA or proteins in animal samples, and the documentary system that is in place for GM feeds under EU legislation. The presence and level of GMO-related DNA and proteins can generally be readily measured in feeds, using established analytical methods such as polymerase chain reaction and immuno-assays, respectively. Various technical challenges remain, such as the simultaneous detection of multiple GMOs and the identification of unauthorized GMOs for which incomplete data on the inserted DNA may exist. Given that transfer of specific GMO-related DNA or protein from consumed feed to the animal had seldom been observed, this cannot serve as an indicator of the individual animal's prior exposure to GM feeds. To explore whether common practices, information exchange and the specific GM feed traceability system in the EU would allow to record GM feed consumption, the dairy chain in Catalonia, where GM maize is widely grown, was taken as an example. It was thus found that this system would neither enable determination of an animal's consumption of specific GM crops, nor would it allow for quantitation of the exposure. PMID- 28847765 TI - Acute disseminated candidiasis with skin lesions: a systematic review. AB - BACKGROUND: Neutropenic patients developing acute disseminated candidiasis may present with skin lesions. AIMS: To evaluate the epidemiology of acute disseminated candidiasis with skin lesions in neutropenic patients, taking into consideration changes caused by different prophylactic strategies. SOURCES: A systematic review of English-language articles found via PubMed (1963-2016) was performed. We asked the following questions: (a) What Candida species are more frequently involved in this syndrome? (b) Has antifungal prophylaxis changed the species causing skin lesions? (c) What are the typical patterns of skin lesions? (d) What is the frequency of skin lesions in neutropenic patients with candidaemia or acute disseminated candidiasis? (e) Has antifungal prophylaxis decreased the incidence of acute disseminated candidiasis with skin lesions? CONTENT: Among 183 studies, 33 were selected, reporting 100 cases of acute disseminated candidiasis with skin lesions in neutropenic patients. It occurred more frequently in the setting of induction therapy for de novo or relapsed acute leukaemia, and the most frequent Candida species were C. tropicalis (68%) and C. krusei (15%). Diffuse maculopapular lesions predominated in cases caused by C. tropicalis and nodular and papular lesions in cases caused by C. krusei. Prophylaxis with fluconazole was reported in six cases, C. krusei in five and C. ciferrii in one. The death rate was 45.4%. IMPLICATIONS: Two patterns were recognized: disseminated maculopapular lesions caused by C. tropicalis in patients not receiving fluconazole prophylaxis, occurring in 39% to 44% of neutropenic patients with acute disseminated candidiasis, and nodular lesions caused by C. krusei in patients receiving fluconazole prophylaxis, occurring less frequently. PMID- 28847767 TI - Combined surgical and endovascular approach to treat a carotid cavernous fistula with associated brainstem venous congestion. AB - Endovascular embolization is the standard approach for management of carotid cavernous fistulas (CCFs) due to the ease of access and reduced level of risk associated with the procedure compared with open surgery. We present here a case of a CCF that eventually led to the development of brainstem venous congestion from perimedullary venous drainage. This fistula was not amenable to endovascular embolization due to lack of either ophthalmic vein or petrosal sinus drainage. Therefore, a craniotomy with direct puncture of the cavernous sinus was performed, followed by coil embolization to completely treat this fistula. This case demonstrates an uncommon progression of venous drainage to Cognard grade V, rare development of symptomatic brainstem venous congestion and a unique method to combine an open surgical approach with endovascular embolization to treat CCFs. PMID- 28847766 TI - Identification of a transitional fibroblast function in very early rheumatoid arthritis. AB - OBJECTIVES: Synovial fibroblasts actively regulate the inflammatory infiltrate by communicating with neighbouring endothelial cells (EC). Surprisingly, little is known about how the development of rheumatoid arthritis (RA) alters these immunomodulatory properties. We examined the effects of phase of RA and disease outcome (resolving vs persistence) on fibroblast crosstalk with EC and regulation of lymphocyte recruitment. METHODS: Fibroblasts were isolated from patients without synovitis, with resolving arthritis, very early RA (VeRA; symptom <=12 weeks) and established RA undergoing joint replacement (JRep) surgery. Endothelial-fibroblast cocultures were formed on opposite sides of porous filters. Lymphocyte adhesion from flow, secretion of soluble mediators and interleukin 6 (IL-6) signalling were assessed. RESULTS: Fibroblasts from non inflamed and resolving arthritis were immunosuppressive, inhibiting lymphocyte recruitment to cytokine-treated endothelium. This effect was lost very early in the development of RA, such that fibroblasts no longer suppressed recruitment. Changes in IL-6 and transforming growth factor beta 1 (TGF-beta1) signalling appeared critical for the loss of the immunosuppressive phenotype. In the absence of exogenous cytokines, JRep, but not VeRA, fibroblasts activated endothelium to support lymphocyte. CONCLUSIONS: In RA, fibroblasts undergo two distinct changes in function: first a loss of immunosuppressive responses early in disease development, followed by the later acquisition of a stimulatory phenotype. Fibroblasts exhibit a transitional functional phenotype during the first 3 months of symptoms that contributes to the accumulation of persistent infiltrates. Finally, the role of IL-6 and TGF-beta1 changes from immunosuppressive in resolving arthritis to stimulatory very early in the development of RA. Early interventions targeting 'pathogenic' fibroblasts may be required in order to restore protective regulatory processes. PMID- 28847769 TI - Correction: Vitamin A deficiency due to chronic malabsorption: an ophthalmic manifestation of a systemic condition. PMID- 28847770 TI - Correction: Cerebral venous sinus thrombosis during superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for maxillary squamous cell carcinoma. PMID- 28847771 TI - An apparent case of non-accidental injury. PMID- 28847768 TI - Examining the predictors of academic outcomes for indigenous Maori, Pacific and rural students admitted into medicine via two equity pathways: a retrospective observational study at the University of Auckland, Aotearoa New Zealand. AB - OBJECTIVE: To determine associations between admission markers of socioeconomic status, transitioning, bridging programme attendance and prior academic preparation on academic outcomes for indigenous Maori, Pacific and rural students admitted into medicine under access pathways designed to widen participation. Findings were compared with students admitted via the general (usual) admission pathway. DESIGN: Retrospective observational study using secondary data. SETTING: 6-year medical programme (MBChB), University of Auckland, Aotearoa New Zealand. Students are selected and admitted into Year 2 following a first year (undergraduate) or prior degree (graduate). PARTICIPANTS: 1676 domestic students admitted into Year 2 between 2002 and 2012 via three pathways: GENERAL admission (1167), Maori and Pacific Admission Scheme-MAPAS (317) or Rural Origin Medical Preferential Entry-ROMPE (192). Of these, 1082 students completed the programme in the study period. MAIN OUTCOME MEASURES: Graduated from medical programme (yes/no), academic scores in Years 2-3 (Grade Point Average (GPA), scored 0-9). RESULTS: 735/778 (95%) of GENERAL, 111/121 (92%) of ROMPE and 146/183 (80%) of MAPAS students graduated from intended programme. The graduation rate was significantly lower in the MAPAS students (p<0.0001). The average Year 2-3 GPA was 6.35 (SD 1.52) for GENERAL, which was higher than 5.82 (SD 1.65, p=0.0013) for ROMPE and 4.33 (SD 1.56, p<0.0001) for MAPAS. Multiple regression analyses identified three key predictors of better academic outcomes: bridging programme attendance, admission as an undergraduate and admission GPA/Grade Point Equivalent (GPE). Attending local urban schools and higher school deciles were also associated with a greater likelihood of graduation. All regression models have controlled for predefined baseline confounders (gender, age and year of admission). CONCLUSIONS: There were varied associations between admission variables and academic outcomes across the three admission pathways. Equity targeted admission programmes inclusive of variations in academic threshold for entry may support a widening participation agenda, however, additional academic and pastoral supports are recommended. PMID- 28847772 TI - A boy with fever, cough and gross haematuria. PMID- 28847773 TI - Seeking help for perinatal psychological distress: a meta-synthesis of women's experiences. AB - BACKGROUND: Women may not seek help for perinatal psychological distress, despite regular contact with primary care services. Barriers include ignorance of symptoms, inability to disclose distress, others' attitudes, and cultural expectations. Much of the evidence has been obtained from North American populations and may not, therefore, extrapolate to the UK. AIM: To understand the factors affecting women's decision to seek help for perinatal distress. DESIGN AND SETTING: Meta-synthesis of the available published qualitative evidence on UK women's experiences of seeking help for perinatal distress. METHOD: Systematic searches were conducted in accordance with PRISMA guidelines. Databases searched were PubMed, Scopus, PsycINFO, PsycARTICLES, CINAHL, and Academic Search Complete. Searches of grey literature and references were also conducted. Studies were eligible for inclusion if they reported qualitative data on UK women's experiences of perinatal distress and contact with healthcare professionals. The synthesis was conducted using meta-ethnography. RESULTS: In all, 24 studies were eligible for inclusion. Metasynthesis identified three main themes: identifying a problem, the influence of healthcare professionals, and stigma. These themes build on current understanding of help seeking by identifying the need for women to be able to frame their experience, for healthcare professionals to educate women about their roles, the need for continuity of care, and the way that being seen as a 'bad mother' causes women to self-silence. CONCLUSION: Perinatal care provision needs to allow for continuity of care and for staff training that facilitates awareness of factors that influence women's help seeking. Further research is required, particularly in relation to effective means of identifying perinatal psychological distress. PMID- 28847774 TI - Improving GP communication in consultations on medically unexplained symptoms: a qualitative interview study with patients in primary care. AB - BACKGROUND: Many GPs find the care of patients with medically unexplained symptoms (MUS) challenging. Patients themselves are often not satisfied with the care they receive. AIM: To explore the problems patients with MUS experience in communication during consultations, with the aim of improving such consultations DESIGN AND SETTING: A qualitative analysis of semi-structured interviews. METHOD: GP consultations were videorecorded and the GPs were asked immediately afterwards whether MUS were presented. Patients in these MUS consultations were asked to reflect on the consultation in a semi-structured interview while watching a recording of their own consultation. RESULTS: Of the 393 videorecorded consultations, 43 contained MUS. Patients who did identified six categories of problems. First, they reported a mismatch between the GP's and their own agenda. Second, patients indicated that the GP evoked an uncomfortable feeling in them during the consultation. Third, they found that GPs did not provide a specific management plan for their symptoms. Fourth, patients indicated that the GP was not well prepared for the consultation. Fifth, they perceived prejudices in the GP during the consultation. Finally, one patient found that the GP did not acknowledge a limited understanding of the origin of the symptoms. CONCLUSION: According to patients, GPs can improve their consultations on MUS by making genuine contact with their patients, by paying more attention to the patient's agenda, and by avoiding evoking uncomfortable feelings and displaying prejudices. They should prepare their consultations and focus on the issues that matter to patients, for example, symptom management. GPs should be honest to patients when they do not understand the origin of symptoms. PMID- 28847776 TI - Individualised assessment is required to establish the most appropriate anticoagulation option for patients. PMID- 28847775 TI - Epidemiology of adult overweight recording and management by UK GPs: a systematic review. AB - BACKGROUND: Primary care guidelines for managing adult overweight/obesity recommend routine measurement of body mass index (BMI) and the offer of weight management interventions. Many studies state that this is rarely done, but the extent to which overweight/obesity is recognised, considered, and documented in routine care has not been determined. AIM: To identify the epidemiology of adult overweight documentation and management by UK GPs. DESIGN AND SETTING: A systematic review of studies since 2006 from eight electronic databases and grey literature. METHOD: Included studies measured the proportion of adult patients with documented BMI or weight loss intervention offers in routine primary care in the UK. A narrative synthesis reports the prevalence and pattern of the outcomes. RESULTS: In total, 2845 articles were identified, and seven were included; four with UK-wide data and three with regional-level data. The proportion of patients with a documented BMI was 58-79% (28-37% within a year). For overweight/obese patients alone, 43-52% had a recent BMI record, and 15-42% had a documented intervention offer. BMI documentation was positively associated with older age, female sex, higher BMI, coexistent chronic disease, and higher deprivation. CONCLUSION: BMI is under-recorded and weight loss interventions are under referred for primary care adult patients in the UK despite the obesity register in the Quality and Outcomes Framework (QOF). The review identified likely underserved groups such as younger males and otherwise healthy overweight/obese individuals to whom attention should now be directed. The proposed amendment to the obesity register QOF could prompt improvements but has not been adopted for 2017. PMID- 28847777 TI - Frailty significantly increases the risk of fractures among middle-aged and older people. PMID- 28847778 TI - New CMAJ policy on sharing study data. PMID- 28847779 TI - It's time to allow assisted injection in supervised injection sites. PMID- 28847781 TI - Pediatric longitudinal melanonychia. PMID- 28847780 TI - Perinatal suicide in Ontario, Canada: a 15-year population-based study. AB - BACKGROUND: Death by suicide during the perinatal period has been understudied in Canada. We examined the epidemiology of and health service use related to suicides during pregnancy and the first postpartum year. METHODS: In this retrospective, population-based cohort study, we linked health administrative databases with coroner death records (1994-2008) for Ontario, Canada. We compared sociodemographic characteristics, clinical features and health service use in the 30 days and 1 year before death between women who died by suicide perinatally, women who died by suicide outside of the perinatal period and living perinatal women. RESULTS: The perinatal suicide rate was 2.58 per 100 000 live births, with suicide accounting for 51 (5.3%) of 966 perinatal deaths. Most suicides occurred during the final quarter of the first postpartum year, with highest rates in rural and remote regions. Perinatal women were more likely to die from hanging (33.3% [17/51]) or jumping or falling (19.6% [10/51]) than women who died by suicide non-perinatally (p = 0.04). Only 39.2% (20/51) had mental health contact within the 30 days before death, similar to the rate among those who died by suicide non-perinatally (47.7% [762/1597]; odds ratio [OR] 0.71, 95% confidence interval [CI] 0.40-1.25). Compared with living perinatal women matched by pregnancy or postpartum status at date of suicide, perinatal women who died by suicide had similar likelihood of non-mental health primary care and obstetric care before the index date but had a lower likelihood of pediatric contact (64.5% [20/31] v. 88.4% [137/155] at 30 days; OR 0.24, 95% CI 0.10-0.58). INTERPRETATION: The perinatal suicide rate for Ontario during the period 1994 2008 was comparable to international estimates and represents a substantial component of Canadian perinatal mortality. Given that deaths by suicide occur throughout the perinatal period, all health care providers must be collectively vigilant in assessing risk. PMID- 28847782 TI - Beware selection bias. PMID- 28847783 TI - The end of forceps deliveries? PMID- 28847784 TI - The authors reply to "The end of forceps deliveries?" and "Beware selection bias". PMID- 28847785 TI - Medical cannabinoids. PMID- 28847786 TI - Research Canada calls for public investment in health research. PMID- 28847787 TI - Tackling Pharma corruption in Ukraine. PMID- 28847788 TI - Minors buy e-cigs online with ease. What about pot? PMID- 28847790 TI - Retraction. PMID- 28847791 TI - Retraction. PMID- 28847792 TI - Retraction. PMID- 28847789 TI - Variation and statistical reliability of publicly reported primary care diagnostic activity indicators for cancer: a cross-sectional ecological study of routine data. AB - OBJECTIVES: Recent public reporting initiatives in England highlight general practice variation in indicators of diagnostic activity related to cancer. We aimed to quantify the size and sources of variation and the reliability of practice-level estimates of such indicators, to better inform how this information is interpreted and used for quality improvement purposes. DESIGN: Ecological cross-sectional study. SETTING: English primary care. PARTICIPANTS: All general practices in England with at least 1000 patients. MAIN OUTCOME MEASURES: Sixteen diagnostic activity indicators from the Cancer Services Public Health Profiles. RESULTS: Mixed-effects logistic and Poisson regression showed that substantial proportions of the observed variance in practice scores reflected chance, variably so for different indicators (between 7% and 85%). However, after accounting for the role of chance, there remained substantial variation between practices (typically up to twofold variation between the 75th and 25th centiles of practice scores, and up to fourfold variation between the 90th and 10th centiles). The age and sex profile of practice populations explained some of this variation, by different amounts across indicators. Generally, the reliability of diagnostic process indicators relating to broader populations of patients most of whom do not have cancer (eg, rate of endoscopic investigations, or urgent referrals for suspected cancer (also known as 'two week wait referrals')) was high (>=0.80) or very high (>=0.90). In contrast, the reliability of diagnostic outcome indicators relating to incident cancer cases (eg, per cent of all cancer cases detected after an emergency presentation) ranged from 0.24 to 0.54, which is well below recommended thresholds (>=0.70). CONCLUSIONS: Use of indicators of diagnostic activity in individual general practices should principally focus on process indicators which have adequate or high reliability and not outcome indicators which are unreliable at practice level. PMID- 28847793 TI - Atrial fibrillation and FLAIR/T2 white matter hyperintensities on MRI. PMID- 28847795 TI - Aspirin Monotherapy Should Not Be Recommended for Cardioprotection in Patients With Symptomatic Peripheral Artery Disease. PMID- 28847794 TI - Impact of sleep-related symptoms on clinical motor subtypes and disability in Parkinson's disease: a multicentre cross-sectional study. AB - OBJECTIVES: To investigate the impact of sleep disturbances on Parkinson's disease (PD) clinical motor subtypes and disease-related disability in a multicentre setting. METHODS: We report a cross-sectional relationship between sleep-related symptoms and clinical motor subtypes (tremor dominant (TD); intermediate; postural instability and gait disturbances (PIGDs)) identified in a multicentre study, including 436 patients with PD and 401 age-matched controls. PD-related sleep problems (PD-SP), excessive daytime sleepiness (EDS) and probable REM sleep behaviour disorder (pRBD) were evaluated using the PD sleep scale (PDSS)-2, Epworth Sleepiness Scale (ESS) and RBD screening questionnaire Japanese version (RBDSQ-J), respectively. RESULTS: PD-SP (PDSS-2 >=18; 35.1% vs 7.0%), EDS (ESS >=10; 37.8% vs 15.5%) and pRBD (RBDSQ-J >=5; 35.1% vs 7.7%) were more common in patients with PD than in controls. The prevalence of restless legs syndrome did not differ between patients with PD and controls (3.4% vs 2.7%). After adjusting for age, sex, disease duration and Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) part III score, the PIGD group had higher PDSS-2 and ESS scores than the TD group. The RBDSQ-J scores did not differ among the TD, intermediate and PIGD groups. A stepwise regression model predicting the MDS-UPDRS part II score identified the Hoehn and Yahr stage, followed by the number of sleep-related symptoms (PD-SP, EDS and pRBD), disease duration, MDS UPDRS part III score, PIGD subtype, depression and MDS-UPDRS part IV score as significant predictors. CONCLUSION: Our study found a significant relationship between sleep disturbances and clinical motor subtypes. An increased number of sleep-related symptoms had an impact on disease-related disability. PMID- 28847796 TI - Maximizing Cardiovascular Event Reduction by Expanding and Intensifying the Targets. PMID- 28847798 TI - Highlights From the Circulation Family of Journals. PMID- 28847799 TI - A Lead to the Culprit. PMID- 28847797 TI - Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors. AB - Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease. PMID- 28847800 TI - The Low-Density Lipoprotein Receptor Genotype Is a Significant Determinant of the Rebound in Low-Density Lipoprotein Cholesterol Concentration After Lipoprotein Apheresis Among Patients With Homozygous Familial Hypercholesterolemia. PMID- 28847801 TI - Letter by Gabet et al Regarding Article, "Age-Specific Trends in Incidence, Mortality, and Comorbidities of Heart Failure in Denmark, 1995 to 2012". PMID- 28847802 TI - Letter by Kaul et al Regarding Article, "Age-Specific Trends in Incidence, Mortality, and Comorbidities of Heart Failure in Denmark, 1995 to 2012". PMID- 28847803 TI - Response by Christiansen et al to Letters Regarding Article, "Age-Specific Trends in Incidence, Mortality, and Comorbidities of Heart Failure in Denmark, 1995 to 2012". PMID- 28847805 TI - Functional Segregation and Development of Mouse Higher Visual Areas. AB - Recent studies suggest that higher visual areas (HVAs) in the mouse visual cortex are segregated anatomically into two visual streams, likely analogous to the ventral and dorsal streams in primates. However, HVAs in mice have yet to be characterized functionally. Moreover, it is unknown when the functional segregation of HVAs occurs during development. Here, we investigated spatiotemporal selectivity of HVAs and their development using wide-field calcium imaging. We found that lateral HVAs in the anatomical ventral stream shared similar spatiotemporal selectivity, whereas the spatiotemporal selectivity of anterior and medial HVAs in the anatomical dorsal stream was not uniform and these areas were segregated functionally into multiple groups. This functional segregation of HVAs developed and reached an adult-like pattern ~10 d after eye opening (EO). These results suggest, not only the functional segregation of ventral and dorsal streams, but also the presence of multiple substreams in the dorsal stream, and indicate that the functional segregation of visual streams occurs gradually after EO.SIGNIFICANCE STATEMENT Investigation of the spatiotemporal selectivity of nine higher visual areas (HVAs) in adult and developing mice revealed that lateral HVAs belonging to the putative ventral stream shared similar spatiotemporal selectivity, whereas the spatiotemporal selectivity of anterior and medial HVAs belonging to the putative dorsal stream was not uniform and these areas were segregated functionally into multiple groups. These results suggest the presence of multiple substreams within the putative dorsal stream for visuospatial processing. Furthermore, we found that initially immature functional segregation among HVAs developed to an adult-like pattern ~10 d after eye opening. These results provide a foundation for using mouse HVAs as a model to understand parallel processing and its developmental mechanism. PMID- 28847804 TI - Glucosylsphingosine Promotes alpha-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease. AB - Glucocerebrosidase 1 (GBA) mutations responsible for Gaucher disease (GD) are the most common genetic risk factor for Parkinson's disease (PD). Although the genetic link between GD and PD is well established, the underlying molecular mechanism(s) are not well understood. We propose that glucosylsphingosine, a sphingolipid accumulating in GD, mediates PD pathology in GBA-associated PD. We show that, whereas GD-related sphingolipids (glucosylceramide, glucosylsphingosine, sphingosine, sphingosine-1-phosphate) promote alpha synuclein aggregation in vitro, glucosylsphingosine triggers the formation of oligomeric alpha-synuclein species capable of templating in human cells and neurons. Using newly generated GD/PD mouse lines of either sex [Gba mutant (N370S, L444P, KO) crossed to alpha-synuclein transgenics], we show that Gba mutations predispose to PD through a loss-of-function mechanism. We further demonstrate that glucosylsphingosine specifically accumulates in young GD/PD mouse brain. With age, brains exhibit glucosylceramide accumulations colocalized with alpha-synuclein pathology. These findings indicate that glucosylsphingosine promotes pathological aggregation of alpha-synuclein, increasing PD risk in GD patients and carriers.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is a prevalent neurodegenerative disorder in the aging population. Glucocerebrosidase 1 mutations, which cause Gaucher disease, are the most common genetic risk factor for PD, underscoring the importance of delineating the mechanisms underlying mutant GBA-associated PD. We show that lipids accumulating in Gaucher disease, especially glucosylsphingosine, play a key role in PD pathology in the brain. These data indicate that ASAH1 (acid ceramidase 1) and GBA2 (glucocerebrosidase 2) enzymes that mediate glucosylsphingosine production and metabolism are attractive therapeutic targets for treating mutant GBA-associated PD. PMID- 28847806 TI - Thermosensory Perceptual Learning Is Associated with Structural Brain Changes in Parietal-Opercular (SII) Cortex. AB - The location of a sensory cortex for temperature perception remains a topic of substantial debate. Both the parietal-opercular (SII) and posterior insula have been consistently implicated in thermosensory processing, but neither region has yet been identified as the locus of fine temperature discrimination. Using a perceptual learning paradigm in male and female humans, we show improvement in discrimination accuracy for subdegree changes in both warmth and cool detection over 5 d of repetitive training. We found that increases in discriminative accuracy were specific to the temperature (cold or warm) being trained. Using structural imaging to look for plastic changes associated with perceptual learning, we identified symmetrical increases in gray matter volume in the SII cortex. Furthermore, we observed distinct, adjacent regions for cold and warm discrimination, with cold discrimination having a more anterior locus than warm. The results suggest that thermosensory discrimination is supported by functionally and anatomically distinct temperature-specific modules in the SII cortex.SIGNIFICANCE STATEMENT We provide behavioral and neuroanatomical evidence that perceptual learning is possible within the temperature system. We show that structural plasticity localizes to parietal-opercular (SII), and not posterior insula, providing the best evidence to date resolving a longstanding debate about the location of putative "temperature cortex." Furthermore, we show that cold and warm pathways are behaviorally and anatomically dissociable, suggesting that the temperature system has distinct temperature-dependent processing modules. PMID- 28847808 TI - Selective Modulation of Orbitofrontal Network Activity during Negative Occasion Setting. AB - Discrete cues can gain powerful control over behavior to help an animal anticipate and cope with upcoming events. This is important in conditions where understanding the relationship between complex stimuli provides a means to resolving situational ambiguity. However, it is unclear how cortical circuits generate and maintain these signals that conditionally regulate behavior. To address this, we established a Pavlovian serial feature-negative conditioning paradigm, where male mice are trained on a trial in which a conditioned stimulus (CS) is presented alone and followed by reward, or a feature-negative trial in which the CS is preceded by a feature cue indicating there is no reward. Mice learn to respond with anticipatory licking to a solitary CS, but significantly suppress their responding to the same cue during feature-negative trials. We show that the feature cue forms a selective association with its paired CS, because the ability of the feature to transfer its suppressive properties to a separately rewarded cue is limited. Next, to examine the underlying neural dynamics, we conduct recordings in the orbitofrontal cortex (OFC). We find that the feature cue significantly and selectively inhibits CS-evoked activity. Finally, we find that the feature triggers a distinct OFC network state during the delay period between the feature and CS, establishing a potential link between the feature and future events. Together, our findings suggest that OFC dynamics are modulated by the feature cue and its associated conditioned stimulus in a manner consistent with an occasion setting model.SIGNIFICANCE STATEMENT The ability of patterned cues to form an inhibitory relationship with ambiguously rewarded outcomes has been appreciated since early studies on learning and memory. However, it was often assumed that these cues, despite their hierarchical nature, still made direct associative links with neural rewarding events. This model was significantly challenged, largely by the work of Holland and colleagues, who demonstrated that under certain conditions cues can inherit occasion setting properties whereby they modulate the ability of a paired cue to elicit its conditioned response. Here we provide some of the first evidence that the activity of a cortical circuit is selectively modulated by such cues, thereby providing insight into the mechanisms of higher order learning. PMID- 28847809 TI - Simultaneously Excitatory and Inhibitory Effects of Transcranial Alternating Current Stimulation Revealed Using Selective Pulse-Train Stimulation in the Rat Motor Cortex. AB - Transcranial alternating current stimulation (tACS) uses sinusoidal, subthreshold, electric fields to modulate cortical processing. Cortical processing depends on a fine balance between excitation and inhibition and tACS acts on both excitatory and inhibitory cortical neurons. Given this, it is not clear whether tACS should increase or decrease cortical excitability. We investigated this using transcranial current stimulation of the rat (all males) motor cortex consisting of a continuous subthreshold sine wave with short bursts of suprathreshold pulse-trains inserted at different phases to probe cortical excitability. We found that when a low-rate, long-duration, suprathreshold pulse train was used, subthreshold cathodal tACS decreased cortical excitability and anodal tACS increased excitability. However, when a high-rate, short-duration, suprathreshold pulse-train was used this pattern was inverted. An integrate-and fire model incorporating biophysical differences between cortical excitatory and inhibitory neurons could predict the experimental data and helped interpret these results. The model indicated that low-rate suprathreshold pulse-trains preferentially stimulate excitatory cortical neurons, whereas high-rate suprathreshold pulse-trains stimulate both excitatory and inhibitory neurons. If correct, this indicates that suprathreshold pulse-train stimulation may be able to selectively control the excitation-inhibition balance within a cortical network. The excitation-inhibition balance then likely plays an important role in determining whether subthreshold tACS will increase or decrease cortical excitability.SIGNIFICANCE STATEMENT Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation method that uses weak sinusoidal electric fields to modulate cortical activity. In healthy volunteers tACS can modulate perception, cognition, and motor function but the underlying neural mechanism is poorly understood. In this study, using rat motor cortex, we found that tACS effects are highly variable: applying the same tACS waveform to the same cortical area does not always give the same change in cortical excitability. An integrate and-fire model incorporating excitatory pyramidal and inhibitory interneurons indicated that tACS effects likely depend on the cortical excitation-inhibition balance. When cortical activity is excitation dominated one particular tACS phase increases excitability, but when the cortical activity is inhibition dominated the same tACS phase actually decreases excitability. PMID- 28847807 TI - The Dopamine Transporter Recycles via a Retromer-Dependent Postendocytic Mechanism: Tracking Studies Using a Novel Fluorophore-Coupling Approach. AB - Presynaptic reuptake, mediated by the dopamine (DA) transporter (DAT), terminates DAergic neurotransmission and constrains extracellular DA levels. Addictive and therapeutic psychostimulants inhibit DA reuptake and multiple DAT coding variants have been reported in patients with neuropsychiatric disorders. These findings underscore that DAT is critical for DA neurotransmission and homeostasis. DAT surface availability is regulated acutely by endocytic trafficking, and considerable effort has been directed toward understanding mechanisms that govern DAT's plasma membrane expression and postendocytic fate. Multiple studies have demonstrated DAT endocytic recycling and enhanced surface delivery in response to various stimuli. Paradoxically, imaging studies have not detected DAT targeting to classic recycling endosomes, suggesting that internalized DAT targets to either degradation or an undefined recycling compartment. Here, we leveraged PRIME (PRobe Incorporation Mediated by Enzyme) labeling to couple surface DAT directly to fluorophore, and tracked DAT's postendocytic itinerary in immortalized mesencephalic cells. Following internalization, DAT robustly targeted to retromer-positive endosomes, and DAT/retromer colocalization was observed in male mouse dopaminergic somatodendritic and terminal regions. Short hairpin RNA-mediated Vps35 knockdown revealed that DAT endocytic recycling requires intact retromer. DAT also targeted rab7-positive endosomes with slow, linear kinetics that were unaffected by either accelerating DAT internalization or binding a high-affinity cocaine analog. However, cocaine increased DAT exit from retromer-positive endosomes significantly. Finally, we found that the DAT carboxy-terminal PDZ-binding motif was required for DAT recycling and exit from retromer. These results define the DAT recycling mechanism and provide a unifying explanation for previous, seemingly disparate, DAT endocytic trafficking findings.SIGNIFICANCE STATEMENT The neuronal dopamine (DA) transporter (DAT) recaptures released DA and modulates DAergic neurotransmission, and a number of DAT coding variants have been reported in several DA-related disorders, including infantile parkinsonism, attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is also competitively inhibited by psychostimulants with high abuse potential. Therefore, mechanisms that acutely affect DAT availability will likely exert significant impact on both normal and pathological DAergic homeostasis. Here, we explore the cellular mechanisms that acutely control DAT surface expression. Our results reveal the intracellular mechanisms that mediate DAT endocytic recycling following constitutive and regulated internalization. In addition to shedding light on this critical process, these findings resolve conflict among multiple, seemingly disparate, previous reports on DAT's postendocytic fate. PMID- 28847810 TI - A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations. AB - Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical-basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (~1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15-30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits.SIGNIFICANCE STATEMENT Chronic depletion of dopamine from the striatum, a part of the basal ganglia, causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters striatal neuron firing in vivo, with an emphasis on defining whether and how spiny projection neurons (SPNs) engage in the synchronized beta-frequency (15-30 Hz) oscillations that become pathologically exaggerated throughout basal ganglia circuits in parkinsonism. We discovered that a select population of so-called "indirect pathway" SPNs not only fire at abnormally high rates, but are also particularly prone to being recruited to exaggerated beta oscillations. Our results provide an important link between two complementary theories that explain the presentation of disease symptoms on the basis of changes in firing rate or firing synchronization/rhythmicity. PMID- 28847811 TI - Restoration of Motor Defects Caused by Loss of Drosophila TDP-43 by Expression of the Voltage-Gated Calcium Channel, Cacophony, in Central Neurons. AB - Defects in the RNA-binding protein, TDP-43, are known to cause a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar dementia. A variety of experimental systems have shown that neurons are sensitive to TDP-43 expression levels, yet the specific functional defects resulting from TDP-43 dysregulation have not been well described. Using the Drosophila TDP-43 ortholog TBPH, we previously showed that TBPH-null animals display locomotion defects as third instar larvae. Furthermore, loss of TBPH caused a reduction in cacophony, a Type II voltage-gated calcium channel, expression and that genetically restoring cacophony in motor neurons in TBPH mutant animals was sufficient to rescue the locomotion defects. In the present study, we examined the relative contributions of neuromuscular junction physiology and the motor program to the locomotion defects and identified subsets of neurons that require cacophony expression to rescue the defects. At the neuromuscular junction, we showed mEPP amplitudes and frequency require TBPH. Cacophony expression in motor neurons rescued mEPP frequency but not mEPP amplitude. We also showed that TBPH mutants displayed reduced motor neuron bursting and coordination during crawling and restoring cacophony selectively in two pairs of cells located in the brain, the AVM001b/2b neurons, also rescued the locomotion and motor defects, but not the defects in neuromuscular junction physiology. These results suggest that the behavioral defects associated with loss of TBPH throughout the nervous system can be associated with defects in a small number of genes in a limited number of central neurons, rather than peripheral defects.SIGNIFICANCE STATEMENT TDP-43 dysfunction is a common feature in neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal lobar dementia, and Alzheimer's disease. Loss- and gain-of function models have shown that neurons are sensitive to TDP-43 expression levels, but the specific defects caused by TDP-43 loss of function have not been described in detail. A Drosophila loss-of-function model displays pronounced locomotion defects that can be reversed by restoring the expression levels of a voltage-gated calcium channel, cacophony. We show these defects can be rescued by expression of cacophony in motor neurons and by expression in two pairs of neurons in the brain. These data suggest that loss of TDP-43 can disrupt the central circuitry of the CNS, opening up identification of alternative therapeutic targets for TDP-43 proteinopathies. PMID- 28847812 TI - The Stem Cell Marker Lgr5 Defines a Subset of Postmitotic Neurons in the Olfactory Bulb. AB - Lgr5, leucine-rich repeat-containing G-protein coupled receptor 5, is a bona fide biomarker for stem cells in multiple tissues. Lgr5 is also expressed in the brain, but the identities and properties of these Lgr5+ cells are still elusive. Using an Lgr5-EGFP reporter mouse line, we found that, from early development to adulthood, Lgr5 is highly expressed in the olfactory bulb (OB), an area with ongoing neurogenesis. Immunostaining with stem cell, glial, and neuronal markers reveals that Lgr5 does not label stem cells in the OB but instead labels a heterogeneous population of neurons with preference in certain subtypes. Patch clamp recordings in OB slices reveal that Lgr5-EGFP+ cells fire action potentials and display spontaneous excitatory postsynaptic events, indicating that these neurons are integrated into OB circuits. Interestingly, R-spondin 3, a potential ligand of Lgr5, is also expressed in the adult OB. Collectively, our data indicate that Lgr5-expressing cells in the OB are fully differentiated neurons and imply distinct roles of Lgr5 and its ligand in postmitotic cells.SIGNIFICANCE STATEMENT Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) is a bona fide stem cell marker in many body organs. Here we report that Lgr5 is also highly expressed in the olfactory bulb (OB), the first relay station in the brain for processing odor information and one of the few neural structures that undergo continuous neurogenesis. Surprisingly, Lgr5 is not expressed in the OB stem cells, but instead in a few subtypes of terminally differentiated neurons, which are incorporated into the OB circuit. This study reveals that Lgr5+ cells in the brain represent a nonstem cell lineage, implying distinct roles of Lgr5 in postmitotic neurons. PMID- 28847813 TI - Corelease of Inhibitory Neurotransmitters in the Mouse Auditory Midbrain. AB - The central nucleus of the inferior colliculus (ICC) of the auditory midbrain, which integrates most ascending auditory information from lower brainstem regions, receives prominent long-range inhibitory input from the ventral nucleus of the lateral lemniscus (VNLL), a region thought to be important for temporal pattern discrimination. Histological evidence suggests that neurons in the VNLL release both glycine and GABA in the ICC, but functional evidence for their corelease is lacking. We took advantage of the GlyT2-Cre mouse line (both male and female) to target expression of ChR2 to glycinergic afferents in the ICC and made whole-cell recordings in vitro while exciting glycinergic fibers with light. Using this approach, it was clear that a significant fraction of glycinergic boutons corelease GABA in the ICC. Viral injections were used to target ChR2 expression specifically to glycinergic fibers ascending from the VNLL, allowing for activation of fibers from a single source of ascending input in a way that has not been previously possible in the ICC. We then investigated aspects of the glycinergic versus GABAergic current components to probe functional consequences of corelease. Surprisingly, the time course and short-term plasticity of synaptic signaling were nearly identical for the two transmitters. We therefore conclude that the two neurotransmitters may be functionally interchangeable and that multiple receptor subtypes subserving inhibition may offer diverse mechanisms for maintaining inhibitory homeostasis.SIGNIFICANCE STATEMENT Corelease of neurotransmitters is a common feature of the brain. GABA and glycine corelease is particularly common in the spinal cord and brainstem, but its presence in the midbrain is unknown. We show corelease of GABA and glycine for the first time in the central nucleus of the inferior colliculus of the auditory midbrain. Glycine and GABA are both inhibitory neurotransmitters involved in fast synaptic transmission, so we explored differences between the currents to establish a physiological foundation for functional differences in vivo In contrast to the auditory brainstem, coreleased GABAergic and glycinergic currents in the midbrain are strikingly similar. This apparent redundancy may ensure homeostasis if one neurotransmitter system is compromised. PMID- 28847814 TI - Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair. AB - The interaction of transplanted stem cells with local cellular and molecular cues in the host CNS microenvironment may affect the potential for repair by therapeutic cell populations. In this regard, spinal cord injury (SCI), Alzheimer's disease, and other neurological injuries and diseases all exhibit dramatic and dynamic changes to the host microenvironment over time. Previously, we reported that delayed transplantation of human CNS-derived neural stem cells (hCNS-SCns) at 9 or 30 d post-SCI (dpi) resulted in extensive donor cell migration, predominantly neuronal and oligodendrocytic donor cell differentiation, and functional locomotor improvements. Here, we report that acute transplantation of hCNS-SCns at 0 dpi resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement in an all-female immunodeficient mouse model. Critically, specific immunodepletion of neutrophils (polymorphonuclear leukocytes) blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function. These data represent novel evidence that a host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population, and support targeting the inflammatory microenvironment in combination with cell transplantation after SCI.SIGNIFICANCE STATEMENT The interaction of transplanted cells with local cellular and molecular cues in the host microenvironment is a key variable that may shape the translation of neurotransplantation research to the clinical spinal cord injury (SCI) human population, and few studies have investigated these events. We show that the specific immunodepletion of polymorphonuclear leukocyte neutrophils using anti-Ly6G inhibits donor cell astrogliosis and rescues the capacity of a donor cell population to promote locomotor improvement after SCI. Critically, our data demonstrate novel evidence that a specific host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population. PMID- 28847816 TI - Chromatin modifiers and remodellers in DNA repair and signalling. PMID- 28847817 TI - Reading chromatin signatures after DNA double-strand breaks. AB - DNA double-strand breaks (DSBs) are DNA lesions that must be accurately repaired in order to preserve genomic integrity and cellular viability. The response to DSBs reshapes the local chromatin environment and is largely orchestrated by the deposition, removal and detection of a complex set of chromatin-associated post translational modifications. In particular, the nucleosome acts as a central signalling hub and landing platform in this process by organizing the recruitment of repair and signalling factors, while at the same time coordinating repair with other DNA-based cellular processes. While current research has provided a descriptive overview of which histone marks affect DSB repair, we are only beginning to understand how these marks are interpreted to foster an efficient DSB response. Here we review how the modified chromatin surrounding DSBs is read, with a focus on the insights gleaned from structural and biochemical studies.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847819 TI - The role of ubiquitin-dependent segregase p97 (VCP or Cdc48) in chromatin dynamics after DNA double strand breaks. AB - DNA double strand breaks (DSBs) are the most cytotoxic DNA lesions and, if not repaired, lead to chromosomal rearrangement, genomic instability and cell death. Cells have evolved a complex network of DNA repair and signalling molecules which promptly detect and repair DSBs, commonly known as the DNA damage response (DDR). The DDR is orchestrated by various post-translational modifications such as phosphorylation, methylation, ubiquitination or SUMOylation. As DSBs are located in complex chromatin structures, the repair of DSBs is engineered at two levels: (i) at sites of broken DNA and (ii) at chromatin structures that surround DNA lesions. Thus, DNA repair and chromatin remodelling machineries must work together to efficiently repair DSBs. Here, we summarize the current knowledge of the ubiquitin-dependent molecular unfoldase/segregase p97 (VCP in vertebrates and Cdc48 in worms and lower eukaryotes) in DSB repair. We identify p97 as an essential factor that regulates DSB repair. p97-dependent extraction of ubiquitinated substrates mediates spatio-temporal protein turnover at and around the sites of DSBs, thus orchestrating chromatin remodelling and DSB repair. As p97 is a druggable target, p97 inhibition in the context of DDR has great potential for cancer therapy, as shown for other DDR components such as PARP, ATR and CHK1.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847818 TI - SUMO, a small, but powerful, regulator of double-strand break repair. AB - The response to a DNA double-stranded break in mammalian cells is a process of sensing and signalling the lesion. It results in halting the cell cycle and local transcription and in the mediation of the DNA repair process itself. The response is launched through a series of post-translational modification signalling events coordinated by phosphorylation and ubiquitination. More recently modifications of proteins by Small Ubiquitin-like MOdifier (SUMO) isoforms have also been found to be key to coordination of the response (Morris et al. 2009 Nature462, 886-890 (doi:10.1038/nature08593); Galanty et al. 2009 Nature462, 935-939 (doi:10.1038/nature08657)). However our understanding of the role of SUMOylation is slight compared with our growing knowledge of how ubiquitin drives signal amplification and key chromatin interactions. In this review we consider our current knowledge of how SUMO isoforms, SUMO conjugation machinery, SUMO proteases and SUMO-interacting proteins contribute to directing altered chromatin states and to repair-protein kinetics at a double-stranded DNA lesion in mammalian cells. We also consider the gaps in our understanding.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847820 TI - ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses. AB - Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase with a master regulatory function in the DNA damage response. In this role, ATM commands a complex biochemical network that signals the presence of oxidative DNA damage, including the dangerous DNA double-strand break, and facilitates subsequent repair. Here, we review the current state of knowledge regarding ATM-dependent chromatin remodelling and epigenomic alterations that are required to maintain genomic integrity in the presence of DNA double-strand breaks and/or oxidative stress. We will focus particularly on the roles of ATM in adjusting nucleosome spacing at sites of unresolved DNA double-strand breaks within complex chromatin environments, and the impact of ATM on preserving the health of cells within the mammalian central nervous system.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847822 TI - DNA repair goes hip-hop: SMARCA and CHD chromatin remodellers join the break dance. AB - Proper signalling and repair of DNA double-strand breaks (DSB) is critical to prevent genome instability and diseases such as cancer. The packaging of DNA into chromatin, however, has evolved as a mere obstacle to these DSB responses. Posttranslational modifications and ATP-dependent chromatin remodelling help to overcome this barrier by modulating nucleosome structures and allow signalling and repair machineries access to DSBs in chromatin. Here we recap our current knowledge on how ATP-dependent SMARCA- and CHD-type chromatin remodellers alter chromatin structure during the signalling and repair of DSBs and discuss how their dysfunction impacts genome stability and human disease.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847821 TI - The tale of a tail: histone H4 acetylation and the repair of DNA breaks. AB - The ability of cells to detect and repair DNA double-strand breaks (DSBs) within the complex architecture of the genome requires co-ordination between the DNA repair machinery and chromatin remodelling complexes. This co-ordination is essential to process damaged chromatin and create open chromatin structures which are required for repair. Initially, there is a PARP-dependent recruitment of repressors, including HP1 and several H3K9 methyltransferases, and exchange of histone H2A.Z by the NuA4-Tip60 complex. This creates repressive chromatin at the DSB in which the tail of histone H4 is bound to the acidic patch on the nucleosome surface. These repressor complexes are then removed, allowing rapid acetylation of the H4 tail by Tip60. H4 acetylation blocks interaction between the H4 tail and the acidic patch on adjacent nucleosomes, decreasing inter nucleosomal interactions and creating open chromatin. Further, the H4 tail is now free to recruit proteins such as 53BP1 to DSBs, a process modulated by H4 acetylation, and provides binding sites for bromodomain proteins, including ZMYND8 and BRD4, which are important for DSB repair. Here, we will discuss how the H4 tail functions as a dynamic hub that can be programmed through acetylation to alter chromatin packing and recruit repair proteins to the break site.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847823 TI - Bromodomain proteins: repairing DNA damage within chromatin. AB - Genome surveillance and repair, termed the DNA damage response (DDR), functions within chromatin. Chromatin-based DDR mechanisms sustain genome and epigenome integrity, defects that can disrupt cellular homeostasis and contribute to human diseases. An important chromatin DDR pathway is acetylation signalling which is controlled by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes, which regulate acetylated lysines within proteins. Acetylated proteins, including histones, can modulate chromatin structure and provide molecular signals that are bound by acetyl-lysine binders, including bromodomain (BRD) proteins. Acetylation signalling regulates several DDR pathways, as exemplified by the preponderance of HATs, HDACs and BRD proteins that localize at DNA breaks to modify chromatin for lesion repair. Here, we explore the involvement of acetylation signalling in the DDR, focusing on the involvement of BRD proteins in promoting chromatin remodelling to repair DNA double-strand breaks. BRD proteins have widespread DDR functions including chromatin remodelling, chromatin modification and transcriptional regulation. We discuss mechanistically how BRD proteins read acetylation signals within chromatin to trigger DDR and chromatin activities to facilitate genome-epigenome maintenance. Thus, DDR pathways involving BRD proteins represent key participants in pathways that preserve genome-epigenome integrity to safeguard normal genome and cellular functions.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847824 TI - DNA replication through a chromatin environment. AB - Compaction of the genome into the nuclear space is achieved by wrapping DNA around octameric assemblies of histone proteins to form nucleosomes, the fundamental repeating unit of chromatin. Aside from providing a means by which to fit larger genomes into the cell, chromatinization of DNA is a crucial means by which the cell regulates access to the genome. While the complex role that chromatin plays in gene transcription has been appreciated for a long time, it is now also apparent that crucial aspects of DNA replication are linked to the biology of chromatin. This review will focus on recent advances in our understanding of how the chromatin environment influences key aspects of DNA replication.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847825 TI - Transcription-associated events affecting genomic integrity. AB - Accurate maintenance of genomic as well as epigenomic integrity is critical for proper cell and organ function. Continuous exposure to DNA damage is, thus, often associated with malignant transformation and degenerative diseases. A significant, chronic threat to genome integrity lies in the process of transcription, which can result in the formation of potentially harmful RNA : DNA hybrid structures (R-loops) and has been linked to DNA damage accumulation as well as dynamic chromatin reorganization. In sharp contrast, recent evidence suggests that active transcription, the resulting transcripts as well as R-loop formation can play multi-faceted roles in maintaining and restoring genome integrity. Here, we will discuss the emerging contributions of transcription as both a source of DNA damage and a mediator of DNA repair. We propose that both aspects have significant implications for genome maintenance, and will speculate on possible long-term consequences for the epigenetic integrity of transcribing cells.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847826 TI - Genome maintenance functions of the INO80 chromatin remodeller. AB - Chromatin modification is conserved in all eukaryotes and is required to facilitate and regulate DNA-templated processes. For example, chromatin manipulation, such as histone post-translational modification and nucleosome positioning, play critical roles in genome stability pathways. The INO80 chromatin-remodelling complex, which regulates the abundance and positioning of nucleosomes, is particularly important for proper execution of inducible responses to DNA damage. This review discusses the participation and activity of the INO80 complex in DNA repair and cell cycle checkpoint pathways, with emphasis on the Saccharomyces cerevisiae model system. Furthermore, the role of ATM/ATR kinases, central regulators of DNA damage signalling, in the regulation of INO80 function will be reviewed. In addition, emerging themes of chromatin remodelling in mitotic stability pathways and chromosome segregation will be introduced. These studies are critical to understanding the dynamic chromatin landscape that is rapidly and reversibly modified to maintain the integrity of the genome.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847827 TI - The INO80 remodeller in transcription, replication and repair. AB - The accessibility of eukaryotic genomes to the action of enzymes involved in transcription, replication and repair is maintained despite the organization of DNA into nucleosomes. This access is often regulated by the action of ATP dependent nucleosome remodellers. The INO80 class of nucleosome remodellers has unique structural features and it is implicated in a diverse array of functions, including transcriptional regulation, DNA replication and DNA repair. Underlying these diverse functions is the catalytic activity of the main ATPase subunit, which in the context of a multisubunit complex can shift nucleosomes and carry out histone dimer exchange. In vitro studies showed that INO80 promotes replication fork progression on a chromatin template, while in vivo it was shown to facilitate replication fork restart after stalling and to help evict RNA polymerase II at transcribed genes following the collision of a replication fork with transcription. More recent work in yeast implicates INO80 in the general eviction and degradation of nucleosomes following high doses of oxidative DNA damage. Beyond these replication and repair functions, INO80 was shown to repress inappropriate transcription at promoters in the opposite direction to the coding sequence. Here we discuss the ways in which INO80's diverse functions help maintain genome integrity.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847830 TI - Ultrasound examination of the pupil suggestive for carotid dissection. PMID- 28847829 TI - Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing. AB - Nucleosome remodelling (NR) regulates transcription in an ATP-dependent manner, and influences gene expression required for development and cellular functions, including those involved in anti-cancer and anti-ageing processes. ATP-utilizing chromatin assembly and remodelling factor (ACF) and Brahma-associated factor (BAF) complexes, belonging to the ISWI and SWI/SNF families, respectively, are involved in various types of DNA repair. Suppression of several BAF factors makes U2OS cells significantly sensitive to X-rays, UV and especially to cisplatin, and these BAF factors contribute to the accumulation of repair proteins at various types of DNA damage and to DNA repair. Recent cancer genome sequencing and expression analysis has shown that BAF factors are frequently mutated or, more frequently, silenced in various types of cancer cells. Thus, those cancer cells are potentially X-ray- and especially cisplatin-sensitive, suggesting a way of optimizing current cancer therapy. Recent single-stem cell analysis suggests that mutations and epigenetic changes influence stem cell functionality leading to cellular ageing. Genetic and epigenetic changes in the BAF factors diminish DNA repair as well as transcriptional regulation activities, and DNA repair defects in turn negatively influence NR and transcriptional regulation. Thus, they build negative feedback loops, which accelerate both cellular senescence and transformation as common and rare cellular events, respectively, causing cellular ageing.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847831 TI - Right Brain: The fragile sense of self in neurodegenerative disease: A brief philosophical examination. PMID- 28847832 TI - Editors' Note. PMID- 28847828 TI - And yet, it moves: nuclear and chromatin dynamics of a heterochromatic double strand break. AB - Heterochromatin is mostly composed of repeated DNA sequences prone to aberrant recombination. How cells maintain the stability of these sequences during double strand break (DSB) repair has been a long-standing mystery. Studies in Drosophila cells revealed that faithful homologous recombination repair of heterochromatic DSBs relies on the striking relocalization of repair sites to the nuclear periphery before Rad51 recruitment and repair progression. Here, we summarize our current understanding of this response, including the molecular mechanisms involved, and conserved pathways in mammalian cells. We will highlight important similarities with pathways identified in budding yeast for repair of other types of repeated sequences, including rDNA and short telomeres. We will also discuss the emerging role of chromatin composition and regulation in heterochromatin repair progression. Together, these discoveries challenged previous assumptions that repair sites are substantially static in multicellular eukaryotes, that heterochromatin is largely inert in the presence of DSBs, and that silencing and compaction in this domain are obstacles to repair.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'. PMID- 28847833 TI - Letter re: Clinical Reasoning: A young woman with respiratory failure, hearing loss, and paraplegia. PMID- 28847834 TI - Author response: Clinical Reasoning: A young woman with respiratory failure, hearing loss, and paraplegia. PMID- 28847835 TI - Letter re: Clinical Reasoning: A young woman with respiratory failure, hearing loss, and paraplegia. PMID- 28847836 TI - Author response: Clinical Reasoning: A young woman with respiratory failure, hearing loss, and paraplegia. PMID- 28847837 TI - Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease. PMID- 28847838 TI - Clinical Reasoning: A 61-year-old man with conjugate gaze deviation, hemiparesis, and asymmetric reflexes. PMID- 28847839 TI - Mystery Case: A case of fulminant encephalopathy in a 69-year-old woman. PMID- 28847840 TI - Teaching NeuroImages: Reversible brain MRI lesions in adult-onset type II citrullinemia. PMID- 28847842 TI - Sudden unexpected death in epilepsy: Taking another look. PMID- 28847841 TI - Teaching Video NeuroImages: Macrosaccadic oscillations induced by horizontal head impulses. PMID- 28847843 TI - Economic insecurity during the Great Recession and metabolic, inflammatory and liver function biomarkers: analysis of the UK Household Longitudinal Study. AB - BACKGROUND: Economic insecurity correlates with adverse health outcomes, but the biological pathways involved are not well understood. We examine how changes in economic insecurity relate to metabolic, inflammatory and liver function biomarkers. METHODS: Blood analyte data were taken from 6520 individuals (aged 25 59 years) participating in Understanding Society. Economic insecurity was measured using an indicator of subjective financial strain and by asking participants whether they had missed any bill, council tax, rent or mortgage payments in the past year. We investigated longitudinal changes in economic insecurity (remained secure, increase in economic insecurity, decrease in economic insecurity, remained insecure) and the accumulation of economic insecurity. Linear regression models were calculated for nine (logged) biomarker outcomes related to metabolic, inflammatory, liver and kidney function (as falsification tests), adjusting for potential confounders. RESULTS: Compared with those who remained economically stable, people who experienced consistent economic insecurity (using both measures) had worsened levels of high-density lipoprotein (HDL)-cholesterol, triglycerides, C reactive protein (CRP), fibrinogen and glycated haemoglobin. Increased economic insecurity was associated with adverse levels of HDL-cholesterol (0.955, 95% CI 0.929 to 0.982), triglycerides (1.077, 95% CI 1.018 to 1.139) and CRP (1.114, 95% CI 1.012 to 1.227), using the measure of financial strain. Results for the other measure were generally consistent, apart from the higher levels of gamma-glutamyl transferase observed among those experiencing persistent insecurity (1.200, 95% CI 1.110 to 1.297). CONCLUSION: Economic insecurity is associated with adverse metabolic and inflammatory biomarkers (particularly HDL-cholesterol, triglycerides and CRP), heightening risk for a range of health conditions. PMID- 28847844 TI - Intake of dietary fibre and lifetime non-steroidal anti-inflammatory drug (NSAID) use and the incidence of colorectal polyps in a population screened for colorectal cancer. AB - BACKGROUND: There is suggestive evidence that increased intake of dietary fibre and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are generally associated with decreased colorectal cancer risk. However, the effects on precursors of colorectal cancer, such as adenomatous polyps, are mixed. We present the associations between dietary fibre intake and NSAID use on the presence and type of colorectal polyps in a screening population. METHODS: A cross-sectional study of 2548 individuals undergoing colonoscopy at the Forzani & MacPhail Colon Cancer Screening Centre (Calgary, Canada) was conducted. Dietary fibre intake and NSAID use were assessed using the Diet History Questionnaire I or II and the Health and Lifestyle Questionnaire. Colorectal outcomes were documented as a polyp or high-risk adenomatous polyp (HRAP; villous histology, high-grade dysplasia, >=10 mm or >=3 adenomas). Crude and ORs and 95% CIs were estimated using unconditional logistic regression. RESULTS: There were 1450 negative colonoscopies and 1098 patients with polyps, of which 189 patients had HRAPs. Total dietary fibre intake was associated with a decreased presence of HRAPs (OR=0.50, 95% CI: 0.29 to 0.86) when comparing the highest to lowest quartiles and was observed with both soluble (OR=0.51, 95% CI: 0.30 to 0.88) and insoluble (OR=0.51, 95% CI: 0.30 to 0.86) fibres. Ever use of NSAIDs was also inversely associated with HRAPs (OR=0.65, 95% CI: 0.47 to 0.89), observed with monthly (OR=0.60, 95% CI: 0.37 to 0.95) and daily (OR=0.53, 95% CI: 0.32 to 0.86) use. CONCLUSIONS: Dietary fibre intake and NSAID use were associated with a decreased risk of having a HRAP at screening. PMID- 28847846 TI - Regarding "Determining the Orientation of Directional Deep Brain Stimulation Electrodes Using 3D Rotational Fluoroscopy". PMID- 28847845 TI - Evolution of Wikipedia's medical content: past, present and future. AB - As one of the most commonly read online sources of medical information, Wikipedia is an influential public health platform. Its medical content, community, collaborations and challenges have been evolving since its creation in 2001, and engagement by the medical community is vital for ensuring its accuracy and completeness. Both the encyclopaedia's internal metrics as well as external assessments of its quality indicate that its articles are highly variable, but improving. Although content can be edited by anyone, medical articles are primarily written by a core group of medical professionals. Diverse collaborative ventures have enhanced medical article quality and reach, and opportunities for partnerships are more available than ever. Nevertheless, Wikipedia's medical content and community still face significant challenges, and a socioecological model is used to structure specific recommendations. We propose that the medical community should prioritise the accuracy of biomedical information in the world's most consulted encyclopaedia. PMID- 28847847 TI - Long Noncoding RNA MEG3 Is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells. AB - The long noncoding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic hepatocyte growth factor (HGF) receptor c-MET in PNETs. Meg3 overexpression in a mouse insulin-secreting PNET cell line, MIN6, downregulates c Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using chromatin isolation by RNA purification and sequencing (ChIRP Seq), we identified Meg3 binding to unique genomic regions in and around the c Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex-forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex-forming oligonucleotides (TFOs), in MIN6 cells suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet beta-cell expansion through c-MET regulation to ameliorate beta-cell loss in diabetes. PMID- 28847848 TI - Candida and Pseudomonas interact to enhance virulence of mucosal infection in transparent zebrafish. AB - Polymicrobial infections often include both fungi and bacteria, and can complicate patient treatment and resolution of infection. Cross-kingdom interactions among bacteria, fungi, and/or the immune system during infection can enhance or block virulence mechanisms and influence disease progression. The fungus C. albicans and the bacterium P. aeruginosa are co-isolated in the context of polymicrobial infection at a variety of sites throughout the body, including mucosal tissues such as the lung. In vitro,C. albicans and P. aeruginosa have a bi-directional and largely antagonistic relationship. Their interactions in vivo remain poorly understood, specifically regarding host responses in mediating infection. In this study, we examine tri-kingdom interactions using a transparent juvenile zebrafish to model mucosal lung infection and show that C. albicans and P. aeruginosa are synergistically virulent. We find that high C. albicans burden, fungal epithelial invasion, swimbladder edema, and epithelial extrusion events serve as predictive factors for mortality in our infection model. Longitudinal analyses of fungal, bacterial and immune dynamics during co-infection suggests that enhanced morbidity is associated with exacerbated C. albicans pathogenesis and elevated inflammation. The P. aeruginosa quorum sensing deficient DeltalasR mutant also enhances C. albicans pathogenicity in co-infection and induces extrusion of the swimbladder. Together, these observations suggest that C. albicans-P. aeruginosa crosstalk in vivo can benefit both organisms to the detriment of the host. PMID- 28847849 TI - Otitis Media and Nasopharyngeal Colonization in ccl3-/- Mice. AB - We previously found CC chemokine ligand 3 (CCL3) to be a potent effector of inflammation during otitis media (OM): exogenous CCL3 rescues the OM phenotype of tumor necrosis factor-deficient mice and the function of macrophages deficient in several innate immune molecules. To further delineate the role of CCL3 in OM, we evaluated middle ear (ME) responses of ccl3-/-mice to nontypeable Haemophilus influenzae (NTHi). CCL chemokine gene expression was evaluated in wild-type (WT) mice during the complete course of acute OM. OM was induced in ccl3-/- and WT mice, and infection and inflammation were monitored for 21 days. Phagocytosis and killing of NTHi by macrophages were evaluated by an in vitro assay. The nasopharyngeal bacterial load was assessed in naive animals of both strains. Many CCL genes showed increased expression levels during acute OM, with CCL3 being the most upregulated, at levels 600-fold higher than the baseline. ccl3-/- deletion compromised ME bacterial clearance and prolonged mucosal hyperplasia. ME recruitment of leukocytes was delayed but persisted far longer than in WT mice. These events were linked to a decrease in the macrophage capacity for NTHi phagocytosis and increased nasopharyngeal bacterial loads in ccl3-/- mice. The generalized impairment in inflammatory cell recruitment was associated with compensatory changes in the expression profiles of CCL2, CCL7, and CCL12. CCL3 plays a significant role in the clearance of infection and resolution of inflammation and contributes to mucosal host defense of the nasopharyngeal niche, a reservoir for ME and upper respiratory infections. Therapies based on CCL3 could prove useful in treating or preventing persistent disease. PMID- 28847851 TI - Factors associated with coronary artery disease and stroke in adults with congenital heart disease. AB - OBJECTIVE: To determine factors associated with coronary artery disease (CAD) and ischaemic stroke in ageing adult congenital heart disease (ACHD) patients. METHODS: We performed a multicentre case-control study, using data from the national CONgenital CORvitia (CONCOR) registry to identify ACHD patients within five participating centres. Patients with CAD were matched (1:2 ratio) with ACHD patients without CAD on age, CHD defect group and gender. Patients with ischaemic stroke (or transient ischaemic attack) were matched similarly. Medical charts were reviewed and a standardised questionnaire was used to determine presence of risk factors. RESULTS: Of 6904 ACHD patients, a total of 55 cases with CAD (80% male, mean age 55.1+/-12.4 years) and 56 cases with stroke (46% male, mean age 46.9+/-15.2) were included and matched with control patients. In multivariable logistic regression analysis, traditional atherosclerotic risk factors (hypertension (OR 2.45; 95% CI 1.15 to 5.23), hypercholesterolaemia (OR 3.99; 95% CI 1.62 to 9.83) and smoking (OR 2.25; 95% CI 1.09 to 4.66)) were associated with CAD. In contrast, these risk factors were not associated with ischaemic stroke. In multivariable analysis, stroke was associated with previous shunt operations (OR 4.20; 95% CI 1.36 to 12.9), residual/unclosed septal defects (OR 2.38; 95% CI 1.03 to 5.51) and left-sided mechanical valves (OR 2.67; 95% CI 1.09 to 6.50). CONCLUSIONS: Traditional atherosclerotic risk factors were associated with CAD in ACHD patients. In contrast, ischaemic stroke was related to factors (previous shunts, septal defects, mechanical valves) suggesting a cardioembolic aetiology. These findings may inform surveillance and prevention strategies. PMID- 28847850 TI - Induction of Type I Interferon through a Noncanonical Toll-Like Receptor 7 Pathway during Yersinia pestis Infection. AB - Yersinia pestis causes bubonic, pneumonic, and septicemic plague, diseases that are rapidly lethal to most mammals, including humans. Plague develops as a consequence of bacterial neutralization of the host's innate immune response, which permits uncontrolled growth and causes the systemic hyperactivation of the inflammatory response. We previously found that host type I interferon (IFN) signaling is induced during Y. pestis infection and contributes to neutrophil depletion and disease. In this work, we show that type I IFN expression is derived from the recognition of intracellular Y. pestis by host Toll-like receptor 7 (TLR7). Type I IFN expression proceeded independent of myeloid differentiation factor 88 (MyD88), which is the only known signaling adaptor for TLR7, suggesting that a noncanonical mechanism occurs in Y. pestis-infected macrophages. In the murine plague model, TLR7 was a significant contributor to the expression of serum IFN-beta, whereas MyD88 was not. Furthermore, like the type I IFN response, TLR7 contributed to the lethality of septicemic plague and was associated with the suppression of neutrophilic inflammation. In contrast, TLR7 was important for defense against disease in the lungs. Together, these data demonstrate that an atypical TLR7 signaling pathway contributes to type I IFN expression during Y. pestis infection and suggest that the TLR7-driven type I IFN response plays an important role in determining the outcome of plague. PMID- 28847852 TI - Association between chronic immune-mediated inflammatory diseases and cardiovascular risk. AB - OBJECTIVE: To examine the association between chronic immune-mediated diseases (rheumatoid arthritis, systemic lupus erythematosus or the following chronic immune-mediated inflammatory diagnoses groups: inflammatory bowel diseases, inflammatory polyarthropathies, systemic connective tissue disorders and spondylopathies) and the 6-year coronary artery disease, stroke, cardiovascular disease incidence and overall mortality; and to estimate the population attributable fractions for all four end-points for each chronic immune-mediated inflammatory disease. METHODS: Cohort study of individuals aged 35-85 years, with no history of cardiovascular disease from Catalonia (Spain). The coded diagnoses of chronic immune-mediated diseases and cardiovascular diseases were ascertained and registered using validated codes, and date of death was obtained from administrative data. Cox regression models for each outcome according to exposure were fitted to estimate HRs in two models 1 : after adjustment for sex, age, cardiovascular risk factors and 2 further adjusted for drug use. Population attributable fractions were estimated for each exposure. RESULTS: Data were collected from 991 546 participants. The risk of cardiovascular disease was increased in systemic connective tissue disorders (model 1: HR=1.38 (95% CI 1.21 to 1.57) and model 2: HR=1.31 (95% CI 1.15 to 1.49)), rheumatoid arthritis (HR=1.43 (95% CI 1.26 to 1.62) and HR=1.31 (95% CI 1.15 to 1.49)) and inflammatory bowel diseases (HR=1.18 (95% CI 1.06 to 1.32) and HR=1.12 (95% CI 1.01 to 1.25)). The effect of anti-inflammatory treatment was significant in all instances (HR=1.50 (95% CI 1.24 to 1.81); HR=1.47 (95% CI 1.23 to 1.75); HR=1.43 (95% CI 1.19 to 1.73), respectively). The population attributable fractions for all three disorders were 13.4%, 15.7% and 10.7%, respectively. CONCLUSION: Systemic connective tissue disorders and rheumatoid arthritis conferred the highest cardiovascular risk and population impact, followed by inflammatory bowel diseases. PMID- 28847853 TI - Holistic needs assessment and care plans for women with gynaecological cancer: do they improve cancer-specific health-related quality of life? A randomised controlled trial using mixed methods. AB - OBJECTIVES: Holistic needs assessment (HNA) and care planning are proposed to address unmet needs of people treated for cancer. We tested whether HNA and care planning by an allied health professional improved cancer-specific quality of life for women following curative treatment for stage I-III gynaecological cancer. METHODS: Consecutive women were invited to participate in a randomised controlled study (HNA and care planning vs usual care) at a UK cancer centre. Data were collected by questionnaire at baseline, 3 and 6 months. The outcomes were 6-month change in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (version 3), global score (primary) and, in EORTC subscales, generic quality of life and self-efficacy (secondary). The study was blinded for data management and analysis. Differences in outcomes were compared between groups. Health service utilisation and quality-adjusted life years (QALY) (from Short Form-6) were gathered for a cost-effectiveness analysis. Thematic analysis was used to interpret data from an exit interview. RESULTS: 150 women consented (75 per group); 10 undertook interviews. For 124 participants (61 intervention, 63 controls) with complete data, no statistically significant differences were seen between groups in the primary endpoint. The majority of those interviewed reported important personal gains they attributed to the intervention, which reflected trends to improvement seen in EORTC functional and symptom scales. Economic analysis suggests a 62% probability of cost-effectiveness at a L30 000/QALY threshold. CONCLUSION: Care plan development with an allied health professional is cost-effective, acceptable and useful for some women treated for stage I-III gynaecological cancer. We recommend its introduction early in the pathway to support person-centred care. PMID- 28847856 TI - Correction. PMID- 28847854 TI - A multidisciplinary rehabilitation programme for cancer cachexia improves quality of life. AB - OBJECTIVES: Patients with cancer cachexia have severely impaired quality of life (QoL). Multidisciplinary, multimodal treatment approaches have potential for stabilising weight and correcting other features of this syndrome, but the impact on QoL is unknown. METHODS: A retrospective analysis of QoL in patients with advanced cancer, referred for the management of cachexia by a specialised multidisciplinary clinic (The McGill Cancer Nutrition Rehabilitation Program clinic at the Jewish General Hospital (CNR-JGH)). QoL was assessed at visits 1-3 using a dedicated QoL tool for cachexia, and the change in QoL was calculated for each patient. The correlation between clinical features and QoL at baseline and subsequent change in QoL was analysed, to determine what factors predict improvements in QoL during the CNR-JGH intervention. RESULTS: 374 patients assessed at visit 1 with mean weight loss of 10.2% over the preceding 6 months. Baseline QoL scores were severely impaired but clinically important improvements were observed over visits 1-3 to the CNR-JGH clinic. Improvements in QoL were not determined by baseline characteristics and were similar in all patient subgroups. However, those patients who gained weight and increased their 6 min walk test (6MWT) had the greatest improvements in QoL. CONCLUSIONS: Improving management of all facets of the cancer cachexia syndrome, including poor QoL, remains a priority. The multimodal approach to management of cancer cachexia offered by the CNR-JGH results in clinically important improvements in QoL. All patients who are able to receive this type of intervention have similar potential to improve their QoL, but the greatest benefits are seen in those who gain weight and improve their 6MWT. PMID- 28847855 TI - Pharmacologic Management of Alcohol Withdrawal Syndrome in Intensive Care Units. PMID- 28847857 TI - New Data of the Digital Age: Big, Dark, and Deep. PMID- 28847858 TI - Pursuing the Clinical Track Faculty Role: From Clinical Expert to Educator. PMID- 28847859 TI - Adiposity: A Formidable Challenge in Acute and Critical Care. PMID- 28847860 TI - Weight Bias and Psychosocial Implications for Acute Care of Patients With Obesity. AB - Obesity is a complex medical condition that has psychosocial and physiological implications for those suffering from the disease. Factors contributing to obesity such as depression, childhood experiences, and the physical environment should be recognized and addressed. Weight bias and stigmatization by health care providers and bedside clinicians negatively affect patients with obesity, hindering those patients from receiving appropriate care. To provide optimal care of patients with obesity or adiposity, health care providers must understand the physiological needs and requirements of this population while recognizing and addressing their own biases. The authors describe psychosocial and environmental factors that contribute to obesity, discuss health care providers' weight biases, and highlight implications for acute care of patients suffering from obesity. PMID- 28847861 TI - Comprehensive Care for Bariatric Surgery Patients. AB - Obesity is a worldwide epidemic, and those suffering from obesity have increased morbidity and mortality rates. There are various causes of obesity and many treatment options for patients suffering from obesity, including nonsurgical treatments. However, bariatric surgery is often the best choice for optimal weight loss and the attenuation of comorbidities. Currently, laparoscopic sleeve gastrectomy is the most common type of bariatric surgery in the United States due to its technical simplicity, feasibility, and overall positive outcomes. This article discusses bariatric surgical criteria and selection, expected perioperative course, potential complications after surgery, and nursing implications for the care of bariatric patients. A case report is used to exemplify stages of surgical care and follow-up treatment for patients who undergo laparoscopic sleeve gastrectomy. PMID- 28847862 TI - Managing Care of Critically Ill Bariatric Patients. AB - Nearly 160 million Americans are overweight, obese, or morbidly obese. Morbid obesity and its numerous comorbidities are threats to a person's health. Moreover, hospitalized individuals living with adiposity-based chronic conditions are at risk for certain immobility hazards. Many individuals who are morbidly obese look to metabolic surgery as a means for achieving sustainable weight loss. This article addresses critical care needs of people living with excess weight or weight maldistribution, along with specific needs of those undergoing metabolic surgery. PMID- 28847863 TI - Adiposity and the Role of Neuroendocrine Hormones in Energy Balance. AB - Obesity is a worldwide health concern and, given the risk for developing associated co-morbidities that increase mortality, obesity has health implications for individuals and populations. Obesity involves multifactorial regulatory mechanisms, and recognition of these mechanisms will enhance the care critical care nurses provide to their patients. This article reviews the general physiological mechanisms of energy storage and the regulation of adiposity related to key neuroendocrine hormones. The authors also highlight the implications for nursing care for critically ill patients suffering from obesity. PMID- 28847864 TI - Importance of Healthy Work Environment Education in Nursing Schools. PMID- 28847865 TI - Toward Everyday Ethics: Strategies for Shifting Perspectives. PMID- 28847866 TI - Early Repolarization: From Benign Variant to Marker of Risk. PMID- 28847867 TI - Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. AB - : Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival. PATIENTS: 407 patients with ACLF and 235 patients with acute decompensation (AD). RESULTS: 152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90 day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%). CONCLUSION: Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies. PMID- 28847868 TI - Dendritic cell and antigen dispersal landscapes regulate T cell immunity. AB - Dendritic cell (DC) subsets with biased capacity for CD4+ and CD8+ T cell activation are asymmetrically distributed in lymph nodes (LNs), but how this affects adaptive responses has not been extensively studied. Here we used quantitative imaging to examine the relationships among antigen dispersal, DC positioning, and T cell activation after protein immunization. Antigens rapidly drained into LNs and formed gradients extending from the lymphatic sinuses, with reduced abundance in the deep LN paracortex. Differential localization of DCs specialized for major histocompatibility complex I (MHC I) and MHC II presentation resulted in preferential activation of CD8+ and CD4+ T cells within distinct LN regions. Because MHC I-specialized DCs are positioned in regions with limited antigen delivery, modest reductions in antigen dose led to a substantially greater decline in CD8+ compared with CD4+ T cell activation, expansion, and clonal diversity. Thus, the collective action of antigen dispersal and DC positioning regulates the extent and quality of T cell immunity, with important implications for vaccine design. PMID- 28847870 TI - Socioeconomic inequity in survival for deliveries at 22-24 weeks of gestation. AB - OBJECTIVE: Guidelines recommend individual decision making on resuscitating infants of 22-24 weeks' gestational age (GA) at birth. When the decision not to resuscitate is made, infants would likely die soon after delivery, and under some circumstances such neonatal deaths may be registered as stillbirths occurring during delivery (intrapartum stillbirth). Thus we assessed whether socioeconomic factors are associated with peridelivery deaths (during or within 1 hour of delivery) of infants delivered at 22-24 weeks' gestation. METHODS: We analysed 14 726 singletons of 22-24 weeks' GA using the 2003-2011 Japanese vital statistics, and assessed how maternal characteristics influence risk of peridelivery death as well as intrauterine fetal death (IUFD) and death after 1 hour of age until 40 weeks postmenstrual age. RESULTS: Living in a municipality with low-average income (lowest tertile (risk ratio 1.32, 95% CI 1.20 to 1.44), middle tertile (risk ratio 1.08, 95% CI 0.98 to 1.19)), younger maternal age (age <20 (risk ratio 1.43, 95% CI 1.17 to 1.75), age 20-34 (risk ratio 1.14, 95% CI 1.03 to 1.27)) and having previous live births (risk ratio 1.08, 95% CI 1.01 to 1.17) increased risk of peridelivery deaths, but did not increase risk of IUFD or deaths after 1 hour of age. Peridelivery death was twice as likely to occur in births to multiparous teenage mothers in a low-income municipality, compared with those of older primiparous mothers in a wealthier municipality. CONCLUSIONS: Socioeconomic factors substantially influence whether births of 22-24 weeks' GA survive delivery and the first hour of life. Such disparities may reflect the impact of socioeconomic situations on decision making for resuscitation. PMID- 28847871 TI - Academic performance of children born preterm: a meta-analysis and meta regression. AB - BACKGROUND: Advances in neonatal healthcare have resulted in decreased mortality after preterm birth but have not led to parallel decreases in morbidity. Academic performance provides insight in the outcomes and specific difficulties and needs of preterm children. OBJECTIVE: To study academic performance in preterm children born in the antenatal steroids and surfactant era and possible moderating effects of perinatal and demographic factors. DESIGN: PubMed, Web of Science and PsycINFO were searched for peer-reviewed articles. Cohort studies with a full-term control group reporting standardised academic performance scores of preterm children (<37 weeks of gestation) at age 5 years or older and born in the antenatal steroids and surfactant era were included. Academic test scores and special educational needs of preterm and full-term children were analysed using random effects meta analysis. Random effects meta-regressions were performed to explore the predictive role of perinatal and demographic factors for between-study variance in effect sizes. RESULTS: The 17 eligible studies included 2390 preterm children and 1549 controls. Preterm children scored 0.71 SD below full-term peers on arithmetic (p<0.001), 0.44 and 0.52 SD lower on reading and spelling (p<0.001) and were 2.85 times more likely to receive special educational assistance (95% CI 2.12 to 3.84, p<0.001). Bronchopulmonarydysplasia explained 44% of the variance in academic performance (p=0.006). CONCLUSION: Preterm children born in the antenatal steroids and surfactant era show considerable academic difficulties. Preterm children with bronchopulmonarydysplasia are at particular risk for poor academic outcome. PMID- 28847869 TI - Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo. AB - Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-A resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors. PMID- 28847872 TI - Empyema necessitans and a persistent air leak associated with rupture of an anaerobic lung abscess due to bacteroides. PMID- 28847873 TI - Antimicrobial use in food-producing animals: a rapid evidence assessment of stakeholder practices and beliefs. AB - Food-producing animals throughout the world are likely to be exposed to antimicrobial (AM) treatment. The crossover in AM use between human and veterinary medicine raises concerns that antimicrobial resistance (AMR) may spread from food-producing animals to humans, driving the need for further understanding of how AMs are used in livestock practice as well as stakeholder beliefs relating to their use. A rapid evidence assessment (REA) was used to collate research on AM use published in peer-reviewed journals between 2000 and 2016. Forty-eight papers were identified and reviewed. The summary of findings highlights a number of issues regarding current knowledge of the use of AMs in food-producing animals and explores the attitudes of interested parties regarding the reduction of AM use in livestock. Variation between and within countries, production types and individual farms demonstrates the complexity of the challenge involved in monitoring and regulating AM use in animal agriculture. Many factors that could influence the prevalence of AMR in livestock are of concern across all sections of the livestock industry. This REA highlights the potential role of farmers and veterinarians and of other advisors, public pressure and legislation to influence change in the use of AMs in livestock. PMID- 28847874 TI - Risk factors for redemption of feline neutering vouchers issued by welfare organisations. AB - Animal welfare organisations in the UK invest substantial resources to fund subsidised neutering vouchers to increase feline neutering rates. Little evidence exists to quantify factors influencing voucher redemption. This cross-sectional study assessed risk factors (including voucher value and expiry period) for redemption of neutering vouchers issued by staff of the feline welfare charity Cats Protection. Data were collected using telephone interview-administered questionnaires of cat owners who were issued a neutering voucher(s) and from Cats Protection voucher payment records. During the four-month study 2655 owners were issued 3935 vouchers. Multivariable logistic regression analysis revealed that owners of cats that had produced >=1 litter before voucher request, owners eligible for a voucher due to receiving benefits and owners who rented their homes or lived with family were less likely to redeem vouchers than owners whose cats had not had a litter, were eligible for a voucher for other reasons and/or owners who owned their home, respectively. PMID- 28847875 TI - Evaluation of three intravenous injectable anaesthesia protocols in healthy adult male alpacas. AB - Few studies have investigated the effects of intravenous injectable anaesthesia in alpacas. The objective of this study was to evaluate three intravenous injectable anaesthesia protocols in healthy adult alpacas exposed to noxious stimulation. A prospective randomised crossover study was done using six healthy adult male alpacas. Cardiopulmonary variables including heart rate, respiratory rate, mean arterial pressure, end-tidal pCO2 and haemoglobin oxygen saturation were collected immediately after and every two minutes following induction of each of three anaesthesia protocols in six male castrated alpacas. A hoof tester was used to apply consistent pressure every two minutes after induction and the response was recorded. Time from induction to muscle contraction and leg withdrawal were recorded, as well as time from induction to extubation, sternal recumbency and standing. There was no significant difference in duration of anaesthesia or cardiopulmonary variables among the three anaesthesia protocols. Total duration of anaesthesia was approximately 20 minutes for each protocol. Hypoxaemia and mild hypercarbia were common among all protocols. Induction and recovery scores were excellent. PMID- 28847876 TI - Levetiracetam monotherapy for treatment of structural epilepsy in dogs: 19 cases (2010-2015). AB - To evaluate the efficacy and tolerability of levetiracetam monotherapy in dogs with structural epilepsy. Retrospective case series. Nineteen client-owned dogs with structural epilepsy. Seizure frequencies after initiation of treatment were used to evaluate the efficacy of levetiracetam monotherapy. Seizure control was considered good if no seizures occurred within three months of starting treatment or poor if seizures returned within one month of starting treatment. Tolerability was evaluated by considering the occurrence and severity of any reported side effects. Ten of the 19 dogs were considered to have a good response to treatment with 7 achieving complete seizure freedom. Nine dogs were considered to have poor response to treatment. There was a statistically significant reduction in the percentage of patients experiencing cluster seizures from 68.4% to 15.8% (p=0.002). Side effects were noted in 8 of the 19 dogs but were considered mild in all cases. Follow-up times ranged from 12 days to 426 days. When used in conjunction with other appropriate therapies, levetiracetam may be an efficacious option for monotherapy in dogs with structural epilepsy. Its tolerability makes it a suitable option for use in a wide variety of patients. PMID- 28847878 TI - Do antibiotics affect cerebrospinal fluid results? PMID- 28847877 TI - A qualitative feasibility study to inform a randomised controlled trial of fluid bolus therapy in septic shock. AB - OBJECTIVE: The Fluids in Shock (FiSh) Trial proposes to evaluate whether restrictive fluid bolus therapy (10 mL/kg) is more beneficial than current recommended practice (20 mL/kg) in the resuscitation of children with septic shock in the UK. This qualitative feasibility study aimed to explore acceptability of the FiSh Trial, including research without prior consent (RWPC), potential barriers to recruitment and participant information for a pilot trial. DESIGN: Qualitative interview study involving parents of children who had presented to a UK emergency department or been admitted to a paediatric intensive care unit with severe infection in the previous 3 years. PARTICIPANTS: Twenty-one parents (seven bereaved) were interviewed 16 (median) months since their child's hospital admission (range: 1-41). RESULTS: All parents said they would have provided consent for the use of their child's data in the FiSh Trial. The majority were unfamiliar with RWPC, yet supported its use. Parents were initially concerned about the change from currently recommended treatment, yet were reassured by explanations of the current evidence base, fluid bolus therapy and monitoring procedures. Parents made recommendations about the timing of the research discussion and content of participant information. Bereaved parents stated that recruiters should not discuss research immediately after a child's death, but supported a personalised postal 'opt-out' approach to consent. CONCLUSIONS: Findings show that parents whose child has experienced severe infection supported the proposed FiSh Trial, including the use of RWPC. Parents' views informed the development of the pilot trial protocol and site staff training. TRIAL REGISTRATION NUMBER: ISRCTN15244462-results. PMID- 28847879 TI - Dedicated paediatric Outpatient Parenteral Antimicrobial Therapy medical support: a pre-post observational study. AB - OBJECTIVE: Despite the many benefits of paediatric Outpatient Parenteral Antimicrobial Therapy (OPAT) programmes, there are risks associated with delivering inpatient-level care outside of hospital. There is a paucity of evidence defining how best to mitigate these risks. We examined the impact of introducing a dedicated medical team to OPAT, to define the role of increased medical oversight in improving patient outcomes in this cohort. DESIGN: A prospective 24-month pre-post observational cohort study. SETTING: The Hospital in the Home (HiTH) programme at Princess Margaret Hospital (PMH) for Children, Western Australia. PATIENTS: All OPAT admissions to HiTH, excluding haematology/oncology patients. INTERVENTIONS: PMH introduced a dedicated OPAT medical support team in July 2015 to improve adherence to best-practice guidelines for patient monitoring and review. MAIN OUTCOME MEASURES: Duration of OPAT, adherence to monitoring guidelines, drug-related and line-related adverse events and readmission to hospital. RESULTS: There were a total of 502 OPAT episodes over 24 months, with 407 episodes included in analyses. Following the introduction of the OPAT medical team, adherence to monitoring guidelines improved (OR 4.90, 95% CI 2.48 to 9.66); significantly fewer patients required readmission to hospital (OR 0.45, 95% CI 0.24 to 0.86) and there was a significant reduction in the proportion of patients receiving prolonged (>=7 days) OPAT (OR 0.67, 95% CI 0.45 to 0.99). CONCLUSION: The introduction of a formal medical team to HiTH demonstrated a positive clinical impact on OPAT patients' outcomes. These findings support the ongoing utility of medical governance in a nurse-led HiTH service. PMID- 28847880 TI - Diastematomyelia in a 3-year-old girl. PMID- 28847881 TI - Childhood bruising distribution observed from eight mechanisms of unintentional injury. AB - OBJECTIVE: To inform the assessment of described mechanisms of bruising in children. DESIGN: Prospective cross-sectional study. SETTING: The emergency department, and children in the local community. PATIENTS: Children aged 0-13 years with bruises from unintentional injuries. EXCLUSIONS: bleeding disorder, medication affecting coagulation or child protection concerns. INTERVENTIONS: Injury incidents were categorised into one of eight causal mechanisms (fall from<1 m, 1-2 m, fall from standing height or less and hitting an object during fall, stairs or impact, crush, sports or motor vehicle collision). MAIN OUTCOME MEASURES: Location, number and mechanism of bruising for each injury mechanism. RESULTS: 372 children had 559 injury incidents, resulting in 693 bruises; 85.2% of children were walking independently, with impact injuries and fall from standing height (including hitting an object) being the predominant mechanisms. A single bruise was observed in 81.7% of all incidents. Stair falls resulted in >=3 bruises only with falls involving >=10 steps (6/16). Bruising was rarely observed on the buttocks, upper arm, back of legs or feet. No bruises were seen in this dataset on ears, neck or genitalia. Petechial bruising was only noted in 1/293 unintentional incidents, involving a high-impact injury in a school-aged child. CONCLUSION: These findings have the potential to aid an assessment of the plausibility of the explanation given for a child with bruising. Certain bruise distributions were rarely observed, namely multiple bruises from a single mechanism, petechiae and bruising to the ears, neck or genitalia. PMID- 28847882 TI - Neurodevelopmental outcomes for high-risk neonates in a low-resource setting. AB - Worldwide, most neonates who survive prematurity and serious illness reside in low-resource settings where developmental outcome data and follow-up care are limited. This study aimed to assess in Fiji, a low-resource Pacific setting, prevalence and risk factors for moderate to severe neurodevelopmental impairment (NDI) in early childhood among high-risk neonates compared with controls. Retrospective cohort study comparing long-term outcomes for high-risk neonatal intensive care unit patients (n=149) compared with matched term, normal birth weight neonates (n=147) discharged from Colonial War Memorial Hospital between November 2008 and April 2010. NDI was defined as one or more of cerebral palsy, moderate to severe hearing or visual impairment, or global developmental delay using Bayley Scales of Infant and Toddler Development Third Edition (ie, score <70 in >=1 of cognitive, language or motor domains). At median (IQR) age 36.1 (28.3, 38.0) months, prevalence of moderate to severe NDI % (95% CI, n) in high risk and control groups was 12 (5 to 17, n=13) and 5 (2 to 12, n=5), respectively, an increased risk ratio (95% CI) of 2.7 (0.8 to 8.9). Median gestational age (weeks (median, IQR)) in the high-risk group was 37.5 (34-40) weeks. Among high-risk neonates, gestational age, birth weight, asphyxia, meningitis and/or respiratory distress were significantly associated with risk of NDI. Prevalence of NDI was high among this predominantly term high-risk neonatal cohort compared with controls. Results, including identified risk factors, inform efforts to strengthen quality of care and models of follow-up for high-risk neonates in this low-resource setting. PMID- 28847883 TI - A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes. AB - Mendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on genetic risk scoring for plasma metabolite levels, utilizing a pathway-based sensitivity analysis to control for nonspecific effects. We focused on 124 circulating metabolites that correlate with fasting glucose in the Erasmus Rucphen Family (ERF) study (n = 2,564) and tested the possible causal effect of each metabolite with glucose and type 2 diabetes and vice versa. We detected 14 paths with potential causal effects by MR, following pathway-based sensitivity analysis. Our results suggest that elevated plasma triglycerides might be partially responsible for increased glucose levels and type 2 diabetes risk, which is consistent with previous reports. Additionally, elevated HDL components, i.e., small HDL triglycerides, might have a causal role of elevating glucose levels. In contrast, large (L) and extra large (XL) HDL lipid components, i.e., XL-HDL cholesterol, XL-HDL-free cholesterol, XL-HDL phospholipids, L-HDL cholesterol, and L-HDL-free cholesterol, as well as HDL cholesterol seem to be protective against increasing fasting glucose but not against type 2 diabetes. Finally, we demonstrate that genetic predisposition to type 2 diabetes associates with increased levels of alanine and decreased levels of phosphatidylcholine alkyl-acyl C42:5 and phosphatidylcholine alkyl-acyl C44:4. Our MR results provide novel insight into promising causal paths to and from glucose and type 2 diabetes and underline the value of additional information from high-resolution metabolomics over classic biochemistry. PMID- 28847884 TI - Tbx15 Defines a Glycolytic Subpopulation and White Adipocyte Heterogeneity. AB - Tbx15 is a member of the T-box gene family of mesodermal developmental genes. We have recently shown that Tbx15 plays a critical role in the formation and metabolic programming of glycolytic myofibers in skeletal muscle. Tbx15 is also differentially expressed among white adipose tissue (WAT) in different body depots. In the current study, using three independent methods, we show that even within a single WAT depot, high Tbx15 expression is restricted to a subset of preadipocytes and mature white adipocytes. Gene expression and metabolic profiling demonstrate that the Tbx15Hi preadipocyte and adipocyte subpopulations of cells are highly glycolytic, whereas Tbx15Low preadipocytes and adipocytes in the same depot are more oxidative and less glycolytic. Likewise, in humans, expression of TBX15 in subcutaneous and visceral WAT is positively correlated with markers of glycolytic metabolism and inversely correlated with obesity. Furthermore, overexpression of Tbx15 is sufficient to reduce oxidative and increase glycolytic metabolism in cultured adipocytes. Thus, Tbx15 differentially regulates oxidative and glycolytic metabolism within subpopulations of white adipocytes and preadipocytes. This leads to a functional heterogeneity of cellular metabolism within WAT that has potential impact in the understanding of human metabolic diseases. PMID- 28847885 TI - Cardiovascular screening practices in US National Governing Bodies and National Paralympic Committees. PMID- 28847886 TI - Hypertension Control in Adults With Diabetes Mellitus and Recurrent Cardiovascular Events: Global Results From the Trial Evaluating Cardiovascular Outcomes With Sitagliptin. AB - Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan-Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP >=140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ~130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91-1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02-1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function. PMID- 28847887 TI - Hypertension, Diabetes Mellitus, and Excess Cardiovascular Risk: Importance of Baseline Systolic Blood Pressure. PMID- 28847888 TI - Unraveling the Role and Complexities of Inflammation in Hypertension. PMID- 28847889 TI - Cardiovascular Risk Associated With White-Coat Hypertension: Con Side of the Argument. PMID- 28847891 TI - Cardiovascular Risk Associated With White-Coat Hypertension: Pro Side of the Argument. PMID- 28847890 TI - Trends in the Prevalence, Awareness, Treatment, and Control of Hypertension Among Young Adults in the United States, 1999 to 2014. AB - Overall hypertension prevalence has not changed in the United States in recent decades although awareness, treatment, and control improved. However, hypertension epidemiology and its temporal trends may differ in younger adults compared with older adults. Our study included 41 331 participants >=18 years of age from 8 National Health and Nutrition Examination Surveys (1999-2014) and estimated temporal trends of hypertension, awareness, treatment, and control among young adults (age, 18-39 years) compared with middle-age (age, 40-59 years) and older adults (age, >=60 years). In 2013 to 2014, 7.3% of the US young adults had hypertension. During 1999 to 2014, young adults saw larger increases in hypertension awareness, treatment, and control than did older adults. However, all of these components of hypertension control were lower among young adults compared with middle-aged or older adults (74.7% younger versus 81.9% middle versus 88.4% older for awareness; 50.0% versus 70.3% versus 83.0% for treatment; and 40.2% versus 56.7% versus 54.4% for control). Worse hypertension awareness, treatment, and control in young adults overall were mostly driven by worse measures in young adult men compared with young adult women. More frequent healthcare visits by young adult women explained ~28% of the sex-related difference in awareness, 60% of the difference in treatment, and 52% of the difference in control. These findings suggest that improved access to and engagement in medical care might improve hypertension control in young adults, particularly young adult men, and reduce life-time cardiovascular risk. PMID- 28847892 TI - Biochemical Screening for Nonadherence Is Associated With Blood Pressure Reduction and Improvement in Adherence. AB - We hypothesized that screening for nonadherence to antihypertensive treatment using liquid chromatography-tandem mass spectrometry-based biochemical analysis of urine/serum has therapeutic applications in nonadherent hypertensive patients. A retrospective analysis of hypertensive patients attending specialist tertiary care centers was conducted in 2 European countries (United Kingdom and Czech Republic). Nonadherence to antihypertensive treatment was diagnosed using biochemical analysis of urine (United Kingdom) or serum (Czech Republic). These results were subsequently discussed with each patient, and data on follow-up clinic blood pressure (BP) measurements were collected from clinical files. Of 238 UK patients who underwent biochemical urine analysis, 73 were nonadherent to antihypertensive treatment. Their initial urinary adherence ratio (the ratio of detected to prescribed antihypertensive medications) increased from 0.33 (0-0.67) to 1 (0.67-1) between the first and the last clinic appointments. The observed increase in the urinary adherence ratio in initially nonadherent UK patients was associated with the improved BP control; by the last clinic appointment, systolic and diastolic BPs were ~19.5 and 7.5 mm Hg lower than at baseline (P=0.001 and 0.009, respectively). These findings were further corroborated in 93 nonadherent hypertensive patients from Czech Republic-their average systolic and diastolic BPs dropped by ~32.6 and 17.4 mm Hg, respectively (P<0.001), on appointments after the biochemical analysis. Our data show that nonadherent hypertensive patients respond to liquid chromatography-tandem mass spectrometry-based biochemical analysis with improved adherence and significant BP drop. Such repeated biochemical analyses should be considered as a therapeutic approach in nonadherent hypertensive patients. PMID- 28847893 TI - Angiogenic Markers Predict Pregnancy Complications and Prolongation in Preeclampsia: Continuous Versus Cutoff Values. AB - To assess the incremental value of a single determination of the serum levels of sFlt-1 (soluble Fms-like tyrosine kinase 1) and PlGF (placental growth factor) or their ratio, without using cutoff values, for the prediction of maternal and fetal/neonatal complications and pregnancy prolongation, 620 women with suspected/confirmed preeclampsia, aged 18 to 48 years, were included in a prospective, multicenter, observational cohort study. Women had singleton pregnancies and a median pregnancy duration of 34 (range, 20-41) weeks. Complications occurred in 118 women and 248 fetuses. The median duration between admission and delivery was 12 days. To predict prolongation, PlGF showed the highest incremental value (R2=0.72) on top of traditional predictors (gestational age at inclusion, diastolic blood pressure, proteinuria, creatinine, uric acid, alanine transaminase, lactate dehydrogenase, and platelets) compared with R2=0.53 for the traditional predictors only. sFlt-1 showed the highest value to discriminate women with and without maternal complications (C-index=0.83 versus 0.72 for the traditional predictors only), and the sFlt-1/PlGF ratio showed the highest value to discriminate fetal/neonatal complications (C-index=0.86 versus 0.78 for the traditional predictors only). Applying previously suggested cutoff values for the sFlt-1/PlGF ratio yielded lower incremental values than applying continuous values. In conclusion, sFlt-1 and PlGF are strong and independent predictors for days until delivery along with maternal and fetal/neonatal complications on top of the traditional criteria. Their use as continuous variables (instead of applying cutoff values for different gestational ages) should now be tested in a prospective manner, making use of an algorithm calculating the risk of an individual woman with suspected/confirmed preeclampsia to develop complications. PMID- 28847894 TI - Evidence for Prohypertensive, Proinflammatory Effect of Interleukin-10 During Chronic High Salt Intake in the Condition of Elevated Angiotensin II Level. AB - IL-10 (interleukin-10) has been suggested to play a protective role in angiotensin II (AngII)-induced cardiovascular disorders. This study examined the role of endogenous IL-10 in salt-sensitive hypertension and renal injury induced by AngII. Responses to chronic AngII (400 ng/min per kilogram body weight; osmotic minipump) infusion were evaluated in IL-10 gene knockout mice fed with either normal salt diet (0.3% NaCl) or high salt (HS; 4% NaCl) diet, and these responses were compared with those in wild-type mice. Normal salt diets or HS diets were given alone for the first 2 weeks and then with AngII treatment for an additional 2 weeks (n=6 in each group). Arterial pressure was continuously monitored by implanted radio-telemetry, and a 24-hour urine collection was performed by metabolic cages on the last day of the experimental period. Basal mean arterial pressure was lower in IL-10 gene knockout mice than in wild-type (98+/-3 versus 113+/-3 mm Hg) mice. Mean arterial pressure responses to normal salt/HS alone or to the AngII+normal salt treatment were similar in both strains. However, the increase in mean arterial pressure induced by the AngII+HS treatment was significantly lower in IL-10 gene knockout mice (15+/-5% versus 37+/-3%) compared with wild-type mice. Renal tissue endothelial nitric oxide synthase expression (~3-folds) and urinary excretion of nitric oxide metabolites, nitrate/nitrite (1.2+/-0.1 versus 0.2+/-0.02 umol/L/24 hours) were higher in IL 10 gene knockout mice compared with wild-type mice. These results indicate that an increase in nitric oxide production helps to mitigate salt-sensitive hypertension induced by AngII and suggest that a compensatory interaction between IL-10 and nitric oxide exists in modulating AngII-induced responses during HS intake. PMID- 28847896 TI - Computed Tomography or Functional Stress Testing for the Prediction of Risk: Can I Have My Cake and Eat It? PMID- 28847895 TI - Prognostic Value of Coronary Artery Calcium in the PROMISE Study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain). AB - BACKGROUND: Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals. However, limited data exist as to how CAC compares with functional testing (FT) in estimating prognosis in symptomatic patients. METHODS: In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain (or dyspnea) and intermediate pretest probability for obstructive coronary artery disease were randomized to FT (exercise electrocardiography, nuclear stress, or stress echocardiography) or anatomic testing. We evaluated those who underwent CAC testing as part of the anatomic evaluation (n=4209) and compared that with results of FT (n=4602). We stratified CAC and FT results as normal or mildly, moderately, or severely abnormal (for CAC: 0, 1-99 Agatston score [AS], 100-400 AS, and >400 AS, respectively; for FT: normal, mild=late positive treadmill, moderate=early positive treadmill or single vessel ischemia, and severe=large ischemic region abnormality). The primary end point was all-cause death, myocardial infarction, or unstable angina hospitalization over a median follow-up of 26.1 months. Cox regression models were used to calculate hazard ratios (HRs) and C statistics to determine predictive and discriminatory values. RESULTS: Overall, the distribution of normal or mildly, moderately, or severely abnormal test results was significantly different between FT and CAC (FT: normal, n=3588 [78.0%]; mild, n=432 [9.4%]; moderate, n=217 [4.7%]; severe, n=365 [7.9%]; CAC: normal, n=1457 [34.6%]; mild, n=1340 [31.8%]; moderate, n=772 [18.3%]; severe, n=640 [15.2%]; P<0.0001). Moderate and severe abnormalities in both arms robustly predicted events (moderate: CAC: HR, 3.14; 95% confidence interval, 1.81-5.44; and FT: HR, 2.65; 95% confidence interval, 1.46-4.83; severe: CAC: HR, 3.56; 95% confidence interval, 1.99-6.36; and FT: HR, 3.88; 95% confidence interval, 2.58-5.85). In the CAC arm, the majority of events (n=112 of 133, 84%) occurred in patients with any positive CAC test (score >0), whereas fewer than half of events occurred in patients with mildly, moderately, or severely abnormal FT (n=57 of 132, 43%; P<0.001). In contrast, any abnormality on FT was significantly more specific for predicting events (78.6% for FT versus 35.2% for CAC; P<0.001). Overall discriminatory ability in predicting the primary end point of mortality, nonfatal myocardial infarction, and unstable angina hospitalization was similar and fair for both CAC and FT (C statistic, 0.67 versus 0.64). Coronary computed tomographic angiography provided significantly better prognostic information compared with FT and CAC testing (C index, 0.72). CONCLUSIONS: Among stable outpatients presenting with suspected coronary artery disease, most patients experiencing clinical events have measurable CAC at baseline, and fewer than half have any abnormalities on FT. However, an abnormal FT was more specific for cardiovascular events, leading to overall similarly modest discriminatory abilities of both tests. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01174550. PMID- 28847897 TI - Derivation and Validation of a Novel Right-Sided Heart Failure Model After Implantation of Continuous Flow Left Ventricular Assist Devices: The EUROMACS (European Registry for Patients with Mechanical Circulatory Support) Right-Sided Heart Failure Risk Score. AB - BACKGROUND: The aim of the study was to derive and validate a novel risk score for early right-sided heart failure (RHF) after left ventricular assist device implantation. METHODS: The EUROMACS (European Registry for Patients with Mechanical Circulatory Support) was used to identify adult patients undergoing continuous-flow left ventricular assist device implantation with mainstream devices. Eligible patients (n=2988) were randomly divided into derivation (n=2000) and validation (n=988) cohorts. The primary outcome was early (<30 days) severe postoperative RHF, defined as receiving short- or long-term right-sided circulatory support, continuous inotropic support for >=14 days, or nitric oxide ventilation for >=48 hours. The secondary outcome was all-cause mortality and length of stay in the intensive care unit. Covariates found to be associated with RHF (exploratory univariate P<0.10) were entered into a multivariable logistic regression model. A risk score was then generated using the relative magnitude of the exponential regression model coefficients of independent predictors at the last step after checking for collinearity, likelihood ratio test, c index, and clinical weight at each step. RESULTS: A 9.5-point risk score incorporating 5 variables (Interagency Registry for Mechanically Assisted Circulatory Support class, use of multiple inotropes, severe right ventricular dysfunction on echocardiography, ratio of right atrial/pulmonary capillary wedge pressure, hemoglobin) was created. The mean scores in the derivation and validation cohorts were 2.7+/-1.9 and 2.6+/-2.0, respectively (P=0.32). RHF in the derivation cohort occurred in 433 patients (21.7%) after left ventricular assist device implantation and was associated with a lower 1-year (53% versus 71%; P<0.001) and 2-year (45% versus 58%; P<0.001) survival compared with patients without RHF. RHF risk ranged from 11% (low risk score 0-2) to 43.1% (high risk score >4; P<0.0001). Median intensive care unit stay was 7 days (interquartile range, 4-15 days) versus 24 days (interquartile range, 14-38 days) in patients without versus with RHF, respectively (P<0.001). The c index of the composite score was 0.70 in the derivation and 0.67 in the validation cohort. The EUROMACS-RHF risk score outperformed (P<0.0001) previously published scores and known individual echocardiographic and hemodynamic markers of RHF. CONCLUSIONS: This novel EUROMACS-RHF risk score outperformed currently known risk scores and clinical predictors of early postoperative RHF. This novel score may be useful for tailored risk-based clinical assessment and management of patients with advanced HF evaluated for ventricular assist device therapy. PMID- 28847898 TI - When VAD Things Happen to Good People. PMID- 28847899 TI - The Tumor Necrosis Factor Family: Family Conventions and Private Idiosyncrasies. AB - The tumor necrosis factor (TNF) cytokine family and the TNF/nerve growth factor (NGF) family of their cognate receptors together control numerous immune functions, as well as tissue-homeostatic and embryonic-development processes. These diverse functions are dictated by both shared and distinct features of family members, and by interactions of some members with nonfamily ligands and coreceptors. The spectra of their activities are further expanded by the occurrence of the ligands and receptors in both membrane-anchored and soluble forms, by "re-anchoring" of soluble forms to extracellular matrix components, and by signaling initiation via intracellular domains (IDs) of both receptors and ligands. Much has been learned about shared features of the receptors as well as of the ligands; however, we still have only limited knowledge of the mechanistic basis for their functional heterogeneity and for the differences between their functions and those of similarly acting cytokines of other families. PMID- 28847900 TI - Making Connections: Guidance Cues and Receptors at Nonneural Cell-Cell Junctions. AB - The field of axon guidance was revolutionized over the past three decades by the identification of highly conserved families of guidance cues and receptors. These proteins are essential for normal neural development and function, directing cell and axon migration, neuron-glial interactions, and synapse formation and plasticity. Many of these genes are also expressed outside the nervous system in which they influence cell migration, adhesion and proliferation. Because the nervous system develops from neural epithelium, it is perhaps not surprising that these guidance cues have significant nonneural roles in governing the specialized junctional connections between cells in polarized epithelia. The following review addresses roles for ephrins, semaphorins, netrins, slits and their receptors in regulating adherens, tight, and gap junctions in nonneural epithelia and endothelia. PMID- 28847901 TI - The Future of the Cytokine Discipline. AB - The study of cytokines has evolved from the detection of functional activities present in tissue culture supernatants to the characterization of the three dimensional molecular structures of the cytokines and their receptors. Investigators studying cytokines need to have specialized expertise in using cytokine assays, assessing their receptor interactions, signal transduction, gene activation, and biological effects, and in the therapeutic utilization of agonists and antagonists. Cytokinology can therefore be considered a discipline. In this article, I have considered studies leading to the identification of novel cytokines, potential producers of cytokine mimics such as viruses and the microbiome, and the complex interactions of the cytokine network with our vital functions. Our ever-increasing success in using cytokines and, in particular, cytokine inhibitors therapeutically suggest that cytokinology will eventually become an independent discipline. PMID- 28847903 TI - T Helper Cell Differentiation, Heterogeneity, and Plasticity. AB - Naive CD4 T cells, on activation, differentiate into distinct T helper (Th) subsets that produce lineage-specific cytokines. By producing unique sets of cytokines, effector Th subsets play critical roles in orchestrating immune responses to a variety of infections and are involved in the pathogenesis of many inflammatory diseases including autoimmunity, allergy, and asthma. The differentiation of Th cells relies on the strength of T-cell receptor (TCR) signaling and signals triggered by polarizing cytokines that activate and/or up regulate particular transcription factors. Several lineage-specific master transcription factors dictate Th cell fates and functions. Although these master regulators cross-regulate each other, their expression can be dynamic. Sometimes, they are even coexpressed, resulting in massive Th-cell heterogeneity and plasticity. Similar regulation mediated by these master regulators is also found in innate lymphoid cells (ILCs) that are innate counterparts of Th cells. PMID- 28847904 TI - Bone Remodeling and the Microbiome. AB - Exposed surfaces of mammals are colonized with 100 trillion indigenous bacteria, fungi, and viruses, creating a diverse ecosystem known as the microbiome. The gastrointestinal tract harbors the greatest numbers of these microorganisms, which regulate human nutrition, metabolism, and immune system function. Moreover, the intestinal microbiota contains pro- and anti-inflammatory products that modulate immune responses and may play a role in maintaining gut barrier function. Therefore, the community composition of the microbiota has profound effects on the immune status of the host and impacts the development and/or progression of inflammatory diseases. Accordingly, numerous studies have shown differences in the microbiota of patients with and without a given inflammatory condition. There is now strong evidence that the gut microbiome regulates bone homeostasis in health and disease, and that prebiotic and probiotics protect against bone loss. Herein, the evidence supporting the role of the microbiota and the effects of prebiotic and probiotics will be reviewed. PMID- 28847905 TI - PI3K: A Crucial Piece in the RAS Signaling Puzzle. AB - RAS proteins are key signaling switches essential for control of proliferation, differentiation, and survival of eukaryotic cells. RAS proteins are mutated in 30% of human cancers. In addition, mutations in upstream or downstream signaling components also contribute to oncogenic activation of the pathway. RAS proteins exert their functions through activation of several signaling pathways and dissecting the contributions of these effectors in normal cells and in cancer is an ongoing challenge. In this review, we summarize our current knowledge about how RAS regulates type I phosphatidylinositol 3-kinase (PI3K), one of the main RAS effectors. RAS signaling through PI3K is necessary for normal lymphatic vasculature development and for RAS-induced transformation in vitro and in vivo, especially in lung cancer, where it is essential for tumor initiation and necessary for tumor maintenance. PMID- 28847902 TI - Beyond Cell-Cell Adhesion: Sensational Cadherins for Hearing and Balance. AB - Cadherins form a large family of proteins often involved in calcium-dependent cellular adhesion. Although classical members of the family can provide a physical bond between cells, a subset of special cadherins use their extracellular domains to interlink apical specializations of single epithelial sensory cells. Two of these cadherins, cadherin-23 (CDH23) and protocadherin-15 (PCDH15), form extracellular "tip link" filaments that connect apical bundles of stereocilia on hair cells essential for inner-ear mechanotransduction. As these bundles deflect in response to mechanical stimuli from sound or head movements, tip links gate hair-cell mechanosensitive channels to initiate sensory perception. Here, we review the unusual and diverse structural properties of these tip-link cadherins and the functional significance of their deafness related missense mutations. Based on the structural features of CDH23 and PCDH15, we discuss the elasticity of tip links and models that bridge the gap between the nanomechanics of cadherins and the micromechanics of hair-cell bundles during inner-ear mechanotransduction. PMID- 28847906 TI - Immunological effects among workers who handle engineered nanoparticles. AB - OBJECTIVE: To determine whether exposure of workers handling engineered nanoparticles (ENPs) may result in increased inflammation and changes in lung function. METHODS: A prospective panel study compared changes in several markers of inflammation for ENP handling and non-ENP handling control workers. Nanoparticle exposure was measured during ENP handling and for controls. Lung function, fraction of exhaled nitric oxide (FeNO), C-reactive protein (CRP), blood cell counts and several serum cytokines were measured at baseline, at the end of the shift and at the end of the working week. RESULTS: Nanoparticle exposure was not higher when ENPs were being handled; nanoparticle counts were higher in offices and in ambient air than in laboratories. There were no differences at baseline in lung function, FeNO, haemoglobin, platelet, white cell counts or CRP levels between those who handled nanoparticles and those who did not, with or without asthmatic participants. There were statistically significant increases in sCD40 and sTNFR2 over the working day for those who handled ENPs. The changes were larger and statistically significant over the working week and sCD62P also showed a statistically significant difference. The changes were slightly smaller and less likely to be statistically significant for atopic than for non-atopic participants. CONCLUSIONS: Even at low ENP exposure, increases in three cytokines were significant over the week for those who handled nanoparticles, compared with those who did not. However, exposure to low and transient levels of nanoparticles was insufficient, to trigger measurable changes in spirometry, FeNO, CRP or blood cell counts. PMID- 28847907 TI - Time to Rethink Our Approach to Patient-Reported Outcome Measures for ESRD. PMID- 28847908 TI - Introduction to Patient-Reported Outcomes Perspectives Series. PMID- 28847909 TI - Considerations and Challenges in Selecting Patient-Reported Outcome Measures for Clinical Trials in Nephrology. PMID- 28847912 TI - A Novel Index of Remodeling in Hypertensive Heart Disease. PMID- 28847910 TI - Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes. AB - OBJECTIVE: To examine the effect of pioglitazone on myocardial insulin sensitivity and left ventricular (LV) function in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Twelve subjects with T2D and 12 with normal glucose tolerance received a euglycemic insulin clamp. Myocardial glucose uptake (MGU) and myocardial perfusion were measured with [18F]fluoro-2-deoxy-d-glucose and [15O]H2O positron emission tomography before and after 24 weeks of pioglitazone treatment. Myocardial function and transmitral early diastolic relation/atrial contraction (E/A) flow ratio were measured with magnetic resonance imaging. RESULTS: Pioglitazone reduced HbA1c by 0.9%; decreased systolic and diastolic blood pressure by 7 +/- 2 and 7 +/- 2 mmHg, respectively (P < 0.05); and increased whole-body insulin-stimulated glucose uptake by 71% (3.4 +/- 1.3 to 5.8 +/- 2.1 mg/kg . min; P < 0.01) in subjects with T2D. Pioglitazone enhanced MGU by 75% (0.24 +/- 0.14 to 0.42 +/- 0.13 MUmol/min . g; P < 0.01) and myocardial perfusion by 16% (0.95 +/- 0.16 to 1.10 +/- 0.25 mL/min . g; P < 0.05). Measures of diastolic function, E/A ratio (1.04 +/- 0.3 to 1.25 +/- 0.4) and peak LV filling rate (349 +/- 107 to 433 +/- 99 mL/min), both increased (P < 0.01). End-systolic volume, end-diastolic volume, peak LV ejection rate, and cardiac output trended to increase (P not significant), whereas the ejection fraction (61 +/- 6 to 66 +/- 7%) and stroke volume increased significantly (71 +/ 20 to 80 +/- 20 L/min; both P < 0.05). CONCLUSIONS: Pioglitazone improves whole body and myocardial insulin sensitivity, LV diastolic function, and systolic function in T2D. Improved myocardial insulin sensitivity and diastolic function are strongly correlated. PMID- 28847911 TI - Novel Index of Maladaptive Myocardial Remodeling in Hypertension. AB - BACKGROUND: Hypertensive left ventricular hypertrophy (HTN-LVH) is a leading cause of heart failure. Conventional patterns of cardiac geometry do not adequately risk-stratify patients with HTN-LVH. Using cardiovascular magnetic resonance, we developed a novel Remodeling Index (RI) that was designed to detect an exaggerated hypertrophic response to hypertension and tested its potential to risk-stratify hypertensive patients. METHODS AND RESULTS: The RI was derived using LaPlace's Law (), and normal RI ranges were established in 180 healthy volunteers. The utility of the RI was examined in 256 asymptomatic hypertensive patients and 10 patients with heart failure with preserved ejection fraction. Hypertensive patients underwent multimodal cardiac assessment: contrast-enhanced cardiovascular magnetic resonance, echocardiograms, 24-hour blood pressure monitoring, and cardiac biomarkers (high-sensitivity cardiac troponins, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and galectin-3). Blood pressure accounted for only 20% of the variance observed in LV mass. Although there was no association between blood pressure and myocardial fibrosis, LV mass was independently associated with fibrosis. Compared with hypertensive patients without LVH (n=191; 74.6%) and those with HTN-LVH and normal RI (n=50; 19.5%), patients with HTN-LVH and low RI (HTN-LVH/low RI; n=15, 5.9%) had an amplified myocardial response: elevated indexed LV masses (83+/-24 g/m2), more fibrosis (73%), and higher biomarkers of myocardial injury and dysfunction (P<0.05 for all). RI was similar in HTN-LVH/low RI and heart failure with preserved ejection fraction (4.1 [3.4-4.5] versus 3.7 [3.4-4.0], respectively; P=0.15). CONCLUSIONS: We suggest that RI provides an approach for stratifying hypertensive patients and is suitable for testing in other disease cohorts to assess its clinical utility. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02670031. PMID- 28847913 TI - Vulnerabilities to Health Disparities and Statin Use in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study. AB - BACKGROUND: Statins may be underutilized in certain vulnerable populations, but the effect of cumulative vulnerabilities within 1 individual is not well described. We sought to determine the likelihood of receiving statins with an increasing number of vulnerabilities in an individual, after controlling for factors known to influence health services utilization. METHODS AND RESULTS: We identified 18 216 participants from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study who had a statin indication or who were taking statins, as verified by pill bottle review. Statin use was assessed with respect to 5 major vulnerability domains alone and in combination: older age, black race, female sex, high area-level poverty, and lack of health insurance. The study included 5286 white men, 4180 black men, 2791 white women, and 4194 black women; 5.6% of the sample had no vulnerabilities, 20.6% had 1 vulnerability, 29.2% had 2 vulnerabilities, 27.3% had 3 vulnerabilities, and 17.3% had 4 or 5 vulnerabilities. All race-sex groups were less likely than white men to use statins; prevalence of use was 0.80 in black women with reference to white men (P<0.0001). In both unadjusted and adjusted models, as the number of vulnerabilities increased, statin use steadily decreased. After adjusting for factors that influence health services utilization, compared with those without any vulnerabilities, statin use prevalence was 0.91, 0.83, 0.74 and 0.68 (P<0.0001) in those with 1, 2, 3, and 4 or 5 vulnerabilities, respectively. CONCLUSIONS: Participants with more simultaneously occurring vulnerabilities experienced the greatest disparities in statin use. Black women and those without health insurance were at particularly high risk of underutilization. PMID- 28847914 TI - Subclinical Cerebrovascular Disease Increases the Risk of Incident Stroke and Mortality: The Northern Manhattan Study. AB - BACKGROUND: The effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples. METHODS AND RESULTS: Stroke free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71+/-9 years, 60% women, 15% non-Hispanic white, 17% non-Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6-9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1-1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0-1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1-4.4). White and black but not Hispanic participants had increased stroke risk (P<0.05 for heterogeneity for all and ischemic stroke). Those with subclinical brain infarct had greater risk for all stroke types (HR: 1.9; 95% CI, 1.1-3.3), ischemic stroke (HR: 2.2; 95% CI, 1.3 3.8), lacunar (HR: 4.0; 95% CI, 1.3-12.3), and cryptogenic stroke (HR: 3.6; 95% CI, 1.0-12.7), without significant heterogeneity across race/ethnic groups. Greater white matter hyperintensity volume increased both vascular (HR: 1.3; 95% CI, 1.1-1.7) and nonvascular (HR: 1.2; 95% CI, 1.0-1.5) mortality among Hispanic and white but not black participants (P=0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only (HR: 2.9; 95% CI, 1.4-5.8). CONCLUSIONS: In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type. PMID- 28847916 TI - Neurological letter from Calcutta. PMID- 28847915 TI - Arterial Stiffness Is Associated With Cytomegalovirus-Specific Senescent CD8+ T Cells. AB - BACKGROUND: Arterial stiffness is a well-known predictor of future cardiovascular events. Search for the underlying mechanism of arterial stiffening is still under way. We investigated the relationship between arterial stiffness and cytomegalovirus infection in terms of T-cell senescence. METHODS AND RESULTS: Arterial stiffness was evaluated using pulse wave velocity measurements in 415 Koreans (age 59+/-12 years). We also investigated the frequency of CD57+ or CD28null senescent T cells in peripheral blood lymphocytes and analyzed which immune parameters were correlated with pulse wave velocity. Furthermore, cytomegalovirus-specific T cells were stimulated with overlapping peptides covering pp65 protein, and T-cell function was evaluated by intracellular cytokine staining of interferon-gamma, tumor necrosis factor-alpha, and CD107a. In a multivariate analysis, it was found that the frequency of CD57+ cells in the CD8+ T-cell subset was independently correlated with pulse wave velocity after adjusting for traditional cardiovascular risk factors such as age, sex, diabetes mellitus history, smoking history, body mass index, blood pressure, serum creatinine, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. Cytomegalovirus pp65-specific T cells were more frequently observed in the CD8+CD57+ population than in the CD8+CD57- population, and multivariate analysis revealed that the frequency of cytomegalovirus pp65-specific interferon gamma+, tumor necrosis factor-alpha+, or CD107a+ cells in the CD8+ T-cell subset was independently correlated with pulse wave velocity as well. CONCLUSIONS: We demonstrate that arterial stiffness is associated with senescent CD57+ T cells and CMV pp65-specific T cells in the CD8+ T-cell subset. The precise role of cytomegalovirus-specific, senescent T cells in vascular aging needs to be further investigated. PMID- 28847917 TI - Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma. AB - This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multikinase inhibitor ponatinib in a patient-derived xenograft model of glioblastoma (GBM). Efficacy studies in GBM6 flank (heterotopic) and intracranial (orthotopic) models showed that ponatinib is effective in the flank but not in the intracranial model, despite a relatively high brain-to-plasma ratio. In vitro binding studies indicated that flank tumor had a higher free (unbound) drug fraction than normal brain. The total and free drug concentrations, along with the tissue-to-plasma ratio (Kp) and its unbound derivative (Kp,uu), were consistently higher in the flank tumor than the normal brain at 1 and 6 hours after a single dose in GBM6 flank xenografts. In the orthotopic xenografts, the intracranial tumor core displayed higher Kp and Kp,uu values compared with the brain-around-tumor (BAT). The free fractions and the total drug concentrations, hence free drug concentrations, were consistently higher in the core than in the BAT at 1 and 6 hours postdose. The delivery disadvantages in the brain and BAT were further evidenced by the low total drug concentrations in these areas that did not consistently exceed the in vitro cytotoxic concentration (IC50). Taken together, the regional differences in free drug exposure across the intracranial tumor may be responsible for compromising efficacy of ponatinib in orthotopic GBM6. PMID- 28847918 TI - Discovering novel pharmacogenomic biomarkers by imputing drug response in cancer patients from large genomics studies. AB - Obtaining accurate drug response data in large cohorts of cancer patients is very challenging; thus, most cancer pharmacogenomics discovery is conducted in preclinical studies, typically using cell lines and mouse models. However, these platforms suffer from serious limitations, including small sample sizes. Here, we have developed a novel computational method that allows us to impute drug response in very large clinical cancer genomics data sets, such as The Cancer Genome Atlas (TCGA). The approach works by creating statistical models relating gene expression to drug response in large panels of cancer cell lines and applying these models to tumor gene expression data in the clinical data sets (e.g., TCGA). This yields an imputed drug response for every drug in each patient. These imputed drug response data are then associated with somatic genetic variants measured in the clinical cohort, such as copy number changes or mutations in protein coding genes. These analyses recapitulated drug associations for known clinically actionable somatic genetic alterations and identified new predictive biomarkers for existing drugs. PMID- 28847919 TI - The Essential Genome of Burkholderia cenocepacia H111. AB - The study of the minimum set of genes required to sustain life is a fundamental question in biological research. Recent studies on bacterial essential genes suggested that between 350 and 700 genes are essential to support autonomous bacterial cell growth. Essential genes are of interest as potential new antimicrobial drug targets; hence, our aim was to identify the essential genome of the cystic fibrosis (CF) isolate Burkholderia cenocepacia H111. Using a transposon sequencing (Tn-Seq) approach, we identified essential genes required for growth in rich medium under aerobic and microoxic conditions as well as in a defined minimal medium with citrate as a sole carbon source. Our analysis suggests that 398 genes are required for autonomous growth in rich medium, a number that represents only around 5% of the predicted genes of this bacterium. Five hundred twenty-six genes were required to support growth in minimal medium, and 434 genes were essential under microoxic conditions (0.5% O2). A comparison of these data sets identified 339 genes that represent the minimal set of essential genes required for growth under all conditions tested and can be considered the core essential genome of B. cenocepacia H111. The majority of essential genes were found to be located on chromosome 1, and few such genes were located on chromosome 2, where most of them were clustered in one region. This gene cluster is fully conserved in all Burkholderia species but is present on chromosome 1 in members of the closely related genus Ralstonia, suggesting that the transfer of these essential genes to chromosome 2 in a common ancestor contributed toward the separation of the two genera.IMPORTANCE Transposon sequencing (Tn-Seq) is a powerful method used to identify genes that are essential for autonomous growth under various conditions. In this study, we have identified a set of "core essential genes" that are required for growth under multiple conditions, and these genes represent potential antimicrobial targets. We also identified genes specifically required for growth under low-oxygen and nutrient-limited environments. We generated conditional mutants to verify the results of our Tn-Seq analysis and demonstrate that one of the identified genes was not essential per se but was an artifact of the construction of the mutant library. We also present verified examples of genes that were not truly essential but, when inactivated, showed a growth defect. These examples have identified so far-underestimated shortcomings of this powerful method. PMID- 28847920 TI - Salmonella FraE, an asparaginase homolog, contributes to fructose-asparagine but not asparagine utilization. AB - Salmonella enterica can utilize fructose-asparagine (F-Asn) as a carbon and nitrogen source. This unusual capability has been attributed to five genes in the fra locus. Previously, we determined that mutations in fraB (deglycase), fraD (kinase), or fraA (transporter) eliminated the ability of Salmonella to grow on F Asn while a mutation in fraE allowed partial growth. We hypothesized that FraE, a putative periplasmic fructose-asparaginase, converts F-Asn to NH4+ and fructose aspartate (F-Asp). FraA could then transport F-Asp into the cytoplasm for subsequent catabolism. Here, we report that growth of the fraE mutant on F-Asn is caused by a partially redundant activity provided by AnsB, a periplasmic asparaginase. Indeed, a fraE ansB double mutant is unable to grow on F-Asn. Moreover, biochemical assays using periplasmic extracts of mutants that only express FraE or AnsB confirmed that each of these enzymes convert F-Asn to F-Asp and NH4+ However, FraE does not contribute to growth on asparagine. We tested and confirmed the hypothesis that a fraE ansB mutant can grow on F-Asp, while mutants lacking fraA, fraD, or fraB cannot. This finding provides strong evidence that FraA transports F-Asp, but not F-Asn, from the periplasm to the cytoplasm. Previously, we determined that F-Asn is toxic to a fraB mutant due to the accumulation of the FraB substrate, 6-P-F-Asp. Here we found that, as expected, a fraB mutant is inhibited by F-Asp as well. Collectively, these findings contribute to a better understanding of F-Asn utilization by SalmonellaImportanceSalmonella is so far the only organism known to be able to utilize fructose-asparagine (F-Asn) as a nutrient. We recently reported that disruption of a deglycase enzyme in the F-Asn utilization pathway inhibits the growth of Salmonella in mice, and thereby recognized that this pathway represents a novel and specific drug target. Here, we characterize the first step in the pathway wherein FraE hydrolyzes F-Asn to release NH4+ and F-Asp in the periplasm of the cell. A fraE mutant continues to grow slowly on F-Asn due to an asparaginase activity encoded by ansB. PMID- 28847921 TI - A Bacterial Multidomain NAD-Independent d-Lactate Dehydrogenase Utilizes Flavin Adenine Dinucleotide and Fe-S Clusters as Cofactors and Quinone as an Electron Acceptor for d-Lactate Oxidization. AB - Bacterial membrane-associated NAD-independent d-lactate dehydrogenase (Fe-S d iLDH) oxidizes d-lactate into pyruvate. A sequence analysis of the enzyme reveals that it contains an Fe-S oxidoreductase domain in addition to a flavin adenine dinucleotide (FAD)-containing dehydrogenase domain, which differs from other typical d-iLDHs. Fe-S d-iLDH from Pseudomonas putida KT2440 was purified as a His tagged protein and characterized in detail. This monomeric enzyme exhibited activities with l-lactate and several d-2-hydroxyacids. Quinone was shown to be the preferred electron acceptor of the enzyme. The two domains of the enzyme were then heterologously expressed and purified separately. The Fe-S cluster-binding motifs predicted by sequence alignment were preliminarily verified by site directed mutagenesis of the Fe-S oxidoreductase domain. The FAD-containing dehydrogenase domain retained 2-hydroxyacid-oxidizing activity, although it decreased compared to the full Fe-S d-iLDH. Compared to the intact enzyme, the FAD-containing dehydrogenase domain showed increased catalytic efficiency with cytochrome c as the electron acceptor, but it completely lost the ability to use coenzyme Q10 Additionally, the FAD-containing dehydrogenase domain was no longer associated with the cell membrane, and it could not support the utilization of d lactate as a carbon source. Based on the results obtained, we conclude that the Fe-S oxidoreductase domain functions as an electron transfer component to facilitate the utilization of quinone as an electron acceptor by Fe-S d-iLDH, and it helps the enzyme associate with the cell membrane. These functions make the Fe S oxidoreductase domain crucial for the in vivo d-lactate utilization function of Fe-S d-iLDH.IMPORTANCE Lactate metabolism plays versatile roles in most domains of life. Lactate utilization processes depend on certain enzymes to oxidize lactate to pyruvate. In recent years, novel bacterial lactate-oxidizing enzymes have been continually reported, including the unique NAD-independent d-lactate dehydrogenase that contains an Fe-S oxidoreductase domain besides the typical flavin-containing domain (Fe-S d-iLDH). Although Fe-S d-iLDH is widely distributed among bacterial species, the investigation of it is insufficient. Fe S d-iLDH from Pseudomonas putida KT2440, which is the major d-lactate-oxidizing enzyme for the strain, might be a representative of this type of enzyme. A study of it will be helpful in understanding the detailed mechanisms underlying the lactate utilization processes. PMID- 28847922 TI - Maintenance of microbial cooperation mediated by public goods in single and multiple traits scenarios. AB - Microbes often form densely populated communities, which favor competitive and cooperative interactions. Cooperation among bacteria often occurs through the production of metabolically costly molecules produced by certain individuals that become available to other neighboring individuals, called public goods. This type of cooperation is susceptible to exploitation, since non-producers of a public good can benefit from it while saving the cost of its production (cheating), gaining a fitness advantage over producers (cooperators). Thus, in mixed cultures, cheaters can increase in frequency in the population, relative to cooperators. Sometimes, and as predicted by simple game-theoretic arguments, such increase in the frequency of cheaters causes loss of the cooperative traits by exhaustion of the public goods, eventually leading to a collapse of the entire population. In other cases, however, both cooperators and cheaters remain in coexistence. This raises the question of how cooperation is maintained in microbial populations. Several strategies to prevent cheating have been described involving a single trait and a unique environmental constraint. In this review, we describe current knowledge on the evolutionary stability of microbial cooperation, discussing recent discoveries describing the mechanisms operating in multiple traits and multiple constraints settings. We conclude with a consideration of the consequences of these complex interactions, and we briefly discuss the potential role of social interactions involving multiple traits and multiple environmental constraints in the evolution of specialization and division of labor in microbes. PMID- 28847923 TI - Ferric Uptake Regulator Fur Is Conditionally Essential in Pseudomonas aeruginosa. AB - In Pseudomonas aeruginosa, the ferric uptake regulator (Fur) protein controls both metabolism and virulence in response to iron availability. Differently from other bacteria, attempts to obtain fur deletion mutants of P. aeruginosa failed, leading to the assumption that Fur is an essential protein in this bacterium. By investigating a P. aeruginosa conditional fur mutant, we demonstrate that Fur is not essential for P. aeruginosa growth in liquid media, biofilm formation, and pathogenicity in an insect model of infection. Conversely, Fur is essential for growth on solid media since Fur-depleted cells are severely impaired in colony formation. Transposon-mediated random mutagenesis experiments identified pyochelin siderophore biosynthesis as a major cause of the colony growth defect of the conditional fur mutant, and deletion mutagenesis confirmed this evidence. Impaired colony growth of pyochelin-proficient Fur-depleted cells does not depend on oxidative stress, since Fur-depleted cells do not accumulate higher levels of reactive oxygen species (ROS) and are not rescued by antioxidant agents or overexpression of ROS-detoxifying enzymes. Ectopic expression of pch genes revealed that pyochelin production has no inhibitory effects on a fur deletion mutant of Pseudomonas syringae pv. tabaci, suggesting that the toxicity of the pch locus in Fur-depleted cells involves a P. aeruginosa-specific pathway(s).IMPORTANCE Members of the ferric uptake regulator (Fur) protein family are bacterial transcriptional repressors that control iron uptake and storage in response to iron availability, thereby playing a crucial role in the maintenance of iron homeostasis. While fur null mutants of many bacteria have been obtained, Fur appears to be essential in Pseudomonas aeruginosa for still unknown reasons. We obtained Fur-depleted P. aeruginosa cells by conditional mutagenesis and showed that Fur is dispensable for planktonic growth, while it is required for colony formation. This is because Fur protects P. aeruginosa colonies from toxicity exerted by the pyochelin siderophore. This work provides a functional basis to the essentiality of Fur in P. aeruginosa and highlights unique properties of the Fur regulon in this species. PMID- 28847924 TI - Pseudomonas aeruginosa Magnesium Transporter MgtE Inhibits Type III Secretion System Gene Expression by Stimulating rsmYZ Transcription. AB - Pseudomonas aeruginosa causes numerous acute and chronic opportunistic infections in humans. One of its most formidable weapons is a type III secretion system (T3SS), which injects powerful toxins directly into host cells. The toxins lead to cell dysfunction and, ultimately, cell death. Identification of regulatory pathways that control T3SS gene expression may lead to the discovery of novel therapeutics to treat P. aeruginosa infections. In a previous study, we found that expression of the magnesium transporter gene mgtE inhibits T3SS gene transcription. MgtE-dependent inhibition appeared to interfere with the synthesis or function of the master T3SS transcriptional activator ExsA, although the exact mechanism was unclear. We now demonstrate that mgtE expression acts through the GacAS two-component system to activate rsmY and rsmZ transcription. This event ultimately leads to inhibition of exsA translation. This inhibitory effect is specific to exsA as translation of other genes in the exsCEBA operon is not inhibited by mgtE Moreover, our data reveal that MgtE acts solely through this pathway to regulate T3SS gene transcription. Our study reveals an important mechanism that may allow P. aeruginosa to fine-tune T3SS activity in response to certain environmental stimuli.IMPORTANCE The type III secretion system (T3SS) is a critical virulence factor utilized by numerous Gram-negative bacteria, including Pseudomonas aeruginosa, to intoxicate and kill host cells. Elucidating T3SS regulatory mechanisms may uncover targets for novel anti-P. aeruginosa therapeutics and provide deeper understanding of bacterial pathogenesis. We previously found that the magnesium transporter MgtE inhibits T3SS gene transcription in P. aeruginosa In this study, we describe the mechanism of MgtE dependent inhibition of the T3SS. Our report also illustrates how MgtE might respond to environmental cues, such as magnesium levels, to fine-tune T3SS gene expression. PMID- 28847926 TI - Generating gradient germanium nanostructures by shock-induced amorphization and crystallization. AB - Gradient nanostructures are attracting considerable interest due to their potential to obtain superior structural and functional properties of materials. Applying powerful laser-driven shocks (stresses of up to one-third million atmospheres, or 33 gigapascals) to germanium, we report here a complex gradient nanostructure consisting of, near the surface, nanocrystals with high density of nanotwins. Beyond there, the structure exhibits arrays of amorphous bands which are preceded by planar defects such as stacking faults generated by partial dislocations. At a lower shock stress, the surface region of the recovered target is completely amorphous. We propose that germanium undergoes amorphization above a threshold stress and that the deformation-generated heat leads to nanocrystallization. These experiments are corroborated by molecular dynamics simulations which show that supersonic partial dislocation bursts play a role in triggering the crystalline-to-amorphous transition. PMID- 28847925 TI - NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. AB - The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1beta secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1beta blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1beta. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea. PMID- 28847927 TI - Phase diagram of URu2-x Fe x Si2 in high magnetic fields. AB - Electrical transport measurements were performed on URu2 - x Fe x Si2 single crystal specimens in high magnetic fields up to 45 T (DC fields) and 60 T (pulsed fields). We observed a systematic evolution of the critical fields for both the hidden-order (HO) and large-moment antiferromagnetic (LMAFM) phases and established the 3D phase diagram of T-H-x In the HO phase, H/H0 scales with T/T0 and collapses onto a single curve. However, in the LMAFM phase, this single scaling relation is not satisfied. Within a certain range of x values, the HO phase reenters after the LMAFM phase is suppressed by the magnetic field, similar to the behavior observed for URu2Si2 within a certain range of pressures. PMID- 28847928 TI - Rome's urban history inferred from Pb-contaminated waters trapped in its ancient harbor basins. AB - Heavy metals from urban runoff preserved in sedimentary deposits record long-term economic and industrial development via the expansion and contraction of a city's infrastructure. Lead concentrations and isotopic compositions measured in the sediments of the harbor of Ostia-Rome's first harbor-show that lead pipes used in the water supply networks of Rome and Ostia were the only source of radiogenic Pb, which, in geologically young central Italy, is the hallmark of urban pollution. High-resolution geochemical, isotopic, and 14C analyses of a sedimentary core from Ostia harbor have allowed us to date the commissioning of Rome's lead pipe water distribution system to around the second century BC, considerably later than Rome's first aqueduct built in the late fourth century BC. Even more significantly, the isotopic record of Pb pollution proves to be an unparalleled proxy for tracking the urban development of ancient Rome over more than a millennium, providing a semiquantitative record of the water system's initial expansion, its later neglect, probably during the civil wars of the first century BC, and its peaking in extent during the relative stability of the early high Imperial period. This core record fills the gap in the system's history before the appearance of more detailed literary and inscriptional evidence from the late first century BC onward. It also preserves evidence of the changes in the dynamics of the Tiber River that accompanied the construction of Rome's artificial port, Portus, during the first and second centuries AD. PMID- 28847929 TI - Null effects of boot camps and short-format training for PhD students in life sciences. AB - Many PhD programs incorporate boot camps and summer bridge programs to accelerate the development of doctoral students' research skills and acculturation into their respective disciplines. These brief, high-intensity experiences span no more than several weeks and are typically designed to expose graduate students to data analysis techniques, to develop scientific writing skills, and to better embed incoming students into the scholarly community. However, there is no previous study that directly measures the outcomes of PhD students who participate in such programs and compares them to the outcomes of students who did not participate. Likewise, no previous study has used a longitudinal design to assess these outcomes over time. Here we show that participation in such programs is not associated with detectable benefits related to skill development, socialization into the academic community, or scholarly productivity for students in our sample. Analyzing data from 294 PhD students in the life sciences from 53 US institutions, we found no statistically significant differences in outcomes between participants and nonparticipants across 115 variables. These results stand in contrast to prior studies presenting boot camps as effective interventions based on participant satisfaction and perceived value. Many universities and government agencies (e.g., National Institutes of Health and National Science Foundation) invest substantial resources in boot camp and summer bridge activities in the hopes of better supporting scientific workforce development. Our findings do not reveal any measurable benefits to students, indicating that an allocation of limited resources to alternative strategies with stronger empirical foundations warrants consideration. PMID- 28847930 TI - Dynamics of nitric oxide controlled by protein complex in bacterial system. AB - Nitric oxide (NO) plays diverse and significant roles in biological processes despite its cytotoxicity, raising the question of how biological systems control the action of NO to minimize its cytotoxicity in cells. As a great example of such a system, we found a possibility that NO-generating nitrite reductase (NiR) forms a complex with NO-decomposing membrane-integrated NO reductase (NOR) to efficiently capture NO immediately after its production by NiR in anaerobic nitrate respiration called denitrification. The 3.2-A resolution structure of the complex of one NiR functional homodimer and two NOR molecules provides an idea of how these enzymes interact in cells, while the structure may not reflect the one in cells due to the membrane topology. Subsequent all-atom molecular dynamics (MD) simulations of the enzyme complex model in a membrane and structure-guided mutagenesis suggested that a few interenzyme salt bridges and coulombic interactions of NiR with the membrane could stabilize the complex of one NiR homodimer and one NOR molecule and contribute to rapid NO decomposition in cells. The MD trajectories of the NO diffusion in the NiR:NOR complex with the membrane showed that, as a plausible NO transfer mechanism, NO released from NiR rapidly migrates into the membrane, then binds to NOR. These results help us understand the mechanism of the cellular control of the action of cytotoxic NO. PMID- 28847931 TI - ER stress and distinct outputs of the IRE1alpha RNase control proliferation and senescence in response to oncogenic Ras. AB - Oncogenic Ras causes proliferation followed by premature senescence in primary cells, an initial barrier to tumor development. The role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in regulating these two cellular outcomes is poorly understood. During ER stress, the inositol requiring enzyme 1alpha (IRE1alpha) endoribonuclease (RNase), a key mediator of the UPR, cleaves Xbp1 mRNA to generate a potent transcription factor adaptive toward ER stress. However, IRE1alpha also promotes cleavage and degradation of ER-localized mRNAs essential for cell death. Here, we show that oncogenic HRas induces ER stress and activation of IRE1alpha. Reduction of ER stress or Xbp1 splicing using pharmacological, genetic, and RNAi approaches demonstrates that this adaptive response is critical for HRas-induced proliferation. Paradoxically, reduced ER stress or Xbp1 splicing promotes growth arrest and premature senescence through hyperactivation of the IRE1alpha RNase. Microarray analysis of IRE1alpha- and XBP1-depleted cells, validation using RNA cleavage assays, and 5' RACE identified the prooncogenic basic helix-loop-helix transcription factor ID1 as an IRE1alpha RNase target. Further, we demonstrate that Id1 degradation by IRE1alpha is essential for HRas-induced premature senescence. Together, our studies point to IRE1alpha as an important node for posttranscriptional regulation of the early Ras phenotype that is dependent on both oncogenic signaling as well as stress signals imparted by the tumor microenvironment and could be an important mechanism driving escape from Ras-induced senescence. PMID- 28847932 TI - Compounding effects of sea level rise and fluvial flooding. AB - Sea level rise (SLR), a well-documented and urgent aspect of anthropogenic global warming, threatens population and assets located in low-lying coastal regions all around the world. Common flood hazard assessment practices typically account for one driver at a time (e.g., either fluvial flooding only or ocean flooding only), whereas coastal cities vulnerable to SLR are at risk for flooding from multiple drivers (e.g., extreme coastal high tide, storm surge, and river flow). Here, we propose a bivariate flood hazard assessment approach that accounts for compound flooding from river flow and coastal water level, and we show that a univariate approach may not appropriately characterize the flood hazard if there are compounding effects. Using copulas and bivariate dependence analysis, we also quantify the increases in failure probabilities for 2030 and 2050 caused by SLR under representative concentration pathways 4.5 and 8.5. Additionally, the increase in failure probability is shown to be strongly affected by compounding effects. The proposed failure probability method offers an innovative tool for assessing compounding flood hazards in a warming climate. PMID- 28847933 TI - Origin, paleoecology, and extirpation of bluebirds and crossbills in the Bahamas across the last glacial-interglacial transition. AB - On low islands or island groups such as the Bahamas, surrounded by shallow oceans, Quaternary glacial-interglacial changes in climate and sea level had major effects on terrestrial plant and animal communities. We examine the paleoecology of two species of songbirds (Passeriformes) recorded as Late Pleistocene fossils on the Bahamian island of Abaco-the Eastern bluebird (Sialia sialis) and Hispaniolan crossbill (Loxia megaplaga). Each species lives today only outside of the Bahamian Archipelago, with S. sialis occurring in North and Central America and L. megaplaga endemic to Hispaniola. Unrecorded in the Holocene fossil record of Abaco, both of these species probably colonized Abaco during the last glacial interval but were eliminated when the island became much smaller, warmer, wetter, and more isolated during the last glacial-interglacial transition from ~15 to 9 ka. Today's warming temperatures and rising sea levels, although not as great in magnitude as those that took place from ~15 to 9 ka, are occurring rapidly and may contribute to considerable biotic change on islands by acting in synergy with direct human impacts. PMID- 28847934 TI - Distribution of lifetime nursing home use and of out-of-pocket spending. AB - Reliable estimates of the lifetime risk of using a nursing home and the associated out-of-pocket costs are important for the saving decisions by individuals and families, and for the purchase of long-term care insurance. We used data on up to 18 y of nursing home use and out-of-pocket costs drawn from the Health and Retirement Study, a longitudinal household survey representative of the older US population. We accumulated the use and spending by individuals over many years, and we developed and used an individual-level matching method to account for use before and after the observation period. In addition, for forecasting, we estimated a dynamic parametric model of nursing home use and spending. We found that 56% of persons aged 57-61 will stay at least one night in a nursing home during their lifetimes, but only 32% of the cohort will pay anything out of pocket. Averaged over all persons, total out-of-pocket expenditures looking forward from age 57 were approximately $7,300, discounted at 3% per year. However, the 95th percentile of spending was almost $47,000. We conclude that the percentage of people ever staying in nursing homes is substantially higher than previous estimates, at least partly due to an increase in nursing home episodes of short duration. Average lifetime out-of-pocket costs may be affordable, but some people will incur much higher costs. PMID- 28847935 TI - LATERAL FLORET 1 induced the three-florets spikelet in rice. AB - The spikelet is a unique inflorescence structure in grass. The molecular mechanisms behind the development and evolution of the spikelet are far from clear. In this study, a dominant rice mutant, lateral florets 1 (lf1), was characterized. In the lf1 spikelet, lateral floral meristems were promoted unexpectedly and could generally blossom into relatively normal florets. LF1 encoded a class III homeodomain-leucine zipper (HD-ZIP III) protein, and the site of mutation in lf1 was located in a putative miRNA165/166 target sequence. Ectopic expression of both LF1 and the meristem maintenance gene OSH1 was detected in the axil of the sterile lemma primordia of the lf1 spikelet. Furthermore, the promoter of OSH1 could be bound directly by LF1 protein. Collectively, these results indicate that the mutation of LF1 induces ectopic expression of OSH1, which results in the initiation of lateral meristems to generate lateral florets in the axil of the sterile lemma. This study thus offers strong evidence in support of the "three-florets spikelet" hypothesis in rice. PMID- 28847936 TI - Mechanisms of ovipositor insertion and steering of a parasitic wasp. AB - Drilling into solid substrates with slender beam-like structures is a mechanical challenge, but is regularly done by female parasitic wasps. The wasp inserts her ovipositor into solid substrates to deposit eggs in hosts, and even seems capable of steering the ovipositor while drilling. The ovipositor generally consists of three longitudinally connected valves that can slide along each other. Alternative valve movements have been hypothesized to be involved in ovipositor damage avoidance and steering during drilling. However, none of the hypotheses have been tested in vivo. We used 3D and 2D motion analysis to quantify the probing behavior of the fruit-fly parasitoid Diachasmimorpha longicaudata (Braconidae) at the levels of the ovipositor and its individual valves. We show that the wasps can steer and curve their ovipositors in any direction relative to their body axis. In a soft substrate, the ovipositors can be inserted without reciprocal motion of the valves. In a stiff substrate, such motions were always observed. This is in agreement with the damage avoidance hypothesis of insertion, as they presumably limit the overall net pushing force. Steering can be achieved by varying the asymmetry of the distal part of the ovipositor by protracting one valve set with respect to the other. Tip asymmetry is enhanced by curving of ventral elements in the absence of an opposing force, possibly due to pretension. Our findings deepen the knowledge of the functioning and evolution of the ovipositor in hymenopterans and may help to improve man-made steerable probes. PMID- 28847937 TI - Seed dispersal increases local species richness and reduces spatial turnover of tropical tree seedlings. AB - Dispersal is thought to be a key process underlying the high spatial diversity of tropical forests. Just how important dispersal is in structuring plant communities is nevertheless an open question because it is very difficult to isolate dispersal from other processes, and thereby measure its effect. Using a unique situation, the loss of vertebrate seed dispersers on the island of Guam and their presence on the neighboring islands of Saipan and Rota, we quantify the contribution of vertebrate seed dispersal to spatial patterns of diversity of tree seedlings in treefall gaps. The presence of vertebrate seed dispersers approximately doubled seedling species richness within canopy gaps and halved species turnover among gaps. Our study demonstrates that dispersal plays a key role in maintaining local and regional patterns of diversity, and highlights the potential for ongoing declines in vertebrate seed dispersers to profoundly alter tropical forest composition. PMID- 28847939 TI - North-south polarization of European electricity consumption under future warming. AB - There is growing empirical evidence that anthropogenic climate change will substantially affect the electric sector. Impacts will stem both from the supply side-through the mitigation of greenhouse gases-and from the demand side-through adaptive responses to a changing environment. Here we provide evidence of a polarization of both peak load and overall electricity consumption under future warming for the world's third-largest electricity market-the 35 countries of Europe. We statistically estimate country-level dose-response functions between daily peak/total electricity load and ambient temperature for the period 2006 2012. After removing the impact of nontemperature confounders and normalizing the residual load data for each country, we estimate a common dose-response function, which we use to compute national electricity loads for temperatures that lie outside each country's currently observed temperature range. To this end, we impose end-of-century climate on today's European economies following three different greenhouse-gas concentration trajectories, ranging from ambitious climate-change mitigation-in line with the Paris agreement-to unabated climate change. We find significant increases in average daily peak load and overall electricity consumption in southern and western Europe (~3 to ~7% for Portugal and Spain) and significant decreases in northern Europe (~-6 to ~-2% for Sweden and Norway). While the projected effect on European total consumption is nearly zero, the significant polarization and seasonal shifts in peak demand and consumption have important ramifications for the location of costly peak generating capacity, transmission infrastructure, and the design of energy efficiency policy and storage capacity. PMID- 28847938 TI - Top-down modulation of sensory cortex gates perceptual learning. AB - Practice sharpens our perceptual judgments, a process known as perceptual learning. Although several brain regions and neural mechanisms have been proposed to support perceptual learning, formal tests of causality are lacking. Furthermore, the temporal relationship between neural and behavioral plasticity remains uncertain. To address these issues, we recorded the activity of auditory cortical neurons as gerbils trained on a sound detection task. Training led to improvements in cortical and behavioral sensitivity that were closely matched in terms of magnitude and time course. Surprisingly, the degree of neural improvement was behaviorally gated. During task performance, cortical improvements were large and predicted behavioral outcomes. In contrast, during nontask listening sessions, cortical improvements were weak and uncorrelated with perceptual performance. Targeted reduction of auditory cortical activity during training diminished perceptual learning while leaving psychometric performance largely unaffected. Collectively, our findings suggest that training facilitates perceptual learning by strengthening both bottom-up sensory encoding and top-down modulation of auditory cortex. PMID- 28847940 TI - Surveying the sequence diversity of model prebiotic peptides by mass spectrometry. AB - The rise of peptides with secondary structures and functions would have been a key step in the chemical evolution which led to life. As with modern biology, amino acid sequence would have been a primary determinant of peptide structure and activity in an origins-of-life scenario. It is a commonly held hypothesis that unique functional sequences would have emerged from a diverse soup of proto peptides, yet there is a lack of experimental data in support of this. Whereas the majority of studies in the field focus on peptides containing only one or two types of amino acids, here we used modern mass spectrometry (MS)-based techniques to separate and sequence de novo proto-peptides containing broader combinations of prebiotically plausible monomers. Using a dry-wet environmental cycling protocol, hundreds of proto-peptide sequences were formed over a mere 4 d of reaction. Sequence homology diagrams were constructed to compare experimental and theoretical sequence spaces of tetrameric proto-peptides. MS-based analyses such as this will be increasingly necessary as origins-of-life researchers move toward systems-level investigations of prebiotic chemistry. PMID- 28847941 TI - Replication and refinement of a vaginal microbial signature of preterm birth in two racially distinct cohorts of US women. AB - Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Previous studies have suggested that the maternal vaginal microbiota contributes to the pathophysiology of PTB, but conflicting results in recent years have raised doubts. We conducted a study of PTB compared with term birth in two cohorts of pregnant women: one predominantly Caucasian (n = 39) at low risk for PTB, the second predominantly African American and at high-risk (n = 96). We profiled the taxonomic composition of 2,179 vaginal swabs collected prospectively and weekly during gestation using 16S rRNA gene sequencing. Previously proposed associations between PTB and lower Lactobacillus and higher Gardnerella abundances replicated in the low-risk cohort, but not in the high-risk cohort. High-resolution bioinformatics enabled taxonomic assignment to the species and subspecies levels, revealing that Lactobacillus crispatus was associated with low risk of PTB in both cohorts, while Lactobacillus iners was not, and that a subspecies clade of Gardnerella vaginalis explained the genus association with PTB. Patterns of cooccurrence between L. crispatus and Gardnerella were highly exclusive, while Gardnerella and L. iners often coexisted at high frequencies. We argue that the vaginal microbiota is better represented by the quantitative frequencies of these key taxa than by classifying communities into five community state types. Our findings extend and corroborate the association between the vaginal microbiota and PTB, demonstrate the benefits of high-resolution statistical bioinformatics in clinical microbiome studies, and suggest that previous conflicting results may reflect the different risk profile of women of black race. PMID- 28847942 TI - Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow. AB - The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid [Formula: see text] that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain's interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space. The space was divided into sheets (i.e., space between two parallel membranes) and tunnels (where three or more membranes meet). Simulation results indicate that even for larger extracellular volume fractions than what is reported for sleep and for geometries with a high tunnel volume fraction, the permeability was too low to allow for any substantial bulk flow at physiological hydrostatic pressure gradients. For two different geometries with the same extracellular volume fraction the geometry with the most tunnel volume had [Formula: see text] higher permeability, but the bulk flow was still insignificant. These simulation results suggest that even large molecule solutes would be more easily cleared from the brain interstitium by diffusion than by bulk flow. Thus, diffusion within the interstitial space combined with advection along vessels is likely to substitute for the lymphatic drainage system in other organs. PMID- 28847943 TI - Investment in secreted enzymes during nutrient-limited growth is utility dependent. AB - Pathogenic bacteria secrete toxins and degradative enzymes that facilitate their growth by liberating nutrients from the environment. To understand bacterial growth under nutrient-limited conditions, we studied resource allocation between cellular and secreted components by the pathogenic bacterium Pseudomonas aeruginosa during growth on a protein substrate that requires extracellular digestion by secreted proteases. We identified a quantitative relationship between the rate of increase of cellular biomass under nutrient-limiting growth conditions and the rate of increase in investment in secreted proteases. Production of secreted proteases is stimulated by secreted signals that convey information about the utility of secreted proteins during nutrient-limited growth. Growth modeling using this relationship recapitulated the observed kinetics of bacterial growth on a protein substrate. The proposed regulatory strategy suggests a rationale for quorum-sensing-dependent stimulation of the production of secreted enzymes whereby investment in secreted enzymes occurs in proportion to the utility they confer. Our model provides a framework that can be applied toward understanding bacterial growth in many environments where growth rate is limited by the availability of nutrients. PMID- 28847944 TI - Amorphous calcium carbonate particles form coral skeletons. AB - Do corals form their skeletons by precipitation from solution or by attachment of amorphous precursor particles as observed in other minerals and biominerals? The classical model assumes precipitation in contrast with observed "vital effects," that is, deviations from elemental and isotopic compositions at thermodynamic equilibrium. Here, we show direct spectromicroscopy evidence in Stylophora pistillata corals that two amorphous precursors exist, one hydrated and one anhydrous amorphous calcium carbonate (ACC); that these are formed in the tissue as 400-nm particles; and that they attach to the surface of coral skeletons, remain amorphous for hours, and finally, crystallize into aragonite (CaCO3). We show in both coral and synthetic aragonite spherulites that crystal growth by attachment of ACC particles is more than 100 times faster than ion-by-ion growth from solution. Fast growth provides a distinct physiological advantage to corals in the rigors of the reef, a crowded and fiercely competitive ecosystem. Corals are affected by warming-induced bleaching and postmortem dissolution, but the finding here that ACC particles are formed inside tissue may make coral skeleton formation less susceptible to ocean acidification than previously assumed. If this is how other corals form their skeletons, perhaps this is how a few corals survived past CO2 increases, such as the Paleocene-Eocene Thermal Maximum that occurred 56 Mya. PMID- 28847945 TI - A-to-I RNA editing is developmentally regulated and generally adaptive for sexual reproduction in Neurospora crassa. AB - Although fungi lack adenosine deaminase acting on RNA (ADAR) enzymes, adenosine to inosine (A-to-I) RNA editing was reported recently in Fusarium graminearum during sexual reproduction. In this study, we profiled the A-to-I editing landscape and characterized its functional and adaptive properties in the model filamentous fungus Neurospora crassa A total of 40,677 A-to-I editing sites were identified, and approximately half of them displayed stage-specific editing or editing levels at different sexual stages. RNA-sequencing analysis with the Deltastc-1 and Deltasad-1 mutants confirmed A-to-I editing occurred before ascus development but became more prevalent during ascosporogenesis. Besides fungal specific sequence and secondary structure preference, 63.5% of A-to-I editing sites were in the coding regions and 81.3% of them resulted in nonsynonymous recoding, resulting in a significant increase in the proteome complexity. Many genes involved in RNA silencing, DNA methylation, and histone modifications had extensive recoding, including sad-1, sms-3, qde-1, and dim-2. Fifty pseudogenes harbor premature stop codons that require A-to-I editing to encode full-length proteins. Unlike in humans, nonsynonymous editing events in N. crassa are generally beneficial and favored by positive selection. Almost half of the nonsynonymous editing sites in N. crassa are conserved and edited in Neurospora tetrasperma Furthermore, hundreds of them are conserved in F. graminearum and had higher editing levels. Two unknown genes with editing sites conserved between Neurospora and Fusarium were experimentally shown to be important for ascosporogenesis. This study comprehensively analyzed A-to-I editing in N. crassa and showed that RNA editing is stage-specific and generally adaptive, and may be functionally related to repeat induced point mutation and meiotic silencing by unpaired DNA. PMID- 28847947 TI - 5-hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes. AB - 5-hydroxymethylcytosine (5hmC) occurs at maximal levels in postmitotic neurons, where its accumulation is cell-specific and correlated with gene expression. Here we demonstrate that the distribution of 5hmC in CG and non-CG dinucleotides is distinct and that it reflects the binding specificity and genome occupancy of methylcytosine binding protein 2 (MeCP2). In expressed gene bodies, accumulation of 5hmCG acts in opposition to 5mCG, resulting in "functional" demethylation and diminished MeCP2 binding, thus facilitating transcription. Non-CG hydroxymethylation occurs predominantly in CA dinucleotides (5hmCA) and it accumulates in regions flanking active enhancers. In these domains, oxidation of 5mCA to 5hmCA does not alter MeCP2 binding or expression of adjacent genes. We conclude that the role of 5-hydroxymethylcytosine in postmitotic neurons is to functionally demethylate expressed gene bodies while retaining the role of MeCP2 in chromatin organization. PMID- 28847948 TI - Reputation offsets trust judgments based on social biases among Airbnb users. AB - To provide social exchange on a global level, sharing-economy companies leverage interpersonal trust between their members on a scale unimaginable even a few years ago. A challenge to this mission is the presence of social biases among a large heterogeneous and independent population of users, a factor that hinders the growth of these services. We investigate whether and to what extent a sharing economy platform can design artificially engineered features, such as reputation systems, to override people's natural tendency to base judgments of trustworthiness on social biases. We focus on the common tendency to trust others who are similar (i.e., homophily) as a source of bias. We test this argument through an online experiment with 8,906 users of Airbnb, a leading hospitality company in the sharing economy. The experiment is based on an interpersonal investment game, in which we vary the characteristics of recipients to study trust through the interplay between homophily and reputation. Our findings show that reputation systems can significantly increase the trust between dissimilar users and that risk aversion has an inverse relationship with trust given high reputation. We also present evidence that our experimental findings are confirmed by analyses of 1 million actual hospitality interactions among users of Airbnb. PMID- 28847946 TI - Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease. AB - Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5' untranslated region of TBEV genomic RNA that act as a cis-acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease. PMID- 28847949 TI - Increasing atmospheric humidity and CO2 concentration alleviate forest mortality risk. AB - Climate-induced forest mortality is being increasingly observed throughout the globe. Alarmingly, it is expected to exacerbate under climate change due to shifting precipitation patterns and rising air temperature. However, the impact of concomitant changes in atmospheric humidity and CO2 concentration through their influence on stomatal kinetics remains a subject of debate and inquiry. By using a dynamic soil-plant-atmosphere model, mortality risks associated with hydraulic failure and stomatal closure for 13 temperate and tropical forest biomes across the globe are analyzed. The mortality risk is evaluated in response to both individual and combined changes in precipitation amounts and their seasonal distribution, mean air temperature, specific humidity, and atmospheric CO2 concentration. Model results show that the risk is predicted to significantly increase due to changes in precipitation and air temperature regime for the period 2050-2069. However, this increase may largely get alleviated by concurrent increases in atmospheric specific humidity and CO2 concentration. The increase in mortality risk is expected to be higher for needleleaf forests than for broadleaf forests, as a result of disparity in hydraulic traits. These findings will facilitate decisions about intervention and management of different forest types under changing climate. PMID- 28847950 TI - Reactive oxygen species extend insect life span using components of the insulin signaling pathway. AB - Reactive oxygen species (ROS) are well-known accelerants of aging, but, paradoxically, we show that physiological levels of ROS extend life span in pupae of the moth Helicoverpa armigera, resulting in the dormant state of diapause. This developmental switch appears to operate through a variant of the conventional insulin-signaling pathway, as evidenced by the facts that Akt, p Akt, and PRMT1 are elevated by ROS, but not insulin, and that high levels of p Akt fail to phosphorylate FoxO through PRMT1-mediated methylation. These results suggest a distinct signaling pathway culminating in the elevation of FoxO, which in turn promotes the extension of life span characteristic of diapause. PMID- 28847951 TI - Shear force-based genetic screen reveals negative regulators of cell adhesion and protrusive activity. AB - The model organism Dictyostelium discoideum has greatly facilitated our understanding of the signal transduction and cytoskeletal pathways that govern cell motility. Cell-substrate adhesion is downstream of many migratory and chemotaxis signaling events. Dictyostelium cells lacking the tumor suppressor PTEN show strongly impaired migratory activity and adhere strongly to their substrates. We reasoned that other regulators of migration could be obtained through a screen for overly adhesive mutants. A screen of restriction enzyme mediated integration mutagenized cells yielded numerous mutants with the desired phenotypes, and the insertion sites in 18 of the strains were mapped. These regulators of adhesion and motility mutants have increased adhesion and decreased motility. Characterization of seven strains demonstrated decreased directed migration, flatness, increased filamentous actin-based protrusions, and increased signal transduction network activity. Many of the genes share homology to human genes and demonstrate the diverse array of cellular networks that function in adhesion and migration. PMID- 28847952 TI - tRNAs and proteins use the same import channel for translocation across the mitochondrial outer membrane of trypanosomes. AB - Mitochondrial tRNA import is widespread, but the mechanism by which tRNAs are imported remains largely unknown. The mitochondrion of the parasitic protozoan Trypanosoma brucei lacks tRNA genes, and thus imports all tRNAs from the cytosol. Here we show that in T. brucei in vivo import of tRNAs requires four subunits of the mitochondrial outer membrane protein translocase but not the two receptor subunits, one of which is essential for protein import. The latter shows that it is possible to uncouple mitochondrial tRNA import from protein import. Ablation of the intermembrane space domain of the translocase subunit, archaic translocase of the outer membrane (ATOM)14, on the other hand, while not affecting the architecture of the translocase, impedes both protein and tRNA import. A protein import intermediate arrested in the translocation channel prevents both protein and tRNA import. In the presence of tRNA, blocking events of single-channel currents through the pore formed by recombinant ATOM40 were detected in electrophysiological recordings. These results indicate that both types of macromolecules use the same import channel across the outer membrane. However, while tRNA import depends on the core subunits of the protein import translocase, it does not require the protein import receptors, indicating that the two processes are not mechanistically linked. PMID- 28847953 TI - Differential HspBP1 expression accounts for the greater vulnerability of neurons than astrocytes to misfolded proteins. AB - Although it is well known that astrocytes are less vulnerable than neurons in neurodegenerative diseases, the mechanism behind this differential vulnerability is unclear. Here we report that neurons and astrocytes show markedly different activities in C terminus of Hsp70-interacting protein (CHIP), a cochaperone of Hsp70. In astrocytes, CHIP is more actively monoubiquitinated and binds to mutant huntingtin (mHtt), the Huntington's disease protein, more avidly, facilitating its K48-linked polyubiquitination and degradation. Astrocytes also show the higher level and heat-shock induction of Hsp70 and faster CHIP-mediated degradation of various misfolded proteins than neurons. In contrast to astrocytes, neurons express abundant HspBP1, a CHIP inhibitory protein, resulting in the low activity of CHIP. Silencing HspBP1 expression via CRISPR-Cas9 in neurons ameliorated mHtt aggregation and neuropathology in HD knockin mouse brains. Our findings indicate a critical role of HspBP1 in differential CHIP/Hsp70 activities in neuronal and glial cells and the greater neuronal vulnerability to misfolded proteins in neurodegenerative diseases. PMID- 28847954 TI - Stabilizing a different cyclooctatetraene stereoisomer. AB - An unconventional cis-cis-cis-trans or (Z,Z,Z,E) structure B of cyclooctatetraene (COT) is calculated to lie only 23 kcal/mol above the well-known tub-shaped (Z,Z,Z,Z) isomer A; one example of this type of structure is known. The barrier for B returning to A is small, 3 kcal/mol. However, by suitable choice of substituents, the (Z,Z,Z,E) isomer can be made to lie in energy below the tub shaped structure. Steric, clamping, and electronic strategies are proposed for achieving this. In the steric strategy, the C8H4(CH3)2(C( t Bu)3)2 structure B is predicted to lie 21 kcal/mol below structure A, which is separated from form B only by a small barrier. A simple clamping strategy, effective for COT planarization, does not influence the A/B isomerization much. But, if the clamping group is aromatic (a fused benzene, pyrrole, thiophene, furan), the subtle interplay of potential aromaticity with clamping can be used to confer persistence if not stability on the (Z,Z,Z,E) isomer. An electronic strategy of a different kind, push-pull substitution on the COT ring, was not very effective in stabilizing the B form. However, it led us to vicinal amine-borane-substituted normal COTs that proved to be quite good at activating H2 in a frustrated Lewis pair scenario. PMID- 28847955 TI - Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression. AB - Sister chromatids are tethered together by the cohesin complex from the time they are made until their separation at anaphase. The ability of cohesin to tether sister chromatids together depends on acetylation of its Smc3 subunit by members of the Eco1 family of cohesin acetyltransferases. Vertebrates express two orthologs of Eco1, called Esco1 and Esco2, both of which are capable of modifying Smc3, but their relative contributions to sister chromatid cohesion are unknown. We therefore set out to determine the precise contributions of Esco1 and Esco2 to cohesion in vertebrate cells. Here we show that cohesion establishment is critically dependent upon Esco2. Although most Smc3 acetylation is Esco1 dependent, inactivation of the ESCO1 gene has little effect on mitotic cohesion. The unique ability of Esco2 to promote cohesion is mediated by sequences in the N terminus of the protein. We propose that Esco1-dependent modification of Smc3 regulates almost exclusively the noncohesive activities of cohesin, such as DNA repair, transcriptional control, chromosome loop formation, and/or stabilization. Collectively, our data indicate that Esco1 and Esco2 contribute to distinct and separable activities of cohesin in vertebrate cells. PMID- 28847956 TI - Neutral high-generation phosphorus dendrimers inhibit macrophage-mediated inflammatory response in vitro and in vivo. AB - Inflammation is part of the physiological response of the organism to infectious diseases caused by organisms such as bacteria, viruses, fungi, or parasites. Innate immunity, mediated by mononuclear phagocytes, including monocytes and macrophages, is a first line of defense against infectious diseases and plays a key role triggering the delayed adaptive response that ensures an efficient defense against pathogens. Monocytes and macrophages stimulation by pathogen antigens results in activation of different signaling pathways leading to the release of proinflammatory cytokines. However, inflammation can also participate in the pathogenesis of several diseases, the autoimmune diseases that represent a relevant burden for human health. Dendrimers are branched, multivalent nanoparticles with a well-defined structure that have a high potential for biomedical applications. To explore new approaches to fight against the negative aspects of inflammation, we have used neutral high-generation phosphorus dendrimers bearing 48 (G3) or 96 (G4) bisphosphonate groups on their surface. These dendrimers show no toxicity and have good solubility and chemical stability in aqueous solutions. Here, we present data indicating that neutral phosphorus dendrimers show impressive antiinflammatory activities both in vitro and in vivo. In vitro, these dendrimers reduced the secretion of proinflammatory cytokines from mice and human monocyte-derived macrophages. In addition, these molecules present efficient antiinflammatory activity in vivo in a mouse model of subchronic inflammation. Taken together, these data suggest that neutral G3-G4 phosphorus dendrimers have strong potential applications in the therapy of inflammation and, likely, of autoimmune diseases. PMID- 28847957 TI - Knots can impair protein degradation by ATP-dependent proteases. AB - ATP-dependent proteases translocate proteins through a narrow pore for their controlled destruction. However, how a protein substrate containing a knotted topology affects this process remains unknown. Here, we characterized the effects of the trefoil-knotted protein MJ0366 from Methanocaldococcus jannaschii on the operation of the ClpXP protease from Escherichia coli ClpXP completely degrades MJ0366 when pulling from the C-terminal ssrA-tag. However, when a GFP moiety is appended to the N terminus of MJ0366, ClpXP releases intact GFP with a 47-residue tail. The extended length of this tail suggests that ClpXP tightens the trefoil knot against GFP, which prevents GFP unfolding. Interestingly, if the linker between the knot core of MJ0366 and GFP is longer than 36 residues, ClpXP tightens and translocates the knot before it reaches GFP, enabling the complete unfolding and degradation of the substrate. These observations suggest that a knot-induced stall during degradation of multidomain proteins by AAA proteases may constitute a novel mechanism to produce partially degraded products with potentially new functions. PMID- 28847958 TI - Role for the EWS domain of EWS/FLI in binding GGAA-microsatellites required for Ewing sarcoma anchorage independent growth. AB - Ewing sarcoma usually expresses the EWS/FLI fusion transcription factor oncoprotein. EWS/FLI regulates myriad genes required for Ewing sarcoma development. EWS/FLI binds GGAA-microsatellite sequences in vivo and in vitro. These sequences provide EWS/FLI-mediated activation to reporter constructs, suggesting that they function as EWS/FLI-response elements. We now demonstrate the critical role of an EWS/FLI-bound GGAA-microsatellite in regulation of the NR0B1 gene as well as for Ewing sarcoma proliferation and anchorage-independent growth. Clinically, genomic GGAA-microsatellites are highly variable and polymorphic. Current data suggest that there is an optimal "sweet-spot" GGAA microsatellite length (of 18-26 GGAA repeats) that confers maximal EWS/FLI responsiveness to target genes, but the mechanistic basis for this remains unknown. Our biochemical studies, using recombinant Delta22 (a version of EWS/FLI containing only the FLI portion), demonstrate a stoichiometry of one Delta22 monomer binding to every two consecutive GGAA-repeats on shorter microsatellite sequences. Surprisingly, the affinity for Delta22 binding to GGAA-microsatellites significantly decreased, and ultimately became unmeasureable, when the size of the microsatellite was increased to the sweet-spot length. In contrast, a fully functional EWS/FLI mutant (Mut9, which retains approximately half of the EWS portion of the fusion) showed low affinity for smaller GGAA-microsatellites but instead significantly increased its affinity at sweet-spot microsatellite lengths. Single-gene ChIP and genome-wide ChIP-sequencing (ChIP-seq) and RNA-seq studies extended these findings to the in vivo setting. Together, these data demonstrate the critical requirement of GGAA-microsatellites as EWS/FLI activating response elements in vivo and reveal an unexpected role for the EWS portion of the EWS/FLI fusion in binding to sweet-spot GGAA-microsatellites. PMID- 28847959 TI - Adaptive-illumination STED nanoscopy. AB - The concepts called STED/RESOLFT superresolve features by a light-driven transfer of closely packed molecules between two different states, typically a nonfluorescent "off" state and a fluorescent "on" state at well-defined coordinates on subdiffraction scales. For this, the applied light intensity must be sufficient to guarantee the state difference for molecules spaced at the resolution sought. Relatively high intensities have therefore been applied throughout the imaging to obtain the highest resolutions. At regions where features are far enough apart that molecules could be separated with lower intensity, the excess intensity just adds to photobleaching. Here, we introduce DyMIN (standing for Dynamic Intensity Minimum) scanning, generalizing and expanding on earlier concepts of RESCue and MINFIELD to reduce sample exposure. The principle of DyMIN is that it only uses as much on/off-switching light as needed to image at the desired resolution. Fluorescence can be recorded at those positions where fluorophores are found within a subresolution neighborhood. By tuning the intensity (and thus resolution) during the acquisition of each pixel/voxel, we match the size of this neighborhood to the structures being imaged. DyMIN is shown to lower the dose of STED light on the scanned region up to ~20-fold under common biological imaging conditions, and >100-fold for sparser 2D and 3D samples. The bleaching reduction can be converted into accordingly brighter images at <30-nm resolution. PMID- 28847960 TI - Affinity of IDPs to their targets is modulated by ion-specific changes in kinetics and residual structure. AB - Intrinsically disordered proteins (IDPs) are characterized by a lack of defined structure. Instead, they populate ensembles of rapidly interconverting conformations with marginal structural stabilities. Changes in solution conditions such as temperature and crowding agents consequently affect IDPs more than their folded counterparts. Here we reveal that the residual structure content of IDPs is modulated both by ionic strength and by the type of ions present in solution. We show that these ion-specific structural changes result in binding affinity shifts of up to sixfold, which happen through alteration of both association and dissociation rates. These effects follow the Hofmeister series, but unlike the well-established effects on the stability of folded proteins, they already occur at low, hypotonic concentrations of salt. We attribute this sensitivity to the marginal stability of IDPs, which could have physiological implications given the role of IDPs in signaling, the asymmetric ion profiles of different cellular compartments, and the role of ions in biology. PMID- 28847962 TI - From coseismic offsets to fault-block mountains. AB - In the Basin and Range extensional province of the western United States, coseismic offsets, under the influence of gravity, display predominantly subsidence of the basin side (fault hanging wall), with comparatively little or no uplift of the mountainside (fault footwall). A few decades later, geodetic measurements [GPS and interferometric synthetic aperture radar (InSAR)] show broad (~100 km) aseismic uplift symmetrically spanning the fault zone. Finally, after millions of years and hundreds of fault offsets, the mountain blocks display large uplift and tilting over a breadth of only about 10 km. These sparse but robust observations pose a problem in that the coesismic uplifts of the footwall are small and inadequate to raise the mountain blocks. To address this paradox we develop finite-element models subjected to extensional and gravitational forces to study time-varying deformation associated with normal faulting. Stretching the model under gravity demonstrates that asymmetric slip via collapse of the hanging wall is a natural consequence of coseismic deformation. Focused flow in the upper mantle imposed by deformation of the lower crust localizes uplift, which is predicted to take place within one to two decades after each large earthquake. Thus, the best-preserved topographic signature of earthquakes is expected to occur early in the postseismic period. PMID- 28847961 TI - Clipping of arginine-methylated histone tails by JMJD5 and JMJD7. AB - Two of the unsolved, important questions about epigenetics are: do histone arginine demethylases exist, and is the removal of histone tails by proteolysis a major epigenetic modification process? Here, we report that two orphan Jumonji C domain (JmjC)-containing proteins, JMJD5 and JMJD7, have divalent cation dependent protease activities that preferentially cleave the tails of histones 2, 3, or 4 containing methylated arginines. After the initial specific cleavage, JMJD5 and JMJD7, acting as aminopeptidases, progressively digest the C-terminal products. JMJD5-deficient fibroblasts exhibit dramatically increased levels of methylated arginines and histones. Furthermore, depletion of JMJD7 in breast cancer cells greatly decreases cell proliferation. The protease activities of JMJD5 and JMJD7 represent a mechanism for removal of histone tails bearing methylated arginine residues and define a potential mechanism of transcription regulation. PMID- 28847963 TI - Direct single-molecule measurements of phycocyanobilin photophysics in monomeric C-phycocyanin. AB - Phycobilisomes are highly organized pigment-protein antenna complexes found in the photosynthetic apparatus of cyanobacteria and rhodophyta that harvest solar energy and transport it to the reaction center. A detailed bottom-up model of pigment organization and energy transfer in phycobilisomes is essential to understanding photosynthesis in these organisms and informing rational design of artificial light-harvesting systems. In particular, heterogeneous photophysical behaviors of these proteins, which cannot be predicted de novo, may play an essential role in rapid light adaptation and photoprotection. Furthermore, the delicate architecture of these pigment-protein scaffolds sensitizes them to external perturbations, for example, surface attachment, which can be avoided by study in free solution or in vivo. Here, we present single-molecule characterization of C-phycocyanin (C-PC), a three-pigment biliprotein that self assembles to form the midantenna rods of cyanobacterial phycobilisomes. Using the Anti-Brownian Electrokinetic (ABEL) trap to counteract Brownian motion of single particles in real time, we directly monitor the changing photophysical states of individual C-PC monomers from Spirulina platensis in free solution by simultaneous readout of their brightness, fluorescence anisotropy, fluorescence lifetime, and emission spectra. These include single-chromophore emission states for each of the three covalently bound phycocyanobilins, providing direct measurements of the spectra and photophysics of these chemically identical molecules in their native protein environment. We further show that a simple Forster resonant energy transfer (FRET) network model accurately predicts the observed photophysical states of C-PC and suggests highly variable quenching behavior of one of the chromophores, which should inform future studies of higher order complexes. PMID- 28847964 TI - Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC. AB - Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy. PMID- 28847965 TI - Plasmon-enhanced light-driven water oxidation by a dye-sensitized photoanode. AB - Dye-sensitized photoelectrosynthesis cells (DSPECs) provide a flexible approach for solar water splitting based on the integration of molecular light absorption and catalysis on oxide electrodes. Recent advances in this area, including the use of core/shell oxide interfacial structures and surface stabilization by atomic layer deposition, have led to improved charge-separation lifetimes and the ability to obtain substantially improved photocurrent densities. Here, we investigate the introduction of Ag nanoparticles into the core/shell structure and report that they greatly enhance light-driven water oxidation at a DSPEC photoanode. Under 1-sun illumination, Ag nanoparticle electrodes achieved high photocurrent densities, surpassing 2 mA cm-2 with an incident photon-to-current efficiency of 31.8% under 450-nm illumination. PMID- 28847966 TI - The molecular dynamics of long noncoding RNA control of transcription in PTEN and its pseudogene. AB - RNA has been found to interact with chromatin and modulate gene transcription. In human cells, little is known about how long noncoding RNAs (lncRNAs) interact with target loci in the context of chromatin. We find here, using the phosphatase and tensin homolog (PTEN) pseudogene as a model system, that antisense lncRNAs interact first with a 5' UTR-containing promoter-spanning transcript, which is then followed by the recruitment of DNA methyltransferase 3a (DNMT3a), ultimately resulting in the transcriptional and epigenetic control of gene expression. Moreover, we find that the lncRNA and promoter-spanning transcript interaction are based on a combination of structural and sequence components of the antisense lncRNA. These observations suggest, on the basis of this one example, that evolutionary pressures may be placed on RNA structure more so than sequence conservation. Collectively, the observations presented here suggest a much more complex and vibrant RNA regulatory world may be operative in the regulation of gene expression. PMID- 28847967 TI - Petroleum dynamics in the sea and influence of subsea dispersant injection during Deepwater Horizon. AB - During the Deepwater Horizon disaster, a substantial fraction of the 600,000 900,000 tons of released petroleum liquid and natural gas became entrapped below the sea surface, but the quantity entrapped and the sequestration mechanisms have remained unclear. We modeled the buoyant jet of petroleum liquid droplets, gas bubbles, and entrained seawater, using 279 simulated chemical components, for a representative day (June 8, 2010) of the period after the sunken platform's riser pipe was pared at the wellhead (June 4-July 15). The model predicts that 27% of the released mass of petroleum fluids dissolved into the sea during ascent from the pared wellhead (1,505 m depth) to the sea surface, thereby matching observed volatile organic compound (VOC) emissions to the atmosphere. Based on combined results from model simulation and water column measurements, 24% of released petroleum fluid mass became channeled into a stable deep-water intrusion at 900- to 1,300-m depth, as aqueously dissolved compounds (~23%) and suspended petroleum liquid microdroplets (~0.8%). Dispersant injection at the wellhead decreased the median initial diameters of simulated petroleum liquid droplets and gas bubbles by 3.2-fold and 3.4-fold, respectively, which increased dissolution of ascending petroleum fluids by 25%. Faster dissolution increased the simulated flows of water-soluble compounds into biologically sparse deep water by 55%, while decreasing the flows of several harmful compounds into biologically rich surface water. Dispersant injection also decreased the simulated emissions of VOCs to the atmosphere by 28%, including a 2,000-fold decrease in emissions of benzene, which lowered health risks for response workers. PMID- 28847968 TI - Injection of T3SS effectors not resulting in invasion is the main targeting mechanism of Shigella toward human lymphocytes. AB - The enteroinvasive bacterium Shigella is a facultative intracellular bacterium known, in vitro, to invade a large diversity of cells through the delivery of virulence effectors into the cell cytoplasm via a type III secretion system (T3SS). Here, we provide evidence that the injection of T3SS effectors does not necessarily result in cell invasion. Indeed, we demonstrate through optimization of a T3SS injection reporter that effector injection without subsequent cell invasion, termed the injection-only mechanism, is the main strategy used by Shigella to target human immune cells. We show that in vitro-activated human peripheral blood B, CD4+ T, and CD8+ T lymphocytes as well as switched memory B cells are mostly targeted by the injection-only mechanism. B and T lymphocytes residing in the human colonic lamina propria, encountered by Shigella upon its crossing of the mucosal barrier, are also mainly targeted by injection-only. These findings reveal that cells refractory to invasion can still be injected, thus extending the panel of host cells manipulated to the benefit of the pathogen. Future analysis of the functional consequences of the injection-only mechanism toward immune cells will contribute to the understanding of the priming of adaptive immunity, which is known to be altered during the course of natural Shigella infection. PMID- 28847970 TI - QnAs with David B. Wake. PMID- 28847969 TI - Evolutionary consequences of multidriver environmental change in an aquatic primary producer. AB - Climate change is altering aquatic environments in a complex way, and simultaneous shifts in many properties will drive evolutionary responses in primary producers at the base of both freshwater and marine ecosystems. So far, evolutionary studies have shown how changes in environmental drivers, either alone or in pairs, affect the evolution of growth and other traits in primary producers. Here, we evolve a primary producer in 96 unique environments with different combinations of between one and eight environmental drivers to understand how evolutionary responses to environmental change depend on the identity and number of drivers. Even in multidriver environments, only a few dominant drivers explain most of the evolutionary changes in population growth rates. Most populations converge on the same growth rate by the end of the evolution experiment. However, populations adapt more when these dominant drivers occur in the presence of other drivers. This is due to an increase in the intensity of selection in environments with more drivers, which are more likely to include dominant drivers. Concurrently, many of the trait changes that occur during the initial short-term response to both single and multidriver environmental change revert after about 450 generations of evolution. In future aquatic environments, populations will encounter differing combinations of drivers and intensities of selection, which will alter the adaptive potential of primary producers. Accurately gauging the intensity of selection on key primary producers will help in predicting population size and trait evolution at the base of aquatic food webs. PMID- 28847971 TI - Correction for Hedrick et al., "NR4A1 Antagonists Inhibit beta1-Integrin Dependent Breast Cancer Cell Migration". PMID- 28847972 TI - Correction for Aebersold et al., "Extracellular Signal-Regulated Kinase 1c (ERK1c), a Novel 42-Kilodalton ERK, Demonstrates Unique Modes of Regulation, Localization, and Function". PMID- 28847973 TI - Correction for Li and Guan, "Human Mitochondrial Leucyl-tRNA Synthetase Corrects Mitochondrial Dysfunctions Due to the tRNALeu(UUR) A3243G Mutation, Associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Symptoms and Diabetes". PMID- 28847974 TI - Erratum for Trotter et al., "Glucocorticoid Receptor Transcriptional Activation via the BRG1-Dependent Recruitment of TOP2beta and Ku70/86". PMID- 28847975 TI - Correction for Guo et al., "Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification". PMID- 28847976 TI - Correction for Zhao et al., "Corepressive Action of CBP on Androgen Receptor Transactivation in Pericentric Heterochromatin in a Drosophila Experimental Model System". PMID- 28847977 TI - Caloric Restriction Prevents Carcinogen-Initiated Liver Tumorigenesis in Mice. AB - Caloric restriction (CR) and endurance exercise elicit wide-ranging health benefits including reduced risk of select cancers. In addition, diet composition influences oncogenesis, although its interactions with exercise and CR are not well understood. Therefore, to investigate the potential interactions between diet and lifestyle interventions on liver tumorigenesis, the carcinogen diethylnitrosamine was administered to 72 male C57Bl/6 mice that were subsequently fed diets enriched with lard (CTL) or olive oil and were further stratified to voluntary wheel running (Ex) or 30% CR for 49 weeks. Although Ex and diet composition did not influence liver oncogenesis, CR prevented hepatic tumor formation. In addition, CR reduced steatosis, hepatocyte ballooning, inflammation, and immune cell infiltration, all of which are hallmarks in the progression of nonalcoholic fatty liver disease to liver tumorigenesis. RNA sequencing of nontransformed liver tissues from CR mice revealed changes in metabolic pathways and reduced inflammation, cytokine production, stellate cell activation and migration, and genes associated with liver injury and oncogenesis. These data demonstrate that CR protects against steatosis, liver inflammation, and liver injury and is a robust deterrent of carcinogen-induced hepatic oncogenesis. Cancer Prev Res; 10(11); 660-70. (c)2017 AACR. PMID- 28847978 TI - Pediatric Integrative Medicine. AB - The American Academy of Pediatrics is dedicated to optimizing the well-being of children and advancing family-centered health care. Related to this mission, the American Academy of Pediatrics recognizes the increasing use of complementary and integrative therapies for children and the subsequent need to provide reliable information and high-quality clinical resources to support pediatricians. This Clinical Report serves as an update to the original 2008 statement on complementary medicine. The range of complementary therapies is both extensive and diverse. Therefore, in-depth discussion of each therapy or product is beyond the scope of this report. Instead, our intentions are to define terms; describe epidemiology of use; outline common types of complementary therapies; review medicolegal, ethical, and research implications; review education and training for select providers of complementary therapies; provide educational resources; and suggest communication strategies for discussing complementary therapies with patients and families. PMID- 28847979 TI - Guidance on Forgoing Life-Sustaining Medical Treatment. AB - Pediatric health care is practiced with the goal of promoting the best interests of the child. Treatment generally is rendered under a presumption in favor of sustaining life. However, in some circumstances, the balance of benefits and burdens to the child leads to an assessment that forgoing life-sustaining medical treatment (LSMT) is ethically supportable or advisable. Parents are given wide latitude in decision-making concerning end-of-life care for their children in most situations. Collaborative decision-making around LSMT is improved by thorough communication among all stakeholders, including medical staff, the family, and the patient, when possible, throughout the evolving course of the patient's illness. Clear communication of overall goals of care is advised to promote agreed-on plans, including resuscitation status. Perceived disagreement among the team of professionals may be stressful to families. At the same time, understanding the range of professional opinions behind treatment recommendations is critical to informing family decision-making. Input from specialists in palliative care, ethics, pastoral care, and other disciplines enhances support for families and medical staff when decisions to forgo LSMT are being considered. Understanding specific applicability of institutional, regional, state, and national regulations related to forgoing LSMT is important to practice ethically within existing legal frameworks. This guidance represents an update of the 1994 statement from the American Academy of Pediatrics on forgoing LSMT. PMID- 28847980 TI - Elimination of Perinatal Hepatitis B: Providing the First Vaccine Dose Within 24 Hours of Birth. AB - After the introduction of the hepatitis B vaccine in the United States in 1982, a greater than 90% reduction in new infections was achieved. However, approximately 1000 new cases of perinatal hepatitis B infection are still identified annually in the United States. Prevention of perinatal hepatitis B relies on the proper and timely identification of infants born to mothers who are hepatitis B surface antigen positive and to mothers with unknown status to ensure administration of appropriate postexposure immunoprophylaxis with hepatitis B vaccine and immune globulin. To reduce the incidence of perinatal hepatitis B transmission further, the American Academy of Pediatrics endorses the recommendation of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention that all newborn infants with a birth weight of greater than or equal to 2000 g receive hepatitis B vaccine by 24 hours of age. PMID- 28847982 TI - Antenatal Corticosteroid Therapy for Fetal Maturation. PMID- 28847981 TI - Early Childhood Home Visiting. AB - High-quality home-visiting services for infants and young children can improve family relationships, advance school readiness, reduce child maltreatment, improve maternal-infant health outcomes, and increase family economic self sufficiency. The American Academy of Pediatrics supports unwavering federal funding of state home-visiting initiatives, the expansion of evidence-based programs, and a robust, coordinated national evaluation designed to confirm best practices and cost-efficiency. Community home visiting is most effective as a component of a comprehensive early childhood system that actively includes and enhances a family-centered medical home. PMID- 28847983 TI - Adverse Events Following Immunization: Will It Happen Again? PMID- 28847984 TI - Racial/Ethnic Disparity in NICU Quality of Care Delivery. AB - BACKGROUND: Differences in NICU quality of care provided to very low birth weight (<1500 g) infants may contribute to the persistence of racial and/or ethnic disparity. An examination of such disparities in a population-based sample across multiple dimensions of care and outcomes is lacking. METHODS: Prospective observational analysis of 18 616 very low birth weight infants in 134 California NICUs between January 1, 2010, and December 31, 2014. We assessed quality of care via the Baby-MONITOR, a composite indicator consisting of 9 process and outcome measures of quality. For each NICU, we calculated a risk-adjusted composite and individual component quality score for each race and/or ethnicity. We standardized each score to the overall population to compare quality of care between and within NICUs. RESULTS: We found clinically and statistically significant racial and/or ethnic variation in quality of care between NICUs as well as within NICUs. Composite quality scores ranged by 5.26 standard units (range: -2.30 to 2.96). Adjustment of Baby-MONITOR scores by race and/or ethnicity had only minimal effect on comparative assessments of NICU performance. Among subcomponents of the Baby-MONITOR, non-Hispanic white infants scored higher on measures of process compared with African Americans and Hispanics. Compared with whites, African Americans scored higher on measures of outcome; Hispanics scored lower on 7 of the 9 Baby-MONITOR subcomponents. CONCLUSIONS: Significant racial and/or ethnic variation in quality of care exists between and within NICUs. Providing feedback of disparity scores to NICUs could serve as an important starting point for promoting improvement and reducing disparities. PMID- 28847986 TI - Health Equity and Quality of Care Assessment: A Continuing Challenge. PMID- 28847985 TI - Risk of Recurrence of Adverse Events Following Immunization: A Systematic Review. AB - CONTEXT: Reimmunizing patients who had an adverse event following immunization (AEFI) is sometimes a challenge because there are limited data on the risk and severity of AEFI recurrence. OBJECTIVE: To summarize the literature on the risk of AEFI recurrence. DATA SOURCES: PubMed, Embase, and Cochrane library. STUDY SELECTION: We included articles in English or French published before September 30, 2016. Articles were selected if they estimated the risk of AEFI recurrence in at least 5 individuals. Studies with experimental vaccines were excluded. DATA EXTRACTION: Data on study design, setting, population, vaccines, and AEFI recurrence were extracted. RESULTS: Twenty-nine articles were included. Among patients with a history of hypotonic hyporesponsive episode (n = 398), anaphylaxis (n = 133), or seizures (n = 60) who were reimmunized, events recurred in 0% to 0.8%. Allergic-like events recurred in 30 of 594 reimmunized patients. Fever recurred in 0% to 84% of 836 reimmunized patients, depending on the vaccine and dose number. Among children with extensive limb swelling after the fourth dose of diphtheria-tetanus-acellular pertussis vaccine, recurrence was higher when the fifth dose was given withthe full-antigen formulation (78%) compared with the reduced-antigen formulation (53%, P = .02) LIMITATIONS: Many studies, included few patients, and those with severe AEFIs were often not reimmunized. CONCLUSIONS: Despite vaccines being administered to millions of people annually, there are few studies in which researchers evaluated AEFI recurrence. Published studies suggest that reimmunization is usually safe. However in these studies, severe cases were often not reimmunized. PMID- 28847987 TI - TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response. AB - Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53 mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 mutants promote lung carcinogenesis through loss-of function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for TRP53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease. Mol Cancer Ther; 16(12); 2913-26. (c)2017 AACR. PMID- 28847989 TI - Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer. AB - Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting. Mol Cancer Ther; 16(11); 2552-62. (c)2017 AACR. PMID- 28847990 TI - Abdominal tuberculosis and spontaneous miscarriage. AB - We present a case report of a 23-year-old Pakistani woman who had a second trimester spontaneous miscarriage while visiting her family in the Kingdom of Saudi Arabia. A dilatation and curettage (D&C) was done after the miscarriage. She developed sepsis and acute respiratory distress syndrome, requiring intensive care unit admission a few days after the D&C. An exploratory laparotomy was done and she was found to have a pelvic abscess. Despite adequate broad spectrum antimicrobial cover, she continued to drain a copious amount of serous fluid from the peritoneal cavity, with persistent fever and a stiff lung with difficult weaning off mechanical ventilation. Tuberculosis PCR of the peritoneal fluid came back positive. A histological finding of necrotising granuloma from the postoperative omental specimen and a positive culture from the ascitic fluid confirmed the diagnosis of Mycobacterium tuberculosis Antituberculous treatment was started and she made a speedy recovery. PMID- 28847988 TI - Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma. AB - Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Currently, treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anticancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug ingenol-3-angelate (PEP005) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal (BET) protein inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL6 production from PEL cells. Using the dosages of these agents that were found to be effective in reactivating HIV (as a means to clear latent virus with highly active antiretroviral therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of the NF-kappaB pathway by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL. Mol Cancer Ther; 16(11); 2627-38. (c)2017 AACR. PMID- 28847991 TI - Dilemma of diagnosing sulphonylurea overdose in children: deliberations and considerations before reaching a diagnosis. AB - A 15-year-old non-diabetic Caucasian girl presented with sudden onset of seizures, unrecordable blood glucose readings and acute renal failure. She denied any medication ingestion and no other precipitating factors were encountered for this acute presentation. She was treated with intravenous glucose infusion and hydrocortisone injection. Investigations showed a non-ketotic hypoglycaemia with high C-peptide and insulin levels. It took several days and multiple investigations to establish the exact cause of her persistent hypoglycaemia before it was concluded to be secondary to gliclazide overdose in a suicide attempt by the young girl. She made a complete recovery in a week with no apparent lasting neurological or renal impairment. PMID- 28847992 TI - Invading beyond bounds: extraintestinal Clostridium difficile infection leading to pancreatic and liver abscesses. AB - Clostridium difficile has become a common healthcare-associated infection over the past few years and gained more attention. C. difficile was estimated to cause almost half a million infections in USA in 2011 and 29 000 died within 30 days of the initial diagnosis. Although colitis due to C. difficile is the most common presentation, there have been reported cases of extraintestinal infections. As per our review of literature, this is the third reported case of liver abscess due to the organism. PMID- 28847993 TI - Hypertensive bipolar: chronic lithium toxicity in patients taking ACE inhibitor. AB - A patient with bipolar I disorder has been treated with lithium and haloperidol for the last 20 years and received an ACE inhibitor for his hypertension since 9 years ago. Despite regular clinic follow-ups and blood monitoring, he recently developed tremors and delirium. On hospital admission, serum level of lithium was far above toxic level. Mental state examination revealed an anxious and disorientated man with irrelevant speech. Immediate discontinuation of lithium resulted in slow reduction of serum lithium levels and gradual resolution of tremor but his delirium persisted for 2 weeks. His condition took a turn for the worse when he developed acute renal failure and arm abscess. We discussed about lithium toxicity and the vulnerability factors which have induced delirium and renal failure in this patient. PMID- 28847994 TI - Elephantiasis nostras verrucosa: a rare complication of lower limb lymphoedema. AB - We reported a case of a 49-year-old man who had chronic lymphoedema of bilateral lower limbs for 30 years, but he did not seek treatment. His disease was complicated with irreversible changes of elephantiasis nostras verrucosa and had recurrent admissions due to infection. He was not keen for surgical intervention. This case report illustrated a rare and non-reversible complication of a common skin disease, lymphoedema and also the importance of identifying and treating it early. PMID- 28847995 TI - Novel oral anticoagulant and kidney injury: apixaban-related acute interstitial nephritis. AB - Non-vitamin K oral anticoagulants (NOACs) are being increasingly prescribed. These drugs act rapidly, have predictable dose-related anticoagulation effect and require no routine laboratory monitoring, making them attractive for both patients and healthcare providers. All NOACs are at least partially excreted thought the kidneys. Renal injury related to NOAC use is being increasingly reported. NOAC-related acute interstitial nephritis (AIN) has only been reported once and that was in context of dabigatran use. We describe the first case of apixaban-related AIN. This case adds an important differential diagnoses that should be considered for any patient presenting with renal injury while being treated with NOACs. PMID- 28847996 TI - Multiple sclerotic fibromas of the skin: an important clue for the diagnosis of Cowden syndrome. AB - Cowden syndrome is a rare autosomal dominant condition characterised by mucocutaneous hamartomas and, most importantly, predisposition to various extracutaneous benign and malignant tumours. This disorder is associated with a germline mutation in the phosphatase and tensin homologue gene, a tumour suppressor gene, located on 10q23 chromosome. The expressivity of this genodermatosis is highly variable, therefore many of the cases remain undiagnosed. Skin and mucous findings are very common in Cowden syndrome and may represent the initial clinical manifestation leading to the diagnosis. The authors describe a case of a 58-year-old man with multiple cutaneous sclerotic fibromas associated with a previously unrecognised Cowden syndrome. PMID- 28847997 TI - CD207+CD1a+ cells circulate in pediatric patients with active Langerhans cell histiocytosis. AB - Langerhans cell histiocytosis (LCH) is a rare disease with an unknown etiology characterized by heterogeneous lesions containing CD207+CD1a+ cells that can arise in almost any tissue and cause significant morbidity and mortality. Precursors of pathological Langerhans cells have yet to be defined. Our aim was to identify circulating CD207+CD1a+ cells and their inducers in LCH. Expression of CD207 and CD1a in the blood myeloid compartment as well as thymic stromal lymphopoietin (TSLP) and transforming growth factor beta (TGF-beta) plasma levels were measured in 22 pediatric patients with active disease (AD) or nonactive disease (NAD). In patients with AD vs those with NAD, the myeloid compartment showed an increased CD11b (CD11bhigh plus CD11b+) fraction (39.7 +/- 3.6 vs 18.6 +/- 1.9), a higher percentage of circulating CD11bhighCD11c+CD207+ cells (44.5 +/ 11.3 vs 3.2 +/- 0.5), and the presence of CD11chighCD207+CD1a+ cells (25.0 +/- 9.1 vs 2.3 +/- 0.5). Blood CD207+CD1a+ cells were not observed in adult controls or umbilical cord. Increased TSLP and TGF-beta levels were detected in patients with AD. Interestingly, plasma from patients with AD induces CD207 expression on CD14+ monocytes. We conclude that CD207+CD1a+ cells are circulating in patients with active LCH, and TSLP and TGF-beta are potential drivers of Langerhans-like cells in vivo. PMID- 28847999 TI - Reclaiming the value of pictorial health warning labels in Jordan. AB - BACKGROUND: In Jordan, four non-graphic pictorial health warning labels (PHWLs) concerning a limited selection of tobacco-caused harms have been used since 2011; however, research suggests that they may be ineffective. OBJECTIVES: To explore Jordanian smokers' reactions to novel PHWLs featuring various health themes and/or graphic and symbolic imagery and to discuss existing PHWLs in light of the novel PHWLs. METHODS: We conducted 14 focus groups (FGs) with smokers who assessed 12 novel PHWLs and commented on four existing PHWLs. Data were analysed using an inductive approach. RESULTS: Six themes emerged from the FG discussions: understanding the overall meaning of PHWLs, the impact of graphic images, magnitude and controllability of harm, personal or vicarious experiences, the futility of quitting and fatalism. PHWLs depicting graphic respiratory and oral tobacco-caused harms resonated with most smokers. Smokers also sought direct, harm-specific taglines when trying to understand the overall PHWL. Some smokers viewed the PHWLs as exaggerated, and while the majority acknowledged that smoking was harmful, they felt that PHWLs would not accomplish their goal of inducing quitting. CONCLUSIONS: Our findings support the use of graphic imagery to communicate tobacco-caused harms (particularly respiratory ones) and the use of specific taglines explaining the mechanism of harm depicted. PMID- 28848000 TI - Use of prescribed smoking cessation pharmacotherapy following release from prison: a prospective data linkage study. AB - BACKGROUND: A significant proportion of people who cycle through prisons express a desire to quit smoking, yet smoking rates in this population are two to four times higher than in the general community. Smoking cessation pharmacotherapy (SCP) is an important component of evidence-based cessation support, yet no studies have examined use of this pharmacotherapy after release from prison. METHODS: We linked data from a survey of 971 smokers who were within 8 weeks of release from prison in Queensland, Australia, with federal Pharmaceutical Benefits Scheme (PBS) records for the 2 years after release, to identify subsidised use of SCP (varenicline, bupropion and nicotine patches). We used Cox proportional hazards regression to identify independent predictors of SCP use. FINDINGS: According to PBS data, 86 participants (8.9%) accessed SCP in the 2 years following release from prison. Participants who were aged 25 years or older (HR 2.51, 95% CI 1.19 to 5.31), employed before prison (HR 1.93, 95% CI 1.14 to 3.28), highly nicotine dependent at baseline (HR 2.21, 95% CI 1.23 to 3.97) and using non-psychotropic medications in prison (HR 2.29, 95% CI 1.24 to 4.22) were more likely to use subsidised SCP during follow-up. CONCLUSION: Despite a very high rate of tobacco use among people cycling through prisons and the very low cost of (subsidised) SCP in Australia, few ex-prisoners obtain pharmaceutical assistance with quitting smoking. Policy attention needs to focus on supporting former prisoners to access SCP, to reduce the high rate of tobacco-related morbidity and mortality in this profoundly marginalised population. PMID- 28848001 TI - The Trauma of Dialysis Initiation. PMID- 28847998 TI - Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. AB - The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], and nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (>=VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and >=VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% [17/18]) than patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507. PMID- 28848003 TI - Evaluation of Urinary KIM-1 for Prediction of Polymyxin B-Induced Nephrotoxicity. PMID- 28848002 TI - In Vitro Interactions of Echinocandins with Triazoles against Multidrug-Resistant Candida auris. AB - We determined the in vitro interactions between echinocandins and azoles against 10 multidrug-resistant Candida auris strains by use of a microdilution checkerboard technique. Our results suggest synergistic interactions between micafungin and voriconazole with fractional inhibitory concentration index (FICI) values of 0.15 to 0.5, and we observed indifferent interactions when micafungin was combined with fluconazole (FICI, 0.62 to 1.5). Combinations of caspofungin with fluconazole or voriconazole exhibited indifferent interactions. No antagonism was observed for any combination. PMID- 28848004 TI - Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model. AB - Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult to-treat isolates remains to be fully explored in vivo Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or >=1 log reduction in 67 isolates with MICs of <=4 MUg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of >=8 MUg/ml, bacterial stasis or >=1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of <=4 MUg/ml, whereas isolates with MICs of >=8 MUg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations. PMID- 28848005 TI - Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus. AB - Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals had an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of Aspergillus fumigatus with itraconazole and terbinafine. By applying the mitochondrion-specific lipid peroxidation probe MitoPerOx, we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in A. fumigatus challenged with antifungal compounds. PMID- 28848006 TI - Amino Acid Substitution in the Major Multidrug Efflux Transporter Protein AcrB Contributes to Low Susceptibility to Azithromycin in Haemophilus influenzae. AB - Clarithromycin-resistant Haemophilus influenzae strains with a nonsense mutation in acrR generally exhibited susceptibility to azithromycin, although one strain was found to be nonsusceptible; we aimed to clarify the differences. This strain had an amino acid substitution, Arg327Ser, in AcrB. Introduction of this substitution into H. influenzae Rd caused an increase in the MIC of azithromycin, suggesting that this substitution contributed to nonsusceptibility. These findings indicate that azithromycin-nonsusceptible isolates could occur through stepwise mutation in the acr region. PMID- 28848007 TI - Potentiation of Tobramycin by Silver Nanoparticles against Pseudomonas aeruginosa Biofilms. AB - Increasing antibiotic resistance among pathogenic bacterial species is a serious public health problem and has prompted research examining the antibacterial effects of alternative compounds and novel treatment strategies. Compounding this problem is the ability of many pathogenic bacteria to form biofilms during chronic infections. Importantly, these communities are often recalcitrant to antibiotic treatments that show effectiveness against acute infection. The antimicrobial properties of silver have been known for decades, but recently silver and silver-containing compounds have seen renewed interest as antimicrobial agents for treating bacterial infections. The goal of this study was to assess the ability of citrate-capped silver nanoparticles (AgNPs) of various sizes, alone and in combination with the aminoglycoside antibiotic tobramycin, to inhibit established Pseudomonas aeruginosa biofilms. Our results demonstrate that smaller 10-nm and 20-nm AgNPs were more effective at synergistically potentiating the activity of tobramycin. Visualization of biofilms treated with combinations of 10-nm AgNPs and tobramycin reveals that the synergistic bactericidal effect may be caused by disrupting cellular membranes. Minimum biofilm eradication concentration (MBEC) assays using clinical P. aeruginosa isolates shows that small AgNPs are more effective than larger AgNPs at inhibiting biofilms, but that the synergy effect is likely a strain-dependent phenomenon. These data suggest that small AgNPs synergistically potentiate the activity of tobramycin against P. aeruginosain vitro and may reveal a potential role for AgNP/antibiotic combinations in treating patients with chronic infections in a strain-specific manner. PMID- 28848008 TI - When Good Bugs Go Bad: Epidemiology and Antimicrobial Resistance Profiles of Corynebacterium striatum, an Emerging Multidrug-Resistant, Opportunistic Pathogen. AB - Infections with Corynebacterium striatum have been described in the literature over the last 2 decades, with the majority being bacteremia, central line infections, and occasionally, endocarditis. In recent years, the frequency of C. striatum infections appears to be increasing; a factor likely contributing to this is the increased ease and accuracy of the identification of Corynebacterium spp., including C. striatum, from clinical cultures. The objective of this study was to retrospectively characterize C. striatum isolates recovered from specimens submitted as part of routine patient care at a 1,250-bed, tertiary-care academic medical center. Multiple strain types were recovered, as demonstrated by repetitive-sequence-based PCR. Most of the strains of C. striatum characterized were resistant to antimicrobials commonly used to treat Gram-positive organisms, such as penicillin, ceftriaxone, meropenem, clindamycin, and tetracycline. The MIC50 for ceftaroline was >32 MUg/ml. Although there are no interpretive criteria for susceptibility with telavancin, it appeared to have potent in vitro efficacy against this species, with MIC50 and MIC90 values of 0.064 and 0.125 MUg/ml, respectively. Finally, as previously reported in case studies, we demonstrated rapid in vitro development of daptomycin resistance in 100% of the isolates tested (n = 50), indicating that caution should be exhibited when using daptomycin for the treatment of C. striatum infections. C. striatum is an emerging, multidrug-resistant pathogen that can be associated with a variety of infection types. PMID- 28848009 TI - Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose. AB - Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of >=1.5 MUg/ml and maintained a TC above 1 MUg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of >=1.5 MUg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 MUg/ml, resulting in a 33% savings in the cost of this very expensive drug. PMID- 28848010 TI - Heterogeneous Genetic Location of mcr-1 in Colistin-Resistant Escherichia coli Isolates from Humans and Retail Chicken Meat in Switzerland: Emergence of mcr-1 Carrying IncK2 Plasmids. AB - We characterized the genetic environment of mcr-1 in colistin-resistant Escherichia coli strains isolated in Switzerland during 2014 to 2016 from humans (n = 3) and chicken meat (n = 6). Whole-genome and plasmid sequencing identified the mcr-1 gene integrated in IncX4 (of which, one strain carried the mcr-1.2 variant), IncI2, IncHI2, and novel IncK2 plasmids (overall, n = 7), as well as in the bacterial chromosome (n = 2) in single or duplicate copies. Our study supports the easy mobilization of mcr-1 across diverse genetic locations. PMID- 28848011 TI - Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. AB - Dabigatran etexilate (DE) is a P-glycoprotein (P-gp) probe substrate, and its active anticoagulant moiety, dabigatran, is a substrate of the multidrug and toxin extrusion protein-1 (MATE-1) transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE at 150 mg alone, followed by ritonavir at 100 mg or cobicistat at 150 mg daily for 2 weeks. DE was then given 2 h before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran pharmacokinetic (PK) exposure or thrombin time (TT) measures were observed with the simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean decrease in dabigatran PK exposure of 29% (90% confidence interval [CI], 18 to 40%) but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (area under the concentration-versus-time curve from time zero to infinity and maximum plasma concentration) by 127% each (90% CI, 81 to 173% and 59 to 196%, respectively) and increased TT measures (33% for the area-under-the-effect curve from time zero to 24 h [90% CI, 22 to 44%] and 51% for TT at 24 h [90% CI, 22 to 78%]) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by 2 h from the administration of dabigatran. In all comparisons, no significant increase in the dabigatran elimination half-life was observed. Therefore, it is likely safe to coadminister ritonavir with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with the coadministration of cobicistat due to the greater net inhibition of intestinal P-gp transport and increased bioavailability. (This study has been registered at ClinicalTrials.gov under identifier NCT01896622.). PMID- 28848012 TI - In Vitro Activities of Luliconazole, Lanoconazole, and Efinaconazole Compared with Those of Five Antifungal Drugs against Melanized Fungi and Relatives. AB - The in vitro activities of novel azoles compared to those of five antifungal drugs against clinical (n = 28) and environmental (n = 102) isolates of black mold and melanized yeast were determined. Luliconazole and lanoconazole had the lowest geometric mean MICs, followed by efinaconazole, against tested isolates compared to the other drugs. Therefore, it appears that these new imidazole and triazole drugs are promising candidates for the treatment of infections due to melanized fungi and their relatives. PMID- 28848014 TI - Intracavitary and Systemic Daptomycin for Successful Treatment of a Postpneumonectomy Intrathoracic Infection. AB - Treatment of an infected postpneumonectomy cavity is very difficult. We present a patient with an infection of a postpneumonectomy cavity by Staphylococcus epidermidis treated with local daptomycin for different dwell times, maintaining high antibiotic levels above the MIC. Clinical and microbiological cure were achieved successfully. PMID- 28848013 TI - Potent beta-Lactam Enhancer Activity of Zidebactam and WCK 5153 against Acinetobacter baumannii, Including Carbapenemase-Producing Clinical Isolates. AB - Multidrug-resistant Acinetobacter baumannii has rapidly spread worldwide, resulting in a serious threat to hospitalized patients. Zidebactam and WCK 5153 are novel non-beta-lactam bicyclo-acyl hydrazide beta-lactam enhancer antibiotics being developed to target multidrug-resistant A. baumannii The objectives of this work were to determine the 50% inhibitory concentrations (IC50s) for penicillin binding proteins (PBP), the OXA-23 inhibition profiles, and the antimicrobial activities of zidebactam and WCK 5153, alone and in combination with beta lactams, against multidrug-resistant A. baumannii MICs and time-kill kinetics were determined for an A. baumannii clinical strain producing the carbapenemase OXA-23 and belonging to the widespread European clone II of sequence type 2 (ST2). Inhibition of the purified OXA-23 enzyme by zidebactam, WCK 5153, and comparators was assessed. All of the compounds tested displayed apparent Ki values of >100 MUM, indicating poor OXA-23 beta-lactamase inhibition. The IC50s of zidebactam, WCK 5153, cefepime, ceftazidime, meropenem, and sulbactam (range of concentrations tested, 0.02 to 2 MUg/ml) for PBP were also determined. Zidebactam and WCK 5153 demonstrated specific high-affinity binding to PBP2 of A. baumannii (0.01 MUg/ml for both of the compounds). The MICs of zidebactam and WCK 5153 were >1,024 MUg/ml for wild-type and multidrug-resistant Acinetobacter strains. Importantly, combinations of cefepime with 8 MUg/ml of zidebactam or WCK 5153 and sulbactam with 8 MUg/ml of zidebactam or WCK 5153 led to 4- and 8-fold reductions of the MICs, respectively, and showed enhanced killing. Notably, several of the combinations resulted in full bacterial eradication at 24 h. We conclude that zidebactam and WCK 5153 are PBP2 inhibitors that show a potent beta lactam enhancer effect against A. baumannii, including a multidrug-resistant OXA 23-producing ST2 international clone. PMID- 28848015 TI - Translational Efficacy of Humanized Exposures of Cefepime, Ertapenem, and Levofloxacin against Extended-Spectrum-beta-Lactamase-Producing Escherichia coli in a Murine Model of Complicated Urinary Tract Infection. AB - Validated animal models are required as bridging tools to assess the utility of novel therapies and potential microbiologic outcomes. Herein, we utilized uropathogenic extended-spectrum-beta-lactamase (ESBL)-producing and non-ESBL producing Escherichia coli in the neutropenic murine complicated urinary tract infection (cUTI) model with humanized exposures of cefepime, ertapenem, and levofloxacin to assess its translational value to human outcomes. Our data support the translational utility of this murine model to cUTI in humans as humanized exposures produced microbiologic outcomes consistent with the phenotypic profiles of the organisms. PMID- 28848016 TI - Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram Positive Bacterial Infections. AB - Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Both previously published and new selective inhibitors were shown to be highly active against Gram-positive bacteria with MICs of <=1.3 MUg/ml against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated that the mechanism of activity was due to the inhibition of protein synthesis. Little activity against Gram-negative bacteria was observed, consistent with the fact that Gram-negative bacterial species contain a different type of MetRS enzyme. The ratio of the MIC to the minimum bactericidal concentration (MBC) was consistent with a bacteriostatic mechanism. The level of protein binding of the compounds was high (>95%), and this translated to a substantial increase in MICs when the compounds were tested in the presence of serum. Despite this, the compounds were very active when they were tested in a Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144, given by oral gavage, resulted in 3- to 4-log decreases in the bacterial load compared to that in vehicle-treated mice, which was comparable to the results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development. PMID- 28848017 TI - Chromosome-Mediated mcr-3 Variants in Aeromonas veronii from Chicken Meat. AB - Two adjacent colistin resistance gene variants, termed mcr-3.3 and mcr-3-like, were identified in the chromosome of an Aeromonas veronii isolate obtained from retail chicken meat. The variants showed 95.20% and 84.19% nucleotide sequence identity, respectively, to mcr-3 from porcine Escherichia coli Functional cloning indicated that only mcr-3.3 conferred polymyxin resistance in both E. coli and Aeromonas salmonicida The mcr-3.3-mcr-3-like segment was also observed in other Aeromonas species, including A. media, A. caviae, and A. hydrophila. PMID- 28848018 TI - Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae. AB - Vaborbactam (formerly RPX7009) is a new beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of beta-lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with beta-lactamases cloned from various classes and a panel of Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent inhibitor of class A carbapenemases, such as KPC, as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to the potencies of vaborbactam in combination with other antibiotics against strains producing the KPC beta-lactamase. Consistent with broad-spectrum beta-lactamase inhibition, vaborbactam reduced the meropenem MICs for engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of extended-spectrum beta-lactamase production, class C beta-lactamase production, and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC had a minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency showed that vaborbactam at 8 MUg/ml results in meropenem MICs of <=2 MUg/ml in the most resistant engineered strains containing multiple mutations. Vaborbactam is a highly active beta-lactamase inhibitor that restores the activity of meropenem and other beta-lactam antibiotics in beta-lactamase-producing bacteria, particularly KPC-producing carbapenem-resistant Enterobacteriaceae. PMID- 28848020 TI - Genomic Characterization of VIM Metallo-beta-Lactamase-Producing Alcaligenes faecalis from Gaza, Palestine. AB - Carbapenemase-producing Gram-negative bacteria (CP-GNB) have increasingly spread worldwide, and different families of carbapenemases have been identified in various bacterial species. Here, we report the identification of five VIM metallo beta-lactamase-producing Alcaligenes faecalis isolates associated with a small outbreak in a large hospital in Gaza, Palestine. Next-generation sequencing analysis showed blaVIM-2 is harbored by a chromosomal genomic island among three strains, while blaVIM-4 is carried by a novel plasmid in two strains. PMID- 28848019 TI - Extinction of West Nile Virus by Favipiravir through Lethal Mutagenesis. AB - Favipiravir is an antiviral agent effective against several RNA viruses. The drug has been shown to protect mice against experimental infection with a lethal dose of West Nile virus (WNV), a mosquito-borne flavivirus responsible for outbreaks of meningitis and encephalitis for which no antiviral therapy has been licensed; however, the mechanism of action of the drug is still not well understood. Here, we describe the potent in vitro antiviral activity of favipiravir against WNV, showing that it decreases virus-specific infectivity and drives the virus to extinction. Two passages of WNV in the presence of 1 mM favipiravir-a concentration that is more than 10-fold lower than its 50% cytotoxic concentration (CC50)-resulted in a significant increase in mutation frequency in the mutant spectrum and in a bias toward A->G and G->A transitions relative to the population passaged in the absence of the drug. These data, together with the fact that the drug is already licensed in Japan against influenza virus and in a clinical trial against Ebola virus, point to favipiravir as a promising antiviral agent to fight medically relevant flaviviral infections, such as that caused by WNV. PMID- 28848021 TI - Real-Time PCR Targeting the penA Mosaic XXXIV Type for Prediction of Extended Spectrum-Cephalosporin Susceptibility in Clinical Neisseria gonorrhoeae Isolates. AB - Neisseria gonorrhoeae isolates with decreased susceptibility to extended-spectrum cephalosporins (ESCs) are increasing. We developed an assay to predict N. gonorrhoeae susceptibility to ESCs by targeting penA mosaic XXXIV, an allele prevalent among U.S. isolates with elevated ESC MICs. The assay was 97% sensitive and 100% specific for predicting at least one ESC MIC above the CDC alert value among clinical isolates, and it could be multiplexed with a previously validated gyrA PCR to predict ciprofloxacin susceptibility. PMID- 28848022 TI - Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters. AB - CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (~133 h in humans, ~70 to 80 h in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e., the time course of CD101 concentrations) influences efficacy. To test this hypothesis, doses which produce the same total area under the concentration-time curve (AUC) were administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single intravenous (i.v.) dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over 7 days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 h following the start of treatment. Fungi grew well in the no treatment control group and showed variable changes in fungal density in the treatment groups. When the CD101 AUC from 0 to 168 h (AUC0-168) was administered as a single dose, a >2 log10 CFU reduction from the baseline at 168 h was observed. When twice-weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1 log10 CFU increase from the baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 administered once per week demonstrated a greater degree of fungal killing than the same dose divided into twice-weekly or daily regimens. PMID- 28848023 TI - Prevalence of age-related macular degeneration in rural southern China: the Yangxi Eye Study. AB - PURPOSE: To describe the prevalence of age-related macular degeneration (AMD) among older adults in rural southern mainland China. METHODS: Eligible persons aged 50 years or over were identified by geographically defined cluster sampling from Yangxi County, Guangdong Province, China. Participants underwent a standardised interview and comprehensive eye examinations from August to November in 2014. Digital retinal photographs were graded for AMD lesions using the Clinical Classification of Age-Related Macular Degeneration developed by the Beckman Initiative for Macular Research Classification Committee. Age standardised prevalence of AMD and AMD lesions was calculated using the 2010 world population data and compared with those of other populations. RESULTS: Of 5825 subjects who participated (90.7% response rate), 4881 (83.8%) had fundus photographs gradable for AMD. Early, intermediate and late AMD were present in 2003 (41.0%), 879 (18.0%) and 42 (0.86%) participants. The age-standardised prevalence of early, intermediate and late AMD was 40.4% (95% CI 39.6% to 41.2%), 17.6% (95% CI 17.0% to 18.2%) and 0.79% (95% CI 0.65% to 0.95%), respectively. Total AMD was more prevalent in men than in women (62.8% vs 57.1%). CONCLUSIONS: AMD is an important public health concern for rural southern China, and the prevalence of AMD was higher in men than in women. PMID- 28848024 TI - Prevalence of amblyopia and its association with refraction in Chinese preschool children aged 36-48 months. AB - PURPOSE: To determine the prevalence of amblyopia and its association with refraction in Chinese preschool children. METHODS: The Yuhuatai Pediatric Eye Disease Study, a cross-sectional, population-based study, was conducted in children aged 36-48 months in Yuhuatai District, Nanjing, China, in 2015. Visual acuity was measured in 1695 eligible children. RESULTS: Of the 1695 subjects, manifested amblyopia was detected in 25 children (1.47%, 95% CI 0.90% to 2.05%), including 11 and 14 with bilateral and unilateral amblyopia, respectively. Amblyopia prevalence did not differ by gender (p=0.77). Significant refractive errors were found in 22 (88.0%) of children with amblyopia, and strabismus was found in 6 (24.0%) children with amblyopia. In multivariate analysis, amblyopia was significantly associated with hyperopia (>=+2.00 dioptres (D); OR 8.81, 95% CI 3.27 to 23.69, p<0.0001), astigmatism (>=2.00 D; OR 17.90, 95% CI 6.78 to 47.21, p<0.0001) and anisometropia (>=2.00 D; OR 5.87, 95% CI 1.52 to 22.77, p<0.05). CONCLUSIONS: The prevalence of amblyopia in children 36-48 months old in Eastern China was 1.47%. The refractive error is a major risk factor for amblyopia. PMID- 28848025 TI - Bullous X linked retinoschisis: clinical features and prognosis. AB - BACKGROUND/AIMS: A subset of patients with X linked retinoschisis (XLRS) have bullous schisis cavities in the peripheral retina. This study describes the characteristics and prognosis of the bullous form of XLRS. METHODS: A retrospective case series was performed of nine patients with molecularly proven bullous XLRS seen at a single tertiary centre. RESULTS: All cases of bullous peripheral schisis were bilateral, with one unilateral case at presentation which developed into bilateral bullous schisis over time. The mean age of onset was 1.9 years (range: 1 month-7 years, SD: 2.1 years) and at clinical diagnosis was 5.9 years (range: 1 month-27 years, SD: 9.0 years). Mean follow-up was 11 years (range: 6 months-36 years, SD: 10.8 years). Strabismus was the most common presentation (n=7). Other presenting complaints included decreased vision, floaters and an irregularly shaped pupil. The most frequently associated ocular features were strabismus (100%), vitreous haemorrhage (4/18 eyes, 22%), nystagmus (2/9, 22%) and persistent fetal vasculature (1/18, 6%). Localised tractional detachment was seen in 2/18 (11%) eyes, total detachment that underwent surgical repair in 1/18 (6%) and pigmented demarcation lines in a further 22% of the eyes. There was one eye with exudative retinal detachment. CONCLUSION: In XLRS, bullous schisis may be congenital or develop soon after birth and most commonly presents with strabismus. Cases may be complicated by some form of retinal detachment, which may be tractional or a Coats-like exudative detachment. PMID- 28848026 TI - Prolonged Prothrombin Time After Discontinuing Vitamin K Antagonist. PMID- 28848027 TI - Commentary. PMID- 28848028 TI - Commentary. PMID- 28848029 TI - Correction. PMID- 28848030 TI - Severe Abdominal Pain with Hyponatremia. PMID- 28848031 TI - Ready to Settle. PMID- 28848032 TI - An Ode to "Measurement Uncertainty". PMID- 28848033 TI - Art at the Time of Turmoil: Max Beckmann. PMID- 28848035 TI - Biodistribution and Dosimetry Results from a Phase 1 Trial of Therapy with the Antibody-Radionuclide Conjugate 177Lu-Lilotomab Satetraxetan. AB - 177Lu-lilotomab satetraxetan is a novel antibody-radionuclide conjugate currently in a phase 1/2a first-in-humans dose escalation trial for patients with relapsed CD37-positive indolent non-Hodgkin lymphoma. The aim of this study was to investigate biodistribution and absorbed doses to organs at risk. Methods: In total, 7 patients treated with 177Lu-lilotomab satetraxetan were included for dosimetry. Patients were grouped on the basis of 2 different predosing regimens (with and without predosing with 40 mg of lilotomab) and were treated with different levels of activity per body weight (10, 15, and 20 MBq/kg). All patients were pretreated with rituximab. Serial planar and SPECT/CT images were used to determine time-activity curves and patient-specific masses for organs with 177Lu-lilotomab satetraxetan uptake. Doses were calculated with OLINDA/EXM. Results: The organs (other than red bone marrow and tumors) with distinct uptake of 177Lu-lilotomab satetraxetan were the liver, spleen, and kidneys. The highest uptake was found in the spleen, with doses ranging from 1.54 to 3.60 mGy/MBq. The liver received 0.70-1.15 mGy/MBq. The kidneys received the lowest dose of the source organs investigated, 0.16-0.79 mGy/MBq. No statistically significant differences in soft-tissue absorbed doses were found between the two predosing regimens. The whole-body dose ranged from 0.08 to 0.17 mGy/MBq. Conclusion: The biodistribution study for patients treated with 177Lu-lilotomab satetraxetan revealed the highest physiologic uptake to be in the liver and spleen (besides the red marrow). For all treatment levels investigated, the absorbed doses were found to be modest when compared with commonly assumed tolerance limits. PMID- 28848034 TI - Rab35 GTPase recruits NDP52 to autophagy targets. AB - Autophagy targets intracellular molecules, damaged organelles, and invading pathogens for degradation in lysosomes. Recent studies have identified autophagy receptors that facilitate this process by binding to ubiquitinated targets, including NDP52. Here, we demonstrate that the small guanosine triphosphatase Rab35 directs NDP52 to the corresponding targets of multiple forms of autophagy. The active GTP-bound form of Rab35 accumulates on bacteria-containing endosomes, and Rab35 directly binds and recruits NDP52 to internalized bacteria. Additionally, Rab35 promotes interaction of NDP52 with ubiquitin. This process is inhibited by TBC1D10A, a GAP that inactivates Rab35, but stimulated by autophagic activation via TBK1 kinase, which associates with NDP52. Rab35, TBC1D10A, and TBK1 regulate NDP52 recruitment to damaged mitochondria and to autophagosomes to promote mitophagy and maturation of autophagosomes, respectively. We propose that Rab35-GTP is a critical regulator of autophagy through recruiting autophagy receptor NDP52. PMID- 28848036 TI - Spatial Relationship of Glioma Volume Derived from 18F-FET PET and Volumetric MR Spectroscopy Imaging: A Hybrid PET/MRI Study. AB - PET imaging of amino acid transport using O-(2-18F-fluoroethyl)-l-tyrosine (18F FET) and proton MR spectroscopy (MRS) imaging of cell turnover measured by the ratio of choline to N-acetyl-aspartate (Cho/NAA) may provide additional information on tumor extent of cerebral gliomas compared with anatomic imaging; however, comparative studies are rare. Methods: In this prospective study, 41 patients (16 women, 25 men; mean age +/- SD, 48 +/- 14 y) with cerebral gliomas (World Health Organization [WHO] grade II: 10 [including 1 patient with 2 lesions], WHO III: 17, WHO IV: 13, without biopsy low-grade: 1, high-grade: 1) were investigated with a hybrid PET/MR scanner. Tumor extent, spatial overlap, and the distance between the corresponding centers of mass in 18F-FET PET and MRS imaging of Cho/NAA, determined by simultaneously acquired, 3-dimensional spatially resolved MRS imaging data, were compared. Results: The average tumor volumes for 18F-FET uptake and increased Cho/NAA were 19 +/- 20 cm3 (mean +/- SD) and 22 +/- 24 cm3, respectively, with an overlap of 40% +/- 25% and separation of the centers of mass by 9 +/- 8 mm. None of the parameters showed a significant correlation with tumor grade. Conclusion:18F-FET uptake and increased Cho/NAA ratio are not always congruent and may represent different properties of glioma metabolism. The relationship to histologic tumor extent needs to be further analyzed. PMID- 28848037 TI - Validation of 2-18F-Fluorodeoxysorbitol as a Potential Radiopharmaceutical for Imaging Bacterial Infection in the Lung. AB - 2-18F-fluorodeoxysorbitol (18F-FDS) has been shown to be a promising agent with high selectivity and sensitivity in imaging bacterial infection. The objective of our study was to validate 18F-FDS as a potential radiopharmaceutical for imaging bacterial infection longitudinally in the lung. Methods: Albino C57 female mice were intratracheally inoculated with either live or dead Klebsiella pneumoniae to induce either lung infection or lung inflammation. One group of mice was imaged to monitor disease progression. PET/CT was performed on days 0, 1, 2, and 3 after inoculation using either 18F-FDS or 18F-FDG (n = 12 for each tracer). The other group was first screened by bioluminescent imaging (BLI) to select only mice with visible infection (region of interest > 108 ph/s) for PET/CT imaging with 18F-FDS (n = 12). For the inflammation group, 5 mice each were imaged with PET/CT using either 18F-FDS or 18F-FDG from days 1 to 4 after inoculation. Results: For studies of disease progression, BLI showed noticeable lung infection on day 2 after inoculation and significantly greater infection on day 3. Baseline imaging before inoculation showed no focal areas of lung consolidation on CT and low uptake in the lung for both PET radiotracers. On day 2, an area of lung consolidation was identified on CT, with a corresponding 2.5-fold increase over baseline for both PET radiotracers. On day 3, widespread areas of patchy lung consolidation were found on CT, with a drastic increase in uptake for both 18F FDS and 18F-FDG (9.2 and 3.9). PET and BLI studies showed a marginal correlation between 18F-FDG uptake and colony-forming units (r = 0.63) but a much better correlation for 18F-FDS (r = 0.85). The uptake ratio of infected lung over inflamed lung was 8.5 and 1.7 for 18F-FDS and 18F-FDG on day 3. Conclusion: Uptake of both 18F-FDS and 18F-FDG in infected lung could be used to track the degree of bacterial infection measured by BLI, with a minimum detection limit of 107 bacteria. 18F-FDS, however, is more specific than 18F-FDG in differentiating K. pneumoniae lung infection from lung inflammation. PMID- 28848038 TI - Comparison of the Accuracy of FMT/CT and PET/MRI for the Assessment of Antibody Biodistribution in Squamous Cell Carcinoma Xenografts. AB - Noninvasive imaging technologies are increasingly used in preclinical drug research for the pharmacokinetic analysis of therapeutic compounds in living animals over time. The different preclinical imaging modalities available differ intrinsically in their detection principle and thus might exhibit limitations for a specific application. Here, we systematically investigated the performance of advanced fluorescence-mediated tomography (FMT)/CT in comparison to PET/MRI for quantitative analysis of the biodistribution of different antibody formats and dependence on the required imaging label in squamous cell carcinoma xenografts. Methods: Different formats of an antibody (monoclonal antibody and the antigen binding fragments F(ab')2 and Fab) targeting epidermal growth factor receptor were labeled with Alexa750 or 64Cu-NODAGA and injected intravenously into separate cohorts of nude mice bearing subcutaneous A-431 tumors. Two and 24 h after injection, the mice were measured by FMT/CT and PET/MRI. Probe accumulation was quantitatively assessed in organs and tumors. In vivo data were compared between modalities and correlated with ex vivo fluorescence, gamma-counting, and electrochemiluminescence immunoassay. Results: Both imaging methods faithfully monitored the biodistribution and elimination routes of the compounds, and organ accumulation measured by FMT/CT and PET/MRI correlated significantly with ex vivo measurements. In addition, the accumulation in kidney, muscle, and tumor tissue correlated between FMT/CT and PET/MRI. However, the pharmacokinetics of the Alexa750-labeled antibody formats showed shorter blood half-times and higher liver uptake than the radiolabeled counterparts. Conclusion: FMT/CT imaging allows quantifying the biodistribution of antibodies in nude mice and provides an alternative to PET analysis in preclinical drug research. However, even for large molecules, such as monoclonal antibodies, Alexa750 labeling can change pharmacokinetics and trigger liver uptake. PMID- 28848039 TI - Noradrenergic Deficits in Parkinson Disease Imaged with 11C-MeNER. AB - Degeneration of noradrenergic neurons may underlie the disabling nonmotor symptoms in patients with Parkinson disease (PD). Quantification of the loss of noradrenergic neurons by means of neuroimaging has been limited by the lack of radioligands that are selective for noradrenergic neurotransmission. The radioligand (S,S)-11C-2-(alpha-(2-methoxyphenoxy)benzyl)morpholine (11C-MeNER) is a highly selective inhibitor of noradrenaline transporters, and PET studies suggest that this radioligand is suitable for quantitative neuroimaging of noradrenergic deficits in human brain in vivo. In the present investigation, we used PET with 11C-MeNER to map the density of noradrenaline transporters in groups of patients with PD and age-matched healthy controls. Methods: After administration of 11C-MeNER, 15 nondemented patients with PD and 10 healthy subjects underwent 90-min dynamic PET. We determined 11C-MeNER binding potential relative to nondisplaceable binding potential (BPND) by multilinear analysis, simplified reference tissue model 2, and multilinear reference tissue model 2. Results: Metabolism of 11C-MeNER did not differ between groups. The simplified reference tissue model 2 and the multilinear reference tissue model 2 were used to determine 11C-MeNER BPND11C-MeNER BPND was reduced in the PD group compared with the control subjects, with regionally significant declines in the thalamus and nucleus ruber. Tremor was associated with higher tracer binding in the PD group on multivariate regression analysis. Conclusion: To our knowledge, this was the first specific quantification of noradrenergic denervation in PD patients in vivo. In agreement with predictions from determinations in vitro, we discovered a decline of noradrenergic projections in vivo in brain of PD patients. PMID- 28848040 TI - Noninvasive 89Zr-Transferrin PET Shows Improved Tumor Targeting Compared with 18F FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer. AB - The current standard for breast PET imaging is 18F-FDG. The heterogeneity of 18F FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. 18F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm3 MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC). Increased surface expression of transferrin receptor (TfR) is a downstream event of MYC upregulation and has been validated as a clinically relevant target for molecular imaging. Transferrin labeled with 89Zr has successfully identified MYC status in many cancer subtypes preclinically and been shown to predict response and changes in oncogene status via treatment with small-molecule inhibitors that target MYC and PI3K signaling pathways. We hypothesized that 89Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of 18F-FDG PET for MYC-overexpressing TNBC. Methods: In this study, 89Zr-transferrin and 18F-FDG imaging were compared in preclinical models of TNBC. TNBC cells (MDA MB-157, MDA-MB-231, and Hs578T) were treated with bromodomain-containing protein 4 (BRD4) inhibitors JQ1 and OTX015 (0.5-1 MUM). Cell proliferation, gene expression, and protein expression were assayed to explore the effects of these inhibitors on MYC and TfR. Results: Head-to-head comparison showed that 89Zr transferrin targets TNBC tumors significantly better (P < 0.05-0.001) than 18F FDG through PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xenografts and a patient-derived xenograft model of TNBC. c-Myc and TfR gene expression was decreased upon treatment with BRD4 inhibitors and c-MYC small interfering RNA (P < 0.01-0.001 for responding cell lines), compared with vehicle treatment. MYC and TfR protein expression, along with receptor-mediated internalization of transferrin, was also significantly decreased upon drug treatment in MDA-MB-231 and MDA-MB-157 cells (P < 0.01-0.001). Conclusion:89Zr transferrin targets human TNBC primary tumors significantly better than 18F-FDG, as shown through PET imaging and biodistribution studies. 89Zr-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC. PMID- 28848042 TI - The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease. AB - Because of their vital function, the wall structures of medium and large arteries are immunoprivileged and protected from inflammatory attack. That vascular immunoprivilege is broken in atherosclerosis and in vasculitis, when wall invading T cells and macrophages (Mphi) promote tissue injury and maladaptive repair. Historically, tissue-residing T cells were studied for their antigen specificity, but recent progress has refocused attention to antigen-nonspecific regulation, which determines tissue access, persistence, and functional differentiation of T cells. The coinhibitory receptor PD-1, expressed on T cells, delivers negative signals when engaged by its ligand PD-L1, expressed on dendritic cells, Mphi, and endothelial cells to attenuate T cell activation, effector functions, and survival. Through mitigating signals, the PD-1 immune checkpoint maintains tissue tolerance. In line with this concept, dendritic cells and Mphis from patients with the vasculitic syndrome giant cell arteritis (GCA) are PD-L1lo ; including vessel-wall-embedded DCs that guard the vascular immunoprivilege. GCA infiltrates in the arterial walls are filled with PD-1+ T cells that secrete IFN-gamma, IL-17, and IL-21; drive inflammation-associated angiogenesis; and facilitate intimal hyperplasia. Conversely, chronic tissue inflammation in the atherosclerotic plaque is associated with an overreactive PD 1 checkpoint. Plaque-residing Mphis are PD-L1hi , a defect induced by their addiction to glucose and glycolytic breakdown. PD-L1hi Mphis render patients with coronary artery disease immunocompromised and suppress antiviral immunity, including protective anti-varicella zoster virus T cells. Thus, immunoinhibitory signals affect several domains of vascular inflammation; failing PD-L1 in vasculitis enables unopposed immunostimulation and opens the flood gates for polyfunctional inflammatory T cells, and excess PD-L1 in the atherosclerotic plaque disables tissue-protective T cell immunity. PMID- 28848043 TI - Fatty acid synthase regulates the pathogenicity of Th17 cells. AB - T cell activation and effector function is characterized by changes in metabolism. Altered metabolism is common to almost all types of activated T cells, but fatty acid synthesis seems to especially drive the formation of Th17 cells. Indeed, research has demonstrated that inhibition of early fatty acid synthesis through targeting of acetyl-CoA carboxylase (ACC1) can inhibit Th17 cell formation and instead promote the generation of regulatory T cells. Fatty acid synthase (FASN) is downstream of ACC, and previous studies have shown that FASN activity influences both cancer and inflammation. However, it remains to be determined whether FASN is a viable target for inhibiting Th17 cell function. Here, we demonstrate that FASN is a critical metabolic control for the generation of inflammatory subsets of Th17 cells. Conversely, inhibiting FASN function promotes IFN-gamma production by Th1 and Th1-like Th17 cells. In vivo, inhibition of FASN, specifically in Th17 cells, leads to reduction of experimental autoimmune encephalomyelitis disease. These studies demonstrate the necessity of FASN in the autoimmune inflammatory function of Th17 cells. PMID- 28848044 TI - Regulation of mitochondrial protein import by the nucleotide exchange factors GrpEL1 and GrpEL2 in human cells. AB - Mitochondria are organelles indispensable for maintenance of cellular energy homeostasis. Most mitochondrial proteins are nuclearly encoded and are imported into the matrix compartment where they are properly folded. This process is facilitated by the mitochondrial heat shock protein 70 (mtHsp70), a chaperone contributing to mitochondrial protein quality control. The affinity of mtHsp70 for its protein clients and its chaperone function are regulated by binding of ATP/ADP to mtHsp70's nucleotide-binding domain. Nucleotide exchange factors (NEFs) play a crucial role in exchanging ADP for ATP at mtHsp70's nucleotide binding domain, thereby modulating mtHsp70's chaperone activity. A single NEF, Mge1, regulates mtHsp70's chaperone activity in lower eukaryotes, but the mammalian orthologs are unknown. Here, we report that two putative NEF orthologs, GrpE-like 1 (GrpEL1) and GrpEL2, modulate mtHsp70's function in human cells. We found that both GrpEL1 and GrpEL2 associate with mtHsp70 as a hetero-oligomeric subcomplex and regulate mtHsp70 function. The formation of this subcomplex was critical for conferring stability to the NEFs, helped fine-tune mitochondrial protein quality control, and regulated crucial mtHsp70 functions, such as import of preproteins and biogenesis of Fe-S clusters. Our results also suggested that GrpEL2 has evolved as a possible stress resistance protein in higher vertebrates to maintain chaperone activity under stress conditions. In conclusion, our findings support the idea that GrpEL1 has a role as a stress modulator in mammalian cells and highlight that multiple NEFs are involved in controlling protein quality in mammalian mitochondria. PMID- 28848041 TI - Chemokines encoded by herpesviruses. AB - Viruses use diverse strategies to elude the immune system, including copying and repurposing host cytokine and cytokine receptor genes. For herpesviruses, the chemokine system of chemotactic cytokines and receptors is a common source of copied genes. Here, we review the current state of knowledge about herpesvirus encoded chemokines and discuss their possible roles in viral pathogenesis, as well as their clinical potential as novel anti-inflammatory agents or targets for new antiviral strategies. PMID- 28848046 TI - Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity. AB - C-type lectin receptors (CLRs) comprise a large family of immunoreceptors that recognize polysaccharide ligands exposed on pathogen surfaces and are conserved among mammals. However, interspecies differences in their ligand spectrums are not fully understood. Dectin-1 is a well-characterized CLR that recognizes beta glucan. We report here that seaweed-derived fucan activates cells expressing human Dectin-1 but not mouse Dectin-1. Low-valency beta-glucan components within fucan appeared to be responsible for this activation, as the ligand activity was eliminated by beta-glucanase treatment. The low-valency beta-glucan laminarin also acted as an agonist for human Dectin-1 but not for mouse Dectin-1, whereas the high-valency beta-glucan curdlan activated both human and mouse Dectin-1. Reciprocal mutagenesis analysis revealed that the ligand-binding domain of human Dectin-1 does not determine its unique sensitivity to low-valency beta-glucan. Rather, we found that its intracellular domain renders human Dectin-1 reactive to low-valency beta-glucan ligand. Substitution with two amino acids, Glu2 and Pro5, located in the human Dectin-1 intracellular domain was sufficient to confer sensitivity to low-valency beta-glucan in mouse Dectin-1. Conversely, the introduction of mouse-specific amino acids, Lys2 and Ser5, to human Dectin-1 reduced the reactivity to low-valency beta-glucan. Indeed, low-valency ligands induced a set of proinflammatory genes in human but not mouse dendritic cells. These results suggest that the intracellular domain, not ligand-binding domain, of Dectin-1 determines the species-specific ligand profile. PMID- 28848045 TI - Palmitoylation of the ciliary GTPase ARL13b is necessary for its stability and its role in cilia formation. AB - Primary cilia are hairlike extensions of the plasma membrane of most mammalian cells that serve specialized signaling functions. To traffic properly to cilia, multiple cilia proteins rely on palmitoylation, the post-translational attachment of a saturated 16-carbon lipid. However, details regarding the mechanism of how palmitoylation affects cilia protein localization and function are unknown. Herein, we investigated the protein ADP-ribosylation factor-like GTPase 13b (ARL13b) as a model palmitoylated ciliary protein. Using biochemical, cellular, and in vivo studies, we found that ARL13b palmitoylation occurs in vivo in mouse kidneys and that it is required for trafficking to and function within cilia. Myristoylation, a 14-carbon lipid, is shown to largely substitute for palmitoylation with regard to cilia localization of ARL13b, but not with regard to its function within cilia. The functional importance of palmitoylation results in part from a dramatic increase in ARL13b stability, which is not observed with myristoylation. Additional results show that blockade of depalmitoylation slows the degradation of ARL13b that occurs during cilia resorption, raising the possibility that the sensitivity of ARL13b stability to palmitoylation may be exploited by the cell to accelerate degradation of ARL13b by depalmitoylating it. Together, the results show that palmitoylation plays a unique and critical role in controlling the localization, stability, abundance, and thus function of ARL13b. Pharmacological manipulation of protein palmitoylation may be a strategy to alter cilia function. PMID- 28848047 TI - Evidence for a direct cross-talk between malic enzyme and the pentose phosphate pathway via structural interactions. AB - Recent studies have revealed that the oxidative pentose phosphate pathway (PPP), malic enzyme (ME), and folate metabolism are the three major routes for generating cellular NADPH, a key cofactor involved in redox control and reductive biosynthesis. Many tumor cells exhibit altered NADPH metabolism to fuel their rapid proliferation. However, little is known about how NADPH metabolism is coordinated in tumor cells. Here we report that ME1 increases the PPP flux by forming physiological complexes with 6-phosphogluconate dehydrogenase (6PGD). We found that ME1 and 6PGD form a hetero-oligomer that increases the capability of 6PGD to bind its substrate 6-phosphogluconate. Through activating 6PGD, ME1 enhances NADPH generation, PPP flux, and tumor cell growth. Interestingly, although ME1 could bind either the dimer-defect mutant 6PGD (K294R) or the NADP+ binding defect 6PGD mutants, only 6PGD (K294R) activity was induced by ME1. Thus, ME1/6PGD hetero-complexes may mimic the active oligomer form of 6PGD. Together, these findings uncover a direct cross-talk mechanism between ME1 and PPP, may reveal an alternative model for signaling transduction via protein conformational simulation, and pave the way for better understanding how metabolic pathways are coordinated in cancer. PMID- 28848048 TI - Heartland virus NSs protein disrupts host defenses by blocking the TBK1 kinase IRF3 transcription factor interaction and signaling required for interferon induction. AB - Heartland virus (HRTV) is a pathogenic phlebovirus related to the severe fever with thrombocytopenia syndrome virus (SFTSV), another phlebovirus causing life threatening disease in humans. Previous findings have suggested that SFTSV can antagonize the host interferon (IFN) system via viral nonstructural protein (NSs) mediated sequestration of antiviral signaling proteins into NSs-induced inclusion bodies. However, whether and how HRTV counteracts the host innate immunity is unknown. Here, we report that HRTV NSs (HNSs) also antagonizes IFN and cytokine induction and bolsters viral replication, although no noticeable inclusion body formation was observed in HNSs-expressing cells. Furthermore, HNSs inhibited the virus-triggered activation of IFN-beta promoter by specifically targeting the IFN stimulated response element but not the NF-kappaB response element. Consistently, HNSs blocked the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3, an IFN-stimulated response element-activating transcription factor). Reporter gene assays next showed that HNSs blockades the antiviral signaling mediated by RIG-I-like receptors likely at the level of TANK-binding kinase 1 (TBK1). Indeed, HNSs strongly interacts with TBK1 as indicated by confocal microscopy and pulldown analyses, and we also noted that the scaffold dimerization domain of TBK1 is required for the TBK1-HNSs interaction. Finally, pulldown assays demonstrated that HNSs expression dose-dependently diminishes a TBK1-IRF3 interaction, further explaining the mechanism for HNSs function. Collectively, these data suggest that HNSs, an antagonist of host innate immunity, interacts with TBK1 and thereby hinders the association of TBK1 with its substrate IRF3, thus blocking IRF3 activation and transcriptional induction of the cellular antiviral responses. PMID- 28848049 TI - Hypoxia-inducible factor 2alpha (HIF-2alpha) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity. AB - Colorectal cancer (CRC) is the third-leading cause of cancer mortality in the United States and other industrialized countries. A hypoxic microenvironment is a hallmark for solid tumors. The hypoxia-induced signal transduction is transcriptionally mediated by hypoxia-inducible factor (HIF). Three major HIF isoforms, HIF-1alpha, HIF-2alpha, and HIF-3alpha, are present in the intestine. Our previous work demonstrates that HIF-2alpha is essential for CRC growth and progression. However, the mechanisms mediating cell proliferation after hypoxia or HIF-2alpha activation in CRC are unclear. Data mining of RNA-Seq experiments with mouse models of intestinal HIF-2alpha or Yes-associated protein 1 (YAP1) overexpression indicates a significant overlap of genes in these conditions. YAP1 is a transcriptional co-activator in the Hippo signaling pathway, and YAP1 induced transcriptional responses are essential in cancer cell proliferation. Here, we report that HIF-2alpha robustly increases YAP1 expression and activity in CRC-derived cell lines and in mouse models. The potentiation of YAP1 activity by HIF-2alpha was not via canonical signaling mechanisms such as Src (non receptor tyrosine kinase), PI3K, ERK, or MAPK pathways. Moreover, we detected no direct interaction of HIF-2alpha with YAP1. Of note, YAP1 activation was critical for cancer cell growth under hypoxia. Our findings indicate that HIF-2alpha increases cancer cell growth by up-regulating YAP1 activity, suggesting that this pathway might be targeted in potential anti-cancer approaches for treating CRC patients. PMID- 28848050 TI - Reactive oxygen species trigger Parkin/PINK1 pathway-dependent mitophagy by inducing mitochondrial recruitment of Parkin. AB - Defective mitophagy linked to dysfunction in the proteins Parkin and PTEN-induced putative kinase 1 (PINK1) is implicated in the pathogenesis of Parkinson's disease. Although the mechanism by which Parkin mediates mitophagy in a PINK1 dependent manner is becoming clearer, the triggers for this mitophagy pathway remain elusive. Reactive oxygen species (ROS) have been suggested as such triggers, but this proposal remains controversial because ROS scavengers fail to retard mitophagy. Here we demonstrate that the role of ROS in mitophagy has been underappreciated as a result of the inefficiency of ROS scavengers to control ROS bursts after high-dose treatment with carbonyl cyanide m-chlorophenylhydrazone. Supporting this, combinatorial treatment with N-acetyl-l-cysteine and catalase substantially inhibited the ROS upsurge and PINK1-dependent Parkin translocation to mitochondria in response to carbonyl cyanide m-chlorophenylhydrazone treatment. In addition to the chemical mitophagy inducer, overexpression of voltage-dependent anion channel 1 (VDAC1) induced Parkin translocation to mitochondria, presumably by stimulating ROS generation. Similarly, combined N acetyl-l-cysteine and catalase treatment also suppressed VDAC1-induced redistribution of Parkin. Alongside these observations, we also found that the elevated protein level of PINK1 was not necessary for Parkin translocation to mitochondria. Thus, our data suggest that ROS may act as a trigger for the induction of Parkin/PINK1-dependent mitophagy. In addition, our study casts doubt on the importance of protein quantity of PINK1 in the recruitment of Parkin to mitochondria. PMID- 28848051 TI - The transcription factor Gbx2 induces expression of Kruppel-like factor 4 to maintain and induce naive pluripotency of embryonic stem cells. AB - The transcription factor Gbx2 (gastrulation brain homeobox 2) is a direct target of the LIF/STAT3 signaling pathway, maintains mouse embryonic stem cell (mESC) self-renewal, and facilitates mouse epiblast stem cell (mEpiSC) reprogramming to naive pluripotency. However, the mechanism by which Gbx2 mediates its effects on pluripotency remains unknown. Here, using an RNA-Seq approach, we identified Klf4 (Kruppel-like factor 4) as a direct target of Gbx2. Functional studies indicated that Klf4 mediates the self-renewal-promoting effects of Gbx2, because knockdown of Klf4 expression abrogated the ability of Gbx2 to maintain the undifferentiated state of mESCs. We also found that Gbx2 largely depends on Klf4 to reprogram mEpiSCs to a mESC-like state. In summary, our study has uncovered a mechanism by which Gbx2 maintains and induces naive pluripotency. These findings expand our understanding of the pluripotency control network and may inform the development of culture conditions for improved ESC maintenance and differentiation. PMID- 28848052 TI - Bacterial PhyA protein-tyrosine phosphatase-like myo-inositol phosphatases in complex with the Ins(1,3,4,5)P4 and Ins(1,4,5)P3 second messengers. AB - myo-Inositol phosphates (IPs) are important bioactive molecules that have multiple activities within eukaryotic cells, including well-known roles as second messengers and cofactors that help regulate diverse biochemical processes such as transcription and hormone receptor activity. Despite the typical absence of IPs in prokaryotes, many of these organisms express IPases (or phytases) that dephosphorylate IPs. Functionally, these enzymes participate in phosphate scavenging pathways and in plant pathogenesis. Here, we determined the X-ray crystallographic structures of two catalytically inactive mutants of protein tyrosine phosphatase-like myo-inositol phosphatases (PTPLPs) from the non pathogenic bacteria Selenomonas ruminantium (PhyAsr) and Mitsuokella multacida (PhyAmm) in complex with the known eukaryotic second messengers Ins(1,3,4,5)P4 and Ins(1,4,5)P3 Both enzymes bound these less-phosphorylated IPs in a catalytically competent manner, suggesting that IP hydrolysis has a role in plant pathogenesis. The less-phosphorylated IP binding differed in both the myo inositol ring position and orientation when compared with a previously determined complex structure in the presence of myo-inositol-1,2,3,4,5,6-hexakisphosphate (InsP6 or phytate). Further, we have demonstrated that PhyAsr and PhyAmm have different specificities for Ins(1,2,4,5,6)P5, have identified structural features that account for this difference, and have shown that the absence of these features results in a broad specificity toward Ins(1,2,4,5,6)P5 These features are main-chain conformational differences in loops adjacent to the active site that include the extended loop prior to the penultimate helix, the extended Omega loop, and a beta-hairpin turn of the Phy-specific domain. PMID- 28848053 TI - Antigen-Presenting Intratumoral B Cells Affect CD4+ TIL Phenotypes in Non-Small Cell Lung Cancer Patients. AB - Effective immunotherapy options for patients with non-small cell lung cancer (NSCLC) are becoming increasingly available. The immunotherapy focus has been on tumor-infiltrating T cells (TILs); however, tumor-infiltrating B cells (TIL-Bs) have also been reported to correlate with NSCLC patient survival. The function of TIL-Bs in human cancer has been understudied, with little focus on their role as antigen-presenting cells and their influence on CD4+ TILs. Compared with other immune subsets detected in freshly isolated primary tumors from NSCLC patients, we observed increased numbers of intratumoral B cells relative to B cells from tumor-adjacent tissues. Furthermore, we demonstrated that TIL-Bs can efficiently present antigen to CD4+ TILs and alter the CD4+ TIL phenotype using an in vitro antigen-presentation assay. Specifically, we identified three CD4+ TIL responses to TIL-Bs, which we categorized as activated, antigen-associated, and nonresponsive. Within the activated and antigen-associated CD4+ TIL population, activated TIL-Bs (CD19+CD20+CD69+CD27+CD21+) were associated with an effector T cell response (IFNgamma+ CD4+ TILs). Alternatively, exhausted TIL-Bs (CD19+CD20+CD69+CD27-CD21-) were associated with a regulatory T-cell phenotype (FoxP3+ CD4+ TILs). Our results demonstrate a new role for TIL-Bs in NSCLC tumors in their interplay with CD4+ TILs in the tumor microenvironment, establishing them as a potential therapeutic target in NSCLC immunotherapy. Cancer Immunol Res; 5(10); 898-907. (c)2017 AACR. PMID- 28848054 TI - Neoadjuvant Interferons: Critical for Effective PD-1-Based Immunotherapy in TNBC. AB - The lack of targeted therapies available for triple-negative breast cancer (TNBC) patients who fail to respond to first-line chemotherapy has sparked interest in immunotherapeutic approaches. However, trials utilizing checkpoint inhibitors targeting the PD-1/PD-L1 axis in TNBC have had underwhelming responses. Here, we investigated the interplay between type I IFN signaling and the PD-1/PD-L1 axis and tested the impact of combining IFN inducers, as immune activators, with anti PD-1, to induce an antimetastatic immune response. Using models of TNBC, we demonstrated an interplay between type I IFN signaling and tumor cell PD-L1 expression that affected therapeutic response. The data revealed that the type I IFN-inducer poly(I:C) was an effective immune activator and antimetastatic agent, functioning better than anti-PD-1, which was ineffective as a single agent. Poly(I:C) treatment induced PD-L1 expression on TNBC cells, and combined poly(I:C) and anti-PD-1 treatment prolonged metastasis-free survival in a neoadjuvant setting via the induction of a tumor-specific T-cell response. Use of this combination in a late treatment setting did not impact metastasis-free survival, indicating that timing was critical for immunotherapeutic benefit. Together, these data demonstrated anti-PD-1 as an ineffective single agent in preclinical models of TNBC. However, type I IFN inducers were effective immune activators, and neoadjuvant trials combining them with anti-PD-1 to induce a sustained antitumor immune response are warranted. Cancer Immunol Res; 5(10); 871 84. (c)2017 AACR. PMID- 28848056 TI - Comparison of the effectiveness of hands-on versus online education in child passenger safety. AB - BACKGROUND: Community paediatricians' knowledge of appropriate child safety seat (CSS) use in vehicles may be inadequate. We compared the effectiveness of hands on and online education in improving and retaining child passenger safety (CPS) knowledge and skills among paediatric trainees. METHODS: Paediatric trainees were randomised to receive hands-on skills training versus a 1-hour online module in CPS. CSS knowledge and installation skills were assessed using a validated 10 item/point questionnaire and an assessment tool respectively at baseline and after 6 months. Preintervention and postintervention knowledge improvement and CSS installation skills between groups were assessed using paired t-tests and effect size (d). RESULTS: Forty-eight students agreed to participate and were randomised. Thirty-nine completed training (hands-on: 23 and online: 15). At entry, no significant differences in learners' demographics and prior CPS education existed. Baseline CPS knowledge scores did not differ significantly between groups (p=0.26). Postintervention, both groups demonstrated a significant increase in knowledge scores (hands-on=3.1 (95% CI 2.4 to 3.7), p<0.0001; online=2.6 (95% CI 1.9 to 3.3), p<0.0001), though the pre-post gain in knowledge scores were not significantly different between groups (p=0.35). At follow-up, both groups demonstrated a significant increase in knowledge scores (hands-on=1.8 (95% CI 1.2 to 2.4), p<0.0001; online=1.1 (95% CI 0.7 to 1.6), p<0.0001) with the hands-on group scores significantly better than the online group (p<0.02). The long-term gain in knowledge scores was not significantly different between groups (p=0.12).Baseline CSS installation skill scores did not significantly differ between groups for forward-facing seats (p=0.16) and rear-facing seats (p=0.51). At follow-up, mean CSS installation skill scores significantly increased for the hands-on group (forward-facing seat: 0.8 (95% CI 0.16 to 1.44), p<0.02; rear facing seat: 1.2 (95% CI 0.6 to 1.7), p<0.001) but not for the online group (forward-facing seat: 0.9 (95% CI -0.08 to 1.9), p=0.07); rear-facing seat: -0.2 (95% CI -1.1 to 0.7), p=0.6). CONCLUSIONS: Among paediatric trainees, hands-on and online CPS education are both effective in improving long-term CPS knowledge. Long-term installation skills for forward-facing and rear-facing CSS persist for hands-on education but are inconclusive for online education. PMID- 28848055 TI - Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis. AB - Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti-PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8+ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNgamma-producing E7-specifc CD8+ T cells in the spleens of mice treated with the combination of PD-1 blockade with anti OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic. Cancer Immunol Res; 5(9); 755-66. (c)2017 AACR. PMID- 28848057 TI - Lifetime prevalence of traumatic brain injury with loss of consciousness. AB - OBJECTIVE: To determine the prevalence of lifetime history of traumatic brain injury (TBI) with loss of consciousness (LOC) among adult, non-institutionalised residents of Ohio. METHODS: We analysed data from 2014 Ohio Behavioral Risk Factor Surveillance System, which included a state-specific module designed to elicit lifetime history of TBI. RESULTS: Of non-institutionalised adults 18 years and over living in Ohio, 21.7% reported at least one lifetime TBI with LOC, 2.6% experienced at least one moderate or severe such injury, 9.1% experienced a TBI with LOC before age 15 years and 10.8% experienced either TBI with LOC before age 15 years or a moderate or severe injury. Males, those with lower incomes and those unable to work were more likely to have incurred at least one TBI with LOC, multiple TBIs with LOC, a moderate or severe TBI and a TBI with LOC before age15. CONCLUSIONS: One in five adults experienced TBIs of sufficient severity to cause LOC; 3% experienced at least one moderate or severe TBI and almost 10% experienced a first TBI with LOC before the age of 15 years. The prevalence of lifetime TBI in the present study suggests that there may be a substantially greater burden of injury than concluded from previous prevalence estimates. PMID- 28848058 TI - Effectiveness of a nationwide intervention to increase helmet use in Dutch skiers and snowboarders: an observational cohort study. AB - OBJECTIVE: Helmet use in Dutch recreational skiers and snowboarders (DRSS) remains low. This study evaluated the effects of exposure to a nationwide intervention on relevant determinants of helmet use and helmet use in DRSS. METHODS: The intervention mapping protocol was used to develop an in-season intervention programme targeted at adult DRSS. A prospective single-cohort study was conducted to evaluate the impact of intervention exposure on determinants of helmet use (ie, knowledge about head injury risk and preventive measures, risk perception, attitudes to head injury risk and helmet use and intention to helmet use) and self-reported helmet use. A random sample of 363 DRSS from an existing panel participated in this study. Data were collected using online questionnaires before and immediately after the 2010/2011 intervention season. In a separate sample of 363 DRSS, intervention reach was assessed after the 2010/2011 season. RESULTS: Overall, no significant associations were found between intervention exposure and the determinants of helmet use. However, subgroup analyses revealed intervention effects on risk perception and knowledge in specific subpopulations. Intervention exposure had a significant, positive effect on helmet use in DRSS (beta=0.23; 95% CI 0.017 to 0.44). Subgroup analyses revealed that this effect was found in: (1) skiers, (2) female DRSS, (3) young skiers and (4) intermediate skiers. Overall, intervention reach was 28.1%, with differences found between skiers and snowboarders. CONCLUSIONS: Exposure to a nationwide intervention programme was associated with increased self-reported helmet use in DRSS. Differences were found in intervention effectiveness and reach between subpopulations. These differences must be taken into account when developing and evaluating future interventions. PMID- 28848059 TI - CTCF deletion syndrome: clinical features and epigenetic delineation. AB - BACKGROUND: Heterozygous mutations in CTCF have been reported in patients with distinct clinical features including intellectual disability. However, the precise pathomechanism underlying the phenotype remains to be uncovered, partly because of the diverse function of CTCF. Here we describe extensive clinical and genetic investigation for two patients with a microdeletion encompassing CTCF. METHODS: We performed genetic examination including comprehensive investigation of X chromosome inactivation and DNA methylation profiling at imprinted loci and genome-wide. RESULTS: Two patients showed comparable clinical features to those in a previous report, indicating that haploinsufficiency of CTCF was the major determinant of the microdeletion syndrome. Despite the haploinsufficiency of CTCF, X chromosome inactivation was normal. DNA methylation at imprinted loci was normal, but hypermethylation at CTCF binding sites was demonstrated, of which PRKCZ and FGFR2 were identified as candidate genes. CONCLUSIONS: This study confirms that haploinsufficiency of CTCF causes distinct clinical features, and that a microdeletion encompassing CTCF could cause a recognisable CTCF deletion syndrome. Perturbed DNA methylation at CTCF binding sites, not at imprinted loci, may underlie the pathomechanism of the syndrome. PMID- 28848061 TI - Hypothesis: lobe A (COG1-4)-CDG causes a more severe phenotype than lobe B (COG5 8)-CDG. AB - The conserved oligomeric Golgi (COG) complex consists of eight subunits organized in two lobes: lobe A (COG1-4) and lobe B (COG5-8). The different functional roles of COG lobe A and lobe B might result in distinct clinical phenotypes in patients with COG-CDG (congenital disorders of glycosylation). This hypothesis is supported by three observations. First, knock-down of COG lobe A components affects Golgi morphology more severely than knock-down of COG lobe B components. Second, nearly all of the 27 patients with lobe B COG-CDG had bi-allelic truncating mutations, as compared with only one of the six patients with lobe A COG-CDG. This represents a frequency gap which suggests that bi-allelic truncating mutations in COG lobe A genes might be non-viable. Third, in support, large-scale exome data of healthy adults (Exome Aggregation Consortium (ExAC)) underline that COG lobe A genes are less tolerant to genetic variation than COG lobe B genes. Thus, comparable molecular defects are more detrimental in lobe A COG-CDG than in lobe B COG-CDG. In a larger perspective, clinical phenotypic severity corresponded nicely with tolerance to genetic variation. Therefore, genomic epidemiology can potentially be used as a photographic negative for mutational severity. PMID- 28848060 TI - Genetic Severity Score predicts clinical phenotype in NF2. AB - : BACKGROUND: The clinical severity of disease in neurofibromatosis type 2 (NF2) is variable. Patients affected with a constitutional truncating NF2 mutation have severe disease, while missense mutations or mosaic mutations present with a milder attenuated phenotype. Genotype-derived natural history data are important to inform discussions on prognosis and management. METHODS: We have assessed NF2 clinical phenotype in 142 patients in relation to the UK NF2 Genetic Severity Score to validate its use as a clinical and research tool. RESULTS: The Genetic Severity Score showed significant correlations across 10 measures, including mean age at diagnosis, proportion of patients with bilateral vestibular schwannomas, presence of intracranial meningioma, spinal meningioma and spinal schwannoma, NF2 eye features, hearing grade, age at first radiotherapy, age at first surgery and age starting bevacizumab. In addition there was moderate but significant correlation with age at loss of useful hearing, and weak but significant correlations for mean age at death, quality of life, last optimum Speech Discrimination Score and total number of major interventions. Patients with severe disease presented at a younger age had a higher disease burden and greater requirement of intervention than patients with mild and moderate disease. CONCLUSIONS: This study validates the UK NF2 Genetic Severity Score to stratify patients with NF2 for both clinical use and natural history studies. PMID- 28848062 TI - Disabling disability amid competing ideologies. AB - This paper critiques current arguments advancing the potential for transhumanism and a range of biological and pharmacological enhancements to better human flourishing. It does so from a historical perspective weighing the individualistic and competitive evolutionary theories of Darwin with the cooperative and communal theories of Prince Peter Kropotkin a generation later. In doing so it proposes the transhumanist and enhancement enthusiasts operate within a paradigm similar to Darwin's, one that is atomist and individualistic. The critique, which considers the status of those with cognitive, sensory and physical limits, advances a vision of society as a cooperative and communal rather than individualistic and competitive. Within this framework the argument is not one of either/or but on the lexicographical superiority of the communal and social over the individualistic and competitive ethos underlying both Darwin and most contemporary transhumanist literature. This reordering of priorities, it is argued, reflects advances in contemporary biology and evolutionary thinking. PMID- 28848063 TI - Do the 'brain dead' merely appear to be alive? AB - The established view regarding 'brain death' in medicine and medical ethics is that patients determined to be dead by neurological criteria are dead in terms of a biological conception of death, not a philosophical conception of personhood, a social construction or a legal fiction. Although such individuals show apparent signs of being alive, in reality they are (biologically) dead, though this reality is masked by the intervention of medical technology. In this article, we argue that an appeal to the distinction between appearance and reality fails in defending the view that the 'brain dead' are dead. Specifically, this view relies on an inaccurate and overly simplistic account of the role of medical technology in the physiology of a 'brain dead' patient. We conclude by offering an explanation of why the conventional view on 'brain death', though mistaken, continues to be endorsed in light of its connection to organ transplantation and the dead donor rule. PMID- 28848065 TI - A Plant-Derived Nucleic Acid Reconciles Type I IFN and a Pyroptotic-like Event in Immunity against Respiratory Viruses. AB - Nucleic acids carrying pathogen-associated molecular patterns trigger innate immune responses and are used to activate host immunity. Although synthetic nucleic acids have been used for that purpose, they have shown limitations for in vivo and clinical applications. To address this issue, we tested a naturally occurring dsRNA extracted from rice bran (rb-dsRNA) and characterized it as a potent ligand of TLR3 and MDA5. In this study, intranasal administration of rb dsRNA induced production of type I IFNs by alveolar macrophages and protected mice from morbidity and mortality resulting from respiratory virus infection, such as influenza A virus. This protection was completely absent in mice lacking both TRIF and MDA5, indicating the essential role of TLR3- and MDA5-dependent pathways. Interestingly, IFNAR1-deficient mice retained residual antiviral protection, which was abolished by pharmacological inhibition of caspase 1, but not IL-1beta signaling. In fact, rb-dsRNA activated caspase 1 via TRIF, resulting in the release of IL-1beta and LDH. In addition to the direct antiviral activity, rb-dsRNA modulated the immune cell population in the lungs by repopulating virus depleted alveolar macrophages. Our data demonstrate that rb-dsRNA orchestrates IFN-dependent and -independent direct antiviral protection and that it is a potent immune stimulator modulating antiviral immunity in the lungs. These findings open doors to a range of precise immune-modulating studies and therapeutic options. PMID- 28848064 TI - Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells. AB - B cell lymphoma-6 (Bcl-6) is a transcriptional repressor that is required for the differentiation of T follicular helper (TFH) cell populations. Currently, the molecular mechanisms underlying the transcriptional regulation of Bcl-6 expression are unclear. In this study, we have identified the Ikaros zinc finger transcription factors Aiolos and Ikaros as novel regulators of Bcl-6. We found that increased expression of Bcl-6 in CD4+ Th cell populations correlated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Furthermore, overexpression of Aiolos or Ikaros, but not the related family member Eos, was sufficient to induce Bcl6 promoter activity. Intriguingly, STAT3, a known Bcl-6 transcriptional regulator, physically interacted with Aiolos to form a transcription factor complex capable of inducing the expression of Bcl6 and the TFH-associated cytokine receptor Il6ra Importantly, in vivo studies revealed that the expression of Aiolos was elevated in Ag-specific TFH cells compared with that observed in non-TFH effector Th cells generated in response to influenza infection. Collectively, these data describe a novel regulatory mechanism through which STAT3 and the Ikaros zinc finger transcription factors Aiolos and Ikaros cooperate to regulate Bcl-6 expression. PMID- 28848070 TI - Correction to: Effect of Long-Term Vascular Care on Progression of Cerebrovascular Lesions: Magnetic Resonance Imaging Substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care). PMID- 28848066 TI - TIM-4 Identifies IFN-gamma-Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection. AB - B cells give rise to polarized subsets, including B effector 1 (Be1) cells and regulatory B cells, which can promote or inhibit immune responses through expression of IFN-gamma and IL-10, respectively. Such subsets likely explain why B cell depletion can either ameliorate or exacerbate inflammatory diseases; however, these cells remain poorly understood because of the absence of specific markers. Although T cell Ig and mucin domain-containing molecule (TIM)-1 broadly identifies IL-10+ regulatory B cells, no similar markers for Be1 cells have been described. We now show that TIM-4 is expressed by a subset of B cells distinct from those expressing TIM-1. Although TIM-1+ B cells are enriched for IL-10, TIM 4+ B cells are enriched for IFN-gamma. TIM-1+ B cells enhanced the growth of B16 F10 melanoma. In contrast, TIM-4+ B cells decreased B16-F10 metastasis and s.c. tumor growth, and this was IFN-gamma dependent. TIM-1+ B cells prolonged islet allograft survival in B-deficient mice, whereas TIM-4+ B cells accelerated rejection in an IFN-gamma-dependent manner. Moreover, TIM-4+ B cells promoted proinflammatory Th differentiation in vivo, increasing IFN-gamma while decreasing IL-4, IL-10, and Foxp3 expression by CD4+ T cells-effects that are opposite from those of TIM-1+ B cells. Importantly, a monoclonal anti-TIM-4 Ab promoted allograft tolerance, and this was dependent on B cell expression of TIM-4. Anti TIM-4 downregulated T-bet and IFN-gamma expression by TIM-4+ B cells and indirectly increased IL-10 expression by TIM-1+ B cells. Thus, TIM-4+ B cells are enriched for IFN-gamma-producing proinflammatory Be1 cells that enhance immune responsiveness and can be specifically targeted with anti-TIM-4. PMID- 28848071 TI - Correction to: Lifestyle Interventions to Prevent Cardiovascular Events After Stroke and Transient Ischemic Attack: Systematic Review and Meta-Analysis. PMID- 28848068 TI - Dual-Specificity Phosphatase 3 Deletion Protects Female, but Not Male, Mice from Endotoxemia-Induced and Polymicrobial-Induced Septic Shock. AB - Dual-specificity phosphatase 3 (DUSP3) is a small phosphatase with poorly known physiological functions and for which only a few substrates are known. Using knockout mice, we recently reported that DUSP3 deficiency confers resistance to endotoxin- and polymicrobial-induced septic shock. We showed that this protection was macrophage dependent. In this study, we further investigated the role of DUSP3 in sepsis tolerance and showed that the resistance is sex dependent. Using adoptive-transfer experiments and ovariectomized mice, we highlighted the role of female sex hormones in the phenotype. Indeed, in ovariectomized females and in male mice, the dominance of M2-like macrophages observed in DUSP3-/- female mice was reduced, suggesting a role for this cell subset in sepsis tolerance. At the molecular level, DUSP3 deletion was associated with estrogen-dependent decreased phosphorylation of ERK1/2 and Akt in peritoneal macrophages stimulated ex vivo by LPS. Our results demonstrate that estrogens may modulate M2-like responses during endotoxemia in a DUSP3-dependent manner. PMID- 28848067 TI - Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity. AB - BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27-IgD- double-negative (DN) B cells, but not CD27-IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4 cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines. PMID- 28848072 TI - Correction to: Long-Term Improvements After Multimodal Rehabilitation in Late Phase After Stroke: A Randomized Controlled Trial. PMID- 28848073 TI - Correction to: Role of Periostin in Early Brain Injury After Subarachnoid Hemorrhage in Mice. PMID- 28848074 TI - Correction to: Optimal Timing of Diffusion-Weighted Imaging to Avoid False Negative Findings in Patients With Transient Ischemic Attack. PMID- 28848075 TI - Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer. AB - BACKGROUND/AIMS: This study investigated the gene expression and DNA methylation of selected DNA repair genes (MBD4, TDG, MLH1, MLH3) and DNMT1 in human bladder cancer in the context of pathophysiological and prognostic significance. METHODS: To determine the relationship between the gene expression pattern, global methylation and promoter methylation status, we performed real-time PCR to quantify the mRNA of selected genes in 50 samples of bladder cancer and adjacent non-cancerous tissue. The methylation status was analyzed by methylation-specific polymerase chain reaction (MSP) or digestion of genomic DNA with a methylation sensitive restriction enzyme and PCR with gene-specific primers (MSRE-PCR). The global DNA methylation level was measured using the antibody-based 5-mC detection method. RESULTS: The relative levels of mRNA for MBD4, MLH3, and MLH1 were decreased in 28% (14/50), 34% (17/50) and 36% (18/50) of tumor samples, respectively. The MBD4 mRNA expression was decreased in 46% of non-muscle invasive tumors (Ta/T1) compared with 11% found in muscle invasive tumors (T2-T4) (P<0.003). Analysis of mRNA expression for TDG did not show any significant differences between Ta/T1 and T2-T4 tumors. The frequency of increased DNMT1 mRNA expression was higher in T2-T4 (52%) comparing to Ta/T1 (16%). The overall methylation rates in tumor tissue were 18% for MBD4, 25% for MLH1 and there was no evidence of MLH3 promoter methylation. High grade tumors had significantly lower levels of global DNA methylation (P=0.04). There was a significant association between shorter survival and increased expression of DNMT1 mRNA (P=0.002), decreased expression of MLH1 mRNA (P=0.032) and the presence of MLH1 promoter methylation (P=0.006). CONCLUSION: This study highlights the importance of DNA repair pathways and provides the first evidence of the role of MBD4 and MLH3 in bladder cancer. In addition, our findings suggest that DNMT1 mRNA and MLH1 mRNA expression, as well as the status of MLH1 promoter methylation, are attractive prognostic markers in this pathology. PMID- 28848076 TI - The XY Body of the Cat (Felis catus): Structural Differentiations and Protein Immunolocalization. AB - The heteromorphic X and Y chromosomes behave in a special way in mammalian spermatocytes; they form the XY body and synapse only partially. The aim of this article was to study the origin and the role of the special differentiations in the XY pair of the domestic cat during pachytene by analyzing its fine structural characteristics and the immunolocalization of the main meiotic proteins SYCP3, SYCP1, SYCE3, SMC3, gamma-H2AX, BRCA1, H3K27me3, and MLH1. The cat XY body shows particularly striking structures: an extreme degree of axial fibrillation in late pachynema and a special location of SYCP3-containing fibrils, bridging different regions of the main X axis, as well as one bridge at the inner end of the pairing region that colocalizes with the single mandatory MLH1 focus. There are sequential changes, first bullous expansions, then subdivision into fibrils, all involving axial thickening. The chromatin of the XY body presents the usual features of meiotic sex chromosome inactivation. An analysis of the XY body of many eutherians and metatherians suggests that axial thickenings are primitive features. The sequential changes in the mass and location of SYCP3-containing fibers vary among the clades because of specific processes of axial assembly/disassembly occurring in different species. PMID- 28848077 TI - Perception of Iterated Rippled Noise Periodicity in Cochlear Implant Users. AB - Pitch perception is more challenging for individuals with cochlear implants (CIs) than normal-hearing subjects because the signal processing by CIs is restricted. Processing and perceiving the periodicity of signals may contribute to pitch perception. Whether individuals with CIs can discern pitch within an iterated rippled noise (IRN) signal is still unclear. In a prospective controlled psychoacoustic study with 34 CI users and 15 normal-hearing control subjects, the difference limen between IRN signals with different numbers of iterations was measured. In 7 CI users and 15 normal-hearing control listeners with single-sided deafness, pitch matching between IRN and harmonic complex tones was measured. The pitch onset response (POR) following signal changes from white noise to IRN was measured electrophysiologically. The CI users could discriminate different numbers of iteration in IRN signals, but worse than normal-hearing listeners. A POR was measured for both normal-hearing subjects and CI users increasing with the pitch salience of the IRN. This indicates that the POR could serve as an objective measure to monitor progress during audioverbal therapy after CI surgery. PMID- 28848078 TI - Targeting the Endocannabinoid/CB1 Receptor System For Treating Major Depression Through Antidepressant Activities of Curcumin and Dexanabinol-Loaded Solid Lipid Nanoparticles. AB - BACKGROUND/AIMS: This study investigated the underlying mechanisms of the antidepressant effects of curcumin and dexanabinol-loaded solid lipid nanoparticles in corticosterone-induced cell and mice depression models. METHODS: Curcumin and dexanabinol-loaded solid lipid nanoparticles (Cur/SLNs-HU-211) were synthesized via an emulsifcation and low-temperature solidification method. Antidepressant activities of nanoparticles in a corticosterone-induced major depression model were investigated by MTT assay, cellular uptake by flow cytometry, behaviour by Forced Swimming Test and rotarod test, neurotransmitters by High Performance Liquid Chromatography, Western blotting, qPCR and immunofluorescence. RESULTS: Treatment with Cur/SLNs-HU-211 induced greater dopamine (DA)/5-hydroxytryptamine (5-HT) release with reduced corticosterone induced apoptotic cell death in PC12 cells. Additionally, in vivo Cur/SLNs-HU-211 significantly induced recovery from depressive behaviour with increased DA/5-HT levels, CB1 mRNA levels and CB1, p-MEK1 and p-ERK1/2 protein expression levels in the hippocampus and striatum. Cur/SLNs-HU-211 improved CB1 expression and inspired the proliferation of astrocytes in the hippocampus and striatum, exerted neuroprotective effects by preventing corticosterone -induced BDNF/NeuN expression reduction. CONCLUSION: Our study implies that Cur/SLNs-HU-211 may be a useful approach for treatment of major depression. PMID- 28848079 TI - Na+/H+ Exchanger Regulates Amino Acid-Mediated Autophagy in Intestinal Epithelial Cells. AB - BACKGROUND/AIMS: Dysfunctional autophagy has been reported to be associated with aberrant intestinal metabolism. Amino acids can regulate autophagic activity in intestinal epithelial cells (IECs). Na+/H+-exchanger 3 (NHE3) has been found to participate in the absorption of amino acids in the intestine, but whether NHE3 is involved in the regulation of autophagy in IECs is unclear. METHODS: In the present study, an amino acid starvation-induced autophagic model was established. Then, the effects of alanine and proline with or without the NHE inhibitor 5-(N ethyl-N-isopropyl) amiloride (EIPA) were evaluated. Autophagy was examined based on the microtubule-associated light chain 3 (LC3) levels, transmission electron microscopy (TEM), tandem GFP-mCherry-LC3 construct, sequestosome-1 (SQSTM1, P62) mRNA and protein levels, and autophagy-related gene (ATG) 5, 7, and 12 expression levels. The autophagic flux was evaluated as the ratio of yellow (autophagosomes) to red (autolysosomes) LC3 puncta. RESULTS: Following amino acid starvation, we found the LC3-II and ATG expression levels were enhanced in the IEC-18 cells. An increase in the number of autophagic vacuoles was concomitantly observed by TEM and confocal microscopy. Based on the results, supplementation with either alanine or proline depressed autophagy in the IEC-18 cells. Consistent with the elevated LC3-II levels, ATG expression increased upon NHE3 inhibition. Moreover, the mCherry-GFP-LC3 autophagic puncta representing both autophagosomes and autolysosomes per cell increased after EIPA treatment. CONCLUSIONS: These results demonstrate that NHE (most likely NHE3) may participate in the amino acid regulation of autophagy in IECs, which would aid in the design of better treatments for intestinal inflammation. PMID- 28848080 TI - The Impact of Discrepancy between Measured versus Stated Weight on Hemorrhagic Transformation and Clinical Outcomes after Intravenous Alteplase Thrombolysis. AB - BACKGROUND: An accurate measurement of patient weight is important in determining the dosage for intravenous alteplase thrombolysis. In most emergency rooms, however, weight is not measured. We investigated the difference between stated and measured weight and its effect on hemorrhagic transformation and clinical outcomes. METHODS: We enrolled 128 consecutive patients who had hyperacute stroke and were treated by alteplase. Alteplase dose was calculated using the weight provided by patient or guardian/caregiver, and the actual weight was measured after administration. Patients were classified into 2 groups: overused group (stated weight >measured weight) and underused group (measured weight >=stated weight). The prevalence of hemorrhagic transformation on follow-up, determined by gradient-recalled echo MRI or non-enhanced CT, was compared between the 2 groups. The predictors for hemorrhage with progression, defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) by a value of 4 or more accompanied by hemorrhage, were determined using multivariable logistic regression analysis and included the overused or underused alteplase and baseline clinical and laboratory findings. RESULTS: Sixty-six (51.6%) of 128 patients were in the underused group and 62 patients (48.4%) in the overused group. The median difference between the stated and measured weights was 1.5 (interquartile range 0.56-3.81) kg, with the largest difference being 25.6 kg. Although there were no significant difference in baseline clinical and laboratory findings between the 2 groups, the overused group showed a significantly higher prevalence of hemorrhagic transformation (p = 0.012) and hemorrhage with progression (p = 0.025). The multivariable logistic regression analysis demonstrated that overused alteplase (OR 7.26; 95% CI 1.24-42.45; p = 0.028), baseline glucose (>144 mg/dL; OR 5.03; 95% CI 1.00-25.26; p = 0.050), and initial NIHSS (OR 1.13 per 1-point NIHSS increase; 95% CI 1.00-1.27; p = 0.047) in model 1 that use alteplase overdose as a categorical variable and overused alteplase (OR 1.67 1-mg increase; 95% CI 1.05-2.66; p = 0.027) in model 2 that use an overused alteplase dose as numerical variable were significant predictors for hemorrhage with progression. CONCLUSION: More alteplase usage than actual weight led to higher hemorrhagic transformation. As one of the predictors for clinical deterioration, it is important to administrate alteplase based on an accurately measured weight. PMID- 28848081 TI - Bifidobacterium Infantis Ameliorates Chemotherapy-Induced Intestinal Mucositis Via Regulating T Cell Immunity in Colorectal Cancer Rats. AB - BACKGROUND/AIMS: Intestinal mucositis (IM) is a commonly encountered side effect in cancer patients receiving chemotherapy. This study aimed to investigate the effect of Bifidobacterium infantis (B. infantis) in attenuating the severity of chemotherapy-induced intestinal mucositis by regulating the T cell subsets in rats with colorectal cancer (CRC). METHODS: Thirty male Sprague-Dawley (SD) rats were injected dimethyl hydrazine (DMH) subcutaneously for 10 weeks, and then injected SW480 cells in rectal mucosa to create a CRC model, and the rats were randomly divided into three groups: Control group (saline + saline), Chemotherapy group (saline + 5-FU+Oxaliplatin), B. infantis group (B. infantis + 5 FU+Oxaliplatin). IM was evaluated based on diarrhea severity, intestinal villus height, crypt depth, pro-inflammatory cytokines (IL-6, IL-1beta, TNF-alpha), T cell subsets (CD4+ IL17A+ cells and CD4+ CD25+ Foxp3+ Tregs) and related cytokine profiles. RESULTS: The results showed that the B. infantis group demonstrated a higher body weight (BW) and intestinal villus height and a deeper crypt depth compared to the Chemotherapy group. The level of IL-6, IL-1beta and TNF-alpha which increased by chemotherapy, was lowered by B. infantis administration. Real time reverse transcription- polymerase chain reaction (RT-PCR) showed B. infantis reduced relative expression of Th17 and Th1 cells related cytokines, and increased relative expression of CD4+ CD25+ Foxp3+ Tregs related cytokines. Furthermore, Flow cytometry analysis showed B. infantis reduced CD4+ IL17A+ cells and increased CD4+ CD25+ Foxp3+ Tregs in mesenteric lymph nodes (MLNs) compared to the Chemotherapy group. CONCLUSION: B. infantis effectively attenuates chemotherapy-induced intestinal mucositis by decreasing Th1 and Th17 response and increasing CD4+ CD25+ Foxp3+ Tregs response. PMID- 28848082 TI - Epinephrine Stimulates Cell Proliferation and Induces Chemoresistance in Myeloma Cells through the beta-Adrenoreceptor in vitro. AB - OBJECTIVES: To explore the effect of the beta-adrenoreceptor signaling pathway on myeloma cells. METHODS: The myeloma U266 cell line was treated with epinephrine and propranolol. Cell proliferation was analyzed by MTS assay. Apoptosis was detected by flow cytometry. The beta-receptor subtype and the key enzyme of epinephrine were identified by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Epinephrine (5-50 MUM) promoted U266 cell growth in a dose dependent manner and neutralized the inhibition effect of bortezomib (25 and 50 ng/mL) in vitro. Cell proliferation was inhibited by a beta-receptor antagonist, propranolol, at a concentration of 50-200 MUM. The proportions of early and late apoptotic cells were enhanced after treatment with propranolol. The expression of caspase 3/7, 8, and 9 was elevated in propranolol-treated myeloma cells. Both beta1- and beta2-adrenoceptor mRNAs were expressed in the U266 cell line. Key enzymes dopamine hydroxylase and tyrosinehydroxylase were identified in myeloma cells. CONCLUSIONS: Our results reveal that epinephrine stimulates myeloma cell growth in vitro while the beta-blocker propranolol has an antiproliferative effect, indicating that stress hormones may trigger the progression of myeloma. PMID- 28848083 TI - Use of Exfoliative Specimens and Fine-Needle Aspiration Smears for Mutation Testing in Lung Adenocarcinoma. AB - OBJECTIVE: Cytology specimens are considered to be a promising alternative for detecting driver mutations in lung cancer patients. We aimed to explore the suitability and utility of various cytology samples of non-small-cell lung cancer (NSCLC) patients for mutation testing. In addition to mutation detection, the importance of preanalytic factors was discussed. DESIGN: A total of 116 cytology samples including 32 controls comprising pleural effusions, bronchial washings, and direct fine-needle aspiration (FNA) smears were included in the study for the detection of EGFR, KRAS, and Her-2/neu gene mutations. Tumor content was checked by microscopic evaluation. Tumor enrichment was done by scraping direct smears. DNA yield was assessed before selecting the method of mutation detection. Sanger sequencing and real-time PCR-based methods were used. RESULTS: Overall, 20.23% EGFR mutations and 2.74% KRAS mutations were observed in this study. Nondriver genetic polymorphisms were observed in EGFR exon 20 in 37% cases. The coexistence of the EGFR mutation and EGFR polymorphism was seen in 7 cases. DNA yield was better in pleural effusions and bronchial washings. Real-time PCR was used in specimens of low DNA yield. CONCLUSIONS: Cytology samples are useful in ascertaining molecular diagnostic information for treatment purposes if they are optimized judiciously in their preanalytic phase. PMID- 28848084 TI - Comparison of Different Sources of Mesenchymal Stem Cells: Palatal versus Lipoaspirated Adipose Tissue. AB - OBJECTIVES: The purpose of this study was to compare the proliferation and differentiation potential of mesenchymal stem cells (MSCs) derived from palatal adipose tissue (PAT) and lipoaspirated adipose tissue (LAT). MATERIALS AND METHODS: PATs were obtained from 2 healthy female patients undergoing surgery for gingival recession, and LATs were obtained from 2 healthy female patients undergoing plastic surgery. LAT- and PAT-derived MSCs were confirmed by flow cytometry using MSC-specific surface markers. The multilineage differentiation capacity of the MSCs was analyzed. The expression of immunophenotyping, embryonic, and differentiation markers was compared between both MSC lines. The proliferation of PAT- and LAT-MSCs was evaluated using a real-time cell analyzer, and telomerase activity was determined using an ELISA-based TRAP assay. Stem cells isolated from PAT and LAT were analyzed by real-time PCR and whole genome array analysis. RESULTS: The cells isolated from PAT had MSC characteristics. In addition, PAT-MSCs had significantly higher alkaline phosphatase activity and osteogenic potential than LAT-MSCs. Although the proliferation and telomerase activities of LAT-MSCs were higher than those of PAT-MSCs, the difference was not statistically significant. The level of embryonic stem cell markers (Oct4 and Nanog) was higher in LAT-MSCs than in PAT-MSCs. The whole genome array analysis demonstrated that 255 gene sequences were differentially expressed, with more than a twofold change in expression. CONCLUSIONS: This is the first comparative analysis of the isolation and characterization of MSCs from PAT and LAT. PAT is an accessible source of MSCs, which could be used in periodontal and craniofacial tissue engineering. PMID- 28848085 TI - Honokiol Attenuates Oligomeric Amyloid beta1-42-Induced Alzheimer's Disease in Mice Through Attenuating Mitochondrial Apoptosis and Inhibiting the Nuclear Factor Kappa-B Signaling Pathway. AB - BACKGROUND: Increasing evidence indicates that amyloid beta oligomer (AbetaO) is toxic to neurons in Alzheimer's disease (AD) brain. The aim of the present study is to evaluate the effects of honokiol on AbetaO-induced learning and memory dysfunction in mice. METHODS: AD mice model was established by AbetaO intrahippocampal injection. The cognitive function was evaluated using Morris water maze (MWM). Nissl staining was used to examine the hippocampal neuron damage. Primary hippocampal neurons were exposed to AbetaO. The apoptosis in the hippocampal tissues and primary neurons was assessed using terminal dexynucleotidyl transferase-mediated dUTP nick end labeling-neuronal nuclei (NeuN) and Hoechst staining, respectively. The mitochondrial membrane potential and radical oxygen species were detected using standard methods. Western blotting assay was used to check the expression levels of apoptotic and nuclear factor kappa-B (NF-kappaB) signaling-associated proteins and electrophoretic mobility shift assay was used to detect NF-kappaB-DNA binding. RESULTS: Honokiol increased the time spend in the target zone of the AD mice in the MWM. In addition, honokiol dose-dependently attenuated AbetaO-induced hippocampal neuronal apoptosis, reactive oxygen species production and loss of mitochondrial membrane potential. Furthermore, AbetaO-induced NF-kappaB activation was inhibited by honokiol, as well as the upregulated amyloid precursor protein and beta secretase. CONCLUSION: Honokiol attenuates AbetaO-induced learning and memory dysfunction in mice and it may be a potential candidate in AD therapy. PMID- 28848086 TI - Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. METHODS: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta amyloid peptide with 42 amino acids (Abeta42), total tau protein (tauT), and tau protein phosphorylated at threonine 181 (tauP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme linked immunosorbent assays were used for measurements. RESULTS: Both ALS and FTD patients presented with higher TDP-43 and tauT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 * tauT / tauP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. CONCLUSION: Combined analysis of TDP-43, tauT, and tauP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD. PMID- 28848087 TI - Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway. AB - BACKGROUND/AIMS: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA-maternally expressed gene 3 (MEG3) was involved in PAH related vascular remodeling. METHODS: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. RESULTS: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3-induced smooth muscle cell proliferation. CONCLUSIONS: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH. PMID- 28848088 TI - The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells. AB - BACKGROUND/AIMS: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and beta-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemo-radio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64CuCl2 and SI113 on human GBM cell lines with variable p53 expression. METHODS: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64CuCl2. RESULTS: We demonstrate here, that i) 64CuCl2 is able to induce a time and dose dependent modulation of cell viability (with different IC50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. CONCLUSIONS: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64CuCl2 in GBM cells. PMID- 28848089 TI - Histopathology of the Human Inner Ear in the Cogan Syndrome with Cochlear Implantation. AB - The Cogan syndrome is a rare disorder characterized by nonsyphilitic interstitial keratitis and audiovestibular symptoms. Profound sensorineural hearing loss has been reported in approximately half of the patients with the Cogan syndrome resulting in candidacy for cochlear implantation in some patients. The current study is the first histopathologic report on the temporal bones of a patient with the Cogan syndrome who during life underwent bilateral cochlear implantation. Preoperative MRI revealed tissue with high density in the basal turns of both cochleae and both vestibular systems consistent with fibrous tissue due to labyrinthitis. Histopathology demonstrated fibrous tissue and new bone formation within the cochlea and vestibular apparatus, worse on the right. Severe degeneration of the vestibular end organs and new bone formation in the labyrinth were seen more on the right than on the left. Although severe bilateral degeneration of the spiral ganglion neurons was seen, especially on the right, the postoperative word discrimination score was between 50 and 60% bilaterally. Impedance measures were generally higher in the right ear, possibly related to more fibrous tissue and new bone found in the scala tympani on the right side. PMID- 28848090 TI - MicroRNA-199a-5p Induced Autophagy and Inhibits the Pathogenesis of Ankylosing Spondylitis by Modulating the mTOR Signaling via Directly Targeting Ras Homolog Enriched in Brain (Rheb). AB - BACKGROUND/AIMS: Ankylosing spondylitis (AS) is an inflammatory and immune disease leading to disability. Autophagy has been identified as a potential player in understanding the pathogenesis of AS. METHODS: MiRNA-199a-5p and autophagy-related gene expression were determined by qRT-PCR or Western blot. Cytokine production was determined using ELISA assays. Proliferation was determined by MTT assay. MiRNA-199a-5p and Ras homolog enriched in brain (Rheb) were upregulated or downregulated by overexpression of plasmid or siRNA transfection. RESULTS: Expression of miRNA-199a-5p, and autophagy-related genes LC3, beclin1, and ATG5 was significantly decreased in T cells of AS patients. Serum concentrations of TNF-alpha, IL-17, and IL-23 were promoted in AS patients, compared to healthy controls. MiRNA-199a-5p expression levels also showed significant negative correlations with the Ankylosing Spondylitis Disease Activity Score (ASDAS) and modified Stoke Ankylosing Spon dylitis Spinal Score (mSASSS) of AS patients. In Jurkat T cells and T cells isolated from AS patients, miRNA-199a-5p overexpression promoted autophagy-related genes expression and decreased TNF-alpha, IL-17, and IL-23 levels, whereas inhibition of miRNA-199a-5p attenuated these effects. As a direct target of miRNA-199a-5p, Rheb inhibition led to a striking decrease in the phosphorylation of the mechanistic target of rapamycin (mTOR) and induced autophagy. Moreover, pcDNA3.1-Rheb effectively reduced the inhibiting effects of mTOR signaling caused by miRNA-199a-5p overexpression. All effects were offset by pretreating with rapamycin (an mTOR antagonist). CONCLUSIONS: AS patients with advanced spinal damage had decreased autophagy levels and that miRNA-199a-5p may induce autophagy and inhibit the pathogenesis of AS by modulating the mTOR signaling via direct targeting Rheb. PMID- 28848091 TI - Exosomes Derived from Mesenchymal Stem Cells Rescue Myocardial Ischaemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy Via AMPK and Akt Pathways. AB - BACKGROUND/AIMS: Reperfusion after an ischaemic insult might cause infarct extension. Mesenchymal stem cell (MSC)-derived exosomes could attenuate myocardial remodelling in animal models of myocardial ischaemia reperfusion injury (MIRI), and the present study aimed to explore the related mechanisms. METHODS: In vitro, rat H9C2 cardiomyocytes (H9C2s) were exposed to H2O2. Cell viability was detected by the CCK-8 assay, apoptosis was detected by Annexin V PE/7-AAD staining, ROS production was detected by fluorescence microscopy and flow cytometry, and apoptosis-related proteins and signalling pathway-related proteins were detected by western blot analysis. Autophagic flux was measured using the tandem fluorescent mRFG-GFP-LC3 assay. MSC-derived exosomes were extracted using the total exosome isolation reagent. Apoptosis, myocardial infarction size, heart function and myocardial LC3B expression were examined in an in vivo I/R model by the TUNEL assay, TTC/Evan blue staining, echocardiography and immunohistochemicalstaining, respectively. RESULTS: In vitro, H2O2 dose dependently increased ROS production and cell apoptosis in H9C2s and blocked autophagic flux after 3 h of exposure; autophagy gradually decreased thereafter, and the lowest level was detected at 12 h after exposure. MSC-derived exosomes reduced H2O2-induced ROS production and cell apoptosis and enhanced autophagy at 12 h after exposure. In H9C2 cells exposed to H2O2 for 12 h, treatment with exosomes enhanced autophagy via the AMPK/mTOR and Akt/mTOR pathways. Likewise, in vivo exosome injections in rats that underwent I/R injury significantly reduced apoptosis and the myocardial infarct size and upregulated myocardial LC3B expression as well as improved heart function. CONCLUSIONS: Our results indicate that MSC-derived exosomes could reduce MIRI by inducing cardiomyocyte autophagy via AMPK/mTOR and Akt/mTOR pathways. PMID- 28848092 TI - Extracellular HSP70 Activates ERK1/2, NF-kB and Pro-Inflammatory Gene Transcription Through Binding with RAGE in A549 Human Lung Cancer Cells. AB - BACKGROUND/AIMS: Heat shock protein 70 (HSP70) has been recently described with extracellular actions, where it is actively released in inflammatory conditions. Acting as DAMPs (damage associated molecular pattern), extracellular HSP70 (eHSP70) interacts with membrane receptors and activates inflammatory pathways. At this context, the receptor for advanced glycation endproducts (RAGE) emerges as a possible candidate for interaction with eHSP70. RAGE is a pattern recognition receptor and its expression is increased in several diseases related to a chronic pro-inflammatory state. One of the main consequences of RAGE ligand binding is the ERK1/2 (extracellular signal-regulated kinases)-dependent activation of NF-kB (nuclear factor kappa B), which leads to expression of TNF alpha (tumor necrosis factor alpha) and other cytokines. The purpose of this work is to elucidate if eHSP70 is able to evoke RAGE-dependent signaling using A549 human lung cancer cells, which constitutively express RAGE. METHODS: Immunoprecipitation and protein proximity assay were utilized to demonstrate the linkage between RAGE and eHSP70. To investigate RAGE relevance on cell response to eHSP70, siRNA was used to knockdown the receptor expression. Signaling pathways activation were evaluated by western blotting, gene reporter luciferase and real time quantitative PCR. RESULTS: Protein eHSP70 shown to be interacting physically with the receptor RAGE in our cell model. Treatment with eHSP70 caused ERK1/2 activation and NF-kappaB transactivation impaired by RAGE knockdown. Moreover, the stimulation of pro-inflammatory cytokines expression by eHSP70 was inhibited in RAGE-silenced cells. Finally, conditioned medium of eHSP70-treated A549 cells caused differential effects in monocytes cytokine expression when A549 RAGE expression is inhibited. CONCLUSIONS: Our results evidence eHSP70 as a novel RAGE agonist capable of influence the cross-talk between cancer and immune system cells. PMID- 28848093 TI - Colonic PDGFRalpha Overexpression Accompanied Forkhead Transcription Factor FOXO3 Up-Regulation in STZ-Induced Diabetic Mice. AB - BACKGROUND: Colonic transit disorder-induced constipation is a major complication in diabetic patients. PDGFRalpha+ (platelet-derived growth factor receptor alpha positive) cells play critical roles in the inhibitory regulation of colonic motility, and FOXO3 (forkhead transcription factor 3) has a broad range of biological functions. The present study was designed to investigate the relationship between FOXO3 and PDGFRalpha+ cell proliferation in streptozotocin (STZ)-induced diabetic mice. METHODS: The major experimental techniques used in this paper are immunohistochemistry, quantitative RT-RCR and Western blotting for the evaluation of specific protein expression; ChIP assay for identifying the interaction between FOXO3 protein and the PDGFRalpha promotor; and lentiviral transfection for the overexpression of short hairpin RNAs (shRNAs) to down regulate FOXO3. RESULTS: In proximal colonic smooth muscle tissue of STZ-induced diabetic mice, there was a significant increase in PDGFRalpha and Ki67 immunoreactivity. PDGFRalpha mRNA and protein expression levels were both significantly increased in colonic smooth muscle tissue, but PDGFRbeta expression was unchanged. Meanwhile, the expression of PDGF ligands, including both PDGFalpha and PDGFbeta, was significantly increased in diabetic colonic smooth muscle tissue. In whole cell and nuclear extracts, the expression of FOXO3 protein was also significantly increased; however, the expression of P-FOXO3 (phosphorylated FOXO3) protein was significantly decreased. When NIH cells were incubated with 50 mmol/L glucose for 12 h, 24 h and 48 h, the expression of PDGFRalpha significantly increased, and in whole cell and nuclear extracts, the expression of FOXO3 protein was significantly increased. However, the expression of P-FOXO3 protein was significantly decreased. FOXO3 could bind to a site on the PDGFRalpha promoter, and the basal expression of PDGFRalpha was significantly reduced when endogenous FOXO3 expression was knocked down with FOXO3 short hairpin RNA (shRNA) in NIH cells. The expression of phosphorylated Akt was significantly down-regulated in diabetic colonic muscle tissue. CONCLUSIONS: These results suggest that diabetes-induced colonic PDGFRalpha+ cell proliferation is mediated by FOXO3 up-regulation. FOXO3 up-regulation may be induced by inhibiting the PI3K/Akt signaling pathway in STZ-induced diabetic mice. PDGFRalpha+ cell proliferation could be a new target for clinical therapy of diabetes-induced colonic transit disorder. PMID- 28848094 TI - Lower Airway Inflammation in Eosinophilic Chronic Rhinosinusitis as Determined by Exhaled Nitric Oxide. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is classified into eosinophilic CRS (ECRS) and non-ECRS. The objectives of this study were to evaluate lower airway inflammation by measuring the fractional concentration of exhaled nitric oxide (FeNO) and to examine the effects of endoscopic sinus surgery (ESS) on FeNO in patients with ECRS compared to non-ECRS. METHODS: CRS patients with nasal polyps (23 with ECRS and 22 with non-ECRS) were enrolled into this study. ECRS was diagnosed based on the definition proposed by the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) study group. Several clinical markers including blood eosinophil counts, percent of eosinophils in white blood cells (WBC), number of eosinophils in nasal polyps, JESREC scores, total IgE, FeNO, and Lund-Mackay paranasal sinus CT scores were compared between ECRS and non-ECRS. These markers were also tested before and 2 months after ESS. RESULTS: FeNO was significantly higher in patients with ECRS than in non-ECRS patients. When all CRS patients were tested, a significant correlation was found between FeNO and eosinophilic markers including blood eosinophil counts, percent of eosinophils in WBC, number of eosinophils in nasal polyps, and JESREC scores. FeNO showed a significant correlation with Lund-Mackay scores only in ECRS patients. Blood eosinophil counts, percent of eosinophils in WBC, and FeNO decreased after ESS only in ECRS patients. CONCLUSIONS: ECRS patients had lower airway inflammation as revealed by an elevated FeNO, which was parallel to the Lund-Mackay CT scores. ESS decreased the blood eosinophils and FeNO, leading to an improvement of the occult pulmonary dysfunction in ECRS patients. PMID- 28848096 TI - The Future of Human Longevity: Time for a Reality Check. AB - Gavrilov and colleagues disagree with our article in Gerontology [Vijg and Le Bourg: Gerontology 2017;63:432-434]. Here we address their arguments regarding human life-history strategies, maximal lifespan, and the proposal that one could live soon for 150 years. PMID- 28848095 TI - Attitudes to Ageing and Change in Frailty Status: The English Longitudinal Study of Ageing. AB - BACKGROUND: Older people with more negative attitudes to ageing are at increased risk of several adverse outcomes, including decline in physical function and increased difficulties with activities of daily living. OBJECTIVE: We investigated whether negative attitudes to ageing increase the risk of the onset or progression of frailty. METHOD: Participants were 3,505 men and women aged 60 years and over from the English Longitudinal Study of Ageing. They completed a 12 item questionnaire on attitudes to ageing. Exploratory factor analysis was used to examine the structure of these items, and a single factor was derived which we labelled "physical and psychological loss." Frailty was assessed by the Fried phenotype of physical frailty at waves 2 and 4, and by a frailty index at waves 2 5. RESULTS: Having a more positive attitude to ageing as regards "physical and psychological loss" was associated with a decreased risk of becoming physically frail or pre-frail at follow-up. For a standard deviation increment in score, the relative risk ratios (95% confidence interval), adjusted for age, sex and baseline level of physical frailty, were 0.86 (0.79, 0.94) for pre-frailty and 0.72 (0.63, 0.83) for frailty. Further adjustment for other potential confounding variables had only slight attenuating effects on these associations: multivariable-adjusted relative risk ratios were 0.89 (0.81, 0.98) for pre frailty and 0.78 (0.68, 0.91) for frailty. Attitude to ageing was not associated with change in the frailty index over time after adjustment for potential confounding variables. CONCLUSION: Older people who have a more positive attitude to ageing are at reduced risk of becoming physically frail or pre-frail. Future research needs to replicate this finding and discover the underlying mechanisms. Attitude to ageing was not a risk factor for change in the more broadly defined frailty index. PMID- 28848097 TI - Alpha-Lipoic Acid Suppresses Extracellular Histone-Induced Release of the Infammatory Mediator Tumor Necrosis Factor-alpha by Macrophages. AB - BACKGROUND/AIMS: This study investigated signaling pathways via which extracellular histones induce the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) release from the macrophage cell line RAW 264.7 and the anti inflammatory efficacy of the antioxidant alpha-lipoic acid (ALA). METHODS: ELISA and western blotting analyses were conducted to detect the release of TNF-alpha from histone-stimulated RAW 264.7 macrophages and the associated phospho activation of MAPKs (ERK and p38) and NF-kappaB p65. The effects of ALA on the release of TNF-alpha and phospho-activation of the MAPKs and NF-kappaB p65 were studied. P < 0.05 was considered statistically significant. RESULTS: Extracellular histones dose-dependently induced TNF-alpha release from RAW 264.7 cells and increased the phosphorylation of p38, ERK, and NF-kappaB p65. TNF-alpha release was markedly suppressed by p38, ERK, and NF-kB inhibitors. ALA reduced histone-induced TNF-alpha release, ERK/p38 MAPK activation, and NF-kB activation without affecting macrophage viability. CONCLUSION: Histones induce TNF-alpha release from macrophages by activating the MAPK and NF-kB signaling pathways, while ALA suppresses this response by inhibiting ERK, p38 and NF-kB. These findings identify potentially critical inflammatory signaling pathways in sepsis and molecular targets for sepsis treatment. PMID- 28848099 TI - Precise Evaluation of Striatal Oxidative Stress Corrected for Severity of Dopaminergic Neuronal Degeneration in Patients with Parkinson's Disease: A Study with 62Cu-ATSM PET and 123I-FP-CIT SPECT. AB - BACKGROUND: This study sought to precisely evaluate striatal oxidative stress and its relationship with the disease severity in Parkinson's disease (PD) using double brain imaging, 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) (62Cu-ATSM) PET and 123I-FP-CIT SPECT. METHODS: Nine PD patients were studied with brain 62Cu ATSM PET for oxidative stress and 123I-FP-CIT SPECT for the density of striatal dopamine transporter. Standardized uptake values (SUVs) were obtained from the delayed phase of dynamic 62Cu-ATSM PET, and striatum-to-cerebellum SUV ratio (SUVR) was calculated. To correct the effect of neuronal loss in the striatum, 62Cu-ATSM SUVR was corrected for striatal specific binding ratio (SBR) values of 123I-FP-CIT (SUVR/SBR). RESULTS: 62Cu-ATSM SUVR without correction was not significantly correlated with disease severity estimated by the Unified Parkinson's Disease Rating Scale (UPDRS) scores or 123I-FP-CIT SBR. In contrast, the SUVR/SBR showed significant correlations with the UPDRS total and motor scores, and 123I-FP-CIT SBR. CONCLUSION: Oxidative stress in the remaining striatal dopaminergic neurons estimated by SUVR/SBR was increased with disease severity in PD patients, suggesting that oxidative stress based on mitochondrial dysfunction contributes to promoting dopaminergic neuronal degeneration in PD. 62Cu-ATSM PET with 123I-FP-CIT SPECT correction would be a promising tool to evaluate dopaminergic neuronal oxidative stress in PD. PMID- 28848098 TI - The Paradoxical Effects of Chronic Intra-Amniotic Ureaplasma parvum Exposure on Ovine Fetal Brain Development. AB - Chorioamnionitis is associated with adverse neurodevelopmental outcomes in preterm infants. Ureaplasma spp. are the microorganisms most frequently isolated from the amniotic fluid of women diagnosed with chorioamnionitis. However, controversy remains concerning the role of Ureaplasma spp. in the pathogenesis of neonatal brain injury. We hypothesize that reexposure to an inflammatory trigger during the perinatal period might be responsible for the variation in brain outcomes of preterms following Ureaplasma-driven chorioamnionitis. To investigate these clinical scenarios, we performed a detailed multimodal study in which ovine neurodevelopmental outcomes were assessed following chronic intra-amniotic Ureaplasma parvum (UP) infection either alone or combined with subsequent lipopolysaccharide (LPS) exposure. We show that chronic intra-amniotic UP exposure during the second trimester provoked a decrease in astrocytes, increased oligodendrocyte numbers, and elevated 5-methylcytosine levels. In contrast, short term LPS exposure before preterm birth induced increased microglial activation, myelin loss, elevation of 5-hydroxymethylcytosine levels, and lipid profile changes. These LPS-induced changes were prevented by chronic preexposure to UP (preconditioning). These data indicate that chronic UP exposure has dual effects on preterm brain development in utero. On the one hand, prolonged UP exposure causes detrimental cerebral changes that may predispose to adverse postnatal clinical outcomes. On the other, chronic intra-amniotic UP exposure preconditions the brain against a second inflammatory hit. This study demonstrates that microbial interactions and the timing and duration of the inflammatory insults determine the effects on the fetal brain. Therefore, this study helps to understand the complex and diverse postnatal neurological outcomes following UP driven chorioamnionitis. PMID- 28848100 TI - Eight Aeroallergen Skin Extracts May Be the Optimal Panel for Allergic Rhinitis Patients in Central China. AB - BACKGROUND: The prevalence of allergic rhinitis (AR) is increasing rapidly in Central China. The skin prick test (SPT) is the standard tool with which to determine the allergen sensitization status in AR patients. Changes in allergen sensitization patterns have been observed within countries and regions due to geographical and seasonal variations. OBJECTIVE: The aim of this study was to evaluate the profile of SPT reactivity to different aeroallergens in AR patients and to suggest a minimal panel of allergens to detect sensitized patients in Central China. METHODS: From January 2015 to December 2016, patients who presented to Tongji Hospital with suspected AR were tested with the same panel of 19 aeroallergens. The results of SPT were analyzed to determine the minimum test battery panel necessary to cover 99% of the cases of SPT sensitization in different age subgroups. RESULTS: A total of 2,416 patients (male:female ratio 1.2:1) were enrolled in our study with an average age of 22.0 years. The overall rate of sensitization to any allergen was 79.0%, and 64.3% of the subjects were monosensitized. The highest sensitized rate was found in the subgroup aged 14-18 years (92.0%), followed by the subgroups of 6-14 years (86.4%), >18 years (75.6%), and <=6 years (74.9%). The most common sensitization was to Dermatophagoides farinae (71.1%). Testing with 8 allergens (D. pteronyssinus, D. farinae, Platanus, Artemisia, Cryptomeria, Blatella germanica, Humulus, and Alternaria) was sufficient to identify over 99% of the sensitized patients. CONCLUSION: An SPT panel covering 8 allergen extracts was able to detect almost all sensitized patients suffering from AR symptoms in Central China. PMID- 28848101 TI - Techniques Used by Bearded Capuchin Monkeys (Sapajus libidinosus) to Access Water in a Semi-Arid Environment of North-Eastern Brazil. AB - The exploratory behaviour and the ability of capuchin monkeys to use tools allows them to thrive at times and places of limited food and water abundance, such as in semi-arid environments. Here, we report the behaviours employed by individuals belonging to a wild group of bearded capuchin monkeys (Sapajus libidinosus) to access natural water sources in a dry forest of north-eastern Brazil. An adult female employed a twig as a tool and her tail to gain access to accumulated rainwater in a tree hole, and other individuals used their hands and mouth to manipulate orchids' pseudobulbs and the liquid endosperm of palm nuts. The behaviour of wild Sapajus to access water from non-food sources may enable them to circumvent the risk of dehydration in environments with reduced availability of fleshy fruits and with ephemeral and rare water sources. Our findings contribute to the still scarce but accumulating reports on primate drinking behaviour and to the knowledge of tool use in wild populations of capuchin monkeys, enriching our understanding of primate strategies to gain access to a vital resource under challenging conditions. PMID- 28848103 TI - Is Omentectomy Necessary for Non-Endometrioid Endometrial Cancer. AB - BACKGROUND: In subtypes of non-endometrioid endometrium cancers (non-ECC), it is not clear whether the omentectomy is a part of debulking if visual assessment is normal. Recently, the ESMO-ESGO-ESTRO Endometrial Consensus Conference Working Group in their report titled "Endometrial Cancer: diagnosis, treatment and follow up" recommended that omentectomy be performed in the serous subtype, but not in carcinosarcoma, undifferentiated endometrial carcinoma or clear cell. In this study, the question is whether omentectomy should be a part of a staging procedure in patients with non-ECC. Besides, the sensitivity and specificity of the visual assessment of omentum were analyzed. METHODS: Patients diagnosed with non-ECC in 2 gynecological oncology clinics between 2005 and 2015 were retrospectively reviewed. Occult (absence of visible lesions) and gross (presence of visible lesions) omental metastasis rates of histological subtypes were analyzed. RESULTS: We identified 218 patients with non-ECC. Thirty-four of them (15.1%) had omental metastases and 44.1% of these metastases (n = 15) were occult metastases. The sensitivity of the surgeon's visual assessment of an omentum (positive or negative) was 0.55. The highest rate of omental metastasis was found in carcinosarcoma followed by serous, mixed subtypes, and clear-cell (20.4, 17.3, 16.6, 10.0%, respectively). Adnexal metastasis was the only factor associated with occult omental metastasis (p = 0.003). CONCLUSION: Omental metastases occur too often to omit omentectomy during surgical procedures for non-ECC regardless of histological subtypes, and visual assessment is insufficient in recognizing the often occult metastases. Omentectomy should be a part of the staging surgery in patients with non-ECC. PMID- 28848102 TI - Plasma BDNF Level in Major Depression: Biomarker of the Val66Met BDNF Polymorphism and of the Clinical Course in Met Carrier Patients. AB - AIMS: Despite the involvement of the brain-derived neurotrophic factor (BDNF) in the physiopathology of major depressive disorder (MDD), the coherence between the components of the BDNF pathway and their link with the clinical features of MDD are insufficiently studied. We aimed to assess in Caucasian depressed patients the impact of the BDNF Val66Met polymorphism on plasma BDNF levels taking into account the clinical characteristics of MDD. METHODS: A total of 328 Caucasian adult MDD patients with a current major depressive episode (MDE) were assessed for the BDNF Val66Met polymorphism, plasma BDNF levels and clinical characteristics of the MDD. RESULTS: Plasma BDNF levels were linearly associated with the BDNF Val66Met genotypes (ValVal: 1,525.9 +/- 1,183.3 pg/mL vs. ValMet: 1,248.7 +/- 1,081.8 vs. MetMet: 1,004.9 +/- 952.8; p = 0.04), Met carriers having lower BDNF levels than ValVal ones. Significant interactions between the Val66Met polymorphism and 3 clinical characteristics - age at onset (p = 0.03), MDD duration (p = 0.04), and number of previous MDE (p = 0.04) - were evidenced for plasma BDNF levels. Indeed, in Met carriers, but not in ValVal ones, plasma BDNF levels were negatively correlated with age at onset and positively correlated with MDD duration and number of previous MDE. CONCLUSION: Our results show a measurable, coherent, and functional BDNF pathway based on the BDNF Val66Met polymorphism and plasma BDNF levels in patients with a current MDE. This pathway is related to the clinical course of major depression, plasma BDNF levels being associated with the long-term history of MDD in Met carriers. Further studies assessing central BDNF are needed to understand the underlying mechanisms of this association. PMID- 28848104 TI - Adenosquamous Carcinoma of the Esophagus: An NCDB-Based Investigation on Comparative Features and Overall Survival in a Rare Tumor. AB - OBJECTIVES: Esophageal adenosquamous carcinoma (ASC) is a rare tumor with characteristics of adenocarcinoma (AC) and squamous cell carcinoma (SCC), the two most common esophageal cancers. Its behavior is aggressive but poorly understood. Using the National Cancer Database (NCDB), the clinical features and overall survival of ASC were compared with AC and SCC. METHODS: The NCDB was queried for patients with esophageal ASC, AC, and SCC. Univariate association of histology with patient characteristics and overall survival were analyzed and socioeconomic characteristics were balanced. RESULTS: Clinical M stage was 0 in a significantly lower proportion of ASC (69.0%) than in AC (70.9%) or SCC (75.6%) (p < 0.001). Median survival was lower in patients with ASC (9.6 months) than with AC (13.5) or SCC (9.7) and 2-year OS was lower in patients with ASC (23.8%) than with AC (34.6%) or SCC (26.5%) (p < 0.001). The OS hazard ratio for ASC was 1.14 when compared to AC (95% CI = 1.016-1.267, p = 0.025) and 1.10 when compared to SCC, but the latter was not significant (95% CI = 0.980-1.222, p = 0.111). CONCLUSION: ASC is a rare tumor among esophageal carcinomas with a greater burden of metastatic disease than AC or SCC and worse OS than AC. PMID- 28848105 TI - Two Ethnic Clusters with Huntington Disease in Israel: The Case of Mountain Jews and Karaites. AB - BACKGROUND: Worldwide prevalence estimates of Huntington disease (HD) vary widely, with no reliable information regarding the Jewish population in Israel. METHODS: This specialized tertiary single-center cross-sectional study assessed clinical, cognitive, and demographic characteristics of 84 HD patients who were treated at the Movement Disorder Unit of the Tel Aviv Medical Center, Israel. RESULTS: Our cohort was composed of one-third Ashkenazi Jews, 27% Mountain Jews (Caucasus Jews), 18% Sephardi Jews, and 21% Karaites, with both Mountain Jews and Karaites over-represented compared to their relevant proportion in the population of the state of Israel, which is less than 1%. No between-group differences were detected regarding the number of CAG (cytosine-adenine-guanine) repeats, age at onset, disease duration, years from symptom onset to diagnosis, gender, years of education, Unified Huntington Disease Rating Scale scores, or the Montreal Cognitive Assessment scores. CONCLUSION: We detected clustering of HD among the population treated at our Medical Center, which has the only specialized HD clinic in the country, with a high percentage of HD among 2 relatively small subpopulations of Jews: Mountain Jews and Karaites. PMID- 28848106 TI - Making Sense of Prognostic Information About Maintenance Dialysis versus Conservative Care for Treatment of Advanced Kidney Disease. PMID- 28848107 TI - Deep Brain Stimulation for the Treatment of Dejerine-Roussy Syndrome. AB - BACKGROUND/AIMS: Patients who suffer from Dejerine-Roussy syndrome commonly experience severe poststroke hemibody pain which has historically been attributed to thalamic lesions. Despite pharmacological treatment, a significant proportion of the population is resistant to traditional therapy. Deep brain stimulation is often appropriate for the treatment of resistant populations. In this review we aim to summarize the targets that are used to treat Dejerine-Roussy syndrome and provide insight into their clinical efficacy. METHODS: In reviewing the literature, we defined stimulation success as achievement of a minimum of 50% pain relief. RESULTS: Contemporary targets for deep brain stimulation are the ventral posterior medial/ventral posterior lateral thalamic nuclei, periaqueductal/periventricular gray matter, the ventral striatum/anterior limb of the internal capsule, left centromedian thalamic nuclei, the nucleus ventrocaudalis parvocellularis internis, and the posterior limb of the internal capsule. CONCLUSIONS: Due to technological advancements in deep brain stimulation, its therapeutic effects must be reevaluated. Despite a lack of controlled evidence, deep brain stimulation has been effectively used as a therapeutic in clinical pain management. Further clinical investigation is needed to definitively evaluate the therapeutic efficacy of deep brain stimulation in treating the drug-resistant patient population. PMID- 28848108 TI - Intrathecal Baclofen Pump Implantation for Type 2 Gaucher Disease. AB - Gaucher disease (GD) is the most common type of lysosomal storage disease, with type 2 being the most severe subtype. Type 2 GD patients suffer significant progressive neurological impairment, including spasticity, opisthotonus, seizure, and apnea. The recently developed enzyme replacement therapy (ERT) has shown therapeutic benefit for GD. However, as the enzymes do not cross the blood-brain barrier, ERT does not ameliorate neurological impairment in GD. Intrathecal baclofen therapy (IBT) is indicated for spastic neurological diseases, such as cerebral palsy, and studies have shown its therapeutic benefit in improving several manifestations of GD, such as scoliosis caused by muscle spasticity and respiratory function. To date, the potential benefits of IBT for treating lysosomal storage diseases such as GD have not been examined. Here we provide the first report of a patient with type 2 GD treated with IBT, and demonstrate its therapeutic benefit in ameliorating the neurological aspects of this disease. PMID- 28848109 TI - Testicular XX (SRY-Negative) Disorder of Sex Development in Cat. AB - In most mammals, the sex of an individual is genetically determined by the Y chromosome-specific SRY gene. The presence of at least one functional copy of this gene determines the development of the primordial gonads into testes. However, testicular tissue does develop in the absence of SRY, albeit rarely, which is the case in testicular XX (SRY-negative) disorder of sex development (DSD). This condition is very important for studying the process of sexual determination because it allows the identification of genetic factors that are able to promote the male developmental pathway in the absence of SRY and thereby enables a better understanding of this process. Until now, this condition has been identified in various animal species but has never been reported in cat. In this study, we describe the first case of an XX (SRY-negative) DSD cat. The cat possesses a tortoiseshell coat associated with male-like external genitalia, including normal scrotum with 2 palpably normal testicles. Histological analysis confirmed the presence of the testes, and cytogenetic and genetic analyses showed a female karyotype associated with the absence of the SRY gene. Finally, sequencing of the RSPO1 gene revealed no mutation, and FISH analysis of the SOX9 locus did not reveal any large abnormalities. PMID- 28848110 TI - Telehealth Stroke Dysphagia Evaluation Is Safe and Effective. AB - BACKGROUND: Rapid evaluation of dysphagia poststroke significantly lowers rates of aspiration pneumonia. Logistical barriers often significantly delay in-person dysphagia evaluation by speech language pathologists (SLPs) in remote and rural hospitals. Clinical swallow evaluations delivered via telehealth have been validated in a number of clinical contexts, yet no one has specifically validated a teleswallow evaluation for in-hospital post-stroke dysphagia assessment. METHODS: A team of 6 SLPs experienced in stroke care and a telestroke neurologist designed, implemented, and tested a teleswallow evaluation for acute stroke patients, in which 100 patients across 2 affiliated, urban certified stroke centers were sequentially evaluated by a bedside and telehealth SLP. Inter-rater reliability was analyzed using percent agreement, Cohen's kappa, Kendall's tau-b, and Wilcoxon matched-pairs signed rank tests. Logistic regression models accounting for age and gender were used to test the impact of stroke severity and stroke location on agreement. RESULTS: We found excellent agreement for both liquid (91% agreement; kappa = 0.808; Kendall's tau-b = 0.813, p < 0.001; Wilcoxon signed rank = -0.818, p = 0.417) and solid (87% agreement; kappa = 0.792; Kendall's tau-b = 0.844, p < 0.001; Wilcoxon signed rank = 0.243, p = 0.808) dietary textures. From regression modeling, there is suggestive but inconclusive evidence that higher National Institute of Health Stroke Scale (NIHSS) scores correlate with lower levels of agreement for liquid diet recommendations (OR [95% CI] 0.895 [0.793-1.01]; p = 0.07). There was no impact of NIHSS score for solid diet recommendations and no impact of stroke location on solid or liquid diet recommendations. Qualitatively, we identified professional, logistical, technical, and patient barriers to implementation, many of which resolved with experience over time. CONCLUSIONS: Dysphagia evaluation by a remote SLP via telehealth is safe and effective following stroke. We plan to implement teleswallow across our multistate telestroke network as standard practice for poststroke dysphagia evaluation. PMID- 28848111 TI - An Asian Perspective on Povidone Iodine in Wound Healing. AB - Antiseptics, with a broader spectrum of antimicrobial efficacy, lower risk of antibiotic resistance development, and minimal collateral damage to host tissues, are important alternatives to control the bioburden in wounds. Povidone iodine (PVP-I), in use for several decades, has the broadest spectrum of activity, a persistent antimicrobial effect, an ability to penetrate biofilms, and a lack of acquired or cross-resistance. It demonstrates good skin tolerance and low cytotoxicity. However, some reports on PVP-I have raised concerns over allergy, ineffective penetration, and toxic effects on host cells. The majority of these concerns are based on in vitro or rodent wound studies with diverse study designs and outcomes; these results may not be directly applicable in the clinical reality in humans. In this paper, we discuss the efficacy and safety of PVP-I and outline its place in wound healing in Asia, based on an appraisal of recent literature and clinical practice across the region. PMID- 28848112 TI - Use of a 3D Skull Model to Improve Accuracy in Cranioplasty for Autologous Flap Resorption in a 3-Year-Old Child. AB - Cranioplasty is considered a simple reconstructive procedure, usually performed in a single stage. In some clinical conditions, such as in children with multifocal flap osteolysis, it could represent a surgical challenge. In these patients, the partially resorbed autologous flap should be removed and replaced with a precustomed prosthesis which should perfectly match the expected bone defect. We describe the technique used for a navigated cranioplasty in a 3-year old child with multifocal autologous flap osteolysis. We decided to perform a cranioplasty using a custom-made hydroxyapatite porous ceramic flap. The prosthesis was produced with an epoxy resin 3D skull model of the patient, which included a removable flap corresponding to the planned cranioplasty. Preoperatively, a CT scan of the 3D skull model was performed without the removable flap. The CT scan images of the 3D skull model were merged with the preoperative 3D CT scan of the patient and navigated during the cranioplasty to define with precision the cranioplasty margins. After removal of the autologous resorbed flap, the hydroxyapatite prosthesis matched perfectly with the skull defect. The anatomical result was excellent. Thus, the implementation of cranioplasty with image merge navigation of a 3D skull model may improve cranioplasty accuracy, allowing precise anatomic reconstruction in complex skull defect cases. PMID- 28848113 TI - Lemur Tyrosine Kinase-3 Suppresses Growth of Prostate Cancer Via the AKT and MAPK Signaling Pathways. AB - BACKGROUND/AIMS: Lemur tyrosine kinase (LMTK)-3 is a member of the receptor tyrosine kinase (RTK) family. Abnormal expression of LMTK-3 exists in various types of cancers, especially in endocrine-resistant breast cancers; however, the precise level of expression and the biological function in prostate cancer are poorly understood. METHODS: In the present study, we determined the expression of LMTK-3 in prostate cancer using immunohistochemistry and Western blotting. We infected PC3 and LNCaP cells with lentivirus-LMTK-3 and observed the biologic characteristics of the PC3 and LNCaP cells in vitro with TUNEL, and migration and invasion assays, respectively. We also established a transplant tumor model of human prostate cancer with infected cells in 15 BALB/c-nu/nu nude mice. RESULTS: LMTK-3 was expressed in prostate epithelial cells. There was a significant decline in the level of LMTK-3 expression in prostate cancers compared to normal tissues. LMTK-3 inhibited PC3 and LNCaP cell growth, migration, and invasion, and induced cell apoptosis in vitro. We also observed that LMTK-3 induced PC3 cell apoptosis in vivo. Further study showed that LMTK-3 inhibited phosphorylation of AKT and ERK, and promoted phosphorylation and activation of p38 kinase and Jun kinase (JNK). CONCLUSION: Recombinant lentivirus with enhanced expression of LMTK 3 inhibited prostate cancer cell growth and induced apoptosis in vitro and in vivo. AKT and MAPK signaling pathways may contribute to the process. PMID- 28848114 TI - Effect of Huaier On the Proliferation of Mesangial Cells in Anti-Thy-1 Nephritis. AB - BACKGROUND/AIMS: To determine whether an aqueous extract of Trametes robiniophila Murr. (Huaier) suppresses anti-Thy-1 mesangial proliferative glomerulonephritis (MsPGN) in vivo and platelet-derived growth factor (PDGF)-BB-induced mesangial cell proliferation in vitro. METHODS: Male Wistar rats were randomly categorized into 5 groups: Sham, Thy-1, and 3 Huaier-treated groups (low, medium, and high dose). Two weeks after treatment, urinary proteins were quantified and renal pathological changes were examined. MAX interactor 1 (Mxi-1) and proliferating cell nuclear antigen (PCNA) expression levels in isolated glomeruli, rat mesangial cell viability, cell-cycle distribution, and cell-cycle pathways were assessed. RESULTS: Huaier diminished the proliferative damages and urinary protein secretion in Thy-1 rats. PCNA was downregulated, whereas Mxi-1 was upregulated in the isolated glomeruli of Huaier-treated groups compared with the Thy-1 group. Huaier inhibited PDGF-BB- stimulated proliferation of rat mesangial cells in a time- and dose-dependent manner (50% inhibitory concentration = 6.19 mg/mL) and induced G2 cell-cycle arrest. Cell-cycle pathway proteins were downregulated, whereas Mxi-1 was upregulated in Huaier-treated mesangial cells compared with PDGF-BB-stimulated cells. CONCLUSION: Huaier reduces urinary protein excretion and relieves hyperplasia in mesangial cells in anti-Thy-1 MsPGN as well as inhibits PDGF-BB-stimulated proliferation and DNA synthesis of rat mesangial cells in vitro, suggesting its novel therapeutic potential in MsPGN. PMID- 28848115 TI - Exogenous Hydrogen Peroxide Induces Lipid Raft-Mediated STAT-6 Activation in T Cells. AB - BACKGROUND/AIMS: CD4+ T cells are a critical component of the adaptive immune response. While the mechanisms controlling the differentiation of the Th1, Th17, and regulatory T cell subsets from naive CD4+ T cells are well described, the factors that induce Th2 differentiation are still largely unknown. METHODS: The effects of treatment with exogenous H2O2 on STAT-6 phosphorylation and activation in T cells were examined by immunoblotting, immunofluorescence and gel shift assay. Anti-CD3 antibody and methyl-beta-cyclodextrin were utilized to induce lipid raft assembly and to investigate the involvement of lipid rafts, respectively. RESULTS: Jurkat and EL-4 T cells that were exposed to H2O2 showed rapid and strong STAT-6 phosphorylation, and the extent of STAT-6 phosphorylation was enhanced by co-treatment with anti-CD3 antibody. The effect of H2O2 on STAT-6 phosphorylation and translocation was inhibited by disruption of lipid rafts. STAT-6 activation in response to H2O2 treatment regulated IL-4 gene expression, and this response was strengthened by treatment with anti-CD3. CONCLUSION: Our results indicate that reactive oxygen species such as H2O2 can act on upstream and initiating factors for activation of STAT-6 in T cells and contribute to formation of a positive feedback loop between STAT-6 and IL-4 in the Th2 differentiation process. PMID- 28848116 TI - Venous Stasis and Cerebrovascular Complications in Cerebral Venous Sinus Thrombosis. AB - BACKGROUND/AIMS: The factors related to cerebrovascular complications in cerebral venous sinus thrombosis (CVST) are controversial. We focused on venous stasis and investigated its relationship with cerebrovascular complications in CVST. METHODS: CVST patients between June 2013 and October 2016 were enrolled. Relationships between cerebrovascular complications, defined as cerebral venous infarction, intracerebral hemorrhage, or subarachnoid hemorrhage, and cerebrum venous stasis and other clinical information were retrospectively analyzed. Venous stasis was evaluated by the prominence of the veins on susceptibility weighted imaging (SWI). The cerebrum was divided into 10 regions according to the venous drainage territories, and venous stasis was quantified by adding one point for venous prominence on SWI for each region (CVST SWI score). RESULTS: All 5 cases in the noncomplicated group had a CVST SWI score of 0. The 3 patients with CVST SWI scores higher than 0 had cerebrovascular complications. The CVST SWI scores were higher in the complicated group than in the noncomplicated group (3.0 vs. 0, p = 0.010). Seizures were seen in all patients with complications and in none of the patients without complications (3 vs. 0, p = 0.018). CONCLUSION: Venous stasis evaluated by SWI can help predict cerebrovascular complications in CVST. A seizure is an important initial symptom that suggests cerebrovascular complications in CVST. PMID- 28848117 TI - Unintentional Head Injury in Children Less than 3 Years of Age: An Insight into Safety Practices in a Developing Country. AB - Being dependent on caretakers for their safety, children under the age of 3 years are particularly vulnerable to unintentional injury. To identify the circumstances and consequences of head injury in this age group and to assess preventability in a setting of low parental educational levels, we conducted a retrospective cohort study of children less than 3 years of age admitted to hospital with a head injury and in addition categorized the degree of preventability of injury. This study included 109 children, representing a third of head-injured children under the age of 16 years, and 23.4% of these were infants. A significant proportion of head injuries, i.e., 20.18%, were designated "serious" and there was an in-hospital mortality rate of 7.3%. Most of the injuries (80%) occurred in the home and 76% could have been prevented through improved parental supervision and safety measures. We conclude that, in a setting of low maternal education, head injuries in preschoolers largely result from a lack of diligence of the caretakers, presenting opportunities for prevention strategies via a multidimensional approach that integrates safety information into the preexisting national health programs. PMID- 28848118 TI - Comparative Study of Two Cohorts of Newly Diagnosed Crohn's Disease Demonstrates Change in Therapeutic Strategies. AB - BACKGROUND: There has been a paradigm shift in the treatment of Crohn's disease (CD) involving the rapid introduction of biologics and/or immunomodulators after diagnosis. We wished to assess whether this was applied to patients with newly diagnosed CD in a tertiary inflammatory bowel disease referral centre in Israel. METHODS: Newly diagnosed CD patients were stratified into 2 groups: the early group was diagnosed between 2005 and 2007 and the late group was diagnosed between 2010 and 2012. Baseline demographics, medical and surgical treatments, disease course and complications during those 2 periods were analyzed. RESULTS: Each group included 60 patients. Significantly higher rates of immunomodulators and biologics were administered to patients in the late group compared to the early group (81.7 and 36.7% compared to 56.7 and 18.3%, p = 0.004 and p = 0.021, respectively). On the other hand, steroid therapy was less prevalent in the late (36.7%) group compared to that of the early group (56.7%), p = 0.059. Medical and surgical CD outcomes, including exacerbations/hospitalizations and surgeries, were comparable for both groups. CONCLUSIONS: There was a change in treatment strategy between 2005-2007 and 2010-2012, as reflected in higher proportions of biologics/immunomodulators for patients with newly diagnosed CD. This was associated with a steroid-sparing effect. PMID- 28848121 TI - Incidence and Management of Umbilical Artery Flow Abnormalities during Open Fetal Surgery. AB - INTRODUCTION: Umbilical artery (UA) Doppler ultrasound is used to assess uteroplacental insufficiency. Absent or reversed end diastolic flow (AREDF) in the UA is associated with increased perinatal mortality in fetuses with intrauterine growth restriction. We describe the incidence of UA Doppler abnormalities during open fetal surgery. METHODS: We conducted a retrospective review of patients undergoing open in utero myelomeningocele (MMC) repair between 2008 and 2015. Intermittent UA Dopplers were performed during key portions of all cases. Our primary outcome was the rate of any AREDF. Secondary outcomes included analysis of absent versus reversed end diastolic flow (EDF), vasopressor use, and volatile anesthetic and clinical outcomes. RESULTS: Thirty-four of 47 fetuses developed UA Doppler abnormalities intraoperatively. Nineteen had absent EDF and 15 had reversed EDF. No AREDF was present before induction, and all AREDF resolved by postoperative day 1. Ten of 19 (52.6%) patients who received sevoflurane had reversed EDF, versus 5/28 (17.9%) for desflurane, odds ratio (95% CI) 5.11 (1.36-19.16), p = 0.02. One intraoperative fetal death occurred in the AREDF group. DISCUSSION: AREDF is a common phenomenon during open MMC repair. Anesthetic agent choice may influence this risk. Future studies of UA flow during fetal surgery are needed to further evaluate the impact of intraoperative AREDF on fetal well-being. PMID- 28848123 TI - Neck Management with Total Laryngectomy and Adjuvant Radiotherapy in Locally Advanced Larynx Cancer. AB - BACKGROUND: The aim of this study was to determine whether patients with clinically node-negative (cN0) locally advanced squamous cell carcinoma (SCC) of the larynx who receive total laryngectomy (TL) benefit from elective neck dissection (END) before adjuvant postoperative radiotherapy (RT). METHODS: A retrospective review of 36 patients who received TL and adjuvant postoperative RT for laryngeal SCC between 1988 and 2013 was carried out. Patients had either T3 (n = 7; 19%) or T4a (n = 29; 81%) primaries, and all had clinically node-negative disease. All patients underwent TL and adjuvant RT. Patients underwent either a planned unilateral END, a bilateral END, or no END. RESULTS: Median follow-up was 3.3 years (range, 0.3-18.4 years). Occult nodal metastases were found in 9 (32%) of 28 patients receiving END. 5-year control and survival rates for all patients were: local-regional control, 92% (END 91% vs. no END 100%; p = 0.4922); cause specific survival, 80%; distant metastasis-free survival, 88%; and overall survival, 52%. Local-regional control and survival were not influenced by END. 5 (14%) patients experienced grade 3 or 4 toxicities. CONCLUSION: In this patient population, those not receiving END at the time of TL had equivalent rates of local-regional control and survival as those receiving END, although our sample size not receiving END was relatively small. PMID- 28848124 TI - Detection of Merkel Cell Polyomavirus in Respiratory Tract Specimens. AB - OBJECTIVE: The role of Merkel cell polyomavirus (MCPyV) as a respiratory pathogen is controversial. The aim of this study was to determine the prevalence of MCPyV in patients with acute respiratory diseases and chronic lung diseases, including lung cancer, in order to evaluate the association between MCPyV infection and respiratory diseases. METHODS: This study included 221 specimens (133 nasopharyngeal swabs and 88 lung biopsy specimens) obtained from patients with acute respiratory diseases and chronic lung diseases, including lung cancer. The detection of MCPyV was performed via nested polymerase chain reaction. RESULTS: MCPyV positivity was 4.3% on average. All nasopharyngeal specimens were obtained from patients with acute respiratory diseases, and 8.2% of them were MCPyV DNA positive. There were no statistically significant differences in MCPyV prevalence according to age or gender. All specimens from nonmalignant chronic lung diseases and lung cancer were MCPyV negative. CONCLUSIONS: MCPyV was observed in specimens from patients with acute respiratory diseases, indicating that there may be a relationship between the virus and these diseases. We were not able to detect MCPyV in samples from patients with chronic lung diseases, including lung cancer, suggesting no association with MCPyV infection and no involvement of this polyomavirus in lung cancerogenesis. PMID- 28848122 TI - Postnatal Prevention of Childhood Obesity in Offspring Prenatally Exposed to Gestational Diabetes mellitus: Where Are We Now? AB - Children exposed to gestational diabetes mellitus (GDM) in utero are at high risk of developing many health problems such as obesity. There is an urgent need to find new strategies to prevent obesity development among high-risk populations such as those children. Accordingly, the aim of this review was to summarize current knowledge on the postnatal prevention of childhood obesity in offspring born from mothers with GDM. Specifically, this review addresses the impact of breastfeeding, complementary feeding practices as well as dietary intake and physical activity during childhood on obesity risk of children exposed to GDM in utero. Furthermore, breast milk composition of diabetic mothers and its potential impact on growth is discussed. According to the available literature, breastfeeding may reduce obesity risk in children exposed to GDM in utero but a longer duration seems necessary to achieve its protective effect against obesity. Detailed analysis of breast milk composition of mothers with GDM will be necessary to fully understand the relationship between breastfeeding and obesity in this specific population. This review highlights the need for more studies addressing the impact of complementary feeding practices and lifestyle habits during childhood on obesity risk of children exposed to GDM in utero. PMID- 28848125 TI - Surgically Managed Pediatric Intracranial Aneurysms: How Different Are They from Adult Intracranial Aneurysms? AB - PURPOSE: Intracranial aneurysms in children are rare compared to those in adults, and their causes, presentations, and outcomes also vary. Thus, they need to be studied intricately and as an independent entity. METHODS: We retrospectively reviewed intracranial saccular aneurysms in 44 children of <19 years of age who had been surgically treated during the last 30 years at our institute. We analyzed presentation, characteristics, size, multiplicity, cause, and eventual outcome, and compared these to the adult cases of aneurysms operated on during the same period. RESULTS: The commonest site of aneurysm was the internal carotid artery (ICA), in 47.7%. Follow-up was available for 38 (86.4%) children. The median duration of follow-up was 14 months (range 1-89 months). A favorable outcome was seen in 31 cases (81.6%) and an unfavorable outcome (including 1 death) in 7 (18.4%). CONCLUSION: Intracranial aneurysms in children present with subarachnoid hemorrhage in a good grade. ICA bifurcation aneurysms are the commonest sites of occurrence. Surgery is safe and effective, and children seem to have a better outcome. PMID- 28848126 TI - The Impact of Treatment Preferences in Second-Line Chemotherapy on the Prognosis of HER2-Negative Metastatic Breast Cancer. AB - OBJECTIVE: We assessed the impact of treatment preferences in second-line chemotherapy on breast cancer prognosis using the SELECT BC study. METHODS: The SELECT BC study was performed in patients with HER2-negative metastatic breast cancer treated with initial chemotherapy. From these patients, 618 were assigned to 2 groups (S-1 group, 309; taxane group, 309). The S-1 and taxane groups were each subdivided into 3 groups: crossover group, protocol-recommended group, and other group, and the analysis of overall survival (OS) was performed using Cox regression with inverse probability weighting, to adjust for postrandomization confounding. RESULTS: In the taxane group, the OS of the crossover group (39.6 months) was better than that of the protocol-recommended group (35.7 months) and the other chemotherapy group (36.9 months) (vs. the protocol-recommended group, HR 0.72 [95% CI 0.52-0.98], p = 0.037; vs. the other chemotherapy group, HR 0.71 [95% CI 0.43-1.18], p = 0.183). In the S-1 group, there was no statistically significant difference in OS between the 3 groups. CONCLUSION: The study of the combination of first-line chemotherapy and second-line chemotherapy showed that S 1 might be recommended as a second-line chemotherapy in patients in whom taxane was the primary chemotherapy. PMID- 28848127 TI - Diagnosis of Cytomegalovirus Infection during Exacerbation of Ulcerative Colitis. AB - BACKGROUND/AIMS: The role of cytomegalovirus (CMV) reactivation during exacerbations of ulcerative colitis (UC) is yet a matter of debate, and assessment of CMV infection in UC patients remains an ongoing challenge. We aimed to identify associated parameters and compare detection methods for CMV infection during UC exacerbation. METHODS: Clinical, pathological and virological parameters were retrospectively analyzed in all patients hospitalized in our institution for UC exacerbation between January 2009 and April 2015, who underwent full evaluation for CMV infection in colonic tissue by histopathology, immunohistochemistry (IHC) and CMV-PCR. RESULTS: Of 28 patients who underwent full examination for tissue CMV-infection, 13 (46.4%) were found to be positive for CMV. Tissue CMV-PCR was more sensitive for the detection of CMV infection than histopathology and IHC. CMV-positive patients had a statistically higher frequency of recent steroid treatment and fever, with higher mean partial Mayo scores and lower mean albumin levels. There were no significant differences between CMV-positive and CMV-negative patients in terms of age, severity of colitis and disease duration. In a multivariable model, only recent steroid treatment and fever were independently associated with colonic CMV infection. CONCLUSIONS: This study provides a clinical model to detect the presence of CMV infection in patients hospitalized with UC exacerbation, which could direct proper investigation and facilitate timely empirical therapy. PMID- 28848128 TI - Germline Development of Genetically Female Nile Tilapia (Oreochromis niloticus) Reared under Different Temperature Regimes. AB - In teleosts, elevated temperature during embryogenesis can act on germline cell development, which in turn plays a role for sexual fate. In Nile tilapia, a species with high-temperature-induced masculinization, little is known about the effects of increased temperature on gonadal development in non-masculinized females. The aim of the present work was to investigate persistent effects on the germline of genetically female (XX) Nile tilapia reared at normal (28 degrees C) or elevated temperature (36 degrees C) during the critical time of gonadal sex differentiation at 10 to 20 days post fertilization. Non-sex-reversed females were compared to control females to determine persistent effects of temperature on subsequent ovarian development using histological approaches. Germline stem cells were identified using the germline marker Vasa in combination with the proliferation marker PCNA. Vasa- and PCNA-positive germline stem cells were found in ovaries of both high-temperature-treated and control females. In both groups, ovarian germline stem cells were located at the germinal epithelium of the ovigerous lamellae. Although no detrimental effects of high temperature on gonadal development in female Nile tilapia were observed, implications on the reproductive fitness caused by elevated temperature need to be investigated in greater depth. PMID- 28848129 TI - Clinical Utility of Endometrial Cell Block Cytology in Postmenopausal Women. AB - OBJECTIVE: To investigate the diagnostic utility of endometrial (EM) cell block (CB) cytology for the detection of intrauterine malignancy in postmenopausal women. METHODS: We reviewed the medical records of 104 postmenopausal women between January 2012 and November 2014. We reviewed symptoms upon admission, body mass index, parity, transvaginal ultrasonographic findings, and histopathological results based on CB and conventional cytology. RESULTS: The mean age was 62.6 (range 48-95) years. The mean menopausal age was 50.8 years and the mean duration of menopause was 12.0 years. The sensitivity of CB and conventional cytology was 82.3% (29/35) and 85.7% (30/35) and the specificity was 98.6% (68/69) and 94.2% (65/69), respectively. The sensitivity and specificity of CB cytology combined with conventional cytology were 82.3% (29/35) and 94.2% (65/69), respectively. The predictive values for EM hyperplasia and type-II carcinoma were 100 and 85.7%, respectively. CONCLUSION: CB cytology provides specimens for examination in a single outpatient session. Additionally, immunohistochemical staining can provide useful information for histological diagnosis. A combination of CB and conventional cytology can improve the diagnostic accuracy of EM lesions and may be a valid method for screening in postmenopausal women. PMID- 28848131 TI - Complementary and Integrative Medicine and Patient Self-Management of Health. PMID- 28848132 TI - How Can We Enhance the Sense of Self-Efficacy in Epilepsy Individual Responses from 2 Qualitative Case Reports. AB - BACKGROUND: Epilepsy is a serious, common and chronic neurological condition characterized by an increased disposition to suffer occasional seizures. Psychological interventions may enhance the well-being of individuals with epilepsy. So far, no qualitative study has investigated the complex effects of psychotherapeutic interventions in epilepsy. METHODS: This study examined the questions as to if and how the participation in a patient-centered 6-month resource-oriented mindfulness-based intervention would enhance an individual's well-being and sense of self-efficacy. Pre- and post-intervention semi-structured interviews were conducted with a total of 9 participants. Qualitative data analysis (Mayring) in an inter-professional group was combined with the evaluation of the Quality of Life in Epilepsy Inventory-31. The case reports follow the CAse REport Guidelines for Anthroposophic Art Therapies (CARE-AAT). To show the diverse nature of individual intervention objectives, we chose the single case study format, contrasting 2 participants with diagnosed focal epilepsy. RESULTS: Pre-intervention deductive and inductive outcome categories revealed high levels of stress regarding personal seizure experience and loss of autonomy, for both participants. Post-intervention interviews consist of increased seizure-related self-efficacy and self-awareness: while minimizing the debilitating impact of the seizures on her life was relevant to Iris, Carl developed a personalized aura interruption technique. CONCLUSIONS: These qualitative case analyses suggest that enhanced psychological well-being and even positive medical results may be achieved when epilepsy care focuses on the wishes that are most meaningful to the individual. The possibility of improving the quantitative evaluation of the effects of psychotherapeutic interventions needs to be explored. PMID- 28848133 TI - Design of a Self-Management Program for Children Aged 6-12 Years with Type 1 Diabetes Mellitus at the Community Hospital Herdecke, Germany. AB - BACKGROUND: Children with type 1 diabetes mellitus (T1DM) must replace lacking endogenous insulin by daily insulin injections or insulin pumps. Standards of treatment include educational programs enabling self-management. The program 'Herdecker Kids with Diabetes' (HeKiDi) is based on an anthroposophic understanding of the human being and intends to provide an individualized, patient-oriented approach to developing diabetes-related and comprehensive human competencies. AIM: Analysis of the HeKiDi program for children (6-12 years) with T1DM as the first part of an evaluation of a complex intervention. METHODS: Ethnographic approach, following the Consolidated Criteria for Reporting Qualitative Research (COREQ), including field observations and interviews with responsible persons, content analysis of materials for determining the structure and the curriculum, presented according to the Template for Intervention Description and Replication (TIDieR). RESULTS: The curriculum follows the standard but adds a learning circle between the child and the therapeutic team comprising 3 stages: (1) perception of the abilities and needs of the individual child supported by adult mentors themselves suffering from T1DM, (2) reflection within the therapeutic team, and (3) daily feedback to the child. Curricular Learning Objectives: Children feel recognized and supported in their individual developmental and diabetes-related competencies and develop motoric, artistic, communicative, and social skills to strengthen their self-efficacy and to understand T1DM as a lifelong awareness process. CONCLUSIONS: The curriculum including its associated learning goals and methods was presented. The program was explained and shown to be reproducible. Whether this program truly leads to better outcomes in regard to self-efficacy and hemoglobin A1c (HbA1c, glycated hemoglobin) and how parents and children perceive this will have to be assessed using a comparative interventional study. PMID- 28848134 TI - Selection of Surgical Methods in the Treatment of Upper Tibia Osteosarcoma and Prognostic Analysis. AB - BACKGROUND: We aimed to explore the clinical effects and prognosis of different surgical methods in upper tibia osteosarcoma. METHODS: Among 112 patients with proximal upper tibia osteosarcoma, 40 patients were treated with amputation, 20 patients were treated with massive osteoarticular allograft, and the remaining 52 cases were treated with tumor resection and artificial joint replacement. RESULTS: Recurrence was observed in 2 cases (5%) in the amputation group, in 6 cases (30%) in the massive osteoarticular allograft group, and in 6 cases (12%) in the tumor resection and artificial joint replacement group (P = 0.021). The lung metastasis rates were 40% in the amputation group, 40% in the massive osteoarticular allograft group, and 38% in the tumor resection and artificial joint replacement group (P = 0.986). The survival rates at 1, 3, and 5 years were 95%, 75%, and 45%, respectively, in the amputation group, 95%, 75%, and 35%, respectively, in the massive osteoarticular allograft group, and 92.3%, 78.8%, and 53.8%, respectively, in the tumor resection and artificial joint replacement group (P > 0.05). CONCLUSIONS: The selection of the optimal surgical method for upper tibia osteosarcoma should be made according to the individual circumstances of the patient. Our study has significance for reducing the incidence of surgical complications and improving the quality of postoperative life. PMID- 28848135 TI - Adiponectin Inhibits TNF-alpha-Activated PAI-1 Expression Via the cAMP-PKA-AMPK NF-kappaB Axis in Human Umbilical Vein Endothelial Cells. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha can upregulate the expression of plasminogen activator inhibitor (PAI)-1, an inhibitor of fibrinolysis. Adiponectin (Adp) antagonizes TNF-alpha by negatively regulating its expression in various tissues. In the present study, the ability of Adp to suppress TNF alpha-induced PAI-1 upregulation and the underlying mechanisms were evaluated. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with TNF alpha in the presence or absence of Adp, and PAI-1 mRNA and antigen expression, activated signaling pathways, and molecular mechanisms were analyzed by qRT-PCR and ELISA. RESULTS: Adp decreased the TNF-alpha-induced upregulation of PAI-1 mRNA and protein expression and suppressed TNF-alpha-induced cAMP-PKA-AMPK inactivation. Adp also suppressed the TNF-alpha-induced NF-kB binding capability on the PAI-1 promoter. Moreover, these Adp-induced effects were further enhanced or prevented by treatment with the cAMP inhibitor Rp-cAMPs or activator forskolin, respectively. CONCLUSIONS: Our data suggest that Adp abrogates TNF alpha-activated PAI-1 expression by activating cAMP-PKA-AMPK signaling to suppress NF-kB binding to the PAI-1 promoter in HUVECs. Given the antifibrotic effect of PAI-1 abrogation, Adp may be utilized as a novel agent in the treatment of fibrotic diseases. PMID- 28848136 TI - Mir-22-3p Inhibits Arterial Smooth Muscle Cell Proliferation and Migration and Neointimal Hyperplasia by Targeting HMGB1 in Arteriosclerosis Obliterans. AB - BACKGROUND: Aberrant vascular smooth muscle cell (VSMC) proliferation and migration contribute to the development of vascular pathologies, such as atherosclerosis and post-angioplasty restenosis. The aim of this study was to determine whether miR-22-3p plays a role in regulating human artery vascular smooth muscle cell (HASMC) function and neointima formation. METHODS: Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to detect miR-22-3p expression in human arteries. Cell Counting Kit-8 (CCK-8) and EdU assays were performed to assess cell proliferation, and transwell and wound closure assays were performed to assess cell migration. Moreover, luciferase reporter assays were performed to identify the target genes of miR-22-3p. Finally, a rat carotid artery balloon-injury model was used to determine the role of miR-22-3p in neointima formation. RESULTS: MiR-22-3p expression was downregulated in arteriosclerosis obliterans (ASO) arteries compared with normal arteries, as well as in platelet-derived growth factor-BB (PDGF-BB)-stimulated HASMCs compared with control cells. MiR-22-3p overexpression had anti-proliferative and anti-migratory effects and dual-luciferase assay showed that high mobility group box-1 (HMGB1) is a direct target of miR-22-3p in HASMCs. Furthermore, miR-22-3p expression was negatively correlated with HMGB1 expression in ASO tissue specimens. Finally, LV-miR-22-3p-mediated miR-22-3p upregulation significantly suppressed neointimal hyperplasia specifically by reducing HMGB1 expression in vivo. CONCLUSIONS: Our results indicate that miR-22 3p is a key molecule in regulating HASMC proliferation and migration by targeting HMGB1 and that miR-22-3p and HMGB1 may be therapeutic targets in the treatment of human ASO. PMID- 28848137 TI - Reliability of Entire Corneal Thickness Mapping in Normal Post-Laser in situ Keratomileusis and Keratoconus Eyes Using Long Scan Depth Spectral Domain Optical Coherence Tomography. AB - PURPOSE: To investigate the repeatability and reproducibility of mapping the entire corneal thickness using spectral domain optical coherence tomography (SD OCT). METHODS: Thirty normal eyes, 30 post-laser in situ keratomileusis (LASIK) surgery eyes, and 30 keratoconus eyes were analyzed. A custom-built long scan depth SD-OCT device was used to obtain entire corneal images. Ten-millimeter diameter corneal thickness maps were generated by an automated segmentation algorithm. Intraclass correlation coefficients of repeatability (ICC1) and reproducibility (ICC2), and coefficients of repeatability (CoR1) and reproducibility (CoR2), were calculated to quantify the precision and accuracy of corneal pachymetry measurements using the Bland-Altman method. RESULTS: For SD OCT measurements in healthy subjects, CoR1 and CoR2 were less than 5.00 and 5.53 MUm. ICC1 and ICC2 were more than 0.997 and 0.996. For SD-OCT measurements in LASIK patients, CoR1 and CoR2 were less than 5.09 and 5.34 MUm. ICC1 and ICC2 were more than 0.997 and 0.996. For SD-OCT measurements in keratoconus patients, CoR1 and CoR2 were less than 11.57 and 10.92 MUm. ICC1 and ICC2 were more than 0.995 and 0.996. CONCLUSIONS: The measurements of corneal pachymetric mapping by long scan depth SD-OCT can be assessed over the entire corneal area with good repeatability and reproducibility. PMID- 28848138 TI - Heat Shock Protein 27, a Novel Regulator of Transforming Growth Factor beta Induced Resistance to Cisplatin in A549 Cell. AB - Lung cancer is one of the major causes of cancer morbidity and mortality around the world, and the resistance to cisplatin is a critical issue to chemotherapy in lung cancer patients. Transforming growth factor beta (TGF-beta) signal pathway abnormality is widely observed in drug resistance during lung cancer chemotherapy. Here, we investigated the effects of heat-shock protein 27 (HSP27) in the TGF-beta-induced cisplatin resistance in lung cancer cell. In this study, our results indicated that the mRNA and protein expression of HSP27 were significantly increased in human lung cancer tissues. TGF-beta induced the mRNA and protein expression of HSP27 in human lung cancer cell (A549). Treatment of TGF-beta-induced cisplatin resistance in A549 cell through blocking the cisplatin induced apoptosis and cell death, which characterized as the increasing of cell viability and decreasing of PARP and caspase3 cleavage in the cisplatin-treated cell. Knockdown of SMAD3 attenuated the TGF-beta-induced HSP27 expression and restored the TGF-beta-induced cisplatin resistance in A549 cell. Additionally, the knockdown of HSP27 blocked TGF-beta-induced cisplatin resistance via decreasing cell viability and increasing cell apoptosis in A549 cell. These data therefore suggested that HSP27 is critical to lung cancer progression and TGF beta-induced cisplatin resistance in human lung cancer cell, and may provide an effective clinical strategy in lung cancer patients with resistance to chemotherapy. PMID- 28848139 TI - Post-Translational Modification of Adiponectin Affects Lipid Accumulation, Proliferation and Migration of Vascular Smooth Muscle Cells. AB - BACKGROUND/AIMS: Adiponectin (Apn) is a multifunctional adipokine that circulates as several oligomeric complexes in the blood stream. Previous reports showed that several conserved lysine residues within the N-terminal collagenous domain of Apn are modified by hydroxylation and glycosylation. Here, we investigated the potential roles of post-translational modifications of Apn on the function of human vascular smooth muscle cells (VSMCs). METHODS: Blood samples of 92 coronary artery disease (CAD) patients and 20 healthy volunteers were collected and total and high molecular weight (HMW) Apn concentration and glycosylation were analyzed. RESULTS: The results revealed that total and HMW Apn derived from blood samples of CAD patients with severe stenosis significantly increased, however the glycosylation of HMW Apn significantly decreased. Functional studies of human VSMCs revealed that glycosylated Apn significantly inhibited the oxidized LDL induced lipid accumulation, proliferation and migration of VSMCs, whereas non glycosylated Apn had no inhibitory effects. CONCLUSION: Taken together, these data suggest that glycosylation of Apn is critically involved in regulating function against atherosclerosis by inhibiting lipid accumulation and proliferation and migration of VSMCs. PMID- 28848140 TI - Dermoscopic Features of Subungual Squamous Cell Carcinoma: A Study of 44 Cases. AB - BACKGROUND: Subungual squamous cell carcinoma (SSCC) is the most frequent tumor of the nail apparatus. Its diagnosis is often missed or delayed because the clinical presentation is atypical and can mimic other conditions. Accurate diagnosis can only be made by performing an appropriate surgical biopsy, but biopsy is painful and often leaves definitive dystrophic scars. The use of dermoscopy, a noninvasive technique, has been described to be useful for the preoperative evaluation of nail diseases. OBJECTIVES: To define the different clinical and dermoscopic presentations of SSCC and to compare them with onychomatricoma-associated clinical and dermoscopic features published in our previous study. METHODS: A retrospective review of 44 cases of SSCC seen in our institution over an 8-year period. Six observers scored 19 clinical criteria and 14 dermoscopic criteria as present or absent. Then, we compared those data to a previously published study about the preoperative diagnosis of onychomatricoma. RESULTS: Only 1 dermoscopic criterion was significantly associated with SSCC compared to onychomatricoma: localized hyperkeratosis (odds ratio, OR = 6.25, p = 0.012, 95% confidence interval CI = 1.50-26.01). In contrast, parallel edges (OR = 0.03, p < 0,001, 95% CI = 0.003-0.20) and sharp demarcation of the lesion (OR = 0.24, p = 0.004, 95% CI = 0.09-0.63) can statistically significantly be considered as in favor of onychomatricoma. By contrast, we believe that the presence of unparalleled lateral edges of the nail lesion or of fuzzy edges are more in favor of SSCC. CONCLUSIONS: Dermoscopy of the nail plate and of the nail free edge in SSCC provides useful information in order to better select cases to be submitted to biopsy. PMID- 28848141 TI - Quantification of Interstitial Fibrosis in Renal Allografts and Clinical Correlates of Long-Term Graft Function. AB - BACKGROUND: The present study investigated interstitial fibrosis (IF) in 144 kidney recipients 0 h and 1 year post transplantation and assessed relationships with Banff code scores, clinical parameters, and long-term graft function. METHODS: A quantitative analysis of IF was performed using the computer-assisted imaging of Sirius red-stained biopsy samples. Percent IF (%IF) in the cortical region was assessed at 0 h and 1 year, and an increase in the ratio of %IF from 0 h to 1 year was calculated. The relationship between %IF and Banff code scores was analyzed. Demographics and trough concentrations of tacrolimus were tested as risk factors in the top 20 patients with increases in %IF. The influence of increases in the ratio of %IF at 1 year on long-term graft function and survival was also assessed in these 20 patients. RESULTS: Median %IF at 0 h and 1 year were 1.55 and 2.80%, respectively. No correlation was found between %IF and Banff code scores. The mean increase in the ratio of %IF from 0 h to 1 year was 4.31 fold. The increase in %IF in the top 20 patients correlated with diabetes mellitus. Graft function, but not graft survival, was lower in the top 20 patients for 10 years post transplantation. CONCLUSIONS: A correlation was not found between %IF and Banff code scores. Greater increases in %IF within 1 year post transplantation may influence long-term graft survival. Computer-analyzed increases in %IF at 1 year may be a surrogate marker for long-term graft function. PMID- 28848142 TI - Brain Malformations Do Not Predict Hypopituitarism in Young Children with Optic Nerve Hypoplasia. AB - BACKGROUND: Optic nerve hypoplasia (ONH), a leading cause of pediatric blindness, is associated with brain malformations and hypopituitarism in the constellation known as septo-optic dysplasia. Neuroimaging is used to anticipate hypopituitarism, but with unconfirmed reliability. We report prospective findings on the association of hypopituitarism with brain malformations. METHODS: Children (<24 months) with ONH (n = 146; 87% bilateral) underwent baseline MRI and annual examinations and hormonal testing. Hypopituitarism status at age 5 years was classified. RESULTS: A total of 74% had brain malformation(s). Hypopituitarism (69%) was not associated with brain malformations (p = 0.351); this persisted after adjusting for the laterality of ONH and the timing of MRI (padj = 0.869). No association was noted for absent septum pellucidum (38%; p = 0.073), corpus callosum abnormality (51%; p = 0.625), and major malformations (22%; p = 0.407). A malformation conferred a positive predictive value of 71% (95% CI: 62%, 80%), and a negative predictive value of 37% (95% CI: 22%, 54%). Overall, 10% (n = 15) of the cohort presented with a triad of absent septum pellucidum, corpus callosum abnormality, and other major malformation; only half (n = 8) of these had hypopituitarism. All 13 subjects with pituitary malformations manifested hypopituitarism, conferring predictive values of 100% (positive) and 34% (negative). CONCLUSIONS: Hypopituitarism and brain malformations are highly prevalent, but have unrelated associations with ONH. Brain MRI in infants and toddlers with ONH is an unreliable screen for hypopituitarism risk. PMID- 28848143 TI - PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer. AB - BACKGROUND/AIMS: PD-L1 (Programmed cell death 1 ligand 1, PD-L1), an essential immune checkpoint molecule in the tumor microenvironment, is an important target for cancer immunotherapy. We have previously reported that its expression in human gastric and esophageal cancer tissues is significantly associated with cancer progression and patients' postoperative prognoses. Its expression in cancer cells is well known to inhibit the T cell-mediated anti-tumor response, and this mechanism of action has been targeted for cancer immunotherapy. As of now, the autonomous effect of PD-L1 on cancer cells is not well understood, thus our present study aimed to examine the role of PD-L1 intervention in cellular biological functions, especially epithelial to mesenchymal transition (EMT), of the human esophageal cancer cell line, Eca-109 cells. METHODS: Immunohistochemistry assay was used to investigate the correlation between expression of PD-L1 and EMT markers in human esophageal cancer tissues. Intervention of PD-L1 by using RNAi and over-expression methods were used to study the role of PD-L1 in regulation of biological behaviors and EMT in Eca-109 cells. RESULTS: Our clinical and pathological data demonstrated that tumor samples in the EMT positive subgroup had higher PD-L1 expression than those in the EMT negative subgroup. By manipulating PD-L1 expression in Eca-109 cells either through ablation or overexpression of wild type and the cytoplasmic domain truncated mutant, we demonstrated that PD-L1 expression significantly promoted the cell viability, migration and EMT phenotype. Furthermore, our study also indicated that PD-1 fusion protein mediated stimulation of PD-L1 and the cytoplasmic domain of PD-L1 played a critical role in promoting EMT phenotype of Eca-109 cells, thereby suggesting that PD-1 receptor usually by triggering the reverse signaling can effect PD-L1 mediated regulation of esophageal cancer cell response. CONCLUSION: Our present study reveals a tumor cell-autonomous role of PD-L1 signaling in promoting EMT in human esophageal cancer. PMID- 28848144 TI - Overexpression of MicroRNA miR-7-5p Is a Potential Biomarker in Neuroendocrine Neoplasms of the Small Intestine. AB - BACKGROUND/AIMS: Neuroendocrine neoplasms of the small intestine (SI-NENs) constitute 25-30% of all gastroenteropancreatic NEN. These tumors arise from enterochromaffin cells, and little is known about their microRNA (miRNA) expression. The purpose of this study was to characterize the expression of miRNAs in SI-NEN and to determine the potential of miRNAs as noninvasive blood based biomarkers. METHODS: miRNA was purified from 15 tumor and 7 control tissue samples, converted to cDNA, and applied to a miScript miRNA PCR. The small nucleolar RNA, SNORD95, was used as an endogenous control. RESULTS: Microarray analysis revealed 7 miRNAs that showed a promising distinction between tumorous and healthy tissue. The miRNAs miR-7-5p and miR-96-5p were clearly upregulated in the tumor compared to the healthy tissue. In contrast, miRNAs miR-9-5p, miR-122 5p, miR-124-3p, miR-143-3p, and miR-144-3p showed a distinct downregulation in the tumor compared to the healthy tissue. These results were validated on a further 15 tumor samples, and the findings held true. As the miR-7-5p was significantly upregulated and revealed a low range across tumor samples, its presence was tested in the sera of 32 tumor patients and 25 healthy controls. Sera from all patients with SI-NENs had significantly higher levels of miR-7-5p than those from the 25 healthy controls (p = 0.0002), whereas there was no correlation with age, gender, or T-stage or UICC stage. CONCLUSION: The miRNA miR 7-5p may be a promising biomarker test for SI-NEN, which should be validated in a large-scale prospective study. PMID- 28848145 TI - CyclinG1 Amplification Enhances Aurora Kinase Inhibitor-Induced Polyploid Resistance and Inhibition of Bcl-2 Pathway Reverses the Resistance. AB - BACKGROUND/AIMS: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. METHODS: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. RESULTS: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. CONCLUSION: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer. PMID- 28848146 TI - Naringin Protects Against High Glucose-Induced Human Endothelial Cell Injury Via Antioxidation and CX3CL1 Downregulation. AB - BACKGROUND/AIMS: The induction of endothelial injury by hyperglycemia in diabetes has been widely accepted. Naringin is a bio-flavonoid. Some studies showed that naringin alleviates diabetic complications, but the exact mechanisms by which naringin improves diabetic anomalies are not yet fully understood. The aim of this research was to study the protective effect of naringin on high glucose induced injury of human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were cultured with or without high glucose in the absence or presence of naringin for 5 days. The expression of CX3CL1 was determined by quantitative real time RT-PCR (qPCR) and western blot. The cellular bioenergetic analysis oxygen consumption rate (OCR) was measured with a Seahorse Bioscience XF analyzer. RESULTS: The production of reactive oxygen species (ROS), the expression of CX3CL1 and the level of AKT phosphorylation were increased in HUVECs cultured with high glucose compared with controls. However, naringin rescued these increases in ROS production, CX3CL1 expression and AKT phosphorylation. Nitric oxide (NO) production and OCR were lower in the high glucose group, and naringin restored the changes induced by high glucose. Molecular docking results suggested that Naringin might interact with the CX3CL1 protein. CONCLUSION: Naringin protects HUVECs from high-glucose-induced damage through its antioxidant properties by downregulating CX3CL1 and by improving mitochondrial function. PMID- 28848147 TI - Evaluation of Transvaginal Ultrasound plus CA-125 Measurement and Prophylactic Salpingo-Oophorectomy in Women at Different Risk Levels of Ovarian Cancer: The Modena Study Group Cohort Study. AB - OBJECTIVE: To evaluate the effectiveness of transvaginal ultrasound (TVU) and serum CA-125 measurement in women at different risk of developing ovarian cancer/fallopian tube cancer (OC/FTC) and the incidence of primary peritoneal cancer (PPC) after risk-reducing salpingo-oophorectomy (RRSO). METHODS: Between 2002 and 2014, 661 women at different risk of OC/FTC/PPC due to a family history or BRCA1/2 gene mutation were offered TVU and CA-125 measurement or RRSO as prevention strategies. The detection rate of OC/FTC/PPC was evaluated, and the sensitivity and specificity for CA-125 measurement and TVU were calculated. Survival and event analysis was performed for diagnosed patients. RESULTS: After a median follow-up of 112 months, 12 OC/FTC/PPC cases were detected (2.6/1,000 persons/year). The screening sensitivity was 70%, with 73% for BRCA carriers. Six (50%) of 12 cancers were stage I or II. Among 41 women who underwent RRSO, 2 BRCA1 carriers developed a PPC (4.9%). At 61-month follow-up, overall and event free survival were 75 and 64%, respectively. CONCLUSIONS: The cancer detection rate in women with BRCA mutation or a strong family history supports the effectiveness of our surveillance program for early diagnosis. Screening for women at lower risk of OC/FTC is not recommended. A residual risk of PPC after RRSO remains for BRCA1 carriers. PMID- 28848148 TI - Acute Intravenous Infusion of Immunoglobulins Protects Against Myocardial Ischemia-Reperfusion Injury Through Inhibition of Caspase-3. AB - BACKGROUND/AIMS: To investigate the cardioprotective effects of intravenous immunoglobulins (IVIG) in rats subjected to regional myocardial ischemia reperfusion (I/R). METHODS: Langendorff-perfused rat hearts were used in this study. Hearts subjected to regional ischemia served as a negative untreated control. The effects of IVIG pre- and post-ischemic treatment on left ventricular function, coronary vascular dynamics and contractility were assessed. IVIG were administered in either a low or high dose. The infarct size was determined using triphenyltetrazolium chloride and through biochemical assays using the measured creatine kinase and lactate dehydrogenase levels. Apoptosis was evaluated by the TUNEL assay, and the caspase-3 expression level was assessed by immunoblotting. The cytokine levels were measured by ELISA. RESULTS: Low and high doses of immunoglobulins administered 2 hours before sacrifice, before the ischemic insult or at reperfusion resulted in a significant improvement in cardiac hemodynamics, coronary vascular dynamics and heart contractility. A significant decrease in the infarct size and cardiac enzymes was also evident compared to those in the control. IVIG administered as an infusion at reperfusion or pre-treatment resulted in a marked decrease in myocyte apoptosis, which was associated with decreased levels of caspase-3 expression in the supernatants of homogenized left ventricles. Infusion of IVIG both pre-ischemia and at reperfusion did not show the same protective effects. CONCLUSIONS: This study demonstrates a novel protection to the heart by low and high doses of IVIG given either pre- or post ischemia. PMID- 28848149 TI - Long Noncoding RNA H19/miR-675 Axis Promotes Gastric Cancer via FADD/Caspase 8/Caspase 3 Signaling Pathway. AB - BACKGROUND: Long noncoding RNA (lncRNA) H19 is emerging as a vital regulatory molecule in the progression of different types of cancer and miR-675 is reported to be embedded in H19's first exon. However, their function and specific mechanisms of action have not been fully elucidated. The aim of this study was to identify a novel lncRNA-microRNA-mRNA functional network in gastric cancer. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the relative expression of H19 and miR-675 in normal (GES-1) and gastric cancer cell lines (SGC-7901, SGC-7901/DDP) as well as in tumor tissues. Gain and loss of function approaches were carried out to investigate the potential roles of H19/miR-675 in cell proliferation and apoptosis. Moreover, Fas associated via death domain (FADD) was validated to be the target of miR-675 via luciferase reporter assay. Western blotting was used to evaluate the protein expression of related signaling pathway. RESULTS: In our study H19 and miR-675 were increased in gastric cancer cell lines and tissues. Overexpression of H19 and miR-675 promoted cell proliferation and inhibited cell apoptosis, whereas knockdown of H19 and miR-675 inhibited these effects. By further examining the underlying mechanism, we showed that H19/miR-675 axis inhibited expression of FADD. FADD downregulation subsequently inhibited the caspase cleavage cascades including caspase 8 and caspase 3. CONCLUSION: Taken together, our results point to a novel regulatory pathway H19/miR-675/ FADD/caspase 8/caspase 3 in gastric cancer which may be potential target for cancer therapy. PMID- 28848150 TI - Reading from the Black Box: What Sensors Tell Us about Resting and Recovery after Real-World Falls. AB - BACKGROUND: Lying on the floor for a long time after falls, regardless of whether an injury results, remains an unsolved health care problem. In order to develop efficient and acceptable fall detection and reaction approaches, it is relevant to improve the understanding of the circumstances and the characteristics of post impact responses and the return or failure to return to pre-fall activities. Falls are seldom observed by others; until now, the knowledge about movement kinematics during falls and following impact have been anecdotal. OBJECTIVE: This study aimed to analyse characteristics of the on-ground and recovery phases after real-world falls. The aim was to compare self-recovered falls (defined as returns to standing from the floor) and non-recovered falls with long lies. METHODS AND PARTICIPANTS: Data from subjects in different settings and of different populations with high fall risk were included. Real-world falls collected by inertial sensors worn on the lower back were taken from the FARSEEING database if reliable information was available from fall reports and sensor signals. Trunk pitch angle and acceleration were analysed to describe different patterns of recovery movements while standing up from the floor after the impact of a fall. RESULTS: Falls with successful recovery, where an upright posture was regained, were different from non-recovered falls in terms of resting duration (median 10.5 vs. 34.5 s, p = 0.045). A resting duration longer than 24.5 s (area under the curve = 0.796) after the fall impact was a predictor for the inability to recover to standing. Successful recovery to standing showed lower cumulative angular pitch movement than attempted recovery in fallers that did not return to a standing position (median = 76 degrees , interquartile range 24-170 degrees vs. median = 308 degrees , interquartile range 30-1,209 degrees , p = 0.06). CONCLUSION: Fall signals with and without successful returns to standing showed different patterns during the phase on the ground. Characteristics of real-world falls provided through inertial sensors are relevant to improve the classification and the sensing of falls. The findings are also important for redesigning emergency response processes after falls in order to better support individuals in case of an unrecovered fall. This is crucial for preventing long lies and other fall-related incidents that require an automated fall alarm. PMID- 28848151 TI - Traumatic Posterior Fossa Subdural Hygroma and Secondary Occlusive Hydrocephalus. AB - BACKGROUND: Infratentorial subdural hygromas causing secondary occlusive hydrocephalus are extremely rare in children. Only a handful of cases have been reported in the literature. METHODS: We present a case of a 6-month-old infant with an occipital fracture and slow enlargement of a posterior fossa subdural hygroma that culminated in obstructive hydrocephalus. We give a review of the literature on post-traumatic posterior fossa hygroma with secondary occlusive hydrocephalus and discuss its pathogenesis and the mechanism of its later resolution, as well as the available treatment options. RESULTS: A temporary external ventricular drain led to acute relief of the hydrocephalus and subsequent complete resolution of the subdural hygroma. CONCLUSION: Temporary external ventricular drain placement led to complete resolution of the subdural hygroma and hydrocephalus. We recommend close clinical follow-up, and imaging if indicated, for as long as 4 weeks after trauma with occipital skull fractures. PMID- 28848153 TI - Spatial and Temporal Analyses of FGF9 Expression During Early Pregnancy. AB - BACKGROUND: Fibroblast growth factors (FGFs), in complex with their receptors (FGFRs), regulate a broad spectrum of biological functions including cellular proliferation, survival, migration, and differentiation. In human endometrial stromal cells, FGF9 is regulated with estrogen (E). METHODS/RESULTS: First, we report that in uterus tissue of ovariectomized wild type mice, FGF9 is present in three isoforms and is regulated with E. Second, we found that during peri implantation, Fgf9 expression reached its peak at day 4.5 of pregnancy. Immunofluorescence analyses demonstrated overlapping FGF9 and COX2 expression surrounding the blastocyst attachment site. Next, we identified FGF9- and CD31 positive cells as a part of the microvessels; however, expression was localized to a distinct population of cells. Finally, our data showed synchronized, spatial expression of FGF9 on the luminal epithelium with FGFR2 present on the trophectoderm. CONCLUSION: Our data suggest that FGF9 is a crucial factor required to establish the appropriate microenvironment for successful implantation and the maintenance of pregnancy. PMID- 28848152 TI - Effect of the Diabetic Environment On the Expression of MiRNAs in Endothelial Cells: Mir-149-5p Restoration Ameliorates the High Glucose-Induced Expression of TNF-alpha and ER Stress Markers. AB - BACKGROUND/AIMS: This study aimed to screen microRNAs and their corresponding target genes that are associated with vascular injury in type two diabetes mellitus (T2DM), investigate the effects of differentially expressed miRNAs and their target genes on high glucose-induced vascular injury and establish the mechanism underlying these effects. METHODS: A high-throughput digital gene expression (DGE) sequencing was performed to sequence microRNAs (miRNAs) and messenger RNAs (mRNAs) and determine their differential expression in human umbilical vein endothelial cells (HUVECs) incubated with serum samples from patients with T2DM and healthy volunteers. The HUVECs were transfected with si TNF-alpha (tumor necrosis factor alpha) and a miR-149-5p inhibitor or mimic in vitro and then treated with normal or high glucose. The relative content of nitric oxide (NO) in the cells was detected using the Griess Reagent System. The mRNA and protein expression of endothelial nitric oxide synthase (eNOS) were determined by qRT-PCR and Western blotting. The content of endothelin-1 (ET-1), von Willebrand factor (vWF), and intercellular adhesion molecular-1 (ICAM-1) were detected using an enzyme-linked immunosorbent assay (ELISA) kit. Apoptosis was determined by flow cytometry using the Annexin V/PI apoptosis detection kit. The mRNA and protein expression levels of ER stress (ERS) markers were determined by qRT-PCR and Western blotting. RESULTS: Based on the high-energy sequencing and in vitro pre-experiment studies, we determined that miR-149-5p and TNF-alpha were a differentially expressed mRNA/miRNA pair in T2DM with vascular injury. The luciferase reporter assay results demonstrated that miR-149-5p could directly target TNF-alpha. The upregulation of miR-149-5p reduced the high glucose-induced dysfunction in the HUVECs by significantly decreasing the levels of ET-1, vWF, and ICAM-1 and increasing the level of NO and the expression of eNOS. Additionally, we found that miR-149-5p can improve cell injury and reduce apoptosis by restoring the ameliorated high glucose-induced expression of ERS markers. CONCLUSION: TNF-alpha and miR-149-5p were differentially expressed in T2DM vascular endothelial injury. The over-expression of miR-149-5p ameliorates the high glucose-induced injury in the HUVECs by regulating the expression of TNF alpha and ERS markers. PMID- 28848154 TI - MMP-9 in Dentinal Fluid Correlates with Caries Lesion Depth. AB - The analysis of molecular cues in dentinal fluid from an excavated cavity could improve diagnostics in the context of minimally invasive caries treatment. In the current clinical trial we assessed whether the dentinal fluid levels of MMP-9 (matrix metalloproteinase-9; neutrophil gelatinase) would increase with the progression of carious lesions. MMP-9 is associated with neutrophil-related tissue breakdown in the pulp. Absolute MMP-9 levels were contrasted against the levels of MMP-2, an enzyme related to normal tissue turnover. Dentinal fluid was collected below deep and shallow caries from molars and premolars within the same patients aged 18 years and older (n = 30, 1 tooth per group/patient). Experimental teeth were isolated under a rubber dam prior to excavation. Dentinal fluid was collected from the bottom of the cavity using a size 25 paper point. MMP levels were assessed using an enzyme-linked immunosorbent assay. Nonparametric methods were applied to test for differences between groups. Significantly more (p < 0.05, Wilcoxon test) MMP-9 was collected from the deep carious lesions than from the shallow counterparts. Pairwise comparison of MMP-9 values within patients revealed that there was more MMP-9 collected from deep lesions than from shallow counterparts in 27 of the 30 individuals under investigation (pairwise Wilcoxon test, p < 0.001). In contrast, no such difference existed for MMP-2. There was a high correlation between MMP-9 from deep and shallow lesions (Spearman's rho = 0.72, p < 0.001), indicating that patients with more MMP-9 in the deep carious lesion also tended to have more MMP 9 in the shallow lesion. PMID- 28848156 TI - Gender Differences of Nonmotor Symptoms Affecting Quality of Life in Parkinson Disease. AB - BACKGROUND/AIMS: Gender differences of health-related quality of life (HRQoL) in patients with various disorders have been reported. Various nonmotor symptoms (NMSs) also affect the patients' lives and HRQoL, even in the early stages of Parkinson disease (PD). Our study aimed to identify whether there are gender differences of HRQoL in PD patients in the early stages, and which NMSs are associated with HRQoL depending on gender. METHOD: Eighty-nine PD patients (47 males, 42 females) and 36 healthy controls were enrolled. We evaluated HRQoL, NMSs, and their associations in each gender. RESULT: The total Parkinson Disease Quality of Life Questionnaire and Beck Anxiety Inventory scores were higher in female patients than in male patients. The correlation analysis revealed no association between NMSs and HRQoL in male patients. In female patients, HRQoL was highly correlated with depression, and moderately associated with fatigue. CONCLUSIONS: Gender differences of an association between HRQoL and NMSs exist in PD. We found that fatigue and depression were the main determinants of poor HRQoL in female patients even in the early stages. We suggest that a gender-specific therapeutic approach is important, and it is necessary to pay special attention to the predictors associated with causing poor HRQoL. PMID- 28848155 TI - Nitrosative Stress in the Rat Retina at the Onset of Streptozotocin-Induced Diabetes. AB - BACKGROUND/AIMS: Nitric oxide is a multifunctional molecule that can modify proteins via nitrosylation; it can also initiate signaling cascades through the activation of soluble guanylate cyclase. Diabetic retinopathy is the leading cause of blindness, but its pathogenesis is unknown. Multiple mechanisms including oxidative-nitrosative stress have been implicated. Our main goal was to find significant changes in nitric oxide (NO) levels and determine their association with nitrosative stress in the rat retina at the onset of diabetes. METHODS: Diabetes was induced by a single intraperitoneal administration of streptozotocin. The possible nitric oxide effects on the rat retina were evaluated by the presence of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), a specific marker for NO-producing neurons, detected by histochemistry performed on whole retinas and retina sections. Immunohistochemistry was also performed on retina sections for iNOS, 3 nitrotyrosine (3-NT) and glial fibrillary acidic protein (GFAP). Retinal nitric oxide levels were assessed by measuring total nitrate/nitrite concentrations. Retinal cGMP levels were determined by radioimmunoassay. Western blots for nitrotyrosine (3-NT) and oxidized proteins were performed. RESULTS: In the present study, we found increased activity of NADPH-diaphorase and iNOS immunoreactivity in the rat retina at the onset of diabetes; this increase correlated with a remarkable increase in NO levels as early as 7 days after the onset of diabetes. However, cGMP levels were not modified by diabetes, suggesting that NO did not activate its signaling cascade. Even so, Western blots revealed a progressive increase in nitrated proteins at 7 days after diabetes induction. Likewise, positive nitrotyrosine immunolabeling was observed in the photoreceptor layer, ganglion cell layer, inner nuclear layer and some Muller cell processes in the retinas of diabetic rats. In addition, levels of oxidized proteins were increased in the retina early after diabetes induction; these levels were reduced by the administration of L-NAME. In addition, stress in Muller cells was determined by immunoreactivity to the glial fibrillary acidic protein. CONCLUSIONS: Our findings indicated the occurrence of nitrosative stress at the onset of diabetes in the rat retina and emphasized the role of NO in retinal function and the pathogenesis of retinopathy. PMID- 28848157 TI - Trends in Minimally Invasive Hysterectomy Techniques for Nonmalignant Conditions in a Defined Population. AB - BACKGROUND: Minimally invasive surgical techniques are increasingly being used for performing hysterectomy. We assessed changes in surgical techniques for hysterectomy that happened during the last decade among the complete Icelandic population. METHODS: Databases in all hospitals in the country were searched to identify all women undergoing hysterectomy during the years 2001-2010 inclusive. Information on age at surgery, indication for surgery, surgical techniques, additional intraoperative procedures, and length of hospital stay was gathered. Two 5-year periods, 2001-2005 and 2006-2010, were compared. The proportion of minimally invasive surgery (MIS) was calculated. RESULTS: There were 5,288 hysterectomies that were performed, giving a mean annual incidence of 352/100,000 women. The proportion of MIS increased from 30 to 74% at the main university hospital (p < 0.0001), where the mean hospital stay decreased from 5.4 to 1.7 days. Fewer oophorectomies were performed during the second 5-year period. The most common diagnoses were fibromyomas and abnormal uterine bleeding. The rate of recorded complications was low. A decreasing yearly incidence was observed from 389/100,000 in 2001 to 266/100,000 by 2010. CONCLUSION: For benign indications, the surgical approach has changed markedly with a high proportion of the operations being performed with minimally invasive techniques, mainly at a secondary/tertiary level. PMID- 28848158 TI - ZNF23 Suppresses Cutaneous Melanoma Cell Malignancy via Mitochondria-Dependent Pathway. AB - BACKGROUND/AIMS: Cutaneous melanoma is one of the leading causes of cancer deaths with an increasing incidence worldwide. A KRAB-containing zinc finger protein member, zinc finger 23 (ZNF23), was reduced in some types of tumors and inhibited cell growth by inducing cell cycle arrest. However, the role of ZNF23 expression is still poorly understood in melanoma. METHODS: The level of ZNF23 expression was detected in cutaneous melanoma, adjacent normal skin tissues and cutaneous melanoma cell lines using immunohistochemistry and western blotting. The correlations between ZNF23 expression and other clinicopathologic parameters were analyzed in melanoma patients. Ectopic expression of ZNF23 plasmid was transfected into melanoma cells, SK-MEL-1 and SK-MEL-28. MTT, flow cytometry and transwell assay were used to measure cell proliferation, apoptosis, invasion and migration abilities, respectively. Mitochondrial functions and structures were detected by mitochondrial membrane potential assay and Transmission electron microscopy (TEM) method in melanoma cells transfected with overexpressing ZNF23 plasmid or empty vector. Western blotting was performed to detect the levels of ZNF23, p53, p27, Bcl-2 and cleaved caspase-3 after overexpressing of ZNF23 in melanoma cells. RESULTS: ZNF23 was elevated in adjacent normal skin tissues compared with melanoma tissues. Patients with low level of ZNF23 expression exhibited higher incidence of lymphoid metastasis, thicker size of tumors and worse outcome. By using Cox's regression analysis, ZNF23 expression, tumor thickness and lymph node metastasis were the independent prognostic factors for overall survival (p < 0.05). Results from cellular experiments indicated that ectopic expression of ZNF23 induced cell apoptosis by activation of caspase-3, p27, p53 expression and down-regulation of Bcl-2 through mitochondria-dependent pathway. CONCLUSIONS: Decreased ZNF23 was contributed to melanoma progression and poor survival with mitochondria-dependent pathway. It indicated that ZNF23 could be a promising therapeutic biomarker candidate for cutaneous melanoma. PMID- 28848159 TI - Plasma Cluster Ions Reduce the IgE-Binding Capacity of House Dust Mite Allergens under a Simulated Indoor Environmental Condition. AB - BACKGROUND: A high level of house dust mite (HDM) allergens in a living environment is a risk factor for both sensitization to these allergens and asthmatic attacks. We previously showed that plasma cluster ions (PCIs) impaired the IgE-binding capacity of atomized crude allergens prepared from Japanese cedar pollen and fungus under experimental conditions. OBJECTIVE: We evaluated the capacity of PCIs to impair the IgE-binding capacity of airborne HDM allergens under a simulated indoor environmental condition. METHODS: For the determination of the effects of PCIs on HDM allergens under an experimental condition, HDM extract was atomized as aqueous mist into a cylindrical experimental apparatus filled with PCIs. For the evaluation of the effects of PCIs under a simulated natural indoor environmental condition, dried HDM allergens were floated as airborne particles in an acryl cubic apparatus in the presence of PCIs. The IgE binding capacities of the PCI- and sham-treated HDM allergens were analyzed by an ELISA. RESULTS: The IgE-binding capacity of the HDM allergens was significantly impaired after PCI treatment compared to that after sham treatment under both experimental and simulated environmental conditions. The ELISA results demonstrated that the IgE-binding capacities of HDM allergens after PCI treatment showed 68 and 74% reductions compared to those after sham treatment under the experimental and simulated environmental conditions, respectively. CONCLUSIONS: PCIs have the capacity to impair the IgE-binding capacity of airborne HDM allergens in a simulated environmental condition. PMID- 28848160 TI - Survival and Associated Risk Factors of Selective Caries Removal Treatments in Primary Teeth: A Retrospective Study in a High Caries Risk Population. AB - OBJECTIVE: The aim of this retrospective study was to analyze the survival probability of selective caries removal (SCR) treatments in the primary teeth of children with high caries experience and factors potentially associated with treatment failure. METHODS: The sample included SCR treatments conducted in anterior and posterior teeth without sedation or general anesthesia among children attending a university dental service. Kaplan-Meier survival analysis was used to estimate the longevity of restorations and multivariate Cox regression with shared frailty was used to assess risk factors. RESULTS: A total of 284 SCR treatments in 88 children (aged 5.2 +/- 1.91 years) with high caries experience (mean dmft/DMFT = 11.1 +/- 5.04) were analyzed. The 3-year survival reached 48.8%, with an annual failure rate of 21.2%. Restorative failures (n = 60) were found more frequently compared to pulp complications (n = 12). SCR performed in anterior primary teeth were more prone to failure (hazard ratio = 3.6, 95% CI: 1.94; 6.71). Patients with a higher amount of visible plaque experienced more failures in SCR treatments (hazard ratio 3.0, 95% CI:1.27; 7.07). CONCLUSIONS: In this retrospective study, SCR showed restricted survival when compared to other prospective clinical trials. Patient-related factors, especially the young age and high caries experience of the children, may represent a challenge for restoration survival. Regardless of the caries removal technique or restorative material, cariogenic biofilm has a negative effect on the survival of restorations, probably by acting directly on material deterioration and, particularly, on the development of new caries lesions of rapid progression. PMID- 28848161 TI - The Protective Effect of Cordycepin On Alcohol-Induced Osteonecrosis of the Femoral Head. AB - BACKGROUND: Alcohol abuse is known to be a leading risk factor for atraumatic osteonecrosis of the femoral head (ONFH), in which the suppression of osteogenesis plays a critical role. Cordycepin benefits bone metabolism; however, there has been no study to determine its effect on osteonecrosis. METHODS: Human bone mesenchymal stem cells (hBMSCs) were identified by multi-lineage differentiation. Alkaline phosphatase (ALP) activity, RT-PCR, western blots, immunofluorescent assay and Alizarin red staining of BMSCs were evaluated. A rat model of alcohol-induced ONFH was established to investigate the protective role of cordycepin against ethanol. Hematoxylin & eosin (H&E) staining and micro computerized tomography (micro-CT) were performed to observe ONFH. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL). Immunohistochemical staining was carried out to detect OCN and COL1. RESULTS: Ethanol significantly suppressed ALP activity, decreased gene expression of OCN and BMP2, lowered levels of RUNX2 protein, and reduced immunofluorescence staining of OCN and COL1 and calcium formation of hBMSCs. However, these inhibitory effects were attenuated by cordycepin co-treatment at concentrations of 1 and 10 ug/mL Moreover, it was revealed that the osteo-protective effect of cordycepin was associated with modulation of the Wnt/beta-catenin pathway. In vivo, by micro-CT, TUNEL and immunohistochemical staining of OCN and COL1, we found that cordycepin administration prevented alcohol-induced ONFH. CONCLUSION: Cordycepin treatment to enhance osteogenesis may be considered a potential therapeutic approach to prevent the development of alcohol-induced ONFH. PMID- 28848162 TI - Intramedullary Thoracic Spine Astrocytoma Presenting as Hydrocephalus in an Infant: A Case Report. AB - We present the case of an intramedullary spinal cord tumor from C7 to T4, classified as a WHO grade I pilocytic astrocytoma, manifesting solely with isolated, acute hydrocephalus and a normal neurological exam in a 5-month-old infant. We discuss the common presenting symptoms of spinal cord tumors in the pediatric population and possible anatomical explanations for this unique presentation and offer recommendations for the management of isolated hydrocephalus in an infant. PMID- 28848163 TI - Knockdown of Lncrna PVT1 Enhances Radiosensitivity in Non-Small Cell Lung Cancer by Sponging Mir-195. AB - BACKGROUND/AIMS: Plasmacytoma variant translocation 1 (PVT1) exerts an oncogenic role in many tumors, including lung cancer. However, the roles of PVT1 in regulating radiosensitivity of NSCLC and its underlying mechanism are still unclear. METHODS: Expression levels of PVT1 and miR-195 in NSCLC tissues and cells were examined by qRT-PCR. Effects of PVT1 and miR-195 on cell proliferation, apoptosis and colony formation abilities were assessed by MTT assay, flow cytometry and colony formation assay. Luciferase reporter assay was performed to confirm the relationship between PVT1 and miR-195. Tumor xenograft experiments were conducted to observe the effect of PVT1 on radiosensitivity of NSCLC in vivo. RESULTS: PVT1 was negatively correlated with miR-195 expression in NSCLC tissues and associated with poor prognosis of NSCLC patients. Expression of PVT1 and miR-195 varied inversely after irradiation in NSCLC cells. PVT1 knockdown or miR-195 overexpression enhanced radiosensitivity of NSCLC in vitro by inhibiting proliferation and inducing apoptosis. PVT1 directly interacted with miR-195 and regulated its expression. Moreover, PVT1 knockdown improved radiosensitivity of NSCLC cells in vitro and in vivo by sponging miR-195. CONCLUSION: Knockdown of PVT1 enhances radiosensitivity of NSCLC by sponging miR 195, providing a novel therapeutic target to improve radiotherapy efficiency in NSCLC. PMID- 28848164 TI - S100A8/A9 (Calprotectin), Interleukin-6, and C-Reactive Protein in Obesity and Diabetes before and after Roux-en-Y Gastric Bypass Surgery. AB - BACKGROUND: In obesity, which is a major contributor to insulin resistance and diabetes, the circulating level of S100A8/A9 (calprotectin) is elevated and declines after Roux-en-Y gastric bypass surgery (RYGB). However, studies on S100A8/A9 and the pathophysiological mechanisms in insulin resistance and diabetes are few and contradictory. METHODS: We studied 48 subjects who underwent RYGB, comprising a non-diabetic control group and two diabetic groups in whom diabetes either regressed or persisted, 6-12 months post-surgically. S100A8/A9, interleukin 6 (IL-6) as well as other inflammatory and diabetes-related markers were measured pre- and post-surgically. RESULTS: Significant and similar decreases of BMI were found in all groups. S100A8/A9 and IL-6 decreased significantly in the group with diabetes remission and in the control group, but not in the group with persistent diabetes. The relative changes in S100A8/A9 and IL-6 correlated significantly (r = 0.905, p = 0.005) only in the group with persistent diabetes. In contrast, leukocyte count and C-reactive protein correlated significantly to S100A8/A9 only in the control group. CONCLUSION: Our study is suggestive of S100A8/A9 and IL-6 being related to a persistent diabetes status post-surgically and of different pathophysiological mechanisms being involved in the post-surgical changes in the three groups, despite similar decreases in BMI. PMID- 28848165 TI - Strategies to Improve Stroke Care Services in Low- and Middle-Income Countries: A Systematic Review. AB - BACKGROUND: The burden of stroke in low- and middle-income countries (LMICs) is large and increasing, challenging the already stretched health-care services. AIMS AND OBJECTIVES: To determine the quality of existing stroke-care services in LMICs and to highlight indigenous, inexpensive, evidence-based implementable strategies being used in stroke-care. METHODS: A detailed literature search was undertaken using PubMed and Google scholar from January 1966 to October 2015 using a range of search terms. Of 921 publications, 373 papers were shortlisted and 31 articles on existing stroke-services were included. RESULTS: We identified efficient models of ambulance transport and pre-notification. Stroke Units (SU) are available in some countries, but are relatively sparse and mostly provided by the private sector. Very few patients were thrombolysed; this could be increased with telemedicine and governmental subsidies. Adherence to secondary preventive drugs is affected by limited availability and affordability, emphasizing the importance of primary prevention. Training of paramedics, care-givers and nurses in post-stroke care is feasible. CONCLUSION: In this systematic review, we found several reports on evidence-based implementable stroke services in LMICs. Some strategies are economic, feasible and reproducible but remain untested. Data on their outcomes and sustainability is limited. Further research on implementation of locally and regionally adapted stroke-services and cost-effective secondary prevention programs should be a priority. PMID- 28848166 TI - Mechanical Thrombectomy for Acute Basilar Artery Occlusion in Early Therapeutic Time Window. AB - BACKGROUND: The natural history of basilar artery occlusion (BAO) is devastating, with morbidity rates increasing up to 80%. However, the efficacy of recanalization therapy for BAO has not been established as yet. OBJECTIVE: We analyzed consecutive cases of BAO treated with mechanical thrombectomy (MT) to evaluate its safety and efficacy and to determine factors associated with the prognosis. METHODS: Between October 2011 and September 2016, MT was performed in 34 patients with BAO. MT was performed using the Penumbra system and stent retriever. CT perfusion was used for evaluating patients. Cerebral blood flow (CBF) maps and cerebral blood volume (CBV) maps were evaluated. CBF/CBV mismatch was defined as >=50% penumbra. Clinical outcomes were correlated with demographic, clinical, and radiographic findings. RESULTS: The median baseline National Institutes of Health Stroke Scale score was 29 (14-33). The recanalization rate (>=thrombolysis in cerebral infarction grades 2b) was 100%. The median onset to recanalization time (OTR) was 197 (160-256) min. Favorable outcomes (modified Rankin Scale <=2) at 90 days occurred in 56% (n = 19 of 34). The mortality rate at 90 days was 12% (n = 4 of 34). In univariate analysis, intravenous (IV) recombinant tissue-type plasminogen activator (rt-PA) use, and OTR were significantly associated with favorable outcomes. In a multivariate logistic regression model, IV rt-PA use and lower National Institute of Health Stroke Scale score were significantly related to favorable outcomes. Conclusion and Relevance: Multimodal endovascular therapy using the Penumbra system and stent retriever demonstrated a high recanalization rate and favorable outcomes for BAO. Both devices were feasible and effective in the treatment of BAO. An approach combining MT with IV thrombolysis provided a better recanalization rate and more favorable clinical outcomes. PMID- 28848167 TI - An Effective Cell Coculture Platform Based on the Electrospun Microtube Array Membrane for Nerve Regeneration. AB - Recently, a novel substrate known as an electrospun polylactic acid (PLLA) microtube array membrane (MTAM) was successfully developed as a cell coculture platform. Structurally, this substrate is made up of one-to-one connected, ultrathin, submicron scale fibers that are arranged in an arrayed formation. Its unique structure confers several key advantages which are beneficial in a cell coculture system. In this study, the interaction between rat fetal neural stem cells (NSC) and astrocytes was examined by comparing the outcome of a typical Transwell-based coculture system and that of an electrospun PLLA MTAM-based coculture system. Compared to tissue culture polystyrene (TCP) and Transwell coculture inserts, a superior cell viability of NSC was observed when cultured in lumens of electrospun PLLA MTAM (with supportive immunostaining images). Reverse transcription polymerase chain reaction revealed a strong interaction between astrocytes and NSC through a higher expression of doublecortin and a lower expression of nestin. These data demonstrate that MTAM is clearly a better coculture platform than the traditional Transwell system. PMID- 28848168 TI - Novel Insights in the Metabolic Syndrome in Childhood and Adolescence. AB - Metabolic syndrome (MetS) is recognized as an escalating major health risk in adults as well as in children and adolescents. Its prevalence ranges from 6 to 39% depending on the applied definition criteria. To date, there is no consensus on a MetS definition for children and adolescents. However, most authors agree on essential components such as glucose intolerance, central obesity, hypertension, and dyslipidemia; each representing a risk for cardiovascular disease. Recently, associations between MetS and non-alcoholic fatty liver disease, hyperuricemia, and sleep disturbances have emerged. Biomarkers like adipocytokines are a subject of current research as they are implicated in the pathogenesis of the MetS. Epigenetics and gestational programming, especially the role of microRNA, comprise a novel, rapidly developing and promising research focus on the topic of MetS. MicroRNAs are increasingly valued for potential roles in the diagnosis, stratification, and therapeutics of MetS. Early detection of risk factors, screening for metabolic disturbances, and the identification of new therapies are major aims to reduce morbidity and mortality related to MetS. Dietary modification and physical activity are currently the only adopted treatment approaches. Pharmacological therapies and bariatric surgery are still contradictory and, therefore, are only recommended in selected high-risk cases. PMID- 28848169 TI - Magnifying Blue Laser Imaging versus Magnifying Narrow-Band Imaging for the Diagnosis of Early Gastric Cancer: A Prospective, Multicenter, Comparative Study. AB - BACKGROUND/AIMS: The diagnostic efficacy of magnifying blue laser imaging (M-BLI) and M-BLI in bright mode (M-BLI-bright) in the identification of early gastric cancer (EGC) was evaluated for comparison to that of magnifying narrow-band imaging (M-NBI). METHODS: This prospective, multicenter study evaluated 114 gastric lesions examined using M-BLI, M-BLI-bright, and M-NBI between May 2012 and November 2012; 104 EGCs were evaluated by each modality. The vessel plus surface classification system was used to evaluate the demarcation line (DL), microvascular pattern (MVP), and microsurface pattern (MSP). RESULTS: M-BLI, M BLI-bright, and M-NBI revealed a DL for 96.1, 98.1, and 98.1% and irregular MVP for 95.1, 95.1, and 96.2% of lesions, respectively, with no significant difference. Irregular MSP was observed by M-BLI, M-BLI-bright, and M-NBI in 97.1, 90.4, and 78.8% of lesions, respectively, with significant differences (p < 0.001). The proportion of moderately differentiated adenocarcinoma with irregular MSP on M-BLI and absent MSP on M-NBI was significantly higher than that with irregular MSP on M-BLI and M-NBI (35.0 and 9.9%, respectively; p = 0.002). CONCLUSION: M-BLI and M-BLI-bright provided excellent visualization of microstructures and microvessels similar to M-NBI. Irregular MSP in a moderately differentiated adenocarcinoma might be frequently visualized using M-BLI and M BLI-bright compared with using M-NBI. PMID- 28848170 TI - Synthetic Cannabinoid Use in a Psychiatric Patient Population: A Pilot Study. AB - BACKGROUND: Consumption of natural cannabis (NC) and synthetic cannabinoids (SCs) has been associated with psychotic disorders. We compared the prevalence of use, consumer profiles, and psychosis-inducing potential of NC and SCs in a specific high-risk population. METHODS: This prospective pilot study included 332 patients (18-64 years, mean 36.83, SD 13.33). Patients' sociodemographics and medical histories as well as illicit substance use and psychiatric symptom histories were collected using a drug consumption survey that assessed the use of new psychoactive substances and the Psychotic Symptoms Interview. RESULTS: In total, 7.2% of all patients, 10.6% of psychotic patients, and 4.5% of nonpsychotic patients reported SC consumption. Compared with SCs, NC was consumed much more frequently by its users (mean 222.73, SD 498.27). NC and SC use induced persistent psychosis. Psychotic symptoms were first experienced by patients with a history of NC or SC use during intoxication and persisted after cessation (>1 year) of drug use. Positive and negative symptoms tended to be more severe in SC and NC users, respectively. CONCLUSIONS: NC and SCs may cause different symptom clusters. These relationships should be further evaluated. PMID- 28848171 TI - Resolution of Middle Fossa Arachnoid Cyst after Minor Head Trauma - Stages of Resolution on MRI: Case Report and Literature Review. AB - Arachnoid cysts (ACs) are frequently encountered in pediatric neurosurgical practice. Their natural history and optimum treatment are not well determined. The authors describe a resolution of asymptomatic middle fossa AC after trivial head trauma in a 7-year-old child. Intracystic bleeding was noticed on interval MRI. Serial MRI follow-up demonstrates stages of resolution of the AC that did not require surgical intervention. Few cases of nonsurgical AC disappearance have been reported, much fewer with trauma as a triggering factor. Here, we present the stages of resolution in images. PMID- 28848172 TI - VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway. AB - BACKGROUND: Diabetic nephropathy (DN) is a major cause of end-stage renal disease and proteinuria is one of the most prominent clinical manifestations. The expression of Vitamin D receptor (VDR) in patients with chronic kidney diseases was decreased, while VDR agonists could partially alleviate the proteinuria of DN in animal models. The present study was designed to determine the expression of VDR in renal tissues and its relationship with proteinuria the diabetic model db/db mice. METHODS: The regulation effects of VDR on the Wnt signaling pathway were analyzed using RNA interference and VDR agonist paricalcitol. RESULTS: With the increase in age of the db/db mice, the VDR protein and mRNA levels in renal tissues were decreased, proteinuria increased, and the protein and mRNA levels of GSK-3beta of and beta-catenin increased. Paricalcitol treatment resulted in the up-regulation of VDR and down-regulation of GSK-3beta and beta-catenin, indicating that VDR had a regulatory effect on the Wnt signaling pathway. CONCLUSION: VDR activation could reduce proteinuria of DN mice and alleviate high glucose-induced injury of kidneys and podocytes by regulating the key molecules of Wnt signaling pathway. PMID- 28848173 TI - Combination Therapy with Capecitabine and Cisplatin as Second-Line Chemotherapy for Advanced Biliary Tract Cancer. AB - BACKGROUND/AIMS: Palliative chemotherapy is the main treatment for advanced biliary tract cancer (BTC). However, there is a lack of established second-line chemotherapy to treat disease progression after first-line chemotherapy. We examined combination therapy with capecitabine and cisplatin for advanced BTC as a second-line regimen. METHODS: We analyzed the medical records of 40 patients diagnosed with BTC who received palliative second-line chemotherapy with capecitabine and cisplatin. RESULTS: The median overall survival from the start of second-line chemotherapy was 6.3 months. The median overall survival from diagnosis was 17.9 months. The median progression-free survival during second line chemotherapy was 2.3 months. Nine (30%) patients experienced adverse events of grade >=3. Eastern Cooperative Oncology Group performance score was an independent predictor of adverse events. CONCLUSIONS: Combination therapy with capecitabine and cisplatin may be an option for second-line chemotherapy in some of patients with advanced BTC. PMID- 28848174 TI - A Case of Severe Anaphylaxis to Polyhexanide: Cross-Reactivity between Biguanide Antiseptics. AB - We present the case of a 77-year-old female patient who suffered from severe anaphylaxis during wound care. Allergologic evaluation yielded specific IgE antibodies to chlorhexidine, but anaphylaxis to chlorhexidine was not congruent with the patient history and dermal provocation tests. However, skin prick tests provided evidence for a sensitization to polyhexanide that was further supported by the detection of specific IgE antibodies to polyhexanide, the results of basophil activation tests and IgE inhibition analysis. We presume cross-reactive IgE antibodies binding to both biguanide antiseptics and identified polyhexanide as the likely cause of the anaphylactic reaction. We recognize polyhexanide as an emerging allergen that has to be considered as a cause of anaphylaxis. PMID- 28848175 TI - Role of Oxytocin in Prolactin Secretion during Late Pregnancy. AB - BACKGROUND/AIMS: During late pregnancy, the blockade of progesterone action by mifepristone (Mp) treatment induces a dopaminergic tone fall that enables naloxone (NAL) administration to release pituitary prolactin (PRL). We determined whether oxytocin (OT), which stimulates PRL secretion acting directly on anterior pituitary lactotrophs, mediates the stimulatory action of Mp and NAL on PRL secretion during late pregnancy. METHODS: On day 19 of pregnancy, circulating and pituitary OT and PRL levels were measured by radioimmunoassay, 10, 20, and 30 min after NAL (given at 17:30 h) in rats pretreated with Mp (at 08:00 h). Pituitary OT receptor (OTR) expression in Mp-treated rats was evaluated by RT-PCR. Activation of OT neurons in Mp-NAL-treated rats was measured counting double immunoreactive neurons for Fos and OT (Fos-OT-ir) in supraoptic nuclei (SON), and medial (PaMM) and lateral magnocellular divisions of paraventricular nuclei. RESULTS: Elevated serum OT and decreased pituitary OT were observed 10 min after NAL administration in both vehicle- and Mp-treated rats. This PRL increase was prevented by previous i.p. administration of an OTR antagonist, but intracerebroventricular OT administration was ineffective. Mp increased pituitary OTR expression at 18:00 h. Only Mp-NAL increased Fos-OT-ir neurons in the PaMM and SON. CONCLUSIONS: These findings suggest that PRL secretion induced by Mp-NAL treatment is preceded by OT release. These results, together with the activation of hypothalamic OT neurons and the higher expression of pituitary OTR, support the hypothesis that, during late pregnancy, OT may act at the pituitary level to facilitate PRL secretion if the inhibitory action of progesterone is blocked. PMID- 28848176 TI - Transformation of Cells by Photoinactivated Murine Gamma-Herpesvirus 68 during Nonproductive and Quiescent Infection. AB - Infection of human MRC-5 cells and mouse NIH-3T3 cells with a murine gamma herpesvirus (MuHV-4 strain 68; MHV-68) photoinactivated by visible light in the presence of methylene blue (MB) resulted in nonproductive infection and the appearance of morphologically transformed cells. Two stably transformed cell lines were derived from both of these cell types and were confirmed to contain both viral DNA and antigen. Next, a quiescent MHV-68 infection in MRC-5 and NIH 3T3 cells was established after cultivation at 41 degrees C in the presence of phosphonoacetic acid. Following the exposure of quiescently infected cells to visible light for 120 s (5 times daily for 6 days) in the presence of MB, both MRC-5 and NIH-3T3 cells were observed to acquire transformed phenotypes. The cytopathic effect was observed in cells after 4-5 passages, after which the cells degenerated. However, when human interferon (IFN)-alpha and mouse IFN-beta were added to the media of quiescently infected MRC-5 and NIH-3T3 cells during the photoinactivating procedure, 2 stable transformed cell lines containing both viral DNA and the antigen were obtained and resembled those attained following nonproductive infection with photoinactivated virus. PMID- 28848177 TI - Abrupt Decline in a Protected Population of Siamangs (Symphalangus syndactylus) in Southern Sumatra. AB - Between 2011 and 2016, approximately 50% of siamangs in the Way Canguk Research Area disappeared, including members of 7 of 12 habituated groups. Demographic data from 1998 to 2015 confirm that the population decline in the habituated groups reflects a larger trend in the local population. There was no evidence of hunting of primates in the area, and ecological data do not suggest substantial changes in food availability or predation pressure during this period. From 2011 to 2014, we monitored the habituated groups only intermittently, and most deaths or disappearances were not observed. However, in 2014-2016, we monitored some groups more intensively, and observed 2 individuals with symptoms including whitened skin on the face, hands, and abdomen, hair loss, swelling of the face, frequent scratching, and lethargy. One affected individual disappeared days after this observation, while the other survived. The spatiotemporal pattern of disappearances in the habituated groups was consistent with that expected if the deaths resulted from disease transmission among neighbouring groups. Thus, the available evidence, while preliminary, suggests that a local disease epizootic may have been a factor driving the population decline. We recommend that researchers establish monitoring protocols to better understand primate disease epidemiology and to guide conservation management. PMID- 28848178 TI - Magnetic Resonance Imaging Susceptibility-Weighted Imaging Lesion and Contrast Enhancement May Represent Infectious Intracranial Aneurysm in Infective Endocarditis. AB - BACKGROUND: Infectious intracranial aneurysm (IIA) can complicate infective endocarditis (IE). We aimed to describe the magnetic resonance imaging (MRI) characteristics of IIA. METHODS: We reviewed IIAs among 116 consecutive patients with active IE by conducting a neurological evaluation at a single tertiary referral center from January 2015 to July 2016. MRIs and digital cerebral angiograms (DSA) were reviewed to identify MRI characteristics of IIAs. MRI susceptibility weighted imaging (SWI) was performed to collect data on cerebral microbleeds (CMBs) and sulcal SWI lesions. RESULTS: Out of 116 persons, 74 (63.8%) underwent DSA. IIAs were identified in 13 (17.6% of DSA, 11.2% of entire cohort) and 10 patients with aneurysms underwent MRI with SWI sequence. Nine (90%) out of 10 persons with IIAs had CMB >5 mm or sulcal lesions in SWI (9 in sulci, 6 in parenchyma, and 5 in both). Five out of 8 persons who underwent MRI brain with contrast had enhancement within the SWI lesions. In a multivariate logistic regression analysis, both sulcal SWI lesions (p < 0.001, OR 69, 95% CI 7.8-610) and contrast enhancement (p = 0.007, OR 16.5, 95% CI 2.3-121) were found to be significant predictors of the presence of IIAs. CONCLUSIONS: In the individuals with IE who underwent DSA and MRI, we found that neuroimaging characteristics, such as sulcal SWI lesion with or without contrast enhancement, are associated with the presence of IIA. PMID- 28848179 TI - Interferon-gamma Is Associated with Cerebral Atrophy in Systemic Lupus Erythematosus. AB - OBJECTIVE: We evaluated the cerebrospinal fluid (CSF) cytokine profile and magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with central nervous system (CNS) involvement. METHODS: Consecutive SLE patients followed at the rheumatology unit were enrolled into this study. Neurologically asymptomatic controls were matched for age and sex and recruited during myelography. SLE patients were assessed for disease activity (Systemic Lupus Erythematosus Disease Activity Index; SLEDAI) and cumulative damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SDI). All subjects underwent MRI scans and blood and CSF withdrawal. Immunoglobulin G (IgG) and albumin were measured by nephelometry and link indexes were calculated according to the literature. Interleukin (IL)-12 p40/p70, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-10 were measured by enzyme-linked immunosorbent assay. RESULTS: We included 20 SLE patients (18 women, mean age 30.2 +/- 9.2 years, range 19-45) with CNS manifestations. Increased IL-12 p40/p70, IFN-gamma, TNF-alpha, and IL-10 CSF levels were observed in SLE patients. Mild pleocytosis was observed in 8 (66%) SLE patients and intrathecal production of IgG was observed in 2 (10%) SLE patients. Three (15%) SLE patients had demyelinating lesions, 5 (25%) patients had cerebral atrophy, and 12 (60%) patients had ischemic lesions on MRI. We observed that the cerebral lesion count was associated with CNS manifestations and SDI scores. We observed a significant cerebral volume reduction in SLE patients compared to controls (p < 0.001). Moreover, a direct correlation between cerebral volume reduction and CSF IFN-gamma levels was observed (r = 0.5, p = 0.01). CONCLUSIONS: IL-12 p40/p70, IFN-gamma, TNF-alpha, and IL-10 CSF levels were increased in SLE patients with CNS manifestations, but only IFN-gamma was associated with a cerebral volume reduction in SLE, suggesting an immunological basis for global atrophy in SLE. PMID- 28848181 TI - Schizophrenia, Self, and Person: Eugen Bleuler and Arthur Kronfeld on a Conceptual Alliance. AB - The conceptual history of schizophrenia is marked by considerable dissent about its nosological status, and the question of whether it represents a distinct disease entity remains hotly debated. Another recurring feature in the conceptual history of schizophrenia is the reference to concepts of self and person. This paper brings in connection these two debates by interrogating the nosological function of "self" and "person" by means of a fictitious dialogue between Eugen Bleuler, the inventor of schizophrenia, and his contemporary Arthur Kronfeld. Introducing their respective accounts of schizophrenia with a special focus on how concepts of self and person figure therein, our analysis suggests that these concepts are primarily employed in an attempt to guarantee the nosological unity of schizophrenia: mediated by the concept of a core disturbance, alterations of the self or the person thus become the essential core of schizophrenia. Yet, rather than providing an easy solution to the nosological problem of the unity of schizophrenia, the concepts of self and person and their assumed disturbances are themselves fraught with debates about unity. We discuss these conceptual challenges in light of present-day nosological debates and the currently abounding research on the self. PMID- 28848180 TI - TGF-beta1 Induces EMT in Bovine Mammary Epithelial Cells Through the TGFbeta1/Smad Signaling Pathway. AB - BACKGROUND/AIMS: Transforming growth factor-beta1 (TGF-beta1) plays a crucial role in chronic inflammation in various tissues, and is related to inflammation caused organ fibrogenesis associated with the epithelial-mesenchymal transition (EMT) and the deposition of the extracellular matrix (ECM). However, the effect of TGF-beta1 on bovine mammary epithelial cells (BMECs) with mastitis, and its mechanism, remain unknown. METHODS: We analyzed the level of TGF-beta1 in inflamed mammary tissues and cells using western blotting. BMECs were treated with TGF-beta1, and EMT-related gene and protein expression changes were evaluated using quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescence. We also inhibited the TGF/Smad signaling pathway using a receptor inhibitor, and analyzed EMT-related protein expression by western blotting. In addition, we injected TGF-beta1 into mice mammary glands to investigate whether it can cause mammary fibrosis in vivo. RESULTS: The TGF beta1 level was up-regulated in mammary tissues with mastitis and in inducible inflammatory BMECs. TGF-beta1 treatment activated the TGF/ Smad signaling pathway in BMECs during their transition to the EMT phenotype, as indicated by morphological changes from a cobblestone-like shape to a spindle-like one. TGF beta1 treatment also up-regulated the expression of alpha-smooth muscle actin, vimentin, and collagen I, albumin, and down-regulated the expression of E cadherin both in mRNA level and protein level. Furthermore, TGF-beta1 enhanced the gene expressions of MMP2, MMP7, and fibronectin in BMECs. TGF-beta1 injection induced mice mammary infection and fibrosis. CONCLUSION: These findings suggested that aberrant up-regulation of TGF-beta1 in bovine mastitic mammary glands might play an important role in bovine mammary fibrosis caused by unresolved inflammation. PMID- 28848183 TI - Effects of Inadequate Amino Acid Mixture Intake on Nutrient Supply of Adult Patients with Phenylketonuria. AB - BACKGROUND: Adult phenylketonuria (PKU) patients often reduce their intake of amino acid mixture (AAM) to less than the prescribed amounts. Effects of reduced AAM intake on nutrient supply were evaluated. METHODS: Nutrient intake was calculated in 20 adult PKU patients based on a structured food record and complemented by laboratory assessment of nutritional status. Patients were classified into 2 groups, (A) regular AAM intake, or (B) AAM intake below calculated requirements. RESULTS: Group B consumed a higher proportion of natural protein (60 +/- 23 vs. 33 +/- 12%, p = 0.002); however, the total protein intake was below the recommended amounts in 60% of patients in group B versus 7% in group A (p = 0.03). Fat intake was higher in group B (39 +/- 9% of energy vs. 31 +/- 6%, p = 0.03), mainly from saturated fats. Selenium, folate, and vitamin B12 intake was below the recommended intake in group B. However, serum concentrations of these analytes remained within the normal range in both groups, although vitamin B12 levels were lower in group B. Plasma tyrosine correlated with AAM intake, and hydroxyproline correlated with the amount of natural protein consumed. CONCLUSION: Relaxed AAM intake resulted in insufficient nutrient supply, despite a compensatory increase in consumption of natural protein. Care needs to be taken to ensure adequate nutrition in adults with PKU. PMID- 28848182 TI - Neutrophil Recovery in Breast Cancer Patients Receiving Docetaxel-Containing Chemotherapy with and without Granulocyte Colony-Stimulating Factor Prophylaxis. AB - OBJECTIVE: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony stimulating factor (G-CSF) on the next cycle blood cell counts. METHODS: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only. RESULTS: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 * 109/L in cycle 1 to 7.5 * 109/L in cycle 6 and from 7.1 * 109/L to 5.5 * 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 * 109/L in cycle 3 to 0.9 * 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 * 109/L in cycles 3 6. All patients had ANC recovery to normal levels (>=1.5 * 109/L) without delay on day 1 of the next cycle. CONCLUSION: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles. PMID- 28848184 TI - Ethanol Decreases Inflammatory Response in Human Lung Epithelial Cells by Inhibiting the Canonical NF-kB-Pathway. AB - BACKGROUND/AIMS: Alcohol (ethanol, EtOH) as significant contributor to traumatic injury is linked to suppressed inflammatory response, thereby influencing clinical outcomes. Alcohol-induced immune-suppression during acute inflammation (trauma) was linked to nuclear factor-kappaB (NF-KB). Here, we analyzed alcohol's effects and mechanisms underlying its influence on NF-KB-signaling during acute inflammation in human lung epithelial cells. METHODS: A549-cells were stimulated with interleukin (IL)-1beta, or sera from trauma patients (TP) or healthy volunteers, with positive/negative blood alcohol concentrations (BAC), and subsequently exposed to EtOH (170 Mm, 1h). IL-6-release and neutrophil adhesion to A549 were analyzed. Specific siRNA-NIK mediated downregulation of non canonical, and IKK-NBD-inhibition of canonical NF-KB signaling were performed. Nuclear levels of activated p50 and p52 NF-KB-subunits were detected using TransAm ELISA. RESULTS: Both stimuli significantly induced IL-6-release (39.79+/ 4.70 vs. 0.58+/-0.8 pg/ml) and neutrophil adhesion (132.30+/-8.80 vs. 100% control, p<0.05) to A549-cells. EtOH significantly decreased IL-6-release (22.90+/-5.40, p<0.05) and neutrophil adherence vs. controls (105.40+/-14.5%, p<0.05). IL-1beta-induced significant activation of canonical/p50 and non canonical/p52 pathways. EtOH significantly reduced p50 (34.90+/-23.70 vs. 197.70+/-36.43, p<0.05) not p52 activation. Inhibition of canonical pathway was further increased by EtOH (less p50-activation), while p52 remained unaltered. Inhibition of non-canonical pathway was unchanged by EtOH. CONCLUSION: Here, alcohol's anti-inflammatory effects are mediated via decreasing nuclear levels of activated p50-subunit and canonical NF-KB signaling pathway. PMID- 28848185 TI - Comparison of Fetomaternal Outcome between 47 Deliveries Following Successful External Cephalic Version for Breech Presentation and 7456 Deliveries Following Spontaneous Cephalic Presentation. AB - BACKGROUND: Achieving a cephalic position after a successful external cephalic version (ECV) is desired to result in delivery and fetal outcomes that are similar to those of deliveries following spontaneous cephalic presentation. METHODS: We performed a retrospective cohort study including patients with successful ECV following fetal breech position (ECV cohort, n = 47) or with a singleton spontaneous cephalic pregnancy at >=37 weeks of gestational age (control group, n = 7,456) attempting a vaginal delivery between 2010 and 2013 at the University Hospital Ulm. The mode of delivery and fetal outcome parameters were compared between these 2 groups using nonparametric statistics. RESULTS: ECV cohort and control group did not differ with respect to maternal age, parity, gestational age at birth, and fetal gender. There were no significant differences between the 2 groups with regard to all parameters indicating fetal outcome. However, the rate of cesarean sections was higher after successful ECV compared to spontaneous cephalic presentation (27.7 vs. 12.8%, OR 2.615). CONCLUSION: While vaginal delivery is less likely to happen after a successful ECV compared to spontaneous cephalic singleton pregnancies, fetal outcome parameters showed no difference between the 2 groups. Physicians should be counseling and encouraging women to attempt ECV, as it is a safe and effective procedure. PMID- 28848186 TI - Imaging Techniques in the Diagnostic Journey of Disorders of Sex Development. AB - Various disorders of sex development (DSD) result in an abnormal development of genitalia that may be recognized at prenatal ultrasonography, immediately after birth, or later in life. Because of the complex nature of DSD, the participation of a multidisciplinary team, including imaging or radiology technologists, is required to address the patient's medical needs. The first steps in the management of DSD are sex evaluation, which is based on factors such as the genotype, the presence, location, and appearance of reproductive organs, the potential for fertility, and the cultural background and beliefs of the patient's family. It is also important to ensure the detection of comorbidity (as in syndromes) and to define the etiology of DSD in order to offer the best prognosis. Ultrasonography is the primary modality for demonstrating internal organs, genitography is used to assess the urethra, vagina, and any fistulas, and magnetic resonance imaging is used as an additional modality to assess internal gonads and genitalia. This review presents the advantages and disadvantages and the sensitivity and specificity for each type of radiological imaging to help in the evaluation of DSD cases before and after birth. PMID- 28848187 TI - The Future of Human Longevity. AB - Recent scientific publications suggest that human longevity records stopped increasing. Our finding that the mortality of centenarians has not decreased noticeably in recent decades (despite a significant mortality decline in younger age groups) is consistent with this suggestion. However, there is no convincing evidence that we have reached the limit of human life span. The future of human longevity is not fixed and will depend on human efforts to extend life span. PMID- 28848188 TI - Chronic Kidney Disease and Idiopathic Pulmonary Fibrosis: Thinking Outside the Box in Disease Management and Prognostication. PMID- 28848189 TI - Role of Stat3 Signaling in Control of EMT of Tubular Epithelial Cells During Renal Fibrosis. AB - BACKGROUND/AIMS: Transforming growth factor beta 1 (TGFbeta1) plays a critical role in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs) during renal injury, a major cause of acute renal failure, renal fibrosis and obstructive nephropathy. However, the underlying molecular mechanisms remain ill-defined. Here, we addressed this question. METHODS: Expression of TGFbeta1, Snail, and phosphorylated Stat3 was examined by immunohistochemistry in the kidney after induction of unilateral ureteral obstruction (UUO) in mice. In vitro, primary TECs were purified by flow cytometry, and then challenged with TGFbeta1 with/without presence of specific inhibitors for phosphorylation of SMAD3 or Stat3. Protein levels were determined by Western blotting. RESULTS: We detected significant increases in Snail and phosphorylated Stat3, an activated form for Stat3, in the kidney after induction of UUO in mice. In vitro, TGFbeta1-challenged primary TECs upregulated Snail, in a SMAD3/Stat3 dependent manner. CONCLUSION: Our study sheds light on the mechanism underlying the EMT of TECs after renal injury, and suggests Stat3 signaling as a promising innovative therapeutic target for prevention of renal fibrosis. PMID- 28848190 TI - Screening for Sex Chromosome Aneuploidy by Cell-Free DNA Testing: Patient Choice and Performance. AB - OBJECTIVE: To study patient choice regarding testing for sex chromosome aneuploidy (SCA) and the performance of cell-free DNA (cfDNA) screening for SCA. METHODS: Patient choice regarding screening for SCA and factors influencing this choice were evaluated in a single center. In a subsequent two-center study, cases that screened positive for SCA were analyzed to determine the positive predictive value (PPV) for each SCA. RESULTS: In all, 1,957 (61.9%) of the 3,162 patients undergoing cfDNA testing opted for SCA screening. Regression analysis demonstrated that independent predictors of a patient's decision for SCA were earlier gestational age, spontaneous conception, and cfDNA chosen as a primary method of screening. A total of 161 cases screened positive for SCA and follow-up data were available for 118 (73.3%). Forty-six of the 61 cases of 45,X were false positive results and 15 were concordant with the fetal karyotype (PPV = 24.6%). Seventeen of the 22 cases of 47,XXX were false positive and 5 concordant (PPV = 22.7%). Eleven of the 30 cases of 47,XXY were false positive and 19 concordant (PPV = 63.3%). All 5 cases of 47,XYY were correctly identified, thus yielding a PPV of 100%. CONCLUSION: More than half of the patients undergoing cfDNA aneuploidy screening also opted for SCA testing, but they were less likely to do so in the presence of an increased risk of trisomy. SCAs involving the X chromosome had a lower PPV than those involving the Y chromosome. PMID- 28848191 TI - Bedside Stereomicroscopy of Fabry Kidney Biopsies: An Easily Available Method for Diagnosis and Assessment of Sphingolipid Deposits. AB - BACKGROUND/AIMS: A previous case report found stereomicroscopic changes typical for Fabry disease in a kidney biopsy. This case series evaluates an expanded diagnostic capacity of the method. METHODS: Bedside stereomicroscopy was performed in a cross-sectional prospective study of 31 consecutive enzyme-treated or treatment-naive male (n = 14) and female Fabry disease patients. The burden of glomerular storage material was scored semiquantitatively on a visual analog scale (range 0-3) and a blinded comparison was done with a reference histologic method. RESULTS: Significant correlations (p < 0.001) were found between the stereomicroscopic scoring of glomerular characteristic white storage material and the amount of podocyte globotriaosylceramide (Gb3) deposits scored by standardized light microscopy. The bedside method correctly identified the variability of podocyte Gb3 accumulation after 10 years of identical agalsidase therapy in 2 brothers aged 24 and 27 years, and also identified tubular cell deposits. Stereomicroscopy correctly verified the absence of sphingolipid deposits in the biopsy of a female index patient with a genetic variant of unknown significance, and the diagnosis of Fabry disease was finally discarded. CONCLUSIONS: Bedside stereomicroscopy of kidney biopsies is an easily available, low-cost microscopy method handled by the clinician. The method carries a high diagnostic sensitivity for Fabry disease, reducing the risk of misdiagnosis in previously unknown cases. An expanded yield of the method is suggested, including the grading of the podocyte Gb3 burden and assessment of effectiveness of enzyme replacement therapy. We recommend the method as complementary to current standard histologic evaluation of Fabry kidney biopsies. PMID- 28848192 TI - Behavioral Conditioning of Immune Responses with Cyclosporine A in a Murine Model of Experimental Autoimmune Uveitis. AB - OBJECTIVE: We examined the role of behavioral conditioning of immune responses with cyclosporine A (CsA) on the development of Th1/Th17-driven experimental autoimmune uveoretinitis (EAU). METHODS: Mice received a 0.2% w/v saccharin solution as conditioned stimulus combined with CsA (20 mg/kg) in 6 association trials at 72-h intervals. For evocation periods, conditioned mice were reexposed to saccharin, whereas the conditioned but not reexposed group received water only. Animals were immunized with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBPp161-180) peptide in complete Freund adjuvant (CFA) and a concomitant injection of pertussis toxin. RESULTS: In naive mice subjected to the behavioral conditioning regimen, mitogen-induced interleukin (IL)-2 production was decreased in conditioned mice compared to conditioned but not reexposed animals. Incidence and severity of EAU were not significantly lower in behaviorally conditioned and immunized mice. ELISA analysis of splenocytes revealed a reduced interferon (IFN)-gamma/IL-17 ratio in CsA-treated, conditioned but not reexposed, and conditioned animals. The adoptive transfer of antigen specific splenocytes from animals behaviorally conditioned with CsA to naive mice decreased the severity of EAU in recipient mice compared to the control group. In vitro activation of splenocytes isolated from immunized mice with agonists targeting TLR2 and NOD2 together with beta2-adrenergic activation (induced by epinephrine, norepinephrine, or salbutamol) resulted in decreased IFN-gamma but increased IL-17 immune responses. The beta2-adrenergic antagonist propranolol could restore IFN-gamma production, whereas only the norepinephrine-induced increase in IL-17 production was abrogated. CONCLUSIONS: We conclude that CsA conditioning in the EAU model mitigates Th1 but enhances Th17 immune responses, and does not ameliorate disease. The results imply that in EAU the mechanism of immune conditioning interacts with CFA components during active immunization, most likely via the TLR2/NOD2 pathway, and induces differentiation of Th17 cells that drive autoimmune diseases. PMID- 28848193 TI - Anemia in the Elderly in Northeastern Thailand: A Community-Based Study Investigating Prevalence, Contributing Factors, and Hematologic Features. AB - This community-based study investigated anemia prevalence and certain hematologic features and their possible relationships to thalassemia and iron deficiency (ID) in a population of older people in Northeastern Thailand. Participants included 319 apparently healthy individuals ranging in age from 60 to 98 years, whose current health status was assessed by means of personal interviews. Blood samples were also collected to determine the following parameters: red blood cell indices, serum ferritin, C-reactive protein, hemoglobin profiles, and the alpha0 thalassemia gene. Based upon established WHO criteria, the overall prevalence of anemia was found to be 47.7%, increasing from 39% within the age group of 60-70 years to 68% in those >80 years. Factors considered to be significant contributors to anemia were classified as ID (3.6%), thalassemia (56.2%), and "unknown" (40.1%). Overall, only 2.4% of participants exhibited any ID. Hematologic changes appear to correlate with age. Our findings provide not only baseline information, potentially useful for implementing appropriate control measures, but also an enhanced awareness and understanding of the factors contributing to anemia among the elderly in the region. PMID- 28848194 TI - Multimorbidities Are Associated to Lower Survival in Ischaemic Stroke: Results from a Brazilian Stroke Cohort (EMMA Study). AB - BACKGROUND: Stroke prognosis is related to the multimorbidity profile. Moreover, performing an individual evaluation of most common cerebrovascular risk factors (CVRF) not always identifies patients with poor prognosis. Thus, we decided to evaluate multimorbidity profile, focusing on the Charlson Comorbidity Index (CCI) validated by Goldstein for ischaemic stroke (IS) patients, a score that measures a burden of comorbidities and its related mortality in the long-term survival of the EMMA Study (Study of Stroke Mortality and Morbidity). METHODS: Nine hundred fifty-nine individuals (median age 70 years) had validated data on the diagnosis of IS, main CVRF and clinical comorbidities pre index event such as atrial fibrillation (AF), stroke recurrence, diabetes, hypertension, heart failure and cancer. CCI modified by Goldstein was calculated, which includes 17 clinical conditions with scores ranging from 1 to 6 (0-31 points). Survival analyses were performed by Kaplan-Meier curves and Cox logistic regression models (cumulative hazard ratio [HR] with [95% CI]) for all-cause mortality at 180 days, and every 3 years up to 9-year follow-up. Mortality analyzes were performed by CCI categorized according to weight added to comorbidities (Reference group: zero, moderate: 1, severe: 2 and very severe: >=3 points). We also tested the modification effect of AF and stroke recurrence including these conditions in the CCI. RESULTS: The overall survival rate was 47% (508 deaths/959). The worst survival (577, 95% CI 381-773 days) and the highest risk of death after stroke were observed in the very severe CCI group (HR 3.18; 95% CI 2.16-4.69) up to 9 years. The inclusion of previous AF and stroke in the CCI slightly increased the risk of death for very severe CCI (HR 3.27; 95% CI 2.07-5.18). CONCLUSIONS: A high burden of comorbidities represented an independent predictor of poor prognosis increasing the risk of dying by 2 to 3 times among IS up to 9 years in the EMMA study. The inclusion of other CVRF such as AF and stroke recurrence slightly modified all-cause mortality risk. PMID- 28848195 TI - The Hemodynamic Changes in Patients with Cerebral Arteriovenous Malformations before and after Interventional Embolization Therapy with Glubran 2 Acrylic Glue. AB - The study explored hemodynamic changes in patients with cerebral arteriovenous malformations (CAVM) before and -after interventional embolization therapy with Glubran 2 acrylic glue and analyzed the related factors. CAVM patients received endovascular embolization therapy with Glubran 2. Patients' systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), blood flow velocity (BFV), and pulsatility index (PI) were measured. The location of malformed vessels, Spetzler-Martin (SM) grade, CAVM size, and type of feeding artery and venous drainage were analyzed. CAVM patients showed increased DBP, SBP, MAP, and PI and decreased average BFV compared to before therapy. CAVM patients with big CAVM size, SM grade IV/V, deep location malformed vessels, deep, and mixed venous drainage, and cortical branch and mixed artery blood supply exhibited lower DBP, SBP, MAP, and PI but higher average BFV. Hypertensive CAVM patients showed lower DBP, SBP, MAP, average BFV, and PI before or after embolization. Hypertension, SM grade, CAVM size, malformed vessels location, venous drainage, and artery blood-supply were correlated to the hemodynamic changes of CAVM patients. Embolization with Glubran 2 acrylic glue could enhance hemodynamics in CAVM patients, and the hemodynamic changes were in correlation with the SM grade, CAVM size, and malformed vessels location. PMID- 28848197 TI - Heterologous Expression of Spinosyn Biosynthetic Gene Cluster in Streptomyces Species Is Dependent on the Expression of Rhamnose Biosynthesis Genes. AB - Spinosyns are a group of macrolide insecticides produced by Saccharopolyspora spinosa. Although S. spinosa can be used for industrial-scale production of spinosyns, this might suffer from several limitations, mainly related to its long growth cycle, low fermentation biomass, and inefficient utilization of starch. It is crucial to generate a robust strain for further spinosyn production and the development of spinosyn derivatives. A BAC vector, containing the whole biosynthetic gene cluster for spinosyn (74 kb) and the elements required for conjugal transfer and site-specific integration, was introduced into different Streptomyces hosts in order to obtain heterologous spinosyn-producing strains. The exconjugants of different Streptomyces strains did not show spinosyn production unless the rhamnose biosynthesis genes from S. spinosa genomic DNA were present and expressed under the control of a strong constitutive ermE*p promoter. Using this heterologous expression system resulted in yields of 1 MUg/mL and 1.5 MUg/mL spinosyns in Streptomyces coelicolor and Streptomyces lividans, respectively. This report demonstrates spinosyn production in 2 Streptomyces strains and stresses the essential role of rhamnose in this process. This work also provides a potential alternative route for producing spinosyn analogs by means of genetic manipulation in the heterologous hosts. PMID- 28848196 TI - TRPA1 Function in Skeletal Muscle Sensory Neurons Following Femoral Artery Occlusion. AB - BACKGROUND/AIMS: Transient receptor potential channel A1 (TRPA1) is engaged in amplified autonomic responses evoked by stimulation of muscle afferent nerves in rats with experimental peripheral arterial disease. The purposes of this study were to characterize current responses induced by activation of TRPA1 in dorsal root ganglion (DRG) neurons of control limbs and limbs with femoral artery occlusion. METHODS: DRG neurons from rats were labeled by injecting the fluorescence tracer DiI into the hindlimb muscles and whole-cell patch clamp experiments were performed to determine TRPA1 currents. RESULTS: Data show that AITC (a TRPA1 agonist) from the concentrations of 50 uM to 200 uM produces a dose dependent increase of amplitudes of inward current responses. Notably, the peak current amplitude induced by AITC is significantly larger in DRG neurons of ligated limbs than that in control limbs. AITC-induced current responses are observed in small and medium size DRG neurons, and there is no difference in size distribution of DRG neurons between control limbs and ligated limbs. However, femoral occlusion increases the percentage of the AITC-sensitive DRG neurons as compared to control. AITC-induced currents in DRG neurons are significantly attenuated by exposure to 10 uM of HC-030031, a potent and selective inhibitor of TRPA1, in both control and femoral occlusion groups. In addition, capsaicin (a TRPV1 agonist) evokes a greater increase in the amplitude of AITC-currents in DRG neurons of ligated limbs than that in control limbs. CONCLUSIONS: A greater current response with activation of TRPA1 is developed in muscle afferent nerves when hindlimb arterial blood supply is deficient under ischemic conditions; and TRPV1 is partly responsible for augmented TRPA1 responses induced by arterial occlusion. PMID- 28848198 TI - Spontaneous Resolution of a Sylvian Arachnoid Cyst in a Child: A Case Report. AB - We report the case of a 7-year-old boy with an incidentally diagnosed left sylvian arachnoid cyst. At a clinical follow-up of 2 years, cranial computed tomography scans found the cyst to be totally resolved. The mechanism of this rare spontaneous resolution of an arachnoid cyst is discussed. PMID- 28848199 TI - A Novel Method of Estimating Small Airway Disease Using Inspiratory-to-Expiratory Computed Tomography. AB - BACKGROUND: Disease accumulates in the small airways without being detected by conventional measurements. OBJECTIVES: To quantify small airway disease using a novel computed tomography (CT) inspiratory-to-expiratory approach called the disease probability measure (DPM) and to investigate the association with pulmonary function measurements. METHODS: Participants from the population-based CanCOLD study were evaluated using full-inspiration/full-expiration CT and pulmonary function measurements. Full-inspiration and full-expiration CT images were registered, and each voxel was classified as emphysema, gas trapping (GasTrap) related to functional small airway disease, or normal using two classification approaches: parametric response map (PRM) and DPM (VIDA Diagnostics, Inc., Coralville, IA, USA). RESULTS: The participants included never smokers (n = 135), at risk (n = 97), Global Initiative for Chronic Obstructive Lung Disease I (GOLD I) (n = 140), and GOLD II chronic obstructive pulmonary disease (n = 96). PRMGasTrap and DPMGasTrap measurements were significantly elevated in GOLD II compared to never-smokers (p < 0.01) and at risk (p < 0.01), and for GOLD I compared to at risk (p < 0.05). Gas trapping measurements were significantly elevated in GOLD II compared to GOLD I (p < 0.0001) using the DPM classification only. Overall, DPM classified significantly more voxels as gas trapping than PRM (p < 0.0001); a spatial comparison revealed that the expiratory CT Hounsfield units (HU) for voxels classified as DPMGasTrap but PRMNormal (PRMNormal- DPMGasTrap = -785 +/- 72 HU) were significantly reduced compared to voxels classified normal by both approaches (PRMNormal-DPMNormal = -722 +/- 89 HU; p < 0.0001). DPM and PRMGasTrap measurements showed similar, significantly associations with forced expiratory volume in 1 s (FEV1) (p < 0.01), FEV1/forced vital capacity (p < 0.0001), residual volume/total lung capacity (p < 0.0001), bronchodilator response (p < 0.0001), and dyspnea (p < 0.05). CONCLUSION: CT inspiratory-to-expiratory gas trapping measurements are significantly associated with pulmonary function and symptoms. There are quantitative and spatial differences between PRM and DPM classification that need pathological investigation. PMID- 28848200 TI - Snail Enhances Glycolysis in the Epithelial-Mesenchymal Transition Process by Targeting FBP1 in Gastric Cancer. AB - BACKGROUND: Snail is a key regulator of epithelial-mesenchymal transition (EMT) in cancer. However, the regulatory role and underlying mechanisms of Snail in gastric cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by Snail in gastric cancer. METHODS: The impact of Snail on glucose metabolism was studied in vitro. Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we further analyzed the correlation between SUVmax and Snail expression in gastric cancer tissues. RESULTS: Increased expression of Snail promoted lactate production, glucose utilization, and decreased FBP1 expression at both mRNA and protein level. The expression level of Snail was positively associated with SUVmax in gastric cancer patients (P=0.022). Snail and FBP1 expression were inversely correlated at both mRNA and protein level (P=0.002 and P=0.015 respectively) in gastric cancer tissues. Further studies demonstrated that Snail inhibited the FBP1 gene expression at the transcriptional level. Restoring FBP1 expression reversed the effects of glycolysis and EMT induced by Snail in gastric cancer cells. CONCLUSIONS: Our results thus reveal that Snail serves as a positive regulator of glucose metabolism through regulation of the FBP1 in gastric cancer. Disrupting the Snail-FBP1 signaling axis may be effective to prevent primary tumor EMT and glycolysis process. PMID- 28848202 TI - Absorption and Effect of Azaspiracid-1 Over the Human Intestinal Barrier. AB - BACKGROUND: Azaspiracids (AZAs) are marine biotoxins produced by the dinoflagellates genera Azadinium and Amphidoma. These toxins cause azaspiracid poisoning (AZP), characterized by severe gastrointestinal illness in humans after the consumption of bivalve molluscs contaminated with AZAs. The main aim of the present study was to examine the consequences of human exposure to AZA1 by the study of absorption and effects of the toxin on Caco-2 cells, a reliable model of the human intestine. METHODS: The ability of AZA1 to cross the human intestinal epithelium has been evaluated by the Caco-2 transepithelial permeability assay. The toxin has been detected and quantified using a microsphere-based immunoassay. Cell alterations and ultrastructural effects has been observed with confocal and transmission electron microscopy Results: AZA1 was absorbed by Caco-2 cells in a dose-dependent way without affecting cell viability. However, modifications on occludin distribution detected by confocal microscopy imaging indicated a possible monolayer integrity disruption. Nevertheless, transmission electron microscopy imaging revealed ultrastructural damages at the nucleus and mitochondria with autophagosomes in the cytoplasm, however, tight junctions and microvilli remained unaffected. CONCLUSION: After the ingestion of molluscs with the AZA1, the toxin will be transported through the human intestinal barrier to blood causing damage on epithelial cells. PMID- 28848201 TI - Angiotensin-(1-7) in Paraventricular Nucleus Contributes to the Enhanced Cardiac Sympathetic Afferent Reflex and Sympathetic Activity in Chronic Heart Failure Rats. AB - BACKGROUND/AIMS: Cardiac sympathetic afferent reflex (CSAR) enhancement contributes to exaggerated sympathetic activation in chronic heart failure (CHF). The current study aimed to investigate the roles of angiotensin (Ang)-(1-7) in CSAR modulation and sympathetic activation and Ang-(1-7) signaling pathway in paraventricular nucleus of CHF rats. METHODS: CHF was induced by coronary artery ligation. Responses of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to epicardial application of capsaicin were used to evaluate CSAR in rats with anesthesia. RESULTS: Ang-(1-7) increased RSNA, MAP, CSAR activity, cAMP level, NAD(P)H oxidase activity and superoxide anion level more significantly in CHF than in sham-operated rats, while Mas receptor antagonist A 779 had the opposite effects. Moreover, Ang-(1-7) augmented effects of Ang II in CHF rats. The effects of Ang-(1-7) were blocked by A-779, adenylyl cyclase inhibitor SQ22536, protein kinase A inhibitor Rp-cAMP, superoxide anion scavenger tempol and NAD(P)H oxidase inhibitor apocynin. Mas and AT1 receptor protein expressions, Ang-(1-7) and Ang II levels in CHF increased. CONCLUSIONS: These results indicate that Ang-(1-7) in paraventricular nucleus enhances CSAR and sympathetic output not only by exerting its own effects but also by augmenting the effects of Ang II through Mas receptor in CHF. Endogenous Ang-(1-7)/Mas receptor activity contributes to CSAR enhancement and sympathetic activation in CHF, and NAD(P)H oxidase-derived superoxide anions and the cAMP-PKA signaling pathway are involved in mediating the effects of Ang-(1-7) in CHF. PMID- 28848203 TI - Role of Dynamic Contrast-Enhanced Perfusion Magnetic Resonance Imaging in Grading of Pediatric Brain Tumors on 3T. AB - BACKGROUND/AIMS: Perfusion magnetic resonance imaging (MRI) is useful for preoperative assessment of brain tumors. Dynamic susceptibility contrast perfusion MRI is commonly used for evaluation of brain tumors. Dynamic contrast enhanced (DCE) MRI is an alternative method that has mainly been used in adult brain tumors. In this preliminary study, we report our initial experience with the DCE perfusion MRI in pediatric brain tumors. METHODS: Sixty-four newly diagnosed pediatric brain tumor patients underwent DCE perfusion MRI on a 3-T scanner. Hemodynamic and kinetic parametric maps were generated and the regions with the highest values were measured on each map. Statistical differences were sought to differentiate between low-grade tumors, high-grade tumors, and medulloblastomas. The perfusion metrics of common posterior fossa tumors were also compared. RESULTS: Relative corrected cerebral blood volume (rCBV) and fractional plasma volume measures differed significantly between high- and low grade tumors (p < 0.05). High-grade tumors could be differentiated from low-grade tumors, with an rCBV cutoff value of 2.41 and 88.6% sensitivity and 65% specificity. There was no significant difference in Ktrans, Kep, Ve, or lambdatr between these 2 groups of tumors. rCBV, relative quantification of the cerebral blood flow, and permeability indices were found to be significantly different in various posterior fossa tumors, i.e., pilocytic astrocytoma, ependymoma, and medulloblastoma (p < 0.05). CONCLUSION: DCE-derived perfusion metrics are useful in differentiating high-grade tumors from low-grade ones and discriminating among various posterior fossa tumors in the pediatric age group. PMID- 28848204 TI - Group Composition and Monandry in Grizzled Langurs, Presbytis comata, on Java. AB - Grizzled langurs, Presbytis comata, a largely sexually monomorphic species, are reported to occur in populations where either the majority of groups comprise 1 adult male with 1 adult female, or where groups comprise 1 adult male with multiple females. As such, they may have a monandrous mating system. I investigated whether 1-male/1-female groups indeed form a significant part of the species' social system, and whether habitat variation (forest fragment size, distance to the forest edge, altitude) affects social organization. I found the species from sea level to 2,565 m above sea level in groups from 1 to 13 individuals. I recorded mostly 1-male/multifemale groups with offspring or, alternatively, all-male groups. Two out of 55 groups comprised 1-male/1-female groups with offspring. Group size was negatively correlated with altitude and forest fragment size, and positively correlated with increasing distance from the forest edge. Altitudinal variation in group sizes was driven mainly by fewer adult females being present in groups at higher elevations; the number of adult males (almost invariably 1), subadults, juveniles, and infants, as well as the infant/adult female ratio, showed little altitudinal variation. One-male/1-female groups have been recorded repeatedly over a 25-year period in a high-altitude population on Mt. Patuha, West Java, but even here, on average, three fifths of the groups comprise 1 adult male with multiple females. At high-altitude sites, P. comata may indeed have a monandrous mating system, but at lower elevations it seems similar to that of other Presbytis langurs. PMID- 28848205 TI - Prognostic Impact of Adjuvant Chemotherapy after Hepatic Resection for Synchronous and Early Metachronous Colorectal Liver Metastases. AB - BACKGROUND: Although the usefulness of adjuvant chemotherapy has been established in the treatment for stages II/III colorectal cancer, its prognostic advantage for colorectal liver metastases (CLM) remains controversial. METHODS: Two hundred and nine patients who underwent curative resection for CLM were reviewed. The potential advantage of adjuvant chemotherapy was investigated in 3 groups stratified by disease-free interval (DFI): synchronous CLM (S-CLM), early metachronous CLM (EM-CLM, DFI <=1 year), and late metachronous CLM (LM-CLM, DFI >1 year). RESULTS: Of the 105 patients who underwent adjuvant chemotherapy after surgery, 47 received uracil-tegafur and leucovorin (UFT/LV) while 58 received the oxaliplatin-based regimen. Five-year recurrence-free survival (RFS) rates in patients with/without adjuvant chemotherapy were 32.8/11.2% in S-CLM (p = 0.002), 43.7/15.2% in EM-CLM (p = 0.002), 44.1/29.6% in LM-CLM (p = 0.163), respectively. Five-year overall survival (OS) rates were 77.9/44.5% in S-CLM (p = 0.021), 81.5/39.5% in EM-CLM (p = 0.015), 76.1/65.4% in LM-CLM (p = 0.411), respectively. Multivariate analyses in S-CLM and EM-CLM indicated that adjuvant chemotherapy is correlated with better RFS and OS irrespective of the regimens, while the incidence of severe adverse event was significantly different between UFT/LV and oxaliplatin (6.8 vs. 50.9%, p < 0.0001). CONCLUSION: Adjuvant chemotherapy might improve the clinical outcomes in S-CLM and EM-CLM. UFT/LV might be a choice for CLM in adjuvant settings in selected patients. PMID- 28848206 TI - Number of Oocytes Retrieved as a Criterion for "Freeze-All" Strategy versus a Single "Rescue" Bolus of Low-Dose Human Chorionic Gonadotropin Following GnRH Agonist for Ovulation Triggering: A Pilot Study. AB - AIM: To evaluate the number of oocytes retrieved as a criterion - when to use a "freeze-all" or low-dose "rescue human chorionic gonadotropin (hCG)" strategy. METHODS: A retrospective study. Instead of the classic hCG trigger, an E2 level of >=3,000 pg/mL was used to trigger ovulation with GnRH agonist. The decision whether to "freeze all" or perform fresh embryo transfer (ET) with a bolus of hCG was made based on a maximum number of 20 oocytes retrieved. Beyond this cut off, a "freeze-all" strategy was implemented. Below this cut-off value, a fresh ET using a single bolus of 62.5 ug hCG on day 3 following oocyte pick-up was performed. The main outcome measures were clinical pregnancy rates and ovarian hyperstimulation syndrome (OHSS). RESULTS: E2 and progesterone levels increased after the rescue hCG bolus administration (E2 from 643.4 +/- 311.1 to 1,086.1 +/- 574.7 pg/mL, p = 0.003 and progesterone from 13.1 +/- 4.8 to 39.2 +/- 28.7 ng/mL, p < 0.0001). The clinical pregnancy rates were 25% in the freeze-all group and 32% in the rescue hCG group (p = 0.57). OHSS was not reported in either group. CONCLUSIONS: Both strategies seem to be efficacious and safe. An upper limit of 20 retrieved oocytes appears to be safe for applying a rescue hCG strategy. PMID- 28848207 TI - Correlations of Galectin-3 Gene Polymorphisms with Risk and Prognosis of Cervical Cancer in Chinese Populations: A Case-Control Study. AB - BACKGROUND: This study explores correlations of galectin-3 gene polymorphisms (rs4644, rs4652, and rs11125) with cervical cancer risk and prognosis in Chinese populations. METHODS: A total of 126 patients with cervical cancer were selected to form the case group, and 102 healthy people were selected for the control group following a physical examination. 3 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The distribution frequencies of the CC+CA genotype of rs4652 and the AT+TT genotype of rs11125 in the case group were remarkably higher than those in the control group. rs4644 only had correlations with tumor diameter, while rs4652 and rs11125 had correlations with tumor diameter, FIGO staging, differentiation grades, clinical staging, lymph node metastasis (LNM), and treatment modality. The 5-years survival rate of patients with CC+CA of rs4652 was lower but the recurrence rate was higher compared to AA type patients. In contrast, AA type patients with rs11125 had a higher 5-year survival rate but a lower recurrence rate than those of AT+TT type. CC+CA genotype of rs4652, AT+TT genotype of rs11125, and treatment modality were independent factors related to overall survival and disease-free survival, and LNM was an independent factor related to OS. CONCLUSION: Our findings provide evidence that allele C of rs4652 and allele T of rs11125 in the galectin-3 gene may be risk factors for cervical cancer. PMID- 28848208 TI - Epidemiology of Multiple Sclerosis in Austria. AB - BACKGROUND: To assess the incidence rate and prevalence ratio of multiple sclerosis (MS) in Austria. METHODS: Hospital discharge diagnosis and MS-specific immunomodulatory treatment prescriptions from public health insurances, covering 98% of Austrian citizens with health insurance were used to extrapolate incidence and prevalence numbers based on the capture-recapture method. RESULTS: A total of 1,392,629 medication prescriptions and 40,956 hospitalizations were extracted from 2 data sources, leading to a total of 13,205 patients. The incidence rate and prevalence ratio of MS in Austria based on the capture-recapture method were 19.5/100,000 person-years (95% CI 14.3-24.7) and 158.9/100,000 (95% CI 141.2 175.9), respectively. Female to male ratio was 1.6 for incidence and 2.2 for prevalence. CONCLUSIONS: Incidence rates and prevalence ratios of MS in our study are within the upper range of comparable studies across many European countries as well as the United States. PMID- 28848209 TI - Cancer Genomics and Public Health. PMID- 28848210 TI - Clinical Effectiveness and Safety Outcomes of Endovascular Treatment for Acute Anterior Circulation Ischemic Stroke in China. AB - BACKGROUNDS AND PURPOSE: This study was aimed at investigating the outcomes and predictors for the poor functional outcome after endovascular treatment (EVT) in a large, mostly Asian population. METHODS: Between January 2014 and June 2016, acute stroke patients with anterior circulation occlusion and EVT were retrospectively enrolled from 21 stroke centers in China. The main outcomes were modified Rankin Scale (0-2 as functional independence, 3-6 as poor) at 90 days, symptomatic intracranial hemorrhage (sICH) at 72 h, and death at 90 days. Logistic regression was used to identify predictors for poor functional outcome at 90 days. RESULTS: Of the 698 patients, 304 (43.6%) patients had functional independence at 90 days. The sICH rate was 15.5% (108/698) and mortality rate at 90 days was 25.4% (177/698). Age (OR 1.04, 95% CI 1.02-1.07), National Institutes of Health Stroke Scale score at admission (11-20 vs. <=10, OR 2.38, 95% CI 1.23 4.59; >=21 vs. <=10, OR 3.66, 95% CI 1.72-7.80), baseline glucose level (OR 1.09, 95% CI 1.01-1.18), onset to groin puncture >6 h (OR 1.88, 95% CI 1.06-3.31), sICH (OR 15.49, 95% CI 5.16-46.43), and pneumonia (OR 3.15, 95% CI 1.86-5.32) were independent predictors of poor functional outcomes, while good recanalization (OR 0.26, 95% CI 0.13-0.54), preoperative Alberta Stroke Program Early CT Score 8-10 (OR 0.48, 95% CI 0.28-0.83), and good collateral flow (OR 0.50, 95% CI 0.32-0.79) were protective factors. CONCLUSIONS: This study provides evidence in real world to support the performance of EVT in acute anterior circulation stroke patients in Chinese population. Patients with small infarct core, successful recanalization, good collateral status, and short treatment delay without sICH or pneumonia may benefit from EVT. PMID- 28848211 TI - Association Between MGMT Promoter Methylation and Breast Cancer: a Meta-Analysis. AB - BACKGROUND/AIMS: Numerous studies have suggested that the promoter methylation status of O6-methylguanine-DNA methyltransferase (MGMT) is significantly associated with breast cancer. However, these studies have not demonstrated consistent results. METHODS: To obtain more accurate results for this possible association, we performed a meta-analysis-based study using the relevant data. A total of 14 articles were included in this meta-analysis. RESULTS: Our study showed that the frequency of MGMT promoter methylation was significantly higher in patients with breast cancer than non-breast cancer subjects with an Odds Ratio (OR) of 4.47, a 95% Confidence Interval (CI) ranging between 1.95 - 10.25 and a P value of 0.0004. Moreover, MGMT methylation was significantly associated with the negative expression of the MGMT protein (OR = 4.65, 95%CI = 2.66 - 8.12, P < 0.00001), Oestrogen Receptor (ER)-negative tumours (OR = 1.79, 95%CI = 1.09 - 2.93, P = 0.02), postmenopausal status (OR =1.84, 95%CI = 1.18 - 2.87, P = 0.007) and histological grade III tumours (OR = 2.49, 95%CI = 1.53 - 4.07, P = 0.0003) in breast cancer patients. However, breast cancer was not significantly correlated with lymph node metastasis (OR = 1.19, 95%CI = 0.83 - 1.70, P = 0.35), Progesterone Receptor (PR) status (OR = 1.08, 95%CI = 0.58 - 2.00, P = 0.81), Human epidermal growth factor receptor - 2(HER-2/neu)status (OR = 1.01, 95%CI = 0.65 - 1.57, P = 0.97), P53 mutation (OR = 1.30, 95%CI = 0.76 - 2.21, P = 0.34) and age > 50 (OR = 1.07, 95%CI = 0.46 - 2.51, P = 0.88). CONCLUSIONS: Our study suggests that MGMT promoter methylation may be an early biomarker for the diagnosis of breast cancer. PMID- 28848212 TI - Comparison of Three Different Cranio-Cervical Decompression Procedures in Children with Chiari Malformation Type I: Does the Surgical Technique Matter? AB - BACKGROUND/AIMS: A broad spectrum of cranio-cervical decompression techniques (CCD) is employed for the treatment of Chiari malformation type I (CM1). The aim of this study was to compare the clinical and radiological outcome of 3 different CCD performed in a single paediatric centre. METHODS: A retrospective analysis of children treated between 2008 and 2014 was performed. Three different surgical techniques were offered to the patients: an extradural osseo-ligamentous bony decompression (BD), or a BD plus opening of the dura either without duroplasty (DOWD) or with watertight expansile duroplasty (DOPD). The primary clinical outcome was measured by utilizing the Chicago Chiari Outcome Scale (CCOS). RESULTS: Forty-six children underwent 51 CCD: 17 BD, 17 DOWD, and 17 DOPD. The median follow-up period was 46 months (16-98 months). Patients who underwent BD had a shorter length of hospital stay than those who underwent DPTC and DOWD. Clinical improvement, defined by the mean CCOS score, was comparable in patients receiving BD (n = 14.6) and DOPD (n = 14.5), but lower in patients with DOWD (n = 12). Post-operative complications were noted in 7 DOWD patients (41%) and 3 DOPD patients (17.6%). CONCLUSIONS: BD is a safe and effective procedure with comparable clinical and radiological outcomes to DOPD in children with CM1. The risk of post-operative complications and worse clinical outcome was noted to be higher when performing a DOWD. PMID- 28848213 TI - Increases in Intracellular Zinc Enhance Proliferative Signaling as well as Mitochondrial and Endolysosomal Activity in Human Melanocytes. AB - BACKGROUND/AIMS: Zinc (Zn) is an important microelement required by skin cells for a variety of biological processes. The role of Zn in melanocyte proliferation and homeostasis has to date not been investigated. METHODS: Human dermal melanocytes were isolated from patients and their proliferative activity determined along with both total and labile Zn content. Subsequently, changes in proliferation as well as in Zn content were determined upon exposure of the dermal melanocytes to external Zn. Further in-depth analyses were undertaken aimed at measuring the expression of proliferation-related proteins (determined by immunoblotting and densitometry), as well as changes in mitochondrial biogenesis and membrane potential (assessed by fluorescence-based cellometry) along with endolysosomal activity (determined by spectrofluorimetrically-measured elevation in fluorescence of lysosomal-aimed non-fuorescent substrate). RESULTS: Human skin melanocytes accumulate externally added Zn, a process which dose dependently enhances their injury or proliferative activity. Enhanced proliferation is accompanied by an increased expression of the proteins AKT3, ERK1/2, c-MYC and CYCD. In addition, Zn-enriched melanocytes exhibit enhanced mitochondrial biogenesis, with individual mitochondria possessing stabilized mitochondrial membrane potential as well as showing elevated ATP and superoxide levels. Moreover, upon external exposure, Zn enters lysosomes/melanosomes, the activity of which is stimulated along with the process of autophagy. CONCLUSION: The determination of the unique Zn-dependent stimulation of melanocytes and in particular the enhancement of the cells' mitochondrial as well as lysosomal/melanosomal activities may prove important in tracing the sequence of steps in the process of melanomagenesis. PMID- 28848214 TI - Cortical Functional Connections and Fluid Intelligence in Adolescent APOE epsilon4 Carriers. AB - AIMS: This study examined differences in corticocortical communication between adolescent epsilon4 carriers (epsilon4+) and noncarriers (epsilon4-) during a fluid intelligence task (Comprehensive Test of Nonverbal Intelligence [CTONI]). METHODS: Sixteen epsilon4+ and 20 epsilon4- individuals aged 13-15 years performed the CTONI while real-time EEG signals were acquired. Inter- and intrahemispheric coherences were analyzed. RESULTS: The epsilon4+ subjects exhibited lower inter- and intrahemispheric coherences than the epsilon4- individuals. CONCLUSION: epsilon4 carriers have lower corticocortical communication than noncarriers during an intelligence task, implying that carrying the epsilon4 allele may reduce brain networking in adolescence, several decades before the onset of Alzheimer disease. PMID- 28848215 TI - Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models. AB - BACKGROUND/AIMS: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. METHODS: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC(r). Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. RESULTS: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. CONCLUSION: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition. PMID- 28848216 TI - Ultrasound-Guided Bipolar Umbilical Cord Occlusion in Complicated Monochorionic Pregnancies: Is There a Learning Curve. AB - INTRODUCTION: Ultrasound-guided bipolar umbilical cord occlusion (UCO) is used in complicated monochorionic multiple pregnancies in Denmark. The aim of this study was to assess a learning curve in the procedure of UCO. MATERIALS AND METHODS: One hundred and two monochorionic pregnancies treated with UCO at Rigshospitalet, Denmark between 2004 and 2015 were included. The procedures were divided into period 1 (2004-2009) and period 2 (2010-2015) to determine a learning curve. Primary outcome measure was survival rate. Secondary outcome measures were time from operation to fetal loss and gestational age (GA) at delivery. RESULTS: Period 1 included 59 cases. The median GA at procedure was 19.9 weeks (range 16.7 25.9) and at delivery 34.7 weeks (range 24.3-40.3). Period 2 included 43 cases. The median GA at procedure was 20.7 weeks (range 16.7-27.6) and at delivery 37.3 weeks (range 29.1-40.3). Survival rate increased from 78% (period 1) to 95% (period 2) (p = 0.02). GA at delivery increased as well. Fetal death within 48 h after surgery decreased from 4 (period 1) to 0 (period 2). DISCUSSION: Our results suggest a learning curve in the procedure of UCO with improved outcome on all measures. PMID- 28848217 TI - The Implications of DNA Methylation on Food Allergy. AB - Food allergy is a major clinical and public health concern worldwide. The risk factors are well defined, however, the mechanisms by which they affect immune development remain largely unknown, and unfortunately the effective treatment or prevention of food allergy is still being researched. Recent studies show that the genes that are critical for the development of food allergy are regulated through DNA methylation. Environmental factors can affect host DNA methylation status and subsequently predispose people to food allergy. DNA methylation is therefore an important mediator of gene-environment interactions in food allergy and key to understanding the mechanisms underlying the allergic development. Indeed, the modification and identification of the methylation levels of specific genetic loci have gained increasing attention for therapeutic and diagnostic application in combating food allergy. In this review, we summarize and discuss the recent developments of DNA methylation in food allergy, including the pathogenesis, therapy, and diagnosis. This review will also summarize and discuss the environmental factors that affect DNA methylation levels in food allergy. PMID- 28848218 TI - Adjuvant Small Pelvic Radiotherapy in Patients with Cervical Cancer Having Intermediate Risk Factors Only - Is It Sufficient? AB - BACKGROUND: We sought to determine the outcomes of adjuvant small pelvic external beam radiotherapy (EBRT) and prognostic factors for survival and disease control. PATIENTS AND METHODS: We retrospectively evaluated 113 cervical cancer patients treated with postoperative median 50.4-Gy small pelvic EBRT. We treated the surgical bed, bilateral parametria, paravaginal soft tissues, upper third of the vagina, and presacral lymphatics. RESULTS: Median follow-up of all patients and survivors was 58 and 67 months, respectively. The 2- and 5-year overall survival (OS) and disease-free survival rates were 91 and 82%, and 85 and 74%, respectively. The locoregional failure rate was 10%. Age was a significant predictor for OS and distant metastasis-free survival (DMFS) on univariate analysis. The number of dissected lymph nodes being < 30 negatively affected the pelvic recurrence-free survival. The only independent predictor on multivariate analysis was older age for DMFS. Although no severe acute toxicity was observed, late grade >= 3 toxicity developed in 8 patients. CONCLUSION: Small pelvic EBRT produces satisfactory survival and locoregional control with acceptable toxicity, and can be an alternative to whole pelvic EBRT in selected cervical cancer patients. PMID- 28848219 TI - Cancer Genomic Resources and Present Needs in the Latin American Region. AB - In Latin America (LA), cancer is the second leading cause of death, and little is known about the capacities and needs for the development of research in the field of cancer genomics. In order to evaluate the current capacity for and development of cancer genomics in LA, we collected the available information on genomics, including the number of next-generation sequencing (NGS) platforms, the number of cancer research institutions and research groups, publications in the last 10 years, educational programs, and related national cancer control policies. Currently, there are 221 NGS platforms and 118 research groups in LA developing cancer genomics projects. A total of 272 articles in the field of cancer genetics/genomics were published by authors affiliated to Latin American institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs, and only few are concerning cancer. Only 14 countries have national cancer control plans, but all of them consider secondary prevention strategies for early diagnosis, opportune treatment, and decreasing mortality, where genomic analyses could be implemented. Despite recent advances in introducing knowledge about cancer genomics and its application to LA, the region lacks development of integrated genomic research projects, improved use of NGS platforms, implementation of associated educational programs, and health policies that could have an impact on cancer care. PMID- 28848220 TI - Clinical Impact of Aprepitant in Patients Receiving High-Dose Chemotherapy prior to Autologous Peripheral Blood Stem Cell Transplantation: A Cost-Effectiveness Analysis. AB - OBJECTIVE: To evaluate the clinical and cost benefits of the administration of aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) during high-dose chemotherapy (HDCT). METHODS: We retrospectively reviewed the charts of patients who received HDCT at our institution between January 2009 and December 2013. Cost-effectiveness was analyzed using direct medical costs. RESULTS: We identified a total of 38 patients (27 with non-Hodgkin lymphoma and 11 with multiple myeloma). Thirteen patients received aprepitant and granisetron (aprepitant group) for CINV prophylaxis, whereas 25 patients received granisetron only (non-aprepitant group). The incidence of severe nausea (>=grade 3) was significantly lower in the aprepitant group than in the non-aprepitant group (p = 0.039). The total mean cost per patient during hospitalization, excluding the cost of HDCT and transplantation, was USD 10,941.8 in the aprepitant group and USD 14,577.2 in the non-aprepitant group (p = 0.041). This cost benefit reflected reductions in the costs of hospitalization, transfusion, and infection treatment. CONCLUSIONS: Our data indicated that the addition of aprepitant for CINV prophylaxis during HDCT reduced the incidence of severe nausea and might also provide economic benefit in the overall management of HDCT prior to autologous peripheral blood stem cell transplantation. PMID- 28848221 TI - Ophthalmic Start-Up Chief Executive Officers' Perceptions of Development Hurdles. AB - PURPOSE: To identify current challenges facing ophthalmic pharmaceutical start ups in developing new products. METHODS: Surveys were distributed to the chief executive officer (CEO) or president of ophthalmic start-ups. RESULTS: The survey attracted 24 responses from 78 surveys distributed (31%). The CEOs stated that a lack of financial capital (n = 18, 75%), FDA regulations (n = 6, 25%), and failure to meet clinical endpoints (n = 6, 25%) were their greatest development hurdles. Risk aversion to medicines in early development (n = 18, 75%), mergers and acquisitions reducing corporate choice for licensing agreements (n = 7, 29%), the emergence of large pharmaceutical-based venture capital funding groups (n = 12, 50%), and the failure of many large pharmaceutical companies to develop their own medicines (n = 10, 42%) were noted as recent prominent trends affecting fundraising. CONCLUSION: The study suggests that development funding, regulatory burden, and meeting clinical endpoints are the greatest development challenges faced by ophthalmic start-up CEOs. PMID- 28848222 TI - Effects of Incubation Temperature on the Expression of Sex-Related Genes in the Chinese Pond Turtle, Mauremys reevesii. AB - Despite widespread temperature-dependent sex determination (TSD) in reptiles, it is still unclear how the molecular network responds to temperature variation and drives the sexual fate. Profiling of sex-related genes is the first step in understanding the sex determination system in reptiles. In this study, we cloned the full-length coding sequences of Cyp19a1, Foxl2, Rspo1, Sf1, and Sox9 in an Asian freshwater turtle (Mauremys reevesii) with TSD and identified the expression patterns of these genes and Dmrt1 at different incubation temperatures to understand their roles in urogenital development. Our results showed that Cyp19a1, Foxl2, and Rspo1 were expressed in the adrenal-kidney-gonadal complex at a high level in females, while Sf1 and Dmrt1 were highly expressed in males. In addition, Foxl2 and Rspo1 showed sex-dimorphic expression in the presumed early thermosensitive period (TSP), Dmrt1 was upregulated at the beginning of the presumed TSP, and Sox9 did not show sex-dimorphic expression until the end of the presumed TSP. These results suggest that Foxl2 and Rspo1 are probably upstream genes involved in female sex determination and that Dmrt1 may be a key factor in male sex determination. Therefore, our study provides a solid foundation for further investigations on the molecular mechanism underlying sex determination in M. reevesii. PMID- 28848223 TI - Mechanistic Evaluation of the Protective Effect of Carnosine on Acute Lung Injury in Sepsis Rats. AB - This study analyzes the sepsis healing therapeutic potential of carnosine against experimentally sepsis-induced male albino rats. Carnosine in 2 different doses, 25 mg/kg and 50 mg/kg, were administered for 30 consecutive days. At the end of the treatment, lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase and myeloperoxidase activities were measured. Lungs weight and total protein content were determined in the bronchoalveolar fluid (BALF). Cytokines such as macrophage inhibitory factor (MIF), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) were determined in the BALF. In addition, the histopathological analysis was also carried out to understand the effect of carnosine in the cellular architecture. Carnosine treatment significantly renormalized the lipid peroxidation and other antioxidant enzymes. IL-beta, TNF alpha, and MIF were found to be reduced after carnosine treatment. After carnosine treatment, the intensity of sepsis was significantly reduced evidenced by histopathological analysis. In western blot analysis, carnosine treatment causes the upregulation of IkappaBalpha together with the downregulation of the expressions of p65 and p-IKKalpha/beta (Ser 180/Ser 181). PMID- 28848224 TI - Bilateral Femoral Neuropathy Following Psoas Muscle Hematomas Caused by Enoxaparin Therapy. AB - BACKGROUND Femoral neuropathy as a result of retroperitoneal hemorrhage most commonly occurs following pelvic and lower extremity trauma, but has been described to develop as a less frequent complication of anticoagulation. CASE REPORT We present the case of a 64-year-old white woman who was being treated for pulmonary embolism and deep venous thrombosis with enoxaparin. In the course of her treatment, she was noted to be hypotensive, with a sudden drop in hematocrit. She had been previously ambulatory, but noted an inability to move her bilateral lower extremities. A diagnosis of bilateral femoral neuropathy as a result of psoas hematomas caused by enoxaparin was made. Anticoagulation was discontinued and she was treated conservatively, with an excellent outcome. At the time of discharge to a rehabilitation center, she had regained most of the motor strength in her lower extremities. CONCLUSIONS We believe this is the first reported case of bilateral femoral nerve neuropathy following use of enoxaparin. A full neurological examination should always be performed when there is sudden loss of function. The constellation of bilateral groin pain, loss of lower extremity mobility, and decreased hematocrit raised the suspicion of massive blood loss into the cavity/compartment. Thus, a high index of suspicion should be maintained by clinicians when presented with such symptoms and signs, as there can be significant morbidity and mortality when prompt diagnosis is not made. PMID- 28848225 TI - Effect of Magnesium Supplements on Insulin Secretion After Kidney Transplantation: A Randomized Controlled Trial. AB - BACKGROUND Hypomagnesemia is associated with a disturbed glucose metabolism. Insulin hypo-secretion predicts diabetes in the general population and in transplant recipients. We aimed to assess whether magnesium improves insulin secretion and glycemic control after transplantation in prevalent hypomagnesemic kidney transplant recipients. MATERIAL AND METHODS We conducted an open-label, randomized, parallel-group study. Eligible participants were adults more than 4 months after kidney transplantation on tacrolimus with persisting serum magnesium concentrations <1.8 mg/dL randomized to magnesium oxide supplementation up to a maximum of 3 times 450 mg daily (N=26) or no supplements (N=26). Insulin secretion was assessed by OGTT-derived, first-phase insulin secretion (FPIR). The primary endpoint was the mean difference in FPIR between baseline and 6 months after randomization. Secondary endpoints were differences in HbA1c and insulin resistance, measured by HOMA. Dietary magnesium was assessed by a food-frequency questionnaire. All analyses were done on an intention-to-treat basis. RESULTS Magnesium with a mean daily dose of 688+/-237mg in the treatment group failed to lead to significant differences between the 2 groups in FPIR, fasting glucose, HbA1c, or HOMA-IR. Persisting hypomagnesemia was very common and associated with more insulin hypo-secretion, glucose intolerance, and lower dietary magnesium intake (142+/-56 versus 202+/-90 mg; p=0.015) as compared to patients with a rise in serum magnesium over 6 months. CONCLUSIONS Magnesium supplementation does not improve insulin secretion in stable hypomagnesemic kidney transplant recipients on tacrolimus. Persisting hypomagnesemia is associated with impaired glucose tolerance, insulin hypo-secretion, and dietary factors. PMID- 28848226 TI - Treatment of Lumbar Tuberculosis by Mini-Open Anterior Approach Focal Cleaning Combined with Posterior Internal Fixation. AB - BACKGROUND The aim of this study was to evaluate the efficiency and clinical outcomes of mini-open anterior approach focal cleaning combined with posterior internal fixation compared to conventional anterior extraperitoneal approach focal cleaning combined with posterior internal fixation in the treatment of lumbar tuberculosis (TB). MATERIAL AND METHODS Medical records from 124 patients were collected from February 2010 to April 2015; patients were divided into two groups: group A (mini-open anterior approach focal cleaning combined with posterior internal fixation) and group B (conventional anterior extraperitoneal approach focal cleaning combined with posterior internal fixation in period I). The data on postoperative mechanical ventilation time, preoperative, postoperative, and last follow-up Cobb angle, visual analog scale (VAS), erythrocyte sedimentation rate (ESR), and Frankel classification were collected and analyzed. Operative complications, internal stability, and bone graft fusion were also observed. RESULTS All patients were followed-up for 12 to 36 months (average 22.5 months). Seven cases (five in group A and two in group B) had side psoas abscess and were cured after secondary drainage surgery. The rest of the cases were all cured after primary surgery, with no formation of sinus, incisional hernia, cerebrospinal fluid leakage, or recurrence of spinal TB, with no TB symptoms. Bone graft fusion ranged from 3 to 8 months (average 4.7 months). Compared to group B, group A, which had less time on postoperative mechanical ventilation, had a higher VAS score. Both groups had distinct improvements in Cobb angle, ESR, and Frankel classification after surgery. CONCLUSIONS Treating lumbar TB by mini-open anterior approach focal cleaning combined with posterior internal fixation was safe and effective. PMID- 28848227 TI - Outcomes of maintenance therapy with lenalidomide or bortezomib in multiple myeloma in the setting of early autologous stem cell transplantation. AB - Post-transplant maintenance is widely used in multiple myeloma (MM); however, there is a lack of data on real-world outcomes. We have analyzed 577 patients with newly diagnosed MM undergoing early auto-transplantation between 2010 and 2015. A total of 341, 132 and 104 patients received no, lenalidomide (Len) or bortezomib (Bort) maintenance, respectively. Patients receiving Len or Bort maintenance had a higher incidence of high-risk cytogenetics by fluorescence in situ hybridization (31% (Len) vs 58% (Bort) vs 8% (No); P<0.001). Len maintenance led to a superior progression-free survival (PFS) compared with no maintenance (median, 37 vs 28 months, respectively; P=0.002; adjusted hazard ratio 0.48 (95% CI, 0.35-0.66)), including in subgroups with ISS stage III disease (median, 40 vs 24 months; P=0.008) and high-risk cytogenetics (median, 27 vs 16 months; P=0.032). Bort maintenance did not confer PFS benefit for the entire cohort, but improved PFS in the high-risk cytogenetic subgroup (median, 28 vs 16 months; P=0.035). Discontinuation due to toxicity was seen in 17 and 7% of patients receiving Len or Bort maintenance, respectively. Our results indicate that post transplant maintenance with Len or Bort is well tolerated in clinical practice and improves PFS in high-risk subgroups of MM patients. PMID- 28848228 TI - Efficient invasion by Toxoplasma depends on the subversion of host protein networks. AB - Apicomplexan parasites are important pathogens of humans and domestic animals, including Plasmodium species (the agents of malaria) and Toxoplasma gondii, which is responsible for toxoplasmosis. They replicate within the cells of their animal hosts, to which they gain access using a unique parasite-driven invasion process. At the core of the invasion machine is a structure at the interface between the invading parasite and host cell called the moving junction (MJ) 1 . The MJ serves as both a molecular doorway to the host cell and an anchor point enabling the parasite to engage its motility machinery to drive the penetration of the host cell 2 , ultimately yielding a protective vacuole 3 . The MJ is established through self-assembly of parasite proteins at the parasite-host interface 4 . However, it is unknown whether host proteins are subverted for MJ formation. Here, we show that Toxoplasma parasite rhoptry neck proteins (RON2, RON4 and RON5) cooperate to actively recruit the host CIN85, CD2AP and the ESCRT-I components ALIX and TSG101 to the MJ during invasion. We map the interactions in detail and demonstrate that the parasite mimics and subverts conserved binding interfaces with remarkable specificity. Parasite mutants unable to recruit these host proteins show inefficient host cell invasion in culture and attenuated virulence in mice. This study reveals molecular mechanisms by which parasites subvert widely conserved host machinery to force highly efficient host cell access. PMID- 28848229 TI - Interactions between fibroblastic reticular cells and B cells promote mesenteric lymph node lymphangiogenesis. AB - Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. Here we demonstrate a crucial role for lymphotoxin-beta receptor (LTbetaR) signaling to fibroblastic reticular cells (FRCs) by lymphotoxin expressing B cells in driving mesenteric lymph node lymphangiogenesis following helminth infection. LTbetaR ligation on fibroblastic reticular cells leads to the production of B-cell-activating factor (BAF F), which synergized with interleukin 4 (IL-4) to promote the production of the lymphangiogenic factors, vascular endothelial growth factors (VEGF)-A and VEGF-C, by B cells. In addition, the BAFF IL-4 synergy augments expression of lymphotoxin by antigen-activated B cells, promoting further B cell-fibroblastic reticular cell interactions. These results underlie the importance of lymphotoxin-dependent B cell-FRC cross talk in driving the expansion of lymphatic networks that function to promote and maintain immune responsiveness.The growth of lymph nodes in response to infection requires lymphangiogenesis. Dubey et al. show that the mesenteric lymph node lymphangiogenesis upon helminth infection depends on the signaling loop between the B and fibroblastic reticular cells (FRCs), whereby the FRCs respond to lymphotoxin secreted by B cells by releasing B cell activating factor. PMID- 28848230 TI - Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation. AB - Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice. Peripheral blood mononuclear cells isolated from CHIKV-infected patients showed elevated NLRP3, caspase-1 and interleukin-18 messenger RNA expression and, using a mouse model of CHIKV infection, we found that high NLRP3 expression was associated with peak inflammatory symptoms. Inhibition of NLRP3 activation using the small-molecule inhibitor MCC950 resulted in reduced CHIKV-induced inflammation and abrogated osteoclastogenic bone loss and myositis, but did not affect in vivo viral replication. Mice treated with MCC950 displayed lower expression levels of the cytokines interleukin-6, chemokine ligand 2 and tumour necrosis factor in joint tissue. Interestingly, MCC950 treatment abrogated disease signs in mice infected with a related arthritogenic alphavirus, Ross River virus, but not in mice infected with West Nile virus-a flavivirus. Here, using mouse models of alphavirus-induced musculoskeletal disease, we demonstrate that NLRP3 inhibition in vivo can reduce inflammatory pathology and that further development of therapeutic solutions targeting inflammasome function could help treat arboviral diseases. PMID- 28848231 TI - Observation of ultrahigh mobility surface states in a topological crystalline insulator by infrared spectroscopy. AB - Topological crystalline insulators possess metallic surface states protected by crystalline symmetry, which are a versatile platform for exploring topological phenomena and potential applications. However, progress in this field has been hindered by the challenge to probe optical and transport properties of the surface states owing to the presence of bulk carriers. Here, we report infrared reflectance measurements of a topological crystalline insulator, (001)-oriented Pb1-x Sn x Se in zero and high magnetic fields. We demonstrate that the far infrared conductivity is unexpectedly dominated by the surface states as a result of their unique band structure and the consequent small infrared penetration depth. Moreover, our experiments yield a surface mobility of 40,000 cm2 V-1 s-1, which is one of the highest reported values in topological materials, suggesting the viability of surface-dominated conduction in thin topological crystalline insulator crystals. These findings pave the way for exploring many exotic transport and optical phenomena and applications predicted for topological crystalline insulators.Probing optical and transport properties of the surface states in topological crystalline insulators remains a challenge. Here, Wang et al. demonstrate that the far-infrared conductivity of Pb1-x Sn x Se (x = 0.23 0.25) single crystals is dominated by the surface states where carriers show a high surface mobility of 40,000 cm2 V-1 s-1. PMID- 28848232 TI - A reporter system coupled with high-throughput sequencing unveils key bacterial transcription and translation determinants. AB - Quantitative analysis of the sequence determinants of transcription and translation regulation is relevant for systems and synthetic biology. To identify these determinants, researchers have developed different methods of screening random libraries using fluorescent reporters or antibiotic resistance genes. Here, we have implemented a generic approach called ELM-seq (expression level monitoring by DNA methylation) that overcomes the technical limitations of such classic reporters. ELM-seq uses DamID (Escherichia coli DNA adenine methylase as a reporter coupled with methylation-sensitive restriction enzyme digestion and high-throughput sequencing) to enable in vivo quantitative analyses of upstream regulatory sequences. Using the genome-reduced bacterium Mycoplasma pneumoniae, we show that ELM-seq has a large dynamic range and causes minimal toxicity. We use ELM-seq to determine key sequences (known and putatively novel) of promoter and untranslated regions that influence transcription and translation efficiency. Applying ELM-seq to other organisms will help us to further understand gene expression and guide synthetic biology.Quantitative analysis of how DNA sequence determines transcription and translation regulation is of interest to systems and synthetic biologists. Here the authors present ELM-seq, which uses Dam activity as reporter for high-throughput analysis of promoter and 5'-UTR regions. PMID- 28848233 TI - The R-loop is a common chromatin feature of the Arabidopsis genome. AB - R-loops are functional structures in chromatin comprising one single-stranded DNA and a DNA:RNA hybrid. Here, we report ssDRIP-seq, a single-strand DNA ligation based library preparation technique for genome-wide identification of R-loops. When applied in Arabidopsis, ssDRIP-seq exhibits high efficiency, low bias and strand specificity. We found that Arabidopsis R-loops are enriched by both AT and GC skews, and are formed in the sense and antisense orientations. R-loops are strongly enriched in gene promoters and gene bodies, and are highly associated with noncoding RNA and repetitive genomic regions. Furthermore, R-loops are negatively correlated with CG DNA hypermethylation, and are prevalent in regions with multiple chromatin modifications, showing strong correlations with the activated and repressed gene loci. Our analyses indicate that R-loops are common features in the Arabidopsis genome and suggest that the R-loops play diverse roles in genome organization and gene regulation, thereby providing insights into plant nuclear genome formation and function. PMID- 28848235 TI - Analysis of the miR-34 family functions in breast cancer reveals annotation error of miR-34b. AB - The microRNAs in the miR-34 family, consisting of miR-34a, miR-34b and miR-34c, are tumour suppressors. The annotated human miR-34b-5p has one additional base at the 5' end of the common miR-34 family seed sequence, compared to miR-34a-5p and miR-34c-5p. This extra base results in a shift of the seed sequence, which would affect the target gene repertoire and have functional consequences. During our studies of miR-34 functions, we investigated the precise sequence of mature miR 34b-5p in human cells by deep sequencing. We found that a miR-34b-5p without the extra base was the predominant form in both non-malignant and malignant cells derived from several human tissues, indicating that the miR-34b annotation is misleading. We evaluated the functional implications of the seed shift, by comparing the effect of mimics representing the alternative miR-34b-5p sequences in MDA-MB-231 cells. In contrast to the annotated miR-34b, the endogenously expressed miR-34b displayed tumour suppressive characteristics in vitro similarly to miR-34c. These data demonstrate the importance of determining the precise sequence of a mature microRNA before exploring miRNA functions. PMID- 28848234 TI - Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder. AB - Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes. PMID- 28848236 TI - Occurrence of Corynebacterium striatum as an emerging antibiotic-resistant nosocomial pathogen in a Tunisian hospital. AB - Corynebacterium striatum is a nosocomial opportunistic pathogen increasingly associated with a wide range of human infections and is often resistant to several antibiotics. We investigated the susceptibility of 63 C. striatum isolated at the Farhat-Hached hospital, Sousse (Tunisia), during the period 2011 2014, to a panel of 16 compounds belonging to the main clinically relevant classes of antimicrobial agents. All strains were susceptible to vancomycin, linezolid, and daptomycin. Amikacin and gentamicin also showed good activity (MICs90 = 1 and 2 mg/L, respectively). High rates of resistance to penicillin (82.5%), clindamycin (79.4%), cefotaxime (60.3%), erythromycin (47.6%), ciprofloxacin (36.5%), moxifloxacin (34.9%), and rifampicin (25.4%) were observed. Fifty-nine (93.7%) out of the 63 isolates showed resistance to at least one compound and 31 (49.2%) were multidrug-resistant. Twenty-nine resistance profiles were distinguished among the 59 resistant C. striatum. Most of the strains resistant to fluoroquinolones showed a double mutation leading to an amino acid change in positions 87 and 91 in the quinolone resistance-determining region of the gyrA gene. The 52 strains resistant to penicillin were positive for the gene bla, encoding a class A beta-lactamase. Twenty-two PFGE patterns were identified among the 63 C. striatum, indicating that some clones have spread within the hospital. PMID- 28848237 TI - Thermally-drawn fibers with spatially-selective porous domains. AB - The control of mass transport using porous fibers is ubiquitous, with applications ranging from filtration to catalysis. Yet, to date, porous fibers have been made of single materials in simple geometries, with limited function. Here we report the fabrication and characterization of thermally drawn multimaterial fibers encompassing internal porous domains alongside non-porous insulating and conductive materials, in highly controlled device geometries. Our approach utilizes phase separation of a polymer solution during the preform-to fiber drawing process, generating porosity as the fiber is drawn. Engineering the preform structure grants control over the geometry and materials architecture of the final porous fibers. Electrical conductivity of the selectrolyte-filled porous domains is substantiated through ionic conductivity measurements using electrodes thermally drawn in the cross-section. Pore size tunability between 500 nm-10 um is established by regulating the phase separation kinetics. We further demonstrate capillary breakup of cylindrical porous structures porous microspheres within the fiber core.Porous polymer fibers show great potential for a range of applications, but their simple structures typically limit their functionality. Here, the authors combine a thermal drawing process with polymer solution phase separation to fabricate porous multimaterial fibers with complex internal architectures. PMID- 28848238 TI - A microfluidics-based in situ chemotaxis assay to study the behaviour of aquatic microbial communities. AB - Microbial interactions influence the productivity and biogeochemistry of the ocean, yet they occur in miniscule volumes that cannot be sampled by traditional oceanographic techniques. To investigate the behaviours of marine microorganisms at spatially relevant scales, we engineered an in situ chemotaxis assay (ISCA) based on microfluidic technology. Here, we describe the fabrication, testing and first field results of the ISCA, demonstrating its value in accessing the microbial behaviours that shape marine ecosystems. PMID- 28848239 TI - Hybrids in the chromatin. PMID- 28848240 TI - Redox reactions and weak buffering capacity lead to acidification in the Chesapeake Bay. AB - The combined effects of anthropogenic and biological CO2 inputs may lead to more rapid acidification in coastal waters compared to the open ocean. It is less clear, however, how redox reactions would contribute to acidification. Here we report estuarine acidification dynamics based on oxygen, hydrogen sulfide (H2S), pH, dissolved inorganic carbon and total alkalinity data from the Chesapeake Bay, where anthropogenic nutrient inputs have led to eutrophication, hypoxia and anoxia, and low pH. We show that a pH minimum occurs in mid-depths where acids are generated as a result of H2S oxidation in waters mixed upward from the anoxic depths. Our analyses also suggest a large synergistic effect from river-ocean mixing, global and local atmospheric CO2 uptake, and CO2 and acid production from respiration and other redox reactions. Together they lead to a poor acid buffering capacity, severe acidification and increased carbonate mineral dissolution in the USA's largest estuary.The potential contribution of redox reactions to acidification in coastal waters is unclear. Here, using measurements from the Chesapeake Bay, the authors show that pH minimum occurs at mid-depths where acids are produced via hydrogen sulfide oxidation in waters mixed upward from anoxic depths. PMID- 28848243 TI - Prominent topologically associated domains differentiate global chromatin packing in rice from Arabidopsis. AB - The non-random three-dimensional organization of genomes is critical for many cellular processes. Recently, analyses of genome-wide chromatin packing in the model dicot plant Arabidopsis thaliana have been reported 1-4 . At a kilobase scale, the A. thaliana chromatin interaction network is highly correlated with a range of genomic and epigenomic features 1-4 . Surprisingly, topologically associated domains (TADs), which appear to be a prevalent structural feature of genome packing in many animal species, are not prominent in the A. thaliana genome 1,2,4-6 . Using a genome-wide chromatin conformation capture approach, Hi C (ref. 7 ), we report high-resolution chromatin packing patterns of another model plant, rice. We unveil new structural features of chromatin organization at both chromosomal and local levels compared to A. thaliana, with thousands of distinct TADs that cover about a quarter of the rice genome. The rice TAD boundaries are associated with euchromatic epigenetic marks and active gene expression, and enriched with a sequence motif that can be recognized by plant specific TCP proteins. In addition, we report chromosome decondensation in rice seedlings undergoing cold stress, despite local chromatin packing patterns remaining largely unchanged. The substantial variation found already in a comparison of two plant species suggests that chromatin organization in plants might be more diverse than in multicellular animals. PMID- 28848242 TI - Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response. AB - The lack of effective chemotherapies for high-grade serous ovarian cancers (HGS OvCa) has motivated a search for alternative treatment strategies. Here, we present an unbiased systems-approach to interrogate a panel of 14 well-annotated HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors and uncover cell death vulnerabilities. Proteomic analysis reveals that PI3K/mTOR inhibition in HGS-OvCa patient-derived xenografts induces both pro apoptotic and anti-apoptotic signaling responses that limit cell killing, but also primes cells for inhibitors of anti-apoptotic proteins. In-depth quantitative analysis of BCL-2 family proteins and other apoptotic regulators, together with computational modeling and selective anti-apoptotic protein inhibitors, uncovers new mechanistic details about apoptotic regulators that are predictive of drug sensitivity (BIM, caspase-3, BCL-XL) and resistance (MCL-1, XIAP). Our systems-approach presents a strategy for systematic analysis of the mechanisms that limit effective tumor cell killing and the identification of apoptotic vulnerabilities to overcome drug resistance in ovarian and other cancers.High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway. PMID- 28848244 TI - Language-Independent and Language-Specific Aspects of Early Literacy: An Evaluation of the Common Underlying Proficiency Model. AB - According to the common underlying proficiency model (Cummins, 1981), as children acquire academic knowledge and skills in their first language, they also acquire language-independent information about those skills that can be applied when learning a second language. The purpose of this study was to evaluate the relevance of the common underlying proficiency model for the early literacy skills of Spanish-speaking language-minority children using confirmatory factor analysis. Eight hundred fifty-eight Spanish-speaking language-minority preschoolers (mean age = 60.83 months, 50.2% female) participated in this study. Results indicated that bifactor models that consisted of language-independent as well as language-specific early literacy factors provided the best fits to the data for children's phonological awareness and print knowledge skills. Correlated factors models that only included skills specific to Spanish and English provided the best fits to the data for children's oral language skills. Children's language-independent early literacy skills were significantly related across constructs and to language-specific aspects of early literacy. Language-specific aspects of early literacy skills were significantly related within but not across languages. These findings suggest that language-minority preschoolers have a common underlying proficiency for code-related skills but not language-related skills that may allow them to transfer knowledge across languages. PMID- 28848245 TI - Relationship of the Content of Systemic and Endobronchial Soluble Molecules of CD25, CD38, CD8, and HLA-I-CD8 and Lung Function Parameters in COPD Patients. AB - The definition of new markers of local and systemic inflammation of chronic obstructive pulmonary disease (COPD) is one of the priority directions in the study of pathogenesis and diagnostic methods improvement for this disease. We investigated 91 patients with COPD and 21 healthy nonsmokers. The levels of soluble CD25, CD38, CD8, and HLA-I-CD8 molecules in the blood serum and exhaled breath condensate (EBC) in moderate-to-severe COPD patients during exacerbation and stable phase were studied. An unidirectional change in the content of sCD25, sCD38, and sCD8 molecules with increasing severity of COPD was detected. The correlations between the parameters of lung function and sCD8, sCD25, and sHLA-I CD8 levels in the blood serum and EBC were discovered in patients with severe COPD. The findings suggest a pathogenetic role of the investigated soluble molecules of the COPD development and allow considering the content of sCD8, sCD25, and sHLA-I-CD8 molecules as additional novel systemic and endobronchial markers of the progression of chronic inflammation of this disease. PMID- 28848246 TI - Advances in Immunotherapy for Melanoma: A Comprehensive Review. AB - Melanomas are tumors originating from melanocytes and tend to show early metastasis secondary to the loss of cellular adhesion in the primary tumor, resulting in high mortality rates. Cancer-specific active immunotherapy is an experimental form of treatment that stimulates the immune system to recognize antigens on the surface of cancer cells. Current experimental approaches in immunotherapy include vaccines, biochemotherapy, and the transfer of adoptive T cells and dendritic cells. Several types of vaccines, including peptide, viral, and dendritic cell vaccines, are currently under investigation for the treatment of melanoma. These treatments have the same goal as drugs that are already used to stimulate the proliferation of T lymphocytes in order to destroy tumor cells; however, immunotherapies aim to selectively attack the tumor cells of each patient. In this comprehensive review, we describe recent advancements in the development of immunotherapies for melanoma, with a specific focus on the identification of neoantigens for the prediction of their elicited immune responses. This review is expected to provide important insights into the future of immunotherapy for melanoma. PMID- 28848248 TI - Techniques for characterization and eradication of potato cyst nematode: a review. AB - Correct identification of species and pathotypes is must for eradication of potato cyst nematodes (PCN). The identification of PCN species after completing the life cycle is very difficult because it is based on morphological and morphometrical characteristics. Genetically different populations of PCN are morphologically same and differentiated based on the host differential study. Later on these traditional techniques have been replaced by biochemical techniques viz, one and two dimensional gel electrophoresis, capillary gel electrophoresis, isozymes, dot blot hybridization and isoelectric focusing etc. to distinguish both the species. One and two dimensional gel electrophoresis has used to examine inter- and intra-specific differences in proteins of Globodera rostochiensis and G. pallida. Now application of PCR and DNA based characterization techniques like RAPD, AFLP and RFLP are the important tools for differentiating inter- and intra specific variation in PCN and has given opportunities to accurate identification of PCN. For managing the PCN, till now we are following integrated pest management (IPM) strategies, however these strategies are not effective to eradicate the PCN. Therefore to eradicate the PCN we need noval management practices like RNAi (RNA interference) or Gene silencing. PMID- 28848249 TI - An overview of parasitic infections of the gastro-intestinal tract in developed countries affecting immunocompromised individuals. AB - In both developed and developing countries, parasitic infections continue to be a frequent cause of mortality and morbidity. Due to the globalization of the world, doctors must be fully prepared to deal with a plethora of parasitic infections. More commonly the gastrointestinal (GI) tract is infected and in developed countries protozoans are more likely to be the cause of infection compared to helminths. These GI protozoa are progressively becoming recognized as important pathogens in patients that are immunocompromised. The number of immunocompromised patients is increasing and therefore the likelihood of similar infections will also increase. This paper aims to highlight the key GI parasites affecting immunocompromised individuals in developed countries, discussing diagnosis, treatment options and also prevention. Cryptosporidium parvum may be the most common GI parasite found in the immunocompromised host closely followed by Cyclospora, however, Giardia duodenalis is the most common GI parasite found in developed countries. The pathogenesis of parasitic infection is not clear, poorly understood and diagnostic testing remains difficult with management continuing to be a challenge. PMID- 28848247 TI - Beyond Immune Cell Migration: The Emerging Role of the Sphingosine-1-phosphate Receptor S1PR4 as a Modulator of Innate Immune Cell Activation. AB - The sphingolipid sphingosine-1-phosphate (S1P) emerges as an important regulator of immunity, mainly by signaling through a family of five specific G protein coupled receptors (S1PR1-5). While S1P signaling generally has the potential to affect not only trafficking but also differentiation, activation, and survival of a diverse range of immune cells, the specific outcome depends on the S1P receptor repertoire expressed on a given cell. Among the S1PRs, S1PR4 is specifically abundant in immune cells, suggesting a major role of the S1P/S1PR4 axis in immunity. Recent studies indeed highlight its role in activation of immune cells, differentiation, and, potentially, trafficking. In this review, we summarize the emerging data that support a major role of S1PR4 in modulating immunity in humans and mice and discuss therapeutic implications. PMID- 28848250 TI - Cystitis due to capillaria infection in a dog and its treatment. AB - Capillaria spp infection was diagnosed in a 3 year old dog with history of pollakiuria, dysuria and haematuria. Confirmatory diagnosis was done by demonstration of the parasitic ova in the urinary sediment, cystitis by ultrasonography, presence of proteins and leukocytes in the urine. Dog was successfully treated with fenbendazole and ivermectin along with supportive therapy. Recovery was noticed after 2 weeks of treatment with clear and transparent urine and absence of parasitic ova in urinary sediment. PMID- 28848251 TI - Morphological, histopathological and molecular characterization of Thelohanellus theinensis n. sp. (Cnidaria: Myxosporea) infecting an Indian major carp, Labeo bata in a cold water wetland in Punjab (India). AB - A myxozoan parasite belonging to the genus Thelohanellus Kudo, 1933 (Myxosporea, Bivalvulida) was isolated from the gill lamellae of Labeo bata (Hamilton, 1822) inhabiting Ranjit Sagar Wetland in Northern parts of Punjab, India. Histopathology of the infected gills indicated lamellar distortion due to the presence of plasmodia. The intensity of infection was recorded to be moderate as indicated by gill plasmodial index (GPI = 2). The plasmodia were microscopic, ovoid, creamish white, 2.0-4.0 mm in diameter containing 300-400 number of myxospores. The myxospores were broadly pyriform in shape, measuring 8.27 * 4.41 um, having a prominent pore at the anterior end. The polar capsule was pyriform in shape, measuring 4.15 * 4.10 um, containing a polar filament coiled perpendicular to the longitudinal axis of myxospore body making 6-7 turns. At molecular level, the analysis of 18S rDNA sequence of T. theinensis n. sp. demonstrated maximum homogeneity of 99 % with T. filli (KR340464) as only 2 gaps were found due to the difference of the last 20 base pairs at the 3' end of T. theinensis n. sp. The current study emphasizes the need for caution when dealing with members of species complex. PMID- 28848252 TI - Ectoparasites and endoparasites community of Ageneiosus ucayalensis (Siluriformes: Auchenipteridae), catfish from Amazon River system in northern Brazil. AB - This study investigated the community of ectoparasites and endoparasites in Ageneiosus ucayalensis (Auchenipteridae) of a tributary from the Amazon River system, in Northern Brazil. Of 34 fish examined, 100% were parasitized by Ichthyophthirius multifiliis, Cosmetocleithrum bulbocirrus, Demidospermus sp., metacercariae of Genarchella genarchella, Clinostomum marginatum and Herpetodiplostomum sp., Procamallanus (Spirocamallanus) belenensis, Cucullanus ageneiosus and larvae of Contracaecum sp. digeneans C. marginatum and Herpetodiplostomum sp. were dominant parasite species, while I. multifiliis was the parasite with higher infection level. Such parasite species showed an aggregated dispersion, except P. (S.) belenensis, which showed a random dispersion. The Brillouin diversity (0.53 +/- 0.29) was high, while evenness (0.28 +/- 0.16) and species richness of parasites (3.7 +/- 1.1) were low. The size of the hosts did not influence diversity, species richness and abundance of parasites. The ectoparasites were characterized by high prevalence and abundance, while endoparasites community presented low prevalence and abundance. The main factors responsible for structuring the parasite community in A. ucayalensis were mainly the behavior of this host and the availability of endoparasites infective stages in the environment. This was the first report of I. multifiliis, C. bulbocirus, Demidospermus sp., Contracaecum sp., C. marginatum, Herpetodiplostomum sp. and G. genarchella for A. ucayalensis. The presence of endohelminth larvae suggests that A. ucayalensis is part of the diet of other fish at the top of the food web in the Amazonian ecosystem studied. PMID- 28848253 TI - Molecular prevalence and haemato-biochemical profile of canine monocytic ehrlichiosis in dogs in and around Hisar, Haryana, India. AB - The present study was planned to investigate the molecular prevalence of canine monocytic ehrlichiosis (CME) in dogs in and around Hisar and to evaluate the haemato-biochemical profile for its better management. A total of 60 dogs presented to Medicine Section, TVCC, LUVAS, Hisar with the history of naturally acquired tick infestation and clinical signs consistent with CME were screened on the basis of blood smear examination, followed by molecular detection by nested PCR assay targeting a portion of 16S rRNA gene of Ehrlichia canis. Nested PCR detected 18 cases positive for E. canis with estimated 30% percent positivity as compared to 8.33% (5 out of 60) by blood smear examination. These 18 dogs confirmed for CME by nested PCR were assessed for clinical and haemato biochemical profile. Breed-wise prevalence indicated maximum number of cases in Labrador retriever, followed by Pug, Rottweiler and German shepherd dog with more number of cases in male dogs. Age-wise prevalence revealed highest number of cases in more than 1 year age group, followed by 6 months to 1 year age group and least in less than 6 months aged dogs. Pyrexia, anorexia and pale to congested mucous membranes were the main clinical signs observed, followed by lethargy, vomiting. Less common clinical signs were epistaxis, lymphadenomegaly, hind limb weakness, malena, ocular discharge, followed by haematuria, corneal opacity, nasal discharge and coughing, icterus, dermal petechiae and ecchymoses. The haematological profile revealed macrocytic hypochromic anaemia, thrombocytopenia, normal leucocyte count with relative lymphocytosis, monocytosis and neutropenia. Serum biochemistry revealed significant rise in values of ALT, AST, GGT, bilirubin total, bilirubin indirect, alkaline phosphatase and A/G ratio in affected dogs as compared to healthy control, suggesting the hepatic dysfunction. The lipid metabolites and kidney function parameters were non-significantly altered from those of healthy control. A high positivity for E. canis detected by nested PCR in dogs in and around Hisar suggests the endemicity of the disease in dogs' population in this region and warrants the screening for the disease in suspected dogs by this technique as compared to routine blood smear examination. The presented haemato-biochemical profile may be useful in presumptive diagnosis of the disease in dogs and their better clinical management. PMID- 28848254 TI - Distribution of larval and pupal stages of Simulium (Diptera: Simuliidae) flies in the Nilgiris hills of Tamil Nadu. AB - Endemicity of onchocerciasis (river blindness) in humans is linked to the location of Simulium spp. (black fly). The distribution of immature stages of Simulium in Sholur, Pykara, Gudalur, Coonoor and Kotagiri streams of the Nilgiris hills of Tamil Nadu was investigated during the months of May and July 2012. Out of these five streams, only Sholur was infested with larval and pupal stages of Simulium spp. Out of six plants collected from various water bodies, larval and pupal stages were found on the leaves and stems of an aquatic plant Nasturtium officinale and on the roots and leaves of Pennisetum glandulosum. The stages of Simulium were observed only during the summer month of May. PMID- 28848255 TI - Prevalence of intestinal parasitic infection among primary school children in southern Iran. AB - A cross-sectional study was carried out to determine the prevalence of intestinal parasites in primary school children in Bandar Abbas, southern Iran during January to March 2016. Single stool samples were collected from 1465 participants by clean stool cup. The questionnaire was prepared on the basis of demographic characteristics. The diagnosis was made on the basis of the direct wet mount, formalin-ether concentration, and Ziehl-Neelsen and trichrome stained slides. Out of the 1465 school children examined, six species of intestinal parasites were identified with an overall prevalence of 95 positive students (6.5%). Prevalence of protozoan infections (6.2%) was significantly higher than helminth infections (0.3%). The most common protozoan species were Giardia lamblia (n = 42, 2.9%) and Blastocystis hominis (n = 31, 2.1%). Only two cases of Hymenolepis nana and two cases of Enterobius vermicularis were detected. The prevalence of parasitic infections was higher in boys (n = 52, 7%) than girls (n = 41, 5.7%), but the difference was not significant. The parasitic infections were higher among the children whose parent's education was less than high school diploma (p = 0.000), and there was also a significant association between the parents' jobs and the intensity of parasitic infection. The prevalence of intestinal parasites, compared to the previous studies in this area, was significantly lower; that is mainly due to an increase in the quality of life and parents' education as well as the accessibility to health services. The most prevalent intestinal parasite was G. lamblia; therefore, it is recommended that more emphasis is applied to controlling and preventing this parasitic infection by washing hands, particularly before each meal course. PMID- 28848256 TI - Chemical composition, larvicidal and antioxidant activities of latex from Garcinia morella (Gaertn.) Desr. AB - The present study revealed that the latex of Garcinia morella (Gaertn.) possessed 204.27 mg/g phenolic acid and 124.92 mg/g of flavonoid content along with other phytochemicals. Gas chromatography-mass spectrometry (GC-MS) revealed the presence of 20 compounds in the latex, with the major compounds identified as 5 Oxohexanenitrile (18.7%), phenol, 2,4-bis(1,1-dimethylethyl)- (24.64%) and Hexadecanoic acid (22.85%). The latex showed toxicity against treated third instar larvae of Culex quinquefasciatus with LC50 and LC90 values of 132.54 and 483.15 ppm. The latex also showed significant antioxidant activities with EC50 values of 205.5 ug/ml in the 1,1-diphenyl-2-picrylhydrazyl (DPPH), 95.53 ug/ml in phosphomolybdate, 308.1 ug/ml in hydrogen peroxide (H2O2) scavenging assays. PMID- 28848257 TI - Solute carrier protein family 11 member 1 (Slc11a1) activation efficiently inhibits Leishmania donovani survival in host macrophages. AB - Visceral leishmaniasis (kala-azar), a life threatening disease caused by L. donovani, is a latent threat to more than 147 million people living in disease endemic South East Asia region of the Indian subcontinent. The therapeutic option to control leishmanial infections are very limited, and at present comprise only two drugs, an antifungal amphotericin B and an antitumor miltefosine, which are also highly vulnerable for parasitic resistance. Therefore, identification and development of alternate control measures is an exigent requirement to control leishmanial infections. In this study, we report that functionally induced expression of solute carrier protein family 11 member 1 (Slc11a1), a transmembrane divalent cationic transporter recruited on the surface of phagolysosomes after phagocytosis of parasites, effectively inhibits Leishmania donovani growth in host macrophages. Further, the increased Slc11a1 functionality also resulted in increased production of NOx, TNF-alpha and IL-12 by activated macrophages. The findings of this study signify the importance of interplay between Slc11a1 expression and macrophages activation that can be effectively used to control of Leishmania growth and survival. PMID- 28848258 TI - Evaluation of different Haemonchus contortus antigens for diagnosis of sheep haemonchosis by ELISA and their cross reactivity with other helminthes. AB - Haemonchus contortus (H. contortus) remains important nematode that infecting sheep all over the world. Truthful diagnosis of haemonchosis needs reliable Enzyme linked immune sorbent assay test as well as the immuno-reactive protein profile of different prepared H. contortus antigens; larval (L), excretory secretory product (ESP) and adult somatic H. contortus (AS). The current study fulfilled that L antigen is the talented antigen for such serological diagnosis. Immunodominant band at molecular weight 57 kDa were answerable for highest specificity and accuracy of positive predictive value of this antigen. Moreover, the highest apparent prevalence value was 92 and 75% obtained by L and ESP antigens, respectively. The results of cross reactivity among AS, Monezia expansa (M. expansa) and Fasciola spp. revealed that AS antigen appeared major cross reactivity with other cestode and trematode. Best dilution of serum was (1:800) to rise above this phenomenon. PMID- 28848259 TI - Population characteristics of black kite lice. AB - A look on literature revealed that the population characteristics of Phthiraptera infesting Black Kite, Milvus migrans Boddaert deserved investigation. Thirty-two kites were sampled in district Rampur (U.P.) India during January 2011-December 2012, for the presence of phthirapteran ectoparasites. Two amblyceran species, Laemobothrion maximum Scopoli and Colpocephalum turbinatum Denny and one ischnoceran louse, Degeeriella regalis Giebel were recovered. The prevalence, intensity of infestation, sample mean abundance, range of infestation, sex ratios, and adult nymph ratios of three lice were recorded. C. turbinatum ranked first in the order of prevalence and intensity of infestation, followed by D. regalis. The prevalence and intensity of L. maximum was quite low. PMID- 28848260 TI - Monocytic anaplasmosis in a cow: a case report. AB - A five year old Holstein-Friesian cross breed cow was brought to Teaching Veterinary Clinical Complex with the history of anorexia, shivering and respiratory distress since a week. On close physical examination, enlarged prescapular lymph nodes and conjunctival mucous membranes with petechiae were noticed. Physiological parameters like rectal temperature, heart rate and respiratory rates were found to be 105.3 degrees F, 86 beats per minute and 48 per minute respectively. On hematological examination, hemoglobin and total erythrocyte count were found to be low i.e., 5.2 g/dl and 3.2 million cells/cmm respectively. Peripheral blood smear examination revealed the presence of Anaplasma bovis organisms in the monocytes. Based on these findings a diagnosis of bovine monocytic anaplasmosis was made and the case was treated with two doses of long acting Oxytetracycline @20 mg/kg body weight 48 h apart, I/M, and Meloxicam @0.5 mg/kg body weight, I/M for 5 days. Improvement was noticed after 3 days of treatment. PMID- 28848261 TI - Circulating oxidative stress caused by Psoroptes natalensis infestation in Indian water buffaloes. AB - The present study reports the circulating oxidative stress associated with Psoroptes natalensis infestation in Indian water buffaloes. Three non-descriptive water buffaloes, age ranging between 4 and 9 years, presented to Referral Veterinary Polyclinic, IVRI, for treatment served as clinical subject. The infested animals were treated with Ivermectin subcutaneously and Amitraz topically along with antioxidant like ascorbic acid, Vitamin E and selenium. The level of lipid peroxidase was significantly higher (3.94 +/- 0.34) in Psoroptes infested buffalo and was reduced significantly (P <= 0.05) after treatment (1.56 +/- 0.40). The significantly higher levels of MDA before treatment signify the role of lipid peroxide mediated skin lesions in P. natalensis infested buffaloes. Similarly the activities of the body antioxidant like GSH and CAT were significantly higher (P <= 0.05) after treatment. The less level of the body antioxidant (GSH) and reduced activities of the antioxidant enzymes like CAT and SOD before treatment imply that Psoroptes mite-infested buffaloes were in a state of significant oxidative stress. The study provides information on oxidative stress indices in P. natalensis infested buffaloes and gives additional insight regarding the pathogenesis of the disease and its management. PMID- 28848263 TI - Leucocytozoon spp. infection in Accipitriformes birds in Iran. AB - Leucocytozoon spp. (Haemosporida, Leucocytozoidae) are vector-borne parasites of various birds. Leucocytozoon can infect different reticuloendothelial tissues and blood cells of birds. In this study peripheral blood samples were collected from Accipitriformes birds [three marsh harriers (Circus aeruginosus) and one tawny eagle (Aquila rapax)] in one birds' garden in Iran. Blood films were observed for identification of hemoparasites. All samples were infected by different Leucocytozoon species. All of the observed species were first reported in Iran in Accipitriformes birds which one of them was described as a new species. PMID- 28848262 TI - Larvicidal and ovicidal activity of Terminalia chebula Retz. (Family: Combretaceae) medicinal plant extracts against Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus. AB - Insect-borne diseases remain to this day a major source of illness and death worldwide. The resistance to chemical insecticides among mosquito species has been considered as a setback in vector control. Mosquito control programs, botanical origin may have the potential to eliminate eggs and larvae. So, the larvicidal and ovicidal activities of crude benzene, hexane, ethyl acetate, chloroform and methanol extracts of Terminalia chebula were assayed for their toxicity against three important vector mosquitoes, viz., Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus. The larval mortality was observed after 24 h of exposure. All extracts showed moderate larvicidal effects; however, the highest larval mortality was found in the methanol extract of T. chebula against the larvae of A. stephensi, A. aegypti, and C. quinquefasciatus with the LC50 values were 87.13, 93.24 and 111.98 ppm, respectively. Mean percent hatchability of the ovicidal activity was observed 48 h post treatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. All the five solvent extracts showed moderate ovicidal activity; however, the maximum egg mortality (zero hatchability) was observed in the methanol extract of T. chebula at 200 and 250 ppm against A. stephensi, A. aegypti and C. quinquefasciatus showed 100% mortality at 300 ppm. No mortality was recorded in the control. The finding of the present investigation revealed that the leaf extract of Terminalia chebula possesses remarkable larvicidal and ovicidal activity against medically important vector mosquitoes and make this plant product promising as an alternative to synthetic insecticide in mosquito control programs. PMID- 28848264 TI - Alterations in oxidative stress parameters and its associated correlation with clinical disease on experimental Cryptosporidium parvum infection in Swiss albino mice. AB - The present study was conducted to evaluate the changes in oxidative stress parameters on experimental infection with Cryptosporidium parvum in Swiss albino mice. The mice were divided into four groups viz., group I-IV, each group comprising of 15 mice. Group I mice served as healthy control. In Group II mice, C. parvum oocysts @ 104/os were administered, mice of group III were given dexamethasone @ 30 ug/ml in drinking water whereas group IV mice were given dexamethasone @ 30 ug/ml along with C. parvum oocysts @ 104/os. Significant changes were seen in oxidative stress parameters which included significant increase in LPO and decrease in levels of SOD, CAT and GSH in liver and intestine in group IV mice at 10th DPI when compared to others indicating an important role played by free radical induced oxidative stress in the development of C. parvum infection in mice which was clinically characterized by loss of body condition, profuse bloody diarrhoea and peak oocyst shedding intensity occurring at 10th DPI. PMID- 28848265 TI - Comparative efficacy of deltamethrin and chlorpyriphos in bovine ticks in and around Jabalpur. AB - Efficacy of chlorpyriphos (Classic*20, 20% EC) and deltamethrin (Butox(r), 1.25% EC) was assessed by spraying these drugs on cattle and buffaloes which were naturally infested with ticks at the concentration of 2.5 and 2 ml/l, respectively. Results of the study demonstrated the prolonged effect of chlorpyriphos when compared with deltamethrin. Moreover, residual effect of chlorpyriphos remained even after 14 days of treatment with 28.57% animals showing reinfestation, while in deltamethrin treated animals; the tick number started increasing after 14th day of treatment with 50% animals showing reinfestation on 14th day post-treatment. PMID- 28848266 TI - A rare case of verminous pneumonia in domestic rabbit. AB - A 3-year-old female rabbit housed in 98 Mob Fd Vet Hospital/Farm at Charri, Himachal Pradesh, was found dead without showing any clinical signs. At necropsy, one foetus was recovered from the uterus of the animal. The histopathological examination showed presence of a very large number of ova and larvae of Protostrongylus sp. in the alveolar spaces in the lungs. Severe verminous pneumonia, a condition which is rarely reported in farm/domestic rabbit, led to the death of the animal. PMID- 28848267 TI - Comparison of parasitological techniques for the diagnosis of intestinal parasitic infections in patients with presumptive malabsorption. AB - Intestinal parasitic infections still remain a public health problem, overall in tropical and subtropical regions. Frequently, patients with malabsorption syndrome can be infected with intestinal parasites, independent that they could be the etiological agents. To compare three coproparasitological techniques Paratest(r), Ritchie and direct wet mount for the diagnosis of intestinal parasitic infections in patients with suspected malabsorption syndrome. A descriptive cross sectional survey was carried out in 82 patients with presumptive symptoms of intestinal malabsorption. Three consecutive stool samples were collected from every patient and they were analyzed by three coproparasitological techniques. The degree of agreement was almost perfect when all parasitological techniques were compared for all protozoan infections. Nevertheless, the agreement between Paratest(r) and Ritchie's methods was slightly lower because this last method was superior for intestinal infections with commensals. The technique of Ritchie showed 100% of sensitivity for protozoa infections in general. However, the direct wet mount and the Paratest(r), showed lower sensitivity. When all techniques were compared only for infections with no pathogenic protozoa, the Paratest(r) had the lowest sensitivity, and less predictive value for negatives. Ritchie's method showed a higher superiority than Paratest(r) for the diagnosis of intestinal protozoa infections in this group of patients. We would recommend the evaluation of new techniques in local conditions before to decide the introduction in the public health network of laboratories. PMID- 28848268 TI - A clinically rare occurrence of rectal mucosal prolapse associated with tenesmus in a calf caused by Eimeria sp. AB - Eimeria sp. is a host-specific intracellular parasite that mostly affects young animals. This parasite causes great economic losses in livestock sector. A 6 weeks old calf was brought to Referral Veterinary Polyclinic, ICAR-Indian Veterinary Research Institute, Izatnagar with the history of inappetance and passage of foul smelling diarrhoeic feces rich in occult blood and mucous for the last 3 days. On clinical examination, calf was found to be present in lateral recumbency and showed severe tenesmus, prolapsed rectal mucosa along with small quantity of blood mixed feces sticking to the perineum and tail regions. Diagnosis was done based on clinical observations and fecal examination which showed oocysts of Eimeria sp. The prolapsed rectal mucosa was corrected aseptically by manual procedure. The calf was treated with a combination of sulfadimidine and amprolium along with supportive therapy. The calf recovered clinically after 5 days of therapy and further fecal examination showed no evidence of oocysts of Eimeria sp. PMID- 28848269 TI - Interactions between gastrointestinal parasitism and pneumonia in Nigerian goats. AB - This study was carried out to determine the burden and interactions between parasitism and pneumonia in Nigerian goats. A total of 430 goats were examined for gastrointestinal (GIT) parasites by faecal analysis using sedimentation by gravity, Modified Winconsin sugar floatation method, McMaster egg counting techniques and for lung consolidation, pathology and morphometry of pneumonia were evaluated by standard techniques. The results from the faecal examination revealed the presence of nine (9) gastrointestinal parasites namely Eimeria, Trichuris, Oesophagostomum, Strongyloides, Moniezia, Haemonchus, Bunostomum, Trichostrongylus, and Nematodirus species and at an overall high prevalence of 74%. Eimeria species was found to have the highest prevalence of 26% for single infection, while co-infection of Eimeria and Trichuris species 21% was highest amongst other parasites, and of the breeds of goats examined for GIT parasites, the Red Sokoto (RS) breed had the highest infection rate 37%. The results from the lungs analysis showed 59% prevalence with the highest consolidation in RS (48.2%), followed by WAD (34.2%). The age of the goats was key in the infection rate of both parasites and pneumonia, which was seen to be highest in younger goats, with a significant (2.10 +/- 0.4 * 103) GI parasite burden in >1-2 years group. The prevalence of GIT infection with lung consolidation in the goats, was observed to influence their Body condition scores (BCS) (p < 0.05). This study showed that body condition score, age and breed of goats may be predisposing factors to gastrointestinal parasites and pneumonia in Nigerian goats. There was a strong correlation (+0.243, p = 0.00) of occurrence of gastrointestinal parasitism and pneumonia in this study. Possibility of combined prophylactic measures should be considered in the nearest future. PMID- 28848270 TI - Molecular identification of Mecistocirrus digitatus and Toxocara vitulorum in the mithun (Bos frontalis) from north-east India. AB - Mecistocirrus digitatus and Toxocara vitulorum are common pathogenic nematode parasites of mithun (Bos frontalis). Species identification by morphological features was confirmed by molecular identification of M. digitatus and T. vitulorum. The internal transcribed spacer-2 (ITS-2) region and beta tubulin gene of M. digitatus were polymerase chain reaction (PCR) amplified and sequenced. ITS 2 sequence analysis showed 100% homology with other isolates of M. digitatus and 83% identity with Haemonchus contortus and H. placei, respectively. Likewise, ITS 1 and ITS-2 sequences of T. vitulorum were PCR amplified and sequenced. Sequence analysis of these internal transcribed spacers from five worms of the parasite from mithun showed no intraspecific variations with T. vitulorum isolates from domestic ruminants. PMID- 28848271 TI - A study on prevalence and factors associated with ectoparasitism in goats of two agro-climatic regions in India. AB - The present study was aimed to evaluate the factors associated with prevalence of various ectoparasites among goats during winter season in two different agro climatic regions of India. A total of 320 goats (Uttarakhand-208; Uttar Pradesh 112) were screened and evaluated for ectoparasitism and associated factors. The occurrence of ectoparasitism in goats was studied in relation with age, sex, breed, housing, agro-climatic region and system of rearing. Prevalence of ectoparasitism among goats of lower Shivalik region (Dehradun and Tehri Garhwal districts) of Uttarakhand and Bareilly district of Uttar Pradesh was 90.38 and 39.29%, respectively. The common ectoparasites observed were chewing lice (Bovicola caprae), sucking lice (Linognathus africanus), fleas (Ctenocephalides felis) and ticks (Haemaphysalis spp.). Among all the ectoparasitic infestation, pediculosis was the most common affection during the study period in both agro climatic region; chewing lice in Uttarakhand and sucking lice in Uttar Pradesh. Agro-climatic region, breed, immune status, system of rearing and hygiene were highly affecting the prevalence and distribution of ectoparasites among goats. High prevalence of ectoparasitism in the study area warrants the need for formulating appropriate intervention strategies to improve control of ectoparasites and awareness among goat farmers. PMID- 28848272 TI - Acute hepatozoonosis in dogs: a case report. AB - Two male dogs aged between 2 and 3 months belonging to German Shepherd and non descript breed were brought to Outpatient unit of Department of Veterinary Medicine, Veterinary College, Bidar with history of anorexia, weakness and going down in body condition since 15 days. Clinical examination revealed fever, enlargement of popliteal and submandibular lymph nodes, pale mucous membranes and cachectic body condition in both the cases. Haemato-biochemical examination revealed anemia, leukocytosis, thrombocytopenia, hypoalbuminemia and elevated levels of blood urea nitrogen, creatinine and alanine amino transferase. On blood smear examination, gamonts of Hepatozoon canis organisms were noticed in neutrophils. Based on these observations a diagnosis of hepatozoonosis was made. Cases were treated with Doxycycline @ 10 mg/kg, PO and uneventful recovery was noticed after 21 days of treatment. PMID- 28848273 TI - Incidence and pathological study of Explanatum explanatum (Creplin, 1847) Fukui, 1929 in goats in Andhra Pradesh, India. AB - Amphistomiasis, caused by species of Paramphistomatidae is an economically important disease in ruminants. Explanatum explanatum is a very common amphistome in bile ducts and gall bladder of cattle and buffaloes worldwide where as in goats, it is exclusively found in Asian countries. Screening of livers from 100 sheep and 154 goats during slaughter at local slaughter houses from October, 2014 to April, 2015 in Andhra Pradesh (India) revealed presence of amphistomes in main bile ducts and gall bladder in three goats (1.9%) and were not observed in livers of sheep. Grossly, the affected livers were congested and the bile ducts were firm, thickened and occluded with amphistomes along with light yellowish foul smelling fluid. There were no apparent changes in gall bladder. Amphistomes were identified as E. explanatum by the standard staining technique using borax caramine. Microscopically, sections of liver revealed areas of haemarrhage, necrosis and infiltration of mononuclear cells in the parenchyma and surrounding the bile ducts. The wall of bile ducts revealed connective tissue proliferation with a characteristic mucosal plug of bile duct drawn into the acetabulum. There was hyperplasia of bile duct epithelium along with marked proliferation of mucosal glands and mononuclear cell infiltration. This paper appears to be the first report of E. explanatum in goats from Andhra Pradesh, India. PMID- 28848274 TI - The role of Linguatula serrata nymph in transmission of enteric bacterial pathogens to internal organs in sheep. AB - Linguatula serrata is a worldwide zoonotic parasite belong to phylum Athropoda. When the eggs are swallowed by intermediate host, the larvae are released in intestine and reach the mesenteric lymph nodes (MLNs) and occasionally liver, lungs, heart, kidneys, spleen, and other body organs by the blood and lymph circulation. There are a few evidences showing transmission of microorganisms by migrating L. serrata. The aim of this study was to determine the role of L. serrata nymph in transmission of enteric bacterial pathogens to internal organs of sheep. For this purpose 11 parasite positive and 11 parasite negative MLNs to L. serrata were obtained from the native slaughtered sheep and were examined microbiologically in terms of bacterial contamination. The average total bacterial count and Escherichia coli count in the parasite positive samples were respectively 6.7 and 3.3 times higher than parasite negative ones (P < 0.05). However no significant differences were found for Salmonella and intestinal enterococci between parasite positive/negative samples. This indicates that L. serrata nymphs play as vehicles for bacteria and so contaminate offal. L. serrata nymphs transfer some bacterial agents to internal organs and enhance post mortem spoilage of the infected organs. It is also able to transfer some bacterial pathogens to internal organs which could potentially be the etiology of severe infectious or even zoonotic diseases. Especially in some regions where the consumption of raw or semi-cooked lymph nodes and other visceral organs are common. PMID- 28848275 TI - Ecological covariates based predictive model of malaria risk in the state of Chhattisgarh, India. AB - Malaria being an endemic disease in the state of Chhattisgarh and ecologically dependent mosquito-borne disease, the study is intended to identify the ecological covariates of malaria risk in districts of the state and to build a suitable predictive model based on those predictors which could assist developing a weather based early warning system. This secondary data based analysis used one month lagged district level malaria positive cases as response variable and ecological covariates as independent variables which were tested with fixed effect panelled negative binomial regression models. Interactions among the covariates were explored using two way factorial interaction in the model. Although malaria risk in the state possesses perennial characteristics, higher parasitic incidence was observed during the rainy and winter seasons. The univariate analysis indicated that the malaria incidence risk was statistically significant associated with rainfall, maximum humidity, minimum temperature, wind speed, and forest cover (p < 0.05). The efficient predictive model include the forest cover [IRR-1.033 (1.024-1.042)], maximum humidity [IRR-1.016 (1.013 1.018)], and two-way factorial interactions between district specific averaged monthly minimum temperature and monthly minimum temperature, monthly minimum temperature was statistically significant [IRR-1.44 (1.231-1.695)] whereas the interaction term has a protective effect [IRR-0.982 (0.974-0.990)] against malaria infections. Forest cover, maximum humidity, minimum temperature and wind speed emerged as potential covariates to be used in predictive models for modelling the malaria risk in the state which could be efficiently used for early warning systems in the state. PMID- 28848276 TI - Genetic diversity of Fasciola spp. isolates from northern part of Iran: comparison with southwestern isolates. AB - Animal and human fascioliasis is a health and economic problem in few of tropical and subtropical areas of the world, including Iran. The present study aimed to determine the genotype diversity of Fasciola isolates in different hosts from Gilan province, northern Iran, and compare it with those isolates from southwestern Iran. Forty-eight adult Fasciola spp. were collected from cattle, sheep, and goats from slaughterhouse in Talesh, north of Iran. DNA was extracted from each fluke and PCR-RFLP was used to find out the species of the isolates. The ribosomal ITS1 and ITS2, and mitochondrial genes of NDI and COI from individual Fasciola isolates of each host were PCR-amplified and the PCR products were sequenced. Genetic variation within and between the isolates was evaluated by comparing the sequences of ribosomal and mitochondrial genes. For analysis of phylogenetic diversity of the flukes, phylogenetic trees were constructed, using ITS1, ITS2, NDI, and COI sequences of the isolates. Based on PCR-RFLP profile, 5 (22.7%) of the total of sheep isolates and 18 (90%) of cattle isolates were identified as F. gigantica and other remaining samples from sheep, cattle and goats were identified as F. hepatica. Based on ITS1 and ITS2 sequences, six and seven nucleotide polymorphism were respectively noted in the isolates. On the other hand, CO1 region sequences showed considerable variation, which laid Talesh (north) isolates in a separate cluster. Findings of the study showed that the sequences of CO1 isolates from north and southwest have substantial differences mainly in CO1 region. PMID- 28848277 TI - Seasonal prevalence of blood parasitic diseases in crossbred cattle of Mysore and its surrounding districts of Karnataka. AB - The present study report the seasonal prevalence of blood parasitic diseases in cross bred cattle in Mysore and its surrounding districts of Karnataka such as Mandya, Chamaraj Nagar and Kodagu. The study was undertaken for a period of 2 years from August 2013 to July 2015. A total of 1655 blood samples were collected from clinically suspected cattle for blood parasitic diseases with clinical symptoms of anorexia, high fever, anaemia, salivation, enlargement of superficial lymphnodes, haemoglobinuria and sudden drop in milk yield. The blood samples were examined by giemsa's staining technique. Of the 1655 blood samples screened, 673 (40.22%) blood samples were found positive for blood parasites. Amid 673 positive samples, 609 (90.49%), 19 (2.82%) and 45 (6.68%) were found positive for Theileria annulata, Babesia bigemina and Anaplasma marginale respectively. The season wise prevalence revealed that, the highest prevalence was observed in summer months (March-June) (43.17%) followed by rainy (July-October) (39.53%) and winter season (November-February) (39.35%). Further, the month wise prevalence showed highest in August (77.64%) (Rainy month) followed by November (38.23%) and January (35.93%). During August-2013 to July 2014 and between August-2014 and July 2015, the highest was found in the month of May (85%) followed by July (70%) and April (69.81%). Theileriosis was most prevalent in summer (92.73%) followed by rainy (90.95%) and winter season (87.61%). Babesiosis was most prevalent in winter season (5.04%) followed by rainy (1.8%) and summer season (1.7%) whereas, Anaplasmosis was most prevalent in rainy season (7.23%) followed by winter (6.88%) and summer season (5.55%) during two years of study period. PMID- 28848278 TI - Population levels of phthirapteran ectoparasites on the goats in Rampur (U.P.). AB - Out of the four phthirapteran species known to occur, only two were recovered from the goats in district Rampur (ischnoceran louse, Bovicola caprae and the anopluran, Linognathus africanus). As many as, 26.5% (n = 250) of the goats examined were found infested with Phthiraptera. The prevalence on two sexes of goats remained similar (X2 = 0.013, P < 0.05). However, lice were more prevalent on younger goats than adults and older ones (X2 = 9.78, P < 0.05). The correlation between the prevalence and mean monthly temperature of Phthiraptera was found significant. On the other hand correlation between prevalence and humidity was found insignificant. As many as, 74.5% of the infested goats carried both the species while 25.4% exhibited single species infestation. The ischnoceran louse, B. caprae was comparatively more prevalent (18.4%) than the anopluran L. africanus (11.2%). The mean intensity (mean number of lice counted per square inch, at 20 anatomical sites) of B. caprae was comparatively higher than that of L. africanus. As far as, the population composition is concerned the females outnumbered the males in natural population. On the other hands, nymphs dominated over adults in natural population. PMID- 28848280 TI - Diagnosis of bovine sarcocystosis by immunoflourescent antibody technique. AB - Studies on sarcocystosis showed an overall sero-prevalence of 79.46% by IFAT which included 80.14% in cattle and 78.59% in buffaloes out of 716 animals screened. The antibody titers of six randomly selected positive samples from different age groups of <2, 2-5, 5-10 and >10 years old bovines ranged from 16 to 64, 32 to 256, 32 to 128 and 16 to 64 with an average titer of 32 +/- 2.92, 106.6 +/- 34, 74.6 +/- 17 and 34.6 +/- 9, respectively. Significantly, lower rates of infection were observed in the cattle of below 2 years (60%) age and an ascending rate of infection in the age groups of 2-5 years (81.33%), 5-10 years (80.52%) and above 10 years (90.9%). PMID- 28848279 TI - Efficacy of entomopathogenic nematodes (Rhabditida: Steinernematidae and Heterorhabditidae) on developmental stages of house fly, Musca domestica. AB - The housefly, Musca domestica is a major domestic, medical and veterinary pest. The management of these flies reliance on insecticide, causes environmental constraints, insecticide resistance and residues in the meat, skin. Therefore one of the eco-friendly alternate methods is by using biological agents such as entomopathogenic nematodes (EPN). In the present study evaluated the survival of EPN species Steinernema feltiae, Heterorhabditis indica, S. carpocapsae, S. glaseri and S. abbasi in poultry manure and also their efficacy against different developmental stages of house fly. After exposing to poultry manure, S. feltiae showed more survival as followed by H. indica, S. carpocapsae, S. glaseri and S. abbasi in all exposition period. When the exposition period extended to 96 h, all nematode species survivability was drastically reduced. After exposing these nematodes to poultry manure at 24 h their virulence capacity against wax moth, Galleria mellonella showed all the nematode species were able cause 100% mortality. However their progeny production was significantly reduced. Fly eggs and pupae were refractory to these nematode infection. Petri dish without artificial diet assay showed that, second and 3rd-instar larvae were highly susceptible to EPNs as compared to larvae provided with artificial diet. H. indica showed high virulence capacity compared to other nematodes tested. Poultry manure assay revealed that, H. indica and S. carpocapsae caused minimal mortality where as S. feltiae, S. glaseri and S. abbasi did not cause any mortality. This may be because of poor survival and limited movement of nematodes in poultry manure which may be due to ammonia, other toxic substances in poultry manure. The decrease in larval mortality in manure suggests that biocontrol of housefly by using EPNs is unlikely. PMID- 28848281 TI - Host pregnancy influences the establishment of Trichinella zimbabwensis in Balb C mice. AB - In order to determine the effect of host pregnancy in the establishment of Trichinella zimbabwensis, 120 female Balb C mice were divided into 4 groups of 30 mice each. Group 1 animals were orally infected with 50 T. zimbabwensis larvae per gram (LPG) of body weight on day 0; group 2 were mated on day 0 and not infected; group 3 were mated at day 0 and infected with 50 LPG at day 7 post mating and Group 4 were control animals which were neither mated nor infected. Six animals from each group were sacrificed and the number of adult parasites in the intestines as well as larvae in the muscles were determined at day 0, 7, 14, 21 and 28 post-infection for group 1; 0, 7, 14, 21 and 28 post-mating for group 2 and days 7, 14, 21, 28 and 35 post-mating for group 3. In addition, levels of progesterone and cortisol were measured in all groups at the same intervals. Our results showed that pregnancy reduced the number of larvae establishing in muscles with progesterone levels significantly higher in pregnant than in non pregnant Balb C mice (P < 0.05). There were no significant differences in cortisol levels between pregnant and non-pregnant mice. High progesterone level in pregnant mice was assumed to have parasiticidal effect on the new-born larvae (NBL). Further research is needed to determine the direct effect of progesterone on Trichinella NBL and how this can be exploited in designing remedies for preventing Trichinella infection in susceptible domestic animals and humans. PMID- 28848282 TI - Microfilaruria by Dirofilaria immitis in a dog: a rare clinical pathological finding. AB - A 6-year-old Labrador with history of hyperpnea, respiratory distress, ascites and paraparesis, presented Dirofilaria immitis microfilariae in the blood smear, cytology of the abdominal fluid and urine. The positive samples were confirmed by multiplex-PCR (COI gene) and sequencing, and presented 98% homology to D. immitis (GenBank accession nos. KC107805.1, EU159111.1, EU163945.1, DQ358815.1, and AJ537512-1). Based on the presented results and the physiopathology of the heartworm disease, molecular techniques may be helpful and accurate in the diagnosis of the disease in vertebrates, and microfilaruria, even uncommon, should be considered on a renal failure evaluation. PMID- 28848283 TI - Occurrence of Oesophagostomum species in slaughtered sheep in area of Hyderabad, Telangana State. AB - A study was conducted in Chengicherla slaughter house of Hyderabad to find the occurrence of Oesophagostomum worms, 594 oesophagostomum positive intestines were examined. Among these, three species of oesophagostomum worms were recovered viz., Oesophagostomum columbianum, Oesophagostomum venulosum and Oesophagostomum asperum were identified by light microscopy as per the keys provided by Soulsby (Helminths, arthropods and protozoa of domesticated animals. Bailliere Tindall, London, 1982) and Singh (Veterinary helminthology. ICAR, Delhi, 2003). PMID- 28848284 TI - Comparison of Para-Selles Bailenger/Kop-Color Fumouze, Para-Selles-Iodesine/Kop Color II Fumouze diagnostic kits with conventional microscopic methods in identifying intestinal parasitic diseases in Senegal. AB - In the context of controlling intestinal parasites, accurate diagnosis is essential. Our objective was to evaluate the performance of new diagnostic kits compared to conventional microscopic methods in identifying intestinal parasites. Faeces collected in rural area in Senegal were subjected to several detection techniques. Thus, the sensitivity, specificity, positive and negative predictive values of new diagnostic techniques were compared to conventional merthiolate iodine-formalin, conventional Bailenger and modified Ritchie. Furthermore, the kappa coefficient was calculated to evaluate the correlation between the new kit and those of modified Ritchie. Out of the 117 patients examined, 102 presented with a parasite, or prevalence of 87.1%. The Fumouze techniques proved to be as effective as the conventional methods in detecting flagellates and helminths with sensitivities ranging from 97 to 100%. However, conventional techniques were slightly more sensitive in identifying Endolimax nana and Blastocystis hominis. The correlation was nearly perfect (k = 0.83 and 1), respectively between Bailenger Fumouze, Iodesine Fumouze and modified Ritchie in identifying helminths while it was just acceptable (k = 0.27 and 0.28) in identifying B. hominis. The modified Ritchie technique routinely used in our laboratory remains a good diagnostic tool. However, the use of kit techniques was interesting when reading the pellet after concentration and the Colour KOP staining was a considerable contribution to the diagnosis of the vegetative forms. Therefore, it would be interesting to determine the cost of a stool test using Fumouze kit techniques to provide the most cost effective way. PMID- 28848285 TI - Prevalence of Toxoplasma gondii infection in household and feral cats in Korea. AB - This study was designed to investigate the prevalence rate of Toxoplasma gondii (T. gondii) infection in household cats in Korea. One hundred household cats and 50 feral cats from nine of the largest cities in Korea were enrolled in this study. The tests performed in this survey was an in-house rapid screen IgG and IgM combo test, faecal PCR test for T. gondii oocysts, and an ELISA immunoassay for IgG antibodies. There were no household cats positive for T. gondii infection detected using the in-house IgG and IgM rapid screen combo test, although 6/50 and 0/50 feral cats were positive in IgG and IgM tests, respectively. This initial finding was confirmed by subsequent ELISA test for IgG antibody and PCR for T. gondii in faeces. Despite the higher prevalence rate of the disease in feral cats in Korea, we did not find any household cats that were either infected or exposed previously to T. gondii in our study population. Our study indicates that there is minimal risk of T. gondii transmission from household cats to human in Korea. PMID- 28848286 TI - Ultrastructural studies of three species of Oesophagostomum (nematoda) by scanning electron microscopy. AB - The surface structure of three predominant intestinal helminth species of Oesophagostomum i.e., Oesophagostomum columbianum, Oesophagostomum venulosum and Oesophagostomum asperum were studied with the help of scanning electron microscopy. Oesophagostomum columbianum has hook like bent structure anteriorly with well developed lateral cervical alae that are interrupted at several intervals. It has external corona radiata (ECR) and internal corona radiata (ICR), ECR comprises of 21 elements and ICR comprises two small elements to each element of ECR. Posterior end of male O. columbianum has bursa with well developed genital cone. On the other hand O. venulosum showed presence of 18 elements in ECR with each element containing two small elements internally constituting ICR. Oesophagostomum asperum had three tier arrangement of the cephalic vesicle with 12 elements in ECR with each element containing two small elements in constituting ICR. Vagina of matured females is covered with copulatory cement. PMID- 28848287 TI - Diagnostic biomarkers in murine Cryptosporidiosis: dose- and age-related infection. AB - Increasing prevalence of Cryptosporidium raises the importance to explore different aspects of its infection. In the absence of reproducible in vitro culturing, animal model is the only experimental method to study Cryptosporidium. Our study evaluated Cryptosporidium infection using coproscopy, copro-antigen and copro-DNA for early detection of murine cryptosporidiosis. Hundred and forty albino mice (neonates and adult) were divided into two groups, control group received sterile PBS solution, and infected groups were inoculated with molecularly characterized Cryptosporidium parvum oocysts and further subdivided into three subgroups for infectious dose response detection. Mice fecal samples were collected every 4 h on the first day and then daily and examined for fecal oocysts, copro-antigen and copro-DNA. Four mice from each subgroup were killed at 12, 24 and 48 h post-infection (P-I), and their intestines were examined for cryptosporidial mucosal DNA. Cryptosporidium copro-antigen and copro-DNA were detected 4 and 8 h P-I in infected neonatal and adult mice, respectively, and intestinal mucosal DNA was detected after 12 h in both. Microscopy was able to detect oocysts 48 h P-I. Inoculated C. parvum oocysts were recovered in feces of infected mice without genotypic changes. Neonate mice showed higher susceptibility for cryptosporidial infection than adults without statistical differences for the given infectious doses. Both copro-immunoassay and copro-nPCR assays can early detect Cryptosporidium infection; however, nPCR was able to identify Cryptosporidium species, making nPCR a reliable biomarker for early detection in murine model. PMID- 28848288 TI - Detection of Babesia infection among human, goats and sheep using microscopic and molecular methods in the city of Kuhdasht in Lorestan Province, West of Iran. AB - Babesiosis is a lethal protozoan disease, responsible for the loss of livestock in Iran and in the world. The purpose of the current study was to detect and identify Babesia spp. infection using microscopic and molecular methods in human, sheep and goats in Kuhdasht region, in the Lorestan Province, west of Iran. During 2013, a total of 384 blood smear samples were collected from 51 goats, 306 sheep suspected of Babesiosis infection and 27 humans from Kuhdasht region. The blood samples were fixed, stained and under light microscopic examined. DNA samples were extracted and amplified by polymerase chain reaction of 18S-rRNA gene. PCR and the semi-nested PCR were performed to identify to Babesi spp. and to differentiate genus of Theileria and Babesia spp. The results of microscopic examination indicated that a total of 47 (12.2%) samples were positive for Babesia spp. infection: 38 (9.9%) belonging to sheep and 9 to goats (2.3%). No Babesia was observed in human samples. The PCR showed a band size of 389 bp, of Babesia spp. and the semi-nested PCR detected B. ovis with a band size of 186 bp. By molecular method, 16 (4.2%) sheep and 2 (0.5%) goat blood samples were infected by Babesia. Totally, 18 samples (4.7%) were observed to have Babesia, while no infection was found in human. Thus, the results of our study have shown sheep and goats could be vulnerable to Babesia spp., especially B. ovis in Lorestan Province, Iran. Therefore, studies on the status of the animal Piroplasmosis especially Theileriosis are recommended. PMID- 28848289 TI - Prevalence of caprine GI helminths in temperate areas of Jammu & Kashmir. AB - Prevalence study on GastroIntestinal (GI) helminths of goats was carried out at Govt. Farms of twin districts of Bandipora and Ganderbal and locally reared goats of district Baramulla of the Kashmir Valley over a period of one year from December 2011 to November 2012. A total of 1016 faecal samples were examined which revealed overall prevalence of GI helminths to be 74.70%, with platyhelminths and nemathelminths in 14.76 and 70.07% animals, respectively. The helminths recorded in the present study were Fasciola spp. (2.75%), Dicrocoelium spp. (3.44%), paramphistomes (3.05%), Moniezia spp. (9.44%), strongyle worms including Nematodirus spp. (68.30%), Strongyloides spp. (5.90%) and Trichuris spp. (4.29%). On coprocultural examination Haemonchus spp. (71.05%) was found to be the most predominant strongyle worm followed by Trichostrongylus spp. (12.86%), Chabertia spp. (8.47%) and Ostertagia spp. (7.62%). Seasonal prevalence of GI helminths was observed highest in summer (78.03%) followed by spring (75.39%), winter (74.90%) and autumn (70.47%), the difference being statistically non-significant (P > 0.05). The prevalence of platyhelminths was found to be non significantly higher in winter (20.00%) followed by spring (15.07%), summer (12.54%) and autumn (11.41%). Nemathelminths were recorded highest in summer (75.68%) followed by spring (71.82%), autumn (68.50%) and winter (64.31%). EPG ranged from 0 to 1500 and an average EPG count was found to be 312.7 +/- 17.76. EPG was found to be highest in summer (453.80 +/- 45.25) followed by spring (313.2 +/- 28.76), autumn (256.1 +/- 17.48) and winter (190.2 +/- 32.0).Overall prevalence of GI helminths was found more in adult goats (77.85%) compared to young ones (67.42%), the difference being statistically significant (P < 0.05). Similarly, it was found to be higher in females (75.89%) as compared to males (66.12%) and the variation being statistically non-significant (P > 0.05). PMID- 28848290 TI - Prevalence of Pneumocystis jirovecii among immunocompromised patients in hospitals of Tehran city, Iran. AB - Pneumocystis jirovecii is an opportunistic organism that can cause extreme complications such as Pneumocystis pneumonia in immunocompromised individuals. There is no comprehensive study was conducted Iran to determine the prevalence of this infection in susceptible individuals. In the present study, 160 sera samples were collected from immunocompromised patients, including acquired immunodeficiency syndrome (AIDS) patients, diabetic patients, Hodgkin lymphoma patients and non-Hodgkin lymphoma patients. The specimens were collected from Imam Khomeini and army's 501 hospitals. The specimens were examined using indirect fluorescent antibody test. The results of the study showed that 39.30% specimens were found positive, with different rates in different groups, including 20, 22.50, 37.50, and 77.50% of diabetic patients, non-Hodgkin patients, Hodgkin lymphoma patients, and AIDS patients, respectively. This occurrence is relatively high and can be a potential life-threatening hazard to infected patients in studied groups, on the other hand the organism can be transmitted from infected people to other susceptible individuals. PMID- 28848291 TI - Trypanosoma evansi infection and major risk factors for Iranian one-humped camels (Camelus dromedarius). AB - Trypanosoma evansi is a cosmopolitan protozoan which affects camelids and may cause illness and economic losses. The present study was aimed to determine the prevalence and geographic distribution of T. evansi in Iranian one-humped camels of South East Iran. A total of 369 camels were randomly examined from three parts of southeastern Iran from March to September 2015. Blood samples were taken from jugular vein and examined by using thin blood smear and mercuric chloride test. Ninety-five out of 369 examined camels (25.75%) with clinical signs (15.8%, 58/369) were found to be infected with T. evansi. The prevalence was significantly higher in camels more than 4 years-old (23.3%) with clinical signs (8.8%) than the other ones. There was no significant difference between the prevalence and sex (6.23% male and 19.51% female). Trypanosoma evansi infection was geographically found in all investigated regions with the highest prevalence in North (17.61%). The results indicated that T. evansi infection was prevalent in Iranian one-humped camels which could be useful finding to lunch control programs in the region. PMID- 28848292 TI - Two unusual cases of generalized Coenurus gaigeri cyst infection in Beetal goats. AB - In the present communication, two unusual cases of generalized Coenurus gaigeri cyst infection in goats presented at Veterinary Teaching Hospital, University of Agriculture Faisalabad, Pakistan has been documented. Clinical (Case I) and postmortem (Case II) findings along with micro and macroscopic examination of excised cysts supported the diagnosis. PMID- 28848293 TI - Life cycle of a plant parasitic mite, Tetranychus sayedi Baker & Pitchard (Acari: Tetranychidae) on two hosts from West Bengal, India. AB - The present paper reports duration of different developmental stages as well as fecundity, longevity, oviposition periods, sex ratio, etc. of Tetranychus sayedi Baker & Pitchard on two medicinal plants, viz. Cryptolepis buchanani Roem & Schult and Justicia adhatoda L. under laboratory condition at 27.5 degrees C and 65% R.H. during February-March, 2016. The two hosts in which the life cycle was studied form two new records of hosts for this mite. It appears that C. buchanani is better host among the two hosts as because the life cycle (egg to adult) was completed in shorter time, recording high fecundity and longer longevity. PMID- 28848294 TI - Isolation and characterization of Toxoplasma gondii from small ruminants (sheep and goats) in Chennai City, South India. AB - The present study aimed for the isolation and genotyping of Toxoplasma gondii from small ruminants (sheep and goats). 14 out of 193 tissue samples (either brain and heart) tested positive by MDAT for anti-T. gondii antibodies, were selected and bioassayed, which resulted 4 samples positive for T. gondii after 40 days of post inoculation. Four samples consisting of 3 numbers of sheep and 1 number of goat tissues out of 14 samples detected by B1 PCR, were genotyped at SAG3 locus by nested polymerase chain reaction-restriction fragment length polymorphism technique (nPCR-RFLP). The results of the present study revealed that the four isolates designated as TgShIn19, TgShIn76, TgShIn77 and TgGtIn27 were circulating in small ruminants, were belonged to genotypes of type II (TgShIn19) and type III (TgShIn76, TgShIn77 and TgGtIn27) which are in concordance with the previously reported genotypes from other animal species and further this presumptive results indicating that the genotype II and III could be the predominant in different animal species including birds and humans in India. PMID- 28848295 TI - Prevalence of bovine microfilariasis in Rayalaseema region of Andhra Pradesh. AB - The Prevalence of microfilariasis of bovines was studied in four districts of Rayalaseema region of Andhra Pradesh with respect to species, age, breed, sex and physiological status viz., lactation, season for a period of 1 year. A total of 1286 blood samples were examined by conventional techniques viz. Wet blood film, blood smear examination and Knott's method with an overall prevalence of 2.72% (35/1286) was recorded in bovines. The prevalence observed in buffaloes and cattle was 2.97% (20/672) and 2.45% (15/614) respectively. With respect to region, higher rate of infection was recorded in Kurnool (3.25%) followed by 3.12, 2.5 and 2.01% in Anantpaur, Chittoor and Kadapa districts, respectively. The infection was higher in female animals (2.79%) whereas no positive case could be detected among the 32 male animals screened. Breed wise analysis revealed, highest prevalence was observed in cross bred cattle (3.04%) and graded Murrah (3.67) than non-descriptive cattle (0.64%) and buffalo (1.89%). Significantly higher prevalence was noticed in the age group of above 9 years (4.72%) followed by 6-9 years (2.98%), 3-6 years (2.05%) and below 3 years (1.04%). In lactating animals significantly higher prevalence was observed (3.47%) followed by non lactating animals (2.65%) and heifers (0.47). Further higher prevalence was detailed during rainy season (3.89%) in comparison to summer (2.87%) and winter (1.25%) season. PMID- 28848296 TI - Oral route of transmission: Trypanosoma evansi in a mice model experiment. AB - Twelve Swiss albino mice of either sex and equal body weight were randomly divided in 2 groups (I and II), consisting of 9 and 3 mice respectively and were used to conduct the study. A dose of 2.5 * 104 number of Trypanosoma evansi was instantly fed to each mouse of group I. Each mouse of group II was inoculated intraperitoneally with same dose of parasites through infected mice blood and kept separate. The tail blood of each mouse was examined daily up to 30 days post infection by examination of wet blood film and Giemsa-stained blood smears for presence of any trypanosomes. Out of 9 mice of group I those were infected orally, 3 (33.33%) mice became positive for presence of T. evansi both by examination of wet blood film and Giemsa-stained blood smears after 4, 6 and 7 days post infection. After 2 days post infection all intraperitoneally infected mice were found positive for T. evansi. Thus incubation period in orally infected mice was longer than the intraperitoneally infected mice. All the positive mice of both the groups died with high parasitaemia after 3-4 days of first appearance of parasitaemia. From the present study, it can be concluded that besides mechanical or parenteral means of transmission, T. evansi could also be transmitted through oral route. Thus zoo carnivores might be infected with T. evansi and develop disease by eating infected blood or flesh of the infected animals, as a prey and predator relationship. PMID- 28848297 TI - Surgically managed human cystic echinococcosis in north-eastern Iran: a single center's experience from 2001 to 2008. AB - Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by the tapeworm Echinococcus granulosus. Although CE has a large geographic distribution, data are lacking on the frequency of infection and epidemiology of CE in many endemic areas of the world, including the Middle East. Demographic and clinical information on surgically managed human CE cases were evaluated from a referral hospital in north-eastern Iran for the years 2001-2008. Of the 400 CE cases, 218 (54.5%) were male. The median age of patients was 35 years (range 2-83 years). The lungs (41.0%) and liver (37.7%) were the most commonly infected organs. However, 12.7% of patients had multiple organ involvement. The majority of cases (54.3%) were diagnosed using ultrasound, with only 12.0% diagnosed with the help of serology. Total white blood cell count was elevated in 26.8% (107/400) of patients, neutrophil count was elevated in 24.0% (96/400) of patients, and eosinophil count was elevated in 13.3% (53/400) of patients. Lymphocyte count was the only complete blood count (CBC) value that differed based on organ location (P = 0.001). Despite some successes in the control of CE, the number of surgical CE cases in north-eastern Iran remains high. Although not diagnostic alone, CBC values allow for clinicians to obtain a more complete clinical picture of CE before, during, and after treatment. While serology has its place, the use of diagnostic imaging continues to be the most commonly used tool for the diagnosis of CE cases. PMID- 28848298 TI - Molecular analysis of a novel species, Gangesia punjabensis (Family: Proteocephalidae, Subfamily: Gangesiinae) infecting an Indian freshwater cat fish, Wallago attu evidencing species complex. AB - In the present study, from August 2015 to July 2016, a total of 159 specimens of Wallago attu Bloch and Scheider, 1801 vern. mully were collected from the Ropar wetland, Punjab, India and were examined for the presence of intestinal tapeworms. The infection rate was 12.5%, out of which, two fishes were heavily infected with a proteocephalidean cestode belonging to the genus Gangesia in the month of February. Gangesia punjabensis sp. nov. was identified and described on the basis of morphology and partial amplification of LSUrDNA (28S rDNA). The histopathogenesis caused by these parasites have also been studied in histological sections. About 9-35 number of worms were collected from a single host. The length of worms ranged from 6.0 to 6.2 cm. The strobila consisted of an armed scolex, neck, immature proglottids (approximately 90 in number) and mature proglottids (approximately 7 in number) and gravid proglottids were not detected. Analysis of 28S large subunit (LSU) rDNA sequence of the isolate of G. punjabensis n. sp. demonstrated maximum similarity of 99% with G. bengalensis, 98% with G. vachai, 97% with G. macrones. The phylogenetic tree based on the final edited alignment (822 bp) with Neighbour-Joining showed the highest bootstrap value of 100 and placed G. punjabensis n. sp. with G. bengalensis and G. macrones in the same clade showing them to be a species complex. The intestinal mucosal lining exhibited blister formation, haemorrhagia and inflammation due to the presence of deeply embedded scolices. Histopathology caused was evident due to disruption of villous surface and cellular infiltration. This is the first report of cestodes belonging to the genus Gangesia from Ropar wetland, Punjab, India. PMID- 28848299 TI - Ruptured pulmonary hydatid cyst: a case report. AB - Ruptured pulmonary hydatid cyst (PHC) is an important clinical problem in endemic areas to echinococcal infection. Herein we present a rare case of ruptured PHC in an adolescent boy that was misdiagnosed as pulmonary tuberculosis in local health center. When sputum specimen was stained by acid-fast staining for detection of Mycobacterium tuberculosis, hooklets of Echinococcus granulosus were observed. A simple chest X-ray showed a multilobulated mass in the lower part of the left lung. Computed tomography scan verified existence of thick walled caviar lesion with irregular air-fluid level. The diagnosis was confirmed at the time of surgery. Misdiagnoses of PHC may even lead to irreparable damages. Therefore, accurate diagnosis is necessary to prevent severe complications. PMID- 28848300 TI - Molecular characterization of Hepatozoon felis in Rhipicephalus sanguineus ticks infested on captive lions (Panthera leo). AB - Hepatozoon spp. are protozoan parasites that infect a wide range of domestic and wild animals. The infection occurs by ingestion of an infected tick. This study was carried out to detect and characterize Hepatozoon spp. in ticks collected from captive lions (Panthera leo) in Thailand based on the partial 18S rRNA gene sequence. A total of 30 ticks were collected and identified as Rhipicephalus sanguineus. The collected ticks were separated into 10 tick pools by sex and life stages. Of the 10 tick pools examined, only one (10%) was found to be infected with the Hepatozoon species. Sequencing and phylogenetic analysis showed a clustering of the partial 18S rRNA gene sequence like that of H. felis from the GenBank database. This is the first report of H. felis in R. sanguineus ticks collected from captive lions in Thailand. Our results indicated that R. sanguineus may be a possible vector of feline Hepatozoon in Thailand. PMID- 28848301 TI - Primary hydatid disease of breast: a case report. AB - Human hydatid disease, or echinococcosis, is a helminthic infection that leads to the formation of fluid-filled cysts in the liver, lungs and other organs. Breast, is a rare primary site of hydatid disease. We report a case of a 45 years old female who presented with a breast lump of 2 years duration. On fine needle aspiration cytology a diagnosis of fibrocystic changes of the breast was made and ultrasonography breast showed a thick walled infected cystic lesion. Intraoperatively, a diagnosis of hydatid cyst was made which was confirmed on histopathology. PMID- 28848303 TI - Lifestyle Strategies for Diabetes Management: The Role of Weight Management. PMID- 28848302 TI - Predicting Interrelated Alzheimer's Disease Outcomes via New Self-Learned Structured Low-Rank Model. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder. As the prodromal stage of AD, Mild Cognitive Impairment (MCI) maintains a good chance of converting to AD. How to efficaciously detect this conversion from MCI to AD is significant in AD diagnosis. Different from standard classification problems where the distributions of classes are independent, the AD outcomes are usually interrelated (their distributions have certain overlaps). Most of existing methods failed to examine the interrelations among different classes, such as AD, MCI conversion and MCI non-conversion. In this paper, we proposed a novel self learned low-rank structured learning model to automatically uncover the interrelations among different classes and utilized such interrelated structures to enhance classification. We conducted experiments on the ADNI cohort data. Empirical results demonstrated advantages of our model. PMID- 28848304 TI - About Marion J. Franz, MS, RDN, CDE: Guest Editor, The Role of Weight Management in Diabetes. PMID- 28848305 TI - Weight Management: Obesity to Diabetes. AB - IN BRIEF Evidence supports the effectiveness of nutrition therapy across the continuum of diabetes management-obesity to prediabetes to diabetes. For people who are overweight/obese or diagnosed with prediabetes, modest weight loss is important. However, the goals of nutrition therapy for type 2 diabetes are improved glycemia, lipids, and blood pressure. To achieve these goals, a reduced energy intake is essential. For some, reducing energy intake may lead to weight loss, while for others, it may maintain weight loss or prevent weight gain. Weight loss medications and metabolic surgery have been shown to be effective weight loss therapies across the continuum. PMID- 28848306 TI - Why Weight Loss Maintenance Is Difficult. AB - IN BRIEF This article reviews studies related to biological mechanisms that make weight loss maintenance difficult. Approximately 50% of weight variance is reported to be determined by genetics and 50% by the environment (energy-dense foods and reduced physical activity). Body weight is tightly regulated by hormonal, metabolic, and neural factors. Hormonal adaptations (decreases in leptin, peptide YY, cholecystokinin, and insulin and increases in ghrelin, glucagon-like peptide 1, gastric inhibitory polypeptide, and pancreatic polypeptide) encourage weight gain after diet-induced weight loss and continue for at least 1 year after initial weight reduction. Weight loss also results in adaptive thermogenesis (decreased resting metabolic rate), which is also maintained long-term. Neural factors such as dopamine also signal the need to respond to an increased desire for fatty foods after weight loss. PMID- 28848307 TI - Role of Physical Activity for Weight Loss and Weight Maintenance. AB - IN BRIEF This article reviews the impact of exercise on weight loss and weight maintenance and the possible reasons that weight loss outcomes resulting from exercise are not consistently realized. PMID- 28848308 TI - Comparative Effectiveness of Clinic-Based Intensive Behavioral Therapy for Obese Adults With Type 2 Diabetes. AB - IN BRIEF In late 2011, the Centers for Medicare & Medicaid Services began reimbursing for intensive behavioral therapy (IBT) in primary care settings for obese, adult beneficiaries. The effectiveness of IBT is understudied, however, with no weight loss estimates available for adults with diabetes. This study compared weight change over 1 year between obese adults with type 2 diabetes who did receive IBT to those who did not. Findings indicated that IBT was modestly effective, resulting in ~3% weight loss over 1 year compared to 1% weight loss in the matched comparison group who did not receive IBT. PMID- 28848309 TI - The Look AHEAD Trial: Translating Lessons Learned Into Clinical Practice and Further Study. AB - IN BRIEF Although the Look AHEAD (Action for Health in Diabetes) trial, which spanned more than 8 years, did not find significant differences in cardiovascular morbidity and mortality between study groups, it did demonstrate significant differences in weight loss and maintenance. Using lessons learned from the Look AHEAD protocol, clinicians can help people with type 2 diabetes lose weight, improve glucose management, increase physical activity, alter eating patterns, and support long-term positive health outcomes. It remains important, however, to avoid assigning a higher priority to weight loss goals than to improvements in glucose management, long-term health outcomes, and quality of life. PMID- 28848310 TI - Mindful Eating: The Art of Presence While You Eat. AB - IN BRIEF Mindfulness, a practice based on Zen Buddhism, has become popular as a way of self-calming and as a method of changing eating behaviors. Mindful eating is being incorporated into behavior change programs along with recommended dietary behavior changes. This article describes mindful eating and offers ideas for how to teach the basics of this practice. PMID- 28848311 TI - In-Hospital Administration of Insulin by Nurses in Northern Greece: An Observational Study. AB - OBJECTIVE: The purpose of this study is to explore current practice regarding insulin administration by nurses in a Greek public hospital. DESIGN AND METHODS: A mixed-methods qualitative data collection design was used with ad hoc nonparticipant observation and post hoc interviews with the staff involved. Insulin management and administration was observed and compared to international guidelines. A sample of 20 nurses from two medical wards was assessed on 100 occasions of insulin administration, and 8 nurses were subsequently interviewed. RESULTS: Inter-rater agreement was found to be satisfactory (average kappa 0.840). In 61% of all instances, nurses washed their hands before administering insulin, and, in 70%, they donned gloves before injections. In 64.5% of all instances, the nurses did not clean the insulin bottle before inserting the needle, and in 42.7% of instances, they did not check for air bubbles in the syringe. In 89.1% of instances, nurses did not check the injection site for appropriateness or other possible complications. However, in 90.9%, they cleaned the skin at the injection site with an alcohol swab. In 70.9% of all instances, the needle was placed vertically to the skin but without a skinfold. In 89.1% of instances, post-injection care was rated as poor. CONCLUSION: Overall, compliance with international guidelines regarding insulin administration techniques, as observed in these sample wards, is not satisfactory. Nurses in this Greek hospital tend to administer subcutaneous injections in ways not reflected in current research findings, practice guidelines, or evidence-based care recommendations. Evidently, Greek nurses in this sample require updating on current evidence-based practice, clinical guidelines, and protocols of care regarding routine insulin administration. PMID- 28848312 TI - Identifying User Preferences for a Digital Educational Solution for Young Seniors With Diabetes. AB - The Eindhoven Diabetes Education Simulator project was initiated to develop an educational solution that helps diabetes patients understand and learn more about their diabetes. This article describes the identification of user preferences for the development of such solutions. Young seniors (aged 50-65 years) with type 2 diabetes were chosen as the target group because they are likely to have more affinity with digital devices than older people and because 88% of the Dutch diabetes population is >50 years of age. Data about the target group were gathered through literature research and interviews. The literature research covered data about their device use and education preferences. To gain insight into the daily life of diabetes patients and current diabetes education processes, 20 diabetes patients and 10 medical experts were interviewed. The interviews were analyzed using affinity diagrams. Those diagrams, together with the literature data, formed the basis for two personas and corresponding customer journey maps. Literature showed that diabetes prevalence is inversely correlated to educational level. Computer and device use is relatively low within the target group, but is growing. The interviews showed that young seniors like to play board, card, and computer games, with others or alone. Family and loved ones play an important role in their lives. Medical experts are crucial in the diabetes education of young senior diabetes patients. These findings are translated into a list of design aspects that can be used for creating educational solutions. PMID- 28848313 TI - Lessons Learned From a Life With Type 1 Diabetes: Adult Perspectives. AB - Adults who have lived much of their life with type 1 diabetes have learned lessons that can benefit health care providers (HCPs), families, and young people who live with the condition. This study was undertaken to gain a better understanding of the challenges of growing up and living with type 1 diabetes from adults who have experienced those challenges and to recommend strategies for parents, caregivers, and HCPs who work with children or adolescents with type 1 diabetes. Thirty-five adults with type 1 diabetes participated in this qualitative study consisting of two in-depth interviews with each participant. Six themes emerged: 1) It's not who you are. 2) Don't let it limit you. 3) Get involved in diabetes support groups. 4) It's going to be OK. 5) Teach them; don't scare them. 6) Don't single kids out. Through hindsight and the more mature perspective of adulthood, study participants were able to share valuable insights that could inform the efforts of those who work with or care for younger people with type 1 diabetes. PMID- 28848314 TI - Interventions to Improve Adherence to a Hypoglycemia Protocol. AB - Background.. A formal evidence-based hypoglycemia protocol and treatment algorithm were developed to provide safe and effective management of hypoglycemia throughout the hospital and to support organization goals to achieve blood glucose control. However, rechecking blood glucose 15 minutes after treatment for hypoglycemia, as outlined in the protocol, was challenging for the nursing staff. Education was delivered several times, and hypoglycemia badge reference cards were provided to reinforce the protocol. Nursing staff observed that hypoglycemia treatment took several minutes, so the recheck was set at 15-30 minutes from the time hypoglycemia was identified. Audits and staff reeducation were performed, but compliance remained low. Objective.. A pilot was conducted to compare two innovative interventions to improve adherence to the protocol. Methods.. To improve timely rechecks, two different interventions were tested. The first required patient care technicians (PCTs) to remain in the patient's room for the full 15 minutes after treatment to perform the recheck. The second incorporated the use of timers to remind PCTs and nurses to perform the recheck. Results.. The timer group had significantly higher compliance with hypoglycemia rechecks than the group staying in the patient's room (84 vs. 52%, P <0.0001). It is difficult for a PCT to remain in a patient's room for a full 15 minutes. Timers enabled nurses and PCTs to perform other tasks without missing the recheck time. After implementation, the hospital achieved 75% compliance with the recheck. Conclusion.. This project demonstrated that the use of timers can be an effective and efficient way to remind busy hospital staff to recheck a patient's blood glucose after hypoglycemia treatment. PMID- 28848315 TI - Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes. AB - The incretin system has become an important target in the treatment of type 2 diabetes in recent years, and glucagon-like peptide 1 (GLP-1) is of particular interest for its glucose-lowering effects. The physiological response to oral ingestion of nutrients, involving the incretin system, is reduced in some patients with type 2 diabetes but may be augmented by administration of GLP-1 receptor agonists. The GLP-1 receptor agonists currently approved in the United States for the treatment of type 2 diabetes include exenatide (administered twice daily), liraglutide and lixisenatide (administered once daily), and the once weekly agents exenatide extended-release, albiglutide, and dulaglutide. These agents have been shown to reduce A1C (by ~0.8-1.6%), body weight (by ~1-3 kg), blood pressure, and lipids. GLP-1 receptor agonists are associated with a low risk of hypoglycemia, and the most common adverse effects are gastrointestinal. Proper patient selection and education can assist in achieving positive treatment outcomes. PMID- 28848316 TI - A Quality Improvement Program to Reduce Potential Overtreatment of Diabetes Among Veterans at High Risk of Hypoglycemia. AB - Background.. Intensive glycemic control confers increased risk of hypoglycemia and little benefit among older individuals with diabetes. The aim of this quality improvement project was to reduce the number of patients treated to A1C levels that might confer greater risk than benefit (i.e., potential overtreatment) in the VA New England Healthcare System. Methods.. A provider report and clinical reminder were created to identify potentially overtreated patients and prompt clinicians to consider treatment de-intensification. Potentially overtreated patients were defined as those on insulin or a sulfonylurea whose most recent A1C was <7.0% and who were >74 years of age or diagnosed with dementia or cognitive impairment. The numbers of patients screened and whose treatment was de intensified using the clinical reminder were counted from January to December 2014. The number of high-risk veterans at baseline was compared with that 6 and 18 months after implementation using t tests. Results.. A total of 2,830 patients were screened using the clinical reminder; 9.6% had their glycemic treatment de intensified. Among the 261 patients reporting hypoglycemia, 37% had their treatment de-intensified. Higher percentages of patients had treatment de intensified when reported symptoms were more severe. The monthly average in the high-risk cohort declined from baseline by 18% at 6 months and by 22% at 18 months (both P <0.005). Conclusions.. A clinical reminder helps clinicians identify and reduce the number of potentially overtreated patients. The large number of screened patients whose treatment was not de-intensified suggests that a clinical reminder should be combined with provider education, national guidelines, and performance measures aligned in the interest of reducing potential overtreatment. PMID- 28848317 TI - Rationalization, Development, and Implementation of a Preoperative Diabetes Optimization Program Designed to Improve Perioperative Outcomes and Reduce Cost. PMID- 28848319 TI - Magnetic resonance imaging study of eye congenital birth defects in mouse model. AB - PURPOSE: Embryonic eyelid closure is a well-documented morphogenetic episode in mammalian eye development. Detection of eyelid closure defect in humans is a major challenge because eyelid closure and reopen occur entirely in utero. As a consequence, congenital eye defects that are associated with failure of embryonic eyelid closure remain unknown. To fill the gap, we developed a mouse model of defective eyelid closure. This preliminary work demonstrates that the magnetic resonance imaging (MRI) approach can be used for the detection of extraocular muscle abnormalities in the mouse model. METHODS: Mice with either normal (Map3k1+/- ) or defective (Map3k1-/- ) embryonic eyelid closure were used in this study. Images of the extraocular muscles were obtained with a 9.4 T high resolution microimaging MRI system. The extraocular muscles were identified, segmented, and measured in each imaging slice using an in-house program. RESULTS: In agreement with histological findings, the imaging data show that mice with defective embryonic eyelid closure develop less extraocular muscle than normal mice. In addition, the size of the eyeballs was noticeably reduced in mice with defective embryonic eyelid closure. CONCLUSIONS: We demonstrated that MRI can potentially be used for the study of extraocular muscle in the mouse model of the eye open-at-birth defect, despite the lack of specificity of muscle group provided by the current imaging resolution. PMID- 28848318 TI - Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status. AB - PURPOSE: Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in OPA1, the gene most commonly involved in dominantly inherited optic atrophy. METHODS: Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in OPA1, OPA3, WFS1, and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing. RESULTS: Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in OPA1. Demographics, clinical history, and clinical features for the group of patients with mutations in OPA1 were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in OPA1 were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in OPA1. OPA1 mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in OPA1 (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of OPA1 mutation positive and 66.0% of OPA1 mutation negative). CONCLUSIONS: Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in OPA1. Patients with mutations in OPA1 were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an OPA1 mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in OPA1, underscores the need for genetic testing to establish an OPA1 genetic diagnosis. PMID- 28848320 TI - Heparanase mediates vascular endothelial growth factor gene transcription in high glucose human retinal microvascular endothelial cells. AB - PURPOSE: To observe the nuclear expression and interaction of heparanase and RNA polymerase II (RNA Pol II), an enzyme that catalyzes the transcription of DNA in eukaryotic cells) in human retinal microvascular endothelial cells (HRECs) under high glucose condition and to investigate the association of heparanase with the transcription activity of the vascular endothelial growth factor (VEGF) gene promoter. METHODS: Cultured HRECs were maintained for 3 days in media with high or normal glucose. The expressions of heparanase and RNA Pol II in each group were analyzed with immunofluorescence. Co-immunoprecipitation was applied to detect the interaction of heparanase and Pol II proteins. Cells in both groups were used for chromatin immunoprecipitation (ChIP) with anti-heparanase and anti RNA Pol II antibodies to identify high-confidence heparanase-binding regions across the entire VEGF gene promoter. Moreover, real-time PCR was used to demonstrate the interaction between heparanase and the VEGF gene promoter region. RESULTS: The immunofluorescence studies showed that the nuclear expression of heparanase was intense in high-glucose HRECs but faint in the normal group; RNA Pol II in the nucleus was also intense in high glucose HRECs, and the distribution of heparanase was consistent with that of RNA Pol II. The co immunoprecipitation data showed that heparanase combined with RNA Pol II in HRECs cells treated with high glucose, and the molecular size of HPA interacted with RNA Pol II was 50 kDa, while no combination of two proteins was evident in normal HRECs cells. Real-time PCR-based ChIP results showed that the high-confidence HPA binding region was -1155 to -1018 (containing hypoxia response element) in the VEGF gene promoter, and the cells treated with high glucose showed increases in heparanase and RNA Pol II in the VEGF gene promoter region compared with the normal glucose treated cells (t = -3.244, p = 0.032; t = -6.096, p = 0.004, respectively). CONCLUSIONS: Nuclear heparanase combines directly with the VEGF gene promoter and is involved in the regulation of VEGF gene transcription in high-glucose HRECs. PMID- 28848321 TI - Association and interaction of myopia with SNP markers rs13382811 and rs6469937 at ZFHX1B and SNTB1 in Han Chinese and European populations. AB - PURPOSE: Previously, a genome-wide association study (GWAS) identified rs13382811 (near ZFHX1B) and rs6469937 (near SNTB1) to be associated with high myopia. The present study evaluates the association of these two single nucleotide polymorphisms (SNPs) with moderate to high myopia in two Chinese cohorts and two cohorts of European populations. METHODS: Two Chinese university student cohorts, including one with 300 unrelated subjects with high myopia and 308 emmetropic controls from Guangzhou and a second with 96 unrelated individuals with moderate to high myopia and 96 emmetropic controls of Chaoshanese origin in Guangzhou, were enrolled in this study. Two SNPs, rs6469937 and rs13382811, were selected for genotyping based on their reported associations with severe myopia. The SNPs were genotyped via DNA sequencing. In addition, association analysis of both SNPs was performed using genotype data from the database of Genotypes and Phenotypes (dbGaP) involving a total of 2,423 samples in two independent cohorts of European derived populations, as follows: Kooperative Gesundheitsforschung in der Region Augsburg (KORA) and TwinsUK. The allelic and genotypic distribution among cases and controls were analyzed using the Chi-square test. Logistic regression was used to evaluate the SNP-SNP interaction. Fisher's exact test was used for two SNP comparisons. RESULTS: In the Guangzhou cohort, SNP rs13382811 near ZFHX1B showed significant association with high myopia (pallelic = 0.0001, pgenotypic = 4.07 * 10-5), with the minor T allele showing an increased risk of high myopia (odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.28-2.20). SNP rs6469937 near SNTB1 showed nominal evidence of association (pallelic = 0.0085, pgenotypic = 0.0166), which did not withstand correction for multiple testing. No significant association was detected in the smaller Chaoshan cohort alone. The association of SNPs rs13382811 and rs6469937 remained significant when both Han Chinese cohorts were combined (pallelic = 0.0033 and 0.0016, respectively), and it was also significant under the genotypic test (pgenotypic = 0.0036 and 0.0053, respectively). When both SNPs were considered together under a recessive model, their significance increased (p = 8.37 * 10-4), as did their effect (OR = 4.09, 95%CI = 1.7-9.8). The association between either of these two SNPs alone and myopia did not replicate significantly in the combined cohorts of European descent, providing only suggestive results (pallelic = 0.0088 for rs13382811 and pallelic = 0.0319 for rs6469937). However, the effects of the combined SNPs showed significant association (p = 8.2 * 10-4; OR = 1.56, 95%CI = 1.2-2.0). While the risk for myopia increased with risk alleles from both SNPs, the increase was additive rather representing a multiplicative interaction in both populations. CONCLUSIONS: Our study confirms that the two susceptibility loci ZFHX1B and SNTB1 are associated with moderate to high myopia in a Han Chinese population, as well as in a European population, when both SNPs are combined. These results confirm previous reports of their associations, extend these observations to a European population, and suggest that additional interactive and possibly population-specific genetic or environmental factors may affect their contribution to myopia. PMID- 28848323 TI - Glaucoma drainage device implantation with adjunctive intravitreal bevacizumab in neovascular glaucoma: 3-year experience. AB - PURPOSE: To evaluate the outcome of glaucoma drainage device (GDD) implantation with and without intravitreal bevacizumab (IVB) injection in treating neovascular glaucoma (NVG) at Cipto Mangunkusumo Hospital Jakarta, Indonesia. PATIENTS AND METHODS: This retrospective study involved 39 eyes with NVG which underwent GDD implantation between 2012 and 2014. Thirty eyes underwent GDD implantation alone (control group) while 9 eyes underwent GDD implantation and IVB injection (IVB group). Visual acuity (VA), intraocular pressure (IOP), number of antiglaucoma medications, and success rate were compared between groups. RESULTS: There were no significant differences in preoperative characteristics. On the last visit, VA was 2.6 (0.2-4.0) logMAR in the control group and 2.3 (0.4-4.0) logMAR in the IVB group (P=0.97). In the control group, final VA was significantly worse compared to initial VA (P<0.01), while in IVB group VA was apparently stable (P=0.24). Final IOP was 16.3+/-10.3 mmHg in the control group and 12.0 (2.0-49.0) mmHg in IVB group (P=0.40). The number of antiglaucoma medications was similar between groups (P=0.57). Surgical success rate in the IVB group (66.7%) was better than the control group (56.7%), but this difference was not statistically significant (P=0.71). Kaplan-Meier survival analysis showed the probability of success 37 months after surgery as 53.6% in the IVB group and 31.6% in the control group. No significant difference was found between the groups (P=0.45). CONCLUSION: In cases of NVG, GDD combined with IVB could maintain VA compared to GDD alone. However, there were no significant differences in final IOP, number of antiglaucoma medications, and surgical success rate. PMID- 28848322 TI - Clinical spectrum and management options in Vogt-Koyanagi-Harada disease. AB - PURPOSE: The aim of this study was to describe the clinical features, treatment options, and visual outcome of Vogt-Koyanagi-Harada (VKH) disease patients over a 9-year period. METHOD: A retrospective chart analysis of 32 patients with VKH, from January 2007 to December 2015, at a tertiary care government medical college eye hospital in South India. RESULTS: A total of 32 patients were diagnosed with VKH. The mean age at diagnosis was 32.03+/-8.8 years. There were 24 patients (42 eyes) with acute VKH and eight patients (16 eyes) with recurrent/chronic VKH. The mean baseline best-corrected visual acuity on presentation in the acute VKH group was 5/60 (1.114+/-0.565) and at last follow-up it was 6/9 (0.225+/-0.157). Intravenous methyl prednisolone (IVMP) was administered for 3 days to all patients with acute and recurrent VKH, followed by posterior subtenon triamcinolone (40 mg/mL) and oral azathioprine. CONCLUSION: VKH-related uveitis is more common in the female gender in this South Indian population. Posterior uveitis is the most common initial manifestation. Initial aggressive treatment with IVMP, peribulbar long-acting corticosteroids, and immunosuppressives, avoiding side effects of systemic steroids, gives a good visual outcome without recurrences. Cases of unilateral VKH, seen in six patients, are the initial manifestations in the natural course of the disease, which if managed aggressively at the acute stage prevents recurrence in the other eye. PMID- 28848324 TI - The Prospective Health Assessment of Cataract Patients' Ocular Surface (PHACO) study: the effect of dry eye. AB - PURPOSE: To determine the incidence and severity of dry eye as determined by the International Task Force (ITF) scale in patients being screened for cataract surgery. PATIENTS AND METHODS: This was a prospective, multi-center, observational study of 136 patients, at least 55 years of age, who were scheduled to undergo cataract surgery. The primary outcome measure was the incidence of dry eye as evaluated by grade on the ITF scale and secondary outcome measures include tear break-up time (TBUT), ocular surface disease index score, corneal staining with fluorescein, conjunctival staining with lissamine green, and a patient questionnaire to evaluate symptoms of dry eye. RESULTS: Mean patient age was 70.7 years. A total of 73.5% of patients were Caucasian and 50% were female. Almost 60% had never complained of a foreign body sensation; only 13% complained of a foreign body sensation half or most of the time. The majority of patients (62.9%) had a TBUT <=5 seconds, 77% of eyes had positive corneal staining and 50% of the eyes had positive central corneal staining. Eighteen percent had Schirmer's score with anesthesia <=5 mm. CONCLUSION: The incidence of dry eye in patients scheduled to undergo cataract surgery in a real-world setting is higher than anticipated. PMID- 28848325 TI - Visual field examination method using virtual reality glasses compared with the Humphrey perimeter. AB - PURPOSE: To present a visual field examination method using virtual reality glasses and evaluate the reliability of the method by comparing the results with those of the Humphrey perimeter. MATERIALS AND METHODS: Virtual reality glasses, a smartphone with a 6 inch display, and software that implements a fast-threshold 3 dB step staircase algorithm for the central 24 degrees of visual field (52 points) were used to test 20 eyes of 10 patients, who were tested in a random and consecutive order as they appeared in our glaucoma department. The results were compared with those obtained from the same patients using the Humphrey perimeter. RESULTS: High correlation coefficient (r=0.808, P<0.0001) was found between the virtual reality visual field test and the Humphrey perimeter visual field. CONCLUSION: Visual field examination results using virtual reality glasses have a high correlation with the Humphrey perimeter allowing the method to be suitable for probable clinical use. PMID- 28848326 TI - Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome: design, development, and potential place in therapy. AB - Cancer anorexia-cachexia syndrome (CACS) is a complex and largely untreatable paraneoplastic complication common in advanced cancer. It is associated with profoundly deleterious effects on quality of life and survival. Since its discovery over a decade ago, anamorelin hydrochloride (anamorelin), a mimetic of the growth hormone secretagogue ghrelin, has shown considerable promise in ameliorating components of CACS when administered to patients with advanced cancer, including loss of lean body mass and reversal of anorexia. This review summarizes the development of anamorelin and its safety and efficacy in clinical investigations. The potential future role of anamorelin in treating CACS is also discussed. PMID- 28848328 TI - Microbial challenge test of a novel epoprostenol sodium formulation. AB - AIM: The aim of the current study was to present a comprehensive display of antimicrobial activity of a novel epoprostenol sodium formulation with respect to seven different microorganisms, two levels of inoculation (102-103 colony forming units [CFU]/mL and 105-106 CFU/mL), two diluents (sterile water for injection [SWI] and sterile saline [sodium chloride 0.9%] for injection [SSI]), two concentrations (3,000 ng/mL and 15,000 ng/mL), and seven different storage time points at two temperatures (up to 10 days at 2 degrees C-8 degrees C and 20 degrees C-25 degrees C). MATERIALS AND METHODS: Antimicrobial activity was evaluated for, 1) solutions at 3,000 ng/mL inoculated with 102-103 CFU/mL and 105 106 CFU/mL; and 2) solutions at 15,000 ng/mL inoculated with 102-103 CFU/mL and 105-106 CFU/mL. All solutions were stored for up to 10 days at 2 degrees C-8 degrees C and 20 degrees C-25 degrees C. Solutions were prepared by reconstitution and further dilution of an epoprostenol sodium formulation using SWI or SSI. Antimicrobial activity was measured after inoculation with seven species of bacteria, yeast, and mold. RESULTS: For all solutions, after 10 days, no microbial growth with respect to initial inoculum was observed, with the exception of a few early time points when using SWI as diluent. Some microorganisms died off completely, whereas others remained stable overall or returned to initial levels. Prior to decreasing, some microorganisms displayed a slight initial increase, presumed to be caused by breakup of clusters. Storage temperature had a negligible influence on the results, whereas choice of diluent (SSI or SWI) impacted growth kinetics in that SSI had a greater antimicrobial effect than SWI. CONCLUSION: Upon reconstitution and further dilution of the novel epoprostenol formulation to concentrations of 3,000 ng/mL and 15,000 ng/mL with SWI or SSI, the resulting solutions did not support growth of the tested microorganisms when stored at 2 degrees C-8 degrees C or 20 degrees C-25 degrees C for up to 10 days. PMID- 28848327 TI - Isatin-benzoazine molecular hybrids as potential antiproliferative agents: synthesis and in vitro pharmacological profiling. AB - In continuation of our endeavor with respect to the development of potent and effective isatin-based anticancer agents, we adopted the molecular hybridization approach to design and synthesize four different sets of isatin-quinazoline (6a-f and 7a-e)/phthalazine (8a-f)/quinoxaline (9a-f) hybrids. The antiproliferative activity of the target hybrids was assessed towards HT-29 (colon), ZR-75 (breast) and A-549 (lung) human cancer cell lines. Hybrids 8b-d emerged as the most active antiproliferative congener in this study. Compound 8c induced apoptosis via increasing caspase 3/7 activity by about 5-fold in the A-549 human cancer cell line. In addition, it exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell cycle effect assay. Furthermore, it displayed an inhibitory concentration 50% value of 9.5 uM against multidrug-resistant NCI H69AR lung cancer cell line. The hybrid 8c was also subjected to in vitro metabolic investigations through its incubation with rat liver microsomes and analysis of the resulting metabolites with the aid of liquid chromatography-mass spectrometry. PMID- 28848329 TI - Effects of carbonated liquid on swallowing dysfunction in dementia with Lewy bodies and Parkinson's disease dementia. AB - BACKGROUND: Swallowing dysfunction is an increasingly recognized problem in patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which can result in aspiration pneumonia and death. Few studies have examined potential ways of improving swallowing function in this fragile patient group. The aim of this study was to evaluate swallowing dysfunction and carbonated liquid using videofluoroscopy in DLB and PDD patients. METHODS: A total of 48 patients with DLB and PDD were referred for a clinical examination with videofluoroscopy. Descriptive overall assessments were provided at the time of the examination regarding swallowing function and the effects of different modifications, including carbonated thin liquid (CTL). Additionally, a repeated measures quantitative retrospective analysis has been performed comparing 1) thin liquids; 2) thickened liquids and 3) CTLs, with regard to the quantitative variables 1) pharyngeal transit time (PTT); 2) pharyngeal retention and 3) tracheal penetration. RESULTS: In all, 40/48 (83%) of the patients had a swallowing dysfunction, which was confirmed on videofluoroscopy, with 34/40 (85%) patients having a pharyngeal-type dysfunction. A total of 14/40 (35%) patients with an objective swallowing impairment did not have any subjective swallowing symptoms. Out of the patients with swallowing dysfunction, 87% had an overall improved swallowing function with carbonated liquid. PTT for carbonated liquid (median 633 ms, interquartile range [IQR] 516-786 ms) was quicker than for thin liquid (760 ms, IQR 613-940 ms, P=0.014) and thickened liquid (880.0 ms, IQR 600 1,500 ms, P<0.001). No significant effect was seen in residue or penetration. CONCLUSION: The majority of patients with DLB or PDD had a swallowing dysfunction, sometimes without subjective swallowing symptoms, which improved with carbonated liquid. This highlights the importance of investigating patients with videofluoroscopy and to carry out a prospective interventional study to further evaluate carbonated liquid, also addressing the effects on quality of life, aspiration and mortality. PMID- 28848330 TI - Yogurt supplemented with probiotics can protect the healthy elderly from respiratory infections: A randomized controlled open-label trial. AB - PURPOSE: To evaluate whether yogurt supplemented with a probiotic strain could protect middle-aged and elderly people from acute upper respiratory tract infections (URTI) using a randomized, blank-controlled, parallel-group design. PATIENTS AND METHODS: Two hundred and five volunteers aged >=45 years were randomly divided into two groups. The subjects in the intervention group were orally administered 300 mL/d of yogurt supplemented with a probiotic strain, Lactobacillus paracasei N1115 (N1115), 3.6*107 CFU/mL for 12 weeks, while those in the control group retained their normal diet without any probiotic supplementation. The primary outcome was the incidence of URTI, and changes in serum protein, immunoglobulins, and the profiles of the T-lymphocyte subsets (total T-cells [CD3+], T-helper cells [CD4+], and T-cytotoxic-suppressor cells [CD8+]) during the intervention were the secondary outcomes. RESULTS: Compared to the control group, the number of persons diagnosed with an acute URTI and the number of URTI events significantly decreased in the intervention group (P=0.038, P=0.030, respectively). The risk of URTI in the intervention group was evaluated as 55% of that in the control group (relative risk =0.55, 95% CI: 0.307-0.969). The change in the percentage of CD3+ cells in the intervention group was significantly higher than in the control group (P=0.038). However, no significant differences were observed in the total protein, albumin, globulin, and prealbumin levels in both groups (P>0.05). CONCLUSION: The study suggested that yogurt with selected probiotic strains such as N1115 may reduce the risk of acute upper tract infections in the elderly. The enhancement of the T-cell-mediated natural immune defense might be one of the important underlying mechanisms for probiotics to express their anti-infective effects. PMID- 28848331 TI - R2(GFR)CHADS2 and R2(GFR)CHA2DS2VASc schemes improved the performance of CHADS2 and CHA2DS2VASc scores in death risk stratification of Chinese older patients with atrial fibrillation. AB - BACKGROUND: This analysis was carried out to refine the CHADS2 and CHA2DS2VASc scores by combining creatinine clearance (CrCl) and glomerular filtration rate (GFR) and evaluate the performance of CrCl-based and GFR-based schemes in death risk stratification of Chinese older patients with atrial fibrillation (AF). METHODS: There were 219 older patients with AF, and all-cause mortality was assessed during the follow-up of 1.11 years. Renal function was evaluated using the CrCl formula and different GFR (Modification of Diet in Renal Disease [MDRD], Chinese MDRD [CMDRD], Mayo Clinic Quadratic [Mayo] and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) formulas, and five kinds of R2CHADS2 and R2CHA2DS2VASc schemes were generated by combining CrCl and GFR with CHADS2 and CHA2DS2VASc scores. RESULTS: In Cox regression multivariate analysis, CrCl <60 mL/min was moderately associated with death risk (P=0.122 and P=0.144). When MDRD, CMDRD, CKD-EPI and Mayo formulas were used to ascertain the GFR, GFR <60 mL/min/1.73 m2 was significantly associated with death risk (P<0.001 for all). In the models with CHADS2 and CHA2DS2VASc scores as the linear covariates, CrCl and GFR as the continuous variables were significantly associated with death risk (P<0.05 for all). C-statistics of CrCl-based schemes - R2(CrCl)CHADS2 and R2(CrCl) CHA2DS2VASc - moderately exceeded that of CHADS2 and CHA2DS2VASc scores (P=0.081 and 0.082). C-statistics of GFR-based schemes - R2(GFR)CHADS2 and R2(GFR)CHA2DS2VASc - significantly exceeded that of CHADS2 and CHA2DS2VASc scores (P<0.05 for all). CONCLUSION: Chinese older patients with AF with lower levels of GFR and GFR <60 mL/min/1.73 m2 had a significantly high death risk, and those with lower levels of CrCl or CrCl <60 mL/min had a significantly or modestly high death risk. There was significantly better performance of GFR-based schemes and moderately better performance of CrCl-based schemes in death risk stratification compared with CHADS2 and CHA2DS2VASc scores. PMID- 28848332 TI - Acute care of severely frail elderly patients in a CGA-unit is associated with less functional decline than conventional acute care. AB - BACKGROUND: A high percentage of individuals treated in specialized acute care wards are frail and elderly. Our aim was to study whether the acute care of such patients in a comprehensive geriatric assessment (CGA) unit is superior to care in a conventional acute medical care unit when it comes to activities of daily living (ADLs), frailty, and use of municipal help services. PATIENTS AND METHODS: A clinical, prospective, controlled trial with two parallel groups was conducted in a large county hospital in West Sweden and included 408 frail elderly patients, age 75 or older (mean age 85.7 years; 56% female). Patients were assigned to the intervention group (n=206) or control group (n=202). Primary outcome was decline in functional activity ADLs assessed by the ADL Staircase 3 months after discharge from hospital. Secondary outcomes were degree of frailty and use of municipal help services. RESULTS: After adjustment by regression analyses, treatment in a CGA unit was independently associated with lower risk of decline in ADLs [odds ratio (OR) 0.093; 95% confidence interval (CI) 0.052-0.164; P<0.0001], and with a less prevalent increase in the degree of frailty (OR 0.229; 95% CI 0.131-0.400; P<0.0001). When ADLs were classified into three strata (independence, instrumental ADL-dependence, and personal ADL-dependence), changes to a more dependence-associated stratum were less prevalent in the intervention group (OR 0.194; 95% CI 0.085-0.444; P=0.0001). There was no significant difference between the groups in increased use of municipal help services (OR 0.682; 95% CI 0.395-1.178; P=0.170). CONCLUSION: Acute care of frail elderly patients in a CGA unit was independently associated with lesser loss of functional ability and lesser increase in frailty after 3 months. PMID- 28848333 TI - MRI assessment of whole-brain structural changes in aging. AB - PURPOSE: One of the central features of brain aging is the accumulation of multiple age-related structural changes, which occur heterogeneously in individuals and can have immediate or potential clinical consequences. Each of these deficits can coexist and interact, producing both independent and additive impacts on brain health. Many of the changes can be visualized using MRI. To collectively assess whole-brain structural changes, the MRI-based Brain Atrophy and Lesion Index (BALI) has been developed. In this study, we validate this whole brain health assessment approach using several clinical MRI examinations. MATERIALS AND METHODS: Data came from three independent studies: the Alzheimer's Disease Neuroimaging Initiative Phase II (n=950; women =47.9%; age =72.7+/-7.4 years); the National Alzheimer's Coordinating Center (n=722; women =55.1%; age =72.7+/-9.9 years); and the Tianjin Medical University General Hospital Research database on older adults (n=170; women =60.0%; age =62.9+/-9.3 years). The 3.0 Tesla MRI scans were evaluated using the BALI rating scheme on the basis of T1 weighted (T1WI), T2-weighted (T2WI), T2-weighted fluid-attenuated inversion recovery (T2-FLAIR), and T2*-weighted gradient-recalled echo (T2*GRE) images. RESULTS: Atrophy and lesion changes were commonly seen in each MRI test. The BALI scores based on different sequences were highly correlated (Spearman r2>0.69; P<0.00001). They were associated with age (r2>0.29; P<0.00001) and differed by cognitive status (chi2>26.48, P<0.00001). T2-FLAIR revealed a greater level of periventricular (chi2=29.09) and deep white matter (chi2=26.65, P<0.001) lesions than others, but missed revealing certain dilated perivascular spaces that were seen in T2WI (P<0.001). Microhemorrhages occurred in 15.3% of the sample examined and were detected using only T2*GRE. CONCLUSION: The T1WI- and T2WI-based BALI evaluations consistently identified the burden of aging and dementia-related decline of structural brain health. Inclusion of additional MRI tests increased lesion differentiation. Further research is to integrate MRI tests for a clinical tool to aid the diagnosis and intervention of brain aging. PMID- 28848334 TI - Predictors of high on-aspirin platelet reactivity in elderly patients with coronary artery disease. AB - OBJECTIVES: Previous studies have illustrated the link between high on-aspirin platelet reactivity (HAPR) with increasing thrombotic risks. The aim of our study was to investigate relative risk factors of HAPR in elderly patients with coronary artery disease. METHODS: Elderly, hospitalized coronary artery disease patients on regular aspirin treatment were enrolled from January 2014 to September 2016. Medical records of each patient were collected, including demographic information, cardiovascular risk factors, concomitant drugs and routine biological parameters. Arachidonic acid (AA, 0.5 mg/mL) and adenosine diphosphate (ADP, 5 umol/L) induced platelet aggregation were measured via light transmission assay (LTA) to evaluate antiplatelet responses, referred as LTA-AA and LTA-ADP. RESULTS: A total of 275 elderly patients were included, with mean age of 77.2+/-8.1 years, and males accounted for 81.8%. HAPR was defined as LTA AA in the upper quartile of the enrolled population. HAPR patients tended to have lower renal function (P=0.052). Higher serum uric acid (SUA) level, as well as lower platelet count, hemoglobin and hematocrit were observed in HAPR patients, with a higher proportion of diuretics use (P<0.05). Multivariate analysis revealed that SUA (OR: 1.004, 95% CI: 1.000-1.007, P=0.048), platelet count (OR: 0.994, 95% CI: 0.989-1.000, P=0.045), hematocrit (OR: 0.921, 95% CI: 0.864-0.981, P=0.011) and concomitant P2Y12 receptor inhibitors use (OR: 1.965, 95% CI: 1.075 3.592, P=0.028) were correlated with HAPR. Spearman's correlation analysis demonstrated an inverse association of LTA-AA with hematocrit (r=-0.234, P<0.001), hemoglobin (r=-0.209, P<0.001) and estimated glomerular filtration rate (r=-0.132, P=0.031). CONCLUSION: SUA, platelet count, hematocrit and P2Y12 receptor inhibitors use were independently correlated with HAPR. These parameters might provide novel therapeutic targets for optimizing antiplatelet therapy. PMID- 28848336 TI - Presence of sarcopenia in asthma-COPD overlap syndrome may be a risk factor for decreased bone-mineral density, unlike asthma: Korean National Health and Nutrition Examination Survey (KNHANES) IV and V (2008-2011). AB - BACKGROUND: Sarcopenia and decreased bone-mineral density (BMD) are common in elderly people, and are major comorbidities of obstructive airway disease (OAD). However, the relationship between sarcopenia and BMD in each OAD phenotype, especially asthma-COPD overlap syndrome (ACOS), is not yet clear. We aimed to evaluate differences in BMD according to the presence of sarcopenia in each OAD phenotype. MATERIALS AND METHODS: Among the research subjects in KNHANES IV and V (2008-2011), 5,562 were >=50 years old and underwent qualified spirometry and dual-energy X-ray absorptiometry. A total of 947 subjects were included in the study: 89 had asthma, 748 COPD, and 110 ACOS. RESULTS: In the COPD and ACOS phenotypes, T-scores were lower in the sarcopenia group than the nonsarcopenia group. Prevalence rates of osteopenia and osteoporosis were higher in the sarcopenia group than the nonsarcopenia group. (P<0.001 and P=0.017, respectively). The sarcopenia group had higher risks of developing osteopenia, osteoporosis, and low BMD than the nonsarcopenia group in the ACOS phenotype (OR 6.620, 95% CI 1.129-38.828 [P=0.036], OR 9.611, 95% CI 1.133-81.544 [P=0.038], and OR 6.935, 95% CI 1.194-40.272 [P=0.031], respectively). However, in the asthma phenotype, the sarcopenia group showed no increased risk compared with the nonsarcopenia group. CONCLUSION: In the ACOS phenotype, individuals with sarcopenia had a higher prevalence rate and higher risks of osteopenia and osteoporosis than those without sarcopenia among all OAD phenotypes. PMID- 28848335 TI - Small airways disease: time for a revisit? AB - It is increasingly acknowledged that delays in the diagnosis of chronic inflammatory lung conditions have hampered our understanding of pathogenesis and thus our ability to design efficacious therapies. This is particularly true for COPD, where most patients are diagnosed with moderate-to-severe airflow obstruction and little is known about the inflammatory processes present in early disease. There is great interest in developing screening tests that can identify those most at risk of developing COPD before airflow obstruction has developed for the purpose of research and clinical care. Landmark pathology studies have suggested that damage to the small airways precedes the development of airflow obstruction and emphysema and, thus, presents an opportunity to identify those at risk of COPD. However, despite a number of physiological tests being available to assess small airways function, none have been adopted into routine care in COPD. The reasons that tests of small airways have not been utilized widely include variability in test results and a lack of validated reference ranges from which to compare results for some methodologies. Furthermore, population studies have not consistently demonstrated their ability to diagnose disease. However, the landscape may be changing. As the equipment that delivers tests of small airways become more widely available, reference ranges are emerging and newer methodologies specifically seek to address variability and difficulty in test performance. Moreover, there is evidence that while tests of small airways may not be helpful across the full range of established disease severity, there may be specific groups (particularly those with early disease) where they might be informative. In this review, commonly utilized tests of small airways are critically appraised to highlight why these tests may be important, how they can be used and what knowledge gaps remain for their use in COPD. PMID- 28848337 TI - A comprehensive analysis of association of medical history with airflow limitation: a cross-sectional study. AB - BACKGROUND: Multiple comorbidity is common and increases the complexity of the presentation of patients with COPD. This study was a comprehensive analysis of the relationship between a medical history of 22 disease categories and the presence of airflow limitation (AL) without any history of asthma or bronchiectasis, compatible with COPD. METHODS: A total of 11,898 Japanese patients aged >=40 years, who underwent spirometry tests, comprising patients with AL (n=2,309) or without AL (n=9,589), were evaluated. Generalized estimating equations were used to assess the relationship between the presence of AL and each disease. The model was adjusted for age, sex, body mass index (BMI) and pack years of smoking. RESULTS: In multivariate analysis, female sex (odds ratio [OR]: 0.59; 95% confidence interval [CI]: 0.52-0.67), age (OR for 10-year age increase: 1.99; CI: 1.90-2.09), BMI (OR for 1 kg/m2 increase: 0.96; CI: 0.95-0.98) and smoking history (<15 vs 15-24, 25-49 and >=50 pack-years; OR: 1.78, 2.6 and 3.69, respectively; CI: 1.46-2.17, 2.24-3.0 and 3.15-4.33, respectively) were significantly associated with the presence of AL. In addition, a history of tuberculosis (OR: 1.72; CI: 1.39-2.11), primary lung cancer (OR: 1.50; CI: 1.28 1.77), myocardial infarction (OR: 1.22; CI: 1.01-1.48), heart failure (OR: 1.53; CI: 1.29-1.81), arrhythmia (OR: 1.19; CI: 1.03-1.38) or heart valve disorder (OR: 1.33; CI: 1.14-1.56) was significantly associated with the presence of AL, after adjustment. CONCLUSION: This study suggests that a history of heart disease leading to abnormal cardiac function may be associated with AL and that the presence of certain types of heart disease provides a rationale to assess lung status and look for respiratory impairment, including COPD. PMID- 28848338 TI - Identification and distribution of COPD phenotypes in clinical practice according to Spanish COPD Guidelines: the FENEPOC study. AB - BACKGROUND: The Spanish Guidelines for COPD (GesEPOC) describe four clinical phenotypes: non-exacerbator (NE), asthma-COPD overlap syndrome (ACO), frequent exacerbator with emphysema (EE), and exacerbator with chronic bronchitis (ECB). The objective of this study was to determine the frequency of COPD phenotypes, their clinical characteristics, and the availability of diagnostic tools to classify COPD phenotypes in clinical practice. MATERIALS AND METHODS: This study was an epidemiological, cross-sectional, and multi-centered study. Patients >=40 years old with a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio of <0.7 and who were smokers or former smokers (with at least 10 pack-years) were included. The availability of diagnostic tools to classify COPD phenotypes was assessed by an ad hoc questionnaire. RESULTS: A total of 647 patients (294 primary care [PC], 353 pulmonology centers) were included. Most patients were male (80.8%), with a mean age (SD) of 68.2 (9.2) years, mean post-bronchodilator FEV1 was 53.2% (18.9%) and they suffered a mean of 2.2 (2.1) exacerbations in the last year. NE was the most frequent phenotype (47.5%) found, followed by ECB (29.1%), EE (17.0%), and ACO (6.5%). Significant differences between the four phenotypes were found regarding age; sex; body mass index; FEV1; body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE)/body mass index, airflow obstruction, dyspnea and exacerbations (BODEx) index; modified Medical Research Council dyspnea scale; respiratory symptoms; comorbidi-ties; hospitalizations; and exacerbations in the last year. Physicians considered that >80% of the diagnostic tools needed to classify COPD phenotypes were available, with the exception of computed tomography (26.9%) and carbon monoxide transfer test (13.5%) in PC, and sputum eosinophilia count in PC and pulmonology centers (40.4% and 49.4%, respectively). CONCLUSION: In Spanish clinical practice, almost half of the patients with COPD presented with NE phenotype. The prevalence of ACO according to the Spanish consensus definition was very low. In general, physicians indicated that they had the necessary tools for diagnosing COPD phenotypes. PMID- 28848339 TI - Hand grip strength in patients with chronic obstructive pulmonary disease. AB - PURPOSE: Hand grip strength (HGS) is a simple way of predicting the risk of cardiovascular disease and all-cause mortality in the general population. However, the practical significance of grip strength in patients with COPD is uncertain. The aim of this study was to compare HGS between subjects with and without COPD and to evaluate its clinical relevance in patients with COPD by using a national survey. METHODS: Data were collected from the Korean National Health and Nutrition Examination Survey. The study included 421 adults with COPD and 2,542 controls who completed questionnaires, spirometry, and a HGS test. HGS was compared between subjects with and without COPD, and the association between grip strength, lung function, and quality of life (QoL) was evaluated. RESULTS: The mean HGS was 33.3+/-9.1 kg in the COPD group and 29.9+/-9.5 kg in the non COPD group; adjusted HGS was 30.9+/-0.33 kg and 30.9+/-0.11 kg, respectively (P=0.99). HGS was not related to forced vital capacity (beta=0.04, P=0.70) or forced expiratory volume in 1 second (beta=0.11, P=0.24) in multivariable analysis. HGS was independently associated with the EQ-5D index, but the relationship was stronger in the COPD group (beta=0.30, P<0.001) than in the non COPD group (beta=0.21, P<0.001). The results were similar for each component of the EQ-5D, including mobility (beta=-0.25, P<0.001), daily activity (beta=-0.19, P=0.01), pain/discomfort (beta=-0.32, P<0.001), and anxiety/depression (beta= 0.16, P=0.01). CONCLUSION: HGS was not different between subjects with and without COPD, but was associated with QoL - including mobility, daily activity, pain/discomfort, and anxiety/depression - in patients with COPD. The HGS test could be used as a marker of QoL in patients with COPD and could assist risk stratification in clinical practice. PMID- 28848340 TI - Network meta-analysis of success rate and safety in antibiotic treatments of bronchitis. AB - The purpose of this study was to compare the relative efficacy and safety of different antibiotic drugs and recommend superior regimens in the treatment of bronchitis. With respect to the antibiotic comparisons against quinolones in terms of intention-to-treat patients, we concluded that quinolones had advantages over placebo, beta-lactams, sulfonamides, and double beta-lactams. Concerning treatment methods for clinically evaluable patients, quinolones demonstrated better performance than beta-lactams and sulfonamides. The secondary effects of macrolides, quinolones, and double beta-lactams were significantly more adverse than beta-lactams with odds ratios (ORs) of 1.5 (95% credible interval [CrI] =1.1 2.0), 1.7 (95% CrI =1.2-2.3), and 2.7 (95% CrI =1.8-4.1), respectively. Significant differences in the prevalence of diarrhea as a secondary effect were only identified among the comparisons of double beta-lactams against beta-lactams and macrolides (OR =5.0, 95% CrI =2.1-12.0; OR =3.0, 95% CrI =1.7-5.4, respectively). Quinolones can be recommended as the superior treatment for bronchitis, in accordance with our cluster analysis with surface under the cumulative ranking curve. The primary outcomes of network meta-analysis indicated that quinolones showed the best performance among the 8 treatments studied, although beta-lactams showed the lowest risk of adverse side effects. Quinolones are recommended as the primary treatment option for bronchitis patients, having taking into account the success rates and safety profiles of the eight drugs studied here. PMID- 28848342 TI - Erratum: In vivo targeted gene delivery to peripheral neurons mediated by neurotropic poly(ethylene imine)-based nanoparticles [Corrigendum]. AB - [This corrects the article on p. 2675 in vol. 11, PMID: 27354797.]. PMID- 28848341 TI - Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts. AB - Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood-brain barrier (BBB) or blood-tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20+/-1.18 ug PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma. PMID- 28848343 TI - Fabrication and physicochemical characterization of porous composite microgranules with selenium oxyanions and risedronate sodium for potential applications in bone tumors. AB - Nanocrystalline hydroxyapatite containing selenite ions (SeHA; 9.6 wt.% of selenium) was synthesized using wet method and subject to careful physicochemical analysis by powder X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, solid-state nuclear magnetic resonance, wavelength dispersive X-ray fluorescence, and inductively coupled plasma optical emission spectrometry. SeHA was then used to develop the selenium-containing hydroxyapatite/alginate (SeHA/ALG) composite granules. Risedronate sodium (RIS) was introduced to the obtained spherical microgranules of a size of about 1.1-1.5 mm in 2 ways: during the granules' preparation (RIS solution added to a suspension of ALG and SeHA), and as a result of SeHA/ALG granules soaking in aqueous RIS solution. The analysis made using 13C and 31P cross-polarization magic angle spinning nuclear magnetic resonance confirmed the presence of RIS and its interaction with calcium ions. Then, the release of selenium (inductively coupled plasma optical emission spectrometry) and RIS (high-performance liquid chromatography) from microgranules was examined. Moreover, cytotoxicity of fabricated granules was assessed by MTT test. Selenium release was biphasic: the first stage was short and ascribed to a "burst release" probably from a hydrated surface layer of SeHA crystals, while the next stage was significantly longer and ascribed to a sustained release of selenium from the crystals' interior. The study showed that the method of obtaining microgranules containing RIS significantly affects its release profile. Performed cytotoxicity test revealed that fabricated granules had high antitumor activity against osteosarcoma cells. However, because of the "burst release" of selenium during the first 10 h, the granules significantly reduced viability of normal osteoblasts as well. PMID- 28848344 TI - Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17beta-estradiol on endometrial regeneration for intrauterine adhesions in a rat model. AB - Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17beta-estradiol (E2) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat's endometrium to form an IUA model. 17beta-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E2-HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E2-HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17beta-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E2-HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E2-HP hydrogel showed a prolonged release of E2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E2-HP hydrogel group. We also demonstrated that E2-HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E2 into the injured endometrium. Therapeutic strategies targeting ER stress using E2 HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions. PMID- 28848345 TI - Important factors for cell-membrane permeabilization by gold nanoparticles activated by nanosecond-laser irradiation. AB - PURPOSE: Pulsed-laser irradiation of light-absorbing gold nanoparticles (AuNPs) attached to cells transiently increases cell membrane permeability for targeted molecule delivery. Here, we targeted EGFR on the ovarian carcinoma cell line OVCAR-3 with AuNPs. In order to optimize membrane permeability and to demonstrate molecule delivery into adherent OVCAR-3 cells, we systematically investigated different experimental conditions. MATERIALS AND METHODS: AuNPs (30 nm) were functionalized by conjugation of the antibody cetuximab against EGFR. Selective binding of the particles was demonstrated by silver staining, multiphoton imaging, and fluorescence-lifetime imaging. After laser irradiation, membrane permeability of OVCAR-3 cells was studied under different conditions of AuNP concentration, cell-incubation medium, and cell-AuNP incubation time. Membrane permeability and cell viability were evaluated by flow cytometry, measuring propidium iodide and fluorescein isothiocyanate-dextran uptake. RESULTS: Adherently growing OVCAR-3 cells can be effectively targeted with EGFR-AuNP. Laser irradiation led to successful permeabilization, and 150 kDa dextran was successfully delivered into cells with about 70% efficiency. CONCLUSION: Antibody targeted and laser-irradiated AuNPs can be used to deliver molecules into adherent cells. Efficacy depends not only on laser parameters but also on AuNP:cell ratio, cell-incubation medium, and cell-AuNP incubation time. PMID- 28848346 TI - Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes. AB - Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios - 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) - of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC50 values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG5000 (PEG TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-alpha from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN. PMID- 28848347 TI - Synergistic interactions between antimicrobial peptides derived from plectasin and lipid nanocapsules containing monolaurin as a cosurfactant against Staphylococcus aureus. AB - Development of effective antibacterial agents for the treatment of infections caused by Gram-positive bacteria resistant to existing antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA), is an area of intensive research. In this work, the antibacterial efficacy of two antimicrobial peptides derived from plectasin, AP114 and AP138, used alone and in combination with monolaurin-lipid nanocapsules (ML-LNCs) was evaluated. Several interesting findings emerged from the present study. First, ML-LNCs and both plectasin derivatives showed potent activity against all 14 tested strains of S. aureus, independent of their resistance phenotype. Both peptides displayed a considerable adsorption (33%-62%) onto ML-LNCs without having an important impact on the particle properties such as size. The combinations of peptide with ML-LNC displayed synergistic effect against S. aureus, as confirmed by two methods: checkerboard and time-kill assays. This synergistic interaction enables a dose reduction and consequently decreases the risk of toxicity and has the potential of minimizing the development of resistance. Together, these results suggest that ML-LNCs loaded with a plectasin derivative may be a very promising drug delivery system for further development as a novel antibacterial agent against S. aureus, including MRSA. PMID- 28848348 TI - Co-delivery nanocarriers targeting folate receptor and encapsulating 2 deoxyglucose and alpha-tocopheryl succinate enhance anti-tumor effect in vivo. AB - A combination administration of chemical agents was highlighted to treat tumors. Recently, tumor cell has been found to be different from normal cell in metabolic manner. Most of cancer cells prefer aerobic glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) to satisfy energy and biomass synthesis requirement to survive, grow and proliferate, which provides novel and potential therapeutic targets for chemotherapy. Here, 2-deoxy-d-glucose (2-DG), a potent inhibitor of glucose metabolism, was used to inhibit glycolysis of tumor cells; alpha tocopheryl succinate (alpha-TOS), a water-insoluble vitamin E derivative, was chosen to suppress OXPHOS. Our data demonstrated that the combination treatment of 2-DG and alpha-TOS could significantly promote the anti-tumor efficiency in vitro compared with administration of the single drug. In order to maximize therapeutic activity and minimize negative side effects, a co-delivery nanocarrier targeting folate receptor (FR) was developed to encapsulate 2-DG and alpha-TOS simultaneously based on our previous work. Transmission electron microscope, dynamic light scattering method and UV-visible spectrophotometers were used to investigate morphology, size distribution and loading efficiency of the alpha-TOS-2-DG-loaded and FR-targeted nanoparticles (TDF NPs). The TDF NPs were found to possess a layer-by-layer shape, and the dynamic size was <100 nm. The final encapsulation efficiencies of alpha-TOS and 2-DG in TDF NPs were 94.3%+/-1.3% and 61.7%+/-7.7% with respect to drug-loading capacities of 8.9%+/ 0.8% and 13.2%+/-2.6%, respectively. Almost no alpha-TOS release was found within 80 h, and release of 2-DG was sustained and slow within 72 h. The results of FR binding assay and fluorescence biodistribution revealed that TDF NPs could target FR highly expressed on tumor cell in vitro and in vivo. Further, in vivo anti tumor experiments showed that TDF NPs had an improved biological function with less toxicity. Thus, our work indicates that the co-delivery TDF NPs have a great potential in tumor therapy. PMID- 28848349 TI - Cyclic hexapeptide-conjugated nanoparticles enhance curcumin delivery to glioma tumor cells and tissue. AB - Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs). The cyclic hexapeptide c(RGDf(N-me) VK)-C (cHP) has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly(d,l-lactide co-glycolide) (PEG-PLGA) conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP modified curcumin nanoparticles (cHP/Cur-NPs) was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur NPs, exhibited improved binding, uptake, and penetration abilities than non targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas. PMID- 28848350 TI - Inhibitory activity of selenium nanoparticles functionalized with oseltamivir on H1N1 influenza virus. AB - As an effective antiviral agent, the clinical application of oseltamivir (OTV) is limited by the appearance of drug-resistant viruses. Due to their low toxicity and excellent activity, the antiviral capabilities of selenium nanoparticles (SeNPs) has attracted increasing attention in recent years. To overcome the limitation of drug resistance, the use of modified NPs with biologics to explore novel anti-influenza drugs is developing rapidly. In this study, OTV surface modified SeNPs with superior antiviral properties and restriction on drug resistance were synthesized. OTV decoration of SeNPs (Se@OTV) obviously inhibited H1N1 infection and had less toxicity. Se@OTV interfered with the H1N1 influenza virus to host cells through inhibiting the activity of hemagglutinin and neuraminidase. The mechanism was that Se@OTV was able to prevent H1N1 from infecting MDCK cells and block chromatin condensation and DNA fragmentation. Furthermore, Se@OTV inhibited the generation of reactive oxygen species and activation of p53 phosphorylation and Akt. These results demonstrate that Se@OTV is a promising efficient antiviral pharmaceutical for H1N1. PMID- 28848351 TI - Dual tumor-targeted poly(lactic-co-glycolic acid)-polyethylene glycol-folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery. AB - Further specific target-ability development of biodegradable nanocarriers is extremely important to promote their security and efficiency in antitumor drug delivery applications. In this study, a facilely prepared poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-folic acid (FA) copolymer was able to self assemble into nanoparticles with favorable hydrodynamic diameters of around 100 nm and negative surface charge in aqueous solution, which was expected to enhance intracellular antitumor drug delivery by advanced dual tumor-target effects, ie, enhanced permeability and retention induced the passive target, and FA mediated the positive target. Fluorescence-activated cell-sorting and confocal laser scanning microscopy results confirmed that doxorubicin (model drug) loaded into PLGA-PEG-FA nanoparticles was able to be delivered efficiently into tumor cells and accumulated at nuclei. In addition, all hemolysis, 3-(4,5-dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, and zebrafish development experiments demonstrated that PLGA-PEG-FA nanoparticles were biocompatible and secure for biomedical applications, even at high polymer concentration (0.1 mg/mL), both in vitro and in vivo. Therefore, PLGA-PEG-FA nanoparticles provide a feasible controlled-release platform for secure and efficient antitumor drug delivery. PMID- 28848353 TI - Interaction of hydroxyapatite nanoparticles with endothelial cells: internalization and inhibition of angiogenesis in vitro through the PI3K/Akt pathway. AB - Nano-hydroxyapatite (nano-HAP) has been proposed as a better candidate for bone tissue engineering; however, the interactions of nano-HAP with endothelial cells are currently unclear. In this study, HAP nanoparticles (HANPs; 20 nm np20 and 80 nm np80) and micro-sized HAP particles (m-HAP; 12 MUm) were employed to explore and characterize cellular internalization, subcellular distribution, effects of HANPs on endothelial cell function and underlying mechanisms using human umbilical vein endothelial cells (HUVECs) as an in vitro model. It was found that HANPs were able to accumulate in the cytoplasm, and both adhesion and uptake of the HANPs followed a function of time; compared to np80, more np20 had been uptaken at the end of the observation period. HANPs were mainly uptaken via clathrin- and caveolin-mediated endocytosis, while macropinocytosis was the main pathway for m-HAP uptake. Unexpectedly, exposure to HANPs suppressed the angiogenic ability of HUVECs in terms of cell viability, cell cycle, apoptosis response, migration and capillary-like tube formation. Strikingly, HANPs reduced the synthesis of nitric oxide (NO) in HUVECs, which was associated with the inhibition of phosphatidylinositol 3-kinase (PI3K) and phosphorylation of eNOS. These findings provide additional insights into specific biological responses as HANPs interface with endothelial cells. PMID- 28848352 TI - Suppression of human arthritis synovial fibroblasts inflammation using dexamethasone-carbon nanotubes via increasing caveolin-dependent endocytosis and recovering mitochondrial membrane potential. AB - Dexamethasone (DEX), a non-particulate glucocorticoid (GC) to inhibit anti inflammatory response, has been widely used for the treatment of various diseases such as arthritis, cancer, asthma, chronic obstructive pulmonary disease, cerebral edema, and multiple sclerosis. However, prolonged and/or high-dose GC therapy can cause various serious adverse effects (adrenal insufficiency, hyperglycemia, Cushing's syndrome, osteoporosis, Charcot arthropathy, etc). In this study, developed DEX-carbon nanotube (CNT) conjugates improved intracellular drug delivery via increased caveolin-dependent endocytosis and ultimately suppressed the expression of major pro-inflammatory cytokines in tumor necrosis factor-alpha (TNF-alpha)-stimulated human fibroblast-like synoviocytes (FLS) at low drug concentrations. Specifically, DEX on polyethylene-glycol (PEG)-coated CNTs induced caveolin uptake, recovered mitochondrial disruption, and inhibited reactive oxygen species production by targeting mitochondria that was released from the early endosome in TNF-alpha-stimulated FLS. The obtained results clearly demonstrated that DEX-PEG-coated CNTs significantly inhibited the inflammation by FLS in rheumatoid arthritis (RA) by achieving greater drug uptake and efficient intracellular drug release from the endosome, thus suggesting a mechanism of effective low-dose GC therapy to treat inflammatory diseases, including RA and osteoarthritis. PMID- 28848354 TI - The value of corneoscleral rim cultures in keratoplasty: a systematic review and cost-effectiveness analysis. AB - PURPOSE: This study evaluated the performance of donor corneoscleral rim cultures for predicting infection after corneal transplantation, and determines if there is a correlation between positive corneoscleral rim cultures and postkeratoplasty infection. DESIGN AND DATA SOURCES: This was a systematic review, prognostic accuracy analysis, and cost-effectiveness analysis. Databases searched were: Medline (Ovid), Embase (Ovid), CINAHL, Cochrane Library, Web of Science, and BioSis Previews. Grey literature was also explored. MATERIALS AND METHODS: A systematic review was conducted to locate published and unpublished studies. All studies examining corneal button contamination and its association with endophthalmitis and keratitis posttransplantation were included. Extracted data were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value. Cost data from the London Laboratory Services Group in London, ON were used to calculate the cost-effectiveness of culturing donor rim cultures. RESULTS: Of 7,870 grafts, 954 had a positive rim culture (12.1%), with 12 patients going on to develop keratitis or endophthalmitis (1.3%). The prevalence of keratitis and endophthalmitis in this study was 0.15%, and the positive predictive value 1.5%. Of the 12 infections, nine were fungal and three bacterial. The estimated cost of a positive and negative test result was CAD$45.99 and $14.15, respectively. The cost to run all 7,870 tests was estimated to be $141,735.86, with an incremental cost-effectiveness ratio of $40,215.70. CONCLUSION: There was a significant divergence between bacterial and fungal rim culture results. Bacterial cultures predicted clinical infection poorly, did not change management, and were expensive. Fungal cultures predicted clinical infection in over 10% of patients, had the potential to change management, and were 40% less expensive than full rim culturing (bacterial and fungal tests). Fungal rim cultures may be considered in areas where fungal infection rates are high. PMID- 28848355 TI - A budget impact analysis of parenteral iron treatments for iron deficiency anemia in the UK: reduced resource utilization with iron isomaltoside 1000. AB - BACKGROUND AND AIMS: The reported prevalence of iron deficiency anemia (IDA) varies widely but estimates suggest that 3% of men and 8% of women have IDA in the UK. Parenteral iron is indicated for patients intolerant or unresponsive to oral iron or requiring rapid iron replenishment. This study evaluated differences in the cost of treating these patients with iron isomaltoside (Monofer(r), IIM) relative to other intravenous iron formulations. METHODS: A budget impact model was developed to evaluate the cost of using IIM relative to ferric carboxymaltose (Ferinject(r), FCM), low molecular weight iron dextran (Cosmofer(r), LMWID), and iron sucrose (Venofer(r), IS) in patients with IDA. To establish iron need, iron deficits were modeled using a simplified dosing table. The base case analysis was conducted over 1 year in patients with IDA with mean bodyweight of 82.4 kg (SD 22.5 kg) and hemoglobin levels of 9.99 g/dL (SD 1.03 g/dL) based on an analysis of patient characteristics in IDA trials. Costs were modeled using UK health care resource groups. RESULTS: Using IIM required 1.3 infusions to correct the mean iron deficit, compared with 1.3, 1.8, and 7.7 with LMWID, FCM, and IS, respectively. Patients using IIM required multiple infusions in 35% of cases, compared with 35%, 77%, and 100% of patients with LMWID, FCM, and IS, respectively. Total costs were estimated to be GBP 451 per patient with IIM or LMWID, relative to GBP 594 with FCM (a GBP 143 or 24% saving with IIM) or GBP 2,600 with IS (a GBP 2,149 or 83% saving with IIM). CONCLUSION: Using IIM or LMWID in place of FCM or IS resulted in a marked reduction in the number of infusions required to correct iron deficits in patients with IDA. The reduction in infusions was accompanied by substantial reductions in cost relative to FCM and IS over 1 year. PMID- 28848356 TI - Review of applications of microneedling in dermatology. AB - Microneedling (MN) is a novel therapeutic modality in dermatology. Through physical trauma from needle penetration, MN induces a wound healing cascade with minimal damage to the epidermis. This allows for enhancement in the absorption of mainstay topical therapies across the thick stratum corneum. MN has become increasingly utilized over the last several years as it is a relatively simple procedure that is cost-effective, well tolerated, and offers both cosmetic and therapeutic benefits. The ability to treat localized areas of disease has led to numerous studies gauging its potential in focal diseases of inflammation, dyschromia, and photodamage. This review discusses the principles and evidence behind the expanding applications of MN. It has shown promising results as an adjuvant therapy for enhanced drug delivery in the treatment of atrophic scars, alopecia, actinic keratoses, and disorders of pigmentation such as melasma. The efficacy in treatment of vitiligo remains limited. Overall, the procedure has few adverse sequelae compared to other therapies, is highly efficacious, and is a viable resurfacing option for skin of color. Future research is needed to determine the frequency, interval, and specific device settings that foster optimal results. Additionally, large controlled trials are needed to shed light on the utility of MN as an evidence-based regimen for the treatment of various dermatologic conditions. PMID- 28848357 TI - Emu oil-based lotion effects on neonatal skin barrier during transition from intrauterine to extrauterine life. AB - Both appropriate hydration and skin surface pH are fundamental in preventing baby skin barrier damage during transition from intrauterine to extrauterine life. However, effects of topical moisturizers on neonatal stratum corneum temperature, pH, hydration, and elasticity have not been scientifically evaluated in vivo. We checked 31 full-term breastfeeding neonates by non-invasive bioengineering method, which is able to evaluate the basal skin barrier (left heel), and assessed at 6+/-1 hours after birth, and at 1 and 24 hours after emu oil-based topical treatment. The basal skin barrier of right heel (no oil exposure) of each newborn was considered as control. We found that a single application of an emu oil-based lotion was effective in improving heel stratum corneum hydration, which increases both skin pH and elasticity without any effect on temperature. Further studies are needed to confirm long-term beneficial effects of this treatment in a very sensitive patient population. PMID- 28848358 TI - Rosacea and Helicobacter pylori: links and risks. AB - Rosacea is a chronic skin disease characterized by facial erythema and telangiectasia. Despite the fact that many hypotheses have been proposed, its etiology remains unknown. In the present review, the possible link and clinical significance of Helicobacter pylori in the pathogenesis of rosacea are being sought. A PubMed and Google Scholar search was performed using the terms "rosacea", "H.pylori", "gastrointestinal disorders and H.pylori", "microorganisms and rosacea", "pathogenesis and treatment of rosacea", and "risk factors of rosacea", and selected publications were studied and referenced in text. Although a possible pathogenetic link between H. pylori and rosacea is advocated by many authors, evidence is still interpreted differently by others. We conclude that further studies are needed in order to fully elucidate the pathogenesis of rosacea. PMID- 28848359 TI - Review of autoantigens in Sjogren's syndrome: an update. AB - Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by inflammation in exocrine glands, resulting in reduced secretion of tears and saliva, manifesting as xerophthalmia and xerostomia, respectively. It is commonly associated with Sjogren's syndrome type A (Ro) and Sjogren's syndrome type B (La) antigens. However, in most patients, the identity of the triggering antigen is not known. Factors such as genetics of histocompatibility, dysregulation of T cells, B-cells and viral infections have been implicated. Several important studies on autoantigens in pSS have been published since a review in 2012, and the aim of this review is to provide an update on further peer-reviewed original articles in this field. Oxidative damage of Ro60 antigen may explain the epitope spreading during the immune activation in pSS. Immune-mediated destruction of the muscarinic receptor-3-expressing cells has been associated with a reduction in parasympathetic function, which could cause reduced secretory function of exocrine glands. Such a process also activates reactive oxidative species and antioxidants, which are linked to the triggering of inflammatory responses. Elevated levels of kallikrein, yet another antigen present in the lacrimal gland and other tissues, are similarly involved in triggering an autoimmune T-cell response against target glands. Studying additional antigens, the platelet selectin and vasoactive intestinal peptides, in patients with pSS can help to elucidate the origin and process of autoimmunity, or even lead to potential biomarkers. In conclusion, the understanding of autoantigens has led to exciting major advances in the biology of pSS and may influence diagnosis and management of pSS in future. PMID- 28848360 TI - Inactivated probiotic Bacillus coagulans GBI-30 induces complex immune activating, anti-inflammatory, and regenerative markers in vitro. AB - OBJECTIVE: The aim of this study was to document the immune activating and anti inflammatory effects of inactivated probiotic Bacillus coagulans GBI-30, 6086 (StaimuneTM) cells on human immune cells in vitro. METHODS: In vitro cultures of human peripheral blood mononuclear cells (PBMC) from healthy blood donors were treated with inactivated B. coagulans GBI-30, 6086 cells for 24 hours. After incubation, the PBMC were stained with fluorochrome-labeled monoclonal antibodies for CD3, CD56, and CD69 to monitor cellular activation by flow cytometry. The culture supernatants were tested for cytokine profile using a 27-plex Luminex array, including pro- and anti-inflammatory cytokines, chemokines, and growth factors. RESULTS: Inactivated B. coagulans GBI-30, 6086 cells induced the CD69 early activation marker on CD3+ CD56- T lymphocytes, CD3+ CD56+ NKT cells, CD3 CD56+ NK cells, and also some cells within the CD3-CD56- non-T non-NK cell subset. Culture supernatants showed robust increases in the immune-activating cytokines IL-1beta, IL-6, IL-17A, and TNF-alpha. IFN-gamma levels were increased, along with three chemokines, MCP-1, MIP-1alpha, and MIP-1beta. The two anti inflammatory cytokines IL-1ra and IL-10 showed increases, as well as the G-CSF growth factor involved in repair and stem cell biology. In contrast, GM-CSF levels showed a mild decrease, showing a highly selective growth factor response. CONCLUSION: The inactivated B. coagulans GBI-30, 6086 cells activated human immune cells and altered the production of both immune activating and anti inflammatory cytokines and chemokines. Of special importance is the novel demonstration of a selective upregulation of the G-CSF growth factor involved in postinjury and postinflammation repair and regeneration. This suggests that important immunogenic cell wall components, such as lipoteichoic acid, are undamaged after the inactivation and retain the complex beneficial biological activities previously demonstrated for the cell walls from live B. coagulans GBI 30, 6086 (GanedenBC30) probiotic bacteria. PMID- 28848361 TI - Opisthorchiasis and cholangiocarcinoma in Southeast Asia: an unresolved problem. AB - The prevalence of cholangiocarcinoma (CCA) in Southeast Asia is much higher than other areas of the world. Eating raw, fermented, or undercooked cyprinid fish, infected with the liver fluke, Opisthorchis viverrini sensu lato (sl), results in chronic biliary inflammation, periductal fibrosis, and increased cancer risk. There may be associated glomerulonephritis. The process of infection is difficult to disrupt because eating practices have proven extremely difficult to change, and the life cycle of the fluke cannot be broken due to high prevalence in canine and feline reservoir hosts. Fecal analysis and enzyme-linked immunosorbent assay tests can be used to diagnose opisthorchiasis. Diagnosis of CCA is complex, partly due to the lack of definitive imaging characteristics but also due to the difficulty of obtaining samples for cytology or histology. This cancer has proven to be resistant to common chemotherapy treatments and so the two avenues of treatment available are surgical resection and liver transplantation, both requiring early detection of the tumor for the best chances of success. Late presentation of symptoms reduces the chances of successful surgical intervention. While liver fluke infections can be treated with praziquantel, individuals will often become reinfected, and multiple reinfections can be more harmful than a singular, long-term infection. A key research on the detection and characterization of novel biomarkers in all parts of the carcinogenic pathway for early diagnosis is needed. PMID- 28848363 TI - Misclassification of hypertrophic cardiomyopathy: validation of diagnostic codes. AB - PURPOSE: To validate diagnostic codes for hypertrophic cardiomyopathy (HCM), analyze misclassfications, and estimate the prevalence of HCM in an unselected Swedish regional cohort. PATIENTS AND METHODS: Using the hospitals' electronic medical records (used for the Swedish National Patient Register), we identified 136 patients from 2006 to 2016 with the HCM-related codes 142.1 and 142.2 (International Classification of Diseases). RESULTS: Of a total of 129 residents in the catchment area, 88 patients were correctly classified as HCM (positive predictive value 68.2%) and 41 patients (31.8%) were misclassified as HCM. Among the 88 HCM patients (52.2% males), 74 were alive and 14 were dead (15.9%). This yields an HCM prevalence of 74/183,337, that is, 4.0 diagnosed cases per 10,000 in the adult population aged >=18 years. The underlying diagnoses of misclassified cases were mainly hypertension (31.7%) and aortic stenosis (22.0%). Other types of cardiomyopathies accounted for several cases of misclassification: dilated (nonischemic or ischemic), left ventricular noncompaction, and Takotsubo. Miscellaneous diagnoses were amyloidosis, pulmonary stenosis combined with ventricular septal defect, aortic insufficiency, athelete's heart, and atrioventricular conduction abnormality. The mean age was not significantly different between HCM and misclassified patients (65.8+/-15.8 vs 70.1+/-13.4 years; P=0.177). There were 47.8% females among HCM and 60.8% females among misclassified (P=0.118). CONCLUSION: One-third of patients diagnosed as HCM are misclassified, so registry data should be interpreted with caution. A correct diagnosis is important for decision-making and implementation of optimal HCM care; efforts should be made to increase awareness of HCM and diagnostic competence throughout the health care system. PMID- 28848362 TI - Vaginal cuff brachytherapy in endometrial cancer - a technically easy treatment? AB - Endometrial cancer (EC) is one of the most common gynecological cancers among women in the developed countries. Vaginal cuff is the main location of relapses after a curative surgical procedure and postoperative radiation therapy have proven to diminish it. Nevertheless, these results have not translated into better survival results. The preeminent place of vaginal cuff brachytherapy (VCB) in the postoperative treatment of high- to intermediate-risk EC was given by the PORTEC-2 trial, which demonstrated a similar reduction in relapses with VCB than with external beam radiotherapy (EBRT), but VCB induced less late toxicity. As a result of this trial, the use of VCB has increased in clinical practice at the expense of EBRT. A majority of the clinical reviews of VCB usually address the risk categories and patient selection but pay little attention to technical aspects of the VCB procedure. Our review aimed to address both aspects. First of all, we described the risk groups, which guide patient selection for VCB in clinical practice. Then, we depicted several technical aspects that might influence dose deposition and toxicity. Bladder distension and rectal distension as well as applicator position or patient position are some of those variables that we reviewed. PMID- 28848364 TI - Determinants of virological failure among patients on highly active antiretroviral therapy in University of Gondar Referral Hospital, Northwest Ethiopia: a case-control study. AB - BACKGROUND: Viral load monitoring is used as an important biomarker for diagnosing treatment failure in patients with HIV infection/AIDS. Ethiopia has started targeted viral load monitoring. However, factors leading to virological failure are not well understood and studied. Thus, the aim of this study was to identify the determinants of virological failure among HIV-infected patients on highly active antiretroviral therapy at the University of Gondar Referral Hospital, Northwest Ethiopia. METHODS: A case-control study was conducted from May to June 2015. Cases were subjects who had already experienced virological failure; controls were those without virological failure. Data were extracted from 153 cases and 153 controls through chart review. A multivariate logistic regression analysis was carried out to identify factors associated with virological failure, and variables with a p-value <0.05 were considered statistically significant. RESULTS: In this study, higher odds of virological failure was observed among patients aged <35 years (adjusted odds ratio [AOR] =2.52, 95% CI: 1.33, 4.77), who had had CD4+ count <200 cells/mm3 (AOR=9.03, 95% CI: 4.40, 18.50), showed poor adherence to antiretroviral therapy (ART) (AOR=15.80, 95% CI: 6.90, 36.50), and had taken ART for longer durations of 25-47 months (AOR=3.00, 95% CI: 1.10, 8.40) and >=48 months (AOR=6.70, 95% CI: 2.70, 16.60). CONCLUSION: This study showed that patients aged <35 years and with recent low CD4 count, poor adherence to treatment, and longer exposure to ART were positively and significantly associated with virological treatment failure. Therefore, evidence-based intervention should be implemented to improve adherence to ART, which in turn helps to boost immunity (CD4) and suppresses viral replication and load. Moreover, attention should be given to younger patients who have had ART for longer periods. PMID- 28848366 TI - Anaphylactic reaction following reversal of nondepolarizing muscle relaxant during general anesthesia: a case report. AB - An anaphylactic reaction during general anesthesia may cause fatal complications. Perioperative anaphylaxis can occur in response to different medications. To our knowledge, pyridostigmine or combination of pyridostigmine with glycopyrrolate induced anaphylactic reaction during general anesthesia has not been reported. We report a case of a suspected anaphylactic reaction to these drugs. To reduce the risk of complicated perioperative anaphylactic events, prompt assessment and treatment are needed. Moreover, any undesirable exposure to confirmed allergens should be avoided as part of secondary prevention. PMID- 28848367 TI - Assessment of counseling practice in medicine retail outlets in Mekelle City, Northern Ethiopia. AB - INTRODUCTION: Patient counseling can ideally be providing medication information orally or in written form to patients or their attendants, and it helps to form a concordant approach on encouraging patient involvement in the pharmaceutical care process and to explore patient's knowledge and understanding. Lack of adequate knowledge on drugs and up-to-date drug information are the major factor that hinders counseling services. This study assessed counseling practice of pharmacy professionals in Mekelle City. METHODS: A facility-based cross-sectional study was conducted. Professionals who volunteered to participate were involved. Self administered questionnaires were used as data collecting tool to grasp professionals' practice on patient counseling, and the data were analyzed by using SPSS version 23. One-way analysis of variance and post hoc statistical tests were done to check for association between sociodemographic and other variables of counseling practice. In the statistical analyses, p-value of 0.05 and 95% confidence interval were considered. RESULTS: The most frequent drug information given by the pharmacy professionals to clients were unit dose (65%), frequency of administration (79%), and duration of therapy (62%). Study participants claimed that lack of knowledge (37%), lack of updated drug information (49%), high patient load (62%), and absence of a private counseling room (51%) were the main factors that prohibit pharmacy professionals from counseling their patients. Those pharmacy professionals whose monthly income was <2000 Ethiopian Birr claimed lack of knowledge (p=0.007), limited access for updated drug information (p=0.009), and lack of experience (p=0.039) as factors for poor counseling practice. Results of the post hoc analysis showed significant difference among the participants with <5 and >10 years of experience in providing information on storage conditions and written materials with p-value of 0.025 and 0.016, respectively. CONCLUSION: This study proves that the level of satisfactory counseling is still very low compared to the expected practice. Lack of knowledge, lack of updated drug information, high patient load, absence of private counseling room, and underestimating the importance of counseling were identified as some of the factors that impede counseling services. PMID- 28848365 TI - The oral microbiome and adverse pregnancy outcomes. AB - Significant evidence supports an association between periodontal pathogenic bacteria and preterm birth and preeclampsia. The virulence properties assigned to specific oral pathogenic bacteria, for example, Fusobacterium nucleatum, Porphyromonas gingivalis, Filifactor alocis, Campylobacter rectus, and others, render them as potential collaborators in adverse outcomes of pregnancy. Several pathways have been suggested for this association: 1) hematogenous spread (bacteremia) of periodontal pathogens; 2) hematogenous spread of multiple mediators of inflammation that are generated by the host and/or fetal immune response to pathogenic bacteria; and 3) the possibility of oral microbial pathogen transmission, with subsequent colonization, in the vaginal microbiome resulting from sexual practices. As periodontal disease is, for the most part, preventable, the medical and dental public health communities can address intervention strategies to control oral inflammatory disease, lessen the systemic inflammatory burden, and ultimately reduce the potential for adverse pregnancy outcomes. This article reviews the oral, vaginal, and placental microbiomes, considers their potential impact on preterm labor, and the future research needed to confirm or refute this relationship. PMID- 28848368 TI - An active learning curriculum improves fellows' knowledge and faculty teaching skills: a medical student perspective. PMID- 28848369 TI - Student-led widening access schemes. AB - Medicine is among the most competitive degrees in the UK. Successfully gaining admission into medical school requires students to demonstrate a variety of academic and nonacademic skills in addition to experience and insights into the profession. However, gaining relevant experience within medicine may not be equally available to all students. The 2012 report from the Social Mobility and Child Poverty Commission stated that in terms of widening access and improving social mobility "medicine lags behind other professions". As president and vice president of Imperial College School of Medicine's student-led widening access society, we can provide an insight into the role of medical students in leading widening participation programs within a large medical school. In this article, we discuss our organizational structure, our core activities and our collaboration with the university's outreach program. PMID- 28848370 TI - Preliminary Results of the Adoption and Application of the Integrated Comprehensive Care Bundle Care Program When Treating Patients with Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: St. Joseph's Health System has implemented an integrated comprehensive care bundle care (ICC) program with the hopes that it would improve patients' care while reducing overall costs. The aim of this analysis was to evaluate the performance of the ICC program within patients admitted with chronic pulmonary obstructive disease (COPD). METHODS: We conducted a retrospective observational cohort study comparing ICC patients to non-ICC patients admitted to St. Joseph's Healthcare Hamilton for COPD being discharged with support services between June 2012 and March 2015, using administrative data. Confounding adjustment was achieved through the use of propensity score matching. Medical resource utilizations during the initial hospitalization and within the 60 days following discharge were compared using regression models. RESULTS: All 76 patients who entered the ICC program (100.0%) were matched 1 : 1 to 76 eligible non-ICC patients (28.4%). Length of stay (6.47 [7.29] versus 9.55 [10.21] days) and resource intensity weights (1.16 [0.80] versus 1.64 [1.69]) were lower in the ICC group within the initial hospitalization but, while favoring the ICC program, healthcare resource use tended not to differ statistically following discharge. INTERPRETATION: The ICC program was able to reduce initial medical resource utilization without increasing subsequent medical resource use. PMID- 28848371 TI - Long-term monitoring of diversity and structure of two stands of an Atlantic Tropical Forest. AB - BACKGROUND: This study aimed to report the long-term monitoring of diversity and structure of the tree community in a protected semideciduous Atlantic Forest in the South of Minas Gerais State, Southeast Brazil. The study was conducted in two stands (B and C), each with 26 and 38 10 m x 30 m plots. Censuses of stand B were conducted in 2000, 2005 and 2011, and stand C in 2001, 2006 and 2011. In both stands, the most abundant and important species for biomass accumulation over the inventories were trees larger than 20 cm of diameter, which characterize advanced successional stage within the forest. NEW INFORMATION: The two surveyed stands within the studied forest presented differences in structure, diversity and species richness over the time. PMID- 28848372 TI - Hydro-edaphic conditions defining richness and species composition in savanna areas of the northern Brazilian Amazonia. AB - BACKGROUND: Studies on plant communities in the Amazon have reported that different hydro-edaphic conditions can affect the richness and the species composition of different ecosystems. However, this aspect is poorly known in the different savanna habitats. Understanding how populations and plant communities are distributed in these open vegetation areas is important to improve the knowledge about which environmental variables influence the occurrence and diversity of plants in this type of regional ecosystem. Thus, this study investigated the richness and composition of plant species in two savanna areas of the northern Brazilian Amazonia, using the coverage (%) of the different life forms observed under different hydro-edaphic conditions as a structural reference. NEW INFORMATION: We report 128 plant species classified in 34 botanical families distributed in three savanna habitats with different levels of hydro-edaphic restrictions. In this study, the habitats are conceptually presented and they integrate environmental information (edaphic factors and drainage type), which determines differences between floristic composition, species richness and coverage (%) of plant life forms. PMID- 28848373 TI - Specimen records of spiders (Arachnida: Araneae) by monthly census for 3 years in forest areas of Yakushima Island, Japan. AB - BACKGROUND: Spiders (Arachnida: Araneae) are a classic indicator taxon for evaluating the health of natural environments. However, studies of spiders' responses to forest succession under natural and anthropogenic disturbance regimes are lacking. Yakushima Island in southwestern Japan has a unique forest ecosystem, and part of the island is designated as a world natural heritage site by UNESCO. Approximately 90% of Yakushima is covered by forest, including both plantations and natural forests. NEW INFORMATION: We made an inventory of spiders on Yakushima Island by collecting specimens in five forests (two plantations and three natural forests) with Malaise and window traps from 2006 to 2008 (a total of 637 traps). We collected 3487 specimens, representing 31 families and 165 species or morphotypes, including undescribed and unidentified species. All specimens were preserved in 70% ethanol, and all data were gathered into a Darwin Core Archives as sample event data. The data set is available from the GBIF network (http://www.gbif.org/dataset/f851fd75-32b2-4a23-8046-9c8ae7013a3c). Because there have been no spider inventories based on such a systematic trapping survey in Japan, this data set provides new insight into the biodiversity on Yakushima Island. PMID- 28848374 TI - Regionalized PM2.5 Community Multiscale Air Quality model performance evaluation across a continuous spatiotemporal domain. AB - The regulatory Community Multiscale Air Quality (CMAQ) model is a means to understanding the sources, concentrations and regulatory attainment of air pollutants within a model's domain. Substantial resources are allocated to the evaluation of model performance. The Regionalized Air quality Model Performance (RAMP) method introduced here explores novel ways of visualizing and evaluating CMAQ model performance and errors for daily Particulate Matter <= 2.5 micrometers (PM2.5) concentrations across the continental United States. The RAMP method performs a non-homogenous, non-linear, non-homoscedastic model performance evaluation at each CMAQ grid. This work demonstrates that CMAQ model performance, for a well-documented 2001 regulatory episode, is non-homogeneous across space/time. The RAMP correction of systematic errors outperforms other model evaluation methods as demonstrated by a 22.1% reduction in Mean Square Error compared to a constant domain wide correction. The RAMP method is able to accurately reproduce simulated performance with a correlation of r = 76.1%. Most of the error coming from CMAQ is random error with only a minority of error being systematic. Areas of high systematic error are collocated with areas of high random error, implying both error types originate from similar sources. Therefore, addressing underlying causes of systematic error will have the added benefit of also addressing underlying causes of random error. PMID- 28848375 TI - Change point estimation in high dimensional Markov random-field models. AB - This paper investigates a change-point estimation problem in the context of high dimensional Markov random field models. Change-points represent a key feature in many dynamically evolving network structures. The change-point estimate is obtained by maximizing a profile penalized pseudo-likelihood function under a sparsity assumption. We also derive a tight bound for the estimate, up to a logarithmic factor, even in settings where the number of possible edges in the network far exceeds the sample size. The performance of the proposed estimator is evaluated on synthetic data sets and is also used to explore voting patterns in the US Senate in the 1979-2012 period. PMID- 28848376 TI - Basal Dendritic Morphology of Cortical Pyramidal Neurons in Williams Syndrome: Prefrontal Cortex and Beyond. AB - Williams syndrome (WS) is a unique neurodevelopmental disorder with a specific behavioral and cognitive profile, which includes hyperaffiliative behavior, poor social judgment, and lack of social inhibition. Here we examined the morphology of basal dendrites on pyramidal neurons in the cortex of two rare adult subjects with WS. Specifically, we examined two areas in the prefrontal cortex (PFC)-the frontal pole (Brodmann area 10) and the orbitofrontal cortex (Brodmann area 11) and three areas in the motor, sensory, and visual cortex (BA 4, BA 3-1-2, BA 18). The findings suggest that the morphology of basal dendrites on the pyramidal neurons is altered in the cortex of WS, with differences that were layer specific, more prominent in PFC areas, and displayed an overall pattern of dendritic organization that differentiates WS from other disorders. In particular, and unlike what was expected based on typically developing brains, basal dendrites in the two PFC areas did not display longer and more branched dendrites compared to motor, sensory and visual areas. Moreover, dendritic branching, dendritic length, and the number of dendritic spines differed little within PFC and between the central executive region (BA 10) and BA 11 that is part of the orbitofrontal region involved into emotional processing. In contrast, the relationship between the degree of neuronal branching in supra- versus infra granular layers was spared in WS. Although this study utilized tissue held in formalin for a prolonged period of time and the number of neurons available for analysis was limited, our findings indicate that WS cortex, similar to that in other neurodevelopmental disorders such as Down syndrome, Rett syndrome, Fragile X, and idiopathic autism, has altered morphology of basal dendrites on pyramidal neurons, which appears more prominent in selected areas of the PFC. Results were examined from developmental perspectives and discussed in the context of other neurodevelopmental disorders. We have proposed hypotheses for further investigations of morphological changes on basal dendrites in WS, a syndrome of particular interest given its unique social and cognitive phenotype. PMID- 28848377 TI - Treadmill Training with HAL Exoskeleton-A Novel Approach for Symptomatic Therapy in Patients with Limb-Girdle Muscular Dystrophy-Preliminary Study. AB - Purpose: Exoskeletons have been developed for rehabilitation of patients with walking impairment due to neurological disorders. Recent studies have shown that the voluntary-driven exoskeleton HAL(r) (hybrid assistive limb) can improve walking functions in spinal cord injury and stroke. The aim of this study was to assess safety and effects on walking function of HAL(r) supported treadmill therapy in patients with limb-girdle muscular dystrophy (LGMD). Materials and Methods: Three LGMD patients received 8 weeks of treadmill training with HAL(r) 3 times a week. Outcome parameters were 10-meter walk test (10 MWT), 6-minute walk test, and timed-up-and-go test (TUG). Parameters were assessed pre and post training and 6 weeks later (follow-up). Results: All patients completed the therapy without adverse reactions and reported about improvement in endurance. Improvements in outcome parameters after 8 weeks could be demonstrated. Persisting effects were observed after 6 weeks for the 10 MWT and TUG test (follow-up). Conclusions: HAL(r) treadmill training in LGMD patients can be performed safely and enables an intensive highly repetitive locomotor training. All patients benefitted from this innovative method. Upcoming controlled studies with larger cohorts should prove its effects in different types of LGMD and other myopathies. PMID- 28848378 TI - Anodal tDCS Over the Left DLPFC Did Not Affect the Encoding and Retrieval of Verbal Declarative Information. AB - Several studies imply that anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) can modulate the formation of verbal episodic memories. The aim of this study was to test if tDCS through a multi-electrode Laplacian montage over the left DLPFC could differentially modulate declarative memory performance depending on the application phase. Two groups of healthy participants (n = 2 * 15) received 1 mA anodal or sham stimulation for 20 min during the encoding or during the recall phase on a delayed cued-recall, using a randomized, double-blinded, repeated-measures experimental design. Memory performance was assessed at two time points: 10 min and 24 h after learning. We found no significant difference between anodal and sham stimulation with regard to the memory scores between conditions (stimulation during encoding or recall) or between time points, suggesting that anodal tDCS over the left DLPFC with these stimulation parameters had no effect on the encoding and the consolidation of associative verbal content. PMID- 28848379 TI - RESOLUTE PET/MRI Attenuation Correction for O-(2-18F-fluoroethyl)-L-tyrosine (FET) in Brain Tumor Patients with Metal Implants. AB - Aim: Positron emission tomography (PET) imaging is a useful tool for assisting in correct differentiation of tumor progression from reactive changes, and the radiolabeled amino acid analog tracer O-(2-18F-fluoroethyl)-L-tyrosine (FET)-PET is amongst the most frequently used. The FET-PET images need to be quantitatively correct in order to be used clinically, which require accurate attenuation correction (AC) in PET/MRI. The aim of this study was to evaluate the use of the subject-specific MR-derived AC method RESOLUTE in post-operative brain tumor patients. Methods: We analyzed 51 post-operative brain tumor patients (68 examinations, 200 MBq [18F]-FET) investigated in a PET/MRI scanner. MR-AC maps were acquired using: (1) the Dixon water fat separation sequence, (2) the ultra short echo time (UTE) sequences, (3) calculated using our new RESOLUTE methodology, and (4) a same day low-dose CT used as reference "gold standard." For each subject and each AC method the tumor was delineated by isocontouring tracer uptake above a tumor(T)-to-brain background (B) activity ratio of 1.6. We measured B, tumor mean and maximal activity (TMEAN, TMAX), biological tumor volume (BTV), and calculated the clinical metrics TMEAN/B and TMAX/B. Results: When using RESOLUTE 5/68 studies did not meet our predefined acceptance criteria of TMAX/B difference to CT-AC < +/-0.1 or 5%, TMEAN/B < +/-0.05 or 5%, and BTV < +/-2 mL or 10%. In total, 46/68 studies failed our acceptance criteria using Dixon, and 26/68 using UTE. The 95% limits of agreement for TMAX/B was for RESOLUTE (-3%; 4%), Dixon (-9%; 16%), and UTE (-7%; 10%). The absolute error when measuring BTV was 0.7 +/- 1.9 mL (N.S) with RESOLUTE, 5.3 +/- 10 mL using Dixon, and 1.7 +/- 3.7 mL using UTE. RESOLUTE performed best in the identification of the location of peak activity and in brain tumor follow-up monitoring using clinical FET PET metrics. Conclusions: Overall, we found RESOLUTE to be the AC method that most robustly reproduced the CT-AC clinical metrics per se, during follow-up, and when interpreted into defined clinical use cut-off criteria and into the patient history. RESOLUTE is especially suitable for brain tumor patients, as these often present with distorted anatomy where other methods based on atlas/template information might fail. PMID- 28848380 TI - A Spiking Neural Network Model of the Lateral Geniculate Nucleus on the SpiNNaker Machine. AB - We present a spiking neural network model of the thalamic Lateral Geniculate Nucleus (LGN) developed on SpiNNaker, which is a state-of-the-art digital neuromorphic hardware built with very-low-power ARM processors. The parallel, event-based data processing in SpiNNaker makes it viable for building massively parallel neuro-computational frameworks. The LGN model has 140 neurons representing a "basic building block" for larger modular architectures. The motivation of this work is to simulate biologically plausible LGN dynamics on SpiNNaker. Synaptic layout of the model is consistent with biology. The model response is validated with existing literature reporting entrainment in steady state visually evoked potentials (SSVEP)-brain oscillations corresponding to periodic visual stimuli recorded via electroencephalography (EEG). Periodic stimulus to the model is provided by: a synthetic spike-train with inter-spike intervals in the range 10-50 Hz at a resolution of 1 Hz; and spike-train output from a state-of-the-art electronic retina subjected to a light emitting diode flashing at 10, 20, and 40 Hz, simulating real-world visual stimulus to the model. The resolution of simulation is 0.1 ms to ensure solution accuracy for the underlying differential equations defining Izhikevichs neuron model. Under this constraint, 1 s of model simulation time is executed in 10 s real time on SpiNNaker; this is because simulations on SpiNNaker work in real time for time steps dt ? 1 ms. The model output shows entrainment with both sets of input and contains harmonic components of the fundamental frequency. However, suppressing the feed-forward inhibition in the circuit produces subharmonics within the gamma band (>30 Hz) implying a reduced information transmission fidelity. These model predictions agree with recent lumped-parameter computational model-based predictions, using conventional computers. Scalability of the framework is demonstrated by a multi-node architecture consisting of three "nodes," where each node is the "basic building block" LGN model. This 420 neuron model is tested with synthetic periodic stimulus at 10 Hz to all the nodes. The model output is the average of the outputs from all nodes, and conforms to the above-mentioned predictions of each node. Power consumption for model simulation on SpiNNaker is ?1 W. PMID- 28848381 TI - G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channel Activation by the p75 Neurotrophin Receptor Is Required for Amyloid beta Toxicity. AB - Alzheimer's disease is characterized by cognitive decline, neuronal degeneration, and the accumulation of amyloid-beta (Abeta). Although, the neurotoxic Abeta peptide is widely believed to trigger neuronal dysfunction and degeneration in Alzheimer's disease, the mechanism by which this occurs is poorly defined. Here we describe a novel, Abeta-triggered apoptotic pathway in which Abeta treatment leads to the upregulation of G-protein activated inwardly rectifying potassium (GIRK/Kir3) channels, causing potassium efflux from neurons and Abeta-mediated apoptosis. Although, GIRK channel activity is required for Abeta-induced neuronal degeneration, we show that it is not sufficient, with coincident signaling by the p75 neurotrophin receptor (p75NTR) also required for potassium efflux and cell death. Our results identify a novel role for GIRK channels in mediating apoptosis, and provide a previously missing mechanistic link between the excitotoxicity of Abeta and its ability to trigger cell death pathways, such as that mediated by p75NTR. We propose that this death-signaling pathway contributes to the dysfunction of neurons in Alzheimer's disease and is responsible for their eventual degeneration. PMID- 28848382 TI - Minimal Window Duration for Accurate HRV Recording in Athletes. AB - Heart rate variability (HRV) is non-invasive and commonly used for monitoring responses to training loads, fitness, or overreaching in athletes. Yet, the recording duration for a series of RR-intervals varies from 1 to 15 min in the literature. The aim of the present work was to assess the minimum record duration to obtain reliable HRV results. RR-intervals from 159 orthostatic tests (7 min supine, SU, followed by 6 min standing, ST) were analyzed. Reference windows were 4 min in SU (min 3-7) and 4 min in ST (min 9-13). Those windows were subsequently divided and the analyses were repeated on eight different fractioned windows: the first min (0-1), the second min (1-2), the third min (2-3), the fourth min (3-4), the first 2 min (0-2), the last 2 min (2-4), the first 3 min (0-3), and the last 3 min (1-4). Correlation and Bland & Altman statistical analyses were systematically performed. The analysis window could be shortened to 0-2 instead of 0-4 for RMSSD only, whereas the 4-min window was necessary for LF and total power. Since there is a need for 1 min of baseline to obtain a steady signal prior the analysis window, we conclude that studies relying on RMSSD may shorten the windows to 3 min (= 1+2) in SU or seated position only and to 6 min (= 1+2 min SU plus 1+2 min ST) if there is an orthostatic test. Studies relying on time- and frequency-domain parameters need a minimum of 5 min (= 1+4) min SU or seated position only but require 10 min (= 1+4 min SU plus 1+4 min ST) for the orthostatic test. PMID- 28848383 TI - The Human "Cochlear Battery" - Claudin-11 Barrier and Ion Transport Proteins in the Lateral Wall of the Cochlea. AB - Background: The cochlea produces an electric field potential essential for hair cell transduction and hearing. This biological "battery" is situated in the lateral wall of the cochlea and contains molecular machinery that secretes and recycles K+ ions. Its functioning depends on junctional proteins that restrict the para-cellular escape of ions. The tight junction protein Claudin-11 has been found to be one of the major constituents of this barrier that maintains ion gradients (Gow et al., 2004; Kitajiri et al., 2004a). We are the first to elucidate the human Claudin-11 framework and the associated ion transport machinery using super-resolution fluorescence illumination microscopy (SR-SIM). Methods: Archival cochleae obtained during meningioma surgery were used for SR SIM together with transmission electron microscopy after ethical consent. Results: Claudin-11-expressing cells formed parallel tight junction lamellae that insulated the epithelial syncytium of the stria vascularis and extended to the suprastrial region. Intercellular gap junctions were found between the barrier cells and fibrocytes. Conclusion: Transmission electron microscopy, confocal microscopy and SR-SIM revealed exclusive cell specialization in the various subdomains of the lateral wall of the human cochlea. The Claudin-11-expressing cells exhibited both conductor and isolator characteristics, and these micro porous separators may selectively mediate the movement of charged units to the intrastrial space in a manner that is analogous to a conventional electrochemical "battery." The function and relevance of this battery for the development of inner ear disease are discussed. PMID- 28848384 TI - Chronic Stress Triggers Expression of Immediate Early Genes and Differentially Affects the Expression of AMPA and NMDA Subunits in Dorsal and Ventral Hippocampus of Rats. AB - Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depressive-like behaviors, anxiety and a reduction in dendritic spine density in hippocampal neurons. In this study, we compared the effect of repeated stress on the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in dorsal and ventral hippocampus (VH). Adult male Sprague-Dawley rats were randomly divided into control and stressed groups, and were daily restrained in their motion (2.5 h/day) during 14 days. We found that chronic stress promotes an increase in c-Fos mRNA levels in both hippocampal areas, although it was observed a reduction in the immunoreactivity at pyramidal cell layer. Furthermore, Arc mRNAs levels were increased in both dorsal and VH, accompanied by an increase in Arc immunoreactivity in dendritic hippocampal layers. Furthermore, stress triggered a reduction in PSD-95 and NR1 protein levels in whole extract of dorsal and VH. Moreover, a reduction in NR2A/NR2B ratio was observed only in dorsal pole. In synaptosomal fractions, we detected a rise in NR1 in dorsal hippocampus (DH). By indirect immunofluorescence we found that NR1 subunits rise, especially in neuropil areas of dorsal, but not VH. In relation to AMPA receptor (AMPAR) subunits, chronic stress did not trigger any change, either in dorsal or ventral hippocampal areas. These data suggest that DH is more sensitive than VH to chronic stress exposure, mainly altering the expression of NMDA receptor (NMDAR) subunits, and probably favors changes in the configuration of this receptor that may influence the function of this area. PMID- 28848386 TI - Pathophysiology and Clinical Utility of Non-coding RNAs in Epilepsy. AB - Epilepsy is a common neurologic disorder. The underlying pathological processes include synaptic strength, inflammation, ion channels, and apoptosis. Acting as epigenetic factors, non-coding RNAs (ncRNAs) participate in the regulation of pathophysiologic processes of epilepsy and are dysregulated during epileptogenesis. Aberrant expression of ncRNAs are observed in epilepsy patients and animal models of epilepsy. Furthermore, ncRNAs might also be used as biomarkers for diagnosis and the prognosis of treatment response in epilepsy. In this review, we will summarize the role of ncRNAs in the pathophysiology of epilepsy and the putative utilization of ncRNAs as diagnostic biomarkers and therapeutic targets. PMID- 28848385 TI - Translational Identification of Transcriptional Signatures of Major Depression and Antidepressant Response. AB - Major depressive disorder (MDD) is a highly prevalent mental illness whose therapy management remains uncertain, with more than 20% of patients who do not achieve response to antidepressants. Therefore, identification of reliable biomarkers to predict response to treatment will greatly improve MDD patient medical care. Due to the inaccessibility and lack of brain tissues from living MDD patients to study depression, researches using animal models have been useful in improving sensitivity and specificity of identifying biomarkers. In the current study, we used the unpredictable chronic mild stress (UCMS) model and correlated stress-induced depressive-like behavior (n = 8 unstressed vs. 8 stressed mice) as well as the fluoxetine-induced recovery (n = 8 stressed and fluoxetine-treated mice vs. 8 unstressed and fluoxetine-treated mice) with transcriptional signatures obtained by genome-wide microarray profiling from whole blood, dentate gyrus (DG), and the anterior cingulate cortex (ACC). Hierarchical clustering and rank-rank hypergeometric overlap (RRHO) procedures allowed us to identify gene transcripts with variations that correlate with behavioral profiles. As a translational validation, some of those transcripts were assayed by RT-qPCR with blood samples from 10 severe major depressive episode (MDE) patients and 10 healthy controls over the course of 30 weeks and four visits. Repeated-measures ANOVAs revealed candidate trait biomarkers (ARHGEF1, CMAS, IGHMBP2, PABPN1 and TBC1D10C), whereas univariate linear regression analyses uncovered candidates state biomarkers (CENPO, FUS and NUBP1), as well as prediction biomarkers predictive of antidepressant response (CENPO, NUBP1). These data suggest that such a translational approach may offer new leads for clinically valid panels of biomarkers for MDD. PMID- 28848387 TI - Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder. AB - Given its prevalence and social impact, Autism Spectrum Disorder (ASD) is drawing much interest. Molecular basis of ASD is heterogeneous and only partially known. Many factors, including disorders comorbid with ASD, like TS (Tourette Syndrome), complicate ASD behavior-based diagnosis and make it vulnerable to bias. To further investigate ASD etiology and to identify potential biomarkers to support its precise diagnosis, we used TaqMan Low Density Array technology to profile serum miRNAs from ASD, TS, and TS+ASD patients, and unaffected controls (NCs). Through validation assays in 30 ASD, 24 TS, and 25 TS+ASD patients and 25 NCs, we demonstrated that miR-140-3p is upregulated in ASD vs.: NC, TS, and TS+ASD (Tukey's test, p-values = 0.03, = 0.01, < 0.0001, respectively). DeltaCt values for miR-140-3p and YGTSS (Yale Global Tic Severity Scale) scores are positively correlated (Spearman r = 0.33; Benjamini-Hochberg p = 0.008) and show a linear relationship (p = 0.002). Network functional analysis showed that nodes controlled by miR-140-3p, especially CD38 and NRIP1 which are its validated targets, are involved in processes convergingly dysregulated in ASD, such as synaptic plasticity, immune response, and chromatin binding. Biomarker analysis proved that serum miR-140-3p can discriminate among: (1) ASD and NC (Area under the ROC curve, AUC: 0.70; sensitivity: 63.33%; specificity: 68%); (2) ASD and TS (AUC: 0.72; sensitivity: 66.66%; specificity: 70.83%); (3) ASD and TS+ASD (AUC: 0.78; sensitivity: 73.33%; specificity: 76%). Characterization of miR-140-3p network would contribute to further clarify ASD etiology. Serum miR-140-3p could represent a potential non-invasive biomarker for ASD, easy to test through liquid biopsy. PMID- 28848389 TI - The Generation of Mouse and Human Huntington Disease iPS Cells Suitable for In vitro Studies on Huntingtin Function. AB - Huntington disease (HD) is an incurable neurodegenerative disorder caused by expansion of CAG repeats in huntingtin (HTT) gene, resulting in expanded polyglutamine tract in HTT protein. Although, HD has its common onset in adulthood, subtle symptoms in patients may occur decades before diagnosis, and molecular and cellular changes begin much earlier, even in cells that are not yet lineage committed such as stem cells. Studies in induced pluripotent stem cell (iPSC) HD models have demonstrated that multiple molecular processes are altered by the mutant HTT protein and suggested its silencing as a promising therapeutic strategy. Therefore, we aimed to generate HD iPS cells with stable silencing of HTT and further to investigate the effects of HTT knock-down on deregulations of signaling pathways e.g., p53 downregulation, present in cells already in pluripotent state. We designed a gene silencing strategy based on RNAi cassette in piggyBAC vector for constant shRNA expression. Using such system we delivered and tested several shRNA targeting huntingtin in mouse HD YAC128 iPSC and human HD109, HD71, and Control iPSC. The most effective shRNA (shHTT2) reagent stably silenced HTT in all HD iPS cells and remained active upon differentiation to neural stem cells (NSC). When investigating the effects of HTT silencing on signaling pathways, we found that in mouse HD iPSC lines expressing shRNA the level of mutant HTT inversely correlated with p53 levels, resulting in p53 level normalization upon silencing of mutant HTT. We also found that p53 deregulation continues into the NSC developmental stage and it was reversed upon HTT silencing. In addition, we observed subtle effects of silencing on proteins of Wnt/beta-catenin and ERK1/2 signaling pathways. In summary, we successfully created the first mouse and human shRNA-expressing HD iPS cells with stable and continuous HTT silencing. Moreover, we demonstrated reversal of HD p53 phenotype in mouse HD iPSC, therefore, the stable knockdown of HTT is well-suited for investigation on HD cellular pathways, and is potentially useful as a stand-alone therapy or component of cell therapy. In addition, the total HTT knock-down in our human cells has further implications for mutant allele selective approach in iPSC. PMID- 28848388 TI - Integrated Computational Analysis of Genes Associated with Human Hereditary Insensitivity to Pain. A Drug Repurposing Perspective. AB - Genes causally involved in human insensitivity to pain provide a unique molecular source of studying the pathophysiology of pain and the development of novel analgesic drugs. The increasing availability of "big data" enables novel research approaches to chronic pain while also requiring novel techniques for data mining and knowledge discovery. We used machine learning to combine the knowledge about n = 20 genes causally involved in human hereditary insensitivity to pain with the knowledge about the functions of thousands of genes. An integrated computational analysis proposed that among the functions of this set of genes, the processes related to nervous system development and to ceramide and sphingosine signaling pathways are particularly important. This is in line with earlier suggestions to use these pathways as therapeutic target in pain. Following identification of the biological processes characterizing hereditary insensitivity to pain, the biological processes were used for a similarity analysis with the functions of n = 4,834 database-queried drugs. Using emergent self-organizing maps, a cluster of n = 22 drugs was identified sharing important functional features with hereditary insensitivity to pain. Several members of this cluster had been implicated in pain in preclinical experiments. Thus, the present concept of machine-learned knowledge discovery for pain research provides biologically plausible results and seems to be suitable for drug discovery by identifying a narrow choice of repurposing candidates, demonstrating that contemporary machine-learned methods offer innovative approaches to knowledge discovery from available evidence. PMID- 28848390 TI - Dietary-Induced Signals That Activate the Gonadal Longevity Pathway during Development Regulate a Proteostasis Switch in Caenorhabditis elegans Adulthood. AB - Cell-non-autonomous signals dictate the functional state of cellular quality control systems, remodeling the ability of cells to cope with stress and maintain protein homeostasis (proteostasis). One highly regulated cell-non-autonomous switch controls proteostatic capacity in Caenorhabditis elegans adulthood. Signals from the reproductive system down-regulate cyto-protective pathways, unless countered by signals reporting on germline proliferation disruption. Here, we utilized dihomo-gamma-linolenic acid (DGLA) that depletes the C. elegans germline to ask when cell-non-autonomous signals from the reproductive system determine somatic proteostasis and whether such regulation is reversible. We found that diet supplementation of DGLA resulted in the maintenance of somatic proteostasis after the onset of reproduction. DGLA-dependent proteostasis remodeling was only effective if animals were exposed to DGLA during larval development. A short exposure of 16 h during the second to fourth larval stages was sufficient and required to maintain somatic proteostasis in adulthood but not to extend lifespan. The reproductive system was required for DGLA-dependent remodeling of proteostasis in adulthood, likely via DGLA-dependent disruption of germline stem cells. However, arachidonic acid (AA), a somatic regulator of this pathway that does not require the reproductive system, presented similar regulatory timing. Finally, we showed that DGLA- and AA-supplementation led to activation of the gonadal longevity pathway but presented differential regulatory timing. Proteostasis and stress response regulators, including hsf-1 and daf-16, were only activated if exposed to DGLA and AA during development, while other gonadal longevity factors did not show this regulatory timing. We propose that C. elegans determines its proteostatic fate during development and is committed to either reproduction, and thus present restricted proteostasis, or survival, and thus present robust proteostasis. Given the critical role of proteostatic networks in the onset and progression of many aging-related diseases, such a choice could impact susceptibility to protein misfolding diseases later in life. PMID- 28848391 TI - Membrane Receptor-Induced Changes of the Protein Kinases A and C Activity May Play a Leading Role in Promoting Developmental Synapse Elimination at the Neuromuscular Junction. AB - Synapses that are overproduced during histogenesis in the nervous system are eventually lost and connectivity is refined. Membrane receptor signaling leads to activity-dependent mutual influence and competition between axons directly or with the involvement of the postsynaptic cell and the associated glial cell/s. Presynaptic muscarinic acetylcholine (ACh) receptors (subtypes mAChR; M1, M2 and M4), adenosine receptors (AR; A1 and A2A) and the tropomyosin-related kinase B receptor (TrkB), among others, all cooperate in synapse elimination. Between these receptors there are several synergistic, antagonic and modulatory relations that clearly affect synapse elimination. Metabotropic receptors converge in a limited repertoire of intracellular effector kinases, particularly serine protein kinases A and C (PKA and PKC), to phosphorylate protein targets and bring about structural and functional changes leading to axon loss. In most cells A1, M1 and TrkB operate mainly by stimulating PKC whereas A2A, M2 and M4 inhibit PKA. We hypothesize that a membrane receptor-induced shifting in the protein kinases A and C activity (inhibition of PKA and/or stimulation of PKC) in some nerve endings may play an important role in promoting developmental synapse elimination at the neuromuscular junction (NMJ). This hypothesis is supported by: (i) the tonic effect (shown by using selective inhibitors) of several membrane receptors that accelerates axon loss between postnatal days P5-P9; (ii) the synergistic, antagonic and modulatory effects (shown by paired inhibition) of the receptors on axonal loss; (iii) the fact that the coupling of these receptors activates/inhibits the intracellular serine kinases; and (iv) the increase of the PKA activity, the reduction of the PKC activity or, in most cases, both situations simultaneously that presumably occurs in all the situations of singly and paired inhibition of the mAChR, AR and TrkB receptors. The use of transgenic animals and various combinations of selective and specific PKA and PKC inhibitors could help to elucidate the role of these kinases in synapse maturation. PMID- 28848392 TI - Jagged1 Is Altered in Alzheimer's Disease and Regulates Spatial Memory Processing. AB - Notch signaling plays an instrumental role in hippocampus-dependent memory formation and recent evidence indicates a displacement of Notch1 and a reduction its activity in hippocampal and cortical neurons from Alzheimer's disease (AD) patients. As Notch activation depends on ligand availability, we investigated whether Jagged1 expression was altered in brain specimen of AD patients. We found that Jagged1 expression was reduced in the CA fields and that there was a gradual reduction of Jagged1 in the cerebrospinal fluid (CSF) with the progression of dementia. Given the role of Notch signaling in memory encoding, we investigated whether targeted loss of Jagged1 in neurons may be responsible for the memory loss seen in AD patients. Using a transgenic mouse model, we show that the targeted loss of Jagged1 expression during adulthood is sufficient to cause spatial memory loss and a reduction in exploration-dependent Notch activation. We also show that Jagged1 is selectively enriched at the presynaptic terminals in mice. Overall, the present data emphasizes the role of the Notch ligand, Jagged1, in memory formation and the potential deficit of the signaling ligand in AD patients. PMID- 28848393 TI - The P2X7 Receptor Primes IL-1beta and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain. AB - Inflammatory responses play a key role in many neural pathologies, with localized signaling from the non-immune cells making critical contributions. The NLRP3 inflammasome is an important component of innate immune signaling and can link neural insult to chronic inflammation. The NLRP3 inflammasome requires two stages to contribute: priming and activation. The priming stage involves upregulation of inflammasome components while the activation stage results in the assembly and activation of the inflammasome complex. The priming step can be rate limiting and can connect insult to chronic inflammation, but our knowledge of the signals that regulate NLRP3 inflammasome priming in sterile inflammation is limited. This study examined the link between mechanical strain and inflammasome priming in neural systems. Transient non-ischemic elevation of intraocular pressure increased mRNA for inflammasome components IL-1beta, NLRP3, ASC, and CASP1 in rat and mouse retinas. The elevation was greater 1 day after the insult, with the rise in IL-1beta most pronounced. The P2X7 receptor was implicated in the mechanosensitive priming of IL-1beta mRNA in vivo, as the antagonist Brilliant Blue G (BBG) blocked the increased expression, the agonist BzATP mimicked the pressure-dependent rise in IL-1beta, and the rise was absent in P2X7 knockout mice. In vitro measurements from optic nerve head astrocytes demonstrated an increased expression of IL-1beta following stretch or swelling. This increase in IL-1beta was eliminated by degradation of extracellular ATP with apyrase, or by the block of pannexin hemichannels with carbenoxolone, probenecid, or 10panx1 peptide. The rise in IL-1beta expression was also blocked by P2X7 receptor antagonists BBG, A839977 or A740003. The rise in IL-1beta was prevented by blocking transcription factor NFkappaB with Bay 11-7082, while the swelling dependent fall in NFkappaB inhibitor IkappaB-alpha was reduced by A839977 and in P2X7 knockout mice. In summary, mechanical trauma to the retina primed NLRP3 inflammasome components, but only if there was ATP release through pannexin hemichannels, and autostimulation of the P2X7 receptor. As the P2X7 receptor can also trigger stage two of inflammasome assembly and activation, the P2X7 receptor may have a central role in linking mechanical strain to neuroinflammation. PMID- 28848394 TI - Resveratrol Attenuates Neurodegeneration and Improves Neurological Outcomes after Intracerebral Hemorrhage in Mice. AB - Intracerebral hemorrhage (ICH) is a devastating type of stroke with a substantial public health impact. Currently, there is no effective treatment for ICH. The purpose of the study was to evaluate whether the post-injury administration of Resveratrol confers neuroprotection in a pre-clinical model of ICH. To this end, ICH was induced in adult male CD1 mice by collagenase injection method. Resveratrol (10 mg/kg) or vehicle was administered at 30 min post-induction of ICH and the neurobehavioral outcome, neurodegeneration, cerebral edema, hematoma resolution and neuroinflammation were assessed. The Resveratrol treatment significantly attenuated acute neurological deficits, neurodegeneration and cerebral edema after ICH in comparison to vehicle treated controls. Further, Resveratrol treated mice exhibited improved hematoma resolution with a concomitant reduction in the expression of proinflammatory cytokine, IL-1beta after ICH. Altogether, the data suggest the efficacy of post-injury administration of Resveratrol in improving acute neurological function after ICH. PMID- 28848395 TI - Few, Activity-Dependent, and Ubiquitous VGLUT1/VGAT Terminals in Rat and Mouse Brain. AB - In the neocortex of adult rats VGLUT1 and VGAT co-localize in axon terminals which form both symmetric and asymmetric synapses. They are expressed in the same synaptic vesicles which participate in the exo-endocytotic cycle. Virtually nothing, however, is known on whether VGLUT1/VGAT co-localization occurs in other brain regions. We therefore mapped the distribution of terminals co-expressing VGLUT1/VGAT in the striatum, hippocampus, thalamus, and cerebellar and cerebral cortices of rats and mice. Confocal microscopy analysis revealed that, in both rat and mouse brain, VGLUT1/VGAT+ terminals were present in all brain regions studied, and that their percentage was low and comparable in both species. These results provide the first demonstration that co-expression of VGLUT1 and VGAT is a widespread phenomenon. Since VGLUT1/VGAT+ axon terminals are regulated in an activity-dependent manner and co-release glutamate and GABA, we hypothesize that, though not numerous, they can contribute to regulating excitation/inhibition balance in physiological conditions, thereby playing a role in several neurological and psychiatric diseases. PMID- 28848396 TI - Regulation of Pannexin 1 Surface Expression by Extracellular ATP: Potential Implications for Nervous System Function in Health and Disease. AB - Pannexin 1 (Panx1) channels are widely recognized for their role in ATP release, and as follows, their function is closely tied to that of ATP-activated P2X7 purinergic receptors (P2X7Rs). Our recent work has shown that extracellular ATP induces clustering of Panx1 with P2X7Rs and their subsequent internalization through a non-canonical cholesterol-dependent mechanism. In other words, we have demonstrated that extracellular ATP levels can regulate the cell surface expression of Panx1. Here we discuss two situations in which we hypothesize that ATP modulation of Panx1 surface expression could be relevant for central nervous system function. The first scenario involves the development of new neurons in the ventricular zone. We propose that ATP-induced Panx1 endocytosis could play an important role in regulating the balance of cell proliferation, survival, and differentiation within this neurogenic niche in the healthy brain. The second scenario relates to the spinal cord, in which we posit that an impairment of ATP induced Panx1 endocytosis could contribute to pathological neuroplasticity. Together, the discussion of these hypotheses serves to highlight important outstanding questions regarding the interplay between extracellular ATP, Panx1, and P2X7Rs in the nervous system in health and disease. PMID- 28848397 TI - Retinoschisin Facilitates the Function of L-Type Voltage-Gated Calcium Channels. AB - Modulation of ion channels by extracellular proteins plays critical roles in shaping synaptic plasticity. Retinoschisin (RS1) is an extracellular adhesive protein secreted from photoreceptors and bipolar cells, and it plays an important role during retinal development, as well as in maintaining the stability of retinal layers. RS1 is known to form homologous octamers and interact with molecules on the plasma membrane including phosphatidylserine, sodium-potassium exchanger complex, and L-type voltage-gated calcium channels (LTCCs). However, how this physical interaction between RS1 and ion channels might affect the channel gating properties is unclear. In retinal photoreceptors, two major LTCCs are Cav1.3 (alpha1D) and Cav1.4 (alpha1F) with distinct biophysical properties, functions and distributions. Cav1.3 is distributed from the inner segment (IS) to the synaptic terminal and is responsible for calcium influx to the photoreceptors and overall calcium homeostasis. Cav1.4 is only expressed at the synaptic terminal and is responsible for neurotransmitter release. Mutations of the gene encoding Cav1.4 cause X-linked incomplete congenital stationary night blindness type 2 (CSNB2), while null mutations of Cav1.3 cause a mild decrease of retinal light responses in mice. Even though RS1 is known to maintain retinal architecture, in this study, we present that RS1 interacts with both Cav1.3 and Cav1.4 and regulates their activations. RS1 was able to co-immunoprecipitate with Cav1.3 and Cav1.4 from porcine retinas, and it increased the LTCC currents and facilitated voltage-dependent activation in HEK cells co-transfected with RS1 and Cav1.3 or Cav1.4, thus providing evidence of a functional interaction between RS1 and LTCCs. The interaction between RS1 and Cav1.3 did not change the calcium dependent inactivation of Cav1.3. In mice lacking RS1, the expression of Cav1.3 and Cav1.4 in the retina decreased, while in mice with Cav1.4 deletion, the retinal level of RS1 decreased. These results provide important evidence that RS1 is not only an adhesive protein promoting cell-cell adhesion, it is essential for anchoring other membrane proteins including ion channels and enhancing their function in the retina. PMID- 28848398 TI - Microglia Morphological Categorization in a Rat Model of Neuroinflammation by Hierarchical Cluster and Principal Components Analysis. AB - It is known that microglia morphology and function are closely related, but only few studies have objectively described different morphological subtypes. To address this issue, morphological parameters of microglial cells were analyzed in a rat model of aseptic neuroinflammation. After the injection of a single dose of the enzyme neuraminidase (NA) within the lateral ventricle (LV) an acute inflammatory process occurs. Sections from NA-injected animals and sham controls were immunolabeled with the microglial marker IBA1, which highlights ramifications and features of the cell shape. Using images obtained by section scanning, individual microglial cells were sampled from various regions (septofimbrial nucleus, hippocampus and hypothalamus) at different times post injection (2, 4 and 12 h). Each cell yielded a set of 15 morphological parameters by means of image analysis software. Five initial parameters (including fractal measures) were statistically different in cells from NA-injected rats (most of them IL-1beta positive, i.e., M1-state) compared to those from control animals (none of them IL-1beta positive, i.e., surveillant state). However, additional multimodal parameters were revealed more suitable for hierarchical cluster analysis (HCA). This method pointed out the classification of microglia population in four clusters. Furthermore, a linear discriminant analysis (LDA) suggested three specific parameters to objectively classify any microglia by a decision tree. In addition, a principal components analysis (PCA) revealed two extra valuable variables that allowed to further classifying microglia in a total of eight sub-clusters or types. The spatio-temporal distribution of these different morphotypes in our rat inflammation model allowed to relate specific morphotypes with microglial activation status and brain location. An objective method for microglia classification based on morphological parameters is proposed. Main points Microglia undergo a quantifiable morphological change upon neuraminidase induced inflammation.Hierarchical cluster and principal components analysis allow morphological classification of microglia.Brain location of microglia is a relevant factor. PMID- 28848399 TI - Methodological Approach for Optogenetic Manipulation of Neonatal Neuronal Networks. AB - Coordinated patterns of electrical activity are critical for the functional maturation of neuronal networks, yet their interrogation has proven difficult in the developing brain. Optogenetic manipulations strongly contributed to the mechanistic understanding of network activation in the adult brain, but difficulties to specifically and reliably express opsins at neonatal age hampered similar interrogation of developing circuits. Here, we introduce a protocol that enables to control the activity of specific neuronal populations by light, starting from early postnatal development. We show that brain area-, layer- and cell type-specific expression of opsins by in utero electroporation (IUE), as exemplified for the medial prefrontal cortex (PFC) and hippocampus (HP), permits the manipulation of neuronal activity in vitro and in vivo. Both individual and population responses to different patterns of light stimulation are monitored by extracellular multi-site recordings in the medial PFC of neonatal mice. The expression of opsins via IUE provides a flexible approach to disentangle the cellular mechanism underlying early rhythmic network activity, and to elucidate the role of early neuronal activity for brain maturation, as well as its contribution to neurodevelopmental disorders. PMID- 28848400 TI - AF-6 Protects Against Dopaminergic Dysfunction and Mitochondrial Abnormalities in Drosophila Models of Parkinson's Disease. AB - Afadin 6 (AF-6) is an F-actin binding multidomain-containing scaffolding protein that is known for its function in cell-cell adhesion. Interestingly, besides this well documented role, we recently found that AF-6 is a Parkin-interacting protein that augments Parkin/PINK1-mediated mitophagy. Notably, mutations in Parkin and PINK1 are causative of recessively inherited forms of Parkinson's disease (PD) and aberrant mitochondrial homeostasis is thought to underlie PD pathogenesis. Given the novel role of AF-6 in mitochondrial quality control (QC), we hypothesized that AF-6 overexpression may be beneficial to PD. Using the Drosophila melanogaster as a model system, we demonstrate in this study that transgenic overexpression of human AF-6 in parkin and also pink1 null flies rescues their mitochondrial pathology and associated locomotion deficit, which results in their improved survival over time. Similarly, AF-6 overexpression also ameliorates the pathological phenotypes in flies expressing the Leucine Rich Repeat Kinase 2 (LRRK2) G2019S mutant, a mutation that is associated with dominantly-inherited PD cases in humans. Conversely, when endogenous AF-6 expression is silenced, it aggravates the disease phenotypes of LRRK2 mutant flies. Aside from these genetic models, we also found that AF-6 overexpression is protective against the loss of dopaminergic neurons in flies treated with rotenone, a mitochondrial complex I inhibitor commonly used to generate animal models of PD. Taken together, our results demonstrate that AF-6 protects against dopaminergic dysfunction and mitochondrial abnormalities in multiple Drosophila models of PD, and suggest the therapeutic value of AF-6-related pathways in mitigating PD pathogenesis. PMID- 28848401 TI - Unconditioned- and Conditioned- Stimuli Induce Differential Memory Reconsolidation and beta-AR-Dependent CREB Activation. AB - Consolidated long-term fear memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus (CS) or unconditioned stimulus (US). Whether CS-retrieval or US-retrieval will trigger different memory reconsolidation processes is unknown. In this study, we introduced a sequential fear conditioning paradigm in which footshock (FS) was paired with two distinct sounds (CS-A and CS-B). The treatment with propranolol, a beta-adrenergic receptor (beta-AR) antagonist, after US (FS)-retrieval impaired freezing behavior evoked by either CS-A or CS-B. Betaxolol, a selective beta1-AR antagonist, showed similar effects. However, propranolol treatment after retrieval by one CS (e.g., CS-A) only inhibited freezing behavior evoked by the same CS (i.e., CS-A), not the other CS (CS-B). These data suggest that beta-AR is critically involved in reconsolidation of fear memory triggered by US- and CS-retrieval, whereas beta-AR blockade after US-retrieval disrupts more CS-US associations than CS-retrieval does. Furthermore, significant CREB activation in almost the whole amygdala and hippocampus was observed after US-retrieval, but CS-retrieval only stimulated CREB activation in the lateral amygdala and the CA3 of hippocampus. In addition, propranolol treatment suppressed memory retrieval-induced CREB activation. These data indicate that US-retrieval activates more memory traces than CS-retrieval does, leading to memory reconsolidation of more CS-US associations. PMID- 28848402 TI - Shared Components of Rhythm Generation for Locomotion and Scratching Exist Prior to Motoneurons. AB - Does the spinal cord use a single network to generate locomotor and scratching rhythms or two separate networks? Previous research showed that simultaneous swim and scratch stimulation ("dual stimulation") in immobilized, spinal turtles evokes a single rhythm in hindlimb motor nerves with a frequency often greater than during swim stimulation alone or scratch stimulation alone. This suggests that the signals that trigger swimming and scratching converge and are integrated within the spinal cord. However, these results could not determine whether the integration occurs in motoneurons themselves or earlier, in spinal interneurons. Here, we recorded intracellularly from hindlimb motoneurons during dual stimulation. Motoneuron membrane potentials displayed regular oscillations at a higher frequency during dual stimulation than during swim or scratch stimulation alone. In contrast, arithmetic addition of the oscillations during swimming alone and scratching alone with various delays always generated irregular oscillations. Also, the standard deviation of the phase-normalized membrane potential during dual stimulation was similar to those during swimming or scratching alone. In contrast, the standard deviation was greater when pooling cycles of swimming alone and scratching alone for two of the three forms of scratching. This shows that dual stimulation generates a single rhythm prior to motoneurons. Thus, either swimming and scratching largely share a rhythm generator or the two rhythms are integrated into one rhythm by strong interactions among interneurons. PMID- 28848403 TI - Endomorphin-2 Decreases Excitatory Synaptic Transmission in the Spinal Ventral Horn of the Rat. AB - Motor impairment is one of the serious side-effects of morphine, which is an exogenous agonist of the MU-opioid receptor (MOR) as well as a widely used analgesic drug in clinical practice for chronic pain treatment. Endomorphins (EMs, including EM-1 and EM-2), the most effective and specific endogenous agonists of the MOR, exert more potent analgesia in acute and neuropathic pain than other opiates, such as morphine. Although EMs had fewer side-effects comparing to other opiates, motor impairment was still one unwanted reaction which limited its clinical application. In order to prevent and treat the motor impairment, it is critical to reveal the neural mechanisms underlying such locomotion disorder. The purpose of the present study was to reveal the neural mechanisms underlying the effects of EM-2 on the activity of motoneurons in the spinal ventral horn. First, we examine the distribution of EM-2-immunoreactive (IR) primary afferent fibers and their synaptic connections with the motoneurons innervating the skeletal muscles of the lower limb revealed by sciatic nerve retrograde tracing. The results showed that EM-2-IR fibers and terminals were sparsely observed in lamina IX and they formed symmetric synaptic connections with the motoneurons within lamina IX of the spinal ventral horn. Then, whole cell patch-clamp technique was used to observe the effects of EM-2 on the spontaneous excitatory postsynaptic current (sEPSC) of motoneurons in lamina IX. The results showed that EM-2 could decrease both the frequency and amplitude of the sEPSC of the motoneurons in lamina IX, which was reversed by the MOR antagonist CTOP. These results indicate that EM-2-IR fibers originated from primary afferent fibers form symmetric synaptic connections with motoneurons innervating skeletal muscles of the lower limbs in lamina IX of the spinal ventral horn and EM-2 might exert inhibitory effects on the activities of these motoneurons through both presynaptic and postsynaptic mechanisms. PMID- 28848405 TI - The Effects of Fat Body Tyramine Level on Gustatory Responsiveness of Honeybees (Apis mellifera) Differ between Behavioral Castes. AB - Division of labor is a hallmark of social insects. In the honeybee (Apis mellifera) each sterile female worker performs a series of social tasks. The most drastic changes in behavior occur when a nurse bee, who takes care of the brood and the queen in the hive, transitions to foraging behavior. Foragers provision the colony with pollen, nectar or water. Nurse bees and foragers differ in numerous behaviors, including responsiveness to gustatory stimuli. Differences in gustatory responsiveness, in turn, might be involved in regulating division of labor through differential sensory response thresholds. Biogenic amines are important modulators of behavior. Tyramine and octopamine have been shown to increase gustatory responsiveness in honeybees when injected into the thorax, thereby possibly triggering social organization. So far, most of the experiments investigating the role of amines on gustatory responsiveness have focused on the brain. The potential role of the fat body in regulating sensory responsiveness and division of labor has large been neglected. We here investigated the role of the fat body in modulating gustatory responsiveness through tyramine signaling in different social roles of honeybees. We quantified levels of tyramine, tyramine receptor gene expression and the effect of elevating fat body tyramine titers on gustatory responsiveness in both nurse bees and foragers. Our data suggest that elevating the tyramine titer in the fat body pharmacologically increases gustatory responsiveness in foragers, but not in nurse bees. This differential effect of tyramine on gustatory responsiveness correlates with a higher natural gustatory responsiveness of foragers, with a higher tyramine receptor (Amtar1) mRNA expression in fat bodies of foragers and with lower baseline tyramine titers in fat bodies of foragers compared to those of nurse bees. We suggest that differential tyramine signaling in the fat body has an important role in the plasticity of division of labor through changing gustatory responsiveness. PMID- 28848404 TI - Short-Term Effects of Chewing on Task Performance and Task-Induced Mydriasis: Trigeminal Influence on the Arousal Systems. AB - Trigeminal input to the ascending activating system is important for the maintenance of arousal and may affect the discharge of the noradrenergic neurons of the locus coeruleus (LC), whose activity influences both vigilance state and pupil size, inducing mydriasis. For this reason, pupil size evaluation is now considered an indicator of LC activity. Since mastication activates trigeminal afferent neurons, the aims of the present study, conducted on healthy adult participants, were to investigate whether chewing a bolus of different hardness may: (1) differentially affect the performance on a cognitive task (consisting in the retrieval of specific target numbers within numerical matrices) and (2) increase the dilatation of the pupil (mydriasis) induced by a haptic task, suggesting a change in LC activation. Results show that chewing significantly increased both the velocity of number retrieval (without affecting the number of errors) and the mydriasis associated with the haptic task, whereas simple task repetition did not modify either retrieval or mydriasis. Handgrip exercise, instead, significantly decreased both parameters. Effects were significantly stronger and longer lasting when subjects chewed hard pellets. Finally, chewing induced improvements in performance and changes in mydriasis were positively correlated, which suggests that trigeminal signals enhanced by chewing may boost the cognitive performance by increasing LC activity. PMID- 28848406 TI - The Time Is Up: Compression of Visual Time Interval Estimations of Bimodal Aperiodic Patterns. AB - The ability to estimate time intervals subserves many of our behaviors and perceptual experiences. However, it is not clear how aperiodic (AP) stimuli affect our perception of time intervals across sensory modalities. To address this question, we evaluated the human capacity to discriminate between two acoustic (A), visual (V) or audiovisual (AV) time intervals of trains of scattered pulses. We first measured the periodicity of those stimuli and then sought for correlations with the accuracy and reaction times (RTs) of the subjects. We found that, for all time intervals tested in our experiment, the visual system consistently perceived AP stimuli as being shorter than the periodic (P) ones. In contrast, such a compression phenomenon was not apparent during auditory trials. Our conclusions are: first, the subjects exposed to P stimuli are more likely to measure their durations accurately. Second, perceptual time compression occurs for AP visual stimuli. Lastly, AV discriminations are determined by A dominance rather than by AV enhancement. PMID- 28848407 TI - Lexical-Semantic Search Under Different Covert Verbal Fluency Tasks: An fMRI Study. AB - Background: Verbal fluency is a measure of cognitive flexibility and word search strategies that is widely used to characterize impaired cognitive function. Despite the wealth of research on identifying and characterizing distinct aspects of verbal fluency, the anatomic and functional substrates of retrieval-related search and post-retrieval control processes still have not been fully elucidated. Methods: Twenty-one native English-speaking, healthy, right-handed, adult volunteers (mean age = 31 years; range = 21-45 years; 9 F) took part in a block design functional Magnetic Resonance Imaging (fMRI) study of free recall, covert word generation tasks when guided by phonemic (P), semantic-category (C), and context-based fill-in-the-blank sentence completion (S) cues. General linear model (GLM), Independent Component Analysis (ICA), and psychophysiological interaction (PPI) were used to further characterize the neural substrate of verbal fluency as a function of retrieval cue type. Results: Common localized activations across P, C, and S tasks occurred in the bilateral superior and left inferior frontal gyrus, left anterior cingulate cortex, bilateral supplementary motor area (SMA), and left insula. Differential task activations were centered in the occipital, temporal and parietal regions as well as the thalamus and cerebellum. The context-based fluency task, i.e., the S task, elicited higher differential brain activity in a lateralized frontal-temporal network typically engaged in complex language processing. P and C tasks elicited activation in limited pathways mainly within the left frontal regions. ICA and PPI results of the S task suggested that brain regions distributed across both hemispheres, extending beyond classical language areas, are recruited for lexical-semantic access and retrieval during sentence completion. Conclusion: Study results support the hypothesis of overlapping, as well as distinct, neural networks for covert word generation when guided by different linguistic cues. The increased demand on word retrieval is met by the concurrent recruitment of classical as well as non-classical language-related brain regions forming a large cognitive neural network. The retrieval-related search and post-retrieval control processes that subserve verbal fluency, therefore, reverberates across distinct functional networks as determined by respective task demands. PMID- 28848408 TI - Networks of VTA Neurons Encode Real-Time Information about Uncertain Numbers of Actions Executed to Earn a Reward. AB - Multiple and unpredictable numbers of actions are often required to achieve a goal. In order to organize behavior and allocate effort so that optimal behavioral policies can be selected, it is necessary to continually monitor ongoing actions. Real-time processing of information related to actions and outcomes is typically assigned to the prefrontal cortex and basal ganglia, but also depends on midbrain regions, especially the ventral tegmental area (VTA). We were interested in how individual VTA neurons, as well as networks within the VTA, encode salient events when an unpredictable number of serial actions are required to obtain a reward. We recorded from ensembles of putative dopamine and non-dopamine neurons in the VTA as animals performed multiple cued trials in a recording session where, in each trial, serial actions were randomly rewarded. While averaging population activity did not reveal a response pattern, we observed that different neurons were selectively tuned to low, medium, or high numbered actions in a trial. This preferential tuning of putative dopamine and non-dopamine VTA neurons to different subsets of actions in a trial allowed information about binned action number to be decoded from the ensemble activity. At the network level, tuning curve similarity was positively associated with action-evoked noise correlations, suggesting that action number selectivity reflects functional connectivity within these networks. Analysis of phasic responses to cue and reward revealed that the requirement to execute multiple and uncertain numbers of actions weakens both cue-evoked responses and cue-reward response correlation. The functional connectivity and ensemble coding scheme that we observe here may allow VTA neurons to cooperatively provide a real-time account of ongoing behavior. These computations may be critical to cognitive and motivational functions that have long been associated with VTA dopamine neurons. PMID- 28848409 TI - Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson's Disease. AB - The use of dopamine replacement therapies (DRT) in the treatment of Parkinson's disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6 hydroxydopamine (6-OHDA)-induced bilateral lesions in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD. PMID- 28848411 TI - Individual Differences in the Speed of Facial Emotion Recognition Show Little Specificity but Are Strongly Related with General Mental Speed: Psychometric, Neural and Genetic Evidence. AB - Facial identity and facial expression processing are crucial socio-emotional abilities but seem to show only limited psychometric uniqueness when the processing speed is considered in easy tasks. We applied a comprehensive measurement of processing speed and contrasted performance specificity in socio emotional, social and non-social stimuli from an individual differences perspective. Performance in a multivariate task battery could be best modeled by a general speed factor and a first-order factor capturing some specific variance due to processing emotional facial expressions. We further tested equivalence of the relationships between speed factors and polymorphisms of dopamine and serotonin transporter genes. Results show that the speed factors are not only psychometrically equivalent but invariant in their relation with the Catechol-O Methyl-Transferase (COMT) Val158Met polymorphism. However, the 5-HTTLPR/rs25531 serotonin polymorphism was related with the first-order factor of emotion perception speed, suggesting a specific genetic correlate of processing emotions. We further investigated the relationship between several components of event related brain potentials with psychometric abilities, and tested emotion specific individual differences at the neurophysiological level. Results revealed swifter emotion perception abilities to go along with larger amplitudes of the P100 and the Early Posterior Negativity (EPN), when emotion processing was modeled on its own. However, after partialling out the shared variance of emotion perception speed with general processing speed-related abilities, brain-behavior relationships did not remain specific for emotion. Together, the present results suggest that speed abilities are strongly interrelated but show some specificity for emotion processing speed at the psychometric level. At both genetic and neurophysiological levels, emotion specificity depended on whether general cognition is taken into account or not. These findings keenly suggest that general speed abilities should be taken into account when the study of emotion recognition abilities is targeted in its specificity. PMID- 28848410 TI - Behavioral and Immunohistochemical Study of the Effects of Subchronic and Chronic Exposure to Glyphosate in Mice. AB - Many epidemiological studies have described an adolescent-related psychiatric illness and sensorimotor deficits after Glyphosate based herbicide (GBH) exposure. GBH exposure in animal models of various ages suggests that it may be neurotoxic and could impact brain development and subsequently, behavior in adulthood. However, its neurotoxic effects on adolescent brain remain unclear and the results are limited. The present study was conducted to evaluate the neurobehavioral effects of GBH following acute, subchronic (6 weeks) and chronic (12 weeks) exposure (250 or 500 mg/kg/day) in mice treated from juvenile age until adulthood. Mice were subjected to behavioral testing with the open field (OF), the elevated plus maze, the tail suspension and Splash tests (STs). Their behaviors related to exploratory activity, anxiety and depression-like were recorded. After completion of the behavioral testing, adult mice were sacrificed and the expression of tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNc) and serotonin (5-HT) in the dorsal raphe nucleus (DRN), the basolateral amygdala (BLA) and the ventral medial prefrontal cortex (mPFC) was evaluated using immunohistochemical procedure. Our results indicate that unlike acute exposure, both subchronic and chronic exposure to GBH induced a decrease in body weight gain and locomotor activity, and an increase of anxiety and depression-like behavior levels. In addition, the immunohistochemical findings showed that only the chronic treatment induced a reduction of TH immunoreactivity. However, both subchronic and chronic exposure produced a reduction of 5-HT-immunoreactivity in the DRN, BLA and ventral mPFC. Taken together, our data suggest that exposure to GBH from juvenile age through adulthood in mice leads to neurobehavioral changes that stem from the impairment of neuronal developmental processes. PMID- 28848412 TI - Commentary: Activation of Pedunculopontine Glutamate Neurons Is Reinforcing. PMID- 28848413 TI - Disrupted Working Memory Circuitry in Adolescent Psychosis. AB - Individuals with schizophrenia (SZ) consistently show deficits in spatial working memory (WM) and associated atypical patterns of neural activity within key WM regions, including the dorsolateral prefrontal cortex (dlPFC) and parietal cortices. However, little research has focused on adolescent psychosis (AP) and potential age-associated disruptions of WM circuitry that may occur in youth with this severe form of illness. Here we utilized each subject's individual spatial WM capacity to investigate task-based neural dysfunction in 17 patients with AP (16.58 +/- 2.60 years old) as compared to 17 typically developing, demographically comparable adolescents (18.07 +/- 3.26 years old). AP patients showed lower behavioral performance at higher WM loads and lower overall WM capacity compared to healthy controls. Whole-brain activation analyses revealed greater bilateral precentral and right postcentral activity in controls relative to AP patients, when controlling for individual WM capacity. Seed-based psychophysiological interaction (PPI) analyses revealed significantly greater co activation between the left dlPFC and left frontal pole in controls relative to AP patients. Significant group-by-age interactions were observed in both whole brain and PPI analyses, with AP patients showing atypically greater neural activity and stronger coupling between WM task activated brain regions as a function of increasing age. Additionally, AP patients demonstrated positive relationships between right dlPFC neural activity and task performance, but unlike healthy controls, failed to show associations between neural activity and out-of-scanner neurocognitive performance. Collectively, these findings are consistent with atypical WM-related functioning and disrupted developmental processes in youth with AP. PMID- 28848414 TI - Detecting and Quantifying Mind Wandering during Simulated Driving. AB - Mind wandering is a pervasive threat to transportation safety, potentially accounting for a substantial number of crashes and fatalities. In the current study, mind wandering was induced through completion of the same task for 5 days, consisting of a 20-min monotonous freeway-driving scenario, a cognitive depletion task, and a repetition of the 20-min driving scenario driven in the reverse direction. Participants were periodically probed with auditory tones to self report whether they were mind wandering or focused on the driving task. Self reported mind wandering frequency was high, and did not statistically change over days of participation. For measures of driving performance, participant labeled periods of mind wandering were associated with reduced speed and reduced lane variability, in comparison to periods of on task performance. For measures of electrophysiology, periods of mind wandering were associated with increased power in the alpha band of the electroencephalogram (EEG), as well as a reduction in the magnitude of the P3a component of the event related potential (ERP) in response to the auditory probe. Results support that mind wandering has an impact on driving performance and the associated change in driver's attentional state is detectable in underlying brain physiology. Further, results suggest that detecting the internal cognitive state of humans is possible in a continuous task such as automobile driving. Identifying periods of likely mind wandering could serve as a useful research tool for assessment of driver attention, and could potentially lead to future in-vehicle safety countermeasures. PMID- 28848415 TI - Dynamic Correlations between Intrinsic Connectivity and Extrinsic Connectivity of the Auditory Cortex in Humans. AB - The arrival of sound signals in the auditory cortex (AC) triggers both local and inter-regional signal propagations over time up to hundreds of milliseconds and builds up both intrinsic functional connectivity (iFC) and extrinsic functional connectivity (eFC) of the AC. However, interactions between iFC and eFC are largely unknown. Using intracranial stereo-electroencephalographic recordings in people with drug-refractory epilepsy, this study mainly investigated the temporal dynamic of the relationships between iFC and eFC of the AC. The results showed that a Gaussian wideband-noise burst markedly elicited potentials in both the AC and numerous higher-order cortical regions outside the AC (non-auditory cortices). Granger causality analyses revealed that in the earlier time window, iFC of the AC was positively correlated with both eFC from the AC to the inferior temporal gyrus and that to the inferior parietal lobule. While in later periods, the iFC of the AC was positively correlated with eFC from the precentral gyrus to the AC and that from the insula to the AC. In conclusion, dual-directional interactions occur between iFC and eFC of the AC at different time windows following the sound stimulation and may form the foundation underlying various central auditory processes, including auditory sensory memory, object formation, integrations between sensory, perceptional, attentional, motor, emotional, and executive processes. PMID- 28848416 TI - Structural Brain Connectivity Constrains within-a-Day Variability of Direct Functional Connectivity. AB - The idea that structural white matter connectivity constrains functional connectivity (interactions among brain regions) has widely been explored in studies of brain networks; studies have mostly focused on the "average" strength of functional connectivity. The question of how structural connectivity constrains the "variability" of functional connectivity remains unresolved. In this study, we investigated the variability of resting state functional connectivity that was acquired every 3 h within a single day from 12 participants (eight time sessions within a 24-h period, 165 scans per session). Three different types of functional connectivity (functional connectivity based on Pearson correlation, direct functional connectivity based on partial correlation, and the pseudo functional connectivity produced by their difference) were estimated from resting state functional magnetic resonance imaging data along with structural connectivity defined using fiber tractography of diffusion tensor imaging. Those types of functional connectivity were evaluated with regard to properties of structural connectivity (fiber streamline counts and lengths) and types of structural connectivity such as intra-/inter-hemispheric edges and topological edge types in the rich club organization. We observed that the structural connectivity constrained the variability of direct functional connectivity more than pseudo-functional connectivity and that the constraints depended strongly on structural connectivity types. The structural constraints were greater for intra-hemispheric and heterologous inter-hemispheric edges than homologous inter-hemispheric edges, and feeder and local edges than rich club edges in the rich club architecture. While each edge was highly variable, the multivariate patterns of edge involvement, especially the direct functional connectivity patterns among the rich club brain regions, showed low variability over time. This study suggests that structural connectivity not only constrains the strength of functional connectivity, but also the within-a-day variability of functional connectivity and connectivity patterns, particularly the direct functional connectivity among brain regions. PMID- 28848417 TI - Computational Stimulation of the Basal Ganglia Neurons with Cost Effective Delayed Gaussian Waveforms. AB - Deep brain stimulation (DBS) has compelling results in the desynchronization of the basal ganglia neuronal activities and thus, is used in treating the motor symptoms of Parkinson's disease (PD). Accurate definition of DBS waveform parameters could avert tissue or electrode damage, increase the neuronal activity and reduce energy cost which will prolong the battery life, hence avoiding device replacement surgeries. This study considers the use of a charge balanced Gaussian waveform pattern as a method to disrupt the firing patterns of neuronal cell activity. A computational model was created to simulate ganglia cells and their interactions with thalamic neurons. From the model, we investigated the effects of modified DBS pulse shapes and proposed a delay period between the cathodic and anodic parts of the charge balanced Gaussian waveform to desynchronize the firing patterns of the GPe and GPi cells. The results of the proposed Gaussian waveform with delay outperformed that of rectangular DBS waveforms used in in-vivo experiments. The Gaussian Delay Gaussian (GDG) waveforms achieved lower number of misses in eliciting action potential while having a lower amplitude and shorter length of delay compared to numerous different pulse shapes. The amount of energy consumed in the basal ganglia network due to GDG waveforms was dropped by 22% in comparison with charge balanced Gaussian waveforms without any delay between the cathodic and anodic parts and was also 60% lower than a rectangular charged balanced pulse with a delay between the cathodic and anodic parts of the waveform. Furthermore, by defining a Synchronization Level metric, we observed that the GDG waveform was able to reduce the synchronization of GPi neurons more effectively than any other waveform. The promising results of GDG waveforms in terms of eliciting action potential, desynchronization of the basal ganglia neurons and reduction of energy consumption can potentially enhance the performance of DBS devices. PMID- 28848418 TI - Approximate Subject Specific Pseudo MRI from an Available MRI Dataset for MEG Source Imaging. AB - Computation of headmodel and sourcemodel from the subject's MRI scan is an essential step for source localization of magnetoencephalography (MEG) (or EEG) sensor signals. In the absence of a real MRI scan, pseudo MRI (i.e., associated headmodel and sourcemodel) is often approximated from an available standard MRI template or pool of MRI scans considering the subject's digitized head surface. In the present study, we approximated two types of pseudo MRI (i.e., associated headmodel and sourcemodel) using an available pool of MRI scans with the focus on MEG source imaging. The first was the first rank pseudo MRI; that is, the MRI scan in the dataset having the lowest objective registration error (ORE) after being registered (rigid body transformation with isotropic scaling) to the subject's digitized head surface. The second was the averaged rank pseudo MRI that is generated by averaging of headmodels and sourcemodels from multiple MRI scans respectively, after being registered to the subject's digitized head surface. Subject level analysis showed that the mean upper bound of source location error for the approximated sourcemodel in reference to the real one was 10 +/- 3 mm for the averaged rank pseudo MRI, which was significantly lower than the first rank pseudo MRI approach. Functional group source response in the brain to visual stimulation in the form of event-related power (ERP) at the time latency of peak amplitude showed noticeably identical source distribution for first rank pseudo MRI, averaged rank pseudo MRI, and real MRI. The source localization error for functional peak response was significantly lower for averaged rank pseudo MRI compared to first rank pseudo MRI. We conclude that it is feasible to use approximated pseudo MRI, particularly the averaged rank pseudo MRI, as a substitute for real MRI without losing the generality of the functional group source response. PMID- 28848419 TI - A Functional Subnetwork Approach to Designing Synthetic Nervous Systems That Control Legged Robot Locomotion. AB - A dynamical model of an animal's nervous system, or synthetic nervous system (SNS), is a potentially transformational control method. Due to increasingly detailed data on the connectivity and dynamics of both mammalian and insect nervous systems, controlling a legged robot with an SNS is largely a problem of parameter tuning. Our approach to this problem is to design functional subnetworks that perform specific operations, and then assemble them into larger models of the nervous system. In this paper, we present networks that perform addition, subtraction, multiplication, division, differentiation, and integration of incoming signals. Parameters are set within each subnetwork to produce the desired output by utilizing the operating range of neural activity, R, the gain of the operation, k, and bounds based on biological values. The assembly of large networks from functional subnetworks underpins our recent results with MantisBot. PMID- 28848420 TI - Studies on Colony Stimulating Factor Receptor-1 and Ligands Colony Stimulating Factor-1 and Interleukin-34 in Alzheimer's Disease Brains and Human Microglia. AB - Microglia are dependent on signaling through the colony stimulating factor-1 receptor (CSF-1R/CD115) for growth and survival. Activation of CSF-1R can lead to cell division, while blocking CSF-1R can lead to rapid microglia cell death. CSF 1R has two ligands, the growth factors colony stimulating factor-1 (CSF-1) and the more recently identified interleukin-34 (IL-34). Studies of IL-34 activation of rodent microglia and human macrophages have suggested it has different properties to CSF-1, resulting in an anti-inflammatory reparative phenotype. The goal of this study was to identify if the responses of human postmortem brain microglia to IL-34 differed from their responses to CSF-1 with the aim of identifying different phenotypes of microglia as a result of their responses. To approach this question, we also sought to identify differences between IL-34, CSF 1, and CSF-1R expression in human brain samples to establish whether there was an imbalance in Alzheimer's disease (AD). Using human brain samples [inferior temporal gyrus (ITG) and middle temporal gyrus (MTG)] from distinct cohorts of AD, control and high pathology, or mild cognitive impairment cases, we showed that there was increased expression of CSF-1R and CSF-1 mRNAs in both series of AD cases, and reduced expression of IL-34 mRNA in AD ITG samples. There was no change in expression of these genes in RNA from cerebellum of AD, Parkinson's disease (PD), or control cases. The results suggested an imbalance in CSF-1R signaling in AD. Using RNA sequencing to compare gene expression responses of CSF 1 and IL-34 stimulated human microglia, a profile of responses to CSF-1 and IL-34 was identified. Contrary to earlier work with rodent microglia, IL-34 induced primarily a classical activation response similar to that of CSF-1. It was not possible to identify any genes expressed significantly different by IL-34 stimulated microglia compared to CSF-1-stimulated microglia, but both cytokines did induce certain alternative activation-associated genes. These profiles also showed that a number of genes associated with lysosomal function and Abeta removal were downregulated by IL-34 and CSF-1 stimulation. Compared to earlier results our data indicate that CSF-1R stimulation by IL-34 or CSF-1 produced similar types of responses by elderly postmortem brain-derived microglia. PMID- 28848422 TI - Age-Related Shift in Neuro-Activation during a Word-Matching Task. AB - Growing evidence from the neuroscience of aging suggests that executive function plays a pivotal role in maintaining semantic processing performance. However, the presumed age-related activation changes that sustain executive semantic processing remain poorly understood. The aim of this study was to explore the executive aspects of semantic processing during a word-matching task with regard to age-related neuro-functional reorganization, as well as to identify factors that influence executive control profiles. Twenty younger and 20 older participants underwent fMRI scanning. The experimental task was based on word matching, wherein visual feedback was used to instruct participants to either maintain or switch a semantic-matching rule. Response time and correct responses were assessed for each group. A battery of cognitive tests was administrated to all participants and the older group was divided into two subgroups based on their cognitive control profiles. Even though the percentage of correct responses was equivalent in the task performance between both groups and within the older groups, neuro-functional activation differed in frontoparietal regions with regards to age and cognitive control profiles. A correlation between behavioral measures (correct responses and response times) and brain signal changes was found in the left inferior parietal region in older participants. Results indicate that the shift in age-related activation from frontal to parietal regions can be viewed as another form of neuro-functional reorganization. The greater reliance on inferior parietal regions in the older compared to the younger group suggests that the executive control system is still efficient and sustains semantic processing in the healthy aging brain. Additionally, cognitive control profiles underlie executive ability differences in healthy aging appear to be associated with specific neuro-functional reorganization throughout frontal and parietal regions. These findings demonstrate that changes in neural support for executive semantic processing during a word-matching task are not only influenced by age, but also by cognitive control profile. PMID- 28848421 TI - The Effects of Home-Based Cognitive Training on Verbal Working Memory and Language Comprehension in Older Adulthood. AB - Effective language understanding is crucial to maintaining cognitive abilities and learning new information through adulthood. However, age-related declines in working memory (WM) have a robust negative influence on multiple aspects of language comprehension and use, potentially limiting communicative competence. In the current study (N = 41), we examined the effects of a novel home-based computerized cognitive training program targeting verbal WM on changes in verbal WM and language comprehension in healthy older adults relative to an active component-control group. Participants in the WM training group showed non-linear improvements in performance on trained verbal WM tasks. Relative to the active control group, WM training participants also showed improvements on untrained verbal WM tasks and selective improvements across untrained dimensions of language, including sentence memory, verbal fluency, and comprehension of syntactically ambiguous sentences. Though the current study is preliminary in nature, it does provide initial promising evidence that WM training may influence components of language comprehension in adulthood and suggests that home-based training of WM may be a viable option for probing the scope and limits of cognitive plasticity in older adults. PMID- 28848423 TI - Altered Functional and Causal Connectivity of Cerebello-Cortical Circuits between Multiple System Atrophy (Parkinsonian Type) and Parkinson's Disease. AB - Lesions of the cerebellum lead to motor and non-motor deficits by influencing cerebral cortex activity via cerebello-cortical circuits. It remains unknown whether the cerebello-cortical "disconnection" underlies motor and non-motor impairments both in the parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD). In this study, we investigated both the functional and effective connectivity of the cerebello-cortical circuits from resting-state functional magnetic resonance imaging (rs-fMRI) data of three groups (26 MSA-P patients, 31 PD patients, and 30 controls). Correlation analysis was performed between the causal connectivity and clinical scores. PD patients showed a weakened cerebellar dentate nucleus (DN) functional coupling in the posterior cingulate cortex (PCC) and inferior parietal lobe compared with MSA-P or controls. MSA-P patients exhibited significantly enhanced effective connectivity from the DN to PCC compared with PD patients or controls, as well as declined causal connectivity from the left precentral gyrus to right DN compared with the controls, and this value is significantly correlated with the motor symptom scores. Our findings demonstrated a crucial role for the cerebello-cortical networks in both MSA-P and PD patients in addition to striatal-thalamo-cortical (STC) networks and indicated that different patterns of cerebello-cortical loop degeneration are involved in the development of the diseases. PMID- 28848424 TI - Does Aerobic Exercise Influence Intrinsic Brain Activity? An Aerobic Exercise Intervention among Healthy Old Adults. AB - Previous studies have indicated that aerobic exercise could reduce age related decline in cognition and brain functioning. Here we investigated the effects of aerobic exercise on intrinsic brain activity. Sixty sedentary healthy males and females (64-78 years) were randomized into either an aerobic exercise group or an active control group. Both groups recieved supervised training, 3 days a week for 6 months. Multimodal brain imaging data was acquired before and after the intervention, including 10 min of resting state brain functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). Additionally, a comprehensive battery of cognitive tasks assessing, e.g., executive function and episodic memory was administered. Both the aerobic and the control group improved in aerobic capacity (VO2-peak) over 6 months, but a significant group by time interaction confirmed that the aerobic group improved more. Contrary to our hypothesis, we did not observe any significant group by time interactions with regard to any measure of intrinsic activity. To further probe putative relationships between fitness and brain activity, we performed post hoc analyses disregarding group belongings. At baseline, VO2-peak was negativly related to BOLD-signal fluctuations (BOLDSTD) in mid temporal areas. Over 6 months, improvements in aerobic capacity were associated with decreased connectivity between left hippocampus and contralateral precentral gyrus, and positively to connectivity between right mid-temporal areas and frontal and parietal regions. Independent component analysis identified a VO2-related increase in coupling between the default mode network and left orbitofrontal cortex, as well as a decreased connectivity between the sensorimotor network and thalamus. Extensive exploratory data analyses of global efficiency, connectome wide multivariate pattern analysis (connectome-MVPA), as well as ASL, did not reveal any relationships between aerobic fitness and intrinsic brain activity. Moreover, fitness-predicted changes in functional connectivity did not relate to changes in cognition, which is likely due to absent cross-sectional or longitudinal relationships between VO2-peak and cognition. We conclude that the aerobic exercise intervention had limited influence on patterns of intrinsic brain activity, although post hoc analyses indicated that individual changes in aerobic capacity preferentially influenced mid-temporal brain areas. PMID- 28848426 TI - A Brain Region-Based Deep Medullary Veins Visual Score on Susceptibility Weighted Imaging. AB - Cerebral venous collagenosis played a role in the pathogenesis of white matter hyperintensities (WMHs) through venous ischemia. Since pathological changes of veins from intramural stenosis to luminal occlusion is a dynamic process, we aimed to create a deep medullary veins (DMVs) visual grade on susceptibility weighted images (SWI) and explore the relationship of DMVs and WMHs based on venous drainage regions. We reviewed clinical, laboratory and imaging data from 268 consecutive WMHs patients and 20 controls. SWI images were used to observe characteristics of DMVs and a brain region-based DMVs visual score was given by two experienced neuroradiologists. Fluid attenuated inversion recovery (FLAIR) images were used to calculate WMHs volume. Logistic-regression analysis and partial Pearson's correlation analysis were used to examine the association between the DMVs score and WMHs volume. We found that the DMVs score was significantly higher in WMHs patients than in controls (p < 0.001). Increased DMVs score was independently associated with higher WMHs volume after adjusting for total cholesterol level and number of lacunes (p < 0.001). Particularly, DMVs scores were correlated with regional PVHs volumes in the same brain region most. The newly proposed DMVs grading method allows the clinician to monitor the course of DMVs disruption. Our findings of cerebral venous insufficiency in WMHs patients may help to elucidate the pathogenic mechanisms and progression of WMHs. PMID- 28848425 TI - Differences in Adipose Tissue and Lean Mass Distribution in Patients with Collagen VI Related Myopathies Are Associated with Disease Severity and Physical Ability. AB - Mutations in human collagen VI genes cause a spectrum of musculoskeletal conditions in children and adults collectively termed collagen VI-related myopathies (COL6-RM) characterized by a varying degree of muscle weakness and joint contractures and which include Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). Given that collagen VI is one of the most abundant extracellular matrix proteins in adipose tissue and its emerging role in energy metabolism we hypothesized that collagen VI deficiency might be associated with alterations in adipose tissue distribution and adipokines serum profile. We analyzed body composition by means of dual-energy X-ray absorptiometry in 30 pediatric and adult COL6-RM myopathy patients representing a range of severities (UCMD, intermediate-COL6-RM, and BM). We found a distinctive pattern of regional adipose tissue accumulation which was more evident in children at the most severe end of the spectrum. In particular, the accumulation of fat in the android region was a distinguishing feature of UCMD patients. In parallel, there was a decrease in lean mass compatible with a state of sarcopenia, particularly in ambulant children with an intermediate phenotype. All children and adult patients that were sarcopenic were also obese. These changes were significantly more pronounced in children with collagen VI deficiency than in children with Duchenne Muscular Dystrophy of the same ambulatory status. High molecular weight adiponectin and leptin were significantly increased in sera from children in the intermediate and BM group. Correlation analysis showed that the parameters of fat mass were negatively associated with motor function according to several validated outcome measures. In contrast, lean mass parameters correlated positively with physical performance and quality of life. Leptin and adiponectin circulating levels correlated positively with fat mass parameters and negatively with lean mass and thus may be relevant to the disease pathogenesis and as circulating markers. Taken together our results indicate that COL6-RM are characterized by specific changes in total fat mass and distribution which associate with disease severity, motor function, and quality of life and which are clinically meaningful and thus should be taken into consideration in the management of these patients. PMID- 28848427 TI - Remote Ischemic Conditioning: A Novel Non-Invasive Approach to Prevent Post Stroke Depression. AB - Post-stroke depression (PSD) is a common neuropsychiatric complication of stroke. However, due to the high expense and side effects of pharmacotherapy and the difficult-to-achieve of psychotherapy, the prevention and treatment of PSD are still far from satisfaction. Inflammation hypothesis is now playing an essential role in the pathophysiological mechanism of PSD, and it may be a new preventive and therapeutic target. Remote ischemic conditioning (RIC) is a non-invasive and easy-to-use physical strategy, which has been used to protect brain (including ischemic and hemorrhagic stroke), heart and many other organs in clinical trials. The underlying mechanisms of RIC include anti-inflammation, anti-oxidative stress, immune system regulation and other potential pathways. Our hypothesis is that RIC is a novel approach to prevent PSD. The important implications of this hypothesis are that: (1) RIC could be widely used in clinical practice to prevent PSD if our hypothesis were verified; and (2) RIC would be thoroughly explored to test its effects on other neurobehavioral disorders (e.g., cognitive impairment). PMID- 28848428 TI - Analysis of DTI-Derived Tensor Metrics in Differential Diagnosis between Low grade and High-grade Gliomas. AB - Purpose: It is critical and difficult to accurately discriminate between high- and low-grade gliomas preoperatively. This study aimed to ascertain the role of several scalar measures in distinguishing high-grade from low-grade gliomas, especially the axial diffusivity (AD), radial diffusivity (RD), planar tensor (Cp), spherical tensor (Cs), and linear tensor (Cl) derived from diffusion tensor imaging (DTI). Materials and Methods: Fifty-three patients with pathologically confirmed brain gliomas (21 low-grade and 32 high-grade) were included. Contrast enhanced T1-weighted images and DTI were performed in all patients. The AD, RD, Cp, Cs, and Cl values in the tumor zone, peritumoral edema zone, white matter (WM) adjacent to edema and contralateral normal-appearing white matter (NAWM) were calculated. The DTI parameters and tumor grades were statistically analyzed, and receiver operating characteristic (ROC) curve analysis was also performed. Results: The DTI metrics in the affected hemisphere showed significant differences from those in the NAWM, except for the AD values in the tumor zone and the RD values in WM adjacent to edema in the low-grade groups, as well as the Cp values in WM adjacent to edema in the high-grade groups. AD in the tumor zone as well as Cs and Cl in WM adjacent to edema revealed significant differences between the low- and high-grade gliomas. The areas under the curve (Az) of all three metrics were greater than 0.5 in distinguishing low-grade from high-grade gliomas by ROC curve analysis, and the best DTI metric was Cs in WM adjacent to edema (Az: 0.692). Conclusion: AD in the tumor zone as well as Cs and Cl in WM adjacent to edema will provide additional information to better classify gliomas and can be used as non-invasive reliable biomarkers in glioma grading. PMID- 28848429 TI - Exploring Tinnitus-Induced Disablement by Persistent Frustration in Aging Individuals: A Grounded Theory Study. AB - Background: Qualitative research can help to improve the management of patients, meet their expectations and assist physicians in alleviating their suffering. The perception of moment-to-moment variability in tinnitus annoyance is an emerging field of exploration. This study sought to enlighten variability in tinnitus induced disablement using a qualitative approach. Methods: Twelve participants (six females, six males, aged 51-79) were recruited via the French Tinnitus Association Journal for participation in recorded semi-structured interviews. Each participant had three interviews lasting 1 h, the sessions being separated one from the other by 2 weeks. Following recommendations of Charmaz (2014), the second and third interviews were aimed at gathering rich data, by enhancing the participants' reflexivity in the circumstances of distress caused by tinnitus. After transcription, the data (n = 36 interviews) were analyzed using the approach to Grounded Theory proposed by Strauss and Corbin (1998). Results: Tinnitus as persistent frustration emerged as being the core category uniting all the other categories of the study. Hence, the core category accounted for the broader scope in participants' experience of chronic tinnitus. It is suggested that tinnitus-induced disablement varied according to the degree of frustration felt by the participants in not being able to achieve their goals. The implications of this were analyzed using the following categories: "Losing body ownership," "Lacking perspectives," and "Persevering through difficulties." Based on these findings, we draw a substantive theory of tinnitus tolerance that promotes an active, disciplined and individualized approach to tinnitus-induced disablement. The model distinguishes pathways from sustained suffering to reduced annoyance (i.e., emerging tolerance). It accounts for difficulties that the participants experienced with a perceived unchanged annoyance over time. Furthermore, this model identifies a set of new attitudes toward oneself and others that tinnitus tolerance would entail. Conclusion: The subjective experience of frustration enlightens tinnitus-induced disablement, offering new perspectives for long-term self-management. Modulation of frustration, rather than moderation of tinnitus interference, is suggested as a new approach to the clinical management of tinnitus-related distress. PMID- 28848430 TI - Balance Training Enhances Vestibular Function and Reduces Overactive Proprioceptive Feedback in Elderly. AB - Objectives: Postural control in elderly people is impaired by degradations of sensory, motor, and higher-level adaptive mechanisms. Here, we characterize the effects of a progressive balance training program on these postural control impairments using a brain network model based on system identification techniques. Methods and Material: We analyzed postural control of 35 healthy elderly subjects and compared findings to data from 35 healthy young volunteers. Eighteen elderly subjects performed a 10 week balance training conducted twice per week. Balance training was carried out in static and dynamic movement states, on support surfaces with different elastic compliances, under different visual conditions and motor tasks. Postural control was characterized by spontaneous sway and postural reactions to pseudorandom anterior-posterior tilts of the support surface. Data were interpreted using a parameter identification procedure based on a brain network model. Results: With balance training, the elderly subjects significantly reduced their overly large postural reactions and approximated those of younger subjects. Less significant differences between elderly and young subjects' postural control, namely larger spontaneous sway amplitudes, velocities, and frequencies, larger overall time delays and a weaker motor feedback compared to young subjects were not significantly affected by the balance training. Conclusion: Balance training reduced overactive proprioceptive feedback and restored vestibular orientation in elderly. Based on the assumption of a linear deterioration of postural control across the life span, the training effect can be extrapolated as a juvenescence of 10 years. This study points to a considerable benefit of a continuous balance training in elderly, even without any sensorimotor deficits. PMID- 28848431 TI - Perilla frutescens Extracts Protects against Dextran Sulfate Sodium-Induced Murine Colitis: NF-kappaB, STAT3, and Nrf2 as Putative Targets. AB - Perilla frutescens is a culinary and medicinal herb which has a strong anti inflammatory and antioxidative effects. In the present study, we investigated the effects of Perilla frutescens extract (PE) against dextran sulfate sodium (DSS) induced mouse colitis, an animal model that mimics human inflammatory bowel disease (IBD). Five-week-old male ICR mice were treated with a daily dose of PE (20 or 100 mg/kg, p.o.) for 1 week, followed by administration of 3% DSS in double distilled drinking water and PE by gavage for another week. DSS-induced colitis was characterized by body weight loss, colon length shortening, diarrhea and bloody stool, and these symptoms were significantly ameliorated by PE treatment. PE administration suppressed DSS-induced expression of proinflammatory enzymes, including cyclooxygenase-2 and inducible nitric oxide synthase as well as cyclin D1, in a dose-dependent fashion. Nuclear factor-kappa B (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) are major transcriptional regulators of inflammatory signaling. PE administration significantly inhibited the activation of both NF-kappaB and STAT3 induced by DSS, while it elevated the accumulation of Nrf2 and heme oxygenase-1 in the colon. In another experiment, treatment of CCD841CoN human normal colon epithelial cells with PE (10 mg/ml) resulted in the attenuation of the tumor necrosis factor-alpha-induced expression/activation of mediators of proinflammatory signaling. The above results indicate that PE has a preventive potential for use in the management of IBD. PMID- 28848432 TI - Hydrogen-Rich Saline Alleviates Kidney Fibrosis Following AKI and Retains Klotho Expression. AB - Purpose: Acute kidney injury (AKI) is a prominent risk factor for the development of chronic kidney disease (CKD). To date, the related mechanism and effective therapy have not been rigorously explored. The present study aims to investigate the reno-protection of hydrogen-rich saline (HRS) against ischemia/reperfusion (IR)-induced AKI. Methods: Adult male C57 mice were randomly allocated into three groups: Sham, IR, IR+HRS. Renal IR injury model was generated via 35 min occlusion of bilateral kidney pedicles, and then, mice were administered with different treatments intraperitoneally in various groups. After 14- or 28-day treatment, mice were perfused and the kidneys were collected following reperfusion. Many proteins were detected by western blots, including renal fibrotic proteins [a-smooth muscle actin (a-SMA), collagen I (Col I)], Klotho, the methylation of Klotho, damage-regulated autophagy modulator (Beclin-1), and microtubule-associated protein light 3-II (LC3-II). Finally, the levels of serum blood urea nitrogen (BUN) and creatinine (Cr) were measured to investigate the renal function. Results: Histological data showed that the HRS treatment significantly decreased the fibrosis in renal tissues when compared with the IR group, and both of BUN and Cr were lower in the HRS group than IR group (8.9 +/- 0.6 vs. 9.9 +/- 0.1 mmol/l, 51 +/- 6.5 vs. 60 +/- 5.8 MUmol/l) (P < 0.05). The expression of fibrotic markers, a-SMA and Col I, showed a robust increase in IR injury models than the Sham group, which was consistent with the result of Trichrome staining. However, the levels of a-SMA and Col I expression were sharply decreased in the IR+HRS group (P < 0.05). IR injury also enhanced LC3-II and Beclin-1 expression, but decreased Klotho level. The Klotho level was alleviated by HRS, but LC3-II and Beclin-1 were starkly enhanced in HRS group (P < 0.05). Conclusion: HRS showed a protective effect in the prevention of renal injury and could inhibit renal fibrosis after IR injury in mice. This role of HRS might be exerted via retaining Klotho expression and activating autophagy in the kidney. PMID- 28848433 TI - Role of Proteases in Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is generally associated with progressive destruction of airways and lung parenchyma. Various factors play an important role in the development and progression of COPD, like imbalance of proteases, environmental and genetic factors and oxidative stress. This review is specifically focused on the role of proteases and their imbalance in COPD. There are three classes (serine, mettalo, and cysteine) of proteases involved in COPD. In serine proteases, neutrophil elastase, cathepsin G, and proteinase-3 are involved in destruction of alveolar tissue. Matrix-mettaloproteinase-9, 12, 13, plays an influential role in severity of COPD. Among cysteine proteases, caspase 3, caspases-8 and caspase-9 play an important role in controlling apoptosis. These proteases activities can be regulated by inhibitors like alpha-1 antitrypsin, neutrophil elastase inhibitor, and leukocyte protease inhibitor. Studies suggest that neutrophil elastase may be a therapeutic target for COPD, and specific inhibitor against this enzyme has potential role to control the disease. Current study suggests that Dipeptidyl Peptidase IV is a potential marker for COPD. Since the expression of proteases and its inhibitors play an important role in COPD pathogenesis, therefore, it is worth investigating the role of proteases and their regulation. Understanding the biochemical basis of COPD pathogenesis using advanced tools in protease biochemistry and aiming toward translational research from bench-to-bedside will have great impact to deal with this health problem. PMID- 28848434 TI - Astragaloside IV Improves Bleomycin-Induced Pulmonary Fibrosis in Rats by Attenuating Extracellular Matrix Deposition. AB - Pulmonary fibrosis is a devastating lung disorder with mysterious pathogenesis and limited treatment options. It is well-recognized that the uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts excessively produce extracellular matrix (ECM) proteins which contribute to the fibrosis change of the lungs. Thus, blocking ECM accumulation would delay fibrosis progression. In this study, we observed the effects of astragaloside IV (ASV) (10 mg/kg/d) on ECM proteins in bleomycin (BLM, 5 mg/kg) treated rats. Our results showed that ASV not only ameliorated BLM-induced body weight loss, lung coefficient increase, histological changes and collagen secretion, but also reduced the levels of type III collagen (Col-III) in lung homogenate, laminin (LN) and hyaluronic acid (HA) in serum, as well as hydroxyproline (HYP) in lung tissue. Besides, ASV significantly down-regulated the levels of high-mobility group box1 (HMGB1) in serum and lung tissue, and inhibited the up-regulated expression of alpha-SMA (marker of myofibroblasts) in the lungs. Taken together, these findings indicate that ASV attenuates BLM induced ECM deposition, supporting its use as a promising candidate to treat lung fibrosis. PMID- 28848435 TI - Interaction between Cannabinoid Type 1 and Type 2 Receptors in the Modulation of Subventricular Zone and Dentate Gyrus Neurogenesis. AB - Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG). Cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CB1R and CB2R in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation). We focused on a putative crosstalk between CB1R and CB2R to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3) Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining), an effect blocked by either CB1R or CB2R selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CB1R and CB2R. Cell proliferation in the SVZ was not affected by the non selective receptor agonist, but it was enhanced by CB1R selective activation. However, either CB1R or CB2R selective antagonists abolished the effect of the CB1R agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging) was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CB1R or CB2R selective agonists and blocked by either CB1R or CB2R selective antagonists, cross-antagonism being evident. In summary, our findings indicate a tight interaction between CB1R and CB2R to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain. PMID- 28848436 TI - Ethnopharmacological Approaches for Therapy of Jaundice: Part II. Highly Used Plant Species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae Families. AB - In many developing countries, jaundice is the common symptom of hepatic diseases which are a major cause of mortality. The use of natural product-based therapies is very popular for such hepatic disorders. A great number of medicinal plants have been utilized for this purpose and some facilitated the discovery of active compounds which helped the development of new synthetic drugs against jaundice. However, more epidemiological studies and clinical trials are required for the practical implementation of the plant pharmacotherapy of jaundice. The focus of this second part of our review is on several of the most prominent plants used against jaundice identified in the analysis performed in the first part of the review viz. Andrographis paniculata (Burm.f.) Nees, Silybum marianum (L.) Gaertn., Terminalia chebula Retz., Glycyrrhiza glabra L. and some species of genus Phyllanthus. Furthermore, we discuss their physiological effects, biologically active ingredients, and the potential mechanisms of action. Some of the most important active ingredients were silybin (also recommended by German commission), phyllanthin and andrographolide, whose action leads to bilirubin reduction and normalization of the levels of relevant serum enzymes indicative for the pathophysiological status of the liver. PMID- 28848437 TI - Progression of Tubulointerstitial Fibrosis and the Chronic Kidney Disease Phenotype - Role of Risk Factors and Epigenetics. AB - Although the kidney has capacity to repair after mild injury, ongoing or severe damage results in scarring (fibrosis) and an associated progressive loss of kidney function. However, despite its universal significance, evidence highlights a population based heterogeneity in the trajectory of chronic kidney disease (CKD) in these patients. To explain the heterogeneity of the CKD phenotype requires an understanding of the relevant risk factors for fibrosis. These factors include both the extrinsic nature of injury, and intrinsic factors such as age, gender, genetics, and perpetual activation of fibroblasts through priming. In many cases an additional level of regulation is provided by epigenetic mechanisms which integrate the various pro-fibrotic and anti-fibrotic triggers in fibrogenesis. In this review we therefore examine the various molecular and structural changes of fibrosis, and how they are influenced by extrinsic and intrinsic factors. Our aim is to provide a unifying hypothesis to help explain the transition from acute to CKD. PMID- 28848439 TI - Antagomirs Targeting MiroRNA-134 Attenuates Epilepsy in Rats through Regulation of Oxidative Stress, Mitochondrial Functions and Autophagy. AB - The effects of the existing anti-epileptic drugs are unsatisfactory to almost one third of epileptic patients. MiR-134 antagomirs prevent pilocarpine-induced status epilepticus. In this study, a lithium chloride-pilocarpine-induced status epilepticus model was established and treated with intracerebroventricular injection of antagomirs targeting miR-134 (Ant-134). The Ant-134 treatment significantly improved the performance of rats in Morris water maze tests, inhibited mossy fiber sprouting in the dentate gyrus, and increased the survival neurons in the hippocampal CA1 region. Silencing of miR-134 remarkably decreased malonaldehyde and 4-hydroxynonenal levels and increased superoxide dismutase activity in the hippocampus. The Ant-134 treatment also significantly increased the production of ATP and the activities of mitochondrial respiratory enzyme complexes and significantly decreased the reactive oxygen species generation in the hippocampus compared with the status epilepticus rats. Finally, the Ant-134 treatment remarkably downregulated the hippocampal expressions of autophagy associated proteins Atg5, beclin-1 and light chain 3B. In conclusion, Ant-134 attenuates epilepsy via inhibiting oxidative stress, improving mitochondrial functions and regulating autophagy in the hippocampus. PMID- 28848440 TI - Oroxyloside A Overcomes Bone Marrow Microenvironment-Mediated Chronic Myelogenous Leukemia Resistance to Imatinib via Suppressing Hedgehog Pathway. AB - Imatinib (IM), as first inhibitor of the oncogenic tyrosine kinase BCR-ABL, has been widely used to treat chronic myeloid leukemia (CML) for decades in clinic. However, resistance to IM usually occurs in CML patients. The bone marrow (BM), as the predominant microenvironment of CML, secretes an abundant amount of cytokines, which may contribute to drug resistance. In current study, we utilized in vitro K562 co-culture model with BM stroma to investigate IM resistance. As a result, co-culturing of K562 with BM stroma was sufficient to cause resistance to IM, which was accompanied with the activation of hedgehog (Hh) signaling pathway and upregulation of BCR-ABL as well as its downstream proteins like phosphorylated Akt, Bcl-xL and survivin, etc. On the other hand, oroxyloside A (OAG), a metabolite of oroxylin A from the root of Scutellaria baicalensis Georgi, which had low toxic effect on K562 cells, was able to sensitize K562 cells co-cultured with BM stroma to IM treatment in vitro and in vivo. We observed that OAG suppressed Hh pathway and subsequently nuclear translocation of GLI1, followed by downregulation of BCR-ABL and its downstream effectors, thus facilitating IM to induce apoptosis of K562 cells. Together, BM microenvironment rendered K562 cells drug resistance through activating Hh signaling, however, OAG could overcome IM resistance of CML cells through inhibiting Hh-BCR-ABL axis in vitro and in vivo. PMID- 28848441 TI - Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound. AB - YZG-331, a synthetic adenosine derivative, express the sedative and hypnotic effects via binding to the adenosine receptor. The current study was taken to investigate the metabolic pathway of YZG-331 as well as species-specific differences in vitro. YZG-331 was reduced by 14, 11, 6, 46, and 11% within 120 min incubation in human, monkey, dog, rat, and mouse liver microsomes (LMs), respectively. However, YZG-331 was stable in human, monkey, dog, rat, and mouse liver cytoplasm. In addition, YZG-331 was unstable in rat or mouse gut microbiota with more than 50% of prototype drug degraded within 120 min incubation. Interestingly, the systemic exposure of M2 and M3 in rats and mice treated with antibiotics were significantly decreased in the pseudo germ-free group. YZG-331 could be metabolized in rat and human liver under the catalysis of CYP enzymes, and the metabolism showed species variation. In addition, 3 phase I metabolites were identified via hydroxyl (M1), hydrolysis (M2), or hydrolysis/ hydroxyl (M3) pathway. Flavin-containing monooxygenase 1 (FMO1) and FMO3 participated in the conversion of YZG-331 in rat LMs. Nevertheless, YZG-331 expressed stability with recombinant human FMOs, which further confirmed the species variation in the metabolism. Overall, these studies suggested that YZG-331 is not stable in LMs and gut microbiota. CYP450 enzymes and FMOs mediated the metabolism of YZG-331, and the metabolic pathway showed species difference. Special attention must be paid when extrapolating data from other species to humans. PMID- 28848438 TI - Advances in the Understanding of Protein-Protein Interactions in Drug Metabolizing Enzymes through the Use of Biophysical Techniques. AB - In recent years, a growing appreciation has developed for the importance of protein-protein interactions to modulate the function of drug metabolizing enzymes. Accompanied with this appreciation, new methods and technologies have been designed for analyzing protein-protein interactions both in vitro and in vivo. These technologies have been applied to several classes of drug metabolizing enzymes, including: cytochrome P450's (CYPs), monoamine oxidases (MAOs), UDP-glucuronosyltransferases (UGTs), glutathione S-transferases (GSTs), and sulfotransferases (SULTs). In this review, we offer a brief description and assessment of the impact of many of these technologies to the study of protein protein interactions in drug disposition. The still expanding list of these techniques and assays has the potential to revolutionize our understanding of how these enzymes carry out their important functions in vivo. PMID- 28848442 TI - Biodegradable Carriers for Delivery of VEGF Plasmid DNA for the Treatment of Critical Limb Ischemia. AB - The safe and efficient delivery of therapeutic nucleic acid is a prerequisite for an effective DNA therapy. In this study, we condensed the low molecular weight polyethylenimine (PEI, 1.8k Da) with 2,6-pyridinedicarboxaldehyde (PDA), both of which are degradable in vivo, to synthesize a biodegradable polycationic material (PDAPEI) to deliver vascular endothelial growth factor (VEGF) plasmid DNA (pDNA). Particle size and zeta potential of this novel degradable PEI derivatives-pDNA nanoparticle were investigated and in vitro cytotoxicity was estimated on human umbilical vein endothelial cells (HUVECs). Using pDNA-encoding VEGF-A and green fluorescence protein (GFP), we also checked transfection efficiency of the vector (PDAPEI) and found its excellent performance at 40 w/w ratio. We successfully established peripheral ischemia animal model on C57/BL6J mice to evaluate the therapeutic effect of PDAPEI/pVEGF-A polyplex system on ischemic disease and a conclusion was made that PDAPEI is a promising gene vector in the treatment of peripheral ischemic artery disease (PAD). PMID- 28848443 TI - Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation. AB - Dexmedetomidine (PrecedexTM) may be used as an alternative sedative in children, maintaining spontaneous breathing, and avoiding tracheal intubation in a non intubated moderate or deep sedation (NI-MDS) approach. This open-label, single arm, multicenter study evaluated the safety of dexmedetomidine in a pediatric population receiving NI-MDS in an operating room or a procedure room, with an intensivist or anesthesiologist in attendance, for elective diagnostic or therapeutic procedures expected to take at least 30 min. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Patients received one of two doses dependent on age: patients aged >=28 weeks' gestational age to <1 month postnatal received dose level 1 (0.1 MUg/kg load; 0.05-0.2 MUg/kg/h infusion); those aged 1 month to <17 years received dose level 2 (1 MUg/kg load; 0.2-2.0 MUg/kg/h infusion). Sedation efficacy was assessed and defined as adequate sedation for at least 80% of the time and successful completion of the procedure without the need for rescue medication. In all, 91 patients were enrolled (dose level 1, n = 1; dose level 2, n = 90); of these, 90 received treatment and 82 completed the study. Eight patients in dose level 2 discontinued treatment for the following reasons: early completion of diagnostic or therapeutic procedure (n = 3); change in medical condition (need for intubation) requiring deeper level of sedation (n = 2); adverse event (AE; hives and emesis), lack of efficacy, and physician decision (patient not sedated enough to complete procedure; n = 1 each). Sixty-seven patients experienced 147 TEAEs. The two most commonly reported AEs were respiratory depression (bradypnea; reported per protocol-defined criteria, based on absolute respiratory rate values for age or relative decrease of 30% from baseline) and hypotension. Four patients received glycopyrrolate for bradycardia and seven patients received intravenous fluids for hypotension. SpO2 dropped by 10% in two patients, but resolved without need for manual ventilation. All other reported AEs were consistent with the known safety profile of dexmedetomidine. Two of the 78 patients in the efficacy-evaluable population met all sedation efficacy criteria. Dexmedetomidine was well-tolerated in pediatric patients undergoing procedure-type sedation. PMID- 28848444 TI - Single Prazosin Infusion in Prelimbic Cortex Fosters Extinction of Amphetamine Induced Conditioned Place Preference. AB - Exposure to drug-associated cues to induce extinction is a useful strategy to contrast cue-induced drug seeking. Norepinephrine (NE) transmission in medial prefrontal cortex has a role in the acquisition and extinction of conditioned place preference induced by amphetamine. We have reported recently that NE in prelimbic cortex delays extinction of amphetamine-induced conditioned place preference (CPP). A potential involvement of alpha1-adrenergic receptors in the extinction of appetitive conditioned response has been also suggested, although their role in prelimbic cortex has not been yet fully investigated. Here, we investigated the effects of the alpha1-adrenergic receptor antagonist prazosin infusion in the prelimbic cortex of C57BL/6J mice on expression and extinction of amphetamine-induced CPP. Acute prelimbic prazosin did not affect expression of amphetamine-induced CPP on the day of infusion, while in subsequent days it produced a clear-cut advance of extinction of preference for the compartment previously paired with amphetamine (Conditioned stimulus, CS). Moreover, prazosin treated mice that had extinguished CS preference showed increased mRNA expression of brain-derived neurotrophic factor (BDNF) and post-synaptic density 95 (PSD-95) in the nucleus accumbens shell or core, respectively, thus suggesting that prelimbic alpha1-adrenergic receptor blockade triggers neural adaptations in subcortical areas that could contribute to the extinction of cue-induced drug seeking behavior. These results show that the pharmacological blockade of alpha1 adrenergic receptors in prelimbic cortex by a single infusion is able to induce extinction of amphetamine-induced CPP long before control (vehicle) animals, an effect depending on contingent exposure to retrieval, since if infused far from or after reactivation it did not affect preference. Moreover, they suggest strongly that the behavioral effects depend on post-treatment neuroplasticity changes in corticolimbic network, triggered by a possible "priming" effect of prazosin, and point to a potential therapeutic power of the antagonist for maladaptive memories. PMID- 28848445 TI - Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice. AB - 3-(3-Morpholinopropyl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (SN30- 000), an analog of the well-studied bioreductive prodrug tirapazamine (TPZ), has improved activity against hypoxic cells in tumor xenografts. However, little is known about its biotransformation in normal tissues. Here, we evaluate implications of biotransformation of SN30000 for its toxicokinetics in NIH-III mice. The metabolite profile demonstrated reduction to the 1-N-oxide (M14), oxidation of the morpholine side-chain (predominantly to the alkanoic acid M18) and chromophore, and subsequent glucuronidation. Plasma pharmacokinetics of SN30000 and its reduced metabolites was unaffected by the presence of HT29 tumor xenografts, indicating extensive reduction in normal tissues. This bioreductive metabolism, as modeled by hepatic S9 preparations, was strongly inhibited by oxygen indicating that it proceeds via the one-electron (radical) intermediate previously implicated in induction of DNA double strand breaks and cytotoxicity by SN30000. Plasma pharmacokinetics of SN30000 and M14 (but not M18) corresponded closely to the timing of reversible acute clinical signs (reduced mobility) and marked hypothermia (rectal temperature drop of ~8 degrees C at nadir following the maximum tolerated dose). Similar acute toxicity was elicited by dosing with TPZ or M14, although M14 did not induce the kidney and lung histopathology caused by SN30000. M14 also lacked antiproliferative potency in hypoxic cell cultures. In addition M14 showed much slower redox cycling than SN30000 in oxic cultures. Thus a non-bioreductive mechanism, mediated through M14, appears to be responsible for the acute toxicity of SN30000 while late toxicities are consistent with DNA damage resulting from its one-electron reduction. A two compartment pharmacokinetic model, in which clearance of SN30000 is determined by temperature-dependent bioreductive metabolism to M14, was shown to describe the non-linear PK of SN30000 in mice. This study demonstrates the importance of non tumor bioreductive metabolism in the toxicology and pharmacokinetics of benzotriazine di-oxides designed to target tumor hypoxia. PMID- 28848446 TI - E-M, an Engineered Endostatin with High ATPase Activity, Inhibits the Recruitment and Alternative Activation of Macrophages in Non-small Cell Lung Cancer. AB - Endostatin recently was reported by our laboratory to possess ATPase activity that is indispensable for its anti-angiogenesis and anti-tumor effects. An engineered endostatin, E-M, which owns higher ATPase activity exhibits stronger inhibitory effects on angiogenesis. Tumor-associated macrophages (TAMs), especially M2-polarized TAMs, contribute to tumor progression by promoting tumor cell proliferation, metastasis, angiogenesis, and immunosuppression, thus emerging as crucial targets for therapeutic intervention. Endostatin reportedly modulated functions of TAMs, but the detailed mechanisms remain unclear. Here, in our study, we demonstrated that E-M exhibited stronger inhibitory effects on macrophages than endostatin and other low ATPase mutants, which indicates that the ATPase activity is required for the inhibitory effects of endostatin on TAMs. Moreover, we elucidated that endostatin co-receptor, nucleolin and integrin alpha5beta1, overexpressed on the surface of M2 macrophages, facilitated the internalization of E-M via the caveolae/lipid raft- and clathrin-dependent pathways. E-M inhibited the migration of TAMs through blockade of p38 MAP kinase and Erk1/2 signaling pathways, and prevented the alternative activation of TAMs. As a result, TAM-induced tumor cell proliferation and angiogenic activities in vitro were dramatically suppressed by E-M. In a transplanted non-small cell lung cancer model, E-M remarkably decreased the density of intratumoral macrophages and blood vessels, leading to tumor regression. This study unravels a novel mechanism of endostatin on regulating TAM recruitment and polarization, and suggests that E-M is a remarkably promising and multifunctional anti-tumor agent. PMID- 28848447 TI - Molecular and Biochemical Methods Useful for the Epigenetic Characterization of Chromatin-Associated Proteins in Bivalve Molluscs. AB - Bivalve molluscs constitute a ubiquitous taxonomic group playing key functions in virtually all ecosystems, and encompassing critical commercial relevance. Along with a sessile and filter-feeding lifestyle in most cases, these characteristics make bivalves model sentinel organisms routinely used for environmental monitoring studies in aquatic habitats. The study of epigenetic mechanisms linking environmental exposure and specific physiological responses (i.e., environmental epigenetics) stands out as a very innovative monitoring strategy, given the role of epigenetic modifications in acclimatization and adaptation. Furthermore, the heritable nature of many of those modifications constitutes a very promising avenue to explore the applicability of epigenetic conditioning and selection in management and restoration strategies. Chromatin provides a framework for the study of environmental epigenetic responses. Unfortunately, chromatin and epigenetic information are very limited in most non-traditional model organisms and even completely lacking in most environmentally and ecologically relevant organisms. The present work aims to provide a comprehensive and reproducible experimental workflow for the study of bivalve chromatin. First, a series of guidelines for the molecular isolation of genes encoding chromatin associated proteins is provided, including information on primers suitable for conventional PCR, Rapid Amplification of cDNA Ends (RACE), genome walking and quantitative PCR (qPCR) experiments. This section is followed by the description of methods specifically developed for the analysis of histone and SNBP proteins in different bivalve tissues, including protein extraction, purification, separation and immunodetection. Lastly, information about available antibodies, their specificity and performance is also provided. The tools and protocols described here complement current epigenetic analyses (usually limited to DNA methylation) by incorporating the study of structural elements modulating chromatin dynamics. PMID- 28848448 TI - Body Size Predicts Cardiac and Vascular Resistance Effects on Men's and Women's Blood Pressure. AB - Key Points Summary We report how blood pressure, cardiac output and vascular resistance are related to height, weight, body surface area (BSA), and body mass index (BMI) in healthy young adults at supine rest and standing.Much inter subject variability in young adult's blood pressure, currently attributed to health status, may actually result from inter-individual body size differences.Each cardiovascular variable is linearly related to height, weight and/or BSA (more than to BMI).When supine, cardiac output is positively related, while vascular resistance is negatively related, to body size. Upon standing, the change in vascular resistance is positively related to size.The height/weight relationships of cardiac output and vascular resistance to body size are responsible for blood pressure relationships to body size.These basic components of blood pressure could help distinguish normal from abnormal blood pressures in young adults by providing a more effective scaling mechanism. Introduction: Effects of body size on inter-subject blood pressure (BP) variability are not well established in adults. We hypothesized that relationships linking stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) with body size would account for a significant fraction of inter-subject BP variability. Methods: Thirty-four young, healthy adults (19 men, 15 women) participated in 38 stand tests during which brachial artery BP, heart rate, SV, CO, TPR, and indexes of body size were measured/calculated. Results: Steady state diastolic arterial BP was not significantly correlated with any index of body size when subjects were supine. However, upon standing, the more the subject weighed, or the taller s/he was, the greater the increase in diastolic pressure. Systolic pressure strongly correlated with body weight and height both supine and standing. Diastolic and systolic BP were more strongly related to height, weight and body surface area than to body mass index. When supine: lack of correlation between diastolic pressure and body size, resulted from the combination of positive SV correlation and negative TPR correlation with body size. The positive systolic pressure vs. body size relationship resulted from a positive SV vs. height relationship. In response to standing: the positive diastolic blood pressure vs. body size relationship resulted from the standing-induced, positive increase in TPR vs. body size relationship. The relationships between body weight or height with SV and TPR contribute new insight into mechanisms of BP regulation that may aid in the prediction of health in young adults by providing a more effective way to scale BP with body size. PMID- 28848449 TI - Molecular Regulation of Arterial Aneurysms: Role of Actin Dynamics and microRNAs in Vascular Smooth Muscle. AB - Aortic aneurysms are defined as an irreversible increase in arterial diameter by more than 50% relative to the normal vessel diameter. The incidence of aneurysm rupture is about 10 in 100,000 persons per year and ruptured arterial aneurysms inevitably results in serious complications, which are fatal in about 40% of cases. There is also a hereditary component of the disease and dilation of the ascending thoracic aorta is often associated with congenital heart disease such as bicuspid aortic valves (BAV). Furthermore, specific mutations that have been linked to aneurysm affect polymerization of actin filaments. Polymerization of actin is important to maintain a contractile phenotype of smooth muscle cells enabling these cells to resist mechanical stress on the vascular wall caused by the blood pressure according to the law of Laplace. Interestingly, polymerization of actin also promotes smooth muscle specific gene expression via the transcriptional co-activator MRTF, which is translocated to the nucleus when released from monomeric actin. In addition to genes encoding for proteins involved in the contractile machinery, recent studies have revealed that several non-coding microRNAs (miRNAs) are regulated by this mechanism. The importance of these miRNAs for aneurysm development is only beginning to be understood. This review will summarize our current understanding about the influence of smooth muscle miRNAs and actin polymerization for the development of arterial aneurysms. PMID- 28848450 TI - FXYD8, a Novel Regulator of Renal Na+/K+-ATPase in the Euryhaline Teleost, Tetraodon nigroviridis. AB - FXYD proteins are important regulators of Na+/K+-ATPase (NKA) activity in mammals. As an inhabitant of estuaries, the pufferfish (Tetraodon nigroviridis) responds to ambient salinity changes with efficient osmoregulation, including alterations in branchial, and renal NKA activities. Previous studies on teleostean FXYDs have mainly focused on the expression and potential functions of FXYD proteins in gills. The goal of the present study was to elucidate the potential role of FXYD8, a member of the fish FXYD protein family, in the modulation of NKA activity in the kidneys of this euryhaline pufferfish by using molecular, biochemical, and physiological approaches. The results demonstrate that T. nigroviridis FXYD8 (TnFXYD8) interacts with NKA in renal tubules. Meanwhile, the protein expression of renal TnFXYD8 was found to be significantly upregulated in hyperosmotic seawater-acclimated pufferfish. Moreover, overexpression of TnFXYD8 in Xenopus oocytes decreased NKA activity. Our results suggest the FXYD8 is able to modulate NKA activity through inhibitory effects upon salinity challenge. The present study further extends our understanding of the functions of FXYD proteins, the regulators of NKA, in vertebrates. PMID- 28848451 TI - Development and Growth of the Avian Pectoralis Major (Breast) Muscle: Function of Syndecan-4 and Glypican-1 in Adult Myoblast Proliferation and Differentiation. AB - Muscle fiber number is determined around the time hatch with continued posthatch muscle growth being mediated by the adult myoblast, satellite cell, population of cells. Satellite cells are dynamic in their expression of proteins including the cell membrane associated proteoglycans, syndecan-4 and glypican-1. These proteoglycans play roles in organizing the extracellular environment in the satellite cell niche, cytoskeletal structure, cell-to-cell adhesion, satellite cell migration, and signal transduction. This review article focuses on syndecan 4 and glypican-1 as both are capable of regulating satellite cell responsiveness to fibroblast growth factor 2. Fibroblast growth factor 2 is a potent stimulator of muscle cell proliferation and a strong inhibitor of differentiation. Proteoglycans are composed of a central core protein defined functional domains, and covalently attached glycosaminoglycans and N-glycosylation chains. The functional association of these components with satellite cell function is discussed as well as an emerging role for microRNA regulation of syndecan-4 and glypican-1. PMID- 28848452 TI - Effects of Elevated Carbon Dioxide on Photosynthesis and Carbon Partitioning: A Perspective on Root Sugar Sensing and Hormonal Crosstalk. AB - Plant responses to atmospheric carbon dioxide will be of great concern in the future, as carbon dioxide concentrations ([CO2]) are predicted to continue to rise. Elevated [CO2] causes increased photosynthesis in plants, which leads to greater production of carbohydrates and biomass. Which organ the extra carbohydrates are allocated to varies between species, but also within species. These carbohydrates are a major energy source for plant growth, but they also act as signaling molecules and have a range of uses beyond being a source of carbon and energy. Currently, there is a lack of information on how the sugar sensing and signaling pathways of plants are affected by the higher content of carbohydrates produced under elevated [CO2]. Particularly, the sugar signaling pathways of roots are not well understood, along with how they are affected by elevated [CO2]. At elevated [CO2], some plants allocate greater amounts of sugars to roots where they are likely to act on gene regulation and therefore modify nutrient uptake and transport. Glucose and sucrose also promote root growth, an effect similar to what occurs under elevated [CO2]. Sugars also crosstalk with hormones to regulate root growth, but also affect hormone biosynthesis. This review provides an update on the role of sugars as signaling molecules in plant roots and thus explores the currently known functions that may be affected by elevated [CO2]. PMID- 28848453 TI - Salivary Glands in Predatory Mollusks: Evolutionary Considerations. AB - Many marine mollusks attain or increase their predatory efficiency using complex chemical secretions, which are often produced and delivered through specialized anatomical structures of the foregut. The secretions produced in venom glands of Conus snails and allies have been extensively studied, revealing an amazing chemical diversity of small, highly constrained neuropeptides, whose characterization led to significant pharmacological developments. Conversely, salivary glands, the other main secretory structures of molluscan foregut, have been neglected despite their shared occurrence in the two lineages including predatory members: Gastropoda and Cephalopoda. Over the last few years, the interest for the chemistry of salivary mixtures increased based on their potential biomedical applications. Recent investigation with -omics technologies are complementing the classical biochemical descriptions, that date back to the 1950s, highlighting the high level of diversification of salivary secretions in predatory mollusks, and suggesting they can be regarded as a pharmaceutical cornucopia. As with other animal venoms, some of the salivary toxins are reported to target, for example, sodium and/or potassium ion channels or receptors and transporters for neurotransmitters such as, glutamate, serotonin, neurotensin, and noradrenaline, thus manipulating the neuromuscular system of the preys. Other bioactive components possess anticoagulant, anesthetic and hypotensive activities. Here, we overview available knowledge on the salivary glands of key predatory molluscan taxa, gastropods, and cephalopods, summarizing their anatomical, physiological and biochemical complexity in order to facilitate future comparative studies on main evolutionary trends and functional convergence in the acquisition of successful predatory strategies. PMID- 28848455 TI - GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies. AB - Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical gamma aminobutyric acid (GABAergic) neurons contribute to the clinical features of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course. PMID- 28848454 TI - Prevention of Mental Health Disorders Using Internet- and Mobile-Based Interventions: A Narrative Review and Recommendations for Future Research. AB - Although psychological interventions might have a tremendous potential for the prevention of mental health disorders (MHD), their current impact on the reduction of disease burden is questionable. Possible reasons include that it is not practical to deliver those interventions to the community en masse due to limited health care resources and the limited availability of evidence-based interventions and clinicians in routine practice, especially in rural areas. Therefore, new approaches are needed to maximize the impact of psychological preventive interventions. Limitations of traditional prevention programs could potentially be overcome by providing Internet- and mobile-based interventions (IMIs). This relatively new medium for promoting mental health and preventing MHD introduces a fresh array of possibilities, including the provision of evidence based psychological interventions that are free from the restraints of travel and time and allow reaching participants for whom traditional opportunities are not an option. This article provides an introduction to the subject and narratively reviews the available evidence for the effectiveness of IMIs with regard to the prevention of MHD onsets. The number of randomized controlled trials that have been conducted to date is very limited and so far it is not possible to draw definite conclusions about the potential of IMIs for the prevention of MHD for specific disorders. Only for the indicated prevention of depression there is consistent evidence across four different randomized trial trials. The only trial on the prevention of general anxiety did not result in positive findings in terms of eating disorders (EDs), effects were only found in post hoc subgroup analyses, indicating that it might be possible to prevent ED onset for subpopulations of people at risk of developing EDs. Future studies need to identify those subpopulations likely to profit from preventive. Disorders not examined so far include substance use disorders, bipolar disorders, stress-related disorders, phobic disorders and panic disorder, obsessive-compulsive disorder, impulse control disorders, somatic symptom disorder, and insomnia. In summary, there is a need for more rigorously conducted large scale randomized controlled trials using standard clinical diagnostic instruments for the selection of participants without MHD at baseline and the assessment of MHD onset. Subsequently, we discuss future directions for the field in order to fully exploit the potential of IMI for the prevention of MHD. PMID- 28848457 TI - Commentary: Sex Differences in the Peripheral Immune System in Patients with Depression. PMID- 28848456 TI - Systematic Review of Cognitive Function in Euthymic Bipolar Disorder and Pre Surgical Temporal Lobe Epilepsy. AB - BACKGROUND: Bipolar disorder (BD) and temporal lobe epilepsy (TLE) overlap in domains including epidemiology, treatment response, shared neurotransmitter involvement and temporal lobe pathology. Comparison of cognitive function in both disorders may indicate temporal lobe mediated processes relevant to BD. This systematic review examines neuropsychological test profiles in euthymic bipolar disorder type I (BD-I) and pre-surgical TLE and compares experimental designs used. METHODS: A search of PubMed, PsychINFO, and Scopus using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. Inclusion criteria were comparison group or pre- to post-surgical patients; reported neuropsychological tests; participants aged 18-60 years. Fifty six studies met criteria: 27 BD-I; 29 TLE. RESULTS: Deficits in BD-I compared to healthy controls (HC) were in executive function, attention span and verbal memory. Deficits in TLE compared to HC were in executive function and memory. In the pre- to post-surgical comparisons, verbal memory in left temporal lobe (LTL) and, less consistently, visuospatial memory in right temporal lobe (RTL) epilepsy declined following surgery. BD-I studies used comprehensive test batteries in well-defined euthymic patients compared to matched HC groups. TLE studies used convenience samples pre- to post-surgery, comparing LTL and RTL subgroups, few included comparisons to HC (5 studies). TLE studies typically examined a narrow range of known temporal lobe-mediated neuropsychological functions, particularly verbal and visuospatial memory. CONCLUSION: Both disorders exhibit deficits in executive function and verbal memory suggestive of both frontal and temporal lobe involvement. However, deficits in TLE are measured pre- to post-surgery and not controlled at baseline pre-surgery. Further research involving a head-to-head comparison of the two disorders on a broad range of neuropsychological tests is needed to clarify the nature and extent of cognitive deficits and potential overlaps. PMID- 28848459 TI - Parenting Styles, Prosocial, and Aggressive Behavior: The Role of Emotions in Offender and Non-offender Adolescents. AB - The aim is to analyse the parenting styles effects (acceptance, negative control and negligence) on prosociality and aggressive behavior in adolescents through the mediator variables empathy and emotional instability, and also, if this model fits to the same extent when we study adolescents institutionalized due to problems with the law and adolescents from the general population, and at the same time, if the values of the different analyzed variables are similar in both groups of adolescents. We carried out a cross-sectional study. 220 participants from schools in the metropolitan area of Valencia took part in the study. Also, 220 young offenders took part recruited from four Youth Detention Centres of Valencia, in which they were carrying out court sentences. The age of the subjects range from 15-18 years. The results indicate that the emotional variables act as mediators in general, in the non-offender adolescents, but it has been observed, in the offender adolescents, a direct effect of support on aggressive behavior in a negative way and on prosociality in a positive way; and of negligence on aggressive behavior and of permissiveness on prosociality in a negative way. PMID- 28848458 TI - Complexity Level Analysis Revisited: What Can 30 Years of Hindsight Tell Us about How the Brain Might Represent Visual Information? AB - Much has been written about how the biological brain might represent and process visual information, and how this might inspire and inform machine vision systems. Indeed, tremendous progress has been made, and especially during the last decade in the latter area. However, a key question seems too often, if not mostly, be ignored. This question is simply: do proposed solutions scale with the reality of the brain's resources? This scaling question applies equally to brain and to machine solutions. A number of papers have examined the inherent computational difficulty of visual information processing using theoretical and empirical methods. The main goal of this activity had three components: to understand the deep nature of the computational problem of visual information processing; to discover how well the computational difficulty of vision matches to the fixed resources of biological seeing systems; and, to abstract from the matching exercise the key principles that lead to the observed characteristics of biological visual performance. This set of components was termed complexity level analysis in Tsotsos (1987) and was proposed as an important complement to Marr's three levels of analysis. This paper revisits that work with the advantage that decades of hindsight can provide. PMID- 28848460 TI - Linking Neural and Symbolic Representation and Processing of Conceptual Structures. AB - We compare and discuss representations in two cognitive architectures aimed at representing and processing complex conceptual (sentence-like) structures. First is the Neural Blackboard Architecture (NBA), which aims to account for representation and processing of complex and combinatorial conceptual structures in the brain. Second is IDyOT (Information Dynamics of Thinking), which derives sentence-like structures by learning statistical sequential regularities over a suitable corpus. Although IDyOT is designed at a level more abstract than the neural, so it is a model of cognitive function, rather than neural processing, there are strong similarities between the composite structures developed in IDyOT and the NBA. We hypothesize that these similarities form the basis of a combined architecture in which the individual strengths of each architecture are integrated. We outline and discuss the characteristics of this combined architecture, emphasizing the representation and processing of conceptual structures. PMID- 28848461 TI - Dispelling the Myth: Training in Education or Neuroscience Decreases but Does Not Eliminate Beliefs in Neuromyths. AB - Neuromyths are misconceptions about brain research and its application to education and learning. Previous research has shown that these myths may be quite pervasive among educators, but less is known about how these rates compare to the general public or to individuals who have more exposure to neuroscience. This study is the first to use a large sample from the United States to compare the prevalence and predictors of neuromyths among educators, the general public, and individuals with high neuroscience exposure. Neuromyth survey responses and demographics were gathered via an online survey hosted at TestMyBrain.org. We compared performance among the three groups of interest: educators (N = 598), high neuroscience exposure (N = 234), and the general public (N = 3,045) and analyzed predictors of individual differences in neuromyths performance. In an exploratory factor analysis, we found that a core group of 7 "classic" neuromyths factored together (items related to learning styles, dyslexia, the Mozart effect, the impact of sugar on attention, right-brain/left-brain learners, and using 10% of the brain). The general public endorsed the greatest number of neuromyths (M = 68%), with significantly fewer endorsed by educators (M = 56%), and still fewer endorsed by the high neuroscience exposure group (M = 46%). The two most commonly endorsed neuromyths across all groups were related to learning styles and dyslexia. More accurate performance on neuromyths was predicted by age (being younger), education (having a graduate degree), exposure to neuroscience courses, and exposure to peer-reviewed science. These findings suggest that training in education and neuroscience can help reduce but does not eliminate belief in neuromyths. We discuss the possible underlying roots of the most prevalent neuromyths and implications for classroom practice. These empirical results can be useful for developing comprehensive training modules for educators that target general misconceptions about the brain and learning. PMID- 28848463 TI - Implicit Age Cues in Resumes: Subtle Effects on Hiring Discrimination. AB - Anonymous resume screening, as assumed, does not dissuade age discriminatory effects. Building on job market signaling theory, this study investigated whether older applicants may benefit from concealing explicitly mentioned age signals on their resumes (date of birth) or whether more implicit/subtle age cues on resumes (older-sounding names/old-fashioned extracurricular activities) may lower older applicants' hirability ratings. An experimental study among 610 HR professionals using a mixed factorial design showed hiring discrimination of older applicants based on implicit age cues in resumes. This effect was more pronounced for older raters. Concealing one's date of birth led to overall lower ratings. Study findings add to the limited knowledge on the effects of implicit age cues on hiring discrimination in resume screening and the usefulness of anonymous resume screening in the context of age. Implications for research and practice are discussed. PMID- 28848462 TI - Quality of Life and Psychopathology in Adults Who Underwent Hematopoietic Stem Cell Transplantation (HSCT) in Childhood: A Qualitative and Quantitative Analysis. AB - Background: Patients who undergo pediatric Hematopoietic Stem Cell Transplantation (HSCT) may experience long-term psychological sequelae and poor Quality of Life (QoL) in adulthood. This study aimed to investigate subjective illness experience, QoL, and psychopathology in young adults who have survived pediatric HSCT. Method: The study involved patients treated with HSCT in the Hematology-Oncology Department between 1984 and 2007. Psychopathology and QoL were investigated using the SCL-90-R and SF-36. Socio-demographic and medical information was also collected. Finally, participants were asked to write a brief composition about their experiences of illness and care. Qualitative analysis of the texts was performed using T-LAB, an instrument for text analysis that allows the user to highlight the occurrences and co-occurrences of lemma. Quantitative analyses were performed using non-parametric tests (Spearman correlations, Kruskal-Wallis and Mann-Whitney tests). Results: Twenty-one patients (9 males) participated in the study. No significant distress was found on the SCL-90 Global Severity Index, but it was found on specific scales. On the SF-36, lower scores were reported on scales referring to bodily pain, general health, and physical and social functioning. All the measures were significantly (p < 0.05) associated with specific socio-demographic and medical variables (gender, type of pathology, type of HSCT, time elapsed between communication of the need to transplant and effective transplantation, and days of hospitalization). With regard to the narrative analyses, males focused on expressions related to the body and medical therapies, while females focused on people they met during treatment, family members, and donors. Low general health and treatment with autologous HSCT were associated with memories about chemotherapy, radiotherapy, and the body parts involved, while high general health was associated with expressions focused on gratitude (V-Test +/- 1.96). Conclusion: Pediatric HSCT survivors are more likely to experience psychological distress and low QoL in adulthood compared with the general population. These aspects, along with survivors' subjective illness experience, show differences according to specific medical and socio-demographic variables. Studies are needed in order to improve the care and long-term follow up of these families. PMID- 28848464 TI - No Long-Term Effect of Physical Activity Intervention on Working Memory or Arithmetic in Preadolescents. AB - We investigate if increased physical activity (PA) leads to enhanced working memory capacity and arithmetic performance, in a 2-year school-based intervention in preadolescent children (age 6-13). The active school (n = 228) increased PA (aimed at increasing cardiovascular fitness) from 2 to 5 days a week while the control school (n = 242) remained at 2 days. Twice a year, participants performed tests of arithmetic as well as verbal and spatial working memory. They also rated stress with a questionnaire at the start and at the end of the intervention. There was no beneficial development of working memory or arithmetic for the active school as compared to the control school. Furthermore, subgroup analyses revealed no favorable intervention effect for high/low baseline fitness, cognition or grit. Unexpectedly, a significant increase in self-rated stress was detected for the active school and this effect was driven by girls rather than boys and by the younger rather than older children. These results indicate that longtime high intensity PA does not lead to a beneficial development of working memory or arithmetic in preadolescent children. PMID- 28848465 TI - Efficacy of 8- and 4-Session Mindfulness-Based Interventions in a Non-clinical Population: A Controlled Study. AB - Background: Many attempts have been made to abbreviate mindfulness programmes in order to make them more accessible for general and clinical populations while maintaining their therapeutic components and efficacy. The aim of this study was to assess the efficacy of an 8-week mindfulness-based intervention (MBI) programme and a 4-week abbreviated version for the improvement of well-being in a non-clinical population. Method: A quasi-experimental, controlled, pilot study was conducted with pre-post and 6-month follow-up measurements and three study conditions (8- and 4-session MBI programmes and a matched no-treatment control group, with a sample of 48, 46, and 47 participants in each condition, respectively). Undergraduate students were recruited, and mindfulness, positive and negative affect, self-compassion, resilience, anxiety, and depression were assessed. Mixed-effects multi-level analyses for repeated measures were performed. Results: The intervention groups showed significant improvements compared to controls in mindfulness and positive affect at the 2- and 6-month follow-ups, with no differences between 8- vs. 4-session programmes. The only difference between the abbreviated MBI vs. the standard MBI was found in self kindness at 6 months, favoring the standard MBI. There were marginal differences in anxiety between the controls vs. the abbreviated MBI, but there were differences between the controls vs. the standard MBI at 2- and 6-months, with higher levels in the controls. There were no differences in depression between the controls vs. the abbreviated MBI, but differences were found between the controls vs. the standard MBI at 2- and 6-months, favoring the standard MBI. There were no differences with regard to negative affect and resilience. Conclusion: To our knowledge, this is the first study to directly investigate the efficacy of a standard 8-week MBI and a 4-week abbreviated protocol in the same population. Based on our findings, both programmes performed better than controls, with similar effect size (ES). The efficacy of abbreviated mindfulness programmes may be similar to that of a standard MBI programme, making them potentially more accessible for a larger number of populations. Nevertheless, further studies with more powerful designs to compare the non-inferiority of the abbreviated protocol and addressing clinical populations are warranted. Clinical Trials.gov Registration ID: NCT02643927. PMID- 28848467 TI - The Association between Motivation, Affect, and Self-regulated Learning When Solving Problems. AB - Self-regulated learning (SRL) skills are essential for learning during school years, particularly in complex problem-solving domains, such as biology and math. Although a lot of studies have focused on the cognitive resources that are needed for learning to solve problems in a self-regulated way, affective and motivational resources have received much less research attention. The current study investigated the relation between affect (i.e., Positive Affect and Negative Affect Scale), motivation (i.e., autonomous and controlled motivation), mental effort, SRL skills, and problem-solving performance when learning to solve biology problems in a self-regulated online learning environment. In the learning phase, secondary education students studied video-modeling examples of how to solve hereditary problems, solved hereditary problems which they chose themselves from a set of problems with different complexity levels (i.e., five levels). In the posttest, students solved hereditary problems, self-assessed their performance, and chose a next problem from the set of problems but did not solve these problems. The results from this study showed that negative affect, inaccurate self-assessments during the posttest, and higher perceptions of mental effort during the posttest were negatively associated with problem-solving performance after learning in a self-regulated way. PMID- 28848466 TI - Mental Toughness and Individual Differences in Learning, Educational and Work Performance, Psychological Well-being, and Personality: A Systematic Review. AB - Mental toughness (MT) is an umbrella term that entails positive psychological resources, which are crucial across a wide range of achievement contexts and in the domain of mental health. We systematically review empirical studies that explored the associations between the concept of MT and individual differences in learning, educational and work performance, psychological well-being, personality, and other psychological attributes. Studies that explored the genetic and environmental contributions to individual differences in MT are also reviewed. The findings suggest that MT is associated with various positive psychological traits, more efficient coping strategies and positive outcomes in education and mental health. Approximately 50% of the variation in MT can be accounted for by genetic factors. Furthermore, the associations between MT and psychological traits can be explained mainly by either common genetic or non shared environmental factors. Taken together, our findings suggest a 'mental toughness advantage' with possible implications for developing interventions to facilitate achievement in a variety of settings. PMID- 28848468 TI - The Importance of Context in Screening in Occupational Health Interventions in Organizations: A Mixed Methods Study. AB - In occupational health interventions, there is a debate as to whether standardized or tailored measures should be used to identify which aspects of the psychosocial work environment should be targeted in order to improve employees' well-being. Using the Job Demands-Resources model, the main aim of the present study is to demonstrate how a mixed methods approach to conducting screening enables the identification of potential context-dependent demands and resources in the workplace, which should to be targeted by the intervention. Specifically, we used a mixed methods exploratory sequential research design. First, we conducted four focus groups (N = 37) in a sample of employees working in grocery stores in Italy. The qualitative results allowed to identify one possible context specific job demand: the use of a work scheduling IT software, whose implementation resulted in a high rotation between different market's departments. From the qualitative results, this context-specific demand seemed to be related to workers' well-being. Thus, in a subsequent questionnaire survey (N = 288), we included this demand together with generic measures of social support and psychological well-being. Results confirmed that this context-specific job demand was related to emotional exhaustion. Furthermore, it was found that social support moderated the relationship between this specific job demand and emotional exhaustion showing among employees whose activities depended on the IT software, employees that perceived higher levels of social support from colleagues experienced lower levels of emotional exhaustion with respect to their colleagues who perceived lower levels of social support. The present study confirms that mixed methods approach is useful in occupational health intervention research and offers a way forward on helping organizations prioritize their intervention activities. PMID- 28848469 TI - Creative Flow as a Unique Cognitive Process. PMID- 28848470 TI - A Temporal Map of Coaching. AB - Economic pressures on companies, technological developments, and less stable career paths pose potential threats to the well-being of employees (e.g., stress, burn-out) and require constant adaptation. In the light of these challenges, it is not surprising that employees often seek the support of a coach. The role of a coach is to foster change by facilitating a coachees' movement through a self regulatory cycle with the ultimate aim of stimulating sustained well-being and functioning. While meta-analytic research indicates that coaching interventions can be effectively applied to assist employees in dealing with change, the current literature on coaching lacks solid theoretical frameworks that are needed to build a cumulative knowledge-base and to inspire evidence-based practice. In this conceptual analysis, we examine the coaching process through a temporal lens. By doing so, we provide an integrated theoretical framework: a temporal map of coaching. In this framework, we link seminal concepts in psychology to the coaching process, and describe which competencies of coachees are crucial in the different stages of change that coaching aims to bring about. During the preparatory contemplation stage, targeting coachees' awareness by enhancing their mindfulness and environmental receptiveness is important. During the contemplation stage, coachees' willingness and perceived ability to change are central competencies. We propose that coaches should therefore foster intrinsic goal orientation and self-efficacy during this stage. During the planning stage, coaches should focus on goal-setting and implementation intentions. Finally, during the maintenance/termination stage, stimulating coachees' reflection is especially important in order to help them to integrate their learning experiences. The framework delineated in this paper contributes to the understanding of coaching as a tool to assist employees in dealing with the challenges of an increasingly dynamic work-environment and yields concrete suggestions for future theory development and research on coaching. PMID- 28848471 TI - The Positive Facet of Self-compassion Predicts Self-reported Use of and Attitudes toward Desirable Difficulties in Learning. AB - Previous research found that introducing difficulties and challenges during learning has desirable outcomes. With the present work, we investigated the question how the use of and the attitudes toward such learning strategies (so called desirable difficulties) are related to self-compassion, a concept that describes the tendency to be understanding and kind to oneself when confronted with negative experiences. Evidence suggests self-compassion to be linked to less fear of failing, and further to higher control beliefs and mastery goals in learning. Given that applying desirable difficulties in self-regulated learning implies increased challenges, and further, a higher likelihood to experience a feeling of failing, we expected that the use of desirable difficulties increases with levels of self-compassion. We tested this hypothesis in an online study (N = 136) in which self-compassion and the self-reported use of and attitudes toward strategies of desirable difficulties were assessed via respective questionnaires. Results of a correlation analysis yielded first evidence for our idea. Decomposing self-compassion into a positive and a negative facet showed that the positive, but not the negative, facet is positively correlated with attitudes toward and the use of desirable difficulties. Additionally, a regression analysis showed that the positive but not the negative facet predicted attitudes toward and use of desirable difficulties, when entering both facets simultaneously as predictors. Practical implications for learners are discussed. PMID- 28848472 TI - Pro-ana versus Pro-recovery: A Content Analytic Comparison of Social Media Users' Communication about Eating Disorders on Twitter and Tumblr. AB - Objectives: To compare how people communicate about eating disorders on two popular social media platforms - Twitter and Tumblr. Materials and Methods: Thematic analysis was conducted to characterize the types of communications posted, and a content analysis was undertaken of between-platform differences. Results: Three types of content (pro-ana, anti-ana, and pro-recovery) were posted on each platform. Overall, across both platforms, extreme pro-ana posts were in the minority compared to anti-ana and pro-recovery. Pro-ana posts (including 'thinspiration') were more common on Twitter than Tumblr, whereas anti-ana and pro-recovery posts were more common on Tumblr. Conclusion: The findings have implications for future research and health care relating to the treatment and prevention of eating disorders. Developers of future interventions targeting negative pro-ana content should remain aware of the need to avoid any detrimental impact on positive online support. PMID- 28848473 TI - Home Language Will Not Take Care of Itself: Vocabulary Knowledge in Trilingual Children in the United Kingdom. AB - Language input is crucial for language acquisition and especially for children's vocabulary size. Bilingual children receive reduced input in each of their languages, compared to monolinguals, and are reported to have smaller vocabularies, at least in one of their languages. Vocabulary acquisition in trilingual children has been largely understudied; only a few case studies have been published so far. Moreover, trilingual language acquisition in children has been rarely contrasted with language outcomes of bilingual and monolingual peers. We present a comparison of trilingual, bilingual, and monolingual children (total of 56 participants, aged 4;5-6;7, matched one-to-one for age, gender, and non verbal IQ) in regard to their receptive and expressive vocabulary (measured by standardized tests), and relative frequency of input in each language (measured by parental report). The monolingual children were speakers of Polish or English, while the bilinguals and trilinguals were migrant children living in the United Kingdom, speaking English as a majority language and Polish as a home language. The trilinguals had another (third) language at home. For the majority language, English, no differences were found across the three groups, either in the receptive or productive vocabulary. The groups differed, however, in their performance in Polish, the home language. The trilinguals had lower receptive vocabulary than the monolinguals, and lower productive vocabulary compared to the monolinguals. The trilinguals showed similar lexical knowledge to the bilinguals. The bilinguals demonstrated lower scores than the monolinguals, but only in productive vocabulary. The data on reported language input show that input in English in bilingual and trilingual groups is similar, but the bilinguals outscore the trilinguals in relative frequency of Polish input. Overall, the results suggest that in the majority language, multilingual children may develop lexical skills similar to those of their monolingual peers. However, their minority language is weaker: the trilinguals scored lower than the Polish monolinguals on both receptive and expressive vocabulary tests, and the bilinguals showed reduced expressive knowledge but leveled out with the Polish monolinguals on receptive vocabulary. The results should encourage parents of migrant children to support home language(s), if the languages are to be retained in a longer perspective. PMID- 28848474 TI - Systems Perspective of Amazon Mechanical Turk for Organizational Research: Review and Recommendations. AB - Amazon Mechanical Turk (MTurk) is becoming a prevalent source of quick and cost effective data for organizational research, but there are questions about the appropriateness of the platform for organizational research. To answer these questions, we conducted an integrative review based on 75 papers evaluating the MTurk platform and 250 MTurk samples used in organizational research. This integrative review provides four contributions: (1) we analyze the trends associated with the use of MTurk samples in organizational research; (2) we develop a systems perspective (recruitment system, selection system, and work management system) to synthesize and organize the key factors influencing data collected on MTurk that may affect generalizability and data quality; (3) within each factor, we also use available MTurk samples from the organizational literature to analyze key issues (e.g., sample characteristics, use of attention checks, payment); and (4) based on our review, we provide specific recommendations and a checklist for data reporting in order to improve data transparency and enable further research on this issue. PMID- 28848476 TI - Burnout Disrupts Anxiety Buffer Functioning Among Nurses: A Three-Way Interaction Model. AB - Over the last 40 years, job burnout has attracted a great deal of attention among researchers and practitioners and, after decades of research and interventions, it is still regarded as an important issue. With the aim of extending the Anxiety Buffer Disruption Theory (ABDT), in this paper we argue that high levels of burnout may disrupt the anxiety buffer functioning that protects people from death concerns. ABDT was developed from Terror Management Theory (TMT). According to TMT, reminders of one's mortality are an essential part of humans' daily experience and have the potential to awake paralyzing fear and anxiety. In order to cope with death concerns, people typically activate an anxiety-buffering system centered on their cultural worldview and self-esteem. Recent ABDT research shows that individuals with post-traumatic stress disorder are unable to activate such anxiety buffering defenses. In line with these results, we hypothesized that the burnout syndrome may have similar effects, and that individuals with higher levels of burnout will be less likely to activate an anxiety buffering response when their mortality is made salient. Participants were 418 nurses, who completed a questionnaire including: a mortality salience (MS) manipulation, a delay manipulation, and measures of burnout, work-related self-efficacy, and representation of oneself as a valuable caregiver. Nurses are daily exposed both to the risk of burnout and to mortality reminders, and thus constituted an ideal population for this study. In line with an anxiety buffer disruption hypothesis, we found a significant three-way interaction between burnout, MS and delay. Participants with lower levels of burnout reported higher levels of self-efficacy and a more positive representation as caregivers in the MS condition compared to the control condition, when there was a delay between MS manipulation and the assessment of the dependent measures. The difference was non-significant for participants with higher levels of burnout. Theoretical and practical implications of findings are discussed. PMID- 28848475 TI - Investigating Direct Links between Depression, Emotional Control, and Physical Punishment with Adolescent Drive for Thinness and Bulimic Behaviors, Including Possible Moderation by the Serotonin Transporter 5-HTTLPR Polymorphism. AB - Objectives: To examine the relationship between psychological and social factors (depression, emotional control, sexual abuse, and parental physical punishment) and adolescent drive for Thinness and Bulimic behaviors in a large community sample, and to investigate possible genetic moderation. Method: Data were drawn from the Australian Temperament Project (ATP), a population-based cohort study that has followed a representative sample of 2443 participants from infancy to adulthood across 16 waves since 1983. A subsample of 650 participants (50.2% female) of Caucasian descent who provided DNA were genotyped for a serotonin transporter promoter polymorphism (5-HTTLPR). Adolescent disordered eating attitudes and behaviors were assessed using the Bulimia and Drive for Thinness scales of the Eating Disorder Inventory-2 (15-16 years). Depression and emotional control were examined at the same age using the Short Mood and Feelings Questionnaire, and an ATP-devised measure of emotional control. History of sexual abuse and physical punishment were assessed retrospectively (23-24 years) in a subsample of 467 of those providing DNA. Results: EDI-2 scores were associated with depression, emotional control, and retrospectively reported parental physical punishment. Although there was statistically significant moderation of the relationship between parental physical punishment and bulimic behaviors by 5 HTTLPR (p = 0.0048), genotypes in this subsample were not in Hardy-Weinberg Equilibrium. No other G*E interactions were significant. Conclusion: Findings from this study affirm the central importance of psychosocial processes in disordered eating patterns in adolescence. Evidence of moderation by 5-HTTLPR was not conclusive; however, genetic moderation observed in a subsample not in Hardy Weinberg Equilibrium warrants further investigation. PMID- 28848477 TI - The Structure and Measurement of Unusual Sensory Experiences in Different Modalities: The Multi-Modality Unusual Sensory Experiences Questionnaire (MUSEQ). AB - Hallucinations and other unusual sensory experiences (USE) can occur in all modalities in the general population. Yet, the existing literature is dominated by investigations into auditory hallucinations ("voices"), while other modalities remain under-researched. Furthermore, there is a paucity of measures which can systematically assess different modalities, which limits our ability to detect individual and group differences across modalities. The current study explored such differences using a new scale, the Multi-Modality Unusual Sensory Experiences Questionnaire (MUSEQ). The MUSEQ is a 43-item self-report measure which assesses USE in six modalities: auditory, visual, olfactory, gustatory, bodily sensations, and sensed presence. Scale development and validation involved a total of 1,300 participants, which included: 513 students and community members for initial development, 32 individuals with schizophrenia spectrum disorder or bipolar disorder for validation, 659 students for factor replication, and 96 students for test-retest reliability. Confirmatory factor analyses showed that a correlated-factors model and bifactor model yielded acceptable model fit, while a unidimensional model fitted poorly. These findings were confirmed in the replication sample. Results showed contributions from a general common factor, as well as modality-specific factors. The latter accounted for less variance than the general factor, but could still detect theoretically meaningful group differences. The MUSEQ showed good reliability, construct validity, and could discriminate non-clinical and clinical groups. The MUSEQ offers a reliable means of measuring hallucinations and other USE in six different modalities. PMID- 28848478 TI - Transformational Leadership and Organizational Citizenship Behavior: A Meta Analytic Test of Underlying Mechanisms. AB - Based on social exchange theory, we examined and contrasted attitudinal mediators (affective organizational commitment, job satisfaction) and relational mediators (trust in leader, leader-member exchange; LMX) of the positive relationship between transformational leadership and organizational citizenship behavior (OCB). Hypotheses were tested using meta-analytic path models with correlations from published meta-analyses (761 samples with 227,419 individuals overall). When testing single-mediator models, results supported our expectations that each of the mediators explained the relationship between transformational leadership and OCB. When testing a multi-mediator model, LMX was the strongest mediator. When testing a model with a latent attitudinal mechanism and a latent relational mechanism, the relational mechanism was the stronger mediator of the relationship between transformational leadership and OCB. Our findings help to better understand the underlying mechanisms of the relationship between transformational leadership and OCB. PMID- 28848479 TI - Deadly Attraction - Attentional Bias toward Preferred Cigarette Brand in Smokers. AB - Numerous studies have shown that biases in visual attention might be evoked by affective and personally relevant stimuli, for example addiction-related objects. Despite the fact that addiction is often linked to specific products and systematic purchase behaviors, no studies focused directly on the existence of bias evoked by brands. Smokers are characterized by high levels of brand loyalty and everyday contact with cigarette packaging. Using the incentive-salience mechanism as a theoretical framework, we hypothesized that this group might exhibit a bias toward the preferred cigarette brand. In our study, a group of smokers (N = 40) performed a dot probe task while their eye movements were recorded. In every trial a pair of pictures was presented - each of them showed a single cigarette pack. The visual properties of stimuli were carefully controlled, so branding information was the key factor affecting subjects' reactions. For each participant, we compared gaze behavior related to the preferred vs. other brands. The analyses revealed no attentional bias in the early, orienting phase of the stimulus processing and strong differences in maintenance and disengagement. Participants spent more time looking at the preferred cigarettes and saccades starting at the preferred brand location had longer latencies. In sum, our data shows that attentional bias toward brands might be found in situations not involving choice or decision making. These results provide important insights into the mechanisms of formation and maintenance of attentional biases to stimuli of personal relevance and might serve as a first step toward developing new attitude measurement techniques. PMID- 28848480 TI - Getting a Grip on the Handgrip Task: Handgrip Duration Correlates with Neuroticism But Not Conscientiousness. AB - Questions regarding the replicability of key findings in the self-regulation literature (e.g., ego-depletion effect) have led some to call for a more thorough evaluation of commonly used measures of self-control. The isometric handgrip task is one such measure. The current study examined correlates of handgrip persistence using data drawn from a larger randomized controlled trial. Handgrip persistence was measured both at baseline and following a physical stressor (cold pressor test). Correlations were examined between handgrip performance and personality traits theoretically closely linked with self-regulation: conscientiousness and neuroticism. Baseline handgrip performance was correlated with several measures drawn from the nomological network of self-regulation including measures of trait neuroticism, mindfulness, anxiety sensitivity, perceived stress, and positive affect, although not with trait conscientiousness. Baseline handgrip predicted aversiveness experienced during the physical stressor, while changes in handgrip performance tracked changes in implicit and explicit negative affect (i.e., affective reactivity). These associations were largely maintained when controlling for variables highly correlated with overall grip strength (i.e., gender, height, and weight), although correlations separated by gender suggest associations were primarily driven by female participants. Results support future research using the handgrip task. PMID- 28848481 TI - Measures of Potential Flexibility and Practical Flexibility in Equation Solving. AB - Researchers interested in mathematical proficiency have recently begun to explore the development of strategic flexibility, where flexibility is defined as knowledge of multiple strategies for solving a problem and the ability to implement an innovative strategy for a given problem solving circumstance. However, anecdotal findings from this literature indicate that students do not consistently use an innovative strategy for solving a given problem, even when these same students demonstrate knowledge of innovative strategies. This distinction, sometimes framed in the psychological literature as competence vs. performance-has not been previously studied for flexibility. In order to explore the competence/performance distinction in flexibility, this study developed and validated measures for potential flexibility (e.g., competence, or knowledge of multiple strategies) and practical flexibility (e.g., performance, use of innovative strategies) for solving equations. The measures were administrated to a sample of 158 Chinese middle school students through a Tri-Phase Flexibility Assessment, in which the students were asked to solve each equation, generate additional strategies, and evaluate own multiple strategies. Confirmatory factor analysis supported a two-factor model of potential and practical flexibility. Satisfactory internal consistency was found for the measures. Additional validity evidence included the significant association with flexibility measured with the previous method. Potential flexibility and practical flexibility were found to be distinct but related. The theoretical and practical implications of the concepts and their measures of potential flexibility and practical flexibility are discussed. PMID- 28848482 TI - Hot and Cold Smells: Odor-Temperature Associations across Cultures. AB - It is often assumed odors are associated with hot and cold temperature, since odor processing may trigger thermal sensations, such as coolness in the case of mint. It is unknown, however, whether people make consistent temperature associations for a variety of everyday odors, and, if so, what determines them. Previous work investigating the bases of cross-modal associations suggests a number of possibilities, including universal forces (e.g., perception), as well as culture-specific forces (e.g., language and cultural beliefs). In this study, we examined odor-temperature associations in three cultures-Maniq (N = 11), Thai (N = 24), and Dutch (N = 24)-who differ with respect to their cultural preoccupation with odors, their odor lexicons, and their beliefs about the relationship of odors (and odor objects) to temperature. Participants matched 15 odors to temperature by touching cups filled with hot or cold water, and described the odors in their native language. The results showed no consistent associations among the Maniq, and only a handful of consistent associations between odor and temperature among the Thai and Dutch. The consistent associations differed across the two groups, arguing against their universality. Further analysis revealed cross-modal associations could not be explained by language, but could be the result of cultural beliefs. PMID- 28848483 TI - Proximity Begins with a Smile, But Which One? Associating Non-duchenne Smiles with Higher Psychological Distance. AB - This study reveals that Duchenne (genuine) and non-Duchenne (non-genuine, polite) smiles are implicitly associated with psychological proximity and distance, respectively. These findings link two extensive research streams from human communication and psychology. Interestingly, extant construal-level theory research suggests the link may work as smiles signaling either a benign situation or politeness, resulting in conflicting predictions for the association between smile type and psychological distance. The current study uses implicit association tests to reveal theoretically and empirically consistent non-Duchenne smile-distance and Duchenne-smile-proximity associations for all four types of psychological distance: temporal, spatial, social, and hypothetical. Practically, the results suggest several useful applications of non-Duchenne smiles in human communication contexts. PMID- 28848484 TI - When Saying Sorry May Not Help: The Impact of Apologies on Social Rejections. AB - If you have to socially reject someone, will it help to apologize? Social rejection is a painful emotional experience for targets, yet research has been silent on recommendations for rejectors. Across three sets of studies, apologies increased hurt feelings and the need to express forgiveness but did not increase feelings of forgiveness. The investigation of hurt feelings arising from a social rejection is challenging because previous research has shown that participants are reluctant to admit they felt hurt by the rejection. The present research addressed the self-report issue in two ways. First, participants rated how much social rejections would hurt someone's feelings as a function of whether an apology was included across various social rejection scenarios (Studies 1a-e). Second, aggressive behavior was measured in response to face-to-face social rejections that were manipulated to include or exclude apologies (Studies 2a-c). More specifically, Studies 1a-e (N = 1096) found that although individuals sometimes use apologies in social rejections, social rejections with apologies are associated with higher levels of explicit hurt feelings. Studies 2a-c (N = 355) manipulated the presence of an apology in face-to-face social rejections and found that social rejections with apologies cause more aggressive behavior. As in previous research, participants are reluctant to admit to feeling hurt. Finally, Study 3 (N = 426) found that in response to social rejections with apologies, individuals feel more compelled to express forgiveness despite not actually feeling more forgiveness. Implications for the role of language in social rejections are discussed. PMID- 28848485 TI - Reconsidering the Imaging Evidence Used to Implicate Prediction Error as the Driving Force behind Learning. PMID- 28848486 TI - Commentary: Experience Sampling Methodology reveals similarities in the experience of passage of time in young and elderly adults. PMID- 28848487 TI - Cerebrospinal Fluid and Microdialysis Cytokines in Aneurysmal Subarachnoid Hemorrhage: A Scoping Systematic Review. AB - OBJECTIVE: To perform two scoping systematic reviews of the literature on cytokine measurement in cerebral microdialysis (CMD) and cerebrospinal fluid (CSF) in aneurysmal subarachnoid hemorrhage (SAH) patients, aiming to summarize the evidence relating cytokine levels to pathophysiology, disease progression, and outcome. METHODS: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. DATA SOURCES: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. STUDY SELECTION: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. DATA EXTRACTION: Patient demographic and study data were extracted to tables. RESULTS: There were 9 studies identified describing the analysis of cytokines via CMD in 246 aneurysmal SAH patients. Similarly, 20 studies were identified describing the analysis of CSF cytokines in 630 patients. The two scoping systematic reviews demonstrated the following: (1) limited literature available on CMD cytokine measurement in aneurysmal SAH with some preliminary data supporting feasibility of measurement and potential association between interleukin (IL)-6 and patient outcome. (2) Various CSF measured cytokines may be associated with patient outcome at 3-6 months, including IL-1ra, IL-6, IL-8, and tumor necrosis factor-alpha. (3) There is a small literature body supporting an association between acute/subacute CSF transforming growth factor levels and the development of chronic hydrocephalus at 2-3 months. CONCLUSION: The evaluation of CMD and CSF cytokines is an emerging area of the literature in aneurysmal SAH. Further large prospective multicenter studies on cytokines in CMD and CSF need to be conducted. PMID- 28848489 TI - Quantitative Assessment of the Arm/Hand Movements in Parkinson's Disease Using a Wireless Armband Device. AB - We present an approach for quantitative assessment of the arm/hand movements in patients with Parkinson's disease (PD), from sensor data acquired with a wearable, wireless armband device (Myo sensor). We propose new Movement Performance Indicators that can be adopted by practitioners for the quantitative evaluation of motor performance and support their clinical evaluations. In addition, specific Movement Performance Indicators can indicate the presence of the bradykinesia symptom. The study includes seventeen PD patients and sixteen age-matched controls. A set of representative arm/hand movements is defined under the supervision of movement disorder specialist. In order to assist the evaluations, and for progress monitoring purposes, as well as for assessing the amount of bradykinesia in PD, a total set of 84 Movement Performance Indicators are computed from the sensor readings. Subsequently, we investigate whether wireless armband device, with the use of the proposed Movement Performance Indicators can be utilized: (1) for objective and precise quantitative evaluation of the arm/hand movements of Parkinson's patients, (2) for assessment of the bradykinesia motor symptom, and (3) as an adequate low-cost alternative for the sensor glove. We conducted extensive analysis of proposed Movement Performance Indicators and results are indicating following clinically relevant characteristics: (i) adequate reliability as measured by ICC; (ii) high accuracy in discrimination between the patients and controls, and between the disease stages (support to disease diagnosis and progress monitoring, respectively); (iii) substantial difference in comparison between the left-hand and the right hand movements across controls and patients, as well as between disease stage groups; (iv) statistically significant correlation with clinical scales (tapping test and UPDRS-III Motor Score); and (v) quantitative evaluation of bradykinesia symptom. Results suggest that the proposed approach has a potential to be adopted by physicians, to afford them with quantitative, objective and precise methods and data during clinical evaluations and support the assessment of bradykinesia. PMID- 28848488 TI - Cognitive Improvement and Brain Changes after Real-Time Functional MRI Neurofeedback Training in Healthy Elderly and Prodromal Alzheimer's Disease. AB - BACKGROUND: Cognitive decline is characteristic for Alzheimer's disease (AD) and also for healthy ageing. As a proof-of-concept study, we examined whether this decline can be counteracted using real-time fMRI neurofeedback training. Visuospatial memory and the parahippocampal gyrus (PHG) were targeted. METHODS: Sixteen healthy elderly subjects (mean age 63.5 years, SD = 6.663) and 10 patients with prodromal AD (mean age 66.2 years, SD = 8.930) completed the experiment. Four additional healthy subjects formed a sham-feedback condition to validate the paradigm. The protocol spanned five examination days (T1-T5). T1 contained a neuropsychological pre-test, the encoding of a real-world footpath, and an anatomical MRI scan of the brain. T2-T4 included the fMRI neurofeedback training paradigm, in which subjects learned to enhance activation of the left PHG while recalling the path encoded on T1. At T5, the neuropsychological post test and another anatomical MRI brain scan were performed. The neuropsychological battery included the Montreal Cognitive Assessment (MoCA); the Visual and Verbal Memory Test (VVM); subtests of the Wechsler Memory Scale (WMS); the Visual Patterns Test; and Trail Making Tests (TMT) A and B. RESULTS: Healthy elderly and patients with prodromal AD showed improved visuospatial memory performance after neurofeedback training. Healthy subjects also performed better in a working memory task (WMS backward digit-span) and in the MoCA. Both groups were able to elicit parahippocampal activation during training, but no significant changes in brain activation were found over the course of the training. However, Granger causality-analysis revealed changes in cerebral connectivity over the course of the training, involving the parahippocampus and identifying the precuneus as main driver of activation in both groups. Voxel-based morphometry showed increases in grey matter volumes in the precuneus and frontal cortex. Neither cognitive enhancements, nor parahippocampal activation were found in the control group undergoing sham-feedback. CONCLUSION: These findings suggest that cognitive decline, either related to prodromal AD or healthy ageing, could be counteracted using fMRI-based neurofeedback. Future research needs to determine the potential of this method as a treatment tool. PMID- 28848490 TI - Relationship between Sleep Duration and Risk Factors for Stroke. AB - Stroke is a leading cause of death and disability worldwide. While various risk factors have been identified, sleep has only been considered a risk factor more recently. Various epidemiologic studies have associated stroke with sleep such as sleep duration, and laboratory and clinical studies have proposed various underlying mechanisms. The pathophysiology is multifactorial, especially considering sleep affects many common risk factors for stroke. This review aims to provide an outline of the effect of sleep duration on common stroke risk factors. Appropriate sleep duration, especially in patients who have stroke risk factors, and increasing awareness and screening for sleep quality may contribute to primary prevention of stroke. PMID- 28848492 TI - Moving Beyond the Brain: Transcutaneous Spinal Direct Current Stimulation in Post Stroke Aphasia. AB - Over the last 20 years, major advances in cognitive neuroscience have clearly shown that the language function is not restricted into the classical language areas but it involves brain regions, which had never previously considered. Indeed, recent lines of evidence have suggested that the processing of words associated to motor schemata, such as action verbs, modulates the activity of the sensorimotor cortex, which, in turn, facilitates its retrieval. To date, no studies have investigated whether the spinal cord, which is functionally connected to the sensorimotor system, might also work as an auxiliary support for language processing. We explored the combined effect of transcutaneous spinal direct current stimulation (tsDCS) and language treatment in a randomized double blind design for the recovery of verbs and nouns in 14 chronic aphasics. During each treatment, each subject received tsDCS (20 min, 2 mA) over the thoracic vertebrae (10th vertebra) in three different conditions: (1) anodic, (2) cathodic and (3) sham, while performing a verb and noun naming tasks. Each experimental condition was run in five consecutive daily sessions over 3 weeks. Overall, a significant greater improvement in verb naming was found during the anodic condition with respect to the other two conditions, which persisted at 1 week after the end of the treatment. No significant differences were present for noun naming among the three conditions. The hypothesis is advanced that anodic tsDCS might have influenced activity along the ascending somatosensory pathways, ultimately eliciting neurophysiological changes into the sensorimotor areas which, in turn, supported the retrieval of verbs. These results further support the evidence that action words, due to their sensorimotor semantic properties, are partly represented into the sensorimotor cortex. Moreover, they also document, for the first time, that tsDCS enhances verb recovery in chronic aphasia and it may represent a promising new tool for language treatment. PMID- 28848493 TI - Progressive Encephalomyelitis with Rigidity and Myoclonus Associated With Anti GlyR Antibodies and Hodgkin's Lymphoma: A Case Report. AB - INTRODUCTION: A 60-year-old man presented with a 6-month history of low back pain and progressive rigidity of the trunk and lower limbs, followed by pruritus, dysphonia, hyperhydrosis, and urinary retention. Brain and spinal imaging were normal. EMG showed involuntary motor unit hyperactivity. Onconeural, antiglutamic acid decarboxylase (anti-GAD), voltage-gated potassium channel, and dipeptidyl peptidase-like protein 6 (DPPX) autoantibodies were negative. CSF was negative. Symptoms were partially responsive to baclofen, gabapentin, and clonazepam, but he eventually developed severe dysphagia. Antiglycine receptor (anti-GlyR) antibodies turned out positive on both serum and CSF. A plasmapheresis cycle was completed with good clinical response. A PET scan highlighted an isolated metabolically active axillary lymphnode that turned out to be a classic type Hodgkin lymphoma (HL), in the absence of bone marrow infiltration nor B symptoms. Polychemotherapy with ABVD protocol was completed with good clinical response and at 1-year follow-up the neurological examination is normal. BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and severe neurological syndrome characterized by muscular rigidity and spasms as well as brain stem and autonomic dysfunction. It can be associated with anti-GAD, GlyR, and DPPX antibodies. All of these autoantibodies may be variably associated with malignant tumors and their response to immunotherapy, as well as to tumor removal, is not easily predictable. CONCLUSION: Progressive encephalomyelitis with rigidity and myoclonus has already been described in association with HL, but this is the first case report of a HL manifesting as anti-GlyR antibodies related PERM. Our report highlights the importance of malignancy screening in autoimmune syndromes of suspected paraneoplastic origin. PMID- 28848494 TI - Optimizing Cardiac Out-Put to Increase Cerebral Penumbral Perfusion in Large Middle Cerebral Artery Ischemic Lesion-OPTIMAL Study. AB - INTRODUCTION: In unsuccessful vessel recanalization, clinical outcome of acute stroke patients depends on early improvement of penumbral perfusion. So far, mean arterial blood pressure (MAP) is the target hemodynamic parameter. However, the correlations of MAP to cardiac output (CO) and cerebral perfusion are volume state dependent. In severe subarachnoid hemorrhage, optimizing CO leads to a reduction of delayed ischemic neurological deficits and improvement of clinical outcome. This study aims to investigate the effect of standard versus advanced cardiac monitoring with optimization of CO on the clinical outcome in patients with large ischemic stroke. METHODS AND ANALYSIS: The OPTIMAL study is a prospective, multicenter, open, into two arms (1:1) randomized, controlled trial. Sample size estimate: sample sizes of 150 for each treatment group (300 in total) ensure an 80% power to detect a difference of 16% of a dichotomized level of functional clinical outcome at 3 months at a significance level of 0.05. Study outcomes: the primary endpoint is the functional outcome at 3 months. The secondary endpoints include functional outcome at 6 months follow-up, and complications related to hemodynamic monitoring and therapies. DISCUSSION: The results of this trial will provide data on the safety and efficacy of advanced hemodynamic monitoring on clinical outcome. ETHICS AND DISSEMINATION: The trial was approved by the leading ethics committee of Freiburg University, Germany (438/14, 2015) and the local ethics committees of the participating centers. The study is performed in accordance with the Declaration of Helsinki and the guidelines of Good Clinical Practice. It is registered in the German Clinical Trial register (DRKS; DRKS00007805). Dissemination will include submission to peer-reviewed professional journals and presentation at congresses. Hemodynamic monitoring may be altered in a specific stroke patient cohort if the study shows that advanced monitoring is safe and improves the functional outcome. PMID- 28848491 TI - Diet and Sleep Physiology: Public Health and Clinical Implications. AB - This mini-review examines the complex relationship between diet and sleep and explores the clinical and public health implications of the current evidence. Dietary quality and intake of specific nutrients can impact regulatory hormonal pathways to alter sleep quantity and quality. Sleep, in turn, affects the intake of total energy, as well as of specific foods and nutrients, through biological and behavioral mechanisms. Initial research in this field focused primarily on the effects of short sleep duration on nutritional quality. However, more recent studies have explored the dynamic relationship between long sleep duration and diet. Current evidence suggests that extremes of sleep duration alter sleep patterns, hormonal levels, and circadian rhythms, which contribute to weight related outcomes and obesity, and other risk factors for the development of chronic disease such as type 2 diabetes and cardiovascular disease. These patterns may begin as early as childhood and have impacts throughout the life course. Given that non-communicable diseases are among the leading causes of death globally, deeper understanding of the interactions between sleep and nutrition has implications for both public health and clinical practice. PMID- 28848495 TI - The Impact of Carotid Artery Stenting on Cerebral Perfusion, Functional Connectivity, and Cognition in Severe Asymptomatic Carotid Stenosis Patients. AB - BACKGROUND AND PURPOSE: Asymptomatic carotid artery stenosis can lead to not only stroke but also cognition impairment. Although it has been proven that carotid artery stenting (CAS) can reduce the risk of future strokes, the effect of CAS on cognition is conflicting. In recent years, pulsed arterial spin labeling (pASL) MRI and resting-state functional MRI (R-fMRI) have been employed in cognitive impairment studies. For the present study, cognition is evaluated in severe asymptomatic carotid artery stenosis patients undergoing CAS, and the mechanisms underlying the cognitive change are explored by pASL MRI and R-fMRI. MATERIALS AND METHODS: We prospectively enrolled 24 asymptomatic, severe (>=70%), unilateral internal carotid artery stenosis patients, who were expecting the intervention of CAS. Cognition assessment (including the Montreal Cognitive Assessment Beijing Version, the Minimum Mental State Examination, the Digit Symbol Test, the Rey Auditory Verbal Learning Test, and the Verbal Memory Test) and an integrated MRI program (pASL MRI, and R-fMRI) were administered 7 days before and 3 months after CAS. RESULTS: 16 subjects completed the follow-up study. After stenting, significant improvement in the scores of the MMSE, the Verbal Memory test, and the delayed recall was found. No significant difference was found in the scores of the Montreal Cognitive Assessment Beijing Version, the Digit Symbol Test, and the immediate recall. After CAS treatment, asymptomatic carotid artery stenosis patients showed increased perfusion in the left frontal gyrus, increased amplitude of low-frequency fluctuation (ALFF) in the right precentral gyrus, and increased connectivity to the posterior cingulate cortex (PCC) in the right supra frontal gyrus. However, no significant correlations were found between these imaging changes and cognition assessments. CONCLUSION: Successful CAS can partly improve cognition in asymptomatic carotid artery stenosis patients. The cognition improvement may be partly attributed to the increased perfusion in the left frontal gyrus, increased ALFF in the right precentral gyrus, and increased connectivity to the PCC in the right supra frontal gyrus. PMID- 28848496 TI - Parent-Reported Behavioral and Psychiatric Problems Mediate the Relationship between Sleep-Disordered Breathing and Cognitive Deficits in School-Aged Children. AB - BACKGROUND: Numerous studies over the past several decades have illustrated that children who suffer from sleep-disordered breathing (SDB) are at greater risk for cognitive, behavioral, and psychiatric problems. Although behavioral problems have been proposed as a potential mediator between SDB and cognitive functioning, these relationships have not been critically examined. METHODS: This analysis is based on a community-based cohort of 1,115 children who underwent overnight polysomnography, and cognitive and behavioral phenotyping. Structural model of the relationships between SDB, behavior, and cognition, and two recently developed mediation approaches based on propensity score weighting and resampling were used to assess the mediational role of parent-reported behavior and psychiatric problems in the relationship between SDB and cognitive functioning. Multiple models utilizing two different SDB definitions further explored direct effects of SDB on cognition as well as indirect effects through behavioral pathology. All models were adjusted for age, sex, race, BMI z-score, and asthma status. RESULTS: Indirect effects of SDB through behavior problems were significant in all mediation models, while direct effects of SDB on cognition were not. The findings were consistent across different mediation procedures and remained essentially unaltered when different criteria for SDB, behavior, and cognition were used. CONCLUSION: Potential effects of SDB on cognitive functioning appear to occur through behavioral problems that are detectable in this pediatric population. Thus, early attentional or behavioral pathology may be implicated in the cognitive functioning deficits associated with SDB, and may present an early morbidity-related susceptibility biomarker. PMID- 28848497 TI - Sarcoidosis and Thyroid Autoimmunity. AB - Most of the studies have shown a higher risk for subclinical and clinical hypothyroidism, antithyroid autoantibodies [overall antithyroid peroxidase antibodies (TPOAb)], and in general, thyroid autoimmunity, overall in the female gender in patients with sarcoidosis (S). A significantly higher prevalence of clinical hypothyroidism and Graves' disease was also described in female S patients with respect to controls. Gallium-67 (Ga-67) scyntigraphy in S patients, in the case of thyroid uptake, suggests the presence of aggressive autoimmune thyroiditis and hypothyroidism. For this reason, ultrasonography and thyroid function should be done in the case of Ga-67 thyroid uptake. In conclusion, thyroid function, TPOAb measurement, and ultrasonography should be done to assess the clinical profile in female S patients, and the ones at high risk (female individuals, with TPOAb positivity, and hypoechoic and small thyroid) should have periodically thyroid function evaluations and suitable treatments. PMID- 28848498 TI - The Emerging Roles of Extracellular Vesicles As Communication Vehicles within the Tumor Microenvironment and Beyond. AB - Tumors evolve in complex and dynamic microenvironments that they rely on for sustained growth, invasion, and metastasis. Within this space, tumor cells and non-malignant cells are in frequent communication. One specific mode of communication that has gained recent attention is the release of extracellular vesicles (EVs). EVs are lipid bilayer-bound vehicles that are released from the cell membrane and carry nucleic acids, proteins, and lipids to neighboring or distant cells. EVs have been demonstrated to influence a multitude of processes that aid in tumor progression including cellular proliferation, angiogenesis, migration, invasion, metastasis, immunoediting, and drug resistance. The ubiquitous involvement of EVs on cancer progression makes them very suitable targets for novel therapeutics. Furthermore, they are being studied as specific markers for cancer diagnostics, prognosis, and even as chemotherapy drug-delivery systems. This review focuses on the most recent advances in EV knowledge, some current and potential problems with their use, and some proposed solutions to consider for the future. PMID- 28848499 TI - Quantification by qPCR of Pathobionts in Chronic Periodontitis: Development of Predictive Models of Disease Severity at Site-Specific Level. AB - Currently, there is little evidence available on the development of predictive models for the diagnosis or prognosis of chronic periodontitis based on the qPCR quantification of subgingival pathobionts. Our objectives were to: (1) analyze and internally validate pathobiont-based models that could be used to distinguish different periodontal conditions at site-specific level within the same patient with chronic periodontitis; (2) develop nomograms derived from predictive models. Subgingival plaque samples were obtained from control and periodontal sites (probing pocket depth and clinical attachment loss <4 mm and >4 mm, respectively) from 40 patients with moderate-severe generalized chronic periodontitis. The samples were analyzed by qPCR using TaqMan probes and specific primers to determine the concentrations of Actinobacillus actinomycetemcomitans (Aa), Fusobacterium nucleatum (Fn), Parvimonas micra (Pm), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Tannerella forsythia (Tf), and Treponema denticola (Td). The pathobiont-based models were obtained using multivariate binary logistic regression. The best models were selected according to specified criteria. The discrimination was assessed using receiver operating characteristic curves and numerous classification measures were thus obtained. The nomograms were built based on the best predictive models. Eight bacterial cluster-based models showed an area under the curve (AUC) >=0.760 and a sensitivity and specificity >=75.0%. The PiTfFn cluster showed an AUC of 0.773 (sensitivity and specificity = 75.0%). When Pm and AaPm were incorporated in the TdPiTfFn cluster, we detected the two best predictive models with an AUC of 0.788 and 0.789, respectively (sensitivity and specificity = 77.5%). The TdPiTfAa cluster had an AUC of 0.785 (sensitivity and specificity = 75.0%). When Pm was incorporated in this cluster, a new predictive model appeared with better AUC and specificity values (0.787 and 80.0%, respectively). Distinct clusters formed by species with different etiopathogenic role (belonging to different Socransky's complexes) had a good predictive accuracy for distinguishing a site with periodontal destruction in a periodontal patient. The predictive clusters with the lowest number of bacteria were PiTfFn and TdPiTfAa, while TdPiTfAaFnPm had the highest number. In all the developed nomograms, high concentrations of these clusters were associated with an increased probability of having a periodontal site in a patient with chronic periodontitis. PMID- 28848500 TI - Alternaria Toxins: Potential Virulence Factors and Genes Related to Pathogenesis. AB - Alternaria is an important fungus to study due to their different life style from saprophytes to endophytes and a very successful fungal pathogen that causes diseases to a number of economically important crops. Alternaria species have been well-characterized for the production of different host-specific toxins (HSTs) and non-host specific toxins (nHSTs) which depend upon their physiological and morphological stages. The pathogenicity of Alternaria species depends on host susceptibility or resistance as well as quantitative production of HSTs and nHSTs. These toxins are chemically low molecular weight secondary metabolites (SMs). The effects of toxins are mainly on different parts of cells like mitochondria, chloroplast, plasma membrane, Golgi complex, nucleus, etc. Alternaria species produce several nHSTs such as brefeldin A, tenuazonic acid, tentoxin, and zinniol. HSTs that act in very low concentrations affect only certain plant varieties or genotype and play a role in determining the host range of specificity of plant pathogens. The commonly known HSTs are AAL-, AK-, AM-, AF , ACR-, and ACT-toxins which are named by their host specificity and these toxins are classified into different family groups. The HSTs are differentiated on the basis of bio-statistical and other molecular analyses. All these toxins have different mode of action, biochemical reactions and signaling mechanisms to cause diseases. Different species of Alternaria produced toxins which reveal its biochemical and genetic effects on itself as well as on its host cells tissues. The genes responsible for the production of HSTs are found on the conditionally dispensable chromosomes (CDCs) which have been well characterized. Different bio statistical methods like basic local alignment search tool (BLAST) data analysis used for the annotation of gene prediction, pathogenicity-related genes may provide surprising knowledge in present and future. PMID- 28848502 TI - In silico Analyses of Subtype Specific HIV-1 Tat-TAR RNA Interaction Reveals the Structural Determinants for Viral Activity. AB - HIV-1 Tat transactivates viral genes through strong interaction with TAR RNA. The stem-loop bulged region of TAR consisting of three nucleotides at the position 23 25 and the loop region consisting of six nucleotides at the position 30-35 are essential for viral transactivation. The arginine motif of Tat (five arginine residues on subtype TatC) is critically important for TAR interaction. Any mutations in this motif could lead to reduce transactivation ability and pathogenesis. Here, we identified structurally important residues (arginine and lysine residues) of Tat in this motif could bind to TAR via hydrogen bond interactions which is critical for transactivation. Natural mutant Ser46Phe in the core motif could likely led to conformational change resulting in more hydrogen bond interactions than the wild type Tat making it highly potent transactivator. Importantly, we report the possible probabilities of number of hydrogen bond interactions in the wild type Tat and the mutants with TAR complexes. This study revealed the differential transactivation of subtype B and C Tat could likely be due to the varying number of hydrogen bonds with TAR. Our data support that the N-terminal and the C-terminal domains of Tat is involved in the TAR interactions through hydrogen bonds which is important for transactivation. This study highlights the evolving pattern of structurally important determinants of Tat in the arginine motif for viral transactivation. PMID- 28848501 TI - Fungal Unspecific Peroxygenases Oxidize the Majority of Organic EPA Priority Pollutants. AB - Unspecific peroxygenases (UPOs) are secreted fungal enzymes with promiscuity for oxygen transfer and oxidation reactions. Functionally, they represent hybrids of P450 monooxygenases and heme peroxidases; phylogenetically they belong to the family of heme-thiolate peroxidases. Two UPOs from the basidiomycetous fungi Agrocybe aegerita (AaeUPO) and Marasmius rotula (MroUPO) converted 35 out of 40 compounds listed as EPA priority pollutants, including chlorinated benzenes and their derivatives, halogenated biphenyl ethers, nitroaromatic compounds, polycyclic aromatic hydrocarbons (PAHs) and phthalic acid derivatives. These oxygenations and oxidations resulted in diverse products and-if at all-were limited for three reasons: (i) steric hindrance caused by multiple substitutions or bulkiness of the compound as such (e.g., hexachlorobenzene or large PAHs), (ii) strong inactivation of aromatic rings (e.g., nitrobenzene), and (iii) low water solubility (e.g., complex arenes). The general outcome of our study is that UPOs can be considered as extracellular counterparts of intracellular monooxygenases, both with respect to catalyzed reactions and catalytic versatility. Therefore, they should be taken into consideration as a relevant biocatalytic detoxification and biodegradation tool used by fungi when confronted with toxins, xenobiotics and pollutants in their natural environments. PMID- 28848503 TI - Rab5 Enhances Classical Swine Fever Virus Proliferation and Interacts with Viral NS4B Protein to Facilitate Formation of NS4B Related Complex. AB - Classical swine fever virus (CSFV) is a fatal pig pestivirus and causes serious financial losses to the pig industry. CSFV NS4B protein is one of the most important viral replicase proteins. Rab5, a member of the small Rab GTPase family, is involved in infection and replication of numerous viruses including hepatitis C virus and dengue virus. Until now, the effects of Rab5 on the proliferation of CSFV are poorly defined. In the present study, we showed that Rab5 could enhance CSFV proliferation by utilizing lentivirus-mediated constitutive overexpression and eukaryotic plasmid transient overexpression approaches. On the other hand, lentivirus-mediated short hairpin RNA knockdown of Rab5 dramatically inhibited virus production. Co-immunoprecipitation, glutathione S-transferase pulldown and laser confocal microscopy assays further confirmed the interaction between Rab5 and CSFV NS4B protein. In addition, intracellular distribution of NS4B-Red presented many granular fluorescent signals (GFS) in CSFV infected PK-15 cells. Inhibition of basal Rab5 function with Rab5 dominant negative mutant Rab5S34N resulted in disruption of the GFS. These results indicate that Rab5 plays a critical role in facilitating the formation of the NS4B related complexes. Furthermore, it was observed that NS4B co-localized with viral NS3 and NS5A proteins in the cytoplasm, suggesting that NS3 and NS5A might be components of the NS4B related complex. Taken together, these results demonstrate that Rab5 positively modulates CSFV propagation and interacts with NS4B protein to facilitate the NS4B related complexes formation. PMID- 28848504 TI - Biology, Bionomics and Molecular Biology of Anopheles sinensis Wiedemann 1828 (Diptera: Culicidae), Main Malaria Vector in China. AB - China has set a goal to eliminate all malaria in the country by 2020, but it is unclear if current understanding of malaria vectors and transmission is sufficient to achieve this objective. Anopheles sinensis is the most widespread malaria vector specie in China, which is also responsible for vivax malaria outbreak in central China. We reviewed literature from 1954 to 2016 on An. sinensis with emphasis on biology, bionomics, and molecular biology. A total of 538 references were relevant and included. An. sienesis occurs in 29 Chinese provinces. Temperature can affect most life-history parameters. Most An. sinensis are zoophilic, but sometimes they are facultatively anthropophilic. Sporozoite analysis demonstrated An. sinensis efficacy on Plasmodium vivax transmission. An. sinensis was not stringently refractory to P. falciparum under experimental conditions, however, sporozoite was not found in salivary glands of field collected An. sinensis. The literature on An. sienesis biology and bionomics was abundant, but molecular studies, such as gene functions and mechanisms, were limited. Only 12 molecules (genes, proteins or enzymes) have been studied. In addition, there were considerable untapped omics resources for potential vector control tools. Existing information on An. sienesis could serve as a baseline for advanced research on biology, bionomics and genetics relevant to vector control strategies. PMID- 28848505 TI - A Putative Type II Secretion System Is Involved in Cellulose Utilization in Cytophaga hutchisonii. AB - Cytophaga hutchinsonii is a gliding cellulolytic bacterium that degrades cellulose in a substrate contact-dependent manner. Specific proteins are speculated to be translocated to its extracellular milieu or outer membrane surface to participate in adhesion to cellulose and further digestion. In this study, we show that three orthologous genes encoding the major components (T2S-D, -F, and -G) of type II secretion system (T2SS) are involved in cellulose degradation but not in cell motility. The individual disruption of the three t2s genes results in a significantly retarded growth on cellobiose, regenerated amorphous cellulose, and Avicel cellulose. Enzymatic analyses demonstrate that, whereas the endoglucanase activity of the t2s mutant cells is increased, the beta glucosidase activity is remarkably reduced compared to that of WT cells. Further analyses reveal that the t2s mutant cells not only exhibit a different profile of cellulose-bound outer membrane proteins from that of wild-type cells, but also display a significant decrease in their capability to adhere to cellulose. These results indicate that a functional link exits between the putative T2SS and cellulose utilization in C. hutchinsonii, and thus provide a conceptual framework to understand the unique strategy deployed by C. hutchinsonii to assimilate cellulose. PMID- 28848506 TI - Complete Mitochondrial Genome of Phytophthora nicotianae and Identification of Molecular Markers for the Oomycetes. AB - Phytophthora nicotianae is one of the most destructive plant pathogens affecting a variety of plants, causing black shank of tobacco, among several other devastating diseases. Herein, we assembled the mitochondrial genome of P. nicotianae and analyzed its gene content and genome structure, performed comparative mitochondrial genomics analysis, and assessed phylogenetic relationships among oomycetes species. The circular mitogenome is 37,561 bp long, with 38 protein-coding genes, 25 transfer RNA (tRNA) genes, and 2 ribosomal RNA genes (rrnl and rrns). The mitochondrial genome showed a biased A/T usage versus G/C. The overall gene content and size of the P. nicotianae mitogenome are identical to those of other published Phytophthora mitogenomes. Interestingly, collinearity analysis using an existing ~10 k inversion region (including 11 genes and 8 tRNAs) revealed that Phytophthora andina, Phytophthora infestans, Phytophthora mirabilis, Phytophthora ipomoeae, and Phytophthora phaseoli differed from Phytophthora nicotianae, Phytophthora sojae, Phytophthora ramorum, and Phytophthora polonica. Moreover, inverted repeat regions were found to be absent among species of the Peronosporales when compared with species from the Pythiales and Saprolegniales. A phylogenomic investigation based on 29 protein-coding genes demonstrated that Phytophthora is monophyletic, and placed P. nicotianae close to the clade including P. mirabilis, P. ipomoeae, P. andina, P. infestans, and P. phaseoli. Furthermore, we discovered six new candidate DNA molecular markers (rpl6, atp8, nad11, rps2, rps3, and rps4) based on these mitogenomes that would be suitable for species identification in the oomycetes, which have the same identification level as the whole mitogenome and ribosomal DNA sequences. These new molecular markers can not only provide a quick preview of the species without mitogenome information, but will also help to gain better understanding of the oomycetes pathogens and developing treatment or monitoring strategies. PMID- 28848507 TI - Biological Soil Crusts of Arctic Svalbard-Water Availability as Potential Controlling Factor for Microalgal Biodiversity. AB - In the present study the biodiversity of biological soil crusts (BSCs) formed by phototrophic organisms were investigated on Arctic Svalbard (Norway). These communities exert several important ecological functions and constitute a significant part of vegetation at high latitudes. Non-diatom eukaryotic microalgal species of BSCs from 20 sampling stations around Ny-Alesund and Longyearbyen were identified by morphology using light microscopy, and the results revealed a high species richness with 102 species in total. 67 taxa belonged to Chlorophyta (31 Chlorophyceae and 36 Trebouxiophyceae), 13 species were Streptophyta (11 Klebsormidiophyceae and two Zygnematophyceae) and 22 species were Ochrophyta (two Eustigmatophyceae and 20 Xanthophyceae). Surprisingly, Klebsormidium strains belonging to clade G (Streptophyta), which were so far described from Southern Africa, could be determined at 5 sampling stations. Furthermore, comparative analyses of Arctic and Antarctic BSCs were undertaken to outline differences in species composition. In addition, a pedological analysis of BSC samples included C, N, S, TP (total phosphorus), and pH measurements to investigate the influence of soil properties on species composition. No significant correlation with these chemical soil parameters was confirmed but the results indicated that pH might affect the BSCs. In addition, a statistically significant influence of precipitation on species composition was determined. Consequently, water availability was identified as one key driver for BSC biodiversity in Arctic regions. PMID- 28848508 TI - Conservation of Species- and Trait-Based Modeling Network Interactions in Extremely Acidic Microbial Community Assembly. AB - Understanding microbial interactions is essential to decipher the mechanisms of community assembly and their effects on ecosystem functioning, however, the conservation of species- and trait-based network interactions along environmental gradient remains largely unknown. Here, by using the network-based analyses with three paralleled data sets derived from 16S rRNA gene pyrosequencing, functional microarray, and predicted metagenome, we test our hypothesis that the network interactions of traits are more conserved than those of taxonomic measures, with significantly lower variation of network characteristics along the environmental gradient in acid mine drainage. The results showed that although the overall network characteristics remained similar, the structural variation was significantly lower at trait levels. The higher conserved individual node topological properties at trait level rather than at species level indicated that the responses of diverse traits remained relatively consistent even though different species played key roles under different environmental conditions. Additionally, the randomization tests revealed that it could not reject the null hypothesis that species-based correlations were random, while the tests suggested that correlation patterns of traits were non-random. Furthermore, relationships between trait-based network characteristics and environmental properties implied that trait-based networks might be more useful in reflecting the variation of ecosystem function. Taken together, our results suggest that deterministic trait based community assembly results in greater conservation of network interaction, which may ensure ecosystem function across environmental regimes, emphasizing the potential importance of measuring the complexity and conservation of network interaction in evaluating the ecosystem stability and functioning. PMID- 28848509 TI - Complete Genome Sequencing and Targeted Mutagenesis Reveal Virulence Contributions of Tal2 and Tal4b of Xanthomonas translucens pv. undulosa ICMP11055 in Bacterial Leaf Streak of Wheat. AB - Bacterial leaf streak caused by Xanthomonas translucens pv. undulosa (Xtu) is an important disease of wheat (Triticum aestivum) and barley (Hordeum vulgare) worldwide. Transcription activator-like effectors (TALEs) play determinative roles in many of the plant diseases caused by the different species and pathovars of Xanthomonas, but their role in this disease has not been characterized. ICMP11055 is a highly virulent Xtu strain from Iran. The aim of this study was to better understand genetic diversity of Xtu and to assess the role of TALEs in bacterial leaf streak of wheat by comparing the genome of this strain to the recently completely sequenced genome of a U.S. Xtu strain, and to several other draft X. translucens genomes, and by carrying out mutational analyses of the TALE (tal) genes the Iranian strain might harbor. The ICMP11055 genome, including its repeat-rich tal genes, was completely sequenced using single molecule, real-time technology (Pacific Biosciences). It consists of a single circular chromosome of 4,561,583 bp, containing 3,953 genes. Whole genome alignment with the genome of the United States Xtu strain XT4699 showed two major re-arrangements, nine genomic regions unique to ICMP11055, and one region unique to XT4699. ICMP110055 harbors 26 non-TALE type III effector genes and seven tal genes, compared to 25 and eight for XT4699. The tal genes occur singly or in pairs across five scattered loci. Four are identical to tal genes in XT4699. In addition to common repeat-variable diresidues (RVDs), the tal genes of ICMP11055, like those of XT4699, encode several RVDs rarely observed in Xanthomonas, including KG, NF, Y*, YD, and YK. Insertion and deletion mutagenesis of ICMP11055 tal genes followed by genetic complementation analysis in wheat cv. Chinese Spring revealed that Tal2 and Tal4b of ICMP11055 each contribute individually to the extent of disease caused by this strain. A largely conserved ortholog of tal2 is present in XT4699, but for tal4b, only a gene with partial, fragmented RVD sequence similarity can be found. Our results lay the foundation for identification of important host genes activated by Xtu TALEs as targets for the development of disease resistant varieties. PMID- 28848510 TI - Crop Establishment Practices Are a Driver of the Plant Microbiota in Winter Oilseed Rape (Brassica napus). AB - Gaining a greater understanding of the plant microbiota and its interactions with its host plant heralds a new era of scientific discovery in agriculture. Different agricultural management practices influence soil microbial populations by changing a soil's physical, chemical and biological properties. However, the impact of these practices on the microbiota associated with economically important crops such as oilseed rape, are still understudied. In this work we investigated the impact of two contrasting crop establishment practices, conventional (plow based) and conservation (strip-tillage) systems, on the microbiota inhabiting different plant microhabitats, namely rhizosphere, root and shoot, of winter oilseed rape under Irish agronomic conditions. Illumina 16S rRNA gene sequence profiling showed that the plant associated microhabitats (root and shoot), are dominated by members of the bacterial phyla Proteobacteria, Actinobacteria and Bacteroidetes. The root and shoot associated bacterial communities displayed markedly distinct profiles as a result of tillage practices. We observed a very limited 'rhizosphere effect' in the root zone of WOSR, i.e., there was little or no increase in bacterial community richness and abundance in the WOSR rhizosphere compared to the bulk soil. The two tillage systems investigated did not appear to lead to any major long term differences on the bulk soil or rhizosphere bacterial communities. Our data suggests that the WOSR root and shoot microbiota can be impacted by management practices and is an important mechanism that could allow us to understand how plants respond to different management practices and environments. PMID- 28848511 TI - Bacillus As Potential Probiotics: Status, Concerns, and Future Perspectives. AB - Spore-forming bacilli are being explored for the production and preservation of food for many centuries. The inherent ability of production of large number of secretory proteins, enzymes, antimicrobial compounds, vitamins, and carotenoids specifies the importance of bacilli in food chain. Additionally, Bacillus spp. are gaining interest in human health related functional food research coupled with their enhanced tolerance and survivability under hostile environment of gastrointestinal tract. Besides, bacilli are more stable during processing and storage of food and pharmaceutical preparations, making them more suitable candidate for health promoting formulations. Further, Bacillus strains also possess biotherapeutic potential which is connected with their ability to interact with the internal milieu of the host by producing variety of antimicrobial peptides and small extracellular effector molecules. Nonetheless, with proposed scientific evidences, commercial probiotic supplements, and functional foods comprising of Bacillus spp. had not gained much credential in general population, since the debate over probiotic vs pathogen tag of Bacillus in the research and production terrains is confusing consumers. Hence, it's important to clearly understand the phenotypic and genotypic characteristics of selective beneficial Bacillus spp. and their substantiation with those having GRAS status, to reach a consensus over the same. This review highlights the probiotic candidature of spore forming Bacillus spp. and presents an overview of the proposed health benefits, including application in food and pharmaceutical industry. Moreover, the growing need to evaluate the safety of individual Bacillus strains as well as species on a case by case basis and necessity of more profound analysis for the selection and identification of Bacillus probiotic candidates are also taken into consideration. PMID- 28848512 TI - Use of MALDI-TOF Mass Spectrometry for the Fast Identification of Gram-Positive Fish Pathogens. AB - Gram-positive cocci, such as Streptococcus agalactiae, Lactococcus garvieae, Streptococcus iniae, and Streptococcus dysgalactiae subsp. dysgalactiae, are found throughout the world, particularly in outbreaks in farmed fish, and are thus associated with high economic losses, especially in the cultivation of Nile Tilapia. The aim of this study was to evaluate the efficacy of matrix-assisted laser desorption ionization (MALDI)-time of flight (TOF) mass spectrometry (MS) as an alternative for the diagnosis of these pathogens. One hundred and thirty one isolates from Brazilian outbreaks assisted by the national authority were identified using a MALDI Biotyper from Bruker Daltonics. The results showed an agreement with respect to identification (Kappa = 1) between this technique and 16S ribosomal RNA gene sequencing for S. agalactiae and L. garvieae. However, for S. iniae and S. dysgalactiae subsp. dysgalactiae, perfect agreement was only achieved after the creation of a custom main spectra profile, as well as further comparisons with 16S ribosomal RNA and multilocus sequence analysis. MALDI-TOF MS was shown to be an efficient technology for the identification of these Gram positive pathogens, yielding a quick and precise diagnosis. PMID- 28848513 TI - Cyanobacterial Allelochemicals But Not Cyanobacterial Cells Markedly Reduce Microbial Community Diversity. AB - The freshwater cyanobacterium Phormidium sp. LEGE 05292 produces allelochemicals, including the cyclic depsipeptides portoamides, that influence the growth of heterotrophic bacteria, cyanobacteria, and eukaryotic algae. Using 16S rRNA gene amplicon metagenomics, we show here that, under laboratory conditions, the mixture of metabolites exuded by Phormidium sp. LEGE 05292 markedly reduces the diversity of a natural planktonic microbial community. Exposure of the same community to the portoamides alone resulted in a similar outcome. In both cases, after 16 days, alpha-diversity estimates for the allelochemical-exposed communities were less than half of those for the control communities. Photosynthetic organisms, but also different heterotrophic-bacteria taxa were found to be negatively impacted by the allelochemicals. Intriguingly, when Phormidium sp. LEGE 05292 was co-cultured with the microbial community, the latter remained stable and closer to non-exposed than to allelochemical-exposed communities. Overall, our observations indicate that although under optimal growth conditions Phormidium sp. LEGE 05292 is able to synthesize potent allelochemicals that severely impact different microorganisms, its allelopathic effect is not pronounced when in contact with a complex microbial community. Therefore, under ecologically relevant conditions, the allelopathic behavior of this cyanobacterium may be regulated by nutrient availability or by interactions with the surrounding microbiota. PMID- 28848514 TI - Seasonal Succession and Spatial Patterns of Synechococcus Microdiversity in a Salt Marsh Estuary Revealed through 16S rRNA Gene Oligotyping. AB - Synechococcus are ubiquitous and cosmopolitan cyanobacteria that play important roles in global productivity and biogeochemical cycles. This study investigated the fine scale microdiversity, seasonal patterns, and spatial distributions of Synechococcus in estuarine waters of Little Sippewissett salt marsh (LSM) on Cape Cod, MA. The proportion of Synechococcus reads was higher in the summer than winter, and higher in coastal waters than within the estuary. Variations in the V4-V6 region of the bacterial 16S rRNA gene revealed 12 unique Synechococcus oligotypes. Two distinct communities emerged in early and late summer, each comprising a different set of statistically co-occurring Synechococcus oligotypes from different clades. The early summer community included clades I and IV, which correlated with lower temperature and higher dissolved oxygen levels. The late summer community included clades CB5, I, IV, and VI, which correlated with higher temperatures and higher salinity levels. Four rare oligotypes occurred in the late summer community, and their relative abundances more strongly correlated with high salinity than did other co-occurring oligotypes. The analysis revealed that multiple, closely related oligotypes comprised certain abundant clades (e.g., clade 1 in the early summer and clade CB5 in the late summer), but the correlations between these oligotypes varied from pair to pair, suggesting they had slightly different niches despite being closely related at the clade level. Lack of tidal water exchange between sampling stations gave rise to a unique oligotype not abundant at other locations in the estuary, suggesting physical isolation plays a role in generating additional microdiversity within the community. Together, these results contribute to our understanding of the environmental and ecological factors that influence patterns of Synechococcus microbial community composition over space and time in salt marsh estuarine waters. PMID- 28848515 TI - An Improved Method for Establishing Accurate Water Potential Levels at Different Temperatures in Growth Media. AB - NaCl, KCl, or PEG (polyethylene glycol)-amended potato dextrose broth (PDB), and potato dextrose agar (PDA) are essential for pure culture studies of water stress on fungi. Direct information on the actual water potential (WP) of this salt amended PDB and PDA is lacking. Much fungal research in the past calculated WP of these salt-amended growth media by adding the WP of their constituents taken from individual salt dilution studies. But the WP of any complex solution will be modified by the level of synergism between its solutes. This study presents evidence of change in NaCl concentration due to synergism for attaining the same level of WP in NaCl solution, and NaCl amended PDB and PDA. The relation between WP and temperature and WP and salt concentration is also modified depending on the number of solutes in a growth medium. The WP of PEG-amended PDB increases with rising temperature, while that of NaCl/KCl amended PDB and PDA decreases with the increase of temperature. These results can be useful for doing pure culture studies on the biology and modeling the growth of air, water, and soil borne fungi important in the food and agriculture industry and in terrestrial and aquatic ecosystems. PMID- 28848516 TI - Editorial: Molecular Tracing of Aquatic Viruses: Where Epidemiology Needs to Meet Genomics. PMID- 28848517 TI - Changes in the Total Fecal Bacterial Population in Individual Horses Maintained on a Restricted Diet Over 6 Weeks. AB - Twelve mature (aged 5-16 years) horses and ponies of mixed breed and type were fed restricted (1.25% BM Dry matter) quantities of one of two fiber based diets formulated to be iso-caloric. Diet 1 comprised of 0.8% body mass (BM) of chaff based complete feed plus 0.45% BM low energy grass hay (the same hay used for both diets). Diet 2 comprised 0.1% BM of a nutrient balancer plus 1.15% BM grass hay. Fecal samples were collected at week 10 and week 16. DNA was extracted and the V1-V2 regions of 16SrDNA were 454-pyrosequenced to investigate the bacterial microbiome of the horse. The two most abundant phyla found in both diets and sampling periods were the Firmicutes and Bacteroidetes. There was a clear reduction in Bacteroidetes with a concordant increase in Firmicutes over time. There was a limited degree of stability within the bacterial community of the hindgut of horses, with 65% of bacteria retained, over a 6 week period whilst on a uniform diet. The presence of a core community defined by being present in all samples (each animal/diet combination) included in the study and being present at 0.1% relative abundance (or greater) was identified. In total 65 operational taxonomic units (OTUs) were identified that fit the definition of core making up 21-28% of the total sequences recovered. As with total population the most abundant phyla were the Bacteroidetes followed by the Firmicutes, however there was no obvious shift in phyla due to period. Indeed, when the relative abundance of OTUs was examined across diets and periods there was no significant effect of diet or period alone or in combination on the relative abundance of the core OTUs. PMID- 28848518 TI - Redfield Ratios in Inland Waters: Higher Biological Control of C:N:P Ratios in Tropical Semi-arid High Water Residence Time Lakes. AB - The canonical Redfield C:N:P ratio for algal biomass is often not achieved in inland waters due to higher C and N content and more variability when compared to the oceans. This has been attributed to much lower residence times and higher contributions of the watershed to the total organic matter pool of continental ecosystems. In this study we examined the effect of water residence times in low latitude lakes (in a gradient from humid to a semi-arid region) on seston elemental ratios in different size fractions. We used lake water specific conductivity as a proxy for residence time in a region of Eastern Brazil where there is a strong precipitation gradient. The C:P ratios decreased in the seston and bacterial size-fractions and increased in the dissolved fraction with increasing water retention time, suggesting uptake of N and P from the dissolved pool. Bacterial abundance, production and respiration increased in response to increased residence time and intracellular nutrient availability in agreement with the growth rate hypothesis. Our results reinforce the role of microorganisms in shaping the chemical environment in aquatic systems particularly at long water residence times and highlights the importance of this factor in influencing ecological stoichiometry in all aquatic ecosystems. PMID- 28848519 TI - Seasonal Analysis of Microbial Communities in Precipitation in the Greater Tokyo Area, Japan. AB - The presence of microbes in the atmosphere and their transport over long distances across the Earth's surface was recently shown. Precipitation is likely a major path by which aerial microbes fall to the ground surface, affecting its microbial ecosystems and introducing pathogenic microbes. Understanding microbial communities in precipitation is of multidisciplinary interest from the perspectives of microbial ecology and public health; however, community-wide and seasonal analyses have not been conducted. Here, we carried out 16S rRNA amplicon sequencing of 30 precipitation samples that were aseptically collected over 1 year in the Greater Tokyo Area, Japan. The precipitation microbial communities were dominated by Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria and were overall consistent with those previously reported in atmospheric aerosols and cloud water. Seasonal variations in composition were observed; specifically, Proteobacteria abundance significantly decreased from summer to winter. Notably, estimated ordinary habitats of precipitation microbes were dominated by animal-associated, soil-related, and marine-related environments, and reasonably consistent with estimated air mass backward trajectories. To our knowledge, this is the first amplicon-sequencing study investigating precipitation microbial communities involving sampling over the duration of a year. PMID- 28848520 TI - Genome Sequencing Reveals the Potential of Achromobacter sp. HZ01 for Bioremediation. AB - Petroleum pollution is a severe environmental issue. Comprehensively revealing the genetic backgrounds of hydrocarbon-degrading microorganisms contributes to developing effective methods for bioremediation of crude oil-polluted environments. Marine bacterium Achromobacter sp. HZ01 is capable of degrading hydrocarbons and producing biosurfactants. In this study, the draft genome (5.5 Mbp) of strain HZ01 has been obtained by Illumina sequencing, containing 5,162 predicted genes. Genome annotation shows that "amino acid metabolism" is the most abundant metabolic pathway. Strain HZ01 is not capable of using some common carbohydrates as the sole carbon sources, which is due to that it contains few genes associated with carbohydrate transport and lacks some important enzymes related to glycometabolism. It contains abundant proteins directly related to petroleum hydrocarbon degradation. AlkB hydroxylase and its homologs were not identified. It harbors a complete enzyme system of terminal oxidation pathway for n-alkane degradation, which may be initiated by cytochrome P450. The enzymes involved in the catechol pathway are relatively complete for the degradation of aromatic compounds. This bacterium lacks several essential enzymes for methane oxidation, and Baeyer-Villiger monooxygenase involved in the subterminal oxidation pathway and cycloalkane degradation was not identified. These results suggest that strain HZ01 degrades n-alkanes via the terminal oxidation pathway, degrades aromatic compounds primarily via the catechol pathway and cannot perform methane oxidation or cycloalkane degradation. Additionally, strain HZ01 possesses abundant genes related to the metabolism of secondary metabolites, including some genes involved in biosurfactant (such as glycolipids and lipopeptides) synthesis. The genome analysis also reveals its genetic basis for nitrogen metabolism, antibiotic resistance, regulatory responses to environmental changes, cell motility, and material transport. The obtained genome data provide us with a better understanding of hydrocarbon-degrading bacteria, which may contribute to the future design of rational strategies for bioremediation of petroleum-polluted marine environments. PMID- 28848521 TI - Establishment and Application of a Universal Coronavirus Screening Method Using MALDI-TOF Mass Spectrometry. AB - There are four human coronaviruses (HCoVs), distributed worldwide, that are associated with a range of respiratory symptoms. The discovery of severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV shows that HCoVs pose a significant threat to human health. Our work aims to develop a sensitive method (mCoV-MS) which can not only identify known HCoVs accurately, but also have the ability to provide clues for the emerging HCoVs. The method was performed using a MassARRAY matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) system. We developed a 17-plex analysis to detect six HCoVs in Panel A and another 17-plex analysis to detect Alphacoronavirus and Betacoronavirus in Panel B. All tested primers and probes for the mCoV-MS method were effective, with no cross reactivity observed with other common respiratory viruses. To confirm the usefulness of the mCoV-MS method we screened 384 pharyngeal and/or anal swab samples collected from bats/rodents, and 131 nasal and throat swabs from human patients. The results showed good concordance with the results of metagenomic analysis or PCR-sequencing. The validation test showed mCoV-MS method can detect potentially pathogenic CoVs in Alphacoronavirus and Betacoronavirus and provide convincingly phylogenetic evidences about unknown CoVs. The mCoV-MS method is a sensitive assay that is relatively simple to carry out. We propose that this method be used to complement next generation sequencing technology for large scale screening studies. PMID- 28848522 TI - Whole Genome Sequencing of Danish Staphylococcus argenteus Reveals a Genetically Diverse Collection with Clear Separation from Staphylococcus aureus. AB - Staphylococcus argenteus (S. argenteus) is a newly identified Staphylococcus species that has been misidentified as Staphylococcus aureus (S. aureus) and is clinically relevant. We identified 25 S. argenteus genomes in our collection of whole genome sequenced S. aureus. These genomes were compared to publicly available genomes and a phylogeny revealed seven clusters corresponding to seven clonal complexes. The genome of S. argenteus was found to be different from the genome of S. aureus and a core genome analysis showed that ~33% of the total gene pool was shared between the two species, at 90% homology level. An assessment of mobile elements shows flow of SCCmec cassettes, plasmids, phages, and pathogenicity islands, between S. argenteus and S. aureus. This dataset emphasizes that S. argenteus and S. aureus are two separate species that share genetic material. PMID- 28848523 TI - Molecular Epidemiology of Rubella Virus Strains Detected Around the Time of the 2012-2013 Epidemic in Japan. AB - A nationwide rubella epidemic occurred from 2012 to 2013 in Japan, resulting in around 17,000 rubella cases and the birth of 45 infants with congenital rubella syndrome. The aim of this study was to genetically characterize the rubella viruses (RVs) circulating around the time of the epidemic in Japan. In total, 221 RV strains detected from 14 prefectures in Japan between 2010 and 2014 were sequenced in the 739 nucleotide-window region within the E1 gene. The virus strains were chronologically and geographically characterized into groups based on phylogenetic analysis. Among the 221 strains analyzed, 192 (87%), 26 (12%), and 3 (1%) strains were classified into genotypes 2B, 1E, and 1J, respectively. The majority (n = 184) of the genotype 2B strains belonged to lineage 2B-L1 and shared nucleotide homology with the strains detected in Southeast and East Asian countries. Phylogenetic analyses demonstrated that at least six distinct clusters of RV strains (clusters 1-6) induced outbreaks in Japan between 2010 and 2014. Among them, strains from clusters 3, 4, and 6 circulated almost simultaneously during 2012-2013. The cluster 3 strains circulated locally, whereas strains from cluster 4 spread nationwide. The findings suggest that RVs were introduced into Japan many times from neighboring countries. The 2012-2013 epidemic was a complex of outbreaks induced by at least three clusters of RV strains. PMID- 28848524 TI - Two Negative-Strand RNA Viruses Identified in Watermelon Represent a Novel Clade in the Order Bunyavirales. AB - Two novel negative-sense, single-stranded (ss) RNA viruses were identified in watermelon plants and named watermelon crinkle leaf-associated virus 1 and 2 (WCLaV-1 and -2), respectively. The multipartite genomes consist of three RNA molecules of ~6.8, 1.4, and 1.3 kb. The genomes and the deduced proteins of RNA1 and RNA3 show features resembling those of members in the genus Phlebovirus and Tenuivirus; however, the predicted proteins encoded by RNA2 are related to the movement protein (MP) in the genus Ophiovirus and Emaravirus. Furthermore, these two viruses define a novel clade in the family Phenuiviridae, order Bunyavirales, which is phylogenetically related to the viruses in the above four genera. Moreover, after mechanical inoculation with WCLaV-1 seedlings of the natural host watermelon plants develop crinkling similar to those observed in the field. These findings enhance our understanding of the evolution and the classification of ssRNA viruses. PMID- 28848525 TI - Oyster RNA-seq Data Support the Development of Malacoherpesviridae Genomics. AB - The family of double-stranded DNA (dsDNA) Malacoherpesviridae includes viruses able to infect marine mollusks and detrimental for worldwide aquaculture production. Due to fast-occurring mortality and a lack of permissive cell lines, the available data on the few known Malacoherpesviridae provide only partial support for the study of molecular virus features, life cycle, and evolutionary history. Following thorough data mining of bivalve and gastropod RNA-seq experiments, we used more than five million Malacoherpesviridae reads to improve the annotation of viral genomes and to characterize viral InDels, nucleotide stretches, and SNPs. Both genome and protein domain analyses confirmed the evolutionary diversification and gene uniqueness of known Malacoherpesviridae. However, the presence of Malacoherpesviridae-like sequences integrated within genomes of phylogenetically distant invertebrates indicates broad diffusion of these viruses and indicates the need for confirmatory investigations. The manifest co-occurrence of OsHV-1 genotype variants in single RNA-seq samples of Crassostrea gigas provide further support for the Malacoherpesviridae diversification. In addition to simple sequence motifs inter-punctuating viral ORFs, recombination-inducing sequences were found to be enriched in the OsHV-1 and AbHV1-AUS genomes. Finally, the highly correlated expression of most viral ORFs in multiple oyster samples is consistent with the burst of viral proteins during the lytic phase. PMID- 28848526 TI - Curcumin Quantum Dots Mediated Degradation of Bacterial Biofilms. AB - Bacterial biofilm has been reported to be associated with more than 80% of bacterial infections. Curcumin, a hydrophobic polyphenol compound, has anti quorum sensing activity apart from having antimicrobial action. However, its use is limited by its poor aqueous solubility and rapid degradation. In this study, we attempted to prepare quantum dots of the drug curcumin in order to achieve enhanced solubility and stability and investigated for its antimicrobial and antibiofilm activity. We utilized a newer two-step bottom up wet milling approach to prepare Curcumin Quantum Dots (CurQDs) using acetone as a primary solvent. Minimum inhibitory concentration against select Gram-positive and Gram-negative bacteria was performed. The antibiofilm assay was performed at first using 96 well tissue culture plate and subsequently validated by Confocal Laser Scanning Microscopy. Further, biofilm matrix protein was isolated using formaldehyde sludge and TCA/Acetone precipitation method. Protein extracted was incubated with varying concentration of CurQDs for 4 h and was subjected to SDS-PAGE. Molecular docking study was performed to observe interaction between curcumin and phenol soluble modulins as well as curli proteins. The biophysical evidences obtained from TEM, SEM, UV-VIS, fluorescence, Raman spectroscopy, and zeta potential analysis confirmed the formation of curcumin quantum dots with increased stability and solubility. The MICs of curcumin quantum dots, as observed against both select gram positive and negative bacterial isolates, was observed to be significantly lower than native curcumin particles. On TCP assay, Curcumin observed to be having antibiofilm as well as biofilm degrading activity. Results of SDS-PAGE and molecular docking have shown interaction between biofilm matrix proteins and curcumin. The results indicate that aqueous solubility and stability of Curcumin can be achieved by preparing its quantum dots. The study also demonstrates that by sizing down the particle size has not only enhanced its antimicrobial properties but it has also shown its antibiofilm activities. Further, study is needed to elucidate the exact nature of interaction between curcumin and biofilm matrix proteins. PMID- 28848528 TI - Biochemical Mechanisms and Microorganisms Involved in Anaerobic Testosterone Metabolism in Estuarine Sediments. AB - Current knowledge on the biochemical mechanisms underlying microbial steroid metabolism in anaerobic ecosystems is extremely limited. Sulfate, nitrate, and iron [Fe (III)] are common electron acceptors for anaerobes in estuarine sediments. Here, we investigated anaerobic testosterone metabolism in anaerobic sediments collected from the estuary of Tamsui River, Taiwan. The anaerobic sediment samples were spiked with testosterone (1 mM) and individual electron acceptors (10 mM), including nitrate, Fe3+, and sulfate. The analysis of androgen metabolites indicated that testosterone biodegradation under denitrifying conditions proceeds through the 2,3-seco pathway, whereas testosterone biodegradation under iron-reducing conditions may proceed through an unidentified alternative pathway. Metagenomic analysis and PCR-based functional assays suggested that Thauera spp. were the major testosterone degraders in estuarine sediment samples incubated with testosterone and nitrate. Thauera sp. strain GDN1, a testosterone-degrading betaproteobacterium, was isolated from the denitrifying sediment sample. This strain tolerates a broad range of salinity (0 30 ppt). Although testosterone biodegradation did not occur under sulfate reducing conditions, we observed the anaerobic biotransformation of testosterone to estrogens in some testosterone-spiked sediment samples. This is unprecedented since biotransformation of androgens to estrogens is known to occur only under oxic conditions. Our metagenomic analysis suggested that Clostridium spp. might play a role in this anaerobic biotransformation. These results expand our understanding of microbial metabolism of steroids under strictly anoxic conditions. PMID- 28848529 TI - Editorial: Industrial and Host Associated Stress Responses in Food Microbes. Implications for Food Technology and Food Safety. PMID- 28848527 TI - Bactericidal and Anti-biofilm Effects of Polyhexamethylene Biguanide in Models of Intracellular and Biofilm of Staphylococcus aureus Isolated from Bovine Mastitis. AB - Staphylococcus aureus infection is a common cause of mastitis, reducing milk yield, affecting animal welfare and causing huge economic losses within the dairy industry. In addition to the problem of acquired drug resistance, bacterial invasion into udder cells and the formation of surface biofilms are believed to reduce antibiotic efficacy, leading to treatment failure. Here, we investigated the antimicrobial activities of enrofloxacin, an antibiotic that is commonly used in mastitis therapy and polyhexamethylene biguanide (PHMB), an antimicrobial polymer. The antimicrobial activities were tested against intracellular S. aureus in infected Mac-T cells (host cells). Also, fluorescein-tagged PHMB was used to study PHMB uptake and localization with S. aureus within the infected Mac-T cells. Anti-biofilm activities were tested by treating S. aureus biofilms and measuring effects on biofilm mass in vitro. Enrofloxacin and PHMB at 15 mg/L killed between 42 to 92 and 99.9% of intracellular S. aureus, respectively. PHMB FITC entered and colocalized with the intracellular S. aureus, suggesting direct interaction of the drug with the bacteria inside the host cells. Enrofloxacin and PHMB at 15 mg/L reduced between 10 to 27% and 28 to 37% of biofilms' mass, respectively. The half-maximal inhibitory concentrations (IC50) obtained from a cytotoxicity assay were 345 +/- 91 and 21 +/- 2 mg/L for enrofloxacin and PHMB, respectively; therefore, both compounds were tolerated by the host cells at high concentrations. These findings suggest that both antimicrobials are effective against intracellular S. aureus and can disrupt biofilm structures, with PHMB being more potent against intracellular S. aureus, highlighting the potential application of PHMB in mastitis therapy. PMID- 28848530 TI - Protection Mechanism of Clostridium butyricum against Salmonella Enteritidis Infection in Broilers. AB - This study was designed to evaluate the protection mechanism of oral administration of Clostridium butyricum against Salmonella enteritidis (SE) colonization in broilers. In the current study, 180 one-day-old healthy Arbor Acres (AA) broilers were meanly grouped into three, with three replicates of 20 birds each. An negative control group was fed basal diet without SE challenge and a positive control (PC) group was fed the basal diet and challenged with SE [106 colony forming unit (CFU)/0.2 mL]. An experimental (EXP) group was fed the basal diet, orally administered with C. butyricum (106 CFU/mL) and challenged with SE (106 CFU/0.2 mL). The results showed that compared to the PC group, the SE loads in livers, spleens, and cecal contents of chickens in EXP group were significantly reduced (P < 0.05) except in spleens at the 2-day post-infection; the production of interferon-gamma, interleukin (IL)-1beta, IL-8, and tumor necrosis factor-alpha in the livers, spleens, and cecal tissues of chickens in EXP group were decreased to different extents. The results of quantitative real time polymerase chain reaction further revealed that the inflammation of chickens in EXP group was alleviated by C. butyricum via down-regulating TLR4, MyD88, and NF-kappaB-dependent pathways. Collectively, these findings indicated that oral administration of C. butyricum could be a suitable alternative for preventing SE infection in broilers. PMID- 28848531 TI - hsdS, Belonging to the Type I Restriction-Modification System, Contributes to the Streptococcus suis Serotype 2 Survival Ability in Phagocytes. AB - Streptococcus suis serotype 2 (SS2) is an important zoonotic agent in swine and humans. Anti-phagocytosis and survival in phagocytic cells and whole blood is essential for bacteria to be pathogenic. In this study, the host specificity determinant specificity subunit (coded by hsdS) of the Type I Restriction Modification system and two peptidoglycan-binding proteins (coded by lysM and lysM', respectively), which were simultaneously found to be subjected to transcript-level influence by hsdS, were identified to facilitate the anti phagocytosis of SS2 to a microglia cell line BV2. Furthermore, they significantly enhanced its survival in BV2, whole blood, and a peroxidation environment (H2O2) (p < 0.05), yet not in the acidic condition based on statistical analysis of the characteristic differences between gene mutants and wild-type SS2. In contrast, another specificity subunit, coded by hsdS', that belonged to the same Type I Restriction-Modification system, only significantly reduced the survival ability of SS2 in the acidic condition when in the form of a gene-deleted mutant (p < 0.05), but it did not significantly influence the survival ability in other conditions mentioned above or have enhanced anti-phagocytosis action when compared with wild-type SS2. In addition, the mutation of hsdS significantly enhanced the secretion of nitric oxide and TNF-alpha by BV2 with SS2 incubation (p < 0.05). The SS2 was tested, and it failed to stimulate BV2 to produce IFN gamma. These results demonstrated that hsdS contributed to bacterial anti phagocytosis and survival in adverse host environments through positively impacting the transcription of two peptidoglycan-binding protein genes, enhancing resistance to reactive oxygen species, and reducing the secretion of TNF-alpha and nitric oxide by phagocytes. These findings revealed new mechanisms of SS2 pathogenesis. PMID- 28848532 TI - Control of Virulence Gene Expression by the Master Regulator, CfaD, in the Prototypical Enterotoxigenic Escherichia coli Strain, H10407. AB - Enterotoxigenic Escherichia coli (ETEC) is the most common bacterial cause of diarrhea in children in developing countries, as well as in travelers to these countries. To cause disease, ETEC needs to produce a series of virulence proteins including enterotoxins, colonization factors and secretion pathways, which enable this pathogen to colonize the human small intestine and deliver enterotoxins to epithelial cells. Previously, a number of studies have demonstrated that CfaD, an AraC-like transcriptional regulator, plays a key role in virulence gene expression by ETEC. In this study, we carried out a transcriptomic analysis of ETEC strain, H10407, grown under different conditions, and determined the complete set of genes that are regulated by CfaD. In this way, we identified a number of new target genes, including rnr-1, rnr-2, etpBAC, agn43, flu, traM and ETEC_3214, whose expression is strongly activated by CfaD. Using promoter-lacZ reporters, primer extension and electrophoretic mobility shift assays, we characterized the CfaD-mediated activation of several selected target promoters. We also showed that the gut-associated environmental signal, sodium bicarbonate, stimulates CfaD-mediated upregulation of its virulence target operons. Finally, we screened a commercial small molecule library and identified a compound (CH-1) that specifically inhibited the regulatory function of CfaD, and by 2-D analoging, we identified a second inhibitor (CH-2) with greater potency. PMID- 28848533 TI - Genome Plasticity and Polymorphisms in Critical Genes Correlate with Increased Virulence of Dutch Outbreak-Related Coxiella burnetii Strains. AB - Coxiella burnetii is an obligate intracellular bacterium and the etiological agent of Q fever. During 2007-2010 the largest Q fever outbreak ever reported occurred in The Netherlands. It is anticipated that strains from this outbreak demonstrated an increased zoonotic potential as more than 40,000 individuals were assumed to be infected. The acquisition of novel genetic factors by these C. burnetii outbreak strains, such as virulence-related genes, has frequently been proposed and discussed, but is not proved yet. In the present study, the whole genome sequence of several Dutch strains (CbNL01 and CbNL12 genotypes), a few additionally selected strains from different geographical locations and publicly available genome sequences were used for a comparative bioinformatics approach. The study focuses on the identification of specific genetic differences in the outbreak related CbNL01 strains compared to other C. burnetii strains. In this approach we investigated the phylogenetic relationship and genomic aspects of virulence and host-specificity. Phylogenetic clustering of whole genome sequences showed a genotype-specific clustering that correlated with the clustering observed using Multiple Locus Variable-number Tandem Repeat Analysis (MLVA). Ortholog analysis on predicted genes and single nucleotide polymorphism (SNP) analysis of complete genome sequences demonstrated the presence of genotype specific gene contents and SNP variations in C. burnetii strains. It also demonstrated that the currently used MLVA genotyping methods are highly discriminatory for the investigated outbreak strains. In the fully reconstructed genome sequence of the Dutch outbreak NL3262 strain of the CbNL01 genotype, a relatively large number of transposon-linked genes were identified as compared to the other published complete genome sequences of C. burnetii. Additionally, large numbers of SNPs in its membrane proteins and predicted virulence-associated genes were identified in all Dutch outbreak strains compared to the NM reference strain and other strains of the CbNL12 genotype. The presence of large numbers of transposable elements and mutated genes, thereof most likely resulted in high level of genome rearrangements and genotype-specific pathogenicity of outbreak strains. Thus, the epidemic potential of Dutch outbreak strains could be linked to increased genome plasticity and mutations in critical genes involved in virulence and the evasion of the host immune system. PMID- 28848534 TI - Mechanisms of Chromium and Uranium Toxicity in Pseudomonas stutzeri RCH2 Grown under Anaerobic Nitrate-Reducing Conditions. AB - Chromium and uranium are highly toxic metals that contaminate many natural environments. We investigated their mechanisms of toxicity under anaerobic conditions using nitrate-reducing Pseudomonas stutzeri RCH2, which was originally isolated from a chromium-contaminated aquifer. A random barcode transposon site sequencing library of RCH2 was grown in the presence of the chromate oxyanion (Cr[VI][Formula: see text]) or uranyl oxycation (U[VI][Formula: see text]). Strains lacking genes required for a functional nitrate reductase had decreased fitness as both metals interacted with heme-containing enzymes required for the later steps in the denitrification pathway after nitrate is reduced to nitrite. Cr[VI]-resistance also required genes in the homologous recombination and nucleotide excision DNA repair pathways, showing that DNA is a target of Cr[VI] even under anaerobic conditions. The reduced thiol pool was also identified as a target of Cr[VI] toxicity and psest_2088, a gene of previously unknown function, was shown to have a role in the reduction of sulfite to sulfide. U[VI] resistance mechanisms involved exopolysaccharide synthesis and the universal stress protein UspA. As the first genome-wide fitness analysis of Cr[VI] and U[VI] toxicity under anaerobic conditions, this study provides new insight into the impact of Cr[VI] and U[VI] on an environmental isolate from a chromium contaminated site, as well as into the role of a ubiquitous protein, Psest_2088. PMID- 28848535 TI - High Spatial and Temporal Variations of Microbial Community along the Southern Catfish Gastrointestinal Tract: Insights into Dynamic Food Digestion. AB - The fish intestinal microbiota is affected by dietary shifts or diet-related seasonal fluctuations making it highly variable and dynamic. It assists with the digestion and absorption of food that is a common, yet dynamic process. However, fundamental dynamics of microbial ecology associated with food digestion in intestine and stomach are poorly understood in fish. We selected the southern catfish, Silurus meridionalis, as the targeted species, owing to its foraging behavior with a large meal that can assure clear periodic rhythms in food digestion, to study spatial variations of the microbial community along the gastrointestinal (GI) tract. We further evaluated temporal microbial dynamics by collecting GI tract samples at time intervals 03, 12, and 24h after feeding. High throughput sequencing results showed higher microbial diversity in the stomach than in the intestine and distinguishable community structures between stomach and intestine. Firmicutes were dominated by both Clostridium and unclassified Clostridiaceae, which was the most abundant taxon in the stomach, whereas Fusobacteria were dominated by Cetobacterium, which prevailed in the intestine. Firmicutes was significantly increased and Fusobacteria was decreased after feeding. Furthermore, inter-stomach microbial variability was greater than inter intestine microbial variability. These results demonstrate that GI microbial assemblies are specific per anatomical site and are highly dynamic during food digestion, indicating that digestive status and/or sampling time are factors potentially influencing the microbial compositions. Furthermore, the finding of high spatial and temporal variations of the microbial community along the GI tract suggests limitations of single sampling regime to study food-derived microbial ecology. PMID- 28848536 TI - Temperature-Dependent Alkyl Glycerol Ether Lipid Composition of Mesophilic and Thermophilic Sulfate-Reducing Bacteria. AB - The occurrence of non-isoprenoid alkyl glycerol ether lipids in Bacteria and natural environments is increasingly being reported and the specificity and diagenetic stability of these lipids make them powerful biomarkers for biogeochemical and environmental studies. Yet the environmental controls on the biosynthesis of these peculiar membrane lipids remain poorly documented. Here, the lipid content of two mesophilic (Desulfatibacillum aliphaticivorans and Desulfatibacillum alkenivorans) and one thermophilic (Thermodesulfobacterium commune) sulfate-reducing bacteria-whose membranes are mostly composed of ether lipids-was investigated as a function of growth temperature (20-40 degrees C and 54-84 degrees C, respectively). For all strains, the cellular lipid content was lower at sub- or supra-optimal growth temperature, but the relative proportions of dialkyl glycerols, monoalkyl glycerols and fatty acids remained remarkably stable whatever the growth temperature. Rather than changing the proportions of the different lipid classes, the three strains responded to temperature changes by modifying the average structural composition of the alkyl and acyl chains constitutive of their membrane lipids. Major adaptive mechanisms concerned modifications of the level of branching and of the proportions of the different methyl branched lipids. Specifically, an increase in temperature induced mesophilic strains to produce less dimethyl branched dialkyl glycerols and 10 methyl branched lipids relative to linear structures, and the thermophilic strain to decrease the proportion of anteiso relative to iso methyl branched compounds. These modifications were in agreement with a regulation of the membrane fluidity. In one mesophilic and the thermophilic strains, a modification of the growth temperature further induced changes in the relative proportions of sn-2 vs sn-1 monoalkyl glycerols, suggesting an unprecedented mechanism of homeoviscous adaptation in Bacteria. Strong linear correlations observed between different ratios of alkyl glycerols and temperature allow to hypothesize the use of these specific lipids as indicators of temperature changes in the environment. PMID- 28848537 TI - Independent Shifts of Abundant and Rare Bacterial Populations across East Antarctica Glacial Foreland. AB - Glacial forelands are extremely sensitive to temperature changes and are therefore appropriate places to explore the development of microbial communities in response to climate-driven deglaciation. In this study, we investigated the bacterial communities that developed at the initial stage of deglaciation using space-for-time substitution in the foreland of an ice sheet in Larsemann Hills. A series of soil samples across the glacial foreland were deeply sequenced with 16S rRNA gene amplicon sequencing to determine the bacterial community, including both abundant bacteria, which contribute more to geobiochemistry, and rare bacteria, which serve as a seed bank for diversity. Our results show that abundant bacterial communities were more sensitive to changing conditions in the early stages of deglaciation than rare community members. Moreover, among the environmental parameters tested, which included total organic carbon, pH, and moisture of the soils, ice thickness was the most influential factor affecting the community structure of abundant bacteria. These results show the different effects of abundant and rare bacteria on community shifts and highlight ice thickness as the primary factor affecting the bacterial community in the early stages of deglaciation. The response of microbial community to climate change can be predicted with more certainty in this polar region. PMID- 28848538 TI - Insights on the Effects of Heat Pretreatment, pH, and Calcium Salts on Isolation of Rare Actinobacteria from Karstic Caves. AB - The phylum Actinobacteria is one of the most ubiquitously present bacterial lineages on Earth. In the present study, we try to explore the diversity of cultivable rare Actinobacteria in Sigangli Cave, Yunnan, China by utilizing a combination of different sample pretreatments and under different culture conditions. Pretreating the samples under different conditions of heat, setting the isolation condition at different pHs, and supplementation of media with different calcium salts were found to be effective for isolation of diverse rare Actinobacteria. During our study, a total of 204 isolates affiliated to 30 genera of phylum Actinobacteria were cultured. Besides the dominant Streptomyces, rare Actinobacteria of the genera Actinocorallia, Actinomadura, Agromyces, Alloactinosynnema, Amycolatopsis, Beutenbergia, Cellulosimicrobium, Gordonia, Isoptericola, Jiangella, Knoellia, Kocuria, Krasilnikoviella, Kribbella, Microbacterium, Micromonospora, Mumia, Mycobacterium, Nocardia, Nocardioides, Nocardiopsis, Nonomuraea, Oerskovia, Pseudokineococcus, Pseudonocardia, Rhodococcus, Saccharothrix, Streptosporangium, and Tsukamurella were isolated from these cave samples. PMID- 28848539 TI - Metagenomic Analysis of Cecal Microbiome Identified Microbiota and Functional Capacities Associated with Feed Efficiency in Landrace Finishing Pigs. AB - Feed efficiency (FE) appears to vary even within closely related pigs, and may be partly affected by the diversity in the composition and function of gut microbes. To investigate the components and functional differences of gut microbiota of low and high FE pigs, high throughput sequencing and de novo metagenomics were performed on pig cecal contents. Pigs were selected in pairs with low and high feed conversion ratio. The microorganisms of individuals with different FE were clustered according to diversity. The genus Prevotella was the most enriched in both groups, and the abundance of species Prevotella sp. CAG:604 was significantly increased in low efficiency individuals compared to that in animals showing high efficiency. In contrast, other differential species, including lactic acid bacteria, were all enriched in the group with good feeding characteristics. Functional analysis based on the Kyoto Encyclopedia of Genes and Genomes databases demonstrated that differential genes for the metabolism of carbohydrates were most abundant in both groups, but pathways of pyruvate-related metabolism were more intense in pigs with higher FE. All these data indicated that the microbial environment was closely related to the growth traits of pigs, and regulating microbial composition could aid developing strategies to improve FE for pigs. PMID- 28848540 TI - Beyond IgE-When Do IgE-Crosslinking and Effector Cell Activation Lead to Clinical Anaphylaxis? AB - Anaphylaxis in humans is inherently difficult to study due to the acuteness of symptoms and the lack of biomarkers serving as risk predictors. Most cases are related to IgE sensitizations to foods, insect venoms, and drugs with mastocytosis patients forming a smaller risk group. However, identifying the relatively small fraction of persons at risk has been exceedingly difficult. In this review, we propose to describe anaphylaxis in a broader context than defined by IgE sensitization alone. Exposure to a trigger, such as an allergen, may lead to anaphylaxis, but in particular, the internal dose sensed by the immune system needs to be established. Moreover, intrinsic patient factors as well as the specific circumstances of the exposure, i.e., the extrinsic factors, need to be thoroughly accounted for. More controversially, other triggers of anaphylaxis, such as increased sensitivity to or reduced catabolism of histamine ("histamine intolerance") or mast cell activation syndrome also named mast cell activation disorder have been suggested, but still with very limited epidemiological evidence that a significant proportion of the observed reactions are caused by these alleged conditions. Thus, when all conditions are considered, it seems as if IgE-mediated reactions are responsible for the vast majority of anaphylactic conditions. PMID- 28848541 TI - Effects of Bone Marrow Mesenchymal Stromal Cell Therapy in Experimental Cutaneous Leishmaniasis in BALB/c Mice Induced by Leishmania amazonensis. AB - Cutaneous leishmaniasis remains both a public health and a therapeutic challenge. To date, no ideal therapy for cutaneous leishmaniasis has been identified, and no universally accepted therapeutic regimen and approved vaccines are available. Due to the mesenchymal stromal cell (MSC) immunomodulatory capacity, they have been applied in a wide variety of disorders, including infectious, inflammatory, and allergic diseases. We evaluated the potential effects of bone marrow MSC therapy in a murine model of cutaneous leishmaniasis. In vitro, coculture of infected macrophages with MSC increased parasite load on macrophages in comparison with controls (macrophages without MSCs). In vivo, BALB/c mice were infected with 2 * 106Leishmania amazonensis (Josefa strain) promastigotes in the footpad. 7 and 37 days after infection, animals were treated with 1 * 105 MSCs, either intralesional (i.l.), i.e., in the same site of infection, or intravenously (i.v.), through the external jugular vein. Control animals received the same volume (50 uL) of phosphate-buffered saline by i.l. or i.v. routes. The lesion progression was assessed by its thickness measured by pachymetry. Forty-two days after infection, animals were euthanized and parasite burden in the footpad and in the draining lymph nodes was quantified by the limiting dilution assay (LDA), and spleen cells were phenotyped by flow cytometry. No significant difference was observed in lesion progression, regardless of the MSC route of administration. However, animals treated with i.v. MSCs presented a significant increase in parasite load in comparison with controls. On the other hand, no harmful effect due to MSCs i.l. administered was observed. The spleen cellular profile analysis showed an increase of IL-10 producing T CD4+ and TCD8+ cells in the spleen only in mice treated with i.v. MSC. The excessive production of IL-10 could be associated with the disease-aggravating effects of MSC therapy when intravenously administered. As a conclusion, in the current murine model of L. amazonensis induced cutaneous disease, MSCs did not control the damage of cutaneous disease and, depending on the administration route, it could result in deleterious effects. PMID- 28848542 TI - Anesthesia and Surgery Impair Blood-Brain Barrier and Cognitive Function in Mice. AB - Blood-brain barrier (BBB) dysfunction, e.g., increase in BBB permeability, has been reported to contribute to cognitive impairment. However, the effects of anesthesia and surgery on BBB permeability, the underlying mechanisms, and associated cognitive function remain largely to be determined. Here, we assessed the effects of surgery (laparotomy) under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h on BBB permeability, levels of junction proteins and cognitive function in both 9- and 18-month-old wild-type mice and 9-month-old interleukin (IL)-6 knockout mice. BBB permeability was determined by dextran tracer (immunohistochemistry imaging and spectrophotometric quantification), and protein levels were measured by Western blot and cognitive function was assessed by using both Morris water maze and Barnes maze. We found that the anesthesia/surgery increased mouse BBB permeability to 10-kDa dextran, but not to 70-kDa dextran, in an IL-6-dependent and age-associated manner. In addition, the anesthesia/surgery induced an age-associated increase in blood IL-6 level. Cognitive impairment was detected in 18-month-old, but not 9-month-old, mice after the anesthesia/surgery. Finally, the anesthesia/surgery decreased the levels of beta-catenin and tight junction protein claudin, occludin and ZO-1, but not adherent junction protein VE-cadherin, E-cadherin, and p120-catenin. These data demonstrate that we have established a system to study the effects of perioperative factors, including anesthesia and surgery, on BBB and cognitive function. The results suggest that the anesthesia/surgery might induce an age associated BBB dysfunction and cognitive impairment in mice. These findings would promote mechanistic studies of postoperative cognitive impairment, including postoperative delirium. PMID- 28848544 TI - CANDLE Syndrome As a Paradigm of Proteasome-Related Autoinflammation. AB - CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) is a rare, genetic autoinflammatory disease due to abnormal functioning of the multicatalytic system proteasome-immunoproteasome. Several recessive mutations in different protein subunits of this system, located in one single subunit (monogenic, homozygous, or compound heterozygous) or in two different ones (digenic and compound heterozygous), cause variable defects in catalytic activity of the proteasome-immunoproteasome. The final result is a sustained production of type 1 interferons (IFNs) that can be very much increased by banal triggers such as cold, stress, or viral infections. Patients start very early in infancy with recurrent or even daily fevers, characteristic skin lesions, wasting, and a typical fat loss, all conferring the patients a unique and unmistakable phenotype. So far, no treatment has been effective for the treatment of CANDLE syndrome; the JAK inhibitor baricitinib seems to be partially helpful. In this article, a review in depth all the pathophysiological, clinical, and laboratory features of CANDLE syndrome is provided. PMID- 28848543 TI - A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells. AB - Herpes simplex virus type 2 (HSV-2) is highly prevalent in the human population producing significant morbidity, mainly because of the generation of genital ulcers and neonatal encephalitis. Additionally, HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter in the coinfected. Despite numerous efforts to create a vaccine against HSV-2, no licensed vaccines are currently available. A long-standing strategy, based on few viral glycoproteins combined with adjuvants, recently displayed poor results in a Phase III clinical study fueling exploration on the development of mutant HSV viruses that are attenuated in vivo and elicit protective adaptive immune components, such as antiviral antibodies and T cells. Importantly, such specialized antiviral immune components are likely induced and modulated by dendritic cells, professional antigen presenting cells that process viral antigens and present them to T cells. However, HSV interferes with several functions of DCs and ultimately induces their death. Here, we propose that for an attenuated mutant virus to confer protective immunity against HSV in vivo based on adaptive immune components, such virus should also be attenuated in dendritic cells to promote a robust and effective antiviral response. We provide a background framework for this idea, considerations, as well as the means to assess this hypothesis. Addressing this hypothesis may provide valuable insights for the development of novel, safe, and effective vaccines against herpes simplex viruses. PMID- 28848545 TI - Primary Immunodeficiency Diseases: Current and Emerging Therapeutics. AB - Primary immunodeficiency diseases (PID) result from defects in genes affecting the immune and other systems in many and varied ways (1, 2). Until the last few years, treatments have been largely supportive, with the exception of bone marrow transplantation. However, recent advances in immunobiology, genetics, and the explosion of discovery and commercialization of biologic modifiers have drastically altered the landscape and opportunities in clinical immunology. Therapeutic options and life expectancy of PID patients have also improved dramatically, in large part as a result of better prevention and treatment of infections as well as better understanding and treatment of autoimmune complications (3). As early-life infection-related mortality declines we should anticipate the emergence of other conditions that were previously not appreciated, including malignancies and degenerative disorders unmasked by increasing longevity (4). The genomic revolution has identified literally hundreds of new genetic etiologies of immune dysfunction, many of which are or will soon be eligible for targeted therapies. These emerging immunomodulatory agents represent new therapeutic options in PIDs (5). PMID- 28848546 TI - Lighting Up T Lymphocyte Signaling with Quantitative Phosphoproteomics. AB - Phosphorylation is the most abundant post-translational modification, regulating several aspects of protein and cell function. Quantitative phosphoproteomics approaches have expanded the scope of phosphorylation analysis enabling the quantification of changes in thousands of phosphorylation sites simultaneously in two or more conditions. These approaches offer a global view of the impact of cellular perturbations such as extracellular stimuli or gene ablation in intracellular signaling networks. Such great potential also brings on a new challenge: to identify, among the thousands of phosphorylations found in global phosphoproteomics studies, the small subset of site-specific phosphorylations expected to be functionally relevant. This review focus on updating and integrating findings on T lymphocyte signaling generated using global phosphoproteomics approaches, drawing attention on the biological relevance of the obtained data. PMID- 28848547 TI - Metabolic Plasticity of Stem Cells and Macrophages in Cancer. AB - In addition to providing essential molecules for the overall function of cells, metabolism plays an important role in cell fate and can be affected by microenvironmental stimuli as well as cellular interactions. As a specific niche, tumor microenvironment (TME), consisting of different cell types including stromal/stem cells and immune cells, is characterized by distinct metabolic properties. This review will be focused on the metabolic plasticity of mesenchymal stromal/stem cells (MSC) and macrophages in TME, as well as on how the metabolic state of cancer stem cells (CSC), as key drivers of oncogenesis, affects their generation and persistence. Namely, heterogenic metabolic phenotypes of these cell populations, which include various levels of dependence on glycolysis or oxidative phosphorylation are closely linked to their complex roles in cancer progression. Besides well-known extrinsic factors, such as cytokines and growth factors, the differentiation and activation states of CSC, MSC, and macrophages are coordinated by metabolic reprogramming in TME. The significance of mutual metabolic interaction between tumor stroma and cancer cells in the immune evasion and persistence of CSC is currently under investigation. PMID- 28848548 TI - Cellular RNA Helicase DDX1 Is Involved in Transmissible Gastroenteritis Virus nsp14-Induced Interferon-Beta Production. AB - Transmissible gastroenteritis virus (TGEV), an enteropathogenic coronavirus (CoV) of porcine, causes lethal watery diarrhea and severe dehydration in piglets and leads to severe economic losses in the swine industry. Unlike most CoVs that antagonize type I interferon (IFN) production, previous studies showed that TGEV infection induces IFN-I production both in vivo and in vitro. However, the underlying mechanism(s) remain largely unknown. In this study, we found that TGEV infection significantly facilitated IFN-beta production as well as activation of the transcription factors IFN regulatory factor 3 (IRF3) and nuclear factor kappaB (NF-kappaB) in porcine kidney (PK-15) cells. Screening of TGEV-encoded proteins demonstrated that non-structural protein 14 (nsp14) was the most potent IFN-beta inducer and induced IFN-beta production mainly by activating NF-kappaB but not IRF3. Further analysis showed that nsp14 interacted with DDX1, a member of the DExD/H helicase family. Knockdown of DDX1 by specific small interfering RNA (siRNA) significantly decreased nsp14-induced IFN-beta production and NF kappaB activation. Furthermore, TGEV-induced IFN-beta production and IFN stimulated gene (ISG) expression were decreased in cells transfected with DDX1 specific siRNA, indicating the vital role of DDX1 to TGEV-induced IFN-beta responses. In summary, our data revealed a potential coactivator role of host RNA helicase DDX1 to the induction of IFN-beta response initiated by TGEV and demonstrated that nsp14 is an important IFN inducer among the TGEV-encoded proteins. PMID- 28848549 TI - Dendritic Cell Subsets in Asthma: Impaired Tolerance or Exaggerated Inflammation? AB - Asthma is a prevalent chronic heterogeneous inflammatory disease of the airways, leading to reversible airway obstruction, in which various inflammatory responses can be observed. Mild to moderate asthma patients often present with a Th2 mediated eosinophilic inflammation whereas in severe asthma patients, a Th17 associated neutrophilic or combined Th2 and Th17-mediated eosinophilic/neutrophilic inflammation is observed. The differentiation of these effector Th2 and Th17-cells is induced by allergen-exposed dendritic cells (DCs) that migrate toward the lung draining lymph node. The DC lineage comprises conventional DCs (cDCs) and plasmacytoid DCs (pDCs), of which the cDC lineage consists of type 1 cDCs (cDC1s) and cDC2s. During inflammation, also monocytes can differentiate into so-called monocyte-derived DCs (moDCs). These DC subsets differ both in ontogeny, localization, and in their functional properties. New identification tools and the availability of transgenic mice targeting specific DC subsets enable the investigation of how these different DC subsets contribute to or suppress asthma pathogenesis. In this review, we will discuss mechanisms used by different DC subsets to elicit or hamper the pathogenesis of both Th2 mediated eosinophilic asthma and more severe Th17-mediated neutrophilic inflammation. PMID- 28848550 TI - Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D. AB - Bi-allelic null mutations affecting UNC13D, STXBP2, or STX11 result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL) in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of this disease, or with HLH later in life. Here, we studied two sisters with lymphocyte degranulation defects secondary to compound heterozygote missense variants in UNC13D. The older sibling presented aged 11 with linear growth arrest and delayed puberty, 2 years prior to developing transient ischemic attacks secondary to neuroinflammation and hypogammaglobulinemia, but no FHL symptoms. Her geno-identical younger sister was initially asymptomatic but then presented at the same age with severe EBV-driven infectious mononucleosis, which was treated aggressively and did not progress to HLH. The sisters had similar natural killer cell degranulation; however, while cytotoxic activity was moderately reduced in the asymptomatic patient, it was completely absent in both siblings during active disease. Following allogeneic bone marrow transplantation at the age of 15, the older child has completely recovered NK cell cytotoxicity, is asymptomatic, and has experienced an exceptional compensatory growth spurt. Her younger sister was also successfully transplanted and is currently disease free. The current study reveals previously unappreciated manifestations of FHL in patients who inherited hypomorphic gene variants and also raises the important question of whether a threshold of minimum NK function can be defined that should protect a patient from serious disease manifestations such as HLH. PMID- 28848551 TI - Neuroimmune Interactions in Inflammation and Acute Kidney Injury. AB - Inflammation contributes to the pathogenesis of a wide variety of disorders including kidney diseases. Recent advances have shown that neural pathways are able to regulate immunity and inflammation. The cholinergic anti-inflammatory pathway (CAP) is a well-studied neural circuit involving the vagus nerve that is thought to contribute to the response to inflammatory disorders. Expression of receptors for neurotransmitters is found in some immune cells, including beta2 adrenergic receptors on CD4 T cells and alpha 7 subunit of the nicotinic acetylcholine (ACh) receptor on macrophages. Once nerves are activated, neurotransmitters such as norepinephrine and ACh are released at nerve terminals, and the neurotransmitters can activate immune cells located in close proximity to the nerve terminals. Thus, vagus nerve stimulation induces activation of immune cells, leading to an anti-inflammatory response. Recent studies demonstrate a non pharmacological organ protective effect of electrical nerve stimulation, pulsed ultrasound treatment, or optogenetic C1 neuron activation. These modalities are thought to activate the CAP and attenuate inflammation. In this review, we will focus on the current understanding of the mechanisms regarding neuroimmune interactions with a particular focus on inflammation associated with kidney disease. PMID- 28848552 TI - Peptidoglycan from Immunobiotic Lactobacillus rhamnosus Improves Resistance of Infant Mice to Respiratory Syncytial Viral Infection and Secondary Pneumococcal Pneumonia. AB - Several research works have demonstrated that beneficial microbes with the capacity to modulate the mucosal immune system (immunobiotics) are an interesting alternative to improve the outcome of bacterial and viral respiratory infections. Among the immunobiotic strains with the capacity to beneficially modulate respiratory immunity, Lactobacillus rhamnosus CRL1505 has outstanding properties. Although we have significantly advanced in demonstrating the capacity of L. rhamnosus CRL1505 to improve resistance against respiratory infections as well as in the cellular and molecular mechanisms involved in its beneficial activities, the potential protective ability of this strain or its immunomodulatory cellular fractions in the context of a secondary bacterial pneumonia has not been addressed before. In this work, we demonstrated that the nasal priming with non viable L. rhamnosus CRL1505 or its purified peptidoglycan differentially modulated the respiratory innate antiviral immune response triggered by toll-like receptor 3 activation in infant mice, improving the resistance to primary respiratory syncytial virus (RSV) infection, and secondary pneumococcal pneumonia. In association with the protection against RSV-pneumococcal superinfection, we found that peptidoglycan from L. rhamnosus CRL1505 significantly improved lung CD3+CD4+IFN-gamma+, and CD3+CD4+IL-10+ T cells as well as CD11c+SiglecF+IFN-beta+ alveolar macrophages with the consequent increases of IFN-gamma, IL-10, and IFN-beta in the respiratory tract. Our results also showed that the increase of these three cytokines is necessary to achieve protection against respiratory superinfection since each of them are involved in different aspect of the secondary pneumococcal pneumonia that have to be controlled in order to reduce the severity of the infectious disease: lung pneumococcal colonization, bacteremia, and inflammatory-mediated lung tissue injury. PMID- 28848553 TI - Clinical Diagnosis of the Dampness and Mold Hypersensitivity Syndrome: Review of the Literature and Suggested Diagnostic Criteria. AB - A great variety of non-specific symptoms may occur in patients living or working in moisture-damaged buildings. In the beginning, these symptoms are usually reversible, mild, and present irritation of mucosa and increased morbidity due to respiratory tract infections and asthma-like symptoms. Later, the disease may become chronic and a patient is referred to a doctor where the assessment of dampness and mold hypersensitivity syndrome (DMHS) often presents diagnostic challenges. Currently, unanimously accepted laboratory tests are not yet available. Therefore, the diagnosis of DMHS is clinical and is based on the patient's history and careful examination. In this publication, I reviewed contemporary knowledge on clinical presentations, laboratory methods, and clinical assessment of DMHS. From the literature, I have not found any proposed diagnostic clinical criteria. Therefore, I propose five clinical criteria to diagnose DMHS: (1) the history of mold exposure in water-damaged buildings, (2) increased morbidity to due infections, (3) sick building syndrome, (4) multiple chemical sensitivity, and (5) enhanced scent sensitivity. If all the five criteria are met, the patient has a very probable DMHS. To resolve the current problems in assigning correct DMHS diagnosis, we also need novel assays to estimate potential risks of developing DMHS. PMID- 28848554 TI - Is It Time to Reconsider the Lipopolysaccharide Paradigm in Acute Graft-Versus Host Disease? PMID- 28848555 TI - Stringently Defined Otitis Prone Children Demonstrate Deficient Naturally Induced Mucosal Antibody Response to Moraxella catarrhalis Proteins. AB - Moraxella catarrhalis (Mcat) is a prominent mucosal pathogen causing acute otitis media (AOM). We studied Mcat nasopharyngeal (NP) colonization, AOM frequency and mucosal antibody responses to four vaccine candidate Mcat proteins: outer membrane protein (OMP) CD, oligopeptide permease (Opp) A, hemagglutinin (Hag), and Pilin A clade 2 (PilA2) from stringently defined otitis prone (sOP) children, who experience the greatest burden of disease, compared to non-otitis prone (NOP) children. sOP children had higher NP colonization of Mcat (30 vs. 22%, P = 0.0003) and Mcat-caused AOM rates (49 vs. 24%, P < 0.0001) than NOP children. Natural acquisition of mucosal antibodies to Mcat proteins OMP CD (IgG, P < 0.0001), OppA (IgG, P = 0.018), Hag (IgG and IgA, both P < 0.0001), and PilA2 (IgA, P < 0.0001) was lower in sOP than NOP children. Higher levels of mucosal IgG to Hag (P = 0.039) and PilA2 (P = 0.0076), and IgA to OMP CD (P = 0.010), OppA (P = 0.030), and PilA2 (P = 0.043) were associated with lower carriage of Mcat in NOP but not sOP children. Higher levels of mucosal IgG to OMP CD (P = 0.0070) and Hag (P = 0.0003), and IgA to Hag (P = 0.0067) at asymptomatic colonization than those at onset of AOM were associated with significantly lower rate of Mcat NP colonization progressing to AOM in NOP compared to sOP children (3 vs. 26%, P < 0.0001). In conclusion, sOP children had a diminished mucosal antibody response to Mcat proteins, which was associated with higher frequencies of asymptomatic NP colonization and NP colonization progressing to Mcat-caused AOM. Enhancing Mcat antigen-specific mucosal immune responses to levels higher than achieved by natural exposure will be necessary to prevent AOM in sOP children. PMID- 28848556 TI - Emerging Roles of Osteoclasts in the Modulation of Bone Microenvironment and Immune Suppression in Multiple Myeloma. AB - Multiple myeloma (MM) is one of the most common forms of hematologic malignancy resulting from cancerous proliferation of mature malignant plasma cells (MPCs). But despite the real improvement in therapeutics in the past years, it remains largely incurable. MM is the most frequent cancer to involve bone due to the stimulation of osteoclast (OCL) differentiation and activity. OCLs have a unique capacity to resorb bone. However, recent studies reveal that they are not restrained to this sole function. They participate in the control of angiogenesis, medullary niches, and immune responses, including in MM. Therefore, therapeutic approaches targeting OCLs probably affect not only bone resorption but also many other functions, and OCLs should not be considered anymore only as targets to improve the bone phenotype but also to modulate bone microenvironment. In this review, we explore these novel contributions of OCLs to MM which reveal their strong implication in the MM physiopathology. We also underline the therapeutic interest of targeting OCLs not only to overcome bone lesions, but also to improve bone microenvironment and anti-tumoral immune responses. PMID- 28848557 TI - Postnatal Innate Immune Development: From Birth to Adulthood. AB - It is well established that adaptive immune responses are deficient in early life, contributing to increased mortality and morbidity. The developmental trajectories of different components of innate immunity are only recently being explored. Individual molecules, cells, or pathways of innate recognition and signaling, within different compartments/anatomical sites, demonstrate variable maturation patterns. Despite some discrepancies among published data, valuable information is emerging, showing that the developmental pattern of cytokine responses during early life is age and toll-like receptor specific, and may be modified by genetic and environmental factors. Interestingly, specific environmental exposures have been linked both to innate function modifications and the occurrence of chronic inflammatory disorders, such as respiratory allergies. As these conditions are on the rise, our knowledge on innate immune development and its modulating factors needs to be expanded. Improved understanding of the sequence of events associated with disease onset and persistence will lead toward meaningful interventions. This review describes the state-of-the-art on normal postnatal innate immune ontogeny and highlights research areas that are currently explored or should be further addressed. PMID- 28848559 TI - Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells. AB - The programmed death-1 (PD-1) and its ligand PD-L1 (B7-H1) signaling pathway has been the focus of much enthusiasm in the fields of tumor immunology and oncology with recent FDA approval of the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies durvalumab, atezolimuab, and avelumab. These therapies, referred to here as PD-L1/PD-1 checkpoint blockade therapies, are designed to block the interaction between PD-L1, expressed by tumor cells, and PD 1, expressed by tumor-infiltrating CD8+ T cells, leading to enhanced antitumor CD8+ T cell responses and tumor regression. The influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined for antitumor CD8+ T cell responses. Although PD-L1 expression by tumor cells has been used as a biomarker in selection of patients for PD-L1/PD-1 checkpoint blockade therapies, patients whose tumor cells lack PD-L1 expression often respond positively to PD-L1/PD-1 checkpoint blockade therapies. This suggests that PD-L1 expressed by non-malignant cells may also contribute to antitumor immunity. Here, we review the functions of PD-L1 expressed by immune cells in the context of CD8+ T cell priming, contraction, and differentiation into memory populations, as well as the role of PD-L1 expressed by tumor cells in regulating antitumor CD8+ T cell responses. PMID- 28848558 TI - RNA Sequencing of Murine Norovirus-Infected Cells Reveals Transcriptional Alteration of Genes Important to Viral Recognition and Antigen Presentation. AB - Viruses inherently exploit normal cellular functions to promote replication and survival. One mechanism involves transcriptional control of the host, and knowledge of the genes modified and their molecular function can aid in understanding viral-host interactions. Norovirus pathogenesis, despite the recent advances in cell cultivation, remains largely uncharacterized. Several studies have utilized the related murine norovirus (MNV) to identify innate response, antigen presentation, and cellular recognition components that are activated during infection. In this study, we have used next-generation sequencing to probe the transcriptomic changes of MNV-infected mouse macrophages. Our in-depth analysis has revealed that MNV is a potent stimulator of the innate response including genes involved in interferon and cytokine production pathways. We observed that genes involved in viral recognition, namely IFIH1, DDX58, and DHX58 were significantly upregulated with infection, whereas we observed significant downregulation of cytokine receptors (Il17rc, Il1rl1, Cxcr3, and Cxcr5) and TLR7. Furthermore, we identified that pathways involved in protein degradation (including genes Psmb3, Psmb4, Psmb5, Psmb9, and Psme2), antigen presentation, and lymphocyte activation are downregulated by MNV infection. Thus, our findings illustrate that MNV induces perturbations in the innate immune transcriptome, particularly in MHC maturation and viral recognition that can contribute to disease pathogenesis. PMID- 28848560 TI - Mycobacterium bovis Bacillus Calmette-Guerin Alters Melanoma Microenvironment Favoring Antitumor T Cell Responses and Improving M2 Macrophage Function. AB - Intralesional Mycobacterium bovis bacillus Calmette-Guerin (BCG) has long been a relatively inexpensive therapy for inoperable cutaneous metastatic melanoma (CMM), although intralesional BCG skin mechanisms remain understudied. We analyzed intralesional BCG-treated CMM lesions combined with in vitro studies to further investigate BCG-altered pathways. Since macrophages play a pivotal role against both cancer and mycobacterial infections, we hypothesized BCG regulates macrophages to promote antitumor immunity. Tumor-associated macrophages (M2) infiltrate melanomas and impair antitumor immunity. BCG-treated, in vitro polarized M2 (M2-BCG) showed transcriptional changes involving inflammation, immune cell recruitment, cross talk, and activation pathways. Mechanistic network analysis indicated M2-BCG potential to improve interferon gamma (IFN-gamma) responses. Accordingly, frequency of IFN-gamma-producing CD4+ T cells responding to M2-BCG vs. mock-treated M2 increased (p < 0.05). Moreover, conditioned media from M2-BCG vs. M2 elevated the frequency of granzyme B-producing CD8+ tumor infiltrating lymphocytes (TILs) facing autologous melanoma cell lines (p < 0.01). Furthermore, transcriptome analysis of intralesional BCG-injected CMM relative to uninjected lesions showed immune function prevalence, with the most enriched pathways representing T cell activation mechanisms. In vitro-infected MM-derived cell lines stimulated higher frequency of IFN-gamma-producing TIL from the same melanoma (p < 0.05). Our data suggest BCG favors antitumor responses in CMM through direct/indirect effects on tumor microenvironment cell types including macrophages, T cells, and tumor itself. PMID- 28848562 TI - Editorial: Immunomodulatory Effects of Drugs for Treatment of Immune-Related Diseases. PMID- 28848561 TI - Analysis of the Phenotype of Mycobacterium tuberculosis-Specific CD4+ T Cells to Discriminate Latent from Active Tuberculosis in HIV-Uninfected and HIV-Infected Individuals. AB - Several immune-based assays have been suggested to differentiate latent from active tuberculosis (TB). However, their relative performance as well as their efficacy in HIV-infected persons, a highly at-risk population, remains unclear. In a study of 81 individuals, divided into four groups based on their HIV-1 status and TB disease activity, we compared the differentiation (CD27 and KLRG1), activation (HLA-DR), homing potential (CCR4, CCR6, CXCR3, and CD161) and functional profiles (IFNgamma, IL-2, and TNFalpha) of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cells using flow cytometry. Active TB disease induced major changes within the Mtb-responding CD4+ T cell population, promoting memory maturation, elevated activation and increased inflammatory potential when compared to individuals with latent TB infection. Moreover, the functional profile of Mtb-specific CD4+ T cells appeared to be inherently related to their degree of differentiation. While these specific cell features were all capable of discriminating latent from active TB, irrespective of HIV status, HLA-DR expression showed the best performance for TB diagnosis [area-under-the-curve (AUC) = 0.92, 95% CI: 0.82-1.01, specificity: 82%, sensitivity: 84% for HIV- and AUC = 0.99, 95% CI: 0.98-1.01, specificity: 94%, sensitivity: 93% for HIV+]. In conclusion, these data support the idea that analysis of T cell phenotype can be diagnostically useful in TB. PMID- 28848563 TI - H-Ras Exerts Opposing Effects on Type I Interferon Responses Depending on Its Activation Status. AB - Using shRNA high-throughput screening, we identified H-Ras as a regulator of antiviral activity, whose depletion could enhance Sindbis virus replication. Further analyses indicated that depletion of H-Ras results in a robust increase in vesicular stomatitis virus infection and a decrease in Sendai virus (SeV) induced retinoic acid-inducible gene-I-like receptor (RLR) signaling. Interestingly, however, ectopic expression of wild-type H-Ras results in a biphasic mode of RLR signaling regulation: while low-level expression of H-Ras enhances SeV-induced RLR signaling, high-level expression of H-Ras significantly inhibits this signaling. The inhibitory effects correlate with the activation status of H-Ras. As a result, oncogenic H-Ras, H-RasV12, strongly inhibits SeV induced IFN-beta promoter activity and type I interferon signaling. Conversely, the positive effects exerted by H-Ras on RLR signaling are independent of its signaling activity, as a constitutively inactive form of H-Ras, H-RasN17, also positively regulates RLR signaling. Mechanistically, we demonstrate that depletion of H-Ras reduces the formation of MAVS-TNF receptor-associated factor 3 signaling complexes. These results reveal that the H-Ras protein plays a role in promoting MAVS signalosome assembly in the mitochondria, whereas oncogenic H-Ras exerts a negative effect on type I IFN responses. PMID- 28848564 TI - Editorial: Danger Signals Triggering Immune Response and Inflammation. PMID- 28848565 TI - A New Strategy in Observer Modeling for Greenhouse Cucumber Seedling Growth. AB - State observer is an essential component in computerized control loops for greenhouse-crop systems. However, the current accomplishments of observer modeling for greenhouse-crop systems mainly focus on mass/energy balance, ignoring physiological responses of crops. As a result, state observers for crop physiological responses are rarely developed, and control operations are typically made based on experience rather than actual crop requirements. In addition, existing observer models require a large number of parameters, leading to heavy computational load and poor application feasibility. To address these problems, we present a new state observer modeling strategy that takes both environmental information and crop physiological responses into consideration during the observer modeling process. Using greenhouse cucumber seedlings as an instance, we sample 10 physiological parameters of cucumber seedlings at different time point during the exponential growth stage, and employ them to build growth state observers together with 8 environmental parameters. Support vector machine (SVM) acts as the mathematical tool for observer modeling. Canonical correlation analysis (CCA) is used to select the dominant environmental and physiological parameters in the modeling process. With the dominant parameters, simplified observer models are built and tested. We conduct contrast experiments with different input parameter combinations on simplified and un simplified observers. Experimental results indicate that physiological information can improve the prediction accuracies of the growth state observers. Furthermore, the simplified observer models can give equivalent or even better performance than the un-simplified ones, which verifies the feasibility of CCA. The current study can enable state observers to reflect crop requirements and make them feasible for applications with simplified shapes, which is significant for developing intelligent greenhouse control systems for modern greenhouse production. PMID- 28848566 TI - Herbicide Safeners Decrease Sensitivity to Herbicides Inhibiting Acetolactate Synthase and Likely Activate Non-Target-Site-Based Resistance Pathways in the Major Grass Weed Lolium sp. (Rye-Grass). AB - Herbicides are currently pivotal to control weeds and sustain food security. Herbicides must efficiently kill weeds while being as harmless as possible for crops, even crops taxonomically close to weeds. To increase their selectivity toward crops, some herbicides are sprayed in association with safeners that are bioactive compounds exacerbating herbicide-degrading pathways reputedly specifically in crops. However, exacerbated herbicide metabolism is also a key mechanism underlying evolved non-target-site-based resistance to herbicides (NTSR) in weeds. This raised the issue of a possible role of safeners on NTSR evolution in weeds. We investigated a possible effect of the respective field rates of the two broadly used safeners cloquintocet-mexyl and mefenpyr-diethyl on the sensitivity of the troublesome global weed Lolium sp. (rye-grass) to the major herbicides inhibiting acetolactate-synthase (ALS) pyroxsulam and iodosulfuron + mesosulfuron, respectively. Three Lolium sp. populations were studied in three series of experiments. The first experiment series compared the frequencies of plants surviving application of each herbicide alone or in association with its safener. Safener co-application caused a net increase ranging from 5.0 to 46.5% in the frequency of plants surviving the field rate of their associated herbicide. In a second series of experiments, safener effect was assessed on individual plant sensitivity using vegetative propagation. A reduction in sensitivity to pyroxsulam and to iodosulfuron + mesosulfuron was observed for 44.4 and 11.1% of the plants in co-treatment with cloquintocet-mexyl and mefenpyr-diethyl, respectively. A third series of experiments investigated safener effect on the expression level of 19 Lolium sp. NTSR marker genes. Safeners showed an enhancing effect on the expression level of 10 genes. Overall, we demonstrated that cloquintocet-mexyl and mefenpyr-diethyl both reduced the sensitivity of Lolium sp. to their associated ALS-inhibiting herbicide and most likely exacerbated herbicide-degrading secondary metabolism pathways. This suggests that genetic variation for safener response is present in Lolium sp. Thus, a possible, uninvestigated way to NTSR evolution could be selection for increased responsiveness to safener action. Delivering safeners exclusively to the crop could mitigate the risk for NTSR evolution in weeds. PMID- 28848568 TI - Effects of Low Temperature Stress on Spikelet-Related Parameters during Anthesis in Indica-Japonica Hybrid Rice. AB - Poor spikelet fertility under low temperature (LT) stress during anthesis limits the possibility of high yield potential in indica-japonica hybrid rice, leading to reduced stability of grain yield. However, the cause for it is still unclear. In this study, three indica-japonica hybrid rice cultivars, Yongyou9, Yongyou17 (both cold sensitive), and Yongyou538, and one japonica inbred rice cultivar, Zhejing88 (cold tolerant), were grown under LT (17 degrees C) and ambient temperature (AT) (25 degrees C) during anthesis to test for their response with respect to spikelet fertility, pollen germination, and spikelet flowering. The results indicated that LT resulted in lower spikelet fertility in cold-sensitive cultivars than in cold-tolerant cultivars. Spikelet fertility was highly correlated with pollen germination on the stigma. The number of pollen grains and germinated pollen were higher in cold-tolerant cultivars than in cold-sensitive cultivars. Pollen fertility and pollen diameter were also higher in cold-tolerant cultivars, although the latter could achieve a high number of spikelets at anthesis in flowering patterns throughout the duration of LT stress. There were significant differences in anther width and volume between genotypes and treatments according to microscopic analyses, but no differences were observed in anther dehiscence. Moreover, variation in the number of pollen grains on stigmas and in spikelet fertility was not related to either the number of spikelets reaching anthesis or anther dehiscence. Overall, improved anther size, better pollen function, and higher spikelet fertility under LT stress were observed in cold-tolerant cultivars than in cold-sensitive cultivars. The results suggest that the increase in spikelet fertility is due to enhanced pollen germination rather than the number of spikelets reaching anthesis. PMID- 28848567 TI - Altered Cell Wall Plasticity Can Restrict Plant Growth under Ammonium Nutrition. AB - Plants mainly utilize inorganic forms of nitrogen (N), such as nitrate (NO3-) and ammonium (NH4+). However, the composition of the N source is important, because excess of NH4+ promotes morphological disorders. Plants cultured on NH4+ as the sole N source exhibit serious growth inhibition, commonly referred to as "ammonium toxicity syndrome." NH4+-mediated suppression of growth may be attributable to both repression of cell elongation and reduction of cell division. The precondition for cell enlargement is the expansion of the cell wall, which requires the loosening of the cell wall polymers. Therefore, to understand how NH4+ nutrition may trigger growth retardation in plants, properties of their cell walls were analyzed. We found that Arabidopsis thaliana using NH4+ as the sole N source has smaller cells with relatively thicker cell walls. Moreover, cellulose, which is the main load-bearing polysaccharide revealed a denser assembly of microfibrils. Consequently, the leaf blade tissue showed elevated tensile strength and indicated higher cell wall stiffness. These changes might be related to changes in polysaccharide and ion content of cell walls. Further, NH4+ toxicity was associated with altered activities of cell wall modifying proteins. The lower activity and/or expression of pectin hydrolyzing enzymes and expansins might limit cell wall expansion. Additionally, the higher activity of cell wall peroxidases can lead to higher cross-linking of cell wall polymers. Overall, the NH4+-mediated inhibition of growth is related to a more rigid cell wall structure, which limits expansion of cells. The changes in cell wall composition were also indicated by decreased expression of Feronia, a receptor-like kinase involved in the control of cell wall extension. PMID- 28848569 TI - The Arabidopsis Mitogen-Activated Protein Kinase Kinase Kinase 20 (MKKK20) Acts Upstream of MKK3 and MPK18 in Two Separate Signaling Pathways Involved in Root Microtubule Functions. AB - Mitogen-activated protein kinase (MAPK) signaling networks represent important means of signal transduction in plants and other eukaryotes, controlling intracellular signaling by linking perception of environmental or developmental cues to downstream targets. In the Arabidopsis MEKK subfamily, the MKKK19, 20, and 21 form a highly supported clade with the Solanaceous Fertilization-Related Kinases. In Arabidopsis, little is known about this group, except for MKKK20, which is involved in osmotic stress. Using a directed MKKK-MKK yeast two-hybrid (Y2H) screen, MKKK20 was found to interact only with MKK3, while a MKKK20 large scale Y2H screen retrieved MPK18 as a direct interactant. In vitro phosphorylation assays showed that MKKK20 phosphorylates both MKK3 and MPK18. However, when all three kinases are combined, no synergistic effect is observed on MPK18 phosphorylation, suggesting a direct access to MPK18, consistent with the absence of interaction between MKK3 and MPK18 in protein-protein interaction assays. Since mpk18 mutant plants were previously shown to be defective in microtubule-related functions, phenotypes of mkkk20 single and mkkk20/mpk18 double mutants were investigated to determine if MKKK20 acts upstream of MPK18. This was the case, as mkkk20 root length was shorter than WT in media containing microtubule-disrupting drugs as previously observed for mpk18 plants. Surprisingly, mkk3 plants were also similarly affected, suggesting the presence of two non-complementary pathways involved in Arabidopsis cortical microtubule function, the first including MKKK20, MKK3 and an unknown MPK; the second, a non canonical MAPK cascade made of MKKK20 and MPK18 that bypasses the need for an MKK intermediate. PMID- 28848570 TI - Transcriptional Regulation of Brassinosteroid Accumulation during Carrot Development and the Potential Role of Brassinosteroids in Petiole Elongation. AB - It is widely known that brassinosteroids (BRs) are involved in various physiological processes during plant growth and development. Roles of BRs have been reported in many plants. However, relevant report is yet not found in carrot. Carrot is a nutrient-rich vegetable from the Apiaceae family. Here, we measured the bioactive contents of BRs at five successive stages and analyzed the expression profiles of genes involved in BR biosynthesis, signaling pathway and catabolism. We found that most biosynthesis regulated genes had higher expression level at the first development stage of carrot and the catabolism gene BAS1/CYP734A1 had significantly high expression level at the first stage in carrot roots and petioles. In addition, we treated carrot plants with exogenous 24-epibrassinolide (24-EBL) and examined the morphological changes after treating. Compared with control plants, carrot plants treated with 24-EBL had higher plant height, more number of petioles and heavier aboveground weight. The expression levels of DcBRI1, DcBZR1, and DcBSU1 in the petioles were significantly up-regulated by treating with exogenous 24-EBL. The expression profiles of DcCYP734A1 were all significantly up-regulated in the three organs when treated with 0.5 mg/L 24-EBL. The elongation of carrot petioles can be promoted by treating with exogenous 24-EBL. These results indicate that BRs playing potential roles during the growth and development of carrot. PMID- 28848571 TI - Transcriptional Regulation of Aluminum-Tolerance Genes in Higher Plants: Clarifying the Underlying Molecular Mechanisms. AB - Aluminum (Al) rhizotoxicity is one of the major environmental stresses that decrease global food production. Clarifying the molecular mechanisms underlying Al tolerance may contribute to the breeding of Al-tolerant crops. Recent studies identified various Al-tolerance genes. The expression of these genes is inducible by Al. Studies of the major Arabidopsis thaliana Al-tolerance gene, ARABIDOPSIS THALIANA ALUMINUM-ACTIVATED MALATE TRANSPORTER 1 (AtALMT1), which encodes an Al activated malate transporter, revealed that the Al-inducible expression is regulated by a SENSITIVE TO PROTON RHIXOTOXICITY 1 (STOP1) zinc-finger transcription factor. This system, which involves STOP1 and organic acid transporters, is conserved in diverse plant species. The expression of AtALMT1 is also upregulated by several phytohormones and hydrogen peroxide, suggesting there is crosstalk among the signals involved in the transcriptional regulation of AtALMT1. Additionally, phytohormones and reactive oxygen species (ROS) activate various transcriptional responses, including the expression of genes related to increased Al tolerance or the suppression of root growth under Al stress conditions. For example, Al suppressed root growth due to abnormal accumulation of auxin and cytokinin. It activates transcription of TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1 and other phytohormone responsive genes in distal transition zone, which causes suppression of root elongation. On the other hand, overexpression of Al inducible genes for ROS-detoxifying enzymes such as GLUTATHIONE-S-TRANSFERASE, PEROXIDASE, SUPEROXIDE DISMUTASE enhances Al resistance in several plant species. We herein summarize the complex transcriptional regulation of an Al-inducible genes affected by STOP1, phytohormones, and ROS. PMID- 28848572 TI - Amaranthin-Like Proteins with Aerolysin Domains in Plants. AB - Amaranthin is a homodimeric lectin that was first discovered in the seeds of Amaranthus caudatus and serves as a model for the family of amaranthin-like lectins. Though these lectins have been purified and characterized only from plant species belonging to the Amaranthaceae, evidence accumulated in recent years suggests that sequences containing amaranthin domains are widely distributed in plants. In this study, 84 plant genomes have been screened to investigate the distribution of amaranthin domains. A total of 265 sequences with amaranthin domains were retrieved from 34 plant genomes. Within this group of amaranthin homologs, 22 different domain architectures can be distinguished. The most common domain combination consists of two amaranthin domains followed by a domain with sequence similarity to aerolysin. The latter protein belongs to the group of beta-pore-forming toxins produced by bacteria such as Aeromonas sp. and exerts its toxicity by making transmembrane pores in the target membrane, as such facilitating bacterial invasion. In addition, amaranthin domains also occur in association with five other protein domains, including the fascin domain, the alpha/beta hydrolase domain, the TRAF-like domain, the B box type zinc finger domain and the Bet v1 domain. All 16 amaranthin-like proteins retrieved from the cucumber genome possess a similar domain architecture consisting of two amaranthin domains linked to one aerolysin domain. Based on phylogenetic differences, four sequences were selected for further investigation. Subcellular localization studies revealed that the amaranthin-like proteins from cucumber reside in the cytoplasm and/or the nucleus. Analyses using qPCR showed that the transcript levels for the amaranthin-like sequences are typically low and expression levels vary among tissues during the development of cucumber plants. Furthermore, the expression of amaranthin-like genes is enhanced after different abiotic stresses, suggesting that these amaranthin-like proteins play a role in the stress response. Finally, molecular modeling was performed to unravel the structure of amaranthin-like proteins and their carbohydrate-binding sites. This study provided valuable information on the distribution, phylogenetic relationships, and possible biological roles of amaranthin-like proteins in plants. PMID- 28848573 TI - Limitation of Unloading in the Developing Grains Is a Possible Cause Responsible for Low Stem Non-structural Carbohydrate Translocation and Poor Grain Yield Formation in Rice through Verification of Recombinant Inbred Lines. AB - Remobilisation of non-structural carbohydrates (NSC) from leaves and stems and unloading into developing grains are essential for yield formation of rice. In present study, three recombinant inbred lines of rice, R91, R156 and R201 have been tested for source-flow-sink related attributes determining the nature of NSC accumulation and translocation at two nitrogen levels in the field. Compared to R91 and R156, R201 had lower grain filling percentage, harvest index, and grain yield. Meanwhile, R201 had significantly lower stem NSC translocation during grain filling stage. Grain filling percentage, harvest index, and grain yield showed the consistent trend with stem NSC translocation among the three lines. In comparison with R91 and R156, R201 had similarity in leaf area index, specific leaf weight, stem NSC concentration at heading, biomass, panicles m-2, spikelets per panicle, remobilization capability of assimilation in stems, sink capacity, sink activity, number and cross sectional area of small vascular bundles, greater number and cross sectional area of large vascular bundles, and higher SPAD, suggesting that source, flow, and sink were not the limiting factors for low stem NSC translocation and grain filling percentage of R201. However, R201 had significant higher stem and rachis NSC concentrations at maturity, which implied that unloading in the developing grains might result in low NSC translocation in R201. The results indicate that stem NSC translocation could be beneficial for enhancement of grain yield potential, and poor unloading into caryopsis may be the possible cause of low stem NSC translocation, poor grain filling and yield formation in R201. PMID- 28848574 TI - Uncovering Male Fertility Transition Responsive miRNA in a Wheat Photo Thermosensitive Genic Male Sterile Line by Deep Sequencing and Degradome Analysis. AB - MicroRNAs (miRNAs) are endogenous small RNAs which play important negative regulatory roles at both the transcriptional and post-transcriptional levels in plants. Wheat is the most commonly cultivated plant species worldwide. In this study, RNA-seq analysis was used to examine the expression profiles of miRNA in the spikelets of photo-thermosenisitive genic male sterile (PTGMS) wheat line BS366 during male fertility transition. Through mapping on their corresponding precursors, 917-7,762 novel miRNAs were found in six libraries. Six novel miRNAs were selected for examination of their secondary structures and confirmation by stem-loop RT-PCR. In a differential expression analysis, 20, 22, and 58 known miRNAs exhibited significant differential expression between developmental stages 1 (secondary sporogenous cells had formed), 2 (all cells layers were present and mitosis had ceased), and 3 (meiotic division stage), respectively, of fertile and sterile plants. Some of these differential expressed miRNAs, such as tae-miR156, tae-miR164, tae-miR171, and tae-miR172, were shown to be associated with their targets. These targets were previously reported to be related to pollen development and/or male sterility, indicating that these miRNAs and their targets may be involved in the regulation of male fertility transition in the PTGMS wheat line BS366. Furthermore, target genes of miRNA cleavage sites were validated by degradome sequencing. In this study, a possible signal model for the miRNA mediated signaling pathway during the process of male fertility transition in the PTGMS wheat line BS366 was developed. This study provides a new perspective for understanding the roles of miRNAs in male fertility in PTGMS lines of wheat. PMID- 28848575 TI - Phenotypic and Comparative Transcriptome Analysis of Different Ploidy Plants in Dendrocalamus latiflorus Munro. AB - Elucidating the differences in gene expression profiles of plants with different ploidy levels and how they affect phenotypic traits is vital to allow genetic improvement of plants such as Ma bamboo (Dendrocalamus latiflorus Munro). We previously obtained triploid (2n = 3X = 36), hexaploid (2n = 6X = 72), and dodecaploid (2n = 12X = 144) Ma bamboo plants from embryogenic callus by anther culturing. Phenotypic differences between these plants appeared to be correlated with differences in ploidy. Here, we performed transcriptome profiling and sequencing of anther-regenerated plants and F1 seedlings of different ploidy levels using RNA-Seq technology. Pair-wise comparisons of the four resulting libraries revealed 8,396 differentially expressed genes. These differentially expressed genes were annotated, functionally classified, and partially validated. We found that the chromosome doubling led to substantially up- or down-regulation of genes that were involved in cell growth and differentiation; the polyploidy levels altered the anatomical, physiological and growth characteristics, such as leaf thickness, fusoid cell and stomatal size, shoot number, photosynthesis and respiration rate and so on. Additionally, two candidate genes, EXPB3 and TCP with potenitial regulatory roles in cell division and differentiation, were identified through gene coexpresseion network analysis. These results highlight the significance of potential applications of polyploidy, and provide valuable information for the genetic breeding of bamboo species. PMID- 28848576 TI - Salt Stress Represses Soybean Seed Germination by Negatively Regulating GA Biosynthesis While Positively Mediating ABA Biosynthesis. AB - Soybean is an important and staple oilseed crop worldwide. Salinity stress has adverse effects on soybean development periods, especially on seed germination and post-germinative growth. Improving seed germination and emergence will have positive effects under salt stress conditions on agricultural production. Here we report that NaCl delays soybean seed germination by negatively regulating gibberellin (GA) while positively mediating abscisic acid (ABA) biogenesis, which leads to a decrease in the GA/ABA ratio. This study suggests that fluridone (FLUN), an ABA biogenesis inhibitor, might be a potential plant growth regulator that can promote soybean seed germination under saline stress. Different soybean cultivars, which possessed distinct genetic backgrounds, showed a similar repressed phenotype during seed germination under exogenous NaCl application. Biochemical analysis revealed that NaCl treatment led to high MDA (malondialdehyde) level during germination and the post-germinative growth stages. Furthermore, catalase, superoxide dismutase, and peroxidase activities also changed after NaCl treatment. Subsequent quantitative Real-Time Polymerase Chain Reaction analysis showed that the transcription levels of ABA and GA biogenesis and signaling genes were altered after NaCl treatment. In line with this, phytohormone measurement also revealed that NaCl considerably down regulated active GA1, GA3, and GA4 levels, whereas the ABA content was up regulated; and therefore ratios, such as GA1/ABA, GA3/ABA, and GA4/ABA, are decreased. Consistent with the hormonal quantification, FLUN partially rescued the delayed-germination phenotype caused by NaCl-treatment. Altogether, these results demonstrate that NaCl stress inhibits soybean seed germination by decreasing the GA/ABA ratio, and that FLUN might be a potential plant growth regulator that could promote soybean seed germination under salinity stress. PMID- 28848577 TI - Ascorbic Acid Alleviates Damage from Heat Stress in the Photosystem II of Tall Fescue in Both the Photochemical and Thermal Phases. AB - L-Ascorbate (Asc) plays important roles in plant development, hormone signaling, the cell cycle and cellular redox system, etc. The higher content of Asc in plant chloroplasts indicates its important role in the photosystem. The objective of this study was to study the roles of Asc in tall fescue leaves against heat stress. After a heat stress treatment, we observed a lower value of the maximum quantum yield for primary photochemistry (phiPo), which reflects the inhibited activity of the photochemical phase of photosystem II (PSII). Moreover, we observed a higher value of efficiency of electron transfer from QB to photosystem I acceptors (deltaR0), which reflects elevated activity of the thermal phase of the photosystem of the tall fescue. The addition of Asc facilitate the behavior of the photochemical phase of the PSII by lowering the ROS content as well as that of the alternative electron donor to provide electron to the tyrosine residue of the D1 protein. Additionally, exogenous Asc reduces the activity of the thermal phase of the photosystem, which could contribute to the limitation of energy input into the photosystem in tall fescue against heat stress. Synthesis of the Asc increased under heat stress treatment. However, under heat stress this regulation does not occur at the transcription level and requires further study. PMID- 28848578 TI - A Wheat R2R3-type MYB Transcription Factor TaODORANT1 Positively Regulates Drought and Salt Stress Responses in Transgenic Tobacco Plants. AB - MYB transcription factors play important roles in plant responses to biotic and abiotic stress. In this study, TaODORANT1, a R2R3-MYB gene, was cloned from wheat (Triticum aestivum L.). TaODORANT1 was localized in the nucleus and functioned as a transcriptional activator. TaODORANT1 was up-regulated in wheat under PEG6000, NaCl, ABA, and H2O2 treatments. TaODORANT1-overexpressing transgenic tobacco plants exhibited higher relative water content and lower water loss rate under drought stress, as well as lower Na+ accumulation in leaves under salt stress. The transgenic plants showed higher CAT activity but lower ion leakage, H2O2 and malondialdehyde contents under drought and salt stresses. Besides, the transgenic plants also exhibited higher SOD activity under drought stress. Our results also revealed that TaODORANT1 overexpression up-regulated the expression of several ROS- and stress-related genes in response to both drought and salt stresses, thus enhancing transgenic tobacco plants tolerance. Our studies demonstrate that TaODORANT1 positively regulates plant tolerance to drought and salt stresses. PMID- 28848579 TI - Pattern of Water Use and Seed Yield under Terminal Drought in Chickpea Genotypes. AB - Drought, particularly terminal drought, reduces the yield of chickpea (Cicer arietinum L.). Terminal drought tolerance and water use patterns were evaluated under controlled conditions in 10 genotypes of desi chickpea. Withholding water from early podding reduced vegetative growth, reproductive growth, seed yield, and water use efficiency for seed yield in all genotypes. The genotype Neelam, which produced the highest seed yield when water was withheld, used the least water when well-watered; however, its aboveground biomass at maturity did not differ significantly from six of the nine other genotypes. Indeed, the water stressed Neelam had the lowest daily transpiration rate during the early stages of water stress and the highest during the later stages, thereby maintaining the highest soil water content in the first 16 days after water was withheld, which enabled higher pod production, lower pod abortion, and better seed filling. Genotypes differed in the threshold value of the fraction of transpirable soil water when flowering and seed set ceased in the water-stress treatment. We conclude that a conservative water use strategy benefits seed yield of chickpea exposed to water shortage during early podding. PMID- 28848580 TI - Nitrate Uptake Affects Cell Wall Synthesis and Modeling. AB - Nowadays, the relationship(s) about N assimilation and cell wall remodeling in plants remains generally unclear. Enzymes involved in cell wall synthesis/modification, and nitrogen transporters play a critical role in plant growth, differentiation, and response to external stimuli. In this review, a co expression analysis of nitrate and ammonium transporters of Arabidopsis thaliana was performed in order to explore the functional connection of these proteins with cell-wall related enzymes. This approach highlighted a strict relationship between inorganic nitrogen transporters and cell wall formation, identifying a number of co-expressed remodeling enzymes. The enzymes involved in pectin and xyloglucan synthesis resulted particularly co-regulated together with nitrate carriers, suggesting a connection between nitrate assimilation and cell wall growth regulation. Major Facilitator Carriers, and one chloride channel, are similarly co-expressed with pectin lyase, pectinacetylesterase, and cellulose synthase. Contrarily, ammonium transporters show little or no connection with those genes involved in cell wall synthesis. Different aspects related to plant development, embryogenesis, and abiotic stress response will be discussed, given the importance in plant growth of cell wall synthesis and nitrate uptake. Intriguingly, the improvement of abiotic stress tolerance in crops concerns both these processes indicating the importance in sensing the environmental constraints and mediating a response. These evaluations could help to identify candidate genes for breeding purposes. PMID- 28848581 TI - Sugar Accumulation in Leaves of Arabidopsis sweet11/sweet12 Double Mutants Enhances Priming of the Salicylic Acid-Mediated Defense Response. AB - In compatible interactions, biotrophic microbial phytopathogens rely on the supply of assimilates by the colonized host tissue. It has been found in rice that phloem localized SWEET sucrose transporters can be reprogrammed by bacterial effectors to establish compatibility. We observed that sweet11/sweet12 double mutants, but not single mutants, exhibited increased resistance toward the fungal hemibiotroph Colletotrichum higginsianum (Ch), both in the biotrophic and the necrotrophic colonization phase. We therefore investigated if the phloem localized transporters AtSWEET11 and AtSWEET12 represent additive susceptibility factors in the interaction of Arabidopsis with Ch. AtSWEET12-YFP fusion protein driven by the endogenous promoter strongly accumulated at Ch infection sites and in the vasculature upon challenge with Ch. However, susceptibility of sweet12 single mutants to Ch was comparable to wild type, indicating that the accumulation of AtSWEET12 at Ch infection sites does not play a major role for compatibility. AtSWEET12-YFP reporter protein was not detectable at the plant pathogen interface, suggesting that AtSWEET12 is not targeted by Ch effectors. AtSWEET11-YFP accumulation in pAtSWEET11:AtSWEET11-YFP plants were similar in Ch infected and mock control leaves. A close inspection of major carbohydrate metabolism in non-infected control plants revealed that soluble sugar and starch content were substantially elevated in sweet11/sweet12 double mutants during the entire diurnal cycle, that diurnal soluble sugar turnover was increased more than twofold in sweet11/sweet12, and that accumulation of free hexoses and sucrose was strongly expedited in double mutant leaves compared to wild type and both single mutants during the course of Ch infection. After 2 days of treatment, free and conjugated SA levels were significantly increased in infected and mock control leaves of sweet11/sweet12 relative to all other genotypes, respectively. Induced genes in mock treated sweet11/sweet12 leaves were highly significantly enriched for several GO terms associated with SA signaling and response compared to mock treated wild-type leaves, indicating sugar-mediated priming of the SA pathway in the double mutant. Infection assays with salicylic acid deficient sweet11/sweet12/sid2 triple mutants demonstrated that reduced susceptibility observed in sweet11/sweet12 was entirely dependent on the SA pathway. We suggest a model how defects in phloem loading of sucrose can influence SA priming and hence, compatibility. PMID- 28848582 TI - Molecular Mapping of Reduced Plant Height Gene Rht24 in Bread Wheat. AB - Height is an important trait related to plant architecture and yield potential in bread wheat (Triticum aestivum L.). We previously identified a major quantitative trait locus QPH.caas-6A flanked by simple sequence repeat markers Xbarc103 and Xwmc256 that reduced height by 8.0-10.4%. Here QPH.caas-6A, designated as Rht24, was confirmed using recombinant inbred lines (RILs) derived from a Jingdong 8/Aikang 58 cross. The target sequences of Xbarc103 and Xwmc256 were used as queries to BLAST against International Wheat Genome Sequence Consortium database and hit a super scaffold of approximately 208 Mb. Based on gene annotation of the scaffold, three gene-specific markers were developed to genotype the RILs, and Rht24 was narrowed to a 1.85 cM interval between TaAP2 and TaFAR. In addition, three single nucleotide polymorphism (SNP) markers linked to Rht24 were identified from SNP chip-based screening in combination with bulked segregant analysis. The allelic efficacy of Rht24 was validated in 242 elite wheat varieties using TaAP2 and TaFAR markers. These showed a significant association between genotypes and plant height. Rht24 reduced plant height by an average of 6.0-7.9 cm across environments and were significantly associated with an increased TGW of 2.0-3.4 g. The findings indicate that Rht24 is a common dwarfing gene in wheat breeding, and TaAP2 and TaFAR can be used for marker-assisted selection. PMID- 28848583 TI - Petroleum Contamination and Plant Identity Influence Soil and Root Microbial Communities While AMF Spores Retrieved from the Same Plants Possess Markedly Different Communities. AB - Phytoremediation is a promising in situ green technology based on the use of plants to cleanup soils from organic and inorganic pollutants. Microbes, particularly bacteria and fungi, that closely interact with plant roots play key roles in phytoremediation processes. In polluted soils, the root-associated microbes contribute to alleviation of plant stress, improve nutrient uptake and may either degrade or sequester a large range of soil pollutants. Therefore, improving the efficiency of phytoremediation requires a thorough knowledge of the microbial diversity living in the rhizosphere and in close association with plant roots in both the surface and the endosphere. This study aims to assess fungal ITS and bacterial 16S rRNA gene diversity using high-throughput sequencing in rhizospheric soils and roots of three plant species (Solidago canadensis, Populus balsamifera, and Lycopus europaeus) growing spontaneously in three petroleum hydrocarbon polluted sedimentation basins. Microbial community structures of rhizospheric soils and roots were compared with those of microbes associated with arbuscular mycorrhizal fungal (AMF) spores to determine the links between the root and rhizosphere communities and those associated with AMF. Our results showed a difference in OTU richness and community structure composition between soils and roots for both bacteria and fungi. We found that petroleum hydrocarbon pollutant (PHP) concentrations have a significant effect on fungal and bacterial community structures in both soils and roots, whereas plant species identity showed a significant effect only on the roots for bacteria and fungi. Our results also showed that the community composition of bacteria and fungi in soil and roots varied from those associated with AMF spores harvested from the same plants. This let us to speculate that in petroleum hydrocarbon contaminated soils, AMF may release chemical compounds by which they recruit beneficial microbes to tolerate or degrade the PHPs present in the soil. PMID- 28848584 TI - The Second Intron Is Essential for the Transcriptional Control of the Arabidopsis thaliana GLABRA3 Gene in Leaves. AB - The GLABRA3 gene is a major regulator of trichome patterning in Arabidopsis thaliana. The regulatory regions important for the trichome-specific expression of GL3 have not been characterized yet. In this study, we used a combination of marker and rescue constructs to determine the relevant promoter regions. We demonstrate that a 1 kb 5' region combined with the second intron is sufficient to rescue the trichome mutant phenotype of gl3 egl3 mutants. Swap experiments of the second intron suggest that it is not sufficient to generally enhance the expression level of GL3. This implies that the second intron contains regulatory regions for the temporal and spatial regulation of GL3. The corresponding GUS marker constructs revealed trichome-specific expression in young trichomes. PMID- 28848586 TI - Auxin Control of Root Organogenesis from Callus in Tissue Culture. PMID- 28848587 TI - Enhancing Brassinosteroid Signaling via Overexpression of Tomato (Solanum lycopersicum) SlBRI1 Improves Major Agronomic Traits. AB - Brassinosteroids (BRs) play important roles in plant growth, development, and stress responses through the receptor, Brassinosteroid-insensitive 1 (BRI1), which perceives BRs and initiates BR signaling. There is considerable potential agricultural value in regulating BR signaling in crops. In this study, we investigated the effects of overexpressing the tomato (Solanum lycopersicum) BRI1 gene, SlBRI1, on major agronomic traits, such as seed germination, vegetative growth, fruit ethylene production, carotenoid accumulation, yield, and quality attributes. SlBRI1 overexpression enhanced the endogenous BR signaling intensity thereby increasing the seed germination rate, lateral root number, hypocotyl length, CO2 assimilation, plant height, and flower size. The transgenic plants also showed an increase in fruit yield and fruit number per plant, although the mean weight of individual fruit was reduced, compared with wild type. SlBRI1 overexpression also promoted fruit ripening and ethylene production, and caused an increase in levels of carotenoids, ascorbic acid, soluble solids, and soluble sugars during fruit ripening. An increased BR signaling intensity mediated by SlBRI1 overexpression was therefore positively correlated with carotenoid accumulation and fruit nutritional quality. Our results indicate that enhancing BR signaling by overexpression of SlBRI1 in tomato has the potential to improve multiple major agronomic traits. PMID- 28848585 TI - The Protein Kinase SmSnRK2.6 Positively Regulates Phenolic Acid Biosynthesis in Salvia miltiorrhiza by Interacting with SmAREB1. AB - Subclass III members of the sucrose non-fermenting-1-related protein kinase 2 (SnRK2) play essential roles in both the abscisic acid signaling and abiotic stress responses of plants by phosphorylating the downstream ABA-responsive element (ABRE)-binding proteins (AREB/ABFs). This comprehensive study investigated the function of new candidate genes, namely SmSnRK2.3, SmSnRK2.6, and SmAREB1, with a view to breeding novel varieties of Salvia miltiorrhiza with improved stress tolerance stresses and more content of bioactive ingredients. Exogenous ABA strongly induced the expression of these genes. PlantCARE predicted several hormones and stress response cis-elements in their promoters. SmSnRK2.6 and SmAREB1 showed the highest expression levels in the leaves of S. miltiorrhiza seedlings, while SmSnRK2.3 exhibited a steady expression in their roots, stems, and leaves. A subcellular localization assay revealed that both SmSnRK2.3 and SmSnRK2.6 were located in the cell membrane, cytoplasm, and nucleus, whereas SmAREB1 was exclusive to the nucleus. Overexpressing SmSnRK2.3 did not significantly promote the accumulation of rosmarinic acid (RA) and salvianolic acid B (Sal B) in the transgenic S. miltiorrhiza hairy roots. However, overexpressing SmSnRK2.6 and SmAREB1 increased the contents of RA and Sal B, and regulated the expression levels of structural genes participating in the phenolic acid-branched and side-branched pathways, including SmPAL1, SmC4H, Sm4CL1, SmTAT, SmHPPR, SmRAS, SmCHS, SmCCR, SmCOMT, and SmHPPD. Furthermore, SmSnRK2.3 and SmSnRK2.6 interacted physically with SmAREB1. In summary, our results indicate that SmSnRK2.6 is involved in stress responses and can regulate structural gene transcripts to promote greater metabolic flux to the phenolic acid-branched pathway, via its interaction with SmAREB1, a transcription factor. In this way, SmSnRK2.6 contributes to the positive regulation of phenolic acids in S. miltiorrhiza hairy roots. PMID- 28848588 TI - A High-Density Consensus Map of Common Wheat Integrating Four Mapping Populations Scanned by the 90K SNP Array. AB - A high-density consensus map is a powerful tool for gene mapping, cloning and molecular marker-assisted selection in wheat breeding. The objective of this study was to construct a high-density, single nucleotide polymorphism (SNP)-based consensus map of common wheat (Triticum aestivum L.) by integrating genetic maps from four recombinant inbred line populations. The populations were each genotyped using the wheat 90K Infinium iSelect SNP assay. A total of 29,692 SNP markers were mapped on 21 linkage groups corresponding to 21 hexaploid wheat chromosomes, covering 2,906.86 cM, with an overall marker density of 10.21 markers/cM. Compared with the previous maps based on the wheat 90K SNP chip detected 22,736 (76.6%) of the SNPs with consistent chromosomal locations, whereas 1,974 (6.7%) showed different chromosomal locations, and 4,982 (16.8%) were newly mapped. Alignment of the present consensus map and the wheat expressed sequence tags (ESTs) Chromosome Bin Map enabled assignment of 1,221 SNP markers to specific chromosome bins and 819 ESTs were integrated into the consensus map. The marker orders of the consensus map were validated based on physical positions on the wheat genome with Spearman rank correlation coefficients ranging from 0.69 (4D) to 0.97 (1A, 4B, 5B, and 6A), and were also confirmed by comparison with genetic position on the previously 40K SNP consensus map with Spearman rank correlation coefficients ranging from 0.84 (6D) to 0.99 (6A). Chromosomal rearrangements reported previously were confirmed in the present consensus map and new putative rearrangements were identified. In addition, an integrated consensus map was developed through the combination of five published maps with ours, containing 52,607 molecular markers. The consensus map described here provided a high-density SNP marker map and a reliable order of SNPs, representing a step forward in mapping and validation of chromosomal locations of SNPs on the wheat 90K array. Moreover, it can be used as a reference for quantitative trait loci (QTL) mapping to facilitate exploitation of genes and QTL in wheat breeding. PMID- 28848589 TI - Withania somnifera: Advances and Implementation of Molecular and Tissue Culture Techniques to Enhance Its Application. AB - Withania somnifera, commonly known as Ashwagandha an important medicinal plant largely used in Ayurvedic and indigenous medicine for over 3,000 years. Being a medicinal plant, dried powder, crude extract as well as purified metabolies of the plant has shown promising therapeutic properties. Withanolides are the principal metabolites, responsible for the medicinal properties of the plant. Availability and amount of particular withanolides differ with tissue type and chemotype and its importance leads to identification characterization of several genes/ enzymes related to withanolide biosynthetic pathway. The modulation in withanolides can be achieved by controlling the environmental conditions like, different tissue culture techniques, altered media compositions, use of elicitors, etc. Among all the in vitro techniques, hairy root culture proved its importance at industrial scale, which also gets benefits due to more accumulation (amount and number) of withanolides in roots tissues of W. somnifera. Use of media compostion and elicitors further enhances the amount of withanolides in hairy roots. Another important modern day technique used for accumulation of desired secondary metabolites is modulating the gene expression by altering environmental conditions (use of different media composition, elicitors, etc.) or through genetic enginnering. Knowing the significance of the gene and the key enzymatic step of the pathway, modulation in withanolide contents can be achieved upto required amount in therapeutic industry. To accomplish maximum productivity through genetic enginnering different means of Withania transformation methods have been developed to obtain maximum transformation efficiency. These standardized transformation procedues have been used to overexpress/silence desired gene in W. somnifera to understand the outcome and succeed with enhanced metabolic production for the ultimate benefit of human race. PMID- 28848591 TI - Proteins in Relation to Vigor and Viability of White Lupin (Lupinus albus L.) Seed Stored for 26 Years. AB - The aim of the study was to evaluate the vigor and viability as well as to determine and compare the contents of selected protein fractions of white lupin (Lupinus albus L.) seeds stored for 26 years at temperatures of -14 degrees C and +20 degrees C. The seeds stored at -14 degrees C germinated in 86.3%, while the seeds stored at +20 degrees C did not germinate at all. The viability evaluation was confirmed by the measuring electroconductivity of seed exudates. In seeds stored at -14 degrees C the contents of gamma, delta, and beta conglutin were 14, 4 and 69 mg g-1 fresh mass, respectively, while in seed stored at +20 degrees C they were 15.5, 3, 65 mg g-1 fresh mass, respectively. One-dimensional electrophoresis of gamma and delta conglutin fractions indicated the presence of several intense polypeptide bands with molecular weights from 23.0 to 10.3 kDa. Polypeptide bands with a molecular weight of 22.4 and 19.8 kDa exhibited almost two times higher expression in the seeds stored at -14 degrees C compared to the seeds stored at +20 degrees C. Electrophoresis revealed 310 protein spots on the maps generated for seeds stored at -14 degrees C, and 228 spots for seeds stored at +20 degrees C. In seeds stored at +20 degrees C most polypeptide subunits had a pI ranging from 4.5 to 7 and a molecular weight of 10-97 kDa. The greatest differences in the contents of polypeptides between the analyzed variants was observed within the range of 20-45 kDa (-14 degrees C: 175, +20 degrees C: 115 protein spots) and within the range of 65-97 kDa (-14 degrees C: 103, +20 degrees C: 75 protein spots). In seeds stored at +20 degrees C, a clear decline in basic (8-10 pI) polypeptides was observed. The study demonstrated that the polypeptides identified as gamma and delta conglutins are probably closely related to vigor and viability of seeds. PMID- 28848590 TI - Transcriptome Profiling to Identify Genes Involved in Mesosulfuron-Methyl Resistance in Alopecurus aequalis. AB - Non-target-site resistance (NTSR) to herbicides is a worldwide concern for weed control. However, as the dominant NTSR mechanism in weeds, metabolic resistance is not yet well-characterized at the genetic level. For this study, we have identified a shortawn foxtail (Alopecurus aequalis Sobol.) population displaying both TSR and NTSR to mesosulfuron-methyl and fenoxaprop-P-ethyl, yet the molecular basis for this NTSR remains unclear. To investigate the mechanisms of metabolic resistance, an RNA-Seq transcriptome analysis was used to find candidate genes that may confer metabolic resistance to the herbicide mesosulfuron-methyl in this plant population. The RNA-Seq libraries generated 831,846,736 clean reads. The de novo transcriptome assembly yielded 95,479 unigenes (averaging 944 bp in length) that were assigned putative annotations. Among these, a total of 29,889 unigenes were assigned to 67 GO terms that contained three main categories, and 14,246 unigenes assigned to 32 predicted KEGG metabolic pathways. Global gene expression was measured using the reads generated from the untreated control (CK), water-only control (WCK), and mesosulfuron-methyl treatment (T) of R and susceptible (S). Contigs that showed expression differences between mesosulfuron-methyl-treated R and S biotypes, and between mesosulfuron-methyl-treated, water-treated and untreated R plants were selected for further quantitative real-time PCR (qRT-PCR) validation analyses. Seventeen contigs were consistently highly expressed in the resistant A. aequalis plants, including four cytochrome P450 monooxygenase (CytP450) genes, two glutathione S-transferase (GST) genes, two glucosyltransferase (GT) genes, two ATP-binding cassette (ABC) transporter genes, and seven additional contigs with functional annotations related to oxidation, hydrolysis, and plant stress physiology. These 17 contigs could serve as major candidate genes for contributing to metabolic mesosulfuron-methyl resistance; hence they deserve further functional study. This is the first large-scale transcriptome-sequencing study to identify NTSR genes in A. aequalis that uses the Illumina platform. This work demonstrates that NTSR is likely driven by the differences in the expression patterns of a set of genes. The assembled transcriptome data presented here provide a valuable resource for A. aequalis biology, and should facilitate the study of herbicide resistance at the molecular level in this and other weed species. PMID- 28848592 TI - New Genetic Loci Associated with Preharvest Sprouting and Its Evaluation Based on the Model Equation in Rice. AB - Preharvest sprouting (PHS) in rice panicles is an important quantitative trait that causes both yield losses and the deterioration of grain quality under unpredictable moisture conditions at the ripening stage. However, the molecular mechanism underlying PHS has not yet been elucidated. Here, we explored the genetic loci associated with PHS in rice and formulated a model regression equation for rapid screening for use in breeding programs. After re-sequencing 21 representative accessions for PHS and performing enrichment analysis, we found that approximately 20,000 SNPs revealed distinct allelic distributions between PHS resistant and susceptible accessions. Of these, 39 candidate SNP loci were selected, including previously reported QTLs. We analyzed the genotypes of 144 rice accessions to determine the association between PHS and the 39 candidate SNP loci, 10 of which were identified as significantly affecting PHS based on allele type. Based on the allele types of the SNP loci, we constructed a regression equation for evaluating PHS, accounting for an R2 value of 0.401 in japonica rice. We validated this equation using additional accessions, which exhibited a significant R2 value of 0.430 between the predicted values and actual measurements. The newly detected SNP loci and the model equation could facilitate marker-assisted selection to predict PHS in rice germplasm and breeding lines. PMID- 28848593 TI - Phytochrome A and B Regulate Primary Metabolism in Arabidopsis Leaves in Response to Light. AB - Primary metabolism is closely linked to plant productivity and quality. Thus, a better understanding of the regulation of primary metabolism by photoreceptors has profound implications for agricultural practices and management. This study aims at identifying the role of light signaling in the regulation of primary metabolism, with an emphasis on starch. We first screened seven cryptochromes and phytochromes mutants for starch phenotype. The phyAB mutant showed impairment in starch accumulation while its biomass, chlorophyll fluorescence parameters, and leaf anatomy were unaffected, this deficiency being present over the whole vegetative growth period. Mutation of plastidial nucleoside diphosphate kinase-2 (NDPK2), acting downstream of phytochromes, also caused a deficit in starch accumulation. Besides, the glucose-1-phosphate adenylyltransferase small subunit (APS1) was down-regulated in phyAB. Those results suggest that PHYAB affect starch accumulation through NDPK2 and APS1. Then, we determined changes in starch and primary metabolites in single phyA, single phyB, double phyAB grown in light conditions differing in light intensity and/or light spectral content. PHYA is involved in starch accumulation in all the examined light conditions, whereas PHYB only exhibits a role under low light intensity (44 +/- 1 MUmol m-2 s-1) or low R:FR (11.8 +/- 0.6). PCA analysis of the metabolic profiles in the mutants and wild type (WT) suggested that PHYB acts as a major regulator of the leaf metabolic status in response to light intensity. Overall, we propose that PHYA and PHYB signaling play essential roles in the control of primary metabolism in Arabidopsis leaves in response to light. PMID- 28848594 TI - Defense-Related Transcriptional Reprogramming in Vitamin E-Deficient Arabidopsis Mutants Exposed to Contrasting Phosphate Availability. AB - Vitamin E inhibits the propagation of lipid peroxidation and helps protecting photosystem II from photoinhibition, but little is known about its possible role in plant response to Pi availability. Here, we aimed at examining the effect of vitamin E deficiency in Arabidopsis thaliana vte mutants on phytohormone contents and the expression of transcription factors in plants exposed to contrasting Pi availability. Plants were subjected to two doses of Pi, either unprimed (controls) or previously exposed to low Pi (primed). In the wild type, alpha tocopherol contents increased significantly in response to repeated periods of low Pi, which was paralleled by increased growth, indicative of a priming effect. This growth-stimulating effect was, however, abolished in vte mutants. Hormonal profiling revealed significant effects of Pi availability, priming and genotype on the contents of jasmonates and salicylates; remarkably, vte mutants showed enhanced accumulation of both hormones under low Pi. Furthermore, expression profiling of 1,880 transcription factors by qRT-PCR revealed a pronounced effect of priming on the transcript levels of 45 transcription factors mainly associated with growth and stress in wild-type plants in response to low Pi availability; while distinct differences in the transcriptional response were detected in vte mutants. We conclude that alpha-tocopherol plays a major role in the response of plants to Pi availability not only by protecting plants from photo-oxidative stress, but also by exerting a control over growth- and defense-related transcriptional reprogramming and hormonal modulation. PMID- 28848596 TI - Water-Deficit Tolerance in Sweet Potato [Ipomoea batatas (L.) Lam.] by Foliar Application of Paclobutrazol: Role of Soluble Sugar and Free Proline. AB - The objective of this study was to elevate water deficit tolerance by improving soluble sugar and free proline accumulation, photosynthetic pigment stabilization, photosynthetic abilities, growth performance and storage root yield in sweet potato cv. 'Tainung 57' using a foliar application of paclobutrazol (PBZ). The experiment followed a Completely Randomized Block Design with four concentrations of PBZ: 0 (control), 17, 34, and 51 MUM before exposure to 47.5% (well irrigation), 32.3% (mild water deficit) or 17.5% (severe water deficit) soil water content. A sweet potato cultivar, 'Japanese Yellow', with water deficit tolerance attributes was the positive check in this study. Total soluble sugar content (sucrose, glucose, and fructose) increased by 3.96-folds in 'Tainung 57' plants treated with 34 MUM PBZ grown under 32.3% soil water content (SWC) compared to the untreated plants, adjusting osmotic potential in the leaves and controlling stomatal closure (represented by stomatal conductance and transpiration rate). In addition, under the same treatment, free proline content (2.15 MUmol g-1 FW) increased by 3.84-folds when exposed to 17.5% SWC. PBZ had an improved effect on leaf size, vine length, photosynthetic pigment stability, chlorophyll fluorescence, and net photosynthetic rate; hence, delaying wilting symptoms and maintaining storage root yield (26.93 g plant-1) at the harvesting stage. A positive relationship between photon yield of PSII (PhiPSII) and net photosynthetic rate was demonstrated (r2 = 0.73). The study concludes that soluble sugar and free proline enrichment in PBZ-pretreated plants may play a critical role as major osmoprotectant to control leaf osmotic potential and stomatal closure when plants were subjected to low soil water content, therefore, maintaining the physiological and morphological characters as well as storage root yield. PMID- 28848595 TI - Genome-Wide Association Study Identifies NBS-LRR-Encoding Genes Related with Anthracnose and Common Bacterial Blight in the Common Bean. AB - Nucleotide-binding site and leucine-rich repeat (NBS-LRR) genes represent the largest and most important disease resistance genes in plants. The genome sequence of the common bean (Phaseolus vulgaris L.) provides valuable data for determining the genomic organization of NBS-LRR genes. However, data on the NBS LRR genes in the common bean are limited. In total, 178 NBS-LRR-type genes and 145 partial genes (with or without a NBS) located on 11 common bean chromosomes were identified from genome sequences database. Furthermore, 30 NBS-LRR genes were classified into Toll/interleukin-1 receptor (TIR)-NBS-LRR (TNL) types, and 148 NBS-LRR genes were classified into coiled-coil (CC)-NBS-LRR (CNL) types. Moreover, the phylogenetic tree supported the division of these PvNBS genes into two obvious groups, TNL types and CNL types. We also built expression profiles of NBS genes in response to anthracnose and common bacterial blight using qRT-PCR. Finally, we detected nine disease resistance loci for anthracnose (ANT) and seven for common bacterial blight (CBB) using the developed NBS-SSR markers. Among these loci, NSSR24, NSSR73, and NSSR265 may be located at new regions for ANT resistance, while NSSR65 and NSSR260 may be located at new regions for CBB resistance. Furthermore, we validated NSSR24, NSSR65, NSSR73, NSSR260, and NSSR265 using a new natural population. Our results provide useful information regarding the function of the NBS-LRR proteins and will accelerate the functional genomics and evolutionary studies of NBS-LRR genes in food legumes. NBS-SSR markers represent a wide-reaching resource for molecular breeding in the common bean and other food legumes. Collectively, our results should be of broad interest to bean scientists and breeders. PMID- 28848597 TI - High Temperature Induced Anthocyanin Inhibition and Active Degradation in Malus profusion. AB - The red fleshed fruits of Malus profusion represent gradual color loss during high temperature in summer, potentially due to active degradation of anthocyanin. The objective of this study was to examine both physiological and molecular evidence of anthocyanin degradation. Malus crabapple fruits were exposed to either room temperature (RT = 18 +/- 2 degrees C: 25 +/- 2 degrees C) or high temperature (HT = 33 +/- 2 degrees C: 25 +/- 2 degrees C) regimens (12 h: 12 h) under hypoxic (2%) or normoxic (21%) oxygen levels. The results showed that the concentration of cyanidin 3-galactoside (cy-3-gal) was dramatically reduced following HT treatments due to a significant down-regulation of anthocyanin biosynthetic genes (MpCHS, MpDFR, MpLDOX, MpUFGT, and MpMYB10). Among other repressor MYBs, MpMYB15 expression was high following HT treatment of the fruit. HT led to the generation of a substantial concentration of H2O2 due to enhanced activities of superoxide dismutase (SOD), methane dicarboxylic aldehyde (MDA) content and cell sap pH value. Similarly, transcript levels of MpVHA-B1 and MpVHA B2 were reduced which are involved in the vacuolar transportation of anthocyanin. The enzymatic degradation of anthocyanin was eventually enhanced coupled with the oxidative activities of peroxidase (POD) and H2O2. Conversely, the RT treatments potentially enhanced anthocyanin content by stabilizing physiological attributes (such as MDA, H2O2, and pH, among others) and sustaining sufficient biosynthetic gene expression levels. Quantitative real-time PCR analysis indicated that the transcription of MpPOD1, MpPOD8 and MpPOD9 genes in fruit tissues was up regulated due to HT treatment and that hypoxic conditions seems more compatible with the responsible POD isoenzymes involved in active anthocyanin degradation. The results of the current study could be useful for understanding as well as elucidating the physiological phenomenon and molecular signaling cascade underlying active anthocyanin degradation in Malus crops. PMID- 28848598 TI - Development of a High-Efficient Mutation Resource with Phenotypic Variation in Hexaploid Winter Wheat and Identification of Novel Alleles in the TaAGP.L-B1 Gene. AB - Mutated genetic resources play an important role in gene/allele characterization. Currently, there are few hexaploid winter wheat mutated resources available. Here, we developed a hexaploid winter wheat resource by inducing mutations via EMS treatment by the single seed descent method. A broad mutation spectrum with high mutation frequency (~19%) on phenotypic variations was identified. These mutations included spike, leaf and seed morphology, plant architecture, and heading date variations. To evaluate the efficiency of the resource for reverse genetic analysis, allelic variations in the TaAGP.L-B1 gene, encoding the AGPase large subunit, were screened by the TILLING approach. Four missense mutations were identified and one allele in line E3-1-3, resulted in an amino acid change predicated to have severe effects on gene function. The other three mutations were predicted to have no effect. Results of gene expression patterns and grain starch content demonstrated that the novel allele in E3-1-3 altered the function of TaAGP.L-B1. Our results indicated that this mutated genetic wheat resource contained broad spectrum phenotypic and genotypic variations, that may be useful for wheat improvement, gene discovery, and functional genomics. PMID- 28848600 TI - A Novel Efficient Graph Model for the Multiple Longest Common Subsequences (MLCS) Problem. AB - Searching for the Multiple Longest Common Subsequences (MLCS) of multiple sequences is a classical NP-hard problem, which has been used in many applications. One of the most effective exact approaches for the MLCS problem is based on dominant point graph, which is a kind of directed acyclic graph (DAG). However, the time and space efficiency of the leading dominant point graph based approaches is still unsatisfactory: constructing the dominated point graph used by these approaches requires a huge amount of time and space, which hinders the applications of these approaches to large-scale and long sequences. To address this issue, in this paper, we propose a new time and space efficient graph model called the Leveled-DAG for the MLCS problem. The Leveled-DAG can timely eliminate all the nodes in the graph that cannot contribute to the construction of MLCS during constructing. At any moment, only the current level and some previously generated nodes in the graph need to be kept in memory, which can greatly reduce the memory consumption. Also, the final graph contains only one node in which all of the wanted MLCS are saved, thus, no additional operations for searching the MLCS are needed. The experiments are conducted on real biological sequences with different numbers and lengths respectively, and the proposed algorithm is compared with three state-of-the-art algorithms. The experimental results show that the time and space needed for the Leveled-DAG approach are smaller than those for the compared algorithms especially on large-scale and long sequences. PMID- 28848599 TI - Two FERONIA-Like Receptor Kinases Regulate Apple Fruit Ripening by Modulating Ethylene Production. AB - Ethylene has long been known to be a critical signal controlling the ripening of climacteric fruits; however, the signaling mechanism underlying ethylene production during fruit development is unknown. Here, we report that two FERONIA like receptor kinases (FERLs) regulate fruit ripening by modulating ethylene production in the climacteric fruit, apple (Malus*domestica). Bioinformatic analysis indicated that the apple genome contains 14 members of the FER family (MdFERL1-17), of these 17 FERLs, MdFERL6 was expressed at the highest level in fruit. Heterologous expression of MdFERL6 or MdFERL1, the apple homolog of Arabidopsis FER, in another climacteric fruit, tomato (Solanum lycopersicum) fruit delayed ripening and suppressed ethylene production. Overexpression and antisense expression of MdFERL6 in apple fruit calli inhibited and promoted ethylene production, respectively. Additionally, virus-induced gene silencing (VIGS) of SlFERL1, the tomato homolog of FER, promoted tomato fruit ripening and ethylene production. Both MdFERL6 and MdFERL1 physically interacted with MdSAMS (S-adenosylmethionine synthase), a key enzyme in the ethylene biosynthesis pathway. MdFERL6 was expressed at high levels during early fruit development, but dramatically declined when fruit ripening commenced, implying that MdFERL6 might limit ethylene production prior to fruit development and the ethylene production burst during fruit ripening. These results indicate that FERLs regulate apple and tomato fruit ripening, shedding light on the molecular mechanisms underlying ripening in climacteric fruit. PMID- 28848601 TI - De Novo Mutation of Paternal IGF2 Gene Causing Silver-Russell Syndrome in a Sporadic Patient. AB - Silver-Russell syndrome (SRS) is a rare, but well-recognized disease characterized by growth disorder. To date, there are two reports arguing IGF2 mutation for the onset of SRS. Herein, we present another sporadic case harboring IGF2 mutation. The male proband was the first and only child of a non consanguineous Chinese couple. He was small for gestational age, with relative macrocephaly at birth. Severe feeding difficulties, low feeding, and growth retardation were revealed during neonatal period. At 4.5 years old, obvious body asymmetry was noted. Whole exome sequencing identified a novel de novo c.101G > A (p.Gly34Asp, NM_000612) variant in IGF2 and Sanger sequencing validated the variant. Amplification refractory mutation system polymerase chain reaction demonstrated that the IGF2 variant was on the paternal allele. Alignment shows the variant is evolutionarily conserved. Structural modeling argues that the variant site might be important for the binding of IGF2 to its receptor. Our study provides further evidence that IGF2 mutation may be another mechanism of SRS, and we consider that IGF2 should be included in a disease specific gene panel in case it is designed for SRS routine diagnostics. PMID- 28848602 TI - Factors Predicting the Adherence to the Therapy of Italian IBD Patients. AB - BACKGROUND: Inflammatory bowel diseases (IBD) are chronic gastrointestinal disorders influencing many aspects of the patient's life and accounting for substantial social costs. They require long-term therapies and regular contact with the clinic of reference. Our aim is to investigate therapy adherence and identify predictors of adherence. METHODS: 151 patients were recruited in IBD clinic at the University of Salerno filled in the modified Morisky Medication Adherence Scale, a standardized questionnaire provided during the visit. RESULTS: Overall, 71.5% of the patients report to take all medications regularly. According to the scale, our population showed a 62.5% medium-high adherence to oral 5-ASA, a 72% medium-high adherence to immunomodulators, a 60% medium-high adherence to oral steroids, and 94.9% adherence to biologics. Younger patients tend to be less compliant to the therapy. The main reasons for the low adherence to therapy were the "hassle of sticking to the medication plan" and "their feeling better." Conclusion. In Italy, where the healthcare system covers most of the expenses for IBD therapy, almost 30% of IBD patients report low compliance to therapy. Healthcare givers should improve the knowledge regarding the disease and favor the development of combined drugs that would simplify the daily medication plan. PMID- 28848603 TI - Baseline Demographic and Clinical Characteristics of Patients with Adrenal Incidentaloma from a Single Center in China: A Survey. AB - AIM: To investigate the clinical and endocrinological characteristics of patients with adrenal incidentaloma (AI). MATERIALS AND METHODS: This retrospective study enrolled 1941 AI patients hospitalized at the Department of Endocrinology, Chinese PLA General Hospital, Beijing, China, between January 1997 and December 2016. The patient gender, age at visits, imaging features, functional status, and histological results were analyzed. RESULTS: Of the 1941 patients, 984 (50.70%) were men. The median age was 52 years (interquartile range: 44-69 years). 140 cases had bilateral AI. Endocrine evaluation showed that 1411 (72.69%) patients had nonfunctional tumor, 152 (7.83%) had subclinical Cushing syndrome (SCS), and 82 (4.33%) had primary hyperaldosteronism. A total of 925 patients underwent operation for removal of 496 cortical adenomas (53.62%), 15 adrenal cortical carcinomas (1.62%), and 172 pheochromocytomas (18.59%). The bilateral group had a higher proportion of SCS (18.57% versus 7.10%, P < 0.001, P = 0.006). A mass size of 46 mm was of great value in distinguishing malignant tumors from the benign tumors, with sensitivity of 88.2% and specificity of 95.5%. CONCLUSIONS: We reported the baseline demographic and clinical characteristics of patients with AI in a large series from a single center in China. PMID- 28848605 TI - Influence of Processing Conditions on the Mechanical Behavior and Morphology of Injection Molded Poly(lactic-co-glycolic acid) 85:15. AB - Two groups of PLGA specimens with different geometries (notched and unnotched) were injection molded under two melting temperatures and flow rates. The mechanical properties, morphology at the fracture surface, and residual stresses were evaluated for both processing conditions. The morphology of the fractured surfaces for both specimens showed brittle and smooth fracture features for the majority of the specimens. Fracture images of the notched specimens suggest that the surface failure mechanisms are different from the core failure. Polarized light techniques indicated birefringence in all specimens, especially those molded with lower temperature, which suggests residual stress due to rapid solidification. DSC analysis confirmed the existence of residual stress in all PLGA specimens. The specimens molded using the lower injection temperature and the low flow rate presented lower loss tangent values according to the DMA and higher residual stress as shown by DSC, and the photoelastic analysis showed extensive birefringence. PMID- 28848604 TI - Morse Taper Connection Implants Placed in Grafted Sinuses in 65 Patients: A Retrospective Clinical Study with 10 Years of Follow-Up. AB - PURPOSE: To investigate the 10-year survival and complication rates of Morse taper connection implants (MTCIs) placed in grafted sinuses. METHODS: This study reports on patients treated with maxillary sinus augmentation (with the lateral window technique (LWT) or the transalveolar osteotomy technique (TOT)) and installed with MTCIs supporting fixed restorations (single crowns (SCs) and fixed partial dentures (FPDs)), in two dental clinics. The outcomes of the study were the 10-year implant survival and complication rates. RESULTS: Sixty-five patients (30 males and 35 females) with a mean age of 62.7 (+/-10.2) years were installed with 142 MTCIs: 79 fixtures were inserted with the LWT and 63 were placed with the TOT. After ten years, five implants failed, for an overall survival rate of 96.5%. Three implants failed in the LWT group, for a survival rate of 96.3%; two implants failed in the TOT group, for a survival rate of 96.9%. The 10-year incidence of biologic complications was 11.9%. Prosthetic complications were all technical in nature and amounted to 7.6%. CONCLUSIONS: MTCIs seem to represent a successful procedure for the prosthetic restoration of the grafted posterior maxilla, in the long term. This study was registered in the ISRCTN registry with number ISRCTN30772506. PMID- 28848606 TI - Time between First and Second Posttonsillectomy Bleeds. AB - OBJECTIVE: To determine the time between first and recurrent posttonsillectomy hemorrhages (PTHs) and find factors related to multiple PTHs. METHODS: Retrospective chart review. RESULTS: Of 112 patients, 91 had one PTH, while 21 had recurrent PTHs. Patients with recurrent bleeds had significant differences (P < 0.05) in indication for tonsillectomy (47.6% had recurrent tonsillitis), prior cardiac conditions (28.6%), transfusions (9.5%), and hematology consults during the initial PTH visit (19%). Bleeding occurred at a mean of 6.1 (range 1-13) days for the first episode and 10 (range 9-18) days for the second episode as compared to 6.65 (range 1-18) days for those who bled once. Recurrent PTH patients were less likely to have had surgical control of the initial bleed (P < 0.05). Patients who bled at 7 days or later were more likely to bleed again within one day (OR 23.0, RR 12). Regression analysis showed that age, failure to have operative control of PTH, and surgical indication were most important in predicting recurrent PTH. CONCLUSIONS: Operative control of PTH is associated with a better outcome than monitoring alone. Patients with PTH within 7 days of tonsillectomy are likely safe to discharge soon after treatment; those who bleed after 7 days should be monitored longer. PMID- 28848607 TI - Electroacupuncture Improved Hippocampal Neurogenesis following Traumatic Brain Injury in Mice through Inhibition of TLR4 Signaling Pathway. AB - The protective role of electroacupuncture (EA) treatment in diverse neurological diseases such as ischemic stroke is well acknowledged. However, whether and how EA act on hippocampal neurogenesis following traumatic brain injury (TBI) remains poorly understood. This study aims to investigate the effect of EA on hippocampal neurogenesis and neurological functions, as well as its underlying association with toll-like receptor 4 (TLR4) signaling in TBI mice. BrdU/NeuN immunofluorescence was performed to label newborn neurons in the hippocampus after EA treatment. Water maze test and neurological severity score were used to evaluate neurological function posttrauma. The hippocampal level of TLR4 and downstream molecules and inflammatory cytokines were, respectively, detected by Western blot and enzyme-linked immunosorbent assay. EA enhanced hippocampal neurogenesis and inhibited TLR4 expression at 21, 28, and 35 days after TBI, but the beneficial effects of EA on posttraumatic neurogenesis and neurological functions were attenuated by lipopolysaccharide-induced TLR4 activation. In addition, EA exerted an inhibitory effect on both TLR4/Myd88/NF-kappaB and TLR4/TRIF/NF-kappaB pathways, as well as the inflammatory cytokine expression in the hippocampus following TBI. In conclusion, EA promoted hippocampal neurogenesis and neurological recovery through inhibition of TLR4 signaling pathway posttrauma, which may be a potential approach to improve the outcome of TBI. PMID- 28848608 TI - Testosterone Therapy Improves the First Year Height Velocity in Adolescent Boys with Constitutional Delay of Growth and Puberty. AB - BACKGROUND: Constitutional delay of growth and puberty (CDGP) can cause significant psychological distress in adolescent boys. Although testosterone usage in this group has not been shown to affect the final adult height, the effect on the first year height velocity has not been widely reported. OBJECTIVES: The aim is to determine whether testosterone treatment improves the first year height velocity in boys with CDGP when compared to boys with CDGP who go through puberty spontaneously. METHODS: Retrospective data from 23 adolescent boys with CDGP was analysed. Ten out of 23 boys (43%) received testosterone injection (testosterone enanthate, 125 mg), once every 6 weeks for 3 doses in total. Both the groups (treated and untreated) had their height, bone age and testicular volume measured at the baseline, The height velocity and final predicted adult height were compared at the end of one year between both the groups. RESULTS: In the testosterone-untreated group, the mean (+/- SD) chronological age, bone age, height standard deviation scores (SDS) and testicular volume were 14.3 years (+/- 0.3),12.1 years (+/- 1.6), -1.9 (+/- 0.8) and 4.7 mL (+/- 1.1) respectively. Within the testosterone-treated group the mean (+/- SD) chronological age, bone age, height SDS and testicular volume at presentation were 14.4 years (+/- 0.4), 11 years (+/- 1.6), -2.1 SD(+/- 0.6) and 4.5 mL (+/- 1.2) respectively. The mean age of treatment with testosterone was 14.4 years (+/- 0.44). The mean height velocity one year after treatment was 8.4 cm/year (+/- 1.7) in the testosterone treated group when compared to 6.1 cm/year (+/- 2.1) in the patients who did not receive treatment (P = 0.01). There was no significant difference in the final predicted height between the 2 groups (P = 0.15). CONCLUSIONS: Testosterone therapy improves the first year height velocity in boys with CDGP, without influencing their final predicted height. PMID- 28848609 TI - Parental Correlates of Body Weight Status Among High School Students in Tehran. AB - This study aimed to determine the parental correlates of body weight status among adolescents in Tehran. The participants were 465 high school students and their parents who resided in Tehran. Body weight and height of the students were measured, and body mass index (BMI)-for-age and body weight status of the students were determined according to the world health organization growth reference (2007). Parents of the students completed a self-administered questionnaire including socio-demographic information, self-reported parental body weight and height, and parental perception of student's body weight status. About half of the parents had an incorrect perception about body weight status of their children with higher rates of underestimation than overestimation. The percentage of parents who correctly perceived body weight status of the students decreased from 100.0% in severe thinness group to 14.0% in obese group. There were no significant associations between marital status, occupation, and education of parents and BMI-for-age of the students. While, both BMI of mother and BMI of father were significantly associated with students' BMI-for-age (r = 0.29 and r = 0.27, respectively; P < 0.05). A great number of parents had incorrect perception regarding body weight status of their offspring; this was true specifically for parents of overweight and obese students. Both parental BMI and parental perception regarding students' body weight status were associated with students' BMI-for-age, indicating the need for parental involvement in weight management programs targeting adolescents. PMID- 28848610 TI - Risk of Coronary Heart Events Based on Rose Angina Questionnaire and ECG Besides Diabetes and Other Metabolic Risk Factors: Results of a 10-Year Follow-up in Tehran Lipid and Glucose Study. AB - BACKGROUND: High-risk individuals for CHD could be diagnosed by some non-invasive and low-priced techniques such as Minnesota ECG coding and rose angina questionnaire (RQ). OBJECTIVES: The present study aimed at determining the risk of incident CHD according to ECG and RQ besides diabetes and other metabolic risk factors in our population. METHODS: Participants comprised of 5431 individuals aged >= 30 years within the framework of Tehran lipid and glucose study. Based on their status on history of CHD, ECG, and RQ at baseline, all participants were classified to 5 following groups: (1) History-Rose-ECG- (the reference group); (2) History-Rose+ECG-; (3) History-Rose-ECG+; (4) History-Rose+ECG+; and (5) History+. We used Cox regression model to find the role of ECG and RQ on CHD, independent of other risk factors. RESULTS: Overall, 562 CHD events were detected during the median of 10.3 years follow-up. CHD incidence rates were 55.9 and 9.09 cases per 1000 person-year for participants with and without history of CHD, respectively. Hazard ratios (HRs) (95% CIs) were 4.11 (3.27 - 5.11) for History + and 2.18 (1.63 - 2.90), 1.92 (1.47 - 2.51), and 2.48 (1.46 - 4.20) for History Rose+ECG-, History-Rose-ECG+, and History-Rose+ECG+, respectively. RQ and ECG had the same HRs as high as those for hypertension and hypercholesterolemia; however, diabetes showed statistically and clinically more effects on CVD than RQ and ECG. CONCLUSIONS: RQ in general and, ECG especially in asymptomatic patients, were good predictors for CHD events in both Iranian males and females; however, their predictive powers were lower than that of diabetes. PMID- 28848611 TI - Effects of Different Types of Statins on Lipid Profile: A Perspective on Asians. AB - CONTEXT: The present review aimed at reviewing the effects of different statins on lipid profile, particularly in Asians. EVIDENCE ACQUISITION: PubMed searches were conducted using the keywords 'statin, effect, and lipid profile' from database inception through March 2016. In this review, 718 articles were retrieved from the primary search. After reviewing the titles, abstracts, and full texts, we found that 59 studies met our inclusion criteria. These also included subsequent reference searches of retrieved articles. RESULTS: CURVES study compared the effect on lipid profile between atorvastatin and other statins. This study demonstrated that low-density lipoprotein cholesterol (LDL C), total cholesterol (TC), and triglycerides (TG) were reduced more with atorvastatin compared to simvastatin, pravastatin, lovastatin, and fluvastatin. However, simvastatin provided a greater elevation of high-density lipoprotein cholesterol (HDL-C) compared to atorvastatin. The STELLAR trial was based on dose to-dose comparisons between atorvastatin and rosuvastatin efficacy in reducing LDL-C. Te present study also revealed that as the doses of rosuvastatin, simvastatin, and pravastatin increased, HDL-C also increased, with rosuvastatin having the greatest effect. However, HDL-C levels decreased as the dose of atorvastatin increased. The DISCOVERY study involving the Asian population revealed that the percentage of patients achieving the European goals for LDL-C and TC at 12 weeks was higher in rosuvastatin group compared to atorvastatin group. CONCLUSIONS: The effects of statins on lipid profile are dose dependent. Most studies showed that rosuvastatin has the best effect on lipid profile. Prescribing lower doses of statins in Asians seems necessary. PMID- 28848612 TI - Relationship of Serum Apolipoprotein A-V Levels, Oxidative Stress and Inflammatory Biomarkers with Hypertriglyceridemia in Type 2 Diabetes Mellitus. AB - BACKGROUND: Serum levels of triglycerides (TGs) are often found to be raised in type 2 diabetes mellitus (T2DM). TG levels >= 2.2 mM, systemic inflammation and oxidative stress (OS) are known to increase the risk of incident cardiovascular disease (CVD) substantially. In recent years, apolipoprotein A-V (Apo A-V protein) has attracted considerably as a modulator of circulating TG levels. OBJECTIVES: The study was conducted in order to evaluate the levels of Apo A - V proteins and markers of inflammation and OS in patients of T2DM with and without hypertriglyceridemia (HTG) and also to assess correlation between them. METHODS: T2DM patients were categorized into two groups of 40 participants, according to criteria for risk of CVD: group 1/ controls (TG <= 1.65 mM, n = 40) and group 2/ cases (TG >= 2.2 mM, n = 40). Despite the routine investigations, serum levels of Apo A-V, interleukin-6 (IL-6) and Insulin were estimated using ELISA, free fatty acids (FFA) with fluorometric assay and malondialdehyde (MDA) was measured using a spectrophotometer. Comparison of levels and correlation between variables was carried out with appropriate statistical tools. RESULTS: Serum Apo A-V protein levels were found significantly lower (P = 0.04) and MDA was significantly higher (P = 0.049) in cases. MDA correlated with TG levels positively (P = 0.000) and negatively with high density lipoproteins (HDL) (P = 0.000). However Apo A-V protein levels did not correlate with TG levels (P = 0.819, r = -0.027), IL-6 (r = 0.135, P = 0.269), FFA (r = 0.128, P = 0.277) and MDA (r = -0.217, P = 0.073). IL-6 levels significantly and positively correlated with HOMA-IR (r = 0.327, P = 0.004) in the all patients. CONCLUSIONS: In patients of T2DM, low levels of Apo A V are associated with HTG, indicating that Apo A-V is linked with TG metabolism. Burden of oxidative stress is greater in HTG of T2DM as is evident from MDA levels and its correlation with TG levels. Since oxidative stress is an important patho-physiological basis which increases the risk of CVD in patients of T2DM with HTG. Further studies are required in order to explore the possible role of Apo A-V in TG metabolism in diabetes. PMID- 28848614 TI - Complementary and Alternative Therapies for Functional Gastrointestinal Diseases 2016. PMID- 28848613 TI - Racial/Ethnic Differences in the Associations of Overall and Central Body Fatness with Circulating Hormones and Metabolic Factors in US Men. AB - BACKGROUND: Racial/ethnic disparities in the associations of body fatness with hormones and metabolic factors remain poorly understood. Therefore, we evaluated whether the associations of overall and central body fatness with circulating sex steroid hormones and metabolic factors differ by race/ethnicity. METHODS: Data from 1,243 non-Hispanic white (NHW), non-Hispanic black (NHB) and Mexican American (MA) adult men in the third national health and nutrition examination survey (NHANES III) were analyzed. Waist circumference (central body fatness) was measured during the physical examination. Percent body fat (overall body fatness) was calculated from bioelectrical impedance. Associations were estimated by using weighted linear regression models to adjust the two measures of body fatness for each other. RESULTS: Waist circumference, but not percent body fat was inversely associated with total testosterone and SHBG in all three racial/ethnic groups after their mutual adjustment (all P < 0.0001). Percent body fat (P = 0.02), but not waist circumference was positively associated with total estradiol in NHB men; no association was present in NHW and MA men (P-interaction = 0.04). Waist circumference, but not body fat was strongly positively associated with fasting insulin (all P < 0.0001) and inversely associated with HDL cholesterol (all P <= 0.003) in all three racial/ethnic groups. Both percent body fat and waist circumference were positively associated with leptin (all P < 0.0001) in all three racial/ethnic groups. CONCLUSIONS: There was no strong evidence in the associations of sex hormones and metabolic factors with body fatness in different racial/ethnic groups. These findings should be further explored in prospective studies to determine their relevance in racial/ethnic disparities of chronic diseases. PMID- 28848615 TI - Clinical Effects of Laser Acupuncture plus Chinese Cupping on the Pain and Plasma Cortisol Levels in Patients with Chronic Nonspecific Lower Back Pain: A Randomized Controlled Trial. AB - OBJECTIVES: Chronic nonspecific lower back pain (LBP) is a common disease. Insufficient data is currently available to conclusively confirm the analgesic effects of laser acupuncture on LBP. This study evaluated the effectiveness of laser acupuncture plus Chinese cupping in LBP treatment. METHODS: Patients with chronic nonspecific LBP were enrolled for a randomized controlled trial and assigned to the laser acupuncture group (laser acupuncture plus Chinese cupping) and control group (sham laser plus Chinese cupping). Laser acupuncture (808 nm; 40 mW; 20 Hz; 15 J/cm2) and Chinese cupping were applied on the Weizhong (BL40) and Ashi acupoints for 5 consecutive days. Plasma cortisol levels were assessed before and after the 5-day treatment session. The visual analog scale (VAS) scores were recorded at baseline and throughout the 5-day treatment session. RESULTS: After the treatment session, the plasma cortisol levels and VAS scores decreased significantly in both groups. In the laser acupuncture group, the VAS scores decreased significantly on days 4 and 5, and an enhanced reduction in VAS scores was observed. CONCLUSION: Laser acupuncture plus Chinese cupping at the Weizhong (BL40) and Ashi acupoints effectively reduced pain and inflammation in chronic nonspecific LBP. This therapy could be a suitable option for LBP treatment in clinical settings. PMID- 28848616 TI - Kangfuxinye Enema Combined with Mesalamine for Ulcerative Colitis: A Systematic Review and GRADE Approach. AB - OBJECTIVES: To critically appraise the efficacy and safety of Kangfuxinye enema combined with mesalamine for the ulcerative colitis (UC) patients and in addition to grade the quality of evidence by using the GRADE (grading of recommendations, assessment, development, and evaluation) approach. METHODS: A literature search was performed in the Cochrane Library, MEDLINE, EMBASE, CBM, CNKI, VIP, and WanFang Databases. The search restrictions were patients with UC and RCTs. Studies including other treatments except Kangfuxinye with mesalamine were excluded. RESULTS: Nineteen studies met the inclusion criteria. We found significant benefits of Kangfuxinye combined with mesalamine against mesalamine alone in improving response rate as well as reducing the recurrence rate and inflammation rate; meanwhile, the increase of the adverse events rate was not observed. Furthermore, the symptoms remission rate and the cure time were insignificant statistically. Additionally, GRADE results indicated that the quality of evidence regarding the above 6 outcomes was rated from very low to moderate quality. CONCLUSIONS: Although Kangfuxinye enema seems effective and safe for treating UC patients in this systematic review, Kangfuxinye enema combined with mesalamine was weakly recommended due to very low to moderate quality of available evidence by the GRADE approach. PMID- 28848617 TI - Electroacupuncture at GV20 and ST36 Exerts Neuroprotective Effects via the EPO Mediated JAK2/STAT3 Pathway in Cerebral Ischemic Rats. AB - BACKGROUND: While electroacupuncture (EA) in cerebral ischemia has been used to promote functional recovery, the underlying mechanism of its protective effect remains poorly understood. OBJECTIVE: We investigated the effects of EA stimulation at GV20 and ST36 to observe the changes in erythropoietin- (EPO-) mediated Janus family tyrosine kinases 2 (JAK2) signal transducers and activators of the transcription 3 (STAT3) cell pathway. METHODS: Thirty-six specific pathogen-free Sprague-Dawley (SD) male rats were randomly assigned to three groups: the sham-operated group (S group), the middle cerebral artery occlusion (MCAO) group (M group), and the EA group. Neurological deficits were assessed through the Ludmila Belayev 12-score test and 2,3,5-triphenyltetrazolium chloride (TTC) staining was shown. The protein and mRNA expression levels of EPO, the EPO receptor (EpoR), p-JAK2, JAK2, p-STAT3, and STAT3 were examined to explore the EA effect on rats with cerebral ischemic reperfusion injury (CIRI). RESULTS: EA significantly decreased infarct size and improved neurological function. Furthermore, target EPO, EpoR, JAK2, and STAT3 mRNA and protein levels significantly increased in the EA group. CONCLUSIONS: EA exerts a neuroprotective effect, possibly via the regulation of the EPO-mediated JAK2/STAT3 cell pathway and downstream apoptotic pathways in a rat CIRI model. PMID- 28848619 TI - The study of the relationship between value creation and customer loyalty with the role of trust moderation and customer satisfaction in Sari hospitals. AB - BACKGROUND: Healthcare providers are competitive, owing to heightened customers' awareness and expectations of health care services. OBJECTIVE: The aim of this study was to determine the relationship between customer value creation and loyalty with mediator trust and customer satisfaction. METHODS: This is a cross sectional survey study. Participants were 196 patients referred to private hospitals in Sari city, Iran from May to June 2014 which were selected by convenience sampling method. Data were collected using questionnaires. Data were analyzed using the structural equation modeling software Smart PLS. RESULTS: The results revealed a relationship between customer value creation and customer loyalty in a Sari city private hospital, and customer satisfaction and trust, mediate the relationship between customer value creation and customer loyalty. The results also revealed significant positive relationship between customer satisfaction and trust (p=0.000 r=0.585). CONCLUSION: customer satisfaction and trust mediate the relationship between customer value creation and customer loyalty. PMID- 28848618 TI - Markers of Oxidative Stress and Inflammation in Ascites and Plasma in Patients with Platinum-Sensitive, Platinum-Resistant, and Platinum-Refractory Epithelial Ovarian Cancer. AB - Diverse proinflammatory biomarkers and oxidative stress are strongly associated with advanced epithelial ovarian cancer (EOC). Objective. To determine the behavior of markers of oxidative stress and inflammation in plasma and ascites fluid in patients with platinum-sensitive, platinum-resistant, and platinum refractory EOC. Methods. A prospective cohort study. The colorimetric method was used to determine levels of the markers 8-isoprostanes (8-IP), lipid peroxidation products (LPO), and total antioxidant capacity (TAC) in plasma and ascites fluid; and with ELISA, the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were determined in patients with EOC. Results. In ascites fluid, a significant increase in 8-IP versus baseline plasma levels was found (p = 0.002). There was an important leakage of the TAC levels in ascites fluid versus baseline plasma levels (p < 0.001). The IL-6 was elevated in ascites fluid versus baseline plasma levels (p = 0.003), and there were diminished levels of TNF-alpha in ascites fluid versus baseline plasma levels (p = 0.001). Discussion. We hypothesize that the ascites fluid influences the behavior and dissemination of the tumor. Deregulation between oxidants, antioxidants, and the proinflammatory cytokines was found to vary among platinum-sensitive, platinum resistant, and platinum-refractory patients. PMID- 28848620 TI - Perceived social support among students of medical sciences. AB - BACKGROUND: Social support is emotional and instrumental assistance from family, friends or neighbors, and has an important but different impact on individuals, mainly depending on contextual factors. OBJECTIVE: To determine the status of perceived social support and related personal and family characteristics of medical sciences students in Ahvaz, Iran. METHODS: In this cross-sectional study, the target population included the students of Ahvaz Jundishapur University of Medical Sciences in the second semester of 2013-2014, of whom 763 were selected by cluster random sampling method. The study tool was a two-part questionnaire containing 48 self-administered questions including 25 questions of measurements of personal and family characteristics and a Persian modified version of Vaux's social support scale (Cronbach's alpha=0.745). Data were analyzed with T test, ANOVA and chi-square and using SPSS version 16 and 0.05 was considered as the level of significance. RESULTS: The mean score of the perceived social support was 17.06+/-3.6 and 60.3% of them reported low social support. There was a significant relationship among the perceived social support and sex (p=0.02), faculty (p<0.0001), ethnicity (p=0.034) and the duration of weekly residence in dormitory (p=0.031). But no significant relationship was found between this variable and other individual and familial characteristics. CONCLUSION: Based on students' low social support and importance of social support in reducing stress and academic failure, the planners need to provide efficient supportive interventions for students. PMID- 28848621 TI - Comparison between the lifestyles of university students with and without premenstrual syndromes. AB - INTRODUCTION: Premenstrual syndrome is a common disorder in reproductive age and it is associated with decreased quality of life in women. In view of various factors contributing to outbreak of PMS (premenstrual syndrome) among women, the present study intended to compare lifestyles of university students with and without premenstrual syndromes living in dormitories of Qazvin University of Medical Sciences in 2015. METHODS: The descriptive cross-sectional study recruited 200 university students with and without PMS from students living in dormitories. Data were collected using questionnaires of premenstrual symptoms, questionnaires for diet, perceived stress, and unhealthy behavior. Data were analyzed using descriptive statistics, independent samples t-test, Mann-Whitney, Chi-square, and logistic regression in SPSS version 23. RESULTS: The results showed that nutrition style (p=0.001), perceived stress (p=0.001), and exposure to passive tobacco smoke (p=0.001) were different between the two groups. Logistic regression analysis showed that nutrition style (p=0.001, OR=0.861), exposure to passive tobacco smoke (p=0.008, OR=2.059), and stress (p=0.001, OR=1.088) were different in both groups. CONCLUSION: The research results proved that lifestyle, especially healthy eating habits, and decreasing stress and unhealthy behavior can influence PMS. Therefore, interventions are recommended to improve PMS symptoms. PMID- 28848622 TI - The association between parental mental health and behavioral disorders in pre school children. AB - BACKGROUND AND AIM: Behavioral disorders among children reflect psychological problems of parents, as mental illness of either parent would increase the likelihood of mental disorder in the child. In view of the negative relationship between parents' and children's illness, the current study intended to determine the correlation between mental health of parents and behavioral disorders of pre school children. METHODS: The present descriptive-correlational research studied 80 children registered at pre-school centers in Pardis Township, Tehran, Iran during 2014-2015 using convenience sampling. The research tools included General Health Questionnaire (GHQ) and Preschool Behavior Questionnaire (PBQ). The resulted data were analyzed using Pearson Product-moment Correlation Coefficient and regression analysis in SPSS 21. RESULTS: The research results showed that there was a significant positive correlation between all dimensions of mental health of parents with general behavioral disorders (p<0.001). The results of the regression analysis showed that parents' depression was the first and the only predictive variable of behavioral disorders in children with 26.8% predictive strength. CONCLUSION: Given the strong relationship between children's behavioral disorders and parents' general health, and the significant role of parents' depression in children's behavioral disorders, it seems necessary to take measures to decrease the impact of parents' disorders on children. PMID- 28848623 TI - The relationship between some demographic characteristics and organizational commitment of nurses working in the Social Security Hospital of Khorramabad. AB - BACKGROUND: Reduction in organizational commitment of nurses results in deficiency of care services. Some demographic factors affect organizational commitment. OBJECTIVE: The present study is intended to determine the organizational commitment of nurses and its relationship with demographic characteristics. METHODS: This study was a descriptive correlation (cross sectional) study in January and February of 2016 on 126 nurses who held Bachelor of Science (B.Sc.) or Master of Science (M.Sc.) and at least one year of work experience in the Social Security Hospital of Khorramabad, selected using the census method. Data collection tools included a demographic characteristics form and Allen and Meyer questionnaire. Data analysis was performed using SPSS 20. Independent-samples t-test and one-way ANOVA were used to determine the relationship between organizational commitment and demographic characteristics. RESULTS: The majority of nurses had moderate organizational commitment, the highest score belonging to the continuance commitment (22.33%), and the lowest score belonging to the normative commitment (19.16%). Also, there was a significant correlation between the continuance commitment and work experience (p=0.001), the staff posts (p=0.01) and shifts (p=0.04). CONCLUSION: Considering the moderate level of subjects' organizational commitment in the present study, managers should take necessary measures to increase the attachment and organizational commitment of nurses and provide the ground for improving nursing services. PMID- 28848624 TI - Breakfast and fast food eating behavior in relation to socio-demographic differences among school adolescents in Sanandaj Province, Iran. AB - INTRODUCTION: Fast food consumption and skipping breakfast has been increasingly prevalent among high school adolescents in recent years. These unhealthy food habits are considered as risk factors of chronic diseases among adolescents and adults. AIM: To determine the consumption amount of fast food, breakfast, and some associated factors in adolescents. METHODS: In this cross-sectional study in 2015, 553 adolescent students aged 14-18 years were randomly selected among high schools of Sanandaj, Iran. Demographic data and also consumption amount of fast food and breakfast in adolescents in addition to the related factors were studied. Data were collected using a researcher-made questionnaire which its reliability and validity were measured by five experts and analyzed with SPSS-16 by Chi-square test and ANOVA. RESULTS: The results show that 69.8 % of subjects consume fast food at least once a week. Fast food and breakfast consumption is related significantly to subjects' fathers' occupation respectively (p=0.005), (p=0.006). Eating breakfast is significantly higher among boys than girls (p<0.001). There is also a significant relationship between adolescents' age and parents' education level, and adolescents' breakfast consumption respectively (p=0.003), (p<0.001). The studied factors affecting adolescents' fast food consumption are: their own and their families and friends' interest and accompaniment, advertisement, close proximity of school and home to fast food stores. CONCLUSION: The consumption of fast food is high among Iranian adolescents. It correlates significantly with variables including father's occupation and all of the associated factors. Breakfast consumption correlates significantly with adolescents' age and gender, as well as parents' occupation and educational level. PMID- 28848625 TI - Exploring perceptions of health caregivers on the causes of caregivers' occupational burnout in institutes of children with cerebral palsy: A qualitative study. AB - BACKGROUND: Providing care for children with cerebral palsy (CP) is hard, energy consuming, and long-term. Consequently, occupational burnout is highly probable for caregivers. OBJECTIVE: This study aimed to explore the perception of health caregivers regarding the causes of caregivers' occupational burnout in institutes of children with CP. METHODS: This qualitative study was conducted using content analysis methodology during an eight-month period in 2016. Nine caregivers, two managers, and one physiotherapist participated in the study. Purposive sampling method was used to select participants. In depth, semi-structure interviews were used to gather the data. All interviews were conducted at their workplace, in Tehran, Iran. The interviews were recorded, transcribed verbatim, and overviewed. Constant comparative analyses were used to analyze the interviews. RESULTS: The results were categorized into three main categories and nine sub-categories. The main categories were as follows: care-related stress, nature of caring occupation, and organizational demands and resources. CONCLUSION: Results of this study showed that several factors are involved in creating burnout among caregivers. The exploration of these factors may help us in designing appropriate interventions for caregivers to correctly implement caring activities so that they less suffer from care-related pressures and also become able to allocate some time for their own activities of interest and for recreational, social, and family activities. PMID- 28848626 TI - Effects of gamma rays on rat testis tissue according to the morphological parameters and immunohistochemistry: radioprotective role of silymarin. AB - OBJECTIVE: To determine the radioprotective effects of Silymarin in adult male Sprague-Dawley rats irradiated with gamma-rays. METHODS: The present experimental study was performed in Tehran University of Medical Sciences, Tehran, Iran from December 2009 to March 2010. The study was performed on 40 rats, which were randomly and equally divided into four groups: 1) control group: neither received Silymarin nor irradiated with gamma-rays; 2) gamma-irradiation group: testis region exposed to 2Gy of gamma-rays; 3) Silymarin & gamma-irradiation: rats received 100 mg/kg of Silymarin 24hrs before exposure to 2Gy of gamma-rays; 4) Silymarin & gamma-irradiation: rats received 200 mg/kg of Silymarin 24hrs before exposure to 2Gy of gamma-rays. After animal experiments and preparing the tissue sections, different histological and histomorphological parameters of seminiferous tubules and the biological characteristics of Leydig cells were evaluated applying quantitative assessment, Johnson scoring, and Leydig cell apoptosis assay by TUNEL method. The data were analyzed applying ANOVA and Tukey's post hoc test, using SPSS software (V.19). RESULTS: Irradiation of 2 Gy gamma-rays to the testis of the rats significantly affected the frequency of spermatogonia, primary spermatocyte, round spermatid, spermatozoa, seminiferous tube and lumen diameters, thickness of the epithelium, Leydig cell nuclear diameter and volume, epithelium height, and apoptotic cells (p<0.05). However, administration of Silymarin improved the mentioned parameters specifically in 200 mg/kg of dosage. CONCLUSION: Silymarin could act as a potent radioprotector and it can be used in modulation as well as improvement to radiation therapy to prevent male reproductive function, specifically seminiferous tubules in an animal model; however, its molecular mechanism is still not clear and needs more molecular researches. PMID- 28848627 TI - Geographic Information System (GIS) capabilities in traffic accident information management: a qualitative approach. AB - BACKGROUND: Traffic accidents are one of the more important national and international issues, and their consequences are important for the political, economical, and social level in a country. Management of traffic accident information requires information systems with analytical and accessibility capabilities to spatial and descriptive data. OBJECTIVE: The aim of this study was to determine the capabilities of a Geographic Information System (GIS) in management of traffic accident information. METHODS: This qualitative cross sectional study was performed in 2016. In the first step, GIS capabilities were identified via literature retrieved from the Internet and based on the included criteria. Review of the literature was performed until data saturation was reached; a form was used to extract the capabilities. In the second step, study population were hospital managers, police, emergency, statisticians, and IT experts in trauma, emergency and police centers. Sampling was purposive. Data was collected using a questionnaire based on the first step data; validity and reliability were determined by content validity and Cronbach's alpha of 75%. Data was analyzed using the decision Delphi technique. RESULTS: GIS capabilities were identified in ten categories and 64 sub-categories. Import and process of spatial and descriptive data and so, analysis of this data were the most important capabilities of GIS in traffic accident information management. CONCLUSION: Storing and retrieving of descriptive and spatial data, providing statistical analysis in table, chart and zoning format, management of bad structure issues, determining the cost effectiveness of the decisions and prioritizing their implementation were the most important capabilities of GIS which can be efficient in the management of traffic accident information. PMID- 28848628 TI - Evaluation of the ability of emergency medicine residents in teaching and supervising emergency medicine interns. AB - BACKGROUND: Approximately 25% of the residents' time in each shift is allocated to educating lower-level assistants and interns. Assistants have played a major role in interns' education. AIM: To assess the teaching abilities of emergency medicine assistants in the training and monitoring of medical interns and undergraduate students. METHODS: This cross-sectional study was performed in 2015 at the emergency center of Imam Reza hospital in Mashhad University of Medical Sciences. We employed a researcher-made questionnaire to search the capability of emergency medicine residents to assess the teaching capabilities of emergency medicine residents to interns. This questionnaire was completed by 106 interns. The Validity of the questionnaire was confirmed by three specialist experts and reliability of the questionnaire was confirmed by Cronbach's alpha (0.94). This questionnaire consists of 24 questions in six areas. The analysis was performed by descriptive statistics using SPSS 16. RESULT: The study showed that the least favorable score was related to "residents get feedback on each shift" and the highest score was given to "a friendly relationship with the Interns and residents". CONCLUSION: Considering the key role of residents in the education and training of future healthcare specialists, training interventions and allocating sufficient time to the proper education of different members of healthcare teams and medical students could largely contribute to the development of clinical training systems. PMID- 28848629 TI - Information management flow for tele-homecare for the elderly; An emerging need for continuity of care. AB - BACKGROUND AND OBJECTIVES: Tele-homecare methods can be used to provide home care for the elderly, if information management is provided. The aim of this study was to compare the places and methods of the data collection and media that use Tele homecare for the elderly in selected countries in 2015. METHODS: A comparative applied library study was conducted in 2015. The study population were five countries, including Canada, Australia, England, Denmark, and Taiwan. The data collection tool was a checklist based on the objectives of study. Persian and English papers from 1998 to 2014, related to the Electronic Health Record, home care and the elderly were extracted from authentic journals and reference books as well as academic and research websites. Data were collected by reviewing the papers. After collecting data, comparative tables were prepared and the weak and strong points of each case were investigated and analyzed in selected countries. RESULTS: Clinical, laboratory, imaging and pharmaceutical data were obtained from hospitals, physicians' offices, clinics, pharmacies and long-term healthcare centers. Mobile and tablet-based technologies and personal digital assistants were used to collect data. Data were published via Internet, online and offline databanks, data exchange and dissemination via registries and national databases. Managed care methods were telehealth management systems and point of service. CONCLUSION: For continuity of care, it is necessary to consider managed care and equipment with regard to obtaining data in various forms from various sources, sharing data with registries and national databanks as well as the Electronic Health Record. With regard to the emergence of wearable technology and its use in home care, it is suggested to study the integration of its data with Electronic Health Records. PMID- 28848630 TI - Moral competency: meta-competence of nursing care. AB - INTRODUCTION: To follow the progress of technology and increasing domain of nurses' duties, ethical challenges can be observed more than ever. Therefore, the growing and dynamic system of nursing requires nurses with professional and ethical competence who can provide optimal care. The aim of the present study was to define and explain dimensions of moral competency among the clinical nurses of Iran. METHODS: This qualitative content analysis study was carried out in the years 2014 and 2015 in Iran. Data were collected through in-depth semistructured interviews and field notes. The resulting data were analyzed by Graneheim and Lundman's method of conventional content analysis. The participants were 12 clinical nurses who were selected using purposive convenient sampling and continued interviews until data saturation. RESULTS: Themes obtained in the present study were posited in three main categories of "moral character," with subcategories of altruism, search for meaning, be pioneering, perfectionism, self control, honesty, and forgiveness; "moral care" with subcategories of dignified care, safe care, fair care, and holistic care; and "moral decision-making" with subcategories of moral sensitivity, moral thinking, moral reasoning, and moral courage. CONCLUSIONS: Findings of the present study suggest that nurses' moral competency is an adorable character with a wide range that includes moral virtues and character, moral decision-making, and ultimately providing moral care; therefore, moral competency is a meta-competence in the field of nursing. Because there are many competencies in different fields. PMID- 28848631 TI - Discharge against medical advice (DAMA): Causes and predictors. AB - BACKGROUND AND AIM: DAMA is a result of patient dissatisfaction, which increases the rate of readmission, mortality, and complications. In this study, the causes and predictors of DAMA in Shahid Labbafinejad Hospital of Tehran were determined. METHODS: The descriptive and analytical study was conducted in 2016 from the information of 1,168 hospitalized patients in the period of 2015 and the first half of 2016. Patients' information was collected using checklists and through clinical records, nursing unit reports, and telephone calls. The collected data were analyzed using SPSS-v18 software and by employing chi-square test and logistic regression modeling. RESULTS: The DAMA rate was estimated at 3.27%. Among the causes of DAMA, the high rates were related to personal problems (39.04%) and going to other centers (34.93%), and the lowest level was related to dissatisfaction with the physician (3.08%). Age groups (19-37, OR=2.17), (38-56 years, OR=1.70), and (57-75, OR=1.62), gender (male, OR=1.47), locations (Tehran city, OR=0.61) and (Tehran Province, OR=0.63) were predictors of DAMA (p<0.05). CONCLUSIONS: The importance of DAMA requires practical measures such as creating a suitable environment for patients, providing consulting services for youth, improving staff relations, providing assistance for patients in need, and removing accommodation problems of patients and their companions to reduce the DAMA. PMID- 28848632 TI - Diagnostic value of ultrasonography in spinal abnormalities among children with neurogenic bladder. AB - BACKGROUND: Nowadays, magnetic resonance imaging (MRI) is the gold standard for evaluation and diagnosis of spinal cord abnormalities, which are considered among the leading causes of neurogenic bladder; however, MRI is a costly imaging method and is not available at all health centers. Sporadic studies have shown the alignment of MRI with ultrasonography results in diagnosis of spinal abnormalities; although none of these studies has expressed the diagnostic value of ultrasonography. OBJECTIVE: The aim of this study was to evaluate the diagnostic value of ultrasonography in detection of spinal abnormalities in children with neurogenic bladder. METHODS: This is a cross-sectional study carried out from January 2014 to November 2015 on patients with neurogenic bladder referred to Department of Radiology, Dr. Sheikh Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. All patients underwent sonography of the spinal cord and soft-tissue masses; also, a spinal MRI scan was performed. The existence of spina bifida, sacral agenesis, posterior vertebral arch defects, mass, tethered cord, myelomeningocele, lipoma and fatty infiltration, dural ectasia, hydromyelia and syringomyelia, and diastomatomyelia was recorded during each imaging scan. Chi-square and Fisher's tests were used for data analysis using SPSS 19.0 software, and the sensitivity and specificity of ultrasonography findings were calculated by MedCale 26 software. RESULTS: Forty patients with neurogenic bladder (22 males/18 females), with an average of 25.73+/-19.15 months, were enrolled. The most common abnormality was found in patients' MRI was tethered cord syndrome (70%). There was a significant relationship between ultrasonographic and MRI findings in spina bifida abnormalities (p=0.016), sacral agenesis (p=0.00), tethered cord (p=0.00), myelomeningocele (p=0.00), and lipoma and fatty infiltration (p=0.01). Ultrasonography had a sensitivity of 20.0%-100% and a specificity of 85.7%-100% depending on the detected type of abnormality. CONCLUSION: It seems that ultrasonography has an acceptable and desirable sensitivity and specificity in the diagnosis of most of the spinal cord abnormalities in children with a neurogenic bladder. PMID- 28848633 TI - Effect of health-belief-model-based training on performance of women in breast self-examination. AB - BACKGROUND: Breast cancer is the most common cause of cancer death among women in the world. With prevention and examinations, including breast self-examination, the death rate will be reduced. OBJECTIVE: The purpose of this study was to determine the effect of health-belief-model-based training on the performance of women in breast self-examination in the province of Fars (Iran). METHODS: An empirical study examined the effect of an eight-week training program based on the health belief model among 144 women who visited health care centers in the city of Abadeh in Fars Province (Iran) in 2015. Data gathered through researcher made questionnaires including awareness, components of the health belief model, performance, and demographic information. IBM-SPSS software version 20, descriptive and inferential statistical tests such as T-test, chi-square, Mann Whitney, and repeated measurements were used for data analysis. RESULTS: After the intervention, a significant difference was seen in average awareness, perceived susceptibility, and performance of women (p<0.05), while it was not significant in benefits constructs, perceived barriers, and perceived severity and practice guide. After intervention, the average score of awareness was increased significantly (p<0.001). Also, the average score of performance in breast self-examination showed a significant difference (p<0.001). CONCLUSION: Due to the low level of awareness of women about breast self-examination, using a health belief model with an increase of the perceived susceptibility could be effective in improving their performance in breast self-examination. PMID- 28848634 TI - Geographic distribution indices of general practitioners, midwives, pediatricians, and gynecologists in the public sector of Iran. AB - BACKGROUND: Health workforce distribution is so important in access posture, coverage and equity. Following millennium development goals (MDGs), special attention to health workforces in relation with maternal and child health is required. OBJECTIVE: The aim of the current study was to determine distribution of maternal and child health related workforces in Iran during 2010-2012, using inequality measures. METHODS: In this cross-sectional study, data about the number of physicians and midwives obtained from Ministry of Health reports and demographic statistics were obtained from the Statistical Center of Iran. Gini coefficient and Robin Hood index were calculated in terms of population ratio, need adjusted index for birth (NAIB) and need adjusted index for mortality (NAIM). For calculations, DAD software version 4.6 was used. RESULTS: Gini coefficient was reduced for general physicians (GPs) and pediatricians, and had increasing and decreasing trends for gynecologists. For achieving equality within provinces, the number of transferable health workforces was more than 1 person per 10 health workforces. CONCLUSION: Health workforce distribution had various trends in Iran. Special attention to deprived provinces is required. Most of the reduction in Gini coefficient is due to the increase in health workforce in developing provinces, and deprived provinces still have serious problems. The health system could achieve better equality by considering deprived provinces and using Gini coefficient and Robin Hood index together. PMID- 28848635 TI - Optimization of the photoneutron target geometry for e-accelerator based BNCT. AB - BACKGROUND AND AIM: Today, electron accelerators are taken into consideration as photoneutron sources. Therefore, for maximum production of epithermal neutron flux, designing a photoneutron target is of significant importance. In this paper, the effect of thickness and geometric shape of a photoneutron target on neutron output were investigated. METHODS: In this study, a pencil photon source with 13, 15, 18, 20 and 25 MeV energies and a diameter of 2 mm was investigated using Monte Carlo simulation method using MCNP code. To optimize the design of the photoneutron target, the tungsten target with various geometries and thicknesses was investigated. RESULTS: The maximum neutron flux produced for all target geometries and thicknesses occurred at neutron energy peak of around 0.46 MeV. As the thickness increased to 2 cm, neutron flux increased and then a decreasing trend was observed. For various geometrical shapes, the determining factor in photoneutron output was the effective target thickness in the photon interaction path that increased by the increase in the area of interaction. Another factor was the angle of the photon's incidence with the target surface that resulted in a significant decrease in photoneutron output in cone-shaped targets. CONCLUSION: Three factors including the total neutron flux, neutrons energy spectrum, and convergence of neutrons plays an important role in the selection of geometry and shape of the target that should be investigated considering beam shaping assembly (BSA) shape. PMID- 28848636 TI - Gastrointestinal symptoms associated with gastroesophageal reflux disease, and their relapses after treatment with proton pump inhibitors: A systematic review. AB - Gastroesophageal reflux disease (GERD) is a common functional gastrointestinal disorder with significant effects on the quality of life. The burden of GERD is soaring in Asia. Preventing symptom relapse is a therapeutic goal in GERD patients. Since proton pump inhibitors (PPI) are the first-line treatment of GERD, drug failure has become a major problem in the treatment procedure. We reviewed the literature in order to find articles related to comorbidities and symptoms affecting GERD from 1980 to 2015 via PubMed and Google Scholar using keywords such as 'Gastroesophageal reflux disease', 'Gastrointestinal symptoms' and Boolean operators (such as AND, OR, NOT). Due to the cost of PPI therapy and the high rate of GERD relapse after PPI therapy, demand for continuing this type of treatment is decreasing. Thus, we need to discover new approaches to treat the disease and also investigate the relationship between the treatment of GERD and its comorbidities and symptoms such as functional constipation. PMID- 28848637 TI - Validity and reliability of the Farsi version of Wijma delivery expectancy questionnaire: an exploratory and confirmatory factor analysis. AB - BACKGROUND: Fear of childbirth may cause complications such as experiencing severe labour pain, postpartum depression, and impaired mother-fetus attachment. OBJECTIVE: To validate the Farsi version of the Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ) (versions A & B) in a sample of Iranian women. METHODS: The WDE-Q (versions A & B) was translated into Farsi, and the content validity of the scales was confirmed. In a cross-sectional study conducted in 2015, 405 pregnant women in the third trimester of pregnancy and 320 postpartum women completed the Farsi W-DEQ versions A & B, respectively. The construct validity and reliability of the scales were examined using exploratory and confirmatory factor analyses (EFA and CFA) and Cronbach's alpha coefficient, respectively. SPSS version 18 and Lisrel version 8.80 were used for statistical analyses. RESULTS: Results of the CFA on 33 items could not confirm the one factor structure proposed by Wijma (RMSEA= 0.14, SRMR=0.11, Chi-square/df=8.95, p<0.05, CFI=0.86, IFI=0.86) or other structures suggested by previous studies. We conducted an EFA on 33-item version A and found six factors with eigenvalue > 1. One item was not loaded on any factor. A CFA on 32 items of the W-DEQ (version B) yielded acceptable fit for the factorial structure found on version A (RMSEA= 0.075 (CI [0.071, 0.08]), SRMR=0.078, Chi-square/df=2.93, p<0.05, CFI=0.95, IFI=0.95). Cronbach's Alpha coefficients for the 32-item Farsi W-DEQ (versions A & B) were 0.914 and 0.919, respectively. CONCLUSIONS: Both Farsi W-DEQ are reliable and valid instruments to assess fear of childbirth in Iranian pregnant and postpartum women. Further research should be designed to examine the validity of the W-DEQ (A) in pregnant women regardless of gestational age. PMID- 28848638 TI - Exploration of the process of interprofessional collaboration among nurses and physicians in Iran. AB - INTRODUCTION: The development of interprofessional collaboration is of great significance for facilitating the flow of information and provision of collaborated services. In fact, only one single profession cannot respond to all demands. Thus, this study was aimed to investigate clinical nurse-physician collaboration in Iran. METHODS: This study was performed with nurses and physicians of university hospitals affiliated to Mashhad University of Medical Sciences, Mashhad, Iran, during September 2013-March 2015, using grounded and synthesis theory. The data were obtained using semi-structured interviews and field notes, and MAXQ DA version 10 was employed for data analysis. RESULTS: The core variable was defined as "management of strategic goals", and the main categories included perception of challenging organizational structures, providing a comprehensive supportive net for patients, seeking professional communication, and building solid confidence. Based on views of the participants, they were aiming to apply a stress management strategy, while maintaining their position in the organization, by making passive compromises to protect themselves against the perceived threats. CONCLUSION: The participants were trying to overcome barriers through reducing and managing the tension, while maintaining their position in the organization using forced, passive coping strategies to protect themselves against the perceived threats. PMID- 28848639 TI - Challenges of using Hospital Information Systems by nurses: comparing academic and non-academic hospitals. AB - BACKGROUND AND AIM: Hospital Information Systems (HIS) are used for easy access to information, improvement of documentation and reducing errors. Nonetheless, using these systems is faced with some barriers and obstacles. This study identifies the challenges and the obstacles of using these systems in the academic and non-academic hospitals in Kerman. METHODS: This is a cross-sectional study which was carried out in 2015. The statistical population in this study consisted of the nurses who had been working in the academic and non-academic hospitals in Kerman. A questionnaire consisting of two sections was used. The first section consisted of the demographic information of the participants and the second section comprised 34 questions about the challenges of HIS use. Data were analyzed by the descriptive and statistical analysis (t-test, and ANOVA) using SPSS 19 software. RESULTS: The most common and important challenges in the academic hospitals were about human environment factors, particularly "negative attitude of society toward using HIS". In the non-academic hospitals, the most common and important challenges were related to human factors, and among them, "no incentive to use system" was the main factor. The results of the t-test method revealed that there was a significant relationship between gender and the mean score of challenges related to the organizational environment category in the academic hospitals and between familiarity with HIS and mean score of human environment factors (p<0.05). The results of the ANOVA test also revealed that the educational degree and work experience in the healthcare environment (years) in the academic hospitals have a significant relationship with the mean score related to the hardware challenges, as well, experience with HIS has a significant relationship, with the mean score related to the human challenges (p<0.05). CONCLUSION: The most important challenges in using the information systems are the factors related to the human environment and the human factors. The results of this study can bring a good perspective to the policy makers and the managers regarding obstacles of using HISs from the nurses' perspective, so that they can solve their problems and can successfully implement these systems. PMID- 28848640 TI - Prevalence of Cryptosporidium spp. in calves under one year old in Ilam county (Iran), from March 2014 to February 2015. AB - INTRODUCTION: Cryptosporidium is a coccidian parasite that can infect most mammals, including humans. This parasite is an important cause of neonatal diarrhea and morbidity in calves, causing substantial economic loss to animal husbandry. Because of the importance of this parasite in calves, this study was designed in order to determine prevalence of Cryptosporidium spp. among calves under one year old in Ilam county (Iran). METHODS: Prevalence of Cryptosporidium spp. was estimated using a cross-sectional study. Fecal samples from 400 calves under 1 year old were collected in Ilam County, from March 2014 to February 2015 and they were microscopically analyzed using modified Ziehl-Neelsen method (mZN). RESULTS: The overall prevalence of Cryptosporidiosis in calves was 16% (64/400). According to age categories, the highest infection was observed in calves under one month old, and the lowest infection occurred in calves 6 to 12 months old. Age was significantly associated with Cryptosporidium spp. infection (p<0.05). The prevalence of Cryptosporidiosis in diarrheic and none diarrheic calves was 27.3 and 12.4 % respectively, which indicated a significant association between positivity and diarrhea (p<0.05). The highest prevalence was observed in winter followed by autumn, spring and summer respectively. No statically difference was found between prevalence of Cryptosporidiosis and seasons of sampling. Also, calves' gender was not associated with Cryptosporidium spp. infection in this study. CONCLUSION: Our results provide useful information about the distribution of Cryptosporidium spp. Also, the role of potential risk factors including age, sex, clinical status and seasons of sampling was indicated in studied calves from Ilam County. PMID- 28848641 TI - Risk factors associated with neural tube defects in infants referred to western Iranian obstetrical centers; 2013-2014. AB - BACKGROUND: Neural tubes defects (NTDs) are known to be the second most prevalent congenital disorder worldwide whose risk factors have not been explicitly addressed yet. AIM: To determine the risk factors affecting NTDs among infants who referred to obstetrical centers in Kurdistan, a western province of Iran. METHODS: This prospective case-control study was conducted in the form of prospective case-control. Sample population included all women (27,153 cases) who referred to obstetrical centers in Kurdistan for either delivery or abortion during 2013 and 2014. Inclusion criterion was the presence of a known NTD in infants, and exclusion criterion was the reluctance of patients to participate in the study. Accordingly, 46 cases participated in the study as the case group, and 138 cases (three times higher than case group) were selected to be the control group. Case and control groups were matched in terms of the number of pregnancies and place of birth. The variables investigated in the present study were as follows: age, occupation, BMI, abortion history, family relation with husband, fetus' sex, number of twins, history of previous children with NTD, receiving prenatal surveillance, consumption of folic acid and multivitamins, smoking, alcohol drinking, passive smoking, and suffering from such diseases as epilepsy and diabetes. Data were analyzed using various statistical tests, including chi square, Fishers' exact test, multiple logistic regression analysis using SPSS version 20. In the study group, inclusion criteria included all women who had an infant with tube defects that their total number was 46 individuals. In the control group inclusion criteria included mothers with healthy infants who were similar to the study group in terms of birth place and frequency of pregnancy. RESULTS: The results of the present study demonstrated that prenatal surveillance (p<0.002), multivitamin consumption (p<0.001), history of having a child with NTD (p<0.001), alcohol drinking (p<0.014), and passive smoking were related to NTDs (p<0.001). CONCLUSION: Before fertilization and during pregnancy, mothers should be examined in terms of exposure to harmful agents, diet, and nutritional status in order to identify possible risk factors and find opportunities to prevent NTDs in infants. PMID- 28848642 TI - Frequency and causes of emergency hysterectomy along with vaginal delivery and caesarean section in Hamadan, Iran. AB - BACKGROUND: Emergency hysterectomy (peripartum) is a high-risk surgery that almost always is done in the treatment or prevention of severe and life threatening bleeding that occurs after vaginal delivery or caesarean. OBJECTIVE: To compare the frequency and causes of emergency hysterectomy along with the vaginal delivery and caesarean section (CS). METHODS: The cross-sectional research was conducted on patients who underwent a peripartum hysterectomy from 2005 to 2015 at Fatemieh Hospital in Hamadan City, Iran. Data collection tools included a questionnaire about demographic features and factors associated with hysterectomy surgery. Data were analyzed using SPSS version 21 and by descriptive statistics, chi-square, paired t-test, and one-way analysis of variance (ANOVA). RESULTS: The mean age of women was 33.4+/-5.09 years. In recent years, 37 cases of hysterectomy were reported, with the peak occurring in 2015. The highest prevalence of hysterectomy was associated with 28 (77.8%) women with a third pregnancy and second parity, while 32 cases (86.5) were related to those with no history of vaginal delivery, 15 (45.5%) were related to repeated CS and second repeated CS; 28 cases (75.7%) to those with no history of placenta previa; 21 cases (56.8) to the majority with the anterior placenta;, 33 cases (97.1%) to those with no over-distance of uterine; and 36 cases (97.3%) to those without a history of uterine myoma. Among 37 cases who had hysterectomy, placenta accreta was observed in 27 cases (77.1%), with placenta increta in three (8.1%) and placental attachment, including percreta, were seen in seven cases (18.9 %). CONCLUSION: The rate of hysterectomy in multiparous women (in their third or fourth pregnancy) was higher. The greatest cause of hysterectomy was related to attached placenta including accreta, uterus atony, a history of CS, multipara, and repeated CS. Therefore, due to the increase in the number of CSs in recent years, planning should be taken into account in order to encourage pregnant women for vaginal delivery. PMID- 28848643 TI - Providing an imputation algorithm for missing values of longitudinal data using Cuckoo search algorithm: A case study on cervical dystonia. AB - BACKGROUND: Missing values in data are found in a large number of studies in the field of medical sciences, especially longitudinal ones, in which repeated measurements are taken from each person during the study. In this regard, several statistical endeavors have been performed on the concepts, issues, and theoretical methods during the past few decades. METHODS: Herein, we focused on the missing data related to patients excluded from longitudinal studies. To this end, two statistical parameters of similarity and correlation coefficient were employed. In addition, metaheuristic algorithms were applied to achieve an optimal solution. The selected metaheuristic algorithm, which has a great search functionality, was the Cuckoo search algorithm. RESULTS: Profiles of subjects with cervical dystonia (CD) were used to evaluate the proposed model after applying missingness. It was concluded that the algorithm used in this study had a higher accuracy (98.48%), compared with similar approaches. CONCLUSION: Concomitant use of similar parameters and correlation coefficients led to a significant increase in accuracy of missing data imputation. PMID- 28848644 TI - Prevalence of depression and anxiety and their association with body mass index among high school students in Qazvin, Iran, 2013-2014. AB - BACKGROUND: Evidence shows that mental disorders among adolescents are associated with suicide, drug abuse, acute infectious diseases and low educational performances. OBJECTIVE: To determine the prevalence of depression and anxiety and their associations with body mass index (BMI) among high school students in Qazvin, Iran in 2013-2014. METHODS: A descriptive and analytical cross-sectional study using cluster-sampling method recruited 1,040 students among high schools in Qazvin, Iran from March 2013 to April 2014. Data were collected using questionnaires including demographic, Beck depression inventory and Beck anxiety inventory, and were analyzed with SPSS-19 by descriptive analyses, t-test, Chi square and Pearson correlation. RESULTS: The prevalence of depression and anxiety was 31.8% and 14.9%, respectively and these amounts were significantly higher in girls than in boys (p<0.05). Respondents showed 23.75% and 11.07% mild to moderate symptoms of depression and anxiety, respectively as well as 8.08 and 3.75% severe symptoms of depression and anxiety, respectively. There was a positive and significant association between depression and anxiety (r=0.256, p<0.001) and between depression and body mass index (BMI) (r=0.333, p<0.001), however there was an inverse association between anxiety and BMI (r=0.086, p<0.006). CONCLUSION: The current study made a significant step forward in assessment of mental disorders and BMI to show the significance of depression and anxiety among adolescents in Qazvin. Therefore, effective interventions are necessary to improve this situation as well as the evaluation of the effectiveness of the interventions. PMID- 28848645 TI - Decision support system for health care resources allocation. AB - BACKGROUND: A study about healthcare resources can improve decisions regarding the allotment and mobilization of medical resources and to better guide future investment in the health sector. AIM: The aim of this work was to design and implement a decision support system to improve medical resources allocation of Bejaia region. METHODS: To achieve the retrospective cohort study, we integrated existing clinical databases from different Bejaia department health sector institutions (an Algerian department) to collect information about patients from January 2015 through December 2015. Data integration was performed in a data warehouse using the multi-dimensional model and OLAP cube. During implementation, we used Microsoft SQL server 2012 and Microsoft Excel 2010. RESULTS: A medical decision support platform was introduced, and was implemented during the planning stages allowing the management of different medical orientations, it provides better apportionment and allotment of medical resources, and ensures that the allocation of health care resources has optimal effects on improving health. CONCLUSION: In this study, we designed and implemented a decision support system which would improve health care in Bejaia department to especially assist in the selection of the optimum location of health center and hospital, the specialty of the health center, the medical equipment and the medical staff. PMID- 28848646 TI - Factors affecting intent to immigration among Iranian health workers in 2016. AB - BACKGROUND: Loss of human resources in the health sector through migration has caused many problems in the delivery of healthcare services in developing countries. OBJECTIVE: The aim of this study was to determine factors influencing intention to migrate in skilled human resources in Iran's healthcare sector. METHODS: This cross-sectional study was carried out in 2016 in Iran. The study population included health sector human resources at the Tehran and Iran University of Medical Sciences. Using multi-stage cluster sampling, 827 people were selected for participation. Participants included four groups: hospital staff, health workers, medical students, and postgraduate students (Masters and PhD). Data were collected using a valid and reliable questionnaire and analyzed by descriptive parameters, chi-square and logistic regression test using SPSS version 18. RESULTS: Inclination to migrate, in the study population, was 54.77%. There was a significant relationship between inclination to migrate and age, work experience, employment status, marital status, familiarity with a foreign language, foreign language skills, foreign language courses, having relatives or family living abroad, and prior experience of being abroad (p<0.05). The most important factors influencing inclination to migrate were: reaching out for better life (81.92+/-21.95), interdisciplinary discrimination (80.83+/-20.75), and experience of living and studying abroad. (80.55+/-18.12). CONCLUSION: Considering the high rate of intention to emigrate in the studied population (54.77%), a lot of whom will emigrate if their situation is ready, it can be a serious problem for the health system in the near future in which it will face lack of skilled health workers, and so requires more attention of health sector authorities. PMID- 28848647 TI - Relationship between hysterectomy and severity of female stress urinary incontinence. AB - BACKGROUND: Stress Urinary Incontinence (SUI) is one of the most reported health dilemmas of women suffering from lower urinary tract symptoms. AIM: To determine the relation between hysterectomy and severity of female SUI using Valsalva Leak Point Pressure (VLPP). METHODS: This case-control study was conducted at a public urology clinic in Tehran in 2015. The study population was all female with SUI complaints who visited the clinic during 2015. We compared Valsalva leak point pressure in two groups of female SUI patients with and without hysterectomy history. The inclusion criteria were: not taking any alpha-blocker or anti cholinergic medicines two weeks prior to the urodynamic test as well as no history of pelvic surgery or cesarean delivery in their lifetime. All qualified patients were invited to participate in the study randomly, and among them, 120 qualified patients agreed to participate by filling out the informed consent form. Data was gathered through direct interview, and double checked by patients' medical records. All the study variables including age, BMI, delivery number, hysterectomy and UTI history were entered and analyzed by estimating ordered logistic regression and by using Stata14.1 software. RESULTS: The mean of VLPP was 70.17 cmH2O in the group with hysterectomy history, and 94.55 cmH2O in those without hysterectomy history. The difference of VLPP pressure between the two studied groups were significant (p<0.05), even after control of confounding variables. Also, the odds of severe SUI among hysterectomy group patients was 6.3 times more than no hysterectomy (OR=6.32, p<0.001). CONCLUSIONS: Our study confirms significant relation between hysterectomy and SUI severity measured by Valsalva leak point pressure. Hysterectomy patients are more likely to suffer from more severe grades of SUI. PMID- 28848648 TI - Nine years' trend of dental caries and severe early childhood caries among 3-6 year-old children in Babol, Northern Iran. AB - BACKGROUND AND OBJECTIVE: Malnutrition, pain, and insomnia are common adverse effects of early dental caries among 3-6-year-old children. To increase our understanding of the dental caries status which will help in the control and prevention of it, this study aimed to assess the trend of dental caries, Severe Early Childhood Caries (S-ECC) and its related factors among 3-6-year-old children during a 9-year period in Babol, Northern Iran. METHODS: This was a cross-sectional study among 2,080 children aged 3-6 years old in Babol, Northern Iran. The studied samples were examined from May 2007 to June 2015. Oral examinations were performed with visual-touch technique. S-ECC was measured as number of decayed, missing, and filled teeth surface (dmfs). Data were evaluated by SPSS software for Windows version 23 and were analyzed using the one-way ANOVA, chi-square test and independent-samples t-test. Level of significance was set at <= 0.05. RESULTS: The trend of dental caries and S-ECC rose among 3-6-year old children over a 9-year period. Of the children, 26.3% were caries free. The mean dmft was increased significantly among boys (p<0.001), among 3-4-year-old children (p=0.01), and those children with both employed parents (p=0.01) and low educated parents (p<0.001) from 2007 to 2015. CONCLUSION: Dental caries status showed an increasing trend over the study period in Babol preschool children, therefore effective preventive strategies are required to decrease the prevalence of dental caries in children. PMID- 28848649 TI - The assessment of the malnutrition in traumatic ICU patients in Iran. AB - BACKGROUND: Despite recognition of the importance of nutritional feedings, the delivery of optimal nutrition remains difficult to achieve in most intensive care units (ICU). OBJECTIVE: To assess the status of malnutrition in traumatically ill patients hospitalized in an ICU in Iran. METHODS: This descriptive, cross sectional study was conducted in Hamadan, Iran, on 123 patients in an ICU ward over six months with the purpose of assessing malnutrition status. Malnutrition and its severity were assessed based on the defined chemical parameters on admission and the end of stay times. Also, body mass index (BMI), weight (W), and height (H) anthropometric indices were assessed simultaneously to be compared with the chemical results. For statistical analysis we used SPSS version 16 software. RESULTS: Overall, 83% of patients had malnutrition on admission to ICU, which was 90% on discharge or near-death condition, indicating increase of the prevalence of malnutrition within hospitalization in this ward. On admission, 11% of patients had mild, 61% moderate, and 11% severe malnutrition that reached to 4%, 63%, and 23%, respectively, by the end of the stay. BMI was significantly different in the patients who completed two weeks in the ICU (p<0.05). Assessment of the correlation between admission and two week completed stay showed that BMI, H, and W were positively correlated (r=0.85), (r=1.0), and (r=0.638), (p<0.05), respectively. There were no significant correlations in these parameters in the fourth week. Assessing the changes in anthropometric parameters showed downward trends of both weight and body mass index within ICU hospitalization. CONCLUSION: As shown in our study, inattention to needs of critically ill patients or lack of facilities results in developing and worsening of malnutrition, which, in turn, considerably worsens the outcome. To supply the needs of these in-hypermetabolic state patients, the importance of nutrition and its effect on outcome must be understood by medical staff; close monitoring of the nutritional status of these patients, along with meticulous calculations and team work, must be done and appropriate supportive routs be used. PMID- 28848650 TI - Counseling-supportive interventions to decrease infertile women's perceived stress: A systematic review. AB - BACKGROUND: Infertility all around the world and in every culture is recognized as a stressful and critical experience that threatens individual, familial, marital, and social stability. Thus, in accordance with the importance of a woman's mental health and the possible impact of mental health on treatment outcome, finding a way to deal with perceived stress in women can help improve pregnancy outcomes. METHODS: This study is a systematic review on reducing perceived infertility stress in infertile women. The current study was undertaken using multiple databases such as SID, Irandoc, Magi ran, Google Scholar, PubMed, Science Direct, Scopus, Cochrane library, and CINAHL selected from articles pertinent to the study. The selection of papers was undertaken from 1990 through May 2016. The methodological quality was assessed. RESULTS: The initial search yielded a list of 725 papers, and then reviewers studied titles and abstracts. Thereafter, 68 papers were incorporated, and researchers reviewed summaries of all of the searched articles. Finally, the researchers utilized the data gained from 29 full articles so as to compile this review paper. Reviewing the studies conducted on reducing infertility perceived stress, the researchers classified related findings into two main categories: supportive and counseling intervention. CONCLUSION: Considering the fact that there is an international agreement that fertility centers need to offer counseling programs for psychological problems of the infertile, it is especially important to recognize counseling-supportive interventions for decreasing infertile women's perceived stress and to program plans for decreasing women's perceived stress. By investigating counseling-supportive stress, we hope that this study has stepped forward toward health care agent's familiarity with decreasing infertile women's perceived stress and, therefore, improving treatment consequences. PMID- 28848651 TI - A General Strategy for Generating Gradients of Bioactive Proteins on Electrospun Nanofiber Mats by Masking with Bovine Serum Albumin. AB - Electrospun nanofibers are widely used in tissue engineering owing to their capability to mimic the structures and architectures of various types of extracellular matrices. However, it has been difficult to incorporate a biochemical cue into the physical cue provided by the nanofibers. Here we report a simple and versatile method for generating gradients of bioactive proteins on nanofiber mats. We establish that the adsorption of bovine serum albumin (BSA) onto nanofibers is a time- and concentration-dependent process. By linearly increasing the volume of BSA solution introduced into a container, a gradient in BSA is readily generated across the length of a vertically oriented strip of nanofibers. Next, the bare regions uncovered by BSA can be filled with the bioactive protein of interest. In demonstrating the potential application, we examine the outgrowth of neurites from dorsal root ganglion (DRG) isolated from chick embryos and then seeded on aligned polycaprolactone nanofibers covered by nerve growth factor (NGF) with a uniform coverage or in a gradient. In the case of uniform coverage, the neurites extending from DRG show essentially the same length on either side of the DRG cell mass. For the sample with a gradient in NGF, the neurites extending along the gradient (i.e., increase of NGF concentration) were significantly longer than the neurites extending against the gradient. PMID- 28848652 TI - Veterinary pharmacovigilance in Europe: a survey of veterinary practitioners. AB - A web-based survey was conducted by the Federation of Veterinarians of Europe with the support of the European Medicines Agency to gain a better insight into the adverse event reporting habits of veterinary practitioners and the level of information on reported adverse events that flows back to them. It was completed by 3545 veterinarians. The findings indicate marked under-reporting and that the system is poorly equipped to deal with lack of expected efficacy, with few cases reported and most found to be inconclusive. It was also found that feedback systems are greatly lacking. In order to increase spontaneous reporting, there is a need to make reporting easier (eg, by developing mobile apps, to incorporate the reporting into the practice management system software) and to make veterinarians better aware of the importance of reporting and the added value it may bring. Feedback systems should be improved. The best way to motivate reporters is to demonstrate that the reports they submit are indeed useful and contribute to the improved use of veterinary medicinal products. The major role veterinarians can play in improving animal health, welfare and public health by reporting adverse events needs to be further promoted. PMID- 28848653 TI - Automated evaluation of ANA under real-life conditions. AB - INTRODUCTION: Visual evaluation of indirect immunofluorescence (IIF) on human epithelial-2 cells is the routine method for screening for antinuclear antibodies (ANA) in connective tissue diseases. Since visual IIF is time-consuming and subjective, automated IIF processors have been developed to offer standardised, valid and cost-efficient IIF assays. OBJECTIVE: The aim of this study was to determine the diagnostic reliability of 2 widely used IIF processors (Aklides, Medipan GmbH and Helios, Aesku Diagnostics) under real-life laboratory working conditions. METHODS: ANA were determined in samples from patients with suspected autoimmune rheumatic disease (n=1008) using both automated IIF processors and compared with the results obtained by visual interpretation. The performance of IIF processors to discriminate positive from negative samples, pattern recognition and end point titre prediction were evaluated. RESULTS: The IIF processors showed moderate agreement with visual interpretation in discriminating positive from negative ANA samples (kappa values: Aklides 0.494; Helios 0.415). The sensitivity/specificity was 89%/59% for Aklides and 87%/54% for Helios. However, both processors correctly identified 99% of definitely positive samples (titre >=1:320). Aklides correctly identified 43% of fluorescence patterns and its light intensity values showed good correlation (Spearman's rho=0.680) with visually obtained titres. CONCLUSIONS: Automated IIF determination under real life laboratory working conditions remains a challenge. Owing to their high sensitivity at clinically relevant ANA titres, automated IIF processors can already support but not totally replace visual IIF. PMID- 28848655 TI - Current Understanding of the Compensatory Actions of Cardiac Natriuretic Peptides in Cardiac Failure: A Clinical Perspective. AB - Natriuretic peptides play a crucial role in maintaining cardiovascular homeostasis. Among their properties are vasodilation, natriuresis, diuresis, and inhibition of cardiac remodeling. As heart failure progresses, however, natriuretic peptides fail to compensate. Knowledge of their processing and signaling pathways has guided the development of pharmacological therapies aimed at bolstering their effects. The drugs that have achieved the most clinical success have also stirred the most controversy. Nesiritide, the synthetic B-type natriuretic peptide, yielded significant symptomatic relief and improved haemodynamics but its use was plagued with questions surrounding its possibly harmful impact on renal function. More recently, compounds containing inhibitors of neprilysin, the enzyme responsible for degrading natriuretic peptides, have demonstrated morbidity and mortality benefit, but have also been linked to possible negative side effects. Clearly, potentiating the actions of natriuretic peptides for the benefit of patients is not as simple as just raising their serum concentration. This article reviews the current understanding of the compensatory actions of cardiac natriuretic peptides in heart failure and how this knowledge is revolutionizing heart failure therapy. PMID- 28848654 TI - Effect of certolizumab pegol over 96 weeks of treatment on inflammation of the spine and sacroiliac joints, as measured by MRI, and the association between clinical and MRI outcomes in patients with axial spondyloarthritis. AB - OBJECTIVE: To report MRI outcomes and explore the relationship between clinical remission and MRI inflammation in patients with axial spondyloarthritis (axSpA) from the RAPID-axSpA trial, including radiographic (r-)axSpA and non-radiographic (nr-)axSpA. METHODS: RAPID-axSpA (NCT01087762) was double-blind and placebo controlled to week 24, dose-blind to week 48 and open-label to week 204. Patients were randomised to certolizumab pegol (CZP) or placebo. Placebo patients entering dose-blind were rerandomised to CZP. MRIs performed at baseline, weeks 12, 48 and 96 were scored by 2 reviewers independently: Spondyloarthritis Research Consortium of Canada (SPARCC) for sacroiliac (SI) joints; Berlin modification of the Ankylosing Spondylitis spine MRI scoring system for disease activity (Berlin) for spine. Inflammation thresholds: SPARCC>=2; Berlin>2. Remission thresholds: SPARCC<2 (SI joints); Berlin<=2 (spine); Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (<1.3, clinical). RESULTS: Across 163 patients in the MRI set (109 CZP; 54 placebo), week 12 mean changes from baseline in MRI scores were greater for CZP versus placebo: SPARCC: -4.8 (SD 8.6) vs -1.6 (7.8; p<0.001); Berlin: -2.9 (4.2) vs 0.2 (4.8; p<0.001). Improvements were maintained to week 96. Week 12 MRI remission was achieved by 52.6% of patients with baseline MRI inflammation in SI joints, 62.0% in the spine and 37.9% of patients with both. MRI remission rates were sustained to week 96, with similar trends in r axSpA and nr-axSpA. At week 96, 57.5% vs 65.9% of patients achieving versus not achieving clinical remission had MRI remission. CONCLUSIONS: CZP reduced inflammation in the spine and SI joints in patients with r-axSpA and nr-axSpA, with improvements maintained over 96 weeks. Substantial proportions of patients achieved MRI remission. Concordance between clinical remission and current definitions of absence of MRI inflammation was limited. TRIAL REGISTRATION NUMBER: NCT01087762; Post-results. PMID- 28848656 TI - Clinical activity and tolerability of FOLFIRI and cetuximab in elderly patients with metastatic colorectal cancer in the CAPRI-GOIM first-line trial. AB - BACKGROUND: In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. METHODS: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by age-groups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (>=65; >=70 and >=75 years). RESULTS: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were >65 years, 86 >70 years and 35 >75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were >65 years, 46 >70 and 17 >75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were >=65 years; 29 were >=70; 9 were >=75. Median PFS was similar within the age-subgroups in the intention-to treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade >=3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients >=75 years and grade >=3 fatigue (31% vs 20%, p=0.01) in patients <75 years. CONCLUSIONS: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade >=3 diarrhoea and neutropaenia in patients >=75 years and grade >=3 fatigue in patients <75 years. TRIAL REGISTRATION NUMBER: 2009-014041-81. PMID- 28848657 TI - Specific CDK4/6 inhibition in breast cancer: a systematic review of current clinical evidence. AB - BACKGROUND: Loss of cell cycle control is a hallmark of cancer, and aberrations in the cyclin-dependent kinase-retinoblastoma (CDK-Rb) pathway are common in breast cancer (BC). Consequently, inhibition of this pathway is an attractive therapeutic strategy. The present review addresses efficacy and toxicity of CDK4/6 inhibition in BC. METHODS: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included. RESULTS: Three specific CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib are tested in clinical trials. A randomised phase II trial of palbociclib plus letrozole versus letrozole and a phase III of palbociclib plus fulvestrant versus fulvestrant showed significantly increased progression-free survival when compared with endocrine therapy alone in first-line and second-line treatment for advanced hormone receptor-positive HER2-negative BC. At the moment several phase III studies are ongoing with all three CDK4/6 inhibitors in hormone receptor-positive HER2-negative BC as well as other subtypes of BC. The predominant toxicity of agents was limited neutropenia. Other common adverse events were infections, fatigue and gastrointestinal toxicity. The toxicities seemed manageable. Yet data are too limited to differentiate between the compounds. Retinoblastoma protein (Rb) is considered a promising biomarker. CONCLUSION: CDK4/6 inhibition might represent a substantial advance for patients with hormone receptor-positive HER2-negative BC. Results must be confirmed in phase III trials before any firm conclusions can be made regarding the future influence of CDK4/6 inhibition. There is an urgent need for prospective biomarker driven trials to identify patients for whom CDK4/6 inhibition is cost-effective. PMID- 28848659 TI - Switching from standard to dose-dense chemotherapy in front-line treatment of advanced ovarian cancer: a retrospective study of feasibility and efficacy. AB - BACKGROUND: Current standard neoadjuvant treatment for advanced ovarian cancer is 3-weekly platinum-based chemotherapy (CP3w). Patients unable to have interval debulking surgery (IDS) or with significant residual disease have a poor outcome to CP3w treatment. We investigated the outcome in patients who were switched to dose-dense chemotherapy. METHODS: We retrospectively analysed 30 patients treated at UCLH in 2009-2013, who switched to dose-dense chemotherapy after neoadjuvant CP3w, having achieved a poor response/progressed and unable to proceed to IDS (n=21), or had >1 cm residual disease after IDS (n=9). Treatment was 3-weekly carboplatin and weekly paclitaxel (n=23), or both drugs weekly (n=7). For comparison, we included 30 matched patients treated with CP3w followed by IDS (n=24, without or <=1 cm residual disease; n=6, with >1 cm residual disease). Time to progression (TTP) and overall survival (OS) were measured from the date of diagnosis until progression (CT scan or CA-125) and death from any cause, respectively. RESULTS: Baseline characteristics were similar in both groups. The response rate to dose-dense chemotherapy was 70% (Gynecological Cancer Intergroup criteria). In the dose-dense group, 24 patients had tumour progression and 16 died; the corresponding numbers in the control group were 24 and 11. Median TTP was 15.8 months with dose-dense therapy, higher than expected for this patient group, and the same as in the control group (15.7 months) undergoing IDS, p=0.27. Median TTP in patients with residual disease postsurgery was 16.5 months (dose dense) and 10.8 months (controls), p=0.02. TTP in dose-dense patients who did not have surgery was 10.4 months. Median OS was 31.3 (dose-dense) and 59.6 months (controls), p=0.06. Dose-dense chemotherapy was well tolerated: only three patients interrupted treatment due to toxicity. CONCLUSION: Switching to dose dense chemotherapy in patients who failed to respond to CT3w neoadjuvant chemotherapy appears to be an effective strategy and requires further investigation. PMID- 28848658 TI - Radiological imaging markers predicting clinical outcome in patients with metastatic colorectal carcinoma treated with regorafenib: post hoc analysis of the CORRECT phase III trial (RadioCORRECT study). AB - OBJECTIVE: To identify imaging markers predicting clinical outcomes to regorafenib in metastatic colorectal carcinoma (mCRC). METHODS: The RadioCORRECT study is a post hoc analysis of a cohort of patients with mCRC treated within the phase III placebo-controlled CORRECT trial of regorafenib. Baseline and week 8 contrast-enhanced CT were used to assess response by RECIST 1.1, changes in the sum of target lesion diameters (DeltaSTL), lung metastases cavitation and liver metastases density. Primary and secondary objectives were to develop ex novo univariable and multivariable models to predict overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: 202 patients were enrolled, 134 (66.3%) treated with regorafenib and 68 (33.7%) with placebo. In the univariate analysis, PFS predictors were lung metastases cavitation at baseline (HR 0.50, 95% CI 0.27 to 0.92, p=0.03) and at week 8 (HR 0.58, 95% CI 0.36 to 0.93, p=0.02). Baseline cavitation (HR 0.23, 95% CI 0.08 to 0.66, p=0.007), RECIST 1.1 (HR 0.23, 95% CI 0.14 to 0.4, p <0.0001) and DeltaSTL (HR 1.16, 95% CI 1.06 to 1.27, p=0.002) predicted OS. We found an increase of 9% of diameter as the best threshold for discriminating OS (HR 2.64, 95% CI 1.61 to 4.34, p <0.001). In the multivariate analysis, baseline and week 8 cavitation remained significant PFS predictors. Baseline cavitation, RECIST 1.1 and DeltaSTL remained predictors of OS in exploratory multivariable models. Assessment of liver metastases density did not predict clinical outcome. CONCLUSIONS: RECIST 1.1 and DeltaSTL predict favourable outcome to regorafenib. In contrast to liver metastases density that failed to be a predictor, lung metastases cavitation represents a novel radiological marker of favourable outcome that deserves consideration. PMID- 28848660 TI - The promise of immunotherapy in head and neck squamous cell carcinoma: combinatorial immunotherapy approaches. AB - The immune system plays a fundamental role in preventing cancer development by recognising and eliminating tumour cells. The recent success in the field of immunotherapy has confirmed the potential to exploit the immune response as a cancer treatment. Head and neck squamous cell carcinoma (HNSCC) is a malignancy characterized by dismal prognosis and high mortality rate; low survival outcomes in combination with significant toxicity of current treatment strategies highlight the necessity for novel therapeutic modalities. HNSCC is a favourable disease for immunotherapy, as immune escape plays a key role in tumour initiation and progression. T-cell checkpoint inhibitors targeting programmed cell death protein-1 have emerged as novel immunotherapy agents showing remarkable efficacy in HNSCC. However, only a minority of patients derive benefit for single-agent immunotherapies. In this regard, combinatorial immunotherapy approaches represent an alternative strategy that might increase the number of patients who respond to immunotherapy. Focusing on HNSCC, this review will summarise novel combinations of immune checkpoint blockade with other immunotherapy treatment modalities. PMID- 28848662 TI - Between January 2009 and April 2016, 134 novel anticancer therapies were approved: what is the level of knowledge concerning the clinical benefit at the time of approval? AB - OBJECTIVE: In the last decade an increasing number of high-priced, new cancer treatments received marketing authorisation in Europe. What is actually known about the clinical benefit of those therapies at the time of approval needs to be elucidated in order to inform decisions about the use and reimbursement of these novel treatment options. Thus, the aim of the current analysis was to systematically investigate oncological therapies approved between January 2009 and April 2016 and extract as well as quantify the level of knowledge of the clinical benefit at the time of marketing authorisation. METHODS: To assess the benefit of new interventions as well as expanded indications, we extracted the median gain of the two study end points: progression-free survival (PFS) and overall survival (OS). Information is based on approval documents provided by the European Medicines Agency and assessments from the Austrian Horizon Scanning programme. We included all cancer therapies approved in Europe between 2009 (January 1) and 2016 (April 15). RESULTS: Cancer drugs for 134 new indications approved since 2009 were identified. In the case of 37 indications (27%), no data were available for PFS or for OS. A positive difference in median OS was reached by 76 licensed indications (55.5%); 22 (16%) of them showed a difference of more than 3 months. Regarding the study end point PFS, an improvement was shown in 90 indications (65.2%). CONCLUSION: Scarce knowledge regarding the clinical benefit of anticancer therapies is available at the time of approval. In addition, the survival benefit of the approved indications is less than 3 months in the majority of approved therapies. PMID- 28848661 TI - Adjuvant treatment following radical cystectomy for muscle-invasive urothelial carcinoma and variant histologies: Is there a role for radiotherapy? AB - Comprehensive molecular characterisation of muscle-invasive urothelial carcinoma and variant histological subtypes has led to the identification of recurrent driver mutations that are distinct in these aggressive subgroups of bladder cancer. While distant metastasis dominates as a pattern of relapse following radical cystectomy or chemoradiotherapy, loco-regional control rates are also suboptimal with single modality local treatment, and likewise, harbour equivocal implications on the long-term prognosis of patients. The role of adjuvant radiotherapy for optimising disease control within the pelvis is controversial, with limited evidence to support its efficacy. Herein, we present a stepwise review on adjuvant radiotherapy post-cystectomy; first, discussing the evidence to date supporting the concept that adjuvant radiotherapy is effective in targeting occult metastases within the pelvis, and adds to the benefits of adjuvant chemotherapy. Next, we outlined the principles underlying the definition of radiotherapy target volumes. To conclude, we addressed the need for appropriate patient stratification for treatment intensification, based on existing clinical models and novel molecular indices of aggression in muscle invasive urothelial cancers and variant histological subtypes. PMID- 28848663 TI - Upper tract urothelial carcinoma: a different disease entity in terms of management. AB - Upper tract urothelial carcinomas (UTUCs) consist of 5%-10% of all urothelial carcinomas, the rest being urothelial carcinomas of the bladder (UCB). There is increasing evidence to show that UTUC is a distinct disease entity from UCB based on phenotypical and genotypical (genetic and epigenetic) differences. This may account for why the natural history of UTUC is different from that of UCB, with >60% of UTUCs and only 15%-25% of UCB presenting with invasion at diagnosis. Management of UTUC is thus different from UCB in a variety of ways, ranging from surgical management, postoperative instillation therapy, postoperative surveillance and medical management (neoadjuvant and adjuvant chemotherapy). This review paper aims to highlight these differences with an emphasis on the distinct management of UTUC, along with the latest updates. PMID- 28848665 TI - Cancer and the arts: the fight for meaning - Akira Kurosawa's "Ikiru". PMID- 28848666 TI - Educational video: the role of PD-L1 in the local tumour microenvironment. AB - Watch the video here. Building on our previous educational video on the interaction between cancer and the immune system, we highlight in this video the role of programmed death ligand 1 (PD-L1) in the tumour microenvironment. We explain the function of important immune cell types found in the tumour microenvironment and how they interact with each other and with cancer cells. Dendritic cells take up tumour antigen and transport it to the regional lymph node for T cell priming. T cells are the main mediators of the adaptive immune system and kill tumour cells via release of cytotoxins. Macrophages are the main effector cells of the innate immune system and have various functions such as phagocytosis and antigen presentation. Therapeutic monoclonal antibodies that bind to PD-1 or PD-L1, so called immune checkpoint inhibitors, prevent the interaction of these immune-suppressive molecules and thus facilitate an effective T cell-mediated antitumour immune response. PMID- 28848664 TI - The European Cancer Patient's Bill of Rights, update and implementation 2016. AB - In this implementation phase of the European Cancer Patient's Bill of Rights (BoR), we confirm the following three patient-centred principles that underpin this initiative:The right of every European citizen to receive the most accurate information and to be proactively involved in his/her care.The right of every European citizen to optimal and timely access to a diagnosis and to appropriate specialised care, underpinned by research and innovation.The right of every European citizen to receive care in health systems that ensure the best possible cancer prevention, the earliest possible diagnosis of their cancer, improved outcomes, patient rehabilitation, best quality of life and affordable health care. The key aspects of working towards implementing the BoR are:Agree our high level goal. The vision of 70% long-term survival for patients with cancer in 2035, promoting cancer prevention and cancer control and the associated progress in ensuring good patient experience and quality of life.Establish the major mechanisms to underpin its delivery. (1) The systematic and rigorous sharing of best practice between and across European cancer healthcare systems and (2) the active promotion of Research and Innovation focused on improving outcomes; (3) Improving access to new and established cancer care by sharing best practice in the development, approval, procurement and reimbursement of cancer diagnostic tests and treatments.Work with other organisations to bring into being a Europe based centre that will (1) systematically identify, evaluate and validate and disseminate best practice in cancer management for the different countries and regions and (2) promote Research and Innovation and its translation to maximise its impact to improve outcomes. PMID- 28848667 TI - Lactobacillus brevis CD2 lozenges prevent oral mucositis in patients undergoing high dose chemotherapy followed by haematopoietic stem cell transplantation. AB - BACKGROUND: Oral mucositis is a common inflammatory complication in patients undergoing high-dose chemotherapy and radiation followed by haematopoietic stem cell transplantation (HSCT). Lactobacillus brevis CD2 has been proven efficacious in preventing chemoradiotherapy-induced oral mucositis in squamous cell carcinoma of head and neck. METHODS: This phase II study aimed to evaluate the safety and efficacy of L. brevis CD2 lozenges in preventing oral mucositis in patients undergoing HSCT. Eligible patients received four to six lozenges of L. brevis CD2 per day, beginning from 4 to 7 days before initiation of chemotherapy and continuing until resolution of mucositis or till day +24. RESULTS: Of 31 patients enrolled, 7 (22.6%) patients did not develop any mucositis, 6 (19.4%) patients developed grade 1, 12 (38.7%) patients developed grade 2, 4 (12.9%) and 2 (6.5%) patients developed grade 3 and grade 4 mucositis, respectively. Median time to onset and for resolution of mucositis were 6 days and 8 days, respectively. No adverse events were reported with usage of study drug. However, one patient died of Klebsiella sepsis. CONCLUSION: Promising results from the study encourage the use of L. brevis CD2 lozenges as a supportive care treatment option; however, a randomised, double-blind, multicentric trial in a larger population is warranted. TRIALS REGISTRATION NUMBER: NCT01480011 at https://www.clinicaltrials.gov/ (Registered on Nov 04, 2011). PMID- 28848668 TI - Biosimilars: a position paper of the European Society for Medical Oncology, with particular reference to oncology prescribers. AB - Biosimilars present a necessary and timely opportunity for physicians, patients and healthcare systems. If suitably developed clinically, manufactured to the correct standards and used appropriately, they can positively impact on the financial sustainability of healthcare systems. A critical consideration regarding the introduction of biosimilars into the clinic centres on the required information concerning all the respective procedures. This position paper aims to describe the issues revolving around biosimilars that are relevant to the field of oncology, especially the prescribers. More specifically, we discuss aspects related to definition, forms of biosimilars, labelling, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, responsibilities among prescribers and pharmacists, potential impact on financial burden in healthcare and the current scenario and future prospects of biosimilars in Europe and the rest of the world. PMID- 28848669 TI - ESMO Women for Oncology 2016: a very personal tale of my professional life in Asia. PMID- 28848670 TI - Cancer drugs, survival and ethics: a critical look from the inside. PMID- 28848671 TI - One year of ESMO Open: Cancer Horizons-where are we going from here? PMID- 28848672 TI - Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort. AB - OBJECTIVE: This phase I clinical study (NCT01415297) evaluated the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a novel small molecule that suppresses the stress induction of GRP78 in tumour cells. GRP78 is a key regulator of misfolded protein processing, and its upregulation in tumours is associated with intrinsic and drug-induced resistance. METHODS: Forty-six patients with advanced solid tumours refractory to treatment received intravenous infusions of IT-139 on days 1, 8 and 15 for every 28 days, and doses were evaluated across nine cohorts at 20, 40, 80, 160, 320, 420, 500, 625 and 780 mg/m2. RESULTS: Overall, IT-139 was well tolerated. The treatment emergent adverse events (AEs) occurring in >=20% of patients were nausea, fatigue, vomiting, anaemia and dehydration. The majority of patients had AEs that were <=grade 2, regardless of relationship with the study drug. Of the total 38 efficacy-evaluable patients, one patient with a carcinoid tumour achieved a durable partial response. Nine additional patients achieved stable disease . The MTD was determined to be 625 mg/m2. IT-139 exhibited first-order linear pharmacokinetics. CONCLUSIONS: IT-139 demonstrated a manageable safety profile at the MTD and modest anti-tumour activity in this study of patients with solid tumours refractory to treatment. The lack of dose-limiting haematological toxicity and the absence of neurotoxicity position IT-139 well for use in combination with a broad spectrum of anticancer drugs. TRIAL REGISTRATION NUMBER: NCT01415297. PMID- 28848673 TI - Essentials for clinicians: head and neck tumours and neuro-oncology. PMID- 28848674 TI - Successful osimertinib treatment for leptomeningeal carcinomatosis from lung adenocarcinoma with the T790M mutation of EGFR. AB - Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) that has been approved for the treatment of metastatic non-small cell lung cancer (NSCLC) positive for the secondary T790M mutation of EGFR. In a preclinical study, it also showed efficacy against leptomeningeal carcinomatosis (LMC) derived from NSCLC resistant to first generation and second-generation EGFR-TKIs. We now report the case of a patient aged 70 years with symptomatic LMC derived from NSCLC with the T790M mutation of EGFR who showed a clinical and radiographic response to osimertinib. PMID- 28848675 TI - New molecular and immunotherapeutic approaches in biliary cancer. AB - Biliary tract carcinoma is a collective term for a group of rare gastrointestinal cancers. This overview outlines the key pathways and specialised therapeutics in biliary cancer and the emerging role of immunotherapy by highlighting the rationale and selected examples of studies in each area. PMID- 28848676 TI - A consensus on liquid biopsy from the 2016 Chinese Lung Cancer Summit expert panel. AB - The diagnosis and treatment of lung cancer have evolved into the era of precision medicine. Liquid biopsy, a minimally invasive approach, has emerged as a promising practice in genetic profiling and monitoring of lung cancer. Translating liquid biopsy from bench to bedside has encountered various challenges, including technique selection, protocol standardisation, data analysis and cost management. Regarding these challenges, the 2016 Chinese Lung Cancer Summit expert panel organised a trilateral forum involving oncologists, clinicians, clinical researchers, and industrial expertise on the 13th Chinese Lung Cancer Summit to formally discuss these controversies. Six consensuses were reached to guide the use of liquid biopsy and perform precision medicine in both clinic and research. PMID- 28848678 TI - PRPF3-Associated Autosomal Dominant Retinitis Pigmentosa and CYP4V2-Associated Bietti's Crystalline Corneoretinal Dystrophy Coexist in a Multigenerational Chinese Family. AB - PURPOSE: To characterize the clinical and molecular genetic characteristics of a large, multigenerational Chinese family showing different phenotypes. METHODS: A pedigree consisted of 56 individuals in 5 generations was recruited. Comprehensive ophthalmic examinations were performed in 16 family members affected. Mutation screening of CYP4V2 was performed by Sanger sequencing. Next generation sequencing (NGS) was performed to capture and sequence all exons of 47 known retinal dystrophy-associated genes in two affected family members who had no mutations in CYP4V2. The detected variants in NGS were validated by Sanger sequencing in the family members. RESULTS: Two compound heterozygous CYP4V2 mutations (c.802-8_810del17insGC and c.992A>C) were detected in the proband who presented typical clinical features of BCD. One missense mutation (c.1482C>T, p.T494M) in the PRPF3 gene was detected in 9 out of 22 affected family members who manifested classical clinical features of RP. CONCLUSIONS: Our results showed that two compound heterozygous CYP4V2 mutations caused BCD, and one missense mutation in PRPF3 was responsible for adRP in this large family. This study suggests that accurate phenotypic diagnosis, molecular diagnosis, and genetic counseling are necessary for patients with hereditary retinal degeneration in some large mutigenerational family. PMID- 28848679 TI - Expression of Concern on "Invisible Victims: Delayed Onset Depression among Adults with Same-Sex Parents". PMID- 28848680 TI - Leukemic Ischemia: A Case of Myocardial Infarction Secondary to Leukemic Cardiac Involvement. AB - We report a case of a 39-year-old male who presented to the emergency department with acute chest pain while being in remission from T-cell acute lymphoblastic leukemia (T-ALL). Cardiac markers were elevated and EKG revealed ischemic changes compatible with acute myocardial ischemia. Coronary computed tomography angiography (CCTA) showed calcium-free coronary arteries and soft tissue myocardial infiltration suggestive of cardiac leukemia. A bone marrow biopsy confirmed recurrence of T-ALL, and patient was successfully treated with chemotherapy. We discuss the prospective diagnosis of myopericardial leukemic involvement and the role of CCTA in diagnosis and perform a literature review. PMID- 28848681 TI - Infectious Endocarditis from Enterococcus faecalis Associated with Tubular Adenoma of the Sigmoid Colon. AB - INTRODUCTION: Enterococcus faecalis (E. faecalis), a constituent of the gut microbiota, can be associated with both colonic lesions and endocarditis. Since this microorganism is one of the endocarditis etiological agents, there is a need for greater study in regard to the association with endocarditis and colonic lesions. CASE PRESENTATION: This is the case description of a 53-year-old man with history of prolapse of the anterior mitral valve leaflet who was diagnosed with endocarditis by E. faecalis and treated with ampicillin and gentamicin. Upon investigation by colonoscopy, he was found to have a tubular adenoma with low grade dysplasia. CONCLUSION: There are a few descriptions in scientific literature of an association between endocarditis by E. faecalis and colonic lesions. However, further studies with significant correlation between the two pathologies are required, so that proper measures can be implemented in clinical practice. PMID- 28848677 TI - A Critical Analysis of the Available In Vitro and Ex Vivo Methods to Study Retinal Angiogenesis. AB - Angiogenesis is a biological process with a central role in retinal diseases. The choice of the ideal method to study angiogenesis, particularly in the retina, remains a problem. Angiogenesis can be assessed through in vitro and in vivo studies. In spite of inherent limitations, in vitro studies are faster, easier to perform and quantify, and typically less expensive and allow the study of isolated angiogenesis steps. We performed a systematic review of PubMed searching for original articles that applied in vitro or ex vivo angiogenic retinal assays until May 2017, presenting the available assays and discussing their applicability, advantages, and disadvantages. Most of the studies evaluated migration, proliferation, and tube formation of endothelial cells in response to inhibitory or stimulatory compounds. Other aspects of angiogenesis were studied by assessing cell permeability, adhesion, or apoptosis, as well as by implementing organotypic models of the retina. Emphasis is placed on how the methods are applied and how they can contribute to retinal angiogenesis comprehension. We also discuss how to choose the best cell culture to implement these methods. When applied together, in vitro and ex vivo studies constitute a powerful tool to improve retinal angiogenesis knowledge. This review provides support for researchers to better select the most suitable protocols in this field. PMID- 28848682 TI - Eyelid Edema: A Rare Cause of a Common Sign. AB - We report a 48-year-old female patient who presented to the emergency room with right eyelid edema, with 3 days of evolution. She had suffered minor trauma to this eye one week before. She reported episodes of right eyelid swelling of spontaneous resolution since the occurrence of a traumatic brain injury 5 years ago. Ophthalmological examination showed a soft and painless eyelid edema of the right eye. Brain computed tomography showed an area of bone discontinuity of the orbital roof with brain herniation and a CSF leak into the eyelid (blepharocele). Magnetic resonance confirmed the result of TC and revealed an area of frontal encephalomalacia. Ibuprofen (800 mg/day) was prescribed, with complete resolution within 20 days. She was evaluated by Neurosurgery with no indication of surgery due to the resolution of the edema and absence of symptoms. Blepharocele is a rare entity that should be considered in the differential diagnosis of unilateral eyelid edema. It can be secondary to an orbital fracture or congenital lesion. PMID- 28848683 TI - Endoscopic Treatment of Sphenoid Sinus Mucocele: Case Report and Surgical Considerations. AB - INTRODUCTION: The paranasal sinuses mucoceles are benign expansive cystic lesions that occur rarely in the sphenoid sinus and contain mucous material enclosed by cylindrical pseudostratified epithelium. OBJECTIVE: To report one case of sphenoid sinus mucocele that occurred with headache and was submitted to surgical treatment through endonasal endoscopy approach. CASE REPORT: 59-year-old male patient with history of increasing frontoorbital, bilateral, fluctuating headache and exophthalmos. There was no other associated clinical abnormality. Computed Tomography (CT) and Magnetic Resonance Image (MRI) scans confirmed an expansive mass of sphenoid sinus, suggesting mucocele. The patient was submitted to endonasal endoscopic surgery with posterior ethmoidotomy, large sphenoidotomy, and marsupialization of the lesion. CONCLUSION: Mucoceles of the sphenoid sinus are a very rare condition with variable clinical and radiological presentation. Surgical treatment is absolutely indicated and early treatment avoids visual damage that can be permanent. Endonasal endoscopic approach with drainage and marsupialization of sphenoid sinus, using a transnasal corridor, is a safe and effective treatment modality. PMID- 28848684 TI - A Rare Case of Cutaneous Plasmacytosis in a Korean Male. AB - Cutaneous and systemic plasmacytosis are reactive disease processes that occur in middle-aged Japanese and Chinese men. Systemic plasmacytosis, defined by plasmacytic infiltration of two organ systems, might rarely progress to lymphoma. Cutaneous plasmacytosis, however, is chronic and benign and is characterized by the development of multiple plasma cell-rich infiltrates in the skin. We present a case of cutaneous plasmacytosis in a 46-year-old Korean male. The patient demonstrated classic features of the disease entity, including disseminated red brown plaques, differentiated plasmacytoid infiltrates on biopsy, hypergammaglobulinemia, and the absence of systemic disease. PMID- 28848685 TI - Bridging the Gaps in Patient Education for DBS Surgery in Parkinson's Disease. AB - INTRODUCTION: Improvements in quality of life, tremor, and other motor features have been recognized as superior in patients with advanced Parkinson's disease (PD) treated with deep brain stimulation (DBS) surgery versus best medical therapy. We studied a group of patients with PD after undergoing DBS surgery in regard to expectations and satisfaction with DBS outcomes to determine gaps in patient education. METHODS: This study was a retrospective, single academic center chart review and outcome questionnaire sent to patients with PD who had undergone DBS surgery between 2007 and 2014. RESULTS: All patients surveyed indicated that benefit from DBS surgery met their overall expectations at least partially, but only 46.4% (SE: 9.6%) were in complete agreement. 3.6% (SE: 3.6%) of participants strongly disagreed that preoperative education prepared them adequately for the procedure and 17.9% (SE: 7.4%) only somewhat agreed. CONCLUSIONS: Our findings demonstrate that patients' expectations of DBS surgery in PD were at least partially met. However, there was a considerable percentage of patients who did not feel adequately prepared for the procedure. A structured, multidisciplinary team approach in educating PD patients throughout the different stages of DBS surgery may be helpful in optimizing patients' experience and satisfaction with surgery outcomes. PMID- 28848686 TI - Chromatographic Characterization and Method Development for Determination of Levetiracetam in Saliva: Application to Correlation with Plasma Levels. AB - Levetiracetam (LVT) is a widely used antiepileptic drug (AED). A less invasive sampling method for therapeutic drug monitoring (TDM) would be very useful particularly for children. Saliva has been shown as an adequate sample for TDM of some AEDs. Due to the high hydrophilicity of LVT its separation on common stationary phases is quite a challenge so that previous methods for determination of LVT in saliva employed either gradient high performance liquid chromatographic (HPLC) system or mass spectrometer as a detector. In this study the retention behavior of LVT on some common stationary phases was examined, with C8 being the most retentive. A simple isocratic HPLC method that is based on simple protein precipitation was developed and validated for the determination of LVT in saliva. The method was applied to a sample group of epileptic children for the purpose of assessing potential correlation with plasma LVT levels and to investigate patient's compliance. The results confirmed a reasonable correlation between plasma and salivary levels of LVT (R = 0.9) which supports the use of saliva for TDM of LVT. The study also revealed a significant percentage of epileptic patients having LVT levels below the estimated therapeutic range. PMID- 28848687 TI - A demographic history of a population of howler monkeys (Alouatta palliata) living in a fragmented landscape in Mexico. AB - Long-term field studies are critical for our understanding of animal life history and the processes driving changes in demography. Here, we present long-term demographic data for the northernmost population of mantled howler monkeys (Alouatta palliata) residing in a highly anthropogenically fragmented landscape in Los Tuxtlas, Mexico. We carried out 454 monthly group visits to 10 groups of mantled howler monkeys between 2000 and 2011. The population remained relatively stable over the 11-year study period, with an overall increase in the total number of individuals. Birth rates and inter-birth intervals were comparable to those of howler monkeys at non-fragmented sites, suggesting that living in a fragmented landscape did not affect the reproductive output of our study population. Moreover, despite the landscape, dispersal events were commonplace, including many secondary dispersals (individuals emigrating from groups that they had previously immigrated into). Finally, we found a marked effect of seasonality on the dynamics of our study population. In particular, the period of lowest temperatures and resource scarcity between November and March was associated with higher mortality and reproductive inhibition, while the period of resource abundance between April and May was associated with the majority of conceptions and weaning of offspring. This, in turn, could be influencing dispersal patterns in our study area, as male howler monkeys seem to time some of their immigrations into new groups to coincide with the start of the period of higher fertility, while females preferentially joined new groups several months before the onset of this period. These data have important implications for the conservation and management of howler monkeys in fragmented landscapes, as well as for our understanding of the effect of seasonality over howler monkey dispersal, reproduction and survival. PMID- 28848688 TI - Structural dynamics in the host-parasitoid system of the pine needle gall midge (Thecodiplosis japonensis) during invasion. AB - The structural dynamics of host-parasitoid populations play a key role in the mechanism of natural community development with invasive species. Species invading new habitats experience coevolution with their newly acquired natural enemies, and their population dynamics are driven by a complex interaction between biological and environmental factors. We examined the biological and environmental factors which potentially influence a community of parasitoids throughout the 25-year invasion history of the pine needle gall midge (PNGM), Thecodiplosis japonensis, an important pest of pines in eastern Asia. We found that differences in establishment sequence and competitive ability among the parasitoids attacking this species determined the parasitoid community's structure and dynamics. In particular, the timing for the initial establishment of the host-parasitoid association, incomplete superiority in competition among parasitoids, and indirect competition by a combination of the parasitoids were important factors for determining community's structure and dynamics. Finally, the history of change in the community composition could be explained by the phenology differences in its member species, mediated by environmental factors. PMID- 28848690 TI - Effects of linear and daily undulating periodized resistance training programs on measures of muscle hypertrophy: a systematic review and meta-analysis. AB - BACKGROUND: Periodization is an important component of resistance training programs. It is meant to improve adherence to the training regimen, allow for constant progression, help in avoiding plateaus, and reduce occurrence and severity of injuries. Previous findings regarding the effects of different periodization models on measures of muscle hypertrophy are equivocal. To provide a more in-depth look at the topic, we undertook a systematic review of the literature and a meta-analysis of intervention trials comparing the effects of linear periodization (LP) and daily undulating periodization (DUP) resistance training programs on muscle hypertrophy. MATERIALS AND METHODS: A comprehensive literature search was conducted through PubMed/MEDLINE, Scopus, Web of Science, SPORTDiscus, Networked Digital Library of Theses and Dissertations (NDLTD) and Open Access Theses and Dissertations (OATD). RESULTS: The pooled standardized mean difference (Cohen's d) from 13 eligible studies for the difference between the periodization models on muscle hypertrophy was -0.02 (95% confidence interval [-0.25, 0.21], p = 0.848). CONCLUSIONS: The meta-analysis comparing LP and DUP indicated that the effects of the two periodization models on muscle hypertrophy are likely to be similar. However, more research is needed in this area, particularly among trained individuals and clinical populations. Future studies may benefit from using instruments that are more sensitive for detecting changes in muscle mass, such as ultrasound or magnetic resonance imaging. PMID- 28848691 TI - A Miocene breeding ground of an extinct baleen whale (Cetacea: Mysticeti). AB - Locating breeding sites is definitely a key to understanding the ecological requirements and maintaining the sustainability of populations/species. Here I re examined published specimens of an extinct baleen whale, Parietobalaena yamaokai, from the lower part of Itahashi Formation (16.1-15.6 Ma, Middle Miocene) in Shobara, Hiroshima, Japan. A critical and previously unnoticed feature, the open suture between the supraoccipital and exoccipital, in one specimen indicates the preservation of a very young individual-under six months old and even close to a new-born calf. Given the occurrence of a new-born whale and relatively abundant assemblage of Parietobalaena yamaokai, I propose a previously hidden and unknown breeding ground for the extinct baleen whale, P. yamaokai, in the Middle Miocene of Shobara (16.1-15.6 Ma), Hiroshima. Discovery of paleo-breeding sites of extinct populations/species should further help us to understand biological extinctions from a long-term perspective as conservation paleobiology aims to offer new insights into policy making for conserving endangered populations/species. PMID- 28848689 TI - The complete mitochondrial genome of the grooved carpet shell, Ruditapes decussatus (Bivalvia, Veneridae). AB - Despite the large number of animal complete mitochondrial genomes currently available in public databases, knowledge about mitochondrial genomics in invertebrates is uneven. This paper reports, for the first time, the complete mitochondrial genome of the grooved carpet shell, Ruditapes decussatus, also known as the European clam. Ruditapes decussatus is morphologically and ecologically similar to the Manila clam Ruditapes philippinarum, which has been recently introduced for aquaculture in the very same habitats of Ruditapes decussatus, and that is replacing the native species. Currently the production of the European clam is almost insignificant, nonetheless it is considered a high value product, and therefore it is an economically important species, especially in Portugal, Spain and Italy. In this work we: (i) assembled Ruditapes decussatus mitochondrial genome from RNA-Seq data, and validated it by Sanger sequencing; (ii) analyzed and characterized the Ruditapes decussatus mitochondrial genome, comparing its features with those of other venerid bivalves; (iii) assessed mitochondrial sequence polymorphism (SP) and copy number variation (CNV) of tandem repeats across 26 samples. Despite using high-throughput approaches we did not find evidence for the presence of two sex-linked mitochondrial genomes, typical of the doubly uniparental inheritance of mitochondria, a phenomenon known in ~100 bivalve species. According to our analyses, Ruditapes decussatus is more genetically similar to species of the Genus Paphia than to the congeneric Ruditapes philippinarum, a finding that bolsters the already-proposed need of a taxonomic revision. We also found a quite low genetic variability across the examined samples, with few SPs and little variability of the sequences flanking the control region (Largest Unassigned Regions (LURs). Strikingly, although we found low nucleotide variability along the entire mitochondrial genome, we observed high levels of length polymorphism in the LUR due to CNV of tandem repeats, and even a LUR length heteroplasmy in two samples. It is not clear if the lack of genetic variability in the mitochondrial genome of Ruditapes decussatus is a cause or an effect of the ongoing replacement of Ruditapes decussatus with the invasive Ruditapes philippinarum, and more analyses, especially on nuclear sequences, are required to assess this point. PMID- 28848692 TI - Histological characterization of denticulate palatal plates in an Early Permian dissorophoid. AB - Denticles are small, tooth-like protrusions that are commonly found on the palate of early tetrapods. Despite their widespread taxonomic occurrence and similar external morphology to marginal teeth, it has not been rigorously tested whether denticles are structurally homologous to true teeth with features such as a pulp cavity, dentine, and enamel, or if they are bony, tooth-like protrusions. Additionally, the denticles are known to occur not only on the palatal bones but also on a mosaic of small palatal plates that is thought to have covered the interpterygoid vacuities of temnospondyls through implantation in a soft tissue covering; however, these plates have never been examined beyond a simple description of their position and external morphology. Accordingly, we performed a histological analysis of these denticulate palatal plates in a dissorophoid temnospondyl in order to characterize their microanatomy and histology. The dentition on these palatal plates has been found to be homologous with true teeth on the basis of both external morphology and histological data through the identification of features such as enamel and a pulp cavity surrounded by dentine. In addition, patterns of tooth replacement and ankylosis support the hypothesis of structural homology between these tiny teeth on the palatal plates and the much larger marginal dentition. We also provide the first histological characterization of the palatal plates, including documentation of abundant Sharpey's fibres that provide a direct line of evidence to support the hypothesis of soft tissue implantation. Finally, we conducted a survey of the literature to determine the taxonomic distribution of these plates within Temnospondyli, providing a broader context for the presence of palatal plates and illustrating the importance of maintaining consistency in nomenclature. PMID- 28848693 TI - Acetylation of N-terminus and two internal amino acids is dispensable for degradation of a protein that aberrantly engages the endoplasmic reticulum translocon. AB - Conserved homologues of the Hrd1 ubiquitin ligase target for degradation proteins that persistently or aberrantly engage the endoplasmic reticulum translocon, including mammalian apolipoprotein B (apoB; the major protein component of low density lipoproteins) and the artificial yeast protein Deg1-Sec62. A complete understanding of the molecular mechanism by which translocon-associated proteins are recognized and degraded may inform the development of therapeutic strategies for cholesterol-related pathologies. Both apoB and Deg1-Sec62 are extensively post-translationally modified. Mass spectrometry of a variant of Deg1-Sec62 revealed that the protein is acetylated at the N-terminal methionine and two internal lysine residues. N-terminal and internal acetylation regulates the degradation of a variety of unstable proteins. However, preventing N-terminal and internal acetylation had no detectable consequence for Hrd1-mediated proteolysis of Deg1-Sec62. Our data highlight the importance of empirically validating the role of post-translational modifications and sequence motifs on protein degradation, even when such elements have previously been demonstrated sufficient to destine other proteins for destruction. PMID- 28848694 TI - Old Solutions for New Troubles in Complications after Thoracic Endovascular Aortic Repair. AB - Background The authors present two cases with type B aortic dissection initially treated by endovascular stent graft who developed aortic complications posttreatment and required surgical treatment. Case Description A 50-year-old woman and a 65-year-old man underwent endovascular treatment for thoracic aortic aneurysm associated with type B dissection and -both of them evolved with endoleak type 1. The first case was related to aortobronchial fistula, and the second one was associated with ascending aortic aneurysm. An extra-anatomical ascending aorta-supraceliac aorta bypass grafting was decided due to the persistent leak. Conclusion Surgery is an excellent choice for complex complications after thoracic endovascular aortic repair with previous failed attempts of endovascular resolution. PMID- 28848695 TI - Fathers Matter: Why It's Time to Consider the Impact of Paternal Environmental Exposures on Children's Health. AB - PURPOSE: Despite accumulating evidence from experimental animal studies showing that paternal environmental exposures induce genetic and epigenetic alterations in sperm which in turn increase the risk of adverse health outcomes in offspring, there is limited epidemiological data on the effects of human paternal preconception exposures on children's health. We summarize animal and human studies showing that paternal preconception environmental exposures influence offspring health. We discuss specific approaches and designs for human studies to investigate the health effects of paternal preconception exposures, the specific challenges these studies may face, and how we might address them. RECENT FINDINGS: In animal studies, paternal preconception diet, stress, and chemical exposures have been associated with offspring health and these effects are mediated by epigenetic modifications transmitted through sperm DNA, histones, and RNA. Most epidemiological studies have examined paternal preconception occupational exposures and their effect on the risk of birth defects and childhood cancer; few have examined the effects of low-level general population exposure to environmental toxicants. While the design and execution of epidemiological studies of paternal preconception exposures face challenges, particularly with regard to selection bias and recruitment, we believe these are tractable and that preconception studies are feasible. SUMMARY: New or augmented prospective cohort studies would be the optimal method to address the critical knowledge gaps on the effect of paternal preconception exposures on prevalent childhood health outcomes. Determining if this period of life represents a window of heightened vulnerability would improve our understanding of modifiable risk factors for children's health and wellbeing. PMID- 28848696 TI - Delayed Diagnosis of Cushing's Disease in a Pediatric Patient due to Apparent Remission from Spontaneous Apoplexy. AB - We report here a pediatric patient whose Cushing's Disease was diagnosed late because of her cyclical presentation, presumably due to subclinical pituitary apoplexy. Starting at age 8, she presented with observable signs of Cushing's but was not clinically assessed for Cushing's Syndrome until the age of 15. Initial tests at age 15 were consistent with Cushing's Disease, however, the patient presented with spontaneous remission of hypercortisolemia just a few short months later. Her cushingoid features never subsided, and at age 17, her MRI showed a partially empty sella; this finding of an empty sella contributed evidence to our suspicion of asymptomatic apoplexy, especially since the patient never reported an episode of acute headache. Pituitary apoplexy in corticotroph adenomas is very uncommon, but even more rare in microadenomas, making this case very unusual. Lost to follow-up, she was not reevaluated for Cushing's Disease until age 25, and her laboratory tests were consistent with an adrenocorticotrophic-dependent pituitary tumor; Pituitary magnetic resonance imaging revealed a 9 mm X 6 mm X 8 mm mass projecting on the superior aspect of pituitary and abutting the wall of the right cavernous sinus. The patient had a transsphenoidal surgery to remove the microadenoma and is planned to undergo radiation therapy. To the best of our knowledge, this is the first report of subclinical apoplexy of a microadenoma in a pediatric patient with Cushing's Disease. It brings to light the importance of long term follow up for pediatric patients presenting with clinical symptoms of Cushing's Syndrome. PMID- 28848697 TI - Magnetic resonance imaging for prostate cancer before radical and salvage radiotherapy: What radiation oncologists need to know. AB - External beam radiotherapy (EBRT) is one of the principal curative treatments for patients with prostate cancer (PCa). Risk group classification is based on prostate-specific antigen (PSA) level, Gleason score, and T-stage. After risk group determination, the treatment volume and dose are defined and androgen deprivation therapy is prescribed, if appropriate. Traditionally, imaging has played only a minor role in T-staging due to the low diagnostic accuracy of conventional imaging strategies such as transrectal ultrasound, computed tomography, and morphologic magnetic resonance imaging (MRI). As a result, a notable percentage of tumours are understaged, leading to inappropriate and imprecise EBRT. The development of multiparametric MRI (mpMRI), an imaging technique that combines morphologic studies with functional diffusion-weighted sequences and dynamic contrast-enhanced imaging, has revolutionized the diagnosis and management of PCa. As a result, mpMRI is now used in staging PCa prior to EBRT, with possible implications for both risk group classification and treatment decision-making for EBRT. mpMRI is also being used in salvage radiotherapy (SRT), the treatment of choice for patients who develop biochemical recurrence after radical prostatectomy. In the clinical context of biochemical relapse, it is essential to accurately determine the site of recurrence - pelvic (local, nodal, or bone) or distant - in order to select the optimal therapeutic management approach. Studies have demonstrated the value of mpMRI in detecting local recurrences - even in patients with low PSA levels (0.3-0.5 ng/mL) - and in diagnosing bone and nodal metastasis. The main objective of this review is to update the role of mpMRI prior to radical EBRT or SRT. We also consider future directions for the use and development of MRI in the field of radiation oncology. PMID- 28848698 TI - Use of programmed cell death protein ligand 1 assay to predict the outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors. AB - The recent discovery of immune checkpoints inhibitors, especially anti-programmed cell death protein 1 (PD-1) and anti-programmed cell death protein ligand 1 (PD L1) monoclonal antibodies, has opened new scenarios in the management of non small cell lung cancer (NSCLC) and this new class of drugs has achieved a rapid development in the treatment of this disease. However, considering the costs of these drugs and the fact that only a subset of patients experience long-term disease control, the identification of predictive biomarkers for the selection of candidates suitable for treatment has become a priority. The research focused mainly on the expression of the PD-L1 receptor on both tumor cells and/or immune infiltrates determined by immunohistochemistry (IHC). However, different checkpoint inhibitors were tested, different IHC assays were used, different targets were considered (tumor cells, immune infiltrates or both) and different expression thresholds were employed in clinical trials. In some trials the assay was used prospectively to select the patients, while in other trials it was evaluated retrospectively. Some confusion emerges, which makes it difficult to easily compare the literature data and to translate them in practice management. This mini-review shows the possibilities and pitfalls of the PD-L1 expression to predict the activity and efficacy of anti PD1/PD-L1 monoclonal antibodies in the treatment of NSCLC. PMID- 28848699 TI - Platinum-induced neurotoxicity: A review of possible mechanisms. AB - Patients treated with platinum-based chemotherapy frequently experience neurotoxic symptoms, which may lead to premature discontinuation of therapy. Despite discontinuation of platinum drugs, these symptoms can persist over a long period of time. Cisplatin and oxaliplatin, among all platinum drugs, have significant neurotoxic potential. A distal dose-dependent symmetrical sensory neuropathy is the most common presentation of platinum neurotoxicity. DNA damage induced apoptosis of dorsal root ganglion (DRG) neurons seems to be the principal cause of neurological symptoms. However, DRG injury alone cannot explain some unique symptoms such as cold-aggravated burning pain affecting distal extremities that is observed with oxaliplatin administration. In this article, we briefly reviewed potential mechanisms for the development of platinum drugs-associated neurological manifestations. PMID- 28848700 TI - Physician approaches to drug shortages: Results of a national survey of pediatric hematologist/oncologists. AB - AIM: To evaluate personnel involved in scarce drug prioritization and distribution and the criteria used to inform drug distribution during times of shortage among pediatric hematologists/oncologists. METHODS: Using the American Society of Pediatric Hematology/Oncology (ASPHO) membership list, a 20 question survey of pediatric hematologists/oncologists was conducted via email to evaluate personnel involved in scarce drug prioritization and distribution and criteria used to inform scarce drug distribution. RESULTS: Nearly 65% of the 191 study respondents had patients directly affected by drug shortages. Most physicians find out about shortages from the pharmacist (n = 179, 98%) or other doctors (n = 75, 41%). One third of respondents do not know if there is a program or policy for handling drug shortages at their institution. The pharmacist was the most commonly cited decision maker for shortage drug distribution (n = 128, 70%), followed by physicians (n = 109, 60%). One fourth of respondents did not know who makes decisions about shortage drug distribution at their institution. The highest priority criterion among respondents was use of the shortage drug for curative, rather than palliative intent and lowest priority criterion was order of arrival or first-come first-served. CONCLUSION: Despite pediatric hematology/oncology physicians and patients being heavily impacted by drug shortages, institutional processes for handling shortages are lacking. There is significant disparity between how decisions for distribution of shortage drugs are currently made and how study respondents felt those decisions should be made. An institution-based, and more importantly, a societal approach to drug shortages is necessary to reconcile these disparities. PMID- 28848701 TI - Trans-arterial chemoperfusion for the treatment of liver metastases of breast cancer and colorectal cancer: Clinical results in palliative care patients. AB - AIM: To evaluate the clinical value and efficiency of trans-arterial chemoperfusion (TACP) in patients with liver metastases from breast cancer (BC) and colorectal cancer (CRC). METHODS: We treated 36 patients with liver metastases of BC (n = 19, 19 females) and CRC (n = 17; 8 females, 9 males) with repeated TACP. The treatment interval was 4 wk. TACP was performed with gemcitabine (1000 mg/m2) and mitomycin (10 mg/m2), administered within 1 h after positioning the catheter tip in the hepatic artery. Before treatment, the size, location, tumour volume, vascularization and number of liver tumours were evaluated using magnetic resonance imaging (MRI). Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: TACP using gemcitabine and mitomycin for metastases from CRC and BC was performed without any serious side effects. The follow-up MRI showed a therapeutic response in 84.2% of the BC patients - stable disease 47.4% and partial response 36.8%. A progression was seen in 15.8%. CRC patients showed a therapeutic response in 52.9% of cases. A progression of the disease was documented in 47.1% of the patients with CRC. These data show that TACP in patients with liver metastases of BC leads to a significantly better therapeutic response compared with CRC patients (P = 0.042). The median survival time was 13.2 mo for the BC patients, which is significantly longer than for CRC patients at 9.3 mo (P = 0.001). CONCLUSION: TACP for liver metastases of BC appears to be a safe and effective palliative treatment with improved outcomes in comparison to patients with CRC. PMID- 28848702 TI - Rescue associating liver partition and portal vein ligation for staged hepatectomy after portal embolization: Our experience and literature review. AB - AIM: To report a single-center experience in rescue associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), after failure of previous portal embolization. We also performed a literature review. METHODS: Between January 2014 and December 2015, every patient who underwent a rescue ALPPS procedure in Toulouse Rangueil University Hospital, France, was included. Every patient included had a project of major hepatectomy and a previous portal vein embolization (PVE) with insufficient future liver remnant to body weight ratio after the procedure. The ALPPS procedure was performed in two steps (ALPPS 1 and ALPPS-2), separated by an interval phase. ALPPS-2 was done within 7 to 9 d after ALPPS-1. To estimate the FLR, a computed tomography scan examination was performed 3 to 6 wk after the PVE procedure and 6 to 8 d after ALPPS-1. A transcystic stent was placed during ALPPS-1 and remained opened during the interval phase, in order to avoid biliary complications. Postoperative liver failure was defined using the 50-50 criteria. Postoperative complications were assessed according to the Dindo-Clavien Classification. RESULTS: From January 2014 to December 2015, 7 patients underwent a rescue ALPPS procedure. Median FLR before PVE, ALPPS-1 and ALPPS-2 were respectively 263 cc (221-380), 450 cc (372 506), and 660 cc (575-776). Median FLR/BWR before PVE, ALPPS-1 and ALPPS-2 were respectively 0.4% (0.3-0.5), 0.6% (0.5-0.8), and 1% (0.8-1.2). Median volume growth of FLR was 69% (18-92) after PVE, and 45% (36-82) after ALPPS-1. The combination of PVE and ALPPS induced a growth of median initial FLR of +408 cc (254-513), leading to an increase of +149% (68-199). After ALPPS-2, 4 patients had stage I-II complications. Three patients had more severe complications (one stage III, one stage IV and one death due to bowel perforation). Two patients suffered from postoperative liver failure according to the 50/50 criteria. None of our patients developed any biliary complication during the ALPPS procedure. CONCLUSION: Rescue ALPPS may be an alternative after unsuccessful PVE and could allow previously unresectable patients to reach surgery. Biliary drainage seems to reduce biliary complications. PMID- 28848703 TI - BRAF V600Q-mutated lung adenocarcinoma with duodenal metastasis and extreme leukocytosis. AB - Driver mutations in patients with non-small cell lung cancer (NSCLC) can lead to distinct behaviors and patterns of metastasis. Mutations in the proto-oncogene B raf (BRAF) occur in approximately 3% of NSCLC cases. In the literature, reports of patients with lung adenocarcinomas metastasizing to the duodenum are rare, and most of the only 21 cases reported were from before the advent of next-generation sequencing. We present here a case involving a 57-year-old female who had a lytic lesion in her lesser trochanter. Biopsy showed metastatic adenocarcinoma of lung origin. Chest X-ray showed a large left upper lobe mass. Next-generation sequencing analysis confirmed the presence of BRAF V600Q mutation. The patient presented with persistent anemia and melena. Esophagogastroduodenoscopy confirmed the presence of duodenal metastasis. She also had suspected paraneoplastic leukemoid reaction. To our knowledge, this is only the second well-documented case of gastrointestinal metastasis from BRAF-mutated lung cancer. PMID- 28848704 TI - Intimal sarcoma of the pulmonary artery with multiple lung metastases: Long-term survival case. AB - Pulmonary artery intimal sarcoma (PAIS) is a rare tumor with a very poor prognosis. Clinical and radiological findings usually mimic thromboembolic disease, leading to diagnostic delays. The treatment of choice is surgery, and adjuvant chemotherapy and radiotherapy have limited results. We report the case of a 48-year-old male patient, initially suspected with pulmonary thromboembolism. The angio-CT revealed a filling defect in the pulmonary artery trunk. The patient underwent surgery, resulting in with complete resection of the mass with a diagnosis of PAIS. The tumor progressed rapidly in the lung, requiring surgery of multiple lung metastases. The patient was treated with stereotactic body radiation therapy (SBRT) on two occasions for new pulmonary lesions. In the last followup (4 years after initial diagnosis), the patient was disease-free. In conclusion, SBRT proved to be an alternative treatment to metastasectomy, allowing palliative chemotherapy to be delayed or omitted, which may result in improved quality of life. PMID- 28848705 TI - Long-term stabilization of metastatic melanoma with sodium dichloroacetate. AB - Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007, based on a publication from Bonnet et al demonstrating that DCA can induce apoptosis (programmed cell death) in human breast, lung and brain cancer cells. Classically, the response of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define "response" by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of recurrent metastatic melanoma for over 4 years' duration, with trivial side effects. This case demonstrates that DCA can be used to reduce disease volume and maintain long-term stability in patients with advanced melanoma. PMID- 28848706 TI - Impaired Expression of Focal Adhesion Kinase in Mesenchymal Stromal Cells from Low-Risk Myelodysplastic Syndrome Patients. AB - The pathogenic role of mesenchymal stromal cells (MSCs) in myelodysplastic syndromes (MDS) development and progression has been investigated by numerous studies, yet, it remains controversial in some aspects (1, 2). In the present study, we found distinct features of MSCs from low-risk (LR)-MDS stromal microenvironment as compared to those from healthy subjects. At the molecular level, focal adhesion kinase, a key tyrosine kinase in control of cell proliferation, survival, and adhesion process, was found profoundly suppressed in expression and activation in LR-MDS MSC. At a functional level, LR-MDS MSCs showed impaired growth and clonogenic capacity, which were independent of cellular senescence and apoptosis. The pro-adipogenic differentiation and attenuated osteogenic capacity along with reduced SDF-1 expression could be involved in creating an unfavorable microenvironment for hematopoiesis. In conclusion, our experiments support the theory that the stromal microenvironment is fundamentally altered in LR-MDS, and these preliminary data offer a new perspective on LR-MDS pathophysiology. PMID- 28848707 TI - Rifaximin for Pertuzumab-Related GI Toxicities. AB - Pertuzumab is a monoclonal antibody against HER2. Diarrhea and abdominal pain are common adverse events of pertuzumab-based therapy, occurring in almost 70% of patients. The incidence of gastrointestinal toxicities intensifies when pertuzumab is given in combination with chemotherapy. Rifaximin, a non-absorbable oral antibiotic, may provide symptomatic relief in patients with refractory gastrointestinal toxicities from pertuzumab-based therapy beyond standard routine antidiarrheal medications. We present a case of HER2-related therapy-induced diarrhea and abdominal pain managed successfully with Rifaximin. PMID- 28848708 TI - Radiation Therapy in Extensive Stage Small Cell Lung Cancer. AB - Lung cancer is the major cancer killer in the Western world, with the small cell lung cancer (SCLC) representing around 15-20% of all lung cancers. Extensive disease small cell lung cancer (ED SCLC) is found in approximately two-thirds of all cases, composed of both metastatic (M1) and non-metastatic (but presumably with tumor burden too large for locoregional-only approach) variant. Standard treatment options involve chemotherapy (CHT) over the past several decades. Radiation therapy (RT) had mostly been used in palliation of locoregional and/or metastatic disease. In contrast to its established role in treating metastatic disease, thoracic RT (TRT) had never been established as important part of the treatment aspects in this setting. In the past two decades, thoracic oncologists have witnessed wide introduction of modern RT and CHT aspects in ED SCLC, which led to more frequent use of RT and rise in the number of clinical studies. Since the pivotal study of Jeremic et al., who were the first to show importance of TRT in ED SCLC, a number of single-institutional studies have reconfirmed this observation, while recent prospective randomized trials (CREST and RTOG 0937) brought more substance to this issue. Similarly, the issue of prophylactic cranial irradiation was investigated in EORTC and the Japanese study, respectively, bringing somewhat conflicting results and calling for additional research in this setting. Future studies in ED SCLC could incorporate questions of RT dose and fractionation as well as the number of CHT cycles and type of combined Rt-CHT (sequential vs concurrent). PMID- 28848709 TI - New Treatment Opportunities in Phosphatase and Tensin Homolog (PTEN)-Deficient Tumors: Focus on PTEN/Focal Adhesion Kinase Pathway. AB - Deep genetic studies revealed that phosphatase and tensin homolog (PTEN) mutations or loss of expression are not early events in cancer development but characterize tumor progression and invasion. Loss of PTEN function causes a full activation of the prosurvival phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, but the treatment with specific inhibitors of PI3K/AKT/mTOR did not produce the expected results. One of the alternative targets of PTEN is the focal adhesion kinase (FAK) kinase, mainly involved in the control of cancer cell spread. The connection between PTEN and FAK has been demonstrated in different tumor types, with reduced PTEN activity often correlated with increased expression and phosphorylation of FAK. FAK inhibition may thus represent a promising strategy, and some clinical trials are testing FAK inhibitors alone or combined with other agents in a number of solid tumors. However, only few preclinical and clinical data described the effects of the combination of PI3K/AKT/mTOR and FAK inhibitors. Increasing knowledge on the PTEN/FAK connection could confirm PTEN as a good prognostic marker for a combination strategy based on concomitant inhibition of PI3K/AKT and FAK signaling, in advanced metastatic malignancies with altered or reduced PTEN expression. PMID- 28848710 TI - The Regulation of Tumor Cell Invasion and Metastasis by Endoplasmic Reticulum-to Mitochondrial Ca2+ Transfer. AB - Cell migration is one of the many processes orchestrated by calcium (Ca2+) signaling, and its dysregulation drives the increased invasive and metastatic potential of cancer cells. The ability of Ca2+ to function effectively as a regulator of migration requires the generation of temporally complex signals within spatially restricted microdomains. The generation and maintenance of these Ca2+ signals require a specific structural architecture and tightly regulated communication between the extracellular space, intracellular organelles, and cytoplasmic compartments. New insights into how Ca2+ microdomains are shaped by interorganellar Ca2+ communication have shed light on how Ca2+ coordinates cell migration by directing cellular polarization and the rearrangement of structural proteins. Importantly, we are beginning to understand how cancer subverts normal migration through the activity of oncogenes and tumor suppressors that impinge directly on the physiological function or expression levels of Ca2+ signaling proteins. In this review, we present and discuss research at the forefront of interorganellar Ca2+ signaling as it relates to cell migration, metastasis, and cancer progression, with special focus on endoplasmic reticulum-to-mitochondrial Ca2+ transfer. PMID- 28848712 TI - Burkholderia pseudomallei Evades Nramp1 (Slc11a1)- and NADPH Oxidase-Mediated Killing in Macrophages and Exhibits Nramp1-Dependent Virulence Gene Expression. AB - Bacterial survival in macrophages can be affected by the natural resistance associated macrophage protein 1 (Nramp1; also known as solute carrier family 11 member a1 or Slc11a1) which localizes to phagosome membranes and transports divalent cations, including iron. Little is known about the role of Nramp1 in Burkholderia infection, in particular whether this differs for pathogenic species like Burkholderia pseudomallei causing melioidosis or non-pathogenic species like Burkholderia thailandensis. Here we show that transfected macrophages stably expressing wild-type Nramp1 (Nramp1+) control the net replication of B. thailandensis, but not B. pseudomallei. Control of B. thailandensis was associated with increased cytokine responses, and could be abrogated by blocking NADPH oxidase-mediated production of reactive oxygen species but not by blocking generation of reactive nitrogen species. The inability of Nramp1+ macrophages to control B. pseudomallei was associated with rapid escape of bacteria from phagosomes, as indicated by decreased co-localization with LAMP1 compared to B. thailandensis. A B. pseudomallei bipB mutant impaired in escape from phagosomes was controlled to a greater extent than the parent strain in Nramp1+ macrophages, but was also attenuated in Nramp1- cells. Consistent with reduced escape from phagosomes, B. thailandensis formed fewer multinucleated giant cells in Nramp1+ macrophages at later time points compared to B. pseudomallei. B. pseudomallei exhibited elevated transcription of virulence-associated genes of Type VI Secretion System cluster 1 (T6SS-1), the Bsa Type III Secretion System (T3SS-3) and the bimA gene required for actin-based motility in Nramp1+ macrophages. Nramp1+ macrophages were found to contain decreased iron levels that may impact on expression of such genes. Our data show that B. pseudomallei is able to evade Nramp1- and NADPH oxidase-mediated killing in macrophages and that expression of virulence-associated genes by pathogenic B pseudomallei is enhanced in macrophages expressing wild-type compared to non-functional Nramp1. B. thailandensis has been proposed as surrogate for B. pseudomallei in the study of melioidosis however our study highlights important differences in the interaction of these bacteria with macrophages. PMID- 28848711 TI - Swiss Army Pathogen: The Salmonella Entry Toolkit. AB - Salmonella causes disease in humans and animals ranging from mild self-limiting gastroenteritis to potentially life-threatening typhoid fever. Salmonellosis remains a considerable cause of morbidity and mortality globally, and hence imposes a huge socio-economic burden worldwide. A key property of all pathogenic Salmonella strains is the ability to invade non-phagocytic host cells. The major determinant of this invasiveness is a Type 3 Secretion System (T3SS), a molecular syringe that injects virulence effector proteins directly into target host cells. These effectors cooperatively manipulate multiple host cell signaling pathways to drive pathogen internalization. Salmonella does not only rely on these injected effectors, but also uses several other T3SS-independent mechanisms to gain entry into host cells. This review summarizes our current understanding of the methods used by Salmonella for cell invasion, with a focus on the host signaling networks that must be coordinately exploited for the pathogen to achieve its goal. PMID- 28848713 TI - A Vibrio vulnificus VvpM Induces IL-1beta Production Coupled with Necrotic Macrophage Death via Distinct Spatial Targeting by ANXA2. AB - An inflammatory form of phagocyte death evoked by the Gram-negative bacterium Vibrio (V.) vulnificus (WT) is one of hallmarks to promote their colonization, but the virulence factor and infectious mechanism involved in this process remain largely unknown. Here, we identified extracellular metalloprotease VvpM as a new virulence factor and investigated the molecular mechanism of VvpM which acts during the regulation of the inflammatory form of macrophage death and bacterial colonization. Mutation of the vvpM gene appeared to play major role in the prevention of IL-1beta production due to V. vulnificus infection in macrophage. However, the recombinant protein (r) VvpM caused IL-1beta production coupled with necrotic cell death, which is highly susceptible to the knockdown of annexin A2 (ANXA2) located in both membrane lipid and non-lipid rafts. In lipid rafts, rVvpM recruited NOX enzymes coupled with ANXA2 to facilitate the production of ROS responsible for the epigenetic and transcriptional regulation of NF-kappaB in the IL-1beta promoter. rVvpM acting on non-lipid rafts increased LC3 puncta formation and autophagic flux, which are required for the mRNA expression of Atg5 involved in the autophagosome formation process. The autophagy activation caused by rVvpM induced NLRP3 inflammasome-dependent caspase-1 activation in the promoting of IL 1beta production. In mouse models of V. vulnificus infection, the VvpM mutant failed to elevate the level of pro-inflammatory responses closely related to IL 1beta production and prevented bacterial colonization. These findings delineate VvpM efficiently regulates two pathogenic pathways that stimulate NF-kappaB dependent IL-1beta production and autophagy-mediated NLRP3 inflammasome via distinct spatial targeting by ANXA2. PMID- 28848714 TI - Genome Reduction for Niche Association in Campylobacter Hepaticus, A Cause of Spotty Liver Disease in Poultry. AB - The term "spotty liver disease" (SLD) has been used since the late 1990s for a condition seen in the UK and Australia that primarily affects free range laying hens around peak lay, causing acute mortality and a fall in egg production. A novel thermophilic SLD-associated Campylobacter was reported in the United Kingdom (UK) in 2015. Subsequently, similar isolates occurring in Australia were formally described as a new species, Campylobacter hepaticus. We describe the comparative genomics of 10 C. hepaticus isolates recovered from 5 geographically distinct poultry holdings in the UK between 2010 and 2012. Hierarchical gene-by gene analyses of the study isolates and representatives of 24 known Campylobacter species indicated that C. hepaticus is most closely related to the major pathogens Campylobacter jejuni and Campylobacter coli. We observed low levels of within-farm variation, even between isolates collected over almost 3 years. With respect to C. hepaticus genome features, we noted that the study isolates had a ~140 Kb reduction in genome size, ~144 fewer genes, and a lower GC content compared to C. jejuni. The most notable reduction was in the subsystem containing genes for iron acquisition and metabolism, supported by reduced growth of C. hepaticus in an iron depletion assay. Genome reduction is common among many pathogens and in C. hepaticus has likely been driven at least in part by specialization following the occupation of a new niche, the chicken liver. PMID- 28848715 TI - HmsC Controls Yersinia pestis Biofilm Formation in Response to Redox Environment. AB - Yersinia pestis biofilm formation, controlled by intracellular levels of the second messenger molecule cyclic diguanylate (c-di-GMP), is important for blockage-dependent plague transmission from fleas to mammals. HmsCDE is a tripartite signaling system that modulates intracellular c-di-GMP levels to regulate biofilm formation in Y. pestis. Previously, we found that Y. pestis biofilm formation is stimulated in reducing environments in an hmsCDE-dependent manner. However, the mechanism by which HmsCDE senses the redox state remains elusive. Using a dsbA mutant and the addition of Cu2+ to simulate reducing and oxidizing periplasmic environments, we found that HmsC protein levels are decreased and the HmsC-HmsD protein-protein interaction is weakened in a reducing environment. In addition, we revealed that intraprotein disulphide bonds are critical for HmsC since breakage lowers protein stability and diminishes the interaction with HmsD. Our results suggest that HmsC might play a major role in sensing the environmental changes. PMID- 28848716 TI - Characterization of Yersinia pestis Interactions with Human Neutrophils In vitro. AB - Yersinia pestis is a gram-negative, zoonotic, bacterial pathogen, and the causative agent of plague. The bubonic form of plague occurs subsequent to deposition of bacteria in the skin by the bite of an infected flea. Neutrophils are recruited to the site of infection within the first few hours and interactions between neutrophils and Y. pestis have been demonstrated in vivo. In contrast to macrophages, neutrophils have been considered non-permissive to Y. pestis intracellular survival. Several studies have shown killing of the vast majority of Y. pestis ingested by human neutrophils. However, survival of 10-15% of Y. pestis after phagocytosis by neutrophils is consistently observed. Furthermore, these surviving bacteria eventually replicate within and escape from the neutrophils. We set out to further characterize the interactions between Y. pestis and human neutrophils by (1) determining the effects of known Y. pestis virulence factors on bacterial survival after uptake by neutrophils, (2) examining the mechanisms employed by the neutrophil to kill the majority of intracellular Y. pestis, (3) determining the activation phenotype of Y. pestis infected neutrophils, and (4) characterizing the Y. pestis-containing phagosome in neutrophils. We infected human neutrophils in vitro with Y. pestis and assayed bacterial survival and uptake. Deletion of the caf1 gene responsible for F1 capsule production resulted in significantly increased uptake of Y. pestis. Surprisingly, while the two-component regulator PhoPQ system is important for survival of Y. pestis within neutrophils, pre-induction of this system prior to infection did not increase bacterial survival. We used an IPTG-inducible mCherry construct to distinguish viable from non-viable intracellular bacteria and determined the association of the Y. pestis-containing phagosome with neutrophil NADPH-oxidase and markers of primary, secondary and tertiary granules. Additionally, we show that inhibition of reactive oxygen species (ROS) production or Src family kinases increased survival of intracellular bacteria indicating that both ROS and granule-phagosome fusion contribute to neutrophil killing of Y. pestis. The data presented here further our understanding of the Y. pestis neutrophil interactions and suggest the existence of still unknown virulence factors involved in Y. pestis survival within neutrophils. PMID- 28848717 TI - Porphyromonas gingivalis Stimulates TLR2-PI3K Signaling to Escape Immune Clearance and Induce Bone Resorption Independently of MyD88. AB - Porphyromonas gingivalis is a gram-negative anaerobic periodontal pathogen that persists in dysbiotic mixed-species biofilms alongside a dense inflammatory infiltrate of neutrophils and other leukocytes in the subgingival areas of the periodontium. Toll-like receptor 2 (TLR2) mediates the inflammatory response to P. gingivalis and TLR2-deficient mice resist alveolar bone resorption following oral challenge with this organism. Although, MyD88 is an adaptor protein considered necessary for TLR2-induced inflammation, we now report for the first time that oral challenge with P. gingivalis leads to alveolar bone resorption in the absence of MyD88. Indeed, in contrast to prototypical TLR2 agonists, such as the lipopeptide Pam3CSK4 that activates TLR2 in a strictly MyD88-dependent manner, P. gingivalis strikingly induced TLR2 signaling in neutrophils and macrophages regardless of the presence or absence of MyD88. Moreover, genetic or antibody-mediated inactivation of TLR2 completely reduced cytokine production in P. gingivalis-stimulated neutrophils or macrophages, suggesting that TLR2 plays a non-redundant role in the host response to P. gingivalis. In the absence of MyD88, inflammatory TLR2 signaling in P. gingivalis-stimulated neutrophils or macrophages depended upon PI3K. Intriguingly, TLR2-PI3K signaling was also critical to P. gingivalis evasion of killing by macrophages, since their ability to phagocytose this pathogen was reduced in a TLR2 and PI3K-dependent manner. Moreover, within those cells that did phagocytose bacteria, TLR2-PI3K signaling blocked phago-lysosomal maturation, thereby revealing a novel mechanism whereby P. gingivalis can enhance its intracellular survival. Therefore, P. gingivalis uncouples inflammation from bactericidal activity by substituting TLR2-PI3K in place of TLR2-MyD88 signaling. These findings further support the role of P. gingivalis as a keystone pathogen, which manipulates the host inflammatory response in a way that promotes bone loss but not bacterial clearance. Modulation of these host response factors may lead to novel therapeutic approaches to improve outcomes in disease conditions associated with P. gingivalis. PMID- 28848718 TI - Vaccinomics Approach to the Identification of Candidate Protective Antigens for the Control of Tick Vector Infestations and Anaplasma phagocytophilum Infection. AB - Anaplasma phagocytophilum is an emerging tick-borne pathogen causing human granulocytic anaplasmosis (HGA), tick-borne fever (TBF) in small ruminants, and other forms of anaplasmosis in different domestic and wild animals. The main vectors of this pathogen are Ixodes tick species, particularly I. scapularis in the United States and I. ricinus in Europe. One of the main limitations for the development of effective vaccines for the prevention and control of A. phagocytophilum infection and transmission is the identification of effective tick protective antigens. The objective of this study was to apply a vaccinomics approach to I. scapularis-A. phagocytophilum interactions for the identification and characterization of candidate tick protective antigens for the control of vector infestations and A. phagocytophilum infection. The vaccinomics pipeline included the use of quantitative transcriptomics and proteomics data from uninfected and A. phagocytophilum-infected I. scapularis ticks for the selection of candidate protective antigens based on the variation in tick mRNA and protein levels in response to infection, their putative biological function, and the effect of antibodies against these proteins on tick cell apoptosis and pathogen infection. The characterization of selected candidate tick protective antigens included the identification and characterization of I. ricinus homologs, functional characterization by different methodologies including RNA interference, immunofluorescence, gene expression profiling, and artificial tick feeding on rabbit antibodies against the recombinant antigens to select the candidates for vaccination trials. The vaccinomics pipeline developed in this study resulted in the identification of two candidate tick protective antigens that could be selected for future vaccination trials. The results showed that I. scapularis lipocalin (ISCW005600) and lectin pathway inhibitor (AAY66632) and I. ricinus homologs constitute candidate protective antigens for the control of vector infestations and A. phagocytophilum infection. Both antigens are involved in the tick evasion of host defense response and pathogen infection and transmission, but targeting different immune response pathways. The vaccinomics pipeline proposed here could be used to continue the identification and characterization of candidate tick protective antigens for the development of effective vaccines for the prevention and control of HGA, TBF, and other forms of anaplasmosis caused by A. phagocytophilum. PMID- 28848719 TI - Secreted Citrate Serves as Iron Carrier for the Marine Pathogen Photobacterium damselae subsp damselae. AB - Photobacterium damselae subsp damselae (Pdd) is a Vibrionaceae that has a wide pathogenic potential against many marine animals and also against humans. Some strains of this bacterium acquire iron through the siderophore vibrioferrin. However, there are virulent strains that do not produce vibrioferrin, but they still give a strong positive reaction in the CAS test for siderophore production. In an in silico search on the genome sequences of this type of strains we could not find any ORF which could be related to a siderophore system. To identify genes that could encode a siderophore-mediated iron acquisition system we used a mini-Tn10 transposon random mutagenesis approach. From more than 1,400 mutants examined, we could isolate a mutant (BP53) that showed a strong CAS reaction independently of the iron levels of the medium. In this mutant the transposon was inserted into the idh gene, which encodes an isocitrate dehydrogenase that participates in the tricarboxylic acid cycle. The mutant did not show any growth impairment in rich or minimal media, but it accumulated a noticeable amount of citrate (around 7 mM) in the culture medium, irrespective of the iron levels. The parental strain accumulated citrate, but in an iron-regulated fashion, being citrate levels 5-6 times higher under iron restricted conditions. In addition, a null mutant deficient in citrate synthase showed an impairment for growth at high concentrations of iron chelators, and showed almost no reaction in the CAS test. Chemical analysis by liquid chromatography of the iron-restricted culture supernatants resulted in a CAS-positive fraction with biological activity as siderophore. HPLC purification of that fraction yielded a pure compound which was identified as citrate from its MS and NMR spectral data. Although the production of another citrate-based compound with siderophore activity cannot be ruled out, our results suggest that Pdd secretes endogenous citrate and use it for iron scavenging from the cell environment. PMID- 28848721 TI - Methods to Illuminate the Role of Salmonella Effector Proteins during Infection: A Review. AB - Intracellular bacterial pathogens like Salmonella enterica use secretion systems, such as the Type III Secretion System, to deliver virulence factors into host cells in order to invade and colonize these cells. Salmonella virulence factors include a suite of effector proteins that remodel the host cell to facilitate bacterial internalization, replication, and evasion of host immune surveillance. A number of diverse and innovative approaches have been used to identify and characterize the role of effector proteins during infection. Recent techniques for studying infection using single cell and animal models have illuminated the contribution of individual effector proteins in infection. This review will highlight the techniques applied to study Salmonella effector proteins during infection. It will describe how different approaches have revealed mechanistic details for effectors in manipulating host cellular processes including: the dynamics of effector translocation into host cells, cytoskeleton reorganization, membrane trafficking, gene regulation, and autophagy. PMID- 28848720 TI - Pathogenic Leptospires Modulate Protein Expression and Post-translational Modifications in Response to Mammalian Host Signals. AB - Pathogenic species of Leptospira cause leptospirosis, a bacterial zoonotic disease with a global distribution affecting over one million people annually. Reservoir hosts of leptospirosis, including rodents, dogs, and cattle, exhibit little to no signs of disease but shed large numbers of organisms in their urine. Transmission occurs when mucosal surfaces or abraded skin come into contact with infected urine or urine-contaminated water or soil. Whilst little is known about how Leptospira adapt to and persist within a reservoir host, in vitro studies suggest that leptospires alter their transcriptomic and proteomic profiles in response to environmental signals encountered during mammalian infection. We applied the dialysis membrane chamber (DMC) peritoneal implant model to compare the whole cell proteome of in vivo derived leptospires with that of leptospires cultivated in vitro at 30 degrees C and 37 degrees C by 2-dimensional difference in-gel electrophoresis (2-D DIGE). Of 1,735 protein spots aligned across 9 2-D DIGE gels, 202 protein spots were differentially expressed (p < 0.05, fold change >1.25 or < -1.25) across all three conditions. Differentially expressed proteins were excised for identification by mass spectrometry. Data are available via ProteomeXchange with identifier PXD006995. The greatest differences were detected when DMC-cultivated leptospires were compared with IV30- or IV37-cultivated leptospires, including the increased expression of multiple isoforms of Loa22, a known virulence factor. Unexpectedly, 20 protein isoforms of LipL32 and 7 isoforms of LipL41 were uniformly identified by DIGE as differentially expressed, suggesting that unique post-translational modifications (PTMs) are operative in response to mammalian host conditions. To test this hypothesis, a rat model of persistent renal colonization was used to isolate leptospires directly from the urine of experimentally infected rats. Comparison of urinary derived leptospires to IV30 leptospires by 2-D immunoblotting confirmed that modification of proteins with trimethyllysine and acetyllysine occurs to a different degree in response to mammalian host signals encountered during persistent renal colonization. These results provide novel insights into differential protein and PTMs present in response to mammalian host signals which can be used to further define the unique equilibrium that exists between pathogenic leptospires and their reservoir host of infection. PMID- 28848722 TI - Use of Digital Droplet PCR to Detect Mycobacterium tuberculosis DNA in Whole Blood-Derived DNA Samples from Patients with Pulmonary and Extrapulmonary Tuberculosis. AB - Tuberculosis (TB) is a chronic infectious disease that has been threatening public health for many centuries. The clinical diagnostic procedure for TB is time-consuming and laborious. In the last 20 years, real-time fluorescence-based quantitative PCR (real-time PCR) has become a better alternative for TB diagnosis in clinics due to its sensitivity and specificity. Recently, digital droplet PCR (ddPCR) has been developed, and it might be an ideal alternative to conventional real-time PCR for microorganism detection. In this study, we aimed to assess the capacity of ddPCR and real-time PCR for detecting low levels of circulating Mycobacterium tuberculosis (MTB) DNA. The study involved testing whole blood samples for an MTB DNA target (known as IS6110). Blood samples were obtained from 28 patients with pulmonary TB, 28 patients with extrapulmonary TB, and 28 healthy individuals. The results show that ddPCR could be used to measure low levels of MTB DNA, and it has the potential to be used to diagnose pulmonary and extrapulmonary TB based on clinical samples. PMID- 28848723 TI - A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect. AB - PURPOSE: To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant. METHODS: Patients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic "danger" response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years. RESULTS: Eighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were <=grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS. CONCLUSION: Intra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity. PMID- 28848724 TI - A Novel Mutation in ERCC8 Gene Causing Cockayne Syndrome. AB - Cockayne syndrome (CS) is a rare autosomal recessive multisystem disorder characterized by impaired neurological and sensory functions, cachectic dwarfism, microcephaly, and photosensitivity. This syndrome shows a variable age of onset and rate of progression, and its phenotypic spectrum include a wide range of severity. Due to the progressive nature of this disorder, diagnosis can be more important when additional signs and symptoms appear gradually and become steadily worse over time. Therefore, mutation analysis of genes involved in CS pathogenesis can be helpful to confirm the suspected clinical diagnosis. Here, we report a novel mutation in ERCC8 gene in a 16-year-old boy who suffers from poor weight gain, short stature, microcephaly, intellectual disability, and photosensitivity. The patient was born to consanguineous family with no previous documented disease in his parents. To identify disease-causing mutation in the patient, whole exome sequencing utilizing next-generation sequencing on an Illumina HiSeq 2000 platform was performed. Results revealed a novel homozygote mutation in ERCC8 gene (NM_000082: exon 11, c.1122G>C) in our patient. Another gene (ERCC6), which is also involved in CS did not have any disease-causing mutations in the proband. The new identified mutation was then confirmed by Sanger sequencing in the proband, his parents, and extended family members, confirming co-segregation with the disease. In addition, different bioinformatics programs which included MutationTaster, I-Mutant v2.0, NNSplice, Combined Annotation Dependent Depletion, The PhastCons, Genomic Evolutationary Rate Profiling conservation score, and T-Coffee Multiple Sequence Alignment predicted the pathogenicity of the mutation. Our study identified a rare novel mutation in ERCC8 gene and help to provide accurate genetic counseling and prenatal diagnosis to minimize new affected individuals in this family. PMID- 28848725 TI - Pulmonary Embolism in Children. AB - Pulmonary embolism (PE) in the pediatric population is relatively rare when compared to adults; however, the incidence is increasing and accurate and timely diagnosis is critical. A high clinical index of suspicion is warranted as PE often goes unrecognized among children leading to misdiagnosis and potentially increased morbidity and mortality. Evidence-based guidelines for the diagnosis, management, and follow-up of children with PE are lacking and current practices are extrapolated from adult data. Treatment options include thrombolysis and anticoagulation with heparins and oral vitamin K antagonists, with newer direct oral anticoagulants currently in clinical trials. Long-term sequelae of PE, although studied in adults, are vastly unknown among children and adolescents. Additional research is needed in order to provide pediatric focused care for patients with acute PE. PMID- 28848726 TI - Peripheral Intravenous Access in Preterm Neonates during Postnatal Stabilization: Feasibility and Safety. AB - BACKGROUND: Current European Guideline for resuscitation recommends a centrally positioned umbilical venous catheter as the best option for administering necessary drugs. Especially in preterm infants, a frequently used alternative is the peripheral venous catheter. METHODS: Two randomized controlled studies were conducted at the Division of Neonatology, Medical University of Graz. During neonatal resuscitation, a standardized protocol was filled out by an uninvolved observer including time points after birth of all attempts of venous puncture, time point of successful venous puncture, and total number of needed attempts. Arterial oxygen saturation (SpO2) and heart rate (HR) were measured using pulse oximetry at the right hand/wrist. In each neonate, either NIRO 200NX (Hamamatsu, Japan) or INVOS 5100C (Covidien-Medtronic, USA) were used to measure cerebral tissue oxygenation index (cTOI) and cerebral regional oxygen saturation (crSO2), respectively. SpO2, HR, and cTOI/crSO2 during and 1 min before and after successful venous punctures were analyzed. RESULTS: 70 protocols were reviewed. Data of 61 preterm neonates were analyzed. Mean gestational age was 31.5 +/- 2.2 weeks, and the mean birth weight was 1,527 +/- 541 g. In median, it needed one attempt [interquartile range (IQR) 1-2] to establish a peripheral venous catheter. In median, intravenous (IV) catheterization was successfully established 5 (IQR 4-9) min after birth. SpO2 and cTOI/crSO2 rose significantly following the percentiles during the first 10 min after the birth. HR did not change significantly. CONCLUSION: Peripheral IV catheterization during postnatal stabilization of preterm infants is feasible and successful in most of the cases at first attempt. PMID- 28848728 TI - Decreased Identification of Vesicoureteral Reflux: A Cautionary Tale. AB - AIM: To find the trend in patient's visits to our centers for vesicoureteral reflux (VUR). We hypothesize that VUR diagnosis and hence possible nephropathy recognition may be diminishing because of changing practice patterns. METHODS: Data were extracted from electronic medical records for new and follow-up patients aged 0-18 years with ICD-9/10 codes to correspond with VUR, VUR unilateral, VUR bilateral, and VUR with reflux nephropathy, as well as new patients with diagnoses of urinary tract infections (UTI) and pyelonephritis at two major pediatric centers from 2012 to 2015. Figures and statistics to reflect absolute clinic visits and annual trends were created with SPSS 2010. Linear regression was applied. RESULTS: Annually, Le Bonheur Children's Hospital and Nationwide Children's Hospital experienced an average decrease of 13 and 17% in total VUR visits, and an average decrease of 22 and 27% in VUR nephropathy visits, respectively, for each institution. Patient visits for UTIs were reduced an average of 16% annually in both centers. Linear regression demonstrated that number of patients (patients/year +/- SE) decreased annually 69 +/- 19 (P = 0.02), 7 +/- 2 (P = 0.02), and 67 +/- 25 (P = 0.04) for VUR, VUR nephropathy, and UTI, respectively. CONCLUSION: We conclude that the decreased number of VUR and VUR nephropathy cases identified in subspecialty clinics (Nephrology/Urology) at two major children's hospitals reflect a possible decreased identification of VUR. This trend may also be due to decreased referral of low grade cases of VUR. We cannot conclude that "undifferentiated UTI" referrals increased concomitantly to account for the decreased VUR as our data reflects a decreased trend in those visits as well. We suggest that clinicians following the American Academy of Pediatrics guidelines ensure that all UTI are accounted for and surveillance is appropriately escalated for recurrent UTI or abnormal imaging results. PMID- 28848727 TI - Lost in Transition: A Systematic Review of Neonatal Electroencephalography in the Delivery Room-Are We Forgetting an Important Biomarker for Newborn Brain Health? AB - BACKGROUND: Electroencephalography (EEG) monitoring is routine in neonatal intensive care units (NICUs) for detection of seizures, neurological monitoring of infants following perinatal asphyxia, and increasingly, following preterm delivery. EEG monitoring is not routinely commenced in the delivery room (DR). OBJECTIVES: To determine the feasibility of recording neonatal EEG in the DR, and to assess its usefulness as a marker of neurological well-being during immediate newborn transition. METHODS: We performed a systematic stepwise search of PubMed using the following terms: infant, newborns, neonate, DR, afterbirth, transition, and EEG. Only human studies describing EEG monitoring in the first 15 min following delivery were included. Infants of all gestational ages were included. RESULTS: Two original studies were identified that described EEG monitoring of newborn infants within the DR. Both prospective observational studies used amplitude-integrated EEG (aEEG) monitoring and found it feasible in infants >34 weeks' gestation; however, technical challenges made it difficult to obtain continuous reliable data. Different EEG patterns were identified in uncompromised newborns and those requiring resuscitation. CONCLUSION: EEG monitoring is possible in the DR and may provide an objective baseline measure of neurological function. Further feasibility studies are required to overcome technical challenges in the DR, but these challenges are not insurmountable with modern technology. PMID- 28848729 TI - Using Intervention Mapping for Program Design and Production of iCHAMPSS: An Online Decision Support System to Increase Adoption, Implementation, and Maintenance of Evidence-Based Sexual Health Programs. AB - In Texas and across the United States, unintended pregnancy, HIV, and sexually transmitted infections (STIs) among adolescents remain serious public health issues. Sexual risk-taking behaviors, including early sexual initiation, contribute to these public health problems. Over 35 sexual health evidence-based programs (EBPs) have been shown to reduce sexual risk behaviors and/or prevent teen pregnancies or STIs. Because more than half of these EBPs are designed for schools, they could reach and impact a considerable number of adolescents if implemented in these settings. Most schools across the U.S. and in Texas, however, do not implement these programs. U.S. school districts face many barriers to the successful dissemination (i.e., adoption, implementation, and maintenance) of sexual health EBPs, including lack of knowledge about EBPs and where to find them, perceived lack of support from school administrators and parents, lack of guidance regarding the adoption process, competing priorities, and lack of specialized training on sexual health. Therefore, this paper describes how we used intervention mapping (Steps 3 and 4, in particular), a systematic design framework that uses theory, empirical evidence, and input from the community to develop CHoosing And Maintaining Effective Programs for Sex Education in Schools (iCHAMPSS), an online decision support system to help school districts adopt, implement, and maintain sexual health EBPs. Guided by this systematic intervention design approach, iCHAMPSS has the potential to increase dissemination of sexual health EBPs in school settings. PMID- 28848730 TI - Promoting Functional Activity Engagement in People with Multiple Disabilities through the Use of Microswitch-Aided Programs. AB - BACKGROUND: People with severe/profound multiple (e.g., intellectual, motor, or sensory-motor) disabilities are frequently restricted to a situation of inactivity and dependence, which may be modified by promoting functional activity engagement through assistive technology. METHODS: This study assessed the possibility of promoting functional activity engagement via microswitch-aided programs with nine participants with multiple disabilities between 10 and 29 years of age. Functional activity consisted of constructive interaction with the immediate environment (e.g., reaching/touching or putting away objects) through the use of response schemes considered practical and beneficial for the participants' physical exercise and general condition. Microswitch-aided programs were used to monitor the participants' responses and to automatically provide stimulation opportunities contingent on those responses. RESULTS: All participants had a large/significant increase in their activity engagement (i.e., response frequencies) during the microswitch-aided programs, when compared to the baseline periods. These data, which are in line with previous findings in the area, indicate that the programs targeted activity and responses suitable for the participants and ensured contingent stimulation effective to motivate them. CONCLUSION: People with severe/profound multiple disabilities can engage in functional activity with the help of microswitch-aided programs. PMID- 28848731 TI - Growth of Global Publishing Output of Health Economics in the Twenty-First Century: A Bibliographic Insight. AB - BACKGROUND: Strong growth of interdisciplinary sciences might find exceptional example in academic health economics. We decided to observe the quantitative output in this science since the beginning of the twenty-first century. METHODS: Electronic search of the published literature was conducted in four different databases: one medical database-MEDLINE/PubMed, two general databases Scopus/Elsevier and Web of Science (WoS), and one specialized health economic database-NHS Economic Evaluation Database (EED). The applied combination of key words was carefully chosen to cover the most commonly used terms in titles of publications dealing with conceptual areas of health economics. All bibliographic units were taken into account. RESULTS: Within the time horizon from January 1, 2000 to December 31, 2016, without language or limitations on bibliographic unit types, we identified an output ranging approximately from 60,345 to 88,246 records with applied search strategy in MEDLINE/PubMed, Scopus/Elsevier, and WoS. In NHS EED, we detected 14,761 records of economic evaluations of health interventions during the period in which database was maintained and regularly updated. With slightly more than one-third of the identified records, USA clearly dominates in this field. United Kingdom takes a strong second place with about 12% of identified records. Consistently, USA and UK universities are the most frequent among the top 15 affiliations/organizations of the authors of the identified records. Authors from Harvard University contributed to the largest number of the identified records. CONCLUSION: There is a clear evidence of both the upward stream of blossoming in health economics publications and its acceleration. Based on this bibliographic data set, it is difficult to distinguish the actual impact growth of this output provided dominantly by academia with modest contribution by pharmaceutical/medicinal device industry and diverse national government-based agencies. Further insight into the citation track record of these individual publications could provide helpful upgrade and a perspective on ongoing development. PMID- 28848732 TI - Platelet-Eosinophil Interactions As a Potential Therapeutic Target in Allergic Inflammation and Asthma. AB - The importance of platelet activation during hemostasis is well understood. An understanding of these mechanisms has led to the use of several classes of anti platelet drugs to inhibit aggregation for the prevention of thrombi during cardiovascular disease. It is now also recognized that platelets can function very differently during inflammation, as part of their role in the innate immune response against pathogens. This dichotomy in platelet function occurs through distinct physiological processes and alternative signaling pathways compared to that of hemostasis (leading to platelet aggregation) and is manifested as increased rheological interactions with leukocytes, the ability to undergo chemotaxis, communication with antigen-presenting cells, and direct anti-pathogen responses. Mounting evidence suggests platelets are also critical in the pathogenesis of allergic diseases such as asthma, where they have been associated with antigen presentation, bronchoconstriction, bronchial hyperresponsiveness, airway inflammation, and airway remodeling in both clinical and experimental studies. In particular, platelets have been reported bound to eosinophils in the blood of patients with asthma and the incidence of these events increases after both spontaneous asthma attacks in a biphasic manner, or after allergen challenge in the clinic. Platelet depletion in animal models of allergic airway inflammation causes a profound reduction in eosinophil recruitment to the lung, suggesting that the association of platelets with eosinophils is indeed an important event during eosinophil activation. Furthermore, in cases of severe asthma, and in animal models of allergic airways inflammation, platelet eosinophil complexes move into the lung through a platelet P-selectin-mediated, eosinophil beta1-integrin activation-dependent process, while platelets increase adherence of eosinophils to the vascular endothelium in vitro, demonstrating a clear interaction between these cell types in allergic inflammatory diseases. This review will explore non-thrombotic platelet activation in the context of allergy and the association of platelets with eosinophils, to reveal how these phenomena may lead to the discovery of novel therapeutic targets. PMID- 28848733 TI - The Predictive Value of Integrated Pulmonary Index after Off-Pump Coronary Artery Bypass Grafting: A Prospective Observational Study. AB - BACKGROUND: The early warning scores may increase the safety of perioperative period. The objective of this study was to assess the diagnostic and predictive role of Integrated Pulmonary Index (IPI) after off-pump coronary artery bypass grafting (OPCAB). MATERIALS AND METHODS: Forty adult patients undergoing elective OPCAB were enrolled into a single-center prospective observational study. We assessed respiratory function using IPI that includes oxygen saturation, end tidal CO2, respiratory rate, and pulse rate. In addition, we evaluated blood gas analyses and hemodynamics, including ECG, invasive arterial pressure, and cardiac index. The measurements were performed after transfer to the intensive care unit, after spontaneous breathing trial and at 2, 6, 12, and 18 h after extubation. RESULTS AND DISCUSSION: The value of IPI registered during respiratory support correlated weakly with cardiac index (rho = 0.4; p = 0.04) and ScvO2 (rho = 0.4, p = 0.02). After extubation, IPI values decreased significantly, achieving a minimum by 18 h. The IPI value <=9 at 6 h after extubation was a predictor of complicated early postoperative period (AUC = 0.71; p = 0.04) observed in 13 patients. CONCLUSION: In off-pump coronary surgery, the IPI decreases significantly after tracheal extubation and may predict postoperative complications. PMID- 28848735 TI - Differences in Recurrence Rate and De Novo Incontinence after Endoscopic Treatment of Vesicourethral Stenosis and Bladder Neck Stenosis. AB - OBJECTIVES: The objective of this study was to compare the recurrence rate and de novo incontinence after endoscopic treatment of vesicourethral stenosis (VUS) after radical prostatectomy (RP) and for bladder neck stenosis (BNS) after transurethral resection of the prostate (TURP). METHODS: Retrospective analysis of patients treated endoscopically for VUS after RP or for BNS after TURP at three German tertiary care centers between March 2009 and June 2016. Investigated endpoints were recurrence rate and de novo incontinence. Chi-squared tests and t tests were used to model the differences between groups. RESULTS: A total of 147 patients underwent endoscopic therapy for VUS (59.2%) or BNS (40.8%). Mean age was 68.3 years (range 44-86), mean follow-up 27.1 months (1-98). Mean time to recurrence after initial therapy was 23.9 months (1-156), mean time to recurrence after prior endoscopic therapy for VUS or BNS was 12.0 months (1-159). Patients treated for VUS underwent significantly more often radiotherapy prior to endoscopic treatment (33.3 vs. 13.3%; p = 0.006) and the recurrence rate was significantly higher (59.8 vs. 41.7%; p = 0.031). The overall success rate of TUR for VUS was 40.2%, success rate of TUR for BNS was 58.3%. TUR for BNS is significantly more successful (p = 0.031). The mean number of TUR for BNS vs. TUR for VUS in successful cases was 1.5 vs. 1.8, which was not significantly different. The rate of de novo incontinence was significantly higher in patients treated for VUS (13.8 vs. 1.7%; p = 0.011). After excluding those patients with radiotherapy prior to endoscopic treatment, the recurrence rate did not differ significantly between both groups (60.3% for VUS vs. 44.2% for BNS; p = 0.091), whereas the rate of de novo incontinence (13.8 for VUS vs. 0% for BNS; p = 0.005) stayed significantly higher in patients treated for VUS. CONCLUSION: Most patients with BNS are successfully treated endoscopically. In patients with VUS, the success rate is lower. Both stenoses differ with respect to de novo incontinence. Patients must be counseled regarding the increased risk of de novo incontinence after endoscopic treatment of VUS, independent of prior radiotherapy. Longer follow-up is warranted to address long-term outcomes. PMID- 28848736 TI - Late Sac Rupture due to a Type IV Endoleak after Previous Endovascular Aortic Aneurysm Repair: A Case Report. AB - Type IV endoleaks have been identified as endoleaks of low flow, and rupture risk has been estimated to be minimal in literature. Therefore, conservative treatment has been recommended in most cases. We are presenting a rare case of late rupture due to type IV endoleak that was treated with open repair applying a novel surgical technique. PMID- 28848734 TI - Regulation of Eosinophil and Group 2 Innate Lymphoid Cell Trafficking in Asthma. AB - Asthma is an inflammatory disease usually characterized by increased Type 2 cytokines and by an infiltration of eosinophils to the airways. While the production of Type 2 cytokines has been associated with TH2 lymphocytes, increasing evidence indicates that group 2 innate lymphoid cells (ILC2) play an important role in the production of the Type 2 cytokines interleukin (IL)-5 and IL-13, which likely amplifies the recruitment of eosinophils from the blood to the airways. In that regard, recent asthma treatments have been focusing on blocking Type 2 cytokines, notably IL-4, IL-5, and IL-13. These treatments mainly result in decreased blood or sputum eosinophil counts as well as decreased asthma symptoms. This supports that therapies blocking eosinophil recruitment and activation are valuable tools in the management of asthma and its severity. Herein, we review the mechanisms involved in eosinophil and ILC2 recruitment to the airways, with an emphasis on eotaxins, other chemokines as well as their receptors. We also discuss the involvement of other chemoattractants, notably the bioactive lipids 5-oxo-eicosatetraenoic acid, prostaglandin D2, and 2 arachidonoyl-glycerol. Given that eosinophil biology differs between human and mice, we also highlight and discuss their responsiveness toward the different eosinophil chemoattractants. PMID- 28848737 TI - Lysine-Directed Post-translational Modifications of Tau Protein in Alzheimer's Disease and Related Tauopathies. AB - Tau is a microtubule-associated protein responsible mainly for stabilizing the neuronal microtubule network in the brain. Under normal conditions, tau is highly soluble and adopts an "unfolded" conformation. However, it undergoes conformational changes resulting in a less soluble form with weakened microtubule stabilizing properties. Altered tau forms characteristic pathogenic inclusions in Alzheimer's disease and related tauopathies. Although, tau hyperphosphorylation is widely considered to be the major trigger of tau malfunction, tau undergoes several post-translational modifications at lysine residues including acetylation, methylation, ubiquitylation, SUMOylation, and glycation. We are only beginning to define the site-specific impact of each type of lysine modification on tau biology as well as the possible interplay between them, but, like phosphorylation, these modifications are likely to play critical roles in tau's normal and pathobiology. This review summarizes the latest findings focusing on lysine post-translational modifications that occur at both endogenous tau protein and pathological tau forms in AD and other tauopathies. In addition, it highlights the significance of a site-dependent approach of studying tau post translational modifications under normal and pathological conditions. PMID- 28848738 TI - Vascular Endothelial Regulation of Obesity-Associated Insulin Resistance. AB - Obesity is a worldwide epidemic that predisposes individuals to metabolic complications, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease, all of which are related to an imbalance between food intake and energy expenditure. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are urgently needed. A well-accepted paradigm is that crosstalk between organs/tissues contributes to diseases. Endothelial dysfunction characterizes metabolic disorders and the related vascular complications. Over the past two decades, overwhelming studies have focused on mechanisms that lead to endothelial dysfunction. New investigations, however, have begun to appreciate the opposite direction of the crosstalk: endothelial regulation of metabolism, although the underlying mechanisms remain to be elucidated. This review summarizes the evidence that supports the concept of endothelial regulation of obesity and the associated insulin resistance in fat, liver, and skeletal muscles, the classic targets of insulin. Outstanding questions and future research directions are highlighted. Identification of the mechanisms of vascular endothelial regulation of metabolism may offer strategies for prevention and treatment of obesity and the related metabolic complications. PMID- 28848741 TI - The "Chinese Mode" of organ donation and transplantation. PMID- 28848740 TI - Limited Associations between Keel Bone Damage and Bone Properties Measured with Computer Tomography, Three-Point Bending Test, and Analysis of Minerals in Swiss Laying Hens. AB - Keel bone damage is a wide-spread welfare problem in laying hens. It is unclear so far whether bone quality relates to keel bone damage. The goal of the present study was to detect possible associations between keel bone damage and bone properties of intact and damaged keel bones and of tibias in end-of-lay hens raised in loose housing systems. Bones were palpated and examined by peripheral quantitative computer tomography (PQCT), a three-point bending test, and analyses of bone ash. Contrary to our expectations, PQCT revealed higher cortical and trabecular contents in fractured than in intact keel bones. This might be due to structural bone repair after fractures. Density measurements of cortical and trabecular tissues of keel bones did not differ between individuals with and without fractures. In the three-point bending test of the tibias, ultimate shear strength was significantly higher in birds with intact vs. fractured keel bones. Likewise, birds with intact or slightly deviated keel bones had higher mineral and calcium contents of the keel bone than birds with fractured keel bones. Calcium content in keel bones was correlated with calcium content in tibias. Although there were some associations between bone traits related to bone strength and keel bone damage, other factors such as stochastic events related to housing such as falls and collisions seem to be at least as important for the prevalence of keel bone damage. PMID- 28848742 TI - Hepatobiliary Surgery and Nutrition is indexed by SCIE: a tremendous step forward. PMID- 28848739 TI - Antimicrobial Resistance in Bacterial Poultry Pathogens: A Review. AB - Antimicrobial resistance (AMR) is a global health threat, and antimicrobial usage and AMR in animal production is one of its contributing sources. Poultry is one of the most widespread types of meat consumed worldwide. Poultry flocks are often raised under intensive conditions using large amounts of antimicrobials to prevent and to treat disease, as well as for growth promotion. Antimicrobial resistant poultry pathogens may result in treatment failure, leading to economic losses, but also be a source of resistant bacteria/genes (including zoonotic bacteria) that may represent a risk to human health. Here we reviewed data on AMR in 12 poultry pathogens, including avian pathogenic Escherichia coli (APEC), Salmonella Pullorum/Gallinarum, Pasteurella multocida, Avibacterium paragallinarum, Gallibacterium anatis, Ornitobacterium rhinotracheale (ORT), Bordetella avium, Clostridium perfringens, Mycoplasma spp., Erysipelothrix rhusiopathiae, and Riemerella anatipestifer. A number of studies have demonstrated increases in resistance over time for S. Pullorum/Gallinarum, M. gallisepticum, and G. anatis. Among Enterobacteriaceae, APEC isolates displayed considerably higher levels of AMR compared with S. Pullorum/Gallinarum, with prevalence of resistance over >80% for ampicillin, amoxicillin, tetracycline across studies. Among the Gram-negative, non-Enterobacteriaceae pathogens, ORT had the highest levels of phenotypic resistance with median levels of AMR against co-trimoxazole, enrofloxacin, gentamicin, amoxicillin, and ceftiofur all exceeding 50%. In contrast, levels of resistance among P. multocida isolates were less than 20% for all antimicrobials. The study highlights considerable disparities in methodologies, as well as in criteria for phenotypic antimicrobial susceptibility testing and result interpretation. It is necessary to increase efforts to harmonize testing practices, and to promote free access to data on AMR in order to improve treatment guidelines as well as to monitor the evolution of AMR in poultry bacterial pathogens. PMID- 28848743 TI - Robotic surgery: the promise and finally the progress. PMID- 28848744 TI - Training robotic hepatectomy: the Hong Kong experience and perspective. AB - The introduction of robotic surgical systems has revolutionized the practice of minimal invasive surgery (MIS). Although little data regarding robotic hepatectomies have been reported, it appears to be similar to conventional laparoscopic approach in terms of blood loss, morbidity rate, mortality rate and hospital stay at least. The application of robotic system in liver surgery was not well evaluated yet, particularly learning curve. Studies were identified by searching MEDLINE and PubMed databases for articles from January 2001 to May 2016 using the keywords "laparoscopic hepatectomy", "robotic hepatectomy", and "learning curve". With the limited data in robotic hepatectomy, the learning curve model of robotic hepatectomy needs to base on the experience of conventional laparoscopic hepatectomy. Based on the learning curve study experience for laparoscopic hepatectomies, the minimal number laparoscopic minor and major hepatectomies to overcome learning curve are 22-64 cases, and 45-75 cases, respectively. Left lateral sectionectomy technique is more standardized, and it is a good start for training of MIS liver surgery. However, the training program required for the robotic liver surgeons still highly depends on the surgeons' experience of previous open and laparoscopic liver surgery, the surgeons' previous experience of other robotic surgeries, the experience of the surgical team including the assistant surgeons and nursing staffs, and the complexity of the diseases. We discourage performance of robotic hepatectomy in the occasional patient by a team that is not well prepared and is not embedded in a specialized center. Knowledge and practical skills are both required in MIS liver surgery and cannot be replaced by newer tools, including the most advanced robotic system. PMID- 28848745 TI - Robotic hepatectomy: the Korean experience and perspective. AB - Since the robotic surgical system was first introduced in 2005, the number of robotic surgery has been gradually increasing in Korea. The proportion of general robotic surgery is relatively higher compared to the western countries, but robotic liver resection is one of the most complex procedures among robotic general surgery. In this article, we introduce the development of robotic liver resection in Korea and describe our standardized techniques. The current data on robotic liver resection in our institute and other centers in Korea are also presented. PMID- 28848746 TI - Setting up a robotic hepatectomy program: a Western-European experience and perspective. AB - Currently the majority of liver resections are performed via open resection. Nevertheless, minimally invasive liver surgery is gaining ground and conventional laparoscopy has proven to be beneficial in different fields of liver surgery compared to open resections. Still, conventional laparoscopy has a few downsides, from which straight instruments, 2-dimensional view and awkward ergonomics are the most obvious. The robotic surgical system is developed to overcome these limitations. It offers several advantages over conventional laparoscopy to optimize conditions in minimally invasive surgery: instruments are wristed with a wide range of motion and the view is 3-dimensional and magnified. With instruments with a greater range of motion than in laparoscopic surgery, the use of a robotic system potentially broadens indications for minimally invasive liver resection. Here, we discuss the steps of setting up a robotic hepatectomy program against the background of the initial experience at our institution. PMID- 28848748 TI - Is sarcopenia a prognostic factor after living donor liver transplantation? PMID- 28848747 TI - Value-based assessment of robotic pancreas and liver surgery. AB - Current healthcare economic evaluations are based only on the perspective of a single stakeholder to the healthcare delivery process. A true value-based decision incorporates all of the outcomes that could be impacted by a single episode of surgical care. We define the value proposition for robotic surgery using a stakeholder model incorporating the interests of all groups participating in the provision of healthcare services: patients, surgeons, hospitals and payers. One of the developing and expanding fields that could benefit the most from a complete value-based analysis is robotic hepatopancreaticobiliary (HPB) surgery. While initial robot purchasing costs are high, the benefits over laparoscopic surgery are considerable. Performing a literature search we found a total of 18 economic evaluations for robotic HPB surgery. We found a lack of evaluations that were carried out from a perspective that incorporates all of the impacts of a single episode of surgical care and that included a comprehensive hospital cost assessment. For distal pancreatectomies, the two most thorough examinations came to conflicting results regarding total cost savings compared to laparoscopic approaches. The most thorough pancreaticoduodenectomy evaluation found non-significant savings for total hospital costs. Robotic hepatectomies showed no cost savings over laparoscopic and only modest savings over open techniques. Lastly, robotic cholecystectomies were found to be more expensive than the gold-standard laparoscopic approach. Existing cost accounting data associated with robotic HPB surgery is incomplete and unlikely to reflect the state of this field in the future. Current data combines the learning curves for new surgical procedures being undertaken by HPB surgeons with costs derived from a market dominated by a single supplier of robotic instruments. As a result, the value proposition for stakeholders in this process cannot be defined. In order to solve this problem, future studies must incorporate (I) quality of life, survival, and return to independent function alongside data such as (II) intent to-treat analysis of minimally-invasive surgery accounting for conversions to open, (III) surgeon and institution experience and operative time as surrogates for the learning curve; and (IV) amortization and maintenance costs as well as direct costs of disposables and instruments. PMID- 28848749 TI - Pretransplant sarcopenia: suffer or fight? PMID- 28848750 TI - A new link between innate immunity and hepatic metabolism: attractive unknown place to visit. PMID- 28848751 TI - Endoscopic therapy for benign biliary strictures: evaluation of metal vs. plastic biliary stents. PMID- 28848752 TI - Resection or ablation for very early hepatocellular carcinoma and the fundamental problem of causal inference. PMID- 28848753 TI - Addressing the increasing global burden of viral hepatitis. PMID- 28848754 TI - The evolution of the burden of viral hepatitis from 1990 to 2013: still an open challenge to global public health policy. PMID- 28848755 TI - Resection versus transplantation for hepatocellular carcinoma exceeding Milan criteria within increasing donor shortage. PMID- 28848756 TI - Resection or transplantation for hepatocellular carcinoma: is the decision clear for patients beyond Milan criteria? PMID- 28848757 TI - Challenges in patient selection for liver resection or transplantation in patients with hepatocellular carcinoma beyond Milan criteria. PMID- 28848758 TI - Persistent bronchobiliary fistula managed by endoscopic biliary stenting. PMID- 28848759 TI - The Promise of Genomic Studies on Human Diseases: From Basic Science to Clinical Application. PMID- 28848760 TI - Transcriptome Analysis of Two Different Developmental Stages of Paeonia lactiflora Seeds. AB - Paeonia lactiflora is a herbaceous flower in the family Paeoniaceae with both hypocotyl and epicotyl dormant seeds. We used high-throughput transcriptome sequencing on two different developmental stages of P. lactiflora seeds to identify seed dormancy and germination-related genes. We performed de novo assembly and annotated a total of 123,577 unigenes, which encoded 24,688 putative proteins with 47 GO categories. A total of 10,714 unigenes were annotated in the KEGG database, and 258 pathways were involved in the annotations. A total of 1795 genes were differentially expressed in the functional enrichment analysis. The key genes for seed germination and dormancy, such as GAI1 and ARF, were confirmed by quantitative reverse transcription-polymerase chain reaction analysis. This is the first report of sequencing the P. lactiflora seed transcriptome. Our results provide fundamental frame work and technical support for further selective breeding and cultivation of Paeonia. Our transcriptomic data also serves as the basis for future genetics and genomics research on Paeonia and its closely related species. PMID- 28848761 TI - Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future. AB - In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the "checkpoint inhibitors." Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years. PMID- 28848762 TI - Surface Hydrophilicity and Antifungal Properties of TiO2 Films Coated on a Co-Cr Substrate. AB - The purpose of this study was to deposit a thin layer of TiO2 on a Co-Cr substrate, serving as a deactivation film protecting the metallic fitting surface. The crystalline structure and surface morphology of the film were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). A scratch tester was used to examine the adhesion strength between the TiO2 film and the Co-Cr substrate. The water contact angles and antifungal efficacy against C. albicans of the TiO2-deposited Co-Cr samples were investigated and further compared with those of uncoated Co-Cr substrates. The results indicated that a pure anatase microstructure and dense and smooth surface texture as well as strong binding to the underlying metallic surface were obtained. The originally hydrophobic Co-Cr alloy surface turned hydrophilic after TiO2 film coating. Most importantly, the TiO2-coated surface showed a superior antifungal capability under UV-irradiation compared to those without TiO2 coating. This work contains meaningful results for the development of a new metallic framework coating with improved hydrophilicity and antifungal properties. PMID- 28848763 TI - Robustification of Naive Bayes Classifier and Its Application for Microarray Gene Expression Data Analysis. AB - The naive Bayes classifier (NBC) is one of the most popular classifiers for class prediction or pattern recognition from microarray gene expression data (MGED). However, it is very much sensitive to outliers with the classical estimates of the location and scale parameters. It is one of the most important drawbacks for gene expression data analysis by the classical NBC. The gene expression dataset is often contaminated by outliers due to several steps involved in the data generating process from hybridization of DNA samples to image analysis. Therefore, in this paper, an attempt is made to robustify the Gaussian NBC by the minimum beta-divergence method. The role of minimum beta-divergence method in this article is to produce the robust estimators for the location and scale parameters based on the training dataset and outlier detection and modification in test dataset. The performance of the proposed method depends on the tuning parameter beta. It reduces to the traditional naive Bayes classifier when beta -> 0. We investigated the performance of the proposed beta naive Bayes classifier (beta-NBC) in a comparison with some popular existing classifiers (NBC, KNN, SVM, and AdaBoost) using both simulated and real gene expression datasets. We observed that the proposed method improved the performance over the others in presence of outliers. Otherwise, it keeps almost equal performance. PMID- 28848764 TI - Prevalence of Prostatitis-Like Symptoms and Outcomes of NIH-CPSI in Outpatients with Lifelong and Acquired PE: Based on a Large Cross-Sectional Study in China. AB - Premature ejaculation (PE) is one of the most common sexual dysfunctions, which were associated with prostatitis-like symptoms (PLS). We intended to explore the prevalence of prostatitis-like symptoms and outcomes of National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) scores in outpatients with lifelong (LPE) and acquired premature ejaculation (APE). From December 2013 to December 2015, a total of 498 consecutive heterosexual men with PE and 322 male healthy subjects without PE were enrolled. Each of them completed a detailed questionnaire on demographics information, sexual and medical histories, and the NIH-CPSI. Assessment of NIH-CPSI and definition of PLS and PE were used to measure the PLS and NIH-CPSI scores and ejaculatory function for all subjects. Finally, a total of 820 subjects (including 498 men in PE group and 322 men in control group) were enrolled in our study. The mean ages were significantly different between PE and no PE groups. Men with PE reported worse PLS and higher NIH-CPSI scores (P < 0.001 for all). Similar findings were also observed between men with LPE and APE. Men with APE also reported higher rates of PLS and scores of NIH-CPSI (P < 0.001 for all). Multivariate analysis showed that PLS and NIH CPSI scores were significantly associated with PE. PMID- 28848765 TI - Counselling about the Risk of Preterm Delivery: A Systematic Review. AB - We aimed to describe the outcomes of counselling for preterm delivery. PubMed, Embase, and PsycInfo were systematically searched (from 2000 to 2016) using the following terms: counselling, pregnancy complications, high-risk pregnancy, fetal diseases, and prenatal care. A total of nine quantitative studies were identified, five randomized and four nonrandomized. All studies were conducted in the USA, and half of them were based on a simulated counselling session. Two main clinical implications can be drawn from the available studies: firstly, providing written information before or during the consultation seems to have a positive effect, while no effect was detected when written material was provided after the consultation. Secondly, parents' choices about treatment seemed to be influenced by spiritual-related aspects and/or preexisting preferences, rather than by the level of detail or by the order with which information was provided. Therefore, the exploration of parents' beliefs is crucial to reduce the risks of misconception and to guarantee choice in line with personal values. More research is necessary to validate these findings in cross-cultural contexts and in real world settings of care. Moreover, the centeredness of conversations and the characteristics of the clinician involved in counselling should be addressed in future studies. PMID- 28848766 TI - Intelligent Physical Exercise Training in a Workplace Setting Improves Muscle Strength and Musculoskeletal Pain: A Randomized Controlled Trial. AB - PURPOSE: To assess effects of 1-year Intelligent Physical Exercise Training (IPET) on musculoskeletal health. METHODS: Office workers were randomized 1 : 1 to a training group, TG (N = 193), or a control group, CG (N = 194). TG received 1 h supervised high intensity IPET every week within working hours for 1 year and was recommended to perform 30 min of moderate intensity physical activity for 6 days a week during leisure. The IPET program was based on baseline health measures. RESULTS: No baseline differences were present. An intention-to-treat analysis showed significant between-group effect for muscle strength but not for musculoskeletal pain. However, a per-protocol analysis of those with an adherence of >=70% demonstrated a significant between-group effect for neck pain during the past three months. Several significant within-group changes were present, where TG and TG >= 70% demonstrated clinically relevant pain reductions whereas minimal reductions were seen for CG. CONCLUSION: IPET and recommendations of moderate intensity physical activity demonstrated significant between-group effect on muscle strength. Interestingly, significant within-group reductions in musculoskeletal pain were seen not only in TG but also in CG. This may underlie the lack of such between-group effect and shows that a possible positive side effect of merely drawing attention can improve musculoskeletal health. PMID- 28848767 TI - Lower Extremity Skeletal Muscle Mass, but Not Upper Extremity Skeletal Muscle Mass, Is Inversely Associated with Hospitalization in Patients with Type 2 Diabetes. AB - AIM: To investigate the association of skeletal muscle mass with metabolic parameters and hospitalization in patients with type 2 diabetes. METHODS: A retrospective observational study was conducted in patients with type 2 diabetes between May 2013 and November 2015. Body composition was measured by bioelectrical impedance analysis. Multiple regression analysis was performed to identify the association between skeletal muscle mass and metabolic parameters. Cox proportional hazard analysis was performed to assess the association between skeletal muscle mass and hospitalization. RESULTS: A total of 121 patients were enrolled in this study. The mean age of patients was 59.4 +/- 14.2 years. During a mean follow-up of 730 +/- 253 days, three patients (2.8%) died and 79 patients (65.3%) were admitted to our hospital. After adjustment for age, sex, height, and weight, it was found that lower extremity skeletal muscle mass (LSM) was inversely associated with brachial-ankle pulse wave velocity (beta = -0.108, P = 0.008). Moreover, LSM was significantly associated with reduced risk of hospitalization (hazard ratio = 0.752; 95% confidence interval, 0.601-0.942; P = 0.013). In contrast, upper extremity skeletal muscle mass (USM) did not exhibit any significant association. CONCLUSION: LSM, but not USM, is important for managing patients with type 2 diabetes. This trial is registered with UMIN000023010. PMID- 28848768 TI - Large Pedunculated Polyp Diagnosed as Inverted Colonic Diverticula. AB - We present a unique case of an inverted diverticulum mimicking a large adenomatous pedunculated polyp. Inverted colonic diverticula (ICD) are typically a few millimeters in size and may resemble a polyp. Our finding was unusual based on its size, location, and appearance. Incorrect management of ICD can lead to serious complications, therefore, endoscopists should be aware of this occurrence and approach suspicious lesions with caution. PMID- 28848769 TI - Pseudo Symmer's Pipe-Stem Fibrosis in Idiopathic Noncirrhotic Portal Hypertension Associated with POEMS Syndrome. PMID- 28848770 TI - Multiple Myeloma Causing Gastric Polyposis. PMID- 28848771 TI - Esophageal Stricture Resulting from Systemic Chemotherapy for Solid Malignancy. AB - Although dysphagia in patients treated for malignancy is usually related to reflux esophagitis, infectious esophagitis, malignant infiltration, or as a complication of radiation therapy, acute esophageal stricture resulting from chemotherapy is very rare. Only 2 prior cases have been described in the treatment of an adult patient with malignancy. We present a unique case of isolated chemotherapy-induced esophageal stricture in a patient receiving treatment for metastatic testicular seminoma without prior history of gastroesophageal reflux disease, caustic ingestion, or other risk factors for esophageal stricture formation. PMID- 28848772 TI - AA Amylodisis Associated with Jugular Paraganglioma as a Rare Cause of Chronic Diarrhea. AB - We report a case of a 64-year-old man with chronic diarrhea who was diagnosed of a systemic reactive (AA) amyloidosis associated with a jugular paraganglioma. This neoplasm was diagnosed 30 years previously and it was not removed after extensive evaluation by a multidisciplinary team. Chronic inflammatory diseases are the major cause of AA amyloidosis. However, benign tumors, such as jugular paragangliomas, are considered to be one of the tumors that can result in AA amyloidosis. PMID- 28848773 TI - A New Publisher, A New Horizon. PMID- 28848774 TI - Bowel Prep: Nurses Do It Better. PMID- 28848775 TI - Clinical Management after Endoscopic Submucosal Dissection for Early Gastric Cancer: Sticking to the Gastroenterologist May Be the Best Option! PMID- 28848776 TI - Evaluation and Management of Gastric Superficial Neoplastic Lesions. AB - Gastric cancer is one of the most common and lethal cancers in the world. In Portugal, it is a major health problem presenting one of the highest incidence rates among European countries. In most Western countries, gastric cancer is generally diagnosed in advanced stages. Nevertheless, with the widespread use of upper endoscopy, gastric superficial neoplastic lesions are being increasingly recognized and diagnosed. However, there are no clear recommendations regarding who should be screened for its presence and only recently guidelines concerning the evaluation and management of these lesions were published. In this review, we summarize the current scientific evidence regarding diagnosis and management of gastric superficial neoplastic lesions. Topics like screening, diagnosis, endoscopic evaluation, management, treatment, pathologic evaluation and follow-up of patients with these lesions are covered and areas of future research are discussed. Whenever possible, evidence-based recommendations are made, and on the other cases expert opinion is presented. PMID- 28848777 TI - Impact of Personalised Patient Education on Bowel Preparation for Colonoscopy: Prospective Randomised Controlled Trial. AB - BACKGROUND: Adequate bowel preparation is one of the most important quality factors of colonoscopy. Our goal was to analyse the impact of personalised patient education on bowel cleansing preparation for colonoscopy. METHODS: We performed a single-blinded, single-centre, prospective randomised trial, where patients were either allocated to a control group, where they received some predefined oral and written information on bowel preparation from the gastroenterologist, or to an intervention group, where patients received additional personalised instructions for bowel preparation and diet from a nurse. The primary outcome was the quality of bowel preparation (Aronchick scale). RESULTS: A total of 229 patients were randomised; 113 to the control group and 116 to the intervention group. In intention-to-treat analysis, bowel preparation was adequate in 62% (95% CI 53-70) of colonoscopies in the intervention group and in 35% (95% CI 26-44) of colonoscopies in the control group (p < 0.001). The absolute risk reduction was 27%, the relative risk was 1.77, and the number needed to treat was 4. Subgroup analysis showed a significant impact of personalised education in patients under 65 years (67 vs. 35%; p < 0.001), in males (60 vs. 33%; p = 0.003), in those with higher educational levels (68 vs. 37%; p = 0.002), in those living in urban areas (68 vs. 40%; p = 0.004), and in those with previous colonoscopy (68 vs. 40%; p = 0.001). Risk factors for inadequate preparation were: male gender (OR = 2.1; 95% CI 1.1-4.1), diabetes mellitus (OR = 3.8; 95% CI 1.2-11.6), chronic constipation (OR = 3.7; 95% CI 1.7 8.2), absence of prior abdominal surgery (OR = 2.2; 95% CI 1.2-4.1), and being in the control group (OR = 2.5; 95% CI 1.4-4.4). CONCLUSIONS: Personalised patient education on bowel preparation for colonoscopy significantly improved the quality of bowel preparation. PMID- 28848778 TI - Acute Liver Failure due to Trazodone and Diazepam. AB - Most antidepressant agents have the potential to cause liver injury, even at therapeutic doses. Nevertheless, drug-induced liver injury (DILI) from antidepressant agents is a rare event. There is no way to prevent idiopathic DILI, but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent. We describe a rare case of a 63-year-old man presenting with acute liver failure after 3 months of trazodone and diazepam administration at normal therapeutic doses, requiring liver transplantation. This report should increase physicians' awareness of this complication and call attention to the regular monitoring of liver tests in patients taking trazodone, in order to prevent life-threatening complications. PMID- 28848779 TI - Superior Mesenteric Artery Syndrome: Weight Loss Can Be a Problem, Weight Gain Can Be a Solution. AB - INTRODUCTION: Superior mesenteric artery syndrome (SMAS) is a rare acquired disorder, which in the present case had an acute and unusual way of presentation. CASE REPORT: We present a 17-year-old female with nausea, vomiting, and intense epigastric pain. In the previous 6 months, she had lost 42% of her body weight. The echography showed a distended stomach that reached the pelvis, and the nasogastric tube that was placed drained 2,000 mL. A computed tomography scan confirmed the SMAS diagnosis. She started a hypercaloric fractionated meal diet, prokinetics, and postural measures. After the 1-year follow-up the patient is asymptomatic. CONCLUSION: This acute presentation is rare but life-threatening due to the possibility of gastric rupture. Medical management is possible in the majority of cases, and surgery is needed only in the refractory ones. PMID- 28848780 TI - Spleen Endoscopy: A sui generis Diagnosis of Colon Cancer. PMID- 28848781 TI - Wilkie Syndrome behind Crohn Disease? Superior Mesenteric Artery Syndrome Mimicking and Complicating Crohn Disease of the Upper Gastrointestinal Tract. PMID- 28848782 TI - Adenoma Detection Rate: Quality Indicators for Colonoscopy. PMID- 28848783 TI - Health-Related Quality of Life in Chronic Hepatitis C. PMID- 28848784 TI - Baveno VI Recommendation on Avoidance of Screening Endoscopy in Cirrhotic Patients: Not Quite There Yet! PMID- 28848785 TI - Adenoma Detection Rate: I Will Show You Mine if You Show Me Yours. AB - BACKGROUND: Colorectal cancer (CRC) is the first cause of cancer-related mortality in Portugal. CRC screening reduces disease-specific mortality. Colonoscopy is currently the preferred method for screening as it may contribute to the reduction of CRC incidence. This beneficial effect is strongly associated with the adenoma detection rate (ADR). AIM: Our aim was to evaluate the quality of colonoscopy at our unit by measuring the currently accepted quality parameters and publish them as benchmarking indicators. METHODS: From 5,860 colonoscopies, 654 screening procedures (with and without previous fecal occult blood testing) were analyzed. RESULTS: The mean age of the patients was 66.4 +/- 7.8 years, and the gender distribution was 1:1. The overall ADR was 36% (95% confidence interval [CI] 32-39), the mean number of adenomas per colonoscopy was 0.66 (95% CI 0.56 0.77), and the sessile serrate lesion detection rate was 1% (95% CI 0-2). The bowel preparation was rated as adequate in 496 (76%) patients. The adjusted cecal intubation rate (CIR) was 93.7% (95% CI 91.7-95.8). Most colonoscopies were performed under monitored anesthesia care (53%), and 35% were unsedated. The use of sedation (propofol or midazolam based) was associated with a higher CIR with an odds ratio of 3.60 (95% CI 2.02-6.40, p < 0.001). CONCLUSION: Our data show an above-standard ADR. The frequency of poor bowel preparation and the low sessile serrated lesion detection rate were acknowledged, and actions were implemented to improve both indicators. Quality auditing in colonoscopy should be compulsory, and while many units may do so internally, this is the first national report from a high-throughput endoscopy unit. PMID- 28848787 TI - Baveno VI Recommendation on Avoidance of Screening Endoscopy in Cirrhotic Patients: Are We There Yet? AB - INTRODUCTION: Recent studies assessed the predictive value of liver transient elastography, combined or not with platelet count, for the presence of esophageal varices in patients with liver cirrhosis, and multiple cutoffs have been proposed. The Baveno VI consensus states that patients with compensated advanced chronic liver disease, liver stiffness <20 kPa, and a platelet count >150,000 have a very low risk of having varices requiring treatment and can avoid screening endoscopy. We aimed to validate this recommendation in a cohort of cirrhotic patients. METHODS: Retrospective analysis of all patients evaluated at the Gastroenterology Department (Centro Hospitalar de Lisboa Central) between September 2009 and October 2015 with a liver stiffness (FibroScan(r)) compatible with liver cirrhosis as well as upper endoscopy and blood tests within 12 months from elastography. Patients on propranolol >=80 mg/day or carvedilol >=12.5 mg/day, as well as those with previous variceal bleeding, variceal endoscopic treatments, or cirrhosis decompensations were excluded. We validated the new Baveno VI recommendation and explored alternative cutoffs. RESULTS: Ninety-seven patients were analyzed, 76.3% (74/97) male, mean age 54.3 +/- 11.2 years. Most patients (55.7%) had no varices and 14.4% had varices requiring treatment. Most patients (78.4%) had cirrhosis related to chronic hepatitis C. If the new Baveno VI recommendation had been applied to this cohort, upper endoscopy would have been avoided in 11.3% (11/97) of patients, none of them with esophageal varices requiring treatment: specificity 100%, sensitivity 13.3%, positive predictive value 100%, and negative predictive value 16.3% for absence of varices requiring treatment. If screening endoscopy had been avoided in those patients with liver stiffness <30 kPa and platelet count >=120,000, endoscopy would have been avoided in 27.8% (27/97) of patients, none of whom with esophageal varices requiring treatment: specificity 100%, sensitivity 32.5%, positive predictive value 100%, and negative predictive value 20% for absence of varices requiring treatment. CONCLUSIONS: The new Baveno VI criteria identified compensated cirrhotic patients without varices requiring treatment in whom screening endoscopy could have been avoided safely. Further studies are needed to confirm these findings and potentially explore more ambitious but still safe cutoffs for those criteria. PMID- 28848786 TI - Health-Related Quality of Life in Portuguese Patients with Chronic Hepatitis C. AB - INTRODUCTION: Chronic hepatitis C virus (HCV) infection impacts multiple health and psychosocial dimensions and encompasses a significant overall burden as it progresses to advanced stages of hepatic disease. AIMS: To evaluate for the first time health-related quality of life (HRQoL) of a subset of Portuguese adult patients with chronic hepatitis C using the Portuguese versions of generic, Short Form 12 Health Survey (SF-12v2), and disease-specific, Chronic Liver Disease Questionnaire (CLDQ), instruments; to assess psychometric properties of CLDQ, Portuguese version. METHODS: HRQoL was evaluated in Portuguese adult outpatients with chronic hepatitis C attending the Hepatology Clinic at Centro Hospitalar do Porto, using SF-12v2 and CLDQ. This transversal study was conducted between April and October 2015. RESULTS: Eighty outpatients with chronic hepatitis C were enrolled, with mean age 57 years (standard deviation 11), 67.5% male, all Caucasian, 76.3% diagnosed for >10 years, 66.3% with C virus genotype 1, 65.0% with hepatic cirrhosis (94.2% of which Child-Pugh A), and 46.3% under current antiviral treatment. For CLDQ internal consistency, Cronbach's alpha was 0.88; for construct validity, correlations ranged from 0.36 to 0.80 (p < 0.01). Mean CLDQ scores ranged from 4.25 (Worry) to 5.78 (Abdominal Symptoms). Lower scores were observed for Worry, Fatigue, and Emotional Function domains. Statistically significant differences were found in median values of Worry (CLDQ) and Role Emotional (SF-12) (p < 0.05) for "current antiviral treatment," with higher scores for patients that concluded therapy. CONCLUSION: HRQoL was negatively affected in several domains in Portuguese patients with chronic hepatitis C; oral antiviral treatment correlated with better quality of life, assuring its benefits on this population; the CLDQ Portuguese version revealed adequate psychometric properties, and was useful in assessing quality of life in Portuguese HCV patients. PMID- 28848788 TI - Paraduodenal Pancreatitis: Three Cases with Different Therapeutic Approaches. AB - BACKGROUND: Paraduodenal pancreatitis is a rare cause of chronic abdominal pain characterized by an inflammatory process and scarring in the groove area between the pancreatic head and the duodenal wall. Besides abdominal pain, symptoms such as vomiting and weight loss are common. Currently, advances in radiological and endoscopic diagnostic methods allow it to be identified without histological confirmation, although the differentiation from pancreatic adenocarcinoma could be challenging in some cases. Many therapeutic options are available nowadays including pharmacological, endoscopic, or surgical treatment. METHODS: We report 3 cases of paraduodenal pancreatitis that had different therapeutic approaches. RESULTS AND CONCLUSION: They show that this pathology should be taken into account in the differential diagnosis of pancreatic masses with duodenal infiltration, and that its management should be individualized and judicious. PMID- 28848789 TI - Dieulafoy's Lesion: The Role of Endoscopic Ultrasonography as a Roadmap. PMID- 28848790 TI - Endoscopic Management of Acute Bleeding from an Ectopic Duodenal Varix. PMID- 28848791 TI - Blue Rubber Bleb Nevus Syndrome: A Delayed Diagnosis. PMID- 28848792 TI - The European Section and Board of Gastroenterology and Hepatology: What's New? PMID- 28848793 TI - Is CA 19-9 of Any Help in the Management of Cholangiocarcinoma? PMID- 28848794 TI - Palliative Stenting for Malignant Large Bowel Obstruction: Stents for All? PMID- 28848795 TI - CA 19-9 as a Marker of Survival and a Predictor of Metastization in Cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma is the second most frequent primitive liver malignancy and is responsible for 3% of the malignant gastrointestinal neoplasms. The aims of this study were to determine the association of serum levels of CA 19 9 at diagnosis with other clinical data and serum liver function tests and to identify possible factors that influence the survival rates during follow-up. METHODS: Retrospective observational study of 89 patients with a diagnosis of cholangiocarcinoma followed at the Department of Gastroenterology during 5 years. Statistical analyses were performed using SPSS version 20.0. RESULTS: Patients were followed up for a median time of 127 days (IQR: 48-564), and the median age at diagnosis was 71.0 years (IQR: 62.0-77.5). The median survival rate was 14.0 months (IQR: 4.3-23.7), and the mortality rate was 79%. Patients with CA 19-9 levels >=103 U/L had lower albumin levels and higher levels of alanine aminotransferase and gamma-glutamyltransferase. CA 19-9 levels >=103 U/L were associated with a higher probability of metastization (p = 0.001) and lower rates of treatment with curative intent (p = 0.024). In a multivariate analysis, CA 19 9 levels <103 U/L and surgery were independent predictors of survival. CONCLUSION: Predictive factors for overall survival were identified, namely presence of metastasis, surgery, and chemotherapy. CA 19-9 levels >=103 U/L were predictive factors for survival and metastization. PMID- 28848796 TI - Predictors of Complications and Mortality in Patients with Self-Expanding Metallic Stents for the Palliation of Malignant Colonic Obstruction. AB - INTRODUCTION: Self-expanding metallic stents (SEMS) for palliative purposes in malignant colonic obstruction are an alternative to surgery that has gained popularity over time. METHODS: We performed a retrospective study of patients submitted to SEMS for palliation of obstructing malignant colorectal cancer from 2005 to 2015 to evaluate predictive clinical factors for complications and mortality. RESULTS: Forty-five patients with high rates of technical and clinical success were included (97.8 and 95.6%, respectively), with complications occurring in 17.8% (8.9% perforations, 4.4% obstructions, and 4.4% migrations). The length of the stenosis was superior in patients with complications (p = 0.01); 11.1% of patients had a re-intervention (2.2% surgery and 8.9% placement of another SEMS). Relief of obstruction without intervention was maintained until death in 77.8% of patients and in 81.4% of patients who had immediate clinical success. The mortality rate was 37.2% at 30 days, 56.5% at 60 days, and 87.5% at 1 year. There were no predictors of survival identified, including age, sex, tumor stage, metastasis, or complications of the procedure. DISCUSSION AND CONCLUSIONS: In this study, SEMS placement was associated with a high rate of technical and clinical success and a low rate of complications, being an option to palliate patients with obstructive neoplasia. The length of the stenosis was associated with a greater risk of complications. The majority of stent-related complications can be managed successfully without surgery. PMID- 28848797 TI - Acute Pancreatitis Etiology Investigation: A Workup Algorithm Proposal. AB - BACKGROUND: Acute pancreatitis represents a significant number of hospital admissions. Most of the patients are admitted in an acute setting. Early identification of its etiology is an essential step toward the rational approach, both for its implications in the immediate therapy and the prevention of recurrence. Although often obvious, the etiological workup of acute pancreatitis can be challenging. CONCLUSION: There are several studies emphasizing the multiple etiologies underlying acute pancreatitis but lacking structured diagnostic workups to allow a rational and organized study. The main goal of this work is to develop an algorithm proposal, which aims to serve as a guide for the investigation of the etiology of acute pancreatitis based on a review of already published literature, adjusted to the reality of our hospital and the available resources. PMID- 28848798 TI - Multisystemic Sarcoidosis with Early Gastrointestinal Symptoms. AB - Sarcoidosis involving the digestive tract is very rare and requires a strict differential diagnosis with other systemic granulomatous diseases. We present a case of multisystemic granulomatosis involving the stomach and colon, causing initial digestive symptoms. Pulmonary nodules, pleural effusion, ascites, hepatomegaly, splenomegaly, and mesenteric as well as retroperitoneal and axillary lymphadenopathy were subsequently identified. The reticulo-endothelial expression, the hypercalcemia and, above all, a rapid and complete resolution after corticosteroids supported the hypothesis of sarcoidosis involving the digestive tract. A brief review of digestive tract involvement in sarcoidosis and of the distinctive features of sarcoidosis with gastrointestinal involvement and Crohn's disease with a rare form of pleuro-pulmonary involvement is presented. PMID- 28848799 TI - Solitary Rectal Ulcer Syndrome: A Paediatric Case Report. AB - INTRODUCTION: Solitary rectal ulcer syndrome (SRUS) is an uncommon benign rectal disease. Mostly young adults are affected, and it is rare in paediatric populations. CLINICAL CASE: We present a 12-year-old girl with a 6-month history of tenesmus, frequent defaecation, and bloody stools with mucus. There was no previous history of constipation or other symptoms. At the first visit, physical examination and routine laboratory test results were normal. A stool examination for bacteria and parasites was negative. Colonoscopy revealed a single ulcer in the distal rectum 6 cm from the anal margin. SRUS was confirmed by biopsy. Despite conservative measures, the symptoms persisted. A defaecation proctography showed a small rectocele with no rectal mucosal prolapse. Because of its proximity to the anal sphincter, no surgical intervention was performed. CONCLUSION: The present case illustrates how difficult the management of SRUS is. Multicentre studies are needed to establish treatment protocols for children. PMID- 28848800 TI - Fistulization of J-PEG Jejunal Tube into the Colon in a Patient Treated with Duodopa(r) Infusion: A Case Report. AB - The continuous delivery of a levodopa/carbidopa gel suspension (Duodopa(r)) into the small bowel through a jejunal tube inserted via percutaneous endoscopic gastrostomy represents a new treatment method in advanced Parkinson disease. Some severe device-related complications have been described in the last few years. Some of them are associated with phytobezoar formation at the pigtail of the catheter. We present the case of a Parkinson disease patient treated with the Duodopa infusion system complicated by jejunal tube fistulization into the colon. We suggest a possible treatment strategy for this complication, which has not been described in the literature to date. PMID- 28848801 TI - Endoscopic Removal of a Gastric Band Completely Migrated into the Gastric Cavity. PMID- 28848802 TI - Sporadic Jejunal Lateral Spreading Tumor: A Rare Cause of Recurrent Jejunojejunal Intussusception. PMID- 28848803 TI - Fortification of Ogi with Whey Increases Essential Amino Acids Content of Fortified Product. AB - The inability of humans to synthesize essential amino acids (EAA) necessitates the need to increase the levels of these nutrient molecules in certain foods in which they are deficient. Maize ogi is a typical food product for both infants and adults in Africa, but with poor EAA content. This study therefore sought to assess the possibility of increasing the EAA content in maize ogi by processing it with cheese whey instead of water. Maize ogi and whey-fortified ogi were prepared by the usual procedure of grain soaking, milling, and drying. Samples from both treatments were subjected to proximate composition and amino acid profile analyses using Waters 616/626 LC (HPLC) instrument. L-lysine, L trytophan, and L-methionine contents in maize ogi remarkably increased from 0.52, 0.15, and 0.90 mg/100 gm sample, respectively, to 0.90, 240, and 1.320 mg/100 gm sample in whey-fortified ogi. There were also significant increases in other EAA contents of whey-fortified ogi relative to its counterpart (normal maize ogi). The sum increase in EAA contents (9,405 mg) correlates with the increase in protein (1 gm) per gram sample. This study demonstrates that cheese whey increases EAA content in maize ogi and suggests that whey-fortified maize ogi may be a preferred alternative to water processed maize ogi. PMID- 28848804 TI - Fractionation of sulfur (S) in beech (Fagus sylvatica) forest soils in relation to distance from the stem base as useful tool for modeling S biogeochemistry. AB - The investigation of the fractionation of S compounds in forest soils is a powerful tool for interpreting S dynamics and S biogeochemistry in forest ecosystems. Beech stands on high pH (nutrient-rich) sites on Flysch and on low pH (nutrient-poor) sites on Molasse were selected for testing the influence of stemflow, which represents a high input of water and dissolved elements to the soil, on spatial patterns of sulfur (S) fractions. Soil cores were taken at six distances from a beech stem per site at 55 cm uphill and at 27, 55, 100, 150 and 300 cm downhill from the stem. The cores were divided into the mineral soil horizons 0-3, 3-10, 10-20, 20-30 and 30-50 cm. Soil samples were characterized for pH, Corg, pedogenic Al and Fe oxides and S fractions. Sequential extraction by NH4Cl, NH4H2PO4 and HCl yielded readily available sulfate-S (RAS), adsorbed sulfate-S (AS) and HCl-soluble sulfate-S (HCS). Organic sulfur (OS) was estimated as the difference between total sulfur (ToS) and inorganic sulfur (RAS + AS + HCS). Organic sulfur was further divided into ester sulfate-S (ES, HI-reduction) and carbon bonded sulfur (CS). On Flysch, RAS represented 3-6%, AS 2-12%, HCS 0 8% and OS 81-95% of ToS. On Molasse, RAS amounted 1-6%, AS 1-60%, HCS 0-8% and OS 37-95% of ToS. Spatial S distribution patterns with respect to the distance from the tree stem base could be clearly observed at all investigated sites. The presented data is a contribution to current reports on negative input-output S budgets of forest watersheds, suggesting that mineralization of OS on nutrient rich soils and desorption of historic AS on nutrient-poor soils are the dominant S sources, which have to be considered in future modeling of sulfur. PMID- 28848805 TI - The Launch of a New COPD Journal. PMID- 28848806 TI - The COPD Foundation: Celebrating a Decade of Progress and Looking Ahead to a Cure. AB - Chronic obstructive pulmonary disease (COPD) affects 15-25 million Americans and over 300 million people around the world. The COPD Foundation is a global organization whose mission is to prevent and cure COPD and to improve the lives of all people affected by it. The year 2014 marks the 10th anniversary of the COPD Foundation. The Foundation works to accomplish its mission through a unique partnership between patients, patient families, health care providers, investigators, academic institutions, government agencies and industry. This partnership has led to real progress in awareness, advocacy, education, and research, but much more needs to be done. PMID- 28848807 TI - Progress in Characterizing Patient-Centered Outcomes in COPD, 2004-2014. PMID- 28848808 TI - Clinical Characteristics of Patients With Biomass Smoke-Associated COPD and Chronic Bronchitis, 2004-2014. AB - Individuals with chronic obstructive pulmonary disease (COPD) associated with biomass smoke inhalation tend to be women born in rural areas with lifelong exposure to open fires while cooking, but can also include persons with prenatal and childhood exposure. Compared with individuals with COPD due to tobacco smoking, individuals exposed to biomass smoke uncommonly have severe airflow obstruction, low diffusing capacity of the lung for carbon monoxide (DLCO) or emphysema in high-resolution computed tomography (HRCT) but cough, phlegm and airway thickening and air trapping are very common. Autopsies of patients with COPD from biomass smoke exposure show increased pulmonary artery small vessel intimal thickening which may explain pulmonary hypertension, in addition to emphysema and airway disease. Research on similarities and differences in lung damage produced by exposure to biomass fuel smoke while cooking vs. smoking tobacco may provide new insights on COPD. As a public health problem, COPD caused by inhalation of smoke from burning solid fuel is as relevant as COPD caused by smoking tobacco but mainly affects women and children from disadvantaged areas and countries and requires an organized effort for its control. Improved vented biomass stoves are currently the most feasible intervention, but even more efficient stoves are necessary to reduce the biomass smoke exposure and reduce incidence of COPD among this population. PMID- 28848809 TI - Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future. AB - Chronic obstructive pulmonary disease (COPD) affects over 10 million Americans.1 This complex disorder demonstrates many different presentations in a wide variety of patients, and results from a combination of environmental exposures and genetic risk factors. Smoking alone does not result in COPD: not all smokers develop COPD and lung function decline among smokers is highly variable. There is growing evidence for genetic risk factors for COPD: early familial aggregation and linkage analysis studies strongly suggested genetic contributions to COPD, and recent genome-wide association studies have identified several genomic regions that are clearly related to COPD susceptibility. However, despite recent advances in COPD genetics, much of the heritability of COPD remains unexplained, and functional studies are only beginning to elucidate a role for the genetic associations that have been identified. Despite this, the future is bright for understanding the genetics of COPD. Improvements in COPD phenotyping, collaborations among COPD study cohorts, and novel integrative approaches to identifying genetic markers all promise to unravel much of this missing heritability and ultimately lead to improvements in our understanding of COPD susceptibility and treatment. PMID- 28848810 TI - The COPD Pipeline, 2004-2014. PMID- 28848812 TI - A Decade of National Heart, Lung, and Blood Institute Programs Supporting COPD Research and Education . AB - The past decade of research in chronic obstructive pulmonary disease (COPD) has seen a new age of understanding both pathogenic mechanisms and clinical manifestations of the disease. The National Heart, Lung, and Blood Institute (NHLBI) has helped guide this progress with a series of initiatives to stimulate COPD research in various ways. These initiatives were designed to promote a precision medicine approach to treating COPD, one that takes advantage of targeting particular molecular pathways and the individual pathobiologies of the diversity of COPD patients. This review describes the strategic objectives of these initiatives, as well as some of their observed and anticipated outcomes. In addition, we address parallel steps NHLBI has taken to promote COPD awareness among the public. As we look toward the immediate future of COPD research and education, we see a time of great progress in terms of understanding and treatment. Furthermore, while this remains a debilitating and disturbingly prevalent disease, as NHLBI looks even farther ahead, we envision emerging efforts toward COPD prevention. PMID- 28848811 TI - Defining COPD-Related Comorbidities, 2004-2014. AB - Chronic obstructive pulmonary disease (COPD) is a disease of aging in combination with genetic, environmental, and behavioral risk factors. Aging and many of these risk factors are shared with other diseases, and, as a result, it is not surprising that patients with COPD often have coexistent diseases. This review of COPD comorbidities uses a framework in which coexistent diseases are considered important comorbidities if they are more frequent, have more severe consequences, influence the progression and outcomes of COPD, or are clustered together into proposed phenotypes, supplemented by a framework in which certain comorbidities are expected to share specific pathogenic mechanisms. This review explores classic COPD comorbidities such as cardiovascular disease, cachexia and sleep apnea, but also looks at more recently described comorbidities, such as gastroesophageal reflux, osteoporosis and depression/anxiety. PMID- 28848813 TI - Progress in Imaging COPD, 2004 - 2014. AB - Computed tomography (CT) has contributed substantially to our understanding of COPD over the past decade. Visual and quantitative assessments of CT in COPD are complementary. Visual assessment should provide assessment of centrilobular, panlobular and paraseptal emphysema, airway wall thickening, bronchiectasis, findings of respiratory bronchiolitis, and enlargement of the pulmonary artery. Quantitative CT permits evaluation of severity of emphysema, airway wall thickening, and expiratory air trapping, and is now being used for longitudinal evaluation of the progression of COPD. Innovative techniques are being developed to use CT to characterize the pattern of emphysema and smoking- related respiratory bronchiolitis. Magnetic resonance imaging (MRI) and positron emission tomography PET-CT are useful research tools in the evaluation of COPD. PMID- 28848814 TI - The COPD Foundation Pocket Consultant Guide. AB - The COPD Foundation Guide to COPD Diagnosis and Treatment is designed to provide practical advice for the health care provider. Available as a hard copy, online and as a mobile device application (app), the Guide serves as an accessible tool for clinicians. To date, over 400,000 cards have been distributed to health care providers nationwide at no charge. The Guide is updated as necessary and suggestions from the COPD physician and health care provider community are integrated into updates. PMID- 28848815 TI - The Association Between Dietary Intake and Phenotypical Characteristics of COPD in the ECLIPSE Cohort. AB - Background: Diet is a potentially modifiable risk factor in the development and progression of many diseases, and there is evidence that diet plays a role in COPD. Objective: Evaluate the relationship between dietary intake and clinical characteristics of COPD in a large and well-characterized population of COPD patients and controls who were part of the ECLIPSE study. Methods: Limited diet records were available from 2,167 participants at 8 time points over a 3-year period. Participants reported the amount they had consumed over the last 24 hours for 8 food categories. Intake of each food group was handled as a dichotomous variable (Yes/last 24 hours at any of the 8 follow-up points vs. No at all 8 points). These 2 groups were then compared using clinical outcome measures at the last available follow-up that included lung function, emphysema, 6-minute walk, St. George's Respiratory Questionaire (SGRQ) scores, the change in these scores over a 3-year period, and inflammatory biomarkers. Multivariate models for each food group and each outcome measure were run to adjust for confounding factors of age, sex, body mass index (BMI), and smoking. Results: Participants who demonstrated recent consumption of foods associated with a healthful diet, including fish, fruit, tea, and dairy products, had greater lung function measures and less decline over time, less emphysema and emphysema progression, greater 6-minute walk and SGRQ scores, and lower levels of certain inflammatory markers. Increasing the number of diet record time points that were included in the analysis improved ability to detect significant associations. Conclusion: Diet as a possible modifiable risk factor in COPD continues to warrant investigation. PMID- 28848817 TI - Patent Foramen Ovale in COPD and Hypoxia: Innocent Bystander or Novel Therapeutic Target? PMID- 28848816 TI - The Effect of a Short Duration, High Intensity Exercise Intervention on Gait Biomechanics in Patients With COPD: Findings From a Pilot Study. AB - Previous work has shown that patients with chronic obstructive pulmonary disease (COPD) demonstrate changes in their gait biomechanics as compared to controls. This pilot study was designed to explore the possibility that biomechanical alterations present in COPD patients might be amenable to treatment by exercise training of skeletal muscle. This study investigated the effect of a 6-week exercise intervention on gait biomechanics in patients with COPD under both a rest and a non-rested condition. Seven patients with COPD underwent a supervised cardio-respiratory and strength training protocol 2-3 times per week for 6-weeks for a total of 16-sessions. Spatiotemporal, kinematic and kinetic gait variables were collected prior to and post intervention. All patients demonstrated significant improvements in strength following the intervention. The knee joint biomechanics demonstrated a significant main effect for intervention and for condition. Step width demonstrated a significant interaction as it decreased from pre- to post-intervention under the rest condition and increased under the non rested condition. It does appear that being pushed (non-rested) has a strong influence at the knee joint. The quadriceps muscles, the primary knee extensors, have been shown to demonstrate muscular abnormalities in patients with COPD and the intervention may have influenced gait patterns through an effect on this skeletal muscle structure and function. Additionally, the intervention influenced step width closer to a more healthy value. Patients with COPD are more likely to fall and step width is a risk factor for falling suggesting the intervention may address fall risk. Whether a longer duration intervention would have more profound effects remains to be tested. PMID- 28848818 TI - Physical Activity Monitoring in Patients with Chronic Obstructive Pulmonary Disease. AB - Reduced physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and mortality (e.g. exacerbations) and eventually leads to disability, depression, and social and physical isolation. Measuring PA in this population is important to accurately characterize COPD and to help clinicians during a baseline evaluation and patient follow-up. Also, it may help increase adherence to PA programs. There are reliable objective and subjective methods available to measure PA. Recently, several new monitors have been developed that have improved accuracy of such measurements. Because these devices provide real-time feedback, they may help to improve participant self-motivation strategies and reinforce daily lifestyle modifications, one of the main goals in COPD management. This review focuses on describing available instruments to measure PA, specifically in patients with COPD. The reliability, validity, advantages, limitations, and clinical applications of questionnaires, pedometers, and accelerometers are discussed. Finally, based on current published literature, we propose recommendations about which methods may be most useful in different research or clinical settings. PMID- 28848821 TI - Saving Time for Patients with Moderate to Severe COPD: Endurance Test Speed Set Using Usual and Fast Walk Speeds. AB - Background: For assessing the effects of interventions on exercise tolerance, the tolerable duration (tlimit) of a high-intensity constant-speed endurance test is recommended. The test intensity is determined by the test speed (stest) which should be individualized to target a tlimit of 3 to 15 minutes. We determined the accuracy of setting the stest to achieve a targeted tlimit of 3 to 15 minutes using the participant's easily measured and non-fatiguing usual (susual) and fast (sfast) walk speeds. Methods: Participants with COPD were asked to walk at their usual and fast walk speeds to establish their susual and sfast. This required that they walk for less than 1 minute. The individualized stest was calculated from a previously developed equation (0.57 x [sfast - susual]) + susual. Participants then completed a constant-speed endurance test, walking at this calculated stest to intolerance, to determine if the resultant tlimit occurred within 3 to 15 minutes. Results: Twenty-nine participants (forced expiratory volume in 1 second [FEV1] standard deviation [SD ]=43 [25] %predicted; FEV1 to forced vital capacity [FVC]ratio= 41 [13]%; susual = 57.3 [10.4] meters per minute (m.min-1 ); sfast = 71.7 [10.7] m.min-1) completed the study. During testing, 24 (83%) participants used supplemental oxygen and 16 (55%) used a walking aid. The derived stest was 65.6 [10.3] m.min-1 with the observed tlimit of 6.0 [5.0] minute. Twenty-four of 29 (83 %) endurance tests were within 3 to 15 minutes. Conclusion: Using the usual and fast walk speeds provides a simple, quick, inexpensive method for clinicians to set an acceptable endurance walk speed. PMID- 28848820 TI - Significance of Patent Foramen Ovale in Patients with GOLD Stage II Chronic Obstructive Pulmonary Disease (COPD). AB - Background: Patent foramen ovale (PFO) is a common finding in adults. A PFO is associated with right to left shunting but its importance in the aetiology of hypoxia in early COPD remains uncertain, although it has not proved possible to demonstrate a role for PFOs in the aetiology of hypoxia in patients with Global Initiative for chronic Obstructive Lung Disease (GOLD) stage III/IV disease. We compared the characteristics of GOLD stage II patients with or without a PFO and assessed its impact on exercise performance. Methods: In 22 GOLD stage II COPD patients we measured exercise performance, arterial oxygen tension and lung function and used contrast transcranial Doppler ultrasonography (TCD) to assess the presence of a PFO. Patients (n=20) underwent TCD measurements during incremental cycle ergometry with respiratory pressures measured using an esophageal balloon catheter (n=13). Results:Twelve individuals (54%) had a PFO. Patients with a PFO were more hypoxic; mean(SD) partial pressure of oxygen in arterial blood (PaO2)10.2(1.1) kilopascals (kPa) vs. 11.7(0.9)kPa (p<0.01), but the presence of a PFO was not associated with reduced exercise performance either on cycle ergometry or a 6 Minute Walk Test (6MWT). A strong relationship was noted between the esophageal pressure swing (PSwingEs) and the degree of shunting observed during exercise (r=0.7; p<0.001). Conclusions:The presence of a PFO in GOLD stage II COPD patients does not appear to influence exercise performance despite increased right-to-left shunting. PMID- 28848819 TI - Prevention of Exacerbations in Chronic Obstructive Pulmonary Disease: Knowns and Unknowns. AB - The 2011 recommendations of the Global initiative for chronic Obstructive Lung Disease (GOLD) constituted a major paradigm shift in COPD management since they set 2 major goals for the assessment and management of patients: (1) the reduction of their current level of symptoms (i.e., treat the patient today); and (2) the reduction of their risk of exacerbations (i.e., prevent them tomorrow). Exacerbations are not only an important clinical endpoint in patients with COPD, but they are also a risk factor themselves for additional adverse outcomes since they have been shown to increase the risk for mortality, to accelerate the decline in pulmonary function, and to decrease health status and quality of life. Despite their importance, many unanswered questions related to exacerbations remain. The purpose of this review is to discuss: (1)knowns and unknowns in our current understanding of exacerbations, (2) what known factors increase their risk, and (3) how to best prevent them. PMID- 28848822 TI - Longitudinal Computed Tomography and Magnetic Resonance Imaging of COPD: Thoracic Imaging Network of Canada (TINCan) Study Objectives. AB - Although the human and societal burden and cost of COPD is staggering, there are few clinical tools that provide earlier diagnoses or a means to regionally monitor disease in a way that might lead to improved therapies and outcomes. In acknowledgement of the current gaps in COPD therapy, the objective of the Thoracic Imaging Network of Canada (TINCan) is to improve COPD patient phenotyping through imaging, to provide methods and imaging-based intermediate endpoints for the development of new treatments, and to evaluate disease progression and patient-based outcomes in COPD patients and those at risk of COPD. Here we summarize and outline the TINCan study protocol and describe our objectives. TINCan is a prospective study that aims to identify and quantify novel COPD phenotypes from thoracic computed tomography (CT) and thoracic hyperpolarized noble gas magnetic resonance imaging (MRI) in 200 ex-smokers, 50 years of age or greater, including asymptomatic ex-smokers with normal pulmonary function and Global initiative for chronic Obstructive Lung Disease (GOLD) Unclassified (U) , and GOLD stages I-IV patients. Baseline and 2-year follow-up measurements will be acquired using spirometry, plethysmography, diffusing capacity of the lung for carbon monoxide (DLCO), St. George's Respiratory Questionnaire (SGRQ), 6-minute walk test (6MWT), thoracic CT and hyperpolarized helium-3 (3He) and xenon 129 (129Xe) MRI. TINCan provides a unique opportunity to quantify and compare novel lung structure-function measurements and investigate their relationship with well-established clinical measurements and outcomes. Such intermediate endpoints of COPD may be used to stratify patients for personalized treatments and to develop new treatments to improve outcomes, a long-standing clinical goal. PMID- 28848823 TI - The 2014 Updated GOLD Strategy: A Comparison of the Various Scenarios. AB - Background: The 2014 updated Global initiative for chronic Obstructive Lung Disease (GOLD) strategy added the St. George's Respiratory Questionnaire (SGRQ) as the fourth possible symptoms measure. The impact of the suggested tools for symptoms of COPD and the different definitions of future risk on the frequency distribution and clinical characteristics of the GOLD groups remain unknown. Methods: Demographic and clinical characteristics were assessed in 542 patients with COPD (57.7% male, age 64.6 [9.0] years, FEV1 54.7 [22.3]% predicted). Health status was assessed by the COPD-specific SGRQ and symptoms of anxiety and depression by the Hospital Anxiety and Depression Scale, anxiety (HADS-A) and depression (HADS-D) subscale. Cohen's Kappa was used to assess agreement between groups. Results: Level of agreement in frequency distribution using the modified Medical Research Council dyspnea (mMRC) scale >=2, COPD Assessment Test (CAT) >=10, Clinical COPD Questionnaire (CCQ) >=1 and SGRQ >=25 was moderate to very good. Best agreement was reached between CCQ and SGRQ (K = 0.838 or 0.851, p<0.001). Patients classified in mMRC GOLD A reported higher SGRQ scores, higher HADS-A and HADS-D scores compared to patients classified in CAT GOLD A or SGRQ GOLD A. Outcomes were comparable between the risk assessment groups. Conclusions: Choice of the symptom measure impacts GOLD groups more than choice of the exacerbation risk assessment. Health care professionals should be aware that patients are heterogeneous in terms of health status and symptoms of anxiety and depression based on the symptom measure used. PMID- 28848825 TI - The COPD Pipeline, XXV. PMID- 28848824 TI - Comorbidity Distribution, Clinical Expression and Survival in COPD Patients with Different Body Mass Index. AB - Rationale: Contrary to the general population, in patients with chronic obstructive pulmonary disease (COPD) a low body mass index (BMI) is associated with excess mortality, while obesity appears protective (obesity paradox). We hypothesized that BMI is associated with a distinct number and expression of comorbidities in patients with COPD. The type of comorbidity may relate to mortality variability. Objectives and Methods: We followed 1659 COPD patients for a median of 51 months [IQR 27-77] with detailed comorbidity records and tracking pulmonary function, exercise capacity, dyspnea, health status, and cause of death. The cohort was categorized into the 5 National Heart Lung and Blood Institute (NHLBI) BMI groups with determination made about each group's relationship to specific comorbidities, clinical parameters and risk for death. Results: Whereas osteoporosis, substance abuse, abdominal aortic aneurism and peripheral arterial disease were more prevalent in patients with low BMI, metabolic and cardiac problems were more frequent in those with high BMI. The BMI was inversely related to the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC)(FEV1 %), BODE (Body mass index, airway Obstruction, Dyspnea, Exercise capacity) index and hyperinflation, had a "U" shape with dyspnea and the St. George's Respiratory Questionaire (SGRQ) score and an inverse "U" with exercise capacity. The crude mortality rate was 60%, 43%, 37%, 36% and 28% from the lowest to highest BMI groups (p<.0001). More respiratory deaths were observed in the lowest BMI group even though they had a lower number of comorbidities. Conclusions: Different BMI categories are associated with distinct clinical expressions of COPD and comorbidity patterns. The relationship between BMI and mortality in patients with COPD remains an unresolved paradox. PMID- 28848826 TI - Fibrinogen and COPD: Now what? PMID- 28848827 TI - Hospital Readmissions for COPD: We Can Meet the Challenge. PMID- 28848828 TI - Risk of Death by Comorbidity Prompting Rehospitalization Following the Initial COPD Hospitalization. AB - Rationale: Chronic obstructive pulmonary disease (COPD) hospitalizations increase short and long-term mortality; multiple COPD hospitalizations track with even higher mortality. While comorbidities such as coronary artery disease (CAD) and congestive heart failure (CHF) are common in COPD, their contribution to mortality risk after a sentinel COPD hospitalization is unknown. Purpose: Assess the effect on mortality of comorbid conditions prompting rehospitalization following COPD exacerbation hospitalization. Methods: We performed a retrospective cohort analysis of patients hospitalized for COPD exacerbations in Pennsylvania from 1990-2010 using the Pennsylvania Health Care Cost Containment Council (PHC4) database. We included patients > 40 years old hospitalized for an acute exacerbation of COPD (AECOPD; International Classification of Diseases Ninth Edition, [ICD-9] #491, 492, 496) by discharge diagnosis. Thirty-day mortality in patients with COPD hospitalization for acute exacerbation who were rehospitalized for COPD < 30days post-discharge was compared to those primarily readmitted for comorbid conditions. Relative risk of death after readmission was determined by diagnosis. Primary end-point was mortality 30 days post-readmission for 14 most common non-COPD diagnoses, including heart failure, pneumonia, pulmonary embolus (PE), and myocardial infarction. Results: Patients were nearly 2 times more likely to die within 30 days when readmitted for pneumonia (p<0.0001) or myocardial infarction (p<0.0001) rather than COPD. Septicemia conferred the highest mortality. Conclusions: COPD patients rehospitalized for comorbid conditions such as myocardial infarction, pneumonia, septicemia or pulmonary heart disease (includes PE) were significantly more likely to die within 30 days than patients readmitted for COPD. Great emphasis is already placed on preventing COPD rehospitalization; however, more attention should focus on preemptive risk reduction for comorbidities in COPD patients. PMID- 28848829 TI - Effects of a Highly Portable Noninvasive Open Ventilation System on Activities of Daily Living in Patients with COPD. AB - Background: For patients with chronic obstructive pulmonary disease (COPD), an increase in exercise tolerance and ability to perform activities of daily living (ADLs) can mean an improved quality of life with fewer exacerbations and lower health care expenses. We evaluated a wearable, noninvasive open ventilation (NIOV) system designed to enhance exercise capacity and increase mobility. Methods: Patients with stable, oxygen-dependent COPD were recruited for this prospective, open-label, crossover study. Inclusion criteria included supplemental oxygen use, elevated dyspnea score, and the ability to perform ADLs. Patients performed a selected ADL for as long as tolerable while using standard oxygen therapy. Following a rest period, the same ADL was repeated using the NIOV system. ADL endurance time, oxyhemoglobin saturation measured by pulse oximeter ( SpO2), dyspnea, fatigue, and discomfort scores were recorded. Results: Thirty patients were enrolled and 29 patients completed the study. Mean ADL endurance increased by 85% (13.4 vs. 7.2 min) using NIOV compared with oxygen therapy (p<0.0001). Mean SpO2 was significantly higher during ADLs using NIOV versus oxygen therapy (p<0.0001). Median dyspnea, fatigue, and discomfort scores were significantly lower using NIOV during ADLs compared to oxygen therapy (p<0.01). No device-related adverse events were observed. Conclusions: This study demonstrated that a novel, portable noninvasive open ventilation system can improve ADL performance in the home setting. Compared to standard oxygen therapy, the NIOV system provided statistically and clinically significant increases in ADL endurance time and oxygenation, while decreasing dyspnea, fatigue, and discomfort. The NIOV system appears to offer a practical option for increasing activity and exercise tolerance in oxygen-dependent patients with COPD. PMID- 28848830 TI - QVA149 Improves Lung Function, Dyspnea, and Health Status Independent of Previously Prescribed Medications and COPD Severity: A Subgroup Analysis from the SHINE and ILLUMINATE Studies. AB - Background: QVA149 is a dual bronchodilator combining the long-acting beta2 agonist(LABA) indacaterol and the long-acting muscarinic antagonist (LAMA) glycopyrronium, for maintenance treatment of COPD. This post hoc analysis evaluated the improvements in lung function, dyspnea, and health status in subgroups of patients based on prior medication use, disease severities, baseline cough score, and baseline rescue medication use, achieved with QVA149 compared with placebo and other active comparators in 2 phase III clinical studies. Methods: In both the SHINE (NCT01202188) and ILLUMINATE (NCT01315249) studies, symptomatic patients aged >=40 years with moderate-to-severe COPD were randomized to once-daily QVA149 (110/50 ug), indacaterol (150 ug), glycopyrronium (50 ug), tiotropium (18 MUg), or placebo (2:2:2:2:1) and once-daily QVA149 (110/50 ug) or twice-daily salmeterol/fluticasone ([SFC]; 50/500 ug), respectively for 26 weeks. Here, we present the improvements in lung function, transition dyspnea index (TDI) and St. George's Respiratory Questionnaire (SGRQ) total score by prior medication use and COPD disease severity separately from both studies. Results: In total, 2144 and 523 patients were randomized in the SHINE and ILLUMINATE studies; 89.1% and 82.6%, respectively, completed the study. QVA149 showed significant improvements in lung function compared with placebo (SHINE study) and SFC (ILLUMINATE study) regardless of prior medication, disease severity, baseline cough score, and rescue medication use. TDI and SGRQ total scores were also improved with QVA149 compared with placebo and SFC in most of the analyzed subgroups. Conclusion: QVA149 showed improvements in lung function, dyspnea, and health status in both moderate and severe COPD patients independent of previous medication use and baseline cough score. PMID- 28848831 TI - Quantification of Improvements in Static and Dynamic Ventilatory Measures Following Lung Volume Reduction Surgery for Severe COPD. AB - Rationale: This study quantitatively measured the effects of lung volume reduction surgery (LVRS) on spirometry, static and dynamic lung and chest wall volume subdivision mechanics, and cardiopulmonary exercise measures. Methods: Patients with severe COPD (mean FEV1 = 23 +/- 6% predicted) undergoing LVRS evaluation were recruited. Spirometry, plethysmography and exercise capacity were obtained within 6 months pre-LVRS and again within 12 months post- LVRS. Ventilatory mechanics were quantified using stationary optoelectronic plethysmography (OEP) during spontaneous tidal breathing and during maximum voluntary ventilation (MVV). Statistical significance was set at P< 0.05. Results:Ten consecutive patients met criteria for LVRS (5 females, 5 males, age: 62+/-6yrs). Post -LVRS (mean follow up 7 months +/- 2 months), the group showed significant improvements in dyspnea scores (pre 4+/-1 versus post 2 +/- 2), peak exercise workload (pre 37+/- 21 watts versus post 50 +/- 27watts ), heart rate (pre 109+/-19 beats per minutes [bpm] versus post 118+/-19 bpm), duty cycle (pre 30.8 +/- 3.8% versus post 38.0 +/- 5.7%), and spirometric measurements (forced expiratory volume in 1 second [FEV1] pre 23 +/- 6% versus post 32 +/- 13%, total lung capacity / residual lung volume pre 50 +/- 8 versus 50 +/- 11) . Six to 12 month changes in OEP measurements were observed in an increased percent contribution of the abdomen compartment during tidal breathing (41.2+/-6.2% versus 44.3+/-8.9%, P=0.03) and in percent contribution of the pulmonary ribcage compartment during MVV (34.5+/-10.3 versus 44.9+/-11.1%, P=0.02). Significant improvements in dynamic hyperinflation during MVV occurred, demonstrated by decreases rather than increases in end expiratory volume (EEV) in the pulmonary ribcage (pre 207.0 +/- 288.2 ml versus post -85.0 +/- 255.9 ml) and abdominal ribcage compartments (pre 229.1 +/- 182.4 ml versus post -17.0 +/- 136.2 ml) during the maneuver. Conclusions: Post-LVRS, patients with severe COPD demonstrate significant favorable changes in ventilatory mechanics, during tidal and maximal voluntary breathing. Future work is necessary to determine if these findings are clinically relevant, and extend to other environments such as exercise. PMID- 28848832 TI - The COPD Pipeline, XXVI. PMID- 28848834 TI - Editorial: Clinical Trial Design for Alpha-1 Antitrypsin Deficiency: A Model for Rare Diseases. PMID- 28848835 TI - Re-Defining Lower Limit of Normal for FEV1/FEV6, FEV1/FVC, FEV3/FEV6 and FEV3/FVC to Improve Detection of Airway Obstruction. AB - Background: Spirometric values of 5880 never-smoking black, Latin, and white men and women in the Third National Health and Nutrition Examination Survey (NHANES 3) reference population were reviewed. Good published equations for forced expiratory volume in 1 second (FEV1) over forced expiratory volume in 6 seconds (FEV6) and FEV1over forced vital capacity (FVC) often significantly mis identified the lower limit of normal (LLN) targets in both younger and older adults. To improve detection of smaller airways disease in adults, we wished to redefine the LLN for these ratios and develop new ones for forced expiratory volume in 3 seconds (FEV3)/FEV6 and FEV3/FVC. Methods: In each of 6 ethnic/gender, never-smoking NHANES-3 groups, arranged sequentially by age from 20.0 to 79.9 years, the values of FEV1/FEV6, FEV1/FVC, FEV3/FEV6, and FEV3/FVC were placed in groups of 40 so that the actual lowest second (5%) ratios could be identified. The slopes and intercepts of the resulting 24 linear equations through these lowest 5% ratios were then each adjusted by multiple iterations to best identify equations which actually identified the lowest 5% in both younger and older adults. Results: In all never-smokers, the new equations were closer to the 5% LLN targets than were those of Hankinson for FEV1/FEV6 and FEV1/FVC and Quanjer for FEV1/FVC. In 3508 NHANES-3 current smokers, the FEV3/FEV6 and FEV3/FVC identified significantly more values below LLN than the FEV1/FEV6 and FEV1/FVC. Conclusion: New simple linear iterative equations for FEV1/FEV6, FEV1/FVC, FEV3/FEV6, and FEV3/FVC to identify LLN are offered. None require exponents or logarithms. The latter 2 detected more abnormalities in current smokers and likely better identify small airways disease in adults. PMID- 28848836 TI - Effects of Tiotropium on Exacerbations in Patients with COPD with Low or High Risk of Exacerbations: A Post-Hoc Analysis from the 4-Year UPLIFT(r) Trial. AB - Background: A history of past exacerbations is a predictor of future events for patients with chronic obstructive pulmonary disease (COPD). Very little is known about the effect of pharmacologic therapies on patients with frequent or infrequent exacerbations. Methods: We conducted a post-hoc analysis of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT(r))trial database. Patients were classified as having a low risk of exacerbations if they experienced <=1 exacerbation and no COPD-related hospitalization(s) in the year preceding trial entry or as high risk of exacerbations if they had >=2 exacerbations (courses of oral steroids/antibiotics) or >=1 COPD-related hospitalization(s) in the year preceding the trial. Results: In patients at low risk or high risk for exacerbations, compared to placebo, tiotropium significantly reduced: 1) the time to first COPD exacerbation (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.74, 0.88; p <0.0001; HR: 0.89; 95% CI: 0.81, 0.97; p=0.0066, respectively); 2) the number of COPD exacerbations (rate ratio [RR]: 0.79; 95% CI: 0.72, 0.86; p<0.0001; RR: 0.88; 95% CI: 0.81; 0.95; p=0.0009). Furthermore, upon treatment with tiotropium, the proportion of patients transitioning from the low- to the high-risk exacerbations group was statistically lower compared to placebo (RR: 0.78; 95% CI: 0.67, 0.92; p=0.0030) Conclusions: This analysis shows that tiotropium reduces the risk of subsequent exacerbation and also prolongs time to first exacerbation, in both the high- and low-risk exacerbator subgroups. It also decreases the proportion of patients who shift from the low- to the high risk exacerbations group compared to placebo. PMID- 28848837 TI - Increased Severity and Mortality of CAP in COPD: Results from the German Competence Network, CAPNETZ. AB - Background:Mortality of community acquired pneumonia (CAP) remains high despite significant research efforts. Knowledge about comorbidities including chronic obstructive pulmonary disease (COPD) might help to improve management and ultimately, survival. The impact of COPD on CAP severity and mortality remains a point of discussion. Objectives:Assess the prevalence and clinical characteristics of COPD in the observational German Competence Network for CAP, CAPNETZ, and to study the impact of COPD on CAP severity and mortality. Methods:1307 consecutive patients with CAP (57.0% males, age 59.0+/-18.5), classified as CAP-only (n=1043; 78.0%) and CAP-COPD (n=264; 20.2%) were followed up for 180 days. Associations between CAP, COPD and mortality were evaluated by univariate/multivariate and Kaplan-Meier survival analyses. Results:CAP-COPD patients were older, more often males, current/former smokers, with higher confusion-urea-respiratory rate-blood pressure, (CURB) scores. Length of hospital stay, urea, glucose and leucocytes plasma levels, and arterial carbon dioxide tension (PaCO2) were significantly increased in CAP-COPD. Thirty, 90- and 180-day mortality rates were significantly increased in CAP-COPD (p=0.046, odds ratio [OR]=2.48, 95% confidence interval [CI] 1.015-6.037; p=0.003, OR=2.80, 95%CI 1.430-5.468; p=0.001, OR=2.57, 95%CI 1.462-4.498; respectively). Intensive care unit (ICU)-admission and age, but not COPD, were identified as independent predictors of short- and long-term mortality. Conclusion:Severity as well as mortality was significantly higher in COPD patients with CAP. To improve CAP management with the aim to decrease its still-too-high mortality, underlying comorbidities, particularly COPD, need to be assessed. PMID- 28848838 TI - Characteristics of Chronic Obstructive Pulmonary Disease (COPD) Patients Reporting Alpha-1 Antitrypsin Deficiency in the WebMD Lung Health Check Database. AB - Objectives: This study compared characteristics of chronic obstructive pulmonary disease (COPD) among patients with and without alpha-1 antitrypsin deficiency (A1AD). Methods: Data from WebMD's Lung Disease Health Check was analyzed for participants who self-reported a COPD diagnosis (N=177,865) and whether or not they had an A1AD diagnosis (based on a positive response to the question "Do you have alpha-1 antitrypsin deficiency?"). We used regression modeling to determine the relation between A1AD status and demographic characteristics, symptoms, lung function, quality of life, comorbidities, and smoking habits. Results: Out of 177,865 participants who reported a COPD diagnosis, 1,619 (0.92%) also reported an A1AD diagnosis. When compared to the total COPD population, those with A1AD were less likely to be female (odds ratio [OR]=0.68, 95% confidence interval [CI] 0.61, 0.75) or current smokers (OR 0.72, 95% CI 0.62, 0.83), and more likely to know their lung function value (OR=3.44, 95% CI 3.07, 3.87). With regard to symptoms, those with A1AD were less likely to report wheezing (OR=0.82, 95% CI 0.75, 0.91) and chronic cough (OR=0.81, 95% CI 0.73, 0.89) and more likely to report tightness in the chest (OR= 1.19, 95% CI 1.08, 1.32). Overall, A1AD participants had a lower quality of life with a higher proportion reporting severe impairment in work life (OR=1.55, 95% CI 1.39, 1.7), home life (OR=1.40, 95% CI 1.26, 1.56), and personal relationships (OR=1.48, 95% CI 1.32, 1.65). Conclusions: COPD patients with A1AD report significantly worse quality of life relative to the non-A1AD COPD population. PMID- 28848839 TI - COPD9: Birmingham, United Kingdom, June 2014. PMID- 28848841 TI - The COPD Pipeline XXVII. PMID- 28848843 TI - CT Scanning in COPD - Is it Time to Move On? PMID- 28848840 TI - Clinical Trial Design for Alpha-1 Antitrypsin Deficiency: A Model for Rare Diseases. AB - Clinical research in rare diseases, including alpha-1 antitrypsin deficiency (AATD), faces challenges not shared by common disease research. These challenges may include the limited number of patient volunteers available for research, lack of natural history studies on which to base many clinical trial interventions, an urgency for the development of drug therapies given the often poor prognosis of rare diseases and uncertainties about appropriate biomarkers and clinical outcomes critical to clinical trial design. To address these challenges and initiate formal discussions among key stakeholders-patients, researchers, industry, federal regulators-the Alpha-1 Foundation hosted the Clinical Trial Design for Alpha-1 Antitrypsin Deficiency: A Model for Rare Diseases conference February 3-4, 2014 in Bethesda, Maryland. Discussions at the conference led to the conclusions that 1) adaptive designs should be considered for rare disease clinical trials yet more dialogue and study is needed to make these designs feasible for smaller trials and to address current limitations; 2) natural history studies, including the identification of appropriate biomarkers are critically needed and precompetitive collaborations may offer a means of creating these costly studies; and 3) patient registries and databases within the rare disease community need to be more publicly available and integrated, particularly for AATD. This report summarizes the discussions leading to these conclusions. PMID- 28848845 TI - Effects of GOLD-Adherent Prescribing on COPD Symptom Burden, Exacerbations, and Health Care Utilization in a Real-World Setting. AB - Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines recommend specific drug therapy protocols for chronic obstructive pulmonary disease (COPD) patients based on symptoms and exacerbation risk. This study used electronic health records (EHRs) to assess the effect of adherence and nonadherence to GOLD prescribing guidelines on COPD symptom burden, exacerbations, and health care resource utilization (HCRU) during the 180 days following index treatment start. Included patients had COPD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 490.xx, 491.xx, 492.xx, 496.xx), a valid GOLD stage within the study period (January 1, 2007 to December 31, 2012), and were 40 to 90 years of age at first GOLD staging (GOLD date). Adherence or nonadherence to GOLD-defined prescribing was based on COPD medication prescribed within 180 days on either side of the GOLD date. Of 4234 patients included in the analysis, approximately 36% were prescribed GOLD-adherent pharmacotherapy. Prevalence of all COPD-related symptoms during the 180 days following index treatment start were significantly reduced in the GOLD-adherent (n=1531) versus the GOLD-nonadherent group (n=2703). GOLD adherent prescribing was associated with significant reductions in proportions of patients with all-cause hospitalizations and emergency department (ED) visits (unadjusted odds ratios [ORs], 0.69 and 0.63, respectively), as well as respiratory-specific ED visits (unadjusted OR, 0.65), compared with GOLD nonadherent prescribing. In analyses that divided patients receiving GOLD nonadherent treatment into undertreated and overtreated patients, undertreatment was associated with significant increases in many COPD symptoms, and both undertreatment and overtreatment were associated with increases in some HCRU endpoints. GOLD-adherent prescribing delivers moderate benefits with respect to COPD symptoms and HCRU. PMID- 28848844 TI - Correlation Between Emphysema and Lung Function in Healthy Smokers and Smokers With COPD. AB - Background: Emphysema is an important component of COPD; however, in previous studies of the correlation between airflow limitation (AFL) and computed tomography (CT) lung density as a surrogate for emphysema has varied. We hypothesised a good correlation between lung function (forced expiratory volume in first second [FEV1]) and emphysema (15th percentile density [PD15]) and that this correlation also exists between loss of lung tissue and decline in lung function even within the time frame of longitudinal studies of relatively short duration. Methods: We combined 2 large longitudinal studies (the Danish Lung Cancer Screening Trial [DLCST] and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [ECLIPSE]) of smokers or former smokers, with a wide range of AFL and CT lung density, and analysed data from 2148 participants who did not change smoking habits and who had at least 2 CT scans and 2 FEV1 measurements at least 3 years apart. Results: Baseline correlation between FEV1 and PD15 was high (r=0.716, 95% confidence interval [CI]: 0.694 0.736, p<0.001) indicating that at least half of the variation in FEV1 can be explained by variation in CT lung density. Correlation between the decline in FEV1 and progression of PD15 was considerably weaker (r= 0.081, 95% CI: 0.038 0.122, p<0.001). Conclusions: Correlation is very high between lung density and lung function in a broad spectrum of smokers and ex-smokers. In contrast, the temporal associations (slopes) are weakly correlated, probably due to uncertainty in the estimation of slopes within a time frame of 3-4 years. PMID- 28848846 TI - Effect of Tiotropium on Outcomes in Patients With COPD, Categorized Using the New GOLD Grading System: Results of the UPLIFT(r) Randomized Controlled Trial. AB - A retrospective analysis of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT(r)) trial data was performed, grading patients by the 2013 Global initiative for chronic Obstructive Lung Disease (GOLD) severity groups. The number of antibiotics/systemic corticosteroids courses and hospitalizations/emergency department (ED) visits for COPD in the preceding year, baseline forced expiratory volume in 1 second (FEV1) and St. George's Respiratory Questionnaire (SGRQ) score were used to grade patients: 357 (6.3%), 1421 (24.9%), 299 (5.2%), and 3636 (63.7%) in Groups A-D, respectively. Mean FEV1 was higher and SGRQ scores lower with tiotropium than usual care (control) in all GOLD groups at all post-baseline time points during treatment. In the control group, mean (95% confidence interval [CI]) exacerbation rates per patient per year were highest in Group D (1.01 [0.96, 1.07]), similar in Groups B (0.63 [0.57, 0.69]) and C (0.72 [0.59, 0.87]), and lowest in Group A (0.48 [0.39, 0.59]). Tiotropium significantly prolonged time to first exacerbation versus control in Groups B and D (hazard ratios [95% CI]: 0.79 [0.69, 0.91] and 0.89 [0.82, 0.96]); in Groups A and C, similar effects were observed, reflecting the small size of these groups. The number of exacerbations per patient-year was lower with tiotropium than control in all GOLD groups (rate ratios 0.64, 0.72, 0.91, and 0.89 for Groups A D; p < 0.005 for all but Group C (p = 0.4978). The incidence rate of major adverse cardiac events was higher in Group D than in Groups A-C but lower within the group in patients treated with tiotropium. In conclusion, tiotropium improved lung function and health status, and reduced exacerbation rates in patients in all GOLD groups. PMID- 28848847 TI - The COPD Pipeline, XXVIII. PMID- 28848849 TI - CD4+ T-Cell Profiles and Peripheral Blood Ex-Vivo Responses to T-Cell Directed Stimulation Delineate COPD Phenotypes. AB - The heterogeneous clinical phenotypes of chronic obstructive pulmonary disease (COPD) challenge successful drug development. To identify COPD subgroups beyond clinical phenotypes, we interrogated blood immune cell profiles and ex-vivo responses of current and former smokers, with or without COPD, in the longitudinal COPD Genetic Epidemiology study (COPDGene) cohort. CD4+ and CD8+ T cells and monocytes were profiled by flow cytometry. Microarray analysis was performed on the RNA from the aforementioned isolated cells. T-cell directed whole blood ex-vivo stimulation was used to assess functional responses. Blood CD4+ T-cell transcript analysis distinguished patients with COPD from control smokers and also enriched for a subset of patients with COPD that had a history of exacerbations of the disease. Analogous analyses of CD8+ T cells and monocytes failed to discriminate patients with COPD from the control population. Patients with COPD had a diminished cytokine response, compared to control smokers, characterized by low levels of granulocyte-monocyte colony stimulation factor (GM CSF), interferon gamma (IFN-gamma), interleukin one-alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha) and tumor necrosis factor-beta (TNF-beta) secreted in response to T-cell directed ex-vivo stimulation. This cytokine response associated with baseline disease severity (forced expiratory volume in 1 second [FEV1]% predicted), rapidly declining lung function, and emphysema. Our observations indicate that COPD phenotypes can be further differentiated based on blood CD4+ T-cell profiles and resultant immune responses, suggesting a role for these cells in COPD pathophysiology. PMID- 28848850 TI - Validation of the St. George's Respiratory Questionnaire in Nepal. AB - The St. George's Respiratory Questionnaire (SGRQ) is a standardized questionnaire for measuring impaired health and perceived well-being in chronic airway disease, but it is not available in the Nepali language. We translated the original SGRQ into Nepali and validated its use in 150 individuals aged 40 to 80 years with and without COPD.We also examined if the SGRQ could be used as a screening tool to identify individuals at risk for COPD. We translated the SGRQ following a standard protocol. The validation study was then conducted in both community and hospital-based settings in Nepal. We enrolled 100 participants from a community setting who were not actively seeking medical care, 50 of which met criteria for chronic obstructive pulmonary disease (COPD) (post-bronchodilator forced expiratory volume in 1 second [FEV1]/ forced vital capacity [FVC]<70%) and 50 who did not. We also enrolled 50 participants with an established diagnosis of COPD who attended outpatient pulmonary clinics. All participants completed the questionnaire. We used linear regressions to compare average SGRQ scores by disease status categories and by lung function values, adjusted for age, sex, height and body mass index (BMI).All 150 participants (mean age 59.8 years, 48% male, mean BMI 20.5 kg/m2) completed the SGRQ. In multivariable regression, the average SGRQ total score was 23.9 points higher in established cases of COPD and 18.1 points higher in community cases of COPD when compared to participants without COPD living in the community (all p<0.001). The SGRQ total score also increased by an average of 2.1 points for each 100 mL decrease in post-FEV1 (p<0.001). The area-under-the-curve for the SGRQ total score as a predictor of COPD was 0.77 (95% confidence interval [CI] 0.68 to 0.85) and the optimal cutoff to identify COPD was 33 points.We developed a Nepali-validated version of SGRQ, which correlated well with both disease status and severity. PMID- 28848851 TI - The Natural History of Lung Function in Severe Deficiency of Alpha-1 Antitrypsin Following Orthotopic Liver Transplantation: A Case Report. AB - PI*ZZ alpha-1 antitrypsin (AAT) deficiency poses risk for lung disease through 2 different mechanisms: a toxic loss of function in which deficient AAT levels cause a depleted proteolytic screen and, separately, a proinflammatory effect of Z polymers produced both by alveolar macrophages and by the liver. Ample data support the first mechanism, while the possible contribution of the second 2 proinflammatory mechanisms is currently unknown. Experience with a 74 year-old PI*ZZ female who underwent single lung transplantation and subsequent orthotopic liver transplantation (OLT) may shed light on the relative contributions of each of the potential mechanisms. Availability of multiple pulmonary function tests (PFT) measurements uniquely permitted calculation of rates of lung function change before and after OLT. The rate of forced expiratory volume in 1 second (FEV1) decline normalized post-OLT (from -60 to -21 ml/yr). Her course suggests that restoring the normal serum AAT levels or, alternately, eliminating liver derived polymers, exerted a greater effect on preventing emphysema progression than local Z polymer production contributed to furthering emphysema. PMID- 28848852 TI - Prevalence and Comorbidities of Chronic Obstructive Pulmonary Disease Among Adults in Kentucky Across Gender and Area Development Districts, 2011. AB - Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in Kentucky, and precise estimates of the prevalence of this disease and its comorbidities are needed. This study aimed to determine the prevalence of both COPD and its comorbidities and risk differences of COPD comorbidities across Area Development Districts (ADDs) and gender. Methods: The demographic characteristics, prevalence of self- reported COPD and its comorbidities were determined by using data from the 2011 Kentucky Behavioral Risk Factor Survey (KyBRFS). Logistic regression was used to estimate adjusted odds ratios (ORs) for COPD and comorbidities. Results: The overall prevalence of age adjusted COPD was 10.09% (95% confidence interval [CI] 9.99, 10.19), 8.85% for men (95% CI 8.76, 8.93), and 10.78% for women (95% CI 10.67, 10.88). Odds ratios for risk of angina or coronary heart disease (CHD), and arthritis among patients with COPD, by sex and ADDs varied significantly (pooled overall OR=3.43, 95% CI 2.70-4.34, heterogeneity p=0.0001) and (pooled overall OR=2.16, 95% CI 1.75-2.67, heterogeneity p=0.0001), respectively. ORs for risk of depression (pooled OR=2.61, 95% CI 1.78-3.70, heterogeneity p=0.028) and hypertension (pooled OR=1.67, 95% CI 1.16-2.42, heterogeneity p=0. 006) only varied significantly in men. Odds ratios for risk of diabetes was not significant across ADDs and gender (pooled overall OR=2.02, 95% CI 1.61-2.53, heterogeneity p=0.709). Conclusion: Gender differences account for the discrepancy in the risk of comorbidities in patients with COPD across Kentucky's Area Development Districts. This should guide public health officials and physicians to create gender-based prevention interventions. PMID- 28848853 TI - High Intensity Non-Invasive Positive Pressure Ventilation (HINPPV) for Stable Hypercapnic Chronic Obstructive Pulmonary Disease (COPD) Patients. AB - Introduction: High intensity non-invasive positive pressure ventilation (HI-NPPV) is an algorithm of non-invasive ventilation that has been shown to improve partial pressure of carbon dioxide (PaCO2), health-related quality of life and mortality in hypercapnic chronic obstructive pulmonary disease (COPD) patients. Objective: Assess 3 months of HI-NPPV in stable hypercapnic COPD patients. Methods: A single arm, non-randomized pilot study of HI-NPPV. Patients were eligible if they had clinically stable COPD and daytime arterial PaCO2 >50 mmHg. Results: Nine patients completed therapy. Patient characteristics: 2 male: 7 female, mean age of 64.4 years (SD +/-6.6), mean forced expiratory volume in 1 second (FEV1) of 26% (SD+/-6.73), 8 patients on long term oxygen therapy (LTOT) and a median body mass index (BMI) of 26.6 (interquartile range [IQR] 25.5 - 32.5). Outcomes: There was a mean reduction in daytime PaCO2 by 4.66 mmHg (p=0.01) and bicarbonate by 2.16 mmHg (p=0.005). There was no statistically significant difference in lung function, maximal inspiratory pressures or 6 minute walk distance. There was no statistically significant difference in sleep duration, efficiency or percentage of sleep stage 3 ( N3) or rapid eye movement (REM). The Chronic Respiratory Questionnaire (CRQ) showed a trend towards improvement with an increase of 2.69 points (p=0.054), the dyspnea domain showed a statistically significant improvement (p=0.03). The Calgary Sleep Apnea Quality of Life Index (SAQLI) detected an improvement in daily functioning (p=0.007). The Severe Respiratory Insufficiency (SRI) Questionnaire showed a trend to improvement overall (p=0.05). Four patients had COPD exacerbations during the follow up period. Conclusions: HI-NPPV is able to substantially reduce PaCO2 in hypercapnic COPD patients; we detected a positive effect on quality of life measures with no significant change in sleep quality. PMID- 28848855 TI - COPD9USA June 2015. PMID- 28848854 TI - Systematic Review of the Association Between Laboratory- and Field-Based Exercise Tests and Lung Function in Patients with Chronic Obstructive Pulmonary Disease. AB - Introduction: Typical symptoms of chronic obstructive pulmonary disease (COPD) include breathlessness and reduced exercise capacity. Several laboratory- and field-based exercise tests are used to assess the exercise capacity of patients with COPD. It is unclear whether these exercise tests reflect the spirometric measures recommended for diagnosis of COPD. We therefore aimed to systematically assess the correlation between these exercise tests and common measures of lung function. Methods: A search of EmbaseTM, MEDLINE(r) and The Cochrane Library identified primary publications in English that reported data on the correlations (Pearson's r or Spearman's rho) between the outcomes of exercise tests and the physiological measures of interest: forced expiratory volume in 1 second (FEV1), forced vital capacity, inspiratory capacity and arterial oxygen saturation. We included studies reporting on the following exercise tests: 6- and 12-minute walk tests (6MWT and 12 MWT), incremental and endurance shuttle walk tests, incremental and endurance cycle ergometer tests, and treadmill tests. Results: Of 1781 articles screened, 45 were ultimately deemed eligible for inclusion in this review. The most commonly reported lung function variable was FEV1 (reported by 39 studies); the most commonly reported exercise test was the 6-minute walk test (reported by 24 studies). FEV1 appears to correlate moderately-to-strongly with 6MWT and 12MWT; and moderately-to-very strongly with incremental cycle ergometer tests (ICET); evidence for other exercise tests was limited. Conclusion: There is evidence that 6MWT, 12MWT and ICET correlate with FEV1 to some degree; - evidence for associations of other exercise tests with measures of lung function in patients with COPD is limited. Clinicians must consider this when deciding to use these tests. Further comparisons of these tests must be made in order to assess which physiological and hemodynamic characteristics they reflect in patients with COPD. PMID- 28848856 TI - Images in COPD: Combined Pulmonary Fibrosis and Emphysema. PMID- 28848857 TI - The COPD Pipeline XXIX. PMID- 28848859 TI - Long-Term Noninvasive Ventilation in COPD: Is High-Intensity NIV The Way To Go? PMID- 28848860 TI - MicroRNAs as Therapeutic Targets in Lung Disease: Prospects and Challenges. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate multiple target genes providing fine-tuned coordinated expression. Growing evidence suggests that miRNAs play important roles in lung development and the pathogenesis of lung disease and that they have great potential as novel therapeutic targets for the treatment of diseases such as lung cancer, asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). We have previously shown that miR 146a is a promising therapeutic target for controlling abnormal inflammatory response in COPD through a series of in vitro experiments in lung fibroblasts. However, further investigations in in vivo experimental models are needed to explore the role of miR-146a in the pathogenesis and therapy of COPD. Recently, miRNAs encapsulated in extracellular vesicles (EVs) have been recognized as modulators of intercellular communication. EVs, therefore, may also have therapeutic potential and show promise for use as biomarkers for various lung diseases. In addition to miRNAs, we briefly discuss a specific long non-coding RNA (lncRNA) that may contribute to the pathogenesis of COPD. The application of miRNA-based therapeutics faces several challenges related to mode of delivery, stability, and tissue specificity. However, recent advances in nanotechnology are expected to prove valuable for the development of miRNA-based therapeutics to treat lung disease. PMID- 28848861 TI - Effect of Megestrol Acetate and Testosterone on Body Composition and Hormonal Responses in COPD Cachexia. AB - Background: Underweight chronic obstructive pulmonary disease (COPD) patients with involuntary weight loss have a poor prognosis; no effective therapy is currently available. We conducted the first clinical trial seeking to determine whether combination therapy with an appetite stimulant and an anabolic steroid would have beneficial effects on body composition for patients with COPD cachexia. Methods: We conducted a 12-week pilot study in which 4 men and 5 women (age 64+/-10 y, forced expiratory volume in 1 second [FEV1] 31+/-9 %pred., body mass index [BMI] 18+/-3 kg/m2) with low-normal testosterone levels (average 532+/ 45ng/dl in men and 12.4+/-5.3ng/dl in women) and weight loss >=10 lbs over the previous year were treated with oral megestrol acetate 800mg/day plus weekly testosterone enanthate injections, initially 125 mg in men and 40 mg in women, with doses subsequently adjusted targeting circulating nadir testosterone levels of 850 and 300 ng/dl, respectively. Results: On treatment, nadir testosterone level increases averaged 160+/-250 ng/dl (NS) in men and 322+/-49 (p<0.001) ng/dl in women. Body weight increased in all individuals, with average end-intervention weight gain of 3.1+/-2.2 kg (p<0.005). Two women and 2 men had COPD exacerbations and did not complete the 12-week study. In the 5 individuals who completed, dual energy x ray absorptiometry (DEXA) scans revealed an average 2.0+/-1.5 kg lean mass and 2.3+/-1.7 kg fat mass increase (each p<0.05). No adverse effects of treatment were detected. Conclusions: Combination therapy reversed the trajectory of involuntary weight loss and increased lean mass in cachectic COPD patients. Though the interventions were apparently well tolerated, participant drop-out rate was high. Larger randomized placebo-controlled long-term studies with functional outcomes are needed. PMID- 28848862 TI - Daily Peak Expiratory Flow Rate and Disease Instability in Chronic Obstructive Pulmonary Disease. AB - Rationale: Chronic obstructive pulmonary disease, (COPD) is a major cause of morbidity and mortality in the United States. Peak expiratory flow rate (PEFR) monitoring could provide a daily objective measurement of lung function in COPD patients at home. We hypothesized that individuals with greater variability in daily PEFR would signal an unstable patient population with worse outcomes. Methods: This was a retrospective analysis of prospectively collected data using an electronic diary to record daily PEFR and symptoms in severe and very severe COPD patients. Rates of PEFR change were used to characterize patients into stable and unstable groups determined by the distribution of slopes. Exacerbation free days, time to first hospitalization, hospitalization rate, length of hospitalization, and all-cause mortality were assessed. Results: A total of 104 severe and very severe COPD patients met entry criteria, and were observed for 37,702 patient-days. There were no significant differences in baseline symptoms, demographics, forced expiratory volume in 1 second (FEV1) or comorbidities between stable versus unstable groups. The unstable group had 34.7 less exacerbation-free days and significantly shorter 6 minute walk distances (6MWD) (227.1 versus 270.7 meters, p=0.031), shorter time to first hospitalization (163 versus 286 days, p=0.017), more frequent hospitalizations (2.6 versus 1.7 per year, p=0.032) and higher all-cause mortality (10.8 versus 5.1%, p= 0.04). Conclusion: Patients with severe to very severe COPD with greater changes in PEFR have shorter 6MWD, reduced time to first hospitalization, more frequent hospitalizations, and higher all-cause mortality despite similar demographic, spirometric and comorbid parameters at baseline. Daily peak flow monitoring can be a useful tool in identifying COPD patients predisposed to worse outcomes. PMID- 28848863 TI - Ambulatory Oxygen for Exercise-Induced Desaturation and Dyspnea in Chronic Obstructive Pulmonary Disease (COPD): Systematic Review and Meta-Analysis. AB - Introduction: Ambulatory oxygen therapy is indicated in patients that use long term oxygen therapy (LTOT) and current guidelines suggest its use in patients who exhibit exertional desaturation if there is a demonstrable improvement in exercise capacity. Evidence for this is largely derived from single assessment studies which have shown clear benefit in this setting when oxygen versus air is used. The long term effects, however, of ambulatory oxygen therapy in this particular group of patients is controversial. Methods: We conducted a systematic review of published literature from 1980 to June 2014 for trials in which ambulatory oxygen was compared to placebo in chronic obstructive pulmonary disease (COPD) patients not on LTOT. We also reviewed the effectiveness of devices delivering ambulatory oxygen. Outcome measures were focused towards exercise capacity, Borg scores and the ability of the delivery devices to maintain oxygen saturations on exercise. Results: Twenty three studies (620 patients) were included in the review. Nine studies evaluated the clinical effectiveness of ambulatory oxygen and 14 studies evaluated the impact of the delivery devices. Ambulatory oxygen had no statistical effect on improving exercise capacity when assessed by the 6-minute walk test (6MWT) or the endurance shuttle walk test (ESWT);p=0.44 and p=0.29 respectively. End of test Borg scores showed no statistical improvement with ambulatory oxygen therapy during 6MWT (p=0.68). Oxygen conserving devices significantly improved oxygen saturations on exercise compared with continuous flow nasal cannulae (p=0.04). Conclusion: Ambulatory oxygen therapy has limited long term benefit in improving functional exercise capacity or Borg dyspnea scores. PMID- 28848864 TI - Overall and Cardiovascular Safety of Aclidinium Bromide in Patients With COPD: A Pooled Analysis of Six Phase III, Placebo-Controlled, Randomized Studies. AB - : Background: Aclidinium bromide, an M3-receptor-selective, twice-daily (BID), long-acting muscarinic antagonist, is rapidly hydrolyzed in human plasma, resulting in low systemic exposure and urinary excretion. We evaluated the overall and cardiovascular (CV) safety of aclidinium in patients with moderate to severe chronic obstructive pulmonary disease (COPD) by pooling data from 6 randomized, double-blind, placebo-controlled, parallel-group studies of >=1 month's duration. METHODS: Patients were current/former smokers aged >=40 years with no history of clinically significant CV conditions. Treatment was administered (morning and evening) via GenuairTM/Pressair.(r)a Adverse events (AEs), major adverse CV events (MACE), cardiac and cerebrovascular AEs, and serious AEs (SAEs) were analyzed. Results: The pooled population included 2781 patients (aclidinium: n=1529; placebo: n=1252). The incidence of AEs was similar with aclidinium (53.5%) and placebo (55.4%), as was the incidence of cardiac (aclidinium: 5.0%; placebo: 4.4%) and cerebrovascular (aclidinium: 0.4%; placebo: 0.5%) events. The incidence of MACE was low (AEs: 0.7%; SAEs: 0.5%) and comparable between groups. The incidence of cardiac and cerebrovascular events was similar for patients with CV risk factors with aclidinium and placebo (rate ratio [RR] [95 %confidence interval (CI)]=1.01[.074, 1.39]). In patients with mild to severe renal impairment, the incidence of cardiac events was similar between groups (RR [95% CI]=0.87 [0.56, 1.36]). Conclusion: Aclidinium 400ug BID has a good safety profile and this pooled analysis found no evidence of increased CV or cerebrovascular risk compared with placebo in patients with moderate to severe COPD. Further studies are needed in high-risk patients. PMID- 28848865 TI - Interventional Options for COPD- LVRS, Bronchoscopic Therapies and the Future. AB - This article serves as aCME available, enduring material summary of the following COPD9USA presentations: "Lung Volume Reduction Surgery" Presenter: William A. Bulman, MD "Bronchoscopic Approaches to Lung Volume Reduction" Presenter: Frank Sciurba, MD "Stem Cell Therapies for Advanced Emphysema" Presenter: Edward P. Ingenito, MD, PhD "Lung Transplantation for COPD" Presenter: Daniel Dilling, MD, FACP, FCCP. PMID- 28848866 TI - Pathophysiology of Emphysema and Implications. AB - This article serves as a CME-available, enduring material summary of the following COPD9USA presentations: "Overview of Lung Injury in COPD: Types and Key Questions" Presenter: Caroline Owen, MD, PhD Emphysema as a Disease of Deficient Tissue Repair/Maintenance" Presenter: Rubin Tuder, MD. PMID- 28848867 TI - COPD Overlap Syndromes: Asthma and Beyond. AB - This article serves as a CME-available, enduring material summary of the following COPD9USApresentations: "COPD and Asthma" Presenter: Prescott Woodruff, MD, MPH "COPD and Lung Cancer" Presenter: William Bulman, MD "COPD and Bronchiectasis" Presenter: Jeremy Clain, MD "COPD and Interstitial Lung Disease" Presenter GeorgeWashko, MD. PMID- 28848868 TI - The Human Microbiome in the Lung: Are Infections Contributing to Lung Health and Disease? AB - This article serves as a CME-available, enduring material summary of the following COPD9USA presentations: "The Human Microbiome in the Lung: The Way Forward" Presenter: Gary B. Huffnagle, PhD "COPD: Is it Just Bacteria?" Presenter: Alison Morris, MD, MS "What We Have Learned From Other Disease States and How It Applies to COPD" Presenter: Fernando Martinez, MD, MS. PMID- 28848869 TI - Back to the Future: Past, Present, and Future is COPD360. AB - The treatment and management of chronic obstructive pulmonary disease (COPD) have gone through significant changes over the past decade. This plenary session, part of the 2015 COPD9USA conference, examines how the diagnosis and management of COPD has become more individualized as new phenotypes have been identified. In addition, new diagnostic and management tools are evaluated and the importance of including the patient perspective when designing a treatment plan is discussed. Finally, the future integration of technology in research, clinical communication, and disease education is introduced, including how the COPD Foundation is encouraging and facilitating these efforts. This article serves as a CME available enduring material summary of the following COPD9USA presentations: "The Past and Present Evidence" presenter: Stephen Rennard, MD "COPD: The Way Forward" presenter: Gerard Turino, MD "E-Cigarettes-Hope, Hype or Danger?" presenter: Russell Bowler, MD, PhD "Looking Forward" presenter Prescott Woodruff, MD "The Future is Now: A Patient Perspective" presenter: Jim Nelson "COPD360 & The Patient-Powered Research Network" presenter: John Walsh. PMID- 28848870 TI - Pulmonary Rehabilitation: Improvement with Movement. AB - This article serves as a CME- available, enduring material summary of the following COPD9USA presentations: - "Lessons Learned from Pulmonary Education Program and On Track with COPD Ongoing Health Management." Presenter: Scott Cerreta, BS, RRT - "Cultivating Memorial Funds for Pulmonary Rehabilitation" Presenter: Valerie McLeod, RRT - "Strategies for Success: Maintenance Program Best Practices" Presenter: David Vines, MHS, RRT - "Strategies for Success Maximizing Participation and Completion Rates," Presenter: Trina M. Limberg, BS, RRT. PMID- 28848871 TI - Developing and Implementing Biomarkers and Novel Imaging in COPD. AB - This article serves as a CME available, enduring material summary of the following COPD9USA presentations: "Computed Tomography and COPD" Presenter: George R. Washko, MD "CT Imaging in Routine Clinical Practice: Are We Ready for Prime Time?" Presenter: Meilan K. Han, MD "Beyond CT: What MRI can Tell Us about COPD" Presenter: R. Graham Barr, MD. PMID- 28848873 TI - The COPD Pipeline XXX. PMID- 28848872 TI - COPD Overdiagnosis, Underdiagnosis, and Treatment. AB - This article serves as a CME-available enduring material summary of the following COPD9USA presentations: - "Spirometry Isn't for Screening - So What Is?" Presenter: David H. Au, MD, MS - "Diagnosis of COPD in a Primary Care Midwest Practice" Presenter: Barbara Yawn, MD, MSc - "What Happens in Primary Care Without Screening?" Presenter: Sandra G. Adams, MD, MS - "From Screening to Diagnosis to Management in a Busy Primary Care Practice"Presenter: Min Joo, MD - "Practical Considerations of How Phenotype and Genotype Can Affect Management Decisions" Presenter: Bartolome Celli, MD. PMID- 28848875 TI - Hospitalizations and ED Visits in COPD: A Collision of Socioeconomic Realities with Chronic Comorbid Medical Illnesses. PMID- 28848876 TI - Forced Expiratory Volume in One Second and Patient-Reported Outcomes: Closer Than You Think. PMID- 28848877 TI - Relationship Between FEV1 and Patient-Reported Outcomes Changes: Results of a Meta-Analysis of Randomized Trials in Stable COPD. AB - Background: This meta-analysis assessed the relationship between change from baseline (CFB) in spirometric measurements (trough forced expiratory volume in 1 second [FEV1] and FEV1 area under the curve [AUC]) and patient-reported outcomes (St. George's Respiratory Questionnaire total score [SGRQ] CFB, Transition Dyspnea Index [TDI] and exacerbation rates) after 6-12 months' follow-up, using study treatment-group level data. Methods: A systematic literature search was performed for randomized controlled trials of >=24 weeks duration in adults with chronic obstructive pulmonary disease (COPD). Studies reporting >=1 spirometric measurement and >=1 patient-reported outcome (PRO) at baseline and at study endpoint were selected. The relationships between PROs and spirometric endpoints were assessed using Pearson correlation coefficient and meta-regression. Results: Fifty-two studies (62,385 patients) were included. Primary weighted analysis conducted at the last assessment showed a large significant negative correlation (r, -0.68 [95% confidence interval (CI); -0.77, -0.57]) between trough FEV1 and SGRQ. Improvement of 100 mL in trough FEV1 corresponded to a 5.9 point reduction in SGRQ. Similarly, a reduction of 4 points on SGRQ corresponded to 40 mL improvement in trough FEV1 (p<0.001). The weighted correlation coefficients of trough FEV1 with TDI, exacerbation rate (all) and exacerbation rate (moderate/severe) at last assessment point were 0.57, -0.69 and -0.57, respectively (all p<0.05). For the analyses excluding placebo groups, the correlations of FEV1 with SGRQ and TDI were lower but significant. Conclusions: A strong association exists between changes in spirometric measurements and changes in PROs. PMID- 28848879 TI - Efficacy and Safety of Twice-Daily Glycopyrrolate Versus Placebo in Patients With COPD: The GEM2 Study. AB - : Long-acting bronchodilators including muscarinic antagonists are central to the management of patients with COPD. The Glycopyrrolate Effect on syMptoms and lung function (GEM2) study assessed the efficacy and safety of twice-daily glycopyrrolate 15.6 MUg in patients with moderate-to-severe airflow limitation. This 12-week multicenter, double-blind study randomized (1:1) patients to glycopyrrolate 15.6 MUg twice daily (b.i.d.) or placebo both delivered via the NeohalerTM device. The primary objective was superiority of glycopyrrolate compared with placebo for forced expiratory volume in 1 second (FEV1) standardized area under curve (AUC) between 0 and 12 hours post dosing (FEV1 AUC0 12h)at week 12. Other outcomes included additional spirometry parameters, health status using St George's Respiratory Questionnaire (SGRQ), dyspnea via Transition Dyspnea Index (TDI), rescue medication use and COPD symptoms reported by patients via the electronic diary. Safety was also assessed. Of the 432 patients randomized (glycopyrrolate, n=216; placebo, n=216), 96% completed the planned treatment phase. The study met its primary objective (superiority of glycopyrrolate compared with placebo for FEV1 AUC0-12h).Compared with placebo, glycopyrrolate showed significant improvements in lung function parameters (p<0.001). Health status (SGRQ total score and COPD assessment test), rescue medication use and daily total COPD symptom scores were significantly improved with glycopyrrolate versus placebo over 12 weeks. Improvements in dyspnea were observed with glycopyrrolate and placebo although the treatment difference was not statistically significant. Overall, differences in the incidences of adverse events and serious adverse events between the groups were not considered clinically meaningful. No deaths were reported. Twice-daily glycopyrrolate 15.6 MUg showed statistically significant and clinically meaningful improvements compared with placebo in lung function, COPD symptoms, health status, and rescue medication usage in COPD patients with moderate-to-severe airflow limitation. CLINICAL TRIAL REGISTRATION: NCT01715298. PMID- 28848878 TI - Characteristics of COPD Patients Using United States Emergency Care or Hospitalization. AB - Rationale: Several chronic obstructive pulmonary disease (COPD) studies have evaluated risk factors for emergency department (ED) visits or hospitalizations, and found insufficient data available about social and demographic factors that drive these behaviors. This U.S. study was designed to describe the characteristics of COPD patients with ED visits or a hospitalization and to investigate how often common COPD comorbidities are present in these individuals. Methods: Data for 7180 COPD patients regarding demographic factors, comorbidities, smoking status, and ED visits or hospitalization was obtained from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) survey. Logistic regression analysis was used to adjust demographic factors and smoking status to model the correlation between patients with ED visits or hospitalizations and morbidities generating odds ratios (OR) and confidence intervals (CI). Results: Among diagnosed COPD patients in the BRFSS, 16.5% had ED visits or hospitalization in the previous year. These individuals were younger, had a lower socio-economic status (lower education, lower income, and more often unemployed) and 23.4% of the individuals could not visit a doctor because of the financial difficulties compared to 16.7% who had no visit (p<0.0001 for all comparisons). The prevalence of comorbidities was higher in those with ED visits or hospitalization compared to those without. Conclusion: In a population representative of COPD patients, lower socio-economic status and higher comorbidities are associated with ED visits or hospitalization. Studies are needed to further elucidate the complex relationship between COPD, comorbidities, and ED visits or hospitalization. PMID- 28848880 TI - Free Urinary Desmosine and Isodesmosine as COPD Biomarkers: The Relevance of Confounding Factors. AB - Background: Desmosine (DES) and isodesmosine (IDES) have been widely discussed as potential biomarkers of COPD. However, their clinical utility and validity remains unproven. Aim: This study aims to progress DES/IDES evaluation as a chronic obstructive pulmonary disease (COPD) biomarker by investigating its urinary excretion in a large sample cohort with respect to a) which factors influence DES/IDES levels in a population of healthy control individuals and COPD individuals; b) whether DES/IDES levels enable the differentiation between COPD individuals and healthy control individuals; c) whether DES/IDES can be used to differentiate between fast and slow decliners in lung function. Methods: Urinary DES and IDES were quantified in 365 individuals (147 healthy control individuals and 218 COPD individuals) from the Evaluation of COPD Longitudinally to Indentify Predictive Surrogate Endpoints (ECLIPSE) study (NCT00292552) by employing a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Results: Age, gender, body mass index (BMI) and smoking have a significant (p<0.05) influence on DES/IDES urinary excretion and need to be corrected for when investigating DES/IDES as a disease biomarker. Urinary DES/IDES allowed a statistically relevant differentiation (p<0.05) between stable COPD individuals and healthy control individuals, however, assay sensitivity and specificity were low (62% and 73%, respectively). Furthermore, urinary DES/IDES does not allow the differentiation of fast and slow decliners in lung function. Conclusions: The present results suggest that while urinary DES/IDES excretion is related to COPD, it is not a sensitive or specific biomarker for COPD diagnosis or prognosis. PMID- 28848881 TI - Hiatal Hernia on Chest High-Resolution Computed Tomography and Exacerbation Rates in COPD Individuals. AB - Background: Gastroesophageal reflux disease (GERD) is associated with frequent chronic obstructive pulmonary disease (COPD) exacerbations. Hiatal hernia (HH) contributes to GERD pathogenesis and is identifiable on chest high-resolution computed tomography (HRCT). We hypothesize that the presence of an HH on HRCT identifies those at increased risk for acute exacerbation of COPD. Methods: We retrospectively reviewed a prospectively enrolled cohort of smokers with and without airflow obstruction. HHs were identified visually on inspiratory HRCT. Individuals' demographic and clinical information was compared with secondary analysis performed using a propensity score generated matched cohort. Results: There were 523 COPD individuals and 607 unobstructed smokers. COPD individuals had more HHs than unobstructed smokers, (11.6% versus 6.1%, p < 0.001). COPD individuals with hernias were older, female, overweight and GERD positive as compared to those without hernia. There was no difference in self-reported exacerbation rates or hospitalizations per year, but similar severity of obstruction, smoking rates and long-term oxygen use. Analysis with the matched cohort revealed no significant difference in exacerbation rates. Conclusions: Presence of HHs on inspiratory HRCT scan did not predict worse symptoms or exacerbation rate in COPD individuals. Those with HHs were older, more obese, and predominantly female compared to those without HHs. PMID- 28848882 TI - High-Dose Versus Low-Dose Systemic Steroids in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Systematic Review. AB - Background: Treatment of an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with systemic steroids reduces treatment failure, shortens hospital length of stay, improves lung function, and reduces dyspnea. However, it can also cause hyperglycemia, delirium, fluid retention, and other side effects. The balance of these desirable and undesirable effects probably varies according to the steroid dose. Methods: We asked the question, "Should patients having an AECOPD receive low-dose or high-dose systemic steroids?" We searched Medline and the Cochran Central Register of Controlled Trials (CENTRAL) using a sensitive search strategy built around the medical subject heading, "COPD," and variations of the keywords exacerbation, steroids, and randomized trials. Our search yielded 1702 articles in Medline and 885 articles in CENTRAL; we reviewed the full text of 35 articles and selected 11 studies that met the following conditions: randomized trial, enrolled patients having an AECOPD, compared one systemic steroid regimen to another, measured clinical outcomes, and was published in a peer-reviewed journal. Results: None of the selected trials directly compared the effects of different systemic steroid doses on clinical outcomes in patients with AECOPD. Four trials compared durations of steroid treatment, 3 trials compared types of steroids, 1 trial compared routes of steroid delivery, and 3 trials compared multiple variables. Conclusion: There is a paucity of data to support the selection of a systemic steroid dose in patients having an AECOPD. Randomized trials that measure patient-centered outcomes and compare doses of systemic steroids in patients having an AECOPD are needed. PMID- 28848883 TI - The COPD Pipeline XXXI. PMID- 28848885 TI - Images in COPD: Alpha-1 Antitrypsin Deficiency and Bronchiectasis. PMID- 28848886 TI - Chronic Obstructive Pulmonary Disease: Reduced Nihilism, But There is Still a Ways to Go. PMID- 28848887 TI - Risk Factors for Pneumonia and the Effect of the Pneumococcal Vaccine in Patients With Chronic Airflow Obstruction. AB - Background: To evaluate the risk factors for pneumonia and the efficacy of the pneumococcal polysaccharide vaccine (PPV) in patients with chronic airflow obstruction. Methods: We retrospectively studied the risk factors for pneumonia in 820 consecutive patients with chronic obstructive pulmonary disease (COPD) (n=509) and patients with asthma-COPD overlap syndrome (ACOS) (n=311). The effects of asthma, age, smoking history, chronic sputum, use of inhaled corticosteroids, percent predicted forced vital capacity (%FVC), percent predicted forced expiratory volume in 1 second (%FEV1), body mass index (BMI), computed tomography (CT)-diagnosed emphysema, and the pneumococcal vaccination on the frequency of pneumonia were assessed. Results: There was no difference in the frequency of pneumonia in patients with COPD and those with ACOS. In a univariate analysis, age (p= 0.031), %FVC (p< 0.001), %FEV1 (p < 0.001), BMI (p = 0.003), the presence of emphysema (p < 0.001) and a history of vaccination with the PPV (p = 0.034) were associated with the frequency of pneumonia. A multivariate analysis identified low BMI, the presence of emphysema and the absence of a pneumococcal vaccination as independent risk factors. The combination index of these factors, the BOVE index, which is calculated from low BMI (<22 kg/m2), low %FEV1 (<60%), vaccination history and emphysema was associated with the overall frequency of pneumonia. Conclusions:The index of multidimensional risk factors is useful to predict the frequency of pneumonia in patients with chronic airflow obstruction. The pneumococcal vaccination was associated with significantly lower incidence of pneumonia. PMID- 28848888 TI - Primary Care Physicians', Nurse Practitioners' and Physician Assistants' Knowledge, Attitudes and Beliefs Regarding COPD: 2007 To 2014. AB - To assess current primary care physicians', nurse practitioners' (NP) and physicians assistants' (PA) knowledge, attitudes and beliefs regarding chronic obstructive pulmonary disease (COPD) and changes from a similar 2007 assessment, we surveyed attendees of 3 regional continuing medical education programs and compared the 2013/2014 responses with responses to a similar survey completed in 2007. Survey data included information on personal demographics, agreement with perceived barriers to COPD diagnosis, awareness, and use of COPD guidelines, and beliefs regarding the value of available COPD therapies. In 2013/2014, 426 primary care clinicians (278 medical doctors [MDs] and doctors of osteopathic medicine [DO] and 148 NPs/PAs) provided useable responses (overall response rate 61%). Overall these physicians were older and more experienced than the NPs/PAs but with few other differences in responses except significantly greater physician reported use of spirometry for COPD diagnosis. About half of the clinicians reported having in-office spirometers but less than two thirds reported using them for all COPD diagnoses. All respondents reported multiple barriers to COPD diagnosis but with fewer than in 2007 reporting lack of knowledge or awareness of COPD guidelines as a major barrier. The most striking difference between 2007 and 2013/2014 responses was the marked increase in beliefs by all clinicians in the ability of COPD treatments to reduce symptoms and numbers of exacerbations. These data affirm that primary care clinicians continue to report multiple barriers to COPD diagnosis including lack of easy access to spirometry and frequent failure to include spirometry in diagnostic confirmation. However, since 2007, the clinicians report a remarkable decline in therapeutic nihilism, which may enhance their interest in learning more about diagnosing and managing COPD. PMID- 28848889 TI - Health Status of Patients With Chronic Obstructive Pulmonary Disease by Symptom Level. AB - Background: Despite receiving treatment, patients with chronic obstructive pulmonary disease (COPD) often continue to experience symptoms that impact their health status. We determined the relationship between overall symptom burden and health status, and assessed the treatments patients were receiving. Methods: Data from 3 cross-sectional surveys of U.S. patients with COPD (2011-2013) were analyzed. Patients receiving inhaled COPD treatment for >=3 months completed the COPD Assessment Test (CAT) symptom burden and respiratory health status measure, EuroQol 5-dimension (EQ-5D-3L) general health status questionnaire, and Jenkins Sleep Evaluation Questionnaire (JSEQ). CAT scores were used to identify high- (CAT >=24) and low-symptom patients (CAT <24), who were matched using 1:1 propensity score matching with replacement. Match balance was assessed with standardized mean differences. EQ-5D-3L and JSEQ scores, and current treatment were compared between groups post-matching. Sensitivity was assessed with Rosenbaum bounds. Results: A total of 638 patients were included. Compared with low-symptom patients, high-symptom patients had worse health status and greater sleep disturbance by EQ-5D utility index (0.85 versus 0.71, respectively; p<0.0001) and JSEQ scores (3.73 versus 7.35, respectively; p<0.0001). High symptom patients were prescribed single-maintenance bronchodilators +/- inhaled corticosteroids (46.0%), triple therapy (40.5%), and short-acting therapy only (8.2%). Results were robust and insensitive to unobserved confounders. Conclusions: Increased COPD symptom burden is associated with worse general health status in patients receiving COPD treatment. High-symptom patients frequently received single inhaled medication. The results suggest that health care providers should monitor and tailor therapy, based on level of symptom burden to improve symptom control and health status. PMID- 28848892 TI - Panlobular Emphysema: Enhancing Visibility with Quantitative Computed Tomography. AB - Rationale: Several chronic obstructive pulmonary disease (COPD) studies have evaluated risk factors for emergency department (ED) visits or hospitalizations, and found insufficient data available about social and demographic factors that drive these behaviors. This U.S. study was designed to describe the characteristics of COPD patients with ED visits or a hospitalization and to investigate how often common COPD comorbidities are present in these individuals. Methods: Data for 7180 COPD patients regarding demographic factors, comorbidities, smoking status, and ED visits or hospitalization was obtained from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) survey. Logistic regression analysis was used to adjust demographic factors and smoking status to model the correlation between patients with ED visits or hospitalizations and morbidities generating odds ratios (OR) and confidence intervals (CI). Results: Among diagnosed COPD patients in the BRFSS, 16.5% had ED visits or hospitalization in the previous year. These individuals were younger, had a lower socio-economic status (lower education, lower income, and more often unemployed) and 23.4% of the individuals could not visit a doctor because of the financial difficulties compared to 16.7% who had no visit (p<0.0001 for all comparisons). The prevalence of comorbidities was higher in those with ED visits or hospitalization compared to those without. Conclusion: In a population representative of COPD patients, lower socio-economic status and higher comorbidities are associated with ED visits or hospitalization. Studies are needed to further elucidate the complex relationship between COPD, comorbidities, and ED visits or hospitalization. PMID- 28848893 TI - The COPD Pipeline XXXII. PMID- 28848894 TI - Journal Club: Phosphodiesterase-4 Inhibitors. PMID- 28848891 TI - The Diagnosis and Management of Alpha-1 Antitrypsin Deficiency in the Adult. AB - Background: The diagnosis and clinical management of adults with alpha-1 antitrypsin deficiency (AATD) have been the subject of ongoing debate, ever since the publication of the first American Thoracic Society guideline statement in 1989.1 In 2003, the "American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency" made a series of evidence-based recommendations, including a strong recommendation for broad-based diagnostic testing of all symptomatic adults with chronic obstructive pulmonary disease (COPD).2 Even so, AATD remains widely under-recognized. To update the 2003 systematic review and clinical guidance, the Alpha-1 Foundation sponsored a committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD. Purpose: To provide recommendations for: (1) the performance and interpretation of diagnostic testing for AATD, and (2) the current management of adults with AATD and its associated medical conditions. Methods: A systematic review addressing the most pressing questions asked by clinicians (clinician-centric) was performed to identify citations related to AATD that were published since the 2003 comprehensive review, specifically evaluating publications between January 2002 and December 2014. Important, more recent publications were solicited from the writing committee members as well. The combined comprehensive literature reviews of the 2003 document and this current review comprise the evidence upon which the committee's conclusions and recommendations are based. Results: Recommendations for the diagnosis and management of AATD were formulated by the committee. Conclusions: The major recommendations continue to endorse and reinforce the importance of testing for AATD in all adults with symptomatic fixed airflow obstruction, whether clinically labeled as COPD or asthma. Individuals with unexplained bronchiectasis or liver disease also should be tested. Family testing of first-degree relatives is currently the most efficient detection technique. In general, individuals with AATD and emphysema, bronchiectasis, and/or liver disease should be managed according to usual guidelines for these clinical conditions. In countries where intravenous augmentation therapy with purified pooled human plasma-derived alpha-1 antitrypsin is available, recent evidence now provides strong support for its use in appropriate individuals with lung disease due to AATD. PMID- 28848890 TI - Evaluation of Individuals at Risk for COPD: Beyond the Scope of the Global Initiative for Chronic Obstructive Lung Disease. AB - The Global initiative for chronic Obstructive Lung Disease (GOLD) Strategy is a valuable tool for clinicians in the diagnosis and management of patients with established chronic obstructive pulmonary disease (COPD). However, there are no recommendations for the evaluation of individuals, exposed to risk factors, who are most likely to develop COPD. Consequently, it is necessary to consider all of the factors that may play a role in the pathogenesis of COPD: genetic factors, gender, socioeconomic status, disadvantageous factors in childhood, lung diseases and exposure to risk factors such as smoking, biomass fuel smoke, occupational hazards and air pollution. Along with the clinical assessment, periodic spirometry should be performed to evaluate lung function and make possible early detection of individuals who will develop the disease through the rate of forced expiratory volume in 1 second (FEV1) decline. The first spirometry, periodicity, and clinically significant decline in FEV1 will encompass the cornerstones of clinical follow up. This approach allows the implementation of important interventions in order to help individuals to cease contact with risk factors and prevent progressive respiratory impairment with the consequent deterioration of quality of life and increased morbidity and mortality. PMID- 28848895 TI - Images in COPD: Giant Bullous Emphysema. PMID- 28848896 TI - A Patient-Centered Walking Program for COPD. PMID- 28848897 TI - Veterans Airflow Obstruction Screening Questionnaire: A Survey to Identify Veterans with Airflow Obstruction. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality within the Veterans Healthcare Administration (VHA) and is frequently under-diagnosed. We developed the Veterans Airflow Screening Questionnaire (VAFOSQ) to improve the identification of Veterans with airflow obstruction (AFO), the most commonly used criterion for the diagnosis of COPD.We created an initial survey with 78 variables that have been associated with AFO. A total of 825 patients in 3 primary care clinics performed spirometry after bronchodilator administration and completed the initial survey. Best sets regression was used to build a model that predicted AFO optimally. A total of 195 of 825 (23.3%) patients had AFO and 7 items positively predicted AFO. When the questionnaire score was greater than 25, the VAFOSQ accurately identified AFO with an area under the receiver operating curve of 0.72. In a prospective validation cohort of 376 participants, the positive predictive value was 32% and negative predictive value 81%. The VAFOSQ is a reliable and valid instrument for the identification of veterans at risk for AFO who would benefit from further evaluation with spirometry and assessment for COPD. The VAFOSQ is straightforward to use and can be easily self-administered and self-scored enabling widespread application within the VHA. PMID- 28848898 TI - Long-Term Maintenance Bronchodilation With Indacaterol/Glycopyrrolate Versus Indacaterol in Moderate-to-Severe COPD Patients: The FLIGHT 3 Study. AB - Background: The objective of the FLIGHT3 study was to evaluate the long-term safety and efficacy of indacaterol/glycopyrrolate* (IND/GLY) versus an active comparator, IND, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) over 52 weeks. Method: FLIGHT3 was a multicenter, randomized, double-blind, parallel-group, 52-week study. Patients were randomized (1:1:1) to IND/GLY (27.5/15.6 or 27.5/31.2 ug twice daily [b.i.d.]) or IND (75 ug once daily [o.d.]), delivered via the Neohaler(r) device. The primary objective was to evaluate the long-term safety and tolerability of IND/GLY versus IND in terms of adverse event (AE)-reporting rates in patients with moderate-to-severe COPD over 52 weeks. The secondary objective was to evaluate the long-term efficacy of IND/GLY versus IND in terms of pre-dose trough forced expiratory volume in 1 second (FEV1) and post-dose 1-h FEV1 over 52 weeks. Results: A total of 85.2% patients completed the study treatment. The overall incidence of AEs (and SAEs) was similar between treatments. Major adverse cardiovascular events (MACE) and/or cardiovascular (CV) events were comparable between treatment groups. The rate of discontinuation of the study treatment due to AEs was lower for IND/GLY than IND. Improvements in pre-dose trough FEV1 and post-dose 1-h FEV1 were consistently superior with IND/GLY than with IND over 52 weeks, demonstrating long-term maintenance of lung function. Conclusions: IND/GLY demonstrated a favorable long-term safety and tolerability profile and provided effective bronchodilation, with maintenance of lung function over 52 weeks in patients with moderate-to-severe COPD. These data support the safety and efficacy of IND/GLY as a treatment option for COPD. Trial registration: ClinTrials.gov identifier NCT01682863 *Glycopyrrolate 15.6 ug (excluding the bromide salt) is equivalent to 12.5 ug glycopyrronium. PMID- 28848899 TI - Identifying Patients With COPD at High Risk of Readmission. AB - Background: Readmission within 30 days of a COPD hospitalization is a common measure of performance for COPD care. However, most studies of COPD readmission risk have been constrained to a single data source, private payer claims, or Medicare claims data, making it difficult to generalize results from these studies to other populations. The purpose of this study was to examine the risk for readmission within 30 days from time of discharge in patients with COPD using the Healthcare Cost and Utilization Project (HCUP) State Inpatient Database for California for the years 2005-2011. This statewide dataset allows us to consider all readmissions for COPD regardless of age or payer status. Methods: The total dataset included 28,265,070 visits among 17,918,374 patients over 480 hospitals. We identified patients with a hospitalization, a primary diagnosis related to COPD, age 40 or older, and discharged alive. We found 286,313 hospitalizations that matched this definition and included information on covariates such as comorbidities, age, and insurance status. To characterize the joint associations of these covariates with readmission within 30 days, we used a generalized linear model. Results: Patients aged 40-64 are more likely to be readmitted to the hospital within 30 days of a COPD-related hospitalization than patients 65 and older. This effect persists after adjustment for patient severity, comorbidities, payer, and demographics. Our model featured an interaction of age with insurance type. We found that younger patients (aged 40-64) on public insurance have the highest readmission rates: 14.77% for Medicare and 16.27% for Medicaid. However, younger patients with private insurance have the lowest readmission rates at 8.25%. Additional significant covariates included whether or not the patient left against medical advice, and diagnoses of congestive heart failure and diabetes. In addition, we found that although admissions for COPD were highest in the winter, this is not true for COPD readmissions, which peak in summer. Also, inpatient mortality for patients admitted for COPD decreased from approximately 3% to 1.25% over the study period. Conclusion: Our results demonstrate that many of the risk factors for readmission may be dependent on the data source used. Furthermore, many of the strongest predictors are clearly related to the patients themselves. This observation may help explain why prior programs to reduce readmissions have had limited success. PMID- 28848900 TI - Psychometric Properties of the COPD-Specific Beliefs About Medicine Questionnaire in an Outpatient Population: A Rasch-Analysis. AB - Background: Understanding non-adherence in patients with chronic obstructive pulmonary disease (COPD) remains challenging. The necessity and the concerns scales of the Beliefs about Medicines Questionnaire (BMQ) are known to correlate with adherence behavior in several chronic diseases including asthma but less is known about COPD. In the present study a COPD-specific BMQ (BMQ-COPD) was translated and administered to Danish COPD outpatients. Our aim was to derive high-quality measures of the 2 dimensions included in the BMQ-COPD. Methods: A total of 168 patients with COPD were included from a Danish respiratory outpatient clinic. The Rasch model was used to evaluate psychometric characteristics of the BMQ-COPD and to obtain necessity and concerns scales fulfilling criteria of unidimensionality and overall fit, and with all items showing individual item fit with no local dependencies, and no differential item functioning. Further, we explored the association with disease-related variables and subsequent adherence behavior. Results: Shortened versions of the original necessity and concerns scales fitted the Rasch model and were at least as good as the original scales as predictors of adherence, although only the necessity scale was significantly associated with adherence. Conclusion: In a Danish COPD setting high-quality measures of necessity and concerns could be derived from the BMQ COPD. The excluded items appear to reflect other dimensions. PMID- 28848901 TI - Efficacy of Indacaterol/Glycopyrronium in Patients with COPD Who Have Increased Dyspnea with Daily Activities. AB - Introduction: The Global initiative for chronic Obstructive Lung Disease (GOLD) recommends treating patients with chronic obstructive pulmonary disease (COPD) based on a combined assessment of symptom severity and airflow limitation and/or exacerbation risk. According to GOLD, patients with mild-to-moderate airflow limitation and distressing symptoms such as dyspnea should be treated with a long acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA). If symptoms persist on monotherapy, GOLD recommends a combination of bronchodilators (LABA/LAMA). Methods: We performed a post-hoc analysis of data from two 26-week, prospective clinical trials to investigate the effect of treating patients with moderate-to-severe dyspnea with the once-daily LABA/LAMA combination indacaterol/glycopyrronium (IND/GLY) 110/50 ug compared with placebo, once-daily tiotropium 18 ug, and twice-daily salmeterol/fluticasone propionate (SFC) 50/500 ug. In this analysis, a Baseline Dyspnea Index (BDI) score <=7 was used to identify dyspneic patients. Results: In dyspneic patients, IND/GLY significantly improved Transition Dyspnea Index (TDI) total scores compared with tiotropium (0.59 units; p<0.05) and SFC (0.97 units; p<0.05), and significantly increased the likelihood of a patient achieving a 1-unit improvement in TDI compared with tiotropium (odds ratio [OR] 1.87; p<0.05). IND/GLY also significantly improved trough forced expiratory volume in 1 second (FEV1) compared with tiotropium and SFC (p<0.001 and p<0.0001, respectively), and significantly reduced rescue medication use compared with tiotropium (p<0.001). Conclusions: Our analysis indicates that IND/GLY provides additional improvements in dyspnea and lung function compared with tiotropium and SFC in dyspneic patients. PMID- 28848902 TI - A Patient-Centered Walking Program for COPD. AB - Background: Pulmonary rehabilitation programs improve dyspnea and health status associated with chronic obstructive pulmonary disease (COPD), but benefits wane when patients return to a sedentary lifestyle. This study tested a simple, low resource, low-cost home walking program. Methods: In this single center, 3-month study, 115 COPD patients were randomized to a control cohort or a goal setting cohort. Each patient met with study staff and received 5 telephone calls at 2 week intervals. During these contacts, the Goal group was assisted by a wellness coach who helped them set personal activity goals. All patients wore a pedometer to record daily steps, the primary study outcome. Results: Over the 12-week interval, the average step-per-days was 36% higher for the Goal cohort patients (Week 12 mean = 4390) than for Control patients (mean = 3790). No group differences emerged on the modified Medical Research Council (mMRC) dyspnea scale, the COPD Assessment Test, or the St. George's Respiratory Questionnaire. Secondary analyses indicated that even patients with greater disease severity, including those with an mMRC score >2 or forced expiratory volume in 1 second (FEV1) % predicted below 50%, increased their walking relative to Control patients. Almost half (48%) of Goal patients successfully reached at least one personal goal such as increasing stamina and activity, or decreasing shortness of breath or weight. Conclusions: A relatively low-resource wellness coaching, goal setting intervention resulted in a small improvement in the activity level of COPD patients over a 12-week period including those with marked pulmonary impairment. Further investigation should be directed at understanding the optimal blend of in person and remote coaching needed to produce the greatest cost-to benefit ratio. PMID- 28848904 TI - Journal Club: COPD and Rehospitalization. PMID- 28848903 TI - The 2nd National COPD Readmissions Summit and Beyond: From Theory to Implementation. AB - Chronic obstructive pulmonary disease (COPD) hospitalizations and readmissions adversely impact the health and quality of life of COPD patients. Under the Hospital Readmissions Reduction Program, the Centers for Medicare & Medicaid Services reduce payments to those hospitals exceeding expected rates of COPD readmissions within 30 days of hospital discharge. It was within this climate that the COPD Foundation held its 2nd COPD Readmissions Summit in March 2015. Experts in attendance: (1) categorized challenges to optimal COPD care, ( 2) analyzed the state of care delivery and readmissions reduction strategies and (3) identified the best available evidence-based approaches to improving care delivery across the continuum, including early diagnosis via spirometry, ongoing device, oxygen and medication reconciliation, treatment that addresses comorbidities and preventive care, robust patient education, prompt post-acute follow up, home health services and pulmonary rehabilitation. Results of this collaborative event formed the basis for PRAXIS, the COPD Foundation's initiative to improve COPD care across the health continuum and to reduce readmissions. PMID- 28848905 TI - Nebulized Long-Acting Beta2-Agonists: More Than Just Bridging Gaps in the Management of Symptomatic COPD. PMID- 28848906 TI - Progressing the Progress Note for COPD. PMID- 28848908 TI - Efficacy of Formoterol Fumarate Delivered by Metered Dose Inhaler Using Co SuspensionTM Delivery Technology Versus Foradil(r) Aerolizer(r) in Moderate-To Severe COPD: A Randomized, Dose-Ranging Study. AB - Background: Co-SuspensionTM Delivery Technology offers a novel pharmaceutical platform for inhaled drug therapy. This randomized, double-blind, placebo controlled, single-dose study (NCT01349868) evaluated the efficacy of a range of doses for formoterol fumarate (FF) delivered using Co-Suspension delivery technology via a pressurized metered dose inhaler (MDI) versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Secondary objectives included determination of non-inferior efficacy and systemic exposure compared with open-label Foradil(r) 12 MUg (Foradil(r) Aerolizer(r); formoterol fumarate dry powder inhaler). Methods: Patients received each of the 6 study treatments (FF MDI [7.2, 9.6 and 19.2MUg], placebo MDI and open-label Foradil(r) [12 and 24ug]), separated by 3-10 days. Spirometry was performed 60 and 30 minutes prior to and at regular intervals up to 12 hours post administration of study drug. The primary outcome measure was the change in forced expiratory volume in 1 second (FEV1) area under the curve between 0 and 12 hours (AUC0-12) relative to test day baseline. Results: A total of 50 patients were randomized to study treatment sequences. All doses of FF MDI demonstrated superiority to placebo (p<0.0001) and non-inferiority to Foradil(r) 12MUg, on bronchodilator outcome measures. No serious adverse events were reported during the study. Conclusions: This study demonstrates non-inferiority of bronchodilator response and bioequivalent exposure of FF MDI 9.6MUg to Foradil(r) 12MUg, with both agents exhibiting a similar safety profile in patients with moderate-to severe COPD. This study supports the selection of FF MDI 9.6ug for further evaluation in Phase III trials. PMID- 28848909 TI - The Effect of Alpha-1 Proteinase Inhibitor on Biomarkers of Elastin Degradation in Alpha-1 Antitrypsin Deficiency: An Analysis of the RAPID/RAPID Extension Trials. AB - The RAPID (NCT00261833; N=180) and RAPID Extension (NCT00670007; N=140) trials demonstrated significantly reduced lung density decline in patients with alpha-1 antitrypsin deficiency (AATD) receiving alpha-1 proteinase inhibitor (A1PI) versus placebo. Desmosine and isodesmosine (DES/IDES) are unique crosslinkers of mature elastin fibers and are utilized as measures of elastin degradation. The aim of this post-hoc study was to determine the effect of A1PI therapy on DES/IDES levels in patients from RAPID/RAPID Extension. Plasma levels of DES/IDES were measured using high-performance liquid chromatography and tandem mass spectrometry. Correlation between changes in DES/IDES levels and computed tomography (CT) lung density decline was assessed. Analysis showed that DES/IDES levels were significantly reduced versus baseline in patients receiving A1PI at all time points, from month 3 through month 48. A significant increase from baseline in DES/IDES was observed with placebo at month 24 (n=54; 0.016; p=0.018). DES/IDES change from baseline was significantly different with A1PI versus placebo at months 3 (-0.021; 95% confidence interval [CI] -0.037, 0.004; p=0.026), 12 (-0.040; 95% CI -0.055, 0.025; p<0.001), and 24 (-0.052; 95% CI 0.070, 0.034; p<0.001). Placebo patients started A1PI therapy at month 24 and showed significant reductions in plasma DES/IDES at months 36 (p<0.001) and 48 (p<0.001). Reduced elastin degradation was associated with slower lung density decline (p=0.005), correlating a chemical index of therapy with an anatomical index by CT. In conclusion, A1PI therapy reduced elastin degradation, including pulmonary elastin, in patients with AATD. These data support using DES/IDES levels as biomarkers to monitor emphysema progression and treatment response. PMID- 28848910 TI - GOLD Stage and Treatment in COPD: A 500 Patient Point Prevalence Study. AB - Background and Objective: The Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines recommend using a combination of spirometry, symptoms and exacerbation history to classify patients into 4 categories (A, B, C, D) to guide treatment decisions along with a stepwise increase in therapy. Our objectives were to identify the GOLD stage of patients in respiratory outpatient clinics and assess how treatment compares to guideline recommendations. Methods: This was a point prevalence study using a convenience sample of 500 patients with chronic obstructive pulmonary disease (COPD) from a single tertiary care outpatient respiratory clinic. Results: Patients' GOLD classification was determined based on symptoms (modified Medical Research Council [mMRC] dyspnea scale, COPD Assessment Test [CAT]), spirometry and self-reported exacerbation history. A total of 8.2% of patients were in the GOLD group A, 28.3% in group B, 4.2% in group C and 59.2% in group D. Conclusions: In this 500 patient point prevalence study we report a low proportion of patients in GOLD group C and a high level of inhaled corticosteroids (ICS)/ long-acting beta2-agonist (LABA) and triple therapy use throughout all GOLD categories. Clinical Implications: The GOLD guidelines have attempted to provide direction to practitioners by grouping patients into 4 groups based on symptoms and exacerbations however, the low prevalence of GOLD group C may indicate that not all of these groupings are clinically relevant. Future research is needed to better identify clinically relevant phenotypes that predict benefit from ICS and methods to promote guideline concordant management in COPD. PMID- 28848907 TI - Guiding Principles for the Use of Nebulized Long-Acting Beta2-Agonists in Patients with COPD: An Expert Panel Consensus. AB - Determining which patients with COPD may benefit from a nebulized long-acting beta2-agonist (LABA) is a challenge in current practice. In the absence of strong clinical guidelines addressing this issue, an expert panel convened to develop guiding principles for the use of nebulized LABA therapy in patients with COPD. This article summarizes these guiding principles and other practical issues discussed during a roundtable meeting. PMID- 28848911 TI - Benefits Among Patients with Alpha-1 Antitrypsin Deficiency Enrolled in a Disease Management and Prevention Program. AB - Rationale: Alpha-1 antitrypsin deficiency (AATD) is characterized by decreased circulating levels or activity of the serum protein, alpha-1 antitrypsin, which increases risk for chronic lung or liver injury and may lead to diseases such as chronic obstructive pulmonary disease (COPD). Currently there is no cure for AATD, and it is largely controlled through disease management and augmentation therapy. This study was designed to describe characteristics of patients enrolled in a disease management and prevention program. Methods: Data from questionnaires administered by AlphaNet were obtained on 4747 AATD patients and included demographic information, medical history, lifestyle choices, and adherence to the Alpha-1 Disease Management and Prevention Program (ADMAPP). A total of 1221 participants (25.72%) had missing adherence information and were excluded, leaving a final study population of 3526. Questionnaire answer dates ranged from May 29, 2008 to February 14, 2015. Logistic regression was used to adjust for demographic factors and comorbidities, comparing the populations stratified by adherence to ADMAPP. Results: After adjustment for age, sex, race, Charlson Comorbidity Index, and income level, individuals who self-reported any adherence to ADMAPP were more likely to feel informed about their condition (odds ratio[OR]adj 4.95, 95% confidence interval[CI][3.24, 7.57]), and be taking preventive measures, such as smoking cessation (ORadj 0.47, 95% CI [0.31, 0.70]), appropriate immunizations, and self-reported exercise (ORadj 2.07, 95% CI [1.74, 2.47]). Conclusions: This study suggests that ADMAPP may be a useful tool for informing and improving preventive measures taken by individuals with AATD. Future studies are needed to clarify the observed associations and study additional outcomes. PMID- 28848912 TI - The COPD Pipeline XXXIII. PMID- 28848913 TI - Journal Club: COPD and Oxygen Therapy. PMID- 28848914 TI - Images in COPD: Combined Pulmonary Emphysema and Fibrosis with Pulmonary Hypertension. PMID- 28848915 TI - Remembering John W. Walsh 1949 - 2017. PMID- 28848916 TI - What's New with the St George's Respiratory Questionnaire and Why Do We Care? PMID- 28848917 TI - Asthma and Chronic Obstructive Pulmonary Disease Overlap: The Effect of Definitions on Measures of Burden. AB - Background: Although the overlap between asthma and COPD has been recognized for years this overlap has only recently been given a name, asthma-COPD overlap syndrome (ACOS), and better defined. Different definitions of the component diseases can affect prevalence and outcome measures of ACOS. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from 2007 2012 to determine the population estimates of ACOS in U.S. adults using 2 different definitions of ACOS (ACOS1= self-reported COPD and current asthma; ACOS2 = spirometric-confirmed COPD [pre-bronchodilator FEV1/FVC < 70%] and current asthma) and to describe variation in other factors, such as lung function impairment and health care utilization, by ACOS definitions. Results: Among U.S. adults aged 20 and older, 1.6% had ACOS1, and 1.9% had ACOS2. Both case definitions were similar with regard to symptoms and impairment of lung function. ACOS1 individuals were more likely to have one or more overnight hospital stays relative to those with neither asthma nor COPD, (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.5, 4.6) than ACOS2 (OR 1.6, 95% CI 0.9, 2.9). Conclusions: Different definitions of ACOS in population-based studies affect both estimates of disease prevalence and outcomes related to the disease. These definitions need to be carefully considered in the design of epidemiologic studies and clinical trials. PMID- 28848918 TI - Subtyping Chronic Obstructive Pulmonary Disease Using Peripheral Blood Proteomics. AB - Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder. COPD patients may have different clinical features, imaging characteristics and natural history. Multiple studies have investigated heterogeneity using statistical methods such as unsupervised clustering to define different subgroups of COPD based largely on clinical phenotypes. Some studies have performed clustering using genetic data or limited numbers of blood biomarkers. Our primary goal was to use proteomic data to find subtypes of COPD within clinically similar individuals. In the Treatment of Emphysema with a gamma-Selective Retinoid Agonist (TESRA) study, multiplex biomarker panels were run in serum samples collected prior to randomization. After implementing an algorithm to minimize missing values, the dataset included 396 COPD individuals and 87 biomarkers. Using hierarchical clustering, we identified 3 COPD subgroups, containing 267 (67.4%), 104 (26.3%), and 25 (6.3%) individuals, respectively. The third cluster had less emphysema on quantitative analysis of chest computed tomography scans (p=0.03) and worse disease-related quality of life based on the St. George's Respiratory Questionnaire (total score cluster 1: 45.6, cluster 2: 45.4, cluster 3: 56.6; p=0.01), despite similar levels of lung function impairment (forced expiratory volume in 1 second (49.2%, 49.2%, 48.2 % predicted, respectively). Enrichment analysis showed the biomarkers distinguishing cluster 3 mapped to platelet alpha granule and cell chemotaxis pathways. Thus, we identified a subgroup which has less emphysema but may have greater inflammation, which could be potentially targeted with anti-inflammatory therapies. PMID- 28848919 TI - The COPD Biomarkers Qualification Consortium St George's Respiratory Questionnaire Manuscripts: Output of a Consortium to Advance Drug Development. PMID- 28848920 TI - The COPD Biomarkers Qualification Consortium Database: Baseline Characteristics of the St George's Respiratory Questionnaire Dataset. AB - The COPD Biomarkers Qualification Consortium (CBQC) is a public-private partnership formed in 2010 with a goal of qualifying biomarkers and clinical assessment tools for use in clinical or nonclinical decision-making and particularly within the regulatory context. The St George's Respiratory Questionnaire (SGRQ) is a measure of health-related quality of life widely used in clinical research. The aim of the CBQC working group on SGRQ was to construct an individual patient level database of clinical trial data that included the SGRQ, to use this to confirm the reliability and validity of the SGRQ as an outcome measure of health status, and investigate its use as a predictor of future events (exacerbations and mortality). This manuscript describes the formulation of the CBQC database and presents the baseline demographic and clinical characteristics of the integrated SGRQ database overall, and by study type (short-term [<=1 year], medium-term [2-4 years] and observational studies). Distribution of baseline SGRQ scores varied little by demographic determinants except for income region in the observational data set (low-middle income countries +10 units compared with high income, p<0.0001) and this observation held across studies. SGRQ scores increased with increasing modified Medical Research Council dyspnea scores (mean differences ranged 6.9-17.9 units) and with increasing airflow limitations (Global initiative for chronic Obstructive Lung Disease grades 1 to 4; differences ranged 4.5-16.1 units), consistent across study types. As a method of cross-sectional comparison, the SGRQ appears to be relatively free of bias from demographic factors although care should be taken when making cross sectional comparisons of scores between patients in countries at different levels of socio-economic development/. PMID- 28848921 TI - Responder Analyses for Treatment Effects in COPD Using the St George's Respiratory Questionnaire. AB - Background: Patient-reported outcomes data in clinical trials are usually reported as mean values, interpreted in comparison to a minimum clinically important difference (MCID) and ignoring the possibility of a sizable proportion of patients experiencing a worthwhile benefit when the majority did not. This analysis tested the reliability of calculated responder rates (from chronic obstructive pulmonary disease [COPD] patients) with the St George's Respiratory Questionnaire (SGRQ) using a range of responder cut-points above and below the MCID (4 units). Methods: Individual patient data (i.e., data from long-acting bronchodilator [LAB] and inhaled corticosteroids [ICS]/long-acting beta2-agonist [LABA] randomized clinical studies) in the COPD Biomarker Qualification Consortium database were used: short-term (<=1-year duration; 14,814 patients,) and medium-term (2-4 years; 12,043 patients). Responder rates versus placebo across SGRQ score change thresholds ranging from -1.5 to -8.0 were tested; differences were expressed as the odds ratio (OR) of a patient exceeding the threshold versus no change or deterioration. Results: The ORs measuring benefit of active treatment were similar across thresholds in short-term studies (LAB, ORs 1.40-1.42; LABA/ICS, 1.50-1.56) and medium-term LAB studies (ORs 1.34-1.43), whereas ORs in medium-term studies with LABA/ICS intervention showed a trend for higher response rates at higher values of threshold cut-points (1.64-1.79). In short-term studies, different thresholds had little effect on the OR between active drugs versus a trend for lower ORs with lower thresholds in medium-term studies. Conclusions: The OR for a treatment effect compared with placebo appears consistent across a range of responder cut-points. In medium-term trials, the treatment difference between active drugs suggests that use of a lower threshold would not increase the odds of observing a measured treatment difference. PMID- 28848922 TI - Baseline Severity as Predictor of Change in St George's Respiratory Questionnaire Scores in Trials of Long-acting Bronchodilators with COPD Patients. AB - Background: In trials oflong-acting bronchodilators, health status is an important trial outcome, however the influence of baseline severity on response measured by St George's Respiratory Questionnaire (SGRQ) is not known. We have compared SGRQ changes between patients with chronic obstructive pulmonary disease (COPD) of mild-moderate severity or dyspnea (Global initiative for chronic Obstructive Lung disease [GOLD] grades 1 and 2; modified Medical Research Council [mMRC] grades 1 and 2) to those with severe-very severe severity or dyspnea (GOLD grades 3 and 4; mMRC grades 3 and 4). Methods: Combined individual patient data from the COPD Biomarkers Qualification Consortium database (trials of long-acting bronchodilators) were used comprising of patients from short-term (<=1-year duration; n=10802) and medium-term (2-4 years' duration; n=8963) studies. A repeated measures analysis of variance (ANOVA) was used to determine the effects of baseline severity (GOLD/mMRC) on SGRQ response to treatment. All treatment arms were combined. Results: In short-term studies, milder patients showed a greater response than those with more severe disease in terms of GOLD grade (partial Eta2 = 0.03, p < 0.0001) and mMRC grade (partial Eta2 = 0.05, p < 0.0001). Similar results were seen in the medium-term studies (partial Eta2 = 0.02, p < 0.0001; mMRC: partial Eta2 = 0.05, p < 0.0001,). Conclusions: Patients with less severe airflow limitation and less severe dyspnea showed larger improvements in SGRQ score than more severely obstructed or dyspneic patients. Although these severity influences are small (2%-5% of the variance in SGRQ score), they do suggest that pre-specified separate analyses are warranted to test for differences in response, based on baseline severity. PMID- 28848923 TI - St George's Respiratory Questionnaire Score Predicts Outcomes in Patients with COPD: Analysis of Individual Patient Data in the COPD Biomarkers Qualification Consortium Database. AB - Background: We aimed to estimate the usefulness of a disease specific health status measure, the St George's Respiratory Questionnaire (SGRQ), to predict outcomes in patients with chronic obstructive pulmonary disease (COPD). Methods: Individual patient-data of 12043 patients from long-term randomized clinical trials (2-4 years' duration) in the COPD Biomarkers Qualification Consortium database were analyzed. The adverse COPD outcomes were: exacerbations of COPD, hospital admissions due to exacerbation and all-cause mortality. Cox proportional hazards regression was used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for quartiles of SGRQ scores at baseline and time to first event, and time from first to second event, where appropriate. Results: The risk of adverse COPD outcomes increased with each increasing quartile of SGRQ score for all time to first event analyses. When comparing the lowest versus the highest quartile, the event risk (HRs [95% CIs]) increased by 40% for exacerbations (1.40 [1.29, 1.51]); 2-fold for hospital admissions (2.01 [1.78, 2.28]) and more than 2-fold for all-cause mortality (2.30 [1.91, 2.78]). For second event analyses in a subset of eligible patients, these trends persisted albeit with reduced risk estimates for exacerbations. Conclusions: Among patients with COPD, health status measured by a SGRQ score predicted exacerbations of COPD, hospital admissions due to exacerbations and their recurrence and death after adjustment. These data support the rationale for a health status measure use as a drug development tool and suggest that a health status measure may also have a role in risk assessment for COPD patients in routine medical care. PMID- 28848924 TI - Socioeconomic Status as a Determinant of Health Status Treatment Response in COPD Trials. AB - Background: Randomized controlled trials (RCTs) often recruit patients from low and high socioeconomic status (SES) countries, but little is known about the effect of SES on clinical outcomes, particularly patient-centered measures of symptomatic benefit. Methods: Combined individual chronic obstructive pulmonary disease (COPD) patient data from the placebo and long-acting bronchodilator arms of 17 RCTs (from the COPD Biomarkers Qualification Consortium database) were analyzed. Health status was measured using the St George's Respiratory Questionnaire (SGRQ) (minimum clinically important difference [MCID]: 4 units). Trials were grouped into short-term (<=12 months) and medium-term (>12 months to 48 months). A participant's country of residence was categorized into Low/Medium or High SES using World Health Organization criteria. Results: Data from 19765 individuals (6109 Low/Medium SES) were available. Patients in Low/Medium SES countries had more severe disease at baseline. Improvement in SGRQ score with placebo was ~2 units greater in Low/Medium than in High SES countries; at its greatest, the improvement from baseline exceeded the MCID in Low/Medium countries. This difference was maintained for at least 1 year. Improvement with bronchodilator was also greater in Low/Medium versus High SES countries; overall there was no evidence that the treatment effect versus placebo was different between countries of different SES status. Conclusions: Participants in Low/Medium SES countries experienced significantly larger treatment effects, irrespective of treatment group (placebo and bronchodilator). Despite this, COPD patients in Low/Medium SES countries experienced a health status gain from long acting bronchodilator treatment that is similar to that seen in High SES countries. PMID- 28848925 TI - The COPD Pipeline XXXIV. PMID- 28848926 TI - Journal Club: Inhaled Corticosteroids- Refining Our Understanding of Their Role in Maintenance Treatment for COPD. PMID- 28848927 TI - Images in COPD: Bullous Emphysema with Mycetoma. PMID- 28848928 TI - Personalization of Device Therapy - Prime Time for Peak Inspiratory Flow Rate. PMID- 28848929 TI - The 2017 Update to the COPD Foundation COPD Pocket Consultant Guide. AB - The COPD Foundation Pocket Consultant Guide (PCG) was first released in 2007 as a practice tool for use at point of service for clinicians, especially primary care clinicians diagnosing and treating patients with chronic obstructive pulmonary disease (COPD). Over the years, the PCG has been supplemented with a mobile app that presents the tool in an online smart phone accessible version that also allows the clinician to enter patient specific data for guidance to next steps of diagnosis or management. In November 2016, a new update of the PCG was released that incorporates a flow diagram for stepped care that includes the newest recommendation for diagnosis, assessment and treatment; including the broad use of dual bronchodilator therapy and consideration of asthma COPD overlap syndrome (ACOS). The current controversy regarding when to add inhaled corticosteroids (ICSs) is addressed to support clinical decision making. The PCG comes in 2 versions, one with generic names for COPD drugs available in the United States and one with trade names for those drugs. The update continues to recommend spirometry for those at highest risk, also emphasizing the need to assess symptoms, exacerbation risks and comorbidity before selecting appropriate non pharmacological as well as pharmacological therapy. The tool is designed to facilitate COPD management in daily practice. PMID- 28848930 TI - A Survey of Corticosteroid Dosing for Exacerbations of Chronic Obstructive Pulmonary Disease Requiring Assisted Ventilation. AB - Background: For over 40 years, systemic corticosteroids have been a mainstay of treatment for patients with exacerbations of chronic obstructive pulmonary disease (COPD). Surprisingly, the optimal dosage of corticosteroids is unknown in critically ill patients requiring assisted ventilation, a group with high morbidity and mortality. Methods: We surveyed 39 academic physicians within the United States Critical Illness and Injury Trials Group (USCIITG) and the Prevention and Early Treatment of Acute Lung Injury Trials Network (PETAL) to determine the range of corticosteroid dosages used to treat patients with COPD exacerbations requiring assisted ventilation. We also asked if these physicians believe that a clinical trial is needed to determine the optimal dosage of corticosteroids in this population. Results: Thirty-two physicians (82%) responded to the survey. Usual practice was to start intravenous methylprednisolone at a median dose of 120 mg/day (range 40-500 mg/day). In the context of a clinical trial, 78% of physicians were comfortable initiating methylprednisolone at a dose as low as 40 mg/day. In contrast, physicians were split on the highest acceptable methylprednisolone dose, with 44% comfortable initiating doses as high as 500 mg/day, 44% at 240 mg/day, and 12% at doses less than 240 mg/day. Ninety-four percent of respondents believed that a randomized controlled trial is needed to determine the optimal corticosteroid dose to treat patients with COPD exacerbations requiring assisted ventilation. Conclusions: These results demonstrate sufficient clinical equipoise to support the conduct of a clinical trial to identify the optimal dose of systemic corticosteroids for patients with COPD exacerbations requiring assisted ventilation. PMID- 28848931 TI - Chronic Pain in People With Chronic Obstructive Pulmonary Disease: Prevalence, Clinical and Psychological Implications. AB - Background: Although pain is a common symptom in chronic obstructive pulmonary disease (COPD), pain characteristics such as frequency, duration and type are unclear. The primary study aim was to identify these pain characteristics in individuals with COPD versus healthy control participants. The secondary aim was to explore the clinical and psychological associations with pain in those with COPD. Methods: Participants with COPD and age and gender-matched, healthy controls completed questionnaires to elicit pain characteristics. Those with COPD also had assessments of dyspnea, health-related quality of life, psychological associations (anxiety and depression) and physical activity. Results: Sixty-four participants with COPD (mean [standard deviation (SD)] age 71[10] , forced expiratory volume in 1 second [FEV1] 38% predicted) and 64 control participants (mean [SD] age 67 [13] , FEV1 91% predicted) were included. Chronic pain was more prevalent in individuals with COPD compared to control participants (41% versus 29%, p=0.03). The pain was more prevalent in the chest and upper back (p=0.04). COPD participants with chest or upper back pain had a higher total lung capacity (mean difference 2.0L, 95% confidence interval [CI] 0.6 to 3.0L) compared to COPD participants without pain. Greater dyspnea (p<0.001), more depression (p=0.02) and lower physical activity levels (p=0.03) were also present in people with COPD experiencing pain. Conclusions: Chronic pain is common in COPD. It is associated with higher dyspnea and depression and lower physical activity. PMID- 28848933 TI - Prevalence of Low Peak Inspiratory Flow Rate at Discharge in Patients Hospitalized for COPD Exacerbation. AB - Background: Low peak inspiratory flow rate (PIFR) (<60 L/min) among patients with chronic obstructive pulmonary disease (COPD) may result in ineffective medication inhalation, leading to poor bronchodilation. Objective: The objectives of this analysis were to evaluate the prevalence of low PIFR at the time of discharge from a COPD-related hospitalization and to examine the real-world treatment patterns and rehospitalizations by PIFR. Methods: Patients at 7 sites in the United States were screened for enrollment at hospital discharge. PIFR was measured using the InCheckTM DIAL to simulate resistance of the DISKUS(r) dry powder inhaler (DPI). An equal number of patients were enrolled into low PIFR (<60 L/min) or normal PIFR (>=60 L/min) cohorts. Demographics, COPD-related clinical characteristics, health status, treatment and rehospitalization data were collected. Results: Mean PIFR was 71+/-22.12 L/min among 268 screened patients; 31.7% (n=85) of patients had low PIFR. Among all enrolled patients (n=170), the low PIFR cohort was older (66.2+/-10.04 years versus 62.1+/-9.41 years, p=0.006) and more likely to be female (61.2% versus 42.4%, p=0.014). There was an increase in DPI use at discharge, compared with admission, in the low PIFR cohort (62.4% versus 70.6%, p=0.020). The incidences of all-cause rehospitalization up to 180 days were similar between the low and normal PIFR cohorts. Conclusions: At discharge following hospitalization for an exacerbation of COPD, approximately one-third of patients had a PIFR <60 L/min. More patients with a low PIFR were discharged with a DPI medication compared with use at admission. There was no difference in the rehospitalization rates by PIFR. PMID- 28848932 TI - Serum Proteins Associated with Emphysema Progression in Severe Alpha-1 Antitrypsin Deficiency. AB - Computed tomography (CT) lung density is an accepted biomarker for emphysema in alpha-1 antitrypsin deficiency (AATD), although concerns for radiation exposure limit its longitudinal use. Serum proteins associated with emphysema, particularly in early disease, may provide additional pathogenic insights. We investigated whether distinct proteomic signatures characterize the presence and progression of emphysema in individuals with severe AATD and normal forced expiratory volume in 1 second (FEV1). QUANTitative lung CT UnMasking emphysema progression in AATD (QUANTUM-1) is a multicenter, prospective 3-year study of 49 adults with severe AATD and FEV1 post-bronchodilator values (Post-BD) >= 80% predicted. All participants received chest CT, serial spirometry, and contributed to the serum biobank. Volumetric imaging display and analysis (VIDA) software defined the baseline 15th percentile density (PD15) which was indexed to CT derived total lung capacity (TLC). We measured 317 proteins using a multiplexed immunoassay (Myriad Discovery MAP(r) panel) in 31 individuals with a complete dataset. We analyzed associations between initial PD15/TLC, PD15/TLC annual decline, body mass index (BMI), and protein levels using Pearson's product moment correlation. C-reactive protein (CRP), adipocyte fatty acid-binding protein (AFBP), leptin, and tissue plasminogen activator (tPA) were found to be associated with baseline emphysema and all but leptin were associated with emphysema progression after adjustments were made for age and sex. All 4 proteins were associated with BMI after further adjustment for multiple comparisons was made. The relationship between these proteins and BMI, and further validation of these findings in replicative cohorts require additional studies. PMID- 28848934 TI - COPD10: Birmingham,United Kingdom, July 2016. PMID- 28848935 TI - The COPD Pipeline XXXV. PMID- 28848936 TI - The Journal Club: COPD Exacerbations. PMID- 28848938 TI - Successful management of post-traumatic vancomycin-resistant enterococcus endophthalmitis. AB - PURPOSE: To highlight good visual outcome with intravitreal amikacin administered 18 days following trauma-inducing vancomycin resistant enterococcal endophthalmitis treated initially with vitrectomy and oral linezolid. OBSERVATIONS: Despite initial vitrectomy, intravitreal vancomycin, ceftazidime and oral linezolid, smoldering vitreous infiltrates prompted treatment with intravitreal amikacin 18 days later and restored vision to 20/40 in a vancomycin resistant traumatic endophthalmitis. CONCLUSIONS AND IMPORTANCE: Good visual outcome was attained with intravitreal injection of amikacin 18 days following penetrating trauma and vancomycin resistant enterococcal endophthalmitis that smoldered following initial treatment of vitrectomy, intravitreal antibiotics and oral linezolid. PMID- 28848937 TI - Model for Studying Anti- Allergic Drugs for Allergic Conjunctivitis in Animals. AB - : Allergic conjunctivitis (AC), which is characterized by ocular itching, hyperemia, and edema, deteriorates quality of life. In this study, effects of anti-allergic drugs were evaluated by assessing eye-scratching behavior, the number of eosinophils in conjunctiva epithelial tissues, and concentrations of chemical mediators in the tears of the guinea pig model of ovalbumin (OA)-induced AC. METHODOLOGY: On day 0, 3-week-old guinea pigs were sensitized by OA subconjunctival injections. On days 15, 17, and 19, OA solution was administered. Anti-allergic eye drops were administered 5 and 15 min before the final OA challenge on day 19. Scratching behavior within 1 h after OA exposure was studied. Eosinophils in the conjunctiva were stained with Giemsa reagent. Histamine and substance P (SP) concentrations in tears were measured using ELISA. RESULTS: Subconjunctivally injected guinea pigs were observed for clinical symptoms. Scratching responses significantly reduced with ketotifen or olopatadine treatment. Eosinophil numbers reduced in animals treated with ketotifen, levocabastine, or tranilast. Histamine and/or SP concentrations in tears were inhibited by some of these anti-allergic drugs. CONCLUSIONS: It is important to assess the anti-allergic AC drugs objectively because there are several of these drugs currently available. This model allows for an objective evaluation of anti-allergic drugs for AC. PMID- 28848939 TI - Fluorescent chirality recognition by simple boronate ensembles with aggregation induced emission capability. AB - Chiral ensembles were spontaneously formed in solution through boronate esterification of structurally defined di(boronic acid)-appended tetraphenylethylene (DB-TPE) and commercially available l- or d-tartaric acid, showing enantioselective aggregation behavior for chiral diamines as well as cinchona alkaloids enabling the fluorescent recognition of their chirality. PMID- 28848940 TI - In situ monitoring the viscosity change of an electrolyte in a Li-S battery. AB - We clarify the reactions in a lithium-sulfur cell by in situ monitoring the change in viscosity of its electrolyte. The results have revealed that Li2S2 is a soluble substance in the electrolyte. This contradicts what was suggested in the literature that it is a solid precipitate on the electrode. PMID- 28848941 TI - A covalent G-site inhibitor for glutathione S-transferase Pi (GSTP1-1). AB - We herein report the first covalent G-site-binding inhibitor for GST, GS-ESF (1), which irreversibly inhibited the GSTP1-1 function. LC-MS/MS and X-ray structure analyses of the covalently linked GST-inhibitor complex suggested that 1 reacted with Tyr108 of GSTP1-1. The mechanism of covalent bond formation was discussed based on MD simulation results. PMID- 28848942 TI - A five-coordinate manganese(iii) complex of a salen type ligand with a positive axial anisotropy parameter D. AB - A new high-spin d4 roughly trigonal-bipyramidal (TBP) manganese(iii) complex with a salen type ligand (H2L), namely MnL(NCS).0.4H2O, has been synthesised and characterised by elemental analysis, ESI mass spectrometry, IR and UV-vis spectroscopy, and spectroelectrochemistry. X-ray diffraction analysis revealed an axial compression of the approximate TBP. Temperature dependent magnetic susceptibility and variable-temperature variable-field (VTVH) magnetisation measurements, as well as high-frequency and -field EPR (HFEPR) spectroscopy, were used to accurately describe the magnetic properties of this complex and, in particular, determine the spin Hamiltonian parameters: g-values and the zero field splitting (ZFS) parameters D and E. The HFEPR spectra allowed the extraction of fourth order ZFS parameters. Quantum chemical calculations reproduced well the electronic and geometric structures of this unusual complex and, in particular, its electronic absorption spectrum along with the spin Hamiltonian parameters. PMID- 28848943 TI - Wheel-like, elongated, circular, and linear geometries in boron-based CnB7-n (n = 0-7) clusters: structural transitions and aromaticity. AB - We report a quantum chemical study on the structural and bonding properties of a series of boron-carbon mixed clusters with seven atoms: CnB7-n (n = 0-7). Global minimum structures were searched using the Coalescence Kick (CK) method, followed by B3LYP/6-311+G(d) calculations for full optimizations and energetics. Top candidate structures were further benchmarked at the single-point CCSD(T) level. Structural transitions were revealed to occur successively between wheel-like, elongated, circular, and linear geometries upon the increase of C contents in the clusters. Chemical bonding was elucidated via canonical molecular orbital (CMO) analyses and adaptive natural density partitioning (AdNDP). The number of delocalized electrons (sigma plus pi) in the clusters was shown to vary by one at a time from 5sigma to 7sigma, as well as from 3pi to 6pi, which allows aromaticity, antiaromaticity, and conflicting aromaticity to be precisely tuned according to the (4n + 2) and 4n Huckel rules. Delocalized pi and sigma bonds and their electron counting appear to dictate the cluster structures of the whole series. Aromaticity in the systems was independently confirmed using nucleus independent chemical shifts (NICSs). The monocyclic B2C5 cluster was shown to possess the greatest NICS values, consistent with its 6pi plus 6sigma electron countings for double aromaticity. Our analyses also shed light on the reason why C in the filled-hexagonal B6C cluster occupies a peripheral site rather than the center and why C avoids hypercoordination in B-C binary clusters. A similar argument should be valid for other B-C clusters in prior reports, such as B6C2-, B7C-, and B8C. PMID- 28848944 TI - Modulation of ICT probability in bi(polyarene)-based O-BODIPYs: towards the development of low-cost bright arene-BODIPY dyads. AB - We report the synthesis, and spectroscopic and electrochemical properties of a selected library of novel spiranic O-BODIPYs bearing a phenol-based bi(polyarene) unit tethered to the boron center through oxygen atoms. These dyes constitute an interesting family of arene-BODIPY dyads useful for the development of photonic applications due to their synthetic accessibility and tunable photonic properties. It is demonstrated that the electron-donor capability of the involved arene moiety switches on a non-emissive intramolecular charge transfer (ICT) state, which restricts the fluorescence efficiency of the dyad. Interestingly, the influence of this non-radiative deactivation channel can be efficiently modulated by the substitution pattern, either at the dipyrrin ligand or at the polyarene moiety. Thus, dyads featuring electron-rich dipyrrin and electron-poor polyarene show lower or almost negligible ICT probability, and hence display bright fluorescence upon dual excitation at far-away spectral regions. This synthetic approach has allowed the easy development of low-cost efficient ultraviolet-absorbing visible-emitting cassettes by selecting properly the substitution pattern of the involved key units, dipyrrin and bi(polyarene), to modulate not only absorption and emission wavelengths, but also fluorescence efficiencies. PMID- 28848945 TI - Structural diversities induced by cation sizes in a series of fluorogermanophosphates: A2[GeF2(HPO4)2] (A = Na, K, Rb, NH4, and Cs). AB - Germanophosphates, in comparison with other metal phosphates, have been less studied but potentially exhibit more diverse structural chemistry with wide applications. Herein we applied a hydro-/solvo-fluorothermal route to make use of both the "tailor effect" of fluoride for the formation of low dimensional anionic clusters and the presence of alkali cations of different sizes to align the anionic clusters to control the overall crystal symmetries of germanophosphates. The synergetic effects of fluoride and alkali cations led to structural changes from chain-like structures to layered structures in a series of five novel fluorogermanophosphates: A2[GeF2(HPO4)2] (A = Na, K, Rb, NH4, and Cs, denoted as Na, K, Rb, NH4, and Cs). Although these fluorogermanophosphates have stoichiometrically equivalent formulas, they feature different anionic clusters, diverse structural dimensionalities, and contrasting crystal symmetries. Chain like structures were observed for the compounds with the smaller sized alkali ions (Na+, K+, and Rb+), whereas layered structures were found for those containing the larger sized cations ((NH4)+ and Cs+). Specifically, monoclinic space groups were observed for the Na, K, Rb, and NH4 compounds, whereas a tetragonal space group P4/mbm was found for the Cs compound. These compounds provide new insights into the effects of cation sizes on the anionic clusters built from GeO4F2 octahedra and HPO4 tetrahedra as well as their influences on the overall structural symmetries in germanophosphates. Further characterization including IR spectroscopy and thermal analyses for all five compounds is also presented. PMID- 28848946 TI - Tandem trifluoromethylthiolation/aryl migration of aryl alkynoates to trifluoromethylthiolated alkenes. AB - A trifluoromethylthiolation initiated aryl migration of aryl alkynoates was disclosed. This protocol employs AgSCF3 as the SCF3 source and MeCN as both the solvent and the hydrogen source. This provides a new access to trifluoromethylthiolated alkenes from readily available substrates and reagents. PMID- 28848947 TI - Hydrogen bond and lifetime dynamics in diluted alcohols. AB - Hydrogen-bonding plays a crucial role in many chemical and biochemical reactions. Alcohols, with their hydrophilic and hydrophobic groups, constitute an important class of hydrogen-bonding molecules with functional tuning possibilities through changes in the hydrophobic tails. Recent studies demonstrated that for solutions of alcohols changes in the hydrophobic tail significantly affect a broad range of dynamics properties of the liquid. Still, the understanding is lacking on the origin of such differences in terms of a solvent- versus a solute-dominated effect. Here we reveal this origin by studying hydrogen-bond dynamics in a number of alcohol molecules - from methanol to butanol - diluted in a hydrogen-bond accepting environment, acetonitrile. The dynamics were investigated by pump-probe and 2D infrared spectroscopy combined with molecular dynamics-spectral simulations, using the OH stretching mode as a reporter. For all the considered alcohols, the vibrational lifetime of the OH stretching mode was found to be ~3 ps. The hydrogen-bond dynamics exhibit similar behavior with a fast (~200 fs) initial relaxation dominated by librational motion and a slow (~4 ps) relaxation due to hydrogen-bond exchange dynamics. The similar dynamics over such a broad range of alcohols led us to conclude that the previously observed differences in dynamics in bulk alcohols originate from the dependence of the solvent properties on the hydrophobic tail, while the solute properties as found herein are essentially independent of the hydrophobic tail. PMID- 28848948 TI - Enhancing thermoelectrochemical properties by tethering ferrocene to the anion or cation of ionic liquids: altered thermodynamics and solubility. AB - Entropic changes inherent within a redox process typically result in significant temperature sensitivity. This can be utilised positively or can be a detrimental process. This study has investigated the thermoelectrochemical properties (temperature-dependant electrochemistry) of the ferrocenium|ferrocene redox couple in an ionic liquid, and in particular the effect of covalently tethering this redox couple to fixed positive or negative charges. As such, the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide was employed to dissolve ferrocene, as well as cationic-tethered ferrocene (the 1-ethyl-3 (methylferrocenyl)imidazolium cation) and anionic-tethered ferrocene (the ferrocenylsulfonyl(trifluoromethylsulfonyl)imide anion). These systems were characterised in terms of their voltammetry (apparent formal potentials, diffusion coefficients and electron transfer rate constants) and thermoelectrochemistry (temperature coefficients of the cell potential or 'Seebeck coefficients', short circuit current densities and power density outputs). The oxidised cationic species behaved like a dicationic species and was thus 6-fold more effective at converting waste thermal energy to electrical power within a thermoelectrochemical cell than unmodified ferrocene. This was almost exclusively due to a significant boost in the Seebeck coefficient of this redox couple. Conversely, the oxidised anionic species was formally a zwitterion, but this zwitterionic species behaved thermodynamically like a neutral species. The inverted entropic change upon going from ferrocene to anion-tethered ferrocene allowed development of a largely temperature-insensitive reference potential based upon a mixture of acetylferrocene and ferricenyl(iii)sulfonyl(trifluoromethylsulfonyl)imide. PMID- 28848949 TI - Correction: Nanocrystalline Fe-Fe2O3 particle-deposited N-doped graphene as an activity-modulated Pt-free electrocatalyst for oxygen reduction reaction. AB - Correction for 'Nanocrystalline Fe-Fe2O3 particle-deposited N-doped graphene as an activity-modulated Pt-free electrocatalyst for oxygen reduction reaction' by Vishal M. Dhavale et al., Nanoscale, 2015, 7, 20117-20125. PMID- 28848950 TI - Particle accumulation and depletion in a microfluidic Marangoni flow. AB - Thermosolutal and thermocapillary Marangoni convection at a liquid-gas interface in a microchannel structure of approximately 100 * 90 MUm2 cross section creates a localized vortex that acts as a trap for micrometer and sub-micrometer sized tracer particles. Next to the vortex, depleted volumes appear that are entirely cleared of particles. This particle redistribution is caused by collisions of the tracers with the meniscus, which push the particles back onto the critical streamline with one particle radius distance to the meniscus. The streamlines between the meniscus and the critical streamline feed the depleted regions. Since the critical streamline depends on the particle radius, the effect leads to a particle fractionation according to their size. Diffusion allows only small particles to escape from the trap. Larger particles are permanently confined and their diffusion is rectified after every revolution at the meniscus, which produces a ratchet effect and increases the particle localization within the vortex. PMID- 28848951 TI - Space irradiation-induced damage to graphene films. AB - Graphene with impressive electrical, optical, chemical and mechanical properties has promising potential applications for photoelectric devices and mechanical components installed on the space facilities, which will probably face hostile environments including high-energy particulate irradiation. Here we explored the effect of simulated space irradiation on the structure and properties of large area single-layer and multi-layer graphene films (about four layers) including atomic oxygen (AO), electron (EL) and proton (PR). AO with strong oxidizing capacity reacts with carbon atoms of graphene films and generates carbon dioxide, high-energy PR leads to polymorphic atomic defects in graphene through collision and excitation effects. Miraculously, EL irradiation causes little damage to the graphene films because of the excellent conductivity. Graphene ripples are broken by irradiation and adapt their shape or structure with respect to the substrate via thermodynamic stability, which causes the change of the physical and mechanical properties of graphene. PMID- 28848952 TI - Piezoelectricity enhancement and bandstructure modification of atomic defect mediated MoS2 monolayer. AB - Piezoelectricity appears in the inversion asymmetric crystal that converts mechanical deformation to electricity. Two-dimensional transition metal dichalcolgenide (TMDC) monolayers exhibit the piezoelectric effect due to inversion asymmetry. The intrinsic piezoelectric coefficient (e11) of MoS2 is ~298 pC m-1. For the single atomic shift of Mo of 20% along the armchair direction, the piezoelectric coefficient (e11) of MoS2 with 5 * 5 unit cells was enhanced up to 18%, and significantly modified the band structure. The single atomic shift in the MoS2 monolayer also induced new energy levels inside the forbidden bandgap. The defect-induced energy levels for a Mo atom shift along the armchair direction are relatively deeper than that for a S atom shift along the same direction. This indicates that the piezoelectricity and band structure of MoS2 can be engineered by a single atomic shift in the monolayer with multi unit cells for piezo- and opto-electric applications. PMID- 28848953 TI - Enantioselective bioreduction of benzo-fused cyclic ketones with engineered Candida glabrata ketoreductase 1 - a promising synthetic route to ladostigil (TV3326). AB - Biocatalysis has been recently emerging as a promising alternative to traditional chemical synthesis because of its "green" characteristics and comparable selectivities, which accord with the concept of sustainable development and demand for asymmetric synthesis. In this study, whole-cell biocatalysts containing glucose dehydrogenase (GDH) and Candida glabrata ketoreductase 1 (CgKR1) variants were constructed. These biocatalysts were applied to the reduction of benzo-fused cyclic ketones and showed good to high activities and enantioselectivities. Particularly, CgKR1 variants displayed high activities (90.6%-98.4% conversions) and enantioselectivities (>99.9% ee) towards 5a, a key intermediate of ladostigil (TV3326). Based on these results, a chemoenzymatic synthesis of (S)-5b was developed by using biocatalytic asymmetric reduction as a key step, giving the product with a total yield of 34.0% and 99.9% ee. PMID- 28848954 TI - A molecular dynamics study of conformations of beta-cyclodextrin and its eight derivatives in four different solvents. AB - Understanding the atomic level interactions and the resulting structural characteristics is required for developing beta-cyclodextrin (betaCD) derivatives for pharmaceutical and other applications. The effect of four different solvents on the structures of the native betaCD and its hydrophilic (methylated betaCD; MEbetaCD and hydroxypropyl betaCD; HPbetaCD) and hydrophobic derivatives (ethylated betaCD; ETbetaCD) was explored using molecular dynamics (MD) simulations and solvation free energy calculations. The native betaCD, 2 MEbetaCD, 6-MEbetaCD, 2,6-DMbetaCD, 2,3,6-TMbetaCD, 6-HPbetaCD, 2,6-HPbetaCD and 2,6-ETbetaCD in non-polar solvents (cyclohexane; CHX and octane; OCT) were stably formed in a symmetric cyclic cavity shape through their intramolecular hydrogen bonds. In contrast, betaCDs in polar solvents (methanol; MeOH and water; WAT) exhibited large structural changes and fluctuations leading to significant deformations of their cavities. Hydrogen bonding with polar solvents was found to be one of the major contributors to this behavior: solvent-betaCD hydrogen bonding strongly competes with intramolecular bonding leading to significant changes in the structural stability of betaCDs. An exception to this is the hydrophobic 2,6-ETbetaCD which retained its spherical cavity in all solvents. Based on this, it is proposed that the 2,6-ETbetaCD can act as a sustained release drug carrier. PMID- 28848955 TI - Mechanism of gas-phase ozonolysis of sabinene in the atmosphere. AB - Sabinene is one of the monoterpenes of biogenic origin in the atmosphere. Ozonolysis is one of the important oxidation removal reactions for sabinene in the atmosphere during the daytime, leading to the formation of secondary organic aerosols. In this study, we investigate the mechanism of gas-phase ozonolysis of sabinene using quantum chemistry and kinetic calculations. The reaction starts with the formation of four primary ozonides (POZs), which decompose to primary product channels CH2OO + sabinaketone and CH2O + two Criegee intermediates (CI-1 and CI-2) with branching ratios of 17%, 45%, and 38%, respectively, at 298 K and 760 Torr. Calculations showed that the stabilized CI-1 would undergo a rapid intramolecular H-shift to a vinyl hydroperoxide (VHP) at a rate of ~2700 s-1 followed by rapid decomposition to an OH radical and a vinoxy-type radical (VTR) and CI-2 would slowly isomerize to dioxirane at a rate of 0.97 s-1. In the atmosphere, CI-2 would instead react with water and the water dimer, forming alpha-hydroxyalkyl hydroperoxides (alphaHAHPs), which would decompose to sabinaketone and H2O2via heterogeneous processes. The reaction of CI-2 with SO2 would also be significant in a dry and cold atmosphere. The yield of sabinaketone of 47%, from primary POZ decomposition and secondary reactions of alphaHAHPs, agrees with the previously measured values of 35-50%. The OH radical, formed from CI-1, could reach 44%, agreeing with the previously reported value of (33 +/- 6)%. Further reaction of the VTR radical would form highly-oxidized multifunctional products containing carboxylic and/or carbonyl groups which might contribute substantially to SOA formation. PMID- 28848956 TI - The effect of intramolecular cross links on the mechanochemical fragmentation of polymers in solution. AB - Addition of intramolecular cross-links to linear polymers significantly improves their resistance to mechanochemical fragmentation, and hence the physical properties of polymer solutions are maintained under shear. However, while fragmentation is suppressed, mechanochemistry of chemical bonds still occurs. In linear polymers, the rate of mechanochemistry has been shown to increase linearly with the degree of polymerisation. Here, we report a systematic study of the mechanochemical fragmentation of a series of polymers with increasing polymer length, linear and intramolecularly collapsed, in order to understand the correlation between destructing and non-damaging mechanochemical events. By comparing the trends of the fragmentation kinetic rate vs. the degree of polymerisation, the effect of intramolecular collapse on fundamental mechanochemistry parameters such as the limiting molecular weight and stabilisation effect can be further understood. PMID- 28848957 TI - Epoxide formation from heterogeneous oxidation of benzo[a]pyrene with gas-phase ozone and indoor air. AB - The formation of two classes of epoxide products from the heterogeneous reaction of benzo[a]pyrene (BaP) with gas-phase ozone was demonstrated. BaP was coated on a Pyrex glass tube and oxidized with different concentrations of ozone. After oxidation, the epoxide products were derivatized by N-acetylcystein (NAC) and then analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results show that in addition to mono-epoxides, diol-epoxides were also formed. BaP exposed to genuine indoor air also produces mono- and diol-epoxides, having similar chromatograms to those produced by oxidation of BaP by low concentrations of ozone. Although it is well recognized that diol-epoxides are formed from BaP oxidation in the human body and that they exhibit carcinogenicity via formation of adducts with DNA, this is the first demonstration that such classes of compounds can be formed by abiotic heterogeneous oxidation. PMID- 28848958 TI - Creep-induced anisotropy in covalent adaptable network polymers. AB - Anisotropic polymers with aligned macromolecule chains exhibit directional strengthening of mechanical and physical properties. However, manipulating the orientation of polymer chains in a fully cured thermoset is almost impossible due to its permanently crosslinked nature. In this paper, we demonstrate that rearrangeable networks with bond exchange reactions (BERs) can be utilized to tailor the anisotropic mechanical properties of thermosetting polymers. When a constant force is maintained at BER activated temperatures, the malleable thermoset creeps in the direction of stress, and macromolecule chains align themselves in the same direction. The aligned polymer chains result in an anisotropic network with a stiffer mechanical behavior in the direction of creep, while with a more compliant behavior in the transverse direction. The degree of network anisotropy is proportional to the amount of creep strain. A multi-length scale constitutive model is developed to study the creep-induced anisotropy of thermosetting polymers. The model connects the micro-scale BER kinetics, orientation of polymer chains, and directional mechanical properties of network polymers. Without any fitting parameters, it is able to predict the evolution of creep strain at different temperatures and anisotropic stress-strain behaviors of CANs after creep. Predictions on the chain orientation are verified by molecular dynamics (MD) simulation. Based on parametric studies, it is shown that the influences of creep time and temperature on the network anisotropy can be generalized into a single parameter, and the evolution of directional modulus follows an Arrhenius type time-temperature superposition principle (TTSP). The presented work provides a facile approach to transform isotropic thermosets into anisotropic ones using simple heating, and their directional properties can be readily tailored by the processing conditions. PMID- 28848959 TI - UV Index monitoring in Europe. AB - The UV Index was established more than 20 years ago as a tool for sun protection and health care. Shortly after its introduction, UV Index monitoring started in several countries either by newly acquired instruments or by converting measurements from existing instruments into the UV Index. The number of stations and networks has increased over the years. Currently, 160 stations in 25 European countries deliver online values to the public via the Internet. In this paper an overview of these UV Index monitoring sites in Europe is given. The overview includes instruments as well as quality assurance and quality control procedures. Furthermore, some examples are given about how UV Index values are presented to the public. Through these efforts, 57% of the European population is supplied with high quality information, enabling them to adapt behaviour. Although health care, including skin cancer prevention, is cost-effective, a proportion of the European population still doesn't have access to UV Index information. PMID- 28848960 TI - Anti-obesity effects of zeaxanthin on 3T3-L1 preadipocyte and high fat induced obese mice. AB - Zeaxanthin, a type of carotenoid, has been proven to exhibit anti-lipogenesis effect; however, the detailed mechanism of this effect is less known. Herein, we evaluated the effects of zeaxanthin on the inhibition of adipogenesis in 3T3-L1 adipocytes and obesity in high-fat diet fed C57BL/6J mice. Zeaxanthin significantly decreased the intracellular lipid content in a dose-dependent manner (5-15 MUM) in adipocytes without causing cytotoxicity. In high-fat-diet induced obese mice, oral administration of 20 mg kg-1 zeaxanthin attenuated the progression of obesity and improved dyslipidemia. It exhibits an anti-adipogenic effect via down-regulating the transcriptional factors and adipocyte-specific genes involved in adipogenesis, both in vitro and in vivo. Furthermore, zeaxanthin treatment reversed the MDI (0.5 mM 3-isobutyl-1-methylxanthine, 1.0 MUM dexamethasone, and 1.0 MUg mL-1 insulin) and HFD (high-fat diet)-induced inhibition of AMPK phosphorylation in adipocytes and epididymal adipose tissues, respectively, thereby modulating the energy metabolism. These results indicated that zeaxanthin plays anti-adipogenic and anti-obesity roles by inducing AMPK activation, inhibiting lipogenesis, and decreasing intracellular lipid content, adipocyte size, and adipose weight. PMID- 28848961 TI - Effects of a phosphonate anchoring group on the excited state electron transfer rates from a terthiophene chromophore to a ZnO nanocrystal. AB - Terthiophene dyes were synthesized having a carboxylate or a phosphonate moiety at the 2-position which serves as an anchoring group to zinc oxide nanocrystals (ZnO NCs). Electronic absorption and fluorescence measurements, combined with reduction potentials, provided estimates of -1.81 and -1.86 V vs. NHE for the excited state reduction potential of the carboxylate and phosphonate, respectively. Static quenching was observed when the dyes were bound to the surface of acetate-capped ZnO NCs having a diameter of 2.8 nm. Stern-Volmer studies conducted at several dye concentrations established that a minor fraction of the adsorbed dye remained unquenched even at 1 : 1 dye to NC ratios. Adsorption isotherm measurements established that the phosphonate binds more strongly than the carboxylate and that saturation coverage was ~1.2 dyes per nm2 for both dyes. Ultrafast transient absorption spectroscopic experiments were used to probe excited state dynamics. In the presence of ZnO NCs, disappearance of the singlet excited state of the dye corresponded to appearance of the spectroscopic signature of the oxidized dye with a time constant of 1.5 +/- 0.1 and 6.1 +/- 0.2 ps, respectively, for the carboxylate and phosphonate dye. The difference in the electron transfer rates was attributed to a larger electronic coupling for the dye having the carboxylate anchoring group. PMID- 28848962 TI - Emergence of epithelial cell density waves. AB - Epithelial cell monolayers exhibit traveling mechanical waves. We rationalize this observation thanks to a hydrodynamic description of the monolayer as a compressible, active and polar material. We show that propagating waves of the cell density, polarity, velocity and stress fields may be due to a Hopf bifurcation occurring above threshold values of active coupling coefficients. PMID- 28848963 TI - Unprecedented tetranuclear complexes with "weighing balance shaped" topology: single crystal structures, unusual EPR spectra, magnetic properties and antioxidant activity. AB - Using the 2-hydroxy-N'-[(E)-phenyl(pyridin-2-yl)methylidene]benzohydrazide ligand and dicarboxylate anions (succinate and malonate), two new copper(ii) complexes of formula [Cu4(MU-L)4(MU-CH2(COO)2)(H2O)3](NO3)2.4H2O (1) and [Cu4(MU-L)4(MU-CH2 CH2(COO)2)(H2O)](NO3)2] (2) have been synthesized and characterized by single crystal X-ray diffraction. Complexes 1 and 2 contain a dicarboxylate bridged tetranuclear Cu(ii) cationic unit with "weighing balance shaped" topology. These compounds have also been studied by variable temperature magnetic susceptibility measurements, X-band EPR spectroscopy and electrochemistry. The unprecedented tetranuclear copper complexes 1 and 2 exhibit antiferromagnetic interactions between adjacent copper(ii) centers with magnetic exchange coupling constants (J) of J1 = -6.8 cm-1, J2 = -20.6 cm-1 and g = 2.03 for 1 and J1 = -3.1 cm-1, J2 = 13.9 cm-1 and g = 2.02 for 2. The goal for our research work is to understand the factors that govern the stability of the Cu-O(-O-C-O-) bond towards reactive oxygen species (ROS) in Cu-containing mimics utilizing a systematic approach. The antioxidant superoxide dismutase measurements indicate that these complexes behave as superoxide dismutase mimics. PMID- 28848964 TI - Biguanides, anion receptors and sensors. AB - Biguanides are strong bases (pKa > 10), their protonated forms bind anions and may therefore act as receptors for anions. We report on easy-to-make anion receptors and fluorescence-based sensors utilizing the biguanide moieties that respond to the presence of anions with a change in fluorescence. The observed changes in fluorescence are anion-specific and even though the biguanide receptors are cross-reactive, these sensors may be used to identify various anions (halides, carboxylates, phosphates). Paper-based analytical arrays were used to assess the discriminatory ability of the sensors in the qualitative and quantitative analysis of multiple anions. PMID- 28848965 TI - Molecular dynamics investigations of an indicator displacement assay mechanism in a liquid crystal sensor. AB - A recently reported liquid-crystal sensor system based on the substrate competitive inclusion effects of beta-cyclodextrin (beta-CD) has been investigated using molecular dynamics simulations in this work. In such a system, the released indicator could induce an orientational transition of liquid crystals from planar to homeotropic. The analyte molecule can thus be easily and efficiently detected by observing the corresponding optical image changing from bright to dark. Here, the different binding affinity of beta-CD for the indicator (sodium dodecyl sulfate, SDS) and the analyte (methylene blue, MB) was identified using molecular dynamics simulations and absolute binding free energy calculations. The inclusion processes calculated using the adaptive biasing force algorithm can completely explain the competitive inclusion between MB and SDS by beta-CD, and thus lead to a significant change in the liquid crystal optical properties. PMID- 28848966 TI - Single and double-doping effects on the thermoelectric properties of two Zintl compounds: Eu11Bi8.07(2)Sn1.93 and Eu10.74(2)K0.26Bi9.14(2)Sn0.86. AB - Two Zintl phase thermoelectric compounds of Eu11-xKxBi10-ySny (x = 0, 0.26(1); y = 0.86(2), 1.93(2)) have been synthesized by a high-temperature solid-state reaction and arc-melting methods. The two isotypic crystal structures are characterized by both single-crystal and powder X-ray diffractions, and adopt a tetragonal Ho11Ge10-type structure (space group I4/mmm, Z = 2, Pearson code tI84) containing nine crystallographically independent asymmetric atomic sites in a unit cell. The chemical compositions are confirmed by EDS analysis. The complex crystal structure of the two title compounds can be described as an assembly of three different types of co-facial polyhedra formed by cations and 3-dimensional anionic frameworks surrounding these polyhedra. A quaternary title compound, Eu10.74(2)K0.26Bi9.14(2)Sn10.86, which simultaneously contains both cationic and anionic p-dopants in a single compound, was successfully crystallized for the first time in the A11M10 (A = alkaline-earth metals, rare-earth metals; M = triels, tetrels, pnictogens) series. In particular, two different types of p dopants K and Sn show particular site-preferences, respectively, where K and Sn prefer to occupy the cationic Wyckoff 4e site and the anionic Wyckoff 8h site. These noticeable site preferences can be elucidated by either a size-factor criterion for the K-doping case or by an electronic-factor criterion for the Sn doping case. The tight-binding linear muffin-tin orbital calculations show that as the double p-doping is applied to the Eu11-xKxBi10-ySny system, some extra holes are generated on the electronic structures according to the density of states curves. However, a series of thermoelectric property measurements prove that this extra hole-carrier doping is hardly effective enough to completely suppress a bipolar conduction of holes and electrons due to the rigid metallic band structure of the title system. PMID- 28848967 TI - Anti-tumor bioactivities of curcumin on mice loaded with gastric carcinoma. AB - Curcumin, a derivative from the dried rhizome of curcuma longa, has been proven to possess anti-tumor effects. However, the detailed molecular mechanisms have not been fully elucidated. In this study, we aimed to explore the anti-tumor mechanisms of curcumin in treating gastric cancer. BALB/C mice grafted with a mouse gastric adenocarcinoma cell line (MFC) were used as the experimental model. Mice received different doses of curcumin after grafting. Tumor size was measured and tumor weight was determined after tumor inoculation. TUNEL assay and flow cytometric analysis were applied to evaluate the apoptosis of the cancer cells. Serum cytokines IFN-gamma, TNF-alpha, granzyme B and perforin were detected by ELISA assay. The anti-tumor effect was determined using cytotoxic T-lymphocyte (CTL) assays and in vivo tumor prevention tests. The expression of DEC1, HIF 1alpha, STAT3 and VEGF in tumor tissues was examined by immunostaining and analyzed using an Image J analysis system. Compared with controls, tumor growth (size and weight) was significantly inhibited by curcumin treatment (P < 0.05). The apoptotic index in gastric cancer cells was significantly increased in the curcumin treatment group. Splenocyte cells from mice treated with curcumin exhibited higher cytolytic effects on MFC cancer cells than those from mice treated with saline (P < 0.01). The expression of DEC1, HIF-1alpha, STAT3 and VEGF in tumor tissues was down-regulated after curcumin treatment. Our results indicate that curcumin inhibits the proliferation of gastric carcinoma by inducing the apoptosis of tumor cells, activating immune cells to secrete a large amount of cytokines, and down-regulating the DEC1, HIF-1alpha, VEGF and STAT3 signal transduction pathways. PMID- 28848968 TI - Merging gold catalysis, organocatalytic oxidation, and Lewis acid catalysis for chemodivergent synthesis of functionalized oxazoles from N-propargylamides. AB - Novel catalytic systems consisting of cationic gold complexes, N hydroxyphthalimide (NHPI), and transition-metal-based Lewis acids have been developed for the one-pot synthesis of functionalized oxazoles from N propargylamides with excellent functional group tolerance. These transformations demonstrated the excellent compatibility of homogeneous gold catalysis with organocatalytic oxidative carbon-nitrogen bond formations using tert-butyl nitrite as the terminal oxidant. Moreover, oxazolecarbonitriles or carboxamides can be easily synthesized in a one-pot protocol according to the different synthetic requirements. PMID- 28848969 TI - Correction: Computationally guided discovery of a reactive, hydrophilic trans-5 oxocene dienophile for bioorthogonal labeling. AB - Correction for 'Computationally guided discovery of a reactive, hydrophilic trans 5-oxocene dienophile for bioorthogonal labeling' by William D. Lambert et al., Org. Biomol. Chem., 2017, 15, 6640-6644. PMID- 28848970 TI - Bio-catalytic nanocompartments for in situ production of glucose-6-phosphate. AB - Cells are sophisticated biocatalytic systems driving a complex network of biochemical reactions. A bioinspired strategy to create advanced functional systems is to design confined spaces for complex enzymatic reactions by using a combination of synthetic polymer assemblies and natural cell components. Here, we developed bio-catalytic nanocompartments that contain phosphoglucomutase protected by a biomimetic polymer membrane, which was permeabilized for reactants through insertion of an engineered alpha-hemolysin pore protein. These bio catalytic nanocompartments serve for production of glucose-6-phosphate, and thus possess great potential for applications in an incomplete glycolysis, pentose phosphate pathway, or in plant biological reactions. PMID- 28848971 TI - Biomimetic nanofibers can construct effective tissue-engineered intervertebral discs for therapeutic implantation. AB - We present a total tissue engineered (TE) intervertebral disc (IVD) to address IVD degradation, which is a major cause of chronic neck and back pain. The TE IVD is comprised of an alginate hydrogel-based nucleus pulposus (NP) and hierarchically organized, concentric ring-aligned electrospun (ES) polycaprolactone (PCL)/poly (d,l-lactide-co-glycolide) (PLGA)/Collagen type I (PPC)-based annulus fibrosus (AF). The TE IVD exhibits excellent hydrophilicity to simulate highly hydrated native IVD. Long-term in vivo implantation assays demonstrate the excellent structural (shape maintenance, hydration, and integration with surrounding tissues) and functional (mechanical supporting and flexibility) performances of the TE IVD. Our study provides a novel approach for treating IVD degeneration. PMID- 28848972 TI - Prevention of aerobic oxidation of copper nanoparticles by anti-galvanic alloying: gold versus silver. AB - Preservation from easy aerobic Cu(0) oxidation in Cu nanoparticles (NPs) is of interest for electronic, sensing, optical and catalytic properties. An anti galvanic (AG) method is presented here for this purpose. Remarkably, alloying CuNPs with AuNPs or AgNPs followed by exposure to air only leads to Cu(0) oxidation to Cu(i) in AgCu alloyed NPs, whereas Cu(0) is not oxidized in AuCu alloyed NPs in which Au(i) forms. This result is also verified by "click" catalysis experiments. PMID- 28848973 TI - Diverse dissolution-recrystallization structural transformations and sequential Forster resonance energy transfer behavior of a luminescent porous Cd-MOF. AB - Metal-organic frameworks (MOFs) with light-harvesting building blocks provide an excellent platform to study energy transfer in networks with well-defined structures. Here, we report the synthesis, dissolution-recrystallization structural transformation (DRST) and the Forster resonance energy transfer (FRET) properties of a 2D microporous MOF {[Cd2(L1)3(Hdabco)2].5DMAc.6H2O}n (Cd-MOF, 1). Complex 1 can be dissolved in water and three other products with different dimensions recrystallized from the aqueous solution under diverse reaction conditions were obtained. Due to the porosity and excellent blue luminescence properties of complex 1, we also studied the FRET process between 1 and guest dyes. Two distinct organic dye molecules viz., acridine orange (AO) and rhodamine B (RhB), are encapsulated in 1 which has honeycomb-type nanochannels, and their influence on fluorescence emission has also been studied. The microporous complex 1 in (AO + RhB)@1 serves as an energy funnel that harvests high energy excitation and channels it onto AO and then onto RhB. The steady-state fluorescence and fluorescence dynamics of emission reveal successfully the process of stepwise vectorial energy transfer. Therefore, MOFs could be a class of promising host materials to be further explored in the field of energy transfer between MOF-host and organic guests. PMID- 28848974 TI - Shape control in concave metal nanoparticles by etching. AB - The shape control of nanoparticles constitutes one of the main challenges in today's nanotechnology. The synthetic procedures are based on trial-and-error methods and are difficult to rationalize as many ingredients are typically used. For instance, concave nanoparticles exhibiting high-index facets can be obtained from Pt with different HCl treatments. These structures present exceptional capacities when are employed as catalysts in electrochemical processes, as they maximize the activity per mass unit of the expensive material. Here we show how atomistic simulations based on density functional theory that take into account the environment can predict the morphology for the nanostructures and how it is even possible to address the appearance of concave structures. To describe the control by etching, we have reformulated the Wulff construction through the use of a geometric model that leads to concave polyhedra, which have a larger surface to-volume ratio compared to that for nanocubes. Such an increase makes these sorts of nanoparticles excellent candidates to improve electrocatalytic performance. PMID- 28848975 TI - Capture of actinides (Th4+, [UO2]2+) and surrogating lanthanide (Nd3+) in porous metal-organic framework MIL-100(Al) from water: selectivity and imaging of embedded nanoparticles. AB - Aluminium-based metal-organic framework MIL-100 was utilized for the capture of actinide ([UO2]2+, Th4+) and lanthanide (Nd3+) cations. The results indicate a very quick sorption process, leading to very high cation uptakes together with selectivity for Th4+. PMID- 28848976 TI - Coherent and incoherent phonon transport in a graphene and nitrogenated holey graphene superlattice. AB - The transition between coherent and incoherent phonon transport in a graphene (GRA) and nitrogenated holey graphene (C2N) superlattice is investigated by non equilibrium molecular dynamics (NEMD) simulation. We find that the thermal conductivity of the GRA-C2N superlattice is much lower than those of graphene and C2N, and exhibits a positive correlation with the system length. Owing to three mechanisms, i.e., phonon wave interference, phonon confinement and phonon interface scattering, the calculated thermal conductivity shows a decreasing trend at small period length scales and gradually increases at large period length scales. The coherence length of the superlattice at 300 K is 4.43 nm, which is independent of the total length. In addition, the effects of temperature and uniaxial tensile strain on phonon transport are investigated. At 100 K, the coherent phonons play a more dominating role in the superlattice and the responding coherence length is enlarged to 7.38 nm. On the other hand, tensile strain can effectively reduce the thermal conductivity, which results from the phonon softening. PMID- 28848977 TI - Interpenetrating polymer networks of liquid-crystalline azobenzene polymers and poly(dimethylsiloxane) as photomobile materials. AB - We developed photomobile polymer materials with interpenetrating polymer network (IPN) structures composed of crosslinked liquid-crystalline azobenzene polymer (PAzo) and poly(dimethylsiloxane) (PDMS). By introducing PDMS into a PAzo template network, IPN was formed without disturbing the alignment of mesogens in the PAzo network. The films showed macroscopic bending behavior upon irradiation with UV and visible light. Although the IPN film showed a phase separated structure, the bending speed was significantly enhanced compared with the pristine film of PAzo, thanks to the soft nature of PDMS. The present method of preparing IPNs can be a promising approach to combine PAzo with various polymers and enhance the mechanical and photoresponsive properties. PMID- 28848978 TI - Diverse gatekeepers for mesoporous silica nanoparticle based drug delivery systems. AB - Conventional cancer chemotherapy is often associated with toxicity issues. Thus, new drug delivery systems (DDSs) are developed as alternatives owing to their potential to selectively target affected cells while sparing normal tissues. Among them, noninvasive and biocompatible mesoporous silica nanoparticle (MSN) based targeted DDSs have developed rapidly. In particular, controlled gatekeepers capping the pore entrances of MSNs play prominent and crucial roles in achieving specific drug release and avoiding premature leakage in the delivery process before the target is reached, and perfect gatekeepers can only be removed under specific internal or external stimuli, such as pH, redox potential, temperature, biomolecules, light, magnetic field and ultrasound, or a combination of these stimuli, which is significant for precise therapeutic treatments and potential applications in human bodies. Thus, the main focus of this review is to highlight the most recent progress on the design of various controlled MSN gatekeepers to achieve 'zero premature release' drug delivery. The diverse gatekeepers are categorised into the following kinds according to their types and characteristics: (1) polymers; (2) inorganic nanomaterials; (3) host-guest assemblies; and (4) biomacromolecules. This review will offer a broad palette of opportunities for researchers with interests including nanomaterial fabrication and modification, targeted drug delivery and stimuli-responsive drug release. PMID- 28848979 TI - Spatial separation of the hydrogen evolution center from semiconductors using a freestanding silica-sphere-supported Pt composite. AB - Spatial separation of the reduction center (photosystem I) and oxidation center (photosystem II) is an obvious characteristic of natural photosynthesis. Enlightened by this natural process, a simple material based on silica-sphere supported Pt nanoparticles (SSP) was designed as a freestanding hydrogen evolution center for semiconductor photocatalysts. In situ photoluminescence characterization showed that the radiation recombination of electron-hole pairs in semiconductors (i.e. TiO2 and CdS) was well suppressed due to the presence of SSP. And the quenching efficiency increases with the hydrogen evolution rate of photocatalysts. These results indicated that SSP could effectively trap electrons from the photoexcited semiconductors during collision between SSP and semiconductor, and then complete the hydrogen evolution reaction over the Pt nanoparticles. Detailed investigation also showed that the performance of SSP was influenced by several factors, including the particle size of the silica sphere and the physical and chemical states of Pt nanoparticles. Besides, it was demonstrated that the loaded metal was not limited to Pt. Pd, Ni and Au can also be used as active sites in this freestanding cocatalyst strategy. PMID- 28848980 TI - Chelated [Zn(cyclam)]2+ Lewis acid improves the reactivity of the electrochemical reduction of CO2 by Mn catalysts with bulky bipyridine ligands. AB - This communication reports the use of a soluble Lewis acid complex, [Zn(cyclam)]2+ (cyclam = 1,4,8,11-tetraazacyclotetradecane) as a co-catalyst coupled with Mn(Mesbpy)(CO)3Br (Mesbpy = 6,6'-dimesityl-2,2'-bipyridine) for the electrochemical reduction of CO2 to CO. Utilization of the soluble chelated Lewis acid avoids the use of sacrificial additives and prevents the formation of insoluble products such as MgCO3 or ZnCO3 that change the thermodynamics of CO2 reduction. The use of soluble Lewis acids greatly improves catalysis compared to previously reported systems that used sacrificial anodes. PMID- 28848981 TI - Vibrational nonlinear optical properties of spatially confined weakly bound complexes. AB - This study focuses on the theoretical description of the influence of spatial confinement on the electronic and vibrational contributions to (hyper)polarizabilities of two dimeric hydrogen bonded systems, namely HCNHCN and HCNHNC. A two-dimensional analytical potential is employed to render the confining environment (e.g. carbon nanotube). Based on the results of the state of-the-art calculations, performed at the CCSD(T)/aug-cc-pVTZ level of theory, we established that: (i) the influence of spatial confinement increases with increasing order of the electrical properties, (ii) the effect of spatial confinement is much larger in the case of the electronic than vibrational contribution (this holds for each order of the electrical properties) and (iii) the decrease in the static nuclear relaxation first hyperpolarizability upon the increase of confinement strength is mainly due to changes in the harmonic term, however, in the case of nuclear relaxation second hyperpolarizability the anharmonic terms contribute more to the drop of this property. PMID- 28848982 TI - Tubulation of liposomes via the interaction of supramolecular nanofibers. AB - We achieved tubulation of self-assembled lipid membranes, liposomes, via the interaction of supramolecular nanofibers, porphyrin J-aggregates. This structural change was reversible, and the deformation of the porphyrin J-aggregates caused reconstruction of the liposomes from the tubes. We discussed the tubulation mechanism and calculated the force provided by porphyrin J-aggregates for tubulation. PMID- 28848983 TI - Correction: The methylsulfinyl radical CH3SO examined. AB - Correction for 'The methylsulfinyl radical CH3SO examined' by Marissa L. Estep et al., Phys. Chem. Chem. Phys., 2016, 18, 22293-22299. PMID- 28848984 TI - Calix[n]arene-based polyradicals: enhancing ferromagnetism by avoiding edge effects. AB - Through-bond interacting organic polyradicals, rendered by customizable capacities of the state-of-the-art synthetic routes, are ideal systems to investigate spin topologies. Relying on Rajca and co-workers' synthetic efforts, hereby we investigate the role of borders in the stability of the high-spin ground state in a series of realistic linear and ring-like arylmethyl polyradical derivatives. We show that, compared to their linear counterpart, the absence of borders in a ring-like arrangement of arylmethyl radicals imposes a larger number of spin-alternation rule violations, which strongly stabilizes the high-spin ground state. In addition, the structural flexibility of the investigated compounds translates into the existence of various structural energy minima for which the ferromagnetic ground state is always maintained. In view of the present results we propose these rings as possible candidates for the development of enhanced high spin single molecule toroics. PMID- 28848985 TI - Laser flash photolysis of nanocrystalline alpha-azido-p-methoxy-acetophenone. AB - Irradiation of nanocrystals of azide 1 results in a solid-to-solid reaction that forms imine 2 in high chemical yield. In contrast, solution photolysis of azide 1 yields a mixture of products, with 7 as the major one. Laser flash photolysis (LFP) of a nanocrystalline suspension of azide 1 in water shows selective formation of benzoyl radical 4 (lambdamax ~ 400 nm), which is short-lived (tau = 833 ns) as it intersystem crosses to form imine 2. In comparison, LFP of azide 1 in methanol reveals the formation of triplet alkylnitrene 10 (lambdamax ~ 340 nm). The selectivity observed in the solid-state is related to stabilization of the triplet ketone with (n,pi*) configuration by the crystal lattice, which results in alpha-cleavage being favored over triplet energy transfer to the azido chromophore. Both the solid-state and solution reaction mechanisms are further supported by density functional theory calculations. Thus, laser flash photolysis has been used to effectively elucidate the medium dependent reaction mechanisms of azide 1. PMID- 28848986 TI - Rapid assessment of crystal orientation in semi-crystalline polymer films using rotational zone annealing and impact of orientation on mechanical properties. AB - Crystal orientation in semi-crystalline polymers tends to enhance their performance, such as increased yield strength and modulus, along the orientation direction. Zone annealing (ZA) orients the crystal lamellae through a sharp temperature gradient that effectively directs the crystal growth, but the sweep rate (VZA) of this gradient significantly impacts the extent of crystal orientation. Here, we demonstrate rotational zone annealing (RZA) as an efficient method to elucidate the influence of VZA on the crystal morphology of thin films in a single experiment using isotactic poly(1-butene), PB-1, as a model semi crystalline polymer. These RZA results are confirmed using standard, serial linear ZA to tune the structure from an almost unidirectional oriented morphology to weakly oriented spherulites. The overall crystallinity is only modestly changed in comparison to isothermal crystallization (maximum of 55% from ZA vs. 48% for isothermal crystallization). However, the average grain size increases and the spherulites become anisotropic from ZA. Due to these structural changes, the Young's modulus of the oriented films, both parallel and perpendicular to the spherulite orientation direction, is significantly increased by ZA. The modulus does become anisotropic after ZA due to the directionality in the crystal structure, with more than a threefold increase in the modulus parallel to the orientation direction for the highest oriented film in comparison to the modulus from isothermal crystallization. RZA enables rapid identification of conditions to maximize orientation of crystals in thin polymer films, which could find utility in determining conditions to improve crystallinity and performance in organic electronics. PMID- 28848987 TI - Monolayer BC2: an ultrahigh capacity anode material for Li ion batteries. AB - There is great interest in developing promising candidate materials for high capacity, low cost, environmentally friendly, longer cycle life anodes for lithium ion batteries. Due to better Li adsorption properties than graphene, boron doped graphene has been considered to be an attractive anode material for Li-ion batteries. Using first principles density functional theory calculations, we investigate the effect of increasing boron concentration on the gravimetric capacity of monolayered boron doped carbon sheets. The calculations are performed for uniformly boron doped carbon sheets, BCx (x = 7, 5, 3, 2 and 1) as well as their non-uniformly doped counterparts, which are found to be energetically preferable for x = 5, 2 and 1. Our results indicate pronounced enhancement in gravimetric capacity with increasing concentration of B, up to x = 2. The storage capacity of the uniformly doped BC2 turns out to be the highest ever reported for B doped graphene sheets, which is 1.9 times (1667 mA h g-1) that of the previously reported value for BC3 (J. Phys. Chem. Lett., 2013, 4, 1737-1742). This dramatic increase in the capacity of uniformly doped BC2 occurs because of the availability of significantly more empty states above the Fermi level compared to the other BCx sheets. Moreover, the diffusion energy barriers and open circuit voltage are found to be lower in uniformly doped BC2, leading to better Li kinetics. For x = 1, Li binds very strongly to the uniformly doped BC and higher diffusion energy barriers are found for non-uniformly doped BC, rendering them ineffective as anode materials. Our study reveals that BC2 is the most promising candidate as an anode material for Li ion batteries owing to its high Li storage capacity combined with low diffusion barrier and low open circuit voltage. PMID- 28848988 TI - Singapore Urological Association Clinical Guidelines for Male Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia. AB - The first clinical guidelines for male lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) were published in 2005. An update is urgently needed in view of BPH being recognised as one of ten chronic illnesses by the Ministry of Health, Singapore. This review summarises the definition of BPH and the epidemiology of male LUTS/BPH in Singapore. BPH can be phenotyped with noninvasive transabdominal ultrasonography, according to intravesical prostatic protrusion and prostate volume, and classified according to severity (staging) for individualised treatment. At the initial evaluation, the majority of patients (59%) can be managed with fluid adjustment, exercise and diet; 32% with medications, using alpha blockers and/or 5-alpha reductase inhibitors for prostates weighing more than 30 g; and 9% with surgical intervention for more advanced disease. The 2015 guidelines comprise updated evidence that will help family medicine practitioners and specialists manage this common ailment more cost-effectively. PMID- 28848989 TI - Clinics in diagnostic imaging (179). Severe rhabdomyolysis complicated by myonecrosis. AB - A 32-year-old man presented to the emergency department with severe right lower limb pain and swelling of three days' duration. He had multiple prior admissions for recurrent seizures and suicide attempts. Markedly elevated serum creatine kinase levels and urine myoglobinuria were consistent with a diagnosis of rhabdomyolysis. Initial magnetic resonance imaging of the right lower limb revealed diffuse muscle oedema and features of myositis in the gluteal muscles and the adductor, anterior and posterior compartments of the thigh. Follow-up magnetic resonance imaging performed 11 days later showed interval development of areas of myonecrosis and haemorrhage. The causes, clinical presentation and imaging features of rhabdomyolysis are discussed. PMID- 28848990 TI - Frank Macfarlane Burnet (1899-1984): Australia's gift to immunology. PMID- 28848991 TI - Managing depression in primary care. AB - Major depression is common in the primary care setting. In the final article of this series, we illustrate the approach to the management of depression in primary care. Psychotherapy has been shown to be as effective as antidepressants for mild to moderate major depression. The common myth that antidepressants are addictive should be addressed. Antidepressants should be started at a subtherapeutic dose to assess tolerability, then gradually increased until a minimally effective dose is achieved. Apart from pharmacotherapy and psychotherapy, management of depression should include managing stressors, engaging social and community support, dealing with stigma and discrimination, and managing concomitant comorbidities. A strong therapeutic relationship and empathic listening are important between the primary care physician and patient. PMID- 28848992 TI - Antimicrobial activity and synergism of ursolic acid 3-O-alpha-L arabinopyranoside with oxacillin against methicillin-resistant Staphylococcus aureus. AB - The objective of the present study was to investigate the antibacterial activity of a single constituent, ursolic acid 3-O-alpha-L-arabinopyranoside (URS), isolated from the leaves of Acanthopanax henryi (Oliv.) Harms, alone and in combination with oxacillin (OXA) against methicillin-resistant Staphylococcus aureus (MRSA). A broth microdilution assay was used to determine the minimal inhibitory concentration (MIC). The synergistic effects of URS and OXA were determined using a checkerboard dilution test and time-kill curve assay. The mechanism of action of URS against MRSA was analyzed using a viability assay in the presence of a detergent and an ATPase inhibitor. Morphological changes in the URS-treated MRSA strains were evaluated via transmission electron microscopy (TEM). In addition, the producing penicillin-binding protein 2a (PBP2a) protein level was analyzed using western blotting. The MIC value of URS against MRSA was found to be 6.25 ug/ml and there was a partial synergistic effect between OXA and URS. The time-kill growth curves were suppressed by OXA combined with URS at a sub-inhibitory level. Compared to the optical density at 600 nm (OD600) value of URS alone (0.09 ug/ml), the OD600 values of the suspension in the presence of 0.09 ug/ml URS and 0.00001% Triton X-100 or 250 ug/ml N,N' dicyclohexylcarbodiimide reduced by 56.6 and 85.9%, respectively. The TEM images of MRSA indicated damage to the cell wall, broken cell membranes and cell lysis following treatment with URS and OXA. Finally, an inhibitory effect on the expression of PBP2a protein was observed when cells were treated with URS and OXA compared with untreated controls. The present study suggested that URS was significantly active against MRSA infections and revealed the potential of URS as an effective natural antibiotic. PMID- 28848993 TI - Integrating microRNA and messenger RNA expression profiles in a rat model of deep vein thrombosis. AB - Deep vein thrombosis (DVT) is a disease involving multiple genes and systems. MicroRNAs (miRNAs) represent a class of non-coding small RNAs that post transcriptionally suppress their target genes. The expression patterns of miRNA and messenger RNA (mRNA) in DVT remain poorly characterized. The aim of the present study was to evaluate miRNA and mRNA expression profiles in a stasis induced DVT rat model. Male SD rats were randomly divided into three groups as follows: DVT, sham and control. The inferior vena cava (IVC) of rats was ligated to construct stasis-induced DVT models. Rats were sacrificed three days after ligation, and morphological changes in the vein tissues were observed by hematoxylin and eosin and Masson staining. The miRNA and mRNA expression profiles were evaluated by microarrays, followed by bioinformatics analysis. The microarray analysis identified 22 miRNAs and 487 mRNAs that were significantly differentially expressed between the experimental and control groups, and between the experimental and sham groups, but not between the control and sham groups (P<=0.05; >=2.0-fold change). By subsequent bioinformatics analysis, a 19 miRNA 98 mRNAs network was constructed in the stasis-induced DVT rat model. Notably, the majority of these miRNAs and mRNAs are reported to be expressed by endothelial cells (ECs) and are associated with the function of ECs. The results provide evidence indicating that the regulatory association of miRNA and mRNA points to key roles played by ECs in thrombosis. These findings advance our understanding of the molecular regulatory mechanisms underlying the pathophysiology of DVT. PMID- 28848994 TI - FoxM1 overexpression promotes cell proliferation and migration and inhibits apoptosis in hypopharyngeal squamous cell carcinoma resulting in poor clinical prognosis. AB - Forkhead box M1 (FoxM1), a member of the Fox family of transcriptional factors, is involved in the development of various human malignancies. However, the expression level of FoxM1 and its functional role in hypopharyngeal squamous cell carcinoma (HSCC) remained unclear to date. The aim of the present study was to investigate the FoxM1 expression in 63 HSCC and 20 adjacent normal tissues, as well as to evaluate its association with the clinicopathological parameters and its diagnostic value in HSCC. To further explore the biological function of FoxM1 in vitro, siRNAs were used to knockdown the expression of FoxM1 in the HSCC cell line Fadu. The results revealed that FoxM1 protein was highly expressed in HSCC tissues and that its high expression was closely associated with HSCC tumor differentiation (P=0.004), tumor size (P=0.002), clinical stage (P=0.001), lymph node metastasis (P=0.002), treatment (P=0.045) and expression of the proliferation marker Ki-67 (P<0.001). Additionally, the elevated expression of FoxM1 in HSCC patients consistently predicted a poor survival time. Knockdown of FoxM1 expression blocked Fadu cell proliferation and promoted apoptosis, and also led to the downregulation of cyclin A1 expression. Furthermore, decreased expression of FoxM1 markedly impeded cell migration and reversed the epithelial mesenchymal transition phenotype, as indicated by decreased expression of vimentin and increased expression of E-cadherin in Fadu cells. These results indicate that FoxM1 may act as an oncogene and serve as a therapeutic target against malignant progression in HSCC. PMID- 28848996 TI - Activation of the ROCK1/MMP-9 pathway is associated with the invasion and poor prognosis in papillary thyroid carcinoma. AB - Rho-associated protein kinase 1 (ROCK1), a serine/threonine kinase, has previously been shown to be over-expressed in various types of human malignant tumors and to play an important role in cancer development and progression. Although ROCK1 has gained growing prominence as an important protein kinase in cancer biology, its potential as a predictive biomarker and a therapeutic target in papillary thyroid carcinoma (PTC) remains unknown. In the present study, ROCK1 expression was examined in 356 formalin-fixed, paraffin-embedded papillary thyroid carcinoma tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. Our results showed that ROCK1 expression was significantly increased in PTC compared with normal tissues, and was significantly associated with tumor size, lymphatic metastasis, distant organ metastasis, extrathyroid invasion, vascular invasion and tumor, node and metastasis (TNM) stage. Patients with strong ROCK1 expression had lower overall survival, disease-free survival, lymph node recurrence-free survival and distant recurrence-free survival rates than those with weak expression. Furthermore, overexpression of ROCK1 in papillary thyroid carcinoma cells was found to increase their invasiveness. Silencing ROCK1 by siRNA, however, caused an inhibition of cell invasion. Knockdown of ROCK1 decreased the volume and weight of the xenograft tumors, while overexpression of ROCK1 showed a proliferative tendency with significantly greater tumor volume and weight in vivo. Moreover, the upregulation of ROCK1 increased the expression of MMP-9, and levels of MMP-9 positively correlated with the ROCK1 levels in PTC tissues, implicating that MMP 9 may be involved in the mechanism of ROCK1 in the development and progression of PTC. These data suggest that ROCK1 might be a potential prognostic marker and therapeutic target for the treatment of PTC. PMID- 28848995 TI - Rho GTPases as therapeutic targets in cancer (Review). AB - Rho GTPases are key molecular switches controlling the transduction of external signals to cytoplasmic and nuclear effectors. In the last few years, the development of genetic and pharmacological tools has allowed a more precise definition of the specific roles of Rho GTPases in cancer. The aim of the present review is to describe the cellular functions regulated by these proteins with focus in deregulated signals present in malignant tumors. Finally, we describe the state of the art in search of different experimental therapeutic strategies with Rho GTPases as molecular targets. PMID- 28848997 TI - Suppression of CIP4/Par6 attenuates TGF-beta1-induced epithelial-mesenchymal transition in NRK-52E cells. AB - Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transition (EMT) primarily via a Smad-dependent mechanism. However, there are few studies available on TGF-beta-induced EMT through the activation of non-canonical pathways. In this study, the Cdc42-interacting protein-4 (CIP4)/partitioning defective protein 6 (Par6) pathway was investigated in TGF-beta1-stimulated NRK 52E cells. Rat NRK-52E cells were obtained and stimulated with TGF-beta1. The expression levels of E-cadherin, alpha-smooth muscle actin (alpha-SMA) and CIP4 were then examined by western blot analyses. Rat NRK-52E cells were transfected with Par6 or CIP4 small interfering RNA (siRNA), and scrambled siRNA as controls. The cells were incubated with 20 ng/ml of TGF-beta1 for 72 h in order to observe the effects of Par6 and CIP4 silencing. Confocal fluorescence microscopy was also applied to reveal the expression and distribution of E-cadherin, alpha-SMA, Par6 and CIP4. The results demonstrated that E-cadherin expression was decreased, and alpha-SMA expression was increased in the TGF-beta1-stimulated cells. Simultaneously, the increased expression of CIP4 and p-Par6 was confirmed by western blot analyses. The results of confocal fluorescence microscopy revealed that rat CIP4 exhibited cluster formations located adjacent to the cell periphery; however, as for the protein expression and distribution of Par6, there was no obvious difference between the control cells and cells exposed to TGF beta1. siRNA molecules capable of CIP4 and Par6 knockdown were used to demonstrate reversed TGF-beta1-induced EMT. Moreover, CIP4 loss of function reversed the increase in p-Par6 protein expression in the TGF-beta1-stimulated NRK-52E cells. A similar result was observed with the decreased CIP4 protein expression due to Par6 loss of function. Our data thus suggest that the CIP4/Par6 complex plays an important role in the occurrence of EMT in TGF-beta1-stimulated NRK-52E cells. The underlying mechanisms are mediated, at least in part, through the upregulation of CIP4, which occurrs due to stimulation with TGF-beta1; subsequently, CIP4 increases the phosphorylation of Par6, which accelerates the process of EMT. PMID- 28848998 TI - Regulated differentiation of WERI-Rb-1 cells into retinal neuron-like cells. AB - The encouraging response and improved survival of acute promyelocytic leukemia patients following retinoic acid treatment has rendered differentiation therapy an attractive option in cancer treatment. Given that terminal differentiation represents a considerable barrier in retinoblastoma tumorigenesis and that retinoblastoma has a significantly higher spontaneous degeneration rate compared with other tumors (1,000-fold change), differentiation therapy represents a promising alternative in the treatment of retinoblastoma. However, the full differentiation potential of retinoblastoma still unknown. The present study was designed to investigate the extend differentiation of the classical retinoblastoma cell line WERI-Rb-1 (W-RBCs). Several critical cell signaling pathways and key genes related to cell proliferation and differentiation were comprehensively regulated to control the fate of W-RBCs. Various strategies were applied to optimize simple and time-saving methods to induce W-RBCs into different types of retinal neuron-like cells (RNLCs) in vitro. Further, the tumorigenesis of these differentiated W-RBCs was tested in nude mice in vivo. W RBCs were found to inherently express both retinal progenitor cell- and embryonic stem cell-related genes or proteins. Moreover, the addition of antagonists of critical cell signals (Wnt, Nodal, BMP4 and Notch), even without atonal bHLH transcription factor 7 gene transfection, could directly induce W-RBCs into RNLCs, and especially into photoreceptor-like and retinal ganglion-like cells. Interestingly, the differentiated cells showed remarkably poorer tumorigenesis in vivo. These findings may offer new insights on the oriented differentiation of W RBCs into RNLCs with low tumorigenicity and provide potential targets for retinoblastoma differentiation therapy. PMID- 28848999 TI - YAP signaling in gastric cancer-derived mesenchymal stem cells is critical for its promoting role in cancer progression. AB - Cancer-associated mesenchymal stem cells (MSCs) are critically involved in tumor development and progression. However, the mechanisms of action for MSCs in cancer remain largely unknown. Herein, we reported that the expression of Yes-associated protein 1 (YAP) was higher in gastric cancer derived mesenchymal stem cells (GC MSCs) than that in bone marrow derived MSCs (BM-MSCs). YAP knockdown not only inhibited the growth, migration and invasion, and stemness of GC-MSCs, but also suppressed their promoting effect on gastric cancer growth in vitro and in vivo. In addition, the interference of YAP expression in GC-MSCs also attenuated the promoting role of gastric cancer cells in endothelial cell tube formation and migration. Mechanistically, YAP knockdown reduced the activation of beta-catenin and its target genes in gastric cancer cells by GC-MSCs. Taken together, these findings suggest that YAP activation in GC-MSCs plays an important role in promoting gastric cancer progression, which may represent a potential target for gastric cancer therapy. PMID- 28849000 TI - Personalized identification of differentially expressed pathways in pediatric sepsis. AB - Sepsis is a leading killer of children worldwide with numerous differentially expressed genes reported to be associated with sepsis. Identifying core pathways in an individual is important for understanding septic mechanisms and for the future application of custom therapeutic decisions. Samples used in the study were from a control group (n=18) and pediatric sepsis group (n=52). Based on Kauffman's attractor theory, differentially expressed pathways associated with pediatric sepsis were detected as attractors. When the distribution results of attractors are consistent with the distribution of total data assessed using support vector machine, the individualized pathway aberrance score (iPAS) was calculated to distinguish differences. Through attractor and Kyoto Encyclopedia of Genes and Genomes functional analysis, 277 enriched pathways were identified as attractors. There were 81 pathways with P<0.05 and 59 pathways with P<0.01. Distribution outcomes of screened attractors were mostly consistent with the total data demonstrated by the six classifying parameters, which suggested the efficiency of attractors. Cluster analysis of pediatric sepsis using the iPAS method identified seven pathway clusters and four sample clusters. Thus, in the majority pediatric sepsis samples, core pathways can be detected as different from accumulated normal samples. In conclusion, a novel procedure that identified the dysregulated attractors in individuals with pediatric sepsis was constructed. Attractors can be markers to identify pathways involved in pediatric sepsis. iPAS may provide a correlation score for each of the signaling pathways present in an individual patient. This process may improve the personalized interpretation of disease mechanisms and may be useful in the forthcoming era of personalized medicine. PMID- 28849001 TI - MicroRNA-1291 promotes endometrial fibrosis by regulating the ArhGAP29-RhoA/ROCK1 signaling pathway in a murine model. AB - Intrauterine adhesions (IUAs) are caused by endometrial damage and are associated with a poor pregnancy prognosis including infertility, oligomenorrhea and recurrent pregnancy loss. Understanding the pathogenesis of IUAs may help prevent and treat this condition more effectively. The aim of the current study was to investigate the function of microRNA-1291 (miR-1291) during the development of IUAs following endometrial damage and elucidate the potential molecular mechanisms involved. The expression of Rho GTPase activating protein 29 (ArhGAP29), a putative target mRNA of miR-1291, was determined by immunohistochemical staining of human endometrial tissue from patients with IUAs and compared with normal endometrial tissues. ArhGAP29 expression was significantly decreased in endometrial tissues with IUAs compared with normal endometrium. Additionally, a murine IUAs model was develo-ped and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that miR-1291 levels were significantly increased in the uterine tissue and plasma of the IUAs group compared with the normal mice. Furthermore, an miR-1291 antagomir was injected into the uterine cavity of experimental IUAs mice to block miR-1291. Hematoxylin and eosin and Masson's stain revealed that blocking miR-1291 significantly ameliorated endometrial fibrosis. Furthermore, levels of epithelial mesenchymal transition (EMT)-associated proteins, and ArhGAP29-RhoA/Rho associated coiled coil containing protein kinase 1 (ROCK1) were measured in uterine tissue by western blot, RT-qPCR analysis and immunofluorescence staining. Levels of the mesenchymal marker proteins, vimentin and N-cadherin, were increased in the IUAs group mice, accompanied by a relative decrease in the epithelial marker proteins, cytokeratin and E-cadherin compared with normal murine endometrium. miR-1291 inhibition decreased RhoA/ROCK1 expression in the EMT pathway, but increased ArhGAP29 expression. Taken together, the findings indicate that miR-1291 acts upstream of ArhGAP29 to negatively regulate the RhoA/ROCK1 EMT pathway, ultimately leading to endometrial fibrosis. These studies may provide new potential therapeutic options and pave the way to use circulating miR-1291 as a clinical biomarker of endometrial fibrosis. PMID- 28849002 TI - Cysteine-rich 61-associated gene expression profile alterations in human glioma cells. AB - The present study aimed to investigate gene expression profile alterations associated with cysteine-rich 61 (CYR61) expression in human glioma cells. The GSE29384 dataset, downloaded from the Gene Expression Omnibus, includes three LN229 human glioma cell samples expressing CYR61 induced by doxycycline (Dox group), and three control samples not exposed to doxycycline (Nodox group). Differentially expressed genes (DEGs) between the Dox and Nodox groups were identified with cutoffs of |log2 fold change (FC)|>0.5 and P<0.05. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for DEGs were performed. Protein-protein interaction (PPI) network and module analyses were performed to identify the most important genes. Transcription factors (TFs) were obtained by detecting the TF binding sites of DEGs using a Whole Genome rVISTA online tool. A total of 258 DEGs, including 230 (89%) upregulated and 28 (11%) downregulated DEGs were identified in glioma cells expressing CYR61 compared to cells without CYR61 expression. The majority of upregulated DEGs, including interferon (IFN)B1, interferon-induced (IFI)44 and interferon regulatory factor (IRF)7, were associated with immune, defense and virus responses, and cytokine-cytokine receptor interaction signaling pathways. Signal transducer and activator of transcription 1 (STAT1) and DEAD-box helicase 58 (DDX58) were observed to have high connection degrees in the PPI network. A total of seven TFs of the DEGs, including interferon consensus sequence-binding protein and IFN-stimulated gene factor-3 were additionally detected. In conclusion, IFNB1, genes encoding IFN-induced proteins (IFI16, IFI27, IFI44 and IFITM1), IRFs (IRF1, IRF7 and IRF9), STAT1 and DDX58 were demonstrated to be associated with CYR61 expression in glioma cells; thus, they may be critical for maintaining the role of CYR61 during cancer progression. PMID- 28849003 TI - Gold-chrysophanol nanoparticles suppress human prostate cancer progression through inactivating AKT expression and inducing apoptosis and ROS generation in vitro and in vivo. AB - Controlled releasing of regulations remains the most convenient method to deliver various drugs. In the present study, we precipitated gold nanoparticles with chrysophanol. The gold-chrysophanol into poly (DL-lactide-co-glycolide) nanoparticles was loaded and the biological activity of chrysophanol nanoparticles on human LNCap prostate cancer cells, was tested to acquire the sustained releasing property. The circular dichroism spectroscopy indicated that chrysophanol nanoparticles effectively resulted in conformational alterations in DNA and regulated different proteins associated with cell cycle arrest. The reactive oxygen species (ROS), apoptosis, cell cycle, DNA damage, Cyto-c and caspase-3 activity were analyzed, and the expression levels of different anti- and pro-apoptotic were studied using immunoblotting analysis. The cytotoxicity assay suggested that chrysophanol nanoparticles preferentially killed prostate cancer cells in comparison to the normal cells. Chrysophanol nanoparticles reduced histone deacetylases (HDACs) to suppress cell proliferation and induce apoptosis by arresting the cell cycle in sub-G phase. In addition, the cell cycle related proteins, including p27, CHK1, cyclin D1, CDK1, p-AMP-activated protein kinase (AMPK) and p-protein kinase B (AKT), were regulated by chrysophanol nanoparticles to prevent human prostate cancer cell progression. Chrysophanol nanoparticles induced apoptosis in LNCap cells by promoting p53/ROS crosstalk to prevent proliferation. Pharmacokinetic study in mice indicated that chrysophanol nanoparticle injection showed high bioavailability compared to the free chrysophanol. Also, in vivo study revealed that chrysophanol nanoparticles obviously reduced tumor volume and weight. In conclusion, the data above suggested that chrysophanol nanoparticles might be effective to prevent human prostate cancer progression. PMID- 28849004 TI - FoxM1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by targeting Snai1. AB - Forkhead box protein M1 (FoxM1) is aberrantly expressed in several types of human malignancy, and serves an important role in tumor metastasis. Epithelial mesenchymal transition (EMT) of cancer cells has been associated cancer metastasis; however, the implication of FoxM1 in EMT and its putative roles in the regulation of cancer metastasis remain to be elucidated. In the present study, the expression of FoxM1, Snai1 and E-cadherin in hepatocellular carcinoma (HCC) cell lines with various metastatic potentials, and in normal liver cells, was investigated using western blot analysis and reverse transcription quantitative polymerase chain reaction. The effects of FoxM1 on the invasive and migratory capabilities of HCC cells were evaluated using wound healing and Transwell migration assays. The present results demonstrated that FoxM1 expression was significantly upregulated in HCC cells compared with in normal hepatocytes (P<0.05). In addition, FoxM1 expression was significantly increased in MHCC-LM3 cells, characterized by higher metastatic potential, compared with in SMMC-7721 cells, which have a lower metastatic potential. Furthermore, overexpression of FoxM1 was demonstrated to be negatively correlated with E cadherin (P<0.05) and positively associated with Snai1 (P<0.05) expression. These observations suggested that FoxM1 may enhance the invasion and migration of cancer cells, and thus promotes their EMT, in a mechanism that may involve the regulation of Snai1. Therefore, it may be hypothesized that FoxM1 has potential as a novel diagnostic marker and therapeutic target for the treatment of patients with HCC. PMID- 28849005 TI - Ethanol extract of Antrodia camphorata inhibits proliferation of HCT-8 human colorectal cancer cells by arresting cell cycle progression and inducing apoptosis. AB - Antrodia camphorata (AC) is well known in Taiwan as a traditional Chinese medicine, with a long history of use in treating cancer and inflammation. Previous studies have revealed that AC exhibits anticancer effects in various cancer cell lines. However, the inhibitory influence of AC on colorectal cancer (CRC) cell growth and survival remains unknown. The present study investigated the effects of AC on the proliferation, survival, and cell cycle- and apoptosis associated gene and protein expression in the HCT-8 human CRC cell line in vitro. The antitumor activity of AC against HCT-8 cells was assessed using cell viability and colony formation assays. Cell cycle distribution was analyzed by flow cytometry. Cell apoptosis and morphological alterations were assessed by Hoechst 33258 staining and microscopy. The mRNA expression of cell cycle- and apoptosis-associated genes was determined by reverse transcription-quantitative polymerase chain reaction, and protein expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2 X associated protein (Bax) cyclin D1, cyclin dependent kinase 4 (CDK4) and MYC proto-oncogene bHLH transcription factor (c-Myc) were determined by western blotting. Treatment of HCT-8 cells with various concentrations of AC (0.4-1.2 mg/ml) resulted in dose- and time-dependent reductions in cell viability. HCT-8 cell cycle was arrested in the G0/G1 phase or G0/G1 and G2/M phases following AC treatment, compared with untreated cells. Furthermore, AC markedly inhibited HCT-8 cell growth with induction of apoptotic alterations and inhibition of proliferation. AC treatment induced HCT-8 cell apoptosis, upregulated expression of the apoptosis gene Bax, and downregulated Bcl-2, cMyc, cyclin D1 and CDK4 protein expression levels. The present data demonstrated that AC exhibited antiproliferative and growth inhibition effects on HCT-8 cells via induction of apoptosis and blocking of cell cycle progression, thus suggesting that it may have anticancer properties valuable for potential future therapeutic application for the treatment of CRC. PMID- 28849006 TI - The impact of HuD protein on the intestinal nervous system in the terminal rectum of animal models of congenital anorectal malformation. AB - Patients with congenital anorectal malformation (ARM) often present with different degrees of defecation dysfunction severity following corrective operations. Therefore, studies on how to improve the postoperative defecation function of patients with ARM are of clinical importance. The present study investigated the expression of the HuD protein in the terminal rectum of ARM embryonic rats and explored the effect of HuD expression on the development of the intestinal nervous system. Pregnant Sprague Dawley rats were randomized into a control or ARM (induced by ethylene thiourea) group. The terminal rectums of the embryonic rats were obtained during pregnancy (20 days). The histological changes of the terminal rectum were observed using hematoxylin and eosin staining. The expression of the HuD protein was assessed by immunohistochemistry and western blot analysis. In the control group, the histological structure of the terminal rectum was well-defined and a large number of submucosal and intermuscular neurons with a rich cytoplasm and strong neuritis were observed. In the ARM group, the histological layers were ill-defined and the number of neurons was small. Immunohistochemistry and western blot analysis demonstrated that the concentration of the HuD protein in the ARM group was significantly lower compared with the control group (312.90+/-53.40:456.40+/-57.13; 0.24+/ 0.05:0.45+/-0.06, P<0.05). HuD was abnormally expressed in the terminal rectum of the ARM embryonic rats and may be involved in the development and maturation of the enteric nervous system. The present study may provide a useful theoretical reference for the treatment of postoperative defecation dysfunction in patients with ARM. PMID- 28849008 TI - microRNA-20b contributes to high glucose-induced podocyte apoptosis by targeting SIRT7. AB - Previous reports have indicated that microRNAs (miRNAs) have an important role in the pathogenesis of diabetic nephropathy (DN). Podocyte apoptosis induced by high glucose (HG) is characteristic of DN. However, the role of miRNAs in HG-induced podocyte apoptosis remains poorly understood. The present study investigated the role and potential underlying mechanism of miRNA-20b (miR-20b) in podocyte apoptosis induced by HG. The results demonstrated that miR-20b was significantly upregulated in HG-treated podocytes, as determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Caspase-3 activity and TUNEL assays indicated that suppression of miR-20b using miR-20b inhibitors significantly inhibited the podocyte apoptosis induced by HG. Sirtuin 7 (SIRT7) was identified as a functional target of miR-20b by a Dual-Luciferase activity reporter assay, RT-qPCR and western blot analysis. Silencing SIRT7 promoted HG induced podocyte apoptosis, as determined by the caspase-3 activity, while SIRT7 overexpression attenuated HG-induced podocyte apoptosis. However, SIRT7 silencing significantly blocked the protective effect of miR-20b suppression against HG induced apoptosis. In conclusion, these results indicate that miR-20b may contribute to HG-induced podocyte apoptosis by targeting SIRT7, providing a potential therapeutic target for the treatment of DN. PMID- 28849009 TI - Thy-1 stimulation of mouse T cells induces a delayed T cell receptor-like signal that results in Ca2+-independent cytotoxicity. AB - Antibody-mediated crosslinking of Thy-1 [also known as cluster of differentiation (CD)90], results in a T cell receptor (TcR)-like signal; however, the impact of Thy-1 stimulation in comparison to TcR stimulation on T cell activation and effector function has yet to be fully elucidated. In the present study, the outcome of Thy-1- and TcR-induced stimulation of T cells was investigated in mice, using fragment crystalizable (Fc) receptor-bound antibodies and costimulatory signals provided by syngeneic lipopolysaccharide-matured bone marrow-derived dendritic cells. Compared with TcR signaling, Thy-1 signaling initiated a less robust proliferative response in T cells, as determined by tritiated-thymidine incorporation. In addition, enzyme-linked immunosorbent assays revealed that interleukin-2 production was reduced, and the expression of CD25 and cyclin D3 was weaker in Thy-1-stimulated cells, as determined by western blotting; however, the expression of cyclin-dependent kinase 6 was similar to that in TcR-induced T cells. Furthermore, western blotting demonstrated that the phosphorylation of zeta-chain-associated protein kinase 70 and extracellular signal-regulated kinase 1/2 was delayed following Thy-1 stimulation. DNA fragmentation assays revealed that cytotoxic effector function was also slower to develop in Thy-1-stimulated T cells, required more time to be effective and was largely Ca2+-independent; these findings suggested that Fas ligand rather than granule-associated perforin was involved in T cell effector function. In conclusion, the present results suggested that Thy-1 signaling may contribute to the regulation of T cell homeostasis and the development of non-specific T cell mediated cytotoxicity. However, further studies are required to elucidate the exact physiological roles of TcR-like signals that result from Thy-1 crosslinking and to investigate the molecular mechanisms that are involved. PMID- 28849007 TI - Curcumin prevents reperfusion injury following ischemic stroke in rats via inhibition of NF-kappaB, ICAM-1, MMP-9 and caspase-3 expression. AB - Reperfusion is the only approved therapy for acute ischemic stroke; however, it can cause excessive inflammation responses and aggravate brain damage. Therefore, supplementary treatment against inflammation caused by reperfusion is required. In a previous study from our group, curcumin was demonstrated to decrease infarction volume, brain edema and blood-brain barrier (BBB) disruption against cerebral ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remain unclear. The present study was conducted to understand whether curcumin protects against cerebral I/R injury through anti-inflammatory and antiapoptotic properties. Ischemia for 1 h was induced in vivo in Wistar rats by middle cerebral artery occlusion (MCAO), followed by reperfusion for 24 h, and curcumin was injected intraperitoneally at 30 min prior to reperfusion. Immunohistochemistry was performed to analyze the expression levels of nuclear factor (NF)-kappaB, intercellular adhesion molecule (ICAM)-1, matrix metalloproteinase (MMP)-9 and caspase-3. The findings revealed that inflammation (NF-kappaB, ICAM-1 and MMP-9) and apoptosis (caspase-3)-related markers were significantly downregulated in the curcumin-treated MCAO group compared with the vehicle-treated MCAO group. Furthermore, brain infarction size, brain edema and neurological dysfunction were attenuated in the curcumin-treated MCAO group compared with the vehicle-treated MCAO group. Taken together, the present results provided evidence that the protective effect of curcumin against cerebral I/R injury might be mediated by anti-inflammatory and anti-apoptotic properties. Therefore, curcumin may be a promising supplementary agent against cerebral I/R injury in the future. PMID- 28849010 TI - C278F mutation in FGFR2 gene causes two different types of syndromic craniosynostosis in two Chinese patients. AB - The current study was performed with aim to investigate the fibroblast growth factor receptor 2 (FGFR2) gene in two Chinese families with two different forms of syndromic craniosynostosis, and to characterize their associated clinical features. Two families underwent complete ophthalmic examinations, and two patients from each family were diagnosed with craniosynostosis. Genomic DNA was extracted from leukocytes of peripheral blood collected from these two families and from 200 unrelated subjects within the same population as controls. Exons 8 and 10 of the FGFR2 gene were amplified by polymerase chain reaction and directly sequenced. Ophthalmic examinations of the two patients revealed shallow orbits and ocular proptosis, accompanied by midface hypoplasia and craniosynostosis. Case 1 had retinal detachment, abnormal limbs and hands, while case 2 exhibited normal hands and feet upon clinical examination. A heterozygous FGFR2 missense mutation c.833G>T (C278F) in exon 8 was identified in these two patients, but not in unaffected family members or the normal controls. Although FGFR2 gene mutations and polymorphisms have been studied in various ethnic groups, we report a mutation of FGFR2 in two different Chinese patients with two different types of syndromic craniosynostosis. PMID- 28849011 TI - Effect of varicocelectomy treatment on spermatogenesis and apoptosis via the induction of heat shock protein 70 in varicocele-induced rats. AB - In the current study, the hypothesis that testicular varicocelectomy improves spermatogenesis and attenuates apoptosis via the induction of heat shock protein 70 (Hsp70) in a rat model of varicocele was investigated. Adult male Wistar rats (n=75) were randomly divided into 5 groups of 15 each: Control, sham, varicocele, varicocelectomy, and varicocelectomy plus Quercetin. A total of 6 weeks after the varicocelectomy, the left testis of all rats was removed for subsequent examination. Histological changes were compared between the groups. The expression of Hsp70 and apoptosis-associated indicators were evaluated based on immunohistochemical, western blot and mRNA expression analyses. Compared with the varicocele group, the varicocelectomy group exhibited a markedly reduced Bcl-2 associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) ratio, and had a decreased expression of caspase-9, cytochrome c (cyt c) and caspase-3 through the intrinsic signal transduction pathways. Quercetin treatment inhibited the protective effects of varicocelectomy. The expression of Hsp70 was increased in the varicocele group which was further elevated by the varicocelectomy. These results indicated that varicocelectomy can reduce the Bax/Bcl-2 ratio, and decrease the levels of caspase-9, cyt c and caspase-3 via the mitochondrial signal transduction pathway. Such protective effects on left testis spermatogenesis and against apoptosis may be due to the induction of Hsp70. The findings of the present study suggested that varicocelectomy has a clear advantage in protecting testicular function and ameliorating spermatogenic cells apoptosis. PMID- 28849012 TI - Long non-coding RNA Z38 promotes cell proliferation and metastasis in human renal cell carcinoma. AB - Long non-coding RNAs (LncRNAs) have been reported to serve roles in various types of malignancy, including human renal cell carcinoma (RCC), which is among the most common types of kidney cancer worldwide. The present study aimed to investigate the effects of a newly-discovered LncRNA, Z38, on cell proliferation and metastasis in RCC cells. Reverse transcription-quantitative polymerase chain reaction analysis was used to detect the transcription levels of Z38 in clinical RCC tissues and cultured RCC cells. The expression of Z38 was notably increased in patients with stage III and IVRCC compared with patients with stage I and II. Knockdown of Z38 with specific short hairpin RNAs notably decreased the proliferation rate of A498 and ACHIN cells. In addition, a colony formation assay was included to investigate the role of Z38 in cell proliferation. Transwell assays demonstrated that Z38 deprivation inhibited the migratory and invasive capability of RCC cells. The association between Z38 and the epithelial mesenchymal transition process was investigated using western blot analysis. The results of the present study demonstrated that Z38 may serve as an important biomarker in the diagnosis and treatment of RCC in the clinic. PMID- 28849013 TI - Renal sympathetic denervation alleviates myocardial fibrosis following isoproterenol-induced heart failure. AB - The aim of the present study was to determine if renal sympathetic denervation (RSD) may alleviate isoproterenol-induced left ventricle remodeling, and to identify the underlying mechanism. A total of 70 rats were randomly divided into control (n=15), sham operation (n=15), heart failure (HF) with sham operation (HF + sham; n=20) and HF with treatment (HF + RSD; n=20) groups. The HF model was established by subcutaneous injection of isoproterenol; six weeks later, 1eft ventricular internal diameter at end-systole (LVIDs), left ventricular systolic posterior wall thickness (LVPWs), 1eft ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured. Plasma norepinephrine (NE), angiotensin II (Ang II) and aldosterone (ALD) levels were measured by ELISA. Myocardial collagen volume fraction (CVF) was determined by Masson's staining. Reverse transcription-quantitative polymerase chain reaction was used to determine the mRNA expression levels of ventricular transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF) and microRNAs (miRs), including miR-29b, miR-30c and miR-133a. The results demonstrated that LVIDs and LVPWs in the HF + RSD group were significantly decreased compared with the HF + sham group. By contrast, LVFS and LVEF in the HF + RSD group were significantly increased compared with the HF + sham group. RSD significantly reduced the levels of plasma NE, Ang II and ALD. CVF in the HF + RSD group was reduced by 38.1% compared with the HF + sham group. Expression levels of TGF-beta and CTGF were decreased, whereas those of miR-29b, miR-30c and miR-133a were increased, in the HF + RSD group compared with the HF + sham group. These results indicated that RSD alleviates isoproterenol-induced left ventricle remodeling potentially via downregulation of TGF-beta/CTGF and upregulation of miR-29b, miR-30c and miR-133a. RSD may therefore be an effective non-drug therapy for the treatment of heart failure. PMID- 28849014 TI - Zinc inhibits high glucose-induced NLRP3 inflammasome activation in human peritoneal mesothelial cells. AB - Zinc (Zn) deficiency is important for inducing nucleotide-binding domain and leucine-rich repeat-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in macrophages. However, its function in the NLRP3 inflammasome activation of peritoneal mesothelial cells (PMCs) remains to be elucidated. In the present study, the human PMC (HPMC) line HMrSV5 was co-treated with high glucose and either ZnSO4 or a Zn chelator. The activity of the NLRP3/caspase-1 inflammasome was assessed via western blot analysis, immunofluorescence, reverse transcription-quantitative polymerase chain reaction and ELISA. In addition, the activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was detected using western blotting, and the level of reactive oxygen species (ROS) was assessed by 2,7-dichlorofluorescein fluorescence and flow cytometry. It was found that Zn supplementation inhibited HG-induced NLRP3 inflammasome activation in the HPMCs by attenuating ROS production. Further experiments revealed that Zn supplementation inhibited the HG induced production of ROS through activation of the Nrf2 antioxidant pathway. These results indicated that Zn inhibited NLRP3 inflammasome activation in the HG treated HPMCs by activating the Nrf2 antioxidant pathway and reducing the production of ROS. PMID- 28849015 TI - Overexpression of microRNA-448 inhibits osteosarcoma cell proliferation and invasion through targeting of astrocyte elevated gene-1. AB - MicroRNAs (miRNAs/miRs) have been implicated in the development and progression of osteosarcoma. miR-448 is emerging as a tumor-associated miRNA in many human cancers. However, the role of miR-448 in osteosarcoma remains unknown. The present study aimed to identify the potential role of miR-448 in osteosarcoma. It was demonstrated that miR-448 was significantly downregulated in osteosarcoma cell lines, as detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-448 mimics were transfected into osteosarcoma cells to overexpress miR-448. Overexpression of miR-448 markedly inhibited cell proliferation and invasion in osteosarcoma cells. Bioinformatics and luciferase reporter assays demonstrated that astrocyte elevated gene-1 (AEG-1) was a target gene of miR-448. RT-qPCR and western blot analysis revealed that miR-448 inhibited AEG-1 expression. Further data revealed that miR-448 overexpression impeded the Wnt and nuclear factor-kappaB signaling pathways. However, restoration of AEG-1 expression could abolish the miR-448-mediated antitumor effects. Taken together, these findings suggested that miR-448 may inhibit osteosarcoma development by targeting AEG-1, providing a novel candidate miRNA for development of miRNA-targeted therapies for osteosarcoma. PMID- 28849016 TI - Transcriptional regulation and influence on replication of the human cytomegalovirus UL138 1.4 kb transcript. AB - Human cytomegalovirus (HCMV) exists in a latent form in hematopoietic progenitors and undifferentiated cells of myeloid lineage. Protein UL138, encoded by the UL/b' region of the viral genome, serves an important role in the establishment and/or persistence of HCMV latency. However, little information about transcriptional regulation of the UL138 gene has been reported thus far. In the present study, the transcriptional regulation element (TRE) of the 1.4 kb UL138 region was identified using a series of dual-luciferase constructs that contain 5' truncated deletion fragments located upstream of the transcription start site of the gene. The results demonstrated that the region from nucleotide 188995 188962 of the Han strain genome exhibits promoter activity and harbors the functional binding motif for transcription factor AP-1 (Ap-1). Using electrophoretic mobility shift assays the physical interaction of the transcription factor to a minimal essential core sequence was demonstrated. Northern blotting revealed that deletion of the TRE in a HCMV bacterial artificial chromosome or inhibition of Ap-1 using RNA interference eliminated or reduced the production of the UL138 1.4 kb mRNA transcript in infected human embryonic lung fibroblast cells (HELF). Deletion of the UL138 1.4 kb transcript resulted in acceleration of HCMV replication in HELF cells. To the best of the authors' knowledge, the present study is the first to analyze the transcriptional regulation of the UL138 1.4 kb transcript. Knowledge of the transcriptional regulation of the UL138 gene will enhance understanding of its mechanism in HCMV latency. PMID- 28849017 TI - miR-491-3p suppresses the growth and invasion of osteosarcoma cells by targeting TSPAN1. AB - Osteosarcoma (OS) is the most common primary bone cancer, and frequently leads to mortality as a result of rapid proliferation and metastasis. Recent data highlight the important role of microRNAs (miRs) in human cancers, including OS, providing a novel method for its diagnosis and treatment. In the present study, it was identified that miR-491-3p expression was frequently decreased in OS tissues and OS cell lines. Restored miR-491-3p expression suppressed the growth and invasion of OS cells. Bioinformatics and experimental analysis indicated that tetraspanin 1 (TSPAN1) is a direct target of miR-491-3p in OS. The TSPAN1 mRNA level was inversely associated with the miR-491-3p level in OS tissues and cell lines. Consistent with this, TSPAN1 knockdown inhibited the growth and invasion of OS cells. In conclusion, these data provide compelling evidence that miR-491 3p functions as a tumor suppressor in OS to attenuate the potential of growth and invasion by targeting TSPAN1. PMID- 28849018 TI - MicroRNA-199b targets the regulation of ZEB1 expression to inhibit cell proliferation, migration and invasion in non-small cell lung cancer. AB - Lung cancer is one of the leading causes of cancer-associated mortality worldwide. Previous evidence suggested that microRNAs (miRs) exhibit important regulatory roles in tumorigenesis and tumor development, including in non-small cell lung cancer (NSCLC). The present study investigated the expression of miR 199b in NSCLC tissues and cell lines, in addition to the biological roles of miR 199b in the carcinogenesis and progression of NSCLC. The results of the present study demonstrated that miR-199b expression was decreased in NSCLC tissues and cell lines compared with matched adjacent healthy tissues and a healthy human bronchial epithelial cell line, respectively. An MTT assay demonstrated that the viability of NSCLC cells was decreased by miR-199b. The migratory and invasive abilities of NSCLC cells were suppressed by miR-199b overexpression. In addition, zinc finger E-box-binding homeobox 1 (ZEB1) was identified to be a novel direct downstream and functional target for miR-199b in NSCLC, using bioinformatics analysis, luciferase reporter assay, the reverse transcription-quantitative polymerase chain reaction and western blotting. ZEB1 underexpression mimicked the roles of miR-199b overexpression in NSCLC cells. In conclusion, the present study demonstrated that miR-199b was downregulated in NSCLC and acted as a tumor suppressor by targeting ZEB1. PMID- 28849019 TI - Licochalcone E protects against carbon tetrachloride-induced liver toxicity by activating peroxisome proliferator-activated receptor gamma. AB - The present study aimed to investigate the hepatoprotective role of Licochalcone E (LCE) and its mechanism of action in a mouse model of carbon tetrachloride (CCl4)-induced liver toxicity. Hepatotoxicity was induced in Kunming mice via an intraperitoneal injection (IP) of CCl4, 10 ml/kg body weight, diluted with corn oil at a 1:500 ratio. LCE was administered once a day for 7 days (IP) as pretreatment at a dose of 5 mg/kg/day. The levels of C-reactive protein (CRP) and tumor necrosis factor (TNF)-alpha were analyzed to determine the inflammation status. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed using ELISA assays. Liver ultrastructure was observed via optical microscopy. The mRNA and protein expression levels of peroxisome proliferator-activated receptor (PPAR)gamma, and nuclear factor (NF) kappaB were assayed using quantitative polymerase chain reaction and western blot analysis, respectively. Pretreatment with LCE decreased levels of ALT, AST, CRP and TNF-alpha, and NF-kappaB expression in the experimental hepatotoxicity mice model induced by CCl4. In addition, LCE increased the expression of PPARgamma and normalized the hepatic histoarchitecture. However, the effects of LCE were reversed by cotreatment with the PPARgamma inhibitor GW9662. The present study suggests that LCE may be used for the treatment of hepatotoxicity, and primarily exhibits its protective role through a PPARgamma/NF-kappaB-mediated pathway. PMID- 28849020 TI - Inhibitory effect of D3 dopamine receptors on neuropeptide Y-induced migration in vascular smooth muscle cells. AB - Abnormal migration of vascular smooth muscle cells (VSMCs) serves an important role in hypertension, atherosclerosis and restenosis following angioplasty, which is regulated numerous hormonal and humoral factors, including neuropeptide Y (NPY) and dopamine. Dopamine and NPY are both sympathetic neurotransmitters, and a previous study reported that NPY increased VSMC proliferation, while dopamine receptor inhibited it. Therefore, the authors wondered whether or not there is an inhibitory effect of dopamine receptor on NPY-mediated VSMC migration. The present study demonstrated that stimulation with NPY dose-dependence (10-10-10 7M, 24 h) increased VSMC migration, the stimulatory effect of NPY was via the Y1 receptor. This is because, in the presence of the Y1 receptor antagonist, BIBP3226 (10-7 M), the stimulatory effect of NPY on VSMC migration was blocked. Activation of the D3 receptor by PD128907 dose-dependence (10-11-10-8 M) reduced the stimulatory effect of NPY on VSMC migration. The effect of PD128907 was via the D3 receptor, because the inhibitory effect of PD128907 on NPY-mediated migration was blocked by the D3 receptor antagonist, U99194. The authors' further study suggested that the inhibitory effect of the D3 receptor was via the PKA signaling pathway, in the presence of the PKA inhibitor, 14-22 (10-6 M), the inhibitory effect of PD128907 on VSMC migration was blocked. Moreover, the inhibitory effect of PD128907 was imitated by PKA activator, Sp-cAMP [S], in the presence of Sp-cAMP [S], the NPY-mediated stimulatory effect on VSMC migration was abolished. The present study indicated that activation of the D3 receptor inhibits NPY Y1-mediated migration on VSMCs, PKA is involved in the signaling pathway. PMID- 28849021 TI - Expression of long non-coding RNAs in chondrocytes from proximal interphalangeal joints. AB - Osteoarthritis (OA) of hand is a common disease, resulting in disability of the hands. The pathogenesis of hand (H) OA remains to be elucidated, and findings from knee and hip joints cannot be simply applied to HOA. To improve knowledge on the specific biology and pathobiology of HOA, the present study performed bioinformatics analyses to analyze the long non-coding (lnc) RNA expression profile in human chondrocytes of proximal interphalangeal (PIP) finger joints and knee joints. Gene expression data were downloaded from the Gene Expression Omnibus database, and PIP and knee chondrocytes were analyzed (n=3/group). Probes of the Affymetrix Human Gene 2.0 ST Microarray were annotated to obtain information about lncRNA expression profile. Compared with chondrocytes from knee joints, chondrocytes derived from PIP joints had significantly different lncRNA expression profiles, and 1,172 lncRNAs were differentially expressed. Compared with chondrocyte from knee joints, 534 lncRNAs were upregulated and 638 lncRNAs were downregulated in chondrocytes from PIP joints. A co-expression network was constructed to analyze the correlation between lncRNAs and protein-coding genes. Function annotation analyses suggested that protein-coding genes that are co expressed with lncRNAs are enriched in the biological processes of bone morphogenesis, bone development and cartilage development. In conclusion, the present study demonstrated that chondrocytes derived from PIP joints exhibit a significant difference in lncRNA expression compared with chondrocytes derived from knee joints. PMID- 28849022 TI - Significance of the TMPRSS2:ERG gene fusion in prostate cancer. AB - The transmembrane protease serine 2:v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion is common in prostate cancer, while its functional role is not fully understood. The present study aimed to investigate the significance of the TMPRSS2:ERG gene fusion in human prostate cancers using bioinformatics tools. Comprehensive alteration analysis of TMPRSS2 and ERG in 148 different human cancer studies was performed by cBioPortal, and the mRNA expression level of the ERG gene was evaluated using Oncomine analysis. Furthermore, lentiviral short hairpin (sh)RNA-mediated knockdown of TMPRSS2:ERG was performed to study the impact of ERG silencing on cell proliferation and cell cycle distribution in prostate cancer cells. The results demonstrated that the TMPRSS2 and ERG genes were mostly altered in prostate cancer, and the most frequent alteration was gene fusion. Oncomine analysis demonstrated that the ERG gene was significantly upregulated in prostate clinical samples compared with the normal prostate gland in four independent datasets, and a positive association was observed between potassium inwardly-rectifying channel subfamily J member 15, down syndrome critical region gene 4, potassium inwardly-rectifying channel subfamily J member 6 and ERG gene expression. There were 272 mutations of the ERG gene identified in the cBioPortal database; among the mutations, 2 missense mutations (R367C and P401H) were regarded as functional mutations (functional impact score >1.938). Furthermore, the present study successfully knocked down ERG gene expression through a lentiviral-mediated gene silencing approach in VCaP prostate cancer cells. The ERG mRNA and protein expression levels were both suppressed significantly, and a cell-cycle arrest at G0/G1 phase was observed after ERG gene silencing. In conclusion, these bioinformatics analyses provide novel insights for TMPRSS2:ERG fusion gene study in prostate cancer. Target inhibition of ERG expression could significantly cause cell growth arrest in prostate cancer cells, which could be a potentially valuable target for prostate cancer treatment. However, the precise mechanism of these results remains unclear; therefore, further studies are required. PMID- 28849023 TI - Saponin extract from Panax notoginseng promotesangiogenesis through AMPK- and eNOS-dependent pathways in HUVECs. AB - Panax notoginseng saponins (PNS) are among the most important compounds extracted from Panax notoginseng root, and have long been used in traditional Chinese medicine to control bleeding. PNS have recently garnered attention for the treatment of circulatory system diseases. The present study aimed to evaluate the effects of PNS on angiogenesis in vitro and to explore the molecular mechanisms underlying their actions. The present results demonstrated that the proliferative ability of human umbilical vein endothelial cells (HUVECs) was augmented following treatment with PNS. In addition, wound healing and Boyden chamber assays indicated that PNS may enhance HUVEC motility and increase the number of capillary-like tube branches in HUVECs. These effects were suppressed by 5' adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) inhibitors. Furthermore, western blot analysis demonstrated that PNS stimulated the phosphorylation of AMPK and eNOS at Thr-172 and Ser-1179, respectively. These results suggested that PNS may promote tube formation in endothelial cells through AMPK- and eNOS-dependent signaling pathways. PMID- 28849024 TI - Inhibitory effect of curcumin in human endometriosis endometrial cells via downregulation of vascular endothelial growth factor. AB - Endometriosis, which affects up to 10% of women of reproductive age, is defined as endometrial-like gland and stroma tissue growths outside the uterine cavity. Despite increasing research efforts, there are no current effective treatment methods for this disease, therefore investigations for therapeutic strategies are of primary concern. In preliminary work, the authors demonstrated that curcumin inhibits endometriosis in vivo. The present in vitro study aimed to investigate the association between endometriotic stromal cells and curcumin and to clarify the underlying mechanism of action. A total of 14 patients with endometriosis were enrolled in the present study. The purity of endometrial stromal cell cultures was proven by standard immunofluorescent staining of vimentin. The cell proliferation and curcumin effects on endometrial stromal cells were assessed by the MTT assay and Hematoxylin and Eosin staining. For cell cycle analysis, phase distribution was detected by flow cytometry. Vascular endothelial growth factor (VEGF) protein expression was examined using immunohistochemistry staining. Apoptosis was assessed using Annexin V-fluorescein isothiocyanate staining. The results indicated that the treatment of curcumin decreased human ectopic and eutopic stromal cell growth. Following treatment with curcumin, human endometriotic stromal cells demonstrated an increased percentage of G1-phase cells and decreased percentages of S-phase cells, particularly in the group treated with 50 umol/l curcumin. Treatment with curcumin additionally decreased expression of VEGF. The data provide evidence that curcumin reduces cell survival in human endometriotic stromal cells, and this may be mediated via downregulation of the VEGF signaling pathway. PMID- 28849025 TI - FcgammaRIIb attenuates TLR4-mediated NF-kappaB signaling in B cells. AB - Toll-like receptors (TLRs) serve a vital role in activating the innate immune system by sensing conserved microbial products. Fc gamma receptor IIb (FcgammaRIIb), the inhibitory Fc receptor, exerts its immune regulatory functions by binding to the immunoglobulin G Fc domain. Although the individual roles of TLRs and FcgammaRIIb have been studied intensively, the cross-talk between FcgammaRIIb and TLR4 on B cells remains unknown. The present study demonstrated that FcgammaRIIb ligation by the immune complex (IC) attenuated the TLR4 triggered nuclear factor (NF)-kappaBeta activation, and decreased the release of interleukin (IL)-6 from B cells, via enhancing LYN proto-oncogene (Lyn) phosphorylation. In addition, IC treatment protected mice from lethal endotoxic shock. Accordingly, IC decreased the LPS-induced serum levels of IL-6, as well as intracellular IL-6 production in B cells in vivo. However, these protective and inhibitory effects of IC were not observed in FcgammaRIIb-/- mice. In conclusion, the present data demonstrated that FcgammaRIIb inhibited TLR4 signaling in B cells by activating Lyn phosphorylation and by inhibiting NF-kappaBeta signaling. The present study elucidated the mechanism associated with the TLR4 and FcgammaRIIb cross-talk in B cells. PMID- 28849026 TI - The effect of Bu Zhong Yi Qi decoction on simulated weightlessness-induced muscle atrophy and its mechanisms. AB - Microgravity has been previously demonstrated to induce skeletal muscle atrophy, loss of muscle force and disorders in myogenesis and metabolism. Current pharmacological strategies exhibit poor efficacy. Bu Zhong Yi Qi decoction (BZ) is a well-known traditional Chinese medicine decoction used for myasthenia gravis. In the present study, its effect on unloading induced muscle atrophy was investigated. The mousetail suspension model was used to simulate weightlessness induced muscle atrophy. The results indicated that BZ could significantly protect muscles from simulated weightlessness-induced atrophy. To elucidate the underlying mechanisms, drugCIPHER-CS methods were introduced to predict its potential targets, significantly enriched pathways and biological processes. The results demonstrated that the calcium signaling pathway, citrate cycle, biosynthetic and lipid metabolic process are affected by BZ. Among the targets, nuclear receptor corepressor 1 (NCoR1) is one of the most important proteins involved in myogenesis and metabolism. The results indicated that BZ significantly downregulated NCoR 1 expression, and further induced muscle differentiation and metabolism by regulating NCoR1-associated gene expression in vivo and in vitro. In summary, the present study indicated that may be effective in combating weightlessness-induced muscle atrophy. Combined with bioinformatics, the underlying mechanism for this decoction was investigated, which provided an improved understanding of this decoction. PMID- 28849027 TI - Identification of CALM as the potential serum biomarker for predicting the recurrence of nasopharyngeal carcinoma using a mass spectrometry-based comparative proteomic approach. AB - To date, there are no serum biomarkers available for the prediction of recurrent nasopharyngeal carcinoma (rNPC). The diagnosis of rNPC mostly depends on imaging and biopsy of diseased tissue; however, both of these methods work mostly if the target tumor is at an advanced stage. Therefore, the identificaqtion of recurrent biomarkers is urgently required. In the present study, we used tandem mass tag (TMT) labeling and high performance liquid chromatography (HPLC) fractionation followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins. Serum was collected from 40 patients with NPC [recurrence (n=20) and no recurrence (n=20)]. Compared to non-recurrent NPC (nrNPC), we found 59 proteins to be significantly dysregulated in rNPC; most of these have been previously reported to play a role in carcinogenesis. The dysregulation of calmodulin (CALM) was confirmed in 74 new patients [recurrence (n=32) and no recurrence (n=42)] by ELISA. Moreover, we performed a preliminary pathway analysis which revealed that oxidative phosphorylation was altered in the patients with rNPC compared to those with nrNPC. Taken together, these data identify a potential diagnostic biomarker for rNPC and elucidate the potential molecular mechanisms that are dysregulated and contribute to the pathogenesis of rNPC. PMID- 28849028 TI - Panax ginseng extract antagonizes the effect of DKK-1-induced catagen-like changes of hair follicles. AB - It is well known that Panax ginseng (PG) has various pharmacological effects such as anti-aging and anti-inflammation. In a previous study, the authors identified that PG extract induced hair growth by means of a mechanism similar to that of minoxidil. In the present study, the inhibitory effect of PG extract on Dickkopf 1 (DKK-1)-induced catagen-like changes in hair follicles (HFs) was investigated in addition to the underlying mechanism of action. The effects of PG extract on cell proliferation, anti-apoptotic effect, and hair growth were observed using cultured outer root sheath (ORS) keratinocytes and human HFs with or without DKK 1 treatment. The PG extract significantly stimulated proliferation and inhibited apoptosis, respectively, in ORS keratinocytes. PG extract treatment affected the expression of apoptosis-related genes Bcl-2 and Bax. DKK-1 inhibited hair growth, and PG extract dramatically reversed the effect of DKK-1 on ex vivo human hair organ culture. PG extract antagonizes DKK-1-induced catagen-like changes, in part, through the regulation of apoptosis-related gene expression in HFs. These findings suggested that PG extract may reduce hair loss despite the presence of DKK-1, a strong catagen inducer via apoptosis. PMID- 28849029 TI - Ca2+/Mg2+ homeostasis-related TRPM7 channel mediates chondrocyte hypertrophy via regulation of the PI3K-Akt signaling pathway. AB - Chondrocytes are specialized cells that form cartilage tissue, and are able to respond to their osmotic environment and exercise important roles in endochondral ossification via undergoing proliferation, hypertrophy and apoptosis. The transient receptor melastatin potential 7 (TRPM7) cation channel can modulate the intracellular and extracellular levels of Ca2+ and Mg2+, and therefore the cellular osmotic environment. However, the molecular pathways involved in TRPM7 mediated signal transduction have yet to be elucidated. In the present study, the expression and functionality of TRPM7 were investigated during chondrocyte proliferation and hypertrophy. The ATDC5 mouse cell line was employed and cellular viability was evaluated using the MTT assay, whereas hypertrophy was monitored via evaluating the expression of chondrogenic marker genes and the activity of alkaline phosphatase (ALP). Gene expression of TRPM7 appeared slightly upregulated during the proliferative stages of chondrocyte development, and significantly upregulated during the hypertrophic stages, suggesting the importance of Ca2+/Mg2+ homeostasis for chondrocyte growth. Low extracellular Ca2+/Mg2+ levels significantly reduced the expression of type X collagen, Indian hedgehog homolog (Ihh) and matrix metalloproteinase (MMP)-13 genes, as well as ALP activity; however, cell viability remained unaffected. Conversely, the gene expression levels of TRPM7 appeared upregulated in ATDC5 cells under low extracellular Ca2+ or Mg2+ conditions. Silencing TRPM7 expression during the chondrocyte differentiation period also reduced type X collagen, Ihh and MMP-13 gene expression, and ALP activity. Furthermore, the phosphatidylinositol-4,5 bisphosphate 3-kinase (PI3K)-Akt signaling pathway was activated following TRPM7 overexpression, and inhibited following TRPM7 silencing. Notably, the actions of TRPM7 on chondrocyte hypertrophy were abolished through the inhibition of PI3K Akt signaling. The present results suggested that TRPM7 may be involved in Ca2+/Mg2+ homeostasis during chondrocyte hypertrophy, and contribute to endochondral ossification via interacting with the PI3K-Akt signaling pathway. PMID- 28849030 TI - Protective effects of Cervus nippon Temminck velvet antler polypeptides against MPP+-induced cytotoxicity in SH-SY5Y neuroblastoma cells. AB - The aim of the present study was to examine the protective effects and mechanism of sika deer (Cervus nippon Temminck) velvet antler polypeptides (VAPs) against MPP+ exposure in the SH-SY5Y human neuroblastoma cell line. MPP+ cytotoxicity and the protective effects of VAPs on the SH-SY5Y cells were determined using an MTT assay. Cell apoptosis and mitochondrial membrane potential were detected using Hoechst 33342 and Rhodamine123 staining, respectively. Endoplasmic reticulum (ER) stress-related reactive oxygen species (ROS) production in the SH-SY5Y cells was detected using 2',7'-dichlorodihydrofluorescein diacetate fluorescent probes. The expression levels of proteins, including caspase-12, glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated c-Jun N-terminal kinase (p-JNK) were detected using western blot analysis. The results showed that the half inhibitory concentration of MPP+ at 72 h was 120.9 umol/l, and that 62.5, 125, and 250 ug/ml concentrations of VAPs protected the SH-SY5Y cells under MPP+ exposure. When exposed to 120.9 umol/l MPP+, changes in cell nucleus morphology, mitochondrial membrane potential and intracellular ROS were observed. VAPs at concentrations of 62.5, 125, 250 ug/ml reduced this damage. Western blot analysis showed that protein expression levels of caspase-12, GRP78 and p-JNK were upregulated in the SH-SY5Y cells exposed to 120.9 umol/l MPP+ for 72 h. In addition, 62.5, 125, and 250 ug/ml VAPs downregulated the expression levels of caspase-12 and p-JNK in a concentration- dependent manner, particularly the p-JNK pathway. The effects of VAPs on GRP78 and CHOP were weak. In conclusion, MPP+-induced SH-SY5Y cell death may be linked to ER stress. VAPs prevented MPP+-induced SH-SY5Y cell death by affecting the p JNK pathway and caspase-12-mediated apoptosis. These findings assist in understanding the mechanism underlying the protective effect of VAPs on neurons. PMID- 28849031 TI - Sanggenon C protects against pressure overload-induced cardiac hypertrophy via the calcineurin/NFAT2 pathway. AB - The effects of Sanggenon C on oxidative stress and inflammation have previously been reported; however, little is currently known regarding the effects of Sanggenon C on cardiac hypertrophy and fibrosis. In the present study, aortic banding (AB) was performed on mice to induce cardiac hypertrophy. After 1 week AB surgery, mice were treated daily with 10 or 20 mg/kg Sanggenon C for 3 weeks. Subsequently, cardiac function was detected using echocardiography and catheter based measurements of hemodynamic parameters. In addition, the extent of cardiac hypertrophy was evaluated by pathological staining and molecular analysis of heart tissue in each group. After 4 weeks of AB, vehicle-treated mice exhibited cardiac hypertrophy, fibrosis, and deteriorated systolic and diastolic function, whereas treatment with 10 and 20 mg/kg Sanggenon C treatment ameliorated these alterations, as evidenced by attenuated cardiac hypertrophy and fibrosis, and preserved cardiac function. Furthermore, AB-induced activation of calcineurin and nuclear factor of activated T cells 2 (NFAT2) was reduced following Sanggenon C treatment. These results suggest that Sanggenon C may exert protective effects against cardiac hypertrophy and fibrosis via suppression of the calcineurin/NFAT2 pathway. PMID- 28849032 TI - Analysis of intestinal microbial communities of cerebral infarction and ischemia patients based on high throughput sequencing technology and glucose and lipid metabolism. AB - Currently, cerebral infarction (CI) is the leading cause of disability and the second leading cause of mortality in China, seriously affecting patient quality of life. Ischemia (IS) is considered to be the early stage of CI. The present study aims to investigate the variation of intestinal microbial communities in patients with CI and IS using high throughput sequencing technology, and then analyze the results to identify a novel potential pathogenic mechanism of CI and IS. In total, 8 patients with CI, 2 patients with IS and 10 healthy volunteers as a control were selected. Throughput sequencing technology was used to analyze the character and microbial population of the gut. The abundance of Escherichia, Bacteroides, Megamonas, Parabacteroides, Akkermansia, Prevotella, Faecalibacterium, Dialister, Bifidobacterium and Ruminococcus was the significant difference in the intestinal microbial communities of the CI and IS patients compared with the healthy group. It was also observed that CI and IS were closely associated with internal glucose metabolism. The intestinal gut disturbance of CI patients may be one of the causes inducing CI by glucose metabolism and maybe considered as a potential method to predict the disease. PMID- 28849033 TI - MicroRNA-302a inhibits cell proliferation and invasion, and induces cell apoptosis in hepatocellular carcinoma by directly targeting VEGFA. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related mortality worldwide. An increasing number of studies have demonstrated that microRNAs may be used as diagnostic, therapeutic and prognostic targets for human cancers, including HCC. The present study aimed to evaluate microRNA (miR)-302a expression and function in HCC, and its underlying mechanisms. The results revealed that miR-302a was expressed at low levels in HCC tissues and cell lines. Reduced miR-302a expression was correlated with tumor-node-metastasis stage and lymph node metastasis in patients with HCC. Additionally, overexpression of miR-302a reduced cell proliferation and invasion, and induced apoptosis in HCC cells. Vascular endothelial growth factor A (VEGFA) was demonstrated to be a direct target gene of miR-302a. VEGFA was highly expressed in HCC tissues and inversely correlated with miR-302a expression. Knockdown of VEGFA expression led to reduced HCC cell proliferation and invasion, and increased apoptosis rates, similar to miR-302a overexpression, which suggested that VEGFA may be a functional downstream target of miR-302a in HCC. These data suggested that this newly identified miR-302a/VEGFA axis may be involved in HCC formation and progression. The present results also provide novel potential targets for the treatments of patients with HCC. PMID- 28849034 TI - Melanogenesis in uveal melanoma cells: Effect of argan oil. AB - The mechanisms underlying cutaneous melanogenesis have been widely studied; however, very little is known about uveal melanogenesis. Melanin is normally produced by uveal melanocytes and gives the color to the iris. A derangement from this normal production may occur, for instance, by iatrogenic events, such as glaucoma therapy with prostaglandins that may enhance cutaneous and iris pigmentation. In this study, we investigated the mechanisms that regulate uveal melanogenesis in human uveal melanoma cells (92.1) and murine cutaneous melanoma cells (B16-F1). In the first part of the study, we compared the effects of known cutaneous pigmenting agents on the B16-F1 and 92.1 cells, showing an opposite response of the two cell lines. Subsequently, using argan oil, a known depigmenting agent for murine cutaneous melanoma cells, on 92.1 cells, we found that in these cells, it also functioned as an inhibitor of melanogenesis and tyrosinase expression. From a molecular perspective, treatment of the 92.1 cells with argan oil decreased melanogenesis-associated transcription factor (MITF) gene expression by inducing MITF phosphorylation at Ser73, thus leading to MITF ubiquitination and disposal. It also led to the downregulation of the extracellular signal-regulated kinase (ERK)1/2 and Akt pathways, also known to be involved in cutaneous melanogenesis, although with an opposing function. Taken together, our data indicate that: i) some differences exist in the regulation of melanogenesis between cutaneous and uveal melanoma cells; and ii) argan oil exerts a depigmenting effect on 92.1 cells through its action on the ERK1/2 and Akt pathways. PMID- 28849035 TI - Alterations in the long non-coding RNA transcriptome in mesangial cells treated with aldosterone in vitro. AB - Clinical and experimental reports indicate that aldosterone (ALD) contributes to the progression of renal failure independent of its hemodynamic effects. However, the mechanisms remain to be completely elucidated. The aim of the present study was to investigate the alterations of long non-coding RNA (lncRNA) in mesangial cells (MCs) treated with ALD. The present study used MCs treated with 10-6 M ALD as experimental cells. Microarray techniques performed by Agilent Technologies were used to identify the profiles of differentially expressed lncRNAs between the ALD group and the control group. Pathway and gene ontology analysis were applied to determine the roles of the differentially expressed lncRNAs. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to quantify the differentially expressed lncRNAs. A total of 8,459 lncRNA and 13,214 mRNAs with differential expression between MCs treated with and without ALD were identified. The expression of lncRNAs was confirmed by RT-qPCR and the results were consistent with the lncRNA array. The biological functions of lncRNAs are associated with responding to external stimuli, positive regulation of biological and apoptotic processes, cell division, mitosis and nuclear division. The pathways include cell cycle and peroxisome proliferator-activated receptor signaling pathways. The present study revealed distinct sets of lncRNA expressed in MCs treated with ALD, suggesting that this class of transcripts may be involved in the pathogenesis of chronic kidney diseases. PMID- 28849036 TI - Knockdown of AQP1 inhibits growth and invasion of human ovarian cancer cells. AB - Aquaporin 1 (AQP1), which is a water channel protein, has been demonstrated to have an important role in cell proliferation and migration of various cancers. However, its specific role in ovarian cancer remains to be elucidated. The present study demonstrated that AQP1 expression was elevated in the majority of patients with ovarian cancer compared with normal ovarian tissues. In addition, a short interfering (si)RNA targeting AQP1 was established, and transfected into the SKOV3 ovarian cancer cell line, to investigate the effects on cell viability, apoptosis, migration and invasion in the ovarian cancer cells using an MTT assay, flow cytometry, wound healing and Transwell invasion chamber assays, respectively. The results of the present study demonstrated that siRNA targeting AQP1 effectively downregulated AQP1 expression at the mRNA and protein levels, markedly suppressed cell viability, migration and invasion and promoted apoptosis of ovarian cancers cells. These results suggested that AQP1 may serve as a novel target for ovarian cancer treatment in the future. PMID- 28849038 TI - Mda-7/IL-24 induces the differentiation of B cell lymphoma via activation of the P38 mitogen activated protein kinase signaling pathway. AB - Interleukin 24 (IL-24) is a unique cytokine encoded by the melanoma differentiation associated gene-7 (Mda-7), and was first discovered inhuman melanoma cells. Exogenous Mda-7/IL-24 has been shown to inhibit the proliferation and invasion of a broad spectrum of human cancer cells, but its effect on the differentiation of B cell lymphoma is not yet clear. To the best of our knowledge, the present study demonstrated for the first time that overexpressing Mda-7/IL-24 can induce differentiation in human B cell lymphomacells, and the underlying mechanism was investigated. The proliferation of stable Mda-7/IL-24 overexpressing Raji and Daudi cells was assessed by the MTS method. The immunophenotype, apoptosis level and cell cycle distribution of Raji and Daudi cells were analyzed by flow cytometry. The expression of PR domain zinc finger protein 1 (Blimp1) and B-cell lymphoma 6 (Bcl6) were analyzed by western blotting. Additionally, western blotting assay was also performed to study the effect of Mda-7/IL-24 on the activity of the P38 mitogen activated protein kinase (MAPK) signaling pathway in Raji and Daudi cells. Proliferation of Raji and Daudi cells overexpressing Mda-7/IL-24 was inhibited significantly, compared with those of parent cells and cells transfected with the empty vector alone. Apoptosis was not involved in the proliferation inhibition, while the cell cycle was arrested in G1 phase in the Raji and Daudi cells overexpressing Mda-7/IL-24. Overexpressing Mda-7/IL-24 resulted in a significantly decreased expression of cluster of differentiation (CD)10, and increased expression of CD45 and CD138 in the cell surface of Raji and Daudi cells. The expression of Blimp1 was upregulated, while the levels of Bcl6 protein was downregulated, in Raji and Daudi cells overexpressing Mda-7/IL-24. Furthermore, the activities of the P38 MAPK signaling pathway in lymphoma cells were upregulated. These results indicated that Mda-7/IL-24 could induce terminal differentiation of B lymphoma cells by regulating the expression of Blimp1 and Bcl6 via altering the P38 MAPK signaling pathway, suggesting that Mda-7/IL-24 may therefore be a potential differentiation therapeutic agent to be applied in clinical treatment of B cell lymphoma. PMID- 28849037 TI - Interferon regulatory factor 4 (IRF4) is overexpressed in human non-small cell lung cancer (NSCLC) and activates the Notch signaling pathway. AB - The transcription factor, interferon regulatory factor 4 (IRF4), serves an essential role in the regulation of immune responses, and has been reported to act as a diagnostic and prognostic marker for various hematological malignancies. The present study aimed to investigate whether IRF4 could exert effects on human non-small cell lung cancer (NSCLC) and to explore the underlying mechanism. The mRNA and protein expression of IRF4 was detected in NSCLC tissues using reverse transcription quantitative polymerase chain reaction and western blotting, respectively. In the in vitro experiment, IRF4 expression was knocked down or overexpressed using lentivirus in human lung adenocarcinoma A549 and lung squamous cell carcinoma LC-AI cell lines. Cell proliferation and colony number were analyzed using MTT and colony formation assays, respectively. The expression levels of IRF4 mRNA and protein were significantly higher in NSCLC tissues (n=54) compared with that in adjacent non-tumor tissues. Similarly, the expression levels of Notch1 and Notch2 mRNA were significantly higher in NSCLC tissues. Furthermore, the expression level of IRF4 mRNA was positively correlated with the levels of Notch1 and Notch2 mRNA in NSCLC tissues. Consequently, using NSCLC cell lines, it was demonstrated that the knockdown of IRF4 expression significantly reduced the cell proliferation rate and colony formation, whereas IRF4 overexpression significantly increased them. Notably, the IRF4 knockdown significantly decreased the expression levels of Notch1 and Notch2 mRNA, and phosphorylated protein kinase B (AKT), whereas IRF4 overexpression resulted in the opposite. The results of the present study indicate that IRF4 is overexpressed and serves as a tumor promoter in human NSCLC, at least partially, through activating the Notch-Akt signaling pathway. PMID- 28849039 TI - Expression of microRNA-222 in serum of patients with Alzheimer's disease. AB - The aim of the present study was to determine the association between Alzheimer's disease (AD) and microRNA-222 in the serum of patients with AD. The expression of microRNAs was detected and the results were verified using microarray analysis and reverse transcription-quantitative polymerase chain reaction. The results indicated that there were 35 strips of microRNA in the mild AD group, in which the difference of expression signal was >500 IU/ml. There were 26 strips of microRNA with a difference in expression signal of >500 IU/ml in the mild and moderate AD groups. The downregulation of microRNA-222 in the mild and moderate groups was statistically significant (P<0.01), and the expression of microRNA-222 in the moderate group was significantly lower, compared with that in the mild AD group (P<0.05). It was concluded that microRNA-222 may affect the occurrence and development of AD through a variety of mechanisms, and may serve as a biomarker for the early diagnosis of AD. PMID- 28849040 TI - Triticum aestivum sprout-derived polysaccharide exerts hepatoprotective effects against ethanol-induced liver damage by enhancing the antioxidant system in mice. AB - Triticum aestivum sprout-derived polysaccharide (TASP) has anti-diabetic properties, but no information is available in regards to its protective effect against ethanol-induced hepatic injury. This study aimed to investigate the mechanism behind the protective role of TASP against ethanol-induced liver injury in vivo. Male C57BL/6 mice were administered ethanol with or without TASP for 10 consecutive days by oral gavage. Silymarin was administered in the same manner as a positive control. TASP reduced ethanol-induced hepatic lipid accumulation and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. TASP also prevented glutathione (GSH) depletion and increased the superoxide dismutase (SOD) in liver tissue. In addition, TASP significantly inhibited ethanol-induced cytochrome P450 2E1 (CYP2E1) activation, and upregulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1), and downregulated NADPH oxidase genes in ethanol fed mice. Furthermore, the upregulation of Nrf2 was found to be regulated by a phosphatidylinositol 3-kinase (PI3K)/Akt pathway. TASP also attenuated hepatic injury by modulation of caspase-3 and apoptosis-associated mitochondrial proteins including B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) in liver tissues of mice. The study demonstrated that TASP treatment protects against ethanol induced hepatic injury via multiple pathways by inhibiting steatosis and improving antioxidant marker levels during hepatic injury. Such properties provide a basis for therapeutic agents against alcohol-induced liver injury. PMID- 28849041 TI - In vitro effects of Staphylococcus aureus enterotoxin C3 on T cell activation, proliferation and cytokine production. AB - The present study aimed to investigate the effects of Staphylococcus aureus enterotoxin C3 (SEC3), including recombinant (r)SEC3 protein and lentivirus mediated SEC3, on the activation, proliferation and cytokine production of human T cells. HeLa cells were infected with SEC3 lentiviral vector (LV-SEC3) and viability was determined using the Cell Counting Kit-8 (CCK-8) assay. Subsequently, infected cells or rSEC3 protein were co-cultured with human peripheral blood mononuclear cells (PBMCs) for 10 days, after which the culture supernatant and T cells were incubated with untreated HeLa cells, which were subjected to a CCK-8 assay to determine cytotoxicity. In addition, IL-6 and IFN gamma expression was detected by chemiluminescence and enzyme-linked immunospot analyses, respectively. Subpopulations of activated T cells were sorted by flow cytometry. The results demonstrated that, following infection with LV-SEC3 or negative control lentiviral vector (LV-NC), >80% of HeLa cells presented green fluorescent protein-positive signals. All five groups of co-cultured T cells exhibited proliferation. Co-culture of PBMCs with rSEC3 protein or LV-SEC infected cells resulted in elevated IL-6 and IFN-gamma secretion. In addition, rSEC3-activated and monocultured T cells were predominantly cluster of differentiation (CD)4+ (62.7 and 59.6%, respectively) whereas phytohemagglutinin stimulated T cells were predominantly CD8+ (57.8%). Compared with the LV-NC group, T cells and culture supernatants from the LV-SEC3 group significantly attenuated proliferation of HeLa cells. These results suggest that rSEC3 protein, and LV-SEC3-infected HeLa cells, are able to potently activate T cells, increasing cytokine production and amplify the antitumor immune response. PMID- 28849042 TI - TREM-2 negatively regulates LPS-mediated inflammatory response in rat bone marrow derived MSCs. AB - To the best of our knowledge, our previous study demonstrated the expression of triggering receptor expressed on myeloid cells 2 (TREM-2) in human bone marrow mesenchymal stem cells (MSCs) for the first time. However, the inflammation regulatory role of TREM-2 in MSCs remain elusive. The aim of the present study was to investigate the immune regulation and the underlying mechanism of TREM-2 in rat bone marrow MSCs. MSCs were divided into three groups: NullMSCs, TREM 2MSCs, and NormMSCs. TREM-2 was expressed in MSCs at the mRNA and protein level. Following stimulation by lipopolysaccharide (LPS), the gene transcription levels of TREM-2 and inflammatory cytokines were increased. The expression levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), in the TREM-2MSCs lentiviral vector group were significantly downregulated, and the expression of IL-10 was significantly upregulated compared with the controls. Western blot analysis revealed that TREM 2 downregulated the LPS-induced inflammatory response in MSCs, which was probably associated with regulating AKT serine/threonine kinase and p38 mitogen-activated protein kinase downstream signaling proteins. The results of the current study demonstrated that TREM-2 negatively regulates the LPS-mediated inflammatory response in MSCs suggesting that TREM-2 is a potential target of immune regulation in rat MSCs. PMID- 28849043 TI - Exogenous leptin protects rat models of sodium taurocholate-induced severe acute pancreatitis through endocrinal and immunological pathways. AB - Acute pancreatitis (AP) is a common non-bacterial disease compromising pancreatic tissues. Adipocyte-derived leptin is closely associated with the severity and clinical outcome of pancreatitis. The potential protective effects of exogenous leptin administration on a rat model of severe AP (SAP) remain to be elucidated, and were examined in the present study. Male Wistar rats were divided into a sham operation group (SO), SAP model group (SAP) and leptin group (LEP). Each group was divided into three sub-groups by observation time (24, 48 and 72 h). The SAP models were prepared by retrograde injection of 6% sodium taurocholate into the pancreatic-bile duct. Following model establishment, exogenous leptin was intraperitoneally injected into mice at 50 mg/kg in the LEP group. Subsequently, serum amylase, lipase and glucose levels at particular time-points were analyzed using a fully-automatic biochemical analyzer, and serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were detected using an enzyme-linked immunosorbent assay. The pathological changes in pancreatic tissues were observed using hematoxylin and eosin staining, and the pancreatic expression of the long form of the leptin receptor (OB-Rb) was detected and evaluated using Nest polymerase chain reaction analysis. The mortality rates of the model rats were compared between the groups. Following the administration of exogenous leptin, the serum level of amylase in the LEP group was significantly decreased at 48 h, compared with that in the SAP group, with serum lipase levels decreased at 48 and 72 h, and blood glucose levels decreased at 72 h. Regarding the serum inflammatory factors, the level of TNF-alpha in the LEP group was significantly lower, compared with that in the SAP group at 24 h; whereas no significant difference was observed in the serum level of IL-10 between the two groups. Regarding the pathological changes in the pancreas, the tissues in the LEP group showed significantly alleviated pancreatic inflammation. In addition, the pancreatic expression of OB-Rb in the LEP group was significantly higher, compared with that in the SAP group at 24 and 48 h. No significant difference in 3-day mortality rates were observed between the SAP group and the LEP group. Taken together, exogenous leptin administration regulated inflammatory factors and the expression of OB-Rb at the early stage of AP, which exerted protective effects by through the immunological and endocrinal pathways. PMID- 28849044 TI - Emodin alleviates severe acute pancreatitis-associated acute lung injury by decreasing pre-B-cell colony-enhancing factor expression and promoting polymorphonuclear neutrophil apoptosis. AB - The present study aimed to evaluate the protective effects of emodin on severe acute pancreatitis (SAP)-associated acute lung injury (ALI), and investigated the possible mechanism involved. SAP was induced in Sprague-Dawley rats by retrograde infusion of 5% sodium taurocholate (1 ml/kg), after which, rats were divided into various groups and were administered emodin, FK866 [a competitive inhibitor of pre-B-cell colony-enhancing factor (PBEF)] or dexamethasone (DEX). DEX was used as a positive control. Subsequently, PBEF expression was detected in polymorphonuclear neutrophils (PMNs) isolated from rat peripheral blood by reverse transcription-quantitative polymerase chain reaction and western blotting. In addition, histological alterations, apoptosis in lung/pancreatic tissues, apoptosis of peripheral blood PMNs and alterations in the expression of apoptosis-associated proteins were examined by hematoxylin and eosin staining, terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assay, Annexin V/propidium iodide (PI) assay and western blotting, respectively. Serum amylase activity and wet/dry (W/D) weight ratios were also measured. An in vitro study was also conducted, in which PMNs were obtained from normal Sprague-Dawley rats and were incubated with emodin, FK866 or DEX in the presence of lipopolysaccharide (LPS). Apoptosis of PMNs and the expression levels of apoptosis-associated proteins were examined in cultured PMNs in vitro by Annexin V/PI assay and western blotting, respectively. The results demonstrated that emodin, FK866 and DEX significantly downregulated PBEF expression in peripheral blood PMNs. In addition, emodin, FK866 and DEX reduced serum amylase activity, decreased lung and pancreas W/D weight ratios, alleviated lung and pancreatic injuries, and promoted PMN apoptosis by regulating the expression of apoptosis associated proteins: Fas, Fas ligand, B-cell lymphoma (Bcl)-2-associated X protein, cleaved caspase-3 and Bcl-extra-large. In addition, the in vitro study demonstrated that emodin, FK866 and DEX significantly reversed the LPS-induced decrease of apoptosis in PMNs by regulating the expression of apoptosis associated proteins. In conclusion, the present study demonstrated that emodin may protect against SAP-associated ALI by decreasing PBEF expression, and promoting PMN apoptosis via the mitochondrial and death receptor apoptotic pathways. PMID- 28849045 TI - Ultrasound and magnetic resonance molecular imaging of atherosclerotic neovasculature with perfluorocarbon magnetic nanocapsules targeted against vascular endothelial growth factor receptor 2 in rats. AB - The aim of the present study was to investigate the feasibility of using ultrasonography (US) and magnetic resonance (MR) for bimodal molecular imaging of atherosclerotic neovasculature with liquid perfluorocarbon magnetic nanocapsules (NCs) targeted to vascular endothelial growth factor receptor 2 (VEGFR-2). By incorporating perfluorooctyl bromide (PFOB) and superparamagnetic iron oxide (SPIO) into polylactic acid, a SPIO-embedded PFOB NC was constructed; subsequently, a VEGFR-2-targeted NC (VTNC) containing dual detectable probes was created by covalently linking a VEGFR-2 antibody onto the surface of the SPIO embedded PFOB NC. Target specificity was verified in vitro by incubating VTNC with VEGFR-2+ or VEGFR-2- endothelial cells. Rats with vulnerable plaques were assigned to receive either an injection of VTNC (Targeted group; n=8) or an injection of NC (Nontargeted group; n=8); control rats also received an injection of VTNC (Control group; n=8). US and MR imaging of the abdominal aorta were performed to detect VTNC by measuring of the ultrasonic grayscale intensity (GSI) and MR contrast-to-noise ratio (CNR) prior to and at successive time points following VTNC and NC injections. The percent positive area (PPA) of CD31+ (PPACD31+) or VEGFR-2+ (PPAVEGFR-2+) expression was quantified by immunohistochemical staining. CD31 was used to verify the existence of endothelial cells as it is widely expressed on the surface of endothelial cells whether activated or not. The results demonstrated that VTNC was able to highly and selectively detect VEGFR-2+ endothelial cells, and GSI, CNR, PPACD31+ and PPAVEGFR-2+ were significantly increased in the targeted group compared with the nontargeted and control groups. In the control group, no atherosclerotic plaques or angiogenesis was identified, thus no expression of PPACD31+ and PPAVEGFR-2 (data not shown). There were strong correlations among GSI, CNR, PPACD31+ and PPAVEGFR-2+. In conclusion, two-probe VTNC is feasible for bimodal US and MR molecular imaging of atherosclerotic neovasculature, which may offer complementary information for the more reliable prediction of plaque vulnerability. PMID- 28849046 TI - MicroRNA-543 inhibits proliferation, invasion and induces apoptosis of glioblastoma cells by directly targeting ADAM9. AB - Glioma is the most common type of malignant brain tumor in humans and accounts for 81% of all malignant brain tumor cases in adults. The abnormal expression of microRNAs (miRs) has been reported to be important in the formation and progression of various types of human cancer, including glioblastoma (GBM). Therefore, studies into the expression, and roles of microRNAs as diagnostic and prognostic markers, as well as their therapeutic value for patients with GBM are warranted. The expression and roles of miR-543 have been reported in several types of human cancer. However, the role of miR-543 in GBM remains unclear. In the current study, the expression pattern of miR-543 in GBM, the effects of miR 543 on GBM cells and the underlying molecular mechanism was determined. The results of the present study demonstrated that miR-543 was significantly downregulated in GBM tissue samples and cell lines. Furthermore, the upregulation of miR-543 inhibited GBM cell proliferation and invasion, as well as promoted cell apoptosis. In addition, a disintegrin and metalloproteinase 9 (ADAM9) was identified to be a direct target gene of miR-543. Furthermore, ADAM9 was significantly upregulated in GBM tissue samples and its expression was inversely correlated with miR-543 expression in GBM tissue, suggesting that miR-543 downregulation may contribute to ADAM9 upregulation in GBM. Finally, the results of the rescue experiment indicated that ADAM9 overexpression significantly reversed the effects of miR-543 on the proliferation, invasion and apoptosis of GBM cells, suggesting that miR-543 serves as a tumor suppressor in GBM through ADAM9 regulation. Overall, these findings indicate that the miR-543/ADAM9 signaling pathway may provide as a potential therapeutic strategy for GBM. PMID- 28849047 TI - Conditioned medium from tonsil-derived mesenchymal stem cells promotes adiponectin production. AB - Mesenchymal stem cells (MSCs) are often considered to be a good source for the development of regenerative medicine. Previously, we reported that tonsil-derived MSC conditioned medium (T-MSC CM) produces visceral fat reducing effects. As reduced visceral adiposity is closely associated with an increase in circulating adiponectin, the present study investigated the effects of T-MSC CM on adiponectin production. T-MSC CM was collected from previously isolated and characterized T-MSCs and injected into senescence-accelerated mouse prone 6 mice, which exhibit characteristics of aging and obesity. The results demonstrated a reduction in mouse weight and epididymal adipose tissue (eAT) mass following injection of T-MSC CM. Significant increases in adiponectin expression in the eAT, and total and high molecular weight (HMW) adiponectin in the circulation were observed in the T-MSC CM-injected mice compared with control mice using reverse transcription-quantitative polymerase chain reaction, western blot analysis and ELISA. In 3T3-L1 adipocytes, T-MSC CM treatment increased adiponectin secretion and multimerization, as detected using western blotting under non-reducing and non-heat-denaturing conditions. Furthermore, glucose oxidase was used to induce oxidative stress in 3T3-L1 adipocytes and it was observed that T-MSC CM reduced reactive oxygen species production and the expression of certain oxidative stress markers. In addition, the results also demonstrated that the production of HMW adiponectin was increased, which indicates that T-MSC CM may enhance adiponectin multimerization via amelioration of oxidative stress. Further studies are required to elucidate anti-oxidant molecules secreted from T-MSCs, and these results highlight the potential therapeutic relevance of T-MSC CM for the treatment of obesity or obesity associated diseases. PMID- 28849048 TI - Lactobacillus plantarum LP-Onlly alters the gut flora and attenuates colitis by inducing microbiome alteration in interleukin-10 knockout mice. AB - The association between inflammatory bowel disease (IBD) and gut microbes has been widely investigated. Our previous study demonstrated that Lactobacillus plantarum LP-Onlly (LP) applied as a probiotic altered the gut flora and attenuated colitis in interleukin (IL)-10 knockout (IL-10-/-) mice. In the present study, metagenome sequencing was performed to investigate the gut microbiome in IL-10-/-mice and the influence of oral administration of LP on microbial composition. Metagenomics sequencing was performed to investigate the influence of IBD on the gut microbiome with and without LP treatment. The alteration of the abundances of various taxonomic and functional groups were investigated across these gut microbiomes. The present study demonstrates that Akkermansia muciniphila was significantly enriched in IL-10-/- mice, and bacteroides were significantly increased following LP administration. In addition, the phylum Bacteroidetes and Firmicutes were significantly influenced by LP administration. Further characterization of functional capacity revealed that in the gut metagenomes of IL-10-/-mice, genes encoding cell cycle control, replication, recombination, repair and cell envelope biogenesis were decreased, but intracellular trafficking, secretion, and vesicular transport were increased. The present findings indicate that the gut metagenome is associated with IBD, and oral administration of LP contributes to prevention of gut inflammation, providing insight into the treatment of IBD. PMID- 28849049 TI - The protective effect of berberine hydrochloride on LPS-induced osteoclastogenesis through inhibiting TRAF6-Ca2+-calcineurin-NFATcl signaling pathway. AB - The present study investigated the protective effect of berberine hydrochloride on lipopolysaccharide (LPS) -induced acute bone destruction through inhibition of the TNF receptor associated factor 6 (TRAF6)-Ca2+-calcineurin-nuclear factor of activated T-cell 1 (NFATc1) signaling pathway. An osteoclast culture system of RAW264.7 cells induced by LPS in vitro was established. A polymerase chain reaction (PCR) assay was applied to determine the effect of berberine hydrochloride on the mRNA expression levels of fos-related antigen 2 (Fra-2), tartrate-resistant acid phosphatase (TRAP), beta3-integrin, cathepsin K, dendritic cell-specific transmembrane protein (DC-STAMP), V-type proton ATPase subunit d 2 (Atp6v0d2) and NFATcl. An ELISA assay was performed to measure the release of tumor necrosis factor-alpha (TNF-alpha). Western blot analysis was used to measure the effect of berberine hydrochloride on the expression of calcineurin in the LPS-induced NFATc1 signaling pathway, as well as the expression levels of phosphoinositide phospholipase C-gammal (PLC-gamma1), toll like receptor 4 (TLR4) and TRAF6. The effect of berberine hydrochloride on Ca2+ concentration was detected using a confocal technique with a Flou-3/acetoxymethyl ester Ca2+ probe. The PCR results demonstrated that berberine hydrochloride inhibited the mRNA expression levels of Fra-2, TRAP, beta3-integrin, cathepsin K, DC-STAMP, Atp6v0d2 and NFATc1. Furthermore, the ELISA results demonstrated that TNF-alpha expression was decreased. The western blot analysis revelead that berberine hydrochloride treatment results in decreased expression levels of PLC gamma1, TLR4 and TRAF6, and inhibition of Ca2+ influx. In conclusion, the results of the present study suggest that berberine hydrochloride targets TRAF6 and NFATc1, thus inhibiting osteoclastogenesis and bone destruction via inhibition of the TRAF6-Ca2+-calcineurin-NFATcl signaling pathway. PMID- 28849050 TI - Naringenin attenuates fibroblast activation and inflammatory response in a mechanical stretch-induced hypertrophic scar mouse model. AB - The pathogenesis and therapy of hypertrophic scars (HS) have not yet been established. The aim of the present study was to investigate the potential effect of naringenin on HS and its underlying mechanisms. The mouse model of HS was prepared by a mechanical stretch device and then treated with naringenin at various concentrations. Histological studies were performed to evaluate scar hypertrophy by hematoxylin and eosin, as well as Masson's trichrome staining. The activation of HS fibroblasts was determined based on reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemical staining. Following observing the retention of inflammation cells by immunohistochemistry, the cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and transforming growth factor (TGF) beta1, mRNA and protein levels were quantitated by RT-qPCR, ELISA and western blotting methods. As a result, naringenin significantly inhibited the formation of HS in a concentration-dependent manner. In addition, naringenin inhibited fibroblast activation and inflammatory cell recruitment. In addition, mRNA and protein expression levels of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 were downregulated following naringenin treatment. The current study highlighted a new pharmacological activity of naringenin on HS. The mechanism of action of naringenin was associated with the inhibition of fibroblast activation and local inflammation. These results suggested that naringenin may serve as a novel agent for treatment of HS. PMID- 28849052 TI - Differentiation of mesenchymal stem cells from human amniotic fluid to cardiomyocyte-like cells. AB - Ischemic heart disease (IHD) is a major factor influencing worldwide mortality rates. Furthermore, IHD has become a significant health problem among the Thai population. Stem cell therapy using mesenchymal stem cells (MSCs) is an alternative therapeutic method that has been applied to improve the quality of life of patients. Amniotic fluid (AF) contains a heterogeneous cell population, including MSCs, which are multipotent stem cells that have the capability to differentiate into mesenchymal lineages. The purpose of the present study was to evaluate the MSC characteristics of human (h)AF and determine its potency regarding cardiogenic differentiation. MSC characterization following flow cytometric analysis revealed that the cells expressed MSC markers, cluster of differentiation (CD)44, CD90, human leukocyte antigen-ABC and CD73. The results of the alamar blue assay demonstrated that cell proliferation rate continuously increased from the early cultivation phase up to 5-fold during days 1 to 5 of cell culturing. The highest rate of cell proliferation was observed on day 17 with a 30-fold increase compared with that on day 1. During the cardiogenic induction stage, morphological changes were observed between day 0 and day 21, and it was revealed that the hAF derived-MSCs in the cardiogenic-induced group exhibited myotube-like morphology after 7 days of cell culturing. Following cardiogenic induction, immunohistochemistry staining was performed on day 21, and reverse transcription-quantitative polymerase chain reaction on day 7 and 21. These steps were performed to detect the protein and gene expression levels of cardiac specific proteins (GATA4, cardiac troponin T, Nkx2.5 and Connexin43). The results of the present study indicated that hAF-MSCs possess the potential to differentiate into cardiomyocyte-like cells. Thus, it was concluded that hAF may be a suitable source of MSCs for stem cell therapy and tissue engineering. PMID- 28849051 TI - MicroRNA-497 inhibits cellular proliferation, migration and invasion of papillary thyroid cancer by directly targeting AKT3. AB - Thyroid cancer is the most common tumor of the endocrine organs. Emerging studies have indicated the critical roles of microRNAs (miRs) in papillary thyroid cancer (PTC) formation and progression through function as tumor suppressors or oncogenes. The present study investigated the expression level and biological roles of miR-497 in PTC and its underlying mechanisms. It was demonstrated that the expression level of miR-497 was reduced in both PTC tissues and cell lines. Enforced expression of miR-497 suppressed PTC cell proliferation, migration and invasion. According to bioinformatics analysis, a luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blotting, RAC-gamma serine/threonine-protein kinase (AKT3) was demonstrated to be the direct target gene of miR-497. In addition, AKT3 expression increased in PTC tissues and negatively correlated with miR-497 expression. Furthermore, downregulation of AKT3 also suppressed cell proliferation, migration and invasion of PTC, which had similar roles to miR-497 overexpression in PTC cells. Taken together, these results suggested that this newly identified miR-497/AKT3 signaling pathway may contribute to PTC occurrence and progression. These findings provide novel potential therapeutic targets for the therapy of PTC. PMID- 28849053 TI - MRI detects protective effects of DAPT treatment with modulation of microglia/macrophages at subacute and chronic stages following cerebral ischemia. AB - Notch homolog 1 (Notch 1) signaling is regarded as a potential therapeutic target for modulating the inflammatory response and exhibiting neuroprotective effects in cerebral injury following stroke. N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S phenylglycine t-butylester (DAPT) efficiently inhibits activation of the Notch 1 signaling pathway in microglia and may protect brain tissue from ischemic damage. However, the temporal proliferation and morphological alterations of microglia/macrophages throughout progression of the disease, as well as the comprehensive alterations of the whole brain following DAPT treatment, remain to be elucidated. The present study evaluated the temporal proliferation and the morphological alterations of microglia/macrophages over the period of the subacute and chronic stages, in addition to dynamic alterations of brain tissue, using the magnetic resonance imaging (MRI) method, following DAPT treatment. Sprague-Dawley rats (n=40) were subjected to 90 min of middle cerebral artery occlusion and were treated with DAPT (n=20) or acted as controls with no treatment (n=20). The two groups of rats underwent MRI scans prior to the induction of stroke symptoms and at 24 h, 7, 14, 21 and 28 days following the stroke. A total of five rats from each group were sacrificed at 7, 14, 21 and 28 days following induction of stroke. Compared with control rats, the MRI data of the ipsilateral striatum in treated rats revealed ameliorated brain edema at the subacute stage and recovered brain tissue at the chronic stage. In addition to this, treatment attenuated the round-shape and promoted a ramified-shape of microglia/macrophages. The present study confirmed the protective effect of DAPT treatment by dynamically monitoring the cerebral alterations and indicated the possibility of DAPT treatment to alter microglial characteristics to induce a protective effect, via inhibition of the Notch signaling pathway. PMID- 28849054 TI - Human papillomavirus E6-regulated microRNA-20b promotes invasion in cervical cancer by targeting tissue inhibitor of metalloproteinase 2. AB - Human papillomavirus (HPV) infection alone is not sufficient for development of cervical cancer and further risk factors are involved, however, the underlying mechanism remains to be elucidated. The authors previously used a microarray assay to reveal microR-20b (miR-20b) as a key node in the miRNA-mRNA network of cervical carcinoma. The present study demonstrated an increased expression of miR 20b in cervical carcinoma tissue. MiR-20b was regulated by HPV E6 oncoprotein in cervical cancer. Furthermore, miR-20b overexpression with mimics induced cell morphological alterations and the epithelial-mesenchymal transition. Treating cervical cancer cells with the miR-20b inhibitor decreased the migration and invasion of cervical cancer cells. Tissue inhibitor of metalloproteinase 2 (TIMP 2), a possible antagonist of matrix metalloproteinase 2, is a metastasis suppressor and predicted to be a potential target of miR-20b. Fluorescence signals were decreased on transducing HeLa cells with a TIMP-2 3'-untranslated region plasmid and miR-20b mimics compared with control. Finally, TIMP-2 was identified as a novel target of miR-20b and was demonstrated to be regulated by the HPV oncoprotein. In addition, miR-20b and TIMP-2 were involved in cell invasion regulated by HPV E6. The present study demonstrated a novel pathway of HPV/miR-20b/TIMP-2 during the process of invasion in cervical cancer cells. PMID- 28849055 TI - Microarray data re-annotation reveals specific lncRNAs and their potential functions in non-small cell lung cancer subtypes. AB - Non-small-cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide. The most common subtypes of NSCLC are adenocarcinoma (AC) and squamous cell carcinoma (SCC). However, the pathophysiological mechanisms contributing to AC and SCC are still largely unknown, especially the roles of long non-coding RNAs (lncRNAs). The present study identified differentially expressed lncRNAs between lung AC and SCC by re-annotation of NSCLC microarray data analysis profiling. The potential functions of lncRNAs were predicted by using coding-non coding gene co-expressing network. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to investigate lncRNA expression levels in AC cell lines (A549 and L78), SCC cell lines (H226 and H520) and normal cells (NL 20). Western blotting analysis was used to investigate the protein expression levels in these cell lines. A total of 65 lncRNAs were differentially expressed between AC and SCC including 28 lncRNAs that were downregulated in SCC subtypes compared with those in AC ones, and 37 upregulated lncRNAs in SCC subtypes compared with AC subtypes. Three lncRNAs, sex determining region Y-box 2 overlapping transcript (SOX2-OT), NCBP2 antisense RNA 2 (NCBP2-AS2) and ubiquitin like with PHD and ring finger domains 1 (UHRF1), were predicted to be associated with lung cancer; RT-qPCR confirmed that SOX2-OT and NCBP2-AS2 were associated with lung cancer. Finally, western blot assays demonstrated that there was no difference in beta-catenin and glycogen synthase kinase 3beta (GSK-3beta) expression in cancer cells compared with NL-20, but increased phosphorylated (p )beta-catenin and p-GSK-3beta was detected in lung cancer cell lines compared with NL-20, particularly in A549 cells. Although these results require further experimental verification, the analysis of lncRNA signatures between AC and SCC has provided insights into the regulatory mechanism of NSCLC development. PMID- 28849056 TI - Protective effects of DL-3-n-butylphthalide in the lipopolysaccharide-induced mouse model of Parkinson's disease. AB - DL-3-n-butylphthalide (NBP) is extracted from rapeseed and exhibits multiple neuroprotective effects, exerted by inhibiting the inflammatory process, including reducing oxidative stress, improving mitochondrial function and reducing neuronal apoptosis. The present study aimed to investigate the neuroprotective effects of NBP in a lipopolysaccharide (LPS)-induced mouse model of Parkinson's disease (PD). The behavior of mice was assessed using the rotarod test and open-field test, the amount of tyrosine hydroxylase in the substantia nigra pars compacta was evaluated by immunohistochemistry, and the levels of phosphorylated c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase 14 (p38) and extracellular signal-regulated kinase 1 were determined by western blotting. It was demonstrated that the LPS-induced behavioral deficits were significantly improved. LPS-induced dopaminergic neurodegeneration was relieved following treatment with NBP, as determined from tyrosine hydroxylase-positive cells. Phosphorylation of JNK and p38 was significantly inhibited following treatment with NBP. Therefore in the present study, a role for NBP has been established in the treatment of a PD murine model, laying the experimental basis for the treatment of PD with this agent. PMID- 28849057 TI - Stable silencing of TIPE2 reduced the Poly I:C-induced apoptosis in THP-1 cells. AB - The present study aimed to determine the underlying mechanism of toll-like receptor (TLR) agonist polyinosinic:polycytidylic acid (Poly I:C)-induced apoptosis in THP-1 cells following silencing the expression of tumor necrosis factor alpha-induced protein 8-like 2 (TIPE2). THP-1 cells were incubated with different concentrations of the TLR agonist. Following incubation, reverse transcription-quantitative polymerase chain reaction was performed to quantify the mRNA expression of TIPE2. Lentiviral technology was used to silence the expression of TIPE2. MTT assay was performed to assess cell proliferation, Annexin V/PI double staining was used to evaluate the apoptosis and western blotting was used to determine the expression levels of caspase-8 following TIPE2 silencing. The TLRs agonist Poly I:C increased the expression level of TIPE2. During the incubation, Poly I:C also inhibited the proliferation of THP-1 cells and induced apoptosis. Following silencing of TIPE2 in THP-1 cells, the Poly I:C induced TIPE2 expression was significantly downregulated. Additionally, the Poly I:C-induced proliferation inhibition and apoptosis in THP-1 cells were significantly reduced following silencing of TIPE2. The findings of the western blot analysis indicated that the active form of caspase-8, p18, was downregulated following silencing of TIPE2. In conclusion, the expression of TIPE2 in THP-1 cells may be upregulated by Poly I:C, which may also inhibit cell proliferation and induce apoptosis. Following the downregulation of TIPE2 the aforementioned effect of Poly I:C treatment was reversed and may be associated with the reduced activity of caspase-8 that was observed in the TIPE2 silenced group. PMID- 28849058 TI - Toll-like receptor 4 is expressed and functional in late endothelial progenitor cells. AB - It has been previously demonstrated that lipopolysaccharides (LPS) inhibit the viability, migration, adhesion and in vitro angiogenesis of late endothelial progenitor cells (EPCs). However, the mechanisms underlying this LPS-induced impairment of late EPC functional activity are unknown. The aim of the present study was to investigate whether Toll-like receptor 4 (TLR4) is expressed and functional on late EPCs, using late EPCs of 3-5 passages. Cells were deprived of serum for 24 h prior to experiments and incubated with 10 ug/ml LPS for 24 h with or without pretreatment with 2 ug/ml TLR4 signaling inhibitor CLI-095 for 30 min. The viability, migration, adhesion and in vitro angiogenesis, as well as the expression of silent information regulator 1 (SIRT1), in late EPCs were evaluated. Treatment with 10 ug/ml LPS decreased the viability, migration and adhesion abilities, and in vitro angiogenesis of late EPCs. Pretreatment with the TLR4 signaling inhibitor reversed this LPS-induced dysfunction of late EPCs. LPS downregulated the expression of SIRT1 protein, however, blocking TLR4 attenuated the effect of LPS on SIRT1 expression. Therefore, the results of the present study indicate that LPS impaired the functional activity of late EPCs via TLR4, which may be associated with decreased SIRT1 expression. PMID- 28849059 TI - Effects of an irinotecan derivative, ZBH-1208, on the immune system in a mouse model of brain tumor and its antitumor mechanism. AB - The present study aimed to evaluate the inhibitory effects of an irinotecan derivative, ZBH-1208, on brain tumors, and to explore the underlying molecular mechanisms. To determine the effects of ZBH-1208, a brain tumor mouse model was established by transplanting B22 cells. Subsequently, the visceral indices of immune organs and white blood cell counts were determined, and the effects of ZBH 1208 on the expression levels of cell cycle-related proteins were assessed by western blotting. The tumor inhibition rates of 20 and 40 mg/kg ZBH-1208 were 11.7 and 54.1%, respectively. Compared with the negative control group, ZBH-1208 barely affected visceral indices or white blood cell count. Furthermore, the expression levels of p53, p21, cyclin-dependent kinase 7 (CDK7), Wee1, phosphorylated (p)-cell division cycle 2 (CDC2) (Tyr15), p-CDC2 (Thr161) and cyclin B1 proteins were upregulated, whereas the expression levels of cyclin E were downregulated, and those of CDC2, CDK2 and CDC25C were barely altered. In conclusion, the present study demonstrated that ZBH-1208 suppressed the growth of B22 mouse brain tumor xenografts, but did not affect their visceral indices or white blood cell counts. It was suggested that ZBH-1208 exerted its effects by regulating the expression of p53, p21, Wee1, p-CDC2 (Tyr15) and cyclin E proteins. PMID- 28849060 TI - Association of BAFF with PI3K/Akt/mTOR signaling in lupus nephritis. AB - Systemic lupus erythematosus is a connective tissue disease characterized by autoimmune inflammation, which leads to specific and nonspecific immune disorders with the formation of various autoantibodies by activated B cells. B-cell activating factor (BAFF) is secreted by macrophages and activated T cells, and is responsible for the proliferation, maturation and differentiation of B cells. However, the mechanism of BAFF involvement in lupus nephritis (LN) remains unclear. The aim of the present study was to investigate the association between BAFF and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling in order to elucidate the pathogenesis of LN. In the present study, 18 patients with LN and 20 controls were included. The clinical data were analyzed and plasma levels of BAFF were measured using an ELISA. The mRNA and protein levels of BAFF, phosphorylated (p)-PI3K, p-Akt and p-mTOR in kidney tissues were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Plasma BAFF levels were significantly increased in patients with LN compared with the controls (P<0.001). mRNA and protein levels of BAFF, p-PI3K, p-Akt and p-mTOR in kidney tissue were significantly increased in patients with LN compared with the controls (all P<0.001). mRNA and protein levels of BAFF in the kidney tissues of patients with LN were positively correlated with the levels of p-PI3K, p-Akt and p-mTOR. The results of the present study revealed a correlation between BAFF and the PI3K/Akt/mTOR signaling pathway, and it is hypothesized that they are involved in the pathogenesis of LN. PMID- 28849061 TI - Comparative proteomic analysis of rats subjected to water immersion and restraint stress as an insight into gastric ulcers. AB - In the present study, comparative proteomic analysis was performed in rats subjected to water immersion-restraint stress (WRS). A total of 26 proteins were differentially expressed and identified using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Among the 26 differentially expressed protein spots identified, 13 proteins were significantly upregulated under WRS, including pyruvate kinase and calreticulin, which may be closely associated with energy metabolism. In addition, 12 proteins were downregulated under WRS, including hemoglobin subunit beta-2 and keratin type II cytoskeletal 8, which may be important in protein metabolism and cell death. Gene Ontology analysis revealed the cellular distribution, molecular function and biological processes of the identified proteins. The mRNA levels of certain differentially expressed proteins were analyzed using fluorescence quantitative polymerase chain reaction analysis. The results of the present study aimed to offer insights into proteins, which are differentially expressed in gastric ulcers in stress, and provide theoretical evidence of a radical cure for gastric ulcers in humans. PMID- 28849062 TI - Knockdown of c-Myc activates Fas-mediated apoptosis and sensitizes A549 cells to radiation. AB - Several studies have demonstrated that cancer radiosensitivity is associated with the deregulation of c-Myc, but the relationship between c-Myc and Fas in radioresistance of lung adenocarcinoma remains unclear. In this study, we established radiation-resistant A549 cell model (A549/R), and investigated the roles of c-Myc and Fas in radiation-induced cytotoxicity of A549 cells. Apoptosis detection showed that there were fewer apoptotic cells in A549/R cells treated with radiation than in A549 cells. Western blotting results demonstrated the inverse expression pattern of c-Myc and Fas in A549 and A549/R cells. Suppression of c-Myc expression by small interfering RNA (siRNA) displayed enhancement of Fas mediated apoptosis in A549/R cells, accompanying a significant decrease of Bid, Bcl-2, pro-caspase-8, -9 and -3 and increase of Bax. In contrast, Fas-mediated apoptosis was attenuated while Fas expression was suppressed by ectopic expression of c-Myc in A549 cells. Moreover, decreased cell viability and increased induction of apoptosis were observed in A549/R cells followed by combinational treatment of c-Myc siRNA and irradiation, whereas, upregulation of c-Myc reduced the sensitivity of A549 cells to irradiation. These results indicated that c-Myc and Fas regulated the sensitivity of A549 cells to irradiation by regulating caspase-8-mediated Bid activation and the subsequent association with the mitochondrial pathway of apoptosis. PMID- 28849063 TI - Hydrogen peroxide promotes the expression of angiopoietin like 4 in RAW264.7 macrophages via MAPK pathways. AB - Previous studies including some vivo experiments and large scale clinical trials have indicated that angiopoietin like 4 (ANGPTL4) is involved in atherosclerosis. However, the specific mechanism underlying the process remains unresolved. Similarly, cumulative evidence indicated that hydrogen peroxide (H2O2) is closely related to the occurrence and development of atherosclerosis. The current study investigated whether H2O2 treatment can affect ANGPTL4 release in macrophage cells cell viability assay, western blot analysis, ELISA and immunofluorescence. It was determined that treatment with 0.25 and 0.5 mM H2O2 resulted in a significant increase in ANGPTL4 protein expression in macrophage cells. Mitogen activated protein kinase (MAPK) pathways were implicated in the secretion of ANGPTL4 regulated by H2O2, and specific inhibitors of MAPK1 (also known as ERK) and p38 MAPK significantly decreased H2O2 induced ANGPTL4 protein expression. Accordingly, it was demonstrated that ANGPTL4 expression was regulated by H2O2 via ERK and p38 MAPK, but not the MAPK8 (also known as JNK) pathway. In view of the effects of H2O2 and ANGPTL4 on atherosclerosis, the influence of H2O2 on ANGPTL4 provided new insight into the mechanism of atherosclerosis. PMID- 28849064 TI - Direct and indirect gene diagnosis of hemophilia A pedigrees in the Chinese population. AB - Hemophilia A (HA) is an X-linked recessive hereditary disorder caused by defects in the coagulation factor VIII (FVIII) gene. In order to diagnose patients with presymptomatic HA and carriers, the present study conducted direct gene diagnosis for the common abnormalities in FVIII and subsequently performed indirect gene diagnosis for the other abnormalities in FVIII for Chinese HA pedigrees. Direct gene diagnosis was performed in 10 HA pedigrees using inverse shifting-polymerase chain reaction to detect intron 22 inversion (inv22), intron 22 deletion, intron 22 duplication and inv1 of FVIII. Pedigrees with no detected mutations were further analyzed using indirect genetic diagnosis (haplotype linkage analysis), where the genetic markers of FVIII included one variable number of tandem repeat, seven short tandem repeats and three restriction fragment length polymorphisms. The results of three pedigrees were taken as examples. Pedigree 1 underwent direct gene diagnosis, which demonstrated that the proband was inv22 distal pattern hemophiliac and the mother was an inv22 distal pattern carrier. The other two pedigrees were subjected to indirect gene diagnosis. In pedigree 2, the detection of DXS52, 13(CA) n, DXS9901(GT) n, intron (int)18, int19 and int22 confirmed the proband's baby brother was normal, the proband's maternal aunt was a carrier and her baby son was normal. Detection of DXS9901(GT)n, int18, int19 and int22 in pedigree 3 demonstrated that the proband's maternal grandmother was not a carrier. As the maternal grandfather was not affected by the disease, it was deduced that a mutation of FVIII occurred in the proband's mother. The combination of direct and indirect gene diagnoses provides reliable evidence for the use of genetic counseling in HA pedigrees, particularly for screening presymptomatic males and female carriers with normal offspring. PMID- 28849065 TI - Proteomic profiling of human HepG2 cells treated with hesperidin using antibody array. AB - Protein array technology not only identifies a large number of proteins but also determines their expression levels. In the present study, antibody array analysis is used to decipher the proteins involved in hesperidin-induced cell death in HepG2 cells. Altered proteins in hesperidin treated cells were compared with that of untreated control cells by using a RayBio(r) Label-based (L series) human antibody array kit. The identified proteins were further confirmed using western blot analysis. STRING software based analysis was used to determine the protein protein interactions. Many proteins related to signal transduction, cellular mechanisms, cell growth and proliferation regulatory proteins were identified. Among the proteins identified Hsp90, Smac/DIABLO, Prdx6 and FRK were significantly reduced in hesperidin treated cells. To the best of the authors' knowledge, the present study is the first to use antibody array for identifying proteins marker in hesperidin-induced cell death in HepG2 cells. The present study provides a novel insight into the anticancer mechanism of hesperidin. PMID- 28849067 TI - Hypoxia suppresses osteogenesis of bone mesenchymal stem cells via the extracellular signal-regulated 1/2 and p38-mitogen activated protein kinase signaling pathways. AB - There is a growing body of evidence indicating an association between osteoporosis and vascular diseases, which are associated with reduced blood supply. Decreased vascular flow results in a hypoxic gradient in the local microenvironment, affecting local bone remodeling. Bone mesenchymal stem cells (BMSCs) have been demonstrated to be the key to bone remodeling. To elucidate the molecular mechanisms involved in vascular supply and osteoporosis, the present study investigated the effect of hypoxia on BMSCs in vitro during osteogenesis. The BMSC osteogenesis process was evaluated by alkaline phosphatase (ALP) activity assay and the mRNA expression of the osteogenic markers runt-related transcription factor 2 (Runx2), ALP and osteocalcin. The function of extracellular signal-regulated kinase (ERK)1/2 and p38 kinase were studied under hypoxia using specific inhibitors. The results demonstrated that hypoxia reduces the osteogenic differentiation of BMSCs by inactivating Runx2, followed by decreased ALP activity and mRNA expression levels of ALP, collagen type I and osteocalcin. Furthermore, these data suggested that the ERK1/2 and p38-mitogen activated protein kinase signaling pathways might participate in hypoxia-induced differentiation of BMSCs toward the osteogenic phenotype. Compared with ERK1/2, the p38-Runx2 signaling pathway might exert a relatively more prominent effect in the above process. These findings may help to elucidate the pathophysiology of osteoporosis caused by decreased vascular supply. PMID- 28849066 TI - WRAP53beta, survivin and p16INK4a expression as potential predictors of radiotherapy/chemoradiotherapy response in T2N0-T3N0 glottic laryngeal cancer. AB - The current treatment recommendation for T2-3N0M0 glottic squamous cell carcinoma (SCC) in the Nordic countries comprises of radiotherapy (RT) and chemoradiotherapy (CRT). Tumor radiosensitivity varies and another option is primary surgical treatment, which underlines the need for predictive markers in this patient population. The aim of the present study was to investigate the relation of the proteins WRAP53beta, survivin and p16INK4a to RT/CRT response and ultimate outcome of patients with T2-T3N0 glottic SCC. Protein expression was determined using immunohistochemistry on tumors from 149 patients consecutively treated with RT or CRT at Helsinki University Hospital, Karolinska University Hospital, and Linkoping University Hospital during 1999-2010. Our results demonstrate a significantly better 5-year relapse-free survival, disease-free survival (DFS), disease-specific survival and overall survival of patients with T3N0 tumors treated with CRT compared with RT alone. Patients with tumors showing a cytoplasmic staining of WRAP53beta revealed significantly worse DFS compared with those with nuclear staining. For survivin, we observed a trend towards better 5-year DFS in patients with strong nuclear survivin expression compared with those with weak nuclear survivin expression (p=0.091). Eleven (7%) tumors showed p16 positivity, with predilection to younger patients, and this age group of patients with p16-positive SCC had a significantly better DFS compared with patients with p16-negative SCC. Taken together, our results highlight WRAP53beta as a potential biomarker for predicting RT/CRT response in T2-T3N0 glottic SCC. p16 may identify a small but distinct group of glottic SCC with favorable outcome. Furthermore, for T3N0 patients better outcome was observed following CRT compared to RT alone. PMID- 28849068 TI - Analysis of the Panax ginseng stem/leaf transcriptome and gene expression during the leaf expansion period. AB - Ginseng (Panax ginseng C.A Meyer) is a widely used herbal remedy, however, the majority of studies have focused on the roots, with less known about the aerial regions of the plant. As the stems and leaves are the primary aerial tissues, the present study characterized their transcriptional profiles using Illumina next generation sequencing technology. The gene expression profiles and the functional genes of ginseng stems (GS) and leaves (GL) were analyzed during the leaf expansion period. cDNA libraries of the GS and GL of 5-year-old ginseng plants were separately constructed. In the GS library, 38,000,000 sequencing reads were produced. These reads were assembled into 99,809 unique sequences with a mean size of 572 bp, and 57,371 sequences were identified based on similarity searches against known proteins. The assembled sequences were annotated using Gene Ontology terms, Clusters of Orthologous Groups classifications and Kyoto Encyclopedia of Genes and Genomes pathways. For GL, >118,000,000 sequencing reads were produced, which were assembled into 73,163 unique sequences, from which 50,523 sequences were identified. Additionally, several genes involved in the regulation of growth-related, stress-related, pathogenesis-related, and chlorophyll metabolism-associated proteins were found and expressed at high levels, with low expression levels of ginsenoside biosynthesis enzymes also found. The results of the present study provide a valuable useful sequence resource for ginseng in general, and specifically for further investigations of the functional genomics and molecular genetics of GS and GL during early growth. PMID- 28849069 TI - Preclinical evaluation of cisplatin-incorporated bio-nanocapsules as chemo radiotherapy for human hepatocellular carcinoma. AB - The incidence of hepatocellular carcinoma (HCC) has continued to increase worldwide, and advanced HCC is difficult to treat using the currently available therapeutics. Chemoradiotherapy with cisplatin (cis-diamminedichloroplatinum, CDDP) is expected to confer a curative benefit on HCC patients; however, its application is limited due to side-effects such as acute nephrotoxicity as well as the conventionally limited application of chemoradiotherapy for HCC. For the practical application of this drug in the clinical setting, we formulated a novel drug carrier-comprising bio-nanocapsule (BNC) and liposomal CDDP (BNC-LP-CDDP) that recognizes the human liver and releases CDDP. BNC-LP-CDDP showed selectively high cytotoxicity for HCC cells, and markedly reduced the survival fractions of HCC when combined with ionizing radiation (IR) treatment in in vitro assays. In particular, the treatment of mice bearing human HCC with BNC-LP-CDDP and 3 Gy IR showed 95.68% growth inhibition, whereas IR treatment alone showed 65.6% growth inhibition. Moreover, BNC-LP-CDDP led to the withdrawal of CDDP-induced nephrotoxicity. These results indicate that BNC-LP-CDDP in combination with IR markedly enhanced the chemo-radiotherapeutic efficacy and eliminated CDDP induced nephrotoxicity, thus, suggesting the potential for its clinical application as human HCC therapy. PMID- 28849070 TI - Betulinic acid prevents high glucose-induced expression of extracellular matrix protein in cardiac fibroblasts by inhibiting the TGF-beta1/Smad signaling pathway. AB - The proliferation and differentiation of cardiac fibroblasts (CFs) is central to cardiac fibrosis. Betulinic acid (BA) is an active compound isolated from the bark of the birch tree Betula spp. (Betulaceae) and has been shown to attenuate hepatic fibrosis. However, the effect of BA on the high glucose-induced fibrosis response in CFs remains to be elucidated, therefore, the present study investigated the effect of BA on high glucose-induced CFs and examined the possible mechanism underlying the effect of BA on CF transdifferentiation. CFs were pre-incubated with various concentrations of BA for 24 h and then stimulated with high glucose (25 mM) for various times. Cell proliferation was evaluated using an MTT assay. The mRNA expression levels of alpha-smooth muscle actin (SMA) and transforming growth factor (TGF)-beta1 were determined using reverse transcription-quantitative polymerase chain reaction analysis. The protein expression levels of alpha-SMA, collagen I, collagen III, fibronectin, TGF-beta1, small mothers against decapentaplegic (Smad)2/3, phosphorylated (p)-Smad2 and p Smad3 and were detected using western blot analysis. The data revealed that BA attenuated the CF proliferation and myofibroblast differentiation induced by high glucose. In addition, BA inhibited the expression of extracellular matrix (ECM) in the CFs induced by high glucose. It was also found that BA inhibited the high glucose-induced phosphorylation of Smad2/3 in the CFs. Taken together, BA suppressed the high glucose-induced increase in the proliferation of CFs and expression of ECM via inhibition of the TGF-beta1/Smad signaling pathway. Thus, BA may offer therapeutic potential towards the treatment of cardiac fibrosis. PMID- 28849071 TI - miR-187 inhibits the growth of cervical cancer cells by targeting FGF9. AB - MicroRNAs (miRNAs) are a cluster of short non-coding RNAs playing critical roles in human cancers. miR-187 was recently found to be a novel cancer-related microRNA. However, the expression and function of miR-187 in cervical cancer have not been investigated. In this study, we found that miR-187 level was decreased in cervical cancer tissues and cell lines. Patients with low level of miR-187 had significantly decreased rate of overall survival (OS) and progression-free survival (DFS). miR-187 overexpression inhibited proliferation and promoted apoptosis of cervical cancer cells, whereas miR-187 knockdown promoted proliferation and inhibited apoptosis of cervical cancer cells. Forced expression of miR-187 inhibited the subcutaneous growth of cervical cancer cells in nude mice. Furthermore, FGF9 was found to be the downstream target of miR-187 in cervical cancer cells. Importantly, targeting FGF9 was required for miR-187 exerting its tumor suppressive roles in cervical cancer cells. PMID- 28849072 TI - c-Myc promotes cholangiocarcinoma cells to overcome contact inhibition via the mTOR pathway. AB - The loss of contact inhibition is a hallmark of a wide range of human cancer cells. Yet, the precise mechanism behind this process is not fully understood. c Myc plays a pivotal role in carcinogenesis, but its involvement in regulating contact inhibition has not been explored to date. Here, we report that c-Myc plays an important role in abrogating contact inhibition in human cholangiocarcinoma (CCA) cells. Our data show that the protein level of c-Myc obviously decreased in contact-inhibited normal biliary epithelial cells. However, CCA cells sustain high protein levels of c-Myc and keep strong proliferation ability in confluent conditions. Importantly, the suppression of c Myc by inhibitor or siRNA induced G0/G1 phase cell cycle arrest in confluent CCA cells. We demonstrate that the inhibition of c-Myc suppressed the activity of mammalian target of rapamycin (mTOR) in confluent CCA cells, and mTOR inhibition induced G0/G1 phase cell cycle arrest in confluent CCA cells. In confluent CCA cells, the activity of Merlin is downregulated, and Yes-associated protein (YAP) sustains high levels of activity. Furthermore, YAP inhibition not only induced G0/G1 phase cell cycle arrest, but also decreased c-Myc expression in confluent CCA cells. These results indicate that Merlin/YAP/c-Myc/mTOR signaling axis promotes human CCA cell proliferation by overriding contact inhibition. We propose that overriding c-Myc-mediated contact inhibition is implicated in the development of CCA. PMID- 28849073 TI - Endothelial cell-derived exosomes protect SH-SY5Y nerve cells against ischemia/reperfusion injury. AB - Cerebral ischemia is a leading cause of death and disability. A previous study indicated that remote ischemic postconditioning (RIP) in the treatment of cerebral ischemia reduces ischemia/reperfusion (I/R) injury. However, the underlying mechanism is not well understood. In the present study, the authors hypothesized that the protective effect of RIP on neurological damage is mediated by exosomes that are released by endothelial cells in femoral arteries. To test this, right middle cerebral artery occlusion/reperfusion with RIP was performed in rats. In addition, an I/R injury cell model was tested that included human umbilical vein endothelial cells (HUVECs) and SH-SY5Y cells. Both the in vivo and in vitro models were examined for injury. Markers of exosomes (CD63, HSP70 and TSG101) were assessed by immunohistochemistry, western blot analysis and flow cytometry. Exosomes were extracted from both animal serum and HUVEC culture medium and identified by electron microscopy. They investigated the role of endothelial cell-derived exosomes in the proliferation, apoptosis, cell cycle, migration and invasion of I/R-injured SH-SY5Y cells. In addition, apoptosis related molecules caspase-3, Bax and Bcl-2 were detected. RIP was determined to increase the number of exosomes and the expression levels of CD63, HSP70 and TSG101 in plasma, but not in brain hippocampal tissue. The size of exosomes released after I/R in HUVECs was similar to the size of exosomes released in rats subjected to RIP. Endothelial cell-derived exosomes partly suppressed the I/R induced cell cycle arrest and apoptosis, and inhibited cell proliferation, migration and invasion in SH-SY5Y nerve cells. Endothelial cell-derived exosomes directly protect nerve cells against I/R injury, and are responsible for the protective role of RIP in I/R. PMID- 28849074 TI - Effect of pioglitazone on the calcification of rat vascular smooth muscle cells through the downregulation of the Wnt/beta-catenin signaling pathway. AB - The aim of the present study was to investigate the effect and possible mechanism of pioglitazone (PIO) on the calcification of rat vascular smooth muscle cells (VSMCs) in vitro. beta-glycerophosphate (beta-GP; 10 mmol/l) was used to induce calcification of VSMCs treated with a range of concentrations (5, 10, 15 and 20 umol/l) of PIO for 12 days. Calcium deposits were revealed by Alizarin red staining. Extracellular calcium content was detected using a calcium assay kit. Western blotting was used to measure the expression of alpha-smooth muscle actin (alpha-SMA), runt-related transcription factor 2 (Runx2), bone morphogenetic protein-2 (BMP2), beta-catenin, glycogen synthase kinase-3beta (GSK-3beta), phosphorylated (p)-GSK-3beta and cyclin-D1. A total of 10 mmol/l beta-GP, 20 umol/l PIO and 20 umol/l peroxisome proliferator-activated receptor gamma (PPAR gamma) antagonist GW9662, was added to the cell culture media. The changes of the above indexes were observed. The calcium content in the calcification group, treated with high phosphorus, increased significantly compared with the controls (P<0.05) and all different concentrations of PIO reduced extracellular calcium content (P<0.05). Alizarin red staining was positive in calcified VSMCs and PIO (20 umol/l) intervention group was almost negative. The expressions of Runx2, beta-catenin, p-GSK-3beta, BMP2 and cyclin-D1 increased significantly in the calcification group, and treatment with 20 umol/l PIO downregulated the expression of all the above proteins, while upregulating the expression of alpha SMA. The PPAR gamma antagonist GW9662 could partly inhibit the effect of PIO on calcified VSMCs. The results of the present study indicated that PIO can alleviate the calcification of rat aortic VSMCs induced by beta-GP via inhibiting the activity of the Wnt/beta-catenin signaling pathway. PMID- 28849075 TI - Methylation of mitochondrial DNA displacement loop region regulates mitochondrial copy number in colorectal cancer. AB - It is not established whether de-methylation of the displacement loop (D-loop) region if mitochondrial DNA (mtDNA) directly influences mtDNA copy number and further alters the cell cycle, apoptosis and cell proliferation in colorectal cancer. The current study employed cell viability assays, cell cycle analysis, and mtDNA methylation analysis using 5 colorectal cancer cell lines. The present results demonstrated that 5-aza-2'-deoxycytidine (5-AZA), a DNA hypomethylating agent, significantly increased proliferation of Lovo and Colo-205 colorectal cancer cell lines. In Colo-205 cells, the proportion of G0/G1 phase cells was increased following 5-AZA treatment. Additionally, the apoptosis rate in Colo-205 cells was decreased by 5-AZA treatment. Compared with their controls, a significantly higher mtDNA copy number was observed in Colo-205 and Lovo cells following 5-AZA treatment. Notably, the Colo-205 and Lovo cells had relatively higher methylation levels at the 4 and 6th/7th CpG sites of D-loop region, respectively, compared with the levels at the corresponding sites following 5-AZA treatment. However, in HCT116, SW480, LS-174T, and HT-29 cells, 5-AZA treatment did not induce a significant change in proliferation, cell cycle, apoptosis and mtDNA copy number. Demethylation at the 4 and 6th/7th CpG sites of the D-loop region of HCT116, SW480, LS-174T and HT-29 cells was not observed following 5-AZA treatment. In conclusion, de-methylation of specific sites on CpG islands of D loop promoter may lead to the elevation of mtDNA copy number in colorectal cancer, triggering alterations in biological behaviors, including increased cell proliferation, reduced apoptosis and a relative cell cycle arrest in G0/G1 phase. PMID- 28849076 TI - Upregulation of GNL3 expression promotes colon cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/beta catenin signaling pathway. AB - G protein nucleolar 3 (GNL3), a nucleolar GTP-binding protein, is highly expressed in progenitor cells, stem cells, and various types of cancer cells. Therefore, it is considered to have an important role in cancer pathogenesis. GNL3 has been reported to play crucial roles in cell proliferation, cell cycle regulation, inhibition of differentiation, ribosome biogenesis, and the maintenance of stemness, genome stability and telomere integrity. Furthermore, GNL3 has recently been shown to be involved in cancer invasion and metastasis. However, the biological significance of GNL3 in the invasion and metastasis of colon cancer remains unclear. This study was performed to address this gap in knowledge. GNL3 expression was upregulated in colon cancer tissue specimens and correlated with tumor differentiation, invasion and metastasis. GNL3 overexpression promoted cell proliferation, invasion, migration and the epithelial-mesenchymal transition (EMT) in colon cancer cells. Moreover, inhibition of the EMT and the Wnt/beta-catenin signaling pathway induced by GNL3 knockdown was partially reversed by lithium chloride (LiCl). Based on these data, GNL3 promotes the EMT in colon cancer by activating the Wnt/beta-catenin signaling pathway. In summary, GNL3 is upregulated in colon cancer and plays an important role in tumor growth, invasion and metastasis. Strategies targeting GNL3 are potential treatments for colon cancer. PMID- 28849077 TI - MicroRNA-643 regulates the expression of ZEB1 and inhibits tumorigenesis in osteosarcoma. AB - Osteosarcoma is among the most malignant types of tumor worldwide and has become a leading contributor to tumor incidence, particularly in adolescents. Resistance to conventional treatment and the complexity of osteosarcoma tumorigenesis has resulted in high mortality rates. MicroRNAs are a class of noncoding RNAs, which regulate numerous biological processes. However, the involvement of miR-643 in osteosarcoma remains to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction, luciferase reporter assay, invasion assay, viability assay, western blot analysis and in vivo implantation were performed to analyze the action of miR-643 in osteosarcoma. The results demonstrated that miR-643 inhibited the progression of osteosarcoma and acted as a potential tumor suppressor. The expression of miR-643 was downregulated in osteosarcoma tissues and cell lines. In addition, miR-643 transfection significantly impaired the proliferation and invasion of osteosarcoma cells. The present study also identified Zinc finger E-box-binding homeobox 1 (ZEB1) as a direct target of miR-643, and the ectopic expression of ZEB1 counteracted the effect of miR-643 transfection. A significant inverse correlation was also found between the expression of miR-643 and ZEB1. A low expression of miR-643 or a high expression of ZEB1 was associated with poor patient survival rates. The results of the present study suggested that the decreased expression of miR-643 may be involved in the mechanism underlying the development of osteosarcoma. The intricate interactions between miR-643 and ZEB1 may serve as a potential therapeutic target in osteosarcoma oncogenesis. PMID- 28849078 TI - Screening and identification of potential biomarkers in triple-negative breast cancer by integrated analysis. AB - Triple-negative breast cancer (TNBC) has attracted great attention due to its unique biology, poor prognosis, and aggressiveness. TNBC patients are more likely to suffer from metastasis. We screened and identified the TNBC-specific genes as potential biomarkers. A total of 167 breast cancer samples (45 TNBC and 122 non TNBC) were used in the integrated analysis. Gene expression microarrays were used to screen the differentially expressed genes. We identified 65 core DEGs. According to the GO and KEGG analysis, the gene function enrichment in TNBC was revealed, such as basal cell carcinoma, prostate cancer, oocyte meiosis and choline metabolism in cancer pathways. Moreover, the PPI network reconstruction would benefit the screening of hubs. A RFS analysis of TNBC-specific genes was also conducted. RT-PCR was used to validate the expression pattern of hubs in TNBC. Finally, nine genes were identified and all of them were novel, specific and higher dysregulation expressed genes in TNBC. Such that, these genes will serve as potential biomarkers in TNBC and benefit further research in TNBC. PMID- 28849079 TI - Betaine attenuates chronic alcohol-induced fatty liver by broadly regulating hepatic lipid metabolism. AB - Betaine has previously been demonstrated to protect the liver against alcohol induced fat accumulation. However, the mechanism through which betaine affects alcohol-induced hepatic lipid metabolic disorders has not been extensively studied. The present study aimed to investigate the effect of betaine on alcoholic simple fatty liver and hepatic lipid metabolism disorders. A total of 36 rats were randomly divided into control, ethanol and ethanol + betaine groups. Liver function, morphological alterations, lipid content and tumor necrosis factor (TNF)-alpha levels were determined. Hepatic expression levels of diacylglycerol acyltransferase (DGAT) 1, DGAT2, sterol regulatory element binding protein (SREBP)-1c, SREBP-2, fatty acid synthase (FAS), 3-hydroxy-3-methyl glutaryl (HMG)-CoA reductase, peroxisome proliferator-activated receptor lambda coactivator (PGC)-1alpha, adiponectin receptor (AdipoR) 1 and AdipoR2 were quantified. Serum and adipose tissue adiponectin levels were assessed using an enzyme-linked immunoassay. The results demonstrated that alcohol-induced ultramicrostructural alterations in hepatocytes, including the presence of lipid droplets and swollen mitochondria, were attenuated by betaine. Hepatic triglyceride, free fatty acid, total cholesterol and cholesterol ester contents and the expression of DGAT1, DGAT2, SREBP-1c, SREBP-2, FAS and HMG-CoA reductase were increased following ethanol consumption, however were maintained at control levels following betaine supplementation. Alcohol-induced decreases in hepatic PGC-1alpha mRNA levels and serum and adipose tissue adiponectin concentrations were prevented by betaine. The downregulation of hepatic AdipoR1 which resulted from alcohol exposure was partially attenuated by betaine. No significant differences in liver function, TNF-alpha, phospholipid and AdipoR2 levels were observed among the control, ethanol and ethanol + betaine groups. Overall, these results indicated that betaine attenuated the alcoholic simple fatty liver by improving hepatic lipid metabolism via suppression of DGAT1, DGAT2, SREBP-1c, FAS, SREBP-2 and HMG-CoA reductase and upregulation of PGC-1alpha. PMID- 28849080 TI - Histone deacetylase inhibitor quisinostat activates caspase signaling and upregulates p53 acetylation to inhibit the proliferation of HepG2 cells. AB - Histone deacetylase inhibitor (HDACi) has been a major target of anticancer agents. Quisinostat (JNJ-26481585), a novel second-generation HDACi, has previously demonstrated antiproliferative activity against non-small cell lung cancer; however, the function of quisinostat in hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, it was revealed that quisinostat suppressed the cell viability of HepG2 cells in vitro and in vivo. Increased cell apoptosis was observed in quisinostat-treated HepG2 cells. The underlying mechanism revealed that quisinostat treatment activates the cleavage of caspase proteins. Furthermore, quisinostat upregulated p53 acetylation at K381/K382 sites by impairing the interaction between histone deacetylase 6 and p53, which resulted in the activation of p53, and triggered cell cycle arrest at the G1 phase. Collectively, the results of the present study demonstrated the antiproliferative effect of quisinostat on HepG2 cells; these results suggest that histone deacetylase may be a promising therapeutic target of HCC. PMID- 28849081 TI - Lercanidipine attenuates angiotensin II-induced cardiomyocyte hypertrophy by blocking calcineurin-NFAT3 and CaMKII-HDAC4 signaling. AB - Previous studies have demonstrated that lercanidipine, a calcium channel blocker, may protect against cardiac hypertrophy; however, the underlying mechanisms remain unclear. In the present study, the effects of lercanidipine on hypertrophy and the mechanisms involved were investigated. Cardiomyocytes isolated from neonatal rats were cultured and treated with angiotensin II (Ang II) in the presence or absence of lercanidipine or tacrolimus (FK506, a calcineurin inhibitor). Reverse transcription-quantitative polymerase chain reaction was used to assess the mRNA expression of genes of interest, whereas the protein expression of calcium-dependent signaling molecules was detected using western blot analysis. In addition, the cell surface area and the nuclear translocation of target proteins were evaluated using immunofluorescence. The results of the present study demonstrated that lercanidipine and FK506 inhibited Ang II-induced cardiomyocyte hypertrophy, as evidenced by decreases in fetal gene (atrial natriuretic peptide and brain natriuretic peptide) expression levels and cell surface area. Notably, lercanidipine suppressed Ang II-induced activation of calcineurin A (CnA) and nuclear factor of activated T cells 3 (NFAT3). In addition, calcium/calmodulin-dependent kinase II (CaMKII)-histone deacetylase 4 (HDAC4) signaling was also inhibited by lercanidipine. In conclusion, the present study demonstrated that lercanidipine may ameliorate cardiomyocyte hypertrophy, possibly partially by blocking Cn-NFAT3 and CaMKII-HDAC4 signaling. PMID- 28849082 TI - Short-term vagus nerve stimulation reduces myocardial apoptosis by downregulating microRNA-205 in rats with chronic heart failure. AB - Previous studies have reported that short-term vagus nerve stimulation (VNS) improves cardiac function in rats with chronic heart failure (CHF). The molecular mechanisms are unclear. The potential effect of microRNA (miR)-205 in apoptosis of short-term VNS was examined. A total of 3 weeks after inducing CHF, the rats were divided into three groups: Sham stimulation in sham operated rats, sham stimulation in CHF rats (CHF-SS), and treated with VNS in CHF rats (CHF-VNS). The right vagus nerve of the neck was stimulated for 72 h in CHF rats with rectangular pulses of 40 msec duration at 1 Hz and 5 V. miR-205 was focused on, which exhibited differential expression in the miRNA microarray analysis of CHF rats, and the effects of VNS on apoptosis were examined. It was verified that the expression level of miR-205 in the CHF-SS group was increased, and the expression was reduced in the CHF-VNS group. Furthermore, mimics or inhibitor of miR-205 was transfected into H9c2 to investigate its function on apoptosis. Baculoviral IAP repeat-containing protein 2 (Birc2) was confirmed a target of miR-205 through a dual luciferase reporter assay and western blotting. It was demonstrated that downregulated miR-205 decreased apoptosis in H9c2 cells. The apoptosis-associated proteins were further detected in H9c2 cells and rat tissue. The mRNA and protein expression levels of caspase-3 and Bcl-2-associated X protein were decreased in the CHF-VNS group, the expression of Birc2 and B-cell lymphoma 2 were increased. The results were consistent with the in vitro study in the miR-205 inhibitor group. The present study demonstrated that short-term VNS decreased apoptosis by downregulating miR-205 in rats with CHF. Therefore, the results of the present study provide basic evidence for short-term VNS in the clinical treatment of CHF. PMID- 28849083 TI - Articular cartilage degradation is prevented by tanshinone IIA through inhibiting apoptosis and the expression of inflammatory cytokines. AB - The present study aimed to investigate the effect of tanshinone IIA on the degradation of articular cartilage in a rat model of osteoarthritis (OA). The OA rat model was established by anterior cruciate ligament transection (ACLT) and medial meniscus resection (MMx). The animals were treated for 28 days with 0.25 0.5 mg/kg doses of tanshinone IIA following ACLT + MMx. The knee joints of the rats in the ACLT + MMx group exhibited marked alterations in articular cartilage histopathology and higher Mankin scores, compared with those in the normal group. Tanshinone IIA treatment at a dose of 0.5 mg/kg significantly inhibited cartilage degradation and improved Mankin scores in the OA rat model (P<0.002). Tanshinone IIA treatment completely inhibited the ACLT + MMx-induced accumulation of inflammatory cells and disintegration of synovial lining in the rats. An increase in the dose of tanshinone IIA between 0.25 and 0.5 mg/kg reduced the proportion of apoptotic chrondrocytes from 41 to 2% on day 29. Treatment of the rats in the ACLT + MMx group with 0.5 mg/kg doses of tanshinone IIA markedly inhibited the expression level of matrix metalloproteinase and increased the expression of tissue inhibitor of metalloproteinase in the rat articular cartilage tissues. Tanshinone IIA treatment significantly reduced the levels of inflammatory cytokines, including interleukin-1beta, tumor necrosis factor-alpha and nitric oxide in rat serum samples. The protein expression levels of bone morphogenetic protein and transforming growth factor-beta were significantly increased by tanshinone IIA in the ACLT + MMx rats. Therefore, tanshinone IIA inhibited articular cartilage degradation through inhibition of apoptosis and expression levels of inflammatory cytokines, offering potential for use in the treatment of OA. PMID- 28849084 TI - Effects of Tribulus terrestris on monosodium iodoacetate-induced osteoarthritis pain in rats. AB - Tribulus terrestris L. (T. terrestris) has been used as a traditional medicine for the treatment of diuretic, lithontriptic, edema and urinary infections. Previous studies have indicated that it is effective in improving inflammation by regulating tumor necrosis factor-alpha (TNF)-alpha, interleukin (IL)-6, IL-10, nitric oxide (NO) and cyclooxygenase (COX)-2. However, the effects and mechanism of action of T. terrestris on osteoarthritis (OA) remain unknown. Therefore, the present study aimed to evaluate the effects of the ethanolic extract of T. terrestris (ETT) in a monosodium iodoacetate (MIA)-induced OA animal model. OA was induced in LEW/SSNHSD rats by intra-articular injection of MIA. Morphometric changes and parameters of the tibial trabecular bone were determined using micro computed tomography. The molecular mechanisms of ETT in OA were investigated using reverse transcription-polymerase chain reaction, western blotting and gelatin zymogram analysis. Treatment with ETT attenuated MIA-induced OA, and this effect was mediated by the downregulation of NO synthase 2, COX-2, TNF-alpha and IL-6. Furthermore, the ETT-mediated attenuation of OA was also dependent on the expression of matrix metalloproteinases-2 and -9. The results of the current study indicate that further evaluation of the mechanisms underlying the attenuation of MIA-induced OA by ETT are required, and may support the development of ETT as a potential therapeutic agent for the treatment of inflammatory diseases such as OA. PMID- 28849085 TI - Involvement of RBP4 in all-trans retinoic acid induced cleft palate. AB - The current study was designed to elucidate the mechanism of retinol binding protein 4 (RBP4) in cleft palate induced by all-trans retinoic acid (atRA). To establish a cleft palate model in C57BL/6J mice, pregnant mice were administered atRA (100 mg/kg) by gavage at the tenth embryonic stage (E10.0). Control groups were given the equivalent volume of corn oil. Pregnant mice were dissected at E12.5, E13.5 and E14.5 to obtain the embryonic palates. The expression levels of RBP4 in the embryonic palatal mesenchyme (EPM) were determined by immunohistochemistry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Human embryonic palatal mesenchymal cells were exposed to atRA to detect the variation in RBP4 induced by atRA in vitro. Small interfering RNA was used to suppress the expression of RBP4, and a plasmid overexpressing RBP4 was used to examine upregulated expression. The cell counting kit-8 assay was used to evaluate the effect of RBP4 on cell proliferation. The expression levels of p27 and cyclin D1 were determined by RT qPCR and western blotting, while the expression levels of extracellular signal related kinase (ERK) 1/2 and protein kinase B (AKT) were assessed by western blotting. At E14.5, RBP4 was strongly expressed in the EPM, while it was downregulated following atRA treatment, which induced cleft palate in vivo. In vitro experiments indicated that atRA suppressed the expression of RBP4 and altered the expression of p27 and cyclin D1 to cause growth inhibition. Knockdown of RBP4 resulted in decreased expression of cyclin D1 and increased p27, and suppressed proliferation. Overexpression of RBP4 reversed the inhibitory effect of atRA and promoted proliferation via the ERK1/2 and AKT signaling pathways. These results suggested that RBP4 was involved in cleft palate induced by atRA and it can be suppressed by atRA to cause growth inhibition in the embryonic palate. PMID- 28849086 TI - Downregulation of microRNA-15a suppresses the proliferation and invasion of renal cell carcinoma via direct targeting of eIF4E. AB - The downregulation of microRNA-15a has been reported in several human tumors. However, its expression and functional importance in renal cell carcinoma (RCC) remain unknown. The aim of the present study was to investigate its expression, biological functions and underlying mechanisms in RCC tumorigenesis. The expression levels of miR-15a were examined by qRT-PCR in 40 RCC specimens and adjacent-paired normal tissues. Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry and Transwell assays were used to explore the potential influence of miR-15a transfection on RCC cell proliferation, the cell cycle, cell apoptosis, and cell invasion. Luciferase reporter assays were performed to confirm the potential target of miR-15a, in combination with qRT-PCR, western blotting and immunohistochemical assays. We found that miR-15a was significantly downregulated in most RCC specimens compared with adjacent normal tissues (P<0.01). Overexpression of miR-15a inhibited cellular growth, suppressed invasion and arrested cells at the G1/G0 phase, and induced cell apoptosis in RCC cells. Luciferase assays revealed that miR-15a directly targeted the binding site of the 3'-untranslated region (3'-UTR) of eIF4E, and inhibited its expression at both mRNA and protein levels. eIF4E expression was negatively associated with miR 15a expression in RCC tissues. eIF4E overexpression treatment partially abrogated the inhibitory effect of miR-15a on cell proliferation and invasion, as well as inactivated P13K/AKT/mTOR signaling in RCC cells. In conclusion, the present study indicated that miR-15a downregulation was associated with cell proliferation and invasion by directly targeting eIF4E during RCC progression. Thus, it may serve as a potential tumor suppressor and therapeutic target for the treatment of RCC. PMID- 28849087 TI - Identification of long non-coding RNA 00312 and 00673 in human NSCLC tissues. AB - Non-small cell lung cancer (NSCLC) is a fatal disease to human health. Despite the advanced progresses in cancer therapy during the past decades, NSCLC still remains the leading cause of cancer death worldwide. The long non-coding RNAs (lncRNAs) recently have been considered as key regulators of tumor malignant. Previous studies identified that long non-coding RNAs, linc00312 and linc00673 are markedly associated with lung cancer. However, current understanding of the two lncRNAs involving in NSCLC remains unclear. The aim of the present study was to profile their expression and clinicopathological significance in 76 patients' NSCLC tissues compared to non-tumor tissues using reverse transcription quantitative polymerase chain reaction. Data have indicated that the linc00312 expression level was significantly decreased in NSCLC tissues (P<0.001), while a higher linc00673 level has been detected in the same tumor tissues (P<0.01). In addition, the low expression of linc00312 was associated with the Tumor-Node Metastasis stage of NSCLC (P<0.05), whereas the high expression of linc00673 was related with the histological types of NSCLC (P<0.05). In conclusion, lncRNA 00312 and 00673 may serve as potential novel biomarkers for lung cancer early diagnosis, which may play a vital role in treatments of NSCLC. PMID- 28849088 TI - Personalized analysis of pathway aberrance induced by sevoflurane and propofol. AB - Anesthetic agents are used in surgical operations to reversibly reduce consciousness and pain. Sevoflurane is an inhalational anesthetic. Propofol is a short-acting intravenous general anesthetic. The mechanism of anesthetic agents at pathway level on individual patients has not been reported to date. In the present study, pathway aberrance in the human atrial tissue in response to anesthetics was examined. Microarray data of anesthesia-treated samples were downloaded from the Array Express database. Pathway information was obtained from the Reactome Pathway Database. The individual pathway aberrance score (iPAS) was introduced to identify dysregulated pathways in individual patients. The present data demonstrated 157 dysregulated pathways in the sevoflurane group, and 44 pathways were identified with the least P-values. A subset of 49 differentially expressed genes (DEGs) that were shared between the expression profiling results and the dysregulated pathways results were constructed into a co-expression network. The top 5 ranked DEGs, nuclear receptor subfamily 4 group A member 3 (NR4A3), JUNB proto-oncogene, MYC proto-oncogene, tachykinin precursor 1 and nicotinamide phosphoribosyltransferase, were identified as important in the topology analysis. In the propofol group, 87 dysregulated pathways were identified and 44 pathways had the least P-values. In total 28 DEGs were constructed into a co-expression network, of which 5 DEGs were important in the topology analysis, NR4A3, suppressor of cytokine signaling 3, cyclin dependent kinase inhibitor 1A, C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 1. A total of 72 dysregulated pathways were identified in common in the two groups. In conclusion, the two types of anesthetics induced partially similar mechanisms. The pathways enriched by DEGs, particularly those that were unique to sevoflurane and propofol, may affect surgical outcomes and aid the prevention of complications from anesthetics. PMID- 28849089 TI - Cardiovascular risk assessment in osteoporotic patients using osteoprotegerin as a reliable predictive biochemical marker. AB - Osteoprotegerin (OPG), a member of the tumour necrosis factor receptor (TNFR) superfamily of proteins known to be involved in a large number of biological systems, plays a pivotal role in bone remodelling. In addition to the roles of OPG in bone metabolism, it has been reported to be associated with a high cardiovascular risk in patients with metabolic syndrome. In most cases, the exact functions of OPG remain to be established; however, the widespread expression of OPG suggests that this molecule may have multiple biological activities, mainly in the cardiometabolic environment. The aim of this study was to evaluate the value of OPG as a predictive marker for cardiovascular and metabolic risk in osteoporotic patients. The study group comprised patients with osteoporosis, in order to evaluate the association between OPG serum levels and cardiovascular pathology. Our results revealed significant correlations between classical biochemical bone and metabolic parameters, such as osteocalcin and parathyroid hormone with lipid and glucose biomarkers, sustaining the crosstalk between calcium and bone parameters and cardiovascular risk. The OPG serum level proved to have a significant and independent predictive value for metabolic syndrome (MetS) as a cardiovascular risk standard in osteoporotic patients. The OPG serum levels were increased in patients with MetS as a protective response against the atherosclerotic lesions. The serum levels of 25-hydroxy vitamin D had significant and independent predictive value for cardiovascular and metabolic risk in our subjects, sustaining the active role of vitamin D beyond the area of bone metabolism. PMID- 28849090 TI - Overexpressed microRNA-506 and microRNA-124 alleviate H2O2-induced human cardiomyocyte dysfunction by targeting kruppel-like factor 4/5. AB - Kruppel-like factors (KLFs) regulate a wide variety of cellular functions and modulate pathological processes. In the present study, a post-translational mechanism of microRNAs (miRs) was investigated in H2O2-induced human cardiomyocyte (HCM) injury. In H2O2-cultured HCM cells, reactive oxygen species and apoptotic cells were measured via flow cytometry. miR-506/-124 mimics and inhibitors were transfected to induce gain or loss of miR-506/-124 function. Cell proliferation was analyzed by an MTT assay. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein expression levels were measured by reverse transcription polymerse chain reaction analysis and western blotting, respectively. The results indicated that H2O2 induced significant apoptosis and increased the concentration of reactive oxygen species (ROS) in HCMs. H2O2 markedly upregulated the expression levels of KLF4 and KLF5, and downregulated the expression levels of miR-506 and miR-124 in the HCMs. In addition, bioinformatics analysis showed the potential miR-506 and miR-124 binding sites within the 3'-untranslated region of KLF4 and KLF5 in the HCMs. The overexpression of miR-506 and miR-124 inhibited the H2O2-induced upregulation of KLF4 and KLF5 in the HCMs. The overexpression of miR-506 and miR-214 reversed the H2O2-induced apoptosis and increase of ROS in the HCMs. In conclusion, the overexpression of miR-506 and miR-214 were confirmed to have a protective effect against H2O2-induced HCM injury by suppressing the expression of KLF4 and KLF5. PMID- 28849092 TI - Mdivi-1 attenuates sodium azide-induced apoptosis in H9c2 cardiac muscle cells. AB - The aim of the current study was to investigate the effect of mitochondrial division inhibitor 1 (Mdivi-1) in sodium azide-induced cell death in H9c2 cardiac muscle cells. Mdivi-1 is a key inhibitor of the mitochondrial division protein dynamin-related protein 1 (Drp1). Mdivi-1 was added to H9c2 cells for 3 h, after which, the cells were treated with sodium azide for 24 h. Cell viability was measured by Cell Counting kit-8 assay. DAPI staining was used to observe nuclear morphology changes by microscopy. To further investigate the role of mitochondria in sodium azide-induced cell death, mitochondrial membrane potential (DeltaPsim) and the cellular ATP content were determined by JC-1 staining and ATP-dependent bioluminescence assay, respectively. Reactive oxygen species (ROS) production was also assessed by use of the specific probe 2',7'-dichlorodihydrofluorescein diacetate. In addition, the expression of Drp1 and of the apoptosis-related proteins BCL2 apoptosis regulator (Bcl-2), and BCL2 associated X (Bax) was determined by western blotting. The present findings demonstrated that pretreatment with Mdivi-1 attenuated sodium azide-induced H9c2 cell death. Mdivi 1 pretreatment also inhibited the sodium azide-induced downregulation of Bcl-2 expression and upregulation of Bax and Drp1 expression. In addition, the mitochondrion was revealed to be the target organelle of sodium azide-induced toxicity in H9c2 cells. Mdivi-1 pretreatment moderated the dissipation of DeltaPsim, preserved the cellular ATP contents and suppressed the production of ROS. The results suggested that the mechanism of sodium azide-induced cell death in H9c2 cells may involve the mitochondria-dependent apoptotic pathway. The present results indicated that Mdivi-1 may have a cardioprotective effect against sodium azide-induced apoptosis in H9c2 cardiac muscle cells. PMID- 28849093 TI - Detection of circulating tumor cells by reverse transcription-quantitative polymerase chain reaction and magnetic activated cell sorting in the peripheral blood of patients with hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Circulating tumor cells (CTCs) are considered a major cause of recurrence and metastasis in cancer; however, the detection of CTCs is challenging owing to their very low numbers in peripheral blood (around 10 CTCs per 1,000,000 erythrocytes). Cancer-testis antigens (CTAs) are specific tumor markers for CTCs. The present study aimed to evaluate the sensitivity and specificity of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for the detection of nine CTAs as well as placenta-specific antigen 1 (PLAC1) in peripheral blood mononuclear cell (PBMC) samples collected from 51 patients with HCC. The effectiveness of magnetic-activated cell sorting (MACS) for tumor-cell enrichment, through the depletion of CD45+ leukocytes in PBMC samples, was also assessed. Immunocytochemistry along with hematoxylin and eosin staining demonstrated that RT-qPCR achieved an overall positive detection rate for CTAs and PLAC1 of 70.6%; the highest rates were observed for melanoma-associated antigen A3 (MAGEA3), synovial sarcoma X breakpoint 1, MAGEA1, NY-ESO-1, L antigen 1 and PLAC1. MACS-detected intact CTCs in PBMCs were confirmed by H&E staining and morphological assessment; 12 out of 19 (63.2%) patients were identified as positive for CTAs. Screening for these five CTAs and PLAC1 by RT-qPCR may offer a potentially valuable prognostic tool with good sensitivity and specificity in patients with HCC that may be enhanced by MACS. PMID- 28849091 TI - Effect of diet and individual dietary guidance on gastrointestinal endocrine cells in patients with irritable bowel syndrome (Review). AB - Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder that is characterized by a combination of abdominal pain or discomfort, bloating and alterations in bowel movements. This review presents recent developments concerning the roles of diet and GI endocrine cells in the pathophysiology of IBS and of individual dietary guidance in the management of IBS. Patients with IBS typically report that food aggravates their IBS symptoms. The interactions between specific types of foodstuffs rich in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and GI endocrine cells induce changes in cell densities. Providing individual dietary guidance about a low FODMAP intake, high soluble-fiber intake, and changing the proportions of protein, fat and carbohydrates helps to reduce the symptoms experienced by patients with IBS and to improve their quality of life. These improvements are due to restoring the densities of the GI endocrine cells back to normal. The reported observations emphasize the role of GI endocrine cells in the pathophysiology of IBS and support the provision of dietary guidance as a first line treatment for managing IBS. PMID- 28849094 TI - Hydrogen sulfide facilities production of nitric oxide via the Akt/endothelial nitric oxide synthases signaling pathway to protect human umbilical vein endothelial cells from injury by angiotensin II. AB - Angiotensin II (Ang II) has been reported as key in inducing endothelial cell injury, and endothelial cells may produce nitric oxide (NO) to protect themselves. However, the underlying mechanism remains elusive. Human umbilical vein endothelial cells (HUVECs) were divided into five treatment groups as follows: Normal control, Ang II, Ang II + sodium hydrosulfide [NaHS; hydrogen sulfide (H2S) donor], Ang II + Akt inhibitors + NaHS, and Ang II + endothelial nitric oxide synthases (eNOS) inhibitors + NaHS. Subsequently, cell viability, apoptosis, migration, proliferation and adhesion ability were determined. In addition, tubular structure formation was observed, and the NO and phosphorylation levels of Akt and eNOS were evaluated. Compared with the normal control group, Ang II treatment reduced the viability of HUVECs and increased the level of cell apoptosis (P<0.05). Furthermore, Ang II treatment inhibited the phosphorylation level of eNOS and Akt, as well as the generation of NO (P<0.05). H2S reversed the above-mentioned effects significantly and increased cell proliferation, adhesion ability and promoted tubular structure formation (P<0.05); however, H2S did not reverse the impact of eNOS and Akt phosphorylation levels after being processed with Akt and eNOS inhibitors, which indicates that H2S is capable of protecting HUVECs via the eNOS/Akt signaling pathway (P<0.05). Thus, H2S stimulates the production of NO and protects HUVECs via inducing the Akt/eNOS signaling pathway. PMID- 28849095 TI - Genetic association study in a three-generation family with seven members with endometriosis. AB - The aim of this study was to investigate whether five single nucleotide polymorphisms (SNPs), associated with endometriosis, may confer new insight towards a genotype-phenotype association with endometriosis. We studied a three generation family with seven women who had endometriosis. Blood specimens were obtained from all the affected female family members. The entire family was genotyped for five SNPs mapped to WNT4, VEZT, FSHB and IL-16 genetic loci. We further evaluated the members of the family with endometriosis and described all obstetric and gynecological complications caused by the disease in these seven women. The five SNPs analyzed did not reveal any genotype-phenotype correlation with the disease. The members of the family with endometriosis showed a variety of clinical manifestations and complications. None of the five genetic markers examined correlated genotype with phenotype in the case of the Greek three generation family examined. Therefore, we conclude that more gene polymorphisms must be investigated in the members of this family to gain insight regarding a genotype-phenotype correlation in endometriosis and the potential development of a personalized care for the patients based on these data. PMID- 28849096 TI - Attention deficit hyperactivity disorder may be a highly inflammation and immune associated disease (Review). AB - Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder. Previous research has indicated that genetic factors, family education, environment and dietary habits are associated with ADHD. It has been determined that in China many children with ADHD also have allergic rhinitis or asthma. These children are more susceptible to the common cold or upper respiratory infections compared with normal healthy children. Additionally, the common cold or an upper respiratory infection may lead to disease recurrence or worsen the symptoms in these children. Previous studies have determined that ADHD may have a close association with allergic disease. Based on the clinically observed phenomenon and previous studies, it was hypothesized that ADHD is a high inflammation and immune-associated disease. Therefore, the authors designed clinical and animal experiments to test this hypothesis in the future. Immune system disorders may be a novel part of the etiology of ADHD. The current report may have implications for future clinical practice. PMID- 28849097 TI - The ROCK inhibitor, thiazovivin, inhibits human corneal endothelial-to mesenchymal transition/epithelial-to-mesenchymal transition and increases ionic transporter expression. AB - Corneal diseases exhibit a high prevalence and are prone to cause blindness; furthermore, maintaining the morphology and ionic transporter expression in corneal endothelial cells (CECs) is crucial for treatment of these diseases. This study aimed to investigate the effects of the novel Rho associated coiled-coil containing protein kinase (ROCK) inhibitor, thiazovivin (2,4-disubstituted thiazole, TZV), on human corneal endothelial-to-mesenchymal transition/epithelial to-mesenchymal transition (EndMT/EMT), cell morphology, junction proteins and ionic transporter expression in human CECs (HCECs) in vitro and then to clarify the mechanisms of action of TZV. In the present study, primary HCECs were cultured in vitro and passaged. The expression levels of adhesion proteins (E cadherin and N-cadherin), the EndMT/EMT marker, alpha smooth muscle actin (alpha SMA), the tight junction protein, Zonula occludens-1 (ZO-1), and the ionic transporter, Na+/K+-ATPase, were detected by immunofluorescence. The proliferative ability of the HCECs was determined by CCK-8 assay. The mRNA expression of the EndMT/EMT-inducing gene, Snail, was examined by RT-PCR. The protein expression levels of ROCK1/2 were evaluated by western blot analysis. The HCECs were cultured with TZV at various concentrations (2, 4, or 6 uM) for different periods of time (24 or 48 h). We found that the the cell states of the HCECs co-cultured with 4 uM TZV for 48 h reached the optimum, and corneal EndMT/EMT was inhibited, as evidenced by the significantly upregulated expression of ZO-1 and E-cadherin, and the markedly downregulated expression of N-cadherin and alpha-SMA. Furthermore, the cells exhibited a normal, tightly connected hexagonal or pentagonal morphology. Additionally, the protein expression of ROCK1/2 and the mRNA expression of Snail were significantly decreased. However, there was no significant difference between the TZV-treated and the control groups as regards HCEC proliferative ability. These findings suggested that the ROCK inhibitor, TZV (4 uM), was effective in improving the morphology, cell junctions and ionic transporter expression of HCECs by inhibiting EndMT/EMT, but had no effect on HCEC proliferation. PMID- 28849098 TI - Phospho-valproic acid inhibits pancreatic cancer growth in mice: enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles. AB - Pancreatic cancer (PC) is one of the most difficult cancers to treat. Since the current chemotherapy is inadequate and various biological approaches have failed, the need for agents that have a potential to treat PC is pressing. Phospho valproic acid (P-V), a novel anticancer agent, is efficacious in xenograft models of human PC and is apparently safe. In the present study, we evaluated whether formulating P-V in nanoparticles could enhance its anticancer efficacy. In a mouse model of Kras/pancreatitis-associated PC, P-V, orally administered, inhibited the incidence of acinar-to-ductal metaplasia by 60%. To improve its efficacy, we formulated P-V in five different polymeric nanoparticles. Poly-(L) lactic acid- poly(ethylene glycol) (PLLA-PEG) nanoparticles proved the optimal formulation. PLLA-PEG improved P-V's pharmacokinetics in mice enhancing the levels of P-V in blood. Compared to control, P-V formulated in PLLA-PEG suppressed the growth of MIA PaCa-2 xenografts by 81%, whereas P-V alone reduced it by 51% (p<0.01). Furthermore, P-V formulated in PLLA-PEG inhibited acinar-to ductal metaplasia in mice with activated Kras, reducing it by 87% (p<0.02). In both disease models, P-V suppressed STAT3 phosphorylation at the Ser727 and Tyr705 residues; STAT3 is the pivotal molecular target of P-V. In conclusion, P-V is a promising agent against PC, and its formulation in PLLA-PEG nanoparticles enhances its efficacy by improving its pharmacokinetics. PMID- 28849099 TI - Functional expression, characterization, and application of human S100B. AB - The EF-hand calcium-binding protein S100B presents a wide range of biological activities and functions. This binding protein is involved in various human diseases, including cancer, brain trauma and ischemia, neuro-degenerative disease (Alzheimer's disease), and psychiatric disorders. In this study, we prepared human S100B protein and its monoclonal antibodies. Human S100B protein was expressed in Escherichia coli, successfully purified by diethylaminoethyl cellulose anion-exchange chromatography, and then identified by western blot analysis. Monoclonal antibodies (mAbs) were produced by the standard hybridoma method and validated by enzyme-linked immunosorbent assay and western blot analysis. The prepared human S100B protein and its mAbs demonstrated potential biological activities. The KD of one mAb is approximately 4.72x10-8 mol/l, and its cross reactivity is low with human S100A4, mouse S100A4, and human S100A1. Recombinant Soluble S100B can promote the migration and invasion of HeLa cells. The expression of S100B protein in tumor tissues can be detected effectively by using the prepared monoclonal antibodies. Increasing concentration of the anti human S100B mAbs showed a reduced expression of the S100B protein. Subsequently, the expression of p53 increased significantly (P<0.05) in A375 cells. A significant increase in apoptosis in A375 cells was observed with increasing S100B mAb concentration. Results showed that our prepared S100B mAbs were suitable for detecting S100B expression in human tissues, furnishing promising tools for further functional investigation and clinical applications. PMID- 28849100 TI - Downregulation of miR-136-5p in hepatocellular carcinoma and its clinicopathological significance. AB - The clinical significance of microRNA (miR)-136-5p in hepatocellular carcinoma (HCC) has not been verified. Therefore, in the current study, the authors aimed to explore miR-136-5p expression and its clinical significance in HCC, as well as to investigate its potential target genes function. The authors detected the levels of miR-136-5p in 101 pairs of HCC and para-cancer tissues via reverse transcription-quantitative polymerase chain reaction. Gene Expression Omnibus database and the Cancer Genome Atlas (TCGA) database were used to further verify the clinical significance of miR-136-5p expression in HCC. The target genes prediction analysis of miR-136-5p, natural language processing (NLP) analysis of HCC in PubMed and gene functional enrichment analysis were conducted. The miR-136 5p level was markedly downregulated in HCC tissue, compared to para-non-tumor tissue. MiR-136-5p expression decreased in HCC patients with metastasis (P=0.004), advance TNM stage (P<0.001), portal vein tumor embolus (P=0.007) and vaso-invasion (P=0.003), compared with those HCC patients with non-metastasis, early TNM stage, non-portal vein tumor embolus and non-vaso-invasion, respectively. In the TCGA database, downregulated miR-136-5p was also observed in HCC tissue compared to normal liver tissue (P<0.001). There were 178 genes obtained from the overlap between predicted targets and NLP analysis. GO and KEGG pathway analyses revealed some significant pathways related to cancers. Downregulation of miR-136-5p may be responsible for the carcinogenesis and aggressiveness of HCC. miR-136-5p may act as an anti-carcinoma miRNA, which is essential for HCC progression through the regulation of various signaling pathways. Thus, miR-136-5p interaction may provide a novel strategy for HCC treatment. PMID- 28849101 TI - CD147 blockade as a potential and novel treatment of graft rejection. AB - Cluster of differentiation (CD)147 is highly involved in the T cell activation process. High CD147 expression is observed on the surfaces of activated T cells, particularly CD4+ T cells. In organ transplantation, it is important to prevent graft rejection resulting from the excessive activation of T cells, particularly CD4+ T cells, which exhibit a key role in amplifying the immune response. The present study aimed to investigate the effects of CD147 blockade in vitro and in vivo and used a transplant rejection system to assess the feasibility of utilizing CD147 antibody-based immunosuppressant drugs for the treatment of graft rejection. The effects of CD147 antibodies were evaluated on lymphocyte proliferation stimulated by phytohemagglutinin or CD3/CD28 magnetic beads and in a one-way mixed lymphocyte reaction (MLR) system in vitro. For the in vivo analysis, an allogeneic skin transplantation mouse model was used. CD147 antibodies were effective against lymphocytes, particularly CD4+T lymphocytes, and were additionally effective in the one-way MLR system. In the allogeneic skin transplantation mouse model, the survival of transplanted skin was extended in the CD147 antibody-treated group. Furthermore, the level of inflammatory cell infiltration in transplanted skin was reduced. CD147 blockade decreased the serum levels of interleukin (IL)-17 and the proportions of peripheral blood CD4+ and CD8+ memory T cells. The data demonstrated that CD147 blockade suppressed skin graft rejection, primarily by suppressing CD4+T and memory T cell proliferation, indicating that CD147 exhibits great potential as a target of immunosuppressant drugs. PMID- 28849103 TI - Long non-coding RNAs on the stage of cervical cancer (Review). AB - Cervical cancer is one of most malignant gynecological tumors. However, effective means for diagnosing and treating cervical cancer have yet to be identified. A few decades ago, long non-coding RNAs (lncRNAs) were regarded as useless parts of the genome, however, increasing data have demonstrated the importance of lncRNAs in the diagnosis and treatment of cervical cancers. The aim of the present study is to summarize the role(s) of HOTAIR, MALAT1, CCAT2, SPRY4-IT1, RSU1P2, CCHE1, lncRNA-EBIC and PVT1. Approximately 14 lncRNAs are involved in cervical cancer and several important proteins, miRNAs and other molecules and play crucial roles in a few traditional signaling pathways that have been proven to be related to those lncRNAs. In conclusion, lncRNAs may be useful as exact treatment targets and diagnostic biomarkers for improving therapies in cervical cancer patients and lncRNAs may contribute to effective diagnosis and treatment methods for cervical cancer. PMID- 28849102 TI - Investigating the mechanisms of papillary thyroid carcinoma using transcriptome analysis. AB - As the predominant thyroid cancer, papillary thyroid cancer (PTC) accounts for 75 85% of thyroid cancer cases. This research aimed to investigate transcriptomic changes and key genes in PTC. Using RNA-sequencing technology, the transcriptional profiles of 5 thyroid tumor tissues and 5 adjacent normal tissues were obtained. The single nucleotide polymorphisms (SNPs) were identified by SAMtools software and then annotated by ANNOVAR software. After differentially expressed genes (DEGs) were selected by edgR software, they were further investigated by enrichment analysis, protein domain analysis, and protein-protein interaction (PPI) network analysis. Additionally, the potential gene fusion events were predicted using FusionMap software. A total of 70,172 SNPs and 2,686 DEGs in the tumor tissues, as well as 83,869 SNPs in the normal tissues were identified. In the PPI network, fibronectin 1 (FN1; degree=31) and transforming growth factor beta receptor 1 (TGFbetaR1; degree=22) had higher degrees. A total of 7 PPI pairs containing the non-synonymous risk SNP loci in the interaction domains were identified. Particularly, the interaction domains involved in the interactions of FN1 and 5 other proteins (such as FN1-tenascin C, TNC) had non synonymous risk SNP loci. Furthermore, 11 and 4 gene fusion events were identified in all of the tumor tissues and normal tissues, respectively. Additionally, the NK2 homeobox 1-surfactant associated 3 (NKX2-1-SFTA3) gene fusion was identified in both tumor and normal tissues. These results indicated that TGFbetaR1 and the NKX2-1-SFTA3 gene fusion may be involved in PTC. Furthermore, FN1 and TNC containing the non-synonymous risk SNP loci might serve a role in PTC by interacting with each other. PMID- 28849104 TI - Killing effect of methionine enkephalin on melanoma in vivo and in vitro. AB - Melanoma is a common cutaneous malignancy, that is also found in specific mucosal sites, and is associated with a poor prognosis. The aim of the present study was to investigate the cytotoxicity of methionine enkephalin (MENK) for B16 melanoma cells in vivo and in vitro. The results of the present study allowed our conclusion that MENK regulates the proliferation of B16 cells, causing cell cycle arrest in the G0/G1 phase and a decrease in the percentage of cells in the S and G2/M phases. Reverse transcription-quantitative polymerase chain reaction demonstrated that MENK increased opioid receptor expression in the B16 cells. Furthermore, the tumor volume and weight in the MENK-treated group were lower than those in the control group (NS) and MENK and naltrexone (NTX)-treated groups. MENK exerted both significant antitumor activity on the growth of B16 cells and a longer survival time in mice. The mice treated with MENK exhibited an increased ratio of CD4+ to CD8+ T cells as tested by flow cytometry (FCM), resulting in a ratio of 2.03 in the control group, 3.69 in the MENK-treated group, and 2.65 in the MENK and NTX group. Furthermore, a significant increase in plasma levels of IL-2, IFN-gamma and TNF-alpha was revealed as assessed by ELISA. In conclusion, the results of the present study indicate that MENK has a cytotoxic effect on B16 melanoma cells in vitro and in vivo, and suggest a potential mechanism for these bioactivities. Therefore, we posit that MENK should be investigated, not only as a primary therapy for melanoma, but also as an adjuvant therapy in combination with chemotherapies. PMID- 28849105 TI - Analysis of gene expression profiling variations induced by hsa-miR-145-5p overexpression in laryngeal squamous cell carcinoma cell line Tu-177. AB - The present study aimed to investigate the variations of the gene network and biological functions induced by hsa-miR-145-5p in the laryngeal squamous cell carcinoma (LSCC) cell line Tu-177. A hsa-miR-145-5p-overexpressed Tu-177 cell model was established, and the gene expression microarray data of miR-145-5p overexpressed cells and negative control (NC) cells were analyzed. The differentially expressed genes (DEGs) between two groups were identified, and their potential functions were predicted by functional enrichment analysis. Furthermore, the targets of miR-145-5p were identified from the DEGs, and their potential functions and protein-protein interactions (PPIs) were analyzed. The mRNA expressions of acetyl-CoA carboxylase beta (ACACB), fibroblast growth factor receptor 1 (FGFR1), protein phosphatase 3 catalytic subunit a (PPP3CA) and spleen associated tyrosine kinase (SYK), were analyzed via quantitative polymerase chain reaction. A total of 1,501 upregulated and 887 downregulated genes were identified in the hsa-miR-145-5p-overexpressed Tu-177 cells, compared with the NC cells. Of these DEGs, 164 upregulated and 221 downregulated genes were predicted to be targeted by hsa-miR-145-5p. The upregulated target genes were primarily associated with functions of immunity, whereas the downregulated target genes were significantly enriched in the p53 signaling pathway. In the PPI network consisting of 267 target genes, the upregulated ACACB had the greatest degree and interacted with downregulated genes including PPP3CA and SYK, in addition to upregulated genes, including FGFR1. The mRNA expressions of ACACB and FGFR1were markedly enhanced in miR-145-5p-overexpressed Tu-177 cells, whereas overexpressing miR-145-5p significantly reduced mRNA expression of PPP3CA and SYK. hsa-miR-145-5p may exhibit an anticancer role in LSCC via regulating multiple cell processes, including cell proliferation and invasion, fatty acid metabolism, immunity and p53 signaling pathway. These findings provide novel information for the future investigation of miR-145-5p functions in LSCC. PMID- 28849107 TI - GATA4 is highly expressed in childhood acute lymphoblastic leukemia, promotes cell proliferation and inhibits apoptosis by activating BCL2 and MDM2. AB - Members of the GATA-binding factor protein family, including GATA1, GATA2 and GATA3, serve an inhibiting role in leukemia. The present study demonstrated that GATA4 was upregulated in children with acute lymphoblastic leukemia (ALL). Results from a number of functional experiments, including cell proliferation analysis, cell cycle analysis, cell apoptosis assay and Transwell migration and invasion analyses, have suggested that high expression of GATA4 may facilitate proliferation and metastasis, and suppress apoptosis in ALL cells. Chromatin immunoprecipitation assay and luciferase reporter assay revealed that GATA4 was a transcription factor that activated mouse double minute 2 homolog (MDM2) and B cell lymphoma 2 (BCL2) expression in ALL cells. BCL2 is a key anti-apoptosis protein that was demonstrated to suppress cell apoptosis. In addition, GATA4 was revealed to regulate p53 through the transcriptional activation of MDM2, subsequently influencing cell cycle and apoptosis. Results from the present study suggested that GATA4 may be a key marker in ALL diagnosis and a potential target of molecular therapy. PMID- 28849106 TI - Advanced glycation end products induce the apoptosis of and inflammation in mouse podocytes through CXCL9-mediated JAK2/STAT3 pathway activation. AB - Diabetic nephropathy (DN) is a serious and one of the most common microvascular complications of diabetes. There is accumulating evidence to indicate that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under conditions of diabetes, play a role in DN. In this study, we found that the serum and urine levels of C-X-C motif chemokine ligand 9 (CXCL9) were significantly elevated in patients with DN compared with healthy controls. Based on an in vitro model of mouse podocyte injury, AGEs decreased the proliferation of podocytes and increased the expression of CXCL9 and C-X-C motif chemokine receptor 3 (CXCR3), and promoted the activation of signal transducer and activator of transcription 3 (STAT3). The knockdown of CXCL9 by the transfection of mouse podoyctes with specific siRNA significantly increased the proliferation and decreased the apoptosis of the podoyctes. Moreover, the levels of inflammatory factors, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were also decreased in the podoyctes transfected with siRNA CXCL9, accompanied by the increased expression of nephrin and podocin, and decreased levels of Bax/Bcl-2 and activated caspase-3. The knockdown of CXCL9 also led to the inactivation of the Janus kinase 2 (JAK2)/STAT3 pathway. Importantly, the use of the JAK2 inhibitor, AG490, and valsartan (angiotensin II receptor antagonist) attenuated the injury induced to mouse podoyctes by AGEs. On the whole, and to the best of our knowledge, this study demonstrates for the first time that AGEs exert pro-apoptotic and pro-inflammatory effects in mouse podoyctes through the CXCL9-mediated activation of the JAK2/STAT3 pathway. Thus, our data provide a potential therapeutic target for DN. PMID- 28849108 TI - Endothelial progenitor cell dysfunction in acute exacerbation of chronic obstructive pulmonary disease. AB - Endothelial progenitor cells (EPCs) are decreased in cardiac dysfunction morbidity associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Therefore, the present study aimed to assess the role of EPCs in AECOPD. Patients with AECOPD (n=27) or stable COPD (n=26) were enrolled. Systemic inflammatory markers (high-sensitivity C-reactive protein) were measured. In addition, EPCs were counted, isolated and cultured, and their proliferative, migratory, adhesive and tube-forming capabilities were determined, in cells from patients with AECOPD and stable COPD. EPC number was lower in patients with AECOPD (5.1+/-2.6x103/ml) compared with patients with stable COPD (6.0+/-3.2x103/ml). Migration assay indicated that the early-EPCs isolated from patients with AECOPD were significantly less mobile than EPCs derived from stable COPD subjects, at a stromal-cell derived factor-1alpha concentration of 100 ng/ml (3,550/30,000 vs. 7,853/30,000, P<0.05). C-X-C chemokine receptor-4 positivity was significantly reduced in AECOPD patients (16.1+/-9.9 vs. 56.33+/-6.3%, P<0.05). Furthermore, fewer early-EPC clusters were formed by EPCs derived from AECOPD, compared with those derived from stable COPD (8.2+/-0.86 vs. 14.4+/-1.36, P=0.027). Stable COPD late-EPCs were markedly deficient in intact tubule formation, however AECOPD late-EPCs formed no tubules. The number of AECOPD- and stable COPD-derived late-EPCs adhering to Matrigel-induced tubules was 36.8+/ 1.85 and 20.6+/-1.36 (P<0.05) respectively, and the cluster of differentiation 31 positivity in late-EPCs was 79.69+/-1.3 and 29.1+/-2.47%, in AECOPD and stable COPD patients, respectively (P<0.001). The findings demonstrated that early-EPCs are decreased and dysfunctional in AECOPD patients, which may contribute to the altered vascular endothelium in this patient population. PMID- 28849109 TI - Anti-inflammatory effect of tribulusamide D isolated from Tribulus terrestris in lipopolysaccharide-stimulated RAW264.7 macrophages. AB - Tribulus terrestris (T. terrestris) has been used as a traditional medicine for the treatment of a variety of diseases, including inflammation, edema and hypertension. The aqueous and ethanol extracts of T. terrestris contain alkaloids, flavonoids, tannins, quinines and phenolic compounds. Tribulusamide D is a compound that has been isolated from the ethanol extract of T. terrestris. The present study investigated the anti-inflammatory effect of tribulusamide D on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Tribulusamide D inhibited the production of LPS-induced nitric oxide and prostaglandin E2, by reducing the expression of inducible nitric oxide synthase and cyclooxygenase-2 expression, respectively. The expression of these genes associated with inflammation was determined using reverse transcription-polymerase chain reaction and western blot analysis. Furthermore, tribulusamide D reduced the expression of LPS-induced inflammatory cytokines, including interleukin (IL)-6, IL-10 and tumor necrosis factor-alpha. They were quantified using an enzyme-linked immunosorbent assay. In addition, the present study confirmed that the inhibitory effects of tribulusamide D on the inflammatory response were mediated through inactivation of mitogen-activated protein kinase p38 and inhibition of nuclear localization of nuclear factor-B, which were also determined by western blot analysis. To the best of our knowledge, the current study is the first to demonstrate that tribulusamide D exerts anti-inflammatory activity by altering the expression of inflammatory mediators and cytokines, indicating that tribulusamide D could be developed as a potential therapeutic agent for the treatment of inflammatory disorders. PMID- 28849110 TI - Identification of a novel FOXL2 mutation in a single family with both types of blepharophimosis--ptosis-epicanthus inversus syndrome. AB - Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease, which has been divided into two types according to whether it involves premature ovarian failure (POF). Mutations in forkhead box L2 (FOXL2) have been identified in the majority of patients with BPES. The present study aimed to identify the causative mutation in FOXL2 in a Chinese family with both types of BPES. Clinical data and genomic DNA were collected from a single Chinese family with BPES. All the coding exons and adjacent regions of FOXL2 were screened in one affected member to detect the causative mutation using Sanger sequencing. The detected mutation was also screened in available family members and in 100 normal control chromosomes. In total, seven family members were recruited in the present study, including four affected and three unaffected members. The patient (II:5) exhibited typical features of type II BPES, characterized by a narrowed horizontal palpehral aperture, ptosis, epicanthus inversus and telecanthus without POF, whereas the patient's three daughters (III:1, III:2 and III:3) were diagnosed with type I BPES, in which a complex eyelid malformation was accompanied with POF. A novel heterozygous mutation in FOXL2 (c.844_860dup17, p.His291Argfs*71) was found in the four affected members, which was absent in the remaining three unaffected members and in the 100 control chromosomes. This novel duplicate mutation (c.844_860dup17, p.His291Argfs*71) in FOXL2 was identified in a Chinese family with both types of BPES. These findings expand current knowledge of the mutation spectrum of the FOXL2 gene and confirmed the intra-family phenotypic heterogeneity of BPES. PMID- 28849111 TI - Overexpression of long non-coding RNA cancer susceptibility 2 inhibits cell invasion and angiogenesis in gastric cancer. AB - Increasing evidence has indicated that long non-coding RNAs (lncRNAs) were aberrantly expressed and acted as key regulators in various types of disease, including cancer. lncRNA cancer susceptibility 2 (CASC2) has been found to be downregulated and acts as a tumor suppressor in various type of cancer, including gastric cancer (GC). However, the precise function of lncRNA CASC2 in GC remains unclear. In the present study, the expression level of lncRNA CASC2 in GC was investigated and the molecular mechanisms by which CASC2 acted as a tumor suppressor in this disease were elucidated. It was found that the expression level of lncRNA CASC2 was decreased, which correlated with TNM stages, vessel invasion, metastasis, and overall survival of patients with GC. Furthermore, overexpression of CASC2 inhibited the invasion and angiogenesis of GC cells. Thus, the present study indicated the important roles and underlying molecular mechanisms of lncRNA CASC2 on GC, and indicated that lncRNA CASC2 may present as a potential therapeutic target for the treatment of GC. PMID- 28849112 TI - Knockdown of RRS1 by lentiviral-mediated RNAi promotes apoptosis and suppresses proliferation of human hepatocellular carcinoma cells. AB - In recent years it was found that the synthesis and biological activity of ribosomes are closely associated with tumor cell growth, tumorigenesis, and malignant transformation. However, the role of regulator of ribosome synthesis 1 (RRS1) in hepatocellular carcinoma (HCC) has not yet been reported. In the present study, we aimed to examine the potential role of RRS1 in tumor cell growth by using a lentivirus-mediated RNA interference (RNAi) system in the HCC cell line SMMC-7721 in vitro. Compared with that of the negative control group (Lv-shCon), the mRNA and protein expression levels of RRS1 in SMMC-7721 cells transfected with Lv-shRRS1 were significantly decreased. Further experiments found that silencing of RRS1 gene expression in SMMC-7721 cells significantly suppressed cell proliferation, inhibited colony formation capacity, increased apoptosis and arrested cells in the G1 phase. These results suggest that the RRS1 gene plays a critical role in cell proliferation, colony formation, cell apoptosis and cell cycle distribution in human HCC cells, and that silencing of RRS1 by RNAi is a promising therapeutic approach for the treatment of HCC, and should be further developed. PMID- 28849113 TI - Scutellaria barbata D. Don inhibits 5-fluorouracil resistance in colorectal cancer by regulating PI3K/AKT pathway. AB - 5-Fluorouracil (5-FU) resistance or multidrug resistance (MDR) has become a major obstacle in clinical treatment of cancers including colorectal cancer (CRC). Aberrant activation of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway may lead to unlimited growth and chemoresistance in CRC cells, which thus could be a promising therapeutic target. As a long-term used traditional Chinese folk-medicine, Scutellaria barbata D. Don (SB) processes specific anticancer activity, but its activity against cancer chemoresistance is less known. Therefore, using a 5-FU-resistant CRC cell line HCT-8/5-FU, in this study we evaluated the therapeutic efficacy of the ethanol extracts of SB (EESB) against 5-FU resistance and explored the possible molecular mechanisms. We found that EESB significantly suppressed proliferation and promoted apoptosis in HCT 8/5-FU cells. Additionally, EESB displayed remarkable effect enhancing the retention of the ATP-binding cassette (ABC) transporter substrate, rhodamine-123 (Rh-123) in HCT-8/5-FU cells. Furthermore, EESB obviously downregulated the expression of cyclin D1, Bcl-2 and ABCG2, while upregulated p21 and Bax expression. Moreover, EESB showed a prominent suppressive effect on the activation of PI3K/AKT pathway. The findings suggested that Scutellaria barbata D. Don was able to inhibit chemoresistance in colorectal cancer by suppression of the PI3K/AKT pathway. PMID- 28849114 TI - Kidins220 and tumour development: Insights into a complexity of cross-talk among signalling pathways (Review). AB - The mechanistic complexes of kinase D-interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning (Kidins220/ARMS) bind and integrate a variety of cellular cues to mediate neuronal activities such as neuronal differentiation, survival, and cytoskeleton remodelling by interacting with a variety of binding partners. Accumulated evidence has also indicated its role in the regulation of vascular development. Mice with Kidins220 knockdown phenotypically present with cardiovascular abnormalities. Kidins220 also contributes to immunomodulation in combination with B cells and T cells. Moreover, emerging evidence has revealed that this protein regulates many crucial cellular processes and thus has been implicated in an increasing number of malignancies. Here, we review recent advances in our understanding of Kidins220 and its role in cancer development. Further investigation is warranted to shed light on the role played by Kidins220 in the dynamic arrangement of the cytoskeleton and epithelial-mesenchymal transition, and its implication in tumourigenesis and cancer progression. PMID- 28849115 TI - Amyloid beta-42 induces neuronal apoptosis by targeting mitochondria. AB - Alzheimer's disease (AD), with a typical pathological hallmark of amyloid-beta (Abeta)-containing plaques and neurofibrillary tangles, is one of the most common types of chronic neurodegenerative diseases. Abeta oligomers serve a crucial role in the pathogenesis of AD, and lead to neuronal loss. However, the precise mechanism of Abeta oligomers in AD remains to be elucidated. The present study demonstrated that 10 uM Abeta-42 activated the caspase signaling pathway, and induced significant apoptosis in primary cultured mouse cerebral cortical neurons. The results of reverse transcription-quantitative polymerase chain reaction and western blotting demonstrated that Abeta-42 (10 uM) also significantly upregulated the transcription and expression of the mitochondrial fission protein dynamin-related protein 1 (Drp1), and downregulated the transcription and expression of mitochondrial fusion proteins, including mitofusin 1/2 (Mfn1/2) and mitochondrial dynamin like GTPase (OPA-1). Neurons were transfected with pDsRed2-Mito for mitochondrial imaging, which revealed that 10 uM Abeta-42 induced mitochondrial fission in cortical neurons. In addition, 2',7'-dichlorodihydrofluorescein diacetate and tetramethylrhodamine ethyl ester staining indicated that Abeta-42 increased the reactive oxygen species (ROS) level and reduced mitochondrial membrane potential in neurons. Inhibition of Drp1 activity by Mdivi-1 efficiently prevented Abeta-42-induced ROS production and disruption of mitochondrial membrane potential. Loss of mitochondrial membrane potential may activate PTEN-induced putative kinase 1 (Pink1), the prominent sensor for mitochondrial damage, and trigger the process of mitophagy to remove the damaged mitochondria. In the present study, western blotting revealed that the levels of autophagy marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) and Pink1 were upregulated after Abeta-42 stimulation. In conclusion, these data indicated that Abeta-42 induces neuronal apoptosis by targeting mitochondria, including promotion of mitochondrial fission, disruption of mitochondrial membrane potential, increasing intracellular ROS level and activation of the process of mitophagy. Therefore, mitochondria may represent a potential therapeutic target for AD in the future. PMID- 28849116 TI - Effect of Scutellarin inhibits collagen-induced arthritis through TLR4/NF-kappaB mediated inflammation. AB - Scutellarin is the major effective constituent of the commonly used Chinese medicine Erigeron breviscapus. It has been applied in the clinic to treat various diseases, and is characterized by high content, a stable source, controllable quality, high efficiency and low toxicity. In addition, its potential pharmacological effects have been increasingly identified and elucidated. The present study was performed to examine the role of scutellarin on collagen induced arthritis (CIA). Mice were injected subcutaneously with bovine collagen type II and administered scutellarin for 2 weeks by gavage 20 mg/kg/day. ELISA kits were used to measure the levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), oxidative stress markers [superoxide dismutase (SOD) and malondialdehyde (MDA)] and caspase-3/-9 activity. Bax, Bcl-2, toll like receptor 4 (TLR4) and nuclear factor (NF)-kappaB protein expression was analyzed using western immunoblot analyses. The present study demonstrated that scutellarin prevented CIA, and inhibited the expression of inflammation factors, IL-1beta, IL-6 and TNF-alpha. In addition, scutellarin reduced the levels of oxidative stress markers, SOD and MDA, as well as intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 in CIA mice. Caspase-3/-9, Bax/Bcl-2, TLR4 and NF-kappaB protein expression were reduced in CIA mice following scutellarin treatment. The results of the current study suggest a novel effect of scutellarin involving the inhibition of TLR4/NF-kappaB-mediated inflammation. PMID- 28849118 TI - Aspirin inhibits the proliferation of human uterine leiomyoma cells by downregulation of K-Ras-p110alpha interaction. AB - Aspirin has been confirmed as an effective antitumor drug in various cancers. However, the relationship between aspirin and uterine leiomyoma is still underexplored. Here, we explored the effects of aspirin on human uterine leiomyoma cells and provide insights into the underlying mechanisms. Cell Counting Kit-8 (CCK-8) and flow cytometry analysis showed that aspirin treatment inhibited cell proliferation and promoted cell cycle arrest at G0/G1 phase in a dose- and time-dependent manner of human uterine leiomyoma cells. Further studies revealed that aspirin blocked the interaction between K-Ras and p110alpha by co immunoprecipitation and immunofluorescence. Western blotting demonstrated K-Ras p110alpha interaction was required for the effects of aspirin-induced inhibition on cell growth and cell cycle transition via cell cycle regulators, including cyclin D1 and cyclin-dependent kinase 2 (CDK2). PI3K/Akt/caspase signaling pathway was involved in human uterine leiomyoma cell growth under aspirin treatment. Taken together, these results suggest that aspirin inhibited human uterine leiomyoma cell growth by regulating K-Ras-p110alpha interaction. Aspirin which targeting on interaction between K-Ras and p110alpha may serve as a new therapeutic drug for uterine leiomyoma treatment. PMID- 28849117 TI - Advanced glycation end products decrease collagen I levels in fibroblasts from the vaginal wall of patients with POP via the RAGE, MAPK and NF-kappaB pathways. AB - The present study was carried out to observe the impact of advanced glycation end products (AGEs) on collagen I derived from vaginal fibroblasts in the context of pelvic organ prolapse (POP), and explore the downstream effects on MAPK and nuclear factor-kappaB (NF-kappaB) signaling. After treating primary cultured human vaginal fibroblasts (HVFs) derived from POP and non-POP cases with AGEs, cell counting was carried out by sulforhodamine B. The expression levels of collagen I, receptor of advanced glycation end products (RAGE), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were detected by western blot analysis and PCR. RAGE, MAPK and NF-kappaB were molecularly and pharmacologically-inhibited by siRNA, SB203580 and PDTC, respectively, and downstream changes were detected by western blot analysis and PCR. Inhibition of HVF proliferation by AGEs occurred more readily in POP patients than that noted in the controls. After treatment with AGEs, collagen I levels decreased and MMP-1 levels increased to a greater extent in the HVFs of POP than that noted in the controls. During this same period, RAGE and TIMP-1 levels remained stable. Following treatment with AGEs and RAGE pathway inhibitors by siRNA, SB203580 and PDTC, the impact induced by AGEs was diminished. The inhibition of p-p38 MAPK alone was not able to block the promoting effect of AGEs on the levels of NF-kappaB, which suggests that AGEs may function through other pathways, as well as p-p38 MAPK. On the whole, this study demonstrated that AGEs inhibited HVF proliferation in POP cases and decreased the expression of collagen I through RAGE and/or p-p38 MAPK and NF-kappaB-p-p65 pathways. Our results provide important insights into the collagen I metabolism in HVFs in POP. PMID- 28849119 TI - Effect of RNA interference of the expression of HMGA2 on the proliferation and invasion ability of ACHN renal cell carcinoma cells. AB - This aim of the present study was to observe the effect of high mobility group AT hook 2 (HMGA2) on the proliferation and invasion ability of ACHN renal cell carcinoma (RCC) cells. Human ACHN cells, an RCC cell line, and HKC normal human renal tubular epithelial cells were cultured. HMGA2 small interfering (si)RNA, Mock-siRNA and their negative control group were designed and synthesized. Subsequently, the ACHN cells were transiently transfected using RNA interference technology. Finally, the mRNA and protein expression levels of HMGA2 were detected using reverse transcription-polymerase chain reaction and western blot analyses. The proliferation ability of the ACHN cells was determined using MTT, and ACHN cell invasion ability was detected using the Transwell method. The results showed that the mRNA and protein expression levels of HMGA2 in the ACHN cells were considerably higher, compared with those in the HKC cells (P<0.01). The RCC cells, in which the expression of HMGA2 was specifically silenced, was successfully constructed. The proliferation rate of cells in the HMGA2-siRNA group was significantly lower, compared with that of cells in the Mock-siRNA group and control group at 24, 48, 72 and 96 h post-transfection (P<0.05). The invasion ability of cells in the HMGA2-siRNA group was significantly lower, compared with that of cells in the Mock-siRNA group and control group (P<0.05) 48 h following transfection. Therefore, the HMGA2 gene may function as an oncogene in the occurrence and development of RCC, and provide specific targets for the targeted therapy of RCC. Further detailed investigations of the HMGA2 gene are important for future gene therapy of RCC. PMID- 28849120 TI - Human urine-derived stem cells contribute to the repair of ischemic acute kidney injury in rats. AB - Acute kidney injury (AKI) is a clinical syndrome associated with high rates of morbidity and mortality. It has previously been reported that stem cells may be considered a potential therapeutic strategy for the treatment of AKI. The present study aimed to determine whether administration of urine-derived stem cells (USCs) to rats with ischemia/reperfusion (I/R)-induced AKI could improve renal function. USCs were isolated and cultured from 8 healthy men. Subsequently, USCs transduced with green fluorescent protein were mixed with hydrogel and were injected into rats with renal I/R injury. Renal tubular injury, proliferation and apoptosis were detected in the I/R model. Hematoxylin and eosin staining was used to detect the morphological of kidney injury. Immunohistochemistry and TUNEL kits used to evaluate the proliferation and apoptosis of the I/R model. The results demonstrated that USCs could be detected in the tubular epithelial lining of the rats and administration of USCs was able to improve renal function in the I/R model. The USCs-treated group exhibited significantly reduced serum creatinine and blood urea nitrogen levels, decreased tubular injury score, an increased number of proliferating cells and a decreased number of apoptotic cells. Compared with the control group, the mRNA expression levels of the anti-inflammatory factors interleukin (IL)-10 and transforming growth factor-beta1 were significantly upregulated, whereas the expression levels of the proinflammatory factors interferon-gamma and IL-1beta were significantly reduced in the USCs treated group. These findings suggested that USCs may promote kidney repair and improve function following ischemic AKI, which may be useful in treating human kidney disease. PMID- 28849121 TI - miR-217 targeting DKK1 promotes cancer stem cell properties via activation of the Wnt signaling pathway in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies and exhibits heterogeneity in terms of clinical outcomes and biological activities. Emerging evidence has demonstrated that cancer stem cells (CSCs) play important roles in the tumorigenesis and progression of HCC. However, the molecular mechanisms underlying the stemness maintenance of CSCs remain largely unknown. In the present study, through real-time PCR, western blotting, luciferase assays, RNA immunoprecipitation, and in vitro and in vivo assays, we demonstrated that miR-217 expression was markedly increased in HCC tissues and cells. Overexpression of miR-217 promoted, while silencing miR-217 suppressed, the fraction of the side population and the expression of cancer stem cell factors in vitro and tumorigenicity in vivo in HCC cells. Our findings further demonstrated that miR-217 promoted the CSC-like phenotype via dickkopf-1 (DKK1) targeting, resulting in constitutive activation of Wnt signaling. Moreover, the stimulatory effects of miR-217 on stem cell properties and Wnt signaling were antagonized by the upregulation of DKK1 in miR-217-overexpressing cells. Conversely, the inhibitory effects of silencing miR-217 on stem cell properties and Wnt signaling were reversed by the downregulation of DKK1 in miR-217-downregulated cells. Therefore, our results indicate that miR-217 plays a vital role in the CSC-like phenotypes of HCC cells and may be used as a potential therapeutic target against HCC. PMID- 28849122 TI - Downregulation of TM7SF4 inhibits cell proliferation and metastasis of A549 cells through regulating the PI3K/AKT/mTOR signaling pathway. AB - Lung cancer is one of the most common types of malignant tumor worldwide. The etiology of lung cancer is complex and, although significant progress has been made in previous investigations, the molecular mechanism responsible for lung cancer remains to be fully elucidated. In the present study, the association between lung cancer and transmembrane 7 superfamily member 4 (TM7SF4) was investigated. Reverse transcription-quantitative polymerase chain reaction technology was used to detect the expression of TM7SF4, and it was expressed at a high level in lung cancer. Furthermore, by overexpressing and inhibiting the expression of TM7SF4, the present study compared cell proliferation and migration rates. It was confirmed that TM7SF4 promoted lung cancer cell proliferation and migration. TM7SF4 was also confirmed to promote cancer cell migration and invasion by modulating the activation of the phosphatidylinositol 3-kinase/Akt pathway in the A549 cells. Correspondingly, the inhibition of TM7SF4 decreased the expression of proteins associated with AKT, whereas the overexpression of TM7SF4 promoted the expression of the relevant proteins. Therefore, the present study confirmed that TM7SF4 was involved in the progression of lung cancer via regulating the activation of AKT. These findings suggested that TM7SF4 may be involved in the progression of lung cancer and may be a novel therapeutic target for this disease. PMID- 28849123 TI - Type II cGMP-dependent protein kinase inhibits the migration, invasion and proliferation of several types of human cancer cells. AB - Previous studies have indicated that type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) could inhibit the proliferation and migration of gastric cancer cells. However, the effects of PKG II on the biological functions of other types of cancer cells remain to be elucidated. Therefore, the aim of the present study was to investigate the effects of PKG II on cancer cells derived from various types of human tissues, including A549 lung, HepG2 hepatic, OS-RC-2 renal, SW480 colon cancer cells and U251 glioma cells. Cancer cells were infected with adenoviral constructs coding PKG II (Ad-PKG II) to up-regulate PKG II expression, and treated with 8-(4-chlorophenylthio) (8 pCPT)-cGMP to activate the kinase. A Cell Counting kit 8 assay was used to detect cell proliferation. Cell migration was measured using a Transwell assay, whereas a terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick-end labeling assay was used to detect cell apoptosis. A pull-down assay was used to investigate the activation of Ras-related C3 botulinum toxin substrate (Rac) 1 and western blotting was used to detect the expression of proteins of interest. The present results demonstrated that EGF (100 ng/ml, 24 h) promoted the proliferation and migration of cancer cells, and it suppressed their apoptosis. In addition, treatment with EGF enhanced the activation of Rac1, and up-regulated the protein expression of proliferating cell nuclear antigen, matrix metalloproteinase (MMP)2, MMP7 and B-cell lymphoma (Bcl)-2, whereas it down regulated the expression of Bcl-2-associated X protein. Transfection of cancer cells with Ad-PKG II, and PKG II activation with 8-pCPT-cGMP, was identified to counteract the effects triggered by EGF. The present results suggested that PKG II may exert inhibitory effects on the proliferation and migration of various types of cancer cells. PMID- 28849124 TI - Time-series expression profile analysis of fracture healing in young and old mice. AB - Bone fracture healing is a complex process, which is associated with several factors, including age and osteoporosis. Certain genes and biological processes that may contribute to fracture healing, have been identified following developments in systems biology and molecular biology technologies, which may benefit the treatment of bone fractures. The present study identified key genes, which may be important in fracture healing through bioinformatics analysis of gene microarray datasets from the Gene Expression Omnibus. Gene clusters, which were consistently up/downregulated through time following a fracture in young (6 week-old) mice and old (8-month-old retired breeders) mice were obtained via soft clustering of differentially expressed genes (DEGs) between samples at 1 and 3 days, 1 and 5 days, and 3 and 5 days post-fracture in the two age groups, based on the Mfuzz package of R. Functional enrichment analysis of gene clusters using the Database for Annotation, Visualization and Integrated Discovery indicated that biological processes and pathways, including those associated with bone development, skeletal system development, amino sugar and nucleotide sugar metabolism, were significantly enriched in these up/downregulated genes. Of note, a total of 207 overlapped consistently upregulated genes were obtained between the two age groups, whereas no overlap was identified between the two lists of consistently downregulated genes. The overlapped genes were found to be associated with the biological processes of blood vessel development, vasculature development and skeletal system development, compared with all genes in the clusters. In addition, certain genes, including epidermal growth factor-like domain multiple 6 (EGFL6), kazal-type serine peptidase inhibitor domain 1 (KAZALD1), olfactomedin 2B (OLFM2B), collagen type III alpha1 (COL3A1), collagen type II alpha1 (COL2A1), von Willebrand factor A domain-containing 1 (VWA1), elastin microfibril interfacer 1 (EMILIN1) and aggrecan (ACAN), of the extracellular matrix organization, a process performed at the cellular level and resulting in the assembly and arrangement of constituent parts, were confirmed to be associated with fracture healing via reverse transcription-quantitative polymerase chain reaction analysis. The present study identified certain genes and biological processes/pathways, which may be associated with fracture healing and may assist in fundamental investigations and treatment in the future. PMID- 28849125 TI - Expression of pro-inflammatory cytokines in the auditory cortex of rats with salicylate-induced tinnitus. AB - Tinnitus often results in severe psychological distress. The present study hypothesized that tinnitus acts as a chronic stressor and induces dysregulation of the production of cytokines. The gap pre-pulse inhibition of acoustic startle paradigm was applied to test tinnitus-like behavior in rats. Following this, the mRNA and protein expression levels of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and N-methyl D-aspartate receptor subunit 2A (NR2A) were measured in rats subjected to acute and chronic salicylate treatment, using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The gap prepulse inhibition of acoustic startle paradigm detected the tinnitus-like behavior of rats. The expression of TNF-alpha and NR2A genes were increased in the auditory cortex (AC) following long-term administration of salicylate, whereas the expression of IFN-gamma genes decreased; however, the mRNA levels reversed back to normal baseline 14 days following the cease of salicylate administration. IL-6 gene expression, however, was not fundamentally altered by salicylate treatment. The data demonstrated that chronic salicylate administration induces tinnitus, in part, via dysregulation of cytokines and specific membrane receptors in the AC. PMID- 28849126 TI - PML(NLS-) protein: A novel marker for the early diagnosis of acute promyelocytic leukemia. AB - Promyelocyte leukemia-retinoic acid receptor alpha (PML-RARalpha) is known as a fusion gene of acute promyelocytic leukemia (APL). Previous studies have reported that neutrophil elastase (NE) cleaves PML-RARalpha in early myeloid cells, which leads to the removal of the nuclear localization signal (NLS) in PML and increases the incidence of APL. The resultant PML without the NLS is termed PML(NLS-). The aim of the present study was to verify the existence and location of the PML(NLS-) protein in NB4 cells. NB4 cells underwent electroporation with the pCMV-HA-NE plasmid to form NB4-HA-NE cells, which were then transplanted to produce tumors in nude mice and samples were collected from patients with APL. Western blot analysis, an immunofluorescence assay, confocal laser microscopy and immunohistochemistry were performed to detect the expression and localization of the PML(NLS-) protein. The findings demonstrated that PML(NLS-) was detectable in the cytoplasm of NB4-HA-NE cells, the tumors in nude mice and in neutrophils from patients with APL. This indicated that PML(NLS-) may be an effective and novel target for the diagnosis of APL. PMID- 28849127 TI - Sepsis decreases the activity of acetylcholinesterase by reducing its expression at the neuromuscular junction. AB - Our previous study demonstrated that sepsis may decrease the activity of acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) of the diaphragm at 24 h, and thus improve the antagonistic action of neostigmine on rocuronium. The present study aimed to determine the effects of sepsis on AChE activity over 2 weeks, which is a more clinically relevant time period. Furthermore, the present study aimed to elucidate the association between AChE activity and its expression at the NMJ during sepsis. Male adult Sprague-Dawley rats were randomly divided into the sham or sepsis groups. Sepsis was induced by cecal ligation and puncture. On days 1, 3, 7 and 14 after surgery, AChE activity at the NMJ of the diaphragm was detected using a modified Karnovsky and Roots method. Furthermore, AChE expression levels at the NMJ, and in the whole muscle fibers of the diaphragm, were detected by immunohistofluorescence staining and western blot analysis, respectively. AChE activity was significantly decreased in the sepsis group, with its lowest level detected on day 7; however, its activity had partially recovered on day 14 (P<0.01). AChE activity was positively correlated (r=0.975, P=0.025) with its expression at the NMJ, which showed a similar trend over 2 weeks of sepsis. The protein expression levels of AChE in the whole muscle fibers of the diaphragm were significantly decreased on days 1, 3 and 7 in the sepsis group (P<0.01), with the lowest level observed on day 3. In conclusion, sepsis decreased AChE activity by reducing its expression at the NMJ over 14 days; the reduced expression of AChE at the NMJ might be as a result of its reduced muscular production. PMID- 28849128 TI - In silico design of colchicine-based bioisosteric inhibitors of tubulin for the treatment of rheumatoid arthritis. AB - The super-saturation of serum with monosodium urate due to hyperuricemia is the core metabolic disorder of rheumatoid arthritis. When the serum urate concentration is >=7 mg/dl, this results in the crystallization of monosodium urate in serum at body temperature (37C/98.6F). Colchicine (COL) is considered to be a first-line medication for acute arthritis when NSAIDs are contraindicated. COL causes severe side effects, including diarrhea, nausea, cramping, abdominal pain and vomiting, in humans. Experimental studies have additionally demonstrated the presence of mutagenic and reproductive effects in humans. In the present study, molecular docking simulation techniqueswere used to design COL-derived bioisosteric inhibitors, with the aim of designing an alternative treatment that exhibitedpotent anti-arthritic activity and was free from the side effects associated with COL. PMID- 28849129 TI - Effect of low- and high-linear energy transfer radiation on in vitro and orthotopic in vivo models of osteosarcoma by activation of caspase-3 and -9. AB - Osteosarcoma (OS) is a malignant tumor of the bone derived from primitive transformed cells of the mesenchymal origin. Local low-linear energy transfer (LET) radiotherapy has limited benefits on OS owing to its radioresistance. Thus, this study aimed to investigate the effects of high-LET radiation on human OS. Therefore, the human OS cell lines, U2O2 and KHOS/NP, were examined in vitro, or an orthotopic mouse xenograft model was studied in vivo after treatment with low LET (gamma-ray) and high-LET (neutron) radiation. Notably, OS cells were significantly more sensitive to high-LET radiation in vitro and in the orthotopic xenograft tumor model. Specifically, neutron radiation treatment increased the relative percentage of apoptotic sub-G1 phase cells via caspase-3/9 activation; increased intracellular reactive oxygen species, autophagy, and DNA damage; and decreased invasion and migration. Similarly, the mean size of gamma-irradiated (8 Gy) orthotopic KHOS/NP OS was 195 mm3 at 6 weeks after gamma-irradiation (8 Gy), but it was only 150 mm3 in mice treated with high-LET neutron radiotherapy. Significantly, our results provide a rationale for the use of high-LET radiotherapy to treat patients with OS. PMID- 28849130 TI - Antimicrobial cathelicidin peptide LL-37 induces NET formation and suppresses the inflammatory response in a mouse septic model. AB - LL-37 is the only known member of the cathelicidin family of antimicrobial peptides in humans. In addition to its broad spectrum of antimicrobial activities, LL-37 may modulate various inflammatory reactions. The authors previously revealed that LL-37 improves the survival of a murine cecal ligation and puncture (CLP) sepsis model. In the present study, the mechanism for the protective action of LL-37 was elucidated using the CLP model, focusing on the effect of LL-37 on the release of neutrophil extracellular traps (NETs). The results indicated that the intravenous administration of LL-37 suppressed the increase of damage-associated molecular patterns (DAMPs), including histone-DNA complex and high-mobility group protein 1, in addition to interleukin-1beta, tumor necrosis-alpha and soluble triggering receptor expressed on myeloid cells (TREM)-1 in plasma and peritoneal fluids. Notably, LL-37 significantly suppressed the decrease of mononuclear cell number in blood, and the increase of polymorphonuclear cell (neutrophil) number in the peritoneal cavity during sepsis. Furthermore, LL-37 reduced the bacterial burden in blood and peritoneal fluids. Notably, LL-37 increased the level of NETs (myeloperoxidase-DNA complex) in plasma and peritoneal fluids. In addition, it was verified that LL-37 induces the release of NETs from neutrophils, and NETs possess the bactericidal activity. Overall, these observations suggest that LL-37 improves the survival of CLP septic mice by possibly suppressing the inflammatory responses as evidenced by the inhibition of the increase of cytokines, soluble TREM-1 and DAMPs (host cell death) and the alteration of inflammatory cell numbers, and bacterial growth via the release of NETs with bactericidal activity. PMID- 28849131 TI - Periostin cross-reacts with the renin-angiotensin system during liver fibrosis development. AB - Periostin is a 90-kDa extracellular matrix protein, which is secreted primarily from fibroblasts and is expressed in the lungs, kidneys and heart valves. Angiotensin II (AT-II) serves pivotal roles in the pathogenesis of several diseases with accompanying fibrosis, including chronic liver diseases. AT-II induces periostin expression by regulating transforming growth factor-beta1 (TGF beta1)/Smad signaling during cardiac fibrosis. The aim of the present study was to investigate the interaction between AT-II and periostin during liver fibrosis development. Fischer 344 rats were fed a choline-deficient L-amino-acid (CDAA) defined diet for 12 weeks to simulate the development of steatohepatitis with liver fibrosis. Losartan, an AT-II type I receptor blocker, was administered to inhibit the effect of AT-II. The therapeutic effect of losartan on hepatic fibrosis development and on periostin expression was then evaluated. Several in vitro experiments were performed to examine the mechanisms underlying the interaction between AT-II and periostin in activated hepatic stellate cells (Ac HSCs). Treatment with losartan suppressed the development of liver fibrosis induced by the CDAA diet, and reduced hepatic periostin expression. In addition, losartan treatment suppressed hepatic Ac-HSC expansion and hepatic TGF-beta1 expression. In vitro analysis using LX2 HSC cells indicated that AT-II can augment TGF-beta1 and collagen type I alpha1 mRNA expression via periostin expression, suggesting that the interaction between AT-II and periostin may serve a role in liver fibrosis development. In conclusion, blockade of AT-II-induced periostin may suppress the progression of liver fibrosis development. PMID- 28849132 TI - Regulatory effects and molecular mechanism of Trigonostemon reidioides on lipopolysaccharide-induced inflammatory responses in RAW264.7 cells. AB - Trigonostemon reidioides (Kurz) Craib has been traditionally used for the treatment of vomiting and asthma in Cambodia. However, the underlying molecular mechanisms of the anti-inflammatory effect of T. reidioides extract remains unknown. The present study investigated the anti-inflammatory activity and molecular action of an ethanol extract of T. reidioides (ETR) in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells. Nitric oxide assays, ELISA, reverse transcription-quantitative polymerase chain reaction and western blot analysis were used. ETR treatment inhibited the production of nitric oxide by downregulating inducible nitric oxide synthase expression, while exhibiting no significant cytotoxicity compared with macrophages treated with LPS-alone. Consequently, ETR decreased the production of certain proinflammatory cytokines, including interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha. Additionally, ETR inhibited the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38 MAPK, as well as the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. These effects were mediated by inhibition of the nuclear localization of nuclear factor kappa-B (NF-kappaB). Taken together, the results of the present study demonstrate that ETR may exert an anti-inflammatory effect by inhibiting the expression of inflammatory mediators and cytokines via downregulation of the NF-kappaB, PI3K/Akt and the MAPK signaling pathways in LPS-stimulated macrophages. Based on these results, we hypothesize that ETR may be a potential therapeutic agent for the treatment of inflammatory disorders. PMID- 28849133 TI - Downregulation of microRNA-195 promotes angiogenesis induced by cerebral infarction via targeting VEGFA. AB - Angiogenesis, the formation of new blood vessels from preexisting endothelium, is a process that involves a series of interassociated and mutually interactive pathophysiological processes. It is accepted that microRNAs (miRNAs) regulate endothelial cell behavior, including their involvement in angiogenesis. However, it remains unclear whether miRNAs are involved in the regulation of angiogenesis following cerebral ischemia. Therefore, the present study aimed to investigate the role of miRNAs in angiogenesis and the underlying mechanism following cerebral ischemia. Expression profiles of miRNAs in rat brain samples following middle cerebral artery occlusion (MCAO) were investigated using a miRNA microarray. The expression of candidate miRNA, miR-195 was further validated using reverse transcription-quantitative polymerase chain reaction. Then, the effects of miR-195 on cell migration and tube formation of human umbilical vein vascular endothelial cells (HUVECs) were investigated following miR-195 silencing, and overexpression. The specific target genes of miR-195 were predicted using microRNA prediction bioinformatics software (http://www.microrna.org/microrna/home.do), and then confirmed using a dual luciferase reporter assay and rescue experiment. It was demonstrated that miR-195 was significantly downregulated in the brains of rats following MCAO and in hypoxia-induced HUVECs. Furthermore, it was revealed that miR-195 overexpression inhibited the invasion ability and tube formation of HUVECs in vitro, while miR 195 silencing enhanced these functions. In addition, vascular endothelial growth factor A (VEGFA) was identified as a direct target of miR-195 and was negatively correlated with miR-195 expression. In addition, the rescue experiment revealed that overexpression of VEGFA reversed the inhibitory effects of miR-195 overexpression on the invasion ability and tube formation of HUVECs. The present study has provided a novel insight into the promoting roles of miR-195 downregulation on angiogenesis following cerebral infarction and suggests that the miR-195/VEGFA signaling pathway is a putative therapeutic target in cerebral ischemia. PMID- 28849134 TI - [Corrigendum] Death receptor 5 expression is inversely correlated with prostate cancer progression. AB - During the preparation of the figures in the above article, the authors inadvertently duplicated in Fig. 1B, a and b (high and low magnification images) the images that had already appeared as Figs. 5A, a and c (high and low magnification images), respectively, of the following paper: Huerta-Yepez S, Baritaki S, Baay-Guzman G, Hernandez-Luna MA, Hernandez-Cueto A, Vega MI and Bonavida B: Contribution of either YY1 or BclXL-induced inhibition by the NO donor DETANONOate in the reversal of drug resistance, both in vitro and in vivo. Nitric Oxide 29: 17-24, 2013. The revised version of Fig. 1 containing the corrected data for Fig. 1B, a and b (high and low magnification images; the YY1 data) is shown opposite protein expression. All those authors whom the corresponding author was able to contact have agreed to this Corrigendum. The authors regret this error, and apologize for any confusion that it may have caused. [the original article was published in the Molecular Medicine Reports 10: 2279-2286, 2014; DOI: 10.3892/mmr.2014.2504 ]. PMID- 28849135 TI - Identification of an lncRNA-miRNA-mRNA interaction mechanism in breast cancer based on bioinformatic analysis. AB - Non-coding RNAs serve important roles in regulating the expression of certain genes and are involved in the principal biological processes of breast cancer. The majority of studies have focused on defining the regulatory functions of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs/miRs), and few studies have investigated how lncRNAs and miRNAs are transcriptionally regulated. In the present study, based on the breast invasive carcinoma dataset from The Cancer Genome Atlas at cBioPortal, and using a bioinformatics computational approach, an lncRNA-miRNA-mRNA network was constructed. The network consisted of 601 nodes and 706 edges, which represented the complex web of regulatory effects between lncRNAs, miRNAs and target genes. The results of the present study demonstrated that miR-510 was the most potent miRNA controller and regulator of numerous target genes. In addition, it was observed that the lncRNAs PVT1, CCAT1 and linc00861 exhibited possible interactions with clinical biomarkers, including receptor tyrosine-protein kinase erbB-2, estrogen receptor and progesterone receptor, demonstrated using RNA-protein interaction prediction software. The network of lncRNA-miRNA-mRNA interactions will facilitate further experimental studies and may be used to refine biomarker predictions for developing novel therapeutic approaches in breast cancer. PMID- 28849136 TI - Effect of the hepatitis B virus S-ecdCD40L vaccine therapy in HBV transgenic mice: A vaccine-induced activation of antigen presenting dendritic cells. AB - The classical hepatitis B virus (HBV) DNA vaccination plasmid only encodes for a single viral antigen, either the S or the PreS2/S antigen. Many strategies have been employed to improve the effect of these DNA vaccines. Our previous study identified that the fusion gene, HBV S-ecd cluster of differentiation 40 ligand (CD40L), may promote the activation of dendritic cells (DCs) and enhance their function in vitro. In the current study, the effect of HBV S-ecdCD40L vaccine therapy on liver DCs was investigated, and its therapeutic potential in HBV transgenic (HBV-Tg) mice was evaluated. The eukaryotic expression plasmid, pcDNA3.1-S-ecdCD40L, was constructed by inserting the HBV S gene and mouse CD40L gene into the vector, pcDNA3.1 (+). HBV-Tg mice were immunized with pcDNA3.1-S ecdCD40L, pcDNA3.1-S, pcDNA3.1 or PBS. Following this, immunophenotyping, cytokine production and T-cell activation were analyzed in the CD11c-enriched DC population obtained from the liver. Vaccine efficacy was further assessed by the detection of serological and biochemical parameters. When comparing with other control groups, DCs from HBV-Tg mice immunized with pcDNA3.1-S-ecdCD40L exhibited increased expression of immunologically important cell molecules (CD86 and major histocompatibility complex class II), pro-inflammatory cytokines (interleukin 12), and enhanced capacity to promote allogeneic T-cell proliferation. Furthermore, the HBV S-ecdCD40L vaccine resulted in a significant inhibition of HBV DNA replication and downregulation of the hepatitis B virus surface antigen (HBsAg) in HBV-Tg mice, without obvious liver injury. In conclusion, the HBV S ecdCD40L vaccine may be a feasible strategy for chronic HBV immunotherapy via promoting DC activation and function. PMID- 28849137 TI - Particulate matter 2.5 regulates lipid synthesis and inflammatory cytokine production in human SZ95 sebocytes. AB - A large body of evidence indicates that particulate matter (PM)2.5 is associated with various negative effects on human health. However, the impact and molecular mechanism of PM2.5 on the skin have not been elucidated. Therefore, the present study aimed to investigate the effects of two types of PM2.5 [water-soluble extracts (W-PM2.5) and non-water-soluble extracts (NW-PM2.5)] on cell proliferation, cell cycle progression, lipid synthesis, and inflammatory cytokine production of human SZ95 sebocytes. The results demonstrated that NW-PM2.5 and W PM2.5 exposure dose-dependently inhibited SZ95 sebocyte proliferation by inducing G1 cell arrest. Furthermore, NW-PM2.5 and W-PM2.5 significantly reduced sebaceous lipid synthesis and markedly promoted the production of inflammatory cytokines, including interleukin-1alpha (IL-1alpha), IL-6 and IL-8 in SZ95 sebocytes. Additionally, the expression of aryl hydrocarbon (Ah) receptor (AhR), AhR nuclear translocator protein (ARNT), as well as cytochrome P450 1A1 were significantly increased following PM2.5 exposure. Thus, these findings indicate that PM2.5 exerts inhibitory effects on cell proliferation and lipid synthesis, and stimulatory effects on inflammatory cytokine production and AhR signaling activation in human SZ95 sebocytes. PMID- 28849138 TI - Construction of a lentiviral vector containing shRNA targeting ADAM17 and its role in attenuating endotoxemia in mice. AB - Systemic inflammatory response syndrome is a pathophysiological inflammatory response mediated largely by tumor necrosis factor-alpha (TNF-alpha), in response to infectious or non-infectious stimuli. TNF-alpha secretion in response to bacterial lipopolysaccharide (LPS) is regulated in part by disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Therefore, the present study aimed to identify an effective inhibitor of ADAM17, in order to control inflammation and associated processes. In the present study, a lentiviral vector expressing short hairpin (sh)RNA targeting the ADAM17 gene was constructed. U937 cells were infected with the lentivirus and stimulated with LPS. ADAM17 expression was assessed by western blotting and TNF-alpha secretion was assessed by ELISA analysis. The lentivirus was additionally tested in vivo in a mouse model of endotoxemia and sTNF-alpha expression was assessed by flow cytometry in peritoneal macrophages. In vitro, the ADAM17 shRNA lentivirus reduced ADAM17 expression, and prevented TNF-alpha maturation in U937 cells. In vivo, mice exposed to the ADAM17 shRNA lentivirus prior to LPS-induced endotoxemia exhibited fewer signs of inflammation and less tissue damage compared with the control mice. In conclusion, the present study successfully constructed a shRNA lentiviral vector targeting the ADAM17 gene that exhibited apparent in vitro and in vivo effects on TNF-alpha processing in response to an LPS challenge. The results of the present study may aid the design and improvement of drugs designed to inhibit the function of ADAM17, and suggested a novel means of controlling inflammation and associated processes. PMID- 28849139 TI - A study of Sirt1 regulation and the effect of resveratrol on synoviocyte invasion and associated joint destruction in rheumatoid arthritis. AB - The aim of the current study was to investigate the role and mechanism of sirtuin 1 (Sirt1) in the regulation of synovial cell invasion and joint destruction in rheumatoid arthritis (RA). The Sirt1 protein and mRNA levels in fibroblast-like synoviocytes (FLS) isolated from RA synovial tissues were compared with normal tissues by western blot and reverse transcription-polymerase chain reaction. RA FLS were then treated with the Sirt1 agonist resveratrol (1, 3 and 10 ug/ml) for 48 h, and their invasiveness and expression of matrix metalloproteinase (MMP) 1 and MMP13 protein and mRNA were measured. Furthermore, a collagen-induced arthritis (CIA) rat model was established and the rats were divided into a model group, and low- and high-dose resveratrol (2.5 and 10 mg/kg/day) groups to receive an intraperitoneal injection of resveratrol for 42 consecutive days. The joint morphology, arthritis index (AI), and MMP1 and MMP13 expression in synovial tissues was monitored. The Sirt1 protein and mRNA levels in RA FLS were significantly lower compared with normal FLS (P<0.01). The resveratrol treatment significantly inhibited the invasive ability of RA FLS (P<0.01) and reduced MMP1 and MMP13 expression (P<0.01). The AI in low- and high-dose groups was significantly lower compared with the model group from day 28 (P<0.01). Resveratrol also reduced the swelling and damage and decreased MMP1 and MMP13 expression levels in CIA rats (P<0.01). The resveratrol-induced upregulation of Sirt1 in RA FLS may significantly inhibit the invasion of these cells and reduce the degree of joint damage, which may be mediated through the inhibition of MMP1 and MMP13 expression. The present results suggested a regulatory role for Sirt1 in RA pathogenesis, and demonstrated the beneficial effects of resveratrol, which may have potential as an alternative therapeutic strategy for the treatment of patients with RA. PMID- 28849140 TI - STAT3 inhibition by WP1066 suppresses the growth and invasiveness of bladder cancer cells. AB - Signal transducer and activator of transcription 3 (STAT3) regulates the expression of genes mediating cell survival, proliferation and angiogenesis and is aberrantly activated in various types of malignancies, including bladder cancer. We examined whether it could be a novel therapeutic target for bladder cancer using the STAT3 inhibitor WP1066. In T24 and UMUC-3 bladder cancer cells, 5 uM WP1066 prevented the phosphorylation of STAT3 and 2.5 uM WP1066 decreased cell survival and proliferation significantly (P<0.01). WP1066 also induced apoptosis accompanied by the suppression of the expression of Bcl-2 and Bcl-xL in T24 cells. Moreover, the covered area in a wound and the number of cells invading through a Matrigel chamber decreased significantly (P<0.01) when cells were treated with WP1066. The activities of MMP-2 and MMP-9 were also decreased by treatment with 10 uM WP1066. Our results revealed that using WP1066 to inhibit the STAT3 signaling pathway suppressed the viability and invasiveness of bladder cancer cells effectively and could be a novel therapeutic strategy against bladder cancer. PMID- 28849141 TI - Tetrahydroxy stilbene glucoside ameliorates H2O2-induced human brain microvascular endothelial cell dysfunction in vitro by inhibiting oxidative stress and inflammatory responses. AB - Tetrahydroxy stilbene glucoside (TSG) is one of the main active ingredients of Polygonum multiflorum and performs various types of biological activity, particularly anti-inflammatory and anti-oxidative activities. However, the beneficial effect of TSG in H2O2-induced human brain microvascular endothelial cell (HBMEC) dysfunction has not been fully elucidated. In the present study, H2O2-induced oxidative stress and inflammatory responses, and the pharmacological effect of TSG were investigated. The results demonstrated that H2O2 appeared to exert a cytotoxic effect on HBMECs, as the cell viability was significantly inhibited in H2O2-treated HBMECs. Conversely, TSG did not exert a toxic effect on HBMECs, and TSG inhibited H2O2-induced HBMEC cytotoxicity in a dose-dependent manner. Furthermore, the findings indicated that TSG restricted the oxidative stress caused by H2O2 via inhibition of malondialdehyde and reactive oxygen species, and upregulation of superoxide dismutase and glutathione. H2O2-induced injury was associated with enhancing the levels of inflammatory cytokines, tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1beta in the cultured HBMECs, which were attenuated by TSG treatment. Furthermore, the findings demonstrated that TSG inhibited necrosis factor-kappaB protein expression levels, which, as an upstream transcription factor, may regulate inflammatory responses. Thus, TSG protected HBMECs from H2O2-induced dysfunction by inhibiting oxidative stress and inflammatory responses. PMID- 28849142 TI - Adhesion, proliferation and osteogenic differentiation of mesenchymal stem cells in 3D printed poly-epsilon-caprolactone/hydroxyapatite scaffolds combined with bone marrow clots. AB - Mesenchymal stem cells (MSCs), a stem cell population capable of multi-lineage differentiation, bound to porous biomaterial scaffolds, are widely used for bone tissue regeneration. However, there is evidence to suggest that MSC collection from bone marrow and expansion in vitro may result in phenotypic changes including a loss of differentiation potential and cell senescence. The aim of the present study was to find a facile and efficient approach to enable MSC adhesion and proliferation to scaffolds with osteogenic differentiation. Unprocessed bone marrow blood from the condyle of the distal femur in the rabbits were added to three-dimensional (3D) printed porous poly-epsilon-caprolactone/hydroxyapatite (PCL/HA) scaffolds with bone marrow clots (MC) formed, using two different methods for Group A (MC enriched scaffolds) and Group B (MC combined scaffolds), and then were cultured in osteogenic medium for 4 weeks. The scaffolds were assessed macroscopically and microscopically. Scaffold bioactivity and the proliferation and osteogenic differentiation of seeded MSCs were measured. Higher cellular viability and greater cell numbers in the scaffolds at later phases of culture were observed in Group B compared with Group A. In addition, Group B was associated with greater osteoinductivity, alkaline phosphatase activity and bony nodule formation, as assessed using scanning electron microscopy. Furthermore, reverse transcription-quantitative polymerase chain reaction analysis revealed that more osteogenic differentiation was present in Group B, compared with Group A. MC combined scaffolds proved to be a highly efficient, reliable and simple novel method for MSC adhesion, proliferation and differentiation. The MC combined PCL-HA multi-scale porosity scaffold may represent a candidate for future bone regeneration studies. PMID- 28849143 TI - Polaprezinc inhibits liver fibrosis and proliferation in hepatocellular carcinoma. AB - Hepatic fibrosis is defined as a pathological process, and activation of hepatic stellate cells (HSCs) is believed to be the key event of liver fibrosis. Additionally, activated HSCs may participate in the formation of the tumor microenvironment. Polaprezinc, a protector of the gastric mucosa, has been recently demonstrated to be an inhibitor of liver fibrosis in a mouse model. Proliferation and colony formation assays were performed to determine the inhibitory effects of polaprezinc on the growth of LX-2 and hepG2 cells. A migration assay was used to evaluate the change in mobility of LX-2 cells and quantitative polymerase chain reaction was performed to detect the expression levels of key markers of fibrosis. Finally, a gene chip assay for polaprezinc treated hepG2 cells was performed to evaluate the effect of polaprezinc on the hepG2 gene expression profile. The proliferation assay indicated that polaprezinc may inhibit the LX-2 cell proliferation and the migration assays confirmed the inhibition of mobility. The expression levels of fibrotic markers such as collagen I, fibronectin and alpha-smooth muscle actin were downregulated following polaprezinc treatment. The proliferation activity of polaprezinc treated hepG2 cells was reduced and the gene chip assay indicated that series of gene expression changes associated with cancer migration, cell skeletal organization and proliferation had occurred. In conclusion, polaprezinc treatment mayinhibit the proliferation of hepatocellular carcinoma cells and reverse liver fibrosis by deactivating HSCs. The present findings suggest that polaprezinc provides a novel treatment for patients with gastritis complicated with cirrhosis. PMID- 28849144 TI - Amplification by (-)-epigallocatechin gallate of prostaglandin F2alpha-stimulated synthesis of osteoprotegerin in osteoblasts. AB - (-)-Epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), major flavonoids in green tea, and coffee, respectively, are recognized as possessing potential benefits in a multitude of human health conditions, including bone disorders. We have previously demonstrated that prostaglandin F2alpha (PGF2alpha), a potent bone remodeling mediator, stimulates the synthesis of osteoprotegerin (OPG) through the activation of p44/p42 mitogen-activated protein kinase (MAPK), p38 MAPK and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, the effects of EGCG and CGA on PGF2alpha-stimulated OPG synthesis in MC3T3-E1 cells were investigated. EGCG significantly upregulated PGF2alpha-stimulated OPG release, whereas CGA did not affect OPG release. The PGF2alpha-induced expression level of OPG mRNA was enhanced by EGCG. Regarding the intracellular signaling underlying the effect of EGCG, EGCG failed to affect PGF2alpha-stimulated phosphorylation of p44/p42 MAPK, p38 MAPK or SAPK/JNK. EGCG by itself markedly induced the phosphorylation of p44/p42 MAP kinase for up to 10 min and the status decreased subsequently, whereas EGCG did not significantly affect the phosphorylation status of p38 MAPK or SAPK/JNK within 60 min. These results indicated that EGCG, but not CGA amplifies the PGF2alpha-stimulated OPG synthesis in osteoblasts. PMID- 28849145 TI - Proteomic profile-based screening of potential protein biomarkers in the urine of patients with nephrotic syndrome. AB - Nephrotic syndrome is not a single disease; rather, it is a term for numerous diseases and pathological types. Renal biopsy is of use in determining the diagnosis and prognosis, and for guiding treatment; however, the use of this intervention is limited due to its invasive nature. Abnormal kidney-derived proteins in the urine of patients provide useful information regarding numerous pathological processes that occur in the kidneys, and may be considered a potential non-invasive biomarker for kidney disease. Proteomic analysis exhibits the advantage of being high-throughput and has previously been used to identify biomarkers of disease. The present study aimed to identify abnormal kidney derived proteins in the urine of patients with nephrotic syndrome using a novel proteomic strategy. Urine samples from 5 patients with nephrotic syndrome were subjected to acetone precipitation and albumin/immunoglobulin G depletion prior to analysis by two-dimensional liquid chromatography tandem mass spectrometry. The resulting data were compared to a publicly available proteomic database of normal human plasma/urine and normal human kidney in PeptideAtlas, and of normal human kidney in the Human Protein Atlas. Candidate biomarkers were validated using ELISA analysis in 60 patients with nephrotic syndrome: 30 with focal segmental glomerulosclerosis (FSGS) and 30 with minimal change disease (MCD), as well as in 30 healthy controls. The initial screening identified 809 proteins in the urine of patients with nephrotic syndrome. A total of 13/809 proteins were additionally present in the kidney proteome of PeptideAtlas and the Human Protein Atlas, although not in normal human urine and normal human plasma according to PeptideAtlas; these were referred to as 'kidney-derived disease-associated proteins'. One of the kidney-derived disease-associated proteins, ubiquitin-60S ribosomal protein L40 (UBA52) was observed to be increased in the urine of patients compared with normal controls [Creatinine, 637 ng/mg (216-1,851) vs. 1.89 ng/mg (1.37-3.33), P<0.001; and 18.58 ng/mg (11.11-46.25) vs. 1.89 ng/mg (1.37-3.33), P<0.001)], and the urinary UBA52 levels were significantly increased in patients with FSGS compared with in patients with MCD (P<0.001). In conclusion, the present study identified potential novel urinary protein biomarkers for nephrotic syndrome, in addition to an extensive urinary proteomic profile of patients with nephrotic syndrome. PMID- 28849146 TI - Nicotine induces H9C2 cell apoptosis via Akt protein degradation. AB - Smoking is highly associated with cardiovascular diseases. However, the effect of nicotine, a key ingredient in smoking products, on cardiomyocyte apoptosis remains controversial. The present study aims to clarify the role of nicotine on cardiomyocyte cell apoptosis and to investigate the underlying mechanism. In the present study, H9C2 cells were exposed to nicotine at various concentrations (0, 10 and 100 uM) for 48 h. Cell Counting Kit-8 and TUNEL assays were performed to assess cell viability and apoptosis, respectively, and reverse transcription quantitative polymerase chain reaction and western blot analysis were used to investigate the mRNA and protein expression. PYR-41, a ubiquitin E1 inhibitor, was employed to investigate whether the ubiquitin-proteasome system was involved in the downregulation of Akt. An Akt1 overexpression plasmid was used to demonstrate the role of Akt in H9C2 cells apoptosis. Tetratricopeptide repeat domain 3 (TTC3) small interfering RNA (siRNA) was used to investigate the effect of TTC3 on Akt protein degradation. The results demonstrated that nicotine induced apoptosis in H9C2 cells compared with control cells (P<0.05). The protein level of Akt was downregulated by nicotine in a concentration-dependent manner (P<0.05). PYR-41 treatment restored the protein level of Akt. The cell viability was significantly improved by Akt overexpression when cells were exposed to nicotine at 10 uM, compared with control cells. Nicotine also upregulated the level of TTC3 mRNA (P<0.05) and the protein level of Akt, and cell viability was recovered by TTC3 siRNA. In conclusion, the current study demonstrated that nicotine induced H9C2 cell apoptosis via Akt protein degradation, which may be mediated by TTC3. PMID- 28849147 TI - Retinoic acid ameliorates photoaged skin through RAR-mediated pathway in mice. AB - Retinoic acid (RA), the bioactive metabolite of vitamin A, has demonstrated efficacy in the treatment of photoaged skin; however, the mechanism of action of RA remains unclear. The aim of the present study was to examine whether the therapeutic effects of RA on photoaged skin are mediated by retinoic acid receptor (RAR) and/or retinoid X receptor (RXR) in mice, and to investigate the underlying mechanism. Photoaged skin in Imprinting Control Region mice was induced by repeated exposure to ultraviolet (UV) irradiation. Mice were randomly divided into nine groups: Normal; UV control; all-trans retinoic acid (ATRA); ATRA + RAR antagonist; ATRA + RXR antagonist; RAR agonist; RAR agonist + RAR antagonist; RXR agonist; and RXR agonist + RXR antagonist. Masson's trichrome staining was used to examine skin collagen fibers. Hydroxyproline assays were used to determine collagen content. The protein expression of matrix metalloproteinase (MMP)-3, MMP-13, type I procollagen, c-Jun and c-Fos was detected using western blot analysis. The results demonstrated that ATRA and RAR agonist ameliorated the UV-induced damage to skin collagen fibers, and increased the collagen content in photoaged skin through RAR. Furthermore, ATRA and RAR agonist stimulated type I procollagen protein expression, and inhibited MMP-3, MMP-13 and c-Jun protein expression through RAR in photoaged skin. However, ATRA and RAR agonist exhibited no significant effect on the protein expression of c Fos in photoaged skin. These findings suggest that RA ameliorates photoaged skin through a RAR-mediated signaling pathway in mice. PMID- 28849148 TI - Subcutaneous injection of dendritic cells aggravates atherosclerosis in ApoE knockout mice by activation of TLR4. AB - Dendritic cells (DCs) are specialized antigen-presenting cells which are important in immune diseases, in particular atherosclerosis, a chronic inflammatory disease, however their role in atherosclerosis-associated immunity is unclear. To evaluate the role of DCs in atherosclerosis, exogenous bone marrow derived DCs were transferred into ApoE-/- mice in the present study. The extent of disease was measured in the aorta and was compared with mice treated with phosphate-buffered saline (PBS) or left untreated and fed a western diet. Mice receiving exogenous DCs demonstrated significantly larger atherosclerotic lesions compared with the mice treated with PBS, with increasing numbers of mature DCs in circulation and enhanced DC infiltration into plaque lesions, in addition to activation of circulating inflammatory components and atherosclerotic lesions. Furthermore, it was demonstrated that exogenous DCs upregulated the expression of Toll-like receptor 4 (TLR4) on DCs, which may be an important mechanism to activate DCs and aggravate atherosclerosis. Therefore the present study concluded that exogenous DCs may induce maturation of endogenous DCs via upregulation of TLR4, further increasing the inflammatory response and accelerating atherosclerosis. PMID- 28849149 TI - Rab5a is overexpressed in oral cancer and promotes invasion through ERK/MMP signaling. AB - Ras-related protein Rab-5A (Rab5a) has been identified to be overexpressed in several types of human cancer. However, its clinical significance and biological roles in oral cancer remain unclear. In the present study, the protein expression of Rab5a was examined in 79 cases of oral squamous cell carcinoma samples using immunohistochemistry. It was demonstrated that Rab5a protein was upregulated in 49.3% (39/79) of cancer samples. Small interfering RNA knockdown was performed on Detroit 562 cells with high endogenous expression. Rab5a transfection was performed in FaDu cells with low endogenous levels. Rab5a depletion was revealed to inhibit cell growth, invasion and colony formation while its overexpression facilitated cell growth, invasion, and colony formation. In addition, Rab5a facilitated cell cycle progression and cell migration. It was also demonstrated that Rab5a depletion downregulated and its overexpression upregulated the expression levels of various cell cycle-associated proteins, and matrix metalloproteinase-2 (MMP-2). Furthermore, Rab5a positively regulated the extracellular signal-regulated kinase (ERK) signaling pathway and promoted epithelial-mesenchymal transition (EMT). ERK inhibitor PD98059 partially inhibited the role of Rab5a on MMP-2, cyclin D1, cell proliferation and invasion. The results of the present study suggest that Rab5a is overexpressed in oral cancer tissue samples and promotes the malignant phenotype through EMT and the ERK/MMP-2 signaling pathway. PMID- 28849150 TI - Novel crosstalk between KLF4 and ZEB1 regulates gemcitabine resistance in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with broad resistance to chemotherapeutic drugs. Kruppel-like factor 4 (KLF4) is a candidate tumor suppressor in PDAC. However, the precise role of KLF4 in gemcitabine resistance of PDAC remains largely unclear. In this study, we demonstrated that gemcitabine inhibited KLF4 expression. Moreover, gemcitabine also reduced the levels of miR-200b and miR-183, but promoted ZEB1 expression in PDAC cells. KLF4 knockdown blocked the expression of miR-200b and miR-183, and inversely, KLF4 overexpression promoted the expression of miR-200b and miR-183, suggesting that KLF4 positively regulated the expression of miR-200b and miR-183. Moreover, KLF4 knockdown enhanced ZEB1 expression and gemcitabine resistance while KLF4 overexpression induced the opposite effect. ChIP assays verified that KLF4 positively regulated the expression of miR-200b and miR-183 by directly binding to their promoters. Then, miR-200b and miR-183 directly inhibited ZEB1 expression by targeting its 3'UTR region. ZEB1 knockdown attenuated gemcitabine resistance in PDAC cells. KLF4 overexpression promoted gemcitabine sensitivity of PDAC in vivo by negatively regulating ZEB1 expression. Our results revealed that novel crosstalk between KLF4 and ZEB1 regulated gemcitabine resistance in PDAC. PMID- 28849151 TI - Effect of silencing the T-Box transcription factor TBX2 in prostate cancer PC3 and LNCaP cells. AB - T-Box (TBX)-2 is a member of the T-box gene family, which is aberrantly expressed in numerous types of malignant tumors, and has previously been demonstrated to be conducive to tumor progression by acting as a transcription factor. However, specific information regarding the expression and function of TBX2 in prostate cancer cells remains to be elucidated. The present study demonstrated that silencing of TBX2 by TBX2 small interfering RNA inhibited cell proliferation and promoted cell senescence. It was demonstrated that knockdown of TBX2 inhibited cell metastatic abilities by upregulating E-cadherin and downregulating N cadherin, Vimentin and fibronectin. In addition, the expression of TBX2 in prostate cancer tissues and tumor adjacent tissues was detected by immunohistochemistry. The results indicated that the expression rates of TBX2 were significantly increased in the cancerous tissues, compared with the healthy tumor adjacent tissue, and TBX2 increased staining was associated with the clinical stage and pathological grade. The findings of the present study therefore suggest that TBX2 expression is markedly increased in prostate cancer and TBX2 may act as a potential beneficial therapeutic target for the future treatment of prostate cancer. PMID- 28849152 TI - Neuroprotective effects of hydrogen sulfide on sodium azide-induced autophagic cell death in PC12 cells. AB - Sodium azide (NaN3) is a chemical of rapidly growing commercial importance. It is very acutely toxic and inhibits cytochrome oxidase (COX) by binding irreversibly to the heme cofactor. A previous study from our group demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator identified, had protective effects against neuronal damage induced by traumatic brain injury (TBI). It is well-known that TBI can reduce the activity of COX and have detrimental effects on the central nervous system metabolism. Therefore, in the present study, it was hypothesized that H2S may provide neuroprotection against NaN3 toxicity. The current results revealed that NaN3 treatment induced non-apoptotic cell death, namely autophagic cell death, in PC12 cells. Expression of the endogenous H2S producing enzymes, cystathionine-beta-synthase and 3-mercaptopyruvate sulfurtransferase, decreased in a dose-dependent manner following NaN3 treatment. Pretreatment with H2S markedly attenuated the NaN3-induced cell viability loss and autophagic cell death in a dose-dependent manner. The present study suggests that H2S-based strategies may have future potential in the prevention and/or therapy of neuronal damage following NaN3 exposure. PMID- 28849153 TI - Hydrogen saline suppresses neuronal cell apoptosis and inhibits the p38 mitogen activated protein kinase-caspase-3 signaling pathway following cerebral ischemia reperfusion injury. AB - Cerebral ischemia-reperfusion injury (CIRI) is a serious pathological disease that is associated with a high rate death and disability. Saturated hydrogen (H2) saline exhibits brain protective functions through anti-inflammatory, antioxidant and antiapoptotic effects. The present study investigated the potential treatment effects of H2 on CIRI. In addition, the potential protective mechanisms of H2 in the prevention of CIRI were investigated. Adult, male Sprague-Dawley rats (n=60) were randomly divided into the following three groups: Sham-operated group; IR group; and IR + H2 group (0.6 mmol/l, 0.5 ml/kg/day). Hematoxylin and eosin, and TUNEL staining were performed for histopathological analysis and investigation of apoptosis, respectively. In addition, the protein expression of caspase-3, p38 mitogen-activated protein kinase (MAPK) and phosphorylated-p38 MAPK in the cortex were measured by western blotting analysis. These results demonstrated that H2 significantly reduced the number of apoptotic cells, and the protein expression of p38 MAPK and caspase-3, compared with the IR group. These effects may be associated with the p38MAPK signaling pathway. PMID- 28849154 TI - MicroRNA-518b functions as a tumor suppressor in glioblastoma by targeting PDGFRB. AB - Glioblastoma (GBM) is the most common and aggressive type of primary human brain tumor in China. Dysregulated microRNA (miRNA/miR) expression has been hypothesized to serve a role in the tumorigenesis and progression of human GBM. To explore the potential mechanisms affecting GBM tumorigenesis, the function of miR-518b in regulating GBM cell proliferation and angiogenesis was examined in vitro by CCK-8 and tube formation assay and in vivo by xenograft assay. The present study demonstrated that the expression of miR-518b was downregulated in GBM tissues and in GBM cell lines (U87 and U251). In addition, the expression levels of miR-518b were highly associated with tumor size, World Health Organization grade and prognosis. Furthermore, overexpression of miR-518b suppressed GBM cell proliferation and angiogenesis, and induced GBM cell apoptosis in vitro and in vivo. Overexpression of miR-518b also inhibited the expression of platelet-derived growth factor receptor beta (PDGFRB), and the present study confirmed that the 3' untranslated region (3'UTR) of PDGFRB was a direct target of miR-518b. In conclusion, to the best of our knowledge, the present study is the first to present evidence suggesting that miR-518b may serve as a potential marker and target in GBM treatment. PMID- 28849155 TI - MicroRNA-130a is upregulated in colorectal cancer and promotes cell growth and motility by directly targeting forkhead box F2. AB - Colorectal cancer (CRC) is one of the most prevalent cancers among males and females worldwide. Despite progress in diagnostic and therapeutic strategies for CRC patients, the prognosis for patients with advanced CRC remains poor. MicroRNAs (miRNAs/miRs) are a class of highly conserved short, endogenously expressed and single-stranded non-coding RNAs. In recent years, increasing studies have demonstrated that dysregulation of miRNAs is closely associated with CRC carcinogenesis and progression. The aim of the present study was to explore the expression, roles and underlying molecular mechanism of miR-130a in CRC. The results indicated that miR-130a was significantly upregulated in CRC, and that miR-130a expression levels were correlated with TNM stage and lymph node metastasis of CRC. Inhibition of miR-130a markedly suppressed colorectal cancer cell proliferation, migration and invasion. Furthermore, forkhead box F2 (FOXF2) was identified as a direct downstream target gene of miR-130a in colorectal cancer. Downregulation of FOXF2 could partially reverse the functions induced by miR-130a under-expression in CRC cells. These findings suggested that miR-130a can regulate FOXF2 and function as an oncogene in CRC. Therefore, miR-130a may serve as a useful therapeutic agent for miRNA-based CRC targeted therapy. PMID- 28849156 TI - MicroRNA-144-3p suppresses tumor growth and angiogenesis by targeting SGK3 in hepatocellular carcinoma. AB - In our previous studies, the Illumine Soledad massively parallel signature sequencing of miRNomes in non-tumor and hepatocellular carcinoma (HCC) tissues revealed that microRNA (miR)-144-3p was significantly downregulated in HCC, but its role in HCC development, especially angiogenesis, remains unclear. In this investigation, we found recovering miR-144-3p expression can significantly suppress the growth, migration and induced angiogenic capacity of HCC cells through both in vivo and in vitro experiments. Moreover, clinical correlation analysis showed that low expression of miR-144-3p was positively correlated to poor disease-free survival (DFS) of HCC patients. Mechanistically, serum and glucocorticoid kinase 3 (SGK3), the putative targets of miR-144-3p, was predicted by Target Scan database and identified to be suppressed by miR-144-3p so that inhibiting the activation of mTOR-VEGF downstream signals was activated by the phosphoinositide 3-kinase (PI3K)-independent pathway. Hence, we concluded that miR-144-3p, which is frequently downregulated in HCC, can inhibit proliferation, migration and repress angiogenesis by regulating SGK3 activation with PI3K independent signal pathway, and acts as a prognostic factor for HCC patients. PMID- 28849157 TI - Molecular characterization of a pedigree carrying the hypertension-associated mitochondrial tRNAGln T4363C mutation. AB - Mitochondrial DNA mutations have been reported to be associated with essential hypertension. The present study reported the clinical and molecular features of a Chinese pedigree with maternally inherited hypertension. A total of 6 matrilineal relatives in this pedigree presented with variable degrees of hypertension; the age of onset ranged between 39 and 63 years, and the average age of onset was 53 years. Analysis of the mitochondrial genome in members of this family demonstrated the occurrence of a homoplasmic T4363C mutation in the transfer (t)RNAGln gene and 25 genetic polymorphisms belonging to mitochondrial haplogroup B4. Notably, the T4363C mutation was localized at the anticodon stem of tRNAGln, which is highly conserved across various species (conventional position 38). To determine its potential pathogenicity, RNA Fold software was used to predict the secondary structure of tRNAGln with and without this mutation. The results indicated that the T4363C mutation induced a significant alteration in the secondary structure of tRNAGln, and may reduce the steady-state levels of tRNAGln. Furthermore, matrilineal relatives carrying the T4363C mutation exhibited different age of onset and variable degrees of blood pressure, thus indicating that the T4363C mutation itself was insufficient to produce the clinical phenotype. Therefore, other modified factors, including environmental factors, and nuclear gene and epigenetic modifications, may be involved in the pathogenesis of hypertension. In conclusion, the present study provided valuable information regarding the association between tRNA mutations and hypertension. PMID- 28849158 TI - Plumbagin induces apoptosis in human osteosarcoma through ROS generation, endoplasmic reticulum stress and mitochondrial apoptosis pathway. AB - Osteosarcoma is the most common primary bone tumor that occurs in children and adolescents. Osteosarcoma has a poor prognosis and is often unresponsive to chemotherapy. Therefore, it remains a challenge to identify a novel strategy to effectively treat osteosarcoma. The present study demonstrated a novel opportunity in osteosarcoma treatment using the natural compound plumbagin. Plumbagin reduced cell viability in osteosarcoma cells but not normal bone cells, as determined by MTT assay and colony formation assay. Plumbagin induced cell apoptosis by mitochondrial dysfunction, which in turn promoted Ca2+ release and endoplasmic reticulum (ER)-stress, as determined by DAPI staining assay, DNA fragmentation assay, flow cytometry and western blotting analysis. In addition, plumbagin improved reactive oxygen species (ROS) generation, as determined by flow cytometry. Finally, these apoptotic cascades activated caspase-3 and caspase 9 to elicit apoptosis response. Our results demonstrated the anticancer effect of plumbagin by inducing cell apoptosis in osteosarcoma cells. In conclusion, plumbagin activated the apoptosis signaling pathway through eliciting ROS, ER stress, mitochondria dysfunction, and finally causing caspase activation. These results indicated that plumbagin may serve as potential antitumor drug by its multifunctional effects in osteosarcoma. PMID- 28849160 TI - Anti-inflammatory actions of gabapentin and pregabalin on the substance P-induced mitogen-activated protein kinase activation in U373 MG human glioblastoma astrocytoma cells. AB - Gabapentin (GBP) and pregabalin (PGB) exert antinociceptive effects on chronic nociceptive responses with neuropathic or inflammatory conditions. Furthermore, it is considered that GBP and PGB exhibit anti-inflammatory effects by modulating the substance P (SP)-mediated neurokinin-1 receptor (NK1R; a SP receptor) response. Thus, in the present study, the effects of GBP and PGB on SP-induced activation were investigated in the human glioblastoma astrocytoma U373 MG cell line, which expresses high levels of functional high-affinity NK1R, and produces interleukin (IL)-6 and IL-8 in response to SP. The results indicated that GBP and PGB suppressed the SP-induced production of IL-6, and IL-8 in U373 MG cells. Furthermore, GBP and PGB inhibited the SP-induced phosphorylation of p38 mitogen activated protein kinase (MAPK) and nuclear factor (NF)-kappaB, and the nuclear translocation of NF-kappaB in U373 MG cells. Together, these observations suggest that GBP and PGB likely prevent SP-induced IL-6 and IL-8 production in U373 MG cells via the inhibition of signaling molecules, including p38 MAPK and NF kappaB, thereby exhibiting antineuroinflammatory effects. PMID- 28849159 TI - Immunolocalization of cannabinoid receptor type 1 and CB2 cannabinoid receptors, and transient receptor potential vanilloid channels in pterygium. AB - Cannabinoids, as multi-target mediators, activate cannabinoid receptors and transient receptor potential vanilloid (TRPV) channels. There is evidence to support a functional interaction of cannabinoid receptors and TRPV channels when they are coexpressed. Human conjunctiva demonstrates widespread cannabinoid receptor type 1 (CB1), CB2 and TRPV channel localization. The aim of the present study was to investigate the expression profile for cannabinoid receptors (CB1 and CB2) and TRPV channels in pterygium, an ocular surface lesion originating from the conjunctiva. Semi-serial paraffin-embedded sections from primary and recurrent pterygium samples were immunohistochemically examined with the use of specific antibodies. All of the epithelial layers in 94, 78, 96, 73 and 80% of pterygia cases, exhibited CB1, CB2, TRPV1, TRPV2 and TRPV3 cytoplasmic immunoreactivity, respectively. The epithelium of all pterygia cases (100%) showed strong, mainly nuclear, TRPV4 immunolocalization. In the pterygium stroma, scattered cells demonstrated intense CB2 immunoreactivity, whereas vascular endothelial cells were immunopositive for the cannabinoid receptors and all TRPV channels. Quantitative analyses of the immunohistochemical findings in epithelial cells demonstrated a significantly higher expression level in conjunctiva compared with primary pterygia (P=0.04) for CB1, but not for CB2 (P>0.05). Additionally, CB1 and CB2 were significantly highly expressed in primary pterygia (P=0.01), compared with recurrent pterygia. Furthermore, CB1 expression levels were significantly correlated with CB2 expression levels in primary pterygia (P=0.005), but not in recurrent pterygia (P>0.05). No significant difference was detected for all TRPV channel expression levels between pterygium (primary or recurrent) and conjunctival tissues (P>0.05). A significant correlation between the TRPV1 and TRPV3 expression levels (P<0.001) was detected independently of pterygium recurrence. Finally, TRPV channel expression was identified to be significantly higher than the expression level of cannabinoid receptors in the pterygium samples (P<0.001). The differentiated expression of cannabinoid receptors in combination with the presence of TRPV channels, in primary and recurrent pterygia, imply a potential role of these cannabinoid targets in the underlying mechanisms of pterygium. PMID- 28849161 TI - EGFR gene status predicts response and survival benefit in a preclinical gastric cancer trial treating patient-derived xenografts with cetuximab. AB - Cetuximab has been evaluated as a first-line treatment with conflicting results. The aim of the present study was to investigate the relationship between epidermal growth factor receptor (EGFR) status, and response and survival benefit following cetuximab treatment in gastric cancer (GC). Using 20 patient-derived GC xenograft (PDX) models, the mice (10 mice/model) were randomly assigned into two groups. The control group and treatment group were treated with PBS and cetuximab, respectively. The drug response was evaluated by monitoring tumor growth. Survival benefit was evaluated by comparing the survival curves corresponding to the time for the tumors to reach 600 mm3. Our results revealed that the PDX models treated with cetuximab had better survival than that noted for the non-treated group (P<0.05). The EGFR status was measured by FISH, qPCR, RNAish and immunohistochemistry, respectively. Four cases in the treated group were identified as responsive to cetuximab. EGFR mRNA and protein overexpression were associated with the response to cetuximab (P<0.05). EGFR amplification, mRNA and protein overexpression were associated with prolonged survival in the cetuximab-treated PDX models. Moreover, in the PDX models with EGFR amplification, mRNA or protein overexpression, cetuximab treatment was associated with a better survival compared with that noted in the untreated group in the PDX models (P<0.05), while the survival was not statistically different in the other cases (P>0.05). In conclusion, cetuximab provided survival benefit in the trial. The level of EGFR amplification and overexpression significantly predicted response and survival benefit, particularly the mRNA and protein expression level. A combination of mRNA and protein expression may predict efficacy of cetuximab more efficiently. PMID- 28849162 TI - ABT-737 potentiates cisplatin-induced apoptosis in human osteosarcoma cells via the mitochondrial apoptotic pathway. AB - ABT-737 is a BH-3 mimetic that inhibits Bcl-2 and induces apoptosis of cancer cells, which has potential for anticancer therapies. Studies have shown that Bcl 2 expression in human osteosarcoma (OS) cells plays a significant role in tumor progression; however, its effects on OS cell apoptosis are still unknown. Therefore, we examined whether ABT-737 was effective in eliminating human U-2OS cells, either alone or in combination with the chemotherapy drug cisplatin [cis diamminedichloroplatinum (II); DDP]. Furthermore, we studied the molecular mechanisms of ABT-737 in combination with DDP to induce apoptosis. To analyze the role of ABT-737 and/or DDP on osteosarcoma progression, CCK-8 viability assay, flow cytometry, Hoechst 33258 staining, and western blots were performed. Combined use of ABT-737 and DDP synergistically suppressed cell viability and induced apoptosis in human U-2OS cells when compared with either compound treated alone at low doses. We found that the combination of ABT-737 and DDP upregulated the expression of the pro-apoptotic protein Bax and downregulated the expression of the pro-survival protein Bcl-2, resulting in a change in the Bax/Bcl-2 ratio, release of cytochrome c, and activation of the mitochondrial apoptotic pathway, which resulted in caspase-9 and caspase-3 activation and PARP cleavage. Our results demonstrated that ABT-737 alone has a nominal influence on human U-2OS cells when treated within the clinically administered range, but when combined with DDP, it can inhibit the proliferation of human U-2OS cells by inducing apoptosis via the mitochondrial apoptotic pathway. PMID- 28849163 TI - Melatonin potentiates the antitumor effect of curcumin by inhibiting IKKbeta/NF kappaB/COX-2 signaling pathway. AB - Curcumin, a natural polyphenolic compound, has commonly been used as a food additive or in many traditional medicine remedies for over 2,000 years in many Asian countries. Melatonin is a hormone secreted from pineal glands of mammals and possesses diverse physiological functions. Both curcumin and melatonin have the effective potential to inhibit proliferation of various types of cancers, but there is no report on their combination for bladder cancer treatment, and the underlying mechanism remains poorly understood. In the present study, we investigated whether the combination of curcumin and melatonin leads to an enhanced inhibition of cell proliferation in bladder cancer cells. Our results showed that the combinational treatment enhanced the repression of nuclear translocation of NF-kappaB and their binding on COX-2 promoter via inhibiting IKKbeta activity, resulting in inhibition of COX-2 expression. In addition, combined treatment with curcumin and melatonin induced cell apoptosis in bladder cancer through enhancing the release of cytochrome c from the mitochondrial intermembrane space into the cytosol. These results, therefore, indicated that melatonin synergized the inhibitory effect of curcumin against the growth of bladder cancer by enhancing the anti-proliferation, anti-migration, and pro apoptotic activities, and provide strong evidence that combined treatment with curcumin and melatonin might exhibit an effective therapeutic option in bladder cancer therapy. PMID- 28849164 TI - Zhi Zhen Fang formula reverses Hedgehog pathway mediated multidrug resistance in colorectal cancer. AB - Zhi-Zhen-Fang (ZZR), a Traditional Chinese Medicine (TCM) formula, has been clinically used in China to treat drug-resistant colorectal cancer (CRC) patients as an adjuvant. In this study, the efficacy of ZZR in suppressing multidrug resistance (MDR) on CRC was evaluated in vitro and in vivo. We observed that ZZR enhanced the sensitivity of chemotherapeutic drugs and induced apoptosis in a dose- and time-dependent mannner in CRC MDR cells. Interestingly, signaling of Hedgehog pathway, particularly Gli1, was also inhibited by ZZR. This effect of ZZR in reversing drug resistance and suppressing Gli1 was attenuated by a Hedgehog activator (SAG). Furthermore, ZZR inhibited MDR CRC tumor growth in a xenograft mouse model as well as downregulated Gli1 levels. This study provided the first direct evidence demonstrating ZZR can attenuate MDR by repressing Hedgehog signaling in human CRC. PMID- 28849165 TI - Polysaccharide purified from Lycium barbarum protects differentiated PC12 cells against L-Glu-induced toxicity via the mitochondria-associated pathway. AB - The present study successfully demonstrated the neuroprotective effects of purified Lycium barbarum polysaccharide (LBPS02) against glutamate (L-Glu) induced differentiated PC12 (DPC12) cell apoptosis. Purified polysaccharide was obtained by using a diethylaminoethyl-52 cellulose anion exchange column and a Sepharose G-100 column. During identification and characterization, LBPS02 was validated to be a fraction with 68 kDa molecular weight, and with a structure containing 1->3, 1->4 and 1->6 linkages. Data further revealed that LBPS02 pretreatment effectively improved cell viability, reduced apoptosis rate, and restored the mitochondrial dysfunction in L-Glu-exposed cells. LBPS02 suppressed L-Glu-induced reactive oxygen species (ROS accumulation in DPC12 cells. N acetylcysteine, a ROS inhibitor, strongly enhanced the efficacy of LBPS02. Furthermore, LBPS02 normalized the levels of anti-apoptotic proteins, and regulated the phosphorylation of extracellular signal-regulated kinases (ERKs) and protein kinase B (Akt) in L-Glu-explored DPC12 cells. In conclusion, LBPS02 mediated neuroprotective effects are at least partially associated with the modulation of Akt and ERKs, and the subsequent inhibition of the mitochondrial apoptotic pathway. LBPS02 may be a candidate for neurodegenerative disease treatment. PMID- 28849167 TI - Mechanisms of N-acetylcysteine in reducing monocrotaline-induced pulmonary hypertension in rats: Inhibiting the expression of Nox1 in pulmonary vascular smooth muscle cells. AB - The aim of the present study was to investigate the impact of N-acetylcysteine (NAC) on the expression of reduced nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1), and the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) in rats exhibiting monocrotaline (MCT)-induced pulmonary hypertension, and to investigate the possible mechanisms and treatment roles of NAC in pulmonary vascular remodeling (PVR). A total of 18 Wistar rats were randomly divided into three groups: The control (C) group; the MCT (M) group; and the NAC (N) group. The right ventricular hypertrophy index (RVHI) and other indicators were recorded 6 weeks subsequently. Groups C and M were divided into two subgroups: Groups C1 and M1 (control); and group C2 and M2 group (treated with ML171). Group N was not sub-divided. PASMCs were isolated, and the vascular remodeling and Nox1 positioning were observed. The expression of Nox mRNA in each group, and the proliferation, apoptosis, and superoxide dismutase (SOD) activity of PASMCs, prior to and following the ML171 treatment, were measured. NAC was able to decrease RVHI and other indicators (P<0.001). The mRNA expression of Nox1 and Nox4 in group M was significantly increased compared with group C (P<0.05), and NAC was able to significantly decrease the expression of these two factors in lung tissue (P<0.001). MCT-PASMCs exhibited differences in Nox1 mRNA expression (P<0.001), and the total SOD activity was Nox1-dependently increased (r=0.949; P<0.001). NAC was able to decrease Nox1-derived reactive oxygen species in PASMCs, thereby improving PVR. Nox1 was able to increase SOD activity, thereby demonstrating its positive effect on the proliferation of MCT-PASMCs. PMID- 28849166 TI - Effects of erythropoietin and methylprednisolone on AQP4 expression in astrocytes. AB - Methylprednisolone sodium succinate (MPSS) has been suggested as a treatment for spinal cord injury (SCI), but its use has been limited due to its adverse effects. Erythropoietin (EPO) has been suggested as a promising candidate for limiting SCI in mammals. The aim of the present study was to investigate the effects of EPO in combination with MPSS on astrocytes following ischemic injury in vitro. Astrocytes were isolated from the cerebral cortex of postnatal day 3 Sprague-Dawley rats and cultured in vitro. Astrocyte ischemic injury was induced by oxygen and glucose deprivation for 4 h, and reperfusion was simulated by subsequent culture under normoxic conditions. The effects of EPO and MPSS on the expression of aquaporin-4 (AQP4) were investigated. Ischemic astrocytes were treated with EPO (10 U/ml), MPSS (10 ug/ml), or EPO (10 U/ml) in combination with MPSS (10 ug/ml) during reperfusion. The cell viability of astrocytes was assessed using an MTT assay. The mRNA and protein expression levels of AQP4 were determined using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The role of the protein kinase C (PKC) signaling pathway in the molecular mechanisms underlying the effects of EPO and MPSS was also investigated. The present results demonstrated that following treatment with EPO and MPSS, the mRNA expression levels of AQP4 were upregulated and cell viability was enhanced. EPO and MPSS effectively inhibited the oxygen and glucose deprivation-mediated downregulation of AQP4 following reperfusion. In addition, the combined treatment with EPO and MPSS exhibited higher AQP4 expression levels and cell viability compared with each treatment alone. Finally, the effects of EPO and MPSS on AQP4 expression were partially reversed by pretreatment with the PKC inhibitor Ro 31-8220. The present study indicated that EPO and MPSS had a synergistic effect on AQP4 expression following reperfusion, and suggest that they may be combined in the treatment of SCI. PMID- 28849168 TI - MicroRNA-503 serves an oncogenic role in laryngeal squamous cell carcinoma via targeting programmed cell death protein 4. AB - Laryngeal squamous cell carcinoma (LSCC), the most common form of laryngeal carcinoma, is an aggressive malignancy that demonstrates the second highest rate of morbidity of all head and neck squamous cell carcinomas. The abnormal expression of microRNAs (miRs) has been demonstrated in a number of types of human cancer, and they have been demonstrated to be oncogenes or tumour suppressor genes. miR-503 has been studied in various types of human cancer; however, the expression level, roles and underlying mechanisms in LSCC remain unknown. In the present study, it was demonstrated that miR-503 was significantly upregulated in LSCC tissues and cell lines. The level of miR-503 in LSCC tissues was correlated with thyroid cartilage invasion, lymph node metastasis, and tumour, node and metastasis stage. In addition, down-regulation of miR-503 inhibited cell proliferation and invasion in LSCC. Programmed cell death protein 4 (PDCD4) was identified to be a direct target gene of miR-503. PDCD4 overexpression could mimic the roles of miR-503 underexpression in LSCC. Furthermore, PDCD4 was down-regulated in LSCC tissues and this correlated with the miR-503 expression level. In conclusion, these results suggested that miR-503 promotes tumour growth and invasion by directly targeting PDCD4. The identification of the miR-503/PDCD4 axis may provide novel targets for LSCC treatment and improve prognosis. PMID- 28849169 TI - Combined analysis of ChIP-seq and gene microarray datasets identify the E2 mediated genes in ERalpha-dependent manner in osteosarcoma. AB - Osteosarcoma is a common bone tumor which is affected by E2, the most representative estrogen. Gene regulation function of E2 is highly dependent on estrogen receptor. The purpose of this study was to explore the gene regulation patterns of E2 through estrogen receptor alpha (ESR1) in osteosarcoma based on the combined analysis of ChIP-seq and gene microarray. All of the datasets were downloaded from the Gene Expression Omnibus (GEO). Differential expression genes (DEGs) in E2 treated U2OS cells expressing ESR1 (U2OS-ERalpha) compared with those treated with vehicle were obtained based on R programming software. ESR1 specific binding sites (peaks) in E2 treated U2OS cells were identified through MACS. Overlaps between DEGs and ESR1 target genes which contained peaks in promoters were considered as reliable E2-mediated genes through ESR1 in osteosarcoma. Moreover, we conducted miRNA-Gene regulation analysis for those genes through miRWalk database to identify potential therapeutic targets for the genes. Functional enrichment analysis of DEGs indicated their potential involvement in cancer, and cell activity-related processes. Fifteen overlaps were identified between DEGs and target genes of ESR1, of which 12 were found to be regulated by miRNA. Several known estrogen response genes and novel genes were obtained in this study and they might provide potential therapeutic targets for osteosarcoma. PMID- 28849170 TI - Ginkgolide B promotes cell growth in endothelial progenitor cells through miR-126 and the Akt signaling pathway. AB - Ginkgolide B is one of the components extracted from Folium Ginkgo. It is a natural antagonist of platelet-activating factor receptor and has multiple pharmacological applications. In the present study, the effect of ginkgolide B on the proliferation of endothelial progenitor cells (EPCs) was examined, as well as its potential underlying mechanism. EPCs were cultured in various concentrations of ginkgolide B (0, 1.25, 5, 20, 80 or 160 ug/ml) for 24 or 48 h and then numbers of viable cells, apoptosis rate and caspace-3 activity were measured. The results demonstrated that ginkgolide B treatment effectively promoted EPC growth, and suppressed cell apoptosis and caspase-3 activity compared with control cells. In addition, ginkgolide B treatment significantly induced the expression of miR-126, vascular endothelial growth factor and endothelial nitric oxide synthase, while it increased phosphorylation of AKT serine/threonine kinase 1 (Akt) and of p38 mitogen-activated protein kinase in EPCs. The present study therefore demonstrated that ginkgolide B promoted cell growth in EPCs through overexpression of miR-126 and activation of the Akt signaling pathway. PMID- 28849171 TI - Ginsenoside Rg1 protects against neuronal degeneration induced by chronic dexamethasone treatment by inhibiting NLRP-1 inflammasomes in mice. AB - Glucocorticoids (GCs) are known to alter neuronal plasticity, impair learning and memory and play important roles in the generation and progression of Alzheimer's disease. There are no effective drug options for preventing neuronal injury induced by chronic GC exposure. Ginsenoside Rg1 (Rg1) is a steroidal saponin found in ginseng. The present study investigated the neuroprotective effect of Rg1 on neuroinflammation damage induced by chronic dexamethasone (5 mg/kg for 28 days) exposure in male mice. Our results showed that Rg1 (2 and 4 mg/kg) treatment increased spontaneous motor activity and exploratory behavior in an open field test, and increased the number of entries into the new object zone in a novel object recognition test. Moreover, Rg1 (2 and 4 mg/kg) treatment significantly alleviated neuronal degeneration and increased MAP2 expression in the frontal cortex and hippocampus. Additionally, inhibition of NLRP-1 inflammasomes was also involved in the mechanisms underlying the effect of Rg1 on GC-induced neuronal injury. We found that Rg1 (2 and 4 mg/kg) treatment increased the expression of glucocorticosteroid receptor and decreased the expression of NLRP-1, ASC, caspase-1, caspase-5, IL-1beta and IL-18 in the hippocampus in male mice. The present study indicates that Rg1 may have protective effects on neuroinflammation and neuronal injury induced by chronic GC exposure. PMID- 28849172 TI - Effects of Artesunate prevent nephritis via the Toll-like receptor 4/nuclear factor-kappaB signaling pathway in rats. AB - The active ingredient in Artemisia carvifolia, artemisinin, may alleviate inflammation and toxicity. Artemisinin and its derivatives are first-line anti malarial drugs currently, which have rapid effects on fever caused by malaria parasites with fewer side effects. The present study investigated the effects of Artesunate in a mouse nephritis model. Mice were injected intraperitoneally with 500 ul pristine to induce nephritis, and were treated with 28.8 mg/kg Artesunate. Subsequently, proteinuria, renal function, and tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 levels were assessed to evaluate the effects of Artesunate on nephritis. Western blot analysis was used to measure the protein expression levels of alpha-smooth muscle actin (SMA), TLR4, myeloid differentiation primary response gene 88 (MyD88), NF-kappaB p65 and transforming growth factor (TGF) beta1 to investigate the underlying mechanisms of Artesunate on nephritis. The results demonstrated that Artesunate reduced proteinuria and preserved renal function in nephritis mice. Artesunate attenuated TNF-alpha and IL-6 levels, suppressed alpha-SMA, TLR4, MyD88, NF-kappaB p65 and TGF-beta1 protein expression, and decreased caspase-3 activity in nephritis mice. These results indicated that the effects of Artesunate may prevent nephritis and inhibit inflammation via the TLR4/NF-kappaB signaling pathway in mice. Therefore, Artesunate may be a potential therapeutic agent to prevent nephritis. PMID- 28849173 TI - Myricitrin inhibits vascular adhesion molecule expression in TNF-alpha-stimulated vascular smooth muscle cells. AB - Increased expression of adhesion molecules is thought to serve an important role in the pathogenesis of atherosclerosis. Myricitrin, a bioactive compound of Myrica cerifera, has been demonstrated to exhibit anti-atherogenic effects. However, the effect of myricitrin on the expression of adhesion molecules in vascular smooth muscle cells (VSMCs) remains unknown. Therefore, the aim of the present study was to evaluate the inhibitory effects of myricitrin on tumor necrosis factor-alpha (TNF-alpha)-induced expression of adhesion molecules in VSMCs in vitro. The results revealed that myricitrin inhibited the adhesion of human THP-1 monocyte cells to TNF-alpha-stimulated mouse MOVAS-1 VSMC cells, and reduced the expression of adhesion molecules in TNF-alpha-stimulated MOVAS-1 cells. In addition, myricitrin significantly inhibited the TNF-alpha-induced expression of nuclear factor (NF)-kappaB p65, and prevented the TNF-alpha-induced degradation of nuclear factor of kappa light chain enhancer in B-cells inhibitor alpha. Furthermore, myricitrin inhibited the production of intracellular reactive oxygen species in TNF-alpha-stimulated MOVAS-1 cells. In conclusion, the results of the present study indicated that myricitrin inhibits the expression of vascular cell adhesion protein-1 and intercellular adhesion molecule-1 in TNF alpha-stimulated MOVAS-1 cells potentially via the NF-kappaB signaling pathway. Therefore, myricitrin may be an effective pharmacological agent for the prevention or treatment of atherosclerosis. PMID- 28849174 TI - TSA increases C/EBP-alpha expression by increasing its lysine acetylation in hepatic stellate cells. AB - CCAAT enhancer binding protein-alpha (C/EBP-alpha) is a transcription factor expressed only in certain tissues, including the liver. It has been previously demonstrated that C/EBP-alpha may induce apoptosis in hepatic stellate cells (HSCs), raising the question of whether acetylation of C/EBP-alpha is associated with HSCs, and the potential associated mechanism. A total of three histone deacetylase inhibitors (HDACIs), including trichostatin A (TSA), suberoylanilide hydroxamic acid and nicotinamide, were selected to determine whether acetylation affects C/EBP-alpha expression. A Cell Counting Kit-8 assay was used to determine the rate of proliferation inhibition following treatment with varying doses of the three HDACIs in HSC-T6 and BRL-3A cells. Western blot analysis was used to examine Caspase-3, -8, -9, and -12 levels in HSC-T6 cells treated with adenoviral C/EBP-alpha and/or TSA. Following treatment with TSA, a combination of reverse transcription-quantitative polymerase chain reaction and western blot analyses was used to determine the inherent C/EBP-alpha mRNA and protein levels in HSC-T6 cells at 0, 1, 2, 4, 8, 12, 24, 36 and 48 h. Nuclear and cytoplasmic proteins were extracted to examine C/EBP-alpha distribution. Co-immunoprecipitation analysis was used to examine the lysine acetylation of C/EBP-alpha. It was observed that TSA inhibited the proliferation of HSC-T6 cells to a greater extent compared with BRL-3A cells, following treatment with the three HDACIs. TSA induced apoptosis in HSC-T6 cells and enhanced the expression of C/EBP-alpha. Following treatment of HSC-T6 cells with TSA, inherent C/EBP-alpha expression increased in a time-dependent manner, and its lysine acetylation simultaneously increased. Therefore, the results of the present study suggested that TSA may increase C/EBP-alpha expression by increasing its lysine acetylation in HSCs. PMID- 28849175 TI - AKAP2 is upregulated in ovarian cancer, and promotes growth and migration of cancer cells. AB - Mutations of A-kinase anchoring protein 2 (AKAP2) have been reported to be associated with adolescent idiopathic scoliosis. However, its role in cancer is poorly understood. In the present study, the mRNA levels of AKAP2 in ovarian cancer tissues were examined using qPCR. The effects of AKAP2 on the growth and migration of cancer cells were examined using crystal violet and Boyden chamber assays. An in vivo image system was used to evaluate the effect of AKAP2 on the metastasis of ovarian cancer cells. The present study demonstrated that the expression of AKAP2 was elevated in ovarian cancer. Furthermore, overexpression of AKAP2 promoted the growth and migration of ovarian cancer cells, whereas knockdown of AKAP2 expression reduced the growth and migration of ovarian cancer cells. Analysis of the molecular mechanism indicated that AKAP2 activated beta catenin/T cell factor signaling and regulated the expression of several target genes. Furthermore, analysis of the in vivo metastatic capacity demonstrated that downregulation of AKAP2 inhibited the invasion of ovarian cancer cells. Taken together, the present study demonstrated an oncogenic role for AKAP2 in ovarian cancer, indicating that AKAP2 may be a therapeutic target for ovarian cancer. PMID- 28849176 TI - Anti-angiogenesis gene therapy for hepatocellular carcinoma via systemic injection of mesenchymal stem cells engineered to secrete soluble Flt-1. AB - Anti-angiogenesis gene therapy has attracted interest as a potential treatment for hepatocellular carcinoma (HCC). Studies have indicated that soluble fms-like tyrosine kinase-1 (sFlt-1) may suppress angiogenesis by sequestering free vascular endothelial growth factor (VEGF) or by forming inactive heterodimers with VEGF receptor-2. Mesenchymal stem cells (MSCs) have been widely used as prospective delivery vehicles for therapeutic agents, owing to their ability to migrate towards tumor sites. In the present study, a subcutaneous HCC mouse model was used to assess the anti-angiogenesis effects of lentivirus-transfected MSCs engineered to secrete sFlt-1 (LV-sFlt-1-MSCs). LV-sFlt-1-MSCs effectively secreted sFlt-1, which inhibited tube formation in vitro. MSCs labeled with green fluorescence protein primarily migrated to tumor sites in vivo. An immunohistochemical assay indicated that microvessel density was reduced in mice treated with LV-sFlt-1-MSCs, compared with the control group treated with PBS. Additionally, LV-sFlt-1-MSCs inhibited tumor growth and prolonged survival in an HCC mouse model via systemic injection. Overall, the present study was designed to investigate the potential of LV-sFlt-1-MSCs for anti-angiogenesis gene therapy in HCC. PMID- 28849177 TI - Suppressive effects of human fetal keratinocytes on the proliferation, differentiation and extracellular matrix synthesis of human hypertrophic scar fibroblasts in vitro. AB - A hypertrophic scar is characterized by fibroblast proliferation and excessive extracellular matrix deposition. Emerging evidence has revealed that fetal keratinocytes (KCs) contribute to scarless wound healing. However, the association between fetal keratinocytesand hypertrophic scarring remains unclear. In the present study, human KCs of different gestational ages were isolated and co-cultured with human hypertrophic scar fibroblasts (HSFbs) or normal skin fibroblasts. Gene expression andprotein levels of fibronectin, collagen 1and alpha-smooth muscle actinin thefibroblasts were measured by reverse transcription quantitative polymerase chain reaction and western blot analyses. It was observed that fetal KCs significantly inhibited the proliferation of HSFbs in vitro. Fetal keratinocytes also affected the expression of fibronectin, collagen 1and alpha smooth muscle actin in HSFbs. In addition, miR-940 may modulate the suppressive effects of fetal KCson the cell proliferation, differentiation and extracellular matrix synthesis of HSFbs by directly targeting transforming growth factor-beta1. Taken together, the results of the present studyprovide evidence to support the potential use of fetal KCsfor cell-based therapeutic grafting in the prevention of hypertrophic scarring. PMID- 28849178 TI - Nerve growth factor pretreatment inhibits lidocaine-induced myelin damage via increasing BDNF expression and inhibiting p38 mitogen activation in the rat spinal cord. AB - The present study aimed to investigate the effect of exogenous nerve growth factor (NGF) pretreatment on demyelination in the spinal cord of lidocaine treated rats, and explored the potential neuroprotective mechanisms of NGF. A total of 36 rats were randomly assigned to three groups (n=12 per group): Sham group; Lido group, received intrathecal injection of lidocaine; NGF group, received intrathecal injection of NGF followed by intrathecal injection of lidocaine. Tail-flick tests were used to evaluate neurobehavioral function. Ultrastructural alternations were analyzed by transmission electron microscopy. Immunofluorescence was used to examine the expression of myelin basic protein (MBP) and brain-derived neurotrophic factor (BDNF). ELISA was used to determine serum levels of MBP and proteolipid protein (PLP). Western blotting was used to detect the expression of phosphorylated mitogen activated protein kinase (MAPK). NGF pretreatment reduced lidocaine-induced neurobehavioral damage, nerve fiber demyelination, accompanied by a decrease in MBP expression in the spinal cord and an increase in MBP and PLP in serum. In addition, NGF pretreatment increased BDNF expression in the spinal cord of lidocaine-treated rats. Furthermore, NGF pretreatment reduced p38 MAPK phosphorylation in the spinal cord of lidocaine treated rats. NGF treatment reduces lidocaine-induced neurotoxicity via the upregulation of BDNF and inhibition of p38 MAPK. NGF therapy may improve the clinical use of lidocaine in intravertebral anesthesia. PMID- 28849179 TI - Role of interferon regulatory factor-1 in lipopolysaccharide-induced mitochondrial damage and oxidative stress responses in macrophages. AB - Sepsis causes many early deaths; both macrophage mitochondrial damage and oxidative stress responses are key factors in its pathogenesis. Although the exact mechanisms responsible for sepsis-induced mitochondrial damage are unknown, the nuclear transcription factor, interferon regulatory factor-1 (IRF-1) has been reported to cause mitochondrial damage in several diseases. Previously, we reported that in addition to promoting systemic inflammation, IRF-1 promoted the apoptosis of and inhibited autophagy in macrophages. In the present study, we hypothesized that lipopolysaccharide (LPS)-induced IRF-1 activation in macrophages may promote mitochondrial damage and oxidative stress. In vitro, LPS was found to promote IRF-1 activation, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) depletion, superoxide dismutase (SOD) consumption, malondialdehyde (MDA) accumulation and mitochondrial depolarization in macrophages in a time- and dose-dependent manner. These effects were abrogated in cells in which IRF-1 was knocked down. Furthermore, IRF-1 overexpression increased LPS-induced oxidative stress responses and mitochondrial damage. In vivo, peritoneal macrophages obtained from IRF-1 knockout (KO) mice produced less ROS and had less mitochondrial depolarization and damage following the administration of LPS, when compared to their wild-type (WT) counterparts. In addition, IRF-1 KO mice exhibited a decreased release of mitochondrial DNA (mtDNA) following the administration of LPS. Thus, IRF-1 may be a critical factor in augmenting LPS-induced oxidative stress and mitochondrial damage in macrophages. PMID- 28849180 TI - Silencing Aurora A leads to re-sensitization of breast cancer cells to Taxol through downregulation of SRC-mediated ERK and mTOR pathways. AB - While Taxol has been reported to improve the clinical survival of breast cancer patients, subsequently developed drug-resistance of the cancer cells limits its final efficacy and applications. Previous studies suggested that Aurora A is involved in the development of the Taxol-resistance of breast cancer. We established Taxol-resistant breast cancer MCF-7/T cells and xenograft models to explore the role of Aurora A in Taxol resistant ER-positive breast cancer. Compared with their parental MCF-7/C cells, the Taxol-resistant MCF-7/T cells exhibited enhanced colony formation, less cell death and higher invasive ability. The resistant cells presented overexpressed Aurora A, elevated phosphorylated SRC and upregulated Ras/Raf/ERK and Akt/mTOR pathways. Silencing of Aurora A reduced the activity of SRC and downregulated the ERK and Akt/mTOR pathways, which led to re-sensitization of the resistant MCF-7/T cells to Taxol in vitro. These results suggested that the activation of Aurora A and the subsequent upregulation of ERK and Akt through SRC induced Taxol-resistance in breast cancer cells, and inhibiting Aurora A and the related SRC/EKT/Akt pathway could restore the sensitivity of breast cancer cells to Taxol. These results might shed light on the development of strategies to circumvent Taxol-related chemoresistance in breast cancer clinical practice. PMID- 28849181 TI - Tacrolimus downregulates inflammation by regulating pro-/anti-inflammatory responses in LPS-induced keratitis. AB - Lipopolysaccharide (LPS)-induced keratitis is a progressive infectious ocular disease in which innate inflammatory responses often cause clinical tissue damage and vision loss. The present study aimed to investigate the effects of tacrolimus, an effective immunomodulator, on LPS-induced innate immune responses. The effects of tacrolimus on the apoptotic rate and viability of human corneal epithelial cells (HCECs), polymorphonuclear neutrophils (PMNs) and monocytes (THP 1 cells) were examined using flow cytome-try and MTT assays. Subsequently, the role of tacrolimus on LPS-induced inflammation in HCECs, PMNs and THP-1 cells was evaluated by detecting the expression levels of pro-inflammatory cytokines, including interleukin (IL)-1beta, IL-6 and matrix metallopeptidase 9; anti inflammatory cytokines, including IL-10 and transforming growth factor-beta; and proangiogenic factors, including vascular endothelial growth factor and tumor necrosis factor-alpha using quantitative polymerase chain reaction. The results demonstrated that tacrolimus had good biocompatibility with HCECs, while promoting apoptosis and decreasing the viability of PMNs and THP-1 cells. Furthermore, tacrolimus effectively reduced the expression levels of pro inflammatory cytokines and increased anti-inflammatory cytokines in LPS-induced keratitis in vitro. Notably, tacrolimus decreased the levels of proangiogenic factors, which are highly increased following LPS stimulation. Conclusively, tacrolimus appears to be a safe and effective treatment to suppress neutrophil and monocyte activity, modulate the balance of pro-/anti-inflammatory cytokines, and reduce the inflammatory response and angiogenic activity in LPS-induced bacterial keratitis. PMID- 28849182 TI - In vitro and in vivo antitumor effects of chloroquine on oral squamous cell carcinoma. AB - Chloroquine, which is a widely used antimalarial drug, has been reported to exert anticancer activity in some tumor types; however, its potential effects on oral squamous cell carcinoma (OSCC) remain unclear. The present study aimed to explore the effects and possible underlying mechanisms of chloroquine against OSCC. MTT and clonogenic assays were conducted to evaluate the effects of chloroquine on the human OSCC cell lines SCC25 and CAL27. Cell cycle progression and apoptosis were detected using flow cytometry. Autophagy was monitored using microtubule associated protein 1A/1B-light chain 3 as an autophagosomal marker. In order to determine the in vivo antitumor effects of chloroquine on OSCC, a CAL27 xenograft model was used. The results demonstrated that chloroquine markedly inhibited the proliferation and the colony-forming ability of both OSCC cell lines in a dose- and time-dependent manner in vitro. Chloroquine also disrupted the cell cycle, resulting in the cell cycle arrest of CAL27 and SCC25 cells at G0/G1 phase, via downregulation of cyclin D1. In addition, chloroquine inhibited autophagy, and induced autophagosome and autolysosome accumulation in the cytoplasm, thus interfering with degradation; however, OSCC apoptosis was barely affected by chloroquine. The results of the in vivo study demonstrated that chloroquine effectively inhibited OSCC tumor growth in the CAL27 xenograft model. In conclusion, the present study reported the in vitro and in vivo antitumor effects of chloroquine on OSCC, and the results indicated that chloroquine may be considered a potent therapeutic agent against human OSCC. PMID- 28849183 TI - FTO expression is associated with the occurrence of gastric cancer and prognosis. AB - Fat mass and obesity associated (FTO) is a protein-coding gene. FTO gene is an obesity related gene, also known as the obesity gene. It has been reported previously that FTO is associated with a variety of malignant cancers, such as breast, thyroid and endometrial cancer. The aim of the present study was investigate the FTO expression of human gastric cancer and to investigate its clinical value. FTO expression was determined by immunohistochemical analysis with tissue microarrays in GC tissues and corresponding adjacent non-tumor tissues. Moreover, the results in protein and mRNA level were confirmed by the real-time PCR and western blot analysis. The relationship between the FTO expression and the pathological characteristics of GC patients was also explored. In addition, by using MTT, clone formation and transwell assays, we studied the effects of FTO expression on biological function of GC cells in vitro. The Kaplan Meier method and the log-rank test were used to compare the overall survival rate between the FTO high-expression group and the low-expression group. We affirmed repeatedly upregulation of FTO expression in both protein and mRNA levels in GC tissues compared to corresponding adjacent non-tumor tissues. Immunohistochemistry by tissue microarray of FTO expression was remarkably increased in GC tissues (72 of 128, 56.3%) compared with adjacent non-tumor tissues (24 of 62, 38.7%). FTO expression level was closely related to low differentiation (P<0.001), lymph node metastasis (P=0.029). The expression of FTO was positively correlated with TNM stage (P<0.001). the Kaplan-Meier analysis showed that high FTO expression was significantly associated with poor prognosis in GC patients. Downregulation of FTO expression significantly inhibited the proliferation, migration and invasion of GC cell lines. On the contrary, overexpression of FTO promoted the proliferation, migration and invasion of GC cell lines. This study indicates that FTO expression may have an important role in promoting the occurrence of GC, and it may be an vital molecular marker in the diagnosis and prognosis of GC patients. PMID- 28849184 TI - Identification of mutations in EXT1 and EXT2 genes in six Chinese families with multiple osteochondromas. AB - The aim of the present study was to identify mutations of major causative genes in six unrelated Chinese families with multiple osteochondromas (MO). Radiographic examinations and genetic analyses were performed in 8 patients exhibiting typical features of MO. Analysis was also performed on unaffected members of the six families and 250 healthy volunteers. Radiographies of the patients revealed multiple exostoses in the cartilage of long bones. A total of five different mutations were identified, one in exostosin-1 (EXT1) and four in exostosin-2 (EXT2). Two novel mutations were detected in EXT2: A missense mutation, c.1385G>A, in exon 8, resulting in p.Trp462X; and a splice site mutation, c.725+1G>C, which consisted of a heterozygous guanine-to-cytosine transition at nucleotide 725+1 in intron 3. Three common EXT mutations were also detected: c.1036C>T in exon 5 of EXT2 resulting in p.Gln346X; c.1299C>A in exon 8 of EXT2 resulting in p.Phe433Leu; and c.1038A>T in exon 2 of EXT1 resulting in p.Arg346Ser. In conclusion, the present study identified a novel missense mutation (c.1385G>A) in exon 8 and a splicing mutation (c.725+1G>C) in intron 3 of the EXT2 gene, which are responsible for MO in certain Chinese patients. The findings are useful for expanding the database of known EXT2 mutations and understanding the genetic basis of MO in Chinese patients, which may improve genetic counseling and the prenatal diagnosis of MO. PMID- 28849185 TI - Human hepatocyte growth factor inhibits early neointima formation in rabbit abdominal aortae following ultrasound-guided balloon injury. AB - The present study investigated the effects of in vivo gene transfer of human hepatocyte growth factor (hHGF) on neointima formation in rabbit abdominal aortae following ultrasound-guided balloon injury. New Zealand white rabbits were randomly divided into four groups: endothelium injury alone (EI), endothelium injury with control vector transfection (EI-V), endothelium injury with hHGF transfection (EI-HGF), and hHGF transfection alone without endothelium injury (HGF). Endothelial injury was established by scraping the abdominal aortic wall using a balloon catheter under the guidance of a transabdominal ultrasound. hHGF gene transfer was performed 7 days following injury. hHGF mRNA and protein expression levels were determined at 3, 7, 14 and 21 days following transfection. Neointima formation was assessed by histopathological analysis at 14 and 28 days following injury. hHGF mRNA and protein expression levels were detected in the target abdominal aortae in EI-HGF and HGF groups with the greatest levels observed 3 days following transfection, and their levels dropped below detection limits at 21 days following transfection. hHGF was not detectable in the EI and EI-V groups throughout the experiment. The neointimal area and the neointima to media ratio in the EI-HGF group were significantly decreased compared with those in the EI or EI-V group at 14 days following injury. However, no differences were observed at 28 days following injury. The present study demonstrated that in vivo hHGF gene transfer inhibits the early formation of neointima in balloon-injured rabbit abdominal aortae. PMID- 28849186 TI - PIM-1 kinase inhibitor SMI-4a exerts antitumor effects in chronic myeloid leukemia cells by enhancing the activity of glycogen synthase kinase 3beta. AB - The development of targeted tyrosine kinase inhibitors (TKIs) has succeeded in altering the course of chronic myeloid leukemia (CML). However, a number of patients have failed to respond or experienced disease relapse following TKI treatment. Proviral integration site for moloney murine leukemia virus-1 (PIM-1) is a serine/threonine kinase that participates in regulating apoptosis, cell cycle, signal transduction and transcriptional pathways, which are associated with tumor progression, and poor prognosis. SMI-4a is a selective PIM-1 kinase inhibitor that inhibits PIM-1 kinase activity in vivo and in vitro. The present study aimed to explore the mechanism underlying the antitumor effect of SMI-4a in K562 and imatinib-resistant K562 (K562/G) cell lines. It was demonstrated that SMI-4a inhibited the proliferation of K562 and K562/G cells using a WST-8 assay. The Annexin V-propidium iodide assay demonstrated that SMI-4a induced apoptosis of K562 and K562/G cells in a dose-, and time-dependent manner. Furthermore, Hoechst 33342 staining was used to verify the apoptosis rate. The clone formation assay revealed that SMI-4a significantly inhibited the colony formation capacity of K562 and K562/G cells. Western blot analysis demonstrated that SMI-4a decreased phosphorylated (p)-Ser9-glycogen synthase kinase (GSK) 3beta/pGSK3beta and inhibited the translocation of beta-catenin. In addition, the downstream gene expression of apoptosis regulator Bax and poly(ADP-ribose) polymerase-1 was upregulated, and apoptosis regulator Bcl-2 and Myc proto-oncogene protein expression levels were downregulated. Immunofluorescence results demonstrated changes in the expression level of beta-catenin in the plasma and nucleus. The results of the present study suggest that SMI-4a is an effective drug to use in combination with current chemotherapeutics for the treatment of imatinib resistant CML. PMID- 28849187 TI - MicroRNA-218 promotes cisplatin resistance in oral cancer via the PPP2R5A/Wnt signaling pathway. AB - Accumulating data suggest that microRNAs (miRNAs) play a pivotal role in the regulation of tumor cell sensitivity to chemotherapeutic agents. Although the roles of a few miRNAs have been identified in cisplatin resistance, little is known in regards to the concerted contribution of miRNA-mediated biological networks. In the present study, we demonstrated that microRNA-218 (miR-218) was significantly upregulated in cisplatin-resistant oral cancer cells. The results of cell viability and apoptosis assay showed that ectopic expression of miR-218 induced cell survival and resistance to cisplatin, whereas suppression of miR-218 caused apoptosis and enhanced sensitivity to cisplatin. Moreover, we identified PPP2R5A as a new direct target of miR-218 by using the dual luciferase reporter assay. Overexpression of miR-218 led to inhibition of PPP2R5A expression, whereas knockdown of miR-218 increased PPP2R5A levels. Introduction of PPP2R5A abrogated miR-218-mediated cell survival and drug resistance. Furthermore, suppression of miR-218 or PPP2R5A significantly promoted or reduced cisplatin-induced apoptosis, respectively. Finally, PPP2R5A overexpression or beta-catenin knockdown inhibited miR-218-mediated Wnt activation and partially restored cell sensitivity. Our data revealed a molecular link between miR-218 and PPP2R5A/Wnt signaling and implicates miR-218 as a potential target for oral cancer therapy. PMID- 28849188 TI - Expression of carbonic anhydrase IX is associated with poor prognosis through regulation of the epithelial-mesenchymal transition in hepatocellular carcinoma. AB - Carbonic anhydrase 9 (CA9) is a plasma membrane-associated isoenzyme that catalyzes pH regulation under hypoxic conditions. CA9 is transcriptionally regulated by hypoxia-inducible factor 1. Recent studies reported that hypoxia also promoted the epithelial-mesenchymal transition (EMT) in various cancers. In the present study, we evaluated the relationship between CA9 expression and EMT in vitro with two hepatoma cell lines. We also examined the clinical significance of CA9 expression in 117 consecutive patients that underwent hepatectomies for hepatocellular carcinoma (HCC). We evaluated CA9 expression and EMT induction under hypoxia with quantitative RT-PCR, western blot analysis and immunofluorescence staining, in HuH7 and HepG2 cells. We knocked down CA9 expression with small interfering RNA to evaluate the relationship between CA9 and EMT. We found that hypoxia induced CA9 expression in HCC cells and promoted EMT, evidenced by a loss of E-cadherin and an increase in N-cadherin. Twist, a transcriptional regulator of EMT, was also upregulated with hypoxia. The CA9 deficiency attenuated hypoxia-induced changes in E-cadherin and N-cadherin. Immunohistochemical evaluations of patient samples showed that CA9 was expressed in 50.4% of patients (59/117). However, patients with and without CA9 expression were not significantly different in clinicopathological factors. Nevertheless, a multivariate analysis showed that CA9 expression was an independent factor for both recurrence and prognosis among patients that underwent curative surgery for HCC. In conclusion, this study revealed that CA9 expression was a pivotal predictive factor for poor prognosis after radical surgery for HCC. Moreover, the CA9 regulation of the expression of EMT-related molecules represented a mechanism that enhanced malignant potential. PMID- 28849189 TI - Screening and validation of differentially expressed extracellular miRNAs in acute pancreatitis. AB - The present study aimed to screen for differentially expressed extracellular microRNAs (miRNAs) during the development of acute pancreatitis (AP) and validate the miRNA expression in the plasma of patients with AP. The culture medium of taurolithocholic acid-3 sulfate-treated rat pancreatic acinar AR42J cells was collected to extract total RNA for miRNA microarray analysis. Compared with the miRNA test results of the AP rats in the GEO databases, the differentially expressed extracellular miRNAs were screened. The TargetScan, miRanda, and PicTar programs were used for target gene prediction of the identified miRNAs, and gene ontology-biological processes (GO-BP) functional annotation was performed. Finally, the results from the combined microarray analyses (in vitro cell line and in vivo rat samples) were validated using plasma samples from patients with mild and moderately severe AP by reverse transcription-polymerase chain reaction. The results demonstrated that extracellular miR-24 was differentially expressed by microarray and bioinformatics analysis in both the cell line and the animal model of AP. Bioinformatics prediction analysis revealed that downstream target genes of miR-24 included Vav2, Syk, Lhcgr, Slc9a3r1, Cacnb1, Cacna1b, Bcl10, and Fgd3. Functional enrichment analysis revealed that the main GO-BP predicted functional presentations were positive regulation of calcium-mediated signaling, activation of c-Jun N-terminal kinase activity, calcium ion transport, regulation of Rho protein signal transduction, negative regulation of the protein kinase B signaling cascade, and the T cell receptor signaling pathway. Validation analysis for the plasma miR-24 expression in humans revealed a significant upregulation of miR-24 in the plasma samples of AP patients compared with the healthy controls, while no significant difference was observed in the miR-24 expression between the mild and the moderately severe AP groups. The present study confirmed the high expression of miR-24 in peripheral blood during AP, suggesting that miR-24 might have an intercellular communication role contributing to the AP-associated distant organ injury. PMID- 28849191 TI - Dopamine and serotonin contribute to Paecilomyces hepiali against chronic unpredictable mild stress induced depressive behavior in Sprague Dawley rats. AB - Paecilomyces hepiali contains identical chemical constituents to Cordyceps sinensis, and it presents antidepressant-like activity via regulating noradrenergic and dopaminergic systems. Behavioral despair depression models serve important roles in scientific screening and evaluation of antidepressants. The present study aims to investigate the antidepressant-like activity of P. hepiali extract (PHC) in chronic unpredictable mild stress (CUMS)-induced rat model of depression. Following four weeks of treatment, similar to fluoxetine at 3 mg/kg (positive drug), PHC at doses from 0.08 to 2.0 g/kg strongly increased sucrose preference and reduced the immobility time of depression-like rats in forced swimming test. The hypo-level of adrenocorticotropic hormone, noradrenaline and glucocorticoid receptor in serum and hypothalamus of depression like rats was enhanced by PHC. PHC normalized CUMS-induced disorders of dihydroxyphenylacetic acid, dopamine, 5-hydroxytryptamine (5-HT) and 5 hydroxyindoleacetic acid in serum and/or hypothalamus of depression-like rats. Moreover, PHC enhanced the expression of tyrosine hydroxylase and reduced the levels of dopamine D2 receptor and 5-HT2A receptor in hypothalamus. These results suggested that the antidepressant-like effects of PHC in CUMS-induced depression are associated with not only the modulation of dopamine, but also the regulation of 5-HT. PMID- 28849190 TI - Trichostatin A attenuates oxidative stress-mediated myocardial injury through the FoxO3a signaling pathway. AB - Trichostatin A (TSA), a histone deacetylase inhibitor, is widely used as an anticancer drug. Recently, TSA has been shown to exert a protective effect on ischemia/reperfusion (I/R) injury; however, the underlying mechanisms remain unclear. Forkhead box O3a (FoxO3a), a unique FoxO family member, has been shown to attenuate myocardial injury by increasing resistance to oxidative stress in mice. The present study aimed to investigate whether TSA exerts its cardioprotective effects through the FoxO3a signaling pathway. For this purpose, healthy male Wistar rats were pre-treated with TSA for 5 days before they were subjected to ligation/relaxation of the left anterior descending branch of the coronary artery and to 30 min of ischemia, followed by 24 h of reperfusion. The activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and superoxide diamutase (SOD), as well as the malondialdehyde (MDA) levels were examined. The H9c2 rat myocardial cell line was cultured in 10% FBS-containing DMEM for 24 h. The cells were incubated with/without TSA (50 nmol/l) for 1 h and then incubated with/without H2O2 (400 uM) for 2 h. Reactive oxygen species (ROS) and mitochondrial membrane potential (Deltapsim) were measured by probe staining in the H9c2 cells. The expression of FoxO3a, mitochondrial SOD2 and catalase was quantified by western blot analysis. The levels of H3 and H4 acetylation of the FoxO3a promoter region were examined by chromatin immunoprecipitation assay. TSA significantly reduced the myocardial infarct size and the activities of serum LDH, AST and CK in the rats. TSA also decreased the levels of MDA and increased the activities of SOD in the myocardial tissue of the rats. Consistent with the reduced injury to the TSA-treated rats, TSA significantly reduced the H2O2-induced levels of ROS and increased Deltapsim. In addition, TSA increased the expression of FoxO3a, SOD2 and catalase, which may be related to increasing the level of H4 acetylation of the FoxO3a promoter region. Our results thus revealed that TSA protected the myocardium from oxidative stress-mediated damage by increasing H4 acetylation of the FoxO3a promoter region, and the expression of FoxO3a, SOD2 and catalase. PMID- 28849192 TI - Chinese herb extract improves liver steatosis by promoting the expression of high molecular weight adiponectin in NAFLD rats. AB - High molecular weight (HMW) adiponectin (APN) is closely correlated with the development of fatty liver and is modulated by the Akt/forkhead box protein O1 (FOXO1) pathway through disulfide-bond A oxidoreductase-like protein (DsbA-L). The Chinese herb extract, QSHX, is used to treat liver diseases. The present study investigated the effects of QSHX on non-alcoholic fatty liver disease (NAFLD) and its underlying mechanism. A rat model of NAFLD was established by feeding of a high-fat and high-sugar diet for 20 weeks. From week 13, the rats were administered with QSHX, or saline as a control, for 8 weeks. The liver function, blood fat and plasma APN were measured using a radioimmunoassay. The hepatic tissue score was measured following staining for pathology. The expression and activities of Akt, FOXO1, DsbA-L and HMW APN in the adipose tissue and primary adipocytes of the rats were measured using western blot analysis. It was found that QSHX significantly decreased the body weight, liver index, and serum levels of aspartate aminotransferase, alanine aminotransferase and triglyceride; and increased the serum level of APN in the NAFLD rats. Following 8 weeks of treatment with QSHX, the hepatic steatosis in the liver tissue improved and the score of hepatic steatosis was significantly decreased. The results of the western blot analysis indicated that QSHX promoted the expression of DsbA-L and HMW APN, and reduced the expression levels of phosphorylated FOXO1 and FOXO1 in adipose tissue and primary adipocytes. It was concluded that QSHX reduced hepatic steatosis by promoting the expression of HMW APN and DsbA-L, which may have been induced by inhibiting the activation and expression of FOXO1 in adipocytes. PMID- 28849193 TI - Fluid shear stress regulates vascular remodeling via VEGFR-3 activation, although independently of its ligand, VEGF-C, in the uterus during pregnancy. AB - Early pregnancy is characterized by an increase in the blood volume of the uterus for embryonic development, thereby exerting fluid shear stress (FSS) on the vascular walls. The uterus experiences vascular remodeling to accommodate the increased blood flow. The blood flow-induced FSS elevates the expression of vascular endothelial growth factors (VEGFs) and their receptors, and regulates vascular remodeling through the activation of VEGF receptor-3 (VEGFR-3). However, the mechanisms responsible for FSS-induced VEGFR-3 expression in the uterus during pregnancy are unclear. In this study, we demonstrate that vascular remodeling in the uterus during pregnancy is regulated by FSS-induced VEGFR-3 expression. We examined the association between VEGFR-3 and FSS through in vivo and in vitro experiments. In vivo experiments revealed VEGFR-3 expression in the CD31-positive region of the uterus of pregnant mice; VEGF-C (ligand for VEGFR-3) was undetected in the uterus. These results confirmed that VEGFR-3 expression in the endometrium is independent of its ligand. In vitro studies experiments revealed that FSS induced morphological changes and increased VEGFR-3 expression in human uterine microvascular endothelial cells. Thus, VEGFR-3 activation by FSS is associated with vascular remodeling to allow increased blood flow in the uterus during pregnancy. PMID- 28849194 TI - Effects of hydrogen sulfide on inducible nitric oxide synthase activity and expression of cardiomyocytes in diabetic rats. AB - The aim of the present study was to investigate the effects of hydrogen sulfide (H2S) on the activity and expression of inducible nitric oxide synthase (iNOS) in the myocardial tissue of type 1 diabetic rats. Rats were divided randomly into four groups: Normal control (NC), diabetes mellitus (DM), DM+DL-Proparglygylcine (DM+PAG) and DM+sodium hydrosulfide (DM+NaHS) groups. Type 1 diabetes was induced in the respective groups by a single intraperitoneal (i.p.) injection of streptozotocin. Rats in the DM+PAG and DM+NaHS groups were injected with PAG and NaHS (i.p.) once a day, respectively. The level of fasting blood glucose (FBG), the heart-weight to body-weight (HW/BW) ratio and the ventricular hemodynamic parameters were measured. The activities of serum total NOS (tNOS), iNOS, lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase MB isozyme (CK-MB), and the content of nitric oxide (NO) were detected. The contents of myocardial malondialdehyde (MDA) and NO, and the activities of superoxide dismutase (SOD), tNOS and iNOS were determined. The myocardial tissue was examined for histological and ultrastructural alterations. The expression level of iNOS at the transcriptional and translational levels in the myocardial tissue was estimated. The level of FBG was increased in the DM group compared with the NC group, verifying the diabetic condition of the rats. The function of the left ventricle, the myocardial histological alterations and ultrastructures were damaged in the DM group. The DM group additionally demonstrated an increase in the serum NO content and tNOS, iNOS, LDH, CK and CK-MB activities. The myocardial MDA, NO content and tNOS levels were additionally increased in this group. The iNOS activity was increased significantly whereas the myocardial SOD activity was decreased. The increase in the iNOS activity was supported by an enhanced expression level of myocardial iNOS mRNA and protein in the DM group. In the DM+PAG group, in the absence of H2S, the dysfunction of the left ventricle and the oxidative stress injury were increased compared with the DM group. The activity and the expression of tNOS and iNOS were increased significantly. However, the rats in the DM+PAG group demonstrated the opposite effects. In conclusion, H2S exhibits a protective effect on the myocardium in type 1 diabetic rats, which may be associated with the suppression of iNOS activity and expression, a decrease in the NO content and the inhibition of oxidative stress injury. PMID- 28849195 TI - Genome-wide DNA methylation analysis in permanent atrial fibrillation. AB - Atrial fibrillation (AF) is a highly heterogeneous genetic disease; however, the pathogenesis of AF cannot be explained by genetic variants alone. DNA methylation is a heritable method of gene expression regulation, and may be a potential regulatory mechanism in AF. Therefore, in the present study, the genome-wide DNA methylation pattern in cells derived from the left atrium of patients with permanent AF (n=7) was compared with that of healthy heart donors (n=4) with a normal sinus rhythm (SR). Enriched biological functions of the differentially methylated genes were assessed. Integrated analysis of genome-wide methylation and mRNA expression profiles was performed, and reverse transcription quantitative-polymerase chain reaction (RT-qPCR) was used to determine the expression levels of four selected genes. A total of 417 differentially methylated CpG sites were identified in the fibrillating atrium (P<0.05; |beta|>0.17); the majority of which were located in gene-body and intergenic regions outside of CpG islands. Aberrantly methylated genes participated in the activation of inflammation, sodium and potassium ion transport, fibrosis and the reduction of lipid metabolism. Hypermethylation in the AF susceptible loci, paired-like homeodomain transcription factor 2 (chromosome 4q25) and coiled-coil domain containing 141 (chromosome 2q31), as well as hypomethylation in the calcium voltage-gated channel subunit alpha1C (chromosome 12p13) locus, were identified in all patients with AF. Of the 420 upregulated and 567 downregulated genes previously identified in patients with AF relative to those with normal SR (fold-change >2.0; P<=0.05), 12 genes were hypomethylated and eight genes were hypermethylated in each group, respectively (|beta|>0.2: P<0.05). RT-qPCR analysis of four of these genes supported the modulatory effect of DNA methylation on gene expression. These results suggest that DNA methylation mediated regulation of gene expression may serve an important role in AF pathogenesis, and several susceptible AF CpG loci were identified which may be involved in the initiation of AF. PMID- 28849196 TI - EGF-induced urokinase plasminogen activator receptor promotes epithelial to mesenchymal transition in human gastric cancer cells. AB - Epidermal growth factor (EGF) signaling has been shown to induce epithelial to mesenchymal transition (EMT) in many types of cancer cells. However, the molecular mechanism of EGF-induced EMT in gastric cancer remains largely unknown. In the present study, we found that human gastric cancer cell lines SGC-7901 and BGC-823 underwent EMT phenotypic changes upon exposure to EGF. The induction of EMT was consistent with aggressive characteristics such as increased cell migration, invasion and clonogenic growth. Additionally, EGF stimulation also led to the upregulation of urokinase plasminogen activator receptor (uPAR) both at mRNA and protein levels. Knockdown of uPAR by siRNA significantly attenuated EMT induction by EGF in SGC-7901 and BGC-823 cells. Furthermore, EGF increased ERK1/2 activity and blocking ERK1/2 signaling with its inhibitor, U0126, markedly inhibited EGF-induced uPAR expression and consequently EMT. Collectively, the present study demonstrated that EGF induced aggressiveness of gastric cancer cells by activating EMT, which involved the activation of the ERK1/2 pathway and, subsequently, uPAR expression. PMID- 28849197 TI - Dioscin enhances osteoblastic cell differentiation and proliferation by inhibiting cell autophagy via the ASPP2/NF-kappabeta pathway. AB - Dioscin, a typical steroid saponin, has been reported to promote osteoblastic cell differentiation. However, the underling mechanisms remain to be elucidated. In the present study, it was identified that dioscin (0.5, 1, 5, 10 and 25 ug/ml) promoted MC3T3-E1 cell proliferation and differentiation in a dose-dependent manner. Western blot analysis showed that dioscin regulated autophagy-associated protein expression in MC3T3-E1 cells; it promoted the expression of apoptosis stimulated protein of p53-2 (ASPP2), and inhibited the expression of nuclear factor (NF)-kappabeta and microtubule-associated protein 1 light chain 3beta, in a concentration-dependent manner. Caffeic acid phenethyl ester (CAPE) was used to inhibit the activation of NF-kappaB and examine the effect of the ASPP2/NF kappabeta pathway on osteoblastic cell differentiation, proliferation and autophagy. It was identified that CAPE reversed the regulation of dioscin on osteoblastic cell differentiation, proliferation and autophagy. In conclusion, the present study revealed that dioscin promoted osteoblast proliferation and differentiation by inhibiting cell autophagy via the ASPP2/NF-kappabeta pathway. These results are the first, to the best of our knowledge, to reveal the involvement of autophagy in the effects of dioscin on the prevention and therapy of osteoporosis. PMID- 28849199 TI - Upregulation of ADAMTS-7 and downregulation of COMP are associated with aortic aneurysm. AB - Aortic aneurysm (AA) remains a fatal condition with high rates of morbidity and mortality, and the associated underlying mechanism influencing its pathology remains to be elucidated. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-7 has previously been demonstrated to be involved in the pathogenesis of vascular atherosclerosis via degradation of cartilage oligomeric matrix protein (COMP). The ADAMTS-7/COMP pathway may therefore act as a potential therapeutic target for vascular disorders. To the best of the author's knowledge, the present study aimed to investigate for the first time, the expression of ADAMTS-7 and COMP in human AA. Human aortic aneurysm samples were collected from patients with AA (n=24), and ascending aorta control samples were harvested from dilated cardiomyopathy patients who underwent heart transplantation (n=18). Expression levels of ADAMTS-7 and matrix metalloproteinase-9 were significantly increased in the AA group, as detected by immunohistochemistry (P<0.05). The COMP protein level was markedly decreased in the AA group when compared with the control group, as demonstrated via immunohistochemistry and western blot analysis (P<0.05). The findings suggest that upregulation of ADAMTS-7 and downregulation of COMP are associated with induction of human AA. ADAMTS-7/COMP pathway may provide therefore act as a potential therapeutic target in human AA for efficient, optimal treatment interventions in the future. PMID- 28849198 TI - Staphylococcus aureus Protein A induces osteoclastogenesis via the NF-kappaB signaling pathway. AB - Staphylococcus aureus (S. aureus) is the most common organism causing osteomyelitis, and Staphylococcus aureus protein A (SpA) is an important virulence factor anchored in its cell wall. However, the precise mechanisms underlying the bone loss caused by SpA have not been well understood. The present study aimed to investigate the effect of SpA on osteoclast differentiation, and the probable mechanism was investigated. Raw264.7 cells were treated with SpA in the absence or presence of receptor-activated (NF)-kappaB ligand for 5 days, and morphological and biochemical assays were used to assess osteoclastogenesis and explore the underlying mechanisms. Data demonstrated that SpA induced osteoclast differentiation and promoted bone resorption in a dose-dependent manner in the absence or presence of RANKL. In addition, the expression of osteoclast-specific genes, such as the tartrate resistant acid phosphatase, matrix metalloproteinase 9, cathepsin K, calcitonin receptors and d2 isoform of the vacuolar ATPase Vo domain, were enhanced by SpA. Furthermore, the SpA-induced osteoclast differentiation was associated with the degradation of inhibitor of kappaB-alpha, phosphorylation of NF-kappaB p65 and increased expression of nuclear factor of activated T-cells. However, by treatment with JSH-23, an NF-kappaB inhibitor, the formation of osteoclast-like cells and resorption pits was significantly reduced, and the expression of osteoclast-specific genes was also inhibited. Collectively, in the present study SpA induced osteoclast differentiation, promoted bone resorption, and the NF-kappaB signaling pathway was involved in this process. PMID- 28849200 TI - Individualized drug screening based on next generation sequencing and patient derived xenograft model for pancreatic cancer with bone metastasis. AB - The efficacy of traditional chemoradiotherapies for pancreatic cancer remains limited, and no effective targeted therapies or screening tests are currently available. Therefore more individualized drug screening is warranted for the clinical treatment of pancreatic cancer. A patient-derived xenograft (PDX) model of pancreatic cancer bone metastasis was established, and next-generation sequencing (NGS) was used to investigate the molecular characteristics of the cancer and screen for potential drugs. Immunohistochemical analysis was performed to validate that the PDX retained the molecular characteristics from the patient. Using NGS technology, 13 pancreatic-cancer-associated polymorphisms/mutations were identified out of 416 genes sequenced. Based on the sequencing results and associated literatures, AZD6244, a highly selective inhibitor against mitogen activated protein kinase kinase 1 (MEK1), was chosen as a potential therapy. AZD6244, a highly selective MEK1 inhibitor, was evaluated as effective for the pancreatic cancer PDX model, and thus may provide potential efficacy in the clinical treatment of the patient with pancreatic cancer investigated in the present study. The feasibility of the novel NGS-PDX based drug-screening pattern was demonstrated, and has a potential to improve individua-lized treatment for cancer. PMID- 28849201 TI - Autophagy may play an important role in varicocele. AB - The present study aimed to determine the expression of autophagy and investigate whether the hypoxia-inducible factor 1alpha (HIF-1alpha)/BCL2 interacting protein (BNIP3)/Beclin-1 autophagy signaling pathway serves an important role in activating autophagy in varicocele (VC) rat testes cells. Furthermore, the current study aimed to explain the possible association between autophagy and apoptosis. A total of 48 adult male Sprague Dawley rats were divided into group A (control), group B (VC 15-day), group C (VC 30-day) and group D (VC 45-day), with 12 rats in each group. The rats in group A did not receive any interventions, and in groups B, C, and D the VC model was established simultaneously. At 0, 15, 30, and 45 days, an orchidectomy on the left testes was performed in groups A-D, each on its respective day. Transmission electron microscopy was used to investigate the expression of autophagy. Compared with groups A and B, it was demonstrated that the expression of autophagy in groups C, and D was significantly increased. Hematoxylin and eosin staining revealed that as the rats survived VC longer, the testicular tissue damage became more serious. Furthermore, the Johnson score revealed that VC impaired the spermeiogenesis function of the male rats. Additionally, it was demonstrated that the apoptosis index of the semini-ferous epithelia cells in VC rat testes increased over time, as measured using TUNEL staining. Immunohistochemical analysis revealed that as the VC was prolonged, the expression of HIF-1alpha gradually increased while the expression of (apoptosis regulator Bcl-2) Bcl-2 gradually decreased. Furthermore, western blot analysis revealed that the protein expression of Bcl-2 decreased and apoptosis regulator Bax increased. Furthermore, HIF-1alpha, BNIP3, Beclin1 and microtubule associated protein 1 light chain 3 alpha (LC3)II/LC3I expression gradually increased. However, significant increases in Beclin 1 and LC3II/LC3I were only observed between the day 0 and day 30 groups. In addition, the expression of p62 significantly increased between day 0 and day 15, but gradually decreased between day 15 and day 45. The results of the present study revealed that VC can lead to testicular tissue hypoxia, and that the HIF-1alpha/BNIP3/Beclin1 autophagy signaling pathway may upregulate autophagy in VC rats testes. Thus, the association between autophagy and apoptosis may serve an important role in male infertility caused by VC. PMID- 28849202 TI - Quercetin alleviates generalized hyperalgesia in mice with induced adenomyosis. AB - Adenomyosis is a common gynecologic disorder characterized by the presence of endometrial glands and stroma within the myometrium. The present study investigated the effect of quercetin in neonatal Imprinting Control Region mice with tamoxifen-induced adenomyosis. The body weight and hotplate response latency of all mice was examined at 4, 8, 12 and 16 weeks after birth. The mice dosed with tamoxifen were divided into four groups: high- or low-quercetin group, valproic acid (VPA) group and untreated group. The group of mice that were neonatally administrated with the solvent only (no tamoxifen), received no treatment and served as a blank control group. After 3 weeks of drug treatment, the potential ability of quercetin to improve the generalized hyperalgesia in mice with induced adenomyosis was evaluated by determining the body weight, pain modulation, examining the myometrial infiltration by histology examination of the uterus and detecting the expression of transient receptor potential cation channel subfamily V member 1 (Trpv-1), phospho (p)-p38 mitogen activated protein kinase p-extracellular signal-regulated kinase (p-ERK) in DRG neurons via immunohistochemistry. The results demonstrated that treatment with quercetin improved the generalized hyperalgesia by extending the hotplate response latency, reduced myometrial infiltration and decreased the expression levels Trpv-1, p-p38 and p-ERK in dorsal root ganglion neurons. The results indicated that quercetin decreases the incidence of hyperalgesia in mice with tamoxifen-induced adenomyosis, and the potential mechanism is through reduced central sensitization, which may be a promising treatment for adenomyosis. PMID- 28849203 TI - siRNA-mediated knockdown of T-bet and RORgammat contributes to decreased inflammation in pre-eclampsia. AB - Abnormal immune response resulting from disordered T helper (Th)1/Th2 and Th17/regulatory T cells (Treg) cytokine expression has been demonstrated to serve an important role in the pathogenesis of preeclampsia (PE). However, the role of transcription factors regulating Th cell differentiation contributing to PE remain unclear. To determine whether a decrease in the expression of the T cell lineage transcription factor T-bet can restore immune balance and alleviate the systemic inflammatory response present in PE, 30 patients diagnosed with PE were assessed and compared with healthy pregnant controls. The expression of the transcription factors T-bet and retinoic acid receptor-related orphan receptor (ROR)gammat were increased in the peripheral blood mononuclear cells of PE patients compared with controls, consistent with the presence of abnormally high T-bet:GATA3 and RORgammat:forkhead box (FOX) P3 ratios. The present study additionally identified a high-efficiency, specific small interfering (si)RNA that can downregulate RORgammat and T-bet mRNA levels and inhibit protein expression. This effective siRNA was transfected into activated CD4+ T cells derived from patients with PE to observe the changes to transcription factor expression and attempt to elucidate the regulatory mechanism of T cell subsets. It was identified that knockdown of RORgammat induced increased expression of FOXP3 and that the ratios of RORgammat:FOXP3 and interleukin (IL)-17A:IL-10 were subsequently decreased. The results suggested that siRNA-mediated knockdown of T bet regulated the immune balance of Th17/Tregs via changes to RORgammat and FOXP3. When siRNA against RORgammat and T-bet were used in combination, a stronger ability to regulate immune balance was observed. These results imply that Th1- and Th17-type immunity is dominant in PE and that the siRNA-mediated knockdown of certain Th1 and Th17 cell transcription factors may be an effective therapeutic target for promoting immune balance in CD4+ T cell subgroups and ameliorating local and generalized inflammation in PE. PMID- 28849204 TI - Comprehensive bioinformatics analysis of the mRNA profile of PLCE1 knockdown in esophageal squamous cell carcinoma. AB - The authors previously reported that Phospholipase C epsilon 1 (PLCE1) exacerbated esophageal squamous cell carcinoma (ESCC), however, the underlying mechanism remains to be fully elucidated. The present study aimed to identify key differentially expressed genes (DEGs) and signaling pathways regulated by PLCE1 in ESCC. EC9706 and Eca109 cell lines were transfected with the specific small interfering (si) RNA of PLCE1, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to detect the expression levels of PLCE1, and subsequently, mRNA array and multiple bioinformatics analysis were conducted. RT-qPCR was used to verify gene expression array results. The findings of the present study indicated that PLCE1 mRNA and protein expression were significantly suppressed (P<0.05) in the PLCE1 siRNA-transfected cells. In addition, a total of 223 DEGs with >2-fold alterations were screened between the PLCE1 siRNA-treated cells, including 168 upregulated and 53 downregulated DEGs. In particular, inflammation or immune associated molecules, including Toll-like receptor (TLR)-4 interleukin-6, -8 and chemokine C-X-C motif ligand 2 were significantly increased following PLCE1 knockdown. Furthermore, Gene Ontology enrichment revealed terms associated with cell proliferation, differentiation, apoptosis, signal transduction, invasion and metastasis, which may potentially be associated with PLCE1 function. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated 46 pathways were disturbed by DEGs, including focal adhesion, mitogen activated protein kinase, TLR, p53 and janus kinase/signal transducer and activator of transcription signaling pathways. The RT-qPCR results for validation of the selected DEGs were consistent with that of the microarray data. Overall, the results of the multiple bioinformatic analysis contributes to a systematic understanding of the roles of PLCE1 in ESCC. PMID- 28849205 TI - Modulation of the immune response in rheumatoid arthritis with strategically released rapamycin. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is associated with symptoms, including synovial membrane inflammatory pain, joint synovitis and stiffness. However, there are no effective methods available to cure this disease. In the present study, rapamycin was used to modulate immunity in RA. To limit the cytotoxicity of rapamycin, rapamycin was loaded into well-characterized biocompatible nanoparticles. In vitro, rapamycin particles downregulated the activation of dendritic cell surface markers, including CD80+ and CD40+, upon interacting with macrophages. The rapamycin particles reduced the secretion of inflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF) and IL-1beta, which are characteristic of RA. In vivo, the rapamycin particles decreased the symptoms of RA in mice, and the production of inflammatory cytokines was associated with the occurrence of RA. The present study partially revealed the interactions between rapamycin and two types of immune cell in RA disease, and may potentially offer a solution to improve the treatment of RA. PMID- 28849206 TI - Maternal diabetes impairs the initiation of meiosis in murine female germ cells. AB - Gestational diabetes mellitus (GDM) is characterized by an initial diagnosis of glucose intolerance during pregnancy. There is increasing evidence supporting the association between GDM and the inhibited development of several organs in offspring. In the present study, a murine GDM model was established in mice by intraperitoneal injection of streptozotocin to evaluate the effect of maternal diabetes on the initiation of meiosis in female germ cells of offspring. The effect of GDM on the initiation of meiosis in the offspring was evaluated by reverse transcription-quantitative polymerase chain reaction, flow cytometry and hematoxylin and eosin staining. The results showed that, compared with the control group, fetal ovary growth was inhibited, the expression levels of meiosis specific genes, stimulated by retinoic acid gene 8, synaptonemal complex protein, and DNA meiotic recombinase were inhibited, and the number of primordial/primary follicles was reduced in the GDM group. These may have been induced by an increase of apoptosis and inhibition of growth, as the mRNA levels of p21, a vital G1 cell cycle inhibitor, and apoptotic genes were upregulated, whereas the expression levels of genes important in folliculogenesis were decreased in the GDM group. In conclusion, the data obtained in the present study suggested that maternal diabetes may impair the initiation of meiosis and ovarian growth via growth inhibition, cell cycle arrest and the induction of apoptosis. PMID- 28849207 TI - Tanshinone IIA induces apoptosis via inhibition of Wnt/beta-catenin/MGMT signaling in AtT-20 cells. AB - A strategy to suppress the expression of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) by inhibition of Wnt/beta-catenin signaling may be useful as a novel treatment for pituitary adenoma. Previous studies have reported that Tanshinone IIA (TSA), a major quinone compound isolated from Salvia miltiorrhiza, had antitumor effects. However, whether TSA has antitumor effects against pituitary adenoma and whether the mechanisms are associated with the Wnt/beta-catenin/MGMT pathway remains to be clarified. In the present study, TSA treatment caused apoptosis in AtT-20 cells in a concentration-dependent manner, as demonstrated by cell viability reduction, phophatidylserine externalization detected by Annexin V staining and mitochondrial membrane potential disruption detected by JC-1 staining, which were associated with activation of caspase-3 and DNA fragmentation detected by TUNEL in AtT-20 cells. T-cell factor (TCF)-lymphoid enhancing factor (LEF) reporter activity was determined by dual luciferase reporter assay and the interaction between beta-catenin and TCF-4 were detected using a co-immunoprecipitation kit. The results indicated TSA treatment increased beta-catenin phosphorylation, inhibited beta-catenin nuclear translocation, reduced beta-catenin/TCF-4 complex formation and TCF-LEF luciferase reporter activity, and subsequently reduced the expression of cyclin D1 and MGMT. Notably, overexpression of MGMT in beta-catenin knock down AtT-20 cells abrogated the TSA mediated effects in AtT-20 cells. In conclusion, TSA induced apoptosis via inhibition of Wnt/beta-catenin-dependent MGMT expression, which may provide novel insights into the understanding of the mechanism of the antitumor effects of Salvia miltiorrhiza. PMID- 28849208 TI - MicroRNA-320a inhibition decreases insulin-induced KGN cell proliferation and apoptosis by targeting PCGF1. AB - MicroRNAs (miRNAs) are widely involved in regulation of cellular processes of polycystic ovary syndrome (PCOS). However, the function of miR-320a in PCOS remains unclear. The present study aimed to explore the effect of miR-320a on PCOS cell proliferation and apoptosis following treatment with insulin, and to clarify the underlying mechanism. PCOS tissues and corresponding normal tissues were collected from 16 female patients with PCOS. KGN cells were pre-treated with insulin, and KGN cells were transfected with ASO-miR-320a, miR-320a mimics and polycomb group ring finger 1 (PCGF1) overexpression plasmids. Expressions of miR 320a and PCGF1 were detected using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Dual-Luciferase reporter assays were performed to investigate the target gene of miR-320a. MTS, colony formation and flow cytometry assays were performed to determine cell viability, colony formation, and apoptosis, respectively. Furthermore, mRNA and protein expression levels of B-cell lymphoma 2 apoptosis regulator (Bcl-2) and Bcl-2 associated protein X apoptosis regulator (Bax) were examined using RT-qPCR and western blotting. The results demonstrated that miR-320a expression was significantly increased in PCOS tissues compared with normal tissues. Moreover, miR-320a was upregulated in insulin-induced cells in a dose-dependent manner. Inhibition of miR-320a suppressed insulin-induced cell viability and colony formation, and promoted apoptosis. Luciferase reporter assays demonstrated that PCGF1 was a target of miR-320a. Additionally, PCGF1 overexpression inhibited cell viability and colony formation and promoted apoptosis. Additionally, the mRNA and protein levels of Bcl-2 were inhibited by miR-320a suppression and PCGF1 overexpression, while Bax expression was promoted by them in insulin-induced cells. The results of the present study demonstrated that miR-320a inhibition decreased insulin induced KGN cell proliferation and apoptosis by targeting PCGF1. These data indicated that miR-320a may serve as a potential diagnostic biomarker for PCOS. PMID- 28849209 TI - Chemotherapy enhances programmed cell death 1/ligand 1 expression via TGF-beta induced epithelial mesenchymal transition in non-small cell lung cancer. AB - In cancer immunology, the programmed cell death 1-programmed cell death 1/ligand 1 (PD-1/PD-L1) pathway plays a major role. Anti-PD-1 and anti-PD-L1 antibodies provide reliable immunotherapy when given as treatment for various types of malignancy including lung cancer. PD-L1 expression in cancer cells has been reported to be a predictive factor for the therapeutic effects of immunotherapy. However, the mechanism of PD-L1 expression remains unclear. Another key process in cancer progression is epithelial-mesenchymal transition (EMT). In the present study, we investigated the mechanism of PD-L1 expression as well as changes in its expression during the EMT process in non-small cell lung cancer (NSCLC). In this study, A549 cells underwent EMT by treatment with TGF-beta or chemotherapeutic agents and then PD-L1 expression was evaluated. The alterations of PD-L1 expression was also examined during the reverse EMT process; mesenchymal epithelial transition (MET). The relationship between for PD-L1 expression and EMT status in clinical specimens with NSCLC after induction chemotherapy were analyzed by immunohistochemical staining. We found that PD-L1 expression was upregulated following TGF-beta induction; in contrast, it was downregulated by TGF-beta receptor-kinase inhibitors and the MET process. Furthermore, chemo treatment increased TGF-beta expression and enhances PD-L1 expression via autocrine TGF-beta induced EMT. Analysis of clinical samples revealed a significant relationship between PD-L1 expression and EMT status (P<0.05). In conclusion, our results suggest that PD-L1 expression is regulated by TGF-beta induced EMT and enhanced by chemo-treatment via the chemo-induced TGF-beta signaling. The anti-PD-1/PD-L1 blockade may provide more effective anticancer activities in combination with chemotherapy in NSCLC. PMID- 28849210 TI - Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities. AB - The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent with high tumor-selective cytotoxicity. The congenital and acquired resistance of some cancer types including malignant melanoma and osteosarcoma impede the current TRAIL therapy of these cancers. Since fine tuning of the intracellular Ca2+ level is essential for cell function and survival, Ca2+ dynamics could be a promising target for cancer treatment. Recently, we demonstrated that mitochondrial Ca2+ removal increased TRAIL efficacy toward malignant melanoma and osteosarcoma cells. Here we report that mitochondrial Ca2+ overload leads to tumor-selective sensitization to TRAIL cytotoxicity. Treatment with the mitochondrial Na+/Ca2+ exchanger inhibitor CGP 37157 and oxidative phosphorylation inhibitor antimycin A and FCCP resulted in a rapid and persistent mitochondrial Ca2+ rise. These agents also increased TRAIL sensitivity in a tumor-selective manner with a switching from apoptosis to a nonapoptotic cell death. Moreover, we found that mitochondrial Ca2+ overload led to increased mitochondrial fragmentation, while mitochondrial Ca2+ removal resulted in mitochondrial hyperfusion. Regardless of their reciprocal actions on the mitochondrial dynamics, both interventions commonly exacerbated TRAIL-induced mitochondrial network abnormalities. These results expand our previous study and suggest that an appropriate level of mitochondrial Ca2+ is essential for maintaining the mitochondrial dynamics and the survival of these cells. Thus, disturbing mitochondrial Ca2+ homeostasis may serve as a promising approach to overcome the TRAIL resistance of these cancers with minimally compromising the tumor-selectivity. PMID- 28849211 TI - Endoplasmic reticulum stress induced by lipopolysaccharide is involved in the association between inflammation and autophagy in INS-1 cells. AB - Type 2 diabetes is a chronic inflammatory disease. Autophagy, the dynamic process of lysosomal degradation of damaged organelles and proteins, may protect beta cells from destruction by inflammation in type 2 diabetes. The present study investigated the role of autophagy, inflammation and endoplasmic reticulum (ER) stress in type 2 diabetes. INS-1 cells were incubated with lipopolysaccharide. The chemical chaperone 4-phenylbutyric acid was used to inhibit ER stress, and 3 methyadenine (3-MA) was used to inhibit autophagy. Apoptosis was detected by flow cytometry and cell proliferation using Cell Counting kit-8 solution. Light chain 3B, interleukin (IL) 1beta, caspase-1 and C/EBP homologous protein production were assessed by western blotting, and rat activating transcription factor 4 and rat binding immunoglobulin heavy chain protein gene expression were determined by real-time reverse transcription-polymerase chain reaction. The results showed that inhibiting autophagy with 3-MA unexpectedly contributed to cell death in beta-cells. This response was associated with an increase in inflammatory cytokines, including IL1beta and caspase-1. Inhibiting ER stress with 4 phenylbutyric acid led to a decrease in cell apoptosis. These results showed that autophagy may have a protective effect by reducing inflammatory cytokines in beta cells. In addition, the inositol-requiring enzyme 1 pathway mediated the ER stress associated with autophagy and inflammatory cytokines (IL1beta and caspase 1). Therefore, inflammatory cytokines may be critical signalling nodes, which are associated with ER stress-mediated beta-cell death. PMID- 28849212 TI - Jueming prescription and its ingredients, semen cassiae and Rhizoma Curcumae Longae, stimulate lipolysis and enhance the phosphorylation of hormone-sensitive lipase in cultured rat white adipose tissue. AB - The present study aimed to investigate the effect of jueming prescription (JMP) and its ingredients, semen cassiae (SC) and Rhizoma Curcumae Longae (RCL), on lipolysis, and to examine their effect on the phosphorylation of hormone sensitive lipase (HSL) in cultured rat white adipose tissue (WAT). Retroperitoneal WAT was aseptically excised from adult male Sprague-Dawley rats, minced into uniform sections and subjected to ex vivo culture for 24 h. The tissue sections were then distributed into a 24-well culture plate and treated with normal saline (vehicle), isoproterenol (ISO), JMP, SC and RCL. Non esterified fatty acid (NEFA) and glycerol release from the intact WAT explants were determined as a measurement of lipolysis, which were measured using NEFA and glycerol assay kits. The phosphorylation of HSL at Ser563 (P-HSL S563) and 660 residues (P-HSL S660) were determined using western blot analysis. The size of the adipocytes was visualized using hematoxylin and eosin (H&E) staining. It was found that JMP-, SC- and RCL-stimulated lipolysis was responsible for increasing the release of NEFAs and glycerol from the intact WAT in vitro. In addition, JMP, SC and RCL increased the levels of P-HSL Ser563: JMP water (JW) extract, 3.52 fold; JMP ethanol (JE) extract, 3.38-fold; SC water (SW) extract, 4.60-fold; SC ethanol (SE) extract, 4.20-fold; RCL water (RW) extract, 6.98-fold; RCL ethanol (RE) extract, 6.60-fold. JMP, SC and RCL also increased the levels of P-HSL Ser660: JW extract, 3.16-fold; JE extract, 2.92-fold; SW extract, 4.57-fold; SE extract, 4.13-fold; RW extract, 5.41-fold; RE 4.96-fold) in the WAT. The RW extract had the most marked effect. The HE staining revealed that JMP, SC and RCL reduced the size of adipocytes in the WAT. In conclusion, JMP and its ingredients, SC and RC, stimulated lipolysis and reduced the size of adipocytes, possibly via the phosphorylation of HSL in cultured rat WAT. PMID- 28849213 TI - Inhibitory effects of oxymatrine on TGF-beta1-induced proliferation and abnormal differentiation in rat cardiac fibroblasts via the p38MAPK and ERK1/2 signaling pathways. AB - Interstitial fibrosis serves a causal role in the development of heart failure following acute and chronic myocardial infarction, and anti-fibrotic therapy represents a promising strategy to mitigate this pathological process. Oxymatrine (OMT) exerts a number of pharmacological effects on the cardiovascular system, but its anti-cardiovascular disease mechanisms remain unclear. The purpose of the present study was to investigate the effect of OMT administration on transforming growth factor (TGF)-beta1-induced cardiac fibroblast (CFB) proliferation and abnormal differentiation, and to elucidate the underlying mechanisms. Primary CFBs were isolated from neonatal rats and used for experimental treatments. TGF beta1 stimulation in CFBs resulted in increased proliferation, increased alpha smooth muscle actin (SMA) and type I and type III collagen expression, and increased p38 mitogen-activated protein kinase (MAPK) and extracellular signal regulated kinase (ERK)1/2 phosphorylation. Treatment with OMT and SB431542 (a TGF beta1 receptor inhibitor) attenuated the proliferation and abnormal differentiation of CFBs induced by TGF-beta1, and decreased p38MAPK and ERK1/2 phosphorylation. In addition, treatment with SB203580 (a p38MAPK inhibitor) or PD98059 (an ERK1/2 inhibitor), but not by SP600125 (a c-jun N-terminal kinase1/2/3 inhibitor), inhibited the TGF-beta1 stimulated CFB proliferation, as well as the elevation of alpha-SMA and the deposition of type I and type III collagen, suggesting that ERK1/2 and p38MAPK signaling may be important in the in the process of myocardial fibrosis. In conclusion, the present study revealed that OMT treatment inhibited CFB proliferation and the CFB-myofibroblast transition induced by TGF-beta1, at least in part through inhibition of ERK1/2 and p38MAPK signaling. PMID- 28849214 TI - Dynamic expression analysis of armc10, the homologous gene of human GPRASP2, in zebrafish embryos. AB - G protein-coupled receptor-associated sorting protein 2 (GPRASP2), a member of the GASP family, has been reported to be involved in the modulation of transcription. However, few studies have revealed the role of GPRASP2 in the development and progression of diseases. As a model organism, zebrafish have been widely used to investigate human diseases. In the present study, zebrafish armadillo repeat-containing 10 (armc10), an orthologous gene of human GPRASP2 was identified, and the spatial and temporal expression patterns of armc10 in zebrafish during early embryonic development were revealed. Bioinformatics analyses showed that ARMC10 protein sequences were highly conserved. Reverse transcription polymerase chain reaction analysis and whole mount in situ hybridization revealed that zebrafish armc10 was maternally expressed and was detected at a weak level up to 12 h post-fertilization (hpf), however, its expression increased to a high level at 24 hpf. At the 75% epiboly stage and 12 hpf, armc10 was widely expressed in the embryo. At 24 hpf, armc10 mRNA was expressed in the nervous system of the zebrafish head. When the embryo was 2 days old, the wide expression of armc10 was maintained in the nervous system of the zebrafish head. At 72 hpf, the mRNA expression of armc10 was located specifically in the otic vesicles in addition to the nervous system of the head. At 96 hpf, the expression of armc10 was maintained in the otic vesicles and the nervous system of the head. The results of the present study provided novel insight into the spatial and temporal mRNA expression of armc10 in zebrafish, for the further investigation of nervous system diseases. PMID- 28849215 TI - Long noncoding RNA colon cancer associated transcript-1 promotes the proliferation, migration and invasion of cervical cancer. AB - Previous studies have revealed significant roles for long noncoding RNA (lncRNA) in the tumorigenesis, metastasis and invasion of various tumors, including cervical cancer. The present study aimed to investigate the potential roles of lncRNA colon cancer associated transcript 1 (CCAT1) in the metastasis and invasion of cervical cancer, and to reveal the potential underlying mechanism. The mRNA expression of lncRNA CCAT1 in cervical cancer tissue was measured using the reverse transcription-quantitative polymerase chain reaction, and the association between lncRNA CCAT1 and the metastasis of cervical cancer was analyzed. The effects of lncRNA CCAT1 expression on HeLa cell viability, and migration and invasion were also analyzed by MTT and Transwell assays. The results demonstrated that lncRNA CCAT1 was highly expressed in the cervical cancer tissue compared with the adjacent normal tissue. High expression of lncRNA CCAT1 was positively associated with tumor size, and there was correlation between high lncRNA CCAT1 expression and a poor survival rate of cervical cancer. The cell viability, and migratory and invasive abilities were suppressed by silencing CCAT1. The results of the present study indicate that lncRNA CCAT1 was highly expressed in cervical cancer, and may serve important roles in promoting the progression and metastasis of cervical cancer. PMID- 28849216 TI - Angelicin inhibits liver cancer growth in vitro and in vivo. AB - Previous studies have reported that angelicin exerted antiproliferative effects on several types of tumor cell. However, to the best of our knowledge, the effects of angelicin monotherapy on human liver cancer remain to be investigated. In the present study, the antitumor activity of angelicin was evaluated in vitro and in vivo, and the molecular mechanisms underlying its effects were investigated. The present results revealed that angelicin induced apoptosis in liver cancer cells in a dose- and time-dependent manner. Furthermore, in HepG2 and Huh-7 cells, angelicin-induced apoptosis was demonstrated to be mitochondria dependent, involving the phosphatidylinositol-4,5-bisphosphate 3-kinase/RAC-alpha serine/threonine-protein kinase signaling pathway. In addition, administration of angelicin to mice bearing liver tumor xenografts inhibited tumor growth, without producing significant secondary adverse effects. These results suggested that angelicin may have potential as a novel therapeutic agent for the treatment of patients with liver cancer. PMID- 28849217 TI - IL-33 enhances glioma cell migration and invasion by upregulation of MMP2 and MMP9 via the ST2-NF-kappaB pathway. AB - As an important member of the interleukin (IL)-1 family, IL-33 plays a significant role in tumor progression. To explore this, we previously analyzed the association between IL-33 expression and the prognosis of patients with glioma. However, the function of the IL-33/ST2 axis in glioma remained unclear. In the present study, immunofluorescent staining results revealed that the expression levels of IL-33 and ST2 receptor in glioma tissues were higher than those in normal brain tissues. Invasion and migration assays demonstrated that IL 33 significantly increased glioma cell invasion and migration in vitro. Furthermore, knockdown of ST2 by siRNA attenuated the IL-33-induced increase in invasion and migration. In addition, ELISA results revealed that IL-33 upregulated the expression of matrix metalloproteinase (MMP)2 and MMP9. Western blot analysis results indicated that IL-33 stimulation increased the phosphorylation of nuclear factor-kappaB (NF-kappaB) in a time- and dose dependent manner. Moreover, silencing of the NF-kappaB pathway by BAY 11-7082 resulted in the inhibition of IL-33-induced invasion and migration, as well as the downregulation of MMP2 and MMP9 production. These findings indicate that IL 33 may be involved in the process of glioma cell invasion and migration by upregulating MMP2 and MMP9 via the ST2-NF-kappaB signaling pathway. Thus, IL-33 may be a novel therapeutic target for glioma. PMID- 28849218 TI - Knockdown of tripartite motif-59 inhibits the malignant processes in human colorectal cancer cells. AB - The aim of the present study was to clarify the clinical implication and functional role of tripartite motif-59 (TRIM59) in colorectal carcinoma (CRC) and explore the underlying mechanism of aberrant high expression of TRIM59 in cancer. We validated that TRIM59 was upregulated in CRC samples, and also demonstrated that its upregulation was associated with advanced tumor stage of CRC patients; and its high expression indicated shorter overall survival and faster recurrence. Knockdown of TRIM59 significantly inhibited cell proliferation, migration and invasion. Cell cycle analysis showed that TRIM59-depleted cells accumulated in S phase. In addition, the cell cycle regulators CDC25C, cyclin B1 and cyclin D1 were decreased by TRIM59 siRNA mediated knockdown. Furthermore, the depletion of TRIM59 promoted apoptosis in cell culture as indicated by the cleavage of caspase 3 and PARP when TRIM59 was depleted. These results suggested that TRIM59 is upregulated in human colorectal tumors compared with non-tumor tissues. The level of TRIM59 is correlated with malignant features of CRC and may serve as potential therapeutic and preventive strategies for CRC. PMID- 28849220 TI - Melatonin counteracts cobalt nanoparticle-induced cytotoxicity and genotoxicity by deactivating reactive oxygen species-dependent mechanisms in the NRK cell line. AB - Cobalt nanoparticles (CoNPs) released from metal-on-metal implants have caused considerable concern. Oxidative stress is associated with the mechanism underlying cobalt-induced cytotoxicity and genotoxicity. The indolamine melatonin exhibits protective effects against damage induced by metals. The present study investigated the in vitro effects of melatonin on the cytotoxicity and genotoxicity induced by CoNPs. CoNPs (20-50 nm in diameter) were employed in the present study. NRK rat kidney cells were exposed to various concentrations of CoNPs for different durations. The results of the current study demonstrated that CoNPs significantly increased reactive oxygen species (ROS) production and reduced cell viability, as determined by dichlorofluorescein diacetate, and Cell Counting Kit-8 and lactate dehydrogenase leakage assays, respectively. Furthermore, western blot analysis demonstrated that CoNPs led to an increase in the ratio of Bcl-2-associated X/Bcl-2, and the expression of cleaved caspase-3 was upregulated, which indicated increased apoptosis levels. Genotoxicity was detected by a comet assay, which revealed a significant induction in DNA damage, as determined by increases in the tail DNA % and olive tail moment. Phosphorylated-histone H2AX foci analyses by immunofluorescence also demonstrated that CoNPs induced DNA-double strand breaks. However, cellular treatment with melatonin reduced the effects of CoNPs on NRK cells by reducing the production of ROS. The results of the present study demonstrated that CoNPs induced cytotoxicity and genotoxicity by increasing oxidative stress, and melatonin may have pharmacological potential in protecting against the damaging effects of CoNPs following total hip arthroplasty. PMID- 28849219 TI - LAMP3 promotes the invasion of osteosarcoma cells via SPP1 signaling. AB - Osteosarcoma is the most common type of primary bone cancer in children and young adults. The prognosis of osteosarcoma is very poor when it is diagnosed with metastasis. Lysosomal-associated membrane protein 3 (LAMP3) is a tumor-specific protein induced by hypoxia, which stimulates invasion and metastasis of various cancer cells via hypoxia-inducible factor (HIF). A previous study from our group has reported that expression of LAMP3 is significantly increased in lung metastatic osteosarcoma compared with primary osteosarcoma using microarray analysis, suggesting that LAMP3 may be involved in metastatic osteosarcoma. The present study therefore aimed to investigate the role of LAMP3 in osteosarcoma metastasis. Knockdown of LAMP3 decreased the invasion of two osteosarcoma cell lines in vitro. Furthermore, knockdown of LAMP3 increased the expression of secreted phosphoprotein 1 (SPP1), cadherin 1, and keratin 19, while it decreased the expression of matrix metallopeptidase 2, collagen type III alpha 1, twist family bHLH transcription factor 1 and cadherin 2. Concurrent knockdown of SPP1 and LAMP3 attenuated the changes in gene expression profile induced by LAMP3 knockdown alone. Gene ontology and KEGG analysis demonstrated that SPP1 was involved in cell adhesion, focal adhesion, and extracellular matrix-receptor interaction. In conclusion, the present results suggest that LAMP3 may be involved in the invasion and metastasis of osteosarcoma via regulating signaling downstream of SPP1. Thus, LAMP3/SPP1 signaling may serve as a potential target in the future to prevent osteosarcoma metastasis. PMID- 28849222 TI - Identification of key mRNAs and microRNAs in the pathogenesis and progression of osteoarthritis using microarray analysis. AB - Osteoarthritis (OA) is a common type of disease affecting the joints that results from the breakdown of joint cartilage and the underlying bone; currently, its pathogenesis is still unclear. The aim of the present study was to identify key mRNAs and miRNAs involved in the pathogenesis and progression of OA using microarray analysis. The gene expression profile of GSE27492 was downloaded from the Gene Expressed Omnibus database, and included 49 arthritic mouse ankle samples collected at 6 time points (0, 1, 3, 7, 12 and 18 days) following the induction of arthritis via serum transfer. Differentially expressed genes (DEGs) were identified in ankle samples taken on days 1, 3, 7, 12 and 18 following serum transfer compared with day 0 samples, and overlapping DEGs in day 3, 7, 12 and 18 samples were identified. The Database for Annotation, Visualization and Integrated Discovery online tool was used to perform functional and pathway enrichment analyses of the overlapping DEGs. The miRWalk database was used to identify potential micro (mi) RNAs regulating the selected overlapping DEGs, and regulatory miRNA-target mRNA pairs were obtained. The Cytoscape platform was used to establish and visualize the miRNA-mRNA regulatory network. The present results revealed that 35, 103, 62 and 75 DEGs were identified in day 3, 7, 12 and 18 samples, respectively. A total of 17 overlapping DEGs were identified among the 4 sample sets, and revealed to be enriched in 14 gene ontology terms and 3 Kyoto Encyclopedia of Genes and Genomes pathways. miRWalk analysis identified 242 potential miRNA-mRNA regulatory pairs and 211 nodes were revealed to be involved in the miRNA-mRNA regulatory network. The present study identified potential genes, including C-type lectin domain family 4 member D, chemokine (C-X-C motif) ligand 1 and C-C motif chemokine ligand, and pathways, including chemokine signaling pathways, cytokine-cytokine receptor interactions and nucleotide binding oligomerization domain-like receptor signaling pathways, which may be involved in the pathogenesis and progression of OA. These findings may help elucidate the molecular mechanisms underlying OA pathophysiology, and may be useful for the development of novel therapeutic targets for the treatment of patients with OA. PMID- 28849221 TI - TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear. AB - In contrast to TP53, cancer development is rarely associated with mutations in the TP63 and TP73 genes. Recently, next generation sequencing analysis revealed that TP63 mutations are frequent, specifically in cutaneous melanomas. Cutaneous melanoma represents 4% of skin cancers but it is responsible for 80% of skin cancer related deaths. In the present study, we first determined whether all three members of the P53 family of transcription factors were found mutated in cutaneous melanomas by retrieving all TP53, TP63 and TP73 mutations from cBioPortal (http://www.cbioportal.org/). TP53 and TP63 were frequently mutated [15.0% (91/605) and 14.7% (89/605), respectively], while TP73 [1.5% (9/605)] was more rarely mutated (p<0.0001). A UV-mutation fingerprint was recognized for TP63 and TP73 genes. Then, we tried to evaluate the potential role of TP63 mutations as drivers or passengers in the tumorigenic process. In the former case, the amino acid substitutions should cause significant functional consequences on the main biochemical activity of the P63 protein, namely transactivation. The predicted effects of specific amino acid substitutions by two bioinformatics tools were rather different. Using a yeast-based functional assay, the observed hotspot mutant R379CP63 protein exhibited a substantial residual activity compared to the wild-type (>70%). This result does not support a major role of the mutant P63 protein in melanomagenesis while it is still consistent with the TP63 gene being a recorder of UV exposure. The TP63 mutation spectrum from cutaneous melanomas, when compared with that observed at the germinal level in patients affected by P63-associated diseases [ectodermal dysplasia syndromes, (EDs)], revealed significant differences. The TP63 mutations were more frequent at CpGs sites (p<0.0001) in EDs and at PyPy sites (p<0.0001) in cutaneous melanomas. The two spectra differed significantly (p<0.0001). We conclude that TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear. PMID- 28849223 TI - Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome-wide association study. AB - An exome-wide association study (EWAS) was performed to identify genetic variants, particularly low-frequency or rare coding variants with a moderate to large effect size, that confer susceptibility to atrial fibrillation in Japanese. The EWAS for atrial fibrillation was performed with 13,166 subjects (884 patients with atrial fibrillation and 12,282 controls) using an Illumina HumanExome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The association of atrial fibrillation with allele frequencies of 41,243 single nucleotide polymorphisms (SNPs) that passed quality control was examined with Fisher's exact test. Based on Bonferroni's correction, a P<1.21x10-6 was considered statistically significant. The EWAS for atrial fibrillation revealed that 122 SNPs were significantly associated with this condition. The association of the identified SNPs to atrial fibrillation was further examined by multivariable logistic regression analysis with adjustment for age, sex and the prevalence of hypertension. Eight SNPs were related (P<0.01) to atrial fibrillation, among which three polymorphisms, rs11552708 [G/A (G67R)]of TNF superfamily member 13 (TNFSF13; dominant model; P=9.36x10-9; odds ratio, 0.58), rs113710653 [C/T (E231 K)] of spermatogenesis and centriole associated 1 like (SPATC1L; dominant model; P=1.09x10-5; odds ratio, 3.27), and rs11231397 [G/C (R300T)] of solute carrier family 22 member 25 (SLC22A25; additive model; P=3.71x10-5; odds ratio, 1.77), were significantly (P<1.02x10-4) associated with this condition. The minor T allele of rs113710653 and the minor C allele of rs11231397 were risk factors for atrial fibrillation, whereas the minor A allele of rs11552708 was protective against this condition. In addition, rs77538589 [C/T (G117R)] of SALL4 exhibited a tendency to be associated with atrial fibrillation (dominant model; P=0.0002; odds ratio, 1.88), with the minor T allele representing a risk factor for this condition. TNFSF13, SPATC1L, SLC22A25 and SALL4 may thus be novel susceptibility loci for atrial fibrillation in the Japanese population. PMID- 28849224 TI - Association of a reduction of G-protein coupled receptor 30 expression and the pathogenesis of preeclampsia. AB - Preeclampsia is a pregnancy-specific disorder, which is a leading cause of maternal and perinatal mortality and morbidity. A lower increase of estrogen, compared with the increase in progesterone, is associated with pathogenesis of the disease during pregnancy. G-protein-coupled receptor 30 (GPR30) mediates the action of estrogen, however remains to be investigated in preeclampsia. The levels of GPR30 were measured in placentae from uncomplicated pregnancies and pregnancies complicated by preeclampsia using immunohistochemistry and western blotting. GPR30 expression was additionally measured in placental HTR8/SVneo cells following 17beta-estrogen (E2) treatment in normal or hypoxia-reoxygenation conditions by western blotting. In addition, the outgrowth of HTR8/SVneo cells following E2 treatment in hypoxia-reoxygenation conditions was measured. Levels of GPR30 were significantly reduced in placentae from women with preeclampsia as compared with uncomplicated pregnancies. Treatment with E2 significantly increased the expression of GPR30 in HTR8/SVneo cells, in normal and hypoxia reoxygenation conditions. Furthermore, treatment with E2 increased the outgrowth of HTR8/SVneo cells in hypoxia-reoxygenation conditions. The present study demonstrated lowered placental expression of GPR30 in preeclampsia. Estrogen treatment increases GPR30 expression in extravillous trophoblast and GPR30 may be involved in extravillous trophoblast invasion. PMID- 28849225 TI - XB130 enhances invasion and migration of human colorectal cancer cells by promoting epithelial-mesenchymal transition. AB - The expression of XB130 is associated with invasion and migration of many tumor cells, but its roles in human colorectal cancer (CRC) remains unknown. To investigate this, protein expression levels of XB130 in numerous human CRC cell lines were compared with a normal colorectal mucosa cell line by western blotting. Knockdown of XB130 using small interfering (si)RNA was performed to assess the effects on cell invasion and migration in a Transwell assay and a scratch test. Western blotting was also used to quantify the levels of proteins associated with epithelial-mesenchymal transition (EMT), including E-cadherin, vimentin, phosphorylated (p)-protein kinase B (AKT), p-forkhead homeobox type O 3a (FOXO3a) and zinc finger E-box-binding homeobox 1 (ZEB-1). The relative expression of XB130 protein was significantly higher in CRC cells compared with control cells (P<0.01). Knockdown of XB130 using siRNA significantly decreased the invasive and migratory responses of CRC cells (P<0.01). In addition, levels of E-cadherin were increased, while vimentin, p-AKT, p-FOXO3a and ZEB-1 were decreased (P<0.01). In conclusion, the present study demonstrated that the expression of XB130 is elevated in CRC cells. Loss of XB130 was associated with decreased invasion and migration of CRC cells, possibly as a result of EMT inhibition. Thus, upregulation of XB130 may underlie some of the tumorigenic events observed in human CRCs. XB130 may be a promising target for CRC therapy in humans; further mechanistic studies exploring the function of XB130 in CRC cells are warranted. PMID- 28849226 TI - Daidzein inhibits choriocarcinoma proliferation by arresting cell cycle at G1 phase through suppressing ERK pathway in vitro and in vivo. AB - Choriocarcinoma is a highly malignant tumor arising from abnormal gestational trophoblast proliferation. Although chemotherapy has dramatically improved the prognosis, there are still some patients who become drug-resistant or relapse. Daidzein has garnered interest in its antitumor activity especially in proliferation inhibition. However, few reports exist on daidzein effect in growth of choriocarcinoma. Therefore, in this study, we performed in vitro and in vivo experiment in JAR and JEG-3 to investigate the effect of daidzein in proliferation of choriocarcinoma. Daidzein inhibited cell growth in a time- and dose-dependent way. Cell cycle was arrested at G1 phase and expression of cyclin D1, c-myc, PCNA was reduced while p21 was upregulated during daidzein treatment. At the same time, the expression of p-ERK was downregulated and translocation into nuclear afterwards was also inhibited. Moreover, ERK agonist ceramide C6 abolished daidzein's effects on cell proliferation. Besides, in vivo experiment also showed daidzein's anti-proliferation function as xenografts growth was inhibited and expressions of c-myc, PCNA and p-ERK were suppressed. In conclusion, results in our study demonstrate daidzein can inhibit choriocarcinoma cell proliferation in vitro and in vivo; underlying mechanism behind the inhibitory effects may probably be suppressing ERK pathway and afterwards arresting cell cycle at G1 phase. PMID- 28849227 TI - Pomolic acid induces apoptosis and inhibits multidrug resistance protein MRP1 and migration in glioblastoma cells. AB - Glioblastoma (GBM), the most aggressive of primary brain tumors, determine short survival and poor quality of life. Therapies used for its treatment are not effective and chemotherapy failure is partially due to multidrug resistance (MDR) mechanisms present in the tumor cells. New therapeutic strategies are needed in order to improve survival in GBM. The present study investigated the activity of the pentacyclic triterpene pomolic acid (PA) in GBM. Pomolic acid decreased the viability and induced apoptosis of GBM cells as demonstrated by DNA fragmentation. It also induced uncoupling of mitochondria membrane potential and activation of caspase-3 and -9. Pomolic acid-induced apoptosis is dependent on reactive oxygen species (ROS) production as it is inhibited by anti-oxidant treatment. Pomolic acid also down-modulated the activity of the multidrug resistance associated protein 1 (MRP1) and inhibited migration of GBM cells. These results show that PA acts on several pathways of GBM drug resistance and therefore may be of potential interest for the treatment of this tumor. PMID- 28849228 TI - Clinicopathological analysis of 114 cases of typical Kaposi's sarcoma in Xinjiang Uygur autonomous region, China. AB - The present study aimed to investigate the clinicopathological features of cases of classic Kaposi's sarcoma (CKS) in Xinjiang Uygur Autonomous Region, China, and analyze its etiology and treatment. A total of 114 patients, who were clinicopathologically diagnosed with CKS at the First Affiliated Hospital of Xinjiang Medical University (Urumqi, China) between 1980 and 2015 were retrospectively analyzed. The clinicopathological features of CKS were summarized, and its demographic distribution, pathogenesis, etiology and treatment were examined. The results revealed that, among the 114 patients with CKS, 100 patients were men and 14 patients were women, with a respective ratio of 7:1. The average age of these patients was 57.5 years old, and 97 of the patients were from the Uygur Autonomous Region (85.1%). Among the 114 patients, 60 patients (52.6%) were from Southern Xinjiang, 50 patients (43.9%) were from Northern Xinjiang and four patients (3.5%) were from Eastern Xinjiang. It was found that CKS in the Uygur ethnic group of Xinjiang Uygur Autonomous Region had unique clinicopathological features. The occurrence of CKS in Xinjiang may be associated with human herpes virus 8 infection, ethnicity-based susceptibility and lifestyle. PMID- 28849230 TI - Tumor necrosis factor-alpha-induced protein-8 like 2 regulates lipopolysaccharide induced rat rheumatoid arthritis immune responses and is associated with Rac activation and interferon regulatory factor 3 phosphorylation. AB - The endogenously activated rheumatoid arthritis (RA) synovial fibroblasts (RSFs) are likely to be the key to curing the disease. RSFs express Toll-like receptors (TLRs) rendering them prone to activation by exogenous and endogenous TLR ligands, resulting in the production of chemokines and cytokines Germline deletion of tumor necrosis factor-alpha-induced protein-8 like 2 (TIPE2, also known as TNFAIP8L2) results in fatal inflammation and hypersensitivity to TLR and T cell receptor stimulation. The present study demonstrates an inverse association between TIPE2 and cytokine gene expression in RSFs following lipopolysaccharide (LPS) stimulation. Enhanced TIPE2 expression decreased Ras related C3 botulinum toxin substrate (Rac) activation and interferon regulatory factor 3 phosphorylation, and phosphoinositide 3-kinase and Rac inhibition significantly diminished LPS-induced cytokine gene expression in RSFs. In conclusion, the findings of the present study demonstrate that TIPE2 serves a negative role in activating the Rac signaling pathway and in the initiation of the immune response by decreasing the activity of proinflammatory cytokines. These results may be useful in designing novel strategies for the prevention and treatment of RA. PMID- 28849229 TI - Electroacupuncture serum inhibits TNF-alpha-mediated chondrocyte inflammation via the Ras-Raf-MEK1/2-ERK1/2 signaling pathway. AB - The Ras-Raf-mitogen-activated protein kinase kinase (MEK)1/2-extracellular signal regulated kinase (ERK)1/2 signaling pathway contributes to the release of chondral matrix-degrading enzymes and accelerates the degradation of articular cartilage. Electroacupuncture (EA) treatment has been widely used for the treatment of osteoarthritis (OA); however, the mechanism underlying the effects of EA on OA remains unclear. Therefore, the present study evaluated the anti inflammatory effects and potential underlying mechanisms of EA serum (EAS) on tumor necrosis factor (TNF)-alpha-mediated chondrocyte inflammation. A total of 30 Sprague Dawley rats were randomly divided into three groups: The blank group; experimental group I, which received 15 min of EA treatment; and experimental group II, which received 30 min of EA treatment. Subsequently, serum samples were obtained. Chondrocytes were isolated from the knee cartilage of Sprague Dawley rats, and were identified using collagen type II immunohistochemistry. TNF-alpha treated chondrocytes were used as a cell model, and subsequently the cells were treated with EAS from each group for various durations. The results demonstrated that EAS treatment significantly promoted the viability and inhibited the apoptosis of TNF-alpha-treated chondrocytes. In addition, interleukin (IL)-1beta concentration was significantly increased in the model group compared with in the control group, whereas EAS significantly reduced IL-1beta concentration in TNF alpha-treated chondrocytes. Furthermore, the protein expression levels of Ras, Raf and MEK1/2 were reduced in the EAS groups compared with in the model group. EAS also significantly inhibited the phosphorylation of ERK1/2, and the expression of downstream regulators matrix metalloproteinase (MMP)-3 and MMP-13. In conclusion, these results indicated that EAS may inhibit TNF-alpha-mediated chondrocyte inflammation via the Ras-Raf-MEK1/2-ERK1/2 signaling pathway in vitro, thus suggesting that EAS may be considered a potential therapeutic strategy for the treatment of OA. PMID- 28849231 TI - Differentiation of cardiomyocytes from amniotic fluid-derived mesenchymal stem cells by combined induction with transforming growth factor beta1 and 5 azacytidine. AB - As a novel type of seed cell, amniotic fluid-derived mesenchymal stem cells (AFMSCs) are promising for the regeneration of myocardial cells. A focus of cardiovascular regenerative medicine is to improve the efficiency of AFMSC differentiation. The present study replaced the traditional method of AFMSC differentiation with a combined induction method, in order to improve the efficiency of directional differentiation. AFMSCs were obtained from rabbit amniotic fluid samples, and western blot analysis was performed to analyze the expression of octamer-binding transcription factor 4 (OCT4), and tumorigenicity experiments were conducted. AFMSCs were divided into the following 4 groups: Induction with transforming growth factor beta1 (TGFbeta1); induction with 5 azacytidine (5Aza); induction with TGFbeta1 and 5Aza combined; and untreated controls. Reverse transcription-quantitative polymerase chain reaction was performed to analyze the expression of cardiac-specific GATA binding protein 4 (GATA4), and immunofluorescence was employed to analyze the expression of cardiac troponin T (cTnT). In addition, western blotting was performed to analyze the expression of connexin 43, and transmission electron microscopy was used to observe the ultrastructure of the differentiated cells. AFMSCs exhibited positive OCT4 expression and were not observed to induce tumor development in nude mice. The expression levels of GATA4, cTnT, and connexin 43 in the combined induction group were markedly higher when compared with the remaining groups. Transmission electron microscopy analysis revealed that differentiated cells exhibited myocardial cell characteristics. In conclusion, AFMSCs are multipotent, non tumorigenic cells that are capable of differentiating into cardiomyocyte-like cells. This combined induction method may improve the efficiency of directed differentiation. PMID- 28849232 TI - Inhibition of NOB1 by microRNA-330-5p overexpression represses cell growth of non small cell lung cancer. AB - MicroRNAs (miRNAs) play critical roles in the development and progression of various cancers, including non-small-cell lung cancer (NSCLC). Studies have suggested that miR-330-5p is involved in the progression of several cancers. However, the role of miR-330-5p in NSCLC remains unclear. We investigated the effect on and mechanism of miR-330-5p in the progression of NSCLC. We found that miR-330-5p was significantly downregulated in NSCLC tissues and cell lines as detected by real-time quantitative polymerase chain reaction (RT-qPCR). The 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), bromodeoxyuridine (BrdU), colony formation and cell cycle assays showed that overexpression of miR-330-5p markedly inhibited cell growth. Annexin V-FITC/PI and caspase-3 activity assays showed that overexpression of miR-330-5p significantly promoted cell apoptosis of NSCLC cells. Bioinformatics analysis and dual-luciferase reporter assays confirmed NIN/RPN12 binding protein 1 (NOB1) as a target gene of miR-330-5p. RT-qPCR and Western blot analysis showed that overexpression of miR-330-5p inhibited the expression of NOB1 as well as cyclin D1 and cyclin-dependent kinase 4 in NSCLC cells. Moreover, overexpression of NOB1 markedly reversed the miR-330-5p-mediated inhibitory effect on NSCLC cell growth. Correlation analysis showed that miR-330-5p expression was inversely correlated with NOB1 mRNA expression in NSCLC tissues. Taken together, our results indicate that miR-330-5p inhibits NSCLC cell growth through downregulation of NOB1 expression. Our study suggests that miR-330-5p may serve as a potential therapeutic target for the treatment of NSCLC. PMID- 28849233 TI - AKT2 is involved in the IL-17A-mediated promotion of differentiation and calcification of murine preosteoblastic MC3T3-E1 cells. AB - Interleukin (IL)-17A exhibits pleiotropic biological activities and serves a role in the progression of periodontitis. However, data describing the association between IL-17 and osteogenesis are not conclusive. It was previously demonstrated that RAC-beta serine/threonine protein kinase (AKT2)-specific knockdown in MC3T3 E1 cells weakened osteogenic effects. The role of AKT2 in the regulation of IL 17A for osteoblast differentiation and calcification remains unclear. The MTT method was adopted in the present study to assess cell proliferation; cell cycle distribution was analyzed by flow cytometry. Following osteogenic induction treatment, the involvement of phosphatidylinositol 3-kinase (PI3K) and phosphorylated-PI3K was evaluated by western blotting. The effects of IL-17A on osteogenesis-associated markers, including Runt-related transcription factor 2 (Runx-2), alkaline phosphatase (ALP) and osteocalcin (OCN) were evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. An ALP activity assay and Alizarin Red S staining were used to assess the differentiation and calcification functions. AKT2 knockdown inhibited MC3T3-E1 cell proliferation, inducing significantly increased G0/G1 cell counts, and reduced S and G2/M cell numbers. IL-17A exerted no significant effects. The protein levels of p-PI3K, gene expression levels of IL-17A, Runx-2, ALP and OCN, and relative ALP activity and calcification areas were increased in the induction group, and these effects were markedly promoted by treatment with IL-17A. AKT2 knockdown in MC3T3-E1 cells resulted in reduced IL-17A-induced differentiation and calcification, although it was not completely inhibited. The results of the present study suggested that AKT2 signaling was required for MC3T3-E1 cell proliferation. IL-17A promoted osteoblast differentiation and calcification in a partly AKT2-dependent manner in MC3T3-E1 cells in vitro, possibly reflecting compensation by other signaling pathways. The results of the present study may offer novel perspectives to guide the clinical strategy for the prevention and treatment of periodontitis. PMID- 28849235 TI - Lung cancer suppressor gene GPRC5A mediates p53 activity in non-small cell lung cancer cells in vitro. AB - Cellular tumor antigen p53 (p53) functions to maintain genomic stability and regulate cell apoptosis, while G protein-coupled receptor class C group 5 member A (GPCR5A) is a lung cancer suppressor gene whose expression is induced by retinoids. The present in vitro study assessed the effects of p53 on the regulation of GPRC5A expression and on non-small cell lung cancer (NSCLC) cells. Human NSCLC H1299 (p53-null) and A549 (wild-type p53) cell lines were subjected to p53 cDNA and small interfering (si)RNA transfection, respectively. GPRC5A expression was analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting, and cell behavior was analyzed using cell viability and apoptosis assays. The results of the present study demonstrated that knockdown of GPRC5A expression markedly upregulated tumor cell viability and reduced tumor cell apoptosis, while p53 overexpression in H1299 cells significantly increased the expression level of GPRC5A. p53 overexpression and GPRC5A induction markedly inhibited tumor cell viability and induced apoptosis, while knockdown of p53 resulted in a decrease in GPRC5A expression, inhibited tumor cell apoptosis and increased tumor cell viability. In serum-free culture conditions, GPRC5A expression was decreased in the two cell lines; this decrease was less marked in p53 cDNA-transfected H1299 cells and more marked in p53 siRNA transfected A549 cells. The results of the present study indicated that p53 antitumor activity may be mediated by GPRC5A in NSCLC cells. PMID- 28849237 TI - Overexpression of Bmi-1 promotes epithelial-mesenchymal transition in CD133+Hep G2 cells. AB - Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical factors contributing to tumor metastasis and recurrence. The BMI1 proto-oncogene (Bmi-1) promotes the development and progression of hematologic malignancies and of several types of solid tumors. The aim of the present study was to explore the mechanism by which Bmi-1 may promote invasion and migration of hepatocellular carcinoma Hep G2 cells. CD133 antigen is a transmembrane glycoprotein and regarded as a cancer stem cells marker in hepatocellular carcinoma. CD133+Hep G2 cells were enriched by magnetic-activated cell sorting and exhibited greater viability compared with CD133-Hep G2 cells, as measured by Cell Counting kit-8 assay. Then, Bmi-1 was overexpressed in CD133+Hep G2 cells by transfection with the Bmi-1/pcDNA3.1(+) expression plasmid, and overexpression was confirmed by reverse-transcription-polymerase chain reaction and western blotting. Overexpression of Bmi-1in CD133+Hep G2 cells resulted in the downregulation of E cadherin and upregulation of Vimentin at the protein level. The invasion and migration abilities of CD133+Hep G2 cells were increased in the Bmi-1/pcDNA3.1(+) transfected group, as measured by Transwell invasion and wound healing assays, respectively. In conclusion, Bmi-1 promoted invasion and migration of CD133+Hep G2 cells most likely through inducing EMT. The present findings may offer a potential novel target for the development of hepatocellular carcinoma therapies. PMID- 28849239 TI - HSP47 is associated with the prognosis of laryngeal squamous cell carcinoma by inhibiting cell viability and invasion and promoting apoptosis. AB - Heat shock protein 47 (HSP47) is a 47 kDa collagen binding protein that has a close relationship with the development and progression of tumours. However, little is known concerning the expression profile of HSP47 in laryngeal squamous cell carcinoma (LSCC) patients and there is still insufficient data concerning the underlying mechanisms. The aim of the present study was to explore the expression of HSP47 in LSCC and provide an overview of its association with tumourigenicity and clinical prognosis. The expression of HSP47 in LSCC and adjacent non-cancerous laryngeal tissues was assessed via western blotting and immunohistochemical studies. The prognostic significance of HSP47 expression was analysed using a Kaplan-Meier survival curve. To investigate the influence of HSP47 on the viability, invasion and apoptosis of a LSCC cell line, we performed an in vitro analysis with plasmid vectors and small interfering RNA (siRNA). Our results showed that HSP47 protein expression in the LSCC tissues was markedly decreased compared to that noted in the adjacent non-cancerous tissues, and low expression of HSP47 was correlated with poor prognosis in LSCC patients. Upregulation of HSP47 via plasmid vectors inhibited the proliferation, reduced the invasive ability, increased the sensitivity to cisplatin chemotherapy, promoted apoptosis, and induced the G1 phase arrest of LSCC cells in vitro. The expression of apoptosis-regulating proteins was also altered when HSP47 was upregulated, involving increased expression of cleaved caspase-7/-8/-9, PARP, and Bax and decreased expression of Bcl-2. Our present data suggest that HSP47 is an important prognostic factor and an attractive therapeutic target in LSCC due to its influence on the biological behaviour of LSCC cells. PMID- 28849236 TI - Upregulated exosomic miR-23b-3p plays regulatory roles in the progression of pancreatic cancer. AB - Pancreatic cancer (PC) is one of the most lethal malignances. Identification of biomarkers for early diagnosis of PC is a key imperative. MicroRNAs (miRNAs) have been shown to be valuable biomarkers in the context of several cancers. Exosomes refer to vesicles released by the tumor cells at the early stage of disease. Thus, detection of miRNA in exosomes can be used as a potential biomarker for PC. In this study, we profiled serum levels of miRNAs in patients with chronic pancreatitis (CP) and PC; the role of miR-23b-3p in PC progression was assessed in vitro. Additionally, we assessed, the expression of miR-23b-3p in exosomes isolated from serum samples and assessed the correlation between the expression of miR-23b-3p and carbohydrate antigen 19-9 (CA19-9). Three serum samples each were randomly selected from healthy controls (n=20), and patients with CP (n=18) and PC (n=16) for miRNA microarray profiling. The dysregulated miRNAs were confirmed using qRT-PCR. Four dysregulated miRNAs common to patients with CP and PC were identified on miRNA microarray analysis and confirmed by qRT-PCR. miR-23b 3p level was consistently higher in serum samples from PC patients as compared to those from healthy controls and CP patients (p<0.05). Overexpression of miR-23b 3p promoted proliferation, migration, and invasion capability of PC cells in vitro (p<0.05). Furthermore, miR-23b-3p was upregulated in exosomes of PC serum samples and the supernatant of pancreatic cancer cells (PANC-1), and the expression levels of miR-23b-3p were associated with those of serum CA19-9 levels. This study provides insights into the potential role of miR-23b-3p as a novel biomarker and target for treatment of PC. PMID- 28849238 TI - Endocrine therapy inhibits proliferation and migration, promotes apoptosis and suppresses survivin protein expression in colorectal cancer cells. AB - The majority of colorectal cancers (CRCs) are hormone-dependent. Thus, endocrine therapy has become an attractive strategy to treat CRC. The aim of the present study was to investigate the inhibitory effect of combined tamoxifen (TAM) plus beta-estradiol (E2) treatment on human DLD-1 CRC cells. The human DLD-1 CRC cell line was treated with different concentrations of TAM, beta-estradiol, or a combination of these two agents. Cell viability was assessed using an MTT assay, while apoptosis was detected using flow cytometry analysis. Alterations in the RNA and protein levels of the apoptosis-associated factors cyclin D1 and survivin were measured in the treated DLD-1 cells using semi-quantitative polymerase chain reaction (sqPCR) and western blot analyses. Alterations in cellular migration ability were monitored using a Transwell migration assay. Treatment with TAM, beta-estradiol and TAM plus beta-estradiol inhibited DLD-1 cell viability. The flow cytometry results revealed that these drugs promoted cell apoptosis, and the Transwell migration assay results indicated that the reduction in cell migration was greater in the TAM+E2 treatment group when compared with each treatment alone. sqPCR and western blot analysis results demonstrated that TAM, E2 and a combination of the two affected survivin expression based on the drug concentration and the treatment duration; however, they demonstrated no significant effect on cyclin D1 expression. In conclusion, treatment of DLD-1 cells with TAM, beta-estradiol, or a combination of these two drugs, inhibited cell viability and migration, promoted cell apoptosis, and reduced the mRNA and protein expression levels of survivin in a dose- and time-dependent manner. These results provide novel experimental basis for hormonal adjuvant therapy for the treatment of CRC. PMID- 28849234 TI - Sanggenon C induces apoptosis of colon cancer cells via inhibition of NO production, iNOS expression and ROS activation of the mitochondrial pathway. AB - Sanggenon C is a well-known, major active agent of the flavonoid derivative of benzopyrone with valuable biological properties, including anticancer, anti inflammatory, antimicrobial, antiviral, antithrombotic, and immune-modulatory activities. In this study, we investigated the molecular mechanisms by which sanggenon C mediated the induction of cell death in colorectal cancer cells (CRC). Treatment of colorectal cancer cells (LoVo, HT-29 and SW480) with sanggenon C (0, 5, 10, 20, 40 and 80 uM) resulted in inhibited proliferation of colon cancer cells. In addition, Sanggenon C (10, 20, 40 uM) induces apoptosis of HT-29 colon cancer cells as well as the increased ROS generation. Furthermore, treatment with sanggenon C increased the level of intracellular Ca2+ and ATP, while inhibited the nitric oxide production via inhibiting inducible nitric oxide synthase expression. This resulted in the activation of mitochondrial apoptosis pathway as evidenced by the decrease in Bcl-2 protein expression. Consistently, the anti-growth and pro-apoptosis effects of sanggenon C on xenograft colon tumor were further confirmed in vivo. Collectively, our results demonstrated sanggenon C induced apoptosis of colon cancer cells by increased reactive oxygen species generation and decreased nitric oxide production, which is associated with inhibition of inducible nitric oxide synthase expression and activation of mitochondrial apoptosis pathway. PMID- 28849240 TI - Chaetocin induces cell cycle arrest and apoptosis by regulating the ROS-mediated ASK-1/JNK signaling pathways. AB - The present study demonstrated that chaetocin, a natural small-molecule product produced by Chaetomium fungal species and a potential anticancer agent, inhibited the viability and invasive ability of the human intrahepatic cholangio-carcinoma cell line CCLP-1 in vivo and in vitro as revealed by CCK-8 and Transwell invasion assays and mouse xenograft tumor experiments. As determined using flow cytometry and intracellular ROS assays, chaetocin was found to induce cell cycle arrest and oxidative stress, leading to CCLP-1 cell apoptosis. Cell apoptosis can be initiated via different apoptotic signaling pathways under oxidative stress. As determined by western blot analysis, expression levels of the apoptosis signal regulating kinase 1 (ASK-1) signalosome and its downstream c-Jun N-terminal kinase (JNK) signaling pathway were increased under oxidative stress stimulation. These findings indicate that chaetocin arrests the cell cycle and induces apoptosis by regulating the reactive oxygen species-mediated ASK-1/JNK signaling pathways. PMID- 28849242 TI - [Retraction Note to: Histopathology reports of findings of prostate needle biopsies]. PMID- 28849241 TI - A novel chalcone-based molecule, BDP inhibits MDA-MB-231 triple-negative breast cancer cell growth by suppressing Hsp90 function. AB - Triple-negative breast cancer (TNBC) is a molecularly diverse and heterogeneous disease and the molecular heterogeneity of TNBC increases the difficulty in improving survival rates. To date, therapeutic approaches for the treatment of TNBC such as hormonal chemotherapy and trastuzumab-based therapy have been limited by the lack of target receptors such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2), emphasizing the urgent need for identifying new therapeutic options. In this regard, heat shock protein 90 (Hsp90) has emerged as an attractive therapeutic target for TNBC. Hsp90 plays a central role in regulating correct folding, stability, and function of numerous oncogenic proteins. In the present study, we evaluated the in vitro effect of a small molecule Hsp90 inhibitor, (E)-3-(2-bromo 3,4,5-trimethoxyphenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (BDP) on TNBC cell line, MDA-MB-231. This study indicated that BDP efficiently inhibited the growth of MDA-MB-231 cells in a dose- and time-dependent manner. BDP induced overall degradation of multiple oncogenic proteins including EGFR, Her2, Met, Akt, c-Raf, and Cdk4, consequently leading to apoptotic cell death. The flow cytometric analysis revealed that BDP promoted cell cycle arrest at G2/M phases. Moreover, BDP treatment attenuated the migration of MDA-MB-231 cells and impaired MMP9 activity, which are essential processes for tumor metastasis. Collectively, BDP represents a new class of Hsp90 inhibitor and shows therapeutic potential for TNBC treatment. PMID- 28849243 TI - Serum lithium levels and suicide attempts: a case-controlled comparison in lithium therapy-naive individuals. AB - BACKGROUND: Several epidemiological studies have shown the inverse association of lithium levels in drinking water and suicide rates; however, it is necessary to perform a clinical study dealing with individual patients. METHODS: We analyzed 199 patients including 31 patients with suicide attempts, 21 patients with self harm, and 147 control patients. All were transferred to a university emergency department suffering from intoxication or injury, were aged 20 or more years, and were alive at the start of the study. The exclusion criteria consisted of suffering from schizophrenia and a past or present history of lithium therapy. These exclusions were applied because it is difficult to determine whether their suicide attempt was induced by the intent to end their life or by psychotic symptoms such as auditory hallucinations, and if the patient had received lithium therapy, the association between the small amount of lithium taken from drinking water and food and serum lithium levels cannot be detected. RESULTS: There was a significant difference (p = 0.043) between the three groups whereby patients with suicide attempts had significantly lower lithium levels than control patients (p = 0.012) in males but not females. Multivariate logistic regression analysis with adjustment for age and gender revealed that patients with suicide attempts had significantly lower lithium levels than control patients (p = 0.032, odds ratio 0.228, 95% CI 0.059-0.883). LIMITATIONS: The limitations of the present study are the nature of observational research which cannot reveal a causal relationship and the relatively small number of subjects. CONCLUSIONS: The present findings suggest that higher serum lithium levels may be protective against suicide attempts in lithium therapy-naive individuals. PMID- 28849244 TI - The shape and orientation of the trochlea run more parallel to the posterior condylar line than generally believed. AB - PURPOSE: This study was set up to identify the native trochlear geometry and define its relationship with the rotational landmarks of the distal femur. METHODS: The rotational landmarks of the distal femur were analysed on CT-scans of 281 patients with end-stage knee osteoarthritis. RESULTS: The anterior trochlear line (ATL) was on average 4.3 degrees (SD 3.3 degrees ) internally rotated relative to the surgical transepicondylar axis (sTEA). The ATL was on average 2.1 degrees (SD 3.0 degrees ) internally rotated relative to the posterior condylar line (PCL). The relationship between the ATL and the sTEA was statistically different in the different coronal alignment groups (p = 0.004): 3.9 degrees (SD 3.0 degrees ) in varus knees, 4.0 degrees (SD 2.9 degrees ) in neutral knees and 5.4 degrees (SD 3.8 degrees ) in valgus knees. The lateralisation of the trochlea, represented by the distance between the perpendicular to PCL and the perpendicular to the posterior parallel line to the sTEA, was on average 2.2 mm (SD 1.8 mm). CONCLUSION: The ATL was on average 4.3 degrees (SD 3.3 degrees ) internally rotated relative to the sTEA and 2.1 degrees (SD 3.0 degrees ) internally rotated relative to the PCL. The ATL is more externally orientated in varus knees and more internally rotated in valgus knees. The trochlear groove is lateralised by only 2.2 mm when the femoral component is externally rotated. LEVEL OF EVIDENCE: III. PMID- 28849246 TI - Buccal Fat Pad: An Effective Option for Facial Reconstruction and Aesthetic Augmentation. AB - INTRODUCTION: Autogenous grafting with lipoaspirate and dermo-fat grafting are popular techniques employed by plastic surgeons for correcting small volume facial defects and contour deformities. These techniques however present certain disadvantages. In this article, we present the use of the buccal fat pad graft as an alternative method of correcting such facial deformities. PATIENTS AND METHODS: Free buccal fat pad grafting was carried out in 15 patients in our institution. All were harvested using an intraoral approach. The buccal fat pad graft was used to correct periorbital contour depressions, nasal tip deformities, as a camouflage graft over exposed silicon nasal implants and as a filler in the depression deformity after mass excision. RESULTS: All 15 patients demonstrated good contour deformity correction without a significant graft resorption up to 3 years of follow-up. There were no donor site complications. The amount used ranged from 1 to 5 cc in volume as a spacer or barrier for the moderate-sized volume defect or depression, even though more than 5 cc of fat graft could be harvested if required. CONCLUSION: In conclusion, the buccal fat pad graft represents an easy, expedient and exceptional tool for the correction of contour deformities, volume replacement or for aesthetic augmentation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28849245 TI - Impact of socioeconomic position and distance on mental health care utilization: a nationwide Danish follow-up study. AB - PURPOSE: To determine the impact of socioeconomic position (SEP) and distance to provider on outpatient mental health care utilization among incident users of antidepressants. METHOD: A nationwide register-based cohort study of 50,374 person-years. RESULTS: Persons in low SEP were more likely to have outpatient psychiatrist contacts [odds ratio (OR) 1.25; confidence interval (CI) 1.17-1.34], but less likely to consult a co-payed psychologist (OR 0.49; CI 0.46-0.53) and to get mental health service from a GP (MHS-GP) (OR 0.81; CI 0.77-0.86) compared to persons in high SEP after adjusting for socio-demographics, comorbidity and car ownership. Furthermore, persons in low SEP who had contact to any of these therapists tended to have lower rates of visits compared to those in high SEP. When distance to services increased by 5 km, the rate of visits to outpatient psychiatrist tended to decrease by 5% in the lowest income group (IRR 0.95; CI 0.94-0.95) and 1% in the highest (IRR 0.99; CI 0.99-1.00). Likewise, contact to psychologists decreased by 11% in the lowest income group (IRR 0.89; CI 0.85 0.94), whereas rate of visits did not interact. CONCLUSION: Patients in low SEP have relatively lower utilization of mental health services even when services are free at delivery; co-payment and distance to provider aggravate the disparities in utilization between patients in high SEP and patients in low SEP. PMID- 28849247 TI - The unusual cellulose utilization system of the aerobic soil bacterium Cytophaga hutchinsonii. AB - Cellulolytic microorganisms play important roles in global carbon cycling and have evolved diverse strategies to digest cellulose. Some are 'generous,' releasing soluble sugars from cellulose extracellularly to feed both themselves and their neighbors. The gliding soil bacterium Cytophaga hutchinsonii exhibits a more 'selfish' strategy. It digests crystalline cellulose using cell-associated cellulases and releases little soluble sugar outside of the cell. The mechanism of C. hutchinsonii cellulose utilization is still poorly understood. In this review, we discuss novel aspects of the C. hutchinsonii cellulolytic system. Recently developed genetic manipulation tools allowed the identification of proteins involved in C. hutchinsonii cellulose utilization. These include periplasmic and cell-surface endoglucanases and novel cellulose-binding proteins. The recently discovered type IX secretion system is needed for cellulose utilization and appears to deliver some of the cellulolytic enzymes and other proteins to the cell surface. The requirement for periplasmic endoglucanases for cellulose utilization is unusual and suggests that cello-oligomers must be imported across the outer membrane before being further digested. Cellobiohydrolases or other predicted processive cellulases that play important roles in many other cellulolytic bacteria appear to be absent in C. hutchinsonii. Cells of C. hutchinsonii attach to and glide along cellulose fibers, which may allow them to find sites most amenable to attack. A model of C. hutchinsonii cellulose utilization summarizing recent progress is proposed. PMID- 28849248 TI - Weak associations between body mass index and self-reported disability in people with unilateral anterior cruciate ligament reconstruction. AB - PURPOSE AND HYPOTHESIS: Individuals with an anterior cruciate ligament reconstruction (ACLR) are susceptible to persistent disability, weight gain and the development of knee osteoarthritis. It remains unclear whether body mass index (BMI) is a factor that influences disability following ACLR. The purpose of this study was to determine the association between BMI and self-reported disability [International Knee Documentation Committee (IKDC) Index] in individuals with a unilateral ACLR. We hypothesized that lower BMI would associate with higher IKDC. METHODS: BMI and IKDC were measured in 668 individuals with a unilateral ACLR (60.9% female, BMI 24.4 +/- 3.7 kg/m2, IKDC 84.7 +/- 11.9%). Bivariate associations were conducted between BMI and IKDC for the entire sample and selected subsets (gender, ACLR graft type and history of meniscal injury). Multiple regression analyses were used to determine the impact of potential covariates (Tegner score, age and months since ACLR) for significant bivariate associations. After accounting for covariates, there were no significant associations between BMI and IKDC when separately evaluating the cohort based on either gender or history of a concomitant meniscal injury. The odds of achieving age- and gender-matched healthy population average IKDC scores for those with low (<25) and high (>=25) BMI were determined. RESULTS: Lower BMI associated with higher IKDC (r = -0.08, P = 0.04). For the entire sample, BMI did not uniquely predict variance in IKDC (DeltaR 2 > 0.001, n.s.) after accounting for covariates. BMI uniquely predicted a significant but negligible amount of variance in IKDC in individuals with a patellar tendon autograft (DeltaR 2 = 0.015, n.s.). Individuals with low BMI demonstrated higher odds (odds ratio = 1.45; 1.05-1.99) of achieving population average IKDC scores compared to participants with high BMI. CONCLUSIONS: There was a significant but negligible correlation between lower BMI and lesser disability in individuals with unilateral ACLR and individuals who are underweight or of normal BMI demonstrated higher odds of achieving population average IKDC scores compared to overweight or obese individuals. While an overall association was found between lower BMI and lesser disability, the magnitude of the association remains negligible; therefore, BMI was not a strong clinical predictor of successful ACLR outcomes in this cohort of patients with unilateral ACLR. LEVEL OF EVIDENCE: Cross-sectional prognostic study, Level II. PMID- 28849249 TI - Protein levels of clusterin and glutathione synthetase in platelets allow for early detection of colorectal cancer. AB - Colorectal cancer (CRC) is one of the most frequent malignancies in the Western world. Early tumor detection and intervention are important determinants on CRC patient survival. During early tumor proliferation, dissemination and angiogenesis, platelets store and segregate proteins actively and selectively. Hence, the platelet proteome is a potential source of biomarkers denoting early malignancy. By comparing protein profiles of platelets between healthy volunteers (n = 12) and patients with early- (n = 7) and late-stage (n = 5) CRCs using multiplex fluorescence two-dimensional gel electrophoresis (2D-DIGE), we aimed at identifying differentially regulated proteins within platelets. By inter-group comparisons, 94 differentially expressed protein spots were detected (p < 0.05) between healthy controls and patients with early- and late-stage CRCs and revealed distinct separations between all three groups in principal component analyses. 54 proteins of interest were identified by mass spectrometry and resulted in high-ranked Ingenuity Pathway Analysis networks associated with Cellular function and maintenance, Cellular assembly and organization, Developmental disorder and Organismal injury and abnormalities (p < 0.0001 to p = 0.0495). Target proteins were validated by multiplex fluorescence-based Western blot analyses using an additional, independent cohort of platelet protein samples [healthy controls (n = 15), early-stage CRCs (n = 15), late-stage CRCs (n = 15)]. Two proteins-clusterin and glutathione synthetase (GSH-S)-featured high impact and were subsequently validated in this independent clinical cohort distinguishing healthy controls from patients with early- and late-stage CRCs. Thus, the potential of clusterin and GSH-S as platelet biomarkers for early detection of CRC could improve existing screening modalities in clinical application and should be confirmed in a prospective multicenter trial. PMID- 28849251 TI - [Syncope, transient ischemic attacks, transient global amnesia and migraine]. AB - Epileptic seizures can manifest with a variety of clinical symptoms. Depending on the dominant symptom, several differential diagnoses have to be considered. Their differentiation can be challenging, especially after the first episode. The review article summarizes the most common differential diagnoses as well as their characteristics compared to epileptic seizures, aiming at providing guidelines for their clinical differentiation. Whenever a clear diagnosis is not possible based on the patient history and clinical signs, diagnostic evaluation with, e. g. an electroencephalogram (EEG) and finally EEG video monitoring can be helpful. PMID- 28849252 TI - [Leucotomy in the early Federal Republic of Germany]. AB - Leucotomy was introduced in 1936 in Europe as a therapy for mental illness. With the end of World War II leucotomy was also introduced in the early Federal Republic of Germany. Leucotomy was applied in cases of, for example schizophrenia, depression, obsessive-compulsive disorders or even some psychopathic disorders. The operations were carried out in neurosurgical departments outside psychiatric hospitals or patients were also transferred to those which had been established in psychiatric and neurological clinics. Based on published conference reports, retrospective case reports, dissertations as well as representative samples from medical files, the use of leucotomy in West Germany until the early 1950s is presented. It becomes obvious that the introduction of leucotomy in West German post-war psychiatry was encouraged by American psychiatry and neurosurgery. PMID- 28849253 TI - Assessing impact of body mass index on risk of acute kidney injury and mortality in elderly patients undergoing hip fracture surgery. PMID- 28849250 TI - Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. AB - BACKGROUND: Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. METHODS: DNA from 667 women enrolled in the CYPTAM study (NTR1509) was genotyped (CYP2D6, CYP3A4*22, and CYP3A5*3). Tamoxifen and metabolite concentrations were measured in serum, and metabolic ratios were calculated. The effect of the CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes in addition to the CYP2D6 genotypes was examined by multiple linear regression analysis. RESULTS: CYP3A4*22 carriers reached significant higher concentrations of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen compared to non carriers, whereas a tendency toward increased endoxifen levels was observed (p = 0.088). The metabolic ratio tamoxifen/N-desmethyl-tamoxifen was significantly higher in CYP3A4*22 individuals (0.59 vs. 0.52, p < 0.001). At the same time, CYP3A4*22 genotype contributed to improving the inter-variability [R 2 of the (log-transformed) metabolic ratio tamoxifen/N-desmethyl-tamoxifen improved from 21.8 to 23.9%, p < 0.001]. CYP3A5*3 marginally improved the explained variability of the (log transformed) metabolic ratio 4-hydroxy-tamoxifen/endoxifen (from 44.9 to 46.2%, p < 0.038). CONCLUSION: Our data demonstrate that CYP3A genotype has a minor effect to explaining the variability between patients in tamoxifen metabolism and has no added value in addition to CYP2D6 genotype. PMID- 28849254 TI - Imaging characteristics of subcutaneous amyloid deposits in diabetic patients: the "insulin ball". AB - OBJECTIVE: The purpose of this study was to describe the imaging characteristics of subcutaneous amyloid deposits occurring at sites of insulin injection, commonly known as "insulin balls," in diabetic patients on ultrasound, CT, and MRI with pathologic correlation. MATERIALS AND METHODS: We retrospectively reviewed the radiographic findings of 14 lesions in 9 patients diagnosed with subcutaneous amyloid deposits at our institution between 2005-2015. Three board certified radiologists analyzed the following: (1) the shape, size, margin, morphologic characteristics, and blood flow on US using the color Doppler signal, (2) shape, size, margin, attenuation, and presence or absence of contrast enhancement on CT, and (3) shape, size, margin, signal intensity, and presence or absence of contrast enhancement on MRI. RESULTS: All lesions showed ill-defined hypovascular subcutaneous nodules with irregular margins. The median diameter of lesions was 50.4 mm on US, 46.8 mm on CT, and 51.4 mm on MRI. The internal echogenicity of subcutaneous amyloid deposits was hypoechoic and heterogeneous on US. All lesions showed isodensity compared to muscle with irregular margins and minimal contrast enhancement on CT. Both T1- and T2-weighted MR images showed low signal intensity compared with subcutaneous fat. Normal diffusion and minimal contrast enhancement were seen. CONCLUSIONS: Subcutaneous amyloid deposits which cause insulin resistance are typically ill-defined and heterogeneous hypovascular subcutaneous nodules with irregular margins on imaging that correspond to insulin injection sites. It is also characteristic that T2WI shows low intensity compared with fat on MRI, reflective of the amyloid content. PMID- 28849255 TI - [Modern coagulation management in bleeding trauma patients : Point-of-care guided administration of coagulation factor concentrates and hemostatic agents]. AB - BACKGROUND: Uncontrolled bleeding with trauma-induced coagulopathy (TIC) is still the leading cause of preventable death following severe multiple injury. Rapid diagnosis and treatment are associated with improved outcome. Early individualized goal-directed therapy and the use of point-of-care technology may be superior to empiric and ratio-based therapies with conventional blood products. MATERIALS AND METHODS: Selective review of the literature considering current recommendations/expert opinion for coagulation management in bleeding trauma patients via individualized goal-directed therapy and the use of viscoelastic point-of-care (ROTEM(r))-guided substitution of coagulation factor concentrates and hemostatic agents. RESULTS: The administration of fibrinogen concentrate in bleeding trauma patients may be considered if ROTEM(r)-FIBTEM A10 < 10 mm (FIBTEM A5 < 9 mm; FIBTEM MCF < 12 mm) and EXTEM A10 < 45 mm (EXTEM A5 < 35 mm; EXTEM MCF < 55 mm); the administration of prothrombin complex concentrate (PCC) may be considered if signs of delayed coagulation initiation (ROTEM(r) EXTEM CT > 80 s). At this stage, no concluding statement can be made for monitoring or treatment guidance with factor XIII by using point-of-care technology. Viscoelastic assays display high sensitivity and specificity for the detection of hyperfibrinolysis with subsequent administration of an antifibrinolytic. CONCLUSIONS: Individualized therapeutic concepts based upon viscoelastic point-of-care (ROTEM(r)) assays present an alternative to empiric and ratio-based therapies with conventional blood products in bleeding trauma patients and may be associated with reduced need for allogenic blood products and morbidity. PMID- 28849256 TI - A Global Assessment of Access to and Use of Medical Information: The State of Evidence-Based Surgery. AB - BACKGROUND: We aimed to assess surgeons' access to and use of medical information, as well as their training and perceptions about evidence-based medicine (EBM), in order to identify priority areas for improvement. STUDY DESIGN: An anonymous survey conducted among surgeons from the USA, Ghana, Peru, and Thailand examined access to, and use and perception of, medical literature. RESULTS: Of 307 participants, 98% reported access to "OK" or "good" internet. Fifty-one percent reported that language was a barrier to accessing needed medical information; most frequently in Peru (73%) and Thailand (64%). Access to priced full-text journals was poorest in Peru, where 54% lacked access, followed by Ghana (42%) and Thailand (32%). US respondents scored highest on the EBM knowledge test (1.4, SD 0.8), followed by Thailand (1.3, SD 0.9), Ghana (1.1, SD 0.8), and Peru (0.9, SD 0.8) (p < 0.001). Adjusted analysis revealed Ghanaians and Peruvians spent 5% and 1% more on medical information, respectively, relative to country income, than persons from other countries (p < 0.01). After adjustment, employment in a large and/or urban hospital and history of EBM training were associated with better EBM test scores, while middle-income origin and public hospital employment were associated with worse scores (p < 0.05). CONCLUSION: Language, access to priced full-text journals, and training are significant barriers to surgeons' practice of EBM globally. The way forward involves collaboration among surgical societies, publishers, hospital employers, and international policymakers in providing surgeons from all country income levels with the access and training necessary to interpret and apply medical information. PMID- 28849257 TI - A phase II study of modified docetaxel, cisplatin, and S-1 (mDCS) chemotherapy for unresectable advanced gastric cancer. AB - PURPOSE: Triplet therapy using docetaxel, cisplatin, and S-1 (DCS) against unresectable gastric cancer as previously reported by us showed high clinical efficacy, with a 87.1% total response rate; however, it also showed a high incidence of grade 3/4 toxicity. With the aim of reducing toxicities, we conducted a phase II study of modified DCS (mDCS), using a reduced dose of docetaxel, and evaluated the clinical efficacy and adverse events of this regimen. METHODS: Patients with unresectable gastric cancer received chemotherapy with S-1 (40 mg/m2 b.i.d) on days 1-14, and docetaxel (50 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks. The primary endpoint was the response rate (RR). Overall (OS) and progression-free survival (PFS), and toxicities were also evaluated. RESULTS: Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240-416 days) and median OS was 722 days (95% CI 411 days-not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%). CONCLUSION: Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential. PMID- 28849261 TI - Fentanyl buccal tablet for breakthrough cancer pain in clinical practice: results of the non-interventional prospective study ErkentNIS. AB - PURPOSE: Several patients with advanced cancer suffer from breakthrough cancer pain (BTcP). BTcP is pain exacerbation despite opioid baseline therapy. Fentanyl buccal tablet (FBT) is a rapid-onset opioid for the treatment of BTcP. The aim of this study is to document the feasibility of FBT in patients with BTcP. METHODS: The study was performed in 64 centers. Basic pain score was rated on a numeric rating scale (NRS) before and after treatment. BTcP episodes, baseline opioid therapy, and FBT dose were rated as well as individual dose titration, findings on tolerability, patient satisfaction, and safety of the drug. RESULTS: Two hundred sixty-three patients were available for analysis. Patients rated a basic pain score of 6 (range 2-10) points on an NRS and described an average of 2 to 5 BTcP episodes per day. After titration of FBT, BTcP control was achieved within 5 min in 36%, within 10 min in 68%, and within 15 min in 95%. Basic pain score decreased to a mean NRS of 4 and BTcP episodes decreased to < 1 to 3 episodes per day. BTcP control, onset of action of FBT, potency of FBT, tolerability of FBT, and safety of FBT were rated as excellent or good by 89 to 99% of the patients. Adverse drug reactions were registered in 3%. CONCLUSIONS: Treatment with FBT led to rapid pain relief and reductions in the number of BTcP episodes and patient satisfaction was rated as excellent or good. PMID- 28849258 TI - Effect of prolonged vibration to synergistic and antagonistic muscles on the rectus femoris activation during multi-joint exercises. AB - PURPOSE: Unique neuromuscular activation of the quadriceps femoris is observed during multi-joint leg extensions: lower activation of the biarticular rectus femoris (RF) than monoarticular vasti muscles. As one of the potential mechanisms for the lower RF activation, Ia afferent-mediated inhibitory connections between synergistic muscles and/or between agonist and antagonist muscles have been proposed. If this is the major factor, it is hypothesized that RF activation during multi-joint leg extensions increases after prolonged vibration to synergistic and/or antagonist muscles. This study tested the hypothesis. METHODS: Fourteen men exerted maximal voluntary isometric knee extension and flexion and performed submaximal parallel squat before and after one of the following three interventions on different days: prolonged vibration to the vastus lateralis (VL, synergist) or biceps femoris (BF, antagonist), or quiet sitting for 30 min. Muscle activations of the quadriceps femoris and hamstrings were determined using surface electromyography. RESULTS: After prolonged VL or BF vibration, VL (21%) or BF (30%) activation during isometric contractions significantly decreased, which was significantly correlated with the reduction of the maximal isometric knee extension or flexion strength. The magnitude of RF activation during squat was significantly lower than those of VL and the vastus medialis. No significant increase in RF activation during squat was observed after vibrations. CONCLUSION: The findings suggest that lower biarticular RF activation compared with the monoarticular vasti muscles during multi-joint exercises does not result from the modulation by peripheral inhibitory input from Ia afferents originating from synergist and/or antagonist muscles. PMID- 28849262 TI - The influence of radiotherapy on ceruloplasmin and transferrin in whole blood of breast cancer patients. AB - Ceruloplasmin and transferrin are proteins which play a potential role in the process of breast cancer development. These molecules contain Cu2+ (ceruloplasmin) or Fe3+ ions (transferrin) and thus constitute paramagnetic centers, which can be studied using electron paramagnetic resonance method. The aim of the study was to determine how paramagnetic centers in whole blood of breast cancer patients change under the influence of radiation therapy. Samples of whole blood were taken from 17 women with breast cancer treated with radiotherapy. The measurements were carried out at 170 K using X-band electron paramagnetic resonance (EPR) spectrometer Bruker EMX-10. Two distinct EPR lines, derived from high-spin Fe3+ in transferrin and Cu2+ from ceruloplasmin, were revealed in all frozen samples. The amplitude and integrated intensity of the EPR signal from Cu2+ in ceruloplasmin significantly decreased in all patients after the delivery of the radiation fraction. When comparing the integral intensity of the signal from Fe3+ in transferrin, three different situations were identified which are patient specific: a significant increase, an insignificant change, or a significant decrease after the irradiation. A decreased level of Cu2+ from ceruloplasmin in patients after radiotherapy means a low level of ceruloplasmin in the plasma or an increased content of reduced Cu+ ions. Differences in the integrated intensity of the EPR signal from transferrin translate directly into the amount of bound iron. The observed changes could indicate how well the organism fights against cancer and how easily it adapts to the situation of biochemical stress. PMID- 28849260 TI - Marital status and gender affect stage, tumor grade, treatment type and cancer specific mortality in T1-2 N0 M0 renal cell carcinoma. AB - PURPOSE: To examine the effect of marital status and gender on stage at diagnosis, tumor grade, treatment type and cancer specific mortality (CSM) in patients with localized renal cell carcinoma (RCC). METHODS: Within Surveillance, Epidemiology, and End Results registry (2001-2013), we identified 57,700 patients with T1-2 N0 M0 RCC. Logistic regression and competing-risks regression models tested the effect of marital status and gender on stage, tumor grade, treatment type and cancer specific mortality (CSM). RESULTS: Of all patients, 8.8, 10.6 and 14.8% were, respectively, widowed, separated/divorced and never married. The three categories accounted for 3.9, 9.0 and 14.9% of males (35,641) and for 16.7, 13.1 and 14.7% of females (22,059). Widowed (OR 1.13, p = 0.04), separated/divorced (OR 1.16, p = 0.02) and never married status (OR 1.38, p < 0.001) predisposed to higher rate of no surgical treatment. Widowed (HR 1.32, p < 0.001) and separated/divorced (HR 1.32, p < 0.001) status predisposed to higher CSM. Male gender predisposed to higher T-stage (OR 1.12, p < 0.001), higher tumor grade (OR 1.35, p < 0.001), no surgical treatment (OR 1.23, p < 0.001) and higher CSM (1.13, p = 0.01). Interaction tests between gender and marital status failed to reach independent predictor status in all analyses. CONCLUSIONS: Male patients are at higher risk of less favorable baseline characteristics. Additionally, male, widowed and separated/divorced patients exhibit worse cancer control outcomes after treatment for T1-2 N0 M0 RCC. These observations indicate the need of more focused attention to those patients prior to, as well as after treatment for localized RCC. PMID- 28849259 TI - Nrf2-peroxiredoxin I axis in polymorphous adenocarcinoma is associated with low matrix metalloproteinase 2 level. AB - Polymorphous adenocarcinoma (PAC) is a malignant epithelial neoplasm that affects almost exclusively the minor salivary glands, generally described as having a relatively good prognosis. Aberrant nuclear factor erythroid 2 (NF-E2)-related factor (Nrf2) activation in tumor cells has been associated with induction of antioxidant enzymes, such as peroxiredoxin I (Prx I) and increased matrix metalloproteinase (MMP) expression. In this context, the aim of the present study was to evaluate the expression of Nrf2 and correlate it with Prx I and MMP-2 secretion in PAC. Thirty-one cases of PAC from oral biopsies were selected and immunohistochemically analyzed for Nrf2 and Prx I. MMP-2 quantification was performed on primary cell cultures derived from PAC. Oral squamous cell carcinoma (OSCC) cell cultures were used as control. A high immunoexpression of Nrf2 was observed in both the cytoplasm and the nucleus of neoplastic cells from PAC. Nuclear staining for Nrf2 suggested its activation in the majority of the PAC cells, which was confirmed by the high expression of its target gene, Prx I. Quantification of MMP-2 secretion showed lower levels in PAC cell cultures when compared to OSCC cell cultures (p < 0.05). In conclusion, although Nrf2 overexpression has been frequently associated with high-grade malignancies, such relationship is not infallible and, in fact, the opposite may occur in low-grade tumors, such as PAC of minor salivary glands. PMID- 28849263 TI - Rare case of acute toxoplasmosis in a domestic rabbit (Oryctolagus cuniculus) in Brazil associated with the type BrIII Brazilian clonal lineage of Toxoplasma gondii. AB - Toxoplasmosis is a widely distributed disease that infects birds and mammals, including humans. Acute clinical course of toxoplasmosis is considered to be rare among domestic rabbits (Oryctolagus cuniculus). The aim of this study was to present the first report of fatal acute disease caused by Toxoplasma gondii type BrIII genotype, a typical Brazilian clonal lineage, in a domestic rabbit. T. gondii was identified in histological sections of spleen and liver tissue, and these tissues were also immunohistochemically positive for T. gondii. After the histopathological and immunohistochemical confirmation of T. gondii, the genotype of this pathogen was determined via PCR-RFLP with 11 markers (SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, Apico, and CS3) and via microsatellite (MS) analysis with 15 markers (TUB2, W35, TgMA, B18, B17, M33, IV.1, X1.1, M48, M102, N60, N82, AA, N61, and N83). This study shows that type BrIII genotype, circulating in Brazil in different hosts, can cause acute disease in a naturally infected animal host. The described case also involves the first reported occurrence of the 291 allele for the typing marker TUB2 in a type BrIII strain, emphasizing the genetic diversity of T. gondii in Brazil. PMID- 28849264 TI - Species identification of adult African blowflies (Diptera: Calliphoridae) of forensic importance. AB - Necrophagous blowflies can provide an excellent source of evidence for forensic entomologists and are also relevant to problems in public health, medicine, and animal health. However, access to useful information about these blowflies is constrained by the need to correctly identify the flies, and the poor availability of reliable, accessible identification tools is a serious obstacle to the development of forensic entomology in the majority of African countries. In response to this need, a high-quality key to the adults of all species of forensically relevant blowflies of Africa has been prepared, drawing on high quality entomological materials and modern focus-stacking photomicroscopy. This new key can be easily applied by investigators inexperienced in the taxonomy of blowflies and is made available through a highly accessible online platform. Problematic diagnostic characters used in previous keys are discussed. PMID- 28849266 TI - Validity of eleven prognostic scores with respect to intra- and extrahepatic recurrence of hepatocellular carcinoma after liver transplantation. AB - INTRODUCTION: Tumor recurrence is the most frequent cause of death after liver transplantation for hepatocellular carcinoma. We selected ten other prognostic classifications to evaluate their potential to predict the risk of recurrence after LT for HCC as compared to the Milan classification. All of the other scores have not been compared with one another in a single cohort. METHODS: Data of 147 consecutive patients transplanted at our department between 1996 and 2014 were analyzed and staged for morphological and functional scores of underlying liver disease. For long-term follow-up, we analyzed intrahepatic (within the liver +/- distant metastases) and extrahepatic (distant metastases only) recurrence separately. RESULTS AND CONCLUSIONS: The median survival time for all patients was 106 months. The 5- and 10-year observed survival rates were 61 and 43%, respectively. The observed cumulative 5- and 10-year recurrence rates were 37 and 39%, respectively, 10-year intrahepatic and extrahepatic recurrence rates were 12 and 27%, respectively. Median survival time after diagnosis of first recurrence was 7.5 (0-120) months; 2 and 18 months for all, intra- and extrahepatic recurrence, respectively. UCSF-, up to seven-, Shanghai Fudan- or Duvoux classifications can identify patients with a cumulative 10-year recurrence rate below 20%. The pre-therapeutic AFP level should be considered in addition to the geometry of the intrahepatic lesions. PMID- 28849265 TI - Safety of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection: a randomized, multicenter, prospective, phase III IOCCRC trial (IOCCRC). AB - PURPOSE: The safety and efficacy of intraoperative chemotherapy in colorectal cancer have not yet been extensively investigated. This randomized control trial was designed to compare the safety and efficacy of intraoperative chemotherapy in combination with surgical resection to those of traditional surgical resection alone. METHODS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled in this study: 341 patients were randomly assigned to the intraoperative chemotherapy, which consist of portal vein chemotherapy, intraluminal chemotherapy and intraperitoneal chemotherapy, plus surgery group, whereas 344 patients were randomized to the control group to undergo surgery alone. Eleven patients withdrew consent. RESULTS: Intraoperative chemotherapy did not increase the rate of surgical complications, and no severe chemotherapy associated side effects were observed. Four patients in each of the intraoperative chemotherapy and the control groups experienced anastomotic leakage and underwent a second operation (1.2 vs. 1.2%, P = 0.99). There were no deaths within 90 days after surgery in the chemotherapy group, whereas one patient died in the control group. Intraoperative chemotherapy did not decrease the rate of patients who received postoperative chemotherapy between the intraoperative group and control group (29.3 vs. 30.2%, P = 0.795). CONCLUSIONS: Intraoperative chemotherapy can be safely performed during colorectal surgery; however, follow-up is necessary for a better assessment of its efficacy. ClinicalTrial.gov Register Number: NCT01465451. PMID- 28849270 TI - Coronal tibiofemoral subluxation is not an independent risk factor for total knee arthroplasty in patients with moderate to severe varus-osteoarthritis: data from the "Osteoarthritis Initiative". AB - PURPOSE: Only few prognostic factors for progression of knee osteoarthritis are well established, including varus malalignment. The purpose of this study was to evaluate whether coronal tibiofemoral subluxation is a predictor for total knee arthroplasty. METHODS: Patients from the progression subcohort of the longitudinal database "Osteoarthritis Initiative" with moderate to severe osteoarthritis and varus malalignment of greater than 3 degrees were included. Patients who underwent total knee arthroplasty were matched with patients treated conservatively. Subluxation was measured on full limb length X-rays. Cox regression analysis was performed to retrospectively evaluate subluxation as a risk factor for total knee arthroplasty and check for a possible association between subluxation and pain at the beginning of the observation period in this study. RESULTS: A total of 215 patients were included. Cox regression demonstrated that varus malalignment increased the hazard to undergo surgery by 16% (HR 1.158, p = 0.008) while subluxation did not (HR 1.12, p = 0.11). Furthermore, subluxation was neither associated with poor WOMAC (OR 1.13, p = 0.194) nor KOOS (OR 1.11, p = 0.256) knee pain scores at the beginning of the observation period. CONCLUSION: The results presented show that subluxation is neither an independent risk factor for total knee arthroplasty, nor for poor pain scores. LEVEL OF EVIDENCE: III. PMID- 28849268 TI - Focal osteonecrosis in the femoral head following stable anatomic fixation of displaced femoral neck fractures. AB - INTRODUCTION: Femoral head (FH) osteonecrosis (ON) and subsequent segmental collapse is a major concern following displaced femoral neck fractures (FNF). We aimed to quantify residual perfusion to the FH following FNF and evaluate the viability of the FH overtime after surgical fixation. MATERIALS AND METHODS: Twenty-three patients with FNF underwent dynamic contrast-enhanced (DCE)-MRI to estimate bone perfusion in the FH, using the contralateral side as control. Following open anatomic reduction and a length/angle-stable fixation, a special MRI sequence evaluated the FH for ON changes over time at 3 and 12 months after surgery. RESULTS: We found significant compromise of both arterial inflow [83.1% initial area under the curve (IAUC) and 73.8%-peak) and venous outflow (243.2% elimination rate (K el)] in the FH of the fractured side. The supero-medial quadrant suffered the greatest decrease in arterial inflow with a significant decrease of 71.6% (IAUC) and 68.5% (peak). Post-operative MRI revealed a high rate (87%-20/23) of small ON segments within the FH, and all developed in the anterior aspect of the supero-medial quadrants. Fracture characteristics, including subcapital FNF, varus deformity, posterior roll-off >=20 degrees and Pauwel's angle of 30 degrees -50 degrees demonstrated a greater decrease in perfusion compared to contralateral controls. CONCLUSION: FNF significantly impaired the vascular supply to the FH, resulting in high incidence of small ON segments in the supero-medial quadrant of the FH. However, maintained perfusion, probably through the inferior retinacular system, coupled with urgent open anatomic reduction and stable fixation resulted in excellent clinical and radiographic outcomes despite a high rate of small ON segments noted on MRI. LEVEL OF EVIDENCE: Level I: Prognostic Investigation. PMID- 28849271 TI - [Multiprofessional inpatient psychotherapy of depression in old age]. AB - Depression is common in old age but is often underdiagnosed and inadequately treated. Although psychotherapy is considered effective for treating elderly patients with depression, it is rarely applied in inpatient settings. Furthermore, treatment on inpatient units specialized for elderly patients and implementation of a psychotherapeutic treatment approach are currently more the exception. From this background, a multiprofessional inpatient behavioral treatment program (MVT) for elderly depressed patients was developed at a specialized unit of a university-affiliated regional psychiatric hospital. The MVT is based on specific and modularized group therapies accompanied by individual therapeutic interventions. While the provision of group therapies (such as psychotherapy, social skills training, relaxation training, euthymic and mindfulness-based methods, exercise and occupational therapy as well as psychoeducational sessions for relatives) is assigned to specific professional groups, a joint multiprofessional treatment planning is of central relevance. First evaluations of different treatment components support the high acceptability of the MVT and highlight that psychotherapeutic inpatient treatment programs for the elderly are feasible. Further research is required to investigate the clinical efficacy of psychotherapy in elderly depressive inpatients. PMID- 28849269 TI - Multicenter, randomized comparison between magnetically navigated and manually guided radiofrequency ablation of atrioventricular nodal reentrant tachycardia (the MagMa-AVNRT-trial). AB - BACKGROUND: Remote magnetic navigation (RMN) is attributed to diminish radiation exposure for both patient and operator performing catheter ablation for different arrhythmia substrates. The purpose of this prospective, randomized study was to compare RMN with manually guided catheter ablation for AV nodal reentrant tachycardia (AVNRT) regarding fluoroscopy time/dosage, acute and long-term efficacy as well as safety. METHODS AND RESULTS: A total of 218 patients with AVNRT undergoing catheter ablation at three centers (male 34%, mean age 50 +/- 17 years) were randomized to a manual approach (n = 113) or RMN (n = 105) using the Niobe(r) magnetic navigation system. The primary study endpoint was total fluoroscopy time/dosage for patient and operator at the end of the procedure. Secondary endpoints included acute success, procedure duration, complications and success rate after 6 months. Fluoroscopy time and dosage for the patient were significantly reduced in the RMN group compared to the manual group (6 +/- 6 vs. 11 +/- 10 min; p < 0.001 and 425 +/- 558 vs. 751 +/- 900 cGycm2, p = 0.002). A reduction in fluoroscopy time/dose also applied to the operator (3 +/- 5 vs. 7 +/ 9 min 209 +/- 444 vs. 482 +/- 689 cGycm2, p < 0.001). Procedure duration was significantly longer in the RMN group (88 +/- 29 vs. 79 +/- 29 min; p = 0.03) and crossover from the RMN group to manual ablation occurred in 7.6% of patients (7.6 vs. 0.1%; p = 0.02). Acute success was achieved in 100% of patients in both groups. Midterm success after 6 months was 97 vs. 98% (p = 0.67). No complications occurred in both groups. CONCLUSION: The use of RMN for catheter ablation of AVNRT compared to a manual approach results in a reduction of fluoroscopy time and dosage of about 50% for both patients and physicians. Acute and midterm success and safety are comparable. RMN is a good alternative to a manual approach for AVNRT ablation. PMID- 28849267 TI - Heart regeneration and the cardiomyocyte cell cycle. AB - Cardiovascular disease and in particular, heart failure are still main causes of death; therefore, novel therapeutic approaches are urgently needed. Loss of contractile substrate in the heart and limited regenerative capacity of cardiomyocytes are mainly responsible for the poor cardiovascular outcome. This is related to the postmitotic state of differentiated cardiomyocytes, which is partly due to their polyploid nature caused by cell cycle variants. As such, the cardiomyocyte cell cycle is a key player, and its manipulation could be a promising strategy for enhancing the plasticity of the heart by inducing cardiomyocyte proliferation. This review focuses on the cardiac cell cycle and its variants during postnatal growth, the different regenerative responses of the heart in dependance of the developmental stage and on manipulations of the cell cycle. Because a therapeutic goal is to induce authentic cell division in cardiomyocytes, recent experimental approaches following this strategy are also discussed. PMID- 28849272 TI - [Gender confirming surgery : Female-to-male and male-to-female]. AB - BACKGROUND: Gender confirming surgery (GCS) represents a new and interdisciplinary urological field of activity. OBJECTIVES: Based on more than 20 years of experience, the development of interdisciplinary strategies in the surgical management of male-to-female (MtF) and female-to-male (FtM) transgenders is summarized. MATERIALS AND METHODS: The current national and international literature, as well as the surgical experience of the authors in the field of GCS, were evaluated, and aspects relevant for urologists are presented in a comprehensive review. RESULTS: Since 1990 more than 1200 primary GCS in MtF transgenders and more than 230 primary GCS in FtM transgenders have been performed in the authors' institutions. Presuming an incidence of at least 1:20,000 for patients with gender dysphoria (GD) in the general population, the overall number of patients is limited. The complex surgical procedures should be realized in an interdisciplinary team, trained and specialized in this field of surgery, given the high rate of complications and secondary procedures with MtF GCS. CONCLUSION: Postoperative satisfaction rates of FtM and MtF transgenders at over 80% are satisfactory. During the last few decades, surgical procedures have been widely standardized. In the field of penile reconstruction, the free forearm lap represents the preferred method, while several surgical alternatives arise from the current literature in this field. PMID- 28849273 TI - A D-genome-originated Ty1/Copia-type retrotransposon family expanded significantly in tetraploid cottons. AB - Retrotransposons comprise of a major fraction of higher plant genomes, and their proliferation and elimination have profound effects on genome evolution and gene functions as well. Previously we found a D-genome-originated Ty1/Copia-type LTR (DOCL) retrotransposon in the chromosome A08 of upland cotton. To further characterize the DOCL retrotransposon family, a total of 342 DOCL retrotransposons were identified in the sequenced cotton genomes, including 73, 157, and 112 from Gossypium raimondii, G. hirsutum, and G. barbadense, respectively. According to phylogenetic analysis, the DOCL family was divided into nine groups (G1-G9), among which five groups (G1-G4 and G9, including 292 members) were proliferated after the formation of tetraploid cottons. It was found that the majority of DOCL retrotransposons (especially those in G2, G3 and G9) inserted in non-allelic loci in G. hirsutum and G. barbadense, suggesting that their proliferations were relatively independent in different tetraploid cottons. Furthermore, DOCL retrotransposons inserted in coding regions largely eliminated expression of the targeted genes in G. hirsutum or G. barbadense. Our data suggested that recent proliferation of retrotransposon families like DOCL was one of important evolutionary forces driving diversification and evolution of tetraploid cottons. PMID- 28849274 TI - Analysis of PLA2R1 and HLA-DQA1 sequence variants in Japanese patients with idiopathic and secondary membranous nephropathy. AB - BACKGROUND: Several recent studies in patients with idiopathic membranous nephropathy (iMN) from Western and Asian counties showed that some single nucleotide polymorphisms (SNPs) within the PLA2R1 and HLA-DQA1 genes are significantly associated with iMN. However, there is only 1 report on analysis of PLA2R1 and HLA regions in Japanese patients with iMN. METHODS: A total of 58 patients with iMN, 26 patients with secondary MN (sMN), and 50 patients with other diseases were enrolled. All patients were Japanese. We selected 6 SNPs within PLA2R1 and 1 SNP within HLA-DQA1, which were significantly associated with iMN in reported white European cohorts, and sequenced these exons using genomic DNA prepared from peripheral mononuclear cells from each patient. We then analyzed differences in PLA2R1 and HLA-DQA1 sequence variants among the 3 groups. RESULTS: Genotypic and allelic frequency distributions for 3 out of 6 SNPs within PLA2R1, rs3749117, rs35771982, and rs2715918 were significantly different between the iMN and control groups. Allelic frequency distributions for SNP rs2187668 within HLA-DQA1 were significantly different between the iMN and control groups. There were no correlations between PLA2R1 and HLA-DQA1 sequence variants and clinical parameters in patients with iMN. There were no significant differences in genotypic or allelic frequency distributions for examined SNPs between the sMN and control groups. CONCLUSIONS: There are some differences in PLA2R1 SNP distributions between previously reported cohorts from other countries and our Japanese cohort of patients with iMN, while there is a significant association between SNP rs35771982 and iMN in most of reported cohorts. PMID- 28849275 TI - Increased levels of sodium chloride directly increase osteoclastic differentiation and resorption in mice and men. AB - : To better understand the association between high salt intake and osteoporosis, we investigated the effect of sodium chloride (NaCl) on mice and human osteoclastogenesis. The results suggest a direct, activating role of NaCl supplementation on bone resorption. INTRODUCTION: High NaCl intake is associated with increased urinary calcium elimination and parathyroid hormone (PTH) secretion which in turn stimulates the release of calcium from the bone, resulting in increased bone resorption. However, while calciuria after NaCl loading could be shown repeatedly, several studies failed to reveal a significant increase in PTH in response to a high-sodium diet. Another possible explanation that we investigated here could be a direct effect of high-sodium concentration on bone resorption. METHODS: Mouse bone marrow macrophage and human peripheral blood mononuclear cells (PBMC) driven towards an osteoclastogenesis pathway were cultivated under culture conditions mimicking hypernatremia environments. RESULTS: In this study, a direct effect of increased NaCl concentrations on mouse osteoclast differentiation and function was observed. Surprisingly, in a human osteoclast culture system, significant increases in the number of tartrate resistant acid phosphatase (TRAP)-positive osteoclasts, calcitonin receptor (CTR) positive osteoclasts, nuclear factor-activated T cells c1 (NFATc1) gene expression, and areal and volumetric resorptions were observed for increasing concentrations of NaCl. This suggests a direct, activating, cell-mediated effect of increased concentrations of NaCl on osteoclasts. CONCLUSIONS: The reported that enhanced bone resorption after high-sodium diets may not only be secondary to the urinary calcium loss but may also be a direct, cell-mediated effect on osteoclastic resorption. These findings allow us to suggest an explanation for the clinical findings independent of a PTH-mediated regulation. PMID- 28849276 TI - Hung Jury. PMID- 28849277 TI - Patient-reported outcome use in oncology: a systematic review of the impact on patient-clinician communication. AB - PURPOSE: Patient-reported outcomes (PROs) are an increasingly popular tool to optimize care and bridge the gap between patient experience and clinician understanding. The aim of this review was to identify mechanisms through which PROs facilitate patient-clinician communication in the adult oncology population. METHODS: We conducted a systematic review of the published literature using the following data sources: MEDLINE, EMBASE, CINAHL, PsycINFO, Cab Direct, and CDSR. Studies included in this review reported on the outcomes of PRO use, used PROs as an intervention and not as a study outcome measurement tool, included cancer patients or survivors as study participants, and analyzed patient-clinician communication. RESULTS: We identified 610 unique records, of which 43 publications met the inclusion and exclusion criteria. Synthesis of the reviewed studies provided evidence of the usefulness of PROs in facilitating patient clinician communication on a variety of topics. We identified mechanisms though which PROs influenced patient-clinician communication to include increasing symptom awareness, prompting discussion, streamlining consultations, and facilitating inter-professional communication. Barriers to PRO use in communication improvement include technical problems impeding its administration and completion, compliance issues due to lack of incentive or forgetfulness, and use of PROs that do not appropriately assess issues relevant to the patient. Facilitators include increased education on PRO use, using PRO tools that patients find more acceptable, and providing patient data summaries in an easily accessible format for clinicians. CONCLUSIONS: Our review suggests that PROs facilitate patient-clinician communication through various mechanisms that could perhaps contribute to improvements in symptom management and survival. The impact of PROs on clinical outcomes, however, remains poorly studied. PMID- 28849280 TI - Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts hepatocellular carcinoma incidence and recurrence in nucleos(t)ide analogue therapy for chronic hepatitis B. AB - BACKGROUND: Hepatocellular carcinoma (HCC) occurs in chronic hepatitis B (CH-B) patients even after treatment with nucleos(t)ide analogues (NAs) by a mechanism involving an association between the oncogenic factors of integrated HBV and liver fibrosis. An association has been demonstrated between advanced chronic liver disease and elevated levels of Wisteria floribunda agglutinin-positive Mac 2 binding protein (WFA(+)-M2BP), a recently discovered serum liver fibrosis marker. Moreover, hepatitis B core-related antigen (HBcrAg) reflects intracellular HBV protein production and its relationship with liver carcinogenesis has been reported. This study aimed to determine whether the incidence and recurrence of HBV-related liver cancer could be predicted using these serum markers. METHODS: We evaluated 141 CH-B cases treated for more than 1 year with NAs. We compared 17 HCC cases with 124 non-HCC cases and evaluated serum WFA(+)-M2BP, HBV markers including HBcrAg, and other clinical factors. We also evaluated 71 CH-B-related HCC cases who started or continued NAs and compared the incidence and recurrence of HCC after successful cancer treatment. RESULTS: Multivariate analysis showed that the incidence of HCC was significantly associated with higher histological stage and grade before NA treatment and with WFA(+)-M2BP and HBcrAg positivity during NA treatment. The cumulative incidence of HCC was strongly associated with higher WFA(+)-M2BP levels and HBcrAg positivity. HCC recurrence after anti-cancer therapy was also significantly associated with higher WFA(+)-M2BP levels compared with those in cases without recurrence during follow-up. CONCLUSION: Serum WFA(+)-M2BP and HBcrAg are useful diagnostic tests for predicting the development and recurrence of HBV-related HCC during NA treatment. PMID- 28849279 TI - Alcohol Use and HIV Risk Within Social Networks of MSM Sex Workers in the Dominican Republic. AB - To examine how alcohol-related HIV risk behaviors within MSM sex workers' social networks (SN) may be associated with individual risk behaviors, respondent-driven and venue-based sampling were used to collect demographic, behavioral and SN characteristics among MSM sex workers in Santo Domingo and Boca Chica (N = 220). The majority of participants reported problem drinking (71.0%) or alcohol use at their last sexual encounter (71.4%). Self-reported problem drinking was associated with SN characteristics (at least one member who recently got drunk aOR = 7.5, no religious/spiritual adviser aOR = 3.0, non-sexual network density aOR = 0.9), while self-reported alcohol use at last sex was associated with individual (drug use at last sex aOR = 4.4) and SN characteristics (at least one member with previous HIV/STI testing aOR = 4.7). Dominican MSM sex workers reported high alcohol use, which may increase their risk for HIV. A better understanding of SN factors associated with individual risk behaviors can help guide appropriate intervention development. PMID- 28849278 TI - The Feasibility of Enhancing Susceptibility of Glioblastoma Cells to IRE Using a Calcium Adjuvant. AB - Irreversible electroporation (IRE) is a cellular ablation method used to treat a variety of cancers. IRE works by exposing tissues to pulsed electric fields which cause cell membrane disruption. Cells exposed to lower energies become temporarily permeable while greater energy exposure results in cell death. For IRE to be used safely in the brain, methods are needed to extend the area of ablation without increasing applied voltage, and thus, thermal damage. We present evidence that IRE used with adjuvant calcium (5 mM CaCl2) results in a nearly twofold increase in ablation area in vitro compared to IRE alone. Adjuvant 5 mM CaCl2 induces death in cells reversibly electroporated by IRE, thereby lowering the electric field thresholds required for cell death to nearly half that of IRE alone. The calcium-induced death response of reversibly electroporated cells is confirmed by electrochemotherapy pulses which also induced cell death with calcium but not without. These findings, combined with our numerical modeling, suggest the ability to ablate up to 3.2* larger volumes of tissue in vivo when combining IRE and calcium. The ability to ablate a larger volume with lowered energies would improve the efficacy and safety of IRE therapy. PMID- 28849281 TI - The insufficient prognostic power of stenosis in patients with esophageal cancer. PMID- 28849282 TI - MRSA prevalence rates detected in a tertiary care hospital in Austria and successful treatment of MRSA positive patients applying a decontamination regime with octenidine. AB - Methicillin-resistant Staphylococcus aureus (MRSA) decontamination regimens predominantly use chlorhexidine bathing in combination with mupirocin nasal ointment. However, resistances in Staphylococcus aureus strains are increasingly common and there is a need of alternative, safe and feasible protocols. This interventional cohort study performed at the Albert Schweitzer Hospital in Graz, Austria, aimed to (1) determine MRSA prevalence at different body sites and (2) assess the efficacy of the decontamination using octenidine-based leave-on products added to existing robust infection control measures. All inpatients of this tertiary care hospital being treated in geriatric medical wards (GWs) and apallic care units (ACUs) were screened for MRSA and decontamination rates were determined after one, two or three decontamination cycles, respectively. At baseline, MRSA was detected in 25 of the 126 patients screened (19.8%). We found MRSA in 13/126 (10.3%) swabs from nasal vestibules, in 12/126 (9.5%) skin swabs, in 11/51 (21.6%) swabs from PEG-stomata or suprapubic catheters and in 8/13 (61.5%) tracheostomata swabs. A maximum of three 5-day decontamination cycles reduced the number of MRSA positive patients by 68.0%. Excluding non-compliant and deceased patients, decontamination reduced MRSA carriage by 93.3% (n = 15). No adverse events related to the applied decontamination regimen occurred. Exclusive screening of the nose might underreport MRSA prevalence rates. In this study, decontamination with octenidine-based leave-on products was safe and effective in a critical patient population. PMID- 28849283 TI - Phylogenetic analysis of VP1 and RdRP genes of Brazilian aichivirus B strains involved in a diarrhea outbreak in dairy calves. AB - Aichivirus B has been reported worldwide in calves and adult cattle with and without diarrhea. The aim of this study was to describe the molecular characteristics of the RdRP and VP1 genes of aichivirus B strains identified as the most frequent etiologic agent in a neonatal diarrhea outbreak in a high production Brazilian dairy cattle herd. Preliminary laboratory analysis ruled out important enteropathogens (Cryptosporidium spp; Eimeria spp., E. coli F5, and bovine coronavirus). Fecal samples from diarrheic (n = 24) and asymptomatic (n = 5) calves up to 30 days old were collected for virological analysis. RT-PCR assays were performed for the detection of aichivirus B RdRP and VP1 genes and for rotavirus A VP7 and VP4 genes in fecal samples. Asymptomatic calves (control group) were negative for both viruses. Aichivirus B and rotavirus A G10P[11] genotypes were found in 54.2% (13/24) and 25% (6/24) of the diarrheic fecal samples, respectively. Aichivirus B was only identified (83.3%, 10/12) in calves up to two weeks old. Phylogenetic analysis based on the RdRP gene grouped the Brazilian strains in a new branch within the aichivirus B group. Comparative analysis of the nucleotide sequence of the VP1 gene of Brazilian and Chinese aichivirus B strains allowed the strains identified in this study to be classified in the putative lineage 1. This is the first description of a high rate of aichivirus B detection in a diarrhea outbreak in dairy calves, and the first phylogenetic study of the VP1 gene of aichivirus B wild-type strains performed in South America. PMID- 28849284 TI - HIV Linkage to Care and Retention in Care Rate Among MSM in Guangzhou, China. AB - Quantifying HIV service provision along the HIV care continuum is increasingly important for monitoring and evaluating HIV interventions. We examined factors associated with linkage and retention in care longitudinally among MSM (n = 1974, 4933 person-years) diagnosed and living in Guangzhou, China, in 2008-2014. We measured longitudinal change of retention in care (>=2 CD4 tests per year) from linkage and antiretroviral therapy initiation (ART). We examined factors associated with linkage using logistic regression and with retention using generalized estimating equations. The rate of linkage to care was 89% in 2014. ART retention rate dropped from 71% (year 1) to 46% (year 2), suggesting that first-year retention measures likely overestimate retention over longer periods. Lower CD4 levels and older age predicted retention in ART care. These data can inform interventions to improve retention about some subgroups. PMID- 28849285 TI - A small proportion of community-associated methicillin-resistant Staphylococcus aureus bacteraemia, compared to healthcare-associated cases, in two South African provinces. AB - We compared the proportion of cases of community-associated and healthcare associated methicillin-resistant Staphylococcus aureus (CA-MRSA and HA-MRSA, respectively) bacteraemia among patients at five hospitals in the Gauteng and Western Cape provinces in South Africa and described the molecular characteristics and antimicrobial susceptibility trends. This was a cross sectional study using data collected by enhanced surveillance for S. aureus bacteraemia. A total of 2511 cases of S. aureus bacteraemia were identified from January 2013 to January 2016. Among 1914 cases of S. aureus, 557 (29.1%) cases were identified as MRSA infection. Forty-four cases (44/1914 [2.3%] of all S. aureus cases) were considered CA-MRSA infection and 513/1914 (26.8% of all cases) had HA-MRSA infection; the majority were neonates. CA-MRSA constituted 7.9% (44/557) of all cases of MRSA infection. Staphylococcus aureus isolates demonstrated significantly reduced susceptibility to the following classes of antimicrobial agents: macrolides, tetracyclines, aminoglycosides and cotrimoxazole, in 2015 compared to 2013 (p < 0.05). Of the 557 MRSA isolates, 484 (87%) were typed for SCCmec elements and spa types: the most common SCCmec type was type III (n = 236, 48.76%), followed by type IV (n = 144, 29.76%). The most common spa types were t037 (n = 229, 47.31%) and t1257 (n = 90, 18.60%). Of 28 isolates selected for multilocus sequence typing (MLST), the most common sequence types (STs) were ST239 and ST612 of clonal complex 8 (CC8) (n = 8 each) and a novel ST (ST4121) was obtained for one isolate. This study demonstrates that S. aureus bacteraemia is common in South African academic centres and characterised by HA-MRSA SCCmec types III and IV. A small proportion of CA-MRSA cases were caused by a few different sequence types. PMID- 28849286 TI - Allo-specific immune response profiles indicative of acute rejection in kidney allografts using an in vitro lymphocyte culture-based model. AB - BACKGROUND: Ability to predict the manner in which a recipient's immune system would respond to a transplanted graft by analyzing cytokine profiles of the "allograft antigen sensitized" recipient lymphocytes in vitro might provide a means to identify patients at risk to adverse clinical endpoints. METHODS: Cytokine/chemokine gene expression profiles of peripheral blood mononuclear cells co-cultured with allograft antigen-pulsed macrophages were studied in 49 renal transplant recipients-12 with acute cellular rejection (ACR) with or without antibody-mediated rejection (AMR), 7 with AMR (without ACR), and 30 with stable allografts (SA). An 86-gene inflammatory cytokines and receptors PCR array was used to measure fold changes in gene expression between pulsed and un-pulsed cultures. RESULTS: On linear discriminant analysis and multivariate analysis of variance, a gene set comprising C3, CCL3, IL1B, TOLLIP, IL10, CXCL5, ABCF1, CCR3, IL10RB, CXCL1, and IL1R1 differentiated the ACR-AMR from the SA group. Similarly, a gene set comprising IL10, C3, IL37, IL1B, CCL3, CARD18, and TOLLIP differentiated the AMR from the SA group. No significant difference was found between the ACR-AMR vs AMR groups. CONCLUSION: Distinct post in vitro stimulation cytokine profiles at the time of transplantation thus correlated with the occurrence of post-transplantation rejection episodes which indicated feasibility of this in vitro model to assess the recipient's anti-graft response at an early stage. PMID- 28849287 TI - Pressure reactivity index: journey through the past 20 years. AB - Autoregulation after traumatic brain injury can be monitored continuously using simple signal processing of intracranial pressure and arterial blood pressure. The pressure reactivity index (PRx) showed several benefits when it was applied to continuous brain monitoring. Among them, a positive and strong correlation with the outcome and possibility of calculation of 'optimal cerebral perfusion pressure' have been listed. For this methodology, prospective clinical trials are missing-few of them are planned in the near future. PMID- 28849289 TI - The Impact of a Community-Based Intervention Including a Monthly Food Ration on Food Insecurity Among HIV-Positive Adults During the First Year of Antiretroviral Therapy. AB - The objective of this study was to examine how food insecurity changed among HIV positive adults during the first 12 months of combination antiretroviral therapy (cART) and whether any change differed according to the receipt of food support, which was provided in the context of a comprehensive community-based intervention. We conducted secondary data analyses of data from a prospective cohort study of the effectiveness of a community-based cART delivery model when added to clinic-based cART delivery in Rwanda. We included patients from four health centers that implemented a clinic-based cART delivery model alone and five health centers that additionally implemented the intervention, which included 10 months of food support. We compared food insecurity at 3, 6, and 12 months, relative to baseline, and stratified by receipt of the intervention. Relative to baseline, median food insecurity score decreased after 3, 6, and 12 months (p value <0.0001 for all) for patients receiving a food ration through the community based model for cART delivery. Among patients receiving care under the clinic based cART model, food insecurity scores remained unchanged at 3 and 12 months and were significantly higher after 6 months. In adjusted analyses, participants enrolled in the community-based intervention with a food ration had a lower risk of severe food insecurity and a lower risk of moderate or severe food insecurity after 12 months. A comprehensive community-based HIV program including a food ration likely contributes to an alleviation of food insecurity among adults newly initiating cART. PMID- 28849288 TI - AMP-activated protein kinase and cAMP response element-binding protein activity are associated with distinct postoperative behavioral changes in rats. AB - PURPOSE: To explore the association of AMP-activated protein kinase (AMPK) and cAMP response element-binding protein (CREB) activity with distinct postoperative behavioral changes in rats. METHODS: We performed partial hepatolobectomy in adult rats and aged rats. The learning and memory ability of rats was evaluated by the Barnes maze test on postoperative days 1-4. The expressions of AMPK and phosphorylated CREB (p-CREB) in the CA1 and DG regions of the hippocampus were detected by immunohistochemical assay at 3, 6, 12 and 24 h postoperatively. RESULTS: Surgery impaired the memory of aged rats but not that of adult rats on postoperative days 2 and 3 (both p < 0.05). Surgery synergistically increased the expressions of AMPK and p-CREB in the CA1 region of hippocampus in aged rats but not in adult rats at 3 and 6 h postoperatively. CONCLUSION: Our data suggest that surgery induces cognitive impairment in aged rats. Surgery-induced expression of AMPK and p-CREB in the CA1 region of hippocampus may be involved in this cognitive impairment. PMID- 28849290 TI - Contextual Challenges and the Mosaic of Support: Understanding the Vulnerabilities of Low-Income Informal Caregivers of Dependent Elders in Singapore. AB - Informal caregivers play an increasingly important and demanding role in providing and ensuring long-term care for elders. To date, few studies have qualitatively explored the challenges and coping strategies adopted by informal caregivers of dependent elders from lower-income households in Singapore. Based on data from in-depth interviews with 19 respondents, this study provides detailed and nuanced accounts of the lived experiences of low-income informal caregivers. The strains associated with the scarcity of resources among low income caregivers are compounded by contextual challenges such as fractured familial relationships, role conflicts, and perceived barriers in their institutional environment. To overcome these challenges, low-income caregivers resort to a mix of informal and formal sources of support. Suggested improvements for policies and service provision to address the vulnerabilities of low-income caregivers will also be discussed in light of current gaps. PMID- 28849291 TI - Senescence is not inevitable. AB - Senescence, the physiological deterioration resulting in an increase in mortality and decline in fertility with age, is widespread in the animal kingdom and has often been regarded as an inescapable feature of all organisms. This essay briefly describes the history of the evolutionary theoretical ideas on senescence. The canonical evolutionary theories suggest that increasing mortality and decreasing fertility should be ubiquitous. However, increasing empirical data demonstrates that senescence may not be as universal a feature of life as once thought and that a diversity of demographic trajectories exists. These empirical observations support theoretical work indicating that a wide range of mortality and fertility trajectories is indeed possible, including senescence, negligible senescence and even negative senescence (improvement). Although many mysteries remain in the field of biogerontology, it is clear that senescence is not inevitable. PMID- 28849292 TI - Climatology of atmospheric circulation patterns of Arabian dust in western Iran. AB - Being in vicinity of vast deserts, the west and southwest of Iran are characterized by high levels of dust events, which have adverse consequences on human health, ecosystems, and environment. Using ground based dataset of dust events in western Iran and NCEP/NCAR reanalysis data, the atmospheric circulation patterns of dust events in the Arabian region and west of Iran are identified. The atmospheric circulation patterns which lead to dust events in the Arabian region and western Iran were classified into two main categories: the Shamal dust events that occurs in warm period of year and the frontal dust events as cold period pattern. In frontal dust events, the western trough or blocking pattern at mid-level leads to frontogenesis, instability, and air uplift at lower levels of troposphere in the southwest of Asia. Non-frontal is other pattern of dust event in the cold period and dust generation are due to the regional circulation systems at the lower level of troposphere. In Shamal wind pattern, the Saudi Arabian anticyclone, Turkmenistan anticyclone, and Zagros thermal low play the key roles in formation of this pattern. Summer and transitional patterns are two sub-categories of summer Shamal wind pattern. In summer trough pattern, the mid tropospheric trough leads to intensify the surface thermal systems in the Middle East and causes instability and rising of wind speed in the region. In synthetic pattern of Shamal wind and summer trough, dust is created by the impact of a trough in mid-levels of troposphere as well as existing the mentioned regional systems which are contributed in formation of summer Shamal wind pattern. PMID- 28849294 TI - The Effect of Histamine on Inward and Outward Currents in Mouse Retinal Amacrine Cells. AB - The expression of H1 receptor has been reported in amacrine cells of mouse and rat retinae. However, we assumed that other types of histamine receptors also function in amacrine cells. In order to confirm that histamine modulates the membrane potential in mouse amacrine cells, we measured voltage-gated currents using whole-cell configuration. Under voltage-clamp conditions, the amplitude of voltage-gated outward currents was enhanced by the application of 100 uM histamine in 65% of amacrine cells. Histamine also increased the amplitudes of voltage-gated inward currents in 72% of amacrine cells. When antagonists of the histamine H1, H2, or H3 receptors were applied to histamine-sensitive amacrine cells, all three types of these inhibitors reduced the effect of histamine. Moreover, we classified recorded cells into seven types based on their morphological characteristics. Two of the seven types, diffuse multistratified cells and AII amacrine cells, responded significantly to histamine. These results indicate that histamine affected the membrane potential via three types of histamine receptors. Furthermore, there were differences in the responses to histamine among types of amacrine cells. Histamine may be one of the important neurotransmitters and/or neuromodulators in the visual processing. PMID- 28849297 TI - [Body weight and mental disorders : Results from a clinical psychiatric cross sectional study of people with intellectual disabilities]. AB - BACKGROUND: People with intellectual disabilities (ID) have a shorter life expectancy and higher mortality rate and more often suffer from various physical and mental disorders (WHO: 3-4 times more often than the general population). Obesity is an important risk factor for various disorders. This cross-sectional study examined the body weight and its risk factors in a clinical population of adults with ID. METHODS: The prevalence of underweight, normal weight, and overweight was determined using the body mass index (BMI) for 633 patients of an outpatient clinic for people with ID and mental disorders. A multiple logistic regression analysis was used to assess factors for alterations in body weight. RESULTS: Approximately one out of two men and two out of three women with ID and mental disorders were overweight. Adults with mild and moderate ID, female gender, increasing age, Down's syndrome, behavioral disorders, and a less supported living situation were associated with a higher rate of obesity. People with dementia and autism spectrum disorders showed a lower rate of obesity. CONCLUSION: Young women with ID and mental disorders were particularly at risk for obesity. The respective factors may support the development of specific prevention programs to reduce the risk of overweight and thereby lead to better mental and physical health in people with ID. PMID- 28849301 TI - [Diabetic emergencies : Hypoglycemia, ketoacidotic and hyperglycemic hyperosmolar nonketotic coma]. AB - The diabetic emergencies diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS) and hypoglycemia represent severe and potentially life-threatening complications of diabetes mellitus that require prompt diagnostics and treatment. Absolute or relative insulin insufficiency is characteristic of DKA und HHS along with severe dehydration. They differ by the prevalence of ketone bodies and the severity of acidosis; however, the treatment regimens are similar. In contrast, hypoglycemia is the limiting factor for achieving ambitious glucose targets. This article decribes the clinical presentation, diagnostics and emergency management of these metabolic derangements. PMID- 28849296 TI - River discharge as a major driving force on spatial and temporal variations in zooplankton biomass and community structure in the Godavari estuary India. AB - Variability in horizontal zooplankton biomass distribution was investigated over 13 months in the Godavari estuary, along with physical (river discharge, temperature, salinity), chemical (nutrients, particulate organic matter), biological (phytoplankton biomass), and geological (suspended matter) properties to examine the influencing factors on their spatial and temporal variabilities. The entire estuary was filled with freshwater during peak discharge period and salinity near zero, increased to ~ 34 psu during dry period with relatively high nutrient levels during former than the latter period. Due to low flushing time (< 1 day) and high suspended load (> 500 mg L-1) during peak discharge period, picoplankton (cyanophyceae) contributed significantly to the phytoplankton biomass (Chl-a) whereas microplankton and nanoplankton (bacillariophyceae, and chlorophyceae) during moderate and mostly microplankton during dry period. Zooplankton biomass was the lowest during peak discharge period and increased during moderate followed by dry period. The zooplankton abundance was controlled by dead organic matter during peak discharge period, while both phytoplankton biomass and dead organic matter during moderate discharge and mostly phytoplankton biomass during dry period. This study suggests that significant modification of physico-chemical properties by river discharge led to changes in phytoplankton composition and dead organic matter concentrations that alters biomass, abundance, and composition of zooplankton in the Godavari estuary. PMID- 28849299 TI - Impact of age on intermittent hypoxia in obstructive sleep apnea: a propensity matched analysis. AB - PURPOSE: To determine independent relationship of aging with chronic intermittent hypoxia, we compared hypoxia-related polysomnographic variables of geriatric patients (aged >= 65 years) with an apnea-hypopnea index (AHI)-, gender-, body mass index (BMI)-, and neck circumference-matched cohort of non-geriatric patients. METHODS: The study was conducted using clinical and polysomnographic data of 1280 consecutive patients who underwent complete polysomnographic evaluation for suspected sleep-disordered breathing (SDB) at a single sleep disorder center. A propensity score-matched analysis was performed to obtain matched cohorts of geriatric and non-geriatric patients, which resulted in successful matching of 168 patients from each group. RESULTS: Study groups were comparable for gender (P = 0.999), BMI (P = 0.940), neck circumference (P = 0.969), AHI (P = 0.935), and severity of SDB (P = 0.089). The oximetric variables representing the duration of chronic intermittent hypoxia such as mean (P = 0.001), the longest (P = 0.001) and total apnea durations (P = 0.003), mean (P = 0.001) and the longest hypopnea durations (P = 0.001), and total sleep time with oxygen saturation below 90% (P = 0.008) were significantly higher in the geriatric patients as compared with younger adults. Geriatric patients had significantly lower minimum (P = 0.013) and mean oxygen saturation (P = 0.001) than non-geriatric patients. CONCLUSIONS: The study provides evidence that elderly patients exhibit more severe and deeper nocturnal intermittent hypoxia than the younger adults, independent of severity of obstructive sleep apnea, BMI, gender, and neck circumference. Hypoxia-related polysomnographic variables in geriatric patients may in fact reflect a physiological aging process rather than the severity of a SDB. PMID- 28849293 TI - PI3K/Akt Pathway is Required for Spinal Central Sensitization in Neuropathic Pain. AB - Phosphatidylinositol-3-kinase (PI3K) has been identified in the expression of central sensitization after noxious inflammatory stimuli. However, its contribution in neuropathic pain remains to be determined. Here we address the role of PI3K signaling in central sensitization in a model of neuropathic pain, and propose a novel potential drug target for neuropathic pain. Chronic constriction injury (CCI) rat model was used in the study as the model for neuropathic pain. Western blotting, whole-cell patch clamp, and von Frey assay were performed to study biochemical, electrical, and behavioral changes in CCI rats, respectively. A steroid metabolite of the fungi (wortmannin) was used to block PI3K signaling and its effects on CCI rats were tested. PI3K/Akt signaling increased in the spinal cord L4-L6 sections in the CCI rats. CCI also facilitated miniature excitatory postsynaptic potential of dorsal horn substantia gelatinosa neurons, increased phosphorylation of glutamate receptor subunit GluA1 and synapsin at the synapse, and induced mechanic allodynia. Wortmannin reversed biochemical, electrical, and behavioral changes in CCI rats. This study is the first to show PI3K/Akt signaling is required for spinal central sensitization in the CCI neuropathic pain model. PMID- 28849298 TI - Varus-valgus stability at 90 degrees flexion correlates with the stability at midflexion range more widely than that at 0 degrees extension in posterior stabilized total knee arthroplasty. AB - INTRODUCTION: Midflexion stability can potentially improve the outcome of total knee arthroplasty (TKA). The purpose of this study was to evaluate the correlation between varus-valgus stability at 0 degrees of extension and 90 degrees of flexion and that at the midflexion range in posterior-stabilized (PS) TKA. MATERIALS AND METHODS: Forty-three knees that underwent PS-TKA were evaluated. Manual mild passive varus-valgus stress was applied to the knees, and the postoperative maximum varus-valgus stability was measured every 10 degrees throughout range of motion, using a navigation system. Correlations between the stability at 0 degrees , 90 degrees of flexion, and that at each midflexion angle were evaluated using Spearman's correlation coefficients. RESULTS: The stability of 0 degrees modestly correlated with that of 10 degrees -20 degrees , but it did not significantly correlate with that of 30 degrees -80 degrees . However, the stability of 90 degrees strongly correlated with that of 60 degrees -80 degrees , modestly correlated with that of 40 degrees -50 degrees , weakly correlated with that of 20 degrees -30 degrees , and did not correlate with that of 10 degrees . CONCLUSIONS: The present study confirmed the importance of acquiring stability at 90 degrees flexion to achieve midflexion stability in PS TKA. However, initial flexion stability did not strongly correlate with the stability at either 0 degrees or 90 degrees . Our findings can provide useful information for understanding varus-valgus stability throughout the range of motion in PS-TKA. Attention to soft tissue balancing is necessary to stabilize a knee at the initial flexion range in PS-TKA. PMID- 28849295 TI - Diet and Respiratory Health in Children from 11 Latin American Countries: Evidence from ISAAC Phase III. AB - BACKGROUND AND AIM: The burden of childhood asthma and its risk factors is an important but neglected public health challenge in Latin America. We investigated the association between allergic symptoms and dietary intake in children from this region. METHODS: As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase III, questionnaire collected dietary intake was investigated in relation to risk of parental/child reported current wheeze (primary outcome) and rhino-conjunctivitis and eczema. Per-country adjusted logistic regressions were performed, and combined effect sizes were calculated with meta-analyses. RESULTS: 143,967 children from 11 countries had complete data. In children aged 6-7 years, current wheeze was negatively associated with higher fruit intake (adjusted odds ratio [aOR] 0.65; 95% CI 0.74, 0.97). Current rhino-conjunctivitis and eczema were statistically negatively associated with fruit intake (aOR 0.72; 95% CI 0.64, 0.82; and OR 0.64, 95% CI 0.56, 0.74, respectively). Vegetable intake was negatively associated with risk of symptoms in younger children, but these associations were attenuated in the 13-14 years old group. Fastfood/burger intake was positively associated with all three outcomes in the older children. CONCLUSION: A higher intake of fruits and vegetables was associated with a lower prevalence of allergic symptoms in Latin American children. Conversely, intake of fastfood was positively associated with a higher prevalence of wheeze in adolescents. Improved dietary habits in children might help reduce the epidemic of allergic symptoms in Latin America. Food interventions in asthmatic children are needed to evaluate the possible public health impact of a better diet on respiratory health. PMID- 28849303 TI - Synthesis, Spectral Characterization, Thermal and Optical Studies of Novel Complexes: 4-(Dimethylamino)benzylidene-4-acetamideaniline and 4 (Dimethylamino)benzylidene-4-nitroaniline. AB - The phase diagram representing solid-liquid equilibrium of entire range of composition and thermodynamic studies of two binary organic systems of 4 dimethylaminobenzaldehyde (DMAB) with two NLO active compounds, p aminoacetanilide (PAA) and p-nitroaniline (PNA), have been studied by solid state synthetic route. Both systems are independently forming a new entity called intermolecular complex (IMC) and two eutectics on either side of intermolecular complexes. The various thermodynamic parameters such as heat of mixing, entropy of fusion, roughness parameter, interfacial energy and excess thermodynamic functions of IMCs and eutectics were calculated using the heat of fusion values. The TGA and DTA studies were performed to understand the physico-chemical, thermal behavior and unique identity of newly synthesized organic complexes, 4 (dimethylamino)benzylidene-4-acetamideaniline (DMABPAA) and 4 (dimethylamino)benzylidene-4-nitroaniline (DMABPNA), and their respective enthalpy of fusion values were found to be 30.01 and 37.26 kJ mol- 1. The higher melting point of both the novel complexes than their parent's compounds reveal the strong molecular interaction between parent components to yield the complex. The FTIR spectral analysis predicts the disappearance of aldehyde peaks of DMAB and NH2 peaks of PAA and PNA while the appearance of entirely new peaks than that of parent's compounds are the supportive for the formation of new molecular entities. These findings are further supported by FTNMR spectrum studies by observation of disappearance of proton peak of aldehyde of DMAB and amine peaks of PAA and PNA rather formation of new imine proton peak or peaks were observed. The appearance of new peaks in Powder XRD of complexes than those of parent components is further indicative for the formation of complexes. The absorption spectrum of DMABPAA and DMABPNA showed intra-molecular charge-transfer (ICT) excited state absorption at 258 and 241 nm, respectively. Both the IMCs, DMABPAA and DMABPNA, show strong fluorescence with quantum yield 0.66 and 0.93, respectively, in methanol solution. PMID- 28849300 TI - TRPC6 channels modulate the response of pancreatic stellate cells to hypoxia. AB - Pancreatic cancer is characterized by a massive fibrosis (desmoplasia), which is primarily caused by activated pancreatic stellate cells (PSCs). This leads to a hypoxic tumor microenvironment further reinforcing the activation of PSCs by stimulating their secretion of growth factors and chemokines. Since many of them elicit their effects via G-protein-coupled receptors (GPCRs), we tested whether TRPC6 channels, effector proteins of many G-protein-coupled receptor pathways, are required for the hypoxic activation of PSCs. Thus far, the function of ion channels in PSCs is virtually unexplored. qPCR revealed TRPC6 channels to be one of the most abundant TRPC channels in primary cultures of murine PSCs. TRPC6 channel function was assessed by comparing PSCs from TRPC6-/- mice and wildtype (wt) littermates. Cell migration, Ca2+ signaling, and cytokine secretion were analyzed as readout for PSC activation. Hypoxia was induced by incubating PSCs for 24 h in 1% O2 or chemically with dimethyloxalylglycine (DMOG). PSCs migrate faster in response to hypoxia. Due to reduced autocrine stimulation, TRPC6-/- PSCs fail to increase their rate of migration to the same level as wt PSCs under hypoxic conditions. This defect could not be overcome by the stimulation with platelet-derived growth factor. In line with these results, calcium influx is increased in wt but not TRPC6-/- PSCs under hypoxia. We conclude that TRPC6 channels of PSCs are major effector proteins in an autocrine stimulation pathway triggered by hypoxia. PMID- 28849302 TI - Caregivers' education vs rhinopharyngeal clearance in children with upper respiratory infections: impact on children's health outcomes. AB - : Upper Respiratory Tract Infections (URTI) are very common in children having no effective pharmacological treatment. This study aimed to compare the effect of caregivers' health education regarding children's respiratory infections and the effect of a rhinopharyngeal clearance protocol in children with URTI. A factorial trial was conducted in 138 children up to 3 years, attending day-care centres. Children were distributed into four groups: control group (CG) (n = 38); education group (EG) (n = 34); intervention group (IG) (n = 35); and education and intervention group (E + IG) (n = 31). A Diary of Records was kept by caregivers during 1 month. There were significant differences between groups concerning: Lower Respiratory Tract Infections (CG = 29.4%; EG = 10.7%; IG = 3.8%; E + IG = 0.0%; p = 0.014); acute otitis media (CG = 32.4%; EG = 7.1%; IG = 11.5%; E + IG = 7.7%; p = 0.014); medical consultations (CG = 70.6%; EG = 42.9%; IG = 38.5%; E + IG = 30.8%; p = 0.021); antibiotics (CG = 44.1%; EG = 7.1%; IG = 23.1%; E + IG = 15.4%; p = 0.006); days missed from day-care (CG = 55 days; EG = 22 days; IG = 14 days; E + IG = 6 days; p = 0.020); days missed from employment (CG = 31 days; EG = 20 days; IG = 5 days; E + IG = 1 day; p = 0.021); and nasal clearance techniques (CG = 41.4%; EG = 78.6%; IG = 57.7%; E + IG = 84.6%; p = 0.011). CONCLUSION: This study showed that the most positive impact on children's health outcomes occurred when combining health education of caregivers, regarding children's respiratory infections, with a rhinopharyngeal clearance protocol in children with URTI. What is Known: * Upper Respiratory Tract Infections are very common in children but still do not have an effective pharmacological treatment. * This generates a great burden of disease for the child and families, increasing the use of antibiotics. What is New: * This study is the first one that aims to analyze the effects of caregivers' health education in comparison to non pharmacological intervention in acute respiratory infections in children. * It shows a positive impact on children's health outcomes, empowering caregivers regarding their child's health and reducing the burden of disease, medical consultations and the use of antibiotics. PMID- 28849305 TI - The application of information theory for the estimation of old-age multimorbidity. AB - Elderly patients are commonly characterized by the presence of several chronic aging-related diseases at once, or old-age "multimorbidity," with critical implications for diagnosis and therapy. However, at the present there is no agreed or formal method to diagnose or even define "multimorbidity." There is also no formal quantitative method to evaluate the effects of individual or combined diagnostic parameters and therapeutic interventions on multimorbidity. The present work outlines a methodology to provide such a measurement and definition, using information theoretical measure of normalized mutual information. A cohort of geriatric patients, suffering from several age-related diseases (multimorbidity), including ischemic heart disease, COPD, and dementia, were evaluated by a variety of diagnostic parameters, including static as well as dynamic biochemical, functional-behavioral, immunological, and hematological parameters. Multimorbidity was formally coded and measured as a composite of several chronic age-related diseases. The normalized mutual information allowed establishing the exact informative value of particular parameters and their combinations about the multimorbidity value. With the currently intensifying attempts to reduce aging-related multimorbidity by therapeutic interventions into its underlying aging processes, the proposed method may outline a valuable direction toward the formal indication and evidence-based evaluation of effectiveness of such interventions. PMID- 28849304 TI - Apnea and heart rate detection from tracheal body sounds for the diagnosis of sleep-related breathing disorders. AB - Sleep apnea is one of the most common sleep disorders. Here, patients suffer from multiple breathing pauses longer than 10 s during the night which are referred to as apneas. The standard method for the diagnosis of sleep apnea is the attended cardiorespiratory polysomnography (PSG). However, this method is expensive and the extensive recording equipment can have a significant impact on sleep quality falsifying the results. To overcome these problems, a comfortable and novel system for sleep monitoring based on the recording of tracheal sounds and movement data is developed. For apnea detection, a unique signal processing method utilizing both signals is introduced. Additionally, an algorithm for extracting the heart rate from body sounds is developed. For validation, ten subjects underwent a full-night PSG testing, using the developed sleep monitor in concurrence. Considering polysomnography as gold standard the developed instrumentation reached a sensitivity of 92.8% and a specificity of 99.7% for apnea detection. Heart rate measured with the proposed method was strongly correlated with heart rate derived from conventional ECG (r 2 = 0.8164). No significant signal losses are reported during the study. In conclusion, we demonstrate a novel approach to reliably and noninvasively detect both apneas and heart rate during sleep. PMID- 28849306 TI - Induction of endoplasmic reticulum stress and changes in expression levels of Zn2+-transporters in hypertrophic rat heart. AB - Clinical and experimental studies have shown an association between intracellular free Zn2+ ([Zn2+]i)-dyshomeostasis and cardiac dysfunction besides [Ca2+]i dyshomeostasis. Since [Zn2+]i-homeostasis is regulated through Zn2+-transporters depending on their subcellular distributions, one can hypothesize that any imbalance in Zn2+-homeostasis via alteration in Zn2+-transporters may be associated with the induction of ER stress and apoptosis in hypertrophic heart. We used a transverse aortic constriction (TAC) model to induce hypertrophy in young male rat heart. We confirmed the development of hypertrophy with a high ratio of heart to body weight and cardiomyocyte capacitance. The expression levels of ER stress markers GRP78, CHOP/Gadd153, and calnexin are significantly high in TAC-group in comparison to those of controls (SHAM-group). Additionally, we detected high expression levels of apoptotic status marker proteins such as the serine kinase GSK-3beta, Bax-to-Bcl-2 ratio, and PUMA in TAC-group in comparison to SHAM-group. The ratios of phospho-Akt to Akt and phospho-NFkappaB to the NFkappaB are significantly higher in TAC-group than in SHAM-group. Furthermore, we observed markedly increased phospho-PKCalpha and PKCalpha levels in TAC-group. We, also for the first time, determined significantly increased ZIP7, ZIP14, and ZnT8 expressions along with decreased ZIP8 and ZnT7 levels in the heart tissue from TAC-group in comparison to SHAM-group. Furthermore, a roughly calculated total expression level of ZIPs responsible for Zn2+-influx into the cytosol (increased about twofold) can be also responsible for the markedly increased [Zn2+]i detected in hypertrophic cardiomyocytes. Taking into consideration the role of increased [Zn2+]i via decreased ER-[Zn2+] in the induction of ER stress in cardiomyocytes, our present data suggest that differential changes in the expression levels of Zn2+-transporters can underlie mechanical dysfunction, in part due to the induction of ER stress and apoptosis in hypertrophic heart via increased [Zn2+]i- besides [Ca2+]i-dyshomeostasis. PMID- 28849308 TI - 18F-Fluorodeoxyglucose-PET/CT in locally advanced head and neck cancer can influence the stage migration and nodal radiation treatment volumes. AB - AIM: To analyze the impact of 18F-fluorodeoxyglucose-PET/CT (PET/CT) in the radiotherapy (RT) planning strategy in HNC, correlating CT-scan and PET/CT performances. MATERIALS AND METHODS: Inclusion criteria were: age >18 years old, histologically proven head and neck cancer (HNC), patients candidate to definitive RT +/- chemotherapy, stage of disease by means of PET/TC and CT-scan performed at our Cancer Care Center. RESULTS: Sixty patients were analyzed. The following primary tumor sites were investigated: nasopharynx (13%), oropharynx (42%), oral cavity (32%) and larynx non-glottic (13%). Globally, PET/CT findings caused changes on nodal radiation treatment volumes in 10% of all the population of study. Specifically, in 5 cases out of 19 oral cavity tumors (26%), PET/CT detected neck-nodes positive (not detected at CT-scan). These findings have allowed to change the patients management, including PET/CT neck-nodes positive in the high-risk RT volumes. CONCLUSION: In the RT planning strategy, the present findings support the use of PET/CT to improve upfront regional staging of HNC disease, particularly for oral cavity tumors. Further investigations are advocated to evaluate if this strategy could impact on long-term outcomes in terms of local control and overall survival. PMID- 28849307 TI - Effects of dietary Kleinhovia hospita and Leucaena leucocephala leaves on rumen fermentation and microbial population in goats fed treated rice straw. AB - The effects of partial replacement of dietary protein by forages on rumen fermentation and microbiology in goats were examined. Four fistulated Boer bucks were used in a 4 * 4 Latin square design. The goats were fed 60% of urea-treated rice straw and 40% dietary treatment (Kleinhovia hospita (KH), Leucaena leucocephala (LL), mixture of K. hospita with L. leucocephala (KHLL)) and concentrate as the control. Rumen fluid from the animals was collected at 0, 2, 4, 6, and 12 h postprandial for analysis. The KHLL diet had a greater (P < 0.05) molar proportion of acetate than the control diet throughout the sampling period. At 6 h postprandial, the KHLL goats had a significantly lower (P < 0.05) ammonia nitrogen than the goats fed other diets. The molar proportion of propionate (24.7 and 25.8 mol/100 mol) was greater in the rumen of KHLL goats compared with those fed other diets at 2 and 12 h postprandial, respectively. The KHLL diet had lower (P < 0.05) butyrate than other dietary treatments. At 4 h postprandial, the control goats had a lower (P < 0.05) population of total bacteria while the KHLL goats had a greater (P < 0.05) population at 4 and 12 h postprandial compared with those fed other diets. The LL, KH, and KHLL goats had lower (P < 0.05) populations of protozoa and methanogens and a greater (P < 0.05) population of Ruminococcus albus compared with the control goats. The KHLL leaves could be fed to goats without compromising rumen metabolism. PMID- 28849309 TI - Heat transfer analysis of cylindrical anaerobic reactors with different sizes: a heat transfer model. AB - The temperature is the essential factor that influences the efficiency of anaerobic reactors. During the operation of the anaerobic reactor, the fluctuations of ambient temperature can cause a change in the internal temperature of the reactor. Therefore, insulation and heating measures are often used to maintain anaerobic reactor's internal temperature. In this paper, a simplified heat transfer model was developed to study heat transfer between cylindrical anaerobic reactors and their surroundings. Three cylindrical reactors of different sizes were studied, and the internal relations between ambient temperature, thickness of insulation, and temperature fluctuations of the reactors were obtained at different reactor sizes. The model was calibrated by a sensitivity analysis, and the calibrated model was well able to predict reactor temperature. The Nash-Sutcliffe model efficiency coefficient was used to assess the predictive power of heat transfer models. The Nash coefficients of the three reactors were 0.76, 0.60, and 0.45, respectively. The model can provide reference for the thermal insulation design of cylindrical anaerobic reactors. PMID- 28849314 TI - Toolbox of Molecular Techniques for Studying Leptospira Spp. AB - This chapter covers the progress made in the Leptospira field since the application of mutagenesis techniques and how they have allowed the study of virulence factors and, more generally, the biology of Leptospira. The last decade has seen advances in our ability to perform molecular genetic analysis of Leptospira. Major achievements include the generation of large collections of mutant strains and the construction of replicative plasmids, enabling complementation of mutations. However, there are still no practical tools for routine genetic manipulation of pathogenic Leptospira strains, slowing down advances in pathogenesis research. This review summarizes the status of the molecular genetic toolbox for Leptospira species and highlights new challenges in the nascent field of Leptospira genetics. PMID- 28849313 TI - Deletion of TpKu70 facilitates gene targeting in Talaromyces pinophilus and identification of TpAmyR involvement in amylase production. AB - Talaromyces pinophilus is a promising filamentous fungus for industrial production of biomass-degrading enzymes used in biorefining, and its genome was recently sequenced and reported. However, functional analysis of genes in T. pinophilus is rather limited owing to lack of genetic tools. In this study, a putative TpKu70 encoding the Ku70 homolog involved in the classic non-homologous end-joining pathway was deleted in T. pinophilus 1-95. DeltaTpKu70 displayed no apparent defect in vegetative growth and enzyme production, and presented similar sensitivity to benomyl, bleomycin, and UV, when compared with the wild-type T. pinophilus strain 1-95. Seven genes that encode putative transcription factors, including TpAmyR, were successfully knocked out in DeltaTpKu70 at 61.5-100% of homologous recombination frequency, which is significantly higher than that noted in the wild-type. Interestingly, DeltaTpAmyR produced approximately 20% of amylase secreted by the parent strain DeltaTpKu70 in medium containing soluble starch from corn as the sole carbon source. Real-time quantitative reverse transcription PCR showed that TpAmyR positively regulated the expression of genes encoding alpha-amylase and glucoamylase. Thus, this study provides a useful tool for genetic analysis of T. pinophilus, and identification of a key role for the transcription factor TpAmyR in amylase production in T. pinophilus. PMID- 28849310 TI - Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma. AB - We characterized health-related quality of life (HRQoL), cognitive, and functional status in newly diagnosed glioblastoma (GBM) patients receiving Tumor treating fields (TTFields) with temozolomide (TMZ) versus TMZ alone in a planned interim analysis of a randomized phase III trial [NCT00916409], which showed significant improvement in progression-free and overall survival with TTFields/TMZ. After radiotherapy with concomitant TMZ, newly diagnosed GBM patients were randomized (2:1) to TTFields/TMZ (n = 210) or TMZ (n = 105). Interim analysis was performed in 315 patients with >=18 months of follow-up. HRQoL, a secondary endpoint, was evaluated in per-protocol patient population and expressed as change from baseline (CFB) at 3, 6, and 9 months for each subscale in the EORTC QLQ-C30/BN20. Karnofsky performance scores (KPS) and Mini-Mental State Examination scores (MMSE) were assessed. CFB in HRQoL was balanced in treatment groups at the 12-month time point. Initially, HRQoL improved in patients treated with TTFields/TMZ (CFB3: 24% and CFB6: 13%) versus TMZ (CFB3: 7% and CFB6: -17%), though this difference was no longer evident at the 9-month point. General scales, including physical and social functioning, showed no difference at 9 and 12 months. TTFields/TMZ group reported higher concerns of "itchy skin". KPS over 12 months was just below 90 in both groups. Cognitive status (MMSE) was stable over time. HRQoL, KPS, and MMSE were balanced in both groups over time. There was no preliminary evidence that HRQoL, cognitive, and functional status is adversely affected by the continuous use of TTFields. PMID- 28849311 TI - Psychometric validation of the SF-36(r) Health Survey in ulcerative colitis: results from a systematic literature review. AB - PURPOSE: To conduct a systematic literature review of the reliability, construct validity, and responsiveness of the SF-36(r) Health Survey (SF-36) in patients with ulcerative colitis (UC). METHODS: We performed a systematic search of electronic medical databases to identify published peer-reviewed studies which reported scores from the eight scales and/or two summary measures of the SF-36 collected from adult patients with UC. Study findings relevant to reliability, construct validity, and responsiveness were reviewed. RESULTS: Data were extracted and summarized from 43 articles meeting inclusion criteria. Convergent validity was supported by findings that 83% (197/236) of correlations between SF 36 scales and measures of disease symptoms, disease activity, and functioning exceeded the prespecified threshold (r >= |0.40|). Known-groups validity was supported by findings of clinically meaningful differences in SF-36 scores between subgroups of patients when classified by disease activity (i.e., active versus inactive), symptom status, and comorbidity status. Responsiveness was supported by findings of clinically meaningful changes in SF-36 scores following treatment in non-comparative trials, and by meaningfully larger improvements in SF-36 scores in treatment arms relative to controls in randomized controlled trials. The sole study of SF-36 reliability found evidence supporting internal consistency (Cronbach's alpha >= 0.70) for all SF-36 scales and test-retest reliability (intraclass correlation coefficient >=0.70) for six of eight scales. CONCLUSIONS: Evidence from this systematic literature review indicates that the SF-36 is reliable, valid, and responsive when used with UC patients, supporting the inclusion of the SF-36 as an endpoint in clinical trials for this patient population. PMID- 28849312 TI - Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing. AB - Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient's genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies. PMID- 28849319 TI - Robotic assisted radical prostatectomy for localised prostate cancer in thalidomide generation. AB - Thalidomide was used in the late 1950s and early 1960s as a sedative for morning sickness in pregnant women. It resulted in thousands of babies being born with various congenital anomalies, such as phocomelia. Subsequently, the drug was banned for this indication. Most of the survivors have become thalidomide adults and now they are in their fifties. We report the first case of a robot-assisted radical prostatectomy in a 54-year-old male with prostate cancer and phocomelia as a result of thalidomide embryopathy. He presented with a PSA of 3.3 and was diagnosed with Gleason 3 + 4 prostate cancer. An extra peritoneal approach was chosen due to his body habitus and to avoid extreme Trendelenburg tilt. Side docking with the da Vinci robot was employed and the prostatectomy was carried out in the standard extra peritoneal fashion. At 6 months' follow-up his PSA is unrecordable and he is voiding well with minimal urinary incontinence, requiring 1 pad/day. We aim to outline our approach and highlight the technical modifications in this rare physically disabling condition. PMID- 28849317 TI - Knee cartilage segmentation and thickness computation from ultrasound images. AB - Quantitative thickness computation of knee cartilage in ultrasound images requires segmentation of a monotonous hypoechoic band between the soft tissue cartilage interface and the cartilage-bone interface. Speckle noise and intensity bias captured in the ultrasound images often complicates the segmentation task. This paper presents knee cartilage segmentation using locally statistical level set method (LSLSM) and thickness computation using normal distance. Comparison on several level set methods in the attempt of segmenting the knee cartilage shows that LSLSM yields a more satisfactory result. When LSLSM was applied to 80 datasets, the qualitative segmentation assessment indicates a substantial agreement with Cohen's kappa coefficient of 0.73. The quantitative validation metrics of Dice similarity coefficient and Hausdorff distance have average values of 0.91 +/- 0.01 and 6.21 +/- 0.59 pixels, respectively. These satisfactory segmentation results are making the true thickness between two interfaces of the cartilage possible to be computed based on the segmented images. The measured cartilage thickness ranged from 1.35 to 2.42 mm with an average value of 1.97 +/- 0.11 mm, reflecting the robustness of the segmentation algorithm to various cartilage thickness. These results indicate a potential application of the methods described for assessment of cartilage degeneration where changes in the cartilage thickness can be quantified over time by comparing the true thickness at a certain time interval. PMID- 28849318 TI - Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a meta-analysis of randomized controlled trials. AB - The aim of this study is to meta-analytically assess the efficacy and safety of adjunctive raloxifene for postmenopausal women with schizophrenia. Six studies with 440 patients, including 225 (51.14%) patients on raloxifene and 215 (48.86%) on placebo who completed 13.71 +/- 5.09 weeks of treatment, were included in this study. Meta-analysis of Positive and Negative Syndrome Scale total scores and positive, negative, and general symptom scores [standard mean difference (SMD) 0.22 to -0.55, 95% confidence interval (CI) -1.01 to -0.02, p = 0.04-0.01; I 2 = 74-79%] revealed an advantage of adjunctive raloxifene treatment over placebo treatment. There was no significant difference regarding discontinuation rate [risk ratio (RR) = 1.38, p = 0.51] and adverse drug reactions (RR = 1.27, p = 0.57) between the two groups. This meta-analysis showed that adjunctive raloxifene appears to be efficacious and safe for postmenopausal women with schizophrenia. Moreover, raloxifene may be efficacious for patients with less severe symptoms. Future studies with a large sample size are needed to confirm these findings. PMID- 28849316 TI - Infrared thermography relationship between the temperature of the vulvar skin, ovarian activity, and pregnancy rates in Braford cows. AB - The objective of this study was to compare the presence of ovarian activity and pregnancy rates to temperature variation at the vulvar skin measured by infrared thermography (IRT). In addition, we also aimed to evaluate the IRT as a non invasive method to evaluate animal breeding from fixed timed artificial insemination (FTAI). The study comprises 150 non-lactating beef Braford cows (5/8 Hereford * 3/8 Nellore) aged between 3 and 10 years. Data were collected along the FTAI protocol period during animal management. Animals were subjected to reproductive ultrasound evaluation and thermal images were performed by an infrared camera. Mean skin vulvar temperature ( degrees C) and ovarian structures data were compared using Tukey's t test used as follow-up test to ANOVA. We observed a statistical difference in the mean vulvar skin temperature between animals that had the presence of ovarian follicles (34.2 +/- 1.8) compared to no activity (35.4 +/- 1.0; P < 0.05). However, vulvar skin temperature were similar between pregnant (34.5 +/- 1.5) compared to non-pregnant (34.3 +/- 1.9) animals (P > 0.05). In conclusion, the IRT technique was efficient to detect changes on vulvar skin temperature observed during FTAI protocol in Braford cows. Therefore, the use of IRT as an indirectly diagnostic tool to detect ovarian activity seems promising and further studies are required to validate their potential in beef cattle production. PMID- 28849320 TI - Triglyceride metabolism in Japanese kidney transplant recipients. AB - BACKGROUND: Residual cardiovascular risk factors, such as triglyceride (TG), can cause cardiovascular disease. The role of TG metabolism in kidney transplantation remains unclear. METHODS: Sixty-three consecutive stable recipients at 1 year after their kidney transplants were included in the study from January to September 2014 at Nagoya Daini Red Cross Hospital. We performed the cookie test to evaluate TG metabolism. TG, blood sugar, and remnant-like particle cholesterol (RLP-C) were measured at fasting (f) and 2 and 4 h after ingestion. Low- and high density lipoprotein cholesterol (LDL-C and HDL-C, respectively) and apoB levels were measured at fasting. RESULTS: Mean TGf and RLP-Cf were 139.4 +/- 62.6 and 5.6 +/- 3.4 mg/dl, respectively, and were within normal ranges; however, both mean TG 2 and 4 h were >200 mg/dl, and both mean RLP-C 2 and 4 h were >9 mg/dl. A negative correlation was seen between TGf and eGFR (r = -0.48, p < 0.001). TGf positively correlated with RLP-C, non-HDL-C, LDL-C/apoB ratio, and body mass index (r = 0.80, p < 0.001; r = 0.47, p < 0.001; r = 0.48, p < 0.001; and r = 0.38, p = 0.002, respectively). LDL-C levels were controlled because of the use of statin, but LDL-C/apoB ratio levels in 50% of the recipients were <1.2, indicating that the rate of small dense LDL-C in LDL-C had increased. CONCLUSION: The prevalence of postprandial hypertriglyceridemia among kidney transplant recipients was high; however, the question of whether or not it should be treated remains unknown. PMID- 28849315 TI - The Treponema pallidum Outer Membrane. AB - The outer membrane (OM) of Treponema pallidum, the uncultivatable agent of venereal syphilis, has long been the subject of misconceptions and controversy. Decades ago, researchers postulated that T. pallidum's poor surface antigenicity is the basis for its ability to cause persistent infection, but they mistakenly attributed this enigmatic property to the presence of a protective outer coat of serum proteins and mucopolysaccharides. Subsequent studies revealed that the OM is the barrier to antibody binding, that it contains a paucity of integral membrane proteins, and that the preponderance of the spirochete's immunogenic lipoproteins is periplasmic. Since the advent of recombinant DNA technology, the fragility of the OM, its low protein content, and the lack of sequence relatedness between T. pallidum and Gram-negative outer membrane proteins (OMPs) have complicated efforts to characterize molecules residing at the host-pathogen interface. We have overcome these hurdles using the genomic sequence in concert with computational tools to identify proteins predicted to form beta-barrels, the hallmark conformation of OMPs in double-membrane organisms and evolutionarily related eukaryotic organelles. We also have employed diverse methodologies to confirm that some candidate OMPs do, in fact, form amphiphilic beta-barrels and are surface-exposed in T. pallidum. These studies have led to a structural homology model for BamA and established the bipartite topology of the T. pallidum repeat (Tpr) family of proteins. Recent bioinformatics has identified several structural orthologs for well-characterized Gram-negative OMPs, suggesting that the T. pallidum OMP repertoire is more Gram-negative-like than previously supposed. Lipoprotein adhesins and proteases on the spirochete surface also may contribute to disease pathogenesis and protective immunity. PMID- 28849321 TI - An Approach to Integrating Health Disparities within Undergraduate Biomedical Engineering Education. AB - Health disparities are preventable differences in the incidence, prevalence and burden of disease among communities targeted by gender, geographic location, ethnicity and/or socio-economic status. While biomedical research has identified partial origin(s) of divergent burden and impact of disease, the innovation needed to eradicate health disparities in the United States requires unique engagement from biomedical engineers. Increasing awareness of the prevalence and consequences of health disparities is particularly attractive to today's undergraduates, who have undauntedly challenged paradigms believed to foster inequality. Here, the Department of Biomedical Engineering at The City College of New York (CCNY) has leveraged its historical mission of access-and-excellence to integrate the study of health disparities into undergraduate BME curricula. This article describes our novel approach in a multiyear study that: (i) Integrated health disparities modules at all levels of the required undergraduate BME curriculum; (ii) Developed opportunities to include impacts of health disparities into undergraduate BME research projects and mentored High School summer STEM training; and (iii) Established health disparities-based challenges as BME capstone design and/or independent entrepreneurship projects. Results illustrate the rising awareness of health disparities among the youngest BMEs-to-be, as well as abundant undergraduate desire to integrate health disparities within BME education and training. PMID- 28849322 TI - EPR Technology as Sensitive Method for Oxidative Stress Detection in Primary and Secondary Keratinocytes Induced by Two Selected Nanoparticles. AB - Exogenous factors can cause an imbalance in the redox state of biological systems, promoting the development of oxidative stress, especially reactive oxygen species (ROS). To monitor the intensity of ROS production in secondary keratinocytes (HaCaT) by diesel exhaust particles and thermoresponsive nanogels (tNG), electron paramagnetic resonance (EPR) spectroscopy after 1 and 24 h of incubation, respectively, was applied. Their cytotoxicity was analyzed by a cell viability assay (XTT). For tNG an increase in the cell viability and ROS production of 10% was visible after 24 h, whereas 1 h showed no effect. A ten times lower concentration of diesel exhaust particles exhibited no significant toxic effects on HaCaT cells for both incubation times, thus normal adult human keratinocytes (NHK) were additionally analyzed by XTT and EPR spectroscopy. Here, after 24 h a slight increase of 18% in metabolic activity was observed. However, this effect could not be explained by the ROS formation. A slight increase in the ROS production was only visible after 1 h of incubation time for HaCaT (9%) and NHK (14%). PMID- 28849325 TI - Tattoo Sarcoidosis. PMID- 28849328 TI - Tirone on Tirone David operation and types. PMID- 28849323 TI - In-Hospital Mortality and Post-Surgical Complications Among Cancer Patients with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) is an important etiologic and prognostic factor for cancer, but few studies have assessed hospitalization outcomes among patients with both conditions. METHODS: Data was obtained from the Healthcare Cost and Utilization project Nationwide Inpatient Sample (HCUP-NIS). Study variables were assessed using ICD-9 codes on adults aged 40 years and over admitted to a US hospital between 2007 and 2011 with primary diagnosis of either breast, colorectal, or prostate cancer. We examined in-hospital mortality, post surgical complications, and discharge disposition among cancer patients with MetS and compared with non-MetS patients. RESULTS: Hospitalized breast (OR: 0.31, 95% CI: 0.20-0.46), colorectal (OR: 0.41, 95% CI: 0.35-0.49), and prostate (OR: 0.28, 95% CI: 0.16-0.49) cancer patients with MetS had significantly reduced odds of in hospital mortality. The odds of post-surgical complications among breast (OR: 1.20, 95% CI: 1.03-1.39) and prostate (OR: 1.22, 95% CI: 1.09-1.37) cancer patients with MetS were higher, but lower by 7% among colorectal cancer patients with MetS. Additionally, breast (OR: 1.21, 95% CI: 1.11-1.32) and colorectal (OR: 1.06, 95% CI: 1.01-1.11) cancer patients with MetS had significantly higher odds for discharge to a skilled nursing facility compared with those without MetS, but this was not statistically significant among prostate cancer patients. CONCLUSIONS: Adverse health outcomes were significantly higher among hospitalized patients with a primary diagnosis of cancer and MetS. Future studies are needed to identify clinical strategies for detecting and managing patients with MetS to reduce the likelihood of poor inpatient outcomes. PMID- 28849331 TI - Self Regulation, Cognitive Capacity and Risk Taking: Investigating Heterogeneity Among Adolescents with Callous-Unemotional Traits. AB - The majority of prior work focuses on understanding the association between callous-unemotional (CU) traits and conduct problems, providing limited information on why some youth who score high on CU traits do not engage in conduct problem behaviors. The current study investigated heterogeneity among a sub-sample of adolescents with CU traits (N = 152; Mage = 13.09, SD = 2.76, 45.6% female) identified from a large community sample. Three groups were compared: control, callous-unemotional traits only (CU-only), and combined callous unemotional and conduct problems (CU + CP). Participants were administered a battery of neuropsychological computerized tasks assessing risk taking, self regulation and cognitive capacity. Results indicated that youth high on CU traits and low on CP scored higher on self-regulation and were less likely to make risky decisions compared to youth with combined CU + CP. In general, the findings provided information that heterogeneity within CU traits can be explained based on differences in neuro-cognitive functioning. In addition, the characteristics of youth high on CU traits only can provide information for interventions aiming to decrease conduct problems among youth high on these traits. PMID- 28849327 TI - The Complex Interplay of Physical Fitness, Protein Intake, and Vitamin D Supplementation After Bariatric Surgery. PMID- 28849329 TI - Analysis of Nausea in Clinical Studies of Lubiprostone for the Treatment of Constipation Disorders. AB - BACKGROUND: Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event. AIMS: To characterize nausea with lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C. METHODS: Data from three 3- and 4-week placebo-controlled studies and three long-term open label studies were pooled for the CIC analysis. The OIC and IBS-C analyses each used pooled data from three 12-week placebo-controlled studies and one 36-week open-label extension study. RESULTS: The populations included the following numbers of patients: CIC, 316 (placebo) and 1113 (lubiprostone 24 mcg twice daily [BID]); OIC, 652 (placebo) and 889 (lubiprostone 24 mcg BID); and IBS-C, 435 (placebo) and 1011 (lubiprostone 8 mcg BID). The incidence of nausea in lubiprostone-treated patients ranged from 11.4 to 31.1%, with the highest incidence in patients with CIC. Among patients with any nausea, most reported only mild or moderate severity (96.5-99.1% across indications) and only one event (83.6-88.7%); most events occurred within the first 5 days of treatment. CONCLUSIONS: Nausea was the most common adverse event following the treatment with lubiprostone. Event rates varied by indication and dose, and the majority of nausea adverse events were mild to moderate in severity. Nausea events predominantly occurred early in the treatment period in all of the pooled study populations. PMID- 28849324 TI - Automated breast ultrasound: basic principles and emerging clinical applications. AB - Automated breast ultrasound (ABUS) is a recently introduced ultrasonography technique, developed with the purpose to standardize breast ultrasonography and overcome some limitations of handheld ultrasound (HHUS), such as operator dependence and the considerable amount of medical time necessary to perform and interpret HHUS. This new ultrasonography technique separates the moment of image acquisition (that may be performed also by a technician) from that of its interpretation, increasing reproducibility, reducing operator-dependence and physician time. Moreover, multiplanar reconstructions, especially the coronal view, introduce new diagnostic information. ABUS, with those advantages, has the potential to be used as an adjunctive tool to screening mammography, especially in the dense breast, where mammography has a relatively low sensitivity. Women's awareness of risks related to breast density is a hot topic, especially in the USA where legislative breast density notification laws increase the demand for supplemental ultrasound screening. Therefore, ABUS might have the potential to respond to this need. The purpose of this article is to present a summary of current state-of-the-art of ABUS technology and applications, with an emphasis on breast cancer screening. This article discusses also how to overcome some ABUS limitations, in order to be familiar with the new technique. PMID- 28849326 TI - [CyberKnife(r): new treatment option for uveal melanoma]. AB - BACKGROUND: CyberKnife(r) stereotactic radiosurgery is a new treatment option for uveal melanoma. OBJECTIVE: This review outlines the technique of robot-assisted CyberKnife(r) therapy, as well as the pros and cons in the treatment of uveal melanoma. METHODS: The study provides a PubMed literature review and own preliminary clinical experiences. RESULTS: CyberKnife(r) therapy for choroidal and ciliary body melanomas shows comparable results concerning local tumor control and overall survival matching those of conventional therapies. With only low complication rates, a high level of quality of life can be conserved by possible preservation of visual acuity as well as the ocular globe. CONCLUSION: Stereotactic radiosurgery using CyberKnife(r) seems to be an efficient and safe therapeutic option for malignant melanomas affecting the choroid and ciliary body. Comparative studies with conventional radiation strategies are now a high priority. PMID- 28849335 TI - The comparability of drug-induced sedation endoscopy classification systems. PMID- 28849334 TI - Cytogenetic evidence for the clonal hematopoietic cell origin of alveolar macrophages in myelodysplastic syndrome-associated pulmonary alveolar proteinosis. PMID- 28849330 TI - Bile Gastritis Following Laparoscopic Single Anastomosis Gastric Bypass: Pilot Study to Assess Significance of Bilirubin Level in Gastric Aspirate. AB - INTRODUCTION: Laparoscopic single anastomosis gastric bypass (SAGB) is increasingly performed for morbidly obese patients. AIM OF WORK: This pilot study aims primarily at evaluating the incidence of bile gastritis after SAGB. The occurrence of reflux oesophagitis and reflux symptoms were also assessed. PATIENTS AND METHODS: This study included 20 patients having no reflux symptoms. All patients underwent a SAGB as a primary bariatric procedure by a single surgeon. Patients included consented to have an upper GI endoscopy done at 6 months postoperatively. Gastric aspirate was sent for bilirubin level assessment. Gastric and esophageal biopsies were submitted for histopathology and campylobacter-like organism (CLO) test. RESULTS: In our study, the rate of bile gastritis was 30%. In 18 patients, the level of bilirubin in gastric aspirate seems to be related to the degree of mucosal inflammation. The remaining two patients had microscopic moderate to severe gastritis with normal aspirate bilirubin level. Two patients with bilirubin level in aspirate more than 20 mg/dl had severe oesophagitis, gastritis with erosions, and metaplasia. Relationship between bilirubin level and histopathological findings of gastric biopsy examination was statistically significant with a P value of 0.001. CONCLUSION: The incidence of bile gastritis in this cohort is higher than reported in the literature, and this may be worrying. The correlation between endoscopic findings and patients' symptoms is poor. Bilirubin level and pH in aspirate might be useful tools to confirm alkaline reflux. Its level might help to choose candidates for revision surgery after SAGB. This needs further validation with larger sample size. PMID- 28849332 TI - Peg-manipulation capabilities during a test of manual dexterity differ for persons with multiple sclerosis and healthy individuals. AB - Manual dexterity declines with advancing age and the development of neurological disorders. Changes in manual dexterity are frequently quantified as the time it takes to complete the grooved pegboard test, which requires individuals to manipulate 25 pegs. The manipulation of each peg involves four phases: selection, transport, insertion, and return. The purpose of the study was to compare the times to complete the four phases of manipulating each peg and the forces applied to the pegboard during peg selection and insertion in persons with multiple sclerosis (MS) and age- and sex-matched healthy adults. Multiple-regression models that could explain the variance in pegboard times for each group of participants were compared to assess the relative significance of the peg manipulation attributes. The performance of 17 persons with MS (52.2 +/- 8.3 years) was compared with 17 control subjects (52.2 +/- 11.5 years). The grooved pegboard test was performed on a force plate. Pegboard times for the MS group (104 +/- 40 s) were longer than those for the Control group (61 +/- 15 s). Regression analysis indicated that the pegboard times for the MS group could be predicted by the time for the peg-selection phase (R 2 = 0.78), whereas the predictors for Control group (R 2 = 0.77) were the times for the peg-transport (partial r = 0.80) and selection (partial r = 0.58) phases. The variance in the time it took the MS participants to complete the grooved pegboard test was strongly related to the time required to select each peg, whereas the pegboard times for the Control subjects depended mostly on the duration of the transport phase but also on the time to select each peg. PMID- 28849333 TI - Novel View on Umbilical Cord Blood and Maternal Peripheral Blood-an Evidence for an Increase in the Number of Circulating Stem Cells on Both Sides of the Fetal Maternal Circulation Barrier. AB - Umbilical cord blood (UCB) is a rich source of stem cells, including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitors cells (EPCs), and very small embryonic-like stem cells (VSELs). These cells most likely are mobilized into UCB in response to hypoxia and delivery stress. We have hypothesized that they may play a role in repairing certain tissue/organ injuries that occur in the newborn child after delivery. Here we asked whether delivery also mobilizes stem cells into maternal blood, as the mother also experiences hypoxia and several types of internal tissue injuries, particularly in the reproductive tract. We observed that the number of HSCs, MSCs, EPCs, and VSELs increases in maternal blood at 24 h after physiological delivery (n = 17). Based on this observation, we propose that delivery stress is associated with an increase in the number of circulating stem cells, not only on the fetal side but also on the maternal side of the fetal-maternal circulatory barrier. PMID- 28849336 TI - From Paternalistic to Patronizing: How Cultural Competence Can Be Ethically Problematic. AB - Cultural competence literature and training aim to equip healthcare workers to better understand patients of different cultures and value systems, in an effort to ensure effective and equitable healthcare services for diverse patient populations. However, without nuanced awareness and contextual knowledge, the values embedded within cultural competence practice may cripple rather than empower the very people they mean to respect. A narrow cultural view can lessen cultural understanding rather than grow it. In its first part, this paper argues that a hasty, unrestrained, and uneducated willingness to accept something as a cultural good, despite being well intentioned, can still cause significant harms particularly when based on false, misinformed, and stereotypical conceptions including the minimization of issues, the reinforcement of stereotypes, and the impediment of cultural change. The second part of this paper examines medical autonomy within the context of Saudi Arabian women. It pushes back on the common perception that Saudi women, by virtue of culture and religion, view dependency on and deference to male relatives as a cultural good. Through a historical examination and a presentation of the current women's movement in Saudi Arabia, it is argued that the continued assumption that personal agency is a value external to Saudi women is false, misguided, and ethically problematic. Lastly, this paper considers some approaches to help providers navigate the narrow grounds between paternalism and patronization when caring for patients. PMID- 28849337 TI - Cognitive functioning and quality of life following chemotherapy in pre- and peri menopausal women with breast cancer. AB - PURPOSE: The purpose of the study was to prospectively examine changes in subjective and objective cognitive functions and quality of life (QOL) for pre- and peri-menopausal women receiving chemotherapy for breast cancer and to explore potential predictors of cognitive changes. METHODS: Participants were assessed as follows: prior to chemotherapy (T1), after cycle 3 (T2), within 2-3 weeks of completing adjuvant chemotherapy (T3) (N = 20), and 8+ years later (T4; n = 18). Objective cognitive function was measured with the High Sensitivity Cognitive Screen (T1, T3, T4). Subjective measures for cognitive function, depressive symptoms, fatigue, and mental and physical QOL were assessed at all time points. Estradiol levels were measured at T1, T2, and T3. The Functional Assessment of Cancer Therapy-Cognition and the MD Anderson Cancer Symptom Inventory item for neuropathy were administered at T4. RESULTS: No significant changes in objective cognitive function were found. However, participants reported decreased cognitive function over the course of treatment accompanied by depressive symptoms and fatigue. Depression and fatigue returned to near-baseline levels at T4, but over half of the participants continued to report mild to moderate depression. Estradiol levels were not associated with cognitive function. Neuropathy and higher body mass index (BMI) were associated with persistent cognitive complaints at T4 (adjusted R 2 = 0.712, p = 0.001). Higher QOL was correlated with better subjective cognitive function (r = 0.705, p = 0.002) and lower body mass index (r = - 0.502, p = 0.017) at T4. CONCLUSIONS: Further investigation of BMI, neuropathy, and depressive symptoms as predictors of persistent cognitive dysfunction following chemotherapy for breast cancer is warranted. PMID- 28849338 TI - Associations Between Peer Network Gender Norms and the Perpetration of Intimate Partner Violence Among Urban Tanzanian Men: a Multilevel Analysis. AB - Male perpetration of intimate partner violence (IPV) against women in sub-Saharan Africa is widespread. Theory and empirical evidence suggest peer networks may play an important role in shaping IPV perpetration, though research on this topic in the region is limited. We assessed the degree to which peer network gender norms are associated with Tanzanian men's perpetration of IPV and examined whether the social cohesion of peer networks moderates this relationship. Using baseline data from sexually active men (n = 1103) nested within 59 peer networks enrolled in an on-going cluster-randomized HIV and IPV prevention trial, we fit multilevel logistic regression models to examine peer network-level factors associated with past-year physical IPV perpetration. Peer network gender norms were significantly associated with men's risk of perpetrating IPV, even after adjusting for their own attitudes toward gender roles (OR = 1.53 , p = . 04). Peer network social cohesion moderated this relationship (OR = 1.50 , p = . 04); the positive relationship between increasingly inequitable (i.e., traditional) peer network gender norms and men's risk of perpetrating IPV became stronger, as peer network social cohesion increased. Characteristics of the peer network context are associated with men's IPV perpetration and should be targeted in future interventions. While many IPV prevention interventions focus on changing individual attitudes, our findings support a unique approach, focused on transforming the peer context. PMID- 28849342 TI - Greenlandic water and sanitation-a context oriented analysis of system challenges towards local sustainable development. AB - Today, as Greenland focuses on more economic and cultural autonomy, the continued development of societal infrastructure systems is vital. At the same time, pressure is put on the systems by a lack of financial resources and locally based professional competences as well as new market-based forms of organization. Against this background, the article discusses the challenges facing Greenland's self-rule in relation to further develop the existing water and wastewater systems so that they can contribute to the sustainable development of Greenland. The article reviews the historical development of the water supply and wastewater system. This leads to an analysis of the sectorisation, which in recent decades has reorganized the Greenlandic infrastructures, and of how this process is influencing local sustainable development. The article discusses the socio economic and human impacts and points to the need for developing the water and sanitation system to support not only hygiene and health, but also local sustainable development. PMID- 28849343 TI - Skin toxicities associated with tumor treating fields: case based review. AB - The novel anti-mitotic based tumor treating fields (TTFields) is FDA approved for recurrent glioblastoma. Recently the phase III upfront trial combining the Novo TTF-100A device, called Optune, with temozolomide following concurrent radiation therapy and chemotherapy, demonstrated improvement in survival. Wider use of this novel therapy is expected. The most common adverse event is dermatologic, which dominates compared to the next most frequently observed adverse event of headaches, the incidence of which was even in both arms in the phase III registration trial for recurrent glioblastoma. Our case review outlines the presentation, treatment, and outcome of representative patients using TTFields. In summary, preventative strategies to inform and educate patients and operators can prevent many of these dermatological events. Skin toxicity in the setting of concurrent use of TTFields with other therapies such as bevacizumab is an unknown and will need to be closely followed. PMID- 28849340 TI - Insulinoma-associated protein 1 (INSM1) is a useful marker for pancreatic neuroendocrine tumor. AB - Insulinoma-associated protein 1 (INSM1) is an important biomarker of Achaete scute homolog-like 1-driven pathways. For diagnosis of pancreatic neuroendocrine tumors (PanNET), chromogranin A (CGA), synaptophysin (SYP), and neural cell adhesion molecule (NCAM) were also considered as potential biomarkers. However, it is often difficult to diagnose it immunohistochemically. Hence, we examined the expression pattern of INSM1 in pancreatic solid tumors. We detected INSM1, CGA, SYP, and NCAM immunohistochemically, in 27 cases of NET [pure type: 25 cases, mixed adenoneuroendocrine carcinoma (MANEC): 2 cases]. We included 5 cases of solid-pseudopapillary neoplasm (SPN), 7 cases of acinar cell carcinoma (ACC), and 15 cases of pancreatic ductal adenocarcinoma (PDAC) as the control group. Nuclear expression of INSM1 was found in all PanNET pure type cases. However, expression of INSM1 was negative in PDAC, ACC, and SPN in all cases, whereas faint expression was seen in the cytoplasm from SPN. MANEC comprises of two components: neuroendocrine carcinoma and adenocarcinoma components. The NET component was positive for INSM1 expression, whereas the PDAC component does not express INSM1, which aids in distinguishing these components. Our results suggest that INSM1 is a useful immunohistochemical marker for diagnosing pancreatic neuroendocrine tumor. PMID- 28849341 TI - [German ophthalmology in developing countries : Partnerships with eye clinics in developing countries - an initiative of the German Ophthalmological Society]. AB - In 1999 the global initiative "Vision 2020 - The Right to Sight" was established by the World Health Organization (WHO), the International Agency for the Prevention of Blindness (IAPB) and several non-governmental organizations (NGOs) with the goal of reducing avoidable blindness. Based on this initiative, the working group "International Ophthalmology" of the German Ophthalmological Society (DOG), which was established in 1994, was converted into a DOG section with the same name in 2004 and represents one of the core components of the DOG; however, even before there were a number of established partnerships of German and African eye hospitals. The first cooperation of this kind was the partnership between the Department of Ophthalmology, Ludwig-Maximilians University Munich and the University of Nairobi, Kenya, which was founded in 1978. As a result of this cooperation, the Department of Ophthalmology in Nairobi has evolved into one of the major centers of ophthalmological training and ophthalmic care in East Africa. Since then a number of similar cooperation projects between several hospitals and numerous further projects (e. g. in Myanmar) have been implemented and some of these are presented in this manuscript. PMID- 28849347 TI - The impact of comorbidities on hip fracture mortality: a retrospective population based cohort study. AB - : The impact of comorbidities on hip fracture-related excess mortality was assessed in a population-based age- and sex-matched cohort over 10 years. On average, only 1 out of 12 excess deaths over 10 years was related to pre-fracture life-threatening comorbidities. The presence of life-threatening comorbidities increased the excess risk of death after hip fracture. PURPOSE: This work aimed to estimate the impact of pre-fracture comorbidities on the 10-year excess risk of all-cause death after hip fracture among Estonian men and women >= 50 years of age. METHODS: Retrospective, population-based 10-year study of people aged >= 50 in two cohorts: those with a hip fracture and an age- and sex-matched random sample from the national health insurance fund for comparison. RESULTS: We found that hip fracture was a strong independent risk factor for death. Upon adjustment for Charlson Comorbidities Index (CCI) score, the impact of life-threatening comorbidities on average hip fracture-related excess mortality was modest: only 8% of excess deaths over 10 years were related to comorbidities. Upon stratification by CCI groups, the excess risk of patients in CCI groups >= 3 and 1-2 exceeded that in the CCI 0 group over 5-7 years, indicating that in patients with life-threatening comorbidities, a hip fracture accelerates the chain of lethal events and brings deaths from other conditions forward. The impact of comorbidities was age- and time-dependent: in younger hip fracture patients, the comorbidities almost doubled the excess risk from a fracture in 10 years; in older patients, the effect was shorter and modest. CONCLUSIONS: The presence of pre-fracture comorbidities increases the risk of excess death in hip fracture patients, but the comorbidity impact on aggregated excess mortality is modest. PMID- 28849339 TI - Growth hormone-producing pituitary adenomas in childhood and young adulthood: clinical features and outcomes. AB - PURPOSE: Growth hormone (GH)-producing pituitary adenomas (PAs) in childhood or young adulthood are rare, and the details surrounding these tumors remain enigmatic. We present the clinical, pathological and genetic features of this disease. METHODS: We identified 25 patients aged 20 years or younger with GH producing PAs who underwent surgery between 2003 and 2016 at Toranomon Hospital in Tokyo. We retrospectively reviewed the clinical data, treatment outcomes and pathological features of these patients to shed light on childhood acromegaly. RESULTS: The cohort comprised 14 male and 11 female patients whose average age at the time of surgery was 17.3 years. Germline AIP mutations were present in 5 of 13 patients examined, and Carney complex was identified in 2 of 25 patients. The mean maximum tumor diameter was 26.7 mm, and total resection assessed during surgery was achieved in 17 patients. Based on their respective pathological findings, patients were divided into the following 4 groups: sparsely granulated adenomas (5), densely granulated (DG) adenomas (6), plurihormonal adenomas (9), and silent subtype 3 (SS3) adenomas (5). During the mean follow-up period of 50.3 months, complete endocrinological remission was achieved in 14 of 25 patients (56%) by surgery alone and in 19 patients (76%) after postoperative adjuvant therapy. CONCLUSIONS: GH-producing PAs in young patients are intriguing and difficult to treat due to their distinct tumor characteristics, including a lower incidence of the DG subtype and a higher incidence of SS3 adenomas and genetic abnormalities. Therefore, multi-modal therapies are essential to achieve optimal clinical outcomes. PMID- 28849346 TI - ATM is required for SOD2 expression and homeostasis within the mammary gland. AB - PURPOSE: ATM activates the NF-kappaB transcriptional complex in response to genotoxic and oxidative stress. The purpose of this study was to examine if the NF-kappaB target gene and critical antioxidant SOD2 (MnSOD) in cultured mammary epithelium is also ATM-dependent, and what phenotypes arise from deletion of ATM and SOD2 within the mammary gland. METHODS: SOD2 expression was studied in human mammary epithelial cells and MCF10A using RNAi to knockdown ATM or the NF-kappaB subunit RelA. To study ATM and SOD2 function in mammary glands, mouse lines containing Atm or Sod2 genes containing LoxP sites were mated with mice harboring Cre recombinase under the control of the whey acidic protein promoter. Quantitative PCR was used to measure gene expression, and mammary gland structure was studied using histology. RESULTS: SOD2 expression is ATM- and RelA-dependent, ATM knockdown renders cells sensitive to pro-oxidant exposure, and SOD mimetics partially rescue this sensitivity. Mice with germline deletion of Atm fail to develop mature mammary glands, but using a conditional knockout approach, we determined that Atm deletion significantly diminished the expression of Sod2. We also observed that these mice (termed AtmDelta/Delta) displayed a progressive lactation defect as judged by reduced pup growth rate, aberrant lobulo-alveolar structure, diminished milk protein gene expression, and increased apoptosis within lactating glands. This phenotype appears to be linked to dysregulated Sod2 expression as mammary gland-specific deletion of Sod2 phenocopies defects observed in AtmDelta/Delta dams. CONCLUSIONS: We conclude that ATM is required to promote expression of SOD2 within the mammary epithelium, and that both ATM and SOD2 play a crucial role in mammary gland homeostasis. PMID- 28849344 TI - Functional characterisation of peroxisomal beta-oxidation disorders in fibroblasts using lipidomics. AB - Peroxisomes play an important role in a variety of metabolic pathways, including the alpha- and beta-oxidation of fatty acids, and the biosynthesis of ether phospholipids. Single peroxisomal enzyme deficiencies (PEDs) are a group of peroxisomal disorders in which either a peroxisomal matrix enzyme or a peroxisomal membrane transporter protein is deficient. To investigate the functional consequences of specific enzyme deficiencies on the lipidome, we performed lipidomics using cultured skin fibroblasts with different defects in the beta-oxidation of very long-chain fatty acids, including ABCD1- (ALD), acyl CoA oxidase 1 (ACOX1)-, D-bifunctional protein (DBP)-, and acyl-CoA binding domain containing protein 5 (ACBD5)-deficient cell lines. Ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry revealed characteristic changes in the phospholipid composition in fibroblasts with different fatty acid beta-oxidation defects. Remarkably, we found that ether phospholipids, including plasmalogens, were decreased. We defined specific phospholipid ratios reflecting the different enzyme defects, which can be used to discriminate the PED fibroblasts from healthy control cells. PMID- 28849348 TI - Thalidomide induces apoptosis in undifferentiated human induced pluripotent stem cells. AB - Thalidomide, which was formerly available commercially to control the symptoms of morning sickness, is a strong teratogen that causes fetal abnormalities. However, the mechanism of thalidomide teratogenicity is not fully understood; thalidomide toxicity is not apparent in rodents, and the use of human embryos is ethically and technically untenable. In this study, we designed an experimental system featuring human-induced pluripotent stem cells (hiPSCs) to investigate the effects of thalidomide. These cells exhibit the same characteristics as those of epiblasts originating from implanted fertilized ova, which give rise to the fetus. Therefore, theoretically, thalidomide exposure during hiPSC differentiation is equivalent to that in the human fetus. We examined the effects of thalidomide on undifferentiated hiPSCs and early-differentiated hiPSCs cultured in media containing bone morphogenetic protein-4, which correspond, respectively, to epiblast (future fetus) and trophoblast (future extra-embryonic tissue). We found that only the number of undifferentiated cells was reduced. In undifferentiated cells, application of thalidomide increased the number of apoptotic and dead cells at day 2 but not day 4. Application of thalidomide did not affect the cell cycle. Furthermore, immunostaining and flow cytometric analysis revealed that thalidomide exposure had no effect on the expression of specific markers of undifferentiated and early trophectodermal differentiated cells. These results suggest that the effect of thalidomide was successfully detected in our experimental system and that thalidomide eliminated a subpopulation of undifferentiated hiPSCs. This study may help to elucidate the mechanisms underlying thalidomide teratogenicity and reveal potential strategies for safely prescribing this drug to pregnant women. PMID- 28849345 TI - Gut microbiota and chronic kidney disease: implications for novel mechanistic insights and therapeutic strategies. AB - The complicated communities of microbiota colonizing the human gastrointestinal tract exert a strong function in health maintenance and disease prevention. Indeed, accumulating evidence has indicated that the intestinal microbiota plays a key role in the pathogenesis and development of chronic kidney disease (CKD). Modulation of the gut microbiome composition in CKD may contribute to the accumulation of gut-derived uremic toxins, high circulating level of lipopolysaccharides and immune deregulation, all of which play a critical role in the pathogenesis of CKD and CKD-associated complications. In this review, we discuss the recent findings on the potential impact of gut microbiota in CKD and the underlying mechanisms by which microbiota can influence kidney diseases and vice versa. Additionally, the potential efficacy of pre-, pro- and synbiotics in the restoration of healthy gut microbia is described in detail to provide future directions for research. PMID- 28849349 TI - Stable expression of alpha1-antitrypsin Portland in MDA-MB-231 cells increased MT1-MMP and MMP-9 levels, but reduced tumour progression. AB - The membrane bound matrix metalloproteinase MT1-MMP plays roles in modulating cell movement, independent of its abilities to remodel the extracellular matrix. Unlike many MMPs, MT1-MMP is activated in the Golgi prior to secretion by a pro protein convertase, primarily furin. Regulation of the activation of pro-MT1-MMP has been methodically investigated, as altering the level of the active protein has broad implications in both activating other pro-MMPs, including pro-MMP-2, and many subsequent remodelling events. Our previous work in MCF-7 cells has demonstrated that modest, and not extremely high, levels of active MT1-MMP manifests into altered cell morphology and movement. At this low but optimal amount of MT1-MMP protein, changes to MT1-MMP levels are always mirrored by MMP-9 and pERK levels, and always opposite to MMP-2 levels. In this study, stable expression of the furin inhibitor alpha1-antitrypsin Portland (alpha1-PDX) in MDA MB-231 cells increased overall MT1-MMP levels, but cells maintained a 21% proportion of pro-MT1-MMP. The increase in MT1-MMP was mirrored by increases in MMP-9 and pERK, but a decrease in MMP-2. These changes were associated with increased NF-kappaB transcription. In vitro analysis showed that alpha1-PDX decreased cell protrusions and migration, and this manifested as decreased tumourigenesis when examined in vivo using a chick CAM assay. PMID- 28849351 TI - Patient autonomy and advance care planning: a qualitative study of oncologist and palliative care physicians' perspectives. AB - IMPORTANCE: Patients' are encouraged to participate in advance care planning (ACP) in order to enhance their autonomy. However, controversy exists as to what it means to be autonomous and there is limited understanding of how social and structural factors may influence cancer patients' ability to exercise their autonomy. OBJECTIVE: The objective of this study is to explore oncologists' and palliative care physicians' understanding of patient autonomy, how this influences reported enactment of decision-making at the end of life (EOL), and the role of ACP in EOL care. DESIGN AND SETTING: Qualitative semi-structured interviews were conducted with consultant oncologists (n = 11) and palliative medicine doctors (n = 7) working in oncology centres and palliative care units across Australia. RESULTS: We found that doctors generally conceptualized autonomy in terms of freedom from interference but that there was a profound disconnect between this understanding of autonomy and clinical practice in EOL decision-making. The clinicians in our study privileged care, relationships and a 'good death' above patient autonomy, and in practice were reluctant to 'abandon' their patients to total non-interference in decision-making. Patient autonomy in healthcare is bounded, as while patients were generally encouraged to express their preferences for care, medical norms about the quality and 'reasonableness' of care, the availability of services and the patients' family relationships act to enhance or limit patients' capacity to realize their preferences. While for many, this disconnect between theory and practice did not diminish the rhetorical appeal of ACP; for others, this undermined the integrity of ACP, as well as its relevance to care. For some, ACP had little to do with patient autonomy and served numerous other ethical, practical and political functions. CONCLUSION: The ethical assumptions regarding patient autonomy embedded in academic literature and policy documents relating to ACP are disconnected from the realities of clinical care. Medical norms and professional boundaries surrounding 'good deaths' have a greater influence on care than patient preference. ACP programs, therefore, may be rejected by healthcare professionals as irrelevant to care or may have the unintended consequence of limiting patient autonomy when used as a professional tool to encourage a 'right' way to die. A singular focus on bureaucratic ACP programs, which reduce patient autonomy to a 'tick box' exercise, may fail to enhance EOL care in any meaningful way. PMID- 28849350 TI - Do Direct Survivors of Terrorism Remaining in the Disaster Community Show Better Long-Term Outcome than Survivors Who Relocate? AB - Little is known about whether, compared to terrorism survivors who relocated to another area, better long-term outcome occurs in terrorism survivors who remain in the community, which may offer social support and formal services as well as ongoing trauma reminders and adversities. A cross-sectional telephone survey of OKC bombing survivors 19 years later assessed current symptoms of PTSD, anxiety and depression; posttraumatic growth; life satisfaction; medical conditions; alcohol use and smoking. We interviewed 138 survivors-114 (82.6%) remaining in OKC area and 24 (17.4%) relocated. Remaining survivors had higher PTS, anxiety and depression and lower posttraumatic growth scores than relocated survivors, and more remaining survivors disagreed with being satisfied with life, with differences not statistically significant. Groups did not differ in major medical problems except heart disease, not significantly different after adjusting for gender. Groups did not differ significantly in smoking or alcohol use. Contrary to expectations, remaining within the community after terrorism was not associated with better long-term psychological or medical outcome. Possible factors relevant to the literature are discussed. PMID- 28849353 TI - Equivalent Treatment and Survival after Resection of Pancreatic Cancer at Safety Net Hospitals. AB - BACKGROUND: Due to disparities in access to care, patients with Medicaid or no health insurance are at risk of not receiving appropriate adjuvant treatment following resection of pancreatic cancer. We have previously shown inferior short term outcomes following surgery at safety-net hospitals. Subsequently, we hypothesized that safety-net hospitals caring for these vulnerable populations utilize less adjuvant chemoradiation, resulting in inferior long-term outcomes. METHODS: The American College of Surgeons National Cancer Data Base was queried for patients diagnosed with pancreatic adenocarcinoma (n = 32,296) from 1998 to 2010. Hospitals were grouped according to safety-net burden, defined as the proportion of patients with Medicaid or no insurance. The highest quartile, representing safety-net hospitals, was compared to lower-burden hospitals with regard to patient demographics, disease characteristics, surgical management, delivery of multimodal systemic therapy, and survival. RESULTS: Patients at safety-net hospitals were less often white, had lower income, and were less educated. Safety-net hospital patients were just as likely to undergo surgical resection (OR 1.03, p = 0.73), achieving similar rates of negative surgical margins when compared to patients at medium and low burden hospitals (70% vs. 73% vs. 66%). Thirty-day mortality rates were 5.6% for high burden hospitals, 5.2% for medium burden hospitals, and 4.3% for low burden hospitals. No clinically significant differences were noted in the proportion of surgical patients receiving either chemotherapy (48% vs. 52% vs. 52%) or radiation therapy (26% vs. 30% vs. 29%) or the time between diagnosis and start of systemic therapy (58 days vs. 61 days vs. 53 days). Across safety-net burden groups, no difference was noted in stage-specific median survival (all p > 0.05) or receipt of adjuvant as opposed to neoadjuvant systemic therapy (82% vs. 85% vs. 85%). Multivariate analysis adjusting for cancer stage revealed no difference in survival for safety net hospital patients who had surgery and survived > 30 days (HR 1.02, p = 0.63). CONCLUSION: For patients surviving the perioperative setting following pancreatic cancer surgery, safety-net hospitals achieve equivalent long-term survival outcomes potentially due to equivalent delivery of multimodal therapy at non safety-net hospitals. Safety-net hospitals are a crucial resource that provides quality long-term cancer treatment for vulnerable populations. PMID- 28849352 TI - Effects of sex and HIV serostatus on spatial navigational learning and memory among cocaine users. AB - Spatial learning and memory are critically dependent on the integrity of hippocampal systems. Functional MRI and neuropathological studies show that hippocampal circuitry is prominently affected among HIV-seropositive individuals, but potential spatial learning and memory deficits have not been studied in detail in this population. We investigated the independent and interactive effects of sex and HIV serostatus on performance of a spatial learning and memory task in a sample of 181 individuals with a history of cocaine dependence. We found that men showed faster times to completion on immediate recall trials compared with women and that delayed recall was significantly poorer among HIV infected compared with HIV-uninfected participants. Additionally, a sex * serostatus effect was found on the total number of completed learning trials. Specifically, HIV-infected men successfully completed more learning trials compared with HIV-infected women. Results are discussed in the context of recent reports of sex and HIV serostatus effects on episodic memory performance. PMID- 28849354 TI - Integration of Primary Care and Psychiatry: A New Paradigm for Medical Student Clerkships. AB - BACKGROUND: Public health crises in primary care and psychiatry have prompted development of innovative, integrated care models, yet undergraduate medical education is not currently designed to prepare future physicians to work within such systems. AIM: To implement an integrated primary care-psychiatry clerkship for third-year medical students. SETTING: Undergraduate medical education, amid institutional curriculum reform. PARTICIPANTS: Two hundred thirty-seven medical students participated in the clerkship in academic years 2015-2017. PROGRAM DESCRIPTION: Educators in psychiatry, internal medicine, and pediatrics developed a 12-week integrated Biopsychosocial Approach to Health (BAH)/Primary Care Psychiatry Clerkship. The clerkship provides students clinical experience in primary care, psychiatry, and integrated care settings, and a longitudinal, integrated didactic series covering key areas of interface between the two disciplines. PROGRAM EVALUATION: Students reported satisfaction with the clerkship overall, rating it 3.9-4.3 on a 1-5 Likert scale, but many found its clinical curriculum and administrative organization disorienting. Students appreciated the conceptual rationale integrating primary care and psychiatry more in the classroom setting than in the clinical setting. CONCLUSIONS: While preliminary clerkship outcomes are promising, further optimization and evaluation of clinical and classroom curricula are ongoing. This novel educational paradigm is one model for preparing students for the integrated healthcare system of the twenty-first century. PMID- 28849355 TI - Robotic repair of symptomatic Spigelian hernias: a series of three cases and surgical technique review. AB - Spigelian hernias are a rare defect in the Spigelian aponeurosis, comprising of 0.1-2% of all hernias. These rare hernias can contain intra-abdominal tissue, and rarely bladder. Spigelian hernias pose a high risk for incarceration or strangulation of its herniated content if not repaired promptly. There are a number of routinely employed operative techniques to repair Spigelian hernias, including open or laparoscopic, suture or mesh repair, transabdominal pre peritoneal approach or totally extraperitoneal approach. Robotic Spigelian repairs have been rarely reported in the literature. We report three cases of incarcerated Spigelian hernias that were successfully repaired robotically with mesh. PMID- 28849356 TI - Hair Zinc: an Index for Zinc Status in Under-Five Children from Low-Income Communities in Kanam Area of North-Central Nigeria. AB - Nutritional deficiencies of trace elements are among the top ten causes of death in Sub Saharan Africa. In Kanam Local Government Area of Nigeria, the problem is compounded by high levels of poverty and illiteracy. Abnormally low hair zinc levels are important, sensitive diagnostic biochemical indices of Zinc deficiency. The purpose of this study is to assess the zinc status of children less than 5 years in Kanam local government area, north-central Nigeria, by measuring the zinc level in hair samples collected from 44 under-5 children across the area. A household survey was made to assess the pattern and frequency of consumption of zinc-rich foods which was done by means of questionnaire. Hair samples were analysed for zinc content by the inductively coupled plasma-mass spectrophotometry (ICP-MS). The data were analysed statistically using the Student's t test, z test, and Pearson correlation, while questionnaire-captured data were analysed by simple arithmetic. The results of the analyses showed that the average hair zinc level was 74.35 +/- 48.05 MUg/g. This was below the normal range of 130-140 MUg/g, for children less than 5 years. Based on the results, 86.36% have hair zinc level below the lower limit of the normal range of 130 MUg/g. Between the gender, boys have higher hair zinc content than girls. Data from the questionnaire showed that 53.45% of the population studied have poor/inadequate intake of zinc-rich foods of animal origin, a dietary behaviour reported to predispose to micronutrient deficiency, including zinc. PMID- 28849357 TI - Curcumin-supplemented diets improve antioxidant enzymes and alter acetylcholinesterase genes expression level in Drosophila melanogaster model. AB - Curcumin, a bioactive polyphenolic compound in turmeric (Curcuma longa) rhizomes has been shown to exert anti-aging properties with limited scientific basis. Hence, this study sought to examine the antioxidant and anti-cholinesterase activities of curcumin-supplemented diets as well as their molecular effect on superoxide dismutase (SOD) and acetylcholinesterase (AChE) genes expression level associated with lifespan extension in Drosophila melanogaster model. In this experiment, D. melanogaster (both genders) of 1 to 3 days old were fed diets either containing no curcumin (control) or supplemented with curcumin at 0.2 and 1.0 mg/g of diet for 7 days. Subsequently, the survival and locomotor activities were determined. In addition, we evaluated RT-PCR expressions of SOD and AChE mRNA genes. Furthermore, catalase, SOD and AChE activities were determined. Curcumin-supplemented diet improves survival ability but did not affect locomotor activity when compared with the control. In addition, there was a significant increase in SOD and catalase with a concomitant decrease of AChE activities when compared with the control. Furthermore, curcumin-supplemented diets suppress AChE mRNA expression but no alteration on SOD gene expression level was observed when compared with control. In conclusion, our present results suggest that a down regulation of AChE gene expression with a concomitant decrease of AChE activity as well as improving antioxidant status could be some possible mechanism in which curcumin exert anti-aging potential and increases lifespan of D. melanogaster. PMID- 28849358 TI - Prevalence of Micronutrient Deficiency in Patients with Morbid Obesity Before Bariatric Surgery. AB - BACKGROUND: Postoperative micronutrient deficiency is a known side effect of bariatric surgery. In this study, we examined the prevalence of micronutrient deficiency in patients with morbid obesity (MO) preoperatively. METHODS: A total of 1732 patients with MO wishing to undergo bariatric surgery (age: 40 +/- 12 years, mean BMI: 44 +/- 9 kg/m2, means +/- SD, 77.3% female) were analyzed in this cross-sectional examination. Iron state, vitamin B12, folic acid, 25hydroxy(OH)-vitamin D, PTH, vitamin A, and vitamin E levels were determined. Subsequently, patients underwent nutritional counseling and were substituted accordingly. RESULTS: A total of 63.2% (n = 1094) of the patients had a deficit in folic acid (< 5.3 ng/ml), 97.5% (n = 1689) in 25OHvitamin D (< 75 nmol/l), and 30.2% (n = 523) had a PTH elevation (> 56.9 pg/ml). A total of 5.1% (n = 88) of the patients presented with a deficit in vitamin B12 (< 188 pg/ml) and 6.2% (n = 107) in vitamin A (< 1.05 MUmol/l). A total of 9.6% (n = 166) exhibited iron deficiency (ferritin < 15 MUg/l). None of the patients had a deficit in vitamin E. There were no gender differences except for ferritin deficiency (women 11.8% vs. men 1.5%, p < 0.001). Patients in the highest BMI tertile had significantly more often a deficit in vitamin D (p = 0.033) and folic acid (p < 0.001). Patients in the lowest age tertile had significantly more often a deficit in folic acid (p < 0.001). CONCLUSIONS: Our data show a high prevalence of micronutrient deficiency in patients with morbid obesity preoperatively and emphasize the importance of exact preoperative evaluation and adequate substitution as well as postoperative surveillance. PMID- 28849359 TI - Two-sample tests for survival data from observational studies. AB - When observational data are used to compare treatment-specific survivals, regular two-sample tests, such as the log-rank test, need to be adjusted for the imbalance between treatments with respect to baseline covariate distributions. Besides, the standard assumption that survival time and censoring time are conditionally independent given the treatment, required for the regular two sample tests, may not be realistic in observational studies. Moreover, treatment specific hazards are often non-proportional, resulting in small power for the log rank test. In this paper, we propose a set of adjusted weighted log-rank tests and their supremum versions by inverse probability of treatment and censoring weighting to compare treatment-specific survivals based on data from observational studies. These tests are proven to be asymptotically correct. Simulation studies show that with realistic sample sizes and censoring rates, the proposed tests have the desired Type I error probabilities and are more powerful than the adjusted log-rank test when the treatment-specific hazards differ in non proportional ways. A real data example illustrates the practical utility of the new methods. PMID- 28849360 TI - Patient Characteristics and Real-World Treatment Patterns Among Early Users of PCSK9 Inhibitors. AB - BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce low-density lipoprotein cholesterol (LDL-C) levels and are approved for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional LDL-C lowering. OBJECTIVE: Our objective was to characterize patients receiving PCSK9i medications in real-world practice and describe physician-reported treatment patterns among dyslipidemia patients using PCSK9i or other lipid-lowering therapy. METHODS: We analyzed data from a point-in time Adelphi dyslipidemia disease-specific programme (DSP) survey conducted in the USA in 2016. Physicians provided treatment history, laboratory values, patient characteristics, and comorbidities for treated patients. To ensure sufficient numbers of PCSK9i-treated patients, we conducted systematic oversampling of patients being prescribed PCSK9i. Outcomes included patient characteristics and physician-reported treatment patterns. RESULTS: The DSP included 159 physicians, who provided information on 1522 patients (304 PCSK9i; 1218 non-PCSK9i). Mean +/- standard deviation (SD) baseline LDL-C levels were 180.0 +/- 39.7 mg/dl for PCSK9i patients and 159.2 +/- 40.5 mg/dl for non-PCSK9i patients. Prior statin use was reported in 69.1% of PCSK9i patients and 19.5% of non-PCSK9i patients, and physician-reported statin intolerance was observed in 31.6% of PCSK9i and 5.3% of non-PCSK9i patients. Use of statins only was reported in 40.5% of PCSK9i and 88.8% of non-PCSK9i patients. The most common physician reported reasons for change to PCSK9i were lack of efficacy (70.2%) and muscle related symptoms (myalgia 28.6%; myopathy 11.1%). CONCLUSIONS: Physicians surveyed appeared to prescribe PCSK9i medications appropriately. PCSK9i-treated patients had higher rates of cardiovascular comorbidities and physician determined statin intolerance, had higher LDL-C levels, and received more lines of therapy than non-PCSK9i patients. PMID- 28849361 TI - Tubulointerstitial nephritis as adverse effect of programmed cell death 1 inhibitor, nivolumab, showed distinct histological findings. AB - Immune-checkpoint inhibitor nivolumab (anti-PD-1 antibody) blocks T cell inhibition and stimulate immunologic response toward cancer cells. It was also revealed that PD-1/PD-L1 interaction crucially controls the effector differentiation of auto-reactive T cells to maintain self-tolerance. Therefore, potential autoimmunological side-effect can occur in any organ. Here, we report a case of 67-year-old Japanese male with lung adenocarcinoma treated with nivolumab who developed acute tubulointerstitial nephritis after the third infusion of nivolumab. Kidney biopsy showed distinct histological findings: Proliferation of CD38 positive and IgG positive plasma cells, and affluent infiltration of FoxP3+ regulatory T cells. Herein, we do pathological discussion concerning acute tubulointerstitial nephritis occurred in this case based on these histological findings. PMID- 28849362 TI - Translating Prevention Research for Evidence-Based Policymaking: Results from the Research-to-Policy Collaboration Pilot. AB - The importance of basing public policy on sound scientific evidence is increasingly being recognized, yet many barriers continue to slow the translation of prevention research into legislative action. This work reports on the feasibility of a model for overcoming these barriers-known as the Research-to Policy Collaboration (RPC). The RPC employs strategic legislative needs assessments and a rapid response researcher network to accelerate the translation of research findings into usable knowledge for policymakers. Evaluation findings revealed that this model can successfully mobilize prevention scientists, engage legislative offices, connect policymakers and experts in prevention, and elicit congressional requests for evidence on effective prevention strategies. On average, the RPC model costs $3510 to implement per legislative office. The RPC can elicit requests for evidence at an average cost of $444 per request. The implications of this work, opportunities for optimizing project elements, and plans for future work are discussed. Ultimately, this project signals that the use of scientific knowledge of prevention in policymaking can be greatly augmented through strategic investment in translational efforts. PMID- 28849364 TI - Clinical utility of magnetic resonance imaging in the evaluation of pregnant females with suspected acute appendicitis. AB - OBJECTIVES: To assess the diagnostic performance of magnetic resonance imaging (MRI) in a large cohort of pregnant females with suspected acute appendicitis and to determine the frequency of non-appendiceal causes of abdominal pain identified by MRI in this population. METHODS: This HIPAA compliant, retrospective study was IRB-approved and informed consent was waived. 212 MRI exams were performed consecutively on pregnant women aged 17-47 years old suspected of having acute appendicitis; eight exams were excluded and analyzed separately due to equivocal findings or lack of clinical follow up. Radiology reports for the MRI and any preceding ultrasound exams were reviewed as well as the patients' electronic medical record for surgical, pathological, or clinical follow up. RESULTS: Fifteen (7.3%) of 204 MRI scans were determined to be positive for appendicitis, 14 of which were proven on surgical pathology, and one was found to have ileocecal diverticulitis. Out of the remaining 189 scans, none were subsequently shown to have acute appendicitis either surgically or based on clinical follow up. Negative predictive value (NPV) was 100% and positive predictive value was 93.3%. Sensitivity and specificity were 100% and 99.5%, respectively. Non appendiceal findings which may have accounted for the patient's abdominal pain were seen in 91 (44.2%) of 189 scans. The most common extra-appendiceal causes of abdominal pain identified on MRI include degenerating fibroids (n = 11), significant hydronephrosis (n = 12), cholelithiasis (n = 6), and pyelonephritis (n = 3). CONCLUSION: Our large study cohort of pregnant patients confirms MRI to be of high diagnostic value in the workup of acute appendicitis with 100% NPV and sensitivity and 99.5% specificity. Furthermore, an alternative diagnosis for abdominal pain in this patient population can be made in nearly half of MRI exams which are deemed negative for appendicitis. PMID- 28849363 TI - Small temperature differences can improve the performance of mesophilic sludge based digesters. AB - OBJECTIVE: To assess the effect of small temperature increases in mesophilic sludge-based digesters in order to develop and evaluate strategies for improving the biogas production in full-scale digesters. RESULTS: Methane production was strongly affected by small temperature differences, and this result was consistent across samples from 15 full-scale digesters. The specific methane yield varied between 42 and 97.5 ml g VS-1 after 15 days of incubation at 35 degrees C, and improved when increasing the digester temperature to 39 degrees C. Only a limited quantity of additional gas was required to balance out the cost of heating and a positive energy balance was obtained. Further increases in temperature, in some cases, negatively affected the production when operated at 42 degrees C compared to 39 degrees C. CONCLUSIONS: Small temperature increases should be applied to mesophilic sludge-based digesters to optimize the biogas production and is applicable to digesters operated in the lower mesophilic temperature range. PMID- 28849365 TI - Searching for mortality predictors in trauma patients: a challenging task. AB - BACKGROUND: We aimed to study the value of new physiological variables compared with ISS and GCS as predictors for trauma mortality in a high-income developing country having a young population. METHODS: Data of 1008 consecutive trauma patients who were included in Al-Ain City Road Traffic Collision Registry were analyzed. Demography of patients, systolic blood pressure, heart rate, shock index, shock index age (SIA), blood pressure age index (BPAI), Glasgow Coma Scale (GCS), injury severity score (ISS), and in-hospital mortality were analyzed. Univariate analysis was used to compare those who died with those who survived. Significant factors were then entered into a backward logistic regression model to define factors predicting mortality. RESULTS: 80.3% of the patients were males. The median (range) age of patients was 26 (1-78) years. Significant factors that predicted mortality were GCS (p < 0.0001), SIA (p = 0.003), ISS (p = 0.007), and BPAI (p = 0.022). CONCLUSIONS: The physiological variables including GCS and shock index age were better predictors for trauma mortality comparted with ISS in our young population. A large global multi-centric study could possibly define an accurate global formula that uses both anatomical and physiological variables for predicting trauma mortality. PMID- 28849366 TI - Is Adjuvant Therapy Necessary for All Patients with Localized Pancreatic Cancer Who Have Received Neoadjuvant Therapy? AB - BACKGROUND: Among patients with localized pancreatic cancer (PC), the benefit of adjuvant therapy after neoadjuvant therapy and surgery is unknown. METHODS: Patients with localized PC who completed all intended neoadjuvant therapy and surgery were categorized based on the receipt of adjuvant therapy and by pathologic lymph node status (LN-/LN+). RESULTS: Data was available from 234 consecutive patients, 121 (52%) with resectable and 113 (48%) with borderline resectable PC. Of the 234 patients, 92 (39%) were LN+ and 142 (61%) were LN-. The median overall survival (OS) for the 234 patients was 39 months, 42.3 months for patients who received any adjuvant therapy and 34.1 months for those who did not (p = 0.29). Of the 92 LN+ patients, the median OS with and without adjuvant therapy was 29.5 and 23.2 months, respectively (p = 0.02). Of the142 LN- patients, the median OS was 45 months with or without adjuvant therapy (p = 0.86). In an adjusted hazard model, additional adjuvant therapy had a significant protective effect among LN+ patients (HR 0.39; 95% CI 0.21-0.70; p = 0.002) but not in LN- patients (HR 0.89; 95% CI 0.53-1.52; p = 0.68). CONCLUSION: Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease. PMID- 28849367 TI - Provision of Lifestyle Counseling and the Prescribing of Pharmacotherapy for Hyperlipidemia Among US Ambulatory Patients: A National Assessment of Office Based Physician Visits. AB - BACKGROUND: An estimated 27.8% of the United States (US) population aged >=20 years has hyperlipidemia, defined as total serum cholesterol of >=240 mg/dL. A previous study of US physician office visits for hyperlipidemia in 2005 found both suboptimal compliance and racial/ethnic disparities in screening and treatment. OBJECTIVE: The aim was to estimate current rates of laboratory testing, lifestyle education, and pharmacotherapy for hyperlipidemia. METHODS: Data were derived from the US National Ambulatory Medical Care Survey (NAMCS), a nationally representative study of office-based physician visits, for 2013-2014. Patients aged >=20 years with a primary or secondary diagnosis of hyperlipidemia were sampled. Study outcomes included receipt or ordering of total cholesterol testing, diet/nutrition counseling, exercise counseling, and pharmacotherapy prescription including statins, ezetimibe, omega-3 fatty acids, niacin, or combination therapies. RESULTS: Compared with previously reported results for 2005, rates of pharmacotherapy have remained static (52.2 vs. 54.6% for 2005 and 2013-2014, respectively), while rates of lifestyle education have markedly declined for diet/nutrition (from 39.7 to 22.4%) and exercise (from 32.1 to 16.0%). Lifestyle education did not vary appreciably by race/ethnicity in 2013 2014. However, rates of lipid testing were much higher for whites (41.6%) than for blacks (29.9%) or Hispanics (34.2%). Tobacco education was ordered/provided in only 4.0% of office visits. CONCLUSION: Compliance with guidelines for the screening and treatment of hyperlipidemia remains suboptimal, and rates of lifestyle education have declined since 2005. There exists an urgent need for enhanced levels of provider intervention to reduce the morbidity and mortality associated with hyperlipidemia. PMID- 28849368 TI - Understanding What Is Most Important to Individuals with Multiple Chronic Conditions: A Qualitative Study of Patients' Perspectives. AB - BACKGROUND: To improve care for individuals living with multiple chronic conditions, patients and providers must align care planning with what is most important to patients in their daily lives. We have a limited understanding of how to effectively encourage communication about patients' personal values during clinical care. OBJECTIVE: To identify what patients with multiple chronic conditions describe as most important to their well-being and health. DESIGN: We interviewed individuals with multiple chronic conditions in their homes and analyzed results qualitatively, guided by grounded theory. PARTICIPANTS: A total of 31 patients (mean age 68.7 years) participated in the study, 19 of which included the participation of family members. Participants were from Kaiser Permanente Washington, an integrated health care system in Washington state. APPROACH: Qualitative analysis of home visits, which consisted of semi-structured interviews aided by photo elicitation. KEY RESULTS: Analysis revealed six domains of what patients described as most important for their well-being and health: principles, relationships, emotions, activities, abilities, and possessions. Personal values were interrelated and rarely expressed as individual values in isolation. CONCLUSIONS: The domains describe the range and types of personal values multimorbid older adults deem important to well-being and health. Understanding patients' personal values across these domains may be useful for providers when developing, sharing, and following up on care plans. PMID- 28849369 TI - Recent trends in practice patterns and comparisons between immunoglobulin and corticosteroid in pediatric immune thrombocytopenia. AB - The clinical benefits and practice patterns of different pharmacologic regimes in acute pediatric immune thrombocytopenia (ITP) remain unclear in Japan. Using a national inpatient database, we analyzed recent trends in practice patterns for acute pediatric ITP, and compared risks of 6-month readmission, total hospitalization costs, and lengths of hospital stay between ITP children treated with intravenous immunoglobulin (IVIG) and corticosteroid, using inverse probability weighting analyses. From 2010 to 2014, the proportions of IVIG use increased from 43.4 to 66.0% (P trend < 0.001), while the proportions of corticosteroid use and watchful waiting decreased from 16.4 to 10% and from 28.6 to 14.3%, respectively (P trend < 0.001). No significant difference in 6-month readmission risk was observed between IVIG and corticosteroid (p = 0.28). Total length of hospital stay in the corticosteroid group was 3.5 days longer than that in IVIG (95% confidence interval, 2.1-4.6 days), whereas total hospitalization cost was greater in IVIG than in corticosteroid (difference, Y 207,994; 95% confidence interval, Y 149586-Y 280728). A trend toward increased IVIG use was observed during the study period. Total hospitalization cost was considerably greater in the IVIG than in the corticosteroid group, whereas readmission risks were similar in both groups. PMID- 28849370 TI - Two kinds of bias in visual comparison illustrate the role of location and holistic/analytic processing differences. AB - A number of studies have shown that two stimuli appearing successively at the same spatial location are more likely to be perceived as the same, even though location is irrelevant to the task. This bias to respond "same" when stimuli are at the same location is termed spatial congruency bias. The experiments reported here demonstrate that the spatial congruency bias extends to letter strings: Participants tend to respond "same" when comparing two strings appearing successively at the same location. This bias may arise because successive stimuli at the same location are more likely to be perceived as a single object. Bias is also affected by the nature of the comparison task. We show that if letters must be compared individually (analytical comparison), there is a bias to respond "different," but if letter strings are compared as unified wholes (holistic comparison), there is no bias or a bias to respond "same." This analytical bias is apparently separate from the spatial congruency bias. It appears whether the task requires localization of differences between strings, or counting the number of differences, or ignoring differences in some parts of the stimuli while attending to others. All of these analytical comparison tasks require that letters be selected individually, and the analytical bias may reflect difficulty in preventing interference from neighboring letters in this selection process. Each type of bias reflects a different aspect of visual processing, and both can be measured to probe how processing changes across different tasks. PMID- 28849372 TI - [Functional genomics of Ewing sarcoma]. AB - Ewing sarcoma is a highly aggressive bone or soft-tissue tumor mostly occurring in children and adolescents. Conventional multi-modal therapies are associated with considerable acute and chronic toxicity. Thus, more effective and in particular less toxic therapeutic strategies are urgently required. Despite the fact that Ewing sarcoma is characterized by specific EWSR1-ETS gene fusions, the resulting fusion oncoproteins are not suitable for targeted therapy due to their low immunogenicity and the ubiquitous expression of their constituents. However, functional genomics revealed several EWSR1-ETS target genes, which are only minimally expressed in normal tissues, and which could serve as surrogate-targets for (immuno-)therapeutic approaches. Moreover, functional genomic analyses yielded first mechanistic explanations for the relatively high incidence of Ewing sarcoma in Europeans, and first studies are exploring the value of circulating free DNA and/or exosomal mRNA of EWSR1-ETS fusion oncogenes as minimal-residual disease markers in Ewing sarcoma. This review summarizes key contributions to these aspects and gives a perspective on their medical relevance. PMID- 28849373 TI - Erratum to: Transoral Resection of Human Papillomavirus (HPV)-Positive Squamous Cell Carcinoma of the Oropharynx: Outcomes with and Without Adjuvant Therapy. PMID- 28849371 TI - MSA prions exhibit remarkable stability and resistance to inactivation. AB - In multiple system atrophy (MSA), progressive neurodegeneration results from the protein alpha-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human alpha-synuclein (TgM83+/-), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between alpha-synuclein prions and PrP scrapie (PrPSc) prions responsible for Creutzfeldt-Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrPSc transmission. When peripherally exposed to MSA via the peritoneal cavity, hind leg muscle, and tongue, TgM83+/- mice developed neurological signs accompanied by alpha-synuclein prions in the brain. Iatrogenic CJD, resulting from PrPSc prion adherence to surgical steel instruments, has been investigated by incubating steel sutures in contaminated brain homogenate before implantation into mouse brain. Mice studied using this model for MSA developed disease, whereas wire incubated in control homogenate had no effect on the animals. Notably, formalin fixation did not inactivate alpha-synuclein prions. Formalin-fixed MSA patient samples also transmitted disease to TgM83+/- mice, even after incubating in fixative for 244 months. Finally, at least 10% sarkosyl was found to be the concentration necessary to partially inactivate MSA prions. These results demonstrate the robustness of alpha-synuclein prions to denaturation. Moreover, they establish the parallel characteristics between PrPSc and alpha-synuclein prions, arguing that clinicians should exercise caution when working with materials that might contain alpha-synuclein prions to prevent disease. PMID- 28849374 TI - Toxicological effects of fludarabine and treosulfan conditioning before allogeneic stem-cell transplantation. AB - We studied early potential treosulfan-related toxicity in 118 patients treated with treosulfan-based conditioning before allogeneic hematopoietic stem-cell transplantation. Most patients (n = 93) had a hematological malignancy. In 80 cases, a HLA-A, -B and -DR matched unrelated donor was used, while 33 patients had a HLA-identical sibling donor, and five received an HLA-A, -B or -DR allele mismatched, unrelated donor. Levels of AST, ALT, and bilirubin were significantly increased 1 week after HSCT compared to before HSCT. However, only a few patients had transaminase levels >2 to 3 * the upper normal level. All patients became neutropenic; 61% were already so at the time of graft infusion. Nearly all patients engrafted, except for three who died very early. Non-relapse mortality was 7.5% at 100 days and 11.9% at 1 year after HSCT. Veno-occlusive disease of the liver occurred in one patient and hemorrhagic cystitis in two patients. This study shows that early regimen-related toxicity after HSCT was low despite similar marrow toxicities compared to myeloablative regimens. PMID- 28849375 TI - Increasing relational memory in childhood with unitization strategies. AB - Young children often experience relational memory failures, which are thought to result from immaturity of the recollection processes presumed to be required for these tasks. However, research in adults has suggested that relational memory tasks can be accomplished using familiarity, a process thought to be mature by the end of early childhood. The goal of the present study was to determine whether relational memory performance could be improved in childhood by teaching young children memory strategies that have been shown to increase the contribution of familiarity in adults (i.e., unitization). Groups of 6- and 8 year-old children were taught to use visualization strategies that either unitized or did not unitize pictures and colored borders. Estimates of familiarity and recollection were extracted by fitting receiver operator characteristic curves (Yonelinas, Journal of Experimental Psychology: Learning, Memory, and Cognition 20, 1341-1354, 1994, Yonelinas, Memory & Cognition 25, 747 763, 1997) based on dual-process models of recognition. Bayesian analysis revealed that strategies involving unitization improved memory performance and increased the contribution of familiarity in both age groups. PMID- 28849376 TI - Surgical Outcomes of Isolated Malignant Pulmonary Nodules in Patients with a History of Breast Cancer. AB - BACKGROUND: The role of surgery for isolated malignant pulmonary nodules in breast cancer patients remains unclear. METHODS: A total of 1286 consecutive breast cancer patients with pulmonary nodules detected by thoracic computed tomography (CT) or positron emission tomography (PET)/CT scan at Shanghai Cancer Center, Fudan University, were reviewed. Overall, 147 breast cancer patients with isolated malignant pulmonary nodules receiving surgery and/or chemotherapy were enrolled in the study. Patients were classified into three groups: patients with primary lung cancer (PLC) receiving surgery (Group 1), patients with lung metastasis receiving surgery (Group 2), and patients with lung metastasis receiving chemotherapy (Group 3). Survival outcomes, including overall survival (OS) and progression-free survival (PFS), were analyzed for patients in all three groups, and prognostic factors for PFS for patients with pulmonary metastasis were evaluated. RESULTS: Patients with PLC receiving surgery had better survival outcomes, including OS and PFS, than patients with lung metastases who received surgical resection. Breast cancer patients with solitary lung metastasis who received metastasectomy had a significantly better PFS than those who did not; however, no statistically significant difference in OS was observed between the two groups. A multivariate analysis conducted in patients with isolated metastatic breast cancer showed that surgery was an independent factor for better PFS. CONCLUSIONS: Surgery should be considered a valid option for the diagnosis and treatment of breast cancer patients presenting with isolated malignant lung nodules. PMID- 28849377 TI - Letter regarding article by Kortram et al.: Risk factors for infectious complications after open fractures: a systematic review and meta-analysis. PMID- 28849378 TI - Factors Affecting the Tendency of Cancer Patients for Religion and Spirituality: A Questionnaire-Based Study. AB - This descriptive, cross-sectional, and analytical study was carried out to identify the factors affecting the tendency of cancer patients for the religion and spirituality. The research was applied on a total of 800 individuals: 400 cancer patients under chemotherapy and 400 non-cancer individuals. Data were collected by personal information form, Ok-Religious Attitude Scale, and spiritual life questions. LISREL 8.7 program was run for the confirmatory factor analysis in order to evaluate the compliance of spiritual life questions. Data from Ok-Religious Attitude Scale and scores collected from spiritual life questions for both cancer and non-cancer individuals were statistically analyzed by two-way ANOVA. Cancer patients (82.8%) prayed more than non-cancer individuals (72.5%). Non-cancer individuals, on the other hand, visited the tombs (13.8%), sacrificed (22.2%), consulted the religious officials (9.2%), and more. The patients had more positive religious attitude than non-cancer individuals (Z = 4.193; p = 0.0001). Religious women were more positive than religious men. Lower education level caused more positive religious attitude. Medical properties of patients did not affect the religious attitude. Forgiveness, spiritual values, and beliefs were stronger in cancer patients than in non-cancer individuals (p = 0.0001). Knowing the factors affecting spiritual life and religious attitudes of patients and determining the spiritual needs of patients with a holistic perspective facilitate compliance of patients with cancer and its treatment. Therefore, containing the spiritual routine in the nursing care is essential. PMID- 28849379 TI - Fine. PMID- 28849381 TI - Effects of Self-Efficacy on Healthy Eating Depends on Normative Support: a Prospective Study of Long-Haul Truck Drivers. AB - PURPOSE: Fruit and vegetable intake (FV) is insufficient in industrialized nations and there is excess of discretionary food choices (DC; foods high in fat, sugar, and salt). Long-haul truck drivers are considered a particularly at-risk group given the limited food choices and normatively reinforced eating habits at truck rest-stops. Self-efficacy and normative support are key determinants of eating behavior yet the processes underlying their effects on behavior are not well understood. We tested the direct and interactive effects of self-efficacy and normative support on healthy eating behaviors in long-haul truck drivers in a prospective correlational study. METHOD: Long-haul truck drivers (N = 82) completed an initial survey containing self-report measures of behavioral intentions, perceived normative support, and self-efficacy for their FV and DC behaviors. Participants completed a follow-up survey 1 week later in which they self-reported their FV and DC behavior. RESULTS: A mediated moderation analysis identified an interactive effect of self-efficacy and normative support on behavior mediated by intention for FV and DC behavior. Specifically, we confirmed a compensation effect in which self-efficacy was more likely to have an effect on FV and DC behavior through intentions in participants with low normative support. CONCLUSION: Results indicate the importance of self-efficacy in predicting FV and DC intentions and behavior in the absence of a supportive normative environment. The compensatory effect of self-efficacy beliefs on behavior through intentions when normative support is low should be confirmed using experimental methods. PMID- 28849380 TI - Formulation Screening and Freeze-Drying Process Optimization of Ginkgolide B Lyophilized Powder for Injection. AB - The purpose of this study was to prepare ginkgolide B (GB) lyophilized powder for injection with excellent appearance and stable quality through a formulation screening and by optimizing the freeze-drying process. Cremophor EL as a solubilizer, PEG 400 as a latent solvent, and mannitol as an excipient were mixed to increase the solubility of GB in water to more than 18 times (about from 2.5 * 10-4 mol/L (0.106 mg/mL) to 1.914 mg/mL). Formulation screening was conducted by orthogonal design where the content of GB in the solution before lyophilization (using external standard method of HPLC) and reconstitution time after lyophilization were the two evaluation indexes. The optimized formulations were GB in an amount of 2 mg/mL, Cremophor EL in an amount of 16% (v/v), PEG 400 in an amount of 9% (v/v), mannitol in an amount of 8% (w/v), and the solution pH of 6.5. Through four single-factor experiments (GB adding order, preparation temperature of GB solution, adding amount, and adsorption time of activated carbon), the preparation process of GB solution was confirmed. The glass transition temperature of maximally GB freeze-concentrated solution was - 17.6 degrees C through the electric resistance method. GB lyophilized powder began to collapse at - 14.0 degrees C, and the fully collapsed temperature was - 13.0 degrees C, which were determined by freeze-drying microscope. When the collapse temperature was determined, the primary drying temperature was obtained. Thereby, the freeze-drying curve of GB lyophilized powder was initially identified. The freeze-drying process was optimized by orthogonal design, the qualified product appearance and residual moisture content were the two evaluation indexes. The optimized process parameters and process were (1) shelf temperature, decreased from room temperature to - 45.0 degrees C, at 0.5 degrees C/min in 2 h; (2) shelf temperature increased from - 45.0 to - 25.0 degrees C, at 0.1 degrees C/min, maintained for 3 h, and the chamber pressure was held at 10 Pa; (3) shelf temperature was increased from - 25.0 to - 15.0 degrees C at 0.1 degrees C/min, maintained for 4 h, and the chamber pressure was held at 10 Pa; and (4) shelf temperature was increased from - 15.0 to 20.0 degrees C at 1.0 degrees C/min, maintained for 4 h, and the chamber pressure was raised up to 80 Pa. In these lyophilization process conditions, the products complied with relevant provisions of the lyophilized powders for injection. Meanwhile, the reproducibility was satisfactory. Post-freezing annealing had no significantly beneficial effects on shortening the freeze-drying cycle and improving the quality of GB lyophilized powder. PMID- 28849383 TI - Amygdalohippocampotomy for mesial temporal lobe sclerosis: Epilepsy outcome 5 years after surgery. AB - BACKGROUND: The goal of the present study is the evaluation of the long-term clinical outcome of epilepsy in patients with mesial temporal lobe sclerosis (MTLS) submitted to amygdalohippocampotomy (AHCo). AHCo consists of the lateral ablation of the amygdala and the peri-hippocampal disconnection instead of amygdalohippocampectomy (AHC), which involves the removal of both structures. We previously reported the short-term results of AHCo, so we here present the long term results (> 5 years of follow-up) of the patients operated on with AHCo. METHOD: Since 2007, 35 patients (22 females) aged 20-61 years (mean: 42 years) were operated on with the AHCo technique, 17 patients on the left side and 18 on the right. Of these patients, 21 (14 females) have been followed up > 5 years (5 to 7.5 years, mean 6.5 years). We compare the present results with those observed shortly after surgery and with the patients operated on with AHC. FINDINGS: In all 21 cases, the diagnosis was mesial temporal lobe sclerosis (histology confirmed in 20), 11 on the left side and 10 on the right. Epilepsy results after 5 years were good/very good in 18 patients (85.7%), with Engel class IA-B in 15 (71.4%) and II in 3 (14.3%), and bad in 3 patients, with Engel Class III in 2 (9.5%) and class IV in 1 (4.8%). Concerning morbidity, one patient had hemiparesis (hypertensive capsular hemorrhage 24 h after surgery), two verbal memory worsening, two quadrantanopia and three late depression that was reversed with medication. Comparatively, the AHC long-term results were 87% Engel class I, 8% Engel class II and 5% Engel class III-IV. The morbidity was equally small. CONCLUSIONS: The good/very good results of AHCo 5 years after surgery are 86%, which is not distinct from the AHC results. So AHCo seems to be effective and potentially safer than AHC in long-term follow-up. PMID- 28849384 TI - Erratum to: Long-term Effect of Ileal Transposition on Adipokine Serum Level in Zucker (Orl)-Lepr fa Fatty Rats. PMID- 28849382 TI - Healthcare Disparities in Outcomes of a Metropolitan Congenital Heart Surgery Center: The Effect of Clinical and Socioeconomic Factors. AB - OBJECTIVE: The purpose of this study is to identify the impact of demographic, socioeconomic, and clinical factors on congenital heart surgery outcomes. STUDY DESIGN: This retrospective cohort study included 234 congenital heart surgery patients from 2011 through 2015, in a racially/ethnically diverse metropolitan children's hospital. Outcomes included length of stay (LOS), age at first echocardiogram, length of mechanical ventilation, and incidence of complications. RESULTS: Compared to others, black children underwent their first echocardiogram at a later age (median 23 versus 2 days, p = 0.014) and were more likely to be diagnosed with congenital heart disease in the emergency room (p = 0.026). Hispanic children were more likely to have major non-cardiac congenital anomalies (p = 0.045). Increased LOS during elective admissions was associated with higher surgical complexity (STAT category 4 and 5 Estimate 3.905 days, p = 0.001), compared to STAT category 1, and number of complications (Estimate = 2.306 days per complication, p < 0.001). Increased LOS in non-elective admissions was associated with the number of complex chronic conditions (Estimate = 15.446 days, p = 0.045) and the number of complications (Estimate = 11.591 days per complication, p < 0.001). However, in multivariate analysis, race and ethnicity was not associated with increased LOS or age at first echocardiogram. CONCLUSION: In this diverse setting, race/ethnicity was not associated with increased LOS, age at first echocardiogram, length of ventilation, or complications. Surgical complexity, chronic conditions, and complications were associated with increased LOS. We discuss some interventions to reduce disparities in congenital heart surgery outcomes. PMID- 28849385 TI - Application of droplet digital PCR to determine copy number of endogenous genes and transgenes in sugarcane. AB - KEY MESSAGE: Droplet digital PCR combined with the low copy ACT allele as endogenous reference gene, makes accurate and rapid estimation of gene copy number in Q208 A and Q240 A attainable. Sugarcane is an important cultivated crop with both high polyploidy and aneuploidy in its 10 Gb genome. Without a known copy number reference gene, it is difficult to accurately estimate the copy number of any gene of interest by PCR-based methods in sugarcane. Recently, a new technology, known as droplet digital PCR (ddPCR) has been developed which can measure the absolute amount of the target DNA in a given sample. In this study, we deduced the true copy number of three endogenous genes, actin depolymerizing factor (ADF), adenine phosphoribosyltransferase (APRT) and actin (ACT) in three Australian sugarcane varieties, using ddPCR by comparing the absolute amounts of the above genes with a transgene of known copy number. A single copy of the ACT allele was detected in Q208 A , two copies in Q240 A , but was absent in Q117. Copy number variation was also observed for both APRT and ADF, and ranged from 9 to 11 in the three tested varieties. Using this newly developed ddPCR method, transgene copy number was successfully determined in 19 transgenic Q208 A and Q240 A events using ACT as the reference endogenous gene. Our study demonstrates that ddPCR can be used for high-throughput genetic analysis and is a quick, accurate and reliable alternative method for gene copy number determination in sugarcane. This discovered ACT allele would be a suitable endogenous reference gene for future gene copy number variation and dosage studies of functional genes in Q208 A and Q240 A . PMID- 28849386 TI - Doping in Two Elite Athletics Competitions Assessed by Randomized-Response Surveys. AB - BACKGROUND: Doping in sports compromises fair play and endangers health. To deter doping among elite athletes, the World Anti-Doping Agency (WADA) oversees testing of several hundred thousand athletic blood and urine samples annually, of which 1 2% test positive. Measures using the Athlete Biological Passport suggest a higher mean prevalence of about 14% positive tests. Biological testing, however, likely fails to detect many cutting-edge doping techniques, and thus the true prevalence of doping remains unknown. METHODS: We surveyed 2167 athletes at two sporting events: the 13th International Association of Athletics Federations Word Championships in Athletics (WCA) in Daegu, South Korea in August 2011 and the 12th Quadrennial Pan-Arab Games (PAG) in Doha, Qatar in December 2011. To estimate the prevalence of doping, we utilized a "randomized response technique," which guarantees anonymity for individuals when answering a sensitive question. We also administered a control question at PAG assessing past-year use of supplements. RESULTS: The estimated prevalence of past-year doping was 43.6% (95% confidence interval 39.4-47.9) at WCA and 57.1% (52.4-61.8) at PAG. The estimated prevalence of past-year supplement use at PAG was 70.1% (65.6-74.7%). Sensitivity analyses, assessing the robustness of these estimates under numerous hypothetical scenarios of intentional or unintentional noncompliance by respondents, suggested that we were unlikely to have overestimated the true prevalence of doping. CONCLUSIONS: Doping appears remarkably widespread among elite athletes, and remains largely unchecked despite current biological testing. The survey technique presented here will allow future investigators to generate continued reference estimates of the prevalence of doping. PMID- 28849387 TI - Evaluation of tablet punch configuration on mitigating capping by a quality by design approach. AB - Capping is a common problem in the manufacture of some types of tablets and unless resolved, the tableting process cannot proceed. Hence, all factors that can help to lessen the likelihood of capping without unnecessarily reduce turret speed and/or compaction force would be tenable. This study investigated the influence of tablet punch configuration on mitigation of tablet capping. Tablets were prepared from high-dose paracetamol-potato starch granules in a rotary tablet press with flat face plain (FFP), flat face bevel edge (FFBE) and flat face radius edge (FFRE) punch configurations. The directly compressible (DC) fillers tested were microcrystalline cellulose (MCC), pre-gelatinised starch (PGS) and lactose. Design of experiments (DoE), a tool of quality by design (QbD) paradigm, was used and the interaction of input variables (compression force, tablet punch configuration and DC filler) affecting the response factors (tablet hardness and capping rating) were evaluated. FFP punches were able to mitigate capping best. FFRE punches showed more potential than FFBE punches at alleviating capping in a particular compression force range, without the limitations of the FFP punches that produce cylindrical tablets that were more friable. Incorporation of PGS in the tablet formulation was observed to be more efficient at mitigating capping than the other DC fillers when FFBE and FFRE punches were used. Overall, this study serves as a model for prospective product development based on the QbD framework and the optimal use of compaction tools. PMID- 28849388 TI - Congenital anomalies of the left brachiocephalic vein detected in adults on computed tomography. AB - PURPOSE: Anomalous left brachiocephalic vein (BCV) is a rare and less known systemic venous anomaly. We evaluated congenital anomalies of the left BCV in adults detected during computed tomography (CT) examinations. MATERIALS AND METHODS: This retrospective study included 81,425 patients without congenital heart disease who underwent chest CT. We reviewed the recorded reports and CT images for congenital anomalies of the left BCV including aberrant and supernumerary BCVs. The associated congenital aortic anomalies were assessed. RESULTS: Among 73,407 cases at a university hospital, 22 (16 males, 6 females; mean age, 59 years) with aberrant left BCVs were found using keyword research on recorded reports (0.03%). Among 8018 cases at the branch hospital, 5 (4 males, 1 female; mean age, 67 years) with aberrant left BCVs were found using CT image review (0.062%). There were no significant differences in incidences of aberrant left BCV between the two groups. Two cases had double left BCVs. Eleven cases showed high aortic arches. Two cases had the right aortic arch, one case had an incomplete double aortic arch, and one case was associated with coarctation. CONCLUSION: Aberrant left BCV on CT examination in adults was extremely rare. Some cases were associated with aortic arch anomalies. PMID- 28849389 TI - Conversion to Complete Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma After Bidirectional Chemotherapy. AB - BACKGROUND: This report aims to describe preliminary results concerning secondary resectability after bidirectional chemotherapy for initially unresectable malignant peritoneal mesothelioma (MPM). METHODS: Between January 2013 and January 2016, 20 consecutive patients treated for diffuse MPM not suitable for upfront surgery received bidirectional chemotherapy associating intraperitoneal and systemic chemotherapy. Evaluation of the response to chemotherapy was assessed clinically and by laparoscopy. RESULTS: The median peritoneal cancer index (PCI) score at staging laparoscopy was 27 (range 15-39). Altogether, 118 intraperitoneal chemotherapy cycles were administered without any specific adverse catheter-related event. Concerning tolerance, 85% of the patients experienced no pain or mild pain during chemotherapy administration. The clinical response rate was 60% after a median of three chemotherapy cycles. At laparoscopic reevaluation, the median PCI was 18 (range 0-35), and a secondary resectability was considered for 55% of the patients. Complete cytoreduction surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) was finally achieved for 10 patients (50%), with a median intraoperative PCI score of 14 (range 6-30). After a median follow-up period of 18 months, the 2-year overall survival rate was 83.3% for the patients treated by CRS followed by HIPEC and 44% for the patients treated by bidirectional chemotherapy. CONCLUSION: Bidirectional chemotherapy is a promising, well-tolerated treatment capable of increasing the resection rate for selected patients with diffuse MPM initially considered as unresectable or borderline resectable. For patients with definitively unresectable disease, bidirectional chemotherapy achieves a higher clinical response rate. PMID- 28849391 TI - [Current status and future of telemonitoring : Scenarios for telemedical care in 2025]. AB - Telemonitoring is an already realized implementation of digital transformation in the healthcare system. It has the potential to support and secure a sustainable and comprehensive provision of healthcare for a rising number of chronically ill patients, e. g. patients with chronic heart failure. Remote regions in particular can profit from the benefits of telemonitoring; however, so far telemonitoring services have not become truly established in the German healthcare market. Together with experts from politics, science and practice, a scenario analysis "Health Care System 2025 - A Place for Telemonitoring?" was carried out with the aim to examine the future development of the healthcare market and to draw conclusions for providers of telemonitoring services or devices. The scenario analysis contained two workshops and an expert survey and was supported by a scenario software. The current drivers and barriers of the diffusion of telemonitoring were identified and the most relevant factors that influence the future development of the healthcare market were discussed. Based on those influencing factors, three different scenarios were determined: (1) administrating rather than shaping, (2) safely into the future and (3) interconnected and digital world. In the subsequent consequence analysis activities were defined, which describe the necessary infrastructure, software instruments, organizational structures and provision of services and discuss possible activities, which prepare telemonitoring solutions for the future. PMID- 28849390 TI - Identification of prognostic markers of high grade prostate cancer through an integrated bioinformatics approach. AB - PURPOSE: Prostate cancer is one of the leading causes of cancer death for male. In the present study, we applied an integrated bioinformatics approach to provide a novel perspective and identified some hub genes of prostate cancer. METHOD: Microarray data of fifty-nine prostate cancer were downloaded from Gene Expression Omnibus. Gene Ontology and pathway analysis were applied for differentially expressed genes between high and low grade prostate cancer. Weighted gene coexpression network analysis was applied to construct gene network and classify genes into different modules. The most related module to high grade prostate cancer was identified and hub genes in the module were revealed. Ingenuity pathway analysis was applied to check the chosen module's relationship to high grade prostate cancer. Hub gene's expression profile was verified with clinical samples and a dataset from The Cancer Genome Atlas project. RESULT: 3193 differentially expressed genes were filtered and gene ontology and pathway analysis revealed some cancer- and sex hormone-related results. Weighted gene coexpression network was constructed and genes were classified into six modules. The red module was selected and ingenuity pathway analysis confirmed its relationship with high grade prostate cancer. Hub genes were identified and their expression profile was also confirmed. CONCLUSION: The present study applied integrate bioinformatics approaches to generate a holistic view of high grade prostate cancer and identified hub genes could serve as prognosis markers and potential treatment targets. PMID- 28849392 TI - Slow gait speed after bilateral total knee arthroplasty is associated with suboptimal improvement of knee biomechanics. AB - PURPOSE: The aim of this study was to investigate gait speed changes 2 years after bilateral total knee arthroplasty (TKA) and identify kinetic and kinematic factors associated with such changes by comparing patients with age- and sex matched controls. METHODS: The study group included 34 female patients with end stage knee osteoarthritis (OA) who underwent bilateral TKA and 42 age- and sex matched controls without knee pain or OA. Standard TKA was performed on all arthritic patients with placement of posterior stabilized fixed-bearing implants. Kinetic and kinematic parameters were evaluated using a commercial optoelectric gait analysis system. Gait speed, kinetic and kinematic changes and determinants of speed were assessed via principal component analysis and multiple regression analysis. RESULTS: The average gait speed of an arthritic patient was 90.2 +/- 18.4 cm/s and improved to 96.0 +/- 12.3 cm/s after TKA (p = 0.032). However, the speed remained slower than that of controls (111.2 +/- 8.2 cm/s, p < 0.001). With regard to kinetics, the peak knee extension moment (KEM) generated by the quadriceps was unchanged after TKA and weaker than that of controls (p < 0.001). The proportions of KEM contributing to the total sagittal moment were also smaller in the pre-/post-operative groups than in the control group (13-14% vs. 19%). On the other hand, the ankle plantar flexion moment (APFM) was increased after TKA (p = 0.007) and its proportion of the total sagittal moment was greater than in controls (46% vs. 42%). With regard to kinematics, knee range of motion (ROM) improved after TKA (p = 0.025), but was smaller than that of controls (p < 0.001). In controls, gait speed was determined principally by hip and knee joint moments. However, in the TKA group, speed was determined by the knee ROM and APFM. CONCLUSIONS: Despite showing improvement, the gait speed of TKA patients remained slower than that of controls. Slow gait speed after bilateral TKA was associated with suboptimal improvement of knee biomechanics. Quadriceps strengthening exercises and the achievement of greater ROM during gait are advised for the further improvement of gait speed. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 28849393 TI - Structural complexity and fish body size interactively affect habitat optimality. AB - Predator-prey interactions are strongly influenced by habitat structure, particularly in coastal marine habitats such as seagrasses in which structural complexity (SC) may vary over small spatial scales. For seagrass mesopredators such as juvenile fishes, optimality models predict that fitness will be maximized at levels of SC that enhance foraging but minimize predation risk, both of which are functions of body size. We tested the hypothesis that in eelgrass (Zostera marina) habitat, optimal SC for juvenile giant kelpfish (Heterostichus rostratus), an abundant eelgrass mesopredator in southern California, changes through ontogeny. To do this, we quantified eelgrass SC effects on habitat associations, relative predation risk, and foraging efficiency for three size classes of juvenile giant kelpfish. We found that habitat selection differed with fish size: small fish selected dense eelgrass, whereas larger fish selected sparse eelgrass. Small kelpfish experienced the lowest relative predation risk in dense eelgrass but also had higher foraging efficiency in dense eelgrass, suggesting that dense eelgrass is selected by these fish because it minimizes risk and maximizes potential for growth. Surprisingly, larger kelpfish did not experience lower predation risk than small kelpfish. However, larger kelpfish experienced higher foraging efficiency in sparse eelgrass vs. dense eelgrass, suggesting that they select sparse eelgrass to maximize foraging efficiency. Our study highlights that trade-offs between predation risk and foraging can occur within a single habitat type, that studies should consider how habitat value changes through ontogeny, and that seagrass habitat value may be maximal when within-patch variability in SC is high. PMID- 28849394 TI - Learning dynamic balancing in the roll plane with and without gravitational cues. AB - We determined the relative contributions of gravity-dependent positional cues and motion cues to the learning of roll balance control. We hypothesized that gravity dependent otolith and somatosensory shear forces related to body orientation would yield better initial performance, more rapid learning, and better retention. Blindfolded subjects rode in a device programmed to roll with inverted pendulum dynamics in a vertical (UPRIGHT) or horizontal plane (SUPINE), and used a joystick to align themselves with the direction of balance. Each subject completed five blocks of four 100 s long trials on two consecutive days in one of four groups (n = 10 per group): Group 1, UPRIGHT balancing both days; Group 2, SUPINE both days; Group 3, UPRIGHT then SUPINE; and Group 4, SUPINE then UPRIGHT. On Day 1, UPRIGHT subjects showed better initial performance and greater improvement in performance than SUPINE subjects, who showed improvements only in having fewer deviations exceeding +/-60 deg from the direction of balance. Subjects tested UPRIGHT on both days showed full retention of learning across days and additional Day 2 learning, but subjects tested SUPINE on both days showed partial retention of their marginal learning from Day 1 and little improvement on Day 2. Subjects tested SUPINE on Day 2 after being tested UPRIGHT on Day 1 showed no better performance than subjects tested SUPINE on Day 1. By contrast, there was transfer from SUPINE on Day 1 to UPRIGHT on Day 2. We conclude that absence of gravitationally dependent otolith and somatosensory cues degrades balance performance. PMID- 28849395 TI - Editorial on IJBM Special Issue-E-Health Interventions for Addictive Behaviors. PMID- 28849396 TI - Investigation of the Influence of Protein-Losing Enteropathy on Monoclonal Antibody Pharmacokinetics in Mice. AB - Protein losing enteropathy (PLE), which is characterized by substantial loss of plasma proteins into the gastrointestinal (GI) tract, is a complication of a variety of GI diseases, including inflammatory bowel disease. Clinical studies have found that the clearance of monoclonal antibodies (mAb) is often increased in subjects with diseases known to cause PLE; however, direct relationships between PLE and mAb pharmacokinetics have not been demonstrated. This study employed a murine model of colitis to examine the influence of PLE on mAb pharmacokinetics. Mice were given dextran sodium sulfate (DSS, 2% w/v) supplemented tap water as drinking source for 6 days to induce colitis and PLE. Mice were then intravenously injected with 8C2, a murine IgG1 mAb. 8C2 plasma concentrations were measured up to 14 days post injection. Fecal alpha-1 antitrypsin (A1AT) clearance was measured as biomarker for PLE. DSS-treated mice developed PLE of clinically relevant severity. They also showed a transient increase in 8C2 plasma clearance and a decrease in 8C2 plasma exposure. The area under the 8C2 plasma concentration-time curve for the length of the study (AUC0 14d) reduced from 1368 +/- 255 to 594 +/- 224 day MUg/ml following DSS treatment (p = 0.001). A quantitative relationship between A1AT clearance and 8C2 clearance was obtained via population pharmacokinetic modeling. DSS treatment substantially increased 8C2 clearance and reduced 8C2 exposure. Increased mAb plasma clearance was highly correlated with A1AT fecal clearance, suggesting the possible utility of A1AT fecal clearance as a mechanistic biomarker to predict the pharmacokinetics of therapeutic antibodies. PMID- 28849398 TI - An Enhanced Method of Transcutaneously Stimulating the Tibial Nerve for the Treatment of Overactive Bladder. AB - Transcutaneous electrical nerve stimulation (TENS) can be used to electrically stimulate the tibial nerve for the purpose of treating overactive bladder. Although clinical benefits can be achieved, the overall therapeutic efficacy of TENS is limited. Inconsistent activation of the intended neural target and co activation of cutaneous sensory fibers are considered key limiting factors. In this study, we propose a novel approach that combines TENS with an implanted, electrically-conductive nerve cuff to reduce the stimulation amplitude needed to activate the tibial nerve. This enhanced version of TENS (called eTENS) was designed using a computational model of the rat tibial nerve and subsequently tested in anesthetized rats. Our computational model showed that eTENS can reduce the nerve activation threshold by a factor of up to 2.6. Similar effects were also achieved by in vivo experiments (1.4 +/- 0.1-fold decrease, n = 5). Among various design parameters, spatial alignment between the surface electrode and the nerve cuff was identified as an important factor. Our results show that eTENS can improve the selective activation of the rat tibial nerve, but further work is needed to evaluate its use in clinical therapies. PMID- 28849397 TI - Anatomical variations of the pronator teres muscle in a Central European population and its clinical significance. AB - The pronator teres (PT) muscle is a forearm flexor with radial and ulnar heads. It is innervated by the median nerve (MN), which passes between these heads. Nerve entrapment, known as "PT syndrome", may occur in this passage. Anatomical variations in this region may be potential risk factors of this pathology. Therefore, the aim of the study was to determine the relationship between morphologic variations of the PT and the MN. In 50 isolated, formalin-fixed upper limbs, the cubital region and the forearm were dissected. The following measurements were taken: origin of the PT muscle heads, the length of these heads, the length of the forearm, diameter of the MN and the number of its muscular branches to the pronator teres muscle. The forearms with the humeral head originating from the medial humeral epicondyle and medial intermuscular septum (72%) were significantly shorter (p = 0.0088) than those where the humeral head originated only from the medial humeral epicondyle. Moreover, in these specimens, the MN was significantly thinner (p = 0.003). The ulnar head was present in 43 limbs (86%). The MN passed between the heads of the PT muscle (74%) or under the muscle (26%). In the majority of cases, it provided two motor branches (66%). There is an association between the morphologic variation of the PT muscle heads and the course and branching pattern of the MN. Both are related to differences in forearm length. This may have an impact on the risk of PT syndrome and the performance of MN electrostimulation. PMID- 28849399 TI - Genetic and phylogenetic analysis of the ticks from the Sinai Massif, Egypt, and their possible role in the transmission of Babesia behnkei. AB - Following the description of Babesia behnkei in the region of St. Katherine, Sinai, the present study was undertaken to determine the role of local tick species as vectors of piroplasms. First we assessed the local fauna of ticks, especially species occurring on rodents, camels and encountered in the environment, and then we compared genotypes of ticks from isolated wadis. Finally, we assessed the role of local tick species as potential vectors of Babesia spp. During our expedition to the Sinai Massif in a 4-week period in August-September 2012, 393 ticks were collected, including 235 adult questing ticks collected from the environment (ground level in the wadis) and 158 engorging ticks from camels and rodents. Amplification and sequencing of a 600 bp fragment of the conservative 18S rDNA and a 440 bp fragment of the more variable mitochondrial (mt) 16S rDNA were carried out to enable the identification of 54 ticks and to assess the genetic variability of ticks collected from two distant isolated wadis. The camel tick Hyalomma dromedarii constituted the majority (80 90%) of adult ticks collected from three wadis in the Sinai Mountains near St. Katherine. Among juvenile ticks collected from rodents, three genotypes were identified: H. dromedarii; Hyalomma sp. showing low homology with H. dromedarii, H. lusitanicum or H. aegyptium; and Rhipicephalus sp. A new genotype of Hyalomma was identified in an isolated montane valley, W. Gebal. Babesia/Theileria DNA was not detected in any of the ticks, which is likely due to the low infection rate in the limited number of ticks that were examined. PMID- 28849400 TI - The prevalence of congenital C1 arch anomalies. AB - PURPOSE: To determine the prevalence, radiographic features and reporting rate of, and the association between the congenital anterior and posterior C1 arch anomalies. METHODS: The computed tomography (CT) images of the cervical spines of all patients over 18 years who had CT examinations in our hospital during the study period were reviewed to evaluate for congenital anomalies of the anterior and posterior C1 arches. Radiology reports of the corresponding CT examinations were reviewed to determine the reporting rate of these defects. RESULTS: Of 3273 subjects, 185 (5.65%) had congenital atlas anomalies: 169 isolated posterior (5.16%), 15 combined anterior and posterior (bipartite, 0.46%), and one isolated anterior (0.031%) arch defects. Females had a higher prevalence than males (7.46 versus 4.72%, P = 0.0013). Eighty-three cases (44.9%) of C1 arch anomalies were not reported. The Currarino type A, B, C and E posterior arch defects accounted for 81.6, 8.1, 1.1, and 0.5% of all arch anomalies while type D was not observed. Fifteen patients (0.46%) had combined anterior and posterior arch anomalies (bipartite atlas) versus only one with an isolated anterior C1 defect, indicating a significant association between the anterior and posterior arch defects (P < 0.0001). CONCLUSIONS: Although some types of congenital C1 arch anomalies are rare, type A defects are relatively common radiological findings that are unreported approximately 45% of the time. Based on the significant association between the anterior and posterior arch defects, we propose possible mechanisms for the formation of the bipartite atlas. PMID- 28849401 TI - A Review of the Use of Secukinumab for Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) is a chronic, seronegative spondyloarthropathy associated with psoriasis (PsO). Treatment options range from non-pharmacologic measures to NSAIDS, DMARDs, and biologics, depending on patient presentation. Secukinumab (Cosentyx(c)) is a new biologic treatment option that was approved for use in treating adult patients with PsA in October 2016. Our paper explores the clinical trial evidence available for secukinumab to examine its safety and efficacy as a therapeutic agent for the treatment of PsA. While indirect comparisons of indicate that secukinumab is as effective as other treatment options, further studies directly comparing available treatments will be necessary to establish its place in treatment guidelines. As these and other trials are conducted, the evidence produced will further elucidate the clinical potential of secukinumab as a treatment option for patients with rheumatologic disease. PMID- 28849403 TI - The cognitive reflection test is robust to multiple exposures. AB - The cognitive reflection test (CRT) is a widely used measure of the propensity to engage in analytic or deliberative reasoning in lieu of gut feelings or intuitions. CRT problems are unique because they reliably cue intuitive but incorrect responses and, therefore, appear simple among those who do poorly. By virtue of being composed of so-called "trick problems" that, in theory, could be discovered as such, it is commonly held that the predictive validity of the CRT is undermined by prior experience with the task. Indeed, recent studies have shown that people who have had previous experience with the CRT score higher on the test. Naturally, however, it is not obvious that this actually undermines the predictive validity of the test. Across six studies with ~ 2,500 participants and 17 variables of interest (e.g., religious belief, bullshit receptivity, smartphone usage, susceptibility to heuristics and biases, and numeracy), we did not find a single case in which the predictive power of the CRT was significantly undermined by repeated exposure. This occurred despite the fact that we replicated the previously reported increase in accuracy among individuals who reported previous experience with the CRT. We speculate that the CRT remains robust after multiple exposures because less reflective (more intuitive) individuals fail to realize that being presented with apparently easy problems more than once confers information about the task's actual difficulty. PMID- 28849402 TI - Pharmacokinetics and Pharmacodynamics of Temocillin. AB - Temocillin, a 6-alpha-methoxy derivative of ticarcillin, is a forgotten antibiotic that has recently been rediscovered, and issues about clinical breakpoints and optimal therapeutic regimens are still ongoing. Temocillin spectrum is almost restricted to Enterobacteriaceae. The addition of the alpha methoxy moiety on ticarcillin confers resistance to hydrolysis by Ambler classes A and C beta-lactamases (extended spectrum beta-lactamases, Klebsiella pneumoniae carbapenemase and AmpC hyperproduced enzymes). Temocillin is bactericidal, and the effect of inoculum size on its activity is relatively mild. The proportion of spontaneous resistant mutants in vitro to temocillin is low, as found in vivo. After intravenous infusion, temocillin showed a prolonged elimination half-life of approximately 5 h. The percentage of protein binding of temocillin is high (approximately 80%), and is concentration-dependent. Temocillin clearance is mainly renal, and urinary recovery is high, ranging from 72 to 82% after 24 h. Furthermore, the penetration of temocillin into bile and peritoneal fluid is high, but poor into cerebrospinal fluid. The cumulative percentage of a 24-h period during which the free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) at steady-state pharmacokinetic conditions seems to be the best pharmacokinetic/pharmacodynamic (PK/PD) index correlating with temocillin efficacy. An fT > MIC of 40-50% is associated with antibacterial effect and survival in vivo. Monte Carlo simulations performed in critically ill patients showed that the 2 g every 12 h and 2 g every 8 h regimens provide a 95% probability of target attainment of 40% fT > MIC up to an MIC of 8 mg/L. In less severely ill patients or in specific foci of infection, such as urinary tract infection, a 4 g daily regimen should be adequate for strains with temocillin MIC up to 16 mg/L. Data regarding actual wild-type MIC distribution, clinical efficacy, PK profiling in volunteers or patients, and PD targets are scarce, and further studies are required to support appropriate dosing recommendations and determination of clinical breakpoints. PMID- 28849404 TI - Lower limb fracture presentations at a regional hospital. AB - : We found that lower limb fractures, which were largely the result of minimal trauma, had high levels of hospitalisation, length of stay and surgery. It is therefore important to prevent fractures at all sites to avoid the associated morbidity and mortality. PURPOSE: Hip fractures are a major cause of morbidity and mortality, particularly in older women. In comparison, less is known about the epidemiology and burden of other lower limb fractures. The study aimed to investigate the epidemiology and burden of these fractures. METHODS: Incident fractures of the hip, femur, tibia/fibula, ankle and foot in women (>= 20 years) managed through the University Hospital Geelong, Australia, were ascertained from 1 Jan. 2014 to 31 Dec. 2014 from radiology reports. Age, cause of fracture, post fracture hospitalisation, surgery, length of stay and discharge location were ascertained from medical records. RESULTS: We identified 585 fractures of the lower limb (209 hip, 42 femur, 41 tibia/fibula, 162 ankle, 131 foot). Most fractures were sustained by women aged >= 50 years. Fractures were largely a result of minimal trauma. Most women with hip or femur fractures were hospitalised; fewer were hospitalised for fractures at other sites. Surgery for fracture followed the same pattern as hospitalisations. Length of stay was the highest for hip and femur fractures and the lowest for foot fractures. Women with hip or femur fractures were discharged to rehabilitation more often than home. Fractures at other sites were most commonly discharged home. CONCLUSIONS: Fractures of the lower limb occurred frequently in older women. Hospitalisation and subsequent surgery were common in cases of hip and femur fractures. It is important for prevention strategies to target fractures at a range of skeletal sites to reduce costs, hospitalisations, loss of independence and reduced quality of life. PMID- 28849405 TI - Comparison of mid-age-onset and late-onset Huntington's disease in Finnish patients. AB - The phenotype of juvenile Huntington's disease (HD) differs clearly from that of adult-onset HD, but information about differences between mid-age-onset HD and late-onset HD (LOHD) is scarce. A national cohort of 206 patients with adult onset HD was identified using national registries and patient records. LOHD was defined as age >=60 years at HD diagnosis. Genetic disease burden was assessed using CAG age product (CAP) score. LOHD comprised 25% of the adult-onset HD cohort giving a point prevalence of 2.38/100,000 in the Finnish population at least 60 years of age. The proportion of LOHD out of new HD diagnoses increased from 21% in 1991-2000 to 33% in 2001-2010. At the time of diagnosis, patients with LOHD had 10.4 units (95% CI 4.8-15.9; p = 0.0003) higher CAP scores, more severe motor impairment and slightly more severe functional impairment than that in patients with mid-age-onset HD. There was no difference in the rate of disease progression or survival between LOHD and mid-age-onset patients. The lifespans of deceased patients were shorter in mid-age-onset HD (p < 0.001) and LOHD (p = 0.002) than their life expectancies. Causes of death differed between the two patient groups (p = 0.025). LOHD comprises a quarter of Finnish HD patients and the proportion appears to be increasing. Our results did not reveal differences in the phenotype between mid-age-onset HD and LOHD, but prospective studies are needed. PMID- 28849406 TI - Plasma and cerebrospinal fluid population pharmacokinetics of vancomycin in postoperative neurosurgical patients after combined intravenous and intraventricular administration. AB - PURPOSE: Combined intravenous and intraventricular administration of vancomycin into the cerebrospinal fluid (CSF) has been increasingly utilized for neurosurgical patients, but little is known about the population pharmacokinetics of vancomycin in the plasma and CSF. The aim of our study was to identify significant factors associated with plasma and CSF vancomycin concentrations to guide clinicians with vancomycin dosing. METHODS: Patients with an indwelling ventricular drainage catheter who received intravenous and intraventricular vancomycin were enrolled in this study. Blood and CSF samples were collected at scheduled times and vancomycin concentrations determined. A three-compartmental model (central, peripheral and CSF compartments) was proposed to describe the in vivo behavior of vancomycin. CSF outflow resulted in vancomycin loss, and the clearance of CSF compartment (CLCSF) was used to describe this loss. The nonlinear mixed-effects modeling method was applied to structure the population model, and the stepwise incorporation of seven covariates into the final model was attempted. Simulation was performed with the goal of CSF concentrations reaching or exceeding the minimum inhibitory concentration during therapy. RESULTS: Serum creatinine clearance had a significant influence on clearance of the central compartment. CLCSF had a positive correlation with drainage amount and a negative correlation with elapsed time. Model validation (bootstrap and visual predictive check) demonstrated the stability and performance of the proposed population model. A simple-to-use dosage regimen table was created based on the simulation results. CONCLUSIONS: The proposed final model may be used to guide clinicians with vancomycin dosing in this specific patient population. PMID- 28849407 TI - Conversion of Minimally Invasive Distal Pancreatectomy: Predictors and Outcomes. AB - BACKGROUND: Data on the risk factors for conversion during minimally invasive distal pancreatectomy (MIDP) and its effect on postoperative outcomes are limited. METHODS: This retrospective study used the pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program database to compare MIDP requiring unplanned conversion with completed MIDP and open distal pancreatectomy (ODP). RESULTS: Of the 2926 cases identified in this study, 48.8% had ODP, 42.8% had MIDP, and 7.9% had conversion to MIDP. The conversion rate was 15.3% overall, 17.3% for laparoscopic surgery, and 8.5% for robotic surgery (p < 0.001). The risk factors associated with conversion were higher body mass index (BMI), low preoperative albumin level, a current smoking habit, and malignant T3/T4 disease or chronic pancreatitis compared with benign tumor smaller than 5 cm. A robotic approach was associated with a lower adjusted conversion rate than laparoscopy (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.19-0.52). After adjustment, conversion was associated with a higher overall complication rate than MIDP (OR 1.89; 95% CI 1.35-2.66) or ODP (OR 1.41; 95% CI 1.00-1.98). CONCLUSIONS: Chronic pancreatitis, large malignant tumors, higher BMI, lower serum albumin, and a current smoking habit were shown to be independent risk factors for conversion during MIDP. A robotic approach was associated with a lower conversion rate than laparoscopic MIDP. Conversion of MIDP was associated with a higher overall complication rate than completed MIDP or ODP. Adequate patient selection for MIDP may prevent conversion and associated increased morbidity. PMID- 28849409 TI - Target objects defined by a conjunction of colour and shape can be selected independently and in parallel. AB - It is generally assumed that during search for targets defined by a feature conjunction, attention is allocated sequentially to individual objects. We tested this hypothesis by tracking the time course of attentional processing biases with the N2pc component in tasks where observers searched for two targets defined by a colour/shape conjunction. In Experiment 1, two displays presented in rapid succession (100 ms or 10 ms SOA) each contained a target and a colour-matching or shape-matching distractor on opposite sides. Target objects in both displays elicited N2pc components of similar size that overlapped in time when the SOA was 10 ms, suggesting that attention was allocated in parallel to both targets. Analogous results were found in Experiment 2, where targets and partially matching distractors were both accompanied by an object without target-matching features. Colour-matching and shape-matching distractors also elicited N2pc components, and the target N2pc was initially identical to the sum of the two distractor N2pcs, suggesting that the initial phase of attentional object selection was guided independently by feature templates for target colour and shape. Beyond 230 ms after display onset, the target N2pc became superadditive, indicating that attentional selection processes now started to be sensitive to the presence of feature conjunctions. Results show that independent attentional selection processes can be activated in parallel by two target objects in situations where these objects are defined by a feature conjunction. PMID- 28849408 TI - Concurrent Social Disadvantages and Chronic Inflammation: The Intersection of Race and Ethnicity, Gender, and Socioeconomic Status. AB - Disadvantaged social statuses, such as being female, poor, or a minority, are associated with increased psychosocial stress and elevated circulating concentrations of C-reactive protein, a biomarker of chronic inflammation and indicator of cardiovascular health. Individuals' experience of embodying psychosocial stress revolves around the multiplicative effects of concurrent gender, socioeconomic, and racial and ethnic identities. This study expands on prior research by examining chronic inflammation at the intersection of race and ethnicity, gender, socioeconomic status, and age group to understand which demographic subgroups in society are most vulnerable to the cumulative effects of social disadvantage. Using data from the National Health and Nutrition Examination Survey 2007-2010, the findings reveal inflammation disparities between non-poor whites and the following demographic subgroups, net of sociodemographic and biological factors: young poor Hispanic women, young poor white men, young poor and non-poor Hispanic men, middle-aged poor and non-poor black women, middle-aged poor and non-poor black men, and middle-aged poor Hispanic men. Disparities in inflammation on account of social disadvantage are most evident among those aged 45-64 years and diminish for those 65 and older in both men and women. PMID- 28849411 TI - Disparities in cancer incidence by area-level socioeconomic status in the French West Indies. AB - PURPOSE: Social inequalities in cancer incidence and mortality have been reported in France, but no data are available for the French overseas territories. Our objective was to explore the association between cancer incidence and the socioeconomic level of the residence area in the French West Indies. METHODS: Cancer incidence data were obtained from the cancer registries of Guadeloupe and Martinique (2009-2010). To assess socioeconomic status, we developed a specific index of social deprivation from census data at a small area level. We used Bayesian methods to evaluate the association between cancer incidence and the deprivation index, for all cancers combined and for the major cancer sites. RESULTS: There was no clear association between area-based deprivation and the incidence of all cancers combined. In men, higher area deprivation was associated with a higher incidence of prostate cancer (relative risk (RR) 1.25, 95% credible interval (CI) 1.04-1.49; RR 1.08, CI 0.91-1.29 in the categories of intermediate and high deprivation, respectively, compared to low deprivation), but was not associated with respiratory cancer. Women living in the most deprived areas had a higher incidence of stomach (RR 1.77, CI 1.12-2.89), breast (RR 1.15, CI 0.90 1.45), and cervical (RR 1.13, CI 0.63-2.01) cancers and a lower incidence of respiratory cancer (RR 0.65, CI 0.38-1.11). CONCLUSION: These first results in the French West Indies suggest specific patterns for some cancer sites that need to be further investigated. PMID- 28849412 TI - Non-amnestic mild cognitive impairment and sleep complaints: a bidirectional relationship? AB - BACKGROUND: Prior studies documented that several sleep disorders may coexist in patients affected by Mild Cognitive Impairment (MCI) and Alzheimer disease (AD), and have a strong bidirectional relationship with cognitive decline. AIM: To assess the self-reported sleep quality and daytime sleepiness among subjects affected by MCI and AD at early-stage and healthy controls, and to verify if sleep disturbances might be an indicator of specific cognitive deficits. METHODS: 139 patients (102 MCI, 37 AD) underwent comprehensive neuropsychological, functional, and behavioral assessment, which also included Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). 80 healthy elderly subjects were used as controls. MCI patients have been divided into Good Sleepers and Bad Sleepers, depending on their reported sleep quality (PSQI global score <=5/>5). RESULTS: MCI patients experienced more subjective daytime sleepiness than AD matches. As for the subjective sleep quality among MCI patients, 54% of Bad Sleepers met diagnostic criteria for non-amnestic MCI; vice-versa, 73% of Good Sleepers were diagnosed with amnestic-MCI (p = 0.005), independently of depression and anxiety. CONCLUSIONS: MCI patients complain of daytime sleepiness and dysfunction more than AD patients; among MCI patients, Bad Sleepers appear mainly characterized by a non-amnestic cognitive profile. PMID- 28849410 TI - Interdisciplinary approach to compensation of hypoglycemia in diabetic patients with chronic heart failure. AB - Diabetes mellitus is a chronic disease requiring lifelong control with hypoglycemic agents that must demonstrate excellent efficacy and safety profiles. In patients taking glucose-lowering drugs, hypoglycemia is a common cause of death associated with arrhythmias, increased thrombus formation, and specific effects of catecholamines due to sympathoadrenal activation. Focus is now shifting from merely glycemic control to multifactorial approach. In the context of individual drugs and classes, this article reviews interdisciplinary strategies evaluating metabolic effects of drugs for treatment of chronic heart failure (CHF) which can mask characteristic hypoglycemia symptoms. Hypoglycemia unawareness and cardiac autonomic neuropathy are discussed. Data suggesting that hypoglycemia modulates immune response are reviewed. The potential role of gut microbiota in improving health of patients with diabetes and CHF is emphasized. Reports stating that nondiabetic CHF patients can have life-threatening hypoglycemia associated with imbalance of thyroid hormones are discussed. Regular glycemic control based on HbA1c measurements and adequate pharmacotherapy remain the priorities in diabetes management. New antihyperglycemic drugs with safer profiles should be preferred in vulnerable CHF patients. Multidrug interactions must be considered. Emerging therapies with reduced hypoglycemia risk, telemedicine, sensor technologies, and genetic testing predicting hypoglycemia risk may help solving the challenges of hypoglycemia in CHF patients with diabetes. Interdisciplinary work may involve cardiologists, diabetologists/endocrinologists, immunologists, gastroenterologists, microbiologists, nutritionists, imaging specialists, geneticists, telemedicine experts, and other relevant specialists. This review emphasizes that systematic knowledge on pathophysiology of hypoglycemia in diabetic patients with CHF is largely lacking and the gaps in our understanding require further discoveries. PMID- 28849414 TI - Imaging appearance of fibrosing diseases of the retroperitoneum: can a definitive diagnosis be made? AB - PURPOSE: To assess the frequency with which previously reported characteristic findings of retroperitoneal fibrosis (RPF) (a circumferential or almost circumferential peri-aortic mass centered at L4, which does not displace the abdominal aorta or proximal common iliac arteries) are present in patients with RPF, in patients with other fibrosing diseases, and in cancer patients referred to a subspecialty clinic with a suspected diagnosis of RPF, in order to determine whether diagnostic percutaneous biopsy can be avoided in some patients. METHODS: This HIPAA-compliant Institutional Review Board-approved retrospective study assessed clinical and CT and MR imaging abnormalities on imaging studies in 92 patients referred to a subspecialty clinic with suspected RPF over a 14-year period. Two reviewers, in consensus, determined the frequency of different CT and MRI findings in three groups of patients (Group 1: those with an eventual diagnosis of RPF, Group 2: those with a fibrosing disease associated with vascular or urologic abnormalities, and Group 3: those with cancer). Assessed imaging features included the presence of retroperitoneal masses, whether masses were single or multiple, whether such masses were circumferential or nearly circumferential, whether they displaced the aorta away from the spine (with the degree of such displacement measured), and whether there were abnormalities outside of the peri-aortic region of the retroperitoneum. The frequency with which findings previously reported as characteristic of RPF were present was determined for each of the three groups. Imaging results were correlated with the final diagnoses. RESULTS: Of 68 subjects eventually diagnosed with retroperitoneal fibrosis (RPF) (Group 1), 47 had peri-aortic retroperitoneal masses, 18 of which displaced the aorta anteriorly away from the spine. Of 12 subjects with fibrosing abnormalities related to vascular or urologic disease (Group 2), six had retroperitoneal masses, none of which displaced the aorta away from the spine. Of 12 subjects with malignancies (Group 3), six had peri-aortic retroperitoneal masses only two of whom had aortic displacement. Only 34 of 68 Group 1 subjects had peri-aortic masses characteristic of RPF, compared with six Group 2 subjects and one Group 3 subject. Subjects with characteristic retroperitoneal masses were significantly more likely to have benign disease than cancer (p = 0.009). CONCLUSION: Many patients with RPF do not have characteristic imaging findings. Contrary to prior publications, absence of aortic displacement is not seen in all patients with RPF and is seen in some cancer patients. Nonetheless, when infiltrative peri-aortic retroperitoneal soft tissue that does not displace the aorta is encountered on CT or MRI, RPF can be diagnosed with a high degree of confidence, obviating the need for biopsy. PMID- 28849413 TI - Prognostic stratification of patients with metastatic nasopharyngeal carcinoma using a clinical and biochemical scoring system. AB - PURPOSE: Metastatic nasopharyngeal cancer (NPC) is known to have poor survival outcomes. Clinical and biochemical parameters may impact survival outcomes among patients with metastatic NPC and may be used for prognostication. METHODS: One hundred and fifty-eight patients with metastatic NPC treated at a single tertiary institution were analyzed retrospectively. Multivariate analysis was carried out on patients who were given disease control treatment (n = 135). A numerical score derived from the regression coefficients of each identified independent variable was used to create prognostic groups (PG). A p value of less than 0.05 was considered significant. RESULTS: Independent negative prognostic factors included ECOG status >1, LDH level >580 U/L, hemoglobin level <12.0 g/dL and having more than one metastatic organ involvement. Three PGs were obtained: low risk (total score = 0), intermediate risk (1-2) and high risk (3-4). Median survivals of the 3 groups (low, intermediate and high risk) were 57.1, 18.1 and 8.0 months for the three different risk groups, respectively (p < 0.001). CONCLUSION: Risk stratification of patients with metastatic nasopharyngeal cancer is possible using a prognostic scoring system based on clinical and biochemical parameters. Patients with low-risk score may achieve good metastatic survival and may benefit from additional therapy for disease control. PMID- 28849415 TI - Segregation of a novel p.(Ser270Tyr) MAF mutation and p.(Tyr56*) CRYGD variant in a family with dominantly inherited congenital cataracts. AB - A bilaterally blind woman, with a three generation family history of autosomal dominant congenital cataracts, variably associated with iris colobomata and microcornea, sought preconception genetic consultation. Whole-exome sequencing was performed in three affected family members, one unaffected first degree relative, and one spouse. The sequence variant c.168C>G; p.(Tyr56*) in CRYGD, previously reported as pathogenic, and a novel mutation c.809C>A; p.(Ser270Tyr) in MAF, were identified in two affected family members; the grandmother, and half brother of the proband. The proband inherited only the MAF mutation, whereas her clinically unaffected sister had the CRYGD change. In silico analysis supported a pathogenic role of p.(Ser270Tyr) in MAF, which was absent from publicly available whole-exome datasets, and 1161 Czech individuals. The frequency of CRYGD p.(Tyr56*) in the ExAC dataset was higher than the estimated incidence of congenital cataract in the general population. Our study highlights that patients with genetically heterogeneous conditions may exhibit rare variants in more than one disease-associated gene, warranting caution with data interpretation, and supporting parallel screening of all genes known to harbour pathogenic mutations for a given phenotype. The pathogenicity of sequence variants previously reported as cataract-causing may require re-assessment in light of recently released datasets of human genomic variation. PMID- 28849417 TI - Additive Damage Models for Cellular Pharmacodynamics of Radiation-Chemotherapy Combinations. AB - Many cancer patients receive combination treatments with radiation and chemotherapy. Available mathematical models for cellular pharmacodynamics have limited ability to represent observed in vitro responses to radiochemotherapy. Here, a family of additive damage models is proposed to describe cell kill resulting from radiochemotherapy with fixed schedule and variable doses. The pathways by which the agents produce cellular damage are assumed to converge in a single cell death process, so that survival depends on total damage, which can be represented as a sum of contributions from the various damage pathways. Heterogeneity in response across the cell population is ascribed to variations in the damage threshold for cell kill. The family of proposed models includes effects of one or two pathways of damage for each agent, saturation in drug responses, and cooperative or antagonistic interactions between agents. Models from this family with 4-7 unknown parameters are tested for their ability to fit 218 in vitro literature data sets for a range of drugs and cell lines. Overall, the additive damage models are found to outperform models based on the existing concept of independent cell kill, according to the corrected Akaike Information Criterion. The results are used to assess the importance of the various effects included in the models. These additive damage models have potential applications to the optimization of treatment and to the analysis and interpretation of in vitro screening data for new drug-radiation combinations. PMID- 28849416 TI - Invasive assessment of coronary artery disease. AB - Coronary artery disease is associated to high mortality and morbidity rates and an accurate diagnostic assessment during heart catheterization has a fundamental role in prognostic stratification and treatment choices. Coronary angiography has been integrated by intravascular imaging modalities, namely intravascular ultrasound and optical coherence tomography, which allow the precise quantification of the atherosclerotic burden of coronary arteries. The hemodynamic relevance of a given coronary stenosis can be assessed using stress or resting indexes: fractional flow reserve and instantaneous wave-free ratio are both coronary flow surrogates, used to guide percutaneous coronary interventions. This review summarizes the current state-of-the-art of invasive diagnostic methods during heart catheterization and highlights the potential role that an integration of anatomical and functional information enables. PMID- 28849418 TI - Urinary arsenic, cadmium, manganese, nickel, and vanadium levels of schoolchildren in the vicinity of the industrialised area of Asaluyeh, Iran. AB - Asaluyeh is one of the most heavily industrialised areas in the world where gas, petrochemical, and many downstream industries are located. This study aims to survey the biomonitoring of four metals and one metalloid in children living in the vicinity of Asaluyeh area. To do this, we analysed the creatinine-adjusted urinary levels of arsenic (As), cadmium (Cd), vanadium (V), manganese (Mn), and nickel (Ni) in 184 elementary schoolchildren (99 boys and 85 girls) living in Asaluyeh and compared them with a reference population. The comparisons were done for two seasons (spring and fall). The results showed that in the case area (Asaluyeh), the levels of As, V, Mn, and Ni were significantly higher and that of Cd was not significantly higher than the reference city for both seasons. The mean concentration of metal(loid)s in Asaluyeh (case) and Sadabad (reference) area as MUg g-1 creatinine was As 2.90 and 2.24, V 0.06 and 0.03, Mn 0.28 and 0.25, Ni 0.54 and 0.29, and Cd 0.31 and 0.28 in spring and As 3.08 and 2.28, V 0.07 and 0.03, Mn 0.30 and 0.26, Ni 0.91 and 0.30, and Cd 0.36 and 0.31 in the fall. Seasonal variations played a key role in determining urinary metal(loid) concentration, as we saw the significant level of As, Cd, V, and Ni in fall than in spring. With regard to the impact of gender on the absorption and accumulation of urinary metal(loid)s, boys showed higher levels of the studied elements, especially for As, than girls as outdoor activities are more popular among boys. Due to the values being lower than those reported in literature, more research is needed on various population groups and other exposure sources in order to judge whether living in the vicinity of the gas and petrochemical industries in Asaluyeh is a threat to nearby residents. PMID- 28849419 TI - Myocardial T1 mapping and extracellular volume quantification: an overview of technical and biological confounders. AB - Novel tissue biomarkers based on the spin-lattice relaxation time T1, a fundamental property in the theory of magnetic resonance physics, have emerged as a new approach for myocardial tissue characterization with many validated clinical applications. This article is intended as an overview of the physical and physiological mechanisms underlying the interpretation and the accuracy of any practical measurement of T1, or derived biomarkers such as extravascular volume fraction, and also includes a discussion of potential pitfalls. Numerous caveats und knowledge gaps related to the precise interpretation of T1-based biomarkers remain, which are being addressed incrementally through ongoing research. Equally important, further careful standardization will pave the way for a wider clinical translation of these novel T1-based biomarkers of tissue remodeling, which have been well validated for their sensitivity to pathophysiological changes, though for the most part in single-center studies. PMID- 28849420 TI - Hair coat characteristics and thermophysiological stress response of Nguni and Boran cows raised under hot environmental conditions. AB - Breed, age, coat colour, month and temperature humidity index (THI) influence on body weight (W), body condition score (BCS), thermophysiological variables (rectal temperature (Tr), skin temperature (Tsk)) and hair length was studied in Nguni (n = 19) and Boran (n = 16). As a result of this study, breed influenced W, BCS and Tsk on the neck and belly (P < 0.05). The BCS and W of Nguni cows were higher than the Boran cows. Hair length of both breeds increased from February to August. The THI influenced thermophysiological variables (P < 0.05). Increased Tr for both breeds was recorded in February and April, respectively (P < 0.05). Month influenced Tsk and June recorded lower values (P < 0.05). Younger cows (3-8 years) had lower weight and high Tr and Tsk (P < 0.05). Nguni cows had high neck and thurl temperatures in June while Boran cows had the highest in August (P < 0.05). Red, dun and white-black Boran cows had increased BCS. Nguni cows with red, fawn and white cows had high BCS. Fawn-coloured Nguni cows and white-brown Boran cows had the more weight than cows with other colours compared in the study. White-red Nguni and Boran cows recorded the highest Tr. For Nguni cows, neck and belly temperatures were significantly (P < 0.001) correlated to thurl temperature. Boran cows had significant (P < 0.001) correlations for THI and neck, belly and thurl temperatures. The current study found that Nguni cows were more adapted to the prevailing bioclimatic changes. However, Boran cows have the potential of performing well under heat stress conditions over time. PMID- 28849421 TI - Review of Mechanical Testing and Modelling of Thrombus Material for Vascular Implant and Device Design. AB - A thrombus or blood clot is a solid mass, made up of a network of fibrin, platelets and other blood components. Blood clots can form through various pathways, for example as a result of exposed tissue factor from vascular injury, as a result of low flow/stasis, or in very high shear flow conditions. Embolization of cardiac or vascular originating blood clots, causing an occlusion of the neurovasculature, is the major cause of stroke and accounts for 85% of all stroke. With mechanical thrombectomy emerging as the new standard of care in the treatment of acute ischemic stroke (AIS), the need to generate a better understanding of the biomechanical properties and material behaviour of thrombus material has never been greater, as it could have many potential benefits for the analysis and performance of these treatment devices. Defining the material properties of a thrombus has obvious implications for the development of these treatment devices. However, to-date this definition has not been adequately established. While some experimentation has been performed, model development has been extremely limited. This paper reviews the previous literature on mechanical testing of thrombus material. It also explores the use of various constitutive and computational models to model thrombus formation and material behaviour. PMID- 28849422 TI - The more from East-Asian, the better: risk prediction of colorectal cancer risk by GWAS-identified SNPs among Japanese. AB - BACKGROUND: Little is known about the difference of genetic predisposition for CRC between ethnicities; however, many genetic traits common to colorectal cancer have been identified. This study investigated whether more SNPs identified in GWAS in East Asian population could improve the risk prediction of Japanese and explored possible application of genetic risk groups as an instrument of the risk communication. METHODS: 558 Patients histologically verified colorectal cancer and 1116 first-visit outpatients were included for derivation study, and 547 cases and 547 controls were for replication study. Among each population, we evaluated prediction models for the risk of CRC that combined the genetic risk group based on SNPs from GWASs in European-population and a similarly developed model adding SNPs from GWASs in East Asian-population. We examined whether adding East Asian-specific SNPs would improve the discrimination. RESULTS: Six SNPs (rs6983267, rs4779584, rs4444235, rs9929218, rs10936599, rs16969681) from 23 SNPs by European-based GWAS and five SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279) among ten SNPs by Asian-based GWAS were selected in CRC risk prediction model. Compared with a 6-SNP-based model, an 11-SNP model including Asian GWAS-SNPs showed improved discrimination capacity in Receiver operator characteristic analysis. A model with 11 SNPs resulted in statistically significant improvement in both derivation (P = 0.0039) and replication studies (P = 0.0018) compared with six SNP model. We estimated cumulative risk of CRC by using genetic risk group based on 11 SNPs and found that the cumulative risk at age 80 is approximately 13% in the high-risk group while 6% in the low-risk group. CONCLUSION: We constructed a more efficient CRC risk prediction model with 11 SNPs including newly identified East Asian-based GWAS SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279). Risk grouping based on 11 SNPs depicted lifetime difference of CRC risk. This might be useful for effective individualized prevention for East Asian. PMID- 28849423 TI - A Novel Acetaldehyde Dehydrogenase with Salicylaldehyde Dehydrogenase Activity from Rhodococcus ruber Strain OA1. AB - Salicylaldehyde dehydrogenase (sALDH) can oxidize salicylaldehyde, which is an intermediate in the naphthalene catabolism in bacteria. However, genes encoding sALDH have not been discovered so far in Rhodococcus. Here, we report the discovery of a novel aldehyde dehydrogenase (ALDH) gene in the naphthalene degrader Rhodococcus ruber OA1 based on phylogenetic analysis. Interestingly, apart from ALDH activity, ALDH of R. ruber OA1 (OA1-ALDH) also showed sALDH activity. Moreover, its sALDH specific activity was higher than its ALDH specific activity. Based on a comparison with the ALDH of Thermomonospora curvata DSM 43,183, a putative active site Cys123 and NAD+ binding site Asn263 were proposed in R. ruber OA1. Multiple alignment of OA1-ALDH with ALDHs from other organisms indicated that the residues Ser122 and Ala124 might influence the enzyme activity and substrate specificity that render OA1-ALDH the ability to catalyze salicylaldehyde better than acetaldehyde. These results support the possibility that OA1-ALDH plays the role of sALDH in the oxidation of salicylaldehyde to salicylate in R. ruber OA1. In summary, our study would contribute to the understanding of the structure and roles of ALDH in Rhodococcus. PMID- 28849424 TI - Papineau technique combined with vacuum-assisted closure for open tibial fractures: clinical outcomes at five years. AB - PURPOSE: Treatment of open tibial fractures with soft tissue and segmental bone defects is difficult. This study reports our results for treating these injuries with a combination of Papineau open bone grafting and vacuum-assisted wound closure (VAC). METHODS: The records of 19 patients with open tibial fractures with soft tissue and segmental bone defects treated with bone grafting and VAC from 2004 to 2010 were retrospectively reviewed. Outcomes included: time to complete granulation tissue coverage, wound healing, and bone union; length of hospitalization; frequency of debridement; number of deep tissue infections. RESULTS: Initial surgery was performed within 48 hours of injury. Ten fractures were Orthopaedic Trauma Association classification 41-A3, one was 41-C3, seven were 43-A3, and one was 43-C3. No surgical complications occurred, and the mean length of hospitalization was 11.0 +/- 3.0 weeks (range, 7-18 weeks). The mean follow-up time was 59.35 +/- 8.76 months. The mean time for complete wound healing was 7.76 +/- 1.52 weeks (range, 6-11 weeks). Bone union was achieved in all patients at a mean of 33.88 +/- 8.37 weeks (range, 23-53 weeks). Only one patient developed a deep tissue infection, which was treated with antibiotics and debridements, and complete bone union wound healing was achieved. Based on Paley grade, five outcomes were excellent, eight were good, and four were fair. CONCLUSIONS: The combination of VAC and open bone grafting results in good outcome for patients with open tibial fractures and severe bone and soft-tissue defects. PMID- 28849425 TI - Contribution of point sources and non-point sources to nutrient and carbon loads and their influence on the trophic status of the Ganga River at Varanasi, India. AB - To determine the possible contributions of point and non-point sources to carbon and nutrient loading in the Ganga River, we analyzed N, P, and organic carbon (OC) in the atmospheric deposits, surface runoff, and in the river along a 37-km stretch from 2013 to 2015. We also assessed the trophic status of the river as influenced by such sources of nutrient input. Although the river N, P, and productivity showed a declining trend with increasing discharge, runoff DOC and dissolved reactive phosphorus (DRP) increased by 88.05 and 122.7% between the Adpr and Rjht sites, indicating contributions from atmospheric deposition (AD) coupled with land use where agriculture appeared to be the major contributor. Point source input led to increased river concentrations of NO3-, NH4+, DRP, and DOC by 10.5, 115.9, 115.2, and 67.3%, respectively. Increases in N, P, and productivity along the gradient were significantly negatively correlated with river discharge (p < 0.001), while river DOC and dissolved silica showed positive relationships. The results revealed large differences in point and non-point sources of carbon and nutrient input into the Ganga River, although these variations were strongly influenced by the seasonality in surface runoff and river discharge. Despite these variations, N and P concentrations were sufficient to enhance phytoplankton growth along the study stretch. Allochthonous input together with enhanced autotrophy would accelerate heterotrophic growth, degrading the river more rapidly in the near future. This study suggests the need for large-scale inter-regional time series data on the point and non-point source partitioning and associated food web dynamics of this major river system. PMID- 28849426 TI - Hospitalization Risk and Potentially Inappropriate Medications among Medicare Home Health Nursing Patients. AB - BACKGROUND: Hospitalizations and potentially inappropriate medication (PIM) use are significant and costly issues among older home health patients, yet little is known about the prevalence of PIM use in home health or the relationship between PIM use and hospitalization risk in this population. OBJECTIVE: To describe the prevalence of PIM use and association with hospitalization among Medicare home health patients. DESIGN: Cross-sectional analysis using data from 132 home health agencies in the US. SUBJECTS: Medicare beneficiaries starting home health nursing services between 2013 and 2014 (n = 87,780). MAIN MEASURES: Prevalence of individual and aggregate PIM use at start of care, measured using the 2012 Beers criteria. Relative risk (RR) of 30-day hospitalization or re-hospitalization associated with individual and aggregate PIM use, compared to no PIM use. KEY RESULTS: In total, 30,168 (34.4%) patients were using at least one PIM, with 5969 (6.8%) taking at least two PIMs according to the Beers list. The most common types of PIMs were those affecting the brain or spinal cord, analgesics, and medications with anticholinergic properties. With the exception of nonsteroidal anti-inflammatory drugs (NSAIDs), PIM use across all classes was associated with elevated risk (10-33%) of hospitalization compared to non-use. Adjusting for demographic and clinical characteristics, patients using at least one PIM (excluding NSAIDs) had a 13% greater risk (RR = 1.13, 95% CI: 1.09, 1.17) of being hospitalized than patients using no PIMs, while patients using at least two PIMs had 21% greater risk (RR = 1.21, 95% CI: 1.12, 1.30). Similar associations were found between PIMs and re-hospitalization risk among patients referred to home health from a hospital. CONCLUSIONS: Given the high prevalence of PIM use and the association between PIMs and hospitalization risk, home health episodes represent opportunities to substantially reduce PIM use among older adults and prevent adverse outcomes. Efforts to address medication use during home health episodes, hospitalizations, and care transitions are justified. PMID- 28849428 TI - Topical Corticosteroid Concerns Among Parents of Children with Psoriasis versus Atopic Dermatitis: A French Multicenter Cross-Sectional Study. AB - BACKGROUND: Atopic dermatitis (AD) and psoriasis are chronic inflammatory cutaneous disorders for which the gold standard treatment is topical corticosteroids. Although fears about topical corticosteroids are known to be a primary cause of poor therapeutic adherence in AD, this has not been evaluated in psoriasis. TOPICOP is a helpful and easy-to-use tool for the evaluation of topical corticosteroid concerns (TCC). It may help clinicians improve adherence to treatment and correct misconceptions. OBJECTIVE: We aimed to compare the TCC of parents of children with psoriasis or AD using the TOPICOP scale and a visual analog scale (VAS). METHODS: We performed a cross-sectional multicenter study in nine French hospitals from 1 October 2015 to 31 May 2016. The TOPICOP scale was developed for patients with AD and comprises 12 questions to assess patients' worries and beliefs about topical corticosteroids, with a maximum score of 36. We used a standardized questionnaire to collect epidemiologic and medical data, and the parents completed the TOPICOP scale and VAS (score 0-10). RESULTS: A total of 122 children were enrolled (61 patients in each group). The mean Physician Global Assessment was 2.1 in the psoriasis group, and the mean SCORing AD index was 33.3 in the AD group. The TOPICOP score was 16.0 in the psoriasis group and 18.8 in the AD group (p = 0.10). The VAS score was 5.6 and 5.1 in the psoriasis and AD groups, respectively (p = 0.18). The mean TOPICOP score was higher if the mother answered (p < 0.0001; odds ratio 12.3; 95% confidence interval 9.2-15.5). In the AD group, the mean TOPICOP score was higher if follow-up for the child was as an outpatient (p = 0.018). In the psoriasis group, the mean TOPICOP score was higher if patients were seen for the first time (p = 0.047). CONCLUSION: Using the TOPICOP questionnaire and a VAS, we found the level of TCC for the parents of pediatric patients with psoriasis to be similar to that for parents of pediatric patients with AD. As TCC is an issue in patients with psoriasis, future research is warranted to assess whether therapeutic education lessens TCC and improves treatment outcomes. PMID- 28849427 TI - Overexpression of cytosolic, plasma membrane bound and extracellular heat shock protein 70 (Hsp70) in primary glioblastomas. AB - A unique feature in several non-CNS-tumors is the overexpression of heat shock protein 70 (Hsp70, HSPA1A) in the cytosol, but also its unusual plasma membrane expression and release. Although in gliomas, cytosolic Hsp70 levels are not associated with histological grading, the role of membrane bound and released Hsp70 is still completely unknown. Membrane bound as well as cytosolic Hsp70 can be detected in viable tumor cells with the monoclonal antibody (mAb) cmHsp70.1. Herein, we analysed membrane bound Hsp70 levels in primary and secondary gliomas of different grades and on isolated glioma subpopulations (endothelial cells, CD133-positive cells, primary cultures) by immunohistochemistry and flow cytometry using cmHsp70.1 mAb. Extracellular Hsp70 was determined by a commercial Hsp70 sandwich ELISA (R&D) in plasma samples of glioblastoma patients and healthy volunteers. We found an overexpression of Hsp70 in primary glioblastomas compared to low-grade, anaplastic, or secondary gliomas as determined by immunohistochemistry. Especially in flow cytometry, a strong plasma membrane Hsp70 expression was only observed in primary but not secondary glioblastomas. Within the heterogeneous tumor mass, CD133-positive tumor-initiating and primary glioblastoma cells showed a high membrane Hsp70 expression density, whereas endothelial cells, isolated from glioblastoma tissues only showed a weak staining pattern. Also in plasma samples, secreted Hsp70 protein was significantly increased in patients harbouring primary glioblastomas compared to those with secondary and low grade glioblastomas. Taken together, we show for the first time that cytosolic, membrane bound and extracellular Hsp70 is uniquely overexpressed in primary glioblastomas. PMID- 28849429 TI - What is the Rate of Revision Discectomies After Primary Discectomy on a National Scale? AB - BACKGROUND: Lumbar discectomy has been shown to be clinically beneficial in numerous studies for appropriately selected patients. Some patients, however, undergo revision discectomy, with previously reported estimates of revisions ranging from 5.1% to 7.9%. No study to date has been able to precisely quantify the rate of revision surgery over numerous years on a national scale. QUESTIONS/PURPOSE: We performed a survival analysis for lumbar discectomy on a national scale using a life-table analysis to answer the following questions: (1) What is the rate of revision discectomy on a national scale over 5 to 7 years for patients undergoing primary discectomy alone? (2) Are there differences in revision discectomy rates based on age of patient, region of the country, or the payer type? METHODS: The Medicare 5% National Sample Administrative Database (SAF5) and a large national database from Humana Inc (HORTHO) were used to catalog the number of patients undergoing a lumbar discectomy. Both of these databases have been cited in numerous peer-reviewed publications during the previous 5 years and routinely are audited by PearlDiver Inc. We identified patients using relevant ICD-9 codes and Current Procedural Terminology (CPT) codes, including ICD-9 72210 (lumbar disc displacement) for disc herniation. We used appropriate CPT codes to identify patients who had a lumbar discectomy. We analyzed patients undergoing additional surgery including those who had repeat discectomy (CPT-63042: laminotomy, reexploration single interspace, lumbar) and patients who had additional more-extensive decompressive procedures with or without fusion after their primary procedure. Revision surgery rates were calculated for patients 65 years and older and those younger than 65 years and for each database (Humana Inc and Medicare). Patients from the two databases also were analyzed based on four distinct geographic regions in the United States where their surgery occurred. There were a total of 7520 patients who underwent a lumbar discectomy for an intervertebral disc displacement with at least 5 years of followup in the HORTHO and SAF5 databases. We used cumulative incidence of revision surgery to estimate the survivorship of these patients. RESULTS: In the HORTHO (2613 patients) and SAF5 (4907 patients) databases, 147 patients (5.6%; 95% CI, 1.8%-9.2%) and 305 patients (6.2%; 95% CI, 3.5%-8.9%) had revision surgery at 7 years after the index discectomy respectively. Survival analysis showed survival rates greater than 93% (95% CI, 91%-98%) for all of the cohorts for a primary discectomy up to 7 years after the surgery. The survivorship was lower for patients younger than 65 years (93% [95% CI, 87%-99%, 1016 of 1091] versus 95% [95% CI, 90%-100%, 1450 of 1522], p = 0.02). When nondiscectomy lumbar surgeries were included, the survivorship of patients younger than 65 years remained lower (83% [95% CI, 76%-89%, 902 of 1091] versus 87% [95% CI, 82%-92%, 1324 of 1522], p = 0.02). There was no difference in revision discectomy rates across geographic regions (p = 0.41) at 7 years. Similarly, there was no difference in additional nondiscectomy lumbar surgery rates (p = 0.68) across geographic regions at 7 years. There was no difference in survivorship rates between patients covered by Medicare (94% [95% CI, 91%-97%], 4602 of 4907) versus Humana Inc (94% [95% CI, 90%-98%], 2466 of 2613) (p = 0.31). CONCLUSIONS: Our study shows rates of cumulative survival after an index lumbar discectomy with revision discectomy as the endpoint. We hope these data allow physicians to offer accurate advice to patients regarding the risk of revision surgery for patients of all ages during 5 to 7 years after their index procedure to enhance shared decision making in spinal surgery. These data also will help public policymakers and accountable care organizations accurately allocate scarce resources to patients with symptomatic lumbar disc herniation. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28849430 TI - A survey of ticks (Acari: Ixodidae) from an over-abundant koala (Phascolarctos cinereus) population in south eastern Australia, with an overview of the ticks and mites of koalas. AB - Within Australia, koala over-abundance has become a serious problem in some areas resulting in significant damage to native forests through defoliation. An over abundant Victorian koala population was surveyed for ticks in the autumn of 2016. During the survey 1036 ticks were collected from 158 koalas. All ticks collected were identified as Ixodes tasmani. Tick prevalence, infestation intensity and on host sex ratios were calculated for the population. An overview of the ticks and mites associated with koalas in Australia is also presented. PMID- 28849431 TI - Roughage levels impact on performance and carcass traits of finishing Nellore cattle fed whole corn grain diets. AB - This study was carried out to evaluate the effects of chopped hay levels in high concentrate diets with whole corn grain (WCG) on performance and carcass traits of finishing Nellore cattle. One hundred and eight 24-month-old Nellore intact males (453 +/- 75 kg) were fed one of three WCG-based diets that differed in roughage level: without roughage (WCG), with 5% chopped hay included (WCG5), or with 12% chopped hay included (WCG12) in a block design (based on initial body weight) for 86 days. Animals fed WCG5 or WCG12 had significantly improved on final body weight, dry matter intake, average daily gain, feed efficiency, hot carcass weight, and dressing percentage when compared to those fed WCG. The Longissimus muscle area (P = 0.1108), backfat thickness (BFT; P = 0.6089), and rump fat thickness (P = 0.1798) were not affected by roughage levels. Therefore, using WCG diets without roughage negatively affects the performance of feedlot Nellore cattle but does not affect carcass traits and does lead to the minimum BFT required by the industry. PMID- 28849433 TI - Profound afternoon depression of ecosystem production and nighttime decline of respiration in a macrophyte-rich, shallow lake. AB - Small, shallow lakes with dense growth of submerged macrophytes are extremely abundant worldwide, but have remained grossly understudied although open water oxygen measurements should be suitable to determine diel fluctuations and test drivers of ecosystem metabolism during the day. We measured the temporal and spatial variability of environmental conditions as well as net ecosystem production (NEP) and respiration (R) in a small, shallow Swedish lake with dense charophyte stands by collecting data from oxygen-, pH-, temperature- and light sensors across horizontal and vertical gradients during different periods between April and June in 3 years. We found reproducible diel oxygen patterns and daily metabolic rates. The charophyte canopy accounted for almost all primary production and respiration of the ecosystem. Two novel discoveries-profound afternoon depression of production and nighttime decline of respiration-occurred on virtually every day. Extensive increase of oxygen-, temperature- and pH-levels and depletion of dissolved inorganic carbon (DIC) and CO2 concentrations could account for maximum NEP-rates before noon and afternoon depression with low NEP rates. Ecosystem respiration declined during the night to 24-70% of rates at sunset, probably because of depletion of respiratory substrates. Afternoon depression of photosynthesis should be widespread in numerous habitats with dense growth of macrophytes, periphyton, or phytoplankton implying that daily photosynthesis and growth are restricted and species with efficient DIC use may have an advantage. PMID- 28849432 TI - EQ-5D studies in musculoskeletal and connective tissue diseases in eight Central and Eastern European countries: a systematic literature review and meta-analysis. AB - EQ-5D is becoming the preferred instrument to measure health-state utilities involved in health technology assessment. The objective of this study is to assess the state of EQ-5D research in musculoskeletal disorders in 8 Central and Eastern European countries and to provide a meta-analysis of EQ-5D index scores. Original research articles published in any language between Jan 2000 and Sept 2016 were included, if they reported any EQ-5D outcome from at least two musculoskeletal patients from Austria, Bulgaria, the Czech Republic, Hungary, Poland, Romania, Slovakia, or Slovenia. Risk of bias was assessed with the Cochrane Collaboration's tool. Twenty-nine articles (5992 patients) were included on rheumatoid arthritis (n = 7), osteoporosis (n = 5), chronic pain (n = 5), osteoarthritis (n = 4), ankylosing spondylitis (n = 2), psoriatic arthritis (n = 2), total hip replacement (n = 2), and scleroderma (n = 2). Low back pain was under-represented, while studies in neck pain, systemic lupus erythematosus, gout, and childhood disorders were lacking. EQ-5D index scores were reported in 24 studies, while the version of the instrument and the value-set was not specified in 41% and 46% of the articles, respectively. Meta-analysis was performed on 24 disease states involving 6876 observation points. Intervention effect was reported in 22 subgroups, out of which risk of bias was low in 41%. This review provides recommendations to improve reporting standards of EQ-5D results and highlights potential areas for future research. Coordinated research in conditions with greatest public health impact as well as a development of a regional value-set could provide locally relevant health-state utilities that are transferable among countries within the region. PMID- 28849434 TI - Acceptability and HIV Prevention Benefits of a Peer-Based Model of Rapid Point of Care HIV Testing for Australian Gay, Bisexual and Other Men Who Have Sex with Men. AB - Frequent HIV testing among gay, bisexual and other men who have sex with men (GBM) is a strategic priority for HIV prevention in Australia. To overcome barriers to testing in conventional clinical services, Australia recently introduced peer HIV rapid point of care (RPOC) testing services for GBM. This mixed methods evaluation describes client acceptability and HIV prevention benefits of a peer HIV testing model. Most aspects of the service model were overwhelmingly acceptable to clients. Two-thirds of survey participants reported preferring testing with peers rather than doctors or nurses and over half reported learning something new about reducing HIV risk. Focus group findings suggested peer-delivered HIV RPOC testing reduced stigma-related barriers to frequent testing and provided novel opportunities for GBM to openly discuss HIV prevention and sexual practices, enhancing their HIV risk-reduction knowledge. Analysis of survey data suggested knowledge transfer occurred particularly among younger and less gay community-attached GBM. PMID- 28849435 TI - A Cohort Study of Healthcare Utilization in Older Adults with Undiagnosed Dementia. PMID- 28849436 TI - YouTube videos in the English language as a patient education resource for cataract surgery. AB - PURPOSE: To assess the quality of the content of YouTube videos for cataract surgery patient education. SETTING: Hotel Dieu Hospital, Kingston, Ontario, Canada. DESIGN: Observational study. METHODS: "Cataract surgery," "cataract surgery for patients," and "cataract surgery patient education" were used as search terms. The first two pages of search results were reviewed. Descriptive statistics such as video length and view count were obtained. Two cataract surgeons devised 14 criteria important for educating patients about the procedure. Videos were analyzed based on the presence or absence of these criteria. Videos were also assessed for whether they had a primary commercial intent. RESULTS: Seventy-two videos were analyzed after excluding 48 videos that were duplicate, irrelevant, or not in English. The majority of videos came from a medical professional (71%) and many depicted a real cataract surgery procedure (43%). Twenty-one percent of the videos had a primary commercial intent to promote a practice or product. Out of a total possible 14 points, the mean number of usefulness criteria satisfied was only 2.28 +/- 1.80. There was no significant difference in view count between the most useful videos and other videos (p = 0.94). Videos from medical organizations such as the National Health Service were more useful (p < 0.0001). CONCLUSIONS: Cataract surgery videos are popular on YouTube, but most are not adequately educational. Patients may be receiving biased information from videos created with primary commercial intent. Physicians should be aware of the type of information patients may be accessing on YouTube. PMID- 28849437 TI - Neuropsychological Functioning in Mid-life Treatment-Seeking Adults with Obesity: a Cross-sectional Study. AB - OBJECTIVE: The aim of this study is to compare cognitive functioning between treatment-seeking individuals with obesity and healthy-weight adults. DESIGN AND METHODS: Sixty-nine bariatric surgery candidates (BMI > 30 kg/m2) and 65 healthy weight control participants (BMI 18.5-25 kg/m2) completed a neuropsychological battery and a self-report psychosocial questionnaire battery. RESULTS: Hierarchical regression analyses indicated that obesity was predictive of poorer performance in the domains of psychomotor speed (p = .043), verbal learning (p < .001), verbal memory (p = .002), complex attention (p = .002), semantic verbal fluency (p = .009), working memory (p = .002), and concept formation and set shifting (p = .003), independent of education. Obesity remained a significant predictor of performance in each of these domains, except verbal memory, following control for obesity-related comorbidities. Obesity was not predictive of visual construction, visual memory, phonemic verbal fluency or inhibition performance. Individuals with obesity also had significantly poorer decision making compared to healthy-weight controls. CONCLUSIONS: Findings support the contribution of obesity to selective aspects of mid-life cognition after controlling for obesity-related comorbidities, while addressing limitations of previous research including employment of an adequate sample, a healthy-weight control group and stringent exclusion criteria. Further investigation into the functional impact of such deficits, the mechanisms underlying these poorer cognitive outcomes and the impact of weight-loss on cognition is required. PMID- 28849438 TI - Improvement in rice straw pulp bleaching effluent quality by incorporating oxygen delignification stage prior to elemental chlorine-free bleaching. AB - Environmental degradation by industrial and other developmental activities is alarming for imperative environmental management by process advancements of production. Pulp and paper mills are now focusing on using nonwood-based raw materials to protect forest resources. In present study, rice straw was utilized for pulp production as it is easily and abundantly available as well as rich in carbohydrates (cellulose and hemicelluloses). Soda-anthraquinone method was used for pulp production as it is widely accepted for agro residues. Bleaching process during paper production is the chief source of wastewater generation. The chlorophenolic compounds generated during bleaching are highly toxic, mutagenic, and bioaccumulative in nature. The objectives of study were to use oxygen delignification (ODL) stage prior to elemental chlorine-free (ECF) bleaching to reduce wastewater load and to study its impact on bleached pulp characteristics. ODL stage prior to ECF bleaching improved the optical properties of pulp in comparison to only ECF bleaching. When ODL stage was incorporated prior to bleaching, the tensile index and folding endurance of the pulp were found to be 56.6 +/- 1.5 Nm/g and 140, respectively, very high in comparison to ECF alone. A potential reduction of 51, 57, 43, and 53% in BOD3, COD, color, and AOX, respectively was observed on adding the ODL stage compared to ECF only. Generation of chlorophenolic compounds was reduced significantly. Incorporation of ODL stage prior to bleaching was found to be highly promising for reducing the toxicity of bleaching effluents and may lead to better management of nearby water resources. Graphical abstract ?. PMID- 28849439 TI - Is Taurine a Biomarker in Autistic Spectrum Disorder? AB - Taurine is a sulfur-containing amino acid which is not incorporated into protein. However, taurine has various critical physiological functions including development of the eye and brain, reproduction, osmoregulation, and immune functions including anti-inflammatory as well as anti-oxidant activity. The causes of autistic spectrum disorder (ASD) are not clear but a high heritability implicates an important role for genetic factors. Reports also implicate oxidative stress and inflammation in the etiology of ASD. Thus, taurine, a well known antioxidant and regulator of inflammation, was investigated here using the sera from both girls and boys with ASD as well as their siblings and parents. Previous reports regarding taurine serum concentrations in ASD from various laboratories have been controversial. To address the potential role of taurine in ASD, we collected sera from 66 children with ASD (males: 45; females: 21, age 1.5 11.5 years, average age 5.2 +/- 1.6) as well as their unaffected siblings (brothers: 24; sisters: 32, age 1.5-17 years, average age 7.0 +/- 2.0) as controls of the children with ASD along with parents (fathers: 49; mothers: 54, age 28-45 years). The sera from normal adult controls (males: 47; females: 51, age 28-48 years) were used as controls for the parents. Taurine concentrations in all sera samples were measured using high performance liquid chromatography (HPLC) using a phenylisothiocyanate labeling technique. Taurine concentrations from female and male children with ASD were 123.8 +/- 15.2 and 145.8 +/- 8.1 MUM, respectively, and those from their unaffected brothers and sisters were 142.6 +/- 10.4 and 150.8 +/- 8.4 MUM, respectively. There was no significant difference in taurine concentration between autistic children and their unaffected siblings. Taurine concentrations in children with ASD were also not significantly different from their parents (mothers: 139.6 +/- 7.7 MUM, fathers: 147.4 +/- 7.5 MUM). No significant difference was observed between adult controls and parents of ASD children (control females: 164.8 +/- 4.8 MUM, control males: 163.0 +/- 7.0 MUM). However, 21 out of 66 children with ASD had low taurine concentrations (<106 MUM). Since taurine has anti-oxidant activity, children with ASD with low taurine concentrations will be examined for abnormal mitochondrial function. Our data imply that taurine may be a valid biomarker in a subgroup of ASD. PMID- 28849440 TI - Functions of Maternally-Derived Taurine in Fetal and Neonatal Brain Development. AB - Taurine (2-aminoethanesulfonic acid) is a sulfur-containing organic acid, which has various physiological functions, including membrane stabilization, cell volume regulation, mitochondrial protein translocation, anti-oxidative activity, neuroprotection against neurotoxicity and modulation of intracellular calcium levels. Taurine also activates GABAA receptors and glycine receptors. Mammalian fetuses and infants are dependent on taurine delivered from their mothers via either the placenta or their mother's milk. Taurine is a molecule that links mother-fetus or mother-infant bonding.This review describes the functions of taurine and the mechanisms of action of taurine in fetal and brain development. Taurine is involved in regulating the proliferation of neural progenitors, migration of newly-generated neurons, and the synapse formation of neurons after migration during fetal and neonatal development. In this review, we also discuss the environmental factors that might influence the functional roles of taurine in neural development. PMID- 28849441 TI - Taurine Supplementation Reduces Renal Nerve Activity in Male Rats in which Renal Nerve Activity was Increased by a High Sugar Diet. AB - This study tests the hypothesis that taurine supplementation reduces sugar induced increases in renal sympathetic nerve activity related to renin release in adult male rats. After weaning, male rats were fed normal rat chow and drank water containing 5% glucose (CG) or water alone (CW) throughout the experiment. At 6-7 weeks of age, each group was supplemented with or without 3% taurine in drinking water until the end of experiment. At 7-8 weeks of age, blood chemistry and renal nerve activity were measured in anesthetized rats. Body weights slightly and significantly increased in CG compared to CW groups but were not significantly affected by taurine supplementation. Plasma electrolytes except bicarbonate, plasma creatinine, and blood urea nitrogen were not significantly different among the four groups. Mean arterial pressure significantly increased in both taurine treated groups compared to CW, while heart rates were not significantly different among the four groups. Further, all groups displayed similar renal nerve firing frequencies at rest and renal nerve responses to sodium nitroprusside and phenylephrine infusion. However, compared to CW group, CG significantly increased the power density of renin release-related frequency component, decreased that of sodium excretion-related frequency component, and decreased that of renal blood flow-related frequency component. Taurine supplementation completely abolished the effect of high sugar intake on renal sympathetic activity patterns. These data indicate that in adult male rats, high sugar intake alters the pattern but not firing frequency of sympathetic nerve activity to control renal function, and this effect can be improved by taurine supplementation. PMID- 28849443 TI - Comparison of Urinary Excretion of Taurine Between Elderly with Dementia and Normal Elderly. AB - The purpose of this study was to investigate the differences in dietary intake, serum level and urinary excretion of taurine between the elderly with dementia and the normal elderly. Subjects with dementia were 22 (8 men, 14 women) and normal were 26 (2 men, 24 women). The general characteristics, anthropometric data were considered together. The blood and urine samples were obtained from the elderly in the morning fasting state. Taurine concentrations in serum and urinary excretion were determined using high performance liquid chromatography (HPLC). Dietary intake data were collected using questionnaires, and analyzed by Computer Aided Nutritional analysis program (CAN-pro 4.0). Statistical analyses were carried out using SPSS 20.0. There were no significant differences in age and BMI (body mass index) between the elderly with dementia and the normal elderly, however, blood total cholesterol, LDL cholesterol and HDL cholesterol levels of the elderly with dementia were relatively higher than the normal elderly. The elderly men with dementia took more lipid, riboflavin higher than the normal elderly men (P < 0.05). The elderly women with dementia took more nutrients except vitamin D, vitamin B12 and taurine than the normal elderly (P < 0.001). There were slight differences in serum taurine level between the two groups. However, urinary excretion of taurine in the elderly with dementia was significantly higher than the normal elderly (41.2%, P < 0.05). PMID- 28849442 TI - Taurine Recovery of Learning Deficits Induced by Developmental Pb2+ Exposure. AB - Lead (Pb2+) is a historically well-documented environmental neurotoxin that produces developmental cognitive learning and memory impairments. These early neurodevelopmental impairments cause increased brain excitability via disruption of Ca2+ mediated signaling during critical periods of synaptogenesis inducing competition with Ica2+ through NMDARs resulting in altered brain development and functioning across the lifespan. Interestingly, Pb2+ has been shown to decrease GABA transport and uptake, decrease spontaneous and depolarization-evoked GABA neurotransmission and lower the expression of glutamic acid decarboxylase (GAD); thereby, limiting excitatory GABAergic influences that regulate early developmental brain excitability and reducing inhibition across mature GABAergic networks. Taurine has been shown to regulate brain excitability in the mature brain through GABAAR mediated inhibition, thereby attenuating improper brain excitability. Mechanistically, taurine is developmentally a potent neuromodulator that acts as a GABAAR agonist and more recently has been reported as a partial agonist for NMDARs through glycine sites. We investigated the effects of developmental Pb2+ exposure on the rat's mature inhibitory cognitive control abilities pharmacologically through anxiety and emotional learning-related behaviors and whether taurine could recover Pb2+ induced neurodevelopmental behavioral deficits later in life. Results showed that Pb2+ increased anxiety symptoms in the open field and hole board test, increased sensitivity to context fear training with cognitive deficits in both acquisition and extinction learning while producing learning deficits and inabilities in acquiring inhibitory learned associations through the acoustic startle response and pre-pulse inhibition (ASR PPI) test. Interestingly, taurine recovered Pb2+ developmentally induced behavioral deficits in the open field and hole board test evidenced by decreased freezing and increased exploration behaviors and facilitated inhibitory dependent ASR-PPI learning to levels higher than controls. In contrast, Baclofen, a GABABR agonist, dose dependently showed no interaction with Pb2+ effects on ASR-PPI learning. Thus, taurine may work as an important neuromodulator at both GABAARs and NMDARs glycine sites, thereby increasing inhibition, enhancing Ca2+-mediated signaling, and decreasing the altered brain excitability, which impedes learning and memory from early Pb2+ exposure. Taken together our data suggests that GABAAR dependent inhibitory learning is altered by early Pb2+ exposure and taurine was able to recover these Pb2+ induced deficits through neuromodulation of GABAARs and potentially NMDARs later in life. These findings may pave the way for further exploration of taurine as a pharmacotherapy for neurodevelopmental lead poisoning in both animal and clinical models. PMID- 28849444 TI - Past Taurine Intake Has a Positive Effect on Present Cognitive Function in the Elderly. AB - This study investigated the associations between dietary history of past taurine intake and cognitive function in the elderly. Subjects of this study were 40 elderly persons with dementia (men 14, women 26) and 37 normal elderly persons (men 5, women 32). Data were collected using questionnaires by investigator-based interview to the elderly and family caregivers. We examined their general characteristics, anthropometric data, cognitive function, and taurine index. Cognitive function was measured using MMSE-DS and higher score means better cognitive function. As dietary history of past taurine intake, taurine index was evaluated by scoring the intake frequency of 41 kinds of taurine-containing foods. Part correlation analysis (sex, age, and school educational period correction) was used to analyze associations between taurine index and cognitive function. The analysis of all data was carried out by the SPSS 20.0 program for windows. The age, height, weight, and BMI of elderly with dementia showed no statistical significance compared to normal elderly. The elderly with dementia had significantly higher school education period (7.4 years) than the normal elderly (4.8 years) (p < 0.01). Nevertheless, the average total score of cognitive function (MMSE-DS) of the elderly with dementia (18.1 points) was significantly lower than score of the normal elderly (21.7 points) (p < 0.05). The average taurine index of the elderly with dementia (104.7 points) was significantly lower than average taurine index of the normal elderly (123.7 points) (p < 0.01). There were positive correlations between total taurine index and total score of cognitive function in all the elderly subjects (p < 0.05). In particular, as taurine index was higher, there were significantly higher scores of cognitive function such as 'time orientation' and 'judgement and abstract thinking' (p < 0.01). In conclusion, these results suggest that past taurine intake may have a positive effect on present cognitive function in the elderly. PMID- 28849445 TI - Dietary Taurine Supplementation in School Meals Has Positive Effect on School Attitude Assessment in Korean High School Students. AB - This study was conducted to evaluate the effect of supplementation with taurine rich foods on school attitude assessment (SAA) in high school students. A total of 134 subjects were divided into a taurine-rich food supplemented (TS) group (68 subjects) and control group (66 subjects). For the TS group, school dinners supplemented with taurine-rich foods were provided for 5 days and average dietary amount of taurine supplementation was 466.2 mg/school dinner. Control group ate dinner at home or at restaurant ad libitum. The school attitude assessment survey revised and 24-h recall method were used for SAA and dietary assessment, respectively. There were no significant differences in scores of dietary attitudes between the TS and control groups by gender. Average dietary taurine intake of the TS group (649.8 mg/day in males, 634.5 mg/day in females) was significantly higher compared to the control group (392.4 mg/day in males, 334.4 mg/day in females) (p < 0.01 in males and p < 0.001 in females, respectively). Total SAA scores in the TS group were significantly higher compared to the control group (p < 0.01) for attitudes toward teachers, goal valuation, and motivation/self-regulation (p < 0.01). Dietary taurine intake was showed positive correlations with scores for academic self-perception (p < 0.05), attitudes towards teachers (p < 0.001), goal valuation (p < 0.01), motivation/self regulation (p < 0.05), and total scores (p < 0.01). According to the results, dietary taurine supplementation in school meals for 5 days had a positive effect on SAA in high school students. Therefore, dietary taurine supplementation in school and home meals may be necessary for improving SAA of high school students. PMID- 28849446 TI - Significance of Taurine in the Brain. AB - Two main functions of taurine in the brain are here discussed: the role of taurine in cell volume regulation and the neuromodulatory actions of taurine liberated by depolarization. Taurine takes part in cell volume regulation with other small-molecular compounds. Extracellular taurine inhibits neuronal firing through GABA and glycine receptors. However, the existence of specific taurine receptors is still not excluded. PMID- 28849447 TI - Neuroprotection by Taurine on HBCD-Induced Apoptosis in PC12 Cells. AB - Hexabromocyclododecane (HBCD) is a widely used brominated flame retardant (BFR). Because of their presence in human issues, including brain tissue, concern has been raised on their possible neurotoxicity. Presently, we explored the neuroprotection of taurine against HBCD-induced apoptotic damages in PC12 cells. Cells were pre-treated with taurine before HBCD exposure and the viability was assayed via the methyl-thiazolyl-tetrazolium (MTT) method. Apoptotic features were observed with Hoechst 33342 staining. Apoptotic ratio was measured using flow cytometry with Annexin V-FITC coupled propidium iodide (PI) double staining. The changes in the levels of Bcl-2 and Bax proteins were quantitated by the western blot. The activity of caspase-3 was tested and the results revealed that presence of HBCD decreased cell survival and led to apoptosis in the tested cells. Further, exposure of HBCD reduced protein expression of Bcl-2, increased expression in Bax protein and activity of caspase-3. Taurine attenuated HBCD induced cell viability loss and cell apoptosis. Moreover, taurine significantly prevented from reducing Bcl-2 protein expression and elevating Bax protein expression and caspase-3 activity induced by HBCD. These results demonstrated that taurine can alleviate HBCD-induced apoptosis by altering Bcl-2 expression and Bax protein and Caspase-3 activity in PC12. PMID- 28849448 TI - Taurine Alleviate Hexabromocyclododecane-Induced Cytotoxicity in PC12 Cells via Inhibiting Oxidative Stress. AB - Hexabromocyclododecane (HBCD) is a widely used brominated flame retardant. Its adverse effects on brain had been observed. Taurine, a sulfur amino acid, take part in many brain physiological functions and exhibits protective effects on a variety of detrimental situations. In this paper, we explored the protections of taurine on cytotoxicity induced by HBCD in PC12 cells. PC12 cells were pretreated with taurine (1 mM, 3 mM and 9 mM) for 30 min before 10 MUM HBCD treatment for 24 h. Then, the cell survival was assayed by the lactate dehydrogenase (LDH) release and trypan blue dyeing method. The formation of reactive oxygen species (ROS) and a collapse of mitochondrial membrane potential (MMP) were evaluated with a fluorescence microplate reader using the non-fluorescent probe 2'7' dichlorofluorescin diacetate (DCFH-DA) and the fluorescent cationic dyestuff Rhodamine 123 (Rh 123), respectively. Further, the activity of many antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and the content of glutathione (GSH) were tested by kits. Our results displayed that taurine significantly decreased the cell death induced by HBCD, prevented ROS production and disruption of mitochondrial membrane potential, and reversed the decline of SOD, CAT, GPx activity and GSH content induced by HBCD. These results suggested that taurine could alleviate cytotoxicity induced by HBCD in PC12 cells through inhibition of oxidative stress. PMID- 28849449 TI - Effects of Taurine on Alterations of Neurobehavior and Neurodevelopment Key Proteins Expression in Infant Rats by Exposure to Hexabromocyclododecane. AB - Hexabromocyclododecanes (HBCDs) is a widely used flame retardant. Studies have found that HBCDs has toxic effects on endocrine and neural development, leading to adverse effects on behavior, learning and memory. This study aimed to investigate the protective effects of taurine on cognitive function, neurotrophic factors expression of infant rats exposured to HBCDs. Sprague-Dawley rats of 10 days old were oral gavaged of different doses (0.3, 3 and 30 mg/kg) of HBCDs and 30 mg/kg HBCDs with 300 mg/kg taurine for 60 consecutive days. Rat cognitive function was detected by the method of Morris water maze test. The protein expressions of brain derived neurotrophic factor (BDNF), nerve growth factor (NGF) and fibroblast growth factor (FGF) were assayed by Western-blotting. Results showed that rats exposed to HBCDs significantly declined rats spatial learning and memory ability by increasing the latency time of seeking the platform (P < 0.05), decreasing the numbers that each rat had crossed the non exits and the time spent in the target quadrant as compared with those in control rats (P < 0.05). Taurine treatment significantly reversed the effects of HBCDs. Western-blotting results showed that expression of BDNF, NGF and FGF proteins in the low dose group were obviously increased compared with those in control rats (P < 0.01), and middle-dose and high dose groups significantly decreased. Taurine treatment increased BDNF and NGF expression as compared with high dose groups while Taurine seemed to have no effects on FGF. These result suggested that higher doses of HBCDs early exposure in the developing rats could decrease neurotrophic factors including BDNF, NGF, FGF, which have an impact on neural development, damage on learning and memory. PMID- 28849450 TI - Taurine Chloramine Suppresses LPS-Induced Neuroinflammatory Responses through Nrf2-Mediated Heme Oxygenase-1 Expression in Mouse BV2 Microglial Cells. AB - The brain is sensitive to the inflammation and oxidative stress that can cause the aging or neurodegenerative diseases. We investigated the anti neuroinflammatory activities of taurine chloramine (TauCl) on lipopolysaccharide (LPS)-treated mouse BV2 microglia mediated through heme oxygenase (HO)-1 expression. TauCl inhibited the protein expressions of prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, nitric oxide (NO), and inducible nitric oxide synthase (iNOS) in LPS-treated BV2 microglia. TauCl markedly inhibited interleukin-6 (IL 6), interleukin-1?? (IL-1??) and tumor necrosis factor-?? (TNF-??) production. These effects were related to the suppression of the degradation and phosphorylation of inhibition of nuclear factor kappa B-?? (I??B-??), translocation of nuclear factor kappa B (NF-??B) as well as DNA binding activity. In addition, TauCl induced the HO-1 expression by increasing the nuclear factor E2-related factor 2 (Nrf2) translocation to the nucleus in mouse BV2 microglia. These findings suggest that TauCl has protective effects of neurodegenerative disorders caused by neuroinflammation. PMID- 28849451 TI - Taurine Chloramine Prevents Neuronal HT22 Cell Damage Through Nrf2-Related Heme Oxygenase-1. AB - Oxidative cell damages are able to contribute to neuronal degeneration in several diseases of the central nervous system (CNS) including stroke as well as ischemia. Heme oxygenase (HO)-1 plays a major role in the pathogenesis of neuronal disorder. Taurine chloramine (TauCl) has been shown to possess strong neuronal activities; however, the direct effects of TauCl on neuronal cell death remain to be determined. Therefore, this study was designed to assess the neuroprotective effect of TauCl using oxidative stress-stimulated mouse hippocampal HT22 cells. TauCl showed protective effects against oxidative stress induced neurotoxicity and inhibited the reactive oxygen species (ROS) production by inducing the heme oxygenase (HO)-1 expression in HT22 cells. TauCl upregulated HO-1 expression and it also increased the nuclear factor E2-related factor 2 (Nrf2) translocation to nuclear. Using an inhibitor of HO-1 activity, we verified that the oxidative stress-related HT22 cell death was significantly suppressed by TauCl. In addition, we found reduced TauCl-induced HO-1 expression and cytoprotection following treatment of the cells with an extracellular signal regulated kinase (ERK) inhibitor (PD98059) or a p38 inhibitor (SB203580), but not following treatment with a SP600125 as a c-Jun NH2-terminal kinase (JNK) inhibitor. These findings suggest that TauCl improves cellular damage induced by glutamate or H2O2 through ERK and p38, Nrf2, and HO-1 pathways in HT22 cells. PMID- 28849452 TI - Taurine Have Neuroprotective Activity against Oxidative Damage-Induced HT22 Cell Death through Heme Oxygenase-1 Pathway. AB - Glutamate-induced oxidative neurotoxicity plays a part role in neuronal degeneration on the disorders of central nervous system (CNS). The expression of heme oxygenase (HO)-1 mediated by Inducible nuclear factor-E2-related factor 2 (Nrf2) functions as an anti-oxidants that is able to play an important role in the pathogenesis of several neuronal disorders. In the present study, taurine showed the inhibitory effect against reactive oxygen species (ROS) induction and protective effects against neurotoxicity induced by glutamate- and H2O2 through induction of HO-1 expression in HT22 cells. Moreover, taurine promoted the Nrf2 nuclear translocation in HT22 cells. We also verified the oxidative stress mediated cell death of HT22 cells was significantly repressed by taurine, using tin protoporphyrin (SnPP) as an HO activity inhibitor. In addition, we found that treatment of the cells with p38 inhibitor (SB203580) suppressed taurine-induced HO-1 expression and cytoprotection, but inhibitors of c-Jun NH2 terminal kinase (JNK) (SP600125) or extracellular signal regulated kinase (ERK) (PD98059) did not. These results suggest that taurine improves the resistance against oxidative damages induced by glutamate in HT22 cells via the p38/Nrf2-dependent HO-1 expression. Our results demonstrated the potential application of taurine as a therapeutic agent for neurodegenerative diseases. PMID- 28849453 TI - Ethanol-Induced Taurine Elevation in the Rat Dorsal Striatum. AB - In the search for the primary mechanism underlying the dopamine elevating properties of ethanol we have established that raised levels of taurine in the nucleus accumbens (nAc) is pivotal. In the nAc, the release of taurine appears to be connected to osmoregulation, and neither taurine nor dopamine is increased if ethanol is administered in a hypertonic saline solution. However, even though the nAc is important for drug-reinforcement, manifestation of addiction has been postulated to recruit the more dorsal parts of the striatum (DS). How ethanol influences dopamine and taurine in the DS and their role in addiction is thus far poorly understood. By means of in vivo microdialysis in freely moving rats we concomitantly monitored extracellular levels of dopamine and taurine in the DS following administration of ethanol diluted either in an isotonic or hypertonic saline solution. In a different set of rats, placed in a voluntary ethanol consumption paradigm (intermittent access to 20% ethanol for 2 months), taurine and dopamine were monitored following an acute injection of ethanol. We found that neither administration of ethanol diluted in a hypertonic saline solution, nor 2 months of moderate ethanol consumption, influence the ethanol-induced increase of taurine in the DS. We propose that there may be regional differences in the relationship between taurine, dopamine and ethanol in the nAc and in the DS. It remains to be determined if this subregion-specificity is important for the transition from recreational drug use to a compulsive habit. PMID- 28849454 TI - Taurine Ameliorates Arsenic-Induced Apoptosis in the Hippocampus of Mice Through Intrinsic Pathway. AB - Our group previously reported that arsenic (As) exposure induced apoptosis in hippocampus neurons. The aim of the present study was to clarify the protective capacity of taurine (Tau) on As-induced neuronal apoptosis and the related mechanism in mouse hippocampus. Mice were divided into: control group, Tau control group, As exposure group and Tau protective group, randomly. The apoptotic rate of mouse hippocampus was determined by TUNEL staining. The levels of Bcl-2 and Bax gene and protein were analyzed by real time RT-PCR and WB, respectively. Furthermore, cytochrome c (Cyt C) release, and the activity of caspase-8 and caspase-3 were also determined. The results showed that Tau treatment induced the decrease of TUNEL-positive cells, prohibited the disturbance of Bcl-2 and Bax expression, and inhibited Cyt C release and caspase 8 and caspase-3 activation significantly. The results indicated that Tau supplement markedly ameliorates As-induced apoptosis by mitochondria-related pathway in mouse hippocampus. PMID- 28849455 TI - Neuroprotective Functions Through Inhibition of ER Stress by Taurine or Taurine Combination Treatments in a Rat Stroke Model. AB - Taurine, as a free amino acid, is found at high levels in many tissues including brain, heart and skeletal muscle and is known to demonstrate neuroprotective effects in a range of disease conditions including stroke and neurodegenerative disease. Using in vitro culture systems we have demonstrated that taurine can elicit protection against endoplasmic reticulum stress (ER stress) from glutamate excitotoxicity or from excessive reactive oxygen species in PC12 cells or rat neuronal cultures. In our current investigation we hypothesized that taurine treatment after stroke in the rat middle cerebral artery occlusion (MCAO) model would render protection against ER stress processes as reflected in decreased levels of expression of ER stress pathway components. We demonstrated that taurine elicited high level protection and inhibited both ATF-6 and IRE-1 ER stress pathway components. As ischemic stroke has a complex pathology it is likely that certain combination treatment approaches targeting multiple disease mechanisms may have excellent potential for efficacy. We have previously employed the partial NMDA antagonist DETC-MeSO to render protection against in vivo ischemic stroke using a rat cerebral ischemia model. Here we tested administration of subcutaneous administration of 0.56 mg/kg DETC-MeSO or 40 mg/kg of taurine separately or as combined treatment after a 120 min cerebral ischemia in the rat MCAO model. Neither drug alone demonstrated protection at the low doses employed. Remarkably however the combination of low dose DETC-MeSO plus low dose taurine conferred a diminished infarct size and an enhanced Neuroscore (reflecting decreased neurological deficit). Analysis of ER stress markers pPERK, peIF-2-alpha and cleaved ATF-6 all showed decreased expression demonstrating that all 3 ER stress pathways were inhibited concurrent with a synergistic protective effect by the post-stroke administration of this DETC-MeSO-taurine combination treatment. PMID- 28849456 TI - Analysis of Neuroprotection by Taurine and Taurine Combinations in Primary Neuronal Cultures and in Neuronal Cell Lines Exposed to Glutamate Excitotoxicity and to Hypoxia/Re-oxygenation. AB - Ischemic stroke is one of the greatest contributors to death and long term disability in developed countries. Ischemia induced brain injury arises due to excessive release of glutamate and involves cell death due to apoptosis and endoplasmic reticulum (ER) stress responses. Despite major research efforts there are currently no effective treatments for stroke. Taurine, a free amino acid found in high concentrations in many invertebrate and vertebrate systems can provide protection against a range of neurological disorders. Here we demonstrate that taurine can combat ER stress responses induced by glutamate or by hypoxia/re oxygenation in neuronal cell lines and primary neuronal cultures. Taurine decreased expression of ER stress markers GRP78, CHOP, Bim and caspase 12 in primary neuronal cultures exposed to hypoxia/re-oxygenation. In analyzing individual ER stress pathways we demonstrated that taurine treatment can result in reduced levels of cleaved ATF6 and decreased p-IRE1 levels. We hypothesized that because of the complex nature of stroke a combination therapy approach may be optimal. For this reason we proceeded to test combination therapies using taurine plus low dose administration of an additional drug: either granulocyte colony stimulating factor (G-CSF) or sulindac a non-steroidal anti-inflammatory drug with potent protective functions through signaling via ischemic preconditioning pathways. When primary neurons were pretreated with 25 mM taurine and 25 ng/mL G-CSF for I hour and then exposed to high levels of glutamate, the taurine/G-CSF combination increased the protective effect against glutamate toxicity to 88% cell survival compared to 75% cell survival from an individual treatment with taurine or G-CSF alone. Pre-exposure of PC12 cells to 5 mM taurine or 25 MUM sulindac did not protect the cells from hypoxia/re-oxygenation stress whereas at these concentrations the combination of taurine plus sulindac provided significant protection. In summary we have demonstrated the protective effect of taurine in primary neuronal cultures against hypoxia with re-oxygenation through inhibition of ATF6 or p-IRE-1 pathway but not the PERK pathway of ER stress. Furthermore the combinations of taurine plus an additional drug (either G-CSF or sulindac) can show enhanced potency for protecting PC 12 cells from glutamate toxicity or hypoxia/re-oxygenation through inhibition of ER stress responses. PMID- 28849457 TI - Minor Adaptations of Ethanol-Induced Release of Taurine Following Chronic Ethanol Intake in the Rat. AB - Alcohol dependence is a puzzling brain disorder causing enormous suffering and financial costs world-wide. One of the few common denominators of all addictive drugs is activation of the mesolimbic dopamine system resulting in increased dopamine levels in the nucleus accumbens. In order to understand the development of addiction and find new efficient treatment strategies we need to understand how addictive drugs increase dopamine following acute and chronic administration of drugs. In the search for mechanisms underlying ethanol's ability to increase dopamine in the nucleus accumbens we have found taurine to be of major importance, although the complete picture remains to be disclosed. The aim of the present study was to explore whether chronic voluntary ethanol intake influences the ethanol-induced elevation of taurine. By means of in vivo micro-dialysis we found that voluntary intake of large amounts of ethanol for 12 weeks only had a modest influence on ethanol-induced elevations of taurine in the rat. PMID- 28849458 TI - Taurine-Carbohydrate Derivative Stimulates Fibrillogenesis of Amyloid-beta and Reduce Alzheimer-Like Behaviors. AB - Amyloid-beta (Abeta) aggregates are a hallmark of Alzheimer's disease (AD). Through the misfolding process of Abeta in the brain, oligomeric forms of Abeta accumulate and significantly damage the brain cells inducing neuronal loss and cognitive dysfunctions that lead to AD. We hypothesized that decrease in Abeta oligomers during the aggregation process might be able to reduce Abeta-dependent brain damage. As taurine-like chemicals are often reported to have direct binding abilities to Abeta, we prepared a chemical library that consisted of taurine carbohydrate derivatives to search for molecules that target Abeta and accelerate its fibrillogenesis. Here, we report that 1-deoxy-1-(2-sulfoethylamino)-D fructose stimulates the formation of relatively less toxic Abeta fibrils leading to prevention of cognitive deficits in AD acute model mice. PMID- 28849459 TI - Taurine Directly Binds to Oligomeric Amyloid-beta and Recovers Cognitive Deficits in Alzheimer Model Mice. AB - Alzheimer's disease (AD) is the most common cause of dementia leading to severe cognitive decline. During the progression of AD, amyloid-beta (Abeta) monomers aggregate into neurotoxic soluble oligomeric Abeta that causes cognitive impairments. Our previous study indicates that oral supplementation of taurine at 1000 mg/kg/day significantly ameliorates hippocampal-dependent cognitive deficits in APP/PS1 transgenic AD mouse model. However, Abeta plaques and oligomeric Abeta levels are not affected after administration of taurine and the oral dosage of taurine was relatively high. Thus, in this study, we focused on direct correlation between taurine and oligomeric Abeta, causing memory deficits in a lower oral dosage of taurine, 250 mg/kg/day. We induced AD-like cognitive impairments to adult normal mice and orally administered taurine via drinking water for 10 days. We confirmed that taurine administration improved cognitive deficits in oligomeric Abeta-infusion mice in Y-maze and passive avoidance tests without activity alteration of mice. In addition, we found that taurine directly bound to oligomeric Abeta in surface plasmon resonance analyses. Our results propose that taurine can ameliorate cognitive impairment by directly binding to oligomeric Abeta in oral administration of 250 mg/kg/day for 10 days. PMID- 28849460 TI - Neuroprotective Effect of Taurine-Rich Cuttlefish (Sepia officinalis) Extract Against Hydrogen Peroxide-Induced Oxidative Stress in SH-SY5Y Cells. AB - Oxidative stress mediates the cell damage in several neurodegenerative diseases, some of which are Alzheimer's disease (AD), multiple sclerosis and Parkinson's disease (PD). In this study, we investigated whether the taurine-rich cuttlefish extract could exert a protective effect on damaged human neuroblastoma SH-SY5Y cells induced by hydrogen peroxide (H2O2). Our results revealed that pre treatment with cuttlefish extract effectively increased the cell viability by protecting the cells from intracellular reactive oxygen species (ROS) induced by H2O2 exposure. Furthermore, apoptosis related proteins Bcl-2 and Bax were investigated by western-blot analysis and results indicated that cuttlefish extract promoted the expression of anti-apoptotic Bcl-2 protein while inhibiting the expression of pro-apoptotic Bax protein. Therefore, cuttlefish extract containing the ability of scavenging excessive ROS, the capacity of anti oxidative stress, could be employed in neurodegenerative disease prevention. In conclusion, the results suggest that cuttlefish extract could be used as a potential candidate for preventing several human neurodegenerative and other disorders caused by oxidative stress. PMID- 28849462 TI - Effects of Taurine Supplementation on Neuronal Excitability and Glucose Homeostasis. AB - In this study we examined the role of chronic taurine supplementation on plasma glucose homeostasis and brain excitability through activation of the insulin receptor. FVB/NJ male mice were supplemented with taurine in drinking water (0.05% w/v) for 4 weeks and subjected to a glucose tolerance test (7.5 mg/kg BW) after 12 h fasting. We found that taurine-fed mice were slightly hypoglycemic prior to glucose injection and showed significantly reduced plasma glucose at 30 and 60 min post-glucose injection when compared to control mice. Previously, we reported that taurine supplementation induces biochemical changes that target the GABAergic system. Those studies show that taurine-fed mice are hyperexcitable, have reduced GABAA receptors expression and increased GAD and somatostatin expression in the brain. In this study, we found that taurine-fed mice had a significant increase in insulin receptor (IR) immuno-reactivity in the pancreas and all brain regions examined. At the mRNA level, we found that the IR showed differential regional expression. Surprisingly, we found that neurons express the gene for insulin and that taurine had a significant role in regulating insulin gene expression. We propose that increased insulin production and secretion in taurine-fed mice cause an increase activation of the central IR and may be partially responsible for the increased neuronal excitability observed in taurine supplemented mice. Furthermore, the high levels of neuronal insulin expression and its regulation by taurine implicates taurine in the regulation of metabolic homeostasis. PMID- 28849461 TI - Protection of Taurine Against Impairment in Learning and Memory in Mice Exposed to Arsenic. AB - To evaluate protection of taurine against arsenic (As)-induced impairment of learning and memory as well as explore its protective mechanism, mice were divided into control, As and taurine protection groups. Mice of As exposure group exposed to drinking water containing 4 ppm As2O3. Mice of taurine protective group received both 4 ppm As2O3 and 150 mg taurine per kilogram. Mice of control group only drank double-distilled water. All animals were treated for 60 days. Morphology of brain was observed by HE staining. Morris water maze (MWM) tests and step-down passive avoidance task were performed to examine cognition function. Moreover, expressions of some genes and proteins related to regulation learning and memory in brain were tested by Real Time RT-PCR and Western Blot. As a result, abnormal morphologic changes in brain tissue and poor performance in cognition functions were observed in As-exposed mice. The expression of TRbeta protein, a regulator of CaMK IV gene, significantly decreased in brains of As exposed mice than in controls. By contrast, impairment in learning and memory, change in brain morphology and disturbance in protein expression were significantly mitigated in mice of taurine protective group. Our results suggest that taurine supplementation protects against neurotoxicity induced by As in mice. PMID- 28849463 TI - Putative Role of Taurine as Neurotransmitter During Perinatal Cortical Development. AB - Neurotransmitters and neuronal activity affect neurodevelopmental events like neurogenesis, neuronal migration, apoptosis and differentiation. Beside glutamate and gamma-amino butyric acid, the aminosulfonic acid taurine has been considered as possible neurotransmitter that influences early neuronal development. In this article I review recent studies of our group which demonstrate that taurine can affect a variety of identified neuronal populations in the immature neocortex and directly modulates neuronal activity. These experiments revealed that taurine evoke dose-dependent membrane responses in a variety of neocortical neuron populations, including Cajal-Retzius cells, subplate neurons and GABAergic interneurons. Taurine responses persist in the presence of GABA(A) receptor antagonists and are reduced by the addition of strychnine, suggesting that glycine receptors are involved in taurine-mediated membrane responses. Gramicidin perforated patch-clamp and cell-attached recordings demonstrated that taurine evokes depolarizing and mainly excitatory membrane responses, in accordance with the high intracellular Cl- concentration in immature neurons. In addition, taurine increases the frequency of postsynaptic GABAergic currents (PSCs) in a considerable fraction of immature pyramidal neurons, indicating a specific activation of presynaptic GABAergic networks projecting toward and exciting pyramidal neurons. In summary, these results suggest that taurine may be critically involved in the regulation of network excitability in the immature neocortex and hippocampus via interactions with glycine receptors. PMID- 28849464 TI - Perinatal Taurine Supplementation Prevents Metabolic and Cardiovascular Effects of Maternal Diabetes in Adult Rat Offspring. AB - This study tests the hypothesis that perinatal taurine supplementation prevents diabetes mellitus and hypertension in adult offspring of maternal diabetic rats. Female Wistar rats were fed normal rat chow and tap water with (Diabetes group) or without diabetic induction by intraperitoneal streptozotocin injection (Control group) before pregnancy. Then, they were supplemented with 3% taurine in water (Control+T and Diabetes+T groups) or water alone from conception to weaning. After weaning, both male and female offspring were fed normal rat chow and tap water throughout the study. Blood chemistry and cardiovascular parameters were studied in 16-week old rats. Body, heart, and kidney weights were not significantly different among the eight groups. Further, lipid profiles except triglyceride were not significantly different among male and female groups, while male Diabetes displayed increased fasting blood glucose, decreased plasma insulin, and increased plasma triglyceride compared to other groups. Compared to Control, mean arterial pressures significantly increased and baroreflex control of heart rate decreased in both male and female Diabetes, while heart rates significantly decreased in male but increased in female Diabetes group. Although perinatal taurine supplementation did not affect any measured parameters in Control groups, it abolished the adverse effects of maternal diabetes on fasting blood glucose, plasma insulin, lipid profiles, mean arterial pressure, heart rate, and baroreflex sensitivity in adult male and female offspring. The present study indicates that maternal diabetes mellitus induces metabolic and cardiovascular defects more in male than female adult offspring, and these adverse effects can be prevented by perinatal taurine supplementation. PMID- 28849465 TI - Taurine Improves Sexual Function in Streptozotocin-Induced Diabetic Rats. AB - Previous studies have identified that diabetic erectile dysfunction is associated with androgen and nitric oxide deficiency resulting from hyperglycemia. It has been demonstrated that taurine can stimulate testosterone secretion, increase nitric oxide synthase (NOS) activity and nitric oxide (NO) production, and reduce blood glucose levels in the diabetic animals. Furthermore, recent studies have found that taurine relaxes both the corpus cavernosum and the vasculature. Accordingly, we hypothesized that taurine might exert beneficial effects on erectile function of the diabetic rats. Here, we assessed the effects of taurine on sexual function in streptozotocin (STZ) -induced diabetic male rats. We observed that taurine treatment could markedly increase sexual response and mating ability of STZ-diabetic rats. The serum concentration of gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) were also significantly increased by taurine administration. Importantly, taurine supplementation notably increased mRNA levels and activity of endothelial NOS (eNOS) and neuronal NOS (nNOS), as well as NO and cGMP content, in the corpus cavernosum of the diabetic rats. In conclusion, the present data indicate that taurine can increase sexual function of STZ-induced diabetic male rats mainly by correcting the diabetes, increasing sexual desire, which is implicated in ameliorating the hypothalamic-pituitary testicular axis function, and by improving penile erection, which requires increased signaling from the penile endothelial- and neuronal-dependent NO-cGMP pathway. PMID- 28849466 TI - Taurine Increases Insulin Expression in STZ-Treated Rat Islet Cells In Vitro. AB - This research aims at figure out the effects and the pathway of taurine on insulin in islet cells cultured in vitro treated by STZ. In the experiment, islet cells were isolated from pancreatic tissue by in situ perfusion with collagenase V. The pancreatic islet cells, maintained in RPMI 1640 culture medium were divided into six groups: C: control, E: supplemented with 10 mmol/L of taurine, group M, T1, T2 and T3 was treated with STZ (0.5 mmol/L), at the same time, taurine were added in group T1,T2 and T3 for 30 min, and then culture medium were collected by centrifugation and then insulin levels were detected by radioimmunoassay, the cells were then rinsed with Hanks, and 0,10, 0, 5, 10, 20 mmol/L of taurine in group C, E, M, T1, T2 and T3 were added for 24 h respectively. Total RNA was extracted, then insulin gene and its transcription regulator such as PDX-1, NeuroD1 were amplified by semi-quantitative RT-PCR. The results showed that, the release of insulin from islet cells treated by STZ could be inhibited by taurine, gene expression of insulin, PDX-1 and NeuroD1 in STZ group decreased significantly, which were up-regulated by taurine administration. In conclusion, taurine exerts a certain degree of protective and reconstructive effects on islet cells treated by STZ. PMID- 28849467 TI - Metabolomics Profiling of the Effects of Taurine Supplementation on Dyslipidemia in a High-Fat-Diet-Induced Rat Model by 1H NMR Spectroscopy. AB - Metabolomics, the comprehensive study of metabolites, has merged as a potent tool for analyzing complex phenotypes and identifying biomarkers of specific physiological responses and has the potential to lead to innovative therapeutic and diagnostic schemes for many diseases. In a former report, we showed that taurine supplementation considerably ameliorated dyslipidemia in rats fed a high caloric diet. In this work, we examined the metabolic changes that occur in rat serum after they were fed a normal diet, a high-fat diet, and a high-fat diet containing 2% taurine (tau) by NMR spectroscopy combined with a multivariate statistical analysis containing PCA, PLS-DA, and OPLS-DA. We obtained 1H-NMR spectra of rat serum and used pattern recognition to identify key metabolites related to taurine supplementation. We found significant changes in creatine, methionine, glutamine, and threonine as well as in lipids, all of which decreased in the Tau group. To use these changes in metabolites as novel therapeutic and diagnostic markers, it should first be investigated whether these results are reproducible in future experiments. Next, researchers should determine how these changes affect serum lipid changes. This study identified some changes in serum metabolites and demonstrated the possibility of using an NMR-based metabolomics method to explore the effects of a taurine supplement on dyslipidemia in a high fat-diet-induced rat model. PMID- 28849468 TI - The Effect of Taurine and Its Immediate Homologs on Diabetes-Induced Oxidative Stress in the Brain and Spinal Cord of Rats. AB - This study has examined the acute effects of taurine (TAU) and of its two immediate homologs aminomethanesulfonic acid (AMSA) and homotaurine (HTAU) on the oxidative stress that develops in the brain of rats as a result of type 2 diabetes mellitus. Male Sprague-Dawley rats, 220-225 g in weight, were divided into groups of 6 each, and treated with a single intraperitoneal (i.p.) dose of streptozotocin (STZ) in 10 mM citrate buffer pH 4.5 (60 mg/kg). The treatment compound (AMSA, HTAU or TAU) was administered by the i.p. route in two equal doses (1.2 mM/kg each) at 75 and 45 min before STZ. Control rats received only 10 mM citrate buffer pH 4.5 or only STZ by the i.p. route. The rats were sacrificed at 24 h after a dosing with STZ under general anesthesia, and their brains and spinal cords collected by the freeze clamp technique. A portion of brain, of a brain area (cerebellum, cortex, brain stem) or of spinal cord from each animal was extracted into 0.1 M PBS pH 7.4, and the extract was used for the assay of malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). An extract for the assay of the reduced (GSH) and disulfide (GGSG) forms of glutathione was prepared in similar manner but using 2% metaphosphoric acid plus 0.1 M PBS pH 8.0 as the extracting medium. Diabetes was found to markedly increase the formation of MDA (by 160-202%), NO (by 138-313%) and GSSG (by 103-241%), and to lower the values of GSH (by 57-65%), GSH/GSSG ratio (79-89%) and activities of CAT (by 61-69%), GPx (by 52-66%) and SOD (by 55-68%) in the brain, brain areas and spinal cord relative to corresponding control values (all at p < 0.001). These effects were reduced to values that were generally at least one-half of those seen in untreated diabetic rats, with TAU providing a greater attenuation of the formation of MDA and NO, an about similar action on the depletion of GSH, and a lower action on the decrease in the GSH/GSSG ratio caused by diabetes than either AMSA or HMTAU. In contrast AMSA and HMTAU were about equipotent with each other and more potent than TAU in preventing the loss of antioxidant enzyme activities associated with diabetes. In short, pretreating diabetic rats with AMSA, HMTAU or TAU is found to protect the brain against changes in biochemical parameters indicative of oxidative stress, with potency differences among the test compounds varying within a narrow range. PMID- 28849469 TI - The Effect of Metformin and Taurine, Alone and in Combination, on the Oxidative Stress Caused by Diabetes in the Rat Brain. AB - This study has compared the effects of metformin (MET) and taurine (TAU), singly and in combination, on the oxidative stress caused by diabetes in the rat brain. For this purpose, male Sprague-Dawley rats, 200-225 g in weight, assigned to groups of 6, were intraperitoneally (i.p.) treated with the diabetogen streptozotocin (STZ, 60 mg/kg, in citrate buffer pH 4.5) on day 1 and, after 14 days, orally (p.o.) with either MET, TAU or MET-TAU (each at 2.4 mM/kg, in water). Control rats received only citrate buffer pH 4.5 (2 mL) or only STZ on day 1 by the i.p. route. All the animals were sacrificed by decapitation on day 57 and their brains collected by the freeze clamp technique. Blood samples were placed in heparinized tubes and used for the assay of the plasma glucose (GLC) and blood insulin (INS) levels. Immediately thereafter, the brains were surgically removed and a portion was used to prepare a homogenate in 0.1 M PBS pH 7.4, which was used for the assay of indices of oxidative stress. Diabetes raised the plasma GLC level (+313%) but lowered that of the blood INS (-76%) compared to corresponding values from nondiabetic rats. In addition it raised the brain malondialdehyde level (+59%) but lowered the reduced/disulfide glutathione ratio (-46%), and activities of catalase (-43%), glutathione peroxidase (-48%), superoxide dismutase (-65%), glutathione reductase (-50%) and glutathione S transferase (-51%) significantly (all at p < 0.001). Except for the greater decrease in GLC (+90% vs. +22%) and increase in INS (-26% vs. -52%) levels seen in rats receiving MET than in rats receiving TAU, these compounds protected the brain against oxidative stress to significant (p <= 0.05%) and rather similar extents. Furthermore, the concurrent administration of MET and TAU to the diabetic rats led to brain values of indices of oxidative stress that were lower than those attained with MET alone, although generally not to a statistically significant degree. PMID- 28849470 TI - Investigation of the Role of a Supplementation with Taurine on the Effects of Hypoglycemic-Hypotensive Therapy Against Diabetes-Induced Nephrotoxicity in Rats. AB - This study has examined the role of supplementing a treatment of diabetic rats with captopril (CAP), metformin (MET) or CAP-MET with the antioxidant amino acid taurine (TAU) on biochemical indices of diabetes-induced metabolic changes, oxidative stress and nephropathy. To this end, groups of 6 male Sprague-Dawley rats (250-375 g) were made diabetic with a single, 60 mg/kg, intraperitoneal dose of streptozotocin (STZ) in 10 mM citrate buffer pH 4.5 and, after 14 days, treated daily for up to 42 days with either a single oral dose of CAP (0.15 mM/kg), MET (2.4 mM/kg) or TAU (2.4 mM/kg), or with a binary or tertiary combination of these agents. Rats receiving only 10 mM citrate buffer pH 4.5 or only STZ served as negative and positive controls, respectively. All rats were sacrificed by decapitation on day 57 and their blood and kidneys collected. In addition, a 24 h urine sample was collected starting on day 56. Compared to normal rats, untreated diabetic ones exhibited frank hyperglycemia (+313%), hypoinsulinemia (-76%) and elevation of the glycated hemoglobin value (HbA1c, +207%). Also they showed increased plasma levels of Na+ (+35%), K+ (+56%), creatinine (+232%), urea nitrogen (+158%), total protein (-53%) and transforming growth factor-beta1 (TGF-beta1, 12.4-fold) values. These changes were accompanied by increases in the renal levels of malondialdehyde (MDA, +42%), by decreases in the renal glutathione redox state (-71%), and activities of catalase (-70%), glutathione peroxidase (-71%) and superoxide dismutase (-85%), and by moderate decreases of the urine Na+ (-33%) and K+ (-39%) values. Following monotherapy, MET generally showed a greater attenuating effect than CAP or TAU on the changes in circulating glucose, insulin and HbA1c levels, urine total protein, and renal SOD activity; and CAP appeared more potent than TAU and MET, in that order, in antagonizing the changes in plasma creatinine and urea nitrogen levels. On the other hand, TAU generally provided a greater protection against changes in glutathione redox state and in CAT and GPx activities, with other actions falling in potency between those of CAP and MET. Adding TAU to a treatment with CAP, but not to one with MET, led to an increase in protective action relative to a treatment with drug alone. On the other hand, the actions of CAP-MET, which were about equipotent with those of MET, became enhanced in the presence of TAU, particularly against the changes of the glutathione redox state and activities of antioxidant enzymes. In short, the present results suggest that the addition of TAU to a treatment of diabetes with CAP or CAP-MET, and sometimes to one with MET, will lead to a gain in protective potency against changes in indices of glucose metabolism and of renal functional impairment and oxidative stress. PMID- 28849471 TI - Increased N-Acetyltaurine in the Skeletal Muscle After Endurance Exercise in Rat. AB - Taurine is metabolized to a novel metabolite, N-acetyltaurine (NAT), through N acetylation with acetate. Furthermore, NAT production increases when the endogenous production of acetate is elevated in some situations, such as alcohol catabolism and endurance exercise. We have previously reported that both the serum concentration and urinary excretion of NAT from humans were increased after endurance exercise, and that NAT was secreted by cultured skeletal muscle cells exposed to both acetate and taurine. The present study evaluated the hypothesis that NAT is synthesized in the skeletal muscle after endurance exercise. Normal rats were loaded to a transient treadmill running until exhaustion. Serum, skeletal muscle, and liver were collected immediately after the exercise. The NAT concentration in the plasma and in the soleus muscle from the exercised rats was significantly increased compared to that in the samples from the sedentary control rats. There was a significant positive correlation in the NAT concentration between the plasma and soleus muscle. The NAT concentration in the liver was unchanged after the endurance exercise. These results confirm that the significantly increased NAT in both the serum and urine after endurance exercise is derived from NAT synthesis in the skeletal muscle. PMID- 28849472 TI - Gestational Protein Restriction in Wistar Rats; Effect of Taurine Supplementation on Properties of Newborn Skeletal Muscle. AB - Taurine ameliorates changes occurring in newborn skeletal muscle as a result of gestational protein restriction in C57BL/6 mice, but taurine supplementation effects may be exaggerated in C57BL/6 mice due to their inherent excessive taurinuria.We examined if maternal taurine supplementation could ameliorate changes in gene expression levels, properties of mitochondria, myogenesis, and nutrient transport and sensing, in male newborn skeletal muscle caused by a maternal low protein (LP) diet in Wistar rats.LP diet resulted in an 11% non significant decrease in birth weight, which was not rescued by taurine supplementation (LP-Tau). LP-Tau offspring had significantly lower birth weight compared to controls. Gene expression profiling revealed 895 significantly changed genes, mainly an LP-induced down-regulation of genes involved in protein translation. Taurine fully or partially rescued 32% of these changes, but with no distinct pattern as to which genes were rescued.Skeletal muscle taurine content in LP-Tau offspring was increased, but no changes in mRNA levels of the taurine synthesis pathway were observed. Taurine transporter mRNA levels, but not protein levels, were increased by LP diet.Nutrient sensing signaling pathways were largely unaffected in LP or LP-Tau groups, although taurine supplementation caused a decrease in total Akt and AMPK protein levels. PAT4 amino acid transporter mRNA was increased by LP, and normalized by taurine supplementation.In conclusion, gestational protein restriction in rats decreased genes involved in protein translation in newborn skeletal muscle and led to changes in nutrient transporters. Taurine partly rescued these changes, hence underscoring the importance of taurine in development. PMID- 28849473 TI - Impaired Energy Production Contributes to Development of Failure in Taurine Deficient Heart. AB - Taurine forms a conjugate in the mitochondria with a uridine residue in the wobble position of tRNALeu(UUR). The resulting product, 5-taurinomethyluridine tRNALeu(UUR), increases the interaction between the UUG codon and AAU anticodon of tRNALeu(UUR), thereby improving the decoding of the UUG codon. We have shown that the protein most affected by the taurine conjugation product is ND6, which is a subunit of complex I of the respiratory chain. Thus, taurine deficiency exhibits reduced respiratory chain function. Based on these findings, we proposed that the taurine deficient heart is energy deficient. To test this idea, hearts were perfused with buffer containing acetate and glucose as substrates. The utilization of both substrates, as well as the utilization of endogenous lipids, was significantly reduced in the taurine deficient heart. This led to a 25% decrease in ATP production, an effect primarily caused by diminished aerobic metabolism and respiratory function. In addition, inefficient oxidative phosphorylation causes a further decrease in ATP generation. The data support the idea that reductions in energy metabolism, including oxidative phosphorylation, ATP generation and high energy phosphate content, contribute to the severity of the cardiomyopathy. The findings are also consistent with the hypothesis that taurine deficiency and reduced myocardial energy content increases mortality of the taurine deficient, failing heart. The clinical implications of these findings are addressed. PMID- 28849474 TI - A Novel Cysteine Sulfinic Acid Decarboxylase Knock-Out Mouse: Immune Function (II). AB - Taurine deficient mice lacking cysteine sulfinic acid decarboxylase (CSAD KO) were developed for investigating the various physiological roles of taurine including the development of the brain and eye as well as immune function. Due to severe abnormalities of immune function in a taurine deficient cat, the immune function including adoptive and innate immunity in taurine-deficient mice have been studied. Previously we demonstrated that B cell function in CSAD KO was reduced in both females and males. However, T cell function was significantly reduced only in females. In this study, we have examined innate immunity using macrophage activation with LPS or/and IFN-gamma and polymorphonuclear leukocytes (PMN) activation with phorbol myristate acetate (PMA). Pro- and anti-inflammatory cytokines including IL-6, TNF-alpha and IL-10 as well as nitric oxide (NO) were determined using ELISA and Griess reagent, respectively. Peritoneal macrophages were activated with 1 MUg/mL of lipopolysaccharide (LPS) and/or 50 U/mL of IFN gamma. In addition, superoxide anion was measured using peritoneal PMN activated with PMA in the presence and absence of superoxide dismutase. Superoxide anion production in activated PMN from CSAD KO homozygotes (HO) was not significantly different from wild-type (WT) with and without 25 mM taurine. IL-10 and TNF-alpha production in both female and male CSAD KO were not significantly different. IL-6 and NO were significantly lower only in females as previously observed in Con A activated cellular proliferation of splenocytes. Cytokine production with 10 mM of taurine was not different, indicating the reduction of NO and IL-6 in females may be due to the absence of the CSAD gene, not due to low taurine concentrations.These data indicate that some measures of innate immunity were altered in female CSAD mice. PMID- 28849475 TI - A Novel Cysteine Sulfinic Acid Decarboxylase Knock-Out Mouse: Taurine Distribution in Various Tissues With and Without Taurine Supplementation. AB - Taurine, a sulfur containing amino acid, has various physiological functions including development of the eye and brain, immune function, reproduction, osmo regulatory function as well as anti-oxidant and anti-inflammatory activities. In order to understand the physiological role, we developed taurine deficient mice deleting a rate-liming enzyme, cysteine sulfinic acid decarboxylase (CSAD) for biosynthesis of taurine. Taurine was measured in various tissues including the liver, brain, lung, spleen, thymus, pancreas, heart, muscle and kidney as well as plasma from CSAD knock-out mice (CSAD KO) with and without treatment of taurine in the drinking water at the age of 2 months (2 M). Taurine was determined using HPLC as a phenylisothiocyanate derivative of taurine at 254 nm. Taurine concentrations in the liver and kidney from homozygotes of CSAD KO (HO), in which CSAD level is high, were 90% and 70% lower than WT, respectively. Taurine concentrations in the brain, spleen and lung, where CSAD level is low, were 21%, 20% and 28% lower than WT, respectively. At 2 M, 1% taurine treatment of HO restored taurine concentrations in all tissues compared to that of WT. To select an appropriate taurine treatment, HO were treated with various concentrations (0.05, 0.2, 1%) of taurine for 4 months (4 M). Restoration of taurine in all tissues except the liver, kidney and lung requires 0.05% taurine to be restored to that of WT. The liver and kidney restore taurine back to WT with 0.2% taurine. To examine which enzymes influence taurine concentrations in various tissues from WT and HO at 2 M, expression of five taurine-related enzymes, two antioxidant enzymes as well as lactoferrin (Lft) and prolactin receptor (Prlr) was determined using RT2 qPCR. The expression of taurine transporter in the liver, brain, muscle and kidney from HO was increased except in the lung. Our data showed expression of glutamate decarboxylase-like 1(Gadl-1) was increased in the brain and muscle in HO, compared to WT, indicating taurine in the brain and muscle from HO was replenished through taurine transporter and increased biosynthesis of taurine by up-regulated Gadl-1. The expression of glutathione peroxidase 3 was increased in the brain and peroxireductase 2 was increased in the liver and lung, suggesting taurine has anti-oxidant activity. In contrast to newborn and 1 month CSAD KO, Ltf and Prlr in the liver from CSAD KO at 2 M were increased more than two times and 52%, respectively, indicating these two proteins may be required for pregnancy of CSAD KO. Ltf in HOT1.0 was restored to WT, while Prlr in HOT1.0 was increased more than HO, explaining improvement of neonatal survival with taurine supplementation.These data are essential for investigating the role of taurine in development of the brain and eye, immune function, reproduction and glucose tolerance. PMID- 28849476 TI - Identification of Taurine-Responsive Genes in Murine Liver Using the Cdo1-Null Mouse Model. AB - The cysteine dioxygenase (Cdo1)-null mouse is unable to synthesize hypotaurine and taurine by the cysteine/cysteine sulfinate pathway and has very low taurine levels in all tissues. The lack of taurine is associated with a lack of taurine conjugation of bile acids, a dramatic increase in the total and unconjugated hepatic bile acid pools, and an increase in betaine and other molecules that serve as organic osmolytes. We used the Cdo1-mouse model to determine the effects of taurine deficiency on expression of proteins involved in sulfur amino acid and bile acid metabolism. We identified cysteine sulfinic acid decarboxylase (Csad), betaine:homocysteine methytransferase (Bhmt), cholesterol 7alpha-hydroxylase (Cyp7a1), and cytochrome P450 3A11 (Cyp3a11) as genes whose hepatic expression is strongly regulated in response to taurine depletion in the Cdo1-null mouse. Dietary taurine supplementation of Cdo1-null mice restored hepatic levels of these four proteins and their respective mRNAs to wild-type levels, whereas dietary taurine supplementation had no effect on abundance of these proteins or mRNAs in wild-type mice. PMID- 28849477 TI - Beta-Catenin and SMAD3 Are Associated with Skeletal Muscle Aging in the Taurine Transpoeter Knockout Mouse. AB - Tissue taurine depletion mediated by knocking out the taurine transporter causes several skeletal muscle abnormalities, including acceleration of cellular aging. In the present study, we investigated the signaling pathway involved in the acceleration of skeletal muscle aging by tissue taurine depletion using the bioinformatic approach of transcriptome data. We previously performed transcriptome analysis on skeletal muscle of taurine transporter knockout (TauTKO) mice using DNA microarray. Bioinformatic analysis of transcriptome data predicted the activation of SMAD3 and beta-catenin as upstream signaling molecules of cyclin-dependent kinase inhibitor 2A (CDKN2A, also called p16INK4A), which is a biomarker gene of cellular senescence. The activation of SMAD3 and beta-catenin in old TauTKO muscle was verified by western blot analysis. These data indicate that SMAD3- and beta-catenin-dependent induction occurs in the TauTKO mouse. PMID- 28849478 TI - Glucose Homeostasis and Retinal Histopathology in CSAD KO Mice. AB - In this study we examined glucose homeostasis and retinal histology in homozygous knockout mice lacking CSAD (CSAD-KO). Two-month-old male mice were used including wild type (WT), homozygotes with without supplementation of taurine in the drinking water (1% w/v). Mice were sacrificed and the eyes processed for histology and immunohistochemistry. Additional mice were subjected to a glucose tolerance test (7.5 mg/kg BW) after 12 h fasting. We found that CSAD-KO and CSAD KO treated with taurine were slightly hypoglycemic prior to glucose injection and showed a significantly reduced plasma glucose at 30, 60 and 120 min post-glucose injection, compared to WT. While glucose homeostasis in CSAD-KO was significantly different compared to WT, CSAD-KO supplemented with taurine was without effect. Analysis of retinas by electron microscopy showed that CSAD-KO without taurine supplementation exhibited substantial retinal degeneration. Remaining photoreceptor outer and inner segments were disorganized. Retinal nuclear and synaptic layers were largely absent and there was apparent reorganization of the pigmented epithelial cells. The choroid and sclera were intact. These histological aberrations were largely rectified by taurine supplementation in the drinking water.These data indicate that taurine deficiency alters glucose homeostasis and retinal structure and taurine supplementation improves these retinal abnormalities, but not in hypoglycemia. PMID- 28849479 TI - Comparative Analysis of Microbicidal and Anti-inflammatory Properties of Novel Taurine Bromamine Derivatives and Bromamine T. AB - Taurine, the most abundant free amino acid in leukocyte cytosol traps hypohalous acids (HOCl and HOBr) to produce N-chlorotaurine (taurine chloramine, NCT and N bromotaurine (taurine bromamine, Tau-NHBr,) respectively. Both haloamines show anti-inflammatory and antimicrobial properties. However, the therapeutic applicability of Tau-NHBr is limited due to its relatively poor stability. To overcome this disadvantage, we have synthesized the stable N-bromotaurine compounds N-monobromo-2,2-dimethyltaurine (Br-612) and N-dibromo-2,2 dimethyltaurine (Br-422). The aim of this study was to compare anti-inflammatory and microbicidal properties of Br-612 and Br-422 with that of Tau-NHBr and bromamine T (BAT). We have shown that all the tested compounds show similar anti inflammatory properties. Importantly, the stable N-bromotaurine compounds exerted even stronger microbicidal activity than Tau-NHBr. Finally, for the purpose of topical application of these compounds we have developed a carbomer-based bioadhesive solid dosage form of BAT and Br-612, featuring sustained release of the active substance. PMID- 28849480 TI - HPLC Determination of Bioactive Sulfur Compounds, Amino Acids and Biogenic Amines in Biological Specimens. AB - There is an increasing interest for analytical methods aimed to detect biological sulfur-containing amines, because of their involvement in human diseases and metabolic disorders. This work describes an improved HPLC method for the determination of sulfur containing amino acids and amines from different biological matrices. We optimized a pre-column derivatization procedure using dabsyl chloride, in which dabsylated products can be monitored spectrophotometrically at 460 nm. This method allows the simultaneous analysis of biogenic amines, amino acids and sulfo-amino compounds including carnosine, dopamine, epinephrine, glutathione, cysteine, taurine, lanthionine, and cystathionine in brain specimens, urines, plasma, and cell lysates. Moreover, the method is suitable for the study of physiological and non-physiological derivatives of taurine and glutathione such as hypotaurine, homotaurine, homocysteic acid and S-acetylglutathione. The present method displays good efficiency of derivatization, having the advantage to give rise to stable products compared to other derivatizing agents such as o-phthalaldehyde and dansyl chloride.With this method, we provide a tool to study sulfur cycle from a metabolic point of view in relation to the pattern of biological amino-compounds, allowing researchers to get a complete scenario of organic sulfur and amino metabolism in tissues and cells. PMID- 28849482 TI - A Proteomic Approach to Study the Effect of Thiotaurine on Human Neutrophil Activation. AB - Thiotaurine, a thiosulfonate related to taurine and hypotaurine, is formed by a metabolic process from cystine and generated by a transulfuration reaction between hypotaurine and thiocysteine. Thiotaurine can produce hydrogen sulfide (H2S) from its sulfane sulfur moiety. H2S is a gaseous signaling molecule which can have regulatory roles in inflammatory process. In addition, sulfane sulfur displays the capacity to reversibly bind to other sulfur atoms. Thiotaurine inhibits PMA-induced activation of human neutrophils, and hinders neutrophil spontaneous apoptosis. Here, we present the results of a proteomic approach to study the possible effects of thiotaurine at protein expression level. Proteome analysis of human neutrophils has been performed comparing protein extracts of resting or PMA-activated neutrophils in presence or in absence of thiotaurine. In particular, PMA-stimulated neutrophils showed high level of glyceraldehyde 3 phosphate dehydrogenase (GAPDH) expression compared to the level of the same glycolytic enzyme in the resting neutrophils. Conversely, decreased expression of GAPDH has been observed when human neutrophils were incubated with 1 mM thiotaurine before activation with PMA. This result, confirmed by Western blot analysis, suggests again that thiotaurine shows a bioactive role in the mechanisms underlying the inflammatory process, influencing the energy metabolism of activated leukocytes and raises the possibility that thiotaurine, acting as a sulfur donor, could modulate neutrophil activation via persulfidation of target proteins, such as GAPDH. PMID- 28849481 TI - Carbonate Anion Radical Generated by the Peroxidase Activity of Copper-Zinc Superoxide Dismutase: Scavenging of Radical and Protection of Enzyme by Hypotaurine and Cysteine Sulfinic Acid. AB - Copper-zinc superoxide dismutase (SOD) is considered one of the most important mammalian antioxidant defenses and plays a relevant role due to its main function in catalyzing the dismutation of superoxide anion to oxygen and hydrogen peroxide. However, interaction between SOD and H2O2 produced a strong copper bound oxidant (Cu(II)*OH) that seems able to contrast the self-inactivation of the enzyme or oxidize other molecules through its peroxidase activity. The bicarbonate presence enhances the peroxidase activity and produces the carbonate anion radical (CO3*-). CO3*- is a freely diffusible reactive species capable of oxidizing several molecules that are unwieldy to access into the reactive site of the enzyme. Cu(II)*OH oxidizes bicarbonate to the CO3*-, which spreads out of the binding site and oxidizes hypotaurine and cysteine sulfinic acid to the respective sulfonates through an efficient reaction. These findings suggest a defense role for sulfinates against the damage caused by CO3*- . The effect of hypotaurine and cysteine sulfinic acid on the CO3*--mediated oxidation of the peroxidase probe ABTS to ABTS cation radical (ABTS*+) has been studied. Both sulfinates are able to inhibit the oxidation of ABTS mediated by CO3*-. The effect of hypotaurine and cysteine sulfinic acid against SOD inactivation by H2O2 (~42% protection of enzyme activity) has also been investigated. Interestingly, hypotaurine and cysteine sulfinic acid partially avoid the H2O2-mediated SOD inactivation, suggesting that the two sulfinates may have access to the SOD reactive site and preserve it by reacting with the copper-bound oxidant. In this way hypotaurine and cysteine sulfinic acid not only intercept CO3*- which could move out from the reactive site and cause oxidative damage, but also prevents the inactivation of SOD. PMID- 28849483 TI - The Interaction of Hypotaurine and Other Sulfinates with Reactive Oxygen and Nitrogen Species: A Survey of Reaction Mechanisms. AB - Considerable strides have been made in understanding the oxidative mechanisms involved in the final steps of the cysteine pathway leading to taurine. The oxidation of sulfinates, hypotaurine and cysteine sulfinic acid, to the respective sulfonates, taurine and cysteic acid, has never been associated with any specific enzyme. Conversely, there is strong evidence that in vivo formation of taurine and cysteic acid is the result of sulfinate interaction with a variety of biologically relevant oxidants. In the last decade, many experiments have been performed to understand whether peroxynitrite, nitrogen dioxide and carbonate radical anion could be included in the biologically relevant reactive species capable of oxidizing sulfinates. Thanks to this work, it has been possible to highlight two possible reaction mechanisms (direct and indirect reaction) of sulfinates with reactive oxygen and nitrogen species.The sulfinates oxidation, mediated by peroxynitrite, is an example of both reaction mechanisms: through a two-electron-direct-reaction with peroxynitrite or through a one-electron indirect-transfer reaction. In the indirect mechanism, the peroxynitrite homolysis releases hydroxyl and nitrogen dioxide radical and in addition the degradation of short-lived adduct formed by peroxynitrite and CO2 can generate carbonate radical anion. The reaction of hypotaurine and cysteine sulfinic acid with peroxynitrite-derived radicals is accompanied by extensive oxygen uptake with the generation of transient intermediates, which can begin a reaction by an oxygen-dependent mechanism with the sulfonates, taurine, and cysteic acid as final products. Due to pulse radiolysis studies, it has been shown that transient sulfonyl radicals (RSO2*) have been produced during the oxidation of both sulfinates by one-electron transfer reaction.The purpose is to analyze all the aspects of the reactive mechanism in the sulfinic group oxidation of hypotaurine and cysteine sulfinic acid through the results obtained from our laboratory in recent years. PMID- 28849484 TI - Protective Effects of An Water Extracts Prepared from Loliolus beka Gray Meat Against H2O2-Induced Oxidative Stress in Chang Liver Cells and Zebrafish Embryo Model. AB - In this study, we first evaluated protective effects of Loliolus beka in a human liver cell line and zebrafish embryo model with its anti-oxidant activity. First, we prepared the water extract from L. beka meat (LBMW) at room temperature for 24 h and revealed it consisted of a rich taurine. LBMW exhibited the scavenging effects against 2,2-azino-bis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and hydrogen peroxide (H2O2) as well as the high value of oxygen radical absorbance capacity (ORAC). Also, the hydroxyl radical-induced DNA damage was dose-dependently reduced by the treatment of LBMW. In addition, LBMW showed no cytotoxicity and reduced the production of reactive oxygen species (ROS) in H2O2-treated hepatocytes. Moreover, LBMW regulated the expression of an anti-apoptotic molecule, Bcl-2 and the expression of pro-apoptotic molecules, Bax and PARP in H2O2-treated hepatocytes as well as the increment of antioxidant mediated-HO-1 and Nrf2 protein expression. In further study, LBMW improved the survival rate and decreased the production of ROS in H2O2-treated zebrafish embryo model. Therefore, our results suggest that Loliolus beka has protective effects against H2O2-induced oxidative stress and may be used as a potential source for functional foods. PMID- 28849485 TI - Protective Effects of An Enzymatic Hydrolysate from Octopus ocellatus Meat against Hydrogen Peroxide-Induced Oxidative Stress in Chang Liver Cells and Zebrafish Embryo. AB - Octopus ocellatus, a marine cephalopod distributed in the coast of South Korea, China, Japan and tropical sea, contains high amounts of taurine. In this study, an enzymatic hydrolysate obtained from O. ocellatus meat was evaluated for its antioxidant effects using a human liver cell line and zebrafish embryo model. Enzymatic hydrolysates of the O. ocellatus meat (OOM) were prepared using six different enzymes. Among the enzymatic hydrolysates, Alcalase hydrolysate of OOM (OOMAH) showed the highest scavenging effects against 2,2-diphenyl-1 picrylhydrazyl (DPPH), 2,2-azino-bis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) radicals and hydrogen peroxide (H2O2). Moreover, it showed a high oxygen radical absorbance capacity (ORAC). OOMAH treatment effectively reduced the hydroxyl radical-induced DNA damage. OOMAH reduced the production of reactive oxygen species (ROS) in H2O2-treated hepatocytes without cytotoxicity. Furthermore, OOMAH improved the survival rate and reduced the intracellular ROS levels in H2O2-treated zebrafish embryos. Compositional analysis of amino acids indicated a high content of taurine in OOMAH. Current results suggest that OOMAH possesses antioxidant bioactivities and could provide protective effects against H2O2-induced oxidative stress. Therefore, OOMAH might be used as a potential resource of functional foods. PMID- 28849486 TI - Hepatoprotective Effects of Xylose-Taurine Reduced Against Hydrogen Peroxide Induced Oxidative Stress in Cultured Hepatocytes. AB - In this study, Xylose-Taurine reduced (X-T-R) was synthesized to enhance biological activities. Hence, we investigated the hepatoprotective effects of X-T R against H2O2-induced hepatocyte damage and apoptosis. The results showed that X T-R led to the cytoprotective effect against H2O2-induced oxidative stress in cultured hepatocytes such as the improvement of cell viability and the reduction of reactive oxygen species (ROS) production. Additionally, pre-treatment with X-T R increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H dehydrogenase:quinone 1 (NQO1) and heme oxygenase 1 (HO-1) in cultured hepatocytes. Furthermore, X-T-R protected the cells against apoptosis via regulating the expression level of Bcl-2/Bax as well as the activation of caspase 3. According to the results obtained, X-T-R may be a bio-material for the therapy of hepatic diseases. PMID- 28849487 TI - Xylose-Taurine Reduced Suppresses the Inflammatory Responses in Lipopolysaccharide-Stimulated Raw264.7 Macrophages. AB - Here, the anti-inflammatory effect of Xylose-Taurine reduced (X-T-R), a taurine derivate was investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. X-T-R reduced the generations of nitric oxide (NO) and prostaglandin E2 (PGE2) induced by the stimulation of LPS in RAW 264.7 by suppressing the protein expression of iNOS and COX-2 known as inflammatory mediators. Also, X-R-T reduced the expression levels of the pro-inflammatory cytokines such as interleukin (IL) 1beta, IL-6 and tumor necrosis factor (TNF-alpha). Moreover, X-T-R inhibited the activation of nuclear factor-kappaB (NF-kappaB) and the phosphorylation of inhibitor kappaB (IkappaB)-alpha. In conclusion, these results first indicate that X-T-R inhibits LPS-induced inflammation by regulating the NF-kappaB signal pathway in macrophages. PMID- 28849488 TI - Protective Effects of Xylose-Taurine Reduced against Damages Caused by Oxidative Stress in Zebrafish Embryos In Vivo Model. AB - The zebrafish (Danio rerio) is useful and convenient vertebrate models in various studies in human disease and drug discovery. In this present study, we first evaluated whether Xylose-Taurine reduced (X-T-R), a taurine derivate protects zebrafish embryos against oxidative stress caused by AAPH (2,2'-Azobis(2 amidinopropane) dihydrochloride). First of all, we selected the concentration of X-T-R showing no toxicity in zebrafish embryos. We identified that X-T-R significantly increased the survival of zebrafish embryo reduced by treatment of AAPH. Also, X-T-R effectively inhibited the productions of reactive oxygen species (ROS) and nitric oxide (NO) as well as the formation of cell death in zebrafish embryos. Moreover, X-T-R down-regulated the expression levels of Bax, caspase-3, caspase-9 and p53 known as pro-apoptotic molecules, whereas up regulated those of Bcl-2, an anti-apoptotic molecule in AAPH-treated zebrafish embryos. From these results, this study reveals that X-T-R, a taurine derivate might be a potential protector against various damages caused by oxidative stress. PMID- 28849489 TI - Anti-inflammatory Effects of Galactose-Taurine Sodium Salt: A Taurine Derivate in Zebrafish In Vivo Model. AB - Taurine, the plentiful amino acids in mammalian cells exerts various biological activities including antioxidant and anti-inflammatory effects. Inflammation can cause several diseases such as cancer, heart disease, rheumatoid arthritis and immune system reactions. Here, we investigated anti-inflammatory effects of Galactose-Taurine sodium salt (Gal-Tau), a newly synthesized taurine derivate in LPS-stimulated zebrafish embryos in vivo model. The result showed that Gal-Tau improved the survival rate and the edema in LPS-treated zebrafish embryos. Also, Gal-Tau effectively reduced the productions of nitric oxide (NO), reactive oxygen species (ROS) and cell death induced by LPS in zebrafish embryos. In addition, Gal-Tau regulated the expression levels of inflammatory mediators such as inducible NOS (iNOS) and cycloxygenase 2 (COX-2) as well as IL-6 and TNF-alpha, inflammatory cytokines known as important key mediators of inflammation. Taken together, this study first indicates that Gal-Tau could be considered as an effective anti-inflammatory material with its anti-inflammatory activity. PMID- 28849490 TI - Effect of N-(D-Ribopyranosyl) Taurine Sodium Salt on the Differentiation of Human Preadipocytes and Expression of Adipokines Through Inhibition of STAT-3 Signaling in Differentiated Human Adipocytes. AB - We investigated whether a taurine-ribose derivative, N-(D-ribopyranosyl)taurine sodium salt, inhibits the differentiation process of preadipocytes or modulates the expression of cytokines from adipocytes as does taurine chloramine (TauCl) in vitro. To know the inhibitory effects of taurine-ribose (Tau-Ribose) on differentiation process and adipokine expression, preadipocytes were incubated with Tau-Ribose in differentiation medium for 14 days. Differentiated adipocytes were also stimulated at the concentration of IL-1beta 1 ng/ml with addition of Tau-Ribose. After 7 days of incubation, the levels of adiponectin, leptin, IL-6, and IL-8 were measured from the culture supernatants. At concentrations of 10-40 mM, Tau-Ribose dose-dependently inhibited the process of adipogenesis. The treatment of Tau-Ribose decreased the expression of transcription factors, which are necessary for adipogenesis and are known as adipocyte marker. Treatment with Tau-Ribose significantly modulated the production of IL-8 and IL-6. However, it did not modulate the production of adiponectin and leptin in IL-1beta-activated adipocytes. As with taurine chloramine, Tau-Ribose also inhibited STAT-3 signaling, independent of MAPK signaling. In conclusion, Tau-Ribose inhibits the signaling pathway of STAT-3 and can change adipokines production; thus, it may have a potential as an agent for treating obesity-related diseases. PMID- 28849491 TI - Synthesis of N-Chloroamino Acids and Their Biological Activities in LPS Stimulated RAW 264.7 Cells. AB - Amino acids (AAs) are essential for protein synthesis, neurotransmission and macro molecule biosynthesis. Ala, Gln, Gly, Lys, Val and taurine (Tau) are the most abundant free AAs in mammals, and some of these react with hypochlorite (HOCl/OCl-) produced by myeloperoxidase in activated phagocytes to form N chloroamino acids (NCAA). In this study, we reacted 20 AAs and Tau with sodium hypochlorite (NaOCl), then classified the products into five types (I-V) based on the change in their absorbance. Type I AAs (Ala, Arg, Gln, Gly, Ile, Lys, Phe, Ser, Tau, Thr and Val) generated a typical monochloramine peak at 252 nm, while Type II AAs (Asn and Tyr) and Type III AAs (Glu and Leu) produced peaks at 275 nm and 225 nm, respectively. The Type IV AAs (His, Met and Trp) did not show any distinct absorption peak, and Type V AAs (Asp, Cys and Pro) did not appear to react with NaOCl. The ArgCl and TauCl were stable, while GlnCl, GlyCl, IleCl, LysCl, PheCl and ValCl were less stable and AlaCl, SerCl and ThrCl were the least stable. Tau is the most abundant non-proteinogenic free AA in cellular fluid and has many physiological functions in the nervous, cardiovascular, renal and immune systems. Tau reacts with HOCl to form TauCl, which inhibits the production of proinflammatory mediators such as superoxide, nitric oxide (NO) and interleukins, while increasing the antioxidant proteins in macrophages. We determined the effects of Type I NCAA on cell viability, NO and TNF-alpha production in LPS activated RAW 264.7 cells. All Type I NCAA showed dose-dependent cytotoxicity and inhibited LPS-induced NO production. However, only GlnCl, GlyCl, IleCl, LysCl, SerCl and TauCl inhibited LPS-induced TNF-alpha production. In summary, Type I NCAA showed dose-dependent cytotoxicity and inhibited NO production, while their effects on TNF-alpha varied. Our results suggest that Type I NCAA may serve as biological regulators similar to TauCl during inflammation. PMID- 28849492 TI - Taurine Promotes Retinal Ganglion Cell Survival Through GABAB Receptor Activation. AB - Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases, either as a primary process like in glaucoma, or secondary to photoreceptor loss and no efficient compound targeting directly RGC neuroprotection is yet available. We previously described that taurine exerts a direct protective effect on RGCs cultured under serum-deprived conditions. Because taurine was known to have an agonist-like activity for GABA/glycine receptors, we investigated here if the taurine-elicited neuroprotective effect may be mediated through the activation of these receptors using selective antagonist ligands. RGCs were purified, seeded in 96-well plate and maintained in culture during 6 days in vitro. Viable cells were labelled with calcein and densities in full-well area were then automatically counted. Here we show that the protective effect of taurine against RGC loss observed under serum deprivation can be mediated through the GABAB receptor stimulation. Hence, two selective agonists, including baclofen, at this metabotropic GABAB receptor were found to reproduce taurine action by enhancing RGC survival in culture. This study suggests that GABAB receptor stimulation provides direct neuroprotection for RGCs. Accordingly, drugs targeting GABAB receptor may represent a new way for the prevention of RGC degeneration. PMID- 28849493 TI - Taurine Administration Mitigates Cisplatin Induced Acute Nephrotoxicity by Decreasing DNA Damage and Inflammation: An Immunocytochemical Study. AB - Cisplatin (CDDP) is one of the most effective chemotherapeutic agent used in the treatment of many kind of solid tumors. Its primary side effect is nephrotoxicity. The aim of this study to investigate the effects of taurine on cisplatin-induced acute nephrotoxicity. A single intraperitoneal injection of CDDP (15 mg/kg, or 25 mg/kg) deteriorated the kidney functions as reflected by histopathological changes. Histopathological changes were observed in all cisplatin groups. In the cisplatin group, oxidative stress was evident in the cisplatin group by observing an increase in 8-OHdG expression, an indicator of oxidative DNA damage. CDDP also resulted to an increase in CD68 expression in the renal tissues of CDDP groups. Taurine transporter (TauT) was down-regulated, and p53 was up-regulated in renal tissues as indicated by immunohistochemical analysis. Administration with taurine prior to a cisplatin injection was able to protect against deterioration of kidney function, to abrogate the decline in anti oxidants and to suppress the increase in DNA damage. Moreover, taurine inhibited p53 activation and improved the pathological changes induced by cisplatin. This study demonstrates the protective effects of taurine in attenuating the expression of pro-inflammatory mediators and in improving antioxidant capacity in the kidney of cisplatin-injected rats. Thus, taurine could be a beneficial dietary supplement to attenuate cisplatin induced nephrotoxicity. PMID- 28849494 TI - Effect of Taurine on iNOS-Mediated DNA Damage in Drug-Induced Renal Injury. AB - Owing to an outstanding wide antitumor spectrum and excellent anti-tumor effect cisplatin has been used in chemotherapy for malignant tumor. However, cisplatin has strong side effects such as renal injury. Taurine has been found to protect against inflammatory tissue damage in a variety of experimental models. The aim of the present study was to investigate the effect of taurine against iNOS dependent DNA damage in cisplatin-induced renal injury in rats. With the help of a rat model of drug-induced kidney damage, we have assessed the nephrotoxic effects of different doses of cisplatin in the presence and absence of taurine. Immunohistochemical methods were used to examine the distribution of arginine, iNOS, citrulline and 8-nitroguanine in renal tissue. The expression levels of citrulline, iNOS, and 8-nitroguanine immunoreactivities were found to increase as a function of the dose of cisplatin used, and to decrease in the presence of taurine. The expression level of arginine immunoreactivity was reduced as a function of the dose of cisplatin used. On the other hand, iNOS, 8-nitroguanine and citrulline immunohistochemical staining showed an intense immunoreactivity in the renal tubule of cisplatin-treated animals; and arginine immunoreactivity was localized in the renal tubule of taurine-treated animals. We also confirmed the decrease of citrulline and iNOS expression in the renal tubule after taurine administration as well as the expression level of 8-nitroguanine, a nitrative stress marker in the same animals. The present results support the concept that taurine may have a protective role in the formation of cisplatin-related DNA lesions arising through iNOS-mediated nitrative stress. PMID- 28849496 TI - Taurine Supplementation Ameliorates the Adverse Effects of Perinatal Taurine Depletion and High Sugar Intake on Cardiac Ischemia/Reperfusion Injury of Adult Female Rats. AB - Perinatal taurine depletion followed by high sugar intake after weaning adversely affects myocardial and arterial pressure function following a myocardial ischemia and reperfusion (IR) insult in adult female rats. This study tests the hypothesis that taurine supplementation ameliorates this adverse effect. Female Sprague Dawley rats were fed normal rat chow and drank water containing beta-alanine from conception until weaning (taurine depletion, TD). After weaning, female offspring were fed normal rat chow and drank either water containing 5% glucose (TDG) or water alone (TDW). At 6-7 weeks of age, half the rats in each group were supplemented with taurine and 1 week later subjected to cardiac IR. Body weight, heart weight, plasma electrolytes, plasma creatinine, blood urea nitrogen, and hematocrit were not significantly different among the four groups. The mean arterial pressures significantly increased in all groups after IR, but values were not significantly different among the four groups. Heart rates were significantly increased after IR only in TDW group. Compared to TDW, TDG displayed increased plasma cardiac injury markers (creatinine kinase-MB, troponin T, and N-terminal prohormone brain natriuretic peptide), increased sympathetic activity, decreased parasympathetic activity, and decreased baroreflex sensitivity after IR. Taurine supplementation completely restored the baroreflex and autonomic dysfunction of TDG to TDW levels and partially decreased myocardial injury after cardiac IR. The present study indicates that in adult female rats, perinatal taurine depletion followed by high sugar intake after weaning exacerbates cardiac IR injury and arterial pressure dysregulation and these adverse effects can be partially prevented by taurine supplementation. PMID- 28849495 TI - Effect of Radiation on the Expression of Taurine Transporter in the Intestine of Mouse. AB - There has been a growing interest on the effects of radiation since the Fukushima nuclear power plant accident of 2011. Taurine has been reported to have a radioprotective effect in irradiated mice. However, the detailed mechanism of this radioprotective effect is still awaiting clarification. The aim of this study was to investigation how radiation affects the expression of taurine and to shed light on the mechanism accounting for radioprotective and radiation mitigating effect. Six-week-old male mice were randomly divided into two groups: IR group (7 Gy irradiation) and IR + Tau group (7 Gy irradiation + taurine 3000 mg/kg/day). We examined the survival rate, the expression of taurine and taurine transporter in the small intestine and the urinary taurine concentration. In this study, no statistically significant difference was found in the survival rate between IR Group and IR + Tau Group. Three days and 7 days after irradiation, the urinary taurine concentration of IR + Tau group increased more than that of IR group. Three days and 10 days after irradiation, the expression of taurine and taurine transporter in the small intestine of IR group and IR + Tau group decreased more than that of normal small intestine. It is reported that radiation exposure increases the urinary taurine concentration. We found that the radiation exposure decreases the expression of the taurine transporter in the small intestine of mouse. This finding suggests that a decrease in the expression of the taurine transporter promotes the release of taurine from the tissue into the urine. PMID- 28849497 TI - Perinatal Taurine Supplementation Alters Renal Function via Renin-Angiotensin System Overactivity in Adult Female Rats. AB - This study tests the hypothesis that perinatal taurine supplementation followed by a high sugar diet since weaning impairs renal function via renin-angiotensin system (RAS) overactivity in adult female rats. Female Sprague-Dawley rats were fed normal rat chow and given water alone or water containing 3% taurine from conception until weaning. After weaning, the female rats received normal rat chow and water with (CG, TSG) or without (CW, TSW) 5% glucose throughout the experiment. At 7-8 weeks of age, renal function at rest and after an acute saline load was tested in conscious female rats after a week of captopril treatment. Body, heart, and kidney weights were not significantly different among the eight groups. Mean arterial pressures and heart rates were also not different among the groups. While effective renal blood flow did not significantly differ among the eight groups, TSG displayed higher renal vascular resistance compared to CW, CG, and TSW groups. Glomerular filtration rate, filtration fraction, and water and sodium excretion did not significantly differ among the groups. Compared to CW, the saline load significantly depressed fractional water excretion in CG and TSW and fractional sodium excretion in CG, TSW, and TSG groups. Captopril treatment abolished these differences but significantly decreased potassium excretion in CG, TSW, and TSG compared to CW and abolished the increased fractional potassium excretion in TSG compared to CG and TSW groups. These data strongly suggest that in adult female rats, perinatal taurine supplementation, particularly followed by high sugar intake, alters renal function via altered RAS activity. PMID- 28849498 TI - Perinatal Taurine Imbalance Followed by High Sugar Intake Alters the Effects of Estrogen on Renal Excretory Function in Adult Female Rats. AB - This study tests the hypothesis that perinatal taurine imbalance impairs renal function in adult female rats via alterations in estrogen activity. Female Sprague-Dawley rats were fed normal rat chow and water containing 3% beta-alanine (TD), 3% taurine (TS) or water alone (C) from conception until weaning. Then, female offspring received normal rat chow and water with (CG, TDG, TSG) or without (CW, TDW, TSW) 5% glucose. At 7-8 weeks of age, renal function at rest and after acute saline load was tested in conscious, restrained female rats treated with non-selective estrogen receptor blocker tamoxifen for a week. Compared to control, TD or TS did not affect mean arterial pressure (MAP). Tamoxifen significantly increased resting MAP only in TDG compared to TDW groups. Although renal blood flow did not significantly differ among the groups, renal vascular resistance increased in TSG compared to CW, CG, and TSW groups. Glomerular filtration rate and water and sodium excretion were not significantly different among the groups. Compared to CW, saline load significantly depressed fractional water excretion in CG, TDW, TDG, and TSW, and fractional sodium excretion in CG, TDW, TDG, TSW, and the TSG groups. Potassium excretion was not significantly different among the corresponding groups. Fractional potassium excretion significantly increased in TDW compared to CG and in TSG compared to CG and TSW groups. These differences were abolished by tamoxifen treatment. These data indicate that in adult female rats, perinatal taurine imbalance, particularly followed by high sugar intake, alters renal function via an estrogenic mechanism. PMID- 28849499 TI - Taurine Inhibits Kupffer Cells Activation Induced by Lipopolysaccharide in Alcoholic Liver Damaged Rats. AB - Taurine, a beta free amino-acid, takes various biological functions including maintain the normal hepatic structure and function. In this study, the regulation mechanism of taurine on lipopolysaccharide (LPS) induced activation of Kupffer cells (KC) in the liver of rats with alcoholic liver disease (ALD) were explored. Male wistar rats were intragastrically administered with alcohol and pyrazole, and ate high-fat diet in order to establish ALD model. Taurine were administered in drinking water simultaneous with and after ALD model establishment. The preventive trial was lasted for 12 weeks, while the curative trial was lasted for 4 weeks. Finally, blood and liver were collected in order to detect the concentrations of plasma LPS and hepatic tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). Hepatic total RNA were extracted, gene expressions of LPS binding protein (LBP), leukocyte differentiation antigen 14 (CD14), toll-like receptors (TLR4), nuclear transcription factor (NF-kappaB) and TNF-alpha were detected by semi-quantitative RT-PCR. The results showed significant elevated levels of plasma LPS, hepatic TNF alpha, IL-1beta and IL-6 in ALD rats (P < 0.05), and heightened gene expressions of LBP, CD14, TLR4, NF-kappaB and TNF-alpha (P < 0.05); Taurine no matter administered preventively or curatively can reduce the levels of plasma LPS, hepatic TNF-alpha, IL-1beta, IL-6, and down-regulate the gene expressions of LBP, CD14, TLR4, NF-kappaB and TNF-alpha. The results demonstrated that taurine can prevent and cure ALD by reducing the production and transformation of LPS as well as inhibiting the opening and the transmission of LPS induced KC activation and the downstream signaling pathway. PMID- 28849500 TI - Taurine Recovers Testicular Steroidogenesis and Spermatogenesis in Streptozotocin Induced Diabetic Rats. AB - A great deal of investigations have verified that diabetic male reproductive impairment is associated with the dysfunction of testicular steroidogenesis and spermatogenesis resulted from insulin deficiency and hyperglycaemia-induced oxidative stress. It has been identified taurine is profitable for diabetes mellitus and diabetic implications through its insulin-like and islet cells protective activity. Furthermore, our previous studies found that taurine could increase testicular antioxidative ability, stimulate the endocrine activity of hypothalamic-pituitary-testicular axis, elevate testosterone level, raise sperm quality, suppress the deterioration of testicular function. Accordingly, we hypothesized that taurine may have beneficial effects on testicular dysfunction under diabetic mellitus status. Here, we investigated the effects of taurine on testicular steroidogenesis and spermatogenesis in streptozotocin (STZ)-induced type I diabetic rats. We observed that taurine treatment can markedly increase the body and testis weights, testicular SDH and G6PDH activities, decrease the serum fasting glucose concentration of diabetic rats. Serum contents of GnRH, LH, FSH, T, and testicular StAR, 3beta-HSD, 17beta-HSD mRNA expression levels were also obviously raised by taurine administration, indicating that taurine can improve testicular steroidogenesis in diabetic animals. Finally, we found taurine supplementation effectively elevated the sperm count and motility, reduced sperm abnormality, suggesting that taurine can increase the testicular spermatogenesis function of diabetic rat. In summary, the present data indicated that taurine can rescue the function of testicular steroidogenesis and spermatogenesis in STZ induced type I diabetic rats possibly by increasing the endocrine activity of hypothalamic-pituitary-testicular axis. PMID- 28849501 TI - Effects of Taurine and L-Arginine on the Apoptosis of Vascular Smooth Muscle Cells in Insulin Resistance Hypertensive Rats. AB - OBJECTIVE: In order to find the effects and mechanism of taurine and L-arginine on the apoptosis of VSMCs in insulin resistance hypertensive rats. METHODS: 25% fructose were administered in the drinking water to Wistar rats for 12 weeks to induce the insulin resistance hypertensive model. Apoptosis of VSMCs was identified by TUNEL. The expressions of Bax protein and Bcl-2 protein were examined by immunohistochemistry. RESULTS: High level of fructose significantly suppressed the apoptosis of VSMCs. Taurine and L-arginine promoted apoptosis of VSMCs via increasing the Bax protein expression and decreasing the Bcl-2 protein expression. CONCLUSIONS: Taurine and L-arginine have obvious anti-hypertensive effects in insulin resistance hypertensive rats, and its mechanism might partially be associated with attenuating vascular remodeling by promoting apoptosis in VSMCs. In addition, the combined medication of taurine and L arginine was more effective than single medication. PMID- 28849502 TI - Taurine Prevents the Electrical Remodeling in Ach-CaCl2 Induced Atrial Fibrillation in Rats. AB - OBJECTIVE: To study the preventive actions and mechanism of taurine on the electrical remodeling in atrial fibrillation (AF) rats. METHODS: Male Wistar rats were injected with the mixture of acetylcholine (Ach) (66 MUg/mL)-CaCl2 (10 mg/mL) (i.v.) for 7 days to establish AF model. Taurine was administered in drinking water 1 week before or at the same time of AF model establishment. The duration of AF was monitored by recording ECG of rats during the model establishment. At the end of the experiment, left atrial appendages were cut down to measure the effective refractory period (ERP) by S1-S2 double stimulation method; atrial tissues were collected in order to detect the concentration of K+ and taurine by flame atomic absorption spectrometry and ELISA respectively; total RNA were extracted from the atrium, gene expressions of Kv1.5, Kv4.3, Kir2.1, Kir3.4 were detected by semi-quantitative RT-PCR. RESULTS: Taurine administration effectively shortened the AF duration of rats and prolonged atrial ERP than the model and taurine depleted rats. In addition, atrial K+ level in taurine treated groups was significantly reduced nearly to the normal level. Moreover, the mRNA expression levels of Kir3.4 and Kv1.5 were significantly increased in the taurine preventive treated groups. CONCLUSIONS: Taurine can prevent the atrial electrical remodeling and decrease the duration of AF in rats by reducing the atrial K+ concentration and up-regulating mRNA expression levels of Kir3.4 and Kv1.5. PMID- 28849503 TI - Taurine Reverses Atrial Structural Remodeling in Ach-Cacl2 Induced Atrial Fibrillation Rats. AB - Taurine has been reported to have anti-arrhythmia effects, but the anti-atrial fibrillation (AF) effects and its mechanism remain incompletely understood. In the present study, the therapy effects and partly mechanisms were investigated. AF animal model was established by intravenous administered with the mixture of acetylcholine (Ach) and CaCl2 (66 MUg/mL + 10 mg/mL) (i.v.) for 7 days. The actions of taurine (99 mg/kg?d, introgastric administration) on the levels of Hs CRP, IL-6, TNF-alpha, MMP-9, AngII, the extent of the fibrosis and ultrastructural changes in left atrial were studied. The data showed that the serum levels of TNF-alpha, IL-6, AngII and the plasma levels of Hs-CRP and MMP-9 were significantly elevated in automatic recovery group relative to the control group (p < 0.01), which were all decreased by taurine administration (p < 0.01) similar to Verapamil treatment. Masson's trichrome staining of the left atrial tissue showed an obvious interstitial fibrosis in rats of automatic recovery group. The alteration could be reversed by additional taurine. Electron microscopy revealed that taurine administration could significantly alleviate the ultrastructural damage of atrial cells, and the effects were similar to the Verapamil treatment. In conclusion, the results suggested that taurine could inhibit the structural remodeling of AF in rats partly by decreasing the levels of inflammatory factors and profibrotic molecules, attenuating the extent of myocardial fibrosis and protecting the integrity of myocardial ultrastructure. PMID- 28849504 TI - Taurine Normalizes the Levels of Se, Cu, Fe in Mouse Liver and Kidney Exposed to Arsenic Subchronically. AB - To evaluate the benefits of taurine on the homeostasis of trace elements induced by toxic metals, we investigated the concentration of Selenium (Se), Copper (Cu), Iron (Fe) and Manganese (Mn) in mouse liver and kidney after arsenic exposure for 2 months. The experimental animals were divided into control group, arsenic exposure group (1, 2, 4 ppm) and taurine protective group randomly. Concentrations of serum, liver and kidney trace elements such as Se, Cu, Fe, Mn were measured by Inductively Coupled Plasma-Mass Spectrometry. Our results showed that the concentration of Cu was higher, however, the concentration of Se and Fe was lower in mice liver and kidney exposed to arsenic. The levels of Se, Cu, Fe were alleviated by co-administered with taurine. Furthermore, there was no difference in the concentration of Mn between the three groups. Our finding suggests that taurine may relieve the disturbed levels of Se, Cu and Fe in liver and kidney induced by arsenic. PMID- 28849505 TI - Taurine Protects Mouse Liver Against Arsenic-Induced Apoptosis Through JNK Pathway. AB - A great number of evidences demonstrated that the increased apoptosis is related to arsenic (As)-induced liver injury. The object of the present study was to explore the protection of taurine (Tau) against As-induced impairment in liver and the related mechanism. Adult mice were divided into control group, As exposure group and Tau protection group. The results of RT-PCR and WB showed that Tau treatment significantly reversed the disturbance of Bax and Bcl-2 expression. The release of cytochrome c and caspase-3 activation in liver both were prohibited by Tau in As-intoxicated mice. Furthermore, Tau markedly attenuated As induced decrease of p-JNK level in mouse liver. These results indicated that Tau attenuated As-induced hepatic injury via JNK pathway. PMID- 28849506 TI - Taurine Attenuates As2O3-Induced Autophagy in Cerebrum of Mouse Through Nrf2 Pathway. AB - We previously reported that the impairment of cerebrum may relate with neurotoxicity induced by arsenic (As) exposure. In the present study, we investigated whether autophagy of the cerebrum neurons were responsible for As induced neurotoxicity and the protective role of taurine (Tau). Forty mice were randomly divided into control group, Tau control group, As exposure group and Tau protection group. The results showed that LC3 II expression was elevated and P62 expression was lower after As exposure, whereas the effects were obviously attenuated by Tau treatment. More important, As induced increase of MDA level and decrease of Nrf2 expression were significantly inversed in protective group. In sum, autophagy inhibition might play a strong role in the neuroprotection of Tau in As-induced toxicity via Nrf2 pathway. PMID- 28849508 TI - Taurine Protects Glutamate Neurotoxicity in Motor Neuron Cells. AB - Amyotrophic lateral sclerosis (ALS) is a fetal neurodegenerative disease that results in motor dysfunction and death. However, there is no cure or effective therapy for ALS. In our previous results, taurine protects motor neurons by repairing for constitutive oxidative stress in an ALS model. ALS is caused by multiple factors including inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction. Especially, glutamate excitotoxicity has been well known as a mediator in the disease process, and may occur from changes in the excitability of the neurons being stimulated. D-serine is known to a key factor of determination on glutamate toxicity in ALS. Therefore, in the present study, we investigated neuroprotective effects of taurine from glutamate excitotoxicity using motor neuron cells, mtSOD1 (G93A) transgenic cell line model of ALS (NSC-34/hSOD1G93A cells). We evidenced that taurine protects cultured motor neurons from neurotoxic injury. Our findings indicated that taurine has neuroprotective properties and may be a good candidate for therapeutic trials in ALS. PMID- 28849507 TI - Effects of Taurine on ACE, ACE2 and HSP70 Expression of Hypothalamic-Pituitary Adrenal Axis in Stress-Induced Hypertensive Rats. AB - The experiment was to elucidate protective mechanism of taurine against stress induced hypertension. Thirty two male Wistar rats were randomly divided into four groups. Normal control group and stress control group were intragastrically administered saline; beta-alanine stress group were fed with beta-alanine (200 mg/kg/day) and taurine stress group with taurine (200 mg/kg/day). The hypertensive model was established by giving rats stress for 3 weeks.Results showed that significant expression levels of angiotensin converting enzyme (ACE) in the hypothalamus, pituitary and adrenal were observed in beta-alanine stress group and stress control group (P < 0.05), but significant mRNA expression levels of angiotensin-converting enzyme 2 (ACE2) in taurine stress group and normal control group (P < 0.05). All the groups showed no significant differences in HSP70 mRNA expression levels in hypothalamus (P > 0.05), while taurine stress group exhibited the highest HSP70 mRNA expression levels both in pituitary and in adrenal (P < 0.05). It was also found that beta-alanine stress group and stress control group had significantly higher protein expression levels of ACE in hypothalamus, pituitary and adrenal (P < 0.05), but significantly lower protein expression of ACE2 compared to taurine stress group and control groups (P < 0.05). The results indicated that taurine regulated the hypothalamus pituitary adrenal (HPA) axis of the renin-angiotensin-aldosterone system (RAAS) by inhibiting ACE gene and protein expressions and promoting ACE2 and HSP70 protein expressions, thereby contributing to the prevention of stress-induced hypertension. PMID- 28849509 TI - Role of Taurine in BDE 209-Induced Oxidative Stress in PC12 Cells. AB - Polybrominated diphenyl ethers (PBDEs) are globally dispersed throughout the environment, and the levels of some PBDEs in the environment may still be increasing. Previous studies showed that BDE 209 exerted neurodevelopmental and neurobehavioral effects in humans and animals. Oxidative stress is a common mechanism reported in PBDEs-induced neurotoxicity. Taurine, as an antioxidant, whether it is effective in alleviating BDE 209-induced neurotoxicity is still unknown. PC12 cells were exposed to various concentrations of BDE 209 (6.25, 12.5, 25, 50, and 100 MUM). 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to assess the cell viability. 2',7' Dichlorofluorescin diacetate (DCFH-DA) detector was used to explore the production of ROS. Acridine orange was used to reflect the permeation of lysosomal membrane. Rhodamine 123 was used to reflect the permeation of mitochondrial membrane. Lactate dehydrogenase and catalase in PC12 cells exposed to BDE 209 were examined by kits. The results showed that taurine could significantly reverse the decreased viability, the serious oxidative stress and abnormal autophagy in PC12 cells exposed to BDE 209. Collectively, our results indicated that taurine could protect PC12 cells from BDE 209-induced neurotoxicity by alleviating oxidative stress. PMID- 28849510 TI - Protection of Taurine Against PFOS-Induced Neurotoxicity in PC12 Cells. AB - As a new member of persistent organic pollutants, the potent neurotoxicity of perfluorooctane sulfonates (PFOS) found in epidemiological studies and laboratory research has drawn increasing attention around the world. Previous studies showed that apoptosis driven by oxidative stress and autophagy were both observed in PFOS-induced toxicity. Taurine has been demonstrated to exert potent protections against oxidative stress as an efficient antioxidant. Whether taurine could protect against the PFOS neurotoxicity is not known. In the present study, PC12 cells were treated with several concentrations of PFOS (31.25, 250 MUM) for 24 h. 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was applied to assess the cell viability. DCFH-DA detector was used to explore the production of ROS. Caspase 3 activity was used to reflect the possible apoptosis pathway. The lyso-tracker red dying was invited to evaluate the autophagy. Our data showed that taurine could significantly reverse the decreased viability and the increased ROS production in PC12 cells treated with PFOS. Moreover, the increased autophagy and apoptosis elicited by PFOS in PC12 cells could also be attenuated by taurine. Collectively, our results indicate that taurine may be an effective antioxidant in fighting against PFOS cytotoxicity and therefore could potentially serve as a preventative and therapeutic agent for environmental pollution-related toxicities. PMID- 28849511 TI - Protection of Taurine Against Arsenic-Induced DNA Damage of Mice Kidneys. AB - The purpose of this study was to explore the protective capacity of taurine on arsenic (As)-induced neurotoxicity. Thirty mice were used and ten rats in each group. We treated the As exposure group with 4 ppm As2O3 for 60 days by drinking water and the protective group with 4 ppm As2O3 and 150 mg/kg taurine. Drinking water was only given in the control group. Pathologic changes and DNA damage in the mice kidney were examined by HE staining, immunohistochemistry and comet assay. Abnormal morphological changes were found in the kidney of As exposed mouse. Moreover, 8-hydroxy-2-deoxyguanosine (8-OHdG) expression and comet number, tail moment, and tail length of comet were markedly elevated in the As intoxication mice. However, histopathological changes and low expression of 8 OHdG were shown in the protective group. Our results indicate that supplementation of taurine protects against the histopathologic changes and DNA damage of mouse kidneys in As exposure group. PMID- 28849512 TI - Mussel (Mytilus coruscus) Water Extract Containing Taurine Prevents LPS-Induced Inflammatory Responses in Zebrafish Model. AB - Mussel (Mytilus coruscus) water extract had strong anti-inflammatory activities, but the effects and its mechanisms of mussel on anti-inflammatory properties in vivo remain to be determined. This study, therefore, was designed to investigate anti-inflammatory activities of mussel water extract containing a large amounts of taurine (151.96 nmol/mg) using the lipopolysaccharide (LPS)-induced inflammatory zebrafish model. In this study, mussel water extract containing taurine shows potent protective effects against the cell death stimulated by LPS exposure in zebrafish embryos. In addition, zebrafish subjected to LPS treatment exhibited significantly increased reactive oxygen species (ROS) and nitric oxide (NO) levels. However, mussel water extract markedly suppressed LPS-induced ROS and NO production. Our results indicate that mussel water extract attenuated inflammation by inhibiting the LPS-induced intracellular ROS and NO production in zebrafish embryos. These findings could demonstrate the anti-inflammatory activity of mussel water extract containing taurine, which might have a protective effects on inflammatory diseases. PMID- 28849513 TI - Anti-inflammatory Effects of Galactose-Taurine Sodium Salt in LPS-Activated RAW 264.7 Cells. AB - In this study, we synthesized Galactose-Taurine sodium salt (G-T) as a functional food ingredient to enhance biological activities of taurine. Also, anti inflammatory effects of G-T were investigated in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. G-T found to reduce the generations of the LPS stimulated nitric oxide (NO) and prostaglandin E2 (PGE2) via down-regulating the expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Also, G-T reduced the secretion of inflammatory cytokines including interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF-alpha) in LPS-treated RAW 264.7 cells. Finally, we identified that G-T inhibits the activation of nuclear factor kappaB (NF-kappaB) and the phosphorylation of inhibitor kappaB (IkappaB)-alpha. From these results, this study first suggests that G-T could be considered as an effective anti-inflammatory agent. PMID- 28849514 TI - Radio-Protective Effects of Octopus ocellatus Meat Consisted of a Plentiful Taurine Against Damages Caused by Gamma Ray Irradiation. AB - Gamma ray irradiation causes immune suppressive responses by inducing oxidative stress such as reduction of cell viability and damages in immune cells. In this present study, we investigated whether Octopus ocellatus meet (OM) consisted of a plentiful taurine has protective effects against damages caused by oxidative stress in murine splenocytes. First of all, we prepared the aqueous extract from OM (OMA) and identified it contained a plentiful taurine content. The result also showed that OMA exhibited the antioxidant activity by scavenging DPPH and ABTS+ radicals and hydrogen peroxide. In addition, OMA improved the cell viability without cytotoxicity in gamma ray-irradiated murine splenocytes. Moreover, OMA significantly reduced the production of reactive oxygen species (ROS) in gamma ray-irradiated splenocytes. In further study, we identified that OMA protected zebrafish embryo via improving the reduced survival rate and decreasing the formation of deformity caused by the exposure of gamma ray irradiation. Also, OMA decreased the production of NO and ROS in gamma ray-irradiated zebrafish embryos as well as the induction of cell death. In these results, this study suggests that the consumption of taurine-rich foods, such as O. ocellatus, may be useful for the useful material for the protection against oxidative stress. PMID- 28849515 TI - The Effect on Blood Biochemical Factors of a ICR-Mice in a High-Fat Diet with Taurine 20. AB - The purpose of this study was to examine the effects of taurine on lipid levels and liver function and the actions of insulin and leptin by biochemically analyzing the blood of albino mice fed a diet containing 20% taurine. The group fed a high-fat diet (HF) containing 20% taurine (HF + taurine 20%) showed higher blood HDL cholesterol levels as well as significantly lower total cholesterol and triglyceride levels (p < 0.05) than the group fed HF. No significant difference was observed among indicators of liver function, such as alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase activities. However, the HF + taurine 20% group showed significantly lower insulin and leptin levels than the HF group (p < 0.05). These findings show that 20% taurine had a significant effect on blood lipid levels and blood sugar maintenance in mice fed an HF. PMID- 28849516 TI - Effects of Replacement of Methionine in Diets with Taurine on Growth Performance and Blood Index in Broilers. AB - We studied effects of replacement of methionine with taurine on growth performance and blood index of AA+ broilers. Six hundred 1 day broilers were divided into 5 groups, with 3 replicates of 40 broilers in each. The experiment lasted for 42 days.The control group were fed on formulated diets containing 2% methionine; the other groups were offered feed with equal nitrogen and calories to the control group, but contained 25, 50, 75 and 100% taurine in place of methionine.Compared with the control group, no significant differences were observed in growth performance of 1-21 days broilers, or the serum LDL-C, TC, IgG and SOD of the experimental groups (P> 0.05). ADG and F/G from days 1-42, ADG, ADFI and F/G from days 22-42 were significantly different between the experimental groups and the control group (P < 0.05). ADFI and Mortality in 50, 75 and 100% taurine groups were significantly different compared with the control group (P < 0.05). IgM and GSH-PX of 50 and 75% taurine groups were significantly different compared with the control group (P < 0.05). Serum HDL-C, T-AOC levels in 50, 75 and 100% taurine groups were significantly different compared with the control group (P < 0.05). Based on the quadratic regression analysis, the best replacement ratios were 58%, 61% and 61% on days 1-21, 22-42, and 1-42, respectively. In conclusion, appropriate levels of taurine supplement can improve growth performance, immune system, T-AOC, and lipid metabolism. PMID- 28849517 TI - Consumer Awareness and Preferences Related to Taurine-Containing Drinks in Korean Female High School Students. AB - The purpose of this cross-sectional study was to investigate awareness, consumption patterns, and preferences related to intake experience of taurine containing drinks (TCD) in Korean female high school students. Study subjects were 335 female high school students residing in Incheon, Korea. Data were collected using self-administered questionnaires. A total of 249 students (74.3%) consumed TCD while 86 students (25.7%) did not. In the TCD consumption group, 66.7% of consumers drank TCD once every 2 or 3 months while most consumers consumed it during the examination period (57.4%). Regarding the effects of TCD intake, 45.8% of students cited 'relieve sleepiness' while 41.8% showed 'no effect'. According to self-reported school records, there were significant differences in intake time of TCD, effects of TCD intake, and degree of interest in TCD (p < 0.05). About 82.7% of all the subjects perceived TCD as an energy drink for fatigue recovery. Degree of interest in TCD (p < 0.001), degree of harmfulness to the body (p < 0.01), and improvement for learning-ability (p < 0.001) had significant effects on intake frequency of TCD. Regarding preferences, 'Vita 500' was preferred by 52.2% of subjects, 'Bacchas' by 20.1%, and 'Hot Six' by 17.3%. Although subjects preferred 'Vita 500' as a caffeine-free TCD, caffeine was perceived as the most abundant ingredients in TCD by 77.1% of subjects, taurine by 16.1%, and vitamin by 4.8%. These results show most Korean female high school students consumed TCD in order to stay awake during the examination periods. Therefore, nutritional education is needed to correct Korean high school students' consumption of TCD. PMID- 28849518 TI - Taurine Intake with Magnesium Reduces Cardiometabolic Risks. AB - WHO-CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study revealed the quintile analyses of 24-h urinary (24 U) taurine (T) and magnesium (Mg) excretions were inversely related with cardiometabolic risks (CMR) such as obesity, hypertension and hypercholesterolemia in 50 population samples in the world. To exclude the influence of ethnicity in the study, 24 U T and Mg excretions were analyzed for the association with CMR in one ethnicity, Japanese population.24 U T/creatinine (C) ratios were divided into 5 quintiles and the ratios of Japanese to the total of each quintile were analyzed from CARDIAC Study samples. The highest 24 U T quintile consisted of 60% Japanese, indicating high seafood consumption in Japanese.Over 600 Japanese aged 30-79 were invited to a health examination for blood pressure measurement and for fasting blood and 24 U samplings. Tertile analysis of 24 U T/C ratios in relation to CMR indicated the third tertile had significantly higher HDL cholesterol, 24 U potassium (K) and 24 U salt than the first (lowest) tertile. Tertile analysis of 24 U Mg/C ratios indicated the third tertile had significantly lower body mass index and significantly higher folic acid, 24 U isoflavones, K and salt than the first tertile after age and gender adjustment. The third tertile of both T/C and Mg/C had significantly lower body mass index, LDL/HDL and Na/K ratios, and significantly higher HDL cholesterol and folic acid than the first tertile, indicating seafood eaters taking Mg rich diets had lower risks of obesity, atherosclerosis, hypertension and higher folic acid, beneficial for healthy longevity. PMID- 28849519 TI - Comparison of Toxicity of Taurine and GABA in Combination with Alcohol in 7-Day Old Mice. AB - Previously, we described the combined toxicity of taurine and alcohol, and assumed hypoglycemia to be one reason of this toxicity. To understand whether taurine-ethanol combined toxicity is exclusively connected to taurine or whether other inhibitory amino acids may have similar effects when combined with ethanol, we tested different doses of gamma-aminobutyric acid (GABA) in combination with ethanol in 7-day-old mice. The minimal dose of GABA in combination with 5 g/kg ethanol which could kill a mouse was 2 g/kg. GABA combined with ethanol at doses of 3 g/kg, 4 g/kg, 6 g/kg induced lethality of 30%, 90% and 100%, correspondingly. Taurine at the doses of 4 and 6 g/kg combined with ethanol induced death in 60 and 100% of mice. Ethanol (5 g/kg), taurine (6 g/kg), GABA (4 g/kg) administered alone and the combination of ethanol (5 g/kg) with taurine (3 g/kg) have no lethal effects. GABA (6 g/kg) applied alone induced 90% lethality. Taurine or GABA alone decreased blood glucose in a dose-depending manner. Ethanol potentiated GABA- and taurine-induced decrease in blood glucose and in some animals it dropped from 8.8 (intact) to a hypoglycemic level 3.1-3.3 mmol/L (GABA 4 g/kg, taurine 6 g/kg), but this may not be considered a single reason of death. We conclude that the combination of GABA and ethanol has a lethal effect and this is stronger than the combined toxicity of ethanol and taurine. PMID- 28849520 TI - Antioxidant Effects of Short-Neck Clam (Tapes philippinarum) Water Extract Containing Taurine Against AAPH-Induced Oxidative Stress in Zebrafish Embryos. AB - The purpose of this study was to investigate the antioxidant activities of short neck clam water extract (SNC-WE) enriched in taurine. In the present study, the half-maximal inhibitory concentration (IC50) values of the SNC-WE for DPPH, superoxide, and alkyl radical scavenging activities determined by an electron spin resonance (ESR) spectrometer were 3.16, 1.54 and 0.58 mg/mL, respectively. Furthermore, we evaluated the inhibitory effect of taurine enriched SNC-WE against the oxidative stress induced by 2,2'-azobis dihydrochloride (AAPH) in zebrafish embryos. In the present study, we observed that taurine enriched SNC-WE significantly suppressed reactive oxygen species (ROS) production, lipid peroxidation as well as cell death in the zebrafish model. These results indicate that taurine enriched SNC-WE might have antioxidant effects in both in vitro and in vivo zebrafish model. PMID- 28849521 TI - Role for Taurine in Development of Oxidative Metabolism After Birth. AB - The heart undergoes a major metabolic transition after birth, a change largely caused by alterations in substrate availability, hormone levels and transcription factor content. However, another factor that could contribute to the resulting upregulation of oxidative metabolism is the increase in taurine levels. We proposed that by increasing UUG decoding and the biosynthesis of mitochondria encoded proteins, elevations in taurine content enhance electron transport flux and increase oxidative metabolism. To test our hypothesis, the effect of reduced taurine content on oxidative metabolism of myocardial mitochondria and neonatal cardiomyocytes was examined. Taurine deficient neonatal mitochondria exhibited impaired oxidation of complex I specific- but not complex II specific-substrates, indicating that taurine deficiency regulates complex I activity. Taurine deficiency also reduced respiration of neonatal cardiomyocytes oxidizing carbohydrate (glucose, lactate and pyruvate). However, cardiomyocytes from 2-3 day-old hearts respiring either beta-hydroxybutyrate, an important substrate in the neonatal heart, or palmitate, which is poorly metabolized during the early neonatal period, were resistant to the metabolic defects of taurine deficiency, These data support the hypothesis that taurine contributes to development of respiratory chain function after birth, which is required for oxidative metabolism of multiple substrates. PMID- 28849522 TI - Beneficial Function of Taurine on Bone Metabolism in Alcohol-Fed OVX Rat Model. AB - The present study investigates the effects of taurine on bone markers and bone mineral density (BMD) in alcohol-fed ovariectomized (OVX) rat model. We divided twenty four rats into Sham and OVX groups. These two groups were thereafter subdivided into two groups: control and experimental diet containing 2 g/kg of taurine. BMD and bone mineral content (BMC) were estimated by PIXImus. As bone markers, we measured serum calcium, phosphorus, ALP activity, osteocalcin and urine calcium, phosphorus and DPD crosslinks value. The results were as follows: weight gain showed no significant difference and serum calcium concentration was in normal range. Urine DPD crosslink value was significantly decreased in taurine fed group (p < 0.05). Serum ALP activity and osteocalcin levels, and urine phosphorus concentration did not show any differences among groups. Also the mineral density and content of spinal and femural bone did not show any differences among groups. However, the femur BMD was significantly increased in taurine-fed group (p < 0.05). In conclusion, taurine supplemented diets may have positive results on bone metabolism in alcohol-fed OVX rat model. PMID- 28849523 TI - Liver Antioxidant Enzyme Activities Increase After Taurine in Ovariectomized Rats. AB - The present study was performed to know the effects of taurine on the lipid level of plasma and liver, lipid peroxidation and antioxidative enzyme activities of liver tissue in ovariectomized (OVX) rats fed cholesterol. Twenty-four female SD rats (200 +/- 5 g) were grouped; sham and ovariectomy groups, which were each randomly subgrouped; fed control and control supplemented with taurine (20 g/kg diet). The serum total cholesterol, TG (triglyceride), LDL-cholesterol, athrogenic index, and HDL-cholesterol of taurine diet group were not statistically different. Also the levels of liver total cholesterol, triglyceride were not considerably different in different diets. The lipid peroxidation of malondialdehyde concentration was considerably lower in taurine-feeding group than control-feeding group in ovariectomy group. The superoxide dismutase activity in liver tissue was significantly higher in rats fed taurine than in rats fed control diet in OVX rats. GSH-Px (glutathione peroxidase) activity was statistically greater at the rats fed taurine diets compared to rats fed control diet in ovariectomy group. Activity of catalase was higher in taurine group than in control group in ovariectomy group, but it was not significantly different. In conclusion, taurine supplementation was beneficial on antioxidative enzyme activities of liver tissue in ovariectomized rats fed cholesterol. PMID- 28849524 TI - Effects of Taurine and Vitamin D on Antioxidant Enzyme Activity and Lipids Profiles in Rats Fed Diet Deficient Calcium. AB - Calcium deficiency is a worldwide problem affecting both developed and developing countries. The deficiency in calcium leads to a marked decrease of superoxide dismutase. It is known that vitamin D protects cells against oxidative damages while taurine plays an anti-inflammatory and antioxidant role. In this study, we examined whether vitamin D and taurine supplementation had a protective effect on oxidative stress in rats fed calcium deficient diet. Female SD rats (mean weight 60 ~ 70 g) were divided into four groups; control, taurine, vitamin D, taurine + vitamin D for 6 weeks (taurine: 2 g/100 g diet, vitamin D: 0.5 mg/100 g diet). We then analyzed the level of triglyceride (TG), total cholesterol (TC), LDL cholesterol (LDL-C), HDL-cholesterol (HDL-C) in serum and level of TC, TG in liver. We investigated antioxidative enzyme activities such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). We observed that weight gain was not significantly different in the experimental groups. Food efficiency ratio (FER) was significantly higher in the normal control group than the taurine and vitamin D groups (p < 0.05). The level of liver TC was significantly lower in taurine, vitamin D, taurine + vitamin D groups than control group (p < 0.05). The concentration of malondialdehyde (MDA) was significantly lower in the taurine group than the control group. The activity of SOD was higher in taurine group than other experimental groups (p < 0.05), but GSH-Px and CAT were not significantly different. In conclusion, taurine has a positive effect on SOD activity but not on vitamin D. Also taurine and vitamin D have a protective effect as observed in liver TC in rats fed with a diet which lacks calcium. PMID- 28849525 TI - Taurine May Modulate Bone in Cholesterol Fed Estrogen Deficiency-Induced Rats. AB - Taurine is thought to affect bone in rats favorably. However, studies on the actions of this estrogen deficiency and high cholesterol diet factors on the bone metabolism are limited. In this study, the protective effect of taurine on bone was determined. Thirty-two 42 days old female SD rats were placed in individual stainless cages. Given to rats was fed to chow (Samyang Corporation, South Korea) and deionized water for a 4 days adaptation period. After the period of adaptation, Half of the rats were induced estrogen deficiency model by ovariectomy (OVX), and the left rats with sham-operated were used control (SHAM). For six weeks, the OVX and SHAM rats had separately a 2% taurine supplemented diet with ad libitum in both the water and the food. DEXA for small animals (PIXImus, GE Lunar co, Wisconsin) was used to determine spinal and femoral bone. The concentrations of serum calcium and phosphorus were also measured. The monitoring of bone formation was done by determining the serum ALP and osteocalcin. Urinary DPD the values were determined as index of bone resorption. Statistical measure was done with SAS (version 9.3). A lower overall intake of the daily food was observed in non-ovariectomized rats than in the OVX rats. At sacrifice, a much greater body weight was observed in ovariectomized group compare to non-operated group. That difference was absent in both fed taurine SHAM and OVX rats. Serum calcium and phosphorus were not statistically different by taurine supplementation. Urinary excretion of calcium was not effected by taurine supplementation. Serum ALP and was significantly decreased by taurine in OVX rats (p < 0.05). For the spine BMD and BMC, there was no difference among SHAM and OVX rats by taurine. Spine BMC per body weight of taurine groups were higher than control groups (p < 0.1). No significant difference was observed after taurine supplementation in femur BMD and BMC. The analysis of the results suggest that taurine supplementation modulates the bone mineral contents in postmenopausal model rats fed with high cholesterol diet. PMID- 28849526 TI - The Taurine Content of Japanese Seaweed. AB - Japanese and South Koreans have a dietary habit of eating seaweed. Although it is known that some seaweed contains taurine, there have been few detailed analyses on the taurine content of seaweed other than the major types of edible seaweed. In the present study, we determined the content of free amino acids, including taurine, in seaweed obtained along the Sea of Japan coast. The taurine content in the seaweed varied according to the species. Among the 29 different types of seaweed that were studied, red algae contained relatively high concentrations of taurine. In contrast, the taurine content was low or undetectable in brown and green algae. The algal alanine level was relatively higher in brown sea algae, which was in sharp contrast to its taurine level. No clear trends were observed with regards to the distribution of the other free amino acids, including aspartic acid, glutamic acid, and phenylalanine. Considering the physiological role of taurine in cellular homeostasis, the algal taurine content may be associated with the growing environment. Taurine-rich red edible algae such as mafunori (Gloiopeltis tenax)/fukurofunori (Gloiopeltis furcata), kabanori (Gracilaria textorii), and ogonori (Gracilaria vermiculophylla) may be used to create functional foods that are rich in naturally occurring taurine. PMID- 28849527 TI - Analysis of Taurine's Anti-Down Syndrome Potential in Caenorhabditis elegans. AB - Down syndrome (DS) patients overexpress human DS critical region gene 1 (hDSCR 1), whose translational product inhibits calcineurin-dependent signaling pathways of genetic transcription. Compared to hDSCR-1, C. elegans rcn-1 has 40% sequence similarity and its proteins share an analogous function with hDSCR-1 in regulating calcineurin. Taurine has had a positive effect on DS patients. According to animal research studies, taurine reduces the expression of MCIP1, a calcineurin inhibitory protein, on C2C12 myotubes and fibroblast in mouse. This study utilizes two C. elegans models for DS: rcn-1 overexpression model, displaying a calcineurin-deficient phenotype, and calcineurin loss-of function mutants. C. elegans larvae were treated with taurine to characterize its effect and mechanism in helping DS patients. RCN-1 expression and behavioral changes were examined in rcn-1 overexpression and calcineurin-deficient models at different concentrations of taurine. When treated with taurine, transgenic worms harboring an rcn-1 reporter (RCN-1::GFP) showed a reduced level of rcn-1 mRNA expression and improved behaviors that were comparable to those in the wild type. These results indicate that taurine exerts a down-regulating effect on the expression of rcn-1 and, consequently, a positive effect on the expression of calcineurins. In summary, taurine may improve the DS symptoms by prompting a positive interaction between RCN-1 and calcineurin. Furthermore, these results suggest that novel mechanisms may regulate interactions among taurine, RCN-1 and calcineurin. PMID- 28849528 TI - Role of 5-HT2 and 5-HT7 Serotonin Receptors, and Protein Kinases C and A on Taurine Transport in Lymphocytes of Rats Treated with Fluoxetine. AB - Fluoxetine, an antidepressant and selective serotonin reuptake inhibitor, modulates immune cells in vitro. The present study investigates the influence of pharmacological agents which acts as agonist and antagonist of serotonin receptors ex vivo over taurine transport in lymphocytes of rats treated with fluoxetine by one week. The treatment with fluoxetine increase taurine transport and the incubation with the agonist of 5-HT2 receptor, 1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane (DOI) counteract this effect, and ketanserin provoked no change in fluoxetine effect. While the agonist of 5-HT7 receptor, 4-[2 (methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphth alenyl)-1-piperazinehexanamide hydrochloride (LP44) had no significant effects, however the differences between Control and Fluoxetine groups were not observed, the antagonist (R)-3-[2-[2-(4 methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no differences. Preincubation of cells with the diacylglycerol analogue, 1 oleoyl-2-acetyl-sn-glycerol (OAG) caused inhibition of fluoxetine treatment effect but this not occurred in presence of the PKC inhibitor, 1-O-hexadecyl-2-O methyl-rac-glycerol (AMG-C16). Forskolin counteracted the effect of fluoxetine on taurine transport, since at the concentrations used, the rate of taurine transport in Fluoxetine group, returned to Control rate. No significant differences were observed with the PKA inhibitor. Although it is not possible to attribute a definitive role of 5-HT2 receptors in fluoxetine effect on taurine transport, its signaling might affect the function of it. Participation of PKC and PKA have an apparently relevant role in lymphocyte taurine transport. PMID- 28849529 TI - Fermented Asterina pectinifera with Cordyceps militaris Mycelia Induced Apoptosis in B16F10 Melanoma Cells. AB - This prime objective of this study was to explore the anti-cancer activity of fermented Asterina pectinifera with Cordyceps militaris mycelia (FACM) in B16F10 murine melanoma cells. The effect of FACM on cell viability was assessed using MTT assay. Furthermore, the effect of FACM was compared with unfermented A. pectinifera on cell viability. The results demonstrated that the fermented FACM extract has a higher inhibitory activity on the proliferation of B16F10 murine melanoma cells than unfermented A. pectinifera. In addition, FACM also promoted the expression of pro-apoptotic protein Bax leading to stimulate apoptosis in B16F10 cells. Therefore the present study demonstrates that the FACM might be a potential effective anti-cancer agent, as a result of its stronger anti proliferative effect and apoptosis inducing effect than A. pectinifera or C. militaris on melanoma cells. PMID- 28849530 TI - Antioxidant Activity of Extract from the Cephalothorax of Fenneropenaeus chinensis. AB - We investigated the antioxidant activity of taurine rich water extract from the cephalothorax of Fenneropenaeus chinensis (FCC). The antioxidant potency of water extract from FCC was assessed using various assay methods, such as DPPH (1,1 diphenyl-2-picrylhydrazyl), alkyl radical scavenging activity, ABTS (2,2' azinobis (3-ethylbenzothiazoline 6-sulfonic acid ammonium salt)) radical scavenging activity and Ferric reducing antioxidant power (FRAP) assay. The DPPH and alkyl radical scavenging activities of FCC were dose-dependently increased. The lipid peroxidation was estimated using ferric thiocyanate (FTC) assay and thiobarbituric acid (TBA) methods. However, a higher lipid peroxidation activity was observed in TBA method than FTC method. The results of the present study suggested that the FCC extract potentially scavenged the free radical and reduced oxidative stress. Therefore, the present study is concluded that the FCC extract could be a potential source of antioxidant activity. PMID- 28849531 TI - Antioxidant Effect of Taurine-Rich Paroctopus dofleini Extracts Through Inhibiting ROS Production Against LPS-Induced Oxidative Stress In Vitro and In Vivo Model. AB - Taurine is an essential amino acid to improve the function of cardiovascular, skeletal muscle, retina, and central nervous system. It also plays a role as an antioxidant agent against reactive oxygen species (ROS) generated by various substances. The aim of the current study was to examine the antioxidant capacity of water extracts of Paroctopus dofleini. Radical scavenging activity of P. dofleini extracts was performed using an ESR spectrophotometer. Protective effects of P. dofleini extracts against lipopolysaccharide (LPS)-induced oxidative stress in RAW264.7 cells were evaluated using flow cytometry. The P. dofleini extracts showed a potent antioxidant activity against LPS-induced oxidative stress on RAW264.7 cells. Furthermore, the in vivo antioxidant activity of P. dofleini extract on LPS-induced oxidative stress was assessed using zebrafish embryos. P. dofleini successfully scavenged the LPS-induced intracellular ROS and prevented lipid peroxidation in zebrafish embryos. The results obtained in this study clearly demonstrate that the P. dofleini significantly scavenge the ROS and prevent lipid peroxidation in both in vitro and in vivo models. PMID- 28849532 TI - Taurine Attenuates Doxorubicin-Induced Toxicity on B16F10 Cells. AB - This study aimed to investigate the effect of doxorubicin co-treatment with taurine on B16F10 melanoma cells. Frequently, Doxorubicin is used in the treatments of many different kinds of cancers, some of which are soft tissue sarcomas, hematological malignancies and carcinomas. However, the clinical application of doxorubicin is compromised by its severe adverse effects, including cardiotoxicity. In the present study, the efficacy of doxorubicin co treatment with taurine was investigated. B16F10 cell viability was evaluated using MTT assays, trypan blue dye exclusion assays, and fluorescent staining technique. Apoptotic cells were detected by flow cytometry and the proteins associated with apoptosis and cellular differentiations were assessed by immunoblotting. Doxorubicin inhibited cell growth and induced cell death in B16F10 cells. Interestingly, doxorubicin co-treatment with taurine inhibited apoptosis in B16F10 cells. These results indicate that doxorubicin co-treatment with taurine attenuates doxorubicin-induced cytotoxicity and reduces ROS production in B16F10 cells. PMID- 28849533 TI - Protective Effect of Taurine on Mice with Doxorubicin-induced Acute Kidney Injury. AB - Nephrotic syndrome is still a therapeutic challenge because an effective treatment has not been developed. Evidence suggests that multidrug therapy is more effective than monotherapy in amelioration of renal injury. Therefore, we examined if taurine exerts a protective effect on doxorubicin-induced acute kidney injury in mice. Eight-week-old male Balb/c nude mice were used in this study. Taurine was orally administered at a dose of 50 mg/kg and 100 mg/kg body weight for 5 days. In the meantime, the mice were administered intraperitoneal injections of doxorubicin at 15 mg/kg body weight. At 24 h after the doxorubicin challenge, the response in the taurine-treated mice was compared with that in the vehicle-treated control mice. The doxorubicin-induced acute kidney injury model displayed a significant increase in the renal expression of apoptosis-related proteins (p53, phospho-p53, caspase 9, and caspase 3), whereas in the taurine treated mice, the augmented expression of renal inflammation-related mRNAs such as NF-kB, COX-2, and iNOS was down-regulated. These results suggest that taurine acts as a renoprotective agent by inhibiting apoptosis and inflammation in the kidney of mice with doxorubicin-induced renal injury. PMID- 28849534 TI - Taurine Attenuates Epithelial-Mesenchymal Transition-Related Genes in Human Prostate Cancer Cells. AB - Prostate cancer is the most common non-cutaneous cancers among men and the second leading cause of cancer-related deaths among men. Aberrant activation of the epithelial to mesenchymal transition (EMT) has been exhibited to be one of the most common causes of treatment failure and death in cancer patients. In cancer cells with metastatic competence, the E-cadherin switch is a well-established hallmark. Suppression of E-cadherin through its transcriptional repressor SNAIL is thus a determining factor for EMT. TWIST1 is an important transcription factor in EMT, which is present under both physiologic (embryogenesis) and pathologic (metastasis) conditions, and enhances the invasiveness and migration ability of cells. In this study, we investigated the inhibitory effects of taurine on EMT related genes, such as E-cadherin, N-cadherin, TWIST1, ZEB1, SNAIL, and vimentin. EMT markers were detected by RT-PCR and western blotting. The results showed that taurine down-regulated the expression of N-cadherin, TWIST1, ZEB1, SNAIL, and vimentin. In contrast, taurine increased E-cadherin expression. Our findings indicate that taurine has EMT inhibitory effects on human prostate cancer cells. PMID- 28849535 TI - The role of mineral elements and other chemical compounds used in balneology: data from double-blind randomized clinical trials. AB - The aims of this study were to conduct a systematic literature review on balneotherapy about the specific therapeutic role of mineral elements and other chemical compounds of mineral waters and derivate peloids/muds and to discuss the study methods used to evaluate it (in musculoskeletal conditions). We searched Medline by PubMed using the following key words: "spa therapy" "balneotherapy" "mud" "peloid" "mud pack Therapy" in combination with "randomized controlled trial" "double blind trial." We also reviewed the reference list of articles retrieved by the Medline search. We selected the double-blind randomized clinical trials that assessed the effects of mineral water or mud treatments compared to tap water, attenuated peloid/mud therapy or similar treatments without the specific minerals or chemical compounds of the treatment group ("non-mineral"). We evaluated the internal validity and the quality of the statistical analysis of these trials. The final selection comprised 27 double-blind randomized clinical trials, 20 related to rheumatology. A total of 1118 patients with rheumatological and other musculoskeletal diseases were evaluated in these studies: 552 of knee osteoarthritis, 47 of hand osteoarthritis, 147 chronic low back pain, 308 of reumathoid arthritis, and 64 of osteoporosis; 293 of these participants were assigned to the experimental groups of knee osteoarthritis, 24 in hand osteoarthritis, 82 of low back pain, 152 with reumathoid arthritis, and 32 with osteoporosis. They were treated with mineral water baths and/or mud/peloid (with or without other forms of treatment, like physical therapy, exercise...). The rest were allocated to the control groups; they received mainly tap water and/or "non-mineral" mud/peloid treatments. Mineral water or mud treatments had better and longer improvements in pain, function, quality of life, clinical parameters, and others in some rheumatologic diseases (knee and hand osteoarthritis, chronic low back pain, rheumatoid arthritis, and osteoporosis) compared to baseline and non-mineral similar treatments. Internal validity and other limitations of the study's methodology impede causal relation of spa therapy on these improvements. Randomized clinical trials are very heterogeneous. Double-blind randomized clinical trials seem to be the key for studying the role of mineral elements and other chemical compounds, observing enough consistency to demonstrate better and longer improvements for mineral waters or derivate compared to tap water; but due to heterogeneity and gaps on study protocol and methodology, existing research is not sufficiently strong to draw firm conclusions. Well-designed studies in larger patients' population are needed to establish the role of minerals and other chemical compounds in spa therapy. PMID- 28849536 TI - Diversity of tick species on domestic animals in Shandong Province, China, using DNA barcoding. AB - Ticks are considered to be second only to mosquitoes as vectors of diseases. In recent years, severe fever with thrombocytopenia syndrome, a new emerging tick borne disease has been detected in many areas of China, including Shandong Province, Eastern China. Here, we report the tick species diversity based on surveys between 2014 and 2016 covering 16 locations in seven cities of Shandong. Based on DNA barcoding, 1859 ticks belonging to three species were identified: Haemaphysalis longicornis, Rhipicephalus turanicus and Haemaphysalis verticalis. Samples of the same species clustered together in a neighbor-joining phylogenetic tree, with intraspecific distances between 0 and 3.0% and interspecific distances ranged between 15.5 and 24.3%. Goats and dogs were the major hosts of ticks and H. longicornis was regarded as predominant tick species of Shandong. In order to reduce tick populations and prevent tick-borne diseases, effective control measures should be implemented on human and domestic animals, respectively. PMID- 28849537 TI - Diagnostic accuracy of 256-row multidetector CT coronary angiography with prospective ECG-gating combined with fourth-generation iterative reconstruction algorithm in the assessment of coronary artery bypass: evaluation of dose reduction and image quality. AB - BACKGROUND: Effective radiation dose in coronary CT angiography (CTCA) for coronary artery bypass graft (CABG) evaluation is remarkably high because of long scan lengths. Prospective electrocardiographic gating with iterative reconstruction can reduce effective radiation dose. OBJECTIVES: To evaluate the diagnostic performance of low-kV CT angiography protocol with prospective ecg gating technique and iterative reconstruction (IR) algorithm in follow-up of CABG patients compared with standard retrospective protocol. METHODS: Seventy-four non obese patients with known coronary disease treated with artery bypass grafting were prospectively enrolled. All the patients underwent 256 MDCT (Brilliance iCT, Philips) CTCA using low-dose protocol (100 kV; 800 mAs; rotation time: 0.275 s) combined with prospective ECG-triggering acquisition and fourth-generation IR technique (iDose4; Philips); all the lengths of the bypass graft were included in the evaluation. A control group of 42 similar patients was evaluated with a standard retrospective ECG-gated CTCA (100 kV; 800 mAs).On both CT examinations, ROIs were placed to calculate standard deviation of pixel values and intra-vessel density. Diagnostic quality was also evaluated using a 4-point quality scale. RESULTS: Despite the statistically significant reduction of radiation dose evaluated with DLP (study group mean DLP: 274 mGy cm; control group mean DLP: 1224 mGy cm; P value < 0.001). No statistical differences were found between PGA group and RGH group regarding intra-vessel density absolute values and SNR. Qualitative analysis, evaluated by two radiologists in "double blind", did not reveal any significant difference in diagnostic quality of the two groups. CONCLUSIONS: The development of high-speed MDCT scans combined with modern IR allows an accurate evaluation of CABG with prospective ECG-gating protocols in a single breath hold, obtaining a significant reduction in radiation dose. PMID- 28849538 TI - The HTA Risk Analysis Chart: Visualising the Need for and Potential Value of Managed Entry Agreements in Health Technology Assessment. AB - BACKGROUND: Recent changes to the regulatory landscape of pharmaceuticals may sometimes require reimbursement authorities to issue guidance on technologies that have a less mature evidence base. Decision makers need to be aware of risks associated with such health technology assessment (HTA) decisions and the potential to manage this risk through managed entry agreements (MEAs). OBJECTIVE: This work develops methods for quantifying risk associated with specific MEAs and for clearly communicating this to decision makers. METHODS: We develop the 'HTA risk analysis chart', in which we present the payer strategy and uncertainty burden (P-SUB) as a measure of overall risk. The P-SUB consists of the payer uncertainty burden (PUB), the risk stemming from decision uncertainty as to which is the truly optimal technology from the relevant set of technologies, and the payer strategy burden (PSB), the additional risk of approving a technology that is not expected to be optimal. We demonstrate the approach using three recent technology appraisals from the UK National Institute for Health and Clinical Excellence (NICE), each of which considered a price-based MEA. RESULTS: The HTA risk analysis chart was calculated using results from standard probabilistic sensitivity analyses. In all three HTAs, the new interventions were associated with substantial risk as measured by the P-SUB. For one of these technologies, the P-SUB was reduced to zero with the proposed price reduction, making this intervention cost effective with near complete certainty. For the other two, the risk reduced substantially with a much reduced PSB and a slightly increased PUB. CONCLUSIONS: The HTA risk analysis chart shows the risk that the healthcare payer incurs under unresolved decision uncertainty and when considering recommending a technology that is not expected to be optimal given current evidence. This allows the simultaneous consideration of financial and data-collection MEA schemes in an easily understood format. The use of HTA risk analysis charts will help to ensure that MEAs are considered within a standard utility-maximising health economic decision-making framework. PMID- 28849540 TI - Caught in the act: migrating intraventricular neurocysticercosis causing intermittent unilateral hydrocephalus due to foramen of Monro obstruction. PMID- 28849541 TI - A safe and effective technique for application of a multi-level cervical epidural blood patch. PMID- 28849539 TI - Revision to Reverse Total Shoulder Arthroplasty Restores Stability for Patients With Unstable Shoulder Prostheses. AB - BACKGROUND: Instability after shoulder arthroplasty remains a complication with limited salvage options. Reoperation for instability with anatomic designs has led to high rates of persistent instability, therefore we aimed to evaluate the use of RSA for treatment of prosthetic instability. QUESTIONS/PURPOSES: (1) After revision shoulder arthroplasty to a reverse prosthesis (RSA), what is the survivorship free from dislocations at 2 and 5 years? (2) What factors are associated with dislocations? (3) What is the survivorship free from revision after revision to RSA? (4) From preoperation to postrevision to RSA, what are the clinical outcomes-the proportion of patients with moderate to severe pain, shoulder elevation and external rotation ROM, American Shoulder and Elbow Surgeons scores, and Simple Shoulder Test scores? METHODS: All shoulder arthroplasties revised for prosthetic instability using RSA components between January 2004 and July 2014 were retrospectively studied. During the period in question, we performed 82 revisions for instability of an anatomic total shoulder arthroplasty (TSA) (n = 62), hemiarthroplasty (n = 13), or reverse TSA (n = 7). We typically used a reverse TSA to treat this problem, but we identified 12 treated in other ways, including revision of a TSA to hemiarthroplasty (n = 3), revision of a reverse TSA to hemiarthroplasty (n = 2), revision of hemiarthroplasty to a hemiarthroplasty (n = 1), and revision of an anatomic TSA to another anatomic TSA (n = 6). This left 70 patients for evaluation; of those, 65 (93%) were available for analysis at a mean of 3 years (range, 2-10 years). A total of seven patients died. Eight of the 65 shoulders were not evaluated during the last 5 years, including three in patients who died earlier. The mean age of the patients at the time of revision RSA was 65 years (range, 40-89 years). Data were obtained from a longitudinally maintained institutional joint registry. Instability was defined as severe subluxation confirmed on clinical and radiographic examinations. We evaluated pain and ROM, and Kaplan-Meier curves were used to estimate survivorship. RESULTS: The survivorship free from dislocation at 2 and 5 years was 87% (95% CI, 80%-94%) and 79% (95% CI, 67%-91%) respectively, with 10 of 65 (15%) patients having an episode of dislocation after revision surgery. Persistent instability was more common in those with a BMI greater than 35 kg/m2 (hazard ratio [HR], 5; 95% CI, 2-16; p = 0.008) and prior hemiarthroplasty (HR, 5; 95% CI, 2-16; p = 0.005), whereas patients who had undergone a previous TSA were less likely to have persistent instability (HR, 0.08; 95% CI, 0.0-0.30; p < 0.001) The survival free from rerevision for any indication at 2 and 5 years was 85% (95% CI, 76%-94%) and 78% (95% CI, 66%-90%) respectively; with the numbers available, we were not able to find associated factors. Fewer patients had moderate or severe pain after revision to RSA (preoperative: 48 of 65 [74%]; postoperative: nine of 65 [14%]; p < 0.001). After surgery, patients showed improvement in shoulder elevation (preoperative: 42 degrees [+/- 30 degrees ], postoperative: 112 degrees [42 degrees ]; mean difference, 70 degrees [95% CI, - 83o to 57 degrees ]; p < 0.001) and external rotation (preoperative: 20 degrees [+/- 22 degrees ], postoperative: 42 degrees [+/- 23 degrees ]; mean difference, 22 degrees [95% CI, - 30 degrees to - 14 degrees ]; p < 0.001). American Shoulder and Elbow Surgeons scores improved (preoperative: 21 [+/- 10], postoperative: 68 [+/- 14], mean difference, 46 [95% CI, - 58 to - 35]; p < 0.001); where a higher score is better. Simple Shoulder Test scores also improved (preoperative: 2/12 [+/- 2], postoperative: 7/12 [+/- 3]; mean difference, 5 [95% CI, - 7 to - 2.17]; p < 0.001); where a higher score is better. CONCLUSIONS: Revision RSA for prosthetic instability after shoulder arthroplasty is associated with reasonable implant survival and few complications. Approximately one in seven patients will have a recurrent dislocation. In patients with persistent instability or with risk factors for instability, consideration should be given for use of larger glenospheres and increasing the lateral offset at the time of RSA. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 28849542 TI - Synthetic biology, metaphors and responsibility. AB - Metaphors are not just decorative rhetorical devices that make speech pretty. They are fundamental tools for thinking about the world and acting on the world. The language we use to make a better world matters; words matter; metaphors matter. Words have consequences - ethical, social and legal ones, as well as political and economic ones. They need to be used 'responsibly'. They also need to be studied carefully - this is what we want to do through this editorial and the related thematic collection. In the context of synthetic biology, natural and social scientists have become increasingly interested in metaphors, a wave of interest that we want to exploit and amplify. We want to build on emerging articles and books on synthetic biology, metaphors of life and the ethical and moral implications of such metaphors. This editorial provides a brief introduction to synthetic biology and responsible innovation, as well as a comprehensive review of literature on the social, cultural and ethical impacts of metaphor use in genomics and synthetic biology. Our aim is to stimulate an interdisciplinary and international discussion on the impact that metaphors can have on science, policy and publics in the context of synthetic biology. PMID- 28849543 TI - The first record of infestation by a native tick (Acari: Ixodidae) on the Australian emu (Dromaius novaehollandiae) and a review of tick paralysis in Australian birds. AB - For the first time, infestation of the Australian emu by a native tick is recorded based on an engorged adult female specimen of the southern paralysis tick (Ixodes cornuatus) taken from a captive emu at Healesville sanctuary, Victoria, Australia. Tick paralysis in Australian birds is discussed. PMID- 28849544 TI - Characteristics of phosphorus components in surface sediments from a Chinese shallow eutrophic lake (Lake Taihu): new insights from chemical extraction and 31P NMR spectroscopy. AB - As a primary factor responsible for lake eutrophication, a deeper understanding of the phosphorus (P) composition and its turnover in sediment is urgently needed. In this study, P species in surface sediments from a Chinese large eutrophic lake (Lake Taihu) were characterized by traditional fractionation and 31P nuclear magnetic resonance (NMR) spectroscopy, and their contributions to the overlying water were also discussed. Fractionation results show that NaOH-P predominated in the algal-dominated zone, accounting for 60.1% to total P in Zhushan Bay. Whereas, refractory fractions including HCl-P and residual-P were the main P burial phases in the macrophyte-dominated zone, the center and lakeshore. Recovery rates of the total P and organic P were greatly improved by using a modified single-step extraction of NaOH-EDTA, ranging from 22.6 to 66.1% and from 15.0 to 54.0%. Ortho-P, monoester-P, and pyro-P are identified as the major P components in the NaOH-EDTA extracts by 31P NMR analysis. Trace amount of DNA-P appeared only in sediments from algal- and macrophyte-dominated zones, ascribing to its biological origin. The relative content of ortho-P is the highest in the algal-dominated zone, while the biogenic P including ester-P and pyro-P is the highest in the macrophyte-dominated zone. Moreover, ortho-P and pyro-P correlated positively with TP and chlorophyll a in the overlying water, whereas only significant relationships were found between monoester-P, biogenic P, and chlorophyll a. These discrepancies imply that inorganic P, mainly ortho-P, plays a vital role in sustaining the trophic level of water body and algal bloom, while biogenic P makes a minor contribution to phytoplankton growth. This conclusion was supported by the results of high proportion of biogenic P in algae, aquatic macrophytes, and suspended particulate from the published literature. This study has significant implication for better understanding of the biogeochemical cycling of endogenous P and its role in affecting lake eutrophication. PMID- 28849545 TI - CAS: Cell Annotation Software - Research on Neuronal Tissue Has Never Been so Transparent. AB - CAS (Cell Annotation Software) is a novel tool for analysis of microscopic images and selection of the cell soma or nucleus, depending on the research objectives in medicine, biology, bioinformatics, etc. It replaces time-consuming and tiresome manual analysis of single images not only with automatic methods for object segmentation based on the Statistical Dominance Algorithm, but also semi automatic tools for object selection within a marked region of interest. For each image, a broad set of object parameters is computed, including shape features and optical and topographic characteristics, thus giving additional insight into data. Our solution for cell detection and analysis has been verified by microscopic data and its application in the annotation of the lateral geniculate nucleus has been examined in a case study. PMID- 28849546 TI - A new Monte Carlo code for light transport in biological tissue. AB - The aim of this work was to develop an event-by-event Monte Carlo code for light transport (called MCLTmx) to identify and quantify ballistic, diffuse, and absorbed photons, as well as their interaction coordinates inside the biological tissue. The mean free path length was computed between two interactions for scattering or absorption processes, and if necessary scatter angles were calculated, until the photon disappeared or went out of region of interest. A three-layer array (air-tissue-air) was used, forming a semi-infinite sandwich. The light source was placed at (0,0,0), emitting towards (0,0,1). The input data were: refractive indices, target thickness (0.02, 0.05, 0.1, 0.5, and 1 cm), number of particle histories, and lambda from which the code calculated: anisotropy, scattering, and absorption coefficients. Validation presents differences less than 0.1% compared with that reported in the literature. The MCLTmx code discriminates between ballistic and diffuse photons, and inside of biological tissue, it calculates: specular reflection, diffuse reflection, ballistics transmission, diffuse transmission and absorption, and all parameters dependent on wavelength and thickness. The MCLTmx code can be useful for light transport inside any medium by changing the parameters that describe the new medium: anisotropy, dispersion and attenuation coefficients, and refractive indices for specific wavelength. PMID- 28849547 TI - Antihyperalgesic effects of ashwagandha (Withania somnifera root extract) in rat models of postoperative and neuropathic pain. AB - The root of Withania somnifera, commonly known as ashwagandha, is a traditional herb in the Indian Ayurvedic system of medicine and is used as a tonic. Here, we investigated whether W. somnifera root extract exhibits analgesic effects in plantar incision (PI) and spared nerve injury (SNI) rat models. Mechanical withdrawal threshold (MWT) was measured by von Frey filaments, and pain-related behavior was determined after operation by ultrasonic vocalization (USV) measurements. Indeed, we examined interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) levels in the isolated dorsal root ganglia (DRG) following SNI in rats using an ELISA cytokine assay. MWT significantly increased 6 and 24 h after PI in rats receiving W. somnifera root extracts (100 and 300 mg/kg). Furthermore, the number of 22-27-kHz USV, which are a distress response, was significantly reduced at 6 and 24 h after PI in W. somnifera-treated rats (100 and 300 mg/kg). SNI induced hyperalgesia and cytokine levels were significantly alleviated after treating with W. somnifera root extracts (100 and 300 mg/kg) for 15 continuous days. The main active compound, withaferin A, from the W. somnifera root extract has shown the CC chemokine family Receptor 2 (CCR2) antagonistic effects on monocyte chemoattractant protein-1 (MCP-1)-induced Ca2+ response in CCR2 stable cell line. These results indicate that W. somnifera root extract has a potential analgesic effect in rat models for both postoperative and neuropathic pain and shows potential as a drug or supplement for the treatment of pain. PMID- 28849549 TI - Sex Differences in Pediatric Rheumatology. AB - Autoimmune diseases affect up to 10% of the world's population and, as a whole, they are far more common in females, although differences exist according to the single disease and also in different age groups. In childhood-onset autoimmune diseases, the sex bias is generally less evident than in adults, probably for the different hormonal milieau, being estrogens strongly implicated in the development of autoimmunity. Still, some rheumatic conditions, such as juvenile idiopathic arthritis (JIA), show a strong predilection for girls (F:M = 3-6.6:1), and differences may coexist between males and females regarding disease outcome. For example, chronic anterior uveitis associated with JIA affects more commonly girls but boys tend to have a more severe course. Systemic lupus erythematosus predominantly affects girls and women (F:M = 3-5:1 in children, F:M = 10-15:1 in adults). Behsigmaet's disease has been reported to be more prevalent in adult males (F:M = 1:1-4); in children, there are no differences. The sex ratio is equal in children and adults for Henoch-Schonlein purpura (F:M = 1:1). A higher male-to-female ratio exists for Kawasaki disease (F:M = 1:1.1-1.6 in children, F:M = 1:1,5 in adults). Juvenile dermatomyositis (F:M = 2-5:1), systemic sclerosis (F:M = 4:1 in children, F:M = 6:1 in adults), and Takayasu arteritis (F:M = 2:1 in children, F:M = 7-9:1 in adults) are more common in girls and women then in boys and men. There is no gender bias for acute rheumatic fever in children, while in adults, the F:M ratio is 2:1. Given that estrogen levels are not different between genders during childhood, pediatric rheumatic diseases could represent good models to study other mechanisms related to the development of autoimmunity. Recently, the levels of miRNA expression, and their variation according to sex chromosomes, have been linked to the development of autoimmune diseases, with different impact among sexes. This review will focus not only on the sex bias reported in the more common rheumatic conditions of childhood, focusing on differences in incidence, but also on outcome and trying to depict the mechanisms underlying those differences. PMID- 28849548 TI - Precision Medicine for Ischemic Stroke, Let Us Move Beyond Time Is Brain. PMID- 28849551 TI - A Systems Biology Approach to Understanding Alcoholic Liver Disease Molecular Mechanism: The Development of Static and Dynamic Models. AB - Alcoholic liver disease (ALD) is a complex disease characterized by damages to the liver and is the consequence of excessive alcohol consumption over years. Since this disease is associated with several pathway failures, pathway reconstruction and network analysis are likely to explicit the molecular basis of the disease. To this aim, in this paper, a network medicine approach was employed to integrate interactome (protein-protein interaction and signaling pathways) and transcriptome data to reconstruct both a static network of ALD and a dynamic model for it. Several data sources were exploited to assemble a set of ALD associated genes which further was used for network reconstruction. Moreover, a comprehensive literature mining reveals that there are four signaling pathways with crosstalk (TLR4, NF- [Formula: see text]B, MAPK and Apoptosis) which play a major role in ALD. These four pathways were exploited to reconstruct a dynamic model of ALD. The results assure that these two models are consistent with a number of experimental observations. The static network of ALD and its dynamic model are the first models provided for ALD which offer potentially valuable information for researchers in this field. PMID- 28849550 TI - Frailty syndrome and rehospitalizations in elderly heart failure patients. AB - BACKGROUND: Heart failure (HF) patients with frailty syndrome (FS) are at higher risk of falling, decreased mobility, ability to perform the basic activities of daily living, frequent hospitalizations, and death. AIMS: The purpose of this study was to evaluate the correlations between FS and hospital readmissions, and to assess which factors are associated with rehospitalizations. METHODS: The study included 330 patients with a mean age of 72.1 +/- 7.9 years, diagnosed with HF. Frailty was measured using the Polish version of the Tilburg Frailty Indicator (TFI). Demographic, sociodemographic, and clinical data, such as the New York Heart Association (NYHA) functional class, ejection fraction (EF), number of rehospitalizations, and the medications taken, were obtained. RESULTS: Positive correlation was observed between the number of hospitalizations and FS. In the single-factor correlation analysis, treatment with diuretics, a higher NYHA class, and a lower left ventricular EF were predictors of a higher number of hospitalizations. Additionally, the physical and psychological components of the TFI, as well as the total TFI score, predisposed HF patients to more frequent hospitalizations. DISCUSSION: It seems that a deterioration of functional capabilities and an increase in symptom severity naturally lead to increased hospitalization frequency in HF. In the own study, regression analysis indicates that high NYHA classes and TFI social component scores are significant predictors of the number of hospitalizations in the studied group. CONCLUSIONS: FS is highly prevalent among elderly HF patients. Higher frailty levels in elderly patients are a determinant of more frequent rehospitalizations in HF. PMID- 28849552 TI - Regenerative Stem Cell Therapy Optimization via Tissue Engineering in Heart Failure with Reduced Ejection Fraction. AB - The prevalence of heart failure (HF) is continuously rising in both the industrialized and non-industrialized nations. Despite current therapeutic advances, prognosis of HF patients remains poor. Presently, therapeutic pharmacological and device strategies for HF with reduced ejection fraction (HFrEF) are mostly palliative and do not induce regeneration of lost myocardial tissue. Stem cell therapy has demonstrated promising results in clinical studies by promoting myocardial restoration in HFrEF subjects. Despite decades of investigation, many challenges remain unanswered to the widespread clinical application of stem cell therapy for HFrEF. This review will describe the foundational work already accomplished in cardiac stem cell therapy, advantages and limitations of the various candidates for tissue restoration, their presumed mechanisms of action, the role of scaffolding materials as well as the challenges that exist for widespread clinical application. PMID- 28849553 TI - Attention enhances apparent perceptual organization. AB - Perceptual organization and selective attention are two crucial processes that influence how we perceive visual information. The former structures complex visual inputs into coherent units, whereas the later selects relevant information. Attention and perceptual organization can modulate each other, affecting visual processing and performance in various tasks and conditions. Here, we tested whether attention can alter the way multiple elements appear to be perceptually organized. We manipulated covert spatial attention using a rapid serial visual presentation task, and measured perceptual organization of two multielements arrays organized by luminance similarity as rows or columns, at both the attended and unattended locations. We found that the apparent perceptual organization of the multielement arrays is intensified when attended and attenuated when unattended. We ruled out response bias as an alternative explanation. These findings reveal that attention enhances the appearance of perceptual organization, a midlevel vision process, altering the way we perceive our visual environment. PMID- 28849554 TI - Corneal Hydrops Secondary to Intrastromal Corneal Ring Intrusion into the Anterior Chamber 7 Years after Implantation: A Case Report. AB - INTRODUCTION: This report describes the first known case of late-onset intrusion of an intrastromal ring segment into the anterior chamber due to posterior migration of a ring segment. To our knowledge, intrastromal ring segment penetration has only been shown to occur in the intraoperative or immediate postoperative period. We postulate that the perforation in this case is due to progressive thinning of the cornea, possibly in combination with habitual eye rubbing. CASE REPORT: A 44-year-old man presented with acute corneal hydrops related to penetration of Descemet's membrane and endothelium by an intrastromal ring segment implanted 7 years prior. Removal of the ring segment resulted in an anterior chamber fistula that directed fluid through the ring segment tunnel to the ocular surface. Leakage of aqueous humor was successfully controlled, and corneal edema gradually resolved. CONCLUSION: This case indicates the need for long term monitoring of ring segment proximity to the posterior corneal surface, especially in patients with ectatic ocular conditions and/or habitual eye rubbing behavior. PMID- 28849555 TI - A Practical Guide to Quantitative Interactor Screening with Next-Generation Sequencing (QIS-Seq). AB - Yeast two-hybrid screens are a powerful approach to identify protein-protein interactions; however, they are typically limited in the number of interactions identified, and lack quantitative values to ascribe confidence scores to the interactions that are obtained. We have developed a high-throughput, quantitative, yeast two-hybrid screening approach coupled with next-generation sequencing. This strategy allows the identification of interacting proteins that are preferentially associated with a bait of interest, and helps eliminate nonspecific interacting proteins. The method is high-throughput, allowing many more baits to be tested and many more candidate interacting proteins to be identified. Quantitative data allows the interactors to be ascribed confidence scores based on their enrichment with particular baits, and can identify both common and rare interacting proteins. PMID- 28849556 TI - sbv IMPROVER: Modern Approach to Systems Biology. AB - The increasing amount and variety of data in biosciences call for innovative methods of visualization, scientific verification, and pathway analysis. Novel approaches to biological networks and research quality control are important because of their role in development of new products, improvement, and acceleration of existing health policies and research for novel ways of solving scientific challenges. One such approach is sbv IMPROVER. It is a platform that uses crowdsourcing and verification to create biological networks with easy public access. It contains 120 networks built in Biological Expression Language (BEL) to interpret data from PubMed articles with high-quality verification available for free on the CBN database. Computable, human-readable biological networks with a structured syntax are a powerful way of representing biological information generated from high-density data. This article presents sbv IMPROVER, a crowd-verification approach for the visualization and expansion of biological networks. PMID- 28849557 TI - Mathematical Justification of Expression-Based Pathway Activation Scoring (PAS). AB - Although modeling of activation kinetics for various cell signaling pathways has reached a high grade of sophistication and thoroughness, most such kinetic models still remain of rather limited practical value for biomedicine. Nevertheless, recent advancements have been made in application of signaling pathway science for real needs of prescription of the most effective drugs for individual patients. The methods for such prescription evaluate the degree of pathological changes in the signaling machinery based on two types of data: first, on the results of high-throughput gene expression profiling, and second, on the molecular pathway graphs that reflect interactions between the pathway members. For example, our algorithm OncoFinder evaluates the activation of molecular pathways on the basis of gene/protein expression data in the objects of the interest.Yet, the question of assessment of the relative importance for each gene product in a molecular pathway remains unclear unless one call for the methods of parameter sensitivity /stiffness analysis in the interactomic kinetic models of signaling pathway activation in terms of total concentrations of each gene product.Here we show two principal points: 1. First, the importance coefficients for each gene in pathways that were obtained using the extremely time- and labor consuming stiffness analysis of full-scaled kinetic models generally differ from much easier-to-calculate expression-based pathway activation score (PAS) not more than by 30%, so the concept of PAS is kinetically justified. 2. Second, the use of pathway-based approach instead of distinct gene analysis, due to the law of large numbers, allows restoring the correlation between the similar samples that were examined using different transcriptome investigation techniques. PMID- 28849558 TI - Bioinformatics Meets Biomedicine: OncoFinder, a Quantitative Approach for Interrogating Molecular Pathways Using Gene Expression Data. AB - We propose a biomathematical approach termed OncoFinder (OF) that enables performing both quantitative and qualitative analyses of the intracellular molecular pathway activation. OF utilizes an algorithm that distinguishes the activator/repressor role of every gene product in a pathway. This method is applicable for the analysis of any physiological, stress, malignancy, and other conditions at the molecular level. OF showed a strong potential to neutralize background-caused differences between experimental gene expression data obtained using NGS, microarray and modern proteomics techniques. Importantly, in most cases, pathway activation signatures were better markers of cancer progression compared to the individual gene products. OF also enables correlating pathway activation with the success of anticancer therapy for individual patients. We further expanded this approach to analyze impact of micro RNAs (miRs) on the regulation of cellular interactome. Many alternative sources provide information about miRs and their targets. However, instruments elucidating higher level impact of the established total miR profiles are still largely missing. A variant of OncoFinder termed MiRImpact enables linking miR expression data with its estimated outcome on the regulation of molecular processes, such as signaling, metabolic, cytoskeleton, and DNA repair pathways. MiRImpact was used to establish cancer-specific and cytomegaloviral infection-linked interactomic signatures for hundreds of molecular pathways. Interestingly, the impact of miRs appeared orthogonal to pathway regulation at the mRNA level, which stresses the importance of combining all available levels of gene regulation to build a more objective molecular model of cell. PMID- 28849559 TI - Strategic Integration of Multiple Bioinformatics Resources for System Level Analysis of Biological Networks. AB - Recent technological advances in genomics allow the production of biological data at unprecedented tera- and petabyte scales. Efficient mining of these vast and complex datasets for the needs of biomedical research critically depends on a seamless integration of the clinical, genomic, and experimental information with prior knowledge about genotype-phenotype relationships. Such experimental data accumulated in publicly available databases should be accessible to a variety of algorithms and analytical pipelines that drive computational analysis and data mining.We present an integrated computational platform Lynx (Sulakhe et al., Nucleic Acids Res 44:D882-D887, 2016) ( http://lynx.cri.uchicago.edu ), a web based database and knowledge extraction engine. It provides advanced search capabilities and a variety of algorithms for enrichment analysis and network based gene prioritization. It gives public access to the Lynx integrated knowledge base (LynxKB) and its analytical tools via user-friendly web services and interfaces. The Lynx service-oriented architecture supports annotation and analysis of high-throughput experimental data. Lynx tools assist the user in extracting meaningful knowledge from LynxKB and experimental data, and in the generation of weighted hypotheses regarding the genes and molecular mechanisms contributing to human phenotypes or conditions of interest. The goal of this integrated platform is to support the end-to-end analytical needs of various translational projects. PMID- 28849560 TI - Functional Analysis of OMICs Data and Small Molecule Compounds in an Integrated "Knowledge-Based" Platform. AB - Analysis of NGS and other sequencing data, gene variants, gene expression, proteomics, and other high-throughput (OMICs) data is challenging because of its biological complexity and high level of technical and biological noise. One way to deal with both problems is to perform analysis with a high fidelity annotated knowledgebase of protein interactions, pathways, and functional ontologies. This knowledgebase has to be structured in a computer-readable format and must include software tools for managing experimental data, analysis, and reporting. Here, we present MetaCoreTM and Key Pathway Advisor (KPA), an integrated platform for functional data analysis. On the content side, MetaCore and KPA encompass a comprehensive database of molecular interactions of different types, pathways, network models, and ten functional ontologies covering human, mouse, and rat genes. The analytical toolkit includes tools for gene/protein list enrichment analysis, statistical "interactome" tool for the identification of over- and under-connected proteins in the dataset, and a biological network analysis module made up of network generation algorithms and filters. The suite also features Advanced Search, an application for combinatorial search of the database content, as well as a Java-based tool called Pathway Map Creator for drawing and editing custom pathway maps. Applications of MetaCore and KPA include molecular mode of action of disease research, identification of potential biomarkers and drug targets, pathway hypothesis generation, analysis of biological effects for novel small molecule compounds and clinical applications (analysis of large cohorts of patients, and translational and personalized medicine). PMID- 28849561 TI - Extracting the Strongest Signals from Omics Data: Differentially Expressed Pathways and Beyond. AB - The analysis of gene sets (in a form of functionally related genes or pathways) has become the method of choice for extracting the strongest signals from omics data. The motivation behind using gene sets instead of individual genes is two fold. First, this approach incorporates pre-existing biological knowledge into the analysis and facilitates the interpretation of experimental results. Second, it employs a statistical hypotheses testing framework. Here, we briefly review main Gene Set Analysis (GSA) approaches for testing differential expression of gene sets and several GSA approaches for testing statistical hypotheses beyond differential expression that allow extracting additional biological information from the data. We distinguish three major types of GSA approaches testing: (1) differential expression (DE), (2) differential variability (DV), and (3) differential co-expression (DC) of gene sets between two phenotypes. We also present comparative power analysis and Type I error rates for different approaches in each major type of GSA on simulated data. Our evaluation presents a concise guideline for selecting GSA approaches best performing under particular experimental settings. The value of the three major types of GSA approaches is illustrated with real data example. While being applied to the same data set, major types of GSA approaches result in complementary biological information. PMID- 28849562 TI - Search for Master Regulators in Walking Cancer Pathways. AB - In this chapter, we present an approach that allows a causal analysis of multiple "-omics" data with the help of an "upstream analysis" strategy. The goal of this approach is to identify master regulators in gene regulatory networks as potential drug targets for a pathological process. The data analysis strategy includes a state-of-the-art promoter analysis for potential transcription factor (TF)-binding sites using the TRANSFAC(r) database combined with an analysis of the upstream signal transduction pathways that control the activity of these TFs. When applied to genes that are associated with a switch to a pathological process, the approach identifies potential key molecules (master regulators) that may exert major control over and maintenance of transient stability of the pathological state. We demonstrate this approach on examples of analysis of multi omics data sets that contain transcriptomics and epigenomics data in cancer. The results of this analysis helped us to better understand the molecular mechanisms of cancer development and cancer drug resistance. Such an approach promises to be very effective for rapid and accurate identification of cancer drug targets with true potential. The upstream analysis approach is implemented as an automatic workflow in the geneXplain platform ( www.genexplain.com ) using the open-source BioUML framework ( www.biouml.org ). PMID- 28849563 TI - Mathematical Modeling of Avidity Distribution and Estimating General Binding Properties of Transcription Factors from Genome-Wide Binding Profiles. AB - The shape of the experimental frequency distributions (EFD) of diverse molecular interaction events quantifying genome-wide binding is often skewed to the rare but abundant quantities. Such distributions are systematically deviated from standard power-law functions proposed by scale-free network models suggesting that more explanatory and predictive probabilistic model(s) are needed. Identification of the mechanism-based data-driven statistical distributions that provide an estimation and prediction of binding properties of transcription factors from genome-wide binding profiles is the goal of this analytical survey. Here, we review and develop an analytical framework for modeling, analysis, and prediction of transcription factor (TF) DNA binding properties detected at the genome scale. We introduce a mixture probabilistic model of binding avidity function that includes nonspecific and specific binding events. A method for decomposition of specific and nonspecific TF-DNA binding events is proposed. We show that the Kolmogorov-Waring (KW) probability function (PF), modeling the steady state TF binding-dissociation stochastic process, fits well with the EFD for diverse TF-DNA binding datasets. Furthermore, this distribution predicts total number of TF-DNA binding sites (BSs), estimating specificity and sensitivity as well as other basic statistical features of DNA-TF binding when the experimental datasets are noise-rich and essentially incomplete. The KW distribution fits equally well to TF-DNA binding activity for different TFs including ERE, CREB, STAT1, Nanog, and Oct4. Our analysis reveals that the KW distribution and its generalized form provides the family of power-law-like distributions given in terms of hypergeometric series functions, including standard and generalized Pareto and Waring distributions, providing flexible and common skewed forms of the transcription factor binding site (TFBS) avidity distribution function. We suggest that the skewed binding events may be due to a wide range of evolutionary processes of creating weak avidity TFBS associated with random mutations, while the rare high-avidity binding sites (i.e., high avidity evolutionarily conserved canonical e-boxes) rarely occurred. These, however, may be positively selected in microevolution. PMID- 28849565 TI - Analysis of cis-Regulatory Elements in Gene Co-expression Networks in Cancer. AB - Analysis of gene co-expression networks is a powerful "data-driven" tool, invaluable for understanding cancer biology and mechanisms of tumor development. Yet, despite of completion of thousands of studies on cancer gene expression, there were few attempts to normalize and integrate co-expression data from scattered sources in a concise "meta-analysis" framework. Here we describe an integrated approach to cancer expression meta-analysis, which combines generation of "data-driven" co-expression networks with detailed statistical detection of promoter sequence motifs within the co-expression clusters. First, we applied Weighted Gene Co-Expression Network Analysis (WGCNA) workflow and Pearson's correlation to generate a comprehensive set of over 3000 co-expression clusters in 82 normalized microarray datasets from nine cancers of different origin. Next, we designed a genome-wide statistical approach to the detection of specific DNA sequence motifs based on similarities between the promoters of similarly expressed genes. The approach, realized as cisExpress software module, was specifically designed for analysis of very large data sets such as those generated by publicly accessible whole genome and transcriptome projects. cisExpress uses a task farming algorithm to exploit all available computational cores within a shared memory node.We discovered that although co-expression modules are populated with different sets of genes, they share distinct stable patterns of co-regulation based on promoter sequence analysis. The number of motifs per co-expression cluster varies widely in accordance with cancer tissue of origin, with the largest number in colon (68 motifs) and the lowest in ovary (18 motifs). The top scored motifs are typically shared between several tissues; they define sets of target genes responsible for certain functionality of cancerogenesis. Both the co-expression modules and a database of precalculated motifs are publically available and accessible for further studies. PMID- 28849564 TI - A Weighted SNP Correlation Network Method for Estimating Polygenic Risk Scores. AB - Polygenic scores are useful for examining the joint associations of genetic markers. However, because traditional methods involve summing weighted allele counts, they may fail to capture the complex nature of biology. Here we describe a network-based method, which we call weighted SNP correlation network analysis (WSCNA), and demonstrate how it could be used to generate meaningful polygenic scores. Using data on human height in a US population of non-Hispanic whites, we illustrate how this method can be used to identify SNP networks from GWAS data, create network-specific polygenic scores, examine network topology to identify hub SNPs, and gain biological insights into complex traits. In our example, we show that this method explains a larger proportion of the variance in human height than traditional polygenic score methods. We also identify hub genes and pathways that have previously been identified as influencing human height. In moving forward, this method may be useful for generating genetic susceptibility measures for other health related traits, examining genetic pleiotropy, identifying at-risk individuals, examining gene score by environmental effects, and gaining a deeper understanding of the underlying biology of complex traits. PMID- 28849566 TI - Rule Mining Techniques to Predict Prokaryotic Metabolic Pathways. AB - It is becoming more evident that computational methods are needed for the identification and the mapping of pathways in new genomes. We introduce an automatic annotation system (ARBA4Path Association Rule-Based Annotator for Pathways) that utilizes rule mining techniques to predict metabolic pathways across wide range of prokaryotes. It was demonstrated that specific combinations of protein domains (recorded in our rules) strongly determine pathways in which proteins are involved and thus provide information that let us very accurately assign pathway membership (with precision of 0.999 and recall of 0.966) to proteins of a given prokaryotic taxon. Our system can be used to enhance the quality of automatically generated annotations as well as annotating proteins with unknown function. The prediction models are represented in the form of human readable rules, and they can be used effectively to add absent pathway information to many proteins in UniProtKB/TrEMBL database. PMID- 28849567 TI - ArrayTrack: An FDA and Public Genomic Tool. AB - A robust bioinformatics capability is widely acknowledged as central to realizing the promises of toxicogenomics. Successful application of toxicogenomic approaches, such as DNA microarrays, inextricably relies on appropriate data management, the ability to extract knowledge from massive amounts of data and the availability of functional information for data interpretation. At the FDA's National Center for Toxicological Research (NCTR), we are developing a public microarray data management and analysis software, called ArrayTrack that is also used in the routine review of genomic data submitted to the FDA. ArrayTrack stores a full range of information related to DNA microarrays and clinical and nonclinical studies as well as the digested data derived from proteomics and metabonomics experiments. In addition, ArrayTrack provides a rich collection of functional information about genes, proteins, and pathways drawn from various public biological databases for facilitating data interpretation. Many data analysis and visualization tools are available with ArrayTrack for individual platform data analysis, multiple omics data integration and integrated analysis of omics data with study data. Importantly, gene expression data, functional information, and analysis methods are fully integrated so that the data analysis and interpretation process is simplified and enhanced. Using ArrayTrack, users can select an analysis method from the ArrayTrack tool box, apply the method to selected microarray data and the analysis results can be directly linked to individual gene, pathway, and Gene Ontology analysis. ArrayTrack is publicly available online ( http://www.fda.gov/nctr/science/centers/toxicoinformatics/ArrayTrack/index.htm ), and the prospective user can also request a local installation version by contacting the authors. PMID- 28849568 TI - Identification of Transcriptional Regulators of Psoriasis from RNA-Seq Experiments. AB - Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the molecular mechanisms of regulation of the disease we performed RNA sequencing (RNA-Seq) analysis of 14 pairs of skin samples collected from psoriatic patients. Subsequent pathway analysis and an extraction of transcriptional regulators governing psoriasis associated pathways was executed using a combination of MetaCore Interactome enrichment tool and cisExpress algorithm, and followed by comparison to a set of previously described psoriasis response elements. A comparative approach has allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFkB, IRF9, JUN, FOS, SRF), activity of T-cells in the psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1, etc.), hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C), and lipid metabolism (TFAP2, RARA, VDR). After merging the ChIP-seq and RNA-seq data, we conclude that the atypical expression of FOXA1 transcriptional factor is an important player in psoriasis, as it inhibits maturation of naive T cells into this Treg subpopulation (CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3-), therefore contributing to the development of psoriatic skin lesions. PMID- 28849570 TI - Semantic Data Integration and Knowledge Management to Represent Biological Network Associations. AB - The vast quantities of information generated by academic and industrial research groups are reflected in a rapidly growing body of scientific literature and exponentially expanding resources of formalized data, including experimental data, originating from a multitude of "-omics" platforms, phenotype information, and clinical data. For bioinformatics, the challenge remains to structure this information so that scientists can identify relevant information, to integrate this information as specific "knowledge bases," and to formalize this knowledge across multiple scientific domains to facilitate hypothesis generation and validation. Here we report on progress made in building a generic knowledge management environment capable of representing and mining both explicit and implicit knowledge and, thus, generating new knowledge. Risk management in drug discovery and clinical research is used as a typical example to illustrate this approach. In this chapter we introduce techniques and concepts (such as ontologies, semantic objects, typed relationships, contexts, graphs, and information layers) that are used to represent complex biomedical networks. The BioXMTM Knowledge Management Environment is used as an example to demonstrate how a domain such as oncology is represented and how this representation is utilized for research. PMID- 28849569 TI - Comprehensive Analyses of Tissue-Specific Networks with Implications to Psychiatric Diseases. AB - Recent advances in genome sequencing and "omics" technologies are opening new opportunities for improving diagnosis and treatment of human diseases. The precision medicine initiative in particular aims at developing individualized treatment options that take into account individual variability in genes and environment of each person. Systems biology approaches that group genes, transcripts and proteins into functionally meaningful networks will play crucial role in the future of personalized medicine. They will allow comparison of healthy and disease-affected tissues and organs from the same individual, as well as between healthy and disease-afflicted individuals. However, the field faces a multitude of challenges ranging from data integration to statistical and combinatorial issues in data analyses. This chapter describes computational approaches developed by us and the others to tackle challenges in tissue-specific network analyses, with the main focus on psychiatric diseases. PMID- 28849571 TI - Knowledge-Based Compact Disease Models: A Rapid Path from High-Throughput Data to Understanding Causative Mechanisms for a Complex Disease. AB - High-throughput profiling of human tissues typically yields the gene lists composed of a variety of more or less relevant molecular entities. These lists are riddle by false positive observations that often obstruct generation of mechanistic hypothesis that may explain complex phenotype. From general probabilistic considerations, the gene lists enriched by the mechanistically relevant targets can be far more useful for subsequent experimental design or data interpretation. Using Alzheimer's disease as example, the candidate gene lists were processed into different tiers of evidence consistency established by enrichment analysis across subdatasets collected within the same experiment and across different experiments and platforms. The cutoffs were established empirically through ontological and semantic enrichment; resultant shortened gene list was reexpanded by Ingenuity Pathway Assistant tool. The resulting subnetworks provided the basis for generating mechanistic hypotheses that were partially validated by mined experimental evidence. This approach differs from previous consistency-based studies in that the cutoff on the Receiver Operating Characteristic of the true-false separation process is optimized by flexible selection of the consistency building procedure. The resultant Compact Disease Models (CDM) composed of the gene list distilled by this analytic technique and its network-based representation allowed us to highlight possible role of the protein traffic vesicles in the pathogenesis of Alzheimer's. Considering the distances and complexity of protein trafficking in neurons, it is plausible to hypothesize that spontaneous protein misfolding along with a shortage of growth stimulation may provide a shortcut to neurodegeneration. Several potentially overlapping scenarios of early-stage Alzheimer pathogenesis are discussed, with an emphasis on the protective effects of Angiotensin receptor 1 (AT-1) mediated antihypertensive response on cytoskeleton remodeling, along with neuronal activation of oncogenes, luteinizing hormone signaling and insulin-related growth regulation, forming a pleiotropic model of its early stages. Compact Disease Model generation is a flexible approach for high-throughput data analysis that allows extraction of meaningful, mechanism-centered gene sets compatible with instant translation of the results into testable hypotheses. PMID- 28849572 TI - Pharmacologic Manipulation of Wnt Signaling and Cancer Stem Cells. AB - Wnt (Wingless-related integration site)-signaling orchestrates self-renewal programs in normal somatic stem cells as well as in cancer stem cells. Aberrant Wnt signaling is associated with a wide variety of malignancies and diseases. Although our understanding has increased tremendously over the past decade, therapeutic targeting of the dysregulated Wnt pathway remains a challenge. Here we review recent preclinical and clinical therapeutic approaches to target the Wnt pathway. PMID- 28849573 TI - Functional Network Disruptions in Schizophrenia. AB - It has been long recognized that schizophrenia, unlike certain other mental disorders, appears to be delocalized, i.e., difficult to attribute to a dysfunction of a few specific brain areas, and may be better understood as a disruption of brain's emergent network properties. In this chapter, we focus on topological properties of functional brain networks obtained from fMRI data, and demonstrate that some of those properties can be used as discriminative features of schizophrenia in multivariate predictive setting. While the prior work on schizophrenia networks has been primarily focused on discovering statistically significant differences in network properties, this work extends the prior art by exploring the generalization (prediction) ability of network models for schizophrenia, which is not necessarily captured by such significance tests. Moreover, we show that significant disruption of the topological and spatial structure of functional MRI networks in schizophrenia (a) cannot be explained by a disruption to area-based task-dependent responses, i.e., indeed relates to the emergent properties, (b) is global in nature, affecting most dramatically long distance correlations, and (c) can be leveraged to achieve high classification accuracy (93%) when discriminating between schizophrenic vs. control subjects based just on a single fMRI experiment using a simple auditory task. PMID- 28849574 TI - Prevalence of Internet Addiction in Medical Students: a Meta-analysis. AB - OBJECTIVE: With the development of online learning, communication, and entertainment, the Internet has become an indispensable tool for university students. Internet addiction (IA) has emerged as a health problem and the prevalence of IA varies from country to country. To date, the global prevalence of IA in medical students remains unknown. The objective of this meta-analysis was to establish precise estimates of the prevalence of IA among medical students in different countries. METHODS: The pooled prevalence of IA among medical students was determined by the random-effects model. Meta-regression and subgroup analysis were performed to identify potential factors that could contribute to heterogeneity. RESULTS: The pooled prevalence of IA among 3651 medical students is 30.1% (95% confidence interval (CI) 28.5-31.8%, Z = -20.66, df = 9, tau 2 = 0.90) with significant heterogeneity (I 2 = 98.12). Subgroup analysis shows the pooled prevalence of IA diagnosed by the Chen's Internet Addiction Scale (CIAS) (5.2, 95% CI 3.4-8.0%) is significantly lower than Young's Internet Addiction Test (YIAT) (32.2, 95% CI 20.9-45.9%) (p < 0.0001). Meta-regression analyses show that the mean age of medical students, gender proportion and the severity of IA are not significant moderators. CONCLUSIONS: In conclusion, this meta-analysis identified the pooled prevalence of IA among medical students is approximately five times than that of the general population. Age, gender, and severity of IA did not account for high heterogeneity in prevalence, but IA assessment questionnaire was a potential source of heterogeneity. Given the high prevalence of IA, medical teachers and medical school administrators should identify medical students who suffer from IA and refer them for intervention. PMID- 28849575 TI - Patients Treated with Preoperative Chemoradiation for Pancreatic Ductal Adenocarcinoma have Impaired Bone Density, a Predictor of Distant Metastasis. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm that spreads to surrounding tissue or distant sites. This study investigated distant metastases in PDAC patients with or without preoperative chemoradiation therapy (CRT), focusing on vitamin D levels and bone density. METHODS: This study included 146 patients with PDAC who underwent surgery from 2007 to 2014. Bone density was evaluated using computed tomography, and the preoperative vitamin D level was calculated by enzyme-linked immunosorbent assay (ELISA) for patients with available plasma (48 cases). RESULTS: When the patients were divided into two groups according to the change in bone density, the group with decreased bone density had a shorter distant metastasis-free survival time (DMFS) after surgery than the other group (p < 0.05). Low vitamin D was a weak predictor of DMFS, but the difference was not significant (p = 0.08), perhaps because of the sample size. Multivariate analysis indicated three significant factors associated with distant metastasis: a decrease in bone density (hazard ratio [HR], 2.17; p = 0.04), normalization of the Dupan-2 value after surgery (hazard ratio [HR], 0.39; p = 0.02), and completion of adjuvant chemotherapy (HR, 0.29; p < 0.01). Univariate analysis showed that a low vitamin D concentration (<20 pg/ml) was a risk factor (p = 0.04) for bone density change. Multivariate analysis found that preoperative CRT was the only factor associated (+/-, OR, 5.8; p = 0.04) with bone density change, suggesting that preoperative CRT significantly decreases bone density in patients with insufficient vitamin D. CONCLUSION: Patients treated with preoperative CRT tend to have impaired bone density, which is a predictor of distant metastasis. Thus, vitamin D supplementation may decrease distant metastasis. PMID- 28849576 TI - Collaborative testing for key-term definitions under representative conditions: Efficiency costs and no learning benefits. AB - Students are expected to learn key-term definitions across many different grade levels and academic disciplines. Thus, investigating ways to promote understanding of key-term definitions is of critical importance for applied purposes. A recent survey showed that learners report engaging in collaborative practice testing when learning key-term definitions, with outcomes also shedding light on the way in which learners report engaging in collaborative testing in real-world contexts (Wissman & Rawson, 2016, Memory, 24, 223-239). However, no research has directly explored the effectiveness of engaging in collaborative testing under representative conditions. Accordingly, the current research evaluates the costs (with respect to efficiency) and the benefits (with respect to learning) of collaborative testing for key-term definitions under representative conditions. In three experiments (ns = 94, 74, 95), learners individually studied key-term definitions and then completed retrieval practice, which occurred either individually or collaboratively (in dyads). Two days later, all learners completed a final individual test. Results from Experiments 1-2 showed a cost (with respect to efficiency) and no benefit (with respect to learning) of engaging in collaborative testing for key-term definitions. Experiment 3 evaluated a theoretical explanation for why collaborative benefits do not emerge under representative conditions. Collectively, outcomes indicate that collaborative testing versus individual testing is less effective and less efficient when learning key-term definitions under representative conditions. PMID- 28849577 TI - Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate. AB - Numerous studies have recently shown that vitamin K2 (VK2) has antitumor effects in a variety of tumor cells, but there are few reports demonstrating antitumor effects of VK2 in vivo. The antitumor effects of VK2 in nanoemulsions are currently not known. Therefore, we sought to characterize the antitumor potential of VK2 nanoemulsions in S180 tumor cells in the present study. Furthermore, a ligand conjugate sialic acid-cholesterol, with enhanced affinity towards the membrane receptors overexpressed in tumors, was anchored on the surface of the nanoemulsions to increase VK2 distribution to the tumor tissue. VK2 was encapsulated in oil-in-water nanoemulsions, and the physical and chemical stability of the nanoemulsions were characterized during storage at 25 degrees C. At 25 degrees C, all nanoemulsions remained physically and chemically stable with little change in particle size. An in vivo study using syngeneic mice with subcutaneously established S180 tumors demonstrated that intravenous or intragastric administration of VK2 nanoemulsions significantly suppressed the tumor growth. The VK2 nanoemulsions modified with sialic acid-cholesterol conjugate showed higher tumor growth suppression than the VK2 nanoemulsions, while neither of them exhibited signs of drug toxicity. In summary, VK2 exerted effective antitumor effects in vivo, and VK2 nanoemulsions modified with sialic acid-cholesterol conjugate enhanced the antitumor activity, suggesting that these VK2 may be promising agents for the prevention or treatment of tumor in patients. PMID- 28849578 TI - Reply to the letter by Finsterer et al. concerning the paper: "Affection of immune-cells by a C10orf2 mutation manifesting as mitochondrial myopathy and transient sensory transverse syndrome" by Galassi G. et al. PMID- 28849579 TI - Variations in Treatment Delivery for Patients with Neovascular AMD in the UK: Results from an Ophthalmology Trainee Clinical Research Network Study. AB - INTRODUCTION: The aim of this study was to determine treatment delivery patterns for patients with neovascular age-related macular degeneration (nAMD) across the UK through an ophthalmology trainee research network delivered observational study. METHODS: Data were collected via an online tool by potential research collaborators identified by the Ophthalmology Trainee Clinical Trial Network (OCTN). Collaborators were asked to comment on periprocedural practices of treatment of nAMD in their eye unit including treatment location and injectors, clinical assessment and routine observation in patients undergoing intravitreal treatment. RESULTS: Data were available from 26 units around the United Kingdom. Survey methodology refinement was approximately 3 months, and the average response time was 4.9 +/- 2.4 days. The majority of responders confirmed that treatment was undertaken as a "one-stop" service (n = 15, 58%), delivered in a clean room (n = 23, 88%). In the majority of units, doctors administered injections (n = 24, 92%), but significant treatment was also given by nurse injectors (n = 21, 81%). All collaborators reported that patients underwent visual acuity testing and optical coherence tomography imaging at all visits, but other imaging including fundus fluorescein angiography (FFA) did not take place in all cases (n = 17, 65%) and only at baseline visit. CONCLUSIONS: These results demonstrate the feasibility of conducting ophthalmology trainee led and delivered observational studies. Our results show that FFA is not routinely used in the diagnosis of nAMD in the units sampled; most injections are carried out in a clean room, and ophthalmic nurses delivering injections is a highly prevalent model of care in the UK. PMID- 28849580 TI - Diminishing-cues retrieval practice: A memory-enhancing technique that works when regular testing doesn't. AB - Retrieval practice has been shown to be a highly effective tool for enhancing memory, a fact that has led to major changes to educational practice and technology. However, when initial learning is poor, initial retrieval practice is unlikely to be successful and long-term benefits of retrieval practice are compromised or nonexistent. Here, we investigate the benefit of a scaffolded retrieval technique called diminishing-cues retrieval practice (Finley, Benjamin, Hays, Bjork, & Kornell, Journal of Memory and Language, 64, 289-298, 2011). Under learning conditions that favored a strong testing effect, diminishing cues and standard retrieval practice both enhanced memory performance relative to restudy. Critically, under learning conditions where standard retrieval practice was not helpful, diminishing cues enhanced memory performance substantially. These experiments demonstrate that diminishing-cues retrieval practice can widen the range of conditions under which testing can benefit memory, and so can serve as a model for the broader application of testing-based techniques for enhancing learning. PMID- 28849581 TI - Erratum to: Variation in caries treatment proposals among dentists in Norway: the best interest of the child. PMID- 28849582 TI - MicroRNAs: a critical regulator under mechanical force. AB - Mechanical force is a kind of mechanical stimuli which actively participates in manipulating cellular activities in numerous types of cells. Progress in molecular and genetic research has uncovered various regulatory mechanisms underlying mechanical force-induced changes in cellular activities, which include both transcriptional regulation and post-transcriptional regulation. MicroRNAs (miRNAs) are 20-25 nucleotide (nt) non-coding RNAs which serve as post transcriptional regulators of multiple physiological processes. To date, considerable research effort has been focused on the expressions and functions of miRNAs in a wide range of biological and pathological processes, including but not limited to development, proliferation, metabolism and osteogenic differentiation. In this review, major emphasis is placed on the biogenesis, expressions and functions of miRNAs in a mechanical environment. PMID- 28849583 TI - Anxious Solitude and Self-Compassion and Self-Criticism Trajectories in Early Adolescence: Attachment Security as a Moderator. AB - Youths' attachment representations with their parents were tested as moderators of the relation between peer-reported anxious solitude and self-compassion and self-criticism trajectories from fifth to seventh grades. Participants were 213 youth, 57% girls, M = 10.65 years of age. Growth curves revealed that attachment representations with both parents moderated the relation between AS and self processes such that AS youth with (a) dual secure attachments demonstrated the most adaptive self-processes, (b) one secure attachment demonstrated intermediately adaptive self-processes, and (c) dual insecure attachments demonstrated the least adaptive self-processes over time. AS youth with dual insecure attachments are of most concern because they demonstrated elevated and increasing self-criticism over time, given evidence for relations between self criticism and internalizing psychopathology. PMID- 28849584 TI - 5-Fluorouracil treatment alters the expression of intestinal transporters in rats. AB - 5-Fluorouracil (5-FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5-FU-induced intestinal damage on the expression of intestinal transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5-FU (30 mg/kg/day, p.o.) for 5 days to induce intestinal damage, and then the upper, middle and lower intestinal segments were removed. The mRNA and protein expression levels of these transporters in each segment were determined using quantitative real-time PCR and Western blotting, respectively. In the 5-FU-treated rats, the protein levels of P-gp and Bcrp in the upper segment were significantly increased to 15- and 2.6-fold of the control, respectively, while those in other segments were unaffected. Pept1 expression was increased by 5-FU in almost all segments. A remarkable increase in P-gp expression was shown, the uptake of digoxin, a P-gp substrate, in each intestinal segment was measured using a rat everted sac. As a result, the uptake of digoxin in the upper segments of 5-FU-treated rats was decreased compared with that of the control. In conclusion, 5-FU-induced intestinal damage was shown to alter the expression of these transporters, especially in the upper intestinal segment, while the characteristics of the influence varied among the transporters. The 5 FU-induced intestinal damage may affect transporter-mediated drug absorption of orally administered drugs in the clinical setting. PMID- 28849585 TI - Simultaneous determination of baicalin, baicalein, wogonoside, wogonin, scutellarin, berberine, coptisine, ginsenoside Rb1 and ginsenoside Re of Banxia xiexin decoction in rat plasma by LC-MS/MS and its application to a pharmacokinetic study. AB - A rapid and high-sensitivity liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for simultaneous determination of nine active constituents (baicalin, baicalein, wogonoside, wogonin, scutellarin, berberine, coptisine, ginsenoside Rb1 and ginsenoside Re) in rat plasma after oral administration of Banxia xiexin decoction (BXD). Biological samples were processed wtih acetone-ethyl acetate (4:1, v/v). The mobile phase consisted of methanol and water (containing 0.1% formic acid) with gradient elution at a flow rate of 0.3 mL/min. Detection was performed on a triple quadrupole mass spectrometer using positive ion and negative ESI in the multiple reaction monitoring mode. The calibration curves for all analytes had good linearity (r > 0.9933). The mean recovery of all the nine active ingredients was >75.2%, and the intra- and inter-day precisions were within 12.0%; the accuracy was between 87.4 and 110.4%. This method was successfully applied to a pharmacokinetic study after administration of BXD. The results of the pharmacokinetic study might be helpful for BXD reasonable clinical application and further studies on mechanism. PMID- 28849586 TI - Adipose-tissue regulatory T cells: Critical players in adipose-immune crosstalk. AB - Obesity and type-2 diabetes (T2D) are associated with metabolic defects and inflammatory processes in fat depots. FoxP3+ regulatory T cells (Tregs) control immune tolerance, and have an important role in controlling tissue-specific inflammation. In this mini-review we will discuss current insights into how cross talk between T cells and adipose tissue shapes the inflammatory environment in obesity-associated metabolic diseases, focusing on the role of CD4+ T cells and Tregs. We will also highlight potential opportunities for how the immunoregulatory properties of Tregs could be harnessed to control inflammation in obesity and T2D and emphasize the critical need for more research on humans to establish mechanisms that are conserved in both mice and humans. PMID- 28849587 TI - Clear Self, Better Relationships: Adolescents' Self-Concept Clarity and Relationship Quality With Parents and Peers Across 5 Years. AB - This study examined reciprocal associations between adolescents' self-concept clarity (SCC) and their relationship quality with parents and best friends in a five-wave longitudinal study from age 13 to 18 years. In all, 497 adolescents (57% boys) reported on their SCC and all informants (i.e., adolescents, both parents, and adolescents' best friends) reported on support and negative interaction. Within-person cross-lagged analyses provided systematic evidence for both parent effects and child effects, with the direction of effects being strongly dependent on the relational context. For example, higher maternal support predicted higher adolescent SCC, supporting a parent effects perspective, whereas higher SCC predicted lower paternal negative interaction, supporting a child effects perspective. Peer effects on adolescent SCC were not consistently found across adolescent and best friend reports. PMID- 28849588 TI - Pregabalin reduces opioid consumption and hyperalgesia but not pain intensity after laparoscopic donor nephrectomy. AB - BACKGROUND: Gabapentinoids are increasingly used to reduce acute postoperative pain, opioid consumption and opioid-related adverse effects. We explored the opioid-sparing, analgesic and anti-hyperalgesic effect of perioperative administered pregabalin in laparoscopic living donor nephrectomy. METHODS: In this randomized controlled trial, 80 patients were recruited and randomized to receive pregabalin 150 mg twice daily or placebo on the day of surgery and the first postoperative day as part of a multimodal analgesic regimen. Primary outcome was opioid consumption 0-48 h after surgery. Secondary outcomes were pain intensity at rest and with movement 0-48 h after surgery using the 0-10 Numeric Rating Scale and incisional hyperalgesia measured 24 h post-surgery and at hospital discharge. Further secondary outcomes were adverse effects. Persistent post-surgical pain was registered 6 weeks, 6 and 12 months after surgery. RESULTS: Pregabalin significantly reduced opioid consumption compared with placebo 0-48 h after surgery (median mg [25th, 75th percentile]); 29.0 (22.0 45.5) vs. 41.8 (25.8-63.6) (P = 0.04). Pain intensity 0-48 h after surgery calculated as area under the pain (NRS) vs. time curve was not statistically different between groups at rest (P = 0.12) or with movement (P = 0.21). Pregabalin decreased incisional hyperalgesia 24 h after surgery (median cm [25th, 75th percentile] 8.5 (1.0-18.5) vs. 15.5 (9.5-24.0) (P = 0.02). Nausea (P <= 0.01), use of antiemetics (P <= 0.01) and pain-related sleep interference (P = 0.02) were reduced with pregabalin. CONCLUSIONS: Perioperative pregabalin added to a multimodal analgesic regimen was opioid-sparing, but made no difference to pain intensity score 0-48 h after surgery. Pregabalin may reduce incisional hyperalgesia on the first day after surgery. PMID- 28849589 TI - alpha-Spinasterol: a COX inhibitor and a transient receptor potential vanilloid 1 antagonist presents an antinociceptive effect in clinically relevant models of pain in mice. AB - BACKGROUND AND PURPOSE: Postoperative pain is one of the most common manifestations of acute pain and is an important problem faced by patients after surgery. Moreover, neuronal trauma or chemotherapeutic treatment often causes neuropathic pain, which induces disabling and distressing symptoms. At present, treatments of both painful conditions are inadequate. alpha-Spinasterol, which is well characterized as a transient receptor potential vanilloid 1 antagonist, has anti-inflammatory, antioxidant and antinociceptive effects. Therefore, we investigated its antinociceptive potential on postoperative and neuropathic pain, as well as its effect on COX-1 and COX-2 activities. EXPERIMENTAL APPROACH: Nociceptive responses in a postoperative pain model (surgical incision-induced) or different neuropathic pain models (trauma or chemotherapy-induced) were investigated in mice. KEY RESULTS: Oral administration of alpha-spinasterol reduced postoperative pain, when given as a pre- (0.5 h before incision) or post treatment (0.5 h after incision), and reduced cell infiltration in the injured tissue. alpha-Spinasterol also reduced the mechanical allodynia induced by partial sciatic nerve ligation and the mechanical and cold allodynia induced by paclitaxel. Moreover, alpha-spinasterol inhibited COX-1 and COX-2 enzyme activities without altering the body temperature of animals. Importantly, alpha spinasterol did not alter spontaneous or forced locomotor activity. Furthermore, it did not cause gastric damage or liver and kidney changes, nor did it alter cell viability in the cerebral cortex and spinal cord slices of mice. CONCLUSION AND IMPLICATIONS: alpha-Spinasterol is an effective and safe COX inhibitor with antinociceptive effects in postoperative and neuropathic pain models. Therefore, it is an interesting prototype for the development of novel analgesic drugs. PMID- 28849590 TI - LRF inhibits p53 expression in colon cancer cells via modulating DAP5 activity. AB - The p53 protein plays a critical role in suppression of tumour growth; its regulation is not fully understood. Leukaemia/lymphoma-related factor (LRF) promotes tumour cell growth. This study tests a hypothesis that LRF inhibits p53 expression in colon cancer cells. In this study, human colon cancer cell lines, LIM1215 and HCT116 cells, were used. The expression of LRF and p53 in the cells was analysed by quantitative reverse transcription polymerase chain reaction and Western blotting. We observed that the expression of protease-activated receptor 2 (PAR2) was detected in both LIM1215 and HCT116 human colon cancer cells. Activation of PAR2 increased the expression of LRF and inhibited the p53 expression in the cancer cells. We also detected a complex of LRF and DAP5, one of the p53 gene transcription factors. The interaction of LRF and DAP5 resulted in the repression of p53 expression in the colon cancer cells. In conclusion, PAR2 activation increases the expression of LRF in colon cancer cells, which interacts with DAP5 to repress the p53 expression. Leukaemia/lymphoma-related factor may be a novel target in the treatment of colon cancer. PMID- 28849591 TI - The lung water cascade in heart failure. AB - In heart failure patients, we hypothesize the occurrence of the "lung water cascade," with the various markers hierarchically ranked in a well-defined time sequence: (1) early, proximal hemodynamic event with increase in pulmonary capillary wedge pressure; (2) intermediate, direct imaging sign of pulmonary edema (easily detectable at bedside by lung ultrasound as B-lines); (3) late, distal clinical symptoms and signs such as dyspnea and pulmonary crackles. Completion of the cascade (from hemodynamic to pulmonary to clinical congestion) can require minutes (as with exercise), hours or even weeks (as with impending acute heart failure). Backward rewind of the downhill cascade can be achieved with timely pulmonary decongestion therapy, such as diuretics or dialysis, restoring a relatively dry lung. Any therapeutic intervention is more likely to succeed in the early steps of the cascade, at the imaging stage of asymptomatic pulmonary congestion, rather than downstream near to the end of the cascade, when clinical instability occurred. PMID- 28849592 TI - An ultra-high field strength MR image-guided robotic needle delivery system for in-bore small animal interventions. AB - PURPOSE: The purpose of this study was to develop and validate an image-guided robotic needle delivery system for accurate and repeatable needle targeting procedures in mouse brains inside the 12 cm inner diameter gradient coil insert of a 9.4 T MR scanner. Many preclinical research techniques require the use of accurate needle deliveries to soft tissues, including brain tissue. Soft tissues are optimally visualized in MR images, which offer high-soft tissue contrast, as well as a range of unique imaging techniques, including functional, spectroscopy and thermal imaging, however, there are currently no solutions for delivering needles to small animal brains inside the bore of an ultra-high field MR scanner. This paper describes the mechatronic design, evaluation of MR compatibility, registration technique, mechanical calibration, the quantitative validation of the in-bore image-guided needle targeting accuracy and repeatability, and demonstrated the system's ability to deliver needles in situ. METHODS: Our six degree-of-freedom, MR compatible, mechatronic system was designed to fit inside the bore of a 9.4 T MR scanner and is actuated using a combination of piezoelectric and hydraulic mechanisms. The MR compatibility and targeting accuracy of the needle delivery system are evaluated to ensure that the system is precisely calibrated to perform the needle targeting procedures. A semi-automated image registration is performed to link the robot coordinates to the MR coordinate system. Soft tissue targets can be accurately localized in MR images, followed by automatic alignment of the needle trajectory to the target. Intra procedure visualization of the needle target location and the needle were confirmed through MR images after needle insertion. RESULTS: The effects of geometric distortions and signal noise were found to be below threshold that would have an impact on the accuracy of the system. The system was found to have negligible effect on the MR image signal noise and geometric distortion. The system was mechanically calibrated and the mean image-guided needle targeting and needle trajectory accuracies were quantified in an image-guided tissue mimicking phantom experiment to be 178 +/- 54 MUm and 0.27 +/- 0.65 degrees , respectively. CONCLUSIONS: An MR image-guided system for in-bore needle deliveries to soft tissue targets in small animal models has been developed. The results of the needle targeting accuracy experiments in phantoms indicate that this system has the potential to deliver needles to the smallest soft tissue structures relevant in preclinical studies, at a wide variety of needle trajectories. Future work in the form of a fully-automated needle driver with precise depth control would benefit this system in terms of its applicability to a wider range of animal models and organ targets. PMID- 28849594 TI - Impact of systemic inflammatory response syndrome and surgical Apgar score on post-operative acute kidney injury. AB - BACKGROUND: Surgical Apgar Score (SAS) is relatively weakly associated with post operative outcomes in emergency surgery, compared with elective surgery. A combination of systemic inflammatory response syndrome (SIRS) and SAS may be useful for prediction of poor outcomes after emergency surgery. METHODS: A retrospective study was conducted in patients who underwent emergency abdominal or cerebral surgery from January 2005 to December 2010. AKI was diagnosed using Acute Kidney Injury Network criteria for 2 days after surgery. Pre-operative SIRS was defined as SIRS score >= 2. Patients were divided into those with SAS >= 5 and < 5. Independent risk factors for post-operative AKI were identified. Ability to predict post-operative AKI was determined using receiver operating characteristic (ROC) curve analysis. RESULTS: Of 742 patients, 175 (24%) had post operative AKI. Pre-operative SIRS (OR 1.9, 95% CI: 1.2-2.9, P < 0.01) and SAS < 5 (OR 2.6, 95% CI: 1.7-4.1, P < 0.01) were independent risk factors for post operative AKI. Patients without SIRS and SAS < 5 had an increased risk of post operative AKI (odds ratio (OR) 3.6, 95% confidence interval (CI) 1.9-6.7, P < 0.01) and those with SIRS and SAS < 5 had increased risks of post-operative AKI (OR 5.9, 95% CI: 3.7-9.3, P < 0.01) and hospital mortality (OR 3.5, 95% CI: 1.9 6.3, P < 0.01). In ROC analysis, the c-statistic using both SIRS and SAS < 5 was 0.81 (95% CI: 0.77-0.84, P < 0.01) and higher than without use of these factors (P < 0.01). CONCLUSION: Pre-operative SIRS and SAS are independently associated with post-operative AKI. Simultaneous use of pre-operative SIRS and SAS may improve prediction of poor post-operative outcomes. PMID- 28849593 TI - Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia-induced pulmonary hypertension. AB - BACKGROUND AND PURPOSE: Sustained pulmonary vasoconstriction and excessive pulmonary vascular remodelling are two major causes of elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension. The purpose of this study was to investigate whether chloroquine induced relaxation in the pulmonary artery (PA) and attenuates hypoxia-induced pulmonary hypertension (HPH). EXPERIMENTAL APPROACH: Isometric tension was measured in rat PA rings pre constricted with phenylephrine or high K+ solution. PA pressure was measured in mouse isolated, perfused and ventilated lungs. Fura-2 fluorescence microscopy was used to measure cytosolic free Ca2+ concentration levels in PA smooth muscle cells (PASMCs). Patch-clamp experiments were performed to assess the activity of voltage-dependent Ca2+ channels (VDCCs) in PASMC. Rats exposed to hypoxia (10% O2 ) for 3 weeks were used as the model of HPH or Sugen5416/hypoxia (SuHx) for in vivo experiments. KEY RESULTS: Chloroquine attenuated agonist-induced and high K+ -induced contraction in isolated rat PA. Pretreatment with l-NAME or indomethacin and functional removal of endothelium failed to inhibit chloroquine-induced PA relaxation. In PASMC, extracellular application of chloroquine attenuated store operated Ca2+ entry and ATP-induced Ca2+ entry. Furthermore, chloroquine also inhibited whole-cell Ba2+ currents through VDCC in PASMC. In vivo experiments demonstrated that chloroquine treatment ameliorated the HPH and SuHx models. CONCLUSIONS AND IMPLICATIONS: Chloroquine is a potent pulmonary vasodilator that may directly or indirectly block VDCC, store-operated Ca2+ channels and receptor operated Ca2+ channels in PASMC. The therapeutic potential of chloroquine in pulmonary hypertension is probably due to the combination of its vasodilator, anti-proliferative and anti-autophagic effects. PMID- 28849595 TI - Assessment of left atrial appendage function by transthoracic pulsed Doppler echocardiography: Comparing against transesophageal interrogation and predicting echocardiographic risk factors for stroke. AB - AIMS: Transesophageal echocardiographic (TEE) findings of left atrial appendage (LAA) thrombus, spontaneous echo contrast (SEC), and LAA dysfunction are established risk factors of cardioembolic stroke. The semi-invasive nature of TEE limits its utility as a routine risk stratification tool. We aim to correlate TEE and transthoracic echocardiography (TTE) pulsed Doppler measurements of LAA flow velocities and use TTE measurements to predict TEE findings. METHODS AND RESULTS: We prospectively measured pulsed Doppler LAA flow velocities in 103 consecutive patients on TEE and TTE. There was a strong correlation between TEE and TTE LAA emptying velocity (LAA E) (r = .88, P < .001) and a moderate correlation between LAA filling velocities (r = .50, P < .001). TTE LAA E predicted the presence of thrombus or SEC independent of atrial fibrillation (AF). To predict the presence of thrombus or SEC, the optimal TTE LAA E cutoff was <=30 cm/s in all patients (75% sensitive, 90% specific) and <=31 cm/s in AF patients (80% sensitive, 79% specific). To predict LAA dysfunction (TEE E <= 20 cm/s), the optimal TTE LAA E cutoff was <=27 cm/s (100% sensitive, 89% specific in all patients and 100% sensitive, 74% specific in AF patients). CONCLUSIONS: TTE assessment of LAA function is feasible and correlates well with the more invasive TEE method. It predicts the presence of thrombus, SEC, and LAA dysfunction on TEE. TTE LAA assessment has incremental value in thromboembolic risk stratification and should be utilized more frequently. PMID- 28849596 TI - Opioid and hypocretin neuromodulation of ventral tegmental area neuronal subpopulations. AB - : The current view of the midbrain dopaminergic system is evolving towards a complex system of subpopulations of neurons with distinct afferent and efferent connections and, importantly, functionally different intrinsic characteristics. Recent literature on the phenotypic diversity of dopaminergic neurons has outlined that in the ventral tegmental area dopaminergic neurons are not as anatomically or electrophysiologically homogeneous as they were once thought to be. Instead, the midbrain dopaminergic system is now understood to be composed of anatomically and functionally heterogeneous dopaminergic subpopulations receiving specific afferent inputs and with different axonal projections. An additional layer of complexity is the neuromodulation of each of these dopaminergic circuits. This review will examine the distinguishing electrophysiological and neuromodulatory characteristics of the afferent and efferent connections of midbrain dopaminergic neurons. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc. PMID- 28849598 TI - Third time mitral valve replacement-lessons learned. AB - We report the management of three iatrogenic injuries involving the aortic valve, left circumflex artery, and left ventricular outflow tract, that occurred during a re-operative mitral valve replacement. PMID- 28849597 TI - Protection of bone marrow, mononuclear, and CD34+ cells by enclosing within the biochemical compound solution during and after transplantation. AB - We have chosen collagen, chitosan acetate, hyaluronic acid, and propolis as model biochemical compound solution to determine the influence of cell carrier mechanics on cell viability and functionality during and after transplantation. Suspending of bone marrow (BM), mononuclear (MN), and CD34+ cells into a biochemical compounds solution is an attractive tool to achieve to protect and ensure reproducible deliver. Hyperglycemic rats were randomly divided into 2 groups: to receive no cell treatment or approximately 1 * 105 of BM, MN, and CD34+ cells within the PBS or biochemical compound solution. These cells were infused into the hyperglycemic rats on day 10 and again on day 20. At each time point, the animals were anaesthetized with ether, and 200 MUL of blood was drawn from the tail vein. Samples were collected to determine whether BM, MN, and CD34+ cell affected glucose content and insulin production. Our results exhibit the use of biochemical compound solution method to overcome the cell transplantation problem during and after injection of these cells into rats. These findings are supported by resulting in significantly greater insulin production and more decreased glucose content than cells injected in PBS only (P < 0.05). These effects displayed the following hierarchy: hyaluronic acid > chitosan acetate > collagen > propolis solution. Our results showed that these compounds demonstrated a capacity to encapsulate the BM, MN, and CD34+ cells. It is proven by decreasing glucose content and increasing insulin secretion by pancreatic cells. The uniqueness of our study is the improvement of current transplantation efficiency. PMID- 28849599 TI - Estrogenic chemicals at body burden levels attenuate energy metabolism in 3T3-L1 adipocytes. AB - The study aimed to examine effects of environmental estrogens at body burden levels on energy metabolism in fat cells. Acclimation of T47D-KBluc cells in estrogen-deprived medium was established for high performance of estrogen responsive luciferase reporter assay. With the assay, relative estrogenic potency of four selected estrogen receptor (ER) agonists, i.e. diethylstilbestrol, beta estradiol, 4-nonylphenol and bisphenol A, were determined. Immunoblot analysis revealed that the ER agonists at both EC80 and EC100 caused rapid and transient phosphorylation of extracellular signal-regulated kinases (ERK) in an ER dependent manner. 3T3-L1 adipocytes treated with the ER agonists at EC80 for 24 hours exhibited significant downregulation in mitochondrial respiration and glycolytic function. Importantly, EC80 values of 4-nonylphenol (6.0 * 10-10 m) and bisphenol A (1.0 * 10-8 m) are in the range of human body burdens. The finding that estrogenic chemicals at body burden levels cause significant impact on fat cell energy metabolism raises an important public health issue that deserves more attention. PMID- 28849600 TI - Assessment of right ventricular systolic function in heart transplant patients: Correlation between echocardiography and cardiac magnetic resonance imaging. Investigation of the accuracy and reliability of echocardiography. AB - BACKGROUND: Right ventricular (RV) function has great impact on the survival of heart transplantation recipients; therefore, careful evaluation is of high clinical importance. However, there is no standard conventional echocardiographic parameter to assess RV systolic function. Herein, we evaluated the correlation between echocardiographic parameters of RV systolic function and ejection fraction assessed by cardiac magnetic resonance imaging (MRI RVEF) in heart transplantation recipients. METHOD AND RESULTS: Forty-three patients with at least 6-month heart transplantation history were included in this study. Each patient had conventional echocardiography and cardiac MRI evaluation, followed by endomyocardial biopsy and right heart catheterization, which were performed in six hours. Echocardiographic parameters of RV systolic function, RV fractional area change (RV FAC), tricuspid annular plane systolic excursion (TAPSE), RV myocardial performance index, and RV global longitudinal strain, were compared with MRI RVEF (P values were <0.001, <0.3, <0.9, and <0.4, respectively). RV FAC was the only parameter to strongly correlate with MRI RVEF (r=0.747, P<0.001); and RV FAC 48.5% value had 90.5% sensitivity and 90.5% specificity to predict the pathologic reference value of MRI RVEF <=50% (AUC:0.96; 95% CI, 0.908-1.013). CONCLUSION: To our knowledge, this is the first prospective study to evaluate the correlation between the echocardiographic parameters for RV systolic function and MRI RVEF in heart transplantation recipients. RV FAC is the only parameter to correlate well with MRI RVEF, and its routine use in the follow-up of heart transplantation recipients should be considered. PMID- 28849601 TI - Effect of orthodontic force on the expression of PI3K, Akt, and P70S6 K in the human periodontal ligament during orthodontic loading. AB - The mammalian target of rapamycin (mTOR) is an atypical serine/threonine protein kinases involved in the regulation of cell growth, proliferation, and differentiation through the PI3K/Akt/mTOR/P70S6 K signalling pathway. P70S6 K as a downstream molecule of mTOR is activated by phosphorylation and subsequently promotes the synthesis of ribosomal and translational proteins. In this study, we investigated the role of PI3K, Akt, and P70S6 K in human periodontal tissue remodelling during orthodontic loading. The prepared tissue specimens taken from 4 extracted premolars were processed for immunolabelling. The changes in the expression of PI3K, Akt, and P70S6 K in the periodontal tissues were detected by real-time quantitative-polymerase chain reaction and Western blot analysis. The results from real-time quantitative-polymerase chain reaction and Western blot both showed that the expression of PI3K, Akt, and P70S6 K in the experimental group began to increase at 3 days and increased significantly at 10 days, then decreased approaching the control group level at 28 days. Our findings showed that the expression of PI3K, Akt, and P70S6 K in human periodontal ligament demonstrated a variability during the orthodontic loading, which suggested that the PI3K/Akt/mTOR/P70S6 K signal pathway was involved in orthodontic tooth movement and played a role in the process of periodontium remodelling. PMID- 28849602 TI - Relationship of cardiac troponin to systolic global longitudinal strain in hypertrophic cardiomyopathy. AB - BACKGROUND: A high proportion of stable hypertrophic cardiomyopathy (HCM) patients have elevated serum cardiac troponin I (cTnI), but its clinical and echocardiographic determinants are unknown. Our objective was to determine the prevalence and clinical predictors of positive troponin (cTnI+) in a well-defined population of HCM patients using a highly sensitive assay. METHODS: We retrospectively interrogated medical records of 167 stable HCM patients from 1/2011 to 3/2014. cTnI >0.04 ng/mL was considered positive. RESULTS: Thirty-four percent were troponin-positive (median cTnI was 0.1 [0.07, 0.2] ng/dL). cTnI as a continuous variable correlated positively with maximal left ventricular wall thickness (LVT), maximal interventricular septal thickness, and global longitudinal strain (GLS) (P<.001). Unadjusted OR (95% CI) for positive troponin was 0.5 (0.3-0.9, P=.05) for obstructive HCM, 3.2 (1.7-5.9, P<.0001) for increased LVT, 0.3 (0.2-0.6, P<.0001) for -5% increase in GLS, 0.2 (0.04-0.9, P=.04) for moderate-to-severe mitral regurgitation, and 1.9 (0.9-3.9, P=.06) for implantable cardioverter defibrillator history. After adjusting for these variables, only maximum LVT (OR 2.5 [95% CI: 1.1-5.7, P=.02]) and GLS (OR 0.3 [95% CI: 0.2-0.6, P=.001]) were independent predictors. The percentage of patients with a positive cTnI increased from 19% to 24% and 57% across tertiles of LVT (P=.003) and decreased from 54% to 33% and 14% across tertiles of GLS (P<.0001). CONCLUSION: In this cohort of HCM patients, the association of reduced GLS and positive troponin was independent of LVT. Further studies are warranted to evaluate whether their combination adds prognostic value in identifying high risk patients to define effective and early intervention strategies. PMID- 28849603 TI - Copper-Catalyzed Borylacylation of Activated Alkenes with Acid Chlorides. AB - A method for the copper-catalyzed borylacylation of activated alkenes is presented. The reaction involves borylcupration of the alkene, followed by capture of the generated alkyl-copper intermediate with an acid chloride. The reactions operated with low catalyst loading and generally occurre within 15 min at room temperature for a range of activated alkenes. In the case of vinyl arenes, enantioselective borylacylation was possible. PMID- 28849604 TI - Regulation of tapetum-specific A9 promoter by transcription factors AtMYB80, AtMYB1 and AtMYB4 in Arabidopsis thaliana and Nicotiana tabacum. AB - Tapetum-specific promoters have been successfully used for developing transgenic based pollination control systems. Although several tapetum-specific promoters have been identified, in-depth studies on regulation of such promoters are scarce. The present study analyzes the regulation of the A9 promoter, one of the first tapetum-specific promoter identified in Arabidopsis thaliana. Transcription factors (TFs) AtMYB80, AtMYB1 (positive regulators) identified by in silico analysis were found to upregulate A9 promoter activity following the over expression of the TFs in transient and stable (transgenic) expression assays in both A. thaliana and tobacco. Furthermore, mutations of binding sites of these TFs in the A9 promoter led to loss of its activity. The role of a negative regulator AtMYB4 was also studied by analyzing the activity of A9 promoter following transient expression of RNAi against the TF and by mutating binding sites for AtMYB4 in the A9 promoter. While no changes were observed in case of A. thaliana, the A9 promoter was activated in the roots of transgenic tobacco plants, highlighting the role of these cis-elements in keeping the A9 promoter repressed in the roots of tobacco. PMID- 28849605 TI - Supportive interventions for enhancing dietary intake in malnourished or nutritionally at-risk adults. PMID- 28849606 TI - Heart failure oral therapies at discharge are associated with better outcome in acute heart failure: a propensity-score matched study. AB - AIMS: Heart failure oral therapies (HFOTs), including beta-blockers (BB), renin angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists, administered before hospital discharge after acute heart failure (AHF) might improve outcome. However, concerns have been raised because early administration of HFOTs may worsen patient's condition. We hypothesized that HFOTs at hospital discharge might be associated with better post-discharge survival. METHODS AND RESULTS: The study population was composed of 19 980 AHF patients from the GREAT registry. The primary and secondary outcomes were 90-day and 1-year all-cause mortality, respectively. Survival was estimated with univariate and covariate adjusted Cox proportional hazards regression models for the whole population and after propensity-score matching. HFOTs at discharge were consistently associated with no excess mortality in the unadjusted and adjusted analyses of the whole and matched cohorts. In the matched cohort, BB and RASi at discharge were associated with lower 90-day mortality risks compared to the respective untreated groups [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.69; and HR 0.53, 95% CI 0.42-0.66, respectively]. The favourable associations of BB and RASi at discharge with 90-day mortality were present in many subgroups including patients with reduced or preserved left ventricular ejection fraction and persisted up to 1 year after discharge. The combination of RASi and BB was associated with an even lower risk of death than RASi or BB alone. CONCLUSIONS: Administration of HFOTs at hospital discharge is associated with better survival of AHF patients. PMID- 28849607 TI - Prevalence and long-term prognostic impact of malignancy in patients with Takotsubo syndrome. PMID- 28849608 TI - Barriers to families' regaining control in ICU: Disconnectedness. AB - BACKGROUND: The nature of interactions between health care professionals and families may have a significant impact on families' experience and outcomes of critical illness. The value of encouraging positive relationships with families is well documented; however, it is argued that the lack of theoretical frameworks to guide practice in this area may be a barrier to improving patient- and family centred care. AIMS: The study on which this paper is based aimed to understand families' experiences of their interactions when a relative is admitted unexpectedly to an Australian intensive care unit and to generate a substantive theory that represents families' interactions that can be used to guide critical care nursing practice when caring for patients' families in this context. DESIGN AND METHODS: A grounded theory methodology was adopted for the study. Data were collected between 2009 and 2013 using in-depth interviews with 25 family members of 21 critically ill patients admitted to a metropolitan, tertiary-level intensive care unit (ICU) in Australia. FINDINGS: A core category of regaining control has been generated from our study. This paper focuses on Disconnectedness, which leads to increased emotional vulnerability and is also a barrier to families' regaining control. Families feel disconnected when staff emotionally and physically disengage from them, when staff interact insensitively and in a manner that offers families limited hope. CONCLUSION: Our findings offer an in-depth understanding of staff engagement with families and its impact on the families' ability to regain control. Although some themes have been previously identified in the literature in isolation, the interrelationships of the categories within a theoretical framework to represent family resilience in the context of an ICU situated in the Australian health care system are a novel finding. RELEVANCE TO CLINICAL PRACTICE: The findings can be used to support patient- and family-centred care interventions in the ICU. PMID- 28849610 TI - Re: Healthcare utilisation, induced labour and caesarean section in the pregnancy after stillbirth: a prospective study. PMID- 28849609 TI - The prognostic value of highly sensitive cardiac troponin assays for adverse events in men and women with stable heart failure and a preserved vs. reduced ejection fraction. AB - AIMS: Circulating biomarkers are important in the diagnosis, risk stratification and management of patients with heart failure (HF). Given the current lack of biomarkers in HF with preserved ejection fraction (HFpEF), we aimed to investigate the prognostic performance of the newly developed high-sensitivity (hs) assays for cardiac troponin I (hsTnI) compared with troponin T (hsTnT) for adverse events in HFpEF vs. HF with reduced ejection fraction (HFrEF). Findings in these two HF subgroups were also compared with those in the recently defined HF with mid-range ejection fraction (HFmrEF) subgroup. METHODS AND RESULTS: Both hsTnI and hsTnT were measured in 1096 patients with HFrEF [left ventricular ejection fraction (LVEF) <50%; n = 853] or HFpEF (LVEF >=50%; n = 243) enrolled in the Singapore Heart Failure Outcomes and Phenotypes (SHOP) study. Both troponin assays were more strongly associated with the composite endpoint (all cause mortality or first rehospitalization for HF) in HFpEF than in HFrEF. The hsTnT assay provided the greatest additional prognostic value in HFpEF in comparison with hsTnI and NT-proBNP. TnI was more strongly associated with composite events in men with HFpEF [hazard ratio (HR) 3.33, 95% confidence interval (CI) 1.82-6.09; P < 0.001 per standard deviation (SD) increase in log transformed hsTnI] than in women with HFpEF (HR 1.35, 95% CI 0.94-1.93; P = 0.10 per SD increase in log-transformed hsTnI). CONCLUSIONS: There is a potential role for the prognostic use of high-sensitivity troponin assays, particularly hsTnT, in men and women with HFpEF. The predictive association of hsTnI with outcome appears strongest in men with HFpEF. PMID- 28849611 TI - Enantioselective Light Harvesting with Perylenediimide Guests on Self-Assembled Chiral Naphthalenediimide Nanofibers. AB - Self-assembling molecular systems often display amplified chirality compared to the monomeric state, which makes the molecular recognition more sensitive to chiral analytes. Herein, we report the almost absolute enantioselective recognition of a chiral perylenediimide (PDI) molecule by chiral supramolecular nanofibers of a bichromophoric naphthalenediimide (NDI) derivative. The chiral recognition was evaluated through the Forster resonance energy transfer (FRET) from the NDI-based host nanofibers to the guest PDI molecules. The excitation energy was successfully transferred to the guest molecule through efficient energy migration along the host nanofiber, thus demonstrating the light harvesting capability of these hybrid systems. Furthermore, circularly polarized luminescence (CPL) was enantioselectively sensitized by the guest molecule as the wavelength band and sign of the CPL signal were switched in response to the chiral guest molecule. PMID- 28849612 TI - Does stress influence sleep patterns, food intake, weight gain, abdominal obesity and weight loss interventions and vice versa? AB - Decades of research have reported only weak associations between the intakes of specific foods or drinks and weight gain and obesity. Randomized controlled dietary intervention trials have only shown very modest effects of changes in nutrient intake and diet composition on body weight in obese subjects. This review summarizes the scientific evidence on the role mental stress (either in or not in association with impaired sleep) may play in poor sleep, enhanced appetite, cravings and decreased motivation for physical activity. All these factors contribute to weight gain and obesity, possibly via decreasing the efficacy of weight loss interventions. We also review evidence for the role that lifestyle and stress management may play in achieving weight loss in stress vulnerable individuals with overweight. PMID- 28849614 TI - Model for the role of auxin polar transport in patterning of the leaf adaxial abaxial axis. AB - Leaf adaxial-abaxial polarity refers to the two leaf faces, which have different types of cells performing distinct biological functions. In 1951, Ian Sussex reported that when an incipient leaf primordium was surgically isolated by an incision across the vegetative shoot apical meristem (SAM), a radialized structure without an adaxial domain would form. This led to the proposal that a signal, now called the Sussex signal, is transported from the SAM to emerging primordia to direct leaf adaxial-abaxial patterning. It was recently proposed that instead of the Sussex signal, polar transport of the plant hormone auxin is critical in leaf polarity formation. However, how auxin polar transport functions in the process is unknown. Through live imaging, we established a profile of auxin polar transport in and around young leaf primordia. Here we show that auxin polar transport in lateral regions of an incipient primordium forms auxin convergence points. We demonstrated that blocking auxin polar transport in the lateral regions of the incipient primordium by incisions abolished the auxin convergence points and caused abaxialized leaves to form. The lateral incisions also blocked the formation of leaf middle domain and margins and disrupted expression of the middle domain/margin-associated marker gene WUSCHEL-RELATED HOMEOBOX 1 (SlWOX1). Based on these results we propose that the auxin convergence points are required for the formation of leaf middle domain and margins, and the functional middle domain and margins ensure leaf adaxial-abaxial polarity. How middle domain and margins function in the process is discussed. PMID- 28849613 TI - The high-quality genome of Brassica napus cultivar 'ZS11' reveals the introgression history in semi-winter morphotype. AB - Allotetraploid oilseed rape (Brassica napus L.) is an agriculturally important crop. Cultivation and breeding of B. napus by humans has resulted in numerous genetically diverse morphotypes with optimized agronomic traits and ecophysiological adaptation. To further understand the genetic basis of diversification and adaptation, we report a draft genome of an Asian semi-winter oilseed rape cultivar 'ZS11' and its comprehensive genomic comparison with the genomes of the winter-type cultivar 'Darmor-bzh' as well as two progenitors. The integrated BAC-to-BAC and whole-genome shotgun sequencing strategies were effective in the assembly of repetitive regions (especially young long terminal repeats) and resulted in a high-quality genome assembly of B. napus 'ZS11'. Within a short evolutionary period (~6700 years ago), semi-winter-type 'ZS11' and the winter-type 'Darmor-bzh' maintained highly genomic collinearity. Even so, certain genetic differences were also detected in two morphotypes. Relative to 'Darmor-bzh', both two subgenomes of 'ZS11' are closely related to its progenitors, and the 'ZS11' genome harbored several specific segmental homoeologous exchanges (HEs). Furthermore, the semi-winter-type 'ZS11' underwent potential genomic introgressions with B. rapa (Ar ). Some of these genetic differences were associated with key agronomic traits. A key gene of A03.FLC3 regulating vernalization-responsive flowering time in 'ZS11' was first experienced HE, and then underwent genomic introgression event with Ar , which potentially has led to genetic differences in controlling vernalization in the semi-winter types. Our observations improved our understanding of the genetic diversity of different B. napus morphotypes and the cultivation history of semi winter oilseed rape in Asia. PMID- 28849615 TI - Sacubitril/valsartan in heart failure with reduced ejection fraction: cost and effectiveness in the Italian context. PMID- 28849616 TI - Reversible S0 /MgSx Redox Chemistry in a MgTFSI2 /MgCl2 /DME Electrolyte for Rechargeable Mg/S Batteries. AB - The redox chemistry of magnesium and its application in rechargeable Mg batteries has received increasing attention owing to the unique benefits of Mg metal electrodes, namely high reversibility without dendrite formation, low reduction potentials, and high specific capacities. The Mg/S couple is of particular interest owing to its high energy density and low cost. Previous reports have confirmed the feasibility of a rechargeable Mg/S battery; however, only limited cycling stability was achieved, and the complicated procedure for the preparation of the electrolytes has significantly compromised the benefits of Mg/S chemistry and hindered the development of Mg/S batteries. Herein, we report the development of the first rechargeable Mg/S battery with a MgTFSI2 /MgCl2 /DME electrolyte (DME=1,2-dimethoxyethane, TFSI=bis(trifluoromethanesulfonyl)imide) and realize the best cycling stability among all reported Mg/S batteries by suppressing polysulfide dissolution. Mechanistic studies show that the battery works via S0 /MgSx redox processes and that the large voltage hysteresis is mainly due to the Mg anode overpotential. PMID- 28849617 TI - Is cardiac wasting accompanied by skeletal muscle loss in breast cancer patients receiving anticancer treatment? PMID- 28849618 TI - Aromatic-Turmerone Attenuates LPS-Induced Neuroinflammation and Consequent Memory Impairment by Targeting TLR4-Dependent Signaling Pathway. AB - SCOPE: Curcuma longa (turmeric) is a folk medicine in South and Southeast Asia, which has been widely used to alleviate chronic inflammation. Aromatic-turmerone is one of the main components abundant in turmeric essential oil. However, little information is available from controlled studies regarding its biological activities and underlying molecular mechanisms against chronic inflammation in the brain. In the current study, we employed a classical LPS model to study the effect and mechanism of aromatic-turmerone on neuroinflammation. METHODS AND RESULTS: The effects of aromatic-turmerone were studied in LPS-treated mice and BV2 cells. The cognitive function assays, protein analyses, and histological examination were performed. Oral administration of aromatic-turmerone could reverse LPS-induced memory disturbance and normalize glucose intake and metabolism in the brains of mice. Moreover, aromatic-turmerone significantly limited brain damage, through inhibiting the activation of microglia and generation of inflammatory cytokines. Further study in vitro revealed that aromatic-turmerone targeted Toll-like receptor 4 mediated downstream signaling, and lowered the release of inflammatory mediators. CONCLUSION: These observations indicate that aromatic-turmerone is effective in preventing brain damage caused by neuroinflammation and may be useful in the treatment of neuronal inflammatory diseases. PMID- 28849619 TI - Stated conclusion about industry funding is opposite to what the paper's data show: letter regarding 'Selective outcome reporting in obesity clinical trials: a cross-sectional review'. PMID- 28849622 TI - Perception of nurse prescribing among nurses and psychiatrists in a developing country: A cross-sectional survey. AB - Nurse prescribing has the potential to improve patients' access to, and experiences of, treatment. The aim of the present study was to examine nurse and psychiatrist attitudes about this extended role in a developing country. We conducted a cross-sectional survey using a previously-used, 65-item, seven subscale measure of attitudes to nurse prescribing in mental health. We achieved a 79% response rate. The majority of participants had trained in developing countries where nurse prescribing has yet to be implemented. Across five subscales (general beliefs, impact, uses, training, and supervision), both groups reported positive attitudes about nurse prescribing. Both groups scored the training subscale particularly highly. Compared with psychiatrists, nurses were more confident about the range of clinical settings where nurse prescribing could be applied (e.g. acute inpatient and substance use). Although both groups had less favourable attitudes on the two subscales relating to clinical and legal responsibility, compared to nurses, psychiatrists were more undesirable. Although, overall, clinician attitudes do not seem to represent a barrier towards the potential implementation of nurse prescribing in the study setting, clarity about clinical and legal responsibility needs to be addressed. PMID- 28849621 TI - Histological, morphometric, protein and gene expression analyses of rat retinas with ischaemia-reperfusion injury model treated with sildenafil citrate. AB - The aim of this study was to better understand the role of apoptosis in a retinal ischaemia-reperfusion injury model and to determine whether sildenafil citrate treatment can prevent retinal cell apoptosis. Thirty-six rats were divided into a control group (n = 6) and two experimentally induced ischaemia-reperfusion groups (7 and 21 days; n = 15 per group). The induced ischaemia-reperfusion groups were treated with sildenafil for 7 and 21 days (n = 10 per group), and 10 animals were treated with a placebo for the same period (n = 5 per group). Paracentesis of the anterior chamber was performed with a 30-G needle attached to a saline solution (0.9%) bag positioned at a height of 150 cm above the eye for 60 min. Intraocular pressure was measured by rebound tonometer (TonoVet(r) ). The eyes were analysed by histology and morphometry, and by immunohistochemistry and qRT-PCR for expression of Caspase-7, Caspase-6, Caspase-9, Tnf-r2, Fas-l, Bcl-2 and Bax. Sildenafil-treated animals showed lower levels of histopathological changes (inflammatory, cellular and tissue) than their placebo-treated counterparts at both 7 and 21 days. The retinal ganglion cell layer (RGC) was preserved in the sildenafil groups (SG), with a cell count closer to control than in the placebo groups (PG). Caspase-7 expression was significantly higher in both treated groups at 7 days compared to controls. Gene expression levels in both treatment groups differed from the controls, but in SG Bax and Caspase-6 expression levels were similar to control animals. These results suggest that the main mechanism of retinal cell death in this model is apoptosis, as there is an increase in pro apoptotic factors and decrease in the anti-apoptotic ones. Also, sildenafil seems to protect the retinal ganglion cell layer from apoptosis. Cell survival was evident in the histological and morphometric analyses, and sildenafil treatment had a protective effect in the apoptosis pathways, with gene expression levels in SG similar to the controls. PMID- 28849623 TI - Phase III randomized trial comparing intravenous to oral iron in patients with cancer-related iron deficiency anemia not on erythropoiesis stimulating agents. AB - AIM: We aimed to find the optimal route of iron supplementation in patients with malignancy and iron deficiency (true or functional) anemia not receiving erythropoiesis stimulating agents (ESA). METHODS: Adult patients with malignancy requiring chemotherapy, hemoglobin (Hb) <12 g/dL and serum ferritin <100 mcg/mL, transferrin saturation <20% or hypochromic red blood cells >10% were randomized to intravenous (IV) iron sucrose or oral ferrous sulfate. The primary endpoint was change in Hb from baseline to 6 weeks. Secondary endpoints included blood transfusion, quality of life (QoL), toxicity, response and overall survival. RESULTS: A total of 192 patients were enrolled over 5 years: 98 on IV arm and 94 on oral arm. Median age was 51 years; over 95% patients had solid tumors. The mean absolute increase in Hb at 6 weeks was 0.11 g/dL (standard deviation [SD]: 1.48) in IV arm and -0.16 g/dL (SD: 1.36) in oral arm, P = 0.23. Twenty-three percent patients on IV iron and 18% patients on oral iron had a rise in Hb of >=1 g/dL at 6 weeks, P = 0.45. Thirteen patients (13.3%) on the IV iron arm and 14 patients (14.9%) on the oral arm required blood transfusion, P = 1.0. Gastrointestinal toxicity (any grade) developed in 41% patients on IV iron and 44% patients on oral iron, P = 1.0. 5 patients on IV iron and none on oral iron had hypersensitivity, P = 0.06. QoL was not significantly different between the two arms. CONCLUSION: IV iron was not superior to oral iron in patients with malignancy on chemotherapy and iron deficiency anemia. PMID- 28849624 TI - Case of Hashimoto's encephalopathy showing atypical clinical course with magnetic resonance imaging abnormalities. PMID- 28849625 TI - Neuroleptic malignant syndrome associated with only one dose of metoclopramide in an older adult. PMID- 28849626 TI - Case of massive hematemesis by secondary aortic duodenal fistula 8 years after abdominal aortic aneurysm repair. PMID- 28849627 TI - Indications, appropriateness and drug interactions of proton pump inhibitors prescribed at hospital discharge in older medical patients. PMID- 28849628 TI - Staged versus index procedure complete revascularization in ST-elevation myocardial infarction: A meta-analysis. AB - BACKGROUND: Complete revascularization of patients with ST-elevation myocardial infarction and multivessel coronary artery disease reduces adverse events compared to infarct-related artery only revascularization. Whether complete revascularization should be done as multivessel intervention during index procedure or as a staged procedure remains controversial. METHOD: We performed a meta-analysis of randomized controlled trials comparing outcomes of multivessel intervention in patients with ST-elevation myocardial infarction and multivessel coronary artery disease as staged procedure versus at the time of index procedure. Composite of death or myocardial infarction was the primary outcome. Mantel-Haenszel risk ratios were calculated using random effect model. RESULTS: Six randomized studies with a total of 1126 patients met our selection criteria. At a mean follow-up of 13 months, composite of myocardial infarction or death (7.2% vs 11.7%, RR: 1.66, 95%CI: 1.09-2.52, P = 0.02), all cause mortality (RR: 2.55, 95%CI: 1.42-4.58, P < 0.01), cardiovascular mortality (RR: 2.8, 95%CI: 1.33 5.86, P = 0.01), and short-term (<30 days) mortality (RR: 3.54, 95%CI: 1.51-8.29, P < 0.01) occurred less often in staged versus index procedure multivessel revascularization. There was no difference in major adverse cardiac events (RR: 1.14, 95%CI: 0.88-1.49, P = 0.33), repeat myocardial infarction (RR: 1.14, 95%CI: 0.68-1.92, P = 0.61), and repeat revascularization (RR: 0.92, 95%CI: 0.66-1.28, P = 0.62). CONCLUSION: In patients with ST-elevation myocardial infarction and multivessel coronary artery disease, a strategy of complete revascularization as a staged procedure compared to index procedure revascularization results in reduced mortality without an increase in repeat myocardial infarction or need for repeat revascularization. PMID- 28849630 TI - Sarcopenia is negatively associated with long-term outcomes in locally advanced rectal cancer. AB - BACKGROUND: The association of sarcopenia and visceral obesity to treatment outcome is not clear for locally advanced rectal cancer. This study evaluates the influence of skeletal muscle and visceral fat on short-term and long-term outcomes in locally advanced rectal cancer patients treated with neoadjuvant chemoradiation therapy followed by curative resection. METHODS: A total of 188 patients with locally advanced cancer were included between January 2009 and December 2013. Neoadjuvant chemoradiotherapy was followed by curative resection. Sarcopenia and visceral obesity were identified in initial staging CT by measuring the muscle and visceral fat area at the third lumbar vertebra level. RESULTS: Among the 188 included patients, 74 (39.4%) patients were sarcopenic and 97 (51.6%) patients were viscerally obese. Sarcopenia and high levels of preoperative carcinoembryonic antigen were significant prognostic factors for overall survival (P = 0.013, 0.014, respectively) in the Cox regression multivariate analysis. Visceral obesity was not associated with overall survival; however, it did tend to shorten disease-free survival (P = 0.079). CONCLUSIONS: Sarcopenia is negatively associated with overall survival in locally advanced rectal cancer patients who underwent neoadjuvant chemoradiation therapy and curative resection. Visceral obesity tended to shorten disease-free survival. Future studies should be directed to optimize patient conditions according to body composition status. PMID- 28849629 TI - Antialbuminuric effect of eplerenone in comparison to thiazide diuretics in patients with hypertension. AB - This study investigated the effects and safety of eplerenone or thiazide diuretics in patients with hypertension and albuminuria (pretreatment urinary albumin/creatinine ratio >=10 mg/gCr) treated with an angiotensin II receptor blocker. The primary end point was the mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks. An efficacy analysis was performed in 195 patients (98 in the eplerenone group and 97 in the thiazide group). Systolic and diastolic blood pressures at 48 weeks were similar in the two groups. The mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks was similar in the two groups (P=.804). In the safety analysis, the withdrawal rates for adverse events were similar in both groups. The antialbuminuric effects and safety of eplerenone therapy were similar to those of thiazide diuretics when combined with an angiotensin II receptor blocker in patients with hypertension and albuminuria. PMID- 28849632 TI - Comparison of 99mTc-UBI 29-41, 99mTc-Ciprofloxacin, 99mTc-Ciprofloxacin dithiocarbamate and 111In-biotin for targeting experimental Staphylococcus aureus and Escherichia coli foreign-body infections: an ex-vivo study. AB - BACKGROUNG: Diagnosis of implant-associated infection is challenging. Several radiopharmaceuticals have been described but direct comparisons are limited. Here we compared in vitro and in an animal model 99mTc-UBI, 99mTc-Ciprofloxacin, 99mTcN-CiproCS2 and 111In-DTPA-biotin for targeting E. coli (ATCC 25922) and S. aureus (ATCC 43335). METHODS: Stability controls were performed with the labelled radiopharmaceuticals during 6 h in saline and serum. The in vitro binding to viable or killed bacteria was evaluated at 37 degrees C and 4 degrees C. For in vivo studies, Teflon cages were subcutaneously implanted in mice, followed by percutaneous infection. Biodistribution of i.v. injected radiolabelled radiopharmaceuticals were evaluated during 24 h in cages and dissected tissues. RESULTS: Labelling efficiency of all radiopharmaceuticals ranged between 94% and 98%, with high stability both in saline and in human serum. In vitro binding assays displayed a rapid but poor bacterial binding for all tested agents. Similar binding kinetic occurred also with heat-killed and ethanol-killed bacteria. In the tissue cage model, infection was detected at different time points: 99mTc-UBI and 99mTcN-CiproCS2 showed higher infected cage/sterile cage ratio at 24 h for both E. coli and S. aureus; 99mTc-Ciprofloxacin at 24 h for both E. coli and at 4 h for S. aureus; 111In-DTPA-biotin accumulates faster in both E. coli and S. aureus infected cages. CONCLUSIONS: 99mTc-UBI, 99mTcN CiproCS2 showed poor in vitro binding but good in vivo binding to E. coli only. 111In-DTPA-biotin showed poor in vitro binding but good in vivo binding to S. aureus and poor to E. coli. 99mTc-Ciprofloxacin showed poor in vitro binding but good in vivo binding to all tested bacteria. The mechanism of accumulation in infected sites remains to be elucidated. PMID- 28849631 TI - Label-free reflectance hyperspectral imaging for tumor margin assessment: a pilot study on surgical specimens of cancer patients. AB - A label-free, hyperspectral imaging (HSI) approach has been proposed for tumor margin assessment. HSI data, i.e., hypercube (x,y,lambda), consist of a series of high-resolution images of the same field of view that are acquired at different wavelengths. Every pixel on an HSI image has an optical spectrum. In this pilot clinical study, a pipeline of a machine-learning-based quantification method for HSI data was implemented and evaluated in patient specimens. Spectral features from HSI data were used for the classification of cancer and normal tissue. Surgical tissue specimens were collected from 16 human patients who underwent head and neck (H&N) cancer surgery. HSI, autofluorescence images, and fluorescence images with 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D glucose (2-NBDG) and proflavine were acquired from each specimen. Digitized histologic slides were examined by an H&N pathologist. The HSI and classification method were able to distinguish between cancer and normal tissue from the oral cavity with an average accuracy of 90%+/-8%, sensitivity of 89%+/-9%, and specificity of 91%+/-6%. For tissue specimens from the thyroid, the method achieved an average accuracy of 94%+/-6%, sensitivity of 94%+/-6%, and specificity of 95%+/-6%. HSI outperformed autofluorescence imaging or fluorescence imaging with vital dye (2-NBDG or proflavine). This study demonstrated the feasibility of label-free, HSI for tumor margin assessment in surgical tissue specimens of H&N cancer patients. Further development of the HSI technology is warranted for its application in image-guided surgery. PMID- 28849633 TI - Clinical utility and research frontiers of neuroimaging in movement disorders. AB - Neuroimaging in Parkinson's disease (PD) and other primary Parkinsonian disorders has been increasingly used in the routine clinical work in the last years. The paradigm has changed from an "exclusionary" use, i.e., to rule out causes of secondary Parkinsonism, to an "inclusionary" one, i.e., finding image and network characteristics allowing to identify a specific disease. This is allowed by analyses spanning from the commonly used visual analysis to the most sophisticated postprocessing leading to the identification of covariance patterns both in morphological and functional neuroimaging. However, paralleling the advancement in covariance and connectivity analyses, the issues of standardization and harmonization of data acquisition, and image reconstruction and postprocessing among centers are emerging in the scientific community. Also, the building of scientific evidence still suffers from the lack of large, formal studies and relies on relatively small cohort studies from one or few centers. Joint actions to face these issues are now ongoing in Europe, supported by specific programs, such as the Joint Programming on Neurodegenerative Diseases (JPND). In the present review, some of the most recent and relevant achievements in the field of diffusion tensor magnetic resonance imaging (MRI), functional MRI, fludeoxyglucose-positron-emission tomography, dopamine transporter single photon emission computed tomography and non-dopaminergic imaging in PD and primary Parkinsonisms are reported. PMID- 28849634 TI - Simultaneous bilateral anterior superior iliac spine avulsion fracture: a challenge to rehabilitation. PMID- 28849635 TI - Reaction of a Co(III)-Peroxo Complex and NO: Formation of a Putative Peroxynitrite Intermediate. AB - A Co(II) complex, [Co(L)2]Cl2, 1 of the ligand L (L = bis(2-ethyl-4 methylimidazol-5-yl)methane) upon reaction with H2O2 in methanol solution at -40 degrees C resulted in the formation of the corresponding Co(III)-peroxo complex [Co(L)2(O2)]+ (2). The addition of NO gas to the freshly generated solution of the complex 2 led to the formation of the Co(II)-nitrato complex 3 through the putative formation of a Co(II)-peroxynitrite intermediate, 2a. The intermediate 2a was found to mediate the nitration of the externally added phenol resembling the nitration of tyrosine in biological systems. PMID- 28849636 TI - Group 4 Half-Sandwich Tris(trimethylsilylmethyl) Complexes: Thermal Decomposition and Reactivity with N,N-Dimethylamine-Borane. AB - The thermal decomposition of group 4 trimethylsilylmethyl derivatives [M(eta5 C5Me5)(CH2SiMe3)3] (M = Ti (1), Zr (2), Hf (3)) in solution and their reactivity with N,N-dimethylamine-borane were investigated. Heating of hydrocarbon solutions of compounds 2 and 3 at 130-200 degrees C results in the elimination of SiMe4 and the clean formation of the singular alkylidene-alkylidyne zirconium and hafnium compounds [{M(eta5-C5Me5)}3{(MU-CH)3SiMe}(MU3-CSiMe3)] (M = Zr (4), Hf (5)). The reaction of 2 and 3 with NHMe2BH3 (>=1 equiv) at room temperature affords the dialkyl(dimethylamidoborane) complexes [M(eta5 C5Me5)(CH2SiMe3)2(NMe2BH3)] (M = Zr (6), Hf (7)). Compounds 6 and 7 are unstable in solution and decompose with formation of the alkyl(dimethylamino)borane [B(CH2SiMe3)H(NMe2)] (8), SiMe4, and other minor byproducts, including the tetranuclear zirconium(III) octahydride complex [{Zr(eta5-C5Me5)}4(MU-H)8] (9) in the decomposition of 6. Addition of NHMe2BH3 to the titanium tris(trimethylsilylmethyl) derivative 1 gives the trinuclear mixed valence Ti(II)/Ti(III) tetrahydride complex [{Ti(eta5-C5Me5)(MU-H)}3(MU3-H)(MU3-NMe2BH2)] (10) at 45-65 degrees C. While the complete conversion of 1 under argon atmosphere requires excess NHMe2BH3 (up to 15 equiv), complex 10 is readily prepared with 3 equiv of NHMe2BH3 under a hydrogen atmosphere indicating that the formation of 10 involves hydrogenolysis of 1 in the presence of (NMe2BH2)2. In absence of amine-borane, the reaction of 1 with H2 leads to the tetranuclear titanium(III) octahydride [{Ti(eta5-C5Me5)}4(MU-H)8] (11), which upon addition of NHMe2BH3 and subsequent heating at 65 degrees C affords complex 10. The X-ray crystal structures of 2, 4, 5, 10, and 11 were determined. PMID- 28849637 TI - Unveiling the Role of CeO2 Atomic Layer Deposition Coatings on LiMn2O4 Cathode Materials: An Experimental and Theoretical Study. AB - An atomic layer deposition (ALD) coating on active materials of a lithium ion battery is a more effective strategy for improving battery performance than other coating technologies. However, substantial uncertainty still remains about the underlying physics and role of the ALD coating in improving battery performance. Although improvement in the stability and capacity of CeO2 thin film coated particles for batteries has been reported, a detailed and accurate description of the mechanism has not been provided. We have developed a multiphysics-based model that takes into consideration stress mechanics, diffusion of lithium ion, and dissolution of transition-metal ions of spinel LiMn2O4 cathode. The model analyzes how different coating thicknesses affect diffusion-induced stress generation and, ultimately, crack propagation. Experimentally measured diffusivity and dissolution rates were incorporated into the model to account for a trade-off between delayed transport and prevention of side reactions. Along with experimental results, density functional theory results are used to explain how a change in volume, due to dissolution of active material, can affect battery performance. The predicted behavior from the model is well-matched with experimental results obtained on coated and uncoated LiMn2O4-Li foil cells. The proposed approach and explanations will serve as important guidelines for thin film coating strategies for various battery materials. PMID- 28849638 TI - Toward a Comprehensive Understanding of Enhanced Photocatalytic Activity of the Bimetallic PdAu/TiO2 Catalyst for Selective Oxidation of Methanol to Methyl Formate. AB - Photocatalytic selective oxidation of alcohols over titania supported with bimetallic nanoparticles represents an energy efficient and sustainable route for the synthesis of esters. Specifically, the bimetallic PdAu/TiO2 system was found to be highly active and selective toward photocatalytic production of methyl formate (MF) from gas-phase methanol. In the current paper, we applied the electronic structure density functional theory method to understand the mechanistic aspects and corroborate our recent experimental measurements for the photocatalytic selective oxidation of methanol to MF over the PdAu/TiO2 catalyst. Our theoretical results revealed the preferential segregation of Pd atoms from initially mixed PdAu nanoclusters to the interface of PdAu/TiO2 and subsequent formation of a unique structure, resembling a core@shell architecture in close proximity to the interface. The analysis of the calculated band gap diagram provides an explanation of the superior electron-hole separation capability of PdAu nanoparticles deposited onto the anatase surface and hence the remarkably enhanced photocatalytic activity, in comparison to their monometallic counterparts. We demonstrated that facile dissociation of molecular oxygen at the triple-point boundary site gives rise to in situ oxidation of Pd. The in situ formed PdO/TiO2 is responsible for total oxidation of methanol to CO2 (no MF formation) in the gas phase. Our investigation provides theoretical guidance for designing highly selective and active bimetallic nanoparticles-TiO2 catalysts for the photocatalytic selective oxidation of methanol to MF. PMID- 28849639 TI - Oxasmaragdyrins as New and Efficient Hole-Transporting Materials for High Performance Perovskite Solar Cells. AB - The high performance of the perovskite solar cells (PSCs) cannot be achieved without a layer of efficient hole-transporting materials (HTMs) to retard the charge recombination and transport the photogenerated hole to the counterelectrode. Herein, we report the use of boryl oxasmaragdyrins (SM01, SM09, and SM13), a family of aromatic core-modified expanded porphyrins, as efficient hole-transporting materials (HTMs) for perovskite solar cells (PSCs). These oxasmaragdyrins demonstrated complementary absorption spectra in the low-energy region, good redox reversibility, good thermal stability, suitable energy levels with CH3NH3PbI3 perovskite, and high hole mobility. A remarkable power conversion efficiency of 16.5% (Voc = 1.09 V, Jsc = 20.9 mA cm-2, fill factor (FF) = 72%) is achieved using SM09 on the optimized PSCs device employing a planar structure, which is close to that of the state-of-the-art hole-transporting materials (HTMs), spiro-OMeTAD of 18.2% (Voc = 1.07 V, Jsc = 22.9 mA cm-2, FF = 74%). In contrast, a poor photovoltaic performance of PSCs using SM01 is observed due to the interactions of terminal carboxylic acid functional group with CH3NH3PbI3. PMID- 28849640 TI - Biointerface Structural Effects on the Properties and Applications of Bioinspired Peptide-Based Nanomaterials. AB - Peptide sequences are known to recognize and bind different nanomaterial surfaces, which has resulted in the screening and identification of hundreds of peptides with the ability to bind to a wide range of metallic, metal oxide, mineral, and polymer substrates. These biomolecules are able to bind to materials with relatively high affinity, resulting in the generation of a complex biointerface between the biotic and abiotic components. While the number of material-binding sequences is large, at present, quantitative materials-binding characterization of these peptides has been accomplished only for a relatively small number of sequences. Moreover, it is currently very challenging to determine the molecular-level structure(s) of these peptides in the materials adsorbed state. Despite this lack of data related to the structure and function of this remarkable biointerface, several of these peptide sequences have found extensive use in creating functional nanostructured materials for assembly, catalysis, energy, and medicine, all of which are dependent on the structure of the individual peptides and collective biointerface at the material surface. In this Review, we provide a comprehensive overview of these applications and illustrate how the versatility of this peptide-mediated approach for the growth, organization, and activation of nanomaterials could be more widely expanded via the elucidation of biointerfacial structure/property relationships. Future directions and grand challenges to realize these goals are highlighted for both experimental characterization and molecular-simulation strategies. PMID- 28849641 TI - Two-Phase and Graph-Based Clustering Methods for Accurate and Efficient Segmentation of Large Mass Spectrometry Images. AB - Clustering is widely used in MSI to segment anatomical features and differentiate tissue types, but existing approaches are both CPU and memory-intensive, limiting their application to small, single data sets. We propose a new approach that uses a graph-based algorithm with a two-phase sampling method that overcomes this limitation. We demonstrate the algorithm on a range of sample types and show that it can segment anatomical features that are not identified using commonly employed algorithms in MSI, and we validate our results on synthetic MSI data. We show that the algorithm is robust to fluctuations in data quality by successfully clustering data with a designed-in variance using data acquired with varying laser fluence. Finally, we show that this method is capable of generating accurate segmentations of large MSI data sets acquired on the newest generation of MSI instruments and evaluate these results by comparison with histopathology. PMID- 28849642 TI - Plasma-Assisted Synthesis of Self-Supporting Porous CoNPs@C Nanosheet as Efficient and Stable Bifunctional Electrocatalysts for Overall Water Splitting. AB - The utilization of a highly active and robust bifunctional catalyst for simultaneously producing H2 and O2 is still a major challenging issue, which is vital for improving the efficiency of overall water splitting. Herein, we employ a novel plasma-assisted strategy to rapidly and conveniently synthesize the three dimensional (3D) porous composite nanosheets assembled on monodispersed Co nanoparticles encapsulated in a carbon framework (CoNPs@C) on a carbon cloth. Such a novel 3D hierarchical porous nanosheet improves the exposure and accessibility of active sites as well as ensures high electroconductibility. Moreover, the coating of a few graphene layers on the surface of catalysts favors improvement of the catalytic activity. Benefited from these multiple merits, the CoNPs@C composite nanosheets enable a low overpotential of 153 mV at -10 mA cm-2 for hydrogen evolution reaction. Furthermore, they are also capable of catalyzing the oxygen evolution reaction with high efficiency to achieve current density of 10 mA cm-2 at the overpotential of 270 mV. Remarkably, when assembled as an alkaline water electrolyzer, the bifunctional CoNPs@C composite nanosheets can afford a water-splitting current density of 10 mA cm-2 at a cell voltage of 1.65 V. PMID- 28849643 TI - Electroreductive Coupling Layer-by-Layer Assembly. AB - Rapid and covalent layer-by-layer (LbL) assembly is of significance for practical applications because of superior chemical and mechanical stability. The electrochemical LbL assembly via an accelerating trigger can be automated and programmable in response to electrical signals to in situ fabricate covalently layered thin films with chemical and mechanical stability. In this paper, electroreductive coupling layer-by-layer assembly is introduced as both covalent and rapid methodology for preparing layered thin films. This assembly is triggered by C-C coupling of peripheral alkynyls, which have own absorption below 300 nm and can transform to optical and electrical inert double/single or triple/single alternative bonding formations significantly without optical or electric alternations of desirable photoelectric building blocks, superior to other linkers among covalent LbL assemblies. Not limited to fabrication of optical thin films, this assembly is readily available for oxygen sensitive substrates or materials and also a powerful addition to electrooxidative coupling LbL assembly for developing the economically dynamoelectric LbL machines without moving or changing experimental gears. PMID- 28849644 TI - Synthesis of Chemically Ordered Pt3Fe/C Intermetallic Electrocatalysts for Oxygen Reduction Reaction with Enhanced Activity and Durability via a Removable Carbon Coating. AB - Recently, Pt3M (M = Fe, Ni, Co, Cu, etc.) intermetallic compounds have been highlighted as promising candidates for oxygen reduction reaction (ORR) catalysts. In general, to form those intermetallic compounds, alloy phase nanoparticles are synthesized and then heat-treated at a high temperature. However, nanoparticles easily agglomerate during the heat treatment, resulting in a decrease in electrochemical surface area (ECSA). In this study, we synthesized Pt-Fe alloy nanoparticles and employed carbon coating to protect the nanoparticles from agglomeration during heat treatment. As a result, Pt3Fe L12 structure was obtained without agglomeration of the nanoparticles; the ECSA of Pt Fe alloy and intermetallic Pt3Fe/C was 37.6 and 33.3 m2 gPt-1, respectively. Pt3Fe/C exhibited excellent mass activity (0.454 A mgPt-1) and stability with superior resistances to nanoparticle agglomeration and iron leaching. Density functional theory (DFT) calculation revealed that, owing to the higher dissolution potential of Fe atoms on the Pt3Fe surface than those on the Pt-Fe alloy, Pt3Fe/C had better stability than Pt-Fe/C. A single cell fabricated with Pt3Fe/C showed higher initial performance and superior durability, compared to that with commercial Pt/C. We suggest that Pt3M chemically ordered electrocatalysts are excellent candidates that may become the most active and durable ORR catalysts available. PMID- 28849645 TI - Bipolar Electrode Array Embedded in a Polymer Light-Emitting Electrochemical Cell. AB - A linear array of aluminum discs is deposited between the driving electrodes of an extremely large planar polymer light-emitting electrochemical cell (PLEC). The planar PLEC is then operated at a constant bias voltage of 100 V. This promotes in situ electrochemical doping of the luminescent polymer from both the driving electrodes and the aluminum discs. These aluminum discs function as discrete bipolar electrodes (BPEs) that can drive redox reactions at their extremities. Time-lapse fluorescence imaging reveals that p- and n-doping that originated from neighboring BPEs can interact to form multiple light-emitting p-n junctions in series. This provides direct evidence of the working principle of bulk homojunction PLECs. The propagation of p-doping is faster from the BPEs than from the positive driving electrode due to electric field enhancement at the extremities of BPEs. The effect of field enhancement and the fact that the doping fronts only need to travel the distance between the neighboring BPEs to form a light-emitting junction greatly reduce the response time for electroluminescence in the region containing the BPE array. The near simultaneous formation of multiple light-emitting p-n junctions in series causes a measurable increase in cell current. This indicates that the region containing a BPE is much more conductive than the rest of the planar cell despite the latter's greater width. The p- and n-doping originating from the BPEs is initially highly confined. Significant expansion and divergence of doping occurred when the region containing the BPE array became more conductive. The shape and direction of expanded doping strongly suggest that the multiple light-emitting p-n junctions, formed between and connected by the array of metal BPEs, have functioned as a single rod-shaped BPE. This represents a new type of BPE that is formed in situ and as a combination of metal, doped polymers, and forward-biased p-n junctions connected in series. PMID- 28849646 TI - Fully Inkjet-Printed Paper-Based Potentiometric Ion-Sensing Devices. AB - A fully inkjet-printed disposable and low cost paper-based device for potentiometric Na+- or K+-ion sensing has been developed. A printed ionophore based all-solid-state ion selective electrode on a graphene/poly(3,4 ethylenedioxythiophene) polystyrenesulfonate (G/PEDOT:PSS) nanocomposite solid contact and a printed all-solid state reference electrode consisting of a pseudosilver/silver chloride electrode coated by a lipophilic salt-incorporating poly(vinyl chloride) membrane overprinted with potassium chloride have been combined on a microfluidically patterned paper substrate. Devices are built on standard filter paper using off-the-shelf materials. Ion sensing has been achieved within 180 s by simple addition of 20 MUL of sample solution without electrode preconditioning. The limits of detection were 32 and 101 MUM for Na+ and K+, respectively. The individual single-use sensing devices showed near Nernstian response of 62.5 +/- 2.1 mV/decade (Na+) and 62.9 +/- 1.1 mV/decade (K+) with excellent standard potential (E0) reproducibilities of 455.7 +/- 5.1 mV (Na+) and 433.9 +/- 2.8 mV (K+). The current work demonstrates the promising possibility of obtaining low-cost and disposable paper-based potentiometric sensing devices potentially manufacturable at large scales with industrial inkjet printing technology. PMID- 28849647 TI - Dendrite-Free Potassium-Oxygen Battery Based on a Liquid Alloy Anode. AB - The safety issue caused by the dendrite growth is not only a key research problem in lithium-ion batteries but also a critical concern in alkali metal (i.e., Li, Na, and K)-oxygen batteries where a solid metal is usually used as the anode. Herein, we demonstrate the first dendrite-free K-O2 battery at ambient temperature based on a liquid Na-K alloy anode. The unique liquid-liquid connection between the liquid alloy and the electrolyte in our alloy anode-based battery provides a homogeneous and robust anode-electrolyte interface. Meanwhile, we manage to show that the Na-K alloy is only compatible in K-O2 batteries but not in Na-O2 batteries, which is mainly attributed to the stronger reducibility of potassium and relatively more favorable thermodynamic formation of KO2 over NaO2 during the discharge process. It is observed that our K-O2 battery based on a liquid alloy anode shows a long cycle life (over 620 h) and a low discharge charge overpotential (about 0.05 V at initial cycles). Moreover, the mechanism investigation into the K-O2 cell degradation shows that the O2 crossover effect and the ether-electrolyte instability are the critical problems for K-O2 batteries. In a word, this study provides a new route to solve the problems caused by the dendrite growth in alkali metal-oxygen batteries. PMID- 28849648 TI - Rational Design of Cobalt-Iron Selenides for Highly Efficient Electrochemical Water Oxidation. AB - Exploring active, stable, earth-abundant, low-cost, and high-efficiency electrocatalysts is highly desired for large-scale industrial applications toward the low-carbon economy. In this study, we apply a versatile selenizing technology to synthesize Se-enriched Co1-xFexSe2 catalysts on nickel foams for oxygen evolution reactions (OERs) and disclose the relationship between the electronic structures of Co1-xFexSe2 (via regulating the atom ratio of Co/Fe) and their OER performance. Owing to the fact that the electron configuration of the Co1-xFexSe2 compounds can be tuned by the incorporated Fe species (electron transfer and lattice distortion), the catalytic activity can be adjusted according to the Co/Fe ratios in the catalyst. Moreover, the morphology of Co1-xFexSe2 is also verified to strongly depend on the Co/Fe ratios, and the thinner Co0.4Fe0.6Se2 nanosheets are obtained upon selenization treatment, in which it allows more active sites to be exposed to the electrolyte, in turn promoting the OER performance. The Co0.4Fe0.6Se2 nanosheets not only exhibit superior OER performance with a low overpotential of 217 mV at 10 mA cm-2 and a small Tafel slope of 41 mV dec-1 but also possess ultrahigh durability with a dinky degeneration of 4.4% even after 72 h fierce water oxidation test in alkaline solution, which outperforms the commercial RuO2 catalyst. As expected, the Co0.4Fe0.6Se2 nanosheets have shown great prospects for practical applications toward water oxidation. PMID- 28849649 TI - Thermoresponsive Memory Behavior in Metallosupramolecular Polymer-Based Ternary Memory Devices. AB - Thermal-sensitive materials, such as metallosupramolecular polymers, have been integrated into devices for a broad range of applications. However, the role of these materials is limited to temperature sensing and the lack of a memory function. Herein, we present novel [PolyCo-L1xL2y-PF6]-based organic resistive memories (ORMs) possessing both a thermal response and ternary memory behavior with three electrical resistance states [high (HRS), intermediate (IRS), and low (LRS)]. Furthermore, the thermal behavior can be memorized by the Al/[PolyCoL1xL2y-PF6]/indium-tin oxide devices. Heating and cooling the devices at a LRS results in a switch from the LRS to a HRS and further to a LRS, indicating that the thermal behavior can be efficiently memorized. Following the heating and cooling process, devices at a HRS retain their ternary memory behavior, while an unstable resistance variation behavior is observed at the IRS. We propose a possible mechanism for the thermoresponsive memory behavior, and this finding provides a guide for the design of future thermoresponsive ORMs. PMID- 28849650 TI - Solvothermal Synthesis of Hierarchical TiO2 Microstructures with High Crystallinity and Superior Light Scattering for High-Performance Dye-Sensitized Solar Cells. AB - In this article, hierarchical TiO2 microstructures (HM-TiO2) were synthesized by a simple solvothermal method adopting tetra-n-butyl titanate as the titanium source in a mixed solvent composed of N,N-dimethylformamide and acetic acid. Due to the high crystallinity and superior light-scattering ability, the resultant HM TiO2 are advantageous as photoanodes for dye-sensitized solar cells. When assembled to the entire photovoltaic device with C101 dye as a sensitizer, the pure HM-TiO2-based solar cells showed an ultrahigh photovoltage up to 0.853 V. Finally, by employing the as-obtained HM-TiO2 as the scattering layer and optimizing the architecture of dye-sensitized solar cells, both higher photovoltage and incident photon-to-electron conversion efficiency value were harvested with respect to TiO2 nanoparticles-based dye-sensitized solar cells, resulting in a high power conversion efficiency of 9.79%. This work provides a promising strategy to develop photoanode materials with outstanding photoelectric conversion performance. PMID- 28849651 TI - Highly Ordered Gold Nanopatterned Indium Tin Oxide Electrodes for Simultaneous Optical and Electrochemical Probing Cell Interactions. AB - The formation of new types of sensitive conductive surfaces for the detection and transduction of cell-extracellular matrix recognition events in a real time, label-free manner is of great interest in the field of biomedical research. To study molecularly defined cell functions, biologically inspired materials that mimic the nanoscale order of extracellular matrix protein fibers and yield suitable electrical charge transfer characteristics are highly desired. Our strategy to achieve this goal is based on the spatial self-organization of patches of cell-adhesive molecules onto a gold-nanoparticle-patterned indium tin oxide electrode. Fibroblast adhesion response to selective ligands for integrins alpha5beta1 and alphavbeta3, which are both relevant in cancer progression, is investigated by simultaneous electrochemical impedance spectroscopy and optical microscopy. Adhesive cells on alpha5beta1-selective nanopatterns showed enhanced membrane dynamics and tighter binding, compared with cells on alphavbeta3 selective nanopatterns. The surface of the electrode exhibits high sensitivity to small changes in surface properties, because of the constitution of specific cell surface interactions. Moreover, such sensitivity enables differentiation between cell types. This is exemplified by analyzing distinct features in the electrochemical readout of MCF-7 breast cancer cells versus MCF-10A mammary epithelial cells, when subjected to individual adhesive nanopatches. PMID- 28849652 TI - Parallel Large-Scale Molecular Dynamics Simulation Opens New Perspective to Clarify the Effect of a Porous Structure on the Sintering Process of Ni/YSZ Multiparticles. AB - Ni sintering in the Ni/YSZ porous anode of a solid oxide fuel cell changes the porous structure, leading to degradation. Preventing sintering and degradation during operation is a great challenge. Usually, a sintering molecular dynamics (MD) simulation model consisting of two particles on a substrate is used; however, the model cannot reflect the porous structure effect on sintering. In our previous study, a multi-nanoparticle sintering modeling method with tens of thousands of atoms revealed the effect of the particle framework and porosity on sintering. However, the method cannot reveal the effect of the particle size on sintering and the effect of sintering on the change in the porous structure. In the present study, we report a strategy to reveal them in the porous structure by using our multi-nanoparticle modeling method and a parallel large-scale multimillion-atom MD simulator. We used this method to investigate the effect of YSZ particle size and tortuosity on sintering and degradation in the Ni/YSZ anodes. Our parallel large-scale MD simulation showed that the sintering degree decreased as the YSZ particle size decreased. The gas fuel diffusion path, which reflects the overpotential, was blocked by pore coalescence during sintering. The degradation of gas diffusion performance increased as the YSZ particle size increased. Furthermore, the gas diffusion performance was quantified by a tortuosity parameter and an optimal YSZ particle size, which is equal to that of Ni, was found for good diffusion after sintering. These findings cannot be obtained by previous MD sintering studies with tens of thousands of atoms. The present parallel large-scale multimillion-atom MD simulation makes it possible to clarify the effects of the particle size and tortuosity on sintering and degradation. PMID- 28849653 TI - Iron and Electron Shuttle Mediated (Bio)degradation of 2,4-Dinitroanisole (DNAN). AB - The Department of Defense has developed explosives with the insensitive munition 2,4-dinitroanisole (DNAN), to prevent accidental detonations during training and operations. Understanding the fate and transport of DNAN is necessary to assess the risk it may represent to groundwater once the new ordnance is routinely produced and used. Experiments with ferrous iron or anthrahydroquinone-2,6 disulfonate (AH2QDS) were conducted from pH 6.0 to 9.0 with initial DNAN concentrations of 100 MUM. DNAN was degraded by 1.2 mM Fe(II) at pH 7, 8, and 9, and rates increased with increasing pH. Greater than 90% of the initial 100 MUM DNAN was reduced within 10 min at pH 9, and all DNAN was reduced within 1 h. AH2QDS reduced DNAN at all pH values tested. Cells of Geobacter metallireducens were added in the presence and absence of Fe(III) and/or anthraquinone-2,6 disulfonate (AQDS), and DNAN was also reduced in all cell suspensions. Cells reduced the compound directly, but both AQDS and Fe(III) increased the reaction rate, via the production of AH2QDS and/or Fe(II). DNAN was degraded via two intermediates: 2-methoxy-5-nitroaniline and 4-methoxy-3-nitroaniline, to the amine product 2,4-diaminoanisole. These data suggest that an effective strategy can be developed for DNAN attenuation based on combined biological-abiotic reactions mediated by Fe(III)-reducing microorganisms. PMID- 28849654 TI - Promoting the Electrochemical Performances by Chemical Depositing of Gold Nanoparticles Inside Pores of 3D Nitrogen-Doped Carbon Nanocages. AB - Carbon Nanomaterials are excellent electrode materials due to their extraordinary conductivity, prolific structures, and morphologies. Herein, a novel nanocarbon based material (Au@NCNC) was synthesized by embedding gold nanoparticles (AuNPs) inside the pores of three-dimensional hierarchical nitrogen-doped carbon nanocages (NCNC) through an in situ chemical deposition method. The resultant Au@NCNC was employed as an electrochemical catalyst for the oxygen reduction reaction (ORR) and as an electrode material for supercapacitors. The conductivity and hydrophilicity of Au@NCNC were much more improved than those of pristine NCNC. Meanwhile, the bubble adhesive force on the Au@NCNC film was much lower underwater than that of NCNC, which provided easy accessibility to the active sites of reactants, such as hydrated O2. Therefore, the deposition of AuNPs inside pores of NCNC facilitated the transfer of electrons and diffusion of ions, promoting the electrocatalytic performance of Au@NCNC. As a result, Au@NCNC exhibited high performance toward ORR, which manifested in high numbers of electron transfer (3.7-3.9), high kinetic current density, enhanced electrocatalytic stability, and remarkable methanol durability. Moreover, Au@NCNC displayed high specific capacitance, good rate capability, and cycling stability with ~97% of its initial capacitance retained at the high current density of 10 A g-1 after 5000 cycles. This could be attributed to the synergetic effect of ultrafine gold nanoparticles, the hierarchical porous structure, and the hydrophilic surface of NCNC as well. This work offers an excellent alternative for Pt-based catalysts in fuel cells, ORR, and supercapacitive electrode materials by enhancing the conductivity and surface hydrophilicity of electrocatalysts. PMID- 28849655 TI - Synthesis and Properties of Carbaporphyrin and Carbachlorin Dimethyl Esters Derived from Cyclopentanedialdehydes. AB - Norbornenes with two ester substituents were prepared by Diels-Alder cycloadditions of cyclopentadiene with dimethyl fumarate and dimethyl 1,1 ethylenedicarboxylate. Oxidation with potassium permanganate gave good yields of related diols that were oxidatively ring-opened to afford cyclopentane dialdehydes. MacDonald-type "3 + 1" condensations with a tripyrrane, followed by oxidation with DDQ in refluxing toluene, gave carbaporphyrin or carbachlorin products in good yields. The macrocyclic products were highly diatropic and produced porphyrin-like UV-vis spectra. The carbaporphyrin was converted into silver(III) and gold(III) organometallic derivatives. Reaction with methyl iodide in the presence of potassium carbonate gave mono- and dialkylation products, and treatment of the former with Ni(OAc)2 or Pd(OAc)2 afforded nickel(II) and palladium(II) complexes. The free base carbaporphyrin and carbachlorin, and the nickel and palladium complexes, were characterized by X-ray crystallography. The carbachlorin also reacted with silver(I) acetate to give a silver(III) derivative. Carbaporphyrins and carbachlorins underwent deuterium exchange at the meso-positions with deuteriated TFA, and this observation indicates that protonation is occurring at the bridging carbons. The new route to carbaporphyrins and carbachlorins has enabled detailed studies on the properties of these systems and provides the foundations for future investigations. PMID- 28849656 TI - Cu-Catalyzed Synthesis of 3-Formyl Imidazo[1,2-a]pyridines and Imidazo[1,2 a]pyrimidines by Employing Ethyl Tertiary Amines as Carbon Sources. AB - A highly efficient synthesis of 3-formyl imidazo[1,2-a]pyridine and imidazo[1,2 a]pyrimidine, under Cu-catalyzed aerobic oxidative conditions and by utilizing ethyl tertiary amines as carbon sources, is disclosed. A novel activation mode of ethyl tertiary amines in which simultaneous selective cleavage of C-C bond and C N bond of ethyl group with molecular oxygen as terminal oxidant in this one-pot protocol is reported for the first time. This reaction features broad substrate scope, good functional group tolerance, as well as diversified and valuable products. PMID- 28849657 TI - Quinine-Based Trifunctional Organocatalyst for Tandem Aza-Henry Reaction Cyclization: Asymmetric Synthesis of Spiroxindole-Pyrrolidine/Piperidines. AB - A quinine-derived trifunctional sulphonamide catalyst has been developed for the effective asymmetric organocatalytic tandem aza-Henry reaction-cyclization of isatin-derived ketimines and nitroalkane-mesylates for the synthesis of spiro pyrrolidine/piperidine-oxindoles. Demethylation of traditional bifunctional catalyst to incorporate an additional hydrogen bonding C6'-OH group plays the key role toward remarkable enantioselectivity. PMID- 28849658 TI - A Stereocontrolled Annulation of the Taccalonolide Epoxy Lactone onto the Molecular Framework of trans-Androsterone. AB - A robust and scalable route to the taccalonolide skeleton starting from trans androsterone is presented. The synthesis features a cyclic hydroboration carbonylation reaction, which effectively establishes the trans-hydrindane DE ring junction in a remarkable annulation reaction, as well as a Claisen rearrangement and a catalytic Ullmann-type cyclization. This work is part of a larger effort to uncover new clinical candidates from the taccalonolide class of anticancer agents through advances in chemical synthesis. PMID- 28849659 TI - Synthesis of a 3'-Fluoro-3'-deoxytetrose Adenine Phosphonate. AB - A new synthetic route to a 3'-fluoro-3'-deoxytetrose adenine phosphonate has been developed. The synthesis starts from l-xylose and key steps include the stereospecific introduction of the phosphonomethoxy group and adenine. In addition, a regioselective fluorination reaction allows access to the desired 3' fluoro-3'-deoxytetrose moiety. This methodology allows the straightforward synthesis of a 3'-fluoro-3'-deoxytetrose adenine phosphonate and can be expanded toward the synthesis of other types of 3'-fluoro nucleoside phosphonates. PMID- 28849661 TI - Synthesis of Chondroitin Sulfate A Bearing Syndecan-1 Glycopeptide. AB - Syndecan-1 chondroitin sulfate glycopeptide was synthesized for the first time using the cassette approach. The sequence of glycosylation to form the octasaccharide serine cassette was critical. The glycopeptide was successfully assembled via a 2+ (3 + 3) glycosylation strategy followed by peptide chain elongation. PMID- 28849660 TI - Proteomics Standards Initiative: Fifteen Years of Progress and Future Work. AB - The Proteomics Standards Initiative (PSI) of the Human Proteome Organization (HUPO) has now been developing and promoting open community standards and software tools in the field of proteomics for 15 years. Under the guidance of the chair, cochairs, and other leadership positions, the PSI working groups are tasked with the development and maintenance of community standards via special workshops and ongoing work. Among the existing ratified standards, the PSI working groups continue to update PSI-MI XML, MITAB, mzML, mzIdentML, mzQuantML, mzTab, and the MIAPE (Minimum Information About a Proteomics Experiment) guidelines with the advance of new technologies and techniques. Furthermore, new standards are currently either in the final stages of completion (proBed and proBAM for proteogenomics results as well as PEFF) or in early stages of design (a spectral library standard format, a universal spectrum identifier, the qcML quality control format, and the Protein Expression Interface (PROXI) web services Application Programming Interface). In this work we review the current status of all of these aspects of the PSI, describe synergies with other efforts such as the ProteomeXchange Consortium, the Human Proteome Project, and the metabolomics community, and provide a look at future directions of the PSI. PMID- 28849662 TI - Radiation-Induced Endothelial Inflammation Is Transferred via the Secretome to Recipient Cells in a STAT-Mediated Process. AB - Radiation is the most common treatment of cancer. Minimizing the normal tissue injury, especially the damage to vascular endothelium, remains a challenge. This study aimed to analyze direct and indirect radiation effects on the endothelium by investigating mechanisms of signal transfer from irradiated to nonirradiated endothelial cells by means of secreted proteins. Human coronary artery endothelial cells (HCECest2) undergo radiation-induced senescence in vitro 14 days after exposure to 10 Gy X-rays. Proteomics analysis was performed on HCECest2 14 days after irradiation with X-ray doses of 0 Gy (control) or 10 Gy using label-free technology. Additionally, the proteomes of control and radiation induced secretomes, and those of nonirradiated HCECest2 exposed for 24 h to secreted proteins of either condition were measured. Key changes identified by proteomics and bioinformatics were validated by immunoblotting, ELISA, bead-based multiplex assays, and targeted transcriptomics. The irradiated cells, their secretome, and the nonirradiated recipient cells showed similar inflammatory response, characterized by induction of interferon type I-related proteins and activation of the STAT3 pathway. These data indicate that irradiated endothelial cells may adversely affect nonirradiated surrounding cells via senescence associated secretory phenotype. This study adds to our knowledge of the pathological background of radiation-induced cardiovascular disease. PMID- 28849663 TI - Carbonyl anti-(alpha-Amino)allylation via Ruthenium Catalyzed Hydrogen Autotransfer: Use of an Acetylenic Pyrrole as an Allylmetal Pronucleophile. AB - A single ruthenium complex catalyzes two discrete transformations resulting in the net conversion of an acetylenic pyrrole and alcohols to products of carbonyl anti-(alpha-amino)allylation. An initial catalytic process enables isomerization of an alkyne to a kinetically more reactive allene. A second catalytic process promotes alcohol-to-allene hydrogen transfer to form an aldehyde-allylruthenium pair that engages in regio- and diastereoselective carbonyl addition. A related reductive coupling of aldehydes mediated by 2-propanol also is described. The present catalytic processes represent rare examples of the use of alkynes as nucleophilic allylmetal precursors. PMID- 28849664 TI - Validation of an Algorithm for Semi-automated Estimation of Voice Relative Fundamental Frequency. AB - OBJECTIVES: Relative fundamental frequency (RFF) has shown promise as an acoustic measure of voice, but the subjective and time-consuming nature of its manual estimation has made clinical translation infeasible. Here, a faster, more objective algorithm for RFF estimation is evaluated in a large and diverse sample of individuals with and without voice disorders. METHODS: Acoustic recordings were collected from 154 individuals with voice disorders and 36 age- and sex matched controls with typical voices. These recordings were split into training and 2 testing sets. Using an algorithm tuned to the training set, semi-automated RFF estimates in the testing sets were compared to manual RFF estimates derived from 3 trained technicians. RESULTS: The semi-automated RFF estimations were highly correlated ( r = 0.82-0.91) with the manual RFF estimates. CONCLUSIONS: Fast and more objective estimation of RFF makes large-scale RFF analysis feasible. This algorithm allows for future work to optimize RFF measures and expand their potential for clinical voice assessment. PMID- 28849665 TI - Development of sensitive indirect enzyme-linked immunosorbent assays for specific detection of antibodies against fowl adenovirus serotypes 1 and 4 in chickens. AB - Conventional serological methods for detection and differentiation of antibodies against fowl aviadenoviruses (FAdVs) are laborious and time-consuming, therefore ELISAs based upon recombinant proteins were developed in the present study to overcome this limitation for clinically relevant serotypes FAdV-1 and FAdV-4. In order to develop serotype-specific ELISAs, the two distinct fibers, fiber-1 (fib 1) and fiber-2 (fib-2), characteristically present only in FAdV-1 and FAdV-4, were applied separately as coating antigens. Sera raised against each recombinant fib-1 and fib-2 of FAdV-1 and FAdV-4 did not react with any of the heterologous fiber ELISAs, as anticipated by the low degree of amino acid identity between those FAdV fibers (23.1-41.2%), indicating that heterologous fibers do not share common epitopes. Testing of 172 monospecific sera, raised against all FAdV serotypes (1-8a and 8b-11), retrieved specificities between 99.3% and 100.0% for the ELISAs, further substantiating the serotype-specificity of fibers. Investigating sera from chickens experimentally inoculated with different FAdV-1 or FAdV-4 strains revealed that ELISAs were equally or more sensitive than the virus-neutralization (VN) test. Furthermore, strong correlations were demonstrated between fiber antibody titres and neutralization activity. Particularly, sera directed against live virus showed a pronounced fiber antibody response, which might be explained by an excessive production of fibers during infection. Application of the newly developed fiber ELISAs on field sera with heterogeneous serological status demonstrated high sensitivity and serotype specificity of this test system, providing for the first time a diagnostic tool for mass screening of chicken flocks against FAdV serotypes, namely FAdV-1 and FAdV-4. PMID- 28849666 TI - Family Coaching as a delivery modality for evidence-based prevention programs. AB - Family Coaching is proposed as a new delivery format for evidence-based prevention programs (EBPPs). Three recent developments in health promotion support the potential efficacy of Family Coaching: (1) renewed interest in integrated prevention programs for multiple risk factors and behavior changes, (2) broad and long-term impacts of family-based interventions, and (3) popular acceptance of "coaching" as a nonstigmatizing, goal-focused intervention strategy. Family coaches are community members and paraprofessionals trained in common elements of EBPP. Family Coaching has specific goals, is short term, and has definable outcomes. Coaches frame the program's goals to be consistent with the family's values, normalize the family's experience, assess their strengths, and help the family set goals and develop skills and routines to problem solve challenging situations. Broad dissemination of EBPP will be facilitated with delivery formats that are flexible to meet families' priorities and providers' desires and capacities to tailor programs to local contexts. PMID- 28849667 TI - An investigation into problematic smartphone use: The role of narcissism, anxiety, and personality factors. AB - Background and aims Over the last decade, worldwide smartphone usage has greatly increased. Alongside this growth, research on the influence of smartphones on human behavior has also increased. However, a growing number of studies have shown that excessive use of smartphones can lead to detrimental consequences in a minority of individuals. This study examines the psychological aspects of smartphone use particularly in relation to problematic use, narcissism, anxiety, and personality factors. Methods A sample of 640 smartphone users ranging from 13 to 69 years of age (mean = 24.89 years, SD = 8.54) provided complete responses to an online survey including modified DSM-5 criteria of Internet Gaming Disorder to assess problematic smartphone use, the Spielberger State-Trait Anxiety Inventory, the Narcissistic Personality Inventory, and the Ten-Item Personality Inventory. Results The results demonstrated significant relationships between problematic smartphone use and anxiety, conscientiousness, openness, emotional stability, the amount of time spent on smartphones, and age. The results also demonstrated that conscientiousness, emotional stability, and age were independent predictors of problematic smartphone use. Conclusion The findings demonstrate that problematic smartphone use is associated with various personality factors and contributes to further understanding the psychology of smartphone behavior and associations with excessive use of smartphones. PMID- 28849668 TI - Relationship between borderline personality symptoms and Internet addiction: The mediating effects of mental health problems. AB - Aim To examine the relationship between borderline personality symptoms and Internet addiction as well as the mediating role of mental health problems between them. Methods A total of 500 college students from Taiwan were recruited and assessed for symptoms of Internet addiction using the Chen Internet Addiction Scale, borderline personality symptoms using the Taiwanese version of the Borderline Symptom List and mental health problems using four subscales from the Symptom Checklist-90-Revised Scale (interpersonal sensitivity, depression, anxiety, and hostility). Structural equation modeling (SEM) was used to test our hypothesis that borderline personality symptoms are associated with the severity of Internet addiction directly and also through the mediation of mental health problems. Results SEM analysis revealed that all paths in the hypothesized model were significant, indicating that borderline personality symptoms were directly related to the severity of Internet addiction as well as indirectly related to the severity of Internet addiction by increasing the severity of mental health problems. Conclusion Borderline personality symptoms and mental health problems should be taken into consideration when designing intervention programs for Internet addiction. PMID- 28849669 TI - Psychological factors, sociodemographic characteristics, and coping mechanisms associated with the self-stigma of problem gambling. AB - Background and aims Few studies have examined the stigma of problem gambling and little is known about those who internalize this prejudice as damaging self stigma. This paper aimed to identify psychological factors, sociodemographic characteristics, and coping mechanisms associated with the self-stigma of problem gambling. Methods An online survey was conducted on 177 Australian adults with a current gambling problem to measure self-stigma, self-esteem, social anxiety, self-consciousness, psychological distress, symptom severity, most problematic gambling form, stigma coping mechanisms, and sociodemographic characteristics. Results All variables significantly correlated with self-stigma were considered for inclusion in a regression model. A multivariate linear regression indicated that higher levels of self-stigma were associated with: being female, being older, lower self-esteem, higher problem gambling severity score, and greater use of secrecy (standardized coefficients: 0.16, 0.14, -0.33, 0.23, and 0.15, respectively). Strongest predictors in the model were self-esteem, followed by symptom severity score. Together, predictors in the model accounted for 38.9% of the variance in self-stigma. Discussion and conclusions These results suggest that the self-stigma of problem gambling may be driven by similar mechanisms as the self-stigma of other mental health disorders, and impact similarly on self esteem and coping. Thus, self-stigma reduction initiatives used for other mental health conditions may be effective for problem gambling. In contrast, however, the self-stigma of problem gambling increased with female gender and older age, which are associated with gaming machine problems. This group should, therefore, be a target population for efforts to reduce or better cope with the self-stigma of problem gambling. PMID- 28849671 TI - Colorectal cancer-targeted delivery of oxaliplatin via folic acid-grafted solid lipid nanoparticles: preparation, optimization, and in vitro evaluation. AB - OBJECTIVE: Colorectal cancer (CRC) ranked second in females and third in males among all type of cancers diagnosed. About 1.4 million cases took place with 693,900 deaths in 2012. It can occur either in colon or rectum. Thus, we aimed to develop and optimize oxaliplatin (OP) loaded solid lipid nanoparticles (SLNs). MATERIALS AND METHODS: SLNs containing tristearin, 1,2-distearoyl-sn-glycero-3 phosphoethanolamine (DSPE), Lipoid S75, and Tween 80 was developed. Box-Behnken design was applied for optimization of SLNs and optimized formulation was selected for conjugation with folic acid (FA). Optimized formulations were evaluated for various physiochemical parameters viz., particle size (PS), zeta potential, %entrapment efficiency (EE), morphology, X-ray diffraction (XRD), and differential scanning calorimetry (DSC). RESULTS AND DISCUSSION: OP loaded uncoupled SLNs (OPSLNs) and OP loaded FA coupled SLNs (OPSLNFs) formulations revealed good EE, 49.2 +/- 0.38% and 43.5 +/- 0.59%, respectively and small PS, 146.2 +/- 4.4 nm, and 158.8 +/- 5.6 nm, respectively. XRD pattern and DSC results confirmed that OP was uniformly distributed in amorphous form within SLNs. In vitro drug release study of OPSLNs and OPSLNFs formulation revealed sustained drug release pattern of OP for up to 6 d. Anticancer activity on HT-29 cell line indicated the highest potency of OPSLNFs as compared to OPSLNs and OP solution. CONCLUSION: The present work illustrated the higher sensitivity of HT-29 cells to the drug entrapped in OPSLNFs as compared to OPSLNs and OP solution. Hence, this novel strategy might be a promising approach for the management of CRC. PMID- 28849672 TI - Impact of educational intervention on willingness-to-pay for suicide prevention: a quasi-experimental study among university students in Japan. AB - Many individuals show negative attitudes toward the use of taxes for suicide prevention. Activities that enhance knowledge and awareness of suicide and suicide prevention may increase willingness to pay (WTP) for suicide prevention. WTP is the amount that a consumer will pay for a product or service. The present study examined the influence of educational activities on enhancing knowledge and awareness of suicide and its prevention on WTP. We conducted a quasi-experimental study to examine the influence of lectures on suicide by comparing the amount of change in WTP between two groups over the same period: an intervention group (n = 92) comprising students who participated in the lectures and a control group (n = 128) comprising general university students recruited through an Internet-based survey. A t-test showed that the amount of change was significantly larger in the intervention group (t (152.31) = 2.25, p = .026). Ordinal logistic regression analysis showed that increased WTP was significantly correlated with an annual household income of JPY 4-6 million or higher. It may be appropriate to conclude that participation in lectures about suicide is effective in increasing WTP for suicide prevention. PMID- 28849674 TI - Beyond memory problems: multiple obstacles to health and quality of life in older people seeking help for subjective memory complaints. AB - BACKGROUND: Preliminary evidence suggests that older people who seek medical help for subjective memory complaints (SMC) may be at risk for depression, poor quality of life (QoL), and functional limitations. This study aims to: (1) further investigate bio-psycho-social characteristics, participation in personally meaningful activities and QoL of help-seekers; and (2) examine the relationship of these characteristics to QoL, and explore the unique contribution of participation to QoL. METHODS: Cognitive, meta-cognitive, emotional, social, participation, and QoL measures were used to compare 51 help-seekers referred from geriatric clinics to 40 age-matched controls who did not seek help for memory problems. RESULTS: Help-seekers exhibited lower participation and QoL, had lower mean cognitive scores, reported more memory mistakes and negative memory beliefs, more depression, worse self-efficacy, and less positive social interaction than non-help-seekers. Quality of life in help-seekers was significantly correlated with most variables. Participation contributed to the explained variance of QoL in help-seekers, beyond that accounted for by cognition and emotional status. DISCUSSION: Help-seekers with SMC exhibited a complex health condition that includes not only SMC, but also objective memory impairment, depression, functional restrictions, negative memory beliefs, low perception of memory abilities, reduced self-efficacy and insufficient social interactions, all associated with lower QoL. This multi-faceted condition should be considered in the treatment of help-seekers. Implications for Rehabilitation Older people who seek help for subjective memory complaints may be facing a larger problem involving bio-psycho-social factors, affecting participation in meaningful activities and quality of life. Quality of life may be improved via treatment of depression, functional restrictions, memory beliefs, self-efficacy, and positive social interactions. Participation in meaningful activities is an especially important target for improving health and quality of life in this population. Interventions for older adults seeking help for subjective memory complaints will benefit from adopting a bio-psycho-social rehabilitation perspective. PMID- 28849673 TI - The effect of methyl jasmonate and light irradiation treatments on the stilbenoid biosynthetic pathway in Vitis vinifera cell suspension cultures. AB - Grape stilbenes are a well-known family of plant polyphenolics that have been confirmed to have many biological activities in relation to health benefits. In the present study, we investigated the effect of methyl jasmonate (MeJA) elicitor at four different concentrations (25, 50, 100 and 200 MUM) in combination or not with high-level light irradiation (10,000 LUX) on a cell line obtained from the pulp of Vitis vinifera cv. Shahani. Our results showed that the stilbene synthesis pathway is inhibited by high-light conditions. A concentration of 50 MUM MeJA was optimum for efficient production and high accumulation of total phenolics and total flavonoids as well as total stilbenoids. Furthermore, we showed that there is a significant negative correlation between the production of these metabolites and cell growth. These data provide valuable information for the future scale-up of cell cultures for the production of these very high value compounds in bioreactor system. PMID- 28849675 TI - Effects of chitosan molecular weight on the physical and dissolution characteristics of amorphous curcumin-chitosan nanoparticle complex. AB - OBJECTIVE: To investigate the effects of varying molecular weight (MW) of chitosan (CHI) used in the complexation with curcumin (CUR) on the physical and dissolution characteristics of the amorphous CUR-CHI nanoparticle complex produced. SIGNIFICANCE: Amorphous CUR-CHI nanoparticle complex (or CUR nanoplex in short) recently emerged as a promising bioavailability enhancement strategy of CUR attributed to its fast dissolution, supersaturation generation capability, and simple preparation. Existing CUR nanoplex prepared using low MW CHI, however, exhibited poor colloidal stability during storage. Herein we hypothesized that the colloidal stability could be improved by using CHI of higher MW. The effects of this approach on the nanoplex's other characteristics were simultaneously investigated. METHODS: The CUR nanoplex was prepared by electrostatically driven self-assembled complexation between CUR and oppositely charged CHI of three different MWs (i.e. low, medium, and high). Besides colloidal stability, the effects of MW variation were investigated for the nanoplex's (1) other physical characteristics (i.e. size, zeta potential, CUR payload, amorphous state stability), (2) preparation efficiency (i.e. CUR utilization rate, yield), and (3) dissolutions under sink condition and supersaturation generation. RESULTS: CUR nanoplex prepared using CHI of high MW exhibited improved colloidal stability, larger size, superior morphology, and prolonged supersaturation generation. On the other hand, the effects of MW variation on the payload, amorphous state stability, preparation efficiency, and dissolution under sink condition were found to be insignificant. CONCLUSIONS: Varying MW of CHI used was an effective means to improve certain aspects of the CUR nanoplex characteristics with minimal adverse effects on the others. PMID- 28849676 TI - Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients. AB - OBJECTIVE: To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) of elderly (>=65 years of age) nonvalvular atrial fibrillation (NVAF) patients initiating apixaban vs. rivaroxaban, dabigatran, or warfarin. METHODS: NVAF patients with Medicare Advantage coverage in the US initiating oral anticoagulants (OACs, index event) were identified from the Humana database (1 January 2013-30 September 2015) and grouped into cohorts depending on OAC initiated. Propensity score matching (PSM), 1:1, was conducted among patients treated with apixaban vs. each other OAC, separately. Rates of S/SE and MB were evaluated in the follow-up. Cox regressions were used to compare the risk of S/SE and MB between apixaban and each of the other OACs during the follow-up. RESULTS: The matched pairs of apixaban vs. rivaroxaban (n = 13,620), apixaban vs. dabigatran (n = 4654), and apixaban vs. warfarin (n = 14,214) were well balanced for key patient characteristics. Adjusted risks for S/SE (hazard ratio [HR] vs. rivaroxaban: 0.72, p = .003; vs. warfarin: 0.65, p < .001) and MB (HR vs. rivaroxaban: 0.49, p < .001; vs. warfarin: 0.53, p < .001) were significantly lower during the follow-up for patients treated with apixaban vs. rivaroxaban and warfarin. Adjusted risks for S/SE (HR: 0.78, p = .27) and MB (HR: 0.82, p = .23) of NVAF patients treated with apixaban vs. dabigatran trended to be lower, but did not reach statistical significance. CONCLUSIONS: In the real-world setting after controlling for differences in patient characteristics, apixaban is associated with significantly lower risk of S/SE and MB than rivaroxaban and warfarin, and a trend towards better outcomes vs. dabigatran among elderly NVAF patients in the US. PMID- 28849678 TI - Corrigendum. PMID- 28849677 TI - ISO 15197: 2013 Evaluation of a Blood Glucose Monitoring System's Measurement Accuracy. PMID- 28849679 TI - Microbial polyhydroxyalkanoates as medical implant biomaterials. AB - Polyhydroxyalkanoates (PHAs), a diverse biopolyester synthesized by many bacteria as intracellular carbon and energy storage materials, have been produced in large quantity for various application researches including medical implants for approximately 30 years. It has been demonstrated by many studies that PHAs possess the required mechanical, biodegradable and tissue-compatible properties for implant applications. Very importantly, common PHA biodegradation products including oligomers and monomers are also not toxic to the cells and tissues. Some PHA degradation products have been studied for pharmaceutical applications. Mechanisms of PHA that stimulate cell growth were revealed. So far, no study has been reported to have any carcinogenesis result induced by any PHA or their biodegradation products. All results point to the feasibility of PHA to be developed into various bio-implant products. PMID- 28849680 TI - Evaluation of the effect of erythropoietin + corticosteroid versus corticosteroid alone in methanol-induced optic nerve neuropathy. AB - PURPOSE: Following methanol intoxication, optic nerve neuropathy may occur, which is currently treated by different therapeutic regimens. Erythropoietin (EPO) has recently been introduced as a good therapeutic option in methanol-induced optic neuropathy. The aim of the current study was to evaluate the efficacy of EPO in improvement of the visual disturbances in methanol-intoxicated patients. MATERIALS AND METHODS: In a case-control study, all patients who had referred to our toxicology centre with confirmed diagnosis of methanol toxicity were considered to be included. Of them, those who had referred with visual disturbances, survived, and their visual disturbances had not improved after haemodialysis were entered. Cases received EPO and corticosteroids while controls only received corticosteroids. They were then compared regarding their visual outcome. RESULTS: All five patients in the control group mentioned that after discharge, their visual acuity had improved while in the cases, three mentioned visual improvement, two mentioned their visual acuity had deteriorated after discharge, two mentioned no change in their visual acuity and three mentioned that their visual acuity had first improved but then deteriorated with a mean two month interval period. In fundoscopic evaluations, two controls had normal fundospcopy while eight cases had abnormal fundoscopy (p = 0.055). CONCLUSIONS: Protective effect of EPO on methanol-induced optic nerve may be strong at the beginning of the intervention but is probably transient. PMID- 28849681 TI - Cognitive frailty: a potential target for secondary prevention of dementia. PMID- 28849682 TI - A randomized, double-blind, placebo-controlled trial of the effect of monthly vitamin D supplementation in mild psoriasis. AB - PURPOSE: To investigate the clinical effect of vitamin D3 supplementation on psoriasis from a community-dwelling population. MATERIALS AND METHODS: Participants with psoriasis in a large randomized controlled trial examining the effect of vitamin D3 supplementation (100,000 IU monthly) in adults aged 50-84 years were invited to participate in a psoriasis sub-study over 12 months. The primary outcome was the Psoriasis Area and Severity Index (PASI) and secondary outcomes were Physicians Global Assessment (PGA), Dermatology Life Quality Index (DLQI), and Psoriasis Disability Index (PDI). Trial identification number ACTRN12611000402943. RESULTS: Twenty-three were allocated to vitamin D and 42 to placebo. There was no significant difference at baseline between the two groups. Mean (SD) baseline 25-hydroxyvitamin D was 65.7 (25.7) nmol/L. There were no significant differences (p > .05) between the groups in all of the psoriasis outcome measures. Mean scores [95% CI] at 12 months for the Placebo versus Vitamin D groups: PASI 2.2 [1.4, 3.0] versus 2.1 [1.0, 3.2]; PGA 1.4 [1.1, 1.7] versus 1.5 [1.1, 1.9]; PDI 2.1 [0.9, 3.2] versus 1.9 [0.4, 3.4]; and DLQI 2.5 [1.4, 3.6] versus 2.0 [0.5, 3.4]. CONCLUSION: Vitamin D3 supplementation (100,000 IU per month) is not recommended as a treatment for mild psoriasis. PMID- 28849683 TI - Do we need another symptom score for childhood eczema? AB - AIM: It is important to objectively measure the severity of atopic dermatitis (AD). This study aims to investigate correlations among various clinical severity scores and determine how a severity score based on symptoms alone performs. METHODS: A Chinese-translated symptom score based on Patient-Oriented Eczema Measure (POEM, a short-term subjective-symptom score), Scoring Atopic Dermatitis (SCORAD, a short-term subjective-symptom and objective-sign score), Nottingham Eczema Severity Score (NESS, a long-term subjective symptoms + objective signs), Children Dermatology Life Quality Index (CDLQI, a short-term subjective-symptom score), skin hydration (SH) and transepidermal water loss (TEWL) were compared and Spearman's rho correlations was evaluated. RESULTS: 126 sets of clinical scores from eczema patients (mean age: 11.4 +/- 5.6 years; 34.7% male) were evaluated. The modified-POEM, objective SCORAD, NESS and CDLQI correlated well with each other. All round, best correlations were obtained with POEM: Objective SCORAD (rho = 0.7, p < 0.001), NESS (rho = 0.69, p < 0.001), SCORAD symptom of itch (rho = 0.75, p < 0.01), SCORAD symptom of sleep loss (rho = 0.64, p < 0.01), CDLQI (rho = 0.77, p < 0.001) and SH (rho= -0.043, p < 0.05). Linear stepwise backward regression demonstrated that POEM was independently associated with CDLQI parameters of pruritus (B: 2.16; p = 0.018), activities (B: 1.80; p = 0.009), sleep disturbance (B: 2.78; p < 0.001) and NESS parameter of sleep disturbance (B: 1.02; p = 0.003). CONCLUSION: Clinical scores for acute, chronic, subjective symptoms and objective signs correlated well with each other. The symptom measures by modified POEM is easy to perform by parents or patients and correlated better with most other clinical scores, making it an all-round ideal symptom-based severity score for research. PMID- 28849684 TI - Early clinical outcome of coverage probability based treatment planning for simultaneous integrated boost of nodes in locally advanced cervical cancer. AB - INTRODUCTION: More than 50% of patients with locally advanced cervical cancer (LACC) have pathological nodes. Coverage probability (CovP) is a new planning technique allowing for relaxed dose at the boost periphery minimising collateral irradiation. The aim was to report the first early clinical outcome data for CovP based simultaneous integrated boost (SIB) in LACC. MATERIAL AND METHODS: Twenty three consecutive node positive patients were analysed. FIGO stage IB2/IIB/IIIB/IVA/IVB was 1/14/3/1/4. Treatment was radio(chemo)therapy (RT) delivering 45 Gy/25 fx whole pelvis +/- para-aortic region (PAN) using volumetric arc therapy (VMAT) followed by magnetic resonance imaging (MRI) guided brachytherapy. PAN RT (13 pts) was given if >2 nodes or if node(s) were present at the common iliac vessels or PAN. Nodal gross tumour volumes (GTV-N) were contoured on both PET-CT and MRI. Clinical target volume (CTV-N) was formed by fusion of GTV-NCT and GTV-NMRI. A 5-mm isotropic margin was used for planning target volume (PTV-N). Nodes in the small pelvis were boosted to 55.0 Gy/25 fx. Common iliac and para-aortic nodes received 57.5 Gy/25 fx. Planning aims for CovP were PTV-N D98 >= 90%, CTV-N D98 >= 100% and CTV-N D50 >= 101.5%. RESULTS: Seventy-four nodes were boosted. A consistent 5.0 +/- 0.7 Gy dose reduction from CTV-N D98 to PTV-N D98 was obtained. In total, 73/74 nodes were in complete remission at 3 months PET-CT and MRI. Pelvic control was obtained in 21/23 patients. One patient (IB2, clear cell) had salvageable local disease, while another (IIB) failed in a boosted node. Two patients failed in un-irradiated PAN. One patient age 88 (IIIB) did not receive PAN RT, despite a common iliac node. The other (IIB) recurred above L1. Two further patients (IVB) failed systemically. CONCLUSION: Since complete remission at 3 months is predictive for favourable long-term nodal control, our study indicates that CovP for SIB is promising. PMID- 28849685 TI - Antioxidant ameliorating effects against H2O2-induced cytotoxicity in primary endometrial cells. AB - Oxidative stress and a disrupted antioxidant system are involved in a variety of pregnancy complications. In the present study, the role of vitamin E (Vit E) and folate as radical scavengers on the GSH homeostasis in stress oxidative induced in rat endometrial cells was investigated. Primary endometrial stromal cell cultures treated with 50 and 200 uM of H2O2 and evaluated the cytoprotective effects of Vit E (5 uM) and folate (0.01 uM) in H2O2-treated cells for 24 h. Following the exposure of endometrial cells to H2O2 alone and in the presence of Vit E and/or folate, cell survival, glutathione peroxidase (GPx) and glutathione reductase activities and the level of reduced glutathione (GSH) were measured. Cell adhesions comprise of cell attachment and spreading on collagen were determined. Flow cytometric analysis using annexin V was used to measure apoptosis. H2O2 treatment showed a marked decrease in cell viability, GPx and GR activities and the level of GSH. Although Vit E or folate had some protective effect, combination therapy with Vit E and folate attenuated all the changes due to H2O2 toxicity. An increasing number of alive cells was showed in the cells exposed to H2O2 (50 uM) accompanied by co-treatment with Vit E and folic acid. The present findings indicate that co-administration of Vit E and folate before and during pregnancy may maintain a viable pregnancy and contribute to its clinical efficacy for the treatment of some idiopathic infertility. PMID- 28849686 TI - Luminally expressed gastrointestinal biomarkers. AB - INTRODUCTION: A biomarker is a measurable indicator of normal biologic processes, pathogenic processes or pharmacological responses. The identification of a useful biomarker is challenging, with several hurdles to overcome before clinical adoption. This review gives a general overview of a range of biomarkers associated with inflammatory bowel disease or colorectal cancer along the gastrointestinal tract. Areas covered: These markers include those that are already clinically accepted, such as inflammatory markers such as faecal calprotectin, S100A12 (Calgranulin C), Fatty Acid Binding Proteins (FABP), malignancy markers such as Faecal Occult Blood, Mucins, Stool DNA, Faecal microRNA (miRNA), other markers such as Faecal Elastase, Faecal alpha-1 antitrypsin, Alpha2-macroglobulin and possible future markers such as microbiota, volatile organic compounds and pH. Expert commentary: There are currently a few biomarkers that have been sufficiently validated for routine clinical use at present such as FC. However, many of these biomarkers continue to be limited in sensitivity and specificity for various GI diseases. Emerging biomarkers have the potential to improve diagnosis and monitoring but further study is required to determine efficacy and validate clinical utility. PMID- 28849687 TI - Supporting Parents' Pain Care Involvement With Their Children With Acute Lymphoblastic Leukemia: A Qualitative Interpretive Description. AB - Children with acute lymphoblastic leukemia experience pain from the disease, treatment, and procedures. Parents can be effective in managing their child's pain, but little is systematically known about how they do this. Appreciative inquiry was used to frame the study within a strengths-based lens and interpretive descriptive methods were used to describe pain sources, parents' pain care role, and key structures supporting parents pain care involvement. Eight paediatric oncology clinic nurses and 10 parents participated. Six key themes per group were identified. Parent themes included establishing therapeutic relationships, relearning how to care for my child, overcoming challenges and recognizing pain, learning parent specific strategies, empowering to take active pain care role, and maintaining relationships. Nurse themes included establishing therapeutic relationships, preparing parents to care for their child, facilitating pain assessment, teaching parents best pain care, empowering parents, and maintaining relationships. These findings can be used to guide clinical practice and future research. PMID- 28849688 TI - A phase I study on stereotactic body radiotherapy of liver metastases based on functional treatment planning using positron emission tomography with 2 [18F]fluoro-2-deoxy-d-galactose. AB - BACKGROUND AND PURPOSE: The galactose analog 2-[18F]fluoro-2-deoxy-d-galactose (FDGal) is used for quantification of regional hepatic metabolic capacity by functional positron emission tomography computerized tomography (PET/CT). In the present study, FDGal PET/CT was used for functional treatment planning (FTP) of stereotactic body radiotherapy (SBRT) of liver metastases with the aim of minimizing radiation dose to the best functioning liver tissue. MATERIAL AND METHODS: Fourteen patients referred for SBRT had FDGal PET/CT performed before and one month after the treatment. The planning CT and the FDGal PET/CT images were deformable co-registered. RESULTS: A reduction in the mean dose of approximately 2 Gy to the best functioning sub-volumes was obtained. One patient developed grade 2 acute morbidity and no patients experienced grade 3 or higher acute morbidities. The regional hepatic metabolic function post-treatment was linearly correlated to the regional radiation dose and for each 10-Gy increase in dose (gamma10Gy), the metabolic function was reduced by 12%. A 50% reduction was seen at 22.9 Gy in 3 fractions (CI 95%: 16.7-30.4 Gy). CONCLUSION: The clinical study demonstrates the feasibility for FTP in patients with liver metastases and it was possible to minimize the radiation dose to the best functioning liver tissue. PMID- 28849689 TI - Facial and limb angioedema with parotitis and Kikuchi-like necrotizing lymphadenitis preceding neuropsychiatric systemic lupus erythematosus in a young African American male. AB - Angioedema has been observed in a few cases secondary to systemic lupus erythematosus (SLE). Herein, we report a rare case where a young healthy male initially presented with angioedema, lymphadenopathy and parotitis and later on developed neuropsychiatric manifestations at the very onset of his SLE disease. This case illustrates the importance of prompt clinical consideration of lupus with unusual and atypical preceding manifestations. PMID- 28849692 TI - Conference Diary. PMID- 28849690 TI - Efficacy of ibrutinib in a patient with transformed lymphoplasmacytic lymphoma and central nervous system involvement. PMID- 28849694 TI - Corrigendum. AB - Cody CA, Mancuso CA, Burket JC, et al. Patient factors associated with higher expectations from foot and ankle surgery. Foot Ankle Int. 2017;38(5):472-478. (Original DOI: 10.1177/1071100717690807) In Table 2 of the above article, the authors reported that there was no significant difference in expectations scores between men and women. Repeat analysis of the data for a secondary study revealed that the data previously reported P value was erroneous and there was in fact a significant difference, with P = .026. All other previously reported results have been re-checked and there are no other errors. PMID- 28849695 TI - Acid - a despicable and offensive weapon. PMID- 28849696 TI - When a suicide becomes a forensic enigma: The role of hanging marks and tools of suspension. AB - Death by hanging is asphyxiation when the body is suspended by means of a ligature. Most deaths by hanging are suicides, though occasionally they are accidental or a homicidal event. The characteristics of the hanging marks depend on the ligature used, the dynamics and on the node position with respect to the neck. When the crime scene is contaminated, the hanging mark must be checked with the type of suspension and ligatures used to establish how the hangings took place. We report on 20 cases (2013-2016) where the bodies were moved at or from the crime scene. We analysed the features of hanging marks, the tools of suspension and the ligatures employed in each case. Judicial inspections and an external examination were also carried out. Analysis of hanging marks enables the pathologist to clarify the manner of death and the type of hanging, and tools used especially where the crime scene has been contaminated and the body has been moved. PMID- 28849697 TI - Liability for providing a prognosis in surgical practice. AB - The common law's development of the doctrine of informed consent has progressively imposed broader obligations on surgeons to provide patients with information about the surgical and alternative treatment choices available. Prognosis is critical because the patient cannot provide informed consent without information about the likely evolution of the physiological or pathological processes involved in the surgery under consideration. But does the duty of care that a surgeon owes a patient require a precise prognosis to be given in every case? A recent decision of the Court of Appeal considers that question. PMID- 28849699 TI - Hearing Outcomes after Ossicular Reconstruction with Removal of the Malleus. AB - Objectives (1) Evaluate hearing outcomes of patients after planned malleus removal during ossicular chain reconstruction. (2) Analyze hearing results for titanium (Ti) and hydroxyapatite (HA) total ossicular prostheses (TOPs) and partial ossicular prostheses (POPs). (3) Compare Ti and HA partial prostheses. Study Design Retrospective case series with chart review. Setting Tertiary health care organization. Subjects and Methods A chart review was conducted of 139 consecutive patients who presented with chronic otitis media with perforation (with or without cholesteatoma) and were treated with initial-stage tympanoplasty (with or without mastoidectomy) and managed with TOP (n = 22) or POP (n = 117) between July 2010 and July 2015. The malleus was completely removed in all cases. Hearing was assessed via bone and air conduction pretone averages (0.5, 1, 2 kHz) pre- and postoperatively. Air-bone gap (ABG) and change in ABG (DeltaABG) were analyzed. Pre- and postoperative values were compared. Results The overall mean ABG decreased from 29.4 +/- 12.3 dB to 18.2 +/- 11.4 dB postoperatively ( P < .001) with a mean DeltaABG of 14.5 dB (95% CI, 12.793-16.203). Overall success was achieved by 69.1%. The POP group achieved higher success (70.9%) than the TOP group (59.1%; P = .0001). Mean ABG decreased significantly within surgical groups (TOP and POP) and prosthesis material groups (Ti and HA; all P < .001). Ti had statistically higher success than HA in both techniques: POP ( P = .0478) and TOP ( P = .0251). There was a 98% graft take rate. Conclusion Planned malleus removal during ossicular chain reconstruction, regardless of disease extent, allows for simpler reconstruction and comparable favorable results to preservation of the malleus and should be considered during surgical planning. PMID- 28849700 TI - Development of Ligand and Structure-based classification models to design novel inhibitors against antibiotic hydrolyzing enzymes: Integration of web server. PMID- 28849698 TI - Imaging Neurotensin Receptor in Prostate Cancer With 64Cu-Labeled Neurotensin Analogs. AB - INTRODUCTION: Neurotensin receptor 1 (NTR-1) is expressed and activated in prostate cancer cells. In this study, we explore the NTR expression in normal mouse tissues and study the positron emission tomography (PET) imaging of NTR in prostate cancer models. MATERIALS AND METHODS: Three 64Cu chelators (1, 4, 7, 10 tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid [DOTA], 1,4,7 triazacyclononane-N,N',N"-triacetic acid [NOTA], or AmBaSar) were conjugated to an NT analog. Neurotensin receptor binding affinity was evaluated using cell binding assay. The imaging profile of radiolabeled probes was compared in well established NTR+ HT-29 tumor model. Stability of the probes was tested. The selected agents were further evaluated in human prostate cancer PC3 xenografts. RESULTS: All 3 NT conjugates retained the majority of NTR binding affinity. In HT 29 tumor, all agents demonstrated prominent tumor uptake. Although comparable stability was observed, 64Cu-NOTA-NT and 64Cu-AmBaSar-NT demonstrated improved tumor to background contrast compared with 64Cu-DOTA-NT. Positron emission tomography/computed tomography imaging of the NTR expression in PC-3 xenografts showed high tumor uptake of the probes, correlating with the in vitro Western blot results. Blocking experiments further confirmed receptor specificity. CONCLUSIONS: Our results demonstrated that 64Cu-labeled neurotensin analogs are promising imaging agents for NTR-positive tumors. These agents may help us identify NTR-positive lesions and predict which patients and individual tumors are likely to respond to novel interventions targeting NTR-1. PMID- 28849702 TI - Daclizumab for the treatment of multiple sclerosis. AB - Daclizumab is a monoclonal antibody that targets the alpha-chain of the IL-2 receptor. Results of Phase II and III clinical trials showed efficacy of daclizumab in relapsing-remitting multiple sclerosis, with reduction of annualized relapse rate by 50-54% versus placebo and 45% versus intramuscular IFN beta-1a. Certain aspects of the immunomodulatory mode of action of daclizumab were only discovered during its clinical development, such as the expansion of a subpopulation of natural killer cells. In this article, we outline the putative mechanisms of action and the key clinical data on daclizumab, with a focus on the efficacy and safety profile. We also evaluate its potential role in future treatment algorithms of multiple sclerosis. PMID- 28849701 TI - Understanding Treatment Burden and Quality of Life Impact of Participating in an Early-Phase Pediatric Oncology Clinical Trial: A Pilot Study. AB - PURPOSE: Early-phase clinical trials (EPTs) have led to new, more effective treatment options for children with cancer. Despite the extensive use of EPTs in pediatric oncology, little is known about parent and child experiences during EPT participation. The purposes of this pilot study were to assess the feasibility and preliminary results of having children with cancer and their parents complete measures of treatment burden and quality of life (QOL) concurrent with EPT participation. METHODS: In this descriptive, longitudinal, pilot study, parents and children were followed for the first 60 days of an EPT. Feasibility was assessed by participant enrollment and retention and completion of measures. Measures completed included the following: demographic form (completed at baseline); Diary of Trial Experiences to capture treatment burden (completed ongoing); and PedsQLTM Quality of Life Inventories, Cancer Modules, and Family Impact Module (completed at baseline, post-first disease evaluation, and off study). Data were analyzed using descriptive statistics. RESULTS: Feasibility goals of enrollment, retention, and measure completion were partially met. Preliminary treatment burden and QOL results are provided. CONCLUSIONS: While QOL assessments may provide insight into EPT experiences, future studies need to be conducted at multiple sites and enrollment goals must account for participant attrition. PMID- 28849703 TI - Factor analysis of the everyday memory questionnaire in persons with traumatic brain injury. AB - OBJECTIVES: To investigate the factor structure of the Everyday Memory Questionnaire (EMQ) in persons with traumatic brain injury (TBI). METHOD: This was a secondary analysis of baseline data from two clinical trials targeting memory impairment after TBI. Participants were 169 persons with complicated mild, moderate, or severe TBI at an average of 41 months post-injury. They completed the EMQ via clinical interview. Exploratory factor analysis was conducted using a three-factor principal axis factoring estimation method with a polychoric correlation matrix and oblique rotation. RESULTS: The three factors accounted for 49.2% of the variance, with moderate correlations observed among the factors. The three factors appeared to represent general everyday memory (prospective and episodic), conversational memory, and spatial or action memory. The three factors added significantly to the variance in age-corrected objective learning test scores predicted by injury severity, education, and sex. CONCLUSIONS: The three factors of the EMQ are consistent with the heterogeneity of memory impairments observed after TBI. The factor scores may be used to target treatments for impaired memory and to evaluate their effectiveness. PMID- 28849704 TI - Ultra-early apparent diffusion coefficient change indicates irradiation and predicts radiotherapy outcome in brain metastases. PMID- 28849705 TI - Auditory Outcomes with Hearing Rehabilitation in Children with Unilateral Hearing Loss: A Systematic Review. AB - Objective Options for management of unilateral hearing loss (UHL) in children include conventional hearing aids, bone-conduction hearing devices, contralateral routing of signal (CROS) aids, and frequency-modulating (FM) systems. The objective of this study was to systematically review the current literature to characterize auditory outcomes of hearing rehabilitation options in UHL. Data Sources PubMed, EMBASE, Medline, CINAHL, and Cochrane Library were searched from inception to January 2016. Manual searches of bibliographies were also performed. Review Methods Studies analyzing auditory outcomes of hearing amplification in children with UHL were included. Outcome measures included functional and objective auditory results. Two independent reviewers evaluated each abstract and article. Results Of the 249 articles identified, 12 met inclusion criteria. Seven articles solely focused on outcomes with bone-conduction hearing devices. Outcomes favored improved pure-tone averages, speech recognition thresholds, and sound localization in implanted patients. Five studies focused on FM systems, conventional hearing aids, or CROS hearing aids. Limited data are available but suggest a trend toward improvement in speech perception with hearing aids. FM systems were shown to have the most benefit for speech recognition in noise. Studies evaluating CROS hearing aids demonstrated variable outcomes. Conclusions Data evaluating functional and objective auditory measures following hearing amplification in children with UHL are limited. Most studies do suggest improvement in speech perception, speech recognition in noise, and sound localization with a hearing rehabilitation device. PMID- 28849706 TI - Utility of the Behavior Rating Inventory of Executive Function - Preschool version (BRIEF-P) in young children with epilepsy. AB - Executive functioning deficits are prominent in children with epilepsy. Although instruments, such as the Behavior Rating Inventory of Executive Function (BRIEF), are useful in detecting executive dysfunction in school-age children with epilepsy, little data are available for younger children. The present study evaluates the ability of the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P) to detect executive dysfunction in preschool-age children with epilepsy. Parents of 51 clinically referred children with epilepsy (age: M = 1.99 years, SD = 1.29 years, range = 2-5 years) completed the BRIEF-P. Using a cutoff t score of >=65 as the threshold for impairment, the BRIEF-P's ability to detect executive dysfunction within this clinical population was established. Additionally, correlational analyses were used to assess the relations between epilepsy severity factors and BRIEF-P indices. Epilepsy severity variables that were significantly related to BRIEF-P indices were entered into a linear regression model to explore their predictive ability. Emergent metacognition (emergent metacognition index [EMI]; 59%) and the global executive composite (43%) were the most frequently elevated indices. The most commonly elevated subscales were working memory (65%), inhibition (37%), and planning/organization (35%). Age of seizure onset, seizure frequency, and number of antiepileptic drugs were not significantly correlated with BRIEF-P indices. However, children with lower intellectual ability were rated as having greater executive dysfunction, specifically with EMI (r = -.30). Still, intellectual functioning only accounted for a small percentage (9%) of the variance in EMI scores. The current pilot study demonstrates that the BRIEF-P shows promise in identifying executive dysfunction in preschool-age children with epilepsy. PMID- 28849707 TI - A new method to assess pulmonary changes using 18F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy. AB - BACKGROUND: 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) may be used for assessing radiation induced alterations in the lung. However, there is a need to further develop methodologies to improve quantification. Using computed tomography (CT), a local structure method has been shown to be superior to conventional CT-based analysis. Here, we investigate whether the local structure method based on 18F-FDG-PET improves radiotherapy (RT) dose-response quantification for lung cancer patients. MATERIAL AND METHODS: Sixteen patients with lung cancer undergoing fractionated RT were examined by 18F-FDG-PET/CT at three sessions (pre, mid, post) and the lung was delineated in the planning CT images. The RT dose matrix was co-registered with the PET images. For each PET image series, mean (MU) and standard deviation (sigma) maps were calculated based on cubes in the lung (3 * 3 * 3 voxels), where the spread in pre-therapy MU and sigma was characterized by a covariance ellipse in a sub-volume of 3 * 3 * 3 cubes. Mahalanobis distance was used to measure the distance of individual cube values to the origin of the ellipse and to further form local structure 'S' maps. The structural difference maps (DeltaS) and mean difference maps (DeltaMU) were calculated by subtracting pre-therapy maps from maps at mid- and post-therapy. Corresponding maps based on CT images were also generated. RESULTS: DeltaS identified new areas of interest in the lung compared to conventional DeltaMU maps. DeltaS for PET and CT gave a significantly elevated lung signal compared to a control group during and post-RT (p < .05). Dose-response analyses by linear regression showed that DeltaS between pre- and post-therapy for 18F-FDG-PET was the only parameter significantly associated with local lung dose (p = .04). CONCLUSIONS: The new method using local structures on 18F-FDG-PET provides a clearer uptake dose-response compared to conventional analysis and CT-based approaches and may be valuable in future studies addressing lung toxicity. PMID- 28849708 TI - The aminopeptidase inhibitor, z-L-CMK, is toxic and induces cell death in Jurkat T cells through oxidative stress. AB - The leucine aminopeptidase inhibitor, benzyloxycarbonyl-leucine chloromethylketone (z-L-CMK), was found to be toxic and readily induce cell death in Jurkat T cells. Dose-response studies show that lower concentration of z-L-CMK induced apoptosis in Jurkat T cells whereas higher concentration causes necrosis. In z-L-CMK-induced apoptosis, both the initiator caspases (-8 and -9) and effector caspases (-3 and -6) were processed to their respective subunits. However, the caspases remained intact in z-L-CMK-induced necrosis. The caspase inhibitor, z-VAD-FMK inhibited z-L-CMK-mediated apoptosis and caspase processing but has no effect on z-L-CMK-induced necrosis in Jurkat T cells. The high mobility group protein B1 (HMGB1) protein was found to be released into the culture medium by the necrotic cells and not the apoptotic cells. These results indicate that the necrotic cell death mediated by z-L-CMK at high concentrations is via classical necrosis rather than secondary necrosis. We also demonstrated that cell death mediated by z-L-CMK was associated with oxidative stress via the depletion of intracellular glutathione (GSH) and increase in reactive oxygen species (ROS), which was blocked by N-acetyl cysteine. Taken together, the results demonstrated that z-L-CMK is toxic to Jurkat T cells and induces apoptosis at low concentrations, while at higher concentrations the cells die of necrosis. The toxic side effects in Jurkat T cells mediated by z-L-CMK are associated with oxidative stress via the depletion of GSH and accumulation of ROS. PMID- 28849709 TI - Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis. AB - OBJECTIVES: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. METHODS: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 - erythrocyte sedimentation rate [ESR] <= 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits. RESULTS: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (DeltamTSS) <=0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and DeltaDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. DeltaSwollen joint count at week six positively correlated with DeltamTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. CONCLUSION: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability. PMID- 28849710 TI - Management of Large-Volume Subperiosteal Abscesses of the Orbit: Medical vs Surgical Outcomes. AB - Objectives To compare clinical variables and outcomes for children with subperiosteal abscesses of the orbit (SPAO) managed medically vs surgically to identify clinical prognosticators. Study Design Case series with chart review. Setting Tertiary children's academic institution. Subjects and Methods The study included 48 children between the age of 1 month and 14 years, with SPAO from 2003 to 2013. Variables included age, sex, physical examination findings, laboratory results, computed tomography (CT) findings, hospital length of stay, length of antibiotic therapy, and placement of a peripherally inserted central catheter (PICC). Intended methods for comparison were the Student t test for continuous variables and Fisher's exact test for categorical variables, and a forward stepwise multiple logistic regression. Results Thirty-two (67%) children were successfully treated with antibiotic therapy only, and 16 (33%) required surgery. Abscess volume, abscess width, and the presence of gaze restriction were statistically different between the 2 groups. A multivariate analysis found abscess volume as the only predictor for surgical intervention. A subgroup analysis including only patients with an abscess volume of >=500 mm3 (n = 26) was performed. Eleven patients were treated medically and 15 treated surgically, with the medical group having longer hospital stays ( P = .048), duration of antibiotic therapy ( P = .035), and higher incidence of PICC placement ( P = .005). Conclusions This is the first study to report that abscess volume has clinical implications, as children with SPAO volume >=500 mm3 treated medically have longer inpatient admissions, antibiotic therapy durations, and PICC placement. When children present with an abscess >=500 mm3, early surgical intervention should be strongly considered, even in the absence of other surgical criteria, to shorten duration of hospitalization and accelerate clinical improvement. PMID- 28849711 TI - Critical Airway Team: A Retrospective Study of an Airway Response System in a Pediatric Hospital. AB - Objective Study the performance of a pediatric critical airway response team. Study Design Case series with chart review. Setting Freestanding academic children's hospital. Subjects and Methods A structured review of the electronic medical record was conducted for all activations of the critical airway team. Characteristics of the activations and patients are reported using descriptive statistics. Activation of the critical airway team occurred 196 times in 46 months (March 2012 to December 2015); complete data were available for 162 activations (83%). For 49 activations (30%), patients had diagnoses associated with difficult intubation; 45 (28%) had a history of difficult laryngoscopy. Results Activation occurred at least 4 times per month on average (vs 3 per month for hospital-wide codes). The most common reasons for team activation were anticipated difficult intubation (45%) or failed intubation attempt (20%). For 79% of activations, the team performed an airway procedure, most commonly direct laryngoscopy and tracheal intubation. Bronchoscopy was performed in 47% of activations. Surgical airway rescue was attempted 4 times. Cardiopulmonary resuscitation occurred in 41 activations (25%). Twenty-nine patients died during or following team activation (18%), including 10 deaths associated with the critical airway event. Conclusion Critical airway team activation occurred at least once per week on average. Direct laryngoscopy, tracheal intubation, and bronchoscopic procedures were performed frequently; surgical airway rescue was rare. Most patients had existing risk factors for difficult intubation. Given our rate of serious morbidity and mortality, primary prevention of critical airway events will be a focus of future efforts. PMID- 28849712 TI - Combination of Fluorescence-Guided Surgery With Photodynamic Therapy for the Treatment of Cancer. AB - Specific visualization of body parts is needed during surgery. Fluorescence guided surgery (FGS) uses a fluorescence contrast agent for in vivo tumor imaging to detect and identify both malignant and normal tissues. There are several advantages and clinical benefits of FGS over other conventional medical imaging modalities, such as its safety, effectiveness, and suitability for real-time imaging in the operating room. Recent advancements in contrast agents and intraoperative fluorescence imaging devices have led to a greater potential for intraoperative fluorescence imaging in clinical applications. Photodynamic therapy (PDT) is an alternative modality to treat tumors, which uses a light sensitive drug (photosensitizers) and special light to destroy the targeted tissues. In this review, we discuss the fluorescent contrast agents, some newly developed imaging devices, and the successful clinical application of FGS. Additionally, we present the combined strategy of FGS with PDT to further improve the therapeutic effect for patients with cancer. Taken together, this review provides a unique perspective and summarization of FGS. PMID- 28849713 TI - Upregulation of CX3CL1 mediated by NF-kappaB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration. AB - Painful peripheral neuropathy is a severe side effect in oxaliplatin therapy that compromises cancer patients' quality of life. However, its underlying pathogenic mechanisms remain largely unknown. Here, we found that intraperitoneal consecutive administration of oxaliplatin significantly increased excitability of small diameter dorsal root ganglion neurons and induced thermal hyperalgesia in rats. Furthermore, the CX3CL1 expression was significantly increased after oxaliplatin treatment, and intrathecal injection of a neutralizing antibody against CX3CL1 markedly attenuated the enhanced excitability of dorsal root ganglion neurons and thermal hyperalgesia. Importantly, the upregulated CX3CL1 is mediated by the NF-kappaB signaling pathway, as inhibition of NF-kappaB p65 activation with pyrrolidine dithiocarbamate or p65 siRNA inhibited the upregulation of CX3CL1, the enhanced excitability of dorsal root ganglion neurons, and thermal hyperalgesia induced by oxaliplatin. Further studies with chromatin immunoprecipitation found that oxaliplatin treatment increased the recruitment of NF-kappaB p65 to the CX3Cl1 promoter region. Our results suggest that upregulation of CX3CL1 in dorsal root ganglion mediated by NF-kappaB activation contributes to the peripheral sensitization and chronic pain induced by oxaliplatin administration. PMID- 28849714 TI - Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain. AB - Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. In this study, we investigated individual variance in both sensory and affective/emotional dimensions of pain behaviors in response to chronic neuropathic pain condition in a mouse model of chronic pain. We found that mice displayed considerably diverse sensitivities in the chronic pain-induced anxiety- and depression-like behaviors of affective pain. Importantly, the mouse group that was more vulnerable to developing anxiety was also more vulnerable to developing depressive behavior under the chronic pain condition. In contrast, there was relatively much less variance in individual responses in the sensory dimension of pain sensitization. Molecular analysis revealed that those mice vulnerable to developing the emotional disorders showed a significant reduction in the protein level of DNA methyltransferase 3a in the emotion-processing central nucleus of the amygdala. In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability. PMID- 28849715 TI - Productivity loss of Japanese patients with rheumatoid arthritis - A cross sectional survey. AB - OBJECTIVE: The objective of this study was (1) to determine productivity costs due to absenteeism and presenteeism among Japanese workers with rheumatoid arthritis (RA), and (2) to identify additional factors associated with productivity loss among workers with RA. METHODS: An online survey of 500 RA Japanese patients was used. The Japanese version of the Stanford Health Assessment Questionnaire (J-HAQ) was used to measure patients' functional disability. The patient health questionnaire-9 item (PHQ-9) was used to measure symptoms and severity of depression. To assess work productivity the 'work productivity and activity impairment questionnaire' for rheumatoid arthritis (WPAI-RA), a six-item validated instrument was used. RESULTS: Percentages of absenteeism and presenteeism were found to be 1% and 23%, respectively. The annual combined productivity costs of both absenteeism and presenteeism was 7877 USD per patient. Factors significantly associated with a higher productivity loss were functional disability, depressive symptoms, and time since RA diagnosis, while age, and biological disease-modifying antirheumatic drugs (bDMARDs) treatment were significantly associated with a lower productivity loss. CONCLUSION: Treatment of RA with bDMARDs would likely result in decreased productivity loss among Japanese patients. PMID- 28849716 TI - Comparing routine inpatient data and death records as a means of identifying children and young people with life-limiting conditions. AB - BACKGROUND: Recent estimates of the number of children and young people with life limiting conditions derived from routine inpatient data are higher than earlier estimates using death record data. AIM: To compare routine inpatient data and death records as means of identifying life-limiting conditions in children and young people. DESIGN: Two national cohorts of children and young people with a life-limiting condition (primary cohort from England with a comparator cohort from Scotland) were identified using linked routinely collected healthcare and administrative data. PARTICIPANTS: A total of 37,563 children and young people with a life-limiting condition in England who died between 1 April 2001 and 30 March 2015 and 2249 children and young people with a life-limiting condition in Scotland who died between 1 April 2003 and 30 March 2014. RESULTS: In England, 16,642 (57%) non-neonatal cohort members had a life-limiting condition recorded as the underlying cause of death; 3364 (12%) had a life-limiting condition related condition recorded as the underlying cause and 3435 (12%) had life limiting conditions recorded only among contributing causes. In all, 5651 (19%) non-neonates and 3443 (41%) neonates had no indication of a life-limiting condition recorded in their death records. Similar results were seen in Scotland (overall, 16% had no indication of life-limiting conditions). In both cohorts, the recording of life-limiting condition was highest among those with haematology or oncology diagnoses and lowest for genitourinary and gastrointestinal diagnoses. CONCLUSION: Using death record data alone to identify children and young people with life-limiting condition - and therefore those who would require palliative care services - would underestimate the numbers. This underestimation varies by age, deprivation, ethnicity and diagnostic group. PMID- 28849717 TI - Heavy metals found in the breathing zone, toenails and lung function of welders working in an air-conditioned welding workplace. AB - Welding operations are rarely conducted in an air-conditioned room. However, a company would set its welding operations in an air-conditioned room to maintain the humidity level needed to reduce hydrogen cracks in the specimen being welded. This study intended to assess the exposure to metal elements in the welders' breathing zone and toenail samples. Heavy metal concentration was analysed using inductively coupled plasma mass spectrometry. The lung function test was also conducted and analysed using statistical approaches. Chromium and manganese concentrations in the breathing zone exceeded the permissible exposure limit stipulated by Malaysian regulations. A similar trend was obtained in the concentration of heavy metals in the breathing zone air sampling and in the welders' toenails. Although there was no statistically significant decrease in the lung function of welders, it is suggested that exposure control through engineering and administrative approaches should be considered for workplace safety and health improvement. PMID- 28849718 TI - Working with community health workers to improve maternal and newborn health outcomes: implementation and scale-up lessons from eastern Uganda. AB - BACKGROUND: Preventable maternal and newborn deaths can be averted through simple evidence-based interventions, such as the use of community health workers (CHWs), also known in Uganda as village health teams. However, the CHW strategy faces implementation challenges regarding training packages, supervision, and motivation. OBJECTIVES: This paper explores knowledge levels of CHWs, describes the coverage of home visits, and shares lessons learnt from setting up and implementing the CHW strategy. METHODS: The CHWs were trained to conduct four home visits: two during pregnancy and two after delivery. The aim of the visits was to promote birth preparedness and utilization of maternal and newborn health (MNH) services. Mixed methods of data collection were employed. Quantitative data were analyzed using Stata version 13.0 to determine the level and predictors of CHW knowledge of MNH. Qualitative data from 10 key informants and 15 CHW interviews were thematically analyzed to assess the implementation experiences. RESULTS: CHWs' knowledge of MNH improved from 41.3% to 77.4% after training, and to 79.9% 1 year post-training. However, knowledge of newborn danger signs declined from 85.5% after training to 58.9% 1 year later. The main predictors of CHW knowledge were age (>= 35 years) and post-primary level of education. The level of coverage of at least one CHW visit to pregnant and newly delivered mothers was 57.3%. Notably, CHW reports complemented the facility-based health information. CHWs formed associations, which improved teamwork, reporting, and general performance, and thus maintained low dropout rates at 3.6%. Challenges included dissatisfaction with the quarterly transport refund of 6 USD and lack of means of transportation such as bicycles. CONCLUSIONS: CHWs are an important resource in community-based health information and improving demand for MNH services. However, the CHW training and supervision models require strengthening for improved performance. Local solutions regarding CHW motivation are necessary for sustainability. PMID- 28849719 TI - Assessing the Needs of Parents of Children Diagnosed With Cancer in China: A Psychometric Study Developing a Needs Assessment Tool. AB - The psychosocial well-being of parents remains integral to the treatment and recovery of children diagnosed with cancer. However, limited research addresses the unique needs of this population. To better understand the supportive care needs of parents of children with cancer, this study tested the reliability and stability of the factorial structure of a revised version of the Cancer Patient Needs Questionnaire (rCPNQ) with Chinese parents of children who have cancer. Analysis of the generalizability of the rCPNQ with this population was determined through principle components analysis with varimax rotation. Reliability coefficient and split sample analyses were performed to determine reliability and stability of the resulting factors. The principal components analysis resulted in a 6-dimension, 8-factor, 29-item survey. Each of the factors had Cronbach's alpha >= .74, indicating satisfactory internal consistency and reliability of the survey with the Chinese population. Similar loadings on splitting of the samples reflects the stability of the factors. Study results provided a preliminary understanding of the needs of Chinese parents of children with cancer and demonstrated that the rCPNQ offers a reliable measure for nurses and other health care providers to partner with Chinese parents throughout their children's treatment and survivorship to determine areas for support. PMID- 28849720 TI - Modeling in vivo relative biological effectiveness in particle therapy for clinically relevant endpoints. AB - BACKGROUND: The relative biological effectiveness (RBE) of particle therapy compared to photon radiotherapy is known to be variable but the exact dependencies are still subject to debate. In vitro data suggested that RBE is to a large extend independent of ion type if parametrized by the beam quality Q. This study analyzed the RBE dependence of pre-clinical data on late toxicity with an emphasis on the beam quality. MATERIAL AND METHODS: Published pre-clinical RBE dose-response data of the spinal cord following one and two fractions of photon and carbon ion irradiation were compiled. The beam quality for each treatment condition was obtained from Monte Carlo simulations. The alphap and betap parameters of the linear-quadratic (LQ) model for particle irradiation were determined from the pre-clinical data and was provided as a function of Q. An introduced model proposed alphap to increase linearly with Q and betap to remain constant. RBE values predicted by the model were compared to the published data. RESULTS: The alphap parameter was highly correlated with Q (R2 = 0.96) with a linear slope of 0.019 Gy-1. No significant variation of betap with Q was found. RBE and Q were also highly correlated (R2 = 0.98) for one and two fractions. The (extrapolated) RBE at Q = 0 (theoretical photon limit) for one and two fractions was 1.22 and significantly larger than 1 (p = .004). The model reproduced the dependence of RBE on fractionation well. CONCLUSIONS: Fraction dose and beam quality Q were sufficient to describe the RBE variability for a late toxicity model within a carbon ion treatment field. Assuming the independence of the identified RBE parameters on the ion type might suggest the translation of variable (pre-) clinical RBE data from carbon ion to proton therapy. PMID- 28849721 TI - Overlap of highly FDG-avid and FMISO hypoxic tumor subvolumes in patients with head and neck cancer. AB - BACKGROUND: PET imaging may be used to personalize radiotherapy (RT) by identifying radioresistant tumor subvolumes for RT dose escalation. Using the tracers [18F]-fluorodeoxyglucose (FDG) and [18F]-fluoromisonidazole (FMISO), different aspects of tumor biology can be visualized. FDG depicts various biological aspects, e.g., proliferation, glycolysis and hypoxia, while FMISO is more hypoxia specific. In this study, we analyzed size and overlap of volumes based on the two markers for head-and-neck cancer patients (HNSCC). MATERIAL AND METHODS: Twenty five HNSCC patients underwent a CT scan, as well as FDG and dynamic FMISO PET/CT prior to definitive radio-chemotherapy in a prospective FMISO dose escalation study. Three PET-based subvolumes of the primary tumor (GTVprim) were segmented: a highly FDG-avid volume VFDG, a hypoxic volume on the static FMISO image acquired four hours post tracer injection (VH) and a retention/perfusion volume (VM) using pharmacokinetic modeling of dynamic FMISO data. Absolute volumes, overlaps and distances to agreement (DTA) were evaluated. RESULTS: Sizes of PET-based volumes and the GTVprim are significantly different (GTVprim>VFDG>VH >VM; p < .05). VH is covered by VFDG or DTAs are small (mean coverage 74.4%, mean DTA 1.4 mm). Coverage of VM is less pronounced. With respect to VFDG and VH, the mean coverage is 48.7% and 43.1% and the mean DTA is 5.3 mm and 6.3 mm, respectively. For two patients, DTAs were larger than 2 cm. CONCLUSIONS: Hypoxic subvolumes from static PET imaging are typically covered by or in close proximity to highly FDG-avid subvolumes. Therefore, dose escalation to FDG positive subvolumes should cover the static hypoxic subvolumes in most patients, with the disadvantage of larger volumes, resulting in a higher risk of dose-limiting toxicity. Coverage of subvolumes from dynamic FMISO PET is less pronounced. Further studies are needed to explore the relevance of mismatches in functional imaging. PMID- 28849722 TI - All-trans retinoic acid induces autophagic degradation of ubiquitin-like modifier activating enzyme 3 in acute promyelocytic leukemia cells. AB - All-trans retinoic acid (ATRA) has demonstrated notable success in the treatment of acute promyelocytic leukemia (APL) by inducing granulocytic differentiation. The underlying mechanisms of ATRA therapeutic effects have not been entirely clarified. Here, we reported that the regulation of neddylation, a ubiquitination like post-translational modification, was involved in the treatment of ATRA on APL. Treating APL cells with ATRA led to the degradation of UBA3, a subunit of neddylation E1. Lysosome-autophagy pathway but not proteasome pathway was responsible for the degradation of UBA3. Neddylation suppression in APL cells was capable of inducing apoptosis, differentiation and proliferation inhibition, suggesting a pivotal role of neddylation in APL cells. ATRA treatment also led to UBA3 degradation in primary APL cells. Taken together, our findings indicated that neddylation was important to maintain the malignant features of APL cells, and suppression of neddylation was involved in the effects of ATRA on APL cells. PMID- 28849723 TI - Maternal and neonatal implementation for equitable systems. A study design paper. AB - BACKGROUND: Evidence on effective ways of improving maternal and neonatal health outcomes is widely available. The challenge that most low-income countries grapple with is implementation at scale and sustainability. OBJECTIVES: The study aimed at improving access to quality maternal and neonatal health services in a sustainable manner by using a participatory action research approach. METHODS: The study consisted of a quasi-experimental design, with a participatory action research approach to implementation in three rural districts (Pallisa, Kibuku and Kamuli) in Eastern Uganda. The intervention had two main components; namely, community empowerment for comprehensive birth preparedness, and health provider and management capacity-building. We collected data using both quantitative and qualitative methods using household and facility-level structured surveys, record reviews, key informant interviews and focus group discussions. We purposively selected the participants for the qualitative data collection, while for the surveys we interviewed all eligible participants in the sampled households and health facilities. Descriptive statistics were used to describe the data, while the difference in difference analysis was used to measure the effect of the intervention. Qualitative data were analysed using thematic analysis. CONCLUSIONS: This study was implemented to generate evidence on how to increase access to quality maternal and newborn health services in a sustainable manner using a multisectoral participatory approach. PMID- 28849724 TI - Molecular-genetic diagnostics of von Hippel-Lindau syndrome (VHL) in Bulgaria: first complex mutation event in the VHL gene. AB - : Von Hippel-Lindau syndrome is an autosomal-dominant disease characterized by the formation of various tumours and cysts in many different parts of the body. Von Hippel-Lindau syndrome is caused by VHL gene mutations leading to production of impaired tumor suppressor Von Hippel-Lindau syndrome protein or its complete absence. PURPOSE: To study five patients with clinically suspected Von Hippel Lindau syndrome, who were referred for molecular genetic testing. METHODS: Sanger sequencing of the coding regions of the VHL gene. RESULTS: Five clinically relevant germline mutations were detected. One of the pathogenic variants has not been previously reported. This novel mutation is a complex mutation event combining a duplication and an indel, rearranging exon 3 of the VHL gene - c. [516_517dupGTCAAGCCT; 532_542delCTGGACATCGTinsATTA], p. (Glu173Serfs*4). CONCLUSION: Overall, our results showed that the diagnosis of Von Hippel-Lindau syndrome in our country is difficult most probably because of its heterogeneous clinical manifestation and insufficient knowledge on the diagnostic criteria for the disease. From genetic point of view our results add some novel data on the mutation profile of the VHL gene. In order to prove or revise the diagnosis, early genetic testing is strongly recommended in affected patients and their family members to ensure appropriate follow-up and treatment of the malignancies. PMID- 28849725 TI - Evaluating the electronic tuberculosis register surveillance system in Eden District, Western Cape, South Africa, 2015. AB - BACKGROUND: Tuberculosis (TB) surveillance data are crucial to the effectiveness of National TB Control Programs. In South Africa, few surveillance system evaluations have been undertaken to provide a rigorous assessment of the platform from which the national and district health systems draws data to inform programs and policies. OBJECTIVE: Evaluate the attributes of Eden District's TB surveillance system, Western Cape Province, South Africa. METHODS: Data quality, sensitivity and positive predictive value were assessed using secondary data from 40,033 TB cases entered in Eden District's ETR.Net from 2007 to 2013, and 79 purposively selected TB Blue Cards (TBCs), a medical patient file and source document for data entered into ETR.Net. Simplicity, flexibility, acceptability, stability and usefulness of the ETR.Net were assessed qualitatively through interviews with TB nurses, information health officers, sub-district and district coordinators involved in the TB surveillance. RESULTS: TB surveillance system stakeholders report that Eden District's ETR.Net system was simple, acceptable, flexible and stable, and achieves its objective of informing TB control program, policies and activities. Data were less complete in the ETR.Net (66-100%) than in the TBCs (76-100%), and concordant for most variables except pre-treatment smear results, antiretroviral therapy (ART) and treatment outcome. The sensitivity of recorded variables in ETR.Net was 98% for gender, 97% for patient category, 93% for ART, 92% for treatment outcome and 90% for pre-treatment smear grading. CONCLUSIONS: Our results reveal that the system provides useful information to guide TB control program activities in Eden District. However, urgent attention is needed to address gaps in clinical recording on the TBC and data capturing into the ETR.Net system. We recommend continuous training and support of TB personnel involved with TB care, management and surveillance on TB data recording into the TBCs and ETR.Net as well as the implementation of a well-structured quality control and assurance system. PMID- 28849726 TI - Palladium(II) complexes of biorelevant ligands. Synthesis, structures, cytotoxicity and rich DNA/HSA interaction studies. AB - In this work, a pair of new palladium(II) complexes, [Pd(Gly)(Phe)] and [Pd(Gly)(Tyr)], (where Gly is glycine, Phe is phenylalanine, and Tyr is tyrosine) were synthesized and characterized by UV-Vis, FT-IR, elemental analysis, 1H-NMR, and conductivity measurements. The detailed 1H NMR and infrared spectral studies of these Pd(II) complexes ascertain the mode of binding of amino acids to palladium through nitrogen of -NH2 and oxygen of -COO- groups as bidentate chelates. The Pd(II) complexes have been tested for in vitro cytotoxicity activities against cancer cell line of K562. Interactions of these Pd(II) complexes with CT-DNA and human serum albumin were identified through absorption/emission titrations and gel electrophoresis which indicated significant binding proficiency. The binding distance (r) between these synthesized complexes and HSA based on Forster's theory of non-radiation energy transfer were calculated. Alterations of HSA secondary structure induced by complexes were confirmed by FT-IR measurements. The results of emission quenching at three temperatures have revealed that the quenching mechanism of these Pd(II) complexes with CT-DNA and HSA were the static and dynamic quenching mechanism, respectively. Binding constants (Kb), binding site number (n), and the corresponding thermodynamic parameters were calculated and revealed that the hydrogen binding and hydrophobic forces played a major role when Pd(II) complexes interacted with DNA and HSA, respectively. We bid that [Pd(Gly)(Phe)] and [Pd(Gly)(Tyr)] complexes exhibit the groove binding with CT-DNA and interact with the main binding pocket of HSA. The complexes follow the binding affinity order of [Pd(Gly)(Tyr)] > [Pd(Gly)(Phe)] with CT-DNA- and HSA-binding. PMID- 28849727 TI - Involvement of palliative care in euthanasia practice in a context of legalized euthanasia: A population-based mortality follow-back study. AB - BACKGROUND: In the international debate about assisted dying, it is commonly stated that euthanasia is incompatible with palliative care. In Belgium, where euthanasia was legalized in 2002, the Federation for Palliative Care Flanders has endorsed the viewpoint that euthanasia can be embedded in palliative care. AIM: To examine the involvement of palliative care services in euthanasia practice in a context of legalized euthanasia. DESIGN: Population-based mortality follow-back survey. SETTING/PARTICIPANTS: Physicians attending a random sample of 6871 deaths in Flanders, Belgium, in 2013. RESULTS: People requesting euthanasia were more likely to have received palliative care (70.9%) than other people dying non suddenly (45.2%) (odds ratio = 2.1 (95% confidence interval, 1.5-2.9)). The most frequently indicated reasons for non-referral to a palliative care service in those requesting euthanasia were that existing care already sufficiently addressed the patient's palliative and supportive care needs (56.5%) and that the patient did not want to be referred (26.1%). The likelihood of a request being granted did not differ between cases with or without palliative care involvement. Palliative care professionals were involved in the decision-making process and/or performance of euthanasia in 59.8% of all euthanasia deaths; this involvement was higher in hospitals (76.0%) than at home (47.0%) or in nursing homes (49.5%). CONCLUSION: In Flanders, in a context of legalized euthanasia, euthanasia and palliative care do not seem to be contradictory practices. A substantial proportion of people who make a euthanasia request are seen by palliative care services, and for a majority of these, the request is granted. PMID- 28849728 TI - Scaling up family planning in Sierra Leone: A prospective cost-benefit analysis. AB - Family planning is commonly regarded as a highly cost-effective health intervention with wider social and economic benefits. Yet use of family planning services in Sierra Leone is currently low and 25.0% of married women have an unmet need for contraception. This study aims to estimate the costs and benefits of scaling up family planning in Sierra Leone. Using the OneHealth Tool, two scenarios of scaling up family planning coverage to currently married women in Sierra Leone over 2013-2035 were assessed and compared to a 'no-change' counterfactual. Our costing included direct costs of drugs, supplies and personnel time, programme costs and a share of health facility overhead costs. To monetise the benefits, we projected the cost savings of the government providing five essential social services - primary education, child immunisation, malaria prevention, maternal health services and improved drinking water - in the scale up scenarios compared to the counterfactual. The total population, estimated at 6.1 million in 2013, is projected to reach 8.3 million by 2035 in the high scenario compared to a counterfactual of 9.6 million. We estimate that by 2035, there will be 1400 fewer maternal deaths and 700 fewer infant deaths in the high scenario compared to the counterfactual. Our modelling suggests that total costs of the family planning programme in Sierra Leone will increase from US$4.2 million in 2013 to US$10.6 million a year by 2035 in the high scenario. For every dollar spent on family planning, Sierra Leone is estimated to save US$2.10 in expenditure on the five selected social sector services over the period. There is a strong investment case for scaling up family planning services in Sierra Leone. The ambitious scale-up scenarios have historical precedent in other sub-Saharan African countries, but the extent to which they will be achieved depends on a commitment from both the government and donors to strengthening Sierra Leone's health system post-Ebola. PMID- 28849729 TI - Effect of a participatory multisectoral maternal and newborn intervention on birth preparedness and knowledge of maternal and newborn danger signs among women in Eastern Uganda: a quasi-experiment study. AB - BACKGROUND: Knowledge of obstetric danger signs and adequate birth preparedness (BP) are critical for improving maternal services utilization. OBJECTIVES: This study assessed the effect of a participatory multi-sectoral maternal and newborn intervention on BP and knowledge of obstetric danger signs among women in Eastern Uganda. METHODS: The Maternal and Neonatal Implementation for Equitable Systems (MANIFEST) study was implemented in three districts from 2013 to 2015 using a quasi-experimental pre-post comparison design. Data were collected from women who delivered in the last 12 months. Difference-in-differences (DiD) and generalized linear modelling analysis were used to assess the effect of the intervention on BP practices and knowledge of obstetric danger signs. RESULTS: The overall BP practices increased after the intervention (DiD = 5, p < 0.05). The increase was significant in both intervention and comparison areas (7-39% vs. 7-36%, respectively), with a slightly higher increase in the intervention area. Individual savings, group savings, and identification of a transporter increased in both intervention and comparison area (7-69% vs. 10-64%, 0-11% vs. 0-5%, and 9 14% vs. 9-13%, respectively). The intervention significantly increased the knowledge of at least three obstetric danger signs (DiD = 31%) and knowledge of at least two newborn danger signs (DiD = 21%). Having knowledge of at least three BP components and attending community dialogue meetings increased the odds of BP practices and obstetric danger signs' knowledge, respectively. Village health teams' home visits, intervention area residence, and being in the 25+ age group increased the odds of both BP practices and obstetric danger signs' knowledge. CONCLUSIONS: The intervention resulted in a modest increase in BP practices and knowledge of obstetric danger signs. Multiple strategies targeting women, in particular the adolescent group, are needed to promote behavior change for improved BP and knowledge of obstetric danger signs. PMID- 28849730 TI - Impact of Type 2 Diabetes Mellitus on Survival in Head and Neck Squamous Cell Carcinoma. AB - Objective To identify any association between type 2 diabetes mellitus (T2DM) and survival outcomes for mucosal squamous cell carcinoma of the head and neck. An association has been demonstrated between T2DM and cancer outcomes at numerous sites, but data for the head and neck are limited. Improving our understanding of the impact that diabetes has on head and neck cancer survival is relevant for making treatment decisions and counseling patients regarding prognosis. Study Design Retrospective cohort study. Setting Academic tertiary referral head and neck cancer center. Subjects and Methods By accessing data retrospectively from prospectively collected databases at the Princess Margaret Cancer Centre, patients were studied who were treated for mucosal head and neck squamous cell cancer between January 2005 and December 2011. Collection of clinical, pathologic, and survival data was completed with an emphasis on T2DM. Results Of 2498 patients identified in the study period, 319 (12.8%) had T2DM. Five-year overall survival was not different between the diabetic (64%, 95% CI = 58%-71%) and nondiabetic (67%, 95% CI = 65%-69%; P = .078) groups. Furthermore, cause specific survival did not demonstrate a statistically significant difference between groups (diabetic: 84%, 95% CI = 79%-88%, vs nondiabetic: 84%, 95% CI = 82%-86%; P = .67). Conclusion Despite contradictory evidence at other cancer sites, the presence of T2DM alone does not appear to adversely affect cancer survival outcomes in head and neck squamous cell cancer. This is encouraging for the diabetic patients with head and neck squamous cell cancer, and it provides guidance for the multidisciplinary team that treats them. PMID- 28849731 TI - Three-dimensional dose evaluation in breast cancer patients to define decision criteria for adaptive radiotherapy. AB - BACKGROUND: Dose-guided adaptive radiation therapy (DGART) is the systematic evaluation and adaptation of the dose delivery during treatment for an individual patient. The aim of this study is to define quantitative action levels for DGART by evaluating changes in 3D dose metrics in breast cancer and correlate them with clinical expert evaluation. MATERIAL AND METHODS: Twenty-three breast cancer treatment plans were evaluated, that were clinically adapted based on institutional IGRT guidelines. Reasons for adaptation were variation in seroma, hematoma, edema, positioning or problems using voluntary deep inspiration breath hold. Sixteen patients received a uniform dose to the breast (clinical target volume 1; CTV1). Six patients were treated with a simultaneous integrated boost to CTV2. The original plan was copied to the CT during treatment (re-CT) or to the stitched cone-beam CT (CBCT). Clinical expert evaluation of the re-calculated dose distribution and extraction of dose-volume histogram (DVH) parameters were performed. The extreme scenarios were evaluated, assuming all treatment fractions were given to the original planning CT (pCT), re-CT or CBCT. Reported results are mean +/- SD. RESULTS: DVH results showed a mean dose (Dmean) difference between pCT and re-CT of -0.4 +/- 1.4% (CTV1) and -1.4 +/- 2.1% (CTV2). The difference in V95% was -2.6 +/- 4.4% (CTV1) and -9.8 +/- 8.3% (CTV2). Clinical evaluation and DVH evaluation resulted in a recommended adaptation in 17/23 or 16/23 plans, respectively. Applying thresholds on the DVH parameters: Dmean CTV, V95% CTV, Dmax, mean lung dose, volume exceeding 107% (uniform dose) or 90% (SIB) of the prescribed dose enabled the identification of patients with an assumed clinically relevant dose difference, with a sensitivity of 0.89 and specificity of 1.0. Re calculation on CBCT imaging identified the same plans for adaptation as re-CT imaging. CONCLUSIONS: Clinical expert evaluation can be related to quantitative DVH parameters on re-CT or CBCT imaging to select patients for DGART. PMID- 28849732 TI - Identification of InhA inhibitors: A combination of virtual screening, molecular dynamics simulations and quantum chemical studies. AB - In the present work, multiple pharmacophore-based virtual screening of the SPECS natural product database was carried out to identify novel inhibitors of the validated biological target, InhA. The pharmacophore models were built from the five different groups of the co-crystallized ligands present within the active site. The generated models with the same features from each group were pooled and subjected to the test set validation, receiver-operator characteristic analysis and Guner-Henry studies. A set of five hypotheses with sensitivity > 0.5, specificity > 0.5, area under curve (AUC) > 0.7, and goodness of hit score > 0.7 were retrieved and exploited for the virtual screening. The common hits (87 molecules) obtained from these hypotheses were processed via drug-likeness filters. The filtered molecules (27 molecules) were compared for the binding modes and the top scored molecules (12 molecules) along with the reference (triclosan (TCL), docking score = -11.65 kcal/mol) were rescored and reprioritized via molecular mechanics-generalized Born surface area approach. Eventually, the stability of reprioritized (10 molecules) docked complexes was scrutinized via molecular dynamics simulations. Moreover, the quantum chemical studies of the dynamically stable compounds (9 molecules) were performed to understand structural features essential for the activity. Overall, the protocol resulted in the recognition of nine lead compounds that can be targeted against InhA. PMID- 28849733 TI - RNA editing of AZIN1 induces the malignant progression of non-small-cell lung cancers. AB - RNA editing is a widespread post-transcriptional mechanism that confers specific and reproducible nucleotide changes in selected RNA transcripts and plays a critical role in many human cancers. However, little is known about how RNA editing operates in non-small-cell lung cancers. Here, we measured the sequence and expression level of genes of antizyme inhibitor 1 and adenosine deaminase acting on RNA family in 30 non-small-cell lung cancer patient samples and 13 cell lines and revealed RNA editing S367G in antizyme inhibitor 1 is a high-frequent molecular events. We determined overexpression of antizyme inhibitor 1 with RNA editing, implying the oncogenic function of this alteration. We also detected the association of adenosine deaminase acting on RNA overexpression with RNA editing occurred in antizyme inhibitor 1. Furthermore, the RNA editing could cause a cytoplasmic-to-nuclear translocation of antizyme inhibitor 1 protein and conferred the malignant phenotype of non-small-cell lung cancer cells. The in vivo experiment confirmed that this RNA editing confers higher capacity of tumor migration as well. In conclusion, antizyme inhibitor 1 RNA editing and its involvement in tumorigenesis of non-small-cell lung cancer pave a new way for potential clinical management of non-small-cell lung cancer. PMID- 28849734 TI - A complete categorization of multiscale models of infectious disease systems. AB - Modelling of infectious disease systems has entered a new era in which disease modellers are increasingly turning to multiscale modelling to extend traditional modelling frameworks into new application areas and to achieve higher levels of detail and accuracy in characterizing infectious disease systems. In this paper we present a categorization framework for categorizing multiscale models of infectious disease systems. The categorization framework consists of five integration frameworks and five criteria. We use the categorization framework to give a complete categorization of host-level immuno-epidemiological models (HL IEMs). This categorization framework is also shown to be applicable in categorizing other types of multiscale models of infectious diseases beyond HL IEMs through modifying the initial categorization framework presented in this study. Categorization of multiscale models of infectious disease systems in this way is useful in bringing some order to the discussion on the structure of these multiscale models. PMID- 28849735 TI - Multiple cortical brain abscesses due to Listeria monocytogenes in an immunocompetent patient. AB - Listeria monocytogenes is an intracellular organism which is well recognised for its ability to cause meningeal infections in neonates, immunosuppressed, debilitated and elderly individuals. 1 Other less common central nervous system (CNS) infections caused by Listeria spp. include rhomboencephalitis, cerebritis and abscesses in the brain, brain stem and spinal cord. The neuroradiological appearance of Listeria brain abscesses is similar to other types and may also mimic primary or metastatic brain tumours. 2 , 3 We report a case of Listeria brain abscesses in a patient who was being treated for atypical parkinsonism. A good clinical outcome was achieved after appropriate antimicrobial therapy. PMID- 28849738 TI - Poster Presentations From the 2017 AAOHN Annual Meeting in New Orleans. PMID- 28849736 TI - Frailty is a predictive factor of readmission within 90 days of hospitalization for acute exacerbations of chronic obstructive pulmonary disease: a longitudinal study. AB - BACKGROUND: Readmission after hospital discharge is common in patients with acute exacerbations (AE) of chronic obstructive pulmonary disease (COPD). Although frailty predicts hospital readmission in patients with chronic nonpulmonary diseases, no multidimensional frailty measures have been validated to stratify the risk for patients with COPD. AIM: The aim of this study was to explore multidimensional frailty as a potential risk factor for readmission due to a new exacerbation episode during the 90 days after hospitalization for AE-COPD and to test whether frailty could improve the identification of patients at high risk of readmission. We hypothesized that patients with moderate-to-severe frailty would be at greater risk for readmission within that period of follow up. A secondary aim was to test whether frailty could improve the accuracy with which to discriminate patients with a high risk of readmission. Our investigation was part of a wider study protocol with additional aims on the same study population. METHODS: Frailty, demographics, and disease-related factors were measured prospectively in 102 patients during hospitalization for AE-COPD. Some of the baseline data reported were collected as part of a previously study. Readmission data were obtained on the basis of the discharge summary from patients' electronic files by a researcher blinded to the measurements made in the previous hospitalization. The association between frailty and readmission was assessed using bivariate analyses and multivariate logistic regression models. Whether frailty better identifies patients at high risk for readmission was evaluated by area under the receiver operator curve (AUC). RESULTS: Severely frail patients were much more likely to be readmitted than nonfrail patients (45% versus 18%). After adjusting for age and relevant disease-related factors in a final multivariate model, severe frailty remained an independent risk factor for 90-day readmission (odds ratio = 5.19; 95% confidence interval: 1.26-21.50). Age, number of hospitalizations for exacerbations in the previous year and length of stay were also significant in this model. Additionally, frailty improved the predictive accuracy of readmission by improving the AUC. CONCLUSIONS: Multidimensional frailty predicts the risk of early hospital readmission in patients hospitalized for AE-COPD. Frailty improved the accuracy of discriminating patients at high risk for readmission. Identifying patients with frailty for targeted interventions may reduce early readmission rates. PMID- 28849739 TI - The Unique Health Needs of Post-9/11 U.S. Veterans. AB - This article applies a hazard-based approach to the identification of physical, mental, and psychosocial health needs of post-9/11 veterans. The weaponry, survival, and population of servicemen and women by the military have evolved over time, particularly during the post-9/11 era. It is evident that military hazards and potential exposures vary depending on not only the deployment era but also the specific location and role. Many individual factors may affect the development of health problems. Recent evidence-based literature about post-9/11 veterans' long-term complex health issues is summarized, so occupational health nurses can advocate for the provision of veteran-sensitive care. PMID- 28849741 TI - The new Health Research Authority framework: still work to do to facilitate high quality public health research in English local authorities. PMID- 28849743 TI - Using motivational interviewing (MI) skills to help people change. PMID- 28849745 TI - Promoting physical activity with Hard-to-Reach women: an iterative and participatory research study. PMID- 28849746 TI - Public health: everyday interactions. PMID- 28849747 TI - Is the UK's food safety control system fit for the 21st century? PMID- 28849749 TI - Films for public health: developing the evidence base for films to support public health goals. PMID- 28849750 TI - Deciphering structural stability and binding mechanisms of potential antagonists with smoothened protein. AB - Identification of new potential inhibitors against Hedgehog pathway activator protein Smoothened (SMO) is considered to be of higher importance to improvise the future cancer therapeutics. Different SMO inhibitors/drugs (e.g. Cyclopamine, Vismodegib, Taladegib) used till date are found to be associated with several drug-related resistivity and toxicity. To explore the ability of new drug/inhibitor molecules, which can show better/similar binding and dynamic stability as compared to known inhibitors, virtual screening against SMO is performed followed by the comparative docking and molecular dynamic studies. 'ZINC12368305' is found to be the best molecule among the entire data-set, as it shows the highest binding affinity and stable conformations. Here, an integrative approach using Dynamic Graph Theory is introduced to gain the molecular insights of the structural integrity of these protein complexes at the residue level by analyzing the corresponding Protein Contact Networks along the Molecular Dynamics trajectories. The study further focuses to understand the detailed binding mechanisms of available inhibitor/drug molecules along with the newly predicted molecule. It is observed that a unique big cluster of low fluctuating residues at the vicinity of the drug binding pocket of the SMO in ZINC12368305-bound complex is present and driving it toward a more stable region. A close inspection on this site reveals the presence of a stable Pi-Pi interaction between the pyrazole group-associated phenanthrene ring of ZINC12368305 and aromatic ring of Phe484 of SMO, which could be the potential factor of ZINC12368305 to create a more stable complex with SMO as compared to the other inhibitors. PMID- 28849751 TI - Commentary on Richardson et al. detecting delirium superimposed on dementia: diagnostic accuracy of a simple combined arousal and attention testing procedure. AB - Consciousness consists of two components: arousal and awareness of the environment and self. Arousal refers to the behavioral continuum that occurs between sleep and wakefulness, while awareness to the content of consciousness (Laureys, 2014). In normal physiological states, with the exception of REM sleep, the level of arousal is positively correlated with awareness (Laureys, 2014) such that arousal is graded and measured by the degree to which it is diminished. This conceptualization appears to have led experts, including the DSM-5, to consider delirium as a condition to not associated with impairments in arousal (Schiff and Plum, 2000, American Psychiatric Association, 2013). However, arousal can be both diminished and heightened, not unlike the performance of an old-fashioned incandescent bulb at different voltages, giving barely sufficient light at low voltages and brightening up unbearably at high voltages (MacIsaac et al., 1999). Delirium is associated with both hypo-arousal and hyper-arousal (Han et al., 2017). A small but significant proportion of delirious older patients (10%; n = 155) in the emergency department in this study had normal arousal at the time of the short arousal assessment (Han et al., 2014). PMID- 28849752 TI - Traditional ecological knowledge underlying herding decisions of pastoralists. AB - Pastoralists have traditional ecological knowledge (TEK), which is important for their livelihoods and for policies and interventions. Pastoralism is under pressure, however, which may result in a decline of pastoral lifestyle and its related TEK. We, therefore, addressed the following objectives (i) to inventorise and assess how pastoralists characterise and value soils and forages in their environment, (ii) to analyse how soil, forage and livestock (i.e. cattle) characteristics relate to herding decisions and (iii) to determine whether TEK underlying herding decisions differs across generations. Data were collected through focus groups and individual interviews with 72 pastoralists, belonging to three generations and to three agro-ecological zones. Using a three-point scale (high, medium, low), four grasses and three tree forages were assessed in terms of nutritional quality for milk, meat, health and strength. Using their own visual criteria, pastoralists identified five different soils, which they selected for herding at different times of the year. Pastoralists stated that Pokuri was the best soil because of its low moisture content, whereas Karaal was the worst because forage hardly grows on it. They stated that perennials, such as Andropogon gayanus and Loxoderra ledermannii, were of high nutritional quality, whereas annuals such as Andropogon pseudapricus and Hyparrhenia involucrata were of low nutritional quality. Afzelia africana was perceived of high quality for milk production, whereas Khaya senegalensis had the highest quality for meat, health and strength. Pastoralists first used soil, then forage and finally livestock characteristics in their herding decisions. Pastoralists' TEK was not associated with their generations, but with their agro-ecological zones. This study suggests that pastoralists had common and detailed TEK about soils, forages and livestock characteristics, underlying their herding decisions. To conclude, pastoralists use a holistic approach, combining soil, vegetation and livestock TEK in herding decisions. Such TEK can guide restoration or improvement of grazing lands, and land use planning. PMID- 28849753 TI - Mapping Chemical Bonds in Semiconductor Devices by Monitoring the Shifts of EELS Edges. AB - Scanning transmission electron microscopy (STEM) in combination with electron energy-loss spectroscopy (EELS) can deliver information about variations of bonding at the nm scale. This is typically performed by analyzing the electron loss near edge structure (ELNES) of given EELS edges. The present paper demonstrates an alternative way of a bonding examination through monitoring the EELS onset positions. Two conditions are essential for their accurate measurement. One (hardware) is using the dual EELS instrumentation that provides near simultaneous acquisition of low-loss and core-loss spectra. Another (software) is the least-square fitting of observed spectra to a reference spectrum. The combination of these hardware and software techniques reveals the positions of EELS onsets with the precision sufficient for mapping tiny variations of bonding. The paper shows that the method is capable of helping to solve practical tasks of nanoscale engineering like the analysis of modern CMOS devices. PMID- 28849754 TI - Microstructural Characterization of Solid State Reaction Phase Formed During Sintering of Hexagonal Boron Nitride with Iron. AB - In the development of dry self-lubricating composites, not only solid lubricant particle size and distribution are important, but also the correct selection of the solid lubricant characteristics, which should be stable, i.e. not reactive, during the whole processing. In this work, Fe+9 vol% h-BN composites were produced by uniaxial cold compaction and sintering, for which a reaction between h-BN and iron was detected after sintering at 1,150 degrees C. The reaction phase was characterized by optical and scanning electron microscopy and identified by X ray diffraction and energy-dispersive X-ray spectroscopy. The newly formed phase had high hardness when compared with the iron matrix. The resulting composites presented a high friction coefficient and high wear. PMID- 28849755 TI - Is Cognitive Behavioural Therapy focusing on Depression and Anxiety Effective for People with Long-Term Physical Health Conditions? A Controlled Trial in the Context of Type 2 Diabetes Mellitus. AB - BACKGROUND: It is unclear as to the extent to which psychological interventions focusing specifically on depression and anxiety are helpful for people with physical health conditions, with respect to mood and condition management. AIMS: To evaluate the effectiveness of a modified evidence-based psychological intervention focusing on depression and anxiety for people with type 2 diabetes mellitus (T2DM), compared with a control intervention. METHOD: Clients (n = 140) who experienced mild to moderate depression and/or anxiety and had a diagnosis of T2DM were allocated to either diabetes specific treatment condition (n = 52) or standard intervention (control condition, n = 63), which were run in parallel. Each condition received a group intervention offering evidence-based psychological interventions for people with depression and anxiety. Those running the diabetes specific treatment group received additional training and supervision on working with people with T2DM from a clinical health psychologist and a general practitioner. The diabetes specific treatment intervention helped patients to link mood with management of T2DM. RESULTS: Both conditions demonstrated improvements in primary outcomes of mood and secondary outcome of adjustment [95% confidence interval (CI) between 0.25 and 5.06; p < 0.05 in all cases]. The diabetes specific treatment condition also demonstrated improvements in secondary outcomes of self-report management of T2DM for diet, checking blood and checking feet, compared with the control condition (95% CIs between 0.04 and 2.05; p < 0.05 in all cases) and in glycaemic control (95% CI: 0.67 to 8.22). The findings also suggested a non-significant reduction in NHS resources in the diabetes specific treatment condition. These changes appeared to be maintained in the diabetes specific treatment condition. CONCLUSIONS: It is concluded that a modified intervention, with input from specialist services, may offer additional benefits in terms of improved diabetic self-management and tighter glycaemic control. PMID- 28849756 TI - Predictors of advance directives among nursing home residents with dementia. AB - : ABSTRACTBackground:Advance directives are important for nursing home residents with dementia; for those with advanced dementia, surrogates determine medical decisions. However, in Taiwan, little is known about what influences the completion of these advance directives. The purpose of this study was to identify factors, which influence the presence of advance directives for nursing home residents with dementia in Taiwan. METHOD: Our cross-sectional study analyzed a convenience sample of 143 nursing home dyads comprised of residents with dementia and family surrogates. Documentation of residents' advance directives, physical and cognitive status was obtained from medical charts. Surrogates completed the stress of end-of-life care decision scale and a questionnaire regarding their demographic characteristics. Nursing home characteristics were obtained from each chief administrator. RESULTS: Less than half of the nursing home residents (39.2%) had advance directives and most (96.4%) had been completed by family surrogates. The following were predictors of an advance directive: surrogates had previously signed a do-not-resuscitate as a proxy and had been informed of advance directives by a healthcare provider; nursing homes had policies for advance directives and a religious affiliation. CONCLUSIONS: Advance directives were uncommon for nursing home residents with dementia. Presence of an advance directive was associated with surrogate characteristics and the nursing home facilities; there was no association with characteristics of the nursing home resident. Our findings emphasize the need to develop policies and strategies, which ensure that all residents of nursing homes and their surrogates are aware of their right to an advance directive. PMID- 28849757 TI - Graded Aerobic Treadmill Testing in Adolescent Traumatic Brain Injury Patients. AB - PURPOSE: To examine the safety and tolerability of clinical graded aerobic treadmill testing in recovering adolescent moderate and severe traumatic brain injury (TBI) patients referred to a multidisciplinary pediatric concussion program. METHODS: We completed a retrospective case series of two moderate and five severe TBI patients (mean age, 17.3 years) who underwent initial Buffalo Concussion Treadmill Testing at a mean time of 71.6 days (range, 55-87) postinjury. RESULTS: Six patients completed one graded aerobic treadmill test each and one patient underwent initial and repeat testing. There were no complications. Five initial treadmill tests were completely tolerated and allowed an accurate assessment of exercise tolerance. Two initial tests were terminated early by the treatment team because of neurological and cardiorespiratory limitations. As a result of testing, two patients were cleared for aerobic exercise as tolerated and four patients were treated with individually tailored submaximal aerobic exercise programs resulting in subjective improvement in residual symptoms and/or exercise tolerance. Repeat treadmill testing in one patient performed after 1 month of treatment with submaximal aerobic exercise prescription was suggestive of improved exercise tolerance. One patient was able to tolerate aerobic exercise following surgery for posterior glottic stenosis. CONCLUSIONS: Preliminary results suggest that graded aerobic treadmill testing is a safe, well tolerated, and clinically useful tool to assess exercise tolerance in appropriately selected adolescent patients with TBI. Future prospective studies are needed to evaluate the effect of tailored submaximal aerobic exercise prescription on exercise tolerance and patient outcomes in recovering adolescent moderate and severe TBI patients. PMID- 28849758 TI - MOST IMPORTANT BARRIERS AND FACILITATORS REGARDING THE USE OF HEALTH TECHNOLOGY ASSESSMENT. AB - OBJECTIVES: Several studies have reported multiple barriers to and facilitators for the uptake of health technology assessment (HTA) information by policy makers. This study elicited, using best-worst scaling (BWS), the most important barriers and facilitators and their relative weight in the use of HTA by policy makers. METHODS: Two BWS object case surveys (one for barriers, one for facilitators) were conducted among sixteen policy makers and thirty-three HTA experts in the Netherlands. A list of twenty-two barriers and nineteen facilitators was included. In each choice task, participants were asked to choose the most important and the least important barrier/facilitator from a set of five. We used Hierarchical Bayes modeling to generate the mean relative importance score (RIS) for each factor and a subgroup analysis was conducted to assess differences between policy makers and HTA experts. RESULTS: The five most important barriers (RIS > 6.00) were "no explicit framework for decision-making process," "insufficient support by stakeholders," "lack of support," "limited generalizability," and "absence of appropriate incentives." The six most important facilitators were: "availability of explicit framework for decision making," "sufficient support by stakeholders," "appropriate incentives," "sufficient quality," "sufficient awareness," and "sufficient support within the organization." Overall, perceptions did not differ markedly between policy makers and HTA experts. CONCLUSIONS: Our study suggests that barriers and facilitators related to "policy characteristics" and "organization and resources" were particularly important. It is important to stimulate a pulse at the national level to create an explicit framework for including HTA in the decision-making context. PMID- 28849759 TI - DO STUDY RESULTS TRANSLATE INTO PRACTICE? INTRACRANIAL STENTING IN GERMANY. AB - OBJECTIVES: Enrolment into the SAMMPRIS trial published in September 2011 had to be stopped due to a 2.5 higher 30-day stroke and death rate in patients with percutaneous transluminal angioplasty and stenting (PTAS) compared with the control group with only medical therapy. After these results were published, one would have expected a change toward a clearer definition of indications for intracranial stent implantation in patients with intracranial artery stenosis, using this treatment only in patients suffering from recurrent strokes despite aggressive medical management. METHODS: The frequency of intracranial stenting and indication parameters in patients with intracranial artery stenosis were assessed from 2010 to 2013 using claims data for all inpatient episodes from Germany's largest provider of statutory health insurance. RESULTS: The number of intracranial stenting procedures decreased slowly from 580 in 2010 to 375 in 2013. With a rate of 29 percent there was no change between 2010 and 2013 of patients who were admitted to hospital for stent implantation, without documentation of an acute stroke or transient ischemic attack (TIA). Before PTAS, one-third of patients were admitted twice because of a stroke or TIA over a period of 5 years, 17 percent of patients had been prescribed platelet aggregation inhibitors and at least two admissions to hospital were for an ischemic cerebrovascular event before PTAS. CONCLUSIONS: Our analysis of German claims data provides little evidence of changed indications for stenting in cases of intracranial atherosclerotic disease which one might expect to be caused by the emergence of high-level evidence. PMID- 28849760 TI - WHAT ARE USER PERSPECTIVES OF EXOSKELETON TECHNOLOGY? A LITERATURE REVIEW. AB - OBJECTIVES: Exoskeletons are electromechanical devices that are worn by a human operator to increase their physical performance. Several exoskeletons have been developed to restore functional movements, such as walking, for those with paralysis due to neurological impairment. However, existing exoskeletons have limitations with respect to affordability, size, weight, speed, and efficiency, which may reduce their functional application. Therefore, the aim of this scoping review is to collect and narratively synthesize the perspectives of users of exoskeleton technology. METHODS: A systematic literature search was conducted across several healthcare related online databases. RESULTS: A total of 4,619 articles were identified, of which 51 were selected for full review. Only three studies were identified that met the inclusion criteria. Of these, one showed an incongruence between users' expectations and experiences of device use; another reported perspectives on potential rather than actual device use, ranking design features in order of perceived importance; and the other reported ratings of ease of device use in training. CONCLUSIONS: The heterogeneity of studies included within this review, leave the authors unable to suggest consensus as to user perspectives of exoskeleton technology. However, it is apparent that users are able to suggest priorities for exoskeleton design and that users' perspectives of exoskeleton technology might change in response to experience of use. The authors, therefore, suggest that exoskeleton design should be an iterative process, whereby user perspectives are sought, incorporated and refined by tangible experience, to ensure that devices developed are acceptable to and usable by the populations they seek to re-enable. PMID- 28849761 TI - A novel role for Ets4 in axis specification and cell migration in the spider Parasteatoda tepidariorum. AB - Organizers play important roles during the embryonic development of many animals. The most famous example is the Spemann organizer that sets up embryonic axes in amphibian embryos. In spiders, a group of BMP secreting mesenchymal cells (the cumulus) functions as an organizer of the dorsoventral axis. Similar to experiments performed with the Spemann organizer, transplantation of the cumulus is able to induce a secondary axis in spiders. Despite the importance of this structure, it is unknown which factors are needed to activate cumulus specific gene expression. To address this question, we performed a transcriptomic analysis of early embryonic development in the spider Parasteatoda tepidariorum. Through this work, we found that the transcription factor Pt-Ets4 is needed for cumulus integrity, dorsoventral patterning and for the activation of Pt-hunchback and Pt twist expression. Furthermore, ectopic expression of Pt-Ets4 is sufficient to induce cell delamination and migration by inducing a mesoderm-like cell fate. PMID- 28849763 TI - Laparoscopic Versus Open Appendectomy for Acute Appendicitis in Children. AB - OBJECTIVE: To compare the efficacy and safety of laparoscopic appendectomy and open appendectomy for acute appendicitis in children. METHODS: This study was conducted as a retrospective comparison of hospital records for postoperative complications, duration of operation, and postoperative length of stay between children (aged <18y) who underwent laparoscopic (n=190) or open (n=199) appendectomy over a six-year period. Quality of life was evaluated immediately and 1 month postoperatively. RESULTS: The major complication rate after surgery in laparoscopic group was significantly lower than that of open appendectomy group (13% vs 27%, P<0.05). The mean (SD) postoperative hospital stay was also shorter in laparoscopic group (2.4 (0.6) days vs 3.7 (1.1) days, P<0.05). The postoperative minor complication rate and hospital expenses were not significantly different between the two groups. The duration of surgery was longer in laparoscopic group (P<0.05). Children in laparoscopic group had less postoperative pain and higher quality of life after one month than those in open appendectomy group. CONCLUSION: Laparoscopic technique seems to be safer than open appendectomy for acute appendicitis in children. PMID- 28849762 TI - Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells. AB - The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior. PMID- 28849764 TI - Carbapenem-resistant Enterobacteriaceae in Pediatric Bloodstream Infections in Rural Southern India. AB - OBJECTIVE: To measure the frequency of antimicrobial resistance in pediatric blood culture isolates of Escherichia coli and Klebsiella spp. with focus on carbapenem resistance. METHODS: Over a period of three years, pediatric blood culture isolates were tested for antimicrobial susceptibility, including molecular investigations for carbapenem resistance. RESULTS: Amikacin, carbapenems, colistin and tigecycline had an antimicrobial efficacy of >70% (n=140). 7 of the 15 randomly selected isolates were positive for carbapenemase gene; among them, five were New Delhi Metallo b-lactamase (NDM). CONCLUSION: There was a high prevalence of Klebsiella spp. in pediatric bacteremia and dissemination of NDM-mediated carbapenem resistance in pediatric wards. PMID- 28849765 TI - Validation of Bioelectric Impedance Analysis against Dual-energy X-Ray Absorptiometry for Assessment of Body Composition in Indian Children Aged 5 to 18 Years. AB - OBJECTIVE: To validate body composition measurements by Bioelectric Impedance Analysis (BIA) against Dual-Energy X-ray Absorptiometry (DXA) as the reference method in healthy children and adolescents. DESIGN: Cross-sectional. SETTING: Schools in and around Pune city, India. PARTICIPANTS: A random sample of 210 (114 boys, 96 girls) apparently healthy Indian children and adolescents (5-18 y). METHODS: Weight, height, Tanner stage (TS) were recorded. Body composition measures: fat-free mass (FFM), fat mass (FM), lean mass (LM), bone mineral content (BMC) and body fat percentage (%BF) were assessed by BIA and DXA on a single day. Agreement between the methods was estimated by Pearson's correlation, and Bland and Altman analysis. MAIN OUTCOME MEASURES: %BF, FM, FFM, LM, BMC. RESULTS: BIA underestimated %BF by 6.7 (3.7)% as compared to DXA. Mean FFM, BMC and LM by BIA were significantly higher than by DXA (P<0.001). These differences remained similar after adjusting for age, BMI and TS. Mean differences between FFM (-2.32 (1.39) kg), BMC (-0.18 (0.15) kg), and LM (-2.15 (1.34) kg) by DXA and BIA were significant (P<0.01). Correlations between BIA and DXA were 0.92 for %BF, 0.96 for LM and 0.98 for FFM and BMC. Both the methods were similar in identifying normal and overfat children as per their respective cut-offs. CONCLUSION: BIA and DXA techniques are not interchangeable for assessment of body composition. However, BIA may be used in the field/clinical setting preferably with ethnicity specific references. PMID- 28849766 TI - Transport-related Adverse Events in Critically-ill Children: The Role of a Dedicated Transport Team. AB - OBJECTIVE: To compare the frequency of transport-related adverse events in children during specialized, non-specialized or unassisted transports. METHODS: Patients were grouped based on transport team involved - specialized (Group-1); non-specialized (Group-2); unassisted transport (Group-3). Demographics, events during transport and condition on arrival were recorded. RESULTS: Group-1 children had a lower incidence of adverse events compared to Group-2 and Group-3 (4.3%, 82.6% and 85.4% respectively; P<0.001). At arrival, children in Group-1 had a lower incidence of respiratory distress and airway compromise (P< 0.001). CONCLUSION: Transport of critically ill children by a specialized transport team is associated with fewer transport-related adverse events. PMID- 28849767 TI - Joint Involvement in Children with Celiac Disease. AB - OBJECTIVE: To determine early joint involvement as detected by ultrasonography in children with newly diagnosed celiac disease, and in children with celiac disease on gluten-free diet for more than 6 months. METHODS: Cross-sectional comparative study evaluating joint abnormalities by ultrasonography. Results: Ultrasonography showed abnormalities in 19 out of 60 (31.7%) children with newly diagnosed celiac disease as compared to 2 (3.3%) out of 60 in those on a gluten-free diet for more than 6 months. CONCLUSION: Subclinical synovitis as detected by ultrasound is a frequent finding in newly diagnosed children with celiac disease. PMID- 28849768 TI - Outcome of 200 Pediatric Living Donor Liver Transplantations in India. AB - OBJECTIVE: To describe our experience of pediatric living donor liver transplantation from India over a period of 12 years. Materials and Methods: A retrospective analysis of 200 living donor liver transplantation in children (18 years or younger) was done for demographic features, indications, donor and graft profile and outcome. Results: Between September 2004 and July 2016, 200 liver transplants were performed on 197 children. Fifty transplants were done in initial 6 years and 150 in next 6 years. All donors (51% mothers) were discharged with a mean stay of 7 days. The leading indications of liver transplants were cholestatic liver disease (46%) followed by metabolic liver disease (33%) and acute liver failure/acute on chronic liver failure (28.5%). Biliary leakage (8.5%), biliary stricture (9%), hepatic artery thrombosis (4.5%) and portal vein thrombosis (4%) were the most common surgical complications; all could be managed by surgical or interventional radiological measures, except in one child who died. Sepsis, acute rejection and CMV hepatitis in first 6 months were seen in 14.5%, 25% and 17% cases, respectively. Post-transplant lymphoproliferative disease was seen in only 1.5%. Re-transplant rate was 1.5%. The overall 1 year survival rate was 94% and 5 year actuarial survival was 87% with no statistically significant difference between children weight <10 kg vs. >10 kg. Outcome in acute liver failure did not differ significantly between those with acute on chronic liver failure vs. those with chronic liver disease. CONCLUSIONS: Advances in medical and surgical techniques associated with multidisciplinary teams including skilled pediatric liver transplant surgeons, anesthetists, dedicated pediatric hepatologists, pediatric intensivists, interventional radiologists and pathologists resulted in an excellent outcome of living related liver transplants in children. Low age and weight of the baby does not seem to be a contraindication for liver transplantation as outcome were comparable in our experience. PMID- 28849769 TI - Drug Utilization in Neonatal Intensive Care Unit of a Tertiary-care Hospital in Mumbai, India. AB - OBJECTIVE: To study the prescription pattern (using applicable WHO indicators), cost analysis and off-label use of drugs in neonatal intensive care unit (NICU) of a tertiary-care hospital. METHODS: The prescriptions of 460 neonates admitted to a NICU during July 2014-March 2015 were studied prospectively. RESULTS: Of 460 neonates, 54.8% were preterm and 73% were low birth weight (LBW). The mean (SD) prescription items per neonate were 5.7 (3.6). Overall off-label use was 12.3%, while 38% neonates received at least one off-label drug. Of 326 off-label drugs, antibiotics (69.6%) followed by non-steroid anti-inflammatory drugs (7%) were commonly used. Premature and LBW babies required more drugs with higher cost and longer stay, compared to full term and normal weight babies (P<0.01), while the pattern of off-label use was similar across both these categories (P>0.05). CONCLUSION: Off-label antibiotics use was common, and prescribing practices were uniform in NICU. PMID- 28849770 TI - Non-Autoimmune Subclinical and Overt Hypothyroidism in Idiopathic Steroid resistant Nephrotic Syndrome in Children. AB - OBJECTIVE: To evaluate the frequency of non-autoimmune subclinical and overt hypothyroidism in children with idiopathic steroid-resistant nephrotic syndrome (SRNS). METHODS: This cross-sectional study recruited 30 children (age 1-18 y) with idiopathic SRNS; and 30 healthy controls. Serum T3, T4 and TSH were performed in cases as well as controls. Anti-thyroid peroxidase and anti thyroglobulin antibody tests were performed in all cases. RESULTS: Non-autoimmune subclinical or overt hypothyroidism was detected in 10 out of 30 children with idiopathic SRNS; 2 had overt hypothyroidism, while 8 patients had subclinical hypothyroidism. Children with SRNS had a mean (SD) TSH value 4.55 (4.64) mIU/L that was higher as compared to controls (1.88 (1.04) mIU/L) (P<0.01). Focal segmental glomerulosclerosis (FSGS) was the commonest histopathological condition, seen in 13 (43.3%). Children with overt hypothyroidism (2 cases) and grade III subclinical hypothyroidism (1 case) were subsequently started on levothyroxine therapy. CONCLUSION: The prevalence of subclinical and overt hypothyroidism seems to be high in idiopathic SRNS, with almost one-third of children having overt or subclinical non-autoimmune hypothyroidism. PMID- 28849771 TI - Body Image and its Relation with Body Mass Index among Indian Adolescents. AB - OBJECTIVE: To evaluate association of body mass index with perception and attitude towards bodyweight, shape and body image among adolescents. Methods: This cross-sectional study was done on 1811 adolescents. Attitude towards body image was assessed by using a self-administered Multidimensional Body-Self Relations Questionnaire. Perceived body shape was measured using the Stunkard scale. RESULTS: Adolescents showed significant difference (P<0.005) in perceptions and behaviors related to appearance, fitness, health, body areas and weight across various body mass index and socioeconomic categories. Girls articulated significantly higher (P<0.005) body dissatisfaction than boys. CONCLUSION: Attitudes and perceptions towards body image differ with sex, body mass index and socioeconomic class. PMID- 28849772 TI - A Prospective Study of Homocysteine and its relation to Body Mass Index and Lipid Profile in School Children. AB - OBJECTIVE: To study the serum Homocysteine levels in children and its relation with body mass index (BMI), lipid profile and plasma glucose. Methods: 138 children (age 5-15 y) were enrolled and categorized into normal, overweight and obese group. Blood homocysteine, lipid profile and plasma glucose were estimated. RESULTS: Out of 138 children, 46 (33%) were normal, 40 (29%) were overweight and 52 (38%) were obese. Hyper-homocysteinemia was found in 34 (24.6%) of children. None of the normal children had hyperhomocysteinemia in contrast to 15 (37.5%) in overweight and 19 (36.5%) in obese group (P=0.001).The median homocysteine levels in obese and overweight children was significantly higher compared to normal children (P=0.001).There was a positive correlation between BMI and homocysteine levels. There was no significant correlation between lipid profile and plasma glucose with homocysteine levels. CONCLUSION: Serum homocysteine levels are significantly higher in both overweight and obese children compared to normal children. PMID- 28849773 TI - Double Dose Versus Standard Dose Hepatitis B Vaccine in HIV-infected Children: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the efficacy of double dose (20 ug) with standard dose (10 ug) of hepatitis B vaccine in HIV-infected children. METHODS: Unvaccinated HIV infected children were randomized to receive 3 doses of double dose (N=27) or standard dose (N=28) of recombinant Hepatitis B vaccine. Anti-HBs antibody titres were measured 3 mo after the last dose. An antibody titre >=10 mIU/mL 12 weaks after the third dose was considered as serporotection. RESULTS: Seroprotection was achieved by 17 (60.7%) children in standard dose group against 20 (74%) in the double dose group [RR (95%CI) 0.8 (0.17-1.7); P=0.29]. CD4 count < 500 cells/mm3 was significantly associated with lower rates of seroprotection. CONCLUSION: Double dose of hepatitis B vaccine does not seem to provide any advantage when compared to standard dose in HIV-infected children. PMID- 28849774 TI - End-of-Life Care: Consensus Statement by Indian Academy of Pediatrics. AB - JUSTIFICATION: The right to life has been accepted as one of the fundamental rights in our constitution. Resuscitation is a procedure performed for all patients suffering from cardiac or respiratory arrest irrespective of the clinical condition. There are no legal guidelines defining process to be adopted in situations where resuscitation is unlikely to be useful. There are no guidelines on withdrawal of care or end of life (EOL) decisions, accepted by the Government, judiciary, professionals, academicians or the community. Process: A National Consultative meet was organized by Indian Medico-Legal and Ethics Association and the Medico-legal group of Indian Academy of Pediatrics (IAP) to formulate the guidelines on 'Do Not Resuscitate' (DNR), and 'End of Life Support'. The meeting was organized on 30th May, 2014 at Ram Manohar Lohia Hospital, New Delhi. The meeting involved professionals from legal and various medical fields as well as administrators, and members from Medical Council of India. OBJECTIVES: To frame the guidelines related to EOL care issues and withdrawal or with-holding treatment in situations where outcome of continued treatment is expected to be poor in terms of ultimate survival or quality of life. RECOMMENDATIONS: (i) DNR or end of life care should not be activated till consensus is achieved between treating team and the next of kin; (ii) Consensus within health care team (including nurses) needs to be achieved before discussion with family members; (iii) Discussion should involve the family members - next of kin and other persons who can influence decisions; (iv) If family members want to include their family physician or a prominent person from the community, it should be encouraged. Similarly if family members want a particular member of treating team, he/she should be included; (v) Treating doctors should have all the facts of the case including investigations available with them before discussion; (vi) Unit in-charge or treating doctor should be responsible for achieving consensus and should initiate the discussion; (vii) After presenting the facts of the cases, family members should be encouraged to ask questions and clear doubts (if any); (viii) At the end of discussion, a summary of the discussion should be prepared and signed by the next of kin and the unit in charge or treating doctors; (ix) DNR orders should be reviewed in the event of unexpected improvement or on request of next of kin. Same should be documented; (x) DNR orders remain valid during transport. PMID- 28849775 TI - Revised Kuppuswamy's Socioeconomic Status Scale: Explained and Updated. AB - Some of the facets of the Kuppuswamy's socioeconomic status scale sometimes create confusion and require explanation on how to classify, and need some minor updates to bring the scale up-to-date. This article provides a revised scale that allows for the real-time update of the scale. PMID- 28849776 TI - Implications of a positive cosmological constant for general relativity. AB - Most of the literature on general relativity over the last century assumes that the cosmological constant [Formula: see text] is zero. However, by now independent observations have led to a consensus that the dynamics of the universe is best described by Einstein's equations with a small but positive [Formula: see text]. Interestingly, this requires a drastic revision of conceptual frameworks commonly used in general relativity, no matter how small [Formula: see text] is. We first explain why, and then summarize the current status of generalizations of these frameworks to include a positive [Formula: see text], focusing on gravitational waves. PMID- 28849777 TI - Corrigendum: Magnetic Tunnel Junction Mimics Stochastic Cortical Spiking Neurons. AB - This corrects the article DOI: 10.1038/srep30039. PMID- 28849778 TI - Fentanyl-Induced Brain Hypoxia Triggers Brain Hyperglycemia and Biphasic Changes in Brain Temperature. AB - Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well characterized as an anesthetic, but the basic physiological effects of fentanyl in the brain when taken as a drug of abuse are largely unknown. We used high-speed amperometry in freely moving rats to examine the effects of intravenous fentanyl at doses within the range of possible human intake (3-40 MUg/kg) on oxygen and glucose levels in nucleus accumbens (NAc). Fentanyl induced a rapid, dose-dependent decrease in NAc oxygen followed by a more delayed and prolonged increase in NAc glucose. Fentanyl induced similar oxygen decreases in the basolateral amygdala, indicating that brain hypoxia could be a generalized phenomenon. We used oxygen recordings in the subcutaneous space to confirm that fentanyl-induced brain hypoxia results from decreases in blood oxygen levels caused by drug-induced respiratory depression. Temperature recordings in the NAc, muscle, and skin showed that fentanyl induces biphasic changes in brain temperature, with an initial decrease that results primarily from peripheral vasodilation, and a subsequent increase driven by metabolic brain activation. The initial vasodilation appears caused by respiratory depression-induced hypoxia and a subsequent rise in CO2 that drives fentanyl-induced increases in NAc glucose. Together, these data suggest that fentanyl-induced respiratory depression triggers brain hypoxia and subsequent hyperglycemia, both of which precede slower changes in brain temperature and metabolic brain activity. PMID- 28849780 TI - Erratum: Daytime warming has stronger negative effects on soil nematodes than night-time warming. AB - This corrects the article DOI: 10.1038/srep44888. PMID- 28849779 TI - Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial. AB - Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time * Treatment: F9,115=2.6, p=0.01) but not the VAS-Anxiety (Time * Treatment: F10,141=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety. PMID- 28849781 TI - Enhanced base editing by co-expression of free uracil DNA glycosylase inhibitor. PMID- 28849782 TI - Erratum: Functional conservation and coherence of HIV-1 subtype A Vpu alleles. AB - This corrects the article DOI: 10.1038/srep44894. PMID- 28849783 TI - Alzheimer disease: Blocking HDAC2-Sp3 interaction - a new approach to AD therapy? PMID- 28849784 TI - Neurometabolic disease: New drug slows Niemann-Pick disease. PMID- 28849785 TI - Diabetes: Falling insulin requirements - a red flag for pre-eclampsia. PMID- 28849787 TI - Therapy: Immunotherapy advance for T1DM. PMID- 28849788 TI - Jamais vu all over again. PMID- 28849789 TI - Loopholes in the DNA contract kill neurons. PMID- 28849790 TI - Is population activity more than the sum of its parts? PMID- 28849786 TI - SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. AB - Cellular lipid metabolism and homeostasis are controlled by sterol regulatory element binding proteins (SREBPs). In addition to performing canonical functions in the transcriptional regulation of genes involved in the biosynthesis and uptake of lipids, genome-wide system analyses have revealed that these versatile transcription factors act as important nodes of convergence and divergence within biological signalling networks. Thus, they are involved in myriad physiological and pathophysiological processes, highlighting the importance of lipid metabolism in biology. Changes in cell metabolism and growth are reciprocally linked through SREBPs. Anabolic and growth signalling pathways branch off and connect to multiple steps of SREBP activation and form complex regulatory networks. In addition, SREBPs are implicated in numerous pathogenic processes such as endoplasmic reticulum stress, inflammation, autophagy and apoptosis, and in this way, they contribute to obesity, dyslipidaemia, diabetes mellitus, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, neurodegenerative diseases and cancers. This Review aims to provide a comprehensive understanding of the role of SREBPs in physiology and pathophysiology at the cell, organ and organism levels. PMID- 28849792 TI - The Zika threat to the periphery. PMID- 28849793 TI - Erratum: Triplet p-wave pairing correlation in low-doped zigzag graphene nanoribbons. AB - This corrects the article DOI: 10.1038/srep42262. PMID- 28849795 TI - Adhesion Evaluation of Dentin Sealing, Micropermeability, and Bond Strength of Current HEMA-free Adhesives to Dentin. AB - PURPOSE: To evaluate dentin sealing (DS), micropermeability (MP), and dentin bond strength (BS) of HEMA-free adhesives after 24 h and one year of artificial saliva storage. MATERIALS AND METHODS: Two HEMA-free (G-aenial Bond and BeautiBond) and All-Bond 3 (the bottle of resin is HEMA-free) adhesives were tested. Adper Single Bond 2, a HEMA-containing adhesive, served as the control. All adhesives were applied according to the manufacturers' instructions and teeth were prepared for DS (n = 5), MP (n = 5), and BS testing (n = 10). DS under a pulpal pressure of 10 psi was performed at 4 time points (when smear layer was present, after EDTA treatment, after adhesive application, and after 1 year). MP was assessed using pulpal pressure of a 20-cm aqueous dye-solution column and confocal laser scanning microscopy. DS, MP, and BS were performed after 24 h or one-year storage. BS and DS data were statistically analyzed using two-way ANOVA, the Tukey-Kramer test (for BS) and Tukey's post-hoc test (for DS) (a = 0.05). A qualitative MP assessment was performed by comparing the accumulation of yellow dye within the resin-dentin interface. RESULTS: Adper Single Bond 2 and All-Bond 3 completely sealed the dentin at 24 h and one year. G-aenial Bond showed statistically significant DS reduction of approximately 15% after one year. BeautiBond showed no DS reduction after one year. The resin-dentin interface created using Adper Single Bond 2 and GA showed dye accumulation primarily after one year. The mean BS of All-Bond 3 was statistically significantly higher than that of other adhesives, while G-aenial Bond and BeautiBond showed statistically significantly lower mean bond strengths than did Adper Single Bond 2 and All-Bond 3. After one-year storage, the mean BS was statistically significantly lower only for G-aenial Bond. CONCLUSION: DS, MP, and BS were not influenced by the absence of HEMA in the tested adhesives. PMID- 28849794 TI - Erratum: Lentiviral vectors can be used for full-length dystrophin gene therapy. AB - This corrects the article DOI: 10.1038/srep44775. PMID- 28849796 TI - Three-year Randomized Clinical Study of a One-step Universal Adhesive and a Two step Self-etch Adhesive in Class II Composite Restorations. AB - PURPOSE: To evaluate in a randomized clinical evaluation the 3-year clinical durability of a one-step universal adhesive and compare it intraindividually with a 2-step self-etch adhesive in Class II restorations. MATERIALS AND METHODS: Each of 57 participants (mean age 58.3 years) received at least two extended Class II restorations that were as similar as possible. The cavities in each of the 60 individual pairs of cavities were randomly distributed to the 1-step universal adhesive (All-Bond Universal: AU) and the control 2-step self-etch adhesive (Optibond XTR: OX). A low shrinkage composite (Aelite LS) was used for all restorations, which were evaluated using slightly modified USPHS criteria at baseline and 1, 2, and 3 years. RESULTS: 114 Class II restorations were evaluated at three years. Eight restorations, 3 AU and 5 OX, failed during the follow-up, resulting in 94.7% (AU) and 91.2% (OX) success rates (p > 0.05). Annual failure rates were 1.8% and 2.9%, respectively.The main reason for failure was composite fracture. CONCLUSION: Class II composite restorations placed with a 1-step universal adhesive showed good short-term efficacy. PMID- 28849791 TI - Functions and dysfunctions of neocortical inhibitory neuron subtypes. AB - Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders. PMID- 28849797 TI - The Bonding Performance of a Universal Adhesive to Artificially-created Caries affected Dentin. AB - PURPOSE: To evaluate the bonding performance of a universal adhesive to sound and artificially-created caries-affected dentin, using either the etch-and-rinse or self-etch strategy. MATERIALS AND METHODS: Flat midcoronal dentin surfaces from 48 third molars were randomly assigned to eight groups according to the substrate (sound dentin and artificially-created caries-affected dentin [pH cycling for 14 days]) and the adhesive or application mode (Scotchbond Universal: self-etch or etch-and-rinse strategies; Adper Single Bond 2 and Clearfil SE Bond, a two-step etch-and-rinse adhesive and a two-step self-etch adhesive as controls, respectively). Then, composite blocks were constructed, the specimens were further stored in water for 24 h, and composite-dentin sticks were prepared (0.8 mm2) and tested under tension at 1.0 mm/min. Data were analyzed with two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: All adhesives tested on artificially-created caries-affected dentin presented similar MUTBS (p > 0.05), and inferior bonding performance when compared to sound dentin (p = 0.000). On sound dentin, Scotchbond Universal presented higher bond strengths when applied in the etch-and-rinse than self-etch mode, but comparable bond strength in each application mode in relation to the respective control adhesive (p = 0.04). CONCLUSION: Scotchbond Universal can be used in different application modes when bonded to artificially-created caries-affected dentin; however, the etch-and rinse strategy improves its bonding ability to sound dentin. Moreover, Adper Single Bond 2 and Clearfil SE Bond presented similar bond strengths, regardless of the dentin condition and comparable performance in relation to each strategy of Scotchbond Universal. PMID- 28849798 TI - Efficacy of Different Surface Treatments for Intraoral Repair of Veneered Zirconia Frameworks. AB - PURPOSE: To evaluate the efficacy of different surface treatments on the repair of veneered zirconia ceramics. MATERIALS AND METHODS: Forty-eight zirconia disks were divided into three groups according to the method of surface treatment: polished surface, air abraded, or ground using a special silicon carbide bur (SiC Grinding Bur). All specimens were primed using a primer containing MDP (Cimara Zircon, Voco) and then bonded to composite in Plexiglas tubes using dual-curing adhesive resin (Bifix QM, Voco). Each of the three groups was further divided into two subgroups (n = 8) stored either in water at 37 degrees C for 3 days without thermocycling or stored in water at 37 degrees C for 150 days with an additional 37,500 thermocycles between 5 degrees C and 55 degrees C. After storage, tensile bond strength (TBS) was measured in a universal testing machine. RESULTS: After 3 days of storage, silicon carbide bur and air-abraded groups showed high TBS that ranged from 32.7 to 41.0 MPa (p <= 0.05). After 150 days of storage with thermocycling, the air-abraded group showed the most durable TBS (34.8 MPa), while the silicon carbide bur group showed a significant reduction in TBS (21.2 MPa); in the polished control group, specimens all debonded spontaneously during storage (p <= 0.05). CONCLUSION: Repair of zirconia ceramic after chipping of its veneers showed durable TBS when surface conditioning with air abrasion or roughening of the zirconia surface with a silicon carbide bur was provided. PMID- 28849799 TI - Effect of Sonic Application of Self-etch Adhesives on Bonding Fiber Posts to Root Canal Dentin. AB - PURPOSE: To evaluate the effect of sonic application of 5 different self-etch adhesives on the push-out bond strength of fiber posts in root canals. MATERIALS AND METHODS: In a preliminary test, 24 teeth were treated with manual and sonically assisted bonding, then a composite cylinder was built up to test the shear bond strength as a proof of principle. In the main test, 120 root canals were endodontically prepared and divided into 10 groups: 5 self-etch adhesives (Futurabond DC, Futurabond M, Futurabond U, Optibond XTR, Universalbond), each applied under manual and sonic application modes. After insertion of the fiber posts using the specific adhesive and a dual-curing composite, the teeth were sectioned and the push-out test was performed. The specimens were analyzed by light and scanning electron microscopy. Statistical analysis was performed using the Shapiro-Wilk test, one-way ANOVA and the Tamhane test. RESULTS: Sonic application of self-etch adhesive systems did not increase the bond strength of fiber posts in root canals. In general, the bond strength decreased from the coronal to the apical part of the root canal, irrespective of the applied method. The best post retention was achieved with Futurabond U and Optibond XTR. CONCLUSION: Sonic application of self-etch adhesives did not improve the fiber post retention in the root canal and can therefore not be recommended. Nevertheless, sonic application of etch-and-rinse adhesives can increase the bond strength to coronal dentin. PMID- 28849800 TI - Effect of 10-Methacryloxydecyl Dihydrogen Phosphate Concentration on Chemical Coupling of Methacrylate Resin to Yttria-stabilized Zirconia. AB - PURPOSE: To test the hypothesis that the concentration of 10-methacryloxydecyl dihydrogen phosphate (MDP) in zirconia primers has no effect on the chemical bonding efficacy of methacrylate resins to yttria-stabilized tetragonal zirconia (Y-TZP). MATERIALS AND METHODS: Shear bond strength testing was performed to evaluate the efficacy of experimental primers containing 5, 10, 15, 20 or 30 wt% MDP (5M, 10M, 15M, 20M, 30M) in improving composite-zirconia bond strength. Bonding without use of MDP-containing primer served as the negative control (Ctr0). Bonding with a commercially available MDP-containing primer served as the positive control (CtrM). Thermogravimetric analysis (TGA), inductively coupled plasma-mass spectrometry (ICP-MS), x-ray photoelectron spectroscopy (XPS), Fourier transform-infrared spectroscopy (FT-IR), and computational simulation of infrared spectra were used to confirm the formation of Zr-O-P bond between MDP and Y-TZP. RESULTS: Results derived from TGA, ICP-MS, XPS, and FT-IR suggested that MDP chemically bonded with Y-TZP. Simulation of IR data supported the FT-IR results. There was a higher concentration of phosphorus on the 10M-conditioned Y TZP surface when compared with the other groups, suggesting bettter formation of Zr-O-P bond in the 10M group. Shear bond strengths were significantly lower for group 5M (p < 0.05), compared to groups 10M to 30M, which were not significantly different from one another (p > 0.05). CONCLUSIONS: MDP improves resin bonding of zirconia through the formation of Zr-O-P bonds with zirconia. 10 wt% MDP appears to be the most optimal concentration for synthesizing zirconia primers for resin bonding. PMID- 28849801 TI - Bonding Behaviour of Polyetherketoneketone to Methylmethacrylate- and Dimethacrylate-based Polymers. AB - PURPOSE: To investigate the impact of pretreatment and conditioning on bonding behavior of polyetherketoneketone (PEKK) to methylmethacrylate(MMA)- and dimethacrylate(DMA)-based polymers. MATERIALS AND METHODS: 1200 PEKK substrates (Pekkton ivory) were fabricated, air abraded (110 um, Al2O3) and divided into 8 pretreatment groups as follows: 1. Visio.link (VL); 2. VL+ opaquer; 3. Pekk Bond (PB); 4. PB + opaquer; 5. plasma; 6. plasma + opaquer; 7. plasma + VL+ opaquer; 8. plasma + PB + opaquer. A low-density cold oxygen plasma was used to treat specimens in groups 5-8. All pretreated PEKK substrates were bonded with either MMA-based polymers (denture acrylic: "Anaxdent acryline") or DMA-based polymers (veneering composites: flowable "Anaxdent dentin flow" or packable "Anaxdent dentin paste"). On denture acrylic, the anaxgum opaquer paste was applied, and on veneering composites, the anaxblend opaquer paste. All specimens were stored in water for 24 h at 37 degrees C, and 20 specimens of each subgroup were additionally thermocycled (5 degrees C/55 degrees C, 10,000x). Tensile bond strength (TBS) was measured and analyzed with the general linear model analysis, Kaplan-Meier survival estimates, and Breslow-Gehan tests. RESULTS: The combination of plasma and VL showed the highest TBS results, followed by VL and the combination of plasma and PB. The lowest TBS was observed among PEKK specimens treated with plasma and without pretreatment, followed by specimens conditioned with PB. The application of an opaquer layer increased the TBS. Bonding to PEKK with MMA-based polymers showed higher TBS results than with DMA based polymers. Among DMA-based polymers, the flowable polymer bonded significantly better to PEKK compared to paste polymer. After thermocycling, the TBS decreased. CONCLUSION: Sufficient bonding to PEKK is possible when plasma treatment is used in combination with the tested adhesives and an opaquer layer. PMID- 28849802 TI - Long-term In Vitro Adhesion of Polyalkenoate-based Adhesives to Dentin. AB - PURPOSE: To study the influence of a polyalkenoate copolymer (VCP) on the immediate (24 h) and 6-month dentin bonding stability of VCP-based adhesives, using microtensile bond strength (MUTBS), nanoleakage (NL), and ultramorphological analyses (FE-SEM). MATERIALS AND METHODS: Eighty-four caries free molars were randomly assigned to seven adhesives: Clearfil SE Bond (CSE, Kuraray Noritake); Adper Single Bond Plus (SB, 3M ESPE); SB without VCP (SBnoVCP, 3M ESPE); Scotchbond Universal Adhesive applied as a etch-and-rinse adhesive (SBU_ER); SBU without VCP applied as an etch-and-rinse adhesive (SBUnoVCP_ER); SBU applied as a self-etch adhesive (SBU_SE, 3M ESPE); SBU without VCP applied as a self-etch adhesive (SBUnoVCP_SE, 3M ESPE). Half of the beams were tested after 24 h, and the other half was aged in water for 6 months prior to testing. For each tooth/evaluation time, two beams were randomly selected for NL analysis. Statistical analyses of uTBS results were performed using two-way ANOVA, Tukey's post-hoc tests, and Student's t-test for paired data (alpha = 0.05). Nanoleakage was statistically analyzed using the Kruskal-Wallis and Mann-Whitney tests, with Wilcoxon's test for paired data. For FE-SEM, four caries-free molars were assigned to each of the seven groups. Dentin disks were restored and cross sectioned into halves. One half was observed at 24 h, and the other at 6 months. RESULTS: The highest 6-month mean MUTBS was obtained with SBU_SE/SBUnoVCP_SE and SBUnoVCP_ER. SBUnoVCP_SE resulted in greater silver deposition at 6 months. FE SEM observations showed that CSE and SBU_SE specimens resulted in a submicron hybrid layer without signs of degradation at 6 months. CONCLUSIONS: VCP may contribute to the long-term bonding stability of VCP-based adhesives. PMID- 28849803 TI - Role of Chlorhexidine on Long-term Bond Strength of Self-adhesive Composite Cements to Intraradicular Dentin. AB - PURPOSE: To examine the effect of CHX pre-treatment on long-term bond strength of fiber posts luted with self-adhesive resin cements. MATERIALS AND METHODS: Seventy-two single-rooted teeth were selected for root canal treatment and post space preparation. The tested self-adhesive cement/post combinations were (N = 36): 1. RelyX Fiber-Posts luted with RelyX Unicem; 2. Rebilda Posts luted with Bifix SE Cement. For both self-adhesive cements, half of the specimens (experimental groups) were luted after the application of a solution of 2% CHX, while no CHX application was performed for the remaining specimens (control groups). Luted specimens were cut and used for push-out bond strength evaluation immediately, and after storage in artificial saliva for 6 months or 1 year. Additional specimens were processed for quantitative interfacial nanoleakage analysis. RESULTS: ANOVA showed that the variable times of storage had a significant influence on the results (p < 0.05), while no influence of the luting procedure (cements with or without CHX) on the final outcome (p > 0.05) was found. Tukey's pairwise post-hoc test showed that the radicular bond strength decreased with time of storage. In particular, a significant difference was found between T0 and T1y, but not between T0 and T6m. In contrast, in terms of pretreatment, no significant reduction in push-out bond strength was observed, irrespective of the aging time. CONCLUSION: CHX pretreatment did not prevent bond strength degradation of fiber posts luted with self-adhesive cements. PMID- 28849804 TI - Two-year clinical performance of sonic-resin placement system in posterior restorations. AB - OBJECTIVE: The objective of this split-mouth randomized controlled study was to compare the 2-year clinical performance of two restorative techniques and materials for posterior permanent carious teeth. METHOD AND MATERIALS: After signing informed consent, 30 patients aged between 7 and 16 received two Class 1 restorations on cavities on permanent first or second molar teeth performed with one of two systems: incrementally placed conventional posterior composite resin (Herculite Ultra, Kerr), and sonic-resin placement system (SonicFill, Kerr) with single-component self-etch adhesive system (Kerr) according to the manufacturers' directions. Two blinded observers evaluated the restorations at three times (baseline, and after 1 and 2 years) according to the US Public Health Service modified criteria. Kruskal-Wallis test and Mann-Whitney U-test were used to compare the clinical performance of the restorative systems. RESULTS: The restorative systems showed similar clinical performance at 2 years. At the end of 2 years in both groups, one restoration's marginal staining Alpha ratings decreased. In the same period, two restorations in the conventional group and one in the SonicFill group received Bravo ratings for color match and surface roughness scorings. CONCLUSION: The sonic-resin placement system demonstrated similar results to incrementally placed conventional composite resin in terms of clinical success. Considering the advantages of providing up to 5 mm in a single layer, and the adjustability of the viscosity, bulk-fill composite restorations seem to be a good alternative to posterior Class 1 composite restorations. CLINICAL RELEVANCE: This study suggests that a new dental material for bulk-fill technology exhibits similar clinical success to incrementally placed composite resin. PMID- 28849805 TI - Association between oral tori, occlusal force, and mandibular cortical index. AB - OBJECTIVE: To assess possible associations between torus palatinus (TP), torus mandibularis (TM), occlusal force (OF), Klemetti's classes, mandibular cortical index (MCI), and sociodemographic variables in a selected sample of Jordanians. Previous studies have suggested that oral tori are benign anatomical variations probably related to several factors such as functional stress, gender predisposition, number of teeth present, and nutritional factors. METHOD AND MATERIALS: A total of 130 Jordanian adults were included. Shape, location, and appearance of tori were recorded from study casts. Size was measured using digital calipers. OF was recorded in Newtons. MCI and Klemetti's classification were assessed using panoramic radiographs. Data were statistically analyzed, and level of significance was set at P < .05. RESULTS: The mean +/- SD recorded OF was 524 +/- 183 N in the tori group, compared to 417 +/- 172 N in controls (P = .001). OF was significantly higher in males compared to females (P < .001), and was significantly higher in subjects with TM only (543 +/- 201 N) (P < .001). TP and TM were predominantly more than 6 mm in size. The average OF in subjects with Klemetti class 3 was 418 +/- 174 N, while OF in Klemetti class 1 subjects amounted to 535 +/- 187 N (P = .043). CONCLUSION: Average OF was significantly higher in tori subjects and in males (if compared to controls and female subjects, respectively). The presence of oral tori, Klemetti's classification, and MCI ratio seems to be positively correlated with OF. PMID- 28849806 TI - Digital cross-mounting: A new opportunity in prosthetic dentistry. AB - The prosthodontic management of complex rehabilitations requires several stages of treatment including one or more provisional restorations. The design and adjustments of the provisional are made to achieve an optimal functional and esthetic outcome for the patient. However, the adjustments needed are both time and cost consuming. Therefore, once a satisfactory provisional is made, the information should not be lost during the following stages of treatment. The purpose of this clinical case is to illustrate "digital cross-mounting," a procedure used to precisely transfer information from the provisional to the final fixed rehabilitation in a digital workflow. PMID- 28849807 TI - Key role of higher order symmetry and electrostatic ligand field design in the magnetic relaxation of low-coordinate Er(iii) complexes. AB - The conceptual framework of electrostatic ligand field modulation based on oblate/prolate type electron density of lanthanide ions is one of the most successful approaches to enhance barrier height in lanthanide-based single-ion magnets. Recently, a tetra coordinated [Er{N(SiMe3)2}s3Cl].2THF (1) complex with an unfavourable ligand field showed slow relaxation of magnetization in zero field and challenges the concept of electrostatic ligand field modulation. To unravel the magnetic relaxation in this complex, we carried out a detailed theoretical investigation on three Er(iii) complexes belonging to the same family of single-ion magnets. The CASSCF/PT2 + RASSI-SO approach highlights that the concept of electrostatic ligand field modulation based on oblate/prolate type is still valid in these complexes, and the relaxation dynamics observed can be rationalized by accounting for both the symmetry and geometrical distortions around the Er(iii) ion. Using ab initio computed blockade barriers and crystal field analysis, we analysed the key components of the magnetic relaxation. Our study suggests that in these structures, the Er(iii) ion shifted out of the triangular plane formed by the three nitrogen donor atoms and this out-of-plane shift (tau) significantly influences the slow-relaxation of magnetization. In order to gain deeper insights into the nature of metal-ligand bonding, and to predict quantitatively the strength of the axial and equatorial ligand field, ELF, QTAIM, and EDA analysis were carried out in these complexes. Our findings highlight that the molecules possessing large barrier height for magnetic relaxation are due to the combined effect of a favourable ligand field and the symmetry around the Er(iii) ion. To understand the intricate role of both effects, several robust magneto-structural correlations were developed. Besides, the lanthanide-halogen covalency was also found to play a vital role in controlling the magnetic anisotropy and thus the magnetic relaxation. A near linear trend was observed between the calculated barrier height and the increase in the Er-X covalency as we move from -F to -I. This offers a de novo approach to increase barrier height in mononuclear lanthanide based complexes. PMID- 28849808 TI - A silver/graphene oxide nanocomposite film as a flexible SERS substrate for reliable quantitative analysis using high-speed spiral scanning spectrometry. AB - Excellent uniformity (~1.5% RSD) in SERS signals was obtained from an Ag/GO decorated adhesive tape on a simple in-house cylindrical scanning system. The calibration curve for the quantitative analysis of CV shows reliable linearity ranging from 75 nM to 50 MUM. This novel method is promising to be an adept tool for universal quantitative analysis and be used complementarily with the conventional Raman mapping method for a more time efficient and reliable analysis. PMID- 28849809 TI - A comprehensive study of the complexation of alkali metal cations by lower rim calix[4]arene amide derivatives. AB - The complexation of alkali metal cations by lower rim N,N-dihexylacetamide (L1) and newly synthesized N-hexyl-N-methylacetamide (L2) calix[4]arene tertiary-amide derivatives was thoroughly studied at 25 degrees C in acetonitrile (MeCN), benzonitrile (PhCN), and methanol (MeOH) by means of direct and competitive microcalorimetric titrations, and UV and 1H NMR spectroscopies. In addition, by measuring the ligands' solubilities, the solution (transfer) Gibbs energies of the ligands and their alkali metal complexes were obtained. The inclusion of solvent molecules in the free and complexed calixarene hydrophobic cavities was also investigated. Computational (classical molecular dynamics) investigations of the studied systems were also carried out. The obtained results were compared with those previously obtained by studying the complexation ability of an N hexylacetamidecalix[4]arene secondary-amide derivative (L3). The stability constants of 1 : 1 complexes were determined in all solvents used (the values obtained by different methods being in excellent agreement), as were the corresponding complexation enthalpies and entropies. Almost all of the examined reactions were enthalpically controlled. The most striking exceptions were reactions of Li+ with both ligands in methanol, for which the entropic contribution to the reaction Gibbs energy was substantial due the entropically favourable desolvation of the smallest lithium cation. The thermodynamic stabilities of the complexes were quite solvent dependent (the stability decreased in the solvent order: MeCN > PhCN ? MeOH), which could be accounted for by considering the differences in the solvation of the ligand and free and complexed alkali metal cations in the solvents used. Comparison of the stability constants of the ligand L1 and L2 complexes clearly revealed that the higher electron-donating ability of the hexyl with respect to the methyl group is of considerable importance in determining the equilibria of the complexation reactions. Additionally, the quite strong influence of intramolecular hydrogen bond formation in compound L3 (not present in ligands L1 and L2) and that of the inclusion of solvent molecules in the calixarene hydrophobic cone were shown to be of great importance in determining the thermodynamic stability of the calixarene-cation complexes. The experimental results were fully supported by those obtained by MD simulations. PMID- 28849810 TI - Cellulose ionics: switching ionic diode responses by surface charge in reconstituted cellulose films. AB - Cellulose films as well as chitosan-modified cellulose films of approximately 5 MUm thickness, reconstituted from ionic liquid media onto a poly(ethylene terephthalate) (PET, 6 MUm thickness) film with a 5, 10, 20, or 40 MUm diameter laser-drilled microhole, show significant current rectification in aqueous NaCl. Reconstituted alpha-cellulose films provide "cationic diodes" (due to predominant cation conductivity) whereas chitosan-doped cellulose shows "anionic diode" effects (due to predominant anion conductivity). The current rectification, or "ionic diode" behaviour, is investigated as a function of NaCl concentration, pH, microhole diameter, and molecular weight of the chitosan dopant. Future applications are envisaged exploiting the surface charge induced switching of diode currents for signal amplification in sensing. PMID- 28849811 TI - Preparation of pillar[5]arene-quinoline Langmuir-Blodgett thin films for detection of volatile organic compounds with host-guest principles. AB - In this study, a novel pillar[5]arene-quinoline (P5-Q) as an organic material is used to fabricate Langmuir-Blodgett (LB) thin films and its organic vapor sensing properties have been investigated. The LB deposition process is characterized by UV-visible spectroscopy, atomic force microscopy (AFM), scanning electron microscopy (SEM) and quartz crystal microbalance (QCM) techniques. The typical frequency shift per layer is obtained as 31.75 Hz per layer and the deposited mass onto a quartz crystal is calculated to be 539.69 ng per layer (2.03 ng mm 2). The fitted surface plasmon resonance (SPR) data were utilized to calculate the film thickness of this material. The thickness of a single layer is calculated to be 1.26 +/- 0.09 nm. QCM and SPR systems are used to investigate gas sensing performance of macrocyclic LB films during exposure to Volatile Organic Compounds (VOCs). The macrocyclic LB thin films are more sensitive to dichloromethane than that of other vapors used in this study. The sensitivity and detection limit performance of the P5-Q QCM sensor to dichloromethane vapor were calculated to be 14.751 Hz ppm-1 and 0.203 ppm, respectively. These results demonstrated that the P5-Q material is promising as an organic vapor sensing device at room temperature. Despite Langmuir-Blodgett being a traditional technique in colloid and interface science, this study presents the first gas sensor application for pillararene LB films. Because of the unique symmetric pillar architecture of P5-Q, self-assembly of pillar[5]arene molecules should afford various characteristic nanometer-scale architectures such as micelles, vesicles, and tubes. PMID- 28849812 TI - Escaping the trap of complication and complexity in multiscale microkinetic modelling of heterogeneous catalytic processes. AB - In this feature article, the development of methods to enable a hierarchical multiscale approach to the microkinetic analysis of heterogeneous catalytic processes is reviewed. This methodology is an effective route to escape the trap of complication and complexity in multiscale microkinetic modelling. On the one hand, the complication of the problem is related to the fact that the observed catalyst functionality is inherently a multiscale property of the reacting system and its analysis requires bridging the phenomena at different time and length scales. On the other hand, the complexity of the problem derives from the system dimension of the chemical systems, which typically results in a number of elementary steps and species, that are beyond the limit of accessibility of present-day computational power even for the most efficient implementation of atomistic first-principles simulations. The main idea behind the hierarchical approach is to tackle the problem with methods of increasing accuracy in a dual feed-back loop between theory and experiments. The potential of the methodology is shown in the context of unravelling the WGS and r-WGS catalytic mechanisms on Rh catalysts. As a perspective, the extension to structure-dependent microkinetic modelling is discussed. PMID- 28849813 TI - Water-soluble clickable nucleic acid (CNA) polymer synthesis by functionalizing the pendant hydroxyl. AB - Synthetic biomacromolecules that mimic natural polymeric structures are of significant interest. For most applications of these materials, however, aqueous solubility is a necessity. Here, we present the synthesis of an intrinsically water soluble single stranded DNA analog formed by the synthesis of a Clickable Nucleic Acid (CNA). These molecules are formed with pendant hydroxyl groups present on the main polymer backbone, and subsequent modification of those hydroxyls with sulfonate moieties further enhances the hydrophilicity of these molecules. PMID- 28849815 TI - A one-pot radioiodination of aryl amines via stable diazonium salts: preparation of 125I-imaging agents. AB - An operationally simple, one-pot, two-step tandem procedure that allows the incorporation of radioactive iodine into aryl amines via stable diazonium salts is described. The mild conditions are tolerant of various functional groups and substitution patterns, allowing late-stage, rapid access to a wide range of 125I labelled aryl compounds and SPECT radiotracers. PMID- 28849816 TI - Characterization of the HCNCO complex and its radiation-induced transformation to HNCCO in cold media: an experimental and theoretical investigation. AB - The HCNCO complex and its X-ray induced transformation to HNCCO in solid noble gas (Ng) matrices (Ng = Ne, Ar, Kr, Xe) was first characterized by matrix isolation FTIR spectroscopy at 5 K. The HCNCO complex was obtained by deposition of HCN/CO/Ng gaseous mixtures. The assignment was based on extensive quantum chemical calculations at the CCSD(T) level of theory. The calculations predicted two computationally stable structures for HCNCO and three stable structures for HNCCO. However, only the most energetically favorable linear structures corresponding to the co-ordination between the H atom of HCN (HNC) and the C atom of CO have been found experimentally. The HCNCO complex demonstrates a considerable red shift of the H-C stretching vibrations (-24 to -38 cm-1, depending on the matrix) and a blue shift of the HCN bending vibrations (+29 to +32 cm-1) with respect to that of the HCN monomer, while the C[double bond, length as m-dash]O stretching mode is blue-shifted by 15 to 20 cm-1 as compared to the CO monomer. The HNCCO complex reveals a strong red shift of the H-N bending (-77 to -118 cm-1) and a strong blue shift of the HNC bending mode (ca. +100 cm-1) as compared to the HNC monomer, whereas the C[double bond, length as m dash]O stretching is blue-shifted by 24 to 29 cm-1 with respect to that of the CO monomer. The interaction energies were determined to be 1.01 and 1.87 kcal mol-1 for HCNCO and HNCCO, respectively. It was found that the formation of complexes with CO had a remarkable effect on the radiation-induced transformations of HCN. While the dissociation of HCN to H and CN is suppressed in complexes, the isomerization of HCN to HNC is strongly catalyzed by the complexation with CO. The astrochemical implications of the results are discussed. PMID- 28849814 TI - Mechanistic insights into thrombin's switch between "slow" and "fast" forms. AB - Thrombin is a multifunctional enzyme that plays an important role in blood coagulation, cell growth, and metastasis. Depending upon the binding of sodium ions, thrombin presents significantly different enzymatic activities. In the environment with sodium ions, thrombin is highly active in cleaving the coagulated substrates and this is referred to as the "fast" form; in the environment without sodium ions, thrombin turns catalytically less active and is in the "slow" form. Although many experimental studies over the last two decades have attempted to reveal the structural and kinetic differences between these two forms, it remains vague and disputed how the functional switch between the "fast" and "slow" forms is mediated by Na+ cations. In this work, we employ microsecond scale all-atom molecular dynamics simulations to investigate the differences in the structural ensembles in sodium-bound/unbound and potassium-bound/unbound thrombin. Our calculations indicate that the regulatory regions, including the 60s, gamma loops, and exosite I and II, are primarily affected by both the bound and unbound cations. Conformational free energy surfaces, estimated from principal component analysis, further reveal the existence of multiple conformational states. The binding of a cation introduces changes in the distribution of these states. Through comparisons with potassium-binding, the binding of sodium ions appears to shift the population toward conformational states that might be catalytically favorable. Our study of thrombin in the presence of sodium/potassium ions suggests Na+-mediated generalized allostery is the mechanism of thrombin's functional switch between the "fast" and "slow" forms. PMID- 28849817 TI - Solvate and protic ionic liquids from aza-crown ethers: synthesis, thermal properties, and LCST behavior. AB - In recent years, solvate and protic ionic liquids (ILs) have attracted much attention. We synthesized both types of ILs from alkyl aza-crown ethers (L = N propyl-1-aza-15-crown-5 (L1) and N-C6F13C2H4-1-aza-15-crown-5 (L2)). The solvate ILs [ML][Tf2N] (M = Na+, K+) were solids (Tm = 58-68 degrees C), whereas the solvate ILs [ML][Tf2N] (M = Li+, Ag+) and protic ILs [HL][Tf2N] were liquids with low glass transition temperatures. The ILs containing Na ions were more crystalline and exhibited higher melting points than the other ILs. The decomposition temperatures of the protic ILs were higher than those of the solvate ILs. A protic IL with a paramagnetic anion, [HL1][FeCl4] (Tm = 70.5 degrees C), was also synthesized and its crystal structure was determined. The solvate ILs [NaL2][X] (X = Cl-, CF3CO2-, TsO-, PhSO3-) exhibited a lower critical solution temperature (LCST)-type behavior in water. The effects of salt addition on the LCST of L2 were also investigated. The LCST of these ILs generally increased with increasing hydrophilicity or basicity of the counter anion. This tendency, which is nearly opposite to that of ILs with quaternary onium cations, is ascribed to the amphiphilic nature of the cation. The corresponding protic ILs did not exhibit LCST behavior. PMID- 28849818 TI - Aggregation-induced accelerating peroxidase-like activity of gold nanoclusters and their applications for colorimetric Pb2+ detection. AB - In this study, we found that Pb2+-induced aggregation can greatly accelerate the peroxidase-like activity of Au nanoclusters (Au-NCs). The catalytic activities of Au-NCs toward peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) oxidation in the presence of H2O2 are nearly 10-fold increased after the Pb2+-induced aggregation. Based on this finding, a simple and reliable colorimetric method for Pb2+ detection was developed. PMID- 28849820 TI - Effectively enhancing the enantioseparation ability of beta-cyclodextrin derivatives by de novo design and molecular modeling. AB - Rational engineering of native beta-CD as an ideal chiral selector for a definite analyte in capillary electrophoresis represents a challenge in separation science. Herein, a rational and systematic strategy that combines the de novo design and molecular modeling is firstly described to expedite the manipulation and selection of effective selector for enantioseparation in capillary electrophoresis. Using beta-adrenoreceptor agonists as model analytes, we demonstrate how this strategy efficiently improves the enantiorecognition in chiral discrimination sites of inclusion complexes. The evolved beta-CD derivative could be utilized as a chiral receptor to achieve the effective enantioseparation (Rs > 1.5) of racemic beta-adrenoreceptor agonists. We highlight a novel strategy for efficiently and rapidly manipulating native CD based on the characteristics of analyte so as to gain an excellent chiral selector. PMID- 28849821 TI - Large magnetic anisotropy and strain induced enhancement of magnetic anisotropy in monolayer TaTe2. AB - Monolayer TaTe2 holds great potential for the realization of large magnetocrystalline anisotropy due to strong spin-orbit coupling (SOC) interactions of Ta. Here, we systematically investigate the electronic structure, magnetism and magnetocrystalline anisotropy of monolayer TaTe2 under different strains by means of first-principles calculations. The results show that monolayer TaTe2 is a ferromagnetic metal and exhibits a large in-plane magnetic anisotropy energy (MAE) of -11.38 meV per TaTe2. It is worth noting that the magnetic moment, magnetic coupling and magnetic anisotropy of monolayer TaTe2 are significantly enhanced by strain. In particular, when tensile strain increases from 0% to 8%, the MAE of monolayer TaTe2 greatly increases from -11.38 to -15.14 meV per TaTe2. By analyzing the density of states and the contribution to magnetocrystalline anisotropy (MCA) from the SOC interaction between two d orbitals of Ta atoms based on second-order perturbation theory, it is concluded that a large MAE of monolayer TaTe2 is mainly contributed by the SOC interaction between opposite spin dxy and dx2-y2 orbitals of Ta atoms and the significant increase of the negative contribution to MCA from the SOC interaction between opposite spin dxy and dx2-y2 orbitals under strain is the reason why the MAE of monolayer TaTe2 is significantly enhanced by strain. Our results indicate that monolayer TaTe2 is a promising candidate suitable for applications in magnetic storage devices. PMID- 28849819 TI - Supramolecular catalysis and dynamic assemblies for medicine. AB - In this review, supramolecular catalysis refers to the integration of the catalytic process with molecular self-assembly driven by noncovalent interactions, and dynamic assemblies are the assemblies that form and dissipate reversibly. Cells extensively employ supramolecular catalysis and dynamic assemblies for controlling their complex functions. The dynamic generation of supramolecular assemblies of small molecules has made considerable progress in the last decade, though the disassembly processes remain underexplored. Here, we discuss the regulation of dynamic assemblies via self-assembly and disassembly processes for therapeutics and diagnostics. We first briefly introduce the self assembly and disassembly processes in the context of cells, which provide the rationale for designing approaches to control the assemblies. Then, we describe recent advances in designing and regulating the self-assembly and disassembly of small molecules, especially for molecular imaging and anticancer therapeutics. Finally, we provide a perspective on future directions of the research on supramolecular catalysis and dynamic assemblies for medicine. PMID- 28849822 TI - Gd3+-Functionalized gold nanoclusters for fluorescence-magnetic resonance bimodal imaging. AB - Multimodal imaging that aims to advance imaging by strategically combining existing technologies with uniquely designed probes has attracted great interest in recent years. In this work, Gd3+-functionalized gold nanoclusters were prepared with a straightforward and scalable approach by using proteins as templates. The impact of the synthesis approach on the conjugation efficiency of Gd chelators to proteins, as well as the fluorescence quantum yield of gold nanoclusters was carefully studied. The effect of protein size on the relaxivities of the probes was also investigated. By using the optimal conditions, dual function probes with intense red fluorescence emission and longitudinal relaxivity as high as 9.7 mM-1 s-1 could be obtained. The probes were applied for cell staining and in vivo contrast-enhanced magnetic resonance imaging (MRI). The MR images showed that the dual function probes circulated freely in the blood pool without undesirable accumulation in the liver and spleen. Meanwhile, the material could be removed from the body through renal clearance, making it attractive for practical multimodal imaging. PMID- 28849823 TI - Probing the geometry reorganization from solution to gas-phase in putrescine derivatives by IRMPD, 1H-NMR and theoretical calculations. AB - Single and double protonated (E)-1,4-diamine-2-butenes were evaluated as a model system to probe isomerization during the ESI processes employing infrared multiple-photon dissociation (IRMPD) spectroscopy and density function theory (DFT) calculations, including implicit and explicit solvation models. Our results show that the preferential protonation takes place at the amines for singly protonated species and that the double bond is not protonated even under double protonation, as expected from known pKa values. This behavior was shown to reflect the (E)-(Z) interconversion rate, as no interconversion was observed nor predicted by implicit solvation model based on density (SMD) calculations even by the olefin protonation pathway. Explicit solvent calculations show that the singly protonated (E) configuration observed in the gas phase is also the most stable configuration in solution due to molecular interactions with the solvent that are absent for the (Z) configuration. The explicit solvation calculation reverts the supposed gas-phase stability of the (Z) configuration in comparison to (E) from -9 kcal mol-1 (in relative Gibbs free energy) in the gas phase to +89 kcal mol-1 (in total potential energy) as depicted by explicit Monte Carlo (MC) simulations. Together with previous results for the saturated 1,4-diamines from Morton and coworkers that show the (Z) configuration related conformation to be the most stable geometry in the gas-phase due to intermolecular hydrogen bonding, our experiments clearly show that conformational reorganizations can take place during the ESI process. These results suggest that gas-phase experiments and vacuum calculations may not be valid as evidence for conformations in solution without prior testing to check for isomerization during the ESI process. PMID- 28849824 TI - Deciphering the mechanisms of selective inhibition for the tandem BD1/BD2 in the BET-bromodomain family. AB - The bromodomain and extra terminal domain (BET) family of bromodomains (BRDs) are well-known drug targets for many human diseases. The active pockets of the two tandem bromodomains BD1/BD2 are highly conserved (sequence similarity is about 95%), thus it is of great medical importance and still a significant challenge to develop BD1/BD2 selective inhibitors. A few BD2 selective inhibitors, such as RVX 208 and RVX-297, have been reported recently. However, their selectivity is insufficient for drug discovery, and the molecular basis of the selective inhibition for BD2 over BD1 remains unknown. In this work, by extensive classical molecular dynamics (MD) simulations and hybrid density functional theory/molecular mechanics (DFT/MM) MD simulations, it is for the first time revealed that the selective inhibitory effect towards BD2 is achieved by the distinctive structural dynamics of the ZA-loop ("in/out" conformations) in BD1 and BD2, which originate from the existence of residue Asp144 in BD1 which is replaced by His433 in BD2. Additionally, the more stable inherent H-bond constructed by a conserved D-Y dyad, as well as the stronger pi-pi stacking interaction formed between His433 and the ligand, are responsible for the higher inhibitory activity of RVX-297 compared to that of RVX-208 in BD2. All these findings should guide further novel inhibitor design and structural modification of validated BD1/BD2 inhibitors to increase the selectivity for BD1/BD2 among the BET family. PMID- 28849825 TI - Synthesis of plasmonic Ti3+ doped Au/Cl-TiO2 mesocrystals with enhanced visible light photocatalytic activity. AB - We successfully synthesized willow leaf-like plasmonic Ti3+ doped Au/Cl-TiO2 mesocrystals by facile modified two-phase vapor hydrolysis and photoreduction methods. In this work, the as-prepared Ti3+ doped TiO2 mesocrystals showed an interesting visible light harvesting capacity and visible light photocatalytic activity for hydrogen production. The plasmonic Ti3+ doped Au/Cl-TiO2 mesocrystals also showed highly enhanced visible light absorption and visible light photocatalytic activity for hydrogen production, and the highest visible light photocatalytic activity reached 480.1 MUmol g-1 h-1, which was 208.70 times as high as that of P25 TiO2 and 1.59 times as high as that of Ti3+ doped TiO2 mesocrystals. Finally, the possible visible light photocatalytic mechanisms of plasmonic Ti3+ doped Au/Cl-TiO2 mesocrystals for hydrogen production were proposed. PMID- 28849826 TI - Multifunctional nanoparticles for co-delivery of paclitaxel and carboplatin against ovarian cancer by inactivating the JMJD3-HER2 axis. AB - Ovarian cancer (OC) is the most lethal gynecologic cancer. Survival statistics have show no significant developments over the last three decades, highlighting the fact that current therapeutic strategies require substantial improvements. In this study, we designed a novel folic acid-PEG-conjugated p-phosphonated calix[4]arene nanoparticle (Fp-PCN) for the simultaneous delivery of paclitaxel (PAC) and carboplatin (CAR) at an optimal ratio (5 : 1, mol : mol) to utilize their potential synergistic effect against OC cells. The Fp-PCNs loaded with PAC and CAR (Fp-PCNPAC+CAR) resulted in a remarkable efficacy in the suppression of OC, both in vitro and in vivo. Compared to free drugs, Fp-PCNPAC+CAR showed stronger apoptosis induction as well as invasion and self-renewal capacity suppression in SKOV-3 cells. The molecular mechanism to address the synergism is that Fp-PCNPAC+CAR downregulated JMJD3 expression to modulate the H3K27me3 epigenetic mark of the promoters of HER2 and MYCN. Furthermore, the expressions of JMJD3 and HER2 were significantly associated with poor outcomes for ovarian patients. Our study demonstrates that co-delivery of PAC and CAR can be achieved with the Fp-PCNs, and reveals a previously unrecognized and unexpected role of the JMJD3-HER2 signaling axis in PAC and CAR treatment of OC. PMID- 28849827 TI - The selective hydrogenolysis of C-O bonds in lignin model compounds by Pd-Ni bimetallic nanoparticles in ionic liquids. AB - beta-O-4 and alpha-O-4 linkages can be selectively cleaved by Pd-Ni bimetallic nanoparticles in ionic liquids using hydrogen gas as the hydrogen donor under ambient pressure and neutral conditions. No hydrogenation of the benzene ring takes place in the catalytic system. An obvious improvement in activity is found compared with single nickel and palladium catalysts based on the results of experiments and characterization. After the reaction, the catalytic system still remains in the reactor by simple extraction, which can be reused without further treatment. PMID- 28849828 TI - Perovskite alkali metal samarium borohydrides: crystal structures and thermal decomposition. AB - A new synthesis method of samarium borohydride, Sm(BH4)2, using tetrahydrofuran borane, THF-BH3, and samarium hydride, SmH2, has been demonstrated and verified. The synthesised Sm(BH4)2 was mechanochemically treated with MBH4, M = K, Rb, Cs. Initially, the formation of KSm(BH4)3 is observed while subsequent heat treatment is necessary to form MSm(BH4)3, M = Rb, Cs. The new compounds crystallise in orthorhombic unit cells adopting perovskite-type 3D frameworks containing distorted [Sm(BH4)6] octahedra. In situ X-ray diffraction studies reveal two second-order polymorphic transitions of alpha-CsSm(BH4)3via a tetragonal intermediate, alpha'-CsSm(BH4)3, into a cubic high-temperature polymorph, beta CsSm(BH4)3, resembling an ideal perovskite structure. The new compounds, MSm(BH4)3, are thermally stable up to T ~ 280 degrees C after which they decompose into mainly MBH4, SmH2 and possibly SmB6 and SmB12H12. Finally, after three cycles of hydrogen release and uptake, the storage capacity was 1.0 wt% for KSm(BH4)3 and 0.84 wt% for RbSm(BH4)3 and CsSm(BH4)3. PMID- 28849830 TI - Fourier transform large amplitude alternating current voltammetry investigations of the split wave phenomenon in electrocatalytic mechanisms. AB - Fourier transform large amplitude alternating current voltammetry (FTACV) studies are reported on an electrocatalytic (EC') mechanistic system which exhibits split wave behavior on both macro- and micro-size working electrodes. The electrochemical characteristics of the EC' mechanism were analysed using the fundamental to fourth harmonic components deduced by the Fourier transform algorithm. The effects of the sinusoidal frequencies of the applied potential, electrode geometry and substrate concentrations are investigated. The split wave phenomenon was observed and explored particularly. PMID- 28849833 TI - Construction of flexible metal-organic framework (MOF) papers through MOF growth on filter paper and their selective dye capture. AB - The conjugation of metal-organic frameworks (MOFs) with other materials is an excellent strategy for the production of advanced materials having desired properties and so appropriate applicability. In particular, the integration of MOFs with a flexible paper is expected to form valuable materials in separation technology. Here we report a simple method for the generation of MOF papers through the compact and uniform growth of MOF nanoparticles on the cellulose surface of a carboxymethylated filter paper. The resulting MOF papers show a selective capture ability for negatively charged organic dyes and they can be used for dye separation through simple filtration of a dye solution on the MOF papers. In addition, MOF papers can be reused after a simple washing process without losing their effective dye capture ability. PMID- 28849829 TI - Kiwifruit actinidin digests salivary amylase but not gastric lipase. AB - Kiwifruit contains the cysteine proteinase actinidin whose strong activity allows kiwifruit to be used as a meat tenderiser. This raises the possibility digestive enzymes, also proteins, are themselves susceptible to degradation by actinidin. Salivary amylase and gastric lipase are exposed to the highest concentrations of actinidin whereas duodenal enzymes are less likely to be inactivated by actinidin due to dilution and inactivation of actinidin by gastric juice. The saliva of six volunteers was exposed to Actinidia deliciosa homogenate and then examined for loss of the starch digesting enzyme, alpha-amylase. In agreement with the known distribution of salivary amylase concentration in saliva, the range of amylase activity within the group of volunteers varied by around 100 fold. Within 5 minutes of incubation of 3 parts saliva to one part green kiwifruit at 37 degrees C, approximately 85% of the amylase activity was lost. The use of E-64, a selective inhibitor of cysteine proteinases, confirmed that the loss of amylase function was due to actinidin. Amylase protein degradation was followed by SDS PAGE and western blotting. Recombinant human gastric lipase resisted digestion with kiwifruit even after 30 minutes incubation and remained functionally active after this time period. However, both mountain papaya and pineapple extracts degraded gastric lipase fully during a 30 minutes digestion period. Under conditions where cooked starch is consumed along with kiwifruit it is possible that starch digestion may be retarded whereas lipid digestion in the stomach is unlikely to be affected by kiwifruit consumption. PMID- 28849835 TI - The biosynthesis of cytochalasans. AB - Covering: up to 2017Cytochalasans are a class of natural products possessing a wide range of important biological activities, yet the full biosynthetic steps towards the formation of their characteristic chemical features remain unknown. This highlight provides an overview of the recent advances made in understanding the biosynthesis of this fascinating class of compounds, complementing and extending a previous comprehensive review of this topic (K. Scherlach, D. Boettger, N. Remme and C. Hertweck, Nat. Prod. Rep., 2010, 27, 869-886). PMID- 28849836 TI - Penrose triangles of the fossil-to-bio-based transition. AB - Transition within the chemical industry from fossil to green feedstocks is a complex process characterized by the generation of commercially viable feedstock process-product triangles. The research in this area encompasses a great diversity of relevant topics. A number of those topics have been addressed within this volume of Faraday Discussions and are summarized in this paper. They are categorized and discussed along with seven general questions arising from the feedstock-process-product triangles. Opportunities are identified that should make more of these triangles technically and economically feasible. The future role of renewable electricity as the primary energy source for the bio-based industry is emphasized. PMID- 28849838 TI - The prediction of a family group of two-dimensional node-line semimetals. AB - Using first-principles calculations, we predict a family group of two-dimensional semimetals MX (M = Pd, Pt; X = S, Se, Te), which has a zig-zag type mono-layer structure in the Pmma (no. 41) layer group. Band structure analysis reveals that node-line features are caused by band inversion and the inversion exists even in the absence of spin-orbital-coupling. First-principles calculations show the robust lattice stability of these predicted materials. This work provides the possibility of making a group of novel two-dimensional materials with semimetal features. PMID- 28849839 TI - Ring expansion of a ring expanded carbene. AB - Reaction of phenylsilane with the ring expanded carbene 6-Mes results in facile Si-H oxidative addition to the carbenic carbon at room temperature. Heating the resultant diorganosilane product induces ring expansion through silicon to carbon migration of either the Si-H or Si-Ph bonds. PMID- 28849840 TI - Self-segregated nanostructure in room temperature ionic liquids. AB - The nanosegregated bulk structure, and its evolution with the cation's alkyl length n, are studied by X-ray scattering for an unprecedentedly broad homologous series of a model room-temperature ionic liquid, [CnMIM][NTf2] (n = 4-22). A tri periodic local structure is found, with the lateral periodicities, dII and dIII independent of n, and a longitudinal one, dI, linearly increasing with n. The results are consistent with a local structure comprising alternating layers of polar headgroups and apolar, interdigitated, partly overlapping, cations' alkyl tails, of an average macroscopic mass density close to that of liquid alkanes. A slope decrease in the linear dI(n) suggests a change from a lower to a higher rate of increase with n of chain overlap for n >= 12. The order decay lengths of the layering, and of the lateral chain packing, increase with n, as expected from the increasing van der Waals interaction's domination of the structure. The headgroups' lateral packing decay length decreases with n, due to increasing frustration between the longer lateral periodicity preferred by the headgroups, and the shorter lateral periodicity preferred by the chains. A comparison of the bulk and surface structures highlights the surface's ordering effect, which, however, does not induce here a surface phase different from the bulk, as it does in liquid crystals and liquid alkanes. PMID- 28849841 TI - Catalytic CVD synthesis of boron nitride and carbon nanomaterials - synergies between experiment and theory. AB - Low-dimensional carbon and boron nitride nanomaterials - hexagonal boron nitride, graphene, boron nitride nanotubes and carbon nanotubes - remain at the forefront of advanced materials research. Catalytic chemical vapour deposition has become an invaluable technique for reliably and cost-effectively synthesising these materials. In this review, we will emphasise how a synergy between experimental and theoretical methods has enhanced the understanding and optimisation of this synthetic technique. This review examines recent advances in the application of CVD to synthesising boron nitride and carbon nanomaterials and highlights where, in many cases, molecular simulations and quantum chemistry have provided key insights complementary to experimental investigation. This synergy is particularly prominent in the field of carbon nanotube and graphene CVD synthesis, and we propose here it will be the key to future advances in optimisation of CVD synthesis of boron nitride nanomaterials, boron nitride - carbon composite materials, and other nanomaterials generally. PMID- 28849842 TI - An enhanced chemotherapeutic effect facilitated by sonication of MSN. AB - Sonodynamic therapy (SDT) is a non-invasive therapeutic modality for cancer treatment. Finding new effective sonosensitizers has attracted great attention in the field of SDT. Mesoporous silica nanoparticles (MSN) have been extensively explored as a drug delivery system because of their good biocompatibility and satisfactory drug loading ability. However, there are relatively few studies devoted to using MSN as an efficient sonosensitizer. In this paper, we found that MSN could be used as an efficient sonosensitizer to induce cell apoptosis after ultrasound (US) treatment. To make the full use of MSN and increase its activity for cancer treatment, a chemotherapeutic drug was encapsulated inside MSN to achieve a chemotherapy-SDT synergistic function. Furthermore, photoinitiated polymerization cross-linked methacrylated hyaluronic acid (m-HA) gel was covered on the surface of DOX@MSN to improve its tumour targeting ability. In vitro and in vivo research studies indicated that the degradation of the m-HA shell by hyaluronidase (HAase) that is concentrated in the tumour environment results in the release of DOX@MSN. Importantly, subsequent US treatment could not only trigger SDT of MSN but also promote DOX release from MSN to show chemotherapeutic activity. PMID- 28849843 TI - A class of diatomic 2-D soft granular crystals undergoing pattern transformations. AB - We propose a class of diatomic 2-D soft granular crystals, which features pattern transformation under compression with lateral confinement. The proposed granular crystals are composed of two different types of cylinders: large soft cylinders and small hard cylinders. The pattern-transformable granular crystals are obtained by exploring perturbed packing patterns as potential configurations, and compression with lateral confinement as the driving force of the transition. As a demonstration of the proof-of-concept, we first show the results of desktop scaled experiments and finite element simulations for a representative case. Then, we present the procedure to obtain these new pattern transformations in soft granular crystals based on the compact packing theory of diatomic circles. The scale-independent compact packing theory serves as an important part of the veiled underlying mechanism of the observed pattern transformations, so the proposed granular crystals can open new avenues in the microstructural design of functional materials towards practical applications. PMID- 28849844 TI - The optical response of monolayer, few-layer and bulk tungsten disulfide. AB - We present a comprehensive optical study of thin flakes of tungsten disulfide (WS2) with thickness ranging from mono- to octalayer and in the bulk limit. It is shown that the optical band-gap absorption of monolayer WS2 is governed by competing resonances arising from one neutral and two distinct negatively charged excitons whose contributions to the overall absorption of light vary as a function of temperature and carrier concentration. The photoluminescence response of monolayer WS2 is found to be largely dominated by disorder/impurity- and/or phonon-assisted recombination processes. The indirect band-gap luminescence in multilayer WS2 turns out to be a phonon-mediated process whose energy evolution with the number of layers surprisingly follows a simple model of a two dimensional confinement. The energy position of the direct band-gap response (A and B resonances) is only weakly dependent on the layer thickness, which underlines an approximate compensation of the effect of the reduction of the exciton binding energy by the shrinkage of the apparent band gap. The A-exciton absorption-type spectra in multilayer WS2 display a non-trivial fine structure which results from the specific hybridization of the electronic states in the vicinity of the K-point of the Brillouin zone. The effects of temperature on the absorption-like and photoluminescence spectra of various WS2 layers are also quantified. PMID- 28849845 TI - Magneto-structural correlations in dirhenium(iv) complexes possessing magnetic pathways with even or odd numbers of atoms. AB - The employment of pyrazine (pyz), pyrimidine (pym) and s-triazine (triz) ligands in ReIV chemistry leads to the isolation of a family of complexes of general formula (NBu4)2[(ReX5)2(MU-L)] (L = pyz, X = Cl (1) or Br (2); L = pym, X = Br (3); L = triz, X = Br (4)). 1-4 are dinuclear compounds where two pentahalorhenium(iv) fragments are connected by bidentate pyz, pym and triz ligands. Variable-temperature magnetic measurements, in combination with detailed theoretical studies, uncover the underlying magneto-structural correlation whereby the nature of the exchange between the metal ions is dictated by the number of intervening atoms. That is, the spin-polarization mechanism present dictates that odd and even numbers of atoms favour ferromagnetic (F) and antiferromagnetic (AF) exchange interactions, respectively. Hence, while the pyz ligand in 1 and 2 mediates AF coupling, the pym and triz ligands in 3 and 4 promote F interactions. PMID- 28849846 TI - Two-dimensional island emulsions in ultrathin, freely-suspended smectic liquid crystal films. AB - We report a novel type of two-dimensional colloidal emulsion, in which arrays of disc-shaped liquid crystal domains are created in ultrathin, freely-suspended, fluid smectic C liquid crystal films. After a film has been drawn across an aperture, an island emulsion is produced by repeatedly compressing and expanding the film while maintaining vigorous shear and extensional air flow across its area. Once formed, these emulsions restructure over a period of a few minutes to a stable state that then changes only slowly, over the course of several days. This stability enables study of the sedimentation of the emulsion under in-plane gravitation produced by tilting the film, during which the original island emulsion segregates into regions with different kinds of emulsions distinguished by the size, density, and degree of order of the islands. We observe a rich array of phenomena that includes the formation of chains of islands organized into two dimensional smectics in the dilute phase, and island deformation and coalescence in the condensed phase. PMID- 28849847 TI - A general strategy for synthesizing high-coercivity L10-FePt nanoparticles. AB - It is extremely desirable but challenging to develop a facile solution phase synthesis to directly prepare well-dispersed L10-FePt nanoparticles (NPs) to meet the requirements of advanced magnets in modern industry and information technology. Here, we report a novel strategy to synthesize hard magnetic L10-FePt NPs via controlled co-reduction of Fe(acac)3 and K2PtCl6 in the presence of oleylamine, in which effective control of the magnetic properties and chemical ordering of L10-FePt NPs was achieved by tuning the mole ratio of the precursors, reaction time and temperature. The highest coercivity of 10.5 kOe can be obtained for the NPs synthesized at 350 degrees C for 8 h, which is much higher than the coercivities reported by the previous studies on solution-synthesized FePt NPs without annealing or the third elemental additive. The reported one-pot synthesis of L10-FePt NPs may provide an ideal class of building blocks for magnetic energy applications. PMID- 28849848 TI - Synthesis of quinolines via copper-catalyzed domino reactions of enaminones. AB - Quinoline derivatives were obtained from enaminones and 2-bromo- or 2 iodobenzaldehydes via copper-catalyzed domino reactions consisting of the aldol reaction, C(aryl)-N bond formation and elimination. The electronic effect of aldehydes played a major role in the reaction outcome. Two simple protocols are disclosed to achieve various quinolines from both cyclic and acyclic enaminones in good yields. With the less-reactive acyclic enaminones, diethyl-2-(2 bromobenzylidene)malonate was shown to be more compatible than the benzaldehydes. PMID- 28849849 TI - Phenyl-doped graphitic carbon nitride: photoluminescence mechanism and latent fingerprint imaging. AB - The photoluminescence (PL) emission mechanism of graphitic carbon nitride (g C3N4) is still ambiguous and the application of PL g-C3N4 powder as a solid sensing platform has not been explored. Herein we highlight a strategy to prepare g-C3N4 powder with strong green PL by doping phenyl groups in a carbon nitride network. Compared with pristine g-C3N4, doping of phenyl groups greatly enhances the PL efficiency and Stokes shift. Theoretical calculations based on density function theory indicate that phenyl groups change the electronic structure of the carbon nitride network and have an obvious contribution to the LUMO of phenyl doped g-C3N4, which may be the main reason for the enhancement of the PL efficiency and Stokes shift. Taking advantage of the high PL efficiency, large Stokes shift and high photo-stability, phenyl-doped g-C3N4 powder shows promising application for the imaging of latent fingerprints. PMID- 28849851 TI - Synthesis of phostones via DABCO-catalyzed bromocyclization of alkenylphosphonic acid monoesters. AB - The bromocyclization of 4-aryl-3-butenylphosphonic acid monoesters could proceed smoothly and rapidly in CH3CN with 1.2 equiv. of NBS in the presence of 0.02 equiv. of DABCO at room temperature, giving exclusively the six-membered ring bromophostones with high endo regioselectivity but poor diastereoselectivity. The diastereomers were separated and their relative configurations were determined based on their NMR analysis and X-ray crystallography. Furthermore, we preliminarily demonstrated that the asymmetric bromocyclization of these kinds of substrates was possible. PMID- 28849852 TI - Defect structure and percolation in the packing of bidispersed particles on a sphere. AB - We study packings of bidispersed spherical particles on a spherical surface. The presence of curvature necessitates defects even for monodispersed particles; bidispersity either leads to a more disordered packing for nearly equal radii, or a higher fill fraction when the smaller particles are accommodated in the interstices of the larger spheres. Variation in the packing fraction is explained by a percolation transition, as chains of defects or scars previously discovered in the monodispersed case grow and eventually disconnect the neighbor graph. PMID- 28849853 TI - A novel supramolecular polymer gel based on naphthalimide functionalized pillar[5]arene for the fluorescence detection of Hg2+ and I- and recyclable removal of Hg2+via cation-pi interactions. AB - The development of novel materials for the detection and removal of Hg2+ is a very important issue due to the acute toxicity of Hg2+. Herein, a novel supramolecular polymer P5BD-DPHB has been constructed by the collaboration of a naphthalimide functionalized-pillar[5]arene host (P5BD) and a bis-bromohexane functionalized-pillar[5]arene guest (DPHB). P5BD-DPHB could form a stable supramolecular gel (P5BD-DPHB-G). Interestingly, P5BD-DPHB-G shows selective fluorescent "turn-on" detection for Hg2+via cation-pi interactions with high selectivity and sensitivity. Furthermore, the Hg2+ coordinated supramolecular gel P5BD-DPHB-HgG can detect I- successively. The detection limits for Hg2+ and I- are 1.65 * 10-9 and 1.84 * 10-8 mol L-1, respectively. Even more significantly, the xerogel of P5BD-DPHB-G could remove Hg2+ from aqueous solution with excellent recyclability and ingestion capacity, and with a Hg2+ removal rate of 98%. PMID- 28849854 TI - A photovoltaic self-powered gas sensor based on a single-walled carbon nanotube/Si heterojunction. AB - We present a novel photovoltaic self-powered gas sensor based on a p-type single walled carbon nanotube (SWNT) and n-type silicon (n-Si) heterojunction. The energy from visible light suffices to drive the device owing to a built-in electric field (BEF) induced by the differences between the Fermi levels of SWNTs and n-Si. PMID- 28849855 TI - Intramolecular addition of benzyl anion to alkyne utilizing [1,2]-phospha-Brook rearrangement under Bronsted base catalysis. AB - A novel reaction system for intramolecular addition of benzyl anions to alkynes was developed by utilizing the [1,2]-phospha-Brook rearrangement under Bronsted base catalysis. The present reaction is a rare example of a catalytic addition reaction of an unstabilized benzyl anion under Bronsted base catalysis. PMID- 28849856 TI - 1D copper nanowires for flexible printable electronics and high ampacity wires. AB - This paper addresses the synthesis and a detailed electrical analysis of individual copper nanowires (CuNWs). One dimensional CuNWs are chemically grown using bromide ions (Br-) as a co-capping agent. By partially replacing alkyl amines with Br-, the isotropic growth on Cu seeds was suppressed during the synthesis. To study the electrical properties of individual CuNWs, a fabrication method is developed which does not require any e-beam lithography process. Chemically grown CuNWs have an ampacity of about 30 million amps per cm2, which is more than one order of magnitude larger than bulk Cu. These good quality, easy to synthesize CuNWs are excellent candidates for creating high ampacity wires and flexible printable electronics. PMID- 28849857 TI - Balancing the electrical double layer capacitance and pseudocapacitance of hetero atom doped carbon. AB - Heteroatom-doped carbonaceous materials derived from polymers are emerging as a new class of promising supercapacitor electrodes. These electrodes have both electrical double layer capacitance (from carbon matrices) and pseudo-capacitance (from hetero-atoms). Balancing the electrical double layer capacitance and pseudo capacitance is a key to achieve large capacitance at ultrafast current densities. Here we investigate the influence of pyrolysis temperature on capacitive performance of hetero-atom (oxygen and nitrogen) doped carbons derived from polypyrrole nanowire arrays. Structural and electrochemical characterization reveal that the concentration of hetero-atoms as well as the ratio of electrical double layer capacitance and pseudo-capacitance can be tuned by varying the pyrolysis temperature. In fact the hetero-atom doped carbon sample obtained at a relatively lower pyrolysis temperature (500 degrees C) exhibits the optimal capacitive performance. It yields an outstanding areal capacitance of 324 mF cm-2 at 1 mA cm-2 (141 F g-1@0.43 A g-1), and more importantly, retains an areal capacitance of 184.7 mF cm-2 (80.3 F g-1@43.5 A g-1) at an ultrahigh current density of 100 mA cm-2. An asymmetric supercapacitor consisting of hetero-atom doped carbon as an anode delivers a maximum volumetric energy density of 1.7 mW h cm-3 at a volumetric power density of 0.014 W cm-3, which is among the best values reported for asymmetric supercapacitors. PMID- 28849858 TI - Dynamic behaviour of multilamellar vesicles under Poiseuille flow. AB - Surfactant solutions exhibit multilamellar surfactant vesicles (MLVs) under flow conditions and in concentration ranges which are found in a large number of industrial applications. MLVs are typically formed from a lamellar phase and play an important role in determining the rheological properties of surfactant solutions. Despite the wide literature on the collective dynamics of flowing MLVs, investigations into the flow behavior of single MLVs are scarce. In this work, we investigate a concentrated aqueous solution of linear alkylbenzene sulfonic acid (HLAS), characterized by MLVs dispersed in an isotropic micellar phase. Rheological tests show that the HLAS solution is a shear-thinning fluid with a power law index dependent on the shear rate. Pressure-driven shear flow of the HLAS solution in glass capillaries is investigated using high-speed video microscopy and image analysis. The so obtained velocity profiles provide evidence for a power-law fluid behaviour of the HLAS solution and images show a flow focusing effect of the lamellar phase in the central core of the capillary. The flow behavior of individual MLVs shows analogies with that of unilamellar vesicles and emulsion droplets. Deformed MLVs exhibit typical shapes of unilamellar vesicles, such as parachute and bullet-like. Furthermore, MLV velocity follows the classical Hetsroni theory for droplets provided that the power law shear dependent viscosity of the HLAS solution is taken into account. The results of this work are relevant for the processing of surfactant-based systems in which the final properties depend on the flow-induced morphology, such as cosmetic formulations and food products. PMID- 28849859 TI - Ecology of melanoma cell. AB - Melanoma represents a cancer with increasing incidence worldwide and limited curability of advanced stages of the disease. Similarly to other types of tumors, the microenvironment is an important factor that participates in the control of melanoma biological properties. This review summarizes data regarding the role of the microenvironment, namely fibroblasts, keratinocytes and infiltrating immune cells, on melanoma growth and spreading. The role of embryonic microenvironment on melanoma cell biological properties is also discussed. The potential of therapeutic targeting of the melanoma microenvironment is demonstrated. PMID- 28849860 TI - [Neuromyelitis optica spectrum disorders: profile of a cohort according to the 2015 diagnostic criteria]. AB - INTRODUCTION: The new 2015 criteria for neuromyelitis optica spectrum disorders (NMOSD) have been recently incorporated in the study of different international cohorts. AIM: To describe clinical-radiological characteristics and prognostic factors in patients with NMOSD according to the 2015 criteria. PATIENTS AND METHODS: Retrospective analysis of 36 patients diagnosed with NMOSD according to serologic AQP4 status (positive, negative, unknown and negative + unknown). Clinical and radiological characteristics were compared and possible disability prognostic factors were evaluated. RESULTS: AQP4 were positive in 7 patients, negative in 12 and unknown in 17. Age of presentation was 36.6 +/- 16 years, with higher female proportion (4:1). Mean disease duration was 7.4 +/- 7.6 years. Most frequent presenting symptoms were acute myelitis (61%), optic neuritis (33%) and area postrema syndrome (11%). Most frequent MRI lesion was longitudinally extensive transverse myelitis (75%). All patients received acute treatment during attacks, and preventive treatment was used in 81% (azathioprine and rituximab mostly prescribed). Median EDSS was 2.0 at the end of follow-up. No differences were observed in any of the variables comparing serologic status. Age of first attack was prognostic, with direct correlation with EDSS. First attack in < 30 years was protective, meanwhile > 50 years old patients had increased risk of disability. CONCLUSIONS: The 2015 criteria allow the description and classification of NMOSD patients within different cohorts. Age of first attack seems to be a prognostic factor for developing disability. PMID- 28849862 TI - [Efficacy of a dynamic orthosis on the upper limbs in the chronic phase of strokes. A longitudinal study]. AB - AIMS: Stroke is the most important medical condition leading to permanent disability in adults. The aim of this study is to evaluate the efficacy of dynamic orthoses in the rehabilitation of the upper limbs in patients who have had a stroke. PATIENTS AND METHODS: We conducted a longitudinal case-control study. The sample used in the study consisted of patients from rehabilitation centres who presented hemiparesis secondary to an ischaemic or haemorrhagic stroke. The patients were randomly distributed into a study group, whose members received a dynamic orthosis on an upper limb for a six-month period, and a control group. Appraisals were performed pre- and post-treatment with the orthosis with Fugl-Meyer Assessment Scale and with Wolf Motor Function to measure their command over body functions and activities. Differences between pre- and post-test were compared using ANCOVA and Student's t. RESULTS: The sample included 40 patients (65% males) who presented chronic hemiparesis secondary to ischaemic (n = 28) or haemorrhagic stroke (n = 12), with a mean age of 58.43 +/- 8.67 years. After the six-month follow-up, improved motor function was observed in both groups, according to both scales. The use of a dynamic orthosis was associated with a tendency towards improved strength in the upper limb. CONCLUSIONS: Rehabilitation following a stroke improves strength and body activities in the upper limb. The use of a dynamic orthosis can further improve the strength in this limb, but additional research is needed to confirm our results. PMID- 28849861 TI - [Environmental-analytical risk factors influence on the phenotype of amyotrophic lateral sclerosis in a rural setting]. AB - INTRODUCTION: There are discrepancies in the different studies that attempt to correlate the risk factors of developing amyotrophic lateral sclerosis (ALS) and the impact on their prognosis. Some of these factors are intrinsic to the rural livelihood. Therefore, we propose to study if any of these influence the onset and/or prognosis of the disease in the health region of Lleida, a predominantly rural area. PATIENTS AND METHODS: Variables related to general factors, clinical, environmental and laboratory were collected and analyzed at the time of diagnosis of ALS in 38 patients and were retrospectively related to the onset of the disease and its survival. RESULTS: The family history of ALS (p < 0.02) and elevated CK (p < 0.0001) were associated with increased survival. Smoking (p < 0.04), physical work (p < 0.03), low creatinine (p < 0.03), elevated CK (p = 0.0005) were associated with an early onset of the disease. The bulbar onset form was significantly related to a late onset of the disease (p < 0,01). Total cholesterol and PCR did not influence the onset or course of ALS. There is a non significant trend at statistical level in favor of moderate physical exercise being associated with a later onset, while intense exercise at an early onset of ALS. CONCLUSIONS: The results suggest that there are a number of factors that influence the development and prognosis of ALS, some of which are more prevalent in rural areas, such as physical work. PMID- 28849863 TI - [Psychosocial factors and cognitive performance in multiple sclerosis: gender differences]. AB - INTRODUCTION: Being a woman increases the risk of developing multiple sclerosis, an illness where biopsychosocial factors (psychological stress, perceived social support, psychological well-being, coping strategies) may have a clinical impact. AIMS: To assess how stress management is affected in remitting-relapsing multiple sclerosis and to analyze gender differences both in terms of stress management and patients' cognitive performance. PATIENTS AND METHODS: 42 patients were neuropsychologically evaluated with the Brief Repeatable Battery of Neuropsychological Tests, four psychosocial questionnaires and Beck's Depression Inventory. Two main analyses were conducted: mean comparisons between men and women for clinical, neuropsychological and psychosocial variables, and a correlation analysis between the psychosocial and clinical variables of the illness in the whole sample, as well as in men and women separately. RESULTS: Men and women showed differences in the outbreak rate and in the attention/executive function domain. The correlation analysis revealed that the strongest correlation was between clinical and psychosocial variables when the group was divided according to gender. Any predominant coping strategy was not detected in the multiple sclerosis group, but it was observed that women had an increased tendency to self-incriminate. CONCLUSION: This study emphasizes the importance of assessing these remitting-relapsing multiple sclerosis patients both cognitively and psychosocially, differentiating them by gender. PMID- 28849864 TI - [Reversible alterations in the dentate nuclei and rapid-onset cerebral atrophy due to neurotoxicity caused by lithium]. AB - INTRODUCTION: Treatment with lithium can cause several neurological side effects, even at therapeutic levels. CASE REPORT: We report the case of a 49-year-old woman, with bipolar disorder and depression, undergoing treatment with lithium, antidepressants and antipsychotics, who was admitted to hospital due to a clinical picture of visual hallucinations with an elevated lithaemia of 2.1 mEq/L (therapeutic range: 0.6-1.2 mEq/L). The patient developed a severe encephalopathy that required the use of assisted ventilation in the intensive care unit. Initial magnetic resonance imaging showed a reversible bilateral symmetrical hyperintensity in the dentate nuclei in T2 and T2-FLAIR sequences. Over the following months she gradually developed a pancerebellar syndrome with evidence of a marked loss of bilateral volume in the cerebellum, above all at the expense of the vermis, which was accompanied by a permanent and disabling cerebellar syndrome. CONCLUSIONS: Although treatment with lithium can cause a variety of neurological side effects, they are usually reversible. However, they occasionally give rise to permanent and disabling sequelae, as in the case of the patient reported here, with a marked and progressive cerebellar atrophy, accompanied by permanent sequelae in the form of a disabling cerebellar syndrome. The cerebellar neurotoxicity of lithium must be taken into account in the broad differential diagnosis of cerebellar ataxia in adults. PMID- 28849865 TI - [Neuropsychology of event-based prospective memory]. AB - INTRODUCTION: Prospective memory is the capacity to remember actions that are to be performed in the future. Different studies from experimental neuropsychology attempt to unravel the neurocognitive processes underlying event-based prospective memory, that is, delayed actions that take place in a predetermined context, which would play the role of an external cue and would therefore contribute to successful intentional recall. DEVELOPMENT: Taking the dynamism and flexibility of multiprocess theory as a reference, the main findings have highlighted the fact that prospective memory is influenced by, among other factors, the type of cue. Thus, when the cue is focal, the person tends to rely on spontaneous retrieval. In contrast, when the cue is not focal, there is usually a tendency towards monitoring. In parallel to this, studies in experimental neuropsychology have determined that the anterior prefrontal cortex and the dorsal frontoparietal network would participate in the cue monitoring processes. Conversely, the ventral frontoparietal network would intervene in automatic retrieval processes. Moreover, the role of the parietal lobe and the medial temporal lobe in prospective tasks is discussed. CONCLUSION: This study defends the idea that both processing pathways (monitored and spontaneous) favour success in recalling the event-based intentional action. It must nevertheless be borne in mind that the moment a person decides to set one type of processing (or another) in motion it is influenced by the type of cue. PMID- 28849866 TI - [Acute symmetrical lesions in the basal ganglia within the context of uremia]. PMID- 28849867 TI - [IX Reunio Anual de les Societats Catalanes de Neurofisiologia Clinica i Electromiografia. Communications]. PMID- 28849868 TI - [Primary lymphoma of the anterior pituitary in an immunocompetent patient]. PMID- 28849869 TI - [Wolf-Hirschhorn syndrome: just a citation omission?] PMID- 28849870 TI - [Wolf-Hirschhorn syndrome: just a citation omission? Reply]. PMID- 28849871 TI - Heated, humidified air for the common cold. AB - BACKGROUND: Heated, humidified air has long been used by people with the common cold. The theoretical basis is that steam may help congested mucus drain better and that heat may destroy the cold virus as it does in vitro. This is an update of a review last published in 2013. OBJECTIVES: To assess the effects of inhaling heated water vapour (steam) in the treatment of the common cold by comparing symptoms, viral shedding, and nasal resistance. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (to February 2017), MEDLINE (1966 to 24 February 2017), Embase (1990 to 24 February 2017), and Current Contents (1998 to 24 February 2017). We also searched World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (8 March 2017) and ClinicalTrials.gov (8 March 2017) as well as reference lists of included studies. SELECTION CRITERIA: Randomised controlled trials using heated water vapour in participants with the common cold or experimentally induced common cold were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Three review authors independently screened titles and abstracts for inclusion of potential studies identified from the search. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram. We used a data collection form for study characteristics and outcome data that was developed and used for previous versions of this review. Two review authors independently extracted data, and a third review author resolved any disagreements. We used Review Manager 5 software to analyse data. MAIN RESULTS: We included six trials from five publications involving a total of 387 participants. We included no new studies in this 2017 update. The 'Risk of bias' assessment suggested an unclear risk of bias in the domain of randomisation and a low risk of bias in performance, detection, attrition, and reporting.It was uncertain whether heated, humidified air provides symptomatic relief for the common cold, as the fixed-effect analysis showed evidence of an effect (odds ratio (OR) 0.30, 95% confidence interval (CI) 0.16 to 0.56; 2 studies, 149 participants), but the random-effects analysis showed no significant difference in the results (OR 0.22, 95% CI 0.03 to 1.95). There is an argument for using either form of analysis. No studies demonstrated an exacerbation of clinical symptom scores. One study conducted in the USA demonstrated worsened nasal resistance, but an earlier Israeli study showed improvement. One study examined viral shedding in nasal washings, finding no significant difference between treatment and placebo groups (OR 0.47, 95% CI 0.04 to 5.19). As judged by the subjective response to therapy (i.e. therapy did not help), the number of participants reporting resolution of symptoms was not significantly higher in the heated humidified group (OR 0.58, 95% CI 0.28 to 1.18; 2 studies, 124 participants). There was significant heterogeneity in the effects of heated, humidified air on different outcomes, therefore we graded the quality of the evidence as low. Some studies reported minor adverse events (including discomfort or irritation of the nose). AUTHORS' CONCLUSIONS: The current evidence does not show any benefits or harms from the use of heated, humidified air delivered via the RhinoTherm device for the treatment of the common cold. There is a need for more double-blind, randomised trials that include standardised treatment modalities. PMID- 28849872 TI - Multi-centre comparison of five eye movement detection algorithms. AB - Although various investigators have suggested algorithms for the automatic detection of eye movements during sleep, objective comparisons of the proposed methods have previously been difficult due to different recording arrangements of different investigators. In this study the results of five eye movement detection algorithms applied to the same data were compared to visually scored data. The percentages of true and false detections are given for various threshold levels in rapid and slow eye movement detections. The methods gave best results when they were used with the same electrode montage they were designed for but the performance decreased when other montages were used. Subtracting the cross-talk of EEG delta activity improved the correctness of eye movement detections. PMID- 28849873 TI - [It is the only theory of the chemical basis of aging that is comprehensive and makes sense]. PMID- 28849874 TI - [On the discontinuity of the annuity curves in Drosophila melanogaster Canton-S strain. IV. Effect of low temperature on the early imaginal stage]. AB - We tested the effect of low temperature (18-20 degrees C) applied at the 13-22 days of imago life. We detected prolongation of individual life span. The effect is due to prolongation of the first phase of the annuity curve and thus to further delay of the next ones. This may lead to delay of mature pathology and prolongation of maximal life span. The effect is not dependent on sample size. PMID- 28849876 TI - [Age-related aspects of the involvement of heat shock proteins in the pathogenesis of osteoarthritis]. AB - The purpose of research - to establish features of heat shock proteins (HSPs) levels change, chemokines and collagen degradation marker in the blood of patients with osteoarthritis in the age aspect. The results of the study shown, HSPs participate in the pathogenesis of osteoarthritis is complex and multi layered process. HSP70 acts as an immunologic adjuvant reactions involving chemokine CXCL17, under the influence of external risk factors. Low levels of HSPs not allow them to act as autoimmune factor interaction with Toll-like receptors of immune cells, but obviously it contributes for CXCL17-dependent activation of dendritic cells and macrophages, which initiate local inflammation involving key cytokines, including TNF-alpha. Chondrocytes and osteoblasts, subjected cytokine attack, are not able to reply fully enhanced expression of HSP70 and HSP27 for whatever reason. With aging, the pathophysiology of osteoarthritis enters the phase of the local tissue reaction, where significant role have processes hypertrophic differentiation of chondrocytes and osteo-like cells of subchondral bone. PMID- 28849875 TI - [Age-related dynamics of the main extracellular matrix components in residents of the Russian Arctic]. AB - The main extracellular matrix components in Arctic residents were studied. Northerners had increased levels of total glycosaminoglycans, hyaluronan, and collagen IV in plasma and both general and peptide-bound hydroxyproline in urine, which indicates an accelerated metabolism of the main extracellular matrix components compared with comparison group (residents of Siberia). Age-related remodeling of extracellular matrix in northerners manifested in changing ratio and quantity of its main components. Levels of total glycosaminoglycans, hyaluronan, fibronectin, hydroxyproline and its fractions increased with age while the level of collagen IV changed insignificantly. Average positive correlation between extracellular matrix components and biological aging indicators is suggestive of relationship between these two processes: aging - which is accelerated in the Arctic and pathological remodeling of extracellular matrix as it is associated with accelerated aging. Changes in local regulation system including those related to matrix metalloproteinases and their tissue inhibitors may be one of the reasons for pathological remodeling of extracellular matrix. PMID- 28849877 TI - [Developmental changes of neurotransmitter properties in sympathetic neurons]. AB - Neurochemical composition of metasympathetic nervous system is characterized by a large variation. The main part of the intramural ganglionic neurons is cholinergic. Along with cholinergic neurons, there are ganglionic neurons containing serotonin, histamine, GABA, and several peptides: cholecystokinin, dynorphin, enkephalin, galanin, gastrin-releasing peptide (bombesin in mammals), neuropeptide Y, neurotensin, somatostatin, tachykinins, neurokinin A, vasoactive intestinal polypeptide and calcitonin gene related peptide. Gases as NO, CO, H2S, also act as neurotransmitters. Separate groups of neurons differ in the content of neuronal calcium-binding proteins, such as calbindin, calretinin and parvalbumin and neurofilaments: low molecular weight, a medium molecular weight and high molecular weight. Neurons of the enteric ganglia are the most different by their neurochemistry. There is a species difference in the ganglia of large animals and humans there are more combinations of chemical transmitters. Synthesis of neurotransmitters takes place even in the embryonic period and by the time of birth the most of neurons contain acetylcholine. In postnatal ontogenesis, the proportion of neurons expressing the NO-synthase decreases in the enteric and cardiac intramural ganglionic neurons. The functional significance of these changes is unclear. PMID- 28849878 TI - [Prediction of life expectancy for prostate cancer patients based on the kinetic theory of aging of living systems]. AB - The article presents a methodical approach for prediction of life expectancy for people diagnosed with prostate cancer based on the kinetic theory of aging of living systems. The life expectancy is calculated by solving the differential equation for the rate of aging for three different stage of life - "normal" life, life with prostate cancer and life after combination therapy for prostate cancer. The mathematical model of aging for each stage of life has its own parameters identified by the statistical analysis of healthcare data from the Zharinov's databank and Rosstat CDR NES databank. The core of the methodical approach is the statistical correlation between growth rate of the prostate specific antigen level (PSA-level) or the PSA doubling time (PSA DT) before therapy, and lifespan: the higher the PSA DT is, the greater lifespan. The patients were grouped under the "fast PSA DT" and "slow PSA DT" categories. The satisfactory matching between calculations and experiment is shown. The prediction error of group life expectancy is due to the completeness and reliability of the main data source. A detailed monitoring of the basic health indicators throughout the each person life in each analyzed group is required. The absence of this particular information makes it impossible to predict the individual life expectancy. PMID- 28849879 TI - [Age women health specialities in peri- and postmenopausal period]. AB - Analysis of the health status of 500 women in the period of perimenopause and postmenopause (age groups 44-49 and 50-64 years) living in a region with special climatic and geographical conditions and low population density, as well as a study of 411 460 reasons for seeking medical help, showed the presence at each woman had an average of up to seven somatic abnormalities in the anamnesis (p<=0,005) developing during the aging process. The results of the analysis testify to the need for the post of obstetrician-gynecologist with knowledge of the age-related pathology of women in perimenopause and postmenopause. Knowledge of the aggregates of age-related changes in women's health determines the individual approach to the provision of medical care in the middle and old age, and the necessity of updating the module for training obstetricians and gynecologists in age-related pathology (somatic and gynecological). PMID- 28849880 TI - [Age-related changes in the expression of lamin B receptors in fibroblasts of human dermis]. AB - The aim of this work was to study lamin B receptors in human skin at different ages. Lamin B receptors, proliferating cells nuclear antigen (PCNA) were detected in sections of the skin by indirect immunohistochemistry. Our results showed that both portion of dermal fibroblasts with positive staining for lamin B receptors and intensity of staining of fibroblasts for lamin B receptors were maximal from birth to 20 years as compared to all other examined age-periods (from 20 weeks of pregnancy to 85 years old). General number of fibroblasts and number of fibroblasts with positive staining for PCNA in dermis were diminished with age. The most significant decrease in the number of fibroblasts and PCNA positive fibroblasts were observed from 20 years old. An increase in the level of lamin B receptors in dermal fibroblasts observed from birth to 20 years old may be regarded as one of start events leading to age-dependent decrease in the number of fibroblasts in human dermis. PMID- 28849881 TI - [Age-related changes in the content of sirtuin 1 in fibroblasts of human dermis]. AB - The goal of our work was to examine content of sirtuin 1 in human skin at different ages to uncover a role of sirtuin 1 in aging of human skin. Sirtuin 1, proliferating cells nuclear antigen (PCNA) were detected by indirect immunohistochemistry in sections of the skin of human fetuses died antenatally from 22 to 40 weeks of pregnancy and humans from birth to 85 years old, died from various causes. Our results showed that the level of sirtuin 1 in dermal fibroblasts was decreased from prenatal period to 85 years old. Both the number of fibroblasts and their proliferative activity were also decreased through life. Age-related decrease in sirtuin 1 content in dermal fibroblasts is statistically significant correlated with age-dependent decrease in proliferation. Therefore, lowering of sirtuin 1 content in dermal fibroblasts occurring with age can be regarded as a mechanism which leads to inhibition of proliferation of dermal fibroblasts. PMID- 28849883 TI - [Stomatological status and quality of life of elderly and senile people]. AB - The stomatological status and the measures of oral health-related quality of life in elderly and senile inhabitants of Novosibirsk were researched. The high prevalence and intensity of the major stomatological diseases, the high need for oral cavity sanation and prosthetics in elderly and senile population were found out. PMID- 28849882 TI - [Cognitive-cytokine effect of nonsteroidal antiinflammatory drugs in the therapy of elderly patients with osteoarthritis]. AB - The purpose of the study was to evaluate the influence of long-term non-steroidal anti-inflammatory drugs (NSAID) therapy on the dynamics of the severity of cognitive deficits and its association with changes in the level of cytokines in elderly patients with osteoarthritis (OA). The authors performed a prospective observational study during 540+/-5,5 days, presented in two stages: phase I - the stage of active NSAID therapy; phase II - the stage of non-pharmacological correction of OA. The first stage included 128 patients with OA from 65 to 75 years (average age 70+/-4,6 years, 10,2% of males and 89,8% female). Patients from the main group were divided into four subgroups: patients of the 1st group (n=30) received the drug etoricoxib at a dose of 60 mg per day; patients of the 2nd group (n=32) - celecoxib at a dose of 200 mg daily, patients of the 3rd group (n=32) - nimesulide in dose of 100 mg per day; patients of the 4th group (n=34) - meloxicam at a dose of 7,5 mg per day. The comparison group consisted of 40 patients with similar clinical and demographic characteristics of OA, not taking NSAIDs in the previous 6 months or during the study. It was determined the pain and stiffness indexes by the WOMAC initially and evaluated the patient status at the MoCA scale and carried out laboratory diagnosis of contents in serum TGF beta1, IL-1beta and IL-6 at all visits. Statistically significant decrease in the level of cytokines was detected during the period of 1st-3rd visits for all patients in the groups receiving NSAID, also there was an increase in cognitive function on a scale of MoCA with a high degree of correlation in relation to the performance of cytokines to the end of the study. The results of our research allow us to speak about possible influence on cognitive functions of NSAID therapy in elderly patients with OA in real clinical practice. PMID- 28849885 TI - [Disability as a medical and social indicator of health status and aging among Russian Population]. AB - According to the State Statistics a comparative analysis of total disability in the Russian Federation in 2010-2016 years was conducted, taking into account the performance of the working-age and over working-age population. The necessity of integration policy towards the older generation and social policy in respect of disabled persons is shown: it is advisable to make adjustments to the national strategies and programs involving the duties of authorities to protect and promote the rights of disabled people, the development of preventive, rehabilitation, medical and social trends in the interests of senior citizens are involved. PMID- 28849884 TI - [Community acquired bacterial pneumonia and comorbidity in elderly patients]. AB - We analyzed the clinical course of pneumonia in 67 elderly patients (39 females and 28 males, mean age 74,4+/-5,2 years) with chronic heart failure and chronic obstructive pulmonary disease (COPD). Patients were divided into 2 groups: 1st group - patients with COPD, 2nd group - patients without COPD. Pharmacological treatment was performed according to temperature, oxygen saturation, acute phase proteins and included ampicillin and sulbactam. The normalization of temperature and oxygen saturation was observed on 3-4 day in patients of the 1st group and on 2 day in patients of the 2nd group, normalization of leukocyte count and erythrocyte sedimentation rate - on 12-13 and 7-8 days, acute phase indicators (C reactive protein, fibrinogen) on 7 and 5 days, correspondingly. Positive dynamics of chest X-ray was observed on 13 day in patients of the 1st group (the second control and the replacement of antibiotic for levofloxacin) and on 8 day in patients of the 2nd group (the first control). PMID- 28849886 TI - [Age aspects of the muscular-tonic and urological syndromes in men with disorders of the pelvic functions: the features of clinic, diagnostics, treatment]. AB - A comparative examination of 100 patients at different ages, suffering from disorders of micturition, erectile function and pelvic pain, identified age related peculiarities of these pathological manifestations. Irritative disorders of urination was detected significantly more frequently among persons of young and middle age than the elderly, and obstructive-related disorders were more frequent in the elderly. In elderly and senile age more prevalent was reducing of the contractility of the detrusor, and at a younger age - increased tone of striated sphincter of the urethra and bladder hyperactivity. It was shown that the participation of long-existing spasm of some muscle formation of the lumbar, pelvic and femoral region in the genesis of urinary symptoms, erectile dysfunction and pelvic pain. When using manual therapy, physiotherapy and botuline-therapy high effectiveness against disorders of micturition, erectile function and pelvic pain was achieved regardless of the age of the patients. It is recommended for the diagnosis of urological pathology to involve specialists in the field of neurology and manual therapy. In cases of diagnosis of musculo tonic disorders not etiologically associated with pathological processes in the organs of the urogenital system, in the complex of therapeutic measures it is recommended to include methods such as manual-therapy, physiotherapy, botuline therapy. PMID- 28849887 TI - [Age dynamics of secretory, absorptive, buffer ability of the mucosa inside the human nose]. AB - The problem of age-related functional changes of organs and systems of the human body is one of the urgent problems of modern physiology and gerontology. The most important, complex system of human body is respiratory system, especially its "first line of defense" - the nasal cavity. Functional parameters of the nasal cavity undergo a number of specific changesat the stages of postnatal ontogenesis, the study of which has not only scientific value but also practical value for experimental physiology and clinical medicine. The article presents data on the age dynamics and adaptability of such functional parameters of the mucous membrane of the nasal cavity of the person, as secretory and suction activity, the air heater function, the buffer properties by endonasal secret. These indicators are examined at the stages of postnatal development in a comparative perspective based on the study of the age gradients. PMID- 28849888 TI - [Interrelation of rates of a biological aging with neurophysiological features at patients with professional neurointoxications]. AB - In the hospital conducted studying of functional activity of a brain of patients with professional neurointoxications for the purpose of detection of neurophysiological features of formation of the accelerated rates of biological aging at the working, being affected neurotoxicant is carried out. During the research it is shown that rates of aging at patients with professional neurointoxications on average in 85% of cases have premature character. The general signs of defeat of structures of a brain at professional intoxication are defined by mercury irrespective of a disease stage at the accelerated biological aging. For toxic impacts on a nervous system the characteristic, uniting sign distinguishing from the accelerated rates of aging of other etiology is the indicator characterizing augmentation of a latence of peak of P2 of the visual caused potentials. Based on the analysis of the received correlations it is set that in case of professional neurointoxications permanent disorganization of the functional activity of a brain in the form of cortical and subcortical violations of sensor regulatory systems of a brain is a consequence of chronic influence of vapors of metal mercury and a complex of toxic substances and the reason of the accelerated biological aging. PMID- 28849889 TI - [Pineamin increased pineal melatonin synthesis in elderly people]. AB - It was investigated the influence of polypeptide complex Pineamin on the 6 sulfatoxymelatonin (aMT6S) excretion in urine by ELISA test of 55 elderly patients with diminished melatoninsynthesis pineal gland function. Pineamin in course dose 100 mg has increased night level of aMT6S urine excretion in 1,9 times in comparison with relevant value untreated. Similar effect was obtained early for medical drug Epithalamin. Epithalamin also restored melatonin level in human and animals during aging. Thus, Pineamin and Epithalamin have similar stimulate effect on melatonin synthesis in elderly people pineal gland. PMID- 28849890 TI - STAT3 as novel drug target for multiple age-related disorders: docking and simulation analysis. AB - Signal transducer and activator of transcription 3 (STAT3) considerably contributes to various age-related disorders (ARDs) for instance cancer, autoimmune disorders, bowel-associated disorders, Alzheimer's disease, Parkinson's disease and age-related macular degeneration. Previous studies have substantiated that obstructing STAT3 activity may cure an amount of ARDs. Studies on STAT3 have proved it as a novel and promising drug target. In this study, a docking-based virtual screening combined with molecular dynamics simulation was executed to ascertain STAT3 dimerization inhibitors. It was indicated that ligand 01 (ZINC20601870) and ligand 02 (ZINC01216760) exhibited remarkably higher binding affinities (binding affinity with ligand 01 = -8,01 Kcal/mol, binding affinity with ligand 02 = -6,91 Kcal/mol) compared to other ligands. These two ligands reached equilibrium with STAT3 in molecular dynamics simulation. Hence, in this work, we suggest ligand 01 and 02 as a promising lead for further optimization and may serve as drug molecules in therapeutics of multiple ARDs. PMID- 28849892 TI - [Cognitive and affective disorders in the elderly]. AB - To develop algorithm of diagnostics of cognitive and affective disorders in elderly and senile age 98 representatives of this age group were examined (1st group - 68 persons 60-74 years, 2nd group - 30 patients older than 75 years). For the diagnosis of cognitive disorders the developed and adapted "Short rating scale of cognitive functions", to diagnose emotional disorders - "Nospital scale of anxiety and depression HADS" were used. Cognitive impairment was revealed in 39,8% of the elderly (1st group - 28,7% in 2nd group - 61,6%). Affective disorders 51,6% of respondents had; however, signs of anxiety - 40,9% and depression - 27,7%. Algorithm for the diagnosis of cognitive and emotional disorders in elderly and senile age, comprising the steps of: screening and diagnostic, clinical and pathopsychological, laboratory and instrumental diagnostic, psychodiagnostic, can be recommended for use in general medical practice (therapists, general practitioners, geriatrics) for an earlier secondary prevention and, if necessary, early correction of mental health disorders. PMID- 28849891 TI - [Effects of saffron (Crocus sativus l. iridaceae) on blood level of follicle stimulating hormone, and number and dynamics of body weight of offspring in female rats]. AB - This paper reviews the effects of saffron Srocus sativus L. Iridaceae which grow in Azerbaijan on blood level of follicle-stimulating hormone (FSH), and number and dynamics of body weight of offspring in female rats. The findings indicated that the per os administration of alcoholic extract of saffron was able to decrease the FSH levels in blood of the 12-month-old rats as compared to that in the control group, involving the animals of the same age which have not received the saffron extract, and was close to the FSH levels reported for the 6-month rats. There was also an increase in number and body weight of pups from rats receiving the saffron extract prior to pairing with the intact males. PMID- 28849893 TI - [Age dynamics of cognitive functions in persons 50-85 years]. AB - The paper presents original study results of cognitive changes associated with aging in the absence of neurodegenerative, vascular and other significant for cognition disorders in period from 50 to 85 years. It was shown that aging is associated with moderate memory decrease predominantly because of retrieval deficit but not acquisition insufficiency. It was also shown that aging is associated with non-severe executive dysfunction (lack of planning and control). According usual neuropsychological approaches pattern of cognitive changes described above reflects anterior cortical dysfunction or/and impaired interaction between frontal lobes and subcortical basal ganglia. Shows what physiological changes occur with age in the field of memory and executive functions, which is of great clinical importance for the differential diagnosis of normal aging and early stages of common in the elderly cerebral diseases. PMID- 28849894 TI - [Donor age affects on the "behavior" and the sensibility bone marrow cells in on copper ion of the primary culture]. AB - The changes of bone marrow cells (BMC) number in the primary culture from 0 to 96 hours, the pattern (the distribution of cells) of cells morphotypes and "lifespan" (the time of cell life after isolation) of myelocytes, metamyelocytes, band and segmented neutrophils, isolated of the young (3 months) and old (20months) animals, were investigated. The number of the BMC obtained from intact old animals increased faster in primary culture, than from young animals. The Cu induced fibrosis had different influence on the rate of BMC culture growth of old and young animals. The adding of 4 mM and 8 mM CuSO4x5H2O in the BMC culture of young and old animals resulted in a dose-dependent inhibition of growth rate of young animal cells. If copper ions were added into the culture of BMC of old animals, the decreased of the BMC number was described less than for cells of young animals. The adding of 8 mM CuSO4x5H2O inhibited proliferation less, than the adding of 4 mM CuSO4x5H2O. The Cu-induced liver fibrosis had accelerated the BMC rate death of both old and young animals. However, this effect was more pronounced in young animals. It is suggested, that during the ontogenesis the BMC undergo such epigenetic changes, which change functional properties. PMID- 28849895 TI - Effectiveness of subgroup-specific pain rehabilitation: a randomized controlled trial in patients with chronic back pain. AB - BACKGROUND: Prospective classification of patients with nonspecific chronic back pain into homogeneous subgroups might be an important objective in order to tailor interventions and improve treatment outcomes. AIM: This study investigated the effect of a subgroup-specific pain rehabilitation program based on the Multidimensional Pain Inventory (MPI) Classification System compared to standard care. DESIGN: Single blinded, parallel group, pragmatic randomized controlled trial. SETTING: Inpatient subjects of a rehabilitation clinic. POPULATION: A total of 139 patients with chronic back pain. METHODS: Patients in both the experimental group and control group received during their 4-week in-house stay at the rehabilitation clinic on average four daily sessions of therapy. The patients in the experimental group received specific interventions, which were tailored to their subgroup classification profile. The patients in the control group participated in state-of-the-art care. The primary outcome was self reported disability measured at 1, 3 and 12 months after randomization with the Oswestry Disability Index (ODI). Secondary outcomes were pain intensity, examiner reported disability, anxiety and depression, catastrophizing, self-efficacy and global perceived effect. RESULTS: Groups were comparable under demographic and clinical characteristics. No significant differences between the experimental group and the control group for any of the outcomes and follow-up times were found in the intention-to-treat analysis. Compared to the 8-10 points considered as minimal clinically important difference for the ODI, effects within groups were small, e.g. the experimental group improved by 2.2 points at 1-month follow up, 3.7 points at 3 months and 5.3 points at 12 months. CONCLUSIONS: This study failed to demonstrate that a subgroup-specific program was more effective than standard care. CLINICAL REHABILITATION IMPACT: Since the subgroup-specific interventions were equally effective as standard pain rehabilitation, subgroup classification and tailoring interventions may be an alternative in clinical care. PMID- 28849896 TI - Co-contraction around the knee and the ankle joints during post-stroke gait. AB - BACKGROUND: Impairments resulting from hemiparetic stroke lead to persistent difficulties with walking. Abnormal co-contraction patterns of lower limb muscles might be a compensatory mechanism to deal with its resulting gait impairments. AIM: The aim of this study was to assess muscle co-contraction obtained from muscle moments in chronic hemiparetic patients presenting a stiff-knee gait (SKG) during walking. DESIGN: Cross-sectional study. SETTING: Clinical movement analysis laboratory in a health center and a community hospital. POPULATION: Twelve hemiparetic patients 6 months' post-stroke (mean+/-SD age 49.3+/-12.5) walking with a SKG and twelve healthy adults (mean+/-SD age 23.5+/-7.7). METHODS: Hemiparetic patients walked at their natural gait speed while healthy adults walked at their natural and slow gait speed. Spatiotemporal, kinetic and kinematic gait parameters were determined for both lower limbs. Co-Contraction Index at the knee and the ankle was calculated from muscle moments estimated using an EMG-driven model during the first (DS1) and second (DS2) double support and the single support (SS) phases and the swing phase (SW). RESULTS: The results revealed that chronic stroke patients have reduced ankle co-contraction and increased knee co-contraction during DS1 phase, increased ankle co-contraction during DS2 phase and increased knee co-contraction during SW phase on the paretic side. On the non-paretic side, muscle co-contraction was higher at the knee during SS phase. CONCLUSIONS: Increased co-contraction during walking in both the paretic and the non-paretic side, in patients with hemiparesis exhibiting a SKG, might be an adaptive strategy to increase walking stability, as it may be related to spasticity, but also could result in a high metabolic cost. CLINICAL REHABILITATION IMPACT: The information obtained in this study may be used to support rehabilitation programs focusing on the selectivity of movement control such as strength or power training. PMID- 28849897 TI - Physical and rehabilitation medicine practice in offices of general practitioners and family doctors in Croatia: controversies and resolution. PMID- 28849898 TI - Catheter directed thrombolysis is not limited to acute limb ischemia treatment- the experience from vascular surgery division. AB - BACKGROUND: Thrombolytic treatment has many potential indications in the era of modern vascular surgery. We aimed to analyze the contemporary experience in the catheter-directed, intraarterial thrombolysis in different clinical scenarios. METHODS: The available data of 121 patients with different types (acute, subacute, complications of vascular procedures) of lower limb ischemia treated by means of the intraarterial, catheter- directed thrombolysis between 11.2011 and 12.2016 were retrospectively analyzed. The basic treatment protocol, utilized in 92% of patients, was a catheter-directed infusion of 40 mg of alteplase within 3.5 hours. Pre- and intraprocedural factors (indications, demographic details, comorbidities, the dose of alteplase utilized, underlying lesions procedures), as well as postoperative outcomes (lysis grade, death, complications, reinterventions, and limb loss after 1- month observation), were analyzed. RESULTS: Successful thrombolysis was achieved in 76.1% (92 out of 121) patients. The success rate was similar for acute, subacute limb ischemia and thrombotic complications of vascular procedures. 67.8% (82 patients) had procedures to correct underlying lesions performed. Overall complication rate was 28.1% however, but the major bleeding was observed in only 5% (6 patients). Neither intracranial bleeding nor gastrointestinal bleeding occurred. No mortality, 1,7% reintervention rate and 10,7% amputation rate were recorded during one-month follow-up. CONCLUSIONS: Accelerated intraarterial thrombolysis is an effective measure in the treatment of acute, sub-acute limb ischemia as well as thromboembolic complications of vascular procedures. It carries a low risk of major bleeding. The location of thrombus in the crural arteries adversely affects the treatment results. Atrial fibrillation increases the risk of amputation while complete thrombus lysis is protective. PMID- 28849899 TI - Management of popliteal vascular injury associated with traumatic knee injury via posterior approach. PMID- 28849901 TI - Families in crisis: the impact of trauma. PMID- 28849900 TI - Hemodynamic significance assessment of equivocal iliac artery stenoses by comparing duplex ultrasonography with intra-arterial pressure measurements. AB - BACKGROUND: This study evaluated the accuracy of duplex ultrasonography (DUS) based peak systolic velocity ratio (PSVR) and ipsilateral common femoral artery (CFA) velocity waveform analysis to identify a hemodynamically significant equivocal iliac artery stenosis (30-75% lumen diameter reduction). Intra-arterial pressure measurements were used as a reference. METHODS: In a previously performed prospective study (NTR5085), 30 patients with 35 iliac artery stenoses underwent intra-arterial angiography. To determine the hemodynamic significance of the iliac artery stenoses, intra-arterial translesional pressure measurements were performed under hyperemic conditions. Preprocedural DUS was obtained of the iliac and femoral arteries. PSVR over the iliac lesions was determined, and ipsilateral CFA velocity waveforms were retrospectively classified. The intraobserver and interobserver agreement for CFA velocity waveform classification were evaluated. Sensitivity, specificity, and overall accuracy were calculated by comparing PSVR, velocity waveform analysis, and a combination of these parameters to the intra-arterial translesional pressure gradient. A translesional pressure gradient >=10 mmHg, PSVR >=2.5, and a monophasic or biphasic CFA velocity waveform were considered to be indicative for a hemodynamically significant iliac artery stenosis. RESULTS: For classification of ipsilateral CFA velocity waveforms, intraobserver and interobserver agreement were 0.94 and 0.82, respectively. A PSVR >=2.5 could identify a hemodynamically significant stenosis with 83% sensitivity, 67% specificity, and an overall accuracy of 77%. When both a monophasic and a biphasic velocity waveform were considered to indicate a hemodynamically significant iliac artery stenosis, sensitivity was 78%, specificity was 50%, and the overall accuracy was 69%. The combination of a PSVR >=2.5 with either a monophasic or a biphasic CFA velocity waveform was found in 20 stenoses and resulted in 94% sensitivity, 75% specificity, and 90% accuracy. When the remainder of the stenoses (N.=15) was classified by means of the PSVR, the overall accuracy remained 77%. CONCLUSIONS: DUS is a very useful noninvasive imaging modality to determine the significance of an iliac artery stenosis. A combination of translesional PSVR >=2.5 with either a monophasic or a biphasic ipsilateral CFA ultrasound waveforms has a good accuracy and helps to select patients that benefit most from follow-up examination by computed tomography angiography or magnetic resonance angiography. PMID- 28849902 TI - Few-Layered Trigonal WS2 Nanosheet-Coated Graphite Foam as an Efficient Free Standing Electrode for a Hydrogen Evolution Reaction. AB - Few-layered tungsten disulfide (WS2) with a controlled-phase ratio (the highest trigonal-phase ratio being 67%) was exfoliated via lithium insertion. The exfoliated WS2 nanosheets were then anchored onto three-dimensional (3D) graphite foam (GF) to fabricate free-standing binder-free electrodes. The 3D GF can increase the interfacial contact between the WS2 nanosheets and the electrolyte and facilitate ion transfer. Without the nonconductive binder, an intimate contact between the WS2 and GF interface can be created, leading to the improvement of electrical conductivity. In comparison to the pure WS2 nanosheets, the overpotential for a hydrogen evolution reaction is significantly decreased from 350 mV to 190 mV at 10 mA/cm2, and no deactivation occurs after 1000 cycles. The density functional theory computations reveal that the efficient catalytic activity of the trigonal-phase WS2/GF electrode is attributed to the lower Gibbs free energy for H* adsorption and higher electrical conductivity. PMID- 28849903 TI - Chemical Protein Synthesis with the alpha-Ketoacid-Hydroxylamine Ligation. AB - The coupling of an alpha-ketoacid and a hydroxylamine (KAHA ligation) affords amide bonds under aqueous, acidic conditions without the need for protecting groups or coupling agents. Translating this finding into a general approach to chemical protein synthesis required the identification of methods to incorporate the key functional groups into unprotected peptide segments-ideally using well established Fmoc solid-phase peptide synthesis protocols. A decade of effort has now led to robust, convenient methods for preparing peptides bearing free or masked C-terminal alpha-ketoacids and N-terminal hydroxylamines. The facile synthesis of the segments and the aqueous, acidic conditions of the KAHA ligation make it ideal for the construction of small proteins (up to 200 residues), including SUMO and related modifier proteins, betatrophin and other protein hormones, nitrophorin 4, S100A4, and the cyclic protein AS-48. Key to the successful development of this protein synthesis platform was the identification and gram-scale synthesis of (S)-5-oxaproline. This hydroxylamine monomer is completely stable toward standard methods and practices of solid-phase peptide synthesis while still performing very well in the KAHA ligation. This reaction partner-in contrast to all others examined-affords esters rather than amides as the primary ligation product. The resulting depsipeptides often offer superior solubility and handling and have been key in the chemical synthesis of hydrophobic and ampiphilic proteins. Upon facile O-to-N acyl shift, peptides bearing a noncanonical homoserine residue at the ligation site are formed. With proper choice of the ligation site, the incorporation of this unnatural amino acid does not appear to affect the structure or biological activity of the protein targets. The development of the chemical methods for preparing and masking peptide alpha-ketoacids and hydroxyalmines, the preparation of several protein targets by convergent ligation strategies, and the synthesis of new hydroxylamine monomers affording either natural or unnatural residues at the ligation site are discussed. By operation under acidic conditions and with a distinct preference for the ligation site, these efforts establish KAHA ligation as a complementary method to the venerable native chemical ligation (NCL) for chemical protein synthesis. This Account documents both the state of the KAHA ligation and the challenges in identifying, inventing, and optimizing new reactions and building blocks needed to interface KAHA ligation with Fmoc solid phase peptide chemistry. With these challenges largely addressed, peptide segments ready for ligation are formed directly upon resin cleavage, facilitating rapid assembly of four to five segments into proteins. This work sets the stage for applications of the KAHA ligation to chemical biology and protein therapeutics. PMID- 28849904 TI - Controlled Electrodeposition Synthesis of Co-Ni-P Film as a Flexible and Inexpensive Electrode for Efficient Overall Water Splitting. AB - Synthesis of highly efficient and robust catalysts with earth-abundant resources for overall water splitting is essential for large-scale energy conversion processes. Herein, a series of highly active and inexpensive Co-Ni-P films were fabricated by a one-step constant current density electrodeposition method. These films were demonstrated to be efficient bifunctional catalysts for both H2 and O2 evolution reactions (HER and OER), while deposition time was deemed to be the crucial factor governing electrochemical performance. At the optimal deposition time, the obtained Co-Ni-P-2 catalyst performed remarkably for both HER and OER in alkaline media. In particular, it requires -103 mV overpotential for HER and 340 mV for OER to achieve the current density of 10 mA cm-2, with corresponding Tafel slopes of 33 and 67 mV dec-1. Moreover, it outperforms the Pt/C//RuO2 catalyst and only needs -160 mV (430 mV) overpotential for HER (OER) to achieve 200 mA cm-2 current density. Co-Ni-P electrodes were also conducted for the proof of-concept exercise, which were proved to be flexible, stable, and efficient, further opening a new avenue for rapid synthesis of efficient, flexible catalysts for renewable energy resources. PMID- 28849905 TI - Single-Electron Transfer Living Radical Polymerization Platform to Practice, Develop, and Invent. AB - The most fundamental aspects of single-electron transfer (SET) principles are presented. They are discussed according to different definitions used by expert practitioners and are applied to SET living radical polymerization (SET-LRP) according to the definition of the division of organic chemistry of IUPAC that relies on principles elaborated by Taube, Eberson, Chanon, and Kochi. Additional definitions are also discussed to help clarify for the nonexpert contradictory literature reports. Subsequently, the principles and evolution of SET-LRP together with the methodologies currently available to practice it are discussed. It is expected that this Perspective will be able to help experts and nonexperts practice, develop, and invent new concepts and methodologies for SET-LRP to advance its status and the status of other living radical polymerization methods to the level of the most precise living polymerization methods. PMID- 28849906 TI - NiO/NiWO4 Composite Yolk-Shell Spheres with Nanoscale NiO Outer Layer for Ultrasensitive and Selective Detection of Subppm-level p-Xylene. AB - NiO/NiWO4 composite yolk-shell spheres with a nanoscale NiO outer layer were prepared using one-pot ultrasonic spray pyrolysis and their gas sensing characteristics were studied. The NiO/NiWO4 yolk-shell spheres exhibited an extremely high response to 5 ppm p-xylene (ratio of resistance to gas and air = 343.5) and negligible cross-responses to 5 ppm ethanol, ammonia, carbon monoxide, hydrogen, and benzene, whereas pure NiO yolk-shell spheres showed very low responses and selectivity to all the analyte gases. The detection limit for p xylene was as low as 22.7 ppb. This ultrasensitive and selective detection of p xylene is attributed to a synergistic catalytic effect between NiO and NiWO4, high gas accessibility with large specific surface area, and increased chemiresistive variation due to the formation of a heterojunction. The NiO/NiWO4 yolk-shell spheres with a thin NiO outer layer can be used to detect subppm-level p-xylene in a highly sensitive and selective manner for monitoring indoor air pollution. PMID- 28849907 TI - Label-Free Optical Biochemical Sensors via Liquid-Cladding-Induced Modulation of Waveguide Modes. AB - We demonstrated modulation of the waveguide mode mismatch via liquid cladding of the controllable refractive index for label-free quantitative detection of concentration of chemical or biological substances. A multimode optical fiber with its core exposed was used as the sensor head with the suitable chemical modification of its surface. Injected analyte liquid itself formed the liquid cladding for the waveguide. We found that modulation of the concentration of analyte injected enables a degree of the waveguide mode mismatch to be controlled, resulting in sensitive change in optical power transmission, which was utilized for its real-time quantitative assay. We applied the device to quantitating concentration of glycerol and bovine serum albumin (BSA) solutions. We obtained experimentally the limit of detection (LOD) of glycerol concentration, 0.001% (volume ratio), corresponding to the resolvable index resolution of ~1.02 * 10-6 RIU (refractive index unit). The presented sensors also exhibited reasonably good reproducibility. In BSA detection, the sensor device response was sensitive to change in the refractive indices not only of liquid bulk but also of layers just above the sensing surface with higher sensitivity, providing the LOD experimentally as ~3.7 ng/mL (mass coverage of ~30 pg/mm2). A theoretical model was also presented to invoke both mode mismatch modulation and evanescent field absorption for understanding of the transmission change, offering a theoretical background for designing the sensor head structure for a given analyte. Interestingly, the device sensing length played little role in the important sensor characteristics such as sensitivity, unlike most of the waveguide-based sensors. This unraveled the possibility of realizing a highly simple structured label-free sensor for point-of-care testing in a real-time manner via an optical waveguide with liquid cladding. This required neither metal nor dielectric coating but still produced sensitivity comparable to those of other types of label-free sensors such as plasmonic fiber ones. PMID- 28849909 TI - Distribution System Operational Deficiencies Coincide with Reported Legionnaires' Disease Clusters in Flint, Michigan. AB - We hypothesize that the increase in reported Legionnaires' disease from June 2014 to November 2015 in Genesee County, MI (where Flint is located) was directly linked to the switch to corrosive Flint River water from noncorrosive Detroit water from April 2014 to October 2015. To address the lack of epidemiological data linking the drinking water supplies to disease incidence, we gathered physiochemical and biological water quality data from 2010 to 2016 to evaluate characteristics of the Flint River water that were potentially conducive to Legionella growth. The treated Flint River water was 8.6 times more corrosive than Detroit water in short-term testing, releasing more iron, which is a key Legionella nutrient, while also directly causing disinfectant to decay more rapidly. The Flint River water source was also 0.8-6.7 degrees C warmer in summer months than Detroit water and exceeded the minimum Legionella growth temperature of 20 degrees C more frequently (average number of days per year for Detroit was 63 versus that for the Flint River, which was 157). The corrosive water also led to 1.3-2.2 times more water main breaks in 2014-2015 compared to 2010-2013; such disruptions have been associated with outbreaks in other locales. Importantly, Legionella spp. and Legionella pneumophila decreased after switching back to Detroit water, in terms of both gene markers and culturability, when August and October 2015 were compared to November 2016. PMID- 28849910 TI - In-Tip Lanthanum Oxide Monolith for the Enrichment of Phosphorylated Biomolecules. AB - Polymeric monoliths fabricated in tips with embedded materials of choice are important in separation science. Polymeric backbone however interferes in the enrichment and thus affects efficiency. This work focuses on the in-tip fabrication of lanthanum oxide porous monolith and its application in the enrichment of phosphorylated peptides and lipids. Polycondensation reaction uses an aqueous solution of LaCl3.7H2O with N-methyl formamide as porogen and propylene oxide as initiator. The aging time of monolith and temperature condition for the reaction are optimized to attain porous monolithic tip. A comparison of (i) solid phase batch extraction using La2O3, (ii) La2O3 embedded in poly(glycidyl methacrylate (GMA)/divinylbenzene (DVB)) tip, and (iii) pure La2O3 monolithic tip shows improved enrichment efficiency in the case of pure La2O3 monolithic tip. The monolithic tip achieves selectivity of 1:4500 as compared to solid phase extraction (SPE)(1:3500) and limit of detection down to 0.25 fmol. The in-tip La2O3 monolith strategy has better batch to batch reproducibility, reduced time of enrichment, and ease of operation in comparison to solid phase batch extraction. The developed strategy enriches phospho- content from biological samples like phosvitin and lipovitellin from egg yolk and phospholipids/phosphopeptides from human serum. The enriched phospho- moieties are analyzed by matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) except the phospholipids where laser desorption ionization (LDI)-MS is employed. PMID- 28849908 TI - Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation. AB - Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for patients suffering from bone loss or osteolytic malignant bone lesions. PMID- 28849911 TI - DNA-Encoded Raman-Active Anisotropic Nanoparticles for microRNA Detection. AB - The development of highly sensitive and selective methods for the detection of microRNA (miRNA) has attracted tremendous attention because of its importance in fundamental biological studies and diagnostic applications. In this work, we develop DNA-encoded Raman-active anisotropic nanoparticles modified origami paper analytical devices (oPADs) for rapid, highly sensitive, and specific miRNA detection. The Raman-active anisotropic nanoparticles were prepared using 10-mer oligo-A, -T, -C, and -G to mediate the growth of Ag cubic seeds into Ag nanoparticles (AgNPs) with different morphologies. The resulting AgNPs were further encoded with DNA probes to serve as effective surface-enhanced Raman scattering (SERS) probes. The analytical device was then fabricated on a single piece of SERS probes loaded paper-based substrate and assembled based on the principles of origami. The addition of the target analyte amplifies the Raman signals on DNA-encoded AgNPs through a target-dependent, sequence specific DNA hybridization assembly. This simple and low-cost analytical device is generic and applicable to a variety of miRNAs, allowing detection sensitivity down to 1 pM and assay time within 15 min, and therefore holds promising applications in point of-care diagnostics. PMID- 28849912 TI - Synthesis and Applications of Boronate Affinity Materials: From Class Selectivity to Biomimetic Specificity. AB - Due to the complexity of biological systems and samples, specific capture and targeting of certain biomolecules is critical in much biological research and many applications. cis-Diol-containing biomolecules, a large family of important compounds including glycoproteins, saccharides, nucleosides, nucleotides, and so on, play essential roles in biological systems. As boronic acids can reversibly bind with cis-diols, boronate affinity materials (BAMs) have gained increasing attention in recent years. However, real-world applications of BAMs are often severely hampered by three bottleneck issues, including nonbiocompatible binding pH, weak affinity, and difficulty in selectivity manipulation. Therefore, solutions to these issues and knowledge about the factors that influence the binding properties are of significant importance. These issues have been well solved by our group in past years. Our solutions started from the synthesis and screening of boronic acid ligands with chemical moieties favorable for binding at neutral and acidic pH. To avoid tedious synthesis routes, we proposed a straightforward strategy called teamed boronate affinity, which permitted facile preparation of BAMs with strong binding at neutral pH. To enhance the affinity, we confirmed that multivalent binding could significantly enhance the affinity toward glycoproteins. More interestingly, we observed that molecular interactions could be significantly enhanced by confinement within nanoscale spaces. To improve the selectivity, we investigated interactions that govern the selectivity and their interplays. We then proposed a set of strategies for selectivity manipulation, which proved to be useful guidelines for not only the design of new BAMs but also the selection of binding conditions. Applications in metabolomic analysis, glycoproteomic analysis, and aptamer selection well demonstrated the great potential of the prepared BAMs. Molecular imprinting is an important methodology for creating affinity materials with antibody-like binding properties. Boronate affinity-based covalent imprinting is a pioneering approach in molecular imprinting, but only a few cases of successful imprinting of glycoproteins by this method were reported. With sound understanding of boronate affinity, we developed two facile and generally applicable boronate affinity based molecular imprinting approaches. The resulting boronate affinity molecularly imprinted polymers (MIPs) exhibited dramatically improved binding properties, including biocompatible binding pH range, enhanced affinity, improved specificity, and superb tolerance to interference. In terms of nanoconfinement effect, we explained why the binding pH range was widened and why the affinity was enhanced. The excellent binding properties made boronate affinity MIPs appealing alternatives to antibodies in promising applications such as disease diagnosis, cancer-cell targeting, and single-cell analysis. In this Account, we survey the key aspects of BAMs, the efforts we made to solve these issues, and the connections between imprinted and nonimprinted BAMs. Through this survey, we wish to pave a sound fundamental basis of the dependence of binding properties of BAMs on the nature and structure of the ligands and the supporting materials, which can facilitate the development and applications of BAMs. We also briefly sketch remaining challenges and directions for future development. PMID- 28849913 TI - Multiplexed sgRNA Expression Allows Versatile Single Nonrepetitive DNA Labeling and Endogenous Gene Regulation. AB - The CRISPR/Cas9 system has made significant contributions to genome editing, gene regulation and chromatin studies in recent years. High-throughput and systematic investigations into the multiplexed biological systems require simultaneous expression and coordinated functioning of multiple sgRNAs. However, current cotransfection based sgRNA coexpression systems remain inefficient, and virus based transfection approaches are relatively costly and labor intensive. Here we established a vector-independent method allowing multiple sgRNA expression cassettes to be assembled in series into a single plasmid. This synthetic biology based strategy excels in its efficiency, controllability and scalability. Taking the flexibility advantage of this all-in-one sgRNA expressing system, we further explored its applications in single nonrepetitive genomic locus imaging as well as coordinated gene regulation in live cells. With its full potency, our method will facilitate the research in understanding genome structure, function and dynamics. PMID- 28849914 TI - Mechanical Properties of Microcrystalline Metal-Organic Frameworks (MOFs) Measured by Bimodal Amplitude Modulated-Frequency Modulated Atomic Force Microscopy. AB - Direct measurement of the mechanical properties of microcrystalline metal-organic framework (MOF) nanoparticles is challenging and rarely explored. In this work, we apply an effective method to realize elastic modulus mapping of a series of isostructural single MOF nanoparticles (100-500 nm) via bimodal amplitude modulated-frequency modulated atomic force microscopy. By probing five types of zirconium (Zr) and hafnium (Hf) isostructural UiO-66-type MOFs, we experimentally found that UiO-66(Hf)-type MOFs possess the higher elastic modulus (46-104 GPa) than that of UiO-66(Zr)-type MOFs (34-100 GPa), both of which are higher than that of reported zinc/copper based MOFs (3-10 GPa). We also experimentally demonstrate that the mechanical properties of MOFs can be tuned by adjusting the chemical functionalities of the ligands or using different metal nodes. In detail, the sterically bulky functional groups increase the mechanical properties of the resultant UiO-66-type MOFs, possibly due to the increased atomic density. These results pave a way to the direct measurement of mechanical properties of MOFs crystalline particles and provide an incisive perspective to the design of MOFs with high mechanical properties. PMID- 28849915 TI - Fluorescent Thrombin Binding Aptamer-Tagged Nanoparticles for an Efficient and Reversible Control of Thrombin Activity. AB - Progress in understanding and treatment of thrombotic diseases requires new effective methods for the easy, rapid, and reversible control of coagulation processes. In this framework, the use of aptamers, and particularly of the thrombin binding aptamer (TBA), has aroused strong interest, due to its enormous therapeutic potential, associated with a large number of possible applications in biotechnological and bioanalytical fields. Here, we describe a new TBA analogue (named tris-mTBA), carrying three different pendant groups: a dansyl residue at the 3'- and a beta-cyclodextrin moiety at the 5'-end-providing a host-guest system which exhibits a marked fluorescence enhancement upon TBA G-quadruplex folding-and a biotin tag, allowing the attachment of the aptamer onto biocompatible streptavidin-coated silica nanoparticles (NPs) of 50 nm hydrodynamic diameter (Sicastar). The use of nanoparticles for the in vivo delivery of TBA, expected to induce per se increased nuclease resistance and improved pharmacokinetic properties of this oligonucleotide, offers as an additional advantage the possibility to exploit multivalency effects, due to the presence of multiple copies of TBA on a single scaffold. In addition, the selected fluorescent system allows monitoring both the presence of TBA on the functionalized NPs and its correct folding upon immobilization, also conferring enhanced enzymatic resistance and bioactivity. The anticoagulant activity of the new tris-mTBA, free or conjugated to Sicastar NPs, was evaluated by dynamic light scattering experiments. Highly effective and reversible inhibition of thrombin activity toward fibrinogen was found for the free tris-mTBA and especially for the tris-mTBA-conjugated NPs, demonstrating great potential for the biomedical control of blood clotting. PMID- 28849916 TI - Ratiometric Catalyzed-Assembly of NanoCluster Beacons: A Nonenzymatic Approach for Amplified DNA Detection. AB - In this work, a novel fluorescent transformation phenomenon of oligonucleotide encapsulated silver nanoclusters (AgNCs) was demonstrated, in which green emissive AgNCs effectively transformed to red-emissive AgNCs when placed in close proximity to a special DNA fragment (denoted as convertor here). Taking advantage of a catalyzed-hairpin-assembly (CHA) amplification strategy, we rationally and compatibly engineered a simple and sensitive AgNC-based fluorescent signal amplification strategy through the ratiometric catalyzed-assembly (RCA) of green emissive NanoCluster Beacon (NCB) with a convertor modified DNA hairpin to induce the template transformation circularly. The proposed ratiometric fluorescent biosensing platform based on RCA-amplified NCB (RCA-NCB) emits intense green fluorescence in the absence of target DNA and will undergo consecutively fluorescent signal transformation from green emission to red emission upon exposure to its target DNA. The ratiometric adaptation of the NCB to CHA circuit advances their general usability as biosensing platform with great improvements in detection sensitivity. By measuring the fluorescence intensity ratio of the red emission and green emission, the proposed RCA-NCB platform exhibits sensitive and accurate analytical performance toward Werner Syndrome-relevant gene, the proof-of-concept target in this work. A low detection limit down to the pM level was achieved, which is lower than most of the reported AgNC-based fluorescent DNA biosensors, making the proposed RCA-NCB biosensing strategy appealing in amplifying the ratiometric fluorescent signal for sensitive DNA detection. Moreover, our proposed RCA-NCB platform shows good recovery toward the target DNA in real human serum samples, illustrating their potential promise for clinical and imaging applications in the future. PMID- 28849917 TI - Tumor Microenvironment Modulation by Cyclopamine Improved Photothermal Therapy of Biomimetic Gold Nanorods for Pancreatic Ductal Adenocarcinomas. AB - Due to the rich stroma content and poor blood perfusion, pancreatic ductal adenocarcinoma (PDA) is a tough cancer that can hardly be effectively treated by chemotherapeutic drugs. Tumor microenvironment modulation or advanced design of nanomedicine to achieve better therapeutic benefits for PDA treatment was widely advocated by many reviews. In the present study, a new photothermal therapy strategy of PDA was developed by combination of tumor microenvironment modulation and advanced design of biomimetic gold nanorods. On one hand, biomimetic gold nanorods were developed by coating gold nanorods (GNRs) with erythrocyte membrane (MGNRs). It was shown that MGNRs exhibited significantly higher colloidal stability in vitro, stronger photothermal therapeutic efficacy in vitro, and longer circulation in vivo than GNRs. On the other hand, tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion. Moreover, cyclopamine treatment significantly increased the accumulation of MGNRs in tumors by 1.8-fold and therefore produced higher photothermal efficiency in vivo than the control group. Finally, cyclopamine treatment combined with photothermal MGNRs achieved the most significant shrinkage of Capan-2 tumor xenografts among all the treatment groups. Therefore, with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNRs, effective photothermal therapy of PDA was achieved. In general, this new strategy of combining tumor microenvironment modulation and advanced design of biomimetic nanoparticles might have great potential in PDA therapy. PMID- 28849918 TI - Porous Aromatic Frameworks for Size-Selective Halogenation of Aryl Compounds. AB - Organic halides are vitally important chemical precursors or intermediates in the fields of agrochemical synthesis, molecular recognition, and material science. However, it is difficult to selectively synthesize these compounds due to the multiple reactive sites in aryl fragments. In this work, we prepared the first fully fluorinated porous aromatic framework (PAF). Its -C-F bond and hierarchical porosity have great benefits for PAF functionalization. After being decorated with different cyclodextrins (CDs), CD-PAF materials can incorporate diverse aryl compounds to protect their ortho sites from being attacked to produce para substituted molecules. This selectivity obviously increased with a decrease in the substrate size (from 0.97 to 0.41 nm). In addition, the CD-PAFs can undergo long-term use in both chlorination and bromination. PMID- 28849919 TI - A Porous Metal-Organic Framework [Zn2(bdc)(l-lac)] as a Coating Material for Capillary Columns of Gas Chromatography. AB - The wide diversity in the structure, pore size, high surface area, adsorption affinity, and selective penetration renders metal-organic frameworks (MOF) attractive as highly efficient adsorbents for chromatographic separation. We report the results of chromatographic separation of four families of biochemically important compounds, viz., linear alkyl hydrocarbons (aldehyde, acid, and ketone), aromatic hydrocarbons (aldehyde, acid, and alcohol), cyclic hydrocarbons (ketone, alcohol, and ester) and aromatic hydrocarbons (ether, ester, and ester with alcohol) with two phenyls, employing the porous MOF [Zn2(bdc)(l-lac)] (l-lac = l-lactate; bdc = 1,4-benzenedicarboxylate) as the retention material of the capillary column. Its good performance relies on the robustness and chemical and thermal stability of the framework, the permanent porosity, and, most importantly, the host-guest interaction sites. The results from this work will also help in understanding the intermolecular forces based on host-guest interaction between the MOF and analytes. PMID- 28849921 TI - Mechanism of Catalytic Oxidation of Styrenes with Hydrogen Peroxide in the Presence of Cationic Palladium(II) Complexes. AB - Kinetic studies, isotope labeling, and in situ high-resolution mass spectrometry are used to elucidate the mechanism for the catalytic oxidation of styrenes using aqueous hydrogen peroxide (H2O2) and the cationic palladium(II) compound, [(PBO)Pd(NCMe)2][OTf]2 (PBO = 2-(pyridin-2-yl)benzoxazole). Previous studies have shown that this reaction yields acetophenones with high selectivity. We find that H2O2 binds to Pd(II) followed by styrene binding to generate a Pd-alkylperoxide that liberates acetophenone by at least two competitive processes, one of which involves a palladium enolate intermediate that has not been previously observed in olefin oxidation reactions. We suggest that acetophenone is formed from the palladium enolate intermediate by protonation from H2O2. We replaced hydrogen peroxide with t-butyl hydroperoxide and found that, although the palladium enolate intermediate was observed, it was not on the major product-generating pathway, indicating that the form of the oxidant plays a key role in the reaction mechanism. PMID- 28849920 TI - Bronsted Acid Catalyzed Synthesis of Functionalized 1,4- and 1,6-Dicarbonyl Monosilyl Enol Ethers under Operationally Practical Conditions. AB - Herein, we report an improved protocol for the concise synthesis of functionalized 1,4- and 1,6-dicarbonyl-derived monosilyl enol ethers via ionization of alpha'-hydroxy silyl enol ethers to generate unsymmetrical silyloxyallyl cations that were subsequently captured by TBS silyl enolates. These transformations were efficiently performed in acetonitrile at room temperature by employing pyridinium triflate as a catalyst. Our new reaction conditions are operationally more practical and broaden the accessibility of various 1,4- and 1,6-dicarbonyl groups, which include diketone, ketoester, and ketothioester functionalities. PMID- 28849922 TI - Design and Feasibility Analysis of a Self-Sustaining Biofiltration System for Removal of Low Concentration N2O Emitted from Wastewater Treatment Plants. AB - N2O is a potent greenhouse gas and ozone-depletion agent. In this study, a biofiltration system was designed for removal of N2O emitted at low concentrations (<200 ppmv) from wastewater treatment plants. The proposed biofiltration system utilizes untreated wastewater from the primary sedimentation basin as the source of electron donor and nutrients and energy requirement is minimized by utilizing gravitational force and pressure differential to direct liquid medium and gas through the biofilter. The experiments performed with laboratory-scale biofilter in two different configurations confirmed the feasibility of the biofiltration system. The biofilter operated with cycling of raw wastewater exhibited up to 94% and 53% removal efficiency with 100 ppmv N2O in N2 and air, respectively, as the feed gas, corroborating that untreated wastewater can serve as a robust source of electron donor and nutrients. The laboratory-scale biofilter operated with a continuous flow-through of synthetic wastewater attained >99.9% removal of N2O from N2 background at the gas flow rate up to 2,000 mL.min-1 and >50% N2O removal from air background at the gas flow rate of 200 mL.min-1. nosZ-containing bacterial genera including Flavobacterium (5.92%), Pseudomonas (4.26%) and Bosea (2.39%) were identified in the biofilm samples collected from the oxic biofilter, indicating these organisms were responsible for N2O removal. PMID- 28849923 TI - Nickel-Catalyzed Defluorinative Reductive Cross-Coupling of gem-Difluoroalkenes with Unactivated Secondary and Tertiary Alkyl Halides. AB - Herein, we described a nickel-catalyzed monofluoroalkenylation through defluorinative reductive cross-coupling of gem-difluoroalkenes with alkyl halides. Key to the success of this strategy is the combination of C-F cleavage with alkyl halides activation. This reaction enables the convenient synthesis of a large variety of functionalized monofluoroalkenes under mild reaction conditions with broad functional group compatibility and excellent Z-selectivity. The combination of Ni catalysis with (Bpin)2/K3PO4 as terminal reductant promoted the efficient C(sp2)-C(sp3) formation especially the generation of all-carbon quaternary centers with high chemoselectivity. PMID- 28849924 TI - Thermal Pure States for Finite and Isolated Quantum Systems. AB - We study an ensemble of quantum pure states, the thermalization resilient ensemble (TRE), providing the statistical characterization of the thermal equilibrium of isolated quantum systems. Following a previous work where the ensemble was defined based on the invariance of the average populations upon thermal contact of identical systems, here we introduce a general methodology to generate quantum states according to the TRE statistic. The sampling is employed to characterize the ensemble distribution of thermodynamic functions like the entropy, internal energy, and temperature. The possibility of defining the temperature also for isolated quantum systems with a limited number of degrees of freedom is a distinctive feature of the TRE statistic which has no counterpart in other quantum statistical ensembles. The results are illustrated by explicit calculations for spin model systems. PMID- 28849925 TI - UV-Induced Hydrogen-Atom-Transfer Processes in 3-Thio-1,2,4-triazole Isolated in Ar and H2 Low-Temperature Matrixes. AB - The UV-induced thione -> thiol phototautomeric reaction has been studied for monomeric 3-thio-1,2,4-triazole (3-ST) isolated in low-temperature Ar and n-H2 (normal hydrogen) matrixes. Prior to any UV irradiation, monomers of 3-ST isolated in solid Ar or solid n-H2 adopted mainly the most stable thione tautomeric form, as revealed by the IR spectra. Upon UV (lambda > 275 nm) irradiation of 3-ST isolated in Ar matrixes, the IR bands due to this thione form decreased, while a set of initially weak bands increased in intensity. Growing bands indicated generation of a photoproduct, which was identified as the thiol tautomer with labile hydrogen atoms attached to sulfur and N(2) atoms. The UV induced spectral changes allowed also identification of another minor thiol tautomer of 3-ST, which was present in the matrix prior to any irradiation and did not change its population upon exposure to UV light. The identification of the observed isomeric forms was supported by comparison of their separated experimental IR spectra with the spectra theoretically predicted for the various structures of 3-ST. The thione -> thiol phototautomerization that was the main UV induced process observed for 3-ST in Ar matrixes did not occur for monomers of the compound trapped in solid n-H2. PMID- 28849926 TI - Site- and Regioselectivity of Nitrile Oxide-Allene Cycloadditions: DFT-Based Semiquantitative Predictions. AB - Nitrile oxide 1,3-dipolar cycloaddition to arylsulfonyl- and dialkylaminoallenes have been investigated within the framework of the Kohn-Sham density functional theory (DFT) at the B3LYP/6-31G(d,p) level. The hitherto-unexplained experimental behavior of sulfonylallenes was rationalized by transition-state calculations which enabled a semiquantitative treatment of the cycloaddition site- and regioselectivity. The reliability of DFT computations was further established by predicting the complete selectivity of the nitrile oxide cycloaddition to dialkylaminoallenes according to previous experimental findings. PMID- 28849927 TI - Mixed-Ligand LMOF Fluorosensors for Detection of Cr(VI) Oxyanions and Fe3+/Pd2+ Cations in Aqueous Media. AB - Zn(II)/Cd(II)-based dual ligand Luminescent Metal-Organic Frameworks (LMOFs) {[M(ATA)(L)]}n.xH2O (1) and (2) were synthesized by versatile synthetic routes, viz., diffusion of precursor solutions, conventional reflux, and green mechanochemical (grinding) reactions from bipyridyl-based Schiff base, (E)-N' (pyridin-4-ylmethylene)isonicotinohydrazide (L) and amino functionalized 2 aminoterephthalic acid (H2ATA) as linkers. Chemical and thermal stability, phase purity, and characterization of both LMOFs were established by various analytical methods. SXRD analysis revealed the 3D framework is composed of two-dimensional [M(ATA)]n nets doubly pillared by L through the terminal nitrogen atom. Selective and sensitive detection of chromate anions (CrO42-/Cr2O72-) and Fe3+/Pd2+ cations in the aqueous phase by fluorescent quenching of the LMOFs 1 and 2 has been established. Competitive experiments in the presence of interfering anions/cations with 1 and 2 revealed no major change in the quenching efficiency. The observed limits of detection (LOD) values by 1 for CrO42-/Cr2O72- were 0.25 MUM (48 ppb)/0.43 MUM (126 ppb) and for Fe3+/Pd2+ were 3.76 MUM (0.61 ppm)/0.20 MUM (35 ppb), whereas LOD values by 2 were 0.18 MUM (35 ppb)/0.19 MUM (55 ppb) and 1.77 MUM (0.29 ppm)/0.10 MUM (18 ppb), respectively. Simple fluorescent-based test paper strips have been developed for reliable and visual detection of the mentioned analytes in practical applications. The present investigation clearly demonstrates selective detection of CrO42-/Cr2O72- and Fe3+/Pd2+ in aqueous media, and the probable mechanism for the quenching phenomena based on structural aspects has also been discussed. PMID- 28849928 TI - Bonding and Electronic Properties of Linear Diethynyl Oligothienoacene-Bridged Diruthenium Complexes and Their Oxidized Forms. AB - A series of five diruthenium diethynyl complexes based on alpha,beta-fused oligothienoacenes in the core of the bridging ligands [{Ru(dppe)Cp*}2(MU-C=C-L C=C)] [dppe = 1,2-bis(diphenylphosphino)ethane, Cp* = eta5-C5Me5; L = thieno[3,2 b]thiophene (4), thieno[2,3-b]thiophene (5), 3,4-dimethylthieno[2,3-b]thiophene (6), dithieno[3,2-b:2',3'-d]thiophene (7), and thieno[3,2 b]thieno[2',3':4,5]thieno[2,3-d]thiophene (8)] have been synthesized and fully characterized electrochemically and spectroscopically. Elongation of the redox noninnocent oligothienoacene bridge core causes a smaller potential difference between the initial two anodic steps, not seen for free dialkyl oligothienoacenes, and increased positive charge delocalization over the conjugated bridge backbone. The highest occupied molecular orbital of the parent complexes resides predominantly on the oligothienoacene core, with strong participation of the ethynyl linkers and slightly smaller contribution from the metallic termini. This bonding character makes the initial one-electron oxidation symmetrical, as revealed by combined voltammetric and spectroscopic (IR, UV-vis near-IR, and electron paramagnetic resonance) methods as well as density functional theory (DFT) and time-dependent DFT calculations of truncated and selected nontruncated models of the studied series. The remarkable gradual appearance of two C=C stretching absorptions in the IR spectra of the monocationic diethynyl complexes is ascribed to increasing vibronic coupling of the IR-forbidden nus(C=C) mode of the oxidized -[C=C-core-C=C]+- bridge with a low-lying pi-pi*(intrabridge)/metal-to-ligand charge-transfer electronic transition in the near-to-mid-IR spectral region. PMID- 28849929 TI - Copper-Catalyzed Regioselective Monodefluoroborylation of Polyfluoroalkenes en Route to Diverse Fluoroalkenes. AB - Monodefluoroborylation of polyfluoroalkenes has been achieved in a regioselective manner under mild conditions via copper catalysis. The method has shown an extremely broad scope of substrates, including (difluorovinyl)arenes, tetrafluoroethylene (TFE), (trifluorovinyl)arenes, and trifluoromethylated monofluoroalkenes. The choice of boron source was important for the efficient transformation of (difluorovinyl)arenes; (Bpin)2 was suitable for substrates with an electron-deficient aryl group and (Bnep)2 for those with an electron-rich aryl group. Derivatization of the (fluoroalkenyl)boronic acid esters to the corresponding potassium trifluoroborate salts has rendered the products easily isolable, which greatly improved the synthetic practicality of the monodefluoroborylation reaction. Stoichiometric experiments indicate that the fate of the regioselectivity depends on the mode of beta-fluorine elimination, which depends on the substrate. Further transformation of the boryl group has allowed facile preparation of fluoroalkene derivatives as exemplified by the synthesis of a fluoroalkene mimic of atorvastatin, which potently inhibited the enzyme activity of HMG-CoA reductase. PMID- 28849930 TI - DMAP-Mediated Synthesis of Fulleropyrrolines: Reaction of [60]Fullerene with Aromatic Aldehydes and Arylmethanamines in the Absence or Presence of Manganese(III) Acetate. AB - A series of scarce fulleropyrrolines were synthesized via DMAP-mediated one-step reaction of [60]fullerene with commercially inexpensive aromatic aldehydes and arylmethanamines in the absence or presence of manganese(III) acetate. In the case of aminodiphenylmethane, novel 2,5,5-trisubstituted fulleropyrrolines could be easily obtained without the addition of manganese(III) acetate. As for arylmethanamines without alpha-substitutions, the addition of manganese(III) acetate was required to suppress the formation of fulleropyrrolidines, in order to generate the desired 2,5-disubstituted fulleropyrrolines. Two tautomers were produced as expected when different aryl groups (Ar1 ? Ar2) from aromatic aldehydes and arylmethanamines were employed in the synthesis. A plausible reaction mechanism for the formation of fulleropyrrolines is proposed. PMID- 28849931 TI - Charge Transfer Complexes Formed by Heterocyclic Thioamides and Tetracyanoethylene: Experimental and Theoretical Study. AB - Tetracyanoethylene (TCNE) as one of the most versatile organic compounds is involved in various chemical reactions with electron transfer. Charge transfer complexes (CTCs) of a few antioxidants, nitrogen containing thioamides [pyrrolidine-2-thione (I), 1,3-H-imidazolidine-2-thione (II), 1,3-H-Imidazoline-2 thione (III), pyridine-2-thione (IV), 5-trifluoromethylpyridine-2-thione (V), 4 trifluoromethylpyrimidine-2-thione (VI), quinoline-2-thione (VII), 3,4,5,6 tetrahydropyrimidine-2-thione (VIII)] as pi-donors and TCNE as pi-acceptor were studied. The DFT PCM/UB3LYP/6-31++G(d,p) and SA-CASSCF quantum chemical calculations were used to study the structures and relative stabilities of these complexes in the ground and lowest excited electronic states. The formation of a weak molecular associates in the chloroform and acetonitrile solutions was confirmed by UV/vis and IR absorption spectroscopy. The stability constants and molar extinction coefficients were estimated by UV/vis spectroscopy. The highest stability in acetonitrile is found for associates formed by quinoline-2-thione and pyridine-2-thione with TCNE, the lowest one is found for CTC formed by imidazolidine-2-thione. Molecular associate formed by pyridine-2-thione and TCNE has the greatest stability in the chloroform solution. 5-Trifluoromethylpyridine 2-thione and 4-trifluoromethylpyrimidine-2-thione do not form CTC in CH3CN due to the presence of an electron acceptor group in the molecules. The molar extinction values of CTC vary within the range of 0.4 * 103 to 1.0 * 104 M-1 cm-1. An analytical strategy of thioamides identification based on wavelength and intensity of CTCs absorption band has been suggested. PMID- 28849932 TI - Quantitating Organoleptic Volatile Phenols in Smoke-Exposed Vitis vinifera Berries. AB - Accurate methods for quantitating volatile phenols (i.e., guaiacol, syringol, 4 ethylphenol, etc.) in smoke-exposed Vitis vinifera berries prior to fermentation are needed to predict the likelihood of perceptible smoke taint following vinification. Reported here is a complete, cross-validated analytical workflow to accurately quantitate free and glycosidically bound volatile phenols in smoke exposed berries using liquid-liquid extraction, acid-mediated hydrolysis, and gas chromatography-tandem mass spectrometry. The reported workflow addresses critical gaps in existing methods for volatile phenols that impact quantitative accuracy, most notably the effect of injection port temperature and the variability in acid mediated hydrolytic procedures currently used. Addressing these deficiencies will help the wine industry make accurate, informed decisions when producing wines from smoke-exposed berries. PMID- 28849933 TI - Concentration-Driven Fascinating Vesicle-Fibril Transition Employing Merocyanine 540 and 1-Octyl-3-methylimidazolium Chloride. AB - In this article, anionic lipophilic dye merocyanine 540(MC540) and cationic surface-active ionic liquid (SAIL) 1-octyl-3-methylimidazolium chloride (C8mimCl) are employed to construct highly ordered fibrillar and vesicular aggregates exploiting an ionic self-assembly (ISA) strategy. It is noteworthy that the concentration of the counterions has exquisite control over the morphology, in which lowering the concentration of both the building blocks in a stoichiometric ratio of 1:1 provides a vesicle to fibril transition. Here, we have reported the concentration-controlled fibril-vesicle transition utilizing the emerging fluorescence lifetime imaging microscopy (FLIM) technique. Furthermore, we have detected this morphological transformation by means of other microscopic techniques such as field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and cryogenic-transmission electron microscopy (cryo-TEM) to gain additional support. Besides, multiwavelength FLIM (MW-FLIM) and atomic force microscopy (AFM) techniques assist us in knowing the microheterogeneity and the height profile of the vesicles, respectively. We have replaced the SAIL, C8mimCl, by an analogous traditional surfactant, n octyltrimethylammonium bromide (OTAB), and it provides a discernible change in morphology similar to that of C8mimCl, whereas 1-octanol is unable to exhibit any structural aggregation and thus reveals the importance of electrostatic interaction in supramolecular aggregate formation. However, the SAILs having the same imidazolium headgroup with different chain lengths other than C8mimCl are unable to display any structural transition and determine the importance of the correct chain length for efficient packing of the counterions to form a specific self-assembly. Therefore, this study reveals the synergistic interplay of electrostatic, hydrophobic, and pi-pi stacking interactions to construct the self assembly and their concentration-dependent morphological transition. PMID- 28849934 TI - Formation of Uniform and High-Coverage Monolayer Colloidal Films of Midnanometer Sized Gold Particles over the Entire Surfaces of 1.5-in. Substrates. AB - We report a simple and facile method for fabricating monolayer colloidal films of alkanethiol-capped gold nanoparticles (AuNPs) on glass substrates. The new method consists of two sequential sonication processes. The first sonication is performed to obtain a well-dispersed state of alkanethiol-capped AuNPs in hexane/acetone in the presence of a substrate. After additional static immersion in the colloidal solution for 5 min, the substrate is subjected to sonication in hexane. By using this method, we succeeded in forming uniform and stable assemblies of midnanometer-sized AuNPs (14, 34, and 67 nm in diameter) over the entire surface of 10-mm square glass substrates in a short processing time of less than 10 min. It was also demonstrated that this method can be applied to a 1.5-in. octagonal glass substrate. The mechanism of monolayer colloidal film formation was discussed based on scanning electron microscopy observations at each preparation step. We found that the second sonication was the key process for uniform and high-surface-coverage colloidal film formation of midnanometer sized AuNPs. The second sonication promotes the migration of AuNPs on top of the monolayer in contact with the substrate surface, decreasing both the multilayer region and the bare surface area. Eventually, a nearly perfect monolayer colloidal film is formed. PMID- 28849935 TI - Layer-by-Layer Epitaxial Growth of Scalable WSe2 on Sapphire by Molecular Beam Epitaxy. AB - Molecular beam epitaxy (MBE) provides a simple but powerful way to synthesize large-area high-quality thin films and heterostructures of a wide variety of materials including accomplished group III-V and II-VI semiconductors as well as newly developing oxides and chalcogenides, leading to major discoveries in condensed-matter physics. For two-dimensional (2D) materials, however, main fabrication routes have been mechanical exfoliation and chemical vapor deposition by making good use of weak van der Waals bonding nature between neighboring layers, and MBE growth of 2D materials, in particular on insulating substrates for transport measurements, has been limited despite its fundamental importance for future advanced research. Here, we report layer-by-layer epitaxial growth of scalable transition-metal dichalocogenide (TMDC) thin films on insulating substrates by MBE and demonstrate ambipolar transistor operation. The proposed growth protocol is broadly applicable to other TMDCs, providing a key milestone toward fabrication of van der Waals heterostructures with various 2D materials for novel properties and functionalities. PMID- 28849936 TI - Organosilane Chemical Gradients: Progress, Properties, and Promise. AB - Chemical gradients play an important role in nature, driving many different phenomena critical to life, including the transport of chemical species across membranes and the transport, attachment, and assembly of cells. Taking a cue from these natural processes, scientists and engineers are now working to develop synthetic chemical gradients for use in a broad range of applications, such as in high-throughput investigations of surface properties, as means to guide the motions and/or assembly of liquid droplets, vesicles, nanoparticles, and cells and as new media for stationary-phase-gradient chemical separations. Our groups have been working to develop new methods for preparing chemical gradients from organoalkoxysilane and organochlorosilane precursors and to obtain a better understanding of their properties on macroscopic to microscopic length scales. This review highlights our recent work on the development of controlled-rate infusion and infusion-withdrawal dip-coating methods for the preparation of gradients on planar glass and silicon substrates, on thin-layer chromatography plates, and in capillaries and monoliths for liquid chromatography. We also cover the new knowledge gained from the characterization of our gradients using sessile drop and Wilhelmy plate dynamic water contact angle measurements, X-ray photoelectron spectroscopy mapping, and single-molecule tracking and spectroscopy. Our studies reveal important evidence of phase separation and cooperative interactions occurring along multicomponent gradients. Emerging concepts and new directions in the preparation and characterization of organosilane-based chemical gradients are also discussed. PMID- 28849937 TI - Mussel-Inspired Polydopamine Coating on Tobacco Mosaic Virus: One-Dimensional Hybrid Nanofibers for Gold Nanoparticle Growth. AB - One-dimensional (1D) hybrid nanofibers with surface-deposited gold nanoparticles (AuNPs) have been fabricated by self-assembly of rod-like tobacco mosaic virus (TMV) with mussel-inspired polymerization of dopamine and in situ reduction of gold ion, providing a method for sensing the endocytic pathway of nanomaterial. PMID- 28849938 TI - Ultralong Radiative States in Hybrid Perovskite Crystals: Compositions for Submillimeter Diffusion Lengths. AB - Organic-inorganic hybrid perovskite materials have recently evolved into the leading candidate solution-processed semiconductor for solar cells due to their combination of desirable optical and charge transport properties. Chief among these properties is the long carrier diffusion length, which is essential to optimizing the device architecture and performance. Herein, we used time-resolved photoluminescence (at low excitation fluence, 10.59 MUJ.cm-2 upon two-photon excitation), which is the most accurate and direct approach to measure the radiative charge carrier lifetime and diffusion lengths. Lifetimes of about 72 and 4.3 MUs for FAPbBr3 and FAPbI3 perovskite single crystals have been recorded, presenting the longest radiative carrier lifetimes reported to date for perovskite materials. Subsequently, carrier diffusion lengths of 107.2 and 19.7 MUm are obtained. In addition, we demonstrate the key role of the organic cation units in modulating the carrier lifetime and its diffusion lengths, in which the defect formation energies for FA cations are much higher than those with the MA ones. PMID- 28849940 TI - Metabolomic Fingerprinting in Various Body Fluids of a Diet-Controlled Clinical Smoking Cessation Study Using a Validated GC-TOF-MS Metabolomics Platform. AB - Untargeted GC-TOF-MS analysis proved to be a suitable analytical platform to determine alterations in the metabolic profile. Several metabolic pathways were found to be altered in a first clinical study comparing smokers against nonsmokers. Subsequently, we conducted a clinical diet-controlled study to investigate alterations in the metabolic profile during the course of 3 months of smoking cessation. Sixty male subjects were included in the study, and plasma, saliva, and urine samples were collected during four 24 h stationary visits: at baseline, while still smoking, after 1 week, after 1 month, and after 3 months of cessation. Additionally, subjects were monitored for their compliance by measurements of CO in exhaled breath and salivary cotinine throughout the study. GC-TOF-MS fingerprinting was applied to plasma, saliva, and urine samples derived from 39 compliant subjects. In total, 52 metabolites were found to be significantly altered including 26 in plasma, 20 in saliva, and 12 in urine, respectively. In agreement with a previous study comparing smokers and nonsmokers, the fatty acid and amino acid metabolism showed significant alterations upon 3 months of smoking cessation. Thus these results may indicate a partial recovery of metabolic pathway perturbations, even after a relatively short period of smoking cessation. PMID- 28849939 TI - Surface Structure of 4-Mercaptopyridine on Au(111): A New Dense Phase. AB - 4-Mercaptopyridine (4MPy) self-assembled on Au(111) has been studied by in situ electrochemical scanning tunneling microscopy (EC-STM) in HClO4, cyclic voltammetry, X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT). Samples prepared by varying the immersion time at constant concentration named short time (30 s) and long time (3 min) adsorption have been studied. Cyclic voltammetry and XPS showed that the chemistry of the adsorbed molecules does not depend on the adsorption time resulting in a well established chemisorbed thiol self-assembled monolayer on Au(111). EC-STM study of the short time adsorption sample revealed a new self-assembled structure after a cathodic desorption/readsorption sweep, which remains stable only if the potential is kept negative to the Au(111) zero charge potential (EPZC). DFT calculations have shown a correlation between the observed structure and a dense weakly adsorbed phase with a surface coverage of theta = 0.4 and a (5 * ?3) lattice configuration. At potentials positive to the EPZC, the weakly adsorbed state becomes unstable, and a different structure is formed due to the chemisorption driven by the electrostatic interaction. Long time adsorption experiments, on the other hand, have shown the typical (5 * ?3) structure with theta = 0.2 surface coverage (chemisorbed phase) and are stable over the whole potential range. The difference observed in long time and short time immersion can be explained by the optimization of molecular interactions during the self-assembly process. PMID- 28849942 TI - Triazolylidene Iridium Complexes for Highly Efficient and Versatile Transfer Hydrogenation of C?O, C?N, and C?C Bonds and for Acceptorless Alcohol Oxidation. AB - A set of iridium(I) and iridium(III) complexes is reported with triazolylidene ligands that contain pendant benzoxazole, thiazole, and methyl ether groups as potentially chelating donor sites. The bonding mode of these groups was identified by NMR spectroscopy and X-ray structure analysis. The complexes were evaluated as catalyst precursors in transfer hydrogenation and in acceptorless alcohol oxidation. High-valent iridium(III) complexes were identified as the most active precursors for the oxidative alcohol dehydrogenation, while a low-valent iridium(I) complex with a methyl ether functionality was most active in reductive transfer hydrogenation. This catalyst precursor is highly versatile and efficiently hydrogenates ketones, aldehydes, imines, allylic alcohols, and most notably also unpolarized olefins, a notoriously difficult substrate for transfer hydrogenation. Turnover frequencies up to 260 h-1 were recorded for olefin hydrogenation, whereas hydrogen transfer to ketones and aldehydes reached maximum turnover frequencies greater than 2000 h-1. Mechanistic investigations using a combination of isotope labeling experiments, kinetic isotope effect measurements, and Hammett parameter correlations indicate that the turnover-limiting step is hydride transfer from the metal to the substrate in transfer hydrogenation, while in alcohol dehydrogenation, the limiting step is substrate coordination to the metal center. PMID- 28849941 TI - Primary Metabolism and Medium-Chain Fatty Acid Alterations Precede Long-Chain Fatty Acid Changes Impacting Neutral Lipid Metabolism in Response to an Anticancer Lysophosphatidylcholine Analogue in Yeast. AB - The nonmetabolizable lysophosphatidylcholine (LysoPC) analogue edelfosine is the prototype of a class of compounds being investigated for their potential as selective chemotherapeutic agents. Edelfosine targets membranes, disturbing cellular homeostasis. Is not clear at this point how membrane alterations are communicated between intracellular compartments leading to growth inhibition and eventual cell death. In the present study, a combined metabolomics/lipidomics approach for the unbiased identification of metabolic pathways altered in yeast treated with sublethal concentrations of the LysoPC analogue was employed. Mass spectrometry of polar metabolites, fatty acids, and lipidomic profiling was used to study the effects of edelfosine on yeast metabolism. Amino acid and sugar metabolism, the Krebs cycle, and fatty acid profiles were most disrupted, with polar metabolites and short-medium chain fatty acid changes preceding long and very long-chain fatty acid variations. Initial increases in metabolites such as trehalose, proline, and gamma-amino butyric acid with a concomitant decrease in metabolites of the Krebs cycle, citrate and fumarate, are interpreted as a cellular attempt to offset oxidative stress in response to mitochondrial dysfunction induced by the treatment. Notably, alanine, inositol, and myristoleic acid showed a steady increase during the period analyzed (2, 4, and 6 h after treatment). Of importance was the finding that edelfosine induced significant alterations in neutral glycerolipid metabolism resulting in a significant increase in the signaling lipid diacylglycerol. PMID- 28849943 TI - Survey on Transfusion-Transmitted Cytomegalovirus and Cytomegalovirus Disease Mitigation. AB - CONTEXT: - Cytomegalovirus (CMV) can be transmitted by cellular blood products, leading to severe disease in immunosuppressed patients such as neonates and transplant recipients. To mitigate transfusion-transmitted CMV (TT-CMV), "CMV safe" blood products (leukoreduced and/or CMV-seronegative) are transfused. Attempts to develop practice guidelines for TT-CMV mitigation have been limited by paucity of high-quality clinical trials. OBJECTIVE: - To assess current TT-CMV mitigation strategies across medical institutions for specific at-risk populations. DESIGN: - Supplemental questions regarding TT-CMV and CMV disease mitigation were added to a College of American Pathologists Transfusion Medicine (Comprehensive) Participant Survey in 2015, addressing whether a given institution provided CMV-safe products for 6 at-risk patient populations. RESULTS: - Ninety percent (2712 of 3032) of institutions reported providing universally leukoreduced blood products. Among institutions without universal leukoreduction, 92% (295 of 320) provided leukoreduced products on the basis of clinical criteria. Eighty-three percent (2481 of 3004) of respondents reported having availability of CMV-seronegative products; however, wide variation in policies was reported governing CMV-seronegative product use. Among all respondents, less than 5% reported using CMV prophylaxis and monitoring in high risk patient groups. Transplant centers reported higher rates of CMV prophylaxis (25% [97 of 394] solid organ) and monitoring (15% [59 of 394] solid organ) for CMV-negative transplant recipients. CONCLUSIONS: - Universal leukoreduction is the primary strategy for mitigating TT-CMV. While most institutions have both CMV seronegative and leukoreduced blood products available, consensus is lacking on which patients should receive these products. High-quality studies are needed to determine if CMV-seronegative and leukoreduced blood products are needed in high risk patient populations. PMID- 28849944 TI - Integrated Pathology Informatics Enables High-Quality Personalized and Precision Medicine: Digital Pathology and Beyond. AB - CONTEXT: - The critical role of pathology in diagnosis, prognosis, and prediction demands high-quality subspecialty diagnostics that integrates information from multiple laboratories. OBJECTIVE: - To identify key requirements and to establish a systematic approach to providing high-quality pathology in a health care system that is responsible for services across a large geographic area. DESIGN: - This report focuses on the development of a multisite pathology informatics platform to support high-quality surgical pathology and hematopathology using a sophisticated laboratory information system and whole slide imaging for histology and immunohistochemistry, integrated with ancillary tools, including electron microscopy, flow cytometry, cytogenetics, and molecular diagnostics. RESULTS: - These tools enable patients in numerous geographic locations access to a model of subspecialty pathology that allows reporting of every specimen by the right pathologist at the right time. The use of whole slide imaging for multidisciplinary case conferences enables better communication among members of patient care teams. The system encourages data collection using a discrete data synoptic reporting module, has implemented documentation of quality assurance activities, and allows workload measurement, providing examples of additional benefits that can be gained by this electronic approach to pathology. CONCLUSION: - This approach builds the foundation for accurate big data collection and high quality personalized and precision medicine. PMID- 28849945 TI - Re: Consumers Report Value of Glucosamine for Rheumatoid Arthritis. PMID- 28849946 TI - Intravenous vernakalant in comparison with intravenous flecainide in the cardioversion of recent-onset atrial fibrillation. AB - BACKGROUND: Pharmacological cardioversion of atrial fibrillation is a reasonable alternative for electrical cardioversion in acute atrial fibrillation. We compared the efficacy and safety of intravenous vernakalant and intravenous flecainide in patients with recent-onset (< 48 h) atrial fibrillation. METHODS: A total of 200 consecutive patients, 100 patients undergoing cardioversion with intravenous vernakalant and 100 patients undergoing cardioversion with intravenous flecainide, were included in this single centre non-randomized retrospective study. The primary endpoint was conversion to sinus rhythm within 120 minutes from the drug administration. RESULTS: Cardioversion was successful in 67% of patients treated with vernakalant and in 46% of patients treated with flecainide ( p=0.003). Vernakalant (odds ratio 1.99, 95% confidence interval 1.08 3.69, p=0.029) and female gender (odds ratio 2.48, 95% confidence interval 1.22 15.05, p=0.012) were significant predictors of successful cardioversion. The success rate of cardioversion was lowest among men treated with flecainide (36.9%). Patients treated with vernakalant were discharged earlier from the emergency department compared with those treated with flecainide (8.2 +/- 4.7 h vs. 12.0 +/- 6.0 h, p < 0.001). There was no difference in the complication rate between the groups. Vernakalant treated patients were older (59.3 +/- 12.5 vs. 55.4 +/- 13.0 years, p=0.03), had higher CHA2DS2-VASc score (1.4 +/- 1.3 vs. 0.9 +/- 1.2, p = 0.002) and were more often on beta-blocker medication (59% vs. 42%, p= 0.016) than flecainide treated patients. CONCLUSION: Vernakalant was safe, more effective and faster than flecainide in the cardioversion of recent-onset atrial fibrillation. The difference in efficacy was especially apparent among men. PMID- 28849947 TI - Editor's Choice- What do small serum creatinine changes tell us about outcomes after acute myocardial infarction? AB - Acute kidney injury (AKI), mostly defined as a rise in serum creatinine concentration of more than 0.5 mg/dl, is a common, serious, and potentially preventable complication of percutaneous coronary intervention and is associated with adverse outcomes including an increased risk of inhospital mortality. Recent data from the National Cardiovascular Data Registry/Cath-PCI registry including 985,737 consecutive patients undergoing percutaneous coronary intervention suggest that approximately 7% experienced AKI with a reported incidence of 3-19%. In patients undergoing primary percutaneous coronary intervention for acute myocardial infarction (AMI), AKI occurs more frequently with rates up to 20% depending on patient and procedural characteristics. However, varying definitions of AKI limit comparisons of AKI rates across different studies. Recently, most studies have adopted the Acute Kidney Injury Network (AKIN) criteria for definition and classification of AKI. Beyond the AKIN criteria for AKI, other classifications such as the risk, injury, failure, loss and end-stage kidney disease (RIFLE) and kidney disease: improving global outcomes (KDIGO) criteria are used to define AKI. Notably, even small increases in serum creatinine beyond AKI may be associated with adverse outcomes including increased hospital length of stay and excess. Acute kidney injury (AKI) is a serious and potentially preventable complication of percutaneous coronary intervention (PCI). Worsening renal function is associated with adverse outcomes including a higher rate of in hospital mortality. In patients undergoing primary PCI for acute myocardial infarction (AMI), AKI occurs up to 20% of such individuals. Varying definitions of AKI limit comparisons of AKI rates across different studies. Additionally, even small increases in serum creatinine beyond lavels meeting AKI definitions may be associated with adverse outcomes including increased hospital length of stay. PMID- 28849948 TI - Machines Learning to Detect Obstructive Sleep Apnea in Children. Are We There Yet? PMID- 28849949 TI - Cell Transplantation: Science at the Highest Level. PMID- 28849951 TI - Second-line treatments of small-cell lung cancers. AB - INTRODUCTION: Second-line therapies for relapsed small cell lung cancer (SCLC) patients remain a challenge, with limited clinical benefit because of rapid tumor growth, early dissemination and the development of drug resistance during the disease. Recent developments in genomic sequencing have provided further insight into the biology of the disease, identifying new targets and new pathways. Areas covered: This review details chemotherapy, targeted therapies and immune checkpoint blockades that have been investigated as second-line treatments for SCLC patients using a PubMed search (period 1990 - 2016, terms used: SCLC, treatments, second line, therapy). Expert commentary: Recent genomic, proteomic and preclinical studies have identified novel therapeutic strategies currently being evaluated in clinical trials. Promising approaches for SCLC management include delta-like ligand-3 (DLL3)-targeted antibody-drug conjugate, combination targeted therapies, or targeted therapy-chemotherapy with an additive effect superior to the efficacy of single agents. The blockade of immune checkpoints has yielded promising preliminary results and is being investigated in ongoing trials. The inclusion of SCLC patients relapsing after platin-doublet induction in well-designed clinical trials remains a major challenge. PMID- 28849952 TI - Fertility awareness-based mobile application. PMID- 28849953 TI - Measurement of the mechanical properties of the human gallbladder. AB - Gallbladder is a small organ of the body which is located in the right side of the liver. It is responsible of storing the bile and releasing it to the intestine. The gallbladder can subject to the mechanical deformation/loading as a result of the cholecystitis, cholesterolosis of the gallbladder, etc. However, so far the mechanical properties of the human gallbladder have not been measured. This study was aimed at conducting an experimental study to measure the mechanical properties of the human gallbladder under the axial and transversal tensile loadings. To do that, the gallbladder tissue of 16 male individuals was excised during the autopsy and subjected to a series of axial and transversal loadings under the strain rate of 5 mm/min. The amount of elastic modulus as well as the maximum/failure stress of the tissues were calculated via the resulted stress-strain diagrams and reported. The results revealed that the axial and transversal elastic modulus were 641.20 +/- 28.12 (mean +/- SD) and 255 +/- 24.55 kPa, respectively. The amount of maximum stresses was also 1240 +/- 99.94 and 348 +/- 66.75 kPa under the axial and transversal loadings, respectively. The results revealed a significantly higher axial stiffness (p < .05, post hoc Scheffe method) compared to the transversal one. These findings have implications not only for understanding the axial and transversal mechanical properties of the human gallbladder tissue, but also for providing a diagnosis tool for the doctors to have a suitable threshold value of the healthy gallbladder tissue. PMID- 28849954 TI - Perceived partner fertility desires and influence on contraceptive use. AB - BACKGROUND: Perceived discordance of fertility desires may be more common among couples with certain sociodemographic characteristics and may lead to lower contraceptive use. METHODS: Using nationally representative data from adults ages 15-49 in France in 2010, we analysed associations between sociodemographic characteristics, perceived discordance of fertility desires and contraceptive use with design-based logistic regression. RESULTS: Only 8% of participants perceived discordant fertility desires while 92% perceived concordance with partner fertility desire. Discordance varied by age and relationship duration and by the presence of children from previous relationships. Perceived discordance was not associated with use of a hormonal or highly effective method. Beyond own intentions, perception of a partner's fertility desires was associated with using a highly effective method among participants using any method. CONCLUSIONS: Engaging men and couples in family planning programmes may be important for achieving both partners' desired fertility goals. PMID- 28849955 TI - A simple method for quantitative assessment of elbow flexion strength. AB - Assessment of elbow flexion strength is an important component of upper limb neurological examination and is necessary for patient screening, planning of surgical interventions and rehabilitation. Medical Research Council (MRC) Scale is the most widely used method for grading muscle strength. The major drawback of MRC grading is that it is observer dependent and imprecise. A quantitative measure of elbow flexion strength is an objective measure that eliminates such bias. Several instruments have been developed for quantifying the elbow flexion power. However, availability, quality and measuring standards vary widely between these instruments most being cumbersome and expensive. We report the design of an instrument that is simple and cost effective for quantifying elbow flexion strength objectively. The validity of elbow flexion strength obtained from normal participants using this in-house instrument supports its clinical use in patients with brachial plexus injury. PMID- 28849956 TI - Cleansing technique using high-velocity steam-air micromist jet spray. AB - Application of a high-velocity steam-air micromist jet spray (HVS-AMJS; micromist average diameter: 2.4 MUm) for cleansing the skin is proposed. Low-pressure steam is mixed with compressed air (pH 6.5) in a nozzle, and then sprayed at a pressure of ?0.25 MPa and a velocity of ?0.34 m/s on the skin or surface of material located approximately 5-10 cm from the nozzle. The temperature on the sprayed surface and water flow rate could be controlled between 42 degrees C and 46 degrees C and at approximately 50 mL/min, respectively. Compared with ultrasonic cleansing with tap water and rubbing with only tap water, the HVS-AMJS successfully removed fluorescent lotion covering pieces of wood and significantly reduced both the number of coliforms and the total viable counts on pieces of wood and gauze. Furthermore, the HVS-AMJS effectively removed oily ink from the skin of hairless rats, and temporarily elevated the skin temperature and blood flow, indicating massage effects. The striking characteristics of this cleansing technique using HVS-AMJS are not only its ability to remove microbes and residue without using any chemicals or detergents but also its massage effects. PMID- 28849959 TI - Abstracts for the 17th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28849957 TI - A novel obstetric medical device designed for autotransfusion of blood in life threatening postpartum haemorrhage. AB - Postpartum haemorrhage (PPH) is an obstetric emergency caused by excessive blood loss after delivery, which is the leading cause of maternal mortality worldwide. PPH can lead to volume depletion, hypovolemic shock, anaemia and ultimately death. The prevalence of PPH is disproportionately higher in low resource settings where there is limited access to skilled medical care and safe blood supplies. Current management strategies target both prevention and treatment of PPH however no alternatives currently exist to address the lack of safe blood supplies which are considered essential in emergency obstetrical care. Autotransfusion is used to salvage blood loss in a variety of clinical settings but has never been used in the context of vaginal delivery. We describe the development and testing of a novel device for the collection, filtration and autotransfusion of blood lost due to PPH. The prototype device is inexpensive and easily operated so that it may be practically deployed in low resource settings. The device is comprised of a blood collection drape, a pump apparatus, three leukocyte reduction filters and a reservoir for filtered blood. Preliminary testing demonstrates efficacy of microbial load reduction of up to 97.3%. To reduce cost and improve safety, the device is modular in design such that the drape, tubing, filters and transfusion bag may be stored sterile, used once and discarded; while the pump apparatus may be used indefinitely without the need for sterilisation. Preliminary results indicate the device confers a low cost and potentially effective means of collecting, pumping, filtering and returning blood to a patient following PPH in settings that lack safe blood supplies. This device shows promise as a method of stabilising patients suffering of PPH in low resource settings until definitive treatment is rendered with the ultimate goal of reducing maternal mortality globally. PMID- 28849961 TI - The feasibility of contraceptive injections at the community pharmacy. AB - PURPOSE: The progestogen-only intramuscular injectable Depo-Provera(r) (depot medroxyprogesterone acetate) is an effective contraceptive method, but users need to attend a clinic every 12-13 weeks for a repeat injection from a doctor/nurse. This limits convenience of the method and may affect continuation rates. We conducted a pilot study to examine the feasibility and acceptability of users receiving the subcutaneous form of the contraception injection from pharmacists in the community pharmacy setting. MATERIALS AND METHODS: Existing users of Depo Provera(r), who wished to switch to the subcutaneous preparation with the same active ingredient (Sayana Press(r)) were invited to attend 1 of 11 community pharmacies for up to three repeat injections, given by a pharmacist. Evaluation consisted of (i) self-administered questionnaires of women and (ii) interviews with participating pharmacists, at study exit on their respective experiences. RESULTS: Global unavailability of the product during the study adversely affected recruitment and retention. 50 women were recruited. Only 48 injections were delivered at the pharmacy out of a possible 150 (34%). About 26 participants received no injections at the pharmacy and only seven (14%) participants received all three injections at the pharmacy. Participants reported mixed experiences, with some welcoming the intervention but others experiencing difficulty with pharmacist availability. Pharmacists were enthusiastic about this expansion of their role, and did not view their availability as a barrier to service delivery. CONCLUSIONS: Delivery of the subcutaneous contraceptive injectable from a community pharmacy may be feasible but availability of sufficient numbers of pharmacists trained in this technique is necessary for a robust model of service delivery. PMID- 28849965 TI - Article Commentary: Stem Cell Research in Cell Transplantation: An Analysis of Geopolitical Influence by Publications. AB - One of the fastest growing fields in researching treatments for neurodegenerative and other disorders is the use of stem cells. These cells are naturally occurring and can be obtained from three different stages of an organism's life: embryonic, fetal, and adult. In the US, political doctrine has restricted use of federal funds for stem cells, enhancing research towards an adult source. In order to determine how this legislation may be represented by the stem cell field, a retrospective analysis of stem cell articles published in the journal Cell Transplantation over a 2-year period was performed. Cell Transplantation is considered a translational journal from preclinical to clinical, so it was of interest to determine the publication outcome of stem cell articles 6 years after the US regulations. The distribution of the source of stem cells was found to be biased towards the adult stage, but relatively similar over the embryonic and fetal stages. The fetal stem cell reports were primarily neural in origin, whereas the adult stem cell ones were predominantly mesenchymal and used mainly in neural studies. The majority of stem cell studies published in Cell Transplantation were found to fall under the umbrella of neuroscience research. American scientists published the most articles using stem cells with a bias towards adult stem cells, supporting the effect of the legislation, whereas Europe was the leading continent with a bias towards embryonic and fetal stem cells, where research is "controlled" but not restricted. Japan was also a major player in the use of stem cells. Allogeneic transplants (where donor and recipient are the same species) were the most common transplants recorded, although the transplantation of human-derived stem cells into rodents was the most common specific transplantation performed. This demonstrates that the use of stem cells is an increasingly important field (with a doubling of papers between 2005 and 2006), which is likely to develop into a major therapeutic area over the next few decades and that funding restrictions can affect the type of research being performed. PMID- 28849960 TI - Risk of bacterial vaginosis, Trichomonas vaginalis and Candida albicans infection among new users of combined hormonal contraception vs LNG-IUS. AB - OBJECTIVE: The study assessed the risk of bacterial vaginosis, Trichomonas vaginalis and Candida albicans infection among new users of either a combined oral contraceptive pill (COC) or the levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: This prospective observational study included 430 women, without active vaginitis at inclusion, who were divided into two groups according to their chosen method of contraception: COC group (n = 236) and LNG-IUS group (n = 194). Participants were examined for bacterial vaginosis, T. vaginalis and C. albicans infection initially and then at 6 weeks, 6 months and 12 months after the start of contraceptive use. Data were collected and statistically analysed. RESULTS: The rates of acquisition of bacterial vaginosis, T. vaginalis and C. albicans infection during follow-up were significantly increased and comparable between the groups (p < .001) and decreased in frequency over time (p < .05). The rates of acquisition of bacterial vaginosis among COC users (Nugent score) were 24.6, 18.6 and 15.2% and among LNG-IUS users 20.6, 13.5 and 9.3% at 6 weeks, 6 months and 12 months, respectively (p < .001). Body mass index >25 kg/m2, history of bacterial vaginosis, history of sexually transmitted infection, vaginal douching more than five times per week and coital frequency more than five times per week were strong risk factors for acquisition of bacterial vaginosis during the follow-up period (p < .001). CONCLUSIONS: The use of COCs and LNG-IUS is associated with an increased, comparable risk of acquisition of bacterial vaginosis, T. vaginalis and C. albicans infections, which is greatest during initial use of the method but which improves over time. PMID- 28849966 TI - Article Commentary: Stem Cell Plasticity and Tissue Replacement. PMID- 28849967 TI - Emerging Strategies in Neural Transplantation and Repair: A Special Section Based on the 10th ASNTR Meeting. PMID- 28849968 TI - Article Commentary: A Perspective on Transplantation Therapy and Stem Cells for Parkinson's Disease. PMID- 28849975 TI - Japanese Society for Regenerative Medicine: Introduction. PMID- 28849976 TI - Erratum. PMID- 28849977 TI - Article Commentary: Stem Cells and Development Publishes Neural Stem Cells Compendium. PMID- 28849983 TI - The burden of multiple sclerosis in Japan. AB - AIMS: Multiple sclerosis (MS) is a disabling autoimmune disease affecting the central nervous system. Few studies have examined the effect of MS on patient outcomes in Japan. The study aim was to quantify MS burden in Japan by comparing MS respondents to matched controls on patient outcomes. MATERIALS AND METHODS: Data from seven administrations of the nationally representative Japan National Health and Wellness Survey (2009-2014 and 2016) were used (n = 181,423). Respondents self-reporting MS diagnosis were compared with respondents not reporting MS. Matched controls were selected using propensity scores. Respondents with MS and matched controls were compared on health-related quality-of-life (HRQoL), work productivity and activity impairment, healthcare resource utilization, and costs. Comparisons were made using Chi-square tests or one-way ANOVAs. RESULTS: A total of 96 respondents with MS and 480 matched controls were included in the analyses. MS respondents reported worse mental (44.35 vs 47.51, p < .05), physical (33.11 vs 49.04, p < .001), and role (37.78 vs 47.11, p < .001) component summary scores (minimally important difference is 3.0). Additionally, MS respondents reported decrements on every health profile sub-scale (p < .001) and 5-Level EuroQoL-5 Dimensions outcome (p < .01). MS respondents also reported more healthcare provider visits (13.78 vs 6.13) and hospitalizations (3.02 vs 0.70; both, p < .001), leading to higher direct costs. For work productivity and activity impairment, MS respondents reported more absenteeism (17.50% vs 5.57%), presenteeism (38.11% vs 21.62%), overall work impairment (46.68% vs 25.27%), and activity impairment (46.88% vs 24.90%, all, p < .001), leading to higher indirect costs. LIMITATIONS: Japan NHWS data are cross-sectional, and causal relationships cannot be established. Due to the self-reported nature of the data, responses could not be independently verified. CONCLUSIONS: Results suggest MS in Japan is associated with poorer HRQoL and greater work and activity impairment, healthcare resource use, and costs. Improved MS management could benefit both patients and society. PMID- 28849984 TI - One, two or three dimensions of work engagement? Testing the factorial validity of the Utrecht Work Engagement Scale on a sample of Polish employees. AB - Work engagement, as conceptualized by the Utrecht Work Engagement Scale (UWES), is a work-related positive state of mind that is characterized by vigour, dedication and absorption; however, it still remains unclear how many dimensions work engagement comprises. This study tested the factorial validity of 11 different UWES factorial models that are available in the literature using a confirmatory factor analysis approach on a large sample of multi-occupational Polish employees (N = 1420). The two-factor UWES-6, comprising vigour and dedication, was found to be reliable and remained invariant across samples drawn from four different organizational positions. It also presented a better fit than the three-factor UWES-9, which is a scale used as a standard in contemporary research on work engagement. The findings suggest that the three-factor UWES-9 might not be an optimal measure of work engagement in Poland. PMID- 28849985 TI - Synergic prooxidant, apoptotic and TRPV1 channel activator effects of alpha lipoic acid and cisplatin in MCF-7 breast cancer cells. AB - BACKGROUND: Resistance to cisplatin (Cisp) in the treatment of breast cancer is a major obstacle. Alpha-lipoic acid (ALA) has both antioxidant and oxidant properties. ALA has been used on stimulation mechanisms of apoptosis and oxidative stress in the treatment of cancer with a combination of chemotherapeutic agents, although its role on molecular mechanisms in the cancer cells has not been clarified yet. The aim of this study was to evaluate if a combination therapy of ALA with Cisp can alter the effect of this chemotherapy drug in the MCF-7 breast cancer cells. MATERIALS: The MCF-7 cells were divided into four treatment groups as control, Cisp (0.025 mM), ALA (0.05 mM), and Cisp + ALA. RESULTS: Apoptosis, mitochondrial membrane depolarization, reactive oxygen species (ROS) production, lipid peroxidation, PARP1, caspase 3 and 9 expression levels are increased through activating TRPV1 in the cells by the Cisp and ALA treatments, although cell viability, reduced glutathione and glutathione peroxidase (GPx) values were decreased by the treatments. The Cisp and ALA induced increase of intracellular free Ca2+ concentration was decreased with the TRPV1 blocker, capsazepine. CONCLUSIONS: Apoptosis and oxidant effects of Cisp were increased by activation of TRPV1 channels, but its action on the values was further increased by the ALA treatment. Combination therapy of ALA and Cisp could be used as an effective strategy in the treatment of breast cancer. PMID- 28849986 TI - Interactive mechanism of working environments and construction behaviors with cognitive work analysis: an elevator installation case study. AB - Unsafe behavior is a leading factor in accidents, and the working environment significantly affects behaviors. However, few studies have focused on detailed mechanisms for addressing unsafe behaviors resulting from environmental constraints. This study aims to delineate these mechanisms using cognitive work analysis (CWA) for an elevator installation case study. Elevator installation was selected for study because it involves operations at heights: falls from heights remain a major cause of construction worker mortality. This study adopts a mixed research approach based on three research methodology stages. This research deconstructs the details of the working environment, the workers' decision-making processes, the strategies chosen given environmental conditions and the conceptual model for workers' behaviors, which jointly depict environment behavior mechanisms at length. By applying CWA to the construction industry, environmental constraints can easily be identified, and targeted engineering suggestions can be generated. PMID- 28849987 TI - Amelioration of ethanol induced apoptotic DNA damage and ulcerative injuries in the mice gastric tissues by starch oral administration. AB - Nowadays, gastric ulcers have become very common gastrointestinal disorders and numerous natural plant extracts exert promising anti-ulcerative effects. Therefore, this study was designed to evaluate the possible protective effect of dietary starch against ethanol induced gastric ulcers in mice. Post administration of dietary starch for three consecutive days caused remarkable ameliorations in hemorrhagic lesions in gastric mucus and significant suppression in % incidence of ulceration, ulcer index and ulcer score induced by ethanol single administration. Indeed, deep ulceration, necrosis, disruption and degeneration in large areas of mucosa layer together with dense inflammatory cells infiltration and edema in sub-mucosal layer induced by ethanol administration were attenuated by starch post-administration and normalized the tissue architecture of the stomach. This potential protective effect could be attributed to the potent anti-oxidative capacity of starch that causes scavenger of the reactive oxygen species and thereby decreasing single and double DNA stranded break inductions and apoptotic DNA damage revealed by returning the p53 and caspase-3 expression levels to the normal level compared to the ethanol treated group. In conclusion, dietary starch has a potent therapeutic effect against ethanol induced gastric ulcer in mice via its free radical scavengers ability. Thus, we recommended further studies on its possible use as antiulcer drugs. PMID- 28849988 TI - Botrytis euroamericana, a new species from peony and grape in North America and Europe. AB - A novel species of Botrytis isolated from peony in Alaska, USA, and grape in Trento District, Italy, was identified based on morphology, pathogenicity, and sequence data. The grape and peony isolates share sequence homology in the glyceraldehyde-3-phosphate dehydrogenase (G3PDH), heat shock protein 60 (HSP60), DNA-dependent RNA polymerase subunit II (RPB2), and necrosis- and ethylene inducing protein 1 and 2 (NEP1 and NEP2) genes that place them in a distinct group closely related to B. aclada, a globally distributed pathogen of onions. Genetic results were corroborated with morphological and pathogenicity trials that included two isolates of B. cinerea and two isolates of B. paeoniae from peony in Alaska and one isolate of B. aclada. The authors observed differences in colony and conidia morphology and ability to cause lesions on different host tissues that suggest that the grape and peony isolates represent a distinct species. Most notably, the grape and peony isolates did not colonize onion bulbs, whereas B. aclada readily produced lesions and prolific sporulation on onion tissue. The new species Botrytis euroamericana is described herein. PMID- 28849989 TI - Pushing, pulling and manoeuvring an industrial cart: a psychophysiological study. AB - One of the most frequent manual occupational tasks involves the pushing and pulling of a cart. Although several studies have associated health risks with pushing and pulling, the effects are not clear since occupational tasks have social, cognitive and physical components. The present work investigates a real case of a pushing and pulling occupational task from a manufacturing company. The study initially characterizes the case in accordance with Standard No. ISO 11228 2:2007 as low risk. An experiment with 14 individuals during three modalities of pushing and pulling was performed in order to further investigate the task with the application of electrophysiology. At the end, a simple questionnaire was given. The results show electrophysiological differences among the three modalities of pushing and pulling, with a major difference between action with no load and fully loaded with a full range of motions on the cart to handle. PMID- 28849990 TI - Protective action of Omega-3 on paraquat intoxication in Drosophila melanogaster. AB - Paraquat (PQ) (1,1'-dimethyl-4-4'-bipyridinium dichloride) is the second most widely used herbicide worldwide; however, in countries different sales and distribution remain restricted. Chronic exposure to PQ leads to several diseases related to oxidative stress and mitochondrial dysfunctions including myocardial failure, cancer, and neurodegeneration and subsequently death depending upon the dose level. The aim of this study was to examine if diet supplementation with eicosapentaenoic and docosahexaenoic acids (EPA and DHA, omega-3 long-chain fatty acids) serves a protective mechanism against neuromuscular dysfunctions mediated by PQ using Drosophila melanogaster as a model with focus on mitochondrial metabolism. PQ ingestion (170 mg/kg b.w. for 3 d) resulted in a decreased life span and climbing ability in D. melanogaster. In the brain, PQ increased thioflavin fluorescence and reduced either 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) nuclei staining and neuronal nuclei protein (NeuN) positive neurons, indicating amyloid formation and neurodegenetation, respectively. In the thorax, PQ ingestion lowered citrate synthase activity and respiratory functions indicating a reduction in mitochondrial content. PQ elevated Ca2+/calmodulin-dependent protein kinase II (CaMKII) mRNA expression levels, indicative of high calcium influx from cytosol to mitochondrial matrix. In brain and thorax, PQ also increased hydrogen peroxide (H2O2) production and impaired acetylcholinesterase (AChE) activity. Concomitant EPA/DHA ingestion (0.31/0.19 mg/kg b.w.) protected D. melanogaster against PQ-induced toxicity preserving neuromuscular function and slowing down the rate of aging. In brain and thorax, these omega-3 fatty acids inhibited excess H2O2 production and restored AChE activity. EPA/DHA delayed amyloid deposition in the brain, and restored low citrate synthase activity and respiratory functions in the thorax. The effects in the thorax were attributed to stimulated mRNA expression level of genes involved either in mitochondrial dynamics or biogenesis promoted by EPA/DHA: dynamin-related protein (DRP1), mitochondrial assembly regulatory factor (MARF), mitochondrial dynamin like GTPase (OPA1), and peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC1alpha). In conclusion, diet supplementation with EPA/DHA appears to protect D. melanogaster muscular and neuronal tissues against PQ intoxication. PMID- 28849991 TI - Occupational safety and health management in the construction industry: a review. AB - The construction industry plays a significant role in contributing to the economy and development globally. During the process of construction, various hazards coupled with the unique nature of the industry contribute to high fatality rates. This review refers to previous published studies and related Malaysian legislation documents. Four main elements consisting of human, worksite, management and external elements which cause occupational accidents and illnesses were identified. External and management elements are the underlying causes contributing to occupational safety and health (OSH), while human and worksite elements are more apparent causes of occupational accidents and illnesses. An effective OSH management approach is required to contain all hazards at construction sites. An approach to OSH management constructed by elements of policy, process, personnel and incentive developed in previous work is explored. Changes to the sub-elements according to previous studies and the related Malaysian legislation are also covered in this review. PMID- 28849992 TI - Racial and ethnic differences in pulmonary arterial hypertension. AB - This study explores the racial and ethnic differences in presentation, severity, and treatment of patients with pulmonary arterial hypertension (PAH) in a large multicenter registry. African American and Hispanic patients are more likely to present with associated PAH compared to non-Hispanic whites. Hispanic patients with PAH were less likely to be treated with PAH-specific medications compared to non-Hispanic whites. PMID- 28849993 TI - Skills and Strategies of African American Parents in the Management of ADHD: A Qualitative Study. AB - OBJECTIVE: The purpose of this study is to use a strengths-based approach to determine African American parents' skills and strategies for management of children with ADHD. METHOD: Four focus groups were conducted to identify African American parent beliefs about appropriate ADHD management. Sixteen parents participated and reported having a total of 21 children diagnosed with ADHD. RESULTS: Participants discussed several parenting challenges but advocated for the child by working closely with the child's school and physician. They also managed relationships with family members to protect the child from possible physical or emotional harm. However, parents desired more social support for management of ADHD. CONCLUSION: African American parents possess key skills and strategies in their management of children with ADHD. Further research is needed to determine the roles and responsibilities of extended family members for children with this disorder, and to identify the social supports parents access to aid with ADHD management. PMID- 28849994 TI - Characterizing combined effects of antiestrogenic chemicals on vitellogenin production in rainbow trout (Oncorhynchus mykiss) hepatocytes. AB - Fish are exposed to a complex mixture of endocrine disrupting compounds (EDC), some of which display antiestrogenic activity leading to suppression of estrogen receptor (ER)- mediated reproductive processes. Although the main mode of action (MoA) of these antiestrogens is to directly interfere with natural ligand binding of the ER, several other MoA have been proposed. The aim of the present study was to characterize single and combined antiestrogenic effects of the aryl hydrocarbon receptor (AhR)-agonist beta-naphthoflavone (BNF) and ER-antagonist 4 hydroxytamoxifen (OHT) on vitellogenin (Vtg) protein using primary rainbow trout (Oncorhynchus mykiss) hepatocytes. Supporting transcriptional analysis of ER responsive genes (estrogen receptor-alpha (er-alpha), vitellogenin-1 (vtg-1), eggshell zona radiata protein (zrp)) and AhR-mediated genes (aryl hydrocarbon receptor-2beta, cytochrome p450-1a (cyp1a)) was performed by qPCR to characterize the antiestrogenic influence on ER- and AhR-mediated responses. Data demonstrated that both BNF and OHT significantly reduced 17beta-estradiol (E2)-induced Vtg protein expression in a concentration responsive manner, whereas exposure to a mixture of these produced an additive antiestrogenic effect. The results observed at the protein level were further supported by transcriptional analysis of ER responsive genes (er-alpha, vtg-1, zrp), where only E2-induced vtg-1 gene expression was significantly decreased by OHT and the mixture of OHT and BNF. E2 induced er-alpha and zrp gene expression was not markedly altered. The significant reduction of E2-induced vtg-1 gene expression by OHT suggested that the antiestrogenic effect of this compound may be associated with ER signaling pathway. Specific genes involved in putative AhR-ER cross-talk were also investigated, however none were directly associated with the compound anti estrogenic MoA. Although the MoA of the single compounds and mixture were not completely characterized, the present study enhanced our knowledge of the combined toxicity mediated by antiestrogens acting through different MoA. PMID- 28849996 TI - The input efficiency of chord keyboards. AB - This study focused on an innovative mobile input device model that integrated ergonomic design principles to create a chord keyboard for use in concert with pointing devices. We conducted usability tests to demonstrate the operating performances of such keyboards using keys with four characters per key. Twelve right-handed subjects between the ages of 20 and 30 years and with no wrist disability participated in the usability tests. We analyzed the resulting data to compare the differences among the means. The results indicated that keyboards with multiple characters per key created some confusion among users but that keys with multiple characters per key nonetheless resulted in better input performance. PMID- 28849995 TI - Effects of chronic crude oil exposure on early developmental stages of the Northern krill (Meganyctiphanes norvegica). AB - Rising oil and gas activities in northern high latitudes have led to an increased risk of petroleum pollution in these ecosystems. Further, seasonal high UV radiation at high latitudes may elevate photo-enhanced toxicity of petroleum pollution to marine organisms. Zooplanktons are a key ecological component of northern ecosystems; therefore, it is important to assess their sensitivity to potential pollutants of oil and gas activity. As ontogenetic development may be particularly sensitive, the aim of this study was to examine the impact of chronic exposure to oil water dispersion (OWD) on development and feeding of early life stages of the Northern krill, Meganyctiphanes norvegica. In a range of experiments, embryonic, nonfeeding, and feeding larval stages were exposed to concentrations of between 0.01 and 0.1 mg/L of oil or photo-modified oil for 19 and 21 d. No significant effects on egg respiration, hatching success, development, length and larval survival were observed from these treatments. Similarly, evolution of fatty acid composition patterns during ontogenetic development was unaffected. The results indicates a high degree of resilience of these early developmental stages to such types and concentrations of pollutants. However, feeding and motility in later calyptopis-stage larvae were significantly impaired at exposure of 0.1 mg/L oil. Data indicate that feeding larval stage of krill was more sensitive to OWD than early nonfeeding life stages. This might be attributed to the narcotic effects of oil pollutants, their direct ingestion, or accumulated adverse effects over early development. PMID- 28849997 TI - Involvement of superoxide in malaoxon-induced toxicity in primary cultures of cortical neurons. AB - Organophosphorus compounds (OP) represent a class of insecticides that are used most globally. The neurotoxic effects are attributed mainly to acetylcholinesterase (AChE) enzyme inhibition, which is responsible for cholinergic manifestations in individuals acutely exposed to OP. However, AChE inhibition alone cannot account for the wide range of symptoms that were reported following OP exposures. In agreement with this, evidence shows that non cholinergic events may be mechanistically linked to OP-induced neurotoxicity. The aim of this study was to investigate the potential occurrence of oxidative stress as a critical step in the toxicity induced by the OP malaoxon(MAL) using primary cultures of mouse cortical neurons, as well as to distinguish MAL-induced oxidative stress and cell toxicity from an action on AChE blockade. Primary cultures of mouse cortical neurons were treated with MAL (0.01; 0.1; 1; 10; or 100 uM) at varying time points (1, 3, 6, 24, 48, or 144 hr) and the following biochemical parameters determined including cell viability, AChE activity, and superoxide production. MAL significantly reduced cell viability in a concentration- and time-dependent manner. Of note, 1 uM MAL significantly inhibited (approximately 75%) AChE activity after 48 hr incubation. Pralidoxime (PRAL) (600 uM), a classical AChE reactivator, significantly protected against MAL-induced AChE blockade; however, PRAL did not affect MAL-mediated fall in cellular viability, indicating that AChE inhibition is not necessarily correlated with insecticide-induced decrease in cell survival. MAL-induced diminished cell viability was preceded by a significant increase in superoxide anion production. The antioxidant agent ascorbic acid (AA) (200 uM), which significantly protected against MAL-induced superoxide anion production, did not alter MAL-induced AChE inhibition and significantly prevented insecticide-mediated fall in cell survival. Data show that increased superoxide anion production is an event that precedes MAL-induced cell toxicity in primary cultures of mouse cortical neurons. Based on the preventative effects of AA against MAL-mediated superoxide anion production and reduced cell viability, evidence indicates that oxidative stress represents an important step mediating MAL-induced toxicity in neurons and that AChE inhibition is not necessarily correlated with lowered cell survival noted in insecticide-exposed cells. PMID- 28849998 TI - Release of chitobiase as an indicator of potential molting disruption in juvenile Daphnia magna exposed to the ecdysone receptor agonist 20-hydroxyecdysone. AB - During arthropod molting, the old exoskeleton is degraded and recycled by the molting fluid. Chitobiase, a major chitinolytic enzyme in the molting fluid, has been widely used as a biomarker to indicate endocrine disruption of molting in arthropods under environmental stress. Although release of chitobiase was extensively studied in organisms exposed to molting-inhibiting chemicals, enzymic association with molting and response of the molting hormone receptor, ecdysone receptor (EcR), is not well understood. The present study was therefore conducted to identify potential linkages between release of chitobiase, molting frequency, and EcR activation in a freshwater crustacean Daphnia magna after short-term (96 hr) exposure to endogenous molting hormone 20-hydroxyecdysone (20E). A suite of bioassays was used for this purpose, including the chitobiase activity, molting frequency, viability, and in vitro EcR activation. Effect concentrations were compared between different assays analyzed. Results showed that exposure to 20E reduced chitobiase release and molting frequency in a concentration-dependent manner. Exposure to as low as 250 nM 20E significantly decreased release of chitobiase after 72 hr exposure, whereas adverse effects on molting frequency and incomplete molting-associated mortality required higher 20E exposure concentrations. The EcR reporter assay further demonstrated that as low as 100 nM 20E may activate EcR in vitro. Data suggest that release of chitobiase may be employed as a sensitive indicator of potential molting disruption in crustaceans after exposure to EcR agonists such as 20E. PMID- 28849999 TI - Approaches for building community participation: A qualitative case study of Canadian food security programs. AB - There is increasing opportunity and support for occupational therapists to expand their scope of practice in community settings. However, evidence is needed to increase occupational therapists' knowledge, confidence, and capacity with building community participation and adopting community-centered practice roles. The purpose of this study is to improve occupational therapists' understanding of an approach to building community participation, through case study of a network of Canadian food security programs. Qualitative case study was utilized. Data were semistructured interviews, field observations, documents, and online social media. Thematic analysis was used to identify and describe four themes that relate to processes used to build community participation. The four themes were use of multiple methods, good leaders are fundamental, growing participation via social media, and leveraging outcomes. Occupational therapists can utilize an approach for building community participation that incorporates resource mobilization. Challenges of sustainability and social exclusion must be addressed. PMID- 28850000 TI - Statistical inference following sample size adjustment based on the 50% conditional-power principle. AB - Sample size adjustment at an interim analysis can mitigate the risk of failing to meet the study objective due to lower-than-expected treatment effect. Without modification to the conventional statistical methods, the type I error rate will be inflated, primarily caused by increasing sample size when the interim observed treatment effect is close to null or no treatment effect. Modifications to the conventional statistical methods, such as changing critical values or using weighted test statistics, have been proposed to address primarily such a scenario at the cost of flexibility or interpretability. In reality, increasing sample size when interim results indicate no or very small treatment effect could unnecessarily waste limited resource on an ineffective drug candidate. Such considerations lead to the recently increased interest in sample size adjustment based on promising interim results. The 50% conditional power principle allows sample size increase only when the unblinded interim results are promising or the conditional power is greater than 50%. The conventional unweighted test statistics and critical values can be used without inflation of type I error rate. In this paper, statistical inference following such a design is assessed. As shown in the numerical study, the bias of the conventional maximum likelihood estimate (MLE) and coverage error of its conventional confidence interval are generally small following sample size adjustment. We recommend use of conventional, MLE-based statistical inference when applying the 50% conditional power principle for sample size adjustment. In such a way, consistent statistics will be used in both hypothesis test and statistical inference. PMID- 28850001 TI - Opportunities and challenges for the cellular immunotherapy sector: a global landscape of clinical trials. AB - Global investments in cellular immunotherapies reflect their curative potential. Our landscape of clinical trials will aid developers, investors, adopters and payers in planning for adoption and implementation along realistic time horizons. Trend data enable stakeholders to adapt their business models and capacity to bring immunotherapies to the clinic. For cancer, trends suggest a shift from cancer vaccines to adoptive cellular transfer, alongside a focus on solid tumors. Academic centers, mainly in the USA, lead in early-phase clinical trials and target identification; but industry involvement has increased fourfold over the past two decades. Trends indicate an increasingly personalized approach to onco immunology, which raises challenges for cost-effective manufacturing and delivery models. Overcoming these challenges provides opportunities for innovative biotechnology firms. PMID- 28850003 TI - Effect of green juice and their bioactive compounds on genotoxicity induced by alkylating agents in mice. AB - Kale juice (Brassica oleracea L. var. acephala D.C.) is a reliable source of dietary carotenoids and typically contains the highest concentrations of lutein (LT) and beta-carotene (BC) among green leafy vegetables. As a result of their antioxidant properties, dietary carotenoids are postulated to decrease the risk of disease occurrence, particularly certain cancers. The present study aimed to (1) examine the genotoxic and antigenotoxic activity of natural and commercially available juices derived from Brassica oleracea and (2) assess influence of LT or BC against DNA damage induced by alkylating agents such as methyl methanesulfonate (MS) or cyclophosphamide (CP) in vivo in mice. Male Swiss mice were divided into groups of 6 animals, which were treated with water, natural, or commercial Brassica oleraceae juices (kale), LT, BC, MMS, or CP. After treatment, DNA damage was determined in peripheral blood lymphocytes using the comet assay. Results demonstrated that none of the Brassica oleraceae juices or carotenoids produced genotoxic effects. In all examined cell types, kale juices or carotenoids inhibited DNA damage induced by MMS or CP administered either pre- or posttreatment by 50 and 20%, respectively. Under our experimental conditions, kale leaf juices alone exerted no marked genotoxic or clastogenic effects. However, a significant decrease in DNA damage induced by MMS or CP was noted. This effect was most pronounced in groups that received juices, rather than carotenoids, suggesting that the synergy among constituents present in the food matrix may be more beneficial than the action of single compounds. Data suggest that the antigenotoxic properties of kale juices may be of therapeutic importance. PMID- 28850004 TI - Optimization of microbial detoxification for an aquatic mercury-contaminated environment. AB - Mercury (Hg) reduction performed by microorganisms is well recognized as a biological means for remediation of contaminated environment. Recently, studies demonstrated that Hg-resistant microorganisms of Tagus Estuary are involved in metal reduction processes. In the present study, aerobic microbial community isolated from a highly Hg-contaminated area of Tagus Estuary was used to determine the optimization of the reduction process in conditions such as the contaminated ecosystem. Factorial design methodology was employed to examine the influence of glucose, sulfate, iron, and chloride on Hg reduction. In the presence of several concentrations of these elements, microbial community reduced Hg in a range of 37-61% of the initial 0.1 mg/ml Hg2+ levels. The response prediction through central composite design showed that the increase of sulfate concentration led to an optimal response in Hg reduction by microbial community, while the rise in chloride levels markedly decreased metal reduction. Iron may exert antagonistic effects depending upon the media composition. These results are useful in understanding the persistence of Hg contamination in Tagus Estuary after inactivation of critical industrial units, as well as data might also be beneficial for development of new bioremediation strategies either in Tagus Estuary and/or in other Hg-contaminated aquatic environments. PMID- 28850005 TI - Mixture toxicity of five biocides with dissimilar modes of action on the growth and photosystem II efficiency of Chlamydomonas reinhardtii. AB - Biocides are extensively used and universally distributed. Some are highly toxic to algae, including antifoulants, herbicides, and fungicides. The inhibition of algal growth is an important regulatory endpoint for toxicity assessment of single compounds. However, in the aquatic environment, mixtures of compounds with unknown toxicities and mode of action (MoA) co-exist, making single toxicity assessment inadequate to ensure protection of the aquatic environment. This study aimed to characterize the combined toxicity of five environmentally relevant biocides-aclonifen, bifenox, dichlofluanid, metribuzin, and triclosan-with different MoA on growth and photosystem (PS) II efficiency of Chlamydomonas reinhardtii. For growth inhibition, herbicides bifenox and metribuzin were the most toxic, whereas triclosan was least. Only aclonifen and metribuzin exerted a significant effect on PSII, which was also correlated with reduced algal growth. The combined effect of the five biocides on growth inhibition was predominantly additive and presumed to act by independent MoA with potential antagonism observed only at low concentrations and at shorter duration of exposure. The binary mixture of metribuzin and aclonifen exhibited additive effects on diminished PSII efficiency, and effects were apparently induced by an independent MoA. Potential synergy of this mixture on growth inhibition was identified at the highest concentrations. Growth inhibition was found to be a more valuable endpoint for regulatory studies than PSII inhibition due to its environmental relevance, integration of multiple MoA and sensitivity. PMID- 28850006 TI - Components of Brief Admission as a Crisis Intervention for Patients With a Borderline Personality Disorder: Results of a Delphi Study. AB - BACKGROUND: Brief admission (BA) is a widely used intervention for patients with a borderline personality disorder but it has not yet clearly defined and still lacks clear operational standards. To fully develop this intervention, the relevant components need to be identified and clearly documented. OBJECTIVE: To obtain consensus on the components of BA as a crisis intervention for patients with a borderline personality disorder. DESIGN: Modified Delphi study. RESULTS: Consensus of 100% was reached for the components: "BA plan must be developed together with the patient"; "The BA intervention should be mentioned in the care plan for the patient"; "Not all behavior on the part of the patient has to be accepted during a BA"; and "The BA can only be offered together with treatment by a community care professional." CONCLUSION: Consensus on the components of BA was reached for 82 of the 90 components. This indicates a substantial degree of agreement on what BA should entail. PMID- 28850007 TI - Anticancer effects of seaweed compounds fucoxanthin and phloroglucinol, alone and in combination with 5-fluorouracil in colon cells. AB - Colorectal cancer therapy with 5-fluorouracil (5-Fu) frequently become ineffective due to resistance to this drug; and thus other effective compounds are essential for therapy. It is well-known marine brown seaweeds contain antioxidant compounds the carotenoid fucoxanthin (Fx) and polyphenolic compound phloroglucinol (Ph) which exerted diverse biological activities including antioxidant and anticancer. The aim of this study was to determine the anticancer activities of Fx or Ph alone as well as combination of each chemical with 5-Fu on two human colorectal cancer cell lines (HCT116 and HT29), with comparison to responses in a normal colon cell line (CCD-18Co). Effects of these compounds on cell viability, induction of DNA damage, and cell death were evaluated using MTT assay, comet assay, nuclear condensation assay, and Western blot. 5-Fu decreased cell viability in a concentration-dependent manner in HCT116 and HT29 cells but was not cytotoxic in CCD-18Co cells. 5-Fu induced DNA damage in HCT116 cells with induction of cell death, while no marked effects on DNA damage and cell death were observed in HT29 cells. Fx or Ph alone also reduced cell viability in both cancer cell lines but no apparent cytotoxic effect in CCD-18Co cells, except for Fx at 50 and 100 uM. Diminished cell viability was accompanied by induction of DNA damage (by Fx) and induction of cell death (by Ph). In combination with 5-Fu, Fx at 10 uM (in HCT116 and HT29 cells), and Ph at 300 uM (in HT29 cells) enhanced the cytotoxic effect of 5-Fu; however, no marked cytotoxicity was noted in CCD 18Co cells. Since Fx and Ph alone reduced cancer cell line viability without an effect on normal cells and when in combination enhanced the cytotoxic effect of 5 Fu only in colon cancer cells, these compounds seem promising as anticancer agents. PMID- 28850002 TI - The role of intracellular compartmentalization on tRNA processing and modification. AB - A signature of most eukaryotic cells is the presence of intricate membrane systems. Intracellular organization presumably evolved to provide order, and add layers for regulation of intracellular processes; compartmentalization also forcibly led to the appearance of sophisticated transport systems. With nucleus encoded tRNAs, it led to the uncoupling of tRNA synthesis from many of the maturation steps it undergoes. It is now clear that tRNAs are actively transported across intracellular membranes and at any point, in any compartment, they can be post-transcriptionally modified; modification enzymes themselves may localize to any of the genome-containing compartments. In the following pages, we describe a number of well-known examples of how intracellular compartmentalization of tRNA processing and modification activities impact the function and fate of tRNAs. We raise the possibility that rates of intracellular transport may influence the level of modification and as such increase the diversity of differentially modified tRNAs in cells. PMID- 28850008 TI - Welfare state and health inequalities under economic recession: Introduction. PMID- 28850009 TI - Tackling health inequality at the local level: Some critical reflections on the future of Norwegian policies. AB - AIM: In this paper we discuss recent developments in the policy to reduce health inequalities in Norway in relation to challenges and opportunities associated with tackling health inequality at the local level. METHODS: We discuss government documents and research findings on the implementation of policies to diminish health inequalities at the municipality level. Recent policy developments are briefly reviewed in relation to the 10-year strategy to reduce health inequalities passed by the Parliament in 2007. We then identify opportunities and obstacles to successful action on health inequalities at the local level. RESULTS: The 2012 Public Health Act represented a powerful reinforcement of the strategy to reduce health inequalities at all three levels of government: the national, the regional and the local. However, some aspects of the policies pursued by the current government are likely to make local action to tackle health inequality an uphill struggle. In particular, health equity policies that have hitherto been based on universalism and had a focus on the gradient seem to be running out of fuel. Other challenges are an insufficient capacity for effective action particularly in smaller municipalities, and a rather weak knowledge base, including systems to monitor social inequalities and a general lack of evaluations of trials and new initiatives. CONCLUSIONS: We conclude that the Public Health Act opened up many new opportunities, but that a number of municipalities face obstacles that they need to overcome to tackle health inequalities comprehensively. Furthermore, local efforts need to be coupled with sustained national momentum to be efficient. PMID- 28850010 TI - A fuzzy set approach to economic crisis, austerity and public health. Part I. European countries' conformity to ideal types during the economic downturn. AB - AIMS: This is the first part of a two-part paper that takes an explorative approach to assess crisis and austerity in European countries during the Great Recession. The ultimate aim of this two-part paper is to explore the "crisis austerity" thesis by Stuckler and Basu and assess whether it is the interplay between austerity and crisis, rather than the current economic crisis per se, that can led to deterioration in population health. In Part I of this paper we offer one way of operationalizing crisis severity and austerity. We examine countries as specific configurations of crisis and policy responses and classify European countries into "ideal types." METHODS: Cases included were 29 countries participating in the European Union Statistics on Income and Living Conditions (EU-SILC) surveys. Based on fuzzy set methodology, we constructed two fuzzy sets, "austerity" and "severe crisis." Austerity was measured by changes in welfare generosity; severe crisis was measured by changes in gross domestic product (GDP) per capita growth. RESULTS: In the initial phase of the Great Recession, most countries faced severe crisis combined with no austerity. From 2010-2011 onward, there was a divide between countries. Some countries consistently showed signs of austerity policies (with or without severe crisis); others consistently did not. CONCLUSIONS: The fuzzy set ideal-type analysis shows that the European countries position themselves, by and large, in configurations of crisis and austerity in meaningful ways that allow us to explore the "crisis-austerity" thesis by Stuckler and Basu. This exploration is the undertaking of Part II of this paper. PMID- 28850011 TI - Social and economic multipliers: What they are and why they are important for health policy in Europe. PMID- 28850012 TI - A fuzzy set approach to economic crisis, austerity and public health. Part II: How are configurations of crisis and austerity related to changes in population health across Europe? AB - AIMS: Based on the ideal type classification of European countries done in Part I of this paper, Part II explores whether the real 'danger' to public health is the interplay between austerity and crisis, rather than recession itself. METHODS: We constructed two fuzzy sets of changes in population health based on a pooled file of European Union Statistics on Income and Living Conditions (EU-SILC) data (2008 and 2013) including 29 European countries. The linear probability analyses of 'limiting long-standing illness' and 'less than good' health were restricted to the age group 20-64 years. We performed fuzzy set qualitative comparative analysis (fsQCA) and studied whether configurations of 'severe crisis' and 'austerity' were linked to changes in population health. RESULTS: Overall, the results of this fsQCA do not support the 'crisis-austerity' thesis. Results on 'less than good' health were highly inconsistent, while results on 'limiting long standing illness', contrary to the thesis, showed a two-path model. Countries with either no severe crisis or no austerity were subsets of the set of countries that experienced deteriorated health. Results also show that several countries combined both paths. CONCLUSIONS: This fuzzy set analysis does not support Stuckler and Basu's 'crisis-austerity' thesis, as those European countries that experienced recession and austerity were not consistently the countries with deteriorating health. There may be multiple reasons for this result, including analytical approach and operationalization of key concepts, but also resilient forces such as family support. We suggest more research on the topic based on more recent data and possibly other, or more, dimensions of austerity. PMID- 28850013 TI - Capacity to reduce inequities in health in Norwegian municipalities. AB - AIMS: One of the goals of the Norwegian Public Health Act is to reduce health inequities. The act mandates the implementation of policies and measures with municipalities and county municipalities to accomplish this goal. The article explores the prerequisites for municipal capacity to reduce health inequities and how the capacity is built and sustained. METHODS: The paper is a literature study of articles and reports using data from two surveys on the implementation of public health policies sent to all Norwegian municipalities: the first, a few months before the implementation of the Public Health Act in 2012; the second in 2014. RESULTS: Six dimensions are included in the capacity concept. Leadership and governance refers to the regulating tool of laws that frame the local implementation of public health policies. Municipalities implement inter-sectoral working groups and public health coordinators to coordinate their public health policies and measures. Financing of public health is fragmented. Possibilities for municipalities to enter into partnerships with county municipalities are not equally distributed. Owing to the organisational structures, municipalities largely define public health as health policy. Workforce and competence refers to the employment of public health coordinators, and knowledge development refers to the mandated production of health overviews in municipalities. CONCLUSIONS: The capacity to reduce health inequities varies among municipalities. However, if municipalities build on the prerequisites they control, establishing inter sectoral working groups and employing public health coordinators in authoritative positions, national governance instruments and regional resources may sustain their capacity. PMID- 28850014 TI - Trachoma in the Democratic Republic of the Congo: Results of 46 Baseline Prevalence Surveys Conducted with the Global Trachoma Mapping Project. AB - PURPOSE: Trachoma was suspected to be endemic in parts of the Democratic Republic of the Congo (DRC). We aimed to estimate prevalences of trachomatous inflammation follicular (TF), trichiasis, and water and sanitation (WASH) indicators in suspected-endemic Health Zones. METHODS: A population-based prevalence survey was undertaken in each of 46 Health Zones across nine provinces of DRC, using Global Trachoma Mapping Project methods. A two-stage cluster random sampling design was used in each Health Zone, whereby 25 villages (clusters) and 30 households per cluster were sampled. Consenting eligible participants (children aged 1-9 years and adults aged >=15 years) were examined for trachoma by GTMP-certified graders; households were assessed for access to WASH. RESULTS: A total of 32,758 households were surveyed, and 141,853 participants (98.2% of those enumerated) were examined for trachoma. Health Zone-level TF prevalence in 1-9-year-olds ranged from 1.9-41.6%. Among people aged >=15 years, trichiasis prevalences ranged from 0.02-5.1% (95% CI 3.3-6.8). TF prevalence in 1-9-year-olds was >=5% in 30 Health Zones, while trichiasis prevalence was >=0.2% in 37 Health Zones. CONCLUSION: Trachoma is a public health problem in 39 of 46 Health Zones surveyed. To meet elimination targets, 37 Health Zones require expanded trichiasis surgery services while 30 health zones require antibiotics, facial cleanliness and environmental improvement interventions. Survey data suggest that trachoma is widespread: further surveys are warranted. PMID- 28850015 TI - Blood manganese levels and associated factors in a population-based study in Southern Brazil. AB - Manganese (Mn) is an essential dietary nutrient for human health serving as a cofactor for many enzymes; however, exposure to excessive quantities of Mn may lead to toxicity with symptoms analogous to Parkinson's disease (PD). Population based biomonitoring is an effective tool for characterizing the body burden of environmental or occupational pollutants, including Mn. The objective of this cross-sectional study was to (1) estimate reference values (RV) for blood Mn in an adult population and (2) assess the variables that were associated with higher blood metal levels. A total of 947 adults, aged 40 years or older, were randomly selected in a city in Southern Brazil. Information on socioeconomic, dietary, lifestyle, and occupational background was collected by trained interviewers. Blood Mn levels (MUg/L) were analyzed by inductively coupled plasma-mass spectrometer (ICP-MS). The RV for blood Mn concentrations were obtained from the upper limits of the 95% confidence intervals (CI) of the 95th percentile distributions. Cluster analysis was performed to identify variables associated with high or low blood Mn concentrations. The RV for blood Mn levels in this study were 18.54 and 20.15 MUg/L for men and women, respectively. Mn blood concentrations decreased with age and were higher in females compared to males. No marked association was noted between blood Mn and smoking or drinking habits, education levels and socioeconomic status. Diastolic blood pressure was higher in a group of women approximately 54 years of age associated with elevated blood Mn levels. Important reference data stratified by demographic and lifestyle factors that may prove useful for future surveillance of environmental exposure to Mn and health risks associated with this metal are presented. PMID- 28850016 TI - Automatic determination of heart rates from microscopy videos of early life stages of fish. AB - Toxic effects of organic hydrophobic contaminants include impacts on fish heart rate (HR) and cardiac functioning. Thus, in ecotoxicology as well as aquaculture and even medicine, fish heart functioning plays an important role in application areas. The aim of this study was to assemble a pipeline of image processing and statistical techniques to extract HR information from microscopy videos of the embryo and larval stages of three species of fish (Atlantic cod, haddock, and Atlantic bluefin tuna). The method enables automatic processing for a large number of individuals, saving a significant amount of time compared with manual processing, while simultaneously eliminating the type of errors such a manual process might incur. PMID- 28850017 TI - Methylmercury exposure for 14 days (short-term) produces behavioral and biochemical changes in mouse cerebellum, liver, and serum. AB - Various studies on methylmercury (MeHg)-induced toxicity focused on the central nervous system (CNS) as a primary target. However, MeHg-mediated toxicity is related to metallic interaction with electrophilic groups, which are not solely restricted to the CNS, but these reactive groups are present ubiquitously in several systems/organs. The aim of this study was thus to examine MeHg-induced systemic toxicity in mice using a standardized neurotoxicology testing exposure model to measure cerebellar neurotoxicity by determining biochemical and behavioral parameters in the cerebellum. After 2 weeks exposure to MeHg (40 ug/ml; diluted in drinking water; ad libitum), adult male Swiss mice showed a marked motor impairment characteristic of cerebellar toxicity as noted in the following tests: rotarod, beam walking, pole, and hind limb clasping. MeHg treatment resulted in Hg deposition in the cerebellum as well as reduction in cerebellar weight, glutathione peroxidase (GPx) activity, and interleukin (IL)-6 levels. MeHg ingestion increased cerebellar glutathione reductase (GR) activity and brain-derived neurotrophic factor (BDNF) levels. In addition to cerebellar toxicity, MeHg treatment also elevated total and non-high density lipoprotein (non-HDL) cholesterol levels, as well as serum aspartate transaminase (AST) and alanine transaminase (ALT) enzymatic activities, systemic parameters. Increased liver weight and reduced serum urea levels were also noted in MeHg-exposed mice. Taken together, our findings demonstrated that a well-standardized exposure protocol to examine MeHg-induced neurotoxicity also produced systemic toxicity in mice, which was characterized by changes in markers of hepatic function as well as serum lipid homeostasis. PMID- 28850018 TI - Parkinson's Disease Subtypes Show Distinct Tradeoffs Between Response Initiation and Inhibition Latencies. AB - OBJECTIVES: In unpredictable situations, individuals often show tradeoffs between response initiation and inhibition speeds. We tested the hypothesis that Parkinson's disease (PD) motor subtypes differentially impact tradeoffs between these two action-oriented processes. We predicted that, compared to tremor dominant (TD) patients, predominant postural instability and gait dysfunction (PIGD) patients would show exacerbated tradeoffs between response initiation and inhibition in situations requiring the sudden potential need to interrupt an action. METHODS: Fifty-one PD patients (subdivided into PIGD [n=27] and TD [n=24]) and 21 healthy controls (HCs) completed a choice reaction task to establish baseline response initiation speed between groups. Subsequently, participants completed a stop-signal task which introduced an occasional, unpredictable stop stimulus. We measured changes in initiation speed in preparation of an unpredictable stop (i.e., proactive slowing) and inhibition latency (i.e., stop-signal reaction time). RESULTS: Compared to HCs, PD patients showed slower response initiation speeds in the choice reaction task. All groups showed proactive slowing in the stop-signal task but the magnitude was considerably larger in PIGD patients, almost twice as large as TD patients. PD patients, irrespective of motor subtype, showed longer inhibition latencies than HCs. CONCLUSIONS: PIGD and TD subtypes both showed exacerbated response inhibition deficits. However, PIGD patients showed much more pronounced proactive slowing in situations with an expected yet unpredictable need to stop action abruptly. This suggests that PIGD is accompanied by exaggerated tradeoffs between response initiation and inhibition processes to meet situational action demands. We discuss putative neural mechanisms and clinical implications of these findings. (JINS, 2017, 23, 665-674). PMID- 28850019 TI - Lipopolysaccharide-binding protein is a sensitive disease activity biomarker for rheumatoid arthritis. AB - OBJECTIVES: This study was performed to evaluate the performance and clinical significance of lipopolysaccharide-binding protein (LBP) as a disease activity biomarker in rheumatoid arthritis (RA). METHODS: LBP levels were measured by enzyme-linked immunosorbent assay (ELISA). The associations between LBP and the clinical and serological features of RA and its clinical significance as a RA disease activity biomarker were analysed. RESULTS: The serum level of LBP in RA was significantly elevated compared to those in OA, SLE, pSS and HC. The level of LBP in RA synovial fluid (SF) was higher than that in OA SF. LBP was significantly correlated with RA disease activity parameters such as ESR, CRP, tender joint counts, swelling joint counts and DAS28. Furthermore, LBP positive RA patients were more likely to show higher disease activity (DAS28>5.1), positive APF, interstitial lung disease and metabolic disorders. The predictive value of LBP on high disease activity was comparable with those of CRP and ESR. In 52.5% of the patients with active disease but negative in CRP /ESR, LBP was still positive and correlated with swelling joint counts. CONCLUSIONS: LBP is a sensitive serum biomarker to evaluate RA disease activity, and it could be a promising laboratory marker to assist RA disease activity assessment in active RA patients with negative ESR or CRP. PMID- 28850020 TI - An exploratory study to determine whether infliximab modifies levels of rheumatoid factor and antibodies to cyclic citrullinated peptides in rheumatoid arthritis patients. AB - OBJECTIVES: The aim of this study was to investigate the relationship between serum infliximab (IFX) levels and changes of RF and ACPA levels in patients with rheumatoid arthritis (RA). METHODS: Enzyme-linked immunosorbent assays (ELISA) [Promonitor(r) IFX R1 (version 2) (Progenika Biopharma, Spain)] were used to measure drug levels and antidrug-antibodies (ADAb) in IFX RA-treated patients (n=19). Disease activity was assessed using DAS28. IgM rheumatoid factor (RF) and IgM, IgA and IgG anti-cyclic citrullinated peptide (ACPA) were determined through ELISA. RESULTS: A significant decrease in RF (p=0.01), ACPA IgG (p=0.007), IgM (p=0.01) and IgA (p=0.03) was observed in patients presenting adequate levels of serum IFX. No significant changes to RF or ACPA were observed in patients with undetectable IFX. CONCLUSIONS: Data from this study support the hypothesis that the anti-TNF antagonist IFX downregulates autoantibody levels in RA patients when IFX levels are detectable. Larger-scale studies need to be performed to establish RF and ACPA presence as therapeutic response predictive factors. PMID- 28850021 TI - Suppression of active, but not total MMP-3, is associated with treatment response in a phase III clinical study of rheumatoid arthritis. AB - OBJECTIVE: Biologics for rheumatoid arthritis (RA) patients with moderate to severe disease may preserve joint function. Matrix metalloproteinase 3 (MMP-3), a key tissue degrading protease, is highly elevated in RA. MMP-3, which measures the total pool of circulating MMP-3 species (cMMP3), is a commonly measured biomarker in rheumatology. The aim was to investigate the association of activated MMP-3 (actMMP3) species with treatment response compared to cMMP-3. METHODS: The LITHE biomarker study (n=741) was a 1-year phase III, double-blind, placebo-controlled, parallel group study of TCZ in RA patients on stable methotrexate. cMMP-3 and actMMP-3 were assessed in fasting serum at baseline, week 4, 16, 24 and 52. Patients not achieving ACR20 remission at week 16 or 28 received rescue treatment (escapers). Spearman's correlation was analysed between biomarker baseline level or biomarker delta and clinical measures. Changes in biomarker levels were studied as a function of time and treatment. RESULTS: ActMMP-3 16-week change in treatment groups was predictive of 1-year radiographic progression; a small change in actMMP3 was equal to worsening radiographics. Baseline cMMP-3 was associated with 52-weeks' radiographic status and cMMP3 16 weeks' change was predictive of 1-year change in disease activity. ActMMP-3 was dose-dependently decreased by TCZ, and escapers decreased in actMMP-3 upon treatment. CONCLUSIONS: ActMMP-3 and cMMP-3 were found to be efficacy biomarkers of TCZ and actMMP-3 were able to differentiated doses. Moreover, the suppression of actMMP3, but not cMMP3 was associated with treatment response. This study illustrates that two biomarkers of the same protein may have different predictive capacities. PMID- 28850022 TI - Cardiovascular risk stratification in axial spondyloarthritis: carotid ultrasound is more sensitive than coronary artery calcification score to detect high cardiovascular risk axial spondyloarthritis patients. AB - OBJECTIVES: To determine the ability of Coronary Artery Calcification Score (CACS) and carotid ultrasonography (US) to detect high cardiovascular (CV) risk axial spondyloarthritis (ax-SpA) patients. METHODS: CACS and carotid plaques were assessed in 66 consecutive ax-SpA patients (51 fulfilling criteria for ankylosing spondylitis and 15 for non-radiological ax-SpA) without history of CV events. The Systematic Coronary Risk Evaluation (SCORE) calculated using total cholesterol (TC-SCORE) was assessed in 64 patients without diabetes mellitus or chronic kidney disease. RESULTS: The mean age of the patients and the median disease duration since the onset of symptoms were 49.3 and 14.5 years. HLA-B27 was positive in 47 (75%) patients. CV risk was categorised according to the TC-SCORE as low (<1%; n=33), moderate (>=1% and<5%; n=30) and high/very high risk (>=5%; n=1). Most patients with low TC-SCORE (27/33; 82%) had normal CACS (zero), and only 1/33 had CACS >100. However, carotid plaques were observed in patients with CACS=0 (12/37; 32%) and CACS 1-100 (10/16; 62%). The sensitivity to detect high/very high CV risk using only the TC-SCORE was very low as the algorithm only detected 1/33 (3%) of patients with high/very high CV risk. Ten of 33 (30%) high/very high CV risk patients were identified using a chart TC-SCORE risk >=5% plus the presence of CACS >=100 in patients with moderate TC-SCORE. The replacement of CACS with carotid US identified a higher number of high/very high CV risk patients (22/33; 67%). CONCLUSIONS: Carotid US is more sensitive than CACS for the detection of high CV risk in ax-SpA patients. PMID- 28850023 TI - Involvement of pentraxin-3 in anti-neutrophil cytoplasmic antibody production induced by aluminum salt adjuvant. AB - OBJECTIVES: Pentraxin 3 (PTX3) is a multifunctional soluble factor. PTX3 can be involved in the regulation of vasculitis and is expressed in the cytoplasm of neutrophils. As anti-neutrophil cytoplasmic antibody (ANCA) is recognised as a cause of vasculitis, we aimed to discover the role of PTX3 in ANCA production in vivo. METHODS: To this end, we used aluminum salt (alum), which induces neutrophil extracellular traps, as an adjuvant for producing anti-myeloperoxidase ANCA (MPO-ANCA). Specifically, we intraperitoneally injected alum and recombinant MPO (rMPO) into MPO-deficient mice and then measured the concentration of anti MPO IgG in their blood. To show the involvement of extracellular PTX3 in this model, we assessed PTX3 protein content and host double-stranded DNA levels in the mice's peritoneal fluid after alum injection. In addition, we simultaneously administered recombinant PTX3, rMPO and alum to MPO-deficient mice to assess the function of PTX3 in producing anti-MPO IgG in vivo. RESULTS: Anti-MPO IgG was produced by the alum + rMPO immunisation model in MPO-deficient but not wildtype mice. Injection of alum induced extracellular PTX3 as well as double-stranded DNA and dead cells in MPO-deficient mice. Simultaneous injection of recombinant PTX3 with rMPO and alum attenuated the production of anti-MPO IgG in MPO-deficient mice. CONCLUSIONS: Our current findings provide evidence that PTX3 attenuates the production of murine MPO-ANCA. PMID- 28850024 TI - Cilostazol inhibits the expression of hnRNP A2/B1 and cytokines in human dermal microvascular endothelial cells. AB - OBJECTIVES: hnRNP A2/B1 has been identified as a target antigen of anti endothelial cell IgA antibody in patients with Behcet's disease (BD). In addition, increased expression of cellular hnRNP A2/B1 is stimulated by Streptococcus sanguinis or the sera from patients with BD. We aimed to investigate the effects of cilostazol on the expression of hnRNP A2/B1 and chemokines in human dermal microvascular endothelial cells (HDMECs). METHODS: Expression of hnRNP A2/B1, cytokines, and chemokines in HDMECs was induced by tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and lipopolysaccharide (LPS). HDMECs were treated with cilostazol (10 MUM) and the inhibitory effects were evaluated with real-time polymerase chain reaction and immunocytochemistry. RESULTS: Expression of hnRNP A2/B1, CXCL1, CXCL2, CXCL8, and IL-1beta mRNA was significantly increased in HDMECs treated with all three stimulants. In addition, mRNA expression of hnRNP A2/B1 and inflammatory mediators was significantly inhibited in HDMECs treated with various stimulants with cilostazol pretreatment. Immunocytochemistry demonstrated that cilostazol pretreatment effectively inhibited the stimulant-induced increased expression of hnRNP A2/B1 in the nucleus and cytoplasm of HDMECs. CONCLUSIONS: Cilostazol pretreatment can reduce the excessive expression of inflammatory cytokines and chemokines and hnRNP A2/B1 by the BD-related stimulants, including TNF-alpha, IL 1beta, and LPS, in HDMECs. We suggest that cilostazol may have therapeutic efficacy in inhibiting the major inflammatory reaction in the pathogenesis of BD. PMID- 28850025 TI - Improved adalimumab dose decision with comprehensive diagnostics data. AB - OBJECTIVES: Monoclonal antibodies are important in the treatment of rheumatoid arthritis (RA). This is the first trial to monitor the effect of adalimumab dose escalation in persistently active RA. The aim of this study was to identify the response to adalimumab to improve the basis for making decision in relation to actual drug capacity in serum. METHODS: The disease activity of RA patients was assessed with CDAI and DAS28 before administration of additional 40 mg adalimumab one week after standard injection. Serum samples were analysed using the recoveryELISA technology, a combination of sandwich ELISA and competitive assay. The recoveryELISA measure the concentrations of free TNF-alpha, drug level, and the remaining active adalimumab in the patients' sera. An adalimumab concentration of 5.0-10.0 g/mL was defined as the targeted therapeutic window. RESULTS: Five of 8 patients achieved moderate EULAR response by dose escalation. The results of the free adalimumab and TNF-alpha neutralisation measurements allowed a separation of the cohort (n=17) into three groups. Group 1 represents 18% of the patients with free adalimumab level higher 30.0 MUg/mL and TNF-alpha neutralisation above 95%. Group 2 (47%) consists of patients within the therapeutic window with balanced free adalimumab and TNF-alpha neutralisation values. Group 3 contains 35% of the cohort with low concentrations of free adalimumab and lowest remaining TNF-alpha-neutralisation capacity. Anti-drug antibodies were detected in four patients but did not prevent response to treatment. CONCLUSIONS: Drug and antigen monitoring using recoveryELISA may support dose decision to avoid unnecessary switch in medication or possible overtreatment. PMID- 28850026 TI - Interleukin-35 inhibits angiogenesis through STAT1 signalling in rheumatoid synoviocytes. AB - OBJECTIVES: We studied the anti-angiogenic effect of interleukin-35 (IL-35) by investigating its effects on signal transmission through the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway in fibroblast-like synoviocytes (FLS). METHODS: Using the collagen-induced arthritis (CIA) model of rheumatoid arthritis (RA), we derived and cultured FLS, stimulated FLS with IL-35 at different concentrations and examined the expression levels of mRNA and protein of both vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), endostatin, TNF-alpha, and IL-6 using reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting. We used Western blotting to study the effects of IL-35 on the function of the JAK-STAT pathway in FLS. RESULTS: IL-35 treatment inhibited the expression of VEGF, FGF-2, TNF-alpha and IL-6, and increased the expression of endostatin in FLS. Western blotting showed that IL-35 treatment of CIA-derived FLS resulted in signalling through STAT1, but not through STAT3 or STAT5. CONCLUSIONS: IL-35 signalling through STAT1 and inhibition of the expression of mediators of angiogenesis and inflammation in FLS provide a likely mechanism for anti-angiogenic effects seen in experimental models of RA. Our data suggest that IL-35 and its signalling pathway represent a therapeutic target for the treatment of RA and other angiogenesis-related diseases. PMID- 28850027 TI - MiR-338-5p suppresses rheumatoid arthritis synovial fibroblast proliferation and invasion by targeting ADAMTS-9. AB - OBJECTIVES: We proposed to find out the role of miR-338-5p played in cell proliferation and invasion of rheumatoid arthritis synovial fibroblasts (RASFs) by regulating ADAMTS-9. METHODS: QRT-PCR was performed to quantify the miR-338-5p and ADAMTS-9 mRNA expression in RA sample tissues and normal synovial tissues. Western blot was performed to evaluate the ADAMTS-9 protein levels in transfected RASFs. Luciferase reporter assays were used to demonstrate whether miR338-5p directly targets ADAMTS-9. MTT, Transwell and wound healing assays were respectively used to evaluate the growth and mobility of RASFs. Flow cytometry was applied to detect cell cycle distributions and apoptosis rates in transfected RASFs. RESULTS: MiR-338-5p was significantly downregulated in rheumatoid arthritis (RA) tissues while ADAMTS-9 was obviously overexpressed (p<0.001). Luciferase reporter assays demonstrated that miR-338-5p directly targeted ADAMTS 9. Moreover, overexpression of miR-338-5p suppressed RASFs biological functions and induced G0/G1 arrest and apoptosis of RASFs (p<0.001), while all the effects could be efficiently attenuated by the upregulation of ADAMTS-9. CONCLUSIONS: By inhibiting ADAMTS-9, miR-338-5p suppressed the proliferation and metastasis of rheumatoid arthritis synovial fibroblasts. Thus, replenishing miR-338-5p may be a potential therapy for the clinic management of RA. PMID- 28850028 TI - Evaluation of non-contrast MRI biomarkers in lupus nephritis. AB - OBJECTIVES: To investigate the association of novel non-contrast MRI biomarkers with standard measurements of renal function and renal disease activity in lupus. METHODS: A pilot study of lupus nephritis (LN) and lupus non-nephritis (LNN) patients, and healthy volunteers (HV), was undertaken. Multi-modal renal MRI was performed including sequences for arterial spin labelling (ASL) measuring blood flow, diffusion tensor imaging (DTI), measuring microstructural disruption, and effective transverse relaxation time (T2*) which is a biomarker of micro haemorrhage. MRI measurements were compared with urinary protein creatinine ratio (uPCR) and estimated glomerular filtration rate (eGFR) measurements in the whole study population, then differences in imaging measurements between the groups were explored. RESULTS: 21 patients (6 LN, 8 LNN and 7 HV) completed the study, although ASL data were not available in 4 subjects. In the whole cohort, eGFR correlated significantly with the apparent diffusion coefficient measurement from DTI in the medulla (r=0.47, p=0.03). uPCR correlated strongly with the fractional anisotropy (FA) DTI measurement in the cortex and moderately with T2* measurements (rho=-0.71, p<0.001 and rho=-0.53, p=0.013, respectively). Delayed blood flow to the medulla was found in LN subjects and there was a trend towards lower FA values in the cortex, suggesting micro-structural disruption (p=0.04 and p=0.07, respectively). CONCLUSIONS: This preliminary study demonstrates that non contrast renal MRI biomarkers are associated with standard measures of disease activity in lupus. The potential utility of these non-invasive biomarkers warrants further investigation, as there is an unmet need for reliable biomarkers of disease activity in lupus nephritis. PMID- 28850029 TI - Liver safety of non-tumour necrosis factor inhibitors in rheumatic patients with past hepatitis B virus infection: an observational, controlled, long-term study. AB - OBJECTIVES: The risk of hepatitis B virus (HBV) reactivation with non-tumour necrosis factor inhibitor (non-TNFi) biologic agents in patients with rheumatic diseases and past HBV infection has not been definively elucidated. We assessed the comparative safety of non-TNFi and TNFi biologic agents in such patients in real-life clinical settings. METGODS: We carried out a retrospective cohort study from the Department of Rheumatology, University Hospital of Heraklion. Patients who received abatacept (ABA), tocilizumab (TCZ) or rituximab (RTX) during the period 2003-2016 and were HbsAg(-), anti-HBc(+), anti-HBs(+/-) at baseline, were monitored for HBV reactivation. Patients treated with TNFi agents during the same period were used as a control group. RESULTS: 101 cases of non-TNFi (39 ABA, 32 RTX and 30 TCZ) and 111 cases of TNFi treatment were identified. In non-TNFi, 76 cases (75.2%) were anti-HBc(+)/anti-HBs(+) and 25 (24.8%) were anti-HBc(+)/anti HBs(-), as compared to 82 (73.9%) and 29 (26.1%) in TNFi-treated, respectively. After a median (IQR) observation of 24.0 (34.7) months, two cases (2.0%) of HBV reactivation were identified in the non-TNFi group; one with ABA, successfully treated with entecavir, and one fatal case with RTX and prior exposure to cyclophosphamide. No reactivation was observed in the TNFi group (p=0.226 vs. non TNFi). Alphanti-HBs titres were significantly reduced compared to baseline in the non-TNFi group [median (IQR) 203.9 (954.7) mIU/ml before treatment versus 144.9 (962.9) mIU/ml after treatment, p=0.03]. CONCLUSIONS: Two cases of HBV reactivation highlight the risk for this complication in patients with past HBV infection under biologic therapy. PMID- 28850030 TI - Increasing suppression of saccade-related transients along the human visual hierarchy. AB - A key hallmark of visual perceptual awareness is robustness to instabilities arising from unnoticeable eye and eyelid movements. In previous human intracranial (iEEG) work (Golan et al., 2016) we found that excitatory broadband high-frequency activity transients, driven by eye blinks, are suppressed in higher-level but not early visual cortex. Here, we utilized the broad anatomical coverage of iEEG recordings in 12 eye-tracked neurosurgical patients to test whether a similar stabilizing mechanism operates following small saccades. We compared saccades (1.3 degrees -3.7 degrees ) initiated during inspection of large individual visual objects with similarly-sized external stimulus displacements. Early visual cortex sites responded with positive transients to both conditions. In contrast, in both dorsal and ventral higher-level sites the response to saccades (but not to external displacements) was suppressed. These findings indicate that early visual cortex is highly unstable compared to higher level visual regions which apparently constitute the main target of stabilizing extra-retinal oculomotor influences. PMID- 28850032 TI - Charlottesville: symptomatic of a broader pain. PMID- 28850033 TI - Minamata Convention on mercury: a contemporary reminder. PMID- 28850034 TI - The UK's inadequate plan for reducing childhood obesity. PMID- 28850031 TI - Repression by PRDM13 is critical for generating precision in neuronal identity. AB - The mechanisms that activate some genes while silencing others are critical to ensure precision in lineage specification as multipotent progenitors become restricted in cell fate. During neurodevelopment, these mechanisms are required to generate the diversity of neuronal subtypes found in the nervous system. Here we report interactions between basic helix-loop-helix (bHLH) transcriptional activators and the transcriptional repressor PRDM13 that are critical for specifying dorsal spinal cord neurons. PRDM13 inhibits gene expression programs for excitatory neuronal lineages in the dorsal neural tube. Strikingly, PRDM13 also ensures a battery of ventral neural tube specification genes such as Olig1, Olig2 and Prdm12 are excluded dorsally. PRDM13 does this via recruitment to chromatin by multiple neural bHLH factors to restrict gene expression in specific neuronal lineages. Together these findings highlight the function of PRDM13 in repressing the activity of bHLH transcriptional activators that together are required to achieve precise neuronal specification during mouse development. PMID- 28850035 TI - Robert Koch Institut: towards digital epidemiology. PMID- 28850036 TI - Time to talk about menstruation: a response. PMID- 28850037 TI - Leonardo's mistake: not evidence-based medicine? PMID- 28850038 TI - The oldest-old in China. PMID- 28850039 TI - The oldest-old in China. PMID- 28850040 TI - The oldest-old in China - Authors' reply. PMID- 28850042 TI - Department of Error. PMID- 28850041 TI - Improving post-surgical management of resected pancreatic cancer. PMID- 28850043 TI - On the critical temperature discontinuity at the theoretical bcc-fcc phase transition in compressed selenium and tellurium superconductors. AB - Recent hydrides-driven advent in the high-pressure phonon-mediated superconductivity motivates research on chemical elements which compound with hydrogen. It is desired that such elements should allow chemical pre-compression of hydrogen to assure the induction of the superconducting phase with the high transition temperature (T C). Herein, we present detailed theoretical insight into the properties of the superconducting state induced under pressure (p) in two of such component elements, namely selenium (Se) and tellurium (Te) at [Formula: see text] GPa and [Formula: see text] GPa, respectively. The assumed external pressure conditions allow us to conduct our analysis just above previously theoretically predicted bcc-fcc structural phase transition of Se and Te, and identify the possible associated discontinuity effect of the critical temperature. In particular, our numerical analysis is conducted within Migdal Eliashberg formalism, due to the confirmed electron-phonon pairing mechanism and relatively high electron-phonon coupling constant in the materials of interest. We predict that T C values in Se and Te equal 8.13 K and 5.96 K, respectively, and mark the highest critical temperature values for these elements within the postulated fcc phase. Additionally, we supplement these results by the estimated maximum values of the superconducting energy band gap and the effective mass of electrons. We predict that all these parameters can be used as a guidelines for experimental observation of the critical temperature discontinuity and the corresponding bcc-fcc phase transition in Se and Te superconductors. Moreover, we show that the thermodynamics of superconducting phase in both elements may exhibit deviations from the conventional estimates of the Bardeen-Cooper Schrieffer theory, and suggest existence of the strong-coupling and retardation effects. Finally, we note that our results can be also instructive for future screening of chemical elements for applications in superconducting hydrides. PMID- 28850044 TI - Non-invasive lung disease diagnostics from exhaled microdroplets of lung fluid: perspectives and technical challenges. AB - The combination of ultra-sensitive assay techniques and recent improvements in the instrumentation used to collect microdroplets of lung fluid (MLF) from exhaled breath has enabled the development of non-invasive lung disease diagnostics that are based on MLF analysis. In one example of this approach, electrospun nylon filters were used to collect MLFs from patients with pulmonary tuberculosis. The filters were washed to obtain liquid probes, which were then tested for human immunoglobulin A (h-IgA) and fractions of h-IgA specific to ESAT 6 and Psts-1, two antigens secreted by Mycobacterium tuberculosis. Probes collected for 10 min contained 100-1500 fg of h-IgA and, in patients with pulmonary tuberculosis, a portion of these h-IgA molecules showed specificity to the secreted antigens. Separate MLFs and their dry residues were successfully collected using an electrostatic collector and impactor developed especially for this purpose. Visualization of MLF dry residues by atomic force microscopy made it possible to estimate the lipid content in each MLF and revealed mucin molecules in some MLFs. This exciting new approach will likely make it possible to detect biomarkers in individual MLFs. MLFs emerging from an infection site ('hot' microdroplets) are expected to be enriched with infection biomarkers. This paper discusses possible experimental approaches to detecting biomarkers in single MLFs, as well as certain technological problems that need to be resolved in order to develop new non-invasive diagnostics based on analysing biomarkers in separate MLFs. PMID- 28850045 TI - Distinguishing advective and powered motion in self-propelled colloids. AB - Self-powered motion in catalytic colloidal particles provides a compelling example of active matter, i.e. systems that engage in single-particle and collective behavior far from equilibrium. The long-time, long-distance behavior of such systems is of particular interest, since it connects their individual micro-scale behavior to macro-scale phenomena. In such analyses, it is important to distinguish motion due to subtle advective effects-which also has long time scales and length scales-from long-timescale phenomena that derive from intrinsically powered motion. Here, we develop a methodology to analyze the statistical properties of the translational and rotational motions of powered colloids to distinguish, for example, active chemotaxis from passive advection by bulk flow. PMID- 28850046 TI - Photoactivity properties of ZnO doped with cerium ions: an EPR study. AB - In the present study, we investigated the effect of cerium doping in zinc oxide matrix, used as photoactive material. Cerium ions into the matrix of ZnO can act like a 'trap' for the electrons, lowering the e -/h + recombination rate and so increasing the photocatalytic efficiency of the ZnO. We synthesised doped samples using a simple precipitation route. The amount of dopant used was, 1 and 10% molar. The samples have been studied via x-ray diffraction measurements for the structural characterisation; UV-visible diffuse reflectance was used for the optical analysis; Branauer-Emmett-Teller (BET) model for the measurement of the surface area. Finally, the samples have been analysed via electron paramagnetic resonance (EPR) spectroscopy for the electronic characterisation and for testing their photoactivity. The spin trapping technique was also use to measure the amount of stable radical adducts formed via reaction of OH* radicals with molecules of the DMPO (5,5-dimethyl-1-pyrroline-N-oxide) spin probe. PMID- 28850047 TI - Superconductivity at 7.4 K in few layer graphene by Li-intercalation. AB - Superconductivity in graphene has been highly sought after for its promise in various device applications and for general scientific interest. Ironically, the simple electronic structure of graphene, which is responsible for novel quantum phenomena, hinders the emergence of superconductivity. Theory predicts that doping the surface of the graphene effectively alters the electronic structure, thus promoting propensity towards Cooper pair instability (Profeta et al (2012) Nat. Phys. 8 131-4; Nandkishore et al (2012) Nat. Phys. 8 158-63) [1, 2]. Here we report the emergence of superconductivity at 7.4 K in Li-intercalated few-layer graphene (FLG). The absence of superconductivity in 3D Li-doped graphite underlines that superconductivity in Li-FLG arises from the novel electronic properties of the 2D graphene layer. These results are expected to guide future research on graphene-based superconductivity, both in theory and experiments. In addition, easy control of the Li-doping process holds promise for various device applications. PMID- 28850048 TI - Role of lattice inhomogeneities on the electronic properties of selenium deficient Bi2Se3. AB - Inter-layer coupling is widely considered to play a crucial role in tuning electronic properties of 3D topological insulators. The aim of this study is to evaluate the role of crystallographic defects on inter-layer coupling in the Se deficient Bi2Se3 (0 0 3) crystal using extended x-ray absorption fine structure spectroscopy (EXAFS) technique. EXAFS measurements at Se-K and Bi-L3 edges reveal distinct local geometry around these atomic sites. It has been observed that short inter-layer Bi-Se and Se-Se bonds emerge in the sample. This additional structural motif coexists with the conventional crystallographic arrangement. Within the quintuple layer Bi-Se bonds are preserved with slight compression in intra-planer Bi-Bi and Se-Se distance and overall reduction in c/a ratio. These findings suggest formation of deformed lattice region, localized and dispersed inhomogeneously within the sample. Such inhomogeneities have also resulted in interesting transport properties such as quantum Hall effect (QHE), large linear magnetoresistance and pi-Berry phase in Shubnikov-de Haas (SdH) oscillations of bulk crystals. Detailed analyses of magnetotransport measurements suggest that tuning of inter-layer coupling by local lattice deformation is the key factor for unusual transport properties. Role of axial strain, and stacking faults generated due to defects and charged Se vacancies are discussed to understand the observed electronic properties. PMID- 28850049 TI - SIMULTANEOUS CHOROIDAL AND RETINAL METASTASES FROM LUNG CARCINOMA. AB - BACKGROUND: Intraocular metastasis is most commonly found within the choroid because of its luxurious blood supply, whereas metastasis to the retina, from a separate blood supply, is very rare. We report a rare case of synchronous metastases from lung carcinoma to the choroid of the right eye and the retina of the left eye and a complaint of low vision in the right eye. METHODS: We report a 63-year-old woman with progressive reduction of vision in her right eye for 1 year without previous history of cancer. The patient underwent comprehensive ophthalmic examination that included a multimodal evaluation: near-infrared reflectance scanning laser ophthalmoscopy, blue autofluorescence, and enhanced depth imaging spectral domain optical coherence tomography (EDI SD-OCT; Heidelberg Engineering, Heidelberg, Germany). RESULTS: Ophthalmoscopic examination revealed a yellow choroidal mass measuring 6 * 6 mm with overlying subretinal fluid and involving the macular area in the right eye. In the left eye, there was a superior juxtapapillary yellow-colored mass involving the retina and measuring 1 * 1 mm. Optical coherence tomography revealed the subretinal fluid contouring a dome-shaped choroidal mass in the right eye and intraretinal nodular tumor superior to the optic disk of the left eye. Chest computed tomography revealed a pulmonary nodule measuring 2.5 mm * 1.4 mm, and biopsy of the liver metastasis confirmed the diagnosis of mucinous lung carcinoma. CONCLUSION: The final diagnosis was presumed choroidal metastasis in the right eye and retinal metastasis in the left eye from underlying mucinous carcinoma of the lung. PMID- 28850050 TI - MACULAR HOLE IN A YOUNG PATIENT AFFECTED BY FAMILIAL EXUDATIVE VITREORETINOPATHY. AB - PURPOSE: To report a case of familial exudative vitreoretinopathy in which genetic testing was used to confirm the diagnosis with a new mutation identified in FZD4 gene. METHODS: A 28-year-old girl was addressed to our clinic for surgical management of a macular hole possibly associated with Coats disease. Multimodal imaging was performed including fundus photography, fundus autofluorescence, optical coherence tomography, fluorescein, and indocyanine green angiography. RESULTS: On examination, visual acuity was light perception secondary to previous retinal detachment and 20/32, respectively, in her right and left eye. Clinical and imaging evaluations showed findings suggestive for familial exudative vitreoretinopathy. Spectral domain optical coherence tomography study of the macula showed a macular pucker with lamellar macular hole and a conservative approach was preferred. After 18 months of observation, the patient underwent surgery secondary to the onset of a full thickness macular hole. After 24 months, the patient's vision was 20/32. Genetic testing was used to confirm the diagnosis demonstrating 2 new mutations in FZD4 gene. CONCLUSION: Our case emphasizes the importance of a prompt recognition of familial exudative vitreoretinopathy disease also using gene testing and a close follow-up to prevent and manage possible complications. PMID- 28850051 TI - EXOGENOUS MENINGOCOCCAL ENDOPHTHALMITIS: A CASE REVIEW. AB - PURPOSE: We describe a rare case of exogenous endophthalmitis due to Neisseria meningitidis, of which only two have previously been published. METHODS: Retrospective audit of patient's medical notes. PATIENTS: An 82-year-old man from The Royal Victoria Eye and Ear Hospital, a tertiary ophthalmic service in Melbourne, Australia. RESULTS: Found to have exogenous endophthalmitis from a leaking, filtering bleb. CONCLUSION: This seems to be the first case in which a conjunctival swab was diagnostic. These cases demonstrate that it is reasonable to consider meningococcal endophthalmitis in systemically well patients with leaky filtering blebs. Of note for occupational health and safety, prophylaxis is not required for staff contacts treating these patients. PMID- 28850052 TI - Prehospital Management of Pediatric Hanging. AB - OBJECTIVES: Hanging may inflict laryngotracheal injuries and increase the potential for difficult airway management. We describe the management of pediatric hangings attended by an urban physician-led prehospital trauma service to provide information on a clinical situation encountered infrequently by most acute care clinicians. METHODS: Retrospective trauma registry-based observational study of all children younger than 16 years attended with hanging as mechanism of injury in the period between 2000 and 2014. RESULTS: Twenty-three thousand one hundred thirty patients were attended; 2415 (10%) of which were children. Of these, 32 cases (<1%) were pediatric hanging (1 case excluded due to missing data). There were 22 (71%) boys and 9 (29%) girls. Median age was 13 years. There was suicidal intent in 23 (74%) cases, and in 8 (26%) cases, hanging was accidental. There were 17 (55%) deaths, of which 14 (82%) were suicides.The doctor-paramedic team intubated 25 (80%) patients, with a 100% success rate. One (3%) patient was managed with a supraglottic airway device, and 5 (16%) patients did not require any advanced airway management. CONCLUSIONS: Pediatric hanging is rare, but has a high mortality rate. Attempted suicide is the leading cause of hangings in children and preventive measures should target psychiatric morbidity. Despite concerns about airway edema or laryngeal injury, experienced doctor paramedic teams had no failed airway attempts. PMID- 28850054 TI - Full Tensor Eigenvector Analysis on Air-Borne Magnetic Gradiometer Data for the Detection of Dipole-Like Magnetic Sources. AB - The detection of dipole-like sources, such as unexploded ordnances (UXO) and other metallic objects, based on a magnetic gradiometer system, has been increasingly applied in recent years. In this paper, a novel dipole-like source detection algorithm, based on eigenvector analysis with magnetic gradient tensor data interpretation is presented. Firstly, the theoretical basis of the eigenvector decomposition of magnetic gradient tensor is analyzed. Then, a detection algorithm is proposed by using the properties of the tensor eigenvector decomposition to locate dipole-like magnetic sources. The algorithm can automatically detect magnetic dipole-like sources without estimating the magnetic moment direction. It performs well for locating weak, anomalous dipole-like sources in air-borne magnetic data through quantitative interpretation. The effectiveness of the proposed algorithm has been demonstrated in the designed synthetic experiment. Finally, an air-borne magnetic field data taken at high altitude with exact source position information is used to validate the practicality of the proposed algorithm. All of the experiments prove that the proposed algorithm is suitable for magnetic dipole-like source detecting and air borne magnetic gradiometer data interpretation. PMID- 28850053 TI - IL-23 and Th17 Disease in Inflammatory Arthritis. AB - IL-23, which is composed of p19 and p40 subunits, is a proinflammatory cytokine that contributes to the formation and maintenance of Th17 cells in inflammatory autoimmune diseases. IL-23 is a human osteoclastogenic cytokine and anti-IL-23 antibody attenuates paw volume and joint destruction in CIA rats. IL-23 levels in serum and synovial fluid are high in rheumatoid arthritis (RA) patients, and IL 23 may be a useful biomarker for the diagnosis of RA. In addition, IL-23 affects the pathogenesis of inflammation and bone destruction through interaction with other cytokines such as IL-17 and TNF-alpha. Furthermore, polymorphisms of IL23R are a risk factor for ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which indicates that IL-23 is also involved in the pathogenesis of spondyloarthritis (SpA). Finally, IL-17 and IL-23 inhibitors reduce the clinical manifestations of SpA. Thus, the IL-23/Th17 pathway is a therapeutic target for the treatment of inflammatory arthritis. PMID- 28850055 TI - Geometric Calibration and Accuracy Verification of the GF-3 Satellite. AB - The GF-3 satellite is the first multi-polarization synthetic aperture radar (SAR) imaging satellite in China, which operates in the C band with a resolution of 1 m. Although the SAR satellite system was geometrically calibrated during the in orbit commissioning phase, there are still some system errors that affect its geometric positioning accuracy. In this study, these errors are classified into three categories: fixed system error, time-varying system error, and random error. Using a multimode hybrid geometric calibration of spaceborne SAR, and considering the atmospheric propagation delay, all system errors can be effectively corrected through high-precision ground control points and global atmospheric reference data. The geometric calibration experiments and accuracy evaluation for the GF-3 satellite are performed using ground control data from several regions. The experimental results show that the residual system errors of the GF-3 SAR satellite have been effectively eliminated, and the geometric positioning accuracy can be better than 3 m. PMID- 28850056 TI - Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features. AB - Microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC) comprises Xp11 tRCC and t(6;11) RCC. Due to the presence of fusion genes, Xp11 tRCC and t(6;11) RCC are also known as TFE3- and TFEB rearranged RCC, respectively. TFE3 and TFEB belong to the MiT family, which regulates melanocyte and osteoclast differentiation, and TFE3- and TFEB rearranged RCC show characteristic clinicopathological and immunohistochemical features. Recent studies identified the fusion partner-dependent clinicopathological and immunohistochemical features in TFE3-rearranged RCC. Furthermore, RCC with chromosome 6p amplification, including TFEB, was identified as a unique subtype of RCC, along with ALK-rearranged RCC. This review summarizes these recent advancements in our tRCC-related knowledge. PMID- 28850057 TI - The Tuning of Optical Properties of Nanoscale MOFs-Based Thin Film through Post Modification. AB - Optical properties, which determine the application of optical devices in different fields, are the most significant properties of optical thin films. In recent years, Metal-organic framework (MOF)-based optical thin films have attracted increasing attention because of their novel optical properties and important potential applications in optical and photoelectric devices, especially optical thin films with tunable optical properties. This study reports the first example of tuning the optical properties of a MOF-based optical thin film via post-modification. The MOF-based optical thin film was composed of NH2-MIL-53(Al) nanorods (NRs) (MIL: Materials from Institute Lavoisier), and was constructed via a spin-coating method. Three aldehydes with different lengths of carbon chains were chosen to modify the MOF optical thin film to tune their optical properties. After post-modification, the structural color of the NH2-MIL-53(Al) thin film showed an obvious change from purple to bluish violet and cyan. The reflection spectrum and the reflectivity also altered in different degrees. The effective refractive index (neff) of MOFs thin film can also be tuned from 1.292 to 1.424 at a wavelength of 750 nm. The success of tuning of the optical properties of MOFs thin films through post-modification will make MOFs optical thin films meet different needs of optical properties in various optical and optoelectronic devices. PMID- 28850058 TI - Does Growing up in Urban Compared to Rural Areas Shape Primary Emotional Traits? AB - Growing up in urban areas represents a possible risk factor in the genesis of psychopathologies. The aim of the present study was to investigate the link between urbanicity variables and indicators for psychiatric disorders. We investigated a potential association between primary emotional traits and urbanicity variables in 324 individuals from Germany and 713 individuals from China. Higher scores in the urbanicity index in childhood were inversely associated with FEAR and SADNESS only in adult Chinese females. These effects seemed to be driven by living in Chinese mega-cities, because a parallel sample from Germany and China (contrasting upbringing in cities with the categories <10,000 inhabitants, >=10,000 inhabitants (but <100,000), and >=100,000 inhabitants) resulted in weaker, but more similar effects in females in both countries. Additional associations could be observed with higher PLAY and urban upbringing in Chinese males. The results seem surprising, given an expectation of adverse emotional effects from growing up in todays' mega-cities compared to rural areas. Although we do not want to over-interpret our findings (given rather small correlations and multiple testing issues), they should encourage researchers to consider including urbanicity variables in personality neuroscience and personality oriented clinical psychiatric research. PMID- 28850059 TI - Short-Range Responses of the Kissing Bug Triatoma rubida (Hemiptera: Reduviidae) to Carbon Dioxide, Moisture, and Artificial Light. AB - The hematophagous bug Triatoma rubida is a species of kissing bug that has been marked as a potential vector for the transmission of Chagas disease in the Southern United States and Northern Mexico. However, information on the distribution of T. rubida in these areas is limited. Vector monitoring is crucial to assess disease risk, so effective trapping systems are required. Kissing bugs utilize extrinsic cues to guide host-seeking, aggregation, and dispersal behaviors. These cues have been recognized as high-value targets for exploitation by trapping systems. A modern video-tracking system was used with a four-port olfactometer system to quantitatively assess the behavioral response of T. rubida to cues of known significance. Also, response of T. rubida adults to seven wavelengths of light-emitting diodes (LED) in paired-choice pitfall was evaluated. Behavioral data gathered from these experiments indicate that T. rubida nymphs orient preferentially to airstreams at either 1600 or 3200 ppm carbon dioxide and prefer relative humidity levels of about 30%, while adults are most attracted to 470 nm light. These data may serve to help design an effective trapping system for T. rubida monitoring. Investigations described here also demonstrate the experimental power of combining an olfactometer with a video tracking system for studying insect behavior. PMID- 28850060 TI - The Differential Distribution of RAPTA-T in Non-Invasive and Invasive Breast Cancer Cells Correlates with Its Anti-Invasive and Anti-Metastatic Effects. AB - Nanoscale secondary ion mass spectrometry (NanoSIMS) combined with transmission electron microscopy (TEM) can be a powerful approach to visualize the exact distribution of drugs at the sub-cellular level. In this work, we exploit this approach to identify the distribution and localisation of the organometallic ruthenium(II)-arene drug Ru(eta6-C6H5Me)(pta)Cl2, termed RAPTA-T, in MDA-MB-231 and MCF-7 human breast cancer cells. These cell lines have been chosen because the former cell lines are highly invasive and resistant to most chemotherapeutic agents and the latter ones are very sensitive to hormonal-based therapies. In the MDA-MB-231 cells, RAPTA-T was found to predominantly localise on the cell membrane and to a lesser extent in the nucleolus. These findings are consistent with the previously reported anti-metastatic properties of RAPTA-T and the observation that once internalized RAPTA-T is associated with chromatin. RAPTA-T shows a lack of membrane accumulation on the non-invasive MCF-7 cells, which correlates well with its selective anti-metastatic properties on invasive cell lines. PMID- 28850061 TI - Changes in Average Sodium Content of Prepacked Foods in Slovenia during 2011 2015. AB - A voluntary gradual reduction in the salt content of processed foods was proposed Slovenia in 2010. Our objective was to determine the sodium content of prepacked foods in 2015 and to compare these results with data from 2011. Labelled sodium content and 12-month sales data were collected for prepacked foods (N = 5759) from major food stores in Slovenia. The average and sales-weighted sodium content, as well as the share in total sodium sales (STSS) were calculated for different food category levels, particularly focusing on processed meat and derivatives (STSS: 13.1%; 904 mg Na/100 g), bread (9.1%; 546 mg), cheese (5.1%; 524 mg), and ready-to-eat meals (2.2%; 510 mg). Reduced sale-weighted sodium content was observed in cheese (57%), a neutral trend was observed in processed meat and derivatives (99%) and bread (100%), and an increase in sodium content was found in ready meals (112%). Similar trends were observed for average sodium levels, but the difference was significant only in the case of ready meals. No statistically significant changes were observed for the matched products, although about one-third of the matched products had been reformulated by lowering the sodium level by more than 3.8%. Additional efforts are needed to ensure salt reduction in processed foods in Slovenia. Such efforts should combine closer collaboration with the food industry, additional consumer education, and setting specific sodium content targets (limits) for key food categories. PMID- 28850063 TI - Most Do, but Some Do Not: CD4+CD25- T Cells, but Not CD4+CD25+ Treg Cells, Are Cytolytic When Redirected by a Chimeric Antigen Receptor (CAR). AB - Evidences are accumulating that CD4+ T cells can physiologically mediate antigen specific target cell lysis. By circumventing major histocompatibility complex (MHC)-restrictions through an engineered chimeric antigen receptor (CAR), CD4+ T cells lyse defined target cells as efficiently as do CD8+ T cells. However, the cytolytic capacity of redirected CD4+CD25- T cells, in comparison with CD4+CD25+ regulatory T (Treg) cells was so far not thoroughly defined. Treg cells require a strong CD28 signal together with CD3zeta for activation. We consequently used a CAR with combined CD28-CD3zeta signalling for redirecting CD4+CD25- T cells and CD4+CD25+ Treg cells from the same donor. CAR redirected activation of these T cell subsets and induced a distinct cytokine pattern with high IL-10 and a lack of IL-2 release by Treg cells. Despite strong antigen-specific activation, CAR Treg cells produced only weak target cell lysis, whereas CD4+CD25- CAR T cells were potent killers. Cytolysis did not correlate with the target cell sensitivity to Fas/FasL mediated killing; CD4+CD25- T cells upregulated perforin and granzyme B upon CAR activation, whereas Treg cells did less. The different cytolytic capacities of CAR redirected conventional CD4+ cells and Treg cells imply their use for different purposes in cell therapy. PMID- 28850062 TI - Urinary Sodium-to-Potassium Ratio Tracks the Changes in Salt Intake during an Experimental Feeding Study Using Standardized Low-Salt and High-Salt Meals among Healthy Japanese Volunteers. AB - The Na/K ratio is considered to be a useful index, the monitoring of which allows an effective Na reduction and K increase, because practical methods (self monitoring devices and reliable individual estimates from spot urine) are available for assessing these levels in individuals. An intervention trial for lowering the Na/K ratio has demonstrated that a reduction of the Na/K ratio mainly involved Na reduction, with only a small change in K. The present study aimed to clarify the relationship between dietary Na intake and the urinary Na/K molar ratio, using standardized low- and high-salt diets, with an equal dietary K intake, to determine the corresponding Na/K ratio. Fourteen healthy young adult volunteers ingested low-salt (3 g salt per day) and high-salt (20 g salt per day) meals for seven days each. Using a portable urinary Na/K meter, participants measured their spot urine at each voiding, and 24-h urine was collected on the last day of each diet period. On the last day of the unrestricted, low-salt, and high-salt diet periods, the group averages of the 24-h urine Na/K ratio were 4.2, 1.0, and 6.9, while the group averages of the daily mean spot urine Na/K ratio were 4.2, 1.1, and 6.6, respectively. The urinary Na/K ratio tracked changes in dietary salt intake, and reached a plateau approximately three days after each change in diet. Frequent monitoring of the spot urine Na/K ratio may help individuals adhere to an appropriate dietary Na intake. PMID- 28850064 TI - Sleep Disorders in a Sample of Adopted Children: A Pilot Study. AB - Sleep disorders occur in up to 25% of children and are more prevalent in children who have attention problems and attachment issues. Research shows that foster children display sleep problems, but limited knowledge exists on sleep problems in adopted children. This pilot study aimed to identify the types of sleep disorders in adopted children and associated psychosocial factors. Parents of adopted children in Ontario, Canada, ages 2-10 years were asked to complete questionnaires evaluating demographic measures, sleep history, and the presence of behavioral problems. Insomnias and parasomnias were reported in adopted children and were associated with attention problems. This pilot study emphasizes the need for further research on the underlying factors governing the relationship between poor sleep and behavioral problems in adopted children. PMID- 28850065 TI - Young People's Use of E-Cigarettes across the United Kingdom: Findings from Five Surveys 2015-2017. AB - Concern has been expressed about the use of e-cigarettes among young people. Our study reported e-cigarette and tobacco cigarette ever and regular use among 11-16 year olds across the UK. Data came from five large scale surveys with different designs and sampling strategies conducted between 2015 and 2017: The Youth Tobacco Policy Survey; the Schools Health Research Network Wales survey; two Action on Smoking and Health (ASH) Smokefree Great Britain-Youth Surveys; and the Scottish Schools Adolescent Lifestyle and Substance Use Survey. Cumulatively these surveys collected data from over 60,000 young people. For 2015/16 data for 11-16 year olds: ever smoking ranged from 11% to 20%; regular (at least weekly) smoking between 1% and 4%; ever use of e-cigarettes 7% to 18%; regular (at least weekly) use 1% to 3%; among never smokers, ever e-cigarette use ranged from 4% to 10% with regular use between 0.1% and 0.5%; among regular smokers, ever e cigarette use ranged from 67% to 92% and regular use 7% to 38%. ASH surveys showed a rise in the prevalence of ever use of e-cigarettes from 7% (2016) to 11% (2017) but prevalence of regular use did not change remaining at 1%. In summary, surveys across the UK show a consistent pattern: most e-cigarette experimentation does not turn into regular use, and levels of regular use in young people who have never smoked remain very low. PMID- 28850066 TI - Association between Blood Pressure and Birth Weight among Rural South African Children: Ellisras Longitudinal Study. AB - The aim of this cross-sectional study was to investigate the association between birth weight, underweight, and blood pressure (BP) among Ellisras rural children aged between 5 and 15 years. Data were collected from 528 respondents who participated in the Ellisras Longitudinal Study (ELS) and had their birth weight recorded on their health clinic card. Standard procedure was used to measure the anthropometric measurements and BP. Linear regression was used to assess BP, underweight variables, and birth weight. Logistic regression was used to assess the association of hypertension risks, low birth weight, and underweight. The association between birth weight and BP was not statistically significant. There was a significant (p < 0.05) association between mean BP and the sum of four skinfolds (beta = 0.26, 95% CI 0.15-0.23) even after adjusting for age (beta = 0.18, 95% CI 0.01-0.22). Hypertension was significantly associated with weight for age z-scores (OR = 5.13, 95% CI 1.89-13.92) even after adjusting for age and sex (OR = 5.26, 95% CI 1.93-14.34). BP was significantly associated with the sum of four skinfolds, but not birth weight. Hypertension was significantly associated with underweight. Longitudinal studies should confirm whether the changes in body weight we found can influence the risk of cardiovascular diseases. PMID- 28850068 TI - Modeling and Design Optimization of Multifunctional Membrane Reactors for Direct Methane Aromatization. AB - Due to the recent increase of natural gas production in the U.S., utilizing natural gas for higher-value chemicals has become imperative. Direct methane aromatization (DMA) is a promising process used to convert methane to benzene, but it is limited by low conversion of methane and rapid catalyst deactivation by coking. Past work has shown that membrane separation of the hydrogen produced in the DMA reactions can dramatically increase the methane conversion by shifting the equilibrium toward the products, but it also increases coke production. Oxygen introduction into the system has been shown to inhibit this coke production while not inhibiting the benzene production. This paper introduces a novel mathematical model and design to employ both methods in a multifunctional membrane reactor to push the DMA process into further viability. Multifunctional membrane reactors, in this case, are reactors where two different separations occur using two differently selective membranes, on which no systems studies have been found. The proposed multifunctional membrane design incorporates a hydrogen selective membrane on the outer wall of the reaction zone, and an inner tube filled with airflow surrounded by an oxygen-selective membrane in the middle of the reactor. The design is shown to increase conversion via hydrogen removal by around 100%, and decrease coke production via oxygen addition by 10% when compared to a tubular reactor without any membranes. Optimization studies are performed to determine the best reactor design based on methane conversion, along with coke and benzene production. The obtained optimal design considers a small reactor (length = 25 cm, diameter of reaction tube = 0.7 cm) to subvert coke production and consumption of the product benzene as well as a high permeance (0.01 mol/s.m2.atm1/4) through the hydrogen-permeable membrane. This modeling and design approach sets the stage for guiding further development of multifunctional membrane reactor models and designs for natural gas utilization and other chemical reaction systems. PMID- 28850067 TI - Engineered Aptamers to Probe Molecular Interactions on the Cell Surface. AB - Significant progress has been made in understanding the nature of molecular interactions on the cell membrane. To decipher such interactions, molecular scaffolds can be engineered as a tool to modulate these events as they occur on the cell membrane. To guarantee reliability, scaffolds that function as modulators of cell membrane events must be coupled to a targeting moiety with superior chemical versatility. In this regard, nucleic acid aptamers are a suitable class of targeting moieties. Aptamers are inherently chemical in nature, allowing extensive site-specific chemical modification to engineer sensing molecules. Aptamers can be easily selected using a simple laboratory-based in vitro evolution method enabling the design and development of aptamer-based functional molecular scaffolds against wide range of cell surface molecules. This article reviews the application of aptamers as monitors and modulators of molecular interactions on the mammalian cell surface with the aim of increasing our understanding of cell-surface receptor response to external stimuli. The information gained from these types of studies could eventually prove useful in engineering improved medical diagnostics and therapeutics. PMID- 28850069 TI - Sujiaonori-Derived Algal Biomaterials Inhibit Allergic Reaction in Allergen Sensitized RBL-2H3 Cell Line and Improve Skin Health in Humans. AB - Sujiaonori, a river alga growing in the Kochi prefecture, Japan, contains several bioactive compounds such as sulfated polysaccharides (ulvans), omega-3 fatty acids, and vitamins. Dietary intake of this alga-based supplement has been reported to increase circulatory adiponectin, a salutary hormone that is reported to be associated with healthy longevity and prevents a number of cardiovascular and metabolic disorders. This report highlights the anti-allergic and skin health enhancing effects of Sujiaonori-derived ulvan (Tosalvan) and supplement, respectively. RBL-2H3 cell line was used to investigate the anti-allergic effect of algal SP through the evaluation of beta-hexosaminidase activity. Algal sulfated polysaccharides or SP (Tosalvan, Yoshino SP) were extracted from powders of dried alga samples provided by local food manufacturers. Report on the effect of daily dietary intake of Sujiaonori-based supplement on skin health is part of a four-week clinical investigation that, in comparison with a supplement made of 70% corn starch powder and 30% spinach powder mixture (twice 3 g daily), explore the beneficial effects of Sujiaonori algal biomaterial (SBM; 3 g taken twice daily) on cardiovascular, gastrointestinal and skin health in a sample of Japanese women. Transepidermal water loss (TEWL) was the skin health marker used in this study and was measured with the use of a corneometer. Significant reduction of beta-hexosaminidase activity was observed in Tosalvan and Yoshino SP treated cells (vs. control; p < 0.05), whereas dietary intake of SBM markedly reduced TEWL level after four weeks of supplementation, as compared to baseline TEWL (p < 0.001). Additionally, SBM improved TEWL better than the control product (p < 0.001). Findings contained in this report suggest that Sujiaonori-derived Tosalvan and Yoshino SP have anti-allergic potential and that the dietary intake of SBM has a beneficial effect on skin health. PMID- 28850070 TI - Effects of Simulated Human Gastrointestinal Digestion of Two Purple-Fleshed Potato Cultivars on Anthocyanin Composition and Cytotoxicity in Colonic Cancer and Non-Tumorigenic Cells. AB - A dynamic human gastrointestinal (GI) model was used to digest cooked tubers from purple-fleshed Amachi and Leona potato cultivars to study anthocyanin biotransformation in the stomach, small intestine and colonic vessels. Colonic Caco-2 cancer cells and non-tumorigenic colonic CCD-112CoN cells were tested for cytotoxicity and cell viability after 24 h exposure to colonic fecal water (FW) digests (0%, 10%, 25%, 75% and 100% FW in culture media). After 24 h digestion, liquid chromatography-mass spectrometry identified 36 and 15 anthocyanin species throughout the GI vessels for Amachi and Leona, respectively. The total anthocyanin concentration was over thirty-fold higher in Amachi compared to Leona digests but seven-fold higher anthocyanin concentrations were noted for Leona versus Amachi in descending colon digests. Leona FW showed greater potency to induce cytotoxicity and decrease viability of Caco-2 cells than observed with FW from Amachi. Amachi FW at 100% caused cytotoxicity in non-tumorigenic cells while FW from Leona showed no effect. The present findings indicate major variations in the pattern of anthocyanin breakdown and release during digestion of purple fleshed cultivars. The differing microbial anthocyanin metabolite profiles in colonic vessels between cultivars could play a significant role in the impact of FW toxicity on tumor and non-tumorigenic cells. PMID- 28850072 TI - Transnational Research Networks in Chinese Scientific Production. An Investigation on Health-Industry Related Sectors. AB - Transnational research networks (TRN) are becoming increasingly complex. Such complexity may have both positive and negative effects on the quality of research. Our work studies the evolution over time of Chinese TRN and the role of complexity on the quality of Chinese research, given the leading role this country has recently acquired in international science. We focus on the fields of geriatrics and gerontology. We build an original dataset of all scientific publications of China in these areas in 2009, 2012 and 2015, starting from the ISI Web of Knowledge (ISI WoK) database. Using Social Network Analysis (SNA), we analyze the change in scientific network structure across time. Second, we design indices to control for the different aspects of networks complexity (number of authors, country heterogeneity and institutional heterogeneity) and we perform negative binomial regressions to identify the main determinants of research quality. Our analysis shows that research networks in the field of geriatrics and gerontology have gradually become wider in terms of countries and have become more balanced. Furthermore, our results identify that different forms of complexity have different impacts on quality, including a reciprocal moderating effect. In particular, according to our analysis, research quality benefits from complex research networks both in terms of countries and of types of institutions involved, but that such networks should be "compact" in terms of number of authors. Eventually, we suggest that complexity should be carefully taken into account when designing policies aimed at enhancing the quality of research. PMID- 28850071 TI - Natural Killer Cells: Angels and Devils for Immunotherapy. AB - In recent years, the relevance of the immune system to fight cancer has led to the development of immunotherapy, including the adoptive cell transfer of immune cells, such as natural killer (NK) cells and chimeric antigen receptors (CAR) modified T cells. The discovery of donor NK cells' anti-tumor activity in acute myeloid leukemia patients receiving allogeneic stem cell transplantation (allo SCT) was the trigger to conduct many clinical trials infusing NK cells. Surprisingly, many of these studies did not obtain optimal results, suggesting that many different NK cell parameters combined with the best clinical protocol need to be optimized. Various parameters including the high array of activating receptors that NK cells have, the source of NK cells selected to treat patients, different cytotoxic mechanisms that NK cells activate depending on the target cell and tumor cell survival mechanisms need to be considered before choosing the best immunotherapeutic strategy using NK cells. In this review, we will discuss these parameters to help improve current strategies using NK cells in cancer therapy. Moreover, the chimeric antigen receptor (CAR) modification, which has revolutionized the concept of immunotherapy, will be discussed in the context of NK cells. Lastly, the dark side of NK cells and their involvement in inflammation will also be discussed. PMID- 28850073 TI - The Effect of Pressure and Solvent on the Supercritical Fluid Chromatography Separation of Tocol Analogs in Palm Oil. AB - There are six tocol analogs present in palm oil, namely alpha-tocopherol (alpha T), alpha-tocomonoenol (alpha-T1), alpha-tocotrienol (alpha-T3), gamma tocotrienol (gamma-T3), beta-tocotrioenol (beta-T3) and delta-tocotrienol (delta T3). These analogs were difficult to separate chromatographically due to their similar structures, physical and chemical properties. This paper reports on the effect of pressure and injection solvent on the separation of the tocol analogs in palm oil. Supercritical CO2 modified with ethanol was used as the mobile phase. Both total elution time and resolution of the tocol analogs decreased with increased pressure. Ethanol as an injection solvent resulted in peak broadening of the analogs within the entire pressure range studied. Solvents with an eluent strength of 3.4 or less were more suitable for use as injecting solvents. PMID- 28850075 TI - NO-Donor Iron Nitrosyl Complex with N-Ethylthiourea Ligand Exhibits Selective Toxicity to Glioma A172 Cells. AB - We studied effects of NO-donor iron nitrosyl complex with N-ethylthiourea ligand (ETM) on normal or tumor-derived cell lines. ETM was mildly toxic to most cell lines studied except the human glioma cell line A172 that proved to be highly sensitive to the complex and underwent cell death after ETM exposure. The high susceptibility of A172 cells to ETM was attributed to its NO-donor properties since no toxicity was detected for the N-ethylthiourea ligand. PMID- 28850076 TI - Spasmolytic Mechanism of Aqueous Licorice Extract on Oxytocin-Induced Uterine Contraction through Inhibiting the Phosphorylation of Heat Shock Protein 27. AB - Licorice derived from the roots and rhizomes of Glycyrrhiza uralensis Fisch. (Fabaceae), is one of the most widely-used traditional herbal medicines in China. It has been reported to possess significant analgesic activity for treating spastic pain. The aim of this study is to investigate the spasmolytic molecular mechanism of licorice on oxytocin-induced uterine contractions and predict the relevant bioactive constituents in the aqueous extract. The aqueous extraction from licorice inhibited the amplitude and frequency of uterine contraction in a concentration-dependent manner. A morphological examination showed that myometrial smooth muscle cells of oxytocin-stimulated group were oval-shaped and arranged irregularly, while those with a single centrally located nucleus of control and licorice-treated groups were fusiform and arranged orderly. The percentage of phosphorylation of HSP27 at Ser-15 residue increased up to 50.33% at 60 min after oxytocin stimulation. Furthermore, this increase was significantly suppressed by licorice treatment at the concentration of 0.2 and 0.4 mg/mL. Colocalization between HSP27 and alpha-SMA was observed in the myometrial tissues, especially along the actin bundles in the oxytocin-stimulated group. On the contrary, the colocalization was no longer shown after treatment with licorice. Additionally, employing ChemGPS-NP provided support for a preliminary assignment of liquiritigenin and isoliquiritigenin as protein kinase C (PKC) inhibitors in addition to liquiritigenin, isoliquiritigenin, liquiritin and isoliquiritin as MAPK-activated protein kinase 2 (MK2) inhibitors. These assigned compounds were docked with corresponding crystal structures of respective proteins with negative and low binding energy, which indicated a high affinity and tight binding capacity for the active site of the kinases. These results suggest that licorice exerts its spasmolytic effect through inhibiting the phosphorylation of HSP27 to alter the interaction between HSP27 and actin. Furthermore, our results provide support for the prediction that potential bioactive constituents from aqueous licorice extract inhibit the relevant up stream kinases that phosphorylate HSP27. PMID- 28850077 TI - Chemical Composition of Pinus roxburghii Bark Volatile Oil and Validation of Its Anti-Inflammatory Activity Using Molecular Modelling and Bleomycin-Induced Inflammation in Albino Mice. AB - The chemical composition of Pinus roxburghii bark essential oil (PRO) was qualitatively and quantitatively determined using GC/FID and GC/MS. The anti inflammatory activity was assessed in vitro by evaluating the binding percentages on the cannabinoids and opioids receptors. Bleomycin (BLM)-induced pulmonary inflammation in albino mice was adopted to assess PRO anti-inflammatory efficacy in vivo. In silico molecular modelling of its major components was performed on human glucocorticoids receptor (GR). Seventy-five components were identified in which longifolene (33.13%) and palmitic acid (9.34%) constituted the predominant components. No binding was observed on cannabinoid receptor type 1 (CB1), whereas mild binding was observed on cannabinoid receptor type 2 (CB2), delta, kappa, and mu receptors accounting for 2.9%, 6.9%, 10.9% and 22% binding. A significant in vivo activity was evidenced by reduction of the elevated malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels by 55.56%, 55.66%, 64.64%, 58.85% and 77.78% with concomitant elevation of superoxide dismutase (SOD) and catalase (CAT) activities comparable to BLM-treated group at 100 mg/kg body weight. In silico studies showed that palmitic acid exerted the fittest binding. PRO could serve as a potent anti-inflammatory natural candidate that should be supported by further clinical trials. PMID- 28850078 TI - Stringent Nucleotide Recognition by the Ribosome at the Middle Codon Position. AB - Accurate translation of the genetic code depends on mRNA:tRNA codon:anticodon base pairing. Here we exploit an emissive, isosteric adenosine surrogate that allows direct measurement of the kinetics of codon:anticodon University of California base formation during protein synthesis. Our results suggest that codon:anticodon base pairing is subject to tighter constraints at the middle position than at the 5'- and 3'-positions, and further suggest a sequential mechanism of formation of the three base pairs in the codon:anticodon helix. PMID- 28850074 TI - Marine Pharmacology in 2012-2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action. AB - The peer-reviewed marine pharmacology literature from 2012 to 2013 was systematically reviewed, consistent with the 1998-2011 reviews of this series. Marine pharmacology research from 2012 to 2013, conducted by scientists from 42 countries in addition to the United States, reported findings on the preclinical pharmacology of 257 marine compounds. The preclinical pharmacology of compounds isolated from marine organisms revealed antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral and anthelmitic pharmacological activities for 113 marine natural products. In addition, 75 marine compounds were reported to have antidiabetic and anti-inflammatory activities and affect the immune and nervous system. Finally, 69 marine compounds were shown to display miscellaneous mechanisms of action which could contribute to novel pharmacological classes. Thus, in 2012-2013, the preclinical marine natural product pharmacology pipeline provided novel pharmacology and lead compounds to the clinical marine pharmaceutical pipeline, and contributed significantly to potentially novel therapeutic approaches to several global disease categories. PMID- 28850079 TI - Effect of Different Silicon Sources on Yield and Silicon Uptake of Rice Grown under Varying Phosphorus Rates. AB - A series of pot experiments were conducted to: (1) evaluate the effects of different Si sources (soil- and foliar-applied) on grain yield and Si accumulation of rice supplied with varying P rates, and (2) evaluate Si absorption of rice using foliar- and soil-applied Si fertilizers. Three P rates, (0, 112, and 224 kg ha-1) combined with five Si treatments (wollastonite and slag applied at 4.5 ton ha-1 and one foliar Si solution applied at 20, 40 and 80 mg Si L-1) and a check were arranged in a randomized complete block design with four replications. The presence of P and Si in the soil created a synergistic effect on soil Al, Mn, and As (P < 0.01), but not on rice growth and P uptake. Wollastonite and slag application were most effective in raising rice Si content than foliar applied Si (P < 0.001). While there was an improvement in biomass (42%) and tiller production (25%) for rice receiving foliar Si, no supporting evidence was obtained in these experiments to verify leaf surface Si absorption. The application of Si-rich materials to soil still remains the most effective method for enhancing Si uptake by plants. PMID- 28850080 TI - The Role of Metal Binding in the Amyotrophic Lateral Sclerosis-Related Aggregation of Copper-Zinc Superoxide Dismutase. AB - Protein misfolding and conformational changes are common hallmarks in many neurodegenerative diseases involving formation and deposition of toxic protein aggregates. Although many players are involved in the in vivo protein aggregation, physiological factors such as labile metal ions within the cellular environment are likely to play a key role. In this review, we elucidate the role of metal binding in the aggregation process of copper-zinc superoxide dismutase (SOD1) associated to amyotrophic lateral sclerosis (ALS). SOD1 is an extremely stable Cu-Zn metalloprotein in which metal binding is crucial for folding, enzymatic activity and maintenance of the native conformation. Indeed, demetalation in SOD1 is known to induce misfolding and aggregation in physiological conditions in vitro suggesting that metal binding could play a key role in the pathological aggregation of SOD1. In addition, this study includes recent advances on the role of aberrant metal coordination in promoting SOD1 aggregation, highlighting the influence of metal ion homeostasis in pathologic aggregation processes. PMID- 28850081 TI - Job Stress and Presenteeism among Chinese Healthcare Workers: The Mediating Effects of Affective Commitment. AB - BACKGROUND: Presenteeism affects the performance of healthcare workers. This study examined associations between job stress, affective commitment, and presenteeism among healthcare workers. METHODS: To investigate the relationship between job stress, affective commitment, and presenteeism, structural equation modeling was used to analyze a sample of 1392 healthcare workers from 11 Class A tertiary hospitals in eastern, central, and western China. The mediating effect of affective commitment on the association between job stress and presenteeism was examined with the Sobel test. RESULTS: Job stress was high and the level of presenteeism was moderate among healthcare workers. Challenge stress and hindrance stress were strongly correlated (beta = 0.62; p < 0.05). Affective commitment was significantly and directly inversely correlated with presenteeism (beta = -0.27; p < 0.001). Challenge stress was significantly positively correlated with affective commitment (beta = 0.15; p < 0.001) but not with presenteeism. Hindrance stress was significantly inversely correlated with affective commitment (beta = -0.40; p < 0.001) but was significantly positively correlated with presenteeism (beta = 0.26; p < 0.001). CONCLUSIONS: This study provides important empirical data on presenteeism among healthcare workers. Presenteeism can be addressed by increasing affective commitment and challenge stress and by limiting hindrance stress among healthcare workers in China. PMID- 28850083 TI - Pharmaceutical Industry in Vietnam: Sluggish Sector in a Growing Market. AB - Vietnam is a fast growing economy in the Asian region with a significantly high population (over 92 million in 2015). Although still expanding (about 1.1% on average during 2000-2015), the Vietnamese population is considered to be entering the ageing stage at a very high rate. The rapid expansion of the middle-income urban class and the ageing people ratio have dramatically pushed up the demand for healthcare goods, particularly in terms of pharmaceutical products. Since the early 1990s the government has addressed the necessities of rising demand for healthcare products by formulating a series of policies aimed at promoting the development of the pharmaceutical industry. However, the implementation of such policies does not seem to have been completely efficient given that the country still needs to import up to 90% of its pharmaceutical consumption. This paper aims to explore the development of the pharmaceutical industry during the years 1990-2015 and to identify a series of weaknesses in the government promotion of the industry. Future developments will also be discussed on how the Vietnamese pharmaceutical industry could increase its participation in the regional supply chain, which is currently being dominated by big players like India and China. PMID- 28850082 TI - Structural Features of Apicomplexan Pore-Forming Proteins and Their Roles in Parasite Cell Traversal and Egress. AB - Apicomplexan parasites cause diseases, including malaria and toxoplasmosis, in a range of hosts, including humans. These intracellular parasites utilize pore forming proteins that disrupt host cell membranes to either traverse host cells while migrating through tissues or egress from the parasite-containing vacuole after replication. This review highlights recent insight gained from the newly available three-dimensional structures of several known or putative apicomplexan pore-forming proteins that contribute to cell traversal or egress. These new structural advances suggest that parasite pore-forming proteins use distinct mechanisms to disrupt host cell membranes at multiple steps in parasite life cycles. How proteolytic processing, secretion, environment, and the accessibility of lipid receptors regulate the membranolytic activities of such proteins is also discussed. PMID- 28850084 TI - Pyrene-Phosphonate Conjugate: Aggregation-Induced Enhanced Emission, and Selective Fe3+ Ions Sensing Properties. AB - A new pyrene-phosphonate colorimetric receptor 1 has been designed and synthesized in a one-step process via amide bond formation between pyrene butyric acid chloride and phosphonate-appended aniline. The pyrene-phosphonate receptor 1 showed aggregation-induced enhanced emission (AIEE) properties in water/acetonitrile (ACN) solutions. Dynamic light scattering (DLS) characterization revealed that the aggregates of receptor 1 at 80% water fraction have an average size of ~142 nm. Field emission scanning electron microscopy (FE SEM) analysis confirmed the formation of spherical aggregates upon solvent evaporation. The sensing properties of receptor 1 were investigated by UV-vis, fluorescence emission spectroscopy, and other optical methods. Among the tested metal ions, receptor 1 is capable of recognizing the Fe3+ ion selectively. The changes in spectral measurements were explained on the basis of complex formation. The composition of receptor 1 and Fe3+ ions was determined by using Job's plot and found to be 1:1. The receptor 1-Fe3+ complex showed a reversible UV-vis response in the presence of EDTA. PMID- 28850085 TI - Acute Kidney Injury in Heart Failure Revisited-The Ameliorating Impact of "Decongestive Diuresis" on Renal Dysfunction in Type 1 Acute Cardiorenal Syndrome: Accelerated Rising Pro B Naturetic Peptide Is a Predictor of Good Renal Prognosis. AB - There is mounting evidence that forward heart failure as manifested by low cardiac output alone does not define the degree of renal dysfunction in cardiorenal syndrome. As a result, the term "congestive renal failure" was coined in 2012 by Ross to depict the role of renal venous hypertension in type 1 acute cardiorenal syndrome. If so, aggressive decongestive therapies, either through mechanical ultrafiltration with dialysis machines or pharmacologic ultrafiltration with potent diuretics, would lead to improved cardio and renal outcomes. Nevertheless, as recently as 2012, a review of this literature had concluded that a renal venous hypertension-directed approach using diuretics to manage cardio-renal syndrome was yet to be fully investigated. We, in this review, with three consecutive case series, describe our experience with pharmacologic decongestive diuresis in this paradigm of care and argue for studies of such therapeutic interventions in the management of cardiorenal syndrome. Finally, based on our observations in the Renal Unit, Mayo Clinic Health System, in Northwestern Wisconsin, we have hypothesized that patients with cardiorenal syndrome presenting with accelerated rising Pro B Naturetic Peptide levels appear to represent a group that would have good cardio- and renal outcomes with such decongestive pharmacologic therapies. PMID- 28850087 TI - Characterization and Applications of Kaolinite Robustly Grafted by an Ionic Liquid with Naphthyl Functionality. AB - Functionalization of the kaolinite (K) interlayer space is challenging. In this work, a new kaolinite-based nanohybridmaterial (K-NI) was successfully synthesized by grafting on the interlayer aluminol surfaces the ionic liquid, 1 (1-methylnaphthyl)-3-(2-hydroxyethyl) imidazolium chloride (NI), using a guest displacement strategy. A substantial increase of the basal spacing (10.8 A) was obtained. This is a grafted derivative of kaolinite possessing one of the largest d-values. Washing in water for several days and other vigorous treatments such as sonication showed a minor effect on the integrity of the material. FTIR and 13C NMR confirmed the conservation of the structure of the ionic liquid after the grafting. Thermal analysis confirmed the presence of grafted material and was used to estimate the abundance of the grafted ionic liquid (0.44 mole per mole of kaolinite structural formula, (Al2Si2O5(OH)4)). By using cyclic voltammetry, the permeability of a film of K-NI for the bulky ferricyanide ions was demonstrated. The accumulation of nitrophenolate anions was effective (maximum capacity of 190 MUmol/g), but was less important than what was expected due to the steric hindrance of the bulky grafted NI. Although the presence of chloride anions reduced the adsorption capacity, the affinity of the modified kaolinite interlayer space for the nitrophenolate anions was demonstrated. PMID- 28850086 TI - Insight into the Genome of Staphylococcus xylosus, a Ubiquitous Species Well Adapted to Meat Products. AB - Staphylococcus xylosus belongs to the vast group of coagulase-negative staphylococci. It is frequently isolated from meat products, either fermented or salted and dried, and is commonly used as starter cultures in sausage manufacturing. Analysis of the S. xylosus genome together with expression in situ in a meat model revealed that this bacterium is well adapted to meat substrates, being able to use diverse substrates as sources of carbon and energy and different sources of nitrogen. It is well-equipped with genes involved in osmotic, oxidative/nitrosative, and acidic stress responses. It is responsible for the development of the typical colour of cured meat products via its nitrate reductase activity. It contributes to sensorial properties, mainly by the the catabolism of pyruvate and amino acids resulting in odorous compounds and by the limiting of the oxidation of fatty acids, thereby avoiding rancidity. PMID- 28850088 TI - Formation Mechanism of Spherical TiC in Ni-Ti-C System during Combustion Synthesis. AB - The formation mechanism of TiC particles in a Ni-Ti-C system were revealed by using differential thermal analysis (DTA), XRD, and SEM to identify the reaction products in different temperature ranges. The results indicated that the synthesis mechanism of TiC in Ni-Ti-C system was complex; several reactions were involved in the combustion synthesis of TiC-Ni composite. The Ni-Ti intermediate phases play important roles during the formation of TiC. Moreover, the influence of heating rate on the size range of TiC was also discussed. PMID- 28850089 TI - Magnetic Nanoparticles: From Design and Synthesis to Real World Applications. AB - The increasing number of scientific publications focusing on magnetic materials indicates growing interest in the broader scientific community. Substantial progress was made in the synthesis of magnetic materials of desired size, morphology, chemical composition, and surface chemistry. Physical and chemical stability of magnetic materials is acquired by the coating. Moreover, surface layers of polymers, silica, biomolecules, etc. can be designed to obtain affinity to target molecules. The combination of the ability to respond to the external magnetic field and the rich possibilities of coatings makes magnetic materials universal tool for magnetic separations of small molecules, biomolecules and cells. In the biomedical field, magnetic particles and magnetic composites are utilized as the drug carriers, as contrast agents for magnetic resonance imaging (MRI), and in magnetic hyperthermia. However, the multifunctional magnetic particles enabling the diagnosis and therapy at the same time are emerging. The presented review article summarizes the findings regarding the design and synthesis of magnetic materials focused on biomedical applications. We highlight the utilization of magnetic materials in separation/preconcentration of various molecules and cells, and their use in diagnosis and therapy. PMID- 28850090 TI - DietaryFish and Long-Chain n-3 Polyunsaturated Fatty Acids Intake and Risk of Atrial Fibrillation: A Meta-Analysis. AB - Findings on the association between long-term intake of fish or long-chain n-3 polyunsaturated fatty acids (PUFAs) and risk of atrial fibrillation (AF) are inconsistent in observational studies. We conducted a meta-analysis of prospective studies to separately examine the associations between fish consumption and dietary intake of n-3 PUFAs with the risk of AF. A systematic search was conducted in PubMed and Embase to identify relevant studies. Risk estimates were combined using a random-effect model. Seven prospective cohort studies covering 206,811 participants and 12,913 AF cases were eligible. The summary relative risk of AF for the highest vs. lowest category of fish consumption and dietary intake of n-3 PUFAs was 1.01(95% confidence interval: 0.94-1.09) and 1.03 (95% confidence interval: 0.97-1.09), respectively. These null associations persisted in subgroup and dose-response analyses. There was little evidence of publication bias. This meta-analysis suggests that neither long-term intake of fish, nor of n-3 PUFAs were significantly associated with lower risk of AF. PMID- 28850091 TI - Investigation on Indoor Air Pollution and Childhood Allergies in Households in Six Chinese Cities by Subjective Survey and Field Measurements. AB - Greater attention is currently being paid to the relationship between indoor environment and childhood allergies, however, the lack of reliable data and the disparity among different areas hinders reliable assessment of the relationship. This study focuses on the effect of indoor pollution on Chinese schoolchildren and the relationship between specific household and health problems suffered. The epidemiological questionnaire survey and the field measurement of the indoor thermal environment and primary air pollutants including CO2, fine particulate matter (PM2.5), chemical pollutants and fungi were performed in six Chinese cities. A total of 912 questionnaires were eligible for statistical analyses and sixty houses with schoolchildren aged 9-12 were selected for field investigation. Compared with Chinese national standards, inappropriate indoor relative humidity (<30% or >70%), CO2 concentration exceeding 1000 ppm and high PM2.5 levels were found in some monitored houses. Di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) were the most frequently detected semi-volatile organic compounds (SVOCs) in house dust. Cladosporium, Aspergillus and Penicillium were detected in both indoor air and house dust. This study indicates that a thermal environment with CO2 exceeding 1000 ppm, DEHP and DBP exceeding 1000 MUg/g, and high level of PM2.5, Cladosporium, Aspergillus and Penicillium increases the risk of children's allergies. PMID- 28850092 TI - Measurement of Telomere Length in Colorectal Cancers for Improved Molecular Diagnosis. AB - All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs) using TRF (Telomere Restriction Fragment) analysis. Telomeric DNA content was also quantified as the ratio of total telomeric (TTAGGG) sequences over that of the invariable Alu sequences. In most of the 125 CRCs analyzed, there was a significant diminution in telomere length compared with that in control healthy tissue. Only 34 tumors exhibited no telomere erosion and, in some cases, a slight telomere lengthening. Telomere length did not correlate with age, gender, tumor stage, tumor localization or stage of tumor differentiation. In addition, while telomere length did not correlate with the presence of a mutation in BRAF (V-raf murine sarcoma viral oncogene homolog B), PIK3CA (phosphatidylinositol 3-kinase catalytic subunit), or MSI status, it was significantly associated with the occurrence of a mutation in KRAS. Interestingly, we found that the shorter the telomeres in healthy tissue of a patient, the larger an increase in telomere length in the tumor. Our study points to the existence of two types of CRCs based on telomere length and reveals that telomere length in healthy tissue might influence telomere maintenance mechanisms in the tumor. PMID- 28850093 TI - Alginate-Based Edible Films Delivering Probiotic Bacteria to Sliced Ham Pretreated with High Pressure Processing. AB - The aim of the present work was to evaluate the efficacy of Na-alginate edible films as vehicles for delivering probiotic bacteria to sliced ham with or without pretreatment using high pressure processing (HPP). Three strains of probiotic bacteria were incorporated in Na-alginate forming solution. Ham slices (with or without pretreatment using HPP at 500 MPa for 2 min) were packed under vacuum in contact with the films and then stored at 4, 8 and 12 degrees C for 66, 47 and 40 days, respectively. Microbiological analysis was performed in parallel with pH and color measurements. Sensory characteristics were assessed, while the presence and the relative abundance of each probiotic strain during storage was evaluated using pulsed field gel electrophoresis. In ham slices without HPP treatment, probiotic bacteria were enumerated above 106 CFU/g during storage at all temperatures. Same results were obtained in cases of HPP treated samples, but pH measurements showed differences with the latter ones exhibiting higher values. Sensory evaluation revealed that probiotic samples had a more acidic taste and odor than the control ones, however these characteristics were markedly compromised in samples treated with HPP. Overall, the results of the study are promising since probiotic bacteria were successfully delivered in the products by edible films regardless of the HPP treatment. PMID- 28850094 TI - Detection of G1138A Mutation of the FGFR3 Gene in Tooth Material from a 180-Year Old Museological Achondroplastic Skeleton. AB - Throughout the last four centuries, many anatomical museums across the world have collected teratological specimens that became precious objects. These can be regarded as spirits of the past which have captured the morphology of diseases through time. These valuable and irreplaceable specimens can be perfectly used in contemporary dysmorphological or genetic research. Unfortunately, due to the historical nature of these specimens and the regularly used aggressive preservation fluids, DNA degradation is often present. Furthermore, the use of material for DNA extraction is restricted to preserve the appearance of these valuable museological specimens. Thus, the most challenging part in this perspective is to harvest sufficient DNA of good quality for further testing without damaging the specimens. Besides fixated specimens, most teratological collections contain dried skeletal and teeth materials which are an excellent source to extract DNA. We here present a DNA-based method that enables genetic identification of the G1138A mutation of the FGFR3 gene in a 180-year-old achondroplastic skeleton, confirming the previously morphologically determined disease. Nuclear DNA was extracted from a premolar tooth and the mutation was found using Sanger sequencing of a small region of the FGFR3 gene. PMID- 28850095 TI - Key Determinants of Human alpha-Defensin 5 and 6 for Enhancement of HIV Infectivity. AB - Defensins are antimicrobial peptides important for mucosal innate immunity. They exhibit a broad spectrum of activity against bacteria, viruses, and fungi. Levels of alpha-defensins are elevated at the genital mucosa of individuals with sexually transmitted infections (STIs). Somewhat paradoxically, human alpha defensin 5 and 6 (HD5 and HD6) promote human immunodeficiency virus (HIV) infectivity, and contribute to STI-mediated enhancement of HIV infection in vitro. Specific amino acid residues of HD5 and HD6 that are crucial for antimicrobial activities have been characterized previously; however, the key determinants of defensins responsible for enhancement of HIV infectivity are not known. Here, we have identified residues of HD5 and HD6 that are required for enhancement of HIV attachment and infection. Most of these residues are involved in hydrophobicity and self-association of defensins. Specifically, we found that mutant defensins L16A-HD5, E21me-HD5, L26A-HD5, Y27A-HD5, F2A-HD6, H27W-HD6, and F29A-HD6 significantly lost their ability to promote HIV attachment and infection. L29A mutation also reduced HIV infection-enhancing activity of HD5. Additionally, a number of mutations in charged residues variably affected the profile of HIV attachment and infectivity. One HD5 charged mutation, R28A, notably resulted in a 34-48% loss of enhanced HIV infectivity and attachment. These results indicate that defensin determinants that maintain high-ordered amphipathic structure are crucial for HIV enhancing activity. In a comparative analysis of the mutant defensins, we found that for some defensin mutants enhancement of HIV infectivity was associated with the reverse transcription step, suggesting a novel, HIV attachment-independent, mechanism of defensin mediated HIV enhancement. PMID- 28850096 TI - Experiences of Parent Peer Nutrition Educators Sharing Child Feeding and Nutrition Information. AB - The aim of this study was to describe the experiences of parents as peer educators disseminating nutrition and child feeding information. Parents of infants aged from birth to three years were trained as peer educators in a face to-face workshop, and then shared evidence-based child feeding and nutrition information via Facebook, email, and printed resources for six months to peers, family, and social media contacts. Semi-structured telephone or group interviews were conducted after a six-month online and face-to-face peer nutrition intervention period investigating peer educator experiences, barriers, enablers of information dissemination, and the acceptability of the peer educator model. Transcripts from interviews were independently coded by two researchers and thematically analysed. Twenty-eight participants completed the study and were assigned to either group or individual interviews. The cohort consenting to the study were predominantly female, aged between 25 and 34 years, non-indigenous, tertiary educated, and employed or on maternity leave. Dominant themes to emerge from the interviews included that the information was trustworthy, child feeding practice information was considered most helpful, newer parents were the most receptive and family members the least receptive to child feeding and nutrition information, and sharing and receiving information verbally and via social media were preferred over print and email. In conclusion, parents reported positive experiences as peer nutrition educators, and considered it acceptable for sharing evidence-based nutrition information. Further research may determine the impact on diet quality and the food-related behaviours of babies and young children on a population level. PMID- 28850097 TI - Bioaccessibility and Human Exposure Assessment of Cadmium and Arsenic in Pakchoi Genotypes Grown in Co-Contaminated Soils. AB - In many countries cadmium (Cd) and arsenic (As) commonly coexist in soils contaminated by mining activities, and can easily enter the human body via consumption of leafy vegetables, like the popularly consumed pakchoi (Brassica chinensis L.), causing major health concerns. In the present study, bioaccessibility and human exposure of Cd and As were assessed in twenty genotypes of pakchoi cultured at two different levels of co-contamination to identify low health risk genotypes. The bioaccessibilities of Cd and As represent a fraction of the total metals content could be bioaccessible for human, in the present study, significant differences in pakchoi Cd and As bioaccessibility were observed among all tested genotypes and co-contaminated levels. Cd and As bioaccessibility of pakchoi were in the ranges of 24.0-87.6% and 20.1-82.5%, respectively, for in the high level co-contaminated soils, which was significantly higher than for low level co-contaminated soils with 7.9-71.8% for Cd bioaccessibility and 16.1-59.0% for As bioaccessibility. The values of bioaccessible established daily intakes (BEDI) and the total bioaccessible target hazard quotients (TBTHQ) of Cd and As were also considerably higher in high level co-contaminated soils than in low level co-contaminated soils. Two genotypes (Meiguanqinggengcai and Zhenqing60F1) contained relatively low concentrations and bioaccessible Cd and As and, their BEDI and TBTHQ for Cd and As ranged below the tolerable limits set by the FAO/WHO (BEDI of Cd < 0.83 MUg kg-1 bw day-1, BEDI of As < 3 MUg kg-1 bw day-1) and United States Environmental Protection Agency (TBTHQ for Cd and As < 1), this applied for both levels of co-contaminated soils for adults and children. Consequently, these findings suggest identification of safe genotypes in leafy vegetable with low health risk via genotypic screening and breeding methods could be a useful strategy to ensure the safety of food crops grown in those Cd and As co-contaminated fields due to mining activities. PMID- 28850099 TI - Vitamin C Intake is Inversely Associated with Cardiovascular Mortality in a Cohort of Spanish Graduates: the SUN Project. AB - Observational studies have found a protective effect of vitamin C on cardiovascular health. However, results are inconsistent, and residual confounding by fiber might be present. The aim of this study was to assess the association of vitamin C with the incidence of cardiovascular disease (CVD) and cardiovascular mortality (CVM) while accounting for fiber intake and adherence to the Mediterranean dietary pattern. We followed up 13,421 participants in the Seguimiento Universidad de Navarra (University of Navarra follow-up) (SUN) cohort for a mean time of 11 years. Information was collected at baseline and every two years through mailed questionnaires. Diet was assessed with a validated semi quantitative food frequency questionnaire. Incident CVD was defined as incident fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, or death due to any cardiovascular cause. CVM was defined as death due to cardiovascular causes. Events were confirmed by physicians in the study team after revision of medical records. Cox proportional hazard models were fitted to assess the associations of (a) energy-adjusted and (b) fiber-adjusted vitamin C intake with CVD and CVM. We found energy-adjusted vitamin C was inversely associated with CVD and CVM after adjusting for several confounding factors, including fiber from foods other than fruits and vegetables, and adherence to the Mediterranean dietary pattern. On the other hand, when vitamin C was adjusted for total fiber intake using the residuals method, we found a significant inverse association with CVM (HR (95% confidence interval (CI)) for the third tertile compared to the first tertile, 0.30 (0.12-0.72), but not with CVD in the fully adjusted model. PMID- 28850100 TI - Automatic Registration of TLS-TLS and TLS-MLS Point Clouds Using a Genetic Algorithm. AB - Registration of point clouds is a fundamental issue in Light Detection and Ranging (LiDAR) remote sensing because point clouds scanned from multiple scan stations or by different platforms need to be transformed to a uniform coordinate reference frame. This paper proposes an efficient registration method based on genetic algorithm (GA) for automatic alignment of two terrestrial LiDAR scanning (TLS) point clouds (TLS-TLS point clouds) and alignment between TLS and mobile LiDAR scanning (MLS) point clouds (TLS-MLS point clouds). The scanning station position acquired by the TLS built-in GPS and the quasi-horizontal orientation of the LiDAR sensor in data acquisition are used as constraints to narrow the search space in GA. A new fitness function to evaluate the solutions for GA, named as Normalized Sum of Matching Scores, is proposed for accurate registration. Our method is divided into five steps: selection of matching points, initialization of population, transformation of matching points, calculation of fitness values, and genetic operation. The method is verified using a TLS-TLS data set and a TLS MLS data set. The experimental results indicate that the RMSE of registration of TLS-TLS point clouds is 3~5 mm, and that of TLS-MLS point clouds is 2~4 cm. The registration integrating the existing well-known ICP with GA is further proposed to accelerate the optimization and its optimizing time decreases by about 50%. PMID- 28850101 TI - 5'-UTR and 3'-UTR Regulation of MICB Expression in Human Cancer Cells by Novel microRNAs. AB - The treatment of cancer through the induction of natural killer group 2, member D (NKG2D) ligands is of interest, but understanding of mechanisms controlling expression of individual ligand is limited. The major histocompatibility complex (MHC) class I chain related protein B (MICB) is a member of NKG2D ligands. We aimed to investigate the role of 3'-untranslated (3'-UTR) and 5'-untranslated regions (5'-UTR) in post-transcriptional regulation of MICB. Nine novel microRNAs (miRNAs) predicted to interact with 3'-UTR and 5'-UTR using TargetScan, RNAhybrid and miBridge were identified. Their regulation of 3'-UTR, 5'-UTR and both 3'- and 5'-UTR sequences of MICB were indicated by the reduction of luciferase activities of luciferase reporter constructs. Mutations of miRNA binding sites at 3'- and 5' UTRs resulted in increased luciferase activities confirming the regulation of nine candidate miRNAs. In addition, overexpression of candidate miRNAs also down regulated the expression of reporter constructs. Consequently, the overexpression and inhibition of candidate miRNAs lead to the decreased and increased. MICB protein expressions on the cells tested, respectively. This study has identified a new role of miRNAs in regulation of MICB expression via both 3'-UTR and 5'-UTR sequences applicable for cancer immunotherapy. PMID- 28850098 TI - Advances in Development of Antimicrobial Peptidomimetics as Potential Drugs. AB - The rapid emergence of multidrug-resistant pathogens has evolved into a global health problem as current treatment options are failing for infections caused by pan-resistant bacteria. Hence, novel antibiotics are in high demand, and for this reason antimicrobial peptides (AMPs) have attracted considerable interest, since they often show broad-spectrum activity, fast killing and high cell selectivity. However, the therapeutic potential of natural AMPs is limited by their short plasma half-life. Antimicrobial peptidomimetics mimic the structure and biological activity of AMPs, but display extended stability in the presence of biological matrices. In the present review, focus is on the developments reported in the last decade with respect to their design, synthesis, antimicrobial activity, cytotoxic side effects as well as their potential applications as anti infective agents. Specifically, only peptidomimetics with a modular structure of residues connected via amide linkages will be discussed. These comprise the classes of alpha-peptoids (N-alkylated glycine oligomers), beta-peptoids (N alkylated beta-alanine oligomers), beta3-peptides, alpha/beta3-peptides, alpha peptide/beta-peptoid hybrids, alpha/gamma N-acylated N-aminoethylpeptides (AApeptides), and oligoacyllysines (OAKs). Such peptidomimetics are of particular interest due to their potent antimicrobial activity, versatile design, and convenient optimization via assembly by standard solid-phase procedures. PMID- 28850102 TI - On the Use of PLA-PHB Blends for Sustainable Food Packaging Applications. AB - Poly(lactic acid) (PLA) is the most used biopolymer for food packaging applications. Several strategies have been made to improve PLA properties for extending its applications in the packaging field. Melt blending approaches are gaining considerable interest since they are easy, cost-effective and readily available processing technologies at the industrial level. With a similar melting temperature and high crystallinity, poly(hydroxybutyrate) (PHB) represents a good candidate to blend with PLA. The ability of PHB to act as a nucleating agent for PLA improves its mechanical resistance and barrier performance. With the dual objective to improve PLAPHB processing performance and to obtain stretchable materials, plasticizers are frequently added. Current trends to enhance PLA-PHB miscibility are focused on the development of composite and nanocomposites. PLA PHB blends are also interesting for the controlled release of active compounds in the development of active packaging systems. This review explains the most relevant processing aspects of PLA-PHB based blends such as the influence of polymers molecular weight, the PLA-PHB composition as well as the thermal stability. It also summarizes the recent developments in PLA-PHB formulations with an emphasis on their performance with interest in the sustainable food packaging field. PLA-PHB blends shows highly promising perspectives for the replacement of traditional petrochemical based polymers currently used for food packaging. PMID- 28850103 TI - Discovery of Phylloseptins that Defense against Gram-Positive Bacteria and Inhibit the Proliferation of the Non-Small Cell Lung Cancer Cell Line, from the Skin Secretions of Phyllomedusa Frogs. AB - The growing occurrence of bacterial resistance to conventional antibiotics has called for the development of new classes of antimicrobial agents. Antimicrobial peptides (AMPs) with broad antimicrobial spectrum derived from frog skin secretions have been demonstrated to be promising candidates for new antibiotic development. A proven rich source of these compounds are the skin secretions of the frogs in the Phyllomedusa genus. In this study, two novel phylloseptin peptides-phylloseptin-PTa and phylloseptin-PHa-were isolated from the skin secretions of the South American frogs, Phyllomedusa tarsius (P. tarsius) and Phyllomedusa hypochondrialis (P. hypochondrialis) through parallel transcriptomic and peptidomic studies. Replicates obtained by chemical synthesis were structurally analysed and shown to adopt an alpha-helix configuration in an amphiphilic environment. Both peptides demonstrated antimicrobial activities against planktonic Gram-positive bacteria strains, including Staphylococcus aureus, Enterococcus faecalis and methicillin-resistant Staphylococcus aureus , biofilms, as well as cytostatic effects on the non-small cell lung cancer cell line, NCI-H157, with relatively low haemolysis on horse erythrocytes and low cytotoxicity on the human microvascular endothelial cell line, HMEC-1. The discovery of phylloseptin peptides may further inspire the development of new types of antibiotics. PMID- 28850104 TI - A Practical Evaluation of a High-Security Energy-Efficient Gateway for IoT Fog Computing Applications. AB - Fog computing extends cloud computing to the edge of a network enabling new Internet of Things (IoT) applications and services, which may involve critical data that require privacy and security. In an IoT fog computing system, three elements can be distinguished: IoT nodes that collect data, the cloud, and interconnected IoT gateways that exchange messages with the IoT nodes and with the cloud. This article focuses on securing IoT gateways, which are assumed to be constrained in terms of computational resources, but that are able to offload some processing from the cloud and to reduce the latency in the responses to the IoT nodes. However, it is usually taken for granted that IoT gateways have direct access to the electrical grid, which is not always the case: in mission-critical applications like natural disaster relief or environmental monitoring, it is common to deploy IoT nodes and gateways in large areas where electricity comes from solar or wind energy that charge the batteries that power every device. In this article, how to secure IoT gateway communications while minimizing power consumption is analyzed. The throughput and power consumption of Rivest-Shamir Adleman (RSA) and Elliptic Curve Cryptography (ECC) are considered, since they are really popular, but have not been thoroughly analyzed when applied to IoT scenarios. Moreover, the most widespread Transport Layer Security (TLS) cipher suites use RSA as the main public key-exchange algorithm, but the key sizes needed are not practical for most IoT devices and cannot be scaled to high security levels. In contrast, ECC represents a much lighter and scalable alternative. Thus, RSA and ECC are compared for equivalent security levels, and power consumption and data throughput are measured using a testbed of IoT gateways. The measurements obtained indicate that, in the specific fog computing scenario proposed, ECC is clearly a much better alternative than RSA, obtaining energy consumption reductions of up to 50% and a data throughput that doubles RSA in most scenarios. These conclusions are then corroborated by a frame temporal analysis of Ethernet packets. In addition, current data compression algorithms are evaluated, concluding that, when dealing with the small payloads related to IoT applications, they do not pay off in terms of real data throughput and power consumption. PMID- 28850105 TI - FANTOM5 CAGE profiles of human and mouse reprocessed for GRCh38 and GRCm38 genome assemblies. AB - The FANTOM5 consortium described the promoter-level expression atlas of human and mouse by using CAGE (Cap Analysis of Gene Expression) with single molecule sequencing. In the original publications, GRCh37/hg19 and NCBI37/mm9 assemblies were used as the reference genomes of human and mouse respectively; later, the Genome Reference Consortium released newer genome assemblies GRCh38/hg38 and GRCm38/mm10. To increase the utility of the atlas in forthcoming researches, we reprocessed the data to make them available on the recent genome assemblies. The data include observed frequencies of transcription starting sites (TSSs) based on the realignment of CAGE reads, and TSS peaks that are converted from those based on the previous reference. Annotations of the peak names were also updated based on the latest public databases. The reprocessed results enable us to examine frequencies of transcription initiations on the recent genome assemblies and to refer promoters with updated information across the genome assemblies consistently. PMID- 28850107 TI - The FANTOM5 collection, a data series underpinning mammalian transcriptome atlases in diverse cell types. AB - The latest project from the FANTOM consortium, an international collaborative effort initiated by RIKEN, generated atlases of transcriptomes, in particular promoters, transcribed enhancers, and long-noncoding RNAs, across a diverse set of mammalian cell types. Here, we introduce the FANTOM5 collection, bringing together data descriptors, articles and analyses of FANTOM5 data published across the Nature Research journals. Associated data are openly available for reuse by all. PMID- 28850108 TI - The neural correlates of obsessive-compulsive disorder: a multimodal perspective. AB - Obsessive-compulsive disorder (OCD) is one of the most debilitating psychiatric conditions. An extensive body of the literature has described some of the neurobiological mechanisms underlying the core manifestations of the disorder. Nevertheless, most reports have focused on individual modalities of structural/functional brain alterations, mainly through targeted approaches, thus possibly precluding the power of unbiased exploratory approaches. Eighty subjects (40 OCD and 40 healthy controls) participated in a multimodal magnetic resonance imaging (MRI) investigation, integrating structural and functional data. Voxel based morphometry analysis was conducted to compare between-group volumetric differences. The whole-brain functional connectome, derived from resting-state functional connectivity (FC), was analyzed with the network-based statistic methodology. Results from structural and functional analysis were integrated in mediation models. OCD patients revealed volumetric reductions in the right superior temporal sulcus. Patients had significantly decreased FC in two distinct subnetworks: the first, involving the orbitofrontal cortex, temporal poles and the subgenual anterior cingulate cortex; the second, comprising the lingual and postcentral gyri. On the opposite, a network formed by connections between thalamic and occipital regions had significantly increased FC in patients. Integrative models revealed direct and indirect associations between volumetric alterations and FC networks. This study suggests that OCD patients display alterations in brain structure and FC, involving complex networks of brain regions. Furthermore, we provided evidence for direct and indirect associations between structural and functional alterations representing complex patterns of interactions between separate brain regions, which may be of upmost relevance for explaining the pathophysiology of the disorder. PMID- 28850109 TI - Genome-wide expression and response to exposure-based psychological therapy for anxiety disorders. AB - Exposure-based psychological treatments for anxiety have high efficacy. However, a substantial proportion of patients do not respond to therapy. Research examining the potential biological underpinnings of therapy response is still in its infancy, and most studies have focussed on candidate genes. To our knowledge, this study represents the first investigation of genome-wide expression profiles with respect to treatment outcome. Participants (n=102) with panic disorder or specific phobia received exposure-based cognitive behavioural therapy. Treatment outcome was defined as percentage reduction from baseline in clinician-rated severity of their primary anxiety diagnosis at post treatment and 6 month follow up. Gene expression was determined from whole blood samples at three time points using the Illumina HT-12v4 BeadChip microarray. Linear regression models tested the association between treatment outcome and changes in gene expression from pre treatment to post treatment, and pre-treatment to follow-up. Network analysis was conducted using weighted gene co-expression network analysis, and change in the detected modules from pre-treatment to post treatment and follow-up was tested for association with treatment outcome. No changes in gene expression were significantly associated with treatment outcomes when correcting for multiple testing (q<0.05), although a small number of genes showed a suggestive association with treatment outcome (q<0.5, n=20). Network analysis showed no association between treatment outcome and change in gene expression for any module. We report suggestive evidence for the role of a small number of genes in treatment outcome. Although preliminary, these findings contribute to a growing body of research suggesting that response to psychological therapies may be associated with changes at a biological level. PMID- 28850110 TI - Omega-6 to omega-3 polyunsaturated fatty acid ratio and subsequent mood disorders in young people with at-risk mental states: a 7-year longitudinal study. AB - While cross-sectional studies suggest that patients with mood disorders have a higher ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) and lower levels of omega-3 PUFAs, it is unknown if a high n-6/3 ratio indicates vulnerability for depression. We tested this hypothesis in a 7-year follow-up study of young individuals with an ultra-high risk (UHR) phenotype. We conducted a secondary analysis of the Vienna omega-3 study, a longitudinal study of omega-3 PUFAs in individuals at UHR for psychosis (n=69). Levels of n-6 and n-3 PUFAs were measured in the phosphatidylethanolamine fraction of erythrocyte membranes at intake into the study. Mood disorder diagnosis was ascertained with the Structured Clinical Interview for DSM-IV-TR and confirmed by review of medical records and interviews of caregivers. A higher n-6/3 PUFA ratio at baseline predicted mood disorders in UHR individuals over a 7-year (median) follow-up (odds ratio=1.89, 95% CI=1.075-3.338, P=0.03). This association remained significant after adjustment for age, gender, smoking, severity of depressive symptoms at baseline and n-3 supplementation. Consistent results were obtained for individual PUFAs, including lower levels of eicosapentaenoic acid and docosahexaenoic acid. The predictive capacity of these findings was specific to mood disorders as no associations were found for any other psychiatric disorder. To our knowledge, our data provide the first prospective evidence that the n-6/3 PUFA ratio is associated with an increased risk for mood disorders in young people exhibiting an UHR phenotype. These findings may have important implications for treatment and risk stratification beyond clinical characteristics. PMID- 28850111 TI - Accelerated DNA methylation age in adolescent girls: associations with elevated diurnal cortisol and reduced hippocampal volume. AB - Numerous studies have linked exposure to stress to adverse health outcomes through the effects of cortisol, a product of the stress response system, on cellular aging processes. Accelerated DNA methylation age is a promising epigenetic marker associated with stress and disease risk that may constitute a link from stress response to changes in neural structures. Specifically, elevated glucocorticoid signaling likely contributes to accelerating DNA methylation age, which may signify a maladaptive stress-related cascade that leads to hippocampal atrophy. We examined the relations among diurnal cortisol levels, DNA methylation age and hippocampal volume in a longitudinal study of 46 adolescent girls. We computed area under the curve from two daily cortisol collection periods, and calculated DNA methylation age using previously established methods based on a set of CpG sites associated with chronological age. We computed a residual score by partialling out chronological age; higher discrepancies reflect relatively accelerated DNA methylation age. We assessed hippocampal volume via T1-weighted images and automated volumetric segmentation. We found that greater diurnal cortisol production was associated with accelerated DNA methylation age, which in turn was associated with reduced left hippocampal volume. Finally, accelerated DNA methylation age significantly mediated the association between diurnal cortisol and left hippocampal volume. Thus, accelerated DNA methylation age may be an epigenetic marker linking hypothalamic-pituitary-adrenal axis dysregulation with neural structure. If these findings are replicated, the current study provides a method for advancing our understanding of mechanisms by which glucocorticoid signaling is associated with cellular aging and brain development. PMID- 28850106 TI - FANTOM5 CAGE profiles of human and mouse samples. AB - In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities. PMID- 28850112 TI - Decreased AGO2 and DCR1 in PBMCs from War Veterans with PTSD leads to diminished miRNA resulting in elevated inflammation. AB - Chronic inflammation is a characteristic of post-traumatic stress disorder (PTSD). The initiation of inflammation and molecules involved are not yet clearly understood. Here, we provide compelling evidence that the inflammation seen in PTSD may result from the dysregulated miRNA processing pathway. Using microarray analysis with a discovery group of peripheral blood mononuclear cell (PBMC) samples from War Veterans with PTSD, we found 183 significantly downregulated miRNAs, several of which target numerous genes categorized to be pro-inflammatory in nature. This observation was further confirmed in a replicate group by including more samples. Furthermore, employing RNA-sequencing, quantitative real time PCR (qRT-PCR) and in vitro experiments, we found that Argonaute 2 (AGO2) and Dicer1 (DCR1) were downregulated in PTSD and provided convincing evidence that their downregulation affects mature miRNA generation. In addition, we noted that STAT3 transcript was reduced in PTSD and this was possibly responsible for reduced AGO2 and DCR1, which in turn affected miRNA synthesis. Furthermore, we observed that activation of CD4+ T cells or monocytes led to reduced mature miRNA availability. Finally, the inflammation seen in PTSD was associated with downregulated miRNA profile. Altogether, the current study demonstrates that the chronic inflammation seen in PTSD may be a result of dysregulated miRNA biogenesis pathway due to diminished expression of the key molecules like AGO2, DCR1 and STAT3. PMID- 28850113 TI - PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia. AB - We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2 chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R) PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND. PMID- 28850116 TI - Corrigendum: Carrier generation and electronic properties of a single-component pure organic metal. PMID- 28850117 TI - Integrin binding: Sticking around vessels. PMID- 28850118 TI - Nanocrystal superlattices: No need to wait. PMID- 28850115 TI - RefEx, a reference gene expression dataset as a web tool for the functional analysis of genes. AB - Gene expression data are exponentially accumulating; thus, the functional annotation of such sequence data from metadata is urgently required. However, life scientists have difficulty utilizing the available data due to its sheer magnitude and complicated access. We have developed a web tool for browsing reference gene expression pattern of mammalian tissues and cell lines measured using different methods, which should facilitate the reuse of the precious data archived in several public databases. The web tool is called Reference Expression dataset (RefEx), and RefEx allows users to search by the gene name, various types of IDs, chromosomal regions in genetic maps, gene family based on InterPro, gene expression patterns, or biological categories based on Gene Ontology. RefEx also provides information about genes with tissue-specific expression, and the relative gene expression values are shown as choropleth maps on 3D human body images from BodyParts3D. Combined with the newly incorporated Functional Annotation of Mammals (FANTOM) dataset, RefEx provides insight regarding the functional interpretation of unfamiliar genes. RefEx is publicly available at http://refex.dbcls.jp/. PMID- 28850119 TI - Material witness: A symphony of materials. PMID- 28850120 TI - Ticking all the boxes. PMID- 28850114 TI - Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome. AB - Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate with mental disorder later in life. DNA methylation was measured genome-wide from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 individuals diagnosed with a psychiatric disorder. Among several CpG sites with P value<10-6, we identified cg23546855 (P-value=2.15 * 10-7) mapping to STK32C to be associated with a later psychiatric diagnosis. Pathway analysis of the top findings resulted in the identification of several Gene Ontology pathways to be significantly enriched (P-value<0.05 after Benjamini-Hochberg correction); among them are the following: neurogenesis, neuron development, neuron projection development, astrocyte development, axonogenesis and axon guidance. In addition, we identified differentially methylated CpG sites in LRP2BP (P-value=5.37 * 10-8) to be associated with intellectual disability (F70-79), in TOP1 (P-value=1.86 * 10-7) with behavioral disorders (F90-98), in NOSIP (P-value=5.12 * 10-8) with disorders of psychological development (F80-89) and in SEMA4B (P-value=4.02 * 10 7) with schizophrenia spectrum disorders (F20-29). In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life in 22q11.2DS individuals. PMID- 28850121 TI - Valleytronics: Magnetization without polarization. PMID- 28850128 TI - Gold-catalyzed para-selective C-H bond alkylation of benzene derivatives with donor/acceptor-substituted diazo compounds. AB - Herein, we report a gold-catalyzed highly site-selective C(sp2)-H functionalization of unactivated arenes with alpha-aryl-alpha-diazoesters with electron-withdrawing substituents as induced groups on aryl rings. Furthermore, the induced groups are useful for further synthetic transformations. PMID- 28850131 TI - Real-time fluorescence quenching-based detection of nitro-containing explosive vapours: what are the key processes? AB - The detection of explosives continues to be a pressing global challenge with many potential technologies being pursued by the scientific research community. Luminescence-based detection of explosive vapours with an organic semiconductor has attracted much interest because of its potential for detectors that have high sensitivity, compact form factor, simple operation and low-cost. Despite the abundance of literature on novel sensor materials systems there are relatively few mechanistic studies targeted towards vapour-based sensing. In this Perspective, we will review the progress that has been made in understanding the processes that control the real-time luminescence quenching of thin films by analyte vapours. These are the non-radiative quenching process by which the sensor exciton decays, the analyte-sensor intermolecular binding interaction, and the diffusion process for the analyte vapours in the film. We comment on the contributions of each of these processes towards the sensing response and, in particular, the relative roles of analyte diffusion and exciton diffusion. While the latter has been historically judged to be one of, if not the primary, causes for the high sensitivity of many conjugated polymers to nitrated vapours, recent evidence suggests that long exciton diffusion lengths are unnecessary. The implications of these results on the development of sensor materials for real time detection are discussed. PMID- 28850122 TI - Distinct transcriptional responses of lymphatic endothelial cells to VEGFR-3 and VEGFR-2 stimulation. AB - Vascular endothelial growth factors (VEGFs) and their receptors play crucial roles in the formation of blood and lymphatic vessels during embryogenesis, and also under pathologic conditions in the adult. Despite intensive efforts over the last decades to elucidate the precise functions of VEGFs, transcriptional responses to VEGF receptor stimulation are still not fully characterized. To investigate the specific transcriptional effects of VEGFR-2 and VEGFR-3 activation, we performed a correlation analysis of previously published CAGE sequencing and microarray data of human lymphatic endothelial cells (LECs) stimulated with distinct VEGFs acting through either VEGFR-2 or VEGFR-3. We identified that specific activation of VEGFR-3 by VEGF-C156S results in the downregulation of many genes involved in immune regulation and inflammation, suggesting that VEGFR-3 stimulation has direct anti-inflammatory effects. Comparing CAGE and microarray data sets, we furthermore identified a small number of genes that showed a receptor-dependent response in LECs, demonstrating that these receptors, despite activating very similar signaling pathways, fulfill overlapping but not identical functions within the same cell type (LECs). PMID- 28850132 TI - The frequency-dependent AC photoresistance behavior of ZnO thin films grown on different sapphire substrates. AB - Zinc oxide (ZnO) thin films were grown by pulsed layer deposition under an N2 atmosphere at low pressures on a- and r-plane sapphire substrates. Structural studies using X-ray diffraction confirmed that all films had a wurtzite phase. ZnO thin films on a- and r-plane sapphire have grown with orientations along the [0002] and [112[combining macron]0] directions, respectively. Room temperature photoluminescence measurements indicate that the presence of native point defects (interstitial zinc, oxygen vacancies, oxygen antisites and zinc vacancies) is more preponderant for ZnO thin films grown on the r-plane sapphire substrate than the sample grown on the a-plane sapphire substrate. Room temperature impedance spectroscopy measurements were performed in an alternating current frequency range from 40 to 105 Hz in the dark and under normal light. An unusual positive photoresistance effect is observed at frequencies above 100 kHz, which we suggest to be due to intrinsic defects present in the ZnO thin films. Furthermore, an analysis of the optical time response revealed that the film grown on the r-plane sapphire substrate responds faster (characteristic relaxation times for tau1, tau2 and tau3 of 0.05, 0.26 and 6.00 min, respectively) than the film grown on the a-plane sapphire substrate (characteristic relaxation times for tau1, tau2 and tau3 of 0.10, 0.73 and 4.02 min, respectively). PMID- 28850134 TI - Insights into the mechanism of the capture of CO2 by K2CO3 sorbent: a DFT study. AB - The adsorption and reactions of CO2 and H2O on both monoclinic and hexagonal crystal K2CO3 were investigated using the density functional theory (DFT) approach. The calculated adsorption energies showed that adsorption of H2O molecules was clearly substantially stronger on the K2CO3 surface than the adsorption of CO2, except on the (001)-1 surface of hexagonal K2CO3, where CO2 is competitively adsorbed with H2O. Carbonation reactions easily occur on pure K2CO3 and involve two parallel paths: one is where adsorbed H2O reacts with molecular CO2 in gas to form the bicarbonate, while the other is where H2O dissociates into OH and H before bicarbonate formation, and then OH reacts with gaseous CO2 to form a bicarbonate. Our results indicate that adding a support or promoter or using a special technique to expose more (001)-1 surfaces in hexagonal K2CO3 may improve the conversion of CO2 to the bicarbonate, which provides a theoretical direction for the experimental preparation of the K2CO3 sorbent to capture CO2. PMID- 28850136 TI - Enabling miniaturised personalised diagnostics: from lab-on-a-chip to lab-in-a drop. AB - The concept of personalised diagnostics is to direct accurate clinical decisions based on an individual's unique disease molecular profile. Lab-on-a-chip (LOC) systems are prime personalised diagnostics examples which seek to perform an entire sample-to-outcome detection of disease nucleic acid (NA) biomarkers on a single miniaturised platform with minimal user handling. Despite the great potential of LOC devices in providing rapid, portable, and inexpensive personalised diagnosis at the point-of-care (POC), the translation of this technology into widespread use has still been hampered by the need for sophisticated and complex engineering. As an alternative miniaturised diagnostics platform free of precision fabrication, there have been recent developments towards a solution-based lab-in-a-drop (LID) system by which an entire laboratory based diagnostics workflow could be downscaled and integrated within a singular fluid droplet for POC detection of NA biomarkers. In contrast to existing excellent reviews on miniaturised LOC fabrication and individual steps of NA biomarker sensing, we herein focus on miniaturised solution-based NA biosensing strategies suited for integrated LID personalised diagnostics development. In this review, we first evaluate the three fundamental bioassay steps for miniaturised NA biomarker detection: crude sample preparation, isothermal target amplification, and detection readout of amplicons. Then, we provide insights into research advancements towards a functional LID system which integrates all three of the above-mentioned fundamental steps. Finally, we discuss perspectives and future directions of LID diagnostic platforms in personalised medicine applications. PMID- 28850137 TI - Self-assembly with colloidal clusters: facile crystal design using connectivity landscape analysis. AB - Recent experimental and theoretical studies demonstrate that prefabricated micron scale colloidal clusters functionalized with DNA oligomers offer a practical way for introducing anisotropic interactions, significantly extending the scope of DNA-mediated colloidal assembly, and enabling the formation of interesting crystalline superstructures that are otherwise inaccessible with short-ranged, spherically symmetric interactions. However, it is apparent that the high dimensional parameter space that defines the geometric and interaction properties of such systems poses an obstacle to assembly design and optimization. Here, we present a geometrical analysis that generates connectivity landscapes for target superstructures, greatly reducing the space over which subsequent experimental trials must search. We focus on several superstructures that are assembled from binary systems comprised of 'merged' or 'sintered' tetrahedral clusters and single spheres. We also validate and extend the analytical constraint approach with direct MD simulations of superstructure nucleation and growth. PMID- 28850133 TI - cis-Tetrachlorido-bis(indazole)osmium(iv) and its osmium(iii) analogues: paving the way towards the cis-isomer of the ruthenium anticancer drugs KP1019 and/or NKP1339. AB - The relationship between cis-trans isomerism and anticancer activity has been mainly addressed for square-planar metal complexes, in particular, for platinum(ii), e.g., cis- and trans-[PtCl2(NH3)2], and a number of related compounds, of which, however, only cis-counterparts are in clinical use today. For octahedral metal complexes, this effect of geometrical isomerism on anticancer activity has not been investigated systematically, mainly because the relevant isomers are still unavailable. An example of such an octahedral complex is trans-[RuCl4(Hind)2]-, which is in clinical trials now as its indazolium (KP1019) or sodium salt (NKP1339), but the corresponding cis-isomers remain inaccessible. We report the synthesis of Na[cis-OsIIICl4(kappaN2-1H ind)2].(Na[1]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H2ind)[OsIVCl5(kappaN1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the formation of cis [OsIVCl4(kappaN2-1H-ind)2] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from kappaN1 to kappaN2 and stabilization of the 1H-indazole tautomer. Fully reversible spectroelectrochemical reduction of [1] in acetonitrile at 0.46 V vs. NHE is accompanied by a change in electronic absorption bands indicating the formation of cis-[OsIIICl4(kappaN2-1H-ind)2]- ([1]-). Chemical reduction of [1] in methanol with NaBH4 followed by addition of nBu4NCl afforded the osmium(iii) complex nBu4N[cis-OsIIICl4(kappaN2-1H-ind)2] (nBu4N[1]). A metathesis reaction of nBu4N[1] with an ion exchange resin led to the isolation of the water-soluble salt Na[1]. The X-ray diffraction crystal structure of [1].Me2CO was determined and compared with that of trans [OsIVCl4(kappaN2-1H-ind)2].2Me2SO (2.2Me2SO), also prepared in this work. EPR spectroscopy was performed on the OsIII complexes and the results were analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [1] and Na[1] on cell viability and proliferation in comparison with trans [OsIVCl4(kappaN1-2H-ind)2] [3] and cisplatin and found a strong reduction of cell viability at concentrations between 30 and 300 MUM in different cancer cell lines (HT29, H446, 4T1 and HEK293). HT-29 cells are less sensitive to cisplatin than 4T1 cells, but more sensitive to [1] and Na[1], as shown by decreased proliferation and viability as well as an increased late apoptotic/necrotic cell population. PMID- 28850138 TI - The relationship between cell adhesion force activation on nano/micro topographical surfaces and temporal dependence of cell morphology. AB - Interaction between adherent cells and extracellular matrix/scaffold surface features performs a crucial role in inducing physiological functions via signal transduction. Topographical design of scaffold surfaces, therefore, has the potential to promote physiological functions such as cell proliferation and differentiation. This study utilizes quantitative evaluation of cell-material interaction to identify how temporal dependence of cell morphology impacts cell adhesion force activation on nano/micro-ordered topographical surfaces. Nano rough and micro-dot/line-patterned poly-lactic acid substrates were prepared to enable: (i) examination of the morphology of lamellipodia/filopodia, focal adhesion coupled with vinculin accumulations, and actin-filaments of osteoblast like cells; and (ii) assay of the cell detachment force by single cell force spectroscopy. The quantitative evaluation results evidenced that in the initial period (cell adhesion time after initial attachment on any location, ta < 1 h), while nano-topographical surface enhanced detachment force of "spherical" cells, micro-topographical surfaces did not have this effect. Significantly, the identical micro-topographical surfaces were able to enhance detachment force of "spreading" cells in intermediate (1 < ta < 12 h) and long-term periods (ta > 24 h). These findings could be utilized in the design of scaffold surfaces to promote cell-material interaction (e.g. strengthening of the cell-substrate adhesion force), in tissue engineering. PMID- 28850141 TI - CuCl-Catalyzed direct C-H alkenylation of benzoxazoles with allyl halides. AB - An efficient and concise CuCl-catalyzed C2-alkenylation reaction of benzoxazoles with allyl halides has been established. The distinctive features of this protocol include the use of an inexpensive copper salt as a catalyst, simple and readily available starting materials, and ligand-free conditions. An important application of this method to the synthesis of 1,3-diene substituted benzoxazoles has also been achieved. PMID- 28850139 TI - Microfluidic device for rapid digestion of tissues into cellular suspensions. AB - The ability to harvest single cells from tissues is currently a bottleneck for cell-based diagnostic technologies, and remains crucial in the fields of tissue engineering and regenerative medicine. Tissues are typically broken down using proteolytic digestion and various mechanical treatments, but success has been limited due to long processing times, low yield, and high manual labor burden. Here, we present a novel microfluidic device that utilizes precision fluid flows to improve the speed and efficiency of tissue digestion. The microfluidic channels were designed to apply hydrodynamic shear forces at discrete locations on tissue specimens up to 1 cm in length and 1 mm in diameter, thereby accelerating digestion through hydrodynamic shear forces and improved enzyme tissue contact. We show using animal organs that our digestion device with hydro mincing capabilities was superior to conventional scalpel mincing and digestion based on recovery of DNA and viable single cells. Thus, our microfluidic digestion device can eliminate or reduce the need to mince tissue samples with a scalpel, while reducing sample processing time and preserving cell viability. Another advantage is that downstream microfluidic operations could be integrated to enable advanced cell processing and analysis capabilities. We envision our novel device being used in research and clinical settings to promote single cell based analysis technologies, as well as to isolate primary, progenitor, and stem cells for use in the fields of tissue engineering and regenerative medicine. PMID- 28850142 TI - 3D Bragg coherent diffractive imaging of five-fold multiply twinned gold nanoparticle. AB - The formation mechanism of five-fold multiply twinned nanoparticles has been a long-term topic because of their geometrical incompatibility. So, various models have been proposed to explain how the internal structure of the multiply twinned nanoparticles accommodates the constraints of the solid-angle deficiency. We investigate the internal structure, strain field and strain energy density of 600 nm sized five-fold multiply twinned gold nanoparticles quantitatively using Bragg coherent diffractive imaging, which is suitable for the study of buried defects and three-dimensional strain distribution with great precision. Our study reveals that the strain energy density in five-fold multiply twinned gold nanoparticles is an order of magnitude higher than that of the single nanocrystals such as an octahedron and triangular plate synthesized under the same conditions. This result indicates that the strain developed while accommodating an angular misfit, although partially released through the introduction of structural defects, is still large throughout the crystal. PMID- 28850143 TI - Biocompatible and blood-brain barrier permeable carbon dots for inhibition of Abeta fibrillation and toxicity, and BACE1 activity. AB - Amyloid-beta peptide (Abeta) fibrillation is pathologically associated with Alzheimer's disease (AD), and this has resulted in the development of an Abeta inhibitor which is essential for the treatment of AD. However, the design of potent agents which can target upstream secretases, inhibit Abeta toxicity and aggregation, as well as cross the blood-brain barrier remains challenging. In, this research carbon dots for AD treatment were investigated in vitro using experimental and computational methods for the first time. The results presented here demonstrate a novel strategy for the discovery of novel antiamyloidogenic agents for AD treatments. PMID- 28850144 TI - Key role of surface oxidation and reduction processes in the coarsening of Pt nanoparticles. AB - Particle coarsening is the main cause for thermal deactivation and lifetime reduction of supported Pt nanocatalysts. Here, Atomic Layer Deposition (ALD) was used to prepare a model system of Pt nanoparticles with high control over the metal loading and the nanoparticle size and coverage. A series of samples with distinct as-deposited size and interparticle spacing was annealed under different oxygen environments while Grazing Incidence Small Angle X-ray Scattering (GISAXS) was employed as in situ tool for monitoring the change in average nanoparticle size. The obtained results revealed three morphological stages during the thermal treatment, which can be explained by (I) the formation of a PtO2 shell on stable Pt nanoparticles at low temperature (below 300 degrees C), (II) the reduction of the PtO2 shell at moderate temperature (300 to 600 degrees C), creating mobile species that trigger particle coarsening until a steady morphological state is reached, and (III) the evaporation of PtO2 at high temperature (above 650 degrees C), causing particle instability and coarsening reactivation. The onset temperatures for stages (II) and (III) were found to depend on the initial particle size and spacing as well as on the O2 partial pressure during annealing, and could be summarized in a morphological stability diagram for Pt nanoparticles. The coarsening model indicates an important role for the reduction of the PtO2 shell in inducing particle coarsening. The key role of the reduction process was corroborated through isothermal experiments under decreasing O2 partial pressure and through forced reduction experiments near room temperature via H2 exposure. PMID- 28850145 TI - Gold-silver catalyzed straightforward one pot synthesis of pyrano[3,4-b]pyrrol 7(1H)-ones. AB - Pyrano[3,4-b]pyrrol-7(1H)-one is a bicyclic structure that is rarely described in the literature but is found in numerous polycyclic natural products as lamellarins. This work presents a one-pot synthesis of pyrano[3,4-b]pyrrol-7(1H) one substituted in the 2- and 5-position. The reaction proceeds via a one-pot two step 5-endo-dig and 6-endo-dig cyclization catalyzed by a cationic gold complex with high regioselectivity. PMID- 28850146 TI - The importance of asking "how and why?" in natural product structure elucidation. AB - Covering: up to 2017This review highlights why careful consideration of the biosynthetic origin (the how) and the biological function (the why) of a natural product can be so useful during the determination of its structure. Recent examples of structural reassignments inspired by biosynthetic and functional insights will be presented. This review will demonstrate the importance of viewing the origin, structure and function of a natural product as intertwined threads of a single story, best viewed as a whole rather than as discrete topics. PMID- 28850147 TI - Sun protection by umbrellas and walls. AB - Solar protection is an important public health issue because solar UV exposure can cause acute and chronic damage to the skin. Seeking shade is a convenient and commonly practiced sun avoidance measure. Shade works by physically shielding the skin from direct UV rays; however UV rays can also reach the skin from other angles. It is not clear how protective the widely-used shade structures like umbrellas and walls are under actual use conditions. In this study, a sky view model was applied to systematically assess the influence of different factors to umbrellas and walls, including the transmission of the shade materials, the reflectivity of the ground or the wall, diffused UV to total UV irradiance ratios, shade geometry, a person's positions and orientations in the shade. We measured the sunburn protection factor (SPF) with a calibrated UV meter at different positions in the shades of an umbrella at different times of the day and compared the measurement results with the modeling. We found that shade structures like umbrellas and walls are more effective when the ratios of diffused UV to total UV irradiance are smaller (mid-day). The effectiveness increases with more coverage, less surface reflectance, and more centralized positions in the shade. The SPF value for a typical umbrella is probably between 3 and 7 in real-life. The low sun protection level offered by a typical shade highlights the importance of educating the public about how to properly protect the skin from the sun and the importance of applying a combination of sun protection measures during extended sun exposures. PMID- 28850148 TI - An advanced selective liquid-metal plating technique for stretchable biosensor applications. AB - This paper presents a novel stretchable pulse sensor fabricated by a selective liquid-metal plating process (SLMP), which can conveniently attach to the human skin and monitor the patient's heartbeat. The liquid metal-based stretchable pulse sensor consists of polydimethylsiloxane (PDMS) thin films and liquid metal functional circuits with electronic elements that are embedded into the PDMS substrate. In order to verify the utility of the fabrication process, various complex liquid-metal patterns are achieved by using the selective wetting behavior of the reduced liquid metal on the Cu patterns of the PDMS substrate. The smallest liquid-metal pattern is approximately 2 MUm in width with a uniform surface. After verification, a transparent flowing LED light with programmed circuits is realized and exhibits stable mechanical and electrical properties under various deformations (bending, twisting and stretching). Finally, based on SLMP, a wireless pulse measurement system is developed which is composed of the liquid metal-based stretchable pulse sensor, a Bluetooth module, an Arduino development board, a laptop computer and a self-programmed visualized software program. The experimental results reveal that the portable non-invasive pulse sensor has the potential to reduce costs, simplify biomedical diagnostic procedures and help patients to improve their life in the future. PMID- 28850151 TI - Association between active brown adipose tissue and coronary artery calcification in healthy men. AB - AIM: We compared various clinical factors between persons with active brown adipose tissue (ABAT) and matched controls, and investigated the relationship between the presence of ABAT and coronary artery calcification (CAC) with respect to arterial inflammation. METHODS: We retrospectively reviewed fluorine-18 labeled fluoro-2-deoxy-D-glucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) data from men who underwent general health check-ups. Sixty seven men with ABAT were identified and were matched with controls at a 1:1 ratio. Peripheral blood samples were obtained and the levels of various laboratory parameters were measured just before FDG PET/CT studies. Arterial inflammation was measured in the ascending aorta, venous mean standardized uptake value (SUV) was collected from the superior vena cava as FDG uptake on PET, and background-corrected SUV was calculated as the target-to-background ratio (TBR) and blood-subtracted SUVmax (bsSUVmax). CAC was assessed using CT images acquired from a PET/CT scanner. RESULTS: The prevalence of fatty liver (p = 0.048) and CAC (p = 0.026) was lower in men with ABAT compared to matched controls. Arterial SUVmax (1.72 +/- 0.23 vs. 1.88 +/- 0.23, p < 0.001), TBR (1.18 +/- 0.14 vs. 1.29 +/- 0.13, p < 0.001), and bsSUVmax (0.25 +/- 0.18 vs. 0.41 +/- 0.16, p < 0.001) were significantly lower in men with ABAT. ABAT (odds ratio [OR] = 0.19, p = 0.024) and high-density lipoprotein cholesterol (OR = 0.95, p = 0.037) were independent factors associated with CAC according to multiple logistic regression analysis. CONCLUSION: ABAT is associated with down-regulated arterial inflammation and may exert a protective effect against the development of atherosclerosis. (p = 0,026) war geringer bei Mannern mit ABAT im Vergleich zu gematchten Kontrollen. Arterieller SUVmax (1,72 +/- 0,23 vs. 1,88 +/- 0,23, p < 0,001), TBR (1,18 +/- 0,14 vs. 1,29 +/- 0,13, p < 0,001) und bsSUVmax (0,25 +/- 0,18 vs. 0,41 +/- 0,16, p < 0,001) waren bei Mannern mit ABAT signifikant geringer. ABAT (Odds ratio [OR] = 0,19, p = 0,024) und HDL-Cholesterol (OR = 0,95, p = 0,037) waren in einer multiplen logistischen Regressionsanalyse unabhangige Faktoren, die mit CAC assoziiert waren. Schlussfolgerung : ABAT ist assoziiert mit einer herunterregulierten arteriellen Entzundung und ubt moglicherweise einen schutzenden Effekt gegen die Entwicklung einer Atherosklerose aus. PMID- 28850152 TI - Development of Multivariable Models to Predict and Benchmark Transfusion in Elective Surgery Supporting Patient Blood Management. AB - BACKGROUND: Blood transfusion is a highly prevalent procedure in hospitalized patients and in some clinical scenarios it has lifesaving potential. However, in most cases transfusion is administered to hemodynamically stable patients with no benefit, but increased odds of adverse patient outcomes and substantial direct and indirect cost. Therefore, the concept of Patient Blood Management has increasingly gained importance to pre-empt and reduce transfusion and to identify the optimal transfusion volume for an individual patient when transfusion is indicated. OBJECTIVES: It was our aim to describe, how predictive modeling and machine learning tools applied on pre-operative data can be used to predict the amount of red blood cells to be transfused during surgery and to prospectively optimize blood ordering schedules. In addition, the data derived from the predictive models should be used to benchmark different hospitals concerning their blood transfusion patterns. METHODS: 6,530 case records obtained for elective surgeries from 16 centers taking part in two studies conducted in 2004 2005 and 2009-2010 were analyzed. Transfused red blood cell volume was predicted using random forests. Separate models were trained for overall data, for each center and for each of the two studies. Important characteristics of different models were compared with one another. RESULTS: Our results indicate that predictive modeling applied prior surgery can predict the transfused volume of red blood cells more accurately (correlation coefficient cc = 0.61) than state of the art algorithms (cc = 0.39). We found significantly different patterns of feature importance a) in different hospitals and b) between study 1 and study 2. CONCLUSION: We conclude that predictive modeling can be used to benchmark the importance of different features on the models derived with data from different hospitals. This might help to optimize crucial processes in a specific hospital, even in other scenarios beyond Patient Blood Management. PMID- 28850153 TI - Computed tomographic study of safe implantation corridors in rabbit lumbar vertebrae. AB - OBJECTIVES: A study was performed to evaluate the lumbar vertebrae of domestic rabbits using computed tomography (CT) in order to identify safe corridors for implant insertion. METHODS: Computed tomography imaging of 20 adult New Zealand white rabbits was evaluated using three-dimensional multiplanar reconstruction, and safe corridors were determined. Following corridor determination, implant placement was performed, and imaging was repeated. RESULTS: The cranial and caudal endplates contained the majority of the vertebral bone stock, and were an average of 3.14 and 3.30 mm in length, respectively. The mean safe corridor angle was 62.9 degrees (range: 58.8-66.7), and the mean width of the corridor was 2.03 mm (range: 1.60- 2.07). Post-placement imaging revealed that 35% of the pins demonstrated errors of placement, most commonly canal impingement. CONCLUSIONS: The results of the corridor evaluation indicate that an insertion angle of approximately 60 degrees relative to the sagittal midline is appropriate for implant insertion in the lumbar vertebrae of New Zealand white rabbits. Additionally, due to the hourglass shape of rabbit vertebrae, the endplates provide maximal bone stock for implant purchase, so insertion should be attempted in these regions. However, the high percentage of errors in placement indicate the need to more clearly define entry points to access the canal, and highlight the challenges of appropriate placement in the small bones of rabbits. PMID- 28850154 TI - A FHIR Human Leukocyte Antigen (HLA) Interface for Platelet Transfusion Support. AB - Platelet transfusions are a cornerstone of therapy for patients who develop thrombocytopenia while undergoing Hematopoietic Stem Cell Transplantation (HSCT). Many patients who develop Platelet Transfusion Refractoriness (PTR) require HLA matched platelets. Identifying these patients early could lead to better utilization of platelets as well as increased platelet counts. We built a SMART on FHIR visualization tool to aid the oncology, blood bank, and blood donor center teams in identifying these patients by showing trends in thrombocytopenia along with a computer generated calculated Panel Reactive Antibody (cPRA) level. To do this, we required a FHIR interface to our HLA database. We describe our methods and outcome for constructing this FHIR interface, as well as the architecture and data flow of HLA data from its proprietary database to the SMART on FHIR environment and application database along with RESTful cPRA web service calculator. Future work will evaluate the clinical impact of this platelet visualization tool and overall success of our FHIR implementation. PMID- 28850156 TI - ? AB - Advances in fetal surgery Fetal surgery is a subspeciality that is evolving rapidly with focus on improving the natural history of congenital malformations and conditions that are either life threatening or cause severe disability. Fetal surgery for myelomeningocele has been shown to improve neurologic outcome, motor function and to reduce the need of ventriculo-peritoneal shunting after birth compared to postnatal care. However, it conveys an increased risk of preterm birth and maternal morbidity. The role of prenatal intervention with endoscopic tracheal occlusion in congenital diaphragmatic hernia is currently the focus of an ongoing multicenter randomized controlled trial. The trial is comparing the effect of fetal surgery as an alternative to standard postnatal management. The main, but not sole, indication for an Ex-utero intrapartum treatment (EXIT) is airway obstruction due to laryngeal atresia and tumors in the head and neck region. It is a complex procedure that should be performed only in experienced centers with a multidisciplinary team. PMID- 28850155 TI - Adipose tissue and serum CCDC80 in obesity and its association with related metabolic disease. AB - Coiled-coil domain-containing 80 (CCDC80) is an adipocyte-secreted protein that modulates glucose homeostasis in response to diet-induced obesity in mice. The objective of this study is to analyze the link between human CCDC80 and obesity. CCDC80 protein expression was assessed in paired visceral (VAT) and subcutaneous (SAT) adipose tissue from 10 subjects (BMI range 22.4-38.8 kg/m2). Circulating CCDC80 levels were quantified in serum samples from two independent cross sectional cohorts comprising 33 lean and 15 obese (cohort 1) and 32 morbid obese (cohort 2) male subjects. Insulin sensitivity, insulin secretion and blood neutrophil count were quantified in serum samples from both cohorts. Additionally, circulating free IGF-1 levels and oral glucose tolerance tests (OGTT) were assessed in cohort 1 whereas C-reactive protein levels and degree of atherosclerosis and hepatic steatosis were studied in cohort 2. In lean subjects, total CCDC80 protein content assessed by immunoblotting was lower in VAT than in SAT. In obese patients, CCDC80 was increased in VAT (P<0.05), but equivalent in SAT compared with lean counterparts. In cohort 1, serum CCDC80 correlated negatively with the acute insulin response to glucose and IGF1 levels, and positively with blood neutrophil count, independently of BMI, but not with insulin sensitivity. In cohort 2, serum CCDC80 was positively linked to the inflammatory biomarker C-reactive protein (r=0.46; P=0.009), atherosclerosis (carotid intima-media thickness, r=0.62; P<0.001) and hepatic steatosis (ANOVA P=0.025). Overall, these results suggest for the first time that CCDC80 may be a component of the obesity-altered secretome in VAT and could act as an adipokine whose circulant levels are linked to glucose tolerance derangements and related to inflammation-associated chronic complications. PMID- 28850157 TI - ? AB - Doxycycline can be given to children without risk of staining of teeth In Sweden, several hundred children are treated for Lyme neuroborreliosis annually, the majority of which are treated with intravenous ceftriaxone. Older tetracycline class antibiotics can cause permanent staining of the teeth. For doxycycline this has never been shown. Three publications on children exposed to doxycycline from three months of age show no risk of staining of the teeth. Changing the recommended treatment for children with Lyme neuroborreliosis to oral doxycycline would markedly simplify treatment for children and parents and reduce healthcare costs. PMID- 28850158 TI - ? PMID- 28850159 TI - ? PMID- 28850161 TI - ? PMID- 28850160 TI - ? PMID- 28850162 TI - ? PMID- 28850163 TI - ? PMID- 28850164 TI - ? PMID- 28850165 TI - ? PMID- 28850166 TI - ? PMID- 28850167 TI - ? AB - Invasive fetal therapy Invasive fetal therapy in Sweden consists of fetoscopic interventions to treat twin-to-twin transfusion syndrome (TTS) or twin anemia polycytemia sequence (TAPS) in monochorionic twin or triplet pregnancies and for selective reduction in monochorionic twins complicated by discordant anomalies or severe growth retardation in one fetus. Alternative methods, such as intrafetal laser ablation and radio frequency ablation, are also used for selective reduction and rarely to treat fetal tumors. Ultrasound guided intrauterine blood transfusions to treat fetal anemia have been performed for a long time with excellent results. Placement of thoraco-amniotic shunts and vesico-amniotic shunts is indicated in a few cases per year in Sweden. Since these rare interventions were centralized to one national center in 2013, the outcome of the fetal interventions has improved consistently. PMID- 28850169 TI - Bridging immunity with infection, inflammation and implantation for better reproductive health, ASRI 37th Annual Meeting, September 17-20, 2017 Chicago, Illinois, USA. PMID- 28850168 TI - Revised CHARMM force field parameters for iron-containing cofactors of photosystem II. AB - Photosystem II is a complex protein-cofactor machinery that splits water molecules into molecular oxygen, protons, and electrons. All-atom molecular dynamics simulations have the potential to contribute to our general understanding of how photosystem II works. To perform reliable all-atom simulations, we need accurate force field parameters for the cofactor molecules. We present here CHARMM bonded and non-bonded parameters for the iron-containing cofactors of photosystem II that include a six-coordinated heme moiety coordinated by two histidine groups, and a non-heme iron complex coordinated by bicarbonate and four histidines. The force field parameters presented here give water interaction energies and geometries in good agreement with the quantum mechanical target data. (c) 2017 Wiley Periodicals, Inc. PMID- 28850170 TI - Preliminary Pages. PMID- 28850171 TI - X-Ray Crystal Structure of Embelin and Its DFT Scavenging of Superoxide Radical. AB - Embelin is a phytochemical component of tropical plants that have a long history of being used in ethnic pharmacology in various parts of the world, including Ayurdvedic and Chinese medicinal texts. Many modern studies confirm its promise as a medicinal compound. The X-ray crystal structure determination of embelin shows a remarkably ordered alkyl chain and particularly strong pi-pi interactions for a nonaromatic system. The molecule has a torsion angle of 67 degrees between the ring and the alkyl chain of the molecule and differs markedly from that seen when embelin is embedded in the plasminogen activator inhibitor-1 (PAI-1) binding site (almost planar-with about 10 degrees torsion angle). This suggests that embelin's flexible structural skeleton can be useful in biological environment. Apart from this, its many biological activities likely depend on embelin's hydrophobic nonpolar tail that allows a variety of interactions. Computationally, we evaluated embelin's sequestering ability toward the superoxide radical and see that embelin executes this reaction in a novel manner. Namely, as shown by our DFT calculations, instead of releasing a H atom to the superoxide radical to form the anionic species O2 H- , embelin prefers to accept an electron from the superoxide radical, which then transforms into molecular oxygen, O2 . (c) 2017 Wiley Periodicals, Inc. PMID- 28850173 TI - Interventions for preventing and managing advanced liver disease in cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. OBJECTIVES: To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search: 06 April 2017.We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 04 January 2017. SELECTION CRITERIA: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both). DATA COLLECTION AND ANALYSIS: Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review. MAIN RESULTS: A comprehensive search of the literature did not identify any published eligible randomised controlled trials. AUTHORS' CONCLUSIONS: In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis. PMID- 28850172 TI - Isoniazid for preventing tuberculosis in HIV-infected children. AB - BACKGROUND: Tuberculosis (TB) is an important cause of illness and death in HIV positive children living in areas of high TB prevalence. We know that isoniazid prophylaxis prevents TB in HIV-negative children following TB exposure, but there is uncertainty related to its role in TB preventive treatment in HIV-positive children. OBJECTIVES: To summarise the effects of TB preventive treatment versus placebo in HIV-positive children with no known TB contact on active TB, death, and reported adverse events. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, Embase and two trial registers up to February 2017. SELECTION CRITERIA: We included trials of HIV positive children with and without known TB exposure, randomized to receive TB preventive treatment or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently used the study selection criteria, assessed risk of bias, and extracted data. We assessed effects using risk, incidence rate and hazard ratios and assessed the certainty of evidence using GRADE. MAIN RESULTS: We included three trials, involving 991 participants, below the age of 13 years, from South Africa and Botswana. Children were randomized to isoniazid prophylaxis or placebo, given daily or three times weekly. The median length of follow-up ranged from 5.7 to 34 months; some were on antiretroviral therapy (ART).In HIV-positive children not on ART, isoniazid prophylaxis may reduce the risk of active TB (hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.11 to 0.87; 1 trial, 240 participants, low certainty evidence), and death (HR 0.46, 95% CI 0.22 to 0.95; 1 trial, 240 participants, low certainty evidence). One trial (182 participants) reported number of children with laboratory adverse events, which was similar between the isoniazid prophylaxis and placebo groups. No clinical adverse events were reported.In HIV-positive children on ART, we do not know if isoniazid prophylaxis reduces the risk of active TB (risk ratio (RR) 0.76, 95% CI 0.50 to 1.14; 3 trials, 737 participants, very low certainty evidence) or death (RR 1.45, 95% CI 0.78 to 2.72; 3 trials, 737 participants, very low certainty evidence). Two trials (714 participants) reported number of clinical adverse events and three trials (795 participants) reported number of laboratory adverse events; for both categories, the number of adverse events were similar between the isoniazid prophylaxis and placebo groups. AUTHORS' CONCLUSIONS: Isoniazid prophylaxis given to all children diagnosed with HIV may reduce the risk of active TB and death in HIV-positive children not on ART in studies from Africa. For children on ART, no clear benefit was detected. . PMID- 28850174 TI - Chemotherapy for advanced gastric cancer. AB - BACKGROUND: Gastric cancer is the fifth most common cancer worldwide. In "Western" countries, most people are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. In people with advanced disease, significant benefits from targeted therapies are currently limited to HER-2 positive disease treated with trastuzumab, in combination with chemotherapy, in first-line. In second-line, ramucirumab, alone or in combination with paclitaxel, demonstrated significant survival benefits. Thus, systemic chemotherapy remains the mainstay of treatment for advanced gastric cancer. Uncertainty remains regarding the choice of the regimen. OBJECTIVES: To assess the efficacy of chemotherapy versus best supportive care (BSC), combination versus single-agent chemotherapy and different chemotherapy combinations in advanced gastric cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase up to June 2016, reference lists of studies, and contacted pharmaceutical companies and experts to identify randomised controlled trials (RCTs). SELECTION CRITERIA: We considered only RCTs on systemic, intravenous or oral chemotherapy versus BSC, combination versus single-agent chemotherapy and different chemotherapy regimens in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies and extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: We included 64 RCTs, of which 60 RCTs (11,698 participants) provided data for the meta-analysis of overall survival. We found chemotherapy extends overall survival (OS) by approximately 6.7 months more than BSC (hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.24 to 0.55, 184 participants, three studies, moderate-quality evidence). Combination chemotherapy extends OS slightly (by an additional month) versus single-agent chemotherapy (HR 0.84, 95% CI 0.79 to 0.89, 4447 participants, 23 studies, moderate-quality evidence), which is partly counterbalanced by increased toxicity. The benefit of epirubicin in three drug combinations, in which cisplatin is replaced by oxaliplatin and 5-FU is replaced by capecitabine is unknown.Irinotecan extends OS slightly (by an additional 1.6 months) versus non-irinotecan-containing regimens (HR 0.87, 95% CI 0.80 to 0.95, 2135 participants, 10 studies, high-quality evidence).Docetaxel extends OS slightly (just over one month) compared to non-docetaxel-containing regimens (HR 0.86, 95% CI 0.78 to 0.95, 2001 participants, eight studies, high quality evidence). However, due to subgroup analyses, we are uncertain whether docetaxel-containing combinations (docetaxel added to a single-agent or two-drug combination) extends OS due to moderate-quality evidence (HR 0.80, 95% CI 0.71 to 0.91, 1466 participants, four studies, moderate-quality evidence). When another chemotherapy was replaced by docetaxel, there is probably little or no difference in OS (HR 1.05; 0.87 to 1.27, 479 participants, three studies, moderate-quality evidence). We found there is probably little or no difference in OS when comparing capecitabine versus 5-FU-containing regimens (HR 0.94, 95% CI 0.79 to 1.11, 732 participants, five studies, moderate-quality evidence) .Oxaliplatin may extend (by less than one month) OS versus cisplatin-containing regimens (HR 0.81, 95% CI 0.67 to 0.98, 1105 participants, five studies, low-quality evidence). We are uncertain whether taxane-platinum combinations with (versus without) fluoropyrimidines extend OS due to very low-quality evidence (HR 0.86, 95% CI 0.71 to 1.06, 482 participants, three studies, very low-quality evidence). S-1 regimens improve OS slightly (by less than an additional month) versus 5-FU containing regimens (HR 0.91, 95% CI 0.83 to 1.00, 1793 participants, four studies, high-quality evidence), however since S-1 is used in different doses and schedules between Asian and non-Asian population, the applicability of this finding to individual populations is uncertain. AUTHORS' CONCLUSIONS: Chemotherapy improves survival (by an additional 6.7 months) in comparison to BSC, and combination chemotherapy improves survival (by an additional month) compared to single-agent 5-FU. Testing all patients for HER-2 status may help to identify patients with HER-2-positive tumours, for whom, in the absence of contraindications, trastuzumab in combination with capecitabine or 5-FU in combination with cisplatin has been shown to be beneficial. For HER-2 negative people, all different two-and three-drug combinations including irinotecan, docetaxel, oxaliplatin or oral 5-FU prodrugs are valid treatment options for advanced gastric cancer, and consideration of the side effects of each regimen is essential in the treatment decision. Irinotecan-containing combinations and docetaxel-containing combinations (in which docetaxel was added to a single-agent or two-drug (platinum/5-FUcombination) show significant survival benefits in the comparisons studied above. Furthermore, docetaxel-containing three-drug regimens have increased response rates, but the advantages of the docetaxel-containing three-drug combinations (DCF, FLO-T) are counterbalanced by increased toxicity. Additionally, oxaliplatin-containing regimens demonstrated a benefit in OS as compared to the same regimen containing cisplatin, and there is a modest survival improvement of S-1 compared to 5-FU-containing regimens.Whether the survival benefit for three-drug combinations including cisplatin, 5-FU, and epirubicin as compared to the same regimen without epirubicin is still valid when second-line therapy is routinely administered and when cisplatin is replaced by oxaliplatin and 5-FU by capecitabine is questionable. Furthermore, the magnitude of the observed survival benefits for the three-drug regimens is not large enough to be clinically meaningful as defined recently by the American Society for Clinical Oncology (Ellis 2014). In contrast to the comparisons in which a survival benefit was observed by adding a third drug to a two-drug regimen at the cost of increased toxicity, the comparison of regimens in which another chemotherapy was replaced by irinotecan was associated with a survival benefit (of borderline statistical significance), but without increased toxicity. For this reason irinotecan/5-FU-containing combinations are an attractive option for first-line treatment. Although they need to be interpreted with caution, subgroup analyses of one study suggest that elderly people have a greater benefit form oxaliplatin, as compared to cisplatin-based regimens, and that people with locally advanced disease or younger than 65 years might benefit more from a three-drug regimen including 5-FU, docetaxel, and oxaliplatin as compared to a two-drug combination of 5-FU and oxaliplatin, a hypothesis that needs further confirmation. For people with good performance status, the benefit of second-line chemotherapy has been established in several RCTs. PMID- 28850175 TI - Commentary on Community Mental Health and the Common Good. AB - This article comments on the core question addressed by this Special Issue: "What's good about public sector mental health?" Theoretical, empirical, and programmatic insights derived from the Issue's six article contributions guide the overall commentary. Several points of thematic overlap are featured in these preliminary observations, and these themes are suggestive for directing future research (e.g., citizenship studies) in the field of community mental health. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28850176 TI - "Life's hurried tangled road": A therapeutic jurisprudence analysis of why dedicated counsel must be assigned to represent persons with mental disabilities in community settings. AB - The right to counsel is a fundamental right for individuals facing criminal processes and involuntary civil commitment. However, individuals with serious mental illnesses are subject to many community proceedings (e.g., being taken by law enforcement to a crisis drop-off center) where counsel is not available. We argue that, unless meaningful counsel is provided in such situations, the cycle of arrest, hospitalization, and stays in the community will continue for these individuals, who are among some of the most disenfranchised citizens in the nation and are often without any meaningful voice. PMID- 28850177 TI - A Review of Complementary and Alternative Medicine Use Among U.S. Adults with Headache or Migraine: Results from the 2012 National Health Interview Survey. PMID- 28850178 TI - Erratum. PMID- 28850179 TI - Herniations of Brain Parenchyma With Surrounding Cerebrospinal Fluid Into the Calvarium; Is It Rare? Is It Related With Symptom? PMID- 28850180 TI - Editorial: The Importance of the Idiopathic Intracranial Hypertension Treatment Trial. PMID- 28850181 TI - Headache Professional Societies: Ethical Challenges and Suggested Solutions. AB - Codes of professional conduct continue to be an essential component of maintaining the integrity of individuals, academic institutions, and medical societies. We review ethical issues of professional conduct focusing on conflicts of interest (COI). We explain how to manage or mitigate COI in the context of professionals involved in headache medicine and its medical specialty societies. We identify the roles of institutional, medical society, and governmental regulation in the protection of patients and maintaining the integrity of physicians and others involved in patient care. PMID- 28850182 TI - Plant size: a key determinant of diversification? AB - Explaining the variation in diversification rate across groups of plants has long been an important goal of botanists. In plants, complex scenarios involving a combination of extrinsic opportunities and intrinsic traits have been used to explain rapid diversification in certain groups. However, we feel that a very simple trait has been neglected from theories of plant diversification, namely plant height. Here, we argue that decreasing plant size should generally lead to an increase in speciation rate and a decrease in extinction rate. Theory suggests that all population genetic processes involved in speciation are influenced by plant size and its correlates, including seed dispersal distance, population size, generation time and the spatial scale at which plants perceive environmental heterogeneity. In addition, several of these variables, notably population size, also influence rates of extinction. We support our arguments with an empirical analysis showing that plant height is indeed negatively correlated with net diversification rate across families of angiosperms. Finally, we outline how the finer aspects of our hypothesis could be tested, at both micro and macroevolutionary scales. In addition to strengthening our understanding of the effect of plant size on evolutionary processes, such a research agenda should contribute novel insights to speciation theory in general. PMID- 28850183 TI - Seeing is believing: imaging the delivery of pathogen effectors during plant infection. PMID- 28850184 TI - Learning from the experts: drought resistance in desert plants. PMID- 28850186 TI - Editors' introduction. PMID- 28850185 TI - Multiparameter imaging of calcium and abscisic acid and high-resolution quantitative calcium measurements using R-GECO1-mTurquoise in Arabidopsis. AB - Calcium signals occur in specific spatio-temporal patterns in response to various stimuli and are coordinated with, for example, hormonal signals, for physiological and developmental adaptations. Quantification of calcium together with other signalling molecules is required for correlative analyses and to decipher downstream calcium-decoding mechanisms. Simultaneous in vivo imaging of calcium and abscisic acid has been performed here to investigate the interdependence of the respective signalling processes in Arabidopsis thaliana roots. Advanced ratiometric genetically encoded calcium indicators have been generated and in vivo calcium calibration protocols were established to determine absolute calcium concentration changes in response to auxin and ATP. In roots, abscisic acid induced long-term basal calcium concentration increases, while auxin triggered rapid signals in the elongation zone. The advanced ratiometric calcium indicator R-GECO1-mTurquoise exhibited an increased calcium signal resolution compared to commonly used Forster resonance energy transfer-based indicators. Quantitative calcium measurements in Arabidopsis root tips using R GECO1-mTurquoise revealed detailed maps of absolute calcium concentration changes in response to auxin and ATP. Calcium calibration protocols using R-GECO1 mTurquoise enabled high-resolution quantitative imaging of resting cytosolic calcium concentrations and their dynamic changes that revealed distinct hormonal and ATP responses in roots. PMID- 28850188 TI - International Health Economics Association: Student prize competition. PMID- 28850191 TI - Corrigendum. PMID- 28850189 TI - An econometric method for estimating population parameters from non-random samples: An application to clinical case finding. AB - The problem of sample selection complicates the process of drawing inference about populations. Selective sampling arises in many real world situations when agents such as doctors and customs officials search for targets with high values of a characteristic. We propose a new method for estimating population characteristics from these types of selected samples. We develop a model that captures key features of the agent's sampling decision. We use a generalized method of moments with instrumental variables and maximum likelihood to estimate the population prevalence of the characteristic of interest and the agents' accuracy in identifying targets. We apply this method to tuberculosis (TB), which is the leading infectious disease cause of death worldwide. We use a national database of TB test data from South Africa to examine testing for multidrug resistant TB (MDR-TB). Approximately one quarter of MDR-TB cases was undiagnosed between 2004 and 2010. The official estimate of 2.5% is therefore too low, and MDR-TB prevalence is as high as 3.5%. Signal-to-noise ratios are estimated to be between 0.5 and 1. Our approach is widely applicable because of the availability of routinely collected data and abundance of potential instruments. Using routinely collected data to monitor population prevalence can guide evidence based policy making. PMID- 28850192 TI - Sustained employability of cancer patients and survivors: are we getting any closer? PMID- 28850193 TI - Examining the influence of personal goal interference and attainability on psychological distress in non-metastatic breast cancer patients. AB - The present study investigated the relationship between two goal-related appraisals - perceived cancer-related interference and perceived attainability of important personal goals - and psychological distress among non-metastatic breast cancer patients across the short-term treatment and recovery period. Forty-five women completed self-report questionnaires at approximately 1 and 6 months following surgery. A mixed idiographic-nomothetic goal methodology assessed perceived cancer-related interference and attainability of self-generated important personal goals. Psychological distress symptoms were assessed with the Depression Anxiety Stress Scales short form. Correlation analyses and general linear modelling were used to evaluate the hypothesised relationships over time. Average cancer-related interference and attainability of important personal goals were significantly associated with concurrent depression, anxiety and stress symptoms at 6 months following surgery. Perceived attainability of highly important goals at 6 months post-surgery uniquely predicted change in psychological distress symptoms over time. The findings suggest that low perceived attainability of important personal goals may be an important predictor of elevated distress symptoms across the short-term following surgery. Further insight into the relationship between these negative goal appraisals and psychological functioning among different groups of cancer patients could inform the provision of targeted psychosocial support across the cancer continuum. PMID- 28850194 TI - Erratum. PMID- 28850195 TI - Anti-HCV immunoblot indeterminate results in blood donors: non-specific reactivity or past exposure to HCV? AB - BACKGROUND AND OBJECTIVE: The significance of anti-HCV immunoblot (IB) indeterminate results can be difficult to determine. We analysed results for blood donors tested on the MP Diagnostics HCV Blot 3.0 IB assay to determine whether indeterminate results representing past exposure to HCV could be distinguished from those due to non-specific reactivity. MATERIALS AND METHODS: Results for all donors tested by IB during the study period (July 2010 to December 2013) were included in this study. RESULTS: Of 131 donors tested by IB, 34 (26.0%) were negative, 38 (29.0%) were indeterminate, and 59 (45.0%) were positive. There was no significant difference in IB band reactivity strength between indeterminate and positive donors. The PRISM HCV chemiluminescent immunoassay (ChLIA) sample to cut-off (s/co) ratio distribution for the indeterminate donors was significantly higher than for those with biological false reactivity (P = 0.037), but significantly lower than for donors who were IB positive/HCV RNA negative (P < 0.001) or IB not tested/HCV RNA positive (P < 0.001). Of donors available for follow-up, 53.1% of the indeterminate group disclosed a putative risk factor for HCV infection compared to 39.4% (P < 0.001) for the IB-negative group, 76.6% (P = 0.065) for the IB-positive group and 83.4% (P < 0.001) for the HCV RNA-positive group. CONCLUSION: The results of this study indicate that PRISM ChLIA s/co ratios >2.00 with IB indeterminate results predict exposure to HCV, particularly in the presence of putative risk factors for HCV infection. These findings may be applied to optimizing counselling of donors with indeterminate HCV results. PMID- 28850197 TI - Assessing the impact of perioperative blood transfusions on the survival of adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for appendiceal carcinomatosis. AB - BACKGROUND AND OBJECTIVES: Perioperative red blood cell transfusions (PBT) may be associated with worse survival. In this study of adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), we investigated whether there was an association between PBT and survival. MATERIALS AND METHODS: A retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis was conducted. Univariate and multivariate analyses were used to identify factors associated with survival. RESULTS: Of the 270 patients analysed, 170 (63%) received PBT. A PBT was not significantly associated with recurrence-free survival (RFS) (HR = 1.03; 95% CI: 0.7-1.51; P = 0.879) or overall survival (OS) (HR = 0.65; 95% CI: 0.38-1.11; P = 0.116). Higher number of PBT units (>=5) was not associated with worse RFS (P = 0.077) or OS (P = 0.079). Independent predictors of poor survival included as follows: estimated blood loss and high tumour grade for RFS (both P < 0.001), and male gender (P = 0.029) and high tumour grade (P < 0.001) for OS. Higher preoperative haemoglobin was independently associated with better RFS (P = 0.011) and OS (P = 0.006). CONCLUSIONS: In this retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis, PBT was not significantly associated with survival. PMID- 28850199 TI - GUIDING PRINCIPLES AND PEARLS IN A STEPWISE SURGICAL TECHNIQUEOF REVISION TOTAL KNEE ARTHROPLASTY. AB - The authors aim at reviewing the guiding principlesin revision total knee arthroplasty according to a stepwiseprocedure. Strict preoperative planning is of paramountimportance for this surgery. Thorough clinical history andphysical exam, the assessment of limb deformity and kneerange of motion as well as knee stability in flexion, extensionand mid-flexion are crucial. Blood exam, standardized radiographicviews, and CT scan are powerful tools for etiologicdiagnosis of total knee arthroplasty failure. Templating isunique and mandatory to provide the surgeon with thecritical data concerning the valgus position of the femoralcomponent, the AP size of the femoral component, and theoptimal position of the joint line; these three parameters aredeterminant for the final clinical outcome. A stepwise surgicaltechnique with close adherence to the guiding principles ofrevision knee arthroplasty should be adopted from skin incisionto closure. Femoral and tibia components with modularstem are ideally set at their optimal position as predeterminedby templating. Any residual implant bone gap is filledwith metallic augment or bone graft. Finally, repositioning ofthe patella on a symmetrical bone cut presents a great valuefor a successful procedure. PMID- 28850200 TI - FOREFOOT ADDUCTION IN CHILDREN.Management and Treatment. AB - Forefoot adduction is a common conditionbetween metatarsus adductus, Z-shaped foot and residualclubfoot. This deformity is located in a pure transverse planeat Lisfranc's joint. Isolated metatarsus adductus is correctedspontaneously for the majority of newborns. In rare uncorrectedcases, it could result in Z-shaped foot with a functionalhindfoot valgus to equilibrate the resistant metatarsusadductus. As well, in residual clubfoot, recurrent metatarsusadductus varus is observed, usually in children over threeyears.In flexible metatarsus adductus the treatment is conservative.The surgery is proposed in toddlers and after failure ofconservative treatment. Procedures carried out on metatarsalsgave good results on short term, but showed a high rateof recurrence and growth disturbance. Osteotomies proximalto the Lisfranc's joint: calcaneo-cuboid fusion, anterior resectionof calcaneus, and opening wedge osteotomy of medialcuneiform, gave permanent correction but they act only onone of the sides of deformity. Therefore, the theory of elongatedlateral column associated with a shortened medialcolumn is crucial in dealing with this deformity: combiningopening wedge osteotomy of cuneiform with closing wedgeosteotomy of cuboid described by Jawish et al. in childrenover 4 years allows - in all causes of metatarsus adductusstiffness - a lateral shifting of forefoot. Concerning the associatedheel's valgus, it is corrected in Z-shaped foot after theassociatedheel's valgus, it is corrected in Z-shaped foot after thedouble osteotomy cuneiform/cuboid. However, in complicatedtreated clubfoot a particular treatment for the posteriortarsal is necessary. PMID- 28850201 TI - PECTUS CARINATUM: A NOVEL METHOD OF STERNAL FIXATION. AB - The traditional method for fixing the sternumduring surgical repair of pectus carinatum is through the useof a stainless steel bar (Adkin's strut). In this article we describea new method of sternal fixation using nonabsorbablesutures which are placed in a transverse and crossedfashion anterior to the sternum. This method provides stablesternal fixation and spares the patient a second operation toremove the steel bar. The absence of metallic implants allowsclearer view of the thoracic structures in future X-rays, CTscans and MRI, and is likely to be more acceptable to patientsthan the implantation of a metallic strut in their chest. In addition,it is less costly. PMID- 28850203 TI - A NEW APPROACH IN THE CLINICAL DECISION-MAKING FOR CEREBRAL PALSYUSING THREE DIMENSIONAL SUBJECT-SPECIFIC MUSCULOSKELETALRECONSTRUCTIONS. AB - Cerebral palsy (CP) is a neurological disorderwhich can cause muscular spasticity. Children with this conditionsuffer from a combination of gait deviations, skeletaldeformities and muscular abnormalities. Precise evaluationof each of these three components is crucial for managementplanning in children with CP. The aim of this study is toreview the latest innovative methods used for three-dimensional(3D) gait analysis and musculoskeletal modeling inchildren with cerebral palsy. 3D gait analysis is a quantitativeobjective method based on the use of infrared cameras.It allows the evaluation of dynamic joint angles, forces andmoments applied on joints and is usually coupled with dynamicelectromyography. Skeletal evaluation is usually basedon two-dimensional X-rays and physical examination in clinicalpractice. However, a novel method based on stereoradiographic3D reconstruction of biplanar low dose X-rays allowsa more thorough evaluation of skeletal deformities, and inparticular torsional anomalies. Muscular evaluation of childrenwith CP is most commonly based on magnetic resonanceimaging, whereby delimitation of lower limb muscleson axial slices allows 3D reconstruction of these muscles.Novel innovative techniques allow similar reconstructions byextrapolation, thus limiting the necessary quantity of axialslices that need to be manually delimitated. PMID- 28850202 TI - THE GLOBAL TILT: EVALUATION OF A PARAMETER CONSIDERING THE GLOBALSPINOPELVIC ALIGNMENT. AB - PURPOSE: Regarding the close interactionbetween the spinal balance and the pelvis orientation noparameter is routinely used to describe and to evaluate theglobal spinopelvic balance, taking into account simultaneouslythe spinal part and the pelvic part of the global alignment.The global tilt was described to analyze malalignment,considering spinal and pelvic imbalance together. From ageometrical point of view, the global tilt is the sum of theC7 vertical tilt and the pelvic tilt. The aim of this study is toevaluate the global tilt by analyzing its correlation with spinalmalalignment. METHODS: A cohort of patients who underwenta lumbar pedicle subtraction osteotomy (PSO) for majorsagittal malalignment was realized. All patients had preoperativeand postoperative full spine EOS radiographies tomeasure spinopelvic parameters. The lack of lordosis wascalculated after prediction of theoretical lumbar lordosis.Correlation analysis between different spinopelvic parameters,including the global tilt, was performed for preoperativeand postoperative values. RESULTS: Thirty-one consecutivepatients were included. All parameters were correlated withspinal malalignment but the global tilt was the most correlatedparameter in preoperative (r = 0.71) and in postoperative(r = 0.78). When spinal and pelvic parameters were analyzedseparately, 19% of patients presented mismatchesbetween spine and pelvis. CONCLUSION: This study highlightsthe interest of a global parameter evaluating the spinalbalance and the pelvic balance together. The global tiltappeared to be the most correlated parameter in this studywith spinal malalignment and could be used for the interpretationof clinical series in spine surgery. PMID- 28850204 TI - WIRELESS TENSION BAND WIRING FOR OLECRANON FRACTURES.Case Series. AB - : This retrospective study evaluates the resultsof wireless tension band wire (WTBW) which is a modifiedtechnique of tension band wires (TBW) for Mayo type II A andIII A olecranon fractures. In this technique the K-wires of theTBW are replaced by a cerclage wire while keeping the figureof eight wiring. MATERIAL AND METHODS: We reviewed retrospectivelyour WTBW cases done between 2000 and 2015where we replaced the K-wires by a cerclage wire. In thistechnique no hardware migration is possible. Patients wereevaluated clinically, radiographicaly and a DASH score wasmeasured. RESULTS: Seventeen patients were reviewed witha mean age of 58.5 years. The mean follow-up period was58.5 months. The mean DASH score was 12 with 7 patientshaving a DASH score of zero. Joint mobility was near normalcompared to the other side with loss of a mean of 4o in elbowextension and a mean of 3o in elbow flexion. In comparisonwith other series, in addition to good results, hardware removalfor medical reasons was the lowest in our technique. Itwas needed in three patients for pain on elbow contact and inone with ulnar nerve irritation. This represents a rate of23.5%. CONCLUSION: Undesirable events related to the use ofK-wires in standard tension band wiring, such as wire migration,wire protrusion through the skin and wire impingement,are absent in the wireless tension band wiring. The high rateof patient satisfaction, good clinical results as well as low rateof needed hardware removal make this technique preferablefor fixing Mayo Type II A olecranon fractures. PMID- 28850205 TI - SURAL NEURO-CUTANEOUS FLAP IN THE MANAGEMENT OF FOOT AND ANKLESOFT TISSUE DEFECTS IN A DIABETIC POPULATION. AB - BACKGROUND: Soft tissue defects in the footand ankle region are challenging conditions particularly indiabetic patients. We evaluated the reliability of the suralflap in treating such defects among a diabetic population. MATERIAL AND METHODS: This is a continuous retrospectiveseries of 14 patients with type 2 diabetes treated with anipsilateral sural flap for soft tissue defects around the rearfoot (11 cases) and over the malleolar areas (3 cases).Three patients had an open tibia fracture (Gustillo IIIb),four had chronic osteitis and seven had a chronic heelulcer. RESULTS: The mean follow-up at 28 months showedhealing of the flap at a mean of 24 days, donor site healingin two weeks, one case of total flap necrosis, threecases of skin edge necrosis, two cases of temporaryvenous congestion and 10 cases of hypoesthesia of thelateral border of the foot. No infection or recurrence ofinfection was encountered. CONCLUSION: We found thesural flap useful, reproducible and reliable in treating softtissue defects in diabetic patients with a low frequency ofserious complications. PMID- 28850206 TI - KAPANDJI TECHNIQUE AS AMINIMALLY INVASIVE PROCEDURE FOR SELECTEDPATIENTS WITH TWO AND THREE-PART FRACTURES OF THE PROXIMAL HUMERUS. AB - Current algorithms for decision making in proximalhumerus fractures consider the fracture pattern along withthe patient characteristics and surgeon's experience. Minimallyinvasive techniques for reduction and internal fixation ofmany types of these fractures have recently been widelypromoted, especially with the use of the newly developedlocking plate systems. Intramedullary flexible nailing is oneof the oldest techniques using minimally invasive reductionand fixation of proximal humerus fractures. Kapandji techniqueuses the "Deltoid V" landmark as entry point for intramedullaryinsertion of the flexible nails into the humeralhead. The authors report their experience with this procedurein twenty-six, relatively young patients with good bonequality, presenting with displaced 2- or 3-part extra-articularfracture of the proximal humerus, treated with percutaneousreduction and intramedullary flexible nailing as described byKapandji. Nineteen medical records were available for thisretrospective review, with 9 to 12 months follow-up. Therewere 15 excellent and 1 good results when patients wereassessed for pain, function and range of motion of the shoulder.The authors submit that Kapandji technique is a valuableprocedure for management of extra-articular displaced2- and 3- part proximal humerus fractures in young patientswith good bone quality. PMID- 28850207 TI - COMPARATIVE STUDY on the MANAGEMENT of GLENOHUMERAL JOINT DISLOCATION.Closed Reduction vs. Arthroscopic Remplissage with Bankart Lesion Repair. AB - BACKGROUND: Conservative treatment of posttraumaticanteroinferior shoulder instability leads to a high failurerate and consequently high recurrence in young and active population.Each recurrence can increase the structural damage ofboth bony structures and soft tissues (Hill-Sachs lesion, Bankartlesion). Remplissage technique combined with Bankart repairhave been proposed as a treatment option. HYPOTHESIS: Earlyarthroscopic treatment for shoulder dislocation will result in betteroutcome and lower recurrence rate than nonoperative management. METHODS: We retrospectively reviewed 60 cases from2010 to 2015 treated by remplissage technique with Bankartrepair or closed reduction for anterior shoulder dislocation. Allsurgeries and closed reductions were done by the same surgeon.Mean age of patients was 30 years, most of them maleshaving experienced one or more recurrent dislocations; meanfollow-up was 2 years. Patients with Hill Sachs lesions < 40% onthe articular surface and < 20% of bone defect in the glenoidcavity were included. Exclusion criteria were: glenohumeralarthritis or other inflammation, fracture around the shoulder joint,elderly patients with osteoporosis. All patients included in thestudy were followed up after 6, 12 and 24 months. Rowe scorewas used to assess the stability of the shoulders and goniometryto assess the range of motion of the glenohumeral joints. RESULTS: The results confirm that the remplissage techniquewith Bankart repair takes the upper hand over the conservativemanagement and does not produce any severe adverse effecton postoperative shoulder range of motion. A slight restriction(~10o) observed in external rotation did not prevent 69% of patientsfrom resuming their preinjury sports activities. At the lastfollow-up, 90% of patients had a stable shoulder. Conservativemanagement was associated with high rate of recurrence limitingthe daily activity of our patients and interfering with theirreturn to sports activities. Except from the recurrence of glenohumeralinstability, no patient had a complication following arthroscopicHill-Sachs remplissage. CONCLUSION: Conservativemanagement after anterior shoulder dislocation including immobilizationin neutral position leads to significantly higher and unacceptablehigh failure rate compared with early arthroscopicremplissage with Bankart repair. The slight restriction in externalrotation post remplissage does not significantly affect the qualityof life and return to sports activities and further supports theuse of this safe, relatively short procedure, in the managementof glenohumeral instability with concurrent Hill-Sachs lesions. PMID- 28850208 TI - TWO ADJACENT LEVELS DISLOCATION OF THE CERVICAL SPINEMANAGED VIAAN ANTERIOR ONLY APPROACH.A Case Report. AB - We report the rare case of a 52-year-old manwho presented an incomplete tetraplegia after a hang glidingaccident. Computed tomography revealed a completebilateral facet fracture-dislocation at the C4C5 level, with aunilateral facet fracture-dislocation on the left side at theC3C4 level; there was also a sagittal fracture of the fifth cervicalvertebra extending through the middle of its body witha second fracture through the posterior arch. The patientwas taken urgently to the operating room and closed reductionmaneuvers were performed under general anesthesia,followed by an anterior prevascular approach for C3 to C5fusion with two iliac crest grafts and a plate. Patient's musclestrength was 3/5 on all four limbs on discharge and between4/5 and 5/5 at one year. He stopped self-catheterization ninemonths after the accident. At two years follow-up, X rays andCT scan showed a stable construct with satisfactory fusion.This is the first paper, in the literature, to describe doublelevel contiguous cervical dislocation with a sagittal split fracture,and managed via an anterior only approach. PMID- 28850210 TI - Route to Improving Photovoltaics Based on CdSe/CdSexTe1-x Type-II Heterojunction Nanorods: The Effect of Morphology and Cosensitization on Carrier Recombination and Transport. AB - One-dimensionally elongated nanoparticles with type-II staggered band offset are of potential use as light-harvesting materials for photovoltaics, but only a limited attention has been given to elucidate the factors governing the cell performance obtainable from such materials. Herein, we describe a combined strategy to enhance charge collection from CdSe/CdSexTe1-x type-II heterojunction nanorods (HNRs) utilized as light harvesters for sensitized solar cells. By integrating morphology- and composition-tuned type-II HNRs into solar cells, factors that yield interfaces favorable both for the electron injection into TiO2 and hole transfer to electrolyte are examined. Furthermore, it is shown that a more efficient photovoltaic system results from cosensitization with CdS quantum dots (QDs) predeposited on a TiO2 scaffold, which improves charge collection from HNRs. Electrochemical impedance spectroscopy (EIS) analysis suggests that such a synergistically enhanced system benefits from the decreased recombination within HNRs and facilitated charge transport through the cosensitized TiO2 electrode, even with the activation of a recombination path presumably related to the photogenerated holes in CdS QDs. PMID- 28850211 TI - Ruthenium Nanoparticles Decorated Tungsten Oxide as a Bifunctional Catalyst for Electrocatalytic and Catalytic Applications. AB - The syntheses of highly stable ruthenium nanoparticles supported on tungsten oxides (Ru-WO3) bifunctional nanocomposites by means of a facial microwave assisted route are reported. The physicochemical properties of these Ru-WO3 catalysts with varied Ru contents were characterized by a variety of analytical and spectroscopic methods such as XRD, SEM/TEM, EDX, XPS, N2 physisorption, TGA, UV-vis, and FT-IR. The Ru-WO3 nanocomposite catalysts so prepared were utilized for electrocatalytic of hydrazine (N2H4) and catalytic oxidation of diphenyl sulfide (DPS). The Ru-WO3-modified electrodes were found to show extraordinary electrochemical performances for sensitive and selective detection of N2H4 with a desirable wide linear range of 0.7-709.2 MUM and a detection limit and sensitivity of 0.3625 MUM and 4.357 MUA MUM-1 cm-2, respectively, surpassing other modified electrodes. The modified GCEs were also found to have desirable selectivity, stability, and reproducibility as N2H4 sensors, even for analyses of real samples. This is ascribed to the well-dispersed metallic Ru NPs on the WO3 support, as revealed by UV-vis and photoluminescence studies. Moreover, these Ru WO3 bifunctional catalysts were also found to exhibit excellent catalytic activities for oxidation of DPS in the presence of H2O2 oxidant with desirable sulfoxide yields. PMID- 28850209 TI - Hydrogen Sulfide and Reactive Sulfur Species Impact Proteome S-Sulfhydration and Global Virulence Regulation in Staphylococcus aureus. AB - Hydrogen sulfide (H2S) is thought to protect bacteria from oxidative stress, but a comprehensive understanding of its function in bacteria is largely unexplored. In this study, we show that the human pathogen Staphylococcus aureus (S. aureus) harbors significant effector molecules of H2S signaling, reactive sulfur species (RSS), as low molecular weight persulfides of bacillithiol, coenzyme A, and cysteine, and significant inorganic polysulfide species. We find that proteome S sulfhydration, a post-translational modification (PTM) in H2S signaling, is widespread in S. aureus. RSS levels modulate the expression of secreted virulence factors and the cytotoxicity of the secretome, consistent with an S-sulfhydration dependent inhibition of DNA binding by MgrA, a global virulence regulator. Two previously uncharacterized thioredoxin-like proteins, denoted TrxP and TrxQ, are S-sulfhydrated in sulfide-stressed cells and are capable of reducing protein hydrodisulfides, suggesting that this PTM is potentially regulatory in S. aureus. In conclusion, our results reveal that S. aureus harbors a pool of proteome- and metabolite-derived RSS capable of impacting protein activities and gene regulation and that H2S signaling can be sensed by global regulators to affect the expression of virulence factors. PMID- 28850212 TI - Novel Iron(III)-Based Metal-Organic Gels with Superior Catalytic Performance toward Luminol Chemiluminescence. AB - Novel metal-organic gels (MOGs) consisting of iron (Fe3+) as the central ion and 1,10-phenanthroline-2,9-dicarboxylic acid (PDA) as the ligand were synthesized by a mild facile strategy. The Fe(III)-containing metal-organic xerogels (Fe-MOXs), obtained after removing the solvents in MOGs, were found to exhibit outstanding performance in the catalysis of luminol chemiluminescence (CL) for the first time even in the absence of extra oxidants such as hydrogen peroxide. The possible CL mechanism was discussed according to the electro/optical measurements, including electron paramagnetic resonance (EPR), UV-vis absorption, and CL spectra, as well as the effects of radical scavengers on Fe-MOXs-catalyzed luminol CL system, suggesting that the CL emission of luminol might originate from the intrinsic oxidase-like catalytic activity of Fe-MOXs on the decomposition of dissolved oxygen. Additionally, the potential practical application of the resulting luminol-Fe-MOXs system was evaluated by the quantitative analysis of dopamine. Good linearity over the range from 0.05 to 0.6 MUM was obtained with the limit of detection (LOD, 3sigma) of 20.4 nM and acceptable recoveries ranging from 98.6 to 105.4% in human urine. These results may open up the promising application of novel metal-organic gels as highly effective catalysts in the field of chemiluminescence. PMID- 28850213 TI - Design of Oxygen Vacancy Configuration for Memristive Systems. AB - Oxide-based valence-change memristors are promising nonvolatile memories for future electronics that operate on valence-change reactions to modulate their electrical resistance. The memristance is associated with the movement of oxygen ionic carriers through oxygen vacancies at high electric field strength via structural defect modifications that are still poorly understood. This study employs a Ce1-xGdxO2-y solid solution model to probe the role of oxygen vacancies either set as "free" or as "immobile and clustered" for the resistive switching performance. The experiments, together with the defect chemical model, show that when the vacancies are set as "free", a maximum in memristance is found for 20 mol % of GdO1.5 doping, which clearly coincides with the maximum in ionic conductivity. In contrast, for higher gadolinia concentration, the oxide exhibits only minor memristance, which originates from the decrease in structural symmetry, leading to the formation of "immobile" oxygen defect clusters, thereby reducing the density of mobile ionic carriers available for resistive switching. The research demonstrates guidelines for engineering of the oxide's solid solution series to set the configuration of its oxygen vacancy defects and their mobility to tune the resistive switching for nonvolatile memory and logic applications. PMID- 28850214 TI - A Rational Solid-State Synthesis of Supported Au-Ni Bimetallic Nanoparticles with Enhanced Activity for Gas-Phase Selective Oxidation of Alcohols. AB - A facile confined solid-state seed-mediated alloying strategy is applied for the rational synthesis of supported Au-Ni bimetallic nanoparticles (BMNPs). The method sequentially deposits nickel salts and AuNP seeds into the ordered array of extra-large mesopores (EP-FDU-12 support) followed by a high-temperature annealing process. The size, structure, and composition of the AuNi BMNPs can be well tuned by varying the AuNP seeds, annealing temperature, and feeding ratio of metal precursors. Kinetic studies and DFT calculations suggest that the introduction of the Ni component can significantly prompt the O2 activation on AuNPs, which is critical for the selective alcohol oxidation using molecular O2 as the oxidant. The optimal Au-Ni BMNP catalyst showed the highest turnover frequency (TOF) (59 000 h-1, 240 degrees C) and highest space-time yield (STY) of benzyl aldehyde (BAD) productivity (9.23 kg.gAu-1.h-1) in the gas-phase oxidation of benzyl alcohol (BA), which is at least about 5-fold higher than that of other supported Au catalysts. PMID- 28850215 TI - AssayR: A Simple Mass Spectrometry Software Tool for Targeted Metabolic and Stable Isotope Tracer Analyses. AB - Metabolic analyses generally fall into two classes: unbiased metabolomic analyses and analyses that are targeted toward specific metabolites. Both techniques have been revolutionized by the advent of mass spectrometers with detectors that afford high mass accuracy and resolution, such as time-of-flights (TOFs) and Orbitraps. One particular area where this technology is key is in the field of metabolic flux analysis because the resolution of these spectrometers allows for discrimination between 13C-containing isotopologues and those containing 15N or other isotopes. While XCMS-based software is freely available for untargeted analysis of mass spectrometric data sets, it does not always identify metabolites of interest in a targeted assay. Furthermore, there is a paucity of vendor independent software that deals with targeted analyses of metabolites and of isotopologues in particular. Here, we present AssayR, an R package that takes high resolution wide-scan liquid chromatography-mass spectrometry (LC-MS) data sets and tailors peak detection for each metabolite through a simple, iterative user interface. It automatically integrates peak areas for all isotopologues and outputs extracted ion chromatograms (EICs), absolute and relative stacked bar charts for all isotopologues, and a .csv data file. We demonstrate several examples where AssayR provides more accurate and robust quantitation than XCMS, and we propose that tailored peak detection should be the preferred approach for targeted assays. In summary, AssayR provides easy and robust targeted metabolite and stable isotope analyses on wide-scan data sets from high resolution mass spectrometers. PMID- 28850216 TI - Plant Metabolomics: Maximizing Metabolome Coverage by Optimizing Mobile Phase Additives for Nontargeted Mass Spectrometry in Positive and Negative Electrospray Ionization Mode. AB - Nontargeted screening methods with ultrahigh-performance liquid chromatography electrospray ionization/quadrupole-time-of-flight mass spectrometry have been extensively applied to plant metabolomics to very diverse scientific issues in plant metabolomics. In this study, different mobile phase additives were tested in order to improve the electrospray ionization process and to detect as many metabolites as possible with high peak intensities in positive and negative ionization mode. Influences of modifiers were examined for nonpolar and polar compounds, as optimal conditions are not always the same. By combining different additives, metabolite coverage could be significantly increased. The best results for polar metabolites in positive ionization mode were achieved by using 0.1% acetic acid and 0.1% formic acid in negative ionization mode. For measurements of nonpolar metabolites in positive ionization mode, the application of 10 mmol/L ammonium formate led to the best findings, while the use of 0.02% acetic acid was more appropriate in negative ionization mode. PMID- 28850217 TI - Simultaneous Quantitation of Glycoprotein Degradation and Synthesis Rates by Integrating Isotope Labeling, Chemical Enrichment, and Multiplexed Proteomics. AB - Protein glycosylation is essential for cell survival and regulates many cellular events. Reversible glycosylation is also dynamic in biological systems. The functions of glycoproteins are regulated by their dynamics to adapt the ever changing inter- and intracellular environments. Glycans on proteins not only mediate a variety of protein activities, but also creates a steric hindrance for protecting the glycoproteins from degradation by proteases. In this work, a novel strategy integrating isotopic labeling, chemical enrichment and multiplexed proteomics was developed to simultaneously quantify the degradation and synthesis rates of many glycoproteins in human cells. We quantified the synthesis rates of 847 N-glycoproteins and the degradation rates of 704 glycoproteins in biological triplicate experiments, including many important glycoproteins such as CD molecules. Through comparing the synthesis and degradation rates, we found that most proteins have higher synthesis rates since cells are still growing throughout the time course, while a small group of proteins with lower synthesis rates mainly participate in adhesion, locomotion, localization, and signaling. This method can be widely applied in biochemical and biomedical research and provide insights into elucidating glycoprotein functions and the molecular mechanism of many biological events. PMID- 28850218 TI - Monodisperse Au-Fe2C Janus Nanoparticles: An Attractive Multifunctional Material for Triple-Modal Imaging-Guided Tumor Photothermal Therapy. AB - Imaging-guided photothermal therapy (PTT) by combination of imaging and PTT has been emerging as a promising therapeutic method for precision therapy. However, the development of multicomponent nanoplatforms with stable structures for both PTT and multiple-model imaging remains a great challenge. Herein, we synthesized monodisperse Au-Fe2C Janus nanoparticles (JNPs) of 12 nm, which are multifunctional entities for cancer theranostics. Due to the broad absorption in the near-infrared range, Au-Fe2C JNPs showed a significant photothermal effect with a 30.2% calculated photothermal transduction efficiency under 808 nm laser irradiation in vitro. Owing to their excellent optical and magnetic properties, Au-Fe2C JNPs were demonstrated to be advantageous agents for triple-modal magnetic resonance imaging (MRI)/multispectral photoacoustic tomography (MSOT)/computed tomography (CT) both in vitro and in vivo. We found that Au-Fe2C JNPs conjugated with the affibody (Au-Fe2C-ZHER2:342) have more accumulation and deeper penetration in tumor sites than nontargeting JNPs (Au-Fe2C-PEG) in vivo. Meanwhile, our results verified that Au-Fe2C-ZHER2:342 JNPs can selectively target tumor cells with low cytotoxicity and ablate tumor tissues effectively in a mouse model. In summary, monodisperse Au-Fe2C JNPs, used as a multifunctional nanoplatform, allow the combination of multiple-model imaging techniques and high therapeutic efficacy and have great potential for precision theranostic nanomedicines. PMID- 28850219 TI - Size Modulation of Zirconium-Based Metal Organic Frameworks for Highly Efficient Phosphate Remediation. AB - Eutrophication of water bodies caused by the excessive phosphate discharge has constituted a serious threat on a global scale. It is imperative to exploit new advanced materials featuring abundant binding sites and high affinity to achieve highly efficient and specific capture of phosphate from polluted waters. Herein, water stable Zr-based metal organic frameworks (MOFs, UiO-66) with rational structural design and size modulation have been successfully synthesized based on a simple solvothermal method for effective phosphate remediation. Impressively, the size of the resulting UiO-66 particles can be effectively adjusted by simply altering reaction time and the amount of acetic acid with the purpose of understanding the crucial effect of structural design on the phosphate capture performance. Representatively, UiO-66 particles with small size demonstrates 415 mg/g of phosphate uptake capacity, outperforming most of the previously reported phosphate adsorbents. Meanwhile, the developed absorbents can rapidly reduce highly concentrated phosphate to below the permitted level in drinking water within a few minutes. More significantly, the current absorbents display remarkable phosphate sorption selectivity against the common interfering ions, which can be attributed to strong affinity between Zr-OH groups in UiO-66 and phosphate species. Furthermore, the spent UiO-66 particles can be readily regenerated and reused for multiple sorption-desorption cycles without obvious decrease in removal performance, rendering them promising sustainable materials. Hence, the developed UiO-66 adsorbents hold significant prospects for phosphate sequestration to mitigate the increasingly eutrophic problems. PMID- 28850220 TI - Hydroxyl-Group-Dominated Graphite Dots Reshape Laser Desorption/Ionization Mass Spectrometry for Small Biomolecular Analysis and Imaging. AB - Small molecules play critical roles in life science, yet their facile detection and imaging in physiological or pathological settings remain a challenge. Matrix assisted laser desorption ionization mass spectrometry (MALDI MS) is a powerful tool for molecular analysis. However, conventional organic matrices (CHCA, DHB, etc.) used in assisting analyte ionization suffer from intensive background noise in the mass region below m/z 700, which hinders MALDI MS applications for small molecule detection. Here, we report that a hydroxyl-group-dominated graphite dot (GD) matrix overcomes limitations of conventional matrices and allows MALDI MS to be used in fast and high-throughput analysis of small biomolecules. GDs exhibit extremely low background noise and ultrahigh sensitivity (with limit of detection <1 fmol) in MALDI MS. This approach allows identification of complex oligosaccharides, detection of low-molecular-weight components in traditional Chinese herbs, and facile analysis of puerarin and its metabolites in serum without purification. Moreover, we show that the GDs provide an effective matrix for the direct imaging or spatiotemporal mapping of small molecules and their metabolites (m/z < 700) simultaneously at the suborgan tissue level. Density functional theory calculations further provide the mechanistic basis of GDs as an effective MALDI matrix in both the positive-ion and negative-ion modes. Collectively, our work uncovered a useful matrix which reshapes MALDI MS technology for a wide range of applications in biology and medicine. PMID- 28850221 TI - Comprehensive Dual Liquid Chromatography with Quadruple Mass Spectrometry (LC1MS2 * LC1MS2 = LC2MS4) for Analysis of Parinari Curatellifolia and Other Seed Oil Triacylglycerols. AB - Online two-dimensional (2D) comprehensive liquid chromatography (LC * LC) has become increasingly popular. Most LC * LC separations employ one or more detectors at the outlet of the second dimension, 2D, with very short runs to avoid undersampling. We used six detectors, including dual parallel mass spectrometry (LC1MS2), for detection of the first dimension, 1D. We made an argentation (silver-ion) UHPLC column from a strong cation exchange column for 2D, coupled with UV and LC1MS2 detection. LC1MS2 in 1D combined with LC1MS2 in 2D, plus five other detectors, constituted LC2MS4 in a comprehensive LC1MS2 * LC1MS2 2D-LC separation. Electrospray ionization (ESI) high resolution accurate mass (HRAM) mass spectrometry (MS) and atmospheric pressure chemical ionization (APCI) MS were used in parallel for 1D detection, while atmospheric pressure photoionization (APPI) MS and ESI-MS were used for detection of 2D. The LC1MS2 used for 1D allowed quantification of triacylglycerol (TAG) molecular species of Parinari curatellifolia and other seed oils, while the 2D allowed isomers of TAG containing 18:3 fatty acyl chains as well as TAG regioisomers to be separated and identified. The LC1MS2 in 1D allowed identification of oxo-TAG species by HRAM MS and quantification of 806.3 +/- 1.3 and 1101 +/- 22 MUg/g of alpha- and gamma- tocopherols, respectively, in P. curatellifolia by APCI-MS. It is now feasible to use silver-ion UHPLC as the 2D separation in LC * LC and to use multiple mass spectrometers across both dimensions to perform conventional quantitative analysis and to take advantage of the newest LC * LC separation technology to identify isomers that are otherwise difficult to separate. PMID- 28850222 TI - Correction to The Effect of Compression Ratio, Fuel Octane Rating, and Ethanol Content on Spark-Ignition Engine Efficiency. PMID- 28850224 TI - Redox Transformations of As and Se at the Surfaces of Natural and Synthetic Ferric Nontronites: Role of Structural and Adsorbed Fe(II). AB - Adsorption and redox transformations on clay mineral surfaces are prevalent in surface environments. We examined the redox reactivity of iron Fe(II)/Fe(III) associated with natural and synthetic ferric nontronites. Specifically, we assessed how Fe(II) residing in the octahedral sheets, or Fe(II) adsorbed at the edge sites alters redox activity of nontronites. To probe the redox activity we used arsenic (As) and selenium (Se). Activation of both synthetic and natural ferric nontronites was observed following the introduction of Fe(II) into predominantly-Fe(III) octahedral sheets or through the adsorption of Fe(II) onto the mineral surface. The oxidation of As(III) to As(V) was observed via catalytic (oxic conditions) and, to a lesser degree, via direct (anoxic conditions) pathways. We provide experimental evidence for electron transfer from As(III) to Fe(III) at the natural and synthetic nontronite surfaces, and illustrate that only a fraction of structural Fe(III) is accessible for redox transformations. We show that As adsorbed onto natural and synthetic nontronites forms identical adsorption complexes, namely inner-sphere binuclear bidentate. We show that the formation of an inner-sphere adsorption complex may be a necessary step for the redox transformation via catalytic or direct oxidation pathways. PMID- 28850223 TI - Cancer-Associated Mutations Mapped on High-Resolution Structures of the U2AF2 RNA Recognition Motifs. AB - Acquired point mutations of pre-mRNA splicing factors recur among cancers, leukemias, and related neoplasms. Several studies have established that somatic mutations of a U2AF1 subunit, which normally recognizes 3' splice site junctions, recur among myelodysplastic syndromes. The U2AF2 splicing factor recognizes polypyrimidine signals that precede most 3' splice sites as a heterodimer with U2AF1. In contrast with those of the well-studied U2AF1 subunit, descriptions of cancer-relevant U2AF2 mutations and their structural relationships are lacking. Here, we survey databases of cancer-associated mutations and identify recurring missense mutations in the U2AF2 gene. We determine ultra-high-resolution structures of the U2AF2 RNA recognition motifs (RRM1 and RRM2) at 1.1 A resolution and map the structural locations of the mutated U2AF2 residues. Comparison with prior, lower-resolution structures of the tandem U2AF2 RRMs in the RNA-bound and apo states reveals clusters of cancer-associated mutations at the U2AF2 RRM-RNA or apo-RRM1-RRM2 interfaces. Although the role of U2AF2 mutations in malignant transformation remains uncertain, our results show that cancer-associated mutations correlate with functionally important surfaces of the U2AF2 splicing factor. PMID- 28850225 TI - Stabilized Nanoscale Zerovalent Iron Mediated Cadmium Accumulation and Oxidative Damage of Boehmeria nivea (L.) Gaudich Cultivated in Cadmium Contaminated Sediments. AB - Nanoparticles can be absorbed by plants, but their impacts on phytoremediation are not yet well understood. This study was carried out to determine the impacts of starch stabilized nanoscale zerovalent iron (S-nZVI) on the cadmium (Cd) accumulation and the oxidative stress in Boehmeria nivea (L.) Gaudich (ramie). Plants were cultivated in Cd-contaminated sediments amended with S-nZVI at 100, 500, and 1000 mg/kg, respectively. Results showed that S-nZVI promoted Cd accumulation in ramie seedlings. The subcellular distribution result showed that Cd content in cell wall of plants reduced, and its concentration in cell organelle and soluble fractions increased at S-nZVI treatments, indicating the promotion of Cd entering plant cells by S-nZVI. In addition, the 100 mg/kg S-nZVI alleviated the oxidative damage to ramie under Cd-stress, while 500 and 1000 mg/kg S-nZVI inhibited plant growth and aggravated the oxidative damage to plants. These findings demonstrate that nanoparticles at low concentration can improve the efficiency of phytoremediation. This study herein develops a promising novel technique by the combined use of nanotechnology and phytoremediation in the remediation of heavy metal contaminated sites. PMID- 28850227 TI - Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry. AB - The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from beta-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group. PMID- 28850226 TI - Making Flavone Thioethers Using Halides and Powdered Sulfur or Na2S2O3. AB - The method for constructing C-S bonds is very important in organic synthesis. Here a new sulfenylation method to generate flavone thioether derivatives was developed by employing aromatic or alkyl halides, S powder and Na2S2O3 as reactants. Good yields of regioselective Calkyl-S and Caryl-S-substituted flavones were generated under relatively environmentally friendly and simple conditions. This method might be potentially applicable to large scale production, and it enriches current sulfenylation methods. PMID- 28850228 TI - The Quantization of the E ? e Jahn-Teller Hamiltonian. AB - The E ? e Jahn-Teller Hamiltonian in the Bargmann-Fock representation gives rise to a system of two coupled first-order differential equations in the complex field, which may be rewritten in the Birkhoff standard form. General leapfrog recurrence relations are derived, from which the quantized solutions of these equations can be obtained. The results are compared to the analogous quantization scheme for the Rabi Hamiltonian. PMID- 28850229 TI - Understanding the CO Dissociation in [Fe(CN)2(CO)2(dithiolate)]2- Complexes with Quantum Chemical Topology Tools. AB - The active site of the [NiFe]-hydrogenase contains a pentacoordinated iron atom; therefore, a vacant coordination site is available for substrate binding. Nonetheless, most organometallic models of the [NiFe]-hydrogenase failed to reproduce this key feature of the active site. In order to rationalize such behavior, quantum chemical calculations were carried out on a series of [Fe(CN)2(CO)n(dithiolate)]2- n = 1,2 complexes, where dithiolate denotes the ligands (CF3)2C2S22-, (CO2Me)2C2S22-, Ph2C2S22-, C6Cl2H2S22-, C6H4S22-, C2H4S22-, and C3H6S22-. Structural and energetic features are discussed, and a topological analysis based on two scalar fields, the one-electron density and the electron localization function (ELF), has been attempted to describe the nature of the metal-ligand bonds. The present approach contributes to better understand the ability of noninnocent dithiolene to strongly labilize one CO whereas innocent dithiolate cannot. The methodology developed throughout the paper could be useful in the field of the CO-releasing molecules. PMID- 28850230 TI - Substrate-Controlled Chemoselective Reactions of Isocyanoacetates with Amides and Lactams. AB - Versatile and chemoselective C-C bond forming methods for the one-pot transformation of amides into other classes of compounds are highly demanding. In this report, we demonstrate the reductive addition of isocyanoacetates to common amides and lactams to produce 5-methoxyoxazoles or bicyclic imidazolines. This one-pot procedure involves partial reduction of amides with Schwartz reagent and chemoselective addition of the carbon of isocyanide group or alpha-carbon in isocyanoacetates. The quite different reactivity of the isocyanoacetate is due to the different steric hindrance of the amides and lactams. PMID- 28850231 TI - Co11Li[(OH)5O][(PO3OH)(PO4)5], a Lithium-Stabilized, Mixed-Valent Cobalt(II,III) Hydroxide Phosphate Framework. AB - A new metastable phase, featuring a lithium-stabilized mixed-valence cobalt(II,III) hydroxide phosphate framework, Co11.0(1)Li1.0(2)[(OH)5O][(PO3OH)(PO4)5], corresponding to the simplified composition Co1.84(2)Li0.16(3)(OH)PO4, is prepared by hydrothermal synthesis. Because the pH-dependent formation of other phases such as Co3(OH)2(PO3OH)2 and olivine-type LiCoPO4 competes in the process, a pH value of 5.0 is crucial for obtaining a single-phase material. The crystals with dimensions of 15 MUm * 30 MUm exhibit a unique elongated triangular pyramid morphology with a lamellar fine structure. Powder X-ray diffraction experiments reveal that the phase is isostructural with the natural phosphate minerals holtedahlite and satterlyite, and crystallizes in the trigonal space group P31m (a = 11.2533(4) A, c = 4.9940(2) A, V = 547.70(3) A3, Z = 1). The three-dimensional network structure is characterized by partially Li-substituted, octahedral [M2O8(OH)] (M = Co, Li) dimer units which form double chains that run along the [001] direction and are connected by [PO4] and [PO3(OH)] tetrahedra. Because no Li-free P31m-type Co2(OH)PO4 phase could be prepared, it can be assumed that the Li ions are crucial for the stabilization of the framework. Co L-edge X-ray absorption spectroscopy demonstrates that the cobalt ions adopt the oxidation states +2 and +3 and hence provides further evidence for the incorporation of Li in the charge balanced framework. The presence of three independent hydroxyl groups is further confirmed by infrared spectroscopy. Magnetization measurements imply a paramagnetic to antiferromagnetic transition at around T = 25 K as well as a second transition at around 9-12 K with a ferromagnetic component below this temperature. The metastable character of the phase is demonstrated by thermogravimetric analysis and differential scanning calorimetry, which above 558 degrees C reveal a two-step decomposition to CoO, Co3(PO4)2, and olivine-type LiCoPO4 with release of water and oxygen. PMID- 28850232 TI - Excited-State Dynamics in O6-Methylguanosine: Impact of O6-Methylation on the Relaxation Mechanism of Guanine Monomers. AB - Absorption of ultraviolet radiation by DNA bases results in ultrafast internal conversion to the ground state, which minimizes photodamage. However, exogenous and endogenous alkylating agents present in the cellular environment can methylate the nucleobases in DNA. In particular, methylation of guanosine at the O6 position in DNA leads to the formation of the O6-methylguanosine adduct, which may alter the photostability of DNA. This contribution demonstrates that O6 methylation of guanosine red shifts its ground-state absorption spectrum and slows down the rate of internal conversion to the ground state by ~40-fold in aqueous solution. The 40-fold decrease in the rate of excited-state decay increases the probability of photodamage within cellular DNA. It is proposed that the longer decay lifetime corresponds to relaxation of the excited-state population in O6-methylguanosine along a C6-puckered reaction coordinate in the 1pipi*(La) potential energy surface that runs parallel to an ultrafast internal conversion pathway along a C2-puckered coordinate. PMID- 28850233 TI - Redefining the Protein-Protein Interface: Coarse Graining and Combinatorics for an Improved Understanding of Amino Acid Contributions to the Protein-Protein Binding Affinity. AB - The ability to intervene in biological pathways has for decades been limited by the lack of a quantitative description of protein-protein interactions (PPIs). Herein we generate and compare millions of simple PPI models for insight into the mechanisms of specific recognition and binding. We use a coarse-grained approach whereby amino acids are counted in the interface, and these counts are used as binding affinity predictors. We perform lasso regression, a modern regression technique aimed at interpretability, with every possible amino acid combination (over 106 unique feature sets) to select only those amino acid predictors that provide more information than noise. This approach circumvents arbitrary binning and assumptions about the binding environment that obscure other binding affinity models. Aggregated analysis of these models trained at various interfacial cutoff distances informs the roles of specific amino acids in different binding contexts. We find that a simple amino acid count model outperforms detailed intermolecular contact and binned residue type models. We identify the prevalence of serine, glycine, and tryptophan in the interface as particularly important for predicting binding affinity across a range of distance cutoffs. Although current sample size limitations prevent a robust consensus model for binding affinity prediction, our approach underscores the relevance of a residue-based description of the protein-protein interface to increase our understanding of specific interactions. PMID- 28850234 TI - Behaviors of the Interfacial Consecutive Multistep Electron Transfer Controlled by Varied Transition Metal Ions in Porphyrin Cores. AB - Almost all life activities involve the process of multistep electron transfer (ET) which occurs on biomembrane. Metalloporphyrins (MTPPs) are a class of molecules which are closely related to life course. Here, the n-step (n = 1, 2) ET behaviors controlled by different metal ions in porphyrin cores were investigated by thin-layer cyclic voltammetry (TLCV). The bimolecular ET was reacted between the MTPP (M = Fe, Zn, Co, Cu, Ni) and Fe(CN)64- in nitrobenzene and aqueous phase, respectively, and the interface between nitrobenzene and aqueous phase was considered as a bionic membrane. The thin-layer theory, which has been revised, was used to calculate the kinetic constants for each step electron transfer reactions. It was shown that the kinetic data were affected dramatically by the different coordinated ions in porphyrin complexes. PMID- 28850235 TI - Low Focal Adhesion Signaling Promotes Ground State Pluripotency of Mouse Embryonic Stem Cells. AB - Mouse embryonic stem cells (mESCs) can be maintained in a pluripotent state when cultured with 2 inhibitors (2i) of extracellular signal-regulated kinase (MEK) and glycogen synthase kinase-3 (GSK3), and Royan 2 inhibitors (R2i) of FGF4 and TGFbeta. The molecular mechanisms that control ESC self-renewal and pluripotency are more important for translating stem cell technologies to clinical applications. In this study, we used the shotgun proteomics technique to compare the proteome of the ground state condition (R2i- and 2i-grown cells) to that of serum. Out of 1749 proteins identified, 171 proteins were differentially expressed (p < 0.05) in the 2i, R2i, and serum samples. Gene ontology (GO) analysis of differentially abundant proteins showed that the focal adhesion signaling pathway significantly down-regulated under ground state conditions. mESCs had highly adhesive attachment under the serum condition, whereas in the 2i and R2i culture conditions, a loss of adhesion was observed and the cells were rounded and grew in compact colonies on gelatin. Quantitative RT-PCR showed reduced expression of the integrins family in the 2i and R2i conditions. The serum culture had more prominent phosphorylation of focal adhesion kinase (FAK) compared to 2i and R2i cultures. Activity of the extracellular signal-regulated kinase (ERK)1/2 decreased in the 2i and R2i cultures compared to serum. Activation of integrins by Mn2+ in the 2i and R2i cultures resulted in reduced Nanog and increased the expression of lineage marker genes. In this study, we demonstrated that reduced focal adhesion enabled mESCs to be maintained in an undifferentiated and pluripotent state. PMID- 28850236 TI - Lipid-Coated Gold Nanoparticles and FRET Allow Sensitive Monitoring of Liposome Clustering Mediated by the Synaptotagmin-7 C2A Domain. AB - Synaptotagmin (Syt) family proteins contain tandem C2 domains, C2A and C2B, which insert into anionic membranes in response to increased cytosolic Ca2+ concentration and facilitate exocytosis in neuronal and endocrine cells. The C2A domain from Syt7 binds lipid membranes much more tightly than the corresponding domain from Syt1, but the implications of this difference for protein function are not yet clear. In particular, the ability of the isolated Syt7 C2A domain to initiate membrane apposition and/or aggregation has been previously unexplored. Here, we demonstrate that Syt7 C2A induces apposition and aggregation of liposomes using Forster resonance energy transfer (FRET) assays, dynamic light scattering, and spectroscopic techniques involving lipid-coated gold nanoparticles (LCAuNPs). Protein-membrane binding, membrane apposition, and macroscopic aggregation are three separate phenomena with distinct Ca2+ requirements: the threshold Ca2+ concentration for membrane binding is lowest, followed by apposition and aggregation. However, aggregation is highly sensitive to protein concentration and can occur even at submicromolar Syt7 C2A; thus, highly sensitive assays are needed for measuring apposition without complications arising from aggregation. Notably, the localized surface plasmon resonance of the LCAuNP is sensitive to <=10 nM Syt7 C2A concentrations. Furthermore, when the LCAuNPs were added into a FRET-based liposome apposition assay, the resultant energy transfer increased; possible explanations are discussed. Overall, LCAuNP based methods allow for highly sensitive detection of protein-induced membrane apposition under conditions that miminize large-scale aggregation. PMID- 28850237 TI - Fast, Robust Evaluation of the Equation of State of Suspensions of Charge Stabilized Colloidal Spheres. AB - Increasing demand is appearing for the fast, robust prediction of the equation of state of colloidal suspensions, notably with a view to using it as input data to calculate transport coefficients in complex flow solvers. This is also of interest in rheological studies, industrial screening tests of new formulations, and the real-time interpretation of osmotic compression experiments, for example. For charge-stabilized spherical particles, the osmotic pressure can be computed with standard liquid theories. However, this calculation can sometimes be lengthy and/or unstable under some physicochemical conditions, a drawback that precludes its use in multiscale flow simulators. As a simple, fast, and robust replacement, the literature reports estimations of the osmotic pressure that have been built by adding the Carnahan-Starling and the cell model pressures (CSCM model). The first contribution is intended to account for colloid-colloid contacts, and the second, for electrostatic effects. This approximation has not yet been thoroughly tested. In this work, the CSCM is evaluated by comparison with data from experiments on silica particles, Monte Carlo simulations, and solutions of the accurate Rogers-Young integral equation scheme with a hard-sphere Yukawa potential obtained from the extrapolated point-charge renormalization method for a wide range of volume fractions, surface charge densities, and interaction ranges. We find that the CSCM is indeed perfectly adequate in the electrostatically concentrated regime, where it can be used from vanishingly small to high surface charge because there is error cancellation between the Carnahan-Starling and cell model contributions at intermediate charge. The CSCM is thus a nice extension of the cell model to liquid-like dense suspensions, which should find application in the domains mentioned above. However, it fails for dilute suspensions with strong electrostatics. In this case, we show that, and explain why, perturbation methods and the rescaled mean spherical approximation are good alternatives in terms of precision, ease of implementation, computational cost, and robustness. PMID- 28850238 TI - Theoretical Study of the Phosphoryl Transfer Reaction from ATP to Dha Catalyzed by DhaK from Escherichia coli. AB - Protein kinases, representing one of the largest protein families involved in almost all aspects of cell life, have become one of the most important targets for the development of new drugs to be used in, for instance, cancer treatments. In this article an exhaustive theoretical study of the phosphoryl transfer reaction from adenosine triphosphate (ATP) to dihydroxyacetone (Dha) catalyzed by DhaK from Escherichia coli (E. coli) is reported. Two different mechanisms, previously proposed for the phosphoryl transfer from ATP to the hydroxyl side chain of specific serine, threonine, or tyrosine residues, have been explored based on the generation of free energy surfaces (FES) computed with hybrid QM/MM potentials. The results suggest that the substrate-assisted phosphoryl and proton transfer mechanism is kinetically more favorable than the mechanism where an aspartate would be activating the Dha. Although the details of the mechanisms appear to be dramatically dependent on the level of theory employed in the calculations (PM3/MM, B3LYP:PM3/MM, or B3LYP/MM), the transition states (TSs) for the phosphoryl transfer step appear to be described as a concerted step with different degrees of synchronicity in the breaking and forming bonds process in both explored mechanisms. Residues of the active site belonging to different subunits of the protein, such as Gly78B, Thr79A, Ser80A, Arg178B, and one Mg2+ cation, would be stabilizing the transferred phosphate in the TS. Asp109A would have a structural role by posing the Dha and other residues of the active site in the proper orientation. The information derived from our calculations not only reveals the role of the enzyme and the particular residues of its active site, but it can assist in the rational design of new more specific inhibitors. PMID- 28850239 TI - Poly(ectoine) Hydrogels Resist Nonspecific Protein Adsorption. AB - The development of nonfouling zwitterionic materials has a wide range of biomedical and engineering applications. This work delineates the design and synthesis of a new zwitterionic material based on a naturally occurring compatible solute, ectoine, which is known to possess additional protective properties that stabilize even whole cells against ultraviolet radiation or cytotoxins. These properties and applications of ectoine inspire us to design a functional monomer containing the natural zwitterion moiety of ectoine imparting nonfouling properties and the methacrylate moiety for polymerization. The synthesis route designed for the ectoine methacrylate monomer is simple with a high yield, which is characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. After monomer synthesis, we have prepared a poly(ectoine) hydrogel via thermal polymerization. The equilibrium water content, degree of cross-linking, mechanical strength, and nonfouling properties are determined for polyectoine hydrogels with different cross-linking conditions. Poly(ectoine) hydrogels are shown to have highly hydrated and excellent nonfouling properties and can be considered to be a promising biomaterial. PMID- 28850240 TI - Understanding of Relationship between Phospholipid Membrane Permeability and Self Diffusion Coefficients of Some Drugs and Biologically Active Compounds in Model Solvents. AB - In this work we measured self-diffusion coefficients of 5 drugs (aspirin, caffeine, ethionamide, salicylic acid, and paracetamol) and 11 biologically active compounds of similar structure in deuterated water and 1-octanol by NMR. It has been found that an increase in the van der Waals volume of the molecules of the studied substances result in reduction of their diffusion mobility in both solvents. The analysis of the experimental data showed the influence of chemical nature and structural isomerization of the molecules on the diffusion mobility. Apparent permeability coefficients of the studied compounds were determined using an artificial phospholipid membrane made of egg lecithin as a model of in vivo absorption. Distribution coefficients in 1-octanol/buffer pH 7.4 system were measured. For the first time the model of the passive diffusion through the phospholipid membrane was validated based on the experimental data. To this end, the passive diffusion was considered as an additive process of molecule passage through the aqueous boundary layer before the membrane and 1-octanol barrier simulating the lipid layer of the membrane. PMID- 28850241 TI - Lymphoma Immunochemotherapy: Targeted Delivery of Doxorubicin via a Dual Functional Nanocarrier. AB - Chemotherapy drug (paclitaxel, PTX) incorporated in a dual functional polymeric nanocarrier, PEG-Fmoc-NLG, has shown promise as an immunochemotherapy in a murine breast cancer model, 4T1.2. The formulation is composed of an amphiphilic polymer with a built-in immunotherapy drug NLG919 that exhibits the immunostimulatory ability through the inhibition of indoleamine 2,3-dioxygenase 1 (IDO-1) in cancer cells. This work evaluates whether the PEG-derivatized NLG polymer can also be used for delivery of doxorubicin (Dox) in treatment of leukemia. The Dox-loaded micelles were self-assembled from PEG-Fmoc-NLG conjugate, which have a spherical shape with a uniform size of ~120 nm. In cultured murine lymphocytic leukemia cells (A20), Dox-loaded PEG-Fmoc-NLG micelles showed a cytotoxicity that was comparable to that of free Dox. For in vivo studies, significantly improved antitumor activity was observed for the Dox/PEG-Fmoc-NLG group compared to Doxil or the free Dox group in an A20 lymphoma mouse model. Flow cytometric analysis showed that treatment with Dox/PEG-Fmoc-NLG micelles led to significant increases in the numbers of both total CD4+/CD8+ T cells and the functional CD4+/CD8+ T cells with concomitant decreases in the numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg). Dox/PEG-Fmoc-NLG may represent a promising immunochemotherapy for lymphoma, which warrants more studies in the future. PMID- 28850242 TI - Synthesis and Properties of meso-Arylated Corrphycenes. AB - A novel synthetic procedure for meso-aryl-substituted corrphycenes has been developed. Suzuki-Miyaura coupling of alpha,alpha'-dibromodipyrrin with vic diborylalkene and o-diborylbenzene afforded ethenylene- and phenylene-bridged bisdipyrrins, respectively, which were transformed to the corresponding corrphycenes upon treatment with palladium acetate. The bridging units significantly affect the macrocyclic pi-conjugation circuits, thus changing the aromatic characters and absorption features of corrphycenes. PMID- 28850243 TI - Quantification of Efficient Plasmonic Hot-Electron Injection in Gold Nanoparticle TiO2 Films. AB - Excitation of localized surface plasmons in metal nanostructures generates hot electrons that can be transferred to an adjacent semiconductor, greatly enhancing the potential light-harvesting capabilities of photovoltaic and photocatalytic devices. Typically, the external quantum efficiency of these hot-electron devices is too low for practical applications (<1%), and the physics underlying this low yield remains unclear. Here, we use transient absorption spectroscopy to quantify the efficiency of the initial electron transfer in model systems composed of gold nanoparticles (NPs) fully embedded in TiO2 or Al2O3 films. In independent experiments, we measure free carrier absorption and electron-phonon decay in the model systems and determine that the electron-injection efficiency from the Au NPs to the TiO2 ranges from about 25% to 45%. While much higher than some previous estimates, the measured injection efficiency is within an upper-bound estimate based on a simple approximation for the Au hot-electron energy distribution. These results have important implications for understanding the achievable injection efficiencies of hot-electron plasmonic devices and show that the injection efficiency can be high for Au NPs fully embedded within a semiconductor with dimensions less than the Au electron mean free path. PMID- 28850244 TI - Engineering Reaction Kinetics by Tailoring the Metal Tips of Metal-Semiconductor Nanodumbbells. AB - Semiconductor-metal hybrid nanostructures are one of the best model catalysts for understanding photocatalytic hydrogen generation. To investigate the optimal structure of metal cocatalysts, metal-CdSe-metal nanodumbbells were synthesized with three distinct sets of metal tips, Pt-CdSe-Pt, Au-CdSe-Au, and Au-CdSe-Pt. Photoelectrochemical responses and transient absorption spectra showed that the competition between the charge recombination at the metal-CdSe interface and the water reduction on the metal surface is a detrimental factor for the apparent hydrogen evolution rate. For instance, a large recombination rate (krec) at the Pt-CdSe interface limits the quantum yield of hydrogen generation despite a superior water reduction rate (kWR) on the Pt surface. To suppress the recombination process, Pt was selectively deposited onto the Au tips of Au-CdSe Au nanodumbbells in which the krec was diminished at the Au-CdSe interface, and the large kWR was maintained on the Pt surface. As a result, the optimal structure of the Pt-coated Au-CdSe-Au nanodumbbells reached a quantum yield of 4.84%. These findings successfully demonstrate that the rational design of a metal cocatalyst and metal-semiconductor interface can additionally enhance the catalytic performance of the photochemical hydrogen generation reactions. PMID- 28850245 TI - Selectivity in the Efflux of Glucuronides by Human Transporters: MRP4 Is Highly Active toward 4-Methylumbelliferone and 1-Naphthol Glucuronides, while MRP3 Exhibits Stereoselective Propranolol Glucuronide Transport. AB - Xenobiotic and endobiotic glucuronides, which are generated in hepatic and intestinal epithelial cells, are excreted via efflux transporters. Multidrug resistance proteins 2-4 (MRP2-MRP4) and the breast cancer resistance protein (BCRP) are efflux transporters that are expressed in these polarized cells, on either the basolateral or apical membranes. Their localization, along with expression levels, affects the glucuronide excretion pathways. We have studied the transport of three planar cyclic glucuronides and glucuronides of the two propranolol enantiomers, by the vesicular transport assay, using vesicles from baculovirus-infected insect cells expressing human MRP2, MRP3, MRP4, or BCRP. The transport of estradiol-17beta-glucuronide by recombinant MRP2-4 and BCRP, as demonstrated by kinetic values, were within the ranges previously reported. Our results revealed high transport rates and apparent affinity of MRP4 toward the glucuronides of 4-methylumbelliferone, 1-naphthol, and 1-hydroxypyrene (Km values of 168, 13, and 3 MUM, respectively) in comparison to MRP3 (Km values of 278, 98, and 8 MUM, respectively). MRP3 exhibited lower rates, but stereoselective transport of propranolol glucuronides, with higher affinity toward the R enantiomer than the S-enantiomer (Km values 154 vs 434 MUM). The glucuronide of propranolol R-enantiomer was not significantly transported by either MRP2, MRP4, or BCRP. Of the tested small glucuronides in this study, BCRP transported only 1 hydroxypyrene glucuronide, at very high rates and high apparent affinity (Vmax and Km values of 4400 pmol/mg/min and 11 MUM). The transport activity of MRP2 with all of the studied small glucuronides was relatively very low, even though it transported the reference compound, estradiol-17beta-glucuronide, at a high rate (Vmax = 3500 pmol/mg/min). Our results provide new information, at the molecular level, of efflux transport of the tested glucuronides, which could explain their disposition in vivo, as well as provide new tools for in vitro studies of MRP3, MRP4, and BCRP. PMID- 28850246 TI - Electron-Lattice Coupling in Correlated Materials of Low Electron Occupancy. AB - In correlated materials including transition metal oxides, electronic properties and functionalities are modulated and enriched by couplings between the electron and lattice degrees of freedom. These couplings are controlled by external parameters such as chemical doping, pressure, magnetic and electric fields, and light irradiation. However, the electron-lattice coupling relies on orbital characters, i.e., symmetry and occupancy, of t2g and eg orbitals, so that a large electron-lattice coupling is limited to eg electron system, whereas t2g electron system exhibits an inherently weak coupling. Here, we design and demonstrate a strongly enhanced electron-lattice coupling in electron-doped SrTiO3, that is, the t2g electron system. In ultrathin films of electron-doped SrTiO3 [i.e., (La0.25Sr0.75)TiO3], we reveal the strong electron-lattice-orbital coupling, which is manifested by extremely increased tetragonality and the corresponding metal-to-insulator transition. Our findings open the way of an active tuning of the charge-lattice-orbital coupling to obtain new functionalities relevant to emerging nanoelectronic devices. PMID- 28850247 TI - S1PR3 Signaling Drives Bacterial Killing and Is Required for Survival in Bacterial Sepsis. AB - RATIONALE: Efficient elimination of pathogenic bacteria is a critical determinant in the outcome of sepsis. Sphingosine-1-phosphate receptor 3 (S1PR3) mediates multiple aspects of the inflammatory response during sepsis, but whether S1PR3 signaling is necessary for eliminating the invading pathogens remains unknown. OBJECTIVES: To investigate the role of S1PR3 in antibacterial immunity during sepsis. METHODS: Loss- and gain-of-function experiments were performed using cell and murine models. S1PR3 levels were determined in patients with sepsis and healthy volunteers. MEASUREMENTS AND MAIN RESULTS: S1PR3 protein levels were up regulated in macrophages upon bacterial stimulation. S1pr3-/- mice showed increased mortality and increased bacterial burden in multiple models of sepsis. The transfer of wild-type bone marrow-derived macrophages rescued S1pr3-/- mice from lethal sepsis. S1PR3-overexpressing macrophages further ameliorated the mortality rate of sepsis. Loss of S1PR3 led to markedly decreased bacterial killing in macrophages. Enhancing endogenous S1PR3 activity using a peptide agonist potentiated the macrophage bactericidal function and improved survival rates in multiple models of sepsis. Mechanically, the reactive oxygen species levels were decreased and phagosome maturation was delayed in S1pr3-/- macrophages due to impaired recruitment of vacuolar protein-sorting 34 to the phagosomes. In addition, S1RP3 expression levels were elevated in monocytes from patients with sepsis. Higher levels of monocytic S1PR3 were associated with efficient intracellular bactericidal activity, better immune status, and preferable outcomes. CONCLUSIONS: S1PR3 signaling drives bacterial killing and is essential for survival in bacterial sepsis. Interventions targeting S1PR3 signaling could have translational implications for manipulating the innate immune response to combat pathogens. PMID- 28850248 TI - Eye Movement Patterns in Response to Anti-Binge Drinking Messages. AB - Health message design combines selected visual and textual components that are thought to work in concert to produce a particular intended message effect. Most health message effects research assumes rather than determines that message recipients attend to those visual and textual components. In contrast, the present research mapped viewing patterns of 50 participants in response to a set of anti-binge drinking print messages using eye-tracking methodology. Results showed that participants primarily viewed faces of persons portrayed in the messages, as well as alcohol use cues and cryptic one-liners. Textual components (e.g., information about consequences of heavy drinking) were viewed infrequently and briefly. Viewing patterns were associated with perceptions of message effectiveness, but more so for women than for men. Additionally, men, for whom anti-binge drinking messages were more self-relevant than for women, viewed message components more often and longer than women. These findings suggest that when message recipients view a self-relevant health message, they may attend primarily to a subset of components that do not necessarily convey the full message. PMID- 28850250 TI - Overselling Sit-Stand Desks: News Coverage of Workplace Sitting Guidelines. AB - The first quantitative, specific recommendations for sitting time at work were released in June 2015. This paper examines the implications of news coverage received by this position statement. Media reports about statement published May, 31-June, 29, 2015 were analyzed according to five recommendations and three caveats extracted from the guidelines' press release. Information about how physical activity was framed and mentions of conflicts of interest were recorded. Of 58 news reports, nine reported all five recommendations in the position paper. The topline recommendation (two hours daily of standing and light activity) was reported in all articles. Alleviating musculoskeletal discomfort by sitting less was not reported by 72% of reports. Physical activity was mentioned in 32 reports: 69% said physical activity did not attenuate the risks of prolonged sitting. No reports mentioned any potential conflicts of interest despite co author links to sit-stand desk industry. These results demonstrate the need to balance public and market demands for public health guidance around sitting; and could encourage more accurate communication of research outcomes. The physical activity component of the "move more and sit less" message requires greater efforts to raise its public salience. PMID- 28850249 TI - Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin induced Lung Fibrosis. AB - Idiopathic pulmonary fibrosis is a progressive lung disease with complex pathophysiology and fatal prognosis. Macrophages (MPhi) contribute to the development of lung fibrosis; however, the underlying mechanisms and specific MPhi subsets involved remain unclear. During lung injury, two subsets of lung MPhi coexist: Siglec-Fhi resident alveolar MPhi and a mixed population of CD11bhi MPhi that primarily mature from immigrating monocytes. Using a novel inducible transgenic system driven by a fragment of the human CD68 promoter, we targeted deletion of the antiapoptotic protein cellular FADD-like IL-1beta-converting enzyme-inhibitory protein (c-FLIP) to CD11bhi MPhi. Upon loss of c-FLIP, CD11bhi MPhi became susceptible to cell death. Using this system, we were able to show that eliminating CD11bhi MPhi present 7-14 days after bleomycin injury was sufficient to protect mice from fibrosis. RNA-seq analysis of lung MPhi present during this time showed that CD11bhi MPhi, but not Siglec-Fhi MPhi, expressed high levels of profibrotic chemokines and growth factors. Human MPhi from patients with idiopathic pulmonary fibrosis expressed many of the same profibrotic chemokines identified in murine CD11bhi MPhi. Elimination of monocyte derived MPhi may help in the treatment of fibrosis. We identify c-FLIP and the associated extrinsic cell death program as a potential pathway through which these profibrotic MPhi may be pharmacologically targeted. PMID- 28850251 TI - Systemic Hypoxia Increases Circulating Concentration of Apelin in Humans. AB - : Heinonen, Ilkka, Olli Vuolteenaho, Juha Koskenvuo, Olli Arjamaa, and Mikko Nikinmaa. Systemic hypoxia increases circulating concentration of apelin in humans. High Alt Med Biol. 18:292-295, 2017. BACKGROUND: Apelin is a hormone that regulates cardiovascular function, and its concentration is increased by hypoxia based on cell culture and animal studies. As it remains unknown as to whether hypoxia could affect apelin levels in humans, we investigated whether breathing normobaric hypoxic gas mixture increases the circulating apelin concentration in healthy male subjects. METHODS: Ten healthy young men (age 29 +/- 5 years, body mass index 24.7 +/- 2.8 kg/m2) breathed normobaric hypoxic gas mixture (11% O2/89% N2) for 1 hour. Venous blood samples were obtained immediately before, and 2 and 24 hours after the start of the hypoxic exposure and analyzed for circulating apelin concentrations. RESULTS: Arterial oxygen saturation decreased steadily from a baseline value of 99% +/- 1% after the initiation hypoxia challenge and reached a steady-state level of 73% +/- 6% within 20-30 minutes. Baseline apelin concentration was 3.3 +/- 1.3 pmol/L and remained comparable (3.3 +/- 1.4 pmol/L) to the baseline concentration at a 2-hour time point. However, apelin concentration at the 24-hour time point (5.5 +/- 2.8 pmol/L) was significantly (by ~67%) higher as compared with at both baseline and 2-hour time points (p < 0.05). CONCLUSION: In conclusion, in line with cell culture and animal studies, acute systemic hypoxia increases circulating apelin concentration also in humans. PMID- 28850253 TI - Deceived, Disgusted, and Defensive: Motivated Processing of Anti-Tobacco Advertisements. AB - A 2 * 2 experiment was conducted, where participants watched anti-tobacco messages that varied in deception (content portraying tobacco companies as dishonest) and disgust (negative graphic images) content. Psychophysiological measures, self-report, and a recognition test were used to test hypotheses generated from the motivated cognition framework. The results of this study indicate that messages containing both deception and disgust push viewers into a cascade of defensive responses reflected by increased self-reported unpleasantness, reduced resources allocated to encoding, worsened recognition memory, and dampened emotional responses compared to messages depicting one attribute or neither. Findings from this study demonstrate the value of applying a motivated cognition theoretical framework in research on responses to emotional content in health messages and support previous research on defensive processing and message design of anti-tobacco messages. PMID- 28850254 TI - Halstead-Reitan characteristics of nonimpact and impact mTBI litigants and insurance claimants. AB - The purpose of this study was to investigate possible neuropsychological differences in Halstead-Reitan characteristics between motor vehicle accident litigants and insurance claimants that sustained uncomplicated mild traumatic brain injury (mTBI) and did or did not sustain direct impact to the head (i.e., Impact vs. Nonimpact mTBI), and to compare these clinical groups with a control group that did not suffer mTBI (No mTBI). The Tactile Form Recognition Test (TFR) was the only level of performance test in the Halstead-Reitan Battery (HRB) that generated statistically significant differences. The TFR resembles a complex reaction time test. TFR response time was significantly longer for Nonimpact mTBI patients than for Impact mTBI and No mTBI participants. Frequency comparisons of abnormal score patterns demonstrated that Nonimpact patients produced significantly more aberrant Impairment Index vs. FSIQ score patterns than Impact and No mTBI participants. Given the components of the score pattern, this finding suggests that Nonimpact patients may experience less recovery from neuropsychological deficits than Impact participants. Complex perceptual reaction times and score patterns comparing sensitive and "hold" test results may represent heuristic avenues of future research in the study of compensation seeking Nonimpact and Impact mTBI patients. PMID- 28850252 TI - The use of ofatumumab in the treatment of B-cell malignancies. AB - Ofatumumab has been extensively studied in the treatment of B-cell malignancies. Currently, it has been approved for the treatment of chronic lymphocytic leukemia in a number of different situations. However, there is still no compelling evidence confirming the superiority of ofatumumab over rituximab in vivo. In this article, we summarize the currently available clinical data supporting the use of ofatumumab in the treatment of B-cell malignancies. The clinical studies were searched from clinicaltrials.gov with the key words ofatumumab, HuMax-CD20. Out of 115 trials available, studies for B-cell malignancies were selected, followed by selection of completed studies with results and active ongoing studies. The results from completed studies were thoroughly analyzed and active ongoing studies were listed in tables. PMID- 28850255 TI - Dynamic CT Scan of the Normal Scapholunate Joint in a Clenched Fist and Radial and Ulnar Deviation. AB - BACKGROUND: Injuries to the scapholunate can have severe long-term effects on the wrist. Early detection of these injuries can help identify pathology. The purpose of this study was to evaluate the motions of the scapholunate joint in normal wrists in a clenched fist and through radial and ulnar deviation using novel dynamic computed tomography (CT) imaging. METHODS: Fifteen participants below 40 years of age consented to have their wrist scanned. Eight participants were randomized to have the right wrist scanned and 7 the left wrist. Volunteers were positioned at the back of the gantry with the wrist placed on the table, palmar side down. Participants began with the hand in a relaxed fist position and then proceeded through an established range of motion protocol. Dynamic CT imaging was captured throughout the range of motion. RESULTS: The movement in the healthy scapholunate joint through a clenched fist and radial and ulnar deviation is minimal. The averages were 1.19, 1.01, and 0.95 mm, representing the middle, dorsal, and volar measurements, respectively. CONCLUSIONS: This novel dynamic CT scan of the wrist is a user-friendly way of measuring of the scapholunate distance, which is minimal in the normal wrist below 40 years of age. PMID- 28850256 TI - Verbal episodic memory profiles in HIV-Associated Neurocognitive Disorders (HAND): A comparison with Huntington's disease and mesial temporal lobe epilepsy. AB - HIV-associated neurocognitive disorders (HAND) commonly feature verbal episodic memory impairment historically characterized by a retrieval deficit, consistent with a classic "subcortical" presentation; however, there are hints of a subtle shift toward a more "cortical" memory profile characterized by a primary encoding deficit. The current study evaluated this possibility by comparing the pattern of HAND-associated verbal episodic memory deficits to those of traditional "subcortical" (i.e., Huntington's disease; HD) versus "cortical" (i.e., left temporal lobe epilepsy with mesial temporal sclerosis; L-MTLE) profiles. Seventy seven individuals with HAND, 47 individuals with HD, 21 individuals with L-MTLE, and 45 healthy participants were administered the California Verbal Learning Test - 2nd Edition (CVLT-II). CVLT-II profiles were classified as reflecting a primary encoding deficit, retrieval deficit, or a normal profile. Among participants with a deficit profile, the HAND group showed the highest rates of retrieval versus encoding profiles (71% vs. 29%), followed by HD (59% vs. 41%), L-MTLE (46% vs. 54%), and healthy (50% vs. 50%) groups. While significant profile heterogeneity was observed across clinical groups, findings suggest that HIV-associated verbal episodic memory impairments are most consistent with a traditional "subcortical," retrieval deficit profile, consistent with the primary frontostriatal neuropathogenesis of HIV disease. PMID- 28850257 TI - CD34 Differentially Regulates Contractile and Noncontractile Elements of Airway Reactivity. AB - Airway hyperresponsiveness (AHR), a major hallmark of asthma, results from alterations of contractile and noncontractile elements of airway reactivity. CD34 is a sialomucin that is expressed on various cells involved in asthma, such as eosinophils and airway smooth muscle precursors, highlighting its potential influence in AHR. To study the role of CD34 in regulating the contractile and noncontractile elements of AHR, AHR was induced by chronic exposure to house dust mite (HDM) antigen. To assess the role of CD34 on the contractile elements of AHR, airway reactivity and airway smooth muscle contractility in response to methacholine were measured. To assess CD34's role in regulating the noncontractile elements of AHR, a chimeric mouse model was used to determine the impact of CD34 expression on inflammatory versus microenvironmental cells in AHR development. Extracellular matrix production, mucus production, and mast cell degranulation were also measured. Whereas wild-type mice developed AHR in response to HDM, a loss of airway reactivity was observed in Cd34-/- mice 24 hours after the last exposure to HDM compared with naive controls. This was reversed when airway reactivity was measured 1 week after the last HDM exposure. Additionally, mast cell degranulation and mucus production were altered in the absence of CD34 expression. Importantly, simultaneous expression of CD34 on cells originating from the hematopoietic compartment and the microenvironment was needed for expression of this phenotype. These results provide evidence that CD34 is required for AHR and airway reactivity maintenance in the early days after an inflammatory episode in asthma. PMID- 28850258 TI - Noncoding RNAs: New Players in Pulmonary Medicine and Sarcoidosis. AB - Noncoding RNAs (ncRNAs) are coded by 98% of human genomic DNA. They are grouped into two major classes according to length: small ncRNAs and long ncRNAs. They regulate genome organization, stability, and physiological processes that maintain cellular homeostasis. Recently, great interest has emerged in ncRNAs because of their significant roles in the development of inflammatory diseases, including sarcoidosis. Some have been introduced as novel markers for disease activity, such as increased levels of microRNA-34a in peripheral blood mononuclear cells of patients with sarcoidosis, re-emphasizing the inflammatory component in sarcoidosis. They are also important factors in the outcome of sarcoidosis. Dysregulation of microRNA-let7f leads to overexpression of profibrotic factors and could be related to the pathogenesis of pulmonary fibrosis in patients with sarcoidosis, owing to their stimulatory effect on collagen expression and deposition. However, many unanswered questions remain about the association of ncRNAs and sarcoidosis. By understanding the functions of ncRNAs in T-helper cell type 1 and T-helper cell type 17, we may uncover the mechanism of action of those cells in sarcoidosis. Further translational research is needed to define the RNA gene fingerprint of different sarcoidosis stages. PMID- 28850260 TI - Use of the Rey 15-Item Test as a performance validity test in an elderly population. AB - The objective of this study was to determine the effectiveness of the Rey 15-Item Test in elderly individuals with and without cognitive impairment and to develop new indices to function with this population, if needed. The sample consisted of 185 individuals referred for outpatient neuropsychological evaluation. All were clinically evaluated and administered the Rey 15-Item Test (RFIT) with recognition as part of this procedure. Significant differences were present between those passing and failing the RFIT on referral question; working status; age; and diagnosis of cognitive impairment. Individuals age 60+ failed the test at rates in excess of 35%. Diagnosis also played a role with those with more severe cognitive diagnosis failing at higher rates; even in those with no diagnosis, however, 19% of elderly individuals did not produce a passing score. The extant cutoff scores commonly used with the RFIT produce unacceptably high false positive error rates to be a useful freestanding Performance Validity Test (PVT) with individuals above age 59. The introduction of a new combination score and use of rare scores and patterns of scores improves the psychometric properties of the RFIT when used with elderly adults. Cautious use of PVTs is warranted until they have been validated with aged populations. PMID- 28850259 TI - Toll-Like Receptor 7/8 Ligand, S28463, Suppresses Ascaris suum-induced Allergic Asthma in Nonhuman Primates. AB - S28463 (S28), a ligand for Toll-like receptor 7/8, has been shown to have antiinflammatory properties in rodent models of allergic asthma. The principle goal of this study was to assess whether these antiinflammatory effects can also be observed in a nonhuman primate (NHP) model of allergic asthma. NHPs were sensitized then challenged with natural allergen, Ascaris suum extract. The animals were treated with S28 orally before each allergen challenge. The protective effect of S28 in NHPs was assessed by measuring various asthma-related phenotypes. We also characterized the metabolomic and proteomic signatures of the lung environment and plasma to identify markers associated with the disease and treatment. Our data demonstrate that clinically relevant parameters, such as wheal and flare response, blood IgE levels, recruitment of white blood cells to the bronchoalveolar space, and lung responsiveness, are decreased in the S28 treated allergic NHPs compared with nontreated allergic NHPs. Furthermore, we also identified markers that can distinguish allergic from nonallergic or allergic and drug-treated NHPs, such as metabolites, phosphocreatine and glutathione, in the plasma and BAL fluid, respectively; and inflammatory cytokines, IL-5 and IL-13, in the bronchoalveolar lavage fluid. Our preclinical study demonstrates that S28 has potential as a treatment for allergic asthma in primate species closely related to humans. Combined with our previous findings, we demonstrate that S28 is effective in different models of asthma and in different species, and has the antiinflammatory properties clinically relevant for the treatment of allergic asthma. PMID- 28850261 TI - Framing Egg Donation: A Dichotomous Split. AB - Reproductive medicine has depended upon the altruistic motivations of women to donate eggs. Donors are lauded for these self-sacrificing actions but are treated as a product during the selection and donation process. This process highlights the contradictory behaviors as evidence to the dichotomous split of the definition of women as "virgins" or "whores," by attracting women to donate as the former and treating them as the latter. PMID- 28850262 TI - Case Study: Composite Material Yoke Versus Wooden Yoke for Bullocks' Comfort. AB - This article addresses the designing of a yoke used to get work output (plowing) from bullocks. The yoke profile was designed in compliance with the profile of the bullock's body for maximum contact area. Unlike the crude, wooden yoke used in rural India, where modern tilling equipment like a tractor is not affordable, the present yoke was smooth, free from sharp edges, and light in weight. A field study was carried out with bullocks using composite and wooden yokes. The fatigue of bullocks was measured in terms of respiration rate and heart rate. Data revealed that bullocks had less fatigue with composite material yoke than with the wooden yoke. The experimental investigation also showed that at a 30o angle of pull, bullocks feel maximum comfort when they are used for plowing purposes. PMID- 28850263 TI - Hospital-Community Partnerships: Facilitating Communication for Population Health on Columbus' South Side. AB - Previous studies have focused on the role anchor institutions play in community development. However, less attention has been directed to how hospitals can effectively partner with community-organizations and residents as part of population health efforts. This article examines community views of one initiative developed by a major American children's hospital in partnership with local community organizations. The data for this study come from 35 in-depth interviews with local residents from the neighborhood adjacent to the hospital and two interviews with hospital administrators. Our findings suggest that the contexts in which hospitals and other non-profit corporations operate pose unique challenges to effective communication. In particular, hospitals and community organizations may think differently about the merits and nature of open communication. Especially when acting as anchor institutions working beyond their formal medical expertise, hospitals may struggle to communicate the scope and goals of their non-medical work in the community. PMID- 28850264 TI - Parents and Physiotherapists Recognition of Non-Verbal Communication of Pain in Individuals with Cerebral Palsy. AB - Pain assessment is difficult in individuals with cerebral palsy (CP). This is of particular relevance in children with communication difficulties, when non-verbal pain behaviors could be essential for appropriate pain recognition. Parents are considered good proxies in the recognition of pain in their children; however, health professionals also need a good understanding of their patients' pain experience. This study aims at analyzing the agreement between parents' and physiotherapists' assessments of verbal and non-verbal pain behaviors in individuals with CP. A written survey about pain characteristics and non-verbal pain expression of 96 persons with CP (45 classified as communicative, and 51 as non-communicative individuals) was performed. Parents and physiotherapists displayed a high agreement in their estimations of the presence of chronic pain, healthcare seeking, pain intensity and pain interference, as well as in non verbal pain behaviors. Physiotherapists and parents can recognize pain behaviors in individuals with CP regardless of communication disabilities. PMID- 28850265 TI - Corrigendum. AB - Huang SW, Wu CW, Lin LF, Liou TH, Lin HW. Gout can increase the risk of receiving rotator cuff tear repair surgery. Am J Sports Med. 2017;45(10):2355-2363. (Original DOI: 10.1177/0363546517704843) There was an error at the beginning of the Discussion section on page 2359 of this article. The corrected text is below. This population-based, retrospective cohort study demonstrated that patients with gout who were aged 50 years or younger (<=50 years old) had a 2.7 times higher risk of receiving rotator cuff repair surgery than did subjects without gout. PMID- 28850266 TI - Examining Factors Influencing Internet Addiction and Adolescent Risk Behaviors Among Excessive Internet Users. AB - In China, public concern continues to mount regarding the risks of excessive Internet use among adolescents. This study investigated the factors influencing Internet addiction and adolescent risk behaviors among excessive Internet users. Proposing a conceptual model with a theoretical origin in risk behavior theory and media dependency theory, this study examined the influence of personality traits, online gaming, Internet connectedness (both the overall index and various scopes), and demographics on Internet addiction and risk behaviors (smoking, drinking, gambling, and risky sexual behaviors). Clinical data (N = 467) were retrieved from one of the earliest and largest Internet addiction clinics in China. The findings reveal that certain personality traits are significantly associated with Internet addiction and risk behaviors. Online gaming had a strong impact on both Internet addiction and risk behaviors among excessive Internet users. The study also reveals that various scopes of Internet connectedness, such as site scope, facilitate addictive Internet use, and risk behaviors among adolescents. The findings can contribute to the prevention of and intervention into Internet addiction and adolescent risk behaviors. PMID- 28850267 TI - KLRG1 expression identifies short-lived Foxp3+ Treg effector cells with functional plasticity in islets of NOD mice. AB - A progressive waning in Foxp3+ regulatory T (Treg) cell function provokes autoimmunity in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), a cellular defect rescued by prophylactic IL-2 therapy. We showed that most islet-infiltrating Treg cells express inducible T-cell co-stimulator (ICOS) in pre-diabetic NOD mice, and that ICOS+ Treg cells display enhanced fitness and suppressive function in situ. Moreover, T1D progression is associated with decreased expansion and suppressive activity of ICOS+Foxp3+ Treg cells, in islets, an observation consistent with the exacerbated T1D seen in NOD.BDC2.5 mice in which the ICOS pathway is abrogated. Here, we show that a large proportion of islet-resident Treg cells express the KLRG1 marker of terminally differentiation, in contrast to islet-infiltrating ICOS- Treg or Teff cells. We hypothesized that KLRG1 expression designates a subpopulation of ICOS+ Treg cells in islets that progressively loses function, and contributes to the immune dysregulation observed at T1D onset. Indeed, KLRG1-expressing ICOS+ Treg cells are prone to apoptosis, and have an impaired proliferative capacity and suppressive function in vitro and in vivo. T1D protective low-dose IL-2 treatment in vivo could not rescue the loss of KLRG1-expressing Treg cells in situ. While the global pool of Foxp3+ Treg cells displays some degree of functional plasticity in vivo, the KLRG1+ ICOS+ Treg cell subset is particularly susceptible to lose Foxp3 expression and reprogram into Th1- or Th17-like effector T (Teff) cells in the pancreas microenvironment. Overall, KLRG1 expression delineates a subpopulation of dysfunctional Treg cells during T1D progression in autoantigen specific TCR transgenic NOD mice. PMID- 28850268 TI - Treatment of post-pulsed dye laser purpura with pulsed dye laser. AB - The pulsed dye laser (PDL) is used for the treatment of a variety of vascular and nonvascular disorders, and its therapeutic efficacy often depends on purpura as an endpoint. However, post-PDL purpura is an undesirable side effect of treatment as it may increase patient dissatisfaction and downtime. Recent studies have suggested that repeat treatment with PDL may speed the resolution of post procedural purpura; however, there is paucity of data on using repeat PDL treatment specifically for post-PDL purpura. We report three cases of 585 nm PDL induced purpura treated with 595 nm PDL with clinically significant improvement. We suggest that treatment with PDL, which targets hemoglobin and its breakdown products, after initial PDL treatment may reduce post-PDL purpura. PMID- 28850269 TI - Decreased bone mineral density in experimental myasthenia gravis in C57BL/6 mice. AB - Experimental autoimmune myasthenia gravis (EAMG), an animal model of myasthenia gravis (MG), can be induced in C57BL/6 (B6, H-2 b) mice by 2-3 injections with Torpedo californica AChR (tAChR) in complete Freund's adjuvant. Some EAMG mice exhibit weight loss with muscle weakness. The loss in body weight, which is closely associated with bone structure, is particularly evident in EAMG mice with severe muscle weakness. However, the relationship between muscle weakness and bone loss in EAMG has not been studied before. Recent investigations on bone have shed light on association of bone health and immunological states. It is possible that muscle weakness in EAMG developed by anti-tAChR immune responses might accompany bone loss. We determined whether reduced muscle strength associates with decreased bone mineral density (BMD) in EAMG mice. EAMG was induced by two injections at 4-week interval of tAChR and adjuvants in two different age groups. The first tAChR injection was either at age 8 weeks or at 15 weeks. We measured BMD at three skeletal sites, including femur, tibia, and lumbar vertebrae, using dual energy X-ray absorptiometry. Among these bone areas, femur of EAMG mice in both age groups showed a significant decrease in BMD compared to control adjuvant injected and to non-immunized mice. Reduction in BMD in induced EAMG at a later age appears to parallel the severity of the disease. The results indicate that anti-tAChR autoimmune response alone can reduce bone density in EAMG mice. BMD reduction was also observed in adjuvant-injected mice in comparison to normal un injected mice, suggesting that BMD decrease can occur even when muscle activity is normal. Decreased BMD observed in both tAChR-injected and adjuvant-injected mice groups were discussed in relation to innate immunity and bone-related immunology involving activated T cells and tumour necrosis factor-related cytokines that trigger osteoclastogenesis and bone loss. PMID- 28850270 TI - Cryolipolysis for submental fat reduction in Asians. AB - BACKGROUND: Cryolipolysis is a noninvasive method for the selective reduction of fat, especially proven to be safe and effective in body contouring. There is a demand for reduction in submental fat, which is related not only with a favorable appearance but also with signs of aging. OBJECTIVE: This study evaluated the efficacy and safety of cryolipolysis for subcutaneous fat reduction in the submental area in Asians. MATERIALS AND METHODS: Ten healthy Koreans were treated using a cryolipolysis contact device (CoolMini applicator, Zeltiq Aesthetics). The device was applied on the participant's neck twice via two lateral approaches. Patient's body weight was measured, and photographs were taken at baseline and during the follow-up visit after 8 weeks. Participants were examined with ultrasound and the depth of the subcutaneous fat layer was measured. RESULTS: The subjective reduction of submental fat was noted in most of the participants. Reduction of the subcutaneous fat layer depth was confirmed by ultrasound after 8 weeks of treatment. CONCLUSION: The results of this study indicate that submental fat can be safely and effectively reduced with use of a cryolipolysis applicator. The present study shows that cryolipolysis can be an option for nonsurgical facial contouring. PMID- 28850271 TI - Unexpected repeat immature oocyte response after IVF stimulation: a case report. AB - The purpose of ovarian stimulation in IVF is to recover mature oocytes at metaphase II stage which are capable of fertilization either when mixed with sperm or after ICSI. However, there have been instances when even after controlled ovarian stimulation (COS) and correct administration of human chorionic gonadotrophin (hCG) trigger for final oocyte maturation, the oocytes were found to be arrested at germinal vesicle (GV) or metaphase I (MI) stage. Similar dilemma is faced in cases of empty follicle syndrome (either genuine or due to inadequate response), however, in this condition, there is no retrieval of oocytes despite presence of mature looking follicles. We present an interesting case where despite presence of normally growing follicles and documentation of correct response to trigger and rise in estradiol levels, two subsequent IVF cycles; one triggered with recombinant hCG and second with GnRH agonist, hCG failed to yield mature oocytes. Both cycles yielded expected number of oocytes but all at immature MI stage even after dual trigger. PMID- 28850272 TI - Combined effect of retinoic acid and calcium on the in vitro differentiation of human adipose-derived stem cells to adipocytes. AB - CONTEXT: It has been shown that adipogenesis can be modulated by factors such as all-trans retinoic acid (ATRA) and calcium. OBJECTIVE: To determine, the combined effect of ATRA and calcium on the differentiation of human adipose-derived stem cells (hADSCs). METHODS: Mesenchymal stem cells (MSCs) were differentiated into the adipocytes by 0.5 and 1 uM of ATRA and 5 and 10 mM calcium separately or in combination. After MTS assay the differentiation of MSCs to adipocyte was evaluated, Oil Red O staining, GLUT4 concentration and gene expression of PPARG2, adiponectin, and GLUT4 were measured by Real-Time PCR. RESULTS: Except 10 mM calcium treated group, other groups and more significantly combination treatments could reduce all adipocyte markers compared to the control. CONCLUSION: These results suggest that ATRA and calcium together have significant inhibitory effect on adipogenesis that can be helpful for finding new mechanisms to prevent or control the adipogenesis. PMID- 28850273 TI - Therapeutic approach for metabolic disorders and infertility in women with PCOS. AB - Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5-10% of women of reproductive age. It generally shows with oligo/amenorrhea, anovulatory cycles, clinical o biochemical hirsutism, polycystic ovaries and, in a significant percentage of cases, insulin resistance. PCOS is defined as a multifactorial pathology, determined by the association of many factors: genetic, endocrine and environmental. The first and most effective treatment of PCOS is to change life-style and lose weight. The use of oral contraceptives has been shown effective in reducing acne and hirsutism and regulates the menstrual cycle. For women with severe hirsutism, the addition of antiandrogens to estrogen-progestin therapy has significantly improved the results. In cases of anovulatory infertility, the drug of first choice is clomiphene citrate, followed by low-dose gonadotropins. Recently, insulin-sensitizing drugs have been widely prescribed for PCOS patients. They are particularly effective in reducing insulin resistance and improving ovulatory performance. Besides insulin-sensitizing drugs, natural substances, such as inositol, seems to have good efficacy, similar to metformin with fewer side effects. New substances that could be used include statins and natural statins, such as monakolin, alone or combined with myo-inositol. These substances do not have side effects and greatly reduce the hyperandrogenic component in these patients. PMID- 28850275 TI - Preface to the Proceedings of the XI Medical Symposium of the Yrjo Jahnsson Foundation. PMID- 28850274 TI - Sleep Patterns and Quality Are Associated with Severity of Obesity and Weight Related Behaviors in Adolescents with Overweight and Obesity. AB - BACKGROUND: Inadequate sleep duration, sleep patterns, and sleep quality have been associated with metabolic, circadian, and behavioral changes that promote obesity. Adolescence is a period during which sleep habits change to include less sleep, later bedtimes, and greater bedtime shift (e.g., difference between weekend and weekday bedtime). Thus, sleep may play a role in adolescent obesity and weight-related behaviors. This study assesses sleep duration, quality, and schedules and their relationships to relative weight and body fat percentage as well as diet, physical activity, and screen time in adolescents with overweight/obesity. METHODS: Adolescents between 12 and 17 years old (n = 186) were weighed and measured, reported typical sleep and wake times on weekdays and weekends, and responded to questionnaires assessing diet, physical activity, and screen time habits. RESULTS: Controlling for sleep duration, later weekend bedtime and greater bedtime shift were associated with greater severity of overweight (beta = 0.20; beta = 0.16) and greater screen time use (beta = 0.22; beta = 0.2). Later bedtimes on the weekdays and weekends were associated with fewer healthy diet practices (beta = -0.26; beta = -0.27). In addition, poorer sleep quality was associated with fewer healthy diet habits (beta = -0.21), greater unhealthy diet habits (beta = 0.15), and less physical activity (beta = 0.22). Sleep duration was not associated with any weight or weight-related behavior. CONCLUSIONS: Sleep patterns and quality are associated with severity of overweight/obesity and various weight-related behaviors. Promoting a consistent sleep schedule throughout the week may be a worthwhile treatment target to optimize behavioral and weight outcomes in adolescent obesity treatment. PMID- 28850276 TI - Cardiovascular disease risk factors in young children in the STRIP baby project. AB - Introducing nutritional principles of preventive cardiology to the care of young children may improve permanently adherence to a low-saturated-fat, low cholesterol diet later in life. This approach has not been readily adapted because of worries of the possible effects of such a diet on the growth and development of children. In the STRIP baby project, 1062 infants were randomized at 7 months of age into an intervention group (n = 540) or a control group (n = 522). The counselling of the intervention children aimed at a fat intake of 30% of energy after the age of 1 year and to a 1:1:1 ratio in saturated:monounsaturated:polyunsaturated fat intake. Dietary intake, growth and serum lipid concentrations were monitored in the children regularly through the first years of life. The intake of total fat, saturated fat and cholesterol were lower and the intake of polyunsaturated fat and the ratio of polyunsaturated to saturated fat (P/S) in the diet were higher in the intervention children than in the controls. During the first 3 years of the trial, the serum cholesterol concentration was 3-6% lower in the intervention children than in the controls (95% CI for the mean difference between groups from -0.27 to-0.12 mmol/L). No differences in the growth of the children were observed between the groups. We conclude that repeated individualized counselling aiming at reduced consumption of saturated fat combined with regular follow-up is effective and does not restrict the growth of children. PMID- 28850277 TI - Cardiovascular Risk in Young Finns Study: general outline and recent developments. AB - The Cardiovascular Risk in Young Finns Study is a collaborative effort of all university departments of paediatrics and several other institutions in Finland to study the risk factors of coronary heart disease (CHD) and their determinants in children and adolescents in different parts of the country. The main cross sectional study carried out in 1980 included 3596 3-18-year-old subjects. Follow up studies have been performed in 1983, 1986, 1989 and 1992; in the last of these studies the subjects were 15-30 years old. The findings in anthropometry, obesity and blood pressure have been rather similar to reports from other countries in Europe. However, serum cholesterol and low-density lipoprotein cholesterol concentrations were higher than in other countries, 4.83 mmol/L and 3.09 mmol/L, respectively in 1980. By 1992 a decrease of 8% took place, probably as a result of dietary changes. Apolipoprotein phenotypes E4E4 or E4E3 were relatively frequent (34%) in the sample. Tracking and clustering have also been studied. Serum insulin levels predicted the clustering of the typical risk factor profile associated with insulin resistance syndrome. The dietary polyunsaturated to saturated fat (P/S) ratio increased from 0.26 in 1980 to 0.39 in 1992, with no significant changes in the total energy derived from fat. 'Hard-driving' was found to be the psychological risk factor most consistently related to the CHD risk factor level. PMID- 28850278 TI - Inflammation and the mental state before an acute coronary event. AB - Feelings of exhaustion have been found to belong to the precursors of acute coronary events. Guided by the current views of the pathogenesis of acute coronary syndromes, a two-stage model describing a feedback relationship between mental state and the disease process is presented. According to the presented model prolonged exposure to stress results in a state of exhaustion leading to increased susceptibility to inflammatory diseases. Inflammation, in turn, amplifies feelings of exhaustion and malaise through cytokine release. Results of a study of 15 exhausted and 15 nonexhausted angioplasty patients, showing elevated levels of interleukin-1beta and tumour necrosis factor-alpha in the exhausted patients, give empirical support to this model. PMID- 28850279 TI - Imaging of subclinical atherosclerosis in children and young adults. AB - Atherosclerosis begins in childhood and has a long preclinical phase before ischaemic symptoms appear. This provides an opportunity for subclinical detection of the disease and identification of high-risk subjects. Recent advances in imaging technology have identified many early functional and structural vascular changes, some of which may reflect subclinical atherosclerosis, and therefore provide areas of potential interest for diagnostic tests of preclinical atherosclerosis. These early events include changes in arterial vasodilatory function, alterations in arterial elasticity, thickening of arterial walls and calcification of atherosclerotic lesions. Clinical testing for presymptomatic atherosclerosis should involve methods that are safe, noninvasive, reliable and reproducible, and which correlate with the extent of the atherosclerotic process. Although no such tests are currently widely used in clinical practice, potential methods for detecting the processes outlined above include ultrasound, positron emission tomography, magnetic resonance imaging and ultrafast computed tomography. With further developments, noninvasive imaging techniques for the study of arterial function and structure may soon provide clinically useful ways of detecting early atherosclerosis in high-risk asymptomatic subjects at a stage where preventive strategies are most likely to have important health benefits. PMID- 28850280 TI - Factors influencing children's food choice. AB - Although food habits arc not stable and unchanging during a person's lifetime, a base for healthy food habits can be created in early childhood. Children's food habits can be assumed to be influenced by their parents' food habits and choices. The aim of this article is to review factors influencing food choice in children as well as in adults. The results demonstrate that the development of children's food habits is influenced by a multitude of factors. Parents play an important role in the formation of food habits and preferences of young children. They can influence their children's food choice by making specific foods available, by acting as models for their children and by their behaviour in specific situations. Children tend to be afraid of new foods and do not readily accept them. However, experience is known to enhance preference, and earlier experiences of a particular food are the major determinants of the development of children's food acceptance patterns. Thus, parents should be encouraged to make healthy foods easily available to the child and serve these foods in positive mealtime situations in order to help their child to develop healthy food habits. PMID- 28850281 TI - Role of genetic factors in childhood obesity and in susceptibility to dietary variations. AB - The concern about the current epidemic of obesity is heightened by recent data showing an increase in the prevalence of overweight and obesity in children and adolescents. As obese children are at increased risk of becoming obese adults, early identification of individuals at risk of becoming obese is important for the implementation of preventive measures. In that context, it is important to assess the role of genetic and nongenetic factors in childhood obesity as well as in susceptibility to dietary variations. This paper reviews recent data regarding the prevalence of obesity in childhood as well as the role of genetic factors in phenotypes related to obesity, with emphasis on studies conducted on children, when available. The existence of severe cases of obesity, such as those encountered in Mendelian syndromes of obesity or those caused by mutations in single genes, provides strong evidence for a role of genetic factors in the aetiology of childhood obesity. Furthermore, results from family studies suggest that the maximal heritability of obesity phenotypes ranges from about 30% to 50% and that the major affectors of body fat content, energy intake and energy expenditure are also influenced by genetic factors. Finally, there is increasing evidence that responsiveness to dietary intervention is genetically determined. PMID- 28850282 TI - An update on familial hypercholesterolaemia. AB - A report of a World Health Organization consultation on familial hypercholesterolaemia (FH) was recently presented in Geneva. The report provides an update on several aspects of FH such as the molecular basis, DNA diagnosis, clinical criteria for the diagnosis, treatment of FH adults and children, the role of diet, psychosocial aspects of FH, contacting and helping relatives with FH and gives suggestions for government cooperation. The report is reviewed here. PMID- 28850283 TI - Nutrition in early life: somatic growth and serum lipids. AB - This paper addresses the questions of whether early nutritional experience affects later somatic growth, the growth of the adipose tissue, or the levels of scrum lipids among well-nourished children. The analyses are based on data from three prospective studies. Postnatal nutrition and growth: there were differences in growth between breast-fed and formula-fed children. There was no association between linear growth and differences in food energy or macronutrient intake. Birth size and postnatal growth: there was no association between ponderal index (PI) at birth and body mass index (BMI) in the second year. For boys, the PI at 3 and 6 months of age was significantly positively correlated with BMI at the ages of 8 and 15 years, but not for girls. Childhood growth and lipids: there was no association between lipids at the age of 8 years and either birth weight or length, but children who had had a low PI at birth had higher lipid levels at the age 8 years. A positive association was found between serum lipids and abdominal fat and BMI. We conclude that, although early diet may influence growth rate beyond infancy, the evidence for fat patterning resulting from differences in fetal or early postnatal nutrition is still open to question. PMID- 28850284 TI - Fetal origins of cardiovascular disease. AB - Low birthweight, thinness and short body length at birth are now known to be associated with increased rates of cardiovascular disease and non-insulin dependent diabetes in adult life. The fetal origins hypothesis proposes that these diseases originate through adaptations which the fetus makes when it is undernourished. These adaptations may be cardiovascular, metabolic or endocrine. They permanently change the structure and function of the body. Prevention of the diseases may depend on prevention of imbalances in fetal growth or imbalances between prenatal and postnatal growth, or imbalances in nutrient supply to the fetus. PMID- 28850285 TI - Laparoscopic Versus Open Liver Resection for Lesions Adjacent to Major Vessels: A Propensity Score Matched Analysis. AB - BACKGROUND: Laparoscopic liver resection (LLR) for lesions adjacent to major vessels was still associated with difficulty and challenge. This study aimed to compare outcomes after LLR and open liver resection (OLR) of lesions adjacent to major vessels. MATERIALS AND METHODS: A retrospective analysis of patients with hepatic tumors close to main or second branches of Glisson's tree, to the major hepatic vein, or to the inferior vena cava within 1 cm between January 2015 and January 2017 was performed based on the propensity score matching (PSM) method. Perioperative and oncological outcomes were then evaluated. RESULTS: A total of 64 patients underwent LLR and 86 patients had OLR. After 1:1 PSM, well-matched 40 patients in each group were obtained. The operative time (240 versus 210 minutes, P = .012) in the LLR group was significantly longer than that in the OLR group, whereas blood loss (200 versus 400 mL, P = .003) was less in the laparoscopic group. The median hospital stay for LLR (6 versus 8 days, P = .032) was shorter than for the open procedure. No statistical differences was noted according to overall postoperative complications, but the OLR group tended to be vulnerable to more severe complications. For patients with hepatocellular carcinoma, the comparable oncological results in terms of 2-year overall survival (P = .898) and disease-free survival (P = .992) were observed. CONCLUSIONS: LLR for tumors adjacent to major vessels appears to be feasible and safe in selected patients. LLR is associated with less blood loss, shorter hospital stay, and similar oncological outcomes compared with OLR. PMID- 28850286 TI - Histochemical Analyses Reveal That Stronger Intrinsic Defenses in Gossypium barbadense Than in G. hirsutum Are Associated With Resistance to Verticillium dahliae. AB - Verticillium wilt, caused by Verticillium dahliae Kleb., is a serious threat to cotton (Gossypium spp.) crop production. To enhance our understanding of the plant's complex defensive mechanism, we examined colonization patterns and interactions between V. dahliae and two cotton species, the resistant G. barbadense and the susceptible G. hirsutum. Microscopic examinations and grafting experiments showed that the progression of infection was restricted within G. barbadense. At all pre- and postinoculation sampling times, levels of salicylic acid (SA) were also higher in that species than in G. hirsutum. Comparative RNA Seq analyses indicated that infection induced dramatic changes in the expression of thousands of genes in G. hirsutum, whereas those changes were fewer and weaker in G. barbadense. Investigations of the morphological and biochemical nature of cell-wall barriers demonstrated that depositions of lignin, phenolic compounds, and callose were significantly higher in G. barbadense. To determine the contribution of a known resistance gene to these processes, we silenced GbEDS1 and found that the transformed plants had decreased SA production, which led to the upregulation of PLASMODESMATA-LOCATED PROTEIN (PDLP) 1 and PDLP6. This was followed by a decline in callose deposition in the plasmodesmata, which then led to increased pathogen susceptibility. This comparison between resistant and susceptible species indicated that both physical and chemical mechanisms play important roles in the defenses of cotton against V. dahliae. PMID- 28850287 TI - Home Parenteral Nutrition and Intravenous Fluid Errors Discovered Through Novel Clinical Practice of Reconciling Compounding Records: A Case Series. AB - Home parenteral nutrition (HPN) and home intravenous (IV) hydration are complex, high-risk life-sustaining therapies for children and adults with severe digestive disorders. HPN compounding errors have the potential to cause serious patient harm. Here we present a retrospective case series at an interdisciplinary pediatric HPN program that includes specialized pharmacists reconciling prescriptions against commercial compounding records. Seven HPN or IV hydration patients were affected by significant errors in anion balance, copper, potassium, sodium, and infusion volume. Outpatient pharmacists' or other clinicians' review of compounding records as part of routine quality assurance process is critical for identifying and preventing errors. PMID- 28850288 TI - Comparison of Methods To Identify Advance Care Planning in Patients with Severe Chronic Obstructive Pulmonary Disease Exacerbation. AB - BACKGROUND: Advance care planning (ACP) is recommended for patients with chronic obstructive pulmonary disease (COPD). Yet, ACP documentation is often inaccessible at the time of impending respiratory failure, which may lead to unwanted and costly medical intensive care unit admissions. Electronic medical records (EMRs) contain directive fields and the ability to search for keywords and phrases, but these strategies to rapidly identify ACP have not been validated. OBJECTIVES: The aim of this study is to identify the percentage of patients with severe COPD exacerbation who have outpatient ACP documentation and validate two EMR-based methods of rapidly identifying ACP documentation. DESIGN: Retrospective cohort analysis. SETTING/SUBJECTS: Patients who required medical intensive care unit admission for exacerbation of COPD at an urban safety-net hospital between 2009 and 2014 were observed. MEASUREMENTS: We analyzed the sensitivity and specificity of two methods to rapidly identify outpatient ACP documentation: (1) documentation in the EMR directive field and (2) text string search of notes for key phrases, compared with a gold standard clinician review. RESULTS: Our cohort (n = 311) was racially diverse and severely ill with obstructive lung disease. One hundred thirty-two patients (43%) had ACP documentation by gold standard chart review. Compared with a gold standard chart review, a parsimonious text string search was both sensitive (95%) and specific (97%), while the directive box was specific (100%), but not sensitive (54%), for identifying outpatient ACP documentation. CONCLUSIONS: EMR directive fields may substantially underestimate ACP when used alone. As full clinician chart reviews are impractical in the emergent setting, text string searches may be a useful strategy to rapidly identify ACP discussions for clinical care and research. PMID- 28850289 TI - Dynamics of Mixed- Candida Species Biofilms in Response to Antifungals. AB - Oral infections caused by Candida species, the most commonly isolated human fungal pathogen, are frequently associated with biofilms. Although Candida albicans is the predominant organism found in patients with oral thrush, a biofilm infection, there is an increasing incidence of oral colonization and infections caused by non- albicans Candida species, including C. glabrata, C. dubliniensis, and C. tropicalis, which are frequently more resistant to antifungal treatment. While single-species Candida biofilms have been well studied, considerably less is known about the dynamics of mixed- Candida species biofilms and how these dynamics are altered by antifungal treatment. To address these questions, we developed a quantitative polymerase chain reaction-based approach to determine the precise species composition of mixed- Candida species biofilms formed by clinical isolates and laboratory strains in the presence and absence of clinically relevant concentrations of 3 commonly used antifungals: fluconazole, caspofungin, and amphotericin B. In monospecies biofilms, fluconazole exposure favored growth of C. glabrata and C. tropicalis, while caspofungin generally favored significant growth of all species to a varying degree. Fluconazole was not effective against preformed mixed- Candida species biofilms while amphotericin B was potent. As a general trend, in mixed- Candida species biofilms, C. albicans lost dominance in the presence of antifungals. Interestingly, presence in mixed versus monospecies biofilms reduced susceptibility to amphotericin B for C. tropicalis and C. glabrata. Overall, our data suggest that antifungal treatment favors the growth of specific non- albicans Candida species in mixed- Candida species biofilms. PMID- 28850290 TI - Hospitalization Rates and Predictors of Rehospitalization Among Individuals With Advanced Cancer in the Year After Diagnosis. AB - Purpose Among individuals with advanced cancer, frequent hospitalization increasingly is viewed as a hallmark of poor-quality care. We examined hospitalization rates and individual- and hospital-level predictors of rehospitalization among individuals with advanced cancer in the year after diagnosis. Methods Individuals diagnosed with advanced breast, colorectal, non small-cell lung, or pancreatic cancer from 2009 to 2012 (N = 25,032) were identified with data from the California Cancer Registry (CCR). After linkage with inpatient discharge data, multistate and log-linear Poisson regression models were used to calculate hospitalization rates and to model rehospitalization in the year after diagnosis, accounting for survival. Results In the year after diagnosis, 71% of individuals with advanced cancer were hospitalized, 16% had three or more hospitalizations, and 64% of hospitalizations originated in the emergency department. Rehospitalization rates were significantly associated with black non-Hispanic (incidence rate ratio [IRR], 1.29; 95% CI, 1.17 to 1.42) and Hispanic (IRR, 1.11; 95% CI, 1.03 to 1.20) race/ethnicity; public insurance (IRR, 1.37; 95% CI, 1.23 to 1.47) and no insurance (IRR, 1.17; 95% CI, 1.02 to 1.35); lower socioeconomic status quintiles (IRRs, 1.09 to 1.29); comorbidities (IRRs, 1.13 to 1.59); and pancreatic (IRR, 2.07; 95% CI, 1.95 to 2.20) and non-small-cell lung (IRR, 1.69; 95% CI, 1.54 to 1.86) cancers versus colorectal cancer. Rehospitalization rates were significantly lower after discharge from a hospital that had an outpatient palliative care program (IRR, 0.90; 95% CI, 0.83 to 0.97) and were higher after discharge from a for-profit hospital (IRR, 1.33; 95% CI, 1.14 to 1.56). Conclusion Individuals with advanced cancer experience a heavy burden of hospitalization in the year after diagnosis. Efforts to reduce hospitalization and provide care congruent with patient preferences might target individuals at higher risk. Future work might explore access to palliative care in the community and related health care use among individuals with advanced cancer. PMID- 28850292 TI - Improvements in Health-Related Quality of Life and Pain: A Cohort Study in Obese Patients After Laparoscopic Sleeve Gastrectomy. AB - OBJECTIVE: The principal aim of the study was to investigate the effect of the sleeve gastrectomy (SG) in the quality of life (QoL) and pain in a population of morbidly obese patients. METHODS: Seventy-two SG patients were assessed in this descriptive observational study, before the surgery and 6 months after that. We evaluated health-related QoL (Gastrointestinal Quality of Life Index [GIQLI]) and pain (spontaneous low back pain by Numerical Point Rate Scale [NPRS] and pressure pain thresholds [PPTs]). RESULTS: The results of the analysis of variance (ANOVA) revealed significant improvements in nearly all of the subscales of GIQLI questionnaire after 6 months: gastrointestinal symptoms (P = .01), physical well being (P < .001), social well-being (P = .03), and total GIQLI score (P < .001), but not for the emotional condition (P = .20). Patients also had improvements in spontaneous low back pain (P = .002), but not in the PPTs in all the body areas explored, including the cervical area, low back, and hands (P > .05). CONCLUSION: Patients receiving SG improved their health-related QoL and low back pain 6 months after the intervention, but this improvement was not so important for pressure pain thresholds in different body areas. PMID- 28850291 TI - Prohibited Contaminants in Dietary Supplements. AB - CONTEXT: With the increasing use of unregulated dietary supplements, athletes are at continued risk from adverse medical events and inadvertent doping. EVIDENCE ACQUISITION: A review of Clinical Key, MEDLINE, and PubMed databases from 2012 to 2017 was performed using search terms, including dietary supplement, contamination, doping in athletes, inadvertent doping, and prohibited substances. The references of pertinent articles were reviewed for other relevant sources. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: Poor manufacturing processes and intentional contamination with many banned substances continue to occur in dietary supplements sold in the United States. Certain sectors, such as weight loss and muscle-building supplements, pose a greater threat because they are more likely to be contaminated. CONCLUSION: Athletes will continue to be at risk for adverse events and failed doping tests due to contaminated dietary supplements until legislation changes how they are regulated. In the interim, there are several steps that can be taken to mitigate this risk, including improved education of medical staff and athletes and use of third party-certified products. PMID- 28850294 TI - Prof. Johan Broerse 1934-2017. PMID- 28850293 TI - Population-Based Study of Tobacco Use Among People Living With HIV in Puerto Rico. AB - BACKGROUND: Despite substantial advances in the era of highly active antiretroviral therapy, HIV-positive persons are at high risk of tobacco-related disease and mortality. This study describes the prevalence and sociodemographic factors associated with current tobacco use among HIV-positive men and women 18 years and older receiving HIV care in Puerto Rico. METHODS: Data from the 2009 Medical Monitoring Project (MMP) was used. A three-stage sampling design was conducted to obtain annual cross-sectional probability samples of HIV-infected adults in care. Factors associated with current tobacco use were identified using logistic regression models. All analyses were performed using STATA version 11.0. RESULTS: The estimated prevalence of current cigarette use among the population was 29.0% (95%CI: 23.5%-35.2%), daily smoking was reported in 76.7% of them. Multivariate logistic regression models, showed that male drug users (injected and noninjected) were up to nine times more likely to be current smokers (OR = 9.9; 95%CI = 3.1, 31.5) as compared to nonusers. CONCLUSION: Findings highlight the need for smoking cessation strategies in this population, particularly among male HIV+ drug users. PMID- 28850295 TI - Fungal Infections Increase the Mortality Rate Three-Fold in Necrotizing Soft Tissue Infections. AB - BACKGROUND: Necrotizing soft-tissue infections (NSTIs) result in significant morbidity and mortality rates, with as many as 76% of patients dying during their index admission. Published data suggest NSTIs rarely involve fungal infections in immunocompetent patients. However, because of the recent recognition of fungal infections in our population, we hypothesized that such infections frequently complicate NSTIs and are associated with higher morbidity and mortality rates. METHODS: A prospectively maintained Acute and Critical Care Surgery (ACCS) database spanning 2008-2015 and including more than 7,000 patients was queried for patients with NSTIs. Microbiologic data, demographics, and clinical outcomes were abstracted. Risk factors and outcomes associated with NSTI with positive intra-operative fungal cultures were determined. Frequencies were compared by chi2 and continuous variables by the Student t-test using SPSS. Because the study included only archived data, no patient permission was needed. RESULTS: A total of 230 patients were found to have NSTIs; 197 had intra-operative cultures, and 21 (10.7%) of these were positive for fungi. Fungal infection was more common in women, patients with higher body mass index (BMI), and patients who had had prior abdominal procedures. There were no significant differences in demographics, co morbidities, or site of infection. The majority of patients (85.7%) had mixed bacterial and fungal infections; in the remaining patients, fungi were the only species isolated. Most fungal cultures were collected within 48 h of hospital admission, suggesting that the infections were not hospital acquired. Patients with positive fungal cultures required two more surgical interventions and had a three-fold greater mortality rate than patients without fungal infections. CONCLUSIONS: This is the largest series to date describing the impact of fungal infection in NSTIs. Our data demonstrate a three-fold increase in the mortality rate and the need for two additional operations. Consideration should be given to starting patients on empiric anti-fungal therapy in certain circumstances. PMID- 28850296 TI - Statistical Learning of Melodic Patterns Influences the Brain's Response to Wrong Notes. AB - The theory of statistical learning has been influential in providing a framework for how humans learn to segment patterns of regularities from continuous sensory inputs, such as speech and music. This form of learning is based on statistical cues and is thought to underlie the ability to learn to segment patterns of regularities from continuous sensory inputs, such as the transition probabilities in speech and music. However, the connection between statistical learning and brain measurements is not well understood. Here we focus on ERPs in the context of tone sequences that contain statistically cohesive melodic patterns. We hypothesized that implicit learning of statistical regularities would influence what was held in auditory working memory. We predicted that a wrong note occurring within a cohesive pattern (within-pattern deviant) would lead to a significantly larger brain signal than a wrong note occurring between cohesive patterns (between-pattern deviant), even though both deviant types were equally likely to occur with respect to the global tone sequence. We discuss this prediction within a simple Markov model framework that learns the transition probability regularities within the tone sequence. Results show that signal strength was stronger when cohesive patterns were violated and demonstrate that the transitional probability of the sequence influences the memory basis for melodic patterns. Our results thus characterize how informational units are stored in auditory memory trace for deviance detection and provide new evidence about how the brain organizes sequential sound input that is useful for perception. PMID- 28850298 TI - The Day the Music Died. PMID- 28850299 TI - Breast cancer awareness, attitude and practices among female university students: A descriptive study from Jordan. AB - The researchers' aim of this study was to assess breast cancer (BC) knowledge, attitude and practices of breast self-examination (BSE) among female university students. Data were collected from 236 participants using self-reported questionnaires. Participants reported inadequate knowledge (45.5%), fairly positive attitude (56.3%) and low BSE practice (37.5%). Analysis revealed significant differences based on participants' demographics. Results are in congruence with international literature, and support worldwide efforts aiming at increasing awareness of BC. In conclusion, raising students' awareness regarding BC and BSE is important for early detection of this increasingly alarming disease. Initiating BC educational programs among university students is highly recommended. PMID- 28850297 TI - Neural Signatures of Spatial Statistical Learning: Characterizing the Extraction of Structure from Complex Visual Scenes. AB - Behavioral evidence has shown that humans automatically develop internal representations adapted to the temporal and spatial statistics of the environment. Building on prior fMRI studies that have focused on statistical learning of temporal sequences, we investigated the neural substrates and mechanisms underlying statistical learning from scenes with a structured spatial layout. Our goals were twofold: (1) to determine discrete brain regions in which degree of learning (i.e., behavioral performance) was a significant predictor of neural activity during acquisition of spatial regularities and (2) to examine how connectivity between this set of areas and the rest of the brain changed over the course of learning. Univariate activity analyses indicated a diffuse set of dorsal striatal and occipitoparietal activations correlated with individual differences in participants' ability to acquire the underlying spatial structure of the scenes. In addition, bilateral medial-temporal activation was linked to participants' behavioral performance, suggesting that spatial statistical learning recruits additional resources from the limbic system. Connectivity analyses examined, across the time course of learning, psychophysiological interactions with peak regions defined by the initial univariate analysis. Generally, we find that task-based connectivity with these regions was significantly greater in early relative to later periods of learning. Moreover, in certain cases, decreased task-based connectivity between time points was predicted by overall posttest performance. Results suggest a narrowing mechanism whereby the brain, confronted with a novel structured environment, initially boosts overall functional integration and then reduces interregional coupling over time. PMID- 28850300 TI - Combined Therapy of Pegylated G-CSF and Alxn4100TPO Improves Survival and Mitigates Acute Radiation Syndrome after Whole-Body Ionizing Irradiation Alone and Followed by Wound Trauma. AB - Exposure to ionizing radiation alone or combined with traumatic tissue injury is a crucial life-threatening factor in nuclear and radiological incidents. Radiation injuries occur at the molecular, cellular, tissue and systemic levels; their mechanisms, however, remain largely unclear. Exposure to radiation combined with skin wounding, bacterial infection or burns results in greater mortality than radiation exposure alone in dogs, pigs, rats, guinea pigs and mice. In the current study we observed that B6D2F1/J female mice exposed to 60Co gamma-photon radiation followed by 15% total-body-surface-area skin wounds experienced an increment of 25% higher mortality over a 30-day observation period compared to those subjected to radiation alone. Radiation exposure delayed wound healing by approximately 14 days. On day 30 post-injury, bone marrow and ileum in animals from both groups (radiation alone or combined injury) still displayed low cellularity and structural damage. White blood cell counts, e.g., neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets, still remained very low in surviving irradiated alone animals, whereas only the lymphocyte count was low in surviving combined injury animals. Likewise, in surviving animals from radiation alone and combined injury groups, the RBCs, hemoglobin, hematocrit and platelets remained low. We observed, that animals treated with both pegylated G CSF (a cytokine for neutrophil maturation and mobilization) and Alxn4100TPO (a thrombopoietin receptor agonist) at 4 h postirradiation, a 95% survival (vehicle: 60%) over the 30-day period, along with mitigated body-weight loss and significantly reduced acute radiation syndrome. In animals that received combined treatment of radiation and injury that received pegylated G-CSF and Alxn4100TPO, survival was increased from 35% to 55%, but did not accelerate wound healing. Hematopoiesis and ileum showed significant improvement in animals from both groups (irradiation alone and combined injury) when treated with pegylated G-CSF and Alxn4100TPO. Treatment with pegylated G-CSF alone increased survival after irradiation alone and combined injury by 33% and 15%, respectively, and further delayed wound healing, but increased WBC, RBC and platelet counts after irradiation alone, and only RBCs and platelets after combined injury. Treatment with Alxn4100TPO alone increased survival after both irradiation alone and combined injury by 4 and 23%, respectively, and delayed wound healing after combined injury, but increased RBCs, hemoglobin concentrations, hematocrit values and platelets after irradiation alone and only platelets after combined injury. Taken together, the results suggest that combined treatment with pegylated G-CSF and Alxn4100TPO is effective for mitigating effects of both radiation alone and in combination with injury. PMID- 28850302 TI - A clinical instrument to guide brief interventions for adolescents with substance use concerns. AB - BACKGROUND: Adolescent substance use is an important public health problem in New Mexico and the United States. The New Mexico Department of Health school-based health centers (SBHCs) universally administer a validated screen, the CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble), for adolescent substance use concerns; however, quality assurance efforts revealed that SBHC providers needed more information at the point of screening to initiate brief interventions for students with positive CRAFFT screens. The CHISPA (Cocaine, Heroin, IV drugs, Synthetic pot, Pot, Alcohol) was developed to gather specific information on recent substance use experience to guide brief interventions. This paper describes the development and initial reliability and validity of data obtained using the CHISPA instrument. METHODS: In 2015, 99 high school-aged SBHC users in Albuquerque, New Mexico, completed the CRAFFT and CHISPA twice over 2 weeks using standard test-retest methods. Using the CHISPA, students reported for the prior 3 months substances used, frequency of use, and signs of addiction or acute danger (adverse events). RESULTS: Retest reliability for the CRAFFT score was 0.82. CHISPA retest reliabilities were 0.75 for alcohol use; 0.91 for having used any substances; 0.92 for number of substances used; 0.81 for frequency of substance use; and 0.79 for number of adverse events. CRAFFT scores correlated with CHISPA measures of number of substances used at 0.62; with frequency of substance use at 0.58; and with number of adverse events at 0.64. CONCLUSIONS: CHISPA measures show preliminary evidence of reliability and validity. SBHC providers and other providers in primary care settings who use the CRAFFT screen may benefit from using the CHISPA to define recent substance use experience to guide brief interventions for adolescents with substance use concerns. The CHISPA instrument is currently being tested in electronic form in selected SBHCs in the state of New Mexico. PMID- 28850301 TI - #DocsOnTwitter: How Physicians use Social Media to Build Social Capital. AB - Using social capital theory, Augustana University healthcare marketing students examined how medical professionals utilize social media to further engage with their communities. The team selected Twitter as the social media network from which to collect data because of its popularity and ease of use. The sample was drawn from 1,000 Twitter profiles that were retrieved from 24 keywords such as MD. A total of 3,378,285 tweets from this sample were collected and analyzed for content, use of hashtags, mobile device use, frequency, longevity, medical relevance, medical specialty, gender, and approximate age. This is an important first look, using Big Data, at how physicians parlay the popularity of social media to build social capital through sharing research with colleagues, connecting with patients and prospective patients, and extending their personal and employer brands to increasingly information-hungry and interactive consumers. PMID- 28850303 TI - Influence of Accelerometer Placement and/or Heart Rate on Energy Expenditure Prediction during Uphill Exercise. AB - Studies using a triaxial accelerometer and heart rate (HR) simultaneously for estimating energy expenditure (EE) during uphill exercise are rare. Exploring the optimal location for placing the accelerometer for predicting EE during uphill exercise is essential. Sixteen healthy male participants (M +/- SEM; age 25.00 +/ 0.61 years; body weight 74.13 +/- 2.51 kg; body height 1.74 +/- 0.01 m; body mass index 24.30 +/- 0.63 kg/m2) exercised on a treadmill under 12 conditions (4 speeds and 3 gradients) on 3 days. Triaxial accelerometers, an HR recorder, and a metabolic measurement system were simultaneously used. Accelerometer outputs from various anatomical locations (upper arm, chest, lower back, waist, thigh, and instep) showed significant positive correlations with EE (0.819, 0.846, 0.816, 0.820, 0.672, and 0.669, respectively; p < .05). The linear regression equation for changes in HR showed the highest coefficient of determination (r2) of .837 with 87.9% reliability. When the HR signal was included, the r2 value (> .842) and reliability (87.9%) between the accelerometer outputs and EE improved. Accelerometer outputs from the waist position alone provide highly accurate EE values. Using both accelerometer outputs and HR for EE estimation during uphill exercise is feasible and improves the accuracy of EE prediction. PMID- 28850304 TI - Symptoms without disease: Exploring experiences of non-Western immigrant women living with chronic pain. AB - The aims of the researchers were to explore the experiences of non-Western immigrant women living with chronic pain in Norway. Nine individual interviews were conducted and analyzed with a phenomenological approach. We found that the women were wavering between different models to explain their pain. Our analysis of the women's stories makes us believe that a complexity of stressful factors in their lives as immigrant women are influencing their experience of pain and that encounters with health care personnel fail to meet their needs. Our findings reflect a need for broader approaches to help immigrant women with chronic pain. PMID- 28850305 TI - In Vitro Bioaccessibility and Effect of Mangifera indica (Ataulfo) Leaf Extract on Induced Dyslipidemia. AB - Cardiovascular diseases (CVDs) are the leading causes of death in the world, and epidemiological evidence points to dietary habits, stress, and obesity as major risk factors promoting pathological conditions like atherosclerosis, hypertension, and thrombosis. Current therapeutic approaches for CVDs rely on lifestyle changes and/or the use of drug agents. However, since the efficacy of such interventions is often limited by poor compliance and/or significant side effects, continued research on new preventive and therapeutic approaches is much needed. Our study is aimed to determine the bioaccessibility, total content of phenolic compounds, and antioxidant capacity (DPPH., ABTS.+) of a methanolic extract from Mangifera indica L. leaves (MEM), and its lipid-lowering effect on an induced dyslipidemia model in Wistar rats. Our results showed that mangiferin is the main component of MEM. The extract showed a total content of polyphenol compounds of 575.28 gallic acid equivalents per dry matter basis (GAE/g db), antioxidant activity 77.68 MUmol Trolox equivalents per gram (TE/g) db as measured by DPPH. and 20,630 MUmol TE/g db by ABTS.+, and 12% of phenolic compounds were bioaccessible, and 100 mg/kg of MEM reduced hyperlipidemia levels induced in Wistar rats. Further study on the potential use of MEM as a nutraceutical to prevent CVDs in high-fat diet consumers is required. PMID- 28850306 TI - Differences between motion capture and video analysis systems in calculating knee angles in elite-standard race walking. AB - Race walking is an event where the knee must be straightened from first contact with the ground until midstance. The aim of this study was to compare knee angle measurements between 2D videography and 3D optoelectronic systems. Passive retroreflective markers were placed on the right leg of 12 race walkers and 3D marker coordinate data captured (250 Hz), with 2D video data (100 Hz) recorded simultaneously. Knee angle data were first derived based on the markers' coordinates, and separately by using a 3D model that also incorporated thigh and shank clusters; the video data were analysed using both automatic tracking and manual digitising, creating four conditions overall. Differences were calculated between conditions for stance (using root mean square values), and at discrete events. There were few differences between systems, although the 3D model produced larger angles at midstance than using automatic tracking and marker coordinates (by 3 - 6 degrees , P < 0.05). These differences might have occurred because of how the 3D model locates the hip joint, and because of the addition of marker clusters. 2D videography gave similar results to the 3D model when using manual digitising, as it allowed for errors caused by skin movement to be corrected. PMID- 28850307 TI - Self-Assessment of Skills and Competencies among Residents Participating in a Pediatric Hospice and Palliative Medicine Elective Rotation. AB - OBJECTIVE: To describe our institutional experience with a four-week pediatric HPM elective rotation and its impact on residents' self-rated competencies. BACKGROUND: In the spirit of bolstering primary hospice and palliative medicine (HPM) skills of all pediatricians, it is unclear how best to teach pediatric HPM. An elective rotation during residency may serve this need. METHODS: An anonymous online survey was distributed to pediatric and internal medicine/pediatrics residents at a single, tertiary academic children's hospital. Respondents were asked to rate education, experience, and comfort with five aspects of communication with families of children with terminal illnesses and six domains of managing the symptoms of terminal illnesses. Self-ratings were recorded on a 1 5 scale: none, minimal, moderate, good, or excellent. Demographic data, including details of training and prior HPM training, were collected. Respondents completed a set of six questions gauging their attitude toward palliative care in general and at the study institution specifically. RESULTS: All respondents desire more HPM training. Those residents who self-selected to complete a pediatric HPM elective rotation had significantly higher self-ratings in 10 of 11 competency/skill domains. Free-text comments expressed concern about reliance on the specialty HPM team. DISCUSSION: A pediatric HPM elective can significantly increase residents' self-rated competency. Such rotations are an under-realized opportunity in developing the primary HPM skills of pediatricians, but wider adoption is restricted by the limited availability of pediatric HPM rotations and limited elective time during training. PMID- 28850309 TI - Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update Summary. PMID- 28850310 TI - Safe Administration of Intracerebral Spinal Fluid Chemotherapy: Time for Guidelines. PMID- 28850308 TI - A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients: A Randomized, Double-Blind, Placebo Controlled, Two-Dose, Three-Arm, and Parallel-Group Study. AB - Rheumatoid arthritis (RA) is an autoimmune, chronic systemic inflammatory disorder. The long-term use of currently available drugs for the treatment of RA has many potential side effects. Natural phytonutrients may serve as alternative strategies for the safe and effective treatment of RA, and curcuminoids have been used in Ayurvedic medicine for the treatment of inflammatory conditions for centuries. In this study, a novel, highly bioavailable form of curcumin in a completely natural turmeric matrix was evaluated for its ability to improve the clinical symptoms of RA. A randomized, double-blind, placebo-controlled, three arm, parallel-group study was conducted to evaluate the comparative efficacy of two different doses of curcumin with that of a placebo in active RA patients. Twelve patients in each group received placebo, 250 or 500 mg of the curcumin product twice daily for 90 days. The responses of the patients were assessed using the American College of Rheumatology (ACR) response, visual analog scale (VAS), C-reactive protein (CRP), Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) values. RA patients who received the curcumin product at both low and high doses reported statistically significant changes in their clinical symptoms at the end of the study. These observations were confirmed by significant changes in ESR, CPR, and RF values in patients receiving the study product compared to baseline and placebo. The results indicate that this novel curcumin in a turmeric matrix acts as an analgesic and anti-inflammatory agent for the management of RA at a dose as low as 250 mg twice daily as evidenced by significant improvement in the ESR, CRP, VAS, RF, DAS28, and ACR responses compared to placebo. Both doses of the study product were well tolerated and without side effects. PMID- 28850311 TI - Reasons to Reject Physician Assisted Suicide/Physician Aid in Dying. PMID- 28850312 TI - Favorable and Durable Response to Pazopanib in Metastatic Refractory Paraganglioma. PMID- 28850313 TI - Hope, Phase I Trials, and Palliative Care: So You're Telling Me There's a Chance? PMID- 28850314 TI - Identifying the Infection Control Areas Requiring Modifications in Thoracic Surgery Units: Results of a Two-Year Surveillance of Surgical Site Infections in Hospitals in Southern Poland. AB - BACKGROUND: Surgical site infection (SSI) is considered to be a priority in infection control. The objective of this study is the analysis of results of active targeted surveillance conducted over a two-year period in the Department of Thoracic Surgery at the Pulmonology and Thoracic Surgery Center in Bystra, in southern Poland. PATIENTS AND METHODS: The retrospective analysis was carried out on the basis of results of active monitoring of SSI in the 45-bed Department of Thoracic Surgery at the Pulmonology and Thoracic Surgery Center in Bystra between April 1, 2014 and April 30, 2016. Surgical site infections were identified based on the definitions of the European Centre for Disease Prevention and Control (ECDC) taking into account the time of symptom onset, specifically, whether the symptoms occurred within 30 d after the surgical procedure. Detection of SSI relied on daily inspection of incisions by a trained nurse, analysis of medical and nursing entries in the computer system, and analysis of all results of microbiologic tests taken in the unit and in the operating room. RESULTS: In the study period, data were collected regarding 1,387 treatment procedures meeting the registration criteria. Forty cases of SSI were detected yielding an incidence rate of 3%. Most cases (55%) were found in the course of hospitalization and 45% were detected after the patient's discharge. The SSIs were classified as follows: superficial, 37.5%; deep infections, 7.5%; and organ/space infection, 55%. Among patients who were diagnosed with SSI, most were male (77.5%). For patients with an American Society of Anesthesiologists (ASA) score I-II the incidence rate was 2%; ASA score III or more, 3.7%. The incidence rate varied from 0.3% in clean surgical site to 6.5% in clean-contaminated site. CONCLUSIONS: The study validated the usefulness of targeted surveillance in monitoring SSIs in patients hospitalized in thoracic surgery departments. Surgical site infection surveillance identified areas of care requiring modifications, namely, organization of post-discharge and microbiologic diagnostics of infection cases. PMID- 28850317 TI - Pediatric Tragedy. PMID- 28850315 TI - Imaging of Groin Pain: Magnetic Resonance and Ultrasound Imaging Features. AB - CONTEXT: Evaluation of groin pain in athletes may be challenging as pain is typically poorly localized and the pubic symphyseal region comprises closely approximated tendons and muscles. As such, magnetic resonance imaging (MRI) and ultrasound (US) may help determine the etiology of groin pain. EVIDENCE ACQUISITION: A PubMed search was performed using the following search terms: ultrasound, magnetic resonance imaging, sports hernia, athletic pubalgia, and groin pain. Date restrictions were not placed on the literature search. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: MRI is sensitive in diagnosing pathology in groin pain. Not only can MRI be used to image rectus abdominis/adductor longus aponeurosis and pubic bone pathology, but it can also evaluate other pathology within the hip and pelvis. MRI is especially helpful when groin pain is poorly localized. Real-time capability makes ultrasound useful in evaluating the pubic symphyseal region, as it can be used for evaluation and treatment. CONCLUSION: MRI and US are valuable in diagnosing pathology in athletes with groin pain, with the added utility of treatment using US-guided intervention. Strength-of Recommendation Taxonomy: C. PMID- 28850318 TI - Physical activity practiced by incarcerated women: A systematic review. AB - Our aim doing this systematic review was to identify and analyze studies about women prison inmates' engagement in sport and physical activities (SPAs). The review was conducted in three areas - SPAs, prison and women - and based on information obtained from different databases. Through a selection process, we singled out 33 empirical and review studies, the quality of which was analyzed. From our analysis, we learn that the benefits women prison inmates derive from SPAs are considerable, although they also reveal that obstacles exist to be overcome if their levels of participation are to rise. PMID- 28850319 TI - Intact Procedural Knowledge in Patients with Alzheimer's Disease: Evidence from Golf Putting. AB - Can Alzheimer's disease (AD) patients efficiently learn to perform a complex motor skill when relying on procedural knowledge? To address this question, the authors compared the golf-putting performance of AD patients, older adults, and younger adults in 2 different learning situations: one that promotes high error rates (thus increasing the reliance on declarative knowledge) or one that promotes low error rates (thus increasing the reliance on procedural knowledge). Motor performance was poorer overall for AD patients and older adults relative to younger adults in the high-error condition but equivalent between similar groups in the low-error condition. Also, AD patients in the low-error condition had better performance at the final putting distance relative to those in the high error condition. This performance facilitation for AD patients likely stems from intact procedural knowledge. PMID- 28850321 TI - To the Guest Editors: Thank You! PMID- 28850320 TI - Effects of traditional practices in the postpartum period on postpartum depression. AB - In this descriptive study, our aim was to assess the effects of traditional practices on postpartum depression. The participants were 461 Muslim mothers with infants aged between 2 weeks and 12 months, without a history of postpartum depression or other psychiatric problems and capable of communicating fluently. The participants were volunteers and were recruited from family health centers in urban Turkey between January 15 and April 15, 2015. Data were collected in a single face-to-face interview with each participant. Mothers in the research locality frequently have recourse to traditional practices in the postpartum period and the incidence of postpartum depression appears to be lower amongst those who use such practices. PMID- 28850323 TI - Touch Precision Modulates Visual Bias. AB - The sensory precision hypothesis holds that different seen and felt cues about the size of an object resolve themselves in favor of the more reliable modality. To examine this precision hypothesis, 60 college students were asked to look at one size while manually exploring another unseen size either with their bare fingers or, to lessen the reliability of touch, with their fingers sleeved in rigid tubes. Afterwards, the participants estimated either the seen size or the felt size by finding a match from a visual display of various sizes. Results showed that the seen size biased the estimates of the felt size when the reliability of touch decreased. This finding supports the interaction between touch reliability and visual bias predicted by statistically optimal models of sensory integration. PMID- 28850324 TI - Negative caregiving representations and postpartum depression: The mediating roles of parenting efficacy and relationship satisfaction. AB - Drawing on Bowlby's (1982) caregiving theoretical framework, this is the first preliminary examination of caregiving to postpartum depression (PPD) as well as the potential mediators to the psychological manifestations of caregiving in PPD. One hundred and fifty Israeli mothers completed four scales assessing PPD, parenting self-efficacy, caregiving representations and marital satisfaction, within 6 months after giving birth. Researchers indicated a significant association between deactivated caregiving and PPD that was mediated by lower levels of parental self-efficacy and lower marital satisfaction. The associations between caregiving hyperactivation and PPD were nonsignificant. Theoretical and practical implications for clinical practice and postpartum risk factor models are discussed. PMID- 28850325 TI - A trauma-informed examination of the hardships experienced by abortion fund patients in the United States. AB - Researchers describe hardships experienced by abortion patients, examining administrative health cases from 2010 to 2015 in the United States. All patients received financial assistance from an abortion fund to help pay for abortion. Case data were analyzed to assess types and numbers of hardships experienced by age, race, and geographic origin. Hardships ranged from homelessness to parenting multiple children. Patients from the geographic South experienced the most hardships, followed by those from the Midwest. Hardships experienced by abortion fund patients are like those reported in other samples of abortion patients; hardships potentially cause or exacerbate trauma. Results are discussed in the context of a trauma-informed perspective. PMID- 28850326 TI - Depressive symptoms among older caregivers raising children impacted by HIV/AIDS in the Omusati Region of Namibia. AB - The study of depressive symptoms among caregivers raising HIV/AIDS-orphans is emerging as an important area of research. However, it has not been explored at length in generational and cultural contexts. In this study, the authors explore the role of financial strain, raising a HIV-infected and/or impacted child, and caregiver knowledge on the depressive symptoms of 89-older caregivers raising HIV/AIDS-orphans in Namibia, Africa. In this study, we found elevated levels of depressive symptoms among this population. Using hierarchical regression, a significant positive association between financial strain and depressive symptoms was found. A significant negative association between caring for an HIV-infected orphan and depression was shown. Our work suggests the need for economic assistance programs and psychosocial interventions for older caregivers. PMID- 28850327 TI - Introductory to Issue 40(4): Growing Our Assessment Toolbox. PMID- 28850329 TI - It's not all in the brain. AB - A clock gene expressed in skeletal muscle plays a bigger role in regulating sleep than it does in the brain. PMID- 28850328 TI - Circular oligomerization is an intrinsic property of synaptotagmin. AB - Previously, we showed that synaptotagmin1 (Syt1) forms Ca2+-sensitive ring-like oligomers on membranes containing acidic lipids and proposed a potential role in regulating neurotransmitter release (Zanetti et al., 2016). Here, we report that Syt1 assembles into similar ring-like oligomers in solution when triggered by naturally occurring polyphosphates (PIP2 and ATP) and magnesium ions (Mg2+). These soluble Syt1 rings were observed by electron microscopy and independently demonstrated and quantified using fluorescence correlation spectroscopy. Oligomerization is triggered when polyphosphates bind to the polylysine patch in C2B domain and is stabilized by Mg2+, which neutralizes the Ca2+-binding aspartic acids that likely contribute to the C2B interface in the oligomer. Overall, our data show that ring-like polymerization is an intrinsic property of Syt1 with reasonable affinity that can be triggered by the vesicle docking C2B-PIP2 interaction and raise the possibility that Syt1 rings could pre-form on the synaptic vesicle to facilitate docking. PMID- 28850330 TI - Diabetes mellitus and hyperlipidaemia as risk factors for frequent pain in the back, neck and/or shoulders/arms among adults in Stockholm 2006 to 2010 - Results from the Stockholm Public Health Cohort. AB - BACKGROUND AND AIMS: Frequent back, neck and/or shoulder pain (BNSP) are common conditions which pose high burden for the society. Results from previous studies suggest that diabetes and hyperlipidaemia may be associated with a higher risk of getting such conditions, but there is in general, few studies based on longitudinal designs. The aim of this study was therefore to compare the risk of developing frequent BNSP in men and women with and without diabetes and/or hyperlipidaemia. METHODS: A longitudinal study based on the Stockholm Public Health Cohort was conducted based on subjects aged 45-84, who were free from pain at the mentioned sites in 2006 and followed up until 2010. The data in the current study is based on questionnaires, except socioeconomic status which was derived from Statistics Sweden. The exposure diabetes and hyperlipidaemia was self-reported and, a categorical variable was created; without any of the conditions, with hyperlipidaemia only, with diabetes only and with both conditions. The outcome frequent BNSP was defined using the following questions in the questionnaire in 2010: "During the past 6months, have you had pain in the neck or upper part of the back?", "During the past 6months, have you had pain in the lower back?", and "During the past 6months, have you had pain in the shoulders/arms?". All questions had three possible response options: no; yes, a couple of days per month or less often and; yes, a couple of days per week or more often. Those who reported weekly pain to at least one of these questions were considered to having frequent BNSP. Binomial regressions were run to calculate the crude and adjusted risk ratio (RR) in men and women separately. Additional analysis was performed in order to control for potential bias derived from individuals lost to follow-up. RESULTS: A total of 10,044 subjects fulfilled the criteria to be included in the study. The mean age of the sample was 60years and evenly distributed by sex. After adjusting for age, body mass index, physical activity, high blood pressure and socioeconomic status, the RR for frequent BNSP among men with diabetes was 1.64 (95% CI: 1.23-2.18) and 1.19 (95% CI: 0.98-1.44) for hyperlipidaemia compared to men with neither diabetes nor hyperlipidaemia. Among women the corresponding RRs were 0.92 (95% CI: 0.60-1.14) and 1.23 (95% CI: 1.03-1.46). Having both diabetes and hyperlipidaemia at baseline was not associated with increased risk of frequent BNSP. Diabetes and hyperlipidaemia seems to be associated with an increased risk for frequent BNSP and the risk may differ between men and women. Behaviours and/or biological underlying mechanisms may explain the results. CONCLUSIONS: This study suggests that metabolic diseases such as diabetes and hyperlipidaemia may have an impact on the pathophysiology of frequent BNSP and thus, contributes to the knowledge in musculoskeletal health. Furthermore, it confirms that men and women may differ in terms of risk factors for BNSP. IMPLICATIONS: Health professionals should contemplate the results from this study when planning primary prevention strategies. PMID- 28850331 TI - Qualitative pain research emphasizes that patients need true information and physicians and nurses need more knowledge of complex regional pain syndrome (CRPS). PMID- 28850333 TI - Home training in sensorimotor discrimination reduces pain in complex regional pain syndrome (CRPS). PMID- 28850332 TI - Adolescents' experience of complex persistent pain. AB - BACKGROUND AND AIMS: Persistent (chronic) pain is a common phenomenon in adolescents. When young people are referred to a pain clinic, they usually have amplified pain signals, with pain syndromes of unconfirmed ethology, such as fibromyalgia and complex regional pain syndrome (CRPS). Pain is complex and seems to be related to a combination of illness, injury, psychological distress, and environmental factors. These young people are found to have higher levels of distress, anxiety, sleep disturbance, and lower mood than their peers and may be in danger of entering adulthood with mental and physical problems. In order to understand the complexity of persistent pain in adolescents, there seems to be a need for further qualitative research into their lived experiences. The aim of this study was to explore adolescents' experiences of complex persistent pain and its impact on everyday life. METHODS: The study has an exploratory design with individual in-depth interviews with six youths aged 12-19, recruited from a pain clinic at a main referral hospital in Norway. A narrative approach allowed the informants to give voice to their experiences concerning complex persistent pain. A hermeneutic analysis was used, where the research question was the basis for a reflective interpretation. RESULTS: Three main themes were identified: (1) a life with pain and unpleasant bodily expressions; (2) an altered emotional wellbeing; and (3) the struggle to keep up with everyday life. The pain was experienced as extremely strong, emerging from a minor injury or without any obvious causation, and not always being recognised by healthcare providers. The pain intensity increased as the suffering got worse, and the sensation was hard to describe with words. Parts of their body could change in appearance, and some described having pain-attacks or fainting. The feeling of anxiety was strongly connected to the pain. Despair and uncertainty contributed to physical disability, major sleep problems, school absence, and withdrawal from leisure activities. Their parents were supportive, but sometimes more emotionally affected than themselves. The adolescents described how they strived for normality and to not become an outsider. Being met with necessary facilitation from school was important, as well as keeping up with friends. These adolescents had all been treated by an interdisciplinary pain team, and stated that they had an optimistic view of the future, despite still having some symptoms. CONCLUSIONS: The study provides new insights into adolescents' own experiences of complex persistent pain occurring unexpectedly, developing dramatically over time, and influencing all parts of their everyday lives. The adolescents entered vicious cycles, with despair and decreased physical and social functioning, with the risk of isolation and role loss. However, these young people seem to have a strong motivation to strive for normalcy. IMPLICATIONS: These findings may encourage healthcare providers to perceive adolescents' persistent pain through the lenses of a biopsychosocial approach. We suggest that further research into adolescents with persistent pain should include longitudinal studies of quality of life and gender perspectives. PMID- 28850334 TI - New knowledge reduces risk of damage to spinal cord from spinal haematoma after epidural- or spinal-analgesia and from spinal cord stimulator leads. PMID- 28850335 TI - Neuraxial blocks and spinal haematoma: Review of 166 case reports published 1994 2015. Part 1: Demographics and risk-factors. AB - BACKGROUND: Bleeding into the vertebral canal causing a spinal haematoma (SH) is a rare but serious complication to central neuraxial blocks (CNB). Of all serious complications to CNBs such as meningitis, abscess, cardiovascular collapse, and nerve injury, neurological injury associated with SH has the worst prognosis for permanent harm. Around the turn of the millennium, the first guidelines were published that aimed to reduce the risk of this complication. These guidelines are based on known risk factors for SH, rather than evidence from randomised, controlled trials (RCTs). RCTs, and therefore meta-analysis of RCTs, are not appropriate for identifying rare events. Analysing published case reports of rare complications may at least reveal risk factors and can thereby improve management of CNBs. The aims of the present review were to analyse case reports of SH after CNBs published between 1994 and 2015, and compare these with previous reviews of case reports. METHODS: MEDLINE and EMBASE were used for identifying case reports published in English, German, or Scandinavian languages, using appropriate search terms. Reference lists were also scrutinised for case reports. Twenty different variables from each case were specifically searched for and filled out on an Excel spreadsheet, and incidences were calculated using the number of informative reports as denominator for each variable. RESULTS: Altogether 166 case reports on spinal haematoma after CNB published during the years between 1994 and 2015 were collected. The annual number of case reports published during this period almost trebled compared with the two preceding decades. This trend continued even after the first guidelines on safe practice of CNBs appeared around year 2000, although more cases complied with such guidelines during the second half of the observation period (2005-2015) than during the first half. Three types of risk factors dominated: (1) Patient-related risk factors such as haemostatic and spinal disorders, (2) CNB-procedure-related risks such as complicated block, (3) Drug-related risks, i.e. medication with antihaemostatic drugs. CONCLUSIONS AND IMPLICATIONS: The annual number of published cases of spinal haematoma after central neuraxial blocks increased during the last two decades (1994-2015) compared to previous decades. Case reports on elderly women account for this increase. Antihaemostatic drugs, heparins in particular, are still major risk factors for developing post-CNB spinal bleedings. Other risk factors are haemostatic and spinal disorders and complicated blocks, especially "bloody taps", whereas multiple attempts do not seem to increase the risk of bleeding. In a large number of cases, no risk factor was reported. Guidelines issued around the turn of the century do not seem to have affected the number of published reports. In most cases, guidelines were followed, especially during the second half of the study period. Thus, although guidelines reduce the risk of a post-CNB spinal haematoma, and should be strictly adhered to in every single case, they are no guarantee against such bleedings to occur. PMID- 28850336 TI - Neuraxial blocks and spinal haematoma: Review of 166 cases published 1994 - 2015. Part 2: diagnosis, treatment, and outcome. AB - BACKGROUND: Bleeding into the vertebral canal causing a spinal haematoma (SH) is a rare but serious complication to central neuraxial blocks (CNB). Of all serious complications to CNBs, neurological injury associated with SH has the worst prognosis. Around the turn of the millennium, the first guidelines aiming to reduce the risk of this complication were published. These guidelines are based on known risk factors for SH, rather than evidence from randomized, controlled trials (RCTs). RCTs, and hence meta-analysis of RCTs, are not appropriate for identifying rare events. Analysing data from a significant number of published case reports of rare complications may reveal risk factors and patterns undetectable in reports on occasional cases, and can thereby help to improve management of CNBs. The aims of the present review were to analyse case reports of SH after CNBs published between 1994 and 2015 with regard to diagnosis, treatment, and outcome of SH after CNB. METHODS: MEDLINE and EMBASE were utilized to find case reports published in English, German, or Scandinavian languages between 1994 and end of 2015, using appropriate search terms. Reference lists were also scrutinized for case reports. We documented initial and worst symptoms and signs of SH, diagnostic methods, treatment, and outcome of the SH. We calculated occurrences in per cent using the number of informative reports as denominator. RESULTS: One hundred and sixty-six case reports on spinal hematomas after CNB published during the years between 1994 and 2015 were identified. Eighty per cent of the patients had severe neurological symptoms (paresis or paralysis). When compared over time, outcomes have improved significantly. Among patients subjected to surgical evacuation of the hematoma, outcomes were best if surgery was performed within 12hours from the first sign of motor dysfunction. However, even patients operated after more than 24hours had relatively favourable outcomes. Whereas the outcomes after surgical evacuation of the epidural haematomas were quite satisfactory, only one of the operations for subdural haematoma (SSDH) resulted in a favourable outcome. CONCLUSIONS AND IMPLICATIONS: Suspicion of a spinal hematoma calls for the consultation of an orthopaedic or neurological surgeon without delay. MRI is the recommended diagnostic tool. Surgical evacuation within 12h from the first sign of motor dysfunction seems to lead to the best outcome, although many patients operated as late as after more than 24hours did regain full motor function. Despite the poor prognosis after surgical evacuation of SSDH, the outcomes after post-CNB spinal haematoma in general have improved significantly over time. PMID- 28850337 TI - CNS-mechanisms contribute to chronification of pain. PMID- 28850338 TI - Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders. AB - BACKGROUND AND AIMS: Reduced pain sensitivity following exercise is termed exercise induced hypoalgesia (EIH). Preliminary evidence suggests that impairment of EIH is evident in individuals with whiplash associated disorders (WAD) following submaximal aerobic exercise. This study aimed to compare EIH responses to isometric and aerobic exercise in patients with chronic WAD and healthy controls and investigate relationships between EIH, conditioned pain modulation (CPM) and psychological factors in patients with chronic WAD. METHODS: A cross sectional pre-post study investigated the effect of a single session of submaximal aerobic cycling exercise and a single session of isometric timed wall squat exercise on EIH in a group of participants with chronic WAD (n=21) and a group of asymptomatic control participants (n=19). Bivariate analyses between EIH and baseline measures of CPM and psychological features (fear of movement, pain catastrophization and posttraumatic stress symptoms) were also investigated. RESULTS: The isometric wall squat exercise but not the aerobic cycling exercise resulted in EIH in both groups (P<.023) with no between-group differences (P>.55) demonstrated for either exercise. There were no significant associations measured between EIH (for either exercise performed), and CPM, or any of the psychological variables. CONCLUSIONS: This study showed that individuals with chronic WAD and mild to moderate pain and disability, and no evidence of dysfunctional CPM, demonstrated reduced pain sensitivity, both in the cervical spine and over the tibialis anterior following an isometric, timed wall squat exercise. Cycling exercise did not increase pain sensitivity. IMPLICATIONS: Individuals with chronic WAD and mild to moderate levels of neck pain and disability may experience less pain sensitivity both locally and remotely following an exercise program directed at non-painful muscles performing isometric exercises. Individuals cycling for 30min at 75% of age-predicted heart rate maximum do not experience increased pain sensitivity. PMID- 28850339 TI - A neurobiologist's attempt to understand persistent pain. AB - This topical review starts with a warning that despite an impressive wealth of neuroscientific data, a reductionist approach can never fully explain persistent pain. One reason is the complexity of clinical pain (in contrast to experimentally induced pain). Another reason is that the "pain system" shows degeneracy, which means that an outcome can have several causes. Problems also arise from lack of conceptual clarity regarding words like nociceptors, pain, and perception. It is, for example, argued that "homeoceptor" would be a more meaningful term than nociceptor. Pain experience most likely depends on synchronized, oscillatory activity in a distributed neural network regardless of whether the pain is caused by tissue injury, deafferentation, or hypnosis. In experimental pain, the insula, the second somatosensory area, and the anterior cingulate gyrus are consistently activated. These regions are not pain-specific, however, and are now regarded by most authors as parts of the so-called salience network, which detects all kinds of salient events (pain being highly salient). The networks related to persistent pain seem to differ from the those identified experimentally, and show a more individually varied pattern of activations. One crucial difference seems to be activation of regions implicated in emotional and body-information processing in persistent pain. Basic properties of the "pain system" may help to explain why it so often goes awry, leading to persistent pain. Thus, the system must be highly sensitive not to miss important homeostatic threats, it cannot be very specific, and it must be highly plastic to quickly learn important associations. Indeed, learning and memory processes play an important role in persistent pain. Thus, behaviour with the goal of avoiding pain provocation is quickly learned and may persist despite healing of the original insult. Experimental and clinical evidence suggest that the hippocampal formation and neurogenesis (formation of new neurons) in the dentate gyrus are involved in the development and maintenance of persistent pain. There is evidence that persistent pain in many instances may be understood as the result of an interpretation of the organism's state of health. Any abnormal pattern of sensory information as well as lack of expected correspondence between motor commands and sensory feedback may be interpreted as bodily threats and evoke pain. This may, for example, be an important mechanism in many cases of neuropathic pain. Accordingly, many patients with persistent pain show evidence of a distorted body image. Another approach to understanding why the "pain system" so often goes awry comes from knowledge of the dynamic and nonlinear behaviour of neuronal networks. In real life the emergence of persistent pain probably depends on the simultaneous occurrence of numerous challenges, and just one extra (however small) might put the network into a an inflexible state with heightened sensitivity to normally innocuous inputs. Finally, the importance of seeking the meaning the patient attributes to his/her pain is emphasized. Only then can we understand why a particular person suffers so much more than another with very similar pathology, and subsequently be able to help the person to alter the meaning of the situation. PMID- 28850340 TI - The triumvirate of co-morbid chronic pain, depression, and cognitive impairment: Attacking this "chicken-and-egg" in novel ways. PMID- 28850341 TI - Pain and pain management in hospitalized patients before and after an intervention. AB - BACKGROUND AND AIM: Studies have shown that pain is common among hospitalized patients and that there is a lack of compliance with pain management guidelines. Improving pain management does not only involve developing new drugs or technology; even more important is an effective organisation that utilises existing expertise. The aim of this study was to investigate whether pain in hospitalized patients can be reduced by implementing evidence-based pain management guidelines, providing education for staff and an organisation that includes pain responsibility nurses. METHODS: A cross-sectional study was carried out between 2009 and 2010 at two hospitals in southwest Sweden, comprising a baseline survey followed by an intervention. The study involved 306 patients, who answered questions about pain intensity at rest and while moving, disturbed sleep due to pain and whether they had used a pain rating scale while in hospital. Medical records were scrutinised for analgesic prescriptions. An intervention then took place, involving implementation of evidence-based guidelines, staff education and the introduction of pain responsibility nurses. A follow-up survey was carried out in 2012, in which 293 patients answered the same questions and their medical records were also reviewed. The baseline results were then compared with those of the follow-up survey. RESULTS: When compared with the baseline survey, the follow-up survey revealed significant differences in the use of validated pain rating instruments as well as the prescription of more appropriate analgesics. Prescription of paracetamol increased significantly in the follow-up survey; 56% of the patients were prescribed paracetamol on a regular basis, compared with 42% at baseline. There was also a significant increase in the use of strong opioids, from 38% at baseline to 55% at follow-up. Prescriptions of weak opioids decreased from 16% at baseline to 4% at follow-up. No significant differences were observed in patient pain levels in the follow-up survey. At baseline, 29% of the patients reported moderate to severe pain at rest (NRS 4-10) and at follow-up that figure was 24% (NRS 4-10). In both surveys, 41% reported moderate to severe pain (NRS 5-10) during movement. Thirty-nine percent reported disturbed sleep at night at both baseline and follow-up. CONCLUSIONS: This study demonstrates that evidence-based guidelines made accessible to all staff as a pocket size booklet and on the intranet, in combination with staff education, pain responsibility nurses who informed other staff on their own wards, improved the prescription of analgesics in the hospitals studied. In order to achieve a noticeable effect for patients, i.e., reduced pain levels, an intervention containing more components than those employed in the present study is required. IMPLICATIONS: Nurses and physicians need greater knowledge about the importance of pain rating. A vital part of pain management at hospitals is continuous evaluation of treatment outcomes to prevent severe pain and disturbed sleep. The complexity of pain and pain management requires commitment, time and knowledge on the part of healthcare staff. Multi-professional pain teams that support ward staff in pain management are necessary in order to reduce suffering and unnecessary pain in hospitalized patients. PMID- 28850342 TI - Pain reduction due to novel sensory-motor training in Complex Regional Pain Syndrome I - A pilot study. AB - BACKGROUND AND AIMS: Patients suffering from Complex Regional Pain Syndrome (CRPS) of the upper limb show a changed cortical representation of the affected hand. The lip area invades the former hand area contralateral to the affected hand. This change in cortical representation is correlated to the intensity of ongoing pain in patients with CRPS. Further studies revealed that restoration of the original representation coincides with a decrease of pain. Sensory-motor training protocols can increase and/or relocate cortical somatosensory and motor representation areas of the fingers, as shown, for example, in Braille reading individuals and professional violin players. Further, there is evidence that sensory-motor discrimination training has a beneficial effect on both the intensity of pain and the mislocalization of sensory-motor cortical areas in CRPS patients. Based on these propositions, we developed a novel sensory-motor self training paradigm for CRPS patients to use in a home-based manner. METHODS: Ten CRPS patients performed the sensory-motor training for 2weeks. The training consists of a braille-like haptic task with different training modes (bi-manual, speed and memory training). During the training, as well as 1week before and after, patients were asked to fill out pain diaries. Furthermore, measures of impairment were acquired at baseline and post training. RESULTS: Patients showed significant pain reduction after the 2week training period. The overall disability as well as the depression scores showed a trend to improve after the 2week training. The reduction in pain was correlated with the total amount of training performed. CONCLUSIONS: This is a first proof of principle study of a novel sensory-motor self-training protocol to reduce pain in CRPS patients. The more consistent the patients trained the larger the pain reduction. Sensory-motor training, which can be performed on a regular basis at home might provide a novel interventional strategy to improve symptoms of CRPS. IMPLICATIONS: Although a larger study needs to be conducted to confirm our findings, including long-term follow-up, the results show, that a sensory-motor home-based training is a strategy worth exploring further for the reduction of pain as well as high frequency training for patients with CRPS. PMID- 28850343 TI - Relationship of musculoskeletal pain and well-being at work - Does pain matter? AB - BACKGROUND AND AIMS: Musculoskeletal pain is a common symptom and many people even with chronic pain continue to work. The aim of our study is to analyze how musculoskeletal pain affects work well-being by comparing work engagement in employees with or without pain, and how pain-related risk of disability is associated with work engagement. In a separate analysis, we also studied, how psychosocial factors are related to work engagement. METHODS: This is a cross sectional study of Finnish female employees of the city of Pori, Finland (PORi To Aid Against Threats (PORTAAT) study). Data was collected by trained study nurses and self-administrated questionnaires. Work well-being was measured by work engagement using Utrecht Work Engagement Scale (UWES-9) questionnaire and the burden of pain was measured by using the short version of Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ). Study population was divided into four groups: those without pain and the groups with low (I), medium (II) or high (III) OMPSQ score, reflecting increasing risk of long term disability due to musculoskeletal pain. The study nurse assessed psychosocial risk factors using defined core questions. RESULTS: We evaluated 702 female employees, 601 (86%) had suffered from musculoskeletal pain over the past 12 months, whereas 101 (14%) reported no pain at all. Pain was chronic (duration at least 3 months) in 465/601 (77%) subjects. Subjects with musculoskeletal pain were older, had higher BMI and were on sick leave more often than subjects without pain. Of the psychosocial risk factors, depression, type D personality, anxiety and hostility were significantly more common among subjects with musculoskeletal pain. Hypertension and the use of non-steroidal anti-inflammatory drugs were significantly more frequent in the musculoskeletal pain group. Quality of sleep and working capability were significantly better among persons without pain. Average weekly working hours were slightly higher among those with musculoskeletal pain. In crude analysis, work engagement (UWES-9) was similar in women without pain and those with musculoskeletal pain (4.96 vs. 4.79; p=0.091). After adjustment for age, education years, BMI, working hours and financial satisfaction, the difference between the groups became statistically significant (p=0.036). Still, there was no difference between the groups of no-pain and low burden of pain (p=0.21, after adjustment). Work engagement was significantly lower in the groups of medium (p=0.024, after adjusted) and high (p<0.001, after adjustment) burden of pain. Linearity across the Linton tertiles was significant (p<0.001). In univariate and multivariate ordered logistic regression analyses relating study variables to the work engagement musculoskeletal pain per se did not enter in the model to explain work engagement. Work and family stress, type D personality and duration of sick leave due to pain reduced work engagement, whereas financial satisfaction, moderate and high leisure time physical activity and higher BMI improved it. CONCLUSIONS: Among women with musculoskeletal pain psychosocial and lifestyle factors significantly correlate with work engagement, while the pain itself does not. IMPLICATIONS: Special attention should be paid to the psychosocial aspects in female employees with musculoskeletal pain to improve work well-being and maintain work ability. PMID- 28850344 TI - Are preoperative experimental pain assessments correlated with clinical pain outcomes after surgery? A systematic review. AB - BACKGROUND: Pain after surgery is not uncommon with 30% of patients reporting moderate to severe postoperative pain. Early identification of patients prone to postoperative pain may be a step forward towards individualized pain medicine providing a basis for improved clinical management through treatment strategies targeting relevant pain mechanisms in each patient. Assessment of pain processing by quantitative sensory testing (QST) prior to surgery has been proposed as a method to identify patients at risk for postoperative pain, although results have been conflicting. Since the last systematic review, several studies investigating the association between postoperative pain and more dynamic measures of pain processing like temporal summation of pain and conditioned pain modulation have been conducted. OBJECTIVES: According to the PRISMA guidelines, the aim of this systematic review was to evaluate whether assessment of experimental pain processing including measures of central pain mechanisms prior to surgery was associated with pain intensity after surgery. METHODS: Systematic database searches in PubMed and EMBASE with the following search components: QST, association, and postoperative pain, for studies that assessed the association between QST and pain after surgery were performed. Two authors independently reviewed all titles and abstracts to assess their relevance for inclusion. Studies were included if (1) QST was performed prior to surgery, (2) pain was assessed after surgery, and (3) the association between QST and pain after surgery was investigated. Forty-four unique studies were identified, with 30 studies on 2738 subjects meeting inclusion criteria. The methodological quality of the include studies was assessed and data extraction included study population, type of surgery, QST variables, clinical pain outcome measure and main result. RESULTS: Most studies showed moderate to high risk of bias. Type of surgery investigated include 7 studies on total knee replacement, 5 studies on caesarean section, 4 studies on thoracic surgery, 2 studies on herniotomy, 2 studies on hysterectomy/myomectomy, 1 study on tubal ligation, 1 study on gynecologic laparoscopy, 1 study on arthroscopic knee surgery, 1 study on shoulder surgery, 1 study on disc herniation surgery, 1 study on cholecystectomy, 1 study on percutaneous nephrolithotomy, 1 study on molar surgery, 1 study on abdominal surgery, and 1 study on total knee replacement and total hip replacement. The majority of the preoperative QST variables showed no consistent association with pain intensity after surgery. Thermal heat pain above the pain threshold and temporal summation of pressure pain were the QST variables, which showed the most consistent association with acute or chronic pain after surgery. CONCLUSIONS: QST before surgery does not consistently predict pain after surgery. High quality studies investigating the presence of different QST variables in combination or along with other pain-related psychosocial factors are warranted to confirm the clinical relevance of QST prior to surgery. IMPLICATIONS: Although preoperative QST does not show consistent results, future studies in this area should include assessment of central pain mechanisms like temporal summation of pressure pain, conditioned pain modulation, and responses to pain above the pain threshold since these variables show promising associations to pain after surgery. PMID- 28850346 TI - Is musculoskeletal pain associated with work engagement? PMID- 28850345 TI - Detection of nociceptive-related metabolic activity in the spinal cord of low back pain patients using 18F-FDG PET/CT. AB - BACKGROUND: Over the past couple of decades, a number of centers in the brain have been identified as important sites of nociceptive processing and are collectively known as the 'pain matrix.' Imaging tools such as functional magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) have played roles in defining these pain-relevant, physiologically active brain regions. Similarly, certain segments of the spinal cord are likely more metabolically active in the setting of pain conditions, the location of which is dependent upon location of symptoms. However, little is known about the physiologic changes in the spinal cord in the context of pain. This study aimed to determine whether uptake of 18F-FDG in the spinal cord on positron emission tomography/computed tomography (PET/CT) of patients with low back pain (LBP) differs from that of patients without LBP. METHODS: We conducted a retrospective review of 18F-FDG PET/CT scans of 26 patients with non-central nervous system cancers, 13 of whom had reported LBP and 13 of whom were free of LBP (controls). No patients had spinal stenosis or significant 18F-FDG contribution of degenerative changes of the spine into the spinal canal. Circular regions of interests were drawn within the spinal canal on transaxial images, excluding bony or discal elements of the spine, and the maximum standardized uptake value (SUVmax) of every slice from spinal nerves C1 to S1 was obtained. SUVmax were normalized by subtracting the SUVmax of spinal nerve L5, as minimal neural tissue is present at this level. Normalized SUVmax of LBP patients were compared to those of LBP-free patients at each vertebral level. RESULTS: We found the normalized SUVmax of patients with LBP to be significantly greater than those of control patients when jointly tested at spinal nerves of T7, T8, T9 and T10 (p<0.001). No significant difference was found between the two groups at other levels of the spinal cord. Within the two groups, normalized SUVmax generally decreased cephalocaudally. CONCLUSIONS: Patients with LBP show increased uptake of 18F-FDG in the caudal aspect of the thoracic spinal cord, compared to patients without LBP. IMPLICATIONS: This paper demonstrates the potential of 18F-FDG PET/CT as a biomarker of increased metabolic activity in the spinal cord related to LBP. As such, it could potentially aid in the treatment of LBP by localizing physiologically active spinal cord regions and guiding minimally invasive delivery of analgesics or stimulators to relevant levels of the spinal cord. PMID- 28850347 TI - Exercising non-painful muscles can induce hypoalgesia in individuals with chronic pain. PMID- 28850348 TI - Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it). AB - OBJECTIVES: To examine the role of pain on cognitive function in adults with major depressive disorder (MDD). METHODS: Adults (18-65) with a Diagnostic and Statistical Manual - Fifth Edition (DSM-5)-defined diagnosis of MDD experiencing a current major depressive episode (MDE) were enrolled (nMDD=100). All subjects with MDD were matched in age, sex, and years of education to healthy controls (HC) (nHC=100) for comparison. Cognitive function was assessed using the recently validated THINC-integrated tool (THINC-it), which comprises variants of the choice reaction time (i.e., THINC-it: Spotter), One-Back (i.e., THINC-it: Symbol Check), Digit Symbol Substitution Test (i.e., THINC-it: Codebreaker), Trail Making Test - Part B (i.e., THINC-it: Trails), as well as the Perceived Deficits Questionnaire for Depression - 5-item (i.e., THINC-it: PDQ-5-D). A global index of objective cognitive function was computed using objective measures from the THINC-it, while self-rated cognitive deficits were measured using the PDQ-5-D. Pain was measured using a Visual Analogue Scale (VAS). Regression analyses evaluated the role of pain in predicting objective and subjective cognitive function. RESULTS: A significant between-group differences on the VAS was observed (p<0.001), with individuals with MDD reporting higher pain severity as evidenced by higher scores on the VAS than HC. Significant interaction effects were observed between self -rated cognitive deficits and pain ratings (p<0.001) on objective cognitive performance (after adjusting for MADRS total score), suggesting that pain moderates the association between self-rated and objective cognitive function. CONCLUSIONS: Results indicated that pain is associated with increased self-rated and objective cognitive deficits in adults with MDD. IMPLICATIONS: The study herein provides preliminary evidence demonstrating that adults with MDD reporting pain symptomatology and poorer subjective cognitive function is predictive of poorer objective cognitive performance. THINC-it is capable of detecting cognitive dysfunction amongst adults with MDD and pain. PMID- 28850349 TI - How do medical students use and understand pain rating scales? AB - BACKGROUND AND AIMS: Pain is a multidimensional experience that is difficult to describe and to assess. To scale current pain, assessment refers to a maximum level of pain, but little is known about this process. Further, clinicians tend to underestimate patients' pain, with or without patients' own reports, and to underestimate to a greater extent with more clinical experience, possibly due to recalibration of a personal pain scale with increasing exposure to severe pain. We sought to determine how medical students rated pain in early years of clinical exposure, and in relation to experience of their own and others' worst pains. METHODS: An online survey sampled medical students' rating and description of their own worst pain and of that witnessed in another; also what would cause the maximum level of pain and what behaviours characterised it. Last, they indicated their preference among pain scales. RESULTS: Thirty-six medical students provided responses, the majority in their first six months of clinical exposure. Students' own worst pain was rated a mean of 6.7/10 (s.d. 1.6) on a numerical scale; causes were diverse but with many bone fractures. Mean worst pain observed in another was rated 8.6/10 (s.d. 1.4); causes included fractures, gallstones, and sickle cell crises. Another's worst pain was significantly higher (mean 9.4, s.d. 0.8 vs mean 8.0 s.d. 1.4) when rated after the student's own pain than before it (presentation order randomised). We found no effect of clinical exposure on estimation of worst pain in another person, nor was there a personal tendency to rate pain using more or less extreme values. Students expected pain of 10/10 to be presented with many verbal, facial and whole body behaviours, and signs of physiological stress. Collectively, behavioural descriptions were rich and varied, but with many incompatibilities: for instance, between 'writhing' and 'rigidity' expected in the person with extreme pain. Most students preferred the numerical rating scale over visual analogue and verbal scales. CONCLUSIONS: The study requires replication, particularly for clinical experience, where we found no significant difference in estimation of another's pain over the first three years of medical students' clinical exposure, but the comparison was underpowered. Despite no systematic individual difference in using pain ratings, there was a marked effect of rating another's worst pain higher when the rater had previously rated his/her own worst pain. This suggests anchoring estimate of another's pain in personal pain experience, and a possible way to mitigate clinicians' underestimation of patients' pain. Medical students' recognition of the importance of facial expression in indicating another's pain severity was encouraging, but most students anticipated only a narrow range of behaviours associated with extreme pain, thereby excluding other authentic behaviours. IMPLICATIONS: Many clinical guidelines mandate regular pain assessment for hospital inpatients, and encourage routine assessment in community and outpatient settings, in order to decide on and monitor treatment. Replication and elaboration of this study could extend our understanding of how clinicians interpret pain scales completed by patients, and how they estimate patients' pain. PMID- 28850350 TI - Patients' subjective acute pain rating scales (VAS, NRS) are fine; more elaborate evaluations needed for chronic pain, especially in the elderly and demented patients. PMID- 28850351 TI - How can pain management be improved in hospitalized patients? PMID- 28850352 TI - Cardiovascular risk reduction as a population strategy for preventing pain? PMID- 28850353 TI - A possible biomarker of low back pain: 18F-FDeoxyGlucose uptake in PETscan and CT of the spinal cord. PMID- 28850354 TI - Acute pain in the emergency department: Effect of an educational intervention. AB - BACKGROUND AND AIMS: Pain management is often inadequate in emergency departments (ED) despite the availability of effective analgesics. Interventions to change professional behavior may therefore help to improve the management of pain within the ED. We hypothesized that a 2-h educational intervention combining e-learning and simulation would result in improved pain treatment of ED patients with pain. METHODS: Data were collected at the ED of Horsens Regional Hospital during a 3 week study period in March 2015. Pain intensity (NRS, 0-10) and analgesic administration were recorded 24h a day for all patients who were admitted to the ED during the first and third study weeks. Fifty-three ED nurses and 14 ED residents participated in the educational intervention, which took place in the second study week. RESULTS: In total, 247 of 796 patients had pain >3 on the NRS at the admission to the ED and were included in the data analysis. The theoretical knowledge of pain management among nurses and residents increased as assessed by a multiple choice test performed before and after the educational intervention (P=0.001), but no change in clinical practice could be observed: The administration for analgesics [OR: 1.79 (0.97-3.33)] and for opioids [2.02 (0.79 5.18)] were similar before and after the educational intervention, as was the rate of clinically meaningful pain reduction (NRS >2) during the ED stay [OR: 0.81 (CI 0.45-1.44)]. CONCLUSIONS: Conduction of a 2-h educational intervention combining interactive case-based e-learning with simulation-based training in an ED setting was feasible with a high participation rate of nurses and residents. Their knowledge of pain management increased after completion of the program, but transfer of the new knowledge into clinical practice could not be found. Future research should explore the effects of repeated education of healthcare providers on pain management. IMPLICATIONS: It is essential for nurses and residents in emergency departments to have the basic theoretical and practical skills to treat acute pain properly. A modern approach including e-learning and simulation lead to increased knowledge of acute pain management. Further studies are needed to show how this increased knowledge is transferred into clinical practice. PMID- 28850355 TI - Opioids and the gut; not only constipation and laxatives. PMID- 28850356 TI - Healthcare resource use and costs of opioid-induced constipation among non-cancer and cancer patients on opioid therapy: A nationwide register-based cohort study in Denmark. AB - BACKGROUND AND AIM: Opioid analgesics are often effective for pain management, but may cause constipation. The aim of this study was to determine healthcare resource use and costs in non-cancer and cancer patients with opioid-induced constipation (OIC). METHODS: This was a nationwide register-based cohort study including patients >=18 years of age initiating >=4 weeks opioid therapy (1998 2012) in Denmark. A measure of OIC was constructed based on data from Danish national health registries, and defined as >=1 diagnosis of constipation, diverticulitis, mega colon, ileus/subileus, abdominal pain/acute abdomen or haemorrhoids and/or >=2 subsequent prescription issues of laxatives. Total healthcare resource utilization and costs (including pharmacy dispense, inpatient , outpatient-, emergency room- and primary care) were estimated according to OIC status, opioid treatment dosage and length, gender, age, marital status, and comorbidities using Generalised Linear Model. RESULTS: We identified 97169 eligible opioid users (77568 non-cancer and 19601 patients with a cancer diagnosis). Among non-cancer patients, 15% were classified with OIC, 10% had previous constipation, and 75% were without OIC. Patients characteristics of non cancer OIC patients showed a higher frequency of strong opioid treatment (69% versus 41%), long-term opioid treatment (1189 days versus 584 days), advanced age (73 years versus 61 years), and cardiovascular disease (31% versus 19%) compared to those without OIC (P<0.001 for all comparisons). Non-cancer patients with OIC had 34% higher total healthcare costs compared to those without OIC (P<0.001) after adjusting for age, gender, opioid usage, marital status and comorbidities. Among cancer patients, 35% were classified with OIC, 14% had previous constipation, and 51% were without OIC. A higher proportion of cancer patients with OIC were continuous opioid users (85% versus 83%) and strong opioid users (97% versus 85%), compared to those without OIC (P<0.001 for both comparisons). Further, the mean number of days on opioids were higher for cancer patients with versus without OIC (329 days versus 238 days, P<0.001). Total healthcare costs were 25% higher for cancer patients with versus without OIC (P<0.001) after adjusting for age, gender, opioid usage, marital status and comorbidities. CONCLUSIONS: The results of this nationwide study based on real life data suggested that both non-cancer patients and cancer patients suffering from opioid induced constipation (OIC) may have higher healthcare resource utilization and higher associated costs compared to those without OIC. IMPLICATIONS: Reducing the number of OIC patients has potential cost savings for the health care system. Special attention should be on patients at potential high risk of OIC, such as strong and long-term opioid treatment, advanced age, and concomitant cardiovascular disease. PMID- 28850357 TI - Preoperative quantitative sensory testing (QST) predicting postoperative pain: Image or mirage? PMID- 28850358 TI - Education of nurses and medical doctors is a sine qua non for improving pain management of hospitalized patients, but not enough. PMID- 28850359 TI - Relief of phantom limb pain using mirror therapy: A bit more optimism from retrospective analysis of two studies. PMID- 28850360 TI - Trajectory of phantom limb pain relief using mirror therapy: Retrospective analysis of two studies. AB - BACKGROUND AND PURPOSE: Research indicates that mirror therapy reduces phantom limb pain (PLP). Objectives were to determine when mirror therapy works in those who respond to treatment, the relevance of baseline PLP to when pain relief occurs, and what pain symptoms respond to mirror therapy. METHODS: Data from two independent cohorts with unilateral lower limb amputation were analyzed for this study (n=33). Mirror therapy consisted of 15-min sessions in which amputees performed synchronous movements of the phantom and intact legs/feet. PLP was measured using a visual analogue scale and the Short-Form McGill Pain Questionnaire. RESULTS: The severity of PLP at the beginning of treatment predicted when pain relief occurred. Those with low baseline PLP experienced a reduction (p<0.05) in PLP by session 7 of treatment, those with medium baseline PLP experienced pain relief by session 14 of treatment, and those with high baseline PLP experienced pain relief by session 21 of treatment. Mirror therapy reduced throbbing, shooting, stabbing, sharp, cramping, aching, tender, splitting, tiring/exhausting, and punishing-cruel pain symptoms. CONCLUSION: The degree of PLP at baseline predicts when mirror therapy relieves pain. IMPLICATIONS: This article indicates that the degree of baseline PLP affects when mirror therapy relieves pain: relief occurs by session 7 in patients with low PLP but by session 21 in patients with high PLP. Clinicians should anticipate slower pain relief in patients who begin treatment with high levels of pain. ClinicalTrials.gov numbers:NCT00623818 and NCT00662415. PMID- 28850361 TI - Perceived sleep deficit is a strong predictor of RLS in multisite pain - A population based study in middle aged females. AB - BACKGROUND: Chronic pain conditions as well as Restless Legs Syndrome (RLS) are known to be associated with subjectively and objectively disturbed sleep. RLS has been recently described as highly prevalent in multisite pain and the role of sleep as a modifying factor in this RLS phenotype is unknown. This study aimed to investigate if perceived sleep deficit and other sleep related parameters predict RLS in subjects with multisite pain. CURRENT KNOWLEDGE/STUDY RATIONALE: We have recently demonstrated a strong association between Restless Legs Syndrome (RLS) and number of pain locations. In the current analysis we hypothesized that impaired sleep predicts RLS in subjects with multisite pain. METHOD: Questionnaire-based data from 2727 randomly selected women aged 18-64 years were used to analyze RLS symptoms, self-reported sleep quality, and the degree of daytime sleepiness (Epworth Sleepiness Scale (ESS)) in relation to type, degree and localization of body pain. Potential confounders including anthropometrics, pain localization, co-morbidities, and medication were adjusted for in the Generalized Linear Models (GLM). RESULTS: Perceived sleep deficit >=90min (OR 2.4 (1.5-3.8), p<0.001) and frequent nocturnal awakenings (OR 2.3 (1.4-3.6), p<0.001) were the strongest sleep related predictors for RLS in subjects with multisite pain. Additional factors include prolonged sleep latency (>=30min, OR 1.8 (1.1 2.8), p=0.01) and daytime symptoms like elevated daytime sleepiness (ESS score >=9, OR 1.8 (1.2-2.7), p=0.005). Accordingly, RLS diagnosis was associated with impaired sleep quality (TST (Total Sleep Time) -8.2min, sleep latency +8.0min, and number of awakenings from sleep +0.4, p<0.01). ESS score increased with RLS diagnosis (+0.74, p<0.01) and number of pain locations (0.5, 1.7, and 1.8 for 1, 3, and 5 pain areas, p<0.001). In addition, confounders like pain severity, the history of psychiatric disease, and current smoking were associated with impaired sleep quality in this group of females. CONCLUSIONS: Perceived sleep deficit and sleep fragmentation are the strongest sleep related predictors of RLS in multisite pain. Potential implication of our results are that clinical management programmes of RLS in subjects with multisite pain need to consider both sleep quality and sleep quantity for individually tailored treatment regimes. STUDY IMPACT: RLS, pain, and sleep disorders are highly interrelated. Our study strongly suggests that clinical management of RLS in patients with multisite pain needs to consider sleep quality as an independent risk factor. PMID- 28850362 TI - Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain. AB - INTRODUCTION: Quantitative sensory tests (QST) can be used for profiling anti nociceptive effects of analgesics. However, anti-nociceptive effects detected by QST are not necessarily associated with analgesic effects in pain patients. As part of a large investigation on low back pain, this paper describes the immediate analgesic and anti-nociceptive effects of oxycodone in chronic low-back pain and ranks different QST according to their ability to reflect this effect. The results are expected to support the selection of QST for future studies on potential novel opioid agonists in human pain. METHODS: In this randomized, placebo-controlled and double-blinded cross-over study, 50 patients with chronic low-back pain received a single oral dose of oxycodone 15mg or active placebo, and underwent multiple QST testing. The intensity of low-back pain was recorded during 2h. The areas under the ROC curves and 95% confidence intervals were determined, whereby responder status (>=30% pain reduction) was set as reference variable and changes in QST from baseline were set as classifiers. RESULTS: Significant analgesic effect on low-back pain as well as anti-nociceptive effects for almost all QST parameters were observed. The QST with the highest area under the curve were heat pain detection threshold (0.65, 95%-CI 0.46 to 0.83), single stimulus electrical pain threshold (0.64, 95%-CI 0.47 to 0.80) and pressure pain detection threshold (0.63, 95%-CI 0.48 to 0.79). CONCLUSIONS: The results suggest that anti-nociceptive effects assessed by QST fairly reflect clinical efficacy of oxycodone on low-back pain. Pressure pain detection threshold, heat pain detection threshold and single-stimulus electrical pain threshold may be more suitable to sort out potential non-responders rather than identifying potential responders to opioid medication. Future pre-clinical human research may consider these results when investigating the analgesic effect of opioid agonists by means of QST. PMID- 28850363 TI - Spatial summation of pain and its meaning to patients. PMID- 28850364 TI - Effects of validating communication on recall during a pain-task in healthy participants. AB - BACKGROUND: Increasing recall of instructions and advice in a pain consultation is important, since it is a prerequisite for adherence to treatment recommendations. However, interference due to pain-related distress may result in poor recall. Whereas there are some indications that recall can be increased by empathic communication that reduces interference, this interesting possibility remains largely untested experimentally. The current experiment aimed at studying effects of empathic communication, and more specifically validation, on recall during a pain test and possible mediators and moderators of this effect. METHOD: Participants received either validating (N=25) or invalidating responses (N=25) from the experimenter during a pain provoking task, followed by self-report measures of interference (affect, situational pain catastrophizing) and recall (accurate and false memories of words). RESULTS: As expected, the validated group exhibited higher accurate recall and less false memories following the pain test as compared to the invalidated group. This was partly due to the effect of interference being counteracted by moderating the relationship between pain catastrophizing and recall. CONCLUSION: These novel results suggest that validating communication can counteract interference due to pain catastrophizing on recall, at least in a controlled experimental setting. IMPLICATIONS: Good communication by health professionals is of utmost importance for adherence to pain management. The current results expand our knowledge on the effects of pain communication by establishing and explaining a clear link between empathic communication and recall, highlighting the role of pain catastrophizing. PMID- 28850365 TI - Comparison of spatial summation properties at different body sites. AB - BACKGROUND AND AIMS: The nociceptive system appears to have evolved a range of protective characteristics that are of great interest in understanding both acute and chronic pain. Spatial summation is one important characteristic, whereby increasing area of a stimulus, or distance between multiple stimuli, results in more intense pain-not only greater area of pain. One of the mysteries of chronic pain is why spinal pain is so prevalent relative to pain at other sites. Since pathological tissue models have failed to fully explain spinal pain, we theorized that body region specific differences in sensory processing-such as a greater propensity for spatial summation-may help to explain its vulnerability. We aimed to examine this by comparing the properties of summation at different body parts: the dorsal forearm, neck, and back. METHODS: Spatial summation of pain was investigated using noxious intra-dermal electrical stimuli in healthy pain-free adults (14 males, 6 females), and the perceived pain intensity was rated on a 0 100 pain scale. Area-based stimulation was investigated by doubling the stimulation area with the addition of a second electrode placed adjacent to the first. Distance-based summation was investigated by randomly varying the separation distance between paired noxious electrical stimuli at separations of 0, 10, 15, and 20cm. RESULTS: This study demonstrated that the properties of area and distance-based summation are uniform across the neck, back, and forearm in healthy adults. Spatial summation of pain was also found to be greatest at 15- and 20-cm paired separations for all body regions tested, confirming that noxious information can be integrated over an extensive anatomical area. CONCLUSION: Data from this investigation refutes the thesis that spatial summation of pain may be a contributing factor for the reported difference in chronicity rates between spinal and peripheral sites. It remains, however, a potentially important mechanism by which noxious inputs from multi-level pathology might integrate and contribute to pain. IMPLICATIONS: While data from this project suggest that there are no regional differences in the properties of spatial summation of noxious stimuli, regional differences in other characteristics of the nociceptive system may yet provide insight into why some spinal pain is so highly prevalent; nociceptive distance-based summation may be highly relevant where two or more conditions co-exist in close proximity. PMID- 28850366 TI - Behavioural inhibition in the context of pain: Measurement and conceptual issues. PMID- 28850367 TI - A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis. AB - BACKGROUND/AIMS: Transient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep. METHODS: In this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50mg mavatrep, 500mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0 10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed. RESULTS: Of 33 patients randomized, 32 completed the study. A statistically significantly (p<0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53]; p=0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30]; p=0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [p=0.049] and 7 [p=0.041], stiffness on day 7 [p=0.075]), and function on day 7 [p=0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred. CONCLUSION: Overall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep's safety profile was consistent with its mechanism of action as a TRPV1 antagonist. IMPLICATIONS: Further studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception. TRIAL REGISTRATION: 2009-010961-21 (EudraCT Number). PMID- 28850368 TI - The Functional Barometer - An analysis of a self-assessment questionnaire with ICF-coding regarding functional/activity limitations and quality of life due to pain - Differences in age gender and origin of pain. AB - : Long standing non-malignant pain leads to a variety of limitations which can be assessed by means of the self-assessment questionnaire Functional Barometer. It is designed to assess the extent and limitations in function, activity and decreased quality-of-life and is adapted to the International Classification of Functioning and Health. AIM: To investigate the outcome and differences in age, gender and origin of pain in patients with long-standing non-malignant pain regarding the subjective experience of functional-, activity- and quality-of-life limitations. METHOD: 300 patients with a median duration of pain of 49 months referred to a Pain Management Centre filled out the Functional Barometer questionnaire, adapted to the International Classification of Functioning and Health. RESULTS: 66% patients were women and 34% were men. Seventy-five percent were in working age, 18-64 years. The duration before being referred to a pain specialist was over 4 years and 65% reported pain from more than three origins. Significant differences in functioning, activity and quality-of-life were found in comparing gender, age and origin of pain. Men more often reported physiological limitations while women more often reported psychological limitations of functioning, activity and quality-of-life. The most important were that men more often had difficulties in walking and climbing stairs, while women reported problems with concentration, stress and psychological demands, family relations and contact with friends. CONCLUSION: The significant differences regarding functioning, activity and quality-of-life between women and men as age and origin of pain must be taken into account when tailoring individual treatment and rehabilitation programmes. PMID- 28850369 TI - Clinical outcome following anterior arthrodesis in patients with presumed sacroiliac joint pain. AB - BACKGROUND: It has been reported that in 13-32% of patients with chronic low back pain, the pain may originate in the sacroiliac (SI) joints. When treatment of these patients with analgesics and physiotherapy has failed, a surgical solution may be discussed. Results of such surgery are often based on small series, retrospective analyses or studies using a minimal invasive technique, frequently sponsored by manufacturers. PURPOSE: To report the clinical outcome concerning pain, function and quality of life following anterior arthrodesis in patients presumed to have SI joint pain using validated questionnaires pre- and post operatively. An additional aim was to describe the symptoms of the patients included and the preoperative investigations performed. MATERIAL AND METHODS: Over a 6 year period we treated 55 patients, all women, with a mean age of 45 years (range 28-65) and a mean pelvic pain duration of 9.1 years (range 2-30). The pain started in connection with minor trauma in seven patients, pregnancy in 20 and unspecified in 28. All patients had undergone long periods of treatment including physiotherapy, manipulation, needling, pelvic belt, massage and chiropractic without success, and 15 had been operated for various spinal diagnoses without improvement. The patients underwent thorough neurological investigation, plain X-ray and MRI of the spine and plain X-ray of the pelvis. They were investigated by seven clinical tests aimed at indicating pain from the SI joints. In addition, all patients underwent a percutaneous mechanical provocation test and extra-articular local anaesthetic blocks against the posterior part of the SI joints. Before surgery all patients answered the generic Short-Form-36 (SF-36) questionnaire, the disease specific Balanced Inventory for Spinal Disorders (BIS) questionnaire and rated their level of pelvic and leg pain (VAS, 0-100). At follow-up at a mean of 2 years 49 patients completed the same questionnaires (89%). RESULTS: At follow-up 26 patients reported a lower level of pelvic pain than before surgery, 16 the same level and six a higher level. Applying Svensson's method RPpelvic pain=0.3976, with 95% CI (0.2211, 0.5740) revealed a statistically significant systematic improvement in pelvic pain. At follow-up 28 patients reported a higher quality of life and 26 reported sleeping better than pre-operatively. In most patients the character of the pelvic pain was dull and aching, often accompanied by a stabbing component in connection with sudden movements. Referred pain down the leg/s even to the feet and toes was noted by half of the patients and 29 experienced frequency of micturition. CONCLUSIONS: It is apparent that in some patients the SI joints may cause long term pain that can be treated by arthrodesis. We speculate that continued pain despite a healed arthrodesis may be due to persistent pain from adjacent ligaments. The next step should be a prospective randomized study comparing posterior fusion and ligament resection with non-surgical treatment. IMPLICATIONS: Anterior arthrodesis can apparently relieve pain in some patients with presumed SI joint pain. The problem is how to identify these patients within the low back pain group. PMID- 28850370 TI - Chronic disruptive pain in emerging adults with and without chronic health conditions and the moderating role of psychiatric disorders: Evidence from a population-based cross-sectional survey in Canada. AB - BACKGROUND AND AIMS: There has been a growth in the proportion of emerging adults vulnerable to pain-related sequelae of chronic health conditions (CHCs). Given the paucity of research during this important developmental period, this study investigated the association between CHCs and chronic disruptive pain among emerging adults and the extent to which psychiatric disorders moderate this association. METHODS: Data come from the 2012 Canadian Community Health Survey - Mental Health (CCHS-MH). This cross-sectional survey included 5987 participants that were 15-30 years of age and self-reported their CHCs (n=2460, 41%) and the extent to which pain impacted daily functioning using items from the Health Utilities Index Mark 3 (HUI 3). Group comparisons between respondents with CHCs and healthy controls were made using chi-square tests. Odds ratios (OR) and 95% confidence intervals (CI) were computed from ordinal logistic regression models adjusting for sociodemographic covariates. Product-term interactions between CHCs and psychiatric disorders were included in the models to explore moderating effects. All analyses were weighted to maintain representativeness of the study sample to the Canadian population. RESULTS: The mean age of participants was 23.5 (SE 0.1) years and 48% were female. Compared to healthy controls, a greater proportion of participants with CHCs reported having chronic pain (20.3% vs. 4.5%, p<0.001). Among those with chronic pain, respondents with CHCs reported a greater number of activities prevented because of chronic disruptive pain (chi2=222.28, p<0.001). Similarly, in logistic regression models, participants with CHCs had greater odds of reporting chronic disruptive pain (OR=4.94, 95% CI=4.08-5.99). Alcohol (beta=-0.66; p=0.025) and drug abuse/dependence disorders (beta=-1.24; p=0.012) were found to moderate the association between CHCs and chronic disruptive pain. Specifically, the probability of chronic disruptive pain was higher for emerging adults without CHCs and with alcohol or drug disorders; however, among participants with CHCs, probability was higher for those without these disorders. CONCLUSIONS: There is a robust association between CHCs and chronic disruptive pain. The moderating effects suggest that alcohol or drug disorders are especially harmful for emerging adults without CHCs and contribute to higher levels of chronic disruptive pain; however, among those with CHCs, alcohol and illicit drugs may be used as a numbing agent to blunt chronic disruptive pain. IMPLICATIONS: Findings from this study have implications for the integration and coordination of services to design strategies aimed at managing chronic disruptive pain and preventing pain-related disabilities later in life. Within the health system, healthcare providers should engage in dialogues about mental health and substance use regularly with emerging adults, be proactive in screening for psychiatric disorders, and continue to monitor the impact of pain on daily functioning. Given the age range of emerging adults, there is tremendous opportunity for clinicians to work cooperatively with colleagues in the education system to support emerging adults with and without CHCs. Overall, clinicians, researchers, educators, and those in social services should continue to be mindful of the complex interrelationships between physical and mental health and chronic disruptive pain and work cooperatively to optimize health outcomes and prevent pain-related disabilities among emerging adults. PMID- 28850371 TI - Management of patients with pain and severe side effects while on intrathecal morphine therapy: A case study. AB - BACKGROUND AND AIMS: The use of intrathecal morphine therapy has been increasing. Intrathecal morphine therapy is deemed the last resort for patients with intractable chronic non-cancer pain (CNCP) who failed other treatments including surgery and pharmaceutical interventions. However, effective treatments for patients with CNCP who "failed" this last resort because of severe side effects and lack of optimal pain control remain unclear. METHODS AND RESULTS: Here we report two successfully managed patients (Ms. S and Mr. T) who had intractable pain and significant complications years after the start of intrathecal morphine therapy. The two patients had intrathecal morphine pump implantation due to chronic consistent pain and multiple failed surgical operations in the spine. Years after morphine pump implantation, both patients had significant chronic pain and compromised function for activities of daily living. Additionally, Ms. S also had four episodes of small bowel obstruction while Mr. T was diagnosed with end stage severe "dementia". The successful management of these two patients included the simultaneous multidisciplinary approach for pain management, opioids tapering and discontinuation. CONCLUSION: The case study indicates that for patients who fail to respond to intrathecal morphine pump therapy due to side effects and lack of optimal pain control, the simultaneous multidisciplinary pain management approach and opioids tapering seem appropriate. PMID- 28850372 TI - Behavioral inhibition, maladaptive pain cognitions, and function in patients with chronic pain. AB - BACKGROUND AND AIMS: Trait behavioral inhibition represents a tendency to react with negative emotions - primarily worry - to cues which signal potential threats. This tendency has been hypothesized by a two-factor model of chronic pain to have direct effects on psychological and physical function in individuals with chronic pain, as well as to influence the associations between pain-related maladaptive cognitions and function. Our aim was to test these hypothesized associations in a sample of individuals who were being screened for possible interdisciplinary chronic pain treatment. METHODS: Eighty-eight patients referred to an interdisciplinary chronic pain management program were administered measures of average pain intensity, trait behavioral inhibition, kinesiophobia, pain catastrophizing, depressive symptoms, and pain interference. We then performed two linear regression analyses to evaluate the direct effects of trait behavioral inhibition on depressive symptoms and pain interference and the extent to which behavioral inhibition moderated the associations between kinesiophobia and pain catastrophizing, and the criterion variables. RESULTS: In partial support of the study hypotheses, the results showed significant (and independent) direct effects of trait behavioral inhibition on depressive symptoms, and behavioral inhibition moderated the association between kinesiophobia and depression, such that there were stronger associations between kinesiophobia and depressive symptoms in those with higher dispositional sensitivity to fear inducing stimuli. However, neither direct nor moderating effects of behavioral inhibition emerged in the prediction of pain interference. CONCLUSIONS: If replicated in additional studies, the findings would indicate that chronic pain treatments which target both reductions in maladaptive cognitions (to decrease the direct negative effects of these on depressive symptoms) and the individual's tendency to respond to pain with worry (as a way to buffer the potential effects of maladaptive cognitions on depressive symptoms) might be more effective than treatments that targeted only one of these factors. IMPLICATIONS: Additional research is needed to further evaluate the direct and moderating effects of pain related behavioral inhibition on function, as well as the extent to which treatments which target behavioral inhibition responses provide benefits to individuals with chronic pain. PMID- 28850373 TI - Comparison of patients diagnosed with "complex pain" and "somatoform pain". AB - BACKGROUND AND AIM: Chronic pain conditions can be diagnosed and treated in both somatic and psychiatric settings. It is still a discussed and unanswered question whether the two groups of patients differ. The purpose of this short article is to inform further reflections concerning the classifications of somatoform pain and complex pain. METHOD: Sociodemographic and questionnaire data concerning anxiety and depression, perceived injustice, well-being, and levels of psycho physiological functioning were compared for patients diagnosed with complex pain (somatic diagnosis) at a pain clinic and somatoform pain (psychiatric diagnosis) at a Liaison-psychiatric clinic. RESULTS: Very little differences were found between patients with complex pain (N=162) and somatoform conditions (N=89). Both patient groups were seriously impaired both physically and mentally. CONCLUSION: These comparisons lend support to the viewpoint of non-segregation of somatoform and complex pain. IMPLICATIONS: Pain treatment might be better-managed in common multidisciplinary centers with specialists in both pain treatment and psychiatric aid. PMID- 28850374 TI - Patient perspectives on wait times and the impact on their life: A waiting room survey in a chronic pain clinic. AB - BACKGROUND AND AIMS: Chronic pain is a debilitating condition that requires prompt access to care for effective treatment. Wait times for care often exceed benchmark recommendations, with potential consequences to patient health outcomes. The goal of this paper is to gain the perspectives of patients attending a chronic pain clinic regarding the acceptability of current wait times and the impact of their experiences of waiting for chronic pain care. METHODS: The study took place in a chronic pain clinic at an academic-affiliated teaching hospital in Ottawa, Canada, which housed seven clinicians at the time of the study. New patients attending the chronic pain clinic between July 14, 2014 and August 5, 2015 were eligible to participate based on the availability of the research and clerical staff who administered the survey on a variety of days over the course of the study. Patients completed a self-administered 29-item survey. The survey took approximately five to ten minutes to complete. Questions pertained to patients' socioeconomic factors, chronicity and burden of pain symptoms, and satisfaction with current wait times. Actual wait times were self reported. Survey results were entered into an Excel spreadsheet, exported to SPSS, and coded numerically to facilitate descriptive analyses using comparative graphs and tables. Open-text responses were reviewed by the authors. RESULTS: Sixty-six patients completed the survey. While 83% of patients stated that their ideal wait time was less than three months, 32% reported receiving an appointment within this period, and 31% reported waiting a year or more. Only 37% of patients felt the wait time for their appointment was appropriate. During their wait, 41% of patients reported receiving written information about chronic pain and 47% were referred to a local chronic pain management group. 94% reported interference with social/recreational activities and normal activities of daily living, 31% had to miss work or school due to the frequency of ongoing symptoms, and 22% reported being unable to attend work or school altogether. Furthermore, 37% of patients reported visiting the emergency room within the previous year and 65% worried about having a serious undiagnosed disease. CONCLUSIONS: Our study found that wait times for chronic pain care, even those triaged as urgent cases, far exceeded what patients considered ideal. Only a third of patients received care within three months of making their appointment, while nearly another third waited over a year. During the waiting period, nearly all patients experienced some impact on their day-to-day activities and work or school attendance, half were unemployed, and nearly a quarter reported a complete inability to attend work or school because of pain. IMPLICATIONS: Wait times for chronic pain care exceed timelines deemed acceptable by patients, causing anxiety and reducing function. The patient perspective must be considered in initiatives attempting to improve access to care for this population with specific needs and goals. Innovative solutions, such as electronic consultation and shared care models, hold promise. PMID- 28850375 TI - New evidence for a pain personality? A critical review of the last 120 years of pain and personality. AB - BACKGROUND: Personality traits may influence development and adjustment to ongoing pain. Over the past 120 years, there has been considerable research into the relationship between pain and personality. This paper presents new evidence for common personality traits found amongst chronic pain sufferers. In particular, it evaluates evidence for Cloninger's biopsychosocial model of personality in distinguishing typical personality features of chronic pain sufferers. It evaluates this evidence in the context of the past 120 years of research including psychodynamic formulations, MMPI studies, personality disorder investigations, and the influence of neuroticism on chronic pain. METHODS: A literature search was conducted using PubMed, Medline, PsycINFO, SCOPUS and Cochrane library. Search terms included chronic pain, pain, personality, neuroticism, harm avoidance, self-directedness, attachment, Temperament and Character Inventory (TCI-R), MMPI, MMPI-2, NEO-PI, EPI, Millon Clinical Multiaxial Inventory, Millon Behavioral Health Inventory, Millon Behavioral Medicine Diagnostic, the Personality Assessment Inventory, the Locus of Control Construct and different combinations of these terms. CONCLUSIONS: Recent descriptive studies using Cloninger's Temperament and Character Inventory (TCI-R) suggest that higher harm avoidance and lower self-directedness may be the most distinguishing personality features of chronic pain sufferers. High harm avoidance refers to a tendency to be fearful, pessimistic, sensitive to criticism, and requiring high levels of re-assurance. Low self-directedness often manifests as difficulty with defining and setting meaningful goals, low motivation, and problems with adaptive coping. Evidence for this personality profile is found across a wide variety of chronic pain conditions including fibromyalgia, headache and migraine, temporomandibular disorder, trigeminal neuropathy, musculo-skeletal disorders and heterogeneous pain groups. Limitations are also discussed. For example, high harm avoidance is also found in those suffering anxiety and depression. While many studies control for such factors, some do not and thus future research should address such confounds carefully. The evidence is also evaluated within the context of past research into the existence of 'a pain personality'. Psychodynamic formulations are found to be deficient in objective scientific methods. MMPI studies lack sufficient evidence to support 'a pain personality' and may be confounded by somatic items in the instrument. More recent neuroticism studies suggest a relationship between neuroticism and pain, particularly for adjustment to chronic pain. Personality disorders are more prevalent in chronic pain populations than non-pain samples. CLINICAL IMPLICATIONS: Because harm avoidance reflects a tendency to developed conditioned fear responses, we suggest that higher harm avoidance may create more vulnerability to developing a fear-avoidance response to chronic pain. Furthermore, lower self-directedness may contribute to keeping a sufferer within this vicious cycle of fear, avoidance and suffering. Moreover, we suggest that harm avoidance and self-directedness are broader and more complex constructs than current clinical targets of CBT such as fear-avoidance and self-efficacy. Thus, assessing such personality traits may help to address the complexity of chronic pain presentations. For example, it may help to identify and treat sufferers more resistant to treatment, more prone to comorbidity and more vulnerable to entering the vicious cycle of chronic pain, suffering and disability. PMID- 28850376 TI - A multi-facet pain survey of psychosocial complaints among patients with long standing non-malignant pain. AB - BACKGROUND AND AIMS: Psychometric inventories and scales intended to measure cognitive, emotional and behavioural concomitants of pain are typically constructed by deducting items from theoretically derived concepts related to pain states, e.g. social support, perceived control, depressiveness, and catastrophizing. The aim of this study was to design a clinically useful, generic pain distress inventory - The Multi-Facet Pain Survey (MFPS) - inductively derived from psychological and social complaints reported by a study group of individuals with severe chronic nonmalignant pain. METHODS: Extensive clinical interviews with hospitalized chronic pain patients were made by clinical psychologists. The purpose was to highlight the patients' pain histories and their beliefs and feelings about the pain, and to determine factors possibly influencing their rehabilitation potential. The types of distress reported were sorted into categories with a procedure similar to content analysis. Distress reports were converted to statements, forming items in a questionnaire, the Multi Facet Pain Survey. RESULTS: Our analyses supported a distress structure including 15 categories, or "facets", comprising in all 190 types of psychosocial distress. Ten of the facets denote beliefs about the present condition and aspects of distress experienced in daily life (e.g. cognitive problems); three facets reflect the illness history, and two the patient's views on future prospects. To improve the clinical utility, we shortened the scale into a 53 items inventory. A factor analysis of these 53 items revealed four clinically meaningful factors: (1) stress-related exhaustion; (2) impact of pain on daily life; (3) self inefficacy in regard to future prospects; and (4) negative experiences of health care. While the second factor represents distress directly related to the pain, the first factor reflects long-term exhaustion effects of the pain condition similar to those seen in individuals exposed to long periods of stress. Items loading in the third factor reflect a pessimistic outlook on the future. The content validity of the scale was explored by predicting and testing correlations between the 15 MFPS facets, and the Symptom Checklist (SCL-90) and the West Haven Yale Multidimensional Pain Inventory (MPI). Some of the MFPS facets showed little or no agreement with any of the subscales of the comparison measures. The homogeneity was satisfactory both for facets and factors. CONCLUSIONS: The Multi Facet Pain Survey (MFPS) facets cover a broad array of experienced psychosocial distress in patients with severe, longstanding pain. Some facets of psychosocial impact of longstanding pain states shown in the qualitatively derived distress facets, or by the latent factors found in the factor analysis, may complement our understanding of the long-term impact of pain. Consequently, MFPS may improve the assessment of psychological and social complaints and complications in patients with chronic pain. IMPLICATIONS: The MFPS will hopefully be an assessment tool supporting the psychological contribution to a biopsychosocial evaluation of patients with severe, longstanding pain. By exposing a broad range of suffering, MFPS may contribute to alternative treatment options and a better prognosis of future rehabilitation. PMID- 28850377 TI - Pain patients' experiences of validation and invalidation from physicians before and after multimodal pain rehabilitation: Associations with pain, negative affectivity, and treatment outcome. AB - BACKGROUND AND AIMS: Validating and invalidating responses play an important role in communication with pain patients, for example regarding emotion regulation and adherence to treatment. However, it is unclear how patients' perceptions of validation and invalidation relate to patient characteristics and treatment outcome. The aim of this study was to investigate the occurrence of subgroups based on pain patients' perceptions of validation and invalidation from their physicians. The stability of these perceptions and differences between subgroups regarding pain, pain interference, negative affectivity and treatment outcome were also explored. METHODS: A total of 108 pain patients answered questionnaires regarding perceived validation and invalidation, pain severity, pain interference, and negative affectivity before and after pain rehabilitation treatment. Two cluster analyses using perceived validation and invalidation were performed, one on pre-scores and one on post-scores. The stability of patient perceptions from pre- to post-treatment was investigated, and clusters were compared on pain severity, pain interference, and negative affectivity. Finally, the connection between perceived validation and invalidation and treatment outcome was explored. RESULTS: Three clusters emerged both before and after treatment: (1) low validation and heightened invalidation, (2) moderate validation and invalidation, and (3) high validation and low invalidation. Perceptions of validation and invalidation were generally stable over time, although there were individuals whose perceptions changed. When compared to the other two clusters, the low validation/heightened invalidation cluster displayed significantly higher levels of pain interference and negative affectivity post treatment but not pre-treatment. The whole sample significantly improved on pain interference and depression, but treatment outcome was independent of cluster. Unexpectedly, differences between clusters on pain interference and negative affectivity were only found post-treatment. This appeared to be due to the pre- and post-heightened invalidation clusters not containing the same individuals. Therefore, additional analyses were conducted to investigate the individuals who changed clusters. Results showed that patients scoring high on negative affectivity ended up in the heightened invalidation cluster post-treatment. CONCLUSIONS: Taken together, most patients felt understood when communicating with their rehabilitation physician. However, a smaller group of patients experienced the opposite: low levels of validation and heightened levels of invalidation. This group stood out as more problematic, reporting greater pain interference and negative affectivity when compared to the other groups after treatment. Patient perceptions were typically stable over time, but some individuals changed cluster, and these movements seemed to be related to negative affectivity and pain interference. These results do not support a connection between perceived validation and invalidation from physicians (meeting the patients pre- and post-treatment) and treatment outcome. Overall, our results suggest that there is a connection between negative affectivity and pain interference in the patients, and perceived validation and invalidation from the physicians. IMPLICATIONS: In clinical practice, it is important to pay attention to comorbid psychological problems and level of pain interference, since these factors may negatively influence effective communication. A focus on decreasing invalidating responses and/or increasing validating responses might be particularly important for patients with high levels of psychological problems and pain interference. PMID- 28850378 TI - Prospective, double blind, randomized, controlled trial comparing vapocoolant spray versus placebo spray in adults undergoing intravenous cannulation. AB - OBJECTIVES: Painful diagnostic and therapeutic procedures are common in the health care setting. Eliminating, or at least, minimizing the pain associated with various procedures should be a priority. Although there are many benefits of providing local/topical anesthesia prior to performing painful procedures, ranging from greater patient/family satisfaction to increased procedural success rates; local/topical anesthetics are frequently not used. Reasons include the need for a needlestick to administer local anesthetics such as lidocaine and the long onset for topical anesthetics. Vapocoolants eliminate the risks associated with needlesticks, avoids the tissue distortion with intradermal local anesthetics, eliminates needlestick pain, have a quick almost instantaneous onset, are easy to apply, require no skills or devices to apply, are convenient, and inexpensive. The aims of this study were to ascertain if peripheral intravenous (PIV) cannulation pain would be significantly decreased by using a vapocoolant (V) versus sterile water placebo (S) spray, as determined by a reduction of at least >=1.8 points on numerical rating scale (NRS) after vapocoolant versus placebo spray, the side effects and incidence of side effects from a vapocoolant spray; and whether there were any long term visible skin abnormalities associated with the use of a vapocoolant spray. MATERIALS AND METHODS: Prospective, randomized, double-blind controlled trial of 300 adults (ages 18-80) requiring PIV placement in a hospital ED, randomized to S (N=150) or V (N=150) prior to PIV. Efficacy outcome was the difference in PIV pain: NRS from 0 (none) to worst (10). Safety outcomes included a skin checklist for local adverse effects (i.e., redness, blanching, edema, ecchymosis, itching, changes in skin pigmentation), vital sign (VS) changes, and before/after photographs of the PIV site. RESULTS: Patient demographics (age, gender, race), comorbidity, medications, and vital signs; and PIV procedure variables (e.g., IV needle size, location, number of IV attempts, type and experience of healthcare provider performing the IV) were not significantly different for the two groups. Median (interquartile range) PIV pain was 4 (2, 7) (S) and 2 (0, 4) (V) (P<0.001). Skin checklist revealed minimal erythema: S 0% (N=0/150), V: 2.7% (4/150), which resolved within 5min, and no blanching, skin pigmentation changes, itching, edema, or ecchymosis. Photographs at 5-10min revealed no visible skin changes in any patient (N=300), vapocoolant (N=150) or placebo groups (N=150). Complaints (N=26) were coolness/cold feeling S 8.7% (N=13), V 7.3% (N=11), coolness/numbness S 0% (N=0), V 0.7% (N=1), and burning S 0.7% (N=1), V 0 (0%). Patient acceptance of the vapocoolant spray was high: 82% (123/150) of the patients stated they would use the spray in the future, while only 40.7% (61/150) of the placebo group stated they would use the placebo spray in the future. CONCLUSIONS AND IMPLICATIONS: Vapocoolant spray significantly decreased peripheral intravenous cannulation pain in adults versus placebo spray and was well tolerated with minor adverse effects that resolved quickly. There were no significant differences in vital signs and no visible skin changes documented by photographs taken within 5 10min postspray/PIV. PMID- 28850379 TI - Long-term treatment in chronic noncancer pain: Results of an observational study comparing opioid and nonopioid therapy. AB - BACKGROUND AND AIMS: Recent studies reveal high prevalence rates of patients receiving long-term opioids. However, well designed studies assessing effectiveness with longer than 3 months follow-up are sparse. The present study investigated the outcomes of long-term opioid therapy compared to nonopioid treatment in CNCP patients with respect to measures of pain, functional disability, psychological wellbeing, and quality of life (QoL). METHODS: Three hundred and thirty three consecutive patients at our pain clinic were included and divided into patients with continuous opioid treatment for at least 3 months (51%) and patients receiving nonopioid analgesics (49%). Further, outcome of different doses of opioid (<120mg vs. >120mg morphine equivalents) and differences between high and low potency opioids were examined. RESULTS: The opioid and nonopioid groups did not differ with regard to pain intensity or satisfaction with analgesic. Patients with continuous opioids treatment reported higher neuropathic like pain, longer duration of pain disorder, lower functional level, wellbeing, and physical QoL in comparison to patients receiving nonopioid analgesics. Higher opioid doses were associated with male gender, intake of high potency opioids and depression but there were no differences with regard to pain relief or improvement of functional level between high and low doses. Similarly, patients on high potency opioids reported more psychological impairment than patients on low potency opioids but no advantage with regard to pain relief. Overall, remaining level of pain, functional disability and poor QoL were quite high irrespective of the analgesic used or opioid dosing. CONCLUSION: In the long term no clear advantage of opioid vs. non-opioid analgesics could be revealed. In terms of remaining pain intensity, functional disability and quality of life, treatment with pain medication proved insufficient. Additionally, with higher doses of opioids the benefit to risk relationship becomes worse and patients on high potency opioids reported more psychological impairment than patients on low potency opioids but no advantage with regard to pain relief. IMPLICATIONS: Our results raise questions about the long-term effectiveness of analgesic treatment regimens irrespective of analgesics type employed and call for more multidisciplinary treatment strategies. PMID- 28850380 TI - COMBAT study - Computer based assessment and treatment - A clinical trial evaluating impact of a computerized clinical decision support tool on pain in cancer patients. AB - BACKGROUND AND AIMS: The prevalence of pain in cancer patients are relatively high and indicate inadequate pain management strategies. Therefore, it is necessary to develop new methods and to improve implementation of guidelines to assess and treat pain. The vast improvement in information technology facilitated development of a computerized symptom assessment and decision support system (CCDS) - the Combat system - which was implemented in an outpatient cancer clinic to evaluate improvement in pain management. METHODS: We conducted a controlled before-and-after study between patient cohorts in two consecutive study periods: before (n=80) and after (n=134) implementation of the Combat system. Patients in the first cohort completed questionnaires with the paper-and-pencil method and this data was not shown to physicians. Patients in the latter cohort completed an electronic questionnaire by using an iPad and the data were automatically transferred and presented to physicians at point of care. Additionally, the system provided computerized decision support at point of care for the physician based on the electronic questionnaires completed by the patients, an electronic CRF completed by physicians and clinical guidelines. RESULTS: The Combat system did not improve pain intensity and there were no significant alterations in the prescribed dose of opiates compared to the cohort of patients managed without the Combat system. CONCLUSION: The Combat system did not improve pain management. This may be explained by several factors, however, we consider lack of proper implementation of the CCDS in the clinic to be the most important factor. As a result, we did not manage to change the behaviour of the physicians in the clinic. IMPLICATIONS: There is a need to conduct larger prospective studies to evaluate the efficacy of modern information technology to improve pain management in cancer patients. Before introducing new information technology in the clinics, it is important to have a well thought out implementation strategy. The trial is registered at Clinialtrials.gov, number NCT01795157. PMID- 28850381 TI - Effect of intrathecal glucocorticoids on the central glucocorticoid receptor in a rat nerve ligation model. AB - BACKGROUND AND AIMS: Despite widespread use, the efficacy of neuraxial glucocorticoids for neuropathic pain is subject to debate. Since most glucocorticoid actions are mediated through its receptor, we explored the effects of intrathecal methylprednisolone acetate (MPA) on total glucocorticoid receptor (tGR) levels and activation of the glucocorticoid receptor (phosphorylated state=pGR) within the spinal dorsal horn (SDH) and dorsal root ganglion (DRG) in a spinal nerve ligation (SNL) model in rats. METHODS: Rats received unilateral ligation of the L5/L6 spinal nerves and were treated with two intrathecal doses of either 400MUg MPA or 0.9% saline with a 72-h interval. Plantar tactile thresholds were measured over time. Seven days after drug treatment, DRG and SDH were harvested to assess tGR and pGR levels using immunohistochemistry and qPCR. RESULTS: Allodynia, defined by lowered tactile withdrawal thresholds after SNL, was unaltered by intrathecal MPA. In saline controls, mRNA levels of tGR did not change after SNL in the DRGs or SDH. tGR and pGR protein levels in the SDH however, significantly increased on the ipsilateral side of SNL compared to the contralateral side and to naive tissue. When treating rats with MPA, tGR mRNA levels were significantly reduced in the SDH compared to saline controls. tGR and pGR protein levels, however were not significantly lower compared to saline controls. CONCLUSIONS: In intrathecal MPA treated rats, tGR mRNA levels decreased after SNL. However this did not result in lower tGR and pGR protein levels compared to saline controls, and did not decrease ligation-induced mechanical hypersensitivity. IMPLICATIONS: Intrathecal MPA treatment after SNL did not result in lower tGR and pGR levels within the SDH and DRG compared to saline controls. In present study we did not differentiate between the various isoforms of the GR which might clarify this finding. PMID- 28850382 TI - Salience, central executive, and sensorimotor network functional connectivity alterations in failed back surgery syndrome. AB - OBJECTIVE: This study examined the altered patterns of functional connectivity in task-positive resting state networks in failed back surgery syndrome (FBSS) patients compared to healthy controls using functional magnetic resonance imaging (fMRI). This work stems from a previous study in which alterations in the task negative default mode network were investigated. DESIGN: Participants underwent a 7-minute resting state fMRI scan in which they lay still, with eyes closed, in the absence of a task. SETTING: Scanning took place at the National Research Council's 3Tesla MRI magnet in Winnipeg, Canada. SUBJECTS: Fourteen patients with FBSS and age- and gender-matched controls participated in this study. Three patients were removed from the analyses due to image artefact (n=1) and effective pain treatment (n=2). Eleven patients (5 female, mean age 52.7 years) and their matched controls were included in the final analyses. METHODS: Resting state fMRI data were analyzed using an independent component analysis, yielding three resting state networks of interest: the salience network (SN), involved in detection of external stimuli, central executive network (CEN), involved in cognitions, and sensorimotor network (SeN), involved in sensory and motor integration. Analysis of Variance contrasts were performed for each network, comparing functional connectivity differences between FBSS patients and healthy controls. RESULTS: Alterations were observed in all three resting state networks, primarily relating to pain and its processing in the FBSS group. Specifically, compared to healthy controls, FBSS patients demonstrated increased functional connectivity in the anterior cingulate cortex within the SN, medial frontal gyrus in the CEN, and precentral gyrus within the SeN. FBSS patients also demonstrated decreased functional connectivity in the medial frontal gyrus in the SeN compared to healthy controls. Interestingly, we also observed internetwork functional connectivity in the SN and SeN. CONCLUSIONS: FBSS is associated with altered patterns of functional connectivity in the SN, CEN, and SeN. Taken together with our previous work, this reveals that a chronic pain condition can have a dramatic effect on the connectivity of multiple resting state networks. IMPLICATIONS: These data suggest that a chronic pain condition-FBSS-is associated with disruptions to networks of functional connectivity in brain areas that are involved in numerous functions, including pain processing, sensation, and movement. It is possible that the alterations in these networks may contribute to other common chronic pain comorbidities, such as disrupted cognitions or anxiety. Previous research shows that during experimentally-induced pain, these networks can return to initial levels of functioning, indicating that these functional alterations are likely not permanent. PMID- 28850383 TI - The effects of a brief educational intervention on medical students' knowledge, attitudes and beliefs towards low back pain. AB - BACKGROUND AND AIMS: Knowledge, attitudes and beliefs towards low back pain (LBP) can significantly impact a health care provider's clinical decision making. Several studies have investigated interventions designed to change practitioner attitudes and beliefs towards LBP, however no such studies involving medical students have been identified. METHODS: This study explored medical students' knowledge, attitudes and beliefs towards LBP before and after a brief educational intervention on LBP. Responses from medical students (n=93) were evaluated before and after a 15-min educational video on back pain. The intervention was developed using CamtasiaTM video editor and screen recorder. Knowledge, attitudes and beliefs were measured using the "Modified Back Beliefs Questionnaire", with items from two previously reported questionnaires on back beliefs. The questionnaire asks participants to indicate their agreement with statements about LBP on a 5 point Likert scale. Preferred responses were based on guidelines for the evidence based management of LBP. The primary analysis evaluated total score on the nine inevitability items of the Back Beliefs Questionnaire ("inevitability score"). RESULTS: Following the brief intervention there was a significant improvement in the inevitability score (post-workshop mean [SD] 20.8 [4.9] vs pre-workshop mean [SD] 26.9 [4.2]; mean difference (MD) 6.1, p<0.001; lower score more favourable1) and large improvements in the proportion of students providing correct responses to items on activity (pre: 49% vs post: 79%), bed rest (41% vs 75%), imaging (44% vs 74%) and recovery (25% vs 66%). CONCLUSIONS: After watching the educational video students' knowledge, beliefs and attitudes towards LBP improved and thus aligned more closely with evidence-based guidelines. IMPLICATIONS: Medical doctors are at the forefront of managing low back pain in the community, however there is a need to strengthen musculoskeletal education in medical training programmes. The results from this research suggest educational interventions on back pain do not need to be extensive in order to have favourable outcomes on medical students' knowledge, attitudes and beliefs towards back pain. The translational effects of these changes into clinical practice are not known. PMID- 28850384 TI - Pain anxiety and fear of (re)injury in patients with chronic back pain: Sex as a moderator. AB - BACKGROUND AND AIMS: Anxiety and fear are increasingly seen as related, but distinct concepts, with anxiety describing a reaction to unclear or future threats, and fear to immediate threats. Anxiety and fear both play influential roles in pain. Yet, the two concepts have not been clearly distinguished in pain research. Their reported intensity differs between the sexes, and sex differences in the way pain anxiety and fear of (re)injury relate to pain intensity have been found separately in previous studies. However, they seem to be of a curious nature: In one study, pain anxiety was associated with elevated pain intensity in men, while in another, fear of (re)injury was associated with elevated pain intensity in women. This indicates a moderator effect of sex. The present study is the first to unite previous findings, and to show a more integrative picture, by examining and discussing this moderator effect of sex in a joint study of both pain-related anxiety and fear in both sexes. METHODS: In 133 patients (mean age 43.6 years, 62% female) with chronic low back pain (mean duration 7.7 years), sex differences were examined with correlations and a multiple linear regression analysis with interaction terms. Differences between subgroups of low and high anxiety/fear were explored via t-tests, following previous studies. RESULTS: Sex was supported as a moderator in the association of pain intensity with pain anxiety (PASS-20), and fear of (re)injury (TSK). Higher pain intensity was linked to higher pain anxiety only in men, and to higher fear of (re)injury only in women. A basic regression model with fear, anxiety, sex and disability as predictors (R2=.14, F(4,123)=3.24, p=.042) was significantly improved by the addition of the interaction terms Fear*Sex and Anxiety*Sex (R2=.18, F(2,121)=4.90, p=.001), which were both shown as significant predictors for pain intensity. Further t-tests revealed a significant difference in pain intensity between high and low anxiety in men (t(47)=-2.34, p=.023, d=-.43), but not in women. Likewise, a significant difference in pain intensity between high and low fear showed in women (t(80)=-2.28, p=.025, d=-.42), but not in men. CONCLUSIONS: The results support a moderator effect of sex and suggest differential mechanisms between the sexes in pain anxiety and fear in development and maintenance of back pain. The current study is the first to report and analyse this moderator effect. As potential underlying mechanisms, evolution and socialization are discussed, which may elucidate why fear might be more relevant for pain in women, and anxiety more relevant for pain in men. IMPLICATIONS: The results indicate the need for a more cautious conceptual separation of fear and anxiety in research. Future studies on fear and anxiety in pain should be aware of the distinction, in order to avoid reporting only half of the picture. The next step would be to solidify the results in different samples, and to examine whether a distinction between anxiety and fear in the sexes could have any benefit in pain treatment. PMID- 28850385 TI - Intraoral QST - Mission impossible or not? PMID- 28850386 TI - The association between adolescent and parental use of non-prescription analgesics for headache and other somatic pain - A cross-sectional study. AB - BACKGROUND AND PURPOSE: Over the last years, concern has been expressed about adolescents' possible liberal attitude towards - and use of - non-prescription analgesics. A high consumption of analgesics is unfortunate as it may lead to various harmful effects and worsening of headache. In order to address this challenge, it is necessary to achieve a more extensive knowledge about adolescent consumption. The main aim of this study was to examine the association between adolescent and parental use of non-prescription analgesics, taking into account headache as well as other somatic pain. The effects of parental prescription analgesics use was a secondary aim. METHODS: The study is based on data from two cross-sectional health studies conducted in 2005 and 2012 in Norway, including 646 adolescents and an accompanying parent. By using sample weights, the final weighted sample used in the analysis was 1326. Data was collected through postal questionnaires to parents and adolescents as well as parental telephone interviews. Questionnaires included questions on different pain locations and the pain for each location was graded according to how troubling the pain was. Medication data on prescription and non-prescription analgesics was from telephone interviews and was quantified based on the pattern over the past 4 weeks. Multivariate logistic regression models and complex samples analyses were used. RESULTS: 20% of adolescents were reported as using non-prescription analgesics during the previous 4 weeks. Girls were more often reported to use non prescription analgesics than boys. Headache and all other somatic pain locations except back pain were reported more frequently among girls while boys more frequently reported back pain. There was a clear association between the use of non-prescription analgesics and headache with 34% of adolescents with headache using non-prescription analgesics versus 19% of adolescents with other somatic pain and 14% of adolescents not reporting pain. Among adolescents reporting headache, 9% were reported to use non-prescription analgesics daily or almost daily versus 3% and 2% among those reporting other somatic pain and reporting no pain respectively. In addition, parental use of non-prescription analgesics was a strong independent predictor of adolescent use (adjusted OR 1.69 for boys, 1.54 for girls). This relationship increased when the adolescents were less bothered by headache themselves. CONCLUSION: Headache is the dominant medication-driving pain for non-prescription analgesics among adolescents but parental medication use of non-prescription analgesics also strongly influences adolescent use. IMPLICATIONS: There is a need for health services to improve information to parents and adolescents about risks associated with use of analgesics and also to work on prophylactic strategies focusing on adolescents. Parents should be made aware that their medicine use strongly influences that of their children. PMID- 28850387 TI - The association between pain characteristics, pain catastrophizing and health care use - Baseline results from the SWEPAIN cohort. AB - BACKGROUND AND AIM: Pain is common and adds to the global burden of disease. However, individuals suffering from pain are a heterogeneous group in terms of pain spreading, intensity and duration. While pain influences overall health care consultation not everyone with pain consult health care. To be able to provide health care matching the patients' needs increased knowledge about what factors determines the decision to consult health care is essential. The aim of this study was to explore the combined importance of pain spreading, intensity, duration and pain catastrophizing for consulting health care. METHODS: In this cross-sectional study we used population based survey data from southeast Sweden (SWEPAIN) including 7792 individuals' aged 16-85 reporting pain. We used Modified Poisson regressions to analyse factors of importance related to the decision to consult health care. RESULTS: High and moderate pain intensity, as compared to low, increases the probability of consulting health care (High PR=1.7 [95% CI 1.51-1.88], moderate PR=1.2 [1.15-1.41]). Having widespread pain, as compared to localised pain, increased the probability of consulting health (PR=1.2 [1.03 1.36). Pain duration was not associated with increased probability of consulting health care (PR=1.0 CI0.88-1.07). However an interaction (p=0.05) between pain duration and pain catastrophizing beliefs was seen indicating a combined importance of the two when consulting health care. CONCLUSION: Our result suggests that pain intensity, pain spreading and pain catastrophizing independently influence the decision to consult health care while there is an interaction effect between pain duration and pain catastrophizing beliefs where the importance of pain catastrophizing believes differ with pain duration; the importance of pain catastrophizing believes differ with pain duration. IMPLICATIONS: Treatment and rehabilitation strategies should incorporate this finding in order to meet the individual's needs focusing on the biopsychosocial model within health care focusing not only on actual pain reliefs but also on for example acceptance and behavioural changes. PMID- 28850388 TI - Cerebral oxygenation for pain monitoring in adults is ineffective: A sequence randomized, sham controlled study in volunteers. AB - BACKGROUND: Pain assessment by Numeric Rating Scale (NRS) is considered to be good clinical practice, but objective pain assessment is still a challenge. Near infrared spectroscopy (NIRS) measures cerebral tissue oxygen saturation (SctO2) that increases with cortical-neuronal activity and may provide point-of-care bedside pain monitoring. Analogous to promising studies in newborns, we hypothesize that different levels of SctO2 can probably quantify pain intensity. SctO2 may increase following painful in contrast to non-painful or sham stimuli and may correlate with pain intensity as assessed by NRS in volunteers. METHODS: Twenty healthy male students (24.2+/-1.9 years), recruited via local advertising, were consecutively included in a sequence-randomized, sham-controlled, single blinded study. SctO2 was recorded continuously with two NIRS sensors on the forehead. After resting, four stimuli were applied in a random order on the right forearm (unexpected and expected electrical pain, expected non-painful and sham stimuli). Blinded subjects were asked to rate each stimulus on NRS. STATISTICS: RM-ANOVA; Wilcoxon or paired Student t-test; Spearman's rank correlation; P<.05. RESULTS: Resting volunteers showed SctO2 of 72.65%+/-3.39. SctO2 significantly increased for about 60 to 70s until a maximum after unexpected painful (74.62%+/ 3.9; P=.022) and sham stimuli (74.07%+/-3.23; P=.014). Expected painful (P=.139) and non-painful stimuli (P=.455) resulted in no changes in SctO2. NRS scores (median, IQR) were rated significantly higher after expected (5.25, 3.5 to 6.75) than after unexpected (4.5, 3 to 5; P=.008) pain. No strong correlation was found between NRS and SctO2. CONCLUSIONS AND IMPLICATIONS: Contrary to our expectations, measuring SctO2 via a two-channel NIRS is not able to remediate the lack of objective bedside pain assessment under standardized experimental conditions in alert adults. TRIAL REGISTRATION: DRKS 00011575 (retrospectively registered). PMID- 28850389 TI - Objective measurement of subjective pain-experience: Real nociceptive stimuli versus pain expectation. PMID- 28850390 TI - Association between adolescent and parental use of analgesics. PMID- 28850391 TI - Spinal analgesia for severe cancer pain: A retrospective analysis of 60 patients. AB - BACKGROUND AND AIMS: Pain is highly prevalent in advanced cancer, and in some patients refractory to conventional opioid treatment. For these patients, invasive methods of pain relief should be considered. Spinal administration of opioids has been shown to be an effective alternative in refractory cancer pain. The aim of this retrospective study was to collect information on the use of spinal analgesia for cancer pain in Helsinki University Hospital. METHODS: A retrospective patient chart study of all cancer patients with spinal analgesia, either intrathecal or epidural, in a single academic center during a five year period (n=60). RESULTS: Forty-four patients were treated with intrathecal (IT) and sixteen with epidural (EP) technique. The most common indication for spinal analgesia was pain refractory to systemic analgesics. Good analgesia was achieved in 50% and 70% of the patients in the EP and IT groups, respectively. The median daily systemic opioid doses prior to spinal analgesia were 874.5mg and 730.5mg as oral morphine equivalents in the IT and EP groups, respectively. The systemic opioid could be discontinued or significantly reduced in 83% of the patients. Morphine was used in all IT infusions and most EP infusions, mostly combined with bupivacaine 10mg (IT) or 66mg (EP). The median starting doses of morphine were 3mg/day (IT) and 19mg/day (EP) and were increased during titration 27% to 3.8mg/day (IT) and 91% to 36.2mg/day (EP). Clonidine (median 0.015mg/day IT and 0.15mg/day EP) and/or ketamine were used as adjuvants. The average titration time to stable analgesia was 7-9 days. Numbness in lower limbs was reported by 24% of the IT group. On average, catheters were placed 98 and 61 days before death in IT and EP groups, respectively. No serious complications occurred. Catheter dislocation occurred in 27% of all sixty patients during follow-up. Treatment was discontinued in 10 patients because of catheter dislocation (n=7) or local infection (n=3). CONCLUSIONS AND IMPLICATIONS: Spinal administration of opioids is a safe and effective method of pain management in patients with severe cancer pain and can greatly reduce the need of systemic opioids. We are implementing closer collaboration with oncologists to provide spinal analgesia to more patients and earlier to reduce suffering. Catheter dislocation led to discontinuation of spinal analgesia in 17% of the patients and we are evaluating new ways to prevent catheter dislocation. The initial median spinal opioid dose was too low in both groups, and we are now using higher initial doses. A common adverse effect was numbness of the lower limbs, regardless of the relatively low doses of spinal bupivacaine. We now use lower doses and introduce the intrathecal catheter higher at L1-2 to reduce motor blockade at the level of conus. As an initial intrathecal infusions we suggest: morphine dose calculated using an oral to intrathecal ratio of 1:100 (unless the patient is elderly or already drowsy), clonidine dose 30MUg/day and bupivacaine dose 7.5mg/day. PMID- 28850392 TI - Analyzing transition from acute back pain to chronic pain with linear mixed models reveals a continuous chronification of acute back pain. PMID- 28850393 TI - NSAIDs relieve osteoarthritis (OA) pain, but cardiovascular safety in question even for diclofenac, ibuprofen, naproxen, and celecoxib: what are the alternatives? PMID- 28850394 TI - Using education and support strategies to improve the way nurses assess regular and transient pain - A quality improvement study of three hospitals. AB - BACKGROUND AND AIMS: Systematic and regular pain assessment has been shown to improve pain management. Well-functioning pain assessments require using strategies informed by well-established theory. This study evaluates documented pain assessments reported in medical records and by patients, including reassessment using a Numeric Rating Scale (NRS) after patients receive rescue medication. METHODS: Documentation surveys (DS) and patient surveys (PS) were performed at baseline (BL), after six months, and after 12 months in 44 in patient wards at the three hospitals in Ostergotland County, Sweden. Nurses and nurse assistants received training on pain assessment and support. The Knowledge to Action Framework guided the implementation of new routines. RESULTS: According to DS pain assessment using NRS, pain assessment increased significantly: from 7% at baseline to 36% at 12 months (p<0.001). For PS, corresponding numbers were 33% and 50% (p<0.001). According to the PS, the proportion of patients who received rescue medication and who had been reassessed increased from 73% to 86% (p=0.003). The use of NRS to document pain assessment after patients received rescue medication increased significantly (4% vs. 17%; p<0.001). CONCLUSIONS: After implementing education and support strategies, systematic pain assessment increased, an encouraging finding considering the complex contexts of in-patient facilities. However, the achieved assessment levels and especially reassessments related to rescue medication were clinically unsatisfactory. Future studies should include nursing staff and physicians and increase interactivity such as providing online education support. A discrepancy between documented and reported reassessment in association with given rescue medication might indicate that nurses need better ways to provide pain relief. IMPLICATIONS: The fairly low level of patient-reported pain via NRS and documented use of NRS before and 12 months after the educational programme stresses the need for education on pain management in nursing education. Implementations differing from traditional educational attempts such as interactive implementations might complement educational programmes given at the work place. Standardized routines for pain management that include the possibility for nurses to deliver pain medication within well-defined margins might improve pain management and increase the use of pain assessments. Further research is needed that examines the large discrepancy between patient-reported pain management and documentation in the medical recording system of transient pain. PMID- 28850395 TI - Couples coping with chronic pain: How do intercouple interactions relate to pain coping? AB - BACKGROUND AND AIMS: Pain is not merely an isolated experience occurring within the person. It takes place in a wider social context, including the immediate social relationships that the person is a part of. The aim of this paper is to provide an overview of how intercouple interactions might influence pain coping in couples coping with chronic pain. METHODS: Four different approaches to understanding the influence of intercouple interactions have been proposed in the literature. In this review, we present and discuss the empirical support for each of these models. A literature search on all studies published up until May 2017 (PubMed and PsycINFO) was performed. The search string consisted of 3 steps: Chronic pain AND couple interaction*/partner validation/marital interaction/chronic pain couple*/spouse response* AND coping/adjustment/disability/function/work participation/sick leave/sickness absence/work disability. RESULTS: The operant model views partner responses from the perspective of conditioned learning and focuses on how such responses might increase or decrease the occurrence of pain behaviour. The notion that partner responses can reinforce pain behaviour generally finds support in the literature. However, when it comes to negative partner responses results are mixed, and the model paints a limited picture of the range of interactions that takes place in a couple. The communal coping model focuses on one specific type of coping (i.e. catastrophizing), and emphasizes the interpersonal aspect of pain coping. There is some evidence that a tendency to catastrophize is related both to couple interactions and pain coping, but it has proved difficult to test this model empirically. The interpersonal process model of intimacy is concerned with patient disclosures of distress and subsequent validating and invalidating partner responses. There is some preliminary support that such mechanisms of validation and invalidation can be linked to pain coping. A dyadic approach focuses on processes where the couple negotiates a shared meaning of events and participates in mutual coping of a shared stressor. This approach has not been investigated explicitly, but preliminary support can be derived from studies conducted within other frameworks. CONCLUSIONS: Each of the four approaches find some support in the research literature, yet none of them can explain the full range of couple interactions. We argue that the different approaches are complementary and that several of the approaches can be integrated in a dyadic understanding of pain coping. IMPLICATIONS: All the models indicate that couple interactions can affect pain coping and that this should be taken into account when developing treatment programmes for chronic pain patients. PMID- 28850396 TI - Cancer-pain intractable to high-doses systemic opioids can be relieved by intraspinal local anaesthetic plus an opioid and an alfa2-adrenoceptor agonist. PMID- 28850397 TI - The wit and wisdom of Wilbert (Bill) Fordyce (1923 - 2009). PMID- 28850398 TI - Scientific presentations at the 2017 annual meeting of the Scandinavian Association for the Study of Pain (SASP). PMID- 28850399 TI - Unjustified extrapolation. PMID- 28850400 TI - Response to: "Letter to the Editor entitled: Unjustified extrapolation" [by authors: Supp G., Rosedale R., Werneke M.]. PMID- 28850401 TI - Functional disability and depression symptoms in a paediatric persistent pain sample. AB - BACKGROUND AND AIMS: Clinicians treating paediatric chronic pain conditions understand that persistent pain, functional ability, and symptoms of depression often co-exist, yet these relationships have only been described to a limited extent by research. This paper more closely examines the relationship between symptoms of depression and subtypes of functional disability. METHODS: Participants included a clinical sample of children and adolescents (N=239) referred to a paediatric multidisciplinary pain clinic for treatment of persistent or recurrent (chronic) pain in Australia. The majority of participants were female, (76.6%), and were aged 7-17 years (mean age at the time of presentation was 13.8 years). Data from standardized instruments and interview data were collected from a clinical file audit. The Pediatric Outcomes Data Collection Instrument (PODCI) was used as a measure of functional difficulties performing activities of daily living, and the Children's Depression Inventory (CDI) was used to measure depressive symptoms. RESULTS: High rates of depression and functional disability were observed, but were not associated with one another beyond relatively weak associations. Contrary to prior studies using different measures of physical functioning, depression symptoms were not associated with PODCI functional disability beyond a minor association with anhedonia symptoms (primarily driven by the pain/comfort subscale of the PODCI). CONCLUSIONS AND IMPLICATIONS: We argue that prior research has measured physical functional limitations in paediatric pain sufferers in a way that is heavily influenced by psychosocial factors, in particular by the symptoms of clinical depression. In contrast, using a measure of physical functioning (PODCI) less influenced by psychosocial factors suggests that the relationship between physical functioning during activities of daily living (e.g., use of upper limbs, basic gross and fine motor skills, basic mobility) and depression is weaker, despite both being heightened in this sample. Unlike other functional disability measures, the Pediatric Outcomes Data Collection Instrument (PODCI) may allow researchers to assess functional limitations somewhat independently of depression symptoms. This conclusion requires replication in further studies, but if confirmed, then the PODCI could be advocated as a useful measure to obtain a more 'pure' measure of functional difficulties due to pain, relatively independent of depression. PMID- 28850402 TI - Chronic pain in multiple sclerosis: A 10-year longitudinal study. AB - BACKGROUND AND PURPOSE: Pain is a common symptom associated with multiple sclerosis (MS), and has lasting effects on an individual's functional capacity and quality of life. A wide range of prevalence rates of pain (between 23% and 90%)have been reported in MS and this is mainly due to the methodological differences amongst the studies such as variability in patient sources, method of sampling and the definition of pain used. Chronic pain in MS, defined as pain lasting for greater than 3-6 months, can have a significant impact on their biopsychosocial health, including negative impact on activities of daily living, relationships and social participation. The long-term course of MS-related pain and its impact in an Australian cohort over a 7-year period has been investigated earlier. The aim of this longitudinal study was to describe the impact of chronic pain, pain-related disability and carer burden in persons with MS over a 10-year period. The aim of this longitudinal study was to describe the impact of chronic pain, pain-related disability and carer burden in persons with MS over a 10-year period. METHODS: This was a prospective longitudinal study conducted at the Rehabilitation Department of Royal Melbourne Hospital (RMH), a tertiary referral hospital in Victoria and Australia. The source of participants was from the RMH MS database and contains detailed MS patient information including demographic data, diagnosis details (using McDonald's criteria), pain characteristics. Structured face-face interviews and validated measures were used, which include the visual analogue scale (VAS); chronic pain grade (CPG); the assessment of quality of life (AQoL) and the carer strain index (CSI). The mean age of the participants (n=70) was 55.3 years and majority (70%) were female. RESULTS: The mean age of the participants (n=70) was 55.3 years and majority (70%) were female. The findings show that over time (10 years), participants report having greater bilateral bodily pain and greater description of pain as 'worse as it could be'. Pain types were similar to 7-years follow-up but remained higher than baseline. There was a significant deterioration in quality of life in those with more severe CPG over time. Almost half of the participants 31 (44%) required care either from a private carer, institution or from a family member. Although fear of taking medications and side effects were common barriers to treatment for pain, there was an increase in the use of pharmacological treatment over time and an increase in the use of healthcare services, mainly neurologists and general practitioners. CONCLUSIONS: The pain measures reported by the participants were similar to those at the 7-year follow-up except there was a greater representation of bilateral pain locations (limb, trunk and facial pain) compared to baseline and 7-year follow-up. At 10-year follow-up, more participants used medications compared to 7-year follow-up and there was an increase in the use of health professionals at the 10-year follow-up. At the 10-year follow up QoL of the participants deteriorated significantly and more participants had progressed to higher CPG III and CPG IV. This study demonstrates that chronic pain is a significant issue over time in MS, with clinical and health implications, impact on quality of life, disability and healthcare utilization. IMPLICATIONS: Greater awareness of chronic pain in pwMS, cognitive classifications and an interdisciplinary approach is required to improve long-term patient outcomes and well-being. PMID- 28850403 TI - The changing face of acute pain services. AB - BACKGROUND AND AIMS: Acute Pain Services have been implemented initially to treat inadequate postoperative pain. This study was undertaken to prospectively review the current challenges of the APS team in an academic hospital assessing the effects of its activity on both surgical and medical pain intensity. It also define the characteristics of the patients and the risk factors influencing the multiple visits from the APS team. METHOD: This prospective cohort study was conducted at Uppsala University Hospital (a Swedish tertiary and quaternary care hospital) during one year. All the patients referred to the APS team were enrolled. A standardized data collection template of demographic data, medical history, pain diagnosis, associated diseases, duration of treatment, number of visits by the APS team and type of treatment was employed. The primary outcomes were pain scores before, after treatment and the number of follow-ups. The patients were visited by APS at regular intervals and divided by the number of visits by APS team into several groups: group 1 (one visit and up to 2 follow ups); group 2 (3 to 4 follow-ups); group 3 (5 to 9 follow-ups); group 4 (10 to 19 follow-ups); group 5 (>20 followups). The difference between groups were analyzed with ordinal logistic regression analyses. RESULTS: Patients (n=730) (mean age 56+/-4, female 58%, men 42%) were distributed by service to medical (41%) and surgical (58%). Of these, 48% of patients reported a pain score of moderate to severe pain and 27% reported severe pain on the first assessment. On the last examination before discharge, they reported 25-30% less pain (P=0.002). The median NRS (numerical rating scores) decreased significantly from 9.6 (95% confidence interval, 8.7-9.9) to 6.3 (6.1-7.4) for the severe pain (P<0.0001), from 3.8 (3.2-4.3) to 2.4 (1.8-2.9) for the moderate pain. The odds ratio for frequent follow-ups of the patients between 18 and 85 years (n=609) was 2.33 (95% CI: 1.35-4.02) if the patient had a history of chronic neuropathic pain, 1.80(1.25-2.60) in case the patient had a history of chronic nociceptive pain, 2.06(1.30-3.26) if he had mental diseases, and 3.35(2.21-5.08) if he had opioid dependency at the time of consultation from APS. Strong predictors of frequent visits included female gender (P=0.04). CONCLUSIONS: Beside the benefits of APS in reducing pain intensity, this study demonstrates that the focus of APS has been shifted from the traditional treatment of acute surgical pain to the clinical challenges of treating hospitalized patients with a high comorbidity of psychiatric diseases, opioid dependency and chronic pain. IMPLICATIONS: The concept of an APS will ultimately be redefined according to the new clinical variables. In the light of the increasing number of patients with complex pain states and chronic pain, opioid dependency and psychiatric comorbidities it is mandatory that the interdisciplinary APS team should include other specialties besides the "classical interdisciplinary APS team", as psychiatry, psychology, rehabilitation and physiotherapy with experience in treating chronic pain patients. PMID- 28850404 TI - Specific symptoms and signs of unstable back segments and curative surgery? PMID- 28850405 TI - Symptoms and signs possibly indicating segmental, discogenic pain. A fusion study with 18 years of follow-up. AB - BACKGROUND: Only two out of the five existing randomized studies have reported better results from fusion surgery for chronic low back pain (CLBP) compared to conservative treatment. In these studies the back symptoms of the patients were described simply as "chronic low back pain". One possible reason for the modest results of surgery is the lack of a description of specified symptoms that might be related to a painful segment/disc, and patient selection may therefore be more or less a matter of chance. Previous prospective studies including facet joint injections and discography and eventually MRI have failed to identify patients with a painful segment/disc that will benefit from fusion surgery. PURPOSE: Our purpose was to analyse in detail the pre-operative symptoms and signs presented by patients who showed substantial relief from their back pain following spinal fusion surgery with the aim of possibly finding a pain pattern indicating segmental, discogenic pain. METHODS: We analysed 40 consecutive patients, mean age 41 years, with a history of disabling low back pain for a mean of 7.7 years. Before surgery the patients completed a detailed questionnaire concerning various aspects of their back pain, and findings at clinical examination were thoroughly noted. Monosegmental posterior lumbar interbody fusion without internal fixation was performed using microsurgical technique. Outcome was assessed at 1, 2 and 4 years after surgery and finally at 18 years, using self-reporting measures and assessment by an independent examiner. Assessment at 18 years applied the Balanced Inventory for Spinal Disorders Questionnaire and the Roland-Morris Disability Questionnaire. RESULTS: According to the independent observer's assessment at two years 27 of the 40 patients were much improved. Analysis of the pre-operative depiction of the back symptoms of this group revealed a rather uniform pattern, the most important being: dominating back pain originating in the midline of the spine, with a dull, aching character and stabbing pain in the same area provoked by sudden movements. Most patients in this group also had diffuse pain radiation of various extension down one or both legs and often bladder dysfunction with frequency. At clinical examination, localized interspinal tenderness was observed within the spinal area in question and the patient's back pain was provoked by pressure in that area and by tapping a neighbouring spinous process. At 18 years after surgery 19 patients assessed themselves as much improved. At that time 5 of them had pension due to age, 7 early pension, one worked full time and six patients part time. Eleven patients were re-operated due to defect bony healing. CONCLUSIONS: The results may suggest that the use of a detailed symptom analysis and clinical examination may make it possible to select a subgroup of patients within the CLBP group likely to have better outcome following fusion surgery. IMPLICATIONS: The next step would be to execute prospective studies and if our findings concerning back pain details and signs among CLPB patients can be confirmed this can provide for more accurate selection of patients suitable for fusion surgery. PMID- 28850406 TI - Pain provocation following sagittal plane repeated movements in people with chronic low back pain: Associations with pain sensitivity and psychological profiles. AB - BACKGROUND AND AIMS: Provocative pain responses following standardised protocols of repeated sagittal plane spinal bending have not been reported in people with chronic low back pain (CLBP). Potential differing pain responses to movement likely reflect complex sensorimotor interactions influenced by physical, psychological and neurophysiological factors. To date, it is unknown whether provocative pain responses following repeated bending are associated with different pain sensitivity and psychological profiles. Therefore the first aim of this study was to determine whether data-driven subgroups with different, clinically-important pain responses following repeated movement exist in a large CLBP cohort, specifically using a standardised protocol of repeated sagittal plane spinal bending. The second aim was to determine if the resultant pain responses following repeated movement were associated with pain and disability, pain sensitivity and psychological factors. METHODS: Clinically-important (>=2 points, 11-point numeric rating scale) changes in pain intensity following repeated forward/backward bending were examined. Participants with different provocative pain responses to forward and backward bending were profiled on age, sex, pain sensitivity, psychological variables, pain characteristics and disability. RESULTS: Three groups with differing provocative pain responses following repeated movements were derived: (i) no clinically-important increased pain in either direction (n=144, 49.0%), (ii) increased pain with repeated bending in one direction only (unidirectional, n=112, 38.1%), (iii) increased pain with repeated bending in both directions (bidirectional, n=38, 12.9%). After adjusting for psychological profile, age and sex, for the group with bidirectional pain provocation responses following repeated spinal bending, higher pressure and thermal pain sensitivity were demonstrated, while for the group with no increase in pain, better cognitive and affective psychological questionnaire scores were evident. However, these associations between provocative pain responses following movement and pain sensitivity and psychological profiles were weak. CONCLUSIONS: Provocative pain responses following repeated movements in people with CLBP appear heterogeneous, and are weakly associated with pain sensitivity and psychological profiles. IMPLICATIONS: To date, suboptimal outcomes in studies examining exercise interventions targeting directional, movement-based subgroups in people with CLBP may reflect limited consideration of broader multidimensional clinical profiles associated with LBP. This article describes heterogeneous provocative pain responses following repeated spinal bending, and their associated pain sensitivity and psychological profiles, in people with CLBP. These findings may help facilitate targeted management. For people with no increase in pain, the lack of pain provocation following repeated spinal bending, in combination with a favourable psychological profile, suggests this subgroup may have fewer barriers to functional rehabilitation. In contrast, those with pain provoked by both forward and backward bending may require specific interventions targeting increased pain sensitivity and negative psychological cognitions and affect, as these may be may be important barriers to functional rehabilitation. PMID- 28850407 TI - Local anaesthesia methods for analgesia after total hip replacement: Problems of anatomy, methodology and interpretation? PMID- 28850408 TI - Local infiltration analgesia or femoral nerve block for postoperative pain management in patients undergoing total hip arthroplasty. A randomized, double blind study. AB - BACKGROUND AND AIMS: Several methods for pain management following total hip arthroplasty (THA) have been described but the best postoperative pain management technique remains uncertain. We compared surgeon applied local infiltration analgesia (LIA) with anaesthesiologist performed femoral nerve block (FNB) using ultrasound. The primary aim was to assess pain intensity 24h after THA. METHODS: In this randomized, double-blind study, 56 patients (ASA I-III) undergoing THA consented to participate. In Group FNB, patients received an ultrasound-guided femoral nerve block using 30ml of ropivacaine 7.5mg/ml (225mg) while Group LIA received a similar volume of saline. Spinal anaesthesia was then performed and bupivacaine heavy, 3-3.5ml injected depending on patient characteristics. During surgery, patients in Group LIA received a mixture of 300mg (150ml) ropivacaine, ketorolac 30mg (1ml) and adrenaline 0.5mg (0.5ml) (total volume 151.5ml) peri articularly and subcutaneously while Group FNB received 151.5ml of saline peri articularly in a systematic way by the surgeon. A multi-hole catheter was placed with the tip placed intra-articularly at the end of surgery in both groups. After 23h, the LIA mixture consisting of 20ml ropivacaine (7.5mg/ml), ketorolac 30mg (1ml), adrenaline 0.1mg (1ml) (total volume 22ml) was injected in Group LIA and the same volume of saline in Group FNB. Postoperative pain, analgesic consumption (postoperative and post-discharge), side effects, home discharge, quality of life and hip function were recorded, the latter up to 6 months after surgery. RESULTS: Postoperative pain intensity was significantly lower in Group LIA compared to Group FNB during mobilization at 24h (primary endpoint), mean difference 1.8 NRS units (95% CI 0.7-2.9) (P=0.006), at rest after 4h (P=0.029) and on standing after 24 (P=0.0003) and 48h (P=0.043). Rescue morphine consumption was also significantly lower in Group LIA during 0-24, mean difference 13.5mg (95% CI, 6.1 20.9) (P=0.002) postoperatively. Motor block was greater at 6h (P=0.029) postoperatively in Group FNB. Two patients (one in each group) had persistent post-surgical pain (NRS>3) at 3 months (3.6%) but none at 6 month. No other differences were found between the groups. CONCLUSION: Local infiltration analgesia significantly reduces pain intensity on standing and mobilization, and rescue analgesic consumption compared to femoral nerve block without causing significant side effects. The superior analgesia in the LIA group may result from the secondary injection at 23h postoperatively and needs to be further evaluated in future studies. No differences were found in home discharge, quality of life and hip dysfunction between the groups. IMPLICATION: Local infiltration analgesia is the preferred method for postoperative pain management following THA compared to single-shot femoral nerve block. PMID- 28850409 TI - The disruptive effects of pain on multitasking in a virtual errands task. AB - BACKGROUND AND AIMS: Pain is known to have a disruptive effect on cognitive performance, but prior studies have used highly constrained laboratory tasks that lack ecological validity. In everyday life people are required to complete more complex sets of tasks, prioritising task completion and recalling lists of tasks which need to be completed, and these tasks continue to be attempted during episodes or states of pain. The present study therefore examined the impact of thermal induced pain on a simulated errand task. METHODS: Fifty-five healthy adults (36 female) performed the Edinburgh Virtual Errands Task (EVET) either during a painful thermal sensation or with no concurrent pain. Participants also completed the Experience of Cognitive Intrusion of Pain (ECIP) questionnaire to measure their self-reported cognitive impact of pain in general life. RESULTS: Participants who completed the EVET task in pain and who self-reported high intrusion of pain made significantly more errors than those who reported lower intrusion on the ECIP. CONCLUSIONS: Findings here support the growing literature that suggests that pain has a significant impact on cognitive performance. Furthermore, these findings support the developing literature suggesting that this relationship is complex when considering real world cognition, and that self report on the ECIP relates well to performance on a task designed to reflect the complexities of everyday living. IMPLICATIONS: If extrapolated to chronic pain populations, these data suggest that pain during complex multitasking performance may have a significant impact on the number of errors made. For people highly vulnerable to cognitive intrusion by pain, this may result in errors such as selecting the wrong location or item to perform tasks, or forgetting to perform these tasks at the correct time. If these findings are shown to extend to chronic pain populations then occupational support to manage complex task performance, using for example diaries/electronic reminders, may help to improve everyday abilities. PMID- 28850410 TI - A longitudinal exploration of pain tolerance and participation in contact sports. AB - BACKGROUND/AIMS: Athletes who choose to engage in contact sports do so with the knowledge that participation will bring pain in the form of contact with others, injury, and from exertion. Whilst athletes who play contact sports have been shown to have higher pain tolerance than those who do not, it is unclear whether this is a result of habituation over time, or as a result of individual differences at the outset. The aim was to compare pain responses over an athletic season in athletes who participated in contact sport and those who disengaged from it. METHODS: One hundred and two new contact athletes completed measures of cold and ischaemic pain tolerance, perceived pain intensity, pain bothersomeness, pain coping styles and attendance at the start, middle (4 months) and end (8 months) of their season. The athletes were drawn from martial arts, rugby and American football. Cluster analysis placed 47 athletes into a participating category and 55 into a non-participating cluster. RESULTS: Participating athletes had higher ischaemic pain tolerance at the start (r=0.27, p=0.05), middle (r=0.41, p<0.0001) and end of the season (r=0.57, p<0.0001) compared to non participating athletes. In addition participating athletes were more tolerant to cold pain at the end of the season (r=0.39, p<0.0001), compared to non participating athletes. Participating athletes also exhibited higher direct coping, catastrophized less about injury pain and also found contact pain to be less bothersome physically and psychologically compared to non-participating athletes. Participating athletes were more tolerant of ischaemic pain at the end of the season compared to the start (r=0.28, p=0.04). Conversely non participating athletes became significantly less tolerant to both pain stimuli by the end of the season (cold pressor; r=0.54, p<0.0001; ischaemia; r=0.43, p=0.006). Pain intensity as measured by a visual analogue scale did not change over the season for both groups. CONCLUSIONS: Those who cease participation in contact sports become less pain tolerant of experimental pain, possibly a result of catastrophizing. The results suggest that athletes who commit to contact sports find pain less bothersome over time, possibly as a result of experience and learning to cope with pain. Athletes who continue to participate in contact sports have a higher pain tolerance, report less bothersomeness and have higher direct coping than those who drop out. In addition, tolerance to ischaemic pain increased over the season for participating athletes. IMPLICATIONS: Having a low pain tolerance should not prevent athletes from taking part in contact sports, as pain becomes less bothersome in athletes who adhere to such activities. Participating in contact sports may result in maintained cold pain tolerance, increased ischaemic pain tolerance, reduced catastrophizing and better coping skills. Coaches can therefore work with athletes to develop pain coping strategies to aid adherence to contact sports. PMID- 28850411 TI - From acute to chronic back pain: Using linear mixed models to explore changes in pain intensity, disability, and depression. AB - BACKGROUND/AIMS: This longitudinal study investigated the pattern of change in pain intensity, disability, and depression in 232 chronic pain patients who were followed up for 2 years since pain onset. Most studies that have investigated changes in these variables over time have used participants who had already been in pain for more than 3 months. Few studies have followed up individuals from the acute phase onward and such studies used traditional statistical methods that cannot identify transition points over time or measure inter-individual variability. METHODS: We followed up individuals with chronic pain from pain onset up to 18 months and we examined their pain intensity, disability and depression trajectories using a modelling approach that allows to account for between and within-individual variability. We compared three patterns of change based on theoretical criterions: a simple linear growth model; a spline model with a 3-month transition point; and a spline model with a 6-month transition point. Time with pain was selected as time metric to characterise the change in these variables in the transition from acute to chronic pain. Sex and age differences were also examined. RESULTS: The results showed that the pain intensity trajectory was best represented by the spline model with a 3-month transition point, whereas disability and depression were best explained by linear growth models. There were sex differences at intercept level in all the models. There were age differences at baseline for pain intensity. No sex or age differences were found for the slope. CONCLUSIONS: Pain intensity decreased in the first 3 months but underwent no further change. Disability and depression slightly but constantly decreased over time. Although women and older individuals are more likely to report higher pain intensity or pain-related disability in the first three months with pain, no differences by sex or age appear to be associated with the changes in pain intensity, depression and disability through the process of chronification. IMPLICATIONS: Our findings suggest that pain chronification could be considered a continuous process and contribute to the ongoing discussion on the utility of standard classifications of pain as acute or chronic from a clinical point of view. Clinical and intervention decisions based in these standard classifications should consider the differences in the trajectories of pain related variables over time. In addition, this article illustrates a statistical procedure that can be of utility to pain researchers. PMID- 28850412 TI - Taking a break in response to pain. An experimental investigation of the effects of interruptions by pain on subsequent activity resumption. AB - BACKGROUND AND AIMS: Interrupting ongoing activities with the intention to resume them again later is a natural response to pain. However, such interruptions might have negative consequences for the subsequent resumption and performance of the interrupted activity. Activity interruptions by pain may be more impairing than interruptions by non-painful stimuli, and also be subjectively experienced as such. These effects might be more pronounced in people high in pain catastrophizing. These hypotheses were investigated in two experiments. METHODS: In Experiment 1, healthy volunteers (n=24) performed an ongoing task requiring a sequence of joystick movements. Occasionally, they received either a painful electrocutaneous or a non-painful vibrotactile stimulus, followed by suspension of the ongoing task and temporary engagement in a different task (interruption task). After performing the interruption task for 30s, participants resumed the ongoing task. As the ongoing task of Experiment 1 was rather simple, Experiment 2 (n=30) included a modified, somewhat more complex version of the task, in order to examine the effects of activity interruptions by pain. RESULTS: Participants made more errors and were slower to initiate movements (Experiment 1 & 2) and to complete movements (Experiment 2) when they resumed the ongoing task after an interruption, indicating that interruptions impaired subsequent performance. However, these impairments were not larger when the interruption was prompted by painful than by non-painful stimulation. Pain catastrophizing did not influence the results. CONCLUSIONS: Results indicate that activity interruptions by pain have negative consequences for the performance of an activity upon its resumption, but not more so than interruptions by non-painful stimuli. Potential explanations and avenues for future research are discussed. IMPLICATIONS: Interrupting ongoing activities is a common response to pain. In two experiments using a novel paradigm we showed that activity interruptions by pain impair subsequent activity resumption and performance. However, this effect seems to not be specific to pain. PMID- 28850413 TI - Glucocorticoids - Efficient analgesics against postherpetic neuralgia? PMID- 28850414 TI - Important new insight in pain and pain treatment induced changes in functional connectivity between the Pain Matrix and the Salience, Central Executive, and Sensorimotor networks. PMID- 28850416 TI - Efficacy and safety of diclofenac in osteoarthritis: Results of a network meta analysis of unpublished legacy studies. AB - BACKGROUND AND AIM: Diclofenac is widely prescribed for the treatment of pain. Several network meta-analyses (NMA), largely of published trials have evaluated the efficacy, tolerability, and safety of non-steroidal anti-inflammatory drugs (NSAIDs). The present NMA extends these analyses to unpublished older (legacy) diclofenac trials. METHODS: We identified randomised controlled trials (RCTs) of diclofenac with planned study duration of at least 4 weeks for the treatment of osteoarthritis (OA) from 'legacy' studies conducted by Novartis but not published in a peer reviewed journal or included in any previous pooled analyses. All studies reporting efficacy and/or safety of treatment with diclofenac or other active therapies or placebo were included. We used a Bayesian NMA model, and estimated relative treatment effects between pairwise treatments. Main outcomes included pain relief measured using visual analogue scale at 2, 4 and 12 weeks and patient global assessment (PGA) at 4 and 12 weeks for efficacy, all-cause withdrawals, and adverse events. RESULTS: A total of 19 RCTs (5030 patients) were included; 18 of which were double-blind and one single-blind. All studies were conducted before cyclooxygenase 2 inhibitors (COXIBs) became commercially available. Data permitted robust efficacy comparison between diclofenac and ibuprofen, but the amount of data for other comparators was limited. Diclofenac 150mg/day was more efficacious than ibuprofen 1200mg/day and had likely favourable outcomes for pain relief compared to ibuprofen 2400mg/day. Diclofenac 100mg/day had likely favourable outcomes compared to ibuprofen 1200mg/day in alleviating pain. Based on PGA, diclofenac 150mg/day was more efficacious and likely to be favourable than ibuprofen 1200mg/day and 2400mg/day, respectively. Risk of withdrawal due to all causes with diclofenac and ibuprofen were comparable. Diclofenac 150mg/day was likely to have favourable efficacy and comparable tolerability with diclofenac 100mg/day. Results comparing diclofenac and ibuprofen were similar to those from NMAs of published trials. CONCLUSIONS: Results from these unpublished 'legacy' studies were similar to those from NMAs of published trials. The favourable efficacy results of diclofenac compared to ibuprofen expand the amount of available evidence comparing these two NSAIDs. The overall benefit-risk profile of diclofenac was comparable to that of ibuprofen in OA. IMPLICATIONS: The present NMA results reassures that the older unpublished blinded trials have similar results compared to more recently published trials and also contributes to increase the transparency of clinical trials performed with diclofenac further back in the past. PMID- 28850415 TI - Sex moderates the effects of positive and negative affect on clinical pain in patients with knee osteoarthritis. AB - BACKGROUND AND AIMS: Sex differences in clinical pain severity and response to experimental pain are commonly reported, with women generally showing greater vulnerability. Affect, including state (a single rating) and stable (average daily ratings over two weeks) positive affect and negative affect has also been found to impact pain sensitivity and severity, and research suggests that affect may modulate pain differentially as a function of sex. The current study aimed to examine sex as a moderator of the relationships between affect and pain-related outcomes among participants with knee osteoarthritis (KOA). METHODS: One hundred and seventy-nine participants (59 men) with KOA completed electronic diaries assessing clinical pain, positive affect, and negative affect. A subset of participants (n=120) underwent quantitative sensory testing, from which a single index of central sensitization to pain was derived. We used multiple regression models to test for the interactive effects of sex and affect (positive versus negative and stable versus state) on pain-related outcomes. We used mixed effects models to test for the moderating effects of sex on the relationships between state affect and pain over time. RESULTS: Sex differences in affect and pain were identified, with men reporting significantly higher stable positive affect and lower central sensitization to pain indexed by quantitative sensory testing, as well as marginally lower KOA-specific clinical pain compared to women. Moreover, there was an interaction between stable positive affect and sex on KOA-specific clinical pain and average daily non-specific pain ratings. Post hoc analyses revealed that men showed trends towards an inverse relationship between stable positive affect and pain outcomes, while women showed no relationship between positive affect and pain. There was also a significant interaction between sex and stable negative affect and sex on KOA-specific pain such that men showed a significantly stronger positive relationship between stable negative affect and KOA-specific pain than women. Sex did not interact with state affect on pain outcomes. CONCLUSIONS: Findings suggest that men may be particularly sensitive to the effects of stable positive affect and negative affect on clinical pain. Future work with larger samples is needed in order to identify potential mechanisms driving the sex-specific effects of affect on pain. IMPLICATIONS: The current study provides novel data that suggesting that the association of positive affect, negative affect, and pain are different in men versus women with KOA. Further understanding of the difference in affective expression between men and women may lead to the development of novel therapeutic interventions and help to identify additional modifiable factors in the prevention and management of pain. PMID- 28850417 TI - Editorial comment on Nina Kreddig's and Monika Hasenbring's study on pain anxiety and fear of (re) injury in patients with chronic back pain: Sex as a moderator. PMID- 28850418 TI - The interference of pain with task performance: Increasing ecological validity in research. PMID- 28850420 TI - Education and support strategies improve assessment and management of pain by nurses. PMID- 28850419 TI - Multifactorial assessment of measurement errors affecting intraoral quantitative sensory testing reliability. AB - BACKGROUND AND PURPOSE (AIMS): Measurement error of intraoral quantitative sensory testing (QST) has been assessed using traditional methods for reliability, such as intraclass correlation coefficients (ICCs). Most studies reporting QST reliability focused on assessing one source of measurement error at a time, e.g., inter- or intra-examiner (test-retest) reliabilities and employed two examiners to test inter-examiner reliability. The present study used a complex design with multiple examiners with the aim of assessing the reliability of intraoral QST taking account of multiple sources of error simultaneously. METHODS: Four examiners of varied experience assessed 12 healthy participants in two visits separated by 48h. Seven QST procedures to determine sensory thresholds were used: cold detection (CDT), warmth detection (WDT), cold pain (CPT), heat pain (HPT), mechanical detection (MDT), mechanical pain (MPT) and pressure pain (PPT). Mixed linear models were used to estimate variance components for reliability assessment; dependability coefficients were used to simulate alternative test scenarios. RESULTS: Most intraoral QST variability arose from differences between participants (8.8-30.5%), differences between visits within participant (4.6-52.8%), and error (13.3-28.3%). For QST procedures other than CDT and MDT, increasing the number of visits with a single examiner performing the procedures would lead to improved dependability (dependability coefficient ranges: single visit, four examiners=0.12-0.54; four visits, single examiner=0.27 0.68). A wide range of reliabilities for QST procedures, as measured by ICCs, was noted for inter- (0.39-0.80) and intra-examiner (0.10-0.62) variation. CONCLUSION: Reliability of sensory testing can be better assessed by measuring multiple sources of error simultaneously instead of focusing on one source at a time. In experimental settings, large numbers of participants are needed to obtain accurate estimates of treatment effects based on QST measurements. This is different from clinical use, where variation between persons (the person main effect) is not a concern because clinical measurements are done on a single person. IMPLICATIONS: Future studies assessing sensory testing reliability in both clinical and experimental settings would benefit from routinely measuring multiple sources of error. The methods and results of this study can be used by clinical researchers to improve assessment of measurement error related to intraoral sensory testing. This should lead to improved resource allocation when designing studies that use intraoral quantitative sensory testing in clinical and experimental settings. PMID- 28850421 TI - Chronic neck pain patients with traumatic or non-traumatic onset: Differences in characteristics. A cross-sectional study. AB - BACKGROUND AND AIMS: Patients with chronic neck pain can present with disability, low quality of life, psychological factors and clinical symptoms. It is unclear whether patients with a traumatic onset differ from those with a non-traumatic onset, by having more complex and severe symptoms. The purpose of this study was to investigate the clinical presentation of chronic neck pain patients with and without traumatic onset by examining cervical mobility, sensorimotor function, cervical muscle performance and pressure pain threshold in addition to the following self-reported characteristics: quality of life, neck pain and function, kinesiophobia, depression, and pain bothersomeness. METHODS: This cross-sectional study included 200 participants with chronic neck pain: 120 with traumatic onset and 80 with non-traumatic onset. Participants were recruited from physiotherapy clinics in primary and secondary health care. For participants to be included, they were required to be at least 18 years of age, have had neck pain for at least 6 months, and experienced neck-related activity limitation as determined by a score of at least 10 on the Neck Disability Index. We conducted the following clinical tests of cervical range of motion, gaze stability, eye movement, cranio cervical flexion, cervical extensors, and pressure pain threshold. The participants completed the following questionnaires: physical and mental component summary of the Short Form Health Survey, EuroQol-5D, Neck Disability Index, Patient-Specific Functional Scale, Pain Bothersomeness, Beck Depression Inventory-II, and TAMPA scale of kinesiophobia. The level of significance for all analyses was defined as p<0.01. Differences between groups for the continuous data were determined using either a Student's t-test or Mann Whitney U test. RESULTS: In both groups, the majority of the participants were female (approximately 75%). Age, educational level, working situation and sleeping patterns were similar in both groups. The traumatic group had symptoms for a shorter duration (88 vs. 138 months p=0.001). Participants in the traumatic group showed worse results on all measures compared with those in the non-traumatic group, significantly on neck muscle function (cervical extension mobility p=0.005, cranio-cervical flexion test p=0.007, cervical extensor test p=0.006) and cervical pressure pain threshold bilateral (p=0.002/0.004), as well on self reported function (Neck Disability Index p=0.001 and Patient-Specific Functional Scale p=0.007), mental quality of life (mental component summary of the Short Form Health Survey p=0.004 and EuroQol-5D p=0.001) and depression (Beck Depression Inventory-II p=0.001). CONCLUSIONS: This study showed significant differences between chronic neck pain patients when differentiated into groups based on their onset of pain. However, no specific clinical test or self-reported characteristic could differentiate between the groups at an individual patient level. IMPLICATIONS: Pressure pain threshold tests, cervical muscle performance tests and patient-reported characteristics about self-perceived function and psychological factors may assist in profiling chronic neck pain patients. The need for more intensive management of those with a traumatic onset compared with those with a non-traumatic onset should be examined further. PMID- 28850422 TI - The meaning and consequences of amputation and mastectomy from the perspective of pain and suffering. AB - BACKGROUND: The concepts 'pain' and 'suffering' are frequently treated as synonymous. However, they are clearly distinct phenomena. Phantom phenomena including pain and sensory disturbances are still recognized as long-lasting problems after limb amputation and after mastectomy. The complex nature of phantom phenomena makes the interpretation of its results ambiguous, regarding the prevalence of pain, sensory disturbances and the accompanying suffering. There is clinical experience that suffering is a great burden for the individual but there is a lack of systematic studies of patients' own evaluations of the suffering caused by their phantom phenomena. OBJECTIVES: The overall aim of this study was to identify and describe patients' suffering related to, and as a part, of their post-amputation situation. METHODS: The present study constitutes a part of a prospective, two-year follow up project investigating interviews of 28 men and women in different ages and who have undergone a limb amputation or mastectomy. The reason for amputation or mastectomy varied among the patients and included vascular diseases, cancer (sarcoma and breast-cancer) and trauma. Our ambition was to extract as much variations as possible in different, individualized aspects of the actual pain and suffering producing situation. The participants were, here, invited to open-ended, narrative-oriented interviews one month after the surgery. The interviews were transcribed verbatim and analyzed within qualitative methodology: thematic content analysis. RESULTS: Twenty-two of 28 interviewees experienced phantom pain and phantom sensations. The two surgical processes amputation and mastectomy meant for a majority of the interviewees a critical event with threatening consequences for everyday life such as loss of function and personal integrity. Nine interviewees felt even stigmatized as a result of their lost body part. Numerous inter-related factors following the amputation/mastectomy, which can inflict severe suffering on the amputee, were uncovered. The context in which the interviewees were informed about the decision to amputate proved to be one such critical and important factor. CONCLUSION: To understand potential suffering in relation to phantom phenomena, it will never be enough merely to have knowledge of the underlying physiological or neurological mechanisms and/or the intensity of phantom pain and phantom sensations. Rather, it is necessary to find out how the loss of the body part and its everyday consequences are experienced by patients. IMPLICATIONS: It is important to create time for real dialogue with the patients both during pre-operative preparation and post-operative rehabilitation in order to clarify and verbalize elements that constitute the patients individual suffering. Hopefully this strategy can alleviate future chronic pain problems, severe psycho-social distress and suffering. Such an approach ought to have impact also for perceived suffering after other types of surgery or different invasive treatments. PMID- 28850423 TI - Invasive intervention for "intractable" Complex Regional Pain Syndromes (CRPS)? PMID- 28850424 TI - Intrathecal management of complex regional pain syndrome: A case report and literature. AB - BACKGROUND AND PURPOSE: Complex regional pain syndrome (CRPS) is a painful condition typically resulting from a traumatic event. Pain control in these patients is often difficult and requires a multimodal approach. Our objectives are to present a single intrathecal pain management regimen for CRPS and provide a literature review of intrathecal pain management options in CRPS. METHODS: Case report from an academic pain management clinic. CASE REPORT: We present the case of a 29-year-old female with a past medical history of multiple lumbar spine surgeries and lumbar post-laminectomy syndrome who presented to clinic with CRPS type II of the bilateral lower extremities. After failing conservative measures, she underwent placement of a successful intrathecal drug delivery system. CONCLUSION: The use of intrathecal medications is useful for pain control in CRPS patients. IMPLICATIONS: We provide a framework for treatment of CRPS, which could be useful for practitioners dealing with this difficult and painful condition. PMID- 28850425 TI - Item response theory analysis of the Pain Self-Efficacy Questionnaire. AB - BACKGROUND AND AIMS: The Pain Self-Efficacy Questionnaire (PSEQ) is a 10-item instrument designed to assess the extent to which a person in pain believes s/he is able to accomplish various activities despite their pain. There is strong evidence for the validity and reliability of both the full-length PSEQ and a 2 item version. The purpose of this study is to further examine the properties of the PSEQ using an item response theory (IRT) approach. METHODS: We used the two parameter graded response model to examine the category probability curves, and location and discrimination parameters of the 10 PSEQ items. In item response theory, responses to a set of items are assumed to be probabilistically determined by a latent (unobserved) variable. In the graded-response model specifically, item response threshold (the value of the latent variable for which adjacent response categories are equally likely) and discrimination parameters are estimated for each item. Participants were 1511 mixed, chronic pain patients attending for initial assessment at a tertiary pain management centre. RESULTS: All items except item 7 ('I can cope with my pain without medication') performed well in IRT analysis, and the category probability curves suggested that participants used the 7-point response scale consistently. Items 6 ('I can still do many of the things I enjoy doing, such as hobbies or leisure activity, despite pain'), 8 ('I can still accomplish most of my goals in life, despite the pain') and 9 ('I can live a normal lifestyle, despite the pain') captured higher levels of the latent variable with greater precision. CONCLUSIONS: The results from this IRT analysis add to the body of evidence based on classical test theory illustrating the strong psychometric properties of the PSEQ. Despite the relatively poor performance of Item 7, its clinical utility warrants its retention in the questionnaire. IMPLICATIONS: The strong psychometric properties of the PSEQ support its use as an effective tool for assessing self-efficacy in people with pain. PMID- 28850426 TI - Objective methods for the assessment of the spinal and supraspinal effects of opioids. AB - BACKGROUND AND PURPOSE: Opioids are potent analgesics. Opioids exert effects after interaction with opioid receptors. Opioid receptors are present in the peripheral- and central nervous system (CNS), but the analgesic effects are primarily mediated via receptors in the CNS. Objective methods for assessment of opioid effects may increase knowledge on the CNS processes responsible for analgesia. The aim of this review was to provide an overview of the most common objective methods for assessment of the spinal and supraspinal effects of opioids and discuss their advantages and limitations. METHOD: The literature search was conducted in Pub Med (http://www.ncbi.nlm.nih.gov/pubmed) from November 2014 to June 2016, using free-text terms: "opioid", "morphine" and "oxycodone" combined with the terms "pupillometry," "magnetic resonance spectroscopy," "fMRI," "BOLD," "PET," "pharmaco-EEG", "electroencephalogram", "EEG," "evoked potentials," and "nociceptive reflex". Only original articles published in English were included. RESULTS: For assessment of opioid effects at the supraspinal level, the following methods are evaluated: pupillometry, proton magnetic resonance spectroscopy, functional resonance magnetic imaging (fMRI), positron emission tomography (PET), spontaneous electroencephalogram (EEG) and evoked potentials (EPs). Pupillometry is a non-invasive tool used in research as well as in the clinical setting. Proton magnetic resonance spectroscopy has been used for the last decades and it is a non-invasive technique for measurement of in vivo brain metabolite concentrations. fMRI has been a widely used non-invasive method to estimate brain activity, where typically from the blood oxygen level-dependent (BOLD) signal. PET is a nuclear imaging technique based on tracing radio labeled molecules injected into the blood, where receptor distribution, density and activity in the brain can be visualized. Spontaneous EEG is typically quantified in frequency bands, power spectrum and spectral edge frequency. EPs are brain responses (assessed by EEG) to a predefined number of short phasic stimuli. EPs are quantified by their peak latencies and amplitudes, power spectrum, scalp topographies and brain source localization. For assessment of opioid effects at the spinal level, the following methods are evaluated: the nociceptive withdrawal reflex (NWR) and spinal EPs. The nociceptive withdrawal reflex can be recorded from all limbs, but it is standard to record the electromyography signal at the biceps femoris muscle after stimulation of the ipsilateral sural nerve; EPs can be recorded from the spinal cord and are typically recorded after stimulation of the median nerve at the wrist. CONCLUSION AND IMPLICATIONS: The presented methods can all be used as objective methods for assessing the centrally mediated effects of opioids. Advantages and limitations should be considered before implementation in drug development, future experimental studies as well as in clinical settings. In conclusion, pupillometry is a sensitive measurement of opioid receptor activation in the CNS and from a practical and economical perspective it may be used as a biomarker for opioid effects in the CNS. However, if more detailed information is needed on opioid effects at different levels of the CNS, then EEG, fMRI, PET and NWR have the potential to be used. Finally, it is conceivable that information from different methods should be considered together for complementary information. PMID- 28850427 TI - Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain. AB - BACKGROUND: The first line pharmacological treatment of cancer pain is morphine and surrogates but a significant pain relief and a reduction of the side-effects of these compounds makes it necessary to combine them with other drugs acting on different targets. The aim of this study was to measure the antinociceptive effect on cancer-induced bone pain resulting from the association of the endogenous opioids enkephalin and non-opioid analgesic drugs. For this purpose, PL265 a new orally active single dual inhibitor of the two degrading enkephalins enzymes, neprilysin (NEP) and aminopeptidase N (APN) was used. It strictly increased the levels of enkephalin at their sites of releases. The selected non opioid compounds are: gabapentin, A-317491 (P2X3 receptor antagonist), ACEA (CB1 receptor antagonist), AM1241 (CB2 receptor antagonist), JWH-133 (CB2 receptor antagonist), URB937 (FAAH inhibitor), and NAV26 (Nav1.7 channel blocker). METHODS: Experiments. Experiments were performed in 5-6 weeks old (26-33g weight) C57BL/6 mice. Cell culture and cell inoculation. B16-F10 melanoma cells were cultured and when preconfluent, treated and detached. Finally related cells were resuspended to obtain a concentration of 2*106 cells/100MUL. Then 105 cells were injected into the right tibial medullar cavity. Control mice were treated by killed cells by freezing. Behavioural studies. Thermal withdrawal latencies were measured on a unilatered hot plate (UHP) maintained at 49+/-0.2 degrees C. Mechanical threshold values were obtained by performing the von Frey test using the "up and down" method. To evaluate the nature (additive or synergistic) of the interactions between PL265 and different drugs, an isobolographic analysis following the method described by Tallarida was performed. RESULTS: The results demonstrate the ability of PL265, a DENKI that prevents the degradation of endogenous ENKs, to counteract cancer-induced bone thermal hyperalgesia in mice, by exclusively stimulating peripheral opioid receptors as demonstrated by used of an opioid antagonist unable to enter the brain. The development of such DENKIs, endowed with druggable pharmacokinetic characteristics, such as good absorption by oral route, can be considered as an important step in the development of much needed novel antihyperalgesic drugs. Furthermore, all the tested combinations resulted in synergistic antihyperalgesic effects. As shown here, the greatest synergistic antinociceptive effect (doses could be lowered by 70%) was produced by the combination of PL265 with the P2X3 receptor antagonist (A-317491), cannabinoid CB1 receptor agonist (exogenous, ACEA and endogenous URB937-protected AEA) and Nav1.7 blocker (NAV26) whose mechanism of action involves the direct activation of the enkephalinergic system. CONCLUSIONS: These multi-target-based antinociceptive strategies using combinations of non-opioid drugs with dual inhibitors of enkephalin degrading enzymes may bring therapeutic advantages in terms of efficacy and safety by allowing the reduction of doses of one of the compounds or of both, which is of the utmost interest in the chronic treatment of cancer pain. IMPLICATIONS: This article presents synergistic antinociceptive effect produced by the combination of PL265 with non-opioid analgesic drugs acting via unrelated mechanisms. These multi-target-based antinociceptive strategies may bring therapeutic advantages by allowing the reduction of doses, which is of great interest in the chronic treatment of cancer pain. PMID- 28850428 TI - Multimodal intrathecal analgesia in refractory cancer pain. AB - BACKGROUND AND AIMS: Cancer pain treatment has improved over the last decades. The majority of this population can be treated effectively with analgesics following the Guidelines of the original World Health Organisation (WHO). Unfortunately 10-15% of these patients still suffer from severe and refractory cancer pain, especially in the terminal phases of disease and require additional pain management modalities. Therefore, end-stage clinical interventions are particularly needed to minimize the perception of pain. With intrathecal therapy (ITT), drugs are delivered close to their site of action in the central nervous system avoiding first-pass metabolism and blood-brain barrier. It may improve analgesia with a smaller dose and possibly achieve a reduction in systemic or cerebral side effects compared to oral supplied medication alone. Multimodal analgesia enables further dose reduction with improved analgesia and fewer side effects. METHODS: In this retrospective research we investigated the effectiveness and side-effect profile of intrathecal morphine, bupivacaine and clonidine. Patients were followed until death occurred. Pain scores and side effects were recorded before initiating ITT (T0), just after initiating ITT (T1), at hospital discharge (T2), in the ambulant setting (T3) and the last obtained scores before death occurred (T4). RESULTS: Nine patients were included who suffered from severe and refractory cancer pain, not reacting to conventional pain management or had intolerable side effects. Primary tumour location was pancreatic (4), urothelial (3) and prostate (2). Primary pain was considered neuropathic or mixed neuropathic-nociceptive. The treatment team consisted of an anaesthetist, specialized nurse in coordination with primary physician, treating oncologist and specialized home care. All patients were free of pain after initiation of the intrathecal therapy. The average follow-up period was 11 weeks in which there was a slight increase in NRS-score. In the last days before death occurred, half the patients were still free of pain. There were no problems during insertion of the catheter, device malfunction or infection. No severe adverse events defined as hypotension requiring inotropes, respiratory depression or neurological deficits were observed. Three patients experienced mild hypotension which gradually decreased after clonidine dose adjustment. Lower extremity weakness occurred in three patients as well. After bupivacaine dose adjustment the weakness disappeared in two patients and in one patient the lower extremity weakness persisted as a result of conus compression by tumour. CONCLUSION AND IMPLICATIONS: Multimodal IT treatment with morphine, bupivacaine and clonidine is effective and safe for treating refractory cancer pain in the terminal phase of disease. The study offers an important contribution to literature where there is still lack of convincing evidence about the benefits and harms of this type of pain management in patients with otherwise refractory cancer pain. PMID- 28850429 TI - Treatment success in neck pain: The added predictive value of psychosocial variables in addition to clinical variables. AB - BACKGROUND AND AIMS: Identification of psychosocial variables may influence treatment outcome. The objective of this study was to prospectively examine whether psychosocial variables, in addition to clinical variables (pain, functioning, general health, previous neck pain, comorbidity), are predictive factors for treatment outcome (i.e. global perceived effect, functioning and pain) in patients with sub-acute and chronic non-specific neck pain undergoing physical therapy or manual therapy. Psychosocial factors included treatment outcome expectancy and treatment credibility, health locus of control, and fear avoidance beliefs. METHODS: This study reports a secondary analysis of a primary care-based pragmatic randomized controlled trial. Potential predictors were measured at baseline and outcomes, in 181 patients, at 7 weeks and 26 weeks. RESULTS: Hierarchical logistic regression models showed that treatment outcome expectancy predicted outcome success, in addition to clinical and demographic variables. Expectancy explained additional variance, ranging from 6% (pain) to 17% (functioning) at 7 weeks, and 8% (pain) to 16% (functioning) at 26 weeks. Locus of control and fear avoidance beliefs did not add significantly to predicting outcome. CONCLUSIONS: Based on the results of this study we conclude that outcome expectancy, in patients with non-specific sub-acute and chronic neck pain, has additional predictive value for treatment success above and beyond clinical and demographic variables. IMPLICATIONS: Psychological processes, health perceptions and how these factors relate to clinical variables may be important for treatment decision making regarding therapeutic options for individual patients. PMID- 28850430 TI - Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study. AB - BACKGROUND: 10-30% of chronic abdominal pain originates in the abdominal wall. A common cause for chronic abdominal wall pain is the Anterior Cutaneous Nerve Entrapment Syndrome (ACNES), in which an intercostal nerve branch is entrapped in the abdominal rectus sheath. Treatment consists of local anaesthetics and neurectomy, and is ineffective in 25% of cases for yet unknown reasons. In some conditions, chronic pain is the result of altered pain processing. This so-called sensitization can manifest as segmental or even generalized hyperalgesia, and is generally difficult to treat. OBJECTIVE: The aim of this study was to assess pain processing in ACNES patients responsive and refractory to treatment by using Quantitative Sensory Testing, in order to explore whether signs of altered central pain processing are present in ACNES and are a possible explanation for poor treatment outcomes. METHODS: 50 patients treated for ACNES with locally orientated treatment were included. They were allocated to a responsive or refractory group based on their response to treatment. Patients showing an improvement of the Visual Analogue Scale (VAS) pain score combined with a current absolute VAS of <40mm were scored as responsive. Sensation and pain thresholds to pressure and electric skin stimulation were determined in the paravertebral bilateral ACNES dermatomes and at four control areas on the non-dominant side of the body, i.e. the musculus trapezius pars medialis, musculus rectus femoris, musculus abductor hallucis and the thenar. The ACNES dermatomes were chosen to signal segmental hyperalgesia and the sum of the control areas together as a reflection of generalized hyperalgesia. Lower thresholds were interpreted as signs of sensitized pain processing. To test for alterations in endogenous pain inhibition, a conditioned pain modulation (CPM) response to a cold pressor task was determined. Also, patients filled in three pain-related questionnaires, to evaluate possible influence of psychological characteristics on the experienced pain. RESULTS: Patients refractory to treatment showed significantly lower pressure pain thresholds in the ACNES dermatomes and for the sum of as well as in two individual control areas. No differences were found between groups for electric thresholds or CPM response. Duration of complaints before diagnosis and treatment was significantly longer in the refractory compared to the responsive group, and refractory patients scored higher on the pain-related psychological surveys. CONCLUSION AND IMPLICATIONS: In this hypothesis-generating exploratory study, ACNES patients refractory to treatment showed more signs of sensitized segmental and central pain processing. A longer duration of complaints before diagnosis and treatment may be related to these alterations in pain processing, and both findings could be associated with less effective locally orientated treatment. In order to validate these hypotheses further research is needed. REGISTRATION NUMBER: NCT01920880 (Clinical Trials Register; http://www.clinicaltrials.gov). PMID- 28850431 TI - Physical and occupational therapy outcomes: Adolescents' change in functional abilities using objective measures and self-report. AB - PURPOSE: This study evaluates the clinical usefulness of patient-rated and objective measures to identify physically-oriented functional changes after an intensive chronic pain program in a pediatric setting. Past studies have demonstrated the importance of adolescents' perception of their abilities and measurement tools used for rehabilitation outcomes within physical and occupational therapy; however, these tools used are not often easily utilized or have not been examined with a pediatric chronic pain population. In chronic pain rehabilitation, it is important to have a primary focus on functional improvement not on pain reduction as a leading outcome. This study examines how both self report and objective physical activity measures can be meaningful constructs and can be used as reliable outcome measures. It was hypothesized that adolescents completing an interdisciplinary pain rehabilitation program would report functional gains from admission to discharge, and that perceived gains in physical ability would be associated with objective physical activities. Further, it was hypothesized that gains in functioning would be associated with mild pain reduction. METHODS: Data from 78 children and adolescents with chronic pain that participated in an intensive multidisciplinary treatment program completed self report measures including the Lower Extremity Functional Scale (LEFS), Upper Extremity Functional Index (UEFI). In addition, adolescents were objectively monitored for repetitions of selected physical activities for 1min intervals. RESULTS: Data demonstrated significant gains in all measures of functioning during the program. Correlations between self-report and objective outcomes suggest they are measuring similar yet distinct factors. CONCLUSIONS: The LEFS, UEFI, and objective exercises provide a meaningful way to track progress in pediatric chronic pain rehabilitation. Despite similarities, they appear to track separate but related aspects of rehabilitation and capture important short-term response to rehabilitation. Both measures appear distinct from pain as an outcome. These findings increase our understanding of rehabilitation practices provide opportunities to promote clinical improvement in pediatric pain. IMPLICATIONS: The use of self-report measures along with objective measures can help therapists gain understanding in regards to a patient's insight and how that may impact their overall outcome compared to the use of a single outcome measure. Viewing these rated measures at any point in the rehabilitation process can be useful to facilitate discussion about challenges they can identify and how therapies can facilitate improvement and functional gains. PMID- 28850432 TI - Treatment success in neck pain: The added predictive value of psychosocial variables in addition to clinical variables. PMID- 28850433 TI - Multi-target treatment of bone cancer pain using synergistic combinations of pharmacological compounds in experimental animals. PMID- 28850434 TI - Terminal cancer pain intractable by conventional pain management can be effectively relieved by intrathecal administration of a local anaesthetic plus an opioid and an alfa2-agonist into the cerebro-spinal-fluid. PMID- 28850435 TI - Patients with chronic neck-pain after trauma do not differ in type of symptoms and signs, but suffer more than patients with chronic neck pain without a traumatic onset. PMID- 28850436 TI - Gain in functions before pain reduction during intensive multidisciplinary paediatric pain rehabilitation programme. PMID- 28850437 TI - Re-enforcing therapeutic effect by positive expectations of pain-relief from our interventions. PMID- 28850438 TI - Objective methods for the assessment of the spinal and supraspinal effects of opioids. PMID- 28850439 TI - Why are some patients with chronic pain from anterior abdominal nerve entrapment syndrome (ACNES) refractory to peripheral treatment with neurectomy? PMID- 28850440 TI - Complex Regional Pain Syndrome (CRPS): High risk of CRPS after trauma in another limb in patients who already have CRPS in one hand or foot: Lasting changes in neural pain modulating systems? PMID- 28850441 TI - The risk of pain syndrome affecting a previously non-painful limb following trauma or surgery in patients with a history of complex regional pain syndrome. AB - BACKGROUND AND PURPOSE: Complex regional pain syndrome (CRPS) is a challenging complication after surgery or trauma. This study sought to determine the incidence of CRPS after a second inciting event in a previously unaffected extremity in patients with a history of an ongoing CRPS diagnosis in another extremity. METHODS: A retrospective review identified patients with CRPS seen in clinic over a 20-month period. The incidence of CRPS after subsequent surgery or injury in a previous unaffected extremity was determined and compared to an average incidence reported in the literature. RESULTS: Ninety-three patients had a diagnosis of primary CRPS. Nineteen (20.4%) developed CRPS in one or more additional extremity compared to the incidence of 23.4 per 100,000 (0.0234%) in the literature (odds ratio 1069.6, p<0.0001, 95% CI 562.0-2035.7). Twenty patients had a documented secondary injury or surgery in a second extremity. Fifteen (75%) developed secondary CRPS compared to a CRPS incidence rate of 6.4% following distal radius fracture, as determined by literature review (odds ratio 11.7, p<0.001, 95% CI 5.9-23.2). CONCLUSIONS: These result suggest that patients with a history of CRPS are more likely to develop secondary CRPS compared to the rates reported in the literature among the general population. IMPLICATIONS: Patients with a history of CRPS should be counselled that they may be at risk for developing secondary CRPS if they undergo surgery or sustain trauma to another extremity. PMID- 28850442 TI - Positive affect could reduce the impact of pain. PMID- 28850443 TI - Effect of expectation on pain assessment of lower- and higher-intensity stimuli. AB - BACKGROUND AND AIMS: Pain modulation via expectation is a well-documented phenomenon. So far it has been shown that expectations about effectiveness of a certain treatment enhance the effectiveness of different analgesics and of drug free pain treatments. Also, studies demonstrate that people assess same-intensity stimuli differently, depending on the experimentally induced expectations regarding the characteristics of the stimuli. Prolonged effect of expectation on pain perception and possible symmetry in conditions of lower- and higher intensity stimuli is yet to be studied. Aim of this study is to determine the effect of expectation on the perception of pain experimentally induced by the series of higher- and lower-intensity stimuli. METHODS: 192 healthy participants were assigned to four experimental groups differing by expectations regarding the intensity of painful stimuli series. Expectations of two groups were congruent with actual stimuli; one group expected and received lower-intensity stimuli and the other expected and received higher-intensity stimuli. Expectations of the remaining two groups were not congruent with actual stimuli; one group expected higher-intensity stimuli, but actually received lower-intensity stimuli while the other group expected lower-intensity stimuli, but in fact received higher intensity ones. Each group received a series of 24 varied-intensity electrical stimuli rated by the participants on a 30 degrees intensity scale. RESULTS: Expectation manipulation had statistically significant effect on pain intensity assessment. When expecting lower-intensity stimuli, the participants underestimated pain intensity and when expecting higher-intensity stimuli, they overestimated pain intensity. The effect size of expectations upon pain intensity assessment was equal for both lower- and higher-intensity stimuli. CONCLUSION: The obtained results imply that expectation manipulation can achieve the desired effect of decreasing or increasing both slight and more severe pain for a longer period of time. Manipulation via expectation before the stimuli series was proven to be effective for pain modulation in the entire series of stimuli which lasted around 10min. The results suggest a potential benefit of manipulating expectations to alleviate emerging pain, since the obtained effects are moderate to large. IMPLICATIONS: It seems that expectation effect is strong enough to "overcome" even the direct effect of stimulus intensity (at least in the low to moderate intensity range), which suggests potential benefits of verbal instructions even in rather painful stimuli. PMID- 28850444 TI - The buffering role of positive affect on the association between pain intensity and pain related outcomes. AB - OBJECTIVES: Chronic pain is a significant problem worldwide and is associated with significant elevations in negative affect, depressive symptoms, sleep problems, and physical dysfunction. Positive affect could potentially buffer the impact of pain on patient functioning. If it does, then positive affect could be directly targeted in treatment to benefit individuals with chronic pain. The purpose of this study was to test for such moderating effects. METHODS: This was a cross-sectional study, we administered measures of pain intensity, depressive symptoms, sleep problems, pain interference, and positive and negative affect to 100 individuals with chronic back or knee pain in a single face-to-face assessment session. RESULTS: The associations between pain intensity and negative affect, and between pain intensity and depressive symptoms were moderated by positive affect. This moderation effect was explained by the fact that participants with low positive affect evidenced strong associations between pain intensity and both depression and negative affect; participants with high positive affect, on the other hand, evidenced weak and non-significant associations between pain intensity and both depression and negative affect. Positive affect did not moderate the associations between pain intensity and either sleep problems or pain interference. CONCLUSION: The findings are consistent with the possibility that positive affect may buffer the impact of pain intensity on negative affect and depressive symptoms. Longitudinal and experimental research is needed to determine the potential benefits of treatments that increase positive affect on negative affect and depressive symptoms in chronic pain populations. IMPLICATIONS: The study findings suggest the possibility that "positive psychology" interventions which increase positive affect could benefit individuals with chronic pain by reducing the impact of pain on negative outcomes. Research to test this possibility is warranted. PMID- 28850445 TI - The meaning and consequences of amputation and mastectomy from the perspective of pain and suffering - Lessons to be learned and relearned. PMID- 28850446 TI - A preliminary investigation into psychophysiological effects of threatening a perceptually embodied rubber hand in healthy human participants. AB - BACKGROUND AND AIMS: Threatening a perceptually embodied rubber hand with noxious stimuli has been shown to generate levels of anxiety similar to that experienced when a real hand is threatened. The aim of this study was to investigate skin conductance response, self-reported anxiety and the incidence, type and location of sensations when a perceptually embodied rubber hand was exposed to threatening and non-threatening stimuli. METHODS: A repeated measures cross-over design was used whereby 20 participants (>=18 years, 14 females) received a threatening (syringe needle) and non-threatening (soft brush) stimulus to a perceptually embodied rubber hand. Perceptual embodiment was achieved using a soft brush to synchronously stroke the participant's real hand (out of view) and a rubber hand (in view). Then the investigator approached the rubber hand with a syringe needle (threat) or soft brush (non-threat). RESULTS: Repeated measures ANOVA found that approaching the perceptually embodied rubber hand with either stimulus produced statistically significant reductions in the rated intensity of response to the following questions (p<0.01): 'How strongly does it feel like the rubber hand is yours?'; 'How strongly does it feel like the rubber hand is part of your body?'; and 'How strongly does it feel you can move the rubber hand?'. However, there were no statistically significant differences in scores between needle and brush stimuli. Repeated measures ANOVA on skin conductance response found statistically significant effects for experimental Events (baseline; stroking; perceptual embodiment; stimuli approaching rubber hand; stimuli touching rubber hand; p<0.001) but not for Condition (needle versus brush p=0.964) or experimental Event*Condition interaction (p=0.160). Ten of the 20 participants (50%) reported that they experienced a sensation arising from the rubber hand when the rubber hand was approached and touched by either the needle and/or brush but these sensations lacked precision in location, timing, and nature. CONCLUSION AND IMPLICATIONS: Our preliminary findings suggest that the increase in arousal in response to stimuli entering the peripersonal space may not be selective for threat. There was tentative evidence that more intense sensations were experienced when a perceptually embodied rubber hand was approached by a threatening stimulus. Our findings provide initial insights and should serve as a catalyst for further research. PMID- 28850447 TI - Opioid-induced constipation, use of laxatives, and health-related quality of life. AB - BACKGROUND AND AIMS: Real-life data on laxative use in patients suffering from opioid-induced constipation (OIC) are very limited, and many OIC patients are only using over the counter laxatives to resolve their constipation. Our aim was to describe laxative utilization and quality of life in participants in Norway who ever experienced OIC. METHODS: This was a cross-sectional online survey conducted between 27th of June and 3rd of July 2014 among participants above 18 years with self-reported OIC and who had agreed to receive information from the pharmacy chain (Boots A/S, Norway). The questionnaire comprised a series of multiple choice, close-ended, and free text questions on abdominal symptoms, laxative use and health-related quality of life. RESULTS: A total of 417 participants met the study eligibility criteria: (1) treated with opioid for a minimum of 4 weeks, (2) actively accepted participation, and (3) confirmed ever experiencing OIC and in addition completed the survey. Among the eligible participants, 86% were females, 85% were younger than 60 years of age, and 57% were currently suffering OIC. More than half of the currently constipated participants were experiencing moderate to very severe abdominal bloating (63%), abdominal pain (55%) and/or pain during bowel movement (50%). Less than every fourth participant (23%) had consulted health care professionals (HCPs) about their constipation. Up to 39% reported that they handled their OIC by self management, e.g., bought laxative, reduced the dose and/or changed opioid without consulting HCP or pharmacy. Less than half (48%) of the laxative users were satisfied with the laxative they were using to relieve their constipation. The EQ 5D health-related quality of life score was mean (SD): 0.587 (0.272). Although not statistically significant (p=0.067), there was a tendency of lower quality of life among the participants who were currently constipated compared with those not currently constipated (difference of mean EQ-5D: 0.629-0.555=0.074). A significantly lower (p=0.001) quality of life was found among participants who were dissatisfied with their laxative [mean (SD): 0.424 (0.350)] than among those who were satisfied or neither satisfied nor dissatisfied [mean (SD): 0.628 (0.235) and 0.673 (0.155), respectively]. CONCLUSIONS: The results suggest a high degree of moderate to very severe abdominal symptoms, a high degree of self management of opioid-induced constipation, a low degree of satisfaction with laxative, and low health-related quality of life of patients suffering from chronic pain necessitating long-term opioid treatment, subsequent constipation and laxatives use. IMPLICATIONS: Patients suffering from OIC with low quality of life and remaining symptoms despite use of two or more laxatives are a vulnerable patient group in need of optimized healthcare management, who also might benefit from more specific and innovative therapy. PMID- 28850448 TI - When touch predicts pain: predictive tactile cues modulate perceived intensity of painful stimulation independent of expectancy. AB - AIMS: Non-nociceptive somatosensory input, such as tactile or proprioceptive information, always precedes nociceptive input during a painful event. This relationship provides clear opportunities for predictive associative learning, which may shape future painful experiences. In this differential classical conditioning study we tested whether pain-associated tactile cues (conditioned stimuli; CS) could alter the perceived intensity of painful stimulation, and whether this depends on duration of the CS-seeing that CS duration might allow or prevent conscious expectation. METHODS: Subjects underwent a classical differential conditioning task in which a tactile cue at location A (CS+) preceded painful electrical stimulation at location B (UShigh), whereas a tactile cue at location C (CS-) preceded non-painful electrical stimulation at location B (USlow). At test, we compared the pain evoked by a moderately painful stimulus (USmed) when preceded by either the CS+ or CS-. CS duration was manipulated between subjects. Participants were assigned to one of three groups: Long CS (4s, allowing conscious expectation), Short CS (110ms) and CS-US indistinguishable (20ms), preventing conscious expectation). We hypothesised that more pain would be evoked by the US when preceded by the CS+ relative to the CS-, and that the effect would be independent of CS duration. RESULTS: Fifty-four healthy participants (31 females, age=26, SD=9) were included in the analysis. The hypotheses were supported in that more intense pain was evoked by the USmed when paired with the tactile CS+, than when paired with the tactile CS-; mean difference 3mm on a 150mm VAS (CI 0.4-4.8mm). CS duration did not moderate the effect. The effect was greater in those participants where calibration was optimal, as indicated by a relatively more painful UShigh. CONCLUSION: We conclude that pain-associated tactile cues can influence pain, and that this effect is not dependent on stimulus duration. This suggests that explicit expectation is not a requirement for predictive cues to modulate pain. That the presence of the CS+ resulted in only a 5.3% higher intensity rating compared with the CS- may reflect a limitation of laboratory studies, where a limited number of trials, an artificial context and the use of experimental pain are likely to reveal only glimpses of what is clinically possible. IMPLICATIONS: Pain associated visual and auditory cues have been shown to enhance pain in laboratory and clinical scenarios, supposedly by influencing expectation of impending harm. We show that pain-associated somatosensory cues can also modulate pain and that this can occur independently of expectation. This points to a larger potential role for associative learning in the development and treatment of pain than has previously been considered. We suggest that research into associative mechanisms underpinning pain, as distinct from those that link pain to pain-related fear and avoidance, is worthwhile. PMID- 28850449 TI - Definition, diagnosis and treatment strategies for opioid-induced bowel dysfunction-Recommendations of the Nordic Working Group. AB - BACKGROUND AND AIMS: Opioid-induced bowel dysfunction (OIBD) is an increasing problem due to the common use of opioids for pain worldwide. It manifests with different symptoms, such as dry mouth, gastro-oesophageal reflux, vomiting, bloating, abdominal pain, anorexia, hard stools, constipation and incomplete evacuation. Opioid-induced constipation (OIC) is one of its many symptoms and probably the most prevalent. The current review describes the pathophysiology, clinical implications and treatment of OIBD. METHODS: The Nordic Working Group was formed to provide input for Scandinavian specialists in multiple, relevant areas. Seven main topics with associated statements were defined. The working plan provided a structured format for systematic reviews and included instructions on how to evaluate the level of evidence according to the GRADE guidelines. The quality of evidence supporting the different statements was rated as high, moderate or low. At a second meeting, the group discussed and voted on each section with recommendations (weak and strong) for the statements. RESULTS: The literature review supported the fact that opioid receptors are expressed throughout the gastrointestinal tract. When blocked by exogenous opioids, there are changes in motility, secretion and absorption of fluids, and sphincter function that are reflected in clinical symptoms. The group supported a recent consensus statement for OIC, which takes into account the change in bowel habits for at least one week rather than focusing on the frequency of bowel movements. Many patients with pain receive opioid therapy and concomitant constipation is associated with increased morbidity and utilization of healthcare resources. Opioid treatment for acute postoperative pain will prolong the postoperative ileus and should also be considered in this context. There are no available tools to assess OIBD, but many rating scales have been developed to assess constipation, and a few specifically address OIC. A clinical treatment strategy for OIBD/OIC was proposed and presented in a flowchart. First-line treatment of OIC is conventional laxatives, lifestyle changes, tapering the opioid dosage and alternative analgesics. Whilst opioid rotation may also improve symptoms, these remain unalleviated in a substantial proportion of patients. Should conventional treatment fail, mechanism-based treatment with opioid antagonists should be considered, and they show advantages over laxatives. It should not be overlooked that many reasons for constipation other than OIBD exist, which should be taken into consideration in the individual patient. CONCLUSION AND IMPLICATIONS: It is the belief of this Nordic Working Group that increased awareness of adverse effects and OIBD, particularly OIC, will lead to better pain treatment in patients on opioid therapy. Subsequently, optimised therapy will improve quality of life and, from a socio-economic perspective, may also reduce costs associated with hospitalisation, sick leave and early retirement in these patients. PMID- 28850450 TI - Aspects of pain attitudes and pain beliefs in children: Clinical importance and validity. PMID- 28850451 TI - Postoperative pain documentation 30 years after. PMID- 28850452 TI - Assessment of persistent pelvic pain after hysterectomy: Neuropathic or nociceptive? PMID- 28850453 TI - Why do we have opioid-receptors in peripheral tissues? Not for relief of pain by opioids. PMID- 28850454 TI - Low back pain among nurses: Common cause of lost days at work and contributing to the worldwide shortage of nurses. PMID- 28850455 TI - Migraine headache and bipolar disorder comorbidity: A systematic review of the literature and clinical implications. AB - BACKGROUND AND AIMS: Psychiatric disorders, e.g., depression, are often comorbid with, and can complicate the treatment of, patients with migraine headache. Although empirical work has increasingly focused on the association between migraine and bipolar disorder, this topic has received little attention in the pain literature. Bipolar disorder is a chronic and recurrent mood disorder characterized by cyclic occurrence of elevated (i.e., manic or hypomanic) and depressed mood states. Bipolar I disorder is diagnosed when patients present with at least one abnormally and persistently elevated manic episode; bipolar II disorder is characterized by the presence of hypomanic episodes. Bipolar disorder warrants attention as depressive phases of the disorder can prevail and are often misconstrued by the unwary clinician as unipolar depression. However, treatment for bipolar disorder is distinct from that of unipolar depression and use of antidepressants, which are often invoked in migraine prophylaxis as well as the treatment of depression, may precipitate significant mood changes among bipolar disorder patients. A systematic review of the literature addressing the co occurrence of bipolar disorder and migraine was conducted. The treatment of dually affected patients is also discussed. METHODS: In order to review the literature to date on migraine and bipolar disorder co-occurrence, a comprehensive search of MEDLINE, EMBASE, PubMed, PsycINFO, Web of Science, and CINAHL for clinic-based and epidemiological studies was conducted using terms related to migraine and bipolar disorder. Studies were selected for review if they included subjects meeting validated diagnostic criteria for bipolar disorder as well as migraine headache and if a quantitative description of prevalence rates of comorbid bipolar disorder and migraine were reported. Weighted means of the prevalence rates were calculated to compare with general epidemiological prevalence trends for migraine and bipolar disorder, respectively. RESULTS: Eleven studies met inclusion criteria. Although findings were constrained by methodological limitations and several low quality studies, clinic- and epidemiological cross-sectional investigations demonstrated a high rate of comorbidity between bipolar disorder and migraine. The weighted mean prevalence rate for migraine headache among bipolar disorder patients was 30.7%; for bipolar disorder among migraineurs, the weighted mean prevalence rates were 9% and 5.9% in clinic-based and epidemiological studies, respectively. The association between bipolar disorder and migraine was most notable among women and patients with the bipolar II disorder subtype. CONCLUSIONS: High rates of comorbidity exist between migraine and bipolar disorder, exceeding estimated prevalence rates for those conditions in the general population. Comorbidity may portend a more serious clinical course for dually afflicted individuals. IMPLICATIONS: Clinicians need to structure treatment approaches to address concurrent migraine and bipolar disorder in dually afflicted individuals. Although further evidence based investigation is warranted to inform optimal treatment approaches for both conditions concurrently, anticonvulsants (e.g., valproate, lamotrigine and topiramate); atypical antipsychotics (e.g., olanzapine or quetiapine); and calcium channel blockers (e.g., verapamil) may be considered. PMID- 28850456 TI - Chronic pain and psychological distress among long-term social assistance recipients - An intolerable burden on those on the lowest steps of the socioeconomic ladder. PMID- 28850457 TI - Migraine headache and bipolar disorders: Common comorbidities. PMID- 28850458 TI - Fifty years on the Visual Analogue Scale (VAS) for pain-intensity is still good for acute pain. But multidimensional assessment is needed for chronic pain. PMID- 28850459 TI - The role of social anxiety in chronic pain and the return-to-work process. PMID- 28850460 TI - The role of catastrophizing in the pain-depression relationship. PMID- 28850461 TI - The mediating role of catastrophizing in the relationship between pain intensity and depressed mood in older adults with persistent pain: A longitudinal analysis. AB - BACKGROUND AND AIMS: Depression is common in older adults with persistent pain. Cognitive-behavioural models of pain propose that the relationship between pain and depression is influenced or mediated by interpretations of events (cognitions), rather than by the event itself. Almost exclusively, the evidence for this position has come from studies of people aged less than 65 years. The role of cognitions in the pain experience of older adults has been unclear due to the limited and conflicting evidence available. The aim of our study was to examine the role of catastrophizing in mediating the relationship between pain intensity and depressed mood in older adults with persistent pain using reliable and valid measures for this population. METHODS: In a two-wave longitudinal design, a sample of 141 patients (89 women, 52 men) 65 years and over with persistent pain participating in an evaluation of a pain self-management programme completed questionnaires measuring usual level of pain intensity (NRS), depressed mood (DASS-21) and the catastrophizing factors of magnification and helplessness (PRSS) at the beginning of the programme and 6 months later. Demographic data and pain history were collected by self-completion questionnaires, which were mailed to patients prior to participating in the programme and returned by post. RESULTS: Change scores for usual level of pain intensity (NRS), depressed mood (DASS-21) and the magnification and helplessness factors on the PRSS-Catastrophizing were calculated by subtracting the scores at 6 months after completion of the study (Time 2) from the scores at the beginning of the study (Time 1). In the longitudinal analyses of mediation, using a series of regression analyses, change scores for both factors (magnification, helplessness) of the measure of catastrophizing (PRSS) totally and significantly mediated the relationship between change scores for pain intensity and depressed mood. The significant relative magnitude of beta between pain intensity and depression reduced from 0.22 to 0.13 and became non-significant after introducing magnification as a mediating variable, whilst the significant relative magnitude of beta reduced from 0.22 to 0.12 and also became non-significant after introducing helplessness as a mediating variable. CONCLUSIONS: These results support a cognitive-behavioural model and highlight the importance of cognitive factors, in this case catastrophizing, in the relationship between pain intensity and depressed mood in older adults with persistent pain. IMPLICATIONS: These findings also have important clinical implications for the treatment of older adults with persistent pain. They highlight the importance of targeting interventions to reduce the influence of catastrophizing as a prerequisite for reducing depressive symptoms in this growing population. PMID- 28850462 TI - Advances in understanding and treatment of opioid-induced-bowel-dysfunction, opioid-induced-constipation in particular: Nordic recommendations based on multi specialist input. PMID- 28850463 TI - Analysis of C-reactive protein (CRP) levels in pain patients - Can biomarker studies lead to better understanding of the pathophysiology of pain? PMID- 28850464 TI - Serum C-reactive protein levels predict regional brain responses to noxious cold stimulation of the hand in chronic whiplash associated disorders. AB - BACKGROUND AND AIMS: Whiplash Associated Disorders (WAD) are a costly health burden. The condition is characterised by sensory disturbances such as widespread hyperalgesia likely indicative of central hyperexcitability. Recently elevated levels of pro-inflammatory biomarkers have also found in acute and chronic WAD. The aim of this cross-sectional study was to investigate the relationship between inflammatory biomarkers and pain processing in people with persistent whiplash associated disorders (WAD). METHODS: Twenty one participants with chronic whiplash (>3 months) were recruited. Venous blood samples were collected and assays performed for C-reactive protein (CRP) and TNF-alpha. Blood oxygen level dependent (BOLD) contrast images of the brain were acquired with a Siemens 1.5T MRI scanner during repeated 24s stimulus blocks of innocuous or painful stimuli (thumbnail pressure and cold stimulation of dorsum of hand) separated by 36s inter-stimulus intervals. Stimulus intensities used during scanning were at the level of participants' thresholds for moderate pain. Parameter estimates representing BOLD signal increases during painful events from each participant were tested for associations with inflammatory biomarkers. RESULTS: Clinically relevant levels of CRP and TNF-alpha were found in 33% and 38% of participants. Levels of CRP showed a positive correlation with levels of cold pain activation in brain regions including the anterior insula, posterior parietal cortex, caudate and thalamus (pcorrected<0.05). Levels of TNF-alpha were not related to activation levels during either noxious pressure or cold. Pressure pain activations also did not show a relationship with CRP levels. CONCLUSIONS: Shared variance between inflammation and increased levels of regional pain-related activation in people with persistent whiplash symptoms is apparent for cold, but not pressure stimuli. IMPLICATIONS: The results highlight cold pain processing as an important aspect of whiplash chronicity, although the implications of this modality-specific effect are not readily apparent. PMID- 28850465 TI - Delayed diagnosis and worsening of pain following orthopedic surgery in patients with complex regional pain syndrome (CRPS). AB - BACKGROUND AND AIMS: Complex regional pain syndrome (CRPS) is a serious and disabling chronic pain condition, usually occurring in a limb. There are two main types, CRPS 1 with no definite nerve lesion and CRPS 2 with an identified nerve lesion. CRPS 1 and 2 may occur following an injury (frequently following fractures), surgery or without known cause. An early diagnosis and start of adequate treatment is considered desirable for patients with CRPS. From the clinical experience of the principal investigator, it became apparent that CRPS often remained undiagnosed and that the clinical conditions of many patients seemed to be worsened following orthopedic surgery subsequent to the initial eliciting event. The aim of the present retrospective study of 55 patients, all diagnosed with either CRPS 1 or 2, was to evaluate the time from injury until diagnosis of CRPS and the effect on pain of orthopedic surgical intervention subsequent to the original injury/surgery. METHODS: Clinical symptoms with an emphasis on pain were assessed by going through the patients' records and by information given during the investigation at Oslo University Hospital, where the patients also were examined clinically and with EMG/neurography. Alteration in pain was evaluated in 27 patients who underwent orthopedic surgery subsequent to the eliciting injury. RESULTS: Of a total of 55 patients, 28 women and 27 men (mean age 38.7 (SD 12.3), 38 patients were diagnosed with CRPS type 1, and 17 with CRPS type 2. Mean time before diagnosis was confirmed was 3.9 years (SD1.42, range 6 months-10 years). The eliciting injuries for both CRPS type 1 and type 2 were fractures, squeeze injuries, blunt injuries, stretch accidents and surgery. A total of 27 patients (14 men and 13 women) were operated from one to 12 times at a later stage (from 6 months to several years) following the initial injury or any primary operation because of fracture. A total of 22 patients reported a worsening of pain following secondary surgical events, while four patients found no alteration and one patient experienced an improvement of pain. None of the 22 patients reporting worsening, were diagnosed with CRPS prior to surgery, while retrospectively, a certain or probable diagnosis of CRPS had been present in 17/22 (77%) patients before their first post-injury surgical event. CONCLUSIONS AND IMPLICATIONS: A mean time delay of 3.9 years before diagnosis of CRPS is unacceptable. A lack of attention to more subtle signs of autonomic dysfunction may be an important contributing factor for the missing CRPS diagnosis, in particular serious in patients reporting worsening of pain following subsequent orthopedic surgery. It is strongly recommended to consider the diagnosis of CRPS in all patients with a long-lasting pain condition. We emphasize that the present report is not meant as criticism to orthopedic surgical practice, but as a discussion for a hopefully increased awareness and understanding of this disabling pain condition. PMID- 28850466 TI - Associative learning mechanisms may trigger increased burden of chronic pain; unlearning and extinguishing learned maladaptive responses should help chronic pain patients. PMID- 28850467 TI - Pain-related factors associated with lost work days in nurses with low back pain: A cross-sectional study. AB - BACKGROUND AND AIMS: Chronic low back pain is known to contribute to lost work days (LWDs) in nurses. However, there is a limited understanding of the factors that moderate the impact of low back pain (LBP) on LWDs - in particular factors that are modifiable and that could therefore be the treatment targets of interventions designed to help nurses more effectively manage LBP. This study aims to identify pain-related factors that are associated with LWDs in nurses with LBP, in order to inform the development of interventions that could reduce LBP-related work dysfunction and improve patient care. METHODS: A cross sectional study was conducted on 111 female nurses who were asked to answer questions regarding demographic information, work history, presence or absence of LBP, number of LWDs due to illness, and a number of factors that could potentially be related to LWDs including: (1) average and worst pain intensity; (2) the temporal pattern of LBP (constant versus intermittent); (3) pain aggravating factors (lifting, bending, walking, and standing); and (4) pain alleviating factors (medications, rest, exercise). RESULTS: Sixty-five percent (n=72) of the sample reported LBP. Constancy of pain and having a LBP problem that was alleviated by rest were significantly associated with the number of LWDs, while maximum and average LBP intensity were only weakly associated. CONCLUSION: The findings provide important new information regarding what is (and of equal importance) what is not associated with LWDs in nurses with LBP. IMPLICATIONS: To effectively reduce LBP-related work disability, interventions may need to teach nurses how to better manage constant pain and remain active despite pain, rather than focus on pain reduction. Research to examine the potential efficacy of such treatment approaches for nurses with LBP is warranted. PMID- 28850468 TI - Characterization of persistent pain after hysterectomy based on gynaecological and sensory examination. AB - BACKGROUND AND AIMS: Previous studies have shown that pelvic pain is common after hysterectomy. It is stated that only a minor part of that pain can be defined as persistent postsurgical pain. Our primary aim was to find out if the pelvic pain after hysterectomy may be classified as postsurgical. Secondary aims were to characterize the nature of the pain and its consequences on the health related quality of life. METHODS: We contacted the 56 women, who had reported having persistent pelvic pain six months after hysterectomy in a previously sent questionnaire. Sixteen women participated. Clinical examinations included gynaecological examination and clinical sensory testing. Patients also filled in quality of life (SF-36) and pain questionnaires. RESULTS: Ten out of sixteen patients still had pain at the time of examination. In nine patients, pain was regarded as persistent postsurgical pain and assessed probable neuropathic for five patients. There were declines in all scales of the SF-36 compared with the Finnish female population cohort. CONCLUSIONS: In this study persistent pelvic pain after vaginal or laparoscopic hysterectomy could be defined as persistent postsurgical pain in most cases and it was neuropathic in five out of nine patients. Pain had consequences on the health related quality of life. IMPLICATIONS: Because persistent postsurgical pain seems to be the main cause of pelvic pain after hysterectomy, the decision of surgery has to be considered carefully. The management of posthysterectomy pain should be based on the nature of pain and the possibility of neuropathic pain should be taken into account at an early postoperative stage. PMID- 28850469 TI - Importance of early diagnosis of complex regional pain syndrome (CRPS-1 and C RPS 2): Delayed diagnosis of CRPS is a major problem. PMID- 28850470 TI - Facilitation of accurate and effective radiation therapy using fentanyl pectin nasal spray (FPNS) to reduce incidental breakthrough pain due to procedure positioning. AB - PURPOSE: To provide effective and accurate radiotherapy (RT) for advanced cancer patients who experience breakthrough pain (BP) due to positioning manoeuvres, through the use of FPNS. Secondary endpoints were the dose and time required to achieve a 50% numeric rating scale (NRS) reduction and conduction of a pharmacoeconomic analysis. PATIENTS AND METHODS: Twenty-seven advanced cancer patients with moderate-severe BP associated with routine radiotherapy procedures and manoeuvres were selected to receive FPNS. Most patients (20/27) had bone metastases. The patients showed a low Karnovsky performance status (mean 54%; range: 30-80). BP intensity was scored with the NRS before and after the procedures that triggered it. All patients were already receiving opioid baseline treatment at a total dose equivalent to 40-160mg oral morphine. Before the procedure, BP was treated with 100-400MUg of FPNS. Data related to tolerance, pain relief, onset of the relief and efficient dose to allow RT to proceed were collected. RESULTS: In 26 patients the BP score was reduced by at least 50% as determined in 15.5min (range 8-35min) after fentanyl pectin intranasal administration, and pain relief started after 7min (range 3-15min); p<0.05 in both cases. The duration of pain reduction facilitated the proceeding of RT. The Mean NRS score before the procedure was 9 (95%CI: 8.6-9.4) and decreased during procedure to 3 (95%CI: 2.5-3.8). The average dose of FPNS for most patients was 100-200MUg to achieve pain control, except in three patients who required progressive doses of up to 300-400MUg. After receiving 300MUg, one patient dropped out of the study due to severe adverse effects (nausea). Seven patients reported minor undesirable effects related to FPNS administration. CONCLUSIONS AND IMPLICATIONS: Certain necessary RT procedures in advanced cancer patients can cause severe BP episodes. A simple, safe, fast acting and strong analgesic is needed. FPNS is a rapidly absorbed opioid analgesic with a pain relief profile that would be particularly well suited for this patient population. By reducing BP, the drug enables the completion of necessary RT procedures without needless patient discomfort. When BP is attenuated, Department productivity is maintained and unnecessary delays are avoided. Further studies and clinical trials are needed to assess therapeutic FPNS dosages with a view to defining efficacy in the correct clinical context. PMID- 28850471 TI - Peripheral morphine reduces acute pain in inflamed tissue after third molar extraction: A double-blind, randomized, active-controlled clinical trial. AB - BACKGROUND: The clinical use of peripheral analgesic effects of opioids has been investigated in numerous controlled clinical trials. The majorities of these have tested the local, intra-articular administration of morphine in knee surgery and have demonstrated marginal postoperative analgesia. OBJECTIVE: We examined direct morphine infiltration of the surgical site in a clinical model of tooth pain under two different conditions. Eighty-eight patients undergoing surgical tooth removal entered into the two prospective, parallel, randomized, double-blind studies. METHODS: Patients undergoing surgical tooth removal received a standard local anaesthetic solution (articaine plus epinephrine) before surgery. Patients were assigned to an injection of peripheral 2mg morphine either into non-inflamed (Trial I) or inflamed (Trial II) submucous tissue before the surgery. Patients who received an intramuscular morphine in the upper arm were concomitantly given 1ml isotonic saline (NaCl) as a submucous injection. Patients who received a submucous injection of morphine peripherally were concomitantly given an intramuscular injection (IM) of 1ml of NaCl in the upper arm. Postoperative pain intensity was assessed by the numeric rating scale every 30min for the first 2h and then every hour for the next 8h after surgery. In addition, patients recorded the occurrence of side effects and the supplemental consumption of ibuprophen and codeine+paracetamol combination tablets. RESULTS: Of the eighty-eight original participants, nine patients (4 patients in Trial I and 5 patients in Trial II) were withdrawn for protocol noncompliance and loss at follow-up. Thirty-one patients in trial I and forty-eight patients in trial II were analyzed. Patients receiving 2mg morphine into non-inflamed tissue did not show any further reduction in pain scores and pain medication consumption compared to IM morphine group (Trial I). In patients receiving 2mg morphine into inflamed tissue, pain scores at rest were reduced to a similar extent in both groups at all measurement times up to 10h in the follow-up (Trial II). At the same time, in the area under the curves pain scores on swallowing between 2 and 6h in the peripheral morphine group (5.2+/-5.6) were significantly lower than in the IM morphine group (9.3+/ 7.3, p=0.03), demonstrating the marginal analgesic efficacy of additional morphine. Sedation scores were significantly higher in the peripheral morphine group only 1h after surgery in Trial I (p=0.008). The time to first analgesic intake was similar between groups. No serious side effects were reported. CONCLUSIONS: Our results showed in patients undergoing surgical tooth removal that injection of 2mg of morphine into inflamed tissue results in significantly lower pain scores on swallowing in the early postoperative state while administration into non-inflamed tissue is not effective. IMPLICATIONS: Our studies indicate that the peripheral administration of opioids, at the doses and conditions set out for these two studies, produces significant analgesia by a pharmacologically specific mechanism that is active in chronically, but not acutely, inflamed tissue. Thus, consistent with preclinical experimental studies, the requirement of an inflammatory process for the occurrence of the peripheral opioid effects is also found in the clinical setting. PMID- 28850472 TI - The co-occurrence of chronic pain and psychological distress and its associations with salient socio-demographic characteristics among long-term social assistance recipients in Norway. AB - BACKGROUND: While lower socioeconomic status increases individual's risk for chronic conditions, little is known about how long-term social assistance recipients (LTRs) with multiple chronic health problems experience chronic pain and/or psychological distress. Social assistance is the last safety net in the Norwegian welfare system and individuals have a legal right to economic assistance if they are unable to support themselves or are entitled to other types of benefits. The purposes of this study were to determine the co-occurrence of both chronic pain and psychological distress and to evaluate for differences in demographic and social characteristics, as well as health-related quality of life, among LTRs. METHODS: This descriptive, cross-sectional study surveyed people receiving long-term social assistance in Norway about their health and social functioning from January-November 2005. The social welfare authority offices in each of 14 municipalities in Norway were responsible to locate the LTRs who met the study's inclusion criteria. The selected municipalities provided geographic variability including both rural and urban municipalities in different parts of the country. LTRs were included in this study if they: had received social assistance as their main source of income for at least 6 of the last 12 months; were between 18 and 60 years of age; and were able to complete the study questionnaire. In this study, 405 LTRs were divided into four groups based on the presence or absence of chronic pain and/or psychological distress. (1) Neither chronic pain nor psychological distress (32%, n=119), (2) only chronic pain (12%, n=44), (3) only psychological distress and (24%, n=87), (4) both chronic pain and psychological distress (32%, n=119). RESULTS: Except for age and marital status, no differences were found between groups in demographic characteristics. Significant differences were found among the four groups on all of the items related to childhood difficulties before the age of 16, except the item on sexual abuse. LTRs with both chronic pain and psychological distress were more likely to have experienced economic problems in their childhood home; other types of abuse than sexual abuse; long-term bullying; and had more often dropped out of school than LTRs with neither chronic pain nor psychological distress. LTRs with both chronic pain and psychological distress, reported more alcohol and substance use/illicit drug use, more feelings of loneliness and a lower mental score on SF 12 than LTRs with only chronic pain. CONCLUSIONS AND IMPLICATIONS: Co-occurrence of chronic pain and psychological distress is common in LTRs and problems in early life are associated with the co-occurrence of chronic pain and psychological distress in adult life. Although this study cannot assign a clear direction or causality to the association between social and demographic characteristics and chronic pain and psychological distress, the findings when examining LTRs' problems in childhood before the age of 16, indicated that incidents in early life create a probability of chronic pain and psychological distress in the adult life of the individuals. Further studies should use life course studies and longitudinal data in to investigate these important questions in LTRs. PMID- 28850473 TI - Patient reported outcome measures of pain intensity: Do they tell us what we need to know? AB - OBJECTIVE: To determine the relationship between chronic pain patients' responses to self-report measures of pain intensity, and self-reported strategies when completing such measures. PARTICIPANTS: Ambulatory outpatients suffering from one of the following chronic pain conditions: painful HIV neuropathy, painful diabetic neuropathy, chronic Low-Back Pain. METHOD: As part of a previously reported study using qualitative methods, participants completed standard pain intensity questionnaires as well as a measure of pain related disturbances in activities of daily living. In the previous study, participants' responses during a focus group were then used to identify their strategies and beliefs about their approach to completing the questionnaires. Among the beliefs were: (1) difficulties averaging pain over different time periods (i.e., "what was your average pain during the last 24h" versus "what was your average pain during the last 2 weeks"); (2) difficulty in comparing pain from different etiologies; (3) difficulties in reporting sensations of pain in a manner unaffected by issues and situations secondary to the pain experience, such as difficulties in activities of daily living. In the present paper we use ANOVA (analysis of variance) and partial correlation to determine whether the qualitatively derived perceptions are reflected in the quantitative pain intensity scores. RESULTS: Participants' belief that it was difficult to "average" pain intensity over different time periods was supported. The data do not support their belief that pain intensity scores are affected by other factors: their specific pain diagnosis, and the extent to which pain interfered with their activities of daily living. CONCLUSIONS: (1) Patients tend to report different levels of pain intensity when asked to report their pain over different periods; (2) insofar as it can be said to exist, the relationship between measures of intensity and interference with activities of daily living is minimal; (3) participants tend to report similar levels of pain intensity, irrespective of etiology. IMPLICATIONS: (1) Chronic pain patients' elicited beliefs and strategies concerning how they complete pain intensity questionnaires are sometimes, but not invariably, reflected in their responses to these measures. Thus, purely qualitative methodologies alone cannot provide completely reliable information and point to the need to use a "mixed methods" approach combining both qualitative and quantitative data; (2) the lack of association between pain intensity measures and interference with activities of daily living, as well as relative insensitivity to different etiologies underlines the problem in relying on pain intensity measures as the primary means of evaluating the success of a treatment, either for pain management or in clinical research. PMID- 28850475 TI - Psychophysiological effects of threatening a rubber hand that is perceptually embodied in healthy human subjects. PMID- 28850474 TI - Postoperative pain documentation in a hospital setting: A topical review. AB - BACKGROUND AND AIMS: Nursing documentation supports continuity of care and provides important means of communication among clinicians. The aim of this topical review was to evaluate the published empirical studies on postoperative pain documentation in a hospital setting. METHODS: The review was conducted through a systematic search of electronic databases: Web of Science, PubMed/Medline, CINAHL, Embase, Ovid/Medline, Scopus and Cochrane Library. Ten studies were included. Study designs, documented postoperative pain information, quality of pain documentation, reported quality of postoperative pain management and documentation, and suggestions for future research and practice improvements were extracted from the studies. RESULTS: The most commonly used study design was a descriptive retrospective patient record review. The most commonly reported types of information were pain assessment, use of pain assessment tools, use of pain management interventions, reassessment, types of analgesics used, demographic information and pain intensity. All ten studies reported that the quality of postoperative pain documentation does not meet acceptable standards and that there is a need for improvement. The studies found that organization of regular pain management education for nurses is important for the future. CONCLUSIONS: Postoperative pain documentation needs to be improved. Regular educational programmes and development of monitoring systems for systematic evaluation of pain documentation are needed. Guidelines and recommendations should be based on the latest research evidence, and systematically implemented into practice. IMPLICATIONS: Comprehensive auditing tools for evaluation of pain documentation can make quality assessment easier and coherent. Specific and clear documentation guidelines are needed and existing guidelines should be better implemented into practice. There is a need to increase nurses' knowledge of postoperative pain management, assessment and documentation. Studies evaluating effectiveness of high quality pain documentation are required. PMID- 28850476 TI - The Survey of Pain Attitudes: A revised version of its pediatric form. AB - BACKGROUND AND AIMS: Valid and reliable measures of patients' pain beliefs are needed by clinicians and researchers to better understand the efficacy and mechanisms of pain treatments. The objective of this work was to address this need by further developing the pediatric version of the Survey of Pain Attitudes (Peds-SOPA), one of the most commonly used measures of pain beliefs. METHODS: A convenience sample of three hundred and seven adolescents (mean age= 14.35; SD=1.62; 59% girls) participated in the study. They rated the intensity of their worst pain experienced in the 3 months prior to the assessment and completed both the Functional Disability Inventory and a revised version of a pediatric version of the Survey of Pain Attitudes (Peds-SOPA-R). RESULTS: Factor analyses confirmed a seven-factor solution of the questionnaire, and the revised version demonstrated improvements in the internal consistency of several of the scales (values ranged between adequate and good: 0.71-0.87), except for the Medical Cure scale which showed an internal consistency value of 0.65. The results support the validity of the Peds-SOPA-R scale scores by showing, as predicted, positive relationships between beliefs thought to be maladaptive (e.g., the belief that one is unable to function because of pain) and pain intensity and disability, and negative relationships with beliefs thought to be adaptive (e.g., the belief that exercise is beneficial for pain management) and these criterion variables. CONCLUSIONS: These findings will be helpful to researchers who wish to study the role that pain beliefs play in adjustment to pain in youth. IMPLICATIONS: The results provide critical psychometric information about a revised version of one of the most used questionnaires to assess pain beliefs. The evidence presented will be helpful to researchers who want to study the role that pain beliefs play in adjustment to chronic pain in young people. PMID- 28850477 TI - Transmucosal fentanyl for severe cancer pain: Nasal mucosa superior to oral mucosa? PMID- 28850478 TI - Social Anxiety, Pain Catastrophizing and Return-To-Work Self-Efficacy in chronic pain: a cross-sectional study. AB - BACKGROUND AND AIMS: Returning to work after periods of sick-leave due to chronic pain problems, involve a number of situations of interpersonal nature (e.g. meeting supervisors/insurance companies to adapt work setting to present functional level, receive help from colleagues, express pain, etc.). Since chronic pain has shown co-morbidity with social anxiety, it is of interest to investigate restraining factors in return to work among chronic pain sufferers from a social perspective. Catastrophizing is identified in both pain and social anxiety as a mechanism that might fuel a continuous bias in how situations are perceived (threat) and by hindering the development of functional behavior strategies. The presence of social anxiety in chronic pain patients might be seen as a stressor that limits the individuals' ability to effectively communicate pain-related needs to colleagues, and/or employers and therefore act as a hindering factor in return-to-work. Hence, the overall aim of this study was to examine the relationship between social anxiety, pain catastrophizing, and perceived ability to communicate pain-related needs to the work environment in a clinical pain population. METHODS: The study employed a cross-sectional design and involved 247 individuals with chronic pain (82.3% women; Mage=44 years). Measures included the Pain catastrophizing Scale, the Social Phobia Screening Questionnaire and the communication of pain-related needs-subscale of the Return To-Work Self-efficacy Questionnaire. Analyzes were run to examine whether social anxiety moderated the relation between pain catastrophizing, and perceived ability to communicate pain-related needs while controlling for pain severity/interference and sick leave. RESULTS: Social anxiety and pain catastrophizing correlated positively with each other and negatively with perceived ability to communicate pain-related needs. No support was obtained for a moderating effect of social anxiety. However, social anxiety and pain interference were each significant predictors of the individual's confidence in being able to communicate pain-related needs to the work environment. CONCLUSIONS: In the context of pain and work-related communication, symptoms of social anxiety was identified as being of similar importance to the outcome as pain interference, while pain severity was not associated with the individual's confidence in communicating one's pain-related needs. IMPLICATIONS: The results implicate that fears relating to pain-related social situations at work might be central in the process of return-to-work and rehabilitation in chronic pain. PMID- 28850479 TI - Genetic susceptibility to postherniotomy pain. The influence of polymorphisms in the Mu opioid receptor, TNF-alpha, GRIK3, GCH1, BDNF and CACNA2D2 genes. AB - BACKGROUND AND AIMS: Despite improvements in surgical technique, 5%-8% of patients undergoing herniorrhaphy still suffer from clinically relevant persistent postherniotomy pain. This is a problem at both individual and society levels. The aim of this study was to determine whether or not a single nucleotide polymorphism in a specific gene contributes to the development of persistent pain after surgery. METHODS: One hundred individuals with persistent postherniotomy pain, along with 100 without pain matched for age, gender and type of surgery were identified in a previous cohort study on patients operated for groin hernia. All patients underwent a thorough sensory examination and blood samples were collected. DNA was extracted and analysed for single nucleotide polymorphism in the Mu opioid receptor, TNF-alpha, GRIK3, GCH1, BDNF and CACNA2D2 genes. RESULTS: Patients with neuropathic pain were found to have a homozygous single nucleotide polymorph in the TNF-alpha gene significantly more often than pain-free patients (P=0.036, one-tailed test). CONCLUSIONS: SNP in the TNF-alpha gene has a significant impact on the risk for developing PPSP. IMPLICATIONS: The result suggests the involvement of genetic variance in the development of pain and this requires further investigation. PMID- 28850480 TI - Pain is prevalent among adolescents and equally related to stress across genders. AB - BACKGROUND: Young people seem increasingly disabled due to pain and stress. Pain and stress are health risks with adverse long-term health effects. Traditionally, these health risks have been most prevalent and strongest associated in females, also regarding children and adolescents. Main objectives in this study were to investigate current gender differences in musculoskeletal pain and perceived stress in adolescents aged 15 and 16 years with respect to prevalence and group differences for various aspects of stress and pain, and to explore the relationship between stress and pain, specified for gender. METHODS: A cross sectional study was conducted with 17 participating public schools. The survey was administrated by the schools in accordance with given procedures, emphasizing the volunteer and anonymous participation of the pupils. Primary study measurements were pain and stress. The pain measurements addressed different aspects of musculoskeletal pain including pain sites, pain duration and pain intensity (measured by a Visual analogue scale; VAS). The stress instrument used was the Perceived stress questionnaire (PSQ) comprising different factors of stress, i.e. worries, tension, joy and demands. The secondary study measurement was body mass index (BMI). RESULTS: The study sample comprised 422 adolescents aged 15 and 16 years; 218 females and 204 males. The pain reporting was high in both genders, 57.3 per cent of the females and 44.6 per cent of the males. In general, the female adolescents reported more pain and stress, although several pain measures corresponded between genders. The pain prevalence was similar across genders with respect to lower extremity pain, back pain and arm pain. Lower extremity pain was the most frequent reported pain in both genders. More females reported head pain (Pearson Chi-Square 7.11, p=.008), severe pain (VAS>=7, Pearson Chi-Square 13.12, p=.004) and moderate to severe stress (PSQ>=0.45, Pearson Chi-Square 29.11, p<.001). Comparison analyses of the continuous pain and stress variables revealed significant mean (95% confidence interval [CI]) differences between genders for all stress variables with the highest mean scores in females. In both genders there were significant (p<.01) correlations between all the continuous pain and stress variables. In 9 out of 15 correlations, the stress-pain associations were strongest in males (Pearson product-moment correlation (r) between 0.34 and 0.38). Only in females, the body mass index (BMI) appeared associated (weakly) to pain and stress, in terms of pain intensity (VAS, r=0.19) and lack of joy (as a factor of stress, r=0.16). CONCLUSION: Pain and stress were prevalent in the adolescent sample, with generally higher reporting among females. Several pain measures corresponded between genders, but stress differed significantly between genders for all variables. Scrutinizing the relationship between pain and stress revealed significant stress-pain associations regarding all variables across genders, i.e. the pain complaints among the adolescents seemed equally related to stress in males and females in the sample. PMID- 28850481 TI - The Brief Pain Inventory (BPI) - Revisited and rejuvenated? PMID- 28850482 TI - Confirmatory factor analysis of 2 versions of the Brief Pain Inventory in an ambulatory population indicates that sleep interference should be interpreted separately. AB - BACKGROUND: The Brief Pain Inventory (BPI-SF) is a widely-used generic pain interference scale, however its factor structure remains unclear. An expanded 10 item version of the Interference subscale has been proposed, but the additional value of the 3 extra items has not been rigorously evaluated. The purpose of this study was to evaluate and contrast the factorial and concurrent validity of the original 7-item and 10-item versions of the BPI-SF in a large heterogeneous sample of patients with chronic pain. METHODS: Exploratory and confirmatory factor analyses were conducted on independent subsets of the sample, and concurrent correlations with scales capturing similar constructs were evaluated. RESULTS: Two independent exploratory factor analyses (n=500 each) supported a single interference factor in both the 7- and 10-item versions, while confirmatory factor analysis (N=1000) suggested that a 2-factor structure (Physical and Affective) provided better fit. A 3-factor model, where sleep interference was the third factor, improved in model fit further. There was no significant difference in model fit between the 7- and 10-item versions. Concurrent associations with measures of general health, pain intensity and pain related cognitions were all in the anticipated direction and magnitude and were not different by version of the BPI-SF. CONCLUSIONS AND IMPLICATIONS: The addition of 3 extra items to the original 7-item Interference subscale of the BPI SF did not improve psychometric properties. The combined results lead us to endorse a 3-factor structure (Physical, Affective, and Sleep Interference) as the more statistically and conceptually sound option. PMID- 28850483 TI - Working memory, optimism and pain: An elusive link. PMID- 28850484 TI - Depressive symptoms are associated with poor outcome for lumbar spine surgery. AB - BACKGROUND AND AIMS: The symptoms of pain and depression often present concomitantly, but little is known as to how the different subtypes of depression affect surgical outcome. The aim of this study was to determine whether there is a difference in outcome after lumbar spine surgery between non-depressed patients and patients with different subtypes of depressive symptoms: non-melancholic (NmDS) and melancholic depression (MDS). METHODS: This was a cross-sectional postal survey. A self-made questionnaire, the Beck Depression Inventory (BDI) and the Oswestery Low Back Disability Questionnaire (ODI) were sent to patients who had undergone lumbar spine surgery in the Oulu University Hospital between June, 2005 and May, 2008. BDI>=10 were further classified into NmDS or MDS. RESULTS: A total of 537 patients (66%) completed the survey. Of these, 361 (67%) underwent disc surgery, 85 (16%) stabilizing surgery and 91 (17%) decompression. Participants were divided into three groups: BDI<10 N=324 (60%), NmDS N=153 (29%) and MDS N=60 (11%). The mean ODI (SD) in the BDI<10 group was 16 (15), in the NmDS group 36 (15), and in the MDS group 41 (18) (p<0.001). The ODI profiles were different between the groups (p<0.001). Pain was more frequent in depressive patients (88% of MDS, 81% in NmDS and 40% in BDI<10 patients experienced pain, p<0.001). The intensity of pain and pain-related disability was lowest among the patients in the BDI<10 group and highest among the MDS patients. Regular pain medication was used by 87% of patients in the MDS group, 93% of patients in the NmDS group, and 71% of patients in the BDI<10 group (p<0.001). Response to pain medication with NRS (0-10) was 5.6 among MDS, 5.8 among NmDS and 6.5 among BDI<10 patients (p<0.001). CONCLUSION: Different types of depressive symptoms are associated with poor outcome after lumbar spine surgery. The outcome was worst in patients suffering from the MDS subtype. This was observed in pain intensity, functional disability and response to pain medication. IMPLICATION: It would be important to evaluate depression pre- and postoperatively. Offering a tailored rehabilitation programme to MDS patients should be considered. PMID- 28850485 TI - Genetic susceptibility to postherniotomy pain. The influence of polymorphisms in the Mu opioid receptor, TNF-alpha, GRIK3, GCH1, BDNF and CACNA2D2 genes. PMID- 28850486 TI - New approach for treatment of prolonged postoperative pain: APS Out-Patient Clinic. AB - BACKGROUND AND AIMS: Persistent postoperative pain (PPP) is a significant clinical problem. Several patient-related risk factors for PPP have been identified, including a previous chronic pain problem, young age, female gender and psychological vulnerability. Intra- and postoperative risk factors include surgical complications such as infections, haematoma, nerve damage and repeated surgery. As the length of hospital stay has been shortened, some patients may be discharged despite ongoing pain and insufficient analgesic medication. The challenge is to identify patients at high risk of developing PPP and to create a targeted care pathway to ensure effective and safe pain treatment especially in the subacute postoperative phase at home. This observational study describes the first two years of the Acute Pain Service Out-Patient Clinic (APS-OPC) at the Helsinki University Hospital. METHODS: Patient characteristics, known risk factors, and details of treatment of PPP for the first 200 patients referred to our APS-OPC were retrospectively collected from the medical records. The APS-OPC clinic functions in close collaboration with the Multidisciplinary Pain Clinic (MPC), and the number of patients in need of physiotherapist, psychologist or psychiatrist counselling was recorded, as well as the number of patients referred to the MPC for further PPP management. RESULTS: Patients were referred to the APS OPC from different surgical specialities, the two most common being thoracic and orthopaedic surgery. Seventy per cent of the patients (139/200) presented symptoms indicating neuropathic postsurgical pain. The patients had, on average, five risk factors for PPP. The median time from surgery to the first contact to the APS-OPC was two months, and the median duration of follow-up was 2.8 months (0-16 months). The median number of contacts with APS-OPC was 3 (range 1-14). Every fourth patient needed only one contact to the APS-OPC. Nineteen per cent of the patients had an appointment with the physiotherapist and 20% with a psychologist or psychiatrist. At discharge after surgery, 54% of the patients were using weak opioids, 32% strong opioids and 71% gabapentinoids; at discharge from the APS-OPC, these numbers were 20%, 6% and 43%, respectively. Twenty-two per cent of the patients were referred to the MPC for further pain management. CONCLUSIONS: The APS-OPC provides a fluent fast-track method of ensuring effective multimodal analgesia in the subacute recovery phase after surgery. Even strong opioids can be safely used after discharge and then tapered off in close supervision of the APS-OPC anaesthesiologist. As the APS-OPC was implemented in close collaboration with the MPC, the multidisciplinary resources are easily available during the course of the APS-OPC treatment. IMPLICATIONS: The first two years of the APS-OPC have shown that a significant number of surgical patients benefit from continuing active pain management after discharge from hospital. This fast-track service provides physician-supervised titration of analgesics to improve pain relief in the subacute phase. An important task of the APS-OPC is to ensure that strong opioids are not inappropriately continued after recovery. Another goal of the APS-OPC is to identify patients in need of multidisciplinary pain management services to prevent chronification. PMID- 28850487 TI - The effects of experimental pain and induced optimism on working memory task performance. AB - BACKGROUND/AIMS: Pain can interrupt and deteriorate executive task performance. We have previously shown that experimentally induced optimism can diminish the deteriorating effect of cold pressor pain on a subsequent working memory task (i.e., operation span task). In two successive experiments we sought further evidence for the protective role of optimism on pain-induced working memory impairments. We used another working memory task (i.e., 2-back task) that was performed either after or during pain induction. METHODS: Study 1 employed a 2 (optimism vs. no-optimism)*2 (pain vs. no-pain)*2 (pre-score vs. post-score) mixed factorial design. In half of the participants optimism was induced by the Best Possible Self (BPS) manipulation, which required them to write and visualize about a life in the future where everything turned out for the best. In the control condition, participants wrote and visualized a typical day in their life (TD). Next, participants completed either the cold pressor task (CPT) or a warm water control task (WWCT). Before (baseline) and after the CPT or WWCT participants working memory performance was measured with the 2-back task. The 2 back task measures the ability to monitor and update working memory representation by asking participants to indicate whether the current stimulus corresponds to the stimulus that was presented 2 stimuli ago. Study 2 had a 2 (optimism vs. no-optimism)*2 (pain vs. no-pain) mixed factorial design. After receiving the BPS or control manipulation, participants completed the 2-back task twice: once with painful heat stimulation, and once without any stimulation (counter-balanced order). Continuous heat stimulation was used with temperatures oscillating around 1 degrees C above and 1 degrees C below the individual pain threshold. RESULTS: In study 1, the results did not show an effect of cold pressor pain on subsequent 2-back task performance. Results of study 2 indicated that heat pain impaired concurrent 2-back task performance. However, no evidence was found that optimism protected against this pain-induced performance deterioration. CONCLUSIONS: Experimentally induced pain impairs concurrent but not subsequent working memory task performance. Manipulated optimism did not counteract pain-induced deterioration of 2-back performance. IMPLICATIONS: It is important to explore factors that may diminish the negative impact of pain on the ability to function in daily life, as pain itself often cannot be remediated. We are planning to conduct future studies that should shed further light on the conditions, contexts and executive operations for which optimism can act as a protective factor. PMID- 28850488 TI - A small group Whiplash-Associated-Disorders (WAD) patients with central neck pain and movement induced stabbing pain, the painful segment determined by mechanical provocation: Fusion surgery was superior to multimodal rehabilitation in a randomized trial. AB - BACKGROUND: The majority of patients suffering from a whiplash injury will recover, but some will have symptoms (Whiplash Associated Disorders, WAD) for years despite conservative treatment. Some of these patients perceive neck pain that might come from a motion segment, possibly the disc. In comprehensive reviews no evidence has been found that fusion operations have a positive treatment effect on neck pain in WAD patients. PURPOSE: Our aim was to evaluate the possibility of (a) selecting a subgroup of chronic WAD patients based on specified symptoms possibly indicating segmental pain, and (b) treating said segmental pain through fusion operation based on non-radiological segment localization. The hypothesis was that fusion operation in this selected subgroup of chronic WAD patients could alleviate perceived neck pain. METHODS: Eligible patients for the study had a traffic accident as the origin for their neck pain, and no previous neck symptoms. Neck pain should be the predominant symptom and the pain origin reported to be in the midline, being dull, aching in character and at sudden movements combined by a stabbing pain in the same area. Forty-nine patients with these specified symptoms were identified among a large number of chronic WAD patients. Those selected had pronounced symptoms for a median of around 50 months and had previously been investigated and fully treated within the ordinary healthcare system without success. No neurological abnormalities were to be found at clinical examination and no specific changes to be seen on X ray and MRI. The patients were randomized to either cervical fusion operation or multimodal rehabilitation. By using a mechanical provocation test the level/s to be fused were identified. In all but one patient the surgery was performed anteriorly using microsurgical technique and a right-sided Smith-Pedersen approach and plate fixation. The multimodal rehabilitation at the Clinic of Medical Rehabilitation, Karolinska Hospital, Stockholm, included outpatient treatment for four days a week for six weeks and included treatment by physician, physiotherapists, occupational therapist, psychologists, social-service worker and nurses. Perceived change in neck pain was assessed using the Balanced Inventory for Spinal Disorders questionnaire at the 2-year-follow-up. RESULTS: Mean age of the patients was 38 and 40 years (surgery and rehabilitation groups, respectively), the most common type of accident being rear-end collision. At clinical examination muscle tenderness was not an outstanding sign. In most patients the mid-cervical region appeared to be the painful area but one patient localized the pain to C1. At follow-up 67% of the patients in the surgery group and 23% in the rehabilitation group assessed improvements in the ITT analysis. Corresponding proportions in the per protocol analysis were 83% and 12%, respectively. CONCLUSIONS: The results support the supposition that among patients with central neck pain for long periods of time following a whiplash injury there are some in whom the neck pain emanates from a motion segment, probably the disc, a situation suitable for fusion surgery. IMPLICATIONS: Thorough individual symptom evaluation in patients with chronic WAD may identify patients who will benefit from cervical fusion surgery. PMID- 28850489 TI - A surgical treatment for chronic neck pain after whiplash injury? PMID- 28850490 TI - Characteristics and consequences of the co-occurrence between social anxiety and pain-related fear in chronic pain patients receiving multimodal pain rehabilitation treatment. AB - BACKGROUND AND AIMS: Chronic pain problems are related to specific pain related fears and maladaptive pain-coping but also commonly co-occur with other anxiety problems. Shared emotional vulnerability factors may explain this comorbidity and may influence treatment outcome. Indeed, pain patients going through multimodal pain treatment are a heterogeneous group and treatment results vary. One understudied anxiety disorder co-occurring with pain is social anxiety. This may be relevant as many pain-related challenges are situated in social contexts. The aim of this study is to investigate the occurrence of subgroups with differential patterns of social anxiety and pain related fear in a sample of chronic pain patients who receive multimodal pain treatment. The aim is also to study the characteristics of these potential subgroups and the consequences of different patterns of social anxiety and pain related fear. METHODS: 180 patients with chronic musculoskeletal pain answered questionnaires before and after a multimodal pain treatment in a hospital rehabilitation setting in middle Sweden. A cluster analysis using pre-treatment scores on the Social Phobia Screening Questionnaire and the Tampa Scale of Kinesiophobia was performed. Subgroups were thereafter validated and compared on impairment due to social anxiety, pain catastrophizing, anxiety, and depression. Moreover, subgroups were described and compared on vulnerability factors (anxiety sensitivity, negative affect) and outcome factors (pain intensity, pain interference, and return to work self efficacy). RESULTS: Four distinct clusters emerged: (1) low scores, (2) pain related fear only, (3) social concern only, and (4) high social anxiety and pain related fear. Patients high on social anxiety and pain-related fear had significantly higher levels of anxiety sensitivity, negative affect, and higher general emotional symptomatology. They also had remaining problems posttreatment. CONCLUSIONS: A subgroup of patients with clinical levels of social anxiety has suboptimal rehabilitation results, with residual emotional problems and high levels of emotional vulnerability. IMPLICATIONS: These patients may be in need of additional treatment efforts that are not being met today. To prevent insufficient treatment results and prolonged work disability, these patients need to be detected during screening and may benefit from pain treatment that takes their emotional problems into account. PMID- 28850491 TI - Chronic compartment syndrome is an under-recognized cause of leg-pain. PMID- 28850492 TI - Is there a place for pulsed radiofrequency in the treatment of chronic pain? PMID- 28850493 TI - Depressive symptoms associated with poor outcome after lumbar spine surgery: Pain and depression impact on each other and aggravate the burden of the sufferer. PMID- 28850494 TI - Important development: Extended Acute Pain Service for patients at high risk of chronic pain after surgery. PMID- 28850495 TI - Transcranial magnetic stimulation, paravertebral muscles training, and postural control in chronic low back pain. PMID- 28850496 TI - Pain-related distress and clinical depression in chronic pain: A comparison between two measures. AB - BACKGROUND AND PURPOSE: Depression is a frequent co-morbid diagnosis in chronic pain, and has been shown to predict poor outcome. Several reviews have described the difficulty in accurate and appropriate measurement of depression in pain patients, and have proposed a distinction between pain-related distress and clinical depression. Aims of the current study were to compare (a) the overlap and differential categorisation of pain patients as depressed, and (b) the relationship to disability between the Structured Interview for DSM-IV (SCID Depression module) and the Hospital Anxiety and Depression Scale (HADS-D). METHODS: Seventy-eight chronic back pain patients were administered the SCID-D, the HADS-D and the Pain Disability Index (PDI). RESULTS: Significantly more patients were categorised with possible and probable depression by the HADS than the SCID-D. Results from Receiver Operating Characteristic (ROC) curve analysis suggested that the HADS-D provided better discriminatory ability to detect disability, demonstrating a better balance between sensitivity and specificity compared to the SCID-D, although a direct comparison between the two measurements showed no difference. CONCLUSIONS: The HADS-D is a reasonably accurate indicator of pain-related distress in chronic pain patients, and captures the link between disability and mood. IMPLICATIONS: It is likely that the SCID-D is better suited to identifying sub-groups with more pronounced psychiatric disturbance. PERSPECTIVE: Several reviews have proposed a distinction between pain-related distress and clinical depression. This study compared the overlap and differential categorisation of pain patients as depressed and the relationship to disability between the Structured Interview for DSM-IV (SCID-D; Depression module) and the Hospital Anxiety and Depression Scale (HADS-D). PMID- 28850497 TI - Pulsed radiofrequency in clinical practice - A retrospective analysis of 238 patients with chronic non-cancer pain treated at an academic tertiary pain centre. AB - BACKGROUND AND AIMS: Pulsed radiofrequency is a non-neurodestructive invasive pain treatment which, in contrast to conventional continuous radiofrequency treatment, does not entail nerve tissue destruction. The aim of this study was to retrospectively analyse the short-term benefits of a broad use of pulsed radiofrequency in clinical practice. METHODS: The medical records of all patients treated with pulsed radiofrequency, or who received a diagnostic test block with a local anaesthetic in view of such a treatment, were retrospectively analysed. The patients had been referred to a tertiary pain centre in Sweden. The treatment effect one month after pulsed radiofrequency was retrospectively graded as follows, based on the wordings of the medical records: major improvement; minor improvement; no change; or worsened. RESULTS: A total of 238 patients received 587 interventions from 2009 to 2014. Chronic low back pain (CLBP) was by far the most common treatment indication (57% of patients), followed by CLBP with sciatica (9%). The age at first pulsed radiofrequency was 55 (15-94) years (mean, range), and 65% were female. Thirty-six patients (15%) underwent only a diagnostic test block using a local anaesthetic, i.e., the test block did not lead to treatment with pulsed radiofrequency. A total of 445 pulsed radiofrequency interventions were performed on 202 patients. Dichotomizing data into responders (i.e., minor or major improvement) and non-responders (i.e., worsened or no change), we found that, out of 63 responders to a median branch diagnostic test block (either at the cervical or lumbar level), 33 were responders to the first following median branch pulsed radiofrequency. Hence the positive predictive value of a median branch test block was 52%. In 127 patients, the lumbar level was targeted for median branch pulsed radiofrequency because of clinically suspected lumbar facetogenic pain. Looking at the first treatment, 30% experienced major improvement after 1 month, 16% minor improvement, 36% no change, 5% a worsened situation, and the effect was not assessable in 13% of patients. Lone dorsal root ganglion L2-treatment for suspected discogenic lumbar pain was done on 39 patients and, after one month, the effect was not assessable in 17% of patients, 14% had major improvement, 14% minor improvement, and 55% had no change. In 40 patients, a dorsal root ganglion or a peripheral nerve was targeted because of a non-axial chronic pain condition. There was a plethora of indications, but the most common was by far related to some form of neuropathic pain (52% of interventions, mainly because of neuralgia), followed by chronic nociceptive shoulder pain (8% of interventions). CONCLUSIONS: This study shows that, after one month, the effect size of a broad and indiscriminate clinical use of pulsed radiofrequency is rather small. IMPLICATIONS: The clinical effectiveness of pulsed radiofrequency has to be investigated further in carefully selected and more homogenous patient groups, in order to define effective treatment niches for this nondestructive invasive treatment method. PMID- 28850498 TI - Prevalence of chronic compartment syndrome of the legs: Implications for clinical diagnostic criteria and therapy. AB - INTRODUCTION: Poorly defined musculoskeletal disorders are a common clinical problem and have considerable psychosocial impact. Chronic compartment syndrome (CCS) of the legs has primarily been noted in young athletes and soldiers. The epidemiology of CCS in the general population has not been studied previously. The aim of this study was to establish the prevalence of CCS of the legs in the general population and to study its association with possible etiological factors. METHODS: A two-stage population survey was performed, using a questionnaire followed by clinical examination. A sample of 3000 individuals aged 25-75 years was randomly selected from the general population. A clinical examination was offered to those answering "Yes" to the following question: "Do you wake up at nights due to leg pains or cramps, causing you to walk around?" Intracompartmental pressures in the leg were measured in 13 persons randomly selected from among those diagnosed with CCS after the clinical examination. RESULTS: Of the 3000 persons contacted, 2308 (76.9%) responders were included in the study. Leg pain or cramps at night was reported by 24% of the respondents. Age, rheumatic disease, use of hormone medication, heart failure, leg oedema, and peripheral arterial disease were all significantly associated with leg pain or cramps (P<0.05). Among 286 persons with leg pain who underwent a subsequent clinical examination, 91 persons (31.9%) were classified as definite CCS. This suggests a CCS prevalence of 7.6% in the total sample ([24%*31.9%/100]). In 13 of the individuals with CCS intracompartmental pressure was measured before and after performance of the step test exercise. One individual had a post-exercise pressure >15mmHg. None had post-exercise pressure past the conventional threshold of >30mmHg. CONCLUSION: Nocturnal leg pain or cramps is a common symptom. A significant part of the general population (7.6%) may have CCS of the legs, with symptoms ranging from very mild to severe. IMPLICATIONS: Considering the high prevalence of CCS found in this study, it is likely that a large proportion of those presenting with muscular pain actually have CCS. These persons are usually advised to increase their physical training to achieve some degree of pain relief. However, CCS patients may instead experience both increased leg pain and a proximal myalgia, which is possibly a referred pain. A demanding "gold standard" test (requiring identification of elevated of intracompartmental pressures), unclear diagnostic criteria, poor long-term results from incomplete surgery, and an uncertain explanation for what may be termed referred pain seem to have delayed the acceptance of CCS as a common cause of leg pain/cramps and numbness. At the same time, the enormous costs to society and the reduced quality of life of patients require that such disease entities are correctly diagnosed as they can be effectively treated by simple, low-risk surgical procedures. PMID- 28850499 TI - Influence of paravertebral muscles training on brain plasticity and postural control in chronic low back pain. AB - BACKGROUND AND PURPOSE: Isometric activation (ISOM) of deep multifidi muscles (MF) can influence postural adjustments and primary motor cortex (M1) function in chronic low back pain (CLBP). In order to better understand how ISOM impacts on CLBP condition, the present study contrasted ISOM after-effects on M1 function, MF postural activation and pain with another training, the global activation of paravertebral muscles (GLOB, hip extension). The main objective of this study was to compare the effects of ISOM and GLOB (3-week training each) on MF postural activation and M1 function in a CLBP population. METHODS: Twenty-four people with CLBP were randomly allocated to ISOM and GLOB groups for a 3-week daily practice. Pre/post-training after-effects were assessed by the onset of superficial MF (MF S) activation during ballistic limb movements (bilateral shoulder flexion in standing; unilateral hip extension in prine lying), MF-S corticomotor control tested by transcranial magnetic stimulation of M1, and assessment of pain, kinesiophobia and disability by standardized questionnaires. RESULTS: Both ISOM and GLOB improved pain and disability. However, only ISOM influenced M1 function (decreased corticospinal excitability and increased intracortical inhibition), fastened MF-S postural activation and decreased kinesiophobia. CONCLUSIONS: Changes of corticospinal excitability and of MF-S postural adjustments suggest that ISOM better influenced brain plasticity. Future studies should further test whether our novel findings relate to an influence of the exercises on the lumbopelvic control of different muscles and on cognitive function. Clinically, individual's evaluation remains warranted before prescribing one or the other of these two conventional exercises for reducing pain. IMPLICATIONS: This original study presents how motor control exercises can influence brain plasticity and postural control in chronic low back pain. This knowledge will impact on the decision of clinicians to prescribe specific exercises with a view of improving motor control in this musculoskeletal condition. PMID- 28850500 TI - Pain research reported at the 40th scientific meeting of the Scandinavian Association for the Study of Pain in Reykjavik, Iceland May 26-27, 2016. PMID- 28850501 TI - Females report higher postoperative pain scores than males after ankle surgery. AB - OBJECTIVES: The majority of patients experience moderate-to-intense pain following ankle surgery. Early, adequate treatment of postoperative pain is desirable for optimal pain relief, which in turn may facilitate optimal pulmonary function, normal respiration pattern, rehabilitation and prevention of a chronic pain condition. In this retrospective study, we aimed to identify possible predictors of moderate-to-intense postoperative pain while in the Post Anaesthesia Care Unit (PACU) in patients operated for ankle fractures. MATERIALS AND METHODS: Social demographics and clinical characteristics from admission throughout the stay in the PACU were collected from the hospital patient record system in retrospect. Pain was assessed using a Visual Analogue Scale (VAS) or a verbal Numeric Rating Scale (vNRS). A VAS/vNRS score 4-6 was classified as moderate and 7-10 as intense pain. Other factors which were investigated were time from ankle fracture to surgery, anaesthetic procedure, pre-, per- and postoperative medical treatment, radiological classification, complexity of fracture, operative technique, and time using tourniquet procedure. RESULTS: Data from 336 patients who underwent surgery to repair an ankle fracture between January 2009 and December 2010 were analysed. None of the following variables had a statistically significant effect on pain; age, weight, smoking, timeframe from fracture to operation, type of anaesthesia, opioids given peroperatively, complexity of the fracture, operation technique or tourniquet inflation procedure. Female sex predicted moderate-to-intense postoperative pain in the PACU with odds ratio 2.31 (95% confidence interval 1.39-3.86), P=0.001. As far as we know, this is the first study to show a sex difference in reporting pain in the first hours after surgery for ankle fracture. CONCLUSION: Female patients operated for ankle fracture report higher pain-intensity-score than male patients while in the PACU. IMPLICATIONS: Our findings suggest that treatment strategies to prevent high peaks of pain should particularly target women operated for an ankle fracture. PMID- 28850502 TI - The relationship between pain and perceived stress in a population-based sample of adolescents - Is the relationship gender specific? PMID- 28850503 TI - More postoperative pain reported by women than by men - Again. PMID- 28850504 TI - Social anxiety and pain-related fear impact each other and aggravate the burden of chronic pain patients: More individually tailored rehabilitation need. PMID- 28850505 TI - Increased deep pain sensitivity in persistent musculoskeletal pain but not in other musculoskeletal pain states. AB - BACKGROUND: Pressure pain thresholds (PPTs) in a non-painful body area are known to be affected in some chronic pain states. The aim of this study is to investigate PPTs in a pain-free body part in relation to pain persistence and intensity in patients with musculoskeletal pain. METHODS: Patients with musculoskeletal pain were divided into three different pain groups: acute pain (pain duration<3 months, n=38), regularly recurrent pain (regularly recurrent pain duration>3 months, n=56), persistent pain (persistent pain duration>3 months, n=52) and a healthy control group (n=51). PPT measures were conducted over the tibialis anterior muscle on the right leg in all groups. RESULTS: The persistent pain group showed significantly lower PPTs over the tibialis anterior muscle compared to controls. No significant differences were found between the acute and regularly recurrent pain groups compared to healthy controls. Significant correlations, albeit small, were found between pain intensity and PPTs. CONCLUSIONS: Increased deep pain sensitivity was found in patients with persistent musculoskeletal pain, but not in regularly recurrent pain or in acute pain. Yet, a limitation of the study is that it did not have sufficient power to detect small levels of increased deep pain sensitivity among the latter groups when compared to healthy controls. IMPLICATIONS: Knowledge about increased general hypersensitivity in persistent musculoskeletal pain could be important in clinical treatment. PMID- 28850506 TI - The relative importance of anxiety and depression in pain impact in individuals with migraine headaches. AB - BACKGROUND: Psychological factors are thought to impact headache as triggering, maintaining, and exacerbating factors. A better understanding of the role that modifiable factors, such as anxiety or depression, play in the impact of migraine could help identify potential treatment targets in this population. OBJECTIVES: The objective of this study was to evaluate the relative importance of anxiety and depression as predictors of the impact of migraine on function. Thus, we aim to understand the relative importance that anxiety and depression have on the impact of migraines by assessing both and some life domains. METHODS: Cross sectional study involving forty-three individuals, mostly females (93%), with migraine headaches aged between 20 and 60 years old. Participants answered questions about headache pain intensity at the time of data collection and the usual in the past 30 days (0-10 Numerical Rating Scales) as well as other pain characteristics (i.e., duration, frequency, and duration), headache impact (vitality and social, role, and cognitive functioning), anxiety and depression by using the Hospital Anxiety and Depression Scale. RESULTS: Anxiety (r=0.56, p<.001), but not depression (r=0.09, p=.59), was significantly associated with headache impact. Thus showing the relative importance that anxiety has on headache impact. CONCLUSIONS: The findings support a larger role for anxiety than depression in the impact of migraine headaches on patient function. There are a number of mechanisms by which anxiety could potentially influence the impact of headache on patient function, and this study highlights that anxiety could potentially be a trigger of headache activity. IMPLICATIONS: The findings thus suggest the possibility that treatments that focus on anxiety might be potentially more important for individuals with migraine than treatments that focus on depression, at least with respect to having a beneficial impact on the interference of headache with activity. Research is needed to evaluate the beneficial impact of anxiety treatment in individuals with migraine headaches. Clinicians should evaluate and consider treating, as appropriate and necessary, anxiety in patients with migraine. PMID- 28850508 TI - Analysis of pain-intensity measurements. PMID- 28850507 TI - Pressure and cold pain threshold reference values in a large, young adult, pain free population. AB - BACKGROUND AND AIMS: Currently there is a lack of large population studies that have investigated pain sensitivity distributions in healthy pain free people. The aims of this study were: (1) to provide sex-specific reference values of pressure and cold pain thresholds in young pain-free adults; (2) to examine the association of potential correlates of pain sensitivity with pain threshold values. METHODS: This study investigated sex specific pressure and cold pain threshold estimates for young pain free adults aged 21-24 years. A cross sectional design was utilised using participants (n=617) from the Western Australian Pregnancy Cohort (Raine) Study at the 22-year follow-up. The association of site, sex, height, weight, smoking, health related quality of life, psychological measures and activity with pain threshold values was examined. Pressure pain threshold (lumbar spine, tibialis anterior, neck and dorsal wrist) and cold pain threshold (dorsal wrist) were assessed using standardised quantitative sensory testing protocols. RESULTS: Reference values for pressure pain threshold (four body sites) stratified by sex and site, and cold pain threshold (dorsal wrist) stratified by sex are provided. Statistically significant, independent correlates of increased pressure pain sensitivity measures were site (neck, dorsal wrist), sex (female), higher waist-hip ratio and poorer mental health. Statistically significant, independent correlates of increased cold pain sensitivity measures were, sex (female), poorer mental health and smoking. CONCLUSIONS: These data provide the most comprehensive and robust sex specific reference values for pressure pain threshold specific to four body sites and cold pain threshold at the dorsal wrist for young adults aged 21-24 years. Establishing normative values in this young age group is important given that the transition from adolescence to adulthood is a critical temporal period during which trajectories for persistent pain can be established. IMPLICATIONS: These data will provide an important research resource to enable more accurate profiling and interpretation of pain sensitivity in clinical pain disorders in young adults. The robust and comprehensive data can assist interpretation of future clinical pain studies and provide further insight into the complex associations of pain sensitivity that can be used in future research. PMID- 28850509 TI - Increased deep pain sensitivity in persistent musculoskeletal pain but not in other musculoskeletal pain states. PMID- 28850510 TI - Anxiety could play a larger role than depression in migraine headache. PMID- 28850511 TI - The intricate relationship amongst pain intensity, fear and avoidance. PMID- 28850512 TI - Is there hope for the most complicated chronic pain patients facing back surgery? PMID- 28850513 TI - Local infiltration analgesia (LIA), risk of local anaesthetic systemic toxicity (LAST) and kidney failure from NSAID in elderly patients. PMID- 28850514 TI - The relationship between chronic pain and cardiovascular disease: Squaring the circle? PMID- 28850515 TI - Cortical reorganization of the healthy hand in upper-limb complex regional pain syndrome (CRPS): Is reorganizations of common beliefs about CRPS necessary? PMID- 28850516 TI - Pain relief during childbirth: Efficacy and safety of prolonging labour-analgesia with morphine directly into the lumbar cerebro-spinal-fluid (CSF). PMID- 28850517 TI - Attitude and belief of pain-therapists are important when trying to help chronic pain patients: The Norwegian version of the Pain Attitudes and Beliefs Scale (PABS) improved by Rasch analysis. PMID- 28850518 TI - Bringing the lab to the people: Experimental pain testing in the general population. PMID- 28850519 TI - Pain management in the Emergency Department - Still a long way to go? PMID- 28850520 TI - Optimists fare better when chronic pain strikes - Or does pain related disability make us pessimists? PMID- 28850521 TI - Construct validity and reliability of Finnish version of Orebro Musculoskeletal Pain Screening Questionnaire. AB - INTRODUCTION: Chronic pain causes suffering for affected individuals and incurs costs to society through work disability. Interventions based on early screening of psychological risk factors for chronic pain using screening tools such as the Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ) have been found to reduce work absenteeism and health care visits and increase perceived health. The aim of the current study was to translate the OMPSQ into Finnish and test its validity and reliability in a patient sample. METHODS: The OMPSQ was forward backward translated and cross-culturally adapted, and applied to our study population (n=69), the members of which had been referred to the Department of Physical and Rehabilitation Medicine of Oulu University Hospital from primary health care centres in Northern Finland due to chronic low back pain. The patients answered the OMPSQ two weeks before the hospital visit, and the follow up questionnaire either during the hospital visit, or after by mail. The reliability of the OMPSQ was evaluated using intraclass correlation coefficients (ICC). Factor analysis was used to group items of the OMPSQ, and internal consistency between the items was determined by calculating Cronbach's alphas. RESULTS: The cross-cultural adaptation revealed only minor semantic and cultural differences. Measurements showed reliability as moderate to nearly perfect for all of the OMPSQ items (ICC values ranged from 0.59 to 0.96). Items loaded into five different factors: disability, psychological symptoms, pain, fear avoidance, and work. All except one (work) showed acceptable internal consistency. The OMPSQ score was positively associated with both intensity of pain and the Oswestry Disability Index. CONCLUSIONS AND IMPLICATIONS: The reliability and construct validity of the Finnish version of the OMPSQ were good. The predictive ability of the OMPSQ in the Finnish population should be evaluated in further studies. PMID- 28850522 TI - Improving pain treatment in children. PMID- 28850523 TI - A randomized controlled trial of amitriptyline versus gabapentin for complex regional pain syndrome type I and neuropathic pain in children. AB - BACKGROUND: Treatment of neuropathic pain in children is challenging, and requires a multimodal approach of pharmacologic, physical, and psychological therapies; however there is little evidence to guide practice. Amitriptyline and gabapentin are first-line drugs for treating neuropathic pain in adults, yet no studies have examined their efficacy, or compared them directly, to determine which might be better for pain relief and sleep disturbance in children. METHODS: After informed consent was obtained, 34 patients aged 7-18 years diagnosed with complex regional pain syndrome type I (CRPS I) or a neuropathic pain condition were randomly allocated to receive either amitriptyline or gabapentin. Patients were followed for 6 weeks and assessed for pain intensity, sleep quality and adverse events. We blinded study personnel, including health-care providers, participants, parents, the research coordinator and the data analyst. Patients then completed quantitative sensory testing (QST) and a psychosocial pain assessment with the team psychologist, within 1-3 days of the start of the trial. RESULTS: At the end of the 6-week trial, patients on both drugs had important reductions in pain, having surpassed the minimally important difference (MID) of 1. The difference between the groups however was not statistically significant. For the secondary outcomes, we found no statistically significant difference between the two drugs in sleep score or adverse events suggesting that both drugs improve sleep score to a similar degree and are equally safe. CONCLUSIONS: Amitriptyline and gabapentin significantly decreased pain intensity scores and improved sleep. There were no significant differences between the two drugs in their effects on pain reduction or sleep disability. IMPLICATIONS: Although larger, multi-centred trials are needed to confirm our findings, including long term follow-up, both drugs appear to be safe and effective in treating paediatric patients in the first-line treatment of CRPS I and neuropathic pain over 6-weeks. PMID- 28850524 TI - Gut gateway to generalized pain. PMID- 28850526 TI - Corrigendum to 'Reliability of pressure pain threshold testing in healthy pain free young adults' [Scand. J. Pain 9 (2015) 38-41]. PMID- 28850525 TI - A low fermentable oligo-di-mono saccharides and polyols (FODMAP) diet reduced pain and improved daily life in fibromyalgia patients. AB - BACKGROUND AND AIMS: Fibromyalgia (FM) is a chronic, rheumatic disease characterized by widespread myofascial pain, of unknown aetiology, having a major impact on quality of life (QOL). Available pharmacotherapy for FM is marginally effective. FM is associated with co-morbidities of gastrointestinal (GI) disorders and Irritable Bowel Syndrome (IBS). There is growing evidence that diets low in FODMAPs, "fermentable oligo-, di- or mono-saccharides and polyols" [Low FODMAP Diet (LFD)], are effective in treating IBS. The aim of this pilot study was to examine the effects of LFDs on symptoms of FM, especially with regard to pain, QOL and GI disorders. METHODS: A longitudinal study using LFD intervention was performed on 38, 51+/-10 year-old, female patients diagnosed with FM for an average of 10 years, based on ACR (American College of Rheumatology) 2010 criteria. The study was conducted from January through May, 2015, using a four-week, repeated-assessment model, as follows: Moment 0 - introduction of the protocol to participants; Moment 1 - first assessment and delivery of individual LFD dietary plans; Moment 2 - second assessment and reintroduction of FODMAPs; Moment 3 - last assessment and final nutritional counselling. Assessment tools used were the following: RFIQ (Revised Fibromyalgia Impact Questionnaire), FSQ (Fibromyalgia Survey Questionnaire), IBS-SSS (Severity Score System), EQ-5D (Euro-QOL quality of life instrument), and VAS (Visual Analogue Scale). Daily consumption of FODMAPs was quantified based on published food content analyses. Statistical analyses included ANOVA, non-parametric Friedman, t-student and Chi-square tests, using SPSS 22 software. RESULTS: The mean scores of the 38 participants at the beginning of the study were: FSQ (severity of FM, 0-31) - 22+/-4.4; RFIQ (0-100) - 65+/-17; IBS-SSS (0-500) - 275+/-101; and EQ-5D (0-100) - 48+/-19. Mean adherence to dietary regimens was 86%, confirmed by significant difference in FODMAP intakes (25g/day vs. 2.5g/day; p<0.01). Comparisons between the three moments of assessment showed significant (p<0.01) declines in scores in VAS, FSQ, and RFIQ scores, in all domains measured. An important improvement was observed with a reduction in the severity of GI symptoms, with 50% reduction in IBS scores to 138+/-117, following LFD therapy. A significant correlation (r=0.36; p<0.05) was found between improvements in FM impact (declined scores) and gastrointestinal scores. There was also a significant correlation (r=0.65; p<0.01) between "satisfaction with improvement" after introduction of LFDs and "diet adherence", with satisfaction of the diet achieving 77% among participants. A significant difference was observed between patients who improved as compared to those that did not improve (Chi-square chi2=6.16; p<.05), showing that the probability of improvement, depends on the severity of the RFIQ score. CONCLUSIONS: Implementation of diet therapy involving FODMAP restrictions, in this cohort of FM patients, resulted in a significant reduction in GI disorders and FM symptoms, including pain scores. These results need to be extended in future larger studies on dietary therapy for treatment of FM. IMPLICATIONS: According to current scientific knowledge, these are the first relevant results found in an intervention with LFD therapy in FM and must be reproduced looking for a future dietetic approach in FM. PMID- 28850527 TI - Measuring outcomes of pain management. PMID- 28850528 TI - Osteoarthritis patients with pain improvement are highly likely to also have improved quality of life and functioning. A post hoc analysis of a clinical trial. AB - BACKGROUND: This analysis evaluated whether osteoarthritis patients achieving the greatest pain control and lowest pain states also have the greatest improvement in functioning and quality of life. METHODS: Patients (n=419) who failed prior therapies and who were switched to etoricoxib 60mg were categorized as pain responders or non-responders at 4 weeks based on responder definitions established by the Initiative on Methods, Measurement, and Pain (IMMPACT) criteria, including changes from baseline of >=15%, >=30%, >=50%, >=70% and a final pain status of <=3/10 (no worse than mild pain). Pain was assessed at baseline and 4 weeks using 4 questions from the Brief Pain Inventory (BPI) (worst pain, least pain, average pain, and pain right now), and also using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. We examined the relationship between pain responses with changes from baseline in two functional measures (the BPI Pain Interference questions and the WOMAC Function Subscale) as well as changes from baseline in quality of life (assessed on the SF-36 Physical and Mental Component Summaries). We also sought to understand whether these relationships were influenced by the choice of the pain instrument used to assess response. We contrast the mean difference in improvements in the functional and quality of life instruments based on pain responder status (responder versus non-responder) and the associated 95% confidence limits around this difference. RESULTS: Patients with better pain responses were much more likely to have improved functional responses and improved quality of life, with higher mean changes in these outcomes versus pain non-responders, regardless of the choice of IMMPACT pain response definition (e.g., using any of 15%, 30%, 50%, 70% change from baseline) or the final pain state of <=3/10. There was an evident gradient, where higher levels of pain response were associated with greater mean improvements in function and quality of life. The finding that greater pain responses led to greater functional improvements and quality of life gains was not dependent on the manner in which pain was evaluated. Five different pain instruments (e.g., the 4 questions on pain from the BPI pain questionnaire and the WOMAC pain subscale) consistently demonstrated that pain responders had statistically significantly greater improvements in function and quality of life compared to pain non-responders. This suggests these results are likely to be generalizable to any validated pain measure for osteoarthritis. CONCLUSIONS: Pain is an efficient outcome measure for predicting broader patient response in osteoarthritis. Patients who do not achieve timely, acceptable pain states over 4 weeks were less likely to experience functional or quality of life improvements. IMPLICATIONS: Good pain improvements in osteoarthritis with a valid pain instrument are a proxy for good improvements in both function and quality of life. Therefore proper osteoarthritis pain assessment can lead to efficient evaluations in the clinic. PMID- 28850529 TI - An exploration into the cortical reorganisation of the healthy hand in upper-limb complex regional pain syndrome. AB - BACKGROUND AND AIMS: Recent evidence demonstrated that complex regional pain syndrome (CRPS) is associated with a larger than normal somatosensory (S1) representation of the healthy hand. The most intuitive mechanism for this apparent enlargement is increased, i.e. compensatory, use of the healthy hand. We investigated whether enlargement of the S1 representation of the healthy hand is associated with compensatory use in response to CRPS. Specifically, we were interested in whether the size of the S1 representation of the healthy hand is associated with the severity of functional impairment of the CRPS-affected hand. We were also interested in whether CRPS duration might be positively associated with the size of the representation of the healthy hand in S1. METHODS: Using functional magnetic resonance imaging (fMRI) data from our previous investigation, the size of the S1 representation of the healthy hand in CRPS patients (n=12) was standardised to that of a healthy control sample (n=10), according to hand dominance. Responses to questionnaires on hand function, overall function and self-efficacy were used to gather information on hand use in participants. Multiple regression analyses investigated whether the S1 representation was associated with compensatory use. We inferred compensatory use with the interaction between reported use of the CRPS-affected hand and (a) reported overall function, and (b) self-efficacy. We tested the correlation between pain duration and the size of the S1 representation of the healthy hand with Spearman's rho. RESULTS: The relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and overall function was small and non-significant (beta=-5.488*10 5, 95% C.I. -0.001, 0.001). The relationship between the size of the S1 representation of the healthy hand and the interaction between use of the affected hand and self-efficacy was also small and non-significant (beta= 6.027*10-6, 95% C.I. -0.001, 0.001). The S1 enlargement of the healthy hand was not associated with pain duration (Spearman's rho=-0.14, p=0.67). CONCLUSION: Our exploration did not yield evidence of any relationship between the size of the healthy hand representation in S1 and the severity of functional impairment of the CRPS-affected hand, relative to overall hand use or to self-efficacy. There was also no evidence of an association between the size of the healthy hand representation in S1 and pain duration. The enlarged S1 representation of the healthy hand does not relate to self-reported function and impairment in CRPS. IMPLICATIONS: While this study had a hypothesis-generating nature and the sample was small, there were no trends to suggest compensatory use as the mechanism underlying the apparent enlargement of the healthy hand in S1. Further studies are needed to investigate the possibility that inter-hemispheric differences seen in S1 in CRPS may be present prior to the development of the disorder. PMID- 28850530 TI - Patient Reported Outcomes (PROs) are sensitive outcome-variables in patients with chronic pain: Importance of self-efficacy. PMID- 28850531 TI - A preoperative interdisciplinary biopsychosocial opioid reduction program in patients on chronic opioid analgesia prior to spine surgery: A preliminary report and case series. AB - BACKGROUND: Spine surgery candidates are commonly treated with long-term opioid analgesia. However, chronic opioid analgesia is associated with poor pain control, psychological distress, decreased functional status and operative complications. Therefore, our medical centre piloted an outpatient biopsychosocial interdisciplinary opioid reduction program for spine surgery candidates on chronic opioid analgesia. METHODS: Our case series reviews the outcomes of the first 5 interdisciplinary program completers. Data was collected on admission to the program, preoperatively at completion of the program, and 1 month postoperatively. We recorded changes in pain interference scores, physical functioning, and symptoms of depression and anxiety as captured by the Patient Reported Outcome Measurement Information System (PROMIS-29) Profile. RESULTS: The mean duration of the preoperative opioid reduction program was 6-7 weeks. The mean morphine equivalent daily dose (SD) decreased from 238.2 (226.9)mg on admission to 157.1 (161.0)mg preoperatively and 139.1 (84.0)mg one month postoperatively. Similarly, the mean pain interference score (SD) decreased from 72.4 (5.1) on admission to 66.5 (6.9) preoperatively and 67.7 (5.4) one month postoperatively. The preoperative opioid dose and pain interference scores decreased in all 5 patients, but one month postoperatively increased in one patient related to a surgical complication. Pre- and post-operative depression, anxiety and fatigue improved in all patients. Satisfaction with participation in social roles, sleep disturbances, and physical functioning improved in most patients. CONCLUSIONS: Pre- and post-operative pain improved despite the opioid dose being tapered. These preliminary data suggest that a short-term outpatient preoperative interdisciplinary biopsychosocial opioid reduction program is safe, feasible, and improves patient-centred outcomes. IMPLICATIONS: Our preliminary data support the rationale for expansion of the opioid reduction program; opioid use and pain should be evaluated in all surgical candidates. These findings need to be replicated in larger studies. PMID- 28850532 TI - Mandatory documentation of pain in the emergency department increases analgesic administration but does not improve patients' satisfaction of pain management. AB - BACKGROUND: Pain is one of the most common symptoms treated in emergency department (ED). Pain may cause suffering and disability for the patient. Inadequate pain management may be associated with increased risk of complications such as sleep disturbance, delirium and depression. Previous studies conclude that pain management in ED is insufficient and inadequate. Yet, little is known about patients' own experience regarding pain management in ED. OBJECTIVE: The aim of this study was to explore the satisfaction of pain management in patients having acute musculoskeletal injuries before and after implementation of mandatory documentation regarding pain assessment in the ED. METHOD: An observational pre-post intervention study design was used. The study was conducted on patients having acute musculoskeletal injuries such as soft tissue injury, back pain or wrist/arm/leg/foot fractures in a 24-h adult (>15 years) ED at a public urban teaching hospital in Stockholm, Sweden. Data was collected by an interview based on a questionnaire. RESULTS: A total of 160 patients answered the questionnaire. In the pre- (n=80) and post-intervention (n=80) groups, 91/95% experienced pain in the ED. A significant difference (p<0.003) was found during the post-intervention period, with more patients receiving analgesics compared to the pre-intervention group. A significant decline (p<0.03) in patients' own reported pain intensity at discharge was found between the groups. Patients' reported satisfaction on pain management in the ED increased in the post intervention group, but the difference was not statistically significantly. CONCLUSION: Patients' satisfaction with pain management increased, but not statistically significantly. However, both percentages of patients receiving analgesic drugs increased and pain intensity decrease at discharge were statistically significant after the intervention that made nurses obliged to register pain. IMPLICATION: According to the findings of this study, mandatory pain documentation facilitates pain management in the ED, but there is still room for improvement. Additional actions are needed to improve patients' satisfaction on pain management in the ED. Mandatory pain documentation in combination with person-centred care could be a way of improving patients' satisfaction on pain management. Effective pain management is an important quality measure, and should be focused on in acute care in the ED. By routinely asking patients to report the pain intensity at discharge, the ED personnel can have direct feedback about the factual pain management. RNs may also be encouraged to use intravenous analgesics in higher extent when the patients have very severe pain. PMID- 28850533 TI - Prolonging the duration of single-shot intrathecal labour analgesia with morphine: A systematic review. AB - BACKGROUND AND AIMS: Single-shot spinal with bupivacaine plus fentanyl or sufentanil is commonly used as analgesia during labour, but the short duration limits the clinical feasibility. Different drugs have been added to prolong the analgesic duration. The additional effect of intra-thecal morphine has been studied during labour pain as well as after surgery. We assessed whether adding morphine to intra-thecal bupivacaine+fentanyl or sufentanil prolongs pain relief during labour. METHODS: Meta-analysis of placebo-controlled randomized clinical trials of analgesia prolongation after single-shot intrathecal morphine <=250MUg during labour when given in combination with bupivacaine+fentanyl or sufentanil. After identifying 461 references, 24 eligible studies were evaluated after excluding duplicate publications, case reports, studies of analgesia after caesarean delivery, and epidural labour analgesia. Mean duration in minutes was the primary outcome measure and was included in the calculation of the standardized mean difference. Duration was defined as the time between a single shot spinal until patient request of rescue analgesia. All reported side effects were registered. Results of individual trials were combined using a random effect model. Cochrane tool was used to assess risk of bias. RESULTS: Five randomized placebo-controlled clinical trials (286 patients) were included in the meta analysis. A dose of 50-250MUg intrathecal morphine prolonged labour analgesia by a mean of 60.6min (range 3-155min). Adding morphine demonstrated a medium beneficial effect as we found a pooled effect of standardized mean difference=0.57 (95% CI: -0.10 to 1.24) with high heterogeneity (I2=88.1%). However, the beneficial effect was statistically non-significant (z=1.66, p=0.096). The lower-bias trials showed a small statistically non-significant beneficial effect with lower heterogeneity. In influential analysis, that excluded one study at a time from the meta-analysis, the effect size appears unstable and the results indicate no robustness of effect. Omitting the study with highest effects size reduces the pooled effect markedly and that study suffers from inadequate concealment of treatment allocation and blinding. Trial quality was generally low, and there were too few trials to explore sources of heterogeneity in meta-regression and stratified analyses. In general, performing meta-analyses on a small number of trials are possible and may be helpful if one is aware of the limitations. As few as one more placebo-controlled trial would increase the reliability greatly. CONCLUSIONS: Evidence from this systematic review suggests a possible beneficial prolonging effect of adding morphine to spinal analgesia with bupivacaine+fentanyl or +sufentanil during labour. The study quality was low and heterogeneity high. No severe side effects were reported. More adequately-powered randomized trials with low bias are needed to determine the benefits and harms of adding morphine to spinal local anaesthetic analgesia during labour. IMPLICATIONS: Epidural analgesia is documented as the most effective method for providing pain relief during labour, but from a global perspective most women in labour have no access to epidural analgesia. Adding morphine to single shot spinal injection of low dose bupivacaine, fentanyl or sufentanil may be efficacious but needs to be investigated. PMID- 28850534 TI - A meta-analysis of fear-avoidance and pain intensity: The paradox of chronic pain. AB - BACKGROUND: The fear-avoidance model of chronic pain has established avoidance as a predictor of negative outcomes in chronic pain patients. Avoidance, or deliberate attempts to suppress or prevent unwanted experiences (e.g., pain), has been studied extensively, with multiple reviews implicating this behavior as a predictor of disability, physical disuse, and depression. Despite hundreds of studies examining the associations between different components of this model (i.e., catastrophizing, fear, avoidance, depression), the association between fear-avoidance and pain intensity has remained unclear. The present study seeks to clarify this association across samples. METHOD: The present analyses synthesize the literature (articles from PsycInfo, PubMed, and ProQuest) to determine if fear-avoidance and pain intensity are consistently correlated across studies, samples, and measures. Eligible studies measured pain intensity and fear avoidance cross-sectionally in chronic pain patients. The search resulted in 118 studies eligible for inclusion. A random-effects model was used to estimate the weighted mean effect size. Comprehensive Meta-Analysis software was used for all analyses. Moderation analyses elucidate the variables that affect the strength of this association. Meta-regression and meta-ANOVA analyses were conducted to examine moderating variables. Moderator variables include demographic characteristics, pain characteristics, study characteristics, and national cultural characteristics (using Hofstede's cultural dimensions). Publication bias was examined using the funnel plot and the p-curve. RESULTS: Results indicate a small-to-moderate positive association between fear-avoidance and pain intensity. The results were stable across characteristics of the sample, including mean age, gender distribution, marital status, and duration of pain. Moderation analyses indicate that the measures utilized and cultural differences affect the strength of this association. Weaker effect sizes were observed for studies that utilized measures of experiential avoidance when compared to studies that utilized pain specific fear-avoidance measures. Studies that utilized multiple measures of fear avoidance had stronger effect sizes than studies that utilized a single measure of fear-avoidance. Three of Hofstede's cultural dimensions moderated the association, including Power Distance Index, Individualism versus Collectivism, and Indulgence versus Restraint. CONCLUSIONS: The present meta-analysis synthesizes the results from studies examining the association between fear avoidance and pain intensity among individuals with chronic pain. The positive association indicates that those with increased fear-avoidance have higher pain intensity, and those with higher pain intensity have increased fear-avoidance. Findings indicate that cultural differences and measurement instruments are important to consider in understanding the variables that affect this association. The significant cultural variations may indicate that it is important to consider the function of avoidance behavior in different cultures in an effort to better understand each patient's cultural beliefs, as well as how these beliefs are related to pain and associated coping strategies. IMPLICATIONS: The results from the current meta-analysis can be used to inform interventions for patients with chronic pain. In particular, those with more intense pain or increased fear-avoidance should be targeted for prevention and intervention work. Within the intervention itself, avoidance should be undermined and established as an ineffective strategy to manage pain in an effort to prevent disability, depression, and physical deconditioning. PMID- 28850535 TI - Local infiltration analgesia in knee and hip arthroplasty efficacy and safety. AB - BACKGROUND: This is a secondary publication of a PhD thesis. Local infiltration analgesia (LIA) is a new multimodal wound infiltration method for treating postoperative pain after knee and hip arthroplasty. This method is based on systematic infiltration of a mixture of ropivacaine, a long acting local anaesthetic, ketorolac, a cyclooxygenase inhibitor (NSAID), and adrenalin around all structures subject to surgical trauma in knee and hip arthroplasty. AIMS: Paper I: to assess whether pain relief after LIA in total knee arthroplasty (TKA) is as effective as femoral block. Paper II: to assess whether the plasma concentration of ropivacaine and ketorolac after LIA in TKA reaches levels linked to toxicity. Paper III: to assess whether the plasma concentration of unbound ropivacaine after LIA in THA reaches levels linked to toxicity and if it is higher in THA as compared to TKA. Paper IV: to assess whether the plasma concentration of ketorolac after LIA in THA reaches levels linked to toxicity, and whether administration of ketorolac in LIA is safer as compared to the intramuscular route. METHODS: Two patient cohorts of 40 patients scheduled for elective total knee arthroplasty (TKA) and 15 patients scheduled for total hip arthroplasty (THA) contributed to this work. In a randomized trial the efficacy of LIA in TKA with regard to pain at rest and upon movement was compared to femoral block. RESULTS: Both methods result in a high quality pain relief and similar morphine consumption during the 24h monitoring period. In the same patient cohort the maximal total plasma concentration of ropivacaine was below the established toxic threshold for most patients. All patients in the THA cohort were subjected to the routine LIA protocol. In these patients both the total and unbound plasma concentration of ropivacaine was determined. The concentration was below the established toxic threshold. As ropivacaine binds to alpha-1 acid glycoprotein (AAG) we assessed the possibility that increased AAG may decrease the unbound concentration of ropivacaine. A 40% increase in AAG was detected during the first 24h after surgery, however the fraction of unbound ropivacaine remained the same. There was a trend towards increased Cmax of ropivacaine with increasing age and decreasing creatinine clearance but the statistical power was too low to draw any conclusion. Administration of 30mg ketorolac according to the LIA protocol both in TKA and THA resulted in a similar Cmax as previously reported after 10mg intramuscular ketorolac. Neither age, nor body weight or BMI, nor creatinine clearance, correlates to maximal ketorolac plasma concentration or total exposure to ketorolac (AUC). CONCLUSION: LIA provides good postoperative analgesia which is similar to femoral block after total knee arthroplasty. The plasma concentration of ropivacaine seems to be below toxic levels in most TKA patients. The unbound plasma concentration of ropivacaine in THA seems to be below the toxic level. IMPLICATION: The use of ketorolac in LIA may not be safer than other routes of administration, and similar restrictions should be applied in patients at risk of developing side effects. PMID- 28850536 TI - How to analyze the Visual Analogue Scale: Myths, truths and clinical relevance. AB - BACKGROUND AND AIMS: The Visual Analogue Scale (VAS) is a popular tool for the measurement of pain. A variety of statistical methods are employed for its analysis as an outcome measure, not all of them optimal or appropriate. An issue which has attracted much discussion in the literature is whether VAS is at a ratio or ordinal level of measurement. This decision has an influence on the appropriate method of analysis. The aim of this article is to provide an overview of current practice in the analysis of VAS scores, to propose a method of analysis which avoids the shortcomings of more traditional approaches, and to provide best practice recommendations for the analysis of VAS scores. METHODS: We report on the current usage of statistical methods, which fall broadly into two categories: those that assume a probability distribution for VAS, and those that do not. We give an overview of these methods, and propose continuous ordinal regression, an extension of current ordinal regression methodology, which is appropriate for VAS at an ordinal level of measurement. We demonstrate the analysis of a published data set using a variety of methods, and use simulation to compare the power of the various methods to detect treatment differences, in differing pain situations. RESULTS: We demonstrate that continuous ordinal regression provides the most powerful statistical analysis under a variety of conditions. CONCLUSIONS AND IMPLICATIONS: We recommend that in the situation in which no covariates besides treatment group are included in the analysis, distribution-free methods (Wilcoxon, Mann-Whitney) be used, as their power is indistinguishable from that of the proposed method. In the situation in which there are covariates which affect VAS, the proposed method is optimal. However, in this case, if the VAS scores are not concentrated around either extreme of the scale, normal-distribution methods (t-test, linear regression) are almost as powerful, and are recommended as a pragmatic choice. In the case of small sample size and VAS skewed to either extreme of the scale, the proposed method has vastly superior power to other methods. PMID- 28850537 TI - Assessing the relationship between chronic pain and cardiovascular disease: A systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Chronic pain is a potentially disabling condition affecting one in three people through impaired physical function and quality of life. While the psychosocial impact of chronic pain is already well established, little is known about the potential biological consequences. Chronic pain may be associated with an increased prevalence of cardiovascular disease, an effect that has been demonstrated across a spectrum of chronic pain conditions including low back pain, pelvic pain, neuropathic pain and fibromyalgia. The aim of this study was to review and summarize the evidence for a link between chronic pain and cardiovascular disease. We sought to clarify the nature of the relationship by examining the basis for a dose-response gradient (whereby increasing pain severity would result in greater cardiovascular disease), and by evaluating the extent to which potentially confounding variables may contribute to this association. METHODS: Major electronic databases MEDLINE, EMBASE, Psychinfo, Cochrane, ProQuest and Web of Science were searched for articles reporting strengths of association between chronic pain (pain in one or more body regions, present for three months or longer) and cardiovascular outcomes (cardiovascular mortality, cardiac disease, and cerebrovascular disease). Meta-analysis was used to pool data analysing the association between chronic pain and the three principal cardiovascular outcomes. The impact of pain severity, and the role of potentially confounding variables were explored narratively. RESULTS: The searches generated 11,141 studies, of which 25 matched our inclusion criteria and were included in the review. Meta-analysis (of unadjusted study outcomes) demonstrated statistically significant associations between chronic pain and mortality from cardiovascular diseases: pooled odds ratio 1.20, (95% confidence intervals 1.05-1.36); chronic pain and cardiac disease: pooled odds ratio 1.73 (95% confidence intervals 1.42-2.04); and chronic pain and cerebrovascular disease: pooled odds ratio 1.81 (95% confidence intervals 1.51-2.10). The systematic review also found evidence supporting a dose-response relationship, with greater pain intensity and distribution producing a stronger association with cardiovascular outcomes. All of the included studies were based on observational data with considerable variation in chronic pain taxonomy, methodology and study populations. The studies took an inconsistent and incomplete approach in their adjustment for potentially confounding variables, making it impossible to pool data after adjustments for confounding variables, so it cannot be concluded that these associations are causal. CONCLUSIONS: Our review supports a possible dose-response type of association between chronic pain and cardiovascular disease, supported by a range of observational studies originating from different countries. Such research has so far failed to satisfactorily rule out that the association is due to confounding variables. What is now needed are further population based longitudinal studies that are designed to allow more robust exploration of a cause and effect relationship. IMPLICATIONS: Given the high prevalence of chronic pain in developed and developing countries our results highlight a significant, but underpublicized, public health concern. Greater acknowledgement of the potentially harmful biological consequences of chronic pain may help to support regional, national and global initiatives aimed at reducing the burden of chronic pain. PMID- 28850538 TI - Constructs of health belief and disabling distal upper limb pain. AB - BACKGROUND: Musculoskeletal pain in the distal upper limb is common and is a cause of disability and healthcare consultation. At the time of presentation individuals reporting similar pain severities may report different levels of related disability. The biopsychosocial model proposes that health beliefs may help explain this difference. The aim of this cross-sectional study was to identify underlying constructs of health belief in those referred to physiotherapy with pain in the distal upper limb and investigate whether these constructs moderated the relationship between pain severity and extent of disability. METHOD: Health beliefs were assessed using an instrument included in a questionnaire completed before randomisation to the Arm Pain Trial (ISRCTN79085082). Ordinal responses to statements about health beliefs were used to generate a polychoric correlation matrix. The output from this matrix was then used for Exploratory Factor Analysis to determine underlying constructs. The moderating influence of the identified health belief constructs was then tested using interaction terms in linear regression models. RESULTS: 476 trial participants contributed data, age range 18-85 (mean 48.8, SD 13.7), 54% female. Five health belief constructs were identified: beliefs about hereditary factors, beliefs about movement and pain, beliefs about locus of control, beliefs about the role of lifecourse/lifestyle factors, and beliefs about prognosis. The only health belief construct found to moderate the pain-disability relationship was beliefs about prognosis, with greater pessimism resulting in higher levels of disability at mild-to-moderate levels of pain severity (B -0.17, 95% CI -0.30, 0.036). CONCLUSION: This exploratory cross-sectional study identified five constructs of health belief from responses to a previously used set of statements investigating fear avoidance and illness beliefs in a clinical population with pain in the distal upper limb. Of these constructs, beliefs about prognosis were found to moderate the relationship between pain and disability. IMPLICATIONS: At the time of referral to physiotherapy it may be beneficial to assess patients' perception of prognosis. For those with higher than expected disability for the presenting level of pain, and pessimism about prognosis, focused reassurance may play an important part in initial consultation. Longitudinal study is required to support the findings from this study and investigate whether a causal relationship exists. Future investigations should confirm the health belief constructs proposed. PMID- 28850539 TI - Rasch analysis resulted in an improved Norwegian version of the Pain Attitudes and Beliefs Scale (PABS). AB - BACKGROUND AND AIM: There is evidence that clinicians' pain attitudes and beliefs are associated with the pain beliefs and illness perceptions of their patients and furthermore influence their recommendations for activity and work to patients with back pain. The Pain Attitudes and Beliefs Scale (PABS) is a questionnaire designed to differentiate between biomedical and biopsychosocial pain attitudes among health care providers regarding common low back pain. The original version had 36 items, and several shorter versions have been developed. Concern has been raised over the PABS' internal construct validity because of low internal consistency and low explained variance. The aim of this study was to examine and improve the scale's measurement properties and item performance. METHODS: A convenience sample of 667 Norwegian physiotherapists provided data for Rasch analysis. The biomedical and biopsychosocial subscales of the PABS were examined for unidimensionality, local response independency, invariance, response category function and targeting of persons and items. Reliability was measured with the person separation index (PSI). Items originally excluded by the developers of the scale because of skewness were re-introduced in a second analysis. RESULTS: Our analysis suggested that both subscales required removal of several psychometrically redundant and misfitting items to satisfy the requirements of the Rasch measurement model. Most biopsychosocial items needed revision of their scoring structure. Furthermore, we identified two items originally excluded because of skewness that improved the reliability of the subscales after re introduction. The ultimate result was two strictly unidimensional subscales, each consisting of seven items, with invariant item ordering and free from any form of misfit. The unidimensionality implies that summation of items to valid total scores is justified. Transformation tables are provided to convert raw ordinal scores to unbiased interval-level scores. Both subscales were adequately targeted at the ability level of our physiotherapist population. Reliability of the biomedical subscale as measured with the PSI was 0.69. A low PSI of 0.64 for the biopsychosocial subscale indicated limitations with regard to its discriminative ability. CONCLUSIONS: Rasch analysis produced an improved Norwegian version of the PABS which represents true (fundamental) measurement of clinicians' biomedical and biopsychosocial treatment orientation. However, researchers should be aware of the low discriminative ability of the biopsychosocial subscale when analyzing differences and effect changes. IMPLICATIONS: The study presents a revised PABS that provides interval-level measurement of clinicians' pain beliefs. The revision allows for confident use of parametric statistical analysis. Further examination of discriminative validity is required. PMID- 28850540 TI - Maintaining protein composition in cilia. AB - The primary cilium is a sensory organelle that is vital in regulating several signalling pathways. Unlike most organelles cilia are open to the rest of the cell, not enclosed by membranes. The distinct protein composition is crucial to the function of cilia and many signalling proteins and receptors are specifically concentrated within distinct compartments. To maintain this composition, a mechanism is required to deliver proteins to the cilium whilst another must counter the entropic tendency of proteins to distribute throughout the cell. The combination of the two mechanisms should result in the concentration of ciliary proteins to the cilium. In this review we will look at different cellular mechanisms that play a role in maintaining the distinct composition of cilia, including regulation of ciliary access and trafficking of ciliary proteins to, from and within the cilium. PMID- 28850541 TI - Targeted degradomics in protein terminomics and protease substrate discovery. AB - Targeted degradomics integrates positional information into mass spectrometry (MS)-based targeted proteomics workflows and thereby enables analysis of proteolytic cleavage events with unprecedented specificity and sensitivity. Rapid progress in the establishment of protease-substrate relations provides extensive degradomics target lists that now can be tested with help of selected and parallel reaction monitoring (S/PRM) in complex biological systems, where proteases act in physiological environments. In this minireview, we describe the general principles of targeted degradomics, outline the generic experimental workflow of the methodology and highlight recent and future applications in protease research. PMID- 28850542 TI - Assessing regional lung mechanics by combining electrical impedance tomography and forced oscillation technique. AB - There is a lack of noninvasive pulmonary function tests which can assess regional information of the lungs. Electrical impedance tomography (EIT) is a radiation free, non-invasive real-time imaging that provides regional information of ventilation volume regarding the measurement of electrical impedance distribution. Forced oscillation technique (FOT) is a pulmonary function test which is based on the measurement of respiratory mechanical impedance over a frequency range. In this article, we introduce a new measurement approach by combining FOT and EIT, named the oscillatory electrical impedance tomography (oEIT). Our oEIT measurement system consists of a valve-based FOT device, an EIT device, pressure and flow sensors, and a computer fusing the data streams. Measurements were performed on five healthy volunteers at the frequencies 3, 4, 5, 6, 7, 8, 10, 15, and 20 Hz. The measurements suggest that the combination of FOT and EIT is a promising approach. High frequency responses are visible in the derivative of the global impedance index DeltaZeit(t,fos). $?Delta {Z_{{?text{eit}}}}(t,{f_{{?text{os}}}}).$ The oEIT signals consist of three main components: forced oscillation, spontaneous breathing, and heart activity. The amplitude of the oscillation component decreases with increasing frequency. The band-pass filtered oEIT signal might be a new tool in regional lung function diagnostics, since local responses to high frequency perturbation could be distinguished between different lung regions. PMID- 28850543 TI - Comparative study of the diagnostic and prognostic value of antibodies against chimeric citrullinated synthetic peptides and CCP3/CCP3.1 assays. AB - BACKGROUND: The objective of the study was to compare the diagnostic yield of home-made ELISA tests based on synthetic chimeric fibrin/filaggrin citrullinated peptides (CFFCPs) with CCP3 and CCP3.1 commercial tests to detect anti citrullinated protein/peptide antibodies (ACPAs) in rheumatoid arthritis (RA) patients. The prognostic value is also studied in a cohort of patients with early RA. Moreover, we transfer immunological assays from microtiter plates to microarray formats to allow the simultaneous analysis of several peptide sequences and reduce the volume of serum from patients. METHODS: The diagnostic study includes: 100 RA patients who fulfilled the 1987 ACR criteria; 100 healthy blood donors; 35 patients with SLE according ACR criteria; 35 patients with PsA fulfilling the Wright and Moll criteria and 30 patients with HCV infection. The prognostic value study includes 50 patients with early RA with follow-up data available. All samples are from outpatients attending the Rheumatology Department of the Hospital Clinic of Barcelona. RESULTS: Similar sensitivity, specificity and predictive values for the diagnosis of RA of CCFCPs compared to CCP3/CCP3.1 were obtained. Although a high concordance is observed between anti-CFFCPs and anti-CCP3/CCP3.1 in the early patients that rendered Larsen radiographic progression, CFFCPs could be a better marker of radiographic outcome. Strong correlations between the microarray and ELISA results were found for individual CFFCPs peptides. CONCLUSIONS: The development of multiplexing techniques combining a different spectrum of markers in a single analysis, including CFFCP peptides, could allow a more detailed analysis of the autoantibodies reactivity found in the sera of patients suffering of this heterogeneous disease. PMID- 28850544 TI - Breast cancer and pregnancy. AB - Background In the past decades the incidence of pregnancy-associated breast cancer (PABC) increased. Possible explanations are the trend to postpone childbearing and the general increase in the incidence of breast cancer. Materials and methods A sytematic review of the literature was performed with the aim to report on incidence, diagnosis, treatment and prognosis of breast cancer during pregnancy. We also cover the issue of pregnancy following a diagnosis of breast cancer including fertility preservation and prognosis. Results Ultrasound is the imaging method of choice in pregnancy, but mammography can also be performed as the fetal irradiation dose is low. To avoid a delay in diagnosis every sonographic mass in pregnant women which does not clearly correspond to a cyst needs further investigation by biopsy. Treatment should follow as close as possible the guidelines for non-pregnant patients. Administration of chemotherapy is possible after the first trimester. There is a large body of evidence for the use of anthracyclines. In contrast radiotherapy, trastuzumab and antihormonal treatment by tamoxifen are contraindicated during pregnancy. Pregnancy does not seem to influence prognosis. Most adverse obstetric outcomes are related to preterm delivery, which should therefore, whenever possible, be avoided. Young patients with breast cancer and incomplete family planning should be referred for counseling about fertility preservation options before the initiation of adjuvant treatment. A pregnancy following breast cancer does not have a negative impact on prognosis. Conclusion Multidisciplinary management of women with breast cancer in pregnancy is mandatory and data should be collected to allow further improvement in management. PMID- 28850545 TI - Endocrine and autocrine/paracrine modulators of brown adipose tissue mass and activity as novel therapeutic strategies against obesity and type 2 diabetes. AB - The dramatically increasing world-wide prevalence of obesity is recognized as a risk factor for the development of various diseases. The growing research on the role of adipose tissue in controlling energy homeostasis and insulin sensitivity has revealed that the promotion of brown adipose tissue (BAT) activity and the browning of white adipose tissue (WAT) leads to multiple health benefits and prevents obesity and type 2 diabetes (T2D). Inducible thermogenic adipocytes do exist in adult humans and are linked with increased energy combustion and lower body fat mass. Thus brown adipocytes are currently placed at the center of attention for novel therapeutic strategies against metabolic diseases such as obesity and diabetes. Besides the classical, norepinephrine-mediated sympathetic recruitment and activation of thermogenic adipocytes, a number of novel circulating factors have been recently identified to have a positive or negative impact on thermogenic adipocyte formation and activity. In this review their mechanism of action and the plausible therapeutic applications will be summarized and discussed. PMID- 28850546 TI - Excessive exercise among adolescents with eating disorders: examination of psychological and demographic variables. AB - Background While a large number of patients with eating disorders (EDs) engage in excessive exercise (EE), both for weight control and mood regulation, there has been minimal research evaluating the relationship between EE and demographic and psychological factors, especially in adolescent patients. Purpose The goals of this study were to identify the occurrence of EE compared to other ED behaviors and to develop a regression model examining psychological, behavioral and demographic predictors of EE among adolescents with EDs. Methods Demographic and clinical information was determined for 217 adolescent patients in several levels of care (126 outpatient, 61 day program, 28 inpatient) with diagnoses of anorexia nervosa (AN) (24.9%), bulimia nervosa (BN) (25.8%), and eating disorder not otherwise specified (EDNOS) (49.3%). These patients presented to a large ED program and completed a series of questionnaires on admission to the program. Descriptive statistics, t-tests, chi-square analyses and multiple logistic regression were utilized to describe the population of adolescent patients and develop the model for predicting EE. Results Forty-seven percent of patients indicated they participated in EE in the past 4 weeks, compared to 32% for binge eating, 35% for vomiting and 15% for laxative use; 42% of patients with anorexia nervosa participated in EE, compared to 54% with bulimia nervosa and 49% with EDNOS. The regression model that was developed to predict EE, which included factors of depression, anxiety, dietary restraint, age, body mass index (BMI), diagnosis and level of care, correctly classified EE in 71.5% of cases. Dietary restraint and BMI were the two factors found to be significantly associated with EE. Conclusions Forty-seven percent of adolescent patients presenting for treatment of an ED reported participating in EE. This was larger than the numbers of patients reporting other ED behaviors that are commonly assessed, indicating the need for psychoeducation for multidisciplinary treatment teams, assessment, prevention, and clinical treatment services for this problematic behavior. It is important that those who treat patients with ED assess for and monitor EE behaviors that can complicate the treatment. PMID- 28850547 TI - Perception of victims of rape and perception of gender social roles among college students in Southwest Nigeria: validation of a 5-item gender scale. AB - Our study focused on the perception of victims of rape and the relationship with the perception of social roles for gender among college students in southwest Nigeria using a 5-item gender social scale and a perception of victims of rape questionnaire. The study was done among 312 college students in Southwest Nigeria and explored the perception of victims of rape and gender social roles. The aim was to determine the relationship between perception of rape victims and view of gender social roles. We used a perception of rape victims questionnaire and a validated 5-item gender social roles scale to assess the views of participants. The findings revealed that females had better perception of victims of rape than males. Females also had more positive views of females' social roles involving gender. However, there was poor perception on work-related social roles and the traditional concept of headship in the varied situations described on the 5-item gender social scale. Old stereotypes of typically blaming victims of rape were not common beliefs among college students. There were no significant correlations between perception of victims of rape and perception of gender social roles among college students. Seemingly, the perception of victims of rape does not have a significant relationship with the concept of gender social roles. PMID- 28850548 TI - Math anxiety in Thai early adolescents: a cognitive-behavioral perspective. AB - With its high prevalence and debilitating impact on students, math anxiety is well studied within the educational context. However, the problem has yet to be examined from the psychological perspective, which is necessary in order to produce a more comprehensive perspective and to pave the way for therapeutic intervention. The current study, therefore, was conducted to identify cognitive and behavioral factors relevant to the occurrence and maintenance of math anxiety. Data were collected from 300 grade 9 students (150 females and 150 males) from public and private schools in Bangkok, Thailand. Participants responded to the measures of math anxiety, negative math beliefs, negative math appraisals and math avoidance. Structural equation modeling was conducted. Model fit indices obtained consistently suggested the good fitness of the model to the data [e.g. chi2/df = 0.42, root mean square error of approximation (RMSEA) = 0.00]. Negative math beliefs, negative math appraisals and math avoidance had a significant direct effect on math anxiety. Additionally, the indirect effect of negative math appraisal was observed between negative math beliefs and math anxiety. In summary, the proposed model accounted for 84.5% of the variance in the anxiety. The findings are discussed with particular focus on implications for therapeutic intervention for math anxiety. PMID- 28850549 TI - Youth friendly communication in a transition clinic aimed at adolescents with chronic illness. AB - Background Good communication skills are considered a cornerstone in a "youth friendly approach". However, research in the field as well as transition guidelines only sparsely explain what doctor-patient communication involves. Furthermore, only few guidelines exist regarding concrete communication skills for health professionals who want to apply a youth friendly communication approach to their practice. Objective To examine how health professionals trained in adolescent medicine practise a youth friendly approach when communicating with adolescents with chronic illness. Methods Data from 10 non-participation observations of transition consultations with adolescents with juvenile idiopathic arthritis (JIA) were analysed using a qualitative positioning analysis approach focusing on the health professionals' reflexive and interactive positionings as well as the decor of the consultation room. Results The health professionals in the transition clinic positioned the adolescent patients as independent interlocutors, children, and adolescents, and they positioned themselves as imperfect/untraditional, appreciative and non-judgmental. The positionings were based on a number of linguistic tools such as affirmation, recognition, examples, asking for the adolescents' own expert knowledge and the decor. The health professionals actively negotiated power. Conclusion Positionings and linguistic tools were inspired by youth friendly tools including the HEADS (Home Education/Eating Activities Drugs Sex/Safety/Self harm) interview, motivational interviewing, and an adolescent medicine practice. A central component was negotiating of power. Limitations of the study include a risk of too positive interpretations of data, i.e. because of the presence of the observer, who could have affected the health professionals' positionings. PMID- 28850550 TI - Ameliorative role of ethyl-acetate fraction of methanolic leaf extract of Camellia sinensis (green tea) on streptozotocin-induced diabetes linked testicular hypofunction in albino rat: A dose-dependent biochemical and genomic transection study. AB - Background The present investigation focuses the diabetes-induced testicular hypofunction and its possible correction by the effective dose of ethyl-acetate fraction of methanolic extract of Camellia sinensis leaves through dose-dependent study in streptozotocin-induced diabetic rat. Methods The androgenic, spermiological, oxidative stress and apoptosis sensors along with testicular genomic sensors were evaluated in a dose-dependent fashion (50 mg or 100 mg or 200 mg/kg body weight). Activities of hepatic transaminases for toxicity assessment were also measured. Results Increased level of fasting blood glucose, testicular cholesterol, seminal vesicular fructose along with a low count, motility and viability of epididymal sperm, low activities of testicular Delta5, 3beta-hydroxy steroid dehydrogenase (HSD), 17beta-HSD, testicular antioxidant enzymes (catalase and superoxide dismutase) and low plasma level of testosterone were noted in diabetic rat in respect to the control. After oral administration of said fraction to diabetic rat, levels of above sensors were resettled toward the control. A significant decrease in the number of different generations of germ cells at the stage VII of spermatogenesis in diabetic rat was noted which were recovered significantly toward the control in the fraction-treated diabetic group. It was supported by the correction in gene expression of testicular Delta5, 3beta- HSD, 17beta- HSD, Bcl-2 and Bax in the fraction-treated diabetic group. Conclusions The threshold dose of ethyl-acetate fraction of methanolic extract of C. sinensis leaves is 100 mg/kg body weight for the recovery of testicular hypofunction in a diabetic rat model. PMID- 28850551 TI - Wearable technology for patients with brain and spinal cord injuries. AB - Studies have shown that patients who practice functional movements at home in conjunction with outpatient therapy show higher improvement in motor recovery. However, patients are not qualified to monitor or assess their own condition that must be reported back to the clinician. Therefore, there is a need to transmit physiological data to clinicians from patients in their home environment. This paper presents a review of wearable technology for in-home health monitoring, assessment, and rehabilitation of patients with brain and spinal cord injuries. PMID- 28850552 TI - Superconductor-superconductor bilayers for enhancing single-photon detection. AB - Here, we optimized ultrathin films of granular NbN on SiO2 and of amorphous alphaW5Si3. We showed that hybrid superconducting nanowire single-photon detectors (SNSPDs) made of 2 nm thick alphaW5Si3 films over 2 nm thick NbN films exhibit advantageous coexistence of timing (<5 ns reset time and 52 ps timing jitter) and efficiency (>96% quantum efficiency) performance. We discuss the governing mechanism of this hybridization via the proximity effect. Our results demonstrate saturated SNSPDs performance at 1550 nm optical wavelength and suggest that such hybridization can significantly expand the range of available superconducting properties, impacting other nano-superconducting technologies. Lastly, this hybridization may be used to tune properties, such as the amorphous character of superconducting films. PMID- 28850553 TI - Osmotic Demyelination Syndrome Revisited: Review With Neuroimaging. AB - Osmotic demyelination syndrome (ODS) is a general term that has become commonplace in the practice of medicine, encompassing both central pontine myelinolysis and extrapontine myelinolysis. Historically ODS arises as a serious complication of rapid correction of hyponatremia, yet its manifestations seem to be influenced by a multifactorial process. Further understanding of this rare demyelinating disease has elucidated the significant role of other electrolyte disturbances and the presence of chronic comorbidities as disease risk factors. This review discusses the current research regarding the pathophysiology, clinical manifestations, neuroimaging features, patient management, and prognosis of osmotic demyelination syndrome. We hope that this review will further endorse and aid in the proper diagnosis of ODS and its suitable management through the understanding of clinical and imaging correlations and outcomes, and the comorbid factors that may predispose the development of ODS in certain patient populations. PMID- 28850554 TI - Pledget Induced Cardiogenic Shock Following a Minimally Invasive Aortic Valve Replacement. AB - Within the last decade, minimally invasive valve replacements have become exceedingly popular, and as a result, so has the rise of technology aimed at refining and simplifying these techniques. With new technology, new complications are inevitable. We present a routine Minimally invasive aortic valve replacement through a right anterior minithoracotomy complicated by pledget impaction in a coronary artery. PMID- 28850555 TI - Obturator Hernia, 'The Little Old Lady Hernia'. AB - Obturator hernia is a rare type of abdominal hernia that classically presents in elderly women. We report the case of 78-year-old woman with progressive vomiting, obstipation, and abdominal pain. Contrast-enhanced computed tomography showed a left-sided obturator hernia, which was confirmed and treated at laparotomy. Demographics, symptoms, imaging findings, and management of obturator hernias is reviewed. PMID- 28850556 TI - An Elderly Man with a Swollen Knee,Significant Ecchymosis, and Minimal Knee Pain. AB - A 72-year-old man presents with left knee pain and swelling over several days. The pain and swelling started after he felt a "pop" when bending to pick up an object off the floor. His past medical history is significant for type 2 diabetes mellitus. Physical exam revealed significant ecchymosis on the anterolateral aspect of the thigh. There was a minimal amount pain upon knee flexion. PMID- 28850557 TI - Postpartum Coronary Arterial Spasm. AB - BACKGROUND: Acute coronary syndrome (ACS) during postpartum period is rare. In the current manuscript we present a case of a postpartum patient who developed ACS attributed to coronary vasospasm in the absence of vasocontrictive medication or smoking. This condition resolved with intracoronary injection of nitroglycerine and verapamil. CASE: A 26-year-old woman, postpartum day five, presented with a sudden onset of chest pain and an acute ST-segment elevation on ECG. Coronary artery catheterization showed multiple areas of spasm, which was relieved by intracoronary injection of nitroglycerine and verapamil. Post catheterization hospital stay was uneventful and the patient was discharged in a stable condition. CONCLUSIONS: Early diagnosis and treatment of ACS in the peripartum period is crucial. Vasospastic coronary disease should be included in the differential diagnosis of peripartum chest pain. Nitrates are still considered the best treatment option with or without calcium channel blockers for both recurrence and prevention. PMID- 28850558 TI - Clinical Case of the Month:: Abdominal Pain in a 39-year-old Man with Recent International Travel. PMID- 28850559 TI - ECG Case of the Month: Wide-QRS Rhythm in a Man with a Clotted Dialysis Fistula. AB - A 57-year-old man with diabetes mellitus, systemic arterial hypertension, and end stage kidney disease came to the hospital because his arteriovenous fistula used for hemodialysis had clotted. His blood hemoglobin level was 12.8 g/dL (reference, 13.5-17.5); and serum chemistry levels were creatinine 6.7 mg/dL (0.7 1.3), sodium 132 mEq/L (136-146), potassium 4.0 mEq/L (3.5-5.1), chloride 94 mEq/L (98-106), carbon dioxide 24 mEQ/L (23-29), calcium 9.1 mg/dL (8.4-10.2), and phosphorus 9.1 mg/dL (2.7-4.5). An electrocardiogram was recorded (Figure 1). PMID- 28850560 TI - Radiology Case of the Month: TB or Not TB... That is the Question. AB - 45-year-old female presenting initially with fever, nonproductive cough, night sweats, pleuritic chest pain, fatigue and weight loss over the past month. PMID- 28850561 TI - Jumping Performance is Preserved but Not Muscle Thickness in Collegiate Volleyball Players After a Taper. AB - Bazyler, CD, Mizuguchi, S, Sole, CJ, Suchomel, TJ, Sato, K, Kavanaugh, AA, DeWeese, BH, and Stone, MH. Jumping performance is preserved but not muscle thickness in collegiate volleyball players after a taper. J Strength Cond Res 32(4): 1020-1028, 2018-The purpose of this study was to examine changes in muscle architecture and jumping performance in NCAA division I women's volleyball players throughout a competitive season and in preparation for conference championships. Ten women volleyball players were tested at preseason (T1), pretaper (T2), and post-taper (T3) on measures of vastus lateralis muscle thickness (MT), pennation angle (PA) and fascicle length (FL) using ultrasonography, and unloaded and loaded squat jump height (SJH) and peak power allometrically scaled to body mass (SJPPa) on a force platform. Rating of perceived exertion training load and strength training volume load were monitored weekly. Player's MT (p < 0.001, Glass's Delta = 2.8) and PA increased (p = 0.02, Delta = 3.9) after in-season training. However, MT decreased after the taper (p = 0.01, Delta = 0.6) but remained elevated above preseason values (p < 0.001, Delta = 1.7). There were no statistical changes in FL, SJH, or SJPPa. Large-to-very large negative relationships (r = -0.51 to -0.81) were observed between preseason relative maximal strength and changes in SJH and SJPPa with various loads over the season. These findings demonstrate that relatively low volumes of strength training and concurrent sport training during a tapering period are capable of preserving jumping performance, but not MT in women's volleyball players; however, jumping performance changes seem to be related to the player's strength level. Stronger players may benefit from an overreaching microcycle before the taper to preserve previously accrued muscular adaptations and jumping performance. PMID- 28850562 TI - The Pneumatization and Adjacent Structure of the Posterior Superior Maxillary Sinus and Its Effect on Nasal Cavity Morphology. AB - BACKGROUND The aim of this study was to observe the pneumatization degree and adjacent structure of the posterior superior maxillary sinus (PSMS) and its effect on nasal cavity morphology. MATERIAL AND METHODS The study included a total of 103 cases whose paranasal sinus CT scans had been analyzed. The pneumatization of the PSMS and its relationship with posterior ethmoid sinus (PEs) and sphenoid sinus (SS) were observed. The effects of the pneumatization of PSMS on nasal cavity width and morphology also were evaluated. RESULTS 1) The PSMS was adjacent to orbit or middle nasal meatus (MNM) as type I in 5.82% of cases. The PSMS was adjacent to the orbit and superior nasal meatus (SNM) as follows: the superior part of medial wall of maxillary sinus (MMS) was not abutting on PEs as type II (4.35%) and abutting on PEs as type III (85.9%). If the type III was not accompanied by MMS shift toward medial it was identified as type IIIa (33.50%), and if it was accompanied MMS shift toward medial, it was identified as type IIIb (45.63%). The ethmomaxillary sinus (EMS) was identified as type IIIc (6.80%). The PSMS directly abutted on the SS as type IV in (3.88%). 2) The higher the degree of the pneumatization of PSMS was, the narrower the width of the upper part of the posterior nasal cavity (p<0.05 respectively). CONCLUSIONS The relationship of PSMS with the orbit, SNM, PEs, and SS should be identified pre-operation; it is important for safety and complete removal of retromaxillary lesions during endoscopic sinus surgery. The pneumatization degree of PSMS also should be considered as it can influence the morphology of posterior nasal cavity. PMID- 28850563 TI - Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer. AB - BACKGROUND: Tyrosine kinase inhibitors (TKIs) have demonstrated clinical benefits in the treatment of several tumour types. However, the emergence of TKI resistance restricts the therapeutic effect. This study uses non-small cell lung cancer (NSCLC) to explore the mechanisms contributing to TKI resistance in tumours. METHODS: Biological phenotypes and RNA microarray expression data were analysed in NSCLC cells with and without TKI pretreatment. Specific inhibitors and siRNAs were used to validate the direct involvement of an AKT/FOXM1/STMN1 pathway in TKI resistance. Patients' tissues were analysed to explore the clinical importance of FOXM1 and STMN1. RESULTS: In vitro and in vivo studies showed that TKIs induced the enrichment of cancer stem cells (CSC), promoted epithelial to mesenchymal transition (EMT), and conferred multidrug resistance on NSCLC cells in a cell type- and TKI class-dependent manner. Mechanistically, TKIs activated an AKT/FOXM1/STMN1 pathway. The crucial role of this pathway in TKI induced enrichment of CSC and drug resistance was verified by silencing FOXM1 and STMN1 or blocking the AKT pathway. Additionally, overexpression of STMN1 was associated with upregulation of FOXM1 in advanced NSCLC patients, and STMN1/FOXM1 upregulation predicted a poor outcome. CONCLUSIONS: Our findings elucidate an additional common mechanism for TKI resistance and provide a promising therapeutic target for reversing TKI resistance in NSCLC. PMID- 28850564 TI - CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas. AB - BACKGROUND: Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis. METHODS: Prospective phase 2 multi-centre trials were conducted in ccRCC patients initiating sunitinib (54 patients) or bevacizumab (45 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). The plasmatic level of CXCL7 at baseline was correlated with progression-free survival (PFS). RESULTS: The cut-off value of CXCL7 for PFS was 250 ng ml-1. Patients with CXCL7 plasmatic levels above the cut-off at baseline (250 ng ml-1) had a significantly longer PFS (hazard ratio 0.323 (95% confidence interval 0.147 0.707), P=0.001). These results were confirmed in a retrospective validation cohort. The levels of CXCL7 did not influence PFS of the bevacizumab-treated patients. CONCLUSIONS: CXCL7 may be considered as a predictive marker of sunitinib efficacy for ccRCC patients. PMID- 28850565 TI - Dovitinib in patients with gastrointestinal stromal tumour refractory and/or intolerant to imatinib. AB - BACKGROUND: This multicentre phase II trial (DOVIGIST) evaluated the antitumour activity of dovitinib as second-line treatment of patients with gastrointestinal stromal tumour (GIST) refractory to imatinib or who do not tolerate imatinib. METHODS: Patients received oral dovitinib 500 mg day-1, 5 days on/2 days off, until GIST progression or unacceptable toxicity, with an objective to evaluate efficacy, assessed as the disease control rate (DCR) at 12 weeks. Tumour assessment and response to dovitinib therapy were evaluated by Response Evaluation Criteria In Solid Tumours (RECIST v1.1) and the Choi criteria. Secondary objectives included assessment of progression-free survival (PFS), safety and tolerability, and DCR at the end of treatment. RESULTS: Thirty-eight of the 39 patients enrolled had histologically confirmed GIST. The DCR at 12 weeks was 52.6% (90% confidence interval (CI), 38.2-66.7%) meeting the preset efficacy criterion for the primary end point. The objective response rate (complete response+partial response) was 2.6% (1 of 38; 90% CI, 0.1-11.9%), and 5.3% (n=2; 90% CI, 0.9-15.7%) at the end of the study. The median PFS was 4.6 months (90% CI, 2.8-7.4 months). Dose interruption was required in 26 patients (66.7%), of which 18 (69.2%) were due to adverse events. The most frequently observed grade 3 adverse events included hypertension (n=7), fatigue (n=5), vomiting (n=4), hypertriglyceridaemia (n=4), and gamma-glutamyltransferase increase (n=4). CONCLUSIONS: Dovitinib is an active treatment for patients with GIST who are intolerant to imatinib or whose GIST progresses on imatinib. PMID- 28850566 TI - Visual affective classification by combining visual and text features. AB - Affective analysis of images in social networks has drawn much attention, and the texts surrounding images are proven to provide valuable semantic meanings about image content, which can hardly be represented by low-level visual features. In this paper, we propose a novel approach for visual affective classification (VAC) task. This approach combines visual representations along with novel text features through a fusion scheme based on Dempster-Shafer (D-S) Evidence Theory. Specifically, we not only investigate different types of visual features and fusion methods for VAC, but also propose textual features to effectively capture emotional semantics from the short text associated to images based on word similarity. Experiments are conducted on three public available databases: the International Affective Picture System (IAPS), the Artistic Photos and the MirFlickr Affect set. The results demonstrate that the proposed approach combining visual and textual features provides promising results for VAC task. PMID- 28850567 TI - Human taste detection of glucose oligomers with low degree of polymerization. AB - Studies have reported that some animals, including humans, can taste mixtures of glucose oligomers (i.e., maltooligosaccharides, MOS) and that their detection is independent of the known T1R2/T1R3 sweet taste receptor. In an effort to understand potential mechanisms underlying the taste perception of glucose oligomers in humans, this study was designed to investigate: 1) the variability of taste sensitivity to MOS with low degree-of-polymerization (DP), and 2) the potential role of hT1R2/T1R3 in the MOS taste detection. To address these objectives, a series of food grade, narrow-DP-range MOS were first prepared (DP 3, 3-4, 5-6, and 6-7) by fractionating disperse saccharide mixtures. Subjects were then asked to discriminate these MOS stimuli as well as glucose (DP 1) and maltose (DP 2) from blanks after the stimuli were swabbed on the tongue. All stimuli were presented at 75 mM with and without a sweet taste inhibitor (lactisole). An alpha-glucosidase inhibitor (acarbose) was added to all test stimuli to prevent oral digestion of glucose oligomers. Results showed that all six stimuli were detected with similar discriminability in normal tasting conditions. When the sweet receptor was inhibited, DP 1, 2, and 3 were not discriminated from blanks. In contrast, three higher-DP paired MOS stimuli (DP 3 4, 5-6, and 6-7) were discriminated from blanks at a similar degree. Overall, these results support the presence of a sweet-independent taste perception mechanism that is stimulated by MOS greater than three units. PMID- 28850568 TI - Unsupervised primaquine for the treatment of Plasmodium vivax malaria relapses in southern Papua: A hospital-based cohort study. AB - BACKGROUND: Primaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria. It is a vital component of global malaria elimination efforts. Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown. We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia. METHODS AND FINDINGS: Routinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone. The omission of primaquine was predominantly due to 3 stock outages. Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital. Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis. The risk of re presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%-34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%-30.4%) after mixed-species infection. The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4% 50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4 24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15-2.31), p < 0.001. Overall, the risk of re-presentation was 37.2% (95% CI 35.6%-38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%-32.3%) in those prescribed either a low (>=1.5 mg/kg and <5 mg/kg) or high (>=5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86-0.95, p < 0.001]). Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85-0.97, p = 0.003). Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up. CONCLUSIONS: Unsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia. New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings. PMID- 28850569 TI - Productivity trends and collaboration patterns: A diachronic study in the eating disorders field. AB - OBJECTIVE: The present study seeks to extend previous bibliometric studies on eating disorders (EDs) by including a time-dependent analysis of the growth and evolution of multi-author collaborations and their correlation with ED publication trends from 1980 to 2014 (35 years). METHODS: Using standardized practices, we searched Web of Science (WoS) Core Collection (WoSCC) (indexes: Science Citation Index-Expanded [SCIE], & Social Science Citation Index [SSCI]) and Scopus (areas: Health Sciences, Life Sciences, & Social Sciences and Humanities) to identify a large sample of articles related to EDs. We then submitted our sample of articles to bibliometric and graph theory analyses to identify co-authorship and social network patterns. RESULTS: We present a large number of detailed findings, including a clear pattern of scientific growth measured as number of publications per five-year period or quinquennium (Q), a tremendous increase in the number of authors attracted by the ED subject, and a very high and steady growth in collaborative work. CONCLUSIONS: We inferred that the noted publication growth was likely driven by the noted increase in the number of new authors per Q. Social network analyses suggested that collaborations within ED follow patters of interaction that are similar to well established and recognized disciplines, as indicated by the presence of a "giant cluster", high cluster density, and the replication of the "small world" phenomenon-the principle that we are all linked by short chains of acquaintances. PMID- 28850570 TI - Apolipoprotein L1 risk variants associate with prevalent atherosclerotic disease in African American systemic lupus erythematosus patients. AB - OBJECTIVE: Atherosclerosis is exaggerated in African American (AA) systemic lupus erythematosus (SLE) patients, with doubled cardiovascular disease (CVD) risk compared to White patients. The extent to which common Apolipoprotein L1 (APOL1) risk alleles (RA) contribute to this trend is unknown. This retrospective cohort study assessed prevalent atherosclerotic disease across APOL1 genotypes in AA SLE patients. METHODS: One hundred thirteen AA SLE subjects were APOL1-genotyped and stratified as having: zero risk alleles, one risk allele, or two risk alleles. Chart review assessed CVD manifestations including abdominal aortic aneurysm, angina, carotid artery disease, coronary artery disease, myocardial infarction, peripheral vascular disease, stroke, and vascular calcifications. Associations between the genotypes and a composite endpoint defined as one or more CVD manifestations were calculated using logistic regression. Symptomatic atherosclerotic disease, excluding incidental vascular calcifications, was also assessed. RESULTS: The 0-risk-allele, 1-risk-allele and 2-risk-allele groups, respectively, comprised 34%, 53%, and 13% of the cohort. Respectively, 13.2%, 41.7%, and 60.0% of the 0-risk allele, 1-risk-allele, and 2-risk-allele groups met the composite endpoint of atherosclerotic CVD (p = 0.001). Adjusting for risk factors-including smoking, ESRD, BMI >25 and hypertension-we observed an association between carrying one or more RA and atherosclerotic CVD (OR = 7.1; p = 0.002). For symptomatic disease, the OR was 3.5 (p = 0.02). In a time-to-event analysis, the proportion of subjects free from the composite primary endpoint, symptomatic atherosclerotic CVD, was higher in the 0-risk-allele group compared to the 1-risk-allele and 2-risk-allele groups (chi2 = 6.5; p = 0.04). CONCLUSIONS: Taken together, the APOL1 RAs associate with prevalent atherosclerotic CVD in this cohort of AA SLE patients, perhaps reflecting a potentiating effect of SLE on APOL1-related cardiovascular phenotypes. PMID- 28850572 TI - Epibenthic communities associated with unintentional artificial reefs (modern shipwrecks) under contrasting regimes of nutrients in the Levantine Sea (Cyprus and Lebanon). AB - Artificial reefs, in the Eastern Mediterranean (Cyprus,) became a popular and frequently used tool, in fisheries and biodiversity conservation management. Even though evaluation studies about the efficacy of artificial reefs are plentiful in the rest of the Mediterranean (Central and Western), in the Eastern Basin they are largely absent. As the Eastern part of the Mediterranean Sea is characterised by unique physical parameters, the necessity to study artificial reefs under these contrasting regimes increases. The epibenthic communities of two unintentional artificial reefs (modern shipwrecks) in Cyprus (Zenobia) and Lebanon (Alice-B) were evaluated in 2010. Both shipwrecks are at similar depth, type of sea bottom, made of the same material (steel) and were sunk approximately the same period of time. However, Alice-B shipwreck off the coast of Lebanon is constantly exposed to higher levels of nutrients than Zenobia in Cyprus. Significant dissimilarities were observed in the composition, percentage of benthic cover of predominant taxonomic groups and development of the epibenthic communities. Differences in physical and chemical parameters between sides lay mainly in the nutrient and thermal regimes affecting the shipwrecks and most likely bring about the differences in the observed community structure. The results of this study suggest that epibenthic communities could be highly impacted by eutrophication caused by anthropogenic activities, leading to less biodiverse communities dominated by specific species that are favoured by the eutrophic conditions. PMID- 28850571 TI - Genomic dissection of conserved transcriptional regulation in intestinal epithelial cells. AB - The intestinal epithelium serves critical physiologic functions that are shared among all vertebrates. However, it is unknown how the transcriptional regulatory mechanisms underlying these functions have changed over the course of vertebrate evolution. We generated genome-wide mRNA and accessible chromatin data from adult intestinal epithelial cells (IECs) in zebrafish, stickleback, mouse, and human species to determine if conserved IEC functions are achieved through common transcriptional regulation. We found evidence for substantial common regulation and conservation of gene expression regionally along the length of the intestine from fish to mammals and identified a core set of genes comprising a vertebrate IEC signature. We also identified transcriptional start sites and other putative regulatory regions that are differentially accessible in IECs in all 4 species. Although these sites rarely showed sequence conservation from fish to mammals, surprisingly, they drove highly conserved IEC expression in a zebrafish reporter assay. Common putative transcription factor binding sites (TFBS) found at these sites in multiple species indicate that sequence conservation alone is insufficient to identify much of the functionally conserved IEC regulatory information. Among the rare, highly sequence-conserved, IEC-specific regulatory regions, we discovered an ancient enhancer upstream from her6/HES1 that is active in a distinct population of Notch-positive cells in the intestinal epithelium. Together, these results show how combining accessible chromatin and mRNA datasets with TFBS prediction and in vivo reporter assays can reveal tissue-specific regulatory information conserved across 420 million years of vertebrate evolution. We define an IEC transcriptional regulatory network that is shared between fish and mammals and establish an experimental platform for studying how evolutionarily distilled regulatory information commonly controls IEC development and physiology. PMID- 28850573 TI - Levels of L-malate and other low molecular weight metabolites in spores of Bacillus species and Clostridium difficile. AB - Dormant spores of Bacillus species lack ATP and NADH and contain notable levels of only a few other common low mol wt energy reserves, including 3 phosphoglyceric acid (3PGA), and glutamic acid. Recently, Bacillus subtilis spores were reported to contain ~ 30 MUmol of L-malate/g dry wt, which also could serve as an energy reserve. In present work, L-malate levels were determined in the core of dormant spores of B. subtilis, Bacillus cereus, Bacillus megaterium and Clostridium difficile, using both an enzymatic assay and 13C-NMR on extracts prepared by several different methods. These assays found that levels of L-malate in B. cereus and B. megaterium spores were <= 0.5 MUmol/g dry wt, and <= 1 MUmol/g dry wt in B. subtilis spores, and levels of L-lactate and pyruvate in B. megaterium and B. subtilis spores were < 0.5 MUmol/g dry wt. Levels of L-malate in C. difficile spores were <= 1 MUmol/g dry wt, while levels of 3PGA were ~ 7 MUmol/g; the latter value was determined by 31P-NMR, and is in between the 3PGA levels in B. megaterium and B. subtilis spores determined previously. 13C-NMR analysis of spore extracts further showed that B. megaterium, B. subtilis and C. difficile contained significant levels of carbonate/bicarbonate in the spore core. Low mol wt carbon-containing small molecules present at > 3 MUmol/g dry spores are: i) dipicolinic acid, carbonate/bicarbonate and 3PGA in B. megaterium, B. subtilis and C. difficile; ii) glutamate in B. megaterium and B. subtilis; iii) arginine in B. subtilis; and iv) at least one unidentified compound in all three species. PMID- 28850574 TI - Benthic macroinfaunal community structure, resource utilisation and trophic relationships in two Canadian Arctic Archipelago polynyas. AB - Climate change driven alterations to patterns of Arctic marine primary production, with increasing phytoplankton- and decreasing ice algal production, have the potential to change the resource utilisation and trophic structure of the benthic communities relying on the algae for food. To predict the benthic responses to dietary changes, we studied the macroinfaunal community compositions, and used the faunal delta13C and delta15N signatures to investigate their main food sources and trophic positions in North Water (NOW) and Lancaster Sound (LS) polynyas in the Canadian Arctic Archipelago. Macroinfaunal density (10 952 ind. m-2) and biomass (3190 mg C m-2) recorded in NOW were higher than previously found in the Arctic at depths >500m, and significantly higher than in LS (8355 ind. m-2 and 2110 mg C m-2). This was attributed to higher particulate organic matter fluxes to seafloor in NOW. Polychaetes were significant taxa at both sites in terms of density and biomass, and in addition crustacean density in NOW and bivalve density in LS were high. Facultative filter and surface deposit feeders were highly prevalent at both sites, suggesting feeding plasticity is a successful strategy for accessing different food sources. The macrofaunal delta13C signatures reflected the signatures of pelagic particulate organic matter at the sites, and an isotope mixing model confirmed phytoplankton as the main food source for most taxa and feeding guilds. The food web length in LS was longer than in NOW (3.2 vs. 2.8 trophic levels). This was attributed to a larger reliance on reworked organic matter by the benthic community in LS, whereas the high export fluxes at the highly productive NOW resulted in higher rates of selective consumption of fresh algal matter. Despite studies suggesting that loss of ice algae from consumer diets in the Arctic might have a negative impact on the benthos, this study suggests that Arctic macrobenthic communities thrive using phytoplankton as their main food source and should thus be able to cope or even benefit from predicted changes to patterns of primary production. PMID- 28850576 TI - Evaluating the impact of Affordable Care Act repeal on America's opioid epidemic. AB - In this month's Editorial, Health Commissioner of the City of Baltimore Leana S. Wen and co-authors discuss why the United States needs Medicaid to address its epidemic of opioid abuse. PMID- 28850575 TI - Minimally-invasive glaucoma surgeries (MIGS) for open angle glaucoma: A systematic review and meta-analysis. AB - BACKGROUND: MIGS have been developed as a surgical alternative for glaucomatous patients. PURPOSE: To analyze the change in intraocular pressure (IOP) and glaucoma medications using different MIGS devices (Trabectome, iStent, Excimer Laser Trabeculotomy (ELT), iStent Supra, CyPass, XEN, Hydrus, Fugo Blade, Ab interno canaloplasty, Goniscopy-assisted transluminal trabeculotomy) as a solo procedure or in association with phacoemulsification. METHODS: Randomized control trials (RCT) and non-RCT (non randomized comparative studies, NRS, and before after studies) were included. Studies with at least one year of follow-up in patients affected by primary open angle glaucoma, pseudoexfoliative glaucoma or pigmentary glaucoma were considered. Risk of Bias assessment was performed using the Cochrane Risk of Bias and the ROBINS-I tools. The main outcome was the effect of MIGS devices compared to medical therapy, cataract surgery, other glaucoma surgeries and other MIGS on both IOP and use of glaucoma medications 12 months after surgery. Outcomes measures were the mean difference in the change of IOP and glaucoma medication compared to baseline at one and two years and all ocular adverse events. The current meta-analysis is registered on PROSPERO (reference n degrees CRD42016037280). RESULTS: Over a total of 3,069 studies, nine RCT and 21 case series with a total of 2.928 eyes were included. Main concerns about risk of bias in RCTs were lack of blinding, allocation concealment and attrition bias while in non-RCTs they were represented by patients' selection, masking of participants and co-intervention management. Limited evidence was found based on both RCTs and non RCTs that compared MIGS surgery with medical therapy or other MIGS. In before-after series, MIGS surgery seemed effective in lowering both IOP and glaucoma drug use. MIGS showed a good safety profile: IOP spikes were the most frequent complications and no cases of infection or BCVA loss due to glaucoma were reported. CONCLUSIONS: Although MIGS seem efficient in the reduction of the IOP and glaucoma medication and show good safety profile, this evidence is mainly derived from non-comparative studies and further, good quality RCTs are warranted. PMID- 28850577 TI - Evaluation of genetic parameters for growth and cold tolerance traits in Fenneropenaeus chinensis juveniles. AB - In this study, genetic parameters were obtained for growth and cold tolerance of 99 Fenneropenaeus chinensis juvenile families by means of indoor artificial cooling (starting from 14 degrees C, 2 degrees C/d). A linear mixed model was fitted to estimate variance components using the ASReml software package. Heritabilities estimated for body weight (BW) and body length (BL) of F. chinensis juveniles were 0.078 +/- 0.124 and 0.131 +/- 0.133, respectively. The estimates of heritability were low in magnitude for both traits. The differences between the heritabilities estimated for the two growth traits were not significant with each other, and the heritabilities were not significantly different from zero (P > 0.05). The phenotypic and genetic correlation coefficients between BW and BL were as high as 0.9408 +/- 0.0040 and 0.9562 +/- 0.0551, respectively, and both were significantly different from zero (P < 0.01). The heritabilities of temperature at death (TAD) and cooling degree hours (CDH) were 0.265 +/- 0.091 and 0.077 +/- 0.058, respectively. The heritability estimates for TAD was moderate and significantly different from zero (P < 0.01). The correlation analysis indicated that the phenotypic correlation coefficient between TAD and CDH was -0.5470 +/- 0.0174, and the genetic correlation coefficient was -0.6707 +/- 0.3635. In the analysis of growth traits and cold tolerance traits, the values of phenotypic correlation coefficient were floating between -0.1055 and 0.1098, both were significantly different from zero (P < 0.05), while the genetic correlation had a larger range (0.0526 ~ 0.9914), and all were not significantly different from zero (P > 0.05). In this study, there was a low correlation between growth and cold tolerance traits, indicating that growth traits and cold tolerance traits should be considered collectively in the breeding program of shrimp. PMID- 28850578 TI - The nasal microbiota of dairy farmers is more complex than oral microbiota, reflects occupational exposure, and provides competition for staphylococci. AB - Allergic and autoimmune diseases had been attributed to lack of exposure to biodiversity, an important factor in regulating immune homeostasis in a healthy host. We posit that the microbiome of healthy dairy farmers (DF) will be richer than non-farmers (NF) living in urban settings due to exposure to a greater biodiversity in the dairy environment. However, no studies have investigated the relationships between microbiota of dairy farmers (DF) compared with urban non farmers (NF). We compared the nasal and oral microbiota of dairy farmers (N_DF, O_DF, respectively) with nasal and oral microbiota of NF in the same geographical area. The N_DF showed high microbial diversity with hundreds of unique genera that reflected environmental/occupational exposures. The nasal and oral microbiomes clustered separately from each other using Principal Coordinate Analysis, and with DF harboring two-fold and 1.5-fold greater exclusive genera in their nose and mouth respectively, than did non-farmers. Additionally, the N_DF group had a lower burden of Staphylococcus spp. suggesting a correlation between higher microbial diversity and competition for colonization by staphylococci. The N_DF samples were negative for the mecA gene, a marker of methicillin-resistance in staphylococci. The lower burden of staphylococci was found to be independent of the abundance of Corynebacterium spp. Exposure to greater biodiversity could enhance microbial competition, thereby reducing colonization with opportunistic pathogens. Future studies will analyze whether exposure to livestock microbiomes offers protection from acute and chronic diseases. PMID- 28850579 TI - Stability and change of lifestyle profiles in cardiovascular patients after their first acute coronary event. AB - BACKGROUND: Acute coronary syndrome (ACS) is a major cause of morbidity and mortality. Lifestyle and health behavior changes play an important role in the primary and secondary prevention of ACS recurrence. Changes in unhealthy lifestyles after an acute coronary event have been analyzed by considering separate behaviors individually, even though research on the healthy population has demonstrated that unhealthy behaviors tend to co-occur. PURPOSE: The aim of this study was to identify lifestyle profiles of ACS patients and to explore their pathways of change for one year after their first coronary event by adopting a typological approach. METHODS: Two hundred and twenty-three patients (84% male; mean age = 57.14) completed self-report measures of health-related behaviors at the beginning of cardiac rehabilitation, and six months and twelve months after. At each wave depression, anxiety and heart rate were also evaluated. Cluster analysis was performed to identify lifestyle profiles and to analyze their change over time. Differences in psychological factors and heart rate among clusters were assessed. RESULTS: Patients' diet, physical activity, and smoking behavior greatly improved six months after their first coronary event. No further improvements were detected after one year. At each wave specific lifestyle profiles were identified, ranging from more maladaptive to healthier clusters. Patients with multiple unhealthy behaviors experience greater difficulties in maintaining a healthier lifestyle over time. Moreover, the results demonstrated the association between lifestyle profiles at twelve months after the acute coronary event and depression measured six months earlier. Finally, the most maladaptive lifestyle profile had many members with elevated heart rate at twelve months after the cardiac rehabilitation. CONCLUSIONS: Current findings may have a strong practical impact in the development and implementation of personalized secondary prevention programs targeting lifestyles of ACS patients. PMID- 28850580 TI - Host species heterogeneity in the epidemiology of Nesopora caninum. AB - Pathogen transmission across species drives disease emergence; however, mechanisms by which multi-host pathogens cross species boundaries are not well identified. This knowledge gap prevents integrated and targeted control in an epidemiologically continuous ecosystem. Our goal is to describe the impact of host species heterogeneity on the epidemiology of Neospora caninum circulating between livestock and wildlife in southeastern Ohio. We collected biological samples from Pere David's deer (Elaphurus davidianus) located at an outdoor wildlife conservation center; from cattle raised at farms adjacent to the center; and from wild white-tailed deer that roamed across farm and center boundaries. We designed nested infectious disease models of competing hypotheses about transmission and used collected data to fit the models, thereby estimating important immunological and transmission quantities which describe the species specific contribution to the persistence of this pathogen in the community. We applied these data and models to suggest appropriate species-specific disease control methods. Results show that immunity in cattle and Pere David's deer wanes over time, while in white-tailed deer immunity appears to be lifelong. Transmission quantities for cattle were estimated at values below the threshold for an outbreak (Rt < 1), meaning that chains of transmission are not maintained within this population and infections must occur due to reintroduction from an outside source. Pere David's deer and white-tailed deer both could maintain continuous chains of transmission within their group (Rt > 1). Therefore, we propose that control of contact with outside sources will be useful for disease control in cattle; boosting immunity with vaccines might be an avenue to prevent infection in cattle and Pere David's deer. White-tailed deer are a potential maintenance host for infection and require further study to determine optimal control methods. Community-level investigations like this allow us to better evaluate heterogeneities in transmission processes that ultimately guide targeted control. PMID- 28850581 TI - Mother-to-child transmission of HIV in Kenya: A cross-sectional analysis of the national database over nine years. AB - OBJECTIVE: To describe factors associated with mother-to-child HIV transmission (MTCT) in Kenya and identify opportunities to increase testing/care coverage. DESIGN: Cross-sectional analysis of national early infant diagnosis (EID) database. METHODS: 365,841 Kenyan infants were tested for HIV from January 2007 July 2015 and results, demographics, and treatment information were entered into a national database. HIV risk factors were assessed using multivariable logistic regression. RESULTS: 11.1% of infants tested HIV positive in 2007-2010 and 6.9% in 2014-2015. Greater odds of infection were observed in females (OR: 1.08; 95% CI:1.05-1.11), older children (18-24 months vs. 6 weeks-2 months: 4.26; 95% CI:3.87-4.69), infants whose mothers received no PMTCT intervention (vs. HAART OR: 1.92; 95% CI:1.79-2.06), infants receiving no prophylaxis (vs. nevirapine for 6 weeks OR: 2.76; 95% CI:2.51-3.05), and infants mixed breastfed (vs. exclusive breastfeeding OR: 1.39; 95% CI:1.30-1.49). In 2014-2015, 9.1% of infants had mothers who were not on treatment during pregnancy, 9.8% were not on prophylaxis, and 7.0% were mixed breastfed. Infants exposed to all three risky practices had a seven-fold higher odds of HIV infection compared to those exposed to recommended practices. The highest yield of HIV-positive infants were found through targeted testing of symptomatic infants in pediatric/outpatient departments (>15%); still, most infected infants were identified through PMTCT programs. CONCLUSION: Despite impressive gains in Kenya's PMTCT program, some HIV-infected infants present late and are not benefitting from PMTCT best practices. Efforts to identify these early and enforce evidence-based practice for PMTCT should be scaled up. Infant testing should be expanded in pediatric/outpatient departments, given high yields in these portals. PMID- 28850582 TI - Comparison of the effects of forefoot joint-preserving arthroplasty and resection replacement arthroplasty on walking plantar pressure distribution and patient based outcomes in patients with rheumatoid arthritis. AB - PURPOSE: The purpose of this retrospective study is to clarify the difference in plantar pressure distribution during walking and related patient-based outcomes between forefoot joint-preserving arthroplasty and resection-replacement arthroplasty in patients with rheumatoid arthritis (RA). METHODS: Four groups of patients were recruited. Group1 included 22 feet of 11 healthy controls (age 48.6 years), Group2 included 36 feet of 28 RA patients with deformed non-operated feet (age 64.8 years, Disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.3), Group3 included 27 feet of 20 RA patients with metatarsal head resection replacement arthroplasty (age 60.7 years, post-operative duration 5.6 years, DAS28-CRP 2.4), and Group4 included 34 feet of 29 RA patients with metatarsophalangeal (MTP) joint-preserving arthroplasty (age 64.6 years, post operative duration 3.2 years, DAS28-CRP 2.3). Patients were cross-sectionally examined by F-SCAN II to evaluate walking plantar pressure, and the self administered foot evaluation questionnaire (SAFE-Q). Twenty joint-preserving arthroplasty feet were longitudinally examined at both pre- and post-operation. RESULTS: In the 1st MTP joint, Group4 showed higher pressure distribution (13.7%) than Group2 (8.0%) and Group3 (6.7%) (P<0.001). In the 2nd-3rd MTP joint, Group4 showed lower pressure distribution (9.0%) than Group2 (14.5%) (P<0.001) and Group3 (11.5%) (P<0.05). On longitudinal analysis, Group4 showed increased 1st MTP joint pressure (8.5% vs. 14.7%; P<0.001) and decreased 2nd-3rd MTP joint pressure (15.2% vs. 10.7%; P<0.01) distribution. In the SAFE-Q subscale scores, Group4 showed higher scores than Group3 in pain and pain-related scores (84.1 vs. 71.7; P<0.01) and in shoe-related scores (62.5 vs. 43.1; P<0.01). CONCLUSIONS: Joint-preserving arthroplasty resulted in higher 1st MTP joint and lower 2nd-3rd MTP joint pressures than resection-replacement arthroplasty, which were associated with better patient-based outcomes. PMID- 28850583 TI - Sex-based differences in myocardial gene expression in recently deceased organ donors with no prior cardiovascular disease. AB - Sex differences in the development of the normal heart and the prevalence of cardiomyopathies have been reported. The molecular basis of these differences remains unclear. Sex differences in the human heart might be related to patterns of gene expression. Recent studies have shown that sex specific differences in gene expression in tissues including the brain, kidney, skeletal muscle, and liver. Similar data is limited for the heart. Herein we address this issue by analyzing donor and post-mortem adult human heart samples originating from 46 control individuals to study whole-genome gene expression in the human left ventricle. Using data from the genotype tissue expression (GTEx) project, we compared the transcriptome expression profiles of male and female hearts. We found that genes located on sex chromosomes were the most abundant ones among the sexually dimorphic genes. The majority of differentially expressed autosomal genes were those involved in the regulation of inflammation, which has been found to be an important contributor to left ventricular remodeling. Specifically, genes on autosomal chromosomes encoding chemokines with inflammatory functions (e.g. CCL4, CX3CL1, TNFAIP3) and a gene that regulates adhesion of immune cells to the endothelium (e.g., VCAM1) were identified with sex-specific expression levels. This study underlines the relevance of sex as an important modifier of cardiac gene expression. These results have important implications in the understanding of the differences in the physiology of the male and female heart transcriptome and how they may lead to different sex specific difference in human cardiac health and its control. PMID- 28850584 TI - Transiently antigen primed B cells can generate multiple subsets of memory cells. AB - Memory B cells are long-lived cells that generate a more vigorous response upon recognition of antigen (Ag) and T cell help than naive B cells and ensure maintenance of durable humoral immunity. Functionally distinct subsets of murine memory B cells have been identified based on isotype switching of BCRs and surface expression of the co-stimulatory molecule CD80 and co-inhibitory molecule PD-L2. Memory B cells in a subpopulation with low surface expression of CD80 and PD-L2 are predominantly non-isotype switched and can be efficiently recruited into germinal centers (GCs) in secondary responses. In contrast, a CD80 and PD-L2 positive subset arises predominantly from GCs and can quickly differentiate into antibody-secreting plasma cells (PCs). Here we demonstrate that single transient acquisition of Ag by B cells may be sufficient for their long-term participation in GC responses and for development of various memory B cell subsets including CD80 and PD-L2 positive effector-like memory cells that rapidly differentiate into class-switched PCs during recall responses. PMID- 28850585 TI - Prevalence of abortion and adverse pregnancy outcomes among working women in Korea: A cross-sectional study. AB - OBJECTIVES: To investigate incidence and distribution of major adverse reproductive health problems related to various kinds of industries in Korea and to compare risks for major reproductive outcomes to assess maternal health in working and non-working women. METHODS: We requested claim data from the Korean National Health Insurance. We defined reference groups as (1) non-working women and (2) workers in the education field. Women working in each industry were compared with reference groups regarding rates of miscarriage, threatened abortion, preterm labor, and intrauterine growth restriction. Logistic regression was used for multivariate analysis, and age and income adjustment was performed. RESULTS: The percentages of all adverse obstetric outcomes were higher in working women than in non-working women. Working women had higher and statistically significant adjusted odds ratios (ORs) for miscarriage in 18 of the 21 industries. The age and income-adjusted OR for miscarriage for all working women was 1.26 (95% confidence interval, 1.23-1.28). Business facilities management and business support services, manufacturing, human health and social work activities, wholesale and retail trade, and professional, scientific, and technical activities were major industries with higher adjusted ORs for adverse obstetric outcomes. CONCLUSIONS: We confirmed that compared to non-working women, working women have a higher risk for adverse pregnancy outcomes. Thus, adverse pregnancy outcomes such as threatened abortion, preterm labor, and intrauterine growth restriction may be associated with working status. This exploratory study identified several industries where in-depth studies are required in future to improve occupational safety in women of reproductive age. PMID- 28850586 TI - Determination of the intracellular concentration of the export chaperone SecB in Escherichia coli. AB - SecB, a small tetrameric chaperone in Escherichia coli, plays a crucial role during protein export via the general secretory pathway by binding precursor polypeptides in a nonnative conformation and passing them to SecA, the ATPase of the translocon. The dissociation constants for the interactions are known; however to relate studies in vitro to export in a living cell requires knowledge of the concentrations of the proteins in the cell. Presently in the literature there is no report of a rigorous determination of the intracellular concentration of SecB. The values available vary over 60 fold and the details of the techniques used are not given. Here we use quantitative immunoblotting to determine the level of SecB expressed from the chromosome in E.coli grown in two commonly used media. In rich medium SecB was present at 1.6 +/- 0.2 MUM and in minimal medium at 2.5 +/- 0.6 MUM. These values allow studies of SecB carried out in vitro to be applied to the situation in the cell as SecB interacts with its binding partners to move precursor polypeptides through the export pathway. PMID- 28850587 TI - Statistical complexity is maximized in a small-world brain. AB - In this paper, we study a network of Izhikevich neurons to explore what it means for a brain to be at the edge of chaos. To do so, we first constructed the phase diagram of a single Izhikevich excitatory neuron, and identified a small region of the parameter space where we find a large number of phase boundaries to serve as our edge of chaos. We then couple the outputs of these neurons directly to the parameters of other neurons, so that the neuron dynamics can drive transitions from one phase to another on an artificial energy landscape. Finally, we measure the statistical complexity of the parameter time series, while the network is tuned from a regular network to a random network using the Watts-Strogatz rewiring algorithm. We find that the statistical complexity of the parameter dynamics is maximized when the neuron network is most small-world-like. Our results suggest that the small-world architecture of neuron connections in brains is not accidental, but may be related to the information processing that they do. PMID- 28850588 TI - New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes. AB - Cell-free DNA (cfDNA) in blood is used as a source of genetic material for noninvasive prenatal and cancer diagnostic assays in clinical practice. Recently we have started a project for new biomarker discovery with a view to developing new noninvasive diagnostic assays. While reviewing literature, it was found that exosomes may be a rich source of biomarkers, because exosomes play an important role in human health and disease. While characterizing exosomes found in human blood plasma, we observed the presence of cfDNA in plasma exosomes. Plasma was obtained from blood drawn into K3EDTA tubes. Exosomes were isolated from cell free plasma using a commercially available kit. Sizing and enumeration of exosomes were done using electron microscopy and NanoSight particle counter. NanoSight and confocal microscopy was used to demonstrate the association between dsDNA and exosomes. DNA extracted from plasma and exosomes was measured by a fluorometric method and a droplet digital PCR (ddPCR) method. Size of extracellular vesicles isolated from plasma was heterogeneous and showed a mean value of 92.6 nm and a mode 39.7 nm. A large proportion of extracellular vesicles isolated from plasma were identified as exosomes using a fluorescence probe specific for exosomes and three protein markers, Hsp70, CD9 and CD63, that are commonly used to identify exosome fraction. Fluorescence dye that stain dsDNA showed the association between exosomes and dsDNA. Plasma cfDNA concentration analysis showed more than 93% of amplifiable cfDNA in plasma is located in plasma exosomes. Storage of a blood sample showed significant increases in exosome count and exosome DNA concentration. This study provide evidence that a large proportion of plasma cfDNA is localized in exosomes. Exosome release from cells is a metabolic energy dependent process, thus suggesting active release of cfDNA from cells as a source of cfDNA in plasma. PMID- 28850589 TI - Towards a social functional account of laughter: Acoustic features convey reward, affiliation, and dominance. AB - Recent work has identified the physical features of smiles that accomplish three tasks fundamental to human social living: rewarding behavior, establishing and managing affiliative bonds, and negotiating social status. The current work extends the social functional account to laughter. Participants (N = 762) rated the degree to which reward, affiliation, or dominance (between-subjects) was conveyed by 400 laughter samples acquired from a commercial sound effects website. Inclusion of a fourth rating dimension, spontaneity, allowed us to situate the current approach in the context of existing laughter research, which emphasizes the distinction between spontaneous and volitional laughter. We used 11 acoustic properties extracted from the laugh samples to predict participants' ratings. Actor sex moderated, and sometimes even reversed, the relation between acoustics and participants' judgments. Spontaneous laughter appears to serve the reward function in the current framework, as similar acoustic properties guided perceiver judgments of spontaneity and reward: reduced voicing and increased pitch, increased duration for female actors, and increased pitch slope, center of gravity, first formant, and noisiness for male actors. Affiliation ratings diverged from reward in their sex-dependent relationship to intensity and, for females, reduced pitch range and raised second formant. Dominance displayed the most distinct pattern of acoustic predictors, including increased pitch range, reduced second formant in females, and decreased pitch variability in males. We relate the current findings to existing findings on laughter and human and non human vocalizations, concluding laughter can signal much more that felt or faked amusement. PMID- 28850590 TI - Associations of Helicobacter pylori infection and peptic disease with diabetic mellitus: Results from a large population-based study. AB - BACKGROUND: Evidence is conflicting regarding the association between Helicobacter pylori infection and diabetes mellitus. The study objective was to examine associations of H. pylori infection, gastric ulcers and duodenal ulcers, with diabetes mellitus. METHODS: This cross-sectional study was undertaken using coded data from the computerized database of Maccabi Health Services in Israel, on 147,936 individuals aged 25-95 years who underwent the urea breath test during 2002-2012. Multiple logistic regression models were conducted, while adjusting for known risk factors for diabetes mellitus. RESULTS: A H. pylori positive test was recorded for 76,992 (52.0%) individuals and diabetes for 12,207 (8.3%). The prevalence of diabetes was similar in individuals with and without H. pylori infection, but this association was modified (P for heterogeneity 0.049) by body mass index (BMI): adjusted odds ratio (aOR) 1.16 (95% confidence intervals (CI) 1.04-1.29) in persons with BMI<25 kg/m2 versus aOR 1.03 (95% CI 0.98-1.08) in persons with BMI>=25 kg/m2. Diabetes mellitus prevalence was higher in persons with gastric (aOR 1.20 (95% CI 1.06-1.34)) and duodenal ulcers (aOR 1.20 (95% CI 1.12-1.28)) compared to persons without these diagnoses. CONCLUSIONS: In this large population-based study, we demonstrated significant positive associations, albeit of small magnitude, of H. pylori infection and peptic disease with diabetes. The long-term gastric inflammation and associated-damage to the gastric mucosa might play a role in such associations. PMID- 28850591 TI - Correction: RESPECT-ED: Rates of Pulmonary Emboli (PE) and Sub-Segmental PE with Modern Computed Tomographic Pulmonary Angiograms in Emergency Departments: A Multi-Center Observational Study Finds Significant Yield Variation, Uncorrelated with Use or Small PE Rates. AB - [This corrects the article DOI: 10.1371/journal.pone.0166483.]. PMID- 28850592 TI - Correction: Do family and neighbourhood matter in secondary school completion? A multilevel study of determinants and their interactions in a life-course perspective. AB - [This corrects the article DOI: 10.1371/journal.pone.0172281.]. PMID- 28850594 TI - MetaZipf. A dynamic meta-analysis of city size distributions. AB - The results from urban scaling in recent years have held the promise of increased efficiency to the societies who could actively control the distribution of their cities' size. However, little evidence exists as to the factors which influence the level of urban unevenness, as expressed by the slope of the rank-size distribution, partly because the diversity of results found in the literature follows the heterogeneity of analysis specifications. In this study, I set up a meta-analysis of Zipf's law which accounts for technical as well as topical factors of variations of Zipf's coefficient. I found 86 studies publishing at least one empirical estimation of this coefficient and recorded their metadata into an open database. I regressed the 1962 corresponding estimates with variables describing the study and the estimation process as well as socio demographic variables describing the territory under enquiry. A dynamic meta analysis was also performed to look for factors of evolution of city size unevenness. The results of the most interesting models are presented in the article, whereas all analyses can be reproduced on a dedicated online platform. The results show that on average, 40% of the variation of Zipf's coefficients is due to the technical choices. The main other variables associated with distinct evolutions are linked to the urbanisation process rather than the process of economic development and population growth. Finally, no evidence was found to support the effectiveness of past planning actions in modifying this urban feature. PMID- 28850593 TI - Multimorbidity in Australia: Comparing estimates derived using administrative data sources and survey data. AB - BACKGROUND: Estimating multimorbidity (presence of two or more chronic conditions) using administrative data is becoming increasingly common. We investigated (1) the concordance of identification of chronic conditions and multimorbidity using self-report survey and administrative datasets; (2) characteristics of people with multimorbidity ascertained using different data sources; and (3) whether the same individuals are classified as multimorbid using different data sources. METHODS: Baseline survey data for 90,352 participants of the 45 and Up Study-a cohort study of residents of New South Wales, Australia, aged 45 years and over-were linked to prior two-year pharmaceutical claims and hospital admission records. Concordance of eight self-report chronic conditions (reference) with claims and hospital data were examined using sensitivity (Sn), positive predictive value (PPV), and kappa (kappa).The characteristics of people classified as multimorbid were compared using logistic regression modelling. RESULTS: Agreement was found to be highest for diabetes in both hospital and claims data (kappa = 0.79, 0.78; Sn = 79%, 72%; PPV = 86%, 90%). The prevalence of multimorbidity was highest using self-report data (37.4%), followed by claims data (36.1%) and hospital data (19.3%). Combining all three datasets identified a total of 46 683 (52%) people with multimorbidity, with half of these identified using a single dataset only, and up to 20% identified on all three datasets. Characteristics of persons with and without multimorbidity were generally similar. However, the age gradient was more pronounced and people speaking a language other than English at home were more likely to be identified as multimorbid by administrative data. CONCLUSIONS: Different individuals, with different combinations of conditions, are identified as multimorbid when different data sources are used. As such, caution should be applied when ascertaining morbidity from a single data source as the agreement between self report and administrative data is generally poor. Future multimorbidity research exploring specific disease combinations and clusters of diseases that commonly co occur, rather than a simple disease count, is likely to provide more useful insights into the complex care needs of individuals with multiple chronic conditions. PMID- 28850595 TI - Subthreshold 577 nm micropulse laser treatment for central serous chorioretinopathy. AB - PURPOSE: To compare the efficacy of the subthreshold micropulse laser (SML) to conventional laser (CL) in treating focal leakages of the retinal pigment epithelium (RPE) in the eyes with central serous chorioretinopathy (CSC). METHODS: Twenty-nine eyes of 28 patients with CSC and typical focal leakage were treated with CL or SML. Both treatments were made with a 577 nm yellow laser (CL: NIDEK MC-500, SML: IRIDEX IQ577). The percentage of eyes with a complete resolution, the distance of the laser burns from the fovea, and injury of the RPE after treatment were studied. RESULTS: A complete resolution was seen in 10 of 15 eyes (66.7%) after CL and 9 of 14 eyes (64.3%) after SML (P = 0.89). The average distance from the foveal center to the leakage point was 1282+/-596 MUm for eyes treated with CL and 1271+/-993 MUm for eyes treated with SML (P = 0.4). Only three eyes treated with SML had treatment sites within 500 MUm of the fovea. RPE damage determined by fundus autofluorescence was found in all eyes treated with CL and only one eye treated with SML (P<.01). CONCLUSIONS: SML achieved equivalent therapeutic effects as CL but without RPE damage in eyes with CSC. PMID- 28850597 TI - The impact of targeting repetitive BamHI-W sequences on the sensitivity and precision of EBV DNA quantification. AB - BACKGROUND: Viral load monitoring and early Epstein-Barr virus (EBV) DNA detection are essential in routine laboratory testing, especially in preemptive management of Post-transplant Lymphoproliferative Disorder. Targeting the repetitive BamHI-W sequence was shown to increase the sensitivity of EBV DNA quantification, but the variability of BamHI-W reiterations was suggested to be a source of quantification bias. We aimed to assess the extent of variability associated with BamHI-W PCR and its impact on the sensitivity of EBV DNA quantification using the 1st WHO international standard, EBV strains and clinical samples. METHODS: Repetitive BamHI-W- and LMP2 single- sequences were amplified by in-house qPCRs and BXLF-1 sequence by a commercial assay (EBV R-geneTM, BioMerieux). Linearity and limits of detection of in-house methods were assessed. The impact of repeated versus single target sequences on EBV DNA quantification precision was tested on B95.8 and Raji cell lines, possessing 11 and 7 copies of the BamHI-W sequence, respectively, and on clinical samples. RESULTS: BamHI-W qPCR demonstrated a lower limit of detection compared to LMP2 qPCR (2.33 log10 versus 3.08 log10 IU/mL; P = 0.0002). BamHI-W qPCR underestimated the EBV DNA load on Raji strain which contained fewer BamHI-W copies than the WHO standard derived from the B95.8 EBV strain (mean bias: - 0.21 log10; 95% CI, -0.54 to 0.12). Comparison of BamHI-W qPCR versus LMP2 and BXLF-1 qPCR showed an acceptable variability between EBV DNA levels in clinical samples with the mean bias being within 0.5 log10 IU/mL EBV DNA, whereas a better quantitative concordance was observed between LMP2 and BXLF-1 assays. CONCLUSIONS: Targeting BamHI-W resulted to a higher sensitivity compared to LMP2 but the variable reiterations of BamHI-W segment are associated with higher quantification variability. BamHI-W can be considered for clinical and therapeutic monitoring to detect an early EBV DNA and a dynamic change in viral load. PMID- 28850596 TI - Harms associated with taking nalmefene for substance use and impulse control disorders: A systematic review and meta-analysis of randomised controlled trials. AB - IMPORTANCE: Nalmefene is a newly approved drug for alcohol use disorder, but the risk of harms has not been evaluated from empirical trial evidence. OBJECTIVE: To assess the harm of nalmefene administered to individuals diagnosed with substance use or impulse control disorders by performing a systematic review and meta analysis of randomised controlled trials. DATA SOURCES: A search was performed in Cochrane Central Register of Controlled Trials (CENTRAL, 2014), MEDLINE via PubMed (1950), EMBASE via Ovid (1974), and Clinicaltrials.gov through December 2014. STUDY SELECTION: This study included only randomised controlled trials with placebo or active controls that administered nalmefene to adult individuals for treating impulse control and/or substance use disorders. Both published and unpublished randomised controlled trials were eligible for inclusion. DATA EXTRACTION AND SYNTHESIS: Internal validity was assessed using the Cochrane risk of-bias tool. Published information from the trials was supplemented by contact between reviewers and industry sponsor. Data were combined using two meta approaches in fixed effects models; Peto Odds Ratios and risk differences were reported with 95% confidence intervals (95%CIs). MAIN OUTCOMES AND MEASURES: Number of patients with serious adverse events, including specific psychiatric serious adverse events and withdrawals due to adverse events. RESULTS: Of 20 potentially relevant studies, 15 randomised controlled trials met the inclusion criteria, and 8 of these provided data enabling the meta-analysis. Overall, serious adverse events did not occur more often in the nalmefene group than in the placebo group (Peto Odds Ratio = 0.97 [95% CI 0.64-1.44]; P = 0.86). Risk of psychiatric serious adverse events was slightly elevated, albeit not at a statistically significant level (Peto Odds Ratio = 1.32 [95% CI 0.62, 2.83]; P = 0.47). Withdrawals due to adverse events were significantly more likely to occur with nalmefene compared to placebo (Peto Odds Ratio = 3.22 [95% CI 2.46-4.22]; P<0.001). CONCLUSIONS AND RELEVANCE: The three-fold increased risk of withdrawal from treatment on nalmefene due to adverse events is a matter of safety concern. The nature of these adverse events cannot be elucidated further without access to individual patients data. PMID- 28850599 TI - Correction: Pathogenic seedborne viruses are rare but Phaseolus vulgaris endornaviruses are common in bean varieties grown in Nicaragua and Tanzania. AB - [This corrects the article DOI: 10.1371/journal.pone.0178242.]. PMID- 28850598 TI - Association of TLR variants with susceptibility to Plasmodium vivax malaria and parasitemia in the Amazon region of Brazil. AB - BACKGROUND: Plasmodium vivax malaria (Pv-malaria) is still considered a neglected disease despite an alarming number of individuals being infected annually. Malaria pathogenesis occurs with the onset of the vector-parasite-host interaction through the binding of pathogen-associated molecular patterns (PAMPs) and receptors of innate immunity, such as toll-like receptors (TLRs). The triggering of the signaling cascade produces an elevated inflammatory response. Genetic polymorphisms in TLRs are involved in susceptibility or resistance to infection, and the identification of genes involved with Pv-malaria response is important to elucidate the pathogenesis of the disease and may contribute to the formulation of control and elimination tools. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective case-control study was conducted in an intense transmission area of Pv-malaria in the state of Amazonas, Brazil. Genetic polymorphisms (SNPs) in different TLRs, TIRAP, and CD14 were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis in 325 patients infected with P. vivax and 274 healthy individuals without malaria history in the prior 12 months from the same endemic area. Parasite load was determined by qPCR. Simple and multiple logistic/linear regressions were performed to investigate association between the polymorphisms and the occurrence of Pv-malaria and parasitemia. The C/T (TLR5 R392StopCodon) and T/T (TLR9 -1486C/T) genotypes appear to be risk factors for infection by P. vivax (TLR5: C/C vs. C/T [OR: 2.116, 95% CI: 1.054-4.452, p = 0.031]; TLR9: C/C vs. T/T [OR: 1.919, 95% CI: 1.159-3.177, p = 0.010]; respectively). Fever (COEF = 7599.46, 95% CI = 3063.80 12135.12, p = 0.001) and the C/C genotype of TLR9 -1237C/T (COEF = 17006.63, 95% CI = 3472.83-30540.44, p = 0.014) were independently associated with increased parasitemia in patients with Pv-malaria. CONCLUSIONS: Variants of TLRs may predispose individuals to infection by P. vivax. The TLR5 R392StopCodon and TLR9 1486C/T variants are associated with susceptibility to Pv-malaria. Furthermore, the TLR9 variant -1237C/C correlates with high parasitemia. PMID- 28850600 TI - What's the best surgical treatment for patients with cervical radiculopathy due to single-level degenerative disease? A randomized controlled trial. AB - BACKGROUND: To investigate the efficacy of adding supplemental fusion or arthroplasty after cervical anterior discectomy for symptomatic mono-level cervical degenerative disease (radiculopathy), which has not been substantiated in controlled trials until now. METHODS: A randomized controlled trial is reported with 9 years follow up comparing anterior cervical anterior discectomy without fusion, with fusion by cage standalone, or with disc prosthesis. Patients suffering from symptomatic cervical disk degeneration at one level referred to spinal sections of department of neurosurgery or orthopedic surgery of a large general hospital with educational facilities were eligible. Neck Disability Index (NDI), McGill Pain Questionnaire Dutch language version (MPQ-DLV), physical component summary (PCS), and mental-component summary (MCS) of the 36-item Short Form Health Survey (SF-36), and re operation rate were evaluated. FINDINGS: 142 patients between 18 and 55 years were allocated. The median follow-up was 8.9+/ 1.9 years (5.6 to 12.2 years). The response rate at last follow-up was 98.5%. NDI at the last follow-up did not differ between the three treatment groups, nor did the secondary outcomes as MPQ-DLV and PCS or MCS from SF-36. The major improvement occurred within the first 6 weeks after surgery. Afterward, it remained stable. Eleven patients underwent surgery for recurrent symptoms and signs due to nerve root compression at the index or adjacent level. CONCLUSIONS: This randomized trial could not detect a difference between three surgical modalities for treating a single-level degenerative disk disease. Anterior cervical discectomy without implant seems to be similar to anterior cervical discectomy with fusion by cage stand-alone or with disk prosthesis. Due to the small study sample size, this statement should be considered as inconclusive so far. TRIAL REGISTRATION: ISRCTN41681847. PMID- 28850601 TI - Correcting for unequal catchability in sex ratio and population size estimates. AB - Wildlife populations often exhibit unequal catchability between subgroups such as males and females. This heterogeneity of capture probabilities can bias both population size and sex ratio estimates. Several authors have suggested that this problem can be overcome by treating males and females as separate populations and calculating a population estimate for each of them. However, this suggestion has received little testing, and many researchers do not implement it. Therefore, we used two simulations to test the utility of this method. One simulated a closed population, while the other simulated an open population and used the robust design to calculate population sizes. We tested both simulations with multiple levels of heterogeneity, and we used a third simulation to test several methods for detecting heterogeneity of capture probabilities. We found that treating males and females as separate populations produced more accurate population and sex ratio estimates. The benefits of this method were particularly pronounced for sex ratio estimates. When males and females were included as a single population, the sex ratio estimates became inaccurate when even slight heterogeneity was present, but when males and females were treated separately, the estimates were accurate even when large biases were present. Nevertheless, treating males and females separately reduced precision, and this method may not be appropriate when capture and recapture rates are low. None of the methods for detecting heterogeneity were robust, and we do not recommend that researchers rely on them. Rather, we suggest separating populations by sex, age, or other subgroups whenever sample sizes permit. PMID- 28850602 TI - Structural studies demonstrating a bacteriophage-like replication cycle of the eukaryote-infecting Paramecium bursaria chlorella virus-1. AB - A fundamental stage in viral infection is the internalization of viral genomes in host cells. Although extensively studied, the mechanisms and factors responsible for the genome internalization process remain poorly understood. Here we report our observations, derived from diverse imaging methods on genome internalization of the large dsDNA Paramecium bursaria chlorella virus-1 (PBCV-1). Our studies reveal that early infection stages of this eukaryotic-infecting virus occurs by a bacteriophage-like pathway, whereby PBCV-1 generates a hole in the host cell wall and ejects its dsDNA genome in a linear, base-pair-by-base-pair process, through a membrane tunnel generated by the fusion of the virus internal membrane with the host membrane. Furthermore, our results imply that PBCV-1 DNA condensation that occurs shortly after infection probably plays a role in genome internalization, as hypothesized for the infection of some bacteriophages. The subsequent perforation of the host photosynthetic membranes presumably enables trafficking of viral genomes towards host nuclei. Previous studies established that at late infection stages PBCV-1 generates cytoplasmic organelles, termed viral factories, where viral assembly takes place, a feature characteristic of many large dsDNA viruses that infect eukaryotic organisms. PBCV-1 thus appears to combine a bacteriophage-like mechanism during early infection stages with a eukaryotic-like infection pathway in its late replication cycle. PMID- 28850603 TI - Spatial distribution, Leishmania species and clinical traits of Cutaneous Leishmaniasis cases in the Colombian army. AB - In Colombia, the cutaneous leishmaniasis (CL) is the most common manifestation across the army personnel. Hence, it is mandatory to determine the species associated with the disease as well as the association with the clinical traits. A total of 273 samples of male patients with CL were included in the study and clinical data of the patients was studied. PCR and sequencing analyses (Cytb and HSP70 genes) were performed to identify the species and the intra-specific genetic variability. A georeferenced database was constructed to identify the spatial distribution of Leishmania species isolated. The identification of five species of Leishmania that circulate in the areas where army personnel are deployed is described. Predominant infecting Leishmania species corresponds to L. braziliensis (61.1%), followed by Leishmania panamensis (33.5%), with a high distribution of both species at geographical and municipal level. The species L. guyanensis, L. mexicana and L. lainsoni were also detected at lower frequency. We also showed the identification of different genotypes within L. braziliensis and L. panamensis. In conclusion, we identified the Leishmania species circulating in the areas where Colombian army personnel are deployed, as well as the high intra specific genetic variability of L. braziliensis and L. panamensis and how these genotypes are distributed at the geographic level. PMID- 28850604 TI - The utility of measles and rubella IgM serology in an elimination setting, Ontario, Canada, 2009-2014. AB - In Canada, measles was eliminated in 1998 and rubella in 2000. Effective measles and rubella surveillance is vital in elimination settings, hinging on reliable laboratory methods. However, low-prevalence settings affect the predictive value of laboratory tests. We conducted an analysis to determine the performance of measles and rubella IgM testing in a jurisdiction where both infections are eliminated. 21,299 test results were extracted from the Public Health Ontario Laboratories database and 1,239 reports were extracted from the Ontario Integrated Public Health Information System (iPHIS) from 2008 and 2010 for measles and rubella, respectively, to 2014. Deterministic linkage resulted in 658 linked measles records (2009-2014) and 189 linked rubella records (2010-2014). Sixty-six iPHIS measles entries were classified as confirmed cases, of which 53 linked to laboratory data. Five iPHIS rubella entries were classified as confirmed, all linked to IgM results. The positive predictive value was 17.4% for measles and 3.6% for rubella. Sensitivity was 79.2% for measles and 100.0% for rubella. Specificity was 65.7% for measles and 25.8% for rubella. Our study confirms that a positive IgM alone does not confirm a measles case in elimination settings. This has important implications for countries that are working towards measles and rubella elimination. PMID- 28850605 TI - Notable fibrolytic enzyme production by Aspergillus spp. isolates from the gastrointestinal tract of beef cattle fed in lignified pastures. AB - Fungi have the ability to degrade vegetal cell wall carbohydrates, and their presence in the digestive tract of ruminants can minimize the effects of lignified forage on ruminal fermentation. Here, we evaluated enzyme production by Aspergillus spp. isolates from the digestive tracts of cattle grazed in tropical pastures during the dry season. Filamentous fungi were isolated from rumen and feces by culture in cellulose-based medium. Ninety fungal strains were isolated and identified by rDNA sequence analysis, microculture, or both. Aspergillus terreus was the most frequently isolated species, followed by Aspergillus fumigatus. The isolates were characterized with respect to their cellulolytic, xylanolytic, and lignolytic activity through qualitative evaluation in culture medium containing a specific corresponding carbon source. Carboxymethyl cellulase (CMCase) activity was quantified by the reducing sugar method. In the avicel and xilan degradation test, the enzyme activity (EA) at 48 h was significantly higher other periods (P < 0.05). Intra- and inter-specific differences in EA were verified, and high levels of phenoloxidases, which are crucial for lignin degradation, were observed in 28.9% of the isolates. Aspergillus terreus showed significantly higher EA for avicelase (3.96 +/-1.77) and xylanase (3.13 +/-.091) than the other Aspergillus species at 48 h of incubation. Isolates AT13 and AF69 showed the highest CMCase specific activity (54.84 and 33.03 U mg-1 protein, respectively). Selected Aspergillus spp. isolates produced remarkable levels of enzymes involved in vegetal cell wall degradation, suggesting their potential as antimicrobial additives or probiotics in ruminant diets. PMID- 28850606 TI - Alleviation of Rosup-induced oxidative stress in porcine granulosa cells by anthocyanins from red-fleshed apples. AB - Anthocyanins are the polyphenolic phytochemicals which have been shown to scavenge free radicals. In this study, we investigated the effects of anthocyanins extracted from red-fleshed apples (Malus sieversii) on reducing oxidative damage by Rosup in porcine granulosa cells (GCs) by measuring intracellular reactive oxygen species (ROS), content of glutathione (GSH), activities of superoxide dismutase (SOD1), catalase (CAT) and glutathione peroxidase (GPX1) and the gene expression of SOD1, CAT, GPX1. Apoptosis was determined with TdT-mediated dUTP-biotin nick end labeling (TUNEL) and apoptosis related proteins were quantified with Western blotting. The results indicate that Rosup increases oxidative stress by inducing reactive oxygen species production in porcine GCs and the oxidative stress could be reduced by anthocyanins. The gene expression of SOD1, CAT, GPX1 and the activities of these enzymes were increased when GCs were treated with anthocyanins and Rosup for 6 hours. Anthocyanins inhibit Rosup-induced apoptosis by increasing expression of antiapoptotic protein Bcl-2 and suppressing the expression of pro-apoptotic protein Bax. Collectively, anthocyanins from red-fleshed apples reduce oxidative stress and inhibit apoptosis in porcine GCs in vitro. This approach indicates that antioxidants might be developed from red-fleshed apples. PMID- 28850607 TI - A Dynamic Energy Budget (DEB) model to describe Laternula elliptica (King, 1832) seasonal feeding and metabolism. AB - Antarctic marine organisms are adapted to an extreme environment, characterized by a very low but stable temperature and a strong seasonality in food availability arousing from variations in day length. Ocean organisms are particularly vulnerable to global climate change with some regions being impacted by temperature increase and changes in primary production. Climate change also affects the biotic components of marine ecosystems and has an impact on the distribution and seasonal physiology of Antarctic marine organisms. Knowledge on the impact of climate change in key species is highly important because their performance affects ecosystem functioning. To predict the effects of climate change on marine ecosystems, a holistic understanding of the life history and physiology of Antarctic key species is urgently needed. DEB (Dynamic Energy Budget) theory captures the metabolic processes of an organism through its entire life cycle as a function of temperature and food availability. The DEB model is a tool that can be used to model lifetime feeding, growth, reproduction, and their responses to changes in biotic and abiotic conditions. In this study, we estimate the DEB model parameters for the bivalve Laternula elliptica using literature extracted and field data. The DEB model we present here aims at better understanding the biology of L. elliptica and its levels of adaptation to its habitat with a special focus on food seasonality. The model parameters describe a metabolism specifically adapted to low temperatures, with a low maintenance cost and a high capacity to uptake and mobilise energy, providing this organism with a level of energetic performance matching that of related species from temperate regions. It was also found that L. elliptica has a large energy reserve that allows enduring long periods of starvation. Additionally, we applied DEB parameters to time-series data on biological traits (organism condition, gonad growth) to describe the effect of a varying environment in food and temperature on the organism condition and energy use. The DEB model developed here for L. elliptica allowed us to improve benchmark knowledge on the ecophysiology of this key species, providing new insights in the role of food availability and temperature on its life cycle and reproduction strategy. PMID- 28850608 TI - Potential role of an antimicrobial peptide, KLK in inhibiting lipopolysaccharide induced macrophage inflammation. AB - Antimicrobial peptides (AMPs) are attractive alternatives to antibiotics. Due to their immune modulatory properties, AMPs are at present emerging as promising agents for controlling inflammatory-mediated diseases. In this study, anti inflammatory potential of an antimicrobial peptide, KLK (KLKLLLLLKLK) and its analogs was evaluated in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. The results herein demonstrated that KLK peptide as well as its analogs significantly inhibited the pro-inflammatory mediator nitric oxide (NO), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) production in LPS-stimulated RAW 264.7 macrophages in dose-dependent manners, and such inhibitory effects were not due to direct cytotoxicity. When considering inhibition potency, KLK among the test peptides exhibited the most effective activity. The inhibitory activity of KLK peptide also extended to include suppression of LPS-induced production of prostaglandin E2 (PGE2). KLK significantly decreased mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as mRNA expression of IL 1beta and TNF-alpha. Moreover, KLK inhibited nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65 and blocked degradation and phosphorylation of inhibitor of kappaB (IkappaB). Taken together, these results suggested that the KLK peptide inhibited inflammatory response through the down-regulation of NF kappaB mediated activation in macrophages. Since peptide analogs with different amino acid sequences and arrangement were investigated for their anti inflammatory activities, the residues/structures required for activity were also discussed. Our findings therefore proved anti-inflammatory potential of the KLK peptide and provide direct evidence for therapeutic application of KLK as a novel anti-inflammatory agent. PMID- 28850609 TI - Dynactin has two antagonistic regulatory domains and exerts opposing effects on dynein motility. AB - Dynactin is a dynein-regulating protein that increases the processivity of dynein movement on microtubules. Recent studies have shown that a tripartite complex of dynein-dynactin-Bicaudal D2 is essential for highly processive movement. To elucidate the regulation of dynein motility by dynactin, we focused on two isoforms (A and B) of dynactin 1 (DCTN1), the largest subunit of dynactin that contains both microtubule- and dynein-binding domains. The only difference between the primary structures of the two isoforms is that DCTN1B lacks the K rich domain, a cluster of basic residues. We measured dynein motility by single molecule observation of recombinant dynein and dynactin. Whereas the tripartite complex containing DCTN1A exhibited highly processive movement, the complex containing DCTN1B dissociated from microtubules with no apparent processive movement. This inhibitory effect of DCTN1B was caused by reductions of the microtubule-binding affinities of both dynein and dynactin, which was attributed to the coiled-coil 1 domain of DCTN1. In DCTN1A, the K-rich domain antagonized these inhibitory effects. Therefore, dynactin has two antagonistic domains and promotes or suppresses dynein motility to accomplish correct localization and functions of dynein within a cell. PMID- 28850611 TI - The RNA-binding protein Rbm38 is dispensable during pressure overload-induced cardiac remodeling in mice. AB - The importance of tightly controlled alternative pre-mRNA splicing in the heart is emerging. The RNA binding protein Rbm24 has recently been identified as a pivotal cardiac splice factor, which governs sarcomerogenesis in the heart by controlling the expression of alternative protein isoforms. Rbm38, a homolog of Rbm24, has also been implicated in RNA processes such as RNA splicing, RNA stability and RNA translation, but its function in the heart is currently unknown. Here, we investigated the role of Rbm38 in the healthy and diseased adult mouse heart. In contrast to the heart- and skeletal muscle-enriched protein Rbm24, Rbm38 appears to be more broadly expressed. We generated somatic Rbm38 -/- mice and show that global loss of Rbm38 results in hematopoietic defects. Specifically, Rbm38 -/- mice were anemic and displayed enlarged spleens with extramedullary hematopoiesis, as has been shown earlier. The hearts of Rbm38 -/- mice were mildly hypertrophic, but cardiac function was not affected. Furthermore, Rbm38 deficiency did not affect cardiac remodeling (i.e. hypertrophy, LV dilation and fibrosis) or performance (i.e. fractional shortening) after pressure-overload induced by transverse aorta constriction. To further investigate molecular consequences of Rbm38 deficiency, we examined previously identified RNA stability, splicing, and translational targets of Rbm38. We found that stability targets p21 and HuR, splicing targets Mef2d and Fgfr2, and translation target p53 were not altered, suggesting that these Rbm38 targets are tissue-specific or that Rbm38 deficiency may be counteracted by a redundancy mechanism. In this regard, we found a trend towards increased Rbm24 protein expression in Rbm38 -/- hearts. Overall, we conclude that Rbm38 is critical in hematopoiesis, but does not play a critical role in the healthy and diseased heart. PMID- 28850612 TI - An application of competitive reporter monitored amplification (CMA) for rapid detection of single nucleotide polymorphisms (SNPs). AB - Single nucleotide polymorphisms (SNPs) are essential parameters in molecular diagnostics and can be used for the early detection and clinical prognosis in various diseases. Available methods for SNP detection are still labor-intensive and require a complex laboratory infrastructure, which are not suitable for the usage in resource-limited settings. Thus, there is an urgent need for a simple, reliable and rapid approach. In this paper we modified the previously developed competitive reporter monitored amplification (CMA) technique for the detection of resistance mediating SNPs in Mycobacterium tuberculosis complex (MTBC) strains. As a proof-of-principle for the application of the CMA-based SNP assay in routine molecular tuberculosis diagnostic, we show that the assay recognizes resistance mediating SNPs for rifampicin, isoniazid and ethambutol from either isolated DNA or heat inactivated M. tuberculosis cell cultures. The CMA-based SNP assay can identify the most prevalent resistance mediating mutations in the genes rpoB, katG, embB, and the promotor region of inhA within one hour. PMID- 28850610 TI - Health risk factors associated with meat, fruit and vegetable consumption in cohort studies: A comprehensive meta-analysis. AB - The aim of this study was to perform a meta-analysis to test the association between red, processed, and total meat, as well as fruit and vegetable consumption, and selected health risk factors, including body weight status, smoking habit, physical activity level, level of education, and alcohol drinking in cohort studies on non-communicable disease. A systematic search of electronic databases was performed to identify relevant articles published up to March 2017. In a two-stage approach, frequency-weighted linear regression coefficients were first calculated for each variable, and then combined across studies through meta regression. Ninety-eight studies including 20 on red meat, 6 on processed meat, 12 on total meat, 37 on fruit and vegetable combined, 21 on fruit and 24 on vegetable consumption were analyzed. Intake of red meat was positively associated with BMI, percentage of overweight and obese, low physical activity, and current and ever smoking and inversely associated with percentage of non-smokers and high physically active individuals. Similar associations were found for red meat were found, although based on fewer data. Intake of fruits and vegetables was positively associated with prevalence of non-smokers, high education and high physical activity, and similar results were found when examining fruit and vegetable consumption separately. Stratification by geographical area revealed that some associations were stronger in US rather than European or Asian cohorts. In conclusions, the distribution of health risk factors associated with high meat and fruit/vegetable consumption may differ from those of low-consumers. Some of these differences may mediate, confound, or modify the relation between diet and non-communicable disease risk. PMID- 28850614 TI - Nitazoxanide is active against Mycobacterium leprae. AB - Nitazoxanide (NTZ) is an anti-parasitic drug that also has activity against bacteria, including Mycobacterium tuberculosis. Our data using both radiorespirometry and live-dead staining in vitro demonstrate that NTZ similarly has bactericidal against M. leprae. Further, gavage of M. leprae-infected mice with NTZ at 25mg/kg provided anti-mycobacterial activity equivalent to rifampicin (RIF) at 10 mg/kg. This suggests that NTZ could be considered for leprosy treatment. PMID- 28850613 TI - Effect of trabeculectomy on visual field progression in Japanese progressive normal-tension glaucoma with intraocular pressure < 15 mmHg. AB - We examined the effectiveness of trabeculectomy in decreasing the slope of mean deviation (MD) in Japanese patients with progressive normal-tension glaucoma (NTG) at low intraocular pressure (IOP) levels. The charts of patients who had undergone initial trabeculectomy with adjunctive mitomycin C for progressive NTG with medically controlled IOP < 15 mmHg in 2010-2013 were retrospectively reviewed. Seventeen eyes of 13 NTG patients who had undergone at least 5 times of visual field (VF) examinations in both of preoperatively and postoperatively with postoperative follow-up of >= 2 years were enrolled. Preoperative and postoperative MD slopes were compared to evaluate the effectiveness of trabeculectomy in slowing progression of VF. Mean IOP (8.1 +/- 2.9 mmHg) and number of IOP-lowering medications (0.8 +/- 1.5) were significantly lower postoperatively than preoperatively (13.9 +/- 0.9 mmHg; P < 0.001 and 3.0+/- 0.4; P < 0.0001). In total, 91.7% of eyes with single-digit IOP postoperatively showed improvement in MD slope, whereas only 20.0% of eyes with IOP >= 10 mmHg postoperatively showed the improvement. Three eyes (17.6%) showed a decrease in visual acuity (VA) of >= 0.1 unit; this group had a lower mean postoperative IOP (6.0 +/- 1.0 vs. 8.6 +/- 3.0 mmHg; P = 0.1717) and a higher mean IOP reduction rate (56.2 vs. 38.5%; P = 0.8296) than eyes with a VA decrease of < 0.1 unit or no change. Thus, in this analysis of Japanese NTG patients with medically controlled IOP < 15 mmHg, achieving an IOP < 10 mmHg with trabeculectomy was beneficial for reducing the VF progression rate in progressive NTG at low IOP levels. However, an IOP < 7 mmHg by surgery would be required careful attention to VA decline. PMID- 28850615 TI - The potential of cell sheet technique on the development of hepatocellular carcinoma in rat models. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is considered the 3rd leading cause of death by cancer worldwide with the majority of patients were diagnosed in the late stages. Currently, there is no effective therapy. The selection of an animal model that mimics human cancer is essential for the identification of prognostic/predictive markers, candidate genes underlying cancer induction and the examination of factors that may influence the response of cancers to therapeutic agents and regimens. In this study, we developed a HCC nude rat models using cell sheet and examined the effect of human stromal cells (SCs) on the development of the HCC model and on different liver parameters such as albumin and urea. METHODS: Transplanted cell sheet for HCC rat models was fabricated using thermo-responsive culture dishes. The effect of human umbilical cord mesenchymal stromal cells (UC-MSCs) and human bone marrow mesenchymal stromal cells (BM-MSCs) on the developed tumour was tested. Furthermore, development of tumour and detection of the liver parameter was studied. Additionally, angiogenesis assay was performed using Matrigel. RESULTS: HepG2 cells requires five days to form a complete cell sheet while HepG2 co-cultured with UC-MSCs or BM-MSCs took only three days. The tumour developed within 4 weeks after transplantation of the HCC sheet on the liver of nude rats. Both UC-MSCs and BM-MSCs improved the secretion of liver parameters by increasing the secretion of albumin and urea. Comparatively, the UC-MSCs were more effective than BM-MSCs, but unlike BM-MSCs, UC-MSCs prevented liver tumour formation and the tube formation of HCC. CONCLUSIONS: Since this is a novel study to induce liver tumour in rats using hepatocellular carcinoma sheet and stromal cells, the data obtained suggest that cell sheet is a fast and easy technique to develop HCC models as well as UC-MSCs have therapeutic potential for liver diseases. Additionally, the data procured indicates that stromal cells enhanced the fabrication of HepG2 cell sheets. This provides the foundation for future research using stromal cells in preclinical and clinical investigations. PMID- 28850616 TI - Effects of gestational age on brain volume and cognitive functions in generally healthy very preterm born children during school-age: A voxel-based morphometry study. AB - OBJECTIVE: To determine whether the relationship of gestational age (GA) with brain volumes and cognitive functions is linear or whether it follows a threshold model in preterm and term born children during school-age. STUDY DESIGN: We studied 106 children (M = 10 years 1 month, SD = 16 months; 40 females) enrolled in primary school: 57 were healthy very preterm children (10 children born 24-27 completed weeks' gestation (extremely preterm), 14 children born 28-29 completed weeks' gestation, 19 children born 30-31 completed weeks' gestation (very preterm), and 14 born 32 completed weeks' gestation (moderately preterm)) all born appropriate for GA (AGA) and 49 term-born children. Neuroimaging involved voxel-based morphometry with the statistical parametric mapping software. Cognitive functions were assessed with the WISC-IV. General Linear Models and multiple regressions were conducted controlling age, sex, and maternal education. RESULTS: Compared to groups of children born 30 completed weeks' gestation and later, children born <28 completed weeks' gestation had less gray matter volume (GMV) and white matter volume (WMV) and poorer cognitive functions including decreased full scale IQ, and processing speed. Differences in GMV partially mediated the relationship between GA and full scale IQ in preterm born children. CONCLUSIONS: In preterm children who are born AGA and without major complications GA is associated with brain volume and cognitive functions. In particular, decreased brain volume becomes evident in the extremely preterm group (born <28 completed weeks' gestation). In preterm children born 30 completed weeks' gestation and later the relationship of GA with brain volume and cognitive functions may be less strong as previously thought. PMID- 28850617 TI - SCREEN: A simple layperson administered screening algorithm in low resource international settings significantly reduces waiting time for critically ill children in primary healthcare clinics. AB - BACKGROUND: In low resource settings, an inadequate number of trained healthcare workers and high volumes of children presenting to Primary Healthcare Centers (PHC) result in prolonged waiting times and significant delays in identifying and evaluating critically ill children. The Sick Children Require Emergency Evaluation Now (SCREEN) program, a simple six-question screening algorithm administered by lay healthcare workers, was developed in 2014 to rapidly identify critically ill children and to expedite their care at the point of entry into a clinic. We sought to determine the impact of SCREEN on waiting times for critically ill children post real world implementation in Cape Town, South Africa. METHODS AND FINDINGS: This is a prospective, observational implementation effectiveness hybrid study that sought to determine: (1) the impact of SCREEN implementation on waiting times as a primary outcome measure, and (2) the effectiveness of the SCREEN tool in accurately identifying critically ill children when utilised by the QM and adherence by the QM to the SCREEN algorithm as secondary outcome measures. The study was conducted in two phases, Phase I control (pre-SCREEN implementation- three months in 2014) and Phase II (post SCREEN implementation-two distinct three month periods in 2016). In Phase I, 1600 (92.38%) of 1732 children presenting to 4 clinics, had sufficient data for analysis and comprised the control sample. In Phase II, all 3383 of the children presenting to the 26 clinics during the sampling time frame had sufficient data for analysis. The proportion of critically ill children who saw a professional nurse within 10 minutes increased tenfold from 6.4% to 64% (Phase I to Phase II) with the median time to seeing a professional nurse reduced from 100.3 minutes to 4.9 minutes, (p < .001, respectively). Overall layperson screening compared to Integrated Management of Childhood Illnesses (IMCI) designation by a nurse had a sensitivity of 94.2% and a specificity of 88.1%, despite large variance in adherence to the SCREEN algorithm across clinics. CONCLUSIONS: The SCREEN program when implemented in a real-world setting can significantly reduce waiting times for critically ill children in PHCs, however further work is required to improve the implementation of this innovative program. PMID- 28850618 TI - Early-onset behavioral and neurochemical deficits in the genetic mouse model of phenylketonuria. AB - Phenylketonuria (PKU) is one of the most common human inborn errors of metabolism, caused by phenylalanine hydroxylase deficiency, leading to high phenylalanine and low tyrosine levels in blood and brain causing profound cognitive disability, if untreated. Since 1960, population is screened for hyperphenylalaninemia shortly after birth and submitted to early treatment in order to prevent the major manifestations of the disease. However, the dietetic regimen (phenylalanine free diet) is difficult to maintain, and despite the recommendation to a strict and lifelong compliance, up to 60% of adolescents partially or totally abandons the treatment. The development and the study of new treatments continue to be sought, taking advantage of preclinical models, the most used of which is the PAHenu2 (BTBR ENU2), the genetic murine model of PKU. To date, adult behavioral and neurochemical alterations have been mainly investigated in ENU2 mice, whereas there are no clear indications about the onset of these deficiencies. Here we investigated and report, for the first time, a comprehensive behavioral and neurochemical assay of the developing ENU2 mice. Overall, our findings demonstrate that ENU2 mice are significantly smaller than WT until pnd 24, present a significant delay in the acquisition of tested developmental reflexes, impaired communicative, motor and social skills, and have early reduced biogenic amine levels in several brain areas. Our results extend the understanding of behavioral and cerebral abnormalities in PKU mice, providing instruments to an early preclinical evaluation of the effects of new treatments. PMID- 28850620 TI - Predicting age groups of Twitter users based on language and metadata features. AB - Health organizations are increasingly using social media, such as Twitter, to disseminate health messages to target audiences. Determining the extent to which the target audience (e.g., age groups) was reached is critical to evaluating the impact of social media education campaigns. The main objective of this study was to examine the separate and joint predictive validity of linguistic and metadata features in predicting the age of Twitter users. We created a labeled dataset of Twitter users across different age groups (youth, young adults, adults) by collecting publicly available birthday announcement tweets using the Twitter Search application programming interface. We manually reviewed results and, for each age-labeled handle, collected the 200 most recent publicly available tweets and user handles' metadata. The labeled data were split into training and test datasets. We created separate models to examine the predictive validity of language features only, metadata features only, language and metadata features, and words/phrases from another age-validated dataset. We estimated accuracy, precision, recall, and F1 metrics for each model. An L1-regularized logistic regression model was conducted for each age group, and predicted probabilities between the training and test sets were compared for each age group. Cohen's d effect sizes were calculated to examine the relative importance of significant features. Models containing both Tweet language features and metadata features performed the best (74% precision, 74% recall, 74% F1) while the model containing only Twitter metadata features were least accurate (58% precision, 60% recall, and 57% F1 score). Top predictive features included use of terms such as "school" for youth and "college" for young adults. Overall, it was more challenging to predict older adults accurately. These results suggest that examining linguistic and Twitter metadata features to predict youth and young adult Twitter users may be helpful for informing public health surveillance and evaluation research. PMID- 28850619 TI - The stability of Fbw7alpha in M-phase requires its phosphorylation by PKC. AB - Fbw7 is a tumor suppressor often deleted or mutated in human cancers. It serves as the substrate-recruiting subunit of a SCF ubiquitin ligase that targets numerous critical proteins for degradation, including oncoproteins and master transcription factors. Cyclin E was the first identified substrate of the SCFFbw7 ubiquitin ligase. In human cancers bearing FBXW7-gene mutations, deregulation of cyclin E turnover leads to its aberrant expression in mitosis. We investigated Fbw7 regulation in Xenopus eggs, which, although arrested in a mitotic-like phase, naturally express high levels of cyclin E. Here, we report that Fbw7alpha, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7alpha inactivation. We show that this PKC-dependent phosphorylation and inactivation of Fbw7alpha also occurs in mitosis during human somatic cell cycles, and importantly is critical for Fbw7alpha stabilization itself upon nuclear envelope breakdown. Finally, we provide evidence that S18 phosphorylation, which lies within the intrinsically disordered N-terminal region specific to the alpha-isoform reduces the capacity of Fbw7alpha to dimerize and to bind cyclin E. Together, these findings implicate PKC in an evolutionarily-conserved pathway that aims to protect Fbw7alpha from degradation by keeping it transiently in a resting, inactive state. PMID- 28850621 TI - MammaPrint versus EndoPredict: Poor correlation in disease recurrence risk classification of hormone receptor positive breast cancer. AB - INTRODUCTION: Correct risk assessment of disease recurrence in patients with early breast cancer is critically important to detect patients who may be spared adjuvant chemotherapy. In clinical practice this is increasingly done based on the results of gene expression assays. In the present study we compared the concordance of the 70-gene signature MammaPrint (MP) with the 12 gene assay EndoPredict (EP). METHODS: Representative tissue of 48 primary tumours was analysed with the MP during routine diagnostic purposes. Corresponding formalin fixed, paraffin-embedded tissue was thereafter analysed by the EP test. Risk categories of both tests were compared. RESULTS: 41 of 48 tumours could be directly compared by both tests. Of the 17 MP low risk cases, only 9 were considered low risk by EP (53% agreement) and of the 24 MP high risk cases, 18 were high risk by EP (75% agreement). Discrepancies occurred in 14 of 41 cases (34.1%). There was only a weak and non-significant correlation between the MP and EP test with an overall concordance of only 66%. The original therapeutic recommendation was based on the MP and would have been changed in 38% of the patients following EP test results. 4 patients developed distant metastases. The respective tumours of these patients were all classified as high risk by the EP, but only 3 were classified as high risk by the MP. CONCLUSION: Both tests resulted in different treatment recommendations for a significant proportion of patients and cannot be used interchangeably. The results underscore the urgent need for further comparative analyses of multi-genomic tests to avoid misclassification of disease recurrence risk in breast cancer patients. PMID- 28850622 TI - CFD study on NACA 4415 airfoil implementing spherical and sinusoidal Tubercle Leading Edge. AB - The Humpback whale tubercles have been studied for more than a decade. Tubercle Leading Edge (TLE) effectively reduces the separation bubble size and helps in delaying stall. They are very effective in case of low Reynolds number flows. The current Computational Fluid Dynamics (CFD) study is on NACA 4415 airfoil, at a Reynolds number 120,000. Two TLE shapes are tested on NACA 4415 airfoil. The tubercle designs implemented on the airfoil are sinusoidal and spherical. A parametric study is also carried out considering three amplitudes (0.025c, 0.05c and 0.075c), the wavelength (0.25c) is fixed. Structured mesh is utilized to generate grid and Transition SST turbulence model is used to capture the flow physics. Results clearly show spherical tubercles outperform sinusoidal tubercles. Furthermore experimental study considering spherical TLE is carried out at Reynolds number 200,000. The experimental results show that spherical TLE improve performance compared to clean airfoil. PMID- 28850623 TI - Continuum of hepatitis C care in France: A 20-year cohort study. AB - BACKGROUND: Hepatitis C virus (HCV)-infected patients require a specific continuum of care (CoC) from HCV screening to treatment. We assessed CoC of HCV infected patients in a longitudinal study. METHODS: We established a cohort of subjects undergoing HCV screening (high alanine aminotransferase levels or risk factors) during preventive consultations at a French regional medical center from 1993 to 2013. Patients were considered to be HCV-infected if HCV RNA was detected in their serum. CoC was assessed as described by Viner et al. (Hepatology 2015): Stage 1, HCV screening; Stage 2, HCV RNA testing; Stage 3, continuing care; Stage 4, antiviral treatment. Cox multivariate analysis was performed to identify factors favoring CoC, defined as at least one course of antiviral treatment. RESULTS: In total, 12,993 HCV tests were performed and 478 outpatients were found to be HCV-seropositive. We included 417 seropositive patients, after excluding false positives and patients lost to follow-up. The baseline characteristics of the patients were: sex ratio (M/F) 1.4; mean age 38.5 years; intravenous drug use (IDU) in 55%; and 28% in unstable social situations, estimated by the EPICES deprivation score. Antiviral treatment was initiated for 179 (42.9%) of the 379 (90.9%) patients attending specialist consultations. CoC was associated with screening after 1997 (HR 2.0, 95%CI 1.4-2.9), age > 45 years (HR 1.5, 95%CI 1.02 2.3), patient acceptance of care (HR 9.3, 95%CI 5.4-16.10), specialist motivation for treatment (HR 10.9, 95%CI 7.4-16.0), and absence of cancer (HR 6.7, 95%CI 1.6 27.9). Other comorbid conditions, such as depression and IDU, were not associated with CoC. CONCLUSIONS: Our 20-year cohort study reveals the real-life continuum of care for HCV-infected patients in France. The number of patients involved in HCV care after positive testing was substantial due to the organization of healthcare in France. An improved CoC along with new direct-acting antivirals should help to decrease chronic HCV infection. PMID- 28850624 TI - Response of a tropical tree to non-timber forest products harvest and reduction in habitat size. AB - Non-timber forest products (NTFPs) are widely harvested by local people for their livelihood. Harvest often takes place in human disturbed ecosystems. However, our understanding of NTFPs harvesting impacts in fragmented habitats is limited. We assessed the impacts of fruit harvest, and reduction in habitat size on the population structures of Pentadesma butyracea Sabine (Clusiaceae) across two contrasting ecological regions (dry vs. moist) in Benin. In each region, we selected three populations for each of the three fruit harvesting intensities (low, medium and high). Harvesting intensities were estimated as the proportion of fruits harvested per population. Pentadesma butyracea is found in gallery forests along rivers and streams. We used the width of gallery forests as a measure of habitat size. We found negative effects of fruit harvest on seedling and adult density but no significant effect on population size class distribution in both ecological regions. The lack of significant effect of fruit harvest on population structure may be explained by the ability of P. butyracea to compensate for the negative effect of fruit harvesting by increasing clonal reproduction. Our results suggest that using tree density and population structure to assess the ecological impacts of harvesting clonal plants should be done with caution. PMID- 28850625 TI - Defects in skeletal muscle subsarcolemmal mitochondria in a non-obese model of type 2 diabetes mellitus. AB - Skeletal muscle resistance to insulin is related to accumulation of lipid-derived products, but it is not clear whether this accumulation is caused by skeletal muscle mitochondrial dysfunction. Diabetes and obesity are reported to have a selective effect on the function of subsarcolemmal and interfibrillar mitochondria in insulin-resistant skeletal muscle. The current study investigated the role of the subpopulations of mitochondria in the pathogenesis of insulin resistance in the absence of obesity. A non-obese spontaneous rat model of type 2 diabetes mellitus, (Goto-Kakizaki), was used to evaluate function and biochemical properties in both populations of skeletal muscle mitochondria. In subsarcolemmal mitochondria, minor defects are observed whereas in interfibrillar mitochondria function is preserved. Subsarcolemmal mitochondria defects characterized by a mild decline of oxidative phosphorylation efficiency are related to ATP synthase and structural alterations of inner mitochondria membrane but are considered unimportant because of the absence of defects upstream as shown with polarographic and spectrophometric assays. Fatty acid transport and oxidation is preserved in both population of mitochondria, whereas palmitoyl-CoA increased 25% in interfibrillar mitochondria of diabetic rats. Contrary to popular belief, these data provide compelling evidence that mitochondrial function is unaffected in insulin-resistant skeletal muscle from T2DM non-obese rats. PMID- 28850626 TI - Development of a graphene oxide-based assay for the sequence-specific detection of double-stranded DNA molecules. AB - Graphene oxide (GO) is a promising material for the development of cost-effective detection systems. In this work, we have devised a simple and rapid GO-based method for the sequence-specific identification of DNA molecules generated by PCR amplification. The csp genes of Escherichia coli, which share a high degree of sequence identity, were selected as paradigm DNA templates. All tested csp genes were amplified with unlabelled primers, which can be rapidly removed at the end of the PCR taking advantage of the preferential binding to GO of single-stranded versus duplex DNA molecules. The amplified DNAs (targets) were heat-denatured and hybridized to a fluorescently-labelled single strand oligonucleotide (probe), which recognizes a region of the target DNAs displaying sequence variability. This interaction is extremely specific, taking place with high efficiency only when target and probe show perfect or near perfect matching. Upon GO addition, the unbound fraction of the probe was captured and its fluorescence quenched by the GO's molecular properties. On the other hand, the probe-target complexes remained in solution and emitted a fluorescent signal whose intensity was related to their degree of complementarity. PMID- 28850627 TI - A facility location model for analysis of current and future demand for sexual health services. AB - In this paper we address the clinic location selection problem for a fully integrated Sexual Health Service across Hampshire. The service provides outpatient services for Genito-Urinary Medicine, contraceptive and reproductive health, sexual health promotion and a sexual assault referral centre. We aim to assist the planning of sexual health service provision in Hampshire by conducting a location analysis using both current and predicted patient need. We identify the number of clinic locations required and their optimal geographic location that minimise patient travel time. To maximise the chances of uptake of results we validate the developed simple algorithm with an exact method as well as three well-known, but complex meta-heuristics. The analysis was conducted using car travel and public transport times. Two scenarios were considered: current clinic locations only; and anywhere within Hampshire. The results show that the clinic locations could be reduced from 28 to 20 and still keep 90% of all patient journeys by public transport (e.g. by bus or train) to a clinic within 30 minutes. The number of clinics could be further reduced to 8 if the travel time is based on car travel times within 15 minutes. Results from our simple solution method compared favourably to the exact solution as well as the complex meta heuristics. PMID- 28850628 TI - Ultrastructural investigation and in vitro recapitulation of spermatid differentiation in a potential bio-indicator species - The marine invertebrate Galeolaria gemineoa (Polychaeta: Serpulidae). AB - Galeolaria gemineoa is a sessile broadcast-spawning marine invertebrate, whose spermatozoa have been regarded as a sensitive indicator for water quality monitoring. In this study, 10 steps of spermiogenesis have been identified at the ultrastructural level and this differentiation process has been recapitulated in vitro up to the point of spermiogenesis (step 7-9 spermatids). On completion of the second meiosis, newly formed spermatids were detached from the seminiferous epithelium and released to the lumen of each germinal chamber. These spermatids were present in pairs and interconnected by a cytoplasmic bridge throughout the entire spermiogenic process. On the basis of morphological events such as formation of the acrosome, elongation of the flagellum, and condensation of the nucleus, spermiogenesis has been temporally divided into Golgi phase, acrosomal phase and maturation phase. During the Golgi phase, proacrosomal vesicles appeared at the posterior pole of the spermatids and gradually fused into a proacrosomal vacuole. Simultaneously, the distal centriole docked onto the plasma membrane and gave rise to a formative flagellum. The acrosomal phase was characterised by differentiation of the acrosome, condensation of the chromatin and formation of a mitochondrial sheath surrounding the initial portion of the flagellum. During the maturation phase, the fully differentiated acrosome migrated to the anterior pole and excess cytoplasm was extruded from the spermatids in the form of residual bodies. In addition, we successfully induced step 1-3 spermatids to differentiate into the step 7-9 spermatids in both male germinal fluid and 10% foetal bovine serum in RPMI 1640 medium, but failed to replicate this process in female or boiled male germinal fluids. This finding supports our concept that spermatid differentiation in this species is dependent on intrinsic developmental programming and does not require input from accompanying nurse cells. PMID- 28850629 TI - Clinical utility of circulating cell-free DNA in advanced colorectal cancer. AB - BACKGROUND: Circulating cell-free DNA (cfDNA) isolated from the plasma of cancer patients (pts) has been shown to reflect the genomic mutation profile of the tumor. However, physician and patient assessment of clinical utility of these assays in patients with metastatic colorectal cancer (mCRC) has not been previously described. METHODS: Patients were prospectively consented to a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]), with collection of blood for cfDNA extraction and sequencing of a 54-gene panel in a CLIA-certified lab. Formalin-fixed, paraffin embedded (FFPE) tissue from prior resections or biopsies underwent 50-gene sequencing. Results from both assays were returned to the treating physicians for patient care and clinical trial selection. Follow-up surveys of treating physicians and chart reviews assessed clinical utility. RESULTS: 128 mCRC pts were enrolled between 6/2014 and 1/2015. Results were returned in median of 13 and 26 days for cfDNA and FFPE sequencing, respectively. With cfDNA sequencing, 78% (100/128) of samples had a detectable somatic genomic alteration. 50% of cfDNA cases had potentially actionable alterations, and 60% of these could be genomically matched to at least one clinical trial in our institution. 50% (15/30) of these pts enrolled onto an identified matched trial. Physicians reported that the cfDNA testing improved the quality of care they could provide in 73% of the cases, and that 89% of pts reported greater satisfaction with the efforts to personalize experimental therapeutic agents. CONCLUSIONS: cfDNA sequencing can provide timely information on potentially actionable mutations and amplifications, thereby facilitating clinical trial enrollment and improving the perceived quality of care. PMID- 28850630 TI - Trans-synaptic degeneration in the optic pathway. A study in clinically isolated syndrome and early relapsing-remitting multiple sclerosis with or without optic neuritis. AB - OBJECTIVE: Increasing evidence suggest that neuronal damage is an early and diffuse feature of Multiple Sclerosis (MS) pathology. Analysis of the optic pathway may help to clarify the mechanisms involved in grey matter damage in MS. Purpose of our study was to investigate the relationship between inflammation and neurodegeneration and to achieve evidence of trans-synaptic degeneration in the optic pathway in MS at clinical onset. METHODS: 50 clinically isolated syndromes/early relapse-onset MS (CIS/eRRMS) with mean disease duration of 4.0+/ 3.5 months, 28 MRI healthy controls (HC) and 31 OCT-HC were studied. Ten patients had optic neuritis at presentation (MSON+), 40 presented with other symptoms (MSON-). MRI examination included 3D-T1, 3D-FLAIR and 3D-DIR sequences. Global cortical thickness (gCTh), pericalcarin CTh (pCTh) and white matter volume (WMV) were analysed by means of Freesurfer on 3D-T1 scans. Optic radiation morphology (OR) and volume (ORV) were reconstructed on the base of the Julich's Atlas. White matter lesion volume (WMLV), OR-WMLV and percent WM damage (WMLV/WMV = WMLV% and OR-WMLV/ORV = ORWMLV%) were obtained by 3D-FLAIR image segmentation. 3D-DIR sequences were applied to identify inflammatory lesions of the optic nerve. Optic coherence tomography (OCT) protocol included the analysis of global peripapillary retinal nerve fiber layer (g-RNFL) and the 6 fundus oculi's sectors (temporal, T RNFL; temporal superior, TS-RNFL; nasal superior, NS-RNFL; nasal, N-RNFL; nasal inferior, NI-RNFL, temporal inferior, TI-RNFL). The retina of both eyes was analyzed. The eyes of ON+ were further divided into affected (aON+) or not (naON+). RESULTS: No difference in CTh was found between CIS/eRRMS and HC, and between MSON+ and MSON-. Moreover, MSON+ and MSON- did not differ for any WM lesion load parameter. The most significant correlations between RNFL thickness and optic radiation WM pathology were found in MSON+. In these patients, the temporal RNFL inversely correlated to ipsilateral optic radiation WM lesion load (T-RNFL: r -0.7, p<0.05; TS-RNFL: r -0.7, p<0.05), while nasal RNFL inversely correlated to contralateral optic radiation WM lesion load (NI: r -0.8, p<0.01; NS-RNFL: r -0.8, p<0.01). CONCLUSIONS: Our findings suggest that in MSON+ the optic pathway is site of a diffuse pathological process that involves both directly and via trans-synaptic degeneration the RNFL. PMID- 28850632 TI - The influence of CSN3 and LGB polymorphisms on milk production and chemical composition in Romanian Simmental cattle. AB - The aim of this study was to assess the influence of genotypes from the CSN3 and LGB loci on milk production and chemical composition in Romanian Simmental cattle (n=114). For the CSN3 locus a significantly higher frequency (P<=0.001) was observed for the allele A (0.785) compared to allele B (0.215) and for AA (0.631) compared to AB (0.307) and BB (0.062) genotypes, respectively. The AA genotype was associated with a higher milk production (5887.76+/-115.7 kg) compared to the yields associated with the BB genotype (5619+/-86.34 kg, P<=0.003), as well as a higher fat percentage (4.19+/-0.05% vs. 4.01+/-0.02%, P<=0.001). A higher milk protein percentage was associated with BB (3.4+/-0.02%) compared to AA (3.27+/ 0.03) and AB (3.29+/-0.03) genotypes, respectively (P<=0.05). For the LGB locus, the frequency of allele A was significantly higher (0.606, P<=0.008) than allele B (0.394). The AB genotype was the most prevalent in the herd (0.579) compared to AA (0.316) and BB genotypes (0.105). The AB genotype was associated with a higher milk production (5906.54+/-166.76 kg) compared with the other two genotypes (P<=0.05). The BB genotype was associated with a higher fat percentage in milk (4.23+/-0.06%) compared with AA (4.17+/-0.06) and AB (4.2+/-0.08) genotypes, respectively (P<=0.01). For the LGB locus, no significant differences (P>0.05) were observed for milk protein percentage. In order to increase the quantity and quality of milk, the outcomes obtained in this study encourage improving genetic structure in cattle based on marker assisted selection for genes with economic values. PMID- 28850631 TI - Free mass distribution of long lasting insecticidal nets lead to high levels of LLIN access and use in Madagascar, 2010: A cross-sectional observational study. AB - BACKGROUND: Madagascar conducted the first two phases of a national free mass distribution campaign of long-lasting insecticidal nets (LLINs) during a political crisis in 2009 aiming to achieve coverage of two LLINs per household as part of the National Malaria Control Strategy. The campaign targeted households in 19 out of 91 total health districts. METHODS: A community-based cross sectional household survey using a three-stage cluster sample design was conducted four months post campaign to assess LLIN ownership, access and use. Multivariable logistic regression analysis was used to identify factors associated with household LLIN access and individual LLIN use. RESULTS: A total of 2211 households were surveyed representing 8867 people. At least one LLIN was present in 93.5% (95% confidence interval [CI], 91.6-95.5%) of households and 74.8% (95% CI, 71.0-78.6%) owned at least two LLINs. Access measured as the proportion of the population that could potentially be covered by household-owned LLINs was 77.2% (77.2% (95% CI, 72.9-81.3%) and LLIN use by all individuals was 84.2% (95% CI, 81.2-87.2%). LLIN use was associated with knowledge of insecticide treated net use to prevent malaria (OR = 3.58, 95% CI, 1.85-6.94), household ownership of more LLINs (OR 2.82, 95% CI 1.85-4.3), presence of children under five (OR = 2.05, 95% CI, 1.67-2.51), having traveled to the distribution point and receiving information about hanging a bednet (OR = 1.56, 95% CI, 1.41-1.74), and having received a post-campaign visit by a community mobilizer (OR = 1.75, 95% CI, 1.26-2.43). Lower LLIN use was associated with increasing household size (OR = 0.81 95% CI 0.77-0.85) and number of sleeping spaces (OR = 0.55, 95% CI, 0.44-0.68). CONCLUSIONS: A large scale free mass LLIN distribution campaign was feasible and effective at achieving high LLIN access and use in Madagascar. Campaign process indicators highlighted potential areas for strengthening implementation to optimize access and equity. PMID- 28850633 TI - Fatty acid amide hydrolase (FAAH) inhibitor PF-3845 reduces viability, migration and invasiveness of human colon adenocarcinoma Colo-205 cell line: an in vitro study. AB - Earlier reports suggest that the endocannabinoids may play a role of endogenous tumor growth modulators. In this study, we investigated whether inhibition of the enzymes involved in the synthesis and degradation of endocannabinoids may reduce colorectal cancer cell invasion and migration. The human colon adenocarcinoma Colo-205 cells were incubated with PF-3845, JZL-184 and RHC-80267 (fatty acid amide hydrolase (FAAH), mono- (MAGL) and diacylglycerol lipase (DAGL) inhibitors, respectively) for 48 h. The MTT colorimetric assay was performed to quantify cell viability. Next, Colo-205 cells were incubated with PF-3845 alone or with PF-3845 together with selected antagonists: AM 251, AM 630, SB 366791, RN 1734 and G-15 (CB1, CB2, TRPV1, TRPV4 and GPR30 antagonists, respectively). Western blot assay was applied to identify the changes in CB1 and CB2 receptor expression. Migration and invasion assays were employed to characterize the effect of PF-3845 on colorectal cancer cell invasion. We found that of all the inhibitors used, the FAAH inhibitor PF-3845 reduced the Colo-205 cell line viability the most effectively (IC50=52.55 MUM). We also showed that the effect of decreased cell viability was enhanced when Colo-205 cells were incubated with PF-3845 and RN 1734, a TRPV4 antagonist (IC50=30.54 MUM). Western blot assay revealed significantly decreased CB1 receptor expression levels, while CB2 expression was increased in response to PF-3845 when compared to control. Furthermore, PF-3845 inhibited migration and invasion of Colo-205 cell line. These results suggest that pharmacological inhibition of FAAH and consequent enhancement of the endocannabinoid levels may reduce the colorectal cancer growth and progression. PMID- 28850634 TI - Dynamics of hyperphenylalaninemia and intellectual outcome in teenagers with phenylketonuria. AB - Insufficient treatment adherence after early childhood is frequently observed in patients with phenylketonuria. Assessment of these individuals' long-term metabolic control could enable early detection of the risk of intellectual deterioration resulting from high blood phenylalanine concentration. However, the predictive value of specific parameters related to individual dynamics of hyperphenylalaninemia is not clear. Here, we assessed the impact of blood phenylalanine fluctuations during the first 12 years of life on cognitive outcome in early and continuously treated teenagers with phenylketonuria. We have analyzed a total of 5141 results of blood phenylalanine measurements in 32 patients. The phenylalanine levels of these patients were usually acceptable during their early childhood, but the control of hyperphenylalaninemia worsened and the average treatment adherence dropped to 40% during the late primary school. Our analysis revealed a strong association between the Wechsler intelligence verbal scores and the mean of the yearly means of phenylalanine concentrations (r=-0.62). The correlations of IQ scores with median phenylalanine concentrations and the variability of blood phenylalanine levels gave weaker associations. The Wechsler verbal scores were also strongly correlated with the treatment adherence level during preschool and late primary school (r=0.61 and 0.72). The mean of the yearly means of blood phenylalanine concentrations appears to be a better predictor of cognitive outcome in children with phenylketonuria than other parameters related to phenylalanine fluctuations. The percentage of acceptable phenylalanine levels below 50-60% should be regarded as a "red flag" due to the risk of intellectual deterioration in patients. PMID- 28850635 TI - Expression analysis of the Arabidopsis thaliana AtSpen2 gene, and its relationship with other plant genes encoding Spen proteins. AB - Proteins of the Split ends (Spen) family are characterized by an N-terminal domain, with one or more RNA recognition motifs and a SPOC domain. In Arabidopsis thaliana, the Spen protein FPA is involved in the control of flowering time as a component of an autonomous pathway independent of photoperiod. The A. thaliana genome encodes another gene for a putative Spen protein at the locus At4g12640, herein named AtSpen2. Bioinformatics analysis of the AtSPEN2 SPOC domain revealed low sequence similarity with the FPA SPOC domain, which was markedly lower than that found in other Spen proteins from unrelated plant species. To provide experimental information about the function of AtSpen2, A. thaliana plants were transformed with gene constructs of its promoter region with uidA::gfp reporter genes; the expression was observed in vascular tissues of leaves and roots, as well as in ovules and developing embryos. There was absence of a notable phenotype in knockout and overexpressing lines, suggesting that its function in plants might be specific to certain endogenous or environmental conditions. Our results suggest that the function of Atspen2 diverged from that of fpa due in part to their different transcription expression pattern and divergence of the regulatory SPOC domain. PMID- 28850636 TI - Allogeneic Descemet's Membrane Transplantation Enhances Corneal Endothelial Monolayer Formation and Restores Functional Integrity Following Descemet's Stripping. AB - Purpose: To characterize the differences in corneal endothelial wound healing in the presence or absence of Descemet's membrane (DM), in vivo. Methods: New Zealand white rabbits were subjected to 7-mm endothelial wound either by scraping (n = 8; DM intact), peeling (n = 6; DM removed), or a combinatory scrape/peel wound (n = 6). In a second experiment, rabbits underwent peel wound with immediate transplantation of pure decellularized human DM (n = 4). In vivo endothelial migration was assessed via trypan blue staining. Recovery of corneal clarity and thickness was performed by using slit-lamp biomicroscopy and optical coherence tomography. Cell proliferation, phenotype, and morphology were assessed by using immunofluorescence and scanning electron microscopy. Results: In vivo wound closure was faster in the presence of DM; 25.4% +/- 1.4%/d versus 5.5% +/- 0.6%/d (P < 0.0001). At day 8, complete wound closure was seen in all of the scrape samples but none of the peel group, with wound closure preceding clinical recovery by approximately 6 days in the scrape group. Endothelial cells in the scraped areas reformed functional monolayers capable of restoring corneal thickness and transparency whilst those in the peeled area underwent mesenchymal like transformation resulting in scar formation. Transplanting decellularized DM in animals receiving a peel wound resulted in clarity and thickness comparable to the scrape group. Endothelial proliferation (Ki67 +ve cells) was higher in scraped versus peeled areas: 54.7% +/- 3.5% vs. 8.8% +/- 0.7%, (P < 0.01). Conclusions: The presence of DM promoted endothelial wound healing, proliferation, and maintenance of a normal phenotype. DM transplantation recovered the abnormal peel phenotype back to that observed after endothelial scraping. PMID- 28850637 TI - Role of the Fc Region in the Vitreous Half-Life of Anti-VEGF Drugs. AB - Purpose: To identify the role of the fragment crystallizable (Fc) region in determining intraocular protein drug pharmacokinetics. Methods: We generated a new VEGF-Trap lacking the Fc region (FcfVEGF-Trap, MWt = 100 kDa) by replacing the Fc region of native VEGF-Trap (MWt = 145 kDa) with a dimerized coiled-coil domain. Forty-two rabbits were injected intravitreally with VEGF-Trap or FcfVEGF Trap (n = 21 each) in one of the eyes, harvested at six time points (1 hour and 1, 2, 4, 14, and 30 days after injections). VEGF-Trap and FcfVEGF-Trap concentrations in the vitreous, aqueous humor, and retina/choroid were measured, and drug pharmacokinetic properties were analyzed. Results: In all three ocular compartments, the maximal concentrations for both FcfVEGF-Trap and VEGF-Trap were observed at 1 hour after injection. Half-lives of FcfVEGF-Trap in the vitreous and retina/choroid (145.02 and 102.12 hours, respectively) were 1.39 and 2.30 times longer than those of VEGF-Trap (103.99 and 44.42 hours, respectively). Total exposure of the aqueous humor and retina/choroid to FcfVEGF-Trap was 13.2% and 39% of the vitreous exposure, respectively, whereas VEGF-Trap concentrations were 25.2% and 26.2%, indicating that FcfVEGF-Trap shows a preference for posterior distribution and elimination. Conclusions: FcfVEGF-Trap, despite its lower molecular weight, showed longer half-lives in vitreous and retina/choroid than VEGF-Trap did, suggesting that Fc receptors in ocular tissues contribute to anti-VEGF drug elimination. Truncation or mutation of the Fc region can prolong the intraocular residence time of VEGF-Trap and possibly reduce the number of VEGF-Trap injections required in clinical practice. PMID- 28850638 TI - Evaluation of the Toxicity of Intravitreally Injected PLGA Microspheres and Rods in Monkeys and Rabbits: Effects of Depot Size on Inflammatory Response. AB - Purpose: Poly(lactic-co-glycolic) acid (PLGA) inserts have been successfully developed for the treatment of posterior eye disease as a means of reducing injection frequency of intravitreally administered therapeutics. PLGA microspheres are also of interest for the delivery of intravitreal drugs, since they offer the advantage of being easily injected without surgical procedures or large injectors. Methods: In the current study, the toxicity of PLGA microspheres and rods was investigated in nonhuman primates (NHPs) and rabbits. An in vitro assessment of cytokine responses to PLGA in peripheral blood mononuclear cells (PBMCs) and macrophages was also performed. Results: Intravitreal administration of 3, 10, or 12.5 mg/eye of PLGA microspheres in NHPs resulted in a severe immune response characterized by a foreign body response. Follow-up studies in the rabbit confirmed this finding for PLGA microspheres ranging in size from 20 to 100 MUm. In contrast, administration of PLGA rod implants with a similar PLGA mass did not elicit a significant immune response. In vitro assays in PBMCs and macrophages confirmed proinflammatory cytokine release upon treatment with PLGA microspheres but not PLGA rods. Conclusions: These data demonstrate a lack of tolerability of PLGA microspheres upon intravitreal injection, and suggest that the size, shape, and/or surface area of PLGA depots are critical attributes in determining ocular toxicity. PMID- 28850639 TI - Does Decreased Static Ocular Counter Rolling Account for Bielschowsky Head Tilt Test in Unilateral Superior Oblique Palsy? AB - Purpose: To understand the relationship of static ocular counter rolling (s-OCR) and clinical manifestations in acquired unilateral superior oblique palsy subjects during the Bielschowsky head tilt test. Methods: Nineteen subjects that were diagnosed with acquired unilateral superior oblique palsy were included. Fundus photographs were obtained at different head tilt angles to evaluate static ocular counter rolling using a fundus camera with a cervical range of motion device. Using a graphics editing program, we calculated s-OCR from fundus photography. Results: The incycloductional s-OCR (OCR-I) in the paretic eye was significantly smaller than the OCR-I in the fellow eye (P = 0.02, <0.001, 0.002 for 10 degrees , 20 degrees , and 30 degrees , respectively, paired t-tests). In contrast, the excycloductional s-OCR (OCR-E) showed no significant difference between the paretic eye and the fellow eye for all angles. There was a significantly positive correlation between the amplitude of OCR-I in the paretic eye and the degree of hypertropia on ipsilesional head tilt (rho = 0.612, 0.679, 0.474, P = 0.02, 0.002, 0.07 for 10 degrees , 20 degrees , and 30 degrees respectively, Spearman's correlation). The amplitude of OCR-I in the paretic eye also showed a positive correlation with head tilt test difference, which is the degree of hyperdeviation difference between ipsilesional and contralesional head tilts (rho = 0.445, 0.694, 0.579, P = 0.09, 0.002, 0.024 for 10 degrees , 20 degrees , and 30 degrees respectively, Spearman's correlation). Conclusions: In unilateral SOP, OCR-I in the paretic eye was smaller than that in the fellow eye, and this was positively associated with the degree of hypertropia during ipsilesional head tilting, as well as the head tilt test difference. PMID- 28850640 TI - Impact of a Strabismus Surgery Suture Course for First- and Second-Year Ophthalmology Residents. AB - PURPOSE: To investigate the effectiveness of an eye muscle surgery course on first- and second-year postgraduate ophthalmology residents. METHODS: This prospective cohort pilot study invited first- and second-year ophthalmology residents to participate in a 2-hour strabismus surgery course at Wills Eye Hospital. The course consisted of a didactic session followed by a wet laboratory session. The wet laboratory session simulated strabismus surgery using a model constructed of chicken breast followed by partial-thickness scleral suture passes in pig eyes. A structured self-assessment evaluation form and a questionnaire in the validated Ophthalmology Surgical Competency Assessment Rubric approved by the International Council of Ophthalmology (ICO-OSCAR:strabismus) were used to assess the effectiveness of the course. RESULTS: A total of 12 residents, 8 (67%) first year and 4 (33%) second-year, were enrolled for this survey. Following the course, most residents felt less anxious (73%). All residents responded that the course was helpful or somewhat helpful in preparation for strabismus surgery. Regarding the distribution of ratings on questions of subjective experience, knowledge of steps, and understanding of potential complications, the residents gave significantly higher ratings after the course (P < .029). The change in the modified ICO-OSCAR:strabismus assessment's mean score was statistically significant before and after training (P = .038). CONCLUSIONS: A strabismus course can play an important role in preparing residents for strabismus surgery. [J Pediatr Ophthalmol Strabismus. 2017;54(6):339-345.]. PMID- 28850641 TI - Preliminary Study of the Differences in Optic Nerve Head Hemoglobin Measures Between Patients With and Without Childhood Glaucoma. AB - PURPOSE: To evaluate the effectiveness of quantifying color changes in the optic nerve head in retinal photographs of patients with childhood glaucoma. METHODS: In this observational study, three photographs of the optic nerve head were obtained in 28 patients with childhood glaucoma and 28 age- and sex-matched healthy participants (the childhood glaucoma and control groups, respectively). The Laguna Optic Nerve Head Hemoglobin (ONhE) software (Insoft SL, Tenerife, Spain) was used to determine hemoglobin levels in the optic nerve head. The following parameters were quantified: the hemoglobin levels in the optic nerve head across the whole disc, in 24 sectors (the optic nerve head divided by two concentric rings and eight 45-degree radial sectors), and in the vertical disc diameter (sectors 8 and 20), and the estimated cup-disc ratio and Glaucoma Discriminant Function, which combines the slope of the hemoglobin amount with the mean vertical disc diameter. RESULTS: Patient ages ranged from 9 to 14 years (median: 11 years) in the childhood glaucoma group, and 7 to 13 years (median: 9 years) in the control group (P < .061). Eyes in the childhood glaucoma group showed a significantly higher cup-disc ratio compared to eyes in the control group (0.6 +/- 0.2 vs 0.5 +/- 0.1, respectively; P < .0001). In the childhood glaucoma group, the Glaucoma Discriminant Function was found to be significantly lower than in the control group (-6.5 +/- 31.1 vs 9.4 +/- 17.1, respectively; P < .0001). There were no significant differences in the hemoglobin levels in the optic nerve head across the whole disc between eyes in the childhood glaucoma and control groups (58.2% +/- 10.9% vs 58.5% +/- 6.7%, respectively; P = .847). The Laguna ONhE software showed good reproducibility in measuring percentages of hemoglobin levels in both groups. CONCLUSIONS: The Laguna ONhE software is useful for patients with childhood glaucoma. However, hemoglobin levels in the optic nerve head across the whole disc may have normal values. This method had good reliability and is easy to implement in routine clinical practice. [J Pediatr Ophthalmol Strabismus. 2017;54(6):387-394.]. PMID- 28850642 TI - Video Game Vision Syndrome: A New Clinical Picture in Children? AB - PURPOSE: To examine a possible relationship between exposure to video games/electronic screens and visual issues in children between 3 and 10 years of age. METHODS: An observational, cross-sectional study of a population of children using video games was employed. All patients between 3 and 10 years of age were recruited at an outpatient unit accredited by the Italian Regional Health Service. Three hundred twenty children (159 boys and 161 girls; mean age = 6.9 +/ 2 years) were observed. Ophthalmological examination included assessment of stereoscopic vision on Lang-Stereotests I and II (LANG-STEREOTEST AG, Kusnacht, Switzerland) and identification of the dominant eye using the Dolman method. Furthermore, a questionnaire was used to record asthenopic symptoms and daily exposure to video games and electronic screens. Two groups of children were examined according to the average amount of time spent playing video games daily: children who played video games for less than 30 minutes per day and not every day (control group) and children who played video games for 30 minutes or more every day (video game group). Both groups were then divided into two subgroups: children using other types of electronic screens (eg, televisions, computers, tablets, and smartphones) for less than 3 hours daily (low electronic use subgroup) and children using other types of electronic screens for 3 hours or more per day (high electronic use subgroup). RESULTS: Asthenopia (especially headache, eyelid tic, transient diplopia, and dizziness), absence of fine stereopsis, and refractive errors were statistically more frequent (mainly in the dominant eye) in children in the video game group. CONCLUSIONS: These symptoms were frequent and peculiar in the video game group and might be part of a video game vision syndrome that has not been defined yet. It is important to recognize these signs as possible functional disorders to avoid erroneous diagnostic and therapeutic interventions. [J Pediatr Ophthalmol Strabismus. 2017;54(6):346 355.]. PMID- 28850643 TI - Toward Achieving 100% Adherence for Retinopathy of Prematurity Screening Guidelines. AB - PURPOSE: To report on the use of a cloud-based electronic medical record (ROP Check; Glacier Medical Software, Anchorage, AK) designed to provide American Academy of Pediatrics (AAP) guideline-adherent retinopathy of prematurity (ROP) care through the scheduling and documenting of ROP examinations. METHODS: Data analysis on 3,155 patients from a de-identified dataset from 13 neonatal intensive care units. RESULTS: All newborns with a gestational age of 22 to 30 weeks (N = 2,278) were entered with a documented ROP examination. Of those, 98% and 97.4% completed their initial and follow-up examinations, respectively, within AAP guidelines. All but 1 of 145 initial treatments were completed within AAP guidelines after a decision for treatment was made. Of 369 newborns older than 30 weeks' gestational age and with a birth weight of less than 1,500 grams, none progressed to treatment; four patients had stage 2 or 3 ROP. Of 508 newborns with a gestational age of 31 to 32 weeks and a birth weight of more than 1,500 grams who were entered to identify unstable newborns, 34% did not need examinations; of those who were examined, one progressed to treatment. Fourteen percent of patients were observed as outpatients before retinal maturity and 12% missed some or all outpatient appointments. A decision was made to treat at the first examination for 2 (10%) newborns with a gestational age of 22 weeks and 2 (2%) newborns with a gestational age of 23 weeks. Each patient was within the AAP guidelines for initial treatment. CONCLUSIONS: A computerized system specifically designed with process improvement and error-free delivery of ROP care as a focus can improve adherence to AAP guidelines and achieve superior results. Such a system creates a standardized and measurable safety net for pediatric ophthalmologists, neonatologists, hospitals, and follow-up pediatricians. [J Pediatr Ophthalmol Strabismus. 2017;54(6):356-362.]. PMID- 28850645 TI - Clinical Uses of Anticonvulsant Drugs Other Than for Epilepsy. PMID- 28850644 TI - Black Mental Health Matters: What Nurses Need to Know About Chronic Stressors of Persons of Color. PMID- 28850646 TI - Attention-Deficit/Hyperactivity Disorder: A Historical Review (1775 to Present). AB - As a new school year approaches, nurses will find themselves faced with students with symptoms of attention-deficit/hyperactivity disorder (ADHD). Navigating the diagnostic label changes and numerous psychopharmacological treatment options can prove time-consuming and confusing. The current article explores the early years of symptom identification, various diagnostic labels, and subsequent psychopharmacological treatments from psychostimulants to non-stimulant alternatives (including a prescription medical food). The current article also serves as a discussion guide for nurses and clinicians when providing education to patients and their loved ones, teachers, coaches, and others who may question the diagnosis and treatment of ADHD. This disorder can have a significant impact on one's ability to function within family, school, work, and social settings. A historical context is provided for the evolution of today's diagnostic criteria and the pharmacotherapy used in the treatment of ADHD. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 10-16.]. PMID- 28850647 TI - The Role of Pleasure Neurobiology and Dopamine in Mental Health Disorders. AB - Recent evidence and research has demonstrated that the pleasure response and associated neurotransmitters and brain circuits play a significant role in substance use disorders (SUDs). It was thought that negative behaviors associated with SUDs resulted from negative choices, but it is now known that chemical changes in the brain drive those behaviors. Several mental health disorders (e.g., eating disorders, non-suicidal self-injury, compulsive sex behaviors, internet gaming, gambling) are also thought to involve those same pleasure responses, neurotransmitters, and brain regions. Studies have shown that the use of naltrexone, a dopamine antagonist, can reduce symptoms of these disorders. It is important for nurses to understand the underlying physiology of mental health disorders that are thought to have an addictive or craving component. This understanding can help reduce stigma. Educating patients about likely neurobiological causes for their disorders can also help reduce guilt and shame. Nurses should educate patients about these disorders and evidence-based treatments, including off-label use of naltrexone. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 17-21.]. PMID- 28850648 TI - Primary Care Advanced Practice RNs' Knowledge of Posttraumatic Stress Disorder and Screening. AB - Individuals with posttraumatic stress disorder (PTSD) may seek treatment for their symptoms within the primary care setting. Research suggests PTSD often goes undiagnosed in primary care. Primary care providers (PCPs) might have deficiencies in their knowledge of PTSD screening and screening practices. A descriptive cross-sectional study design was used to examine primary care advanced practice RNs' (APRN) knowledge of PTSD screening and screening practices, along with subjective norms, attitudes, and self-efficacy regarding PTSD screening. Deficiencies in knowledge of PTSD screening and screening practices were identified. Discrepancies were found between reported subjective norms and screening practices, and most participants reported low self-efficacy and stated screening was not important. Numerous barriers to screening were identified. Additional education and training may be needed to improve primary care APRNs' PTSD screening knowledge and screening practices. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 23-32.]. PMID- 28850649 TI - Hope, Core Self-Evaluations, Emotional Well-Being, Health-Risk Behaviors, and Academic Performance in University Freshmen. AB - The purpose of the current online cross-sectional study was to examine the relationship between hope, core self-evaluations (CSE), emotional well-being, health-risk behaviors, and academic performance in students enrolled in their first year of college. Freshmen (N = 495) attending a large public university in the Northeastern United States completed an online survey between February 1 and 13, 2017. Linear regression, path analysis, and structural equation modeling procedures were performed. CSE mediated the relationship between hope and emotional well-being and academic performance. Contrary to the hypotheses, higher hope predicted more sexual risk-taking behaviors and alcohol use. CSE is an important component of Hope Theory, which is useful for predicting emotional well being and academic performance, but not as useful for predicting drug use, alcohol use, and sexual risk taking. Hope and CSE interventions are needed to improve academic performance and emotional well-being in university freshmen. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 33-42.]. PMID- 28850650 TI - Evaluating the Psychometric Properties of the Arabic Version of the Diabetes Distress Scale. AB - The current study evaluated the psychometric properties of the Arabic version of the Diabetes Distress Scale (DDS-A) among Arab patients with diabetes mellitus (DM) using a descriptive cross-sectional design. Participants' DDS-A total scores significantly correlated with depressive symptoms (r = 0.288, p = 0.000) as well as two subscales, emotional burden (r = 0.276, p = 0.000) and regimen distress (r = 0.265, p = 0.000). Participants' DDS-A scores had significant negative correlations with income, DM self-management, and knowledge (r = -0.184, p = 0.008; r = -0.310, p = 0.000; r = -0.174, p = 0.003, respectively) and a positive correlation with HbA1c level (r = 0.153, p = 0.018). Factor analysis revealed a four-factor solution that retained all items and explained a variance of 65.59%. Cronbach's alpha was 0.822 for the total scale and 0.778 to 0.881 for the subscales, indicating a high internal consistency. The DDS-A was found to be a psychometrically sound measure to evaluate DM-related distress among Arab patients. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 43 51.]. PMID- 28850651 TI - Untitled by Roger Castro. PMID- 28850652 TI - Small, Insignificant, and Important Words: Prepositions, Adjectives, and Adverbs Matter. PMID- 28850653 TI - Interprofessional Continuing Education in the Ambulatory Care Setting. AB - Ambulatory care is a rapidly growing specialty practice area. This article describes how interprofessional continuing education can serve as a platform to support this growth and how the nursing professional development practitioner can use their skills to lead the way. J Contin Educ Nurs. 2017;48(9):390-391. PMID- 28850654 TI - The Doctor of Nursing Practice in the Workplace: Now What? AB - The rapid proliferation of Doctor of Nursing Practice programs and graduates has proliferated to create a critical mass of practice scholars in the workplace. Addressed in this article is how to optimize the knowledge, skills, and abilities of the practice scholar and how to strengthen clinical learning for those completing the practice hours and the doctoral project in the workplace. J Contin Educ Nurs. 2017;48(9):392-394. PMID- 28850655 TI - Giving and Receiving Feedback: Part I. AB - Feedback is one of the most difficult interactions educators/leaders have with learners and staff. Giving feedback effectively with the least amount of defensiveness from the recipient is challenging and is addressed in Part I of this article. Receiving constructive feedback will be addressed in Part II. J Contin Nurs Educ. 2017;48(9):395-396. PMID- 28850656 TI - A Simulation-Based Blended Curriculum for Short Peripheral Intravenous Catheter Insertion: An Industry-Practice Collaboration. AB - Despite peripheral intravenous catheter (PIVC) insertion being a commonly performed skill, practicing nurses may receive little substantive education, training, or opportunities to practice this skill at a competent level. This article describes a collaboration between private industry and a hospital to modify, implement, and evaluate a simulation-based blended PIVC insertion continuing education program for staff nurses. Included is an overview of the practical and theoretical rationale for the initial development of the curriculum to address an identified PIVC insertion education gap, the collaborative modification and implementation of the program, and an evaluation of the program. The curriculum combined self-paced e-learning and classroom-based deliberate practice with simulation tools of varying fidelity in a peer-to-peer learning environment. Given the mutual challenges of resource allocation in industry training and clinical nursing education departments, interprofessional partnerships may be an effective option for sharing instructional knowledge and resources to promote innovation and improve patient care. J Contin Educ Nurs. 2017;48(9):397-406. PMID- 28850657 TI - Teaching and Implementing Evidence-Based Practice in a Hospital Unit With Secondary Vocational Trained Nurses: Lessons Learned. AB - Evidence-based practice (EBP) was systematically implemented using the implementation model by Grol et al. Barriers and facilitators for change were diagnostically analyzed. Implementation strategies were directed at the barriers. The two main implementation interventions were (a) a tailored interactive outreach training course about EBP and (b) a patient case discussion based on EBP principles. The authors learned that it is important to simplify the five EBP steps to suit the level of education of the nurses by formulating PICO questions around major patient care topics such as pain, and having a search strategy focusing on (Dutch) clinical practice guidelines and other summarized evidence, such as systematic reviews and critically appraised topics. The authors advised the hospital management to appoint nurse practitioners or other nurses with a master's degree to help the nurses on the ward with the EBP process steps, especially regarding efficiently searching the research literature and critically appraising the evidence. J Contin Educ Nurs. 2017;48(9):407-412. PMID- 28850658 TI - Effectiveness of Nursing Education to Prevent Inpatient Suicide. AB - BACKGROUND: Inpatient suicide is recognized by The Joint Commission as a preventable sentinel event associated with inadequate patient and environmental assessments. Strategies are needed to meet this Joint Commission requirement. METHOD: Community hospital nurses were provided with classes to increase knowledge of inpatient suicide, patient assessments, and appropriate care. Independent pre- and postclass assessments were performed to measure nurses' confidence when talking to patients about suicidal thoughts and to assess nursing knowledge of actions to take when an at-risk patient is identified. RESULTS: Education significantly increased nurses' confidence talking to patients about three of four confidence measures and increased their knowledge of actions to take when suicidal thoughts are identified. Confidence was lower in nurses with more experience; therefore, experience does not appear to increase confidence, and education is needed. CONCLUSION: This study demonstrated that a focused in service education program can increase nurses' confidence to dialogue with patients about suicidal thoughts and nurses' knowledge of actions to prevent inpatient suicide. J Contin Educ Nurs. 2017;48(9):413-419. PMID- 28850659 TI - Nursing Librarians Cultivating Evidence-Based Practice Through an Asynchronous Online Course. AB - In response to a request from the Nursing Shared Governance Evidence-Based Practice Council, librarians created an online evidence-based practice (EBP) continuing education course for clinical nurses. The curriculum was adapted from a previously created face-to-face course and was offered online through a learning management system. Although many nurses registered for the course, only a small sample was able to complete all modules. Feedback revealed that nurses appreciated the ease of online use, but they experienced technical barriers. Overall, nurses completing the course agreed that all learning objectives were met. An online asynchronous course for nurses is a viable option for teaching EBP, but hospital computer limitations must be taken into account to allow for participants' full immersion into the material. J Contin Educ Nurs. 2017;48(9):420-424. PMID- 28850660 TI - Critical Thinking Disposition of Nurse Practitioners in Taiwan. AB - BACKGROUND: Critical thinking disposition (CTD) is crucial for nurse practitioners who face complex patient care scenarios. This study explored the CTD of nurse practitioners and related factors. METHOD: The study was a cross sectional descriptive design. A purposive sample was recruited from a medical center and its hospital branches in central Taiwan. A structured questionnaire was used to collect data from 210 nurse practitioners. RESULTS: The participants obtained the highest average score on systematicity and analyticity. CTD had a significant positive correlation with fundamental knowledge readiness, professional knowledge readiness, and confidence in making clinical decisions. Professional knowledge readiness, education level, and on-the-job training predicted the score of the participants on overall CTD. CONCLUSION: On-the-job training and education level may influence the CTD of nurse practitioners. Providing formal or on-the-job continuing education training to nurse practitioners may help enhance their CTD. J Contin Educ Nurs. 2017;48(9):425-430. PMID- 28850661 TI - Effects of an Online Educational Module on School Nurses' Knowledge of HPV Vaccination. AB - BACKGROUND: Results of a previous state-wide survey revealed generally low knowledge levels about HPV vaccination among school nurses in Missouri. A short, online educational module targeted to address the specific low-scoring items was then created. METHOD: All 440 lead school nurses in Missouri were invited by e mail to participate in an online HPV educational module and study. The e-mail contained a link to the module that included a consent form, a test, and a downloadable completion certificate. The test consisted of 12 multiple choice and true-or-false items based directly on the content contained in the module. An independent samples t test was used to determine pre-post differences in mean test scores. RESULTS: Scores improved significantly (p < .05) pre-post intervention; however, surveillance or epidemiology-related questions were still commonly missed. CONCLUSION: Using brief, targeted, online trainings to improve knowledge of specific health-related content may be a practical option for busy school nurses. J Contin Educ Nurs. 2017;48(9):431-436. PMID- 28850662 TI - Macromolecular Traits in the African Rice Oryza glaberrima and in Glaberrima/Sativa Crosses, and Their Relevance to Processing. AB - : Molecular properties of proteins and starch were investigated in 2 accessions of Oryza glaberrima and Oryza sativa, and in one NERICA cross between the 2 species, to assess traits that could be relevant to transformation into specific foods. Protein nature and organization in O. glaberrima were different from those in O. sativa and in NERICA. Despite the similar cysteine content in all samples, thiol accessibility in O. glaberrima proteins was higher than in NERICA or in O. sativa. Inter-protein disulphide bonds were important for the formation of protein aggregates in O. glaberrima, whereas non-covalent protein-protein interactions were relevant in NERICA and O. sativa. DSC and NMR studies indicated only minor differences in the structure of starch in these species, as also made evident by their microstructural features. Nevertheless, starch gelatinization in O. glaberrima was very different from what was observed in O. sativa and NERICA. The content of soluble species in gelatinized starch from the various species in the presence/absence of treatments with specific enzymes indicated that release of small starch breakdown products was lowest in O. glaberrima, in particular from the amylopectin component. These findings may explain the low glycemic index of O. glaberrima, and provide a rationale for extending the use of O. glaberrima in the production of specific rice-based products, thus improving the economic value and the market appeal of African crops. PRACTICAL APPLICATION: The structural features of proteins and starch in O. glaberrima are very different from those in O. sativa and in the NERICA cross. These results appear useful as for extending the use of O. glaberrima cultivars in the design and production of specific rice-based products (for example, pasta), that might, in turn, improve the economic value and the market appeal of locally sourced raw materials, by introducing added-value products on the African market. PMID- 28850663 TI - Accuracy of second trimester prediction of preterm preeclampsia by three different screening algorithms. AB - AIM: To compare the performance of three different screening methods (National Institute for Health and Clinical Excellence (NICE) guidelines, American College of Obstetricians and Gynecologists (ACOG) recommendations and Fetal Medicine Foundation (FMF) algorithm) for second trimester prediction of preeclampsia. METHODS: This was a prospective non-intervention study in singleton pregnancies, including women attending for second trimester morphologic ultrasound at 19-22 weeks. Maternal characteristics, medical history, mean arterial pressure and mean uterine artery Doppler pulsatility index were recorded and used for risk assessment. Outcomes measured were preeclampsia with delivery before 34, before 37 and after 37 weeks gestation. Detection rates, false positive rates and positive likelihood ratios were calculated, and receiver operating characteristic curves were produced. RESULTS: We screened 543 women during the study. The incidence of preeclampsia before 34, before 37 and after 37 weeks was 0.5, 1.4 and 3.4%, respectively. Detection rates for prediction of preterm preeclampsia were 75% (95% CI 34.9-96.8), 87% (95% CI 47.3-99.6), 100% (95% CI 63.0-100) and 100% (95% CI 63.0-100) for NICE guidelines, ACOG recommendations, FMF algorithm with a 1:100 cut-off and FMF algorithm at 1:60 cut-off, respectively. False positive rates were, 22, 67, 19 and 12% for NICE guidelines, ACOG recommendations, FMF algorithm with a 1:100 cut-off and FMF algorithm at 1:60 cut off, respectively. CONCLUSION: Second trimester combined screening for preterm preeclampsia by maternal history, mean arterial pressure and mean uterine artery Doppler pulsatility index (FMF algorithm) was superior to screening by maternal factors alone (NICE guidelines and ACOG recommendations). PMID- 28850665 TI - In situ oxidation and reduction of triangular nickel nanoplates via environmental transmission electron microscopy. AB - Understanding the oxidation and reduction mechanisms of transition metals, such as nickel (Ni), is important for their use in industrial applications of catalysis. A powerful technique for investigating the redox reactive species is in situ environmental transmission electron microscopy (ETEM), where oxidation and reduction can be tracked in real time. One particular difficulty in understanding the underlying reactions is understanding the underlying morphology of the starting structure in a reaction, in particular the defects contained in the material, and the exposed surface facets. Here-in, we use a colloidal nanoparticle synthesis in a continuous flow reactor to form nanoplates of nickel coated with oleylamine as a capping agent. We utilise an in situ heating procedure at 300 degrees C in vacuum to remove the oleylamine ligands, and then oxidise the Ni nanoparticles at 25 degrees C with 2 Pa oxygen, and follow the nanoparticles initial oxidation. After that, the nanoparticles are oxidised at 200 and 300 degrees C, making the size of the oxide shell increase to ~4 nm. The oxide shell could be reduced under 2 Pa hydrogen at 500 degrees C to its initial size of ~1 nm. High temperature oxidation encouraged the nanoparticles to form pure NiO nanoparticles, which occurred via the Kirkendall effect leading to hollowing and void formation. PMID- 28850664 TI - Molecular Weight Affected Antioxidant, Hypoglycemic and Hypotensive Activities of Cold Water Extract from Pleurotus citrinopileatus. AB - Cold water extract of P. citrinopileatus (CWEPC) was fractioned into 4 fractions, PC-I (<1 kDa), PC-II (1-3.5 kDa), PC-III (3.5-10 kDa), and PC-IV (>10 kDa), by ultrafiltration. The antioxidant activities, the inhibition of pancreatic alpha amylase, intestinal alpha-glucosidase, and hypertension-linked angiotensin converting enzyme (ACE), as well as the contents of polysaccharides, protein, and phenolic compounds of 4 fractions were determined. The results showed that lower MW fractions exerted a higher antioxidant activity, which was correlated to phenolic contents. The high molecular fraction (PC-IV) exhibited significantly higher inhibitory activity on alpha-amylase, alpha-glucosidase, and ACE compared to CWEPC and the other 3 lower MW fractions (<10 kDa), which was more related to protein contents. The inhibition capability of CWEPC and PC-IV on alpha-amylase activity was 1/13.4 to 1/2.7 relative to that of acarbose, respectively. Kinetic data revealed that PC-IV fraction followed a noncompetitive inhibition pattern on alpha-glucosidase activity. The study demonstrated that various MW fractions and types of components contribute to different biological functions of P. citrinopileatus and it is protein constituents but not peptides responsible for the hypoglycemic potential of CWEPC. PMID- 28850666 TI - Subsequent pregnancy outcome after mid-trimester termination of pregnancy for preeclampsia. AB - BACKGROUND: In this study we determined the outcome of subsequent pregnancies after termination of pregnancy for preeclampsia, with the purpose of presenting data useful for counselling these women on future pregnancies. STUDY DESIGN: The cohort consisted of 131 women with a history of termination of pregnancy for preeclampsia. RESULTS: Data of 79 pregnancies were available for analysis, including 13 women with chronic hypertension and 16 women with thrombophilia. There were seven miscarriages (8.8%) and 72 ongoing pregnancies. Low-dose aspirin was prescribed for 64 women (89%). The mean gestational age at delivery was 356/7 +/- 4 weeks with a mean birth weight of 2571 +/- 938 g. Overall recurrence rate for preeclampsia was 29% at a mean gestational age of 32 weeks. Thirty-eight women had an uncomplicated pregnancy (53%). The women with chronic hypertension had the highest recurrence rate of 38%. Neonatal mortality was 4%. CONCLUSION: The course of subsequent pregnancies after mid-trimester termination for preeclampsia is uncomplicated in 53% with a recurrence rate for preeclampsia of 29%. The mean gestational age at delivery was 11 weeks later and birth weight 2000 g higher than in the index pregnancy. PMID- 28850667 TI - Training intraverbal bidirectional naming to establish generalized equivalence class performances. AB - The purpose of this study was to evaluate the effects of tact and intraverbal training on the establishment of generalized equivalence classes. Seventeen college students were exposed to tact training, listener testing, and intraverbal training (A'B' and B'C') in two experiments. Visual-visual matching-to-sample and intraverbal tests measured performances consistent with the formation of equivalence classes. Generalization was assessed with four novel sets of stimuli. In the second experiment, matching-to-sample tests for baseline relations (AB, BC) were eliminated to control for the possibility that equivalence classes were developed through exposure to these visual stimulus-stimulus relations. Thirteen of 17 participants passed all matching-to-sample and intraverbal posttests. Results suggest that when trained and emergent intraverbal relations were not maintained or were faulty, participants did not respond correctly during matching to-sample posttests. PMID- 28850669 TI - RNA-virus proteases counteracting host innate immunity. AB - Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen-associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern-recognition receptors of the host, and innate immune responses are induced. Through production of type-I and type-III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive-sense single-stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses. PMID- 28850668 TI - On the relationship between calcified neurocysticercosis and epilepsy in an endemic village: A large-scale, computed tomography-based population study in rural Ecuador. AB - OBJECTIVE: Using a large-scale population-based study, we aimed to assess prevalence and patterns of presentation of neurocysticercosis (NCC) and its relationship with epilepsy in community-dwellers aged >=20 years living in Atahualpa (rural Ecuador). METHODS: In a three-phase epidemiological study, individuals with suspected seizures were identified during a door-to-door survey and an interview (phase I). Then, neurologists evaluated suspected cases and randomly selected negative persons to estimate epilepsy prevalence (phase II). In phase III, all participants were offered noncontrast computed tomography (CT) for identifying NCC cases. The independent association between NCC (exposure) and epilepsy (outcome) was assessed by the use of multivariate logistic regression models adjusted for age, sex, level of education, and alcohol intake. CT findings were subsequently compared to archived brain magnetic resonance imaging in a sizable subgroup of participants. RESULTS: Of 1,604 villagers aged >=20 years, 1,462 (91%) were enrolled. Forty-one persons with epilepsy (PWE) were identified, for a crude prevalence of epilepsy of 28 per 1,000 population (95% confidence interval [CI] = 20.7-38.2). A head CT was performed in 1,228 (84%) of 1,462 participants, including 39 of 41 PWE. CT showed lesions consistent with calcified parenchymal brain cysticerci in 118 (9.6%) cases (95% CI = 8.1-11.4%). No patient had other forms of NCC. Nine of 39 PWE, as opposed to 109 of 1,189 participants without epilepsy, had NCC (23.1% vs. 9.2%, p = 0.004). This difference persisted in the adjusted logistic regression model (odds ratio = 3.04, 95% CI = 1.35-6.81, p = 0.007). SIGNIFICANCE: This large CT-based study demonstrates that PWE had three times the odds of having NCC than those without epilepsy, providing robust epidemiological evidence favoring the relationship between NCC and epilepsy. PMID- 28850670 TI - Stimuli previously associated with reinforcement mitigate resurgence. AB - Resurgence refers to the recurrence of an extinguished target behavior following subsequent suspension of alternative reinforcement. Delivery of reinforcers during extinction of alternative behavior has been shown to mitigate resurgence. The present experiment aimed to determine whether delivering stimuli associated with reinforcers during resurgence testing similarly mitigates resurgence. Three groups of rats pressed target levers for food according to variable-interval 15-s schedules during Phase 1. In Phase 2, lever pressing was extinguished, and an alternative nose-poke response produced alternative reinforcement according to a variable-interval 15-s schedule. Food reinforcement was always associated with illumination of the food aperture and an audible click from the pellet dispenser during Phases 1 and 2. Phase 3 treatments differed between groups. For one group, nose poking continued to produce food and food-correlated stimuli. Both of these consequences were suspended for a second group. Finally, nose poking produced food-correlated stimuli but not food for a third group. Target-lever pressing resurged in the group that received no consequences and in the group that received only food-correlated stimuli for nose poking. Resurgence, however, was smaller for the group that received food-correlated stimuli than for the group that received no consequences for nose poking. Target-lever pressing did not increase between phases in the group that continued to receive food and associated stimuli. Thus, delivery of stimuli associated with food reinforcement after suspension of food reduced but did not eliminate resurgence of extinguished lever pressing. These findings contribute to potential methodologies for preventing relapse of extinguished problem behavior in clinical settings. PMID- 28850671 TI - Anti-ictogenic and antiepileptogenic properties of perampanel in mature and immature rats. AB - OBJECTIVE: Perampanel (PER) is a selective noncompetitive antagonist at alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, the first of its class approved for the adjunctive treatment of partial onset seizures and generalized seizures. This study explored anti-ictogenic and antiepileptogenic effects of PER in rats at different stages of development. METHODS: Using a rapid kindling model in postnatal day 14 (P14), P21, P28, and P60 rats, we studied two doses of PER: 1 and 2 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of PER 30 min after the injection. RESULTS: PER 2 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas PER at 1 mg/kg increased ADT only in P21 rats. PER 2 mg/kg also shortened the afterdischarge duration in P14 and P28 rats. PER increased the number of stimulations required to achieve a stage 4-5 seizure in a dose-dependent manner in P14 and P21 rats, with almost complete elimination of stage 4-5 seizures. At P28, only PER 2 mg/kg increased the number of stimulations required to develop a stage 4-5 seizure. In contrast, PER had no effect on the number of stage 4-5 seizures at P60. We did not observed any age-dependent significant difference in the serum and brain levels of PER 30 min after the injection. SIGNIFICANCE: PER exerted anti-ictogenic effects from P14 to P60 independent of brain maturation. PER also exhibited antiepileptogenic effects with a stronger effect in the younger animals. PMID- 28850672 TI - Anti-interleukin-6 signalling therapy rebalances the disrupted cytokine production of B cells from patients with active rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is associated with abnormal B cell-functions implicating antibody-dependent and -independent mechanisms. B cells have emerged as important cytokine-producing cells, and cytokines are well-known drivers of RA pathogenesis. To identify novel cytokine-mediated B-cell functions in RA, we comprehensively analysed the capacity of B cells from RA patients with an inadequate response to disease modifying anti-rheumatic drugs to produce cytokines in comparison with healthy donors (HD). RA B cells displayed a constitutively higher production of the pathogenic factors interleukin (IL)-8 and Gro-alpha, while their production of several cytokines upon activation via the B cell receptor for antigen (BCR) was broadly suppressed, including a loss of the expression of the protective factor TRAIL, compared to HD B cells. These defects were partly erased after treatment with the IL-6-signalling inhibitor tocilizumab, indicating that abnormal IL-6 signalling contributed to these abnormalities. Noteworthy, the clinical response of individual patients to tocilizumab therapy could be predicted using the amounts of MIP-1beta and beta NGF produced by these patients' B cells before treatment. Taken together, our study highlights hitherto unknown abnormal B-cell functions in RA patients, which are related to the unbalanced cytokine network, and are potentially relevant for RA pathogenesis and treatment. PMID- 28850673 TI - Effect of Micronutrient Powder Addition on Sensory Properties of Foods for Older Adults. AB - : Micronutrient fortification can improve nutrient intake of older adults in long term care. However, previous studies indicate that micronutrient fortification can alter food sensory attributes and, potentially, consumer liking. Others have found no effect of fortification on liking. This research investigates the effect of micronutrient powder addition on the sensory properties of selected foods commonly served in long-term care. A micronutrient powder containing 9 vitamins and 3 minerals was added to tomato soup and oatmeal at different levels. Using projective mapping, changes in sensory properties were observed with powder addition. Descriptive analysis, used to quantify these changes, showed that both the tomato soup and oatmeal had reduced flavor as the amount of added micronutrient powder increased. Oatmeal also showed changes in texture with fortification. Consumer liking scores for tomato soup showed that micronutrient addition affected liking when 100% of a daily dose was added into the soup. Addition of 50% of the daily dose did not affect liking. Oatmeal liking did not differ between fortified and unfortified samples. PRACTICAL APPLICATION: Results from this research can be used to decide whether a micronutrient powder of selected vitamins and minerals can be added to foods served to older adults in long-term care. Although sensory properties of the foods will be altered, fortification of both tomato soup and oatmeal with the developed powder is possible without reducing consumer liking to the point where it is disliked. PMID- 28850674 TI - Reinforcement value and fixed-interval performance. AB - The concept of reinforcement value summarizes the effect of different variables, such as reinforcement delay, reinforcement magnitude, and deprivation level, on behavior. In the present set of experiments, we evaluated the effect of reinforcement devaluation on performance under FI schedules. The literature on timing and reinforcement value suggests that devaluation generates longer expected times to reinforcement than the same intervals trained under control conditions. We devalued reinforcement with delay in Experiments 1A, 1B, and 2, and diminished deprivation in Experiments 3A and 3B. Devaluation reduced response rates, increased the number of one-response intervals, and lengthened postreinforcement pauses, but had inconsistent effects on other timing measures such as quarter life and breakpoint. The results of delayed reinforcement and diminished deprivation manipulations are well summarized as reinforcement devaluation effects. These results suggest that devaluation may reduce stimulus control. In addition, we argue that the process by which delayed reinforcement affects behavior might also explain some effects observed in other devaluation procedures through the concept of reinforcement value. PMID- 28850676 TI - Addressing Pharmaceutical Injuries: The US Landscape. AB - The legal landscape for addressing an injury related to the use of a pharmaceutical product varies from country to country. Approximately 10 countries have adopted some form of no-fault compensation, in which an individual must establish that they sustained an injury caused by the medicine, but need not demonstrate that the manufacturer acted negligently in order to recover. This commentary compares and contrasts the approach taken in Japan with that in the United States. PMID- 28850675 TI - Brivaracetam does not modulate ionotropic channels activated by glutamate, gamma aminobutyric acid, and glycine in hippocampal neurons. AB - Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A), recently approved as adjunctive treatment for drug-refractory partial-onset seizures in adults. BRV binds SV2A with higher affinity than levetiracetam (LEV), and was shown to have a differential interaction with SV2A. Because LEV was reported to interact with multiple excitatory and inhibitory ligand-gated ion channels and that may impact its pharmacological profile, we were interested in determining whether BRV directly modulates inhibitory and excitatory ionotropic receptors in central neurons. Voltage-clamp experiments were performed in primary cultures of mouse hippocampal neurons. At a supratherapeutic concentration of 100 MUm, BRV was devoid of any direct effect on currents gated by gamma-aminobutyric acidergic type A, glycine, kainate, N-methyl d-aspartate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Similarly to LEV, BRV reveals a potent ability to oppose the action of negative modulators on the inhibitory receptors. In conclusion, these results show that BRV contrasts with LEV by not displaying any direct action on inhibitory or excitatory postsynaptic ligand-gated receptors at therapeutic concentrations and thereby support BRV's role as a selective SV2A ligand. These findings add further evidence to the validity of SV2A as a relevant antiepileptic drug target and emphasize the potential for exploring further presynaptic mechanisms as a novel approach to antiepileptic drug discovery. PMID- 28850677 TI - A longitudinal simulation-based ethical-legal curriculum for otolaryngology residents. AB - OBJECTIVE: To develop, implement, and evaluate a longitudinal, simulation-based ethics and legal curriculum designed specifically for otolaryngology residents. METHODS: Otolaryngology residents were recruited to participate in a yearly half day ethical-legal module, the curriculum of which spanned 4 years. Each module included: three simulated scenarios, small-group multisource feedback, and large group debriefings. Scenarios involved encounters with standardized patients. Residents' ethical-legal knowledge was assessed pre- and postmodule with multiple choice questions, and ethical reasoning was assessed by a variety of evaluators during the simulated scenario using a locally developed assessment tool. Participants completed an exit survey at the end of each module. RESULTS: Eighteen residents completed four modules from the academic years of 2008 to 2009 to 2011 to 2012. The first year was considered a pilot module, and data were collected for the following 3 years. Knowledge of legal issues improved significantly among residents (mean at pre = 3.40 and post = 4.60, P < 0.05). Residents' ethical reasoning skills also improved across years (mean 3.60/5 in 2009-2010, 3.76/5 in 2010-2011, and 4.33 in 2011-2012, P < 0.05). Survey results revealed a statistically significant self-perceived improvement in ethics reasoning skills (mean pre = 3.62, post = 4.86, P < 0.05). Participants reported that the curriculum was relevant to their practice (85%), that the debriefings were of high quality (83%), and that they would recommend this module to others (88%). CONCLUSION: To our knowledge, this is the first study exploring a longitudinal simulation-based ethical-legal curriculum tailored to otolaryngology head and neck surgery residents. This educational program resulted in a both objective and subjective improvement in legal and ethics knowledge and skills. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2501-2509, 2017. PMID- 28850678 TI - Exclusion of known gene loci for cerebellar abiotrophy in the Australian Working Kelpie. PMID- 28850679 TI - Hemodynamic parameters predict the risk of atrial fibrillation after cardiac surgery in adults. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery and is associated with poorer prognosis. This study attempted to evaluate whether hemodynamic parameters determined by a right heart catheter predict the occurrence of POAF. HYPOTHESIS: We hypothesized that atrial fibrillation after cardiac surgery can be predicted by hemodynamic parameters determined by a right heart catheter. METHODS: Between October 2015 and January 2017, 126 patients with preoperative sinus rhythm undergoing coronary artery bypass grafting and/or aortic valve replacement were enrolled in this study. Complete echocardiographic examination was performed preoperatively, and hemodynamic parameters were recorded via a right heart catheter before anesthesia induction. Postoperative telemetry strips and electrocardiogram were used to detect atrial fibrillation until discharge. Multivariate logistic regression was used to identify risk factors of POAF. RESULTS: The overall incidence of POAF was 40/126 (31.7%). Multivariate logistic regression analysis determined that left atrial dimension (LAD) (adjusted odds ratio [OR]: 1.118, 95% confidence interval [CI]: 1.020-1.227, P = 0.018), pulmonary capillary wedge pressure (PCWP) (adjusted OR: 1.225, 95% CI: 1.082-1.387, P = 0.001), and pulmonary artery systolic pressure (PASP) (adjusted OR: 1.076, 95% CI: 1.019-1.137, P = 0.008) were significant predictors of POAF. CONCLUSIONS: The present study suggested that LAD, PCWP, and PASP were robust predictors of POAF. These parameters may indicate a patient's susceptibility toward developing POAF and help to identify patients who need preventive treatment. PMID- 28850680 TI - Genome-wide association study for tobiano spotting coat color in Korean Jeju * Thoroughbred horse population. PMID- 28850681 TI - A randomized controlled trial of corticosteroids for pain after transoral robotic surgery. AB - OBJECTIVE: To determine if an extended perioperative course of corticosteroids will improve pain control following transoral robotic surgery (TORS). STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. METHODS: Patients undergoing TORS for initial treatment of oropharyngeal squamous cell carcinoma received a single intraoperative dose of 10-mg dexamethasone and then were randomized to receive 8-mg dexamethasone every 8 hours, or placebo, for up to 4 days after surgery. Pain, measured by visual analog scale (VAS), was the primary outcome measure. Secondary outcome measures included length of stay, dysphagia assessments, and complications. RESULTS: VAS pain scores were similar between steroid and placebo cohorts on postoperative day (POD) 1, 2, and 7 through 21, although they significantly improved in the steroid cohort on POD 3. The steroid cohort also demonstrated a decreased hospital length of stay (median 1 day) and improvement in diet consistency, as measured by the performance status scale on POD 7 through 21. There was no difference in complications between the steroid and placebo cohorts. CONCLUSION: Extended perioperative corticosteroids after TORS is safe and may allow earlier improvement in diet consistency and decreased length of hospital stay, although postoperative pain appears minimally affected. LEVEL OF EVIDENCE: 1b. Laryngoscope, 127:2558-2564, 2017. PMID- 28850682 TI - Perinatal Outcomes Associated With Isolated Velamentous Cord Insertion in Singleton and Twin Pregnancies. AB - OBJECTIVES: To evaluate perinatal outcomes in singleton and twin pregnancies with pathologically confirmed velamentous cord insertion without vasa previa. METHODS: This retrospective case-control study included all nonanomalous singleton and twin pregnancies with pathologically confirmed velamentous cord insertion delivered in a single institution between January 1, 2005, and July 1, 2015, and having an ultrasound examination by maternal-fetal medicine. For each case, the next 2 consecutive deliveries matched for gestational age at delivery +/- 1 week and, in twins, amnionicity and chorionicity served as controls. Primary outcomes included surgical delivery for a nonreassuring intrapartum fetal heart rate tracing, umbilical arterial cord pH of less than 7.2, 5-minute Apgar score of less than 7, birth weight below the 10th percentile, neonatal intensive care unit admission, fetal or neonatal death, and cord avulsion necessitating manual placental extraction. RESULTS: Outcomes were available for 53 singletons with 103 matched controls and 33 twin pregnancies with 65 matched controls. In singletons, velamentous cord insertion was associated with cord pH of less than 7.2 (odds ratio [OR] 3.5; 95% confidence interval [CI], 1.1-11.2; P = .039), 5-minute Apgar score of less than 7 (OR, 5.3; 95% CI, 0.99-28.1; P = .045), and cord avulsion requiring manual placental extraction (7.5% versus 0%; P = .012). Associations were suggested with increased surgical delivery for a nonreassuring intrapartum fetal heart rate tracing (OR, 2.4; 95% CI, 0.9-6.9; P = .14), birth weight below the 10th percentile (OR, 2.1; 95% CI, 0.8-5.9; P = .21), and fetal or neonatal death (3.8% versus 0%; P = .11). Velamentous cord insertions were also associated with placental abruption in singletons (7.5% versus 0%; P = .013). Among twins, velamentous cord insertion was associated with fetal or neonatal death (9.1% versus 0%; P = .036). CONCLUSIONS: Isolated confirmed velamentous cord insertion is associated with adverse perinatal outcomes in singleton and twin gestations. PMID- 28850683 TI - A robust interrupted time series model for analyzing complex health care intervention data. AB - Current health policy calls for greater use of evidence-based care delivery services to improve patient quality and safety outcomes. Care delivery is complex, with interacting and interdependent components that challenge traditional statistical analytic techniques, in particular, when modeling a time series of outcomes data that might be "interrupted" by a change in a particular method of health care delivery. Interrupted time series (ITS) is a robust quasi experimental design with the ability to infer the effectiveness of an intervention that accounts for data dependency. Current standardized methods for analyzing ITS data do not model changes in variation and correlation following the intervention. This is a key limitation since it is plausible for data variability and dependency to change because of the intervention. Moreover, present methodology either assumes a prespecified interruption time point with an instantaneous effect or removes data for which the effect of intervention is not fully realized. In this paper, we describe and develop a novel robust interrupted time series (robust-ITS) model that overcomes these omissions and limitations. The robust-ITS model formally performs inference on (1) identifying the change point; (2) differences in preintervention and postintervention correlation; (3) differences in the outcome variance preintervention and postintervention; and (4) differences in the mean preintervention and postintervention. We illustrate the proposed method by analyzing patient satisfaction data from a hospital that implemented and evaluated a new nursing care delivery model as the intervention of interest. The robust-ITS model is implemented in an R Shiny toolbox, which is freely available to the community. PMID- 28850684 TI - Word onset phonetic properties and motor artifacts in speech production EEG recordings. AB - Electrophysiological research using verbal response paradigms faces the problem of muscle artifacts that occur during speech production or in the period preceding articulation. In this context, this paper has two related aims. The first is to show how the nature of the first phoneme influences the alignment of the ERPs. The second is to further characterize the EEG signal around the onset of articulation, both in temporal and frequency domains. Participants were asked to name aloud pictures of common objects. We applied microstate analyses and time frequency transformations of ERPs locked to vocal onset to compare the EEG signal between voiced and unvoiced labial plosive word onset consonants. We found a delay of about 40 ms in the set of stable topographic patterns for /b/ relative to /p/ onset words. A similar shift was observed in the power increase of gamma oscillations (30-50 Hz), which had an earlier onset for /p/ trials (~150 ms before vocal onset). This 40-ms shift is consistent with the length of the voiced proportion of the acoustic signal prior to the release of the closure in the vocal responses. These results demonstrate that phonetic features are an important parameter affecting response-locked ERPs, and hence that the onset of the acoustic energy may not be an optimal trigger for synchronizing the EEG activity to the response in vocal paradigms. The indexes explored in this study provide a step forward in the characterization of muscle-related artifacts in electrophysiological studies of speech and language production. PMID- 28850685 TI - Practical characteristics of adaptive design in phase 2 and 3 clinical trials. AB - WHAT IS KNOWN AND OBJECTIVE: Adaptive design methods are expected to be ethical, reflect real medical practice, increase the likelihood of research and development success and reduce the allocation of patients into ineffective treatment groups by the early termination of clinical trials. However, the comprehensive details regarding which types of clinical trials will include adaptive designs remain unclear. We examined the practical characteristics of adaptive design used in clinical trials. METHODS: We conducted a literature search of adaptive design clinical trials published from 2012 to 2015 using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, with common search terms related to adaptive design. We systematically assessed the types and characteristics of adaptive designs and disease areas employed in the adaptive design trials. RESULTS AND DISCUSSION: Our survey identified 245 adaptive design clinical trials. The number of trials by the publication year increased from 2012 to 2013 and did not greatly change afterwards. The most frequently used adaptive design was group sequential design (n = 222, 90.6%), especially for neoplasm or cardiovascular disease trials. Among the other types of adaptive design, adaptive dose/treatment group selection (n = 21, 8.6%) and adaptive sample-size adjustment (n = 19, 7.8%) were frequently used. The adaptive randomization (n = 8, 3.3%) and adaptive seamless design (n = 6, 2.4%) were less frequent. Adaptive dose/treatment group selection and adaptive sample-size adjustment were frequently used (up to 23%) in "certain infectious and parasitic diseases," "diseases of nervous system," and "mental and behavioural disorders" in comparison with "neoplasms" (<6.6%). For "mental and behavioural disorders," adaptive randomization was used in two trials of eight trials in total (25%). Group sequential design and adaptive sample-size adjustment were used frequently in phase 3 trials or in trials where study phase was not specified, whereas the other types of adaptive designs were used more in phase 2 trials. Approximately 82% (202 of 245 trials) resulted in early termination at the interim analysis. Among the 202 trials, 132 (54% of 245 trials) had fewer randomized patients than initially planned. This result supports the motive to use adaptive design to make study durations shorter and include a smaller number of subjects. WHAT IS NEW AND CONCLUSION: We found that adaptive designs have been applied to clinical trials in various therapeutic areas and interventions. The applications were frequently reported in neoplasm or cardiovascular clinical trials. The adaptive dose/treatment group selection and sample-size adjustment are increasingly common, and these adaptations generally follow the Food and Drug Administration's (FDA's) recommendations. PMID- 28850686 TI - Estradiol promotes epithelial-to-mesenchymal transition in human benign prostatic epithelial cells. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is involved in pathogenesis of human benign prostatic hyperplasia (BPH). Estrogenic signaling pathways may stimulate the induction of EMT. However, the details of estradiol (E2) and estrogen receptors (ERs) effects on EMT, as well as E2-induced modulation of benign prostatic epithelial cell phenotype in vitro have not been completely clarified. METHODS: The effects of E2 on EMT markers and cytokeratins (CKs) expression were evaluated in benign epithelial cell lines BPH-1 and RWPE-1, which were cultured both in two-dimensional (2D) culture and three-dimensional (3D) culture model using hanging drop technique or 3D Matrigel model. ER antagonist, ICI182,780, was used to confirm the regulatory effects of E2 on EMT and phenotypic modulation. In 3D culture, immunohistochemical stainings were performed to detect the specific phenotype of cells that underwent EMT in acinar like spheroids formed by RWPE-1. To illustrate the exact function of ERs in E2 induced EMT and phenotypic modulation, specific short interfering RNAs (siRNAs), and agonists were used to knockdown or activate individual ERs, respectively. RESULTS: E2-induced EMT was observed both in 2D and 3D culture, with related regulation of EMT markers expression at both mRNA and protein level. In addition, E2 down-regulated luminal cell type markers CK18 and CK8 and up-regulated basal cell type markers CK5 and CK14. E2 also increased intermediate type markers CK15 and CK17, while it attenuated CK19 in 3D culture. ICI182,780 blocked E2-induced EMT and cell phenotypic switching. In 3D Matrigel culture, Vimentin was co expressed with ERalpha and CK17, as well as with SMemb, which is related to cell status switching and proliferation. Knockdown of ERalpha but not GPR30 inhibited EMT, while ERbeta knockdown facilitated EMT process. Knockdown of ERalpha blocked E2-induced EMT both in RWPE-1 and BPH-1. MRNA expression of EMT markers was stimulated by ERalpha-specific agonist PPT and inhibited by ERbeta-specific agonist DPN. CONCLUSIONS: Estrogenic effect mediated by ERalpha can promote EMT. E2 is also an inductive factor of cell phenotypic switching. Cell type modulation is associated with E2-induced EMT in benign prostatic epithelial cells. Taken together the results support a contribution of estrogens to the pathogenesis of BPH in elderly men. PMID- 28850687 TI - Challenges in the implementation of the EAACI AIT guidelines: A situational analysis of current provision of allergen immunotherapy. AB - PURPOSE: The European Academy of Allergy and Clinical Immunology (EAACI) has produced Guidelines on Allergen Immunotherapy (AIT). We sought to gauge the preparedness of primary care to participate in the delivery of AIT in Europe. METHODS: We undertook a mixed-methods, situational analysis. This involved a purposeful literature search and two surveys: one to primary care clinicians and the other to a wider group of stakeholders across Europe. RESULTS: The 10 papers identified all pointed out gaps or deficiencies in allergy care provision in primary care. The surveys also highlighted similar concerns, particularly in relation to concerns about lack of knowledge, skills, infrastructural weaknesses, reimbursement policies and communication with specialists as barriers to evidence based care. Almost all countries (92%) reported the availability of AIT. In spite of that, only 28% and 44% of the countries reported the availability of guidelines for primary care physicians and specialists, respectively. Agreed pathways between specialists and primary care physicians were reported as existing in 32%-48% of countries. Reimbursement appeared to be an important barrier as AIT was only fully reimbursed in 32% of countries. Additionally, 44% of respondents considered accessibility to AIT and 36% stating patient costs were barriers. CONCLUSIONS: Successful working with primary care providers is essential to scaling-up AIT provision in Europe, but to achieve this, the identified barriers must be overcome. Development of primary care interpretation of guidelines to aid patient selection, establishment of disease management pathways and collaboration with specialist groups are required as a matter of urgency. PMID- 28850688 TI - Evaluation of Tubal Pregnancy After Treatment With Methotrexate by Ultrasound Elastography. AB - OBJECTIVES: The purpose of this study was to evaluate the application of ultrasound elastography in the assessment of methotrexate (MTX) treatment for tubal pregnancy and the association with the elasticity score and human chorionic gonadotropin (hCG) concentration. METHODS: A total of 73 cases of unruptured tubal pregnancy were diagnosed and treated systemically with MTX. The sonographic characters of conventional transvaginal sonography and elastography and serum hCG concentrations before and after MTX therapy were retrospectively reviewed and analyzed. RESULTS: The mean elasticity score was statistically significantly lower for the ectopic tubal masses of the success group (mean +/- SD, 2.58 +/- 0.68) than for the failure group (3.33 +/- 0.47) on day 7 (P < .001) and similar on day 0. The median elasticity score for the success group on day 7 was 3, and for the failure group, it was 4. When elasticity scores of 3 and 2 were used for the criterion of successful MTX treatment, the elastography had 94.5% sensitivity, 61.1% specificity, 88.1% positive predictive value, and 78.6% negative predictive value. Elastography of the ectopic masses and subsequent hCG concentration at 1 week after the MTX injection in the success group had a strong relationship. CONCLUSIONS: Our results suggest that transvaginal elastography was a useful tool in the evaluation of tubal pregnancy after pharmacologic management. PMID- 28850689 TI - Improving phase II oncology trials using best observed RECIST response as an endpoint by modelling continuous tumour measurements. AB - In many phase II trials in solid tumours, patients are assessed using endpoints based on the Response Evaluation Criteria in Solid Tumours (RECIST) scale. Often, analyses are based on the response rate. This is the proportion of patients who have an observed tumour shrinkage above a predefined level and no new tumour lesions. The augmented binary method has been proposed to improve the precision of the estimator of the response rate. The method involves modelling the tumour shrinkage to avoid dichotomising it. However, in many trials the best observed response is used as the primary outcome. In such trials, patients are followed until progression, and their best observed RECIST outcome is used as the primary endpoint. In this paper, we propose a method that extends the augmented binary method so that it can be used when the outcome is best observed response. We show through simulated data and data from a real phase II cancer trial that this method improves power in both single-arm and randomised trials. The average gain in power compared to the traditional analysis is equivalent to approximately a 35% increase in sample size. A modified version of the method is proposed to reduce the computational effort required. We show this modified method maintains much of the efficiency advantages. PMID- 28850690 TI - The short-term impact of the catheter ablation on noninvasive autonomic nervous system parameters in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: The autonomic nervous system (ANS) is a potentially potent modulator of the initiation and perpetuation of atrial fibrillation (AF), whereas the presence of AF can activate and alter the ANS. The catheter ablation of AF (AFCA) may cause the cardiac ANS dysfunction, whereas restoration of sinus rhythm or sympathovagal imbalance by AFCA can reverse this process. Our principal goal was to investigate the short-term effect of AFCA on ANS functions evaluated by noninvasive chronotropic (CI), resting heart rate (RHR), and heart rate recovery (HRR) indices. METHOD: A total of 45 patients were enrolled with symptomatic, drug refractory paroxysmal AF undergoing first cryoballoon (CB) pulmonary vein antrum isolation (PVAI) with one 28-mm CB using single 3-minute freeze techniques without bonus applications. All patients underwent symptom-limited exercise treadmill testing to evaluate noninvasive parameters of ANS before PVAI. For those patients who remained in sinus rhythm, an additional exercise test was repeated after 1 and 3 months after discharge. RESULTS: The autonomic CI and RHR/HRR indices were impaired after PVAI and persisted post-PVAI 3 months. However, these parameters were not different in patients with and without recurrence. CONCLUSION: This study demonstrated that the successful AFCA might concurrently impair the ANS parameters. The autonomic imbalance between the sympathetic and parasympathetic activity after AFCA could either become antiarrhythmic and/or proarrhythmic based on which of the two components was going to prevail after successful AFCA. The impaired ANS balance after PVAI might also be another hypothetical mechanism for AF recurrence particularly in the absence of PV reconnection. PMID- 28850691 TI - Comprehensive Ultrasound Assessment of the Craniocervical Circulation in Transient Global Amnesia. AB - OBJECTIVES: Structural changes and metabolic stress have been reported on diffusion-weighted magnetic resonance imaging in the cornu ammonis 1 area of the hippocampus in patients with transient global amnesia (TGA), but a consensus on pathogenesis is still lacking. The aim of our study was to perform a comprehensive ultrasound analysis of the cerebrovascular circulation in our population of patients with TGA. METHODS: One hundred patients with TGA and 50 age- and sex-matched control participants underwent ultrasound examinations of the cervicocranial circulation. RESULTS: The most significant risk factor for TGA was arterial hypertension (P < .01). There were no significant atherosclerotic lesions on the large arteries of the neck (mean internal carotid artery stenosis +/- SD, 28.7% +/- 11.7%) or on the large intracerebral arteries (good structural and hemodynamic status; P > .05). Rarely detected microembolic signals or a right left cardiopulmonary shunt excluded an emboligenic mechanism of TGA (P > .05). The internal jugular vein valves were incompetent in 54% of patients with TGA, and this condition was associated with an increased risk of TGA (odds ratio, 4.16; 95% confidence interval, 1.91-9.04). The mean values of the breath holding index and pulsatility index, as parameters of small-vessel function, were within normal ranges and without differences between the TGA and control groups (P > .05). CONCLUSIONS: Our ultrasound examination did not detect significant structural atherosclerotic changes of cervicocranial arteries, and an emboligenic mechanism was excluded. Only a significant rise of blood pressure in TGA and significant valvular insufficiency of the internal jugular vein were established. New research should clarify whether these simultaneous functional circulatory changes have relevance for metabolic stress in the cornu ammonis of the hippocampus. PMID- 28850692 TI - Utility and Safety of Repeated Ultrasound-Guided Core Needle Biopsy of Focal Liver Masses. AB - OBJECTIVES: To evaluate the accuracy and safety of repeated ultrasound-guided core needle biopsy (CNB) for hepatic focal lesions and to assess the predictive factors for success of repeated CNB. METHODS: For 5 years, 3085 CNBs were performed for focal hepatic lesions using an automated biopsy gun with an 18 gauge needle. Seventy-eight patients underwent repeated CNB because of pathologically inconclusive or unexpected results. Twelve patients were excluded because of unavailable additional tissue or follow-up imaging by radiofrequency ablation (n = 5), repeated CNB greater than than 3 months after the first CNB (n = 5), and insufficient follow-up time (n = 2). Sixty-six patients were finally enrolled after the exclusion criteria were applied. We retrospectively evaluated tumor necrosis, tumor size, number of passes, lesion site, depth, tumor conspicuity, and complications. Continuous data and the total scores of the grading system were analyzed by the Student t test, and categorical data and each category were analyzed by the Fisher exact test. RESULTS: The repeated CNB rate was 2.5% (78 of 3085). The diagnostic accuracy of the repeated biopsies was 83.3% (55 of 66). Comparing the diagnostic group with the nondiagnostic group, no variable (ie, size, depth, necrosis, lesion site [segment], and number of passes) had a statistically significant difference. Tumor conspicuity was a significant factor for predicting successful repeated biopsy (P < .001). The cumulative complication rate was 10.6% (7 of 66), with only minor complications. CONCLUSIONS: Repeated CNB is an accurate and safe procedure for obtaining a histologic diagnosis of hepatic focal lesions if the initial biopsy fails. High tumor conspicuity showed a significant correlation with successful repeated CNB. PMID- 28850693 TI - Enteral feeding and its impact on family mealtime routines for caregivers of children with cerebral palsy: A mixed method study. AB - BACKGROUND/AIM: Enteral feedings are part of the daily mealtime experience for many caregivers of children with cerebral palsy. The scope of occupational therapy practice incorporates multiple aspects of the enteral feeding process. Yet, the research in this area is very limited. The purpose of this study was to provide practitioners with better understanding of the impact enteral feedings of children with cerebral palsy have on family mealtime routines. METHODS: Using a complimentary mixed method approach, data were obtained through an online survey containing the Satisfaction Questionnaire with Gastrostomy Feeding (SAGA-8) and supplementary questions, and qualitative semi-structured phone interviews. Participants were caregivers of children with cerebral palsy who receive their primary nutrition through a gastrostomy tube. RESULTS: This study's cohort consisted of n = 36, SAGA-8, and n = 6 in-depth interviews. The mean age of children of was 9.4 (6.94 SD) with a mean age of 3.4 (5.35 SD) when enteral feeding was introduced. While families' overall situations positively changed after the gastronomy tube placement, environmental barriers and length of feeding time continued to present a challenge to mealtime routines. The mixed methods data analysis revealed that successful adjustment to having a child with a gastronomy tube and problem solving are closely linked and a consistent part of mealtime experience. CONCLUSION: Findings highlighted the necessity of comprehensive support from health professionals in achieving positive mealtime experience. Themes in this study indicated that caregivers would benefit from a professional with knowledge in the development and integration of rituals and routines to support positive outcomes. PMID- 28850694 TI - Splicing variant profiles and single nucleotide polymorphisms of the glucocorticoid receptor gene in relation to glucocorticoid sensitivity of B-cell precursor acute lymphoblastic leukaemia. AB - Glucocorticoid (GC) shows antileukaemic activity via binding to the GC receptor (GR). The human GR gene has 4 splicing variants besides the functional isoform GRalpha, but their significance in GC sensitivity of acute lymphoblastic leukaemia (ALL) has been inconsistent. Additionally, several studies evaluated the relevance of GR gene single nucleotide polymorphisms (SNPs) in the GC sensitivity of ALL, but the current cumulative evidence appears inconclusive. Addressing limitations in previous studies, we used a large series of B-cell precursor ALL (BCP-ALL) cell lines established from Japanese patients to comprehensively examine all 5 splicing variants of the GR gene and candidate SNPs, and their association with GC-sensitivity. We performed real-time reverse transcription polymerase chain reaction (RT-PCR) analyses with 10 sets of primers that differentially quantify the 5 isoforms in different combinations, and the strongest correlations with GC sensitivity were observed for the real-time RT-PCR of exons 7 and 8 (prednisolone sensitivity; r = -0.534, R2 = 0.29, P = 1.4 * 10 6 ) and exons 8 and 9a (r = -0.583, R2 = 0.34, P = 7.6 * 10-8 ), both specific for GRalpha and GRgamma isoforms. In contrast, the real-time RT-PCR of junction of exons 3g and 4 and exon 4, specific for GRgamma isoform alone, did not show significant correlation with GC sensitivity (prednisolone sensitivity; r = 0.403, R2 = 0.16, P = 4.6 * 10-4 ). These observations are consistent with the notion that GRalpha plays a central role in the GC-mediated proapoptotic activity in BCP-ALL. In addition, a promoter region SNP genotype (rs72555796) showed a significant association with GC sensitivity (prednisolone sensitivity; P = .010) and tended to show an association with GR gene expression (RT-PCR of exons 7 and 8; P = .170). These findings indicate that isoform profiles and SNP genotypes of the GR gene may be useful indicators of GC sensitivity in BCP-ALL. PMID- 28850695 TI - Isolated Single Umbilical Artery and Fetal Echocardiography: A 25-Year Experience at a Tertiary Care City Hospital. AB - OBJECTIVES: To review our 25-year experience with a single umbilical artery and fetal echocardiography to estimate the need for this test in cases of an isolated single umbilical artery. METHODS: We conducted a retrospective review of 436 patients with a diagnosis of a single umbilical artery at our institution between 1990 and 2015. Two hundred eighty-eight women had both an anatomic survey and a fetal echocardiogram. Pregnancies with concurrent extracardiac anomalies or aneuploidy were excluded. The study population was divided into 3 groups based on cardiac views on the anatomic survey: normal, incomplete, and suspicious. Echocardiographic results were compared among the 3 groups. The primary outcome measure was the incidence of cardiac anomalies in the normal group at fetal echocardiography. The data were analyzed by the chi2 test or Fisher exact test. RESULTS: The mean maternal age +/- SD of the group was 29.2 +/- 6.2 years; 44.1% were primiparas. The mean gestational age at diagnosis was 22.6 +/- 5.2 weeks, and the mean gestational age at fetal echocardiography was 25.1 +/- 3.6 weeks. In the normal group, 99.1% (230 of 232) of women had a normal fetal echocardiogram; the 2 abnormal cases were ventricular septal defects. Normal echocardiograms were obtained in 81.8% (36 of 44) and 25.0% (3 of 12) of the "incomplete" and "suspicious" groups, respectively. CONCLUSIONS: Fetuses with a single umbilical artery, in the absence of structural abnormalities, and with normal cardiac views at the time of the anatomic survey do not warrant an echocardiogram. PMID- 28850696 TI - Algorithms for evaluating reference scaled average bioequivalence: power, bias, and consumer risk. AB - The determination of the bioequivalence between highly variable drug products involves the evaluation of reference scaled average bioequivalence. The European and US regulatory authorities suggest different algorithms for the implementation of this approach. Both algorithms are based on approximations reflected in lower than the achievable power or higher than the nominal consumer risk of 5%. To overcome these deficiencies, a new class of algorithms, the so-called Exact methods, was earlier introduced. However, their applicability was limited. We propose 2 modifications which make their computation simpler and also applicable with any study design. Four algorithms were evaluated in simulated 3-period and 4 period bioequivalence studies: Hyslop's approach recommended by the US FDA, the method of average bioequivalence with expanding limits requested by the European EMA, and 2 versions of the new Exact methods. At small sample sizes, the Exact methods had substantially higher statistical power than Hyslop's algorithm and had lower consumer risk than the method of average bioequivalence with expanding limits. Similarly to the Hyslop's algorithm, higher than 5% consumer risk was observed only with either unbalanced study design or with additional regulatory requirements. The improved Exact algorithms compare favorably with the alternative procedures. They are based on the bias correction method of Hedges. The recognition that the scaled difference statistics is measured with bias has important practical implications when results of pilot bioequivalence studies are evaluated and, at the same time, calls for the revision of the statistical theory of RSABE and its related methods. PMID- 28850698 TI - Remotely sensed canopy height reveals three pantropical ecosystem states: a comment. PMID- 28850697 TI - A longitudinal evaluation of health-related quality of life in patients with AL amyloidosis: associations with health outcomes over time. AB - Light chain (AL) amyloidosis is a rare disease associated with significant, irreversible organ dysfunction and high case fatality. An observational study was conducted to assess health-related quality of life (HRQoL) in patients treated for AL amyloidosis between 1994 and 2014 with both high dose melphalan and stem cell transplantation (HDM/SCT) or non-SCT chemotherapy regimens. The SF-36v1(r) Health Survey (SF-36) was administered to assess HRQoL during clinic visits. Analysis of variance was used to compare pre- and post-treatment HRQoL within each treatment group to an age- and gender-adjusted general population (GP) normative sample. Cox proportional hazard models were fit to examine associations between pre-treatment levels of HRQoL and mortality within 1 and 5 years after initiating specific treatment regimens (HDM/SCT: n = 402; non-SCT chemotherapy regimens: n = 172). Among patients who received HDM/SCT, there were significant improvements following treatment in vitality, social functioning, role-emotional and mental health. Worse pre-treatment SF-36 physical component scores were associated with a greater risk of mortality in both treatment groups and follow up periods (P <= 0.005 for both). [Correction added on 20 October 2017, after first online publication: This P value has been corrected]. Using HRQoL assessments in every physician visit or treatment may provide valuable insights for treating rare conditions like AL amyloidosis. PMID- 28850700 TI - Basal cell carcinoma of the temporal bone and external auditory canal. AB - OBJECTIVES/HYPOTHESIS: To review the presenting features, treatment, and outcomes for patients with basal cell carcinoma (BCC) involving the temporal bone or external auditory canal (EAC). STUDY DESIGN: Retrospective case series. METHODS: Presenting characteristics, treatment strategies, and outcomes for patients with BCC involving the temporal bone or EAC were reviewed. Main outcome measures included rates of overall and disease-free survival at 5 years. RESULTS: Forty two patients met the inclusion criteria (mean age, 67 years). The most common presenting symptoms were hearing loss (15 patients, 36%) and otorrhea (11 patients, 26%). The 5-year overall survival rate was 78%, and the 5-year disease free survival rate was 77%. Patients who had undergone surgery elsewhere and presented with facial weakness had significantly worse overall survival (P = .004). Ten patients (24%) underwent sacrifice of at least a portion of the facial nerve at the time of their initial procedure at our institution. Two patients (5%) developed regional nodal disease. There was a trend toward better disease free survival for patients who received adjuvant radiation therapy after surgery at our institution (P = .06). CONCLUSIONS: BCC originating from or extending to the temporal bone can exhibit a wide range of behavior, ranging from superficial lesions readily managed with surgery to extensive locally invasive tumors with propensity for recurrence, treated with multimodality therapy. BCC may be associated with better prognosis than other temporal bone malignancies. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1425-1430, 2018. PMID- 28850699 TI - Clinical outcomes in adult patients with aplastic anemia: A single institution experience. AB - Newer treatment modalities are being investigated to improve upon historical outcomes with standard immunosuppressive therapy (IST) in aplastic anemia (AA). We analyzed outcomes of adult patients with AA treated with various combinatorial anti-thymoglobulin-based IST regimens in frontline and relapsed/refractory (R/R) settings. Pretreatment and on-treatment clinical characteristics were analyzed for relationships to response and outcome. Among 126 patients reviewed, 95 were treatment-naive (TN) and 63, R/R (including 32 from the TN cohort); median ages were 49 and 50 years, respectively. Overall survival (OS) was superior in IST responders (P < .001). Partial response to IST was associated with shorter relapse-free survival (RFS), as compared with complete response (P = .03). By multivariate analysis, baseline platelet and lymphocyte count predicted for IST response at 3 and 6 months, respectively. While additional growth factor interventions led to faster count recovery, there were no statistically significant differences in RFS or OS across the various frontline IST regimens (i.e., with/without G-CSF or eltrombopag). While marrow cellularity did not correlate with peripheral-blood counts at 3 months, cytomorphological assessment revealed dyspoietic changes in all nonresponders with hypercellular-marrow indices. Covert dysplasia, identified through early bone marrow assessment, has implications on future therapy choices after IST failure. Salvage IST response depended upon prior response to ATG: prior responders (46%) vs. primary refractory (0%) (P < .01). In the R/R setting, there was no survival difference between IST and allogeneic stem cell transplant groups, with a trend toward superior OS in the former. Transplant benefits in the R/R setting may be underrealized due to transplant-related mortality. PMID- 28850701 TI - Elevated PT, APPT and PT/INR possibly associated with doxycycline and cefoperazone co-administration: A case report. AB - WHAT IS KNOWN AND OBJECTIVE: Little is known regarding changes in blood coagulation parameters associated with tetracycline antibiotics. We report a possible case of elevated PT, APPT and PT/INR associated with doxycycline and cefoperazone co-administration. CASE SUMMARY: An 83-year-old Chinese male inpatient with severe pneumonia, chronic renal insufficiency and malnutrition experienced elevated PT, APPT and PT/INR which occurred within a few days of doxycycline added to his cefoperazone treatment and returned to normal after removal of it. WHAT IS NEW AND CONCLUSION: Very close monitoring of coagulation parameters might be advisable in those subjects when administering doxycycline and cefoperazone concomitantly. PMID- 28850702 TI - Dynamic Sonography for Snapping Knee Syndrome Caused by the Gracilis Tendon. PMID- 28850703 TI - Mendelian randomization incorporating uncertainty about pleiotropy. AB - Mendelian randomization (MR) requires strong assumptions about the genetic instruments, of which the most difficult to justify relate to pleiotropy. In a two-sample MR, different methods of analysis are available if we are able to assume, M1 : no pleiotropy (fixed effects meta-analysis), M2 : that there may be pleiotropy but that the average pleiotropic effect is zero (random effects meta analysis), and M3 : that the average pleiotropic effect is nonzero (MR-Egger). In the latter 2 cases, we also require that the size of the pleiotropy is independent of the size of the effect on the exposure. Selecting one of these models without good reason would run the risk of misrepresenting the evidence for causality. The most conservative strategy would be to use M3 in all analyses as this makes the weakest assumptions, but such an analysis gives much less precise estimates and so should be avoided whenever stronger assumptions are credible. We consider the situation of a two-sample design when we are unsure which of these 3 pleiotropy models is appropriate. The analysis is placed within a Bayesian framework and Bayesian model averaging is used. We demonstrate that even large samples of the scale used in genome-wide meta-analysis may be insufficient to distinguish the pleiotropy models based on the data alone. Our simulations show that Bayesian model averaging provides a reasonable trade-off between bias and precision. Bayesian model averaging is recommended whenever there is uncertainty about the nature of the pleiotropy. PMID- 28850705 TI - Possible Strategies to Make Warfarin Dosing Algorithm Prediction More Accurately in Patients With Extreme Dose. PMID- 28850704 TI - Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) in thalassemia remains a challenge. We reported a single-centre case-control study of a large cohort of 516 children and adult patients treated with HSCT or blood transfusion support and iron chelation therapy; 258 patients (median age 12, range 1-45) underwent sibling (67%) or unrelated (33%) HSCT; 97 patients were adults (age >= 16 years). The median follow-up after HSCT was 11 years (range 1-30). The conditioning regimen was busulfan (80.6%) or treosulfan-based (19.4%). A cohort of 258 age-sex matched conventionally treated (CT) patients was randomly selected. In transplanted patients the 30-year overall survival (OS) and thalassemia-free survival (TFS) were 82.6 +/- 2.7% and 77.8 +/- 2.9%, compared to the OS of 85.3 +/- 2.7% in CT patients (P = NS); The incidence of grade II-IV acute and chronic graft versus host disease (GvHD) was 23.6% and 12.9% respectively. The probability of rejection was 6.9%. Transplant-related mortality (TRM) (13.8%) was similar to the probability of dying of cardiovascular events in CT patients (12.2%). High-risk Pesaro score (class 3) was associated with lower OS (OR = 1.99, 95% C.I.=1.31-3.03) and TFS (OR = 1.54, 95% C.I.=1.12-2.12). In adult patients, the 23-years OS and TFS after HSCT were 70 +/- 5% and 67.3 +/- 5%, compared to 71.2 +/- 5% of OS in CT (P = NS). Finally, treosulfan was associated with lower risk of acute GvHD (P = .004; OR = 0.28, 95% C.I.=0.12-0.67). In conclusion, the 30-year survival rate of ex-thalassemia patients after HSCT was similar to that expected in CT thalassemia patients, with the vast majority of HSCT survivors cured from thalassemia. PMID- 28850707 TI - Ectopic Intrathyroidal Thymic Tissue Mimicking Thyroid Nodules in Children. AB - Ectopic intrathyroidal thymic tissue is a benign lesion of nonthyroid origin occasionally found in the pediatric thyroid gland. Accurate diagnosis of such lesions is critical to avoid unnecessary biopsy or surgery. Twelve children referred to our center for the concern of thyroid nodules were found to have intrathyroidal thymic tissue. Most of the lesions had a classic sonographic appearance of a hypoechoic mass with sharp margins and multiple focal internal nonshadowing echogenicities identical to thymic tissue. Sonography and, in select cases, fine-needle aspiration can be used to diagnose benign thymic tissue within the thyroid and avoid unnecessary surgery. PMID- 28850706 TI - Outcomes of childbearing Medicaid beneficiaries engaged in care at Strong Start birth center sites between 2012 and 2014. AB - BACKGROUND: Variations in care for pregnant women have been reported to affect pregnancy outcomes. METHODS: This study examined data for all 3136 Medicaid beneficiaries enrolled at American Association of Birth Centers (AABC) Center for Medicare and Medicaid Innovation Strong Start sites who gave birth between 2012 and 2014. Using the AABC Perinatal Data Registry, descriptive statistics were used to evaluate socio-behavioral and medical risks, and core perinatal quality outcomes. Next, the 2082 patients coded as low medical risk on admission in labor were analyzed for effective care and preference sensitive care variations. Finally, using binary logistic regression, the associations between selected care processes and cesarean delivery were explored. RESULTS: Medicaid beneficiaries enrolled at AABC sites had diverse socio-behavioral and medical risk profiles and exceeded quality benchmarks for induction, episiotomy, cesarean, and breastfeeding. Among medically low-risk women, the model demonstrated effective care variations including 82% attendance at prenatal education classes, 99% receiving midwifery-led prenatal care, and 84% with midwifery- attended birth. Patient preferences were adhered to with 83% of women achieving birth at their preferred site of birth, and 95% of women using their preferred infant feeding method. Elective hospitalization in labor was associated with a 4-times greater risk of cesarean birth among medically low-risk childbearing Medicaid beneficiaries. CONCLUSIONS: The birth center model demonstrates the capability to achieve the triple aims of improved population health, patient experience, and value. PMID- 28850708 TI - The association between subclinical thyroid dysfunction and dementia: The Health, Aging and Body Composition (Health ABC) Study. AB - OBJECTIVE: Data on the association between subclinical thyroid dysfunction and dementia are limited and conflicting. We aimed to determine whether subclinical thyroid dysfunction was associated with dementia and cognitive decline. DESIGN: Population-based prospective cohort study. PATIENTS: Adults aged 70-79 years with measured thyroid function, but no dementia at baseline, and Modified Mini-Mental State (3MS) at baseline and follow-up. MEASUREMENTS: Primary outcome was incident adjudicated dementia, based on 3MS, hospital records and dementia drugs. Secondary outcome was change in 3MS. Models were adjusted for age, sex, race, education and baseline 3MS, and then further for cardiovascular risk factors. RESULTS: Among 2558 adults, 85% were euthyroid (TSH 0.45-4.49mIU/L), 2% had subclinical hyperthyroidism with mildly decreased TSH (TSH 0.10-0.44 mIU/L), 1% subclinical hyperthyroidism with suppressed TSH (TSH < 0.10 mIU/L with normal free thyroxine [FT4]) and 12% subclinical hypothyroidism (TSH 4.50-19.99 mIU/L with normal FT4). Over 9 years, 22% developed dementia. Compared to euthyroidism, risk of dementia was higher in participants with subclinical hyperthyroidism with suppressed TSH (HR 2.38, 95% CI = 1.13;5.04), while we found no significant association in those with mildly decreased TSH (HR 0.79, 95% CI = 0.45;1.38) or with subclinical hypothyroidism (HR 0.91, 95% CI = 0.70;1.19). Participants with subclinical hyperthyroidism with suppressed TSH had a larger decline in 3MS ( 3.89, 95% CI = -7.62; -0.15). CONCLUSIONS: Among older adults, subclinical hyperthyroidism with a TSH < 0.10 mIU/L was associated with a higher risk of dementia and a larger cognitive decline, while subclinical hyperthyroidism with mildly decreased TSH or subclinical hypothyroidism were not. PMID- 28850709 TI - How are learning strategies reflected in the eyes? Combining results from self reports and eye-tracking. AB - BACKGROUND: Up until now, empirical studies in the Student Approaches to Learning field have mainly been focused on the use of self-report instruments, such as interviews and questionnaires, to uncover differences in students' general preferences towards learning strategies, but have focused less on the use of task specific and online measures. AIMS: This study aimed at extending current research on students' learning strategies by combining general and task-specific measurements of students' learning strategies using both offline and online measures. We want to clarify how students process learning contents and to what extent this is related to their self-report of learning strategies. SAMPLE: Twenty students with different generic learning profiles (according to self report questionnaires) read an expository text, while their eye movements were registered to answer questions on the content afterwards. METHODS: Eye-tracking data were analysed with generalized linear mixed-effects models. RESULTS: The results indicate that students with an all-high profile, combining both deep and surface learning strategies, spend more time on rereading the text than students with an all-low profile, scoring low on both learning strategies. CONCLUSIONS: This study showed that we can use eye-tracking to distinguish very strategic students, characterized using cognitive processing and regulation strategies, from low strategic students, characterized by a lack of cognitive and regulation strategies. These students processed the expository text according to how they self-reported. PMID- 28850710 TI - Family nurture intervention in preterm infants increases early development of cortical activity and independence of regional power trajectories. AB - AIM: Premature delivery and maternal separation during hospitalisation increase infant neurodevelopmental risk. Previously, a randomised controlled trial of Family Nurture Intervention (FNI) in the neonatal intensive care unit demonstrated improvement across multiple mother and infant domains including increased electroencephalographic (EEG) power in the frontal polar region at term age. New aims were to quantify developmental changes in EEG power in all brain regions and frequencies and correlate developmental changes in EEG power among regions. METHODS: EEG (128 electrodes) was obtained at 34-44 weeks postmenstrual age from preterm infants born 26-34 weeks. Forty-four infants were treated with Standard Care and 53 with FNI. EEG power was computed in 10 frequency bands (1-48 Hz) in 10 brain regions and in active and quiet sleep. RESULTS: Percent change/week in EEG power was increased in FNI in 132/200 tests (p < 0.05), 117 tests passed a 5% False Discovery Rate threshold. In addition, FNI demonstrated greater regional independence in those developmental rates of change. CONCLUSION: This study strengthens the conclusion that FNI promotes cerebral cortical development of preterm infants. The findings indicate that developmental changes in EEG may provide biomarkers for risk in preterm infants as well as proximal markers of effects of FNI. PMID- 28850712 TI - Effectiveness of fluoride varnish in preventing early childhood caries in rural areas without access to fluoridated drinking water: A randomized control trial. AB - OBJECTIVES: Early childhood caries (ECC) constitutes a serious public health issue, especially in communities without water fluoridation. We assessed the effectiveness of biannual fluoride varnish applications to prevent ECC in children from nonfluoridated rural areas. METHODS: A triple-blind randomized control trial with two parallel arms was conducted with 275 two- to three-year old children without cavitated carious lesions from 28 rural public preschools in Chile. The preschools were located in areas of low socioeconomic status without access to fluoridated water. An oral health education component was administered to children, parents and educators. A new toothbrush and toothpaste for each child was delivered to the parents at baseline and at four follow-up visits. The participants were randomly allocated to receive fluoride varnish or placebo applications every six months. Trained, calibrated dentists blind to the treatment arm performed visual dental assessments at 6, 12, 18 and 24 months. The primary endpoint was the development of cavitated carious lesions in children during the 24-month follow-up period using WHO criteria, and the secondary outcomes were an increase in caries measured as a change in the index of decayed, missing or filled teeth (dmft) since the beginning of the study and the development of adverse effects. An intention-to-treat (ITT) approach was used for the primary analysis. RESULTS: We included 131 participants in the intervention group and 144 participants in the placebo group; of these children, 89 (67.9%) in the intervention group and 100 (69.4%) in the control group completed the protocol. The comparative ITT analysis of caries incidence after 24 months of follow-up showed a between-group prevention fraction of 18.9% (-2.9%-36.2%). Caries incidence was 45.0% for the experiment group and 55.6% for the control group (P = .081), with a mean dmft of 1.6 (SD = 2.4) and 2.1 (SD = 2.5), respectively. No adverse effects were reported. CONCLUSIONS: In conclusion, biannual fluoride varnish application is not effective in preschool children from rural nonfluoridated communities at a high risk of caries. PMID- 28850711 TI - ADAMTS-4 in oligodendrocytes contributes to myelination with an impact on motor function. AB - Myelination is a late developmental process regulated by a set of inhibitory and stimulatory factors, including extracellular matrix components. Accordingly, chondroitin sulfate proteoglycans (CSPGs) act as negative regulators of myelination processes. A disintegrin and metalloproteinase with thrombospondin motifs type 4 (ADAMTS-4) is an extracellular protease capable of degrading CSPGs. Although exogenous ADAMTS-4 has been proven to be beneficial in several models of central nervous system (CNS) injuries, the physiological functions of endogenous ADAMTS-4 remain poorly understood. We first used Adamts4/LacZ reporter mice to reveal that ADAMTS-4 is strongly expressed in the CNS, especially in the white matter, with a cellular profile restricted to mature oligodendrocytes. Interestingly, we evidenced an abnormal myelination in Adamts4-/- mice, characterized by a higher diameter of myelinated axons with a shifting g-ratio. Accordingly, lack of ADAMTS-4 is accompanied by motor deficits and disturbed nervous electrical activity. In conclusion, we demonstrate that ADAMTS-4 is a new marker of mature oligodendrocytes contributing to the myelination processes and thus to the control of motor capacities. PMID- 28850713 TI - Triggering a false alarm: wounding mimics prey capture in the carnivorous Venus flytrap (Dionaea muscipula). AB - In the carnivorous plant Venus flytrap (Dionaea muscipula), the sequence of events after prey capture resembles the well-known plant defence signalling pathway in response to pathogen or herbivore attack. Here, we used wounding to mimic prey capture to show the similarities and differences between botanical carnivory and plant defence mechanisms. We monitored movement, electrical signalling, jasmonate accumulation and digestive enzyme secretion in local and distal (systemic) traps in response to prey capture, the mechanical stimulation of trigger hairs and wounding. The Venus flytrap cannot discriminate between wounding and mechanical trigger hair stimulation. Both induced the same action potentials, rapid trap closure, hermetic trap sealing, the accumulation of jasmonic acid (JA) and its isoleucine conjugate (JA-Ile), and the secretion of proteases (aspartic and cysteine proteases), phosphatases and type I chitinase. The jasmonate accumulation and enzyme secretion were confined to the local traps, to which the stimulus was applied, which correlates with the propagation of electrical signals and the absence of a systemic response in the Venus flytrap. In contrast to plant defence mechanisms, the absence of a systemic response in carnivorous plant may represent a resource-saving strategy. During prey capture, it could be quite expensive to produce digestive enzymes in the traps on the plant without prey. PMID- 28850714 TI - The complexity of school racial climate: Reliability and validity of a new measure for secondary students. AB - BACKGROUND: The conceptualization of the role of race and culture in students' experience of school has been limited. This study presents a more comprehensive and multidimensional framework than previously conceptualized and includes the two domains of (1) intergroup interactions (frequency of interaction, quality of interaction, equal status, and support for positive interaction) and (2) school racial socialization (cultural socialization, mainstream socialization, promotion of cultural competence, colourblind socialization, critical consciousness socialization, and stereotyping) (Byrd, 2015, Journal of Educational Research, 108, 10). AIMS: The scale presents a measure of school racial climate for middle and high school students and tests for evidence of reliability and validity in two independent, nationwide samples. SAMPLE AND METHOD: Participants were 819 children aged 12-18 (M = 15.27, SD = 1.58) who completed the School Climate for Diversity - Secondary Scale and a number of validating measures: general school climate, perceived discrimination, culturally responsive teaching, grades, and academic motivation. RESULTS AND CONCLUSIONS: Confirmatory factor analyses and reliability analyses showed support for the 10-factor structure of the scale, and the subscales were associated with the validating measures in expected ways. PMID- 28850716 TI - Thalidomide induces haematologic responses in patients with beta-thalassaemia. AB - OBJECTIVE: This study aimed to evaluate the clinical and laboratory outcomes of a group of patients with beta-thalassaemia major or intermedia treated with thalidomide. METHODS: Clinical and laboratory data were obtained by analysing medical records of beta-thalassaemia patients. Using the self-control method, the levels of haemoglobin (Hb), foetal haemoglobin (HbF), white blood cells (WBC) and platelets were detected before and after the treatment, and adverse reactions were recorded. RESULTS: Data from the medical records of 9 patients were analysed. The median haemoglobin levels of these patients increased from 5.13 +/- 2.15 g/dL before treatment to 10.38 +/- 1.19 g/dL after treatment. The average spleen size decreased from a pretreatment length of 8.19 +/- 3.10 to 5.49 +/- 1.80 cm below the costal margin after treatment. The mean HbF levels increased from a pretreatment value of 35.67% +/- 26.82% to 75.67% +/- 14.64% after treatment in the 9 patients for whom these measurements were available. All patients no longer needed transfusions by 1 month after treatment. No serious adverse reactions were observed in any of the thalidomide-treated patients. CONCLUSION: In this study, thalidomide showed an outstanding effect on beta thalassaemia patients who required frequent red-cell transfusions. Thalidomide increased haemoglobin levels without causing serious adverse reactions, but the long-term curative outcomes and other side effects should be observed continuously. PMID- 28850715 TI - Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11beta-hydroxysteroid dehydrogenase type-1 inhibitor BMS 823778. AB - AIMS: BMS-823778 is an inhibitor of 11beta-hydroxysteroid dehydrogenase type-1, and thus a potential candidate for Type 2 diabetes treatment. Here, we investigated the metabolism and pharmacokinetics of BMS-823778 to understand its pharmacokinetic variations in early clinical trials. METHODS: The metabolism of BMS-823778 was characterized in multiple in vitro assays. Pharmacokinetics were evaluated in healthy volunteers, prescreened as CYP2C19 extensive metabolizers (EM) or poor metabolizers (PM), with a single oral dose of [14 C]BMS-823778 (10 mg, 80 MUCi). RESULTS: Three metabolites (<5%) were identified in human hepatocytes and liver microsomes (HLM) incubations, including two hydroxylated metabolites (M1 and M2) and one glucuronide conjugate (M3). As the most abundant metabolite, M1 was formed mainly through CYP2C19. M1 formation was also correlated with CYP2C19 activities in genotyped HLM. In humans, urinary excretion of dosed radioactivity was significantly higher in EM (68.8%; 95% confidence interval 61.3%, 76.3%) than in PM (47.0%; 43.5%, 50.6%); only small portions (<2%) were present in faeces or bile from both genotypes. In plasma, BMS-823778 exposure in PM was significantly (5.3-fold, P = 0.0097) higher than in EM. Furthermore, total radioactivity exposure was significantly higher (P < 0.01) than BMS-823778 exposure in all groups, indicating the presence of metabolites. M1 was the only metabolite observed in plasma, and much lower in PM. In urine, the amount of M1 and its oxidative metabolite in EM was 7-fold of that in PM, while more glucuronide conjugates of BMS-823778 and M1 were excreted in PM. CONCLUSIONS: CYP2C19 polymorphisms significantly impacted systemic exposure and metabolism pathways of BMS-823778 in humans. PMID- 28850717 TI - Genetics of Cushing's disease. AB - Cushing's disease (CD) is a rare disabling condition caused by Adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary. The majority of corticotropic adenomas are monoclonal and occur sporadically. Only rarely does CD arise in the context of genetic familial syndromes. Targeted sequencing of oncogenes and tumour suppressor genes commonly mutated in other tumours did not identify recurrent mutations. In contrast, next generation sequencing allowed us recently to clarify the genetic basis of CD: we identified somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene in a significant portion of corticotropinomas. These mutations represent a novel and unique mechanism leading to ACTH excess. Inhibition of USP8 or its downstream signalling pathways could represent a new therapeutic approach for the management of CD. In this review, we will focus on this new evidence and its implication for clinical care of affected patients. PMID- 28850718 TI - The management of hodgkin lymphomas in pregnancies. AB - Hodgkin lymphoma is the most common hematological malignancy in pregnancy. Its management presents several unique challenges, as decisions have to take both maternal and fetal risks into consideration. Using three hypothetical cases, we review current evidence and guidelines and suggest our recommendations for managing pregnant Hodgkin lymphoma patients. The opportunity for a prompt and accurate diagnosis should not be missed; this may be achieved by vigilance to suggestive symptoms, performance of biopsy which is not contraindicated during pregnancy and use of MRI for staging. Most patients should receive treatment with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) after completion of the first trimester. Bridging therapy with corticosteroids or vinblastine should be considered during the first trimester. In most cases of early disease, the addition of chemotherapy cycles to the treatment plan seems preferable to radiation therapy. Diagnosis at relapse raises unique dilemmas regarding second line chemotherapeutic regimens and timing of consolidation with high-dose therapy and autologous stem cell transplantation, an approach which is contraindicated during pregnancy. Considering the excellent outcomes of Hodgkin lymphoma outside pregnancy, every effort should be made to strive toward a curative treatment plan while balancing the multiple issues and dilemmas which arise when treating this malignancy in a pregnant patient. PMID- 28850720 TI - A population-based analysis of verrucous carcinoma of the oral cavity. AB - OBJECTIVES: To describe the incidence and determinants of survival of patients with verrucous carcinoma (VC) of the oral cavity between the years of 1973 and 2012 using the Surveillance, Epidemiology, and End Results (SEER) database. STUDY DESIGN: Retrospective cohort study using a national database. METHODS: The SEER registry was utilized to calculate survival trends for patients with VC of the oral cavity between 1973 and 2012. Patient data was then analyzed with respect to histopathology, age, sex, race, stage, grade, and treatment modalities (surgery and radiation therapy). Overall survival (OS) and disease-specific survival (DSS) were calculated. RESULTS: A total of 1,481 cases of VC of the oral cavity were identified. The cohort was composed of 50.5% males. The mean age at diagnosis was 69.5 years. The oral tongue was the most common primary site (28.9%), followed by the alveolar ridge (21.4%) and buccal mucosa (19.0%). The vast majority of cases (79.1%) presented with stage I and stage II disease. Nodal disease was present in only 1.6% of cases. The median OS was 94.6 months. Eighty-seven percent of cases underwent surgery, and 11.5% received both surgery and radiation therapy. Overall survival at 2, 5, and 10 years was 83%, 64%, and 42%, respectively. On multivariate analysis, advanced age (P < 0.001) and stage (P < 0.001) were associated with worse OS, whereas surgery improved OS (P = 0.047). CONCLUSION: We provide the first population-based analysis of prognostic factors affecting survival outcomes in patients with oral cavity VC. Verrucous carcinoma of the oral cavity is associated with a generally favorable prognosis. Age, stage, nodal status, and surgical therapy are independent predictors of OS. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:393-397, 2018. PMID- 28850722 TI - Reflecting on Some Discoveries of 40 Years and Their Outcomes. PMID- 28850719 TI - Complement 3a receptor in dorsal horn microglia mediates pronociceptive neuropeptide signaling. AB - The complement 3a receptor (C3aR1) participates in microglial signaling under pathological conditions and was recently shown to be activated by the neuropeptide TLQP-21. We previously demonstrated that TLQP-21 elicits hyperalgesia and contributes to nerve injury-induced hypersensitivity through an unknown mechanism in the spinal cord. Here we determined that this mechanism requires C3aR1 and that microglia are the cellular target for TLQP-21. We propose a novel neuroimmune signaling pathway involving TLQP-21-induced activation of microglial C3aR1 that then contributes to spinal neuroplasticity and neuropathic pain. This unique dual-ligand activation of C3aR1 by a neuropeptide (TLQP-21) and an immune mediator (C3a) represents a potential broad-spectrum mechanism throughout the CNS for integration of neuroimmune crosstalk at the molecular level. PMID- 28850721 TI - The Arabidopsis CPSF30-L gene plays an essential role in nitrate signaling and regulates the nitrate transceptor gene NRT1.1. AB - Plants have evolved sophisticated mechanisms to adapt to fluctuating environmental nitrogen availability. However, more underlying genes regulating the response to nitrate have yet to be characterized. We report here the identification of a nitrate regulatory mutant whose mutation mapped to the Cleavage and Polyadenylation Specificity Factor 30 gene (CPSF30-L). In the mutant, induction of nitrate-responsive genes was inhibited independent of the ammonium conditions and was restored by expression of the wild-type 65 kDa encoded by CPSF30-L. Molecular and genetic evidence suggests that CPSF30-L works upstream of NRT1.1 and independently of NLP7 in response to nitrate. Analysis of the 3'-UTR of NRT1.1 showed that the pattern of polyadenylation sites was altered in the cpsf30 mutant. Transcriptome analysis revealed that four nitrogen-related clusters were enriched in the differentially expressed genes of the cpsf30 mutant. Nitrate uptake was decreased in the mutant along with reduced expression of the nitrate transporter/sensor gene NRT1.1, while nitrate reduction and amino acid content were enhanced in roots along with increased expression of several nitrate assimilatory genes. These findings indicate that the 65 kDa protein encoded by CPSF30-L mediates nitrate signaling in part by regulating NRT1.1 expression, thus adding an important component to the nitrate signaling network. PMID- 28850723 TI - Evaluation of Neonatal Brain Parenchyma Using 2-Dimensional Shear Wave Elastography. AB - OBJECTIVES: The aim of this study was to evaluate the stiffness of the neonatal brain using 2-dimensional shear wave elastography in term and preterm neonates and to investigate possible stiffness differences between groups. METHODS: A total of 83 neonates, including 44 term and 39 preterm, were included in the study. Shear wave elastographic measurements of the thalamus and occipital periventricular white matter were conducted via the anterior fontanel. The Pearson correlation coefficient was used to determine the association between the birth week and stiffness values of the thalamus and periventricular white matter. A receiver operating characteristic analysis was applied to determine the power of the stiffness of the thalamus and periventricular white matter in predicting a significant preterm classification. P < .05 was considered significant. RESULTS: The brain parenchymal stiffness values measured from both the thalamus and periventricular white matter were found to be significantly lower in the preterm group compared with the term group. The periventricular white matter stiffness values were found to be lower than thalamus stiffness values in both groups. According to the receiver operating characteristic curve, the optimal cutoff values for determining prematurity were defined to be less than 8.28 kPa for the mean thalamus stiffness and less than 6.59 kPa for the periventricular white matter. CONCLUSIONS: This study shows that differences between brain stiffness values in preterm and term neonates can be shown by using 2-dimensional shear wave elastography, and the results may be reference points for evaluating neonatal brain stiffness in research on patients with various illnesses. PMID- 28850724 TI - Botulinum toxin in management of synkinesis in patients with unilateral and bilateral vocal fold paralysis. PMID- 28850725 TI - Risk factors for thirty-day readmission following flap reconstruction of oncologic defects of the head and neck. AB - OBJECTIVES: Unplanned 30-day readmission rate following hospital discharge is an important metric of healthcare quality. This study sought to characterize the rate, risk factors, and common causes of readmission in head and neck cancer patients following free or pedicled flap reconstruction. STUDY DESIGN: Retrospective cohort study. METHODS: Charts were reviewed of all patients who underwent free or pedicled flap reconstruction following resection of head and neck cancer at the Massachusetts Eye and Ear Infirmary 2009 to 2014. Readmission risk factors were evaluated by univariate and multivariate analysis. RESULTS: Of 682 patients with free (76%) or pedicled flap reconstruction, 135 patients (19.8%) were readmitted. Factors not associated with readmission included age, gender, American Society of Anesthesiologists status, operative time, prior radiation therapy, primary cancer site, and free (vs. pedicled) flap type. Significant readmission risk factors included surgical site infections (SSI) (45.2% vs. 9.9%), use of hardware (18.5% vs. 11.3%), and clean-contaminated or contaminated surgery (15.2% vs. clean 8.2%). Surgical site infections (P < 0.001) and use of hardware (P = 0.03) remained predictive of readmission on multiple regression analysis. Primary reasons for readmission included wound complications (61.5%) and supportive care (15.6%). The median time to readmission was 8 days, and 41% of readmissions occurred within 1 week. Seventy percent of readmissions occurred within 2 weeks, including 77% of readmissions for SSIs and 86% for supportive care. CONCLUSION: Readmissions occurred in nearly one-fifth of patients following flap surgery. SSIs and use of hardware were risk factors, whereas wound complications were the most common cause of readmission. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:343-349, 2018. PMID- 28850726 TI - Does a short self-compassion intervention for students increase healthy self regulation? A randomized control trial. AB - The primary aim of this study was to examine the effects of a two-week self compassion course on healthy self-regulation (personal growth self-efficacy and healthy impulse control) and unhealthy self-regulation (self-judgment and habitual negative self-directed thinking) in university students. We also examined the effects on self-compassion, anxiety and depression. Students (N = 158, 85% women, mean age = 25 years) were randomized to an intervention group and a waiting-list control group in a multi-baseline randomized control trial. Healthy self-control was measured by the Personal Growth Initiative Scale (PGIS) and the Self-Control Scale; unhealthy self-control was measured by the Non judgement subscale from the Five-Facet Mindfulness Questionnaire (reversed) and the Habit Index of Negative Thinking (HINT). Secondary outcomes were measured by the State-Trait Anxiety Inventory (STAI-trait), the Major Depression Inventory (MDI), and the Self-Compassion Scale (SCS). A 2 * 3 repeated measures analysis of variance (ANOVA) showed gains for the intervention-group in personal growth self efficacy and healthy impulse-control and reductions in self-judgment and habitual negative self-directed thinking, as well as increases in self-compassion and reductions in anxiety and depression. After all participants had completed the course, the groups were combined and repeated measures ANOVAs showed that changes remained at six-month follow-up for personal growth self-efficacy, self-judgment and habitual negative self-directed thinking; as well as for self-compassion, anxiety and depression. Concluding, a short self-compassion course seems an effective method of increasing self-compassion and perceived control over one's life for university students, as well as increasing mental health. PMID- 28850727 TI - Pyogenic granuloma of the penis following chancre. PMID- 28850728 TI - Rupioid lesions, PLEVA and superposition phenomenon in malignant syphilis: two case reports in HIV-infected patients. PMID- 28850729 TI - Reply to: Reduced Bone Mineral Density in m.3243A>G Carriers May Be Multifactorial. PMID- 28850730 TI - Minimally elevated preoperative parathyroid hormone level influences the management of primary hyperparathyroidism. AB - OBJECTIVES/HYPOTHESIS: To determine the effect of preoperative parathyroid hormone (PTH) level on the extent of surgery and the accuracy of parathyroid imaging in primary hyperparathyroidism. STUDY DESIGN: Retrospective cohort. METHODS: Final diagnosis of single-gland adenoma and its location versus multigland disease was established in this retrospective cohort study. Positive predictive value, negative predictive value, and accuracy of imaging were analyzed in relation to preoperative PTH levels. RESULTS: Eighty-seven percent of the 218 patients enrolled in the study underwent unilateral targeted operation and had a 97.9% (95% confidence interval: 95.8%-100%) success rate. However, in patients with PTH <65 pg/mL, 28.6% had bilateral exploration compared to 10.3% in those with PTH >=65 pg/mL (P = .042). In patients with PTH <65 pg/mL, 7/21 (33.3%) had inaccurate sestamibi findings compared to 24/174 (13.8%) in patients with PTH >=65 pg/mL (P = .047). CONCLUSIONS: Accuracy of sestamibi drops significantly, by threefold, in patients with mild primary hyperparathyroidism and PTH <65 pg/mL. Patients with PTH < 65 pg/mL have a 2.5-fold higher rate of bilateral operation to identify the hypersecreting gland(s) compared to patients with PTH >=65 pg/mL. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1016-1021, 2018. PMID- 28850731 TI - The role of beta-blockers in dermatological treatment: a review. AB - Many systemic medications have been used off-label in cutaneous diseases. Use of beta-adrenergic-blocking agents has risen in popularity among dermatologists since the discovery of their efficacy in treating infantile haemangioma. There has also been an increase in the interest of the applications of beta-blockers in other skin disorders. Overall, beta-blockers are effective in treating diseases of vascular origin and promote wound healing. They are relatively safe and inexpensive medications that could be included in the armamentarium against skin diseases. PMID- 28850732 TI - Teledermoscopy images acquired in primary health care and hospital settings - a comparative study of image quality. AB - BACKGROUND: The incidence of melanoma and non-melanoma skin cancer is increasing, which has also lead to an increase in referrals between primary health care (PHC) and dermatology departments, putting a strain on healthcare services. Teledermoscopy (TDS) referrals from PHC can improve the triage process for patients with suspicious skin tumours, but the quality of the images included could potentially affect its usefulness. OBJECTIVE: To critically appraise the quality of the dermoscopic images of a smartphone TDS system, by comparing the TDS referral images with images of the same tumours acquired at the department of dermatology. METHODS: Two dermatologists rated the image quality of two image sets from 172 skin tumours separately. The dermatologists also decided on a main diagnosis, differential diagnoses and described the visible dermoscopic structures. RESULTS: The images acquired in PHC were rated as having slightly lower quality, but there was no significant difference. PHC images and dermatology images were of intermediate-to-high quality in 95.5%-97.7% and 96.5% 98.8%, respectively. There was no difference in agreement between the TDS diagnosis based on the two image sets with the final clinical or histopathological diagnosis. Most image pairs (81.4% and 83.7%) received the same main diagnosis by the two evaluators. When this was not the case, the most common reasons were poor focus, excessive pressure applied when acquiring the image or inadequate amount of zoom. CONCLUSION: TDS performed in PHC with a smartphone based system does not seem to negatively affect the usefulness of TDS referrals. Thus, physicians at PHC do not necessarily need to be trained photographers to ensure adequate TDS image quality. Knowledge about technical difficulties could however be used when training PHC staff, to improve the image quality further. PMID- 28850733 TI - Highly Efficient, Conventional, Fluorescent Organic Light-Emitting Diodes with Extended Lifetime. AB - Highly efficient, yellow-fluorescent organic light-emitting diodes with a maximum external quantum efficiency exceeding 25.0% and extended lifetime are reported using iridium-complex sensitizers doped in an exciplex host. Energy transfer processes reduce the lifetime of the exciplex and excitons on the Ir complexes and enable an excited state to exist in a conventional fluorescent emitter, thereby increasing device lifetime. The device stability depends on the location of the excited state. PMID- 28850734 TI - The time dependency of renal allograft histology. AB - Much of the complexity of the histological appearance of kidney transplant biopsies depends on the time at which the biopsies are obtained. It is well established that many elementary histological lesions and diagnoses have a time dependent occurrence. While some "active" inflammatory lesions are noted primarily early after transplantation, other lesions are "chronic" and accumulate over time post-transplant, sometimes closely related to the prior active inflammatory lesions. With time after transplantation, the complexity of histology increases, by the co-occurrence of chronic damage and specific diseases. This leads to difficulties in clinical interpretation of the histological picture. We discuss the time-dependent prevalence of active and chronic lesions in kidney allograft biopsies and their associations with outcome. We also elaborate on the importance of time post-transplant in the interpretation of complex histological lesions or mixed diagnoses and illustrate that further research is necessary to evaluate whether time post-transplant is important for prognostication of graft injury processes. Adding a multidimensional prognostic layer to the current diagnostic Banff classification, including graft functional characteristics and time after transplantation, could become an interesting aid in the interpretation of complex histological lesions and mixed diagnoses, and in therapeutic decision-making. PMID- 28850735 TI - Lower quality of life in young men after pediatric kidney transplantation when compared to healthy controls and survivors of childhood leukemia-a cross sectional study. AB - Data about health-related quality of life (HRQOL) in adult recipients after pediatric kidney transplantation (KTx) are scarce. In this nationwide questionnaire-based study, HRQOL and social status in young adult men having undergone KTx during childhood (n = 29) were studied and compared to age- and gender-matched healthy controls (n = 56) and survivors of childhood acute lymphoblastic leukemia (n = 52) comprising controls with another chronic disease of childhood. Altogether 41% of the KTx recipients, 50% of the leukemia survivors and 80% of the healthy controls lived in a permanent relationship. When compared with leukemia survivors, the KTx recipients reported significantly more bodily pain and worse general health (RAND-36). Older age at time of study, longer duration of dialysis, multiple transplantations and diminished graft function correlated with lower scores. The KTx recipients had a significantly higher mean Beck Depression Inventory (BDI) score than the leukemia survivors (P = 0.000) or the healthy controls (P = 0.006). BDI scores were highest in patients who lived without a partner or children had lower educational level or were unemployed. KTx recipients had significantly lower HRQOL scores than their healthy and controls with childhood chronic disease. Early detection of psychosocial problems and poor physical functioning among these patients is warranted. PMID- 28850736 TI - Giant Incident Photon-to-Current Conversion with Photoconductivity Gain on Nanostructured Bismuth Oxysulfide Photoelectrodes under Visible-Light Illumination. AB - Nanostructured layered bismuth oxysulfide films synthesized by chemical bath deposition reveal a giant incident photon-to-current conversion efficiency (IPCE). This study shows that surprisingly for the cathodic photocurrent in the photoreduction process, the IPCE reaches ~2500% in aqueous solutions containing [Fe(CN)6 ]3- . The giant IPCE is observed starting from a certain minimal oxidizer concentration (c > 10-3 m for [Fe(CN)6 ]3- ) and decreases nonlinearly with an increase of illumination intensity. Giant IPCE is determined by the decrease in resistivity of the bismuth oxysulfide film under illumination with photoconductivity gain, which provides the possibility of charge carriers from an external circuit to participate in the photoreduction process. Giant IPCE is observed not only in [Fe(CN)6 ]3- solutions, but also in electrolytes containing other photoelectron acceptors: Fe3+ , I3- , quinone, H2 O2 . In all, solution processed layered bismuth oxysulfide films offer large-area coverage, nontoxicity, low cost, and compatibility with a wide range of substrates. Abnormally high photoelectrochemical activity, as well as a band gap energy value favorable for efficient conversion of solar light (1.38 eV, direct optical transitions), proves the potential of bismuth oxysulfide photoelectrodes for a new generation of high-performance photoconverters. PMID- 28850737 TI - The ELPAT living organ donor Psychosocial Assessment Tool (EPAT): from 'what' to 'how' of psychosocial screening - a pilot study. AB - Thorough psychosocial screening of donor candidates is required in order to minimize potential negative consequences and to strive for optimal safety within living donation programmes. We aimed to develop an evidence-based tool to standardize the psychosocial screening process. Key concepts of psychosocial screening were used to structure our tool: motivation and decision-making, personal resources, psychopathology, social resources, ethical and legal factors and information and risk processing. We (i) discussed how each item per concept could be measured, (ii) reviewed and rated available validated tools, (iii) where necessary developed new items, (iv) assessed content validity and (v) pilot tested the new items. The resulting ELPAT living organ donor Psychosocial Assessment Tool (EPAT) consists of a selection of validated questionnaires (28 items in total), a semi-structured interview (43 questions) and a Red Flag Checklist. We outline optimal procedures and conditions for implementing this tool. The EPAT and user manual are available from the authors. Use of this tool will standardize the psychosocial screening procedure ensuring that no psychosocial issues are overlooked and ensure that comparable selection criteria are used and facilitate generation of comparable psychosocial data on living donor candidates. PMID- 28850738 TI - Gold(I) Metallo-Tweezers for the Recognition of Functionalized Polycyclic Aromatic Hydrocarbons by Combined pi-pi Stacking and H-Bonding. AB - Two gold(I)-based metallo-tweezers with bis(Au-NHC) pincers and a carbazole connector have been obtained and used for the recognition of polycyclic aromatic hydrocarbons (PAHs). In the case of the tweezer with pyrene-NHC ligands, the presence of the pyrene fragment and the N-H bond in the carbazole linker enable the receptor to show significant enhanced binding abilities toward PAHs functionalized with H-bonding groups, through combined pi-pi stacking and H bonding. PMID- 28850739 TI - Three-Dimensional Virtual Sonographic Cystoscopy for Detection of Ureterocele in Duplicated Collecting Systems in Children. AB - OBJECTIVES: Ureterocele is a sac-like dilatation of terminal ureter. Precise anatomic delineation is of utmost importance to proceed with the surgical plan, particularly in the ectopic subtype. However, the level of ureterocele extension is not always elucidated by the existing imaging modalities and even by conventional cystoscopy, which is considered as the gold standard for evaluation of ureterocele. This study aims to evaluate the accuracy of three-dimensional virtual sonographic cystoscopy (VSC) in the characterization of ureterocele in duplex collecting systems. METHODS: Sixteen children with a mean age of 5.1 (standard deviation 1.96) years with transabdominal ultrasonography-proven duplex system and ureterocele were included. They underwent VSC by a single pediatric radiologist. All of them subsequently had conventional cystoscopy, and the results were compared in terms of ureterocele features including anatomy, number, size, location, and extension. RESULTS: Three-dimensional VSC was well tolerated in all cases without any complication. Image quality was suboptimal in 2 of 16 patients. Out of the remaining 14 cases, VSC had a high accuracy in characterization of the ureterocele features (93%). Only the extension of one ureterocele was not precisely detected by VSC. CONCLUSIONS: The results of this study suggest three-dimensional sonography as a promising noninvasive diagnostic modality in the evaluation of ectopic ureterocele in children. PMID- 28850740 TI - Diagnostic Performance of Superb Microvascular Imaging and Other Sonographic Modalities in the Assessment of Lateral Epicondylosis. AB - OBJECTIVES: The aim of this study was to compare the diagnostic performance of different sonographic modalities for diagnosing lateral epicondylosis. METHODS: A total of 50 symptomatic and 50 asymptomatic common extensor tendons in 44 patients with lateral epicondylosis, and 25 healthy participants were prospectively examined by B-mode sonography, color Doppler imaging, power Doppler imaging, Superb Microvascular Imaging (SMI; Toshiba Medical Systems Corporation, Tokyo, Japan), and strain elastography. We evaluated blood flow in common extensor tendons by using a grading system with color Doppler imaging, power Doppler imaging, and SMI. The diagnostic performance of the modalities was compared. RESULTS: When a cutoff value of hypoechogenicity was used for the mean strain ratio, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy rates were 92.0%, 94%.0, 93.9%, 92.2%, and 93.0%, respectively. When a cutoff point of grade 1 was used, the sensitivity, specificity, PPV, NPV, and accuracy rates were 26.0%, 10.0%, 10.0%, 57.5%, and 63.0, for color Doppler imaging; 40.0%, 10.0%, 10.0%, 62.5%, and 70.0% for power Doppler imaging; and 84.0%, 94.0%, 93.0%, 85.5%, and 89.0% for SMI. When a cutoff value of 3.94 was used for the mean strain ratio, the sensitivity, specificity, PPV, NPV, and accuracy rates were 78.0%, 92.0%, 90.7%, 80.7%, and 85.0%, respectively. A statistically significant correlation was detected between SMI, strain elastography, and visual analog scale scores (P < .001). CONCLUSIONS: The combination of SMI and B-mode sonography was found to have excellent diagnostic performance for lateral epicondylosis. Neovascularzation in patients' tendons with lateral epicondylosis was identified much better with SMI compared to color or power Doppler imaging. PMID- 28850741 TI - Marital status and stage of cancer at diagnosis: A systematic review. AB - Early cancer detection is fundamental to the promotion of better health in the community, but disparities remain in the likelihood of cancer being detected at an early stage, some of which relate to socio-demographic factors such as marital status. The aim of this study was to conduct a systematic review of research on the association between marital status and stage at diagnosis of different types of cancer. A comprehensive systematic literature search was run in the Medline and Scopus databases (from January 1990 to June 2014), identifying 245 and 208 articles on PubMed and Scopus respectively. Of these 453 studies, 18 were judged eligible for this systematic review. A quality assessment was performed on the studies using the 22 items in the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist. This review confirmed the important influence of being married on the earlier detection of cancer. None of the studies considered identified more cases of cancer in a later stage among married patients, and the majority of them reported a statically significant association between marital status and stage at diagnosis, with a positive effect of marriage on the likelihood of cancer being diagnosed at an early stage, for various types of malignancy. In particular, our meta-analysis showed that the unmarried have higher odds of having a later stage of breast cancer (OR = 1.287 95% CI: 1.025-1.617) or melanoma (OR = 1.350 95% CI: 1.161-1.570) at diagnosis. Specific interventions should be developed for the unmarried population to improve their chances of any neoplasms being diagnosed at an early stage, thereby reducing health disparities in the population at large. PMID- 28850742 TI - Clinical Value of Contrast-Enhanced Ultrasound Enhancement Patterns for Differentiating Focal Pancreatitis From Pancreatic Carcinoma: A Comparison Study With Conventional Ultrasound. AB - OBJECTIVES: We explored the clinical value of using contrast-enhanced ultrasound (US) enhancement patterns for the differential diagnosis of focal pancreatitis from pancreatic carcinoma. METHODS: A total of 136 solid pancreatic lesions with final diagnoses from January 2010 to February 2016 were enrolled in this study. Twenty-five cases were focal pancreatitis; 86 cases were pancreatic carcinoma; and 25 cases were other types. All of the patients received conventional and contrast-enhanced US examinations. Two experienced US physicians analyzed the contrast-enhanced US enhancement patterns and made diagnoses according to the conventional and contrast-enhanced US manifestations. The inter-rater agreement for the contrast enhancement patterns between the readers was analyzed. The diagnostic efficiency of contrast enhancement patterns for differentiating focal pancreatitis from pancreatic carcinoma was analyzed and compared with that of conventional US. RESULTS: The kappa test showed good concordance for contrast enhancement patterns between the readers (P < .05). The diagnostic sensitivity, specificity, and accuracy of isoenhancement or isoenhancement with focal hypoenhancement in both the early and late phases for diagnosing focal pancreatitis were 72.0%, 95.5%, and 91.2%, respectively. The diagnostic sensitivity of isoenhancement or isoenhancement with focal hypoenhancement in both the early and late phases greatly increased for diagnosing focal pancreatitis in comparison with isoenhancement (72.0% versus 32.0%; P < .05). The diagnostic accuracy of contrast-enhanced US was greatly increased over that of conventional US (85.6% versus 49.5%; P < .001). CONCLUSIONS: Contrast-enhanced US is a valuable tool for differentiating focal pancreatitis from pancreatic carcinoma and can greatly increase the diagnostic accuracy over conventional US. PMID- 28850744 TI - Functional-Polymer Library through Post-Polymerization Modification of Copolymers Having Oleate and Pentafluorophenyl Pendants. AB - Poly[2-(methacryloyloxy)ethyl oleate-co-pentafluorophenyl methacrylate] [P(MAEO co-PFPMA)] random copolymers with oleate and pentafluorophenyl side-chain pendants were synthesized. These copolymers were utilized as dual-reactive polymeric scaffolds in a range of post-polymerization modification strategies involving thiol-ene and para-fluoro-thiol substitution, amidation, trans esterification, and epoxidation followed by amidation. The 2 (methacryloyloxy)ethyl oleate (MAEO) functional handle in the copolymer is open to functionalization at its internal double bond through thermally initiated thiol-ene reaction, whereas the pentafluorophenyl moiety of the pentafluorophenyl methacrylate (PFPMA) unit undergoes para-fluoro-thiol substitution under basic conditions at room temperature. By means of these modification approaches, the P(MAEO-co-PFPMA) copolymer was orthogonally ligated with thiol compounds having, for example, alkyl, hydroxyl, and protected amine functional groups. Furthermore, different functional groups such as benzyl, allyl, methacrylate, pyrene, and water-soluble poly(ethylene glycol) were easily introduced into the side chain of the P(MAEO-co-PFPMA) copolymer by amidation, trans-esterification, and epoxidation followed by amidation. Functionalization of both the reactive pendants with the various organic substituents was confirmed by 1 H and 19 F NMR spectroscopy, gel permeation chromatography, and fluorescence spectroscopy. PMID- 28850743 TI - Copper Guanidinoquinoline Complexes as Entatic State Models of Electron-Transfer Proteins. AB - The electron-transfer abilities of the copper guanidinoquinoline (GUAqu) complexes [Cu(TMGqu)2 ]+/2+ and [Cu(DMEGqu)2 ]+/2+ (TMGqu=tetramethylguanidinoquinoline, DMEGqu=dimethylethylguanidinoquinoline) were examined in different solvents. The determination of the electron self exchange rate based on the Marcus theory reveals the highest electron-transfer rate of copper complexes with pure N-donor ligands (k11 =1.2*104 s-1 m-1 in propionitrile). This is supported by an examination of the reorganisation energy of the complexes by using Eyring theory and DFT calculations. The low reorganisation energies in nitrile solvents correspond with the high electron transfer rates of the complexes. Therefore, the [Cu(GUAqu)2 ]+/2+ complexes act as good entatic states model of copper enzymes. The structural influence of the complexes on the kinetic parameters shows that the TMGqu system possesses a higher electron-transfer rate than DMEGqu. Supporting DFT calculations give a closer insight into the kinetics and thermodynamics (Nelsen's four-point method and isodesmic reactions) of the electron transfer. PMID- 28850745 TI - Simulating the life course of psoriasis patients: the interplay between therapy intervention and marital status. AB - BACKGROUND: Psoriasis, a chronic relapsing inflammatory disease affecting primarily the skin, shows multiple comorbidities including depression, cardiovascular diseases and other relevant conditions. Psoriasis patients experience social isolation, job loss, financial difficulties and partnership problems. Inversely, psychosocial impairments may negatively influence the disease course. OBJECTIVE: To explore the feasibility of a model describing the interaction of psychosocial and clinical factors over the life course of patients. METHODS: We considered only seven states for members of a hypothetical population: single and healthy, single and having a psoriasis flare, single and 'cured', coupled and healthy, coupled and having a psoriasis flare, coupled and 'cured', and dead. Transition probabilities between states were taken from the Norwegian Population Register for the healthy population and from epidemiological research articles. Clinical experience allowed adjustments on the assumed parameters. RESULTS: Our macromodel, which simulates the effect of therapy intervention on patients' partnership status, yields a description of the transitions between the seven states. Treatment efficacy shows only a negligible effect on the chances of living with a partner. CONCLUSIONS: Mathematical modelling of interactions between social and health variables is in principle feasible. However, complex models, comprising more variables (for instance: employment status, depression level, obesity etc.), are needed for more realistic simulations for the interactions studied. As increasing the number of variables leads to an exponential increase of the model's state space, switching to micromodelling (representing each individual separately) may be necessary. PMID- 28850746 TI - First-trimester screening for pre-eclampsia: time for reflection. PMID- 28850747 TI - Electrostatic Modification for Promotion of Flavin-Mediated Oxidation of a Probe for Flavin Detection. AB - Electrostatic effects on the redox photochemistry of synthetic probes (1, 2, and 1-Zn) are examined by adjusting the thermodynamic driving force of their oxidation reactions. The redox photochemistry was simply controlled by introducing a zinc binding site (2,2'-dipicolylamine (DPA)) on the coumarin moiety of probe 2. Zinc complexation produced a positively charged environment on the coumarin (1-Zn), which lowered the electron density of a nearby 9 H-xanthene ring, attenuating the auto-oxidation of 1-Zn by 45 % compared with that of probe 1 at 298 K. The positive net charge of 1-Zn also provided an attractive Coulombic force toward the phosphate of flavin mononucleotide and flavin adenine dinucleotide, which lowered the reduction potential of the electron acceptor (isoalloxazine) and improved intermolecular electron transfer from the 9 H xanthene ring to isoalloxazine. The flavin-mediated oxidation rate of 1-Zn was increased to 1.5 times that of probe 2. Probe 1-Zn showed highly selective sensing behaviour toward flavins, producing an intense brightness (epsilonPhiF =2.80*103 m-1 cm-1 ) in the long-wavelength regions (lambdamax =588 nm) upon flavin-mediated oxidation. Furthermore, probes 1-Zn and 2 were successfully applied to eosinophil imaging and the differential diagnosis of eosinophilia; this demonstrates their use as diagnostic tools. PMID- 28850749 TI - Evaluation of a Novel Out-of-Plane Needle Guide. AB - OBJECTIVES: Most ultrasound-guided regional procedures use an in-plane approach. Out-of-plane approaches may be desirable in some situations but can be difficult because of an inability to visualize the needle until it intersects the plane of the ultrasonic beam. Here we present a novel out-of-plane needle guide, using a retreating depth stop, and compare its performance with unguided in-plane and out of-plane techniques. METHODS: First- and third-year medical students with no or minimal ultrasound experience were recruited for the study. After a brief training session on in-plane and out-of-plane needling techniques, as well as use of the retreating-stop needle guide, they attempted to place a needle as close as possible to a target embedded in porcine tissue. The total time to complete the procedure was measured. Accuracy was measured by a skilled sonographer, who identified the needle tip and measured the distance to the target. The data were tested for significance using an analysis of variance. RESULTS: The mean total time spent differed significantly between groups (novel needle guide, 34 seconds; in-plane, 120 seconds; out-of-plane, 113 seconds; P = .021). Needle proximity was on average more accurate with the needle guide, although this difference was not statistically significant (novel needle guide, 8 mm; in-plane, 15 mm; out-of plane, 14 mm; P = .289). CONCLUSIONS: In relatively inexperienced sonographers, the retreating-stop needle guide reduced the procedure time compared with in plane and out-of-plane techniques. No significant changes in needling accuracy were observed. PMID- 28850748 TI - Sequence analysis of ABO and its homologues is valid for species identification. AB - BACKGROUND: ABO and its paralogues, such as A3GALT2 and GGTA1, encoding alpha1,3 Gal(NAc) transferases, belong to the glycosyltransferase 6 (GT6) gene family. We have developed an alternative method for the identification of species based on sequence variations within the GT6 gene family, which is applicable to degraded DNA. METHODS/MATERIALS: DNA samples prepared from control mammalian species, together with an unknown sample, were polymerase chain reaction (PCR)-amplified using one universal primer pair targeting the sequences in the last coding exons of the GT6 gene family, yielding 141-bp products derived from those multiple loci. After cloning, sequence determination and Basic Local Alignment Search Tool analysis, phylogenetic trees were constructed. RESULTS: Comparison of the sequences obtained with those references showed good concordance with each of the starting species of mammals. This system was able to identify 'mouse' or 'rodent' as the origin of the unknown sample. CONCLUSION: For the identification of species, genotyping of ABO and its homologues would be applicable for the analysis of degraded DNA samples. Although the method employed in this study is likely valid for mammals, it would not be suitable for birds, fish and reptiles. It may be possible to improve the present method for use with other species by employing an alternative universal primer set. PMID- 28850750 TI - Nail apparatus melanoma: dermoscopic and histopathologic correlations on a series of 23 patients from a single centre. AB - BACKGROUND: Nail apparatus melanoma (NAM) is an uncommon tumour, and there are few studies focused on its dermoscopic features. OBJECTIVE: The aims of our study were to evaluate the diagnostic accuracy of dermoscopy in NAM. A diagnostic algorithm for adult patients with suspected NAM is proposed. METHODS: We collected NAM dermoscopic images of patients with a proven histopathology from 2008 until 2015. Clinical and dermoscopic images were blindly examined by two dermatologists, and correlations between histopathological aspects and dermoscopic features were investigated. RESULTS: We retrospectively collected NAM dermoscopic images associated with a proven histopathology of 23 Caucasian patients. Only cases with available both preoperative dermoscopic images and bioptic specimens were included. Seventeen women and six men were included. The mean age at diagnosis was 63 years (range 18-92). CONCLUSION: We created an algorithm to indicate the correct way to follow an adult patient with suspected NAM. This algorithm may ameliorate management in case of suspected NAM and possibly facilitate an early diagnosis. PMID- 28850751 TI - Rational Design of Rod-Like Liquid Crystals Exhibiting Two Nematic Phases. AB - Recently, a polar, rod-like liquid-crystalline material was reported to exhibit two distinct nematic mesophases (termed N and NX ) separated by a weakly first order transition. Herein, we present our initial studies into the structure property relationships that underpin the occurrence of the lower-temperature nematic phase, and report several new materials that exhibit this same transformation. We have prepared material with significantly enhanced temperature ranges, allowing us to perform a detailed study of both the upper- and lower temperature nematic phases by using small-angle X-ray scattering. We observed a continuous change in d spacing rather than a sharp change at the phase transition, a result consistent with a transition between two nematic phases, structures of which are presumably degenerate. PMID- 28850752 TI - Optimization of Rate Capability and Cyclability Performance in Li3 VO4 Anode Material through Ca Doping. AB - A series of Ca-doped lithium vanadates Li3-x Cax VO4 (x=0, 0.01, 0.03, and 0.05) are synthesized successfully through a simple sol-gel method. XRD patterns and energy-dispersive X-ray spectroscopy (EDS) mappings reveal that the doped Ca2+ ions enter into the lattice successfully and are distributed uniformly throughout the Li3 VO4 (LVO) grains. XRD spectra and SEM images show that Ca doping can lead to an enlarged lattice and refined Li3 VO4 particles. A small quantity of V ions will transfer from V5+ to V4+ in the Ca-doped samples, as demonstrated by the X ray photoelectron spectroscopy (XPS) analysis, which leads to an increase of an order of magnitude in the electronic conductivity. Improved rate capability and cycling stability are observed for the Ca-doped samples, and Li2.97 Ca0.03 VO4 exhibits the best electrochemical performance among the studied materials. The initial charge/discharge capacities at 0.1 C increase from 480/645 to 527/702 mA h g-1 as x varies from 0 to 0.03. The charge capacity of Li2.97 Ca0.03 VO4 at 1 C retains 95.3 % of its initial value after 180 cycles, whereas the capacity retention is only 40 % for the pristine sample. Moreover, Li2.97 Ca0.03 VO4 maintains a high discharge capacity of 301.7 mA h g-1 at a high discharge rate (4 C), whereas the corresponding value is only 95.2 mA h g-1 for the pristine LVO sample. The enhanced cycling and rate performances are ascribed to the increased lithium ion diffusivity and electrical conductivity induced by Ca doping. PMID- 28850753 TI - Predictive performance of PAMG-1 vs fFN test for risk of spontaneous preterm birth in symptomatic women attending an emergency obstetric unit: retrospective cohort study. AB - OBJECTIVE: To compare the performance of the placental alpha microglobulin-1 (PAMG-1) and fetal fibronectin (fFN) tests for the prediction of spontaneous preterm delivery in patients presenting to an emergency obstetric unit with threatened preterm labor, by conducting a retrospective audit of patient medical records from separate 1-year periods during which either fFN or PAMG-1 was used as the standard-of-care biochemical test. METHODS: This was a retrospective cohort study based on chart review of electronic medical records of women with threatened preterm labor presenting at a level-III maternity hospital over two different periods: (1) the 'baseline' period (year 2012), during which the qualitative fFN test with a cut-off of 50 ng/mL was used as the standard-of-care biochemical test for the risk assessment of preterm delivery, and (2) the 'comparative' period (year 2016), during which the PAMG-1 test with a cut-off of 1 ng/mL was used as the standard-of-care biomarker test. Patients with a singleton pregnancy between 24 + 0 and 34 + 6 weeks' gestation with symptoms of early preterm labor, clinically intact membranes and cervical dilatation < 3 cm, who did not have a medically indicated preterm delivery within 14 days of testing, were selected for chart review and included in the analysis. Key parameters used for the analysis were biochemical test results, time of testing and time of delivery. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, and positive and negative likelihood ratios (LR+ and LR-) for the prediction of spontaneous preterm delivery <= 7 and <= 14 days of presentation were calculated for the PAMG-1 and fFN tests. RESULTS: Four hundred and twenty patients were identified as having presented with threatened preterm labor during the baseline period, of whom 378 (90.0%) met the eligibility criteria. Of these, 38 (10.1%) were fFN positive and 10 (2.6%) had spontaneous preterm delivery <= 7 days of presentation. PPV, NPV, LR+ and LR- of fFN were 7.9%, 97.9%, 3.2 and 0.8, respectively, for spontaneous preterm delivery <= 7 days. Four hundred and ten patients were identified as having presented with threatened preterm labor during the comparative period and 367 (89.5%) subjects met the eligibility criteria. Of these, 17 (4.6%) were PAMG-1 positive and 12 (3.3%) had spontaneous preterm delivery <= 7 days of presentation. PAMG-1 PPV and NPV were 35.3% and 98.3%, respectively, and LR+ and LR- were 16.1 and 0.5, respectively, for spontaneous preterm delivery <= 7 days. CONCLUSIONS: Before switching to PAMG-1, fFN was the standard-of-care test for the risk assessment of spontaneous preterm delivery. This retrospective audit of each test's performance over separate 1-year periods shows that we were more than twice as likely to get a positive fFN test than a positive PAMG-1 test, while the rate of discharging women who ultimately delivered spontaneously within 14 days of testing was not affected. Furthermore, a positive PAMG-1 test was more than four times more reliable than a positive fFN test in predicting imminent spontaneous preterm delivery. The use of a more reliable biomarker that is associated with fewer false-positive results could lead to a reduction in unnecessary admissions, interventions and use of hospital resources. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28850754 TI - Verbal memory in breast cancer patients treated with chemotherapy with doxorubicin and cyclophosphamide. AB - Memory is one of the crucial human cognitive functions, and deficits in memory processes may lead to difficulties in everyday functioning. The aim of this study was to analyse the effect of anthracycline-based adjuvant chemotherapy (AC) used in breast cancer treatment on verbal memory and learning. We also evaluated the relationship between verbal memory and psychological, somatic and socio demographic factors. The study was carried out on a group of 31 women with early breast cancer treated with adjuvant chemotherapy and 30 healthy controls. The patients underwent neuropsychological assessment using the Rey Auditory Verbal Learning Test at three time points: before chemotherapy, mid-chemotherapy and post-chemotherapy. The examination in the controls was conducted at the same time intervals. We found an association between AC-schema chemotherapy and deficits in delayed memory. A deterioration in performance after treatment was observed in 19% of patients. The results showed no deterioration of immediate memory or the verbal learning process. Moreover, a positive relationship was shown between the level of education, physical fitness and the functioning of verbal memory. The results of the study also indicate that age and hormonal status are factors that may increase the possibility of deficits in verbal memory after AC-schema chemotherapy. PMID- 28850755 TI - Continuous flow reduced-pressure infrared laser desorption/ionization mass spectrometry. AB - RATIONALE: Continuous flow ionization methods using infrared (IR) lasers have several favorable characteristics, including ionization without any additional matrices and tolerance to contaminants such as detergents and buffer salts. However, poor sensitivity due to low ion-transfer efficiency from the sample plate to the inlet capillary of the mass spectrometer under atmospheric pressure remains a serious problem. METHODS: We developed a new continuous flow IR laser desorption/ionization (IR-LDI) method using a frit plate and wavelength-tunable mid-IR laser with an optical parametric oscillator. Continuous flow samples were directly injected into the ion source without any additional matrices. The ion source was covered with a decompression chamber, and could vary the pressure of the ion source from 21 to 101 kPa. RESULTS: Reduction of the pressure of the IR LDI source from 101 to 71 kPa increased the signal intensity for the [M + H]+ ion of angiotensin II by 1.8-fold. On the other hand, the ion signal intensity was reduced at pressures lower than 71 kPa. It became clear that reducing pressure was more effective when ionization occurred with lower laser pulse energy and lower ion source temperature. In addition, signal intensities for the [M + 2H]2+ and [M + 3H]3+ ions of insulin were also increased, by 1.4-fold and 1.1-fold, respectively, upon reduction of the pressure to 91 and 81 kPa. CONCLUSIONS: Although many studies have described IR-LDI using a differential pumping mass spectrometer, the optimal pressure of the ion source has never been investigated. We found that a slight reduction in pressure enhances sensitivity. This knowledge may be applicable to a number of ambient ionization methods using IR lasers. PMID- 28850756 TI - Porphobilinogen deaminase HEMC interacts with the PPR-protein AtECB2 for chloroplast RNA editing. AB - The pentatricopeptide repeat-DYW protein AtECB2 affects plastid RNA editing at seven sites, including accD-794, accD-1568, ndhF-290, ndhG-50, petL-5, rpoA-200 and rpoC1-488. To understand the mechanism of its involvement in RNA editing, a transgenic line was constructed with AtECB2 fused to a 4xMYC tag that could complement the atecb2 phenotype. RNA immunoprecipitation analysis indicated that AtECB2 is associated with the transcripts of accD, ndhF, ndhG and petL. Co immunoprecipitation and mass spectrometry experiments showed that multiple organelle RNA editing factor 2 (MORF2) and porphobilinogen deaminase HEMC are associated with AtECB2. Biochemical analysis showed that AtECB2 directly interacts with HEMC through its E domain, while HEMC interacts with MORF8/RIP1. Deletion analysis showed that the E domain is essential for RNA editing. The hemc 1 mutant showed an albino and seedling-lethal phenotype. Of the seven editing sites affected in atecb2, the editing of accD-794 and ndhF-290 was also reduced in hemc-1. RNA immunoprecipitation analysis suggested that HEMC is associated with the editing sites of ndhF transcripts. These results showed that both HEMC and multiple organellar RNA editing factor (MORF) proteins are associated with AtECB2 for RNA editing in plastids. PMID- 28850757 TI - Mechanistic Study on Nickel-Catalyzed Silylation of Aryl Methyl Ethers. AB - The mechanism of the nickel-catalyzed silylation of aryl methyl ethers has been systematically investigated by using DFT methods. This theoretical study supports a catalytic cycle that involves the formation of a nickel-silyl complex, C-O bond cleavage, C-Si reductive elimination, the addition of methoxide to boron, and finally regeneration of the catalyst. Notably, it was found that activation of the C-O bond proceeded through an oxidative addition pathway with a three centered transition state. The silyl anion generated in situ works as a ligand to the nickel center and promotes this process. Meanwhile, the role of the base added (KOtBu) is also elucidated. The potassium cation helps to stabilize the oxidative addition transition state through noncovalent interactions, while the resting state is destabilized due to steric repulsion introduced by the tert butoxide anion. This is further confirmed by a comparison made computationally between the reaction with KOtBu and that with KOMe or NaOtBu as the base. PMID- 28850758 TI - Ultrasound-based three-dimensional printed medical model for multispecialty team surgical rehearsal prior to fetoscopic myelomeningocele repair. PMID- 28850759 TI - Leap frog in slow motion: Divergent responses of tree species and life stages to climatic warming in Great Basin subalpine forests. AB - In response to climate warming, subalpine treelines are expected to move up in elevation since treelines are generally controlled by growing season temperature. Where treeline is advancing, dispersal differences and early life stage environmental tolerances are likely to affect how species expand their ranges. Species with an establishment advantage will colonize newly available habitat first, potentially excluding species that have slower establishment rates. Using a network of plots across five mountain ranges, we described patterns of upslope elevational range shift for the two dominant Great Basin subalpine species, limber pine and Great Basin bristlecone pine. We found that the Great Basin treeline for these species is expanding upslope with a mean vertical elevation shift of 19.1 m since 1950, which is lower than what we might expect based on temperature increases alone. The largest advances were on limber pine-dominated granitic soils, on west aspects, and at lower latitudes. Bristlecone pine juveniles establishing above treeline share some environmental associations with bristlecone adults. Limber pine above-treeline juveniles, in contrast, are prevalent across environmental conditions and share few environmental associations with limber pine adults. Strikingly, limber pine is establishing above treeline throughout the region without regard to site characteristic such as soil type, slope, aspect, or soil texture. Although limber pine is often rare at treeline where it coexists with bristlecone pine, limber pine juveniles dominate above treeline even on calcareous soils that are core bristlecone pine habitat. Limber pine is successfully "leap-frogging" over bristlecone pine, probably because of its strong dispersal advantage and broader tolerances for establishment. This early-stage dominance indicates the potential for the species composition of treeline to change in response to climate change. More broadly, it shows how species differences in dispersal and establishment may result in future communities with very different specific composition. PMID- 28850761 TI - Zebrafish sin3b mutants are viable but have size, skeletal, and locomotor defects. AB - BACKGROUND: The transcriptional co-repressor Sin3 is highly conserved from yeast to vertebrates and has multiple roles controlling cell fate, cell cycle progression, and senescence programming. Sin3 proteins recruit histone deacetylases and other chromatin modifying factors to specific loci through interactions with transcription factors including Myc, Rest, p53 and E2F. Most vertebrates have two Sin3 family members (sin3a and sin3b), but zebrafish have a second sin3a paralogue. In mice, sin3a and sin3b are essential for embryonic development. Sin3b knockout mice show defects in growth as well as bone and blood differentiation. RESULTS: To study the requirement for Sin3b during development, we disrupted zebrafish sin3b using CRISPR-Cas9, and studied the effects on early development and locomotor behavior. CONCLUSIONS: Surprisingly, Sin3b is not essential in zebrafish. sin3b mutants show a decrease in fitness, small size, changes to locomotor behavior, and delayed bone development. We did not detect a role for Sin3b in cell proliferation. Our analysis of the sin3b mutant revealed a more nuanced requirement for zebrafish Sin3b than would be predicted from analysis of mutants in other species. Developmental Dynamics 246:946-955, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28850760 TI - MicroRNA-induced silencing in epilepsy: Opportunities and challenges for clinical application. AB - MicroRNAs are master regulators of gene expression. Single microRNAs influence multiple proteins within diverse molecular pathways and networks. Therefore, changes in levels or activity of microRNAs can have profound effects on cellular function. This makes dysregulated microRNA-induced silencing an attractive potential disease mechanism in complex disorders like epilepsy, where numerous cellular pathways and processes are affected simultaneously. Indeed, several years of research in rodent models have provided strong evidence that acute or recurrent seizures change microRNA expression and function. Moreover, altered microRNA expression has been observed in brain and blood from patients with various epilepsy disorders, such as tuberous sclerosis. MicroRNAs can be easily manipulated using sense or antisense oligonucleotides, opening up opportunities for therapeutic intervention. Here, we summarize studies using these techniques to identify microRNAs that modulate seizure susceptibility, describe protein targets mediating some of these effects, and discuss cellular pathways, for example neuroinflammation, that are controlled by epilepsy-associated microRNAs. We critically assess current gaps in knowledge regarding target- and cell specificity of microRNAs that have to be addressed before clinical application as therapeutic targets or biomarkers. The recent progress in understanding microRNA function in epilepsy has generated strong momentum to encourage in-depth mechanistic studies to develop microRNA-targeted therapies. Developmental Dynamics 247:94-110, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28850763 TI - Understanding tamoxifen adherence in women with breast cancer: A qualitative study. AB - OBJECTIVE: Non-adherence to tamoxifen is common in breast cancer survivors and is associated with poor clinical outcomes. This study aimed to understand womens' experiences of taking tamoxifen and to identify factors which may be associated with non-adherence. DESIGN: A qualitative study using semi-structured interviews. METHODS: Thirty-two breast cancer survivors who had been prescribed tamoxifen took part in interviews conducted face to face or over the telephone. They were transcribed verbatim and analysed using inductive thematic analysis with elements of grounded theory. RESULTS: A key theme identified in the data was weighing up costs and benefits of treatment, which resulted in women falling into three groups; tamoxifen is keeping me alive, tamoxifen is not worth the reduced risk of recurrence, or conflicting beliefs about the harms and benefits of treatment. Additional themes were living with risk of recurrence and information & support. CONCLUSIONS: Women who believed that the necessity of tamoxifen outweighed its costs were more likely to be adherent, whereas women who thought that the benefits did not outweigh the side effects were more likely to have discontinued. A third more ambivalent group believed strongly in the importance of treatment, but were struggling with side effects and were often non-adherent. Patients sometimes felt unsupported and discussed a need for more comprehensive information. To increase adherence, future research needs to explore ways to increase beliefs around tamoxifen necessity and how to help women cope with side effects. Statement of contribution What is already known on this subject? Non adherence to tamoxifen is associated with increased risk of recurrence and mortality. Up to 50% of patients are non-adherent to tamoxifen by the fifth year of treatment Few consistent predictors of tamoxifen non-adherence have been identified. What does this study add? Many women report not knowing how to manage their side effects. Non-adherence is related to how women weigh up their side effects against their medication beliefs. Interventions aiming to increase necessity beliefs and improve symptom management may be effective. PMID- 28850764 TI - Spatial distributions of Southern Ocean mesozooplankton communities have been resilient to long-term surface warming. AB - The biogeographic response of oceanic planktonic communities to climatic change has a large influence on the future stability of marine food webs and the functioning of global biogeochemical cycles. Temperature plays a pivotal role in determining the distribution of these communities and ocean warming has the potential to cause major distributional shifts, particularly in polar regions where the thermal envelope is narrow. We considered the impact of long-term ocean warming on the spatial distribution of Southern Ocean mesozooplankton communities through examining plankton abundance in relation to sea surface temperature between two distinct periods, separated by around 60 years. Analyses considered 16 dominant mesozooplankton taxa (in terms of biomass and abundance) in the southwest Atlantic sector of the Southern Ocean, from net samples and in situ temperature records collected during the Discovery Investigations (1926-1938) and contemporary campaigns (1996-2013). Sea surface temperature was found to have increased significantly by 0.74 degrees C between the two eras. The corresponding sea surface temperature at which community abundance peaked was also significantly higher in contemporary times, by 0.98 degrees C. Spatial projections indicated that the geographical location of community peak abundance had remained the same between the two eras despite the poleward advance of sea surface isotherms. If the community had remained within the same thermal envelope as in the 1920s-1930s, community peak abundance would be 500 km further south in the contemporary era. Studies in the northern hemisphere have found that dominant taxa, such as calanoid copepods, have conserved their thermal niches and tracked surface isotherms polewards. The fact that this has not occurred in the Southern Ocean suggests that other selective pressures, particularly food availability and the properties of underlying water masses, place greater constraints on spatial distributions in this region. It further demonstrates that this community is thermally resilient to present levels of sea surface warming. PMID- 28850762 TI - Effectiveness of bereavement counselling through a community-based organization: A naturalistic, controlled trial. AB - This controlled, longitudinal investigation tested the effectiveness of a bereavement counselling model for adults on reducing complicated grief (CG) symptoms. Participants (N = 344; 79% female; mean age: 49.3 years) were adult residents of Scotland who were bereaved of a close relation or partner, experiencing elevated levels of CG, and/or risks of developing CG. It was hypothesized that participants who received intervention would experience a greater decline in CG levels immediately following the intervention compared to the control participants, but the difference would diminish at follow-up (due to relapse). Data were collected via postal questionnaire at 3 time points: baseline (T), post-intervention (T + 12 months), and follow-up (T + 18 months). CG, post traumatic stress, and general psychological distress were assessed at all time points. Multilevel analyses controlling for relevant covariates were conducted to examine group differences in symptom levels over time. A stepwise, serial gatekeeping procedure was used to correct for multiple hypothesis testing. A main finding was that, contrary to expectations, counselling intervention and control group participants experienced a similar reduction in CG symptoms at postmeasure. However, intervention participants demonstrated a greater reduction in symptom levels at follow-up (M = 53.64; d = .33) compared to the control group (M = 62.00). Results suggest community-based bereavement counselling may have long term beneficial effects. Further longitudinal treatment effect investigations with extensive study intervals are needed. PMID- 28850765 TI - Ocean acidification alters zooplankton communities and increases top-down pressure of a cubozoan predator. AB - The composition of local ecological communities is determined by the members of the regional community that are able to survive the abiotic and biotic conditions of a local ecosystem. Anthropogenic activities since the industrial revolution have increased atmospheric CO2 concentrations, which have in turn decreased ocean pH and altered carbonate ion concentrations: so called ocean acidification (OA). Single-species experiments have shown how OA can dramatically affect zooplankton development, physiology and skeletal mineralization status, potentially reducing their defensive function and altering their predatory and antipredatory behaviors. This means that increased OA may indirectly alter the biotic conditions by modifying trophic interactions. We investigated how OA affects the impact of a cubozoan predator on their zooplankton prey, predominantly Copepoda, Pleocyemata, Dendrobranchiata, and Amphipoda. Experimental conditions were set at either current (pCO2 370 MUatm) or end-of-the-century OA (pCO2 1,100 MUatm) scenarios, crossed in an orthogonal experimental design with the presence/absence of the cubozoan predator Carybdea rastoni. The combined effects of exposure to OA and predation by C. rastoni caused greater shifts in community structure, and greater reductions in the abundance of key taxa than would be predicted from combining the effect of each stressor in isolation. Specifically, we show that in the combined presence of OA and a cubozoan predator, populations of the most abundant member of the zooplankton community (calanoid copepods) were reduced 27% more than it would be predicted based on the effects of these stressors in isolation, suggesting that OA increases the susceptibility of plankton to predation. Our results indicate that the ecological consequences of OA may be greater than predicted from single-species experiments, and highlight the need to understand future marine global change from a community perspective. PMID- 28850766 TI - Long-term ecological changes in marine mammals driven by recent warming in northwestern Alaska. AB - Carbon and nitrogen isotopes analyses were performed on marine mammal bone collagen from three archaeological sites (ad 1170-1813) on Cape Espenberg (Kotzebue Sound, northwestern Alaska) as well as modern animals harvested from the same area to examine long-term trends in foraging ecology and sea ice productivity. We observed significant and dramatic changes in ringed seal stable isotope values between the early 19th and early 21st centuries, likely due to changing sea ice productivity and reduced delivery of organic matter to the benthos driven by recent warming in the Arctic. These data highlight the importance of the archaeological record for providing a long-term perspective on environmental variation and interpreting recent changes driven by anthropogenic processes. PMID- 28850767 TI - Recent controversies about MDR and XDR-TB: Global implementation of the WHO shorter MDR-TB regimen and bedaquiline for all with MDR-TB? AB - Tuberculosis (TB) is now the biggest infectious disease killer worldwide. Although the estimated incidence of TB has marginally declined over several years, it is out of control in some regions including in Africa. The advent of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) threatens to further destabilize control in several regions of the world. Drug resistant TB constitutes a significant threat because it underpins almost 25% of global TB mortality, is associated with high morbidity, is a threat to healthcare workers and is unsustainably costly to treat. The advent of highly resistant TB with emerging bacillary resistance to newer drugs has raised further concern. Encouragingly, in addition to preventative strategies, several interventions have recently been introduced to curb the drug-resistant TB epidemic, including newer molecular diagnostic tools, new (bedaquiline and delamanid) and repurposed (linezolid and clofazimine) drugs and shorter and individualized treatment regimens. However, there are several controversies that surround the use of new drugs and regimens, including whether, how and to what extent they should be used, and who specifically should be treated so that outcomes are optimally improved without amplifying the burden of drug resistance, and other potential drawbacks, thus sustaining effectiveness of the new drugs. The equipoise surrounding these controversies is discussed and some recommendations are provided. PMID- 28850768 TI - Annual killifish adaptations to ephemeral environments: Diapause i in two austrolebias species. AB - BACKGROUND: Many organisms are able to survive in extreme environments by entering a state of dormancy. In dormancy, vital activities are reduced until environmental conditions are compatible with active life. Annual killifishes show a special developmental pattern characterized by a phase of dispersion reaggregation of the blastomeres that separates epiboly from organogenesis, and the capability to enter dormancy in diapause. High tolerance to environmental stress confers annual killifish embryos the condition of extremophiles. At present, the questions of our research group are focused on the understanding of the mechanisms involved in diapause regulation through an interdisciplinary approach. As a first step, it is necessary to characterize diapauses at morphological and physiological levels and to evaluate induction cues under laboratory conditions. In this context, we characterized diapause I in two Austrolebias species. RESULTS: Our experimental approach to induce diapause I was successful and revealed the co-existence of two diapause I phenotypes named A and B instead of one. These phenotypes showed a tendency for lower total extractable RNA content compared with active developmental stages (80-100% epiboly and early reaggregate). CONCLUSIONS: These phenotypes are alternative diapause I stages and may have ecological relevance because both were found in embryos in natural ponds. Developmental Dynamics 246:848-857, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28850769 TI - Expression of genes and proteins of the pax-six-eya-dach network in the metamorphic sea urchin: Insights into development of the enigmatic echinoderm body plan and sensory structures. AB - BACKGROUND: Photoreception-associated genes of the Pax-Six-Eya-Dach network (PSEDN) are deployed for many roles in addition to photoreception development. In this first study of PSEDN genes during development of the pentameral body in sea urchins, we investigated their spatial expression in Heliocidaris erythrogramma. RESULTS: Expression of PSEDN genes in the hydrocoele of early (Dach, Eya, Six1/2) and/or late (Pax6, Six3/6) larvae, and the five hydrocoele lobes, the first morphological expression of pentamery, supports a role in body plan development. Pax6, Six1/2, and Six3/6 were localized to the primary and/or secondary podia and putative sensory/neuronal cells. Six1/2 and Six3/6 were expressed in the neuropil region in the terminal disc of the podia. Dach was localized to spines. Sequential up-regulation of gene expression as new podia and spines formed was evident. Rhabdomeric opsin and pax6 protein were localized to cells in the primary podia and spines. CONCLUSIONS: Our results support roles for PSEDN genes in development of the pentameral body plan, contributing to our understanding of how the most unusual body plan in the Bilateria may have evolved. Development of sensory cells within the Pax-Six expression field is consistent with the role of these genes in sensory cell development in diverse species. Developmental Dynamics 247:239-249, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28850770 TI - Molecular insights into Abeta42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study. AB - The aggregation of amyloid beta-peptide (Abeta42 ) into toxic oligomers, fibrils, has been identified as a key process in Alzheimer's disease (AD) progression. The role of halogen-substituted compounds have been highlighted in the disassembly of Abeta protofibril. However, the underlying inhibitory mechanism of Abeta42 protofibril destabilization remains elusive. In this regard, a combined molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of a fluorinated compound, D744, which has been reported previously for potential in vitro and in vivo inhibitory activity against Abeta42 aggregation and reduction in the Abeta-induced cytotoxicity. The molecular docking analysis highlights that D744 binds and interacts with chain A of the protofibril structure with hydrophobic contacts and orthogonal multipolar interaction. MD simulations reveal destabilization of the protofibril structure in the presence of D744 due to the decrease in beta-sheet content and a concomitant increase of coil and bend structures, increase in the interchain D23 K28 salt bridge distance, decrease in the number of backbone hydrogen bonds, increase in the average distance between Calpha atoms, and decrease in the binding affinity between chains A and B of the protofibril structure. The binding free-energy analysis between D744 and the protofibril structure with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) reveal that residues Leu17, Val18, Phe19, Phe20, Ala21, Glu22, Asp23, Leu34, Val36, Gly37, and Gly38 of chain A of the protofibril structure contribute maximum towards binding free energy (DeltaGbinding = -44.87 kcal/mol). The insights into the underlying inhibitory mechanism of small molecules that show potential in vitro anti-aggregation activity against Abeta42 will be beneficial for the current and future AD therapeutic studies. PMID- 28850771 TI - A functional U-statistic method for association analysis of sequencing data. AB - Although sequencing studies hold great promise for uncovering novel variants predisposing to human diseases, the high dimensionality of the sequencing data brings tremendous challenges to data analysis. Moreover, for many complex diseases (e.g., psychiatric disorders) multiple related phenotypes are collected. These phenotypes can be different measurements of an underlying disease, or measurements characterizing multiple related diseases for studying common genetic mechanism. Although jointly analyzing these phenotypes could potentially increase the power of identifying disease-associated genes, the different types of phenotypes pose challenges for association analysis. To address these challenges, we propose a nonparametric method, functional U-statistic method (FU), for multivariate analysis of sequencing data. It first constructs smooth functions from individuals' sequencing data, and then tests the association of these functions with multiple phenotypes by using a U-statistic. The method provides a general framework for analyzing various types of phenotypes (e.g., binary and continuous phenotypes) with unknown distributions. Fitting the genetic variants within a gene using a smoothing function also allows us to capture complexities of gene structure (e.g., linkage disequilibrium, LD), which could potentially increase the power of association analysis. Through simulations, we compared our method to the multivariate outcome score test (MOST), and found that our test attained better performance than MOST. In a real data application, we apply our method to the sequencing data from Minnesota Twin Study (MTS) and found potential associations of several nicotine receptor subunit (CHRN) genes, including CHRNB3, associated with nicotine dependence and/or alcohol dependence. PMID- 28850772 TI - Mesenchymal stromal cell engagement in cancer cell epithelial to mesenchymal transition. AB - Due to coexistence of stromal and epithelial tumor cells, their dynamic interactions have been widely recognized as significant cellular components to the tumor tissue integrity. Initiation and outcome of epithelial to mesenchymal transition (EMT) in tumor cells are dependent on their interaction with adjacent or recruited mesenchymal stromal cells (MSCs). A plethora of mechanisms are involved in MSCs-controlled employment of the developmental processes of EMT that contribute to loss of epithelial cell phenotype and acquisition of stemness, invasiveness and chemoresistance of tumor cells. Interplay of MSCs with tumor cells, including interchange of soluble biomolecules, plasma membrane structures, cytoplasmic content, and organelles, is established through cell-cell contact and/or by means of paracrine signaling. The main focus of this review is to summarize knowledge about involvement of MSCs in cancer cell EMT. Understanding the underlying cellular and molecular mechanism involved in the interplay between MSCs and cancer EMT is essential for development of effective therapy approaches, which in combination with current treatments may improve the control of tumor progression. Developmental Dynamics 247:359-367, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28850773 TI - A synthetic biology approach for consistent production of plant-made recombinant polyclonal antibodies against snake venom toxins. AB - Antivenoms developed from the plasma of hyperimmunized animals are the only effective treatment available against snakebite envenomation but shortage of supply contributes to the high morbidity and mortality toll of this tropical disease. We describe a synthetic biology approach to affordable and cost effective antivenom production based on plant-made recombinant polyclonal antibodies (termed pluribodies). The strategy takes advantage of virus superinfection exclusion to induce the formation of somatic expression mosaics in agroinfiltrated plants, which enables the expression of complex antibody repertoires in a highly reproducible manner. Pluribodies developed using toxin binding genetic information captured from peripheral blood lymphocytes of hyperimmunized camels recapitulated the overall binding activity of the immune response. Furthermore, an improved plant-made antivenom (plantivenom) was formulated using an in vitro selected pluribody against Bothrops asper snake venom toxins and has been shown to neutralize a wide range of toxin activities and provide protection against lethal venom doses in mice. PMID- 28850774 TI - Area-Selective Atomic Layer Deposition of SiO2 Using Acetylacetone as a Chemoselective Inhibitor in an ABC-Type Cycle. AB - Area-selective atomic layer deposition (ALD) is rapidly gaining interest because of its potential application in self-aligned fabrication schemes for next generation nanoelectronics. Here, we introduce an approach for area-selective ALD that relies on the use of chemoselective inhibitor molecules in a three-step (ABC type) ALD cycle. A process for area-selective ALD of SiO2 was developed comprising acetylacetone inhibitor (step A), bis(diethylamino)silane precursor (step B), and O2 plasma reactant (step C) pulses. Our results show that this process allows for selective deposition of SiO2 on GeO2, SiNx, SiO2, and WO3, in the presence of Al2O3, TiO2, and HfO2 surfaces. In situ Fourier transform infrared spectroscopy experiments and density functional theory calculations underline that the selectivity of the approach stems from the chemoselective adsorption of the inhibitor. The selectivity between different oxide starting surfaces and the compatibility with plasma-assisted or ozone-based ALD are distinct features of this approach. Furthermore, the approach offers the opportunity of tuning the substrate-selectivity by proper selection of inhibitor molecules. PMID- 28850775 TI - Calcium-Triggered Pulsatile Delivery of Parathyroid Hormone from Microbeads for Osteoporosis Treatment. AB - Recombinant human parathyroid hormone 1-34 (rhPTH 1-34) is the most potent anabolic drug recommended for patients with osteoporosis who do not respond to conventional treatment. However, subcutaneous intermittent injection is the only effective regimen due to its unusual action of mechanism. This regimen is inconvenient and is a big hurdle in clinical applications. In this study, we designed polyelectrolyte microbeads that can deliver rhPTH 1-34 in response to Ca2+ concentration, which indicates the osteoporotic status. Dextran photopolymer was synthesized, mixed with anionic monoacrylate, and photopolymerized by passing through capillary microfluidics to obtain the microbeads. The anionic property of microbeads was confirmed by toluidine blue staining. One microbead, loaded with a 1 day dose of rhPTH 1-34 (23.4 +/- 0.9 MUg), released rhPTH 1-34 in a triggered manner following the addition of Ca2+ ion. In vitro cell study demonstrated that rhPTH 1-34 released in a pulsatile manner from the microbeads induced osteogenic markers (ALP, RUNX2, and OPN) and precipitated mineral disposition more effectively. PMID- 28850776 TI - Reverse Microemulsion Synthesis of Sulfur/Graphene Composite for Lithium/Sulfur Batteries. AB - Due to its high theoretical capacity, high energy density, and easy availability, the lithium-sulfur (Li-S) system is considered to be the most promising candidate for electric and hybrid electric vehicle applications. Sulfur/carbon cathode in Li-S batteries still suffers, however, from low Coulombic efficiency and poor cycle life when sulfur loading and the ratio of sulfur to carbon are high. Here, we address these challenges by fabricating a sulfur/carboxylated-graphene composite using a reverse (water-in-oil) microemulsion technique. The fabricated sulfur-graphene composite cathode, which contains only 6 wt % graphene, can dramatically improve the cycling stability as well as provide high capacity. The electrochemical performance of the sulfur-graphene composite is further enhanced after loading into a three-dimensional heteroatom-doped (boron and nitrogen) carbon-cloth current collector. Even at high sulfur loading (~8 mg/cm2) on carbon cloth, this composite showed 1256 mAh/g discharge capacity with more than 99% capacity retention after 200 cycles. PMID- 28850778 TI - High Density Glycopolymers Functionalized Perylene Diimide Nanoparticles for Tumor-Targeted Photoacoustic Imaging and Enhanced Photothermal Therapy. AB - Near-infrared (NIR) absorbing nanoagents with functions of photoacoustic imaging (PAI) and photothermal therapy (PTT) have received great attention for cancer therapy. However, endowing them with multifunctions, especially targeting ability, for enhancing in vivo PAI/PTT generally suffers from the problems of synthetic complexity and low surface density of function groups. We herein report high density glycopolymers coated perylenediimide nanoparticles (PLAC-PDI NPs), self-assembled by poly(lactose)-modified perylenediimide (PLAC-PDI), as tumor targeted PAI/PTT nanoagents. Atom transfer radical polymerization and click reaction were used in sequence to prepare PLAC-PDI, which can accurately control the content of poly(lactose) (PLAC) in PLAC-PDI and endow PLAC-PDI NPs with high density PLAC surface. The high density PLAC surface provided NPs with long-time colloidal stability, outstanding stability in serum and light, and specific targeting ability to cancer cells and tumors. Meanwhile, PLAC-PDI NPs also presented high photothermal conversion efficiency of 42% by virtue of strong pi pi interactions among perylenediimide molecules. In living mice, PAI experiments revealed that PLAC-PDI NPs exhibited effective targeting ability and enhanced PTT efficacy to HepG2 tumor compared with control groups, lactose blocking, and ASGP R negative tumor groups. Overall, our work provids new insights for designing glycopolymers-based therapeutic nanoagents for efficient tumor imaging and antitumor therapy. PMID- 28850777 TI - Controlling Protein Surface Orientation by Strategic Placement of Oligo-Histidine Tags. AB - We report oriented immobilization of proteins using the standard hexahistidine (His6)-Ni2+:NTA (nitrilotriacetic acid) methodology, which we systematically tuned to give control of surface coverage. Fluorescence microscopy and surface plasmon resonance measurements of self-assembled monolayers (SAMs) of red fluorescent proteins (TagRFP) showed that binding strength increased by 1 order of magnitude for each additional His6-tag on the TagRFP proteins. All TagRFP variants with His6-tags located on only one side of the barrel-shaped protein yielded a 1.5 times higher surface coverage compared to variants with His6-tags on opposite sides of the so-called beta-barrel. Time-resolved fluorescence anisotropy measurements supported by polarized infrared spectroscopy verified that the orientation (and thus coverage and functionality) of proteins on surfaces can be controlled by strategic placement of a His6-tag on the protein. Molecular dynamics simulations show how the differently tagged proteins reside at the surface in "end-on" and "side-on" orientations with each His6-tag contributing to binding. Also, not every dihistidine subunit in a given His6-tag forms a full coordination bond with the Ni2+:NTA SAMs, which varied with the position of the His6-tag on the protein. At equal valency but different tag positions on the protein, differences in binding were caused by probing for Ni2+:NTA moieties and by additional electrostatic interactions between different fractions of the beta-barrel structure and charged NTA moieties. Potential of mean force calculations indicate there is no specific single-protein interaction mode that provides a clear preferential surface orientation, suggesting that the experimentally measured preference for the end-on orientation is a supra-protein, not a single-protein, effect. PMID- 28850779 TI - Ion Diffusion-Directed Assembly Approach to Ultrafast Coating of Graphene Oxide Thick Multilayers. AB - The layer-by-layer (LbL) assembly approach has been widely used to fabricate multilayer coatings on substrates with multiple cycles, whereas it is hard to access thick films efficiently. Here, we developed an ion diffusion-directed assembly (IDDA) strategy to rapidly make multilayer thick coatings in one step on arbitrary substrates. To achieve multifunctional coatings, graphene oxide (GO) and metallic ions were selected as the typical building blocks and diffusion director in IDDA, respectively. With diffusion of metallic ions from substrate to negatively charged GO dispersion spontaneously (i.e., from high-concentration region to low-concentration region), GO was assembled onto the substrate sheet-by sheet via sol-gel transformation. Because metallic ions with size of subnanometers can diffuse directionally and freely in the aqueous dispersion, GO was coated on the substrate efficiently, giving rise to films with desired thickness up to 10 MUm per cycle. The IDDA approach shows three main merits: (1) high efficiency with a MUm-scale coating rate; (2) controllability over thickness and evenness; and (3) generality for substrates of plastics, metals and ceramics with any shapes and morphologies. With these merits, IDDA strategy was utilized in the efficient fabrication of functional graphene coatings that exhibit outstanding performance as supercapacitors, electromagnetic interference shielding textiles, and anticorrosion coatings. This IDDA approach can be extended to other building blocks including polymers and colloidal nanoparticles, promising for the scalable production and application of multifunctional coatings. PMID- 28850780 TI - Morphology and Characteristics of Starch Nanoparticles Self-Assembled via a Rapid Ultrasonication Method for Peppermint Oil Encapsulation. AB - Starch nanoparticles (SNPs) and peppermint oil (PO)-loaded SNPs were fabricated via an ultrasonic bottom-up approach using short linear glucan debranched from waxy maize starch. The effects of the glucan concentration, ultrasonic irradiation time, and chain length on the SNPs' characteristics were investigated. Under the optimal conditions, i.e., short linear glucan concentration of 5% and ultrasonication time of 8-10 min, SNPs were successfully prepared. The as-prepared SNPs showed good uniformity and an almost perfect spherical shape, with diameters of 150-200 nm. The PO-loaded SNPs also exhibited regular shapes, with sizes of approximately 200 nm. The loading capacity, encapsulation efficiency, and yield of PO-loaded SNPs were ~25.5%, ~87.7%, and ~93.2%, respectively. After encapsulation, PO possessed enhanced stability against thermal treatment (80 degrees C). The pseudo-first-order kinetics model accurately described the slow-release properties of PO from SNPs. This new approach of fabricating SNPs is rapid, high yield, and nontoxic, showing great potential in the encapsulation and sustained release of labile essential oils or other lipids. PMID- 28850781 TI - Enhancing Multifunctionalities of Transition-Metal Dichalcogenide Monolayers via Cation Intercalation. AB - We have demonstrated that multiple functionalities of transition-metal dichalcogenide (TMDC) monolayers may be substantially improved by the intercalation of small cations (H+ or Li+) between the monolayers and underlying substrates. The functionalities include photoluminescence (PL) efficiency and catalytic activity. The improvement in PL efficiency may be up to orders of magnitude and can be mainly ascribed to two effects of the intercalated cations: p-doping to the monolayers and reducing the influence of substrates, but more studies are necessary to better understand the mechanism for the improvement in the catalytic functionality. The cation intercalation may be achieved by simply immersing substrate-supported monolayers into the solution of certain acids or salts. It is more difficult to intercalate under the monolayers interacting with substrates stronger, such as as-grown monolayers or the monolayers on 2D material substrates. This result presents a versatile strategy to simultaneously optimize multiple functionalities of TMDC monolayers. PMID- 28850782 TI - Active Janus Particles at Interfaces of Liquid Crystals. AB - We report an investigation of the active motion of silica-palladium Janus particles (JPs) adsorbed at interfaces formed between nematic liquid crystals (LCs) and aqueous phases containing hydrogen peroxide (H2O2). In comparison to isotropic oil-aqueous interfaces, we observe the elasticity and anisotropic viscosity of the nematic phase to change qualitatively the active motion of the JPs at the LC interfaces. Although contact line pinning on the surface of the JPs is observed to restrict out-of-plane rotational diffusion of the JPs at LC interfaces, orientational anchoring of nematic LCs on the silica (planar) and palladium (homeotropic) hemispheres biases JP in-plane orientations to generate active motion almost exclusively along the director of the LC at low concentrations of H2O2 (0.5 wt %). In contrast, displacements perpendicular to the director exhibit the characteristics of Brownian diffusion. At higher concentrations of H2O2 (1-3 wt %), we observe an increasing population of JPs propelled parallel and perpendicular to the LC director in a manner consistent with active motion. In addition, under these conditions, we also observe a subpopulation of JPs (approximately 10%) that exhibit active motion exclusively perpendicular to the LC director. These results are discussed in light of independent measurements of the distribution of azimuthal orientations of the JPs at the LC interfaces and calculations of the elastic energies that bias JP orientations. We also contrast our observations at LC interfaces to past studies of self-propulsion of particles within and at the interfaces of isotropic liquids. PMID- 28850783 TI - Command Surface of Self-Organizing Structures by Radical Polymers with Cooperative Redox Reactivity. AB - Robust radical-substituted polymers with ideal redox capability were used as "command surfaces" for liquid crystal orientation. The alignment of the smectic liquid crystal electrolytes with low-dimensional ion conduction pathways was reversible and readily switched in response to the redox states of the polymers. In one example, a charge storage device with a cooperative redox effect was fabricated. The bulk ionic conductivity of the cell was significantly decreased only after the electrode was fully charged, due to the anisotropic ionic conductivity of the electrolytes (ratio >103). The switching enabled both a rapid cell response and long charge retention. Such a cooperative command surface of self-assembled structures will give rise to new highly energy efficient supramolecular-based devices including batteries, charge carriers, and actuators. PMID- 28850784 TI - Photoswitching of Green mEos2 by Intense 561 nm Light Perturbs Efficient Green-to Red Photoconversion in Localization Microscopy. AB - Green-to-red photoconvertible fluorescent proteins (PCFPs) such as mEos2 and its derivatives are widely used in PhotoActivated Localization Microscopy (PALM). However, the complex photophysics of these genetically encoded markers complicates the quantitative analysis of PALM data. Here, we show that intense 561 nm light (~1 kW/cm2) typically used to localize single red molecules considerably affects the green-state photophysics of mEos2 by populating at least two reversible dark states. These dark states retard green-to-red photoconversion through a shelving effect, although one of them is rapidly depopulated by 405 nm light illumination. Multiple mEos2 switching and irreversible photobleaching is thus induced by yellow/green and violet photons before green-to-red photoconversion occurs, contributing to explain the apparent limited signaling efficiency of this PCFP. Our data reveals that the photophysics of PCFPs of anthozoan origin is substantially more complex than previously thought, and suggests that intense 561 nm laser light should be used with care, notably for quantitative or fast PALM approaches. PMID- 28850785 TI - Time-Lapse Single-Biomolecule Atomic Force Microscopy Investigation on Modified Graphite in Solution. AB - Atomic force microscopy (AFM) of biomolecular processes at the single-molecule level can provide unique information for understanding molecular function. In AFM studies of biomolecular processes in solution, mica surfaces are predominantly used as substrates. However, owing to its high surface charge, mica may induce high local ionic strength in the vicinity of its surface, which may shift the equilibrium of studied biomolecular processes such as biopolymer adsorption or protein-DNA interaction. In the search for alternative substrates, we have investigated the behavior of adsorbed biomolecules, such as plasmid DNA and E. coli RNA polymerase sigma70 subunit holoenzyme (RNAP), on highly oriented pyrolytic graphite (HOPG) surfaces modified with stearylamine and oligoglycine hydrocarbon derivative (GM) monolayers using AFM in solution. We have demonstrated ionic-strength-dependent DNA mobility on GM HOPG and nativelike dimensions of RNAP molecules adsorbed on modified HOPG surfaces. We propose an approach to the real-time AFM investigation of transcription on stearylamine monolayers on graphite. We conclude that modified graphite allows us to study biomolecules and biomolecular processes on its surface at controlled ionic strength and may be used as a complement to mica in AFM investigations. PMID- 28850786 TI - Cross-Linkable Gelatins with Superior Mechanical Properties Through Carboxylic Acid Modification: Increasing the Two-Photon Polymerization Potential. AB - The present work reports on the development of photo-cross-linkable gelatins sufficiently versatile to overcome current biopolymer two-photon polymerization (2PP) processing limitations. To this end, both the primary amines as well as the carboxylic acids of gelatin type B were functionalized with photo-cross-linkable moieties (up to 1 mmol/g) resulting in superior and tunable mechanical properties (G' from 5000 to 147000 Pa) enabling efficient 2PP processing. The materials were characterized in depth prior to and after photoinduced cross-linking using fully functionalized gelatin-methacrylamide (gel-MOD) as a benchmark to assess the effect of functionalization on the protein properties, cross-linking efficiency, and mechanical properties. In addition, preliminary experiments on hydrogel films indicated excellent in vitro biocompatibility (close to 100% viability) both in the presence of MC3T3 preosteoblasts and L929 fibroblasts. Moreover, 2PP processing of the novel derivative was superior in terms of applied laser power (>=40 vs >=60 mW for gel-MOD at 100 mm/s) as well as post-production swelling (0 20% vs 75-100% for gel-MOD) compared to those of gel-MOD. The reported novel gelatin derivative (gel-MOD-AEMA) proves to be extremely suitable for direct laser writing as both superior mimicry of the applied computer-aided design (CAD) was obtained while maintaining the desired cellular interactivity of the biopolymer. It can be anticipated that the present work will also be applicable to alternative biopolymers mimicking the extracellular environment such as collagen, elastin, and glycosaminoglycans, thereby expanding current material related processing limitations in the tissue engineering field. PMID- 28850787 TI - Family of Bioactive Heparin-Coated Iron Oxide Nanoparticles with Positive Contrast in Magnetic Resonance Imaging for Specific Biomedical Applications. AB - Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH) are well known for their anticoagulant properties. There is also currently a growing interest in using LMWH in targeted cancer therapy. In particular, several types inhibit heparanase, a key enzyme overexpressed in the tumor microenvironment that promotes angiogenesis progression and metastasis spreading. Here, we propose iron oxide nanoparticles (HEP-IONP) coated with different heparins of distinct anticoagulant/anti-heparanase activity ratios and suitable for positive contrast in magnetic resonance imaging. As a proof of concept, magnetic resonance angiography (MRA) was conducted in mice up to 3 h after intravenous administration. This new IONP-based positive contrast appropriate for clinic together with the long vascular circulating times can enable innovative theranostic applications if combined with the various bioactivities of the heparins. Indeed, we showed, using advanced in vitro tests, how HEP-IONP anticoagulant or anti-heparanase activities were maintained depending on the heparin species used for the coating. Overall, the study allowed presenting an IONP coated with a commercial LMWH (Lovenox) suggested as a theranostic translational probe for MRA diagnostic and treatment of thrombosis, and an antitumor IONP coated with a specific depolymerized heparin to be used in targeted therapy and diagnostic modalities. PMID- 28850788 TI - Tuning and Predicting Mesh Size and Protein Release from Step Growth Hydrogels. AB - Hydrogel-based depots are of growing interest for release of biopharmaceuticals; however, a priori selection of hydrogel compositions that will retain proteins of interest and provide desired release profiles remains elusive. Toward addressing this, in this work, we have established a new tool for the facile assessment of protein release from hydrogels and applied it to evaluate the effectiveness of mesh size estimations on predicting protein retention or release. Poly(ethylene glycol) (PEG)-based hydrogel depots were formed by photoinitiated step growth polymerization of four-arm PEG functionalized with norbornene (PEG-norbornene, 4% w/w to 20% w/w, Mn ~ 5 to 20 kDa) and different dithiol cross-linkers (PEG Mn ~ 1.5 kDa or enzymatically degradable peptide), creating well-defined, robust materials with a range of mesh sizes estimated with Flory-Rehner or rubber elasticity theory (~5 to 15 nm). A cocktail of different model proteins was released from compositions of interest, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was used to facilely and quantitatively analyze temporal release profiles. Mesh size was predictive of retention of relatively large proteins and release of relatively small proteins. Proteins with diameters comparable to the mesh size, which is often the case for growth factors, were released by hindered diffusion and required experimental assessment of retention and release. With this knowledge, hydrogels were designed for the controlled release of a therapeutically relevant growth factor, PDGF-BB. PMID- 28850789 TI - Predicting high-cost privately insured patients based on self-reported health and utilization data. AB - OBJECTIVES: To examine how well self-reported data on health, health behaviors, and healthcare utilization by a sample of privately insured patients predict whether they will incur high healthcare costs the following year. STUDY DESIGN: A 2012 mail survey of autoworkers from Chrysler, Ford, and General Motors, with 3983 survey respondents linked to their health insurance claims data for 2012 and 2013. METHODS: High healthcare costs are defined as being in the 75th percentile or higher of healthcare expenditures. Models that include combinations of claims based measures of expenditures and morbidity and self-reported measures of health, health behaviors, and healthcare utilization are compared. RESULTS: Claims-based measures of healthcare costs and comorbidity for 2012 were strong predictors of whether a patient would incur high healthcare costs in 2013 (C statistic = 0.78). Self-reported measures of chronic conditions, health status, health behaviors, and hospital use are also good predictors of high healthcare costs. However, even the most comprehensive model that included self-reported measures was not as accurate in predicting high healthcare costs (C statistic = 0.73). CONCLUSIONS: Efficient targeting of high-cost patients is crucial to the success of innovative care delivery models that attempt to lower costs and improve quality of care through more intensive care management of patients. The results of this study show that in the absence of claims data on prior use and expenditures, patient-reported measures of health status and prior healthcare use are reasonable predictors of future healthcare costs for a privately insured population. PMID- 28850791 TI - Twitter accounts followed by Congressional health staff. AB - OBJECTIVES: Although health policy research should inform policy making, the communication gap between researchers and policy makers limits successful translation. Social media represents a new opportunity to connect researchers and policy makers. Our objective was to assess who Congressional health policy staff follow on a major social media platform. STUDY DESIGN: Cross-sectional study. METHODS: Our study measured Congressional health policy staff's use of Twitter and the types of individuals and organizations they follow. To focus on more influential Twitter accounts, we restricted our sample to those followed by at least 3 individual Congressional staff members. RESULTS: Of the 30,843 accounts followed by the 115 Congressional health policy staff, 1273 were potentially policy-related and followed by 3 or more staff. Of these, few were academically affiliated (2.4%) or explicitly health-related (5.6%) sites; many were general news media sources (50.9%) and political and governmental sources (36.4%). Health focused accounts were frequently connected to the news media or government rather than academia. Top accounts followed (ie, highest quintile) were most likely to be national news organizations (odds ratio [OR], 5.88; 95% confidence interval [CI], 1.75-19.7) and elected officials (OR, 8.22; 95% CI, 1.75-38.6) compared with advocacy and interest groups. CONCLUSIONS: Health-related and academic sources are largely absent from the Twitter conversations with US Congressional health policy staff. Even within social media, traditional and political news media are important information intermediaries that researchers and journals should target to disseminate health policy evidence. PMID- 28850790 TI - Leveraging EHRs for patient engagement: perspectives on tailored program outreach. AB - OBJECTIVES: Electronic health records (EHRs) present healthcare delivery systems with scalable, cost-effective opportunities to promote lifestyle programs among patients at high risk for type 2 diabetes, yet little consensus exists on strategies to enhance patient engagement. We explored patient perspectives on program outreach messages containing content tailored to EHR-derived diabetes risk factors-a theory-driven strategy to increase the persuasiveness of health communications. STUDY DESIGN: Convergent mixed methods. METHODS: Within an integrated healthcare delivery system, women with a history of gestational diabetes participated in 1 of 6 ethnic-specific focus groups to elicit diverse perspectives and a survey yielding quantitative data to contextualize qualitative responses. RESULTS: The sample included 35 participants (80% racial/ethnic minorities; mean age = 36 years). Themes regarding tailored messages centered on diabetes risk communication (opposing attitudes about whether to feature diabetes risk factors), privacy (how and whether patient data should be accessed), authenticity (perceiving messages as personalized vs generically computer generated), and preferences for messages sent by one's personal physician. Trust in the medical profession and perceived risk for diabetes were similar to levels reported in comparable samples. CONCLUSIONS: Patient reactions highlight the challenges of leveraging EHRs for tailored messages. Some viewed messages as caring reminders to take preventive action and others raised concerns over intrusiveness. Optimal lifestyle program outreach to improve quality of care for women at high risk for diabetes may require communication from personal physicians, careful development to mitigate concerns over privacy and authenticity, and techniques to counteract the threatening nature of personalized risk communication. PMID- 28850792 TI - Adaptation of an asthma management program to a small clinic. AB - OBJECTIVES: Asthma management programs, such as the Breathmobile program, have been extremely effective in reducing asthma morbidity and increasing disease control; however, their high start-up costs may preclude their implementation in smaller health systems. In this study, we extended validated asthma disease management principles from the Breathmobile program to a smaller clinic system utilizing existing resources and compared clinical outcomes. STUDY DESIGN: Cox regression analyses were conducted to determine the cumulative probability that a new patient entering the program would achieve improved clinical control of asthma with each subsequent visit to the program. METHODS: A weekly asthma disease management clinic was initiated in an existing multi-specialty pediatric clinic in collaboration with the Breathmobile program. Existing nursing staff was utilized in conjunction with an asthma specialist provider. Patients were referred from a regional healthcare maintenance organization and patients were evaluated and treated every 2 months. Reduction in emergency department (ED) visits and hospitalizations, and improvements in asthma control were assessed at the end of 1 year. RESULTS: A total of 116 patients were enrolled over a period of 1 year. Mean patient age was 6.4 years at the time of their first visit. Patient ethnicity was self-described predominantly as Hispanic or African American. Initial asthma severity for most patients, classified in accordance with national guidelines, was "moderate persistent." After 1 year of enrollment, there was a 69% and 92% reduction in ED/urgent care visits and hospitalizations, respectively, compared with the year before enrollment. Up to 70% of patients achieved asthma control by the third visit. Thirty-six different patients were seen during 1 year for a total of $15,938.70 in contracted reimbursements. CONCLUSIONS: A large-scale successful asthma management program can be adapted to a stationary clinic system and achieve comparable results. PMID- 28850793 TI - Medication adherence and improved outcomes among patients with type 2 diabetes. AB - OBJECTIVES: Examine the association between adherence to glucose-lowering agents (GLAs) and patient outcomes in an adult type 2 diabetes (T2D) population. STUDY DESIGN: Retrospective analysis. METHODS: Truven's Commercial Claims and Encounters database supplied data from July 1, 2009, to June 30, 2014. Patients 18 to 64 years with T2D were included if they received a GLA from July 1, 2010, through June 30, 2011. Multivariable analyses examined the relationships among 3 year patient outcomes and adherence, defined as proportion of days covered 80% or more. Outcomes included all-cause medical costs, acute care resource utilization, and acute complications. RESULTS: Although there was no statistically significant difference in total costs when comparing adherent and nonadherent patients ($38,633 vs $38,357; P = .0720), acute care costs ($12,153 vs $8233; P <.0001) and outpatient costs ($16,964 vs $15,457; P <.0001) were significantly lower for adherent patients. Adherence was also associated with a lower probability of hospitalization (22.71% vs 17.65%; P <.0001) and emergency department (ED) visits (45.61% vs 38.47%; P <.0001), fewer hospitalizations (0.40 vs 0.27; P <.0001) and ED visits (1.23 vs 0.83; P <.0001), and a shorter hospital length of stay (2.16 vs 1.25 days; P <.0001). Adherent patients were also less likely to be diagnosed with an acute complication in the 3-year post period (12.54% vs 9.64%; P <.0001). CONCLUSIONS: Compared with nonadherence, adherence to GLAs among patients with T2D was associated with a significant reduction in acute care costs and resource utilization, outcomes that may positively impact the welfare of patients. PMID- 28850794 TI - Gene expression profiling analysis reveals fur development in rex rabbits (Oryctolagus cuniculus). AB - Fur is an important economic trait in rabbits. The identification of genes that influence fur development and knowledge regarding the actions of these genes provides useful tools for improving fur quality. However, the mechanism of fur development is unclear. To obtain candidate genes related to fur development, the transcriptomes of tissues from backs and bellies of Chinchilla rex rabbits were compared. Of the genes analyzed, 336 showed altered expression in the two groups (285 upregulated and 51 downregulated, P <= 0.05, fold-change >=2 or <=0.5). Using GO and KEGG to obtain gene classes that were differentially enriched, we found several genes to be involved in many important biological processes. In addition, we identified several signaling pathways involved in fur development, including the Wnt and MAPK signaling pathways, revealing mechanisms of skin and hair follicle development, and epidermal cell and keratinocytes differentiation. The obtained rabbit transcriptome and differentially expressed gene profiling data provided comprehensive gene expression information for SFRP2, FRZB, CACNG1, SLC25A4, and SLC16A3. To validate the RNA-seq data, the expression levels of eight differentially expressed genes involved in fur development were confirmed by qRT-PCR. The results of rabbit transcriptomic profiling provide a basis for understanding the molecular mechanisms of fur development. PMID- 28850795 TI - Performance of Patient-Generated Subjective Global Assessment (PG-SGA) in Patients With Advanced Cancer in Palliative Care. AB - BACKGROUND: The purpose of this study was to evaluate the prognostic significance of the Patient-Generated Subjective Global Assessment (PG-SGA) in patients receiving palliative care for advanced cancer. METHODS: The PG-SGA was used to assess nutrition status of 120 patients admitted to the Palliative Care Unit at the National Cancer Institute in Brazil. RESULTS: According to the PG-SGA, 94.2% (n = 113) of the patients were evaluated as malnourished. The PG-SGA evaluated that xerostomia was the only symptom associated with a short survival (odds ratio [OR], 2.54; 95% confidence interval [CI], 1.2-5.38; P = .014). Survival was found to be significantly higher in well-nourished (PG-SGA A) than malnourished (PG-SGA B [ P = .021] or C [ P = .013]) patients. Total PG-SGA score (hazard ratio [HR], 1.06; 95% CI, 1.001-1.09; P = .045) and Karnofsky Performance Status of 20%-30% (HR, 15.4; 95% CI, 1.63-92.9; P = .001) and 40%-50% (HR, 10.0; 95% CI, 1.22-64.9; P = .031) were found to be independent prognostic survival factors. CONCLUSION: The scored PG-SGA is an independent prognostic factor of survival and thus can be a useful tool for nutrition evaluation in palliative care. PMID- 28850796 TI - Spasmodic Dysphonia: A Review. Part 2: Characterization of Pathophysiology. AB - Objective The purpose of this review is to describe the recent advances in characterizing spasmodic dysphonia. Spasmodic dysphonia is a task-specific focal laryngeal dystonia characterized by irregular and uncontrolled voice breaks. The pathophysiology is poorly understood, and there are diagnostic difficulties. Data Sources PubMed, Google Scholar, and Cochrane Library. Review Methods The data sources were searched using the following search terms: ( spasmodic dysphonia or laryngeal dystonia) and ( etiology, aetiology, diagnosis, pathogenesis, or pathophysiology). Conclusion The diagnosis of spasmodic dysphonia can be difficult due to the lack of a scientific consensus on diagnostic criteria and the fact that other voice disorders may present similarly. Confusion can arise between spasmodic dysphonia and muscle tension dysphonia. Spasmodic dysphonia symptoms are tied to particular speech sounds, whereas muscle tension dysphonia is not. With the advent of more widespread use of high-speed laryngoscopy and videokymography, measures of the disruptions in phonation and delays in the onset of vocal fold vibration after vocal fold closure can be quantified. Recent technological developments have expanded our understanding of the pathophysiology of spasmodic dysphonia. Implications for Practice A 3-tiered approach, involving a questionnaire, followed by speech assessment and nasolaryngoscopy is the most widely accepted method for making the diagnosis in most cases. More experimental and invasive techniques such as electromyography and neuroimaging have been explored to further characterize spasmodic dysphonia and aid in diagnosing difficult cases. PMID- 28850797 TI - A Rapid Phenotypic Whole-Cell Screening Approach for the Identification of Small Molecule Inhibitors That Counter beta-Lactamase Resistance in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic human pathogen that is prevalent in hospitals and continues to develop resistance to multiple classes of antibiotics. Historically, beta-lactam antibiotics have been the first line of therapeutic defense. However, the emergence of multidrug-resistant (MDR) strains of P. aeruginosa, such as AmpC beta-lactamase overproducing mutants, limits the effectiveness of current antibiotics. Among AmpC hyperproducing clinical isolates, inactivation of AmpG, which is essential for the expression of AmpC, increases bacterial sensitivity to beta-lactam antibiotics. We hypothesize that inhibition of AmpG activity will enhance the efficacy of beta-lactams against P. aeruginosa. Here, using a highly drug-resistant AmpC-inducible laboratory strain PAO1, we describe an ultra-high-throughput whole-cell turbidity assay designed to identify small-molecule inhibitors of the AmpG. We screened 645,000 compounds to identify compounds with the ability to inhibit bacterial growth in the presence of cefoxitin, an AmpC inducer, and identified 2663 inhibitors that were also tested in the absence of cefoxitin to determine AmpG specificity. The Z' and signal-to-background ratio were robust at 0.87 +/- 0.05 and 2.2 +/- 0.2, respectively. Through a series of secondary and tertiary studies, including a novel luciferase-based counterscreen, we ultimately identified eight potential AmpG-specific inhibitors. PMID- 28850798 TI - Identification of Novel Single-Domain Antibodies against FGF7 Using Phage Display Technology. AB - Fibroblast growth factor 7 (FGF7) is a member of the fibroblast growth factor (FGF) family of proteins. FGF7 is of stromal origin and produces a paracrine effect on epithelial cells. In the current investigation, we aimed to identify new single-domain antibodies (sdAbs) against FGF7 using phage display technology. The vector harboring the codon-optimized DNA sequence for FGF7 protein was transformed into Escherichia coli BL21 (DE3) pLysS, and then the protein was expressed at the optimized condition. Enzyme-linked immunosorbent assay, circular dichroism spectropolarimetry, and in vitro scratch assay experiments were used to confirm the proper folding and functionality of the purified FGF7 protein. The purity of the produced FGF7 was 92%, with production yield of 3.5 mg/L of culture. Panning against the purified FGF7 was performed, and the identified single-domain antibodies showed significant affinity. Further investigation on one of the selected sdAb displaying phage clones showed concentration-dependent binding to FGF7. The selected sdAb can be used for developing novel tumor suppressing agents where inhibition of FGF7 is required. PMID- 28850799 TI - Microbial community structure and diversity within hypersaline Keke Salt Lake environments. AB - Keke Salt Lake is located in the Qaidamu Basin of China. It is a unique magnesium sulfate-subtype hypersaline lake that exhibits a halite domain ecosystem, yet its microbial diversity has remained unstudied. Here, the microbial community structure and diversity was investigated via high-throughput sequencing of the V3 V5 regions of 16S rRNA genes. A high diversity of operational taxonomic units was detected for Bacteria and Archaea (734 and 747, respectively), comprising 21 phyla, 43 classes, and 201 genera of Bacteria and 4 phyla, 4 classes, and 39 genera of Archaea. Salt-saturated samples were dominated by the bacterial genera Bacillus (51.52%-58.35% relative abundance), Lactococcus (9.52%-10.51%), and Oceanobacillus (8.82%-9.88%) within the Firmicutes phylum (74.81%-80.99%), contrasting with other hypersaline lakes. The dominant Archaea belonged to the Halobacteriaceae family, and in particular, the genera (with an abundance of >10% of communities) Halonotius, Halorubellus, Halapricum, Halorubrum, and Natronomonas. Additionally, we report the presence of Nanohaloarchaeota and Woesearchaeota in Qinghai-Tibet Plateau lakes, which has not been previously documented. Total salinity (especially Mg2+, Cl-, Na+, and K+) mostly correlated with taxonomic distribution across samples. These results expand our understanding of microbial resource utilization within hypersaline lakes and the potential adaptations of dominant microorganisms that allow them to inhabit such environments. PMID- 28850800 TI - The Distribution of Gastrointestinal Parasites in Two Populations of Common Mole Rats ( Cryptomys hottentotus hottentotus). AB - The spread of parasites through a host population is based on the variation in behavior and immune function between individuals and is rarely uniform. We studied the gastrointestinal parasites of common mole-rats ( Cryptomys hottentotus hottentotus, Lesson 1826) from 2 sites and assessed the levels of infection based on host sex, breeding status, and season. Only nematode species were found: Neoheligmonella sp. and Mammalakis macrospiculum (Ortlepp, 1939) and a single specimen of Trichuris sp., all of which have direct life cycles. Parasite burden and species richness was greater in the mesic habitat. The abundance of Neoheligmonella sp. differed significantly between seasons, and the season of peak abundance differed between sites, perhaps due to differences in host densities between sites. In addition, parasite burden did not differ between the sexes, but breeding animals had higher infections of Neoheligmonella sp. and M. macrospiculum than non-breeding animals. This and previous studies thus suggest that the subterranean environment is beneficial in reducing parasite diversity, although the restrictions on movement may lead to certain individuals suffering higher parasite burdens. PMID- 28850801 TI - Spasmodic Dysphonia: A Review. Part 1: Pathogenic Factors. AB - Objective The purpose of this review is to describe the recent advances in identifying possible factors involved in the pathogenesis of spasmodic dysphonia. Spasmodic dysphonia is a task-specific focal laryngeal dystonia characterized by irregular and uncontrolled voice breaks. Pathogenesis of the disorder is poorly understood. Data Sources PubMed, Google Scholar, and Cochrane Library. Review Methods The data sources were searched using the following search terms: ( spasmodic dysphonia or laryngeal dystonia) and ( etiology, aetiology, diagnosis, pathogenesis, or pathophysiology). Conclusions Several potential etiological factors have been proposed by epidemiological, genetic, and neuropathological studies. Spasmodic dysphonia is a rare disorder primarily affecting females beginning in their 40s. Vocal tremor co-occurs in 30% to 60%. Large cohort studies identified risk factors such as a family history of neurological disorders including dystonia and tremor, recent viral illness, and heavy voice use. As none are rare events, a complex interactive process may contribute to pathogenesis in a small proportion of those at risk. Consequences to pathogenesis are neurological processes found in spasmodic dysphonia: loss of cortical inhibition, sensory processing disturbances, and neuroanatomical and physiological differences in the laryngeal motor control system. Implications for Practice Diagnosis of spasmodic dysphonia usually includes speech and laryngoscopic assessment. However, as diagnosis is sometimes problematic, measurement of neurophysiological abnormalities may contribute useful adjuncts for the diagnosis of spasmodic dysphonia in the future. PMID- 28850803 TI - High Serum Essential Amino Acids as a Predictor of Skeletal Muscle Depletion in Patients With Cachexia and Advanced Gastrointestinal Cancers. AB - BACKGROUND: In recent years, the number of patients with cancer has increased. These patients are prone to sarcopenia as a result of the decrease in muscle mass and muscle weakness that occur in cancer cachexia. Amino Index Cancer Screening is carried out to evaluate cancer cachexia risk by examining amino acid concentration and analyzing amino acid balance. METHODS: We conducted a retrospective chart review of consecutive patients with unresectable advanced gastrointestinal cancer (stage IV) receiving chemotherapy treatment (December 2012-September 2015) in an outpatient or in-hospital setting at our institution (N = 46). Data included characteristics, psoas muscle area per computed tomography, and biochemical blood test and serum amino acid profiles. Method 1: Comparison of biomarkers between 2 groups: psoas muscle index change rate (DeltaPMI) decrease vs increase. Method 2.1: Correlation between DeltaPMI and biomarkers. Method 2.2: Multiple regression of DeltaPMI and biomarkers. RESULTS: EAA/TAA ratio (essential amino acids/total amino acids) in the decrease group was significantly higher than that in the increase group. Among all parameters, serum C-reactive protein (CRP), leucine, and isoleucine were negatively related to DeltaPMI (correlation coefficients = -0.604, -0.540, -0.518; P = .004, .011, .016, respectively). On multiple regression analysis, serum CRP value was strongly related to DeltaPMI ( r2 = 0.452, beta = -0.672, P = .001). CONCLUSIONS: Higher serum EAA/TAA ratio and CRP were associated with depletion in psoas muscle area, which led to a diagnosis of sarcopenia, in patients with advanced gastrointestinal cancers. These parameters at baseline could be predictors of cancer cachexia. PMID- 28850806 TI - Erratum. PMID- 28850805 TI - An Electrochemical Biosensor for Rapid Detection of Pediatric Bloodstream Infections. AB - Bloodstream infections are major contributing factors of morbidity and mortality among children. Precise and timely identification of causative agents can improve the clinical management and outcome of the infection, potentially saving lives. Electrochemical biosensors previously described by Gao et al. (2017) have the potential to deliver greater speed and discrimination. However, to date there are no data that determine whether the age of the host would cause bacteria to demonstrate different growth characteristics, or whether pediatric samples would behave differently using this electrochemical biosensor. The importance of this knowledge gap is clear: the preclinical testing phase of this line of research is limited by the relative lack of pediatric healthy blood volunteers to complete this work. Therefore, in this study we have applied this novel technology to diagnose bacteria spiked into pediatric blood and compared directly with adult blood samples. Only 180 uL of blood was utilized from both adult and pediatric volunteers and inoculated with Escherichia coli 67, and the signals generated at different time points were compared. We were able to demonstrate that the signals generated by adult and pediatric blood were not significantly different with this detection technology. PMID- 28850807 TI - Milk-fat globule epidermal growth factor 8 (MFGE8) is expressed at the embryo? and fetal?maternal interface in equine pregnancy. AB - Milk-fat globule epidermal growth factor (EGF) 8 protein (MFGE8), also known as lactadherin, promotes cell adhesion in an Arg-Gly-Asp (RGD)-dependent modus via integrins. In the present study, the expression of MFGE8 was examined in equine endometrium during oestrus and at Days 12 and 16 after ovulation in pregnant and non-pregnant mares and in mares during the 5th month of gestation. Results demonstrated that MFGE8 is expressed at the embryo- and fetal-maternal interface in equine pregnancy. In non-pregnant endometrium its expression was upregulated by oestrogen, a finding that was confirmed using endometrial explant culture. MFGE8 was expressed at similar levels by conceptuses collected 13 and 14 days after ovulation and by allantochorion sampled during the 5th month of gestation. Pericytes of endometrial blood vessels displayed strong MFGE8 expression upon in situ hybridisation. During the 5th month of gestation, the fetal side of the allantochorionic villi in particular displayed pronounced staining upon in situ hybridisation, confirming that MFGE8 expression is not restricted to early pregnancy but persists and is present at the fetal-maternal interface. Potential roles of MFGE8 in equine pregnancy include mediating cell-cell adhesion, promotion of angiogenesis and placental transfer of fatty acids. PMID- 28850808 TI - Removal of 1,2-Dichloroethane from real industrial wastewater using a sub-surface batch system with Typha angustifolia L. AB - 1,2-Dichloroethane (1,2-DCA) is widely present in urban wastewaters and can be remediated by green technology. Subsurface batch system constructed wetlands (SSCWs) using macrophyte species of T. angustifolia L. were examined to remove 1,2-DCA using real wastewater from a petrochemical industry with a 1,2-DCA concentration of 390mg/L. We conducted an experiment with four pilot-scale constructed wetlands (0.81m2) in a greenhouse. Three SSCWs (T2, T3 and T4) were fed with real wastewater, and another one (T1) was fed with tap water (as plant control) to assess the role of T. angustifolia L. and their associated rhizobacteria to remediate 1,2-DCA. Tank T2 contained only sand without plants acting as contaminant control, tank T3 contained sand with plants and finally tank T4 contained plants with mixture of sand, soil and compost (3:2:1). The results show that the green technology has improved the removal of 1,2-DCA from the contaminated water through biodegradation with a remediation efficiency of 100% in T4 within 42 days. The removal efficiency was enhanced in T4 with 18% more than in T3 due to the compost addition, giving evidence for the potential application of SSCWs to treat chlorinated hydrocarbon in real field. PMID- 28850804 TI - Emerging Microtechnologies and Automated Systems for Rapid Bacterial Identification and Antibiotic Susceptibility Testing. AB - Rapid bacterial identification (ID) and antibiotic susceptibility testing (AST) are in great demand due to the rise of drug-resistant bacteria. Conventional culture-based AST methods suffer from a long turnaround time. By necessity, physicians often have to treat patients empirically with antibiotics, which has led to an inappropriate use of antibiotics, an elevated mortality rate and healthcare costs, and antibiotic resistance. Recent advances in miniaturization and automation provide promising solutions for rapid bacterial ID/AST profiling, which will potentially make a significant impact in the clinical management of infectious diseases and antibiotic stewardship in the coming years. In this review, we summarize and analyze representative emerging micro- and nanotechnologies, as well as automated systems for bacterial ID/AST, including both phenotypic (e.g., microfluidic-based bacterial culture, and digital imaging of single cells) and molecular (e.g., multiplex PCR, hybridization probes, nanoparticles, synthetic biology tools, mass spectrometry, and sequencing technologies) methods. We also discuss representative point-of-care (POC) systems that integrate sample processing, fluid handling, and detection for rapid bacterial ID/AST. Finally, we highlight major remaining challenges and discuss potential future endeavors toward improving clinical outcomes with rapid bacterial ID/AST technologies. PMID- 28850809 TI - Soil properties influence kinetics of soil acid phosphatase in response to arsenic toxicity. AB - Soil phosphatase, which plays an important role in phosphorus cycling, is strongly inhibited by Arsenic (As). However, the inhibition mechanism in kinetics is not adequately investigated. In this study, we investigated the kinetic characteristics of soil acid phosphatase (ACP) in 14 soils with varied properties, and also explored how kinetic properties of soil ACP changed with different spiked As concentrations. The results showed that the Michaelis constant (Km) and maximum reaction velocity (Vmax) values of soil ACP ranged from 1.18 to 3.77mM and 0.025-0.133mMh-1 in uncontaminated soils. The kinetic parameters of soil ACP in different soils changed differently with As contamination. The Km remained unchanged and Vmax decreased with increase of As concentration in most acid and neutral soils, indicating a noncompetitive inhibition mechanism. However, in alkaline soils, the Km increased linearly and Vmax decreased with increase of As concentration, indicating a mixed inhibition mechanism that include competitive and noncompetitive. The competitive inhibition constant (Kic) and noncompetitive inhibition constant (Kiu) varied among soils and ranged from 0.38 to 3.65mM and 0.84-7.43mM respectively. The inhibitory effect of As on soil ACP was mostly affected by soil organic matter and cation exchange capacity. Those factors influenced the combination of As with enzyme, which resulted in a difference of As toxicity to soil ACP. Catalytic efficiency (Vmax/Km) of soil ACP was a sensitive kinetic parameter to assess the ecological risks of soil As contamination. PMID- 28850810 TI - Multigenerational effects of triclosan on the demography of Plationus patulus and Brachionus havanaensis (ROTIFERA). AB - Triclosan is a personal care product widely used in North America, Europe and Asia as antimicrobial ingredient in many consumer chemical products. In Mexico concentrations of triclosan have been reported in aquatic systems. However, there is no law regulating the presence of chemicals such as triclosan, in aquatic systems. The scarce data about this chemical has increased concern among ecotoxicologists regarding possible effects on aquatic organisms. Moreover, multigenerational studies are rarely studied and the results vary depending on the contaminant. Rotifers, are a dominant group of zooplankton, and have been used in aquatic risk assessments of personal care products due to their sensitivity and high reproductive rates. Plationus patulus and Brachionus havanaensis are common rotifers distributed in aquatic ecosystems of Mexico and have been used in ecotoxicological bioassays. In this study, the median lethal concentration (LC50, 24h) of P. patulus and B. havanaensis exposed to triclosan was determined. Based on the LC50, we tested three sublethal concentrations of triclosan to quantify the demographic responses of both rotifers for two successive generations (F0, and F1). The 24h LC50 of triclosan for P. patulus and B. havanaensis were 300 and 500ugL-1 respectively. Despite the concentration, triclosan had an adverse effect on both Plationus patulus and Brachionus havanaensis in both generations exposed. Experiments show that P. patulus was more sensitive than B. havanaensis when exposed to triclosan. When exposed to triclosan the parental generation (F0) of P. patulus was far more affected than F1. PMID- 28850811 TI - Evaluation of the mobility and pollution index of selected essential/toxic metals in paddy soil by sequential extraction method. AB - Comparative distribution and mobility of selected essential and toxic metals in the paddy soil from district Sargodha, Pakistan was evaluated by the modified Community Bureau of Reference (mBCR) sequential extraction procedure. Most of the soil samples showed slightly alkaline nature while the soil texture was predominantly silty loam in nature. The metal contents were quantified in the exchangeable, reducible, oxidisable and residual fractions of the soil by flame atomic absorption spectrophotometry and the metal data were subjected to the statistical analyses in order to evaluate the mutual relationships among the metals in each fraction. Among the metals, Ca, Sr and Mn were found to be more mobile in the soil. A number of significant correlations between different metal pairs were noted in various fractions. Contamination factor, geoaccumulation index and enrichment factor revealed extremely severe enrichment/contamination for Cd; moderate to significant enrichment/contamination for Ni, Zn, Co and Pb while Cr, Sr, Cu and Mn revealed minimal to moderate contamination and accumulation in the soil. Multivariate cluster analysis showed significant anthropogenic intrusions of the metals in various fractions. PMID- 28850812 TI - Pre-selection and assessment of green organic solvents by clustering chemometric tools. AB - The study presents the result of the application of chemometric tools for selection of physicochemical parameters of solvents for predicting missing variables - bioconcentration factors, water-octanol and octanol-air partitioning constants. EPI Suite software was successfully applied to predict missing values for solvents commonly considered as "green". Values for logBCF, logKOW and logKOA were modelled for 43 rather nonpolar solvents and 69 polar ones. Application of multivariate statistics was also proved to be useful in the assessment of the obtained modelling results. The presented approach can be one of the first steps and support tools in the assessment of chemicals in terms of their greenness. PMID- 28850813 TI - Clinical application of the Newborn Behavioral Observation (NBO) System to characterize the behavioral pattern of newborns at biological and social risk. AB - OBJECTIVE: To compare the behavior of preterm newborns and full-term newborns using the Newborn Behavioral Observation and to evaluate the mothers' experience when participating in this observation. METHOD: This was a cross-sectional study performed at a referral hospital for high-risk births, involving mothers and neonates before hospital discharge. The mothers answered the sociodemographic questionnaire, participated in the Newborn Behavioral Observation session, and evaluated the experience by answering the parents' questionnaire at the end. The characteristics of the preterm newborn and full-term newborn groups and the autonomic, motor, organization of states, and responsiveness scores were compared. Linear regression was performed to test the association of the characteristics of mothers and neonates with the scores in the autonomic, motor, organization of states, and responsiveness domains. RESULTS: The Newborn Behavioral Observation was performed with 170 newborns (eight twins and 77% preterm newborns). Approximately 15% of the mothers were adolescents and had nine years of schooling, on average. The groups differed regarding weight for gestational age, age at observation, APGAR score, feeding, and primiparity. The linear regression adjusted for these variables showed that only prematurity remained associated with differences in the scores of the motor (p=0.002) and responsiveness (p=0.02) domains. No statistical difference was observed between the groups in the score attributed to one's own knowledge prior to the session (p=0.10). After the session, these means increased in both groups. This increase was significantly higher in the preterm newborn group (p=0.02). CONCLUSIONS: The Newborn Behavioral Observation increased the mothers' knowledge about the behavior of their children, especially in mothers of preterm newborns, and identified differences in the behavior of preterm newborns and full-term newborns regarding the motor and responsiveness domains. PMID- 28850814 TI - Glucose alteration and insulin resistance in asymptomatic obese children and adolescents. AB - OBJECTIVE: Obesity is associated with the abnormal glucose metabolism preceding type 2 diabetes mellitus. Thus, further investigation on the prediction of this lethal outcome must be sought. The objective was the profile glycemic assessment of asymptomatic obese children and adolescents from Salvador, Brazil. METHOD: A fasting venous blood sample was obtained from 90 consecutive obese individuals aged 8-18 years, of both sexes, for laboratory determinations of glycated hemoglobin, basal insulin, and the Homeostasis Model Assessment Insulin Resistance index. The clinical evaluation included weight, height, waist circumference, assessment of pubertal development, and acanthosis nigricans research. The body mass index/age indicator was used for the severity of overweight assessment. RESULTS: Glycemic alterations were evidenced clinically and biochemically, although these individuals had no complaints or symptoms related to blood sugar levels. Quantitative and qualitative variables were respectively expressed measures of central tendency/dispersion and simple/relative frequency, using the SPSS, version 20.0. A p-value <0.05 was considered significant. CONCLUSION: Notably, this study found a high prevalence of glucose and insulin disorders in asymptomatic obese children and adolescents. PMID- 28850816 TI - Elongated Styloid Process. PMID- 28850817 TI - Mandibular Osteomyelitis Following Implant Placement. AB - PURPOSE: Mandibular osteomyelitis is relatively rare except in cases of osteoradionecrosis or medication-related osteonecrosis. The purpose of this case report is to highlight a rare but devastating complication of dental implant surgery. MATERIALS AND METHODS: The case of a patient who developed mandibular osteomyelitis after implant placement, which was resistant to long-term antibiotic therapy and required radical surgical treatment with fibular free flap reconstruction, is reviewed as is the related literature. RESULTS: The most frequent etiologies are odontogenic and traumatic; however, hematogenous spread also exists. It usually affects patients with systemic conditions, such as diabetes mellitus, malnutrition, malignancy, or immune deficiency. The infection is usually polymicrobial. Concerning dental implant complications, the literature is comprehensive on the mechanical etiologies of implant failure and the infectious etiologies of peri-implantitis. Mandibular osteomyelitis treatment is a long and challenging process requiring long-term antibiotic therapy and multiple surgeries. CONCLUSION: The pathophysiology and treatment of mandibular osteomyelitis are discussed. PMID- 28850818 TI - Is It Truly Wise to Remove the "Safe Surgery Checklist Use" Reporting Requirements? PMID- 28850819 TI - Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity. AB - Gene regulation is essential for cellular differentiation and plasticity. Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), develop from neural crest cells to mature myelinating SCs and can at early developmental stage differentiate into various cell types. After a PNS lesion, SCs can also convert into repair cells that guide and stimulate axonal regrowth, and remyelinate regenerated axons. What controls their development and versatile nature? Several recent studies highlight the key roles of chromatin modifiers in these processes, allowing SCs to regulate their gene expression profile and thereby acquire or change their identity and quickly react to their environment. PMID- 28850815 TI - Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research. AB - Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. The identification of causative genetic defects has allowed for creation of transgenic NDD mouse models that have revealed pathophysiological mechanisms of disease phenotypes in a neural circuit- and cell type-specific manner. Mouse models of several syndromes, including Rett syndrome, Fragile X syndrome, Angelman syndrome, Neurofibromatosis type 1, etc., exhibit abnormalities in the structure and function of dopaminergic circuitry, which regulates motivation, motor behavior, sociability, attention, and executive function. Recent advances in technologies for functional circuit mapping, including tissue clearing, viral vector-based tracing methods, and optical readouts of neural activity, have refined our knowledge of dopaminergic circuits in unperturbed states, yet these tools have not been widely applied to NDD research. Here, we will review recent findings exploring dopaminergic function in NDD models and discuss the promise of new tools to probe NDD pathophysiology in these circuits. PMID- 28850820 TI - Mechanisms of Muller glial cell morphogenesis. AB - Muller Glia (MG), the radial glia cells of the retina, have spectacular morphologies subserving their enormous functional complexity. As early as 1892, the great neuroanatomist Santiago Ramon y Cajal studied the morphological development of MG, defining several steps in their morphogenesis [1,2]. However, the molecular cues controlling these developmental steps remain poorly understood. As MG have roles to play in every cellular and plexiform layer, this review discusses our current understanding on how MG morphology may be linked to their function, including the developmental mechanisms involved in MG patterning and morphogenesis. Uncovering the mechanisms governing glial morphogenesis, using transcriptomics and imaging, may provide shed new light on the pathophysiology and treatment of human neurological disorders. PMID- 28850821 TI - Ultrasonographic evaluation of intra-abdominal fat distribution and study of its influence on subclinical atherosclerosis in women with polycystic ovarian syndrome. AB - OBJECTIVES: To evaluate abdominal fat distribution and cardiovascular disease (CVD) risk factors in women with polycystic ovarian syndrome (PCOS) and to determine the independent risk factors for subclinical atherosclerosis. STUDY DESIGN: One hundred and twenty-four women with PCOS were compared with 118 age and BMI-matched controls. Abdominal obesity was assessed as the waist-to-hip ratio (WHR) and abdominal fat distribution was measured as subcutaneous fat thickness (SFT), pre-peritoneal fat thickness (PFT) and visceral fat thickness (VFT) using Ultrasound (US). Markers of subclinical atherosclerosis (carotid intima-media thickness (CIMT) and brachial artery flow-mediated dilation (FMD)) and other CVD risk factors such as fasting glucose, fasting insulin (FIN), insulin resistance (HOMA-IR), androgens and lipid levels were measured. RESULTS: In comparison to controls, PCOS women had increased VFT and subclinical atherosclerosis. PCOS women also had higher FIN and lower levels of high-density lipoprotein cholesterol (HDL-C) and an elevated total cholesterol (TC) to HDL-C ratio. In PCOS women, VFT showed a strong association with CIMT and WHR showed a strong association with FIN and HOMA-IR; however these associations were weak in controls. Multiple regression analysis revealed VFT as the strongest independent predictor of CIMT in PCOS women whereas age was the only independent predictor of CIMT and FMD in controls. CONCLUSIONS: While age can be an independent baseline risk factor for subclinical atherosclerosis in normal menstruating women, excess visceral fat accumulation is the most important predictor of atherosclerosis in PCOS patients. PMID- 28850822 TI - A retrospective analysis on 1901 women with high grade cervical intraepithelial neoplasia by colposcopic biopsy. AB - OBJECTIVE: Clinically, an unbefitting management for high grade squamous intraepithelial lesion (HSIL) may result from an inaccurate diagnosis by colposcopy bioposy.The study aimed to assess the diagnostic accuracy by colposcopic biopsy and evaluate the associated factors in diagnosing HSIL. STUDY DESIGN: Clinical data of 1901 women who were primarily diagnosed as HSIL by colposcopic biopsy and then underwent definitive surgery within six-month interval in Women's Hospital, School of Medicine, Zhejiang University during 2009 2015, were retrospectively collected. The diagnostic accuracy of HSIL by colposcopic biopsy was assessed and the correlations between diagnostic accuracy and clinic-pathological variables were calculated by univariate and multivariate analysis using the pathological diagnosis by definitive surgery as a reference standard. RESULTS: The accordance rate of HSIL diagnosis between colposcopic biopsy and definitive surgery was 80.6%, with an under-diagnosis rate of 5.8% and an over-diagnosis rate of 13.6%. Cytology<=low grade squamous intraepithelial lesion(LSIL) (OR:1.599;95%CI:1.185-2.160), colposcopy<=LSIL (OR:2.083;95%CI:1.537 2.824), endocervical curettage (ECC)<=LSIL(OR:2.813;95%CI:2.051-3.857), and lesion without gland involved (OR:1.751;95%CI:1.299-2.361) were independent risk factors for over-diagnosis of HSIL. Women with>=3 risk factors had a 5.078-flod higher risk for over-diagnosis of HSIL compared to those with<=1 risk factor. Irregular vaginal bleeding (OR:2.570,95%CI:1.668-3.960), colposcopy=HSIL (OR:1.699,95%CI:1.022-2.824), ECC=HSIL (OR:2.666, 95%CI:1.728-4.113), and multiple biopsies (OR:1.818, 95%CI:1.153-2.868) were independent risk factors for under-diagnosis of HSIL. Women with >=3 risk factors had a 5.710-flod higher risk for under-diagnosis of HSIL compared to those with <=1 risk factor. CONCLUSIONS: The diagnostic accuracy of HSIL by colposcopic biopsy is about 80% and associated with some factors including symptom, cytology result, colposcopy diagnosis, and biopsy number. These variables may be predictors for over-diagnosis or under diagnosis of HSIL by colposcopic biopsy. PMID- 28850823 TI - Trimetallic Pd@Au@Pt nanocomposites platform on -COOH terminated reduced graphene oxide for highly sensitive CEA and PSA biomarkers detection. AB - In this paper, a trimetallic Pd@Au@Pt nanocomposites platform on -COOH terminated reduced graphene oxide (COOH-rGO) was newly developed for sensing carcinoembryonic antigen (CEA) and prostate specific antigen (PSA) biomarkers. Trimetallic electro-catalytic surfaces were prepared by the electrodeposition of noble metals (Pd@Au@Pt) nanoparticles on COOH- rGO. After EDC/NHS treatment, the anti-CEA and anti-PSA were immobilized separately on two different platforms. Under optimized conditions, the platforms were analyzed by cyclic voltammetry and differential pulse voltammetry (DPV). The platform shows good electro catalytic activity, high sensitivity, and acceptable stability for sensing CEA and PSA biomarkers. For CEA, we obtained sensitivity of 0.099 +/- 0.007uAng-1ml, wide linear range from 12pgml-1 to 85ngml-1 and a limit of detection (LOD) of 8pgml-1, while for PSA sensitivity is 0.267 +/- 0.02uAng -1 ml, wide linear range from 3pgml-1 to 60ngml-1 and LOD of 2pgml-1. The validation of the platform was observed through standard addition method. Thus, the sensing platform could be used for the point of care detection of CEA and PSA. PMID- 28850824 TI - Hybrid localized surface plasmon resonance and quartz crystal microbalance sensor for label free biosensing. AB - We report on the design and fabrication of a hybrid sensor that integrates transmission-mode localized surface plasmonic resonance (LSPR) into a quartz crystal microbalance (QCM) for studying biochemical surface reactions. The coupling of LSPR nanostructures and a QCM allows optical spectra and QCM resonant frequency shifts to be recorded simultaneously and analyzed in real time for a given surface adsorption process. This integration simplifies the conventional combination of SPR and QCM and has the potential to be miniaturized for application in point-of-care (POC) diagnostics. The influence of antibody-antigen recognition effect on both the QCM and LSPR has been analyzed and discussed. PMID- 28850825 TI - Electrochemiluminescent resonance energy transfer of polymer dots for aptasensing. AB - This work designed a three-component polymer for the preparation of polymer dots (Pdots). The polymer contained 9-(diphenylmethylene)-9H-fluorene (DPF), 9,9 dioctyl-9H-fluorene (DOF) and 1,1'-binaphthyl moieties, and was synthesized via Pd-catalyzed Suzuki reaction. It exhibited obvious yellow-colored aggregation induced emission (AIE) for fluorescence enhancement at 543nm via an intramolecular fluorescence resonance energy transfer from DOF moiety to DPF moiety. The Pdots prepared by nanoprecipitation could be conveniently cast on electrode surface and showed a stable anodic electrochemiluminescence (ECL) emission in the presence of triethylamine as a co-reactant. The ECL emission could be effectively quenched by rhodamine B via resonance energy transfer, which led to an "off-on" switch for the design of ECL sensing methodology. Using Pb2+ as a target model, an ECL aptasensor for the detection of trace Pb2+ was proposed, which showed a linear range of 100pM to 1.0MUM with a detection limit down to 38.0pM This work demonstrated the first Pdots prepared with AIE-active polymer for highly efficient ECL sensing. PMID- 28850827 TI - A new approach in evaluating the surface beta contamination using the direct method of measurement. AB - This paper describes a new approach in evaluating the surface beta contamination using the direct method of measurement. It makes use of previous results obtained in numerical modeling of electron transport in planar geometry and is mainly based on the estimation of the efficiency of contamination sources for beta radiation and its standard uncertainty using the available information concerning the component materials of the sources and their main parameters. Experimental results illustrate the appropriateness of the new approach for surface beta contamination measurements. PMID- 28850826 TI - Experienced job autonomy among maternity care professionals in The Netherlands. AB - OBJECTIVE: High levels of experienced job autonomy are found to be beneficial for healthcare professionals and for the relationship with their patients. The aim of this study was to assess how maternity care professionals in the Netherlands perceive their job autonomy in the Dutch maternity care system and whether they expect a new system of integrated maternity care to affect their experienced job autonomy. DESIGN: A cross-sectional survey. The Leiden Quality of Work Life Questionnaire was used to assess experienced job autonomy among maternity care professionals. SETTING: Data were collected in the Netherlands in 2015. PARTICIPANTS: 799 professionals participated of whom 362 were primary care midwives, 240 obstetricians, 93 clinical midwives and 104 obstetric nurses. FINDINGS: The mean score for experienced job autonomy was highest for primary care midwives, followed by obstetricians, clinical midwives and obstetric nurses. Primary care midwives scored highest in expecting to lose their job autonomy in an integrated care system. KEY CONCLUSIONS: There are significant differences in experienced job autonomy between maternity care professionals. IMPLICATIONS FOR PRACTICE: When changing the maternity care system it will be a challenge to maintain a high level of experienced job autonomy for professionals. A decrease in job autonomy could lead to a reduction in job related wellbeing and in satisfaction with care among pregnant women. PMID- 28850828 TI - Determination of trapping parameters in BeO ceramics in both quenched as well as reconstructed thermoluminescence glow curves using various analysis methods. AB - The trapping parameters of BeO thermoluminescence peaks 2 and 3 (with delocalization temperatures of 192 and 308 degrees C respectively, obtained with heating rate of 1K/s) have been calculated using various analysis techniques, including the peak shape methods, isothermal decay, variable heating rates, the fractional glow technique and de-convolution. However, as BeO has been reported to undergo thermal quenching, both intensity as well as trapping parameters are affected, because the glow curve is distorted. Therefore, trapping parameters were calculated for both quenched and unquenched data of the aforementioned thermoluminescence peaks. The unquenched glow curves were determined by reconstructing the corresponding quenched; the following thermal quenching parameters were adopted: W = 0.60eV and C = 1.3 * 106 for peak 2 and W = 0.80eV and C = 1.2 * 107 for peak 3. The obtained activation energies and frequency factors before and after reconstruction were compared both for every method and also to previous studies. This study emphasizes the importance of reconstruction process on trapping parameters for peak 3, as this peak lies within a special temperature range where the efficiency gets values < 0.54. The main dosimetric peak is mildly affected by thermal quenching; thus before and after reconstruction the corresponding values do not yield significant variations. The average values for the activation energy and frequency factor after reconstruction were calculated as 1.14 +/- 0.07eV and 9.9 * 1010 +/- 0.4 * 1010 s 1 for peak 2; the corresponding values for peak 3 are 1.34 +/- 0.08eV, 6.9 * 1011 +/- 0.6 * 1011 s-1 respectively. Both peaks are described by first order of kinetics even after reconstruction has occurred. Individual peculiarities of each analysis technique has been both presented and discussed. PMID- 28850830 TI - Comparison of clinical features and surgical outcome in focal cortical dysplasia type 1 and type 2. AB - INTRODUCTION: Recent ILAE classification defined focal cortical dysplasia (FCD) patients with accompanying epileptic lesions as a separate group. We investigated data of patients with sole FCD lesions regarding long-term seizure outcome and different characteristics of FCD type 1 and type 2 patients. METHODS: Eighty children and adult patients underwent surgery for FCD were included to the analysis of factors differentiating FCD type 1 and type 2 groups and their effect on long-term outcome. RESULTS: FCD type 2 patients had earlier epilepsy onset (8.1 vs. 6.1 years. p=0.019) and underwent surgery younger than type 1 (18.2 vs. 23.7 years. p=0.034). FCD type 2 patients were more prominently MR positive (77.8% vs. 53.8%. p=0.029), which increased within FCD type 2 group as patients become younger (p=0.028). FCD Type 1 lesions showed mostly multilobar extension and FCD type 2 mostly located in frontal lobe. Seizure freedom was achieved in 65.4% of FCD type 1 patients and 70.4% of FCD type 2 patients. Seven patients had permanent de novo neurological deficits. Mean follow-up time was 5.5 years (Range: 1-11 years). CONCLUSION: Surgical intervention in carefully selected patients may facilitate favorable seizure outcome leading to better quality of life. FCD type 1 and type 2 groups present with evident differences, which may promote medical and surgical management of these pathologies. PMID- 28850829 TI - ORF73 LANA homologs of RRV and MneRV2 contain an extended RGG/RG-rich nuclear and nucleolar localization signal that interacts directly with importin beta1 for non classical nuclear import. AB - The latency-associated nuclear antigens (LANA) of KSHV and macaque RFHVMn, members of the RV1 rhadinovirus lineage, are closely related with conservation of complex nuclear localization signals (NLS) containing bipartite KR-rich motifs and RG-rich domains, which interact distinctly with importins alpha and beta1 for nuclear import via classical and non-classical pathways, respectively. RV1 LANAs are expressed in the nucleus of latently-infected cells where they inhibit replication and establish a dominant RV1 latency. Here we show that LANA homologs of macaque RRV and MneRV2 from the more distantly-related RV2 lineage, lack the KR-rich NLS, and instead have a large RG-rich NLS with multiple RG dipeptides and a conserved RGG motif. The RG-NLS interacts uniquely with importin beta1, which mediates nuclear import and accumulation of RV2 LANA in the nucleolus. The alternative nuclear import and localization of RV2 LANA homologs may contribute to the dominant RV2 lytic replication phenotype. PMID- 28850831 TI - Region-specific connectivity in patients with periventricular nodular heterotopia and epilepsy: A study combining diffusion tensor imaging and functional MRI. AB - OBJECTIVES: Periventricular nodular heterotopia (PNH) is an important cause of chronic epilepsy. The purpose of this study was to evaluate region-specific connectivity in PNH patients with epilepsy and assess correlation between connectivity strength and clinical factors including duration and prognosis. METHODS: Diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) were performed in 28 subjects (mean age 27.4years; range 9-56years). The structural connectivity of fiber bundles passing through the manually-selected segmented nodules and other brain regions were analyzed by tractography. Cortical lobes showing functional correlations to nodules were also determined. RESULTS: For all heterotopic gray matter nodules, including at least one in each subject, the most frequent segments to which nodular heterotopia showed structural (132/151) and functional (146/151) connectivity were discrete regions of the ipsilateral overlying cortex. Agreement between diffusion tensor tractography and functional connectivity analyses was conserved in 81% of all nodules (122/151). In patients with longer duration or refractory epilepsy, the connectivity was significantly stronger, particularly to the frontal and temporal lobes (P<0.05). CONCLUSIONS: Nodules in PNH were structurally and functionally connected to the cortex. The extent is stronger in patients with longstanding or intractable epilepsy. These findings suggest the region-specific interactions may help better evaluate prognosis and seek medical or surgical interventions of PNH-related epilepsy. PMID- 28850832 TI - Behavior of antibiotic resistance genes under extremely high-level antibiotic selection pressures in pharmaceutical wastewater treatment plants. AB - Pharmaceutical wastewater treatment plants (PWWTPs), which receive wastewater containing extremely high levels of antibiotics, are regarded as potential hot spots for antibiotic-resistance development in the environment. Six sampling campaigns in six PWWTPs in Southeastern China were carried out to assess the prevalence and fate of antibiotic resistance genes (ARGs). Different genes were monitored in different PWWTPs (PWWTP A: lincosamides; PWWTP B: aminoglycosides and macrolides; PWWTP C: quinolones; PWWTP D: macrolides and quinolones; PWWTP E: cephalosporins; and PWWTP F: quinolones and macrolides) using real-time quantitative polymerase chain reactions (PCRs), according to the antibiotic type produced. The levels of typical ARG subtypes in the final effluents ranged from (1.03+/-0.91)*101 to (6.78+/-0.21)*107copies/mL. The absolute abundance of ARGs in effluents accounted for 0%-577% of influents to the six PWWTPs with a median value of 6%. Most of the ARGs are transported to the dewatered sludge, with concentrations from (1.38+/-0.21)*105 to (6.84+/-0.43)*1010copies/g dry weight (dw). In different treatment units (before/after biological units), a clear trend of proliferation or attenuation was not observed for the ARGs, aside from a strong attenuation in moving bed bio-film reactor (MBBR) in PWWTP C. Through correlation analyses, this study demonstrated that the bacterial abundance and antibiotic concentrations within the PWWTPs influenced the fate of the associated ARGs, and this was possibly related primarily to the intrinsic resistance mechanisms of corresponding ARGs. Macrolide ARGs, which tend to locate in plasmids and transposons, positively correlate weakly with total macrolide antibiotic concentrations but positively correlate strongly with 16S rRNA concentrations. Furthermore, ARG concentrations in the wastewater from fermentation were significantly higher than in the wastewater from chemical synthesis and preparation. This is the first comprehensive study on the behavior of antibiotic resistance genes under extremely high-level antibiotic selection pressures in pharmaceutical wastewater treatment plants (PWWTPs) in Southeastern China. PMID- 28850833 TI - Low concentrations of persistent organic pollutants (POPs) in air at Cape Verde. AB - Ambient air is a core medium for monitoring of persistent organic pollutants (POPs) under the Stockholm Convention and is used in studies of global transports of POPs and their atmospheric sources and source regions. Still, data based on active air sampling remain scarce in many regions. The primary objectives of this study were to (i) monitor concentrations of selected POPs in air outside West Africa, and (ii) to evaluate potential atmospheric processes and source regions affecting measured concentrations. For this purpose, an active high-volume air sampler was installed on the Cape Verde Atmospheric Observatory at Cape Verde outside the coast of West Africa. Sampling commenced in May 2012 and 43 samples (24h sampling) were collected until June 2013. The samples were analyzed for selected polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), hexachlorobenzene (HCB) and chlordanes. The concentrations of these POPs at Cape Verde were generally low and comparable to remote sites in the Arctic for several compounds. Seasonal trends varied between compounds and concentrations exhibited strong temperature dependence for chlordanes. Our results indicate net volatilization from the Atlantic Ocean north of Cape Verde as sources of these POPs. Air mass back trajectories demonstrated that air masses measured at Cape Verde were generally transported from the Atlantic Ocean or the North African continent. Overall, the low concentrations in air at Cape Verde were likely explained by absence of major emissions in areas from which the air masses originated combined with depletion during long-range atmospheric transport due to enhanced degradation under tropical conditions (high temperatures and concentrations of hydroxyl radicals). PMID- 28850834 TI - Pollution characteristics, risk assessment, and source apportionment of heavy metals in road dust in Beijing, China. AB - To analyze the spatial distribution patterns, risks, and sources of heavy metals (As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Zn, Fe), 36 road dust samples were collected from an urbanized area of Beijing in June 2016. The mean concentration of most metals, except As and Mn, exceeded their corresponding background values, with the mean concentration of Cd being 8 times that of its background. Spatially, for most heavy metals, except As and Mn, the high concentration areas were mainly within the 5th ring road, especially the northern area. The geo-accumulation index of Cd and Cu indicated moderate contamination at many sites. The entire study area was prone to potential ecological risks, with higher risks within the 4th ring road. Cd caused high potential ecological risk at most sites. According to the health risk assessment results, the non-carcinogenic risks that human beings suffered from heavy metals were insignificant. However, the carcinogenic risks due to Ni and Cr exceeded the acceptable level. Based on the source apportionment using positive matrix factorization, four factors were defined for the heavy metals. Factor 1, which was traffic-related exhaust, accounted for 34.47% of the concentration of heavy metals. The contributions of Factors 2 and 3 were approximately 25% each. Factor 2 was potentially related to coal combustion, while Factor 3 could be related to the manufacture and use of metal components. Factor 4, which could be related to the use of pesticides, fertilizers, and medical devices, accounted for 14.88%, which was the lowest. PMID- 28850835 TI - Arsenic in groundwater of West Bengal, India: A review of human health risks and assessment of possible intervention options. AB - This paper reviews how active research in West Bengal has unmasked the endemic arsenism that has detrimental effects on the health of millions of people and their offspring. It documents how the pathways of exposure to this toxin/poison have been greatly expanded through intensive application of groundwater in agriculture in the region within the Green Revolution framework. A goal of this paper is to compare and contrast the similarities and differences in arsenic occurrence in West Bengal with those of other parts of the world and assess the unique socio-cultural factors that determine the risks of exposure to arsenic in local groundwater. Successful intervention options are also critically reviewed with emphasis on integrative strategies that ensure safe water to the population, proper nutrition, and effective ways to reduce the transfer of arsenic from soil to crops. While no universal model may be suited for the vast areas of the world affected with by natural contamination of groundwater with arsenic, we have emphasized community-specific sustainable options that can be adapted. Disseminating scientifically correct information among the population coupled with increased community level participation and education are recognized as necessary adjuncts for an engineering intervention to be successful and sustainable. PMID- 28850836 TI - Characteristics and classification of PM2.5 pollution episodes in Beijing from 2013 to 2015. AB - During the period of 2013-2015, a total of 34 PM2.5 pollution episodes occurred in Beijing, each of which remained for at least 2days. Among that, 28 times occurred in winter half year with the average concentration of 243.1MUg/m3 and summer half year with the average concentration of 194.1MUg/m3. These episodes were mainly associated with lower wind speed and lower visibility as well as higher relative humidity, indicating that they belonged to heavy pollution under static stability. The PM2.5 pollution was classified into two categories according to the back trajectory analysis and meteorological background field. Category I, accounting for 22 times among all the pollution episodes, was due to air mass transport from Beijing's southern regions with north-south direction pressure gradient and sparse isopiestic. And category II was mainly led by northwestern air masses accompanied with a large area of uniform pressure field. Then, a typical case study was conducted for each category to recognize the sub region contribution to Beijing's PM2.5 pollution based on WRF-CAMx modeling system, and the simulation results indicated that local emission source contribution decreased significantly during the accumulation phase for category I, but increased during that of category II, with an average contribution of 47.3% and 77.1% during the entire pollution period of each category, respectively. Two red alerts of air pollution occurred in December 2015 were also analyzed based on the episode classification. It was found that the second red alert pollution episode belonged to category II. The emission control measures in Beijing worked more obviously with the reduction effect ratio of 15.4% compared to the first red alert period (9.7%). PMID- 28850837 TI - Standardised index for measuring atmospheric grass-pollen emission. AB - Grass pollen is the main cause of pollen allergy in Europe, and-given its marked allergenic potential and elevated airborne concentrations-constitutes a major public health risk. This study sought to identify the grass species triggering allergies during the highest-risk periods, and to measure the contribution of each species to airborne grass pollen concentrations. This type of research is particularly useful with a view to optimising the prevention and diagnosis of pollen allergies and developing the most effective immunological treatments. To that end, a total of 28 species potentially responsible for allergies were analysed. In order to assess the potential contribution of these species to overall airborne pollen concentrations, an index was designed (Pollen Contribution Index) based on the following parameters for each species: flowering phenology, pollen grain size (polar and equatorial axes), abundance of the species in the area and pollen production. The species contributing most to airborne pollen concentrations were, in order: Dactylis glomerata subsp. hispanica, Lolium rigidum, Trisetum paniceum and Arrhenatherum album. These species all shared certain features: small grain size (and thus greater buoyancy in air), high pollen production and considerable abundance. This Index was applied to a case study in a Mediterranean-climate area of the central Iberian Peninsula, but could equally be applied to other areas and other allergenic pollens. Findings showed that a small number of species were responsible for most airborne grass pollen. PMID- 28850838 TI - Potential of biochar filters for onsite sewage treatment: Adsorption and biological degradation of pharmaceuticals in laboratory filters with active, inactive and no biofilm. AB - This study investigated the potential of biochar filters as a replacement or complement for sand filters for removal of pharmaceutically active compounds (PhACs) from wastewater in onsite sewage facilities (OSSF). Specifically, the study investigated the effects of biodegradation, adsorption and a combination of these processes on removal of four model PhACs from wastewater in biochar filters operated under hydraulic loading conditions mimicking those found in onsite infiltration beds. Concentrations and removal of the four PhACs (i.e. carbamazepine, metoprolol, ranitidine and caffeine) were investigated over 22weeks in four treatments: biochar (BC) with active or inactive biofilm (BC active-biofilm, BC-inactive-biofilm), biochar without biofilm (BC-no-biofilm) and sand with active biofilm (Sand-active-biofilm). The adsorption of carbamazepine was high in BC-no-biofilm (99% removal after 22weeks), while biodegradation was very low in Sand-active-biofilm (7% removal after 22weeks). Removal of carbamazepine in BC-active-biofilm was high and stable over the 22weeks (>98%), showing a significant role of biofilm in filter biogeneration. However, carbamazepine removal declined over time in BC-inactive-biofilm, from 99% in week 13 to 73% in week 22. Metoprolol was poorly degraded in Sand-active-biofilm (37% after 22weeks), while adsorption seemed to be the major pathway for removal of metoprolol in biochar. Ranitidine and caffeine were efficiently removed by either adsorption (97% and 98%, respectively, after 22weeks) or biodegradation (99% and >99%, respectively, after 22weeks). In conclusion, biochar is a promising filter medium for OSSF, especially for persistent PhACs such as carbamazepine and metoprolol. PMID- 28850839 TI - Seasonal variability of PM2.5 and PM10 composition and sources in an urban background site in Southern Italy. AB - Comparison of fine and coarse fractions in terms of sources and dynamics is scarce in southeast Mediterranean countries; differences are relevant because of the importance of natural sources like sea spray and Saharan dust advection, because most of the monitoring networks are limited to PM10. In this work, the main seasonal variabilities of sources and processes involving fine and coarse PM (particulate matter) were studied at the Environmental-Climate Observatory of Lecce (Southern Italy). Simultaneous PM2.5 and PM10 samples were collected between July 2013 and July 2014 and chemically analysed to determine concentrations of several species: OC (organic carbon) and EC (elemental carbon) via thermo-optical analysis, 9 major ions via IC, and 23 metals via ICP-MS. Data was processed through mass closure analysis and Positive Matrix Factorization (PMF) receptor model characterizing seasonal variabilities of nine sources contributions. Organic and inorganic secondary aerosol accounts for 43% of PM2.5 and 12% of PM2.5-10 with small seasonal changes. SIA (secondary inorganic aerosol) seasonal pattern is opposite to that of SOC (secondary organic carbon). SOC is larger during the cold period, sulphate (the major contributor to SIA) is larger during summer. Two forms of nitrate were identified: NaNO3, correlated with chloride depletion and aging of sea-spray, mainly present in PM2.5-10; NH4NO3 more abundant in PM2.5. Biomass burning is a relevant source with larger contribution during autumn and winter because of the influence of domestic heating, however, is not negligible in spring and summer, because of the contributions of fires and agricultural practices. Mass closure analysis and PMF results identify two soil sources: crustal associated to long range transport and carbonates associated to local resuspended dust. Both sources contributes to the coarse fraction and have different dynamics with crustal source contributing mainly in high winds from SE conditions and carbonates during high winds from North direction. PMID- 28850840 TI - Development of a diatom-based multimetric index for acid mine drainage impacted depressional wetlands. AB - Acid mine drainage (AMD) from coal mining in the Mpumalanga Highveld region of South Africa has caused severe chemical and biological degradation of aquatic habitats, specifically depressional wetlands, as mines use these wetlands for storage of AMD. Diatom-based multimetric indices (MMIs) to assess wetland condition have mostly been developed to assess agricultural and urban land use impacts. No diatom MMI of wetland condition has been developed to assess AMD impacts related to mining activities. Previous approaches to diatom-based MMI development in wetlands have not accounted for natural variability. Natural variability among depressional wetlands may influence the accuracy of MMIs. Epiphytic diatom MMIs sensitive to AMD were developed for a range of depressional wetland types to account for natural variation in biological metrics. For this, we classified wetland types based on diatom typologies. A range of 4-15 final metrics were selected from a pool of ~140 candidate metrics to develop the MMIs based on their: (1) broad range, (2) high separation power and (3) low correlation among metrics. Final metrics were selected from three categories: similarity to reference sites, functional groups, and taxonomic composition, which represent different aspects of diatom assemblage structure and function. MMI performances were evaluated according to their precision in distinguishing reference sites, responsiveness to discriminate reference and disturbed sites, sensitivity to human disturbances and relevancy to AMD-related stressors. Each MMI showed excellent discriminatory power, whether or not it accounted for natural variation. However, accounting for variation by grouping sites based on diatom typologies improved overall performance of MMIs. Our study highlights the usefulness of diatom-based metrics and provides a model for the biological assessment of depressional wetland condition in South Africa and elsewhere. PMID- 28850841 TI - Effect of biochar on photosynthetic microorganism growth and iron cycling in paddy soil under different phosphate levels. AB - The surplus of exogenous and endogenous phosphate in submerged paddy fields could increase the risk of algal blooms, the photosynthesis of which might further influence the redox processes of iron. This work investigated the effects of biochar on photosynthetic microorganism growth and iron redox under different phosphate (P) levels to understand the dynamics of P and thereby control non point source pollution by biochar addition. Paddy soils were incubated anaerobically with phosphate and biochar addition under controlled illumination conditions to determine the variation in chlorophyll a (Chl a), ferrous iron [Fe(II)], soil pH and water-soluble phosphate (W-P) with incubation time. Biochar addition significantly inhibited the photosynthetic microorganism growth, with Chl a decreased by 4.74-15.78mg.g-1 when compared with the control. Fe(III) reduction was significantly stimulated in response to biochar addition, while Fe(II) oxidation was inhibited because of the suppression of photosynthetic microorganism growth. The enhanced Fe(III) reduction and suppressed Fe(II) oxidation decreased the P solubility in the tested soils. These findings provide a cost-effective approach for inhibiting photosynthetic microorganism growth in paddy field and valuable insight into the effect of iron cycling on P retention for further management of eutrophication from exogenous and endogenous P loading. PMID- 28850842 TI - Vegetation recovery in an oil-impacted and burned Phragmites australis tidal freshwater marsh. AB - In-situ burning of oiled marshes is a cleanup method that can be more effective and less damaging than intrusive manual and mechanical methods. In-situ burning of oil spills has been examined for several coastal marsh types; however, few published data are available for Phragmites australis marshes. Following an estimated 4200gallon crude oil spill and in-situ burn in a Phragmites tidal freshwater marsh at Delta National Wildlife Refuge (Mississippi River Delta, Louisiana), we examined vegetation impacts and recovery across 3years. Oil concentrations in marsh soils were initially elevated in the oiled-and-burned sites, but were below background levels within three months. Oiling and burning drastically affected the marsh vegetation; the formerly dominant Phragmites, a non-native variety in our study sites, had not fully recovered by the end of our study. However, overall vegetation recovery was rapid and local habitat quality in terms of native plants, particularly Sagittaria species, and wildlife value was enhanced by burning. In-situ burning appears to be a viable response option to consider for future spills in marshes with similar plant species composition, hydrogeomorphic settings, and oiling conditions. In addition, likely Phragmites stress from high water levels and/or non-native scale insect damage was also observed during our study and has recently been reported as causing widespread declines or loss of Phragmites stands in the Delta region. It remains an open question if these stressors could lead to a shift to more native vegetation, similar to what we observed following the oil spill and burn. Increased dominance by native plants may be desirable as local patches, but widespread loss of Phragmites, even if replaced by native species, could further acerbate coastal erosion and wetland loss, a major concern in the region. PMID- 28850843 TI - Source, health risk and composition impact of outdoor very fine particles (VFPs) to school indoor environment in Xi'an, Northwestern China. AB - Very fine particles (VFPs, PM0.25) are able to travel deeply into the respiratory tract and can produce adverse health effects, especially to children. Information on the VFPs in schools is generally lacking. We investigated the chemical compositions, sources and health risks of VFPs in a junior secondary school of Xi'an, China, during May 16th to 30th, 2012. The results showed that organic matter (37% and 39%), SO42- (13% and 11%) and geological material (20% and 24%) were the major components of VFPs both outdoors and indoors. The VFP species indoors, such as SO42- and elemental carbon, are mainly from outdoor origins, e.g. coal burning and traffic emissions. But particle resuspension by student activities, chalk dust and import from outdoors of soil dust also contributed to deteriorate air quality in the classroom. By contrast to outdoors, several indoor factors, like higher room temperature, limited volume and longer suspension time of classroom particles, can even lead to significant secondary pollutant production. Heavy metals (mainly from outside) bound to indoor VFPs are supposedly associated to non-cancer health risks, especially Pb through ingestion pathway and Mn through dermal contact. Outdoor VFPs may be associated to PAHs cancer health risks via inhalation way. This study confirms that both indoor and outdoor sources had contributions to indoor VFPs, and that VFPs health risk should be of higher concern in urban areas of Northwestern China. PMID- 28850844 TI - Metal enrichment in estuarine sediments proximal to acid sulfate soils as a novel palaeodrought proxy. AB - Persistent drought over eastern Australia at the turn of the last millennium reduced stream flow in Australia's largest and most economically important drainage basin. Low water levels in the basin's terminal lakes triggered widespread pyrite oxidation, which altered surface water chemistry and released metals into the environment. The frequency of these events, and the links between drought and acid sulfate soil activation, are not known because the historical and instrumental records are short. Here, we present a Holocene-aged record of trace metal enrichment from Lake Albert-part of the terminal Lower Lakes system of the Murray-Darling Basin, Australia-that demonstrates the potential of trace elements mobilised during acidification events for palaeodrought reconstructions. Symptomatic metals were measured from a core of clayey sediment to form a multi element assemblage that reveals acidification events in the geological past. Correlation with regional climate proxies suggests that climate forcing is significant in driving metal flux to estuarine sinks in acid sulfate soil rich landscapes, although the intensity of a drought is not the only variable responsible for acidification intensity. The constructed record indicates that regional climate moved from a generally humid climate phase with intermittent droughts, to a more arid climate at ~5.2ka which prevailed until ~1.7ka. Following conditions were relatively wet with low climatic variability through till European Settlement. Enrichment is observed coincident with both the 1982-83 drought and Millennium Drought, the latter of which reaching an intensity unsurpassed in the last ~4.8ka, likely a product of anthropogenic changes to the Lower Murray-Darling Basin system. PMID- 28850845 TI - The potential value of biochar in the mitigation of gaseous emission of nitrogen. AB - Nitrogen (N) losses through gaseous emission of ammonia (NH3) and nitrous oxide (N2O) can contribute to both economic loss and environmental degradation. This study examined the effect of biochar and a chemical nitrification inhibitor, dicyandiamide (DCD), on N transformation and N losses via gaseous emission of NH3 and N2O from agricultural soils treated with a range of organic and inorganic N sources. The addition of DCD reduced N2O emission from both organic and inorganic N sources treated soils by 75%, but increased ammonium (NH4+) concentration and subsequently induced high NH3 emission from the soils. In contrast, the addition of biochar reduced both N2O and NH3 emissions from organic and inorganic N sources treated soils by 23% and 43%, respectively. The effectiveness of biochar and DCD in reducing NH3 volatilization and N2O emission depends on the nature of the N sources and their initial mineral N concentration. The study demonstrated that biochar can be used to mitigate N losses resulting from NH3 volatilization and N2O emission. PMID- 28850846 TI - Metal pollutants in Indian continental coastal marine sediment along a 3700km transect: An electron paramagnetic resonance spectroscopic study. AB - We report the analysis and geographical distribution of anthropogenically impacted marine surficial sediments along a 3700km transect around the continental shelf of India. Sediments have been studied using a mixed analytical approach; high sensitivity electron paramagnetic resonance (EPR), chemical analysis and environmental magnetism. Indian coastal marine deposits are heavily influenced by monsoon rains flushing sediment of geological and anthropogenic origin out of the subcontinental river systems. That is, climatic, hydro-, geo- and anthropogenic spheres couple strongly to determine the nature of Indian coastal sediments. Enrichment of Ni, Cu and Cr is observed in shelf sediments along both east and west coasts associated with industrialised activities in major urban areas. In the Gulf of Cambay and the Krishna and Visakhapatnam deltaic regions, levels of Ni and Cr pollutants (>=80 and >=120ppm respectively) are observed, sufficient to cause at least medium adverse biological effects in the marine ecosystem. In these areas sediment EPR spectra differ in characteristic from those of less impacted ones. Modelling enables deconvolution of EPR spectra. In conjunction with environmental magnetism techniques, EPR has been used to characterise species composition in coastal depositional environments. Paramagnetic species can be identified and their relative concentrations determined. EPR g-values provide information about the chemical and magnetic environment of metals. We observe g-values of up to 5.5 and large g shifts indicative of the presences of a number of para and ferrimagnetic impurities in the sediments. EPR has enabled the characterisation of species composition in coastal depositional environments, yielding marine sediment environmental 'fingerprints'. The approach demonstrates the potential of EPR spectroscopy in the mapping and evaluation of the concentration and chemical speciation in paramagnetic metals in sediments from marine shelf environments and their potential for source apportionment and environmental impact assessment. PMID- 28850847 TI - Free indium concentration determined with AGNES. AB - Indium is increasingly used in electronic devices, from which it can be mobilized towards environmental compartments. Speciation of In in waters is important for its direct ecotoxicological effects, as well as for the fate of this element in the environment (e.g. fluxes from or towards sediments). Free indium concentrations in the environment can be extremely low due to hydrolysis, especially important in trivalent cations, to precipitation and to complexation with different ligands. In this work, the free indium concentration (which is a toxicologically and geochemically relevant fraction) in aqueous solutions at pH3 has been measured with an adapted version of the electroanalytical technique AGNES (Absence of Gradients and Nernstian Equilibrium Stripping). Speciation measurements in mixtures of indium with the ligands NTA (nitrilotriacetic acid) and oxalate indicate that the values of their stability constants in the NIST46.6 database are less adequate than those published in some more recent literature. The extraordinary lability and mobility of In-oxalate complexes allow the measuring of free indium concentrations below nmol/L in just 25s of deposition time. PMID- 28850848 TI - A reassessment of the carnivorous status of salmonids: Hepatic glucokinase is expressed in wild fish in Kerguelen Islands. AB - Salmonids belong to a high trophic level and are thus considered as strictly carnivorous species, metabolically adapted for high catabolism of proteins and low utilisation of dietary carbohydrates. However they conserved a "mammalian type" nutritional regulation of glucokinase encoding gene and its enzymatic activity by dietary carbohydrates which remains puzzling regarding their dietary regime. The present study investigates the hypothesis that this conservation could be linked to a real consumption by trout of this nutrient in their natural habitat. To do so, brown trout were sampled in the sub-Antarctic Kerguelen Islands, a site presenting oligotrophic hydrosystems and no local freshwater fish fauna prior the introduction of salmonids fifty years ago. Qualitative and quantitative analysis of carbohydrate content within Kerguelen trout stomachs demonstrate that these animals are fed on food resources containing digestible carbohydrates. Additionally, glycaemia and more particularly gck mRNA level and gck enzymatic activity prove that Kerguelen trout digest and metabolise dietary carbohydrates. Physiological and molecular analyses performed in the present study thus strongly evidence for consumption of dietary carbohydrates by wild trout in natural environments. Investigating differences between Kerguelen individuals, we found that smaller individuals presented higher glycaemia, as well as higher carbohydrates contents in stomach. However no relationship between scaled mass index and any physiological indicator was found. Thus it appears that Kerguelen trout do not turn to carbohydrate diet because of a different condition index, or that the consumption of carbohydrates does not lead to a generally degraded physiological status. As a conclusion, our findings may explain the evolutionary conservation of a "mammalian-type" nutritional regulation of gck by dietary carbohydrates in these carnivorous fish. PMID- 28850849 TI - Inactivation of enteric indicator bacteria and system stability during dry co digestion of food waste and pig manure. AB - Provision of digestate with satisfactory biosafety is critical to land application of digestate and to the anaerobic digestion approach to treating manure and food waste (FW). No studies have been conducted on digestate biosafety in dry co-digestion systems. The aim of this study was to assess the inactivation efficiency and possible inactivation mechanism for three enteric indicator bacteria and the system stability during dry mesophilic anaerobic co-digestion of FW and pig manure (PM). The effects of two different inocula were examined at a rate of 50% based on volatile solids (VS): digestate taken from existing dry co digestion digesters and dewatered anaerobic sludge from a local wastewater treatment plant. The FW/PM ratios of 50:50 and 75:25 on a VS basis were also assessed. The results showed that using digestate as the inoculum and a FW/PM ratio of 50:50 led to stable dry co-digestion, with the specific methane yield (SMY) of 252mL/gVSadded. Total volatile fatty acid (VFA) concentration was a significant inhibition factor for methane production during dry co-digestion (P<0.001). The data also showed that dry co-digestion of FW and PM effectively inactivated enteric indicator bacteria. E. coli and total coliforms counts decreased below the limit of detection (LOD, 102CFU/g) within 4-7days, with free VFA identified as a significant inactivation factor. Enterococci were more resistant but nonetheless the counts decreased below the LOD within 12days in the digestate inoculum systems and 26-31days in the sludge inoculum systems. The residence time was the most significant inactivation factor for enterococci, with the free VFA concentration playing a secondary role at high FW/PM ratio in the sludge inoculum system. In conclusion, digestate as inoculum and the FW/PM ratio of 50:50 were preferable operation conditions to realize system stability, methane production and enteric indicator bacteria inactivation. PMID- 28850850 TI - Spatial modeling of sediment transfer and identification of sediment sources during snowmelt in an agricultural watershed in boreal climate. AB - Sediment transfer patterns during snowmelt were studied in a small Finnish agricultural watershed. Erosion rates were high as a consequence of high runoff volumes over saturated soil that partly lacked vegetation cover. Automatic high frequency monitoring data of sediment and phosphorus concentrations in stream showed a clock-wise hysteresis loop as a dominant pattern. GIS-based modeling of runoff and soil erosion, using LiDAR DTM data, suggested that runoff and erosion mostly came from cropland that had the highest sediment contribution index. Also sediment fingerprinting with Cesium-137 suggested cropland and stream bank were the most important sources of suspended sediments in streams. Because a major part of annual sediment transfer takes place during snowmelt, it is a critical period for annual losses of pollutants. Management practices that minimize springtime sediment and pollutant losses from cropland would be needed to make a marked impact on annual pollution transfer to stream waters. PMID- 28850851 TI - Suspended solids moderate the degradation and sorption of waste water-derived pharmaceuticals in estuarine waters. AB - This study focuses on the fate of pharmaceuticals discharged into an estuarine environment, particularly into the Turbidity Maximum Zone (TMZ). Batch experiments were set up to investigate the factors regulating the degradation of 53 selected pharmaceuticals. Treated effluents from Bordeaux city (France) were mixed with water from the estuarine Garonne River during 4weeks under 6 characterized conditions in order to assess the influence of suspended particulates, sterilization, untreated wastewater input and dilution on the degradation kinetics. Of the 53 pharmaceuticals monitored, 43 were quantified at the initial time. Only 7 exhibited a persistent behavior (e.g. carbamazepine, meprobamate) while biotic degradation was shown to be the main attenuation process for 38 molecules (e.g. abacavir, ibuprofen highly degradable). Degradation was significantly enhanced by increasing concentrations of suspended solids. A persistence index based on the half-lives of the compounds has been calculated for each of the 43 pharmaceuticals to provide a practical estimate of their relative stability. The stability of pharmaceuticals in estuarine environments is likely to be highly variable and attenuated primarily by changes in suspended solid concentration. PMID- 28850852 TI - Occurrence and growth of Listeria monocytogenes in packaged raw milk. AB - The increased availability of packaged raw drinking milk necessitates the investigation of the occurrence and growth of Listeria monocytogenes in raw milk during distribution and storage. The occurrence of L. monocytogenes in 105 retailed raw milk bottles, 115 bulk tank milk samples, 23 in-line milk filter socks and in 50 environmental samples collected from an on-farm dairy establishment were investigated. Growth of inoculated low-level L. monocytogenes contamination was also investigated in two types of raw milk packaging, namely in 1-litre plastic bottles and 3-litre bag-in-boxes, both stored at three different storage temperatures of 6, 8 and 10 degrees C. The occurrence of L. monocytogenes was higher (4.8%) in bottled raw milk stored until the use-by-date of the package compared to fresh bulk tank milk (1.7%). L. monocytogenes counts were <=13CFU/ml in bottled raw milk and <=1CFU/ml in bulk tank milk. L. monocytogenes was not detected in the packaging facility, but occurred very frequently (39%) in the milk filter socks. Subtyping of L. monocytogenes isolates using pulsed-field gel electrophoresis revealed seven pulsotypes, of which two occurred in multiple samples. Targeted inoculum levels of 1-2CFU/ml yielded L. monocytogenes counts>=100CFU/ml within seven days of storage in 22% of the raw milk packages stored at 6 degrees C, and in all of the raw milk packages stored at 8 degrees C. The frequent occurrence of L. monocytogenes in raw milk and the ability of a low level L. monocytogenes contamination to grow at refrigeration temperatures highlight the importance of consumer education regarding the appropriate raw milk storage and handling. PMID- 28850853 TI - Quantitative genetic analysis of anxiety trait in bipolar disorder. AB - BACKGROUND: Bipolar disorder type I (BPI) affects approximately 1% of the world population. Although genetic influences on bipolar disorder are well established, identification of genes that predispose to the illness has been difficult. Most genetic studies are based on categorical diagnosis. One strategy to overcome this obstacle is the use of quantitative endophenotypes, as has been done for other medical disorders. METHODS: We studied 619 individuals, 568 participants from 61 extended families and 51 unrelated healthy controls. The sample was 55% female and had a mean age of 43.25 (SD 13.90; range 18-78). Heritability and genetic correlation of the trait scale from the Anxiety State and Trait Inventory (STAI) was computed by using the general linear model (SOLAR package software). RESULTS: we observed that anxiety trait meets the following criteria for an endophenotype of bipolar disorder type I (BPI): 1) association with BPI (individuals with BPI showed the highest trait score (F = 15.20 [5,24], p = 0.009), 2) state independence confirmed after conducting a test-retest in 321 subjects, 3) co segregation within families 4) heritability of 0.70 (SE: 0.060), p = 2.33 * 10-14 and 5) genetic correlation with BPI was 0.20, (SE = 0.17, p = 3.12 * 10-5). LIMITATIONS: Confounding factors such as comorbid disorders and pharmacological treatment could affect the clinical relationship between BPI and anxiety trait. Further research is needed to evaluate if anxiety traits are specially related to BPI in comparison with other traits such as anger, attention or response inhibition deficit, pathological impulsivity or low self-directedness. CONCLUSIONS: Anxiety trait is a heritable phenotype that follows a normal distribution when measured not only in subjects with BPI but also in unrelated healthy controls. It could be used as an endophenotype in BPI for the identification of genomic regions with susceptibility genes for this disorder. PMID- 28850854 TI - Thyroid peroxidase antibodies during early gestation and the subsequent risk of first-onset postpartum depression: A prospective cohort study. AB - BACKGROUND: During the postpartum period, women are at risk for the new onset of both auto-immune thyroid disorders and depression. The presence of thyroid peroxidase antibodies (TPO-ab) during early gestation is predictive for postpartum auto-immune thyroid dysfunction. The aim of this study was to investigate the association between TPO-ab status during early gestation and first-onset postpartum depression. METHODS: Prospective cohort study (n = 1075) with follow-up during pregnancy up to one year postpartum. Thyroid function and TPO-ab status were measured during early gestation. Depressive symptomatology was assessed during each trimester and at four time points postpartum with the Edinburgh Depression Scale (EDS). Women with antenatal depression were not eligible for inclusion. Self-reported postpartum depression was defined with an EDS cut-off of >= 13. RESULTS: The cumulative incidence of self-reported first onset depression in the first postpartum year was 6.3%. A positive TPO-ab status was associated with an increased risk for self-reported first-onset depression at four months postpartum (adjusted OR 3.8; 95% CI 1.3-11.6), but not at other postpartum time points. Prevalence rates of self-reported postpartum depression declined after four months postpartum in the TPO-ab positive group, but remained constant in the TPO-ab negative group. LIMITATIONS: Depression was defined with a self-rating questionnaire (EDS). CONCLUSIONS: Women with an increased TPO-ab titer during early gestation are at increased risk for self-reported first-onset depression. The longitudinal pattern of self-reported postpartum depression in the TPO-ab positive group was similar to the typical course of postpartum TPO-ab titers changes. This suggests overlap in the etiology of first-onset postpartum depression and auto-immune thyroid dysfunction. Thyroid function should be evaluated in women with first-onset postpartum depression. PMID- 28850855 TI - Specificity and overlap of attention and memory biases in depression. AB - BACKGROUND: Attentional and memory biases are viewed as crucial cognitive processes underlying symptoms of depression. However, it is still unclear whether these two biases are uniquely related to depression or whether they show substantial overlap. METHODS: We investigated the degree of specificity and overlap of attentional and memory biases for depressotypic stimuli in relation to depression and anxiety by means of meta-analytic commonality analysis. By including four published studies, we considered a pool of 463 healthy and subclinically depressed individuals, different experimental paradigms, and different psychological measures. RESULTS: Memory bias is reliably and strongly related to depression and, specifically, to symptoms of negative mood, worthlessness, feelings of failure, and pessimism. Memory bias for negative information was minimally related to anxiety. Moreover, neither attentional bias nor the overlap between attentional and memory biases were significantly related to depression. LIMITATIONS: Limitations include cross-sectional nature of the study. CONCLUSIONS: Our study showed that, across different paradigms and psychological measures, memory bias (and not attentional bias) represents a primary mechanism in depression. PMID- 28850856 TI - Suicidality and associated risk factors in outpatients attending a general medical facility in rural Kenya. AB - BACKGROUND: Low-and-Middle-Income-Countries (LMICs) account for 75% of global suicides. While primary care populations in high-income countries (HIC) typically have higher prevalence of suicidal behavior relative to general populations, few studies have explored suicidal behavior among general medical outpatients in LMICs. This study addresses the research gap by characterizing potential risk factors for suicidal ideation in a large general medical outpatient setting in rural Kenya. METHODS: A cross-sectional study of adult general medical outpatients attending a rural sub-county hospital in Kaloleni, Kenya. Primary outcomes included major depressive disorder (MDD), posttraumatic stress disorder (PTSD) and suicidal behavior measured by the Mini International Neuropsychiatric Interview (MINI 5.0). We use binary logistic regression to model suicidality, mental disorders, intimate partner violence, and lifetime abuse. RESULTS: 394 outpatients completed the assessment. The prevalence of SI over the past month was 20%. 18% of those with suicidal ideation over the past month also attempted suicide in the past month. Participants who met criteria for MDD (suicidality item removed) were 19 times [CI: 4.56, 79.05] more likely to report suicidal ideation compared to those without MDD (adjusted odds ratio 12.15 [CI: 2.66, 55.49]). LIMITATIONS: This was a cross sectional study design with convenience sampling and hence vulnerable to selection and recall bias. CONCLUSION: The prevalence of SI and its strong association with actual suicide attempt in this population, make an urgent public health case for intervention. These data identify MDD as a highly significant correlate of SI. PMID- 28850857 TI - Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta analysis. AB - BACKGROUND: Gene-environment interaction contributes to the risks of psychiatric disorders. Interactions between FKBP5 gene variants and early-life stress may enhance the risk not only for mood disorder, but also for a number of other behavioral phenotypes. The aim of the present study was to review and conduct a meta-analysis on the results from published studies examining interaction between FKBP5 gene variants and early-life stress and their associations with stress related disorders such as major depression and PTSD. METHODS: A literature search was conducted using PsychINFO and PubMed databases until May 2017. A total of 14 studies with a pooled total of 15109 participants met the inclusion criteria, the results of which were combined and a meta-analysis was performed using the differences in correlations as the effect measure. Based on literature, rs1360780, rs3800373, and rs9470080 SNPs were selected within the FKBP5 gene and systematic review was conducted. RESULTS: Based on the Comprehensive Meta Analysis software, no publication bias was detected. Sensitivity analysis and credibility of meta-analysis results also indicated that the analyses were stable. The meta-analysis showed that individuals who carry T allele of rs1360780, C-allele of rs3800373 or T-allele of rs9470080 exposed to early-life trauma had higher risks for depression or PTSD. LIMITATIONS: The effects of ethnicity, age, sex, and different stress measures were not examined due to limited sample size. CONCLUSIONS: These results provide strong evidence of interactions between FKBP5 genotypes and early-life stress, which could pose a significant risk factor for stress-associated disorders such as major depression and PTSD. PMID- 28850858 TI - Associations between fine particulate matter and mortality in the 2001 Canadian Census Health and Environment Cohort. AB - BACKGROUND: Large cohort studies have been used to characterise the association between long-term exposure to fine particulate matter (PM2.5) air pollution with non-accidental, and cause-specific mortality. However, there has been no consensus as to the shape of the association between concentration and response. METHODS: To examine the shape of this association, we developed a new cohort based on respondents to the 2001 Canadian census long-form. We applied new annual PM2.5 concentration estimates based on remote sensing and ground measurements for Canada at a 1km spatial scale from 1998 to 2011. We followed 2.4 million respondents who were non-immigrants aged 25-90 years and did not reside in an institution over a 10 year period for mortality. Exposures were assigned as a 3 year mean prior to the follow-up year. Income tax files were used to account for residential mobility among respondents using postal codes, with probabilistic imputation used for missing postal codes in the tax data. We used Cox survival models to determine hazard ratios (HRs) for cause-specific mortality. We also estimated Shape Constrained Health Impact Functions (a concentration-response function) for selected causes of death. RESULTS: In models stratified by age, sex, airshed, and population centre size, and adjusted for individual and neighbourhood socioeconomic variables, HR estimates for non-accidental mortality were HR = 1.18 (95% CI: 1.15-1.21) per 10MUg/m3 increase in concentration. We observed higher HRs for cardiovascular disease (HR=1.25; 95% CI: 1.19-1.31), cardio-metabolic disease (HR = 1.27; 95% CI: 1.21-1.33), ischemic heart disease (HR = 1.36; 95% CI: 1.28-1.44) and chronic obstructive pulmonary disease (COPD) mortality (HR = 1.24; 95% CI: 1.11-1.39) compared to HR for all non-accidental causes of death. For non-accidental, cardio-metabolic, ischemic heart disease, respiratory and COPD mortality, the shape of the concentration-response curve was supra-linear, with larger differences in relative risk for lower concentrations. For both pneumonia and lung cancer, there was some suggestion that the curves were sub-linear. CONCLUSIONS: Associations between ambient concentrations of fine particulate matter and several causes of death were non-linear for each cause of death examined. PMID- 28850859 TI - Prevalence and correlates of smoking and e-cigarette use among young men who have sex with men and transgender women. AB - BACKGROUND: Although the prevalence of cigarette smoking in the United States has decreased, rates remain elevated among sexual and gender minorities (SGMs). This study examined rates and correlates of tobacco use among young men who have sex with men (YMSM) and transgender women. METHODS: Participants (N=771) were drawn from the baseline assessment of an ongoing longitudinal cohort study of racially diverse MSM aged 16-29 years. Data collection took place in 2015-2016. Socio demographic and SGM-specific (e.g., gender identity, sexual identity, physical attraction) correlates of cigarette smoking and electronic cigarette (e cigarette) use were identified using logistic regression. RESULTS: Twenty-one percent were current cigarette smokers. Nearly 40% ever tried an e-cigarette, but regular e-cigarette use was low (3.8%). Smokers were more likely to be older (vs. aged 16-18), less educated, homeless, bisexual or identify as some other sexual minority (vs. gay), attracted to males and females equally or more attracted to females than males (vs. males only), and HIV-positive. E-cigarette users were more likely to be transgender women (vs. cisgender men), White (vs. Black), more educated, and mostly attracted to females. CONCLUSIONS: Findings highlight important risk factors for tobacco use among SGM youth. Correlates of smoking mirrored findings observed in the general population, but also included factors specific to SGM youth (e.g., sexual orientation, HIV status, homelessness). Although some variables (gender identity, attraction) demonstrated similar relationships with smoking and e-cigarette use, others (race/ethnicity, education) demonstrated opposite patterns. Findings underscore the urgent need for tobacco prevention and cessation interventions for SGM youth. PMID- 28850860 TI - Cardiac injuries caused by trauma: Review and case reports. AB - Assessment of suspected cardiac injuries in a trauma setting is a challenging and time-critical matter, with clinical and imaging findings having complementary roles in the formation of an accurate diagnosis. In this article, we review the supporting literature for the pathophysiology, classification and evaluation of cardiac injuries caused by trauma. We also describe 4 cardiac trauma patients seen at a tertiary referral hospital. PMID- 28850861 TI - Volatile lipophilic substances management in case of fatal sniffing. AB - Death due to inhalation of aliphatic hydrocarbons such as butane and propane is a particularly serious problem worldwide, resulting in several fatal cases of sniffing these volatile substances in order to "get high". Despite the number of cases published, there is not a unique approach to case management of fatal sniffing. In this paper we illustrate the volatile lipophilic substances management in a case of a prisoner died after sniffing a butane-propane gas mixture from prefilled camping stove gas canisters, discussing the comprehensive approach of the crime scene, the autopsy, histology and toxicology. A large set of accurate values of both butane and propane was obtained by gas chromatography mass spectrometry analyzing the following post-mortem biological samples: peripheral blood, heart blood, vitreous humor, liver, lung, heart, brain/cerebral cortex, fat tissue, kidney, and allowed an in depth discussion about the cause of death. A key role is played by following the proper sampling approach during autopsy. PMID- 28850862 TI - Accurate recognition and feature qualify for flavonoid extracts from Liang-wai Gan Cao by liquid chromatography-high resolution-mass spectrometry and computational MS/MS fragmentation. AB - In this study, Liquid Chromatography (LC) separation combined with quadrupole Time-Of-Flight Mass Spectrometry (qTOF-MS) detection was used to analyze the characteristic ions of the flavonoids from Liang-wai Gan Cao (Radix Glycyrrhizae uralensis). First, accurate mass measurement and isotope curve optimization could provide reliable molecular prediction after noise deduction, baseline calibration and "ghost peak recognition". Thus, some spectral features in the LC-MS data could be clearly explained. Secondly, the chemical structure of flavonoids was deduced by MS/MS fragment ions, and the in-silico spectra by MS-FINDER program provided strong support for overcoming the bottleneck of phytochemical identification. For a predicted formula and experimental MS/MS spectrum, the MS FINDER program could sort the candidate compounds in the public database based on a comprehensive weighted score, and we took the first 20 reliable compounds to seek the target compound in an in-house database. Certainly, those fragmentation pathways could also be deduced and described as Retro-Diels-Alder (RDA) fragmentation reaction, losses of C4H8, C5H8, CH3, CO, CO2 and others. Accordingly, 63 flavonoids were identified, and their in-silico bioactivity were clearly disclosed by some bioinformatics tools. In this experiment, the flavonoids obtained by the four extraction processes were tested by LC-qTOF-MS. We looked for possible Q-markers from these data matrices and then quantified them; their similarities/differences were also described. The results also indicated that the Macroporous Adsorption Resins (MARs) purification is a low cost, environmentally friendly and effective approach. PMID- 28850863 TI - Determination of higenamine in dietary supplements by UHPLC/MS/MS method. AB - From 1st January 2017 higenamine was added on the WADA (World Anti-doping Agency) Prohibited list under S3 group beta-2 agonists as at all times banned substance for the athletes. The main origine of higenamine (or norcoclaurine) are different plants including Nandina domestica, Aconitum carmichaelii, Asarum heterotropioides, Galium divaricatum, Annona squamosa, Nelumbo nucifera etc. Higenamine main use is related to weight loss and it could be found (un)labeled in different dietary supplements. The objective of this study was development of sensitive and reliable UHPLC/MS/MS method for determination of higenamine in various dietary supplement samples. In order to obtain high method sensitivity, hydrophilic interaction liquid chromatography (HILIC) mode was applied. Separation was carried out on UHPLC Acquity BEH HILIC analytical column (2.1mm*100mm, 1.7MUm particle size). Mobile phase consisted of 0.1% formic acid in water and acetonitrile, respectively, was mixed in ratio of 30:70, v/v. Flow rate was set at 0.2mLmin-1. Quercetin was used as an internal standard. ESI (+) source ionization mode using multi reaction monitoring (MRM) mode was utilized and three ion transitions of higenamine were followed 272.08->107.01, 272.08 >161.07 and 272.08->77.08. Developed method was fully validated and applied for identification and quantification of higenamine in different dietary supplements. According to the results, the most of investigated supplements were free of higenamine, and on the other hand, presence of higenamine was confirmed in some samples while it was not declared on the label. PMID- 28850865 TI - The evolutionary roots of prosociality: the case of instrumental helping. AB - Comparative studies with closely related primate species are crucial to understand the origins of human prosociality. One type of prosocial behaviour that probably relies on evolutionary ancient skills and motivations is instrumental helping. Recent experimental studies have shown that bonobos and chimpanzees will help others achieve their action goals. Chimpanzees have shown to help others picking up and giving objects to a recipient, opening locked doors for conspecifics struggling to open them, and releasing stuck rewards that recipients were trying to reach. Recent studies have now replicated some of these results with bonobos. However, whereas chimpanzee's helping emerges mainly in response to recipients' signals of need, bonobos also help proactively. This difference could rely on bonobos' enhanced socio-cognitive skills. PMID- 28850864 TI - Sample preparation composite and replicate strategy case studies for assay of solid oral drug products. AB - Drug product assay is one of several tests required for new drug products to ensure the quality of the product at release and throughout the life cycle of the product. Drug product assay testing is typically performed by preparing a composite sample of multiple dosage units to obtain an assay value representative of the batch. In some cases replicate composite samples may be prepared and the reportable assay value is the average value of all the replicates. In previously published work by Harrington et al. (2014) [5], a sample preparation composite and replicate strategy for assay was developed to provide a systematic approach which accounts for variability due to the analytical method and dosage form with a standard error of the potency assay criteria based on compendia and regulatory requirements. In this work, this sample preparation composite and replicate strategy for assay is applied to several case studies to demonstrate the utility of this approach and its application at various stages of pharmaceutical drug product development. PMID- 28850866 TI - Resolving mass spectral overlaps in atom probe tomography by isotopic substitutions - case of TiSi15N. AB - Mass spectral overlaps in atom probe tomography (APT) analyses of complex compounds typically limit the identification of elements and microstructural analysis of a material. This study concerns the TiSiN system, chosen because of severe mass-to-charge-state ratio overlaps of the 14N+ and 28Si2+ peaks as well as the 14N2+ and 28Si+ peaks. By substituting 14N with 15N, mass spectrum peaks generated by ions composed of one or more N atoms will be shifted toward higher mass-to-charge-state ratios, thereby enabling the separation of N from the predominant Si isotope. We thus resolve thermodynamically driven Si segregation on the nanometer scale in cubic phase Ti1-xSix15N thin films for Si contents 0.08 <= x <= 0.19 by APT, as corroborated by transmission electron microscopy. The APT analysis yields a composition determination that is in good agreement with energy dispersive X-ray spectroscopy and elastic recoil detection analyses. Additionally, a method for determining good voxel sizes for visualizing small scale fluctuations is presented and demonstrated for the TiSiN system. PMID- 28850867 TI - Developing an in situ environmental TEM set up for investigations of resistive switching mechanisms in Pt-Pr1-xCaxMnO3-delta-Pt sandwich structures. AB - Non-volatile resistance change under electric stimulation in many metal-oxides is a promising path to next generation memory devices. However, the underlying mechanisms are still not fully understood. In situ transmission electron microscopy experiments provide a powerful tool to elucidate these mechanisms. In this contribution, we demonstrate a TEM lamella geometry for in situ biasing with two fixed electrode contacts ensuring low and stable contact resistances. We use Pr1-xCaxMnO3-delta sandwiched by Pt electrodes as model system. The evolution of manganese valence state during electric stimulation in different environments is mapped by means of electron energy loss spectroscopy with high spatial resolution in STEM. Correlation of Mn valence with local oxygen content is found. In addition to electrically driven switching, beam-induced redox reactions in oxygen environment are observed. This effect might be restricted to thin lamellae. In general, our results support that bulk oxygen electromigration is the relevant mechanism for non-volatile resistive switching in PCMO. PMID- 28850868 TI - Effects of nitrogen-deficiency on efficiency of light-harvesting apparatus in radish. AB - Nitrogen starvation has been stated to reduce chlorophyll a and accessory pigments, decrease photosynthetic efficiency, as well as modify chloroplast thylakoid membranes. However, the impact of N-deficiency on light-dependent reactions of photosynthesis has not been well understood. In this study, efficiency and structure of light-harvesting complex under N-deficiency conditions were investigated in two radish cultivars (Raphanus sativus var. sativus 'Fluo HF1' and 'Suntella F1'). Light-dependent reactions of photosynthesis were investigated by measuring in vivo chlorophyll a prompt fluorescence signal. Acquired data were utilised in two ways: by plotting fast induction curves and calculating OJIP-test biophysical parameters. Detailed analysis of difference curves as well as OJIP-test results showed that major disturbances were associated with photosystem II and its subunits, including decoupling of light-harvesting complexes, dysfunction of oxygen-evolving complex, and reaction centres inactivation. The maximum quantum yield of photosystem II primary photochemistry was severely restricted, causing an inhibition in electron transport through successive protein complexes in the thylakoid membrane. Structural changes were demonstrated by recording images using Transmission Electron Microscopy (TEM). TEM investigations showed intensive starch accumulation under N-deficiency. Rare thylakoid stacks distributed in tiny layers of stroma around grains and chloroplast periphery were observed in cells of N deficient plants. The application of principal component analysis (PCA) on OJIP test results allowed characterizing the dynamics of stress response and separating parameters according to their influence on plants stress response. 'Suntella F1' genotype was found to be more sensitive to nitrogen deficiency as compared to 'Fluo HF1' genotype. PMID- 28850869 TI - Influence of bacterial strains on Oryza sativa grown under arsenic tainted soil: Accumulation and detoxification response. AB - The present study was conducted to study the role of bacterial inoculants in growth, accumulation and tolerance responses in rice grown in arsenic (As) contaminated soil. Results revealed that out of five isolated bacterial strains, strain BBAU/MMM1 (Babasaheb Bhimrao Ambedkar University/Mari Matamandir) exhibited resistant to As(III) to the level of 400 MUM As(III) in comparison to other strain which showed toxicity. The isolated strain BBAU/MMM1 1was characterized as gram negative, rod shape, showed positive test nitrate, citrate, catalase and phosphate solubilization with high production of IAA and siderophore. Arsenic treated rice seedlings supplemented with bacterial inoculants BBAU/MMM1 showed increased growth characteristics viz., root length (35.41%), shoot length (32.8%) and fresh weight (30.31%) in comparison to rice treated with As(III) only. In addition, reduced lipid peroxidation and induces cysteine, GSH (reduced glutathione), GSSG (Oxidized glutathione) and antioxidant enzymatic activities were also observed in bacterial supplemented rice seedlings. Further, reduced metal accumulation in root (1351.46-968.67 MUg g-1fw), shoot (488.01-378.02 MUg g-1fw) and reduced translocation factor (0.583-0.390) in As(III) treated rice seedlings inoculated with bacterial strains clearly reflect protective response of bacterial strain against As toxicity. Thus, isolated bacterial strain could be used as bioremediator as well as growth inducer in paddy field contaminated with arsenic. PMID- 28850870 TI - Novel age estimation model based on development of permanent teeth compared with classical approach and other modern data mining methods. AB - In order to analyze and improve the dental age estimation in children and adolescents for forensic purposes, 22 age estimation methods were compared to a sample of 976 orthopantomographs (662 males, 314 females) of healthy Czech children and adolescents aged between 2.7 and 20.5 years. All methods are compared in terms of the accuracy and complexity and are based on various data mining methods or on simple mathematical operations. The winning method is presented in detail. The comparison showed that only three methods provide the best accuracy while remaining user-friendly. These methods were used to build a tabular multiple linear regression model, an M5P tree model and support vector machine model with first-order polynomial kernel. All of them have mean absolute error (MAE) under 0.7 years for both males and females. The other well-performing data mining methods (RBF neural network, K-nearest neighbors, Kstar, etc.) have similar or slightly better accuracy, but they are not user-friendly as they require computing equipment and the implementation as computer program. The lowest estimation accuracy provides the traditional model based on age averages (MAE under 0.96 years). Different relevancy of various teeth for the age estimation was found. This finding also explains the lowest accuracy of the traditional averages-based model. In this paper, a technique for missing data replacement for the cases with missing teeth is presented in detail as well as the constrained tabular multiple regression model. Also, we provide free age prediction software based on this wining model. PMID- 28850872 TI - Enhanced bioremoval of lead by earthworm-Lumbricus terrestris co-cultivated with bacteria-Klebsiella variicola. AB - Lead is a toxic heavy metal having devastating effects on the environment. The current study was focussed on bioremoval of lead using earthworm and lead resistant bacteria. Earthworms were subjected to various concentrations of lead in the soil bioaugmented with lead resistant bacteria (VITMVCJ1) to enhance the uptake of lead from the contaminated soil. Significant increase was observed in the length and body weight of the earthworms supplemented with lead resistant bacteria. Similarly, there was a substantial increase in the locomotion rate of the earthworms treated with lead resistant bacteria in comparison with the control. The gut micro flora of bacterial treated earthworms had increased number of bacterial cells than the untreated earthworms. The histopathological studies revealed the toxic effects of lead on the gut of earthworms indicating severe damage in lead resistant bacteria untreated worms, whereas the cells were intact in lead resistant bacteria treated worms. COMET assay showed increased DNA damage with higher tail DNA percent in the untreated earthworms. Further, the colonisation of the bacteria supplemented, onto the gut region of earthworms was observed by scanning electron microscopy. Atomic absorption spectrophotometry indicated a fair 50% uptake of lead within the biomass of earthworm treated with lead resistant bacteria. PMID- 28850871 TI - Postmortem distribution and redistribution of MDAI and 2-MAPB in blood and alternative matrices. AB - Intoxication cases involving new psychoactive substances (NPS) provide several challenges for forensic toxicologists as data on pharmacodynamic and pharmacokinetic properties are lacking, especially on potency and toxicity. Furthermore, reference values and information on postmortem redistribution (PMR) do not exist so far for most NPS. A fatal case involving the amphetamine derivatives MDAI (5,6-methylenedioxy-2-aminoindane) and 2-MAPB (1-(benzofuran-2 yl)-N-methylpropan-2-amine) was investigated at the Zurich Institute of Forensic Medicine. At admission at the institute approx. 11h after death (first time point, t1), femoral and heart blood (right ventricle) was collected using computed tomography (CT)-guided biopsy sampling. At autopsy (t2), samples from the same body regions as well as various tissue samples were collected manually. In addition, an antemortem blood sample collected 6h before death was available. MDAI and 2-MAPB were quantified using a validated LC-MS/MS method. A significant concentration decrease between the antemortem and the first peripheral postmortem blood sample was observed, which most probably can be explained by remaining metabolism and excretion within the last 6h prior to death. No significant concentration change was observed between the two postmortem heart blood and peripheral blood samples. Accordingly, MDAI and 2-MAPB did not seem to undergo relevant postmortem redistribution in peripheral and heart blood in the presented case. This is the first study on postmortem redistribution of the new psychoactive substances MDAI and 2-MAPB. However, more studies covering more cases are necessary to generate universal statements on the PMR with these two NPSs. PMID- 28850873 TI - Grower networks support adoption of innovations in pollination management: The roles of social learning, technical learning, and personal experience. AB - Management decisions underpinning availability of ecosystem services and the organisms that provide them in agroecosystems, such as pollinators and pollination services, have emerged as a foremost consideration for both conservation and crop production goals. There is growing evidence that innovative management practices can support diverse pollinators and increase crop pollination. However, there is also considerable debate regarding factors that support adoption of these innovative practices. This study investigated pollination management practices and related knowledge systems in a major crop producing region of southwest Michigan in the United States, where 367 growers were surveyed to evaluate adoption of three innovative practices that are at various stages of adoption. The goals of this quantitative, social survey were to investigate grower experience with concerns and benefits associated with each practice, as well as the influence of grower networks, which are comprised of contacts that reflect potential pathways for social and technical learning. The results demonstrated that 17% of growers adopted combinations of bees (e.g. honey bees, Apis mellifera, with other species), representing an innovation in use by early adopters; 49% of growers adopted flowering cover crops, an innovation in use by the early majority 55% of growers retained permanent habitat for pollinators, an innovation in use by the late majority. Not all growers adopted innovative practices. We found that growers' personal experience with potential benefits and concerns related to the management practices had significant positive and negative relationships, respectively, with adoption of all three innovations. The influence of these communication links likely has different levels of importance, depending on the stage of the adoption that a practice is experiencing in the agricultural community. Social learning was positively associated with adopting the use of combinations of bees, highlighting the potentially critical roles of peer-to-peer networks and social learning in supporting early stages of adoption of innovations. Engaging with grower networks and understanding grower experience with benefits and concerns associated with innovative practices is needed to inform outreach, extension, and policy efforts designed to stimulate management innovations in agroecosystems. PMID- 28850874 TI - Focused classification and refinement in high-resolution cryo-EM structural analysis of ribosome complexes. AB - Cryo electron microscopy (cryo-EM) historically has had a strong impact on the structural and mechanistic analysis of protein synthesis by the prokaryotic and eukaryotic ribosomes. Vice versa, studying ribosomes has helped moving forwards many methodological aspects in single particle cryo-EM, at the level of automated data collection and image processing including advanced techniques for particle sorting to address structural and compositional heterogeneity. Here we review some of the latest ribosome structures, where cryo-EM allowed gaining unprecedented insights based on 3D structure sorting with focused classification and refinement methods helping to reach local resolution levels better than 3A. Such high-resolution features now enable the analysis of drug interactions with RNA and protein side-chains including even the visualization of chemical modifications of the ribosomal RNA. These advances represent a major breakthrough in structural biology and show the strong potential of cryo-EM beyond the ribosome field including for structure-based drug design. PMID- 28850875 TI - Intestinal patch systems for oral drug delivery. AB - Intestinal patches provide a unique platform for oral delivery of drugs which possess poor oral bioavailability, necessitating their administration by injections. Intestinal patch based devices prevent drug degradation in the gastrointestinal tract, facilitate their intestinal absorption through forming a localized drug depot at the delivery site and provide unidirectional, controlled drug release while preventing luminal drug loss. Consequently, intestinal patch based devices are being developed for oral delivery of several drugs such as insulin, exenatide, calcitonin, interferon-alpha, erythropoietin and human granulocyte colony-stimulating factor for the treatment of diabetes, osteoporosis, hepatitis or for chemotherapy. This technology shows promise as a needle-free alternative to injectable drugs that would improve the quality of lives of millions of people requiring chronic administration of injectable drugs. PMID- 28850876 TI - Co-trained convolutional neural networks for automated detection of prostate cancer in multi-parametric MRI. AB - Multi-parameter magnetic resonance imaging (mp-MRI) is increasingly popular for prostate cancer (PCa) detection and diagnosis. However, interpreting mp-MRI data which typically contains multiple unregistered 3D sequences, e.g. apparent diffusion coefficient (ADC) and T2-weighted (T2w) images, is time-consuming and demands special expertise, limiting its usage for large-scale PCa screening. Therefore, solutions to computer-aided detection of PCa in mp-MRI images are highly desirable. Most recent advances in automated methods for PCa detection employ a handcrafted feature based two-stage classification flow, i.e. voxel level classification followed by a region-level classification. This work presents an automated PCa detection system which can concurrently identify the presence of PCa in an image and localize lesions based on deep convolutional neural network (CNN) features and a single-stage SVM classifier. Specifically, the developed co-trained CNNs consist of two parallel convolutional networks for ADC and T2w images respectively. Each network is trained using images of a single modality in a weakly-supervised manner by providing a set of prostate images with image-level labels indicating only the presence of PCa without priors of lesions' locations. Discriminative visual patterns of lesions can be learned effectively from clutters of prostate and surrounding tissues. A cancer response map with each pixel indicating the likelihood to be cancerous is explicitly generated at the last convolutional layer of the network for each modality. A new back propagated error E is defined to enforce both optimized classification results and consistent cancer response maps for different modalities, which help capture highly representative PCa-relevant features during the CNN feature learning process. The CNN features of each modality are concatenated and fed into a SVM classifier. For images which are classified to contain cancers, non-maximum suppression and adaptive thresholding are applied to the corresponding cancer response maps for PCa foci localization. Evaluation based on 160 patient data with 12-core systematic TRUS-guided prostate biopsy as the reference standard demonstrates that our system achieves a sensitivity of 0.46, 0.92 and 0.97 at 0.1, 1 and 10 false positives per normal/benign patient which is significantly superior to two state-of-the-art CNN-based methods (Oquab et al., 2015; Zhou et al., 2015) and 6-core systematic prostate biopsies. PMID- 28850877 TI - An in silico analysis of primary and secondary structure specificity determinants for human peptidylarginine deiminase types 2 and 4. AB - Human peptidylarginine deiminases (hPADs) are a family of five calcium-dependent enzymes that facilitate citrullination, which is the post-translational modification of peptidyl arginine to peptidyl citrulline. The isozymes hPAD2 and hPAD4 have been implicated in the development and progression of several autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. To better characterize the primary and secondary structure determinants of citrullination specificity, we mined the literature for protein sequences susceptible to citrullination by hPAD2 or hPAD4. First, protein secondary structure classification (alpha-helix, beta-sheet, or coil) was predicted using the PSIPRED software. Next, we used motif-x and pLogo to extract and visualize statistically significant motifs within each data set. Within the data sets of peptides predicted to lie in coil regions, both hPAD2 and hPAD4 appear to favor citrullination of glycine-containing motifs, while distinct hydrophobic motifs were identified for hPAD2 citrullination sites predicted to reside within alpha helical and beta-sheet regions. Additionally, we identified potential substrate overlap between coil region citrullination and arginine methylation. Together, these results confirm the importance and offer some insight into the role of secondary structure elements for citrullination specificity, and provide biological context for the existing hPAD specificity and arginine post translational modification literature. PMID- 28850878 TI - Transcriptome sequencing reveals potential mechanisms of diapause preparation in bivoltine silkworm Bombyx mori (Lepidoptera: Bombycidae). AB - In the bivoltine strain of the silkworm, Bombyx mori, embryonic diapause is induced transgenerationally as a maternal effect. Progeny diapause ability is determined by the environmental condition such as temperature and lightness that mothers experience during their own embryonic development. Diapause preparation is a crucial phase of this process; diapause-destined individuals undergo a series of preparatory events before the entry into developmental arrest. However, the molecular regulatory mechanisms of diapause preparation have largely remained unknown. In the present study, we sequenced the transcriptome of bivoltine silkworm Qiufeng's ovaries resulted in laying of diapause destined or non diapause eggs, using high-throughput RNA-Seq technology. Differential expression analyses identified 183 genes with higher expression, and 106 with lower expression under diapause-inducing conditions. GO and KEGG analysis revealed that the enrichment of several functional terms related to peroxisome, glycerolipid metabolism, steroid biosynthesis, longevity regulating pathway - multiple species, three signaling transductions, insect hormone biosynthesis, and cytoskeleton components. We conducted a detailed comparison of transcript profile data of ovaries from diapause-inducing and non-diapause conditions, the results imply up-regulation of peroxisomal metabolism, triacylglycerides accumulation, cryoprotectant production, and ecdysteroid biosynthesis in diapause-inducing group. Differential expression of genes related to actin cytoskeleton implies the occurrence of shifts in cellular structure and composition between diapause inducing and non-diapause-inducing groups. The Hippo and FOXO signaling pathways may play an important role in preparing for entering diapause. This study provides an insight into the molecular events of insect diapause, in particular for the preparatory phase. PMID- 28850879 TI - Sedentary behavior is associated with lower serum concentrations of vitamin D in Brazilian children. PMID- 28850880 TI - Laparoscopic guided continuous type 1 quadratus lumborum block - "Sindwani technique with case series". PMID- 28850881 TI - Ventricular fibrillation caused by electrocautery for pericardium hemostasis during thoracotomy. PMID- 28850882 TI - Tone-grammar association within words: Concurrent ERP and fMRI show rapid neural pre-activation and involvement of left inferior frontal gyrus in pseudoword processing. AB - Using a concurrent ERP/fMRI paradigm, we investigated how listeners take advantage of morphologically relevant tonal information at the beginning of words to predict and pre-activate likely word endings. More predictive, low tone word stems gave rise to a 'pre-activation negativity' (PrAN) in the ERPs, a brain potential which has previously been found to increase along with the degree of predictive certainty as regards how a word is going to end. It is suggested that more predictive, low tone stems lead to rapid access to word endings with processing subserved by the left primary auditory cortex as well as the supramarginal gyrus, while high tone stems - which are less predictive - decrease predictive certainty, leading to increased competition between activated word endings, which needs to be resolved by the left inferior frontal gyrus. PMID- 28850883 TI - Environmental gamma radiation analysis for Ulsan city with the highest nuclear power plant density in Korea. AB - This study presents a real-time measurement-based rapid radiation distribution visualization system for radionuclide recognition, which can quickly scan a contaminated environment. The system combines a portable detector with a digital map and a program for quick data treatment. Radiation information at the measurement location is transferred between a detector and a laptop. It includes environmental and artificial components, specific radionuclides, and total radionuclides. After scanning the area, the radiation distributions are comprehensively displayed in 2D and 3D maps corresponding to the measured area, all in a few tens of seconds. The proposed method was verified using the standard 137Cs and 60Co sources. The gamma radiation distribution of the areas measured in Ulsan city, which included non-destructive testing and radioisotope treatment facilities, hospitals, transportation spots, and residential and commercial areas, showed that Ulsan city has maintained safe levels of radiation. The system performed well. In addition, it was found that this system could detect unexpected hot spots quickly in affected environments. PMID- 28850884 TI - Neuropsychological assessment and perinatal risk: A study amongst very premature born 4- and 5-year old children. AB - BACKGROUND: Prematurity and its consequences are serious problems that can result in numerous neurosensory disabilities and cerebral cognitive dysfunctions. The Perinatal Risk Index (PERI) might provide a predictive measure of these problems. AIM: This study compared the cognitive development of prematurely born children at 4 and 5 years of age with age-matched peers born at term. The secondary objective was to determine whether a correlation exists between perinatal risk and performance on neuropsychological tests among premature children. METHODS: A total of 54 children between four and five years of age were evaluated; 27 were born very premature (premature group; PG), and 27 were born at term (term group; TG). Executive function, attention, memory, language, visual perception, and spatial structuring were evaluated. Subtests from the Kaufman Assessment Battery for Children, the Rey Complex Figure Test, the McCarthy Scales of Children's Abilities, the Peabody Picture Vocabulary Test, Test A, Trails A and B, the spatial structuring questionnaire from the Child Neuropsychological Maturity Questionnaire, and the Wechsler Intelligence Scale for Children were used. A PERI score was also obtained for the PG. RESULTS: The PG showed significantly lower scores than the TG in all the studied cognitive domains. Visual-perceptive scores were significantly and negatively correlated with the PERI scores of the PG. CONCLUSIONS: The PG showed neurocognitive deficits compared with the TG. The PERI can be used to predict the development of visual-perceptive abilities in children between four and five years of age. PMID- 28850886 TI - Solar light irradiation significantly reduced cytotoxicity and disinfection byproducts in chlorinated reclaimed water. AB - Chlorinated reclaimed water is widely used for landscaping and recreational purposes, resulting in human exposure to toxic disinfection byproducts. Although the quality of chlorinated reclaimed water might be affected by sunlight during storage, the effects of solar light irradiation on the toxicity remain unknown. This study investigated the changes in cytotoxicity and total organic halogen (TOX) of chlorinated reclaimed water exposed to solar light. Irradiation with solar light for 12 h was found to significantly reduce the cytotoxicity of chlorinated reclaimed water by about 75%, with ultraviolet light being responsible for the majority of this reduction. Chlorine residual in reclaimed water tended to increase the cytotoxicity, and the synergy between solar light and free chlorine could not enhance the reduction of cytotoxicity. Adding hydroxyl radical scavengers revealed that the contribution of hydroxyl radical to cytotoxicity reduction was limited. Solar light irradiation concurrently reduced TOX. The low molecular weight (<1 kDa) fraction was the major contributor of cytotoxicity and TOX in chlorinated reclaimed water. Detoxification of the low molecular weight fraction by light irradiation was mainly a result of TOX dehalogenation, while detoxification of the high molecular weight (>1 kDa) fraction was probably caused by photoconversion from high toxic TOX to low toxic TOX. PMID- 28850885 TI - Quantifying behavior to solve sensorimotor transformations: advances from worms and flies. AB - The development of new computational tools has recently opened up the study of natural behaviors at a precision that was previously unachievable. These tools permit a highly quantitative analysis of behavioral dynamics at timescales that are well matched to the timescales of neural activity. Here we examine how combining these methods with established techniques for estimating an animal's sensory experience presents exciting new opportunities for dissecting the sensorimotor transformations performed by the nervous system. We focus this review primarily on examples from Caenorhabditis elegans and Drosophila melanogaster-for these model systems, computational approaches to characterize behavior, in combination with unparalleled genetic tools for neural activation, silencing, and recording, have already proven instrumental for illuminating underlying neural mechanisms. PMID- 28850887 TI - Computational and experimental analysis of organic degradation positively regulated by bioelectrochemistry in an anaerobic bioreactor system. AB - Methane production was tested in membrane-less microbial electrolysis cells (MECs) under closed-circuit (RCC) and open-circuit (ROC) conditions, using glucose as a substrate, to understand the regulatory effects of bioelectrochemistry in anaerobic digestion systems. A dynamic model was built to simulate methane productions and microbial dynamics of functional populations, which were colonized in groups RCC and ROC during the start-up stage. The experiment results showed significantly greater methane production in RCC than ROC, the average methane production of RCC was 0.131 m3/m3/d, which was 1.4 times higher than that of ROC (0.055 m3/m3/d). The simulation results revealed that bioelectrochemistry had a significant influence on the abundance of microorganisms involved in acidogenesis and methanogenesis. The abundance of glucose-uptaking microorganisms was 87% of the total biomass in ROC without applied voltage, which was 20% higher than that in RCC (67%) when external voltages were applied between the anode and cathode. The abundance of hydrogenotrophic methanogens in RCC was 6% higher than that in ROC. The simulation results were verified through 16S rDNA high-throughput sequencing analysis. An electron balance analysis revealed that alteration of the acidogenesis type led to more acetate and hydrogen production from glucose fermentation, compared with the situation without bioelectrochemistry. An additional pathway from acetate to hydrogen was introduced by bioelectrolysis. These two factors resulted in significant enhancement of methane production in RCC. Bioelectrolysis process directly contributed to 26% of the total methane production after the start-up stage. When the applied voltages were cut down or decreased, RCC could maintain considerable methane productions, because the microbial communities and electron transfer pathways were already formed. Starting-up with high voltage, but operating under low voltage, could be an energy-favorable strategy for accelerating biogas production in bioelectro anaerobic bioreactors. PMID- 28850888 TI - Bio-dispersive liquid liquid microextraction based on nano rhaminolipid aggregates combined with magnetic solid phase extraction using Fe3O4@PPy magnetic nanoparticles for the determination of methamphetamine in human urine. AB - In the present investigation, extraction and preconcentration of methamphetamine in human urine samples was carried out using a novel bio-dispersive liquid liquid microextraction (Bio-DLLME) technique coupled with magnetic solid phase extraction (MSPE). Bio-DLLME is a kind of microextraction technique based nano materials which have potential capabilities in many application fields. Bio-DLLME is based on the use of a binary part system consisting of methanol and nano rhaminolipid biosurfactant. Use of this binary mixture is ecologically accepted due to their specificity, biocompatibility and biodegradable nature. The potential of nano rhaminolipid biosurfactant as a biological agent in the extraction of organic compounds has been investigated in recent years. They are able to partition at the oil/water interfaces and reduce the interfacial tension in order to increase solubility of hydrocarbons. The properties of the prepared Fe3O4@PPy magnetic nanoparticles were characterized using Fourier transform infrared spectroscopy and X-ray diffraction methods The influences of the experimental parameters on the quantitative recovery of analyte were investigated. Under optimized conditions, the enrichment factor was 310, the calibration graph was linear in the methamphetamine concentration range from 1 to 60MUgL-1, with a correlation coefficient of 0.9998. The relative standard deviations for six replicate measurements was 5.2%. PMID- 28850889 TI - Gas chromatographic quadrupole time-of-flight full scan high resolution mass spectrometric screening of human urine in antidoping analysis. AB - This paper presents the development and validation of a high-resolution full scan (FS) electron impact ionization (EI) gas chromatography coupled to quadrupole Time-of-Flight mass spectrometry (GC/QTOF) platform for screening anabolic androgenic steroids (AAS) in human urine samples. The World Antidoping Agency (WADA) enlists AAS as prohibited doping agents in sports, and our method has been developed to comply with the qualitative specifications of WADA to be applied for the detection of sports antidoping prohibited substances, mainly for AAS. The method also comprises of the quantitative analysis of the WADA's Athlete Biological Passport (ABP) endogenous steroidal parameters. The applied preparation of urine samples includes enzymatic hydrolysis for the cleavage of the Phase II glucuronide conjugates, generic liquid-liquid extraction and trimethylsilyl (TMS) derivatization steps. Tandem mass spectrometry (MS/MS) acquisition was applied on few selected ions to enhance the specificity and sensitivity of GC/TOF signal of few compounds. The full scan high resolution acquisition of analytical signal, for known and unknown TMS derivatives of AAS provides the antidoping system with a new analytical tool for the detection designer drugs and novel metabolites, which prolongs the AAS detection, after electronic data files' reprocessing. The current method is complementary to the respective liquid chromatography coupled to mass spectrometry (LC/MS) methodology widely used to detect prohibited molecules in sport, which cannot be efficiently ionized with atmospheric pressure ionization interface. PMID- 28850890 TI - Comprehensive characterization and identification of antioxidants in Folium Artemisiae Argyi using high-resolution tandem mass spectrometry. AB - Antioxidants from natural sources, such as vegetables and fruits, are attracting more and more interest. In this work, we evaluated the antioxidant potential of Folium Artemisia Argyi, a traditional Chinese herb medicine and food supplement. The total phenolic content, total flavonoid content, and antioxidant ability of the crude extracts and fractions obtained from consecutively partition of n hexane, ethyl acetate, and n-butanol were measured and compared. Ethyl acetate fraction shows the highest total phenolic and flavonoid contents and highest antioxidant capability with regard to DPPH, ABTS, superoxide anion free radical scavenging ability, and ferric-reducing antioxidant power. In addition, the potential antioxidant components were screened by DPPH-UHPLC-MS experiments and subsequently characterized by using high-resolution tandem mass spectrometry. This work finally identified 45 antioxidants, including organic acids, phenolic compounds, flavonoids, and methoxylated flavonoids. The results suggested that Folium Artemisiae Argyi is a potential inexpensive resource of natural antioxidants. PMID- 28850891 TI - One-step lipid extraction for plasma lipidomics analysis by liquid chromatography mass spectrometry. AB - In the past decade, various lipidomics methodologies have been developed using mass spectrometry based analytical technologies, enabling wide coverage lipid detection in a quantitative manner. Hence, lipidomics has become a widely accepted approach for biomarker discovery and mechanism elucidation in both medical and biology research fields; however, there are still technical challenges. In this study, focusing on the sample preparation procedure, a single step deproteinization by a water-soluble organic solvent, such as methanol (MeOH), ethanol (EtOH), isopropanol (IPA) or acetonitrile (ACN), was evaluated and proved to be satisfactory for lipidomics analysis. Moreover, during this investigation ACN deproteinization was revealed to not be an effective method for lipid extraction because lipid decomposition was observed during the protein precipitation process through lipase activation, potentially due to the insufficient protein denaturation. Therefore, excluding ACN, protein precipitation by alcohol was evaluated as the lipid extraction reagent. Moreover, adding the MTBE-MeOH (mMM) method, one of the major liquid-liquid extraction methods for shotgun lipidomics, these four approaches were compared. Lipids were extracted from mouse plasma by these four methods and used for exhaustive lipid profiling by liquid chromatography mass spectrometry (LC/MS) analysis. Comparison of these four methods revealed that alcohol based protein precipitation was a useful sample preparation procedure for LC/MS based lipidomics analysis. Whereas MeOH extraction was appropriate for hydrophilic lipid species, IPA was effective for hydrophobic lipids such as triacylglycerols (TG). In practice, EtOH extraction is thought to be the best approach to cover wide range of lipid species using a simple preparation procedure. PMID- 28850892 TI - A computational insight into cyclopropenone activated dehydration reaction of alcohols. AB - The cyclopropenone activated dehydration reaction of alcohols is a promising alternative to alcohol substitution reactions to avoid hazardous byproducts and harsh reaction conditions. Density functional theory calculations at M062X/6 31+G(d,p) level were performed for two proposed reaction mechanisms of the cyclopropenone activated chlorodehydration reaction where alkyl chloride product can be obtained from both of the proposed reaction mechanisms but chloroxalate has only one alternative. The calculations enabled us to explain the rection mechanisms in detail. Additionally, the effects of the various substituents on the cyclopropenone ring for the product distribution ratio was clarified.The substitution with electron donating group on para position of the phenyl ring of cyclopropenone has no effect on the relative free energy of the rate-determining step where the electron-withdrawing group increase the energy values independent from the position. The product ratio values that were calculated from energy barriers are in harmony with the experimentally obtained ones pointing out the reaction mechanism preference. PMID- 28850893 TI - Host-guest interactions between sildenafil and cyclodextrins: Spectrofluorometric study and molecular dynamic modeling. AB - Sildenafil (SF) was included in cyclodextrins (CD) to enhance its solubility. Spectrofluorometry was used to confirm the complexation constant (stability constant). The orientations of SF inside the beta-CDs and gamma-CDs were fully illustrated. Molecular dynamics simulations were performed on two inclusion complexes (beta-CD/SF and gamma-CD/SF) in the aqueous system. The polar methylpiperazine group was found to locate inside the beta-CD cavity, both in the wide and narrow side and was positioned 2 degrees A from the center. In contrast, the methylpiperazine group did not fit well within the gamma-CD cavity. Moreover, these results also confirmed hydrogen bonding that the highest number of bonding formed between the polar methylpiperazine sulfonyl structure and the hydroxyl group of beta-CD. The simulated binding free energy of the methylpiperazine-beta CD inclusion complex (-6.01kcal/mol), featured a large contribution from electrostatic and van der Waals forces, which was the most stable complex. The association constant of beta-CD/SF (12.3) was higher than gamma-CD/SF (3.3) and confirmed with in silico measurements of binding free energy. In summary, SF forms a stable complex with beta-CD. PMID- 28850894 TI - Protocol for fast screening of multi-target drug candidates: Application to Alzheimer's disease. AB - The treatment of many diseases may require drugs that are capable to attack multiple targets simultaneously. Obviously, the virtual screening of multi-target drug candidates is much more time consuming compared to the single-target case. This, in particular, concerns the last step of virtual screening where the binding free energy is computed by conventional molecular dynamics simulation. To overcome this difficulty we propose a simple protocol which is relied on the fast steered molecular dynamics simulation and on available experimental data on binding affinity of reference ligand to a given target. Namely, first we compute non-equilibrium works generated during pulling ligands from the binding site using the steered molecular dynamics method. Then as top leads we choose only those compounds that have the non-equilibrium work larger than that of a reference compound for which the binding free energy has been already known from experiment. Despite many efforts no cures for AD (Alzheimer's disease) have been found. One of possible reasons for this failure is that drug candidates were developed for a single target, while there are exist many possible pathways to AD. Applying our new protocol to five targets including amyloid beta fibril, peroxisome proliferator-activated receptor gamma, retinoic X receptor alpha, beta and gamma-secretases, we have found two potential drugs (CID 16040294 and CID 9998128) for AD from the large PubChem database. We have also shown that these two ligands can interfere with the activity of popular Acetylcholinesterase target through strong binding towards it. PMID- 28850895 TI - Scrutinizing human MHC polymorphism: Supertype analysis using Poisson-Boltzmann electrostatics and clustering. AB - Peptide-binding MHC proteins are thought the most variable across the human population; the extreme MHC polymorphism observed is functionally important and results from constrained divergent evolution. MHCs have vital functions in immunology and homeostasis: cell surface MHC class I molecules report cell status to CD8+ T cells, NKT cells and NK cells, thus playing key roles in pathogen defence, as well as mediating smell recognition, mate choice, Adverse Drug Reactions, and transplantation rejection. MHC peptide specificity falls into several supertypes exhibiting commonality of binding. It seems likely that other supertypes exist relevant to other functions. Since comprehensive experimental characterization is intractable, structure-based bioinformatics is the only viable solution. We modelled functional MHC proteins by homology and used calculated Poisson-Boltzmann electrostatics projected from the top surface of the MHC as multi-dimensional descriptors, analysing them using state-of-the-art dimensionality reduction techniques and clustering algorithms. We were able to recover the 3 MHC loci as separate clusters and identify clear sub-groups within them, vindicating unequivocally our choice of both data representation and clustering strategy. We expect this approach to make a profound contribution to the study of MHC polymorphism and its functional consequences, and, by extension, other burgeoning structural systems, such as GPCRs. PMID- 28850896 TI - Intermolecular hydrogen bonds between 1,4-benzoquinones and HF molecule: Synergetic effects, reduction potentials and electron affinities. AB - Some biological activities of quinones can be attributed to the H-bonding ability of acceptor oxygen atoms. According to the results obtained from the quantum mechanical calculations performed on a wide variety of complexes between the 1,4 benzoquinone (BQ) derivatives and HF molecules, the interplay between H-bonds and individual H-bond interaction energies (EHB) can be affected by the substituents placed on the six-membered ring of BQ. The total binding energies of complexes become more negative by the electron donating substituents (EDSs) while the changes are reversed by the electron withdrawing substituents (EWSs). The mutual interplay between the X-BQ?(HF)n (n=1-3) interactions has been investigated using the geometrical parameters, synergetic energies (SE) and the EHB values. Hydrogen bonding decreases the reduction potentials (E0red) and increases the electron affinities (EA) of X-BQ derivatives. Linear relationships have been observed between the E0red (and EA) values and the Hammett constants of substituents. PMID- 28850897 TI - Mutational analysis of microbial hydroxycinnamoyl-CoA hydratase-lyase (HCHL) towards enhancement of binding affinity: A computational approach. AB - Improving the industrial enzyme for better yield of the product is important and a challenging task. One of such important industrial enzymes is microbial Hydroxycinnamoyl-CoA hydratase-lyase (HCHL). It converts feruloyl-CoA to vanillin. We place our efforts towards the improvement of its catalytic activity with comprehensive computational investigation. Catalytic core of the HCHL was explored with molecular modeling and docking approaches. Site-directed mutations were introduced in the catalytic site of HCHL in a sequential manner to generate different mutants of HCHL. Basis of mutation is to increase the interaction between HCHL and substrate feruloyl-CoA through interatomic forces and hydrogen bond formation. A rigorous molecular dynamics (MD) simulation was performed to check the stability of mutant's structure. Root mean square deviation (RMSD), root mean square fluctuation (RMSF), dynamic cross correlation (DCCM) and principal component analysis (PCA) were also performed to analyze flexibility and stability of structures. Docking studies were carried out between different mutants of HCHL and feruloyl-CoA. Investigation of the different binding sites and the interactions with mutant HCHLs and substrate allowed us to highlight the improved performance of mutants than wild type HCHL. This was further validated with MD simulation of complex consisting of different mutants and substrate. It further confirms all the structures are stable. However, mutant-2 showed better affinity towards substrate by forming hydrogen bond between active site and feruloyl-CoA. We propose that increase in hydrogen bond formation might facilitate in dissociation of vanillin from feruloyl-CoA. The current work may be useful for the future development of 'tailor-made' enzymes for better yield of vanillin. PMID- 28850898 TI - A filter feature selection method based on the Maximal Information Coefficient and Gram-Schmidt Orthogonalization for biomedical data mining. AB - A filter feature selection technique has been widely used to mine biomedical data. Recently, in the classical filter method minimal-Redundancy-Maximal Relevance (mRMR), a risk has been revealed that a specific part of the redundancy, called irrelevant redundancy, may be involved in the minimal redundancy component of this method. Thus, a few attempts to eliminate the irrelevant redundancy by attaching additional procedures to mRMR, such as Kernel Canonical Correlation Analysis based mRMR (KCCAmRMR), have been made. In the present study, a novel filter feature selection method based on the Maximal Information Coefficient (MIC) and Gram-Schmidt Orthogonalization (GSO), named Orthogonal MIC Feature Selection (OMICFS), was proposed to solve this problem. Different from other improved approaches under the max-relevance and min redundancy criterion, in the proposed method, the MIC is used to quantify the degree of relevance between feature variables and target variable, the GSO is devoted to calculating the orthogonalized variable of a candidate feature with respect to previously selected features, and the max-relevance and min-redundancy can be indirectly optimized by maximizing the MIC relevance between the GSO orthogonalized variable and target. This orthogonalization strategy allows OMICFS to exclude the irrelevant redundancy without any additional procedures. To verify the performance, OMICFS was compared with other filter feature selection methods in terms of both classification accuracy and computational efficiency by conducting classification experiments on two types of biomedical datasets. The results showed that OMICFS outperforms the other methods in most cases. In addition, differences between these methods were analyzed, and the application of OMICFS in the mining of high-dimensional biomedical data was discussed. The Matlab code for the proposed method is available at https://github.com/lhqxinghun/bioinformatics/tree/master/OMICFS/. PMID- 28850899 TI - Multivariate modeling using quantitative CT metrics may improve accuracy of diagnosis of bronchiolitis obliterans syndrome after lung transplantation. AB - BACKGROUND: To assess how quantitative CT (qCT) metrics compare to pulmonary function testing (PFT) and semi-quantitative image scores (SQS) to diagnose bronchiolitis obliterans syndrome (BOS), manifestation of chronic lung allograft dysfunction after lung transplantation (LTx), according to the type of LTx (unilateral or bilateral). METHODS: Paired inspiratory-expiratory CT scans and PFTs of 176 LTx patients were analyzed retrospectively, and separated into BOS (78) and non-BOS (98) cohorts. SQS were assessed by 2 radiologists and graded (0 3) for features including mosaic attenuation and bronchiectasis. qCT metrics included lung volumes and air trapping volumes. Multivariate logistic regression (MVLR) and support vector machines (SVM) were used for the classification task. RESULTS: MVLR and SVM models using PFT metrics demonstrated highest accuracy for bilateral LTx (max AUC 0.771), whereas models using qCT metrics-only outperformed models using SQS or PFTs in unilateral LTx (max AUC 0.817), to diagnose BOS. Adding PC (principal components) from qCT on top of PFT improved model diagnostic accuracy for all transplant types. CONCLUSIONS: Combinations of qCT metrics augment the diagnostic performance of PFTs, are superior to SQS to predict BOS status, and outperform PFTs in the unilateral LTx group. This suggests that latent information on paired volumetric CT may allow early diagnosis of BOS in LTx patients, particularly in unilateral LTx. PMID- 28850900 TI - A multivariate extension of mutual information for growing neural networks. AB - Recordings of neural network activity in vitro are increasingly being used to assess the development of neural network activity and the effects of drugs, chemicals and disease states on neural network function. The high-content nature of the data derived from such recordings can be used to infer effects of compounds or disease states on a variety of important neural functions, including network synchrony. Historically, synchrony of networks in vitro has been assessed either by determination of correlation coefficients (e.g. Pearson's correlation), by statistics estimated from cross-correlation histograms between pairs of active electrodes, and/or by pairwise mutual information and related measures. The present study examines the application of Normalized Multiinformation (NMI) as a scalar measure of shared information content in a multivariate network that is robust with respect to changes in network size. Theoretical simulations are designed to investigate NMI as a measure of complexity and synchrony in a developing network relative to several alternative approaches. The NMI approach is applied to these simulations and also to data collected during exposure of in vitro neural networks to neuroactive compounds during the first 12 days in vitro, and compared to other common measures, including correlation coefficients and mean firing rates of neurons. NMI is shown to be more sensitive to developmental effects than first order synchronous and nonsynchronous measures of network complexity. Finally, NMI is a scalar measure of global (rather than pairwise) mutual information in a multivariate network, and hence relies on less assumptions for cross-network comparisons than historical approaches. PMID- 28850901 TI - Betel nut chewing associated with increased risk of arterial stiffness. AB - BACKGROUND: Betel nut chewing is associated with certain cardiovascular outcomes. Subclinical atherosclerosis may be one link between betel nut chewing and cardiovascular risk. Few studies have examined the association between chewing betel nut and arterial stiffness. The aim of this study was thus to determine the relationship between betel nut chewing and arterial stiffness in a Taiwanese population. METHODS: We enrolled 7540 eligible subjects in National Cheng Kung University Hospital from October 2006 to August 2009. The exclusion criteria included history of cerebrovascular events, coronary artery disease, and taking lipid-lowering drugs, antihypertensives, and hypoglycemic agents. Increased arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) >=1400cm/s. According to their habit of betel nut use, the subjects were categorized into non-, ex-, and current chewers. RESULTS: The prevalence of increased arterial stiffness was 32.7, 43.3, and 43.2% in non-, ex- and current chewers, respectively (p=0.011). Multiple logistic regression analysis revealed that ex-chewers (odds ratio [OR] 1.69, 95% confidence interval (CI)=1.08-2.65) and current chewers (OR 2.29, 95% CI=1.05-4.99) had elevated risks of increased arterial stiffness after adjustment for co-variables. CONCLUSIONS: Both ex- and current betel nut chewing were associated with a higher risk of increased arterial stiffness. Stopping betel nut chewing may thus potentially be beneficial to reduce cardiovascular risk, based on the principals of preventive medicine. PMID- 28850903 TI - Confirmed marijuana use and lymphocyte count in black people living with HIV. AB - BACKGROUND: Marijuana is a commonly used recreational substance with purported analgesic and mood enhancing properties. Many people living with HIV identify marijuana as a palliative substance. However, through its main psychoactive component, tetrahydrocannabinol (THC), is known to influence the immune system. The effects of marijuana use in people with HIV are still controversial, with very scant literature in Black adults. METHODS: The current study determined the differences in the lymphocyte count, specifically the number cluster differentiation 4 and 8 (CD4+ and CD8+), among patients who urine drug tested negative for THC (n=70) and those who tested positive for THC (n=25). The sample included 95 Black people living with HIV, 51% female, with a mean age of 46+/ 11years. Participants provided a urine sample for substance use testing and a trained researcher extracted clinical data from clinical charts on the day of appointment. RESULTS: After adjusting for demographic and HIV-related covariates, THC-positive patients had significantly higher CD4+ and CD8+ counts than their THC-negative counterparts. CONCLUSION: These results extend previous HIV-related immunity findings in an underrepresented group, and suggest that THC use does not reduce immune function as measured by CD count. Further research is warranted on the overall effects of THC on immune function in HIV positive patients. PMID- 28850902 TI - Determinants of hazardous drinking among black South African men who have sex with men. AB - BACKGROUND: There is a known heavy burden of hazardous drinking and its associated health risks among black South African MSM; however, no study to date has identified risk factors for hazardous drinking among this nor any other African MSM population. METHODS: A cross-sectional survey was conducted among 480 black South African MSM recruited using respondent-driven sampling. All analyses were adjusted using an RDS II estimator. Multivariable logistic regression was used to assess the relationship between demographic characteristics, psychosocial factors, behavioral attributes and hazardous drinking. RESULTS: More than half of the men (62%, 95%CI=56%-68%) screened positive as hazardous drinkers. In multivariable analyses, living in a township (versus the city of Pretoria) (aOR=1.9, 95%CI=1.2-3.1, p<.01), more gender dysphoria (aOR=1.4, 95%CI=1.0-1.8, p=.03), having ever received money or other incentives in return for sex (aOR=2.4, 95%CI=1.3-4.3, p<.01), having been sexually abused as a child (aOR=2.6, 95%CI=1.1-6.4, p=.03), having anxiety (aOR=5.4, 95%CI=1.2-24.3, p=.03), and social network drinking behavior (aOR=5.4, 95%CI=1.2-24.3, p=.03) were positively associated with hazardous drinking. Being sexually attracted only to men (aOR=0.3, 95%CI=0.1-0.8, p=.01) was negatively associated with hazardous drinking. DISCUSSION: Hazardous drinking is highly prevalent among black South African MSM. Multiple indicators of social vulnerability were identified as independent determinants of hazardous drinking. These findings are of heightened concern because these health problems often work synergistically to increase risk of HIV infection and should be taken into consideration by efforts aimed at reducing hazardous drinking among this critical population. PMID- 28850905 TI - The inflammation paradox in the evolution of mammalian pregnancy: turning a foe into a friend. AB - A widely discussed physiological puzzle of mammalian pregnancy is the immunological paradox, which asks: why is the semi-allogenic fetus not attacked by the mother's adaptive immune system? Here, we argue that an additional, and perhaps more fundamental paradox is the question: why is embryo implantation so similar to inflammation while inflammation is also the greatest threat to the continuation of pregnancy? Equally puzzling is the question of how this arose during evolution. We call this the inflammation paradox. We argue that acute endometrial inflammation was ancestrally a natural maternal reaction to the attaching blastocyst, a situation still observed in the opossum. Eutherian implantation arose through a transformation of the acute inflammation into a process essential for implantation by causing vascular permeability and matrix reorganization as well as by suppressing the effects deleterious to the fetus. We propose that this model allows us to understand the differences between 'good inflammation' and 'bad inflammation'. Further, it allows us to understand the influence of inflammation on the outcome of pregnancy and maternal health. PMID- 28850904 TI - Over-expression of CD8+ T-cell activation is associated with decreased CD4+ cells in patients seeking treatment of Alcohol Use Disorder. AB - INTRODUCTION: Harmful alcohol consumption may have an impact on the adaptive immune system through an imbalance in T cell subpopulations and changes in cell activation. We aimed to analyze profiles of CD4 and CD8T cell activation in patients with alcohol use disorder (AUD). METHODS: We used a cross-sectional study with patients seeking treatment of the disorder. Blood samples for immunophenotyping were obtained at admission. Profiles of T cell activation were defined: (I) CD38+/HLA-DR+, (II) CD38+/HLA-DR-, (III) CD38-/HLA-DR+, (IV) CD38 /HLA-DR- and compared with healthy controls. We calculated a CD8+ T cell activation indicator (AI) that was defined as the quotient of non-activated cells (CD38-/HLA-DR-) and activated cells (CD38+/HLA-DR+). RESULTS: 60 patients were eligible (83%M); median age was 49 years [IQR: 44-54] and alcohol consumption was 145g/day [IQR: 90-205]. Mean+/-SD of CD38+/HLA-DR- was 50.3+/-50.6 cells/MUL in patients and 33.5+/-24.5 cells/MUL in controls (p=0.03), for the CD38-/HLA-DR+ it was 61+/-62.2 cells/MUL in patients and 21.2+/-17.3 cells/MUL in controls (p<0.001) and for the CD38+/HLA-DR+ it was 20.2+/-15.6 cells/MUL in patients and 10.8+/-10.3 cells/MUL in controls (p<0.001). In patients, an inverse correlation was observed between absolute number and percentage of CD4+ T cells, and the percentage of CD38+/HLA-DR+CD8+ T cells (r=0.37, p=0.003; r=0.2, p=0.086, respectively). CONCLUSIONS: Patients with AUD have an increased expression of immune activation with respect to healthy individuals. This excess of activated CD8+ T cells correlates with the absolute CD4+ T cells. PMID- 28850906 TI - Optimization of hydrogen peroxide-to-hemoglobin ratio for biocatalytic mineralization of polycyclic aromatic hydrocarbons (PAHs)-contaminated soils. AB - This study investigates the efficiency of hemoglobin (Hb)-catalyzed biocatalytic reactions for removal of polycyclic aromatic hydrocarbons (PAHs) in a historically PAHs-contaminated soil and of benzo(a)pyrene (BaP) in an artificially BaP-contaminated soil. PAHs removal tests at various H2O2-to-Hb mass ratios (0-3.7) showed that the PAHs removal was greater at H2O2-to-Hb mass ratio of >=3. This was attributed to the greater removal of high molecular weight PAHs at higher H2O2-to-Hb mass ratios. The BaP removal increased from 36% to 85% with increasing H2O2-to-Hb mass ratio from 1 to 3, and further increase in H2O2-to-Hb mass ratio decreased the BaP removal. Thus, the optimal H2O2-to-Hb mass ratio for BaP removal was determined to be 3 in the artificially BaP-contaminated soil. The BaP removal in the presence of only Hb can be attributed to the capture of BaP by Hb. The increased BaP removal in the presence of H2O2 is likely due to BaP mineralization as the BaP removal and the CO2 generated showed a strong positive correlation (R2 = 0.999). Overall, this study shows that the Hb-catalyzed biocatalytic reactions can effectively remove PAHs in soil. PMID- 28850907 TI - Source analysis of radiocesium in river waters using road dust tracers. AB - Following the Fukushima Dai-ichi Nuclear Power Station accident, regional road dust, heavily contaminated with radiocesium, now represents a potential source of radiocesium pollution in river water. To promote effective countermeasures for reducing the risk from radiocesium pollution, it is important to understand its sources. This study evaluated the utility of metals, including Al, Fe, and Zn as road dust tracers, and applied them to analyze sources of 137Cs in rivers around Fukushima during wet weather. Concentrations of Zn in road dust were higher than agricultural and forest soils, whereas concentrations of Fe and Al were the opposite. Concentrations of Zn were weakly but significantly correlated with benzothiazole, a molecular marker of tires, indicating Zn represents an effective tracer of road dust. Al, Fe, and Zn were frequently detected in suspended solids in river water during wet weather. Distribution coefficients of these metals and 137Cs exceeded 104, suggesting sorptive behavior in water. Although concentrations of Al, Fe, Zn, and 137Cs were higher in fine fractions of road dust and soils than in coarse fractions, use of ratios of 137Cs to Al, Fe, or Zn showed smaller differences among size fractions. The results demonstrate that combinations of these metals and 137Cs are useful for analyzing sources of radiocesium in water. These ratios in river water during wet weather were found to be comparable with or lower than during dry weather and were closer to soils than road dust, suggesting a limited contribution from road dust to radiocesium pollution in river water. PMID- 28850908 TI - Arbuscular mycorrhizal fungus modulates the phytotoxicity of Cd via combined responses of enzymes, thiolic compounds, and essential elements in the roots of Phragmites australis. AB - The positive effects of arbuscular mycorrhizal (AM) fungi on host plants under heavy metal (HM) stress conditions have been widely recognized. HMs are known to induce phytotoxicity through 1) the production of reactive oxygen species (ROS), 2) the direct interaction with thiol groups or 3) the competition with essential elements. However, how AM fungus inoculation can affect defense mechanisms against cadmium (Cd) stress, which can regulate and alleviate the phytotoxicity via different pathways, is still unclear. We hypothesized that one or some factors in each pathway of phytotoxicity were involved in detoxifying Cd by inoculating with AM fungus. In this study, the involvements of enzymes, thiolic compounds, and divalent essential elements in the roots of Phragmites australis (Cav.) Trin. ex Steud. were assessed. In addition, we also worked to elucidate the significant factors among three possible pathways involved in biosynthesis with AM fungus inoculation, using principal component analysis (PCA). The results presented here indicate that AM symbiosis can result in a marked tolerance to Cd via accumulating Cd with a shorter exposure treatment time, and obvious fluorescence in the roots was also observed. The decrease in phytotoxicity was mainly accomplished by changes in superoxide dismutase (SOD), catalase (CAT), non protein thiols (NPT), calcium (Ca), manganese (Mn), and copper (Cu). These results provide comprehensive insights for elucidating the defense mechanisms by which inoculation with AM fungus has beneficial roles in helping P. australis cope with the deleterious effects of Cd. PMID- 28850909 TI - Trace element occurrence in the Pacific oyster Crassostrea gigas from coastal marine ecosystems in Italy. AB - The Pacific oyster is one of the world's most widespread bivalves and a suitable species for biomonitoring trace elements in marine environments thanks to its bioaccumulation ability. As it is also an edible mollusc, concentrations of harmful elements in its tissues must be monitored. For these purposes, 464 wild individuals were collected from 12 sites along the Italian coasts. The concentration of fourteen trace elements (Al, As, Cd, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Se, Sn, Tl, and Zn) in their tissues was quantified. Among the three heavy metals, cadmium, lead, and mercury, none exceeded the maximum limit for in food set by European Union regulations but Cd in one sample from the Varano Lagoon resulted extremely close to this value. Contamination by Hg of the northern Adriatic and Orbetello Lagoons was also observed. Moreover, there was a positive association between the lagoon's environmental conditions and the bioaccumulation of this element in oysters. Despite the ban instituted 15 years ago on the use of Sn in antifouling paints, this element is still present in several marine environments, as demonstrated in the oysters sampled from harbour areas. Samples collected from harbours also showed very high concentrations of Cu and Zn due to the ability of oysters to accumulate these elements, which have replaced Sn in antifouling paints. Analysis of the samples from most sites indicated a low risk of human exposure to harmful elements through oyster consumption; nonetheless, chemical sanitary controls should focus primarily on Cd, Cu, and Zn. PMID- 28850910 TI - Role of humic substances in the photodegradation of naproxen under simulated sunlight. AB - Humic substances (HS) including humic acid (HA) and fulvic acid (FA) are ubiquitous in the natural waters. Although numerous studies documented their role in photodegradation of organic pollutants, the competitive effects of photosensitization and light-screening of HS on the photodegradation of pollutants are not yet clear. In this work, the role of HS in the photodegradation of the pharmaceutical naproxen (NP) was studied under simulated sunlight. The direct photodegradation quantum yield of NP in deionized water was 2.1 * 10-2, and the apparent quantum yields for photosensitized degradation of NP in the presence of FA and HA were 2.3 * 10-4 and 2.6 * 10-5, respectively. Both direct and photosensitized photodegradation decreased with increasing pH, consistent with the trend of singlet oxygen (1O2) reaction rate constants of NP. HA inhibited the photodegradation of naproxen thoroughly. In contrast, FA accelerated the photodegradation of NP at lower substrate concentration and light intensity, and vice versa. Direct photodegradation of NP declined sharply with spectral radiation attenuation of UV region, when HS-mediated photosensitization predominantly accounted for the photodegradation. The direct photodegradation was ascribed to decomposition of excited triplet state of naproxen (3NP*) and self sensitization effect involving 1O2. The FA-mediated photodegradation was mainly attributed to 1O2 oxidation in aerated solution. These findings are important for assessing the competitive effects of humic substances on the photodegradation of pollutants under various conditions in natural waters. PMID- 28850911 TI - Influence of Mo(VI) immobilization and temperature on As(V) sorption onto magnetic separable poly p-phenylenediamine-thiourea-formaldehyde polymer. AB - The immobilization of Mo(VI) on magnetic poly p-phenylenediamine-thiourea formaldehyde composite polymer (MpPDTF) (through an intermediary adsorption step) increased sorption of As(V) ions: retention capacity increased from 35.15mg As g 1 for MpPDTF to 99.04mg As g-1 for MpPDTF immobilized Mo(VI) at 298+/-1K. The impact of temperature and Mo(VI) immobilization on the kinetic and equilibrium constants of As(V) sorption on MpPDTF was evaluated. The thermodynamic study shows that Mo(VI) immobilization on MpPDTF changes the sorption process of As(V) on MpPDTF from exothermic associated with entropy decrease to endothermic associated with entropy increase. Also the impact of phosphate competition was studied. MpPDTF immobilized Mo(VI) was successfully tested for As(V) removal from the industrial effluents of insecticides manufacturing industry. NaHCO3 solution (0.5M) can be efficiently used for sorbent regeneration for at least 3 cycles with limited decrease in sorption performance. PMID- 28850912 TI - Aluminum nanopowder: A substance to be handled with care. AB - Aluminum nanopowders are increasingly used in various areas of research in materials and physical chemistry. Their unconventional properties are still little understood and make their handling sometimes quite hazardous. In this article, we report the case of apparently benign mixtures of Al with sulfuric acid (H2SO4), which violently explode when they are exposed to a flame. The explosions of 100mg samples were observed by high speed video (60000fr/s). These experiments have showed a three-step mechanism, in which the primary hydrogen combustion ignites and disperses the nano-Al/H2SO4 paste in clusters with high velocities (~100m/s). The combustion of the paste increases the hydrogen release and initiates the explosion of the H2/air mixture, which propagates at high velocities (760-1060m/s). This effect was not observed with micron-sized Al powders, and it is a good illustration of new hazards with nano-Al. Extreme caution is hence recommended to chemists who handle such materials. PMID- 28850913 TI - Synthesis of silver phosphate/graphene oxide composite and its enhanced visible light photocatalytic mechanism and degradation pathways of tetrabromobisphenol A. AB - In the present study, silver phosphate/graphene oxide (Ag3PO4/GO) composite was synthesized by ultrasound-precipitation processes. Afterwards, physicochemical properties of the resulting samples were studied through scanning electron microscope, transmission electron microscope, X-ray diffraction, N2 adsorption/desorption, UV-vis diffuse reflectance spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, surface photovoltage spectroscopy and photoelectrochemical measurements. Results indicated that spherical Ag3PO4 displayed an average diameter of 150 nm and body-centered cubic crystal phase, which was integrated with GO. In addition, the visible light absorbance, charge separation efficiency and lifetime of Ag3PO4 were significantly improved by integration with GO. In addition, Ag3PO4/GO composite was applied to decompose tetrabromosphenol A (TBBPA) in water body. It was found that TBBPA could be completely decomposed within 60 min illumination. Furthermore, several scavenger experiments were conducted to distinguish the contribution of reactive species to the photoctalytic efficiency. Moreover, the enhanced visible light mechanism of Ag3PO4/GO was proposed and discussed. Eventually, several PC decomposition pathways of TBBPA were identified including directly debromination and oxidation, and subsequently further oxidation and hydroxylation processes. PMID- 28850914 TI - Efficient mineralization of antibiotic ciprofloxacin in acid aqueous medium by a novel photoelectro-Fenton process using a microwave discharge electrodeless lamp irradiation. AB - In this study, a novel photoelectro-Fenton (PEF) process using microwave discharge electrodeless lamp (MDEL) as a UV irradiation source was developed for the removal of antibiotic ciprofloxacin (CIP) in water. Comparative degradation of 200mgL-1 CIP was studied by direct MDEL photolysis, anodic oxidation (AO), AO in presence of electrogenerated H2O2 (AO-H2O2), AO-H2O2 under MDEL irradiation (MDEL-AO-H2O2), electro-Fenton (EF) and MDEL-PEF processes. Higher oxidation power was found in the sequence: MDEL photolysis < AO < AO-H2O2< MDEL-AO-H2O2< EF < MDEL-PEF. Effects of current density, pH, initial Fe2+ concentration and initial CIP concentration on TOC removal in MDEL-PEF process were examined, and the optimal conditions were ascertained. The releases of three inorganic ions (F , NH4+ and NO3-) and two carboxylic acids (oxalic and formic acids) were qualified. Seven aromatic intermediates mainly generated from hydroxylation, dealkylation and defluorination of CIP were detected by UPLC-QTOF-MS/MS technology. Therefore, plausible degradation sequences for CIP degradation in MDEL-PEF process including all detected products were proposed. PMID- 28850915 TI - Development of a carbonate crust on alkaline nuclear waste sludge at the Hanford site. AB - Hard crusts on aging plutonium production waste have hindered the remediation of the Hanford Site in southeastern Washington, USA. In this study, samples were analyzed to determine the cause of a hard crust that developed on the highly radioactive sludge during 20 years of inactivity in one of the underground tanks (tank 241-C-105). Samples recently taken from the crust were compared with those acquired before the crust appeared. X-ray diffraction and scanning electron microscopy (SEM) indicated that aluminum and uranium phases at the surface had converted from (hydr)oxides (gibbsite and clarkeite) into carbonates (dawsonite and cejkaite) and identified trona as the cementing phase, a bicarbonate that formed at the expense of thermonatrite. Since trona is more stable at lower pH values than thermonatrite, the pH of the surface decreased over time, suggesting that CO2 from the atmosphere lowered the pH. Thus, a likely cause of crust formation was the absorption of CO2 from the air, leading to a reduction of the pH and carbonation of the waste surface. The results presented here help establish a model for how nuclear process waste can age and can be used to aid future remediation and retrieval activities. PMID- 28850916 TI - Performance and extracellular polymers substance analysis of a pilot scale anaerobic membrane bioreactor for treating tetrahydrofuran pharmaceutical wastewater at different HRTs. AB - Tetrahydrofuran (THF) is one of the most representative characteristics of pollutant in pharmaceutical industry usually has high biological toxicity, making it difficult to treat. In this study, a pilot scale anaerobic membrane bioreactor (AnMBR) was employed to treat THF pharmaceutical wastewater under different hydraulic retention time (HRT). During the 80-day operating time, chemical oxygen demand (COD) and THF removal efficiencies reached 95.3% and 98.5% when HRT was above 24h. Mixed liquid suspended solids (MLSS) and mixed liquor volatile suspended solids (MLVSS) in the attached sludge on membrane surface showed a trend of rising on first 28days (48h-36h) and then decreasing. Protein is the major component of extracellular polymeric substances (EPS) independent of changes in HRT. The study concludes that THF pharmaceutical wastewater can be effectively remedied in the AnMBR system at low HRT. PMID- 28850917 TI - Facile loading of Ag nanoparticles onto magnetic microsphere by the aid of a tannic acid-Metal polymer layer to synthesize magnetic disinfectant with high antibacterial activity. AB - In this article, Ag nanoparticles (NPs) were easily loaded onto magnetic material through a tannic acid-metal polymer (PTA) intermedia layer to synthesize Fe3O4@PTA@Ag magnetic composite and the potential application as bactericidal agent for water disinfection was investigated. The as-obtained composite, with a Fe3O4 core of 150nm, has plenty of Ag NPs of 15nm adhered onto the PTA layer outside the core. The PTA layer, like the famous polydopamine complex, possesses excellent adhesive capacity to load more Ag NPs tightly and has specific antibacterial activity due to the numerous catechol groups. Therefore, remarkable bactericidal activity was achieved and 31.25mgL-1 of Fe3O4@PTA@Ag disinfectant could inactivate more than 99% of the tested strains within 60min. At the same time, the catechol groups also endow the PTA layer with reduction ability so that additional reductant is unnecessary during the formation of Ag NPs and the PTA complex can be fabricated much more rapidly. As a result, the magnetic composite can be synthesized simply with less cost. Moreover, the composite has a high magnetic saturation value of 55.47emug-1 owing to the Fe3O4 core and the magnetic separation ability can play an important role in the recovery of the disinfectant. PMID- 28850918 TI - Normal composite face effects in developmental prosopagnosia. AB - Upright face perception is thought to involve holistic processing, whereby local features are integrated into a unified whole. Consistent with this view, the top half of one face appears to fuse perceptually with the bottom half of another, when aligned spatially and presented upright. This 'composite face effect' reveals a tendency to integrate information from disparate regions when faces are presented canonically. In recent years, the relationship between susceptibility to the composite effect and face recognition ability has received extensive attention both in participants with normal face recognition and participants with developmental prosopagnosia. Previous results suggest that individuals with developmental prosopagnosia may show reduced susceptibility to the effect suggestive of diminished holistic face processing. Here we describe two studies that examine whether developmental prosopagnosia is associated with reduced composite face effects. Despite using independent samples of developmental prosopagnosics and different composite procedures, we find no evidence for reduced composite face effects. The experiments yielded similar results; highly significant composite effects in both prosopagnosic groups that were similar in magnitude to the effects found in participants with normal face processing. The composite face effects exhibited by both samples and the controls were greatly diminished when stimulus arrangements were inverted. Our finding that the whole face binding process indexed by the composite effect is intact in developmental prosopagnosia indicates that other factors are responsible for developmental prosopagnosia. These results are also inconsistent with suggestions that susceptibility to the composite face effect and face recognition ability are tightly linked. While the holistic process revealed by the composite face effect may be necessary for typical face perception, it is not sufficient; individual differences in face recognition ability likely reflect variability in multiple sequential processes. PMID- 28850919 TI - Graded functionalization of biomaterial surfaces using mussel-inspired adhesive coating of polydopamine. AB - Biomaterials with graded functionality have various applications in cell and tissue engineering. In this study, by controlling oxidative polymerization of dopamine, we demonstrated universal techniques for generating chemical gradients on various materials with adaptability for secondary molecule immobilization. Diffusion-controlled oxygen supply was successfully exploited for coating of polydopamine (PD) in a gradient manner on different materials, regardless of their surface chemistry, which resulted in gradient in hydrophilicity and surface roughness. The PD gradient controlled graded adhesion and spreading of human mesenchymal stem cells (hMSCs) and endothelial cells. Furthermore, the PD gradient on these surfaces served as a template to allow for graded immobilization of different secondary biomolecules such as cell adhesive arginine glycine-aspartate (RGD) peptides and siRNA lipidoid nanoparticles (sLNP) complex, for site-specific adhesion of human mesenchymal stem cells, and silencing of green fluorescent protein (GFP) expression on GFP-HeLa cells, respectively. In addition, the same approach was adapted for generation of nanofibers with surface in graded biomineralization under simulated body fluid (SBF). Collectively, oxygen-dependent generation of PD gradient on biomaterial substrates can serve as a simple and versatile platform that can be used for various applications realizing in vivo tissue regeneration and in vitro high-throughput screening of biomaterials. PMID- 28850920 TI - Influence of the state of phase of lipid bilayer on the exposure of glucose residues on the surface of liposomes. AB - The presence of carbohydrate-binding proteins (i.e. lectins) on the surface of various bacterial strains and their overexpression in some tumor tissues makes the use of glycosylated liposomes a promising approach for the specific drug delivery in antibacterial and anti-cancer therapies. However, the functionalization of liposome surface with sugar moieties by glycosylated amphiphiles does not ensure the binding of sugar-coated vesicles with lectins. In fact, the composition and properties of lipid bilayer play a pivotal role in the exposure of sugar residues and in the interaction with lectins. The influence of the length of the hydrophilic spacer that links the sugar to liposome surface and of the presence of saturated or unsaturated phospholipids in the lipid bilayer on the ability of glucosylated liposomes to interact with a model lectin, Concanavalin A, was investigated. Our results demonstrate that both the chain length and the prensece of unsaturation, parameters that strongly affect the fluidity of the lipid bilayer, affect agglutination. In particular, agglutination is favored when liposomes are in the gel phase within a defined range of temperature. Moreover, the obtained results confirm that the length of the PEG spacer, that influences both lipid organization and the exposure of sugar moieties to the bulk, plays a crucial role in liposome/lectin interaction. PMID- 28850921 TI - In vivo recording of the vestibular microphonic in mammals. AB - BACKGROUND: The Vestibular Microphonic (VM) has only featured in a handful of publications, mostly involving non-mammalian and ex vivo models. The VM is the extracellular analogue of the vestibular hair cell receptor current, and offers a tool to monitor vestibular hair cell activity in vivo. OBJECTIVE: To characterise features of the VM measured in vivo in guinea pigs, using a relatively simple experimental setup. METHODS: The VM, evoked by bone-conducted vibration (BCV), was recorded from the basal surface of either the utricular or saccular macula after surgical removal of the cochlea, in 27 guinea pigs. RESULTS: The VM remained after vestibular nerve blockade, but was abolished following end-organ destruction or death. The VM reversed polarity as the recording electrode tracked across the utricular or saccular macula surface, or through the utricular macula. The VM could be evoked by BCV stimuli of frequencies between 100 Hz and 5 kHz, and was largest to vibrations between 600 Hz and 800 Hz. Experimental manipulations demonstrated a reduction in the VM amplitude with maculae displacement, or rupture of the utricular membrane. CONCLUSIONS: Results mirror those obtained in previous ex vivo studies, and further demonstrate that vestibular hair cells are sensitive to vibrations of several kilohertz. Changes in the VM with maculae displacement or rupture suggest utricular hydrops may alter vestibular hair cell sensitivity due to either mechanical or ionic changes. PMID- 28850922 TI - Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2 yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC. AB - Recently, more and more concomitant EGFR mutations and ALK rearrangement are observed from the clinic, which still lacks effective single-agent therapy. Starting from ALK inhibitor 14 (TAE684), we have developed a highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically. Compound 18 significantly inhibited the proliferation of EGFR mutant and EML4-ALK driven NSCLC cell lines. In the cellular context it strongly affected EGFR and ALK mediated signaling pathways, induced apoptosis and arrested cell cycle at G0/G1 phase. In the in vivo studies, 18 significantly suppressed the tumor growth in H1975 cell inoculated xenograft model (40 mg/kg/d, TGI: 99%) and H3122 cell inoculated xenograft model (40 mg/kg/d, TGI: 78%). Compound 18 might be a potential drug candidate for EGFR- or ALK-individual as well as concomitant EGFR/ALK NSCLC. PMID- 28850923 TI - Investigating the properties and interaction mechanism of nano-silica in polyvinyl alcohol/polyacrylamide blends at an atomic level. AB - The nano-silica can be incorporated into polymers for improved mechanical properties. Notably, the interaction between nano-silica and polymer is of a microscopic phenomenon and thus, hard to observe and study by using experimental methods. Based on molecular dynamics, this paper presents a study on the properties and the interaction mechanism of nano-silica in the polyvinyl alcohol (PVA)/polyacrylamide (PAM) blends at an atomic level. Specifically, six blends of PVA/PAM with varying concentrations of nano-silica (0-13wt%) and two interfacial interaction models of polymers on the silica surface were designed and analyzed at an atomic level in terms of concentration profile, mechanical properties, fractional free volume (FFV), dynamic properties of polymers and X-ray diffraction patterns. The concentration profile results and micromorphologies of equilibrium models suggest PAM molecular chains are easier to be adsorbed on the silica surface than PVA molecular chains in blends. The incorporation of nano silica into the PVA/PAM blends can increase the blend mechanical properties, densities, and semicrystalline character. Meanwhile, the FFV and the mobility of polymer chain decrease with the silica concentration, which agrees with the results of mechanical properties, densities, and semicrystalline character. Our results also illustrate that an analysis of binding energies and pair correlation functions (PCF) allows for the discovery of the interaction mechanism of nano silica in PVA/PAM blends; and that hydrogen bond interactions between polar functional groups of polymer molecular chains and the hydroxyl groups of the silica surface are involved in adsorption of the polymers on the silica surface, thus affecting the interaction mechanism of nano-silica in PVA/PAM blend systems. PMID- 28850924 TI - Reinforcing the inner phase of the filled hydrogels with CNTs alters drug release properties and human keratinocyte morphology: A study on the gelatin- tamarind gum filled hydrogels. AB - The study reports the synthesis and characterization of gelatin-tamarind gum (TG) based filled hydrogels for drug delivery applications. In this study, three different types of carbon nanotubes (CNTs) were incorporated within the dispersed TG phase of the filled hydrogels. The prepared hydrogels were thoroughly characterised using bright field microscope, FESEM, FTIR spectroscopy, differential scanning calorimeter, and mechanical tester. The swelling and the drug (salicylic acid) release properties of the filled hydrogels were also evaluated. The micrographs revealed the formation of biphasic systems. The internal phase appeared as agglomerates, and the CNTs were confined within the dispersed TG phase. FTIR and XRD studies revealed that CNTs promoted associative interactions among the components of the hydrogel, which promoted the formation of large crystallite size. The mechanical study indicated better resistance to the breakdown of the architecture of the CNT-containing filled hydrogels. Drug release studies, both passive and iontophoretic, suggested that the non-Fickian diffusion of the drug was prevalent during its release from hydrogel matrices. The prepared hydrogels were cytocompatible with human keratinocytes. The results suggested the probable use of such hydrogels in wound healing, tissue engineering and drug delivery applications. PMID- 28850925 TI - Mechanical properties of a collagen fibril under simulated degradation. AB - Collagen fibrils are a very important component in most of the connective tissue in humans. An important process associated with several physiological and pathological states is the degradation of collagen. Collagen degradation is usually mediated by enzymatic and non-enzymatic processes. In this work we use molecular dynamics simulations to study the influence of simulated degradation on the mechanical properties of the collagen fibril. We applied tensile stress to the collagen fiber at different stages of degradation. We compared the difference in the fibril mechanical priorities due the removal of enzymatic crosslink, surface degradation and volumetric degradation. As anticipated, our results indicated that, regardless of the degradation scenario, fibril mechanical properties is reduced. The type of degradation mechanism (crosslink, surface or volumetric) expressed differential effect on the change in the fibril stiffness. Our simulation results showed dramatic change in the fibril stiffness with a small amount of degradation. This suggests that the hierarchical structure of the fibril is a key component for the toughness and is very sensitive to changes in the organization of the fibril. The overall results are intended to provide a theoretical framework for the understanding the mechanical behavior of collagen fibrils under degradation. PMID- 28850926 TI - Ameliorative effects of Diospyros lotus leaf extract against UVB-induced skin damage in BALB/c mice. AB - The aim of this study was to investigate the protective effect of Diospyros lotus leaf extract (DLE) on UVB-induced skin damage in mice. UVB irradiation of mice skin incurred significant damage to mice skin; increased thiobarbituric acid reactive substance level; decreased superoxide dismutase; and glutathione levels in mice skin tissues. More so, UVB irradiation led to collagen degradation and infiltration of mast cell and neutrophils into mice skin leading to inflammation. However, topical application of DLE significantly reversed these conditions with the result comparable to l-ascorbic acid. Myricitrin, gallic acid, astragalin, myricetin-3-O-glactosside, and myricetin through high-performance liquid chromatography analysis were further determined to be the primary active compounds in DLE. In conclusion, our study showed that DLE has potentials as local therapeutic materials against skin damage by inhibiting oxidative stress and UVB-induced skin damage. PMID- 28850927 TI - Inhibition of airway remodeling and inflammation by isoforskolin in PDGF-induced rat ASMCs and OVA-induced rat asthma model. AB - Isoforskolin (ISOF) has been reported to play an important role in many illnesses including respiratory, cardiovascular and ophthalmologic diseases. In our study, we aimed to investigate how ISOF regulates airway remodeling and inflammation in asthma. Based on SO2-stimulated mouse cough model, we assessed the role of ISOF in cough and secretion of phlegm. Afterwards, platelet derived growth factor (PDGF)-induced primary rat airway smooth muscle cell (ASMC) model and ovalbumin (OVA)-induced rat asthma model were used to continue our following research. Our results showed that ISOF could prolong the cough latent period, reduce the cough times in two minutes, and increase the excretion of red phenol, which suggested the antitussive and expectorant effects of ISOF. Besides, ISOF pretreatment reversed the hypotonicity and cytoskeleton remodeling in PDGF-induced ASMCs, and reduced mucus hypersecretion and collagen overdeposition in OVA-induced rat asthma model, which indicated its inhibition on airway remodeling in vitro and in vivo. Moreover, ISOF reduced the invasion of inflammatory cells into bronchoalveolar lavage fluid (BALF) and lungs, which revealed its inhibitory role in airway inflammation. The down-regulation of transforming growth factor beta1 (TGF-beta1) and interleukin-1beta (IL-1beta) upon ISOF treatment might be responsible for its anti-remodeling and anti-inflammation roles. In conclusion, ISOF can reduce cough and sputum, as well as inhibit airway remodeling and inflammation by regulating the expression of TGF-beta1 and IL-1beta. These data indicate the potency of ISOF in treating asthma and also provide insights into the development of new anti-asthma agent. PMID- 28850928 TI - Chemical profiling of Pterolobium hexapetalum leaves by HPLC analysis and its productive wound healing activities in rats. AB - Research on wound healing agents is one of the developing areas in modern biomedical sciences. Several drugs have been used in the management of wounds and a large variety of treatment modalities are available for wound repair. Among these medicines, herbal origin has been the basis of treatment and cure for healing of wounds. Pterolobium hexapetalum is well known medicinal plant of Caesalpiniaceae family was used by many tribal groups for wound treatment in India. Different extracts of P. hexapetalum leaves are evaluated for its antiradical activity and in vivo wound healing activity by excision, incision, and dead space wound models in Wistar rats, further respective phyto constituents are profiled using High Performance Liquid Chromatography. In this present study methanol extract of leaves depicted the maximum amount of phenolics and flavonoids content and also registered highest DPPH (IC50: 3.40MUg/mL), ABTS+(8869.36MUM TE/g extract) and Superoxide (87.72%) radical scavenging activity. Methanolic leaf extract are further studied for wound healing property, highest wound contraction percentage and lowest epithelialization period (16.33days) of 5% methanolic extract treated group exhibits highest wound healing activity compare to control group and it was confirmed by histopathology results and scoring analysis. Maximum tensile strain (110.69%) of incision and highest hydroxyproline (16.28mg/g) content of dead space wound model are comparable with standard 5% Neomycin. HPLC employed quantification of phyto constituents explores the presence of catechin (367.54MUg/mg), caffeic acid (87MUg/mg), rutin (289.20MUg/mg), quercetin (239.39MUg/mg) and naringenin (24.42MUg/mg). From the results leaves of P. hexapetalum significantly stimulate wound contraction, braking strength and hydroxyproline content of treated group. It showed remarkable wound healing activity and may be recommended for treating various type of wound. PMID- 28850929 TI - Chemical characterization and cytotoxic activity evaluation of Lebanese propolis. AB - Chemical composition, anti-proliferative and proapoptotic activity as well as the effect of various fractions of Lebanese propolis on the cell cycle distribution were evaluated on Jurkat leukemic T-cells, glioblastoma U251 cells, and breast adenocarcinoma MDA-MB-231 cells using cytotoxic assays, flow cytometry as well as western blot analysis. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that ferulic acid, chrysin, pinocembrin, galangin are major constituents of the ethanolic crude extract of the Lebanese propolis, while the hexane fraction mostly contains chrysin, pinocembrin, galangin but at similar levels. Furthermore chemical analysis was performed using gas chromatography-mass spectrometry (GC-MS) to identify major compounds in the hexane fraction. Reduction of cell viability was observed in Jurkat cells exposed to the ethanolic crude extract and the hexane fraction, while viability of U251 and MDA-MB-231 cells was only affected upon exposure to the hexane fraction; the other fractions (aqueous phase, methylene chloride, and ethyl acetate) were without effect. Maximum toxic effect was obtained when Jurkat cells were cultivated with 90MUg/ml of both the crude extract and hexane faction. Toxicity started early after 24h of incubation and remained till 72h. Interestingly, the decrease in cell viability was accompanied by a significant increase in p53 protein expression levels and PARP cleavage. Cell cycle distribution showed an increase in the SubG0 fraction in Jurkat, U251 and MDA-MB-231 cells after 24h incubation with the hexane fraction. This increase in SubG0 was further investigated in Jurkat cells by annexinV/PI and showed an increase in the percentage of cells in early and late apoptosis as well as necrosis. In conclusion, Lebanese propolis exhibited significant cytotoxicity and anti-proliferative activity promising enough that warrant further investigations on the molecular targets and mechanisms of action of Lebanese propolis. PMID- 28850930 TI - Thiamine in septic shock patients with alcohol use disorders: An observational pilot study. AB - PURPOSE: Alcohol-use disorders (AUDs) have been associated with increased sepsis related mortality. As patients with AUDs are often thiamine deficient, we investigated practice patterns relating to thiamine administration in patients with AUDs presenting with septic shock and explored the association between receipt of thiamine and mortality. MATERIALS: We performed a retrospective cohort study of patients presenting with septic shock between 2008 and 2014 at a single tertiary care center. We identified patients with an AUD diagnosis, orders for microbial cultures and use of antibiotics, vasopressor dependency, and lactate levels>=4mmol/L. We excluded those who received thiamine later than 48h of sepsis onset. RESULTS: We included 53 patients. Thirty-four (64%) patients received thiamine. Five patients (15%) received their first thiamine dose in the emergency department. The median time to thiamine administration was 9 (quartiles: 4, 18) hours. The first thiamine dose was most often given parenterally (68%) and for 100mg (88%). In those receiving thiamine, 15/34 (44%) died, compared to 15/19 (79%) of those not receiving thiamine, p=0.02. CONCLUSIONS: A considerable proportion of patients with AUDs admitted for septic shock do not receive thiamine. Thiamine administration in this patient population was associated with decreased mortality. PMID- 28850931 TI - Timing of venous thromboembolism chemoprophylaxis after traumatic brain injury. AB - OBJECTIVES: Currently no national standard exists on optimal timing to initiate VTE chemoprophylaxis after traumatic brain injury (TBI). We designed this survey to assess current practice regarding the timing of VTE chemoprophylaxis after TBI. METHODS: All the EAST members were surveyed online. Participants reported demographics, and responses to questions regarding VTE chemoprophylaxis in TBI and timing of chemoprophylaxis in 2 hypothetical clinical scenarios of TBI. RESULTS: Three hundred and ninety-one full responses were collected (response rate 30.9%). Most respondents (75%) reported the decision to initiate VTE chemoprophylaxis with a consensus between the neurosurgery and trauma/critical care services. While 76% of respondents reported experience of seeing pulmonary embolism without chemoprophylaxis, 44% witnessed progression of TBI after VTE chemoprophylaxis. Approximately 50% considered their practice of VTE chemoprophylaxis in TBI patients to be conservative. Almost 50% reported no standardized protocol in their institutions. While 1/3 of the members believed guidelines exist, another 1/3 believed no guidelines available. Responses to two clinical scenarios showed various approaches regarding the timing of VTE chemoprophylaxis. CONCLUSIONS: Currently there is a wide variability in the practice patterns regarding the timing of VTE chemoprophylaxis in TBI patients. This survey reinforces the need for further investigation to guide clinical practice. PMID- 28850932 TI - Resilients, overcontrollers and undercontrollers: A systematic review of the utility of a personality typology method in understanding adult mental health problems. AB - The person-centred typological approach to personality makes the distinction between overcontrolled and undercontrolled personality types. This review systematically searched for research on the utility of these personality types in adult mental health. A total of 43 papers were included, which were divided broadly into cross-sectional studies, longitudinal studies and studies with clinical populations. Three personality types have been largely replicated in both normal and clinical populations: resilients, overcontrollers and undercontrollers. These types show utility in predicting long-term functioning and mental health, understanding heterogeneous personalities within clinical subgroups and have implications for treatment. Some disagreement on the number of personality types deemed replicable across samples and differing methodologies do exist, with some finding a dimensional approach to personality to have greater predictive utility. These personality types have been shown to be important in a number of mental health problems such as eating disorders, which may prove helpful in developing new psychological interventions. These studies point to the importance of overcontrolled personality types as well as undercontrolled in mental health. More research is needed with a greater range of clinical populations. PMID- 28850933 TI - Low molecular weight hydrogels derived from urea based-bolaamphiphiles as new injectable biomaterials. AB - There is a critical need for soft materials in the field of regenerative medicine and tissue engineering. However, designing injectable hydrogel scaffolds encompassing both adequate mechanical and biological properties remains a key challenge for in vivo applications. Here we use a bottom-up approach for synthesizing supramolecular gels to generate novel biomaterial candidates. We evaluated the low molecular weight gels candidates in vivo and identified one urea-containing molecule, compound 16, that avoid foreign body reactions in mice. The self-assembly of bolaamphiphiles creates a unique hydrogel supramolecular structures featuring fast gelation kinetics, high elastic moduli, thixotropic, and thermal reversibility properties. This soft material, which inhibits recognition by macrophages and fibrous deposition, exhibits long-term stability after in vivo injection. PMID- 28850935 TI - Reductions in fish-community contamination following lowhead dam removal linked more to shifts in food-web structure than sediment pollution. AB - Recent increases in dam removals have prompted research on ecological and geomorphic river responses, yet contaminant dynamics following dam removals are poorly understood. We investigated changes in sediment concentrations and fish community body burdens of mercury (Hg), selenium (Se), polychlorinated biphenyls (PCB), and chlorinated pesticides before and after two lowhead dam removals in the Scioto and Olentangy Rivers (Columbus, Ohio). These changes were then related to documented shifts in fish food-web structure. Seven study reaches were surveyed from 2011 to 2015, including controls, upstream and downstream of the previous dams, and upstream restored vs. unrestored. For most contaminants, fish community body burdens declined following dam removal and converged across study reaches by the last year of the study in both rivers. Aldrin and dieldrin body burdens in the Olentangy River declined more rapidly in the upstream-restored vs. the upstream-unrestored reach, but were indistinguishable by year three post dam removal. No upstream-downstream differences were observed in body burdens in the Olentangy River, but aldrin and dieldrin body burdens were 138 and 148% higher, respectively, in downstream reaches than in upstream reaches of the Scioto River following dam removal. The strongest relationships between trophic position and body burdens were observed with PCBs and Se in the Scioto River, and with dieldrin in the Olentangy River. Food-chain length - a key measure of trophic structure - was only weakly related to aldrin body burdens, and unrelated to other contaminants. Overall, we demonstrate that lowhead dam removal may effectively reduce ecosystem contamination, largely via shifts in fish food-web dynamics versus sediment contaminant concentrations. This study presents some of the first findings documenting ecosystem contamination following dam removal and will be useful in informing future dam removals. PMID- 28850934 TI - Association between the neighborhood obesogenic environment and colorectal cancer risk in the Multiethnic Cohort. AB - BACKGROUND: Information on the role of the neighborhood environment and colorectal cancer risk is limited. We investigated the association between a comprehensive suite of possible obesogenic neighborhood attributes (socioeconomic status, population density, restaurant and retail food environments, numbers of recreational facilities and businesses, commute patterns, traffic density, and street connectivity) and colorectal cancer risk in the Multiethnic Cohort Study. METHODS: Among 81,197 eligible participants living in California (35,397 males and 45,800 females), 1973 incident cases (981 males and 992 females) of invasive colorectal cancer were identified between 1993 and 2010. Separately for males and females, multivariable Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for colorectal cancer risk overall and by racial/ethnic group (African American, Japanese American, Latino, white). RESULTS: In males, higher traffic density was associated with an increased risk of colorectal cancer (HR=1.29, 95% CI: 1.03-1.61, p=0.03, for quintile 5 vs. quintile 1; p-trend=0.06). While this association may be due to chance, this pattern was seen (albeit non-statistically significant) in all racial/ethnic groups except whites. There were no other significant associations between other neighborhood obesogenic attributes and colorectal cancer risk. CONCLUSION: Findings from our large racial/ethnically diverse cohort suggest neighborhood obesogenic characteristics are not strongly associated with the risk of colorectal cancer. PMID- 28850936 TI - Evaluation of VOC concentrations in indoor and outdoor microenvironments at near road schools. AB - A 14-week air quality study, characterizing the indoor and outdoor concentrations of 18 VOCs at four El Paso, Texas elementary schools, was conducted in Spring 2010. Three schools were in an area of high traffic density and the fourth school, considered as a background school, was situated in an area affected minimally by stationary and mobile sources of air pollution. Passive samplers were deployed for monitoring and analyzed by GC/MS. Differences in the concentration profiles of the BTEX species between the high and low traffic density schools confirmed the pre-defined exposure patterns. Toluene was the predominant compound within the BTEX group and the 96-hr average outdoor concentrations varied from 1.16 to 4.25 MUg/m3 across the four schools. Outdoor BTEX species were strongly correlated with each other (0.63 < r < 1.00, p < 0.05) suggesting a common source: vehicular traffic emissions. As expected, the strength of the associations between these compounds was more intense at each of the three high-exposure schools in contrast to the low-exposure school. This was further corroborated by the results obtained from the BTEX inter-species ratios (toluene: benzene and m, p- xylenes: ethylbenzene). Certain episodic events during the study period resulted in very elevated concentrations of some VOCs such as n-pentane. Indoor concentration of compounds with known indoor sources such as alpha -pinene, d-limonene, p-dichlorobenzene, and chloroform were generally higher than their corresponding outdoor concentrations. Cleaning agents, furniture polishes, materials used in arts and crafts activities, hot water usage, and deodorizing cakes used in urinal pots were the likely major sources for these high indoor concentrations. Finally, retrospective assessment of average ambient BTEX concentrations over the last twenty years suggest a gradual decrement in this border region. PMID- 28850938 TI - Short-term association between personal exposure to noise and heart rate variability: The RECORD MultiSensor Study. AB - BACKGROUND: Studies revealed long-term associations between noise exposure and cardiovascular health, but the underlying short-term mechanisms remain uncertain. OBJECTIVES: To explore the concomitant and lagged short-term associations between personal exposure to noise and heart rate variability (HRV) in a real life setting in the Ile-de-France region. METHODS: The RECORD MultiSensor Study collected between July 2014 and June 2015 noise and heart rate data for 75 participants, aged 34-74 years, in their living environments for 7 days using a personal dosimeter and electrocardiography (ECG) sensor on the chest. HRV parameters and noise levels were calculated for 5-min windows. Short-term relationships between noise level and log-transformed HRV parameters were assessed using mixed effects models with a random intercept for participants and a temporal autocorrelation structure, adjusted for heart rate, physical activity (accelerometry), and short-term trends. RESULTS: An increase by one dB(A) of A weighted equivalent sound pressure level (Leq) was associated with a 0.97% concomitant increase of the Standard deviation of normal to normal intervals (SDNN) (95% CI: 0.92, 1.02), of 2.08% of the Low frequency band power (LF) (95% CI: 1.97, 2.18), of 1.30% of the High frequency band power (HF) (95% CI: 1.17, 1.43), and of 1.16% of the LF/HF ratio (95% CI: 1.10, 1.23). The analysis of lagged exposures to noise adjusted for the concomitant exposure illustrates the dynamic of recovery of the autonomic nervous system. Non-linear associations were documented with all HRV parameters with the exception of HF. Piecewise regression revealed that the association was almost 6 times stronger below than above 65 Leq dB(A) for the SDNN and LF/HF ratio. CONCLUSION: Personal noise exposure was found to be related to a concomitant increase of the overall HRV, with evidence of imbalance of the autonomic nervous system towards sympathetic activity, a pathway to increased cardiovascular morbidity and mortality. PMID- 28850937 TI - Effect modification by apoptosis-related gene polymorphisms on the associations of phthalate exposure with spermatozoa apoptosis and semen quality. AB - BACKGROUND: Human studies indicate that phthalate exposure is associated with adverse male reproductive health, and this association may be modified by genetic polymorphisms. OBJECTIVES: We investigated whether apoptosis-related gene polymorphisms modified the associations of phthalate exposure with spermatozoa apoptosis and semen quality. METHODS: In this Chinese population who sought for semen examination in an infertility clinic, we measured 8 phthalate metabolites in two urine samples to assess the individual's exposure levels. Apoptosis related gene (Fas, FasL, and caspase3) polymorphisms were performed by real-time PCR. Spermatozoa apoptosis and semen quality parameters were evaluated by Annexin V/PI assay and computer-aided semen analysis, respectively. RESULTS: We found that Fas rs2234767, FasL rs763110, and caspase3 rs12108497 gene polymorphisms significantly modified the associations between urinary phthalate metabolites and spermatozoa apoptosis. For example, urinary monobutyl phthalate (MBP) associated with an increased percentage of Annexin V+/PI- spermatozoa of 25.11% (95% CI: 4.08%, 50.53%) were only observed among men with CT/TT genotype of FasL rs763110. In addition, we found that caspase3 rs12108497 gene polymorphisms significantly modified the associations of urinary mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with decreased sperm concentration and sperm count (both p-values for interactions = 0.02). CONCLUSION: Our results provided the first evidence that apoptosis-related gene polymorphisms might contribute to the effects of phthalate exposure on male reproductive health. PMID- 28850939 TI - Lead accumulation (adsorption and absorption) by the freshwater bivalve Corbicula fluminea in sediments contaminated by TiO2 nanoparticles. AB - With the increasing production and applications of TiO2 nanoparticles (NPs), their presence in aquatic environments, especially in sediments, will inevitably increase over time. Most studies investigating the influence of TiO2 NPs on the bioaccumulation of co-existing contaminants have focused on the aqueous phase; however, few have examined the sediment phase, which contains more TiO2 NPs and contaminants. We investigated the effects of TiO2 NPs on Pb accumulation by Corbicula fluminea in sediments, and explored extracellular and intracellular Pb concentrations in the various soft tissues of the bivalve. Pb was spiked with 50 mg/kg in sediment and TiO2 NPs/sediments ratios were within the range 0.2-3.0%. The results showed that TiO2 NPs presented larger adsorption capacity and affinity to Pb ions than the sediments. In addition, the large adsorption capacity of TiO2 NPs and the strong adsorption affinity to Pb ions caused part of the Pb ions released from sediments to aqueous phase were re-adsorbed by TiO2 NPs in sediments. The concentration of TiO2 NPs in C. fluminea tissues significantly increased with increasing TiO2 NP content in sediments, following the order: gill > mantle > foot > visceral mass, which differed from the results found in the aqueous phase. In addition, the proportions of extracellular and intracellular Pb concentrations changed significantly in all the tissues as a result of TiO2 NP contamination of sediments. TiO2 NPs promote increased extracellular Pb in foot, mantle, and gill tissues, and increased intracellular Pb in the visceral mass. These results may be beneficial to more scientifically evaluate and predict the environmental risks of TiO2 NPs to benthic organisms in sediments contaminated by heavy metals. PMID- 28850940 TI - Reductive solubilization of arsenic in a mining-impacted river floodplain: Influence of soil properties and temperature. AB - Mining activities have contaminated many riverine floodplains with arsenic (As). When floodplain soils become anoxic under water-saturated conditions, As can be released from the solid phase. Several microbially-driven As solubilization processes and numerous influential factors were recognized in the past. However, the interplay and relative importance of soil properties and the influence of environmental factors such as temperature remain poorly understood, especially considering the (co)variation of soil properties in a floodplain. We conducted anoxic microcosm experiments at 10, 17.5, and 25 degrees C using 65 representative soils from the mining-impacted Ogosta River floodplain in Bulgaria. To investigate the processes of As solubilization and its quantitative variation we followed the As and Fe redox dynamics in the solid and the dissolved phase and monitored a range of other solution parameters including pH, Eh, dissolved organic C, and dissolved Mn. We related soil properties to dissolved As observed after 20 days of microcosm incubation to identify key soil properties for As solubilization. Our results evidenced reductive dissolution of As-bearing Fe(III)-oxyhydroxides as the main cause for high solubilization. The availability of nutrients, most likely organic C as the source of energy for microorganisms, was found to limit this process. Following the vertical nutrient gradient common in vegetated soil, we observed several hundred MUM dissolved As after 1-2 weeks for some topsoils (0-20 cm), while for subsoils (20-40 cm) with comparable total As levels only minor solubilization was observed. While high Mn contents were found to inhibit As solubilization, the opposite applied for higher temperature (Q10 2.3-6.1 for range 10-25 degrees C). Our results suggest that flooding of nutrient-rich surface layers might be more problematic than water-saturation of nutrient-poor subsoil layers, especially in summer floodings when soil temperature is higher than in winter or spring. PMID- 28850941 TI - Emotional maltreatment is associated with atypical responding to stimulation of endogenous oxytocin release through mechanically-delivered massage in males. AB - The neuropeptide oxytocin plays an important role in social behavior, parenting, and affectionate touch and there is some evidence that oxytocin release can be stimulated by massage or affectionate touch. We examined the effects of massage applied by a massage seat cover on salivary oxytocin levels in two exploratory studies using within-subject designs. In Study 1 massage effects on oxytocin levels were examined in a sample of N=20 healthy female participants. Effects of a 15-min massage session were compared to a control condition during which participants sat on a comfortable chair without a massage seat cover. Salivary oxytocin levels were measured at baseline and up to three hours after the session. We found that massage attenuated oxytocin decreases over time, indicating that massage stimulates oxytocin release. In Study 2, we examined whether effects of massage in N=46 healthy male participants depend on experiences of emotional maltreatment. In addition, we examined whether enhanced oxytocin levels after massage affect the use of excessive handgrip force in response to infant crying and laughter as measured with a handgrip dynamometer. Our findings show that massage results in elevated oxytocin levels compared to a control condition, but that the effects of massage are dependent on experiences of emotional maltreatment. Men with experiences of emotional maltreatment showed lower oxytocin levels, which did not increase after massage. Furthermore, we found that high oxytocin levels after massage were related to reduced handgrip force during exposure to infant crying and laughter, indicating that massage stimulates a sensitive response to infant signals by stimulating oxytocin release. Although massage did not affect oxytocin levels in individuals with experiences of maltreatment, it reduced the use of handgrip force in response to infant crying and laughter in these individuals. Our findings indicate that emotional maltreatment is associated with atypical responding to stimulation of endogenous oxytocin release. PMID- 28850942 TI - Cumulative effects of ibuprofen and air emersion in zebra mussels Dreissena polymorpha. AB - Municipal effluents are major source of pharmaceutical products in the environment. The purpose of this study was to examine the toxicity of a largely used drug, ibuprofen (Ibu), in Dresseina polymorpha mussels and its impact on air survival time. The mussels were exposed to increasing concentration of Ibu (0, 1, 10 and 100MUg/L) for 96 at 15 degrees C and a sub-group of mussels was maintain in air for another 96h. Post-exposure mussels (Ibu and Ibu+Air) were analyzed for weight loss, total triglycerides, neutral lipids, lipid peroxidation (LPO), arachidonate-dependent cyclooxygenase (COX) and glutathione S-transferase activity. Lipid extracts of mussel tissues were also analyzed by 1H-nuclear resonance spectroscopy. The data revealed that mussels exposed to Ibu had increased signs of lipid oxidation, neutral lipids and decreased triglycerides, LPO and GST activity. COX activity was significantly reduced by Ibu in keeping with mode of action of the drug. Following exposure to air, increased weight loss, neutral lipids (lipid degradation), were observed in mussels exposed to Ibu but no changes in COX activity were observed. Air stress limited the decrease in triglycerides and the increase in GST in mussels exposed to 100MUg/L Ibu indicating decreased anti-oxidant response/phase II biotransformation and limited lipid metabolism. In conclusion, exposure to Ibu has some anti-inflammatory effects to mussels based on COX activity but resulted in increased oxidative damage and lipid catabolism. Exposure to air stress could enhance some of these responses and contribute to decreased resistance to air exposures. PMID- 28850943 TI - Imidacloprid insecticide exposure induces stress and disrupts glucose homeostasis in male rats. AB - In the present study, we evaluated the stress response in adult rats who were administered imidacloprid (IMI) orally in two doses (0.5 and 1.0mg/kg bw for 60days). It led to an alteration in the levels of cortisone and catecholamines and induced behavioral deficits, particularly in the animals exposed to the dose of 1.0mg/kg. IMI was further analyzed for the effect on glucose homeostasis in developing and adult rats at a dose of 1.0mg/kg bw where it elicited a hyperglycemic effect. Moreover, we observed an alteration in the mRNA levels of glucose transporters. Histopathological and immunohistochemical data displayed structural perturbations in pancreatic tissue with a decline in the expression of insulin and GLUT4, particularly in the developing rats. Collectively, IMI treatment resulted in stress represented by behavioral and biochemical changes, particularly at a dose of 1.0mg/kg bw. Moreover, IMI perturbed the glucose regulation through hyperglycemic activity in both developing and adult rats, an observation clearly evident in the developing rats. PMID- 28850944 TI - The effects of an online basic life support course on undergraduate nursing students' learning. AB - Objectives: To describe learning outcomes of undergraduate nursing students following an online basic life support course (BLS). Methods: An online BLS course was developed and administered to 94 nursing students. Pre- and post-tests were used to assess theoretical learning. Checklist simulations and feedback devices were used to assess the cardiopulmonary resuscitation (CPR) skills of the 62 students who completed the course. Results: A paired t-test revealed a significant increase in learning [pre-test (6.4 +/- 1.61), post-test (9.3 +/- 0.82), p < 0.001]. The increase in the average grade after taking the online course was significant (p<0.001). No learning differences (p=0.475) had been observed between 1st and 2nd year (9.20 +/- 1.60), and between 3rd and 4th year (9.67 +/- 0.61) students. A CPR simulation was performed after completing the course: students checked for a response (90%), exposed the chest (98%), checked for breathing (97%), called emergency services (76%), requested for a defibrillator (92%), checked for a pulse (77%), positioned their hands properly (87%), performed 30 compressions/cycle (95%), performed compressions of at least 5 cm depth (89%), released the chest (90%), applied two breaths (97%), used the automated external defibrillator (97%), and positioned the pads (100%). Conclusions: The online course was an effective method for teaching and learning key BLS skills wherein students were able to accurately apply BLS procedures during the CPR simulation. This short-term online training, which likely improves learning and self-efficacy in BLS providers, can be used for the continuing education of health professionals. PMID- 28850945 TI - Histological Properties of Main and Accessory Olfactory Bulbs in the Common Hippopotamus. AB - The olfactory system of mammals comprises a main olfactory system that detects hundreds of odorants and a vomeronasal system that detects specific chemicals such as pheromones. The main (MOB) and accessory (AOB) olfactory bulbs are the respective primary centers of the main olfactory and vomeronasal systems. Most mammals including artiodactyls possess a large MOB and a comparatively small AOB, whereas most cetaceans lack olfactory bulbs. The common hippopotamus (Hippopotamus amphibius) is semiaquatic and belongs to the order Cetartiodactyla, family Hippopotamidae, which seems to be the closest extant family to cetaceans. The present study evaluates the significance of the olfactory system in the hippopotamus by histologically analyzing the MOB and AOB of a male common hippopotamus. The MOB comprised six layers (olfactory nerve, glomerular, external plexiform, mitral cell, internal plexiform, and granule cell), and the AOB comprised vomeronasal nerve, glomerular, plexiform, and granule cell layers. The MOB contained mitral cells and tufted cells, and the AOB possessed mitral/tufted cells. These histological features of the MOB and the AOB were similar to those in most artiodactyls. All glomeruli in the AOB were positive for anti-Galphai2, but weakly positive for anti-Galphao, suggesting that the hippopotamus vomeronasal system expresses vomeronasal type 1 receptors with a high affinity for volatile compounds. These findings suggest that the olfactory system of the hippopotamus is as well developed as that of other artiodactyl species and that the hippopotamus might depend on its olfactory system for terrestrial social communication. PMID- 28850946 TI - The Role of Age and Initial Deformation on Final Cranial Asymmetry in Infants with Plagiocephaly Treated with Helmet Therapy. AB - BACKGROUND/AIMS: To characterize the impact of cranial asymmetry and age at initiation of therapy on final cranial asymmetry in infants with deformational plagiocephaly treated with helmet orthotics. METHODS: We conducted a single center retrospective review of 45 pediatric patients <12 months of age with deformational plagiocephaly who underwent STARband cranial orthotic helmet treatment. Cranial asymmetry was measured using a 3-dimensional laser surface scanner and defined as a cranial vault asymmetry index (CVAI) >3.5%. RESULTS: Twenty-one patients (47%) were <6 months of age at the start of helmet therapy. A greater initial CVAI or age at therapy initiation correlated with a greater final CVAI (univariate analysis, r = 0.53, p < 0.001; r = 0.42, p = 0.004). Subgroup analysis of 18 patients beginning therapy at 4-5 months of age and 20 patients beginning therapy at 6-8 months of age revealed that only a change in the initial CVAI was associated with a change in the final CVAI (r = 0.43, p = 0.007). CONCLUSION: In a comparison of patients who initiated helmet therapy at 4-5 and 6 8 months of age, only cranial asymmetry at the outset of therapy was correlated with final cranial asymmetry (r = 0.43, p = 0.007). PMID- 28850947 TI - Adaptation of the Score for Allergic Rhinitis in the Chinese Population: Psychometric Properties and Diagnostic Accuracy. AB - BACKGROUND: Allergic rhinitis (AR) is a worldwide health problem with rising prevalence. To enhance the estimation of AR prevalence in epidemiological studies, the Score for AR (SFAR), a screening tool, has been developed and widely used. An 8-item SFAR is a handy, self-administered instrument assessing the information on nasal and eye symptoms, seasonal increase in symptoms, skin test results, and previous AR diagnoses. This study aimed to adapt the SFAR to the Chinese population (CSFAR) and validate it by testing its psychometric properties and diagnostic accuracy. METHODS: This methodological study involved translation and validation phases. Different batches of participants were recruited for the above purposes. RESULTS: In phase 1, the CSFAR obtained satisfactory item (80 100%) and scale level (97.8%) semantic equivalence, content validity index (96.7%), comprehensibility (100%), cross-language testing (kappa = 0.44-0.83 for item-to-item agreement; intraclass correlation coefficient [ICC] = 0.95, p < 0.05 0.001). In phase 2, CSFAR showed satisfactory internal consistency (alpha = 0.83), 1-month (ICC = 0.88) and 1-year stability (ICC = 0.85), and construct validity (significant correlation between CSFAR and impairments induced by AR: r = 0.47, p < 0.001). Based on the receiver-operating characteristic curve, comparing the CSFAR with diagnosis made by specialists, an optimal cutoff value was 6 (sensitivity 81.8% and specificity 80.3%). CONCLUSION: SFAR was translated into a Chinese version, the CSFAR. Satisfactory results were obtained for its equivalence, appropriateness, comprehensibility, and relevance, as well as its reliability and validity. A cutoff value of 6 was recommended to increase the diagnostic accuracy in environments with less pollen. This study provides evidence that the SFAR we adapted for the Chinese population is a valuable tool in AR screening. PMID- 28850948 TI - Differences in the Anaphylactic Response between C3H/HeOuJ and BALB/c Mice. AB - BACKGROUND: Anaphylaxis is a severe and potentially lethal allergic reaction whose incidence is increasing. Murine models can elucidate the underlying mechanisms and pave the way for appropriate therapeutic options. However, differences in strains and protocols hamper comparisons of data between researchers. We performed a parallel study of clinical and immune responses with 2 strains of mice, BALB/c and C3H/HeOuJ, in an allergen-induced systemic anaphylaxis protocol. Both strains have been widely used in allergy models, although they have not been compared in an intraperitoneal systemic model. METHODS: Groups of 5-week-old female BALB/c and C3H/HeOuJ mice were intraperitoneally sensitized with peanut in the presence of adjuvants. Specific immunoglobulin (sIg) G1, sIgG2a, sIgE, total IgE, histamine release, and specific stimulated splenocyte cytokines, interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, and interferon (IFN)-gamma, were assessed. At week 6, mice were intraperitoneally challenged with peanut. Anaphylaxis was evaluated by recognition of clinical symptoms and changes in body temperature. RESULTS: All peanut-sensitized mice induced sIg and developed anaphylactic symptoms upon challenge. Nonetheless, the C3H/HeOuJ strain demonstrated earlier and persistently higher sIgG1 and sIgG2a production, elevated sIgE, and more severe clinical symptoms and histamine release than the BALB/c strain. In contrast, BALB/c exhibited higher release of IL-4, IL-5, IL-10, IL-13, and IFN-gamma. CONCLUSIONS: Both models are suitable for studying anaphylaxis. Consequently, they could be used in research on the pathogenesis and therapy of anaphylaxis. However, according to the type of study performed, differences in the specific clinical, humoral, and cellular responses to antigens have to be considered. PMID- 28850949 TI - White Matter Lesion Progression and Cognitive Function Over 5 Years in a Young Susceptible Population. PMID- 28850950 TI - Importance of Serum Testicular Protein Hormone Measurement in the Assessment of Disorders of Sex Development. AB - Commonly known for testosterone secretion, the testes also produce the protein hormones anti-mullerian hormone (AMH), inhibin B, and insulin-like factor 3 (INSL3). AMH and inhibin B are secreted by Sertoli cells, whereas INSL3 is a Leydig cell product. AMH is involved in fetal sex differentiation and induces the regression of the anlagen of the uterus and fallopian tubes. INSL3 participates in fetal testicular descent. Serum testicular protein hormone assessment can be very useful and complementary to testosterone measurements in patients with DSD. AMH and inhibin B determination is extremely helpful during childhood, when basal testosterone is normally low. Serum AMH and inhibin B above the female range are indicative of the presence of testicular tissue, and their circulating levels reflect the amount of functional Sertoli cells. In DSD patients with normal male levels of AMH and inhibin B, the diagnosis of gonadal dysgenesis can be ruled out, and isolated androgen secretion deficiency or androgen insensitivity should be suspected. In externally virilized XY patients with persistent mullerian ducts, serum AMH levels determine the diagnosis to AMH deficiency or resistance. At pubertal age, inhibin B levels serve to predict spermatogenic development. PMID- 28850951 TI - Urethroplasty and Quality of Life: Psychometric Validation of a Dutch Version of the Urethral Stricture Surgery Patient Reported Outcome Measures. AB - PURPOSE: The study aimed to translate the Urethral Stricture Surgery Patient Reported Outcome Measures (USS-PROM) questionnaire in Dutch. To validate this translated questionnaire, the study evaluates its psychometric properties in a different population, a different environment, and a different health care system. Questions about urinary incontinence and sexual functioning were added. MATERIALS AND METHODS: Between December 2014 and January 2017, Dutch-speaking adult men scheduled for urethroplasty at Ghent University Hospital were prospectively enrolled in this study. Patients completed the USS-PROM before surgery, 3-6 months after surgery, and 1 year after surgery. Psychometric criteria included content validity, criterion validity, internal consistency, reproducibility, responsiveness, and floor and ceiling effects. (EC/2014/0438). RESULTS: A total of 100 patients were included, 39 patients completed both the preoperative and the postoperative questionnaire, and 30 patients completed the USS-PROM twice within a short period of time in order to evaluate test-retest reliability. Pearson correlation coefficients showed no statistical significant correlation between lower urinary tract symptoms (LUTS) scores and maximum flow rates. Cronbach's alpha was 0.81 and 0.89, respectively, for the LUTS score and the summative Male Sexual Health Questionnaire Ejaculatory Dysfunction short form (MSHQ-EjD short form) score. The intraclass correlation coefficients ranged from 0.72 to 0.94. Significant changes were observed in all items except the MSHQ-EjD short form scores. All values exceeded the predefined thresholds. CONCLUSIONS: The Dutch version of the USS-PROM has adequate psychometric properties and is a valid instrument to assess patient-reported outcome measures in men undergoing urethroplasty. PMID- 28850952 TI - Influence of NanoLC Column and Gradient Length as well as MS/MS Frequency and Sample Complexity on Shotgun Protein Identification of Marine Bacteria. AB - Protein identification by shotgun proteomics, i.e., nano-liquid chromatography (nanoLC) peptide separation online coupled to electrospray ionization (ESI) mass spectrometry (MS)/MS, is the most widely used gel-free approach in proteome research. While the mass spectrometer accounts for mass accuracy and MS/MS frequency, the nanoLC setup and gradient time influence the number of peptides available for MS analysis, which ultimately determine the number of proteins identifiable. Here, we report on the influence of (i) analytical column length (15, 25, or 50 cm) coupled to (ii) the applied gradient length (120, 240, 360, 480, or 600 min), as well as (iii) MS/MS frequency on peptide/protein identification by shotgun proteomics of (iv) 2 marine bacteria. Longer gradients increased the number of peptides/proteins identified as well as the reproducibility of identification. Furthermore, longer analytical columns strictly enlarge the covered proteome complement. Notably, the proteome complement identified with a short column and applying a long gradient is also covered when using longer columns with shorter gradients. Coverage of the proteome complement further increases with higher MS/MS frequency. Compilation of peptide lists of replicate analyses (same gradient length) improves protein identification, while compilation of analyses with different gradient lengths yields a similar or even higher number of proteins using comparable or even less total analysis time. PMID- 28850953 TI - Genomic Organization and Physical Mapping of Tandemly Arranged Repetitive DNAs in Sterlet (Acipenser ruthenus). AB - Acipenseriformes represent a phylogenetically basal clade of ray-finned fish characterized by unusual genomic traits, including paleopolyploid states of extant genomes with high chromosome numbers and slow rates of molecular evolution. Despite a high interest in this fish group, only a limited number of studies have been accomplished on the isolation and characterization of repetitive DNA, karyotype standardization is not yet complete, and sex chromosomes are still to be identified. Here, we applied next-generation sequencing and cluster analysis to characterize major fractions of sterlet (Acipenser ruthenus) repetitive DNA. Using FISH, we mapped 16 tandemly arranged sequences on sterlet chromosomes and found them to be unevenly distributed in the genome with a tendency to cluster in particular regions. Some of the satellite DNAs might be used as specific markers to identify individual chromosomes and their paralogs, resulting in the unequivocal identification of at least 18 chromosome pairs. Our results provide an insight into the characteristic genomic distribution of the most common sterlet repetitive sequences. Biased accumulation of repetitive DNAs in particular chromosomes makes them especially interesting for further search for cryptic sex chromosomes. Future studies of these sequences in other acipenserid species will provide new perspectives regarding the evolution of repetitive DNA within the genomes of this fish order. PMID- 28850954 TI - Usage of Multilevel Paravertebral Block as the Main Anesthesia for Mini-Invasive PCNL: Retrospective Review of 45 Cases with Large Stones. AB - INTRODUCTION: To evaluate the efficiency and safety of the paravertebral block (PVB) as the single main anesthesia for unilateral mini-invasive percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: Forty-five American Society of Anesthesiologists grade I/II/III patients with large upper urinary tract stones were included in our retrospective study. All patients received multilevel PVB from T10 to L1 with 10 mL of 0.5% ropivacaine for each segment. After the block was confirmed, unilateral mini-invasive PCNL was performed. Intraoperative and postoperative pain management and associated adverse events were observed to investigate the feasibility of PVB in mini-invasive PCNL as the main anesthesia. RESULTS: Successful blocking was confirmed 20 min after paravertebral injections. The mean operation time was 59 min. None of the patients experienced severe pain or hemodynamic dysfunction. Stone-free rate was 93.1% and no blood transfusion was required. The mean time to first analgesic requirement was 160 min, and the mean consumption of diclofenac sodium suppositories was 150 mg. All patients contained normal muscle strength on the contralateral side. Patients could recover ambulation within 1 h after the operation. CONCLUSIONS: Multilevel PVB was proved to be suitable as the main anesthesia for unilateral mini-invasive PCNL, providing feasible pain relief and quick postoperative recovery. PMID- 28850955 TI - The Lung in Hereditary Hemorrhagic Telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder with an estimated prevalence of 1 in 6,000, characterized by recurrent epistaxis, cutaneous telangiectasia, and arteriovenous malformations (AVMs) that affect many organs including the lungs, gastrointestinal tract, liver, and brain. Its diagnosis is based on the Curacao criteria, and is considered definite if at least 3 of the 4 following criteria are fulfilled: (1) spontaneous and recurrent epistaxis, (2) telangiectasia, (3) a family history, and (4) pulmonary, liver, cerebral, spinal, or gastrointestinal AVMs. The focus of this review is on delineating how HHT affects the lung. PMID- 28850956 TI - Cognitive Impairments in Unipolar Depression: The Impact of Rumination. AB - BACKGROUND: Major depressive disorder (MDD) is associated with impairments in several cognitive domains. People with depression also tend to focus on and think about their problems ("ruminate") more than people without depression. Recent studies indicate that depressive rumination is connected to cognitive impairments in MDD. However, there is little scientific understanding of the role of rumination in these deficits. SAMPLING AND METHODS: The current study examined the performance of 62 outpatients suffering from unipolar major depression with a low tendency to ruminate versus outpatients with a high tendency to ruminate using a neuropsychological battery covering the 5 cognitive domains: attention, memory, working memory, executive functions and processing speed. RESULTS: The results indicated that high ruminators show a lower performance than low ruminators with regard to processing speed and executive function tasks with low effect sizes. However, these findings were not significant after Bonferroni correction. Hierarchical linear regression revealed that the effect on processing speed could be partially attributed to rumination, but an effect on executive functions was not established. CONCLUSIONS: The current study is the first to systematically investigate the impact of rumination on cognitive impairments in MDD, exploring a broad range of cognitive domains. The results partially support the hypothesis that rumination has an impact on single cognitive domains and highlight the necessity for further investigations in order to generalize these findings. PMID- 28850957 TI - Expression of Mitochondrial Respiratory Chain Complexes in the Vaginal Wall in Postmenopausal Women with Pelvic Organ Prolapse. AB - BACKGROUND/AIMS: Pelvic organ prolapse (POP) is a common disease affecting adult women. It is a result of the vaginal wall disorder as well as damage of the supportive structures contributing to the integrity of the pelvic floor. Mitochondrial disorders may have an important role in the vaginal wall degeneration leading to POP. The goal of this research is to examine if POP is associated with an altered expression of mitochondrial respiratory chain complexes. METHODS: Samples of vaginal tissue were collected from 16 postmenopausal women: 10 had POP and 6 had other forms of benign gynecological disease. Using western blot, samples were analyzed to assess the expression of mitochondrial proteins including citrate synthase (CS), individual complexes of the mitochondrial respiratory chain and alpha smooth muscle actin (SMA). RESULTS: A significantly reduced expression of SMA and complex II in vaginal tissue of women with POP was found, compared to the control group (p < 0.05), with a tendency for a reduced expression of CS (p = 0.06) and other complexes in the POP group. CONCLUSIONS: Our results indicate that there is a decreased quantity of the smooth muscle and a decreased expression of mitochondrial markers in the vaginal wall of women with prolapse suggesting their possible role in the pathogenesis of POP. PMID- 28850958 TI - Quality Standards for Herbal Drugs and Herbal Drug Preparations - Appropriate or Improvements Necessary? AB - Standards for quality control as defined in the European Pharmacopoeia contribute significantly to a consistent and high quality of herbal drugs, herbal drug preparations, and herbal medicinal products. The minimum content of single plant constituents is considered of high relevance. Therefore, nearly all monographs on herbal drugs or herbal drug preparations contain an obligatory assay.However, a critical evaluation of the data published for such assayed constituents reveals that in most cases these constituents have to be considered as purely analytical markers without correlation to quality or efficacy. Examples where the assay does not meet its objective support the need to adapt current quality standards. Moreover, the trend to increase the content of certain constituents may lead to significant modifications to traditional manufacturing processes.In order to initiate a scientific discussion, the role of the assay in the context of quality requirements, quality documentation in the manufacturing process, safety, and efficacy is discussed and possible alternatives to the single marker assay are examined. PMID- 28850959 TI - Epileptic Seizures Under Antidepressive Drug Treatment: Systematic Review. AB - OBJECTIVE: This paper is a systematic review on seizures under treatment with substances licensed for major depression. METHOD: Systematic review protocol is available in PROSPERO registration number CRD42016034010. Twenty-five substances were selected according to frequencies of prescriptions and publications. A PubMed search was conducted with "substance name" and "seizure." RESULTS: A total of 2291 articles were screened, out of which 164 fulfilled inclusion criteria. Data synthesis was possible only to a limited extent due to heterogeneity of included patients, observation periods, methods, and outcomes. Evidence for an at most moderate, but still low, risk (>0.1% under regular doses) was found highest for clomipramine, followed by quetiapine, amitriptyline, venlafaxine, citalopram, sertraline, trazodone, mirtazapine, paroxetine, bupropion, and escitalopram. For fluoxetine and duloxetine, the risk seems to be negligible. For the other, mostly newer, substances, sufficient evidence was not available. An increased risk for lithium, as reported in many reviews and textbooks, could not be confirmed. CONCLUSIONS: Antidepressive treatment is rather safe in terms of risk of seizures and also can be generally recommended in the treatment of patients with epilepsy. PMID- 28850960 TI - [Frequency and Timing of Decisions to Limit Intensive Medical Care and Tumor Specific Therapy in University Hematology and Oncology]. AB - Background Decisions to limit treatment (DLT) are important in order to prevent overtreatment at the end of life. However, they are not always discussed with the patient in advance or sufficiently documented. In a study to improve DLT in patients with an advanced hematological/ oncological disease we examined how often DLT precede deaths and how early they are determined. Methods In a period of 6 months, 567 patients with advanced hematological/ oncological neoplasias had been recruited for the cross-sectional study at the University hospital in Munich. Using a standardized registration form an embedded researcher documented which DLT were determined for the patients and which of them were implemented until death. Results For 26 % (n = 147) of the 567 patients a DLT was determined. These DLT were mostly documented in writing from the beginning on (90 %; n = 132), 20 % (n = 30) were modified. The proportion of deceased patients with DLT was 82 % (n = 62 of 76 deceased). The median time between the initial determination of a DLT and the patient's death was 6 days at normal ward and 10.5 days at palliative ward. Compared to hematological patients, DLT were more frequently diagnosed in patients with an oncological disease (64 vs. 36 %) and the decisions were made slightly earlier (7 vs. 5 days before death). Conclusion Our results show that DLT precede the death of many patients with a hematological/ oncological disease, but usually are made in the last week of life. This leads to the risk that the remaining few days to death are not sufficient for discussions with all parties involved and the planning of the end of life. These findings resulted in the development of an ethics policy for treatment limitation in cancer patients, which should support the concept of advance care planning. The project is funded by the German Cancer Aid. PMID- 28850962 TI - ? PMID- 28850961 TI - [Chronic Kidney Diseases]. PMID- 28850963 TI - [Multiple Hemorrhagic Skin Lesions in a 52-Year-Old Patient with Liver Cirrhosis]. PMID- 28850964 TI - [Epidemiology of Chronic Kidney Disease - Ever More Patients?] AB - Chronic kidney disease (CKD) is a common disorder that often occurs as a complication of other common diseases such as diabetes, obesity, hypertension, or heart failure. Here we review the methodological pitfalls both in measuring kidney function and in determining the epidemiology of kidney disease. CKD is defined as the coincidence of three criteria: A reduced glomerular filtration rate, an anatomical lesion, and a duration of more than three months. Glomerular filtration rate declines with increasing age, but this alone does not constitute kidney disease. In epidemiological studies, exact measurement of glomerular filtration rate is often not feasible. Estimates of glomerular filtration rate depend on serum levels of creatinine or cystatin C, both of which are influenced by extrarenal factors. Anatomical lesion and duration of disease are almost never ascertained in epidemiological studies. Somewhat surprisingly, large-scale statistical modeling by the Global Burden of Disease Study suggests a decline in the world-wide prevalence of CKD in the past decades. In Germany, no longitudinal data is available for lack of a national register. Cross-sectional investigations report prevalences between 6 and 26 percent, depending on age, comorbidities, and geographical region. In the future, better control of risk factors may precede a decline in the incidence of CKD, with prevalences remaining stable due to better medical care and improved survival. In the long run, there is reason to believe that there will not be ever more patients with CKD. PMID- 28850965 TI - [How to Retard Progression of Chronic Kidney Disease]. AB - End stage chronic kidney disease (CKD) requiring renal replacement therapy is related to poor quality of life and high mortality. Thus, slowing the progression of CKD is an important purpose of therapy. Some general therapeutic approaches aim to slow the decline of renal function and they can be applied in all patients with CKD - irrespective of the underlying cause of CKD. A key intervention is lowering blood pressure (target: <= 140/90 mmHg, and in patients with albuminuria <= 130/80 mmHg). Inhibitors of the renin angiotensin system preferentially should be used in case of albuminuria, depending on the diabetic status and the level of albuminuria: in diabetics with albuminuria >= 30 mg/d, in non-diabetics with albuminuria > 300 mg/d. Mineralocorticoid receptor blockers and endothelin receptors blockers promise novel anti-proteinuric strategies - but still validation of their positive effects on retarding CKD progression is necessary. In patients with diabetic kidney disease, glycemic control aiming for an HbA1c of ~ 7.0 % has been established to slow CKD progression. Furthermore, SGLT-2 inhibition with empagliflozin may be considered as a new therapeutic approach that provides additional cardiovascular and renal protection. Finally, recent studies suggest: correction of metabolic acidosis and avoidance of episodes of acute renal failure may provide protection against the progression of CKD. PMID- 28850966 TI - [Management of Patients with CKD in Clinical Practice]. AB - Chronic kidney disease (CKD) affects between 3 and 17 % of the population in Europe, especially elderly persons. CKD is a clinical syndrome which may develop in patients with e. g. diabetes mellitus, arterial hypertension or autoimmune diseases. A poorer renal function - especially in old age - is to be considered irrespective of the medication. Many antibiotics and painkillers require dose adjustments. Therapy should be done in a manner which is suitable for indication. Polypharmacy should be avoided as far as possible. Diuretics and RAAS inhibitors are useful drugs in therapy of CKD. Changes of lifestyle are important, so as weight reduction, restriction of salt and fructose, sufficient drinking, strict control of blood glucose, blood pressure and hypercholesterolaemia. Additional acute lesions have to be avoided ("acute-on-chronic renal failure"). PMID- 28850967 TI - [Ulcerative Colitis and Adenocarcinoma of the Appendix: Is there a Causal Link?] AB - Anamnesis We report the case of a 57-year-old patient initially seen with stool irregularities and malignant ascites. Diagnostics Through further examinations we diagnosed a long standing untreated ulcerative colitis with endoscopic signs of a massive chronic inflammation of the entire colon. The origin of the malignant cells in the ascites remained unknown despite the exhaustion of all diagnostic means available. As an ultima ratio we performed a colectomy and an advanced adenocarcinoma of the appendix was found. Clinical course The patient's condition deteriorated very fast so that chemotherapy wasn't an option. Following his wishes he received palliative care in his home environment. Conclusion Patients with an inflammatory bowel disease have a higher risk of developing colorectal cancer. This is a well-known fact. But an adenocarcinoma of the appendix is still a rarity. Here we illuminate the possible link between the appendix and ulcerative colitis. PMID- 28850968 TI - [Botulism: Diagnosis and Therapy]. AB - Background Botulism is a rare, life-threatening, time-critical neuroparalytic disease that is frequently a subject of differential diagnostic considerations. But there is much uncertainty regarding diagnosis and therapy. Rapid diagnosis, early antitoxin dose, consistent food hygiene and the sensitization of the population can help to reduce incidence, morbidity and mortality. Methods This overview is based on an epidemiological data inquiry (RKI, ECDC, CDC, WHO) and a selective literature research (pubmed till March 2017). Additionally, the German botulism guideline (2012) and own diagnostical experiences were taken into account. Results The incidence of botulinum toxin intoxication induced by ubiquitous spore-forming Clostridium botulinum (main representative) is < 0.01/100 000 EU citizens. Foodborne botulism is a pure intoxication syndrome (most common form) due to improperly prepared or incorrectly stored food. Wound and infant botulism are kinds of "toxico-infections". A "bulbar" neuroparalysis is a main symptom progressing to a flaccid tetraparesis up to respiratory paralysis. Infant botulism is presented non-specific and is treated only symptomatically; but a special human-derived antitoxin is available at international pharmacies. In case of suspected foodborne or wound botulism antitoxin must be administered as soon as possible, which may also be effective 24 hours after symptoms onset. There is no evidence for adjuvant treatment except of intensive care unit (ICU) therapy. Conclusion Despite typical symptomatology botulism is often diagnosed too late. Early antitoxin administration and ICU therapy are crucial for survival. A consultant laboratory should be contacted for advice. PMID- 28850969 TI - [Statins as a Therapy of Chronic Liver Disease?] AB - Statins have proven effects in the primary and secondary prevention of coronary disease. Besides lowering LDL-cholesterol beneficial pleiotropic consequences of statin therapy are increasingly discussed. Retrospective analyses of large cohort studies have shown favorable effects on the sequels of chronic viral induced liver disease and of non alcoholic fatty liver disease. These findings are substantiated by experimental work showing that statins reduce inflammation, fibrosis and proliferation in the diseased liver. Prospective controlled trials are necessary to elucidate whether, when and where statins have a role in the therapeutic armamentarium for liver disease. PMID- 28850970 TI - ? PMID- 28850971 TI - ? PMID- 28850972 TI - Video Comment on David J. Tate et al. PMID- 28850973 TI - Video Comment on Frank Lenze et al. PMID- 28850974 TI - Video Comment on Toshio Kuwai et al. PMID- 28850975 TI - Is the West finally reaching the East in endoscopic submucosal dissection? The gastric cancer case. PMID- 28850976 TI - Pancreatic cyst ablation: why are we not doing more of these procedures? PMID- 28850977 TI - Flail, flay, or fail: needle-knife versus transpancreatic sphincterotomy to access the difficult-to-cannulate bile duct during ERCP. PMID- 28850978 TI - The role of a second endoscopic procedure after a failed first endoscopic mucosal resection for colorectal polyps. PMID- 28850979 TI - Scissor-type needle-knife for colorectal endoscopic submucosal dissection. PMID- 28850980 TI - [French comment on article Clinical utility of a functional lumen imaging probe in management of dysphagia following head and neck cancer therapies]. PMID- 28850981 TI - [French comment on article Endoscopic submucosal dissection for early gastric cancer: are expanded resection criteria safe for Western patients?] PMID- 28850982 TI - [French comment on article Long-term outcomes after endoscopic ultrasound-guided ablation of pancreatic cysts]. PMID- 28850983 TI - [French comment on article Transpancreatic sphincterotomy has a higher cannulation success rate than needle-knife precut papillotomy - a meta-analysis]. PMID- 28850985 TI - ? PMID- 28850984 TI - [French comment on article Post-polypectomy bleeding in the English National Health Service Bowel Cancer Screening Programme]. PMID- 28850986 TI - [Editor's Comment]. PMID- 28850987 TI - ? PMID- 28850988 TI - ? PMID- 28850989 TI - ? PMID- 28850990 TI - [Not Available]. PMID- 28850991 TI - [Cancer and nutrition - a paradigma shift]. AB - Substantial international differences in the prevalence of cancer disease suppose that nutrition may be an important factor in the development of cancer. Many experts believe, that nutritional factors may contribute up to 35 % to the development of malignant tumors. Many patients have lost substantial body weight already at the time of the diagnosis of the disease as consequence of undernutrition and malnutrition, respectively. During the course of the disease the nutritional status often is deteriorating further. Caused by both the cancer disease itself and the treatment, loss of appetite, changes in taste, nausea and vomiting may additionally contribute to undernutrition. Undernutrition is a relevant factor for the outcome of the disease and for the tolerance of the treatment as well. Therefore, supporting the heavily impaired patients in nutritional intake is of paramount importance and an urgent task for physicians and nurses. In view of physiology, pathophysiology, genetics and molecular biology, metabolic processes in cancer are highly complex regulated and there is increasing evidence that a diet rich in fat and protein is favourable. This, however, implies a paradigma shift away from the "healthy" balanced diet rich in fruit, vegetable and complex carbohydrates. So far, the evidence based data of this new concept is, however, a controversial issue. PMID- 28850992 TI - ? AB - The BEMED study (BMJ 2016; 352: DOI 10.1136) was designed as multi-centric, double-blind, plaebo-controlled study in patients with Meniere's disease. It should compare a low-level (2 * 24 mg/d) vs. high-level (3 * 48 mg/d) betahstine intake vs. placebo. The primary endpoint was the "number of vertigo attacks lasting longer than 20 min as documented in a patient's diary". The main finding of the study was that betahistine did not significantly better reduced the number of vertigo attacks than placebo. Therefore, the BEMED study should be critically discussed in the present paper. PMID- 28850993 TI - [Benign and malignant disorders of the jaw]. PMID- 28850994 TI - ? PMID- 28850995 TI - [Not Available]. PMID- 28850996 TI - ? PMID- 28850997 TI - ? PMID- 28850998 TI - Medical Termination of Delayed Miscarriage: Four-Year Experience with an Outpatient Protocol. AB - Purpose To evaluate the efficacy of an outpatient protocol with vaginal misoprostol to treat delayed miscarriage. Methods Retrospective analysis of prospectively collected data on women medically treated for missed abortion with an outpatient protocol. The inclusion criteria were: ultrasound-based diagnosis of missed abortion with less than 10 weeks; no heavy bleeding, infection, inflammatory bowel disease or misoprostol allergy; no more than 2 previous spontaneous abortions; the preference of the patient regarding the medical management. The protocol consisted of: 1) a single dose of 800 ug of misoprostol administered intravaginally at the emergency department, after which the patients were discharged home; 2) clinical and ultrasonographic evaluation 48 hours later if the intrauterine gestational sac was still present, the application of 800 ug of vaginal misoprostol was repeated, and the patients were discharged home; 3) clinical and ultrasonography evaluation 7 days after the initiation of the protocol - if the intrauterine gestational sac was still present, surgical management was proposed. The protocol was introduced in January 2012. Every woman received oral analgesia and written general recommendations. We also gave them a paper form to be presented and filled out at each evaluation. Results Complete miscarriage with misoprostol occurred in 340 women (90.2%). Surgery was performed in 37 (9.8%) patients, representing the global failure rate of the protocol. Miscarriage was completed after the first misoprostol administration in 208 (55.2%) women, with a success rate after the second administration of 78.1% (132/169). The average age of the women with complete resolution using misoprostol was superior to the average age of those who required surgery (33.99 years versus 31.74 years; p = 0.031). Based on the ultrasonographic findings in the first evaluation, the women diagnosed with fetal loss achieved greater success rates compared with those diagnosed with empty sac (p = 0.049). Conclusions We conclude this is an effective and safe option in the majority of delayed miscarriage cases during the first trimester, reducing surgical procedures and their consequences. PMID- 28850999 TI - [Research for us! Which Topics are Relevant for Patients with Depression?] AB - OBJECTIVE: To identify and prioritize research questions about treatment and care of depression which are relevant to patients, carers and clinicians. The importance of involvement of those stakeholder groups in health services research is increasingly recognized internationally. METHODS: Research topics were collected in an online survey using unipark software. Patients, carers and clinicians wrote down research topics, i. e. uncertainties they experienced when dealing with depression. The stated research topics were summarized by the authors to generate research questions. Patients, carers and clinicians rated the importance of the identified research questions using a 7 point likert-scale in a further online-survey. RESULTS: Respondents rated research questions with regard to accessibility and organization of care as especially relevant. A research question regarding the effectiveness of self-help and coping-strategies was rated as most important. Further relevant research questions refer to decide on and find effective therapy. CONCLUSION: According to patients, carers and clinicians more research about self-help and access to treatment should be conducted. PMID- 28851000 TI - [Implementation of the Internet-Based Self-Management Program "moodgym" in Patients with Depressive Disorders in Inpatient Clinical Settings - Patient and Expert Perspectives]. AB - OBJECTIVE: The study aims to assess the acceptance, chances and barriers of an online self-management program (moodgym) for depression from the perspective of experts and patients in inpatient psychiatric settings. METHODS: Paper-pencil interviews were conducted with n = 181 depressed inpatients (n = 181, pre-post assessment after 8 weeks) and n = 31 medical experts. Two regression models were carried out to investigate factors associated with the uptake and the user acceptance of moodgym. Chances and barriers were analysed qualitatively. RESULTS: Experts and patients reported moderate to high user acceptance. 59 % (n = 107) of the patients logged in to moodgym. Factors associated with the uptake were the educational level and treatment preferences. The user acceptance was influenced by the patients' self-rated health and the frequency of using moodgym. Relevant barriers anticipated by experts were limited computer skills, difficulties in concentration and a severe course of depression. Patients highlighted the ease of use, the moodgym characters and the flexible availability. CONCLUSIONS: moodgym may represent a complementary treatment option for depressive disorders in an inpatient setting. PMID- 28851001 TI - [The Promotion of Adherence to Psychodynamic Psychotherapy by Means of Psychoeducational Intervention]. AB - OBJECTIVE: This study investigates the promotion of adherence of patients to a psychodynamic treatment program by means of a psycho educational program in the context of randomized field study. METHOD: A sample of a whole year of admittances of patients convicted for forensic treatment due to S 64 of the german penal code were randomized assigned in two groups. An early intervention group received after a 6-week introduction period a specially designed modular psycho educational treatment program parallel to an psychodynamic treatment program. The late intervention group underwent the same psychodynamic treatment program but received psychoeducation 3 month later. The study investigated the drop-out rate and the differences of the two groups in relevant areas. RESULTS: After 7 month significantly more patients of the early intervention group are still in psychodynamic treatment CONCLUSIONS: The study shows positive effects concerning the adherence of forensic inpatients for a psychodynamic orientated therapy. PMID- 28851002 TI - [Indication and Evidence of Internationally Developed Online Coaches as Intervention for Mental Illness - a Meta-Review]. AB - OBJECTIVE: The aim of the study was to investigate the current state of research concerning internationally developed Online Coaches for treatment support and prevention of mental disorders. Evidence and effectiveness of the Online Coaches ought to be explored. METHODS: A systematic literature search was performed in international databases in order to provide a meta-review of existing Online Coaches for mental disorders. The assessment of the methodological quality and evidence of the studies was based on the established guidelines of the Scottish Intercollegiate Guideline Network. RESULTS: 52 studies (24 meta-analyses, 16 systematic reviews, 2 health-technology assessment reports, and 10 RCT studies) were identified. The efficacy was demonstrated for a variety of Online Coaches for mental disorders, especially for anxiety and depressive disorders, insomnia, and post-traumatic stress disorders, with predominantly acceptable and high quality. CONCLUSION: The present work provides an overview of internationally developed Online Coaches in the field of mental health care. Online Coaches can serve as a useful supplement to the treatment and prevention of mental disorders. PMID- 28851003 TI - Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance. AB - Tumor blood vessels play an important role in tumor progression and metastasis. We previously reported that tumor endothelial cells (TEC) exhibit several altered phenotypes compared with normal endothelial cells (NEC). For example, TEC have chromosomal abnormalities and are resistant to several anticancer drugs. Furthermore, TEC contain stem cell-like populations with high aldehyde dehydrogenase (ALDH) activity (ALDHhigh TEC). ALDHhigh TEC have proangiogenic properties compared with ALDHlow TEC. However, the association between ALDHhigh TEC and drug resistance remains unclear. In the present study, we found that ALDH mRNA expression and activity were higher in both human and mouse TEC than in NEC. Human NEC:human microvascular endothelial cells (HMVEC) were treated with tumor conditioned medium (tumor CM). The ALDHhigh population increased along with upregulation of stem-related genes such as multidrug resistance 1, CD90, ALP, and Oct-4. Tumor CM also induced sphere-forming ability in HMVEC. Platelet-derived growth factor (PDGF)-A in tumor CM was shown to induce ALDH expression in HMVEC. Finally, ALDHhigh TEC were resistant to fluorouracil (5-FU) in vitro and in vivo. ALDHhigh TEC showed a higher grade of aneuploidy compared with that in ALDHlow TEC. These results suggested that tumor-secreting factor increases ALDHhigh TEC populations that are resistant to 5-FU. Therefore, ALDHhigh TEC in tumor blood vessels might be an important target to overcome or prevent drug resistance. PMID- 28851004 TI - Telomere length is reflected by plumage coloration and predicts seasonal reproductive success in the barn swallow. AB - Individuals differ in realized fitness but the genetic/phenotypic traits that underpin such variation are often unknown. Telomere dynamics may be a major source of variation in fitness traits because physiological telomere shortening depends on environmental and genetic factors and may impair individual performance. Here, we showed that, in a population of a socially monogamous, biparental passerine bird, the barn swallow (Hirundo rustica), breeding in northern Italy, telomere length (TL) of both adult males and females positively correlated with seasonal reproductive and fledging success, as expected because long telomeres are supposed to boost performance. Telomere length was correlated with sexually dimorphic coloration in both sexes, showing for the first time in any species that coloration reliably reflects TL and may mediate mutual mate choice, leading to the observed positive assortative mating for TL in the barn swallow. Thus, TL appears to be associated with variation in a major fitness trait and may be an ultimate target of mate choice, as individuals of both sexes can use coloration to adaptively choose high-quality mates that possess long telomeres. PMID- 28851006 TI - Bi2 MoO6 Nanostrip Networks for Enhanced Visible-Light Photocatalytic Reduction of CO2 to CH4. AB - A three-dimensional Bi2 MoO6 nanostrip architecture was synthesized by the hydrothermal method using sodium oleate as a surfactant. The generated Bi2 MoO6 nanostrips intercross with each other to form a unique network structure with a band gap of 2.92 eV, corresponding to visible-light wavelength. Time-evolution experiments reveal the formation mechanism of the Bi2 MoO6 network. The photocatalytic reduction of CO2 to CH4 catalyzed by the Bi2 MoO6 architecture was evaluated and compared with the process catalyzed by a Bi2 MoO6 nanoplate analogue synthesized in the absence of sodium oleate as well as with the solid state reaction. The Bi2 MoO6 nanostrips exhibit the best photocatalytic activity, which can be attributed to their high specific surface area, high light absorption intensity, suitable thickness for fast charge-carrier migration, and the presence of pores for reactant transport. PMID- 28851005 TI - Colonic immune cells in irritable bowel syndrome: A systematic review and meta analysis. AB - BACKGROUND & AIMS: Increases in mucosal immune cells have frequently been observed in irritable bowel syndrome (IBS) patients. However, this finding is not completely consistent between studies, possibly due to a combination of methodological variability, population differences and small sample sizes. We performed a meta-analysis of case-control studies that compared immune cell counts in colonic biopsies of IBS patients and controls. METHODS: PubMed and Embase were searched in February 2017. Results were pooled using standardized mean difference (SMD) and were considered significant when zero was not within the 95% confidence interval (CI). Heterogeneity was assessed based on I2 statistics where I2 <= 50% and I2 > 50% indicated fixed and random effect models, respectively. KEY RESULTS: Twenty-two studies on 706 IBS patients and 401 controls were included. Mast cells were increased in the rectosigmoid (SMD: 0.38 [95% CI: 0.06-0.71]; P = .02) and descending colon (SMD: 1.69 [95% CI: 0.65 2.73]; P = .001) of IBS patients. Increased mast cells were observed in both constipation (IBS-C) and diarrhea predominant IBS (IBS-D). CD3+ T cells were increased in the rectosigmoid (SMD: 0.53 [95% CI: 0.21-0.85]; P = .001) and the descending colon of the IBS patients (SMD: 0.79, 95% CI [0.28-1.30]; P = .002). This was possibly in relation to higher CD4+ T cells in IBS (SMD: 0.33 [95% CI: 0.01-0.65]; P = .04) as there were no differences in CD8+ T cells. CONCLUSIONS & INFERENCES: Mast cells and CD3+ T cells are increased in colonic biopsies of patients with IBS vs non-inflamed controls. These changes are segmental and sometimes IBS-subtype dependent. The diagnostic value of the quantification of colonic mucosal cells in IBS requires further investigation. PMID- 28851007 TI - LCST Phase Behavior and Complexation with Water of an Ionic Liquid Incorporating the 5-Phenyltetrazolate Anion. AB - The use of 5-phenyltetrazole, a bioisostere of benzoic acid, as an anion source to prepare an ionic liquid is described for the first time. Tetrabutylphosphonium 5-phenyltetrazolate undergoes phase separation from water with lower critical solution temperature phase behavior, in contrast to completely water miscible tetrabutylphosphonium benzoate, and also exhibits strong complexation with water with both eutectic and peritectic behavior that has not previously been observed in ionic liquid+water systems. The anhydrous and trihydrate salts were isolated and characterized by single crystal X-ray diffraction. PMID- 28851009 TI - Reply to Letter 'Morning dosing for dolutegravir-related insomnia and sleep disorders' by Capetti et al. PMID- 28851008 TI - The potassium channel FaTPK1 plays a critical role in fruit quality formation in strawberry (Fragaria * ananassa). AB - Potassium (K+ ), an abundant cation in plant cells, is important in fruit development and plant resistance. However, how cellular K+ is directed by potassium channels in fruit development and quality formation of strawberry (Fragaria * ananassa) is not yet fully clear. Here, a two-pore K+ (TPK) channel gene in strawberry, FaTPK1, was cloned using reverse transcription-PCR. A green fluorescent protein subcellular localization analysis showed that FaTPK1 localized in the vacuole membrane. A transcription analysis indicated that the mRNA expression level of FaTPK1 increased rapidly and was maintained at a high level in ripened fruit, which was coupled with the fruit's red colour development, suggesting that FaTPK1 is related to fruit quality formation. The down- and up-regulation of the FaTPK1 mRNA expression levels using RNA interference and overexpression, respectively, inhibited and promoted fruit ripening, respectively, as demonstrated by consistent changes in firmness and the contents of soluble sugars, anthocyanin and abscisic acid, as well as the transcript levels of ripening-regulated genes PG1 (polygalacturonase), GAL6 (beta galactosidase), XYL2 (D-xylulose reductase), SUT1 (sucrose transporter), CHS (chalcone synthase) and CHI (chalcone flavanone isomerase). Additionally, the regulatory changes influenced fruit resistance to Botrytis cinerea. An isothermal calorimetry analysis showed that the Escherichia coli-expressed FaTPK1 recombinant protein could bind K+ with a binding constant of 2.1 * 10-3 m-1 and a dissociation constant of 476 MUm. Thus, the strawberry TPK1 is a ubiquitously expressed, tonoplast-localized two-pore potassium channel that plays important roles in fruit ripening and quality formation. PMID- 28851010 TI - Nematicidal activity of grammicin produced by Xylaria grammica KCTC 13121BP against Meloidogyne incognita. AB - BACKGROUND: The endolichenic fungus Xylaria grammica KCTC 13121BP showed strong nematicidal activity against Meloidogyne incognita. This study aimed to identify the nematicidal metabolites and to evaluate the efficacy of the strain as a biocontrol agent under pot and field conditions. RESULTS: Bioassay-guided fractionation and instrumental analyses led to grammicin being identified as the nematicidal metabolite. Because patulin is a mycotoxic isomer of grammicin and is known to have strong antibacterial and cytotoxic activities, several biological activities of the two compounds were compared. Grammicin showed strong second stage juvenile killing and egg-hatching inhibitory effects, with a 50% effective concentration at 72 h (EC50/72 h ) of 15.9 ug/mL and a 50% effective concentration at 14 days (EC50/14 days ) of 5.87 ug/mL, respectively, whereas patulin was virtually inactive in both respects. Patulin was strongly active toward various phytopathogenic bacteria in vitro, whereas grammicin was weakly so. Patulin at the concentration range of 0.1-10 ug/mL also showed dose-dependent cytotoxicity toward the human first-trimester trophoblast cell line SW.71, whereas grammicin was not toxic toward this cell line. In pot and field experiments, a wettable powder-type formulation and fermentation broth filtrate of X. grammica KCTC 13121BP effectively suppressed the development of root-knot nematode disease on tomato and melon plants. CONCLUSION: The results suggest that X. grammica and grammicin may have potential applications for control of root knot nematode disease of various crops. (c) 2017 Society of Chemical Industry. PMID- 28851011 TI - Determination of betaine, l-carnitine, and choline in human urine using a self packed column and column-switching ion chromatography with nonsuppressed conductivity detection. AB - A simple method for the determination of betaine, l-carnitine, and choline in human urine was developed based on column-switching ion chromatography coupled with nonsuppressed conductivity detection by using a self-packed column. A pretreatment column (50 mm * 4.6 mm, id) packed with poly(glycidyl methacrylate divinylbenzene) microspheres was used for the extraction and cleanup of analytes. Chromatographic separation was achieved within 10 min on a cationic exchange column (150 mm * 4.6 mm, id) using maleic anhydride modified poly(glycidyl methacrylate-divinylbenzene) as the particles for packing. The detection was performed by ion chromatography with nonsuppressed conductivity detection. Parameters including column-switching time, eluent type, flow rates of eluent, and interfering effects were optimized. Linearity (r2 >= 0.99) was obtained for the concentration range of 0.50-100, 0.75-100, and 0.25-100 MUg/mL for betaine, l carnitine, and choline, respectively. Detection limits were 0.12, 0.20, and 0.05 MUg/mL for betaine, l-carnitine, and choline, respectively. The intra- and interday accuracy and precision for all quality controls were within +/-10.11%. Satisfactory recovery was observed between 92.5 and 105.0%. The validated method was successfully applied for the determination of betaine, l-carnitine, and choline in urine samples from healthy people. PMID- 28851012 TI - Measurement Properties of the Central Sensitization Inventory: A Systematic Review. AB - BACKGROUND AND OBJECTIVE: Central sensitization (CS) is a phenomenon associated with several medical diagnoses, including postcancer pain, low back pain, osteoarthritis, whiplash, and fibromyalgia. CS involves an amplification of neural signaling within the central nervous system that results in pain hypersensitivity. The purpose of this systematic review was to gather published studies of a widely used outcome measure (the Central Sensitization Inventory [CSI]), determine the quality of evidence these publications reported, and examine the measurement properties of the CSI. DATABASES AND DATA TREATMENT: Four databases were searched for publications from 2011 (when the CSI was developed) to July 2017. The Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist was applied to evaluate methodological quality and risk of bias. In instances when COSMIN did not offer a scoring system for measurement properties, qualitative analyses were performed. RESULTS: Fourteen studies met inclusion criteria. Quality of evidence examined with the COSMIN checklist was determined to be good to excellent for all studies for their respective measurement property reports. Interpretability measures were consistent when publications were analyzed qualitatively, and construct validity was strong when examined alongside other validated measures relating to CS. CONCLUSIONS: An assessment of the published measurement studies of the CSI suggest the tool generates reliable and valid data that quantify the severity of several symptoms of CS. PMID- 28851013 TI - Body size-adjusted dose analysis of pirfenidone in patients with interstitial pneumonia. AB - BACKGROUND AND OBJECTIVE: Pirfenidone is an effective anti-fibrotic agent for idiopathic pulmonary fibrosis (IPF). Although adverse events (AE) sometimes prevent patients from continuing treatment, current dose adjustment guidance does not consider patient body size or weight (BW). The aim of this study was to evaluate the importance of pirfenidone dose adjustment by body surface area (BSA) or BW for preventing AE and permitting continuous treatment in patients with interstitial pneumonia (IP). METHODS: Sixty-seven Japanese patients with IP including 46 patients with IPF treated with pirfenidone between 2009 and 2015 were retrospectively evaluated. Pirfenidone doses were adjusted by BSA or BW and were compared with clinical parameters. RESULTS: Forty-two of 67 patients (62.7%) with IP showed AE, most commonly gastrointestinal symptoms (77.5%). Patients having AE received significantly higher adjusted doses of pirfenidone by both BSA and BW (P = 0.024 and P = 0.010, respectively), while unadjusted doses did not differ. BSA-adjusted dose discriminated patients with AE from those without (area under the curve = 0.666 at 1085 mg/m2 ). Six of seven patients (85.7%) who discontinued pirfenidone due to AE took >=1085 mg/m2 of pirfenidone. In a subgroup with IPF, patients taking a medium dose (median: 876 median-1085 mg/m2 ) showed a lower annual decline in % forced vital capacity than patients taking a lower dose (P = 0.025). CONCLUSION: BSA-adjusted pirfenidone dosing may be useful to prevent AE whilst achieving a long-term treatment effect in patients with IP. PMID- 28851014 TI - Mental training in surgical education: a systematic review. AB - BACKGROUND: Pressures on surgical education from restricted working hours and increasing scrutiny of outcomes have been compounded by the development of highly technical surgical procedures requiring additional specialist training. Mental training (MT), the act of performing motor tasks in the 'mind's eye', offers the potential for training outside the operating room. However, the technique is yet to be formally incorporated in surgical curricula. This study aims to review the available literature to determine the role of MT in surgical education. METHODS: EMBASE and Medline databases were searched. The primary outcome measure was surgical proficiency following training. Secondary analyses examined training duration, forms of MT and trainees level of experience. Study quality was assessed using Consolidated Standards of Reporting Trials scores or Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group. RESULTS: Fourteen trials with 618 participants met the inclusion criteria, of which 11 were randomized and three longitudinal. Ten studies found MT to be beneficial. Mental rehearsal was the most commonly used form of training. No significant correlation was found between the length of MT and outcomes. MT benefitted expert surgeons more than medical students or novice surgeons. CONCLUSION: The majority studies demonstrate MT to be beneficial in surgical education especially amongst more experienced surgeons within a well-structured MT programme. However, overall studies were low quality, lacked sufficient methodology and suffered from small sample sizes. For these reasons, further research is required to determine optimal role of MT as a supplementary educational tool within the surgical curriculum. PMID- 28851015 TI - A New Class of Fluorinated A2A Adenosine Receptor Agonist with Application to Last-Step Enzymatic [18 F]Fluorination for PET Imaging. AB - The A2A adenosine receptor belongs to a family of G-coupled protein receptors that have been subjected to extensive investigation over the last few decades. Due to their prominent role in the biological functions of the heart, lungs, CNS and brain, they have become a target for the treatment of illnesses ranging from cancer immunotherapy to Parkinson's disease. The imaging of such receptors by using positron emission tomography (PET) has also been of interest, potentially providing a valuable tool for analysing and diagnosing various myocardial and neurodegenerative disorders, as well as offering support to drug discovery trials. Reported herein are the design, synthesis and evaluation of two new 5' fluorodeoxy-adenosine (FDA)-based receptor agonists (FDA-PP1 and FDA-PP2), each substituted at the C-2 position with a terminally functionalised ethynyl unit. The structures enable a synthesis of 18 F-labelled analogues by direct, last-step radiosynthesis from chlorinated precursors using the fluorinase enzyme (5'-fluoro 5'-deoxyadenosine synthase), which catalyses a transhalogenation reaction. This delivers a new class of A2A adenosine receptor agonist that can be directly radiolabelled for exploration in PET studies. PMID- 28851016 TI - Effect of Intravenous Corticosteroids on Pain Management and Early Rehabilitation in Patients Undergoing Total Knee or Hip Arthroplasty: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Corticosteroids are frequently used for the treatment of postoperative nausea and vomiting, and have also been reported to have an effect on postoperative analgesia. This study was conducted to assess the pain management effect of perioperative intravenous corticosteroids in patients undergoing total knee or hip arthroplasty and evaluate their early rehabilitation. METHOD: Randomized controlled trials (RCTs) were searched from electronic databases, including PubMed, Web of Science, Embase (Ovid interface), and the Cochrane Library (Ovid interface). Among 932 records identified, 14 RCTs involving 1,023 patients were eligible for data extraction and meta-analysis. RESULTS: The use of intravenous steroids was associated with reduced pain at rest and with activity during the first 24 hours after operation (P < 0.05). Patient steroid groups had less opioid consumption (P < 0.05). Additionally, patients using intravenous corticosteroids had better outcomes, in terms of nausea and vomiting (both P < 0.05). Moreover, corticosteroids were effective in decreasing the inflammatory marker interleukin-6 (P < 0.05). Complications such as deep infection and pruritus showed similar occurrence in both the corticosteroid groups and control groups (P > 0.05), while the occurrence of venous thromboembolism was lower in the corticosteroid groups, with a marginally significant difference. In addition, no significant difference in length of hospital stay was observed, irrespective of whether patients received intravenous corticosteroids (P > 0.05). CONCLUSION: Our results show that intravenous corticosteroids have good efficacy and safety when used perioperatively in total knee or hip arthroplasty. PMID- 28851017 TI - Maternal Body Mass Index and Amniotic Fluid Index in Late Gestation. AB - OBJECTIVES: To determine the effect, if any, of an increasing maternal body mass index (BMI) on sonographically diagnosed oligohydramnios in late gestation and how it subsequently affects obstetric and neonatal outcomes. METHODS: This retrospective cohort study evaluated all women with singleton gestations who had a sonographic examination at 40 to 42 weeks' gestational age at North Shore University Hospital from 2010 through 2013. Underweight women (prepregnancy BMI < 18.5 kg/m2 ) were excluded because of higher rates of oligohydramnios and fetal growth restriction. Patients were classified into 5 groups by late-pregnancy BMI. The primary variable of interest was the diagnosis of oligohydramnios (amniotic fluid index < 5 cm). Secondary variables of interest included the mode of delivery and indication for primary cesarean delivery. A multivariable logistic regression analysis was performed. RESULTS: Oligohydramnios was identified in 189 of 1671 patients (11.3%). There was no significant difference in the amniotic fluid index between BMI groups. The rate of primary cesarean delivery increased with each successive BMI group (P < .001) such that women in the class III obesity group had an approximately 3-fold higher rate of primary cesarean delivery than women in the normal BMI group and a 2-fold higher rate than women in the overweight BMI group. In the final multivariable logistic regression model, a high BMI, nulliparity, and excessive gestational weight gain were associated with primary cesarean delivery. However, oligohydramnios did not contribute significantly to the model. CONCLUSIONS: The maternal BMI is not associated with oligohydramnios in late gestation. An increasing maternal BMI significantly increases the risk of primary cesarean delivery. PMID- 28851018 TI - Strong indirect herbicide effects on mycorrhizal associations through plant community shifts and secondary invasions. AB - Million of acres of U.S. wildlands are sprayed with herbicides to control invasive species, but relatively little is known about non-target effects of herbicide use. We combined greenhouse, field, and laboratory experiments involving the invasive forb spotted knapweed (Centaurea stoebe) and native bunchgrasses to assess direct and indirect effects of the forb-specific herbicide picloram on arbuscular mycorrhizal fungi (AMF), which are beneficial soil fungi that colonize most plants. Picloram had no effect on bunchgrass viability and their associated AMF in the greenhouse, but killed spotted knapweed and reduced AMF colonization of a subsequent host grown. Results were similar in the field where AMF abundance in bunchgrass-dominated plots was unaffected by herbicides one year after spraying based on 16:1omega5 phospholipid fatty acid (PLFA) and neutral lipid fatty acid (NLFA) concentrations. In spotted-knapweed-dominated plots, however, picloram application shifted dominance from spotted knapweed, a good AMF host, to bulbous bluegrass (Poa bulbosa), a poor AMF host. This coincided with a 63% reduction in soil 16:1omega5 NLFA concentrations but no reduction of 16:1omega5 PLFA. Because 16:1omega5 NLFA quantifies AMF storage lipids and 16:1omega5 PLFA occurs in AMF membrane lipids, we speculate that the herbicide-mediated reduction in host quality reduced fungal carbon storage, but not necessarily fungal abundance after one year in the field. Overall, in greenhouse and field experiments, AMF were only affected when picloram altered host quantity and quality. This apparent lack of direct effect was supported by our in-vitro trial where picloram applied to AMF mycelia did not reduce fungal biomass and viability. We show that the herbicide picloram can have profound, indirect effects on AMF within one year. Depending on herbicide-mediated shifts in host quality, rapid interventions may be necessary post herbicide applications to prevent loss of AMF abundance. Future research should assess consequences of these potential shifts for the restoration of native plants that differ in mycorrhizal dependency. PMID- 28851019 TI - Modelling the effects of spatial heterogeneity and temporal variation in extinction probability on mosquito populations. AB - Spatial synchrony plays an important role in dictating the dynamics of spatial and stage-structured populations. Here we argue that, unlike the Moran effect where spatial synchrony is driven by exogenous factors, spatial correlation in intrinsic/local-scale processes can affect the level of spatial synchrony among distinct sub-populations, and therefore the persistence of the entire population. To explore this mechanism, we modelled the consequences of spatial heterogeneity in aquatic habitat quality, and that of temporal variation in local extinction probability, on the persistence of stage-structured mosquito populations. As a model system, we used two widely distributed mosquito species, Aedes albopictus and Culex pipiens, both key vectors of a range of infectious diseases. Spatial heterogeneity in aquatic habitat quality led to increased population persistence, and this pattern was more pronounced at intermediate dispersal rates, and in the long-dispersing species (C. pipiens). The highest regional persistence was obtained at high dispersal rates. This is probably because dispersal, in our model, did not carry any additional costs. Population persistence of both species was negatively correlated with increased temporal variation in local extinction probability. These differences were stronger in the short-dispersing species (A. albopictus), especially at intermediate dispersal rates. The dispersal of A. albopictus adults in each time step was limited to the nearest habitat patches, weakening the positive effect of spatial heterogeneity in aquatic habitat quality on population persistence. In contrast, C. pipiens adults could disperse into more remote sub-populations, resulting in much higher recolonization rates. Hence, the negative effect of temporal variation in local extinction probability on patch occupancy disappeared at intermediate dispersal rates. We suggest that effectively controlling these two mosquito species requires making few spatially synchronized control efforts (i.e., generating high temporal variation in local extinction probability), rather than many asynchronized local control efforts. Finally, our model can be easily fitted to other organisms characterized by complex life cycles, and it can be also used to examine alternative scenarios, including the effect of spatial configuration of local habitat patches and dispersal kernel shape on population persistence. PMID- 28851020 TI - Left renal vein ligation for large splenorenal shunt during liver transplantation. AB - Adequate hepatopetal portal vein blood flow is obligatory to ensure proper liver function after liver transplantation. Large collateral veins as shunts impair portal vein flow and even cause hepatofugal blood flow and portal steal syndrome. In particular, splenorenal shunts in liver transplant recipients can lead to allograft dysfunction and possible allograft loss or hepatic encephalopathy. Restoration of portal flow through left renal vein ligation (LRVL) is a treatment option, which is much easier compared to splenectomy, renoportal anastomosis and shunt closure, but bears the risk of moderate and temporary impairment of renal function. In addition, a patent portal vein is mandatory for LRVL. However, although LRVL has been reported to be an effective, safe and easy method to control portacaval shunts and increase hepatopetal flow in some studies, indications and safety are still not clear. In this review, we summarize existing studies on LRVL during liver transplantation. PMID- 28851021 TI - Skin findings of 21st-century movie characters. PMID- 28851022 TI - Spectral separability and mapping potential of cassava leaf damage symptoms caused by whiteflies (Bemisia tabaci). AB - BACKGROUND: This study examines whether leaf spectra can be used to measure damage to cassava plants from whitefly (Bemisia tabaci), and the potential to translate measurements from leaf to landscape scale in eastern Africa. Symptoms of the cassava brown streak disease (CBSD) and cassava mosaic disease (CMD) viruses, and sooty mould (SM) blackening of lower leaves from whiteflies feeding on the upper leaves, were measured at the leaf scale with a high-resolution spectroradiometer and a single photon avalanche diode (SPAD) meter, which retrieves relative chlorophyll concentration. Spectral measurements were compared to the five-level visual scores used to assess the severity of each of the three damaging agents in the field, and also to leaf chemistry data. RESULTS: Leaves exhibiting severe CBSD and CMD were spectrally indistinguishable from leaves without any symptoms. Severe SM was spectrally distinctive but is likely to be difficult to map because of its occurrence in the lower crown. SPAD measurements were highly correlated with most foliar chemistry measurements and field scores of disease severity. Regression models between simulated Sentinel 2 bands, field scores and SPAD measurements were strongest using wavelengths with high importance weightings in random forest models. CONCLUSION: SPAD measurements are highly correlated to many foliar chemistry parameters, and should be considered for use in mapping disease severity over larger areas. Remaining challenges for mapping relate to the subtle expression of symptoms, the spatial distribution of disease severity within fields, and the small size and complex structure of the cassava fields themselves. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 28851023 TI - Journey Heading towards Enantioselective Synthesis Assisted by Organocatalysis. AB - This personal account summarizes the design of various organocatalysts derived from amino acids and Cinchona alkaloids and their applications in enantioselective carbon-carbon and carbon-nitrogen bond formation reactions. This account begins with the short description of the background of asymmetric organocatalysis. Various types of reactions like aldol reaction, Michael reaction, aza-Henry reaction, Morita-Baylis-Hillman reaction are described in this account. PMID- 28851025 TI - An investigation into the nutritional composition and cost of gluten-free versus regular food products in the UK. AB - BACKGROUND: The gluten-free (GF) food market has expanded considerably, although there is limited comparative evidence for the nutritional quality and cost of GF food products. The present study aims to compare the nutrient composition and cost of GF and gluten-containing (regular) foods across 10 food categories in the UK. METHODS: Nutritional information and the cost of GF foods available in the UK (n = 679) and comparable regular foods (n = 1045) were systematically collected from manufacturer and supermarket websites. Foods were classified using UK front of-pack labelling for content of fat, saturated fat, sugar and salt and nutrient content, and cost per 100 g were identified and compared between GF and regular foods. RESULTS: Overall, more GF foods were classified as containing high and medium fat, saturated fat, sugar and salt than regular foods, although this was not universally consistent. More GF bread and flour products contained high fat and sugar, whereas fewer GF crackers contained high fat and sugar compared to regular foods. High salt content was found more frequently in GF than regular products. On average, GF products were 159% more expensive than regular (L0.44/100 g versus L1.14/100 g). GF items were also more likely to be lower in fibre and protein content than regular foods. CONCLUSIONS: Differences exist in the nutritional composition of GF and regular food. GF food is unlikely to offer healthier alternatives to regular foods, except for those who require a GF diet for medically diagnosed conditions, and it is associated with higher costs. PMID- 28851024 TI - Longitudinal Relations of Economic Hardship and Effortful Control to Active Coping in Latino Youth. AB - How Latino youth cope with stressors may have implications for their adjustment. We examined how a temperamental characteristic (effortful control) and a contextual factor (economic hardship) were associated with Latino youth's coping. Individual differences in effortful control, a core facet of self-regulation, may contribute to coping as effortful control is consistently linked to adaptive behaviors during adolescence. We examined relations of effortful control and economic hardship to active coping in a sample of Mexican-origin youth (N = 674) across three time points (fifth to ninth grades). Although economic hardship negatively predicted coping and effortful control, effortful control positively predicted coping (controlling for prior levels). Findings support a resilience perspective by suggesting that effortful control may contribute to coping and thus counteract the negative effects of economic hardship. PMID- 28851026 TI - Towards good dementia care: Awareness and uptake of an online Dementia Pathways tool for rural and regional primary health practitioners. AB - OBJECTIVE: To explore the awareness and usage of an online dementia pathways tool (including decision tree and region-specific dementia services) for primary health practitioners (GPs and nurses) in regional Victoria. DESIGN: Quantitative pilot study using surveys and Google Analytics. SETTING: A large regional area (48 000 square kilometres, population 220 000) in Victoria. PARTICIPANTS: Two hundred and sixty-three GPs and 160 practice nurses were invited to participate, with 42 respondents (GPs, n = 21; practice nurses, n = 21). MAIN OUTCOME MEASURES: Primary care practitioners' awareness and usage of the dementia pathways tool. RESULTS: Survey respondents that had used the tool (n = 14) reported accessing information about diagnosis, management and referral. Practitioners reported improvements in knowledge, skills and confidence about core dementia topics. There were 9683 page views between August 2013 and February 2015 (monthly average: 509 page views). The average time spent on page was 2.03 min, with many visitors (68%) spending more than 4 min at the site. This research demonstrates that the tool has been well received by practitioners and has been consistently used since its launch. Health practitioners' valued the content and the availability of local resources. CONCLUSION: Primary health practitioners reported that the dementia pathways tool provided access to region-specific referral and management resources for all stages of dementia. Such tools have broad transferability in other health areas with further research needed to determine their contribution to learning in the practice setting and over time. PMID- 28851028 TI - Mental health and retirement savings: Confounding issues with compounding interest. AB - The questionable ability of the U.S. pension system to provide for the growing elderly population combined with the rising number of people affected by depression and other mental health issues magnifies the need to understand how these household characteristics affect retirement. Mental health problems have a large and significant negative effect on retirement savings. Specifically, psychological distress is associated with decreasing the probability of holding retirement accounts by as much as 24 percentage points and decreasing retirement savings as a share of financial assets by as much as 67 percentage points. The magnitude of these effects underscores the importance of employer management policy and government regulation of these accounts to help ensure households have adequate retirement savings. PMID- 28851027 TI - NMR secondary structure and interactions of recombinant human MOZART1 protein, a component of the gamma-tubulin complex. AB - Mitotic-spindle organizing protein associated with a ring of gamma-tubulin 1 (MOZART1) is an 8.5 kDa protein linked to regulation of gamma-tubulin ring complexes (gammaTuRCs), which are involved in nucleation of microtubules. Despite its small size, MOZART1 represents a challenging target for detailed characterization in vitro. We described herein a protocol for efficient production of recombinant human MOZART1 in Escherichia coli and assessed the properties of the purified protein using a combination of size exclusion chromatography coupled with multiangle light scattering (SEC-MALS), dynamic light scattering (DLS), and nuclear magnetic resonance (NMR) experiments. MOZART1 forms heterogeneous oligomers in solution. We identified optimal detergent and buffer conditions for recording well resolved NMR experiments allowing nearly full protein assignment and identification of three distinct alpha-helical structured regions. Finally, using NMR, we showed that MOZART1 interacts with the N-terminus (residues 1-250) of GCP3 (gamma-tubulin complex protein 3). Our data illustrate the capacity of MOZART1 to form oligomers, promoting multiple contacts with a subset of protein partners in the context of microtubule nucleation. PMID- 28851029 TI - Design and Evaluation of a Boron Dipyrrin Electrophore for Redox Flow Batteries. AB - A boron dipyrrin (BODIPY) dye was designed as a molecular single-component electrophore for redox flow batteries. All positions of the BODIPY core were assessed on the basis of literature data, in particular cyclic voltammetry and density functional calculations, and a minimum required substitution pattern was designed to provide solubility, aggregation, radical cation and anion stabilities, a large potential window, and synthetic accessibility. In-depth electrochemical and physical studies of this electrophore revealed suitable cathodic behavior and stability of the radical anion but rapid anodic decomposition of the radical cation. The three products that formed under the conditions of controlled oxidative electrolysis were isolated, and their structures were determined by spectroscopy and comparison with a synthetic model compound. From these structures, a benzylic radical reactivity, initiated by one electron oxidation, was concluded to play the major role in this unexpected decomposition. PMID- 28851030 TI - Recent advances in analytical methods for the therapeutic drug monitoring of immunosuppressive drugs. AB - Therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISDs) with a narrow therapeutic index is an increasingly popular tool for minimizing drug toxicity while maximizing the prevention of graft loss and organ rejection. This review focuses on trends regarding analytical methods for the TDM of ISDs since 2011. The five most commonly prescribed immunosuppressive medications are critically reviewed: cyclosporine A, tacrolimus, sirolimus (rapamycin), everolimus, and mycophenolic acid. This review introduces the general background of TDM and ISDs and presents the recent developments in using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassays for the TDM of ISDs. Finally, a future perspective for these analytical methods is briefly discussed. PMID- 28851031 TI - Immunologic properties and therapeutic efficacy of a multivalent epitope-based vaccine against four Helicobacter pylori adhesins (urease, Lpp20, HpaA, and CagL) in Mongolian gerbils. AB - BACKGROUND: Therapeutic vaccination is a desirable alternative for controlling Helicobacter pylori (H. pylori) infection. Attachment to the gastric mucosa is the first step in establishing bacterial colonization, and adhesins, which are on the surface of H. pylori, play a pivotal role in binding to human gastric mucosa. MATERIALS AND METHODS: In the present study, we constructed a multivalent epitope based vaccine named CFAdE with seven carefully selected antigenic fragments from four H. pylori adhesins (urease, Lpp20, HpaA and CagL). The specificity, immunogenicity and ability to produce neutralizing antibodies of CFAdE were evaluated in BALB/c mice. After that, its therapeutic efficacy and protective immune mechanisms were explored in H. pylori-infected Mongolian gerbils. RESULTS: The results indicated that CFAdE could induce comparatively high levels of specific antibodies against urease, Lpp20, HpaA and CagL. Additionally, oral therapeutic immunization with CFAdE plus polysaccharide adjuvant (PA) significantly decreased H. pylori colonization compared with oral immunization with urease plus PA, and the protection was correlated with IgG and sIgA antibody and antigen-specific CD4+ T cells. CONCLUSIONS: This study indicated that the multivalent epitope-based vaccine, which targeted multiple adhesins in adherence of H. pylori to the gastric mucosa, is more effective than the univalent vaccine targeting urease only. This multivalent epitope-based vaccine may be a promising therapeutic candidate vaccine against H. pylori infection. PMID- 28851032 TI - Staff's perceptions of a pressure mapping system to prevent pressure injuries in a hospital ward: A qualitative study. AB - AIM: To describe staff's perceptions of a continuous pressure mapping system to prevent pressure injury in a hospital ward. BACKGROUND: Pressure injury development is still a problem in hospitals. It is important to understand how new information and communication technologies can facilitate pressure injury prevention. METHOD: A descriptive design with qualitative focus group interviews was used. RESULTS: Five categories were identified: "Need of information, training and coaching over a long period of time," "Pressure mapping - a useful tool in the prevention of pressure injury in high risk patients," "Easy to understand and use, but some practical issues were annoying," "New way of working and thinking," and "Future possibilities with the pressure mapping system." CONCLUSION: The pressure mapping system was an eye-opener for the importance of pressure injury prevention. Staff appreciated the real-time feedback on pressure points, which alerted them to the time for repositioning, facilitated repositioning and provided feedback on the repositioning performed. IMPLICATIONS FOR NURSING MANAGEMENT: A continuous pressure mapping system can be used as a catalyst, increasing staff's competence, focus and awareness of prevention. For successful implementation, the nurse managers should have a shared agenda with the clinical nurse leaders, supporting the sustaining and spread of the innovation. PMID- 28851033 TI - Reducing radiotherapy waiting times for palliative patients: The role of the Advanced Practice Radiation Therapist. AB - INTRODUCTION: Palliative radiotherapy is effective in reducing symptom burden and improving quality of life in patients with symptomatic metastatic cancer and should be delivered in a timely manner. The aim of this study was to determine whether referring patients directly to a Palliative Advanced Practice Radiation Therapist (APRT) improves access to palliative radiotherapy and reduces time from referral to treatment. METHODS: At Radiation Oncology Mater Center (ROMC) in Brisbane, Australia a new referral pathway was developed which involved patients requiring palliative radiotherapy, being referred directly to the APRT from a single external hospital medical oncology and palliative care departments. Over a 5 months period, patient demographics and time in working days from referral to treatment were compared for consecutive palliative patients seen within our department. Patients were stratified by method of referral i.e. via the new referral pathway (NP) or via standard referral pathway (SP). RESULTS: Between October 2014 and March 2015, a total of 150 patients were referred for palliative radiotherapy. Of these patients, 48 were referred and processed via the NP. There was a significant reduction in the number of days from referral to treatment for patients referred through the NP. Patients referred through the NP via the APRT had a mean and median wait time of 3.5 and 3 days respectively compared with 8.1 and 5 days for patients referred through the SP (P = <0.001). Patients were also more likely to have the treatment completed with less visits to the hospital (P < 0.001). CONCLUSIONS: The new referral pathway utilising a dedicated palliative APRT decreased waiting times for patients receiving palliative radiotherapy and improved timely access to the radiotherapy service for both referrers and patients. PMID- 28851034 TI - MDA, MDMA, and other "mescaline-like" substances in the US military's search for a truth drug (1940s to 1960s). AB - This article describes the context in which 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and other mescaline-like compounds were explored as hallucinogens for military and intelligence purposes from the 1940s to the 1960s. Germans first tested mescaline as a "truth drug" in a military context. In the 1940s, the United States military started testing hallucinogenic substances as truth drugs for interrogation and behavior manipulation. After tests carried out using mescaline and other drugs in 1950, some derivatives of mescaline were synthesized by the Army for the exploration of possible "speech inducing" effects. After insufficient animal testing, the substances were given to patients at the New York State Psychiatric Institute (NYSPI). 3,4 Methylenedioxy-N-ethylamphetamine (MDE), a compound almost identical to MDMA, was among the compounds delivered for testing at the NYSPI. During tests with other derivatives (3,4-dimethoxyphenethylamine (DMA), 3,4-methylenedioxyphenethylamine (MDPEA), MDA) in 1952-53, an unwitting patient died in these tests, which was kept secret from the public. Research was interrupted and toxicological animal testing procedures were initiated. The secret animal studies run in 1953/1954 revealed that some of the "mescaline derivatives" tested (e.g. MDA, MDE, DMA, 3,4,5-trimethoxyamphetamine (TMA), MDMA) were considered for further testing in humans. In 1955, the military changed focus to lysergic acid diethylamide (LSD), but some interest in mescaline-like compounds remained for their ability to change mood and habit without interfering with cognition and sensory perception. Based on the known documents, it remains unclear (but probable) whether any of the mescaline derivatives tested were being used operationally. PMID- 28851035 TI - Challenges in providing end-of-life care for people with intellectual disability: Health services access. AB - BACKGROUND: Increasing life expectancy for people with intellectual disability is resulting in greater need for end-of-life care services. However, limited knowledge is available regarding what barriers to accessing end-of-life care support are evident, particularly comparatively across rural and metropolitan locations. METHODS: Focus group interviews were undertaken with 35 direct-care staff from four rural and two metropolitan locations. A semistructured interview guide was used, with a focus on health service access. All focus group data were independently transcribed, with thematic analysis then performed. RESULTS: Frequency analysis identified 262 statements relating to health services access. Thematic analysis identified four key areas of "isolation," "support from doctors," "general health support access" and "internal staffing issues." CONCLUSIONS: Improved access to end-of-life services is urgently required across both rural and metropolitan areas. Development of specialist training and support models for both disability and general healthcare staff may assist to reduce some identified barriers. PMID- 28851036 TI - Rational Design of a Robust Fluorescent Probe for the Detection of Endogenous Carbon Monoxide in Living Zebrafish Embryos and Mouse Tissue. AB - Carbon monoxide (CO) is one of the most important gaseous signal molecules in biological systems. However, the investigation of the functions of CO in living organisms is restricted by the lack of functional molecular tools. To address this critical challenge, we present herein the rational design, synthesis, and in vivo imaging studies of a powerful two-photon excited near-infrared fluorescent probe (1-Ac) for endogenous CO monitoring. The advantageous features of the new probe include high stability, low background fluorescence, large fluorescence enhancement, high sensitivity, and two-photon excitation with emission in the near-infrared region. Significantly, these merits of the probe enable the tracking of endogenous CO in zebrafish embryos and mouse tissues for the first time. PMID- 28851038 TI - Hypersensitivity pneumonitis: A protean and challenging disease. PMID- 28851037 TI - The effects of a lipid-based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron, copper, and zinc in milk from HIV-infected Malawian mothers and associations with maternal and infant biomarkers. AB - We evaluated effects of antiretroviral (ARV) therapy and lipid-based nutrient supplements (LNSs) on iron, copper, and zinc in milk of exclusively breastfeeding HIV-infected Malawian mothers and their correlations with maternal and infant biomarkers. Human milk and blood at 2, 6, and 24 weeks post-partum and blood during pregnancy (<=30 weeks gestation) were collected from 535 mothers/infant pairs in the Breastfeeding, Antiretrovirals, and Nutrition study. The participants received ARV, LNS, ARV and LNS, or no intervention from 0 to 28 weeks post-partum. ARVs negatively affected copper and zinc milk concentrations, but only at 2 weeks, whereas LNS had no effect. Among all treatment groups, approximately 80-90% of copper and zinc and <50% of iron concentrations met the current adequate intake for infants at 2 weeks and only 1-19% at 24 weeks. Pregnancy haemoglobin was negatively correlated with milk iron at 2 and 6 weeks (r = -.18, p < .02 for both). The associations of the milk minerals with each other were the strongest correlations observed (r = .11-.47, p < .05 for all); none were found with infant biomarkers. At 2 weeks, moderately anaemic women produced milk higher in iron when ferritin was higher or TfR lower. At 6 weeks, higher maternal alpha-1-acid glycoprotein and C-reactive protein were associated with higher milk minerals in mildly anaemic women. Infant TfR was lower when milk mineral concentrations were higher at 6 weeks and when mothers were moderately anaemic during pregnancy. ARV affects copper and zinc milk concentrations in early lactation, and maternal haemoglobin during pregnancy and lactation could influence the association between milk minerals and maternal and infant iron status and biomarkers of inflammation. PMID- 28851039 TI - A nationwide registry-based cohort study of incidence of tonsillectomy in Denmark, 1991-2012. AB - OBJECTIVE: To update tonsillectomy incidence rates in Denmark and identify whether the incidence rates vary between geographical areas in the country during the period 1991-2012. DESIGN: This was a retrospective nationwide cohort study using data from the comprehensive Danish patient registries. Data included surgical code, gender and date of birth, date and place of surgery. SETTING: Hospitals and private oto-, rhino-, laryngology (ORL) offices. PARTICIPANTS: Danes who underwent tonsillectomy in the period 1991-2012. MAIN OUTCOME MEASURE: Tonsillectomy. RESULTS: In the 22-year period, 177 211 tonsillectomies were conducted, and the overall incidence of tonsillectomy decreased significantly over time. The overall annual incidence of tonsillectomies decreased from 155.7 per 100 000 inhabitants in 1991 to 129.4 per 100 000 inhabitants in 2012. In 1991, 5.5% of tonsillectomies were performed in office settings, while in 2012, it had increased to 26.6% (P < .01). The highest incidence of tonsillectomy was found in children between 3 and 4 years of age (predominance of males, P < .01) and in 15- to 19-year-olds (predominance of females, P < .01). Each year, 0.44% of children underwent tonsillectomy, and by the age of 20, 7.7% of the Danish people has had a tonsillectomy. There were significant regional differences in the number of tonsillectomies. CONCLUSION: The incidence rate of tonsillectomies in Denmark decreased significantly in the study period, but with great regional variance. PMID- 28851040 TI - Authors' reply re: Association between inadequate antenatal care utilisation and severe perinatal and maternal morbidity: an analysis in the PreCARE cohort. PMID- 28851041 TI - Insulin resistance is higher in prepubertal girls but switches to become higher in boys at age 16: A Cohort Study (EarlyBird 57). AB - BACKGROUND: The risk of type 2 diabetes is increasing in teenage girls, and is associated with their greater insulin resistance (IR). HYPOTHESIS: We hypothesized that the adverse metabolic profile of girls (compared with boys) would persist from childhood through adolescence. PATIENTS AND METHODS: Community based longitudinal cohort of 292 children (147 boys) studied annually from 9 to 16 years. MEASURES: IR (homeostasis-model-assessment-2), high-density lipoprotein cholesterol (HDL-C), triglycerides, % body-fat (dual-energy x-ray absorptiometry), pubertal stage (age at peak height velocity), physical activity (accelerometry). Multi-level modelling established the age-related trends in IR and lipids and the influence of covariates. RESULTS: Each year from 9 to 15 years, girls had 21% to 63% higher IR than boys (girls mean IR 0.73-1.33, boys 0.51-0.89, P < .005). At 16 years the gender difference was not significant (girls IR 0.60, boys 0.56, P = .45). Girls had lower HDL-C from 9 to 12 years, higher triglycerides from 9 to 14 years, greater adiposity throughout, and earlier puberty, but boys were more active than girls (all P < .05). After adjustment for %-fat, puberty and activity, the gender difference in IR between girls and boys aged 9 to 15 years became non-significant (IR girls 0.66-1.01, boys 0.65-1.04, P > .07). However, after adjustment at 16 years, girls' IR was 25% lower than boys' (girls 0.44, boys 0.63, P = .001), and they had 22% higher HDL-C (P < .001) and 20% lower triglycerides (P = .003). CONCLUSIONS: The higher IR of prepubertal and early pubertal girls diminishes during late puberty, and boys begin to exhibit greater metabolic risk. Despite being leaner and more active, boys at 16 years have higher IR than girls, suggesting future higher risk for diabetes, thus we reject our hypothesis. PMID- 28851043 TI - Can MR spectroscopy and muscle biopsy findings be correlated with MELAS and CPEO? PMID- 28851042 TI - Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and NLRP3 signaling in mice with bilateral carotid artery stenosis. AB - AIMS: Vascular dementia (VaD) is a heterogeneous brain disorder for which there are no effective approved pharmacological treatments available. We aimed to evaluate the effect of calmodulin inhibitor, DY-9836, and its loaded nanodrug carrier system on cognitive impairment and gain a better understanding of the protective mechanisms in mice with bilateral carotid artery stenosis (BCAS). RESULTS: DY-9836 (0.5 or 1 mg/kg) or DY-9836 (0.25 mg/kg)-encapsulated polysialic acid-octadecylamine (PSA-ODA) micelles (PSA-ODA/DY) were given to BCAS mice for 4 weeks. Administration of DY-9836 or PSA-ODA/DY reduced escape latency in space exploration and working memory test compared with vehicle group. Vehicle-treated mice showed reduced phospho-CaMKII (Thr286/287) levels in the hippocampus, whereas partially restored by DY-9836 (1 mg/kg) or PSA-ODA/DY (0.25 mg/kg) treatment. In accordance with the pharmacological profile of DY-9836 observed during behavioral studies, experimental molecular and biochemical markers induced by BCAS, such as protein tyrosine nitration, Nod-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1beta, were reduced by DY-9836 and PSA-ODA/DY treatment. CONCLUSIONS: These data disclose novel findings about the therapeutic potential of DY-9836, and its encapsulated nanodrug delivery system significantly enhanced the cognitive function via inhibitory effect on nitrosative stress and NLRP3 signaling in VaD mice. PMID- 28851044 TI - And Yet it is Modified-Holding a Candle to the Dark Matter of White Matter. AB - The multilamellar membrane myelin sheath of the CNS, that enwraps axons to facilitate saltatory conduction in higher vertebrates, is held together by myelin basic protein (MBP). Yet this generalization masks how enigmatic MBP is, much like cosmological "dark matter." First, the casual use of the singular form for "protein" distracts that there are multiple, developmentally regulated "classic" splice isoforms ranging from 14 to 21.5 kDa, each with extensive PTMs. Second, the static image of MBP adhering two cytoplasmic leaflets of the oligodendrocyte membrane together in close apposition, suggests it to be inaccessible to modifying enzymes. And yet it is modified (to paraphrase Galileo's phrase on the earth's motion). In this issue of Proteomics, Sarg et al. apply an integrated CE MS approach to investigate the PTMs of 18.5 kDa MBP from mouse brains of different ages. They identify new sites and types of modification, as well as confirming previously known PTMs. Innovative tools for unraveling the intricacies of the myelin basic proteome and how it organizes CNS myelin (much like basic histones organize chromatin), will help us understand white matter development and plasticity in health, during ageing, and in demyelinating diseases such as multiple sclerosis. PMID- 28851045 TI - A case of rectal neuroendocrine carcinoma in a patient with long-standing ulcerative colitis involving alterations of the p16-Rb pathway. AB - The patient was a 54-year-old male who had been suffering from extensive ulcerative colitis (UC) for 17 years. Colonoscopy revealed an elevated lesion in the affected rectum, and its biopsy demonstrated neuroendocrine carcinoma (NEC). The surgical specimen obtained on laparoscopic high anterior resection showed extensive active inflammatory and dysplastic lesions and three grossly visible multifocal malignant lesions: a polypoid fungating tumor of NEC (type 1, 20 mm in diameter, pT3) that had been preoperatively noticed, a polypoid fungating tumor of adenocarcinoma (type 1, 22 mm, pT2) and a protruded sessile polypoid tumor (0 Is, 5 mm, pTis) of adenocarcinoma. The NEC was adjacently accompanied by dysplasia-carcinoma sequential lesions and showed a diffuse immunohistochemical overexpression of p53 and p16 proteins and the loss of Rb with no abnormal immunohistochemical staining of microsatellite instability markers and no KRAS mutations. Fifteen months later, the patient showed liver metastasis from the NEC component, followed by bone and spinal metastasis; he died 22 months after the initial diagnosis. A rare case of lethal NEC arising from long-standing extensive UC was reported. The NEC appeared to be UC-related, not incidental, and complicated by progression from dysplasia to carcinoma involving alterations of the p16-Rb pathway. PMID- 28851046 TI - Rise of PD-L1 expression during metastasis of colorectal cancer: Implications for immunotherapy. AB - OBJECTIVE: Programmed death-ligand 1 (PD-L1) expression in colorectal cancer (CRC) was implicated in predicting anti-PD-1/PD-L1 therapy efficacy. However, therapeutic response has also been found in patients without PD-L1 expression in the primary tumor. In the present study, we aimed to clarify the prevalence of PD L1 in primary and metastatic CRC. METHODS: The expression of PD-L1 was determined by immunohistochemistry in matched primary and metastatic CRC. RESULTS: PD-L1 expression was significantly more prevalent in metastatic CRCs than in primary tumors, and the expression of PD-L1 in primary CRC may not represent the tumors that spread to distant organs. Positive expression of PD-L1 was found in 81.8% of metastatic CRC, being significantly more prevalent than in primary CRC (40.9%; P = 0.012, Fisher's exact test). While comparing the primary and metastatic lesions of the same patients, we found that PD-L1 expression frequently increased during the metastatic process. However, PD-L1 expression was rarely decreased in metastatic lesions. Intratumoral heterogeneity expression of PD-L1 was found in both metastatic CRC (22.2%) and primary CRCs (33.3%). PD-L1 was prevalently expressed in metastatic CRC, and increased PD-L1 expression was frequently found in metastatic CRC as compared to primary tumors. CONCLUSION: PD-L1 expression in metastatic CRC should be considered as an independent factor while evaluating the suitability of patients for immunotherapy. PMID- 28851047 TI - Association between maternal prepregnancy obesity and breastfeeding duration: Data from a nationwide prospective birth cohort. AB - Association of maternal obesity with shorter breastfeeding duration may involve different factors and might be modified by parity. In a national birth cohort, we aimed to estimate the association between prepregnancy body mass index (pBMI) and breastfeeding duration after adjustment for sociodemographic, pregnancy, and other characteristics and assess the effect modification of parity in such associations. In 2012, 3,368 mother-infant dyads were randomly included at birth in the French Epifane cohort. Breastfeeding information was collected in maternity wards and by phone interview at 1, 4, 8, and 12 months postpartum. Poisson regression analyses estimated the association of pBMI with the number of days of "any breastfeeding" (ABF) and "exclusive breastfeeding" (EBF) in unadjusted and adjusted models. Interactions between parity and pBMI were tested. Obesity before pregnancy was independently associated with shorter ABF duration (incidence rate ratio [IRR] = 0.86, 95%CI [0.74, 0.99]) compared to normal-weight status. Parity showed an effect modification only with EBF duration. Among primiparae, no association was found for obesity, but overweight was significantly associated with shorter EBF duration independently of all covariates (IRR = 0.74 [0.58, 0.95]). Among multiparas, obesity was associated with shorter EBF duration after controlling for sociodemographic factors (IRR = 0.71 [0.53, 0.95]). This association was no longer statistically significant after controlling for other covariates. Obesity appears to be a strong risk factor in shorter ABF duration. Furthermore, parity is a key factor in the relationship of pBMI to shorter EBF duration. Overweight primiparous and obese multiparous women need additional support to prolong breastfeeding duration. PMID- 28851048 TI - Retirement planning and work-related variables in Chinese older nurses: A cross sectional study. AB - AIM: To explore the situation of older nurses approaching retirement with regard to their retirement planning, and the relationship of their retirement planning behaviour with the job environment and job satisfaction under their current employment arrangements and other work-related variables. BACKGROUND: Nurse shortage has become a global phenomenon that can be alleviated by retaining older nurses in service. The Chinese government proposed the "Incremental Delay Retirement Age Policy." However, older nurses face delayed retirement but lack retirement plans. METHOD: A cross-sectional questionnaire survey was conducted among a convenience sample of older retiring nurses (n = 152; 84.92% response rate) recruited from every department of four large general hospitals in Changchun, Jilin Province from June to August 2016. RESULT: The majority of the respondents presented poor retirement planning (n = 122, 80.3%). The independent variables of information exchange with patients, teamwork and personal growth and development explained approximately 16.6% of the variance in retirement planning. Nurse-patient communication and personal growth and development can promote retirement planning, but teamwork is negatively related to retirement planning. CONCLUSION: Retirement planning by Chinese older nurses is related to certain work-related variables. However, many other work-related variables were not associated with retirement planning and require further research. Overall, Chinese older retiring nurses must improve their retirement planning practices. PMID- 28851049 TI - Lipidomics of the sea sponge Amphimedon queenslandica and implication for biomarker geochemistry. AB - Demosponges are a rich natural source of unusual lipids, some of which are of interest as geochemical biomarkers. Although demosponges are animals, they often host dense communities of microbial symbionts, and it is therefore unclear which lipids can be synthesized by the animal de novo, and which require input from the microbial community. To address this uncertainty, we analyzed the lipids of Amphimdeon queenslandica, the only demosponge with a published genome. We correlated the genetic and lipid repertoires of A. queenslandica to identify which biomarkers could potentially be synthesized and/or modified by the sponge. The fatty acid profile of A. queenslandica is dominated by an unusual Delta5,9 fatty acid (cis-5,9-hexacosadienoic acid)-similar to what has been found in other members of the Amphimdeon genus-while the sterol profile is dominated by C27 -C29 derivatives of cholesterol. Based on our analysis of the A. queenslandica genome, we predict that this sponge can synthesize sterols de novo, but it lacks critical genes necessary to synthesize basic saturated and unsaturated fatty acids. However, it does appear to have the genes necessary to modify simpler products into a more complex "algal-like" assemblage of unsaturated fatty acids. Ultimately, our results provide additional support for the poriferan affinity of 24-isopropylcholestanes in Neoproterozoic-age rocks (the "sponge biomarker" hypothesis) and suggest that some algal proxies in the geochemical record could also have animal contributions. PMID- 28851051 TI - Gesellschaft Deutscher Chemiker Prizes and Honors. PMID- 28851052 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 37/2017. PMID- 28851050 TI - The Art of Building Small: From Molecular Switches to Motors (Nobel Lecture). AB - A journey into the nano-world: The ability to design, use and control motor-like functions at the molecular level sets the stage for numerous dynamic molecular systems. In his Nobel Lecture, B. L. Feringa describes the evolution of the field of molecular motors and explains how to program and control molecules by incorporating responsive and adaptive properties. PMID- 28851053 TI - Returning to work from extended leave: A trainee perspective. PMID- 28851054 TI - 'Now she has become my daughter': parents' early experiences of skin-to-skin contact with extremely preterm infants. AB - BACKGROUND: Based on the Family-Centred Care philosophy, skin-to-skin contact is a key activity in neonatal care, and use of this practice is increasing also with extremely preterm infants. Little is known about parents' immediate experiences of and readiness for skin-to-skin contact, while their fragile infant may still not be 'on safe ground'. Knowledge about parents' experiences might reduce doubt and reluctance among healthcare professionals to use skin-to-skin contact with extremely preterm infants and thus increase its dissemination in practice. AIMS AND OBJECTIVES: To explore parents' immediate experiences of skin-to-skin contact with extremely preterm infants <28-week postmenstrual age. METHODOLOGICAL DESIGN: A qualitative study using thematic analysis. RESEARCH METHODS: Thirteen semi structured interviews conducted in 2008 with 16 parents after skin-to-skin contact with their extremely preterm infants analysed using inductive thematic analysis. FINDINGS: Parents' experiences were related to the process before, during and after skin-to-skin contact and moved from ambivalence to appreciating skin-to-skin contact as beneficial for both parents and infant. The process comprised three stages: (i) overcoming ambivalence through professional support and personal experience; (ii) proximity creating parental feelings and an inner need to provide care; (iii) feeling useful as a parent and realising the importance of skin-to-skin contact. Having repeatedly gone through stages 2 and 3, parents developed an overall confidence in the value of bonding, independent of the infant's survival. CONCLUSIONS: Parents progressed from ambivalence to a feeling of fundamental mutual needs for skin-to-skin contact. Parents found the bonding facilitated by skin-to-skin contact to be valuable, regardless of the infant's survival. PMID- 28851055 TI - The effect of adjunctive telmisartan treatment on psychopathology and cognition in patients with schizophrenia. AB - OBJECTIVE: This study examined the effect of adjunctive telmisartan on psychopathology and cognition in olanzapine- or clozapine-treated patients with schizophrenia. METHOD: In a 12-week randomized, double-blind, placebo-controlled study, patients diagnosed with schizophrenia or schizoaffective disorder received either telmisartan (80 mg once per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessment of Negative Symptoms (SANS), and a neuropsychological battery was used to assess cognitive performance. Assessments for psychopathology and cognition were conducted at baseline and week 12. RESULTS: Fifty-four subjects were randomized, and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). After 12-weeks of treatment, the telmisartan group had a significant decrease in PANSS total score compared withthe placebo group (mean +/ SD: - 4.1 +/- 8.1 vs. 0.4 +/- 7.5, P = 0.038, SCohen's d = 0.57). There were no significant differences between the two groups in change from baseline to week 12 in PANSS subscale scores, SANS total score, or any cognitive measures (P > 0.100). CONCLUSION: The present study suggests that adjunctive treatment with telmisartan may improve schizophrenia symptoms. Future trials with larger sample sizes and longer treatment durations are warranted. PMID- 28851056 TI - Influenza in patients with hematological malignancies: Experience at two comprehensive cancer centers. AB - The burden of influenza infections in patients with hematological malignancies (HMs) is not well defined. We describe the clinical presentation and associated outcomes of influenza at two comprehensive cancer centers (center 1 in the United States and center 2 in Mexico). Clinical and laboratory data on patients with HMs and influenza infection diagnosed from April 2009 to May 2014 at the two centers were reviewed retrospectively. A total of 190 patients were included, the majority were male (63%) with a median age of 49 years (range, 1-88 years), and had active or refractory HMs (76%). Compared to center 1, patients in center 2 were significantly sicker (active cancer, decreased albumin levels, elevated creatinine levels, or hypoxia at influenza diagnosis) and experienced higher lower respiratory tract infection (LRI) rate (42% vs 7%; P < 0.001). In multivariable logistic regression analysis (odds ratio, 95% confidence interval), leukemia, (3.09, 1.23-7.70), decreased albumin level (3.78, 1.55-9.20), hypoxia at diagnosis (14.98, 3.30-67.90), respiratory co-infection (5.87, 1.65-20.86), and corticosteroid use (2.71, 1.03-7.15) were significantly associated with LRI; and elevated creatinine level (3.33, 1.05-10.56), hypoxia at diagnosis (5.87, 1.12-30.77), and respiratory co-infection (6.30, 1.55-25.67) were significantly associated with 60 day mortality in both centers. HM patients with influenza are at high risk for serious complications such as LRI and death, especially if they are immunosuppressed. Patients with respiratory symptoms should seek prompt medical care during influenza season. PMID- 28851057 TI - Employee effort - reward balance and first-level manager transformational leadership within elderly care. AB - BACKGROUND: Negative aspects, staff dissatisfaction and problems related to internal organisational factors of working in elderly care are well-known and documented. Much less is known about positive aspects of working in elderly care, and therefore, this study focuses on such positive factors in Swedish elderly care. We combined two theoretical models, the effort-reward imbalance model and the Transformational Leadership Style model. The aim was to estimate the potential associations between employee-perceived transformational leadership style of their managers, and employees' ratings of effort and reward within elderly care work. METHODS: The article is based on questionnaires distributed at on-site visits to registered nurses, occupational therapists, physiotherapists (high-level education) and assistant nurses (low-level education) in nine Swedish elderly care facilities. In order to grasp the positive factors of work in elderly care, we focused on balance at work, rather than imbalance. RESULTS: We found a significant association between employees' effort-reward balance at work and a transformational leadership style among managers. An association was also found between employees' level of education and their assessments of the first level managers. CONCLUSIONS: We conclude that the first-level manager is an important actor for achieving a good workplace within elderly care, since she/he influences employees' psychosocial working environment. We also conclude that there are differences and inequalities, in terms of well-being, effort and reward at the work place, between those with academic training and those without, in that the former group to a higher degree evaluated their first-level manager to perform a transformational leadership style, which in turn is beneficial for their psychosocial work environment. Consequently, this (re)-produce inequalities in terms of well-being, effort and reward among the employees at the work place. PMID- 28851058 TI - Visual processing of one's own body over the course of time: Evidence for the vigilance-avoidance theory in adolescents with anorexia nervosa? AB - OBJECTIVE: The vigilance-avoidance theory postulates a specific threat-related pattern of attention deployment, characterized by initial orientation towards fear-evoking stimuli and subsequent directing of attention away from them. The current eye-tracking study was the first to examine the applicability of the theory for patients with eating disorders, who perceive their own body as a highly aversive, threat-evoking stimulus. METHOD: N = 56 female adolescents with anorexia nervosa (AN) and n = 43 healthy controls (HC) aged 13-18 viewed own-body pictures while their eye movements were recorded. Relative fixation times on self defined unattractive body areas were compared between the groups by sequencing the overall presentation time of 6,000 ms into six intervals a 1,000 ms. RESULTS: Participants with AN showed a significantly stronger attentional bias for unattractive body areas than HC within the time intervals 1, 2, and 3. However, for intervals 4, 5, and 6, no significant group differences occurred. Within the AN group, the bias for unattractive body areas was significantly stronger in interval 1 compared to intervals 4, 5, and 6; whereas within the HC group, a stable pattern of attention deployment emerged. In AN, early attention deployment was positively correlated with the negative affect reported after photo presentation. DISCUSSION: The early vigilance in AN and the subsequent decrease in attention to unattractive body parts is in line with our assumptions. However, no indication of attentional avoidance was found. The current findings partially support the vigilance-avoidance theory for the exposure to one's own body in adolescents with AN. PMID- 28851059 TI - A covalent capillary coating of diazoresin and polyglycerol dendrimer for protein analysis using capillary electrophoresis. AB - Overcoming proteins adsorption on the inner surface of capillary has attracted increasing attention recently. By using the unique photochemistry reaction of diazoresin (DR), a new covalent capillary coating was prepared on the fused silica capillary through layer-by-layer self-assembly of DR with polyglycerol (PG) dendrimer. The separation performance of covalently DR/PG-dendrimer coated capillary noticeably exceeded the bare capillary and the noncovalently linked DR/PG-dendrimer capillary. A baseline separation of lysozyme, myoglobin, bovine serum albumin, and ribonuclease A was achieved using CE within 20 min. Besides, the covalently linked DR/PG-dendrimer coating has the remarkable stability and reproducibility. Especially, compared with the traditional method which use highly toxic and moisture-sensitive silane coupling agent, this method seems to be a simple and environmental friendly way to prepare the covalently coated capillaries for CE. PMID- 28851060 TI - Psychometric testing of the Iceland Health Care Practitioner Illness Beliefs Questionnaire among school nurses. AB - BACKGROUND: Beliefs have been found to have an effect on how people deal with illness. Therefore, knowing healthcare practitioners' beliefs about specific high frequency illnesses are vital when caring for vulnerable populations such as school-age children with chronic illnesses or disorders. AIM: To psychometrically test the Iceland Health Care Practitioner Illness Beliefs Questionnaire for healthcare professionals who are working with families of school-age children with asthma and attention deficit/hyperactivity disorder. DESIGN: The Iceland Health Care Practitioner Illness Beliefs Questionnaire is a 7-item Likert-type instrument with four additional open-ended questions that was developed from the Iceland Family Illness Belief Questionnaire. The questionnaire is designed to measure a provider's beliefs about their understanding of the meaning of the illness situation for families. The questionnaire was administered to 162 school nurses in Iceland and the state of Minnesota. METHOD: Two condition-specific versions of the Iceland Health Care Practitioner Illness Beliefs Questionnaire were developed in this study: one to measure beliefs about families of children with asthma and one to measure beliefs about families of children with attention deficit hyperactivity disorder. Higher scores on the questionnaire indicate that healthcare professionals are more confident in their illness beliefs. After initial development, the questionnaire was translated into English. Participants completed the questionnaire using an online survey platform and parallel study procedures in both countries. RESULTS: Based on exploratory factor analysis using principal component analysis, the Iceland Health Care Practitioner Illness Beliefs Questionnaire was found to have a one-factor solution with good construct validity (Cronbach's alpha = 0.91). Confirmatory factor analysis supported the one-factor solution (Cronbach's alpha = 0.91). CONCLUSION: This instrument is a promising tool for measuring illness beliefs among healthcare practitioners in clinical and research settings. PMID- 28851062 TI - Bilateral sympathectomy for treatment of refractory ventricular tachycardia. AB - Ventricular tachycardia (VT) commonly occurs in patients with ischemic or nonischemic cardiomyopathy and requires antiarrhythmic drugs, ablation, or advanced circulatory support. However, life-threatening VT may be refractory to these therapies, and may cause frequent implantable cardioverter defibrillator (ICD) discharges. Left cardiac sympathetic denervation reduces the occurrence of these fatal arrhythmias by inhibiting the sympathetic outflow to the cardiac tissue. We present a 69-year-old man with nonischemic cardiomyopathy, life threatening VT, and hemodynamic instability with numerous ICD discharges, who remained refractory to antiarrhythmic drug therapy and ablation attempts. He was effectively treated with bilateral cardiac sympathectomy. Six months later, he remained free of VT with no ICD discharges. PMID- 28851061 TI - The approximate number system and domain-general abilities as predictors of math ability in children with normal hearing and hearing loss. AB - Many children with hearing loss (CHL) show a delay in mathematical achievement compared to children with normal hearing (CNH). This study examined whether there are differences in acuity of the approximate number system (ANS) between CHL and CNH, and whether ANS acuity is related to math achievement. Working memory (WM), short-term memory (STM), and inhibition were considered as mediators of any relationship between ANS acuity and math achievement. Seventy-five CHL were compared with 75 age- and gender-matched CNH. ANS acuity, mathematical reasoning, WM, and STM of CHL were significantly poorer compared to CNH. Group differences in math ability were no longer significant when ANS acuity, WM, or STM was controlled. For CNH, WM and STM fully mediated the relationship of ANS acuity to math ability; for CHL, WM and STM only partially mediated this relationship. ANS acuity, WM, and STM are significant contributors to hearing status differences in math achievement, and to individual differences within the group of CHL. Statement of contribution What is already known on this subject? Children with hearing loss often perform poorly on measures of math achievement, although there have been few studies focusing on basic numerical cognition in these children. In typically developing children, the approximate number system predicts math skills concurrently and longitudinally, although there have been some contradictory findings. Recent studies suggest that domain-general skills, such as inhibition, may account for the relationship found between the approximate number system and math achievement. What does this study adds? This is the first robust examination of the approximate number system in children with hearing loss, and the findings suggest poorer acuity of the approximate number system in these children compared to hearing children. The study addresses recent issues regarding the contradictory findings of the relationship of the approximate number system to math ability by examining how this relationship varies across children with normal hearing and hearing loss, and by examining whether this relationship is mediated by domain-general skills (working memory, short-term memory, and inhibition). PMID- 28851063 TI - Cognitive behavioural therapy and mindfulness for stress and burnout: a waiting list controlled pilot study comparing treatments for parents of children with chronic conditions. AB - BACKGROUND: Parents of children with chronic conditions often experience a crisis with serious mental health problems for themselves as a consequence. The healthcare focus is on the children; however, the parents often worry about their children's health and future but are seldom offered any counselling or guidance. AIM: The aim of this study was to investigate the effectiveness of two group based behavioural interventions on stress and burnout among parents of children with chronic conditions. DESIGN, PARTICIPANTS AND SETTING: After a waiting list control period (n = 28), parents were offered either a cognitive behavioural (CBT, n = 10) or a mindfulness program (MF, n = 9). RESULTS: Both interventions decreased significantly stress and burnout. The within-group effect sizes were large in both interventions (CBT, g = 1.28-1.64; MF, g = 1.25-2.20). CONCLUSIONS: Hence, the results of this pilot study show that treating a group using either CBT or mindfulness can be an efficient intervention for reducing stress levels and burnout in parents of children with chronic conditions. PMID- 28851064 TI - Structural and Community Change Outcomes of the Connect-to-Protect Coalitions: Trials and Triumphs Securing Adolescent Access to HIV Prevention, Testing, and Medical Care. AB - Connect to Protect (C2P), a 10-year community mobilization effort, pursued the dual aims of creating communities competent to address youth's HIV-related risks and removing structural barriers to youth health. We used Community Coalition Action Theory (CCAT) to examine the perceived contributions and accomplishments of 14 C2P coalitions. We interviewed 318 key informants, including youth and community leaders, to identify the features of coalitions' context and operation that facilitated and undermined their ability to achieve structural change and build communities' capability to manage their local adolescent HIV epidemic effectively. We coded the interviews using an a priori coding scheme informed by CCAT and scholarship on AIDS-competent communities. We found community mobilization efforts like C2P can contribute to addressing the structural factors that promote HIV-risk among youth and to community development. We describe how coalition leadership, collaborative synergy, capacity building, and local community context influence coalitions' ability to successfully implement HIV related structural change, demonstrating empirical support for many of CCAT's propositions. We discuss implications for how community mobilization efforts might succeed in laying the foundation for an AIDS-competent community. PMID- 28851065 TI - The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose recombinant activated factor VII in patients with haemophilia A or B. AB - : Monitoring recombinant activated factor VII (rFVIIa) treatment outcomes remains challenging. Thromboelastography (TEG) and the thrombin generation assay (TGA), measure coagulation dynamics over time and are being assessed as potential methods for evaluating and monitoring haemophilia treatment. Lack of standardized TEG/TGA methods makes it difficult to compare results and to establish a correlation with clinical outcomes. AIMS: To compare the pharmacokinetics (PK) of rFVIIa after 3*90 MUg kg-1 doses vs a single dose (270 MUg kg-1 ) in haemophilia patients and to evaluate TEG/TGA results postdosing to determine how these assays relate to PK findings. METHODS: Patients in this open-label, single-centre, randomized, crossover trial received one injection of 270 MUg kg-1 rFVIIa crossed over with three injections of 90 MUg kg-1 rFVIIa in a non-bleeding state. For TEG, kaolin and tissue factor were used as activators; TGA was performed on frozen platelet-rich and platelet-poor plasma, with and without corn trypsin inhibitor. FVIIa activity was evaluated using in vivo samples. RESULTS: TGA showed a dose-dependent effect of rFVIIa on thrombin generation; TEG revealed lower dose-dependent effects. Both showed some differences between single /multiple-dose rFVIIa; both supported the PK findings. CONCLUSION: While TEG and TGA are not yet clinically predictive, both supported the PK results. Data suggest that, while a single dose of 270 MUg kg-1 rFVIIa provides slightly higher haemostatic potential than the multiple-dose regimen of 3*90 MUg kg-1 , the latter results in prolonged activity levels compared with a higher single dose. PMID- 28851066 TI - The determinants of meaning of pain following an acute traumatic injury. AB - RATIONALE AND AIMS: Meaning is an integral aspect of life that drives behaviours, actions and emotions. Perception of pain is believed to be affected by the meaning of pain. Our primary aim was to investigate and discuss the determinants of meaning in acute pain following a traumatic injury. METHODOLOGICAL DESIGN: Using the Interpretive Description approach, a method of qualitative inquiry, 13 adults hospitalised due to their accidental injuries were recruited. Semi structured interviews that were digitally recorded were used to collect the data. Ethical approval was received by our local Health Research Ethics Board, and all relevant ethical standards were followed as outlined in the approved ethics proposal. FINDINGS: The three primary determinants of meaning during an acute pain event, or the experience of acute pain include permanence of injuries, incongruence of care quality, and personal responses to the injury and care received. Although the permanence of an injury is lasting, we did not find any emotional response to this fact while the participants were hospitalised. The emotion characterising the personal response to the perceived poor quality of hospital care received was anxiety. CONCLUSION: Both the technical and personal components of healthcare quality have the potential to increase the perception of pain. Meanings in an acute pain event are primarily related to the determinants of incongruent care and the personal response to that determinant: anxiety. PMID- 28851067 TI - Refractory lupus nephropathy and acquired Factor VIII and IX deficiencies in a patient with systemic lupus erythematosus treated with rituximab. PMID- 28851068 TI - Rotationally Active Ligands: Dialing-Up Multiple Interlocked Co-Conformations for Silver(I) Coordination. AB - A novel [2]rotaxane ligand has been prepared that contains a bidentate N,N' chelate as part of a rigid, H-shaped axle and a 24-membered crown ether macrocycle containing six ether O-atoms and a trans olefinic group as the wheel. This unique interlocked connectivity allows access to a number of different donor sets, which are shown to be capable of binding AgI metal ions. PMID- 28851069 TI - Envisioning the future as expressed within family health conversations by families of persons suffering from stroke. AB - BACKGROUND: The whole family is affected when a person suffers from stroke, but few studies have focused on families' expectations following the stroke. OBJECTIVE: The aim of this study was to illuminate what persons with stroke and their family members talk about in Family Health Conversations (FamHCs) with focus on the future and how nurses leading these conversations apprehended the families' future shown in closing letters based on these conversations. METHOD: In this study, seven families with a member <=65 years who had suffered a stroke participated in FamHC in their homes after the person with stroke had been discharged from the rehabilitation clinic. The FamHC comprised a series of three conversations conducted every other week and a closing letter sent by the nurses to the family to conclude the series. In this study, the third conversations were recorded and they and the closing letters were transcribed and analysed using qualitative content analysis. RESULT: The family members including the persons with stroke were found to be able to tell their stories and express their feelings, worries, losses, hopes and wishes for the future within the context of the Family Health Conversations. Support within the family was highlighted as essential to the satisfactory management of future situations. CONCLUSION: The persons with stroke and their belonging family members' vision of the future was reflected over in the light of theories about beliefs, possible selves, hope and suffering, and the findings highlight the need for broader use of family conversations to support persons with stroke and their families to manage the future. PMID- 28851070 TI - Comparative study of hematopoietic stem and progenitor cells between sexes in mice under physiological conditions along time. AB - Hematopoietic stem and progenitor cells (HSPCs) are attractive targets in regenerative medicine, although the differences in their homeostatic maintenance between sexes along time are still under debate. We accurately monitored hematopoietic stem cells (HSCs), common lymphoid progenitors (CLPs), and common myeloid progenitors (CMPs) frequencies by flow cytometry, by performing serial peripheral blood extractions from male and female B6SJL wild-type mice and found no significant differences. Only modest differences were found in the gene expression profile of Slamf1 and Gata2. Our findings suggest that both sexes could be used indistinctly to perform descriptive studies in the murine hematopoietic system, especially for flow cytometry studies in peripheral blood. This would allow diminishing the number of animals needed for the experimental procedures. In addition, the use of serial extractions in the same animals drastically decreases the number of animals needed. PMID- 28851071 TI - Wnt5a regulates the cell proliferation and adipogenesis via MAPK-independent pathway in early stage of obesity. AB - The early stage of obesity is an important stage in the development of obesity. However, there are few studies which explored the property or changes in obesity at early stage especially involving Wnt5a. The associated gene expression of Wnt5a on cell regeneration and the effect of Wnt5a on rat adipose-derived stem cell (rASC) proliferation and adipogenesis need additional study. Here, we investigated the changes in obesity at early stage and how Wnt5a regulates rASC regeneration, proliferation, and adipogenesis. Our data revealed that obesity at early stage measured by Lee index presented a state with impaired adipogenesis and more infiltrated inflammatory cells but without significant changes in adipocyte sizes and inflammatory factors. The process might be associated with anti-canonical Wnt pathway and a reciprocal Wnt5a/JNK pathway. Besides the gene expression of Wnt5a decreased from cell passage 1 to passage 3. The cell proliferation was regulated by increasing dose of Wnt5a with the maximal effect at 50 ng/mL and 50 ng/mL Wnt5a suppressed adipogenic differentiation at middle late stage of adipogenesis via anti-beta-catenin and a mitogen-activated protein kinase (MAPK) signaling-independent manner. Accordingly, the research helps to gain further insights into the early stage of obesity and its associated changes on a cellular and molecular level. PMID- 28851072 TI - Association of zinc and copper with clinical parameters in the preterm newborn. AB - BACKGROUND: Given that preterm infants are born at a time of rapid fetal growth, they are at risk of deficiency of essential nutrients for brain development, including zinc (Zn) and copper (Cu). This study evaluate the relationship between serum Cu or Zn, gestational age (GA) and anthropometric parameters at birth in preterm infants. METHODS: This was a retrospective study of infants <35 weeks' GA from January 2010 to August 2012. We collected the data from medical records of 59 preterm infants at birth with regard to GA, anthropometric parameters, and serum Cu and Zn levels. Correlation of Cu, Zn, and GA with anthropometric parameters at birth was then done. RESULTS: Zn was inversely correlated with GA, bodyweight (BW), body length (BL), and head circumference (HC), and Cu was inversely correlated with the standard deviation (SD) score for BW, BL, and HC. On stepwise multiple regression analysis, GA was a significant independent predictor of Zn level, and HC SD score was a significant independent predictor of Cu level. CONCLUSIONS: Prematurity influences Zn, and intrauterine head growth restriction influences Cu at birth in preterm infants. Further research is needed to evaluate the relationship between intrauterine growth restriction and brain Cu metabolism. PMID- 28851073 TI - 4-Phenybutyric acid promotes gastric cancer cell migration via histone deacetylase inhibition-mediated HER3/HER4 up-regulation. AB - Dysregulation of histone acetylation plays an important role in tumor development. Histone acetylation regulates gene transcription and expression, which is reversibly regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). As an HDAC inhibitor, 4-phenylbutyric acid (4-PBA) can increase histone acetylation levels by inhibiting HDAC activity. While 4-PBA inhibits proliferation of tumor cells in vitro, clinical trials have failed to show benefits of 4-PBA for refractory solid tumors. Here, we found that 4-PBA could enhance the migration capacity of gastric cancer cells. Upregulation of HER3/HER4 and activation of HER3/HER4-ERK pathway was shown to be involved in 4 PBA-induced gastric cancer cell migration. Knockdown of HER3/HER4 blocked HER3/HER4-ERK activation and partially prevented 4-PBA-induced cell migration. Consistently, the ERK inhibitor PD98059 also partially prevented 4-PBA-induced cell migration. Moreover, enhanced levels of acetyl-histones were detected following 4-PBA-treatment, and histone3 acetylation in promoter regions of HER3 and HER4 were confirmed by ChIP. These results demonstrate that 4-PBA promotes gastric cancer cells migration through upregulation of HER3/HER4 subsequent to increased levels of acetyl-histone and activation of ERK signaling. These novel findings provide important considerations for the use of 4-PBA in cancer therapeutics. PMID- 28851074 TI - Macrophage migration inhibitory factor (MIF) promotes rat airway muscle cell proliferation and migration mediated by ERK1/2 and FAK signaling. AB - Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that contributes to asthmatic airway remodeling; however, little is known regarding the effects of MIF on airway smooth muscle cells (ASMCs). In the present study, we found that an enhanced expression of MIF promoted ASMC proliferation, increased the population of cells in the S/G2 phase, downregulated P21 expression, and upregulated cyclin D1, cyclin D3, and Cdk6 expression. In addition, the apoptosis of ASMCs was significantly decreased in response to MIF overexpression, compared with the negative control. Moreover, MIF facilitated the migration of ASMCs by upregulating the expression of matrix metalloproteinase (MMP)-2. Finally, we showed that MIF increased the phosphorylation of extracellular regulated protein kinases (ERK) 1/2 and focal adhesion kinase (FAK), which are associated with proliferation and migration. In conclusion, this study demonstrated that MIF overexpression promotes the proliferation and migration of ASMCs by upregulating the activity of the ERK1/2 and FAK signaling pathways in these cells, further indicating that inhibition of MIF may prove to be an effective strategy for treating asthma patients with airway remodeling. PMID- 28851075 TI - Congenital central hypoventilation syndrome: A pictorial demonstration of absent electrical diaphragmatic activity using non-invasive neurally adjusted ventilatory assist. PMID- 28851076 TI - Molecular characteristics of multifocal invasive mucinous adenocarcinoma of the lung: Report of a rare case. AB - Invasive mucinous adenocarcinoma (IMA) is an uncommon entity in the lung, with a poor prognosis. Multifocal IMA of the lung is even more unusual, and there is little experience with effective treatments. Herein, we present a case of multifocal IMA diagnosed in a 36 year-old man by video-assisted thoracoscopic surgery. A right middle lobe and a nodule in the right upper lobe were resected, as were mediastinal lymph nodes, leaving behind an autonomous right lower lobe nodule. To explore the feasibility of molecular treatment, next-generation sequencing of genetic mutations was performed after four cycles of chemotherapy (pemetrexed + cisplatin). Ultimately, a KIAA1468-RET fusion gene was detected at a disproportionate level (~67.3%), indicating that targeted therapy may be efficacious in treating this disease. PMID- 28851077 TI - Bullous systemic lupus erythematosus in a 6-year-old boy. AB - Bullous systemic lupus erythematosus (BSLE) is a rare subepidermal blistering disorder characterized by an acute vesiculobullous eruption in a subset of individuals with systemic lupus erythematosus. BSLE most commonly affects young women and only rarely affects children. Herein we report a rare case of BSLE in a 6-year-old boy. PMID- 28851078 TI - Increased basement membrane turnover and strongly attenuated interstitial matrix turnover is a key pathological feature of haemophilia. PMID- 28851080 TI - Prevalence and risk of metabolic syndrome in patients with systemic lupus erythematosus: A meta-analysis. AB - PURPOSE: To conduct a systematic review and meta-analysis assessing the prevalence of metabolic syndrome (MetS) in patients with systemic lupus erythematosus (SLE) and the association between SLE and MetS. METHOD: A database search of PubMed, the Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Weipu database and Wanfang database updated until March 2017 was conducted. The pooled prevalence, the odds ratio (OR) and 95% confidence intervals (CI) were calculated. Publication bias was assessed with Egger's test method. RESULTS: In the study of the prevalence of MetS in patients with SLE, 47 studies containing 8367 subjects were included. These studies were published from 2006 to 2016. The pooled prevalence of MetS in patients with SLE was 0.26 (95% CI: 0.23-0.29). In the study of the relationship between SLE and MetS, 24 studies involving 2744 cases and 3028 controls were included. Comparing to control, the SLE patients had high risk of MetS (OR = 1.88, 95% CI: 1.54-2.30, P = 0.000). CONCLUSION: The systematic review and meta-analysis demonstrated the prevalence of MetS in patients with SLE was 26% and the patients with SLE were more prone to having MetS than the control population. The analysis was a basic summary of all relevant researches and provided valuable evidence for prevention and treatment. PMID- 28851079 TI - Genome-wide significant locus for Research Diagnostic Criteria Schizoaffective Disorder Bipolar type. AB - Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP, we have performed a replication study using independent RDC-SABP cases (n = 144) and controls (n = 6,559), focusing on the 10 loci that reached a p-value <10-5 for RDC-SABP in the Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder sample. Combining the WTCCC and replication datasets by meta-analysis (combined RDC-SABP, n = 423, controls, n = 9,494), we observed genome-wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIP on chromosome 3p21.31 (p-value, 4.37 * 10-8 ). This locus did not reach genome-wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder. PMID- 28851082 TI - Polypyrrole-magnetite dispersive micro-solid-phase extraction combined with ultraviolet-visible spectrophotometry for the determination of rhodamine 6G and crystal violet in textile wastewater. AB - Polypyrrole-magnetite dispersive micro-solid-phase extraction method combined with ultraviolet-visible spectrophotometry was developed for the determination of selected cationic dyes in textile wastewater. Polypyrrole-magnetite was used as adsorbent due to its thermal stability, magnetic properties, and ability to adsorb Rhodamine 6G and crystal violet. Dispersive micro-solid-phase extraction parameters were optimized, including sample pH, adsorbent amount, extraction time, and desorption solvent. The optimum polypyrrole-magnetite dispersive micro solid phase-extraction conditions were sample pH 8, 60 mg polypyrrole-magnetite adsorbent, 5 min of extraction time, and acetonitrile as the desorption solvent. Under the optimized conditions, the polypyrrole-magnetite dispersive micro-solid phase extraction with ultraviolet-visible method showed good linearity in the range of 0.05-7 mg/L (R2 > 0.9980). The method also showed a good limit of detection for the dyes (0.05 mg/L) and good analyte recoveries (97.4-111.3%) with relative standard deviations < 10%. The method was successfully applied to the analysis of dyes in textile wastewater samples where the concentration found was 1.03 mg (RSD +/-7.9%) and 1.13 mg/L (RSD +/- 4.6%) for Rhodamine 6G and crystal violet, respectively. It can be concluded that this method can be adopted for the rapid extraction and determination of dyes at trace concentration levels. PMID- 28851081 TI - Drones in medicine-The rise of the machines. AB - This is a medical kitty hawk moment. Drones are pilotless aircrafts that were initially used exclusively by the military but are now also used for various scientific purposes, public safety, and in commercial industries. The healthcare industry in particular can benefit from their technical capabilities and ease of use. Common drone applications in medicine include the provision disaster assessments when other means of access are severely restricted; delivering aid packages, medicines, vaccines, blood and other medical supplies to remote areas; providing safe transport of disease test samples and test kits in areas with high contagion; and potential for providing rapid access to automated external defibrillators for patients in cardiac arrest. Drones are also showing early potential to benefit geriatric medicine by providing mobility assistance to elderly populations using robot-like technology. Looking further to the future, drones with diagnostic imaging capabilities may have a role in assessing health in remote communities using telemedicine technology. The Federal Aviation Administration (FAA) in the United States and the European Aviation Safety Agency (EASA) in the European Union are some examples of legislative bodies with regulatory authority over drone usage. These agencies oversee all technical, safety, security and administrative issues related to drones. It is important that drones continue to meet or exceed the requirements specified in each of these regulatory areas. The FAA is challenged with keeping pace legislatively with the rapid advances in drone technology. This relative lag has been perceived as slowing the proliferation of drone use. Despite these regulatory limitations, drones are showing significant potential for transforming healthcare and medicine in the 21st century. PMID- 28851083 TI - Association of daytime napping with prediabetes and diabetes in a Chinese population: Results from the baseline survey of the China Health and Retirement Longitudinal Study. AB - BACKGROUND: Only a few studies have investigated the effects of daytime napping on diabetes, and these studies have reported conflicting results. The aim of the present study was to examine whether daytime napping is associated with a higher risk of prediabetes and diabetes. METHODS: The present cross-sectional study of napping duration in relation to prediabetes and diabetes was conducted in 12 277 participants. Data from the first wave (2011) of the China Health and Retirement Longitudinal Study were used. Daytime napping was divided into four groups: no napping (reference) and napping for 1-30, 31-90, and >90 min. Multinomial logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Individuals who reported taking daily afternoon naps accounted for 53.39% of all participants. Nappers had a higher prevalence of prediabetes and diabetes than non-nappers. Compared with the reference group, the weighted fully adjusted ORs (95% CI) were 1.36 (1.10-1.68) and 1.61 (1.22-2.13) for napping >90 min in prediabetic and diabetic patients, respectively. CONCLUSIONS: Long daytime napping duration was positively associated with prediabetes and diabetes. Further physiological and cohort studies are needed to confirm these results and elucidate potential mechanisms. PMID- 28851084 TI - Simultaneous determination of alcohols including diols and triols by HPLC with ultraviolet detection based on the formation of a copper(II) complex. AB - We developed a reversed-phase high-performance liquid chromatography method with ultraviolet detection using on-line complexation with Cu(II) ion for analysis of five alcohols including diols and triol (methanol, ethanol, 1,2-propanediol, 1,3 propanediol, and glycerol). The Cu(II) ion concentration in the mobile phase had a great influence on the peak areas of these alcohols, but not on their retention times. Column temperature (25-40 degrees C) and pH of the mobile phase did not affect the separation of analytes. The optimum separation conditions were determined as 5 mM CuSO4 , 3 mM H2 SO4 , and 3 mM NaOH at 30 degrees C. The ratio of the peak areas for three alcohols (methanol, 1,2-propanediol, and glycerol) was in good agreement with that calculated from the obtained stability constants, molar absorption coefficients for the 1:1 Cu(II) complexes with the three alcohols, and the injected molar quantities. This fact strongly suggests that the observed high-performance liquid chromatography signals resulted from formation of the 1:1 Cu(II)-alcohol complexes. Using the proposed method, these five alcohols in spirit, liquid for electronic cigarette, mouthwash, and nail enamel remover samples were successfully analyzed with only a simple pretreatment. PMID- 28851085 TI - The effect of APOE, CETP, and PCSK9 polymorphisms on simvastatin response in Thai hypercholesterolemic patients. AB - AIM: To investigate the effect of apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP) and proprotein convertase subtilisin kexin type 9 (PCSK9) polymorphisms on the lipid-lowering response to simvastatin therapy in Thai hypercholesterolemic patients. METHOD: Two hundred and twenty-five hypercholesterolemic patients in southern Thailand were enrolled and treated with simvastatin 20 or 40 mg per day for 3 months. Serum lipids were measured before and after the therapy. APOE, CETP TaqIB, and PCSK9 (R46L, I474V, and E670G) polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: After 3 months of simvastatin therapy, subjects with APOE2 (Total cholesterol [TC]: -30.89% vs-13.56%, P < .05, LDL-C: 45.00% vs -17.73%, P < .05) and APOE3 carriers (TC: -26.22% vs -13.56%, P < .05, LDL-C: -37.14% vs -17.73%, P < .05) had greater TC and LDL-C reduction compared to APOE4 carriers, whereas CETP TaqIB B2B2 genotype showed lower TC (-16.37% vs 24.92%, P = .016) and LDL-C (-22.54% vs -35.19%, P = .028) reduction compared to CETP TaqIB B1 carriers. In addition, PCSK9 474IV carriers showed greater LDL-C ( 50.57% vs -32.99%) reduction compared to PCSK9 474II carriers. Combined effect analyses showed that individuals carrying more risk alleles tended to have lower TC and LDL-C (P for trend = .000 and .000, respectively) reduction in response to simvastatin therapy. CONCLUSION: APOE4 carriers and the CETP TaqIB B2B2 genotype were associated with a decreased response, but PCSK9 474IV carriers tended to be associated with an increased response to simvastatin therapy in Thai hypercholesterolemic patients. PMID- 28851086 TI - Sutureless nerve repair with ECM bioscaffolds and laser-activated chitosan adhesive. AB - The outcome of peripheral nerve repair following transection is influenced by a number of factors but almost all approaches require anastomosis of the nerve using technically demanding microsurgical procedures. However, the use of sutures presents a number of unavoidable challenges including additional nerve trauma, stimulation of an inflammatory response, and endoneural fibrosis. The objective of the present study was to determine the efficacy of a sutureless approach to nerve repair. A rat sciatic nerve transection model was used with a laser activated, chitosan-based adhesive (SurgiLux), combined with different forms of extracellular matrix (ECM), known to promote Schwann cell proliferation and nerve growth both in peripheral nerve applications. Following a 5 mm transection of the sciatic nerve, nerve guide wraps were prepared using: (1) laser-activated adhesive (SurgiLux) alone, (2) SurgiLux incorporating ECM (SurgiLux ECM), (3) ECM secured using SurgiLux, and (4) ECM secured using 8-0 Prolene sutures. A no treatment groups was used as a negative control. Evaluation of tissue remodeling was conducted with histolomorphometric assessment of neuroma, integrity of repair, nerve immunolabeling, ratio of myelinated to non-myelinated fibers, and amount of connective tissue. Quantitative and semi-quantitative analysis of the repaired nerve transections at 6 and 12 weeks showed that that SurgiLux incorporating powdered ECM (SurgiLux ECM), SurgiLux alone and ECM alone all improved the healing response compared to no-treatment controls, with less fibrotic tissue and more nerve staining. Histologic scoring showed that the SurgiLux ECM group showed the greatest increase in histologic score between the two time points tested. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1698-1711, 2018. PMID- 28851087 TI - Survey of factors influencing learner engagement with simulation debriefing among nursing students. AB - Simulation-based education has escalated worldwide, yet few studies have rigorously explored predictors of learner engagement with simulation debriefing. The purpose of this cross-sectional, descriptive survey was to identify factors that determine learner engagement with simulation debriefing among nursing students. A convenience sample of 296 Korean nursing students enrolled in the simulation-based course completed the survey. A total of five instruments were used: (i) Characteristics of Debriefing; (ii) Debriefing Assessment for Simulation in Healthcare - Student Version; (iii) The Korean version of the Simulation Design Scale; (iv) Communication Skills Scale; and (v) Clinical-Based Stress Scale. Multiple regression analysis was performed using the variables to investigate the influencing factors. The results indicated that influencing factors of learning engagement with simulation debriefing were simulation design, confidentiality, stress, and number of students. Simulation design was the most important factor. Video-assisted debriefing was not a significant factor affecting learner engagement. Educators should organize and conduct debriefing activities while considering these factors to effectively induce learner engagement. Further study is needed to identify the effects of debriefing sessions targeting learners' needs and considering situational factors on learning outcomes. PMID- 28851088 TI - Diacylglycerol Enhances the Effects of Alpha-Linolenic Acid Against Visceral Fat: A Double-Blind Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effect of alpha-linolenic acid-rich diacylglycerol (ALA-DAG) compared with alpha-linolenic acid-rich triacylglycerol (ALA-TAG) on visceral fat area (VFA) in people with overweight. METHODS: Subjects with overweight were recruited to a randomized, double-blind, controlled, parallel group designed trial and randomly allocated to two groups that consumed either 2.5 g/d ALA-TAG or ALA-DAG for 12 weeks. Two 4-week nontreatment periods were placed before and after the treatment period. One hundred fourteen subjects (n = 57 in the ALA-TAG group, n = 57 in the ALA-DAG group) were enrolled into the analysis set for efficacy evaluation. RESULTS: The VFA and BMI were significantly decreased by the ALA-DAG treatment with a treatment-by-time interaction compared with the ALA-TAG treatment (P < 0.05). Additionally, the change from baseline of the fasting serum TAG concentration at week 12 was significantly decreased by ALA DAG treatment compared with ALA-TAG treatment (P < 0.05). Safety parameters such as urinary measurements, hematologic parameters and blood biochemistry, and the incidence of adverse events did not differ significantly between groups, and no ALA-DAG-associated adverse effects were detected. CONCLUSIONS: Incorporation of ALA-DAG in a regular diet for 12 weeks may lead to a reduction in VFA, BMI, and serum TAG in men and women with overweight. PMID- 28851089 TI - Comparison of the performance in detection of HPV infections between the high risk HPV genotyping real time PCR and the PCR-reverse dot blot assays. AB - A new multiplex real-time PCR assay, the high-risk HPV genotyping real time PCR assay (HR HPV RT-PCR), has been developed to detect 15 high-risk HPV types with respective viral loads. In this report, a total of 684 cervical specimens from women diagnosed with vaginitis were assessed by the HR HPV RT-PCR and the PCR reaction and reverse dot blot (PCR-RDB) assays, using a PCR-sequencing method as a reference standard. A total coincidence of 97.7% between the HR HPV RT PCR and the PCR-RDB assays was determined with a Kappa value of 0.953. The HR HPV RT PCR assay had sensitivity, specificity, and concordance rates (accuracy) of 99.7%, 99.7%, and 99.7%, respectively, as confirmed by PCR-sequencing, while the PCR-RDB assay had respective rates of 98.8%, 97.1%, and 98.0%. The overall rate of HPV infection, determined by PCR-sequencing, in women diagnosed with vaginitis was 49.85%, including 36.26% of single infection and 13.6% of multiple infections. The most common infections among the 15 high-risk HPV types in women diagnosed with vaginitis were HPV-52, HPV-16, and HPV-58, with a total detection rate of 10.23%, 7.75%, and 5.85%, respectively. We conclude that the HR HPV RT PCR assay exhibits better clinical performance than the PCR-RDB assay, and is an ideal alternative method for HPV genotyping. In addition, the HR HPV RT PCR assay provides HPV DNA viral loads, and could serve as a quantitative marker in the diagnosis and treatment of single and multiple HPV infections. PMID- 28851090 TI - Association Between Sleep Duration and Body Mass Index Among US Low-Income Preschoolers. AB - OBJECTIVE: To verify whether sleep duration was related to body mass index z scores (zBMI) and whether bedtimes or ethnicity was a moderator of the sleep duration-zBMI association among preschoolers from low-income families. METHODS: Two hundred twenty-eight African American and Hispanic parents and their preschoolers were recruited from Head Start Centers. Parents reported their preschoolers' sleep duration and bedtimes (using the Children's Sleep Habits Questionnaire) and their television watching. Food intake was measured using multiple days of digital photography to estimate energy intake at dinner. The Parenting Stress Index and the Center for Epidemiologic Studies Depression Scale were used to measure stress and depression. Parents' and preschoolers' height and weight were measured by trained staff. RESULTS: Longer sleep duration was significantly associated with lower zBMI when controlling for demographics, bedtimes, energy intake at dinner, and television watching, but not when also controlling for parents' demographics, BMI, stress, and depression. Preschoolers' sleep duration-zBMI association was not moderated by bedtimes or ethnicity. CONCLUSIONS: Longer sleep duration was associated with lower zBMI among low income preschoolers when controlling for preschoolers' characteristics, but this was no longer the case when also controlling for parents' characteristics. Additional studies are needed on the moderators of the sleep duration-zBMI association among low-income preschoolers. PMID- 28851091 TI - Nerve infiltration by benign biliary glands - a diagnostic dilemma. PMID- 28851092 TI - An optical method for carbon dioxide isotopes and mole fractions in small gas samples: Tracing microbial respiration from soil, litter, and lignin. AB - RATIONALE: Carbon dioxide isotope (delta13 C value) measurements enable quantification of the sources of soil microbial respiration, thus informing ecosystem C dynamics. Tunable diode lasers (TDLs) can precisely measure CO2 isotopes at low cost and high throughput, but are seldom used for small samples (<=5 mL). We developed a TDL method for CO2 mole fraction ([CO2 ]) and delta13 C analysis of soil microcosms. METHODS: Peaks in infrared absorbance following constant volume sample injection to a carrier were used to independently measure [12 CO2 ] and [13 CO2 ] for subsequent calculation of delta13 C values. Using parallel soil incubations receiving differing C substrates, we partitioned respiration from three sources using mixing models: native soil organic matter (SOM), added litter, and synthetic lignin containing a 13 C label at Cbeta of the propyl side chain. RESULTS: Once-daily TDL calibration enabled accurate quantification of delta13 C values and [CO2 ] compared with isotope ratio mass spectrometry (IRMS), with long-term external precision of 0.17 and 0.310/00 for 5 and 1 mL samples, respectively, and linear response between 400 and 5000 MUmol mol-1 CO2 . Production of CO2 from native soil C, added litter, and lignin Cbeta varied over four orders of magnitude. Multiple-pool first-order decay models fitted to data (R2 > 0.98) indicated substantially slower turnover for lignin Cbeta (17 years) than for the dominant pool of litter (1.3 years) and primed soil C (3.9 years). CONCLUSIONS: Our TDL method provides a flexible, precise, and high throughput (60 samples h-1 ) alternative to IRMS for small samples. This enables the use of C isotopes in increasingly sophisticated experiments to test biogeochemical controversies, such as the fate of lignins in soil. PMID- 28851093 TI - The accuracy of an oscillometric ankle-brachial index in the diagnosis of lower limb peripheral arterial disease: A systematic review and meta-analysis. AB - INTRODUCTION: Peripheral arterial disease (PAD) remains underdiagnosed and undertreated, partly because of limitations in the Doppler ankle-brachial index (ABI), the non-invasive gold standard. OBJECTIVE: This systematic review and meta analysis aims to compare the diagnostic accuracy of the oscillometric ABI and the Doppler ABI, and to examine the influence of two approaches to analysis: legs vs subjects and inclusion of oscillometric errors as PAD equivalents vs exclusion. METHODS: Systematic searches in EMBASE, MEDLINE, Web of Science and the Cochrane Library databases were performed, from inception to February 2017. Random-effects models were computed with the Moses-Littenberg constant. Hierarchical summary receiver operating characteristic curves (HSROC) were used to summarise the overall test performance. RESULTS: Twenty studies (1263 subjects and 3695 legs) were included in the meta-analysis. The pooled diagnostic odds ratio (dOR) for the oscillometric ABI was 32.49 (95% CI: 19.6-53.8), with 65% sensitivity (95% CI: 57-74) and 96% specificity (95%CI: 93-99). In the subgroup analysis, the "per subjects" group showed a better performance than the "per legs" group (dOR 36.44 vs 29.03). Similarly, an analysis considering oscillometric errors as PAD equivalents improved diagnostic performance (dOR 31.48 vs 28.29). The time needed for the oscillometric ABI was significantly shorter than that required for the Doppler ABI (5.90 vs 10.06 minutes, respectively). CONCLUSIONS AND RELEVANCE: The oscillometric ABI showed an acceptable diagnostic accuracy and feasibility, potentially making it a useful tool for PAD diagnosis. We recommend considering oscillometric errors as PAD equivalents, and a "per subject" instead of a "per leg" approach, in order to improve sensitivity. Borderline oscillometric ABI values in diabetic population should raise concern of PAD. PMID- 28851094 TI - Effects of a large wildfire on vegetation structure in a variable fire mosaic. AB - Management guidelines for many fire-prone ecosystems highlight the importance of maintaining a variable mosaic of fire histories for biodiversity conservation. Managers are encouraged to aim for fire mosaics that are temporally and spatially dynamic, include all successional states of vegetation, and also include variation in the underlying "invisible mosaic" of past fire frequencies, severities, and fire return intervals. However, establishing and maintaining variable mosaics in contemporary landscapes is subject to many challenges, one of which is deciding how the fire mosaic should be managed following the occurrence of large, unplanned wildfires. A key consideration for this decision is the extent to which the effects of previous fire history on vegetation and habitats persist after major wildfires, but this topic has rarely been investigated empirically. In this study, we tested to what extent a large wildfire interacted with previous fire history to affect the structure of forest, woodland, and heath vegetation in Booderee National Park in southeastern Australia. In 2003, a summer wildfire burned 49.5% of the park, increasing the extent of recently burned vegetation (<10 yr post-fire) to more than 72% of the park area. We tracked the recovery of vegetation structure for nine years following the wildfire and found that the strength and persistence of fire effects differed substantially between vegetation types. Vegetation structure was modified by wildfire in forest, woodland, and heath vegetation, but among-site variability in vegetation structure was reduced only by severe fire in woodland vegetation. There also were persistent legacy effects of the previous fire regime on some attributes of vegetation structure including forest ground and understorey cover, and woodland midstorey and overstorey cover. For example, woodland midstorey cover was greater on sites with higher fire frequency, irrespective of the severity of the 2003 wildfire. Our results show that even after a large, severe wildfire, underlying fire histories can contribute substantially to variation in vegetation structure. This highlights the importance of ensuring that efforts to reinstate variation in vegetation fire age after large wildfires do not inadvertently reduce variation in vegetation structure generated by the underlying invisible mosaic. PMID- 28851095 TI - Toward the identification of adaptive functioning intervention targets for intellectually-able, transition-aged youth with autism: An examination of caregiver responses on the Vineland-II. AB - : Little is known about specific adaptive functioning impairments in intellectually-able individuals with autism spectrum disorder. In adolescents (n = 22) and young adults (n = 22) matched on composite IQ scores, this study examined profiles of cognitive and adaptive functioning, and caregiver responses on individual Vineland-II items. Adaptive functioning standard scores were significantly lower than IQ scores, and the adult group had significantly lower adaptive functioning standard scores than the adolescent group. Examination of caregiver responses to individual Vineland-II items identified more than 100 potential intervention targets. Differences favoring the adult group were observed on only 16 items across all three adaptive functioning domains, suggesting that little skill development is occurring during the transition to adulthood. Future research will examine the relevance of identified intervention targets to optimal outcomes. Autism Res 2017, 10: 2023-2036. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Adolescents and young adults with autism spectrum disorder (ASD) without intellectual disability demonstrated impaired adaptive functioning skills (i.e., age appropriate skills necessary for independent living). Development of adaptive functioning skills appears to slow with age among individuals without intellectual disability. Findings clarify the specific adaptive functioning skills that transition-aged youth with ASD have difficulty completing independently and will inform the development of interventions to increase the likelihood of independent living in adulthood. PMID- 28851096 TI - Quantifying Macrophages and Hemosiderin in Pediatric Dura Mater. AB - Determining the age of a subdural hematoma at autopsy is of great interest for medicolegal purposes. The appearance of pigment-laden macrophages is often referenced as evidence that the subdural hematoma is 3-4 days old. However, understanding the significance of macrophages and hemosiderin requires understanding the histology of infant dura. Samples of grossly unremarkable dura taken from 17 pediatric autopsies were identified and histologically confirmed to lack subdural neomembrane. CD68 immunostaining and Prussian blue staining was performed. The CD68-positive cells per high-power field were quantified, and the presence of iron-containing cells was recorded. CD68-positive cells were present in all cases, even in the dural border layer. Iron-containing cells were identified in 59% of cases, and in the dural border layer in 29%. Therefore, CD68 positive and iron-containing cells can be present in pediatric dura without neomembrane or macroscopic subdural hemorrhage, and this requires consideration when estimating the age of a subdural hematoma. PMID- 28851097 TI - Synergistic antiviral activity of Sofosbuvir and type-I interferons (alpha and beta) against Zika virus. AB - Zika virus (ZIKV) is transmitted by mosquitoes and causes Dengue-like illness, neurological symptoms such as Guillain-Barre Syndrome and microcephaly in children born to infected pregnant mothers. Recently, the World Health Organization (WHO) declared ZIKV infection as a Global Health Emergency. However, there are no known prophylactic or therapeutic measures against this virus. As a proof of concept toward combination therapeutic strategy against ZIKV, combinations of host-targeted (Interferon-alpha and Interferon-beta) and direct acting (Sofosbuvir) antivirals were evaluated in a hepatic cell line (Huh7) using a Cytoprotection (CP) assay. The combination of these antivirals resulted in synergistic inhibition of ZIKV infection in the in vitro CP assay. Additional testing in a ZIKV yield assay demonstrated that combination treatment of these antivirals conferred >2-log reduction in the release of viral RNA. Measurement of ZIKV proteins in the cells infected with multiple ZIKV strains isolated from different geographical regions (Americas, Asia, and Africa) using an immunofluorescence assay confirmed the effective antiviral activity of this combination against ZIKV. These results demonstrate the in vitro proof of concept (POC) for using a combination approach utilizing the strengths of both virus and host-targeted antivirals. These results suggest the effectiveness of the combination strategy in combating ZIKV, in the in vitro systems. Further evaluation of such combination therapies in vivo might provide an impetus for the development of effective ZIKV therapeutic strategies. PMID- 28851098 TI - Dermoscopy prior to Mohs micrographic surgery does not improve tumour margin assessment and leads to fewer Mohs stages. PMID- 28851099 TI - Relationship of cytokine levels and clinical effect on platelet-rich plasma treated lateral epicondylitis. AB - Lateral epicondylitis (LE) is difficult to manage and can result in significant patient morbidity. Currently, the clinical use of platelet-rich plasma (PRP) for painful tendons has received attention, but its efficacy remains controversial. This study aimed to investigate the clinical effects of PRP and its biological components. A total of 156 patients with LE were randomly divided into group 1, treated with a single injection of 2-ml autologous PRP, and group 2, treated with a control received only physical therapy without injection. Both groups used a tennis elbow strap and performed stretching and strengthening exercises during 24 weeks' follow-up. Pain and functional improvements were assessed using the visual analog scale (VAS), Modified Mayo Clinic Performance Index for the elbow, and magnetic resonance imaging (MRI). White blood cell count, platelet count, and levels of platelet-derived growth factor-AB (PDGF-AB), PDGF-BB, transforming growth factor-beta (TGF-beta), vascular endothelial growth factor, epithelial growth factor, and interleukin-1 beta in PRP were measured and investigated for statistical correlation with the clinical score. At 24 weeks, all pain and functional variables, including VAS score, Mayo Clinic performance scores, and MRI grade, improved significantly in group 1 (p < 0.05). PDGF-AB, PDGF-BB, and TGF-beta levels were more significantly increased in PRP than in whole blood. TGF beta level significantly correlated with Mayo Clinic performance score and MRI grade improvement. Thus, TGF-beta level in PRP is considered to play a pivotal role in tendon healing. These results may contribute to identifying the best protocol for PRP application in tendinopathies. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:913-920, 2018. PMID- 28851102 TI - Simultaneous Occurrence of Quadruple Lewis Acid-Base Interactions between Selenium Atoms in Selenocarbonyl Dimers. AB - High-level quantum chemical calculations are performed to investigate C=Se???Se=C interactions. Bounded structures are found with binding energies between -4 and 7 kJ mol-1 . An energy decomposition analysis shows that dispersion is the more attractive term, and in all cases save one, the electrostatic interaction is attractive despite each selenium atom having a positive sigma-hole at the extension of the C=Se bond. The topological analysis of the molecular electrostatic potential and L(r)=-?2 rho(r) function, and natural bond orbital analysis reveal that these particular Se???Se contacts can be considered to be quadruple Lewis acid-base interactions. PMID- 28851100 TI - Interlaboratory concordance of PD-L1 immunohistochemistry for non-small-cell lung cancer. AB - AIMS: Programmed death ligand 1 (PD-L1) immunohistochemistry has become a mandatory diagnostic test in the treatment of lung cancer. Several research initiatives have started to harmonise the five PD-L1 immunohistochemistry assays that have been used in clinical trials. Here, we report data on interlaboratory and interassay concordance for commercial assays ('assays') and laboratory developed tests (LDTs) at 10 German testing sites. METHODS AND RESULTS: To assess interlaboratory concordance, a tissue microarray containing 21 pulmonary carcinoma specimens was centrally prepared. Pre-cut sections were stained at 10 sites by the use of assays 28-8, 22C3, SP263, and SP142, as well as 11 LDTs. Assay performance was evaluated with a second tissue microarray containing 11 cell lines with defined PD-L1 expression. Quality control was centrally performed by manual and digital analyses. The assays yielded reproducible IHC staining patterns at all sites. In agreement with previous studies, 22C3, 28-8 and SP263 showed similar staining patterns, whereas SP142 was distinct. Among the LDTs, six of 11 protocols showed staining patterns similar to those of assays 22C3 and 28 8. Interlaboratory concordance of tumour cell scoring by use of a six-step system was moderate (Light's kappa = 0.43-0.69), whereas the clinically approved cut offs of >=1% and >=50% showed substantial concordance (kappa = 0.73-0.89). Immune cell scoring by the use of SP142 yielded moderate concordance (kappa = 0.42). CONCLUSIONS: The data confirm the previously described staining patterns of the assays, and show that they can be reproducibly employed at different sites. LDTs with staining results similar to those of the assays are implementable, but have to be carefully validated. PMID- 28851101 TI - Validated Method for Strigolactone Quantification by Ultra High-Performance Liquid Chromatography - Electrospray Ionisation Tandem Mass Spectrometry Using Novel Deuterium Labelled Standards. AB - INTRODUCTION: Strigolactones (SLs) are important plant hormones. They are difficult to analyse because they occur in very small concentrations especially in comparison with other plant hormones and other substances can interfere with their detection. OBJECTIVE: To develop a procedure for the extraction, purification and quantification of SLs from plant roots. METHODOLOGY: Samples were prepared by extraction of plant root tissues with ethyl acetate. Then the extracts were further purified with silica column chromatography. The natural SLs in the final extracts were quantified using novel deuterium labelled SLs. The results of the methodology were compared with those of the procedure of Yoneyama and coworkers. RESULTS: This procedure required about 1-g root samples to detect and quantify simultaneously the SLs (orobanchyl acetate and fabacyl acetate) concentration with high reliability. CONCLUSION: A method was developed for determining endogenous fabacyl acetate and orobanchyl acetate in plant tissue based on novel deuterium labelled standards. A method of orobanchol quantification using a synthetic SL GR24 as internal standard was proposed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28851103 TI - Conjugated Polymer with Intrinsic Alkyne Units for Synergistically Enhanced Raman Imaging in Living Cells. AB - Development of Raman-active materials with enhanced and distinctive Raman vibrations in the Raman-silent region (1800-2800 cm-1 ) is highly required for specific molecular imaging of living cells with high spatial resolution. Herein, water-soluble cationic conjugated polymers (CCPs), poly(phenylene ethynylene) (PPE) derivatives, are explored for use as alkyne-state-dependent Raman probes for living cell imaging due to synergetic enhancement effect of alkyne vibrations in Raman-silent region compared to alkyne-containing small molecules. The enhanced alkyne signals result from the integration of alkyne groups into the rigid backbone and the delocalized pi-conjugated structure. PPE-based conjugated polymer nanoparticles (CPNs) were also prepared as Raman-responsive nanomaterials for distinct imaging application. This work opens a new way into the development of conjugated polymer materials for enhanced Raman imaging. PMID- 28851105 TI - Optimizing a micro-computed tomography-based surrogate measurement of bone implant contact. AB - Histology and backscatter scanning electron microscopy (bSEM) are the current gold standard methods for quantifying bone-implant contact (BIC), but are inherently destructive. Microcomputed tomography (MUCT) is a non-destructive alternative, but attempts to validate MUCT-based assessment of BIC in animal models have produced conflicting results. We previously showed in a rat model using a 1.5 mm diameter titanium implant that the extent of the metal-induced artefact precluded accurate measurement of bone sufficiently close to the interface to assess BIC. Recently introduced commercial laboratory MUCT scanners have smaller voxels and improved imaging capabilities, possibly overcoming this limitation. The goals of the present study were to establish an approach for optimizing MUCT imaging parameters and to validate MUCT-based assessment of BIC. In an empirical parametric study using a 1.5 mm diameter titanium implant, we determined 90 kVp, 88 uA, 1.5 MUm isotropic voxel size, 1600 projections/180 degrees , and 750 ms integration time to be optimal. Using specimens from an in vivo rat experiment, we found significant correlations between bSEM and MUCT for BIC with the manufacturer's automated analysis routine (r = 0.716, p = 0.003) or a line-intercept method (r = 0.797, p = 0.010). Thus, this newer generation scanner's improved imaging capability reduced the extent of the metal-induced artefact zone enough to permit assessment of BIC. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:979-986, 2018. PMID- 28851106 TI - DXAGE: A New Method for Age at Death Estimation Based on Femoral Bone Mineral Density and Artificial Neural Networks. AB - Age at death estimation in adult skeletons is hampered, among others, by the unremarkable correlation of bone estimators with chronological age, implementation of inappropriate statistical techniques, observer error, and skeletal incompleteness or destruction. Therefore, it is beneficial to consider alternative methods to assess age at death in adult skeletons. The decrease in bone mineral density with age was explored to generate a method to assess age at death in human remains. A connectionist computational approach, artificial neural networks, was employed to model femur densitometry data gathered in 100 female individuals from the Coimbra Identified Skeletal Collection. Bone mineral density declines consistently with age and the method performs appropriately, with mean absolute differences between known and predicted age ranging from 9.19 to 13.49 years. The proposed method-DXAGE-was implemented online to streamline age estimation. This preliminary study highlights the value of densitometry to assess age at death in human remains. PMID- 28851107 TI - The clinical features of alcohol use disorders in biological and step-fathers that predict risk for alcohol use disorders in offspring. AB - Given that Alcohol Use Disorder (AUD) is clinically heterogeneous, can we, in a large epidemiological sample using public registries, identify clinical features of AUD cases in biological and step-fathers that index, respectively, genetic and familial-environmental risk for AUD in their offspring? From all father-offspring pairs where the father had AUD and the offspring was born 1960-1990, we identified not-lived-with (NLW) biological fathers (n = 38,376) and step-father pairs (n = 9,711). The relationship between clinical and historical features of the father's AUD and risk for AUD in offspring was assessed by linear hazard regression. Age at first registration for AUD and recurrence of AUD registration were significantly stronger predictors of risk for AUD in the offspring of NLW fathers than in step-fathers. By contrast, number of AUD registrations in NLW fathers and step-fathers were equally predictive of risk for AUD in offspring. However, while the number of step-father AUD registrations that occurred when he was living them with significantly predicted risk for AUD in his step-children, the number of registrations that occurred when not residing with his step children was unassociated with their AUD risk. In an epidemiological sample, we could meaningfully differentiate between features of AUD in fathers that indexed genetic risk which was transmitted to biological offspring (early age at onset and recurrence) versus indexed environmental risk (registrations while rearing) which increased risk in step-children. PMID- 28851108 TI - The identification and analytical characterization of 2,2'-difluorofentanyl. AB - New psychoactive substances (NPS) have expanded their distribution and become widely available in the global market in recent years. The illicit use of fentanyl and its analogs has become an important worldwide concern linked to their high potency and risk of fatal overdose. This study describes the analytical characterization of a new fentanyl derivative N-(1-(2-fluorophenethyl) 4-piperidinyl)-N-(2-fluorophenyl)propionamide (2,2'-difluorofentanyl). Identification was based on ultra-high-performance liquid chromatography quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS), gas chromatography mass spectrometry (GC-MS), Fourier transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. To our knowledge, this study is the first to report on analytical data for this compound. The most abundant fragment ion in the electrospray ionization (ESI) mass spectrum under collision induced dissociation (CID) mode was formed by the cleavage between the piperidine ring and the N-phenyl-amide moiety of the protonated molecule. Two diagnostic ions in the electron ionization (EI) mass spectrum were formed by the loss of a tropylium ion (M-91), and by the degradation of the piperidine ring and dissociate of the COC2 H5 moiety altogether, respectively. PMID- 28851104 TI - A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains. AB - This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis. PMID- 28851110 TI - The visiting speaker: Some tips and some traps. PMID- 28851109 TI - Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS). AB - AIMS: There is a large population of people with type 2 diabetes mellitus (T2DM) who are Muslim and fast during Ramadan. Changes in the pattern and amount of meal and fluid intake during Ramadan, in addition to the long fasting hours, may increase the risk of hypoglycaemia, hyperglycaemia, and dehydration. The Canagliflozin in Ramadan Tolerance Observational Study (CRATOS) evaluated the tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, compared with sulphonylureas among patients with T2DM who fast during Ramadan. METHODS: This non-randomised, parallel-cohort, prospective, comparative, observational study was conducted in the Middle East during Ramadan and enrolled patients who were taking canagliflozin (n=162) or any sulphonylurea (n=159) added to metformin+/-dipeptidyl peptidase-4 inhibitor. The proportion of patients who experienced hypoglycaemia events was assessed as the primary end-point. Between cohort comparisons were adjusted using propensity score analysis. RESULTS: During Ramadan, fewer patients experienced symptomatic hypoglycaemia with canagliflozin vs sulphonylurea (adjusted odds ratio: 0.273 [95% CI: 0.104, 0.719]). Of hypoglycaemia events for which blood glucose was measured, two of six with canagliflozin and 27 of 37 with sulphonylurea were confirmed by blood glucose <3.9 mmol/L. More patients treated with canagliflozin experienced volume depletion events compared with sulphonylurea (adjusted odds ratio: 3.5 [95% CI: 1.3, 9.2]). Missed fasting days were few and medication adherence was high in both groups. No patients treated with canagliflozin and 9.4% treated with sulphonylurea adjusted their medication dose near the beginning of Ramadan. Both treatments were generally well tolerated, with low rates of adverse events and no serious adverse events in either group. CONCLUSIONS: Overall, these findings support the use of canagliflozin for the treatment of adults with T2DM who fast during Ramadan. CLINICALTRIALS. GOV IDENTIFIER: NCT02737657. PMID- 28851111 TI - CO2 Activation over Catalytic Surfaces. AB - This article describes the main strategies to activate and convert carbon dioxide (CO2 ) into valuable chemicals over catalytic surfaces. Coherent elements such as common intermediates are identified in the different strategies and concisely discussed based on the reactivity of CO2 with the aim to understand the decisive factors for selective and efficient CO2 conversion. PMID- 28851113 TI - Subjective Social Standing and Conflict Tactics Among Young Kenyan Men. AB - Efforts to reduce intimate partner violence in sub-Saharan Africa generally approach the issue through the lens of women's empowerment. These efforts include foci on women's relative power in the relationship, educational background, and earning potential. The social status of men has largely been ignored, reducing the potential to involve them in efforts to demote intimate partner violence. In this study we consider whether a man's perceived social status predicts conflict tactics, and whether these tactics are mediated by loneliness and collective self esteem from a community-based sample in semi-rural Kenya (n = 263). We find that men who reported lower perceived social status also reported significantly more frequent violent conflicts with their intimate partners. This association was significantly, and completely, mediated by lower collective self-esteem and higher loneliness. There was no direct association between subjective social status and negotiation-based conflict tactics, although there was an indirect association. Men with higher perceived social status reported higher collective self-esteem, and men with higher collective self-esteem reported more negotiation based conflict tactics. These findings inform efforts to reduce intimate partner violence by involving men, showing potential to reduce violence by building self esteem among men-particularly those with lower perceived social status. PMID- 28851112 TI - Dynamic imaging demonstrates that pulsed electromagnetic fields (PEMF) suppress IL-6 transcription in bovine nucleus pulposus cells. AB - Inflammatory cytokines play a dominant role in the pathogenesis of disc degeneration. Pulsed electromagnetic fields (PEMF) are noninvasive biophysical stimulus that has been used extensively in the orthopaedic field for many years. However, the specific cellular responses and mechanisms involved are still unclear. The objective of this study was to assess the time-dependent PEMF effects on pro-inflammatory factor IL-6 expression in disc nucleus pulposus cells using a novel green fluorescence protein (GFP) reporter system. An MS2-tagged GFP reporter system driven by IL-6 promoter was constructed to visualize PEMF treatment effect on IL-6 transcription in single living cells. IL-6-MS2 reporter labeled cells were treated with IL-1alpha to mimic the in situ inflammatory environment of degenerative disc while simultaneously exposed to PEMF continuously for 4 h. Time-lapse imaging was recorded using a confocal microscope to track dynamic IL-6 transcription activity that was demonstrated by GFP. Finally, real-time RT-PCR was performed to confirm the imaging data. Live cell imaging demonstrated that pro-inflammatory factor IL-1alpha significantly promoted IL-6 transcription over time as compared with DMEM basal medium condition. Imaging and PCR data demonstrated that the inductive effect of IL 1alpha on IL-6 expression could be significantly inhibited by PEMF treatment in a time-dependent manner (early as 2 h of stimulus initiation). Our data suggest that PEMF may have a role in the clinical management of patients with chronic low back pain. Furthermore, this study shows that the MS2-tagged GFP reporter system is a useful tool for visualizing the dynamic events of mechanobiology in musculoskeletal research. (c) 2017 The Authors. Journal of Orthopaedic Research(r) Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:778-787, 2018. PMID- 28851114 TI - Altered attentional processing in male and female rats in a prenatal valproic acid exposure model of autism spectrum disorder. AB - : Attention is foundational to efficient perception and optimal goal driven behavior. Intact attentional processing is crucial for the development of social and communication skills. Deficits in attention are therefore likely contributors to the core pathophysiology of autism spectrum disorder (ASD). Clinical evidence in ASD is suggestive of impairments in attention and its control, but the underlying mechanisms remain elusive. We examined sustained, spatially divided attention in a prenatal valproic acid (VPA) model of ASD using the 5-choice serial reaction time task (5-CSRTT). As compared to controls, male and female VPA rats had progressively lower accuracy and higher omissions with increasing attentional demands during 5-CSRTT training, and showed further performance decrements when subjected to parametric task manipulations. It is noteworthy that although VPA exposure induced attentional deficits in both sexes, there were task parameter specific sex differences. Importantly, we did not find evidence of impulsivity or motivational deficits in VPA rats but we did find reduced social preference, as well as sensorimotor deficits that suggest pre-attentional information processing impairments. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. To the best of our knowledge, this is the first study examining attentional functions in a VPA model. Our work underscores the need for studying both sexes in ASD animal models and validates the use of the VPA model in the quest for mechanistic understanding of aberrant attentional functions and for evaluating suitable therapeutic targets. Autism Res 2017, 10: 1929-1944. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied rats prenatally exposed to valproic acid (VPA), an established rodent model of autism. Both male and female VPA rats had a range of attentional impairments with sex-specific characteristics. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. Our work validates the use of the VPA model in the quest for evaluating suitable therapeutic targets for improving attentional performance. PMID- 28851115 TI - Chronic hepatitis B virus infection and preterm labor(birth) in pregnant women-an updated systematic review and meta-analysis. AB - We aimed to explore whether maternal chronic hepatitis B virus (HBV) infection certainly affects preterm labor (birth) in pregnant women. Four databases were systematically searched up to May 31, 2017, without language restriction. Any study was included if it clearly defined exposure to chronic HBV infection, reported risk of preterm labor or birth in pregnant women, and reported relative risks (RRs) or odds ratios (ORs) or provided data for estimation. RRs (or ORs) with 95% confidence intervals were pooled using random-effects models. Statistical heterogeneity was assessed with Cochran's Q statistic and I2 statistic. Twenty-two observational studies involving 6 141 146 pregnant women (three prospective cohort studies, n = 1 116 799; 15 retrospective cohort studies, n = 5 022 513 and four case-control studies, n = 1834) were included. The risk of preterm labor was significantly intensified with chronic HBV infection compared with uninfected women, with substantial heterogeneity. Chronic HBV infection was also significantly associated with a 16% increase in the risk of preterm birth, with substantial heterogeneity. The risk of preterm birth significantly increased by 21% in HBsAg+/HBeAg+ pregnant women compared with uninfected pregnant women. Chronic HBV infection intensifies the risk of preterm labor and birth in pregnant women, but this conclusion should be interpreted with caution given the possibility of residual confounding and be confirmed by well designed studies in the future. PMID- 28851117 TI - Median canaliform dystrophy of Heller after cryotherapy. AB - Cryotherapy, widely used in the treatment of common warts, can cause long-term side effects when used in the treatment of warts near the nail bed. Here we present the case of a 11-year-old girl who developed canaliform dystrophy and long-term hypopigmentation following cryotherapy of warts on the proximal nail folds. PMID- 28851116 TI - A Comprehensive Study of the Interaction between Peptidoglycan Fragments and the Extracellular Domain of Mycobacterium tuberculosis Ser/Thr Kinase PknB. AB - The Mycobacterium tuberculosis Ser/Thr kinase PknB is implicated in the regulation of bacterial cell growth and cell division. The intracellular kinase function of PknB is thought to be triggered by peptidoglycan (PGN) fragments that are recognized by the extracytoplasmic domain of PknB. The PGN in the cell wall of M. tuberculosis has several unusual modifications, including the presence of N glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues and amidation of d-Glu in the peptide chains. Using synthetic PGN fragments incorporating these diverse PGN structures, we analyzed their binding characters through biolayer interferometry (BLI), NMR spectroscopy, and native mass spectrometry (nMS) techniques. The results of BLI showed that muropeptides containing 1,6-anhydro-MurNAc and longer glycan chains exhibited higher binding potency and that the fourth amino acid of the peptide stem, d-Ala, was crucial for protein recognition. Saturation transfer difference (STD) NMR spectroscopy indicated the major involvement of the stem peptide region in the PASTA-PGN fragment binding. nMS suggested that the binding stoichiometry was 1:1. The data provide the first molecular basis for the specific interaction of PGN with PknB and firmly establish PGNs as the effective ligands of PknB. PMID- 28851118 TI - Detection of Saffold viruses from children with acute respiratory infections in Yamagata, Japan, between 2008 and 2015. AB - Although Saffold virus (SAFV) was reported as a novel human cardiovirus in 2007, no causative association between SAFV and clinical disease has been proven and the longitudinal epidemiology of SAFVs is not available. To establish the relationship between SAFVs and acute respiratory infections (ARIs) and to clarify the longitudinal epidemiology of SAFVs, 7258 nasopharyngeal specimens were collected from children with ARIs in Yamagata, Japan between 2008 and 2015. The specimens were inoculated on a microplate including six cell lines as part of routine surveillance, and molecular screening was performed for SAFVs using a reverse transcription (RT)-PCR method. Throughout the study period, 95 (1.3%) SAFV genotype 2 (SAFV2), and 28 (0.4%) SAFV3 were detected, mainly between September and November. There were two outbreaks of SAFV2 in 2009 and 2013, and one outbreak of SAFV3 in 2012 and the positive rates during these outbreaks were 12.1% (53/439), 11% (35/319), and 4.4% (20/453), respectively. Sixty-three SAFV2 and 28 SAFV3 strains were detected as a single virus from children with ARIs such as pharyngitis, herpangina, and tonsillitis. These results suggested that SAFV2 and SAFV3 are possible causative agents of ARIs among children and their infections occur mainly in the autumn season in Japan. PMID- 28851119 TI - Oxygen needs during resuscitation and surfactant to achieve stabilisation were independent risks factors for pulmonary interstitial emphysema in preterm infants. AB - AIM: Pulmonary interstitial emphysema is a severe complication of mechanical ventilation in preterm infants that leads to air leakage and, or, chronic lung disease. We determined the associated risk factors. METHODS: This was a retrospective case-control study from 2005 to 2014 at a regional referral centre in Valencia, Spain. The cases were 54 preterm infants up to 30 weeks' gestation and, or, born weighing less than 1500 g, who were diagnosed with pulmonary interstitial emphysema (PIE). The 54 controls were preterm infants without PIE matched by gestational age. Univariate analysis and multivariate analysis were performed to assess the independent predicting factors. RESULTS: Infants with PIE had been resuscitated with higher mean fractional inspired oxygen concentration (FiO2 ) (p = 0.008), had received higher peak mean positive end expiratory pressure (p = 0.00) and higher mean airway pressure (p = 0.026) 24 hours before diagnosis. PIE patients also received more surfactant (p = 0.00) and had higher mortality (p = 0.034). A Cox regression model identified that independent risk factors were the total amount of surfactant administered and the mean FiO2 during the 24 hours before diagnosis. CONCLUSION: Independent risk factors for pulmonary interstitial emphysema in preterm infants were higher oxygen during resuscitation and a higher need for surfactant and ventilatory pressures before diagnosis. PMID- 28851120 TI - Evaluation of discharge documentation after hospitalization for stroke patients discharged home in Australia: A cross-sectional, pilot study. AB - In this cross-sectional study, we evaluated the quality of discharge documentation for stroke patients discharged home. Participants were stroke patients discharged from a regional tertiary acute and rehabilitation hospital in Australia from 2014 to 2015. Compliance with expected discharge documentation and its relationship with readmission was measured using an audit instrument for stroke patients (n = 54), and a post-discharge survey of carers was conducted. There were deficits in the documentation of the mechanism of stroke (70%), functional assessments (58%), pending test results (39%), types of support services required after discharge (35%), and patient/carer meetings with the multi-disciplinary stroke team (20%). Readmission was associated with lower compliance scores for information provided to patients or their carer. The survey results suggested that carer burden was high for carers of stroke patients discharged home. Documentation of carer/family meetings with the stroke team, functional assessments, medications, and adequate support services needs to be improved. General practitioners and carers need this information, so that they can address the post-discharge needs of these vulnerable patients. PMID- 28851121 TI - The effects of nutritional guideline implementation on nursing home staff performance: a controlled trial. AB - RATIONALE: Suboptimal nutritional practices in elderly care settings may be resolved by an efficient introduction of nutritional guidelines. AIMS: To compare two different implementation strategies, external facilitation (EF) and educational outreach visits (EOVs), when introducing nutritional guidelines in nursing homes (NHs), and study the impact on staff performance. METHODOLOGICAL DESIGN: A quasi-experimental study with baseline and follow-up measurements. OUTCOME MEASURES: The primary outcome was staff performance as a function of mealtime ambience and food service routines. INTERVENTIONS/RESEARCH METHODS: The EF strategy was a 1-year, multifaceted intervention that included support, guidance, practice audit and feedback in two NH units. The EOV strategy comprised one-three-hour lecture about nutritional guidelines in two other NH units. Both strategies were targeted to selected NH teams, which consisted of a unit manager, a nurse and 5-10 care staff. Mealtime ambience was evaluated by 47 observations using a structured mealtime instrument. Food service routines were evaluated by 109 food records performed by the staff. RESULTS: Mealtime ambience was more strongly improved in the EF group than in the EOV group after the implementation. Factors improved were laying a table (p = 0.03), offering a choice of beverage (p = 0.02), the serving of the meal (p = 0.02), interactions between staff and residents (p = 0.02) and less noise from the kitchen (p = 0.01). Food service routines remained unchanged in both groups. CONCLUSIONS: An EF strategy that included guidance, audit and feedback improved mealtime ambience when nutritional guidelines were introduced in a nursing home setting, whereas food service routines were unchanged by the EF strategy. PMID- 28851122 TI - Echovirus plays major roles in the natural recombination of Coxsackievirus B3. AB - Coxsakievirus B3 (CVB3) is a member of enterovirus B (EVB) group, which can cause serious heart diseases such as viral myocarditis. In order to analyze the evolution of CVB3, we performed a recombination analysis of all viral genomes of enterovirus B, and found that there were 19 putative recombination events that produced CVB3. A total of 11 serotypes were found to be involved in the generation of CVB3 progeny virus. These recombination events involved echovirus, EcoV (which includes EcoV6, EcoV9, EcoV14, EcoV15, EcoV17, EcoV21, EcoV24, and EcoV25), CVB4, CVB5, and EVB81, as major or minor parents. The most active, EcoV, which was involved in the 14 of 19 recombination events, acts as one of the parental viruses for CVB3 strains among molecular evolution and recombination events in circulating CVB3. Our study indicates that, EcoV plays major roles in CVB3 recombination, and is involved in the production of 11 new CVB3 recombinant strains. PMID- 28851123 TI - Factors affecting trap catch in pheromone-based monitoring of saddle gall midge Haplodiplosis marginata (Diptera: Cecidomyiidae). AB - BACKGROUND: The saddle gall midge, Haplodiplosis marginata (von Roser) (Diptera: Cecidomyiidae), is a pest of cereal crops in Europe. Outbreaks are difficult to predict and effective monitoring tools are required to ensure the effectiveness of pest management options. The female sex pheromone (R)-2-nonyl butyrate provides the basis of a highly effective lure for this insect. Here, we demonstrate how the success of this lure can be influenced by parameters such as trap location, lure age, and interference between traps fitted with these lures. RESULTS: A pheromone lure containing (R)-2-nonyl butyrate attracted male midges for at least 9 weeks under field conditions. Pheromone-baited traps performed best when situated away from field margins and below the height of the crop. Interference between nearby traps was evident at distances <20 m. CONCLUSION: The results presented here offer new insights into the behavioural responses of male H. marginata to the female sex pheromone and provide practical recommendations for the use of H. marginata pheromone traps in the field. (c) 2017 Society of Chemical Industry. PMID- 28851124 TI - MRI proton density fat fraction is robust across the biologically plausible range of triglyceride spectra in adults with nonalcoholic steatohepatitis. AB - BACKGROUND: Proton density fat fraction (PDFF) estimation requires spectral modeling of the hepatic triglyceride (TG) signal. Deviations in the TG spectrum may occur, leading to bias in PDFF quantification. PURPOSE: To investigate the effects of varying six-peak TG spectral models on PDFF estimation bias. STUDY TYPE: Retrospective secondary analysis of prospectively acquired clinical research data. POPULATION: Forty-four adults with biopsy-confirmed nonalcoholic steatohepatitis. FIELD STRENGTH/SEQUENCE: Confounder-corrected chemical-shift encoded 3T MRI (using a 2D multiecho gradient-recalled echo technique with magnitude reconstruction) and MR spectroscopy. ASSESSMENT: In each patient, 61 pairs of colocalized MRI-PDFF and MRS-PDFF values were estimated: one pair used the standard six-peak spectral model, the other 60 were six-peak variants calculated by adjusting spectral model parameters over their biologically plausible ranges. MRI-PDFF values calculated using each variant model and the standard model were compared, and the agreement between MRI-PDFF and MRS-PDFF was assessed. STATISTICAL TESTS: MRS-PDFF and MRI-PDFF were summarized descriptively. Bland-Altman (BA) analyses were performed between PDFF values calculated using each variant model and the standard model. Linear regressions were performed between BA biases and mean PDFF values for each variant model, and between MRI PDFF and MRS-PDFF. RESULTS: Using the standard model, mean MRS-PDFF of the study population was 17.9 +/- 8.0% (range: 4.1-34.3%). The difference between the highest and lowest mean variant MRI-PDFF values was 1.5%. Relative to the standard model, the model with the greatest absolute BA bias overestimated PDFF by 1.2%. Bias increased with increasing PDFF (P < 0.0001 for 59 of the 60 variant models). MRI-PDFF and MRS-PDFF agreed closely for all variant models (R2 = 0.980, P < 0.0001). DATA CONCLUSION: Over a wide range of hepatic fat content, PDFF estimation is robust across the biologically plausible range of TG spectra. Although absolute estimation bias increased with higher PDFF, its magnitude was small and unlikely to be clinically meaningful. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:995-1002. PMID- 28851125 TI - Preference-based valuation of treatment attributes in haemophilia A using web survey. AB - INTRODUCTION: Clinical trials have shown promising results for extended half-life factor VIII concentrates but little is known about individuals' valuation of haemophilia treatment attributes. AIM: To assess patient/caregiver and population valuation of treatment attributes of prophylactic regimens for people with severe haemophilia A. METHODS: Members >=16 years of the Swedish Haemophilia Society (FBIS) and of a web-panel representative of the Swedish population were invited to participate in a web-survey investigating preferences for haemophilia treatment attributes using the Time Trade-Off methodology which ranks health states on a scale 0 (dead) to 1 (full health). All respondents assessed the same four treatment scenarios for severe haemophilia A, each described by three stylized attributes: injection interval (every 2nd or 5th day); participation in physical activity (Y/N); annual risk of bleed (1-2 or 5-6 bleeds). RESULTS: The survey had 1657 respondents (68% complete responses; 184/1233 from FBIS/web-panel gave informed consent; mean age 52 years, 51% men). Respondents from FBIS and from the web-panel had the same preference ranking of the four treatment scenarios, but members of FBIS consistently rated significantly higher health utilities; range 0.67-0.73 vs 0.54-0.60. Participation in physical activity implied +0.023 (95% confidence interval 0.015-0.030); a longer injection interval implied +0.038 (0.03; 0.45); and fewer bleeds implied +0.022 (0.015-0.029) utility points. CONCLUSIONS: Patient/caregiver and population preferences indicate that treatment attributes such as frequency of injections and the possibility of participating in physical activity are important attributes impacting quality of life in addition to the control and prevention of bleeding episodes. PMID- 28851126 TI - Occult cancer screening in patients with venous thromboembolism: guidance from the SSC of the ISTH. PMID- 28851127 TI - Topological Defects in Hyperbranched Glycopolymers Enhance Binding to Lectins. AB - Central scaffold topology and carbohydrate density are important features in determining the binding mechanism and potency of synthetic multivalent of poly- versus monodisperse carbohydrate systems against a model plant toxin (Ricinus communis agglutinin (RCA120 )). Lower densities of protein receptors favour the use of heterogeneous, polydisperse glycoconjugate presentations, as determined by surface plasmon resonance and dynamic light scattering. PMID- 28851128 TI - Current status, pitfalls and future directions in the diagnosis and therapy of lymphatic malformation. AB - Lymphatic malformations are complex congenital vascular lesions composed of dilated, abnormal lymphatic channels of varying size that can result in significant esthetic and physical impairment due to relentless growth. Lymphatic malformations comprised of micro-lymphatic channels (microcystic) integrate and infiltrate normal soft tissue, leading to a locally invasive mass. Ultrasonography and magnetic resonance imaging assist in the diagnosis but are unable to detect microvasculature present in microcystic lymphatic malformations. In this review, we examine existing tools and elaborate on alternative diagnostic methods in assessing lymphatic malformations. In particular, photoacoustics, low toxicity nanoparticles and optical clearing can overcome existing challenges in the examination of lymphatic channels in vivo. In combination with photothermal scanning and flow cytometry, Photoacoustic techniques may provide a versatile tool for lymphatic-related clinical applications, potentially leading to a single diagnostic and therapeutic platform to overcome limitations in current imaging techniques and permit targeted theranostics of microcystic lymphatic malformations. PMID- 28851130 TI - In reply to: Lawless et al. Stalk versus base invasion in pT1 papillary cancers of the bladder: improved substaging system predicting the risk of progression. PMID- 28851129 TI - Congenital neurodevelopmental anomalies in pediatric and young adult cancer. AB - Congenital anomalies that are diagnosed in at least 120,000 US infants every year are the leading cause of infant death and contribute to disability and pediatric hospitalizations. Several large-scale epidemiologic studies have provided substantial evidence of an association between congenital anomalies and cancer risk in children, suggesting potential underlying cancer-predisposing conditions and the involvement of developmental genetic pathways. Electronic medical records from 1,107 pediatric, adolescent, and young adult oncology patients were reviewed. The observed number (O) of congenital anomalies among children with a specific pediatric cancer subtype was compared to the expected number (E) of anomalies based on the frequency of congenital anomalies in the entire study population. The O/E ratios were tested for significance using Fisher's exact test. The Kaplan-Meier method was used to compare overall and neurological malignancy survival rates following tumor diagnosis. Thirteen percent of patients had a congenital anomaly diagnosis prior to their cancer diagnosis. When stratified by congenital anomaly subtype, there was an excess of neurological anomalies among children with central nervous system tumors (O/E = 1.56, 95%CI 1.13-2.09). Male pediatric cancer patients were more likely than females to have a congenital anomaly, particularly those <5 years of age (O/E 1.35, 95%CI 0.97 1.82). Our study provides additional insight into the association between specific congenital anomaly types and pediatric cancer development. Moreover, it may help to inform the development of new screening policies and support hypothesis-driven research investigating mechanisms underlying tumor predisposition in children with congenital anomalies. PMID- 28851131 TI - Graded isavuconazole introduction in a patient with voriconazole allergy. AB - Triazole antifungal drugs may rarely cause serious allergic reactions including angioedema. No standardized tests are available to predict cross-reactivity within the azole class and little guiding information exists on whether to change therapy within the class or to another class after a serious allergic reaction. Herein we report the first successful use, to our knowledge, of graded isavuconazole introduction for treatment of aspergillosis in a liver transplant recipient with severe voriconazole allergy. PMID- 28851132 TI - Fall prevention by nursing assistants among community-living elderly people. A randomised controlled trial. AB - Falls among elderly are a major public health issue in Sweden. The aim was to determine whether nursing assistants can prevent falls by supervising community living elderly individuals with a history of falling in performing individually designed home exercise programmes. A randomised controlled trial was performed in Sweden, in eight municipalities in the county of Orebro, during 2007-2009. Community-living persons 65 years or older having experienced at least one fall during the last 12 months were included. The intervention group consisted of 76 participants, and there were 72 in the control group. The interventions were free of charge and were shared between a physiotherapist and a nursing assistant. The former designed a programme aiming to improve balance, leg strength and walking ability. The nursing assistant supervised the performance of activities during eight home visits during a 5-month intervention period. The measures and instruments used were health-related quality of life (SF-36), activity of daily living (ADL-staircase), balance, (Falls Efficacy Scale, and Berg Balance Scale), walking ability (Timed Up and Go and the 3-metre walking test), leg strength, (chair stand test). All participants were asked to keep a structured calendar of their physical exercise, walks and occurrence of falls during their 12-month study period. Hospital healthcare consumption data were collected. Although the 5 month intervention did not significantly decrease the risk for days with falls, RR 1.10 (95% CI 0.58, 2.07), p = 0.77, significant changes in favour of the intervention group were noted for balance (p = 0.03), ADL (p = 0.035), bodily pain (p = 0.003) and reported health transition over time (p = 0.008) as well as less hospital care due to fractures (p = 0.025). Additional studies with more participants are needed to establish whether or not falls can be significantly prevented with this model which is workable in home-based fall prevention. PMID- 28851133 TI - Patient powered prophylaxis: A 12-month study of individualized prophylaxis in adults with severe haemophilia A. AB - INTRODUCTION: Adults with severe haemophilia A (SHA) may experience breakthrough bleeds despite standard weight-based FVIII prophylaxis three times weekly. Individualized prophylaxis has evolved to optimize patient outcomes. AIMS: This study aimed to evaluate the impact of a standardized approach to individualized prophylaxis on annualized bleeding rates (ABR), factor utilization, physical activity and quality of life in adults with SHA. METHODS: In this prospective cohort study, patients with baseline FVIII:C <2% and ABR >3 on weight-based prophylaxis received a standardized approach to individualized prophylaxis. Changes in ABR, annualized FVIII consumption and adherence from the 12-month prestudy and 12-month intervention period were compared. Changes in Haemo-QoL-A total score, Physical Functioning (PF) subscale and physical activity level measured by accelerometry were also examined. RESULTS: Eighteen patients participated (median age 26 years). Individualized prophylaxis decreased total bleeds in the population by 69% and traumatic bleeds by 73%. The median ABR decreased from 7.5 to 2 (P<.001). Annualized factor consumption increased by 7.3%, as a result of 66% reduction in factor utilization for treatment of bleeds and 25% increase in factor utilization for prophylaxis. Adherence scores for frequency and dosing did not change. There was a significant increase in the Haemo-QoL-A total score (P=.02) and PF score (P=.01) from baseline to 4 months but no change in physical activity. CONCLUSION: Patients with SHA who switched from standard to individualized prophylaxis show reduced ABR and increased FVIII consumption, and also improved their health-related quality of life. The mechanism is independent of adherence to prescribed prophylactic regimen. PMID- 28851134 TI - Convolutional neural network-based malaria diagnosis from focus stack of blood smear images acquired using custom-built slide scanner. AB - The present paper introduces a focus stacking-based approach for automated quantitative detection of Plasmodium falciparum malaria from blood smear. For the detection, a custom designed convolutional neural network (CNN) operating on focus stack of images is used. The cell counting problem is addressed as the segmentation problem and we propose a 2-level segmentation strategy. Use of CNN operating on focus stack for the detection of malaria is first of its kind, and it not only improved the detection accuracy (both in terms of sensitivity [97.06%] and specificity [98.50%]) but also favored the processing on cell patches and avoided the need for hand-engineered features. The slide images are acquired with a custom-built portable slide scanner made from low-cost, off-the shelf components and is suitable for point-of-care diagnostics. The proposed approach of employing sophisticated algorithmic processing together with inexpensive instrumentation can potentially benefit clinicians to enable malaria diagnosis. PMID- 28851135 TI - Children who commute to school unaccompanied have greater autonomy and perceptions of safety. AB - AIM: We explored the rates of children who actively commuted to school, both accompanied and unaccompanied, and identified their safety perceptions. METHODS: This cross-sectional study focused on 745 children, aged 6-12 years, from public schools in the Spanish Granada region. They completed a questionnaire, providing personal data, their school grade, safety perceptions, whether they were accompanied to school and how they travelled to school. We analysed how active commuters were accompanied to school by age group and assessed the associations between safety perceptions and whether or not they were accompanied. RESULTS: Children aged 10-12 years were more likely to travel to school unaccompanied, more likely to travel actively and had better safety perceptions than younger children. We also found differences in how active commuters between 10 and 12 years and children aged 6-7 and 8-9 years (all p < 0.001) were accompanied to school. Children aged 10-12 years who actively commuted unaccompanied had a better understanding of safety issues than accompanied children (p < 0.010). CONCLUSION: Older children who actively commuted to school unaccompanied had better safety perceptions than other children in this sample of children aged 6 12. PMID- 28851136 TI - Effect of the combined application of microencapsulated synthetic oviposition pheromone (MSP) with different larvicidal agents on the oviposition of Culex pipiens biotype molestus. AB - BACKGROUND: Attract-and-kill strategies, in which a behavior-modifying stimulus (e.g. a pheromone) is integrated with a pest control agent, have lately attracted increased interest for mosquito control. Previously, it was demonstrated that the polyurea microencapsulated synthetic oviposition pheromone 6-acetoxy-5 hexadecanolide (MSP) was sufficiently attractive to gravid females of Culex pipiens L. biotype molestus Forskal (Diptera: Culicidae) for a period of 40 days. Furthermore, it was shown that MSP could be effectively combined with the organophosphate temephos to achieve efficient mosquito control. In the present study, the effect of the combined application of MSP with commonly used larvicides on the oviposition response of Cx. p. biotype molestus females over time was investigated in two-choice oviposition bioassays. As larvicides, the insect growth regulator diflubenzuron and the bacterial insecticide spinosad were evaluated at their lowest recommended label dose, whereas temephos was used as a control. RESULTS: When MSP was applied in combination with diflubenzuron, the attractancy of MSP to gravid females was in all cases negatively affected, as fewer egg rafts were laid in pots treated with MSP and diflubenzuron compared with MSP alone. Spinosad did not reduce, but rather increased, the attractive effect of the oviposition pheromone at the beginning of the bioassay (at 2 days of ageing) when co-applied; however, the observed attractive effect was significantly reduced after 7 days of ageing and remained stable at the same level until the termination of the bioassay. Finally, the oviposition pattern of egg rafts laid on the pot with MSP and temephos was similar to that of egg rafts laid on the pot with MSP alone, showing that temephos did not significantly affect MSP activity. CONCLUSION: The results of the present study highlight the effects of the combined application of MSP with spinosad and diflubenzuron on the oviposition of gravid Cx. p. biotype molestus females, which in most cases eliminated the attractive effect of MSP. (c) 2017 Society of Chemical Industry. PMID- 28851137 TI - Negative affect and binge eating: Reconciling differences between two analytic approaches in ecological momentary assessment research. AB - OBJECTIVE: Ecological momentary assessment (EMA) research has produced contradictory findings regarding the trajectory of negative affect after binge eating episodes. Given the clinical implications, the objective of the current study was to reconcile these inconsistencies by comparing the two most commonly employed statistical approaches used to analyze these data. METHOD: Data from two EMA studies were analyzed separately. Study 1 included 118 adult females with full- or subthreshold DSM-IV anorexia nervosa. Study 2 included 131 adult females with full-threshold DSM-IV bulimia nervosa. For each dataset, the single most proximal negative affect ratings preceding and following a binge-eating episode were compared. The times at which these ratings were made, relative to binge eating episodes, were also compared. RESULTS: The results indicate that the average proximal pre-binge ratings of negative affect were significantly higher than the average proximal post-binge ratings of negative affect. However, results also indicate that the average proximal post-binge ratings of negative affect were made significantly closer in time to the binge-eating episodes (~20 min post binge) than the average proximal pre-binge ratings of negative affect (~2.5 hr pre-binge). A graphical representation of the results demonstrates that the average proximal pre-binge and post-binge ratings map closely onto the results of previous studies. DISCUSSION: These data provide one possible explanation for the inconsistent findings regarding the trajectory of negative affect after binge eating. Moreover, they suggest that the findings from previous studies are not necessarily contradictory, but may be complementary, and appear to bolster support for the affect regulation model of binge eating. PMID- 28851138 TI - SIRT1 mediates salidroside-elicited protective effects against MPP+ -induced apoptosis and oxidative stress in SH-SY5Y cells: involvement in suppressing MAPK pathways. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease, leading to tremor, rigidity, bradykinesia, and gait impairment. Salidroside has been reported to exhibit antioxidative and neuroprotective properties in PD. However, the underlying neuroprotective mechanisms effects of salidroside are poorly understood. Recently, a growing body of evidences suggest that silent information regulator 1 (SIRT1) plays important roles in the pathophysiology of PD. Hence, the present study investigated the roles of SIRT1 in neuroprotective effect of salidroside against N-methyl-4-phenylpyridinium (MPP+ )-induced SH-SY5Y cell injury. Our findings revealed that salidroside attenuates MPP+ -induced neurotoxicity as evidenced by the increase in cell viability, and the decreases in the caspase-3 activity and apoptosis ratio. Simultaneously, salidroside pretreatment remarkably increased SIRT1 activity, SIRT1 mRNA and protein levels in MPP+ -treated SH-SY5Y cell. However, sirtinol, a SIRT1 activation inhibitor, significantly blocked the inhibitory effects of salidroside on MPP+ -induced cytotoxicity and apoptosis. In addition, salidroside abolished MPP+ -induced the production of reactive oxygen species (ROS), the up-regulation of NADPH oxidase 2 (NOX2) expression, the down-regulations of superoxide dismutase (SOD) activity and glutathione (GSH) level in SH-SY5Y cells, while these effects were also blocked by sirtinol. Finally, we found that the inhibition of salidroside on MPP+ -induced phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) were also reversed by sirtinol in SH-SY5Y cells. Taken together, these results indicated that SIRT1 contributes to the neuroprotection of salidroside against MPP+ -induced apoptosis and oxidative stress, in part through suppressing of mitogen-activated protein kinase (MAPK) pathways. PMID- 28851139 TI - Ground beetle communities in a mountain river subjected to restoration: The Raba River, Polish Carpathians. AB - Effects of passive restoration of mountain rivers on the organisms inhabiting exposed riverine sediments are considerably less understood than those concerning aquatic biota. Thus, the effects of a recovery of the Raba River after abandonment of maintenance of its channelization scheme on ground beetle (Coleoptera: Carabidae) communities were investigated by comparing 6 unmanaged cross-sections and 6 cross-sections from adjacent channelized reaches. In each cross-section, ground beetles were collected from 12 sampling sites in spring, summer, and autumn, and 8 habitat parameters characterizing the cross-sections and sampling sites were determined. Within a few years after abandonment of the Raba River channelization scheme, the width of this gravel-bed river increased up to three times and its multi-thread pattern became re-established. Consequently, unmanaged river cross-sections had significantly larger channel width and more low-flow channels and eroding cutbanks than channelized cross-sections. Moreover, sampling sites in the unmanaged cross-sections were typified by significantly steeper average surface slope and larger average distance from low-flow channels than the sites in channelized cross-sections. In total, 3992 individuals from 78 taxa were collected during the study. The ground beetle assemblages were significantly more abundant and richer in species in the unmanaged than in the channelized cross-sections but no significant differences in carabid diversity indices between the two cross-section types were recorded. Redundancy Analysis indicated active river zone width as the only variable explaining differences in abundance and species richness among the cross-sections. Multiple regression analysis indicated species diversity to predominantly depend on the degree of plant cover and substrate grain size. The study showed that increased availability of exposed sediments in the widened river reaches allowed ground beetles to increase their abundance and species richness within a few years after the onset of river restoration, but more time may be needed for development of more diverse carabid communities. PMID- 28851140 TI - A spatial evaluation of global wildfire-water risks to human and natural systems. AB - The large mediatic coverage of recent massive wildfires across the world has emphasized the vulnerability of freshwater resources. The extensive hydrogeomorphic effects from a wildfire can impair the ability of watersheds to provide safe drinking water to downstream communities and high-quality water to maintain riverine ecosystem health. Safeguarding water use for human activities and ecosystems is required for sustainable development; however, no global assessment of wildfire impacts on water supply is currently available. Here, we provide the first global evaluation of wildfire risks to water security, in the form of a spatially explicit index. We adapted the Driving forces-Pressure-State Impact-Response risk analysis framework to select a comprehensive set of indicators of fire activity and water availability, which we then aggregated to a single index of wildfire-water risk using a simple additive weighted model. Our results show that water security in many regions of the world is potentially vulnerable, regardless of socio-economic status. However, in developing countries, a critical component of the risk is the lack of socio-economic capability to respond to disasters. Our work highlights the importance of addressing wildfire-induced risks in the development of water security policies; the geographic differences in the components of the overall risk could help adapting those policies to different regional contexts. PMID- 28851141 TI - Reducing the environmental impact of global diets. AB - It is well established in the literature that reducing the amount of meat in global diets would reduce the environmental impacts of food production. However, changes to livestock production systems also have significant potential to reduce environmental impacts from meat production, and yet are not as widely discussed in the literature. Modern, intensive livestock systems, especially for beef, offer substantially lower land requirements and greenhouse gas emissions per kilogram of meat than traditional, extensive ones. The land sparing potential of beef sector intensification is especially relevant for high priority conservation regions like the Brazilian Amazon. Leveraging livestock production systems in addition to dietary change greatly expands the opportunity to achieve conservation and climate goals in the coming decades. PMID- 28851142 TI - Seasonal variations of metal (Cd, Pb, Mn, Cu, Zn) accumulation in a voluntary species, Salix subfragilis, in unpolluted wetlands. AB - Willow trees are generally valuable bioindicators. Flooding during the rainy season affects the life history of Salix subfragilis, a voluntary willow species that grows in submerged wetlands, as it causes senescence of old leaves and emergence of new shoots. In this study, we assessed the potential of S. subfragilis, a Northeast Asian willow species, as a bioindicator. We also investigated seasonal variations in the concentrations of Cd, Pb, Mn, Cu, and Zn in the leaves and stems of willows growing in submerged wetlands containing low concentrations of metals, over the growing season after flooding caused by heavy rain. A significant difference in the concentrations of metals in the sediments was reflected in the leaves for Cd and Pb and in the stems for Cd, Pb, Mn, and Zn. Higher bioconcentration factors in the samples collected in spring suggest that the best monitoring time for S. subfragilis is from April to May. Whereas the concentrations of Cd, Pb, and Mn appeared to increase, especially in the leaves, the concentrations of Cu and Zn in the leaves and stems decreased toward the end of the growing season, regardless of the emergence period. Higher concentrations of Cd, Pb, and Zn were generally noted for the stems than for the leaves whereas Mn and Cu were consistently present at higher concentrations in the leaves than in the stems. These results suggest that S. subfragilis can be a useful bioindicator for Pb, as well as for Cd and Zn. Particularly, samples of new stems collected in spring could provide a good index for environmental pollution. PMID- 28851143 TI - Exposure and effects of sediment-spiked fludioxonil on macroinvertebrates and zooplankton in outdoor aquatic microcosms. AB - Information from effects of pesticides in sediments at an ecosystem level, to validate current and proposed risk assessment procedures, is scarce. A sediment spiked outdoor freshwater microcosm experiment was conducted with fludioxonil (lipophilic, non-systemic fungicide) to study exposure dynamics and treatment related responses of benthic and pelagic macroinvertebrates and zooplankton. Besides blank control and solvent control systems the experiment had six different treatment levels (1.7-614mga.s./kg dry sediment) based around the reported 28-d No Observed Effect Concentration (NOEC) for Chironomus riparius (40mga.s./kg dry sediment). Twelve systems were available per treatment of which four were sacrificed on each of days 28, 56 and 84 after microcosm construction. Fludioxonil persisted in the sediment and mean measured concentrations were 53 82% of the initial concentration after 84days. The dissipation rate increased with the treatment level. Also exposure concentrations in overlying water were long-term, with highest concentrations 28days after initiation of the experiment. Sediment-dwelling Oligochaeta and pelagic Rotifera and Cladocera showed the most pronounced treatment-related declines. The most sensitive sediment-dwelling oligochaete was Dero digitata (population NOEC 14.2mga.s./kg dry sediment). The same NOEC was calculated for the sediment-dwelling macroinvertebrate community. The most sensitive zooplankton species was the cladoceran Diaphanosoma brachyurum (NOEC of 1.6MUga.s./L in overlying water corresponding to 5.0mga.s./kg dry sediment). At the two highest treatments several rotifer taxa showed a pronounced decrease, while the zooplankton community-level NOEC was 5.6MUga.s./L (corresponding to 14.2mga.s./kg dry sediment). Zooplankton taxa calanoid Copepoda and Daphnia gr. longispina showed a pronounced treatment-related increase (indirect effects). Consequently, an assessment factor of 10 to the chronic laboratory NOECs of Chironomus riparius (sediment) and Daphnia magna (water) results in a regulatory acceptable concentration that is sufficiently protective for both the sediment-dwelling and pelagic organisms in the microcosms. PMID- 28851144 TI - Effective rhizoinoculation and biofilm formation by arsenic immobilizing halophilic plant growth promoting bacteria (PGPB) isolated from mangrove rhizosphere: A step towards arsenic rhizoremediation. AB - Arsenic (As) uptake by plants is largely influenced by the presence of microbial consortia and their interactions with As. In the coastal region of Bengal deltaic plain of Eastern India, the As-contaminated groundwater is frequently used for irrigation purposes resulting in an elevated level of soil As in agricultural lands. The health hazards associated with As necessitates development of cost effective remediation strategies to reclaim contaminated agricultural lands. Among the available technologies developed in recent times, bioremediation using bacteria has been found to be the most propitious. In this study, two As resistant halophilic bacterial strains Kocuria flava AB402 and Bacillus vietnamensis AB403 were isolated, identified and characterized from mangrove rhizosphere of Sundarban. The isolates, AB402 and AB403, could tolerate 35mM and 20mM of arsenite, respectively. The effect of As on the exopolysaccharide (EPS) synthesis, biofilm formation, and root association was evaluated for both the bacterial strains. Arsenic adsorption on the cell surfaces and intracellular accumulation in both the bacterial strains were promising under culture conditions. Moreover, both the strains when used as inoculum, not only promoted the growth of rice seedlings but also decreased As uptake and accumulation in plants. PMID- 28851145 TI - Influence of risk factors and past events on flood resilience in coastal megacities: Comparative analysis of NYC and Shanghai. AB - Coastal flood protection measures have been widely implemented to improve flood resilience. However, protection levels vary among coastal megacities globally. This study compares the distinct flood protection standards for two coastal megacities, New York City and Shanghai, and investigates potential influences such as risk factors and past flood events. Extreme value analysis reveals that, compared to NYC, Shanghai faces a significantly higher flood hazard. Flood inundation analysis indicates that Shanghai has a higher exposure to extreme flooding. Meanwhile, Shanghai's urban development, population, and economy have increased much faster than NYC's over the last three decades. These risk factors provide part of the explanation for the implementation of a relatively high level of protection (e.g. reinforced concrete sea-wall designed for a 200-year flood return level) in Shanghai and low protection (e.g. vertical brick and stone walls and sand dunes) in NYC. However, individual extreme flood events (typhoons in 1962, 1974, and 1981) seem to have had a greater impact on flood protection decision-making in Shanghai, while NYC responded significantly less to past events (with the exception of Hurricane Sandy). Climate change, sea level rise, and ongoing coastal development are rapidly changing the hazard and risk calculus for both cities and both would benefit from a more systematic and dynamic approach to coastal protection. PMID- 28851146 TI - Do environmental factors affect male fathead minnow (Pimephales promelas) response to estrone? Part 1. Dissolved oxygen and sodium chloride. AB - Laboratory exposures indicate that estrogens and their mimics can cause endocrine disruption in male fishes, yet while studies of resident fish populations in estrogen-polluted waters support these findings, biomarker expression associated with field versus laboratory exposure to estrogenic endocrine disruptors (EDs) often differ dramatically. Two of the environmental parameters often found to vary in dynamic aquatic ecosystems were chosen (dissolved oxygen [DO] and sodium chloride concentrations) to assess their potential impact on ED exposure. In separate experiments, male fathead minnows (Pimephales promelas) were exposed to estrone (E1) a natural ED, under either two concentrations of DO, or two concentrations of sodium chloride, in a laboratory flow-through system. Morphological and hematological parameters were assessed. While vitellogenin concentrations were elevated with exposure to estrone (29 to 390ng/L), the effect on other indices were variable. Estrone exposure altered SSC, blood glucose, hematocrit, and hepatic and gonado-somatic index in 1 of 4 experiments, while it decreased body condition factor in 3 of 4 experiments. At the concentrations tested, no main effect differences (P<0.05) were found associated with DO or sodium chloride treatments, except in one experiment low DO resulted in a decrease in secondary sex characteristic score (SSC). The combination of DO or sodium chloride and E1 altered blood glucose in one experiment each. These results indicate the variability of fathead minnow response to estrone, even within the confines of controlled laboratory conditions. PMID- 28851147 TI - Using alternative forage species to reduce emissions of the greenhouse gas nitrous oxide from cattle urine deposited onto soil. AB - Grazed pastures are a major contributor to emissions of the greenhouse gas nitrous oxide (N2O), and urine deposition from grazing animals is the main source of the emissions. Incorporating alternative forages into grazing systems could be an approach for reducing N2O emissions through mechanisms such as release of biological nitrification inhibitors from roots and increased root depth. Field plot and lysimeter (intact soil column) trials were conducted in a free draining Horotiu silt loam soil to test whether two alternative forage species, plantain (Plantago lanceolate L.) and lucerne (Medicago sativa L.), could reduce N2O emissions relative to traditional pasture species, white clover (Trifolium repens L.) and perennial ryegrass (Lolium perenne L.). The amounts of N2O emitted from the soil below each forage species, which all received the same cow urine at the same rates, was measured using an established static chamber method. Total N2O emissions from the plantain, lucerne and perennial ryegrass controls (without urine application) were generally very low, but emissions from the white clover control were significantly higher. When urine was applied in autumn or winter N2O emissions from plantain were lower compared with those from perennial ryegrass or white clover, but this difference was not found when urine was applied in summer. Lucerne had lower emissions in winter but not in other seasons. Incorporation of plantain into grazed pasture could be an approach to reduce N2O emissions. However, further work is required to understand the mechanisms for the reduced emissions and the effects of environmental conditions in different seasons. PMID- 28851148 TI - The best data design for applying the taxonomic distinctness index in lotic systems: A case study of the Southern Morava River basin. AB - The taxonomic distinctness (Delta+) index has been recognized as a robust measure to assess human impacts on marine biodiversity. However, its applicability in freshwater ecosystems has still not been confirmed. We aimed to propose the most suitable data design for calculating the Delta+ index for application in assessing anthropogenically caused degradation in lotic environments. We calculated the values of Delta+ based on different taxa groups and taxa resolutions, in order to examine its utility as a potential metric in bioassessment programs. We found that the exclusion of non-insect taxa and selected insect orders significantly increased the index sensitivity. Thus, we believe that an appropriate data design for Delta+ calculation based on macroinvertebrate assemblages is the main prerequisite for the effective estimation of degradation in lotic environments. In addition, we argue that a decrease in taxonomic resolution up to genus level is completely acceptable, as it results in only minor information loss. Bearing this in mind would significantly facilitate its application in rapid bioassessment programs. Despite the observed correlation, the utility of Delta+ as a potential bioassessment metric is rather limited, since its fails to detect fine differences in environmental stress, and instead only roughly distinguishes between two basic classes of degradation level, unimpacted and impacted. PMID- 28851149 TI - Do organic matter metrics included in lake surveillance monitoring in Europe provide a broad picture of brownification and enrichment with oxygen consuming substances? AB - Organic matter (OM) has numerous geochemical and ecological functions in inland waters and can affect water quality. Different parameters of aquatic OM are measured with various methods as no single analytical tool can provide definitive structural or functional information about it. In the present paper we review different OM metrics used in the European Union (EU) lake surveillance monitoring programmes and assess their suitability to provide sufficient data about the brownification and enrichment with oxygen consuming substances in European lakes. In the EU Water Framework Directive (WFD), metrics of OM are not mandatory physico-chemical parameters, but only recommended parameters to characterize water transparency, oxygenation conditions or acidification status. Our analysis shows that, as lake OM is monitored under the WFD in only 14 countries, no Europe wide conclusions on the situation regarding brownification and organic enrichment can be drawn based on these data. Applied parameters in lake surveillance monitoring programmes are biochemical oxygen demand (BOD), chemical oxygen demand (COD), total organic carbon (TOC), dissolved organic carbon (DOC), water colour (WCol), and yellow substance. Different national OM metrics used avoid getting a broad picture of lake OM concentration changes in Europe over the last decades. Furthermore, our results demonstrate that the possibilities to convert different OM parameters to each other are limited because empirical relationships between them are region-specific. OM sensors for continuous measurements and remote sensing surveys could improve the effectiveness of lake OM monitoring, especially its temporal and spatial representativeness. It would be highly suggested to include in lake monitoring programmes also methods (e.g. absorbance or fluorescence spectroscopy) allowing to characterize the composition of OM as it influences strongly the biogeochemical role of OM in lakes. PMID- 28851150 TI - Modeling nutrient sources, transport and management strategies in a coastal watershed, Southeast China. AB - Integrated watershed management requires an analytical model capable of revealing the full range of impacts that would be caused by the uses and developments in the watershed. The SPAtially Referenced Regressions On Watershed Attributes (SPARROW) model was developed in this study to provide empirical estimates of the sources, transport of total nitrogen (TN) and total phosphorus (TP) and to develop nutrient management strategies in the Jiulong River Watershed, southeast China that has enormous influence on the region's ecological safety. We calibrated the model using data related to daily streamflow, monthly TN and TP concentrations in 2014 at 30 locations. The model produced R2 values for TN with 0.95 and TP with 0.94. It was found that for the entire watershed, TN came from fertilizer application (43%), livestock breeding (39%) and sewage discharge (18%), while TP came from livestock breeding (46%), fertilizer application (46%), and industrial discharge (8%). Fifty-eight percent of the TN and 80% of the TP in upstream reaches are delivered to the outlets of North and West rivers. A scenario analysis with SPARROW was coupled to develop suitable management strategies. Results revealed that controlling nutrient sources was effective in improving water quality. Normally sharp reduction in nutrient sources is not operational feasible. Hence, it is recommended that preventing nutrient on land from entering into the river as a suitable strategy in watershed management. PMID- 28851151 TI - Utility of fur as a biomarker for persistent organic pollutants in Australian fur seals (Arctocephalus pusillus doriferus). AB - Persistent Organic Pollutants (POPs) can cause toxic effects in many species which include endocrine dysfunction, immunotoxicity, developmental defects and neoplasia. Species dominating the upper trophic level are vulnerable to these effects due to bioaccumulation. In Bass Strait, the Australian fur seal (Arctocephalus pusillus doriferus) is an important top order predator and sentinel species for ecosystem health. An alopecia syndrome is seen at high prevalence in juvenile, female Australian fur seals at Lady Julia Percy Island, Victoria, Australia. Previous investigations suggest causality could be due to an endocrine-like toxicant. The alopecia syndrome has significance for thermoregulation and is a likely risk factor for mortality. Fur collected from case (alopecic) and control (unaffected) seals sampled at Lady Julia Percy Island were analysed for POPs. To investigate the utility of fur for monitoring POPs concentrations in pinnipeds, a comparison of POPs concentrations in the fur and blubber of Australian fur seals stranded along the Victorian coast was undertaken. The concentration of selected POPs including polychlorinated dibenzo p-dioxins and dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (dl PCBs), polybrominated diphenyl ethers (PBDEs) and perfluorooctane sulfonate/perfluorooctanoic acid (PFOS/PFOA) were determined in fur using either High Resolution Gas Chromatography-Mass Spectrometry or Liquid Chromatography Mass Spectrometry. Results indicate detectable, and in some individuals, elevated levels of dl-PCBs, PCDD/Fs and PBDEs in juvenile fur seals sampled on Lady Julia Percy Island, with significantly higher levels of dl-PCBs in case compared to control seals. Elevated levels of dl-PCBs and PCDD/Fs were found in blubber samples collected from stranded fur seals with significant correlations between blubber and fur concentrations seen, particularly for dl-PCBs. This study discusses the significance of POPs concentrations in relation to the causality of an alopecia syndrome in the Australian fur seal, and assesses the utility of fur as a non-invasive biomarker to monitor POPs exposure in this sentinel species. PMID- 28851152 TI - Humic acids facilitated microbial reduction of polymeric Pu(IV) under anaerobic conditions. AB - Flavins and humic substances have been extensively studied with emphasis on their ability to transfer extracellular electrons to insoluble metal oxides. Nevertheless, whether the low-solubility Pu(IV) polymers are microbially reduced to aqueous Pu(III) remains uncertain. Experiments were conducted under anaerobic and slightly alkaline conditions to study the difference between humic acids and flavins to transport extracellular electrons to Pu(IV) polymers. Our study demonstrates that Shewanella putrefaciens was unable to directly reduce polymeric Pu(IV) with a notably low reduction rate (3.4*10-12mol/L Pu(III)aq within 144h). The relatively high redox potential of flavins reveals the thermodynamically unfavorable reduction: Eh(PuO2(am)/Pu3+)=53% of the observed toxicity). However, toxicity of Cu NP(total) in the presence of DOC at a concentration ranging from 5 to 50mg C/L largely resulted from the NP(particle) (57%-85%), which could be attributable to the large reduction of the concentration of Cu NP(ion) and the enhancement of the stability of Cu NP(particle) when DOC was added. Our results indicate that water chemistry needs to be explicitly taken into consideration when evaluating the role of NP(particle) and NP(ion) in the observed toxicity of NP(total). PMID- 28851155 TI - In situ calibration of polar organic chemical integrative samplers to monitor organophosphate flame retardants in river water using polyethersulfone membranes with performance reference compounds. AB - Passive sampler is an innovative way of monitoring chemicals in different environmental. A modified polar organic chemical integrative sampler (m-POCIS) with a performance reference compound (PRC) was used to evaluate the concentrations of 8 organophosphate flame retardants (OPFRs) under field conditions. The m-POCIS was deployed for 15days under laboratory conditions and 21days under in situ conditions to determine the concentrations of OPFRs. The analytes were trapped in the sorbent and the microporous polyethersulfone (PES) membrane of the m-POCIS. Sampling rates (Rs) were determined for the studied compounds and ranged from 0.02+/-0.0003L/d (triphenylphosphine oxide, TPPO) to 0.24+/-0.021L/d (tripropyl phosphate, TPrP) in the laboratory. The membranes accumulation increased with usage and was correlated to the logKow. Among the tested compounds, tripentylphosphate (TPeP) and triphenylphosphate (TPhP) had the highest logKow values and were mostly detected in the membranes. This behavior resulted in a lag-phase, which was measured by extrapolating the data from the last third of the uptake phase (quasilinear) to the x-axis using a linear regression, before the compounds transferred into the sorbent. TPhP was the only compound with a lag-phase of 3.9days during the 15days experiment. Deuteratedtributyl phosphate (TBP-d27) and desisopropyl atrazine-d5 (DIA-d5) were identified through specific experiments as potential PRC. The results from the PRC calibrations suggested that DIA-d5 (ke (in situ)=0.075+/-0.0048day-1) can be used as a PRC for the evaluation of OPFRs using m-POCISs. The time-weighted average (TWA) concentrations estimated by the m-POCIS with or without a PRC were significantly correlated with the corresponding values determined from the grab samples. After the PRC calibration, the TWA concentrations of the tested OPFRs in an aquatic environment were lower than those estimated using the laboratory sampling rates (Rs). The m-POCIS with a PRC correction was a suitable tool for estimating OPFRs TWA concentrations in the Yangtze River. PMID- 28851156 TI - The influence of permanently submerged macrophytes on sediment mercury distribution, mobility and methylation potential in a brackish Norwegian fjord. AB - Macrophytes are shown to affect the microbial activity in different aqueous environments, with an altering of the sediment cycling of mercury (Hg) as a potential effect. Here, we investigated how a meadow with permanently submerged macrophytes in a contaminated brackish fjord in southern Norway influenced the conditions for sulfate reducing microbial activity, the methyl-Hg (MeHg) production and the availability of MeHg. Historically discharged Hg from a chlor alkali plant (60-80tons, 1947-1987) was evident through high Hg concentrations (491mgTot-Hgkg-1, 268MUgMeHgkg-1) in intermediate sediment depths (10-20cm) outside of the meadow, with reduced concentrations within the meadow. Natural recovery of the fjord was revealed by lower sediment surface concentrations (1.9 15.5mgTot-Hgkg-1, 1.3-3.2MUgMeHgkg-1). Within the meadow, vertical gradients of sediment hydrogen sulfide (H2S) Eh and pH suggested microbial sulfate reduction in 2-5cm depths, coinciding with peak values of relative MeHg levels (0.5% MeHg). We assume that MeHg production rates was stimulated by the supply and availability of organic carbon, microbial activity and a sulfide oxidizing agent (e.g. O2) within the rhizosphere. Following this, % MeHg in sediment (0-5cm) within the meadow was approximately 10* higher compared to outside the meadow. Further, enhanced availability of MeHg within the meadow was demonstrated by significantly higher fluxes (p<0.01) from sediment to overlying water (0.1-0.6ngm 2d-1) compared to sediment without macrophytes (0.02-0.2ngm-2d-1). Considering the productivity and species richness typical for such habitats, submerged macrophyte meadows located within legacy Hg contaminated sediment sites may constitute important entry points for MeHg into food webs. PMID- 28851157 TI - Stream temperature under contrasting riparian forest cover: Understanding thermal dynamics and heat exchange processes. AB - Climate change is likely to increase summer temperatures in many river environments, raising concerns that this will reduce their thermal suitability for a range of freshwater fish species. As a result, river managers have pursued riparian tree planting due to its ability to moderate stream temperatures by providing shading. However, little is known about the relative ability of different riparian forest types to moderate stream temperatures. Further research is therefore necessary to inform best-practise riparian tree planting strategies. This article contrasts stream temperature and energy fluxes under three riparian vegetation types common to Europe: open grassland terrain (OS), semi-natural deciduous woodland (SNS), and commercial conifer plantation (CS). Data was recorded over the course of a year by weather stations installed in each of the vegetation types. Mean daily stream temperature was generally warmest at OS and coolest at CS. Energy gains at all sites were dominated by shortwave radiation, whereas losses where principally due to longwave and latent heat flux. The magnitude of shortwave radiation received at the water surface was strongly dependent upon vegetation type, with OS and SNS woodland sites receiving approximately 6* and 4* (respectively) the incoming solar radiation of CS. Although CS lost less energy through longwave or latent fluxes than the other sites, net surface heat flux was ordered OS>SNS>CS, mirroring the stream temperature results. These findings demonstrate that energy fluxes at the air water interface vary substantially between different riparian forest types and that stream temperature response to bankside vegetation depends upon the type of vegetation present. These results present new insights into the conditions under which riparian vegetation shading is optimal for the reduction of surface heat fluxes and have important implications for the development of 'best-practice' tree planting strategies to moderate summer temperature extremes in rivers. PMID- 28851158 TI - Development of an integrated process to produce d-mannose and bioethanol from coffee residue waste. AB - A novel, integrated process for economical high-yield production of d-mannose and ethanol from coffee residue waste (CRW), which is abundant and widely available, was reported. The process involves pretreatment, enzymatic hydrolysis, fermentation, color removal, and pervaporation, which can be performed using environmentally friendly technologies. The CRW was pretreated with ethanol at high temperature and then hydrolyzed with enzymes produced in-house to yield sugars. Key points of the process are: manipulations of the fermentation step that allowing bioethanol-producing yeasts to use almost glucose and galactose to produce ethanol, while retaining large amounts of d-mannose in the fermented broth; removal of colored compounds and other components from the fermented broth; and separation of ethanol and d-mannose through pervaporation. Under optimized conditions, approximately 15.7g dry weight (DW) of d-mannose (approximately 46% of the mannose) and approximately 11.3g DW of ethanol from 150g DW of ethanol-pretreated CRW, were recovered. PMID- 28851159 TI - Evaluation of chlorine dioxide as a supplementary pretreatment reagent for lignocellulosic biomass. AB - Chlorine dioxide (ClO2) is a bleaching reagent used in paper industry. Two different types of pretreatment methods were investigated incorporating ClO2 as a secondary reagent: (a) alkaline followed by ClO2 treatment; (b) dilute-sulfuric acid followed ClO2 treatment. In these methods, ClO2 treatment has shown little effect on delignification. Scheme-a has shown a significant improvement in enzymatic digestibility of glucan far above that treated by ammonia alone. On the contrary, dilute-acid followed by ClO2 treatment has shown negative effect on the enzymatic hydrolysis. The main factors affecting the enzymatic hydrolysis are the changes of the chemical structure of lignin and its distribution on the biomass surface. ClO2 treatment significantly increases the carboxylic acid content and reduces phenolic groups of lignin, affecting hydrophobicity of lignin and the H bond induced association between the enzyme and lignin. This collectively led to reduction of unproductive binding of enzyme with lignin, consequently increasing the digestibility. PMID- 28851160 TI - Comparison of sodium hydroxide and calcium hydroxide pretreatments on the enzymatic hydrolysis and lignin recovery of sugarcane bagasse. AB - Sodium hydroxide (NaOH) and calcium hydroxide (Ca(OH)2) respectively dissolved in water and 70% glycerol were applied to treat sugarcane bagasse (SCB) under the condition of 80 degrees C for 2h. NaOH solutions could remove more lignin and obtain higher enzymatic hydrolysis efficiency of SCB than Ca(OH)2 solutions. Compared with the alkali-water solutions, the enzymatic hydrolysis of SCB treated in NaOH-glycerol solution decreased, while that in Ca(OH)2-glycerol solution increased. The lignin in NaOH-water pretreatment liquor could be easily recovered by calcium chloride (CaCl2) at room temperature, but that in Ca(OH)2-water pretreatment liquor couldn't. NaOH pretreatment is more suitable for facilitating enzymatic hydrolysis and lignin recovery of SCB than Ca(OH)2 pretreatment. PMID- 28851161 TI - Inhibitory effects of phenolic compounds of rice straw formed by saccharification during ethanol fermentation by Pichia stipitis. AB - In this study, it was found that the type of phenolic acids derived from rice straw was the major factor affecting ethanol fermentation by Pichia stipitis. The aim of this study was to investigate the inhibitory effect of phenolic acids on ethanol fermentation with rice straw. Different cellulases produced different ratios of free phenolic acids to soluble conjugated phenolic acids, resulting in different fermentation efficiencies. Free phenolic acids exhibited much higher inhibitory effect than conjugated phenolic acids. The flow cytometry results indicated that the damage to cell membranes was the primary mechanism of inhibition of ethanol fermentation by phenolic acids. The removal of free phenolic acids from the hydrolysates increased ethanol productivity by 2.0-fold, indicating that the free phenolic acids would be the major inhibitors formed during saccharification. The integrated process for ethanol and phenolic acids may constitute a new strategy for the production of low-cost ethanol. PMID- 28851162 TI - Simultaneous production of bioethanol and value-added d-psicose from Jerusalem artichoke (Helianthus tuberosus L.) tubers. AB - In this study, the production of bioethanol and value added d-psicose from Jerusalem artichoke (JA) was attempted by an enzymatic method. An enzyme mixture used for hydrolysis of 100mgmL-1 JA. The resulting concentrations of released d fructose and d-glucose were measured at approximately 56mgmL-1 and 15mgmL-1, respectively. The d-psicose was epimerized from the JA hydrolyzate, and the conversion rate was calculated to be 32.1%. The residual fructose was further converted into ethanol at 18.0gL-1 and the yield was approximately 72%. Bioethanol and d-psicose were separated by pervaporation. This is the first study to report simultaneous d-psicose production and bioethanol fermentation from JA. PMID- 28851163 TI - An innovative intermittent-vacuum assisted thermophilic anaerobic digestion process for effective animal manure utilization and treatment. AB - Intermittent-vacuum stripping (IVS) was developed as a pretreatment for thermophilic anaerobic digestion (TAD) to improve methanogenesis and hydrolysis activity through preventing free ammonia and hydrogen sulfide (H2S) inhibition from liquid swine manure (LSM). Over 98% of ammonia and 38% organic nitrogen were removed in 60min from 55 degrees C to 85 degrees C with vacuum pressure (from 100.63+/-3.79mmHg to 360.91+/-7.39mmHg) at initial pH 10.0 by IVS. Thermophilic methanogenesis and hydrolysis activity of pretreated LSM increased 52.25% (from 11.56+/-1.75% to 17.60+/-0.49%) in 25days and 40% (from 10days to 6days) in bio methane potential assay. Over 80% H2S and total nitrogen were removed by IVS assistance, while around 70% nitrogen was recycled as ammonium sulfate. Therefore, IVS-TAD combination could be an effective strategy to improve TAD efficiency, whose elution is more easily utilized in algae cultivation and/or hydroponic system. PMID- 28851165 TI - [Strengthening the management of advanced maternal age to ensure the safty of both mother and fetus]. PMID- 28851164 TI - Selective VFA production potential from organic waste streams: Assessing temperature and pH influence. AB - This study explored the volatile fatty acid (VFA) production potential of seven waste streams from urban and agroindustrial sources. For that purpose, batch assays were performed under acidic (pH 5.5) and alkaline (pH 10) conditions at both mesophilic (35 degrees C) and thermophilic (55 degrees C) temperature. Overall, the VFA yield was influenced by temperature, and it was positively affected by pH, ranging between 220 and 677mgCODg-1CODfed for liquid waste streams and between 127 and 611mgCODg-1CODfed for solid waste streams and urban sludge. The highest VFA concentration and highest VFA/sCOD ratio was obtained during the organic fraction of municipal solid waste (OFMSW) fermentation, with 8,320mgCODL-1 and 94% at alkaline pH and mesophilic temperature. The results of this study suggest that selective VFA production, i.e. via propionic, butyric and acetic acid production, might be feasible for scaling-up purposes with specific waste streams by adjusting the process parameters. PMID- 28851166 TI - [Clinic characteristics of women with advanced maternal age and perinatal outcomes]. AB - Objective: To explore the association between maternal age and perinatal outcomes. Methods: Totally, 3 151 women with advanced maternal age and 6 098 women younger than 35 years old who delivered in Beijing Obstetrics and Gynecology Hospital in 2016 were recruited. Their clinic characteristics and perinatal outcomes were collected to divide into 3 groups based on delivery age, Group 1 (aged 35-39 years, 2 683 cases), Group 2 (aged >=40 years, 366 cases) and the control group (aged<35 years, 6 098 cases). The association between maternal age and adverse perinatal outcomes were analyzed, including hypertensive disorder complicating pregnancy, gestational diabetes mellitus (GDM), preterm birth and postpartum hemorrhage. Results: The rate of cesarean section history (27.39%, 33.61%, 5.53%) or previous myomectomy history (2.80%, 5.46%, 0.72%) were compared between the advanced maternal age groups and the control group, and the differences were statistically significant (P<0.05). The percentage of prepregnancy overweight and obesity (29.67%, 27.05%, 18.47%), complicated with myoma (14.83%,19.95%, 5.64%) were compared among the three groups, and the differences were statistically significant (P<0.05). The percentage of pregnancy through assisted reproductive technology (9.84%, 15.03%, 3.12%) also had statistically significant differences (P<0.05). The incidence of fetal chromosomal abnormalities (1.23%, 3.01%, 0.36%) and fetal malformations (1.94%, 4.37%, 0.48%) increased with the maternal age, with statistically significant differences (P<0.01). The mobidity of hypertensive disorders (9.84%, 13.11%, 9.23%), pregestational diabetes mellitus (1.83%, 2.19%, 0.72%), gestational diabetes mellitus (22.70%, 28.42%, 14.87%), premature rupture of membranes (25.57%, 19.40%, 31.42%), placenta previa (2.05%, 2.46%, 0.92%), preterm birth(8.35%, 11.20%, 5.51%), postpartum hemorrhage (25.11%, 18.31%, 20.27%) and forceps delivery (5.42%, 2.33%, 5.71%) were compared, and the differences were statistically significant (P<0.05). The cesarean section rate in primipara (45.42%, 75.74%, 21.33%) and multipara (51.46%, 61.54%, 30.95%) had statistically significant difference (P<0.05). The proportion of macrosomia (10.80%, 8.85%, 7.96%) and neonates transferred into neonatal ICU (9.63%, 11.48%, 5.21%) in term neonates had statistically significant difference (P<0.05). Conclusions: Women with advanced maternal age increase after new family planning policy put into effect, so do the risk of adverse perinatal outcomes. Attention and interventions should be made to cope with the occurrence of adverse perinatal outcomes. PMID- 28851167 TI - [Effect of maternal age on pregnancy outcomes in Beijing]. AB - Objective: To evaluate the maternal age at delivery in Beijing and the effect of maternal age on pregnancy outcomes. Methods: A retrospective analysis was conducted on 14 970 singleton pregnancies from 15 hospitals in Beijing from June 20(th) to November 30(th) in 2013. These hospitals were sorted by the numbers of delivery and chosen as clusters by systemic cluster sampling method. The data of age, diagnosis with gestational diabetes mellitus (GDM) and pre-eclampsia (PE), neonatal birth weight, gestational age at delivery, postpartum hemorrhage and infants admitted to the neonatal ICU (NICU) were collected. The 14 970 women were divided into 5 groups according to their ages at delivery: (1) less than 20 years (n=205), (2)20-<30 years (n=9 228), (3)30-<35 years (n=4 365), (4)35-<40 years (n=1 017), and(5) 40 years and older (n=155). T-test and chi(2) test were used for between-group comparison, and logistic regression analysis was used to examine the association between age and the risk of adverse pregnancy outcomes. Results: (1) The mean maternal age at delivery in 2013 in Beijing was (28+/-4) years old. Among them, 205 (1.4%, 205/14 970) delivered under 20 years of age; 1 172 (7.8%, 1 172/14 970) >=35 years; and 155 (1.0%, 155/14 970) at 40 years and older. (2) The prevalence of diabetes, hypertension, overweight and obesity increased with age, and the incidence of these conditions were 3.4%, 4.3% and 31.4% in women with advanced age, respectively. (3) Compared with 20-<30 years group, less than 20 years was associated with significantly lower incidence of GDM [adjust OR (aOR)=0.393, 95%CI: 0.222-0.696] and cesarean section rate (aOR=0.549, 95%CI: 0.391-0.771), and higher incidence of preterm birth (aOR=2.144, 95%CI: 1.256-3.662). Moreover, 30-<35 years, 35-<40 years and 40 years and older groups all had significantly higher risk of GDM (30-34 years, aOR=1.513, 95%CI: 1.374-1.666; 35-<40 years, aOR=2.094, 95%CI: 1.786-2.455; >=40 years, aOR=2.174, 95%CI: 1.492-3.167), preterm birth (aOR=1.219, 95%CI: 1.021 1.455; aOR=1.644, 95%CI: 1.251-2.161; aOR=2.141, 95%CI: 1.209-3.792), cesarean section (aOR=1.373, 95%CI: 1.268-1.486; aOR=2.960, 95%CI: 2.550-3.435; aOR=4.332, 95%CI: 2.920-6.426) and NICU admission rate (aOR=1.236, 95%CI: 1.059-1.443; aOR=1.337, 95%CI: 1.018-1.756; aOR=2.389, 95%CI: 1.385-4.121), when compared to the 20-<30 years of age group. Higher incidence of PE (aOR=1.292, 95%CI: 1.007 1.659) and postpartum hemorrhage (aOR=1.224, 95%CI: 1.048-1.429) were also noted in women of 30-<35 years, compared to 20-<30 years group respectively. Conclusion: Both advanced maternal age and adolescent pregnancy are associated with increasing risk of adverse pregnancy outcomes. PMID- 28851168 TI - [Outcome of vaginal birth after cesarean section in women with advanced maternal age]. AB - Objective: To explore the perinatal outcome of vaginal birth after cesarean (VBAC) in women with advanced age. Methods: Totally 2 587 women delivered after one or two prior cesarean sections (gestational age>=28 weeks) in the First Affiliated Hospital of Kunming Medical University from July 2013 to February 2017. 909 trial of labor after cesarean(TOLAC) cases of singleton pregnancy with one prior cesarean section were studied retrospectively. According to the age, of the 909 TOLAC cases, 237 were the advanced age group, and 672 cases were the low age group. The maternal and neonatal outcomes between the two groups were compared. Results: The percentage of TOLAC in women with advanced age was 32.4% (237/731), and VBAC rate was 88.2% (209/237). The percentage of TOLAC in younger women was 36.2% (672/1 856), and VBAC rate was 82.4% (554/672). The difference of the TOLAC rate between the two groups was not significant (P>0.05), and the VBAC rate of the advanced age group was higher than the low age group (P<0.05). In the comparison of the two groups, the proportion of bachelor degree or above(55.7%,132/237), the prepregnancy BMI (22.4+/-3.0) kg/m(2), pregnant interval time (68.5+/-38.3) months, the proportion of gestational hypertension (8.4%,20/237), the proportion of gestational diabetes(34.6%,82/237) and the rate of the neonatal ICU admission (18.1%,43/237) in the advanced age group were higher than those of the low age group (P<0.05), respectively. And there were no significant differences in the rate of postpartum hemorrhage, the rate of postpartum hemorrhage>=1 500 ml, the rate of postpartum transfusion, puerperal morbidity, neonatal birth weight, neonatal 5 min Apgar score<7 score, umbilical artery blood pH<7.0, neonatal tracheal intubation and respiratory distress syndrome (all P>0.05). In all TOLAC cases, the rate of uterine rupture was 0.11%(1/909) and there was no maternal and neonatal death. Conclusion: VBAC is a safe and feasible way of delivery for singleton pregnancy after one prior cesarean section in women with advanced age. PMID- 28851169 TI - [Clinical characteristics and risk factors of pelvic mass in women after hysterectomy for benign disease]. AB - Objective: To explore how to reduce the incidence of pelvic mass after hysterectomy, and to evaluate clinical characteristics and the risks. Methods: A retrospective study was carried out in 85 patients who returned for surgery due to a pelvic mass after prior hysterectomy for benign disease at Peking Union Medical College Hospital from January 2011 to June 2016. Results: The majority of pelvic masses arising after hysterectomy and requiring surgery were benign (74%, 63/85), while 19% (16/85) were malignant and 7% (6/85) were borderline. The most common type was ovarian endometrioma (24%, 20/85) which usually occurs within the 5 years (16 cases), however, ovarian tumors (18 cases) were more likely to occur >=10 years after hysterectomy. Characteristics associated with significantly increased likelihood of ovarian endometrioma were mainly ascribed to younger age [(47+/-5) years old], prior presence of endometriosis or adenomyosis (65%, 13/20) and shorter time to pelvic mass onset [(3+/-3) years], as opposed to ovarian tumors (all P<0.01). Additionally, higher number of prior abdominal surgeries significantly intensified the risk (RR=9.410, 95%CI: 1.099-80.564, P=0.041). Conclusions: The occurrence of pelvic mass after hysterectomy is tightly related to prior histologic findings, and particularly for ovarian endometrioma. Higher number of prior abdominal surgery will exacerbated the risk. It is effective to prevent the pelvic mass in women after hysterectomy if treat patients for the purpose of the risk factors. PMID- 28851170 TI - [Clinical analysis of leiomyomatosis peritonealis disseminate after laparoscopic uterine myomectomy in ten cases]. AB - Objective: To investigate the clinicopathological features, treatment and prognosis of leiomyomatosis peritonealis disseminata (LPD). Methods: A total of 10 patients suffered from LPD after laparoscopic uterine myomectomy were collected in the First Affiliated Hospital of Zhengzhou University from September 2012 to September 2016, and all clinical database were retrospectively analyzed. Results: (1)Clinical features: the age of 10 cases was 25-50 years old, and 8 cases of them were in child-bearing age, while 2 cases were in perimenopausal period. Of 10 cases, 2 cases manifested as discontinuous lower abdominal pain, and the other cases were seen the doctor for the examinations found tumors of pelvis or abdomen. All 10 cases had a history of laparoscopic uterine myomectomy under went power morcellation with an average of (4.0+/-2.2) years (range 1.3 to 8.1 years), 2 cases of them had a history of oral hormone treatment after the first myoma morcellation. (2) Treatment methods and postoperative pathologic diagnosis: during intraoperative exploration, LPD nodules were most distributed in Douglas pouch (10 cases), and next in mesentery (7 cases), abdominal peritoneum (6 cases) and omentum majus (4 cases), etc. Seven of the 8 cases of child-bearing age were performed laparoscopic LPD nodules removal, 1 case gone combined with laparotomy and resecting LPD nodules; 2 cases in perimenopausal period done laparotomy oophorotomy and resected all LPD nodules and omentum. (3) Postoperative relapse and reproductive outcomes: the follow-up time of all cases was 2.8 years, and no recurrence was found during the follow-up period; 2 cases had natural conception and term vaginal birth during the follow-up period. Conclusions: LPD is mainly related to iatrogenic planting and spreading, which is a benign disease and characterized by multiple smooth muscle nodules throughout abdominopelvic cavity, and the nodules of LPD is commonly located in Douglas pouch, mesenteric and omentaum majus, etc. The preferred method of LPD should be individual operative treatment according to different situations, and in which patients may be have better prognosis. PMID- 28851171 TI - [Study on the changes of gonadotropin releasing hormone agonist in pinopodes]. AB - Objective: To study the changes of gonadotropin releasing hormone agonist (GnRH a) in pinopodes during luteal phase and to explore the possible mechanism of GnRH a in luteal phase support of assisted reproductive technology (ART). Methods: Totally 40 primary infertility women who were treated with ART due to male factors were enrolled, according to the order of the group they were randomly divided into experimental group and control group. On the 7th day after ovulation, the experimental group received a subcutaneous injection of 0.1 mg of GnRH-a, while the control group received a subcutaneous injection of placebo only (0.9% saline 2 ml), 3 days later they came to the clinic again. Serum estradiol and progesterone levels were measured before and after treatment in each group. Pinopodes were collected for electron microscopic examination. Levels of ER and PR were detected by western blot. Results: (1) There was no significant difference between the experimental group and the control group in the estrogen level before and after the treatment (all P>0.05). The level of progesterone in the experimental group after treatment [(66.8+/-14.9) nmol/L] was significantly higher than that before treatment(P<0.05); also significantly higher than the same period of the control group (P<0.05). (2) There was no significant difference in the expression of ER protein in the experimental group before and after treatment (P>0.05). The expression of PR in the experimental group after treatment was significantly lower than that before treatment (P<0.05); also lower than the same period of the control group (P<0.05). (3) Expression amount of pinopodes in the experimental group after treatment was significantly higher than that before treatment [65% (13/20) versus 25% (5/20), P<0.05], and the development trend was more mature [the percentage of maturation:75% (15/20) versus 35% (7/20), P<0.05]. Expression amount of pinopodes after treatment and the percentage of maturation in the experimental group were significantly higher than those in the same period of control group (P<0.05). Conclusion: GnRH-a in luteal phase support may play a role through the corpus luteum, which may promote the secretion of progesterone, downregulation of PR expression, promote the growth of pinopodes, and improve the endometrial receptivity. PMID- 28851172 TI - [Experiment research of natural killer cells amplification in vitro and the killing effect on ovarian cancer cells]. AB - Objective: To amplify natural killer (NK) cells in vitro and explore its killing effect on ovarian cancer cells. Methods: (1) The separation of NK cells and identification. A total of 20 ml peripheral blood of one healthy volunteer was collected in Nov. 2015, Peking University People's Hospital. The peripheral blood mononuclear cells of normal volunteers were isolated, cultured in vitro and amplificated cultivation for 14 days with K562 cells transfected and expressing interleukin 21 (IL-21-K562) as nourish cells. The number and dynamic state of the growth cells were monitored during the cultured process. Cells were harvested and counted after 14 days cultured. The NK cells phenotypes were detected by flow cytometry. (2) The killing effect of NK cells on ovarian cancer cells: the ratio of effector cells (NK cells) and target cells (ovarian cancer cells and its control) was 50?1, 20?1, 10?1, 5?1 or 1?1, NK cells killing effect on ovarian cancer cells was detected by the lactate dehydrogenase (LDH) release experiments. Results: (1) The results of NK cells establishment and phenotypic characterization: the cells were induced in vitro for 14 days by amplification culture. With the extension of incubation time, the number of NK cells increased constantly, from 2.0*10(7) on day 0 to 5.1*10(9) on day 14. Obvious amplification of the total number of cells were detected for 255 times. Living cells unstained by trypan blue eventually reached 95% above. Before and after the induction and amplification in vitro, the percentage of NK cells(CD(3)(-)CD(5)(6+)cells) in CD(3)- cells were 2.33% and 85.32%, respectively (P<0.01), which covered the whole lymphocytes 1.06% and 69.42%, respectively (P<0.01), which showed that NK was the main cell type in the amplificated lymphocytes. (2) The killing rate of NK cells on ovarian cancer cells in vitro: the results detected by LDH release experiments showed that NK cells could performed strong nonspecific killing effect on ovarian cancer cell lines SKOV3, HOC1A, 3AO and CAOV3, as well the normal ovarian cell line T29 and NK sensitive cell line K562, and the killing effect increased significantly along with the increase of effector cells and target cells ratio (P<0.01). When the ratio was 1?1, the killing rate was 37% for K562, while the rate of killing of other cells was around 10% (P<0.05). When the effect-target ratio was 20?1 and 50?1, in addition to CAOV3 cells (more than 70%), NK cells had a kill rate of more than 80% for other ovarian cancer cells lines and their control cell K562 and T29 cells (P>0.05). Conclusion: NK cells could be established in vitro and have a good non-specific killing effect on ovarian cancer cells. PMID- 28851173 TI - [Bcl-2 associated athanogene 3 affects the epithelial-mesenchymal transition in human cervical cancer]. AB - Objective: To investigate the expression of Bcl-2 associated athanogene 3 (BAG3) in cervical cancer tissues and cells and its role in epithelial mesenchymal transition (EMT) of cervical cancer. Methods: (1) Cervical cancer samples were collected from September 2015 to March 2017 in the Qilu Hospital of Shandong University and Shangdong Provincial Hospital. While, 50 normal tissues were collected from August 2015 to March 2017 in the Dezhou Municiple Hospital, which were obtained from patients with uterine myoma underwent hysterectomy and patients with cervical biopsy. Reverse transcription (RT)-PCR and western blot were used to detect the expression of BAG3 mRNA and protein, and their clinical significances were analyzed. (2) The expression of BAG3 mRNA and protein was detected using RT-PCR and western blot method in HeLa and SiHa cell lines and normal cervical epithelial cells. The experiment was divided into two groups, BAG3 small interfering RNA transfected group (si-BAG3) and the control group transfected with small interfering RNA (siRNA). Cell counting kit 8 (CCK-8) analysis was used to detect cell proliferation of two groups. Wound-healing and transwell assay were used to detect the migration and invasion ability of HeLa and SiHa cells. The xenograft model of cervical cancer in nude mice was used to observe the effect of BAG3 on tumor xenografts and the tumor-related biomarkers were tested by western blot. Results: (1) The expression levels of BAG3 mRNA and protein in cervical carcinoma tissues were 1.20+/-0.15 and 1.10+/-0.16, which were significantly higher than that in normal cervical tissue, 0.23+/-0.04 and 0.29+/-0.03 (both P<0.01). The results showed that the expression levels of BAG3 mRNA and protein were significantly correlated with cervical carcinoma staging and lymph node metastasis (P<0.05).However, its expression was not correlated with the patient's age, pathological grade, and diameter of tumor (all P>0.05). (2) Compared with normal cervical epithelial cells, the expression of BAG3 mRNA and protein levels in HeLa and SiHa cells were significantly increased (P<0.01), the expression levels of BAG3 mRNA and protein in HeLa and SiHa cells transfected with si-BAG3 were significantly lower than that in control group (all P<0.01). After post-transfected 72 hours, A value of HeLa and SiHa with transfection were significantly lower than those in control group [(0.88+/-0.08) vs (1.22+/-0.13), (0.92+/-0.09) vs (1.35+/-0.12); both P<0.01]. After post-transfected 24 hours, the migration level of HeLa and SiHa cells with transfection were significantly lower than those in the control group [(20.1+/-2.1)% vs (58.6+/-5.6)%, and (21.1+/-2.1)% vs (61.7+/-5.4)%; both P<0.01]. The transmembrane cell number in HeLa and SiHa cells with transfection were 76+/-11 and 71+/-8, which were significantly less than those in control group (131+/-12 and 129+/-14; both P<0.01). After the inoculation into nude mice, tumor formation time of HeLa and SiHa cells with transfection were (9.5+/-0.5) and (10.5+/-1.3) days, respectively, which were significantly longer than those in control group [(4.5+/ 0.5) and (5.2+/-1.1) days; both P<0.05]. Compared with those in the control group, the expression level of Slug, N-cadherin and matrix metalloproteinase-2 (MMP-2) protein in HeLa and SiHa cells with transfected in tumor tissues were significantly decreased (all P<0.01), while the expression level of E-cadherin protein was significantly increased (P<0.01). Conclusion: BAG3 could be involved in the proliferation, migration and invasion of cervical cancer cells by affecting cervical cancer EMT, and BAG3 may be an effective target for the treatment of cervical cancer. PMID- 28851174 TI - [Review on the set up process of Chinese Society of Cardiology]. PMID- 28851175 TI - [Retrospect of the work achieved by the third and fourth committee of Chinese Society of Cardiology]. PMID- 28851177 TI - [Carrying forward the cause and forging ahead into the fruitful future of cardiovascular rehabilitation in China]. PMID- 28851176 TI - [Chinese Society of Cardiology at the turn of the Century]. PMID- 28851178 TI - [Following our original aspiration, keeping continuous inheritance and innovation: the way to promote the widespread development of cardiovascular science in China]. PMID- 28851179 TI - [Development of percutaneous coronary intervention in China]. PMID- 28851180 TI - [Status, development and future of cardiovascular imaging]. PMID- 28851182 TI - [Development, current status and future prospective of transcatheter interventional therapy for valvular heart diseases]. PMID- 28851181 TI - [Historical review and prospect of atherosclerosis studies in China]. PMID- 28851183 TI - [Fortieth anniversary of cardiac arrhythmia:development and prospect]. PMID- 28851184 TI - [Establishment of prevention and management system and development of interventional therapy for patients with congenital heart disease]. PMID- 28851185 TI - [Heart failure: past, present and future]. PMID- 28851186 TI - [Historical review and academic development strategy of cardiac rehabilitation in China]. PMID- 28851187 TI - [Hypertension: development history, current progress status and future prospective]. PMID- 28851188 TI - [Effect of nicorandil on ventricular arrhythmia in patients with acute ST-segment elevation myocardial infarction underwent emergent percutaneous coronary intervention treatment]. AB - Objective: To investigate the effect of nicorandil on ventricular arrhythmia in patients with acute ST-segment elevation myocardial infarction (STEMI) treated with emergent percutaneous coronary intervention (PCI). Methods: A total of 120 acute STEMI patients treated with emergent PCI in our hospital from January 2015 to June 2016 were randomly divided into control group and experiment group (n=60 each). Patients in both groups received conventional therapy.Patients in experiment group took 10 mg nicorandil orally before PCI and received oral nicorandil treatment (15 mg/d, three times daily) for 3 days.QT disperse(QTd), correct QTd(QTcd) and the occurrence rate of ventricular arrhythmia were compared between two groups. Results: QTd at 6, 24, 48 and 72 hours((70.6+/-4.4), (67.2+/ 5.3), (55.7+/-8.5), (48.2+/-8.2) ms, respectively) after PCI was significantly lower in the experiment group than those of control group ((77.1+/-7.1), (71.3+/ 6.5), (65.1+/-8.1), (57.2+/-5.4) ms, all P<0.05). The level of QTd was also significantly lower in the experiment group at 6, 24, 48 and 72 hours((77.5+/ 7.7), (67.7+/-8.6), (61.2+/-7.5), (52.9+/-8.4) ms, respectively) after PCI comared to those of control group ((88.6+/-8.1), (79.2+/-7.8), (74.4+/-7.4), (69.6+/-8.6) ms, all P<0.05). There was no significant difference in the incidence of reperfusion arrhythmia during PCI procedure between the two groups.The prevalence of the ventricular premature beat in the experiment group (25/60, 41.7%) was significantly lower than in the control group(45/60, 75.0%) within 3 days after PCI(P<0.01), the prevalence of the no sustained ventricular tachycardia and ventricular fibrillation in the experiment group(6/60, 10.0%) was also significantly lower than in the control group (18/60, 30.0%, P<0.01) within 3 days after PCI. Conclusions: Nicorandil use prior and post PCI could decrease the occurrence rate of ventricular arrhythmia in STEMI patients undergoing emergent PCI, and this effect might be related with reduced QTd and QTcd post medication. PMID- 28851189 TI - [Feasibility and efficacy of the regional cooperative ST-segment elevation myocardial infarction rescue network among the prefectural-level city hospitals]. AB - Objective: To investigate the feasibility and efficacy of the establishment of regional cooperative acute ST-segment elevation myocardial infarction (STEMI) rescue network among the prefectural-level city hospitals in China. Methods: Based on real-time remote electrocardiogram transmission and "120" emergency systems, we established a regional collaborative STEMI treatment network with our hospital as the network unclears including 8 second-class affiliated hospitals of Jiangsu University in 2013. STEMI treatment time, therapeutic effects and economic indexes were compared before (from January 2010 to December 2012, 180 cases, pre-network) and after (From January 2013 to December 2015, 374 cases, post-network) the establishment of the regional collaborative STEMI treatment network. Results: Post establishment of the rescue network, mean first medical contact (FMC) to balloon (FMC-to-B) time, referral time and obtaining informed consent time were all significantly decreased from (191+/-41), (94+/-18), (25+/ 9) minutes to (93+/-19), (53+/-18), (7+/-5) minutes, respectively, in comparison with the pre-network era(all P<0.05). There was a trend of prolonged FMC-to-B time in proportion to aging of STEMI patients(trend P<0.05). Three months post discharge, LVEF was higher (55.3%+/-10.7% vs. 48.8%+/-12.1%, P<0.05) and LVEDd was lower ((49.1+/-10.8)mm vs.(51.8+/-9.2)mm, P<0.05) in the post-network group compared to pre-network group.In-hospital mortality was also significantly reduced post the establishment of the rescue network (2.14%(8/374) vs. 3.89%(7/180), P<0.05). The results also showed that the total costs (42 017(25 069, 75 148)yuan vs.51 030(28 137, 105 861)yuan), days of hospitalization ((9.1+/ 4.5) days vs. (15.3+/-4.8)days) and percentage of medicine and consumables were all significantly decreased in the post-network group compared to pre-network group(all P<0.05). Conclusion: Establishment of the regional cooperative rescue network is feasible among the prefectural-level city hospitals in China. Establishment of such network can improve the prognosis and decrease the FMC-to-B time, the rate of in-hospital mortality and financial burden of patients with STEMI, and serves as an effective strategy to improve the rescue ability for STEMI patients. PMID- 28851190 TI - [Pathological characteristics of the heart and coronary artery from elderly heart failure patients with preserved ejection fraction and coronary artery disease]. AB - Objective: To analyze the pathological feathers of the heart in elderly (60-99 years old) heart failure patients with preserved ejection fraction (HFpEF) and coronary artery disease (CAD) and to explore the misdiagnosis and missed diagnosis rates. Method: This retrospective study included 154 HFpEF (left ventricular ejection fraction (LVEF)>=50%) cases and 49 heart failure with reduced ejection fraction (HFrEF) (LVEF<=40%) cases aged 60-99 years old out of 1 485 consecutive autopsy cases. Pathological changes of the heart and coronary artery were compared between patients with HFpEF and HFrEF. The misdiagnosis and missed diagnosis rates of HFpEF were analyzed based on pathological examination. Results: Patients with HFpEF were older than those with HFrEF ((85.7+/-7.4) vs. (82.9+/-7.8) years old, P=0.017). Among all the cases, CAD was diagnosed in 105 (68.2%) HFpEF patients and 38 (77.6%) HFrEF patients. Compared with patients with HFrEF, HFpEF patients displayed less acute myocardial infarction (12.3%(19/154) vs. 59.2%(29/49), P<0.01) and more chronic myocardial ischemia (18.2%(28/154) vs. 6.1%(3/49), P=0.041). 51.9% (80/154) HFpEF and 71.4% (35/49) HFrEF patients (P=0.017) displayed >50% left anterior descending artery stenosis. Prevalence of >75% coronary arterial stenosis (51% (25/49) vs. 20.1%(31/154), P<0.001) and more than one vessel lesions (55.1%(27/49) vs. 33.8%(52/154), P=0.008) were significantly higher in HFrEF patients than in HFpEF patients. The misdiagnosis rate of CAD in HFpEF was 63.3% (31/49). Among HFpEF, the missed diagnosis rate of acute myocardial infarction was 57.9% (11/19) and the missed diagnosis rate of old myocardial infarction was 57.7% (45/78). Conclusions: CAD and chronic myocardial ischemia are common in elderly patients with HFpEF. Chronic myocardial ischemia may play an important role in the development of HFpEF of elderly CAD patients. Among HFpEF patients, the misdiagnosis rate of CAD and missed diagnosis rate of myocardial infarction are high, so the accurate evaluation of myocardial ischemia status is of great importance. PMID- 28851191 TI - [A pilot study on the noninvasive fluid hemodynamic investigation of coronary plaque]. AB - Objective: To characterize the hemodynamic force towards coronary plaque based on noninvasive coronary computed tomographic angiography and to investigate its relationship with plaque features and stenosis severity by computational fluid dynamics. Methods: Twenty-six patients underwent invasive fractional flow reserve measurement following coronary computed tomography angiography examination from March to September 2016 were retrospectively included. Computational fluid dynamics was applied and wall shear stress (WSS) and axial plaque stress (APS), which extracted the axial component of hemodynamic stress acting on stenotic lesions, were calculated based on the results of noninvasive coronary computed tomographic angiography. Plaque analysis was performed to elucidate plaque features and relative plaque burden. The fluid dynamics distributions in lesions with different stenosis severity were investigated. Results: Thirty-one coronary plaques with satisfactory imaging quality were analyzed, there were 11 (35.5%) dominant low WSS (<1 Pa) lesion and 20 high WSS lesion (64.5%), 8(25.8%) net retrograde APS lesion and 23(74.2%) anterograde lesion. Plaque volume was (78.5+/ 48.6) mm(3) and plaque burden was (69.1+/-12.1)% in the low WSS group, which was(60.5+/-57.3) mm(3), and(57.5+/-14.0)%, respectively in the high WSS group, the plaque burden was significantly higher in the low WSS group than in the high WSS group (P=0.028), while the percentage of calcified plaque, fibrotic plaque and lipid core volume were similar between the two groups (P>0.05). Plaque volume was (79.7+/-69.1) mm(3) and plaque burden was(68.7+/-13.7)% in the group with anterograde-dominant APS plaque, which was(61.7+/-24.9)mm(3), and(68.9+/-10.4)%, respectively in the net retrograde APS lesion group (P>0.05). Percentage of lipid core area was significantly higher in the anterograde lesion group than in the retrograde lesion group ((25.1+/-18.1)% vs.(10.8+/-12.7)%, P=0.049). Both WSS and APS were significant higher in the severe obstructive coronary stenosis group than in non-severe obstructive coronary stenosis group (P<0.05). Although there was no difference in WSS between functional coronary ischemia group and non functional coronary ischemia group ( (13.3+/-8.7) Pa vs. (12.5+/-14.2) Pa, P>0.05), the distribution of APS was different between the functional coronary ischemia group and non-functional coronary ischemia group ((1 698.8+/-652.6) Pa vs. (981.4+/-787.5) Pa, P<0.05). Conclusion: WSS and APS can uniquely characterize the stenotic segment and has a strong relationship with lesion geometry. APS may be related to the necrotic core plaque and functional coronary ischemia. Clinical application of these hemodynamic and geometric indices may be helpful to assess the future risk of plaque progress and plaque rupture, which will be helpful on determining respective treatment strategy for patients with coronary artery disease. PMID- 28851192 TI - [Analysis of pulmonary valve function in patients with tetralogy of Fallot after radical surgery]. AB - Objective: To analyze the pulmonary valve function in patients with tetralogy of Fallot after radical surgery. Methods: Clinical data of 263 patients (119 male, mean age (33.2+/-11.5) years old) with tetralogy of Fallot underwent radical surgery in our hospital from January 2010 to June 2016 were retrospectively analyzed. According to age, patients were divided into 14-17 years old group (14 cases), 18-29 years old group (100 cases), 30-39 years old group (61 cases) and above 40 years old group (87 cases). The patients were divided into pulmonary regurgitation group (87 cases) and control group (176 cases) according to weather they have moderate or severe pulmonary regurgitation. Echocardiographic data were compared among groups. Results: A total of 83 patients received re-operation. The median age of the primary radical operation was 9 (5, 13) years, and the median time from the primary radical operation to echocardiographic follow-up was 5 (1, 13) years. Among the 263 enrolled patients, prevalence of pulmonary regurgitation was 36.1% (95/263), and pulmonary stenosis was evidenced in 28 patients (10.6%). The ratio of moderate to severe tricuspid regurgitation was 14.3% (2/14), 27.0% (27/100), 32.8% (20/61) and 37.9% (33/87) in 14-17 years old group, 18-29 years old group, 30-39 years old group and above 40 years old group, respectively (P=0.029), while prevalence of moderate and severe pulmonary regurgitation, moderate and severe pulmonary valve stenosis, pulmonary valve transvalvular pressure >40 mmHg (1 mmHg=0.133 kPa), right atrial and right ventricular enlargement ratio were similar among groups (all P>0.05). The ratio of moderate and severe tricuspid regurgitation and right ventricular enlargement in the pulmonary regurgitation group was significantly higher than in the control group (40.2% (35/87) vs. 27.3% (48/176) and 96.6% (84/87) vs. 87.5% (154/176), all P<0.05), while left ventricular ejection fraction, right atrial enlargement, and right ventricular wall thickness were similar between the two groups (all P>0.05). Conclusion: Pulmonary regurgitation is a common clinical feature among survivors of tetralogy of Fallot patients after radical surgery, and moderate to severe pulmonary regurgitation increases the risk of tricuspid regurgitation and enlargement of the right ventricle. PMID- 28851193 TI - [Research on the metabolic syndrome and gut microbiota]. PMID- 28851194 TI - [Pay attention to the application of the international intraocular retinoblastoma classification and sequential multiple modality treatment]. AB - Retinoblastoma (RB) is the most common intraocular malignancy in childhood. It may seriously affect vision, and even threaten the life. The early diagnosis rate of RB in China remains low, and the majority of patients are at late phase with high rates of enucleation and mortality. The International Intraocular Retinoblastoma Classification and TNM staging system are guidances for therapeutic choices and bases for prognosis evaluation. Based on the sequential multi-method treatment modality, chemotherapy combined with local therapy is the mainstream in dealing with RB, which may maximize the results of eye saving and even vision retaining. New therapeutic techniques including supra-selective ophthalmic artery interventional chemotherapy and intravitreal chemotherapy can further improve the efficacy of treatment, especially the eye salvage rate. The overall level of RB treatment should be improved by promoting the international staging, new therapeutic techniques, and the sequential multiple modality treatment. (Chin J Ophthalmol, 2017, 53: 561-565). PMID- 28851195 TI - [The key points in intravenous chemotherapy and intra-arterial chemotherapy on retinoblastoma treatment]. AB - Intravenous chemotherapy and intra-arterial chemotherapy (IAC) both are the first line treatment for retinoblastoma (RB) in clinical. There is a controversy on if intra-arterial chemotherapy can substitute the intravenous chemotherapy due to its high eye salvage rate in retinoblastoma therapy. The advantages and disadvantages of these two therapies were retrospectively reviewed here to suggest an individualized and comprehensive regimen for getting the proximal results for retinoblastoma afflicted children. (Chin J Ophthalmol, 2017, 53: 566 569). PMID- 28851196 TI - [Short-term efficacy of intravitreal injection of melphalan for refractory vitreous seeding from retinoblastoma]. AB - Objective: To evaluate the efficacy and safety of intravitreal chemotherapy for refractory vitreous seeding from retinoblastoma. Methods: Retrospective series of case studies. Nine patients (13 eyes) with the diagnosis of refractory vitreous seeding were enrolled in Department of Ophthalmology of Eye& ENT Hospital of Fudan University from March 2014 to October 2015.There were 6 males and 3 females. Children aged 8 to 40 months, median age of 18 months. In the 13 eyes, 3 eyes were E period, 9 eyes were D period, and 1 eyes were C period. The fundus was examined by indirect ophthalmoscope and recorded by RetcamIII. Systemic chemotherapy was performed using the VEC protocol, that is vincristine, etoposide, and carboplatin. Local treatment also involves cryotherapy and/or thermotherapy. All patients were treated with intravitreal injection of melphalan. They underwent intravitreal melphalan, once every 4 weeks, with an average of 3 times of injections. The treatment dose of melphalan is 20 to 40 MUg per dose. Observe the vitreous seed control and complications of therapy. Results: Vitreous seeds control was attained in all cases. There was no case of orbital extension or remote metastasis. Complications included retinal pigment epithelial and choroidal atrophy in 7 eyes, pupillary synechia and iris atrophy in 2 eyes,retinal vasculitis and vascular occlusion in 2 eyes, optic atrophy in 2 eyes, vitreous hemorrhage in 1 eye, and temporary hypotony in 3 eyes. Conclusions: Intravitreal melphalan is an effective treatment for refractory vitreous seeding from retinoblastoma. High dose may lead to local adverse reactions. (Chin J Ophthalmol, 2017, 53: 570-574). PMID- 28851197 TI - [The influence factors of quality-of-life in patients with thyroid-associated ophthalmopathy]. AB - Objective: To assess the risk factors associated with decreased quality-of-life in patients with thyroid-associated ophthalmopathy (TAO). Methods: Cross sectional study. One hundred and twelve patients with TAO and 68 controls were recruited to answer the Graves' ophthalmopathy quality-of-life questionnaire (GO QOL) from January 2014 to April 2016. The GO-QOL included two subscales: the visual functioning and the psychosocial consequences. The differences in the GO QOL scores between TAO patients and controls were analyzed. The influences of multiple factors on the GO-QOL scores among TAO patients were explored. Results: Among 112 TAO patients, 63 were male and 49 were female, with an average age of (45.4+/-13.1) years. Among 68 controls, 36 were male and 32 were female, with an average age of (39.5+/-10.8) years. Independent sample t test showed that TAO patients had significantly lower scores than controls in the visual functioning subscale and the psychosocial consequences subscale (55.63+/-29.02 vs 97.48+/ 6.96, t=-14.58, P<0.01; 57.61+/-29.97 vs100+/-0.00, t=-14.97, P<0.01). Among TAO patients, smokers were associated with significantly lower psychological subscale scores than non-smokers (t=-2.284, P=0.024). Patients with abnormal primary position of eye scored significantly lower than those with normal alignment in functional (t=-3.979, P<0.001) and psychological subscales (t=-2.154, P=0.034) Patients with abnormal eye movement had significantly lower functional scores than those without (t=-2.975, P=0.004). One-way analysis of variance showed that higher CAS scores were significantly related to lower psychological subscale scores (F=3.178, P=0.018). Patients with upper eyelid retraction had significantly lower psychological subscale scores than those without (F=3.562, P=0.032). Pearson correlation analysis showed that age was negatively correlated with functional subscale scores (r=-0.366; P<0.01). TAO course was negatively correlated with functional (r=-0.235, P<0.05) and psychological subscale scores (r=-0.320, P<0.01). The degree of exophthalmos was negatively correlated with psychological subscale scores (r=-0.209, P<0.01). Multivariable linear regression analysis showed that only primary position of eye (P=0.013) and TAO course (P=0.007) were negatively correlated with functional subscale scores and only CAS scores (P=0.022) and TAO course (P=0.024) were negatively correlated with psychological subscale scores. Conclusion: Risk factors associated with lower quality-of-life among TAO patients included abnormal primary position of eye, higher CAS scores, and longer TAO course.(Chin J Ophthalmol,2017,53: 575-582). PMID- 28851198 TI - [Analysis of clinicopathologic characteristics of 422 conjunctival melanocytic nevi specimens]. AB - Objective: To describe the clinicopathologic characteristics of 422 conjunctival melanocytic nevi and detect the incidence of malignancy in those patients. Methods: Retrospective case series study. A retrospective study was conducted by reviewing 422 conjunctival melanocytic nevi specimens obtained at Beijing Tongren Eye Center from June, 2004 to May, 2016. The data included the information of gender, age, clinical and histopathological diagnosis of all collected conjunctival melanocytic nevi cases. All patients were divided into three groups according to age: juvenile groups (<18 years old), young group (18-40 years old) and the elderly group (>40 years old). The histopathology change and its malignant incidence of conjunctival nevi in different age and sex were analyzed by SPSS 18.0 software package. Results: Of the 422 cases, 195 were males and 227 were females (male?female=0.89?1). The average age at surgery was (27.9+/-17.9) years old. The pathological types of conjunctival nevi included compound nevus, intraepithelial nevus and junctional nevus. The most common type of conjunctival nevus was compound nevus (256 cases, 60.7%; mean age (22.2+/-15.4) years old). The second was intraepithelial nevus (130 cases, 30.8%; mean age (37.7+/-16.6) years old). The least was junctional nevus (36 cases, 8.5%, mean age was (32.7+/ 22.4) years old).The average age of patients with different types of conjunctival nevi was statistically significant (F=3.169, P=0.031). Occurrence of conjunctival compound nevus was most common in juvenile group (44.1%), followed by the young group (40.6%), and the elderly group (only 15.2%). Occurrence of conjunctival intraepithelial nevus was the most common in youth group (45.4%), followed by the elderly group (44.6%), and youth group was relatively rare (only 10%). The junctional nevus appeared mainly in elderly group (44.4%), but the junior group also had 13 cases (36.1%) and younger group had 7 cases (19.4%). Among 422 cases of conjunctival nevi, 37 cases transformed into malignant tumor. The canceration rate was 8.8%. The average age of malignant patients was (48.6+/-12.1) years old. Comparing with the patients without malignant, the age was age (25.3+/-4.2) years old and there was a significant difference (t=4.252, P=0.002). Among them, 24 cases (64.9%) came from conjunctival compound nevus and 13 cases (35.1%) came from the junctional nevus. Non malignant cases occurred in patients with conjunctival intradermal nevus. The male and female average age of patients with malignant transformation from compound nevus and junctional nevus were not statistically significant (P=0.730, 0.993). Thirteen cases were occurred malignant change in 36 cases of patients with junctional nevus, accounting for 36.1% of all patients with junctional nevus. It was obviously higher than the average malignant incidence of conjunctival nevi (8.8%). Non malignant junctional nevus were most common in juvenile group, and malignant junctional nevus were most common in the elderly group. Conclusions: The pathological type distribution of conjunctival melanocytic nevi in different age groups was different, and the onset age of different types of melanocytic nevi was also different. Patients with junctional nevus were prone to malignant change, and most of them were middle-aged and elderly patients. (Chin J Ophthalmol, 2017, 53: 583-587). PMID- 28851199 TI - [Clinical analysis of orbital and periorbital abscess in 17 patients]. AB - Objective: To discuss the etiology, clinical features and treatment principles of the orbital and periorbital abscess. Methods: A retrospective case series of 17 cases with orbital and periorbital abscess between July 2010 and November 2015 were conducted. All patients(,) clinical data including medical history, etiology, abscess location, paranasal sinus involvement, eye involvement, microbiological test results, imaging features, treatment and prognosis were summarized and analyzed. Results: In all 17 patients, there were 10 males and 7 females with age from 3.0 to 71.0 years (the average age was 33.9 years).Eight patients(,) bacterial cultures of the pus and secretion were positive in all 17 patients. Orbital and periorbital abscess patients could manifest decreased vision, redness and swelling of eyelid, conjunctival congestion and edema, ocular motility disorders, displacement of eyeball, increased orbital pressure, abscess rupture etc. CT showed us the soft tissue mass, accompanied with sinusitis or paranasal sinus mass. MR performed with the long T(1) and T(2) signals. The signals of the abscess cavity were not uniform. For the etiology,11 cases were secondary to sinusitis, including 1 case of diabetes; 2 cases with orbital fractures.One case was secondary to orbital fracture repairment surgery. One case was secondary to the remnant of sequestrum and foreign bodys in the wound after repairment surgery. One case was injured by the hard object. One case was secondary to paranasal sinuses large B-cell lymphoma. One case had diabetic history and the blood sugar was controlled unstablly. For the treatment, 7 cases were treated by the drainage surgery which was performed via the sinus with endoscopic and abscess resection performed via the skin.Two cases were treatment by the abscess resection only.One case was treated by the drainage surgery performed via the sinus with endoscopic only. Six cases were treated by the drainage surgery performed via the skin. One case was only administered intravenous antibiotic. Sixteen cases acquired well prognosis without serious complications except 1 case which occurred central retinal artery and vein occlusion. Conclusions: The orbital and periorbital abscess is mainly a complication of paranasal sinus infection, or secondary to trauma, surgery, tumor, etc; Orbital and periorbital abscess always manifest inflammatory neoplastic clinical features, the key of the diagnosis is to make sure the etiology; Incision and drainage of the abscess is the main treatment method when necessary. We can do the surgery with other departments to avoid the occurrence of serious complications.(Chin J Ophthalmol, 2017, 53: 588-593). PMID- 28851200 TI - [Clinical analysis of visual loss caused by facial cosmetic fillers injection]. AB - Objective: To investigate the risk factors, clinical manifestations, and treatment of visual loss caused by cosmetic fillers injection. Methods: It was a retrospetive case series study. Collect the clinical data of 18 cases (18 eyes) which were diagnosed as visual loss caused by facial cosmetic fillers injection in the Second Hospital of Dalian Medical University during December, 2014 to June, 2016. Summarize the general condition, medical history, clinical examination results (including visual acuity, intraocular pressure, fundus condition, etc.) and the patient's facial appearance at the time of admission. Take the examinations such as VEP, FFA, OCT, etc. Confirm the composition of the fillers according to the medical history and the product packaging. After the diagnosis, all patients were treated generally combined with intraocular pressure reduction treatment and other treatment measures. Results: All the patients were female, 24-45 years old, with average age of 33.4. The fillers were mainly consisted of hyaluronic acid or autologous fat. For 6 patients the fillers were injected in the forehead, 8 patients were in the nose, the other 4 patients were in both sites. The mean time was 31.7 hours since the onset to the acceptance of medical treatment. All the patients manifested as no light perception, injection site ischemia, different degree of ptosis and fundus examination showed artery occlusion signs. Seventeen patients were central retinal artery occlusion, one was posterior ciliary artery occlusion. After active treatment, 2 patients' visual acuity improved to light perception, one improved to hand movements, while the others had no significant improvement. Conclusions: Most patients who suffered visual loss after cosmetic injections are young or middle-aged women, with most common injection sites at nose or forehead. The visual loss is mainly caused by central retinal artery occlusion which leads to an ineffective clinical treatment. The main factors that may induce artery occlusion are: injection done by informal medical organization, use of non-standard drugs, inadequate understanding of facial anatomy of the operator, and improper injection methods.(Chin J Ophthalmol, 2017, 53: 594-598). PMID- 28851202 TI - [The analysis of the change of the constitution of the admitted patients with glaucoma]. AB - Objective: To analysis of the change of the constitution of the admitted patients with glaucoma in Capital Medical University affiliated Beijing Tongren Hospital between 2003-2005(group 2003) and 2013-2015(group 2013). Methods: The medical charts information of inpatient with glaucoma were collected by ICD-10 of the disease diagnosis. Statistical analysis was conducted for the change of the proportion of types, gender and age. The age difference between two groups was analyzed by rank sum test and the difference of different types of glaucoma was analyzed by chi square test. Results: Totally, 8 160 inpatients cases were included. There were 2 878 cases in the group of 2003 and 5 282 cases in the group of 2013. Between two groups, there was no statistical difference in age. The ratio of male patients decreased from 55.8% (1 607/2 878) to 51.7%(2 732/5 282) (chi(2)=23.73, P<0.05).Primary angle-closure glaucoma(PACG) was the main type (2 987/8 160, 36.6%) followed by secondary glaucoma (SG, 2 172/8 160, 26.6%). PACG reduced from 40.0% (1 151/2 878) to 34.8%(1 836/5 282) (chi(2)=21.99, P<0.01). Congenital glaucoma(CG) increased from 4.6%(132/2 878) to 8.3%(437/5 282)(chi(2)=39.04, P<0.01). Glaucoma related with trauma reduced from 27.2%(208/764) to 18.2%(256/1 408)(chi(2)=24.11, P<0.01). Glaucoma with syndrome increased from 3.8%(29/764) to 7.2%(102/1 408)(chi(2)=10.39, P<0.01). Conclusions: The constitution of the admitted patients with glaucoma in our hospital changed during the ten years. PACG was still the major type of inpatient glaucoma.(Chin J Ophthalmol, 2017, 53: 610-615). PMID- 28851201 TI - [Long-term clinical observation of aspheric multifocal intraocular lens implantation]. AB - Objective: To observe the clinical effect of long term visual quality after the implantation of the aspheric diffractive multifocal intraocular lens. Methods: This was a retrospective cohort study.One hundred and thirty cases of age-related cataract (170 eyes) after phacoemulsification cataract extraction combined with IOL implantation were collected from September of 2009 to January of 2011 in the First Affiliated Hospital of Zhengzhou University.There were 42 patients (57 eyes) with aspheric multifocal group, 43 patients (57 eyes) in the aspheric group and 45 patients (56 eyes) in the spherical group according to the different types of IOL implanted.At 1 year, 3 years and 5 years after operation, the following parameters were assessed: uncorrected and best corrected distance, medium and near vision acuity, contrast sensitivity, wavefront aberrations, modulation transfer functions (MTF), stereopsis, visual function and quality of life (VF/QOL) questionnaire survey. Results: At 1 year, 3 years and 5 years after operation, the uncorrected medium visual acuity in aspheric diffractive multifocal IOL group(0.30(0.10, 0.50), 0.30(0.10, 1.00), 0.30(0.10, 0.50)) was better than that of eyes in aspheric IOL group(0.40 (0.10, 0.0), 0.40 (0.20, 1.00), 0.40 (0.20, 0.50)) (Z(1)=-3.32,-1.73,-3.01, P(1)=0.00, 0.01, 0.00) and spherical IOL group (0.40(0.30, 1.00), 0.40(0.20, 1.00), 0.40(0.20, 1.00)) (Z(2)= 5.77,-3.19,-4.49, P(2)=0.00, 0.00, 0.00).And the near vision in aspheric diffractive multifocal IOL group(0.25(0.00, 1.00), 0.30(0.00, 1.00), 0.30(0.00, 1.00)) was also obviously better than that of eyes in aspheric IOL group (0.50(0.18, 1.00), 0.50(0.18, 1.00), 0.50(0.18, 1.00)) (Z(1)=-5.57,-5.37,-4.93, P(1)=0.00, 0.00, 0.00) and spherical IOL group(0.60(0.18, 1.00), 0.60(0.18, 1.00), 0.60(0.18, 1.00)) (Z(2)=-7.00,-6.91,-6.53, P(2)=0.00, 0.00, 0.00). At 5 years after operation, the mean higher-order aberration for 3.0mm and 5.0mm optical zone in aspheric diffractive multifocal IOL group (0.21(0.03, 0.46), 0.37(0.12, 2.01)) were significantly lower than that in spherical IOL group (0.43(0.10, 1.91), 0.46 (0.10, 1.91) ) (Z(2)=-4.81,-1.97, P(2)=0.00, 0.01).But there was no statistical difference between the aspheric diffractive multifocal and aspheric IOL group (0.21(0.03, 1.17), 0.34(0.06, 1.74)) (Z(1)=-0.10,-1.81, P(1)=0.92, 0.07).The mean spherical aberration for 3.0mm and 5.0mm optical zone in aspheric diffractive multifocal IOL group (0.01(-0.01, 0.20), 0.03(-0.10, 0.20)) were significantly lower than that in spherical IOL group (0.29(0.10, 0.99), 0.32(0.10, 0.99)) (Z(2)=-8.48,-8.54, P(2)=0.00, 0.01).But there was no statistical differences between the aspheric diffractive multifocal and aspheric IOL group (0.02(-0.09, 0.37), 0.04(-0.09, 0.37)) (Z(1)=-0.60,-0.73, P(1)=0.55, 0.46).About 86% of patients in aspheric diffractive multifocal IOL group do not need to wear glasses, it was better than the other two groups (chi(2)=17.83, 24.45, P=0.00, 0.00).The incidence of night glare and halo in aspheric diffractive multifocal IOL group 16/50(32%) was higher than that of aspherical IOL group 5/50(10%) and spherical IOL group 3/50(6%), and the difference was statistically significant (chi(2)=7.29, 10.98, P=0.00, 0.00).The overall satisfaction in aspheric diffractive multifocal IOL group was 45/50 (90%), better than that of aspherical IOL group 29/50(58%) and spherical IOL group 20/50(40%), and the difference was statistically significant (chi(2)=13.31, 27.47, P=0.00, 0.00). Conclusions: The aspheric diffractive multifocal IOL can provide patients with good and stable far, medium and near vision, to meet the needs of patients without glasses.At the same time, it can effectively reduce the high order aberrations and spherical aberration, improve visual quality.But due to night glare and glow, it does not apply to professional drivers and nighttime drivers. (Chin J Ophthalmol, 2017, 53: 599-609). PMID- 28851203 TI - [The progress in the diagnosis and management of orbital lymphoma]. AB - Lymphoma is one of the most common malignant tumor of the orbit in adults. Orbital lymphoma mainly consists of extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, infrequent NK/T cell lymphoma and Burkitt lymphoma. Diagnosis on orbital lymphoma remains challenging in that it is difficult to distinguish it from benign lesions, especially for low degree lymphomas. Combined examinations of histological, cytological and molecular features are required to make final differentiation. There are many treatment options for diagnosis of orbital lymphoma, such as surgical resection, radiotherapy, chemotherapy, monoclonal antibody targeted therapy, immunotherapy. The appropriate scenario of treatment on orbital lymphoma should be made based on the Ann Arbor or TNM staging system to determine the stage of orbital lymphoma at the moment for maximizing the results. The latest concepts on diagnosis and management of orbital lymphoma are reviewed in this paper. (Chin J Ophthalmol, 2017, 53: 632-636). PMID- 28851204 TI - [Prostaglandin-associated periorbitopathy]. AB - Glaucoma is one of the leading causes of blindness in the world, second to cataract. The treatment of glaucoma mainly includes drugs, laser and operation, which can slow down the progress of the disease. Prostaglandin is the first-line medication at present. With the constant promotion of clinical application, the local side effects have been found, such as conjunctival congestion, lash lengthening, periorbital and iris pigment deepening, blepharitis and macular edema. As people pay more attention to appearance, periorbitopathy caused by prostaglandin has been reported in recent years, including upper eyelid ptosis and dermatochalasis, deepening of the upper eyelid sulcus, periorbital fat loss, enophthalmos and inferior scleral exposure. The mechanism, performance and treatment methods of these prostaglandin-associated periorbitopathies are reviewed. (Chin J Ophthalmol, 2017, 53: 637-640). PMID- 28851205 TI - Designing Signal Peptides for Efficient Periplasmic Expression of Human Growth Hormone in Escherichia coli. AB - The secretion efficiency of a protein in a Sec-type secretion system is mainly determined by an N-terminal signal peptide and its combination with its cognate protein. Five signal peptides, namely, two synthetic Sec-type and three Bacillus licheniformis alpha-amylase-derived signal peptides, were compared for periplasmic expression of the human growth hormone (hGH) in E. coli. Based on in silico predictions on the signal peptides' cleavage efficiencies and their corresponding mRNA secondary structures, a number of amino acid substitutions and silent mutations were considered in the modified signal sequences. The two synthetic signal peptides, specifically designed for hGH secretion in E. coli, differ in their N-terminal positively charged residues and hydrophobic region lengths. According to the mRNA secondary structure predictions, combinations of the protein and each of the five signal sequences could lead to different outcomes, especially when accessibility of the initiator ATG and ribosome binding sites were considered. In the experimental stage, the two synthetic signal peptides displayed complete processing and resulted in efficient secretion of the mature hGH in periplasmic regions, as was demonstrated by protein analysis. The three alpha-amylase-derived signal peptides, however, were processed partially from their precursors. Therefore, to achieve efficient secretion of a protein in a heterologous system, designing a specific signal peptide by using a combined approach of optimizations of the mRNA secondary structure and the signal peptide H-domain and cleavage site is recommended. PMID- 28851206 TI - Improvement of the Thermostability of Xylanase from Thermobacillus composti through Site-Directed Mutagenesis. AB - Thermostability is an important property of xylanase because high temperature is required for its applications, such as wood pulp bleaching, baking, and animal feedstuff processing. In this study, XynB from Thermobacillus composti, a moderately thermophilic gram-negative bacterium, was modified via site-directed mutagenesis (based on its 3D structure) to obtain thermostable xylanase, and the properties of this enzyme were analyzed. Results revealed that the half-life of xylanase at 65 degrees C increased from 10 to 50 min after a disulfide bridge was introduced between the alpha-helix and its adjacent beta-sheet at S98 and N145. Further mutation at the side of A153E named XynB-CE in the C-terminal of this alpha-helix enhanced the half-life of xylanase for 60 min at 65 degrees C. Therefore, the mutant may be utilized for industrial applications. PMID- 28851207 TI - Antibacterial Activity of Pharbitin, Isolated from the Seeds of Pharbitis nil, against Various Plant Pathogenic Bacteria. AB - This study aimed to isolate and characterize antibacterial metabolites from Pharbitis nil seeds and investigate their antibacterial activity against various plant pathogenic bacteria. The methanol extract of P. nil seeds showed the strongest activity against Xanthomonas arboricola pv. pruni (Xap) with a minimum inhibition concentration (MIC) value of 250 MUg/ml. Among the three solvent layers obtained from the methanol extract of P. nil seeds, only the butanol layer displayed the activity with an MIC value of 125 MUg/ml against Xap. An antibacterial fraction was obtained from P. nil seeds by repeated column chromatography and identified as pharbitin, a crude resin glycoside, by instrumental analysis. The antibacterial activity of pharbitin was tested in vitro against 14 phytopathogenic bacteria, and it was found to inhibit Ralstonia solanacearum and four Xanthomonas species. The minimum inhibitory concentration values against the five bacteria were 125-500 MUg/ml for the n-butanol layer and 31.25-125 MUg/ml for pharbitin. In a detached peach leaf assay, it effectively suppressed the development of bacterial leaf spot, with a control value of 87.5% at 500 MUg/ml. In addition, pharbitin strongly reduced the development of bacterial wilt on tomato seedlings by 97.4% at 250 MUg/ml, 7 days after inoculation. These findings suggest that the crude extract of P. nil seeds can be used as an alternative biopesticide for the control of plant diseases caused by R. solanacearum and Xanthomonas spp. This is the first report on the antibacterial activity of pharbitin against phytopathogenic bacteria. PMID- 28851208 TI - Whole-Body Microbiota of Sea Cucumber (Apostichopus japonicus) from South Korea for Improved Seafood Management. AB - Sea cucumber (Apostichopus japonicus) is a popular seafood source in Asia, including South Korea, and its consumption has recently increased with recognition of its medicinal properties. However, because raw sea cucumber contains various microbes, its ingestion can cause foodborne illness. Therefore, analysis of the microbiota in the whole body of sea cucumber can extend our understanding of foodborne illness caused by microorganisms and help to better manage products. We collected 40 sea cucumbers from four different sites in August and November, which are known as the maximum production areas in Korea. The microbiota was analyzed by an Illumina MiSeq system, and bacterial amounts were quantified by real-time PCR. The diversity and bacterial amounts in sea cucumber were higher in August than in November. Alpha-, Beta-, and Gammaproteobacteria were common dominant classes in all samples. However, the microbiota composition differed according to sampling time and site. Staphylococcus warneri and Propionibacterium acnes were commonly detected potential pathogens in August and November samples, respectively. The effect of experimental Vibrio parahaemolyticus infection on the indigenous microbiota of sea cucumber was analyzed at different temperatures, revealing clear alterations of Psychrobacter and Moraxella; thus, these shifts can be used as indicators for monitoring infection of sea cucumber. Although further studies are needed to clarify and understand the virulence and mechanisms of the identified pathogens of sea cucumber, our study provides a valuable reference for determining the potential of foodborne illness caused by sea cucumber ingestion and to develop monitoring strategies of products using microbiota information. PMID- 28851210 TI - A Comparative Study of Central Hemodynamics in Parkinson's Disease. AB - OBJECTIVE: To explore the central aortic pressure in patients with Parkinson's disease (PD). METHODS: We investigated central arterial stiffness by measurement of the augmentation index (AIx) in PD patients. Patients were eligible for the study if they were de novo PD and 45 years of age or older. The patients' demographics, vascular risk factors, and neurologic examinations were collected at baseline. The AIx was measured by applanation tonometry. RESULTS: A total of 147 subjects (77 in control and 70 in PD groups) were enrolled in the study. While there was no significant difference in peripheral systolic blood pressure (SBP), diastolic blood pressure (DBP), or mean arterial pressure between groups, peripheral pulse pressure (PP) was significantly lower in the PD group than in the control group (p = 0.012). Regarding central pressure, aortic DBP was significantly higher and PP was significantly lower in the PD group (p = 0.001, < 0.0001). Although there was no significant difference in the AIx between the groups, a trend toward a lower AIx was observed in the PD group (31.2% vs. 28.1%, p = 0.074). CONCLUSION: This study showed that peripheral and central PP was significantly lower in the PD group than in the control group. Our study suggests that PD patients may have a low risk of a cardiovascular event by reason of a lower PP. PMID- 28851209 TI - Quantitative Gait Analysis in Patients with Huntington's Disease. AB - OBJECTIVE: Gait disturbance is the main factor contributing to a negative impact on quality of life in patients with Huntington's disease (HD). Understanding gait features in patients with HD is essential for planning a successful gait strategy. The aim of this study was to investigate temporospatial gait parameters in patients with HD compared with healthy controls. METHODS: We investigated 7 patients with HD. Diagnosis was confirmed by genetic analysis, and patients were evaluated with the Unified Huntington's Disease Rating Scale (UHDRS). Gait features were assessed with a gait analyzer. We compared the results of patients with HD to those of 7 age- and sex-matched normal controls. RESULTS: Step length and stride length were decreased and base of support was increased in the HD group compared to the control group. In addition, coefficients of variability for step and stride length were increased in the HD group. The HD group showed slower walking velocity, an increased stance/swing phase in the gait cycle and a decreased proportion of single support time compared to the control group. Cadence did not differ significantly between groups. Among the UHDRS subscores, total motor score and total behavior score were positively correlated with step length, and total behavior score was positively correlated with walking velocity in patients with HD. CONCLUSION: Increased variability in step and stride length, slower walking velocity, increased stance phase, and decreased swing phase and single support time with preserved cadence suggest that HD gait patterns are slow, ataxic and ineffective. This study suggests that quantitative gait analysis is needed to assess gait problems in HD. PMID- 28851211 TI - Comment on "Clinical significance of changes in the corrected QT interval in stress-induced cardiomyopathy". PMID- 28851212 TI - Lignosulfonate Improves Photostability and Bioactivity of Abscisic Acid under Ultraviolet Radiation. AB - Abscisic acid (ABA), as a commonly used plant growth regulator, is easy to be degraded and lose its bioactivity under sunshine. To select an eco-friendly and efficient photoprotectant for the improvement of photostability and bioactivity of ABA when exposed to ultraviolet (UV) light, we tested the effects of three biodegradable natural-derived high polymers, sodium lignosulfonates 3A [molecular weight (MW) > 50000, with degree of sulfonation (DS) of 0.48] and NA (20000 < MW < 50000, with DS of 0.7) and calcium lignosulfonate CASA (MW < 20000, with DS of 0.7), on the photodegradation of ABA. Lignosulfonates 3A, NA, and CASA showed significant photostabilizing capability on ABA. Lignosulfonate 3A showed preferable photostabilizing effects on ABA compared to CASA, while NA showed an intermediate effect. That indicated that lignosulfonate with a high MW and low DS had a stronger UV absorption and the hollow aggregate micelles formatted by lignosulfonate protect ABA from UV damage. Approximately 50% more ABA was kept when 280 mg/L ABA aqueous solution was irradiated by UV light for 2 h in the presence of 2000 mg/L lignosulfonate 3A. The bioactivity on wheat (JIMAI 22) seed germination was greatly kept by 3A in comparison to that of ABA alone. The 300 times diluent of 280 mg/L ABA plus 2000 mg/L 3A after 2 h of irradiation showed 20.8, 19.3, and 9.3% more inhibition on shoot growth, root growth, and root numbers of wheat seed, separately, in comparison to ABA diluent alone. We conclude that lignosulfonate 3A was an eco-friendly and efficient agent to keep ABA activity under UV radiation. This research could be used in UV-sensitive and water-soluble agrichemicals and to optimize the application times and dosages of ABA products. PMID- 28851214 TI - Experimental and Computational Investigation of Salophen-Zn Gas Phase Complexes with Cations: A Source of Possible Interference in Anionic Recognition. AB - We explore the possibility that protonated molecular ions might be an unexpected source of interference in the recognition process of anions and neutral species by Zn-salophen receptors. Zn-salophen complexes are known to bind anions and neutral molecules in solution. We present here evidence (from computational work and IRMPD spectroscopy) that these complexes can also be the binding site for protonated pyridine or quinuclidine. The resulting binding pattern does not involve the Zn ion, but one of the oxygen atoms directly attached to it. The resulting complex therefore turns out to have a positive charge adjacent to the Zn-salophen binding site. This finding seems to point to the existence of an interfering factor in the quantification of the experimental data about the association constant. PMID- 28851213 TI - Dynamics at a Peptide-TiO2 Anatase (101) Interface. AB - The interface between biological matter and inorganic materials is a widely investigated research topic due to possible applications in biomedicine and nanotechnology. In this context, the molecular level adsorption mechanism that drives specific recognition between small peptide sequences and inorganic surfaces represents an important topic likely to provide much information useful for designing bioderived materials. Here, we investigate the dynamics at the interface between a Ti-binding peptide sequence (AMRKLPDAPGMHC) and a TiO2 anatase surface by using molecular dynamics (MD) simulations. In the simulations the adsorption mechanism is characterized by diffusion of the peptide from the bulk water phase toward the TiO2 surface, followed by the anchoring of the peptide to the surface. The anchoring is mediated by the interfacial water layers by means of the charged groups of the side chains of the peptide. The peptide samples anchored and dissociated states from the surface and its conformation is not affected by the surface when anchored. PMID- 28851215 TI - LiF as an Artificial SEI Layer to Enhance the High-Temperature Cycle Performance of Li4Ti5O12. AB - Li4Ti5O12 (LTO) is a promising anode material for electric vehicles (EVs) and electrochemical energy storage applications because of its safety, good rate capability, and long cycle life. At elevated temperature, such as 60 degrees C, it always shows poor cycle performance because of the instability between the electrode material and electrolyte, which may also lead to a serious gassing issue. In this article, a facile hydrothermal method is adopted to coat the LTO powder with a thin LiF layer, in which the LiF acts as an artificial solid electrolyte interface (SEI) layer to prevent the direct contact of LTO and electrolyte, thus improving the high-temperature cycle performance. Electrochemical tests prove that the LiF coating layer has no influence on the kinetics at ambient temperature and greatly enhances the high-temperature cycle stability, and the LTO@LiF composite material keeps 87% of its initial discharge capacity in 300 1C cycles at 60 degrees C. Moreover, the LiF coating layer exhibits a special self-driven reforming process during the initial cycles, which makes it uniform and more effective at enhancing the stability between electrode/electrolyte interfaces. PMID- 28851216 TI - Activation Thermodynamics and H/D Kinetic Isotope Effect of the Hox to HredH+ Transition in [FeFe] Hydrogenase. AB - Molecular complexes between CdSe nanocrystals and Clostridium acetobutylicum [FeFe] hydrogenase I (CaI) enabled light-driven control of electron transfer for spectroscopic detection of redox intermediates during catalytic proton reduction. Here we address the route of electron transfer from CdSe->CaI and activation thermodynamics of the initial step of proton reduction in CaI. The electron paramagnetic spectroscopy of illuminated CdSe:CaI showed how the CaI accessory FeS cluster chain (F-clusters) functions in electron transfer with CdSe. The Hox >HredH+ reduction step measured by Fourier-transform infrared spectroscopy showed an enthalpy of activation of 19 kJ mol-1 and a ~2.5-fold kinetic isotope effect. Overall, these results support electron injection from CdSe into CaI involving F clusters, and that the Hox->HredH+ step of catalytic proton reduction in CaI proceeds by a proton-dependent process. PMID- 28851218 TI - Surface Properties of Al-Functionalized Mesoporous MCM-41 and the Melting Behavior of Water in Al-MCM-41 Nanopores. AB - We report an experimental investigation of structural and adhesive properties for Al-containing mesoporous MCM-41 and MCM-41 surfaces. In this work, highly ordered hexagonal mesoporous structures of aluminosilica with two different Si/Al molar ratios equal to 50 and 80 and silica samples were studied; Al was incorporated into the MCM-41 structures using the direct synthesis method, with CTAB as a surfactant. The incorporation of aluminum was evidenced simultaneously without any change in the hexagonal arrangement of cylindrical mesopores. The porous materials were examined by techniques such as low-temperature nitrogen sorption, energy-dispersive spectroscopy, and scanning and transmission electron microscopy. Surface properties were determined through X-ray photoelectron spectroscopy, potentiometric titration, and static contact angle measurements. It was shown that an increase in surface acidity leads to an increase in the wetting energy of the surface. To investigate the influence of acidity on the confinement effects, the melting behavior of water in Al-MCM-41 and MCM-41 with the same pore size was determined by using dielectric relaxation spectroscopy and differential scanning calorimetry methods. We found that the melting-point depression of water in pores is larger in the functionalized pores than in pure silica pores of the same pore diameter. PMID- 28851217 TI - Mechanism of Nitrogenase H2 Formation by Metal-Hydride Protonation Probed by Mediated Electrocatalysis and H/D Isotope Effects. AB - Nitrogenase catalyzes the reduction of dinitrogen (N2) to two ammonia (NH3) at its active site FeMo-cofactor through a mechanism involving reductive elimination of two [Fe-H-Fe] bridging hydrides to make H2. A competing reaction is the protonation of the hydride [Fe-H-Fe] to make H2. The overall nitrogenase rate limiting step is associated with ATP-driven electron delivery from Fe protein, precluding isotope effect measurements on substrate reduction steps. Here, we use mediated bioelectrocatalysis to drive electron delivery to the MoFe protein allowing examination of the mechanism of H2 formation by the metal-hydride protonation reaction. The ratio of catalytic current in mixtures of H2O and D2O, the proton inventory, was found to change linearly with the D2O/H2O ratio, revealing that a single H/D is involved in the rate-limiting step of H2 formation. Kinetic models, along with measurements that vary the electron/proton delivery rate and use different substrates, reveal that the rate-limiting step under these conditions is the H2 formation reaction. Altering the chemical environment around the active site FeMo-cofactor in the MoFe protein, either by substituting nearby amino acids or transferring the isolated FeMo-cofactor into a different peptide matrix, changes the net isotope effect, but the proton inventory plot remains linear, consistent with an unchanging rate-limiting step. Density functional theory predicts a transition state for H2 formation where the S-H+ bond breaks and H+ attacks the Fe-hydride, and explains the observed H/D isotope effect. This study not only reveals the nitrogenase mechanism of H2 formation by hydride protonation, but also illustrates a strategy for mechanistic study that can be applied to other oxidoreductase enzymes and to biomimetic complexes. PMID- 28851219 TI - Not All beta-Sheets Are the Same: Amyloid Infrared Spectra, Transition Dipole Strengths, and Couplings Investigated by 2D IR Spectroscopy. AB - We report the transition dipole strengths and frequencies of the amyloid beta sheet amide I mode for the aggregated proteins amyloid-beta1-40, calcitonin, alpha-synuclein, and glucagon. According to standard vibrational coupling models for proteins, the frequencies of canonical beta-sheets are set by their size and structural and environmental disorder, which determines the delocalization length of the vibrational excitons. The larger the delocalization the lower the frequency of the main infrared-allowed transition, A?. The models also predict an accompanying increase in transition dipole strength. For the proteins measured here, we find no correlation between transition dipole strengths and amyloid beta sheet transition frequency. To understand this observation, we have extracted from the protein data bank crystal structures of amyloid peptides from which we calculate the amide I vibrational couplings, and we use these in a model beta sheet Hamiltonian to simulate amyloid vibrational spectra. We find that the variations in amyloid beta-sheet structures (e.g., dihedral angles, interstrand distances, and orientations) create significant differences in the average values for interstrand and nearest neighbor couplings, and that those variations encompass the variation in measured A? frequencies. We also find that off diagonal disorder about the average values explains the range of transition dipole strengths observed experimentally. Thus, we conclude that the lack of correlation between transition dipole-strength and frequency is caused by variations in amyloid beta-sheet structure. Taken together, these results indicate that the amide I frequency is very sensitive to amyloid beta-sheet structure, the beta-sheets of these 4 proteins are not identical, and the assumption that frequency of amyloids scales with beta-sheet size cannot be adopted without an accompanying measurement of transition dipole strengths. PMID- 28851220 TI - Biomimetic Strategy To Reversibly Trigger Functionality of Catalytic Nanocompartments by the Insertion of pH-Responsive Biovalves. AB - We describe an innovative strategy to generate catalytic compartments with triggered functionality at the nanoscale level by combining pH-reversible biovalves and enzyme-loaded synthetic compartments. The biovalve has been engineered by the attachment of stimuli-responsive peptides to a genetically modified channel porin, enabling a reversible change of the molecular flow through the pores of the porin in response to a pH change in the local environment. The biovalve functionality triggers the reaction inside the cavity of the enzyme-loaded compartments by switching the in situ activity of the enzymes on/off based on a reversible change of the permeability of the membrane, which blocks or allows the passage of substrates and products. The complex functionality of our catalytic compartments is based on the preservation of the integrity of the compartments to protect encapsulated enzymes. An increase of the in situ activity compared to that of the free enzyme and a reversible on/off switch of the activity upon the presence of a specific stimulus is achieved. This strategy provides straightforward solutions for the development of catalytic nanocompartments efficiently producing desired molecules in a controlled, stimuli responsive manner with high potential in areas, such as medicine, analytical chemistry, and catalysis. PMID- 28851221 TI - Combined Effects of Early Season Leaf Removal and Climatic Conditions on Aroma Precursors in Sauvignon Blanc Grapes. AB - Early leaf removal around the cluster zone is a common technique applied in cool climate viticulture, to regulate yield components and improve fruit quality. Despite the increasing amount of information on early leaf removal and its impact on total soluble solids, anthocyanins, and polyphenols, less is known regarding aroma compounds. In order to verify the hypothesis that defoliation, applied before or after flowering, could impact the biosynthesis of thiol precursors, we performed a two year (2013 and 2014) experiment on Sauvignon blanc. We provided evidence that differential accumulation of thiol precursors in berries is affected by the timing of defoliation, and this impact was related to modifications in the biosynthetic pathway. Furthermore, the possible interaction between leaf removal treatment and seasonal weather conditions, and its effect on the biosynthesis of volatile precursors are discussed. Our results suggested that in Sauvignon blanc the relative proportion of 4-S-glutathionyl-4-methylpentan-2 one (G-4MSP) and 3-S-glutathionylhexan-1-ol (G-3SH) precursors can be affected by defoliation, and this could be related to the induction of two specific genes encoding glutathione-S-transferases (VvGST3 and VvGST5), while no significant effects on basic fruit chemical parameters, polyphenols, and methoxypyrazines were ascertained under our experimental conditions. PMID- 28851222 TI - Highly Selective Sub-ppm Naked-Eye Detection of Hydrazine with Conjugated-1,3 Diketo Probes: Imaging Hydrazine in Drosophila Larvae. AB - A pair of pyrene- and anthracene-based turn-on fluorescent probes (1 and 2, respectively) reported here can be easily synthesized in a single-step process and also exhibit outstanding sensing behavior toward hydrazine over various competing nucleophilic species and environmentally relevant ions. The probes display dramatic enhancements in the emission intensity with as high as 83- and 173-fold increases in the presence of hydrazine. Nitrogenous bases, thiols, and lanthanides do not interfere in the fluorometric detection. These probes enable the detection of hydrazine with the naked eye well below sub-ppm concentrations (ca. 30 ppb) with analytical detection limits of 5.4 ppb for 1 and 7.7 ppb for 2, which are far exceeded by the accepted lower limit for hydrazine (10 ppb) set by the US EPA. Simple paper strips based on these probes could be used for the detection of hydrazine even in the gas phase. Both of the probes could selectively detect hydrazine even in pond water samples efficiently. The probes were successfully applied to visualize, for the first time, accumulation of hydrazine in live fruit-fly larvae using epifluorescence microscopy. The novel and interesting detection mechanism, proposed on the basis of spectroscopic evidence and single crystal XRD results, indicates that the detection pathway proceeds via the initial step of a five-membered ring formation upon attack of the hydrazine, followed by a dehydration step for gaining aromaticity. PMID- 28851223 TI - Binding of Thioflavin T and Related Probes to Polymorphic Models of Amyloid-beta Fibrils. AB - Alzheimer's disease is a challenge of the utmost importance for contemporary society. An early diagnosis is essential for the development of treatments and for establishing a network of support for the patient. In this light, the deposition in the brain of amyloid-beta fibrillar aggregates, which is a distinctive feature of Alzheimer, is key for an early detection of this disease. In this work we propose an atomistic study of the interaction of amyloid tracers with recently published polymorphic models of amyloid-beta 1-40 and 1-42 fibrils, highlighting the relationship between marker architectures and binding affinity. This work uncovers the importance of quaternary structure, and in particular of junctions between amyloid-beta protofilaments, as the key areas for marker binding. PMID- 28851224 TI - A Pulse of Mercury and Major Ions in Snowmelt Runoff from a Small Arctic Alaska Watershed. AB - Atmospheric mercury (Hg) is deposited to Polar Regions during springtime atmospheric mercury depletion events (AMDEs) that require halogens and snow or ice surfaces. The fate of this Hg during and following snowmelt is largely unknown. We measured Hg, major ions, and stable water isotopes from the snowpack through the entire spring melt runoff period for two years. Our small (2.5 ha) watershed is near Barrow (now Utqiagvik), Alaska. We measured discharge, made 10 000 snow depths, and collected over 100 samples of snow and meltwater for chemical analysis in 2008 and 2009 from the watershed snowpack and ephemeral stream channel. Results show an "ionic pulse" of mercury and major ions in runoff during both snowmelt seasons, but major ion and Hg runoff concentrations were roughly 50% higher in 2008 than in 2009. Though total discharge as a percent of total watershed snowpack water equivalent prior to the melt was similar in both years (36% in 2008 melt runoff and 34% in 2009), it is possible that record low precipitation in the summer of 2007 led to the higher major ion and Hg concentrations in 2008 melt runoff. Total dissolved Hg meltwater runoff of 14.3 (+/- 0.7) mg/ha in 2008 and 8.1 (+/- 0.4) mg/ha in 2009 is five to seven times higher than that reported from other arctic watersheds. We calculate 78% of snowpack Hg was exported with snowmelt runoff in 2008 and 41% in 2009. Our results suggest AMDE Hg complexed with Cl- or Br- may be less likely to be photochemically reduced and re-emitted to the atmosphere prior to snowmelt, and we estimate that roughly 25% of the Hg in snowmelt is attributable to AMDEs. Projected Arctic warming, with more open sea ice leads providing halogen sources that promote AMDEs, may provide enhanced Hg deposition, reduced Hg emission and, ultimately, an increase in snowpack and snowmelt runoff Hg concentrations. PMID- 28851226 TI - Tailored polyelectrolyte thin film multilayers to modulate cell adhesion. AB - The layer-by-layer assembly of polyelectrolyte multilayers (PEMs) from natural or synthetic polyelectrolytes constitutes a very versatile and simple strategy to modify surfaces and modulate cell behavior. PEMs assembled from natural polyelectrolytes are very appealing for biological and medical applications due to their high biocompatibility. However, PEMs from natural polyelectrolytes display poor cell adhesion as they are soft materials with an elasticity modulus of a few kilopascal. In this report, the authors present results on the modulation of cell adhesion of different immortalized cell lines by PEMs. Two strategies are employed to vary cell adhesion: (1) a heterogeneous polyelectrolyte multilayer is assembled employing a rigid bottom block including a synthetic polyelectrolyte with a soft upper block of natural polyelectrolytes and (2) polyelectrolyte multilayers from natural polyelectrolytes are thermally annealed after assembly. The physicochemical characteristics of the PEMs change upon thermal treatment. Depending on the composition of the polyelectrolyte multilayer, cell adhesion may be enhanced or reduced. Based on the impact on PEM properties and cell adhesion caused by thermal annealing, a temperature gradient is applied to a PEM of poly-l-lysine/alginate to induce a spatial variation of PEM properties, resulting in a gradient in cell adhesion. The strategies shown here can be employed as simple alternatives to tailor PEM properties by means of fully biocompatible procedures. PMID- 28851227 TI - Caspofungin on ARGET-ATRP grafted PHEMA polymers: Enhancement and selectivity of prevention of attachment of Candida albicans. AB - There is a need for coatings for biomedical devices and implants that can prevent the attachment of fungal pathogens while allowing human cells and tissue to appose without cytotoxicity. Here, the authors study whether a poly(2 hydroxyethylmethacrylate) (PHEMA) coating can suppress attachment and biofilm formation by Candida albicans and whether caspofungin terminally attached to surface-tethered polymeric linkers can provide additional benefits. The multistep coating scheme first involved the plasma polymerization of ethanol, followed by the attachment of alpha-bromoisobutyryl bromide (BiBB) onto surface hydroxyl groups of the plasma polymer layer. Polymer chains were grafted using surface initiated activators regenerated by electron transfer atom transfer radical polymerization with 2-hydroxyethylmethacrylate, yielding PHEMA layers with a dry thickness of up to 89 nm in 2 h. Hydroxyl groups of PHEMA were oxidized to aldehydes using the Albright-Goldman reaction, and caspofungin was covalently immobilized onto them using reductive amination. While the PHEMA layer by itself reduced the growth of C. albicans biofilms by log 1.4, the addition of caspofungin resulted in a marked further reduction by >4 log units to below the threshold of the test. The authors have confirmed that the predominant mechanism of action is caused by antifungal drug molecules that are covalently attached to the surface, rather than out-diffusing from the coating. The authors confirm the selectivity of surface-attached caspofungin in eliminating fungal, not mammalian cells by showing no measurable toxicity toward the myeloid leukaemia suspension cell line KG-1a. PMID- 28851228 TI - Rural multidisciplinary training: opportunity to focus on interprofessional rapport-building. AB - In 2016, the Australian Government committed further funds in support of quality rural health education to improve the health and wellbeing of rural and remote communities. The stated funding requirement for longer rural placements in all disciplines is an exciting opportunity for greater investment in interprofessional education to foster collaborative practice, a global system imperative for health care. This commentary explores how findings from earlier research, which investigated how students in a co-located area learn to work with other health professions, can be translated into practice. While recognising the importance of an individual's interpersonal capabilities, this commentary focuses on how the core contextual conditions for interprofessional rapport-building opportunities (shared space, adequate time and balance of disciplines) were considered in one rural centre. Educational leaders and academics globally should recognise that offering health professional students opportunity to live and work together in extended placements in rural settings has potential benefits for interprofessional education. Understanding the contextual conditions for building rapport between health professional learners, and reflecting on these, potentially will lay the foundation for collaborative practice when these learners become health professionals. Through the reflective questions we pose, policy-makers, health managers and clinical leaders from all health disciplines can build on this foundation by considering the interpersonal capability and contextual conditions for rapport building in the health workforce to foster a collaborative practice environment for graduates to embrace when they enter the health workplace. PMID- 28851229 TI - The California HIV/AIDS Research Program: History, Impact, and HIV Cure Initiative. AB - This Special Issue of AIDS Research and Human Retroviruses features results from the HIV Cure Initiative, funded by the California HIV/AIDS Research Program (CHRP). As a publicly funded grant maker, CHRP has served for more than three decades as a unique resource for innovative researchers in California, whose work seeks to address all aspects of the HIV epidemic and the communities affected by it. Early initiatives at CHRP pioneered what would become enduring cornerstones of HIV science: isolation of the virus; efficacy and toxicities of the first HIV treatments; the emergence of drug resistance; the first biospecimen banks for HIV related research; the first community-based laboratory service for HIV diagnostic serology; and the first longitudinal case-control study of progression from HIV to AIDS-The San Francisco General Hospital Cohort. More recently, CHRP-funded conceptual studies of zinc-finger nuclease-mediated disruption of CCR5 genomic sequences and the safety of solid organ transplantation for HIV-positive patients have progressed from brilliant ideas to clinical realities, and CHRP is currently funding the first multisite trial of HIV preexposure prophylaxis for transgender persons in the United States. The present article outlines the founding of CHRP, our current grantmaking process, and our impact on HIV research over time. In 2013, CHRP launched a new initiative aimed at moving the then nascent frontier of HIV cure science forward: the CHRP HIV Cure Initiative provided over $1.4 million to multiple basic biomedical research projects, and selected results are presented in this Special Issue. PMID- 28851230 TI - Post-stroke depression as a predictor of caregivers burden of acute ischemic stroke patients in China. AB - Our aim was to explore the independent attribution of Post-stroke depression (PSD) to caregiver burden of acute ischemic stroke patients. A cross-sectional survey was performed with 271 acute ischemic stroke patients in the Huai-He Hospital and First People's Hospital of Kaifeng City in China. PSD was assessed by Self-rating Depressive Scale, and caregiver burden was assessed by Zarit Caregiver Burden Interview. Clustered logistic regression was applied to identify the impact of PSD on caregiver burden. As results, female patients, normal muscle strength and PSD were associated with caregiver burden. PSD correlated with an independent influence of 17.2% on the risk of caregiver burden, The independent influence of PSD on caregiver burden was smaller than that of social-demographics of caregivers and clinical factors of stroke patients This study suggests that PSD may have a modest influence on caregiver burden. PMID- 28851231 TI - In-Law Preferences in China: What Parents Look for in the Parents of Their Children's Mates. AB - Across different times and cultures, parents play an important role in influencing their children's mating decisions. When they do so, they aim to forge useful alliances with other parents which raises the question of what parents look for in the latter. The current research aims to address this question. In particular, we employed an online sample of 925 Chinese parents who were asked to rate the desirability of 88 traits in the parents of prospective mates for their children. Principal components analysis classified these traits in eight factors for the mothers and 10 factors of interest for the fathers of their children's mates. We also found that parents had a well-defined hierarchy of preferences, fathers, and mothers were in agreement in what they looked for in a prospective in-law, but their preferences were contingent to the sex of the in-law. PMID- 28851232 TI - Renewing the call for public health advocacy against nuclear weapons. PMID- 28851233 TI - Shuttle walk tests in people with COPD who demonstrate exercise-induced oxygen desaturation: An analysis of test repeatability and cardiorespiratory responses. AB - Exercise-induced oxygen desaturation (EID) is prevalent in people with chronic obstructive pulmonary disease (COPD). This article reports a sub-analysis from a randomized controlled trial (RCT) in people with COPD and EID (COPD/EID). The primary aim, in people with COPD/ EID, was to determine the repeatability of the distance and time walked in the incremental shuttle walk test (ISWT) and endurance shuttle walk test (ESWT), respectively. A secondary aim was to determine whether any participant characteristics predicted those who did not demonstrate improvements on a repeat ISWT or ESWT. Participants with nadir oxygen saturation (SpO2) < 90% on the 6-minute walk test were recruited to the RCT. Two ISWTs and two ESWTs were then performed as part of the baseline assessments, and participants were included in this sub-analysis if their nadir SpO2 was <90% during the better of two ISWTs. Repeatability of the tests was analysed using Bland-Altman plots and paired t-tests. Participant characteristics of age, lung function, level of nadir SpO2 and end-test dyspnoea were used to predict those who were not likely to demonstrate improvements on a repeat test using receiver operating curves. Eighty-seven participants (mean age (standard deviation, SD) 70 (7) years; forced expiratory volume in one second (FEV1) 47 (17)% predicted) were included. The mean differences (coefficient of repeatability) for the ISWTs and ESWTs were 9 m (55 m) and 19 seconds (142 seconds) respectively ( p < 0.05). No participant characteristic predicted the absence of improvement on the second ISWT (area under the curve (AUC) ranged from 0.49 to 0.58, all p > 0.2) or the second ESWT (AUC ranged from 0.43 to 0.52, all p > 0.3). Although repeating the tests showed only small improvements in distance (ISWT) and time (ESWT) walked in people with COPD/EID, the variability was large making definite conclusions about test repeatability in these individuals difficult. PMID- 28851235 TI - An Incentivized, Workplace Physical Activity Intervention Preferentially Increases Daily Steps in Inactive Employees. AB - : Although physical activity (PA) is associated with decreased risk of chronic diseases, fewer than half of American adults meet the recommendations for daily PA, in part, due to large amounts of sedentary time in the workplace. PURPOSE: To determine the efficacy of an incentivized workplace PA intervention. DESIGN: Retrospective cohort design. SETTING: Large southeastern university. PARTICIPANTS: Of the 16 588 eligible employees working >=8 h/wk, 6246 (37.6%) participated and 2206 (13.3%) were included in data analysis. INTERVENTION: Six week PA intervention with tiered incentives (value: $10.50-$29.00). MEASURES: Steps/day measured via consumer-grade PA monitors for 1-week pre-, 6-weeks during, and 1-week postintervention. ANALYSIS: Participants were grouped by preintervention PA into 4 groups: <6000 (I); 6000 to 7999 (II); 8000 to 9999 (III); and >=10 000 (IV) steps/d ( n = 481, 540, 485, and 700, respectively) in accordance with the tiered incentive schedule. Statistical comparisons were made by repeated-measures analysis of variance. RESULTS: During the intervention, participants achieving >=10 000 steps/d increased by 60%. Groups I, II, and III significantly increased steps/day during the intervention (46%, 24%, and 11%, respectively), which was partially maintained in groups I and II 1-week postintervention. Group IV did not increase steps/day during the intervention and significantly decreased steps/day 1-week postintervention. The estimated cost per participant of this intervention increased with from group I ($55.41) to IV ($71.90). CONCLUSION: An incentivized, workplace PA intervention preferentially increases PA and is most cost-effective among university employees with low initial PA who may benefit substantially from increased levels of PA. PMID- 28851234 TI - Depression Screening and Health Outcomes in Children and Adolescents: A Systematic Review. AB - OBJECTIVE: Depression screening among children and adolescents is controversial. In 2009, the United States Preventive Services Task Force first recommended routine depression screening for adolescents, and this recommendation was reiterated in 2016. However, no randomized controlled trials (RCTs) of screening were identified in the original 2009 systematic review or in an updated review through February 2015. The objective of this systematic review was to provide a current evaluation to determine whether there is evidence from RCTs that depression screening in childhood and adolescence improves depression outcomes. METHOD: Data sources included the MEDLINE, MEDLINE In-Process, EMBASE, PsycINFO, Cochrane CENTRAL and LILACS databases searched February 2, 2017. Eligible studies had to be RCTs that compared depression outcomes between children or adolescents aged 6 to 18 years who underwent depression screening and those who did not. RESULTS: Of 552 unique title/abstracts, none received full-text review. No RCTs that investigated the effects of screening on depression outcomes in children or adolescents were identified. CONCLUSIONS: There is no direct RCT evidence that supports depression screening among children and adolescents. Groups that consider recommending screening should carefully consider potential harms, as well as the use of scarce health resources, that would occur with the implementation of screening programs. PMID- 28851236 TI - Factors That Influence Blood Pressure in 3- to 5-Year-Old Children: A Pilot Study. AB - While incident elevations in blood pressure (BP) are apparent in preschool years, factors influencing BP in this population have received little attention. The purposes of this pilot study were to determine the feasibility of collecting data from preschoolers and their mothers and to determine effect sizes of relationships between BP and sex, race, birth status, body mass index (BMI), waist circumference (WC), geographic location, serum C-reactive protein (CRP), and salivary cortisol (morning, afternoon). A hypothesis-generating correlational design was used; 56 children, aged 3-5 years, were enrolled from six rural and urban Head Start programs in a southeastern state. On Day 1 of data collection, mothers completed demographic questionnaires and children had blood drawn by finger stick. On Day 2, children gave saliva samples for cortisol, were measured for height by stadiometer, weight by digital scales, and WC by tape measure and had their BP measured by Dinamap. Incident elevations in BP were found in 30% of children (17/56), the majority of which were of systolic BP; 65% of those with elevations were of normal weight. Data collection was feasible with few problems. Small-to-medium effect sizes were noted for BP status (normal, prehypertensive, and hypertensive) and cortisol p.m. and birth status (parent-reported prematurity or term); small effect sizes were seen for BP status and BMI, race, sex, and geographic location. CRP and cortisol had medium- and small-to-medium effect sizes, respectively, with diastolic blood pressure. Studies with larger, more diverse samples need to be conducted to test hypotheses posited from these estimated effect sizes. PMID- 28851237 TI - "She Gave Me the Confidence to Open Up": Bridging Communication by Promotoras in a Childhood Obesity Intervention for Latino Families. AB - Childhood obesity is a public health threat that disproportionally affects Latino youth in the United States. Active and Healthy Families (AHF) is a culturally tailored, family-based program for addressing obesity disparities in a predominantly immigrant Latino population. AHF was the first primary care, culturally tailored intervention for Latino children to significantly reduce BMI in a randomized controlled trial. The 10-week AHF intervention reduced BMI (kg/m2) among overweight or obese children by 0.5, compared with an increase of 0.3 in the control group, yielding a -0.8 difference ( p < .01). A unique aspect of the program is its provider team: a physician, dietitian, and promotora. Because early feedback from families highlighted the importance of promotoras specifically, we sought to understand the unique mechanisms of promotora effectiveness in AHF. We conducted in-depth, semistructured interviews with the AHF providers ( n = 5) and parent participants ( n = 23) by phone between November 2012 and May 2013. In a grounded theory analysis, three main categories encompassing five themes emerged: (a) bridging communication by promotoras; (b) promotoras' personal qualities, including themes of kindness and caring and shared experiences with patients; and (c) impactful task performance, including themes of motivation, positive environment, and self-efficacy. Together, the themes serve as the basis of a conceptual model illustrating the process through which promotoras may enhance the impact of team-based obesity programs for the Latino community. Because this study identifies the specific ways through which promotoras can bridge cultural, linguistic, and other divides, it may inform development and dissemination of evidence-based approaches for obesity prevention in the Latino community. PMID- 28851238 TI - The effects of four days of intensive mindfulness meditation training (Templestay program) on resilience to stress: a randomized controlled trial. AB - The interest in mindfulness meditation interventions has surged due to their beneficial effects in fostering resilience and reducing stress in both clinical and non-clinical populations. However, the relaxation benefits that may occur while practicing mindfulness meditation and long-term benefits of these interventions remain unclear. Fifty-one participants were recruited and randomized into the experimental and control groups, which underwent 4 days of Intensive Meditation (Templestay program, n = 33) and Relaxation (Control, n = 18), respectively. The self-report measures of Cognitive and Affective Mindfulness Scale-Revised (CAMS) and the modified Korean version of the Resilience Quotient Test (RQT) were administered pre-, post- and 3 months after the intervention to measure participants' levels of mindfulness and resilience. Participants in both the Templestay program and Control groups showed significant increases in their scores on CAMS and RQT after completing the program. During the 3-month follow-up, a significant interaction effect of the intervention method and time was revealed for the individuals' CAMS and RQT scores. Our findings support the hypothesis that while relaxation practices may have certain stress reduction effects, the effects are predominantly mediated by the mindfulness meditation practice. Furthermore, the long-term benefits of increased resilience observed in the Templestay program group suggest that the practice may be a possible treatment strategy in clinical populations, such as patients with depression and anxiety. PMID- 28851239 TI - A correlation between sickness or injury within two weeks, chronic diseases and fatigue among adults aged 18-45 years. AB - To investigate the prevalence of fatigue, the relationship between sickness or injury within two weeks, chronic diseases and fatigue among adults aged 18-45 years. Thousand five hundred and seventy nine individuals were included in this cross-sectional study. The Chalder Fatigue Scale (CFS) was used to assess fatigue defined as CFS score >=4. The prevalence of fatigue was 25% in this study. Our results showed that only sickness or injury within two weeks (odds ratio [OR]: 2.440) and chronic diseases (OR: 1.727) were significantly related to fatigue. Moreover, their ORs for fatigue remained the same in all models (binary logistic regression models with adjusting for demographic and health-related characteristics one by one). In conclusion, fatigue was prevalent among adults aged 18-45 years. Sickness or injury within two weeks and chronic diseases were the risk factors for fatigue independent of demographic and health-related characteristics. PMID- 28851240 TI - African American Women and Obesity Through the Prism of Race. AB - BACKGROUND: There are minimal studies focusing on African American women and obesity, and there are even fewer studies examining obesity through a critical race theoretical framework. African American obesity research has largely focused on individual and community interventions, which have not been sufficient to reverse the obesity epidemic. PURPOSE: The purpose of this study was to examine the relationship between race and body mass index (BMI) for African American women. METHOD: Previously collected data from the National Survey of American Life Self-Administered Questionnaire, 2001-2003 (NSAL-SAQ) was analyzed for this study. The NSAL-SAQ dedicated a section to the exploration of group and personal identity, along with having anthropometric data and health habit questions to be able to conduct analyses for associations between the racial identity dimensions and obesity. RESULTS: Multiple linear regression was used to examine the constructs of racial identity on BMI comparing standardized coefficients (beta) and R2adj values. Results indicated participants ascribing more to the stereotype of "Blacks giving up easily" (beta = 0.527, p = .000) showed an increased BMI. Additionally, the negative stereotype of "Blacks being violent" (beta = 0.663, p = .000) and "Blacks being lazy" (beta = 0.506, p = .001) was associated with an increased BMI. CONCLUSIONS: Based on these finds high negative racial regard is associated with increased weight. This study contributes uniquely to the scientific literature, focusing on the construct of racial identity and obesity in African American women. PMID- 28851241 TI - Obesity's impact on intrapartum electronic fetal monitoring. AB - OBJECTIVE: The objective of this study is to evaluate the impact maternal obesity has on the percentage of unmonitored electronic fetal monitoring (EFM). STUDY DESIGN: Women undergoing induction of labor at term were categorized into three groups: Group 1 (body mass index (BMI) < 30 kg/m2), Group 2 (30 < BMI < 40 kg/m2), and Group 3 (BMI >= 40 kg/m2). External EFM tracings were reviewed from the time of induction of labor until amniotomy; the percentage of time off of EFM was calculated. Statistical analysis was performed using commercially available software. RESULTS: Three hundred and thirty-seven patients were stratified into the following groups: 104 patients in Group 1, 156 patients in Group 2, and 77 in Group 3. No significant differences were found between groups when analyzed for gestational age, bishop score, parity, race, and 5 min APGAR less than 7 or admission to the NICU. The mean percentage unmonitored by EFM was 5% for Group 1, 7% for Group 2 and 11% for Group 3. There was a significant association between percent of time unmonitored by EFM and BMI (r = 0.344 p < .0001). CONCLUSION: At term gestation, the fetuses of obese women spend more time unmonitored by external intrapartum EFM than non-obese women. This represents a disparity among a high-risk group that may result in poor pregnancy outcomes if fetal distress is present. PMID- 28851242 TI - Evaluation of agreement of placental growth factor (PlGF) tests and the soluble FMS-like tyrosine kinase 1 (sFlt-1)/PlGF ratio, comparison of predictive accuracy for pre-eclampsia, and relation to uterine artery Doppler and response to aspirin. AB - OBJECTIVES: The objective of this study is to evaluate agreement between PlGF and sFlt-1/PlGF ratio tests and compare their predictive accuracy for pre-eclampsia in high-risk women. Also, to examine for associations of abnormal PlGF or sFlt 1/PlGF ratio with abnormal uterine artery Doppler and platelet response to aspirin. METHODS: Prospective cohort study, 150 pregnant women at high risk of pre-eclampsia prescribed 75 mg aspirin daily. Uterine artery Dopplers were assessed at 20+0-23+6 weeks. At 33+0-35+6 weeks platelet function aspirin metabolites, PlGF and the sFlt-1/PlGF ratio were measured. OUTCOME: Measures were all pre-eclampsia and pre-eclampsia requiring delivery prior to 37 weeks. RESULTS: Overall percent agreement was 89.3% for PlGF tests but 74.7-78% for PlGF tests and the sFlt-1/PlGF ratio. AUCs were 0.70-0.75 for prediction of any pre eclampsia and 0.92-0.99 for preterm pre-eclampsia. We found a significant association between abnormal PlGF or sFlt-1/PlGF ratio and abnormal uterine artery Doppler (chi2 5.47, p = .019), but no association with platelet response to aspirin (chi2 0.12, p = .913). There were no associations between suboptimal aspirin adherence and either abnormal angiogenic markers or uterine artery Dopplers (chi2 0.144, 0.038, p = .704, .846, respectively). CONCLUSIONS: There was good agreement between PlGF tests and limited agreement between PlGF tests and the sFlt-1/PlGF ratio. All tests have heightened predictive accuracy for preterm pre-eclampsia. Abnormal PlGF or sFlt-1/PlGF ratio relates to abnormal uterine artery Doppler but not platelet response to aspirin. PMID- 28851243 TI - Binimetinib for the treatment of NRAS-mutant melanoma. AB - INTRODUCTION: Activating NRAS mutations occur in approximately 15-20% of melanomas and are the second most common oncogenic driver mutation in this disease, after BRAF mutations. There is an unmet medical need for new targeted therapy opportunities in metastatic patients whose tumors harbor an NRAS mutation. Binimetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, has shown clinical activity in this group of patients. Areas covered: The purpose of this paper was to review the safety, activity and efficacy of the MEK inhibitor binimetinib for the treatment of NRAS-mutant melanoma, as well as to discuss future therapeutic perspectives such as multiple pathways, targeted therapy, and combinations with immunotherapy. Expert commentary: Only a modest progression-free survival (PFS) benefit was observed in NRAS-mutated patients who received binimetinib compared with dacarbazine in a randomized phase 3 clinical trial, with no improvement in overall survival. Nevertheless, binimetinib represents another promising treatment option for advanced melanoma and the first molecularly targeted therapy for the NRAS-mutant population. Binimetinib may also have a role in treating NRAS-mutated melanoma patients after failure of immunotherapy. PMID- 28851244 TI - Preliminary evaluation of a novel non-linear frequency compression scheme for use in children. AB - OBJECTIVE: The primary goal of this study was to evaluate a new form of non linear frequency compression (NLFC) in children. The new NLFC processing scheme is adaptive and potentially allows for a better preservation of the spectral characteristics of the input sounds when compared to conventional NLFC processing. DESIGN: A repeated-measures design was utilised to compare the speech perception of the participants with two configurations of the new adaptive NLFC processing to their performance with the existing NLFC. The outcome measures included the University of Western Ontario Plurals test, the Consonant-Nucleus Consonant word recognition test, and the Phonak Phoneme Perception test. STUDY SAMPLE: Study participants included 14 children, aged 6-17 years, with mild-to severe low-frequency hearing loss and severe-to-profound high-frequency hearing loss. RESULTS: The results indicated that the use of the new adaptive NLFC processing resulted in significantly better average word recognition and plural detection relative to the conventional NLFC processing. CONCLUSION: Overall, the adaptive NLFC processing evaluated in this study has the potential to significantly improve speech perception relative to conventional NLFC processing. PMID- 28851245 TI - Pharmacoeconomic analysis for pemetrexed as a maintenance therapy for NSCLC patients with patient assistance program in China. AB - OBJECTIVE: This study is to evaluate the costs, clinical efficacy, and social benefits of a patient assistance program (PAP) implemented by the China Primary Healthcare Foundation for the use of pemetrexed as a first-line non-squamous non small cell lung cancer (NSCLC) maintenance therapy in China. METHODS: A survival analysis was conducted on the clinical data of 1,366 patients who participated in the PAP. The progression-free survival (PFS) and median maintenance treatment cycle of pemetrexed were analyzed. A 36-month Markov model from a payer's perspective was constructed to analyze the cost and effectiveness associated with the PAP for pemetrexed. The inputs of the model were sourced from the PAP clinical database and published literature. The study estimated the incremental quality adjusted life-years (QALYs) (pemetrexed plus best supportive care [BSC] vs BSC only), the cost saving of the PAP, the impact on the percentage of catastrophic health expenditures (CHE), and poverty headcount ratio (HCR). RESULTS: The median of PFS and maintenance treatment cycles were 187 days and five cycles (total nine cycles, which included four cycles of induction therapy), respectively. The pemetrexed plus BSC treatment with PAP resulted in an additional 0.12 QALYs over BSC only. The total cost was $48,034.46 and $96,191.57 for the patients who had or had not joined the PAP in 3 years, respectively. Compared to the patients without PAP, the percentage of CHE and HCR with PAP was reduced from 98.39% to 19.91% and 66.98% to 4.89%, respectively, indicating that the PAP substantially decreased the number of patients who had CHE and fallen into poverty. CONCLUSION: The study concluded that the pemetrexed PAP generated noticeable clinical and economic benefits to society and to patients. The program also increased patients' compliance with chemotherapy by allowing patients, for whom the pemetrexed treatment was unaffordable, to continue to receive it. PMID- 28851246 TI - Single center validation of mortality scores in patients with acute decompensation of cirrhosis with and without acute-on-chronic liver failure. AB - OBJECTIVES: Acute decompensation (AD) of cirrhosis is characterized by high mortality. We aimed to validate the performance in predicting mortality of both the chronic-liver-failure-consortium (CLIF-C) acute-on-chronic liver failure (ACLF) and CLIF-C AD scores in a cohort of patients admitted for AD. METHODS: In this prospective cohort study, patients were followed-up during their hospital stay and for 365 days thereafter. RESULTS: About 182 patients with AD were enrolled including 78 (42.8%) who met the criteria for ACLF (ACLF-group) while the remaining had AD without ACLF (AD-group). 56.4% and 56.7% of the ACLF- and AD groups, respectively, had alcoholic cirrhosis and 85.9% of the ACLF-group hepatic encephalopathy. Only few patients were hospitalized in the intensive care unit (ICU) or transplanted. The probabilities of death estimated for both scores were similar to the overall mortality rates observed at all time points. The model had a good fit in the AD-group at 90 days (p = .974) but a worse, yet adequate, in the ACLF-group at 28 days (p = .08). The CLIF-C ACLF or AD scores had an adequate, predictive discrimination ability for mortality at all time points, with Harrel's concordance index-C ranging between 0.64 and 0.65 or 0.64 and 0.68, respectively. Both scores showed a similar predictive accuracy for mortality compared to those of MELD, MELD-Na and Child-Pugh. CONCLUSIONS: In this population without access to appropriate ICU treatment, the CLIF-C ACLF and AD performed worse than in studies with patients having ICU access. In addition, the CLIF scores were not superior to classical ones in this setting. PMID- 28851248 TI - Long-term testosterone treatment during pregnancy does not alter insulin or glucose profile in a sheep model of polycystic ovary syndrome. AB - The administration of testosterone to pregnant sheep to resemble fetal programming of the polycystic ovary syndrome could alter other hormones/factors of maternal origin with known effects on fetal growth. Hence, we studied the weekly profile of insulin, progesterone and glucose during a treatment with testosterone propionate given biweekly from weeks 5 to 17 of pregnancy (term at 21 weeks) and checked the outcome of their fetuses at 17 weeks of gestation after C-section. Control dams were only exposed to the vehicle of the hormone. The testosterone administration did not cause any significant change in the maternal weekly profile of insulin, progesterone or glucose concentration, although the plasma levels of testosterone in the treated dams were inversely correlated to the levels of progesterone. Testosterone treatment also induced an inverse correlation between mean maternal insulin levels and fetal insulin levels; however, the fetal zoometric parameters, body weight, or insulin levels did not differ between exposed and not exposed fetuses. Therefore, treatment with testosterone during pregnancy does not cause significant impact on insulin levels in the mother, leading to less effect on the programming of fetal growth. PMID- 28851247 TI - A novel vehicle for local protein delivery to the inner ear: injectable and biodegradable thermosensitive hydrogel loaded with PLGA nanoparticles. AB - Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon alpha-2 b (IFN alpha-2 b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi solid gel at 37 degrees C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy. PMID- 28851249 TI - Bacterial pneumonia in patients with liver cirrhosis, with or without HIV co infection: a possible definition of antibiotic prophylaxis associated pneumonia (APAP). AB - : Introducion: Bacterial infections frequently complicate liver cirrhosis. The aim of this study was to identify risk factors and clinical impact of bacterial pneumonia in patients with cirrhosis. MATERIALS AND METHODS: Bacterial infection prevalence study: consecutive patients with cirrhosis were enroled over a six month period in 13 Italian centres. Pneumonia and other infections were diagnosed by standard methods. Pneumonia study: cirrhotic patients with pneumonia were enroled for an additional six-month period and HIV-positive patients were included. RESULTS: Pneumonia was the fourth most frequent infection. In the two parts of the study, 79 cases of pneumonia were recorded and 441 patients with cirrhosis without infections served as controls. Seventy-eight patients had extra pulmonary infections. There were no clinical differences between HIV-negative and -positive cases with pneumonia. Previous gastro-intestinal bleeding (p = .02) and long-term prophylactic antibiotic use (p < .0001) were associated with pneumonia. Hospital stay was longer and renal failure more frequent than in patients without infections. Pneumonia was hospital acquired (HAP) in 6 cases, healthcare associated (HCAP) in 24 and community acquired (CAP) in 28. A new category of antibiotic prophylaxis associated pneumonia (APAP) was proposed for 21 cases. Cultures were positive in 21/79 patients (26.6%) with Gram-positive isolates in 57%. Unfavourable outcomes were recorded in 11.4% of the cases (3.6% of CAP, 33% of HAP, 12.5% of HCAP and 14.3% of APAP). CONCLUSIONS: Receiving antibiotic prophylaxis was associated with pneumonia and the study identified a new sub group of patients, who require broad spectrum initial antibiotic therapy. PMID- 28851250 TI - Influence of External Beam Radiotherapy on the Properties of Polymethyl Methacrylate-Versus Silicone-Induced Membranes in a Bilateral Segmental Bone Defect in Rats. AB - INTRODUCTION: Standard care for malignant tumors arising next to a bone structure is surgical removal with safety margins, followed by external beam radiotherapy (EBRT). Complete tumor removal can result in large bone defects. A two-step bone reconstruction technique using the induced membrane (IM) technique has proven its efficacy to bridge gap nonunion. During the first step, a spacer is placed in the bone gap. The spacer then is removed and the IM around it is filled with autologous cancellous bone graft. However, the feasibility of this technique with the addition of adjuvant EBRT between the two reconstruction steps has not yet been studied. Polymethyl methacrylate (PMMA) used to be the standard spacer material for the first step. Silicone spacers could replace them owing to their good behavior when submitted to EBRT and their easier removal from the surgical site during the second step. The aim of this study was to evaluate the influence of EBRT on the histological and biochemical properties of IM induced using PMMA or silicone as spacer. MATERIALS AND METHODS: The analyses were performed on PMMA or silicone-IM with and without EBRT in a 6-mm bilateral femoral defect in 32 rats. Thickness and vessel content were measured in both groups. Bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF) content in lysates of the crushed membranes were measured by enzyme immunoassay. Finally, alkaline phosphatase activity was analyzed in human bone marrow stromal cell cultures in contact with the same lysates. RESULTS: EBRT did not change the histological structure of the cellular internal layer or the fibrous outer layer. The nature of the spacer only influenced IM thickness, PMMA-IM with external radiotherapy being significantly thicker. EBRT decreased the vascular density of IM but was less effective on VEGF/BMP2 production. In vitro, IM could have an osteoinductive potential on human bone marrow stem cells. CONCLUSION: EBRT did not modify the histological properties of IMs but decreased their vascular density. VEGF and BMP2 production within IMs was not affected by EBRT. Silicone spacers are able to induce membranes with similar histological characteristics to PMMA-IM. PMID- 28851252 TI - Fetal heart rate changes observed on the CTG trace during instrumental vaginal delivery. AB - INTRODUCTION: Instrumental vaginal delivery (IVD) helps expedite delivery during second stage of labour so as to avoid a second stage caesarean section. However, due to mechanical effects on the fetal head, vacuum and forceps may cause cardiotocograph (CTG) abnormalities due to vigal stimulation as well as increased intracranial pressure. OBJECTIVE: To determine the features observed on the CTG during IVD in term pregnancy and correlate them to perinatal outcomes. METHODS: A retrospective analysis of 445 cases who had vacuum deliveries (227) and forceps deliveries (218) at St. George's University Hospitals NHS Foundation Trust during a 12-month period was performed. CTG features were analysed at 10 minutes prior to and immediately after applications of the chosen instrument till delivery. Specific abnormalities were correlated to Apgar score and umbilical blood pH. RESULTS: Specific CTG abnormalities after applications of vacuum and forceps were: tachycardia (99 (43.61%) versus 88 (40.37%)), increased baseline fetal heart rate (FHR) [14 (6.17%) versus 4 (1.83%) p = .0204], baro-receptor-mediated "variable" deceleration (101 (44.49%) versus 85 (38.99%)), chemoreceptor-mediated "late" deceleration (62 (27.31%) versus 76 (34.86%)), prolonged deceleration (32 (14.10%) versus 24 (11.01%)), saltatory pattern [35 (15.42%) versus 76 (34.86%) p < .0001], and reduced baseline variability (10 (4.41%) versus 7 (3.21%)). There were no significant differences in the mean Apgar Scores at 1 and 5 minutes between ventouse and forceps delivery (8 and 9, respectively) or the umbilical blood pH (both >7.20). CONCLUSIONS: After application of instruments, 90% of CTG traces showed abnormal features. Tachycardia, baro- and chemoreceptor-mediated decelerations, and saltatory patterns were the most common abnormalities. Increased baseline FHR during vacuum as compared to forceps delivery was possibly secondary to pain/pressure and resultant sympathetic overactivity. The saltatory pattern was more common in forceps deliveries, possibly secondary to increased intracranial pressure and resultant autonomic instability. Despite these CTG abnormalities, the perinatal outcomes were good. PMID- 28851251 TI - Targeting Aging with Functional Food: Pasta with Opuntia Single-Arm Pilot Study. AB - Interventions to extend life span represent the new perspective in aging investigation. Healthy dietary habits are important modifiable factors that can favor a healthy aging phenotype. Many studies have demonstrated benefits for metabolic syndrome and type 2 diabetes mellitus resulting from the traditional Mediterranean foods. Opuntia Ficus Indica (OFI), widespread in the Mediterranean basin, belongs to the Cactaceae family. It is known for its antioxidant and anti inflammatory properties. Moreover, products containing extracts from OFI fruits or cladodes have been used to control obesity and other metabolic parameters, such as glycemia and lipid profile. The aim of this study was to analyze the antioxidant and anti-inflammatory effect of pasta with 3% of OFI cladode extracts added to show its beneficial effect in human health. We performed a single arm longitudinal intervention study in 42 healthy volunteers, administrating 500 g/week of this functional pasta for 30 days. Our pasta had antioxidant and anti inflammatory properties with putative effect on the aging process and related metabolic diseases. We also demonstrated a hypoglycemic effect. The results are preliminary, but it is possible to speculate that our pasta could be considered an effective food for the prevention of age-related metabolic disorders. PMID- 28851253 TI - Pedicled Transplantation of Axially Vascularized Bone Constructs in a Critical Size Femoral Defect. AB - INTRODUCTION: Axial vascularization represents a mandatory requirement for clinically applied larger scale vascularized bone grafts. The aim of this study was to combine the arteriovenous (AV) loop model in the rat with a critically sized femoral bone defect and to successfully transplant axially vascularized bone constructs into the defect. MATERIALS AND METHODS: In Groups A and C, an AV loop together with a clinically approved hydroxyapatite and beta-tricalcium phosphate (HA/beta-TCP) matrix, mesenchymal stem cells, and recombinant human bone morphogenetic protein 2 were implanted into a newly designed porous titanium chamber with an integrated osteosynthesis plate in the thighs of rats, whereas in Groups B and D, the same matrix composition without AV loop and, in Group E, only the HA/beta-TCP matrix were implanted. After 6 weeks, the constructs were transplanted into a 10 mm femoral defect created in the same leg, in Groups A and C, under preservation of the AV loop pedicle. Group F served as a control group with an empty chamber. Ten days (Groups A and B) and 12 weeks (Groups C-F) after transplantation, the femora together with the constructs were explanted and investigated using computed tomography (CT), micro-CT, X-ray, histology, and real time polymerase chain reaction (RT-PCR). RESULTS: Ten days after transplantation, Group A showed a maintained vascular supply leading to increased vascularization, cell survival in the scaffold center, and bone generation compared to Group B. After 12 weeks, there was no difference detectable among all groups regarding total vessel number, although Group C, using the AV loop, still showed increased vascularization of the construct center compared to Groups D and E. In Group C, there was still enhanced bone generation detectable compared to the other groups and increased bony fusion rate at the proximal femoral stump. CONCLUSIONS: This study shows the combination of the AV loop model in the rat with a critically sized femoral defect. By maintenance of the vascular supply, the constructs initially showed increased vascularization, leading to increased bone formation and bony fusion in the long term. PMID- 28851254 TI - Quantitative prediction of the extent of drug-drug interaction using a physiologically based pharmacokinetic model that includes inhibition of drug metabolism determined in cryopreserved hepatocytes. AB - 1. A physiologically based pharmacokinetic (PBPK) model that includes inhibition constant evaluated in cryopreserved hepatocytes was used to predict drug-drug interactions (DDIs) between orally administered nifedipine, a CYP substrate, and fluconazole or ketoconazole, CYP inhibitors, in rats. 2. The Kp,uu, ratio of unbound inhibitor concentration in liver ([I]liver,u) to that in plasma ([I]sys,u), of fluconazole and ketoconazole was 1.0 and 13.0, indicating that ketoconazole accumulates in liver. The ratios of inhibition constants in rat liver microsomes (Ki,mic,u) to that in rat cryopreserved hepatocytes (Ki,hep,u) for fluconazole and ketoconazole were 1.5 and 25.5, which were similar to the Kp,uu and suggested that cryopreserved hepatocytes could mimic the hepatic accumulation of inhibitors. 3. The increases in AUC of nifedipine predicted by the minimal PBPK model using [I]liver,u/Ki,mic,u and [I]sys,u/Ki,hep,u were within 1.5-fold of the observed values for both inhibitors, whereas the model using [I]sys,u/Ki,mic,u underestimated the AUC increase caused by ketoconazole 21 fold. 4. These results indicated that hepatic accumulation factor of an inhibitor is required for a precise DDI projection and that cryopreserved hepatocytes would be useful to obtain the Ki including hepatic accumulation factor. It was demonstrated that PBPK model using Ki,hep,u could be a valuable approach for quantitative DDI projection. PMID- 28851255 TI - Comparison of radial access versus femoral access with the use of a vascular closure device for the prevention of vascular complications and mortality after percutaneous coronary intervention. AB - BACKGROUND: Radial access (RA) and vascular closure devices (VCD) have been shown to be superior to transfemoral access (TFA) with regard to the prevention of vascular complications after percutaneous coronary intervention (PCI). OBJECTIVE: The present study evaluates whether RA is associated with less vascular complications and a lower mortality than VCD. METHODS: A total of 6999 consecutive PCI patients were studied through a single-centre prospective registry from January 2011 to August 2015. RA was applied in 1385 patients (20%), VCDs with Angio-Seal were implanted in 2145 patients (30%) and manual compression of TFA was performed in 3468 patients (50%). RESULTS: RA and VCD patients had comparable baseline risk profiles. The overall vascular complication rate was 2.0% (n = 137) and was composed of false aneurysms (n = 85), clinically relevant haematomas (n = 27), arteriovenous fistulas (n = 12), arterial occlusions (n = 11) and local infections (n = 2). Vascular complications occurred in 0.6% of RA patients, 1.8% of VCD patients and 2.6% of TFA patients (p < .01). In-hospital mortality was 0.8% in RA patients, 0.8% in VCD patients and 3.8% in TFA patients (p < .01). In a multivariate logistic regression model, RA, compared to VCD, was found to be independently associated with a lower rate of vascular complications (OR: 0.34, 95% CI: 0.16-0.75), but not with lower mortality rates (OR: 1.20, 95% CI: 0.51-2.85). CONCLUSION: In this large all-comers PCI population, the radial approach, compared to the femoral approach with VCD use (Angio-Seal), was independently associated with a reduction of vascular complications, but not with lower mortality rates. PMID- 28851256 TI - Preparation and in vivo evaluation of anti-plasmodial properties of artemisinin loaded PCL-PEG-PCL nanoparticles. AB - PURPOSE: Artemisinin (ART) has anti-inflammatory, antimicrobial, antioxidant, anti-amyloid, and anti-malarial effects, but its application is limited due to its low water solubility and poor oral bioavailability. In this study, the bioavailability, water solubility, and anti-plasmodial property of ART were improved by PCL-PEG-PCL tri-block copolymers. METHODS: The structure of the copolymers was characterized by 1H NMR, FT-IR, DSC, and GPC techniques. ART was encapsulated within micelles by a single-step nano-precipitation method, leading to the formation of ART-loaded PCL-PEG-PCL micelles. The obtained micelles were characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). The in vivo anti-plasmodial activity of ART-loaded micelles was measured against Plasmodium berghei infected Swiss albino mice. RESULTS: The results showed that the zeta potential of ART-loaded micelles was about -8.37 mV and the average size was 91.87 nm. ART was encapsulated into PCL-PEG-PCL micelles with a loading capacity of 19.33 +/- 0.015% and encapsulation efficacy of 87.21 +/- 3.32%. In vivo anti-plasmodial results against P. berghei showed that multiple injections of ART-loaded micelles could prolong the circulation time and increase the therapeutic efficacy of ART. CONCLUSION: These results suggested that PCL-PEG PCL micelles would be a potential carrier for ART for the treatment of malaria. PMID- 28851257 TI - Social participation in working-age adults with aphasia: an updated systematic review. AB - BACKGROUND: A previous systematic review found limited data regarding social participation in working-age people with aphasia (PWA). A review of recent studies may reveal more information on challenges in reestablishing social roles. METHOD: The aim was to provide an updated systematic review on social participation in PWA under 65 years of age. Studies from 2005 to 2017 were searched from Scopus, Pubmed, and Psychinfo. Search terms were derived from the International Classification of Functioning, Disability and Health (ICF) and the Aphasia- Framework for Outcomes Measures (A-FROM). Aspects of domestic life, interpersonal relations and interactions, education and employment, and community, civic, and social life were investigated. RESULTS: From 2864 initial hits, 11 studies were identified, all of which were on the American Speech Language-Hearing Association (ASHA) Level III of evidence. The studies indicated that participation in domestic life is reduced and PWA showed reduced social networks, loss of friendships and changes in the quality of marital relations. Few PWA returned to work or spent time on education. Limitations in community, civic, and social life were noted and there were contradictory findings on the impact of contextual factors on social participation. There was an increase in research into contextual factors impacting on social participation in PWA and in the use of conceptual frameworks in the last decade. CONCLUSIONS: While the ICF conceptual framework is increasingly used, no studies used the A-FROM. There is greater use of standardized assessments and larger sample sizes. PMID- 28851258 TI - In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits. AB - Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect. PMID- 28851259 TI - Does transient elastography correlate with liver fibrosis in patients with PSC? Laennec score-based analysis of explanted livers. AB - BACKGROUND AND AIMS: Previous studies demonstrated a close correlation between transient elastography (TE) and liver histology in chronic liver diseases. Data on the accuracy of TE in primary sclerosing cholangitis (PSC) remains scarce. Here, we investigated the association between TE, serum marker of liver injury and histology of explanted livers in PSC patients. METHODS: Thirty patients were prospectively recruited. TE (Fibroscan(r)) and blood sampling were performed during evaluation for liver transplantation (LT); the second blood sampling was performed on the day of LT. Fibrosis of explanted livers according to the seven point Laennec staging system and liver collagen contents were measured. RESULTS: TE correlated with Laennec stages of fibrosis (p = .001), collagen contents (p < .001) and with diameter of thickest septa (p = .034) in explanted livers. It also correlated with serum indices of liver injury, namely AST, bilirubin as well as FIB-4 and APRI scores (all p < .05). In a multivariate model, only liver fibrosis, according to either Laennec score (p = .035) or collagen contents (p = .005), was significantly associated with TE. Finally, patients with cirrhosis had increased liver stiffness (p = .002) and the TE cut-off of 13.7 kPa showed the best predictive value (AUC = .90, 95% CI: 0.80-1.00, p < .001) for detecting cirrhosis. CONCLUSIONS: TE correlates with liver fibrosis and markers of liver injury in patients with PSC. However, liver fibrosis seems to be the strongest predictor of liver stiffness assessed with TE. Hence, we postulate that TE is a reliable tool for non-invasive monitoring of PSC. PMID- 28851261 TI - Do Lower-Risk Thyroid Cancer Patients Who Live in Regions with More Aggressive Treatments Have Better Outcomes? AB - BACKGROUND: The management of differentiated thyroid cancer has traditionally consisted of total thyroidectomy with or without adjuvant radioactive iodine. However, in the last two decades, this approach has been challenged, with the consideration of more conservative approaches such as less radical surgery and deferring adjuvant treatment, especially in lower-risk patients. The objective of this study was to consider the effectiveness of current treatment options by comparing the survival outcomes from different geographic regions with different treatment philosophies. This study design was based on the concept of natural experiments in patient care that occur when physicians in different regions treat the spectrum of typical patients with varying treatments. METHOD: This population based retrospective cohort study investigated 2444 patients with differentiated thyroid cancer <=4 cm between 1990 and 2001 from Ontario, Canada. Extent of disease and extent of surgery were abstracted from pathology reports and were linked to downstream administrative medical information on treatments and outcomes. Patient demographics, tumor characteristics, treatments, and outcomes were compared between those geographic regions with more aggressive treatments and those regions with less aggressive treatments. RESULTS: Treatment varied across the province. When comparing outcomes in regions where patients had more extensive treatment to those in regions where patients had less extensive therapy, similar rates were found for 15-year survival, recurrence, and survival after recurrence. CONCLUSION: There were significant variations in treatment but no differences in outcomes for regions with more versus less aggressive approaches. These findings support the trend toward more conservative management approaches in the treatment of thyroid cancer. PMID- 28851260 TI - Effect of hypercortisolism on bone mineral density and bone metabolism: A potential protective effect of adrenocorticotropic hormone in patients with Cushing's disease. AB - Objective To investigate the effects of Cushing's disease (CD) and adrenal dependent Cushing's syndrome (ACS) on bone mineral density (BMD) and bone metabolism. Methods Data were retrospectively collected for 55 patients with hypercortisolism (CD, n = 34; ACS n = 21) from January 1997 to June 2014. BMD was examined in all patients, and bone turnover markers were tested in some patients. Healthy controls (n = 18) were also recruited. Results The lumbar spine and femoral neck BMD were significantly lower in the ACS and CD groups than in the control group. Lumbar BMD was significantly lower in the ACS than CD group. The collagen breakdown product (CTX) concentrations were significantly higher while the osteocalcin and procollagen type I N-terminal propeptide (PINP) concentrations were significantly lower in the ACS and CD groups than in the control group. The PINP concentration was significantly lower while the CTX concentration was significantly higher in the ACS than CD group. In the CD group only, lumbar BMD and serum adrenocorticotropic hormone had a significant positive correlation. Conclusions Bone turnover markers indicated suppressed osteoblast and enhanced osteoclast activities. PINP and CTX changes might indicate bone mass deterioration. Adrenocorticotropic hormone might be protective for lumbar BMD in patients with CD. PMID- 28851262 TI - A technique for an arthroscopic proximal biceps tenodesis using a fork anchor. AB - Pathology to the proximal biceps tendon has the potential to be a major source of pain in the shoulder, secondary to complex superior labrum from anterior to posterior (SLAP) lesions, partial biceps tears, and subluxations. In order to restore function and improve the patient's quality of life, repair of these injuries is crucial. Tenodesis has long been the ideal treatment of persistent pain caused by pathology of the proximal biceps tendon. A biceps tenodesis helps prevent biceps pain and cramping during movement and avoids the cosmetic deformity associated with a biceps tenotomy. However, the location of the tenodesis and technique of the procedure itself have been debated throughout the literature. We present an arthroscopic biceps tenodesis technique in which the tendon is secured to the implant prior to implantation into the humerus to gain complete control of the tendon and ensure adequate fixation and tension. PMID- 28851263 TI - Efficacy of a computed tomography-based navigation system for placement of the acetabular component in total hip arthroplasty for developmental dysplasia of the hip. AB - PURPOSE: Developmental dysplasia of the hip (DDH) presents a considerable surgical challenge in total hip arthroplasty (THA). Although the usefulness of computed tomography (CT)-based navigation in cup alignment has been reported, few reports have evaluated three-dimensional (3-D) cup positioning against the acetabulum specifically in patients with DDH. The purpose of this study was to evaluate the efficacy of a CT-based navigation system for alignment and spatial positioning of the cup in THA for patients with DDH. METHODS: We reviewed 174 DDH THA cases in which CT-based navigation was used, and 75 cases in which a mechanical guide was used as a control group. Postoperative cup alignment and spatial positioning were evaluated by superimposition of a 3-D cup template onto the actual implanted cup using postoperative CT images, with pelvic coordinates matching the preoperative planning. RESULTS: The proportion within the combined target zone (inclination and anteversion) was 97.7% in the navigation group and 61.3% in the non-navigation group. The mean absolute error between the intraoperative record and the postoperative measurement was 1.5 degrees +/- 1.3 degrees for inclination and 2.1 degrees +/- 1.8 degrees for anteversion in the navigation group. For acetabular cup positioning, the mean discrepancy between the preoperative planning and the postoperative measurements was 1.9 +/- 1.6 mm on the transverse axis, 2.8 +/- 2.3 mm on the longitudinal axis, and 1.7 +/- 1.3 mm on the sagittal axis. CONCLUSION: THA using a CT-based navigation system achieved quite high accuracy of cup alignment angles and spatial cup positioning in primary THA for patients with DDH. PMID- 28851264 TI - Gap healing after medial open-wedge high tibial osteotomy using injectable beta tricalcium phosphate. AB - PURPOSE: The study aim was to evaluate gap healing after medial open-wedge high tibial osteotomy (MOWHTO) using novel injectable beta-tricalcium phosphate (beta TCP) as gap filler. We also aimed to evaluate radiographic and clinical outcome of MOWHTO using injectable beta-TCP. METHODS: Consecutive 28 patients underwent MOWHTO using anatomical locking plate fixation, and beta-TCP was injected as gap filler. Serial radiographs and computed tomography were taken at postoperative 3 and 12 months, and gap healing was assessed. Lower extremity alignment was measured on radiographs, and clinical outcome was evaluated by determining International Knee Documentation Committee, Western Ontario and McMaster Universities Arthritis Index, and visual analogue scales for pain scores. RESULTS: Progress of bone union was found on plain radiographs, and the mean ratio (beta-TCP/host bone) of computed tomography attenuation values significantly changed from postoperative 3 months to 12 months, which indicates maturation of beta-TCP. The average mechanical femoro-tibial angle changed from 4.1 degrees varus (preoperative) to 4.8 degrees valgus (3 months) and maintained until 12 months (4.3 degrees valgus). All clinical outcome scores were significantly improved and no significant complication occurred. CONCLUSION: Using injectable beta-TCP as gap filler for MOWHTO resulted in satisfactory gap healing without complication. Radiographic and clinical results were satisfactory. The injectable beta-TCP can be a safe and effective option for gap filling after MOWHTO. PMID- 28851265 TI - Post-operative fever in orthopaedic surgery: How effective is the 'fever workup?' AB - BACKGROUND: Defining the appropriate threshold at which to initiate a fever workup is imperative to promote patient safety, appropriate resource utilization, and antibiotic stewardship. Our group performed a systematic review of the available literature on perioperative fever (POF) workups in orthopaedic patients to evaluate the frequency, timing and utility of blood cultures (BC) and other investigations in the POF workup, to determine the clinical relevance of any infections and to evaluate their cost effectiveness. METHODS: Studies were identified by searching MEDLINE, EMBASE, Pubmed, Cochrane and Google Scholar for articles through September 2016. Forty-nine articles were retrieved and 22 articles met the pre-determined inclusion criteria. Proportions of positive studies were noted and averaged using random effects analysis. RESULTS: Post operative pyrexia ranged in prevalence between 8.1% and 87.3%. The studies routinely performed during a fever workup had wide ranges of diagnostic yield, including chest X-rays from 0% to 40%, urinalyses from 8.2% to 38.7%, urine cultures from 0% to 22.4% and BC from 0% to 13.3%. Only two patients with positive BC developed clinical sepsis. Cost per fever evaluation ranged from $350 to $950. CONCLUSION: The findings of this review suggest that early post operative fever is an expected event following orthopaedic surgery. Based on the available literature, any kind of workup in the absence of localizing symptoms in the third post-operative day or before is unwarranted and is an inappropriate use of hospital resources. PMID- 28851266 TI - Different Mixed Astrocyte Populations Derived from Embryonic Stem Cells Have Variable Neuronal Growth Support Capacities. AB - Central nervous system injury often leads to functional impairment due, in part, to the formation of an inhibitory glial scar following injury that contributes to poor regeneration. Astrocytes are the major cellular components of the glial scar, which has led to the belief that they are primarily inhibitory following injury. Recent work has challenged this by demonstrating that some astrocytes are required for spinal cord regeneration and astrocytic roles in recovery depend on their phenotype. In this work, two mixed populations containing primarily either fibrous or protoplasmic astrocytes were derived from mouse embryonic stem cells (mESCs). Motoneuron and V2a interneuron growth on live cultures, freeze-lysed cultures, or decellularized extracellular matrix (ECM) from astrocytes were assessed. Both neuronal populations were found to extend significantly longer neurites on protoplasmic-derived substrates than fibrous-derived substrates. Interestingly, neurons extended longer neurites on protoplasmic-derived ECM than fibrous-derived ECM. ECM proteins were compared with in vivo astrocyte expression profiles, and it was found that the ESC-derived ECMs were enriched for astrocyte specific proteins. Further characterization revealed that protoplasmic ECM had significantly higher levels of axon growth promoting proteins, while fibrous ECM had significantly higher levels of proteins that inhibit axon growth. Supporting this observation, knockdown of spondin-1 improved neurite growth on fibrous ECM, while laminin alpha5 and gamma1 knockdown decreased neurite growth on protoplasmic ECM. These methods allow for scalable production of specific astrocyte subtype-containing populations with different neuronal growth support capacities, and can be used for further studies of the functional importance of astrocyte heterogeneity. PMID- 28851267 TI - Expression profiling of genes regulated by sphingosine kinase1 signaling in a murine model of hyperoxia induced neonatal bronchopulmonary dysplasia. AB - BACKGROUND: Sphingosine- 1-Phosphate (S1P) is a bioactive lipid and an intracellular as well as an extracellular signaling molecule. S1P ligand specifically binds to five related cell surface G-protein-coupled receptors (S1P1 5). S1P levels are tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases, lipid phosphate phosphatases and S1P lyase. We previously reported that knock down of SphK1 (Sphk1 -/- ) in a neonatal mouse BPD model conferred significant protection against hyperoxia induced lung injury. To better understand the underlying molecular mechanisms, genome-wide gene expression profiling was performed on mouse lung tissue using Affymetrix MoGene 2.0 array. RESULTS: Two-way ANOVA analysis was performed and differentially expressed genes under hyperoxia were identified using Sphk1 -/- mice and their wild type (WT) equivalents. Pathway (PW) enrichment analyses identified several signaling pathways that are likely to play a key role in hyperoxia induced lung injury in the neonates. These included signaling pathways that were anticipated such as those involved in lipid signaling, cell cycle regulation, DNA damage/apoptosis, inflammation/immune response, and cell adhesion/extracellular matrix (ECM) remodeling. We noted hyperoxia induced downregulation of the expression of genes related to mitotic spindle formation in the WT which was not observed in Sphk1 -/- neonates. Our data clearly suggests a role for SphK1 in neonatal hyperoxic lung injury through elevated inflammation and apoptosis in lung tissue. Further, validation by RT-PCR on 24 differentially expressed genes showed 83% concordance both in terms of fold change and vectorial changes. Our findings are in agreement with previously reported human BPD microarray data and completely support our published in vivo findings. In addition, the data also revealed a significant role for additional unanticipitated signaling pathways involving Wnt and GADD45. CONCLUSION: Using SphK1 knockout mice and differential gene expression analysis, we have shown here that S1P/SphK1 signaling plays a key role in promoting hyperoxia induced DNA damage, inflammation, apoptosis and ECM remodeling in neonatal lungs. It also appears to suppress pro-survival cellular responses involved in normal lung development. We therefore propose SphK1 as a therapeutic target for the development drugs to combat BPD. PMID- 28851268 TI - The satellite DNA AflaSAT-1 in the A and B chromosomes of the grasshopper Abracris flavolineata. AB - BACKGROUND: Satellite DNAs (satDNAs) are organized in repetitions directly contiguous to one another, forming long arrays and composing a large portion of eukaryote genomes. These sequences evolve according to the concerted evolution model, and homogenization of repeats is observed at the intragenomic level. Satellite DNAs are the primary component of heterochromatin, located primarily in centromeres and telomeres. Moreover, satDNA enrichment in specific chromosomes has been observed, such as in B chromosomes, that can provide clues about composition, origin and evolution of this chromosome. In this study, we isolated and characterized a satDNA in A and B chromosomes of Abracris flavolineata by integrating cytogenetic, molecular and genomics approaches at intra- and inter population levels, with the aim to understand the evolution of satDNA and composition of B chromosomes. RESULTS: AflaSAT-1 satDNA was shared with other species and in A. flavolineata, was associated with another satDNA, AflaSAT-2. Chromosomal mapping revealed centromeric blocks variable in size in almost all chromosomes (except pair 11) of A complement for both satDNAs, whereas for B chromosome, only a small centromeric signal occurred. In distinct populations, variable number of AflaSAT-1 chromosomal sites correlated with variability in copy number. Instead of such variability, low sequence diversity was observed in A complement, but monomers from B chromosome were more variable, presenting also exclusive mutations. AflaSAT-1 was transcribed in five tissues of adults in distinct life cycle phases. CONCLUSIONS: The sharing of AflaSAT-1 with other species is consistent with the library hypothesis and indicates common origin in a common ancestor; however, AflaSAT-1 was highly amplified in the genome of A. flavolineata. At the population level, homogenization of repeats in distinct populations was documented, but dynamic expansion or elimination of repeats was also observed. Concerning the B chromosome, our data provided new information on the composition in A. flavolineata. Together with previous results, the sequences of heterochromatic nature were not likely highly amplified in the entire B chromosome. Finally, the constitutive transcriptional activity suggests a possible unknown functional role, which should be further investigated. PMID- 28851269 TI - Improved protein structure reconstruction using secondary structures, contacts at higher distance thresholds, and non-contacts. AB - BACKGROUND: Residue-residue contacts are key features for accurate de novo protein structure prediction. For the optimal utilization of these predicted contacts in folding proteins accurately, it is important to study the challenges of reconstructing protein structures using true contacts. Because contact-guided protein modeling approach is valuable for predicting the folds of proteins that do not have structural templates, it is necessary for reconstruction studies to focus on hard-to-predict protein structures. RESULTS: Using a data set consisting of 496 structural domains released in recent CASP experiments and a dataset of 150 representative protein structures, in this work, we discuss three techniques to improve the reconstruction accuracy using true contacts - adding secondary structures, increasing contact distance thresholds, and adding non-contacts. We find that reconstruction using secondary structures and contacts can deliver accuracy higher than using full contact maps. Similarly, we demonstrate that non contacts can improve reconstruction accuracy not only when the used non-contacts are true but also when they are predicted. On the dataset consisting of 150 proteins, we find that by simply using low ranked predicted contacts as non contacts and adding them as additional restraints, can increase the reconstruction accuracy by 5% when the reconstructed models are evaluated using TM-score. CONCLUSIONS: Our findings suggest that secondary structures are invaluable companions of contacts for accurate reconstruction. Confirming some earlier findings, we also find that larger distance thresholds are useful for folding many protein structures which cannot be folded using the standard definition of contacts. Our findings also suggest that for more accurate reconstruction using predicted contacts it is useful to predict contacts at higher distance thresholds (beyond 8 A) and predict non-contacts. PMID- 28851271 TI - Erratum to: Sequence differences in the seed dormancy gene Qsd1 among various wheat genomes. PMID- 28851270 TI - Expression dynamics and relations with nearby genes of rat transposable elements across 11 organs, 4 developmental stages and both sexes. AB - BACKGROUND: TEs pervade mammalian genomes. However, compared with mice, fewer studies have focused on the TE expression patterns in rat, particularly the comparisons across different organs, developmental stages and sexes. In addition, TEs can influence the expression of nearby genes. The temporal and spatial influences of TEs remain unclear yet. RESULTS: To evaluate the TEs transcription patterns, we profiled their transcript levels in 11 organs for both sexes across four developmental stages of rat. The results show that most short interspersed elements (SINEs) are commonly expressed in all conditions, which are also the major TE types with commonly expression patterns. In contrast, long terminal repeats (LTRs) are more likely to exhibit specific expression patterns. The expression tendency of TEs and genes are similar in most cases. For example, few specific genes and TEs are in the liver, muscle and heart. However, TEs perform superior over genes on classing organ, which imply their higher organ specificity than genes. By associating the TEs with the closest genes in genome, we find their expression levels are correlated, independent of their distance in some cases. CONCLUSIONS: TEs sex-dependently associate with nearest genes. A gene would be associated with more than one TE. Our works can help to functionally annotate the genome and further understand the role of TEs in gene regulation. PMID- 28851272 TI - Diversification and spatial structuring in the mutualism between Ficus septica and its pollinating wasps in insular South East Asia. AB - BACKGROUND: Interspecific interactions have long been assumed to play an important role in diversification. Mutualistic interactions, such as nursery pollination mutualisms, have been proposed as good candidates for diversification through co-speciation because of their intricate nature. However, little is known about how speciation and diversification proceeds in emblematic nursery pollination systems such as figs and fig wasps. Here, we analyse diversification in connection with spatial structuring in the obligate mutualistic association between Ficus septica and its pollinating wasps throughout the Philippines and Taiwan. RESULTS: Ceratosolen wasps pollinating F. septica are structured into a set of three vicariant black coloured species, and a fourth yellow coloured species whose distribution overlaps with those of the black species. However, two black pollinator species were found to co-occur on Lanyu island. Microsatellite data on F. septica indicates the presence of three gene pools that broadly mirrors the distribution of the three black clades. Moreover, receptive fig odours, the specific message used by pollinating wasps to locate their host tree, varied among locations. CONCLUSIONS: F. septica and its black pollinator clades exhibited similar geographic structuring. This could be due originally to geographic barriers leading to isolation, local adaptation, and finally co structuring. Nevertheless, the co-occurrence of two black pollinator species on Lanyu island suggests that the parapatric distribution of the black clades is now maintained by the inability of migrating individuals of black pollinators to establish populations outside their range. On the other hand, the distribution of the yellow clade strongly suggests an initial case of character displacement followed by subsequent range extension: in our study system, phenotypic or microevolutionary plasticity has allowed the yellow clade to colonise hosts presenting distinct odours. Hence, while variation in receptive fig odours allows specificity in the interaction, this variation does not necessarily lead to coevolutionary plant-insect diversification. Globally, our results evidence evolutionary plasticity in the fig-fig wasp mutualism. This is the first documentation of the presence of two distinct processes in pollinating fig wasp diversification on a host species: the formation of vicariant species and the co occurrence of other species over large parts of their ranges probably made possible by character displacement. PMID- 28851273 TI - EL_PSSM-RT: DNA-binding residue prediction by integrating ensemble learning with PSSM Relation Transformation. AB - BACKGROUND: Prediction of DNA-binding residue is important for understanding the protein-DNA recognition mechanism. Many computational methods have been proposed for the prediction, but most of them do not consider the relationships of evolutionary information between residues. RESULTS: In this paper, we first propose a novel residue encoding method, referred to as the Position Specific Score Matrix (PSSM) Relation Transformation (PSSM-RT), to encode residues by utilizing the relationships of evolutionary information between residues. PDNA-62 and PDNA-224 are used to evaluate PSSM-RT and two existing PSSM encoding methods by five-fold cross-validation. Performance evaluations indicate that PSSM-RT is more effective than previous methods. This validates the point that the relationship of evolutionary information between residues is indeed useful in DNA binding residue prediction. An ensemble learning classifier (EL_PSSM-RT) is also proposed by combining ensemble learning model and PSSM-RT to better handle the imbalance between binding and non-binding residues in datasets. EL_PSSM-RT is evaluated by five-fold cross-validation using PDNA-62 and PDNA-224 as well as two independent datasets TS-72 and TS-61. Performance comparisons with existing predictors on the four datasets demonstrate that EL_PSSM-RT is the best performing method among all the predicting methods with improvement between 0.02 0.07 for MCC, 4.18-21.47% for ST and 0.013-0.131 for AUC. Furthermore, we analyze the importance of the pair-relationships extracted by PSSM-RT and the results validates the usefulness of PSSM-RT for encoding DNA-binding residues. CONCLUSIONS: We propose a novel prediction method for the prediction of DNA binding residue with the inclusion of relationship of evolutionary information and ensemble learning. Performance evaluation shows that the relationship of evolutionary information between residues is indeed useful in DNA-binding residue prediction and ensemble learning can be used to address the data imbalance issue between binding and non-binding residues. A web service of EL_PSSM-RT ( http://hlt.hitsz.edu.cn:8080/PSSM-RT_SVM/ ) is provided for free access to the biological research community. PMID- 28851274 TI - The core regulatory network of the abscisic acid pathway in banana: genome-wide identification and expression analyses during development, ripening, and abiotic stress. AB - BACKGROUND: Abscisic acid (ABA) signaling plays a crucial role in developmental and environmental adaptation processes of plants. However, the PYL-PP2C-SnRK2 families that function as the core components of ABA signaling are not well understood in banana. RESULTS: In the present study, 24 PYL, 87 PP2C, and 11 SnRK2 genes were identified from banana, which was further supported by evolutionary relationships, conserved motif and gene structure analyses. The comprehensive transcriptomic analyses showed that banana PYL-PP2C-SnRK2 genes are involved in tissue development, fruit development and ripening, and response to abiotic stress in two cultivated varieties. Moreover, comparative expression analyses of PYL-PP2C-SnRK2 genes between BaXi Jiao (BX) and Fen Jiao (FJ) revealed that PYL-PP2C-SnRK2-mediated ABA signaling might positively regulate banana fruit ripening and tolerance to cold, salt, and osmotic stresses. Finally, interaction networks and co-expression assays demonstrated that the core components of ABA signaling were more active in FJ than in BX in response to abiotic stress, further supporting the crucial role of the genes in tolerance to abiotic stress in banana. CONCLUSIONS: This study provides new insights into the complicated transcriptional control of PYL-PP2C-SnRK2 genes, improves the understanding of PYL-PP2C-SnRK2-mediated ABA signaling in the regulation of fruit development, ripening, and response to abiotic stress, and identifies some candidate genes for genetic improvement of banana. PMID- 28851276 TI - Effects of horticultural therapy on elderly' health: protocol of a randomized controlled trial. AB - BACKGROUND: Due to a rapidly ageing population in the world, it is increasingly pertinent to promote successful ageing strategies which are cost-effective, easily accessible, and more likely to be acceptable to the elderly. Past research associates exposure to natural environments and horticultural therapy (HT) with positive psychological, social and physical health benefits. This Randomized Controlled Trial (RCT) is designed to evaluate the efficacy of HT in promoting Asian elderly' mental health, cognitive functioning and physical health. METHODS/DESIGN: 70 elderly participants aged 60 to 85 years old will be randomized to participate in either the active horticultural therapy group or be in the waitlist control. Sessions will be weekly for 12 weeks, and monthly for 3 months. Mental health will be assessed through self-reports of depressive and anxiety symptomatology, life satisfaction, social connectedness and psychological well-being, collaborated with immunological markers. Outcome measures of cognitive functioning and physical health include neuropsychological tests of cognitive function and basic health screening. Outcomes will be assessed at baseline, 3 months and 6 months post-intervention. DISCUSSION: This RCT comprehensively investigates the efficacy of a non-invasive intervention, HT, in enhancing mental health, cognitive functioning and physical health. The results have tremendous potential for supporting future successful ageing programs and applicability to larger populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT02495194 . Trial registration date: July 13, 2015. Retrospectively registered. PMID- 28851275 TI - Gapless genome assembly of Colletotrichum higginsianum reveals chromosome structure and association of transposable elements with secondary metabolite gene clusters. AB - BACKGROUND: The ascomycete fungus Colletotrichum higginsianum causes anthracnose disease of brassica crops and the model plant Arabidopsis thaliana. Previous versions of the genome sequence were highly fragmented, causing errors in the prediction of protein-coding genes and preventing the analysis of repetitive sequences and genome architecture. RESULTS: Here, we re-sequenced the genome using single-molecule real-time (SMRT) sequencing technology and, in combination with optical map data, this provided a gapless assembly of all twelve chromosomes except for the ribosomal DNA repeat cluster on chromosome 7. The more accurate gene annotation made possible by this new assembly revealed a large repertoire of secondary metabolism (SM) key genes (89) and putative biosynthetic pathways (77 SM gene clusters). The two mini-chromosomes differed from the ten core chromosomes in being repeat- and AT-rich and gene-poor but were significantly enriched with genes encoding putative secreted effector proteins. Transposable elements (TEs) were found to occupy 7% of the genome by length. Certain TE families showed a statistically significant association with effector genes and SM cluster genes and were transcriptionally active at particular stages of fungal development. All 24 subtelomeres were found to contain one of three highly conserved repeat elements which, by providing sites for homologous recombination, were probably instrumental in four segmental duplications. CONCLUSION: The gapless genome of C. higginsianum provides access to repeat-rich regions that were previously poorly assembled, notably the mini-chromosomes and subtelomeres, and allowed prediction of the complete SM gene repertoire. It also provides insights into the potential role of TEs in gene and genome evolution and host adaptation in this asexual pathogen. PMID- 28851278 TI - Toscana virus meningo-encephalitis: an important differential diagnosis for elderly travellers returning from Mediterranean countries. AB - BACKGROUND: Elderly patients have a long list of differentials for causes of acute confusion and altered consciousness levels, including infectious agents. In addition, elderly, retired patients often have more time to travel for tourism, particularly to exotic, warmer locations. Mediterranean countries such as Spain and Italy are popular holiday destinations for British and other tourists, especially during the winter months. However, these warm climates allow insect vectors to proliferate, increasing the risk of exposure to endemic vectorborne viral infections whilst on vacation. Such infections may not be routinely considered by geriatric medical teams. CASE PRESENTATION: An 87-year old gentleman presented with a three-day history of worsening confusion, lethargy, ataxia, and fevers following a trip to Spain, where he may have sustained a sandfly bite. By the time of admission, he had a reduced GCS, was hallucinating, and was incontinent of urine and faeces, though blood pressure and heart rate were normal. He also appeared hyperaesthetic, and found even capillary blood sugar testing extremely painful. He had no history of cognitive defect or other neurological conditions. He had been previously independently active, with frequent trips to Spain where he maintained a holiday home. He probably sustained a sandfly bite during this most recent trip, whilst cleaning out a shed. Acute and convalescent sera demonstrated IgG antibodies to Toscana virus at extremely high titres of >=1:10,000 by immunofluorescence assay, though no Toscana virus RNA was detectable in these sera by the time of presentation. CONCLUSIONS: Toscana virus should be included in the differential diagnosis of any patients presenting with meningo-encephalitis who have recently returned from a Mediterranean country. Testing for Toscana virus infection is performed by serological testing on acute/convalescent paired sera, and/or a polymerase chain reaction (PCR) assay on blood or cerebrospinal fluid (CSF) if presenting within 5 days of illness onset. Making a diagnosis of Toscana virus meningitis/encephalitis (where no other pathogen is detected) has additional clinical utility in reducing or preventing unnecessary use of antibiotics, as well as reassuring the patient and family that generally, this illness is generally self-limiting and full recovery within a few weeks is expected, as in the case reported here. PMID- 28851277 TI - Variation and evolution of polyadenylation profiles in sauropsid mitochondrial mRNAs as deduced from the high-throughput RNA sequencing. AB - BACKGROUND: Genes encoded in vertebrate mitochondrial DNAs are transcribed as a polycistronic transcript for both strands, which is later processed into individual mRNAs, rRNAs and tRNAs, followed by modifications, such as polyadenylation at the 3' end of mRNAs. Although mechanisms of the mitochondrial transcription and RNA processing have been extensively studied using some model organisms, structural variability of mitochondrial mRNAs across different groups of vertebrates is poorly understood. We conducted the high-throughput RNA sequencing to identify major polyadenylation sites for mitochondrial mRNAs in the Japanese grass lizard, Takydromus tachydromoides and compared the polyadenylation profiles with those identified similarly for 23 tetrapod species, featuring sauropsid taxa (reptiles and birds). RESULTS: As compared to the human, a major polyadenylation site for the NADH dehydrogenase subunit 5 mRNA of the grass lizard was located much closer to its stop codon, resulting in considerable truncation of the 3' untranslated region for the mRNA. Among the other sauropsid taxa, several distinct polyadenylation profiles from the human counterpart were found for different mRNAs. They included various truncations of the 3' untranslated region for NADH dehydrogenase subunit 5 mRNA in four taxa, bird specific polyadenylation of the light-strand-transcribed NADH dehydrogenase subunit 6 mRNA, and the combination of the ATP synthase subunit 8/6 mRNA with a neighboring mRNA into a tricistronic mRNA in the side-necked turtle Pelusios castaneus. In the last case of P. castaneus, as well as another example for NADH dehydrogenase subunit 1 mRNAs of some birds, the association between the polyadenylation site change and the gene overlap was highlighted. The variations in the polyadenylation profile were suggested to have arisen repeatedly in diverse sauropsid lineages. Some of them likely occurred in response to gene rearrangements in the mitochondrial DNA but the others not. CONCLUSIONS: These results demonstrate structural variability of mitochondrial mRNAs in sauropsids. The efficient and comprehensive characterization of the mitochondrial mRNAs will contribute to broaden our understanding of their structural and functional evolution. PMID- 28851279 TI - Intravenous theophylline is the most effective intervention to prolong EEG seizure duration in patients undergoing electroconvulsive therapy. AB - BACKGROUND: Seizure duration in electroconvulsive therapy (ECT) is positively related with patients' outcome. This study sought to investigate the impact of anesthetic management on seizure duration, and the impact of selected drugs (theophylline, remifentanil, S-ketamine) on seizure duration. METHODS: Retrospective analysis of all patients undergoing ECT at our institution from January 2011 to April 2012 was performed based on electronic medical chart and review of existing quality improvement data. Patient data (N = 78), including gender, age, height, weight, and administered drugs, energy levels, and electroencephalic seizure duration were analyzed. Statistical analysis was performed using a generalized linear model. RESULTS: A total of 78 patients (male = 39, female = 39, age 51 +/- 12 years) were included. Average number of session was 10 +/- 6 (1-30). In our patient population, theophylline administration was the only parameter, which significantly prolonged seizure duration, whereas S ketamine, remifentanil, thiopental, age, sex, session or energy level had no significant effect. CONCLUSION: Theophylline can be a useful adjunct for patients with inadequate seizure duration. If there is a concomitant beneficial effect on patients' outcome needs to be investigated in further studies. PMID- 28851280 TI - Post-traumatic stress disorder and its predictors in emergency medical service personnel: a cross-sectional study from Karachi, Pakistan. AB - BACKGROUND: Emergency medical service (EMS) personnel who work to provide emergency medical care at the scene and during transportation are exposed to various kinds of stressors and are particularly susceptible to developing stress reactions. This study assesses symptoms of post-traumatic stress disorder and its predictors among the personnel of a selected EMS in Karachi, Pakistan. METHODS: Data were gathered from 518 personnel working in an EMS setting from February to May 2014. Participants were screened for post-traumatic stress symptoms using the Impact of Event Scale-Revised (IES-R). Demographic and work-related characteristics, coping styles and the social support systems of the participants were assessed. Linear regression was used on the IES-R to identify predictors of post-traumatic stress symptoms. RESULTS: The mean score of the IES-R was 23.9 +/- 12.1. EMS personnel with a dysfunctional coping style (beta = 0.67 CI 0.39 - 0.95), anxiety, and depression (beta = 0.64 CI 0.52 - 0.75) were more likely to have increased severity of post-traumatic stress symptoms. Age was found to have an inverse relationship with stress symptoms (beta = -0.17 CI 0.33 - -0.023), indicating the susceptibility of younger EMS personnel to stress. CONCLUSION: The EMS personnel in this setting were found to have a moderate level of post traumatic stress symptoms. The significant predictors of post-traumatic stress symptoms in this EMS population were age, coping style, and levels of anxiety and depression. These predicting factors can be a potential avenue for interventions to improve the mental health of these frontline workers. PMID- 28851281 TI - Growth phase-dependent expression profiles of three vital H-NS family proteins encoded on the chromosome of Pseudomonas putida KT2440 and on the pCAR1 plasmid. AB - BACKGROUND: H-NS family proteins are nucleoid-associated proteins that form oligomers on DNA and function as global regulators. They are found in both bacterial chromosomes and plasmids, and were suggested to be candidate effectors of the interaction between them. TurA and TurB are the predominantly expressed H NS family proteins encoded on the chromosome of Pseudomonas putida KT2440, while Pmr is encoded on the carbazole-degradative incompatibility group P-7 plasmid pCAR1. Previous transcriptome analyses suggested that they function cooperatively, but play different roles in the global transcriptional network. In addition to differences in protein interaction and DNA-binding functions, cell expression levels are important in clarifying the detailed underlying mechanisms. Here, we determined the precise protein amounts of TurA, TurB, and Pmr in KT2440 in the presence and absence of pCAR1. RESULTS: The intracellular amounts of TurA and TurB in KT2440 and KT2440(pCAR1) were determined by quantitative western blot analysis using specific antibodies. The amount of TurA decreased from the log phase (~80,000 monomers per cell) to the stationary phase (~20,000 monomers per cell), while TurB was only detectable upon entry into the stationary phase (maximum 6000 monomers per cell). Protein amounts were not affected by pCAR1 carriage. KT2440(pCAR1pmrHis), where histidine-tagged Pmr is expressed under its original promotor, was used to determine the intracellular amount of Pmr, which was constant (~30,000 monomers per cell) during cell growth. Quantitative reverse transcription PCR demonstrated that the transcriptional levels of turA and turB were consistent with protein expression, though the transcriptional and translational profiles of Pmr differed. CONCLUSION: The amount of TurB increases as TurA decreases, and the amount of Pmr does not affect the amounts of TurA and TurB. This is consistent with our previous observation that TurA and TurB play complementary roles, whereas Pmr works relatively independently. This study provides insight into the molecular mechanisms underlying reconstitution of the transcriptional network in KT2440 by pCAR1 carriage. PMID- 28851282 TI - Psychological determinants of influenza vaccination. AB - BACKGROUND: Previous studies investigated the determinants of individuals' decision to vaccinate against influenza primarily focusing on social as well as certain proximal determinants, for example, behavioral beliefs. Thus, so far, the analysis of psychological factors as determinants of influenza vaccination was mainly limited to beliefs, attitudes or perceptions that were directly related to influenza vaccination and its perceived impact. However, considering general psychological factors, like general self-efficacy, optimism or subjective well being, might further enhance the understanding of why certain people vaccinate while others do not. The aim was to investigate the relationship between various general psychological factors and older people's decision to vaccinate against seasonal flu. METHODS: The data of individuals aged 60 or older (n = 5037; in 2014) were used from the Germany Ageing Survey. The data were collected in face to-face interviews and in self-administered questionnaires. They include questions on the use of influenza vaccination and the psychological factors of optimism, self-efficacy, self-esteem, perceived stress, self-regulation, life satisfaction, and negative affect as well as positive affect. The psychological determinants of regular influenza vaccination were investigated using multiple logistic regressions. RESULTS: 53.2% of all participants were regular users of influenza vaccination. There were significant bivariate correlations of all cited psychological factor with influenza vaccination except for life satisfaction and negative affect. After controlling for numerous potential socio-demographic, morbidity- and lifestyle-related confounders, regular influenza vaccination was still positively associated with lower levels of self-esteem and a higher level of perceived stress. CONCLUSIONS: There are significant associations of general individual psychological constructs with the decision to vaccinate against influenza. Future research might determine the impact of psychological factors on the decision to vaccinate in longitudinal research designs. This might be helpful to understand the causal mechanisms behind this relationship, which could help to design interventions that increase vaccination rates in certain target groups. PMID- 28851283 TI - Performance of risk prediction for inflammatory bowel disease based on genotyping platform and genomic risk score method. AB - BACKGROUND: Predicting risk of disease from genotypes is being increasingly proposed for a variety of diagnostic and prognostic purposes. Genome-wide association studies (GWAS) have identified a large number of genome-wide significant susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC), two subtypes of inflammatory bowel disease (IBD). Recent studies have demonstrated that including only loci that are significantly associated with disease in the prediction model has low predictive power and that power can substantially be improved using a polygenic approach. METHODS: We performed a comprehensive analysis of risk prediction models using large case-control cohorts genotyped for 909,763 GWAS SNPs or 123,437 SNPs on the custom designed Immunochip using four prediction methods (polygenic score, best linear genomic prediction, elastic-net regularization and a Bayesian mixture model). We used the area under the curve (AUC) to assess prediction performance for discovery populations with different sample sizes and number of SNPs within cross-validation. RESULTS: On average, the Bayesian mixture approach had the best prediction performance. Using cross-validation we found little differences in prediction performance between GWAS and Immunochip, despite the GWAS array providing a 10 times larger effective genome-wide coverage. The prediction performance using Immunochip is largely due to the power of the initial GWAS for its marker selection and its low cost that enabled larger sample sizes. The predictive ability of the genomic risk score based on Immunochip was replicated in external data, with AUC of 0.75 for CD and 0.70 for UC. CD patients with higher risk scores demonstrated clinical characteristics typically associated with a more severe disease course including ileal location and earlier age at diagnosis. CONCLUSIONS: Our analyses demonstrate that the power of genomic risk prediction for IBD is mainly due to strongly associated SNPs with considerable effect sizes. Additional SNPs that are only tagged by high-density GWAS arrays and low or rare-variants over-represented in the high-density region on the Immunochip contribute little to prediction accuracy. Although a quantitative assessment of IBD risk for an individual is not currently possible, we show sufficient power of genomic risk scores to stratify IBD risk among individuals at diagnosis. PMID- 28851284 TI - Anesthetic management of a pediatric patient with Electron Transfer Flavoprotein Dehydrogenase deficiency (ETFDH) and acute appendicitis: case report and review of the literature. AB - BACKGROUND: Mitochondria are the energy producing organelles practically in every human cell except erythrocytes. Indeed mitochondria are widespread in high energy requiring organs like brain, heart and muscles. Currently there are no clinical trials supporting with clear evidence which is the most suitable surgical or anesthetic management of a patient with known mitochondrial disease presenting with surgical disorders. This condition poses possible hazardous problems to the medical attention of those patients. CASE PRESENTATION: A case of an 8 year old child with known Electron Transfer Flavoprotein Dehydrogenase deficiency (ETFDH deficiency) requiring surgery for acute appendicitis is presented. Our approach for anesthesia revealed a combination of fentanyl, low dose propofol and nitrous oxide. CONCLUSION: The choice of the safest pharmacological anesthetic agents for patients with ETFDH deficiency is challenging given that most of the general anesthetic medications have multiple effects on mitochondria, fatty acids metabolism and striated muscles. Anesthetists are expected to individualize anesthetic care for the patient based on current publications for similar cases, medical history and knowledge of pharmacology and physiology. PMID- 28851285 TI - The impact of drug resistance on the risk of tuberculosis infection and disease in child household contacts: a cross sectional study. AB - BACKGROUND: The relative fitness of organisms causing drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) is unclear. We compared the risk of TB infection and TB disease in young child household contacts of adults with confirmed DS-TB and MDR-TB. METHODS: In this cross-sectional analysis we included data from two community-based contact cohort investigation studies conducted in parallel in Cape Town, South Africa. Children <5 years of age with household exposure to an infectious TB case were included between August 2008 to June 2011. Children completed investigation for TB infection (tuberculin skin test) and TB disease (symptom evaluation, chest radiograph, bacteriology) in both studies using standard approaches. The impact of MDR-TB exposure on each covariate of TB infection and TB disease was assessed using univariable and multivariable logistic regression. RESULTS: Of 538 children included, 312 had DS-TB and 226 had MDR-TB exposure. 107 children with DS-TB exposure had TB infection (34.3%) vs. 101 (44.7%) of children with MDR-TB exposure (adjusted Odds Ratio [aOR]: 2.05; 95% confidence interval [CI]: 1.34-3.12). A total of 15 (6.6%) MDR-TB vs. 27 (8.7%) DS-TB child contacts had TB disease at enrolment (aOR: 0.43; 95% CI: 0.19 0.97). CONCLUSIONS: Our results suggest a higher risk of TB infection in child contacts with household MDR-TB vs. DS-TB exposure, but a lower risk of TB disease. Although potentially affected by residual confounding or selection bias, our results are consistent with the hypothesis of impaired virulence in MDR-TB strains in this setting. PMID- 28851286 TI - Influence of the postoperative inflammatory response on cognitive decline in elderly patients undergoing on-pump cardiac surgery: a controlled, prospective observational study. AB - BACKGROUND: The role of non-infective inflammatory response (IR) in the aetiology of postoperative cognitive dysfunction (POCD) is still controversial. The aim of this controlled, prospective observational study was to assess the possible relationship between the grade of IR, defined by procalcitonin (PCT) changes, and development of POCD related to cardiac surgery. METHODS: Forty-two patients, who were >= 60 years of age and scheduled for elective cardiac surgery, were separated into the low inflammatory (LIR) and high inflammatory (HIR) response groups based on their PCT levels measured on the first postoperative day. A matched normative control group of 32 subjects was recruited from primary care practice. The PCT and C-reactive protein (CRP) levels were monitored daily during the first five postoperative days. The cognitive function and mood state were preoperatively tested with a set of five neurocognitive tests and two mood inventories and at the seventh postoperative day. The Reliable Change Index modified for practice (RCIp) using data from normative controls was applied to determine the significant decline in test performance. RESULTS: The LIR (n = 20) and HIR (n = 22) groups differed significantly in the PCT (p < 0.001) but not in the CRP time courses. The incidence of POCD at the first postoperative week was 35.7% in the cohort. The LIR and HIR groups did not vary in the RCIp Z scores of neurocognitive tests and frequencies of POCD (7 vs 8 cases, respectively, p > 0.05). Additionally, there was no difference in the mood states, anxiety levels and perioperative parameters known to influence the development of POCD. CONCLUSIONS: In this study, the magnitude of the non-infective inflammatory response generated by on-pump cardiac surgery did not influence the development of POCD in the early postoperative period in elderly patients. PMID- 28851287 TI - EphA receptors and ephrin-A ligands are upregulated by monocytic differentiation/maturation and promote cell adhesion and protrusion formation in HL60 monocytes. AB - BACKGROUND: Eph signaling is known to induce contrasting cell behaviors such as promoting and inhibiting cell adhesion/spreading by altering F-actin organization and influencing integrin activities. We have previously demonstrated that EphA2 stimulation by ephrin-A1 promotes cell adhesion through interaction with integrins and integrin ligands in two monocyte/macrophage cell lines. Although mature mononuclear leukocytes express several members of the EphA/ephrin-A subclass, their expression has not been examined in monocytes undergoing during differentiation and maturation. RESULTS: Using RT-PCR, we have shown that EphA2, ephrin-A1, and ephrin-A2 expression was upregulated in murine bone marrow mononuclear cells during monocyte maturation. Moreover, EphA2 and EphA4 expression was induced, and ephrin-A4 expression was upregulated, in a human promyelocytic leukemia cell line, HL60, along with monocyte differentiation toward the classical CD14++CD16- monocyte subset. Using RT-PCR and flow cytometry, we have also shown that expression levels of alphaL, alphaM, alphaX, and beta2 integrin subunits were upregulated in HL60 cells along with monocyte differentiation while those of alpha4, alpha5, alpha6, and beta1 subunits were unchanged. Using a cell attachment stripe assay, we have shown that stimulation by EphA as well as ephrin-A, likely promoted adhesion to an integrin ligand coated surface in HL60 monocytes. Moreover, EphA and ephrin-A stimulation likely promoted the formation of protrusions in HL60 monocytes. CONCLUSIONS: Notably, this study is the first analysis of EphA/ephrin-A expression during monocytic differentiation/maturation and of ephrin-A stimulation affecting monocyte adhesion to an integrin ligand-coated surface. Thus, we propose that monocyte adhesion via integrin activation and the formation of protrusions is likely promoted by stimulation of EphA as well as of ephrin-A. PMID- 28851288 TI - Evaluation of microplate immunocapture method for detection of Vibrio cholerae, Salmonella Typhi and Shigella flexneri from food. AB - BACKGROUND: Improved methods with better separation and concentration ability for detection of foodborne pathogens are in constant need. The aim of this study was to evaluate microplate immunocapture (IC) method for detection of Salmonella Typhi, Shigella flexneri and Vibrio cholerae from food samples to provide a better alternative to conventional culture based methods. RESULTS: The IC method was optimized for incubation time, bacterial concentration, and capture efficiency. 6 h incubation and log 6 CFU/ml cell concentration provided optimal results. The method was shown to be highly specific for the pathogens concerned. Capture efficiency (CE) was around 100% of the target pathogens, whereas CE was either zero or very low for non-target pathogens. The IC method also showed better pathogen detection ability at different concentrations of cells from artificially contaminated food samples in comparison with culture based methods. Performance parameter of the method was also comparable (Detection limit- 25 CFU/25 g; sensitivity 100%; specificity-96.8%; Accuracy-96.7%), even better than culture based methods (Detection limit- 125 CFU/25 g; sensitivity 95.9%; specificity-97%; Accuracy-96.2%). CONCLUSION: The IC method poses to be the potential to be used as a method of choice for detection of foodborne pathogens in routine laboratory practice after proper validation. PMID- 28851289 TI - Coral cell separation and isolation by fluorescence-activated cell sorting (FACS). AB - BACKGROUND: Generalized methods for understanding the cell biology of non-model species are quite rare, yet very much needed. In order to address this issue, we have modified a technique traditionally used in the biomedical field for ecological and evolutionary research. Fluorescent activated cell sorting (FACS) is often used for sorting and identifying cell populations. In this study, we developed a method to identify and isolate different cell populations in corals and other cnidarians. METHODS: Using fluorescence-activated cell sorting (FACS), coral cell suspension were sorted into different cellular populations using fluorescent cell markers that are non-species specific. Over 30 different cell markers were tested. Additionally, cell suspension from Aiptasia pallida was also tested, and a phagocytosis test was done as a downstream functional assay. RESULTS: We found that 24 of the screened markers positively labeled coral cells and 16 differentiated cell sub-populations. We identified 12 different cellular sub-populations using three markers, and found that each sub-population is primarily homogeneous. Lastly, we verified this technique in a sea anemone, Aiptasia pallida, and found that with minor modifications, a similar gating strategy can be successfully applied. Additionally, within A. pallida, we show elevated phagocytosis of sorted cells based on an immune associated marker. CONCLUSIONS: In this study, we successfully adapted FACS for isolating coral cell populations and conclude that this technique is translatable for future use in other species. This technique has the potential to be used for different types of studies on the cellular stress response and other immunological studies. PMID- 28851290 TI - Genetic basis of brain size evolution in cetaceans: insights from adaptive evolution of seven primary microcephaly (MCPH) genes. AB - BACKGROUND: Cetacean brain size expansion is an enigmatic event in mammalian evolution, yet its genetic basis remains poorly explored. Here, all exons of the seven primary microcephaly (MCPH) genes that play key roles in size regulation during brain development were investigated in representative cetacean lineages. RESULTS: Sequences of MCPH2-7 genes were intact in cetaceans but frameshift mutations and stop codons was identified in MCPH1. Extensive positive selection was identified in four of six intact MCPH genes: WDR62, CDK5RAP2, CEP152, and ASPM. Specially, positive selection at CDK5RAP2 and ASPM were examined along lineages of odontocetes with increased encephalization quotients (EQ) and mysticetes with reduced EQ but at WDR62 only found along odontocete lineages. Interestingly, a positive association between evolutionary rate (omega) and EQ was identified for CDK5RAP2 and ASPM. Furthermore, we tested the binding affinities between Calmodulin (CaM) and ASPM IQ motif in cetaceans because only CaM combined with IQ, can ASPM perform the function in determining brain size. Preliminary function assay showed binding affinities between CaM and IQ motif of the odontocetes with increased EQ was stronger than for the mysticetes with decreased EQ. In addition, evolution rate of ASPM and CDK5RAP2 were significantly related to mean group size (as one measure of social complexity). CONCLUSIONS: Our study investigated the genetic basis of cetacean brain size evolution. Significant positive selection was examined along lineages with both increased and decreased EQ at CDK5RAP2 and ASPM, which is well matched with cetacean complex brain size evolution. Evolutionary rate of CDK5RAP2 and ASPM were significantly related to EQ, suggesting that these two genes may have contributed to EQ expansion in cetaceans. This suggestion was further indicated by our preliminary function test that ASPM might be mainly linked to evolutionary increases in EQ. Most strikingly, our results suggested that cetaceans evolved large brains to manage complex social systems, consisting with the 'social brain hypothesis', as evolutionary rate of ASPM and CDK5RAP2 were significantly related to mean group size. PMID- 28851291 TI - Honokiol improved chondrogenesis and suppressed inflammation in human umbilical cord derived mesenchymal stem cells via blocking nuclear factor-kappaB pathway. AB - BACKGROUND: Cartilage degradation is the significant pathological process in osteoarthritis (OA). Inflammatory cytokines, such as interleukin-1beta (IL 1beta), activate various downstream mediators contributing to OA pathology. Recently, stem cell-based cartilage repair emerges as a potential therapeutic strategy that being widely studied, whereas, the outcome is still far from clinical application. In this study, we focused on an anti-inflammatory agent, honokiol, which is isolated from an herb, investigated the potential effects on human umbilical cord derived mesenchymal stem cells (hUC-MSCs) in IL-1beta stimulation. METHODS: Second passage hUC-MSCs were cultured for multi differentiation. Flow cytometry, qRT-PCR, von Kossa stain, alcian blue stain and oil red O stain were used for characterization and multi-differentiation determination. Honokiol (5, 10, 25, 50 MUM) and IL-1beta (10 ng/ml) were applied in hUC-MSCs during chondrogenesis. Analysis was performed by MTT, cell apoptosis evaluation, ELISA assay, qRT-PCR and western blot. RESULTS: hUC-MSC was positive for CD73, CD90 and CD105, but lack of CD34 and CD45. Remarkable osteogenesis, chondrogenesis and adipogenesis were detected in hUC-MSCs. IL-1beta enhanced cell apoptosis and necrosis and activated the expression of caspase-3, cyclooxygenase 2 (COX-2), interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-1, -9, 13 in hUC-MSCs. Moreover, the expression of SRY-related high-mobility group box 9 (SOX 9), aggrecan and col2alpha1 was suppressed. Honokiol relieved these negative impacts induced by IL-1beta and suppressed Nuclear factor-kappaB (NF-kappaB) pathway by downregulating expression of p-IKKalpha/beta, p-IkappaBalpha and p-p65 in dose-dependent and time-dependent manner. CONCLUSIONS: Honokiol improved cell survival and chondrogenesis of hUC-MSCs and inhibited IL-1beta-induced inflammatory response, which suggested that combination of anti-inflammation and stem cell can be a novel strategy for better cartilage repair. PMID- 28851292 TI - Combined spinal-epidural anesthesia for cesarean delivery in a patient with cor triloculare biventriculare. AB - BACKGROUND: Cor triloculare biventriculare accounts for approximately 0.31% of cases of congenital heart disease (CHD). Moreover, people with cor triloculare biventriculare always have shorter life spans, and cases of gestation are rare. There have been various related reports of cor triloculare biventriculare in recent years. CASE PRESENTATION: We described an emergency cesarean section of a 30-year-old, 38-weeks-pregnant woman suffering from cardiac insufficiency and fetal distress. Combined spinal-epidural anesthesia was performed safely, and a male baby was smoothly delivered 10 min after the procedure without any adverse outcome on the mother or newborn. After surgery, we advised that the patient submit to an echocardiogram examination, which revealed the congenital heart disease cor triloculare biventriculare. CONCLUSIONS: Combined spinal-epidural anesthesia was administered to a patient with cor triloculare biventricularethis with good effect, ensuring the patient's safety and meeting the need for emergency surgery. PMID- 28851293 TI - Precisao e confiabilidade de um teste imuno-cromatografico rapido NS1 para diagnostico DENV-1 no ponto de atendimento e no laboratorio. AB - BACKGROUND: Rapid immunochromatographic tests (ICT) for dengue non-structural protein 1 (NS1) have shown good performance for diagnosing acute-phase dengue in serum in laboratory settings, but rarely have been assessed in whole blood and at point of care (POC). This study compare the accuracy and inter- and intra observer reliability of the NS1 BioeasyTM ICT in whole blood at POC versus serum in the laboratory, during a DENV-1 epidemic. METHODS: Cross-sectional study involving 144 adults spontaneously demanding care in an emergency department within 4 days of onset of acute febrile illness. Accuracy of NS1 BioeasyTM ICT was compared in whole blood and serum, both at 15 and 30 min, blinded to the reference RT-PCR or NS1 ELISA. Non-dengue patients were also tested for Zika virus with RT-PCR. Reliability of whole blood and serum readings by the same or different observers was measured by simple kappa (95% CI). RESULTS: At 15 min, sensitivity (Sn) of NS1 BioeasyTM ICT in whole blood/POC was 76.7% (95% CI: 68.0 84.1) and specificity (Sp) was 87.0% (95% CI: 66.4-97.2). Sn in serum/laboratory was 82% (95% CI: 74.1-88.6) and Sp 100% (95% CI: 85.8-100). Positive likelihood ratio was 5.9 (95% CI: 2.0-17.0) for whole blood/POC and 19.8 (95% CI: 2.9-135.1) for serum/laboratory. Reliability of matched readings of whole blood/POC and serum/laboratory by the same observer (k = 0.83, 95% CI: 0.74-0.93) or different observers (k = 0.81, 95% CI: 0.72-0.92) was almost perfect, with higher discordant levels in the absence of dengue. Results did not differ statistically at 5%. CONCLUSIONS: NS1 BioeasyTM ICT in DENV-1 epidemics is a potentially confirmatory test. Invalid results at 15 min should be reread at 30 min. To optimize impact of implementing ICT in the management of false-negatives it should be incorporated into an algorithm according to setting and available specimen. TRIAL REGISTRATION: UTN U1111-1145-9451 . PMID- 28851294 TI - Landscape review of current HIV 'kick and kill' cure research - some kicking, not enough killing. AB - BACKGROUND: Current antiretroviral therapy (ART) used to treat human immunodeficiency virus (HIV) patients is life-long because it only suppresses de novo infections. Recent efforts to eliminate HIV have tested the ability of a number of agents to reactivate ('Kick') the well-known latent reservoir. This approach is rooted in the assumption that once these cells are reactivated the host's immune system itself will eliminate ('Kill') the virus. While many agents have been shown to reactivate large quantities of the latent reservoir, the impact on the size of the latent reservoir has been negligible. This suggests that the immune system is not sufficient to eliminate reactivated reservoirs. Thus, there is a need for more emphasis on 'kill' strategies in HIV cure research, and how these might work in combination with current or future kick strategies. METHODS: We conducted a landscape review of HIV 'cure' clinical trials using 'kick and kill' approaches. We identified and reviewed current available clinical trial results in human participants as well as ongoing and planned clinical trials. We dichotomized trials by whether they did not include or include a 'kill' agent. We extracted potential reasons why the 'kill' is missing from current 'kick and kill' strategies. We subsequently summarized and reviewed current 'kill' strategies have entered the phase of clinical trial testing in human participants and highlighted those with the greatest promise. RESULTS: The identified 'kick' trials only showed promise on surrogate measures activating latent T-cells, but did not show any positive effects on clinical 'cure' measures. Of the 'kill' agents currently being tested in clinical trials, early results have shown small but meaningful proportions of participants remaining off ART for several months with broadly neutralizing antibodies, as well as agents for regulating immune cell responses. A similar result was also recently observed in a trial combining a conventional 'kick' with a vaccine immune booster ('kill'). CONCLUSION: While an understanding of the efficacy of each individual component is crucial, no single 'kick' or 'kill' agent is likely to be a fully effective cure. Rather, the solution is likely found in a combination of multiple 'kick and kill' interventions. PMID- 28851295 TI - Assessing advances in regional anesthesia by their portrayals in meta-analyses: an alternative view on recent progress. AB - BACKGROUND: The aim of this study was to delineate research reflecting advances in regional/local anesthesia where recent clinical progress was clearly defined by meta-analysis. METHODS: We conducted a search to identify all articles with meta-analyses of randomized clinical trials related to the field of regional/local anesthesia. From 279 titles, after multiple exclusions, 16 meta analyses on important clinical practice developments with high potential for a positive conclusion on the effectiveness of the treatment were left for the assessment. The assessment was performed in two steps. The first step was related to verification of proof-of-concept: the effect is statistically reliable (p value, effect size, heterogeneity across different RCTs) and the risk of bias not too high. The second step was devoted to attempts to form an opinion on the real clinical benefits of a new development. RESULTS: The assessment revealed that seven recent developments passed the proof-of-concept step. At the same time, positive conclusion on real clinical benefits was reached only by one of these seven developments: ultrasound guidance for peripheral nerve blocks (at least with some of the blocks). Meaningful clinical improvements with other developments remains uncertain. The assessment of the relationships between analyzed advancements over the past 30 years and earlier similar developments indicated that their evolution was usually incremental. The most original advancement was found to be the introduction of the transversus abdominis plane block. CONCLUSION: The assessment of recent advances in regional/local anesthesia, based on the evaluation of related meta-analyses, revealed only incremental progress with mostly marginal benefits. The progress was the most notable with ultrasound guidance for some of peripheral nerve blocks. PMID- 28851297 TI - An Agamma-globin G->A gene polymorphism associated with beta039 thalassemia globin gene and high fetal hemoglobin production. AB - BACKGROUND: Increase of the expression of gamma-globin gene and high production of fetal hemoglobin (HbF) in beta-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify beta-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea). METHODS: Agamma-globin gene sequencing was performed on genomic DNA isolated from a total of 75 beta-thalassemia patients, including 31 beta039/beta039, 33 beta039/beta+IVSI-110, 9 beta+IVSI-110/beta+IVSI-110, one beta0IVSI-1/beta+IVSI-6 and one beta039/beta+IVSI-6. RESULTS: The results show that the rs368698783 polymorphism is present in beta-thalassemia patients in the 5'UTR sequence (+25) of the Agamma-globin gene, known to affect the LYAR (human homologue of mouse Ly 1 antibody reactive clone) binding site 5'-GGTTAT-3'. This Agamma(+25 G->A) polymorphism is associated with the Ggamma-globin-XmnI polymorphism and both are linked with the beta039-globin gene, but not with the beta+IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the Agamma(+25 G->A) and Ggamma-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from beta039/beta039 thalassemia patients. CONCLUSIONS: As a potential explanation of our findings, we hypothesize that in beta-thalassemia the Ggamma-globin XmnI/Agamma-globin-(G->A) genotype is frequently under genetic linkage with beta0 thalassemia mutations, but not with the beta+-thalassemia mutation here studied (i.e. beta+IVSI-110) and that this genetic combination has been selected within the population of beta0-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the Agamma-globin gene associated in beta039 thalassemia patients with high HbF in erythroid precursor cells. PMID- 28851296 TI - Design and rationale of the Procalcitonin Antibiotic Consensus Trial (ProACT), a multicenter randomized trial of procalcitonin antibiotic guidance in lower respiratory tract infection. AB - BACKGROUND: Overuse of antibiotics is a major public health problem, contributing to growing antibiotic resistance. Procalcitonin has been reported to be commonly elevated in bacterial, but not viral infection. Multiple European trials found procalcitonin-guided care reduced antibiotic use in lower respiratory tract infection, with no apparent harm. However, applicability to US practice is limited due to trial design features impractical in the US, between-country differences, and residual safety concerns. METHODS: The Procalcitonin Antibiotic Consensus Trial (ProACT) is a multicenter randomized trial to determine the impact of a procalcitonin antibiotic prescribing guideline, implemented with basic reproducible strategies, in US patients with lower respiratory tract infection. DISCUSSION: We describe the trial methods using the Consolidated Standards of Reporting Trials (CONSORT) framework, and the rationale for key design decisions, including choice of eligibility criteria, choice of control arm, and approach to guideline implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02130986 . Registered May 1, 2014. PMID- 28851298 TI - Vitamin D receptor gene polymorphisms in association with diabetic nephropathy: a systematic review and meta-analysis. AB - BACKGROUND: A large amount of researches have demonstrated that vitamin D receptor (VDR) gene polymorphisms are associated with diabetic nephropathy (DN) risk in diabetes mellitus (DM) patients. Nevertheless, the results are inconclusive and inconsistent. METHODS: We screened PubMed, Embase, Chinese National Knowledge Infrastructure and Chinese Wanfang databases for those relevant studies updated in May 2016. RESULTS: 7 studies involving 2564 subjects were recruited. We evaluated the genotypic and allelic differences between DN patients and DM controls. Overall analysis showed that no significant association was found among the ApaI, BsmI, FokI,TaqI gene polymorphisms and DN susceptibility in diabetic patients (all P values > 0.05). In the stratified analysis, TT genotype was related to DN susceptibility in Asians (TT vs Tt + tt: OR =2.21, 95% CI: 1.05-4.67, p = 0.04). The sensitivity analysis showed that the results in overall populations, Caucasians and Asians were dependable. CONCLUSIONS: No significant association was found among the ApaI, BsmI, FokI, TaqI polymorphisms and DN risk in overall populations, the TaqI variants might related to DN susceptibility in Asians. Further researches are required to testify our meta-analysis. PMID- 28851299 TI - The role of Community Mobilization in maternal care provision for women in sub Saharan Africa- A systematic review of studies using an experimental design. AB - BACKGROUND: While the role of community mobilization in improving maternal health outcomes of HIV positive women in sub-Saharan Africa is continuously emphasized, little is known about how legitimate these claims are. The aim of this study is to systematically review the empirical evidence on this issue. METHODS: A systematic search was conducted in PuBMed, Scopus, Web of Science, MEDLINE, COCHRANE, Allied Health Literature, and Cumulative Index to Nursing. RESULTS: Our search identified 14 publications on the role of community mobilization in maternal care provision in sub-Saharan Africa, including both HIV negative women and women with HIV, that have used experimental research designs. Regarding HIV negative women, literature has demonstrated that community mobilization is a useful strategy for promoting both positive maternal process results and maternal health outcomes. Most of the literature on women with HIV has focused only on demonstrating the causal link between community mobilization and process results. There has been very little focus on demonstrating the causal link between community mobilization and maternal outcomes for women living with HIV. Overall, the results show that while there is some empirical evidence on a causal link between community mobilization and maternal health outcomes for HIV negative women, this kind of evidence is still missing for HIV positive women. Moreover, as shown by the studies, community mobilization as a maternal health strategy is still in its infancy. CONCLUSION: Given the gaps identified in our review, we recommend further research with the aim of providing sound evidence on the role of community mobilization in improving maternal health outcomes of women with HIV in sub-Saharan Africa. PMID- 28851300 TI - Presence of immune cells, low tumor proliferation and wild type BRAF mutation status is associated with a favourable clinical outcome in stage III cutaneous melanoma. AB - BACKGROUND: The variable prognosis in stage III cutaneous melanoma is partially due to unknown prognostic factors. Improved prognostic tools are required to define patients with an increased risk of developing metastatic disease who might benefit from adjuvant therapies. The aim was to examine if cellular immune markers in association with tumor proliferation rate and BRAF mutation status have an impact on prognosis in stage III melanoma. METHODS: We have used two sets of case series with stage III disease: 23 patients with short survival (<= 13 months) and 19 patients with long survival (>= 60 months). Lymph node metastases were analyzed for Ki67, CD8 and FOXP3 protein expression using immunohistochemistry. BRAF mutation status was analyzed in a previous study on the same samples. RESULTS: Low tumor proliferation rate was significantly associated with a better prognosis (p = 0.013). Presence of FOXP3+ T cells was not correlated to adverse clinical outcome. A highly significant trend for a longer survival was found in the presence of an increasing number of markers; CD8+ and FOXP3+ T cells, low tumor proliferation and BRAF wildtype status (p = 0.003). Presence of at least three of these four markers was found to be an independent favorable prognostic factor (OR 19.4, 95% CI 1.9-197, p = 0.012), when adjusting for ulceration and number of lymph node metastases. Proliferation alone remained significant in multivariate analyses (OR 26.1, 95% CI 2.0-344, p = 0.013) but with a wider confidence interval. This panel still remained independent when also adjusting for a previously identified prognostic glycolytic pigment panel. CONCLUSIONS: We have demonstrated that presence of immune cells in association with tumor proliferation and BRAF mutation status may further contribute to identify stage III melanoma patients with high risk of relapse. PMID- 28851301 TI - Clinical features and the degree of cerebrovascular stenosis in different types and subtypes of cerebral watershed infarction. AB - BACKGROUND: Whether there are differences in pathogenesis among different types and subtypes of cerebral watershed infarction (WSI) is controversial since they have been combined into a single group in most previous studies. METHODS: We prospectively identified 340 supratentorial WSI patients at Beijing Chao-Yang Hospital, Capital Medical University, China and classified them based on diffusion-weighted imaging(DWI) templates. Baseline characteristics, clinical courses and neuroradiological features were compared among patients with different types and subtypes of WSI. RESULTS: We identified 92 patients with cortical watershed infarction (CWI), 112 with internal watershed infarction (IWI) and 136 with mixed-type infarction. Compared with CWI patients, more IWI patients had critical stenosis of internal carotid artery (ICA) (P < 0.001). For the CWI group, patients with anterior watershed infarction (AWI) were more prone to critical ICA stenosis than those with posterior watershed infarction (PWI) (P = 0.011). For the IWI group, critical ICA stenosis was more prevalent in patients with partial IWI (P-IWI) than in those with confluent IWI (C-IWI) (P = 0.026). IWI patients were more frequently found to have clinical deterioration during the first 7 days of hospitalization and a poor prognosis at the 90th day than in CWI patients (P = 0.003 and P = 0.014, respectively). CONCLUSIONS: IWI, especially the P-IWI subtype, is associated with hemodynamic impairment (HDI), whereas CWI has a weaker correlation with ICA steno-occlusion. Furthermore, IWI patients are more prone to poor prognosis. PMID- 28851302 TI - Maternal mortality audit in Suriname between 2010 and 2014, a reproductive age mortality survey. AB - BACKGROUND: The fifth Millennium Development Goal (MDG-5) aimed to improve maternal health, targeting a maternal mortality ratio (MMR) reduction of 75% between 1990 and 2015. The objective of this study was to identify all maternal deaths in Suriname, determine the extent of underreporting, estimate the reduction, audit the maternal deaths and assess underlying causes and substandard care factors. METHODS: A reproductive age mortality survey was conducted in Suriname (South-American upper-middle income country) between 2010 and 2014 to identify all maternal deaths in the country. MMR was compared to vital statistics and a previous confidential enquiry from 1991 to 1993 with a MMR 226. A maternal mortality committee audited the maternal deaths and identified underlying causes and substandard care factors. RESULTS: In the study period 65 maternal deaths were identified in 50,051 live births, indicating a MMR of 130 per 100.000 live births and implicating a 42% reduction of maternal deaths in the past 25 years. Vital registration indicated a MMR of 96, which marks underreporting of 26%. Maternal deaths mostly occurred in the urban hospitals (84%) and the causes were classified as direct (63%), indirect (32%) or unspecified (5%). Major underlying causes were obstetric and non-obstetric sepsis (27%) and haemorrhage (20%). Substandard care factors (95%) were mostly health professional related (80%) due to delay in diagnosis (59%), delay or wrong treatment (78%) or inadequate monitoring (59%). Substandard care factors most likely led to death in 47% of the cases. CONCLUSION: Despite the reduction in maternal mortality, Suriname did not reach MDG-5 in 2015. Steps to reach the Sustainable Development Goal in 2030 (MMR <= 70 per 100.000 live births) and eliminate preventable deaths include improving data surveillance, installing a maternal death review committee, and implementing national guidelines for prevention and management of major complications of pregnancy, childbirth and puerperium. PMID- 28851303 TI - Are the anomalous vertebral arteries more hypoplastic?: retrospective linear mixed model approach. AB - BACKGROUND: Small or hypoplastic vertebral artery (VA) is one of the risk factor for posterior circulation stroke. We assess whether various types of VA anomaly contribute to its diameter. METHODS: We screened 238 patients who underwent neck CT and MR angiography within 1 month. A V1 anomaly was defined as the abnormal origin of the VA on a three-dimensional MR angiography and a V2 anomaly was defined as the VA not passing through the 6th cervical transverse foramen (TF) on an axial CT image. A linear mixed model was used to evaluate the determinants of VA size. RESULTS: Among participants, 24 (10.1%) subjects exhibited an anomalous VA and, of the 476 VAs examined, 11 (2.3%) had an aortic origin and 27 (5.7%) had an abnormal entrance into the C6 TF. Presence of the V1 anomaly was positively associated with the V2 anomaly (P for chi-square < 0.001) and a linear mixed model revealed that being male (0.2 mm larger, P = 0.015), having a right VA anomaly (0.3 mm smaller, P < 0.001), having a V1 anomaly (0.9 mm smaller, P < 0.001), and having a V2 anomaly (0.7 mm smaller, P < 0.001) were significant predictor of VA diameter. CONCLUSION: The diameters of VAs with an anomalous aortic origin or an abnormal entrance of the TF were significantly smaller than those of normal VAs. These findings suggest that anomalies of the VA detected in 3-dimensional CTA or MRA may be clues for vertebral artery hypoplasia. PMID- 28851304 TI - Temporal influence of endocrine therapy with tamoxifen and chemotherapy on nutritional risk and obesity in breast cancer patients. PMID- 28851305 TI - Nephrolithiasis and Osteomalacia associated with adefovir-induced Fanconi syndrome in a patient with hepatitis B. AB - BACKGROUND: An increasing number of case reports suggest that acquired renal Fanconi syndrome may be associated with prolonged use of adefovir against hepatitis B virus. Renal Fanconi syndrome is an uncommon disease, and its complication with nephrolithiasis is quite rare. Herein, we report a rare coexistence of nephrolithiasis and acquired renal Fanconi syndrome in a chronic hepatitis B-positive patient with prolonged adefovir therapy. CASE PRESENTATION: The patient presented with osteomalacia and nephrolithiasis. Consequently, extracorporeal shock-wave lithotripsy and left double-J ureteral stent insertion were considered for obstructive nephropathy, which was caused by nephrolithiasis. However, osteomalacia had been misdiagnosed as osteoporosis before admission to our hospital. On admission, a complexity of multiple fractures, hypophosphataemia, glycosuria without hyperglycaemia and non-anion-gap metabolic acidosis indicated a diagnosis of acquired renal Fanconi syndrome induced by adefovir. After switching from adefovir to entecavir, the patient's symptoms and laboratory findings improved significantly. CONCLUSIONS: The mechanism responsible for nephrolithiasis in renal Fanconi syndrome is still unclear. We recommend regularly monitoring renal function and serum calcium and serum phosphate to prevent renal Fanconi syndrome during the prolonged use of adefovir for hepatitis B virus. PMID- 28851306 TI - Urbanization and kidney function decline in low and middle income countries. AB - Urbanization is expected to increase in low and middle-income countries (LMICs), and might contribute to the increased disease burden. The association between urbanization and CKD is incompletely understood among LMICs. Recently, Inoue et al., explored the association of urbanization on renal function from the China Health and Nutrition Survey. The study found that individuals living in an urban environment had a higher odds of reduced renal function independent of behavioral and cardiometabolic measures, and this effect increased in a dose dependent manner. In this commentary, we discuss the results of these findings and explain the need for more surveillance studies among LMICs. PMID- 28851307 TI - The Birth Satisfaction Scale-Revised Indicator (BSS-RI). AB - BACKGROUND: The current study sought to develop a short birth satisfaction indicator utilising items from the Birth Satisfaction Scale-Revised (BSS-R) for use as a brief measure of birth satisfaction and as a possible key performance indicator for perinatal service delivery evaluation. Building on the recently developed BSS-R, the study aimed to develop a simplified version of the instrument to assess birth satisfaction easily that could work as a short evaluative measure of clinical service delivery for labour and birth that is consistent with policy documents, placing women at the centre of the birth experience. METHODS: The six item Birth Satisfaction Scale-Revised Indicator (BSS RI) was embedded within the 2014 National Maternity Survey for England. A random selection of mothers who had given birth in a two week period in England were surveyed three months after the birth. Using a two-stage design and split-half dataset, exploratory factor analysis, confirmatory factor analysis, internal consistency, convergent, divergent and known-groups discriminant validity evaluation were conducted in a secondary analysis of the survey data. RESULTS: Using this large population based survey of recent mothers the short revised measure was found to comprise two distinct domains of birth satisfaction, 'stress and emotional response to labour and birth' and 'quality of care'. The psychometric qualities of the tool were robust as were the indices of validity and reliability evaluated. CONCLUSION: The BSS-RI represents a short easily administered and scored measure of women's satisfaction with care and the experience of labour and birth. The instrument is potentially useful for researchers, service evaluation and policy makers. PMID- 28851308 TI - Patterns and determinants of pathways to reach comprehensive emergency obstetric and neonatal care (CEmONC) in South Sudan: qualitative diagrammatic pathway analysis. AB - BACKGROUND: Maternity referral systems have been under-documented, under researched, and under-theorised. Responsive emergency referral systems and appropriate transportation are cornerstones in the continuum of care and central to the complex health system. The pathways that women follow to reach Emergency Obstetric and Neonatal Care (EmONC) once a decision has been made to seek care have received relatively little attention. The aim of this research was to identify patterns and determinants of the pathways pregnant women follow from the onset of labour or complications until they reach an appropriate health facility. METHODS: This study was conducted in Renk County in South Sudan between 2010 and 2012. Data was collected using Critical Incident Technique (CIT) and stakeholder interviews. CIT systematically identified pathways to healthcare during labour, and factors associated with an event of maternal mortality or near miss through a series of in-depth interviews with witnesses or those involved. Face-to-face stakeholder interviews were conducted with 28 purposively identified key informants. Diagrammatic pathway and thematic analysis were conducted using NVIVO 10 software. RESULTS: Once the decision is made to seek emergency obstetric care, the pregnant woman may face a series of complex steps before she reaches an appropriate health facility. Four pathway patterns to CEmONC were identified of which three were associated with high rates of maternal death: late referral, zigzagging referral, and multiple referrals. Women who bypassed nonfunctional Basic EmONC facilities and went directly to CEmONC facilities (the fourth pathway pattern) were most likely to survive. Overall, the competencies of the providers and the functionality of the first point of service determine the pathway to further care. CONCLUSIONS: Our findings indicate that outcomes are better where there is no facility available than when the woman accesses a non-functioning facility, and the absence of a healthcare provider is better than the presence of a non-competent provider. Visiting non-functioning or partially functioning healthcare facilities on the way to competent providers places the woman at greater risk of dying. Non-functioning facilities and non-competent providers are likely to contribute to the deaths of women. PMID- 28851309 TI - Differences in elongation of very long chain fatty acids and fatty acid metabolism between triple-negative and hormone receptor-positive breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TN) is more aggressive than other subtypes of breast cancer and has a lower survival rate. Furthermore, detailed biological information about the disease is lacking. This study investigated characteristics of metabolic pathways in TN. METHODS: We performed the metabolome analysis of 74 breast cancer tissues and the corresponding normal breast tissues using LC/MS. Furthermore, we classified the breast cancer tissues into ER positive, PgR-positive, HER2-negative breast cancer (EP+H-) and TN, and then the differences in their metabolic pathways were investigated. The RT-PCR and immunostaining were carried out to examine the expression of ELOVL1, 2, 3, 4, 5, 6, and 7. RESULTS: We identified 142 of hydrophilic metabolites and 278 of hydrophobic lipid metabolites in breast tissues. We found the differences between breast cancer and normal breast tissues in choline metabolism, glutamine metabolism, lipid metabolism, and so on. Most characteristic of comparison between EP+H- and TN were differences in fatty acid metabolism was which were related to the elongation of very long chain fatty acids were detected between TN and EP+H-. Real-time RT-PCR showed that the mRNA expression levels of ELOVL1, 5, and 6 were significantly upregulated by 8.5-, 4.6- and 7.0-fold, respectively, in the TN tumors compared with their levels in the corresponding normal breast tissue samples. Similarly, the mRNA expression levels of ELOVL1, 5, and 6 were also significantly higher in the EP+H- tissues than in the corresponding normal breast tissues (by 4.9-, 3.4-, and 2.1-fold, respectively). The mRNA expression level of ELOVL6 was 2.6-fold higher in the TN tumors than in the EP+H- tumors. During immunostaining, the TN and EP+H- tumors demonstrated stronger ELOVL1 and 6 staining than the corresponding normal breast tissues, but ELOVL5 was not stained strongly in the TN or EP+H- tumors. Furthermore, the TN tumors exhibited stronger ELOVL1 and 6 staining than the EP+H- tumors. CONCLUSIONS: Marked differences in fatty acid metabolism pathways, including those related to ELOVL1 and 6, were detected between TN and EP+H-, and it was suggested that ELOVL1 and 6-related fatty acid metabolism pathways may be targets for therapies against TN. PMID- 28851310 TI - Prostate cancer-specific survival among warfarin users in the Finnish Randomized Study of Screening for Prostate Cancer. AB - BACKGROUND: Venous thromboembolic events (VTE) are common in cancer patients and associated with higher mortality. In vivo thrombosis and anticoagulation might be involved in tumor growth and progression. We studied the association of warfarin and other anticoagulant use as antithrombotic medication and prostate cancer (PCa) death in men with the disease. METHODS: The study included 6,537 men diagnosed with PCa during 1995-2009. Information on anticoagulant use was obtained from a national reimbursement registry. Cox regression with adjustment for age, PCa risk group, primary therapy and use of other medication was performed to compare risk of PCa death between warfarin users with 1) men using other types of anticoagulants and 2) non-users of anticoagulants. Medication use was analyzed as a time-dependent variable to minimize immortal time bias. RESULTS: In total, 728 men died from PCa during a median follow-up of 9 years. Compared to anticoagulant non-users, post-diagnostic use of warfarin was associated with an increased risk of PCa death (overall HR 1.47, 95% CI 1.13 1.93). However, this was limited to low-dose, low-intensity use. Otherwise, the risk was similar to anticoagulant non-users. Additionally, we found no risk difference between warfarin and other types of anticoagulants. Pre-diagnostic use of warfarin was not associated with the risk of PCa death. CONCLUSIONS: We found no reduction in risk of PCa death associated with warfarin use. Conversely, the risk was increased in short-term use, which is probably explained by a higher risk of thrombotic events prompting warfarin use in patients with terminal PCa. PMID- 28851311 TI - Distinct preoperative clinical features predict four histopathological subtypes of high-grade serous carcinoma of the ovary, fallopian tube, and peritoneum. AB - BACKGROUND: The Cancer Genome Atlas Research Network reported that high-grade serous carcinoma (HGSC) can be classified based on gene expression profiles into four subtypes, termed "immunoreactive," "differentiated," "proliferative," and "mesenchymal." We previously established a novel histopathological classification of HGSC, corresponding to the gene expression subtypes: immune reactive (IR), papillo-glandular (PG), solid and proliferative (SP), and mesenchymal transition (MT). The purpose of this study is to identify distinct clinical findings among the four pathological subtypes of HGSC, as well as to predict pathological subtype based on preoperative images. METHODS: We retrospectively assessed 65 HGSC cases (IR: 17, PG: 7, SP: 14, MT: 27) and analyzed preoperative images. RESULTS: All IR cases originated from either the ovary or fallopian tube (P = 0.0269). Significantly more IR cases were diagnosed at earlier stages (P = 0.0013), and IR cases displayed lower levels of ascites (P = 0.0014), fewer peritoneal lesions (P = 0.0080), a sporadic pattern of peritoneal lesions (P = 0.0016), a lower incidence of omental cake (P = 0.0416), and fewer distant metastases (P = 0.0146) compared with the other subtypes. MT cases were more likely to be of peritoneal origin (P = 0.0202), presented at advanced stages with higher levels of ascites (P = 0.0008, 0.0052, respectively), and more frequently had a diffuse pattern of peritoneal lesions (P = 0.0059), omental cake (P = 0.0179), and distant metastasis (P = 0.0053). A decision tree analysis estimated the histopathological subtypes based on preoperative images, with a sensitivity of 67.3%. CONCLUSIONS: Pathological subtypes of HGSC have distinct clinical behaviors, and preoperative images enable better prediction of pathological subtype. These findings may lead to individualized treatment plans if the effect of treatment based on the HGSC subtype is elucidated. PMID- 28851313 TI - Minding the gap and overlap: a literature review of fragmentation of primary care for chronic dialysis patients. AB - BACKGROUND: Care coordination is a challenge for patients with kidney disease, who often see multiple providers to manage their associated complex chronic conditions. Much of the focus has been on primary care physician (PCP) and nephrologist collaboration in the early stages of chronic kidney disease, but less is known about the co-management of the patients in the end-stage of renal disease. We conducted a systematic review and synthesis of empirical studies on primary care services for dialysis patients. METHODS: Systematic literature search of MEDLINE/PubMED, CINAHL, and EmBase databases for studies, published until August 2015. Inclusion criteria included publications in English, empirical studies involving human subjects (e.g., patients, physicians), conducted in US and Canadian study settings that evaluated primary care services in the dialysis patient population. RESULTS: Fourteen articles examined three major themes of primary care services for dialysis patients: perceived roles of providers, estimated time in providing primary care, and the extent of dialysis patients' use of primary care services. There was general agreement among providers that PCPs should be involved but time, appropriate roles, and miscommunication are potential barriers to good primary care for dialysis patients. Although many dialysis patients report having a PCP, the majority rely on primary care from their nephrologists. Studies using administrative data found lower rates of preventive care services than found in studies relying on provider or patient self-report. DISCUSSION: The extant literature revealed gaps and opportunities to optimize primary care services for dialysis patients, foreshadowing the challenges and promise of Accountable Care / End-Stage Seamless Care Organizations and care coordination programs currently underway in the United States to improve clinical and logistical complexities of care for this commonly overlooked population. Studies linking the relationship between providers and patients' receipt of primary care to outcomes will serve as important comparisons to the nascent care models for ESRD patients, whose value is yet to be determined. PMID- 28851312 TI - Prognostic significance of E-cadherin and N-cadherin expression in Gliomas. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT), principally involving an E cadherin to N-cadherin shift, linked to tumor invasion or metastasis, and therapeutic resistance in various human cancer. A growing body of recent evidence has supported the hypothesis that EMT play a crucial role in the invasive phenotype of gliomas. To evaluate the prognostic connotation of EMT traits in glioma, expression of E-cadherin and N-cadherin was explored in a large series of glioma patients in relation to patient survival rate. METHODS: Expressions of E- and N-cadherin were examined using immunohistochemical analysis in 92 glioma cases diagnosed at our hospital. These markers expressions were also explored in 21 cases of fresh frozen glioma samples and in glioma cell lines by Western blot analysis. RESULTS: Expression of E-cadherin was observed in eight cases (8.7%) with weak staining intensity in the majority of the immunoreactive cases (7/8). Expression of N-cadherin was identified in 81 cases (88.0%) with high expression in 64 cases (69.5%). Fresh frozen tissue samples and glioma cell lines showed similar results by Western blot analysis. There was no significant difference in either overall survival (OS) or progression-free survival (PFS) according to E cadherin expression (P > 0.05). Although the OS rates were not affected by N cadherin expression levels (P = 0.138), PFS increased in the low N-cadherin expression group with marginal significance (P = 0.058). The survival gains based on N-cadherin expression levels were significantly augmented in a larger series of publicly available REMBRANDT data (P < 0.001). CONCLUSIONS: E- and N-cadherin, as representative EMT markers, have limited prognostic value in glioma. Nonetheless, the EMT process in gliomas may be compounded by enhanced N-cadherin expression supported by unfavorable prognostic outcomes. PMID- 28851314 TI - Adherence and feasibility of 2 treatment schedules of S-1 as adjuvant chemotherapy for patients with completely resected advanced lung cancer: a multicenter randomized controlled trial. AB - BACKGROUND: We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA non small cell lung cancer patients. METHODS: Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary endpoints were relative total administration dose, toxicity, and 3-year disease-free survival. RESULTS: From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients (73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). Grade 1-3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94). CONCLUSIONS: The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1-3 elevation of bilirubin. TRIAL REGISTRATION: This randomized multicenter study was retrospectively registered with the UMIN-CTR (UMIN000016086, registration date December 30, 2014). PMID- 28851315 TI - Propensity score matching analysis of a phase II study on simultaneous modulated accelerated radiation therapy using helical tomotherapy for nasopharyngeal carcinomas. AB - BACKGROUND: Using propensity score matching method (PSM) to evaluate the feasibility and clinical outcomes of simultaneous modulated accelerated radiation therapy (SMART) using helical tomotherapy (HT) in patients with nasopharyngeal carcinoma (NPC). METHODS: Between August 2007 and January 2016, 381 newly diagnosed NPC patients using HT were enrolled in pre-PSM cohort, including 161 cases in a prospective phase II study (P67.5 study, with a prescription dose of 67.5Gy in 30 fractions to the primary tumour and positive lymph nodes) and 220 cases in a retrospective study (P70 study, with a prescription dose of 70Gy in 33 fractions to the primary tumour and positive lymph nodes). Acute and late toxicities were assessed according to the established RTOG/EORTC criteria and Common Terminology Criteria for Adverse Events (CTCAE) V 3.0. Survival rate were assessed with Kaplan-Meier method, log-rank test and Cox regression. RESULTS: After matching, 148 sub-pairs of 296 patients were generated in post-PSM cohort. The incidence of grade 3-4 leukopenia, thrombocytopenia and anemia in the P67.5 group was significantly higher than in the P70 study, but no significant different was found in other acute toxicities or late toxicities between the two groups. The median follow-up was 33 months in the P67.5 and P70 group, ranging 12 54 months and 6-58 months, respectively. No significant differences in 3-year local-regional recurrence free survival (LRRFS), distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) were observed between the 2 groups. Univariate analysis showed that age, T stage, clinical stage were the main factors effecting survival. Cox proportional hazards model showed that 67.5Gy/30F pattern seemed superior in 3-year OS (HR = 0.476, 95% CI: 0.236-0.957). CONCLUSIONS: Through increasing fraction dose and shortening treatment time, the P67.5 study achieved excellent short-term outcomes and potential clinical benefits, with acceptable acute and late toxicities. TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry on 5 July 2014 with a registration code of ChiCTRONC-14,004,895. PMID- 28851316 TI - A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol. AB - BACKGROUND: Metastatic pancreatic cancer has a dismal prognosis, with a mean six month progression-free survival of approximately 50% and a median survival of about 11 months. Despite intensive research, only slight improvements of clinical outcome could be achieved over the last decades. Hence, new and innovative therapeutic strategies are urgently required. ParvOryx is a drug product containing native parvovirus H-1 (H-1PV). Since H-1PV was shown to exert pronounced anti-neoplastic effects in pre-clinical models of pancreatic cancer, the drug appears to be a promising candidate for treatment of this malignancy. METHODS: ParvOryx02 is a non-controlled, single arm, open label, dose-escalating, single center trial. In total seven patients with pancreatic cancer showing at least one hepatic metastasis are to be treated with escalating doses of ParvOryx according to the following schedule: i) 40% of the total dose infused intravenously in equal fractions on four consecutive days, ii) 60% of the total dose injected on a single occasion directly into the hepatic metastasis at varying intervals after intravenous infusions. The main eligibility criteria are: age >= 18 years, disease progression despite first-line chemotherapy, and at least one hepatic metastasis. Since it is the second trial within the drug development program, the study primarily explores safety and tolerability after further dose escalation of ParvOryx. The secondary objectives are related to the evaluation of certain aspects of anti-tumor activity and clinical efficacy of the drug. DISCUSSION: This trial strongly contributes to the clinical development program of ParvOryx. The individual hazards for patients included in the current study and the environmental risks are addressed and counteracted adequately. Besides information on safety and tolerability of the treatment after further dose escalation, thorough evaluations of pharmacokinetics and intratumoral spread as well as proof-of-concept (PoC) in pancreatic cancer will be gained in the course of the trial. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT02653313 , Registration date: Dec. 4th, 2015. PMID- 28851317 TI - The dynamics of the metabolism of acetate and bicarbonate associated with use of hemodialysates in the ABChD trial: a phase IV, prospective, single center, single blind, randomized, cross-over, two week investigation. AB - BACKGROUND: In the United States, hemodialysis (HD) is generally performed via a bicarbonate dialysate. It is not known if small amounts of acid used in dialysate to buffer the bicarbonate can meaningfully contribute to overall buffering administered during HD. We aimed to investigate the metabolism of acetate with use of two different acid buffer concentrates and determine if it effects blood bicarbonate concentrations in HD patients. METHODS: The Acid-Base Composition with use of hemoDialysates (ABChD) trial was a Phase IV, prospective, single blind, randomized, cross-over, 2 week investigation of peridialytic dynamics of acetate and bicarbonate associated with use of acid buffer concentrates. Eleven prevalent HD patients participated from November 2014 to February 2015. Patients received two HD treatments, with NaturaLyte(r) and GranuFlo(r) acid concentrates containing 4 and 8 mEq/L of acetate, respectively. Dialysate order was chosen in a random fashion. The endpoint was to characterize the dynamics of acetate received and metabolized during hemodialysis, and how it effects overall bicarbonate concentrations in the blood and dialysate. Acetate and bicarbonate concentrations were assessed before, at 8 time points during, and 6 time points after the completion of HD. RESULTS: Data from 20 HD treatments for 11 patients (10 NaturaLyte(r) and 10 GranuFlo(r)) was analyzed. Cumulative trajectories of arterialized acetate were unique between NaturaLyte(r) and GranuFlo(r) (p = 0.003), yet individual time points demonstrated overlap without remarkable differences. Arterialized and venous blood bicarbonate concentrations were similar at HD initiation, but by 240 min into dialysis, mean arterialized bicarbonate concentrations were 30.2 (SD +/- 4.16) mEq/L in GranuFlo(r) and 28.8 (SD +/- 4.26) mEq/L in NaturaLyte(r). Regardless of acid buffer concentrate, arterial blood bicarbonate was primarily dictated by the prescribed bicarbonate level. Subjects tolerated HD with both acid buffer concentrates without experiencing any related adverse events. CONCLUSIONS: A small fraction of acetate was delivered to HD patients with use of NaturaLyte(r) and GranuFlo(r) acid buffers; the majority of acetate received was observed to be rapidly metabolized and cleared from the circulation. Blood bicarbonate concentrations appear to be determined mainly by the prescribed concentration of bicarbonate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 11 Dec 2014 ( NCT02334267 ). PMID- 28851319 TI - Absolute and estimated values of macular pigment optical density in young and aged Asian participants with or without age-related macular degeneration. AB - BACKGROUND: Lutein and zeaxanthin are suggested micronutrient supplements to prevent the progression of age-related macular degeneration (AMD), a leading cause of blindness worldwide. To monitor the levels of lutein/zeaxanthin in the macula, macular pigment optical density (MPOD) is measured. A commercially available device (MPSII(r), Elektron Technology, Switzerland), using technology based on heterochromatic flicker photometry, can measure both absolute and estimated values of MPOD. However, whether the estimated value is applicable to Asian individuals and/or AMD patients remains to be determined. METHODS: The absolute and estimated values of MPOD were measured using the MPSII(r) device in 77 participants with a best-corrected visual acuity (BCVA) > 0.099 (logMAR score). RESULTS: The studied eyes included 17 young (20-29 years) healthy, 26 aged (>50 years) healthy, 18 aged and AMD-fellow, and 16 aged AMD eyes. The mean BCVA among the groups were not significantly different. Both absolute and estimated values were measurable in all eyes of young healthy group. However, absolute values were measurable in only 57.7%, 66.7%, and 43.8%, of the aged healthy, AMD-fellow, and AMD groups, respectively, and 56.7% of the eyes included in the 3 aged groups. In contrast, the estimated value was measurable in 84.6%, 88.9% and 93.8% of the groups, respectively, and 88.3% of eyes in the pooled aged group. The estimated value was correlated with absolute value in individuals from all groups by Spearman's correlation coefficient analyses (young healthy: R2 = 0.885, P = 0.0001; aged healthy: R2 = 0.765, P = 0.001; AMD-fellow: R2 = 0.851, P = 0.0001; and AMD: R2 = 0.860, P = 0.013). Using the estimated value, significantly lower MPOD values were found in aged AMD-related eyes, which included both AMD-fellow and AMD eyes, compared with aged healthy eyes by Student's t-test (P = 0.02). CONCLUSIONS: Absolute, in contrast to estimated, value was measurable in a limited number of aged participants; however, it was correlated with estimated value both in young and aged Asian populations with or without AMD. These results may inform future clinical studies investigating the measurement of MPOD in understanding the role of macular pigments in the pathogenesis of AMD. PMID- 28851318 TI - Population-based colorectal cancer screening programmes using a faecal immunochemical test: should faecal haemoglobin cut-offs differ by age and sex? AB - BACKGROUND: The Basque Colorectal Cancer Screening Programme has both high participation rate and high compliance rate of colonoscopy after a positive faecal occult blood test (FIT). Although, colorectal cancer (CRC) screening with biannual (FIT) has shown to reduce CRC mortality, the ultimate effectiveness of the screening programmes depends on the accuracy of FIT and post-FIT colonoscopy, and thus, harms related to false results might not be underestimated. Current CRC screening programmes use a single faecal haemoglobin concentration (f-Hb) cut-off for colonoscopy referral for both sexes and all ages. We aimed to determine optimum f-Hb cut-offs by sex and age without compromising neoplasia detection and interval cancer proportion. METHODS: Prospective cohort study using a single sample faecal immunochemical test (FIT) on 444,582 invited average-risk subjects aged 50-69 years. A result was considered positive at >=20 MUg Hb/g faeces. Outcome measures were analysed by sex and age for a wide range of f-Hb cut-offs. RESULTS: We analysed 17,387 positive participants in the programme who underwent colonoscopy. Participation rate was 66.5%. Men had a positivity rate for f-Hb of 8.3% and women 4.8% (p < 0.0001). The detection rate for advanced neoplasia (cancer plus advanced adenoma) was 44.00/00 for men and 15.90/00 for women (p < 0.0001). The number of colonoscopies required decreased in both sexes and all age groups through increasing the f-Hb cut-off. However, the loss in CRC detection increased by up to 28.1% in men and 22.9% in women. CRC missed were generally at early stages (Stage I-II: from 70.2% in men to 66.3% in women). CONCLUSIONS: This study provides detailed outcomes in men and women of different ages at a range of f-Hb cut-offs. We found differences in positivity rates, neoplasia detection rate, number needed to screen, and interval cancers in men and women and in younger and older groups. However, there are factors other than sex and age to consider when consideration is given to setting the f-Hb cut-off. PMID- 28851321 TI - Rare triad of periampullary carcinoid, duodenal gastrointestinal stromal tumor and plexiform neurofibroma at hepatic hilum in neurofibromatosis type 1: a case report. AB - BACKGROUND: Neurofibromatosis type 1 is a relatively common inherited disorder. Patients with neurofibromatosis type 1 are at high risk of developing neurogenic, neuroendocrine and mesenchymal intra-abdominal tumors. Although coexistence of multiple tumors of different types is frequent in neurofibromatosis type 1, simultaneous occurrence of abdominal tumors of three types in very rare. CASE PRESENTATION: A 66-year-old lady with neurofibromatosis type 1 presented with painless progressive jaundice for six months. Laboratory investigations revealed iron deficiency anemia and conjugated hyperbilirubinemia. Tumor markers were normal. Abdominal computed tomography showed a 3 * 2 cm heterogenous mass in the periampullary region with mild dilation of the common bile duct and another 2 * 1.7 cm mass in the fourth portion of the duodenum. Endoscopic biopsy confirmed the diagnosis of periampullary carcinoid. At surgery, multiple small nodules were detected at the hepatic hilum. Frozen section suggested them to be neurofibromas. Patient underwent pancreatoduodenectomy and had uneventful recovery with no recurrence at two months. Microscopic examination of the resected specimen confirmed presence of three tumors: periampullary well differentiated neuroendocrine tumor, gastrointestinal stromal tumor of the fourth part of duodenum and plexiform neurofibroma at the hepatic hilum. CONCLUSION: Patients of neurofibromatosis type 1 with abdominal symptoms should be treated with high index of clinical suspicion and thoroughly evaluated to rule out multiple tumors. PMID- 28851320 TI - Cilostazol improves endothelial function in acute cerebral ischemia patients: a double-blind placebo controlled trial with flow-mediated dilation technique. AB - BACKGROUND: In order to evaluate the impact of cilostazol on endothelial function, we compared the changes of flow-mediated dilation (FMD) between aspirin and cilostazol groups in patients with acute cerebral ischemia. METHODS: Patients presenting with acute cerebral ischemic events were randomly assigned into aspirin (n = 40) or cilostazol (n = 40) group in a double-blinded manner. FMD was measured at baseline (T0) and 90 days (T1). We measured L-arginine at baseline (a precursor of biologically active nitric oxides). Serious and non-serious adverse events were described. RESULTS: Despite no difference in the baseline FMD values (p = 0.363), there was a significant increase of FMD values in cilostazol group (7.9 +/- 2.4 to 8.9 +/- 2.3%, p = 0.001) and not in aspirin group (8.5 +/- 2.6 to 9.3 +/- 2.8%, p = 0.108). In the multiple regression analysis performed in cilostazol group, serum L-arginine levels were inversely correlated with FMD at T1 (beta = -0.050, SE: 0.012, p < 0.001) with age, total cholesterol levels, and C-reactive protein as confounders. While T0 FMD values in both aspirin and cilostazol groups did not show any correlation with serum L-arginine levels, the correlation is restored in the cilostazol group at T1 (r = 0.467, p = 0.007), while such is not shown in the aspirin group. There was no difference of serious adverse events between the two groups (p = 0.235). Adverse events were more common in the cilostazol group (35/40 vs. 25/40, p = 0.010), due to frequent headaches (14/40 vs. 3/30, p = 0.003) which was well tolerated. CONCLUSION: Cilostazol improved endothelial function in acute cerebral ischemia patients. It also restored an inverse correlation between 3-month FMD and baseline L-arginine levels. TRIAL REGISTRATION: NCT03116269 , 04/12/2017, retrospectively registered. PMID- 28851322 TI - Portable OCT-assisted surgical treatment of intracorneal pre-Descemet epithelial cyst: a case report. AB - BACKGROUND: Intracorneal epithelial cysts are a rare clinical condition that can occur anywhere in the corneal tissue; however, they appear most commonly in the stroma. They are sometimes challenging to treat because of their location, depth, and visual outcomes. Herein, we report a pre-Descemet epithelial cyst that was successfully treated surgically, with guidance from Fourier-domain optical coherence tomography (FD-OCT). CASE PRESENTATION: This interventional case report presents a patient with gradually decreasing vision caused by a pre-Descemet epithelial cyst. A 4-year-old girl with no history of trauma or ocular surgery showed a deep-seated intracorneal cyst in her left eye (8 o'clock corneoscleral area, dissecting into the pre-Descemet cornea). The cyst was threatening the visual axis. An epithelial cyst was diagnosed after drainage on the basis of the cyst contents. We irrigated inside the cyst using 10% trichloroacetic acid (TCA), distilled water, and 1% 5-fluorouracil (5-FU) solutions for chemical cyto destruction of the lining epithelial cells of the cystic wall. We used a portable FD-OCT during operation to guide this procedure, without perforating the Descemet's membrane and endothelial layer. Recurrence could be prevented after removal of the cystic tissue located in the sclera area outside of the limbus. No recurrence was noted during the 4-year follow-up. CONCLUSION: When treating centrally deep-seated intracorneal epithelial cysts, clinicians must consider recurrence, endothelial damage, and visual outcome. Herein we report the case of a deep-seated, intracorneoscleral epithelial cyst that was completely resolved with chemical cyto-destruction and removal of the intrascleral cystic tissue under the guidance with FD-OCT; thus, endothelial damage could be minimized. PMID- 28851323 TI - Evoked potentials after painful cutaneous electrical stimulation depict pain relief during a conditioned pain modulation. AB - BACKGROUND: Conditioned pain modulation (CPM) evaluates the pain modulating effect of a noxious conditioning stimulus (CS) on another noxious test stimulus (TS), mostly based solely on subjective pain ratings. We used painful cutaneous electrical stimulation (PCES) to induce TS in a novel CPM-model. Additionally, to evaluate a more objective parameter, we recorded the corresponding changes of cortical evoked potentials (PCES-EP). METHODS: We examined the CPM-effect in 17 healthy subjects in a randomized controlled cross-over design during immersion of the non-dominant hand into 10 degrees C or 24 degrees C cold water (CS). Using three custom-built concentric surface electrodes, electrical stimuli were applied on the dominant hand, inducing pain of 40-60 on NRS 0-100 (TS). At baseline, during and after CS we assessed the electrically induced pain intensity and electrically evoked potentials recorded over the central electrode (Cz). RESULTS: Only in the 10 degrees C-condition, both pain (52.6 +/- 4.4 (baseline) vs. 30.3 +/- 12.5 (during CS)) and amplitudes of PCES-EP (42.1 +/- 13.4 MUV (baseline) vs. 28.7 +/- 10.5 MUV (during CS)) attenuated during CS and recovered there after (all p < 0.001). In the 10 degrees C-condition changes of subjective pain ratings during electrical stimulation and amplitudes of PCES-EP correlated significantly with each other (r = 0.5) and with CS pain intensity (r = 0.5). CONCLUSIONS: PCES-EPs are a quantitative measure of pain relief, as changes in the electrophysiological response are paralleled by a consistent decrease in subjective pain ratings. This novel CPM paradigm is a feasible method, which could help to evaluate the function of the endogenous pain modulation processes. TRIAL REGISTRATION: German Clinical Trials Register DRKS-ID: DRKS00012779 , retrospectively registered on 24 July 2017. PMID- 28851324 TI - Cancer incidence in eastern Morocco: cancer patterns and incidence trends, 2005 2012. AB - BACKGROUND: Cancer is one of the major health problems worldwide. In this article, we present for the first time the cancer incidence trends, the distribution and the socioeconomic profile of incident cancer cases in Eastern Morocco over a period of eight years. METHODS: Retrospective descriptive study of patients diagnosed with cancer at the Hassan II Regional Oncology Center (ROC) since it was created in October 2005 until December 2012. During the study period, the ROC was the only hospital specialized in cancer care in Eastern Morocco. RESULTS: A total of 7872 incident cases of cancer were registered in Eastern Morocco. Among these incident cases 5220 cases were women and 2652 were men, with a female to male ratio of 1.97. The mean age at diagnosis was 58 years for males and 52 for females and 94% of the patients aged over 30 years. For both sexes combined and for all cancer sites, breast cancer was the commonest followed by cervix uteri, colon-rectum, lung, nasopharynx, and stomach cancers. The most common cancer in women was breast cancer, followed respectively by cervix uteri cancer, colon-rectum cancer, ovary cancer, and stomach cancer. In men, the lung cancer ranked first, followed respectively by colon-rectum cancer, nasopharynx cancer, prostate cancer, and stomach cancer. For most cancers, crude incidence rates (CR) have increased significantly. The CR for all cancers combined has increased from 56.6 to 80.3 per 100,000 females and from 32.3 to 42.6 per 100,000 males during the study period. Patients profile analysis showed that 79% of cancer patients were from urban areas, 83% were unemployed and 85% had no health insurance. CONCLUSIONS: The distribution of cancers in Eastern Morocco is different from those observed in other regions of Morocco. Unlike most countries, women were much more affected with cancer than men in Eastern Morocco. More importantly, the rates of many cancers are rising. Therefore, our data justify the need to develop effective programs for cancer control and prevention in Eastern Morocco. A better access to cancer care should be a priority of the health policies, given that the majority of cancer patients in Eastern Morocco are unemployed, and do not have medical care coverage. PMID- 28851325 TI - Novel FOXG1 mutations in Chinese patients with Rett syndrome or Rett-like mental retardation. AB - BACKGROUND: We aimed to delineate clinical phenotypes associated with FOXG1 mutations in Chinese patients with Rett syndrome (RTT) or RTT-like mental retardation (MR). METHODS: Four hundred and fifty-one patients were recruited, including 418 with RTT and 33 with RTT-like MR. Gene mutations were identified by a target capture method and verified by Sanger sequencing. RESULTS: Four FOXG1 mutations were detected in four patients (three with RTT and one with RTT-like MR), including one previously described mutation and three novel mutations. These mutations included one missense and three micro-insertion mutations. Overall, 0.7% (3/418) of patients who had RTT in our cohort had FOXG1 mutations. All patients had early global developmental delays followed later by severe mental retardation. None of the patients acquired speech or purposeful hand movements, and all of them presented with severe hypotonia, epilepsy, and hypoplasia of the corpus callosum. CONCLUSIONS: Our findings extend the spectrum of FOXG1 mutations and the clinical features of RTT in Chinese patients. We recommend that patients with congenital RTT and Rett-like MR, especially those with brain malformations, such as hypoplasia of the corpus callosum, should be tested for FOXG1 mutations. PMID- 28851326 TI - Dilemma of treating schizophrenia during pregnancy: a Case series and a review of literature. AB - BACKGROUND: The choice of antipsychotic treatment during pregnancy remains controversial, mainly due to a lack of exposure and outcome data. Randomized clinical trials are practically impossible due to ethical reasons. Our reports describe three cases of closely monitored female patients with schizophrenia who were treated with olanzapine during pregnancy. The novelty of reports is that all patients were previously treated with olanzapine long acting injectable (LAI) for an average period of 3.8 years. During the LAI treatment period they were in remission and then refused to continue with LAI mainly due to treatment modality (injectable administration). CASE PRESENTATION: The patients were relatively young, diagnosed with schizophrenia and were previously successfully treated with long acting injectable. The women were pregnant for the first time. In two cases, the patients had become pregnant during remission and they continued treatment with oral olanzapine. In the third case, olanzapine treatment was initiated during admission for a relapse. CONCLUSIONS: There are no controlled studies for the use of olanzapine therapy in pregnant women. More studies are needed to determine the effects of antipsychotics, including olanzapine, on pregnant women and the developing fetus. Schizophrenia relapse during pregnancy may expose the mother and the fetus to high risk if olanzapine is stopped. It is important to assess the risks and benefits of treating pregnant or breastfeeding women with antipsychotics, and weigh these against possible risks of anomalies and developmental problems to the fetus or child. PMID- 28851327 TI - GS-E3D, a new pectin lyase-modified red ginseng extract, inhibited diabetes related renal dysfunction in streptozotocin-induced diabetic rats. AB - BACKGROUND: GS-E3D is a newly developed pectin lyase-modified red ginseng extract. The purpose of this study was to investigate the therapeutic effects of GS-E3D on diabetes-related renal dysfunction in streptozotocin-induced diabetic rats. METHOD: GS-E3D (25, 50, and 100 mg/kg body weight per day) was administered for 6 weeks. The levels of blood glucose and hemoglobin A1c, and of urinary albumin, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and advanced glycation end products (AGEs) were determined. Kidney histopathology, renal accumulation of AGEs, and expression of alpha-smooth muscle actin (alpha-SMA) were also examined. RESULTS: Administration of GS-E3D for 6 weeks reduced urinary levels of albumin, 8-OHdG, and AGEs in diabetic rats. Mesangial expansion, renal accumulation of AGEs, and enhanced alpha-SMA expression were significantly inhibited by GS-E3D treatment. Oral administration of GS-E3D dose-dependently improved all symptoms of diabetic nephropathy by inhibiting renal accumulation of AGEs and oxidative stress. CONCLUSION: The results of this study indicate that the use of GS-E3D as a food supplement may provide effective treatment of diabetes-induced renal dysfunction. PMID- 28851328 TI - Measurement of acetabular inclination and anteversion via CT generated 3D pelvic model. AB - BACKGROUND: Inclination and anteversion were the main factors that determined the reliability of the acetabulum. Inclination and anteversion measurements included anatomical, operational and radiographic methods. The aim of our present study was to exhibit divergence of inclination and anteversion via the three measurements. METHODS: Inclination and anteversion were defined according to the definitions put forward by Murray. Three-dimensional models of pelvis of CT data were brought forth. Acetabular axis was determined by the rim of acetabula. Reference planes were established by bone landmarks including anterior superior iliac spine, pubic tubercles and sacral crests. Inclinations and anteversions were calculated according to the definitions. RESULTS: Forty-nine cases were involved in the research. Data of inclination form anatomical, operational and radiographic showed 37.48 +/- 11.07, 45.12 +/- 14.76 and 48.76 +/- 14.36, and anteversion were 18.12 +/- 7.59, 24.97 +/- 9.68, 14.30 +/- 5.64. A substantial deviation was noted in the inclinations (P < 0.01) and anteversions (P < 0.01). CONCLUSION: Our findings suggested that the inclinations and anteversions of the three measurements varied, which might in turn interfere the decision of orthopedists. PMID- 28851329 TI - Process evaluation results of a cluster randomised controlled childhood obesity prevention trial: the WAVES study. AB - BACKGROUND: Increasing prevalence of childhood obesity and its related consequences emphasises the importance of developing and evaluating interventions aimed at prevention. The importance of process evaluation in health intervention research is increasingly recognised, assessing implementation and participant response, and how these may relate to intervention success or failure. A comprehensive process evaluation was designed and undertaken for the West Midlands ActiVe lifestyle and healthy Eating in School children (WAVES) study that tested the effectiveness of an obesity prevention programme for children aged 6-7 years, delivered in 24 UK schools. The four intervention components were: additional daily school-time physical activity (PA); cooking workshops for children and parents; Villa Vitality (VV), a 6-week healthy lifestyle promotion programme run by a local football club; and signposting to local PA opportunities. METHODS: Data relating to six dimensions (Fidelity, Reach, Recruitment, Quality, Participant Responsiveness, Context) were collected via questionnaires, logbooks, direct observations, focus groups and interviews. Multiple data collection methods allowed for data triangulation and validation of methods, comparing research observations with teacher records. The 6-stage WAVES study model ((i) Data collection, (ii) Collation, (iii) Tabulation, (iv) Score allocation and discussion, (v) Consultation, (vi) Final score allocation) was developed to guide the collection, assimilation and analysis of process evaluation data. Two researchers independently allocated school scores on a 5 point Likert scale for each process evaluation dimension. Researchers then discussed school score allocations and reached a consensus. Schools were ranked by total score, and grouped to reflect low, medium or high intervention implementation. RESULTS: The intervention was predominantly well-implemented and well-received by teachers, parents and children. The PA component was identified as the most challenging, VV the least. Median implementation score across schools was 56/75 (IQR, 51.0 - 60.8). Agreement between teacher logbooks and researcher observations was generally high, the main discrepancies occurred in session duration reporting where in some cases teachers' estimations tended to be higher than researchers'. CONCLUSIONS: The WAVES study model provides a rigorous and replicable approach to undertaking and analysing a multi-component process evaluation. Challenges to implementing school-based obesity prevention interventions have been identified which can be used to inform future trials. TRIAL REGISTRATION: ISRCTN97000586 . 19 May 2010. PMID- 28851331 TI - "I would rather be told than not know" - A qualitative study exploring parental views on identifying the future risk of childhood overweight and obesity during infancy. AB - BACKGROUND: Risk assessment tools provide an opportunity to prevent childhood overweight and obesity through early identification and intervention to influence infant feeding practices. Engaging parents of infants is paramount for success however; the literature suggests there is uncertainty surrounding the use of such tools with concerns about stigmatisation, labelling and expressions of parental guilt. This study explores parents' views on identifying future risk of childhood overweight and obesity during infancy and communicating risk to parents. METHODS: Semi-structured qualitative interviews were conducted with 23 parents and inductive, interpretive and thematic analysis performed. RESULTS: Three main themes emerged from the data: 1) Identification of infant overweight and obesity risk. Parents were hesitant about health professionals identifying infant overweight as believed they would recognise this for themselves, in addition parents feared judgement from health professionals. Identification of future obesity risk during infancy was viewed positively however the use of a non judgemental communication style was viewed as imperative. 2) Consequences of infant overweight. Parents expressed immediate anxieties about the impact of excess weight on infant ability to start walking. Parents were aware of the progressive nature of childhood obesity however, did not view overweight as a significant problem until the infant could walk as viewed this as a point when any excess weight would be lost due to increased energy expenditure. 3) Parental attributions of causality, responsibility, and control. Parents articulated a high level of personal responsibility for preventing and controlling overweight during infancy, which translated into self-blame. Parents attributed infant overweight to overfeeding however articulated a reluctance to modify infant feeding practices prior to weaning. CONCLUSION: This is the first study to explore the use of obesity risk tools in clinical practice, the findings suggest that identification, and communication of future overweight and obesity risk is acceptable to parents of infants. Despite this positive response, findings suggest that parents' acceptance to identification of risk and implementation of behaviour change is time specific. The apparent level of parental responsibility, fear of judgement and self-blame also highlights the importance of health professionals approach to personalised risk communication so feelings of self blame are negated and stigmatisation avoided. PMID- 28851330 TI - Childhood obesity and adult cardiovascular disease risk factors: a systematic review with meta-analysis. AB - BACKGROUND: Overweight and obesity is a major public health concern that includes associations with the development of cardiovascular disease (CVD) risk factors during childhood and adolescence as well as premature mortality in adults. Despite the high prevalence of childhood and adolescent obesity as well as adult CVD, individual studies as well as previous systematic reviews examining the relationship between childhood obesity and adult CVD have yielded conflicting results. The purpose of this study was to use the aggregate data meta-analytic approach to address this gap. METHODS: Studies were included if they met the following criteria: (1) longitudinal and cohort studies (including case-cohort), (2) childhood exposure and adult outcomes collected on the same individual over time, (3) childhood obesity, as defined by the original study authors, (4) English-language articles, (5) studies published up to June, 2015, (6) one or more of the following CVD risk factors [systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), non-high-density lipoprotein cholesterol (non-HDL), and triglycerides (TG)], (7) outcome(s) not self-reported, and (8) exposure measurements (child's adiposity) assessed by health professionals, trained investigators, or self-reported. Studies were retrieved by searching three electronic databases as well as citation tracking. Fisher's r to z score was calculated for each study for each outcome. Pooled effect sizes were calculated using random-effects models while risk of bias was assessed using the STROBE instrument. In order to try and identify sources of heterogeneity, random-effects meta-regression was also performed. RESULTS: Of the 4840 citations reviewed, a total of 23 studies were included in the systematic review and 21 in the meta-analysis. The findings suggested that childhood obesity is significantly and positively associated with adult SBP (Zr = 0.11; 95% CI: 0.07, 0.14), DBP (Zr = 0.11; 95% CI: 0.07, 0.14), and TG (Zr =0.08; 95% CI: 0.03, 0.13), and significantly and inversely associated with adult HDL (Zr = -0.06; 95% CI: -0.10, -0.02). For those studies that adjusted for adult body mass index (BMI), associations were reversed, suggesting that adult BMI may be a potential mediator. Nine studies had more than 33% of items that placed them at an increased risk for bias. CONCLUSIONS: The results of this study suggest that childhood obesity may be a risk factor for selected adult CVD risk factors. However, a need exists for additional, higher-quality studies that include, but are not limited to, both unadjusted and adjusted measures such as BMI before any definitive conclusions can be reached. SYSTEMATIC REVIEW AND META-ANALYSIS: PROSPERO 2015: CRD42015019763 . PMID- 28851332 TI - Validation of Bengali perceived stress scale among LGBT population. AB - BACKGROUND: Lesbian, gay, bisexual and transgender (LGBT) population encounter more stressful life circumstances compared to general population. Perceived Stress Scale (PSS) can be a useful tool for measuring their stress. However, psychometric properties of PSS have never been tested on LGBT population. METHODS: This cross sectional study employed a two-stage sampling strategy to collect data from 296 LGBT participants from six divisional districts of Bangladesh. Exploratory (EFA) and confirmatory factor analysis (CFA) were carried out on PSS 10 along with analysis of reliability and validity. RESULTS: EFA revealed a two-factor structure of PSS for LGBT population explaining 43.55% - 51.45% of total variance. This measurement model was supported by multiple fit indices during CFA. Acceptable Cronbach's alpha indicated internal consistency reliability and high correlations with Self Reporting Questionnaire 20 demonstrated construct validity of PSS 10 for LGBT population. CONCLUSION: This study provided evidence of satisfactory psychometric properties of Bengali PSS 10 in terms of factor structure, internal consistency and validity among LGBT population. PMID- 28851333 TI - A gonadotropin-releasing hormone antagonist reduces serum adrenal androgen levels in prostate cancer patients. AB - BACKGROUND: Adrenal androgens play an important role in the development of castration-resistant prostate cancer therapeutics. The effect of gonadotropin releasing hormone (GnRH) antagonists on adrenal androgens has not been studied sufficiently. We measured testicular and adrenal androgen levels in patients treated with a GnRH antagonist. METHODS: This study included 47 patients with histologically proven prostate cancer. All of the patients were treated with the GnRH antagonist degarelix. The mean patient age was 73.6 years. Pre-treatment blood samples were collected from all of the patients, and post-treatment samples were taken at 1, 3, 6, and 12 months after starting treatment. Testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17beta-estradiol (E2), and androstenedione (A-dione) were measured by liquid chromatography-mass spectrometry. Dehydroepiandrosterone-sulfate (DHEA-S), luteinizing hormone, and follicle-stimulating hormone levels were measured by electro-chemiluminescence immunoassays. RESULTS: A significant reduction in T level (97.3% reduction) was observed in the patients 1 month after initiating treatment. In addition, levels of DHT, E2, DHEA-S, and A-dione decreased 1 month after initiating treatment (93.3, 84.9, 16.8, and 35.9% reduction, respectively). T, DHT, E2, DHEA-S, and A dione levels remained significantly suppressed (97.1, 94.6, 85.3, 23.9, and 40.5% reduction, respectively) 12 months after initiating treatment. A significant decrease in DHEA level (15.4% reduction) was observed 12 months after initiating treatment. CONCLUSIONS: Serum adrenal androgen levels decreased significantly in patients treated with a GnRH antagonist. Thus, long-term GnRH antagonist treatment may reduce serum adrenal androgen levels. PMID- 28851334 TI - Piloting a low-cost hardware intervention to reduce improper disposal of solid waste in communal toilets in low-income settlements in Dhaka, Bangladesh. AB - BACKGROUND: Bangladesh faces daunting challenges in addressing the sanitation needs of its urban poor. Maintaining the cleanliness and functionality of communal toilets is dependent upon periodic emptying of fecal sludge, and cooperation between users of communal toilets. Trash disposal into latrines can block the outflow pipes, rendering the toilets non-functional. METHODS: Pre intervention: We conducted in-depth interviews with five operators of fecal sludge emptying equipment and five adult residents who were also caregivers of children. We identified factors contributing to improper disposal of trash into communal toilets, a barrier to operation of the equipment, in low-income communities of Dhaka, Bangladesh. Intervention design: We developed behavior change communication materials to discourage waste disposal in toilets, and promote use of waste bins. We conducted six focus group discussions with adult male, female, landlord and children to select the preferred design for waste bins to be placed inside toilets, and finalize communication materials. Post intervention: We then pilot-tested an intervention package to promote appropriate trash disposal practices and thus facilitate periodic removal of fecal sludge when the latrine pits become full. We conducted 20 in-depth interviews and four focus group discussions with community residents, landlords and cleaners of communal toilets. RESULTS: Barriers to appropriate waste disposal included lack of private location for disposal of menstrual hygiene products, limited options for formal trash collection and disposal, and the use of plastic bags for disposing children's feces. A pilot intervention including behavior change communication and trash bins was implemented in two urban slum communities. Spot checks confirmed that the bins were in place and used. Respondents described positive improvements in the appearance of the toilet and surrounding environment. CONCLUSION: The current practice on the part of local residents of disposing of waste into toilets impedes the safe removal of fecal sludge and impairs toilet functionality. Residents reported positive changes in toilet cleanliness and usability resulting from this intervention, and this both improves the user experience with toilets, and also promotes the sustainability of the entrepreneurial model of Vacutug operators supported by WSUP. PMID- 28851335 TI - Reference Equations for the Six-Minute Walk Distance in the Healthy Chinese Han Population, Aged 18-30 Years. AB - BACKGROUND: The six-minute walk test (6MWT) is a safe, simple, inexpensive tool for evaluating the functional exercise capacity. However, there is a lack of standard reference equations for the six-minute walk distance (6MWD) in the healthy Chinese Han population with an age of 18-30 years. The aims of the present study were as follows: 1) to measure the anthropometric data and the walking distance in a sample of healthy Chinese Han population, aged 18-30 years; 2) to construct reference equations for the 6MWD; 3) to compare the measured 6MWD of our cohort with previously published equations. METHODS: The anthropometric data, demographic, lung function and the walking distance of Chinese Han population, aged 18-30 years, were prospectively measured using a standardized protocol. Informed consent was obtained from each participant and the approval was obtained from the ethics committee of Wenzhou People's Hospital. The 6MWT was performed twice and the longer 6MWD was used for further analysis. RESULTS: A total of 355 subjects (176 female and 179 male) completed the 6MWT, and the average walking distance was 627.3 +/- 52.88 m. The walking distance was achieved by females compared with males (607.4 +/- 51.00 m vs. 646.9 +/- 47.15 m; p < 0.0001) and active subjects compared with non-active subjects (646.1 +/- 48.27 m vs. 611.6 +/- 51.52 m; p < 0.0001). Univariate analysis showed age, height, body mass index, resting blood pressure, heart rate and blood pressure after the walk test and difference in heart rate before and after the walk test were significantly correlated with the 6MWD. Stepwise multiple regression analysis showed that height and difference in heart rate before and after the walk test were independent predictors associated with the 6MWD. The reference equations from Caucasian, Canadian and Chilean populations tend to overestimate the walking distance in our subjects, while Brazilian and Arabian equations tend to underestimate the walking distance. There was no significant difference in the walking distance between Korean equations and the current study. CONCLUSION: In summary, height and difference in heart rate before and after the walk test were the most significant predictors of the 6MWD, and the regression equations could explain approximately 38% and 31% of the distance variance in the female and male groups, respectively. PMID- 28851336 TI - Inhibition of human cytomegalovirus immediate-early gene expression and replication by the ethyl acetate (EtOAc) fraction of Elaeocarpus sylvestris in vitro. AB - BACKGROUND: In immunocompromised patients, human cytomegalovirus (HCMV) infection can lead to severe, life-threatening diseases, such as pneumonitis, hepatitis, gastrointestinal tract disease, and retinitis. We previously reported that a 70% ethanol extract of Elaeocarpus sylvestris leaves (ESE) inhibits human cytomegalovirus (HCMV) replication in vitro. In the present study, we determined the solvent fraction of ESE that inhibits HCMV replication using activity-guided fractionation. METHODS: Activity-guided fractionation of ESE was performed to determine the solvent fraction that inhibits HCMV replication. Effects of solvent fractions on HCMV lytic gene expression and major immediate-early (MIE) enhancer/promoter activity were further investigated. RESULTS: Among the solvent fractions tested, the EtOAc fraction of ESE markedly reduced HCMV lytic gene expression and viral replication in vitro without exerting significant cytotoxic effects against human foreskin fibroblasts (HFF). Furthermore, the EtOAc fraction negatively affected HCMV MIE enhancer/promoter activity. CONCLUSION: Our data collectively indicate that the EtOAc fraction of ESE contains active constituents that inhibit HCMV MIE enhancer/promoter activity and viral replication. The EtOAc fraction of ESE is a good source of novel drug candidates for treatment of HCMV associated diseases. PMID- 28851337 TI - Which online format is most effective for assisting Baby Boomers to complete advance directives? A randomised controlled trial of email prompting versus online education module. AB - BACKGROUND: Completion of Advance Directives (ADs), being financial and healthcare proxy or instructional documents, is relatively uncommon in Australia. Efforts to increase completion rates include online education and prompting which past literature suggests may be effective. The aim of this randomized controlled trial was to assess computer-based online AD information and email prompting for facilitating completion of ADs by Australian Baby Boomers (b.1946-1965) as well as factors which may impede or assist completion of these documents by this generation when using the online environment. METHODS: Two hundred eighty-two men and women aged 49-68 years at the time of the trial were randomly assigned to one of 3 intervention groups: education module only; email prompt only; email prompt and education module; and a control group with no education module and no email prompt. The randomized controlled trial was undertaken in participants' location of choice. Randomization and allocation to trial group were carried out by a central computer system. The primary analysis was based on a final total of 189 participants who completed the trial (n = 52 education module only; n = 44 email prompt only; n = 46 email prompt and education module; and n = 47 control). The primary outcome was the number of individuals in any group completing any of the 4 legal ADs in South Australia within 12 months or less from entry into the trial. Frequency analysis was conducted on secondary outcomes such as reasons for non-completion. RESULTS: Mean follow-up post-intervention at 12 months showed that 7% of overall participants completed one or more of the 4 legal ADs but without significant difference between groups (delta = 1%, p = .48 Prompt/Non Prompt groups, delta = 5%, p = .44 education/non-education groups). Reasons offered for non-completion were too busy (26%) and/or it wasn't the right time (21%). CONCLUSION: Our results suggest that neither email prompting nor provision of additional educational material online were sufficient to significantly impact AD completion rates for this generational cohort. Research with this cohort over longer periods of time exploring online preferences for engagement with ADs as they age may provide better insight into using this environment for ADs with this group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000425493 . PMID- 28851338 TI - A modified neo-vagina procedure in a low resource urogynecological unit: a case report of a 21 year old with Mayer-Rokitansky-Kuster-Hauser (mrkh) Syndrome operated at Mbarara referral hospital, Southwestern Uganda. AB - BACKGROUND: Although vaginal agenesis as may occur in Mayer-Rokitansky-Kuster Hauser (MRKH) syndrome is a rare condition, it is associated with not only anatomical problems but also serious psychological and social problems like painful sexual intercourse, primary amenorrhea and infertility. Surgery, which is aimed at reconstruction of a vagina of adequate length and width to serve the function, is the main method of treatment. Many methods for vaginal reconstruction have been described but each has its complications and limitations. The most commonly preferred procedure for treating this condition is the McIndoe vaginoplasty which involves dissection into the recto-vesical space, inserting two split thickness skin grafts folded over a mold in this newly created space and regular dilatation of the neovagina postoperatively to avoid stenosis. However surgeons with this expertise in this part of the world are rare to find and where they are available, the special molds on which to fold the skin grafts into the neovaginal space are not readily available. CASE PRESENTATION: A 21-year-old female with vaginal agenesis was operated on using a modification of the McIndoe procedure using a cylinder of a 60cm3 syringe as a vaginal mold/form and kept in place. We left a Foley in place for 10 days and we did a dye test after removing the syringe to ensure that there was no leakage resulting from fistula formation. CONCLUSION: The operation was successful and on subsequent monthly reviews of the patient, she has a patent functional vagina of about 9 cm in length at 8 months after the operation with resumption of sexual intercourse. PMID- 28851339 TI - Comorbid post-traumatic stress disorder in alcohol use disorder: relationships to demography, drinking and neuroimmune profile. AB - BACKGROUND: This study examined how alcohol use disorder (AUD) patients with post traumatic stress disorder (PTSD) differed from those without PTSD in terms of demography, drinking patterns and C-reactive protein, inflammatory cytokines, tryptophan metabolism parameters, and brain-derived neurotrophic factor (BDNF). METHODS: A consecutive sample (N = 187) of treatment-receiving AUD individuals were recruited from Nepalese facilities. They underwent fully structured psychiatric interviews. Serum levels of inflammatory cytokines [interleukin (IL) 6, IL-1 Receptor antagonist (IL-1Ra), IL-10, tumor necrosis factor-alpha (TNF alpha), and interferon-gamma (IFN-gamma)] were determined by a multiplex assay, kynurenine and tryptophan levels by high-performance liquid chromatography, and BDNF by enzyme-linked immunosorbent assay (ELISA). RESULTS: The prevalence of exposure to severe trauma and PTSD was 74% and 17%, respectively. PTSD comorbidity was not associated with age, gender, or socioeconomic status, but with co-occurring major depression, history of attempted suicide, earlier peak of drinking problems, higher drinking quantity and withdrawal symptoms, experiencing alcoholic blackouts, and drinking problems among parents. None of the assessed neuroimmune parameters was related to comorbid PTSD. CONCLUSIONS: The findings support routine trauma screening in AUD treatment samples and screening for risky drinking in trauma populations to help guide interventions. The expected aberrations in neuroimmune functioning may not be found when examined in a sample with multiple psychiatric morbidities. PMID- 28851340 TI - Observable phenomena that reveal medical students' clinical reasoning ability during expert assessment of their history taking: a qualitative study. AB - BACKGROUND: During their clerkships, medical students are meant to expand their clinical reasoning skills during their patient encounters. Observation of these encounters could reveal important information on the students' clinical reasoning abilities, especially during history taking. METHODS: A grounded theory approach was used to analyze what expert physicians apply as indicators in their assessment of medical students' diagnostic reasoning abilities during history taking. Twelve randomly selected clinical encounter recordings of students at the end of the internal medicine clerkships were observed by six expert assessors, who were prompted to formulate their assessment criteria in a think-aloud procedure. These formulations were then analyzed to identify the common denominators and leading principles. RESULTS: The main indicators of clinical reasoning ability were abstracted from students' observable acts during history taking in the encounter. These were: taking control, recognizing and responding to relevant information, specifying symptoms, asking specific questions that point to pathophysiological thinking, placing questions in a logical order, checking agreement with patients, summarizing and body language. In addition, patients' acts and the course, result and efficiency of the conversation were identified as indicators of clinical reasoning, whereas context, using self as a reference, and emotion/feelings were identified by the clinicians as variables in their assessment of clinical reasoning. CONCLUSIONS: In observing and assessing clinical reasoning during history taking by medical students, general and specific phenomena to be used as indicators for this process could be identified. These phenomena can be traced back to theories on the development and the process of clinical reasoning. PMID- 28851341 TI - A qualitative exploration of student perceptions of the impact of progress tests on learning and emotional wellbeing. AB - BACKGROUND: Progress testing was introduced to the MBChB programme at the University of Auckland in 2013. As there has been a focus in published literature on aspects relating to the format or function of progress tests, the purpose of this study was to explore a qualitative student perspective on the introduction of progress testing and its impact on approaches to learning and perceived stress. METHODS: This article presents the qualitative aspects of a longitudinal evaluation study. The qualitative data were derived from eight focus groups of Year 2-5 medical students in the University of Auckland medical programme. RESULTS: Two themes, 'Impact on Learning' and 'Emotional Wellbeing' and their subthemes offered insight into student perceptions and behaviour. Students described a variety of learning responses to progress testing that clustered around the employment of a range of learning strategies based on their experience of sitting progress tests and their individualised feedback. A range of emotional responses were also expressed, with some finding progress tests stressful, while others enjoyed not needing to intensively cram before the tests. CONCLUSIONS: Progress tests appear to influence the approach of students to their learning. They employ a mix of learning strategies, shaped by their performance, individualised feedback and the learning environment. While students expressed some stress and anxiety with respect to sitting progress tests, this form of testing was viewed by these students as no worse, and sometimes better than traditional assessments. PMID- 28851343 TI - Teaching the pediatric ear exam and diagnosis of Acute Otitis Media: a teaching and assessment model in three groups. AB - BACKGROUND: The serious consequences of inaccurate diagnosis of acute otitis media have led to a call for greater education to develop proficient pediatric otoscopy skills. Despite the clinical and educational needs, peer-reviewed standardized curricula with validated assessment instruments remain limited. This study evaluated a pediatric otoscopy curriculum incorporated into the Pediatric medical student clerkship with use of outcome measures that included assessment of skills with real patients. The objective was to determine whether students who received the intervention would demonstrate significant gains in pediatric otoscopy skills when compared with students with only routine immersion learning exposure. METHODS: During their Pediatric clerkship, an intervention group (IG) of 100 medical students received routine instruction and a curriculum intervention. A non-intervention group (NIG) of 30 students received only routine instruction. Outcome measures included written tests and assessment of skills with real patients. A retention group (RG) consisted of 79 students in the IG who completed a written test at the end of medical school. Paired t-tests were used to compare differences in pre-intervention, post-intervention, and retention scores for the IG, NIG, and RG, while analysis of covariance tests were used to compare differences in scores between the IG and NIG. RESULTS: Pre-intervention scores were similar for the IG and NIG for the written test (mean/SD of 12.9/2.9 for IG and 12.9/1.8 for NIG, p = 0.78) and skills checklist (mean/SD of 11.1/4.4 for IG and 10.9/4.0 for NIG, p = 0.88). The IG had significantly higher post intervention scores than the NIG for the written test (mean/SD of 22.6/1.7 for IG and 13.9/2.5 for NIG, p < 0.001) and skills checklist (mean/SD of 19.2/3.4 for IG and 11.0/3.8 for NIG, p < 0.001). The IG also had significantly higher gain in scores than the NIG for the written test (mean/SD +9.6/2.8 for IG and +1.0/2.3 for NIG, p < 0.001) and skills checklist (mean/SD of +8.1/4.8 for IG and +0.1/4.5 for NIG, p < 0.001). For the RG, there was a significant decrease (p < 0.001) from the post-intervention scores to retention scores (mean/SD of -7.4/2.7) but a significant increase (p < 0.001) from the pre-intervention score to retention score (mean + 2.6/3.3). CONCLUSIONS: Medical students who received a formal curriculum intervention demonstrated significant gains in pediatric otoscopy skills when compared with students with only routine immersion learning exposure. However, learning gains diminished over time, emphasizing the need for continued practice opportunities to reinforce students' skills. Our study provides a formal curriculum to meet identified educational gaps in the important topic of pediatric otoscopy and offers a model for teaching of other clinical skills using rigorous outcome measures including assessment of skills in real patients. PMID- 28851342 TI - eHealth interventions for the prevention of depression and anxiety in the general population: a systematic review and meta-analysis. AB - BACKGROUND: Anxiety and depression are associated with a range of adverse outcomes and represent a large global burden to individuals and health care systems. Prevention programs are an important way to avert a proportion of the burden associated with such conditions both at a clinical and subclinical level. eHealth interventions provide an opportunity to offer accessible, acceptable, easily disseminated globally low-cost interventions on a wide scale. However, the efficacy of these programs remains unclear. The aim of this study is to review and evaluate the effects of eHealth prevention interventions for anxiety and depression. METHOD: A systematic search was conducted on four relevant databases to identify randomized controlled trials of eHealth interventions aimed at the prevention of anxiety and depression in the general population published between 2000 and January 2016. The quality of studies was assessed and a meta-analysis was performed using pooled effect size estimates obtained from a random effects model. RESULTS: Ten trials were included in the systematic review and meta analysis. All studies were of sufficient quality and utilized cognitive behavioural techniques. At post-treatment, the overall mean difference between the intervention and control groups was 0.25 (95% confidence internal: 0.09, 0.41; p = 0.003) for depression outcome studies and 0.31 (95% CI: 0.10, 0.52; p = 0.004) for anxiety outcome studies, indicating a small but positive effect of the eHealth interventions. The effect sizes for universal and indicated/selective interventions were similar (0.29 and 0.25 respectively). However, there was inadequate evidence to suggest that such interventions have an effect on long term disorder incidence rates. CONCLUSIONS: Evidence suggests that eHealth prevention interventions for anxiety and depression are associated with small but positive effects on symptom reduction. However, there is inadequate evidence on the medium to long-term effect of such interventions, and importantly, on the reduction of incidence of disorders. Further work to explore the impact of eHealth psychological interventions on long-term incidence rates. PMID- 28851344 TI - Measurement properties of the Health Literacy Questionnaire (HLQ) among older adults who present to the emergency department after a fall: a Rasch analysis. AB - BACKGROUND: Health literacy is an important concept associated with participation in preventive health initiatives, such as falls prevention programs. A comprehensive health literacy measurement tool, appropriate for this population, is required. The aim of this study was to evaluate the measurement properties of the Health Literacy Questionnaire (HLQ) in a cohort of older adults who presented to a hospital emergency department (ED) after a fall. METHODS: Older adults who presented to an ED after a fall had their health literacy assessed using the HLQ (n = 433). Data were collected as part of a multi-centre randomised controlled trial of a falls prevention program. Measurement properties of the HLQ were assessed using Rasch analysis. RESULTS: All nine scales of the HLQ were unidimensional, with good internal consistency reliability. No item bias was found for most items (43 of 44). A degree of overall misfit to the Rasch model was evident for six of the nine HLQ scales. The majority of misfit indicated content overlap between some items and does not compromise measurement. A measurement gap was identified for this cohort at mid to high HLQ score. CONCLUSIONS: The HLQ demonstrated good measurement properties in a cohort of older adults who presented to an ED after a fall. The summation of the HLQ items within each scale, providing unbiased information on nine separate areas of health literacy, is supported. Clinicians, researchers and policy makers may have confidence using the HLQ scale scores to gain information about health literacy in older people presenting to the ED after a fall. TRIAL REGISTRATION: This study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614000336684 (27 March 2014). PMID- 28851345 TI - Ethical acceptability of offering financial incentives for taking antipsychotic depot medication: patients' and clinicians' perspectives after a 12-month randomized controlled trial. AB - BACKGROUND: A randomized controlled trial 'Money for Medication'(M4M) was conducted in which patients were offered financial incentives for taking antipsychotic depot medication. This study assessed the attitudes and ethical considerations of patients and clinicians who participated in this trial. METHODS: Three mental healthcare institutions in secondary psychiatric care in the Netherlands participated in this study. Patients (n = 169), 18-65 years, diagnosed with schizophrenia, schizoaffective disorder or another psychotic disorder who had been prescribed antipsychotic depot medication, were randomly assigned to receive 12 months of either treatment as usual plus a financial reward for each depot of medication received (intervention group) or treatment as usual alone (control group). Structured questionnaires were administered after the 12-month intervention period. Data were available for 133 patients (69 control and 64 intervention) and for 97 clinicians. RESULTS: Patients (88%) and clinicians (81%) indicated that financial incentives were a good approach to improve medication adherence. Ethical concerns were categorized according to the four-principles approach (autonomy, beneficence, non-maleficence, and justice). Patients and clinicians alike mentioned various advantages of M4M in clinical practice, such as increased medication adherence and improved illness insight; but also disadvantages such as reduced intrinsic motivation, loss of autonomy and feelings of dependence. CONCLUSIONS: Overall, patients evaluated financial incentives as an effective method of improving medication adherence and were willing to accept this reward during clinical treatment. Clinicians were also positive about the use of this intervention in daily practice. Ethical concerns are discussed in terms of patient autonomy, beneficence, non-maleficence and justice. We conclude that this intervention is ethically acceptable under certain conditions, and that further research is necessary to clarify issues of benefit, motivation and the preferred size and duration of the incentive. TRIAL REGISTRATION: Nederlands Trial Register, number NTR2350 . PMID- 28851346 TI - Metachronous solitary splenic metastasis arising from early gastric cancer: a case report and literature review. AB - BACKGROUND: The metastasis of malignant tumors to the spleen is rare, and only a small percentage of cases can be treated surgically, as splenic metastases generally occur in the context of multivisceral metastatic cancer at a terminal stage. We report a rare case of metachronous solitary splenic metastasis arising from early gastric cancer. CASE PRESENTATION: A 75-year-old man was initially referred to our hospital for examination of gastric cancer, diagnosed at a medical check-up. Esophagogastroduodenoscopy showed a slightly elevated lesion with a central irregular depression in the upper-third of the stomach. Biopsy specimens of the lesion showed a moderately-differentiated adenocarcinoma, and abdominal computed tomography showed no evidence of distant metastases. Endoscopic submucosal dissection was performed, with histological confirmation of a moderately-differentiated adenocarcinoma invading the submucosal layer. The patient subsequently underwent laparoscopic total gastrectomy with regional lymph node dissection, resulting in no residual carcinoma and no lymph node metastasis. Computed tomography, 28 months later, showed a well-defined mass measuring 4.2 cm in diameter in the spleen, and the patient underwent a splenectomy, since there was no evidence of further metastatic lesions in any other organs. Histological examination confirmed the diagnosis of a poorly-differentiated adenocarcinoma originating from the previous gastric cancer. The patient was alive 2 months after surgical resection of the splenic metastasis without any recurrence. CONCLUSION: To the best of our knowledge, this is only the second case of a solitary splenic metastasis from early gastric cancer to be reported in the English literature. The present case suggests surgical resection may be the preferred treatment of choice for patients with a solitary splenic metastasis from gastric cancer. PMID- 28851347 TI - Erratum to: Household preferences for reducing greenhouse gas emissions in four European high-income countries: Does health information matter? A mixed-methods study protocol. PMID- 28851348 TI - Assessment of nutrition and physical activity environments in family child care homes: modification and psychometric testing of the Environment and Policy Assessment and Observation. AB - BACKGROUND: Early care and education (ECE) settings play an important role in shaping the nutrition and physical activity habits of young children. Increasing research attention is being directed toward family child care homes (FCCHs) specifically. However, existing measures of child care nutrition and physical activity environments are limited in that they have been created for use with center-based programs and require modification for studies involving FCCHs. This paper describes the modification of the Environment and Policy Assessment and Observation (EPAO) for use in FCCHs. METHODS: The EPAO underwent a through modification process that incorporated an updated format for the data collection instrument, assessment of emerging best practices, tailoring to the FCCH environment, and creation of a new scoring rubric. The new instrument was implemented as part of a larger randomized control trial. To assess inter-rater reliability, observations on 61 different days were performed independently by two data collectors. To assess construct validity, associations between EPAO scores and measures of children's dietary intake (Healthy Eating Index (HEI) score) and physical activity (accelerometer-measured minutes per hour of moderate to vigorous physical activity, MVPA) were examined. RESULTS: The modified EPAO assesses 38 nutrition and 27 physical activity best practices, which can be summarized into 7 nutrition-related and 10 physical activity-related environmental sub- scores as well as overall nutrition and overall physical activity scores. There was generally good agreement between data collectors (ICC > 0.60). Reliability was slightly lower for feeding practices and physical activity education and professional development (ICC = 0.56 and 0.22, respectively). Child HEI was significantly correlated with the overall nutrition score (r = 0.23), foods provided (r = 0.28), beverages provided (r = 0.15), nutrition education and professional development (r = 0.21), and nutrition policy (r = 0.18). Child MVPA was significantly associated with overall time provided for activity (r = 0.18) and outdoor playtime (r = 0.20). There was also an unexpected negative association between child MVPA and screen time (-0.16) and screen time practices (r = -0.21). CONCLUSIONS: The EPAO for the FCCH instrument is a useful tool for researchers working with this unique type of ECE setting. It has undergone rigorous development and testing and appears to have good psychometric properties. TRIAL REGISTRATION: NCT01814215 , March 15, 2013. PMID- 28851349 TI - The utilization of traditional Chinese medicine in patients with dysfunctional uterine bleeding in Taiwan: a nationwide population-based study. AB - BACKGROUND: Many patients with gynecological disorders seek traditional medicine consultations in Asian countries. This study intended to investigate the utilization of traditional Chinese medicine (TCM) in patients with dysfunctional uterine bleeding (DUB) in Taiwan. METHODS: We analyzed a cohort of one million individuals randomly selected from the National Health Insurance Research Database in Taiwan. We included 46,337 subjects with newly diagnosed DUB (ICD-9 CM codes 626.8) from January 1, 1997 to December 31, 2010. The patients were categorized into TCM seekers and non-TCM seekers according to their use of TCM. RESULTS: Among the subjects, 41,558 (89.69%) were TCM seekers and 4,779 (10.31%) were non-TCM seekers. Patients who were younger tended to be TCM seekers. Most of the patients had also taken Western medicine, especially tranexamic acid and non steroidal anti-inflammatory drugs (NSAIDs). More than half of TCM seekers (55.41%) received combined treatment with both Chinese herbal remedies and acupuncture. The most commonly used TCM formula and single herb were Jia-Wei-Xiao Yao-San (Bupleurum and Peony Formula) and Yi-Mu-Cao (Herba Leonuri), respectively. The core pattern of Chinese herbal medicine for DUB patients consisted of Jia-Wei-Xiao-Yao-San, Xiang-Fu (Rhizoma Cyperi), and Yi-Mu-Cao (Herba Leonuri). CONCLUSIONS: TCM use is popular among patients with DUB in Taiwan. Further pharmacological investigations and clinical trials are required to validate the efficacy and safety of these items. PMID- 28851350 TI - Preventive effects of the novel antimicrobial peptide Nal-P-113 in a rat Periodontitis model by limiting the growth of Porphyromonas gingivalis and modulating IL-1beta and TNF-alpha production. AB - BACKGROUND: P-113 (AKRHHGYKRKFH-NH2) is a 12-amino-acid histidine-rich peptide derived from histatin 5 that is highly degradable in high salt concentrations and biological fluids such as serum, plasma and saliva. Nal-P-113, a novel antimicrobial peptide whose histidine residues are replaced by the bulky amino acids beta-naphthylalanine, causes the antimicrobial peptide to retain its bactericidal activity even in physiological environments. This study evaluated the effect of the novel antimicrobial peptide Nal-P-113 in a rat periodontitis model and the mechanisms of action of Nal-P-113 for suppressing periodontitis. METHODS: Periodontitis was induced in mandibular first molars in rats receiving a ligature and infected with Porphyromonas gingivalis. Animals were randomly divided into six groups: a, P. gingivalis W83 alone; b, P. gingivalis W83 with 6.25 MUg/mL of Nal-P-113; c, P. gingivalis W83 with 25 MUg/mL of Nal-P-113; d, P. gingivalis W83 with 100 MUg/mL of Nal-P-113; e, P. gingivalis W83 with 400 MUg/mL of Nal-P-113; and f, control without P. gingivalis W83 or Nal-P-113. Morphometric analysis was used to evaluate alveolar bone loss. Microbiological assessment of the presence of Porphyromonas gingivalis and total bacteria was performed using absolute quantitative real-time PCR and scanning electron microscopy. Gingival tissue was collected for western blot and immunohistochemical assays of IL-1beta and TNF-alpha levels. RESULTS: Alveolar bone loss was inhibited by 100 MUg/mL or 400 MUg/mL of Nal-P-113 compared to the control group (P < 0.05). Lower amounts of P. gingivalis and total bacteria were found in groups d and e compared with group a (P < 0.05). A decrease in the levels of IL-1beta and TNF-alpha was detected in group d and group e compared to the control group (P < 0.05). The amount of P. gingivalis was positively correlated with IL-1beta and TNF-alpha expression in periodontal tissue (P < 0.05). CONCLUSIONS: Nal-P-113 exhibited protective effects on Porphyromonas gingivalis-induced periodontitis in rats by limiting the amount of bacteria and modulating IL-1beta and TNF-alpha production. The use of Nal-P-113 in vivo might serve as a beneficial preventive or therapeutic approach for periodontitis. PMID- 28851351 TI - Community pharmacists' knowledge, practices and beliefs about complementary and alternative medicine in Palestine: a cross-sectional study. AB - BACKGROUND: Complementary and alternative medicine (CAM) utilization is dramatically increasing among patients. As community pharmacies are a major provider of CAM products, community pharmacists need to have the sufficient knowledge and information to advice their patients, answer their inquiries and to be proactive in the healthcare process to ensure optimal therapy outputs and minimize both drug-drug and drug-herb interactions. Therefore, the main objective of this study was to assess the knowledge, beliefs, and practices of community pharmacists in Palestine about CAM. METHODS: The study was conducted in a cross sectional design in which a questionnaire was administered on a sample of licensed community pharmacists from Palestine. The questionnaire was of 5 sections: demographic and practice details of the participants, practice, beliefs, and knowledge about CAM. Mann-Whitney-U or Kruskal-Wallis tests were used to comparison of different issues as appropriate. P-values of <0.05 were considered significant. RESULTS: A total of 284 community pharmacists were surveyed, however, 281 were included in the analysis as they met inclusion criteria. Out of the 281, 149 (53.0%) of the participants were males and the rest were females. About 40% of the participants were between 20 to 29 years old. Pharmacists frequently recommended CAM modalities. Exercises (84.0%) and food supplements (82.6%) were the most commonly recommended modalities. In the last year, vitamin B12 was the most frequently prescribed supplement. The median knowledge score was 5 out of 8 and the median beliefs about CAM score was 4.0 out of 7.0. CONCLUSIONS: CAM recommendations by pharmacists appear to be commonplace. Although their knowledge scores were fair to average, pharmacists still need more education and training about CAM in order to be more qualified to provide better pharmaceutical care and improve their patient's outcome. PMID- 28851352 TI - Prognostic roles of pathology markers immunoexpression and clinical parameters in Hepatoblastoma. AB - BACKGROUND: Hepatoblastoma, a leading primary hepatic malignant tumor in children, is originated from primitive hepatic stem cells. We aimed to elucidate the relationships between the histological distribution of beta-catenin and hepatic stem cell markers with the clinical outcomes of hepatoblastoma. METHODS: Immunohistochemistry was applied to detect beta-catenin and hepatic stem cell markers expression in 31 hepatoblastoma tumors. We analyzed the relationship between the stem cell markers and the clinical course of hepatoblastoma. RESULTS: Thirty-one hepatoblastoma patients were diagnosed at a mean age of 2.58 +/- 3.78 years, and 7 (22.58%) died. A lack of anticipated decrease in alpha-fetal protein levels after neoadjuvant chemotherapy indicated a higher mortality rate. Nuclear beta-catenin expression was significantly associated with membranous epithelial cell adhesion molecule (EpCAM) expression in hepatoblastoma tumor specimens. The co-expression of nuclear beta-catenin and membranous EpCAM together with an age at diagnosis <=1.25 years were predictive of an alpha-fetoprotein level < 1200 ng/mL after neoadjuvant chemotherapy (P < 0.05). An alpha-fetoprotein level < 1200 ng/mL after neoadjuvant chemotherapy and age at hepatoblastoma diagnosis <=1.25 years are both predictors of better overall and native liver survival in hepatoblastoma patients. CONCLUSIONS: Presence of membranous EpCAM with nuclear beta-catenin and younger diagnostic age of hepatoblastoma are predictive of serum alpha-fetoprotein levels drop after chemotherapy. Younger diagnostic age and lower alpha-fetoprotein levels after neoadjuvant chemotherapy and are predictive of better overall and native liver survival in hepatoblastoma patients. PMID- 28851353 TI - Exploring the concurrent validity of the nationwide assessment of permanent nursing home residence in Denmark - A cross-sectional data analysis using two administrative registries. AB - BACKGROUND: Many register studies make use of information about permanent nursing home residents. Statistics Denmark (StatD) identifies nursing home residents by two different indirect methods, one based on reports from the municipalities regarding home care in taken place in a nursing home, and the other based on an algorithm created by StatD. The aim of the present study was to validate StatD's nursing home register using dedicated administrative municipality records on individual nursing home residents as gold standard. METHODS: In total, ten Danish municipalities were selected. Within each Danish Region, we randomly selected one municipality reporting to Stat D (Method 1) and one not reporting where instead an algorithm created by StatD was used to discover nursing home residents (Method 2). Method 1 means that municipalities reported to Stat D whether home care has taken place in a nursing home or in a private home. Method 2 is based on an algorithm created by Stat D for the municipalities where Method 1 is not applicable. Our gold standard was the information from the local administrative system in all ten selected municipalities. Each municipality provided a list with all individuals > 65 years living in a nursing home on January 1st, 2013 as well as the central personal number. This was compared to the list of individuals >65 living in nursing home facilities in the same ten municipalities on January 1st, 2013 retrieved from StatD. RESULTS: According to the data received directly from the municipalities, which was used as our gold Standard 3821 individuals were identified as nursing home residents. The StatD register identified 6,141 individuals as residents. Additionally, 556 of the individuals identified by the municipalities were not identified in the StatD register. Overall sensitivity for the ten municipalities in the StatD nursing home register was 0.85 (95% CI 0.84 0.87) and the PPV was 0.53 (95% CI 0.52-0.54). The municipalities for which nursing home status was based on the StatD algorithm (method 2) had a sensitivity of 0.84 (95% CI 0.82-0.86) and PPV of 0.48 (95% CI 0.46-0.50). Both slightly lower than the reporting municipalities (method 1) where the sensitivity was 0.87(95% CI 0.85-0.88) and the PPV was 0.57 (95% CI 0.56-0.59). Additionally, the sensitivity and PPV of the Stat D register varied heavily among the ten municipalities from 0.51 (95% CI 0.43-0.59) to 0.96 (95% CI 0.95-0.98) and PPV correspondingly, from 0.14 (95% CI: 0.11-0.17) to 0.73 (95% CI 0.69-0.77). CONCLUSIONS: The overall PPV of StatD nursing home register was low and differences between municipalities existed. Even in countries with extensive nation-wide registers, validating studies should be conducted for outcomes based on these registers. PMID- 28851354 TI - The relationship between working conditions and self-rated health among medical doctors: evidence from seven waves of the Medicine In Australia Balancing Employment and Life (Mabel) survey. AB - BACKGROUND: Psychosocial job stressors, such as low control and high demands, have been found to influence the health and wellbeing of doctors. However, past research in this area has relied on cross-sectional data, which limits causal inferences about the influence of psychosocial job stressors on health. In this study, we examine this relationship longitudinally while also assessing whether the relationship between psychosocial job stressors and health is modified by gender. METHODS: The data source was seven annual waves of the Medicine in Australia: Balancing Employment and Life (MABEL) survey. The outcome was self rated health (measured using the SF-12), and key exposures reflected job control, job demands, work-life balance variables, employment arrangements, and aggression experienced at work. We used longitudinal fixed and random effects regression models to assess within and between-person changes in health. RESULTS: Excessive job demands, low job control, feelings of not being rewarded at work, and work life imbalance were associated with higher within-person odds of poorer self rated health. Gender differences were apparent. For female doctors, work arrangements and work-life imbalance were associated with poorer self-rated health whilst task-based job stressors were associated with poorer self-rated health in male doctors. CONCLUSIONS: These results suggest the importance of addressing adverse working environments among doctors. TRIAL REGISTRATION: Not applicable. PMID- 28851355 TI - Integrative model of leukocyte genomics and organ dysfunction in heart failure patients requiring mechanical circulatory support: a prospective observational study. AB - BACKGROUND: The implantation of mechanical circulatory support devices in heart failure patients is associated with a systemic inflammatory response, potentially leading to death from multiple organ dysfunction syndrome. Previous studies point to the involvement of many mechanisms, but an integrative hypothesis does not yet exist. Using time-dependent whole-genome mRNA expression in circulating leukocytes, we constructed a systems-model to improve mechanistic understanding and prediction of adverse outcomes. METHODS: We sampled peripheral blood mononuclear cells from 22 consecutive patients undergoing mechanical circulatory support device (MCS) surgery, at 5 timepoints: day -1 preoperative, and postoperative days 1, 3, 5, and 8. Clinical phenotyping was performed using 12 clinical parameters, 2 organ dysfunction scoring systems, and survival outcomes. We constructed a strictly phenotype-driven time-dependent non-supervised systems representation using weighted gene co-expression network analysis, and annotated eigengenes using gene ontology, pathway, and transcription factor binding site enrichment analyses. Genes and eigengenes were mapped to the clinical phenotype using a linear mixed-effect model, with Cox models also fit at each timepoint to survival outcomes. RESULTS: We inferred a 19-module network, in which most module eigengenes correlated with at least one aspect of the clinical phenotype. We observed a response of advanced heart failure patients to surgery orchestrated into stages: first, activation of the innate immune response, followed by anti inflammation, and finally reparative processes such as mitosis, coagulation, and apoptosis. Eigengenes related to red blood cell production and extracellular matrix degradation became predictors of survival late in the timecourse corresponding to multiorgan dysfunction and disseminated intravascular coagulation. CONCLUSIONS: Our model provides an integrative representation of leukocyte biology during the systemic inflammatory response following MCS device implantation. It demonstrates consistency with previous hypotheses, identifying a number of known mechanisms. At the same time, it suggests novel hypotheses about time-specific targets. PMID- 28851356 TI - Fatal infection in three Grey Slender Lorises (Loris lydekkerianus nordicus) caused by clonally related Trueperella pyogenes. AB - BACKGROUND: Trueperella pyogenes is a worldwide known bacterium causing mastitis, abortion and various other pyogenic infections in domestic animals like ruminants and pigs. In this study we represent the first case report of three unusual fatal infections of Grey Slender Lorises caused by Trueperella pyogenes. Meanwhile, this study represents the first in-depth description of the multilocus sequence analysis (MLSA) on T. pyogenes species. CASE PRESENTATION: Three Trueperella pyogenes were isolated from three different Grey Slender Lorises, which died within a period of two years at Frankfurt Zoo (Frankfurt am Main - Germany). The three Grey Slender Loris cases were suffering from severe sepsis and died from its complication. During the bacteriological investigation of the three cases, the T. pyogenes were isolated from different organisms in each case. The epidemiological relationship between the three isolates could be shown by four genomic DNA fingerprint methods (ERIC-PCR, BOX-PCR, (GTG)5-PCR, and RAPD-PCR) and by multilocus sequence analysis (MLSA) investigating four different housekeeping genes (fusA-tuf-metG-gyrA). CONCLUSION: In this study, we clearly showed by means of using three different rep-PCRs, by RAPD-PCR and by MLSA that the genomic fingerprinting of the investigated three T. pyogenes have the same clonal origin and are genetically identical. These results suggest that the same isolate contaminated the animal's facility and subsequently caused cross infection between the three different Grey Slender Lorises. To the best of our knowledge, this is the first epidemiological approach concentrating on T. pyogenes using MLSA. PMID- 28851357 TI - De novo assembly and characterization of breast cancer transcriptomes identifies large numbers of novel fusion-gene transcripts of potential functional significance. AB - BACKGROUND: Gene-fusion or chimeric transcripts have been implicated in the onset and progression of a variety of cancers. Massively parallel RNA sequencing (RNA Seq) of the cellular transcriptome is a promising approach for the identification of chimeric transcripts of potential functional significance. We report here the development and use of an integrated computational pipeline for the de novo assembly and characterization of chimeric transcripts in 55 primary breast cancer and normal tissue samples. METHODS: An integrated computational pipeline was employed to screen the transcriptome of breast cancer and control tissues for high-quality RNA-sequencing reads. Reads were de novo assembled into contigs followed by reference genome mapping. Chimeric transcripts were detected, filtered and characterized using our R-SAP algorithm. The relative abundance of reads was used to estimate levels of gene expression. RESULTS: De novo assembly allowed for the accurate detection of 1959 chimeric transcripts to nucleotide level resolution and facilitated detailed molecular characterization and quantitative analysis. A number of the chimeric transcripts are of potential functional significance including 79 novel fusion-protein transcripts and many chimeric transcripts with alterations in their un-translated leader regions. A number of chimeric transcripts in the cancer samples mapped to genomic regions devoid of any known genes. Several 'pro-neoplastic' fusions comprised of genes previously implicated in cancer are expressed at low levels in normal tissues but at high levels in cancer tissues. CONCLUSIONS: Collectively, our results underscore the utility of deep sequencing technologies and improved bioinformatics workflows to uncover novel and potentially significant chimeric transcripts in cancer and normal somatic tissues. PMID- 28851358 TI - Treatment-seeking patterns for malaria in pharmacies in five sub-Saharan African countries. AB - BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended as the first-line anti-malarial treatment strategy in sub-Saharan African countries. WHO policy recommends parasitological confirmation by microscopy or rapid diagnostic test (RDT) in all cases of suspected malaria prior to treatment. Gaps remain in understanding the factors that influence patient treatment-seeking behaviour and anti-malarial drug purchase decisions in the private sector. The objective of this study was to identify patient treatment-seeking behaviour in Ghana, Kenya, Nigeria, Tanzania, and Uganda. METHODS: Face-to-face patient interviews were conducted at a total of 208 randomly selected retail outlets in five countries. At each outlet, exit interviews were conducted with five patients who indicated they had come seeking anti-malarial treatment. The questionnaire was anonymous and standardized in the five countries and collected data on different factors, including socio-demographic characteristics, history of illness, diagnostic practices (i.e. microscopy or RDT), prescription practices and treatment purchase. The price paid for the treatment was also collected from the outlet vendor. RESULTS: A total of 994 patients were included from the five countries. Location of malaria diagnosis was significantly different in the five countries. A total of 484 blood diagnostic tests were performed, (72.3% with microscopy and 27.7% with RDT). ACTs were purchased by 72.5% of patients who had undergone blood testing and 86.5% of patients without a blood test, regardless of whether the test result was positive or negative (p < 10-4). A total of 531 patients (53.4%) had an anti-malarial drug prescription, of which 82.9% were prescriptions for an ACT. There were significant differences in prescriptions by country. A total of 923 patients (92.9%) purchased anti-malarial drugs in an outlet, including 79.1% of patients purchasing an ACT drug: 98.0% in Ghana, 90.5% in Kenya, 80.4% in Nigeria, 69.2% in Tanzania, and 57.7% in Uganda (p < 10-4). Having a drug prescription was not a significant predictive factor associated with an ACT drug purchase (except in Kenya). The number of ACT drugs purchased with a prescription was greater than the number purchased without a prescription in Kenya, Nigeria and Tanzania. CONCLUSIONS: This study highlights differences in drug prescription and purchase patterns in five sub-Saharan African countries. The private sector is playing an increasingly important role in fever case management in sub-Saharan Africa. Understanding the characteristics of private retail outlets and the role they play in providing anti-malaria drugs may support the design of effective malaria interventions. PMID- 28851359 TI - Efficacy of one dose vaccination against experimental infection with two Mycoplasma hyopneumoniae strains. AB - BACKGROUND: Mycoplasma hyopneumoniae (M. hyopneumoniae) is the primary agent of enzootic pneumonia in pigs. Pigs are often infected with different M. hyopneumoniae strains. This study assessed the efficacy of vaccination against experimental infection with two genetically different M. hyopneumoniae strains in weaned piglets. At 33 days of age (D0), 45 M. hyopneumoniae-free piglets were randomly assigned to three different groups: 1) negative control group (NCG; n = 5): not vaccinated, not infected, 2) positive control group (PCG; n = 20): not vaccinated, infected, and 3) vaccination group (VG; n = 20): single vaccination with an inactivated whole-cell M. hyopneumoniae vaccine (Hyogen(r), Ceva) (D1), infected. The PCG and VG were endotracheally inoculated with 7 * 107 CCU in 7 ml of the highly virulent M. hyopneumoniae strain F7.2C (D24) and 7 * 107 CCU in 7 ml low virulent strain F1.12A (D25). A respiratory disease score (RDS) was assessed from D24 until D53. At D53 (euthanasia), macroscopic lung lesions (MLL) were scored, log copies of M. hyopneumoniae DNA (qPCR) and IL-1 and IL-6 concentrations (ELISA) on bronchoalveolar lavage fluid were determined. RESULTS: The RDS and MLL at euthanasia were respectively 0, 1.20 and 0.55 (P < 0.001) and 0, 7.56 and 0.68 (P < 0.001) for NCG, PCG and VG, respectively. The qPCR results for PCG and VG were 3.99 and 1.78 log copies (P < 0.001), respectively, with a significant difference between PCG and VG. The IL-1 and IL-6 results at euthanasia for NCG, PCG and VG were 17.61, 1283.39 and 53.04 pg/ml (P < 0.001) and 148.10, 493.35 and 259.80 pg/ml (P = 0.004), respectively with a significant difference between PCG and VG. CONCLUSIONS: Vaccination with Hyogen(r) in pigs was efficacious against an experimental challenge with both a low and highly virulent M. hyopneumoniae strain as the vaccinated pigs coughed significantly less, and showed significantly less lung lesions compared to the non-vaccinated challenged pigs: the vaccinated animals showed a 52.9% lower RDS and 91.0% lower MLL compared to the PCG. In the bronchoalveolar lavage fluid collected at the necropsy of the vaccinated pigs, a significantly lower amount of M. hyopneumoniae DNA and a significantly lower IL-1 and IL-6 concentration was found compared to the pigs of the PCG. PMID- 28851361 TI - Health-related quality of life of HIV infected adults with and without Visceral Leishmaniasis in Northwest Ethiopia. AB - BACKGROUND: Health-related quality of life (HRQoL) is an important outcome measure among HIV infected patients receiving antiretroviral therapy (ART). When HIV infected patients coinfected with Visceral Leishmaniasis (VL) the problem become severe because VL accelerates HIV replication and disease progression. The impact of VL on the quality of life of HIV infected patients has not been studied. In this study in Ethiopia, we compared the quality of life of HIV infected patients with and without VL. METHODS: A cross-sectional study was conducted from October 2015 to September 2016 in selected health centers and hospitals, in Northwest Ethiopia. Data on quality of life was collected by trained nurses. The instrument used to collect the data was the short Amharic version of the World Health Organization Quality of Life for HIV clients (WHOQoL HIV). Depression was assessed using the validated version of Kessler scale. Data was entered and analyzed using SPSS version 20. Descriptive statistics, bivariate and multivariate linear regression model was used to summarize the results. RESULTS: A total of 590 study participants were included in the study with response rate of 95%. Of the 590 patients included in our study 125 (21%) were HIV-VL coinfection. HIV-VL coinfected patients had a lower quality of life in all the domains as compared to HIV patients without VL. Depression was consistently and strongly associated with all the quality of life domains of both groups. Also, in HIV infected patients a longer duration in ART was associated with higher HRQoL domains except for the spiritual and level of independence domains. With regard to HIV-VL coinfected patients, a longer duration in ART was associated with psychological, spiritual and level of independence domains of HRQoL. Demographics, clinical, and treatment characteristics resulted few significant associations with HRQoL domains of both groups. CONCLUSION: HIV-VL coinfected patients had a poor quality of life in all the domains of the WHOQoL HIV instrument. Depression, duration of ART and education were strongly associated with the quality of life. Depression should be targeted for intervention to improve the quality of life. PMID- 28851360 TI - Phospholipid Phosphatase 4 promotes proliferation and tumorigenesis, and activates Ca2+-permeable Cationic Channel in lung carcinoma cells. AB - BACKGROUND: Phospholipid phosphatase 4 (PPAPDC1A or PLPP4) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to investigate the clinical significance and biological roles of PLPP4 in lung carcinoma. METHODS: PLPP4 expression was examined in 8 paired lung carcinoma tissues by real-time PCR and in 265 lung carcinoma tissues by immunohistochemistry (IHC). Statistical analysis was performed to evaluate the clinical correlation between PLPP4 expression and clinicopathological features and survival in lung carcinoma patients. In vitro and in vivo assays were performed to assess the biological roles of PLPP4 in lung carcinoma. Fluorescence activated cell sorting, Western blotting and luciferase assays were used to identify the underlying pathway through which PLPP4 silencing mediates biological roles in lung carcinoma. RESULTS: PLPP4 is differentially elevated in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SQC) tissues. Statistical analysis demonstrated that high expression of PLPP4 significantly and positively correlated with clinicopathological features, including pathological grade, T category and stage, and poor overall and progression-free survival in lung carcinoma patients. Silencing PLPP4 inhibits proliferation and cell cycle progression in vitro and tumorigenesis in vivo in lung carcinoma cells. Our results further reveal that PLPP4 silencing inhibits Ca2+-permeable cationic channel, suggesting that downregulation of PLPP4 inhibits proliferation and tumorigenesis in lung carcinoma cells via reducing the influx of intracellular Ca2+. CONCLUSION: Our results indicate that PLPP4 may hold promise as a novel marker for the diagnosis of lung carcinoma and as a potential therapeutic target to facilitate the development of novel treatment for lung carcinoma. PMID- 28851362 TI - Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study. AB - AIMS: Secreted frizzled-related protein (Sfrp)5 has beneficial effects on insulin sensitivity, inflammation and cardiovascular risk in different mouse models, but its relevance for cardiometabolic diseases in humans is controversial. We aimed to characterise associations of circulating SFRP5 with cardiometabolic risk factors and prediabetes/type 2 diabetes in a large population-based cohort. METHODS: Cross-sectional associations between serum SFRP5 and cardiometabolic risk factors as well as prediabetes/type 2 diabetes were investigated in 1096 participants aged 62-81 years from the German KORA F4 study, of whom 666 had prediabetes or type 2 diabetes. Multivariable linear regression models were adjusted for potential confounders including age, sex, body mass index (BMI), lifestyle factors, lipids, hypertension, kidney function and myocardial infarction. RESULTS: Higher serum SFRP5 levels were associated with lower HbA1c, BMI, systolic blood pressure, estimated glomerular filtration rate and high sensitivity C-reactive protein levels and with higher levels of high-density lipoprotein cholesterol and adiponectin in the fully adjusted model (all P < 0.009). In contrast, favourable associations between SFRP5 and glycaemia, insulin, insulin resistance and other cardiometabolic risk factors were attenuated after adjustment for BMI. Serum SFRP5 levels were lower in participants with prediabetes or type 2 diabetes [(median (25th; 75th percentile) 48.8 (35.5; 65.7) ng/ml] compared to participants with normal glucose tolerance [55.9 (42.6; 69.6) ng/ml] (P < 0.001). In the fully adjusted model, higher SFRP5 was associated with lower odds of prediabetes/type 2 diabetes [OR (95% CI) (0.72 (0.58; 0.89)) per doubling of SFRP5, P < 0.01]. CONCLUSIONS: Higher serum SFRP5 was inversely associated with multiple risk factors for type 2 diabetes and cardiovascular diseases. However, BMI represents a strong confounder of some of these associations. Higher circulating SFRP5 was also associated with lower odds of prediabetes/type 2 diabetes, and this association was independent of BMI. Thus, SFRP5 emerges as novel biomarker that merits further research in the context of prevention of cardiometabolic diseases. PMID- 28851364 TI - "Always paracetamol, they give them paracetamol for everything": a qualitative study examining Eastern European migrants' experiences of the UK health service. AB - BACKGROUND: The enlargement of the European Union since 2004 has led to an increase in the number of Eastern European migrants living in the UK. The health of this group is under-researched though some mixed evidence shows they are at higher risk of certain physical health conditions such as heart attacks, strokes, HIV and alcohol use and have poorer mental health. This is compounded by poor or insecure housing, low pay, isolation and prejudice. We aimed to understand the health needs and health service experiences of the Eastern European population in a town in Northern England. METHODS: Five semi structured one-to-one and small group interviews and five focus groups were conducted with 42 Eastern European participants between June and September 2014. The majority of participants were Polish and other participants were from Belarus, Hungary, Latvia, Russia, Slovakia and Ukraine. The data were analysed using thematic framework analysis. RESULTS: Key findings included a good understanding the UK health service structure and high registration and use of general practice/primary care services. However, overall, there were high levels of dissatisfaction, frustration and distrust in General Practitioners (GP). The majority of participants viewed the GP as unhelpful and dismissive; a barrier to secondary/acute care; reluctant to prescribe antibiotics; and that GPs too often advised them to take paracetamol (acetaminophen) and rest. CONCLUSIONS: Overwhelmingly participants had strong opinions about access to primary care and the role of the general practitioners. Although the design of the UK health service was well understood, participants were unhappy with the system of GP as gatekeeper and felt it inferior to the consumer-focused health systems in their country of origin. More work is needed to promote the importance of self-care, reduce antibiotic and medication use, and to increase trust in the GP. PMID- 28851363 TI - The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness. AB - BACKGROUND: The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). METHODS: In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). RESULTS: In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells. CONCLUSIONS: Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa. PMID- 28851365 TI - Primary care clinical practice guidelines in South Africa: qualitative study exploring perspectives of national stakeholders. AB - BACKGROUND: Clinical practice guidelines (CPGs) are common tools in policy and clinical practice informing clinical decisions at the bedside, governance of health facilities, health insurer and government spending, and patient choices. South Africa's health sector is transitioning to a national health insurance system, aiming to build on other primary health care initiatives to transform the previously segregated, inequitable services. Within these plans CPGs are an integral tool for delivering standardised and cost effective care. Currently, there is no accepted standard approach to developing, adapting or implementing CPGs efficiently or effectively in South Africa. We explored the current players; drivers; and the context and processes of primary care CPG development from the perspective of stakeholders operating at national level. METHODS: We used a qualitative approach. Sampling was initially purposeful, followed by snowballing and further sampling to reach representivity of primary care service providers. Individual in-depth interviews were recorded and transcribed verbatim. We used thematic content analysis to analyse the data. RESULTS: We conducted 37 in-depth interviews from June 2014-July 2015. We found CPG development and implementation were hampered by lack of human and funding resources for technical and methodological work; fragmentation between groups, and between national and provincial health sectors; and lack of agreed systems for CPG development and implementation. Some CPG contributors steadfastly work to improve processes aiming to enhance communication, use of evidence, and transparency to ensure credible guidance is produced. Many interviewed had shared values, and were driven to address inequity, however, resource gaps were perceived to create an enabling environment for commercial interests or personal agendas to drive the CPG development process. CONCLUSIONS: Our findings identified strengths and gaps in CPG development processes, and a need for national standards to guide CPG development and implementation. Based on our findings and suggestions from participants, a possible way forward would be for South Africa to have a centrally coordinated CPG unit to address these needs and aspects of fragmentation by devising processes that support collaboration, transparency and credibility across sectors and disciplines. Such an initiative will require adequate resourcing to build capacity and ensure support for the delivery of high quality CPGs for South African primary care. PMID- 28851366 TI - A widespread family of polymorphic toxins encoded by temperate phages. AB - BACKGROUND: Polymorphic toxins (PTs) are multi-domain bacterial exotoxins belonging to distinct families that share common features in terms of domain organization. PTs are found in all major bacterial clades, including many toxic effectors of type V and type VI secretion systems. PTs modulate the dynamics of microbial communities by killing or inhibiting the growth of bacterial competitors lacking protective immunity proteins. RESULTS: In this work, we identified a novel widespread family of PTs, named MuF toxins, which were exclusively encoded within temperate phages and their prophages. By analyzing the predicted proteomes of 1845 bacteriophages and 2464 bacterial genomes, we found that MuF-containing proteins were frequently part of the DNA packaging module of tailed phages. Interestingly, MuF toxins were abundant in the human gut microbiome. CONCLUSIONS: Our results uncovered the presence of the MuF toxin family in the temperate phages of Firmicutes. The MuF toxin family is likely to play an important role in the ecology of the human microbiota where pathogens and commensal species belonging to the Firmicutes are abundant. We propose that MuF toxins could be delivered by phages into host bacteria and either influence the lysogeny decision or serve as bacterial weapons by inhibiting the growth of competing bacteria. PMID- 28851368 TI - Perception and attitude of Korean physicians towards generic drugs. AB - BACKGROUND: In 2012, a new pharmaceutical policy was introduced in Korea. According to the new policy, off-patent brand-name drugs (original drugs) and generic drugs must be priced the same. METHODS: This study aims to investigate the perception and attitude of Korean physicians towards generic drugs before and after the policy reform. Surveys were conducted with registered doctors at the Health Insurance Review Agency (HIRA) twice, in 2011 and 2013, by means of email and HIRA online survey systems. RESULTS: In the 2011 survey, 82% knew about the bioequivalent (BE) guideline, whereas only 25.7% trusted BE testing results. More than half preferred original drugs to generic drugs because of clinical experience and generic drugs confidence limits. 64.2% pointed out that the Korean generic drugs prices are more expensive than in other counties. In the 2013 survey, 73% preferred original drugs to generic drugs because of believed difference in drug effectiveness. After the pricing policy reform, 35.5% stated that they didn't change their prescribing pattern, whereas 29.7% stated that they began prescribing generic drugs. CONCLUSIONS: The Korean government has revised and strengthen the guideline on BE test to improve the quality and confidence of generic drugs. Although generic drugs prescription was increased slightly more than the 2011 survey, 2013 survey showed that around 70% of respondents still preferred original drugs. PMID- 28851369 TI - Evaluation of the effect of different sitting assistive devices in reclining wheelchair on interface pressure. AB - BACKGROUND: Reclining wheelchair users often add one or more sitting assistive devices to their wheelchairs, but the effect of these additional sitting assistive devices on the risk of pressure ulcers has rarely been investigated. This study examined the four modes of reclining wheelchair without and with different sitting assistive devices, namely the back reclined mode, the lumbar support with back reclined mode, the femur upward with back reclined mode, and the lumbar support with femur upward with back reclined mode, in terms of their effects on human-wheelchair interface pressure. METHODS: This study recruited 16 healthy participants to undergo the aforementioned four modes in random order and have their human-wheelchair interface pressure measured. The initial setting of experimental reclining wheelchair backrest was pushed backward to reach a 150 degrees recline. The data on interface pressure were collected for 5 s while the participant maintained a stable sitting position. The contact area, average pressure, and peak pressure on the back area, ischial area, and femur area were recorded and calculated. RESULTS: Among all tested modes, the lumbar support with femur upward with back reclined mode provided the most significant reduction in stress load on the ischial area (P <= 0.010) and shifted part of the load to the femur area (P <= 0.009). CONCLUSIONS: This study quantified the effects of and differences between various reclining wheelchair-sitting assistive device combination modes. These findings are useful for the decision-making processes of rehabilitation physicians, wheelchair users, and manufacturers. PMID- 28851367 TI - Role of exosomal proteins in cancer diagnosis. AB - Exosomes are emerging as a new type of cancer biomarkers. Exosome is a bilayered nano-sized vesicle secreted by various living cells in all body fluids. Based on the expanding albeit incomplete knowledge of their biogenesis, secretion by cells and cancer cell-specific molecular and genetic contents, exosomes are viewed as promising, clinically-relevant surrogates of cancer progression and response to therapy. Preliminary proteomic, genetic and functional profiling of cancer cell derived or cancer plasma-derived exosomes confirms their unique characteristics. Alterations in protein or nucleic acid profiles of exosomes in plasma correlate with pathological processes of many diseases including cancer. However, previous studies on exosome application in cancer diagnosis and treatment mainly focussed on miRNAs. With the development of rapid large-scale production, purification, extraction and screening of exosomal contents, exosomal protein application can be explored for early stage cancer diagnosis, monitoring and prognosis evaluation. Here, we summarized the recent developments in application of exosomal proteins for cancer diagnosis. PMID- 28851370 TI - Comparing microbiota profiles in induced and spontaneous sputum samples in COPD patients. AB - BACKGROUND: Induced and spontaneous sputum are used to evaluate the airways microbiota. Whether the sputum types can be used interchangeably in microbiota research is unknown. Our aim was to compare microbiota in induced and spontaneous sputum from COPD patients sampled during the same consultation. METHODS: COPD patients from Bergen, Norway, were followed between 2006/2010, examined during the stable state and exacerbations. 30 patients delivered 36 sample pairs. DNA was extracted by enzymatic and mechanical lysis methods. The V3-V4 region of the 16S rRNA gene was PCR-amplified and prepared for paired-end sequencing. Illumina Miseq System was used for sequencing, and Quantitative Insights Into Microbial Ecology (QIIME) and Stata were used for bioinformatics and statistical analyses. RESULTS: Approximately 4 million sequences were sorted into 1004 different OTUs and further assigned to 106 different taxa. Pair-wise comparison of both taxonomic composition and beta-diversity revealed significant differences in one or both parameters in 1/3 of sample pairs. Alpha-diversity did not differ. Comparing abundances for each taxa identified, showed statistically significant differences between the mean abundances in induced versus spontaneous samples for 15 taxa when disease state was considered. This included potential pathogens like Haemophilus and Moraxella. CONCLUSION: When studying microbiota in sputum samples one should take into consideration how samples are collected and avoid the usage of both induced and spontaneous sputum in the same study. PMID- 28851371 TI - A study on the equality and benefit of China's national health care system. AB - BACKGROUND: This study is designed to evaluate whether the benefit which the residents received from the national health care system is equal in China. The perceived equality and benefit are used to measure the personal status of health care system, health status. This study examines variations in perceived equality and benefit of the national health care system between urban and rural residents from five cities of China and assessed their determinants. METHODS: One thousand one hundred ninty eight residents were selected from a random survey among five nationally representative cities. The research characterizes perceptions into four population groupings based on a binary assessment of survey scores: high equality & high benefit; low equality & low benefit; high equality & low benefit; and low equality & high benefit. RESULTS: The distribution of the four groups above is 30.4%, 43.0%, 4.6% and 22.0%, respectively. Meanwhile, the type of health insurance, educational background, occupation, geographic regions, changes in health status and other factors have significant impacts on perceived equality and benefit derived from the health care system. CONCLUSION: The findings demonstrate wide variations in perceptions of equality and benefit between urban and rural residents and across population characteristics, leading to a perceived lack of fairness in benefits and accessibility. Opportunities exist for policy interventions that are targeted to eliminate perceived differences and promote greater equality in access to health care. PMID- 28851372 TI - Diagnostic testing for Legionnaires' disease. AB - Legionnaires' disease is commonly diagnosed clinically using a urinary antigen test. The urinary antigen test is highly accurate for L. pneumophila serogroup 1, however other diagnostic tests should also be utilized in conjunction with the urinary antigen as many other Legionella species and serogroups are pathogenic. Culturing of patient specimens remains the gold standard for diagnosis of Legionnaires' disease. Selective media, BYCE with the addition of antibiotics, allows for a high sensitivity and specificity. Culturing can identify all species and serogroups of Legionella. A major benefit of culturing is that it provides the recovery of a patient isolate, which can be used to find an environmental match. Other diagnostic tests, including DFA and molecular tests such as PCR and LAMP, are useful tests to supplement culturing. Molecular tests provide much more rapid results in comparison to culture, however these tests should not be a primary diagnostic tool given their lower sensitivity and specificity in comparison to culturing. It is recommended that all laboratories develop the ability to culture patient specimens in-house with the selective media. PMID- 28851373 TI - A pragmatic lifestyle modification programme reduces the incidence of predictors of cardio-metabolic disease and dysglycaemia in a young healthy urban South Asian population: a randomised controlled trial. AB - BACKGROUND: There is an increasing incidence of type 2 diabetes mellitus (T2DM) in young urban South-Asians. We tested the effect of a pragmatic trimonthly lifestyle modification (LSM) programme (P-LSM) versus a less-intensive 12-monthly control LSM (C-LSM) intervention on a primary composite endpoint of predictors of cardio-metabolic disease (new onset T2DM, hypertension, impaired glucose tolerance (IGT), impaired fasting glycaemia (IFG) and markers of cardio-renal disease) in participants aged 5-40 years with risk factors for T2DM. METHODS: This was a randomised controlled trial performed at the National Diabetes Centre, Sri-Lanka. We individually randomised 4672 participants at risk of T2DM, of whom 3539 (mean age 22.5 (range 6-40 years, 48% males) received either trimonthly (P LSM n = 1726) or 12-monthly (C-LSM n = 1813) peer educator advice aimed at reducing weight, improving diet, reducing psychological stress and increasing physical activity. RESULTS: During a median follow-up of 3 years, the cumulative incidence of the primary endpoint was n = 479 in P-LSM (74 per 1000 person years) vs. 561 in C-LSM (96 per 1000 person years), with an incident rate ratio (IRR) of 0.89 (95% CI 0.83-0.96, P = 0.02). In post hoc analyses, new onset dysglycaemia (T2DM, IFG and IGT), was the major contributor to the composite and was significantly reduced by P-LSM (IRR 0.9, 95% CI 0.83-0.97, P = 0.01). A significant impact of P-LSM on the incidence of the composite endpoint was noted in 1725 participants (P-LSM n = 850, C-LSM n = 875) aged below 18; P-LSM n = 140 (48 per 1000 person years) versus C-LSM n = 174 (55.4 per 1000 person years), with an IRR of 0.83 (95% CI 0.73-0.94, P = 0.004). CONCLUSIONS: In a young at risk South-Asian population, a pragmatic LSM programme significantly reduces the incidence of predictors of cardio-metabolic disease. Our results highlight the importance of early intervention in young at-risk subjects. TRIAL REGISTRATION: World Health Organization international clinical trial registry platform ( SLCTR/2008/003 ). Registration Date: March 28, 2008. Retrospectively registered. PMID- 28851374 TI - Behavioral Health and the Comprehensive Primary Care (CPC) Initiative: findings from the 2014 CPC behavioral health survey. AB - BACKGROUND: Incorporating behavioral health care into patient centered medical homes is critical for improving patient health and care quality while reducing costs. Despite documented effectiveness of behavioral health integration (BHI) in primary care settings, implementation is limited outside of large health systems. We conducted a survey of BHI in primary care practices participating in the Comprehensive Primary Care (CPC) initiative, a four-year multi-payer initiative of the Centers for Medicare and Medicaid Services (CMS). We sought to explore associations between practice characteristics and the extent of BHI to illuminate possible factors influencing successful implementation. METHOD: We fielded a survey that addressed six substantive domains (integrated space, training, access, communication and coordination, treatment planning, and available resources) and five behavioral health conditions (depression, anxiety, pain, alcohol use disorder, and cognitive function). Descriptive statistics compared BHI survey respondents to all CPC practices, documented the availability of behavioral health providers, and primary care and behavioral health provider communication. Bivariate relationships compared provider and practice characteristics and domain scores. RESULTS: One hundred sixty-one of 188 eligible primary care practices completed the survey (86% response rate). Scores indicated basic to good baseline implementation of BHI in all domains, with lowest scores on communication and coordination and highest scores for depression. Higher scores were associated with: having any behavioral health provider, multispecialty practice, patient-centered medical home designation, and having any communication between behavioral health and primary care providers. CONCLUSIONS: This study provides useful data on opportunities and challenges of scaling BHI integration linked to primary care transformation. Payment reform models such as CPC can assist in BHI promotion and development. PMID- 28851375 TI - Health-related quality of life and influencing factors among migrant children in Shaoxing, China. AB - BACKGROUND: Due to increasing export of labor service, many children following their parents leave from rural areas to urban areas in China. These migrant children might have psychological stress and lower quality of life. However, even up to this day, little is known about the health-related quality of life (HRQoL) of the migrant children. This study aims at investigating their living conditions and exploring the influencing factors of migrant children's HRQoL. METHODS: A cross-sectional survey of 856 migrant children, aged between 7 and 17, was conducted in Shaoxing. The 4 PedsQL 4.0 Generic Core Scales (Physical, Emotional, Social, School) were administered to reveal migrant children's quality of life, while demographic data questionnaire, Egna Minnen av. Barndoms Uppfostran and Social Support Rating Scale were used to reflect the influencing factors. RESULTS: For 824 effective questionnaires(all items were completed without any inconsistency in a questionnaire and all the information in the questionnaire is believable), the average age of these children was 12.80 +/- 1.91.The average years that they stayed in Shaoxing were 6.41 years. The average score of HRQoL was 81.13 +/- 10.77, Physical Functioning was 84.83 +/- 12.49, Emotional Functioning was 71.32 +/- 18.34, Social Functioning was 86.28 +/- 14.12, and School Functioning was79.28 +/- 13.16. There was no obvious difference (F = 0.138, P = 0.711) between boys and girls as for PedsQL. The score of PedsQL did not show significant association with migrant children's gender and their school records, while school grade, the relationships with classmates, parental rearing style and social support showed significant correlations. Linear regression analysis showed that mother's rejection, subjective support, father's rejection, relationships with classmates, mother's overprotection and level of using social support were influencing factors on PedsQL of migrant children. CONCLUSIONS: Migrant children scored lower on health-related quality of life, which was associated with parental rejection, mother's overprotection, less subjective support, badly getting along with classmates and that they cannot use social support well. PMID- 28851376 TI - Detection rate of prostate cancer following biopsy among the northern Han Chinese population: a single-center retrospective study of 1022 cases. AB - BACKGROUND: Prostate cancer is known to have ethnic and regional differences. The study aimed to clinically evaluate the detection rate of prostate cancer on transrectal ultrasonography (TRUS)-guided prostate biopsy and analyze its characteristics among the northern Han Chinese population at a single center. METHODS: Between October 2009 and September 2016, a total of 1027 Chinese men, who had undergone TRUS-guided prostate biopsy at Qingdao Municipal Hospital, were retrospectively analyzed. Prostate biopsies were performed in the case of an abnormally elevated serum PSA level, and/or abnormal digital rectal examination (DRE) findings, and/or suspicious prostatic imaging findings. RESULTS: Of the 1022 men enrolled in the analysis, 438 patients (42.8%) were diagnosed with prostate adenocarcinoma histologically. When serum PSA levels were divided into five subgroups (less than 4.0, 4.0 to 10.0, 10.0 to 20.0, 20.0 to 100.0, and >= 100.0 ng/ml), the detection rates of prostate cancer were 12.4, 15.9, 34.1, 66.2, and 93.8%, respectively. With serum PSA levels of 4.0 to 10.0 ng/ml, the cancer detection rates for a normal DRE and a suspect DRE finding were 13.5 and 58.2%, respectively. Accordingly, the cancer detection rates for a normal imaging and a suspect imaging finding were 13.5 and 58.2%, respectively. Besides, a large proportion of the patients were in the clinically advanced stage. CONCLUSIONS: The present study data reported a relatively higher prostate cancer detection rate of 42.8% and that the majority of the patients presented with clinically advanced prostate cancers within a local clinical urologic practice. An early detection and screening program for prostate cancer is of great need to reduce the burden from this disease among the northern Han Chinese population. PMID- 28851378 TI - In silico prediction of novel therapeutic targets using gene-disease association data. AB - BACKGROUND: Target identification and validation is a pressing challenge in the pharmaceutical industry, with many of the programmes that fail for efficacy reasons showing poor association between the drug target and the disease. Computational prediction of successful targets could have a considerable impact on attrition rates in the drug discovery pipeline by significantly reducing the initial search space. Here, we explore whether gene-disease association data from the Open Targets platform is sufficient to predict therapeutic targets that are actively being pursued by pharmaceutical companies or are already on the market. METHODS: To test our hypothesis, we train four different classifiers (a random forest, a support vector machine, a neural network and a gradient boosting machine) on partially labelled data and evaluate their performance using nested cross-validation and testing on an independent set. We then select the best performing model and use it to make predictions on more than 15,000 genes. Finally, we validate our predictions by mining the scientific literature for proposed therapeutic targets. RESULTS: We observe that the data types with the best predictive power are animal models showing a disease-relevant phenotype, differential expression in diseased tissue and genetic association with the disease under investigation. On a test set, the neural network classifier achieves over 71% accuracy with an AUC of 0.76 when predicting therapeutic targets in a semi-supervised learning setting. We use this model to gain insights into current and failed programmes and to predict 1431 novel targets, of which a highly significant proportion has been independently proposed in the literature. CONCLUSIONS: Our in silico approach shows that data linking genes and diseases is sufficient to predict novel therapeutic targets effectively and confirms that this type of evidence is essential for formulating or strengthening hypotheses in the target discovery process. Ultimately, more rapid and automated target prioritisation holds the potential to reduce both the costs and the development times associated with bringing new medicines to patients. PMID- 28851377 TI - Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts. AB - PURPOSE: The present review aimed to assess the role of exosomal miRNAs in cancer associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancer cells. The roles of exosomal miRNAs and miRNA dysregulation in CAF formation and activation were summarized. METHODS: All relevant publications were retrieved from the PubMed database, with key words such as CAFs, CAF, stromal fibroblasts, cancer associated fibroblasts, miRNA, exosomal, exosome, and similar terms. RESULTS: Recent studies have revealed that CAFs, NFs, and cancer cells can secrete exosomal miRNAs to affect each other. Dysregulation of miRNAs and exosomal miRNAs influence the formation and activation of CAFs. Furthermore, miRNA dysregulation in CAFs is considered to be associated with a secretory phenotype change, tumor invasion, tumor migration and metastasis, drug resistance, and poor prognosis. CONCLUSIONS: Finding of exosomal miRNA secretion provides novel insights into communication among CAFs, NFs, and cancer cells. MicroRNA dysregulation is also involved in the whole processes of CAF formation and function. Dysregulation of miRNAs in CAFs can affect the secretory phenotype of the latter cells. PMID- 28851379 TI - Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient. AB - BACKGROUND: The FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged. CASE PRESENTATION: We describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived. We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy. CONCLUSIONS: We found that for the 45 cases with available data, the median age was 70 years, and the male-female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery. PMID- 28851380 TI - Vaccine-draining lymph nodes of cancer patients for generating anti-cancer antibodies. AB - BACKGROUND: Our research is focused on using the vaccine draining lymph node to better understand the immune response to cancer vaccines and as a possible source of anti-cancer reagents. We evaluated vaccine draining lymph nodes archived from a clinical study in melanoma patients and determined the reaction of B cells to the vaccine peptides. METHODS: Mononuclear cells (MNCs) were recovered from cryopreserved lymph nodes that were directly receiving drainage from multi peptide melanoma vaccine. The patients were enrolled on a vaccine study (NCT00089219, FDA, BB-IND No. 10825). B cell responses in the vaccine-draining lymph nodes were studied under both stimulated and un-stimulated conditions. Cryopreserved cells were stimulated with CD40L, stained with multiple human cell surface markers (CD19, CD27, IgM) to identify different categories of B cell sub populations with flow cytometry. Hybridomas were generated from the lymph node cells after CD40L-stimulation. Cells were fused to murine plasmacytoma P3X63.Ag8.653 using Helix electrofusion chamber. ELISA was used to evaluate hybridoma derived antibody binding to vaccine peptides. RESULTS: Viable MNCs were satisfactorily recovered from lymph nodes cryopreserved from six vaccine study patients 8-14 years previously. B cell ELISPOT demonstrated responses for each patient to multiple vaccine peptides. CD40L stimulation of lymph node cells increased the proportion of CD19+ CD27+ cells from 12 to 65% of the sample and increased the proportion of class-switched cells. Screening of IgG secreting clones demonstrated binding to melanoma vaccine peptides. CONCLUSIONS: B cells were successfully recovered and expanded from human cryopreserved vaccine draining lymph nodes. Individual B cells were identified that secreted antibodies that bound to cancer vaccine peptides. The ability to reliably generate in vitro the same antibodies observed in the blood of vaccinated patients will facilitate research to understand mechanisms of human antibody activity and possibly lead to therapeutic antibodies. PMID- 28851381 TI - Glucocorticoid attenuates acute lung injury through induction of type 2 macrophage. AB - BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe inflammatory lung diseases. Methylprednisolone (MP) is a common drug against inflammation in clinic. In this study, we aim to investigate the protective effect of MP on ALI and potential mechanisms. METHODS: Male BABL/c mice were injected through tail vein using lipopolysaccharide (LPS, 5 mg/kg) with or without 5 mg/kg MP. Lung mechanics, tissue injury and inflammation were examined. Macrophage subsets in the lung were identified by flow cytometry. Macrophages were cultured from bone marrow of mice with or without MP. Then, we analyzed and isolated the subsets of macrophages. These isolated macrophages were then co-cultured with CD4+ T cells, and the percentage of regulatory T cells (Tregs) was examined. The expression of IL-10 and TGF-beta in the supernatant was measured. The Tregs immunosuppression function was examined by T cell proliferation assay. To disclose the mechanism of the induction of Tregs by M2c, we blocked IL-10 or/and TGF-beta using neutralizing antibody. RESULTS: Respiratory physiologic function was significantly improved by MP treatment. Tissue injury and inflammation were ameliorated in the MP-treated group. After MP treatment, the number of M1 decreased and M2 increased in the lung. In in vitro experiment, MP promoted M2 polarization rather than M1. We then induced M1, M2a and M2c from bone marrow cells. M1 induced more Th17 while M2 induced more CD4+CD25+Fxop3+ Tregs. Compared with M2a, M2c induced more Tregs, and this effect could be blocked by anti-IL-10 and anti-TGF-beta antibodies. However, M2a and M2c have no impact on Tregs immunosuppression function. CONCLUSION: In conclusion, MP ameliorated ALI by promoting M2 polarization. M2, especially M2c, induced Tregs without any influence on Tregs immunosuppression function. PMID- 28851383 TI - A system approach to improving maternal and child health care delivery in Kenya: innovations at the community and primary care facilities (a protocol). AB - BACKGROUND: Maternal, fetal and neonatal mortality are higher in low-income compared to high-income countries due to weak health systems including poor access and utilization of health services. Despite enormous recent improvements in maternal, neonatal and under 5 health indicators, more rapid progress is needed to meet the targets including the Development Goal 3(SDG). In Kenya these indicators are still high and comprehensive systems are needed to attain the targets of the SDG 3 by 2030. We describe the structure and methods of a study to assess the impact of an innovative system approach on maternal, neonatal and under-five children outcomes. This will be implemented in two clusters in the Counties of Busia and Bungoma in Kenya. There will be 4 control clusters in Kakamega, UasinGishu, Trans Nzoia and Elgeyo Marakwet Counties in Kenya. The study population will be pregnant women, newborns and under-five children identified over the study period. The objective of the study is to improve access, utilization and quality of Maternal and Child Health care through a predesigned Enhanced Health Care System (EHC) that embodies six WHO pillars of the health system and community owned initiatives including Community Based Organisations and Income Generating Activities. METHODS/DESIGN: A five year quasi experimental design will be used to compare the outcomes of the implementation of the EHC using the Find Link Treat and retain (FLTR) strategy in one cluster, community owned initiatives in one cluster and four control clusters at baseline and at the end of the study. A Baseline survey will be conducted in year one and an endline in the fifth year in which maternal, neonatal and underfive childhood outcomes will be compared. DISCUSSION: The expected findings from the study include showing trends in improvement in the intervention clusters for morbidity, mortality, health service utilization and access indicators. Use of the health systems approach in health care provision is expected to provide a holistic improvement in the quality of care in the study populations in the intervention clusters that will lead to improved health indicators including morbidity and mortality. It is expected that the findings will inform health policy of the national and county governments in Kenya and worldwide. PMID- 28851382 TI - A realist synthesis of cross-border patient movement from low and middle income countries to similar or higher income countries. AB - Patient travel across borders to access healthcare is becoming increasingly common and widespread. Patients moving from high income to middle income countries for healthcare is well documented, with patients seeking treatments that are cheaper or more readily available than at home. Less well understood is when patients move from one low income country to another or from a low income country to a higher income country. In this paper, a realist review was undertaken to explore why, in what contexts and how patients from lower income countries travel to countries with the same, or more advanced, economies for planned healthcare. Based on an initial scoping of the literature and discussions with key informants, we generated an initial theory and set of propositions about why, how, who and in what contexts people cross international borders for planned healthcare. We then systematically located and synthesized (1) peer-reviewed studies from the Scopus, Embase, Web of Science and Econlit databases; (2) non indexed reports using key informants and Google; and (3) papers from the reference lists of included documents, to glean supportive or contradictory evidence for our initial propositions. As we reviewed the literature and extracted our data, we drew on the work of Pierre Bourdieu to understand the interplay between material and non-material capital and cognitive processes in decisions to cross borders for healthcare. Patient travel was largely undertaken due to a lack of services in the home country and/or unacceptability of local services, with decisions on when, and where, to travel, usually made within the patient's social networks. They were able to travel via use of multiple resources, including social networks, economic and cultural capital, and habitus. Those patients with greater volumes of the aforementioned factors had greater healthcare options; however, even those with limited resources engaged in patient travel. Patient movement challenges traditional ways of thinking about public health and the notion of health systems contained within the nation state. Further research is needed to better understand the effects of patient travel, and how to harness the benefits of patient travel without exacerbating existing health inequalities. PMID- 28851384 TI - Health-related quality of life in pregnant women living with HIV: a comparison of EQ-5D and SF-12. AB - BACKGROUND: This paper investigates the properties and performance of the two generic measures, EQ-5D and SF-12, for Health-Related Quality of Life (HRQoL) assessments of pregnant women living with HIV in Kunming City, Yiliang County, Daguan County, Longchuan County, Tengchong County, Longling County and Fengqing County in Yunnan Province, China. METHODS: As part of a screening programme for the prevention of mother-to-child transmission of HIV (PMTCT), a retrospective cross-sectional survey was conducted in the seven Maternal and Infant Health Care centers in Yunnan Province, China, between April and June of 2016. The demographic and HIV infection-related information used in the study was collected through questionnaires designed by the study's staff. HRQoL information was collected using two generic scales: EQ-5D and SF-12. RESULTS: A total sample of one hundred and one pregnant women with a mean age of 30.4 +/- 5.1 years was investigated. Average time elapsed since infection diagnoses was 5.8 +/- 3.4 years. Only one infant (1.0%) was HIV positive, and 56 (55.4%) infants were HIV negative. The HIV status of 44 (43.6%) infants was unknown. The relationship between the EQ-5D functional dimensions and the PCS-12 and the relationship between the EQ-5D anxiety/depression dimension and the MCS-12 were stronger. Those whose PCS-12 and MCS-12 scores were at the median or lower were classified as being in worse health, while those over the median were classified as being in better health. Respondents who reported no problem on each of the EQ-5D dimensions was divided according to the median SF-12 component scores. Those who scored at the median or lower than the median were classified as being in worse health, while those higher than the median were classified as being in better health. The VAS scores were also significantly different than the median split of the SF-12 scores for these subjects. CONCLUSION: EQ-5D and SF-12 showed a discrimination ability in measuring the HRQoL of pregnant women living with HIV. The construct validity was identified for EQ-5D and SF-12 in the study. The respective constructs of EQ-5D and EQ-VAS may not overlap. Pregnant women living with HIV in the study gave more weight to their mental health when they provided a total health rating in EQ-VAS. EQ-VAS could explain the limitations of the EQ 5D dimension scores with ceiling effects in the survey. The results of our study could help to determine the suitable HRQoL instruments for pregnant women living with HIV and provide evidence for the proper comparison of EQ-5D and SF-12. PMID- 28851385 TI - Factors associated with dietary supplement use in Saudi pregnant women. AB - BACKGROUND: The aim was to investigate the prevalence of dietary supplement use among pregnant Saudi women and its associations between various demographics. METHODS: In this cross-sectional study, a total of 137 pregnant women attending prenatal care from King Salman Hospital completed a self-administered questionnaire including socio-demographic characteristics, general awareness, attitude and behavior towards use of dietary supplements during pregnancy. RESULTS: Dietary supplement use among Saudi women in pregnancy was high (71.5%) and was significantly associated with level of education (p = 0.005), family income (p = 0.039) and number of children (p = 0.007). No significant association was observed between neonatal health outcomes and dietary supplement use during pregnancy. In all participants, 81.6% believed that supplement use is important for nutritional status and more favorable neonatal outcomes. For the majority of participants, the primary source of information for dietary supplement use was a doctor's advice. The majority of the participants [65.7% (n = 90)] responded that dietary supplement use is safe. Folic acid was found to be the most common type of dietary supplement used (95.9%; n = 94); however, 53.1% (n = 52) did not take folic acid supplements 3 months prior to pregnancy. Other common supplements used were iron, calcium and vitamin D (88.8, 81.6, and 41%, respectively). CONCLUSIONS: This study provided new information on dietary supplement use and its correlates in Saudi pregnant women. The prevalence of dietary supplement use was high in this group and was associated with socio-demographic and lifestyle characteristics. PMID- 28851387 TI - Erratum to: Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation. PMID- 28851386 TI - The decreased expression of TIPE2 protein in the decidua of patients with missed abortion and possible significance. AB - BACKGROUND: Missed abortion is a common occurrence for otherwise healthy women. Immunological factor is one of the most important reasons. Tumor necrosis factor alpha-induced protein-8 like-2 (TIPE2) is a novel negative immune regulator related to several human diseases. However, the expression level and clinical significance of TIPE2 in missed abortion remain unclear. METHODS: The expression of TIPE2 mRNA and protein in decidua and chorion from 36 missed abortion patients and 36 healthy controls was detected using quantitative real-time PCR, western blot and immunohistochemistry. In addition, serum TNF-alpha and IL-10 levels were measured using flow cytometry. Serum estradiol and progesterone levels were measured by radioimmunoassay test. The correlations of TIPE2 protein levels with TNF-alpha, IL-10, estradiol and progesterone were further analyzed. RESULTS: TIPE2 protein levels were significantly lower in decidual tissues of missed abortion patients than those in healthy controls. The patients with missed abortion had significantly higher levels of serum TNF-alpha, and lower levels of serum IL-10, estradiol and progesterone compared with healthy controls. The TIPE2 protein levels were positively related to serum IL-10 levels. CONCLUSION: Our data indicate TIPE2 could play important roles in maintaining the maternal-fetal tolerance and decreased TIPE2 expression in the decidua may be related to the development of missed abortion. PMID- 28851388 TI - Promoting equitable global health research: a policy analysis of the Canadian funding landscape. AB - BACKGROUND: Recognising radical shifts in the global health research (GHR) environment, participants in a 2013 deliberative dialogue called for careful consideration of equity-centred principles that should inform Canadian funding polices. This study examined the existing funding structures and policies of Canadian and international funders to inform the future design of a responsive GHR funding landscape. METHODS: We used a three-pronged analytical framework to review the ideas, interests and institutions implicated in publically accessible documents relevant to GHR funding. These data included published literature and organisational documents (e.g. strategic plans, progress reports, granting policies) from Canadian and other comparator funders. We then used a deliberative approach to develop recommendations with the research team, advisors, industry informants and low- and middle-income country (LMIC) partners. RESULTS: In Canada, major GHR funders invest an estimated CA$90 M per annum; however, the post-2008 re-organization of funding structures and policies resulted in an uncoordinated and inefficient Canadian strategy. Australia, Denmark, the European Union, Norway, Sweden, the United Kingdom and the United States of America invest proportionately more in GHR than Canada. Each of these countries has a national strategic plan for global health, some of which have dedicated benchmarks for GHR funding and policy to allow funds to be held by partners outside of Canada. Key constraints to equitable GHR funding included (1) funding policies that restrict financial and cost burden aspects of partnering for GHR in LMICs; and (2) challenges associated with the development of effective governance mechanisms. There were, however, some Canadian innovations in funding research that demonstrated both unconventional and equitable approaches to supporting GHR in Canada and abroad. Among the most promising were found in the International Development Research Centre and the (no longer active) Global Health Research Initiative. CONCLUSION: Promoting equitable GHR funding policies and practices in Canada requires cooperation and actions by multiple stakeholders, including government, funding agencies, academic institutions and researchers. Greater cooperation and collaboration among these stakeholders in the context of recent political shifts present important opportunities for advancing funding policies that enable and encourage more equitable investments in GHR. PMID- 28851389 TI - Immunohistochemical staining with non-phospho beta-catenin as a diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with extra-peritoneal desmoid-type fibromatosis. AB - BACKGROUND: Immunohistochemical staining with conventional anti-beta-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatosis (DF). This study aimed to evaluate the diagnostic and prognostic value of immunohistochemical staining with anti-non-phospho beta-catenin antibody, which might more accurately reflect the aggressiveness of DF, in comparison to the conventional anti-beta-catenin antibody. METHODS: Between 2003 and 2015, 40 patients with extra-peritoneal sporadic DF were prospectively treated with meloxicam or celecoxib, a COX-2 inhibitor, therapy. The efficacy of this treatment was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Immunohistochemical staining was performed on formalin-fixed material to evaluate the expression of beta-catenin and non-phospho beta-catenin, and the positivity was grouped as negative, weak, moderate, and strong. DNA was isolated from frozen tissue or formalin-fixed materials, and the CTNNB1 mutation status was determined by direct sequencing. RESULTS: Of the 40 patients receiving COX-2 inhibitor treatment, there was one with complete remission, 12 with partial remission, 7 with stable disease, and 20 with progressive disease. The mutation sites in CTNNB1 were detected in 22 (55%) of the 40 cases: T41A (17 cases), S45F (3 cases), and T41I and S45P (1 each). The positive nuclear expression of non phospho beta-catenin showed a significant correlation with positive CTNNB1 mutation status detected by Sanger method (p = 0.025), and poor outcome in COX-2 inhibitor therapy (p = 0.022). In contrast, nuclear expression of beta-catenin did not show a significant correlation with either CTNNB1 mutation status (p = 0.43) or outcome of COX-2 inhibitor therapy (p = 0.38). CONCLUSIONS: Nuclear expression of non-phospho beta-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho beta catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF. PMID- 28851390 TI - Tumoral LINE-1 hypomethylation is associated with poor survival of patients with intrahepatic cholangiocarcinoma. AB - BACKGROUND: DNA methylation changes occurring in cancer cells are featured with both promoter CpG island hypermethylation and diffuse genomic hypomethylation. Long interspersed element-1 (LINE-1) is repeated in an interspersed manner with an estimated 500,000 copies per genome. LINE-1 has its CpG sites of the 5' untranslated region methylated heavily in normal cells and undergoes demethylation in association with cancerization. However, little information is available regarding LINE-1 hypomethylation and its prognostic implication in intrahepatic cholangiocarcinomas. METHODS: A total of 172 cases of intrahepatic cholangiocarcinomas were analyzed for their methylation levels at four CpG sites of LINE-1 using bisulfite pyrosequencing. We examined the relation between tumoral LINE-1 methylation level and clinicopathological features, including survival. RESULTS: Tumor differentiation, lymphatic invasion, and T stage were associated with a low average methylation level of LINE-1 at the four CpG sites; LINE-1 methylation level tended to be lower in high-grade differentiation, lymphatic emboli, and higher T stage. LINE-1 hypomethylation was significantly linked with lower cancer-specific survival in patients with intrahepatic cholangiocarcinoma and was found to be an independent prognostic parameter. CONCLUSIONS: Our findings suggest that tumoral LINE-1 hypomethylation could be a molecular biomarker heralding poor prognosis of patients with intrahepatic cholangiocarcinoma. Our findings need to be validated in further study. PMID- 28851391 TI - Surface EMG signals in very late-stage of Duchenne muscular dystrophy: a case study. AB - BACKGROUND: Robotic arm supports aim at improving the quality of life for adults with Duchenne muscular dystrophy (DMD) by augmenting their residual functional abilities. A critical component of robotic arm supports is the control interface, as is it responsible for the human-machine interaction. Our previous studies showed the feasibility of using surface electromyography (sEMG) as a control interface to operate robotic arm supports in adults with DMD (22-24 years-old). However, in the biomedical engineering community there is an often raised skepticism on whether adults with DMD at the last stage of their disease have sEMG signals that can be measured and used for control. FINDINGS: In this study sEMG signals from Biceps and Triceps Brachii muscles were measured for the first time in a 37 year-old man with DMD (Brooke 6) that lost his arm function 15 years ago. The sEMG signals were measured during maximal and sub-maximal voluntary isometric contractions and evaluated in terms of signal-to-noise ratio and co activation ratio. Beyond the profound deterioration of the muscles, we found that sEMG signals from both Biceps and Triceps muscles were measurable in this individual, although with a maximum signal amplitude 100 times lower compared to sEMG from healthy subjects. The participant was able to voluntarily modulate the required level of muscle activation during the sub-maximal voluntary isometric contractions. Despite the low sEMG amplitude and a considerable level of muscle co-activation, simulations of an elbow orthosis using the measured sEMG as driving signal indicated that the sEMG signals of the participant had the potential to provide control of elbow movements. CONCLUSIONS: To the best of our knowledge this is the first time that sEMG signals from a man with DMD at the last-stage of the disease were measured, analyzed and reported. These findings offer promising perspectives to the use of sEMG as an intuitive and natural control interface for robotic arm supports in adults with DMD until the last stage of the disease. PMID- 28851392 TI - The paradox of falling job satisfaction with rising job stickiness in the German nursing workforce between 1990 and 2013. AB - BACKGROUND: Literature reports a direct relation between nurses' job satisfaction and their job retention (stickiness). The proper planning and management of the nursing labor market necessitates the understanding of job satisfaction and retention trends. The objectives of the study are to identify trends in, and the interrelation between, the job satisfaction and job stickiness of German nurses in the 1990-2013 period using a flexible specification for job satisfaction that includes different time periods and to also identify the main determinants of nurse job stickiness in Germany and test whether these determinants have changed over the last two decades. METHODS: The development of job stickiness in Germany is depicted by a subset of data from the German Socio-Economic Panel (1990-2013), with each survey respondent assigned a unique identifier used to calculate the year-to-year transition probability of remaining in the current position. The changing association between job satisfaction and job stickiness is measured using job satisfaction data and multivariate regressions assessing whether certain job stickiness determinants have changed over the study period. RESULTS: Between 1990 and 2013, the job stickiness of German nurses increased from 83 to 91%, while their job satisfaction underwent a steady and gradual decline, dropping by 7.5%. We attribute this paradoxical result to the changing association between job satisfaction and job stickiness; that is, for a given level of job (dis)satisfaction, nurses show a higher stickiness rate in more recent years than in the past, which might be partially explained by the rise in part-time employment during this period. The main determinants of stickiness, whose importance has not changed in the past two decades, are wages, tenure, personal health, and household structure. CONCLUSIONS: The paradoxical relation between job satisfaction and job stickiness in the German nursing context could be explained by historical downsizing trends in hospitals, an East-West German nurse compensation gap, and an increase in the proportion of nurses employed on a part-time basis. A clearer analysis of each of these trends is thus essential for the development of evidence-based policies that enhance the job satisfaction and efficiency of the German nursing workforce. PMID- 28851393 TI - Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis. AB - BACKGROUND: The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity. OBJECTIVE: The aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis. METHODS: Findings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively. RESULTS: Oligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (P < 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so called MRZ reaction) was previously reported in 60-80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood-CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (P < 0.005, P < 0.009 and P < 0.006, respectively). CONCLUSIONS: Patients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and blood-CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS. PMID- 28851394 TI - Barriers and enablers in the implementation of a program to reduce cesarean deliveries. PMID- 28851395 TI - Molecular targeting in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogenous disease associated with distinct genetic and molecular abnormalities. Somatic mutations result in dysregulation of intracellular signaling pathways, epigenetics, and apoptosis of the leukemia cells. Understanding the basis for the dysregulated processes provides the platform for the design of novel targeted therapy for AML patients. The effort to devise new targeted therapy has been helped by recent advances in methods for high-throughput genomic screening and the availability of computer-assisted techniques for the design of novel agents that are predicted to specifically inhibit the mutant molecules involved in these intracellular events. In this review, we will provide the scientific basis for targeting the dysregulated molecular mechanisms and discuss the agents currently being investigated, alone or in combination with chemotherapy, for treating patients with AML. Successes in molecular targeting will ultimately change the treatment paradigm for the disease. PMID- 28851396 TI - The genetic structure of Turnip mosaic virus population reveals the rapid expansion of a new emergent lineage in China. AB - BACKGROUND: Turnip mosaic virus (TuMV) is one of the most widespread and economically important virus infecting both crop and ornamental species of the family Brassicaceae. TuMV isolates can be classified to five phylogenetic lineages, basal-B, basal-BR, Asian-BR, world-B and Orchis. RESULTS: To understand the genetic structure of TuMV from radish in China, the 3'-terminal genome of 90 TuMV isolates were determined and analyzed with other available Chinese isolates. The results showed that the Chinese TuMV isolates from radish formed three groups: Asian-BR, basal-BR and world-B. More than half of these isolates (52.54%) were clustered to basal-BR group, and could be further divided into three sub groups. The TuMV basal-BR isolates in the sub-groups I and II were genetically homologous with Japanese ones, while those in sub-group III formed a distinct lineage. Sub-populations of TuMV basal-BR II and III were new emergent and in a state of expansion. The Chinese TuMV radish populations were under negative selection. Gene flow between TuMV populations from Tai'an, Weifang and Changchun was frequent. CONCLUSIONS: The genetic structure of Turnip mosaic virus population reveals the rapid expansion of a new emergent lineage in China. PMID- 28851398 TI - Exploring the dynamics of food-related policymaking processes and evidence use in Fiji using systems thinking. AB - BACKGROUND: Obesity and non-communicable diseases are significant public health issues globally and particularly in the Pacific. Poor diet is a major contributor to this issue and policy change is a powerful lever to improve food security and diet quality. This study aims to apply systems thinking to identify the causes and consequences of poor evidence use in food-related policymaking in selected government ministries in Fiji and to illicit strategies to strengthen the use of evidence in policymaking. METHODS: The Ministry of Health and Medical Services and the Ministry of Agriculture in Fiji were invited through their respective Permanent Secretaries to participate in the study. Three 180-minute group model building (GMB) workshops were conducted separately in each ministry over three consecutive days with selected policymakers who were instrumental in developing food-related policies designed to prevent non-communicable diseases. The GMB workshops mapped the process of food-related policymaking and the contribution of scientific and local evidence to the process, and identified actions to enhance the use of evidence in policymaking. RESULTS: An average of 10 policymakers participated from each ministry. The causal loop diagrams produced by each ministry illustrated the causes and consequences of insufficient evidence use in developing food policies or precursors of the specific actions. These included (1) consultation, (2) engagement with stakeholders, (3) access and use of evidence, and (4) delays in policy processes. Participants agreed to potential leverage points on the themes above, addressing pertinent policymaker challenges in precursor control, including political influence, understanding of trade policies, competing government priorities and level of awareness on the problem. Specific actions for strengthening evidence use included training in policy development and research skills, and strengthening of coordination between ministries. CONCLUSIONS: The GMB workshops improved participants' understanding of how different parts of the policy system interact. The causal loop diagrams and subsequent action plans enabled the identification of systems-level interventions in both ministries to improve evidence-informed policy development. A guide for integrating multi-sectoral consultation and stakeholder engagement in developing cross-cutting policies is currently being developed. PMID- 28851397 TI - NF-kappaB-regulated microRNA-574-5p underlies synaptic and cognitive impairment in response to atmospheric PM2.5 aspiration. AB - BACKGROUND: PM2.5 (particulate matter <= 2.5 MUm) is one of the leading environmental risk factors for the global burden of disease. Whereas increasing evidence has linked the adverse roles of PM2.5 with cardiovascular and respiratory diseases, limited but growing emerging evidence suggests that PM2.5 exposure can affect the nervous system, causing neuroinflammation, synaptic dysfunction and cognitive deterioration. However, the molecular mechanisms underlying the synaptic and cognitive deficits elicited by PM2.5 exposure are largely unknown. METHODS: C57BL/6 mice received oropharyngeal aspiration of PM2.5 (1 and 5 mg/kg bw) every other day for 4 weeks. The mice were also stereotaxically injected with beta-site amyloid precursor protein cleaving enzyme 1 (beta-secretase, BACE1) shRNA or LV-miR-574-5p lentiviral constructs in the absence or presence of PM2.5 aspiration at 5 mg/kg bw every other day for 4 weeks. Spatial learning and memory were assessed with the Morris water maze test, and synaptic function integrity was evaluated with electrophysiological recordings of long-term potentiation (LTP) and immunoblot analyses of glutamate receptor subunit expression. The expression of alpha-secretase (ADAM10), BACE1, and gamma-secretase (nicastrin) and the synthesis and accumulation of amyloid beta (Abeta) were measured by immunoblot and enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA) expression was screened with a microRNA microarray analysis and confirmed by real-time quantitative reverse transcription PCR (qRT PCR) analysis. Dual-luciferase reporter gene and chromatin immunoprecipitation (ChIP) analyses were used to detect the binding of miR-574-5p in the 3'UTR of BACE1 and NF-kappaB p65 in the promoter of miR-574-5p, respectively. RESULTS: PM2.5 aspiration caused neuroinflammation and deteriorated synaptic function integrity and spatial learning and memory, and the effects were associated with the induction of BACE1. The action was mediated by NF-kappaB p65-regulated downregulation of miR-574-5p, which targets BACE1. Overexpression of miR-574-5p in the hippocampal region decreased BACE1 expression, restored synaptic function, and improved spatial memory and learning following PM2.5 exposure. CONCLUSIONS: Taken together, our findings reveal a novel molecular mechanism underlying impaired synaptic and cognitive function following exposure to PM2.5, suggesting that miR-574-5p is a potential intervention target for the prevention and treatment of PM2.5-induced neurological disorders. PMID- 28851399 TI - A mixed-methods feasibility and external pilot study to inform a large pragmatic randomised controlled trial of the effects of surgical wound dressing strategies on surgical site infections (Bluebelle Phase B): study protocol for a randomised controlled trial. AB - BACKGROUND: Surgical site infections (SSIs) are common, occurring in up to 25% of > 4 million operations performed in England each year. Previous trials of the effect of wound dressings on the risk of developing a SSI are of poor quality and underpowered. METHODS/DESIGN: This study is a feasibility and pilot trial to examine the feasibility of a full trial that will compare simple dressings, no dressing and tissue-glue as a dressing. It is examining the overall acceptability of trial participation, identifying opportunities for refinement, testing the feasibility of and validating new outcome tools to assess SSI, wound management issues and patients' wound symptom experiences. It is also exploring methods for avoiding performance bias and blinding outcome assessors by testing the feasibility of collecting wound photographs taken in theatre immediately after wound closure and, at 4-8 weeks after surgery, taken by participants themselves or their carers. Finally, it is identifying the main cost drivers for an economic evaluation of dressing types. Integrated qualitative research is exploring acceptability and reasons for non-adherence to allocation. Adults undergoing primary elective or unplanned abdominal general surgery or Caesarean section are eligible. The main exclusion criteria are abdominal or other major surgery less than three months before the index operation or contraindication to dressing allocation. The trial is scheduled to recruit for nine months. The findings will be used to inform the design of a main trial. DISCUSSION: This pilot trial is the first pragmatic study to randomise participants to no dressing or tissue-glue as a dressing versus a simple dressing. Early evidence from the ongoing pilot shows that recruitment is proceeding well and that the interventions are acceptable to participants. Combined with the qualitative findings, the findings will inform whether a main, large trial is feasible and, if so, how it should be designed. TRIAL REGISTRATION: ISRCTN49328913 . Registered on 20 October 2015. PMID- 28851401 TI - Knowledge sharing in global health research - the impact, uptake and cost of open access to scholarly literature. AB - BACKGROUND: In 1982, the Annals of Virology published a paper showing how Liberia has a highly endemic potential of Ebola warning health authorities of the risk for potential outbreaks; this journal is only available by subscription. Limiting the accessibility of such knowledge may have reduced information propagation toward public health actors who were indeed surprised by and unprepared for the 2014 epidemic. Open access (OA) publication can allow for increased access to global health research (GHR). Our study aims to assess the use, cost and impact of OA diffusion in the context of GHR. METHOD: A total of 3366 research articles indexed under the Medical Heading Subject Heading "Global Health" published between 2010 and 2014 were retrieved using PubMed to (1) quantify the uptake of various types of OA, (2) estimate the article processing charges (APCs) of OA, and (3) analyse the relationship between different types of OA, their scholarly impact and gross national income per capita of citing countries. RESULTS: Most GHR publications are not available directly on the journal's website (69%). Further, 60.8% of researchers do not self-archive their work even when it is free and in keeping with journal policy. The total amount paid for APCs was estimated at US$1.7 million for 627 papers, with authors paying on average US$2732 per publication; 94% of APCs were paid to journals owned by the ten most prominent publication houses from high-income countries. Researchers from low- and middle income countries are generally citing less expensive types of OA, while researchers in high-income countries are citing the most expensive OA. CONCLUSIONS: Although OA may help in building global research capacity in GHR, the majority of publications remain subscription only. It is logical and cost efficient for institutions and researchers to promote OA by self-archiving publications of restricted access, as it not only allows research to be cited by a broader audience, it also augments citation rates. Although OA does not ensure full knowledge transfer from research to practice, limiting public access can negatively impact implementation and outcomes of health policy and reduce public understanding of health issues. PMID- 28851402 TI - Context and scale: Distinctions for improving debates about physician "rationing". AB - Important discussions about limiting care based on professional judgment often devolve into heated debates over the place of physicians in bedside rationing. Politics, loaded rhetoric, and ideological caricature from both sides of the rationing debate obscure precise points of disagreement and consensus, and hinder critical dialogue around the obligations and boundaries of professional practice. We propose a way forward by reframing the rationing conversation, distinguishing between the scale of the decision (macro vs. micro) and its context (ordinary allocation vs. extraordinary re-allocation) avoiding the word "rationing." We propose to shift the terminology, using specific, descriptive words to defuse conflict and re-focus the debate towards substantive issues. These distinctions can clarify the real ethical differences at stake and facilitate a more constructive conversation about the clinical and social responsibilities of physicians to use resources ethically at the bedside and their role in allocating medical resources at a societal level. PMID- 28851400 TI - HIV-associated synaptic degeneration. AB - Human immunodeficiency virus (HIV) infection induces neuronal injuries, with almost 50% of infected individuals developing HIV-associated neurocognitive disorders (HAND). Although highly activate antiretroviral therapy (HAART) has significantly reduced the incidence of severe dementia, the overall prevalence of HAND remains high. Synaptic degeneration is emerging as one of the most relevant neuropathologies associate with HAND. Previous studies have reported critical roles of viral proteins and inflammatory responses in this pathogenesis. Infected cells, including macrophages, microglia and astrocytes, may release viral proteins and other neurotoxins to stimulate neurons and cause excessive calcium influx, overproduction of free radicals and disruption of neurotransmitter hemostasis. The dysregulation of neural circuits likely leads to synaptic damage and loss. Identification of the specific mechanism of the synaptic degeneration may facilitate the development of effective therapeutic approaches to treat HAND. PMID- 28851403 TI - A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial. AB - BACKGROUND: Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a 'good' mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a 'poor response' identifies an adverse prognostic group which may benefit from additional pre operative therapy. METHODS/DESIGN: TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. DISCUSSION: The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016. PMID- 28851404 TI - Computer-assisted stereology and automated image analysis for quantification of tumor infiltrating lymphocytes in colon cancer. AB - BACKGROUND: Precise prognostic and predictive variables allowing improved post operative treatment stratification are missing in patients treated for stage II colon cancer (CC). Investigation of tumor infiltrating lymphocytes (TILs) may be rewarding, but the lack of a standardized analytic technique is a major concern. Manual stereological counting is considered the gold standard, but digital pathology with image analysis is preferred due to time efficiency. The purpose of this study was to compare manual stereological estimates of TILs with automatic counts obtained by image analysis, and at the same time investigate the heterogeneity of TILs. METHODS: From 43 patients treated for stage II CC in 2002 three paraffin embedded, tumor containing tissue blocks were selected one of them representing the deepest invasive tumor front. Serial sections from each of the 129 blocks were immunohistochemically stained for CD3 and CD8, and the slides were scanned. Stereological estimates of the numerical density and area fraction of TILs were obtained using the computer-assisted newCAST stereology system. For the image analysis approach an app-based algorithm was developed using Visiopharm Integrator System software. For both methods the tumor areas of interest (invasive front and central area) were manually delineated by the observer. RESULTS: Based on all sections, the Spearman's correlation coefficients for density estimates varied from 0.9457 to 0.9638 (p < 0.0001), whereas the coefficients for area fraction estimates ranged from 0.9400 to 0.9603 (P < 0.0001). Regarding heterogeneity, intra-class correlation coefficients (ICC) for CD3+ TILs varied from 0.615 to 0.746 in the central area, and from 0.686 to 0.746 in the invasive area. ICC for CD8+ TILs varied from 0.724 to 0.775 in the central area, and from 0.746 to 0.765 in the invasive area. CONCLUSIONS: Exact objective and time efficient estimates of numerical densities and area fractions of CD3+ and CD8+ TILs in stage II colon cancer can be obtained by image analysis and are highly correlated to the corresponding estimates obtained by the gold standard based on stereology. Since the intra-tumoral heterogeneity was low, this method may be recommended for quantifying TILs in only one histological section representing the deepest invasive tumor front. PMID- 28851405 TI - The ERM protein Moesin is essential for neuronal morphogenesis and long-term memory in Drosophila. AB - Moesin is a cytoskeletal adaptor protein that plays an important role in modification of the actin cytoskeleton. Rearrangement of the actin cytoskeleton drives both neuronal morphogenesis and the structural changes in neurons that are required for long-term memory formation. Moesin has been identified as a candidate memory gene in Drosophila, however, whether it is required for memory formation has not been evaluated. Here, we investigate the role of Moesin in neuronal morphogenesis and in short- and long-term memory formation in the courtship suppression assay, a model of associative memory. We found that both knockdown and overexpression of Moesin led to defects in axon growth and guidance as well as dendritic arborization. Moreover, reduction of Moesin expression or expression of a constitutively active phosphomimetic in the adult Drosophila brain had no effect on short term memory, but prevented long-term memory formation, an effect that was independent of its role in development. These results indicate a critical role for Moesin in both neuronal morphogenesis and long-term memory formation. PMID- 28851406 TI - Effectiveness of an online social support intervention for caregivers of people with dementia: the study protocol of a randomised controlled trial. AB - BACKGROUND: Caregivers of people with dementia (PwD) face burden, feelings of loneliness, and social isolation. Previous studies have shown promising effects of online e-health interventions. Using social media may facilitate support for dementia caregiver networks. In an iterative step-wise approach, a social support tool entitled "Inlife" was developed. This paper describes the design of a study evaluating the effects of Inlife and its process characteristics. METHODS: A mixed-method, randomised controlled trial with 122 caregivers of PwD will be conducted. Participants will be assigned to either the Inlife social support intervention or a waiting-list control group. After 16 weeks, the control group will obtain access to the Inlife environment. Data will be collected at baseline (T0) and at 8-week (T1), 16-week (T2) and 42-week follow up (T3). The 16-week follow-up assessment (T2) is the primary endpoint to evaluate the results on the primary and secondary outcomes, measured by self-reported questionnaires. The primary outcomes include feelings of caregiver competence and perceived social support. The secondary outcomes include received support, feelings of loneliness, psychological complaints (e.g., anxiety, stress), and quality of life. A process evaluation, including semi-structured interviews, will be conducted to examine the internal and external validity of the intervention. DISCUSSION: Using a mixed method design, our study will provide valuable insights into the usability, effectiveness, and factors related to implementation of the Inlife intervention. Our study results will indicate whether Inlife could be a valuable social support resource in future routine dementia care. TRIAL REGISTRATION: Dutch trial register, NTR6131 . Registered on 20 October 2016. PMID- 28851408 TI - Knowledge of obstetric danger signs among recently-delivered women in Chamwino district, Tanzania: a cross-sectional study. AB - BACKGROUND: Low knowledge of danger signs has been shown to delay seeking obstetric care which leads to high maternal mortality and morbidity worldwide. In Tanzania about half of pregnant women are informed about obstetric danger signs during antenatal care, but the proportion of those who have full knowledge of these obstetric danger signs is not known. This study assessed the knowledge of obstetric danger signs and its associated factors among recently-delivered women in Chamwino District, Tanzania. METHODS: A community-based cross-sectional study was conducted in January 2014 in Chamwino District, Tanzania. A woman was considered knowledgeable if she spontaneously mentioned at least five danger signs in any of the three phases of childbirth (pregnancy, childbirth and postpartum) with at least one in each phase. Multistage cluster sampling was used to recruit study participants. Descriptive and bivariate analyses were conducted. Multivariable logistic regression analyses were performed to control for confounding and other important covariates. RESULTS: A total of 428 women were interviewed. The median age (IQR) was 26.5 (22-33) years. Only 25.2% of respondents were knowledgeable about obstetric danger signs during pregnancy, childbirth/labour and postpartum. Significant explanatory variables of being knowledgeable about obstetric danger signs were found to be maternal education (AOR = 1.96; 95% CI: 1.01, 3.82), maternal occupation (AOR = 2.23; 95% CI; 1.10, 4.52), spouse occupation (AOR = 2.10; 95% CI: 1.02, 4.32) and counseling on danger signs (AOR = 3.42; 95% CI: 1.36, 8.62) after controlling for the clustering effect, confounding and important covariates. CONCLUSION: A low proportion of women was found to be knowledgeable about obstetric danger signs in Chamwino district. Therefore, we recommend the Ministry of Health to design and distribute the maternal health booklets that highlight the obstetric danger signs, and encourage antenatal care providers and community health workers to provide frequent health education about these danger signs for every pregnant woman in order to increase their level of knowledge about obstetric danger signs. PMID- 28851407 TI - REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): study protocol for a pilot randomised controlled trial. AB - BACKGROUND: Guidelines recommend an initial intravenous (IV) fluid bolus of 30 ml/kg isotonic crystalloid for patients with sepsis and hypotension. However, there is a lack of evidence from clinical trials to support this. Accumulating observational data suggest harm associated with the injudicious use of fluids in sepsis. There is currently equipoise regarding liberal or restricted fluid-volume resuscitation as first-line treatment for sepsis-related hypotension. A randomised trial comparing these two approaches is, therefore, justified. METHODS/DESIGN: The REstricted Fluid REsuscitation in Sepsis-associated Hypotension trial (REFRESH) is a multicentre, open-label, randomised, phase II clinical feasibility trial. Participants will be patients presenting to the emergency departments of Australian metropolitan hospitals with suspected sepsis and a systolic blood pressure of < 100 mmHg, persisting after a 1000-ml fluid bolus with isotonic crystalloid. Participants will be randomised to either a second 1000-ml fluid bolus (standard care) or maintenance rate fluid only, with the early commencement of a vasopressor infusion to maintain a mean arterial pressure of > 65 mmHg, if required (restricted fluid). All will receive further protocolised fluid boluses (500 ml or 250 ml, respectively), if required during the 6-h study period. The primary outcome measure is total volume administered in the first 6 h. Secondary outcomes include fluid volume at 24 h, organ support 'free days' to day 28, 90-day mortality, and a range of feasibility and process of-care measures. Participants will also undergo serial measurement, over the first 24 h, of biomarkers of inflammation, endothelial cell activation and glycocalyx degradation for comparison between the groups. DISCUSSION: This is the first randomised trial examining fluid volume for initial resuscitation in septic shock in an industrialised country. A pragmatic, open-label design will establish the feasibility of undertaking a large, international, multicentre trial with sufficient power to assess clinical outcomes. The embedded biomarker study aims to provide mechanistic plausibility for a larger trial by defining the effects of fluid volume on markers of systemic inflammation and the vascular endothelium. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry, ID: ACTRN12616000006448. Registered on 12 January 2016. PMID- 28851409 TI - Mobile phones in cryptogenic strOke patients Bringing sIngle Lead ECGs for Atrial Fibrillation detection (MOBILE-AF): study protocol for a randomised controlled trial. AB - BACKGROUND: Recently published randomised clinical trials indicate that prolonged electrocardiom (ECG) monitoring might enhance the detection of paroxysmal atrial fibrillation (AF) in cryptogenic stroke or transient ischaemic attack (TIA) patients. A device that might be suitable for prolonged ECG monitoring is a smartphone-compatible ECG device (Kardia Mobile, Alivecor, San Francisco, CA, USA) that allows the patient to record a single-lead ECG without the presence of trained health care staff. The MOBILE-AF trial will investigate the effectiveness of the ECG device for AF detection in patients with cryptogenic stroke or TIA. In this paper, the rationale and design of the MOBILE-AF trial is presented. METHODS: For this international, multicentre trial, 200 patients with cryptogenic stroke or TIA will be randomised. One hundred patients will receive the ECG device and will be asked to record their ECG twice daily during a period of 1 year. One hundred patients will receive a 7-day Holter monitor. DISCUSSION: The primary outcome of this study is the percentage of patients in which AF is detected in the first year after the index ischaemic stroke or TIA. Secondary outcomes include markers for AF prediction, orally administered anticoagulation therapy changes, as well as the incidence of recurrent stroke and major bleeds. First results can be expected in mid-2019. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02507986 . Registered on 15 July 2015. PMID- 28851410 TI - The influence of socioeconomic factors on choice of infant male circumcision provider in rural Ghana; a community level population based study. AB - BACKGROUND: The influence of socio-economic determinants on choice of infant male circumcision provider is not known in areas with high population coverage such as rural Africa. The overall aim of this study was to determine the key socio economic factors which influence the choice of infant male circumcision provider in rural Ghana. METHODS: The study investigated the effect of family income, distance to health facility, and cost of the circumcision on choice of infant male circumcision provider in rural Ghana. Data from 2847 circumcised infant males aged under 12 weeks and their families were analysed in a population-based cross-sectional study conducted from May to December 2012 in rural Ghana. Multivariable logistic regression models were adjusted for income status, distance to health facility, cost of circumcision, religion, maternal education, and maternal age. RESULTS: Infants from the lowest income households (325, 84.0%) were more likely to receive circumcision from an informal provider compared to infants from the highest income households (260, 42.4%) even after adjusting for religious affiliation (adjusted odds ratio [aOR] 4.42, 95% CI 3.12-6.27 p = <0.001). There appeared to be a dose response with increasing risk of receiving a circumcision from an informal provider as distance to a health facility increased (aOR 1.25, 95 CI 1.30-1.38 P = <0.001). Only 9.0% (34) of families in the lowest socio-economic quintile received free circumcision services compared to 27.9% (171) of the highest income families. CONCLUSIONS: The Government of Ghana and Non-Government Organisations should consider additional support to poor families so they can access high quality free infant male circumcision in rural Ghana. PMID- 28851411 TI - Tissue-based associations of mammographic breast density with breast stem cell markers. AB - BACKGROUND: Mammographic breast density is a well-established, strong breast cancer risk factor but the biology underlying this association remains unclear. Breast density may reflect underlying alterations in the size and activity of the breast stem cell pool. We examined, for the first time, associations of CD44, CD24, and aldehyde dehydrogenase family 1 member A1 (ALDH1A1) breast stem cell markers with breast density. METHODS: We included in this study 64 asymptomatic healthy women who previously volunteered for a unique biopsy study of normal breast tissue at the Mayo Clinic (2006-2008). Mammographically identified dense and non-dense areas were confirmed/localized by ultrasound and biopsied. Immunohistochemical analysis of the markers was performed according to a standard protocol and the staining was assessed by a single blinded pathologist. In core biopsy samples retrieved from areas of high vs. low density within the same woman, we compared staining extent and an expression score (the product of staining intensity and extent), using the signed rank test. All tests of statistical significance were two-sided. RESULTS: A total of 64, 28, and 10 women were available for CD44, CD24, and ALDH1A1 staining, respectively. For all three markers, we found higher levels of staining extent in dense as compared to non dense tissue, though for CD24 and ALDH1A1 the difference did not reach statistical significance (CD44, 6.3% vs. 2.0%, p < 0.001; CD24, 8.0% vs. 5.6%, p = 0.10; and ALDH1A1, 0.5% vs. 0.3%, p = 0.12). The expression score for CD44 was significantly greater in dense as compared to non-dense tissue (9.8 vs.3.0, p < 0.001). CONCLUSIONS: Our findings suggest an increased presence and/or activity of stem cells in dense as compared to non-dense breast tissue. PMID- 28851412 TI - Influence of motor skills training on children's development evaluated in the Motor skills in PreSchool (MiPS) study-DK: study protocol for a randomized controlled trial, nested in a cohort study. AB - BACKGROUND: Good motor skills are considered important for children's physical, social, and psychological development, but the relationship is still poorly understood. Preschool age seems to be decisive for the development of motor skills and probably the most promising time-window in relation to preventive strategies based on improved motor skills. This research program has four overall aims: (1) investigation of the effect of a structured program aimed at improving motor skills in 3-6-year-old children on current and future motor skills, health, cognition, and wellbeing; (2) establish reference data on motor skills in 3-6 year-olds; (3) description of early development of musculoskeletal problems; and (4) establishment of a population-based cohort of 3-6-year-olds. METHODS: Over a four-year period, all preschools in a Danish municipality, Svendborg, will implement a new program aimed at optimizing children's motor skills. By introducing the program into a subset of the preschools at onset and comparing these children to another subset (control) that will not receive the intervention the first three years, it is possible to document a potential effect of the intervention. At the same time, a cohort will be established including all children attending preschools in the municipality with extensive baseline data collection: gross and fine motor skills; movement patterns; musculoskeletal complaints; physical activity; anthropometry; general wellbeing; cognitive abilities; language status; medical history; demographic background; and more. The children are aged 3-6 years at baseline. A total of 1461 children have been invited into the cohort, 368 to the intervention arm and 359 to the control arm. Follow-up time for the trial is 2.5 years. The cohort is planned to run at least until the children leave school at age 15-16 years. Longer follow-up will depend on future funding. DISCUSSION: If the results of the trial are positive, the intervention can be implemented in other similar settings with reasonable ease and at a relatively low initial cost. This is due to the extensive end-user involvement, the broad population base, and the pragmatic nature of the intervention. The cohort will provide important information about the influence of early motor skills on children's development across many domains and the potential interactions between these domains. TRIAL REGISTRATION: ISRCTN registry, ISRCTN23701994 . Registered on 13 October 2016. PMID- 28851413 TI - A large cluster randomized trial of outcome-based pathways to improve home-based wound care. AB - BACKGROUND: Although not always recognized as a pressing health care problem, wounds are a common, complex and costly condition. The burden of treating wounds is growing rapidly due to increasing health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity worldwide. The Integrated Client Care (ICC) Project was a multi-year initiative to develop and test a new, integrated model of wound care within the home care sector in Ontario, Canada to improve health outcomes for patients and decrease system costs. METHODS: Cluster randomized trial, with allocation of intervention randomized at the cluster level (14 home care centers) and analysis of outcomes based on individual-level data (patients). Primary analysis was an intention-to-treat (ITT) analysis. Two wound types, diabetic foot ulcers and pilonidal sinus, were selected as tracer conditions to assess the impact of the intervention on two different patient populations. Time to successful discharge from home care was analyzed using multivariable Cox proportional hazards regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: A total of 12,063 diabetic foot ulcer patients and 1954 pilonidal sinus patient records were available for analysis. No appreciable differences were observed between patients in the control and intervention arms for either of the primary or secondary analyses in either condition group. In the diabetic foot ulcer group, 72.7% patients in the control arm and 73.6% patients in the intervention arm were discharged in the follow-up period (HR 1.05; 95% CI 0.94 to 1.17). In the pilonidal sinus group, 91.0% patients in the control arm and 89.0% patients in the intervention arm were discharged in the follow-up period (HR 0.96; 95% CI 0.82 to 1.12). CONCLUSION: As implemented, the ICC intervention was not effective, most likely due to failure of implementation, and is, therefore, not ready for widespread implementation in Ontario. Significant work remains to be done to correct the implementation process so that the concept of outcome-based health care can be properly evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01573832 . Registered on 12 January 2012. PMID- 28851414 TI - Density-dependent sex ratio and sex-specific preference for host traits in parasitic bat flies. AB - BACKGROUND: Deviation of sex ratios from unity in wild animal populations has recently been demonstrated to be far more prevalent than previously thought. Ectoparasites are prominent examples of this bias, given that their sex ratios vary from strongly female- to strongly male-biased both among hosts and at the metapopulation level. To date our knowledge is very limited on how and why these biased sex ratios develop. It was suggested that sex ratio and sex-specific aggregation of ectoparasites might be shaped by the ecology, behaviour and physiology of both hosts and their parasites. Here we investigate a highly specialised, hematophagous bat fly species with strong potential to move between hosts, arguably limited inbreeding effects, off-host developmental stages and extended parental care. RESULTS: We collected a total of 796 Nycteribia kolenatii bat flies from 147 individual bats using fumigation and subsequently determined their sex. We report a balanced sex ratio at the metapopulation level and a highly variable sex ratio among infrapopulations ranging from 100% male to 100% female. We show that infrapopulation sex ratio is not random and is highly correlated with infrapopulation size. Sex ratio is highly male biased in small and highly female biased in large infrapopulations. We show that this pattern is most probably the result of sex-specific preference in bat flies for host traits, most likely combined with a higher mobility of males. We demonstrate that female bat flies exert a strong preference for high host body condition and female hosts, while the distribution of males is more even. CONCLUSIONS: Our results suggest that locally biased sex ratios can develop due to sex-specific habitat preference of parasites. Moreover, it is apparent that the sex of both hosts and parasites need to be accounted for when a better understanding of host-parasite systems is targeted. PMID- 28851415 TI - Association of pre-chemotherapy peripheral blood pro-inflammatory and coagulation factors with reduced relative dose intensity in women with breast cancer. AB - BACKGROUND: Chemotherapy decreases the risk of relapse and mortality in early stage breast cancer (BC), but it comes with the risk of toxicity. Chemotherapy efficacy depends on relative dose intensity (RDI), and an RDI < 85% is associated with worse overall survival. The pro-inflammatory (interleukin (IL)-6, C-reactive protein (CRP)) and coagulation factors (D-dimer) serve as biomarkers of aging. The purpose of this study is to determine if these biomarkers are associated with reduced RDI in women with stage I-III BC. METHODS: This study enrolled women with stage I-III BC. Prior to adjuvant or neoadjuvant chemotherapy, peripheral blood was collected for biomarker measurement. Dose reductions and delays were captured and utilized to calculate the RDI delivered. Univariate and multivariate analyses were performed to describe the association between pre-chemotherapy IL-6, CRP, and D-dimer levels and an RDI < 85%, controlling for relevant tumor and patient factors (age, stage, receptor status, chemotherapy regimen, and pre-chemotherapy physical function and comorbidity). RESULTS: A total of 159 patients (mean age 58 years, range 30-81, SD 11.3) with stage I-III BC were enrolled. An RDI < 85% occurred in 22.6% (N = 36) of patients and was associated with higher pre chemotherapy IL-6 (OR 1.14, 95% CI 1.04-1.25; p = 0.006) and D-dimer (OR 2.32, 95% CI 1.27-4.24; p = 0.006) levels, increased age (p = 0.001), increased number of comorbidities (p = 0.01), and decreased physical function by the Medical Outcomes Survey Activities of Daily Living (ADL) Scale (p = 0.009) in univariate analysis. A multivariate model, including two biomarkers (IL-6 and D-dimer), age, ADL, BC stage, and chemotherapy regimen, demonstrated a significant association between the increased biomarkers and reduced RDI < 85% (OR 2.54; p = 0.04). CONCLUSIONS: Increased pre-chemotherapy biomarkers of aging (IL-6 and D-dimer) are associated with reduced RDI (<85%). Future studies are underway to validate these findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01030250 . Registered on 3 November 2016. PMID- 28851416 TI - Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test. AB - BACKGROUND: A 31-gene expression profile (GEP) test that provides risk classification of cutaneous melanoma (CM) patients has been validated in several retrospective studies. The objective of the reported study was a prospective evaluation of the GEP performance in patients enrolled in two clinical registries. METHODS: Three-hundred twenty two CM patients enrolled in the EXPAND (NCT02355587) and INTEGRATE (NCT02355574) registries met the criteria of age >= 16 years, successful GEP result and >=1 follow-up visit for inclusion in this interim analysis. Primary endpoints were recurrence-free (RFS), distant metastasis-free (DMFS), and overall survival (OS). RESULTS: Median follow-up was 1.5 years for event-free patients. Median age for subjects was 58 years (range 18 87) and median Breslow thickness was 1.2 mm (range 0.2-12.0). Eighty-eight percent (282/322) of cases had stage I/II disease and 74% (237/322) had a SLN biopsy. Seventy-seven percent (248/322) had class 1 molecular profiles. 1.5-year RFS, DMFS, and OS rates were 97 vs. 77%, 99 vs. 89%, and 99 vs. 92% for class 1 vs. class 2, respectively (p < 0.0001 for each). Multivariate Cox regression showed Breslow thickness, mitotic rate, and GEP class to significantly predict recurrence (p < 0.01), while tumor thickness was the only significant predictor of distant metastasis and overall survival in this interim analysis. CONCLUSIONS: Interim analysis of patient outcomes from a combined prospective cohort supports the 31-gene GEP's ability to stratify early-stage CM patients into two groups with significantly different metastatic risk. RFS outcomes in this real-world cohort are consistent with previously published analyses with retrospective specimens. GEP testing complements current clinicopathologic features and increases identification of high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02355574 and NCT02355587. PMID- 28851418 TI - Survey of integrative lumbar spinal stenosis treatment in Korean medicine doctors: preliminary data for clinical practice guidelines. AB - BACKGROUND: Considering that large variations exist amongst practitioners in lumbar disorder management and the significant costs that lumbar disorders incur, determining clinical practice patterns to provide preliminary data for standardization should be given higher priority. Lumbar spinal stenosis (LSS) is commonly treated using integrative non-surgical methods by Korean medicine doctors (KMDs) in Korea, and this is the first study to assess current Korean medicine practice trends for LSS. METHODS: A survey on KMD diagnosis, treatment, prognosis and decision-making in LSS treatment was developed in a 3-step procedure of preliminary drafting, revision based on extramural expert opinion, and final editing. The survey was conducted at the internal conference of a spine specialty Korean medicine hospital on January 25th, 2015. RESULTS: The response rate was high at 79.19% (n = 118/149). Participants replied that they treated 7.3 +/- 6.8 LSS patients/day using a multimodal treatment method consisting of acupuncture, pharmacopuncture, herbal medicine, Chuna manipulation, and electroacupuncture. Acupuncture mainly used Ashi points and MSAT, and pharmacopuncture mainly Shinbaro solution. The most frequently prescribed herbal medicine was Chungpa-jun, and the most commonly applied Chuna techniques were sidelying lumbar extension dysfunction correction technique, and prone lumbosacral joint distraction method. Radiological findings were mainly referred to for diagnosis, and clinical symptoms, age, radiological findings, and medical history were regarded to be important for prognosis. Participants replied that 7.8 +/- 3.3 weeks were required for 50% reduction in pain, and 16.1 +/- 7.7 weeks for 80% reduction. CONCLUSIONS: These results suggest that KMDs in Korea combine a conventional approach to LSS and a Korean medicine approach to low back pain for integration of empirical- and evidence-based diagnosis and treatment. The findings may contribute in bridging the divide between evidence and clinical practice guidelines for Korean medicine treatment of LSS and real-world clinical practice in future research. PMID- 28851419 TI - Cesarean sections in a secondary level care hospital of Cameroon: an analysis of their six-year trends and adverse neonatal outcomes. AB - BACKGROUND: The objectives of this study were to determine the trends of CS in a regional hospital in Cameroon and to explore its association with adverse neonatal outcomes. METHODS: The study was conducted in the Buea Regional Hospital (BRH), Cameroon. A 6-year retrospective records analysis was used to determine the trends in rates of CS and neonatal adverse outcomes. In a 3-month prospective phase, indications of CS were identified. RESULTS: Of a total of 4941 records reviewed from the year 2007 to 2012, the overall CS rate was 20.4%. The rates increased from 17.1% in 2007 to 20.9% in 2012, with a peak of 22.7% in 2011, but this time-trend was not significant (p-trend =0.06). Three of the 25 cases of CS (12%) in the prospective phase were done at the request of mothers. The odds of having a low first minute APGAR (APGAR <7) in neonates born from CS were higher than in neonates born from a normal delivery (OR = 6.6 and 95% CI 5.7-7.7; p < 0.01). CONCLUSION: One out of every five women give birth through a CS in the BRH. This rate of CS is relatively high for a suburban population in a developing country. Strategies to reduce these rates should be investigated and instituted in the BRH to reduce health expenditures. PMID- 28851417 TI - Development of conventional and real-time multiplex PCR-based assays for estimation of natural infection rates and Trypanosoma cruzi load in triatomine vectors. AB - BACKGROUND: Chagas disease is a complex anthropozoonosis with distinct domestic and sylvatic mammal species acting as potential reservoirs. The diversity of vector species and their habitats are among the factors that hinder the control of the disease. Control programs periodically monitor the prevalence of T. cruzi infection in insect bugs through microscopical observation of diluted feces. However, microscopy presents limited sensitivity in samples with low parasite numbers, difficulties in examining all evolutionary stages of the insect and may in turn be limited to differentiate T. cruzi from other morphologically similar trypanosomatids. Here, we report two highly sensitive and accurate methodologies to infer T. cruzi infection rates and to quantify parasite load in the gut of field-collected triatomines. METHODS: Triatomines were manually collected in the period 2011-2012 and 2014-2015, in domestic, peridomestic or sylvatic habitats in rural areas of 26 municipalities, encompassing three distinct Brazilian biomes: Caatinga, Cerrado and Atlantic Rainforest. Following morphological and taxonomical identification, the search for flagellated protozoa was performed by optical microscopy. A conventional PCR targeting T. cruzi kDNA and a TaqMan qPCR directed to the parasite nuclear satellite DNA (SAT) were developed, both in multiplex, with the triatomine 12S subunit ribosomal RNA gene, used as internal amplification control. Both methods were used for detection (kDNA-PCR) and parasite load quantification (SAT-DNA-qPCR), to investigate T. cruzi infection in captured triatomines. RESULTS: The combined methods were assayed on a panel of 205 field-collected triatomine samples. Diagnostic analysis revealed 21% positivity for the kDNA-PCR, whereas microscopic examination enabled identification of T. cruzi in only 7.0% of the PCR-positive samples. Negative PCR results were confirmed by the absence of T. cruzi flagellates using microscopy. Caatinga biome yielded the highest T. cruzi infection rate (60%), followed by the Atlantic Rainforest and Cerrado with 7.1 and 6.1%, respectively. In addition, a wide range distribution of parasite load, varying from 8.05 * 10-2 to 6.31 * 1010 was observed with a median of 2.29 * 103 T. cruzi/intestine units. When parasite load was analyzed by triatomine species, a significantly higher median was found for Panstrongylus lutzi in comparison with Triatoma brasiliensis. CONCLUSIONS: Our results demonstrate highly sensitive PCR-based methodologies to monitor T. cruzi infection in triatomines. In addition, the qPCR assay offers the possibility of further evaluation parasite load, as a promising biomarker of the vectorial capacity of triatomines in Chagas disease endemic areas. PMID- 28851420 TI - Randomized study exploring the combination of radiotherapy with two types of acupuncture treatment (ROSETTA): study protocol for a randomized controlled trial. AB - BACKGROUND: Adverse effects such as fatigue, pain, erythema, nausea and vomiting are commonly known in patients undergoing irradiation (RT) alone or in combination with chemotherapy (RCHT). Patients suffering from these symptoms are limited in their daily life and their quality of life (QOL) is often reduced. As addressed in several trials, acupuncture can cause amelioration of these specific disorders. Especially for pain symptoms, several groups have shown efficacy of acupuncture. To what extent the difference between traditional acupuncture (verum acupuncture) and false acupuncture (sham acupuncture) is in reducing side effects and improvement of QOL is not clear. METHODS/DESIGN: ROSETTA is a prospective randomized phase II trial (version 1.0) to examine the efficacy of traditional acupuncture in patients with RT-related side effects. In the experimental (verum) arm (n = 37) an experienced acupuncture-trained person will treat dedicated acupuncture points. In the control (sham) arm (n = 37) sham acupuncture will be performed to provide a blinded comparison of results. DISCUSSION: This is the first randomized prospective trial to evaluate the effect of traditional acupuncture on RT-related side effects such as fatigue and QOL. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02674646 . Registered on 8 December 2015. PMID- 28851421 TI - Engaging and staying engaged: a phenomenological study of barriers to equitable access to mental healthcare for people with severe mental disorders in a rural African setting. AB - BACKGROUND: In low-and middle-income countries, integration of mental health into primary care is recommended to reduce the treatment gap. In this study we explored barriers to initial and ongoing engagement of people with severe mental disorders (SMD) in rural Ethiopia after implementing integrated primary mental healthcare services. METHODS: A qualitative approach was employed. In-depth interviews were conducted with 50 key informants: service users/caregivers engaged with care (n = 17), non-engagers and their caregivers (n = 10), those who had initiated treatment but disengaged and their caregivers (n = 12) and primary healthcare professionals (n = 11). Two focus group discussions were conducted with community health workers (10 per group). Thematic analysis was used. RESULTS: Most respondents reported improved access to care, usually equated with medication, and were motivated to remain engaged due to experienced benefits of care. However, four main barriers to engagement emerged. (1) Poverty: resulting in inability to pay for medication and undermining vital social support affected engagement for all respondents. (2) Unreliable medication supplies and lack of second line options for inadequate response or intolerable side-effects. (3) The long-term nature of the illness: expectations of cure, stigma of chronic illness, low awareness about the illness and treatment and declining social support over time. (4) The nature of SMD: difficulty conveying the person when acutely disturbed and no flexibility for proactive outreach or legal frameworks to provide care when patients lacked capacity. In those who never engaged, geographical inaccessibility was an important barrier. Alternative cultural explanations for illness were only mentioned as a barrier only by two of the respondents. CONCLUSION: Economic interventions may be needed to support ongoing engagement in care for people with SMD. Systems of care for chronic illness need to be strengthened in combination with legal frameworks. Expanded options for affordable and effective medication and psychosocial interventions are required for person-centred care. PMID- 28851422 TI - Are exosomes the vehicle for protein aggregate propagation in neurodegenerative diseases? AB - Abnormal protein aggregation has been implicated in neurodegenerative processes in human neurological disorders, such as Alzheimer's disease and Parkinson's disease. Recently, studies have established a novel concept that protein aggregates are transmitted among neuronal cells. By extension, such interneuronal aggregate transmission has been hypothesized to be the underlying mechanism for the pathological and clinical disease progression. However, the precise mechanism of the interneuronal aggregate transmission remains ill-defined. Recent reports have suggested that exosomes, a specific group of extracellular vesicles that are involved in intercellular transfer of cellular macromolecules such as proteins and RNAs, could play an important role in the aggregate transmission among neurons. Here, we review various types of extracellular vesicles and critically evaluate the evidence supporting the role of exosomes in interneuronal aggregate transmission and neurodegeneration. We also discuss the competing mechanisms other than the exosome-mediated transmission. By doing so, we aim to assess the current state of knowledge on the mechanism of interneuronal aggregate transmission and suggest the future directions of research towards understanding the mechanism. PMID- 28851424 TI - Sand fly (Diptera, Psychodidae, Phlebotominae) abundance and diversity in areas affected by the Sao Francisco River transposition project in Ceara State, Brazil. AB - BACKGROUND: Entomological surveillance of sand fly vectors was carried out to support leishmaniasis prevention and control measures in areas affected by the Sao Francisco River Transposition Project. METHODS: Sand flies were collected monthly between May 2011 and December 2014 in seven municipalities: Missao Velha, Brejo Santo, Lavras da Mangabeira, Iguatu, Mauriti, Jaguaribe and Jaguaretama, in dwellings, peridomicile and forest areas for three consecutive days, for a period of 12 h each day (18:00 to 06:00 h). Differences in species composition between sites were tested with Shannon's diversity index, the similarity between habitats was estimated by the Sorensen's qualitative similarity index and, for the most abundant species in each municipality, a standardized index of species abundance was applied. The influence of climatic factors on sand fly population densities was analyzed using Spearman's correlation coefficients. RESULTS: A total of 214,213 sand fly specimens belonging to 18 species were captured. The most abundant species in all municipalities was Lutzomyia longipalpis (Lutz & Neiva, 1912). The municipalities of Mauriti and Missao Velha stand out in terms of high species richness, with the latter exhibiting the greatest diversity. The number of sand flies in the Iguatu, Jaguaribe and Jaguaretama municipality was higher during the rainy months, whereas the populations declined in the drier months; the sand fly population density in other municipalities (Missao Velha, Brejo Santo, Lavras de Mangabeira and Mauriti) showed negative correlation with rainfall. CONCLUSIONS: This study confirms the presence of several Leishmania spp. vectors in the seven municipalities affected by the Sao Francisco River Transposition Project, with Lu. longipalpis being the most abundant species at all study sites. Vector populations in these municipalities should be monitored, ultimately to assess the associations between environmental changes and sand fly population dynamics and leishmaniasis transmission risk. PMID- 28851423 TI - The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. AB - BACKGROUND: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. METHODS: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic complete response in the V-C and control arms alone using Fisher's exact test, and the relative performance between arms (biomarker * treatment interaction, likelihood ratio p < 0.05) using a logistic model and adjusting for hormone receptor status (HR). RESULTS: We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p = 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p = 0.023) after correcting for HR. CONCLUSIONS: A genomic based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone. TRIAL REGISTRATION: I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379 . PMID- 28851425 TI - Direct evidence for an expanded circulation area of the recently identified Balkan virus (Sandfly fever Naples virus species) in several countries of the Balkan archipelago. AB - BACKGROUND: Recently, Balkan virus (BALKV, family Phenuiviridae, genus Phlebovirus) was discovered in sand flies collected in Albania and genetically characterised as a member of the Sandfly fever Naples species complex. To gain knowledge concerning the geographical area where exposure to BALKV exists, entomological surveys were conducted in 2014 and 2015, in Croatia, Bosnia and Herzegovina (BH), Kosovo, Republic of Macedonia and Serbia. RESULTS: A total of 2830 sand flies were trapped during 2014 and 2015 campaigns, and organised as 263 pools. BALKV RNA was detected in four pools from Croatia and in one pool from BH. Phylogenetic relationships were examined using sequences in the S and L RNA segments. Study of the diversity between BALKV sequences from Albania, Croatia and BH showed that Albanian sequences were the most divergent (9-11% [NP]) from the others and that Croatian and BH sequences were grouped (0.9-5.4% [NP]; 0.7-5% [L]). The sand fly infection rate of BALKV was 0.26% in BH and 0.27% in Croatia. Identification of the species content of pools using cox1 and cytb partial regions showed that the five BALKV positive pools contained Phlebotomus neglectus DNA; in four pools, P neglectus was the unique species, whereas P. tobbi DNA was also detected in one pool. CONCLUSIONS: We report here (i) the first direct evidence that the Balkan virus initially described in coastal Albania has a much wider dissemination area than originally believed, (ii) two real-time RT-PCR assays that may be useful for further screening of patients presenting with fever of unknown origin that may be caused by Balkan virus infection, (iii) entomological results suggesting that Balkan virus is likely transmitted by Phlebotomus neglectus, and possibly other sand fly species of the subgenus Larroussius. So far, BALKV has been detected only in sand flies. Whether BALKV can cause disease in humans is unknown and remains to be investigated. PMID- 28851426 TI - Galleria mellonella (greater wax moth) larvae as a model for antibiotic susceptibility testing and acute toxicity trials. AB - BACKGROUND: Infectivity trials and toxicity testing in rodents are important prerequisites to the use of compounds in man. However, trials in rats and mice are expensive and there are ethical considerations. Galleria mellonella (greater wax moth) larvae are a potential alternative. We have assessed the use of these insects in infectivity trials and toxicity testing. FINDINGS: Using four bacterial species (two Gram-negative and two Gram-positive) we have assessed the efficacy of four antibiotics against infections in Galleria and compared the antibiotic susceptibility with that in humans. In general, we find a good correlation. Similarly, we have assessed 11 compounds (initially tested blind) for their toxicity in Galleria and compared this with toxicity trials in mice and rats. Again we found a good correlation between toxicity in Galleria and that in rodents. CONCLUSION: We have found, in our hands, that G. mellonella larvae can be used in infectivity trials and toxicity testing, and that these assays represent an inexpensive and readily executable alternative to testing in rodents. PMID- 28851427 TI - The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. AB - Mutations in the telomerase reverse transcriptase gene promoter (TERTp) are common in glioblastomas (GBMs) and oligodendrogliomas (ODGs), and therefore, have a key role in tumorigenesis and may be of prognostic value. However, the extent of their prognostic importance in various gliomas is controversial. We studied 168 patients separated into five groups: Group 1: 65 patients with ODG carrying an IDH1 or IDH2 mutation (IDH-mutant) and 1p/19q-codeletion, Group 2: 23 patients with anaplastic astrocytoma (AA), IDH-mutant, Group 3: 13 patients with GBM, IDH mutant, Group 4: 15 patients with AA, IDH-wildtype (WT), and Group 5: 52 patients with GBM, IDH-WT. TERTp mutations were found in 96.9%, 4.4%, 76.9%, 20.0%, and 84.6% of patients in Groups 1, 2, 3, 4, and 5, respectively. The R132H mutation in IDH1 was found in 60.5% (23/38) of patients in the AA cohort (Groups 2 and 4) and 20.0% (13/65) of patients from our GBM cohort (Groups 3 and 5), whereas all patients with ODG (Group 1) had a mutation either in IDH1 (n = 62) or IDH2 (n = 3). Using Kaplan Meier survival analysis, we found that the TERTp mutation was correlated with poor overall survival (OS) in Groups 2 and 4 combined (P = 0.001) and in Group 4 (P = 0.113), and in multivariate analysis, the TERTp mutant group was associated with significantly poor survival in Group 5 (P = 0.045). However, IDH mutation, MGMT methylation, and younger patient age (<55 years old) were significantly correlated with favorable OS (all P < 0.05) in our cohort of astrocytic and ODGs. In patients with ODG (Group 1), mutant IDH and TERTp did not have prognostic value because these mutations were universally present. Based on the revised 2016 WHO classification of gliomas, we found that TERTp mutation was frequently present in patients with GBM or ODG and because it was strongly correlated with poor survival outcome in patients with IDH-WT GBM in multivariate analysis, it may be of prognostic value in this subgroup of patients with gliomas. PMID- 28851428 TI - Social and economic value of Portuguese community pharmacies in health care. AB - BACKGROUND: Community pharmacies are major contributors to health care systems across the world. Several studies have been conducted to evaluate community pharmacies services in health care. The purpose of this study was to estimate the social and economic benefits of current and potential future community pharmacies services provided by pharmacists in health care in Portugal. METHODS: The social and economic value of community pharmacies services was estimated through a decision-model. Model inputs included effectiveness data, quality of life (QoL) and health resource consumption, obtained though literature review and adapted to Portuguese reality by an expert panel. The estimated economic value was the result of non-remunerated pharmaceutical services plus health resource consumption potentially avoided. Social and economic value of community pharmacies services derives from the comparison of two scenarios: "with service" versus "without service". RESULTS: It is estimated that current community pharmacies services in Portugal provide a gain in QoL of 8.3% and an economic value of 879.6 million euros (M?), including 342.1 M? in non-remunerated pharmaceutical services and 448.1 M? in avoided expense with health resource consumption. Potential future community pharmacies services may provide an additional increase of 6.9% in QoL and be associated with an economic value of 144.8 M?: 120.3 M? in non-remunerated services and 24.5 M? in potential savings with health resource consumption. CONCLUSIONS: Community pharmacies services provide considerable benefit in QoL and economic value. An increase range of services including a greater integration in primary and secondary care, among other transversal services, may add further social and economic value to the society. PMID- 28851429 TI - Development of prediction equations for estimating appendicular skeletal muscle mass in Japanese men and women. AB - BACKGROUND: This study aimed to develop and cross-validate prediction equations for estimating appendicular skeletal muscle mass (ASM) and to examine the relationship between sarcopenia defined by the prediction equations and risk factors for cardiovascular diseases (CVD) or osteoporosis in Japanese men and women. METHODS: Subjects were healthy men and women aged 20-90 years, who were randomly allocated to the following two groups: the development group (D group; 257 men, 913 women) and the cross-validation group (V group; 119 men, 112 women). To develop prediction equations, stepwise multiple regression analyses were performed on data obtained from the D group, using ASM measured by dual-energy X ray absorptiometry (DXA) as a dependent variable and five easily obtainable measures (age, height, weight, waist circumference, and handgrip strength) as independent variables. RESULTS: When the prediction equations for ASM estimation were applied to the V group, a significant correlation was found between DXA measured ASM and predicted ASM in both men and women (R 2 = 0.81 and R 2 = 0.72). Our prediction equations had higher R 2 values compared to previously developed equations (R 2 = 0.75-0.59 and R 2 = 0.69-0.40) in both men and women. Moreover, sarcopenia defined by predicted ASM was related to risk factors for osteoporosis and CVD, as well as sarcopenia defined by DXA-measured ASM. CONCLUSIONS: In this study, novel prediction equations were developed and cross-validated in Japanese men and women. Our analyses validated the clinical significance of these prediction equations and showed that previously reported equations were not applicable in a Japanese population. PMID- 28851430 TI - Evolution of gender representation among Canadian OTL-HNS residents: a 27-year analysis. AB - BACKGROUND: The proportion of females enrolling into medical schools has been growing steadily. However, the representation of female residents among individual specialties has shown considerable variation. The purpose of this study was to compare the trends of gender representation in Otolaryngology - Head and Neck Surgery (OTL-HNS) residency programs with other specialty training programs in Canada. In order to contextualize these findings, a second phase of analysis examined the success rate of applicants of different genders to OTL-HNS residency programs. METHOD: Anonymized data were obtained from the Canadian Residency Matching Service (CaRMS) and from the Canadian Post-M.D. Education Registry (CAPER) from 1988 to 2014. The differences in gender growth rates were compared to other subspecialty programs of varying size. Descriptive analysis was used to examine gender representation among OTL-HNS residents across years, and to compare these trends with other specialties. Bayesian hierarchical models were fit to analyze the growth in program rates in OTL-HNS based on gender. RESULTS: CaRMS and CAPER data over a 27 year period demonstrated that OTL-HNS has doubled its female representation from 20% to 40% between 1990 and 1994 and 2010-2014. The difference in annual growth rate of female representation versus male representation in OTL-HNS over this time period was 2.7%, which was similar to other large specialty programs and surgical subspecialties. There was parity in success rates of female and male candidates ranking OTL-HNS as their first choice specialty for most years. CONCLUSIONS: Female representation in Canadian OTL-HNS residency programs is steadily increasing over the last 27 years. Large variation in female applicant acceptance rates was observed across Canadian universities, possibly attributable to differences in student body or applicant demographics. Factors influencing female medical student career selection to OTL-HNS require further study to mitigate disparities in gender representation and identify barriers to prospective female OTL-HNS applicants. PMID- 28851432 TI - Erratum to: Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p. PMID- 28851431 TI - Pesticide exposure assessed through agricultural crop proximity and risk of amyotrophic lateral sclerosis. AB - BACKGROUND: Epidemiologic studies have raised the possibility that some pesticide compounds induce the neurodegenerative disease amyotrophic lateral sclerosis (ALS), though the available evidence is not entirely consistent. METHODS: We conducted a population-based case-control study in two Italian populations to assess the extent to which residence in the vicinity of agricultural crops associated with the application of neurotoxic pesticides is a risk factor for ALS, using crop acreage in proximity to the residence as an index of exposure. RESULTS: Based on 703 cases and 2737 controls, we computed an ALS odds ratio of 0.92 (95% confidence interval 0.78-1.09) for those in proximity to agricultural land. Results were not substantially different when using alternative exposure categories or when analyzing specific crop types, with the exception of a higher risk related to exposure to citrus orchards and olive groves in Southern Italy, though based on few exposed subjects (N = 89 and 8, respectively). There was little evidence of any dose-response relation between crop proximity and ALS risk, and using long-term residence instead of current residence did not substantially change our estimates. CONCLUSIONS: Though our index of exposure is indirect and subject to considerable misclassification, our results offer little support for the hypothesis that neurotoxic pesticide exposure increases ALS risk. PMID- 28851433 TI - Systematic review of effectiveness of universal self-regulation-based interventions and their effects on distal health and social outcomes in children and adolescents: review protocol. AB - BACKGROUND: Growing evidence suggests that childhood and adolescence self regulation contributes to multiple health, educational and social outcomes. Considering the potential impact of self-regulation skills on improved life chances in conjunction with evidence suggesting that self-regulation can be modified by interventions, there is a need to identify interventions which are most effective in improving childhood and adolescence self-regulation. The present systematic review was designed to determine the effectiveness of universal interventions focused on enhancing the self-regulation of children and adolescents. As secondary outcomes, we will also examine the effectiveness of such interventions on distal health and social outcomes. METHODS: Eligible studies include randomised controlled trials (including cluster randomised trials) reporting on universal interventions designed to improve self-regulation in childhood and adolescence (age 0-19 years). The following databases will be searched for peer-reviewed publications using an iterative search strategy: Medline, PsycINFO, EMBASE, ERIC, CINAHL Plus, British Education Index, Child Development & Adolescent Studies and CENTRAL without applying language or date filters. Additionally, reference lists and citations of included studies will be searched for eligible studies. A 10% proportion of the total titles and abstracts will be randomly selected and screened independently by two reviewers (AP and DH). Results will be compared to ensure less than 5% discrepancy, followed by screening of all results by one reviewer (AP). Full-text review and data collection will be independently performed by two reviewers. Any discrepancies will be solved by mutual discussion, and if unresolved, a third reviewer (RV) will be consulted. Meta-analysis will be conducted to quantify trial effects, if the data is sufficiently homogenous to allow quantitative synthesis. Otherwise, results will be described narratively. DISCUSSION: The evidence derived from the systematic review will strengthen the evidence base to inform planning of effective interventions targeting self-regulation skills in childhood and adolescence. This will benefit policy makers, academicians, researchers, health professionals, and also, young people who will benefit from policy and interventions informed by this review. SYSTEMATIC REVIEW REGISTRATION: CRD42016047661 . PMID- 28851435 TI - First-dollar cost-sharing for skilled nursing facility care in medicare advantage plans. AB - BACKGROUND: The initial days of a Medicare-covered skilled nursing facility (SNF) stay may have no cost-sharing or daily copayments depending on beneficiaries' enrollment in traditional Medicare or Medicare Advantage. Some policymakers have advocated imposing first-dollar cost-sharing to reduce post-acute expenditures. We examined the relationship between first-dollar cost-sharing for a SNF stay and use of inpatient and SNF services. METHODS: We identified seven Medicare Advantage plans that introduced daily SNF copayments of $25-$150 in 2009 or 2010. Copays began on the first day of a SNF admission. We matched these plans to seven matched control plans that did not introduce first-dollar cost-sharing. In a difference-in-differences analysis, we compared changes in SNF and inpatient utilization for the 172,958 members of intervention and control plans. RESULTS: In intervention plans the mean annual number of SNF days per 100 continuously enrolled inpatients decreased from 768.3 to 750.6 days when cost-sharing changes took effect. Control plans experienced a concurrent increase: 721.7 to 808.1 SNF days per 100 inpatients (adjusted difference-in-differences: -87.0 days [95% CI ( 112.1,-61.9)]). In intervention plans, we observed no significant changes in the probability of any SNF service use or the number of inpatient days per hospitalized member relative to concurrent trends among control plans. CONCLUSIONS: Among several strategies Medicare Advantage plans can employ to moderate SNF use, first-dollar SNF cost-sharing may be one influential factor. TRIAL REGISTRATION: Not applicable. PMID- 28851436 TI - Postmenopausal mild hirsutism and hyperandrogenemia due to granulosa cell tumor of the ovary: a case report. AB - BACKGROUND: Among classes of ovarian tumor, granulosa cell tumors are the least common. In approximately 10% of cases of granulosa cell tumor, androgen will be secreted which will present with hirsutism and hyperandrogenemia. We describe a woman with ovarian granulosa cell tumor who presented with hirsutism. CASE PRESENTATION: A 50-year-old woman of Amhara ethnicity, para III, abortion I (induced), presented with excessive hair on her face and lower abdomen of 4 years' duration which affected her quality of life. Her menopause started 7 years ago. Her body mass index was 29.8 kg/m2. She had hair on her upper lip, chin, and lower abdomen; she had a Ferriman-Gallwey score of 10. A pelvic examination revealed that her uterus was of normal size and there was no adnexal mass. Ultrasound finding: her right ovary measured 5 * 4 cm. Her serum testosterone was 254 ng/dl; she was counseled to undergo an exploratory laparotomy but she declined. She presented to our out-patient department 10 months later with a complaint of excessive vaginal bleeding of 18 days' duration. A sonographic evaluation showed a 12 by 15 cm right adnexal cystic mass. With preoperative diagnosis of testosterone-producing sex cord-stromal tumor of the ovary, an exploratory laparotomy was performed. The laparotomy revealed a 20 by 30 cm right ovarian mass with pathology result of adult granulosa cell tumor. CONCLUSION: In postmenopausal women with new hirsutism that is severe or rapidly progressive, the possibility of an androgen-secreting tumor must be suspected and a thorough evaluation is needed before initiating treatment for idiopathic hirsutism. PMID- 28851434 TI - Effect and process evaluation of a kindergarten-based, family-involved cluster randomised controlled trial in six European countries on four- to six-year-old children's steps per day: the ToyBox-study. AB - BACKGROUND: The ToyBox-intervention is a theory- and evidence-based intervention delivered in kindergartens to improve four- to six-year-old children's energy balance-related behaviours and prevent obesity. The current study aimed to (1) examine the effect of the ToyBox-intervention on increasing European four- to six year-old children' steps per day, and (2) examine if a higher process evaluation score from teachers and parents was related to a more favourable effect on steps per day. METHODS: A sample of 2438 four- to six-year-old children (51.9% boys, mean age 4.75 +/- 0.43 years) from 6 European countries (Belgium, Bulgaria, Germany, Greece, Poland and Spain) wore a motion sensor (pedometer or accelerometer) for a minimum of two weekdays and one weekend day both at baseline and follow-up to objectively measure their steps per day. Kindergarten teachers implemented the physical activity component of the ToyBox-intervention for 6 weeks in total, with a focus on (1) environmental changes in the classroom, (2) the child performing the actual behaviour and (3) classroom activities. Children's parents received newsletters, tip cards and posters. To assess intervention effects, multilevel repeated measures analyses were conducted for the total sample and the six intervention countries separately. In addition, process evaluation questionnaires were used to calculate a total process evaluation score (with implementation and satisfaction as a part of the overall score) for teachers and parents which was then linked with the physical activity outcomes. RESULTS: No significant intervention effects on four- to six-year-old children' steps per weekday, steps per weekend day and steps per average day were found, both in the total sample and in the country-specific samples (all p > 0.05). In general, the intervention effects on steps per day were least favourable in four- to six-year-old children with a low teachers process evaluation score and most favourable in four- to six-year-old children with a high teachers process evaluation score. No differences in intervention effects were found for a low, medium or high parents' process evaluation score. CONCLUSION: The physical activity component of the ToyBox-intervention had no overall effect on four- to six-year-old children' steps per day. However, the process evaluation scores showed that kindergarten teachers that implemented the physical activity component of the ToyBox-intervention as planned and were satisfied with the physical activity component led to favourable effects on children's steps per day. Strategies to motivate, actively involve and engage the kindergarten teachers and parents/caregivers are needed to induce larger effects. PMID- 28851437 TI - Development and use of a content search strategy for retrieving studies on patients' views and preferences. AB - BACKGROUND: Identifying scientific literature addressing patients' views and preferences is complex due to the wide range of studies that can be informative and the poor indexing of this evidence. Given the lack of guidance we developed a search strategy to retrieve this type of evidence. METHODS: We assembled an initial list of terms from several sources, including the revision of the terms and indexing of topic-related studies and, methods research literature, and other relevant projects and systematic reviews. We used the relative recall approach, evaluating the capacity of the designed search strategy for retrieving studies included in relevant systematic reviews for the topic. We implemented in practice the final version of the search strategy for conducting systematic reviews and guidelines, and calculated search's precision and the number of references needed to read (NNR). RESULTS: We assembled an initial version of the search strategy, which had a relative recall of 87.4% (yield of 132/out of 151 studies). We then added some additional terms from the studies not initially identified, and re tested this improved version against the studies included in a new set of systematic reviews, reaching a relative recall of 85.8% (151/out of 176 studies, 95% CI 79.9 to 90.2). This final version of the strategy includes two sets of terms related with two domains: "Patient Preferences and Decision Making" and "Health State Utilities Values". When we used the search strategy for the development of systematic reviews and clinical guidelines we obtained low precision values (ranging from 2% to 5%), and the NNR from 20 to 50. CONCLUSIONS: This search strategy fills an important research gap in this field. It will help systematic reviewers, clinical guideline developers, and policy-makers to retrieve published research on patients' views and preferences. In turn, this will facilitate the inclusion of this critical aspect when formulating heath care decisions, including recommendations. PMID- 28851438 TI - Distribution of health care resources in Mongolia using the Gini coefficient. AB - BACKGROUND: Attaining the perfect balance of health care resources is probably impracticable; however, it is possible to achieve improvements in the distribution of these resources. In terms of the distribution of health resources, equal access to these resources would make health services available to all people. The aim of this study was to compare the distributions of health care resources in urban, suburban, and rural areas of Mongolia. METHODS: We compared urban and rural areas using the Mann-Whitney U test and further investigated the distribution equality of physicians, nurses, and hospital beds throughout Mongolia using the Gini coefficient-a common measure of distribution derived from the Lorenz curve. Two indicators were calculated: the distribution per 10 000 population and the distribution per 1000 km2 area. RESULTS: Urban and rural areas were significantly different only in the distribution of physicians per population. However, in terms of the distribution per area, there were statistical differences in physicians, nurses, and hospital beds. We also found that distributions per population unit were equal, with Gini coefficients for physicians, nurses, and hospital beds of 0.18, 0.07, and 0.06, respectively. Distributions per area unit were highly unequal, with Gini coefficients for physicians, nurses, and hospital beds of 0.74, 0.67, and 0.69, respectively. CONCLUSIONS: Although the distributions of health care resources per population were adequate for the population size, a striking difference was found in terms of the distributions per geographical area. Because of the nomadic lifestyle of rural and remote populations in Mongolia, geographical imbalances need to be taken into consideration when formulating policy, rather than simply increasing the number of health care resources. PMID- 28851439 TI - On the global CRISPR array behavior in class I systems. AB - BACKGROUND: Much effort is underway to build and upgrade databases and tools related to occurrence, diversity, and characterization of CRISPR-Cas systems. As microbial communities and their genome complements are unearthed, much emphasis has been placed on details of individual strains and model systems within the CRISPR-Cas classification, and that collection of information as a whole affords the opportunity to analyze CRISPR-Cas systems from a quantitative perspective to gain insight into distribution of CRISPR array sizes across the different classes, types and subtypes. CRISPR diversity, nomenclature, occurrence, and biological functions have generated a plethora of data that created a need to understand the size and distribution of these various systems to appreciate their features and complexity. RESULTS: By utilizing a statistical framework and visual analytic techniques, we have been able to test several hypotheses about CRISPR loci in bacterial class I systems. Quantitatively, though CRISPR loci can expand to hundreds of spacers, the mean and median sizes are 40 and 25, respectively, reflecting rather modest acquisition and/or retention overall. Histograms uncovered that CRISPR array size displayed a parametric distribution, which was confirmed by a goodness-of fit test. Mapping the frequency of CRISPR loci on a standardized chromosome plot revealed that CRISPRs have a higher probability of occurring at clustered locations along the positive or negative strand. Lastly, when multiple arrays occur in a particular system, the size of a particular CRISPR array varies with its distance from the cas operon, reflecting acquisition and expansion biases. CONCLUSIONS: This study establishes that bacterial Class I CRISPR array size tends to follow a geometric distribution; these CRISPRs are not randomly distributed along the chromosome; and the CRISPR array closest to the cas genes is typically larger than loci in trans. Overall, we provide an analytical framework to understand the features and behavior of CRISPR-Cas systems through a quantitative lens. REVIEWERS: This article was reviewed by Eugene Koonin (NIH-NCBI) and Uri Gophna (Tel Aviv University). PMID- 28851440 TI - Plk1 is essential for proper chromosome segregation during meiosis I/meiosis II transition in pig oocytes. AB - BACKGROUND: Polo-like kinase 1 (Plk1), as a characteristic regulator in meiosis, organizes multiple biological events of cell division. Although Plk1 has been implicated in various functions in somatic cell mitotic processes, considerably less is known regarding its function during the transition from metaphase I (MI) to metaphase II (MII) stage in oocyte meiotic progression. METHODS: In this study, the possible role of Plk1 during the MI-to-MII stage transition in pig oocytes was addressed. Initially, the spatiotemporal expression and subcellular localization pattern of Plk1 were revealed in pig oocytes from MI to MII stage using indirect immunofluorescence and confocal microscopy imaging techniques combined with western blot analyses. Moreover, a highly selective Plk1 inhibitor, GSK461364, was used to determine the potential role of Plk1 during this MI-to-MII transition progression. RESULTS: Upon expression, Plk1 exhibited a specific dynamic intracellular localization, and co-localization of Plk1 with alpha tubulin was revealed in the meiotic spindle of pig oocyte during the transition from MI to MII stage. GSK461364 treatment significantly blocked the first polar body (pbI) emission in a dose-dependent manner and resulted in a failure of meiotic maturation, with a larger percentage of the GSK461364-treated oocytes arresting in the anaphase-telophase I (ATI) stage. Further subcellular structure examination results showed that inhibition of Plk1 with GSK461364 had no visible effect on spindle assembly but caused a significantly higher proportion of the treated oocytes to have obvious defects in homologous chromosome segregation at ATI stage. CONCLUSIONS: Thus, these results indicate that Plk1 plays an essential role during the meiosis I/meiosis II transition in porcine oocytes, and the regulation is associated with Plk1's effects on homologous chromosome segregation in the ATI stage. PMID- 28851441 TI - Parkinson's disease is associated with DNA methylation levels in human blood and saliva. AB - BACKGROUND: Several articles suggest that DNA methylation levels in blood relate to Parkinson's disease (PD) but there is a need for a large-scale study that involves suitable population based controls. The purposes of the study were: (1) to study whether PD status is associated with DNA methylation levels in blood/saliva; (2) to study whether observed associations relate to blood cell types; and (3) to characterize genome-wide significant markers ("CpGs") and clusters of CpGs (co-methylation modules) in terms of biological pathways. METHODS: In a population-based case control study of PD, we studied blood samples from 335 PD cases and 237 controls and saliva samples from another 128 cases and 131 controls. DNA methylation data were generated from over 486,000 CpGs using the Illumina Infinium array. We identified modules of CpGs (clusters) using weighted correlation network analysis (WGCNA). RESULTS: Our cross-sectional analysis of blood identified 82 genome-wide significant CpGs (including cg02489202 in LARS2 p = 8.3 * 10-11 and cg04772575 in ABCB9 p = 4.3 * 10-10). Three out of six PD related co-methylation modules in blood were significantly enriched with immune system related genes. Our analysis of saliva identified five significant CpGs. PD-related CpGs are located near genes that relate to mitochondrial function, neuronal projection, cytoskeleton organization, systemic immune response, and iron handling. CONCLUSIONS: This study demonstrates that: (1) PD status has a profound association with DNA methylation levels in blood and saliva; and (2) the most significant PD-related changes reflect changes in blood cell composition. Overall, this study highlights the role of the immune system in PD etiology but future research will need to address the causal structure of these relationships. PMID- 28851442 TI - Outcome of surgical repair of Pectus Excavatum in adults. AB - BACKGROUND: Pectus Excavatum (PEx) is the most common congenital chest wall deformity, accounting for over 90% of all chest wall deformities. Surgical correction is recommended because severe PEx can affect the physical and psychological development of patients. The aim of our study was to assess the impact of surgical repair of Pectus Excavatum in adults during hospital course and results after 1 year. METHODS: Prospective study was carried out on 86 adult patients aged >= 15 years, 52 males and 34 females (mean age was 26 +/- 1.5 years). All cases were divided into two groups, group I: (15-25 years old) and group II: (> 25 years old). Preoperative, operative, and postoperative data were reviewed. Statistical analysis was performed. RESULTS: Statistical analyses revealed significant improvement postoperatively of cosmetic satisfaction (P value < 0.0001), pain (P-value =0.0003), exertional dyspnea (p-value <0.05) and exercise tolerance. The degree of chest compression was significantly improved after surgical correction within 12 months and the estimated measurement postoperatively of Haller Index showed significant reduction (p-value <0.001). Patient satisfaction postoperatively was excellent in 77.9% of all cases. CONCLUSION: Surgical correction of Pectus Excavatum using open technique in adults had excellent post-operative outcome in the short term follow up that encourage performing the procedure for all cases. Long term results need longer period for follow up. Etiology and predisposing factors still need further research. PMID- 28851443 TI - The PD COMM trial: a protocol for the process evaluation of a randomised trial assessing the effectiveness of two types of SLT for people with Parkinson's disease. AB - BACKGROUND: The PD COMM trial is a phase III multi-centre randomised controlled trial whose aim is to evaluate the effectiveness and cost-effectiveness of two approaches to speech and language therapy (SLT) compared with no SLT intervention (control) for people with Parkinson's disease who have self-reported or carer reported problems with their speech or voice. Our protocol describes the process evaluation embedded within the outcome evaluation whose aim is to evaluate what happened at the time of the PD COMM intervention implementation and to provide findings that will assist in the interpretation of the PD COMM trial results. Furthermore, the aim of the PD COMM process evaluation is to investigate intervention complexity within a theoretical model of how the trialled interventions might work best and why. METHODS/DESIGN: Drawing from the Normalization Process Theory and frameworks for implementation fidelity, a mixed method design will be used to address process evaluation research questions. Therapists' and participants' perceptions and experiences will be investigated via in-depth interviews. Critical incident reports, baseline survey data from therapists, treatment record forms and home practice diaries also will be collected at relevant time points throughout the running of the PD COMM trial. Process evaluation data will be analysed independently of the outcome evaluation before the two sets of data are then combined. DISCUSSION: To date, there are a limited number of published process evaluation protocols, and few are linked to trials investigating rehabilitation therapies. Providing a strong theoretical framework underpinning design choices and being tailored to meet the complex characteristics of the trialled interventions, our process evaluation has the potential to provide valuable insight into which components of the interventions being delivered in PD COMM worked best (and what did not), how they worked well and why. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN12421382 . Registered on 18 April 2016. PMID- 28851444 TI - Falling giants and the rise of gene editing: ethics, private interests and the public good. AB - This paper considers the tensions created in genomic research by public and private for-profit ideals. Our intent is to strengthen the public good at a time when doing science is strongly motivated by market possibilities and opportunities. Focusing on the emergence of gene editing, and in particular CRISPR, we consider how commercialisation encourages hype and hope-a sense that only promise and idealism can achieve progress. At this rate, genomic research reinforces structures that promote, above all else, private interests, but that may attenuate conditions for the public good of science. In the first part, we situate genomics using the aphorism that 'on the shoulders of giants we see farther'; these giants are infrastructures and research cultures rather than individual 'heroes' of science. In this respect, private initiatives are not the only pivot for successful discovery, and indeed, fascination in those could impinge upon the fundamental role of public-supported discovery. To redress these circumstances, we define the extent to which progress presupposes research strategies that are for the public good. In the second part, we use a 'falling giant' narrative to illustrate the risks of over-indulging for-profit initiatives. We therefore offer a counterpoint to commercialised science, using three identifiable 'giants'-scientists, publics and cultures-to illustrate how the public good contributes to genomic discovery. PMID- 28851446 TI - Daily volume of cases in emergency call centers: construction and validation of a predictive model. AB - BACKGROUND: Variations in the activity of emergency dispatch centers are an obstacle to the rationalization of resource allocation. Many explanatory factors are well known, available in advance and could predict the volume of emergency cases. Our objective was to develop and evaluate the performance of a predictive model of daily call center activity. METHODS: A retrospective survey was conducted on all cases from 2005 to 2011 in a large medical emergency call center (1,296,153 cases). A generalized additive model of daily cases was calibrated on data from 2005 to 2008 (1461 days, development sample) and applied to the prediction of days from 2009 to 2011 (1095 days, validation sample). Seventeen calendar and epidemiological variables and a periodic function for seasonality were included in the model. RESULTS: The average number of cases per day was 507 (95% confidence interval: 500 to 514) (range, 286 to 1251). Factors significantly associated with increased case volume were the annual increase, weekend days, public holidays, regional incidence of influenza in the previous week and regional incidence of gastroenteritis in the previous week. The adjusted R for the model was 0.89 in the calibration sample. The model predicted the actual number of cases within +/- 100 for 90.5% of the days, with an average error of 13 cases (95% CI: -17 to 8). CONCLUSIONS: A large proportion of the variability of the medical emergency call center's case volume can be predicted using readily available covariates. PMID- 28851445 TI - Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia. AB - Currently, conventional therapies for acute myeloid leukemia (AML) have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR) T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML. PMID- 28851447 TI - Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort. AB - BACKGROUND: The natural history and disease mechanisms of Alzheimer's disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting edge biomarker measurements. METHODS: In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR] <1). Baseline data collection included neurological and physical examinations as well as extensive neuropsychological testing. To be included in the MEMENTO cohort, participants had to agree to undergo both brain magnetic resonance imaging (MRI) and blood sampling. Cerebral 18F-fluorodeoxyglucose positon emission tomography and lumbar puncture were optional. Automated analyses of cerebral MRI included assessments of volumes of whole-brain, hippocampal and white matter lesions. RESULTS: The 2323 participants, recruited from April 2011 to June 2014, were aged 71 years, on average (SD 8.7), and 62% were women. CDR was 0 in 40% of participants, and 30% carried at least one apolipoprotein E epsilon4 allele. We observed that more than half (52%) of participants had amnestic mild cognitive impairment (17% single domain aMCI), 32% had non-amnestic mild cognitive impairment (16.9% single-domain naMCI) and 16% had isolated SCCs. Multivariable analyses of neuroimaging markers associations with cognitive categories showed that participants with aMCI had worse levels of imaging biomarkers than the others, whereas participants with naMCI had markers at intermediate levels between SCC and aMCI. The burden of white matter lesions tended to be larger in participants with aMCI. Independently of CDR, all neuroimaging and neuropsychological markers worsened with age, whereas differences were not consistent according to sex. CONCLUSIONS: MEMENTO is a large cohort with extensive clinical, neuropsychological and neuroimaging data and represents a platform for studying the natural history of ADRD in a large group of participants with different subtypes of MCI (amnestic or not amnestic) or isolated SCCs. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01926249 . Registered on 16 August 2013. PMID- 28851449 TI - Patient satisfaction with E-Oral Health care in rural and remote settings: a systematic review protocol. AB - BACKGROUND: Individuals living in rural and remote settings face oral health problems and access-to-care barriers due to the shortage of oral health care providers in these areas, geographic remoteness, lack of appropriate infrastructure and lower socio-economic status. E-Oral Health technology could mitigate these barriers by providing the delivery of some aspects of health care and exchange of information across geographic distances. This review will systematically evaluate the literature on patient satisfaction with received E Oral Health care in rural and remote communities. METHODS: This systematic review will include interventional and observational studies in which E-Oral Health technology is used as an intervention in rural and remote communities of any country worldwide. Conventional oral health care will be used as a comparator when provided. Patient satisfaction with received E-Oral Health care will be considered as a primary outcome for this review. Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Global Health will be searched using a comprehensive search strategy. Two review authors will independently screen results to identify potentially eligible studies and independently extract the data from the included studies. A third author will resolve any discrepancies between reviewers. Two independent researchers will assess the risk of bias and the Grading of Recommendations Assessment, Development, and Evaluation. DISCUSSION: The potential implications and benefits of E-Oral Health care can inform policymakers and health care professionals to take advantage of this technology to address health care challenges in these areas. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016039942 . PMID- 28851448 TI - Dietary arachidonic acid increases deleterious effects of amyloid-beta oligomers on learning abilities and expression of AMPA receptors: putative role of the ACSL4-cPLA2 balance. AB - BACKGROUND: Polyunsaturated fatty acids play a crucial role in neuronal function, and the modification of these compounds in the brain could have an impact on neurodegenerative diseases such as Alzheimer's disease. Despite the fact that arachidonic acid is the second foremost polyunsaturated fatty acid besides docosahexaenoic acid, its role and the regulation of its transfer and mobilization in the brain are poorly known. METHODS: Two groups of 39 adult male BALB/c mice were fed with an arachidonic acid-enriched diet or an oleic acid enriched diet, respectively, for 12 weeks. After 10 weeks on the diet, mice received intracerebroventricular injections of either NaCl solution or amyloid beta peptide (Abeta) oligomers. Y-maze and Morris water maze tests were used to evaluate short- and long-term memory. At 12 weeks on the diet, mice were killed, and blood, liver, and brain samples were collected for lipid and protein analyses. RESULTS: We found that the administration of an arachidonic acid enriched diet for 12 weeks induced short-term memory impairment and increased deleterious effects of Abeta oligomers on learning abilities. These cognitive alterations were associated with modifications of expression of alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid receptors, postsynaptic density protein 95, and glial fibrillary acidic protein in mouse cortex or hippocampus by the arachidonic acid-enriched diet and Abeta oligomer administration. This diet also led to an imbalance between the main omega-6 fatty acids and the omega-3 fatty acids in favor of the first one in erythrocytes and the liver as well as in the hippocampal and cortical brain structures. In the cortex, the dietary arachidonic acid also induced an increase of arachidonic acid-containing phospholipid species in phosphatidylserine class, whereas intracerebroventricular injections modified several arachidonic acid- and docosahexaenoic acid-containing species in the four phospholipid classes. Finally, we observed that dietary arachidonic acid decreased the expression of the neuronal form of acyl-coenzyme A synthetase 4 in the hippocampus and increased the cytosolic phospholipase A2 activation level in the cortices of the mice. CONCLUSIONS: Dietary arachidonic acid could amplify Abeta oligomer neurotoxicity. Its consumption could constitute a risk factor for Alzheimer's disease in humans and should be taken into account in future preventive strategies. Its deleterious effect on cognitive capacity could be linked to the balance between arachidonic acid-mobilizing enzymes. PMID- 28851450 TI - Open vascular treatment of median arcuate ligament syndrome. AB - BACKGROUND: Median arcuate ligament syndrome is a rare condition with abdominal symptoms. Accepted treatment options are open release of median arcuate ligament, laparoscopic release of edian arcuate ligament, robot-assisted release of median arcuate ligament and open vascular treatment. Here we aimed to evaluate the central priority of open vascular therapy in the treatment of median arcuate ligament syndrome. METHODS: We conducted a monocentric retrospective study between January 1996 and June 2016. Thirty-one patients with median arcuate ligament syndrome underwent open vascular surgery, including division of median arcuate ligament in 17 cases, and vascular reconstruction of the celiac artery in 14 cases. RESULTS: In a 20-year period, 31 patients (n = 26 women, n = 5 men) were treated with division of median arcuate ligament (n = 17) or vascular reconstruction in combination with division of median arcuate ligament (n = 14). The mean age of patients was 44.8 +/- 15.13 years. The complication rate was 16.1% (n = 5). Revisions were performed in 4 cases. The 30-day mortality rate was 0%. The mean in-hospital stay was 10.7 days. Follow-up data were obtained for 30 patients. The mean follow-up period was 52.2 months (range 2-149 months). Patients were grouped into a decompression group (n = 17) and revascularisation group (n = 13). The estimated Freedom From Symptoms rates were 93.3, 77.8, and 69.1% for the decompression group and 100, 83.3, and 83.3% for the revascularisation group after 12, 24 and 60 months respectively. We found no significant difference in the Freedom From Re-Intervention CA rates of the decompression (100% at 12, 24 and 60 months post-surgery) and revascularisation (100% at 12 months, and 91.7% at 24 and 60 months post-surgery) groups during follow-up (p = 0.26). CONCLUSIONS: Open vascular treatment of median arcuate ligament syndrome is a safe, low mortality-risk procedure, with low morbidity rate. Treatment choice depends on the clinical and morphological situation of each patient. PMID- 28851451 TI - Structured physical exercise improves neuropsychiatric symptoms in acute dementia care: a hospital-based RCT. AB - BACKGROUND: The primary objective of this trial is to investigate the effects of a short-term exercise program on neuropsychiatric signs and symptoms in acute hospital dementia care. METHODS: Within a hospital-based randomized controlled trial, the intervention group conducted a 2-week exercise program with four 20 min exercise sessions on 3 days per week. The control group conducted a social stimulation program. Effects on neuropsychiatric signs and symptoms were measured via the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, the Neuropsychiatric Inventory, and the Cohen-Mansfield Agitation Inventory. The antipsychotic and sedative dosage was quantified by olanzapine and diazepam equivalents. RESULTS: Eighty-five patients were randomized via minimization to an intervention group (IG) and a control group (CG). Seventy patients (82%) (mean age 80 years, 33 females, mean Mini Mental State Examination score 18.3 points) completed the trial. As compared to the CG (n = 35), the IG (n = 35) showed significantly reduced neuropsychiatric signs and symptoms. Especially, agitated behavior and lability improved. There were no between-group differences concerning antipsychotic and benzodiazepine medication. CONCLUSIONS: This exercise program is easily applicable in hospital dementia care and significantly reduces neuropsychiatric signs and symptoms in patients suffering from predominantly moderate stages of dementia. TRIAL REGISTRATION: German Clinical Trial Register DRKS00006740 . Registered 28 October 2014. PMID- 28851453 TI - Equality in the distribution of health material and human resources in Guangxi: evidence from Southern China. AB - OBJECTIVE: The aim of this study was to assess the equality in the distribution of health material and human resources in Guangxi, and put forward proposal to improve the equality status of the health material and human resources. RESULTS: We used concentration index to evaluate the degree of income-related equality of health material and human resources. The concentration index values of the five resources ranged from -0.0847 to 0.1416 from 2011 to 2015. Health institution was concentrated among the poorer populations, while other four resources were concentrated among the richer populations. Overall, the equality status of health institutions, health care beds, health technical personnel, and certified nurses got better from 2011 to 2015. However, the equality status of practicing physicians has got worse since 2014. PMID- 28851452 TI - Enhanced exosome secretion in Down syndrome brain - a protective mechanism to alleviate neuronal endosomal abnormalities. AB - A dysfunctional endosomal pathway and abnormally enlarged early endosomes in neurons are an early characteristic of Down syndrome (DS) and Alzheimer's disease (AD). We have hypothesized that endosomal material can be released by endosomal multivesicular bodies (MVBs) into the extracellular space via exosomes to relieve neurons of accumulated endosomal contents when endosomal pathway function is compromised. Supporting this, we found that exosome secretion is enhanced in the brains of DS patients and a mouse model of the disease, and by DS fibroblasts. Furthermore, increased levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Importantly, CD63 knockdown diminished exosome release and worsened endosomal pathology in DS fibroblasts. Taken together, these data suggest that increased CD63 expression enhances exosome release as an endogenous mechanism mitigating endosomal abnormalities in DS. Thus, the upregulation of exosome release represents a potential therapeutic goal for neurodegenerative disorders with endosomal pathology. PMID- 28851454 TI - Duck enteritis virus (DEV) UL54 protein, a novel partner, interacts with DEV UL24 protein. AB - BACKGROUND: UL24 is a multifunctional protein that is conserved among alphaherpesviruses and is believed to play an important role in viral infection and replication. RESULTS: In this paper, to investigate putative UL24-binding proteins and to explore the functional mechanisms of DEV UL24, yeast two-hybrid (Y2H) was carried out, and further verified the interaction between UL24 and partners by co-immunoprecipitation and fluorescence microscopy experiments. Interaction partners of UL24 protein were screened by yeast two-hybrid (Y2H) with the cDNA library of DEV-CHv strain post-infection DEF cells. A novel partner, DEV UL54 protein, was discovered by Y2H screening and bioinformatic. Co immunoprecipitation experiments suggested that DEV UL24 interacted with UL54 proteins. And distribution of a part of UL54 protein was changed from nucleus to cytoplasm in DF-1 cells of co-subcellular localization experiments which also showed that DEV UL24 interacted with UL54 proteins. CONCLUSIONS: The interaction between the DEV UL24 and UL54 proteins was discovered for the first time. Thus, DEV UL54 protein as a novel partner interacted with DEV UL24 protein. PMID- 28851456 TI - Formulation of an aloe-based product according to Iranian traditional medicine and development of its analysis method. AB - BACKGROUND: Currently, people are more interested to traditional medicine. The traditional formulations should be converted to modern drug delivery systems to be more acceptable for the patients. In the present investigation, a poly herbal medicine "Ayarij-e-Faiqra" (AF) based on Iranian traditional medicine (ITM) has been formulated and its quality control parameters have been developed. METHODS: The main ingredients of AF including barks of Cinnamomum zeylanicum Blume and Cinnamomum cassia J. Presl, the rhizomes of Nardostachys jatamansi DC., the fruits of Piper cubeba L.f., the flowers of Rosa damascena Herrm., the oleo gum resin of Pistacia terebinthus L. and Aloe spp. dried juice were powdered and used for preparing seven tablet formulations of the herbal mixture. Flowability of the different formulated powders was examined and the best formulations were selected (F6&F7). The tablets were prepared from the selected formulations compared according to the physical characteristics and finally, F7 was selected and coated. Physicochemical characters of core and coated AF tablets were determined and the HPLC method for quantitation of aloin as a marker of tablets was selected and verified according to selectivity, linearity, precision, recovery, LOD and LOQ. RESULTS: The results showed that core and coated AF tablets were in agreement with USP requirements for herbal drugs. They had acceptable appearance, disintegration time, friability, hardness, dissolution behavior, weight variation and content uniformity. The amount of aloin in tablets was found 123.1 mg/tab. The HPLC method for aloin determination in AF tablets was verified according to selectivity, linearity (5-500 MUg/ml, r2:0.9999), precision (RSD: 1.62%), recovery (108.0%), LOD & LOQ (0.0053 & 0.0161 MUg/ml). CONCLUSIONS: The formulated tablets could be a good substitute for powder and capsules of AF in ITM clinics with a feasible and precise method for its quality control. Ayarij-e Faiqra formulation. PMID- 28851455 TI - The complexity of TRIM28 contribution to cancer. AB - Since the first discovery in 1996, the engagement of TRIM28 in distinct aspects of cellular biology has been extensively studied resulting in identification of a complex nature of TRIM28 protein. In this review, we summarize core biological functions of TRIM28 that emerge from TRIM28 multi-domain structure and possessed enzymatic activities. Moreover, we will discuss whether the complexity of TRIM28 engagement in cancer biology makes TRIM28 a possible candidate for targeted anti cancer therapy. Briefly, we will demonstrate the role of TRIM28 in regulation of target gene transcription, response to DNA damage, downregulation of p53 activity, stimulation of epithelial-to-mesenchymal transition, stemness sustainability, induction of autophagy and regulation of retrotransposition, to provide the answer whether TRIM28 functions as a stimulator or inhibitor of tumorigenesis. To date, number of studies demonstrate significant upregulation of TRIM28 expression in cancer tissues which correlates with worse overall patient survival, suggesting that TRIM28 supports cancer progression. Here, we present distinct aspects of TRIM28 involvement in regulation of cancer cell homeostasis which collectively imply pro-tumorigenic character of TRIM28. Thorough analyses are further needed to verify whether TRIM28 possess the potential to become a new anti-cancer target. PMID- 28851457 TI - PIM-1 mRNA expression is a potential prognostic biomarker in acute myeloid leukemia. AB - BACKGROUND: High expression of proviral integration site for Moloney murine leukemia virus-1 (PIM-1), a serine/threonine kinase, is associated with many cancers. The main purpose of this study were to investigate that the correlation between PIM-1 mRNA levels and clinicopathologic features and its clinical significance in acute myeloid leukemia (AML). METHODS: qRT-PCR was performed for 118 de novo AML and 20 AML complete remission patients and 15 normal individuals. All statistical analysis were performed using Graphpad Prism5 software. RESULTS: We observed that expression of PIM-1 mRNA was higher in AML patients than in healthy individuals and in complete remission AML patients (P = 0.0177). Further, high PIM-1 mRNA levels were more associated with high-risk FLT3+ AML patients than the FLT3- group (P = 0.0001) and were also associated with clinical factors such as risk stratification (P = 0.0029) and vital status (P = 0.0322). Kaplan Meier survival analysis indicated that PIM-1 mRNA expression correlated with overall survival (OS), disease free survival (DFS), and relapse rate (RR) in AML patients. Most importantly, the high PIM-1-expressing patients took longer to achieve complete remission than the low expression group (P = 0.001). In addition, the complete remission rate was significantly lower in the high PIM-1 group (P = 0.0277) after induction therapy. CONCLUSIONS: Above results suggest that PIM-1 mRNA levels may be an independent prognostic factor in AML. PMID- 28851458 TI - Differential gene expression in Anopheles stephensi following infection with drug resistant Plasmodium yoelii. AB - BACKGROUND: The transmission of drug-resistant parasites by the mosquito may be influenced by the altered biological fitness of drug-resistant parasites and different immune reactions or metabolic change in the mosquito. At this point, little is known about the variations in mosquito immunity and metabolism when mosquitoes are infected with drug-resistant parasites. To understand the differential gene expression in Anopheles following infection with drug-resistant Plasmodium, we conducted a genome-wide transcriptomic profiling analysis of Anopheles stephensi following feeding on mice with drug-resistant or drug sensitive P. yoelii, observed changes in gene expression profiles and identified transcripts affected by the drug-resistant parasite. RESULTS: To study the impact of drug-resistant Plasmodium infections on An. stephensi gene transcription, we analyzed the three major transition stages of Plasmodium infections: at 24 h and 13 and 19 days after blood-feeding. Six cDNA libraries (R-As24h, R-As13d, R As19d,S-As24h, S-As13dand S-As19d) were constructed, and RNA sequencing was subsequently performed. In total, approximately 50.1 million raw reads, 47.9 million clean reads and 7.18G clean bases were obtained. Following differentially expressed gene (DEG) analysis, GO enrichment analysis of DEGs, and functional classification by KEGG, we showed that the variations in gene expression in An. stephensi infected by the drug-resistant P. yoelii NSM occurred mainly at 13 days after blood meal during sporozoite migration through the hemolymph. The differentially expressed genes included those functioning in some important immune reaction and iron metabolism pathways, such as pattern recognition receptors, regulators of the JNK pathway, components of the phagosome pathway, regulators of the melanization response, activators of complement reactions, insulin signaling cascade members, oxidative stress and detoxification proteins. CONCLUSIONS: Our study shows that drug-resistant P. yoelii NSM has an impact on the transcript abundance levels of An.stephensi mostly at 13 days after blood meal during sporozoite migration through the hemolymph and that most differentially expressed genes were downregulated. Our results highlight the need for a better understanding of selective pressures from these differentially expressed genes of the drug-resistant Plasmodium in the mosquito and the different transmission patterns of drug-resistant Plasmodium by Anopheles. PMID- 28851460 TI - Erratum to: Wine glass size and wine sales: a replication study in two bars. PMID- 28851459 TI - Psychometric assessment of three newly developed implementation outcome measures. AB - BACKGROUND: Implementation outcome measures are essential for monitoring and evaluating the success of implementation efforts. Yet, currently available measures lack conceptual clarity and have largely unknown reliability and validity. This study developed and psychometrically assessed three new measures: the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). METHODS: Thirty-six implementation scientists and 27 mental health professionals assigned 31 items to the constructs and rated their confidence in their assignments. The Wilcoxon one sample signed rank test was used to assess substantive and discriminant content validity. Exploratory and confirmatory factor analysis (EFA and CFA) and Cronbach alphas were used to assess the validity of the conceptual model. Three hundred twenty-six mental health counselors read one of six randomly assigned vignettes depicting a therapist contemplating adopting an evidence-based practice (EBP). Participants used 15 items to rate the therapist's perceptions of the acceptability, appropriateness, and feasibility of adopting the EBP. CFA and Cronbach alphas were used to refine the scales, assess structural validity, and assess reliability. Analysis of variance (ANOVA) was used to assess known-groups validity. Finally, half of the counselors were randomly assigned to receive the same vignette and the other half the opposite vignette; and all were asked to re rate acceptability, appropriateness, and feasibility. Pearson correlation coefficients were used to assess test-retest reliability and linear regression to assess sensitivity to change. RESULTS: All but five items exhibited substantive and discriminant content validity. A trimmed CFA with five items per construct exhibited acceptable model fit (CFI = 0.98, RMSEA = 0.08) and high factor loadings (0.79 to 0.94). The alphas for 5-item scales were between 0.87 and 0.89. Scale refinement based on measure-specific CFAs and Cronbach alphas using vignette data produced 4-item scales (alpha's from 0.85 to 0.91). A three-factor CFA exhibited acceptable fit (CFI = 0.96, RMSEA = 0.08) and high factor loadings (0.75 to 0.89), indicating structural validity. ANOVA showed significant main effects, indicating known-groups validity. Test-retest reliability coefficients ranged from 0.73 to 0.88. Regression analysis indicated each measure was sensitive to change in both directions. CONCLUSIONS: The AIM, IAM, and FIM demonstrate promising psychometric properties. Predictive validity assessment is planned. PMID- 28851461 TI - 3D mosquito screens to create window double screen traps for mosquito control. AB - BACKGROUND: Mosquitoes are vectors for many diseases such as malaria. Insecticide treated bed nets and indoor residual spraying of insecticides are the principal malaria vector control tools used to prevent malaria in the tropics. Other interventions aim at reducing man-vector contact. For example, house screening provides additive or synergistic effects to other implemented measures. We used commercial screen materials made of polyester, polyethylene or polypropylene to design novel mosquito screens that provide remarkable additional benefits to those commonly used in house screening. The novel design is based on a double screen setup made of a screen with 3D geometric structures parallel to a commercial mosquito screen creating a trap between the two screens. Owing to the design of the 3D screen, mosquitoes can penetrate the 3D screen from one side but cannot return through the other side, making it a unidirectional mosquito screen. Therefore, the mosquitoes are trapped inside the double screen system. The permissiveness of both sides of the 3D screens for mosquitoes to pass through was tested in a wind tunnel using the insectary strain of Anopheles stephensi. RESULTS: Among twenty-five tested 3D screen designs, three designs from the cone, prism, or cylinder design groups were the most efficient in acting as unidirectional mosquito screens. The three cone-, prism-, and cylinder-based screens allowed, on average, 92, 75 and 64% of Anopheles stephensi mosquitoes released into the wind tunnel to penetrate the permissive side and 0, 0 and 6% of mosquitoes to escape through the non-permissive side, respectively. CONCLUSIONS: A cone-based 3D screen fulfilled the study objective. It allowed capturing 92% of mosquitoes within the double screen setup inside the wind tunnel and blocked 100% from escaping. Thus, the cone-based screen effectively acted as a unidirectional mosquito screen. This 3D screen-based trap design could therefore be used in house screening as a means of avoiding infective bites and reducing mosquito population size. PMID- 28851462 TI - Effects of a brief, pedometer-based behavioral intervention for individuals with COPD during inpatient pulmonary rehabilitation on 6-week and 6-month objectively measured physical activity: study protocol for a randomized controlled trial. AB - BACKGROUND: Pulmonary rehabilitation programs often fail to substantially enhance long-term physical activity in patients with chronic obstructive pulmonary disease (COPD). The reasons for successful physical activity changes in patients with COPD are not well understood. The need to better understand the determinants of physical activity in patients with COPD and effective rehabilitation strategies to improve physical activity is evident. METHODS/DESIGN: The STAR study (Stay Active after Rehabilitation) investigates, in a randomized controlled trial, the additional effect of a pedometer-based behavior-change intervention during inpatient pulmonary rehabilitation on objectively measured physical activity 6 weeks and 6 months post rehabilitation. The intervention uses the behavior-change techniques (1) instruction on how, where and when to perform the behavior, (2) prompt goal setting for physical activity, (3) prompt self monitoring of behavior, and (4) feedback on behavior. The primary outcome of physical activity will be measured using a physical activity monitor (Actigraph wGT3X-BT) for a period of 7 days, firstly 2 weeks before rehabilitation begins (t0) as well as 6 weeks and 6 months after rehabilitation (t3, t4). Additionally, to predict physical activity progression after rehabilitation, a complex personal diagnostics battery, including questionnaires as well as functional assessments, is to be carried out at the start and end of rehabilitation (t1, t2). This battery is based on the foundational ideas of the Physical Activity-Related health Competence model. Five hundred and two patients with COPD, aged 18 years or older and admitted for an approved pulmonary rehabilitation, will be enrolled in the STAR study. DISCUSSION: The STAR study is designed as a randomized controlled trial to gain a better understanding of the personal determinants of physical activity in patients with COPD and to evaluate a pedometer-based physical activity-change intervention in the context of inpatient pulmonary rehabilitation. The results enable the future identification of patients with COPD who will find it difficult to engage in long-term physical activity after rehabilitation. Based on this, intervention strategies to promote physical activity in the content of pulmonary rehabilitation can be optimized. TRIAL REGISTRATION: Clinicaltrials.gov, ID: NCT02966561 . Registered retrospectively after the start of the recruitment in June 2016 on 22 November 2016. All protocol modifications will be registered in the trial registry. PMID- 28851464 TI - Development and Application of a Sample Holder for In Situ Gaseous TEM Studies of Membrane Electrode Assemblies for Polymer Electrolyte Fuel Cells. AB - Polymer electrolyte fuel cells hold great potential for stationary and mobile applications due to high power density and low operating temperature. However, the structural changes during electrochemical reactions are not well understood. In this article, we detail the development of the sample holder equipped with gas injectors and electric conductors and its application to a membrane electrode assembly of a polymer electrolyte fuel cell. Hydrogen and oxygen gases were simultaneously sprayed on the surfaces of the anode and cathode catalysts of the membrane electrode assembly sample, respectively, and observation of the structural changes in the catalysts were simultaneously carried out along with measurement of the generated voltages. PMID- 28851465 TI - SAMHD1 Mutations Are Also Responsible for Aicardi-Goutieres in the Cree Population. PMID- 28851466 TI - Study sponsorship and the nutrition research agenda: analysis of cohort studies examining the association between nutrition and obesity. AB - OBJECTIVE: To categorize the research topics covered by a sample of cohort studies exploring the association between nutrition and obesity; to describe their funding sources; and to explore the association between funding sources and research topics. DESIGN: Cross-sectional study. SUBJECTS: Cohort studies retrieved from MEDLINE and PubMed published between 2010 and 2016. RESULTS: One hundred and twenty-one studies were included. Funding source and conflicts of interest were disclosed in 95.0 and 90.1 % of the studies, respectively. Food industry sponsorship was disclosed in 8.3 % of the studies. Half of the studies analysed the consumption of a single food or food groups, 18.2 % included an analysis of dietary patterns and 17.4 % focused on specific nutrients. Highly processed foods were considered in 48.8 % of the studies and 27.3 % considered dietary behaviours (e.g. eating away from home). No statistically significant differences in research topics were observed between industry- and non-industry funded studies. CONCLUSIONS: Cohort studies focused on more complex exposures (e.g. food or dietary patterns) rather than single nutrients. No significant differences in the research agenda by funding sources were observed. The analysis was limited by the low proportion of studies with disclosed food industry sponsorship. PMID- 28851467 TI - The major types of added sugars and non-nutritive sweeteners in a sample of Australian packaged foods. AB - OBJECTIVE: Limiting the intake of added sugars in the diet remains a key focus of global dietary recommendations. To date there has been no systematic monitoring of the major types of added sugars used in the Australian food supply. The present study aimed to identify the most common added sugars and non-nutritive sweeteners in the Australian packaged food supply. DESIGN: Secondary analysis of data from the Australian FoodSwitch database was undertaken. Forty-six added sugars and eight non-nutritive sweetener types were extracted from the ingredient lists of 5744 foods across seventeen food categories. SETTING: Australia. SUBJECTS: Not applicable. RESULTS: Added sugar ingredients were found in 61 % of the sample of foods examined and non-nutritive sweetener ingredients were found in 69 %. Only 31 % of foods contained no added sugar or non-nutritive sweetener. Sugar (as an ingredient), glucose syrup, maple syrup, maltodextrin and glucose/dextrose were the most common sugar ingredient types identified. Most Australian packaged food products had at least one added sugar ingredient, the most common being 'sugar'. CONCLUSIONS: The study provides insight into the most common types of added sugars and non-nutritive sweeteners used in the Australian food supply and is a useful baseline to monitor changes in how added sugars are used in Australian packaged foods over time. PMID- 28851468 TI - Persistent fifth aortic arch: the "great pretender" in clinical practice. AB - Persistence of the embryonic "fifth aortic arch" in postnatal life is a rare, enigmatic - and at times controversial - condition, with variable anatomical forms and physiological consequences. First described in humans over 40 years ago by Van Praagh, the condition was labelled the "great pretender" by Gerlis 25 years later, because of its apparent propensity to mimic anatomically similar structures. Despite many subsequent case reports citing the condition, the true developmental origin of these structures remains unresolved, and has been the subject of debate among embryologists for more than a century. A persistent fifth aortic arch has been defined as an extrapericardial structure, arising from the ascending aorta opposite or proximal to the brachiocephalic artery, and terminating in the dorsal aorta or pulmonary arteries via a persistently patent arterial duct. This description may therefore encompass various anatomical forms, such as a unilateral double-lumen aortic arch, an unrestrictive aortopulmonary shunt, or a critical vascular channel for either the systemic or pulmonary circulation. The physiological properties of these vessels, such as their response to prostaglandins, may also be unpredictable. In this article, we demonstrate a number of cases that fulfil the contemporary definition of "persistent fifth aortic arch" while acknowledging the embryological controversies associated with this term. We also outline the key diagnostic features, particularly with respect to the use of new cross-sectional imaging techniques. PMID- 28851469 TI - Community Resilience, Psychological Resilience, and Depressive Symptoms: An Examination of the Mississippi Gulf Coast 10 Years After Hurricane Katrina and 5 Years After the Deepwater Horizon Oil Spill. AB - OBJECTIVE: This study examined the role of community resilience and psychological resilience on depressive symptoms in areas on the Mississippi Gulf Coast that have experienced multiple disasters. METHODS: Survey administration took place in the spring of 2015 to a spatially stratified, random sample of households. This analysis included a total of 294 subjects who lived in 1 of the 3 counties of the Mississippi Gulf Coast at the time of both Hurricane Katrina in 2005 and the Deepwater Horizon oil spill in 2010. The survey included the Communities Advancing Resilience Toolkit (CART) scale, the Connor-Davidson Resilience Scale (CD-RISC 10), and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: There was a significant inverse relationship between psychological resilience and depressive symptoms and a significant positive relationship between community resilience and psychological resilience. The results also revealed that community resilience was indirectly related to depressive symptoms through the mediating variable of psychological resilience. CONCLUSIONS: These findings highlight the importance of psychological resilience in long-term disaster recovery and imply that long-term recovery efforts should address factors associated with both psychological and community resilience to improve mental health outcomes. (Disaster Med Public Health Preparedness. 2018;12:241 248). PMID- 28851470 TI - Bereavement, multimorbidity and mortality: a population-based study using bereavement as an indicator of mental stress. AB - BACKGROUND: Mental stress is associated with higher mortality, but it remains controversial whether the association is causal or a consequence of a higher physical disease burden in those with a high mental stress load. Understanding causality is important when developing targeted interventions. We aimed to estimate the effect of mental stress on mortality by performing a 'natural' experiment using spousal bereavement as a disease-independent mental stressor. METHODS: We followed a population-based matched cohort, including all individuals in Denmark bereaved in 1997-2014, for 17 years. Prospectively recorded register data were obtained for civil and vital status, 39 mental and physical diagnoses, and socioeconomic factors. RESULTS: In total, 389 316 bereaved individuals were identified and 137 247 died during follow-up. Bereaved individuals had higher all cause mortality than non-bereaved references in the entire study period. The relative mortality in the bereaved individuals was highest shortly after the loss (adjusted hazard ratio (aHR), first month: 2.50, 95% confidence interval (CI) 2.37-2.63; aHR, 6-12 months: 1.38, 95% CI 1.34-1.42). The excess mortality rate associated with bereavement rose with increasing number of physical diseases (1.33 v. 7.00 excess death per 1000 person-months for individuals with 0 v. ?3 physical conditions during the first month) and was exacerbated by the presence of mental illness. The excess mortality among bereaved individuals was primarily due to death from natural causes. CONCLUSIONS: Bereavement was associated with increased short-term and long-term mortality, even after adjustment for morbidities, which suggests that mental stress may play a causal role in excess mortality. PMID- 28851463 TI - RNA biology of disease-associated microsatellite repeat expansions. AB - Microsatellites, or simple tandem repeat sequences, occur naturally in the human genome and have important roles in genome evolution and function. However, the expansion of microsatellites is associated with over two dozen neurological diseases. A common denominator among the majority of these disorders is the expression of expanded tandem repeat-containing RNA, referred to as xtrRNA in this review, which can mediate molecular disease pathology in multiple ways. This review focuses on the potential impact that simple tandem repeat expansions can have on the biology and metabolism of RNA that contain them and underscores important gaps in understanding. Merging the molecular biology of repeat expansion disorders with the current understanding of RNA biology, including splicing, transcription, transport, turnover and translation, will help clarify mechanisms of disease and improve therapeutic development. PMID- 28851471 TI - A systematic evaluation of impulsive-aggressive behavior in psychogeriatric inpatients using the staff observation aggression scale-revision (SOAS-R). AB - BACKGROUND: Impulsive-aggressive behavior is a significant challenge in geriatric psychiatry and requires professional evaluation and management. METHODS: SOAS-R scales (Staff Observation Aggression Scale-Revision) completed by medical staff on three secure psychiatric wards were analyzed during a period of 12 months. Patients were subdivided into the following two diagnostic subgroups: dementia and other diagnoses. RESULTS: A total of 146 aggressive incidents involving 66 patients were reported (8.8% of patients treated during this period, n = 752). Fifty-seven percent of the incidents involved patients with dementia. In 20% of the incidents, no precipitating event could be identified; this was more common in patients without dementia (p = 0.005). The medical condition of the patient was considered the trigger in 55% of the cases. Aggression was directed at nurses in 82% of the cases. Visible injury was reported in 12 cases, 3 of which required medical treatment. Male gender, the presence of previous aggressive incidents, and the evening shift (in the case of dementia patients) were identified as risk factors. CONCLUSIONS: Aggression in dementia is often reactive and seems to be more predictable than if occurring with other diagnoses. Prevention measures such as de-escalations techniques, warning notes in the patient's file with previous aggressive behavior and stepping up for evening shifts are of crucial importance. As nurses were primarily affected, employer support programs, and mental health interventions are proposed to avoid long-term consequences. PMID- 28851472 TI - The partnership between the Brazilian School Feeding Program and family farming: a way for reducing ultra-processed foods in school meals. AB - OBJECTIVE: To evaluate the profile of food acquisition in the National School Feeding Program according to the extent and purpose of food processing in three municipalities of southern Brazil during the implementation period of Law 11.947/2009. DESIGN: Descriptive cross-sectional study. Data for 2008-2010 involved quantities, prices and types of suppliers for food items purchased. In total, 1529 purchases were analysed. The items were classified into the following groups: G1 (unprocessed/minimally processed), G2 (culinary ingredients), G3 (processed), G4 (ultra-processed). Quantities of purchased foods were converted into energy and average prices ($US/4184 kJ (1000 kcal)) were calculated. The proportion of each food group in total purchases was expressed as both a percentage of total energy and a percentage of total expenditure. Data analysis was carried out in Stata version 12.1. SETTING: Three municipalities in southern Brazil. RESULTS: Relative contribution to total energy purchased was high for G1 (49.8 %; G2, 23.8 %; G3, 4.5 %; G4, 21.8 %). Among acquisitions from family farming, G1 represented 51.3 % of the total energy purchased; G2, 9.9 %; G3, 19.7 %; G4, 19.0 %. Total cost was as follows: G1, 61.6 %; G2, 3.9 %; G3, 18.5 %; G4, 16.0 %. Prices for food products from family farms were consistently higher. Average price from family farms was 1.3; from conventional suppliers, 0.9. CONCLUSIONS: The implementation of Law 11.947/2009 produced a positive effect on the regional profile of food purchases for the School Feeding Program. However, there is still considerable potential to promote health by strengthening relationships between family farming and school feeding. PMID- 28851473 TI - Quality of food choices of Brazilian adolescents according to individual earnings. AB - OBJECTIVE: To evaluate the quality of food choices according to adolescent individual earnings in Brazil. DESIGN: Adolescents were classified according to their individual earnings as having or not having spending power for their own expenses. Food records from two non-consecutive days of the Brazilian National Dietary Survey (NDS 2008-2009) were used to estimate food intake. Quality of food choices was based on two approaches: (i) the NOVA classification, which classifies processed and ultra-processed foods and drinks as unhealthy food groups; and (ii) traditional classification, with beans, milk, fruits and vegetables as healthy food groups, and soft drinks, sweets, snacks and crackers classified as unhealthy. We compared mean food intake (g/kJ or ml/kJ) according to per capita household income (tertiles) and adolescent individual earnings, with adolescent earnings adjusted for household income, using multiple linear regression. SETTING: Brazilian households (n 13 569). SUBJECTS: Adolescents aged 14-18 years (n 3673). RESULTS: Males without individual earnings had higher per capita household income than those with individual earnings. Household income was associated with all three food groups of the NOVA classification and seven of the eight groups of the traditional classification. However, only beans and snacks were consumed in significantly greater quantities by adolescents with individual earnings compared with those without earnings. CONCLUSIONS: Adolescent individual earnings were not the main driver of food choices; however, per capita household income was associated with food choices. The consumption of both healthy and unhealthy items increased with increasing household income. PMID- 28851475 TI - Disaster Mental Health Services Review of Care for Older Persons After Disasters. AB - As older persons make up an ever greater proportion of the world's population, a range of concerns are being voiced by policy-makers, program managers, and care providers about best or optimal practices for serving this population's needs during all stages of disasters. Given that age-related vulnerabilities are common in late life, this article describes existing systems of care in the United States for the provision of disaster mental health services. Second, it evaluates the evidence for disaster treatment interventions with this subgroup of the population. Third, it synthesizes the findings of recent studies focusing on screening, assessment, and treatment approaches. To advance our current system of care and to adequately respond to the mental health needs of older persons, it is advantageous to periodically review progress, identify current gaps and unmet needs, and describe opportunities for improvement. (Disaster Med Public Health Preparedness. 2018; 12: 366-372). PMID- 28851474 TI - Maternal pre-pregnancy BMI and offspring body composition in young adulthood: the modifying role of offspring sex and birth order. AB - OBJECTIVE: To investigate if the association between maternal pre-pregnancy BMI and offspring's body composition in late adolescence and young adulthood varies by offspring birth order and sex. DESIGN: Family cohort study, with data from registers, questionnaires and physical examinations. The main outcome under study was offspring body composition (percentage fat mass (%FM), percentage lean mass (%LM)) measured by dual-energy X-ray absorptiometry. SETTING: Uppsala, Sweden. SUBJECTS: Two hundred and twenty-six siblings (first-born v. second-born; average age 19 and 21 years) and their mothers. RESULTS: In multivariable linear regression models, maternal pre-pregnancy BMI was positively associated with daughter's %FM, with stronger estimates for first-born (beta=0.97, 95 % CI 0.14, 1.80) v. second-born daughters (beta=0.64, 95 % CI 0.08, 1.20). Mother's BMI before her first pregnancy was associated with her second-born daughter's body composition (beta=1.05, 95 % CI 0.31, 1.79 (%FM)) Similar results albeit in the opposite direction were observed for %LM. No significant associations were found between pre-pregnancy BMI and %FM (beta=0.59, 95 % CI-0.27, 1.44 first-born; beta=-0.13, 95 % CI-0.77, 0.52 second-born) or %LM (beta=-0.54, 95 % CI-1.37, 0.28 first-born; beta=0.11, 95 % CI-0.52, 0.74 second-born) for sons. CONCLUSIONS: A higher pre-pregnancy BMI was associated with higher offspring %FM and lower offspring %LM in late adolescence and young adulthood, with stronger associations for first-born daughters. Preventing obesity at the start of women's reproductive life might reduce the risk of obesity in her offspring, particularly for daughters. PMID- 28851476 TI - Analysis of pathogenic variants from the ClinVar database in healthy people using next-generation sequencing. AB - Next-generation sequencing (NGS) became an effective approach for finding novel causative genomic variants of genetic disorders and is increasingly used for diagnostic purposes. Public variant databases that gather data of pathogenic variants are being relied upon as a source for clinical diagnosis. However, research of pathogenic variants using public databases data could be carried out not only in patients, but also in healthy people. This could provide insights into the most common recessive disorders in populations. The study aim was to use NGS and data from the ClinVar database for the identification of pathogenic variants in the exomes of healthy individuals from the Lithuanian population. To achieve this, 96 exomes were sequenced. An average of 42 139 single-nucleotide variants (SNVs) and 2306 short INDELs were found in each individual exome. Pooled data of study exomes provided a total of 243 192 unique SNVs and 31 623 unique short INDELs. Three hundred and twenty-one unique SNVs were classified as pathogenic. Comparison of the European data from the 1000 Genomes Project with our data revealed five pathogenic genomic variants that are inherited in an autosomal recessive pattern and that statistically significantly differ from the European population data. PMID- 28851477 TI - Strategies for public health initiatives targeting dairy consumption in young children: a qualitative formative investigation of parent perceptions. AB - OBJECTIVE: Dairy products contain essential nutrients to ensure healthy growth and bone development in children. However, a significant proportion of children in developed countries fail to consume the daily recommended intake of dairy products. Parents are the gatekeepers of familial nutritional intake and represent a potential vehicle through which to increase dairy consumption in children. As such, formative research was conducted to gain insight into parents' perceived barriers to and benefits of purchasing and consuming dairy products and to develop innovative message content that could be utilized in future public health campaigns. DESIGN: Seven in-depth group interviews were conducted in two phases between February and May 2015. SETTING: Interviews were conducted in local recreational centres and libraries in British Columbia, Canada. SUBJECTS: Mothers (n 21, mean age 38 (sd 5) years) and fathers (n 9, mean age 38 (sd 3) years) of children aged 4-10 years. RESULTS: Parents perceived both positive and negative physical outcomes associated with consuming dairy. Lack of trustworthy information was a frequently discussed barrier theme to purchasing and consuming dairy products. Mothers were concerned about the cost of dairy products. Differences in purchasing and consumption strategies were reported between parents of children who consumed adequate dairy and those who did not. Parents believed the most appropriate communication channel was through print material. CONCLUSIONS: Messages targeting parents, as a means of increasing dairy consumption in children, should address barriers identified by parents. In addition, practical tips should be provided to promote purchasing and consumption of dairy products. PMID- 28851478 TI - Household income is associated with food and nutrient intake in Japanese schoolchildren, especially on days without school lunch. AB - OBJECTIVE: The present study aimed to examine the association between household income and the intake of foods and nutrients by Japanese schoolchildren, and any differences between days with and without school lunch. DESIGN: This was a cross sectional study. Children, with the support of their parents, kept dietary records with photographs for 4 d (2 d with school lunch and 2 d without). The socio-economic status of each family was obtained from a questionnaire completed by the parents. SETTING: Japan. SUBJECTS: All students in 5th grade (10-11 years old) at nineteen schools in four prefectures and their parents (1447 pairs of students and parents) were invited to take part in the study; 836 pairs of complete data sets were analysed. RESULTS: The average results of four days of dietary records showed that lower income level was associated with a lower intake of fish/shellfish, green vegetables and sugar at the food group level, a lower intake of protein and several micronutrients, and a higher energy intake from carbohydrates at the nutrient level among the children. These associations between income and food/nutrient intake were not significant on days with school lunches, but were significant on days without school lunch. CONCLUSIONS: Our study confirmed an association between household income and the amount of foods and nutrients consumed by Japanese schoolchildren, and suggested that school lunches play a role in reducing disparities in the diets of children from households with various incomes. PMID- 28851480 TI - Erratum for the Appendix of "Measuring small compartment dimensions by probing diffusion dynamics via Non-uniform Oscillating-Gradient Spin-Echo (NOGSE) NMR" [J. Magn. Reson. 237 (2013) 49-62]. PMID- 28851479 TI - Detection of Paralytic Shellfish Toxins in Mussels and Oysters Using the Qualitative Neogen Lateral-Flow Immunoassay: An Interlaboratory Study. AB - Paralytic shellfish toxins (PSTs) in bivalve molluscs represent a public health risk and are controlled via compliance with a regulatory limit of 0.8 mg saxitoxin (STX)?2HCl equivalents per kilogram of shellfish meat (eq/kg). Shellfish industries would benefit from the use of rapid immunological screening tests for PSTs to be used for regulation, but to date none have been fully validated. An interlaboratory study involving 16 laboratories was performed to determine the suitability of the Neogen test to detect PSTs in mussels and oysters. Participants performed the standard protocol recommended by the manufacturer and a modified protocol with a conversion step to improve detection of gonyautoxin 1&4. The statistical analysis showed that the protocols had good homogeneity across all laboratories, with satisfactory repeatability, laboratory, and reproducibility variation near the regulatory level. The mean probability of detection (POD) at 0.8 mg STX?2HCl eq/kg using the standard protocol in mussels and oysters was 0.966 and 0.997, respectively, and 0.968 and 0.966 using the modified protocol. The estimated LOD in mussels was 0.316 mg STX?2HCl eq/kg with the standard and 0.682 mg STX?2HCl eq/kg with the modified protocol, and 0.710 and 0.734 mg STX?2HCl eq/kg for oysters, respectively. The Neogen test may be acceptable for regulatory purposes for oysters in accordance with European Commission directives in which the standard protocol provides, at the regulatory level, a probability of a negative response of 0.033 on 95% of occasions. Its use for mussels is less consistent at the regulatory level due to the wide prediction interval around the POD. PMID- 28851481 TI - Possible impact of electronegative LDL on atherosclerosis in type 2 diabetes. PMID- 28851482 TI - Bioinformatics analyses of pathways and gene predictions in IL-1alpha and IL 1beta knockout mice with spinal cord injury. AB - PURPOSE: This study aimed to explore the potential genes and pathways regulated in spinal cord injury (SCI) model mice with IL-1alpha and IL-1beta knockout (KO). METHODS: Gene expression profile GSE70302, which includes data from injured spinal cord of 4 IL-1alpha-KO mice, 4 IL-1beta-KO mice and 4 C57BL with 6 mice as controls was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) of the IL-1alpha-KO or IL-1beta-KO vs. control, and IL-1alpha-KO vs. IL-1beta-KO groups were screened, followed by function enrichment and protein-protein interaction (PPI) analyses. Finally, miRNAs associated with SCI that may target the DEGs were predicted. RESULTS: A total of 579 and 992 DEGs were selected from the IL-1alpha-KO vs. control group and the IL-1beta-KO vs. control group, respectively, and 208 genes common between the 2 comparison groups were identified. Additionally, 526 DEGs were identified from the IL-1alpha-KO vs. IL-1beta-KO groups. These DEGs were significantly enriched in functions and pathways associated with ion transport, neuron apoptotic processes and inflammatory responses. The common genes were enriched in the pathways for cytokine-cytokine receptor interaction. DEGs of IL-1alpha-KO vs. IL-1beta-KO were significantly enriched in the immune system, hematopoietic cell lineage and PI3K-Akt signalling pathway-associated biological processes and pathways. The PPI network consisted of 76 nodes, such as Saa2, Kcna1, Scn8a, Ccl5, Ccl28 and Pink1. A total of 94 miRNAs, including mir-17-5P and mir-30a-5p were predicted that could target the DEGs. CONCLUSION: IL-1alpha and IL-1beta may play important roles in SCI by regulating ion transport, inflammation and neuron apoptotic processes and their associated genes or miRNAs. Compared with IL-1beta KO, IL-1alpha-KO may improve the outcome of SCI via the alteration of hematopoietic cell lineage and PI3K-Akt signalling pathways. PMID- 28851483 TI - Reply to "Current issues in implementing do-not-resuscitate orders for cardiac patients". PMID- 28851484 TI - Reply to the letter by Trasancos-Escura at al. "Current issues in implementing do not-resuscitate orders for cardiac patients". PMID- 28851485 TI - RECALMIN II. Eight years of hospitalisation in Internal Medicine Units (2007 2014). What has changed? AB - OBJECTIVES: To analyse the evolution of care provided by the internal medicine units (IMU) of the Spanish National Health System from 2007 to 2014. MATERIAL AND METHODS: We analysed all discharges from the IMU of the Spanish National Health System in 2007 and 2014, using the Minimum Basic Data Set. We compared the risk factors by episode, mortality and readmissions between the two periods. We prepared specific fits for the risk for mortality and readmissions in heart failure, pneumonia and chronic obstructive pulmonary disease, as well as the Charlson index for all activity. RESULTS: Discharges from the IMU between the two periods increased 14%. The average patient age increased by 2.8 years (71.2+/ 17.1 vs. 74+/-16.2; p<.001), with a marked increase in comorbidity (Charlson index, 4+/-3.7 vs. 4.7+/-3.9; p<.001; 24% increase in risk factors per episode). The adjusted mortality rates decreased slight but significantly, with a slight increase in readmissions. CONCLUSIONS: During the analysed period, there was an increase of almost 3 years in the mean age of patients treated in the IMU of the Spanish National Health System, with a marked increase in comorbidity. These results should lead to a more appropriate assignment of nurse workloads and an increased implementation of good practices in clinical management. PMID- 28851487 TI - Improving prediction for postoperative morbidity and mortality. PMID- 28851486 TI - Geriatric rescue after surgery (GRAS) score to predict failure-to-rescue in geriatric emergency general surgery patients. AB - BACKGROUND: Geriatric-patients(GP) undergoing emergency-general-surgery(EGS) are vulnerable to develop adverse-outcomes. Impact of patient-level-factors on Failure-to-Rescue(FTR) in EGS-GP remains unclear. Aim of our study was to determine factors associated with FTR(death from major-complication) and devise simple-bedside-score that predicts FTR in EGS-GP. METHODS: 3-year(2013-15) analysis of patients, age>=65y on acute-care-surgery-service and underwent EGS. Regression analysis used to analyze factors associated with FTR and natural logarithm of significant odds-ratio used to calculate estimated-weights for each factor. Geriatric-Rescue-After-Surgery(GRAS)-score calculated for each-patient. AUROC used to assess model discrimination. RESULTS: 725 EGS-patients analyzed. 44.6%(n = 324) had major-complications. The FTR-rate was 11.5%. Overall-mortality rate was 15.3%. On regression, significant-factors with their estimated-weights were:Age>=80y(2), Chronic-Obstructive-Pulmonary-Disease(COPD)(1), Chronic-renal failure(CRF)(2), Congestive-heart-failure(CHF)(1), Albumin<3.5(1) and ASA score>3(2). AUROC of score was 0.787. CONCLUSION: GRAS-score is first score based on preoperative assessment that can reliably predict FTR in EGS-GP. Preoperative identification of patients at increased-risk of FTR can help in risk stratification and timely-mobilization of resources for successful rescue of these patients. PMID- 28851488 TI - Membrane-enclosed multienzyme (MEME) synthesis of 2,7-anhydro-sialic acid derivatives. AB - Naturally occurring 2,7-anhydro-alpha-N-acetylneuraminic acid (2,7-anhydro Neu5Ac) is a transglycosylation product of bacterial intramolecular trans sialidases (IT-sialidases). A facile one-pot two-enzyme approach has been established for the synthesis of 2,7-anhydro-sialic acid derivatives including those containing different sialic acid forms such as Neu5Ac and N glycolylneuraminic acid (Neu5Gc). The approach is based on the use of Ruminoccocus gnavus IT-sialidase for the release of 2,7-anhydro-sialic acid from glycoproteins, and the conversion of free sialic acid by a sialic acid aldolase. This synthetic method, which is based on a membrane-enclosed enzymatic synthesis, can be performed on a preparative scale. Using fetuin as a substrate, high-yield and cost-effective production of 2,7-anhydro-Neu5Ac was obtained to high-purity. This method was also applied to the synthesis of 2,7-anhydro-Neu5Gc. The membrane enclosed multienzyme (MEME) strategy reported here provides an efficient approach to produce a variety of sialic acid derivatives. PMID- 28851489 TI - Interfacial tensiometry and dilational surface visco-elasticity of biological liquids in medicine. AB - Dynamic surface tensions and dilational visco-elasticity are easy accessible parameters of liquids. For human body liquids, such as urine, blood serum, amniotic fluid, gastric juice, saliva and others, these parameters are very characteristic for the health status of people. In case of a disease the composition of certain liquids specifically changes and the measured characteristics of dynamic surface tension of the dilational surface elasticity and viscosity reflect these changes in a clear way. Thus, this kind of physico chemical measurements represent sensitive tools for evaluating the severity of a disease and can serve as control tool for the efficiency of applied therapies. The overview summarises the results of a successful work over about 25years on this subject and gives specific insight into a number of diseases for which the diagnostics as well as the therapy control have been significantly improved by the application of physico-chemical experimental techniques. PMID- 28851490 TI - Retrospective analysis of technical success rate and procedure-related complications of 867 percutaneous CT-guided needle biopsies of lung lesions. AB - AIM: To investigate the technical success rate and procedure-related complications of computed tomography (CT)-guided needle biopsy of lung lesions and to identify the factors that are correlated with the occurrence of procedure related complications. MATERIALS AND METHODS: This was a single- institution retrospective study of 867 consecutive CT-guided needle biopsies of lung lesions performed on 772 patients in a tertiary cancer centre. The technical success rate and complications were correlated with patient, lung lesion, and procedure related variables. RESULTS: The technical success rate was 87.2% and the mortality rate was 0.12%. Of the 867 total biopsies 25.7% were associated with pneumothorax, and 6.5% required chest tube drainage. The haemothorax rate was 1.8%. There was positive correlation between the development of pneumothorax and smaller lesion diameter (p<0.001), longer transparenchymal distance (p<0.001), and prone position (p=0.027). There was positive correlation between the need for chest tube placement and longer transparenchymal distance (p=0.007) and smaller lesion diameter (p=0.018). Lesions in the left lower lobe had the lowest rates of pneumothorax (p=0.008) and chest tube drainage (p=0.018). Patients whose pneumothoraces were diagnosed on the follow-up chest X-ray, but not on the immediate post-procedural CT scan had significantly higher requirement for chest tube drainage (p=0.039). CONCLUSION: CT-guided lung biopsy has a high rate of technical success and a low rate of major complications. The present study has revealed several variables that can be used to identify high-risk procedures. A post-procedural chest X-ray within hours after the procedure is highly recommended to identify high-risk patients who require chest tube placement. PMID- 28851491 TI - Radiofrequency ablation versus resection for hepatocellular carcinoma in patients with Child-Pugh A liver cirrhosis: a meta-analysis. AB - AIM: To evaluate whether radiofrequency ablation (RFA) or surgical resection (RES) has superior overall survival (OS) and disease-free survival (DFS) in patients with hepatocellular carcinoma and Child-Pugh class A liver cirrhosis. MATERIALS AND METHODS: Meta-analysis was used to compare 1-, 3-, and 5-year OS and DFS between RFA and RES. Those studies meeting inclusion criteria and published prior to 1 June 2015 were included. The odds ratio (OR) was used as the treatment effect measure. A priori defined sensitivity analyses of study subgroups was performed. RESULTS: Fifteen studies were included in this analysis. Subgroup analyses based on predetermined patient characteristics were performed to minimise bias. No difference in 1-year OS, 3-year OS, and 3-year DFS was found in analyses limited to studies where patients were equally eligible for both therapies. There was also not a significant difference in OS and DFS between RFA and RES when studies were limited to those with only solitary tumours or tumours <3 cm. CONCLUSION: The data suggest the equivalence of RFA and RES in patients with solitary tumours <3 cm and good liver status based on Child-Pugh score. PMID- 28851492 TI - Concentrations of mercury and other trace elements in two offshore skates: sandy ray Leucoraja circularis and shagreen ray L. fullonica. AB - Trace metal concentrations in muscle and liver tissues from two offshore species of skate were examined. Concentrations of mercury in muscle of Leucoraja circularis (n=20; 23-110.5cm total length, 157-490m water depth) and L. fullonica (n=24; 28.5-100cm total length, 130-426m water depth) were 0.02-1.8 and 0.04 0.61mgkg-1, respectively. Concentrations of both As and Hg increased with total length. Only the largest specimen had a concentration of Hg in muscle >1.0mgkg-1. Data were limited for specimens>90cm long, and further studies on contaminants in larger-bodied skates could usefully be undertaken. PMID- 28851493 TI - Evaluation of quantitative FTD-Pneumocystis jirovecii kit for Pneumocystis infection diagnosis. AB - We evaluated the Fast track Diagnostics (FTD) Pneumocystis PCR kit, targeting the mitochondrial large subunit ribosomal RNA gene (mtLSU rRNA) of Pneumocystis jirovecii (P. jirovecii). A hundred and thirty-three patients were prospectively enrolled. Respiratory specimens were examined using both microscopy and the PCR assay. Twenty-six patients led to P. jirovecii detection. Fourteen patients presented with Pneumocystis pneumonia (PCP) whereas 12 patients were considered to be colonized. The median copy numbers in bronchoalveolar lavage fluid were significantly different in the PCP and colonization groups (1.35*108/ml vs. 1.45*105/ml, P < 0.0001). Lower and upper cut-off values of 3.9*105 copies/ml and 3.2*106 copies/ml allowed differentiating PCP and colonization. The FTD P. jirovecii assay was secondarily compared to an in-house reference PCR assay targeting the mtLSUrRNA gene. A concordance rate of 97.5% was observed (Cohen's kappa coefficient kappa=0.935). The FTD Pneumocystis PCR kit showed good performance and represents an alternative method to diagnose P. jirovecii infections. PMID- 28851494 TI - Vena cava filter migration after magnetic resonance imaging. PMID- 28851495 TI - Intensity-modulated radiotherapy in head and neck cancer - an update for oral and maxillofacial surgeons. AB - Intensity-modulated radiation therapy (IMRT), a relatively new method of delivering radiotherapy, can precisely target a point within a specific tumour and reduce the dose to nearby anatomical structures. This is particularly important in the head and neck where radiotherapy can easily and irreparably damage the salivary glands, spinal cord, and eyes, and where, with increasingly better outcomes and survival, late complications of conventional radiotherapy (including osteoradionecrosis of the cervical spine) can be difficult to manage. IMRT has the potential advantage of reducing side effects including xerostomia and myelopathy of the cervical spinal cord. Several clinical trials have recently been published, and in this update we give an overview of IMRT for oral and maxillofacial surgeons, and discuss what the future may hold for radiotherapy. PMID- 28851496 TI - Diagnostic dilemma between medication-related osteonecrosis and oral squamous cell carcinoma in a mandibular lytic lesion. AB - Osteolytic lesions of the mandible are common, and there are two important differential diagnoses that must be considered: medication-related osteonecrosis of the jaws (MRONJ) and squamous cell carcinoma (SCC). In patients with a history of taking antiresorptive medication as well as risk factors for neoplasia it can be difficult to differentiate between the two. We describe two cases in both of which a mandibular osteolytic lesion was inadequately identified as either MRONJ or SCC because of confusing clinical and histopathological features. We also reviewed relevant publications to identify similar cases. Here we discuss our clinical dilemma when faced with two different conditions that present with similar clinical and histopathological features. PMID- 28851497 TI - Effects of humic acid on the interactions between zinc oxide nanoparticles and bacterial biofilms. AB - The effects of humic acid (HA) on interactions between ZnO nanoparticles (ZnO NPs) and Pseudomonas putida KT2440 biofilms at different maturity stages were investigated. Three stages of biofilm development were identified according to bacterial adenosine triphosphate (ATP) activity associated with biofilm development process. In the initial biofilm stage 1, the ATP content of bacteria was reduced by more than 90% when biofilms were exposed to ZnO NPs. However, in the mature biofilm stages 2 and 3, the ATP content was only slightly decreased. Biofilms at stage 3 exhibited less susceptibility to ZnO NPs than biofilms at stage 2. These results suggest that more mature biofilms have a significantly higher tolerance to ZnO NPs compared to young biofilms. In addition, biofilms with intact extracellular polymeric substances (EPS) showed higher tolerance to ZnO NPs than those without EPS, indicating that EPS play a key role in alleviating the toxic effects of ZnO NPs. In both pure ZnO NPs and ZnO-HA mixtures, dissolved Zn2+ originating from the NPs significantly contributed to the overall toxicity. The presence of HA dramatically decreased the toxicity of ZnO NPs due to the binding of Zn2+ on HA. The combined results from this work suggest that the biofilm maturity stages and environmental constituents (such as humic acid) are important factors to consider when evaluating potential risks of NPs to ecological systems. PMID- 28851498 TI - Point-of-care ultrasound leads to diagnostic shifts in patients with undifferentiated hypotension. AB - OBJECTIVE: To assess the impact of an ultrasound hypotension protocol in identifying life-threatening diagnoses that were missed in the initial evaluation of patients with hypotension and shock. METHODS: A subset of cases from a previously published prospective study of hypotensive patients who presented at the Emergency Department in a single, academic tertiary care hospital is described. An ultrasound-trained emergency physician performed an ultrasound on each patient using a standardized hypotension protocol. In each case, the differential diagnosis and management plan was solicited from the treating physician immediately before and after the ultrasound. This is a case series of patients with missed diagnoses in whom ultrasound led to a dramatic shift in diagnosis and management by detecting life threatening pathologies. RESULTS: Following a published prospective study of the effect on an ultrasound protocol in 118 hypotensive patients, we identified a series of cases that ultrasound protocol unexpectedly determined serious life threatening diagnoses such as Takotsubo cardiomyopathy, pulmonary embolism, pericardial effusion with tamponade physiology, abdominal aortic aneurysm and perforated viscus resulting in proper diagnoses and management. These hypotensive patients had completely unsuspected but critical diagnoses explaining their hypotension, who in every case had their management altered to target the newly identified life-threatening condition. CONCLUSIONS: A hypotension protocol is an optimal use of ultrasound that exemplifies "right time, right place", and impacts decision-making at the bedside. In cases with undifferentiated hypotension, ultrasound is often the most readily available option to ensure that the most immediate life-threatening conditions are quickly identified and addressed in the order of their risk potential. PMID- 28851499 TI - The Cardiac Arrest Sonographic Assessment (CASA) exam - A standardized approach to the use of ultrasound in PEA. PMID- 28851500 TI - Controversies and carfentanil: We have much to learn about the present state of opioid poisoning. PMID- 28851502 TI - Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents. AB - Resistance to conventional and target specific antitumor drugs still remains one of the major cause of treatment failure and patience death. This condition often involves ATP-binding cassette (ABC) transporters that, by pumping the drugs outside from cancer cells, attenuate the potency of chemotherapeutics and negatively impact on the fate of anticancer therapy. In recent years, several tyrosine kinase inhibitors (TKIs) (e.g., imatinib, nilotinib, dasatinib, ponatinib, gefitinib, erlotinib, lapatinib, vandetanib, sunitinib, sorafenib) have been reported to interact with ABC transporters (e.g., ABCB1, ABCC1, ABCG2, ABCC10). This finding disclosed a very complex scenario in which TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, affinity for transporters and types of co-administered agents. In this context, in-depth investigation on TKI chemosensitizing functions might provide a strong rationale for combining TKIs and conventional therapeutics in specific malignancies. The reposition of TKIs as antagonists of ABC transporters opens a new way towards anticancer therapy and clinical strategies aimed at counteracting drug resistance. This review will focus on some paradigmatic examples of the complex and not yet fully elucidated interaction between clinical available TKIs (e.g. BCR-ABL, EGFR, VEGFR inhibitors) with the main ABC transporters implicated in multidrug resistance. PMID- 28851501 TI - TET1 inhibits EMT of ovarian cancer cells through activating Wnt/beta-catenin signaling inhibitors DKK1 and SFRP2. AB - OBJECTIVE: Epithelial ovarian cancer (EOC) is the deadliest type of ovarian cancer, but the mechanisms contributing to its tumorigenesis are not well understood. Herein, we will elucidate the role of Ten-eleven translocation 1 (TET1) in EOC development. METHODS: The expression of TET1 in EOC cell lines and primary samples was examined by western blot and immunohistochemistry. The biological role of ectopic TET1 overexpression was revealed by a series of in vitro functional studies. Its downstream signaling pathway was predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of microarray data. The methylation level and expression of Wnt/beta-catenin signaling inhibitors Dikkopf 1 (DKK1) and secreted Fzd receptor protein 2 (SFRP2) were examined by Chromatin immunoprecipitation (ChIP) assay, EpimarkTM 5hmC and 5mC level analysis and quantitative RT-PCR. Small interference RNA (siRNA) technology was used to investigate the biological roles of DKK1 and SFRP2. RESULTS: TET1 expression was inversely correlated with clinical stage in patients with EOC by tissue microarray (TMA). TET1 expression was undetected in 6 types of EOC cell lines. Ectopic expression of TET1 inhibited colony formation, cell migration and invasion in SKOV3 and OVCAR3 cells. Furthermore, TET1 overexpression reversed the epithelial-mesenchymal transition (EMT) process of SKOV3 cells. Mechanistically, TET1 potently inhibited canonical Wnt/beta-catenin signaling by demethylating and upregulating two upstream antagonists of this pathway, SFRP2 and DKK1, which was associated with inhibition of EMT and cancer cell metastasis. CONCLUSION: This study uncovers that TET1 has potent tumor-suppressive effects in EOC by activating Wnt/beta-catenin signaling inhibitors DKK1 and SFRP2. PMID- 28851503 TI - An overview on the recent developments of 1,2,4-triazine derivatives as anticancer compounds. AB - The synthesis, the antitumor activity, the SAR and, whenever described, the possible mode of action of 1,2,4-triazine derivatives, their N-oxides, N,N' dioxides as well as the benzo- and hetero-fused systems are reported. Herein are treated derivatives disclosed to literature from the beginning of this century up to 2016. Among the three possible triazine isomers, 1,2,4-triazines are the most studied ones and many derivatives having remarkable antitumor activity have been reported in the literature and also patented reaching advanced phases of clinical trials. PMID- 28851504 TI - Ultrathin, bioresorbable polymer sirolimus-eluting stents versus thin, durable polymer everolimus-eluting stents in patients undergoing coronary revascularisation (BIOFLOW V): a randomised trial. AB - BACKGROUND: The development of coronary drug-eluting stents has included use of new metal alloys, changes in stent architecture, and use of bioresorbable polymers. Whether these advancements improve clinical safety and efficacy has not been shown in previous randomised trials. We aimed to examine the clinical outcomes of a bioresorbable polymer sirolimus-eluting stent compared with a durable polymer everolimus-eluting stent in a broad patient population undergoing percutaneous coronary intervention. METHODS: BIOFLOW V was an international, randomised trial done in patients undergoing elective and urgent percutaneous coronary intervention in 90 hospitals in 13 countries (Australia, Belgium, Canada, Denmark, Germany, Hungary, Israel, the Netherlands, New Zealand, South Korea, Spain, Switzerland, and the USA). Eligible patients were those aged 18 years or older with ischaemic heart disease undergoing planned stent implantation in de-novo, native coronary lesions. Patients were randomly assigned (2:1) to either an ultrathin strut (60 MUm) bioresorbable polymer sirolimus-eluting stent or to a durable polymer everolimus-eluting stent. Randomisation was via a central web-based data capture system (mixed blocks of 3 and 6), and stratified by study site. The primary endpoint was 12-month target lesion failure. The primary non inferiority comparison combined these data from two additional randomised trials of bioresorbable polymer sirolimus-eluting stent and durable polymer everolimus eluting stent with Bayesian methods. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02389946. FINDINGS: Between May 8, 2015, and March 31, 2016, 4772 patients were recruited into the study. 1334 patients met inclusion criteria and were randomly assigned to treatment with bioresorbable polymer sirolimus-eluting stents (n=884) or durable polymer everolimus-eluting stents (n=450). 52 (6%) of 883 patients in the bioresorbable polymer sirolimus-eluting stent group and 41 (10%) of 427 patients in the durable polymer everolimus-eluting stent group met the 12-month primary endpoint of target lesion failure (95% CI -6.84 to -0.29, p=0.0399), with differences in target vessel myocardial infarction (39 [5%] of 831 patients vs 35 [8%] of 424 patients, p=0.0155). The posterior probability that the bioresorbable polymer sirolimus-eluting stent is non-inferior to the durable polymer everolimus eluting stent was 100% (Bayesian analysis, difference in target lesion failure frequency -2.6% [95% credible interval -5.5 to 0.1], non-inferiority margin 3.85%, n=2208). INTERPRETATION: The outperformance of the ultrathin, bioresorbable polymer sirolimus-eluting stent over the durable polymer everolimus eluting stent in a complex patient population undergoing percutaneous coronary intervention suggests a new direction in improving next generation drug-eluting stent technology. FUNDING: BIOTRONIK. PMID- 28851505 TI - Clostridium difficile on YouTube: A need for greater focus on prevention. AB - The purpose of this study was to describe the content of the most popular YouTube videos related to Clostridium difficile. Across all sources, the kinds of content most likely to be included in the videos was general information, overuse of antibiotics, and symptomatic diarrhea. Health professionals can contribute to existing social media messages related to C. difficile with comprehensive messages that include means for prevention. PMID- 28851506 TI - Swiss Epilepsy Center, Zurich, Switzerland. PMID- 28851507 TI - Why talking about psychiatric comorbidity in PNES? PMID- 28851508 TI - Long-term housing subsidies and SSI/SSDI income: Creating health-promoting contexts for families experiencing housing instability with disabilities. AB - BACKGROUND: Though disability and housing instability are discussed separately in public health literature, few studies address families at their intersection. As a result, little is known about families who experience both homelessness and disability, how many receive disability benefits like SSI and SSDI, or the influence of those benefits on health-promoting outcomes like housing stability and self-sufficiency. Moreover, no previous research compares the ability of different housing and service interventions to increase disability benefit access. OBJECTIVE: We examine relationships between disabilities and SSI/SSDI income reported when families enter emergency shelters and later health-promoting outcomes (housing stability and self-sufficiency) and how housing interventions affect SSI/SSDI receipt. METHODS: Families in the (name removed) Study (N = 1857) were interviewed in emergency shelters, randomly offered of one of three housing interventions or usual care (i.e., no immediate referral to any intervention beyond shelter), and re-interviewed 20 months later. RESULTS: A third of families reported a disability at shelter entry. SSI/SSDI coverage of these families increased nearly 10% points over 20 months but never exceeded 40%. Disabilities predicted greater housing instability, food insecurity, and economic stress and less work and income. Among families reporting disabilities, SSI/SSDI receipt predicted fewer returns to emergency shelter, and more income despite less work. Offers of long-term housing subsidies increased SSI/SSDI receipt. CONCLUSIONS: Many families experiencing homelessness have disabilities; those receiving SSI/SSDI benefits have better housing and income outcomes. Providing families experiencing homelessness with long-term housing subsidies and SSI/SSDI could improve public health. PMID- 28851509 TI - Treatment of varicocele in children and adolescents: A systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND: The prevalence of varicoceles is as high as 15% in children and adolescents. Optimal management of varicoceles has not been consolidated. Options include observation, radiological intervention, or surgical varicocelectomy. OBJECTIVE: Herein, we aim to assess the outcomes of radiological and surgical interventions for varicocele in children and adolescents evaluated by RCTs. STUDY DESIGN: The study subjects were children and adolescents up to 21 years old, diagnosed with varicocele and allocated to receive either "surgical or radiological intervention" or "no treatment". MATERIALS AND METHODS: We searched MEDLINE and EMBASE (Ovid platform), Web of Science, CINAHL, Cochrane Central Register of Controlled Trials, Google Scholar, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform for RCTs reporting on varicocele treatment in children and adolescents up to June 23, 2016. Only RCTs with patients aged under 21 years were included. Main outcomes of interest included changes in testicular size, semen analysis parameters, surgical adverse events and failures. RESULTS: Nine eligible studies were included in the systematic review. Meta-analysis based on available outcomes data demonstrated an improvement in testicular volume (mean difference 3.18 mL, 95% CI 1.94-4.42) and in sperm count (mean difference 25.54 * 106/mL, 95% CI 12.84-38.25) in patients who underwent radiological or surgical treatment compared with conservative management. CONCLUSIONS: Based on current available randomized controlled trials, there is low to moderate level of evidence that radiological or surgical treatment of adolescent varicocele is associated with improved testicular size/growth and sperm concentration. The ultimate effects on fertility and paternity rates are not known. PMID- 28851510 TI - Early discharge in Mild Acute Pancreatitis. Is it possible? Observational prospective study in a tertiary-level hospital. AB - BACKGROUND AND AIMS: In acute pancreatitis (AP), first 24 h are crucial as this is the period in which the greatest amount of patients presents an organ failure. This suggests patients with Mild AP (MAP) could be early identified and discharged. This is an observational prospective trial with the aim to demonstrate the safety of early discharge in Mild Acute Pancreatitis (MAP). METHODS: Observational prospective study in a third level single centre. Consecutive patients with AP from March 2012 to March 2014 were collected. INCLUSION CRITERIA: MAP, tolerance to oral intake, control of pain, C Reactive Protein <150 mg/dL and blood ureic nitrogen < 5 mg/dL in two samples. EXCLUSION CRITERIA: pregnant, lack of family support, active comorbidities, temperature and serum bilirubin elevation. Patients with MAP, who met the inclusion criteria, were discharged within the first 48 h. Readmissions within first week and first 30 days were recorded. Adverse effects related to readmissions were also collected. RESULTS: Three hundred and seventeen episodes were collected of whom 250 patients were diagnosed with MAP. From these, 105 were early discharged. Early discharged patients presented a 30-day readmission rate of 15.2% (16 patients out of 105) corresponding to the readmission rates in Acute Pancreatitis published to date. Any patient presented adverse effects related to readmissions. CONCLUSION: Early discharge in accurately selected patients with MAP is feasible, safe and efficient and leads to a decrease in median stay with the ensuing savings per process and with no increase in readmissions or inmorbi-mortality. PMID- 28851511 TI - Polypharmacy, potentially inappropriate medications and drug-drug interactions in geriatric patients with hematologic malignancy: Observational single-center study of 122 patients. AB - OBJECTIVES: Geriatric patients with hematologic malignancies (HMs) are prescribed targeted and supportive care treatments that add to the preexisting polypharmacy (PP). PP is associated with an increased risk of potentially inappropriate medications (PIM) and drug-drug interactions (DDI) resulting in increased hospitalization and mortality in the elderly. As very few data exist on these medication issues in the context of HMs, the objective of this study was to evaluate prevalence of PP, DDI and PIM use at baseline and 3months among elderly patients with HMs who received baseline geriatric assessment. METHODS: PP, DDI and PIM use were assessed by a clinical pharmacist at two time points in patients over 75years with HMs undergoing chemotherapy. PP was defined as the concurrent use of five or more medications. DDIs were evaluated according to the literature and prescription analysis software. PIMs were assessed according to the Laroche list. RESULTS: 122 patients (mean age 81.5; 6.6 medications) were included and after 3months, 86 patients (5.8 medications) were available for a second assessment. Prevalence of PP, PIM and DDI at inclusion was 75.4%, 34.4% and 71.3%, respectively. PP was the only medication risk that was significantly reduced (p<0.05) at 3months (65.1%) compared to admission. CONCLUSION: This observational study highlighted that PP decreased over time but neither DDI nor PIM use were reduced. A pharmacist-led evaluation might help to manage these medication issues. PMID- 28851512 TI - Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naive and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials. AB - Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (beta-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine, lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and monitoring of patients with GD. This retrospective, exploratory analysis of data from phase 3 clinical trials of velaglucerase alfa in patients with type 1 GD evaluated the potential of lyso-Gb1 as a specific and sensitive biomarker for GD. A total of 22 treatment-naive patients and 21 patients previously treated with imiglucerase (switch patients) were included in the analysis. Overall, demographics between the two groups were similar. Mean lyso-Gb1 concentrations were reduced by 302.2ng/mL from baseline to week 209 in treatment-naive patients and by 57.3ng/mL from baseline to week 161 in switch patients, corresponding to relative reductions of 82.7% and 52.0%, respectively. In both the treatment-naive and switch groups, baseline mean lyso-Gb1 was higher for patients with at least one N370S mutation (363.9ng/mL and 90.7ng/mL, respectively) than for patients with non-N370S mutations (184.6ng/mL and 28.3ng/mL, respectively). Moderate correlations between decreasing lyso-Gb1 levels and increasing platelet counts, and with decreasing spleen volumes, were observed at some time points in the treatment-naive group but not in the switch group. These findings support the utility of lyso-Gb1 as a sensitive and reliable biomarker for GD, and suggest that quantitation of this biomarker could serve as an indicator of disease burden and response to treatment. PMID- 28851513 TI - Flavoprotein fluorescence imaging-based electrode implantation for subfield targeted chronic recording in the mouse auditory cortex. AB - BACKGROUND: Chronic neural recording in freely moving animals is important for understanding neural activities of cortical neurons associated with various behavioral contexts. In small animals such as mice, it has been difficult to implant recording electrodes into exact locations according to stereotactic coordinates, skull geometry, or the shape of blood vessels. The main reason for this difficulty is large individual differences in the exact location of the targeted brain area. NEW METHODS: We propose a new electrode implantation procedure that is combined with transcranial flavoprotein fluorescence imaging. We demonstrate the effectiveness of this method in the auditory cortex (AC) of mice. RESULTS: Prior to electrode implantation, we executed transcranial flavoprotein fluorescence imaging in anesthetized mice and identified the exact location of AC subfields through the skull in each animal. Next, we surgically implanted a microdrive with a tungsten electrode into exactly the identified location. Finally, we recorded neural activity in freely moving conditions and evaluated the success rate of recording auditory responses. COMPARISON WITH EXISTING METHOD(S): These procedures dramatically improved the success rate of recording auditory responses from 21.1% without imaging to 100.0% with imaging. We also identified large individual differences in positional relationships between sound-driven response areas and the squamosal suture or blood vessels. CONCLUSIONS: Combining chronic electrophysiology with transcranial flavoprotein fluorescence imaging before implantation enables the realization of reliable subfield-targeted neural recording from freely moving small animals. PMID- 28851514 TI - A novel calcium-independent phospholipase A2 and its physiological roles in development and immunity of a lepidopteran insect, Spodoptera exigua. AB - Phospholipase A2 (PLA2) catalyzes hydrolysis of ester linkage at sn-2 position of phospholipids. At least 15 groups (I-XV) of PLA2 gene superfamily are associated with various physiological processes such as digestion, secretion, immunity, and maintenance of membrane integrity. This study suggests that various insects encode putative Group VI PLA2s representing intracellular and calcium-independent PLA2s (iPLA2). These insect iPLA2s are separated into at least two subgroups: iPLA2A (Group VIA-like) and iPLA2B (non-Group VIA). Most insects encode genes of iPLA2B type, although their biological functions are currently unknown. This study predicted a novel iPLA2 from Spodoptera exigua (a lepidopteran insect) (SeiPLA2B) and analyzed its physiological functions by RNA interference (RNAi). SeiPLA2B encodes 336 amino acid sequence with a predicted size of about 36.6 kDa and an isoelectric point at pH 8.61. It possesses a lipase catalytic site, but does not have ankyrin repeats in the amino terminal region. Phylogenetic analysis indicated that SeiPLA2B was clustered with other Group VI iPLA2s, in which SeiPLA2B was closely associated with Group VIF gene while SeiPLA2A was closely related to Group VIA gene. SeiPLA2B was expressed in all developmental stages of S. exigua. In larval stage, SeiPLA2B was expressed in fat body, hemocyte, and epidermis, but not in digestive tract. SeiPLA2B RNAi significantly reduced PLA2 enzyme activities and resulted in developmental retardation and immunosuppression. Though RNAi treatment did not significantly change fatty acid composition in fat body lipids, it significantly increased lipid peroxidation. Taken together, our results suggest that SeiPLA2B plays important roles in the development and immunity of S. exigua. PMID- 28851516 TI - Brominated and organophosphate flame retardants target different neurodevelopmental stages, characterized with embryonic neural stem cells and neuronotypic PC12 cells. AB - In addition to their activity as endocrine disruptors, brominated and organophosphate flame retardants are suspected to be developmental neurotoxicants, although identifying their specific mechanisms for that activity has been elusive. In the current study, we evaluated the effects of several flame retardants on neurodifferentiation using two in vitro models that assess distinct "decision nodes" in neural cell development: embryonic rat neural stem cells (NSCs), which evaluate the origination of neurons and glia from precursors, and rat neuronotypic PC12 cells, which characterize a later stage where cells committed to a neuronal phenotype undergo neurite outgrowth and neurotransmitter specification. In NSCs, both brominated and organophosphate flame retardants diverted the phenotype in favor of glia and away from formation of neurons, leading to an increased glia/neuron ratio, a common hallmark of the in vivo effects of neurotoxicants. For this early decision node, the brominated flame retardants were far more potent than the organophosphates. In PC12 cells, the brominated flame retardants were far less effective, whereas tris (1,3-dichloro-2 propyl) phosphate, an organophosphate, was more effective. Thus, the two classes of flame retardants differentially impact the two distinct vulnerable periods of neurodifferentiation. Furthermore, the effects on neurodifferentiation were separable from outright cytotoxicity, an important requirement in establishing a specific effect of these agents on neural cell development. These results reinforce the likelihood that flame retardants act as developmental neurotoxicants via direct effects on neural cell differentiation, over and above other activities that can impact nervous system development, such as endocrine disruption. PMID- 28851518 TI - Editorial. PMID- 28851517 TI - An integrative appraisal of mechano-electric feedback mechanisms in the heart. AB - Mechanically-induced alterations in cardiac electrophysiology are referred to as mechano-electric feedback (MEF), and play an important role in electrical regulation of cardiac performance. The influence of mechanical stress and strain on electrophysiology has been investigated at all levels, however the role of MEF in arrhythmia remains poorly understood. During the normal contraction of the heart, mechano-sensitive processes are an implicit component of cardiac activity. Under abnormal mechanical events, stretch-activated mechanisms may contribute to local or global changes in electrophysiology (EP). While such mechanisms have been hypothesised to be involved in mechanically-initiated arrhythmias, the details of these mechanisms and their importance remain elusive. We assess the theoretical role of stretch mechanisms using coupled models of cellular electrophysiology and sarcomere contraction dynamics. Using models of single ventricular myocytes, we first investigated the potential MEF contributions of stretch-activated currents (SAC), and stretch-induced myofilament calcium release, to test how strain and fibrosis may alter cellular electrophysiology. For all models investigated, SACs were alone not sufficient to create a pro arrhythmic perturbation of the action potential with stretch. However, when combined with stretch-induced myofilament calcium release, the action potential could be shortened depending on the timing of the strain. This effect was highly model dependent, with a canine epicardial EP model being the most sensitive. These model results suggest that known mechanisms of mechano-electric coupling in cardiac myocyte may be sufficient to be pro-arrhythmic, but only in combination and under specific strain patterns. PMID- 28851520 TI - Exercise intensity and inflammation in type 2 diabetes. PMID- 28851519 TI - Bioactive glass ceramic nanoparticles-coated poly(l-lactic acid) scaffold improved osteogenic differentiation of adipose stem cells in equine. AB - Horses with big bone fractures have low chance to live mainly due to the lake of a proper treatment strategy. We believe that further attempts in equine bone tissue engineering will probably be required to meet all the needs for the lesion therapies. Therefore in this study we aimed to investigate the osteogenic differentiation capacity of equine adipose-derived stem cells (e-ASCs) on nano bioactive glass (nBGs) coated poly(l-lactic acid) (PLLA) nanofibers scaffold (nBG PLLA). Using electrospinning technique, PLLA scaffold was prepared successfully and coated with nBGs. Fabricated nanofibers were characterized by MTT, SEM, and FTIR analyses, and then osteogenic differentiation potential of isolated e-ASCs was investigated by the most key osteogenic markers, namely Alizarin red-S, ALP, calcium content and bone related (RUNX2, Collagen I, Osteonectin, and ALP) gene markers. Our results indicated that nBGs was successfully coated on PLLA scaffold and this scaffold had no negative (p>0.05) effect on cell growth rate as indicated by MTT assay. Moreover, e-ASCs that differentiated on nBGs-PLLA scaffold showed a higher (p<0.05) ALP activity, more (p<0.05) calcium content, and higher (p<0.05) expression of bone-related genes than that on uncoated PLLA scaffold and TCPS. According to the results, a combination of bioceramics and biopolymeric nanofibers hold valuable promising potentials to use for bone tissue engineering application and regenerative medicine. PMID- 28851515 TI - Alterations in the E3 ligases Parkin and CHIP result in unique metabolic signaling defects and mitochondrial quality control issues. AB - E3 ligases are essential scaffold proteins, facilitating the transfer of ubiquitin from E2 enzymes to lysine residues of client proteins via isopeptide bonds. The specificity of substrate binding and the expression and localization of E3 ligases can, however, endow these proteins with unique features with variable effects on mitochondrial, metabolic and CNS function. By comparing and contrasting two E3 ligases, Parkin and C-terminus of HSC70-Interacting protein (CHIP) we seek to highlight the biophysical properties that may promote mitochondrial dysfunction, acute stress signaling and critical developmental periods to cease in response to mutations in these genes. Encoded by over 600 human genes, RING-finger proteins are the largest class of E3 ligases. Parkin contains three RING finger domains, with R1 and R2 separated by an in-between region (IBR) domain. Loss-of-function mutations in Parkin were identified in patients with early onset Parkinson's disease. CHIP is a member of the Ubox family of E3 ligases. It contains an N-terminal TPR domain and forms unique asymmetric homodimers. While CHIP can substitute for mutated Parkin and enhance survival, CHIP also has unique functions. The differences between these proteins are underscored by the observation that unlike Parkin-deficient animals, CHIP null animals age prematurely and have significantly impaired motor function. These properties make these E3 ligases appealing targets for clinical intervention. In this work, we discuss how biophysical and metabolic properties of these E3 ligases have driven rapid progress in identifying roles for E3 ligases in development, proteostasis, mitochondrial biology, and cell health, as well as new data about how these proteins alter the CNS proteome. PMID- 28851521 TI - Incidence of bone protection and associated fragility injuries in patients with proximal femur fractures. AB - OBJECTIVES: Our aim was to investigate whether patients presenting with fragility fractures of the proximal femur are receiving osteoporosis treatment and to assess the number of other fragility fractures they have sustained prior to admission. METHODS: All patients presenting to our institution with fragility fractures of the proximal femur within an 18-month period (January 2012-August 2013) were included. Patient demographics; fracture classification (AO/OTA); American Society of Anesthesiologists (ASA) grade; Abbreviated Mental Test Score (AMTS) on admission; type of operation; time to operation; peri-operative complications; length of hospital stay (LOS); walking status; osteoporotic medication; Dual-energy X-ray absorptiometry (DEXA) results; additional fragility fractures; and mortality were collected and analysed. RESULTS: A total of 1004 patients (278 male) met the inclusion criteria and were included into the study. The mean age was 82.01 years and mean LOS was 19.54days. Fifty-four per cent of the patients were admitted from their own homes whereas 43% were capable to walk indoors without any aids before their injury. Mean time to surgery was 2.06days (Median: 1.31, range: 0-26days). Three hundred and six patients (30.5%) had at least another fragility fracture before the index episode (mean 1.40 fractures; SD: 0.71 fractures; range: 1-6 fractures). Only 16.4% were under complete osteoporosis treatment on admission, defined as receiving calcium with vitamin D and a bisphosphonate or an alternative agent. When we compared patients without a history of a previous fragility fracture (Group A) and patients with at least another previous fragility fracture (Group B), we found that patients in Group B had a significantly lower AMTS score, lower bone mineral density (BMD) as evident on the DEXA scan, an inferior mobility before admission and a higher incidence of extracapsular fractures (p<0.05). On discharge, patients in Group B had a higher chance of receiving complete bone protection compared to group A (27.9% versus 41.7%; p<0.01). Following discharge, 11.2% of the patients sustained an additional fragility fracture. The mean time from the index episode to the additional fracture was 0.65 years, whilst these injuries were more frequent in Group B (RR=1.638; p<0.05). CONCLUSION: Patients presenting with a hip fracture are generally under-treated for osteoporosis. Post-operative assessment by a designated geriatrician and use of a standardised protocol is of paramount importance for reducing the risk of additional fragility fractures. Additionally, screening of the elderly population for identifying the patients who suffer from osteoporosis can potentially reduce the risk of sustaining a further fragility fracture. PMID- 28851522 TI - Dementia and fragility fractures: Issues and solutions. AB - Dementia and fragility fractures are two conditions that pose significant morbidity and mortality to the elderly population. The occurrence of the 'gerontic' boom as a result of improved healthcare meant a continued increase in the prevalence of fragility fractures and dementia. This represents a major public health problem with significant socioeconomic repercussions. It is therefore important for healthcare professionals to gain a better understanding on the relationship between these two commonly co-existing conditions. In this review, we present the available literature surrounding the relationship between fragility fractures and dementia, and the common challenges faced in the management of these two conditions. Combining evidence from the literature along with our current clinical practice, we propose a management pathway aimed at early diagnosis, prevention and management of these two often co-existing conditions. This alongside with a multidisciplinary approach will not only translate to improved patient outcomes and survivorship, but also reduced healthcare cost and socio-economic burden. To date, there is insufficient evidence from the literature to suggest whether dementia is the cause or effect for fragility fractures, or if indeed there is a bidirectional relationship between the two conditions. Further studies are required to shed light onto this important clinical topic. PMID- 28851523 TI - Hip osteoarthritis as a predictor of the fracture pattern in proximal femur fractures. AB - INTRODUCTION: Several authors have suggested a correlation between the fracture patterns of proximal femur fractures and the degree of hip osteoarthritis (HOA), but the current evidence to support this are insufficient. The aim of our study was to demonstrate whether there is an association between the grade of HOA and fracture pattern observed, in patients presenting with a fragility fracture of the proximal femur. MATERIALS AND METHODS: We contacted a retrospective review of all patients presenting to our institution with fragility fractures involving the proximal femur, between March 2012 and October 2013. Pathological fractures, high energy injuries and patients with less than one year of follow-up were excluded from further analysis. Admission radiographs and severity of HOA were assessed according to Kellgren and Lawrence scale (minimal: Grades 1-2; severe: Grades 3 4). Fractures were classified according to AO/OTA classification. RESULTS: A total of 1003 patients (725 females; 1003 fractures) met the inclusion criteria, having a mean age of 81.5 (46-106 years). With regards to fracture classification, 417 (41.6%) fractures were classified as extracapsular and 586 (58.4%) as intracapsular. A total of 939 (93.9%) patients presented with minimal HOA, whilst 61 (6.1%) of the patients presented with severe HOA. Of the 61 patients presenting with severe HOA, 42 patients (68.9%) sustained a 31A interthrocanteric fracture and 19 patients (31.1%) sustained a 31B-intracapsular fracture. Regarding the patients presenting with minimal HOA (832 patients in total), 323 patients (38.8%) sustained 31A-intertrochanteric fracture and 509 patients (61.2%) sustained a 31B-intracapsular fracture. Patients presenting with severe HOA were found to have a statistically significant chance to present with an extracapsular fracture (p<0.01). CONCLUSIONS: The degree of HOA is related to the fracture pattern in patients presenting following simple mechanical falls. More specifically, higher grades of HOA are associated with extracapsular fracture patterns, whereas lower grades of HOA are associated with intracapsular fracture patterns. PMID- 28851524 TI - Separation of oligopeptides, nucleobases, nucleosides and nucleotides using capillary electrophoresis/electrochromatography with sol-gel modified inner capillary wall. AB - The aim of this article is to study the modification of an inner capillary wall with sol-gel coating (pure silica sol-gel or silica sol-gel containing porphyrin brucine conjugate) and determine its influence on the separation process using capillary electrophoresis/electrochromatography method. After modification of the inner capillary surface the separation of analytes was performed using two different phosphate buffers (pH 2.5 and 9.0) and finally the changes in electrophoretic mobilities of various samples were calculated. To confirm that the modification of the inner capillary surface was successful, the parts of the inner surfaces of capillaries were observed using scanning electron microscopy. The analytes used as testing samples were oligopeptides, nucleosides, nucleobases and finally nucleotides. PMID- 28851525 TI - Application of a new procedure for liquid chromatography/mass spectrometry profiling of plasma amino acid-related metabolites and untargeted shotgun proteomics to identify mechanisms and biomarkers of calcific aortic stenosis. AB - Calcific aortic valve stenosis (CAS) increasingly affects our ageing population, but the mechanisms of the disease and its biomarkers are not well established. Recently, plasma amino acid-related metabolite (AA) profiling has attracted attention in studies on pathology and development of biomarkers of cardiovascular diseases, but has not been studied in CAS. To evaluate the potential relationship between CAS and AA metabolome, a new ion-pairing reversed-phase liquid chromatography-tandem mass spectrometry (IP-RPLC-MS/MS) method has been developed and validated for simultaneous determination of 43 AAs in plasma of stenotic patients and age-matched control subjects. Furthermore, untargeted mass spectrometry-based proteomic analysis and confirmatory ELISA assays were performed. The method developed offered high accuracy (intra-assay imprecision averaged 4.4% for all compounds) and sensitivity (LOQ within 0.01-0.5MUM). We found that 22 AAs and three AA ratios significantly changed in the CAS group as compared to control. The most pronounced differences were observed in urea cycle related AAs and branched-chain AA (BCAA)-related AAs. The contents of asymmetric dimethylarginine (ADMA) and its monomethylated derivative (NMMA) were increased by 30-64% with CAS. The arginine/ADMA and Fischer's ratios as well as arginine, homoarginine, ADMA, symmetric dimethylarginine, hydroxyproline, betaine and 3 methylhistidine correlated with cardiac function-related parameters and concomitant systemic factors in the CAS patients. The results of proteomic analysis were consistent with involvement of inflammation, lipid abnormalities, hemostasis and extracellular matrix remodeling in CAS. In conclusion, changes in plasma AA profile and protein pattern that we identified in CAS provide information relevant to pathomechanisms and may deliver new biomarkers of the disease. PMID- 28851526 TI - Gas chromatography and isotope ratio mass spectrometry of Pinot Noir wine volatile compounds (delta13C) and solid residues (delta13C, delta15N) for the reassessment of vineyard water-status. AB - This paper describes a novel approach to reassess the water status in vineyards based on compound-specific isotope analysis (CSIA) of wine volatile organic compounds (delta13CVOC/VPDB) and bulk carbon and nitrogen isotopes, and the C/N molar ratios of the wine solid residues (delta13CSR/VPDB, delta15NSR/Air-N2). These analyses link gas chromatography/combustion and elemental analysis to isotope ratio mass spectrometry (GC/C/IRMS, EA/IRMS). Field-grown cultivars of Pinot Noir grapevines were exposed during six growing seasons (2009-2014) to controlled soil water availability, while maintaining identical the other environmental variables and agricultural techniques. Wines were produced from the grapes by the same oenological protocol. This permitted for the assessment of the effects in the biochemistry of wines solely induced by the changes in the plant soil water status. This mimicked the more recurrent and prolonged periods of soil water deficiency due to climate changes. Water stress in grapevine was assessed by the measurement of the predawn leaf water potential (Psipd) and the stable carbon isotope composition of the berry sugars during harvest (must sugars). For quantitation purposes and the normalization of the measured stable carbon isotope ratios of the VOCs, the wine samples were spiked with three standard compounds with known concentration and delta13CVPDB values. VOCs were extracted by liquid liquid extraction and analyzed by gas chromatography/flame ionization detection (GC/FID), gas chromatography/mass spectrometry (GC/MS), and GC/C/IRMS. delta13C values were obtained for eighteen VOCs. The solid residues were obtained by freeze-drying wine aliquots and were analyzed for their C and N content and isotope composition by EA/IRMS. All the isotopic ratios (delta13CSR, delta15NSR, delta13CVOC) are highly correlated with the Psipd values, indicating that the proposed gas chromatography and isotope ratio mass spectrometry approach is a useful tool to assess the changes in the water status of grapevine cultivars in different terroirs. The combined analytical approach was used for the first time to complement the assessment of soil water availability effects on the grapevine. The delta13C values of the volatile compounds helped confirm (or establish) their main source(s) and biosynthetic pathway(s). Importantly, we also show for the first time that the combination of C/N and delta15N values of freeze-dried wines have an unexplored potential for the study of nitrogen dynamics in soil/grape/wine systems. PMID- 28851527 TI - Determination of 3-hydroxypropylmercapturic acid in urine by three column switching high-performance liquid chromatography with electrochemical detection using a diamond electrode. AB - A three column-switching high-performance liquid chromatography (HPLC) using an electrochemical detector (ECD) equipped with a diamond electrode was established to determine 3-hydroxypropylmercapturic acid (3-HPMA) in urine. An extracted urine sample was consecutively fractionated using a strong anion-exchange column (first column) and a C8 column (second column) via a switching valve before application on an Octa Decyl Silyl (ODS) column (third column), followed by ECD analysis. The% recovery of 3-HPMA standard throughout the three-column process and limit of detection (LOD) were 94+/-1% and 0.1pmol, respectively. A solid phase extraction step is required for the sensitive analysis of 3-HPMA in urine by column-switching HPLC-ECD despite a decreased% recovery (55%) of urine sample spiked with 100pmol of 3-HPMA. To test the utility of our column-switching HPLC ECD method, 3-HPMA levels of 27 urine samples were determined, and the correlation between HPLC-ECD and LC-Electrospray ionization (ESI)-MS/MS method was examined. As a result, the median values of MUmol 3-HPMA/g Creatinine (Cre) in urine obtained by column-switching HPLC-ECD and LC-MS/MS were 2.19+/ 2.12MUmol/g Cre and 2.13+/-3.38MUmol/g Cre, respectively, and the calibration curve (y=1.5171x-1.007) exhibited good linearity within a defined range (r2=0.907). These results indicate that the combination of column-switching HPLC and ECD is a powerful tool for the specific, reliable detection of 3-HPMA in urine. PMID- 28851528 TI - Liquid chromatography-tandem mass spectrometry multiresidue method for the analysis of quaternary ammonium compounds in cheese and milk products: Development and validation using the total error approach. AB - Quaternary ammonium compounds (QACs) are both cationic surfactants and biocidal substances widely used as disinfectants in the food industry. A sensitive and reliable method for the analysis of benzalkonium chlorides (BACs) and dialkyldimethylammonium chlorides (DDACs) has been developed that enables the simultaneous quantitative determination of ten quaternary ammonium residues in dairy products below the provisional maximum residue level (MRL), set at 0.1mgkg 1. To the best of our knowledge, this method could be the one applicable to milk and to three major processed milk products selected, namely processed or hard pressed cheeses, and whole milk powder. The method comprises solvent extraction using a mixture of acetonitrile and ethyl acetate, without any further clean-up. Analyses were performed by liquid chromatography coupled with electrospray tandem mass spectrometry detection (LC-ESI-MS/MS) operating in positive mode. A C18 analytical column was used for chromatographic separation, with a mobile phase composed of acetonitrile and water both containing 0.3% formic acid; and methanol in the gradient mode. Five deuterated internal standards were added to obtain the most accurate quantification. Extraction recoveries were satisfactory and no matrix effects were observed. The method was validated using the total error approach in accordance with the NF V03-110 standard in order to characterize the trueness, repeatability, intermediate precision and analytical limits within the range of 5-150MUgkg-1 for all matrices. These performance criteria, calculated by e.noval(r) 3.0 software, were satisfactory and in full accordance with the proposed provisional MRL and with the recommendations in the European Union SANTE/11945/2015 regulatory guidelines. The limit of detection (LOD) was low (<1.9MUgkg-1) and the limit of quantification (LOQ) ranged from 5MUgkg-1 to 35MUgkg-1 for all matrices depending on the analytes. The validation results proved that the method is suitable for quantifying quaternary ammoniums in foodstuffs from dairy industries at residue levels, and could be used for biocide residues monitoring plans and to measure the exposition consumer to biocides products. PMID- 28851529 TI - Foam separation of Rhodamine-G and Evans Blue using a simple separatory bottle system. AB - A simple separatory glass bottle was used to improve separation effectiveness and cost efficiency while simultaneously creating a simpler system for separating biological compounds. Additionally, it was important to develop a scalable separation method so this would be applicable to both analytical and preparative separations. Compared to conventional foam separation methods, this method easily forms stable dry foam which ensures high purity of yielded fractions. A negatively charged surfactant, sodium dodecyl sulfate (SDS), was used as the ligand to carry a positively charged Rhodamine-G, leaving a negatively charged Evans Blue in the bottle. The performance of the separatory bottle was tested for separating Rhodamine-G from Evans Blue with sample sizes ranged from 1 to 12mg in preparative separations and 1-20MUg in analytical separations under optimum conditions. These conditions including N2 gas pressure, spinning speed of contents with a magnetic stirrer, concentration of the ligand, volume of the solvent, and concentration of the sample, were all modified and optimized. Based on the calculations at their peak absorbances, Rhodamine-G and Evans Blue were efficiently separated in times ranging from 1h to 3h, depending on sample volume. Optimal conditions were found to be 60psi N2 pressure and 2mM SDS for the affinity ligand. This novel separation method will allow for rapid separation of biological compounds while simultaneously being scalable and cost effective. PMID- 28851530 TI - Van de Graaff generator for capillary electrophoresis. AB - A new approach for high voltage capillary electrophoresis (CE) is proposed, which replaces the standard high voltage power supply with a Van de Graaff generator, a low current power source. Because the Van de Graaff generator is a current limited source (10MUA), potentials exceeding 100kV can be generated for CE when the electrical resistance of the capillary is maximized. This was achieved by decreasing the capillary diameter and reducing the buffer ionic strength. Using 2mM borate buffer and a 5MUm i.d. capillary, fluorescently labeled amino acids were separated with efficiencies up to 3.5 million plates; a 5.7 fold improvement in separation efficiency compared to a normal power supply (NPS) typically used in CE. This separation efficiency was realized using a simple set-up without significant Joule heating, making the Van de Graaff generator a promising alternative for applying the high potentials required for enhancing resolution in the separation and analysis of highly complex samples, for example mixtures of glycans. PMID- 28851531 TI - Impact of old Schistosomiasis infection on the use of transient elastography (Fibroscan) for staging of fibrosis in chronic HCV patients. AB - BACKGROUND AND AIM: In tropical regions, Hepatitis C virus (HCV) - Schistosomiasis coinfection remains one of the health problems. With the new era of HCV treatment and the variety of methods of assessment of liver fibrosis so we aimed to evaluate the effectiveness of FibroScan for staging hepatic fibrosis in HCV-Schistosomiasis coinfected patients. METHODOLOGY: Three groups of patients were enrolled. Group 1: chronic HCV with out antischistosomal antibody (122 patients), Group 2: chronic HCV with positive antischistosomal antibodies and without periportal tract thickening (122 patients), Group 3: chronic HCV with positive antischistosomal antibodies and ultrasonographic picture of periportal tract thickening (108 patients). Routine laboratory workup, serum Antischistosomal antibody, and Schistosomal antigen in serum were performed. Ultrasound guided liver biopsy with histopathological examination; abdominal ultrasound and fibroscan examination were done for all patients. RESULTS: The agreement between results of liver biopsy and results of fibroscan in the staging of fibrosis was the best in group 1 (55.7%), Although the agreement was higher among those with no periportal tract thickening (70.7%) and the disagreement was higher among those with positive schistosomal serology (66.5%), yet this relation was not statistically significant. Multivariate logistic regression analysis showed that disagreement is significantly associated with older age, higher BMI (>=30), and increase in anti Schistosomal antibody titer. CONCLUSION: Fibroscan is a reliable, non-invasive tool for staging hepatic fibrosis among HCV schistosomiasis co-infected patients with no effect of the induced periportal tract thickening on the readings. Only higher antischistosomal antibody titres may cause disagreement between liver biopsy and fibroscan. PMID- 28851532 TI - Adult sepsis - A nationwide study of trends and outcomes in a population of 23 million people. AB - OBJECTIVES: To determine the trend of incidence and outcome of sepsis based on a nationwide administrative database. METHODS: We analyzed the incidence and mortality of both emergency department treated and hospital treated sepsis from 2002 through 2012 using the entire health insurance claims data of Taiwan. The national health insurance covers 99% of residents in Taiwan. Sepsis patients were identified using a set of validated ICD-9CM codes conforming to the sepsis-3 definition. The 30-day all-cause mortality was verified by linked death certificate database. RESULTS: During the 11-year study period, a total of 1,259,578 episodes of sepsis was identified. The mean incidence rate was 639 per 100,000 person-years, increasing from 637.8/100,000 persons in 2002 to 772.1/100,000 persons in 2012 (annual increase: 1.9%). The mortality rate, however, has decreased from 27.8% in 2002 to 22.8% in 2012 (annual decrease: 0.45%). The trend of incidence and mortality did not change after standardization by age and gender using 2002 as the reference standard. CONCLUSION: We showed that the incidence of sepsis has increased while the mortality has decreased in Taiwan. Despite the decreasing trend in sepsis mortality, the total number of sepsis mortality remains increasing due to the rapid increase in sepsis incidence. PMID- 28851533 TI - In utero exposure to malaria is associated with metabolic traits in adolescence: The Agogo 2000 birth cohort study. AB - OBJECTIVES: Malaria in pregnancy (MiP) contributes to fetal undernutrition and adverse birth outcomes, and may constitute a developmental origin of metabolic diseases in the offspring. In a Ghanaian birth cohort, we examined the relationships between MiP-exposure and metabolic traits in adolescence. METHODS: MiP at delivery was assessed in 155 mother-child pairs. Among the now teenaged children (mean age, 14.8 years; 53% male), we measured fasting plasma glucose (FPG), body mass index (BMI), and systolic and diastolic blood pressure (BP). Associations of MiP with the adolescents' FPG, BMI, and BP were examined by linear regression. RESULTS: At delivery, 45% were MiP-exposed, which increased FPG in adolescence, adjusted for mother's age at delivery, parity and familial socio-economic status (infected vs. uninfected: mean DeltaFPG = 0.20 mmol/L; 95% confidence interval (CI): 0.01, 0.39; p = 0.049). As a trend,this was discernible for BP, particularly for microscopic infections (mean Deltasystolic BP = 5.43 mmHg; 95% CI: 0.00, 10.88; p = 0.050; mean Deltadiastolic BP = 3.67 mmHg; 95% CI: -0.81, 8.14; p = 0.107). These associations were largely independent of birth weight, gestational age and teenage BMI. Adolescent BMI was not related to MiP. CONCLUSIONS: In rural Ghana, exposure to malaria during fetal development contributes to metabolic conditions in young adulthood. PMID- 28851534 TI - Growth, blood health, antioxidant status, immune response and resistance to Aeromonas hydrophila of juvenile yellow catfish exposed to di-2-ethylhexyl phthalate (DEHP). AB - Triplicate groups of juvenile yellow catfish Pelteobagrus fulvidraco were exposed to three levels of DEHP (0, 0.1 and 0.5mgL-1) for 56days. Fish survival (100%) was not affected by different levels of ambient DEHP. Final body weight, weight gain, specific growth rate and feed intake of fish exposed to 0.5mgL-1 DEHP were the highest. On the contrary, hepatosomatic index of fish exposed to 0.1 and 0.5mgL-1 DEHP were the lowest. Serum total protein, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, glucose and triglycerides increased with the increasing concentrations of DEHP exposure. Superoxide dismutase and glutathione peroxidase activities of fish exposed to 0.5mgL-1 DEHP were the lowest, but malondialdehyde contents of fish exposed to 0.1 and 0.5mgL-1 DEHP were higher than that of control fish. Phagocytic indices of the control group were the highest. After being intraperitoneally injected with Aeromonas hydrophila, fish in the control group had the highest expression of toll like receptor 5, and the expression of myeloid differentiation factor 88 of fish exposed to 0.5mgL-1 DEHP was the lowest. This study indicates that DEHP exerts its toxic effects by interfering with hepatic metabolism, inducing ROS generation and malondialdehyde accumulation, leading to blood deterioration and immunosuppression. PMID- 28851535 TI - Comment on "An evaluation of oxidative and nitrosative stress in children-who stutter and its relationship to severity". PMID- 28851536 TI - Radiation induced transcriptional and post-transcriptional regulation of the hsa miR-23a~27a~24-2 cluster suppresses apoptosis by stabilizing XIAP. AB - The non-coding transcriptome, in particular microRNAs (miRNA), influences cellular survival after irradiation. However, the underlying mechanisms of radiation-induced miRNA expression changes and consequently target expression changes are poorly understood. In this study we show that a single dose of 5Gy gamma-radiation decreases expression of the miR-23a~27a~24-2 cluster in the human endothelial cell-line EA.hy926 and the mammary epithelial cell-line MCF10A. In the endothelial cells this was facilitated through transcriptional regulation by promoter methylation and also at the post-transcriptional level by reduced miRNA processing through phosphorylation of Argonaute (AGO). Furthermore, we demonstrate that all three mature cluster miRNAs reduce apoptosis by increasing expression of the common target protein XIAP. These findings link a temporal succession of transcriptional and post-transcriptional regulatory mechanisms of the miR~23a~24-2~27a cluster, enabling a dynamic stress response and assuring cellular survival after radiation exposure. PMID- 28851537 TI - Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca-Charles River Laboratories strategic relationship. AB - In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies. PMID- 28851538 TI - Unusual loss of chymosin in mammalian lineages parallels neo-natal immune transfer strategies. AB - Gene duplication and loss are powerful drivers of evolutionary change. The role of loss in phenotypic diversification is notably illustrated by the variable enzymatic repertoire involved in vertebrate protein digestion. Among these we find the pepsin family of aspartic proteinases, including chymosin (Cmy). Previous studies demonstrated that Cmy, a neo-natal digestive pepsin, is inactivated in some primates, including humans. This pseudogenization event was hypothesized to result from the acquisition of maternal immune immunoglobulin G (IgG) transfer. By investigating 94 mammalian subgenomes we reveal an unprecedented level of Cmy erosion in placental mammals, with numerous independent events of gene loss taking place in Primates, Dermoptera, Rodentia, Cetacea and Perissodactyla. Our findings strongly suggest that the recurrent inactivation of Cmy correlates with the evolution of the passive transfer of IgG and uncovers a noteworthy case of evolutionary cross-talk between the digestive and the immune system, modulated by gene loss. PMID- 28851539 TI - Corrigendum to "Negative feedback regulation between microRNA let-7g and LOX-1 mediated hypoxia-induced PASMCs proliferation" [Biochem. Biophys. Res. Comm. 488 (4) (2017) 655-663]. PMID- 28851540 TI - Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP). AB - BACKGROUND: Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies. RESULTS: Using an injury induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions. CONCLUSIONS: This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition. PMID- 28851541 TI - Serotonin transporter and behavioral traits. PMID- 28851543 TI - Type 1 Diabetes, Coronary Disease Complexity, and Optimal Revascularization Strategy. PMID- 28851542 TI - An experience sampling study on the ecological validity of the SWN-20: Indication that subjective well-being is associated with momentary affective states above and beyond psychosis susceptibility. AB - Subjective well-being (SWB) is associated with treatment adherence and symptom outcome in people with psychotic disorders. Also, it is associated with psychosis susceptibility and it is partly hereditable. The SWN-20 is a widely used tool to assess subjective well-being in patients; it was also found to be suitable for assessing SWB in healthy populations. Yet it is unclear how this retrospectively measured construct may be associated with momentary affective state, which is the proposed underlying mechanism of subjective well-being. This study therefore investigated the ecological validity of the SWN-20 in people at different risk for psychosis. In 63 patients with a psychotic disorder and 61 siblings of patients with a psychotic disorder we assessed whether subjective well-being as measured with the SWN-20, was associated with momentary positive affect, negative affect, reward experience and stress-sensitivity as measured by the experience sample method (ESM). Higher subjective well-being was associated with higher momentary positive affect and lower negative affect, and this association was not conditional on psychosis vulnerability. Subjective well-being was not associated with stress-sensitivity or reward-experience. SWN-20 is an easy-to-use and ecologically valid tool to measure subjective well-being in people with different vulnerability for psychosis. PMID- 28851544 TI - PCI Versus CABG in Patients With Type 1 Diabetes and Multivessel Disease. AB - BACKGROUND: It is unknown if coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) may offer a survival benefit in patients with type 1 diabetes (T1D) in need of multivessel revascularization. OBJECTIVES: This study sought to determine if patients with T1D and multivessel disease may benefit from CABG compared with PCI. METHODS: In an observational cohort study, the authors included all patients with T1D who underwent a first multivessel revascularization in Sweden from 1995 to 2013. The authors used the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) register, the Swedish National Diabetes Register, and the Swedish National Patient Register to retrieve information about patient characteristics and outcomes. They estimated hazard ratios (HRs) adjusted for confounders with 95% confidence intervals (CIs) for all cause and coronary heart disease mortality, myocardial infarction, repeat revascularization, stroke, and heart failure using inverse probability of treatment weighting based on propensity scores. RESULTS: In total, 683 patients who underwent CABG and 1,863 patients who underwent PCI were included. During a mean follow-up of 10.6 years, 53% of patients in the CABG group and 45% in the PCI group died. PCI, compared with CABG, was associated with a similar risk of all-cause mortality (HR: 1.14; 95% CI: 0.99 to 1.32), but higher risks of death from coronary heart disease (HR: 1.45; 95% CI: 1.21 to 1.74), myocardial infarction (HR: 1.47; 95% CI: 1.23 to 1.78), and repeat revascularization (HR: 5.64; 95% CI: 4.67 to 6.82). No differences in risks of stroke or heart failure were found. CONCLUSIONS: Notwithstanding the inclusion of patients with T1D who might not have been able to undergo CABG in the PCI group we found that PCI, compared with CABG, was associated with higher rates and risks of coronary heart disease mortality, myocardial infarction, and repeat revascularizations. Our findings indicate that CABG may be the preferred strategy in patients with T1D in need of multivessel revascularization. PMID- 28851545 TI - Extraction and determination of bioactive compounds from bee pollen. AB - Since ancient times bee pollen has been considered a good source of bioactive substances and energy. Taking into account the current demand for healthy and natural foods, it is not surprising that bee pollen has been attracting commercial interest in recent years, making it one of the most widely consumed food supplements. It has been extensively reported that bee pollen contains several health-promoting compounds, such as proteins, amino acids, lipids, phenolic compounds, vitamins or minerals. Thus, this study aims to give an overview of the extraction and determination techniques of several of the above mentioned compounds which have been published in the last few years (2011-2017). The design of the study is in accordance with the different families of bioactive compounds, and the extraction procedures together with the analytical techniques employed and their determination are discussed. A list of some of the most relevant applications is provided for each category, including a brief summary of the experimental conditions. The references included will provide the reader with a comprehensive overview of and insight into the analysis of bioactive compounds from bee pollen. PMID- 28851547 TI - Key factors regulating protein carbonylation by alpha,beta unsaturated carbonyls: A structural study based on a retrospective meta-analysis. AB - Protein carbonylation represents one of the most important oxidative-based modifications involving nucleophilic amino acids and affecting protein folding and function. Protein carbonylation is induced by electrophilic carbonyl species and is an highly selective process since few nucleophilic residues are carbonylated within each protein. While considering the great interest for protein carbonylation, few studies investigated the factors which render a nucleophilic residue susceptible to carbonylation. Hence, the present study is aimed to delve into the factors which modulate the reactivity of cysteine, histidine and lysine residues towards alpha,beta unsaturated carbonyls by a retrospective analysis of the available studies which identified the adducted residues for proteins, the structure of which was resolved. Such an analysis involved different parameters including exposure, nucleophilicity, surrounding residues and capacity to attract carbonyl species (as derived by docking simulations). The obtained results allowed a meaningful clustering of the analyzed proteins suggesting that on average carbonylation selectivity increases with protein size. The comparison between adducted and unreactive residues revealed differences in all monitored parameters which are markedly more pronounced for cysteines compared to lysines and histidines. Overall, these results suggest that cysteine's carbonylation is a finely (and reasonably purposely) modulated process, while the carbonylation of lysines and histidines seems to be a fairly random event in which limited differences influence their reactivity. PMID- 28851548 TI - Aspergillus - From Catholic ceremonies to invasive disease. PMID- 28851549 TI - Effect of pregnancy in women with a history of primary immune thrombocytopenia considered as cured. PMID- 28851550 TI - Comparison of radiocesium concentration changes in leguminous and non-leguminous herbaceous plants observed after the Fukushima Dai-ichi Nuclear Power Plant accident. AB - Transfer of radiocesium from soil to crops is an important pathway for human intake. In the period from one to two years after the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, food monitoring results showed that radiocesium concentrations in soybean (a legume) were higher than those in other annual agricultural crops; in these crops, root uptake is the major pathway of radiocesium from soil to plant. However, it was not clear whether or not leguminous and non-leguminous herbaceous plants have different Cs uptake abilities from the same soil because crop sample collection fields were different. In this study, therefore, we compared the concentrations of 137Cs in seven herbaceous plant species including two leguminous plants (Trifolium pratense L. and Vicia sativa L.) collected in 2012-2016 from the same sampling field in Chiba, Japan that had been affected by the FDNPP accident fallout. Among these species, Petasites japonicus (Siebold & Zucc.) Maxim. showed the highest 137Cs concentration in 2012-2016. The correlation factor between all concentration data for 137Cs and those for 40K in these seven plants was R = 0.54 (p < 0.001) by t-test, thus potassium uptake ability by species would affect radiocesium uptake; however, for each species, no correlation between 137Cs and 40K was found. Interestingly, 40K concentrations in T. pratense, V. sativa and Poaceae family plants did not differ significantly, but 137Cs data in the Poaceae family plants were significantly lower than those in T. pratense (p < 0.001) and V. sativa (p = 0.017). The results indicated that leguminous species would have higher 137Cs uptake ability than Poaceae family plants. PMID- 28851551 TI - Vitamin D supplementation in the critically ill: Should meta-analysis be used? PMID- 28851552 TI - Adductor pollicis muscle thickness has a low association with lean mass in women. AB - BACKGROUND & AIM: Lean mass (LM) is a functional component of body composition and is an important parameter of nutritional status assessment. The adductor pollicis muscle thickness (APMT) has been used as a predictor of LM, but it is not well known if this method presents a higher prediction of LM than simple anthropometric measurements, such as weight. Thus, we aimed to associate APMT (alone and plus weight) with LM in women. METHODS: This cross-sectional study was conducted with 82 young and postmenopausal women. Body weight (Filizola(r)) and height (Welmy(r)) was quantified and APMT was measured by Lange(r) caliper. Body composition (LM and fat percentage) was estimated by dual-energy X-ray absorptiometry. RESULTS: APMT was positively correlated with LM (r = 0.35; p = 0.001), however, weight was strongly correlated with LM (r = 0.81; p < 0.001). APMT showed a prediction of 12% of LM (beta = 0.346, R2 = 0.120, p < 0.001), and weight explained the variations of LM by 65% (beta = 0.808, R2 = 0.654, p < 0.001). When weight and APMT were evaluated together, there was an increase of only 0.06% in LM prediction (beta = 0.820, R2 = 0.655, p < 0.001), compared to weight alone. CONCLUSION: When compared to weight, APMT showed a low association with LM. These results suggest that a simpler anthropometric measurement, such as weight, can be a better predictor of LM than APMT. PMID- 28851553 TI - How to consider animal data in tDCS safety standards. PMID- 28851546 TI - Chronic traumatic encephalopathy-integration of canonical traumatic brain injury secondary injury mechanisms with tau pathology. AB - In recent years, a new neurodegenerative tauopathy labeled Chronic Traumatic Encephalopathy (CTE), has been identified that is believed to be primarily a sequela of repeated mild traumatic brain injury (TBI), often referred to as concussion, that occurs in athletes participating in contact sports (e.g. boxing, American football, Australian football, rugby, soccer, ice hockey) or in military combatants, especially after blast-induced injuries. Since the identification of CTE, and its neuropathological finding of deposits of hyperphosphorylated tau protein, mechanistic attention has been on lumping the disorder together with various other non-traumatic neurodegenerative tauopathies. Indeed, brains from suspected CTE cases that have come to autopsy have been confirmed to have deposits of hyperphosphorylated tau in locations that make its anatomical distribution distinct for other tauopathies. The fact that these individuals experienced repetitive TBI episodes during their athletic or military careers suggests that the secondary injury mechanisms that have been extensively characterized in acute TBI preclinical models, and in TBI patients, including glutamate excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, free radical-induced oxidative damage and neuroinflammation, may contribute to the brain damage associated with CTE. Thus, the current review begins with an in depth analysis of what is known about the tau protein and its functions and dysfunctions followed by a discussion of the major TBI secondary injury mechanisms, and how the latter have been shown to contribute to tau pathology. The value of this review is that it might lead to improved neuroprotective strategies for either prophylactically attenuating the development of CTE or slowing its progression. PMID- 28851555 TI - Sagittal abdominal diameter predicts cardiovascular events. PMID- 28851554 TI - Transcranial direct current stimulation versus caffeine as a fatigue countermeasure. AB - BACKGROUND: To assess the efficacy of using transcranial direct current stimulation (tDCS) to remediate the deleterious effects of fatigue induced by sleep deprivation and compare these results to caffeine, a commonly used fatigue countermeasure. OBJECTIVE/HYPOTHESIS: Based on previous research, tDCS of the dorsolateral prefrontal cortex (DLPFC) can modulate attention and arousal. The authors hypothesize that tDCS can be an effective fatigue countermeasure. METHODS: Five groups of ten participants each received either active tDCS and placebo gum at 1800, caffeine gum with sham tDCS at 1800, active tDCS and placebo gum at 0400, caffeine gum with sham tDCS at 0400, or sham tDCS with placebo gum at 1800 and 0400 during 36-h of sustained wakefulness. Participants completed a vigilance task, working memory task, psychomotor vigilance task (PVT), and a procedural game beginning at 1800 h and continued every two hours throughout the night until 1900 the next day. RESULTS: tDCS dosed at 1800 provided 6 h of improved attentional accuracy and reaction times compared to the control group. Caffeine did not produce an effect. Both tDCS groups also had an improved effect on mood. Participants receiving tDCS reported feeling more vigor, less fatigue, and less bored throughout the night compared to the control and caffeine groups. CONCLUSIONS: We believe tDCS could be a powerful fatigue countermeasure. The effects appear to be comparable or possibly more beneficial than caffeine because they are longer lasting and mood remains more positive. PMID- 28851556 TI - Visceral adiposity index and 10-year cardiovascular disease incidence: The ATTICA study. AB - BACKGROUND AND AIMS: Visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue accumulation/dysfunction. Our aim was to evaluate potential associations between the VAI and the 10-year cardiovascular disease (CVD) incidence. METHODS AND RESULTS: During 2001-2002, 3042 Greek adults (1514 men; age: >=18 years) without previous CVD were recruited into the ATTICA study, whilst the 10-year study follow-up was performed in 2011-2012, recording the fatal/non-fatal CVD incidence in 2020 (1010 men) participants. The baseline VAI scores for these participants were calculated based on anthropometric and lipid variables, while VAI tertiles were extracted for further analyses. During the study follow-up a total of 317 CVD events (15.7%) were observed. At baseline, the participants' age and the prevalence of hypertension, diabetes, hypercholesterolemia and metabolic syndrome increased significantly across the VAI tertiles. After adjusting for multiple confounders, VAI exhibited a significantly independent positive association with the 10-year CVD incidence (OR = 1.05, 95%CI: 1.01, 1.10), whereas the association of the body mass index (HR = 1.03, 95%CI: 0.99, 1.08), or the waist circumference (HR = 1.01, 95%CI: 0.99, 1.02) was less prominent. Sex-specific analysis further showed that VAI remained significantly predictive of CVD in men alone (HR = 1.06, 95%CI: 1.00, 1.11) but not in women (HR = 1.06, 95%CI: 0.96, 1.10). CONCLUSIONS: Our findings show for the first time in a large-sample, long-term, prospective study in Europe that the VAI is independently associated with elevated 10-year CVD risk, particularly in men. This suggests that the VAI may be utilized as an additional indicator of long-term CVD risk for Caucasian/Mediterranean men without previous CVD. PMID- 28851557 TI - Optimising orthopaedic follow-up care through a virtual clinic. PMID- 28851558 TI - Consumer lay theories on healthy nutrition: A Q methodology application in Germany. AB - Food is an important driver of individual health, and an important subject in public policy and health intervention research. Viewpoints on what constitutes healthy nutrition, however, are manifold and highly subjective in nature, suggesting there is no one-size-fits-all behavioral change intervention. This research explores fundamental lay theories regarding healthy nutrition with consumers in Germany. The study aimed at identifying and characterizing distinct groups of consumers based on similarities and differences in the lay theories individuals hold by means of Q methodology. Thirty German consumers ranked a Q set of 63 statements representing a vast spectrum of individual opinions and beliefs on healthy nutrition into a quasi-normal distribution. Factor analysis identified four major lay theories on healthy nutrition: (1) "Healthy is what tastes good, in moderation", (2) "Healthy nutrition is expensive and inconvenient", (3) "Healthy is everything that makes me slim and pretty", and (4) "Only home-made, organic, and vegetarian food is healthy". Consensus existed among the theories about the question of whom to trust regarding nutritional information and the low relevance of information from official sources. Disagreement existed concerning the overall importance of healthy nutrition in day-to-day lives and whether food healthiness is related to organic or conventional production methods. The findings underscore that specific consumer groups should be engaged separately when intervening in healthy nutrition issues. Implications for public policies and intervention strategies are discussed. PMID- 28851559 TI - Unsold is unseen ... or is it? Examining the role of peripheral vision in the consumer choice process using eye-tracking methodology. AB - In visual marketing, the truism that "unseen is unsold" means that products that are not noticed will not be sold. This truism rests on the idea that the consumer choice process is heavily influenced by visual search. However, given that the majority of available products are not seen by consumers, this article examines the role of peripheral vision in guiding attention during the consumer choice process. In two eye-tracking studies, one conducted in a lab facility and the other conducted in a supermarket, the authors investigate the role and limitations of peripheral vision. The results show that peripheral vision is used to direct visual attention when discriminating between target and non-target objects in an eye-tracking laboratory. Target and non-target similarity, as well as visual saliency of non-targets, constitute the boundary conditions for this effect, which generalizes from instruction-based laboratory tasks to preference based choice tasks in a real supermarket setting. Thus, peripheral vision helps customers to devote a larger share of attention to relevant products during the consumer choice process. Taken together, the results show how the creation of consideration set (sets of possible choice options) relies on both goal-directed attention and peripheral vision. These results could explain how visually similar packaging positively influences market leaders, while making novel brands almost invisible on supermarket shelves. The findings show that even though unsold products might be unseen, in the sense that they have not been directly observed, they might still have been evaluated and excluded by means of peripheral vision. This article is based on controlled lab experiments as well as a field study conducted in a complex retail environment. Thus, the findings are valid both under controlled and ecologically valid conditions. PMID- 28851560 TI - Nutritional composition and heavy metal content of the human placenta. AB - Despite the vital and diverse roles of the placenta, remarkably little is known about its actual composition. Moreover, as placentophagy becomes increasingly popular, understanding the nutritional and heavy metal composition of the human placenta has practical implications. Here we evaluated the carbohydrate, sugar, protein, fat, cholesterol, vitamin, and heavy metal composition of the human placenta from uncomplicated singleton pregnancies and found that it contains a significant amount of cholesterol, protein, iron, and selenium, but no detectable levels of cadmium, arsenic, or mercury. PMID- 28851561 TI - Ovarian development of captive F1 wreckfish (hapuku) Polyprion oxygeneios under constant and varying temperature regimes - Implications for broodstock management. AB - In order to better understand how photo-thermal conditions affect oogenesis in captive-bred F1 hapuku, a wreckfish considered for aquaculture in New Zealand, juvenile (pre-pubertal) fish were assigned to one of two regimes: exposed to a constant temperature of 17 degrees C (CT group) or to seasonally varying temperatures (VT group range: 10-17 degrees C), both under simulated ambient photoperiod, for nearly 2years. Development in females was monitored through repeated gonadal biopsies (histology; target gene mRNA levels) and blood sampling (plasma levels of estradiol-17beta; E2). Very little evidence of advancing oogenesis was found in the first year of study, when fish were in their 4th year. In the subsequent year, a proportion of fish reached the pre-spawning stage (fully-grown ovarian follicles); the proportion of females reaching this stage was notably higher in the VT (62%) than the CT (28%) group. Of the few females that did reach maturity in the CT group, significantly lower levels of plasma E2 were observed relative to those in fish from the VT group possibly indicating a temperature-induced endocrine impairment during oogenesis. Interestingly, females that did not reach the pre-spawning stage presented with a small transient, but significant increase in oocyte diameters and plasma E2, suggestive of a dummy run. Clear seasonality was observed for fish under both photo-thermal regimes, and this was reflected in plasma E2 levels and transcript abundances of aromatase, fshr and luteinizing hormone receptor in the ovary; these end points all peaked in maturing females during the late or post-vitellogenic stage. We conclude that captive female F1 hapuku first mature as five-year-olds and that exposure to a decreased temperature is important for appropriate progression of oogenesis. PMID- 28851563 TI - Ultrasound imaging and guidance in the management of cervical dystonia: A caveat on the compartmentalization of sternocleidomastoid muscle. PMID- 28851565 TI - [Brain abscess and pulmonary arteriovenous malformation]. PMID- 28851562 TI - Viral Load Affects the Immune Response to HBV in Mice With Humanized Immune System and Liver. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) infects hepatocytes, but the mechanisms of the immune response against the virus and how it affects disease progression are unclear. METHODS: We performed studies with BALB/c Rag2-/-Il2rg-/ SirpaNODAlb-uPAtg/tg mice, stably engrafted with human hepatocytes (HUHEP) with or without a human immune system (HIS). HUHEP and HIS-HUHEP mice were given an intraperitoneal injection of HBV. Mononuclear cells were isolated from spleen and liver for analysis by flow cytometry. Liver was analyzed by immunohistochemistry and mRNA levels were measured by quantitative reverse transcription polymerase chain reaction (PCR). Plasma levels of HBV DNA were quantified by PCR reaction, and antigen-specific antibodies were detected by immunocytochemistry of HBV transfected BHK-21 cells. RESULTS: Following HBV infection, a complete viral life cycle, with production of HBV DNA, hepatitis B e (HBe), core (HBc) and surface (HBs) antigens, and covalently closed circular DNA, was observed in HUHEP and HIS HUHEP mice. HBV replicated unrestricted in HUHEP mice resulting in high viral titers without pathologic effects. In contrast, HBV-infected HIS-HUHEP mice developed chronic hepatitis with 10-fold lower titers and antigen-specific IgGs, (anti-HBs, anti-HBc), consistent with partial immune control. HBV-infected HIS HUHEP livers contained infiltrating Kupffer cells, mature activated natural killer cells (CD69+), and PD-1+ effector memory T cells (CD45RO+). Reducing the viral inoculum resulted in more efficient immune control. Plasma from HBV infected HIS-HUHEP mice had increased levels of inflammatory and immune suppressive cytokines (C-X-C motif chemokine ligand 10 and interleukin 10), which correlated with populations of intrahepatic CD4+ T cells (CD45RO+PD-1+). Mice with high levels of viremia had HBV-infected liver progenitor cells. Giving the mice the nucleoside analogue entecavir reduced viral loads and decreased liver inflammation. CONCLUSION: In HIS-HUHEP mice, HBV infection completes a full life cycle and recapitulates some of the immunopathology observed in patients with chronic infection. Inoculation with different viral loads led to different immune responses and levels of virus control. We found HBV to infect liver progenitor cells, which could be involved in hepatocellular carcinogenesis. This is an important new system to study anti-HBV immune responses and screen for combination therapies against hepatotropic viruses. PMID- 28851564 TI - X-linked Parkinsonism with Intellectual Disability caused by novel mutations and somatic mosaicism in RAB39B gene. AB - BACKGROUND: RAB39B pathogenic variants cause X-linked Parkinsonism associated with Intellectual Disability, known as Waisman syndrome, a very rare disorder that has been mainly identified through exome sequencing in large Parkinson's disease cohorts. In this study we searched for pathogenic variants in RAB39B in two Italian families affected by X-linked early-onset Parkinsonism and Intellectual Disability. METHODS: Three patients received neurological evaluation and underwent RAB39B sequencing. RESULTS: Two novel RAB39B frameshift variants were found to result in the absence of RAB39B protein (family 1: c.137dupT; family 2: c.371delA). Patients showed unilateral rest tremor and bradykinesia; one of them also displayed an early-onset postural tremor. Paramagnetic substance deposition in the substantia nigra, globus pallidi, red nucleus, putamen and pulvinar was assessed by brain imaging. Two patients also showed moderate calcification of globus pallidi. CONCLUSION: In this study we highlight the evidence that X-linked early-onset Parkinsonism associated with Intellectual Disability occurs as a pattern of clinical and neuroimaging features attributable to RAB39B pathogenic variants. PMID- 28851566 TI - [Long QT syndrome due to Fluoxetine]. PMID- 28851567 TI - Association of down-regulation of calcitonin gene-related peptide and substance P with increase of myocardial vulnerability in diabetic neuropathic rats. AB - Diabetic patients present high co-morbidities of neuropathy and severer consequences of coronary heart disease. But the pathological mechanism is still unclear. Here we investigated a potential association of diabetic impairment of sensory nerves with increase of vulnerability of myocardium in acute myocardial ischemia/reperfusion. A rat model of diabetes mellitus was induced by high fat and sugar diet plus a small dose of streptozotocin. Impairment of sensory nerves was evaluated by measurement of changes in tail flick latency to noxious thermal stimulation and calcitonin gene-related peptide (CGRP) and substance P (SP) in the dorsal root ganglia (DRG) and the myocardium of the heart were examined. The myocardial injury was examined by infarct size, apoptosis ratio of cardiomyocytes and cardiac troponin I in the animals underwent acute myocardial ischemia (for 30min) and reperfusion (for 120min). The effects of CGRP and SP on cardiomyocyte injury induced by high glucose and hypoxia/reoxygenation were tested in cultured myocytes. The diabetic animals presented significant elevation of noxious thermal threshold with obvious reduction of the contents of CGRP and SP in the DRG and the myocardium. Importantly, the diabetic animals showed significant increases of infarct size, myocyte apoptosis and serum cardiac troponin I after acute myocardial ischemia/reperfusion, compared to the non-diabetic control. Furthermore, exogenously administered CGRP and SP attenuated the myocyte injury induced by the high concentration of glucose and hypoxia/reoxygenation. These findings suggested that impairment of sensory nerves with significant reduction of CGRP and SP in DRG, ventricular myocardium and serum may be associated with increase of myocardial vulnerability in acute myocardial ischemia/reperfusion in streptozotocin-induced diabetic rats. PMID- 28851568 TI - Angiotensin AT1 receptors modulate the anxiogenic effects of angiotensin (5-8) injected into the rat ventrolateral periaqueductal gray. AB - Losartan and PD 123,319 are non-peptide angiotensin (Ang) receptor antagonists for the AT1 and AT2 subtypes of Ang II receptors, respectively. The tetrapeptide Ang (5-8) is the smallest Ang-peptide that elicits anxiogenic effects on unconditioned and conditioned experimental models upon injection into the ventrolateral column of the periaqueductal gray (vlPAG), and Ang (5-8) can be synthesized (from Ang II or Ang III) and inactivated in this mesencephalic structure. The vlPAG is also known to play a central role in mechanisms of fear and anxiety. We therefore utilized male Wistar rats to examine the effects of losartan and PD 123,319 injections, selective antagonists of the AT1 and AT2 receptors, respectively, into the vlPAG in the elevated plus-maze, a classic rat model of anxiety, and against the anxiogenic effect of Ang (5-8) (0.4 nmol/0.25MUL) upon injection into the same region. The anxiolytic profile was dependent on the dose of intra-vlPAG losartan, whereas no effects on experimental anxiety were observed in the plus-maze following PD 123,319 injection. The anxiogenic effect of Ang (5-8) injection into the vlPAG remained unchanged in the PD 123,319-pretreated rats, but the effect did not occur in losartan-pretreated rats. The results led us to suggest that the anxiogenic effect of Ang (5-8) injection into the vlPAG may depend on the local activation of AT1, but not AT2 receptors. Activation of AT1 receptors in structures nearby vlPAG may be tonically involved in fear and experimental anxiety. PMID- 28851569 TI - [Hand grip of frail bedridden elderly. Observational longitudinal study]. PMID- 28851570 TI - Biodegradation of mono-, di- and trifluoroacetate by microbial cultures with different origins. AB - This work focused on the biodegradation of three structurally related fluoroacetates (FAs), mono- (MFA), di- (DFA) and trifluoroacetate (TFA), using as microbial inocula samples collected from a site with a long history of industrial contamination and activated sludge obtained from a municipal wastewater treatment plant. Biodegradation experiments were carried out under different modes of substrate supplementation, which included (i) FAs fed as sole carbon sources; (ii) FAs (only for DFA and TFA) fed in co-metabolism with sodium acetate; and (iii) mixtures of MFA with DFA or TFA. Biodegradation of the target compounds was assessed through fluoride ion release. Defluorination was obtained in the cultures fed with MFA, while DFA and TFA were recalcitrant in all tested conditions. When present in mixture, DFA was shown to inhibit biodegradation of MFA, while TFA had no effect. A total of 13 bacterial isolates obtained from MFA degrading cultures were found to degrade 20mgL-1 of this compound, as single strains, when supplemented as a sole carbon source. Sequencing of the 16S rRNA gene indicated that among these degrading bacteria only Delftia acidovorans had been previously reported to be able to degrade MFA. This work shows that, despite their similar chemical structures, biodegradation of the three tested FAs is very distinct and draws attention to the unknown impacts that the accumulation of DFA and TFA may have in the environment as a result of their high recalcitrance. PMID- 28851571 TI - Comparative analysis of different transformed Saccharomyces cerevisiae strains based on high-throughput Fourier transform infrared spectroscopy. AB - This study shows the application of the Fourier transform mid-infrared spectroscopy (FT-MIR) associated with high-throughput technology to study the biochemical fingerprints of different Saccharomyces cerevisiae strains transformed with the same expression system along the similar cultivation in bioreactor. The phenotype, as well as the cellular metabolism and recombinant cyprosin biosynthesis, were determined. The differences observed were confirmed by conventional cyprosin activity protocol, and the metabolic evolution was analyzed using high-performance liquid chromatography technique. The spectral analysis based on chemometrics tools, such as the principal component analysis, is a useful methodology for the phenotypes characterization as well as the specific metabolic states along the cultivations according to the clusters created. The ratio bands of spectra also represented a useful tool to evaluate the metabolic and biochemical differences between both expression systems, allowing to have an additional parameter to the biomolecular comparison. Therefore, high-throughput FT-MIR spectroscopy associated with multivariate data analysis represent a valuable strategy for extracting significant specific biomolecular information along the cultivation, providing a complete bioprocess analysis, once it detects slight molecular changes which it will be useful for screening and optimization process in the biotechnological or pharmaceutical industry. PMID- 28851572 TI - Zebrafish as an early stage screening tool to study the systemic circulation of nanoparticulate drug delivery systems in vivo. AB - Nanomedicines have gained much attention for the delivery of small molecules or nucleic acids as treatment options for many diseases. However, the transfer from experimental systems to in vivo applications remains a challenge since it is difficult to assess their circulation behavior in the body at an early stage of drug discovery. Thus, innovative and improved concepts are urgently needed to overcome this issue and to close the gap between empiric nanoparticle design, in vitro assessment, and first in vivo experiments using rodent animal models. This study was focused on the zebrafish as a vertebrate screening model to assess the circulation in blood and extravasation behavior of nanoparticulate drug delivery systems in vivo. To validate this novel approach, monodisperse preparations of fluorescently labeled liposomes with similar size and zeta potential were injected into transgenic zebrafish lines expressing green fluorescent protein in their vasculature. Phosphatidylcholine-based lipids differed by fatty acid chain length and saturation. Circulation behavior and vascular distribution pattern were evaluated qualitatively and semi-quantitatively using image analysis. Liposomes composed of lipids with lower transition temperature (<28 degrees C) as well as PEGylated liposomes showed longer circulation times and extravasation. In contrast, liposomes composed of lipids with transition temperatures>28 degrees C bound to venous parts of the vasculature. This circulation patterns in the zebrafish model did correlate with published and experimental pharmacokinetic data from mice and rats. Our findings indicate that the zebrafish model is a useful vertebrate screening tool for nanoparticulate drug delivery systems to predict their in vivo circulation behavior with respect to systemic circulation time and exposure. PMID- 28851573 TI - X-ray microfluorescence for biodistribution studies of nanomedicines. AB - Currently, the in vivo distribution of drugs is investigated by non-spatial quantitative techniques. With the emergence of personal therapies using nanomedicines, deeper investigations are required to precisely know the in vivo fate of entrapped drugs, especially to predict possible toxicity. Here, we assess the capabilities of SR-MUXRF for i) detecting drugs into nanomedicines without adding any marker, ii) mapping their distribution into tissues and iii) locally quantifying the drugs loaded into nanomedicines. To prepare the nanomedicine model, we used the bioconjugate diamine(dichloro)platinum (SQ-CDD) developed in the TERNANOMED Grant Project. Nanomedicines were intravenously injected into a nude mice model bearing a pancreatic tumour (PANC-1). The X-ray microfluorescence experiments were performed on embeds tissue sections of kidney and tumor at 2h and 24h after nanoparticles injection. Data collection was performed on the micro imaging beamline ID13 of the European Synchrotron Radiation Facility (ESRF). A quantitative study was performed by atomic absorption spectroscopy (AAS), allowing to compare the platinum concentrations with those measured by X-ray. This study shows that the synchrotron radiation-based MUXRF analysis is sensitive enough to detect and map the distribution of a drug entrapped into nanomedicine. A quantitative local analysis is possible with a tissue element as reference, or semi-quantitatively if the tissue reference is not homogenous. PMID- 28851574 TI - Levofloxacin-loaded bone cement delivery system: Highly effective against intracellular bacteria and Staphylococcus aureus biofilms. AB - Staphylococcus aureus is a major pathogen in bone associated infections due to its ability to adhere and form biofilms on bone and/or implants. Moreover, recrudescent and chronic infections have been associated with S. aureus capacity to invade and persist within osteoblast cells. With the growing need of novel therapeutic tools, this research aimed to evaluate some important key biological properties of a novel carrier system composed of acrylic bone cement (polymethylmethacrylate - PMMA), loaded with a release modulator (lactose) and an antibiotic (levofloxacin). Levofloxacin-loaded bone cement (BC) exhibited antimicrobial effects against planktonic and biofilm forms of S. aureus (evaluated by a flow chamber system). Moreover, novel BC formulation showed high anti-bacterial intraosteoblast activity. This fact led to the conclusion that levofloxacin released from BC matrices could penetrate the cell membrane of osteoblasts and be active against S. aureus strains in the intracellular environment. Furthermore, levofloxacin-BC formulations showed no significant in vitro cytotoxicity and no allergic potential (measured by the in vivo chorioallantoic membrane assay). Our results indicate that levofloxacin-loaded BC has potential as a local antibiotic delivery system for treating S. aureus associated bone infections. PMID- 28851575 TI - Mother-newborn separation at birth in hospitals: A possible risk for neurodevelopmental disorders? AB - In the 20th century, mother-infant separation shortly after birth in hospitals became routine and unique to humans. However, this hospital birth practice is different from the practice in our evolutionary history, where newborn survival depended on close and essentially continuous maternal contact. This time shortly after birth represents a psychophysiologically sensitive or critical period for programming future physiology and behaviour. We hypothesize that early maternal separation as conducted in conventional hospital practice may induce similar epigenetic changes similar to those found in various mental diseases that may also be implicated in neurodevelopmental disorders. PMID- 28851576 TI - Toward an understanding of the neural mechanisms underlying dual-task performance: Contribution of comparative approaches using animal models. AB - The study of dual-task performance in human subjects has received considerable interest in cognitive neuroscience because it can provide detailed insights into the neural mechanisms underlying higher-order cognitive control. Despite many decades of research, our understanding of the neurobiological basis of dual-task performance is still limited, and some critical questions are still under debate. Recently, behavioral and neurophysiological studies of dual-task performance in animals have begun to provide intriguing evidence regarding how dual-task information is processed in the brain. In this review, we first summarize key evidence in neuroimaging and neuropsychological studies in humans and discuss possible reasons for discrepancies across studies. We then provide a comprehensive review of the literature on dual-task studies in animals and provide a novel working hypothesis that may reconcile the divergent results in human studies toward a unified view of the mechanisms underlying dual-task processing. Finally, we propose possible directions for future dual-task experiments in the framework of comparative cognitive neuroscience. PMID- 28851577 TI - Anorexia nervosa and bulimia nervosa: A meta-analysis of executive functioning. AB - OBJECTIVE: Research investigating the link between eating disorder (ED) diagnosis and executive dysfunction has had conflicting results, yet no meta-analyses have examined the overall association of ED pathology with executive functioning (EF). METHOD: Effect sizes were extracted from 32 studies comparing ED groups (27 of anorexia nervosa, 9 of bulimia nervosa) with controls to determine the grand mean effect on EF. Analyses included effects for individual EF measures, as well as an age-based subgroup analysis. RESULTS: There was a medium effect of ED diagnosis on executive functioning, with bulimia nervosa demonstrating a larger effect (Hedges's g=-0.70) than anorexia nervosa (g=-0.41). Within anorexia nervosa studies, subgroup analyses were conducted for age and diagnostic subtype. The effect of anorexia nervosa on EF was largest in adults; however, subgroup differences for age were not significant. CONCLUSIONS: Anorexia and bulimia nervosa are associated with EF deficits, which are particularly notable for individuals with bulimia nervosa. The present analysis includes recommendations for future studies regarding study design and EF measurement. PMID- 28851578 TI - Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201). AB - : Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F xenografts. Moreover, darolutamide inhibited the transcriptional activity of AR mutants identified in the plasma of CRPC patients progressing on traditional therapies. In particular, darolutamide significantly inhibited the transcriptional activity of the F877L, H875Y/T878A, F877L/T878A, and the previously unreported T878G AR mutants, that transform enzalutamide into a partial agonist. In silico cheminformatics computer modeling provided atomic level insights confirming darolutamide antagonist effect in F877L and T878G AR mutants. In conclusion, our results provide a rationale for further clinical evaluation of darolutamide in enzalutamide-resistant CRPC, in particular in combination with circulating tumor DNA assays that detect AR mutants sensitive to darolutamide, in a precision oncology setting. PATIENT SUMMARY: In this study we evaluated the novel drug darolutamide in preclinical models of prostate cancer. We found that darolutamide delays growth of enzalutamide-resistant prostate cancer, in particular in cells with mutated forms of the androgen receptor after previous treatment. Our data supports further evaluation of darolutamide in clinical trials. PMID- 28851579 TI - Re: Robot-assisted Laparoscopic Prostatectomy Versus Open Radical Retropubic Prostatectomy: Early Outcomes from a Randomised Controlled Phase 3 Study. PMID- 28851580 TI - Improved Recovery of Erectile Function in Younger Men after Radical Prostatectomy: Does it Justify Immediate Surgery in Low-risk Patients? AB - BACKGROUND: Although active surveillance is increasingly used for the management of low-risk prostate cancer, many eligible patients are still nonetheless subject to curative treatment. One argument for considering surgery rather than active surveillance is that the probability of postoperative recovery of erectile function is age dependent, that is, patients who delay surgery may lose the window of opportunity to recover erectile function after surgery. OBJECTIVE: To model erectile function over a 10-yr period for immediate surgery versus active surveillance. DESIGN, SETTING, AND PARTICIPANTS: Data from 1103 men who underwent radical prostatectomy at a tertiary referral center were used. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients completed the International Index of Erectile Function (IIEF-6) pre- and postoperatively as a routine part of clinical care. Preoperative IIEF-6 scores were plotted against age to assess the natural rate of functional decline due to aging. Reported erectile scores in the 2-yr period following surgery were used to assess post-surgical recovery. RESULTS AND LIMITATIONS: Each year increase in patient age resulted in a 0.27 reduction in IIEF scores. In addition to IIEF reducing with increased age, the amount of erectile function that is recovered from presurgery to 12-mo postsurgery also decreases (-0.16 IIF points/yr, 95% confidence interval -0.27, -0.05, p=0.006). However, delayed radical prostatectomy increased the mean IIEF-6 score over a 10 yr period compared with immediate surgery (p=0.001), even under the assumption that all men placed on active surveillance are treated within 5 yr. CONCLUSIONS: Small differences in erectile function recovery in younger men are offset by a longer period of time living with decreased postoperative function. Better erectile recovery in younger men should not be a factor used to recommend immediate surgery in patients suitable for active surveillance, even if crossover to surgery is predicted within a short period of time. PATIENT SUMMARY: Younger men have better recovery of erectile function after surgery for prostate cancer. This has led to the suggestion that delaying surgery for low-risk disease may lead patients to miss a window of opportunity to recover erectile function postoperatively. We conducted a modeling study and found that predicted erectile recovery was far superior on delayed treatment because slightly better recovery in younger men is offset by a longer period of time living with poorer postoperative function in those choosing immediate surgery. PMID- 28851581 TI - Topography of Prostate Cancer Recurrence After Radiation Therapy: A Detailed Mapping Study of Salvage Radical Prostatectomy Specimens. AB - : In men who do not respond to initial radiation therapy, accurate knowledge of the site of cancer recurrence or persistence is necessary to understand treatment failure. We evaluated the pathologic characteristics of recurrent/persistent prostate cancer with tumor maps from the whole-mount slides of salvage radical prostatectomies performed between 2000 and 2014. Of 216 consecutive patients, detailed tumor maps were available for 77. Sixty-nine patients (90%) were found to have tumor in the apex, of which 46% occurred in the most apical 3mm. Fifty three patients (69%) had tumors at a distance of <=5mm from the urethra. Five patients had tumor directly involving the urethra, all of whom had urethral invasion at the apex. Seminal vesicle involvement was seen in 32 patients (42%), two of whom had tumor only in the seminal vesicles. Sixty-two patients (81%) had tumors in the distal apex, periurethral area, or seminal vesicles, that is, areas that are not routinely biopsied. Targeting these areas could improve the accuracy of biopsy when cancer recurrence is suspected. PATIENT SUMMARY: When recurrence is suspected, clinicians should include biopsy of the distal apex, areas surrounding the urethra, and seminal vesicles. This information will help tailor successful salvage treatments. PMID- 28851582 TI - Long-term Psychological and Quality-of-life Effects of Active Surveillance and Watchful Waiting After Diagnosis of Low-risk Localised Prostate Cancer. AB - BACKGROUND: Long-term psychological well-being and quality-of-life are important considerations when deciding whether to undergo active treatment for low-risk localised prostate cancer. OBJECTIVE: To assess the long-term effects of active surveillance (AS) and/or watchful waiting (WW) on psychological and quality-of life outcomes for low-risk localised prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS: The Prostate Cancer Care and Outcome Study is a population based prospective cohort study in New South Wales, Australia. Participants for these analyses were low-risk localised prostate cancer patients aged <70 yr at diagnosis and participated in the 10-yr follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Validated instruments assessed outcomes relating to six health-related quality-of-life and nine psychological domains relevant to prostate cancer patients. Adjusted mean differences (AMDs) in outcome scores between prostate cancer treatment groups were estimated using linear regression. RESULTS AND LIMITATIONS: At 9-11 yr after diagnosis, patients who started AS/WW initially had (1) higher levels of distress and hyperarousal than initial radiation/high-dose-rate brachytherapy patients (AMD=5.9; 95% confidence interval or CI [0.5, 11.3] and AMD=5.4; 95% CI [0.2, 10.5], respectively), (2) higher levels of distress and avoidance than initial low-dose-rate brachytherapy patients (AMD=5.3; 95% CI [0.2, 10.3] and AMD=7.0; 95% CI [0.5, 13.5], respectively), (3) better urinary incontinence scores than initial radical prostatectomy patients (AMD=-9.1; 95% CI [-16.3, -2.0]), and (4) less bowel bother than initial radiation/high-dose-rate brachytherapy patients (AMD=-16.8; 95% CI [-27.6, -6.0]). No other significant differences were found. Limitations include participant attrition, inability to assess urinary voiding and storage symptoms, and nonrandom treatment allocation. CONCLUSIONS: Notwithstanding some long-term differences between AS/WW and various active treatment groups in terms of distress, hyperarousal, avoidance, urinary incontinence, and bowel bother, most long-term outcomes were similar between these groups. PATIENT SUMMARY: This study assessed the long-term psychological and quality-of-life impacts of initially monitoring rather than actively treating low-risk prostate cancer. The results suggest that initial monitoring rather than active treatment has only a minor impact on subsequent long-term psychological and quality-of-life outcomes. PMID- 28851584 TI - Both physiology and epidemiology support zero tolerable blood lead levels. AB - Inorganic lead is one of the most common causes of environmental metal poisonings, and its adverse effects on multiple body systems are of great concern. The brain, along with the kidneys, are critically susceptible to lead toxicity for their hosting of high affinity lead binding proteins, and very sensitive physiology. Prolonged low-lead exposure frequently remains unrecognized, causes subtle changes in these organ systems, and manifests later at an irreversible stage. With the repeated documentation of "no safe blood lead level", the pernicious effects of lead at any measurable concentration need to be emphasized. In this review, we surveyed articles on chronic low-level lead exposures with a blood lead concentrations <10MUg/dL and the development of neurobehavioral or renal disorders. The negative impacts of lead on both nervous and renal systems were obvious at a blood lead concentration of 2MUg/dL, with the absence of any detectable threshold. The deleterious effect of lead on two different organ systems at such low concentrations drew our attention to the various extracellular and intracellular events that might be affected by minimal concentration of body lead, especially blood lead. Is there a true common ground between low-level lead toxicity in both the nervous system and the kidney? PMID- 28851583 TI - Chemical Transport Knockout for Oxidized Vitamin C, Dehydroascorbic Acid, Reveals Its Functions in vivo. AB - Despite its transport by glucose transporters (GLUTs) in vitro, it is unknown whether dehydroascorbic acid (oxidized vitamin C, DHA) has any in vivo function. To investigate, we created a chemical transport knockout model using the vitamin C analog 6-bromo-ascorbate. This analog is transported on sodium-dependent vitamin C transporters but its oxidized form, 6-bromo-dehydroascorbic acid, is not transported by GLUTs. Mice (gulo-/-) unable to synthesize ascorbate (vitamin C) were raised on 6-bromo-ascorbate. Despite normal survival, centrifugation of blood produced hemolysis secondary to near absence of red blood cell (RBC) ascorbate/6-bromo-ascorbate. Key findings with clinical implications were that RBCs in vitro transported dehydroascorbic acid but not bromo-dehydroascorbic acid; RBC ascorbate in vivo was obtained only via DHA transport; ascorbate via DHA transport in vivo was necessary for RBC structural integrity; and internal RBC ascorbate was essential to maintain ascorbate plasma concentrations in vitro/in vivo. PMID- 28851585 TI - Development of a sensitive, generic and easy to use organophosphate skin disclosure kit. AB - Various organophosphorus compounds (OP), primarily the nerve agent VX and other V agents, are highly toxic to humans after skin exposure. Percutaneous exposure by such OP results in a delayed onset of toxic signs which enables the initiation of specific countermeasures if contamination is detected rapidly. Presently available mobile detection systems can hardly detect skin exposure by low volatile OP. In order to fill this gap an OP skin disclosure kit was developed which should fulfill different requirements, i.e. a high sensitivity, coverage of human toxic OP, easy handling, rapid results, small dimension and weight. The kit includes a cotton swab to sample skin, human AChE as target and chemicals for a color reaction based on the Ellman assay which is recorded by visual inspection. OP is dissolved from the sampler in a test tube filled with phosphate buffer (0.1M, pH 7.4) and incubated with lyophilized human AChE for 1min. The reaction with acetylthiocholine and 5,5'-dithio-bis-2-nitrobenzoic acid (1min) results in a rich yellow color in the absence of OP and in contrast, in transparent or pale yellow buffer in the presence of OP. At the recommended conditions, the limit of detection is 100ng VX and Russian VX and 50ng Chinese VX on plain surface and 200ng VX on rat skin. With activated pesticides, paraoxon and malaoxon, a concentration of ~10MUg can be detected on plain surface. The ready-to-use kit has a weight of 16g and a size of 10*12*1cm. In the end, this kit has the potential to fill a major gap and to enable timely detection of OP skin exposure and initiation of life-saving countermeasures. PMID- 28851587 TI - Exploration of variations in proteome and metabolome for predictive diagnostics and personalized treatment algorithms: Innovative approach and examples for potential clinical application. AB - Genome mutually interacts with internal and external environmental factors to result in different phenome that contains two important elements of proteins and metabolites, which link genome to predictive, preventive and personalized medicine (PPPM) or precision medicine (PM). Proteomic variations are the final presentation of the genomic and transcriptomic variations, and are involved in a wide range of variations including copy number of protein, splicing, post translational modifications, translocation/re-distribution, spatial conformation, and pathway-network systems. Metabolomic variations are the comprehensive results originated from all types of in vivo substances, and are involved in a wide range of alterations of metabolites generated from sugars, lipids, proteins, and nucleic acids, and metabolic network systems. Currently the studies on variations in proteome and in metabolome are much insufficient in the width and depth in the fields of proteomics and metabolomics. The development of high-throughput, high sensitivity, and especially high-reproducibility approaches is necessary to maximize the coverage of variations in proteome and in metabolome. The studies of proteomic and metabolomic variations directly result in the discovery of effective biomarkers to clarify molecular mechanisms of a disease, determine reliable therapeutic targets, and benefit precise prediction, diagnosis, and prognosis assessment. It has more important scientific values in PPPM or PM. BIOLOGICAL SIGNIFICANCE. PMID- 28851588 TI - Do sedation and analgesia contribute to long-term cognitive dysfunction in critical care survivors? AB - Deep sedation during stay in the Intensive Care Unit (ICU) may have deleterious effects upon the clinical and cognitive outcomes of critically ill patients undergoing mechanical ventilation. Over the last decade a vast body of literature has been generated regarding different sedation strategies, with the aim of reducing the levels of sedation in critically ill patients. There has also been a growing interest in acute brain dysfunction, or delirium, in the ICU. However, the effect of sedation during ICU stay upon long-term cognitive deficits in ICU survivors remains unclear. Strategies for reducing sedation levels in the ICU do not seem to be associated with worse cognitive and psychological status among ICU survivors. Sedation strategy and management efforts therefore should seek to secure the best possible state in the mechanically ventilated patient and lower the prevalence of delirium, in order to prevent long-term cognitive alterations. PMID- 28851589 TI - The impact of health expenditure on the number of chronic diseases. AB - We investigate the impact of health expenditure on health outcomes on a large sample of Europeans aged above 50 using individual and regional level data. We find a negative and significant effect of lagged health expenditure on subsequent changes in the number of chronic diseases. This effect varies according to age, health behavior, gender, income, and education. Our empirical findings are confirmed also when health expenditure is instrumented with parliament political composition. PMID- 28851586 TI - Clinical models of decision making in addiction. AB - As research on decision making in addiction accumulates, it is increasingly clear that decision-making processes are dysfunctional in addiction and that this dysfunction may be fundamental to the initiation and maintenance of addictive behavior. How drug-dependent individuals value and choose among drug and nondrug rewards is consistently different from non-dependent individuals. The present review focuses on the assessment of decision-making in addiction. We cover the common behavioral tasks that have shown to be fruitful in decision-making research and highlight analytical and graphical considerations, when available, to facilitate comparisons within and among studies. Delay discounting tasks, drug demand tasks, drug choice tasks, the Iowa Gambling Task, and the Balloon Analogue Risk Task are included. PMID- 28851590 TI - Shelter from the Storm: Roles, responsibilities, and challenges in United States housing policy governance. AB - Housing is a critical social determinant of health. Housing policy not only affects health by improving housing quality, affordability, and insecurity; housing policy affects health upstream through the politics that shape housing policy design, implementation, and management. These politics, or governance strategies, determine the successes or failures of housing policy programs. This paper is an overview of challenges in housing policy governance in the United States. I examine the important relationship between housing and health, and emphasize why studying housing policy governance matters. I then present three cases of housing governance challenges in the United States, from each pathway by which housing affects health - housing quality, affordability, and insecurity. Each case corresponds to an arm of the TAPIC framework for evaluating governance (Krieger and Higgins) [1], to assess mechanisms of housing governance in each case. While housing governance has come a long way over the past century, political decentralization and the expansion of the submerged state have increased the number of political actors and policy conflict in many areas. This creates inherent challenges for improving accountability, transparency, and policy capacity. In many instances, too, reduced government accountability and transparency increases the risk of harm to the public and lessens governmental integrity. PMID- 28851591 TI - Prognostic Role of N-cadherin Expression in Patients With Invasive Bladder Cancer. AB - BACKGROUND: We assessed the role of N-cadherin as a prognostic biomarker in patients with invasive bladder cancer (BCa) who had undergone radical cystectomy (RC). PATIENTS AND METHODS: The present retrospective single-center study included 433 BCa patients who had undergone RC and bilateral lymph node dissection. Formalin-fixed paraffin tissue microarrays were stained with an anti N-cadherin monoclonal mouse antibody. N-cadherin expression was considered positive if any immunoreactivity was detected. Multivariable Cox regression models were created to evaluate the prognostic effect of N-cadherin on survival. RESULTS: N-cadherin expression was observed in 189 patients (43.7%). It was associated with advanced pathologic stage (P = .001) and lymph node metastasis (P < .001). During a median follow-up period of 10.6 years, N-cadherin expression was associated with worse recurrence-free survival, overall survival, and cancer specific survival (P < .001, P = .001, and P < .001, respectively). On multivariable analysis adjusted for the effects of standard clinicopathologic features, N-cadherin expression retained its association with worse recurrence free survival (hazard ratio, 1.41; 95% confidence interval, 1.02-1.92; P = .032) but not cancer-specific survival (P = .07) and overall survival (P = .3). CONCLUSION: N-cadherin was expressed in approximately 40% of patients with invasive BCa. Its expression was associated with features of biologically and pathologically adverse disease and worse recurrence-free survival. N-cadherin could be a part of a marker panel to help clinical decision-making and therapy for BCa. PMID- 28851592 TI - Smoking and Disease Outcomes in Patients With Malignant Germ Cell Tumors. AB - BACKGROUND: To our knowledge, no studies have evaluated the association between smoking and stage at diagnosis or survival among men with germ cell tumors (GCTs). We therefore evaluated the association between smoking and GCT presentation and outcomes. METHODS: Electronic medical records of 1161 patients with GCT treated at Dana-Farber Cancer Institute between 1997 and 2013 were reviewed. Outcomes of interest were stage at diagnosis, relapse from clinical stage I (CSI) disease, relapse after first-line chemotherapy, and death from disease. Logistic regression models evaluated the association between smoking and tumor characteristics at diagnosis. Multivariable Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between smoking at diagnosis and risk of relapse and GCT cancer death. RESULTS: In men diagnosed with CSI disease, smokers were 86% more likely to have a large tumor (>= 4 cm) compared with nonsmokers (odds ratio [OR] 1.86; 95% CI, 1.28-2.71) and had a statistically significant increased risk of relapse (HR 2.05; 95% CI, 1.41-2.97). Among men with metastatic disease at diagnosis, the heaviest smokers (> 15 pack-years) were more likely to present with intermediate- or poor-risk disease compared with nonsmokers (OR 3.12; 95% CI, 1.29-7.55) and any smoking was associated with a statistically significant increased risk of relapse (HR 1.86; 95% CI, 1.26-2.73) and GCT death (HR 2.56; 95% CI, 1.55-4.23). CONCLUSION: Smoking is associated with more advanced disease at diagnosis and poorer GCT outcomes, including increased risk of relapse, for both CSI and metastatic disease. PMID- 28851595 TI - European Society for Vascular Surgery Guidelines on the Management of Atherosclerotic Carotid and Vertebral Artery Disease. PMID- 28851593 TI - Role of cystathionine-gamma-lyase in hypoxia-induced changes in TASK activity, intracellular [Ca2+] and ventilation in mice. AB - Cystathionine-gamma-lyase (CSE) is a multifunctional enzyme, and hydrogen sulfide (H2S) is one of its products. CSE and H2S have recently been proposed to be critical signaling molecules in hypoxia-induced excitation of carotid body (CB) glomus cells and the chemosensory response. Because the role of H2S in arterial chemoreception is still debated, we further examined the role of CSE by studying the effects of hypoxia on TASK K+ channel activity, cell depolarization, [Ca2+]i and ventilation using CSE+/+ and CSE-/- mice. As predicted, hypoxia reduced TASK activity and depolarized glomus cells isolated from CSE+/+ mice. These effects of hypoxia were not significantly altered in glomus cells from CSE-/- mice. Basal [Ca2+]i and hypoxia-induced elevation of [Ca2+] were also not significantly different in glomus cells from CSE+/+ and CSE-/- mice. In whole-body plethysmography, hypoxia (10%O2) increased minute ventilation in both CSE+/+ and CSE-/- mice equally well, and no significant differences were found in either males or females when adjusted by body weight. Together, these results show that deletion of the CSE gene has no effects on hypoxia-induced changes in TASK, cell depolarization, [Ca2+]i and ventilation, and therefore do not support the idea that CSE/H2S signaling is important for CB chemoreceptor activity in mice. PMID- 28851594 TI - Editor's Choice - Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). PMID- 28851596 TI - Editor's Choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). PMID- 28851598 TI - Atomic force microscopy of virus shells. AB - Microscopes are used to characterize small specimens with the help of probes, such as photons and electrons in optical and electron microscopies, respectively. In atomic force microscopy (AFM) the probe is a nanometric tip located at the end of a microcantilever which palpates the specimen under study as a blind person manages a white cane to explore the surrounding. In this way, AFM allows obtaining nanometric resolution images of individual protein shells, such as viruses, in liquid milieu. Beyond imaging, AFM also enables the manipulation of single protein cages, and the characterization of every physico-chemical property able of inducing any measurable mechanical perturbation to the microcantilever that holds the tip. Here we describe several AFM approaches to study individual protein cages, including imaging and spectroscopic methodologies for extracting mechanical and electrostatic properties. In addition, AFM allows discovering and testing the self-healing capabilities of protein cages because occasionally they may recover fractures induced by the AFM tip. Beyond the protein shells, AFM also is able of exploring the genome inside, obtaining, for instance, the condensation state of dsDNA and measuring its diffusion when the protein cage breaks. PMID- 28851599 TI - Membrane tension: A challenging but universal physical parameter in cell biology. AB - The plasma membrane separates the interior of cells from the outside environment. The membrane tension, defined as the force per unit length acting on a cross section of membrane, regulates many vital biological processes. In this review, we summarize the first historical findings and the latest advances, showing membrane tension as an important physical parameter in cell biology. We also discuss how this parameter must be better integrated and we propose experimental approaches for key unanswered questions. PMID- 28851597 TI - Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage. AB - Iron is essential for basic cellular functions but in excess is highly toxic. For this reason, free iron and iron storage are controlled in the periphery by elaborate regulatory mechanisms. In contrast, iron regulation in the central nervous system (CNS) is not well defined. Given that excess iron is present after trauma, hemorrhagic stroke and neurodegeneration, understanding normal iron regulation and promoting iron uptake in CNS pathology is crucial. Peripherally, toll-like receptor 4 (TLR4) activation promotes iron sequestration by macrophages. Notably, iron-rich sites of CNS pathology typically contain TLR4 agonists, which may promote iron uptake. Indeed, our recent work showed impaired iron storage after acute spinal cord injury in mice with TLR4 deficiency. Here we used a reductionist model to ask if TLR4 activation in the CNS stimulates iron uptake and promotes neuroprotection from iron-induced toxicity. For this, we measured the ability of microglia/macrophages to sequester exogenous iron and prevent pathology with and without concomitant intraspinal TLR4 activation. Results show that, similar to the periphery, activating intraspinal TLR4 via focal LPS injection increased mRNA encoding iron uptake and storage proteins and promoted iron sequestration into ferritin-expressing macrophages. However, this did not prevent oligodendrocyte and neuron loss. Moreover, replacement of oligodendrocytes by progenitor cells - a normally robust response to in vivo macrophage TLR4 activation - was significantly reduced if iron was present concomitant with TLR4 activation. Thus, while TLR4 signaling promotes CNS iron uptake, future work needs to determine ways to enhance iron removal without blocking the reparative effects of innate immune receptor signaling. PMID- 28851601 TI - Reduced brain response to a sweet taste in Hispanic young adults. AB - Hispanics have an increased risk for metabolic disorders, which evidence suggests may be due to interactions between lifespan biological, genetic, and lifestyle factors. Studies show the diet of many U.S. Hispanic groups have high sugar consumption, which has been shown to influence future preference for and consumption of high-sugar foods, and is associated with increased risk for insulin-related disorders and obesity. Taste is a primary determinant of food preference and selection. Differences in neural response to taste have been associated with obesity. Understanding brain response to sweet taste stimuli in healthy Hispanic adults is an important first step in characterizing the potential neural mechanisms for this behavior. We used fMRI to examine brain activation during the hedonic evaluation of sucrose as a function of ethnicity in Hispanic and non-Hispanic young adults. Taste stimuli were administered orally while subjects were scanned at 3T. Data were analyzed with AFNI via 3dROIstats and 3dMEMA, a mixed effects multi-level analysis of whole brain activation. The Hispanic group had significantly lower ROI activation in the left amygdala and significantly lower whole brain activation in regions critical for reward processing, and hedonic evaluation (e.g. frontal, orbitofrontal, and anterior cingulate cortices) than the non-Hispanic group. Differences in processing of sweet tastes have important clinical and public health implications, especially considering increased risk of metabolic syndrome and cognitive decline in Hispanic populations. Future research to better understanding relationships between health risk and brain function in Hispanic populations is warranted to better conceptualize and develop interventions for these populations. PMID- 28851602 TI - PLACK syndrome resulting from a new homozygous insertion mutation in CAST. PMID- 28851600 TI - Oxygen-responsive transcriptional regulation of lipid homeostasis in fungi: Implications for anti-fungal drug development. AB - Low oxygen adaptation is essential for aerobic fungi that must survive in varied oxygen environments. Pathogenic fungi in particular must adapt to the low oxygen host tissue environment in order to cause infection. Maintenance of lipid homeostasis is especially important for cell growth and proliferation, and is a highly oxygen-dependent process. In this review, we focus on recent advances in our understanding of the transcriptional regulation and coordination of the low oxygen response across fungal species, paying particular attention to pathogenic fungi. Comparison of lipid homeostasis pathways in these organisms suggests common mechanisms of transcriptional regulation and points toward untapped potential to target low oxygen adaptation in antifungal development. PMID- 28851603 TI - The physiopathologic role of oxidative stress in skeletal muscle. AB - Muscle senescence is a complex mechanism that is usually associated with a decrease in mass, strength and velocity of contraction. This state, known as sarcopenia, is a multifactorial process and it may be the consequence of several events, including accumulation of oxidative stress. The role of oxidative stress in the physiopathology of skeletal muscle is quite complex. Transiently increased levels of oxidative stress might reflect a potentially health promoting process, while an uncontrolled accumulation might have pathological implication. The physiopathological role of oxidative stress on skeletal muscle, its involvement in aging-induced sarcopenia, and potential countermeasures will be discussed. PMID- 28851605 TI - New-onset atrial fibrillation and clinical outcome in non-cardiac intensive care unit patients. AB - BACKGROUND: Data regarding new onset atrial fibrillation (nAF) in general, non cardiac, intensive care unit (ICU) patients are limited. However, it has been suggested that nAF is associated with worse clinical outcome in these patients. OBJECTIVE: The purpose of the present work was to study the prognostic impact of nAF, in this setting. METHODS: We prospectively studied all patients admitted to a single ICU for a period of 12 months. Patients admitted for brief post operative monitoring, patients with chronic, intermittent atrial fibrillation and atrial fibrillation present upon admission, were excluded. Death during ICU stay (ICUD) was the pre-specified study end-point. Length of stay (LOS) for survivors was also reported. A number of factors related to the occurrence of nAF and the present disease were recorded for each patient. RESULTS: The study population was comprised of 133 patients. Twenty (15%) of them manifested nAF. The end-point of ICUD was observed in 27.1% of the patients. The median LOS reported was 8 days. Patients with nAF seemed to have significantly worse prognosis, compared to those who did not manifest nAF (OR=3.35, 95%CI:1.26-8.92; P=0.016). Additionally, nAF patients appear to require significantly extended LOS (P=0.01). Nevertheless, when the effect of nAF on ICUD was adjusted for sepsis, there was no statistically significant difference between those that manifested nAF and the rest of the patients. CONCLUSION: Patients suffering nAF seem to have worse prognosis during ICU stay. However, a direct impact of nAF on mortality was not documented. PMID- 28851604 TI - Regulatory Logic Underlying Diversification of the Neural Crest. AB - The neural crest is a transient, multipotent population of cells that arises at the border of the developing nervous system. After closure of the neural tube, these cells undergo an epithelial-to-mesenchymal transition (EMT) to delaminate and migrate, often to distant locations in the embryo. Neural crest cells give rise to a diverse array of derivatives including neurons and glia of the peripheral nervous system, melanocytes, and bone and cartilage of the face. A gene regulatory network (GRN) controls the specification, delamination, migration, and differentiation of this fascinating cell type. With increasing technological advances, direct linkages within the neural crest GRN are being uncovered. The underlying circuitry is useful for understanding important topics such as reprogramming, evolution, and disease. PMID- 28851606 TI - Clinical evaluation of a newly developed automated massively parallel sequencing assay for hepatitis C virus genotyping and detection of resistance-association variants. Comparison with a line probe assay. AB - Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Recently, HCV was classified into 6 major genotypes (GTs) and 67 subtypes (STs). Efficient genotyping has become an essential tool for prognosis and indicating suitable treatment, prior to starting therapy in all HCV-infected individuals. The widely used genotyping assays have limitation with regard to genotype accuracy. This study was a comparative evaluation of exact HCV genotyping in a newly developed automated-massively parallel sequencing (MPS) system, versus the established Line probe assay 2.0 (LiPA), substantiated by Sanger sequencing, using 120 previously identified-HCV RNA positive specimens. LiPA gave identical genotypes in the majority of samples tested with MPS. However, as much as 25% of LiPA did not identify subtypes, whereas MPS did, and 0.83% of results were incompatible. Interestingly, only MPS could identify mixed infections in the remaining cases (1.67%). In addition, MPS could detect Resistance-Associated Variants (RAVs) simultaneously in GT1 in 56.82% of the specimens, which were known to affect drug resistance in the HCV NS3/NS4A and NS5A genomic regions. MPS can thus be deemed beneficial for guiding decisions on HCV therapy and saving costs in the long term when compared to traditional methods. PMID- 28851607 TI - RIFM fragrance ingredient safety assessment, acetaldehyde, diphenethyl acetal, CAS Registry Number 122-71-4. PMID- 28851608 TI - RIFM fragrance ingredient safety assessment, 3-methyl-2-pentylcyclopentan-1-one, CAS Registry Number 13074-63-0. PMID- 28851609 TI - Pharmacokinetics, excretion balance, and tissue distribution of [14C]-labeled glycolipids and long chain fatty acids from Dacryopinax spathularia in rats. AB - The pharmacokinetics, excretion balance, and tissue distribution of [14C]-labeled glycolipids from Dacryopinax spathularia (herein referred to as "AM-1") and [14C] LCFA equivalents following single or repeated administration to Sprague Dawley rats were evaluated to support the safety assessment of these naturally derived jelly mushroom glycolipids for use as a food ingredient. Rats received equimolar doses of either [14C]-AM-1 or [14C]-LCFA via oral or intravenous administration followed by collection of biological samples at specified intervals. Approximately 88%-101% of the administered dose was recovered in expired air, urine, feces, and carcass following single or repeated oral administration of [14C]-AM-1 at 100 mg/kg or equimolar doses of [14C]-LCFA at 46 mg/kg. Cmax and AUClast for [14C]-AM-1- and [14C]-LCFA-equivalents-derived radioactivity detected by quantitative whole body autoradiography was highest in the tissues of the GI tract, as expected following oral administration. The remaining tissues had low concentrations of test article equivalents relative to the administered dose and no target tissues for residence or accumulation were identified. AM-1 and LCFA are poorly absorbed by the oral route and are primarily eliminated in the feces without absorption. Oral bioavailability of both AM-1 and LCFA including their metabolites is low at approximately 11%. PMID- 28851610 TI - RIFM fragrance ingredient safety assessment, phenylacetaldehyde diethyl acetal, CAS Registry Number 6314-97-2. PMID- 28851611 TI - The efficacy of infliximab combined with surgical treatment of fistulizing perianal Crohn's disease: Comparative analysis according to fistula subtypes. AB - BACKGROUND/OBJECTIVE: Infliximab is regarded as an effective therapeutic to treat Crohn's disease. This study aimed to assess the efficacy of infliximab combined with surgery and to analyze clinical manifestations according to fistula subtypes in patients with fistulizing perianal Crohn's disease. METHODS: From April 2013 to December 2015, 47 patients with perianal Crohn's disease in two hospitals of South Korea (Goo Hospital, Gangnam Severance Hospital) were evaluated retrospectively. Patients were categorized into two groups as simple fistula (n = 20) and complex fistula group (n = 27). All patients received 5 mg/kg of infliximab intravenously at 0, 2, and 6 weeks after surgical treatments. Then every eight weeks, the responders continued to receive 5 mg/kg infliximab for maintenance therapy. RESULTS: Complete response of induction therapy was 72.3%, and partial response was 27.7%. After maintenance therapy, complete response was 97.9% and partial response was 2.1%. There was no patient without a response to infliximab in this study. The median time to the first fistula closure was 6.00 +/- 8.00 weeks. Infliximab was used on average 2.13 +/- 0.71 times until the first fistula closure. The rate of recurrence was 8.5% and adverse events were 4.2%. In comparison with clinical manifestations between simple and complex fistula groups, there was no significant difference except for the coexistence of perianal abscess. CONCLUSIONS: Combined surgical and infliximab therapy was efficacious to treat fistulizing perianal Crohn's disease with rapid treatment response and favorable clinical outcomes. It is expected that this top-down strategy with combining surgeries can overcome previous limitations in treating perianal Crohn's disease. PMID- 28851612 TI - "All-in-one mesh" hernioplasty: A new procedure for primary inguinal hernia open repair. AB - BACKGROUND: We propose a new open mesh hernia repair procedure for the treatment of inguinal hernias in adults aiming to improve patients' comfort and to reduce the incidence of chronic neuralgia. METHODS: From September 2012 to August 2015, 250 consecutive patients were treated with "all in-one" mesh hernioplasty procedure in our Institution. According to the devised technique, a new smaller prosthesis was placed on the floor of the inguinal canal in order to strengthen all areas of weakness from which hernias may originate. The mesh was enveloped by a fibro-cremasteric sheath avoiding contact with neural structures. Follow-up was carried out at 3, 6, 12, 18 and 24 months for evaluation of postoperative pain using Visual Analogue Scale score, need of medication, patients' comfort and short or long-term complications. RESULTS: All patients were discharged within 24 h from surgery. Slight pain was reported by the majority of patients and 47.6% of them did not require pain medication at home. After the 1st postoperative week 96.8% reported no pain and no other symptoms. No relevant limitation of normal activities was reported. There has been no postoperative neuralgia. One recurrence was observed. CONCLUSIONS: This new hernioplasty technique respects the anatomy of the inguinal canal, uses a smaller mesh, and seems to avoid neuralgia with maximum comfort for the patients. PMID- 28851614 TI - Histo-anatomical basis of the gastroepiploic vascularized lymph node flap: The overlooked "micro" lymph nodes. PMID- 28851613 TI - Characterization of the visfatin gene and its expression pattern and effect on 3T3-L1 adipocyte differentiation in chickens. AB - Visfatin is a newly identified adipocytokine that plays an important role in the determination of fat traits. In this study, we investigated the characterization of visfatin and the relationship between gene expression and chicken development to provide a theoretical basis for studying visfatin functions. The main results are summarized as follows: The 1482-bp full coding sequence of the visfatin gene of silky fowl was obtained and found to encode 493 amino acids. This gene contains 26 phosphorylation sites and a conserved domain of the NAPRTase family but no signal peptide sequence. It exhibits six functional motifs, including an amidation site. In chickens, visfatin is a highly conserved protein. The highest expression of visfatin was found in breast muscle and the lowest in bone marrow. There was no difference in expression between visceral fat and subcutaneous fat. However, the expression of visfatin in the bone marrow, liver, kidneys, and subcutaneous and visceral fat of broiler chickens was significantly higher than that in silky fowl (P<0.05). Visfatin mRNA levels in the bone marrow decreased with development (P<0.05) but increased in the liver and leg muscle. Visfatin gene expression in the liver, heart and bone marrow did not differ in silky fowl according to sex. A visfatin fusion protein caused a significant increase in the expression of adipocyte differentiation markers (PPARgamma, aP2, C/EBPalpha, and FAS) compared with the control group and a decrease compared with the insulin group. Taken together, the results of the present study contribute to a better understanding of the expression and role of the visfatin gene in chickens. PMID- 28851616 TI - Regulation of gonadotropins by urocortin 2 in gonadotropic tumor LbetaT2 cells. AB - A close interaction has been shown between the hypothalamo-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis. Urocortin 2 (Ucn2) has a very high affinity for the corticotropin-releasing factor (CRF) type 2 (CRF2) receptor. Pituitary Ucn2 regulates expression and secretion of gonadotropins in response to stress. The CRF2 receptor in the pituitary contributes to the modulation of gonadotropins. To explore the possible function of Ucn2 and the CRF2 receptor in pituitary gonadotropic tumor cells, we examined the direct regulation of gonadotropins by Ucn2 in a representative pituitary gonadotropic tumor, mouse LbetaT2 cells. LbetaT2 cells were found to express CRF1 receptor and CRF2 receptor mRNA. Ucn2 decreased CRF1 receptor mRNA levels, while it increased CRF2 receptor mRNA levels. Ucn2 directly decreased the mRNA levels of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in LbetaT2 cells. Ucn2 also decreased gonadotropin-releasing hormone receptor (GnRHR) mRNA levels. A selective CRF2 receptor antagonist suppressed the Ucn2-induced decreases in LH, FSH, and GnRHR mRNA levels. Ucn2 acts on gonadotrophs expressing the CRF2 receptor, and inhibits the production of gonadotropins in the pituitary gonadotropic tumor cells. (177 words). PMID- 28851615 TI - Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine. AB - Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a beta-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the beta-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4 methylmethamphetamine. To test this hypothesis, l-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by l-DOPA. Mephedrone remained non-neurotoxic when combined with either l-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4 methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to beta-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28851617 TI - Working memory performance impaired after exposure to acute social stress: The evidence comes from ERPs. AB - Using event-related potentials (ERPs), we examined the time course of 39 healthy novice drivers during a blocked working memory task (numerical N-back) under acute social stress or control conditions, which were induced by the Trier Social Stress Task (TSST) or control procedure. Subjective measures were used to assess stress manipulation throughout the experiment. An elevated negative effect in response to a stress condition indicated a successful stress induction. The behavioral results showed that the stress group had a longer response time and larger differences in accuracy than the control group. On a neural level, the control group had larger P3 amplitude in the 1-back condition than in the 2-back condition; this load effect, however, disappeared in the stress group. These results revealed that acute social stress had a disruptive effect on both working memory behavioral performance and cognitive neural process. These findings provide us with a basis to understand the correlation between acute stress and cognitive processes of working memory at a cognitive neural level. PMID- 28851618 TI - What can ERPs tell us about the generation effect? AB - The present experiment aimed to gain further understanding of the generation effect by investigating its neural correlates during encoding using event-related potentials (ERPs). Participants first encoded pairs of words under either a read or a generate condition and then completed a cued-recall task. Results confirmed the benefit of generation on memory performance. In addition, ERPs associated with the successfully encoded words had greater magnitude for generated than read words, from 900 to 1800ms post-stimulus, on middle and bilateral frontal and parietal electrodes sites, mostly on the right hemisphere. Analyses also revealed that this greater activity was significantly correlated with executive control abilities but not with semantic knowledge. These findings show that generation is associated with greater later neural activity, suggesting the use of additional processes. Our findings also provide some evidence in support of the cognitive effort hypothesis of the generation effect. PMID- 28851619 TI - Molecular characterization of Babesia species in wild animals and their ticks in Turkey. AB - To date, no study has investigated Babesia ecology in wild boars, hares or foxes in Turkey. This study aimed to determine and characterize Babesia spp. in wild animals and their ticks. We identified a novel Babesia genotype and four known Babesia species in wild animals and their ticks. We detected Babesia spp. molecularly in hares for the first time. In addition, we identified B. vulpes in foxes for the first time in Turkey. The presence of B. rossi, B. crassa and B. occultans was also revealed in ticks collected from wild boars and hares. This is only the second report of B. rossi in ticks outside of Africa and suggests that B. rossi is circulating in ticks in Turkey. Therefore B. rossi poses a significant threat to domestic dogs. Here we demonstrate the role of wild animals in the life cycle of Babesia species in Turkey and contribute to Babesia ecological and taxonomic information. PMID- 28851620 TI - Diagnosis of congenital toxoplasmosis in a renal transplant recipient mother. AB - We report the case of a first trimester toxoplasmosis infection in a renal transplant recipient. Real-time polymerase chain reaction in amniotic fluid at 18 weeks was negative for Toxoplasma gondii but at 26 weeks major fetal hydrocephalus was discovered leading to medical termination of pregnancy. Pathological examination confirmed lesions consistent with congenital toxoplasmosis. The herein case report, as well as data from the French reference centre for congenital Toxoplamosis (1835 cases in the past eight years), suggests that the strategy of management of pregnancy's first trimester Toxoplasmosis infection in patients treated by immunosuppressive therapy needs to be reconsidered. PMID- 28851621 TI - Pulmonary Arterial Hypertension Associated With Systemic Lupus Erythematosus: Results From the French Pulmonary Hypertension Registry. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare complication of systemic lupus erythematosus (SLE). METHODS: We identified all patients with SLE and PAH (SLE-PAH) who were enrolled in the French Pulmonary Hypertension Registry with a diagnosis confirmed by right heart catheterization (RHC). A control group of 101 patients with SLE without known PAH was selected from SLE expert centers participating in the Pulmonary Hypertension Registry. Survival was estimated by the Kaplan-Meier method. Hazard ratios associated with potential predictors of death were estimated using Cox proportional hazard models. RESULTS: Of the 69 patients with SLE-PAH identified in the French Pulmonary Hypertension Registry, 51 were included in the study. They did not differ from the control group regarding age, sex, or duration of SLE at the time of the analysis but had a higher frequency of anti-SSA and anti-SSB antibodies. The delay between SLE diagnosis and PAH diagnosis was 4.9 years (range, 2.8-12.9) years. The 3- and 5 year overall survival rates were 89.4% (95% CI, 76.2%-96.5%) and 83.9% (95% CI, 68.8%-92.1%), respectively. The survival rate was significantly better in patients with anti-U1-RNP antibodies (P = .04). CONCLUSIONS: Patients with SLE PAH have an overall 5-year survival rate of 83.9% after the PAH diagnosis. Anti SSA/SSB antibodies may be a risk factor for PAH, and the presence of anti-U1-RNP antibodies appears to be a protective factor regarding survival. PMID- 28851622 TI - Improved stem cell therapy of spinal cord injury using GDNF-overexpressed bone marrow stem cells in a rat model. AB - The use of stem cell base therapy as an effective strategy for the treatment of spinal cord injury (SCI) is very promising. Although some strategy has been made to generate neural-like cells using bone marrow mesenchymal stem cells (BMSCs), the differentiation strategies are still inefficiently. For this purpose, we improved the therapeutic outcome with utilize both of N-neurotrophic factor derived Gelial cells (GDNF) gene and differentiation medium that induce the BMSCs into the neural-like cells. The differentiated GDNF overexpressed BMSCs (BMSCs GDNF) were injected on the third day of post-SCI. BBB score test was performed for four weeks. Two weeks before the end of BBB, biotin dextranamin was injected intracrebrally and at the end of the fourth week, the tissue was stained. BBB scores were significantly different in BMSCs-GDNF injected and control animals. Significant difference in axon counting was observed in BMSCs-GDNF treated animals compared to the control group. According to the results, differentiated BMSCs-GDNF showed better results in comparison to the BMSCs without genetic modification. This study provides a new strategy to investigate the role of simultaneous in stem cell and gene therapy for future neural-like cells transplantation base therapies for SCI. PMID- 28851623 TI - Diethylcarbamazine: A potential treatment drug for pulmonary hypertension? AB - The present study demonstrated the potential effects of diethylcarbamazine (DEC) on monocrotaline (MCT)-induced pulmonary hypertension. MCT solution (600mg/kg) was administered once per week, and 50mg/kg body weight of DEC for 28days. Three C57Bl/6 male mice groups (n=10) were studied: Control; MCT28, and MCT28/DEC. Echocardiography analysis was performed and lung tissues were collected for light microscopy (hematoxylin-eosin and Masson's trichrome staining), immunohistochemistry (alphaSMA, FADD, caspase 8, caspase 3, BAX, BCL2, cytochrome C and caspase 9) western blot (FADD, caspase 8, caspase 3, BAX, BCL2, cytochrome C and caspase 9) and qRt-PCR (COL-1alpha and alphaSMA). Echocardiography analysis demonstrated an increase in the pulmonary arterial blood flow gradient and velocity in the systole and RV area in the MCT28 group, while treatment with DEC resulted in a significant reduction in these parameters. Deposition of collagen fibers and alphaSMA staining around the pulmonary arteries was evident in the MCT28 group, while treatment with DEC reduced both. Western blot analysis revealed a decrease in BMPR2 in the MCT28 group, in contrast DEC treatment resulted in a significant increase in the level of BMPR2. DEC also significantly reduced the level of VEGF compared to the MCT28 group. Apoptosis extrinsic and intrinsic pathway markers were reduced in the MCT28 group. After treatment with DEC these levels returned to baseline. The results of this study indicate that DEC attenuates PH in an experimental monocrotaline-induced model by inhibiting a series of markers involved in cell proliferation/death. PMID- 28851624 TI - Effect of conservative mutations (L94V and L94I) on the structure and stability of horse cytochrome c. AB - A sequence alignment of horse cytochrome c (cyt c) with all known cyts c shows that Leu at position 94 is conserved, except in 14 species which have either Val or Ile at this position. It is also known that Leu94 of the mammalian cyt c plays an important role in folding and stability. The important question here is as to what will happen in terms of folding and stability if Leu94 of the mammalian cyt c is substituted by Val or Ile. To answer this question, we introduced natural substitutes of Leu94 by Val and Ile in horse cyt c. The purified L94V and L94I mutants under native condition (pH 6.0, 25 degrees C) were characterized using far-UV, near-UV and Soret- circular dichroism, visible absorbance, Trp and ANS (1 anilino-8-napthaline sulphonate) fluorescence and dynamic light scattering measurements. Furthermore, stability parameters Tm (mid-point of denaturation) and DeltaGD0 (Gibbs free energy change at 25 degrees C) were also determined using spectroscopic and differential scanning calorimetric methods. All these measurements led us to conclude that both mutants exist as molten globule and are less stable than the wild-type protein. These observations are supported well by examining the structure of horse cyt c (PDB ID, 1HRC). PMID- 28851625 TI - Reconciling the Mitscherlich's law of diminishing returns with Liebig's law of the minimum. Some results on crop modeling. AB - Reliable fertilizer recommendations depend on the correctness of the crop production models fitted to the data, but generally the crop models are built empirically, neglecting important physiological aspects related with response to fertilizers, or they are based in laws of plant mineral nutrition seen by many authors as conflicting theories: the Liebig's Law of the Minimum and Mitscherlich's Law of Diminishing Returns. We developed a new approach to modelling the crop response to fertilizers that reconcile these laws. In this study, the Liebig's Law is applied at the cellular level to explain plant production and, as a result, crop models compatible with the Law of Diminishing Returns are derived. Some classical crop models appear here as special cases of our methodology, and a new interpretation for Mitscherlich's Law is also provided. PMID- 28851626 TI - Stochastic sensitivity technique in a persistence analysis of randomly forced population systems with multiple trophic levels. AB - Motivated by important ecological applications we study how noise can reduce a number of trophic levels in hierarchically related multidimensional population systems. A nonlinear model with three trophic levels under the influence of external stochastic forcing is considered as a basic conceptual example. We analyze a probabilistic mechanism of noise-induced extinction of separate populations in this "prey-predator-top predator" system. We propose a new general mathematical approach for the estimation of the proximity of equilibrium regimes of this stochastic model to hazardous borders where abrupt changes in dynamics of ecological systems can occur. Our method is based on the stochastic sensitivity function technique and visualization method of confidence domains. Constructive abilities of this mathematical approach are demonstrated in the analysis of different scenaria of noise-induced reducing of the number of trophic levels. PMID- 28851627 TI - Charting the dynamic epigenome during B-cell development. AB - The epigenetic landscape undergoes a widespread modulation during embryonic development and cell differentiation. Within the hematopoietic system, B cells are perhaps the cell lineage with a more dynamic DNA methylome during their maturation process, which involves approximately one third of all the CpG sites of the genome. Although each B-cell maturation step displays its own DNA methylation fingerprint, the DNA methylome is more extensively modified in particular maturation transitions. These changes are gradually accumulated in specific chromatin environments as cell differentiation progresses and reflect different features and functional states of B cells. Promoters and enhancers of B cell transcription factors acquire activation-related epigenetic marks and are sequentially expressed in particular maturation windows. These transcription factors further reconfigure the epigenetic marks and activity state of their target sites to regulate the expression of genes related to B-cell functions. Together with this observation, extensive DNA methylation changes in areas outside gene regulatory elements such as hypomethylation of heterochromatic regions and hypermethylation of CpG-rich regions, also take place in mature B cells, which intriguingly have been described as hallmarks of cancer. This process starts in germinal center B cells, a highly proliferative cell type, and becomes particularly apparent in long-lived cells such as memory and plasma cells. Overall, the characterization of the DNA methylome during B-cell differentiation not only provides insights into the complex epigenetic network of regulatory elements that mediate the maturation process but also suggests that late B cells also passively accumulate epigenetic changes related to cell proliferation and longevity. PMID- 28851628 TI - PDE8 controls CD4+ T cell motility through the PDE8A-Raf-1 kinase signaling complex. AB - The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4+ T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells, we used a cell permeable peptide that selectively disrupts the PDE8A-Raf-1 interaction. The disruptor peptide inhibits the Teff-endothelial cell interaction more potently than the enzymatic inhibitor. Furthermore, the LFA-1/ICAM-1 interaction was identified as a target of disruptor peptide mediated reduction of adhesion, spreading and locomotion of Teff cells under flow. Mechanistically, we observed that disruption of the PDE8A-Raf-1 complex profoundly alters Raf-1 signaling in Teff cells. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase complex disruptors decreases Teff cell adhesion and migration under flow, and represents a novel approach to target T cells in inflammation. PMID- 28851629 TI - Immunogenicity of virus-like Semliki Forest virus replicon particles expressing Indian HIV-1C gag, env and polRT genes. AB - Development of a vaccine targeting human immunodeficiency virus-1 subtype C (HIV 1C) is an important public health priority in regions with a high prevalence of the clade C virus. The present study demonstrates the immunogenicity of recombinant Semliki Forest virus (SFV)-based virus-like replicon particles (VRPs) expressing Indian HIV-1C env/gag/polRT genes. Immunization of mice with recombinant VRPs in a homologous prime-boost protocol, either individually or in combination, elicited significant antigen-specific IFN-gamma T cell responses as detected by the ELISPOT assay. Additionally, Gag-specific TNF-alpha secreting CD8+ and CD4+ T cells and Env-specific IL-2 secreting T cells were also elicited by mice immunized with Gag and Env constructs, respectively, as estimated by intracellular cytokine staining assay. Moreover, an HIV Pol-specific TNF-alpha response was elicited in mice immunized with a combination of the three VRP constructs. Furthermore, HIV-1C Gag and Env-specific binding antibodies were elicited as verified by gp120 ELISA and p24 Gag ELISA, respectively. The immunogenicity of VRPs was found to be higher as compared to that of RNA replicons and VRPs may therefore be promising preventive and therapeutic candidate vaccines for the control and management of HIV/AIDS. PMID- 28851630 TI - WITHDRAWN: The anti-cancer properties in parallel with toxic effects of indole-3 carbinol derivatives. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28851631 TI - Strain-specific helper T cell profile in the gut-associated lymphoid tissue. AB - C57BL/6, BALB/c and NOD mice are among the most frequently used strains in autoimmunity research. NOD mice spontaneously develop type 1 diabetes (T1D) and they are prone to induction of experimental autoimmune encephalomyelitis (EAE). Both diseases can be routinely induced in C57BL/6 mice, but not in BALB/c mice. Also, C57BL/6 mice are generally considered T helper (Th)1-biased and BALB/c Th2 biased mice. Having in mind increasingly appreciated role of gut associated lymphoid tissue (GALT) cells in autoimmunity, especially in relation to gut Th17 and regulatory T (Treg) cells, our aim was to determine if there are differences in proportion of CD4+ T cell populations in mesenteric lymph nodes and Peyer's patches of these mouse strains. Lower proportion of Treg was observed in NOD PP, Th2 cells dominated in BALB/c mice in mesenteric lymph nodes (MLN) and Peyer's patches (PP), while Th1 cells prevailed in C57BL/6 MLN. Intradermal immunization of mice with complete Freund's adjuvant resulted in significant difference in Th cell distribution in GALT of NOD mice. Differences were less pronounced in C57BL/6 mice, while GALT of BALB/c mice was almost unresponsive to the immunization. The observed strain- and tissue-dependent changes in Treg proportion after the immunization was probably a consequence of different CCR2 or CCR6-related migration patterns and/or in situ Treg proliferation. In conclusion, NOD, a highly autoimmunity-prone mouse strain, exhibits more profound GALT related immune response upon immunization compared to the strains that are less prone to autoimmunity. PMID- 28851632 TI - Effects of sex and early rearing condition on adult behavior, health, and well being in captive chimpanzees (Pan troglodytes). AB - Scientific evaluation of management strategies for captive species is part of the establishment of best practices for animal welfare. Here we report the effects of sex, rearing, and a sex-by-rearing interaction on adult, captive chimpanzees' (Pan troglodytes) behavior, health, well-being, personality, and orientation towards humans based on multiple methods (observation, animal records, and surveys). Chimpanzees raised in three conditions, mother-reared (MR), standard nursery (ST) and an experimental nursery (RC), were assessed approximately 20 years after their differential rearing experiences concluded. Sex had a significant effect on behavior towards conspecifics (aggression [M > F]; affiliation [F > M]), on abnormal behavior (rocking [M > F]), and on likelihood of incurring at least one injury (between ages 6 and 10 [M > F]). Rearing condition had a significant impact on behavior towards humans (negative solicitation [RC = ST > MR = ST]; neutral behavior [RC > ST > MR], yawning (RC = ST > MR = ST), subjective well-being (MR = ST > RC = ST), and on GI illness frequency (RC > ST = MR). Sex interacted with rearing on aggression towards humans (for males, RC > MR = ST), frequency of upper respiratory infection (URI: for males RC > MR = ST)) and likelihood of at least one URI between the ages of 11 and 15 (RC males > ST males). Our findings support the conclusion that there are long-term effects of both early rearing and sex on captive adult chimpanzee welfare. PMID- 28851633 TI - Acute postinfectious glomerulonephritis associated with scabies in the elderly: A case report. AB - Acute postinfectious glomerulonephritis (GN) secondary to scabies were mainly documented as early as in 1980s, and in all these published cases no histopathological evidence of renal biopsy were reported regarding scabies and renal damage. The delay in scabies treatment can result in a greater risk of secondary bacterial infections that can become invasive and/or lead to severe post-infective complications such as post-streptococcal glomerulonephritis. In diagnostic procedures, the clinical presentation of scabies is often atypical especially in elderly people patients. However, early diagnosis is necessary to prevent disease progression. Here, we present a case of acute glomerulonephritis caused by scabies in a 79-year-old male patient who presented with papular rash, asthma, haematuria, proteinuria, hypertension and variable azotaemia. The aim is to provide more details of the clinical features and the histopathologic characteristics, and to increase the vigilance among physicians in patients with acute GN. PMID- 28851634 TI - Molecular cloning, structural modeling and production of recombinant Aspergillus terreusl. asparaginase in Escherichia coli. AB - l-Asparaginase (EC 3.5.1.1) is an important medical enzyme that catalysis the hydrolysis of l-asparagine to aspartic acid and ammonium. For over four decades l. asparaginase utic agent for the treatment of a variety of lymphoproliferative disorders and lymphoma such as acute lymphoblastic leukemia. In the present study A. terreus full length l. asparaginase gene, 1179bp was optimized for expression in Escherichia coli BL21 (DE3) pLysS. The full length A. terreusl. asparaginase gene encoding a protein of 376 amino acids with estimated molecular weight of 42.0kDa and a theoretical isoelectric point (pI) of 5.0. BLAST and phylogeny analysis revealed that the A. terreusl. asparaginase shared high similarity with other known fungal l. asparaginase (75% homology with A. nomius and 71% with A. nidulans). The recombinant protein was overexpressed in the form of amorphous submicron proteinaceous inclusion bodies upon induction with 1mM IPTG at 37 degrees C for 18h. PMID- 28851635 TI - A novel polyurethane/nano ZnO matrix for immobilization of chitinolytic enzymes and optical sensing of chitin. AB - Purified chitinase from Vigna mungo and N-acetyl beta glucosaminidase (NAGase) from Canavalia ensiformis were immobilized on to the novel polyurethane (PU)/zinc oxide nanoparticles (nano ZnO) composite matrix with a conjugation yield of 0.785+/-0.01mg/cm2 and 96.19+/-0.85% retention of specific activity. Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FTIR) also confirmed the presence of nano ZnO and enzymes on the PU support. Thus synthesized PU/nano ZnO/chitinase/NAGase conjugates were optimized with respect to pH, temperature and substrate concentration and successfully employed for development of an absorbance based optical biosensor for chitin determination in stored wheat grains. The limit of detection was 0.01mM with linearity from 0.1 to 10.0mM. The% recoveries of added chitin (0.1 and 0.2mM) were >95.0% and >96.5% respectively and within-day and between-day coefficients of variations were 1.03% and 1.78% respectively. The method showed good correlation (R2=0.996) with the popular 3,5-dinitrosalicylic acid method. PU/nano ZnO bound chitinase/NAGase showed good thermal and storage stabilities and could be reused 10 times without any appreciable loss of activity. PMID- 28851636 TI - SLE autoantibodies are well recognized by peroxynitrite-modified-HSA: Its implications in the pathogenesis of SLE. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder where the role of inflammatory processes in the etiopathogenesis is well documented. Despite extensive research, the trigger for initiation of the disease has not been identified. Peroxynitrite, a strong nitrating/oxidizing agent has been reported in SLE and other autoimmune diseases. In this study, human serum albumin (HSA) was exposed to peroxynitrite for 30min at 37 degrees C. The structure of HSA was grossly perturbed when examined by various physico-chemical techniques. Peroxynitrite mediated nitration of HSA was confirmed by LCMS/MS. Furthermore, increase in hydrodynamic radius of peroxynitrite-modified-HSA suggests the attachment of nitro group(s). Aggregation in peroxynitrite-modified-HSA was evident in a TEM scan. Nitration, oxidation, cross linking, aggregation etc conferred immunogenicity on peroxynitrite-modified-HSA. High titre antibodies were elicited in rabbits immunized with peroxynitrite-modified-HSA. Induced antibodies were highly specific for peroxynitrite-modified-HSA but showed considerable binding with other nitrated molecules. Direct binding/inhibition ELISA carried out with autoantibodies in SLE sera showed preferential binding with peroxynitrite-modified-HSA. Anti-nDNA positive IgG from SLE sera showed preference for peroxynitrite-modified-HSA when subjected to immunoassay (direct binding and inhibition) and mobility shift assay. Our results reinforce the role of augmented inflammation in SLE progression. PMID- 28851637 TI - The antioxidative and anti-aging effects of acidic- and alkalic-extractable mycelium polysaccharides by Agrocybe aegerita (Brig.) Sing. AB - Two extractable polysaccharides of Ac-MPS and Al-MPS were extracted from the mycelium of Agrocybe aegerita (Brig.) Sing and the in vitro antioxidant activities and in vivo anti-aging activities in a d-gal-induced aging mice were investigated in the present study. The in vitro antioxidant analysis showed that Ac-MPS showed superior scavenging effects on hydroxyl of 68.62+/-2.59% and DPPH of 85.19+/-3.26% at the concentration of 4500MUg/mL. Biochemical indices and antioxidant analysis in vivo showed that Ac-MPS had better effects in raising hepatic activities of SOD, CAT, GPx and T-AOC, inhibiting hepatic contents of LPO and MDA, as well as improving serum lipid levels of LDL-C, HDL-C, LDL-C/HDL-C, TG and TC. Furthermore, HYP measurements suggested that skin collagen in aging mice could be maintained. This study suggested that both Ac-MPS and Al-MPS could be used as potential natural agents or dietary supplements in attenuating aging and its complications. PMID- 28851638 TI - Ultrasound-triggered PLGA microparticle destruction and degradation for controlled delivery of local cytotoxicity and drug release. AB - In this study, we investigated the low intensity ultrasound (US)-controlled delivery of local cytotoxicity and drug release via induced destruction and degradation of microparticles (MPs) made of poly(lactic-co-glycolic acid) (PLGA). This study was conducted in vitro with potential application towards tumor treatment in conjunction with direct injection. MPs, either loaded with or without doxorubicin (DOX), were prepared using a double-emulsion solvent evaporation technique. First, the MPs were exposed to US with duty cycle (DC) modulation. The destruction and degradation of MPs were evaluated using light and scanning electron microscopy. Second, the effects of US-mediated destruction/degradation of MPs on the local cytotoxicity as well as DOX release were evaluated. US-triggered MP destruction/degradation significantly enhanced nearby cell death and DOX release. These affects occurred in proportion to the DC. Our findings indicate that controlled cytotoxicity and DOX release by US could be useful in developing the minimally invasive therapeutic applications for tumor treatment. PMID- 28851639 TI - Polyelectrolyte complex of carboxymethyl gum katira-chitosan: Preparation and characterization. AB - In the present study polyelectrolyte complex between carboxymethyl gum katira and chitosan were prepared and evaluated for drug delivery using ofloxacin as model drug. The carboxymethyl gum katira-chitosan polyelectrolyte complex was characterized by FTIR, DSC, TGA, DTG, XRD and SEM. The influence of concentration of CMGK/CH and drug loading (%) on yield (%) and drug entrapment (%) was studied using response surface methodology. The result of the study revealed that increasing the relative proportion of CMGK/CH in carboxymethyl gum katira chitosan polyelectrolyte complex decreases the % yield and increases the % drug entrapment. The optimal calculated parameters were polymer ratio (CMGK/CH) 2.13 and drug loading 50 (%w/w). The optimized batch of carboxymethyl gum katira chitosan polyelectrolyte complex had yield of 69.04%, entrapment efficiency of ofloxacin 84.86%. Further, the optimized batch of carboxymethyl gum katira chitosan polyelectrolyte complex releases ofloxacin 84.32% following Higuchi's square-root kinetics. PMID- 28851640 TI - Interaction of heat shock protein 90 B1 (Hsp90B1) with liposome reveals its potential role in protection the integrity of lipid membranes. AB - Heat shock proteins of 90kDa (Hsp90) are molecular chaperones essential for protein homeostasis. Besides chaperone activity, Hsp90 exhibits other cellular functions at membranes, yet how it interacts with membranes remains elusive. We report here that Hsp90B1 interacts with phospholipid membranes. We first cloned the full-length open reading frame of Hsp90B1 from Anas platyrhnchos (ApHsp90B1), and the gene was then heterologously expressed and purified. SPR analysis show the purified ApHsp90B1 interacts with phospholipid membranes with high affinity (KD 176+/-25nM), and the interaction occurs over a wide range of pH, which is especially distinct under acidic conditions. Tryptophan fluorescence and far-UV CD spectra studies find that the interaction of ApHsp90B1 with phospholipid membrane induces microenvironment changes of tryptophan residues and conformational change of some regions in ApHsp90B1, which might be the reason of its increased ATPase activity upon addition phospholipid vesicles. Importantly, the interaction of ApHsp90B1 with phospholipid vesicles significantly reduces lipolysis of the membrane phospholipid, suggesting that the interaction of Hsp90B1 with membrane could preserve membrane integrity. The present study therefore demonstrates for the first time that Hsp90B1 exhibits high affinity for phospholipid membrane and suggest Hsp90B1 play an important role in membrane stabilizing via its interaction with membrane phospholipids. PMID- 28851641 TI - Polyphenolic contents, antioxidant activities and UPLC-ESI-MS analysis of Haplophyllum tuberculatum A. Juss leaves extracts. AB - The aim of this study is to determine the phytochemical profile, the total polyphenolic contents and the antioxidant activities of Haplophyllum tuberculatum leaves extracts. The most active extracts were analyzed by ultra-high performance liquid chromatography coupled to electrospray ionization mass spectrometry. Antioxidant activities were screened by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) test and measured by the 2,2-diphenyl-1 picrylhydrazyl (DPPH), 2,2-azinobis 3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and beta-carotene bleaching inhibition assays. Phytochemical screening of the extracts revealed the presence of various secondary metabolites. The ethyl acetate extract was the richest extract in phenolics and flavonoids with 262mg gallic acid equivalents/g and 99.1mg quercetin equivalent/g of dry weight, respectively. The same extract showed an important scavenging effect on DPPH, ABTS and beta-carotene/linoleic acid with IC50 of 0.020mg/mL, 0.029mg/mL and 0.022mg/mL, respectively. The correlations between the antioxidant capacities and the polyphenolic content were ranging between 0.889 and 0.256 and occasionally found to be significant. The UPLC-ESI-MS analysis showed the presence of polyphenolic and alkaloid compounds. Arabelline, majidine, dictamine and a qudsine derivative are found for the first time in H. tuberculatum. The results indicate that polyphenolic and alkaloid compounds may be major contributors to the antioxidant activity of these extracts. PMID- 28851642 TI - Cu nanoparticles synthesis using biological molecule of P. granatum seeds extract as reducing and capping agent: Growth mechanism and photo-catalytic activity. AB - In view of extended applications of nanoparticles, the nanoparticles synthesis is an extensive research field and green synthesis is one of the co-friendly methodologies. Plant extract mediated synthesis of nanoparticles has gained much attention in current decade. In current investigation, copper nanoparticles (CuNPs) were prepared using P. granatum seeds extract (biological molecules) from copper(II) chloride salt. The synthesized CuNPs were characterized by UV-vis spectroscopy, X-ray diffraction measurements (XRD), scanning electron microscopy (SEM), Energy Dispersive X- Ray Spectroscopy (EDX), Fourier transform infra-red spectroscopy (FTIR) and atomic force microscopy techniques. The CuNPs formation occurred through reduction of metal ions followed by nucleation. The size of the CuNPs was in the range of 40-80nm (average particle size was 43.9nm) with semi spherical shape and uniformly distribution. Photocatalytic activity was evaluated by degrading methylene blue dye (150mg/L) at various CuNPs doses (10mg/L 100mg/L). The synthesized CuNPs showed excellent PCA for the degradation of methylene blue (MB) under solar light irradiation and up to 87.11% degradation was achieved. The oxidative degradation mechanism for MB was proposed. In view of efficient PCA, the use of biological molecules of P. granatum seeds extracts for the synthesis of CuNPs. PMID- 28851643 TI - Structure, chaperone-like activity and allergenicity profile of bovine caseins upon peroxynitrite modification: New evidences underlying mastitis pathomechanisms. AB - Mastitis, an inflammatory reaction frequently develops in response to intra mammary bacterial infection??, may induce the generation of peroxynitrite (PON)? which is a highly potent reactive oxygen and nitrogen species. Caseins as the intrinsically unfolded proteins seem feasible substrates to react with PON. Therefore, in the current study, structural and functional aspects of both beta casein (beta-CN) and whole casein fraction (WCF) were evaluated after PON modification, using a variety of techniques. Modification of the bovine caseins with PON results in an important enhancement in the carbonyl, nitrotryptophan, nitrotyrosine and dityrosine content of these proteins?. The results of fluorescence and far UV-CD assessments suggested significant structural alteration of caseins upon PON-modification. The chaperone-like activity of beta casein was significantly altered after PON modification. The results of scanning electron microscopy suggest that bovine caseins display unique morphological features after treatment with PON. Also, the PON-modified caseins preserved their allergenicity profile and displayed partial resistance against digestion by the pancreatic proteases. Ascorbic acid, an important antioxidant component of milk, was also capable to significantly prevent the PON-induced structural damages in bovine milk caseins. In conclusion, our results suggest that PON may have significant role in the structural and functional alteration of milk caseins. Also, the PON-induced structural damaging effects of caseins might be effectively prevented by a sufficient level of milk antioxidant components particularly by ascorbic acid. PMID- 28851644 TI - Bactericidal finishing of loomstate, scoured and bleached cotton fibres via sustainable in-situ synthesis of silver nanoparticles. AB - Loomstate-, scoured- and bleached cotton fabrics were first activated by treatment with ethanolamine and; thus obtained three fabrics were submitted independently to in-situ formation of silver nanoparticles (AgNPs) using different concentrations of silver nitrate (AgNO3) in absence of other external precursor. The magnitude of AgNPs on the fabric increases by increasing AgNO3 concentrations during synthesis of AgNPs loaded fabrics irrespective of the fabric used. Loomstate- and scoured cotton fabrics with the highest amount of AgNPs exhibit spherical shape with less aggregates; opposite to their bleached mate where AgNPs are irregularly shaped with bigger size due to aggregation. The formation of AgNPs is confirmed through monitoring UV-vis absorption peak. Results signify also the formation of high density coating of silver on the surface of cotton fabric. Fabrics loaded with AgNPs exhibit superior antibacterial activity. Treatment with distilled water of AgNPs loaded scoured cotton fabric filtered by centrifugation verify the very slow launching of AgNPs indicating excellent durability; a point which advocates the use of such fabrics in infection prevention applications. Indeed, the basic and practice entailed in current studies can be nominated strongly for cleaner bactericidal finishing of cotton. PMID- 28851645 TI - Superabsorbent crosslinked carboxymethyl cellulose-PEG hydrogels for potential wound dressing applications. AB - This study focused on the synthesis and comprehensive characterization of environmentally friendly hydrogel membranes based on carboxymethyl cellulose (CMC) for wound dressing and skin repair substitutes. These new CMC hydrogels were prepared with two degrees of functionalization (DS=0.77 and 1.22) and chemically crosslinked with citric acid (CA) for tuning their properties. Additionally, CMC-based hybrids were prepared by blending with polyethylene glycol (PEG, 10wt.%). The results demonstrated that superabsorbent hydrogels (SAP) were produced with swelling degree typically ranging from 100% to 5000%, which was significantly dependent on the concentration of CA crosslinker and the addition of PEG as network modifier. The spectroscopical characterizations indicated that the mechanism of CA crosslinking was mostly associated with the chemical reaction with CMC hydroxyl groups and that PEG played an important role on the formation of a hybrid polymeric network. These hydrogels presented very distinct morphological features depended on the degree of crosslinking and the surface nanomechanical properties (e.g., elastic moduli) were drastically affected (from approximately 0.08GPa to 2.0GPa) due to the formation of CMC-PEG hybrid nanostructures. These CMC-based hydrogels were cytocompatible considering the in vitro cell viability responses of over 95% towards human embryonic kidney cells (HEK293T) used as model cell line. PMID- 28851646 TI - Stability and activity improvement of horseradish peroxidase by covalent immobilization on functionalized reduced graphene oxide and biodegradation of high phenol concentration. AB - The covalent bonding process was applied to immobilize horseradish peroxidase (HRP) onto a functionalized reduced graphene oxide with size of 60nm through glutaraldehyde as a cross-linker. The catalytic constant, kcat, and the catalytic efficiency, kcat/Km, increased 6.5 and 8.5 times, respectively, after immobilization. The circular dichroism analysis revealed that the alpha-helical content decreased from 18% to 10% after immobilization. The reusability of HRP was improved by immobilization and 70% of initial activity retained after 10 cycles. Due to the buffering effect, the immobilized HRP was less sensitive to pH changes than the free HRP. At 40 degrees C, the immobilized HRP retained 90% of the initial activity while 60% initial activity remained for the free HRP after 120minutes. After 35-day storage, the activity reached 97% of initial activity for the immobilized HRP. The removal efficiency for high phenol concentration (2500mg/L) was 100% and 55% for the immobilized HRP and free HRP, respectively. PMID- 28851647 TI - Mechanisms of sleep plasticity due to sexual experience in Drosophila melanogaster. AB - Sleep can be altered by an organism's previous experience. For instance, female Drosophila melanogaster experience a post-mating reduction in daytime sleep that is purportedly mediated by sex peptide (SP), one of many seminal fluid proteins (SFPs) transferred from male to female during mating. In the present study, we first characterized this mating effect on sleep more fully, as it had previously only been tested in young flies under 12h light/12h dark conditions. We found that mating reduced sleep equivalently in 3-day-old or 14-day-old females, and could even occur in females who had been mated previously, suggesting that there is not a developmental critical period for the suppression of sleep by mating. In conditions of constant darkness, circadian rhythms were not affected by prior mating. In either constant darkness or constant light, the sleep reduction due to mating was no longer confined to the subjective day but could be observed throughout the 24-hour period. This suggests that the endogenous clock may dictate the timing of when the mating effect on sleep is expressed. We recently reported that genetic elimination of SP only partially blocked the post-mating female siesta sleep reduction, suggesting that the effect was unlikely to be governed solely by SP. We found here that the daytime sleep reduction was also reduced but not eliminated in females mated to mutant males lacking the vast majority of SFPs. This suggested that SFPs other than SP play a minimal role in the mating effect on sleep, and that additional non-SFP signals from the male might be involved. Males lacking sperm were able to induce a normal initial mating effect on female sleep, although the effect declined more rapidly in these females. This result indicated that neither the presence of sperm within the female reproductive tract nor female impregnation are required for the initial mating effect on sleep to occur, although sperm may serve to prolong the effect. Finally, we tested for contributions from other aspects of the mating experience. NorpA and eya2 mutants with disrupted vision showed normal mating effects on sleep. By separating males from females with a mesh, we found that visual and olfactory stimuli from male exposure, in the absence of physical contact, could not replicate the mating effect. Further, in ken/barbie male flies lacking external genitalia, courtship and physical contact without ejaculation were also unable to replicate the mating effect. These findings confirmed that the influence of mating on sleep does in fact require male/female contact including copulation, but may not be mediated exclusively by SP transfer. PMID- 28851648 TI - Food-rewarded conditioning and neurophysiological analysis of cheliped gripping behavior in crayfish. AB - Animals act on their environment to intentionally manipulate it with a defined purpose. This behavior generally needs a special organ suited for the purpose and a highly complex neural mechanism to perform voluntary motor control. Crustaceans with a pair of chelipeds show various manipulative behavior for dietary, exploratory, and reproductive purposes, but the neuronal mechanism underlying the cheliped manipulative behavior has not been clarified yet. In the present study, we trained crayfish Procambarus clarkii to perform a cheliped manipulative task by a newly developed operant paradigm in which animals gripped a specific object for food reward when a visual cue was presented. Animals were then tethered in an operant chamber during the task to enable reliable physiological recordings from the central nervous system. Neural activities descending from the brain were recorded extracellularly from the connective nerves between the brain and the subesophageal ganglion in the trained animals. We found those units showing spike activities that were significantly correlated with cheliped muscle activities, but not with strict timing of visual cue presentation. Although we could not test if those descending activities were necessary or sufficient for initiating the cheliped action by their selective stimulation, the present findings suggest that neural activities for controlling operant gripping behavior are formulated in the brain rather than in the subesophageal ganglion where cheliped motoneurons are present and visual information is transmitted through the brain. PMID- 28851649 TI - Cholestatic pregnancy is associated with reduced VCAM1 expression in vascular endothelial cell of placenta. AB - OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disease which is closely correlated with abnormal placental vascular formation and deficient vascular maturation. This study intends to explore the role of VCAM 1 in the vascular formation in the placenta of ICP. METHODS: Patients with ICP or healthy puerperant were respectively used as ICP group and control group. The umbilical vein endothelial cell Eahy926 was selected as in vitro cell model. Immunohistochemistry and western blot were used for analysis of protein expression. MRNA expression was assayed by real time-PCR and the cell viability was detected by the MTT method. Cell proliferation and cell apoptosis were probed by the flow cytometer. Luciferase report assay was used for the interaction analysis between the microRNA and the 3'UTR of gene VCAM-1. RESULTS: Immunohistochemistry indicated that the expression of VCAM-1 was reduced in the ICP group compared to that in control group. The cell culture and cell behavior assays indicated that the TCA (Taurocholic acid) could reduce the expression of gene VCAM-1 and inhibit the cell proliferation and enhance the cell apoptosis. In order to probe its reduction mechanism, the potential microRNAs were detected and gene VCAM-1 was confirmed to be the target of miR-590-3p by western blot and luciferase report assays. CONCLUSIONS: The expression pattern of gene VCAM-1 was suppressed by TCA through miR-590-3p, which participated in the regulation of cell growth, cell proliferation and cell apoptosis. PMID- 28851650 TI - Exosomes expressing carbonic anhydrase 9 promote angiogenesis. AB - Exosomes or microvesicles that are secreted from cells are considered to play important roles in tumor microenvironment. Carbonic anhydrase 9 (CA9), which is induced by hypoxia-inducible factor 1 (HIF1) in response to hypoxia, is overexpressed in many types of cancer including renal cell carcinoma (RCC). We examined the expression level of CA9 in several RCC cell lines and found that the basal level of CA9 was much higher in OSRC-2 cells than in Caki-1, KMRC-1 and 786 O cells. Consistent with the intracellular expression levels, CA9 was abundantly detected in exosomes isolated by ultracentrifugation from OSRC-2 cells. Density gradient centrifugation of OSRC-2 and 786-O exosomes confirmed the co-presence of CA9 with exosomal markers. Upon hypoxia and treatment with CoCl2, a hypoxia mimic agent, the CA9 level in exosomes was increased for all cell lines. In order to examine the effects of CA9 exosomes on angiogenesis, we generated stably transfected HEK293 cells expressing CA9. Immunocytochemical staining demonstrated the uptake of CA9 exosomes by human umbilical vein endothelial cells (HUVEC). In vitro angiogenesis assays using HUVEC revealed that CA9 exosomes promoted migration and tube formation. Lastly, MMP2 expression was increased by treatment with CA9 exosomes in HUVEC. Taken together, our results suggest the possibility that CA9 exosomes released from hypoxic RCC may enhance angiogenesis in microenvironment, thereby contributing to cancer progression. PMID- 28851651 TI - Pectolinarigenin, an aglycone of pectolinarin, has more potent inhibitory activities on melanogenesis than pectolinarin. AB - Pectolinarin and pectolinarigenin have been reported to be major compounds in Cirsium setidens. In the present study, we demonstrated inhibitory effects of pectolinarin and pectolinarigenin from C. setidens on melanogenesis. Melanin synthesis was decreased in both pectolinarin- and pectolinarigenin-treated melan a cells and in a reconstructed human skin model. However, pectolinarigenin treatment showed more potent inhibitory activity of melanin synthesis than did pectolinarin treatment. The concentrations of pectolinarin and pectolinarigenin in C. setidens water extracts were determined by HPLC. Unfortunately, the amount of pectolinarigenin of C. setidens water extract was lower than that of pectolinarin. To increase the pectolinarigenin content in C. setidens water extract, several component conversion methods were studied. Consequently, we identified that microwave irradiation under 1% acetic acid was an optimum sugar elimination method. PMID- 28851652 TI - Interdisciplinary approaches to the study of flavivirus. PMID- 28851653 TI - Investigation on temperature-induce conformational change of immobilized beta2 adrenergic receptor. AB - The beta2 adrenergic receptor (beta2-AR) is a prototypical family A G protein coupled receptor (GPCR) and an excellent model system for studying the mechanism of GPCR activation. Purified beta2-AR was immobilized on macroporous silica gel to obtain liquid chromatographic stationary phase. The resulting phase was packed into a stainless steel column (4.6 * 50 mm, 7 MUm) and used for on-line chromatographic system. When column oven temperature increased from 20.0 degrees C to 40.0 degrees C, uncomplete separate chromatographic peaks of ephedrine and pseudoephedrine as receptor conformational probe were gradually merged into one peak, meanwhile retention time and resolution of the probes were reduced correspondingly, which suggested that temperature could regulate protein conformation. Temperature-induced conformational change of immobilized beta2-AR, especially changes at higher temperatures, indicated that constructed receptor chromatography could simulate fever disease state of human body and clarify receptor conformation change at pathological condition. At the same time this study could also provide new ideas for screening active components in pathological conditions. PMID- 28851654 TI - IL-1beta suppresses nephronectin expression in osteoblasts via ERK1/2 and JNK. AB - Nephronectin (Npnt), an extracellular matrix protein, is considered to play critical roles in development of various tissues and their functions. In basic science experiments, we found that interleukin-1beta (IL-1beta), well known to have an important role in inflammatory response, inhibited Npnt gene expression in MC3T3-E1 cells, a mouse osteoblastic cell line. The purpose of this study was to investigate mechanisms that govern the regulation of Npnt gene expression by IL-1beta in osteoblasts. PMID- 28851655 TI - Dp71 is regulated by phosphorylation and ubiquitin-proteasome system in neuronal cells. AB - The Dystrophin (Dp) gene is responsible for Duchenne muscular dystrophy (DMD), which is characterized by progressive muscular degeneration and variable degrees of cognitive impairment. Although Dp71 is the most abundant among the Dp isoforms in the brain, the regulatory mechanisms of the related expression levels have not been elucidated. In this study, we found that the constitutive expression levels of Dp71 in PC12 cells were sensitive to proteasomal inhibition. The ectopic expression of FLAG-tagged ubiquitin revealed that Dp71 was ubiquitinated intracellularly. Interestingly, proteasomal inhibition was accompanied by a posttranslational accumulation of modified Dp71, which was restored by protein phosphatase treatment in vitro, indicating that phosphorylation is responsible for the modification and affects the proteasome-dependent degradation of Dp71. Proteasomal activity-sensitive phosphorylated Dp71 is closely associated with syntrophin, a well-known binding partner of Dp71, and syntrophin is also regulated by proteasomal activity in a similar way to Dp71, suggesting that the posttranslational regulatory machinery for Dp71 level is coupled with Dp71 syntrophin molecular complex. Taken together, our results indicated that the expression levels of Dp71 are posttranslationally regulated by the phosphorylation-ubiquitin-proteasomal pathway, which may indicate the presence of regulatory mechanisms underlying the proteostasis of both Dp and its molecular complex, which may lead to better therapeutic approaches for the treatment of Dp related diseases. PMID- 28851656 TI - Cholemic nephropathy - Historical notes and novel perspectives. AB - Acute kidney injury is common in patients with liver disease and associated with significant morbidity and mortality. Besides bacterial infections, fluid loss, and use of nephrotoxic drugs AKI in liver disease may be triggered by tubular toxicity of cholephiles. Cholemic nephropathy, also known as bile cast nephropathy, supposedly represents a widely underestimated but important cause of renal dysfunction in cholestasic or advanced liver diseases with jaundice. Cholemic nephropathy describes impaired renal function along with characteristic histomorphological changes consisting of intratubular cast formation and tubular epithelial cell injury directed towards distal nephron segments. The underlying pathophysiologic mechanisms are not entirely understood and clear defined diagnostic criteria are still missing. This review aims to summarize (i) the present knowledge on clinical and morphological characteristics of cholemic nephropathy, (ii) available preclinical models, (iii) potential pathomechanisms especially the potential role of bile acids, and (iv) future diagnostic and therapeutic strategies for cholemic nephropathy. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. PMID- 28851657 TI - Computer simulation and experimental self-assembly of irradiated glycine amino acid under magnetic fields: Its possible significance in prebiotic chemistry. AB - Ionizing radiation may have played a relevant role in chemical reactions for prebiotic biomolecule formation on ancient Earth. Environmental conditions such as the presence of water and magnetic fields were possibly relevant in the formation of organic compounds such as amino acids. ATR-FTIR, Raman, EPR and X ray spectroscopies provide valuable information about molecular organization of different glycine polymorphs under static magnetic fields. gamma-glycine polymorph formation increases in irradiated samples interacting with static magnetic fields. The increase in gamma-glycine polymorph agrees with the computer simulations. The AM1 semi-empirical simulations show a change in the catalyst behavior and dipole moment values in alpha and gamma-glycine interaction with the static magnetic field. The simulated crystal lattice energy in alpha-glycine is also affected by the free radicals under the magnetic field, which decreases its stability. Therefore, solid alpha and gamma-glycine containing free radicals under static magnetic fields might have affected the prebiotic scenario on ancient Earth by causing the oligomerization of glycine in prebiotic reactions. PMID- 28851658 TI - Benzodiazepines use and breast cancer risk: A population-based study and gene expression profiling evidence. AB - The aim of this study was to investigate whether long-term use of Benzodiazepines (BZDs) is associated with breast cancer risk through the combination of population-based observational and gene expression profiling evidence. We conducted a population-based case-control study by using 1998 to 2009year Taiwan National Health Insurance Research Database and investigated the association between BZDs use and breast cancer risk. We selected subjects age of >20years old and six eligible controls matched for age, sex and the index date (i.e., free of any cancer at the case diagnosis date) by using propensity scores. A bioinformatics analysis approach was also performed for the identification of oncogenesis effects of BZDs on breast cancer. We used breast cancer gene expression data from the Cancer Genome Atlas and perturbagen signatures of BZDs from the Library of Integrated Cellular Signatures database in order to identify the oncogenesis effects of BZDs on breast cancer. We found evidence of increased breast cancer risk for diazepam (OR, 1.16; 95%CI, 0.95-1.42; connectivity score [CS], 0.3016), zolpidem (OR, 1.11; 95%CI, 0.95-1.30; CS, 0.2738), but not for lorazepam (OR, 1.04; 95%CI, 0.89-1.23; CS, -0.2952) consistently in both methods. The finding for alparazolam was contradictory from the two methods. Diazepam and zolpidem trends showed association, although not statistically significant, with breast cancer risk in both epidemiological and bioinformatics analyses outcomes. The methodological value of our study is in introducing the way of combining epidemiological and bioinformatics approaches in order to answer a common scientific question. Combining the two approaches would be a substantial step towards uncovering, validation and further application of previously unknown scientific knowledge to the emerging field of precision medicine informatics. PMID- 28851659 TI - Improving trend in ventricular fibrillation/pulseless ventricular tachycardia out of-hospital cardiac arrest in Rochester, Minnesota: A 26-year observational study from 1991 to 2016. AB - BACKGROUND: Mortality from out-of-hospital cardiac arrest (OHCA) is characterized by substantial regional variation. The Institute of Medicine (IOM) recently recommended enhancing the capabilities of EMS systems to improve outcome. In this study, we analyzed the trend in outcome from ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) OHCA in Rochester, MN. Survival from these forms of arrest is commonly employed as a benchmark of Emergency Medical Services (EMS) system performance. METHODS: Using a population-based Utstein-style registry in Rochester, MN where a first responder early defibrillation system is utilized, we evaluated outcome from all EMS-treated VF/pVT arrests and the subgroup of bystander-witnessed VF/pVT from 1991 to 2016. Outcome measurement was neurologically intact survival to discharge, defined as Cerebral Performance Category (CPC) 1 or 2. We divided the 26-year study into three periods: 1991 1997, 1998-2008, and 2009-2016, based on initiation of the first responder system of police officers in 1991 and fire-rescue personnel in 1998, and the latter period for comparison with our previous report in 2009. RESULTS: We observed 355 all VF/pVT arrests and 292 bystander-witnessed VF/pVT arrests between 1991 and 2016. In 2009-2016, neurologically intact survival to discharge from overall VF/pVT and bystander-witnessed VF/pVT increased to 53.7% and 65.2%, respectively, compared with 39.5% and 43.4% in 1991-1997. Using multivariable analysis, survival significantly increased in 2009-2016 among all VF/pVT arrests (adjusted OR, 3.10; 95% CI, 1.54-6.40) and bystander-witnessed VF/pVT (adjusted OR, 4.28; 95% CI, 2.01-9.50), compared with those in 1991-1997. CONCLUSIONS: We observed a significant improving secular trend in neurologically intact survival from VF/pVT cardiac arrests with a relatively high recent survival rate in this EMS System. PMID- 28851660 TI - Thymoma: a clinicopathological correlation of 1470 cases. AB - We present 1470 surgical resections for thymoma identified in the pathology files of 14 institutions from 11 countries with the purpose of determining and correlating a simplified histological classification of thymoma and pathological staging with clinical outcome. The study population was composed of 720 men and 750 women between the ages of 12 and 86 years (average, 54.8 years). Clinically, 137 patients (17%) had a history of myasthenia gravis, 31 patients (3.8%) of other autoimmune disease, and 55 (6.8%) patients of another neoplastic process. Surgical resection was performed in all patients. Histologically, 1284 (87.13%) cases were thymomas (World Health Organization types A, B1, and B2, and mixed histologies), and 186 (12.7%) were atypical thymomas (World Health Organization type B3). Of the entire group, 630 (42.9%) were encapsulated thymomas, and 840 (57.9%) were invasive thymomas in different stages. Follow-up information was obtained in 1339 (91%) patients, who subsequently were analyzed by univariate and multivariate statistical analysis. Follow-up ranging from 1 to 384 months was obtained (mean, 69.2 months) showing tumor recurrence in 136 patients (10.1%), whereas 227 died: 64 (28.2%) due to tumor and 163 (71.8%) due to other causes. Statistical analysis shows that separation of these tumors into thymoma and atypical thymoma is statistically significant (P = .001), whereas tumor staging into categories of encapsulated, minimally invasive, and invasion into adjacent organs offers a meaningful clinical assessment with a P = .038. Our findings suggest that our simplified histological schema and pathological staging system are excellent predictors of clinical outcome. PMID- 28851661 TI - J chain and myocyte enhancer factor 2B are useful in differentiating classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. AB - Although most classical Hodgkin lymphomas (CHLs) are easily distinguished from nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and primary mediastinal large B-cell lymphoma (PMBL), cases with significant CD20 expression cause diagnostic confusion. Although the absence of OCT-2 and BOB.1 are useful in these circumstances, a variable proportion of CHLs are positive for these antigens. We investigated the utility of J chain and myocyte enhancer factor 2B (MEF2B) in the diagnosis of CHL; NLPHL; PMBL; T-cell/histiocyte-rich large B-cell lymphoma (TCRLBL); and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL, compared with OCT-2 and BOB.1. J chain and MEF2B highlighted lymphocyte predominant (LP) cells in 20/20 (100%) NLPHLs and were negative in 43/43 (100%) CHLs. Fourteen of 15 (93%) PMBLs and 4/4 (100%) TCRLBLs were MEF2B positive, whereas 67% of PMBLs and 50% of TCRLBLs were J chain positive. Three of 3 B-cell lymphomas, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL, were negative for J chain and MEF2B. J chain and MEF2B were 100% sensitive and specific for NLPHL versus CHL. MEF2B was 100% sensitive and 98% specific for PMBL versus CHL. Whereas loss of OCT-2 and/or BOB.1 expression had a sensitivity of only 86% and specificity of 100% for CHL versus NLPHL, PMBL, and TCRLBL, lack of both J chain and MEF2B expression was 100% sensitive and 97% specific. J chain and MEF2B are highly sensitive and specific markers of NLPHL versus CHL; are particularly useful in highlighting LP cells; and, with rare exception, are of greater utility than OCT 2 and BOB.1 in differentiating CHL from NLPHL and other large B-cell lymphomas. PMID- 28851662 TI - Association of PD-L1 expression and PD-L1 gene polymorphism with poor prognosis in lung adenocarcinoma and squamous cell carcinoma. AB - Programmed cell death 1 receptor (PD-1)/programmed death-1 ligand-1 (PD-L1) interaction has been linked to tumor immune evasion. PD-L1 expression has been indicated in identifying non-small cell lung carcinoma (NSCLC) patients for treatment with anti-PD-1 or anti-PD-L1 therapy. The goal of this study was to evaluate the clinicopathologic values of PD-L1 expression and single-nucleotide polymorphisms (SNPs) in the PD-L1 gene in lung adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). The 147 NSCLC tissues consisted of 84 samples of ADC and 63 samples of SqCC. All tissue microarray paraffin blocks were used for PD-L1 immunohistochemical assays with 22C3, SP263, and SP142 clones. Three SNPs in the PD-L1 gene, rs4143815, rs822336, and rs822337, were genotyped using SNP pyrosequencing. The PD-L1 expression was significantly higher in SqCC than in ADC. Among ADCs, PD-L1 expression was significantly higher in papillary and solid types than in lepidic and acinar types. Statistical associations of the PD-L1 expression with a shorter disease-free survival outcome and lymph node metastasis in the ADCs were found but no associations in SqCCs. Among the three SNPs, the rs4143815 genotype CC was statistically associated with positive 22C3 PD-L1 labeling in NSCLCs. The rs4143815 genotype GG instead showed a trend of shorter survival outcomes but did not reach statistical significance in the ADCs. Our results showed a significantly higher prevalence of positive PD-L1 expression in lung SqCC than in ADC. However, the PD-L1 expression and rs4143815 genotype GG might be useful for the prediction of poor prognosis in lung ADC cases. PMID- 28851663 TI - Aldehyde dehydrogenase 1A1 (ALDH1A1) expression by immunohistochemistry is associated with chemo-refractoriness in patients with high-grade ovarian serous carcinoma. AB - Aldehyde dehydrogenase-1A1 (ALDH1A1), CD133, CD44, and CD24 have been reported as cancer stem cell markers in ovarian cancers. The goal of our study was to assess the prognostic significance of these markers in patients with advanced serous ovarian cancer. Formalin-fixed, paraffin-embedded tissues from 347 ovarian cancers were used to construct a microarray. Immunohistochemical studies for ALDH1A1, CD133, CD44, and CD24 were performed and scored semiquantitatively by 2 pathologists based on intensity and percent of positive immunoreactive cells. Immunohistochemistry was compared to clinical parameters and survival. Of the 347 cases, early stage disease, nonserous tumors, cases with incomplete therapy, and cores with no tumor were excluded. Immunohistochemistry was interpretable in 124 of the 136 stage III and IV ovarian serous carcinoma. ALDH1A1, CD24, and CD44 were variably detected in both tumor and stromal cells, and immunoreactivity in tumor was stronger than in stromal cells. CD133 immunoreactivity was not quantified due to nonspecific staining in tumor and stroma. Statistical analyses using chi2 and Student t test revealed that ALDH1A1-positive (n=53) carcinoma were 3 times more likely to demonstrate platinum refractoriness than ALDH1A1 negative (n=71) tumors (17% vs. 6%, respectively; p=.04); however, neither progression free nor overall survival was influenced by ALDH1A1 status in this cohort. The expression of CD44 and CD24 had no clinicopathological associations in the present study. Our study supports that ALDH1A1 expression is associated with poor response to platinum-based therapy in patients with high-grade ovarian serous carcinoma. Further study of this relationship is needed to understand how this could impact clinical care. PMID- 28851664 TI - Pediatric soft tissue tumor of the upper arm with LMNA-NTRK1 fusion. AB - A 6-year-old girl was admitted to our hospital because of the presence of a slow growing tumor in her right elbow. Biopsy specimens showed a round to spindle cell neoplasm with uncertain malignant potential, leading to the decision of surgical resection. Histologically, the resected tumor was encapsulated by fibrous tissue but focally invaded the surrounding skeletal muscles. The tumor was composed of ganglion cell-like short spindle cells with lymphocytic infiltration in the collagenous background. Tumor cells with large bizarre nuclei were occasionally observed, and multinucleated giant cells were scattered at the periphery. Hemangiopericytoma-like patterns and adipose tissue elements were not evident, and mitotic figures were rarely observed (<1 per 10 high-power fields). Immunohistochemically, the tumor cells were positive for S-100 and CD34 and focally positive for epithelial membrane antigen and AE1/AE3. RNA sequencing and subsequent reverse-transcription polymerase chain reaction revealed alternative splicing forms of LMNA-NTRK1 fusion (Ex2-Ex10 and Ex2-Ex15). PMID- 28851665 TI - Downregulation of miR-130a promotes cell growth and epithelial to mesenchymal transition by activating HMGB2 in glioma. AB - Aberrant expression of miR-130a is usually found in cancer studies; however, the role of miR-130a has seldom been reported in glioma. We explored miR-130a's function and the underlying mechanism in glioma. It was found that miR-130a expression was significantly down-regulated in glioma tissues and cell lines. Overexpression of miR-130a decreased glioma cell growth and invasion both in vitro and in vivo. We identified the oncogene HMGB2 as a downstream target of miR 130a by using luciferase and western blot assays. Knockdown of HMGB2 mimicked the effect of miR-130a in glioma cells. Taken together, our study demonstrate that miR-130a may function as a tumor suppressor in glioma and suggest that miR-130a is a potential therapeutic target for glioma patients. PMID- 28851666 TI - A comprehensive review of cryogels and their roles in tissue engineering applications. AB - : The extracellular matrix is fundamental in providing an appropriate environment for cell interaction and signaling to occur. Replicating such a matrix is advantageous in the support of tissue ingrowth and regeneration through the field of tissue engineering. While scaffolds can be fabricated in many ways, cryogels have recently become a popular approach due to their macroporous structure and durability. Produced through the crosslinking of gel precursors followed by a subsequent controlled freeze/thaw cycle, the resulting cryogel provides a unique, sponge-like structure. Therefore, cryogels have proven advantageous for many tissue engineering applications including roles in bioreactor systems, cell separation, and scaffolding. Specifically, the matrix has been demonstrated to encourage the production of various molecules, such as antibodies, and has also been used for cryopreservation. Cryogels can pose as a bioreactor for the expansion of cell lines, as well as a vehicle for cell separation. Lastly, this matrix has shown excellent potential as a tissue engineered scaffold, encouraging regrowth at numerous damaged tissue sites in vivo. This review will briefly discuss the fabrication of cryogels, with an emphasis placed on their application in various facets of tissue engineering to provide an overview of this unique scaffold's past and future roles. STATEMENT OF SIGNIFICANCE: Cryogels are unique scaffolds produced through the controlled freezing and thawing of a polymer solution. There is an ever-growing body of literature that demonstrates their applicability in the realm of tissue engineering as extracellular matrix analogue scaffolds; with extensive information having been provided regarding the fabrication, porosity, and mechanical integrity of the scaffolds. Additionally, cryogels have been reviewed with respect to their role in bioseparation and as cellular incubators. This all-inclusive view of the roles that cryogels can play is critical to advancing the technology and expanding its niche within biomaterials and tissue engineering research. To the best of the authors' knowledge, this is the first comprehensive review of cryogel applications in tissue engineering that includes specific looks at their growing roles as extracellular matrix analogues, incubators, and in bioseparation processes. PMID- 28851667 TI - Estrogen and progesterone signalling in the normal breast and its implications for cancer development. AB - The ovarian hormones estrogen and progesterone are master regulators of the development and function of a broad spectrum of human tissues, including the breast, reproductive and cardiovascular systems, brain and bone. Acting through the nuclear estrogen (ER) and progesterone receptors (PR), both play complex and essential coordinated roles in the extensive development of the lobular alveolar epithelial structures of the normal breast during puberty, the normal menstrual cycle and pregnancy. The past decade has seen major advances in understanding the mechanisms of action of estrogen and progesterone in the normal breast and in the delineation of the complex hierarchy of cell types regulated by ovarian hormones in this tissue. There is evidence for a role for both ER and PR in driving breast cancer, and both are favourable prognostic markers with respect to outcome. In this review, we summarize current knowledge of the mechanisms of action of ER and PR in the normal breast, and implications for the development and management of breast cancer. PMID- 28851668 TI - Spaced sessions of avoidance extinction reduce spontaneous recovery and promote infralimbic cortex activation. AB - Extinction-based therapies (EBT) are the psychological treatments of choice for certain anxiety disorders, such as post-traumatic stress disorder. However, some patients relapse and suffer spontaneous recovery (SR) of anxiety symptoms and persistence of avoidance behaviour, which underlines the need for improving EBT. In rats, recent evidence has highlighted the relevance of the temporal distribution of extinction sessions in reducing SR of auditory fear conditioning, although it has seldom been studied in procedures involving proactive avoidance responses, such as two-way active avoidance conditioning (TWAA). We examined whether the temporal distribution of two extinction sessions separated by 24h or 7days (contiguous versus spaced extinction paradigms, respectively), influences SR after 28days of a TWAA task. c-Fos expression, as a marker of neuronal activation, was also measured by immunohistochemistry 90min after the SR test in the amygdala and the medial prefrontal cortex. The temporal distribution of extinction sessions did not affect the degree of extinction learning. However, only the rats that underwent the 7-day spaced extinction paradigm maintained the level of extinction in the long term, showing no SR in TWAA. This behavioural finding was consistent with a greater number of c-Fos-labelled neurons in the infralimbic cortex in the 7-day group, and in the Lateral and Central nuclei of the amygdala in the 24-hour group. These findings show that a time-spaced extinction paradigm reduces the spontaneous recovery of active avoidance behaviour, and that this behavioural advantage appears to be related to the activation of the infralimbic cortex. PMID- 28851669 TI - Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury. AB - The nod-like receptor protein 3 (NLRP3) inflammasome has a critical role in inflammation damage in ischemic injury, and the activation of the inflammasome is closely related to the interaction with thioredoxin interacting protein (TXNIP), which dissociates from the thioredoxin1 (Trx1)/TXNIP complex under oxidative stress. However, the negative regulator of NLRP3 inflammasome activation has not been fully investigated. Nuclear factor erythroid 2-related factor 2 (Nrf2) takes on a critical part in the antioxidant stress system, that controls the driven genes of antioxidant response element (ARE). Activate Nrf2 could inhibit the activation of NLRP3 inflammasome in acute liver injury and severe lupus nephritis. We aimed to explore the protective effect of Nrf2 in inhibiting the NLPR3 inflammasome formulation through the Trx1/TXNIP complex in cerebral ischemia reperfusion (cerebral I/R) injury. Middle cerebral artery occlusion/reperfusion (MCAO/R) model was used to imitate ischemic insult. Nrf2 was activated by tert-butylhydroquinone (tBHQ) intraperitoneally (i.p.) injection (16.7mg/kg), Nrf2,Trx1 and NLRP3 siRNAs were infused into the left paracele (12MUl per rat), protein and mRNA levels were assessed by Western blot, qRT-PCR. ELISA was used for IL-1beta and IL-18 activity measurements. After upregulating Nrf2, the expression of TXNIP in cytoplasm, NLRP3 inflammasome, and downstream factors caspase-1, IL-18, and IL-1beta were significantly reduced, and Nrf2 knockdown yielded the opposite results. Trx1 knockdown produced the same effect of Nrf2 inhibition and the protective effect of Nrf2 was mostly abolished. Our results suggested that Nrf2 acted as a protective regulator against NLRP3 inflammasome activation by regulating the Trx1/TXNIP complex, which could possibly represent an innovative insight into the treatment of ischemia and reperfusion injury. PMID- 28851670 TI - The human vaginal microbial community. AB - Monopolization of the vaginal econiche by a limited number of Lactobacillus species, resulting in low pH of 3.5-4.5, has been shown to protect women against vaginal dysbiosis, sexually transmitted infections and adverse pregnancy outcomes. Still, controversy exists as to which characteristics of lactobacilli are most important with regard to colonization resistance and to providing protection. This review addresses the antimicrobial and anti-inflammatory roles of lactic acid (and low pH) and hydrogen peroxide (and oxidative stress) as means of lactobacilli to dominate the vaginal econiche. PMID- 28851671 TI - Phylogenetic diversity and antagonistic traits of root and rhizosphere pseudomonads of bean from Iran for controlling Rhizoctonia solani. AB - Fluorescent pseudomonads from bean root and rhizosphere in Iran were investigated for biocontrol of the fungal pathogen Rhizoctonia solani. Phylogenetic analysis of concatenated 16S rRNA, gyrB and rpoD sequences for 33 Pseudomonas isolates showed that 15 belonged to four clusters within the 'P. fluorescens' group, i.e. one corresponding to P. thivervalensis, two others including P. moraviensis or P. baetica, and the last one without closely-related established species. The 18 other isolates belonged to five clusters within the 'P. putida' group, one including P. mosselii and P. entomophila, another including strains currently described as P. putida, and three without closely-related species described. Ten isolates were selected based on in vitro inhibition of R. solani. Cellulase activity was identified in three pseudomonads, chitinase activity in two pseudomonads, extracellular protease activity in nine pseudomonads and hydrogen cyanide production in two pseudomonads. Genes coding for production of phenazine, pyoluteorin, pyrrolnitrin and 2,4-diacetylphloroglucinol were not found, whereas the 1-aminocyclopropane-1-carboxylate deamination gene acdS was present in three pseudomonads. The antagonistic acdS+ strain VKh13 from the 'P. putida' group effectively protected soil-grown bean from R. solani AG 4-HGI. Results show that pseudomonads from uncharacterized taxa were readily obtained from Iranian soils and displayed biocontrol potential against R. solani. PMID- 28851673 TI - Mitochondrial DNA haplogroup K as a contributor to protection against thyroid cancer in a population from southeast Europe. AB - We aimed to analyze the contribution of mitochondrial DNA (mtDNA) haplogroups of the mtDNA control region to thyroid cancer risk in a population from southeastern Europe consisting of 235 thyroid tumor patients, including 114 patients with thyroid follicular adenoma, 121 patients with papillary thyroid carcinoma, and 419 healthy controls. Binary logistic regression with adjustment for age and gender revealed that mtDNA haplogroup K was significantly associated with a protective role for thyroid cancer in the combined tumor group versus controls. These results indicate a potential role for mtDNA haplogroups as important candidate susceptibility markers for the patients with thyroid nodules. PMID- 28851672 TI - Role and mechanism of AMH in the regulation of Sertoli cells in mice. AB - Sertoli cells produce anti-Mullerian hormone (AMH), a glycoprotein belonging to the transforming growth factor-beta family. AMH mediates the regression of Mullerian ducts in the developing male fetus. However, the role of AMH in the regulation of primary Sertoli cells remains unclear. The present study was designed to investigate the effect of AMH on the viability and proliferation of Sertoli cells, with an additional focus on stem cell factor (SCF). Treatment of Sertoli cells with increasing concentrations of rh-AMH (0, 10, 50, 100, and 800ng/ml) for two days revealed that AMH, at high concentrations, increased apoptosis. These results were confirmed by a significant increase in Caspase-3 and Bax and a decrease in Bcl-2 protein and mRNA expression (P<0.01). Paradoxically, treatment with a low concentration of rh-AMH (10ng/ml), but not higher concentrations (50-800ng/ml), promoted Sertoli cell proliferation, which was verified by an increase in PCNA mRNA (P<0.05). Furthermore, only low concentrations of rh-AMH activated the non-canonical ERK signaling pathway. Similarly, low concentrations of rh-AMH (10-50ng/ml) significantly increased (P<0.05) SCF mRNA and SCF protein levels. These findings indicate that AMH differentially regulates the fate of Sertoli cells in vitro by promoting proliferation at low concentrations and apoptosis at high concentrations. In addition, AMH increased the expression of SCF, an important regulator of Sertoli cell development. Therefore, AMH may play a role in Sertoli cell development. PMID- 28851674 TI - A Validation Study of the Web Screening Questionnaire (WSQ) Compared With the Mini-International Neuropsychiatric Interview-Plus (MINI-Plus). AB - BACKGROUND: There is a need for brief screening methods for psychiatric disorders in clinical practice. This study assesses the validity and accuracy of a brief self-report screening questionnaire, the Web Screening Questionnaire (WSQ), in detecting psychiatric disorders in a study group comprising the general population and psychiatric outpatients aged 18 years and older. OBJECTIVE: The aim of this study was to investigate whether the WSQ is an adequate test to screen for the presence of depressive and anxiety disorders in clinical practice. METHODS: Participants were 1292 adults (1117 subjects from the general population and 175 psychiatric outpatients), aged 18 to 65 years. The discriminant characteristics of the WSQ were examined in relation to the ("gold standard") Mini-International Neuropsychiatric Interview-Plus (MINI-Plus) disorders, by means of sensitivity, specificity, area under the curve (AUC), and positive and negative predictive values (PPVs, NPVs). RESULTS: The specificity of the WSQ to individually detect depressive disorders, anxiety disorders, and alcohol abuse or dependence ranged from 0.89 to 0.97 for most disorders, with the exception of post-traumatic stress disorder (0.52) and specific phobia (0.73). The sensitivity values ranged from 0.67 to 1.00, with the exception of depressive disorder (0.56) and alcohol abuse or dependence (0.56). Given the low prevalence of separate disorders in the general population sample, NPVs were extremely high across disorders (>=0.97), whereas PPVs were of poor strength (range 0.02-0.33). CONCLUSIONS: In this study group, the WSQ was a relatively good screening tool to identify individuals without a depressive or anxiety disorder, as it accurately identified those unlikely to suffer from these disorders (except for post traumatic stress disorders and specific phobias). However, in case of a positive WSQ screening result, further diagnostic procedures are required. PMID- 28851676 TI - Engaging Adolescents to Inform the Development of a Mobile Gaming App to Incentivize Physical Activity. AB - BACKGROUND: Involving youth in the development of a mobile game designed to increase physical activity may increase relevancy and adoption. OBJECTIVE: To share the development process used to create a gaming app aimed at incentivizing physical activity in high school students. METHODS: Five focus groups were conducted with high school students (N=50) to understand gaming behaviors. A subset of students from the focus groups chose to complete a Web-based survey (N=10). Four different versions of gaming artwork and concept design based on student input were pilot tested (N=35), and group consensus building determined the direction of the game. The 4 game versions differed in their artwork style and gaming concept with some requiring competition versus cooperation, or being more individual versus team based. Group consensus building meant that all artwork and game concept options were displayed at the front of a classroom. Students could then vote for their top artwork and concept choices by putting stickers on the top 1 or 2 artwork and concept options that they liked best. Once all votes were cast, investigators discussed the voting results with students, and brainstormed ways to incorporate popular aspects of the 3 "losing" artwork and game concepts into the winning ideas. RESULTS: Focus group transcripts were analyzed for common themes. Artwork and gaming concept-voting data was tallied at the time of voting to share with students in real time. Focus groups and survey results revealed important themes for a successful gaming app: (1) competition, (2) balanced in-game rewards, (3) accessibility, and (4) aesthetic features. Consensus voting indicated the popularity of a collaborative competitive content design (35/66, 53%) and playful art (27/71, 38%). CONCLUSIONS: To ensure saliency and effectiveness of game-based physical activity interventions, youth need to be included in design and implementation. Furthermore, the unique preferences and social constructs of high school students need to be considered during intervention development. PMID- 28851675 TI - Internet Use and Access, Behavior, Cyberbullying, and Grooming: Results of an Investigative Whole City Survey of Adolescents. AB - BACKGROUND: According to the Digital Agenda for Europe, the way children use the Internet and mobile technologies has changed dramatically in the past years. OBJECTIVE: The aims of this study were to: (1) breakdown the modalities of access and use of the Internet by teenagers to assess risks and risky behaviors; and (2) provide scientific data to evaluate and counsel safe use of the Internet and new technologies by teenagers. METHODS: The study was conducted under the program "Strategies for a Better Internet for Children" started in May 2012 by the European Commission. It represents the main result of the project launched by Telecom Italia, "Anche io ho qualcosa da dire" (I too have something to say), thanks to which many contributions were collected and used to develop a survey. The questionnaire was structured in 45 questions, covering three macro areas of interest. It was approved by the Department Board at University of Magna Graecia's School of Medicine. After authorization from the regional high school authority, it was administered to all 1534 students (aged 13-19 years) in the city of Catanzaro, Italy. RESULTS: The data was broken down into three main groups: (1) describing education and access to the Internet; (2) methods of use and social networking; and (3) perception and evaluation of risk and risky behaviors. Among noteworthy results in the first group, we can mention that the average age of first contact with information technologies was around 9 years. Moreover, 78.87% (1210/1534) of the interviewed students reported having access to a smartphone or a tablet. Among the results of the second group, we found that the most used social networks were Facebook (85.78%, 1316/1534), YouTube (61.14%, 938/1534), and Google+ (51.56%, 791/1534). About 71.31% (1094/1534) of the interviewed teenagers use their name and surname on social networks, and 40.09% (615/1534) of them knew all their Facebook contacts personally. Among the results of the third group, we found that 7.69% (118/1534) of the interviewed teenagers have uploaded pictures or movies of which they felt ashamed; 27.05% (415/1534) have received invitations from people they met on the Internet to meet in real life; and 8.67% (133/1534) have accepted such invitations. CONCLUSIONS: The results offer a breakdown of the teenagers' use of the Internet, focusing on how teenagers learn to use and access it while taking into account factors such as parental coaching, schooling, or self-education. It describes how they approach and interact with social networks and how they perceive risks and risky behaviors on the Internet. Information technology must be seen as an instrument and not as a hindrance. For this to happen, parental guidance, schooling, and medical counseling are needed for a sound development of the child in this critical stage. PMID- 28851677 TI - Engagement as a Driver of Growth of Online Health Forums: Observational Study. AB - BACKGROUND: The emerging research on nurturing the growth of online communities posits that it is in part attributed to network effects, wherein every increase in the volume of user-generated content increases the value of the community in the eyes of its potential new members. The recently introduced metric engagement capacity offers a means of quantitatively assessing the ability of online platform users to engage each other into generating content; meanwhile, the quantity engagement value is useful for quantifying communication-based platform use. If the claim that higher engagement leads to accelerated growth holds true for online health forums (OHFs), then engagement tracking should become an important tool in the arsenal of OHF managers. Indeed, it might allow for quantifying the ability of an OHF to exploit network effects, thus predicting the OHF's future success. OBJECTIVE: This study aimed to empirically analyze the relationship between internal OHF use (quantified using engagement measurement), and external growth. METHODS: We collected data from 7 OHFs posted between the years 1999 and 2016. Longitudinal analyses were conducted by evaluating engagement in the OHFs over time. We analyzed 2-way causality effects between the engagement value and metrics evaluating OHF growth using Granger causality tests. User activity metrics per week were correlated with engagement metrics, followed by linear regression analyses. RESULTS: Observational data showed a 1-way causal relationship between the OHF engagement value and reach (P=.02). We detected a 2 way causal relationship between the engagement value and delurking, with further analysis indicating that the engagement value was more likely to cause delurking (P<.001 with lag 2; for the reverse hypothesis, P=.01 with lag 2). Users who engaged each other more were more likely (up to 14 times, depending on how much one user engaged another) to develop personal connections. Finally, we found that the more engaging an OHF user was in a given week, the more likely (up to 2 times, depending on their ability to engage others) they were to remain active in the OHF in the following week. CONCLUSIONS: This study supports the claim that network effects play an important role in accelerating OHF growth, opening the door to exploiting these effects in calculated ways. In such efforts, engagement metrics can be used to monitor the "health" of an OHF and to identify the users most important to its success. PMID- 28851678 TI - Automating Construction of Machine Learning Models With Clinical Big Data: Proposal Rationale and Methods. AB - BACKGROUND: To improve health outcomes and cut health care costs, we often need to conduct prediction/classification using large clinical datasets (aka, clinical big data), for example, to identify high-risk patients for preventive interventions. Machine learning has been proposed as a key technology for doing this. Machine learning has won most data science competitions and could support many clinical activities, yet only 15% of hospitals use it for even limited purposes. Despite familiarity with data, health care researchers often lack machine learning expertise to directly use clinical big data, creating a hurdle in realizing value from their data. Health care researchers can work with data scientists with deep machine learning knowledge, but it takes time and effort for both parties to communicate effectively. Facing a shortage in the United States of data scientists and hiring competition from companies with deep pockets, health care systems have difficulty recruiting data scientists. Building and generalizing a machine learning model often requires hundreds to thousands of manual iterations by data scientists to select the following: (1) hyper-parameter values and complex algorithms that greatly affect model accuracy and (2) operators and periods for temporally aggregating clinical attributes (eg, whether a patient's weight kept rising in the past year). This process becomes infeasible with limited budgets. OBJECTIVE: This study's goal is to enable health care researchers to directly use clinical big data, make machine learning feasible with limited budgets and data scientist resources, and realize value from data. METHODS: This study will allow us to achieve the following: (1) finish developing the new software, Automated Machine Learning (Auto-ML), to automate model selection for machine learning with clinical big data and validate Auto-ML on seven benchmark modeling problems of clinical importance; (2) apply Auto-ML and novel methodology to two new modeling problems crucial for care management allocation and pilot one model with care managers; and (3) perform simulations to estimate the impact of adopting Auto-ML on US patient outcomes. RESULTS: We are currently writing Auto-ML's design document. We intend to finish our study by around the year 2022. CONCLUSIONS: Auto-ML will generalize to various clinical prediction/classification problems. With minimal help from data scientists, health care researchers can use Auto-ML to quickly build high-quality models. This will boost wider use of machine learning in health care and improve patient outcomes. PMID- 28851679 TI - The Use of Facebook in Recruiting Participants for Health Research Purposes: A Systematic Review. AB - BACKGROUND: Social media is a popular online tool that allows users to communicate and exchange information. It allows digital content such as pictures, videos and websites to be shared, discussed, republished and endorsed by its users, their friends and businesses. Adverts can be posted and promoted to specific target audiences by demographics such as region, age or gender. Recruiting for health research is complex with strict requirement criteria imposed on the participants. Traditional research recruitment relies on flyers, newspaper adverts, radio and television broadcasts, letters, emails, website listings, and word of mouth. These methods are potentially poor at recruiting hard to reach demographics, can be slow and expensive. Recruitment via social media, in particular Facebook, may be faster and cheaper. OBJECTIVE: The aim of this study was to systematically review the literature regarding the current use and success of Facebook to recruit participants for health research purposes. METHODS: A literature review was completed in March 2017 in the English language using MEDLINE, EMBASE, Web of Science, PubMed, PsycInfo, Google Scholar, and a hand search of article references. Papers from the past 12 years were included and number of participants, recruitment period, number of impressions, cost per click or participant, and conversion rate extracted. RESULTS: A total of 35 studies were identified from the United States (n=22), Australia (n=9), Canada (n=2), Japan (n=1), and Germany (n=1) and appraised using the Critical Appraisal Skills Programme (CASP) checklist. All focused on the feasibility of recruitment via Facebook, with some (n=10) also testing interventions, such as smoking cessation and depression reduction. Most recruited young age groups (16-24 years), with the remaining targeting specific demographics, for example, military veterans. Information from the 35 studies was analyzed with median values being 264 recruited participants, a 3-month recruitment period, 3.3 million impressions, cost per click of US $0.51, conversion rate of 4% (range 0.06 29.50), eligibility of 61% (range 17-100), and cost per participant of US $14.41. The studies showed success in penetrating hard to reach populations, finding the results representative of their control or comparison demographic, except for an over representation of young white women. CONCLUSIONS: There is growing evidence to suggest that Facebook is a useful recruitment tool and its use, therefore, should be considered when implementing future health research. When compared with traditional recruitment methods (print, radio, television, and email), benefits include reduced costs, shorter recruitment periods, better representation, and improved participant selection in young and hard to reach demographics. It however, remains limited by Internet access and the over representation of young white women. Future studies should recruit across all ages and explore recruitment via other forms of social media. PMID- 28851680 TI - Remote Monitoring Systems for Chronic Patients on Home Hemodialysis: Field Test of a Copresence-Enhanced Design. AB - BACKGROUND: Patients undertaking long-term and chronic home hemodialysis (HHD) are subject to feelings of isolation and anxiety due to the absence of physical contact with their health care professionals and lack of feedback in regards to their dialysis treatments. Therefore, it is important for these patients to feel the "presence" of the health care professionals remotely while on hemodialysis at home for better compliance with the dialysis regime and to feel connected with health care professionals. OBJECTIVE: This study presents an HHD system design for hemodialysis patients with features to enhance patient's perceived "copresence" with their health care professionals. Various mechanisms to enhance this perception were designed and implemented, including digital logbooks, emotion sharing, and feedback tools. The mechanism in our HHD system aims to address the limitations associated with existing self-monitoring tools for HHD patients. METHODS: A field trial involving 3 nurses and 74 patients was conducted to test the pilot implementation of the copresence design in our HHD system. Mixed method research was conducted to evaluate the system, including surveys, interviews, and analysis of system data. RESULTS: Patients created 2757 entries of dialysis cases during the period of study. Altogether there were 492 entries submitted with "Very Happy" as the emotional status, 2167 entries with a "Happy" status, 56 entries with a "Neutral" status, 18 entries with an "Unhappy" status, and 24 entries with a "Very unhappy" status. Patients felt assured to share their emotions with health care professionals. Health care professionals were able to prioritize the review of the entries based on the emotional status and also felt assured to see patients' change in mood. There were 989 entries sent with short notes. Entries with negative emotions had a higher percentage of supplementary notes entered compared to the entries with positive and neutral emotions. The qualitative data further showed that the HHD system was able to improve patients' feelings of being connected with their health care professionals and thus enhance their self-care on HHD. The health care professionals felt better assured with patients' status with the use of the system and reported improved productivity and satisfaction with the copresence enhancement mechanism. The survey on the system usability indicated a high level of satisfaction among patients and nurses. CONCLUSIONS: The copresence enhancement design complements the conventional use of a digitized HHD logbook and will further benefit the design of future telehealth systems. PMID- 28851682 TI - On a mission to relieve the global epidemic of untreated pain. PMID- 28851681 TI - Is There Evidence of Cost Benefits of Electronic Medical Records, Standards, or Interoperability in Hospital Information Systems? Overview of Systematic Reviews. AB - BACKGROUND: Electronic health (eHealth) interventions may improve the quality of care by providing timely, accessible information about one patient or an entire population. Electronic patient care information forms the nucleus of computerized health information systems. However, interoperability among systems depends on the adoption of information standards. Additionally, investing in technology systems requires cost-effectiveness studies to ensure the sustainability of processes for stakeholders. OBJECTIVE: The objective of this study was to assess cost-effectiveness of the use of electronically available inpatient data systems, health information exchange, or standards to support interoperability among systems. METHODS: An overview of systematic reviews was conducted, assessing the MEDLINE, Cochrane Library, LILACS, and IEEE Library databases to identify relevant studies published through February 2016. The search was supplemented by citations from the selected papers. The primary outcome sought the cost effectiveness, and the secondary outcome was the impact on quality of care. Independent reviewers selected studies, and disagreement was resolved by consensus. The quality of the included studies was evaluated using a measurement tool to assess systematic reviews (AMSTAR). RESULTS: The primary search identified 286 papers, and two papers were manually included. A total of 211 were systematic reviews. From the 20 studies that were selected after screening the title and abstract, 14 were deemed ineligible, and six met the inclusion criteria. The interventions did not show a measurable effect on cost effectiveness. Despite the limited number of studies, the heterogeneity of electronic systems reported, and the types of intervention in hospital routines, it was possible to identify some preliminary benefits in quality of care. Hospital information systems, along with information sharing, had the potential to improve clinical practice by reducing staff errors or incidents, improving automated harm detection, monitoring infections more effectively, and enhancing the continuity of care during physician handoffs. CONCLUSIONS: This review identified some benefits in the quality of care but did not provide evidence that the implementation of eHealth interventions had a measurable impact on cost effectiveness in hospital settings. However, further evidence is needed to infer the impact of standards adoption or interoperability in cost benefits of health care; this in turn requires further research. PMID- 28851683 TI - Delayed extrusion of embolic coils into the airway after embolization of an external carotid artery pseudoaneurysm. AB - Carotid blowout syndrome (CBS) is a known devastating complication of head and neck surgery. The risk of developing CBS increases in the setting of radiation therapy, wound breakdown, or tumor recurrence. Traditionally, the treatment of choice for CBS is surgical ligation of the bleeding artery; however, recently, endovascular occlusion has become a more common option. If a pseudoaneurysm is present, treatment consists of trapping with endovascular coils or occlusion with a liquid embolic agent. Delayed migration of embolization coils into the airway causing acute respiratory distress is a rare occurrence. This report presents a case of a 57-year-old woman who presented to her otolaryngologist after experiencing an episode of acute respiratory distress which resolved when she expectorated embolization coil material from her tracheostomy tube. Three months prior to the episode she underwent coil embolization of an external carotid artery pseudoaneurysm for life-threatening hemorrhage. PMID- 28851684 TI - Demystifying a thickened and calcified gall bladder in the era of multimodality imaging. PMID- 28851685 TI - Junior doctors are threatened with GMC referral for refusing locum work. PMID- 28851686 TI - Margaret McCartney: Why GPs are always running late. PMID- 28851687 TI - ADC Approval Likely to Spur More Research. AB - The FDA's decision to approve inotuzumab ozogamicin for patients with relapsed or refractory acute lymphoblastic leukemia could open up further uses for the drug. It is being tested as a first-line treatment in combination with chemotherapy. The decision could also stimulate research into other antibody-drug conjugates. PMID- 28851688 TI - Surrogate Endpoint ID'd for Prostate Cancer Trials. AB - Metastasis-free survival is a strong surrogate for overall survival for men with localized prostate cancer, a meta-analysis shows. The intermediate outcome measure could help accelerate the evaluation of novel adjuvant therapies in this patient population. PMID- 28851689 TI - The Second-Generation PGI2 Analogue Treprostinil Fails to Chemoprevent Tumors in a Murine Lung Adenocarcinoma Model. AB - Prostacyclin (prostaglandin I2, PGI2) overproduction in FVB/N mice prevents the formation of carcinogen and tobacco smoke-induced adenomas, and administration of the oral prostacyclin analogue iloprost to wild-type mice also prevented carcinogen-induced mouse lung adenoma formation. Former smokers taking oral iloprost showed improved bronchial dysplasia histology compared with placebo. Next-generation oral prostacyclin analogues, like treprostinil, were developed for the treatment of pulmonary arterial hypertension (PAH). On the basis of our prior studies with iloprost, we performed preclinical studies examining the ability of treprostinil to chemoprevent urethane-induced murine lung adenocarcinoma. We determined the MTD in chow (prior studies had delivered treprostinil by gavage), and this dose produced serum levels in the experimental animals similar to those found in PAH patients treated with treprostinil. We then examined the chemopreventive efficacy of treprostinil exposure initiated both before (1 week) and after (6 weeks) urethane exposure to better model chemoprevention studies conducted in former smokers. Neither of these dosing strategies prevented murine lung cancer; however, we did detect changes in pulmonary inflammatory cell infiltrate and expression of CXCR4 (a chemokine receptor previously shown to increase in response to treprostinil exposure) in tumor-bearing, treprostinil-treated animals, indicating that the drug was bioavailable. One potential explanation stems from iloprost and treprostinil differentially activating cell surface prostaglandin receptors and intracellular peroxisome proliferator-activated receptors. When murine lung tumor cells were treated with treprostinil, their proliferation rate increased; in contrast, iloprost had no effect on proliferation. Future investigations comparing these two agents will provide insight into iloprost's chemopreventive mechanisms. Cancer Prev Res; 10(11); 671-9. (c)2017 AACR. PMID- 28851692 TI - Photodynamic-Immune Checkpoint Therapy Eradicates Local and Distant Tumors by CD8+ T Cells. AB - Photodynamic therapy (PDT) is a clinically applied tumor ablation method that reduces tumor burden and may induce T-cell responses, providing a therapeutic option for mutated tumors. In this study, we applied PDT in two mouse tumor models and assessed its effect on outgrowth of PDT-treated and distant untreated tumors. PDT of established tumors resulted in complete tumor eradication in most mice, which were then protected against tumor rechallenge. Correspondingly, the therapeutic effect was abrogated upon systemic depletion of CD8+ T cells, indicating PDT-induced tumor antigen cross-presentation and T-cell activation. In a double-tumor model, PDT of primary tumors induced enhanced infiltration of untreated distant tumors by CD8+ T cells, which significantly delayed their outgrowth. Combination therapy of PDT and CTLA-4-blocking antibodies significantly improved therapeutic efficacy and survival of double-tumor-bearing mice. These results show that local tumor ablation by PDT induces CD8+ T-cell responses crucial for systemic tumor eradication, which can be further enhanced by combination with immune checkpoint blockade. This combination of two clinically applied therapies may be a treatment strategy for advanced cancer without previous knowledge of tumor-specific antigens. Cancer Immunol Res; 5(10); 832-8. (c)2017 AACR. PMID- 28851690 TI - Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer. AB - Smoking is a major risk factor for the development of bladder cancer; however, the functional consequences of the carcinogens in tobacco smoke and bladder cancer-associated metabolic alterations remain poorly defined. We assessed the metabolic profiles in bladder cancer smokers and non-smokers and identified the key alterations in their metabolism. LC/MS and bioinformatic analysis were performed to determine the metabolome associated with bladder cancer smokers and were further validated in cell line models. Smokers with bladder cancer were found to have elevated levels of methylated metabolites, polycyclic aromatic hydrocarbons, DNA adducts, and DNA damage. DNA methyltransferase 1 (DNMT1) expression was significantly higher in smokers than non-smokers with bladder cancer. An integromics approach, using multiple patient cohorts, revealed strong associations between smokers and high-grade bladder cancer. In vitro exposure to the tobacco smoke carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (BaP) led to increase in levels of methylated metabolites, DNA adducts, and extensive DNA damage in bladder cancer cells. Cotreatment of bladder cancer cells with these carcinogens and the methylation inhibitor 5-aza-2' deoxycytidine rewired the methylated metabolites, DNA adducts, and DNA damage. These findings were confirmed through the isotopic-labeled metabolic flux analysis. Screens using smoke-associated metabolites and DNA adducts could provide robust biomarkers and improve individual risk prediction in bladder cancer smokers. Noninvasive predictive biomarkers that can stratify the risk of developing bladder cancer in smokers could aid in early detection and treatment. Cancer Prev Res; 10(10); 588-97. (c)2017 AACR. PMID- 28851694 TI - Dose optimisation of intravenous tranexamic acid for elective hip and knee arthroplasty: The effectiveness of a single pre-operative dose. AB - OBJECTIVES: We have increased the dose of tranexamic acid (TXA) in our enhanced total joint recovery protocol at our institution from 15 mg/kg to 30 mg/kg (maximum 2.5 g) as a single, intravenous (IV) dose. We report the clinical effect of this dosage change. METHODS: We retrospectively compared two cohorts of consecutive patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) surgery in our unit between 2008 and 2013. One group received IV TXA 15 mg/kg, maximum 1.2 g, and the other 30 mg/kg, maximum 2.5 g as a single pre-operative dose. The primary outcome for this study was the requirement for blood transfusion within 30 days of surgery. Secondary measures included length of hospital stay, critical care requirements, re-admission rate, medical complications and mortality rates. RESULTS: A total of 1914 THA and 2537 TKA procedures were evaluated. In THA, the higher dose of TXA was associated with a significant reduction in transfusion (p = 0.02, risk ratio (RR) 0.74, 95% confidence interval (CI) 0.58 to 0.96) and rate of re-admission (p < 0.001, RR 0.50, 95% CI 0.35 to 0.71). There were reductions in the requirement for critical care (p = 0.06, RR 0.55, 95% CI 0.31 to 1.00), and in the length of stay from 4.7 to 4.3 days (p = 0.02). In TKA, transfusion requirements (p = 0.049, RR 0.64, 95% CI 0.41 to 0.99), re-admission rate (p = 0.001, RR 0.56, 95% CI 0.39 to 0.80) and critical care requirements (p < 0.003, RR 0.34, 95% CI 0.16 to 0.72) were reduced with the higher dose. Mean length of stay reduced from 4.6 days to 3.6 days (p < 0.01). There was no difference in the incidence of deep vein thrombosis, pulmonary embolism, gastrointestinal bleed, myocardial infarction, stroke or death in THA and TKA between cohorts. CONCLUSION: We suggest that a single pre operative dose of TXA, 30 mg/kg, maximum 2.5g, results in a lower transfusion requirement compared with a lower dose in patients undergoing elective primary hip and knee arthroplasty. However, these findings should be interpreted in the context of the retrospective non-randomised study design.Cite this article: R. J. M. Morrison, B. Tsang, W. Fishley, I. Harper, J. C. Joseph, M. R. Reed. Dose optimisation of intravenous tranexamic acid for elective hip and knee arthroplasty: The effectiveness of a single pre-operative dose. Bone Joint Res 2017;6:499-505. DOI: 10.1302/2046-3758.68.BJR-2017-0005.R1. PMID- 28851695 TI - Thompson hemiarthroplasty versus modular unipolar implants for patients requiring hemiarthroplasty of the hip: A systematic review of the evidence. AB - OBJECTIVES: The objective of this study was to assess all evidence comparing the Thompson monoblock hemiarthroplasty with modular unipolar implants for patients requiring hemiarthroplasty of the hip with respect to mortality and complications. METHODS: A literature search was performed to identify all relevant literature. The population consisted of patients undergoing hemiarthroplasty of the hip for fracture. The intervention was hemiarthroplasty of the hip with a comparison between Thompson and modular unipolar prostheses.Pubmed, Embase, CINAHL, Web of Science, PROSPERO and the Cochrane Central Register of Controlled Trials.The study designs included were randomised controlled trials (RCTs), well designed case control studies and retrospective or prospective cohort studies. Studies available in any language, published at any time until September 2015 were considered. Studies were included if they contained mortality or complications. RESULTS: The initial literature search identified 4757 items for examination. Four papers were included in the final review. The pooled odds ratio for mortality was 1.3 (95% confidence Interval 0.78 to 2.46) favouring modular designs. The pooled odds ratio for post-operative complications was 1.1 (95% CI 0.79 to 1.55) favouring modular designs. Outcomes were reported at 12 or six months. These papers all contained potential sources of bias and significant clinical heterogeneity. CONCLUSION: The current evidence comparing monoblock versus modular implants in patients undergoing hemiarthroplasty is weak. Confidence intervals around the pooled odds ratios are broad and incorporate a value of one. Direct comparison of outcomes from these papers is fraught with difficulty and, as such, may well be misleading. A well designed randomised controlled trial would be helpful to inform evidence-based implant selection.Cite this article: A. L. Sims, A. J. Farrier, M. R. Reed, T. A. Sheldon. Thompson hemiarthroplasty versus modular unipolar implants for patients requiring hemiarthroplasty of the hip: A systematic review of the evidence. Bone Joint Res 2017;6:-513. DOI: 10.1302/2046-3758.68.BJR-2016-0256.R1. PMID- 28851693 TI - The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells. AB - To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two alpha-fetoprotein-specific CD8+ T cells (Tet499 and Tet212) that had different antitumor effects. We found that Tet499 required high antigen doses for reactivation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet212 had a low threshold of reactivation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo, Tet499 cells expanded more than Tet212 upon reencountering antigen and generated stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet212 and Tet499 cells correlated with their activation and differentiation states. Compared with Tet212, the population of Tet499 cells was less activated and contained more stem like memory T cells (Tscm) that could undergo expansion in vivo The TCR signaling strength on Tet499 was weaker than Tet212, correlating with more severe Tet499 TCR downregulation. Weak TCR signaling may halt T-cell differentiation at the Tscm stage during immune priming and also explains why Tet499 reactivation requires a high antigen dose. Weak TCR signaling of Tet499 cells in the effector stage will also protect them from exhaustion and apoptosis when they reencounter persistent antigen in tumor lesion, which generates antitumor effects. Further investigation of TCR downregulation and manipulation of TCR signaling strength may help design cancer vaccines to elicit a mix of tumor-specific CD8+ T cells, including Tscm, capable of surviving antigen restimulation to generate antitumor effects. Cancer Immunol Res; 5(10); 908-19. (c)2017 AACR. PMID- 28851696 TI - Sixty seconds on . . . brisk walking. PMID- 28851697 TI - Five minutes with . . . Matt Mayer. PMID- 28851698 TI - Uncovering the mystery of opposite circadian rhythms between mouse and human leukocytes in humanized mice. AB - Many immune parameters show circadian rhythms during the 24-hour day in mammals. The most striking circadian oscillation is the number of circulating immune cells that display an opposite rhythm between humans and mice. The physiological roles and mechanisms of circadian variations in mouse leukocytes are well studied, whereas for humans they remain unclear because of the lack of a proper model. In this study, we found that consistent with their natural host species, mouse and human circulating leukocytes exhibited opposite circadian oscillations in humanized mice. This cyclic pattern of trafficking correlated well with the diurnal expression levels of C-X-C chemokine receptor 4, which were controlled by the intracellular hypoxia-inducible factor 1alpha/aryl hydrocarbon receptor nuclear translocator-like heterodimer. Furthermore, we also discovered that p38 mitogen-activated protein kinases/mitogen-activated 2 had opposite effects between mice and humans in generating intracellular reactive oxygen species, which subsequently regulated HIF-1alpha expression. In conclusion, we propose humanized mice as a robust model for human circadian studies and reveal insights on a novel molecular clock network in the human circadian rhythm. PMID- 28851700 TI - Model-based projection of health and economic effects of screening for hepatitis C in Canada. AB - BACKGROUND: Because most hepatitis C virus (HCV) infections are asymptomatic and often unrecognized, screening for hepatitis C has been proposed as a plausible public health strategy. We examined the health and economic consequences of a selective one-time hepatitis C screening program for specific populations in the context of current treatment patterns. METHODS: We used a state-transition model to evaluate 2 general strategies: no screening, and screen and treat with direct acting antiviral agents. We examined these strategies for 4 different target populations (scenarios): 1) asymptomatic people not at high risk for HCV infection, 2) immigrant populations with high prevalence, 3) a birth cohort of people aged 25-64 years and 4) a birth cohort of people aged 45-64 years of age. We obtained model data from the published literature and expert opinions. We used a payer perspective, a lifetime time horizon and a 5% discount rate. RESULTS: Screening would prevent 49.7%, 57.4%, 64.1% and 49.6% of HCV-related deaths over the lifetime of the cohort for scenarios 1, 2, 3 and 4, respectively. Screening would produce incremental-cost-effectiveness ratios between $31 468/quality adjusted life-year and $50 490/quality-adjusted life-year. Probabilistic sensitivity analyses indicated that the chance that screening would be cost effective at $50 000 willingness-to-pay threshold was 39.5%, 63.2%, 58.4% and 58.1% for scenarios 1, 2, 3 and 4, respectively. INTERPRETATION: Our analyses suggest that a one-time hepatitis C screening and treatment program in Canada is likely to be cost-effective for scenarios 2, 3 and 4. The screening programs we have evaluated would identify asymptomatic people with chronic HCV infection and would enable medical treatment to be offered if needed before the development of advanced liver disease. PMID- 28851701 TI - David Oliver: Caveats about collaborative health. PMID- 28851699 TI - An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD. AB - B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8, each critical to B-cell differentiation and fate. All-trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4-to-IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5, but not BLIMP1 (a gene expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity. PMID- 28851702 TI - Identification of Novel Circulating Biomarkers Predicting Rapid Decline in Renal Function in Type 2 Diabetes: The Fremantle Diabetes Study Phase II. AB - OBJECTIVE: To assess the ability of plasma apolipoprotein (apo) A-IV (apoA4), apo C-III, CD5 antigen-like (CD5L), complement C1q subcomponent subunit B (C1QB), complement factor H-related protein 2, and insulin-like growth factor binding protein 3 (IBP3) to predict rapid decline in estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS: Mass spectrometry was used to measure baseline biomarkers in 345 community-based patients (mean age 67.0 years, 51.9% males) from the Fremantle Diabetes Study Phase II (FDS2). Multiple logistic regression was used to determine clinical predictors of rapid eGFR decline trajectory defined by semiparametric group-based modeling over a 4 year follow-up period. The incremental benefit of each biomarker was then assessed. Similar analyses were performed for a >=30% eGFR fall, incident chronic kidney disease (eGFR <60 mL/min/1.73 m2), and eGFR decline of >=5 mL/min/1.73 m2/year. RESULTS: Based on eGFR trajectory analysis, 35 participants (10.1%) were defined as "rapid decliners" (mean decrease 2.9 mL/min/1.73 m2/year). After adjustment for clinical predictors, apoA4, CD5L, and C1QB independently predicted rapid decline (odds ratio 2.40 [95% CI 1.24-4.61], 0.52 [0.29-0.93], and 2.41 [1.14-5.11], respectively) and improved model performance and fit (P < 0.001), discrimination (area under the curve 0.75-0.82, P = 0.039), and reclassification (net reclassification index 0.76 [0.63-0.89]; integrated discrimination improvement 6.3% [2.1-10.4%]). These biomarkers and IBP3 contributed to improved model performance in predicting other indices of rapid eGFR decline. CONCLUSIONS: The current study has identified novel plasma biomarkers (apoA4, CD5L, C1QB, and IBP3) that may improve the prediction of rapid decline in renal function independently of recognized clinical risk factors in type 2 diabetes. PMID- 28851703 TI - Multifamily therapy may add to the effectiveness of single-family therapy for adolescents with anorexia nervosa. PMID- 28851704 TI - Psychrophilic proteases dramatically reduce single-cell RNA-seq artifacts: a molecular atlas of kidney development. AB - Single-cell RNA-seq is a powerful technique. Nevertheless, there are important limitations, including the technical challenges of breaking down an organ or tissue into a single-cell suspension. Invariably, this has required enzymatic incubation at 37 degrees C, which can be expected to result in artifactual changes in gene expression patterns. Here, we describe a dissociation method that uses a protease with high activity in the cold, purified from a psychrophilic microorganism. The entire procedure is carried out at 6 degrees C or colder, at which temperature mammalian transcriptional machinery is largely inactive, thereby effectively 'freezing in' the in vivo gene expression patterns. To test this method, we carried out RNA-seq on 20,424 single cells from postnatal day 1 mouse kidneys, comparing the results of the psychrophilic protease method with procedures using 37 degrees C incubation. We show that the cold protease method provides a great reduction in gene expression artifacts. In addition, the results produce a single-cell resolution gene expression atlas of the newborn mouse kidney, an interesting time in development when mature nephrons are present yet nephrogenesis remains extremely active. PMID- 28851705 TI - Distinct functions for netrin 1 in chicken and murine semicircular canal morphogenesis. AB - The vestibular system of the inner ear detects head position using three orthogonally oriented semicircular canals; even slight changes in their shape and orientation can cause debilitating behavioral defects. During development, the canals are sculpted from pouches that protrude from the otic vesicle, the embryonic anlage of the inner ear. In the center of each pouch, a fusion plate forms where cells lose their epithelial morphology and the basement membrane breaks down. Cells in the fusing epithelia intercalate and are removed, creating a canal. In mice, fusion depends on the secreted protein netrin 1 (Ntn1), which is necessary for basement membrane breakdown, although the underlying molecular mechanism is unknown. Using gain-of-function approaches, we found that overexpression of Ntn1 in the chick otic vesicle prevented canal fusion by inhibiting apoptosis. In contrast, ectopic expression of the same chicken Ntn1 in the mouse otic vesicle, where apoptosis is less prominent, resulted in canal truncation. These findings highlight the importance of apoptosis for tissue morphogenesis and suggest that Ntn1 may play divergent cellular roles despite its conserved expression during canal morphogenesis in chicken and mouse. PMID- 28851707 TI - Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity. AB - Tissue fluid drains through blind-ended lymphatic capillaries, via smooth muscle cell (SMC)-covered collecting vessels into venous circulation. Both defective SMC recruitment to collecting vessels and ectopic recruitment to lymphatic capillaries are thought to contribute to vessel failure, leading to lymphedema. However, mechanisms controlling lymphatic SMC recruitment and its role in vessel maturation are unknown. Here, we demonstrate that platelet-derived growth factor B (PDGFB) regulates lymphatic SMC recruitment in multiple vascular beds. PDGFB is selectively expressed by lymphatic endothelial cells (LECs) of collecting vessels. LEC-specific deletion of Pdgfb prevented SMC recruitment causing dilation and failure of pulsatile contraction of collecting vessels. However, vessel remodelling and identity were unaffected. Unexpectedly, Pdgfb overexpression in LECs did not induce SMC recruitment to capillaries. This was explained by the demonstrated requirement of PDGFB extracellular matrix (ECM) retention for lymphatic SMC recruitment, and the low presence of PDGFB-binding ECM components around lymphatic capillaries. These results demonstrate the requirement of LEC-autonomous PDGFB expression and retention for SMC recruitment to lymphatic vessels, and suggest an ECM-controlled checkpoint that prevents SMC investment of capillaries, which is a common feature in lymphedematous skin. PMID- 28851706 TI - DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes. AB - Mouse oocytes carrying DNA damage arrest in meiosis I, thereby preventing creation of embryos with deleterious mutations. The arrest is dependent on activation of the spindle assembly checkpoint, which results in anaphase promoting complex (APC) inhibition. However, little is understood about how this checkpoint is engaged following DNA damage. Here, we find that within minutes of DNA damage checkpoint proteins are assembled at the kinetochore, not at damage sites along chromosome arms, such that the APC is fully inhibited within 30 min. Despite this robust response, there is no measurable loss in k-fibres, or tension across the bivalent. Through pharmacological inhibition we observed that the response is dependent on Mps1 kinase, aurora kinase and Haspin. Using oocyte specific knockouts we find the response does not require the DNA damage response kinases ATM or ATR. Furthermore, checkpoint activation does not occur in response to DNA damage in fully mature eggs during meiosis II, despite the divisions being separated by just a few hours. Therefore, mouse oocytes have a unique ability to sense DNA damage rapidly by activating the checkpoint at their kinetochores. PMID- 28851708 TI - miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage. AB - Cartilage originates from mesenchymal cell condensations that differentiate into chondrocytes of transient growth plate cartilage or permanent cartilage of the articular joint surface and trachea. MicroRNAs fine-tune the activation of entire signaling networks and thereby modulate complex cellular responses, but so far only limited data are available on miRNAs that regulate cartilage development. Here, we characterize a miRNA that promotes the biosynthesis of a key component in the RAF/MEK/ERK pathway in cartilage. Specifically, by transcriptome profiling we identified miR-322 to be upregulated during chondrocyte differentiation. Among the various miR-322 target genes in the RAF/MEK/ERK pathway, only Mek1 was identified as a regulated target in chondrocytes. Surprisingly, an increased concentration of miR-322 stabilizes Mek1 mRNA to raise protein levels and dampen ERK1/2 phosphorylation, while cartilage-specific inactivation of miR322 in mice linked the loss of miR-322 to decreased MEK1 levels and to increased RAF/MEK/ERK pathway activation. Such mice died perinatally due to tracheal growth restriction and respiratory failure. Hence, a single miRNA can stimulate the production of an inhibitory component of a central signaling pathway to impair cartilage development. PMID- 28851709 TI - Imp and Syp RNA-binding proteins govern decommissioning of Drosophila neural stem cells. AB - The termination of the proliferation of Drosophila neural stem cells, also known as neuroblasts (NBs), requires a 'decommissioning' phase that is controlled in a lineage-specific manner. Most NBs, with the exception of those of the mushroom body (MB), are decommissioned by the ecdysone receptor and mediator complex, causing them to shrink during metamorphosis, followed by nuclear accumulation of Prospero and cell cycle exit. Here, we demonstrate that the levels of Imp and Syp RNA-binding proteins regulate NB decommissioning. Descending Imp and ascending Syp expression have been shown to regulate neuronal temporal fate. We show that Imp levels decline slower in the MB than in other central brain NBs. MB NBs continue to express Imp into pupation, and the presence of Imp prevents decommissioning partly by inhibiting the mediator complex. Late-larval induction of transgenic Imp prevents many non-MB NBs from decommissioning in early pupae. Moreover, the presence of abundant Syp in aged NBs permits Prospero accumulation that, in turn, promotes cell cycle exit. Together, our results reveal that progeny temporal fate and progenitor decommissioning are co-regulated in protracted neuronal lineages. PMID- 28851710 TI - Notch signaling patterns neurogenic ectoderm and regulates the asymmetric division of neural progenitors in sea urchin embryos. AB - We have examined regulation of neurogenesis by Delta/Notch signaling in sea urchin embryos. At gastrulation, neural progenitors enter S phase coincident with expression of Sp-SoxC. We used a BAC containing GFP knocked into the Sp-SoxC locus to label neural progenitors. Live imaging and immunolocalizations indicate that Sp-SoxC-expressing cells divide to produce pairs of adjacent cells expressing GFP. Over an interval of about 6 h, one cell fragments, undergoes apoptosis and expresses high levels of activated Caspase3. A Notch reporter indicates that Notch signaling is activated in cells adjacent to cells expressing Sp-SoxC. Inhibition of gamma-secretase, injection of Sp-Delta morpholinos or CRISPR/Cas9-induced mutation of Sp-Delta results in supernumerary neural progenitors and neurons. Interfering with Notch signaling increases neural progenitor recruitment and pairs of neural progenitors. Thus, Notch signaling restricts the number of neural progenitors recruited and regulates the fate of progeny of the asymmetric division. We propose a model in which localized signaling converts ectodermal and ciliary band cells to neural progenitors that divide asymmetrically to produce a neural precursor and an apoptotic cell. PMID- 28851712 TI - Downregulation of Insulin Sensitivity After Oral Glucose Administration: Evidence for the Anti-Incretin Effect. AB - Intestinal nutrients stimulate insulin secretion more potently than intravenous (IV) glucose administration under similar plasma glucose levels (incretin effect). According to the anti-incretin theory, intestinal nutrients should also cause a reduction of insulin sensitivity and/or secretion (anti-incretin effect) to defend against hyperinsulinemia-hypoglycemia. An exaggerated anti-incretin effect could contribute to insulin resistance/type 2 diabetes, whereas reduction of anti-incretin signals might explain diabetes improvement after bariatric surgery. In this study, we tested some of the predictions made by the anti incretin theory. Eight healthy volunteers and eight severely obese subjects with insulin resistance were studied. Insulin secretion, insulin sensitivity, Ra, and disposition index were measured after oral glucose tolerance test and isoglycemic IV glucose injection (IGIV). Obese subjects were studied before and after intestinal bypass surgery (biliopancreatic diversion [BPD]). The d-xylose test and lactulose-to-rhamnose ratio were used to test for possible malabsorption of glucose after surgery. Monte Carlo mathematical simulations were used to test whether insulin secretion induced by oral glucose could cause hypoglycemia when coupled with the levels of insulin sensitivity measured during IGIV. Despite isoglycemic conditions, insulin sensitivity was lower during oral than during IV glucose administration. This difference was amplified in obese subjects and reduced to normal after BPD. No evidence of glucose malabsorption was found. Mathematical simulations showed that hypoglycemia would occur if insulin sensitivity were not reduced by oral glucose stimulation. This study demonstrates an anti-incretin effect of intestinal glucose stimulation, which downregulates insulin sensitivity. The findings support a new model for how foodborne factors can induce insulin-resistance and provide a possible explanation for the improvement of insulin resistance/diabetes after gastrointestinal bypass surgery. PMID- 28851711 TI - Perturbing phosphoinositide homeostasis oppositely affects vascular differentiation in Arabidopsis thaliana roots. AB - The plant vascular network consists of specialized phloem and xylem elements that undergo two distinct morphogenetic developmental programs to become transport functional units. Whereas vacuolar rupture is a determinant step in protoxylem differentiation, protophloem elements never form a big central vacuole. Here, we show that a genetic disturbance of phosphatidylinositol 4,5-bis-phosphate [PtdIns(4,5)P2] homeostasis rewires cell trafficking towards the vacuole in Arabidopsis thaliana roots. Consequently, an enhanced phosphoinositide-mediated vacuolar biogenesis correlates with premature programmed cell death (PCD) and secondary cell wall elaboration in xylem cells. By contrast, vacuolar fusion events in protophloem cells trigger the abnormal formation of big vacuoles, preventing cell clearance and tissue functionality. Removal of the inositol 5' phosphatase COTYLEDON VASCULAR PATTERN 2 from the plasma membrane (PM) by brefeldin A (BFA) treatment increases PtdIns(4,5)P2 content at the PM and disrupts protophloem continuity. Conversely, BFA application abolishes vacuolar fusion events in xylem tissue without preventing PCD, suggesting the existence of additional PtdIns(4,5)P2-dependent cell death mechanisms. Overall, our data indicate that tight PM phosphoinositide homeostasis is required to modulate intracellular trafficking contributing to oppositely regulate vascular differentiation. PMID- 28851714 TI - Takayasu arteritis presenting as embolic stroke. AB - A 52-year-old Caucasian woman presented to the emergency department with symptoms of acute ischaemic stroke (right-side weakness, confusion and aphasia) that resolved completely after administration of tissue plasminogen activator. During stroke work-up, she was found to have an enhancing infiltrate of the aorta at the level of the take-off of the great vessels, most consistent with early Takayasu arteritis. After being discharged home on steroids and dual antiplatelet therapy, she returned 2 days later with re-presentation of weakness and aphasia. Further work-up revealed two intraluminal clots in the left common carotid and left internal carotid arteries that had not been discovered during previous testing. This case illustrates the need to screen for sources of embolic stroke in patients with Takayasu arteritis, especially those with recurring symptoms. PMID- 28851713 TI - SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation. AB - FoxO1 and FoxO3a (collectively FoxO1/3a) proteins regulate a wide array of cellular processes, including hepatic gluconeogenesis. Phosphorylation of FoxO1/3a is a key event that determines its subcellular location and transcriptional activity. During glucose synthesis, the activity of FoxO1/3a is negatively regulated by Akt-mediated phosphorylation, which leads to the cytoplasmic retention of FoxO1/3a. However, the nuclear phosphatase that directly regulates FoxO1/3a remains to be identified. In this study, we discovered a nuclear phosphatase, SCP4/CTDSPL2 (SCP4), that dephosphorylated FoxO1/3a and promoted FoxO1/3a transcription activity. We found that SCP4 enhanced the transcription of FoxO1/3a target genes encoding PEPCK1 and G6PC, key enzymes in hepatic gluconeogenesis. Ectopic expression of SCP4 increased, while knockdown of SCP4 inhibited, glucose production. Moreover, we demonstrated that gene ablation of SCP4 led to hypoglycemia in neonatal mice. Consistent with the positive role of SCP4 in gluconeogenesis, expression of SCP4 was regulated under pathophysiological conditions. SCP4 expression was induced by glucose deprivation in vitro and in vivo and was elevated in obese mice caused by genetic (Avy) and dietary (high-fat) changes. Thus, our findings provided experimental evidence that SCP4 regulates hepatic gluconeogenesis and could serve as a potential target for the prevention and treatment of diet-induced glucose intolerance and type 2 diabetes. PMID- 28851715 TI - Oesophageal mastocytosis: eosinophilic oesophagitis without eosinophils? AB - A 59-year-old male with a history of lifelong asthma, allergic rhinitis and hypercholesterolaemia presented to the emergency department for management of severe substernal chest pain with radiating pain to his left arm, nausea and diaphoresis. Physical examination was unrevealing and a cardiac workup including cardiac enzymes, ECG, chest radiographs were negative for an underlying ischaemic event. A subsequent gastrointestinal workup including oesophageal manometry and oesophagogastroduodenoscopy revealed elevated lower oesophageal pressures and histopathology suggestive of mast cell proliferation, respectively. These findings were suggestive of oesophageal mastocytosis. Treatment with omeprazole sodium bicarbonate, cetirizine, montelukast and oral budesonide promptly ameliorated his symptoms which have not recurred. PMID- 28851716 TI - Continuous remission of renal cell carcinoma with tumour thrombus after severe adverse events following short-term treatment with sunitinib. AB - A 64-year-old Japanese man with renal cell carcinoma (RCC) and tumour thrombus in the inferior vena cava was treated with sunitinib. Two weeks after treatment, he was hospitalised for disturbance of consciousness. Laboratory tests revealed high grade hypoglycaemia, hyponatraemia, liver dysfunction and thrombocytopaenia with disseminated intravascular coagulation. Sunitinib was discontinued and the patient recovered after a protracted platelet transfusion. At 5 months after treatment, CT revealed that the tumour thrombus had disappeared and other lesions had regressed. MRI at 15 months revealed further regression and suggested the possibility of histological remission according to the signal intensity of fibrosis. A partial response persisted at 20 months after treatment, despite residual accumulation in the renal tumour evident on positron emission tomography. In summary, we present a case of locally advanced RCC accompanied by severe adverse events that showed a significant and durable response to treatment with sunitinib for just 2 weeks. PMID- 28851717 TI - Outflow Graft Occlusion of the HeartMate 3 Left Ventricular Assist Device. PMID- 28851718 TI - Acute and Midterm Outcomes of Transcatheter Pulmonary Valve Replacement for Treatment of Dysfunctional Left Ventricular Outflow Tract Conduits in Patients With Aortopulmonary Transposition and a Systemic Right Ventricle. AB - BACKGROUND: Transcatheter pulmonary valve replacement (TPVR) is an established therapy for dysfunctional right ventricular (RV) outflow tract conduits. TPVR in patients with congenitally corrected transposition of the great arteries, subpulmonary left ventricle, and left ventricular outflow tract (LVOT) conduit dysfunction has not been studied. Unique anatomic and physiological aspects of this population may contribute to distinct risks and outcomes. METHODS AND RESULTS: Across 10 US centers, 27 patients with a dysfunctional LVOT conduit were evaluated in the catheterization laboratory between December 2008 and August 2015 with the intent to perform TPVR. TPVR was successful in 23 patients (85%). Five serious adverse events occurred in 4 cases (15%), including pulmonary hemorrhage, hypotension requiring vasoactive support, conduit disruption requiring covered stent (n=2), and acute RV dysfunction with flash pulmonary edema. After TPVR, the LVOT peak systolic ejection gradient decreased from median of 35 to 17 mm Hg (P<0.001); pulmonary insufficiency was trivial/none in all but 1 patient, where it was mild. Worsening of systemic RV dysfunction or tricuspid regurgitation was seen in 12 patients (57%) and was associated with a significantly lower post-TPVR LVOT peak systolic ejection gradient (median 17 versus 21 mm Hg; P=0.02) and higher post-TPVR RV sphericity index (median 0.88 versus 0.52; P=0.004). Post TPVR, there were 2 late deaths because of RV failure and 1 cardiac transplantation because of progressive RV dysfunction and tricuspid regurgitation. CONCLUSIONS: TPVR in dysfunctional LVOT conduits is feasible but associated with an important rate of TPV nonimplantation and procedural serious adverse events. Worsening systemic RV function and tricuspid regurgitation may develop after LVOT TPVR. PMID- 28851719 TI - Surgical and Catheter-Based Reinterventions Are Common in Long-Term Survivors of the Fontan Operation. AB - BACKGROUND: There are limited follow-up studies examining surgical and catheter based reinterventions in long-term survivors of the Fontan operation. METHODS AND RESULTS: All 773 patients who underwent Fontan at our institution between 1992 and 2009 were retrospectively reviewed. Current information regarding post-Fontan intervention was available for 70%. By 20 years after Fontan, 65% of patients had experienced either surgical or transcatheter intervention. The median time to first reintervention was 9.8 years. Freedom from reoperation was 69% at 15 years and 63% at 20 years. The most common operations were pacemaker placement and Fontan revision. Risk factors for pacemaker placement included systemic left ventricle (hazard ratio [HR], 2.2; P=0.006) and lateral tunnel Fontan (HR, 4.3; P=0.001). Freedom from interventional catheterization was 53% at 15 years and 50% at 20 years. The most common procedures performed were fenestration closure and pulmonary artery intervention. Catheter intervention for anatomic indications was associated with Fontan after 2002 (HR, 2.1; P=0.007), Norwood operation (HR, 2.3; P=0.001), and longer cardiopulmonary bypass time (HR, 1.1 per 10 minutes; P=0.001). Catheter intervention for physiological indications was associated with prolonged post-Fontan pleural drainage (HR, 4.0; P<0.001) and hypoplastic left heart syndrome (HR, 2.0; P=0.01). CONCLUSIONS: In this study of Fontan survivors, two thirds of patients required surgical or catheter-based reintervention by 20 years. Families should be counseled that the Fontan is typically not the final stage of single-ventricle palliation. PMID- 28851720 TI - Fully Transradial Versus Transfemoral Approach for Percutaneous Intervention of Coronary Chronic Total Occlusions Applying the Hybrid Algorithm: Insights From RECHARGE Registry. AB - BACKGROUND: Small observational studies demonstrate the feasibility of transradial approach for chronic total occlusion (CTO) percutaneous coronary intervention. The aim of the current study is to assess technical success, complication rates, and procedural efficiency in fully transradial approach (fTRA) and transfemoral approach (TFA) in a large prospective European registry adopting the hybrid algorithm for CTO percutaneous coronary intervention (Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom, RECHARGE registry). METHODS AND RESULTS: We analyzed 1253 CTO percutaneous coronary intervention procedures performed according to the hybrid protocol in 17 European centers, comparing fTRA (single or biradial access) and TFA (single or bifemoral or combined radial and femoral access). fTRA was applied in 306 (24%) and TFA in 947 (76%) cases. The average Japanese CTO score was 2.1+/ 1.2 in fTRA and 2.3+/-1.1 in TFA (P=0.06). Technical success was achieved in 85% in fTRA and 86% in TFA (P=0.51). Technical success was comparable for fTRA and TFA in different Japanese CTO score subgroups after multivariable analysis and after propensity adjustment. In-hospital major adverse cardiac and cerebral events occurred in 2.0% in fTRA and 2.9% in TFA (P=0.40). Major access site bleeding occurred in 0.3% in fTRA and 0.5% in TFA (P=0.66). fTRA compared with TFA had similar procedural duration (80 minutes [54-120 minutes] versus 90 minutes [60-121 minutes]; P=0.07), similar radiation dose (dose area product 89 Gray*cm2 [52-163 Gray*cm2] versus 101 Gray*cm2 [59-171 Gray*cm2]; P=0.06), and lower contrast agent use (200 mL [150-310 mL] versus 250 mL [200-350 mL]; P<0.01). CONCLUSIONS: fTRA CTO percutaneous coronary intervention is a valid alternative to TFA with a high rate of success, low complication rates, and no decrease in procedural efficiency. PMID- 28851721 TI - Advances in stem cells and regenerative medicine: single-cell dynamics, new models and translational perspectives. AB - An international cohort of over 300 stem cell biologists came together in Heidelberg, Germany in May 2017 as delegates of the 'Advances in Stem Cells and Regenerative Medicine' conference run through the European Molecular Biology Organization. This Meeting Review highlights the novel insights into stem cell regulation, new technologies aiding in discovery and exciting breakthroughs in the field of regenerative medicine that emerged from the meeting. PMID- 28851723 TI - The nature and dynamics of spermatogonial stem cells. AB - Spermatogonial stem cells (SSCs) are crucial for maintaining spermatogenesis throughout life, and understanding how these cells function has important implications for understanding male infertility. Recently, various populations of cells harbouring stem cell-like properties have been identified in rodent seminiferous tubules, but deciphering how these cells might fuel spermatogenesis has been difficult, and various models to explain SSC dynamics have been put forward. This Review provides an overview of the organization and timing of spermatogenesis and then discusses these models in light of recent studies of SSC markers, heterogeneity and cell division dynamics, highlighting the evidence for and against each model. PMID- 28851722 TI - Microtubule organization, dynamics and functions in differentiated cells. AB - Over the past several decades, numerous studies have greatly expanded our knowledge about how microtubule organization and dynamics are controlled in cultured cells in vitro However, our understanding of microtubule dynamics and functions in vivo, in differentiated cells and tissues, remains under-explored. Recent advances in generating genetic tools and imaging technologies to probe microtubules in situ, coupled with an increased interest in the functions of this cytoskeletal network in differentiated cells, are resulting in a renaissance. Here, we discuss the lessons learned from such approaches, which have revealed that, although some differentiated cells utilize conserved strategies to remodel microtubules, there is considerable diversity in the underlying molecular mechanisms of microtubule reorganization. This highlights a continued need to explore how differentiated cells regulate microtubule geometry in vivo. PMID- 28851725 TI - Correction: Primary malignant melanoma of the cervix: a rare disease. PMID- 28851724 TI - Hes5 regulates the transition timing of neurogenesis and gliogenesis in mammalian neocortical development. AB - During mammalian neocortical development, neural stem/progenitor cells (NSCs) sequentially give rise to deep layer neurons and superficial layer neurons through mid- to late-embryonic stages, shifting to gliogenic phase at perinatal stages. Previously, we found that the Hes genes inhibit neuronal differentiation and maintain NSCs. Here, we generated transgenic mice that overexpress Hes5 in NSCs of the central nervous system, and found that the transition timing from deep to superficial layer neurogenesis was shifted earlier, while gliogenesis precociously occurred in the developing neocortex of Hes5-overexpressing mice. By contrast, the transition from deep to superficial layer neurogenesis and the onset of gliogenesis were delayed in Hes5 knockout (KO) mice. We found that the Hmga genes (Hmga1/2) were downregulated in the neocortical regions of Hes5 overexpressing brain, whereas they were upregulated in the Hes5 KO brain. Furthermore, we found that Hes5 expression led to suppression of Hmga1/2 promoter activity. These results suggest that Hes5 regulates the transition timing between phases for specification of neocortical neurons and between neurogenesis and gliogenesis, accompanied by alteration in the expression levels of Hgma genes, in mammalian neocortical development. PMID- 28851726 TI - Disseminated Pseudomonas aeruginosa sepsis as presenting diagnosis of X-linked agammaglobulinaemia in a previously well 16-month-old child. AB - We report a previously healthy 16-month-old child who presented to us with membranous pharyngitis and ecthyma gangrenosum. In this patient, Pseudomonas aeruginosa was isolated from throat swab, cerebrospinal fluid, skin swab, urine, blood and synovial fluid in a single admission. In further workup, this child was diagnosed as a case of X-linked agammaglobulinaemia. The child was treated successfully with antipseudomonal antibiotics for 6 weeks and intravenous immunoglobulin. PMID- 28851727 TI - Cysticercosis of the eyelid. PMID- 28851728 TI - Description of Abnormal Breathing Is Associated With Improved Outcomes and Delayed Telephone Cardiopulmonary Resuscitation Instructions. AB - BACKGROUND: Emergency 9-1-1 callers use a wide range of terms to describe abnormal breathing in persons with out-of-hospital cardiac arrest (OHCA). These breathing descriptors can obstruct the telephone cardiopulmonary resuscitation (CPR) process. METHODS AND RESULTS: We conducted an observational study of emergency call audio recordings linked to confirmed OHCAs in a statewide Utstein style database. Breathing descriptors fell into 1 of 8 groups (eg, gasping, snoring). We divided the study population into groups with and without descriptors for abnormal breathing to investigate the impact of these descriptors on patient outcomes and telephone CPR process. Callers used descriptors in 459 of 2411 cases (19.0%) between October 1, 2010, and December 31, 2014. Survival outcome was better when the caller used a breathing descriptor (19.6% versus 8.8%, P<0.0001), with an odds ratio of 1.63 (95% confidence interval, 1.17-2.25). After exclusions, 379 of 459 cases were eligible for process analysis. When callers described abnormal breathing, the rates of telecommunicator OHCA recognition, CPR instruction, and telephone CPR were lower than when callers did not use a breathing descriptor (79.7% versus 93.0%, P<0.0001; 65.4% versus 72.5%, P=0.0078; and 60.2% versus 66.9%, P=0.0123, respectively). The time interval between call receipt and OHCA recognition was longer when the caller used a breathing descriptor (118.5 versus 73.5 seconds, P<0.0001). CONCLUSIONS: Descriptors of abnormal breathing are associated with improved outcomes but also with delays in the identification of OHCA. Familiarizing telecommunicators with these descriptors may improve the telephone CPR process including OHCA recognition for patients with increased probability of survival. PMID- 28851730 TI - Atrial Fibrillation: Atrial High-Rate Events (AHRES): Look and You Will Find-Then What? PMID- 28851729 TI - Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation: The REHEARSE-AF Study. AB - BACKGROUND: Asymptomatic atrial fibrillation (AF) is increasingly common in the aging population and implicated in many ischemic strokes. Earlier identification of AF with appropriate anticoagulation may decrease stroke morbidity and mortality. METHODS: We conducted a randomized controlled trial of AF screening using an AliveCor Kardia monitor attached to a WiFi-enabled iPod to obtain ECGs (iECGs) in ambulatory patients. Patients >=65 years of age with a CHADS-VASc score >=2 free from AF were randomized to the iECG arm or routine care (RC). iECG participants acquired iECGs twice weekly over 12 months (plus additional iECGs if symptomatic) onto a secure study server with overread by an automated AF detection algorithm and by a cardiac physiologist and/or consultant cardiologist. Time to diagnosis of AF was the primary outcome measure. The overall cost of the devices, ECG interpretation, and patient management were captured and used to generate the cost per AF diagnosis in iECG patients. Clinical events and patient attitudes/experience were also evaluated. RESULTS: We studied 1001 patients (500 iECG, 501 RC) who were 72.6+/-5.4 years of age; 534 were female. Mean CHADS-VASc score was 3.0 (heart failure, 1.4%; hypertension, 54%; diabetes mellitus, 30%; prior stroke/transient ischemic attack, 6.5%; arterial disease, 15.9%; all CHADS VASc risk factors were evenly distributed between groups). Nineteen patients in the iECG group were diagnosed with AF over the 12-month study period versus 5 in the RC arm (hazard ratio, 3.9; 95% confidence interval=1.4-10.4; P=0.007) at a cost per AF diagnosis of $10 780 (L8255). There was a similar number of stroke/transient ischemic attack/systemic embolic events (6 versus 10, iECG versus RC; hazard ratio=0.61; 95% confidence interval=0.22-1.69; P=0.34). The majority of iECG patients were satisfied with the device, finding it easy to use without restricting activities or causing anxiety. CONCLUSIONS: Screening with twice-weekly single-lead iECG with remote interpretation in ambulatory patients >=65 years of age at increased risk of stroke is significantly more likely to identify incident AF than RC over a 12-month period. This approach is also highly acceptable to this group of patients, supporting further evaluation in an appropriately powered, event-driven clinical trial. CLINICAL TRIAL REGISTRATION: URL: https://www.isrctn.com. Unique identifier: ISRCTN10709813. PMID- 28851731 TI - Exploring Coronary Circulatory Response to Stenosis and Its Association With Invasive Physiologic Indexes Using Absolute Myocardial Blood Flow and Coronary Pressure. AB - BACKGROUND: Although invasive physiological assessment for coronary stenosis has become a standard practice to guide treatment strategy, coronary circulatory response and changes in invasive physiological indexes, according to different anatomic and hemodynamic lesion severity, have not been fully demonstrated in patients with coronary artery disease. METHODS: One hundred fifteen patients with left anterior descending artery stenosis who underwent both 13N-ammonia positron emission tomography and invasive physiological measurement were analyzed. Myocardial blood flow (MBF) measured with positron emission tomography and invasively measured coronary pressures were used to calculate microvascular resistance and stenosis resistance. RESULTS: With progressive worsening of angiographic stenosis severity, both resting and hyperemic transstenotic pressure gradient and stenosis resistance increased (P<0.001 for all) and hyperemic MBF (P<0.001) and resting microvascular resistance (P=0.012) decreased. Resting MBF (P=0.383) and hyperemic microvascular resistance (P=0.431) were not changed and maintained stable. Both fractional flow reserve and instantaneous wave-free ratio decreased as angiographic stenosis severity, stenosis resistance, and transstenotic pressure gradient increased and hyperemic MBF decreased (all P<0.001). When the presence of myocardial ischemia was defined by both low hyperemic MBF and low coronary flow reserve, the diagnostic accuracy of fractional flow reserve and instantaneous wave-free ratio did not differ, regardless of cutoff values of hyperemic MBF and coronary flow reserve. CONCLUSIONS: This study demonstrated how the coronary circulation changes in response to increasing coronary stenosis severity using 13N-ammonium positron emission tomography-derived MBF and invasively measured pressure data. Currently used resting and hyperemic pressure-derived invasive physiological indexes have similar patterns of relationships to the different anatomic and hemodynamic lesion severities. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01366404. PMID- 28851732 TI - Interferon Regulatory Factor 4 Inhibits Neointima Formation by Engaging Kruppel Like Factor 4 Signaling. AB - BACKGROUND: The mechanisms underlying neointima formation remain unclear. Interferon regulatory factors (IRFs), which are key innate immune regulators, play important roles in cardiometabolic diseases. However, the function of IRF4 in arterial restenosis is unknown. METHODS: IRF4 expression was first detected in human and mouse restenotic arteries. Then, the effects of IRF4 on neointima formation were evaluated with universal IRF4-deficient mouse and rat carotid artery injury models. We performed immunostaining to identify IRF4-expressing cells in the lesions. Smooth muscle cell (SMC)-specific IRF4-knockout (KO) and transgenic (TG) mice were generated to evaluate the effects of SMC-IRF4 on neointima formation. We used microarray, bioinformatics analysis, and chromatin immunoprecipitation assay to identify the downstream signals of IRF4 and to verify the targets in vitro. We compared SMC-IRF4-KO/Kruppel-like factor 4 (KLF4) TG mice with SMC-IRF4-KO mice and SMC-specific IRF4-TG/KLF4-KO mice with SMC specific IRF4-TG mice to investigate whether the effect of IRF4 on neointima formation is KLF4-dependent. The effect of IRF4 on SMC phenotype switching was also evaluated. RESULTS: IRF4 expression in both the human and mouse restenotic arteries is eventually downregulated. Universal IRF4 ablation potentiates neointima formation in both mice and rats. Immunostaining indicated that IRF4 was expressed primarily in SMCs in restenotic arteries. After injury, SMC-IRF4-KO mice developed a thicker neointima than control mice. This change was accompanied by increased SMC proliferation and migration. However, SMC-specific IRF4-TG mice exhibited the opposite phenotype, demonstrating that IRF4 exerts protective effects against neointima formation. The mechanistic study indicated that IRF4 promotes KLF4 expression by directly binding to its promoter. Genetic overexpression of KLF4 in SMCs largely reversed the neointima-promoting effect of IRF4 ablation, whereas ablation of KLF4 abolished the protective function of IRF4, indicating that the protective effects of IRF4 against neointima formation are KLF4-dependent. In addition, IRF4 promoted SMC dedifferentiation. CONCLUSIONS: IRF4 protects arteries against neointima formation by promoting the expression of KLF4 by directly binding to its promoter. Our findings suggest that this previously undiscovered IRF4-KLF4 axis plays a key role in vasculoproliferative pathology and may be a promising therapeutic target for the treatment of arterial restenosis. PMID- 28851733 TI - Brown adipose tissue activation in a rat model of Parkinson's disease. AB - Loss of body weight and fat mass is one of the nonmotor symptoms of Parkinson's disease (PD). Weight loss is due primarily to reduced energy intake and increased energy expenditure. Whereas inadequate energy intake in PD patients is caused mainly by appetite loss and impaired gastrointestinal absorption, the underlying mechanisms for increased energy expenditure remain largely unknown. Brown adipose tissue (BAT), a key thermogenic tissue in humans and other mammals, plays an important role in thermoregulation and energy metabolism; however, it has not been tested whether BAT is involved in the negative energy balance in PD. Here, using the 6-hydroxydopamine (6-OHDA) rat model of PD, we found that the activity of sympathetic nerve (SN), the expression of Ucp1 in BAT, and thermogenesis were increased in PD rats. BAT sympathetic denervation blocked sympathetic activity and decreased UCP1 expression in BAT and attenuated the loss of body weight in PD rats. Interestingly, sympathetic denervation of BAT was associated with decreased sympathetic tone and lipolysis in retroperitoneal and epididymal white adipose tissue. Our data suggeste that BAT-mediated thermogenesis may contribute to weight loss in PD. PMID- 28851734 TI - Cardiac overexpression of perilipin 2 induces dynamic steatosis: prevention by hormone-sensitive lipase. AB - Cardiac intracellular lipid accumulation (steatosis) is a pathophysiological phenomenon observed in starvation and diabetes mellitus. Perilipin 2 (PLIN2) is a lipid droplet (LD)-associated protein expressed in nonadipose tissues, including the heart. To explore the pathophysiological function of myocardial PLIN2, we generated transgenic (Tg) mice by cardiac-specific overexpression of PLIN2. Tg hearts showed accumulation of numerous small LDs associated with mitochondrial chains and high cardiac triacylglycerol (TAG) content [8-fold greater than wild type (WT) mice]. Despite massive steatosis, cardiac uptake of glucose, fatty acids and VLDL, systolic function, and expression of metabolic genes were comparable in the two genotypes, and no morphological changes were observed by electron microscopy in the Tg hearts. Twenty-four hours of fasting markedly reduced steatosis in Tg hearts, whereas WT mice showed accumulation of LDs. Although activity of adipose triglyceride lipase in heart homogenate was comparable between WT and Tg mice, activity of hormone-sensitive lipase (HSL) was 40-50% less in Tg than WT mice under both feeding and fasting conditions, suggesting interference of PLIN2 with HSL. Mice generated through crossing of PLIN2-Tg mice and HSL-Tg mice showed cardiac-specific HSL overexpression and complete lack of steatosis. The results suggest that cardiac PLIN2 plays an important pathophysiological role in the development of dynamic steatosis and that the latter was prevented by upregulation of intracellular lipases, including HSL. PMID- 28851735 TI - Oleate activates SREBP-1 signaling activity in SCD1-deficient hepatocytes. AB - Stearoyl-CoA desaturase-1 (SCD1) is a key player in lipid metabolism. SCD1 catalyzes the synthesis of monounsaturated fatty acids (MUFA). MUFA are then incorporated into triacylglycerols and phospholipids. Previous studies have shown that Scd1 deficiency in mice induces metabolic changes in the liver characterized by a decrease in de novo lipogenesis and an increase in beta-oxidation. Interestingly, Scd1-deficient mice show a decrease in the expression and maturation of the principal lipogenic transcription factor sterol receptor element binding protein-1 (SREBP-1). The mechanisms mediating this effect on de novo lipogenesis and beta-oxidation have not been fully elucidated. We evaluated the role of SCD1 on de novo lipogenesis and beta-oxidation in HepG2 cells. We also used Scd1-deficient mice and two strains of transgenic mice that produce either oleate (GLS5) or palmitoleate (GLS3) in a liver-specific manner. We demonstrate that the expression of beta-oxidation markers increases in SCD1 deficient hepatocytes and suggest that this is due to an increase in cellular polyunsaturated fatty acid content. We also show that the changes in the level of SREBP-1 expression, for both the precursor and the mature forms, are mainly due to the lack of oleate in SCD1-deficient hepatocytes. Indeed, oleate treatment of cultured HepG2 cells or hepatic oleate production in chow-fed GLS5 mice can restore SREBP-1 expression and increase hepatic de novo lipogenesis. Finally, we show that oleate specifically increases SREBP-1 nuclear accumulation, suggesting a central role for oleate in SREBP-1 signaling activity. PMID- 28851736 TI - Short-term changes in diet composition do not affect in vivo hepatic protein synthesis in rats. AB - Protein synthesis is critical to protein homeostasis (proteostasis), and modifications in protein synthesis influence lifespan and the development of comorbidities associated with obesity. In the present study, we examined the acute response of liver protein synthesis to either high-fat or high-sucrose diets in order to elucidate nutrient-mediated regulation of hepatic protein synthesis in the absence of body fat accumulation. Total and endoplasmic reticulum-associated protein syntheses were assessed by use of the stable isotope, deuterium oxide (2H2O), in rats provided a control diet or diets enriched in polyunsaturated fat, saturated fat, or sucrose for 2, 4, or 7 days. The three experimental diets increased hepatic triglycerides 46-91% on day 7 and fasting insulin levels 83-117% on day 7, but did not result in differences in body weight when compared with control ( n = 6/diet/time). The fraction of newly synthesized proteins in total liver lysates and microsomes was not significantly different among dietary groups ( n = 3/diet/time). To determine whether the experimental diets provoked a transcriptional response to enhance the capacity for protein synthesis, we also measured a panel of genes linked to amino acid transport, synthesis, and processing. There were no significant differences in any of the genes measured among groups. Therefore, dietary treatments that have been linked to impaired proteostasis and that promote hepatic steatosis and insulin resistance, did not result in significant changes in total or ER associated protein synthesis in the liver over a 7-day period. PMID- 28851737 TI - Cholesterol metabolism and Cx43, Cx46, and Cx50 gap junction protein expression and localization in normal and diabetic and obese ob/ob and db/db mouse testes. AB - Decreased fertility and birth rates arise from metabolic disorders. This study assesses cholesterol metabolism and Cx46, Cx50, and Cx43 expression in interstitium- and seminiferous tubule-enriched fractions of leptin-deficient ( ob/ob) and leptin receptor-deficient ( db/db) mice, two type 2 diabetes and obesity models associated with infertility. Testosterone levels decreased and glucose and free and esterified cholesterol (FC and EC) levels increased in serum, whereas FC and EC levels decreased in the interstitium, in ob/ob and db/db mice. In tubules, a decrease in EC caused FC-to-EC ratios to increase in db/db mice. In tubules, only acyl coenzyme A:cholesterol acyl transferase type 1 and 2 protein levels significantly decreased in ob/ob, but not db/db, mice compared with wild-type mice, and imbalances in the cholesterol transporters Niemann-Pick C1 (NPC1), ATP-binding cassette A1 (ABCA1), scavenger receptor class B member I (SR-BI), and cluster of differentiation 36 (CD36) were observed in ob/ob and db/db mice. In tubules, 14-kDa Cx46 prevailed during development, 48- to 49- and 68- to 71-kDa Cx46 prevailed during adulthood, and total Cx46 changed little. Compared with wild-type mice, 14-kDa Cx46 increased, whereas 48- to 49- and 68- to 71-kDa Cx46 decreased, in tubules, whereas the opposite occurred in the interstitium, in db/db and ob/ob mice. Total and 51-kDa Cx50 increased in db/db and ob/ob interstitium and tubules. Cx43 levels decreased in ob/ob interstitium and tubules, whereas Cx43 decreased in db/db interstitium but increased in db/db tubules. Apoptosis levels measured by ELISA and numbers of apostain-labeled apoptotic cells significantly increased in db/db, but not ob/ob, tubules. Testicular db/db capillaries were Cx50-positive but weakly Cx43-positive with a thickened lamina, suggesting altered permeability. Our findings indicate that the db mutation-induced impairment of meiosis may arise from imbalances in cholesterol metabolism and upregulated Cx43 expression and phosphorylation in tubules. PMID- 28851739 TI - Quality Improvement Strategies for Population Management of Children With Medical Complexity. AB - BACKGROUND AND OBJECTIVES: Children with medical complexity require the expertise of specialists and hospitals but may lack primary care to provide preventive, acute, and chronic care management. The Complex Care Center (CCC) at Cincinnati Children's Hospital Medical Center employed quality improvement methodologies in 3 initiatives to improve care for this fragile population. METHODS: Improvement activities focused on 3 main areas: population identification and stratification for care support, reliable delivery of preventive and chronic care, and planned care to identify and coordinate needed services. RESULTS: The percent of patients who attended a well-child care visit in the previous 13 months increased 91% and was sustained for the next year. The median monthly no-show rate remained unchanged. Within 10 months of implementing the interventions, >90% of CCC patients <7 years of age were receiving all recommended vaccines. Seventy-two percent of all CCC patients received their annual influenza vaccine. A sustained 98% to 100% of children with a complex chronic disease received previsit planning (PVP) for their well-child care and chronic condition management visits, whereas only 1 new patient did not receive PVP. CONCLUSIONS: Children with medical complexity require adaptations to typical primary care processes to support preventive health practices, chronic and acute care management, immunization, and collaborative care with their multiple specialists and support providers. We used quality improvement methodology to identify patients with the highest needs, reliably deliver appropriate preventive and chronic care, and implement PVP. PMID- 28851738 TI - Phosphoproteomic Analysis Reveals the Importance of Kinase Regulation During Orbivirus Infection. AB - Bluetongue virus (BTV) causes infections in wild and domesticated ruminants with high morbidity and mortality and is responsible for significant economic losses in both developing and developed countries. BTV serves as a model for the study of other members of the Orbivirus genus. Previously, the importance of casein kinase 2 for BTV replication was demonstrated. To identify intracellular signaling pathways and novel host-cell kinases involved during BTV infection, the phosphoproteome of BTV infected cells was analyzed. Over 1000 phosphosites were identified using mass spectrometry, which were then used to determine the corresponding kinases involved during BTV infection. This analysis yielded protein kinase A (PKA) as a novel kinase activated during BTV infection. Subsequently, the importance of PKA for BTV infection was validated using a PKA inhibitor and activator. Our data confirmed that PKA was essential for efficient viral growth. Further, we showed that PKA is also required for infection of equid cells by African horse sickness virus, another member of the Orbivirus genus. Thus, despite their preference in specific host species, orbiviruses may utilize the same host signaling pathways during their replication. PMID- 28851740 TI - Patient and Researcher Engagement in Health Research: A Parent's Perspective. PMID- 28851742 TI - Platelets in Wiskott-Aldrich syndrome: Victims or executioners? AB - Microthrombocytopenia is the clinical hallmark of WAS, a rare X-linked immunodeficiency that is characterized by eczema, autoimmunity, and cancer susceptibility. This disease is caused by mutations in the WAS gene, which is expressed in hematopoietic cells and regulates actin cytoskeleton remodeling thereby modulating various cellular functions, including motility, immunologic synapse assembly, and signaling. Despite extensive studies that have provided great insight into the relevance of this molecule to innate and cellular immunity, the exact mechanisms of microthrombocytopenia in WAS are still unknown. This review focuses on the recent progress made in dissecting the pathogenesis of platelet defects in patients with WAS and their murine counterparts. In parallel, we will provide an overview of the state-of-the art platelets as immune modulators at the interface between hemostasis and the immune system, which suggests that these cells may have a direct role in the pathogenesis of immune dysregulation in WAS. PMID- 28851743 TI - Can hypothermia save dying military trauma patients? PMID- 28851741 TI - Gpr158 mediates osteocalcin's regulation of cognition. AB - That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16 mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158, an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes. PMID- 28851747 TI - Vascular Endothelial (VE)-Cadherin, Endothelial Adherens Junctions, and Vascular Disease. AB - Endothelial cell-cell adherens junctions (AJs) supervise fundamental vascular functions, such as the control of permeability and transmigration of circulating leukocytes, and the maintenance of existing vessels and formation of new ones. These processes are often dysregulated in pathologies. However, the evidence that links dysfunction of endothelial AJs to human pathologies is mostly correlative. In this review, we present an update of the molecular organization of AJ complexes in endothelial cells (ECs) that is mainly based on observations from experimental models. Furthermore, we report in detail on a human pathology, cerebral cavernous malformation (CCM), which is initiated by loss-of-function mutations in the genes that encode the three cytoplasmic components of AJs (CCM1, CCM2, and CCM3). At present, these represent a unique example of mutations in components of endothelial AJs that cause human disease. We describe also how studies into the defects of AJs in CCM are shedding light on the crucial regulatory mechanisms and signaling activities of these endothelial structures. Although these observations are specific for CCM, they support the concept that dysfunction of endothelial AJs can directly contribute to human pathologies. PMID- 28851744 TI - Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. AB - Mucus hyper-secretion is a hallmark feature of asthma and other muco-obstructive airway diseases. The mucin proteins MUC5AC and MUC5B are the major glycoprotein components of mucus and have critical roles in airway defense. Despite the biomedical importance of these two proteins, the loci that regulate them in the context of natural genetic variation have not been studied. To identify genes that underlie variation in airway mucin levels, we performed genetic analyses in founder strains and incipient lines of the Collaborative Cross (CC) in a house dust mite mouse model of asthma. CC founder strains exhibited significant differences in MUC5AC and MUC5B, providing evidence of heritability. Analysis of gene and protein expression of Muc5ac and Muc5b in incipient CC lines (n = 154) suggested that post-transcriptional events were important regulators of mucin protein content in the airways. Quantitative trait locus (QTL) mapping identified distinct, trans protein QTL for MUC5AC (chromosome 13) and MUC5B (chromosome 2). These two QTL explained 18 and 20% of phenotypic variance, respectively. Examination of the MUC5B QTL allele effects and subsequent phylogenetic analysis allowed us to narrow the MUC5B QTL and identify Bpifb1 as a candidate gene. Bpifb1 mRNA and protein expression were upregulated in parallel to MUC5B after allergen challenge, and Bpifb1 knockout mice exhibited higher MUC5B expression. Thus, BPIFB1 is a novel regulator of MUC5B. PMID- 28851748 TI - Hold Me, but Not Too Tight-Endothelial Cell-Cell Junctions in Angiogenesis. AB - Endothelial cell-cell junctions must perform seemingly incompatible tasks during vascular development-providing stable connections that prevent leakage, while allowing dynamic cellular rearrangements during sprouting, anastomosis, lumen formation, and functional remodeling of the vascular network. This review aims to highlight recent insights into the molecular mechanisms governing endothelial cell-cell adhesion in the context of vascular development. PMID- 28851745 TI - A Key Regulator of the Glycolytic and Gluconeogenic Central Metabolic Pathways in Sinorhizobium meliloti. AB - The order Rhizobiales contains numerous agriculturally, biotechnologically, and medically important bacteria, including the rhizobia, and the genera Agrobacterium, Brucella, and Methylobacterium, among others. These organisms tend to be metabolically versatile, but there has been relatively little investigation into the regulation of their central carbon metabolic pathways. Here, RNA sequencing and promoter fusion data are presented to show that the PckR protein is a key regulator of central carbon metabolism in Sinorhizobium meliloti; during growth with gluconeogenic substrates, PckR represses expression of the complete Entner-Doudoroff glycolytic pathway and induces expression of the pckA and fbaB gluconeogenic genes. Electrophoretic mobility shift assays indicate that PckR binds an imperfect palindromic sequence that overlaps the promoter or transcriptional start site in the negatively regulated promoters, or is present in tandem upstream the promoter motifs in the positively regulated promoters. Genetic and in vitro electrophoretic mobility shift assay experiments suggest that elevated concentrations of a PckR effector ligand results in the dissociation of PckR from its target binding site, and evidence is presented that suggests phosphoenolpyruvate may function as the effector. Characterization of missense pckR alleles identified three conserved residues important for increasing the affinity of PckR for its cognate effector molecule. Bioinformatics analyses illustrates that PckR is limited to a narrow phylogenetic range consisting of the Rhizobiaceae, Phyllobacteriaceae, Brucellaceae, and Bartonellaceae families. These data provide novel insights into the regulation of the core carbon metabolic pathways of this pertinent group of alpha proteobacteria. PMID- 28851749 TI - The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system. AB - Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1's effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha mRNA in the iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure. PMID- 28851750 TI - Food in synchrony with melatonin and corticosterone relieves constant light disturbed metabolism. AB - Circadian disruption is associated with metabolic disturbances such as hepatic steatosis (HS), obesity and type 2 diabetes. We hypothesized that HS, resulting from constant light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine-driven suprachiasmatic nucleus (SCN) outputs. Indeed, exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with the development of HS. We investigated whether providing temporal signals such as 12-h food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5 ug/kg) and melatonin (2.5 mg/kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL-exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food-elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone. PMID- 28851751 TI - mRNA pseudouridylation affects RNA metabolism in the parasite Toxoplasma gondii. AB - RNA contains over 100 modified nucleotides that are created post transcriptionally, among which pseudouridine (Psi) is one of the most abundant. Although it was one of the first modifications discovered, the biological role of this modification is still not fully understood. Recently, we reported that a pseudouridine synthase (TgPUS1) is necessary for differentiation of the single celled eukaryotic parasite Toxoplasma gondii from active to chronic infection. To better understand the biological role of pseudouridylation, we report here gel based and deep-sequencing methods to identify TgPUS1-dependent Psi's in Toxoplasma RNA, and the use of TgPUS1 mutants to examine the effect of this modification on mRNAs. In addition to identifying conserved sites of pseudouridylation in Toxoplasma rRNA, tRNA, and snRNA, we also report extensive pseudouridylation of Toxoplasma mRNAs, with the Psi's being relatively depleted in the 3'-UTR but enriched at position 1 of codons. We show that many Psi's in tRNA and mRNA are dependent on the action of TgPUS1 and that TgPUS1-dependent mRNA Psi's are enriched in developmentally regulated transcripts. RNA-seq data obtained from wild-type and TgPUS1-mutant parasites shows that genes containing a TgPUS1-dependent Psi are relatively more abundant in mutant parasites, while pulse/chase labeling of RNA with 4-thiouracil shows that mRNAs containing TgPUS1 dependent Psi have a modest but statistically significant increase in half-life in the mutant parasites. These data are some of the first evidence suggesting that mRNA Psi's play an important biological role. PMID- 28851753 TI - Effectiveness of interventions based on implantable devices: meta-analyses or systematic reviews that fail to indicate which device brands were used. PMID- 28851752 TI - Transcription elongation rate has a tissue-specific impact on alternative cleavage and polyadenylation in Drosophila melanogaster. AB - Alternative polyadenylation (APA) is a mechanism that generates multiple mRNA isoforms with different 3'UTRs and/or coding sequences from a single gene. Here, using 3' region extraction and deep sequencing (3'READS), we have systematically mapped cleavage and polyadenylation sites (PASs) in Drosophila melanogaster, expanding the total repertoire of PASs previously identified for the species, especially those located in A-rich genomic sequences. Cis-element analysis revealed distinct sequence motifs around fly PASs when compared to mammalian ones, including the greater enrichment of upstream UAUA elements and the less prominent presence of downstream UGUG elements. We found that over 75% of mRNA genes in Drosophila melanogaster undergo APA. The head tissue tends to use distal PASs when compared to the body, leading to preferential expression of APA isoforms with long 3'UTRs as well as with distal terminal exons. The distance between the APA sites and intron location of PAS are important parameters for APA difference between body and head, suggesting distinct PAS selection contexts. APA analysis of the RpII215C4 mutant strain, which harbors a mutant RNA polymerase II (RNAPII) with a slower elongation rate, revealed that a 50% decrease in transcriptional elongation rate leads to a mild trend of more usage of proximal, weaker PASs, both in 3'UTRs and in introns, consistent with the "first come, first served" model of APA regulation. However, this trend was not observed in the head, suggesting a different regulatory context in neuronal cells. Together, our data expand the PAS collection for Drosophila melanogaster and reveal a tissue-specific effect of APA regulation by RNAPII elongation rate. PMID- 28851754 TI - Implementation of a Communication Bundle for High-Risk Patients. AB - BACKGROUND: Interventions that facilitate early identification and management of hospitalized pediatric patients who are at risk for deterioration are associated with decreased mortality. In our large pediatric hospital with a history of success in decreasing unrecognized deterioration, patients at higher risk of deterioration are termed "watchers." Because communication errors often contribute to unrecognized deterioration, clear and timely communication of watcher status to all team members and contingency planning was desired. OBJECTIVES: Increase the percentage of eligible watchers with a complete communication, teamwork, and planning bundle within 2 hours of identification from 28% to 80%. METHODS: Watchers admitted to Hospital Medicine on 2 targeted units were eligible. Stakeholders were educated to facilitate ownership. Daily data analysis enabled real-time failure identification. Automated physician notification provided reminders for timely communication. RESULTS: The percentage of watchers with a complete situation awareness bundle within 2 hours increased from 28% to 81% and was sustained for more than 2 years. There was no change in rates of rapid response team calls or ICU transfers on our intervention units, but these both increased throughout the hospital. Education facilitated modest improvement, with marked improvements and sustainment through use of technology. CONCLUSIONS: A novel bundle that included contingency planning and communication expectations was created to improve situation awareness for watchers. Multidisciplinary engagement and use of automated technology facilitated by an electronic health record helped implement and sustain bundle adherence. PMID- 28851755 TI - Engaging veterinarians and farmers in eradicating bovine viral diarrhoea: a systematic review of economic impact. AB - Bovine viral diarrhoea (BVD) is a significant drain on efficient and successful cattle production in both dairy and beef systems around the world. Several countries have achieved eradication of this disease, but always through the motivation of stakeholders who accept the benefits of eradication. These include increased cattle welfare and fitness of cattle to withstand other diseases, and decreased costs of production, the latter resulting from both decreased costs spent on managing the disease and decreased losses. This paper provides a systematic review of 31 papers, published between 1991 and 2015, that address the economic impact of BVD. Each paper takes a different approach, in either beef or dairy production or both. However with the breadth of work collated, a stakeholder engaged in BVD eradication should find an economic figure of most relevance to them. The reported economic impact ranges from L0 to L552 per cow per year (L2370 including outliers). This range represents endemic or subclinical disease situations seen in herds with stable BVD virus infection, and epidemic or severe acute situations, most often seen in naive herds. The outcome of infection is therefore dependent on the immune status of the animal and severity of the strain. The variations in figures for the economic impact of BVD relate to these immune and pathogenicity factors, along with the variety of impacts monitored. PMID- 28851757 TI - Psychosocial job stressors and suicidality: a meta-analysis and systematic review. AB - OBJECTIVES: Job stressors are known determinants of common mental disorders. Over the past 10 years, there has been evidence that job stressors may also be risk factors for suicidality. The current paper sought to examine this topic through the first comprehensive systematic review and meta-analysis of the literature to date. METHODS: We used a three-tier search strategy of seven electronic databases. Studies were included if they reported on a job stressor or job related stress as an exposure and suicide ideation, self-harm, suicide attempt or suicide as an outcome. Two researchers independently screened articles. All extracted effect estimates were converted to log-transformed ORs. RESULTS: There were 22 studies that were included in meta-analysis. Overall, exposure to job stressors was associated with elevated risk of suicide ideation and behaviours. The OR for suicide ideation (14 studies) ranged from 1.45 (95% CI 1.01 to 2.08) for poor supervisor and colleague support to 1.91 (95% CI 1.22 to 2.99) for job insecurity. For suicide (six studies), exposure to lower supervisor and collegial support produced an OR of 1.16 (95% CI 0.98 to 1.38), while low job control resulted in an OR of 1.23 (95% CI 1.00 to 1.50). There were only two studies that examined suicide attempt, both of which suggested an adverse effect of exposure to job stressors. CONCLUSIONS: This study provides some evidence that job stressors may be related to suicidal outcomes. However, as most studies in the area were cross-sectional and observational in design, there is a need for longitudinal research to assess the robustness of observed associations. PMID- 28851756 TI - Metal worker's lung: spatial association with Mycobacterium avium. AB - BACKGROUND: Outbreaks of hypersensitivity pneumonitis (HP) are not uncommon in workplaces where metal working fluid (MWF) is used to facilitate metal turning. Inhalation of microbe-contaminated MWF has been assumed to be the cause, but previous investigations have failed to establish a spatial relationship between a contaminated source and an outbreak. OBJECTIVES: After an outbreak of five cases of HP in a UK factory, we carried out blinded, molecular-based microbiological investigation of MWF samples in order to identify potential links between specific microbial taxa and machines in the outbreak zone. METHODS: Custom quantitative PCR assays, microscopy and phylogenetic analyses were performed on blinded MWF samples to quantify microbial burden and identify potential aetiological agents of HP in metal workers. MEASUREMENTS AND MAIN RESULTS: MWF from machines fed by a central sump, but not those with an isolated supply, was contaminated by mycobacteria. The factory sump and a single linked machine at the centre of the outbreak zone, known to be the workstation of the index cases, had very high levels of detectable organisms. Phylogenetic placement of mycobacterial taxonomic marker genes generated from these samples indicated that the contaminating organisms were closely related to Mycobacterium avium. CONCLUSIONS: We describe, for the first time, a close spatial relationship between the abundance of a mycobacterium-like organism, most probably M. avium, and a localised outbreak of MWF-associated HP. The further development of sequence based analytic techniques should assist in the prevention of this important occupational disease. PMID- 28851759 TI - Finding Hope in Uncertain Times. PMID- 28851758 TI - Orthodox Seeds and Resurrection Plants: Two of a Kind? PMID- 28851761 TI - In Reply. PMID- 28851760 TI - Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents. AB - : Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B-cell lymphoma-2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control. IMPLICATIONS FOR PRACTICE: Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for TLS in patients with tumors characterized by rapid growth, high tumor burden, and/or high sensitivity to treatment. In this review, prevention strategies and management of patients with CLL who develop TLS are described. PMID- 28851762 TI - ClinVar Is a Critical Resource to Advance Variant Interpretation. PMID- 28851763 TI - The innate immune receptor MDA5 limits rotavirus infection but promotes cell death and pancreatic inflammation. AB - Melanoma differentiation-associated protein 5 (MDA5) mediates the innate immune response to viral infection. Polymorphisms in IFIH1, the gene coding for MDA5, correlate with the risk of developing type 1 diabetes (T1D). Here, we demonstrate that MDA5 is crucial for the immune response to enteric rotavirus infection, a proposed etiological agent for T1D. MDA5 variants encoded by minor IFIH1 alleles associated with lower T1D risk exhibit reduced activity against rotavirus infection. We find that MDA5 activity limits rotavirus infection not only through the induction of antiviral interferons and pro-inflammatory cytokines, but also by promoting cell death. Importantly, this MDA5-dependent antiviral response is specific to the pancreas of rotavirus-infected mice, similar to the autoimmunity associated with T1D. These findings imply that MDA5-induced cell death and inflammation in the pancreas facilitate progression to autoimmune destruction of pancreatic beta-cells. PMID- 28851764 TI - FTBMT, a Novel and Selective GPR52 Agonist, Demonstrates Antipsychotic-Like and Procognitive Effects in Rodents, Revealing a Potential Therapeutic Agent for Schizophrenia. AB - GPR52 is a Gs-coupled G protein-coupled receptor that is predominantly expressed in the striatum and nucleus accumbens (NAc) and was recently proposed as a potential therapeutic target for schizophrenia. In the current study, we investigated the in vitro and in vivo pharmacologic activities of a novel GPR52 agonist, 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1 yl)-2-methylbenzamide (FTBMT). FTBMT functioned as a selective GPR52 agonist in vitro and in vivo, as demonstrated by the activation of Camp signaling in striatal neurons. FTBMT inhibited MK-801-induced hyperactivity, an animal model for acute psychosis, without causing catalepsy in mice. The c-fos expression also revealed that FTBMT preferentially induced neuronal activation in the shell of the Nac compared with the striatum, thereby supporting its antipsychotic-like activity with less catalepsy. Furthermore, FTBMT improved recognition memory in a novel object-recognition test and attenuated MK-801-induced working memory deficits in a radial arm maze test in rats. These recognitive effects were supported by the results of FTBMT-induced c-fos expression in the brain regions related to cognition, including the medial prefrontal cortex, entorhinal cortex, and hippocampus. Taken together, these findings suggest that FTBMT shows antipsychotic and recognitive properties without causing catalepsy in rodents. Given its unique pharmacologic profile, which differs from that of current antipsychotics, FTBMT may provide a new therapeutic option for the treatment of positive and cognitive symptoms of schizophrenia. PMID- 28851765 TI - History of breast feeding and risk of incident endometriosis: prospective cohort study. AB - Objective To investigate the association between lifetime breast feeding, exclusive breast feeding, postpartum amenorrhea, and incidence of endometriosis among parous women.Design Prospective cohort study.Setting Nurses' Health Study II, 1989-2011.Participants 72 394women who reported having one or more pregnancies that lasted at least six months, 3296 of whom had laparoscopically confirmed endometriosis. For each pregnancy, women reported duration of total breast feeding, exclusive breast feeding, and postpartum amenorrhea. Main outcome measures Incident self reported laparoscopically confirmed endometriosis (96% concordance with medical record) in parous women. Multivariable Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for diagnosis of endometriosis.Results Duration of total and exclusive breast feeding was significantly associated with decreased risk of endometriosis. Among women who reported a lifetime total length of breast feeding of less than one month, there were 453 endometriosis cases/100 000 person years compared with 184 cases/100 000 person years in women who reported a lifetime total of >=36 months of breast feeding. For every additional three months of total breast feeding per pregnancy, women experienced an 8% lower risk of endometriosis (hazard ratio 0.92, 95% confidence interval 0.90 to 0.94; P<0.001 for trend) and a 14% lower risk for every additional three months of exclusive breast feeding per pregnancy (0.86, 0.81 to 0.90; P<0.001 for trend). Women who breastfed for >=36 months in total across their reproductive lifetime had a 40% reduced risk of endometriosis compared with women who never breast fed (0.60, 0.50 to 0.72). The protective association with breast feeding was strongest among women who gave birth within the past five years (P=0.04 for interaction). The association with total breast feeding and exclusive breast feeding on endometriosis was partially influenced by postpartum amenorrhea (% mediated was 34% (95% confidence interval 15% to 59%) for total breast feeding and 57% (27% to 82%) for exclusive breast feeding).Conclusion Among women who experienced at least one pregnancy that lasted at least six months, breast feeding was inversely associated with risk of incident endometriosis. This association was partially, but not fully, influenced by postpartum amenorrhea, suggesting that breast feeding could influence the risk of endometriosis both through amenorrhea and other mechanisms. Given the chronic and incurable nature of endometriosis, breast feeding should be further investigated as an important modifiable behavior to mitigate risk for pregnant women. PMID- 28851766 TI - Modelling the cost of community interventions to reduce child mortality in South Africa using the Lives Saved Tool (LiST). AB - OBJECTIVE: To estimate the costs and impact on reducing child mortality of scaling up interventions that can be delivered by community health workers at community level from a provider's perspective. SETTING: In this study, we used the Lives Saved Tool (LiST), a module in the spectrum software. Within the spectrum software, LiST interacts with other modules, the AIDS Impact Module, Family Planning Module and Demography Projections Module (Dem Proj), to model the impact of more than 60 interventions that affect cause-specific mortality. PARTICIPANTS: DemProj Based on National South African Data. INTERVENTIONS: A total of nine interventions namely, breastfeeding promotion, complementary feeding, vitamin supplementation, hand washing with soap, hygienic disposal of children's stools, oral rehydration solution, oral antibiotics for the treatment of pneumonia, therapeutic feeding for wasting and treatment for moderate malnutrition. PRIMARY AND SECONDARY OUTCOME MEASURES: Reducing child mortality. RESULTS: A total of 9 interventions can prevent 8891 deaths by 2030. Hand washing with soap (21%) accounts for the highest number of deaths prevented, followed by therapeutic feeding (19%) and oral rehydration therapy (16%). The top 5 interventions account for 77% of all deaths prevented. At scale, an estimated cost of US$169.5 million (US$3 per capita) per year will be required in community health worker costs. CONCLUSION: The use of community health workers offers enormous opportunities for saving lives. These programmes require appropriate financial investments. Findings from this study show what can be achieved if concerted effort is channelled towards the identified set of life-saving interventions. PMID- 28851767 TI - A qualitative study exploring the factors influencing admission to hospital from the emergency department. AB - OBJECTIVE: The number of emergency admissions to hospital in England and Wales has risen sharply in recent years and is a matter of concern to clinicians, policy makers and patients alike. However, the factors that influence this decision are poorly understood. We aimed to ascertain how non-clinical factors can affect hospital admission rates. METHOD: We conducted semistructured interviews with 21 participants from three acute hospital trusts. Participants included 11 emergency department (ED) doctors, 3 ED nurses, 3 managers and 4 inpatient doctors. A range of seniority was represented among these roles. Interview questions were developed from key themes identified in a theoretical framework developed by the authors to explain admission decision-making. Interviews were recorded, transcribed and analysed by two independent researchers using framework analysis. FINDINGS: Departmental factors such as busyness, time of day and levels of senior support were identified as non-clinical influences on a decision to admit rather than discharge patients. The 4-hour waiting time target, while overall seen as positive, was described as influencing decisions around patient admission, independent of clinical need. Factors external to the hospital such as a patient's social support and community follow-up were universally considered powerful influences on admission. Lastly, the culture within the ED was described as having a strong influence (either negatively or positively) on the decision to admit patients. CONCLUSION: Multiple factors were identified which go some way to explaining marked variation in admission rates observed between different EDs. Many of these factors require further inquiry through quantitative research in order to understand their influence further. PMID- 28851768 TI - Educational attainment and differences in relative survival after acute myocardial infarction in Norway: a registry-based population study. AB - BACKGROUND: Although there is a broad societal interest in socioeconomic differences in survival after an acute myocardial infarction, only a few studies have investigated how such differences relate to the survival in general population groups. We aimed to investigate education-specific survival after acute myocardial infarction and to compare this with the survival of corresponding groups in the general population. METHODS: Our study included the entire population of Norwegian patients admitted to hospitals for acute myocardial infarction during 2008-2010, with a 6- year follow-up period. Patient survival was measured relative to the expected survival in the general population for three educational groups: primary, secondary and tertiary. Education, sex, age and calendar year-specific expected survival were obtained from population life tables and adjusted for the presence of infarction-related mortality. RESULTS: Six-year patient survivals were 56.3% (55.3-57.2) and 65.5% (65.6-69.3) for the primary and tertiary educational groups (95% CIs), respectively. Also 6 year relative survival was markedly lower for the primary educational group: 70.2% (68.6-71.8) versus 81.2% (77.4-84.4). Throughout the follow-up period, patient survival tended to remain lower than the survival in the general population with the same educational background. CONCLUSION: Both patient survival and relative survival after acute myocardial infarction are positively associated with educational level. Our findings may suggest that secondary prevention has been more effective for the highly educated. PMID- 28851769 TI - What role does performance information play in securing improvement in healthcare? a conceptual framework for levers of change. AB - OBJECTIVE: Across healthcare systems, there is consensus on the need for independent and impartial assessment of performance. There is less agreement about how measurement and reporting performance improves healthcare. This paper draws on academic theories to develop a conceptual framework-one that classifies in an integrated manner the ways in which change can be leveraged by healthcare performance information. METHODS: A synthesis of published frameworks. RESULTS: The framework identifies eight levers for change enabled by performance information, spanning internal and external drivers, and emergent and planned processes: (1) cognitive levers provide awareness and understanding; (2) mimetic levers inform about the performance of others to encourage emulation; (3) supportive levers provide facilitation, implementation tools or models of care to actively support change; (4) formative levers develop capabilities and skills through teaching, mentoring and feedback; (5) normative levers set performance against guidelines, standards, certification and accreditation processes; (6) coercive levers use policies, regulations incentives and disincentives to force change; (7) structural levers modify the physical environment or professional cultures and routines; (8) competitive levers attract patients or funders. CONCLUSION: This framework highlights how performance measurement and reporting can contribute to eight different levers for change. It provides guidance into how to align performance measurement and reporting into quality improvement programme. PMID- 28851770 TI - Shifting tasks from pharmacy to non-pharmacy personnel for providing antiretroviral therapy to people living with HIV: a systematic review and meta analysis. AB - OBJECTIVES: Lay people or non-pharmacy health workers with training could dispense antiretroviral therapy (ART) in resource-constrained countries, freeing up time for pharmacists to focus on more technical tasks. We assessed the effectiveness of such task-shifting in low-income and middle-income countries. METHOD: We conducted comprehensive searches of peer-reviewed and grey literature. Two authors independently screened search outputs, selected controlled trials, extracted data and resolved discrepancies by consensus. We performed random effects meta-analysis and assessed certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Three studies with 1993 participants met the inclusion criteria, including two cluster trials conducted in Kenya and Uganda and an individually randomised trial conducted in Brazil. We found very low certainty evidence regarding mortality due to the low number of events. Therefore, we are uncertain whether there is a true increase in mortality as the effect size suggests, or a reduction in mortality between pharmacy and non-pharmacy models of dispensing ART (risk ratio (RR) 1.86, 95% CI 0.44 to 7.95, n=1993, three trials, very low certainty evidence). There may be no differences between pharmacy and non pharmacy models of dispensing ART on virological failure (risk ratio (RR) 0.92, 95% CI 0.73 to 1.15, n=1993, three trials, low certainty evidence) and loss to follow-up (RR 1.13, 95% CI 0.68 to 1.91, n=1993. three trials, low certainty evidence). We found some evidence that costs may be reduced for the patient and health system when task-shifting is undertaken. CONCLUSIONS: The low certainty regarding the evidence implies a high likelihood that further research may find the effects of the intervention to be substantially different from our findings. If resource-constrained countries decide to shift ART dispensing and distribution from pharmacy to non-pharmacy personnel, this should be accompanied by robust monitoring and impact evaluation. PMID- 28851771 TI - Initial protocol for a national evaluation of an area-based intervention programme (A Better Start) on early-life outcomes: a longitudinal cohort study with comparison (control) cohort samples. AB - INTRODUCTION: Pregnancy and the first few years of a child's life are important windows of opportunity in which to equalise life chances. A Better Start (ABS) is an area-based intervention being delivered in five areas of socioeconomic disadvantage across England. This protocol describes an evaluation of the impact and cost-effectiveness of ABS. METHODS AND ANALYSIS: The evaluation of ABS comprises a mixed-methods design including impact, cost-effectiveness and process components. It involves a cohort study in the 5 ABS areas and 15 matched comparison sites (n=2885), beginning in pregnancy in 2017 and ending in 2024 when the child is age 7, with a separate cross-sectional baseline survey in 2016/2017. Process data will include a profiling of the structure and services being provided in the five ABS sites at baseline and yearly thereafter, and data regarding the participating families and the services that they receive. Eligible participants will include pregnant women living within the designated sites, with recruitment beginning at 16 weeks of pregnancy. Data collection will involve interviewer-administered and self-completion surveys at eight time points. Primary outcomes include nutrition, socioemotional development, speech, language and learning. Data analysis will include the use of propensity score techniques to construct matched programme and comparison groups, and a range of statistical techniques to calculate the difference in differences between the intervention and comparison groups. The economic evaluation will involve a within-cohort study economic evaluation to compare individual-level costs and outcomes, and a decision analytic cost-effectiveness model to estimate the expected incremental cost per unit change in primary outcomes for ABS in comparison to usual care. ETHICS AND DISSEMINATION: Ethical approval to conduct the study has been obtained. The learning and dissemination workstream involves working within and across the sites to generate learning via communities of practice and a range of learning and dissemination events. PMID- 28851772 TI - Determining the sample size required to establish whether a medical device is non inferior to an external benchmark. AB - OBJECTIVES: The use of benchmarks to assess the performance of implants such as those used in arthroplasty surgery is a widespread practice. It provides surgeons, patients and regulatory authorities with the reassurance that implants used are safe and effective. However, it is not currently clear how or how many implants should be statistically compared with a benchmark to assess whether or not that implant is superior, equivalent, non-inferior or inferior to the performance benchmark of interest.We aim to describe the methods and sample size required to conduct a one-sample non-inferiority study of a medical device for the purposes of benchmarking. DESIGN: Simulation study. SETTING: Simulation study of a national register of medical devices. METHODS: We simulated data, with and without a non-informative competing risk, to represent an arthroplasty population and describe three methods of analysis (z-test, 1-Kaplan-Meier and competing risks) commonly used in surgical research. PRIMARY OUTCOME: We evaluate the performance of each method using power, bias, root-mean-square error, coverage and CI width. RESULTS: 1-Kaplan-Meier provides an unbiased estimate of implant net failure, which can be used to assess if a surgical device is non-inferior to an external benchmark. Small non-inferiority margins require significantly more individuals to be at risk compared with current benchmarking standards. CONCLUSION: A non-inferiority testing paradigm provides a useful framework for determining if an implant meets the required performance defined by an external benchmark. Current contemporary benchmarking standards have limited power to detect non-inferiority, and substantially larger samples sizes, in excess of 3200 procedures, are required to achieve a power greater than 60%. It is clear when benchmarking implant performance, net failure estimated using 1-KM is preferential to crude failure estimated by competing risk models. PMID- 28851773 TI - Mortality and readmission following hip fracture surgery: a retrospective study comparing conventional and fast-track care. AB - OBJECTIVE: To compare the efficacies of two pathways-conventional and fast-track care-in patients with hip fracture. DESIGN: Retrospective single-centre study. SETTING: University hospital in middle Norway. PARTICIPANTS: 1820 patients aged >=65 years with hip fracture (intracapsular, intertrochanteric or subtrochanteric). INTERVENTIONS: 788 patients were treated according to conventional care from April 2008 to September 2011, and 1032 patients were treated according to fast-track care from October 2011 to December 2013. PRIMARY AND SECONDARY OUTCOME: Primary: mortality and readmission to hospital, within 365 days follow-up. Secondary: length of stay. RESULTS: We found no statistically significant differences in mortality and readmission rate between patients in the fast-track and conventional care models within 365 days after the initial hospital admission. The conventional care group had a higher, no statistical significant mortality HR of 1.10 (95% CI 0.91 to 1.31, p=0.326) without and 1.16 (95% CI 0.96 to 1.40, p=0.118) with covariate adjustment. Regarding the readmission, the conventional care group sub-HR was 1.02 (95% CI 0.88 to 1.18, p=0.822) without and 0.97 (95% CI 0.83 to 1.12, p=0.644) with adjusting for covariates. Length of stay and time to surgery was statistically significant shorter for patients who received fast-track care, a mean difference of 3.4 days and 6 hours, respectively. There was no statistically significant difference in sex, type of fracture, age or Charlson Comorbidity Index score at baseline between patients in the two pathways. CONCLUSIONS: There was insufficient evidence to show an impact of fast-track care on mortality and readmission. Length of stay and time to surgery were decreased. TRIAL REGISTRATION NUMBER: NCT00667914; results. PMID- 28851774 TI - Does 'Time Together' increase quality of interaction and decrease stress? A study protocol of a multisite nursing intervention in psychiatric inpatient care, using a mixed method approach. AB - INTRODUCTION: Despite the long-known significance of the nurse-patient relationship, research in psychiatric inpatient care still reports unfulfilled expectations of, and difficulties in, interactions and relationships between patients and staff. Interventions that create structures to allow quality interactions between patients and staff are needed to solve these problems. The aim of this project is to test effects of the nursing intervention Time Together and to evaluate the intervention process. METHODS AND ANALYSIS: This is a multisite study with a single-system experimental design using frequent measures. The primary outcomes are quality interactions for patients and perceived stress for staff. Secondary outcomes are levels of symptoms of anxiety and depression for patients and stress of conscience for staff. A process evaluation is performed to describe contextual factors and experiences. Data are collected using questionnaires, participant observations and semistructured interviews. For analysis of quantitative data, both visual and statistical methods will be used. Qualitative data will be analysed using qualitative content analysis. ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethical Review Board in the region (Dnr 2016/339-31). The findings will contribute to the development of nursing interventions in general, but more specifically to the development of the intervention. This is relevant both nationally and internationally as similar interventions are needed but sparse. The findings will be disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT02981563. PMID- 28851775 TI - Gender and psychosocial factors associated with healthy lifestyle in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) cohort: a cross sectional study. AB - OBJECTIVES: It has been estimated that over 50% of the premature deaths occurring in Western countries can be attributed to causes rooted in lifestyle. In turn, leading a healthy lifestyle has also been associated with a wide range of psychosocial factors. Today, it is known that these differ among men and women. The present article aimed to identify, from a gender-based perspective, the psychosocial factors associated with healthy lifestyles in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) cohort, the largest study concerning adult health conducted in Latin America to date. DESIGN: This cross sectional study was conducted using ELSA-Brasil baseline data, collected between 2008 and 2010. SETTING: Six Brazilian public higher education and research institutions. PARTICIPANTS: The ELSA-Brasil cohort consists of approximately 15 000 employees (8218 women and 6887 men), both currently working and retired. MAIN OUTCOME MEASURES: The lifestyle indicator was constructed by summing the scores attributed to four different behaviours. RESULTS: The women of the ELSA-Brasil cohort have healthier lifestyles than men. In women, strong associations were found between a healthy lifestyle and age 60 years or older, Asian race and university level of education or higher. In men, being 60 years or older, of Asian or Caucasian race, having a high-school equivalent level of education or higher, being retired, having a housekeeper, having a good or very good self perception of health and being satisfied with body image were the psychosocial factors associated with leading a healthy lifestyle. CONCLUSIONS: The factors that influenced healthy lifestyles were found to differ among men and women, a fact that must be addressed when developing programmes designed to promote health. PMID- 28851776 TI - The moderating role of personal resources in the relationship between psychosocial job demands and health: a cross-sectional study. AB - OBJECTIVE: The main objective of this research was to investigate the buffering effects of an individual's physical, mental and social resources in the relationship between psychosocial job demands and (1) health symptoms, (2) mental strain and (3) the body mass index (BMI), respectively. METHODS: We performed moderated regression analysis to examine data from a large cross-sectional survey of an Austrian employee sample (n=9434). RESULTS: The results revealed a robust association between psychosocial job demands and health symptoms as well as mental strain, but only a weak relationship between psychosocial job demands and BMI. Although the personal resources showed a positive effect on health symptoms and mental strain, only weak evidence was found for the hypothesised interaction with psychosocial job demands. Solely the physical fitness of a person was found to mitigate the impact of psychosocial job demands on health symptoms. CONCLUSIONS: In conclusion, personal resources substantially accounted for the prediction of health. However, the interactions between psychosocial job demands and personal resources only slightly contributed to explaining the variation in health. PMID- 28851777 TI - Signs and symptoms preceding the diagnosis of Alzheimer's disease: a systematic scoping review of literature from 1937 to 2016. AB - OBJECTIVE: Late diagnosis of Alzheimer's disease (AD) may be due to diagnostic uncertainties. We aimed to determine the sequence and timing of the appearance of established early signs and symptoms in people who are subsequently diagnosed with AD. METHODS: We used systematic review methodology to investigate the existing literature. Articles were reviewed in May 2016, using the following databases: MEDLINE, PsycINFO, CINAHL, British Nursing Index, PubMed central and the Cochrane library, with no language restriction. Data from the included articles were extracted independently by two authors and quality assessment was undertaken with the quality assessment and diagnostic accuracy tool-2 (QUADAS tool-2 quality assessment tool). RESULTS: We found that depression and cognitive impairment were the first symptoms to appear in 98.5% and 99.1% of individuals in a study with late-onset AD (LOAD) and 9% and 80%, respectively, in early-onset AD (EOAD). Memory loss presented early and was experienced 12 years before the clinically defined AD dementia in the LOAD. However, the rapidly progressive late onset AD presented predominantly with 35 non-established focal symptoms and signs including myoclonus (75%), disturbed gait (66%) and rigidity. These were misdiagnosed as symptoms of Creutzfeldt-Jacob disease (CJD) in all the cases. The participant with the lowest mini-mental state examination score of 25 remained stable for 2 years, which is consistent with the score of the healthy family members. CONCLUSIONS: The findings of this review suggest that neurological and depressive behaviours are an early occurrence in EOAD with depressive and cognitive symptoms in the measure of semantic memory and conceptual formation in LOAD. Misdiagnosis of rapidly progressive AD as CJD and the familial memory score can be confounding factors while establishing a diagnosis. However, the study was limited by the fact that each one of the findings was based on a single study. PMID- 28851778 TI - Seroprevalence of hepatitis C virus infection in Cameroon: a systematic review and meta-analysis. AB - OBJECTIVE: Better knowledge of hepatitis C virus (HCV) seroprevalence at the national level can help to implement pertinent strategies to address the HCV related burden. The aim of this paper was to estimate the seroprevalence of HCV infection in Cameroon. DESIGN: Systematic review and meta-analysis. PARTICIPANTS: People residing in Cameroon. DATA SOURCES: Electronic databases including PubMed/MEDLINE, AJOL, WHO-Afro Library, Africa Index Medicus, National Institute of Statistics and National AIDS Control Committee, Cameroon from 1 January 2000 to 15 December 2016 were searched. English and French languages papers were considered. Two independent investigators selected studies. The methodological quality of the studies was assessed using the Newcastle-Ottawa scale. RESULTS: 31 studies including 36 407 individuals were finally considered. There was no national representative study. The overall pooled prevalence was 6.5% (95% CI 4.5% to 8.8%; I2=98.3%). A sensitivity analysis of individuals at low risk of HCV infection showed a pooled prevalence of 3.6% (95% CI 2.3% to 5.2%, I2=97.7%, 18 studies) among 22 860 individuals (general population, blood donors and pregnant women), which was higher than for a high-risk population (healthcare workers and people with other identified comorbidities), 12.2% (95% CI 4.9% to 22.2%; I2=98.3%, 13 studies); p=0.018. The prevalence was higher in the East region, in rural settings, and when using an enzyme immunoassay technique for detecting HCV antibodies. Sex, sites, study period, sample size, timing of data collection and methodological quality of studies were not sources of heterogeneity. LIMITATION: One-third of studies (29.0%) had a low risk bias in their methodology and most were facility-based (87.1%). CONCLUSION: The seroprevalence of HCV infection in Cameroon indicates the need for comprehensive and effective strategies to interrupt HCV transmission in the Cameroonian population. Specific attention is needed for the East region of the country, rural settings and high-risk populations. A national representative study is needed to provide better estimates. PMID- 28851779 TI - Protocol for a randomised, double-masked, sham-controlled phase 4 study on the efficacy, safety and tolerability of intravitreal aflibercept monotherapy compared with aflibercept with adjunctive photodynamic therapy in polypoidal choroidal vasculopathy: the ATLANTIC study. AB - PURPOSE: The purpose of this study is to compare the efficacy and safety of intravitreal aflibercept (IVA) with sham photodynamic therapy (sPDT) versus IVA with verteporfin PDT (vPDT) in a Caucasian population with treatment-naive polypoidal choroidal vasculopathy (PCV), enrolling into a treat and extend (T&E) regimen. METHODS AND ANALYSIS: Randomised, double-masked, sham-controlled, multicentre phase 4 investigator-driven clinical trial. The primary outcomes are (1) change in best-corrected visual acuity (BCVA) from baseline and (2) polyp regression at week 52, assessed by indocyanine green angiography (ICGA). Fifty patients with treatment-naive PCV will be recruited from Portuguese and Spanish clinical sites. Eligible patients will receive monthly IVA for 3 months (week 0, week 4 and week 8). At week 16, all patients will repeat ICGA and undergo central randomisation (1:1 ratio) into one of the following groups: Group 1-IVA T&E + vPDT; Group 2-IVA T&E + sPDT. PDT will be performed at week 16, week 28 and week 40 in the presence of active polyps. After week 16, the presence of macular fluid on optical coherence tomography will determine the schedule of observations. When present, the interval between visits/injections will decrease 2 weeks (minimum 6 weeks). When not, the interval between visits/injections will increase 2 weeks (maximum 12 weeks). Efficacy will be evaluated based on BCVA, central retinal thickness and polyp regression. Safety parameters will include assessment of intraocular pressure, adverse events and serious adverse events. ETHICS AND DISSEMINATION: This study was designed and shall be implemented and reported in accordance with the International Conference on Harmonisation (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations and with the ethical principles laid down in the Declaration of Helsinki. The study received approval from Comissao de Etica para a Investigacao Clinica and Comite Etico de investigacion Clinica del Hospital Universitari de Bellvitge. TRIAL REGISTRATION NUMBER: This study is registered under the EudraCT number: 2015-001368-20 and the ClinicalTrials.gov Identifier: NCT02495181. PMID- 28851780 TI - Mortality and risk of cardiac complications among immediate survivors of accidental electric shock: a Danish nationwide cohort study. AB - OBJECTIVE: Exposure to electric shock has been associated with an increased risk of developing delayed cardiac arrhythmias and cardiac diseases. We examined whether electric shock patients have an increased risk of developing cardiac disease, cardiac arrhythmias or death compared with the general Danish population. DESIGN: Matched cohort study. SETTING: A nationwide study in Denmark from 1994 to 2011. PARTICIPANTS: We identified 11 462 Danish patients who visited an emergency ward or were admitted to a hospital due to electric shock from 1994 to 2011. Each patient was matched for age and sex with five random controls from the Danish population. MAIN OUTCOME MEASURES: Mortality, cardiac procedures and cardiac diseases following electric shock. RESULTS: A total of 7390 electric shock patients were seen at an emergency ward and 4072 electric shock patients were admitted to a hospital. The median patient age was 28.6 years (Q1-Q3, 21.3 37.7) for the emergency ward patients and 26.4 years (Q1-Q3, 18.3-37.4) for admitted patients. In both groups, most patients were male (74.0% and 76.8%). Few of the electric shock patients had a record of cardiovascular disease at baseline (364/11 462, 3.2%). The 5-year cumulative incidence of death was 0.47% (95% CI 0.29% to 0.65%) for emergency ward patients and 1.04% (95% CI 0.71% to 1.37%) for admitted patients. No difference in 5-year survival was observed compared with matched controls (emergency ward, p=0.10; admitted patients, p=0.80). Fewer than four patients received a pacemaker within 30 days. CONCLUSIONS: This nationwide study did not demonstrate an increase in mortality among patients seen at hospitals after accidental electric shock compared with a background population. Cardiac procedures and diseases following electric shock were very rare. We suggest that nearly all patients can be discharged safely from the emergency room after electric shock without further observation. PMID- 28851781 TI - Protocol for a nationwide survey of primary health care in China: the China PEACE (Patient-centered Evaluative Assessment of Cardiac Events) MPP (Million Persons Project) Primary Health Care Survey. AB - INTRODUCTION: China has pioneered advances in primary health care (PHC) and public health for a large and diverse population. To date, the current state of PHC in China has not been subjected to systematic assessments. Understanding variations in primary care services could generate opportunities for improving the structure and function of PHC. METHODS AND ANALYSIS: This paper describes a nationwide PHC study (PEACE MPP Primary Health Care Survey) conducted across 31 provinces in China. The study leverages an ongoing research project, the China Patient-centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project (MPP). It employs an observational design with document acquisition and abstraction and in-person interviews. The study will collect data and original documents on the structure and financing of PHC institutions and the adequacy of the essential medicines programme; the education, training and retention of the PHC workforce; the quality of care; and patient satisfaction with care. The study will provide a comprehensive assessment of current PHC services and help determine gaps in access and quality of care. All study instruments and documents will be deposited in the Document Bank as an open-access source for other researchers. ETHICS AND DISSEMINATION: The central ethics committee at the China National Centre for Cardiovascular Disease (NCCD) approved the study. Written informed consent has been obtained from all patients. Findings will be disseminated in future peer reviewed papers, and will inform strategies aimed at improving the PHC in China. TRIAL REGISTRATION NUMBER: NCT02953926. PMID- 28851782 TI - Evaluating Maternity Units: a prospective cohort study of freestanding midwife led primary maternity units in New Zealand-clinical outcomes. AB - OBJECTIVE: To compare maternal and neonatal birth outcomes and morbidities associated with the intention to give birth in a freestanding primary level midwife-led maternity unit (PMU) or tertiary level obstetric-led maternity hospital (TMH) in Canterbury, Aotearoa/New Zealand. DESIGN: Prospective cohort study. PARTICIPANTS: 407 women who intended to give birth in a PMU and 285 women who intended to give birth at the TMH in 2010-2011. All of the women planning a TMH birth were 'low risk', and 29 of the PMU cohort had identified risk factors. PRIMARY OUTCOMES: Mode of birth, Apgar score of less than 7 at 5 min and neonatal unit admission. SECONDARY OUTCOMES: labour onset, analgesia, blood loss, third stage of labour management, perineal trauma, non-pharmacological pain relief, neonatal resuscitation, breastfeeding, gestational age at birth, birth weight, severe morbidity and mortality. RESULTS: Women who planned a PMU birth were significantly more likely to have a spontaneous vaginal birth (77.9%vs62.3%, adjusted OR (AOR) 1.61, 95% CI 1.08 to 2.39), and significantly less likely to have an instrumental assisted vaginal birth (10.3%vs20.4%, AOR 0.59, 95% CI 0.37 to 0.93). The emergency and elective caesarean section rates were not significantly different (emergency: PMU 11.6% vs TMH 17.5%, AOR 0.88, 95% CI 0.55 to 1.40; elective: PMU 0.7% vs TMH 2.1%, AOR 0.34, 95% CI 0.08 to 1.41). There were no significant differences between the cohorts in rates of 5 min Apgar score of <7 (2.0%vs2.1%, AOR 0.82, 95% CI 0.27 to 2.52) and neonatal unit admission (5.9%vs4.9%, AOR 1.44, 95% CI 0.70 to 2.96). Planning to give birth in a primary unit was associated with similar or reduced odds of intrapartum interventions and similar odds of all measured neonatal well-being indicators. CONCLUSIONS: The results of this study support freestanding midwife-led primary-level maternity units as physically safe places for well women to plan to give birth, with these women having higher rates of spontaneous vaginal births and lower rates of interventions and their associated morbidities than those who planned a tertiary hospital birth, with no differences in neonatal outcomes. PMID- 28851783 TI - Prevalence, incidence and associated mortality of cardiovascular disease in patients with chronic kidney disease in low- and middle-income countries: a protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Chronic kidney disease (CKD) is a global public health problem, with cardiovascular disease (CVD) being the major cause of mortality in these patients. Despite a high burden of CKD among patients in low/middle-income countries (LMICs), evidence on the distribution of CVD among these patients is lacking. This review seeks to determine the prevalence, incidence and mortality risks of CVD in patients with CKD in LMICs. METHODS AND ANALYSIS: A systematic search of Medline, Scopus, Embase, Cumulative Index of Nursing and Allied Health and WHO Global Health Library databases for published studies reporting on the prevalence, incidence and associated mortality risk of CVD in CKD patients in LMICs will be conducted from 1 May 1987 to 1 July 2017 with no language restriction. Two authors will independently screen, select studies, extract data and assess the risk of bias in each study. Clinically homogeneous studies will be pooled after assessing for clinical and statistical heterogeneity using the chi2 test on Cochrane's Q statistic which is quantified by I2 values; assuming that I2 values of 25%, 50% and 75% represent low, medium and high heterogeneity, respectively. Funnel-plot analysis and Egger's test will be used to detect publication bias. Results will be presented according to WHO Regions (Africa, Americas, Eastern Mediterranean, Europe, South-East Asia and Western Pacific). ETHICS AND DISSEMINATION: This proposed study will not require ethical approval as it will be based on published data. We will publish the final report of this review in a peer-reviewed journal, and the findings will be disseminated to the appropriate health authorities. PMID- 28851784 TI - The effects of vitamin B12 supplementation in pregnancy and postpartum on growth and neurodevelopment in early childhood: Study Protocol for a Randomized Placebo Controlled Trial. AB - INTRODUCTION: Vitamin B12 is crucial for normal cell division and differentiation, and necessary for the development and myelination of the central nervous system. Pregnant mothers in resource poor settings are at risk for poor vitamin B12 status. Poor vitamin B12 status in infancy is linked to poor growth and neurodevelopment. Brain development starts from conception, and pregnancy is a period of rapid growth and development for the brain. METHODS AND ANALYSIS: The study is an individually randomised double-blind placebo controlled trial in 800 pregnant Nepalese women randomised in a 1:1 ratio. A daily dose of 50 ug of vitamin B12 or placebo is given to women from early pregnancy, not later than week 15, until 6 months after birth. Weekly visits are conducted in order to record compliance, growth and morbidity. The primary outcomes are scores on the cognitive, language and motor subscales of the Bayley Scales of Infant and Toddler Development, Third Edition, measured at 6 and 12 months of age, and growth (length and weight) measured at 6 and 12 months of age. ETHICS AND DISSEMINATION: National Health and Research Council, Nepal (NHRC 253/2016) and Regional Committee for Medical and Health Research Ethics of Western Norway (2016/1620/REK vest) have approved the study. Investigators who have contributed to the conceptualising, conducting, as well as being involved in the data analyses and manuscript writing will be eligible for authorship and be responsible to share outcomes with different stakeholders through publications and workshops. The results from this study may support new dietary guidelines for Nepalese and possibly South Asian pregnant women that can lead to improved pregnancy outcomes, neurodevelopment and cognitive functioning in children. TRIAL REGISTRATION NUMBER: Universal Trial Number: U1111-1183-4093. TRIAL REGISTRATION: clinicaltrials.gov: NCT03071666. Protocol date: version 1.2, 1 June 2017. PMID- 28851785 TI - Validation of two case definitions to identify pressure ulcers using hospital administrative data. AB - OBJECTIVE: Pressure ulcer development is a quality of care indicator, as pressure ulcers are potentially preventable. Yet pressure ulcer is a leading cause of morbidity, discomfort and additional healthcare costs for inpatients. Methods are lacking for accurate surveillance of pressure ulcer in hospitals to track occurrences and evaluate care improvement strategies. The main study aim was to validate hospital discharge abstract database (DAD) in recording pressure ulcers against nursing consult reports, and to calculate prevalence of pressure ulcers in Alberta, Canada in DAD. We hypothesised that a more inclusive case definition for pressure ulcers would enhance validity of cases identified in administrative data for research and quality improvement purposes. SETTING: A cohort of patients with pressure ulcers were identified from enterostomal (ET) nursing consult documents at a large university hospital in 2011. PARTICIPANTS: There were 1217 patients with pressure ulcers in ET nursing documentation that were linked to a corresponding record in DAD to validate DAD for correct and accurate identification of pressure ulcer occurrence, using two case definitions for pressure ulcer. RESULTS: Using pressure ulcer definition 1 (7 codes), prevalence was 1.4%, and using definition 2 (29 codes), prevalence was 4.2% after adjusting for misclassifications. The results were lower than expected. Definition 1 sensitivity was 27.7% and specificity was 98.8%, while definition 2 sensitivity was 32.8% and specificity was 95.9%. Pressure ulcer in both DAD and ET consultation increased with age, number of comorbidities and length of stay. CONCLUSION: DAD underestimate pressure ulcer prevalence. Since various codes are used to record pressure ulcers in DAD, the case definition with more codes captures more pressure ulcer cases, and may be useful for monitoring facility trends. However, low sensitivity suggests that this data source may not be accurate for determining overall prevalence, and should be cautiously compared with other prevalence studies. PMID- 28851786 TI - Barriers and facilitators to the implementation of a community-based, multidisciplinary, family-focused childhood weight management programme in Ireland: a qualitative study. AB - OBJECTIVE: To explore the barriers and facilitators experienced by those implementing a government-funded, community-based childhood weight management programme. DESIGN: Qualitative using semistructured interviews. SETTING: Two geographical regions in the south and west of Ireland. PARTICIPANTS: 29 national level and local-level stakeholders responsible for implementing the programme, including professionals from dietetics, psychology, public health nursing, physiotherapy, health promotion and administration. METHODS: Framework analysis was used to identify barriers and facilitators, which were mapped onto six levels of factors influencing implementation outlined by Grol and Wensing: the innovation, the individual professional, the patient, the social context, the organisational context and the external environment. RESULTS: Most barriers occurred at the level of the organisational context. For all stakeholders, barriers arose due to the multidisciplinary nature of the programme, including the lack of role clarity and added complexity of working in different locations. Health professionals' low-perceived self-efficacy in approaching the subject of weight with parents and parental resistance to hearing about their child's weight status were barriers to programme implementation at the individual professional and patient levels, respectively. The main facilitators of implementation, occurring at the level of the health professional, included stakeholders' recognition of the need for a weight management programme and personal interest in the area of childhood obesity. Having a local lead and supportive colleagues were further implementation drivers. CONCLUSIONS: This study highlights the complexities associated with implementing a multidisciplinary childhood weight management programme, particularly translating such a programme to a community setting. Our results suggest the assignment of clear roles and responsibilities, the provision of sufficient practical training and resources, and organisational support play pivotal roles in overcoming barriers to change. This evidence can be used to develop an implementation plan to support the translation of interventions into real-world settings. PMID- 28851787 TI - A qualitative study exploring the social and environmental context of recently acquired HIV infection among men who have sex with men in South-East England. AB - OBJECTIVES: A key UK public health priority is to reduce HIV incidence among gay and other men who have sex with men (MSM). This study aimed to explore the social and environmental context in which new HIV infections occurred among MSM in London and Brighton in 2015. DESIGN: A qualitative descriptive study, comprising in-depth interviews, was carried out as a substudy to the UK Register of HIV Seroconverters cohort: an observational cohort of individuals whose date of HIV seroconversion was well estimated. An inductive thematic analysis was conducted in NVivo, guided by a socio-ecological framework. SETTING: Participants were recruited from six HIV clinics in London and Brighton. Fieldwork was conducted between January and April 2015. PARTICIPANTS: All MSM eligible for the UK Register Seroconverter cohort (an HIV-positive antibody test result within 12 months of their last documented HIV-negative test or other laboratory evidence of HIV seroconversion) diagnosed within the past 12 months and aged >=18 were eligible for the qualitative substudy. 21 MSM participated, aged 22-61 years and predominantly white. RESULTS: A complex interplay of factors, operating at different levels, influenced risk behaviours and HIV acquisition. Participants saw risk as multi-factorial, but the relative importance of factors varied for each person. Individual psycho-social factors, including personal history, recent life stressors and mental health, enhanced vulnerability towards higher risk situations, while features of the social environment, such as chemsex and social media, and prevalent community beliefs regarding treatment and HIV normalisation, encouraged risk taking. CONCLUSIONS: Recently acquired HIV infection among MSM reflects a complex web of factors operating at different levels. These findings point to the need for multi-level interventions to reduce the risk of HIV acquisition among high-risk MSM in the UK and similar settings. PMID- 28851788 TI - Regional transarterial hypothermic infusion in combination with endovascular thrombectomy in acute ischaemic stroke with cerebral main arterial occlusion: protocol to investigate safety of the clinical trial. AB - INTRODUCTION: Acute cerebral ischaemia with main cerebral artery occlusion requires treatment with intravenous tissue plasminogen activator administration and/or endovascular thrombectomy. However, some patients fail to recover even after recanalisation because of ischaemia/reperfusion (I/R) injury. We hypothesised that regional transarterial hypothermic infusion would be effective for patients with I/R injury. The aim of this study is to validate the safety of this procedure. METHODS AND ANALYSIS: This is a clinical exploratory study to evaluate safety of regional transarterial hypothermic infusion in combination with endovascular thrombectomy. Patients with acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 5-29 who require endovascular thrombectomy are eligible for the study. When no improvement in NIHSS score after the recanalisation is achieved by thrombectomy, cold saline (15 degrees C) will be administered through a microcatheter located in the ipsilateral internal carotid artery. The primary endpoints of this study are mortality and morbidity. The secondary endpoint is deleterious effects on clinical data such as symptoms, radiographic findings and physiological data. The primary and secondary endpoints will be accumulated as case series because this study will be conducted on a small sample of seven patients. ETHICS AND DISSEMINATION: All protocols and the informed consent form comply with the Ethics Guideline for Clinical Research (Japanese Ministry of Health, Labour and Welfare). Ethics review committees at the Hokkaido University Hospital approved the study protocols. The results of the study will be disseminated at several research conferences and also contributed to peer-reviewed journals. The study will be implemented and reported in line with the SPIRIT statement. TRIAL REGISTRATION NUMBER: UMIN Clinical Trails Registry (UMIN000018255); pre-results. PMID- 28851789 TI - Brain stimulation for arm recovery after stroke (B-STARS): protocol for a randomised controlled trial in subacute stroke patients. AB - INTRODUCTION: Many patients with stroke have moderate to severe long-term sensorimotor impairments, often including inability to execute movements of the affected arm or hand. Limited recovery from stroke may be partly caused by imbalanced interaction between the cerebral hemispheres, with reduced excitability of the ipsilesional motor cortex while excitability of the contralesional motor cortex is increased. Non-invasive brain stimulation with inhibitory repetitive transcranial magnetic stimulation (rTMS) of the contralesional hemisphere may aid in relieving a post-stroke interhemispheric excitability imbalance, which could improve functional recovery. There are encouraging effects of theta burst stimulation (TBS), a form of TMS, in patients with chronic stroke, but evidence on efficacy and long-term effects on arm function of contralesional TBS in patients with subacute hemiparetic stroke is lacking. METHODS AND ANALYSIS: In a randomised clinical trial, we will assign 60 patients with a first-ever ischaemic stroke in the previous 7-14 days and a persistent paresis of one arm to 10 sessions of real stimulation with TBS of the contralesional primary motor cortex or to sham stimulation over a period of 2 weeks. Both types of stimulation will be followed by upper limb training. A subset of patients will undergo five MRI sessions to assess post-stroke brain reorganisation. The primary outcome measure will be the upper limb function score, assessed from grasp, grip, pinch and gross movements in the action research arm test, measured at 3 months after stroke. Patients will be blinded to treatment allocation. The primary outcome at 3 months will also be assessed in a blinded fashion. ETHICS AND DISSEMINATION: The study has been approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, The Netherlands. The results will be disseminated through (open access) peer-reviewed publications, networks of scientists, professionals and the public, and presented at conferences. TRIAL REGISTRATION NUMBER: NTR6133. PMID- 28851790 TI - Antenatal antiarrhythmic treatment for fetal tachyarrhythmias: a study protocol for a prospective multicentre trial. AB - INTRODUCTION: Several retrospective or single-centre studies demonstrated the efficacy of transplacental treatment of fetal tachyarrhythmias. Our retrospective nationwide survey showed that the fetal therapy will be successful at an overall rate of 90%. For fetuses with hydrops, the treatment success rate will be 80%. However, standard protocol has not been established. The objective of this study is to evaluate the efficacy and safety of the protocol-defined transplacental treatment of fetal tachyarrhythmias. Participant recruitment began in October 2010. METHODS AND ANALYSIS: The current study is a multicentre, single-arm interventional study. A total of 50 fetuses will be enrolled from 15 Japanese institutions. The protocol-defined transplacental treatment is performed for singletons with sustained fetal tachyarrhythmia >=180 bpm, with a diagnosis of supraventricular tachycardia or atrial flutter. Digoxin, sotalol, flecainide or a combination is used for transplacental treatment. The primary endpoint is disappearance of fetal tachyarrhythmias. The secondary endpoints are fetal death related to tachyarrhythmia, proportion of preterm birth, rate of caesarean section attributable to fetal arrhythmia, improvement in fetal hydrops, neonatal arrhythmia, neonatal central nervous system disorders and neonatal survival. Maternal, fetal and neonatal adverse events are evaluated at 1 month after birth. Growth and development are also evaluated at 18 and 36 months of corrected age. ETHICS AND DISSEMINATION: The Institutional Review Board of the National Cerebral and Cardiovascular Center of Japan has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry UMIN000004270. PMID- 28851791 TI - Organ damage in sickle cell disease study (ORDISS): protocol for a longitudinal cohort study based in Ghana. AB - INTRODUCTION: Sickle cell disease is highly prevalent in Africa with a significant public health burden. Nonetheless, morbidity and mortality in sickle cell disease that result from the progression of organ damage is not well understood. The Organ Damage in Sickle Cell Disease Study (ORDISS) is designed as a longitudinal cohort study to provide critical insight into cellular and molecular pathogenesis of chronic organ damage for the development of future innovative treatment. METHODS AND ANALYSIS: ORDISS aims to recruit children aged 0-15 years who attend the Kumasi Centre for Sickle Cell Disease based at the Komfo Anokye Teaching Hospital in Kumasi, Ghana. Consent is obtained to collect blood and urine samples from the children during specified clinic visits and hospitalisations for acute events, to identify candidate and genetic markers of specific organ dysfunction and end-organ damage, over a 3 year period. In addition, data concerning clinical history and complications associated with sickle cell disease are collected. Samples are stored in biorepositories and analysed at the Kumasi Centre for Collaborative Research in Tropical Medicine, Ghana and the Centre for Translational and International Haematology, University of Pittsburgh, USA. Appropriate statistical analyses will be performed on the data acquired. ETHICS AND DISSEMINATION: Research ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals, and the key findings presented at national and international conferences. PMID- 28851792 TI - The clinical academic workforce of the future: a cross-sectional study of factors influencing career decision-making among clinical PhD students at two research intensive UK universities. AB - OBJECTIVES: To examine clinical doctoral students' demographic and training characteristics, career intentions, career preparedness and what influences them as they plan their future careers. DESIGN AND SETTING: Online cross-sectional census surveys at two research-intensive medical schools in England in 2015-2016. PARTICIPANTS: All medically qualified PhD students (N=523) enrolled at the University of Oxford and University College London were invited to participate. We report on data from 320 participants (54% male and 44% female), who were representative by gender of the invited population. MAIN OUTCOME MEASURES: Career intentions. RESULTS: Respondents were mainly in specialty training, including close to training completion (25%, n=80), and 18% (n=57) had completed training. Half (50%, n=159) intended to pursue a clinical academic career (CAC) and 62% (n=198) were at least moderately likely to seek a clinical lectureship (CL). However, 51% (n=163) had little or no knowledge about CL posts. Those wanting a CAC tended to have the most predoctoral medical research experience (chi2 (2, N=305)=22.19, p=0.0005). Key reasons cited for not pursuing a CAC were the small number of senior academic appointments available, the difficulty of obtaining research grants and work-life balance. CONCLUSIONS: Findings suggest that urging predoctoral clinicians to gain varied research experience while ensuring availability of opportunities, and introducing more flexible recruitment criteria for CL appointments, would foster CACs. As CL posts are often only open to those still in training, the many postdoctoral clinicians who have completed training, or nearly done so, do not currently gain the opportunity the post offers to develop as independent researchers. Better opportunities should be accompanied by enhanced career support for clinical doctoral students (eg, to increase knowledge of CLs). Finally, ways to increase the number of senior clinical academic appointments should be explored since their lack seems to significantly influence career decisions. PMID- 28851793 TI - Advanced chronic liver disease in the last year of life: a mixed methods study to understand how care in a specialist liver unit could be improved. AB - OBJECTIVE: To identify the limitations in palliative care provision in the last year of life for people with liver cirrhosis and potential barriers to and enablers of palliative care. DESIGN: Mixed methods, including a retrospective case note review, qualitative focus groups and individual interviews. SETTING: A tertiary referral liver centre in the south of England (UK). PARTICIPANTS: Purposively selected case notes of 30 people with cirrhosis who attended the tertiary referral liver centre and died during an 18-month period; a purposive sample of 22 liver health professionals who participated in either focus groups or individual interviews. PRIMARY AND SECONDARY OUTCOMES: Data collected from case notes included hospital admissions, documented discussions of prognosis and palliative care provision. Qualitative methods explored management of people with cirrhosis, and barriers to and enablers of palliative care. RESULTS: Participants had high rates of hospital admissions and symptom burden. Clinicians rarely discussed prognosis or future care preferences; they lacked the skills and confidence to initiate discussions. Palliative care provision occurred late because clinicians were reluctant to refer due to their perception that reduced liver function is reversible, poor understanding of the potential of a palliative approach; palliative care was perceived negatively by patients and families. CONCLUSIONS: People dying with cirrhosis have unpredictable trajectories, but share a common pathway of frequent admissions and worsening symptoms as death approaches. The use of clinical tools to identify the point of irreversible deterioration and joint working between liver services and palliative care may improve care for people with cirrhosis. PMID- 28851794 TI - Integrating national surveys to estimate small area variations in poor health and limiting long-term illness in Great Britain. AB - OBJECTIVES: This study aims to address, for the first time, the challenges of constructing small area estimates of health status using linked national surveys. The study also seeks to assess the concordance of these small area estimates with data from national censuses. SETTING: Population level health status in England, Scotland and Wales. PARTICIPANTS: A linked integrated dataset of 23 374 survey respondents (16+ years) from the 2011 waves of the Health Survey for England (n=8603), the Scottish Health Survey (n=7537) and the Welsh Health Survey (n=7234). PRIMARY AND SECONDARY OUTCOME MEASURES: Population prevalence of poorer self-rated health and limiting long-term illness. A multilevel small area estimation modelling approach was used to estimate prevalence of these outcomes for middle super output areas in England and Wales and intermediate zones in Scotland. The estimates were then compared with matched measures from the contemporaneous 2011 UK Census. RESULTS: There was a strong positive association between the small area estimates and matched census measures for all three countries for both poorer self-rated health (r=0.828, 95% CI 0.821 to 0.834) and limiting long-term illness (r=0.831, 95% CI 0.824 to 0.837), although systematic differences were evident, and small area estimation tended to indicate higher prevalences than census data. CONCLUSIONS: Despite strong concordance, variations in the small area prevalences of poorer self-rated health and limiting long-term illness evident in census data cannot be replicated perfectly using small area estimation with linked national surveys. This reflects a lack of harmonisation between surveys over question wording and design. The nature of small area estimates as 'expected values' also needs to be better understood. PMID- 28851795 TI - Trends in disability of instrumental activities of daily living among older Chinese adults, 1997-2006: population based study. AB - BACKGROUND: Data on trends for disability in instrumental activity of daily living (IADL) are sparse in older Chinese adults. OBJECTIVES: To assess trends in prevalence and incidence of IADL disability among older Chinese adults and to explore contributing factors. DESIGN: Population based study. SETTING: 15 provinces and municipalities in China. SUBJECTS: Participants (age >=60) were from four waves of the China Health and Nutrition Survey, conducted in 1997 (n=1533), 2000 (n=1581), 2004 (n=2028) and 2006 (n=2256), and from two cohorts constructed within the national survey: cohort 1997-2004 (n=712) and cohort 2000 2006 (n=823). MEASUREMENTS: IADL disability was defined as inability to perform one or more of the following: shopping, cooking, using transportation, financing and telephoning. Data were analysed with logistic regression and generalised estimating equation models. RESULTS: The prevalence of IADL disability significantly decreased from 1997 to 2006 in the total sample and in all of the subgroups by age, sex, living region and IADL items (all ptrend <0.05). The incidence of IADL disability remained stable from cohort 1997-2004 to cohort 2000 2006 in the total sample and in all of the subgroups (all p>0.10). The recovery rate from IADL disability significantly increased over time in those aged 60-69 years (p=0.03). Living in a rural area or access to local clinics for healthcare was less disabling over time (ptrend <0.02). CONCLUSIONS: The prevalence of IADL disability decreased among older Chinese adults during 1997-2006, whereas the incidence remained stable. The declining prevalence of IADL disability might be partly due to the decreased duration of IADL disability, and to improvements in living conditions and healthcare facilities over time. PMID- 28851796 TI - Determinants of severe acute malnutrition among children under 5 years of age in Nepal: a community-based case-control study. AB - BACKGROUND: Malnutrition is one of the leading causes of morbidity and mortality among children under the age of 5 years in low and middle income countries like Nepal. Children with severe acute malnutrition (SAM) are nine times more likely to die than children without malnutrition. The prevalence of SAM has increased in Nepal over the past 15 years; however, the determinants of SAM have not been clearly assessed in the country. OBJECTIVE: To assess the determinants of SAM among children aged 6-59 months in the Bara district of Nepal. SETTING: A community-based case-control study was conducted in 12 randomly selected Village Development Committees (VDCs) of the Bara district of Nepal. PARTICIPANTS: A random sample of 292 children aged 6-59 months (146 as cases and 146 as controls) from 12 VDCs were included in this study. RESULTS: The prevalence of SAM among children under the age of 5 years was 4.14%. The following factors were significantly associated with SAM: low socioeconomic status (adjusted odds ratio (AOR) 17.13, 95% CI 5.85 to 50.13); mother's age at birth <20 or >35 years (AOR 3.21, 95% CI 1.30 to 7.94); birth interval <24 months (AOR 4.09, 95% CI 1.87 to 8.97); illiterate father (AOR 3.65, 95% CI 1.62 to 8.20); bottle feeding (AOR 2.19, 95% CI 1.73 to 12.03); and not initiating complementary feeding at the age of 6 months (AOR 2.91, 95% CI 1.73 to 12.03). Mother's educational level, initiation of breastfeeding, colostrum feeding, and exclusive breastfeeding were not significantly associated with SAM. CONCLUSION: The mother's age at birth, birth interval, socioeconomic status, father's educational level and initiation of complementary feeding at the age of 6 months were important determinants of SAM among children. A multi-sector approach is essential to address SAM. There is a need for further studies not only focusing on SAM but also moderate acute malnutrition. PMID- 28851797 TI - Psychometric evaluation of the Chinese version of the Person-centred Climate Questionnaire - Staff version (PCQ-S). AB - OBJECTIVES: The aim of the study was to evaluate the psychometric properties of a Chinese translation of the English version of the Person-centred Climate Questionnaire - Staff version (PCQ-S) for Chinese palliative care staff in a hospital context. DESIGN: This was a cross-sectional design. The 14-item English PCQ-S was translated and backtranslated using established procedures. Construct validity and reliability including internal consistency and test-retest reliability were assessed among hospital staff. Construct validity was tested using principal component analysis (PCA), internal consistency was assessed using Cronbach's alpha, and test-retest reliability was evaluated with the weighted kappa (Kp), Pearson correlation coefficient (r) and intra-class correlation coefficient (ICC). SETTING: This study was conducted in three hospitals in Kunming, the capital of Yunnan province in south-west China. PARTICIPANTS: A sample of hospital staff (n=163) on duty in the palliative care departments of three hospitals in Kunming consented to participate in the study. RESULTS: The 14 item Chinese PCQ-S consists of the three subscales also present in other language versions. It showed strong internal consistency, with a Cronbach's alpha of 0.94 for the total scale, 0.87 for the safety subscale, 0.90 for the everydayness subscale and 0.88 for the community subscale. The Chinese PCQ-S had high test retest reliability as evidenced by a high Kp coefficient and a high correlation coefficient for all scales between test and retest scores, on 'a climate of safety' (Kp=0.77, r=0.88, p<0.01), 'a climate of everydayness' (Kp=0.82, r=0.91, p<0.01), 'a climate of community' (Kp=0.75, r=0.79, p<0.01), and on overall scale scores (Kp=0.85, r=0.93, p<0.01). The ICC to evaluate the test-retest reliability was 0.97 (95% CI 0.95 to 0.98). CONCLUSIONS: The Chinese version of the PCQ-S showed satisfactory reliability and validity for assessing staff perceptions of person-centred care in Chinese hospital environments. PMID- 28851798 TI - Study protocol for a multi-institutional, randomised, double-blinded, placebo controlled phase III trial investigating additive efficacy of duloxetine for neuropathic cancer pain refractory to opioids and gabapentinoids: the DIRECT study. AB - INTRODUCTION: Management of patients with cancer suffering from neuropathic pain refractory to opioids and gabapentinoids remains an important challenge. Duloxetine is one of the choices after first-line treatment fails. The efficacy of duloxetine has been reported in patients with non-cancer disease and in chemotherapy-induced peripheral neuropathy, but no randomised clinical trials have examined its effects on neuropathic cancer pain refractory to first-line treatment. The objective of this study is to assess the analgesic efficacy of duloxetine in patients suffering from neuropathic cancer pain refractory to opioids and gabapentinoids. METHODS AND ANALYSIS: A multi-institutional, prospective, randomised, double-blind, placebo-controlled, two-parallel trial is planned. The inclusion criteria are adult patients with cancer suffering from neuropathic cancer pain refractory to opioids and gabapentinoids, patients with a Numerical Rating Scale (NRS) pain score of 4 or higher and patients with a total Hospital Anxiety and Depression Scale score of less than 20. Patients with chemotherapy-induced peripheral neuropathy are excluded. The study will take place at 14 sites across Japan. Participants will be randomised (1:1 allocation ratio) to a duloxetine intervention group or a placebo control group. Evaluations will be made at baseline (T0 randomisation), day 0 (T1), day 3 (T2) and day 10 (T3). The primary endpoint is defined as the difference in NRS score for pain intensity (average over the previous 24 hours) at T3 between the duloxetine and placebo groups. A sample size of 70 patients will be examined between July 2015 and March 2018. ETHICS AND DISSEMINATION: Ethics approval was obtained at all participating sites.The results of this study will be submitted for publication in international peer-reviewed journals and the key findings presented at international scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000017647; Pre-results. PROTOCOL VERSION: 2.2, 26 April 2017. PMID- 28851799 TI - Excisional treatment in women with cervical adenocarcinoma in situ (AIS): a prospective randomised controlled non-inferiority trial to compare AIS persistence/recurrence after loop electrosurgical excision procedure with cold knife cone biopsy: protocol for a pilot study. AB - INTRODUCTION: Adenocarcinoma in situ (AIS) of the uterine cervix is the precursor to invasive endocervical adenocarcinoma. An excisional biopsy such as a cold knife cone biopsy (CKC) should be performed to exclude invasive adenocarcinoma. Loop electrosurgical excision procedure (LEEP) is an alternative modality to CKC but is controversial in AIS. There is a perception that there is a greater likelihood of incomplete excision of AIS with LEEP because the depth of excised tissue tends to be smaller and the tissue margins may show thermal artefact which can interfere with pathology assessment. In the USA, guidelines recommend that any treatment modality can be used to excise AIS, provided that the specimen remains intact with interpretable margins. However, there are no high-quality studies comparing LEEP with CKC and well-designed prospective studies are needed. If such a study were to show that LEEP was non-inferior to CKC for the outcomes of post-treatment persistence, recurrence and adenocarcinoma, LEEP could be recommended as an appropriate treatment option for AIS in selected patients. This would benefit women because, unlike CKC, LEEP does not require general anaesthesia and may be associated with reduced morbidity. METHODS AND ANALYSIS: The proposed exploratory study is a parallel group trial with an allocation ratio of 2:1 in favour of the intervention (LEEP: CKC). Participants are women aged >=18 to <=45 years diagnosed with AIS on cervical screening and/or colposcopically directed biopsy in Australia and New Zealand, who are to receive excisional treatment in a tertiary level centre. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the St John of God Healthcare Human Research Ethics Committee (reference number #1137). Results from the study will be presented at conferences and published in a peer-reviewed scientific journal. REGISTRATION: ANZCTR registration number ACTRN12617000132347 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372173&isReview= rue. PMID- 28851800 TI - The Chinese version of the Severe Respiratory Insufficiency questionnaire for patients with chronic hypercapnic chronic obstructive pulmonary disease receiving non-invasive positive pressure ventilation. AB - OBJECTIVES: The Severe Respiratory Insufficiency (SRI) questionnaire is the best assessment tool for health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) receiving non-invasive positive pressure ventilation (NIPPV). This study aimed to translate the SRI Questionnaire into Chinese and to validate it. DESIGN: Prospective validation study. SETTING AND PARTICIPANTS: A total of 149 participants with chronic hypercapnic COPD receiving NIPPV completed the study. METHODS: The SRI questionnaire was translated into Chinese using translation and back-translation. Reliability was gauged using Cronbach's alpha coefficient. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to assess construct validity. Content validity was confirmed by evaluating the relationship between the score of each item and the total score of the relevant subscale. RESULTS: Cronbach's alpha coefficients for each subscale and summary scale were above 0.7. Using EFA, one factor was extracted from the anxiety and summary scales and two factors were extracted from the remaining six subscales. Based on the EFA results, subsequent CFA revealed a good model fit for each subscale, but the extracted factors of each subscale were correlated. Content validity was confirmed by the good relationship between the score of each item and the total score of the relevant subscale. CONCLUSION: The Chinese version of the SRI questionnaire is valid and reliable for patients with chronic hypercapnic COPD receiving NIPPV in China. TRIAL REGISTRATION NUMBER: NCT02499718. PMID- 28851801 TI - Generalisability of vaccine effectiveness estimates: an analysis of cases included in a postlicensure evaluation of 13-valent pneumococcal conjugate vaccine in the USA. AB - OBJECTIVES: External validity, or generalisability, is the measure of how well results from a study pertain to individuals in the target population. We assessed generalisability, with respect to socioeconomic status, of estimates from a matched case-control study of 13-valent pneumococcal conjugate vaccine effectiveness for the prevention of invasive pneumococcal disease in children in the USA. DESIGN: Matched case-control study. SETTING: Thirteen active surveillance sites for invasive pneumococcal disease in the USA. PARTICIPANTS: Cases were identified from active surveillance and controls were age and zip code matched. OUTCOME MEASURES: Socioeconomic status was assessed at the individual level via parent interview (for enrolled individuals only) and birth certificate data (for both enrolled and unenrolled individuals) and at the neighbourhood level by geocoding to the census tract (for both enrolled and unenrolled individuals). Prediction models were used to determine if socioeconomic status was associated with enrolment. RESULTS: We enrolled 54.6% of 1211 eligible cases and found a trend toward enrolled cases being more affluent than unenrolled cases. Enrolled cases were slightly more likely to have private insurance at birth (p=0.08) and have mothers with at least some college education (p<0.01). Enrolled cases also tended to come from more affluent census tracts. Despite these differences, our best predictive model for enrolment yielded a concordance statistic of only 0.703, indicating mediocre predictive value. Variables retained in the final model were assessed for effect measure modification, and none were found to be significant modifiers of vaccine effectiveness. CONCLUSIONS: We conclude that although enrolled cases are somewhat more affluent than unenrolled cases, our estimates are externally valid with respect to socioeconomic status. Our analysis provides evidence that this study design can yield valid estimates and the assessing generalisability of observational data is feasible, even when unenrolled individuals cannot be contacted. PMID- 28851802 TI - Healthcare seeking patterns of families of infants with circumcision-related morbidities from two population-based cohort studies in Ghana. AB - OBJECTIVE: This study assessed healthcare seeking patterns of families of infants with circumcision-related morbidities and families of infants with acute illnesses in rural Ghana. DESIGN: Two population-based cohort studies. SETTING: Brong Ahafo Region of central rural Ghana. PARTICIPANTS: A total of 22 955 infants enrolled in a large population-based trial (Neovita trial) from 16 August 2010 to 7 November 2011 and 3141 infants in a circumcision study from 21 May 2012 to 31 December 2012. PRIMARY OUTCOME: Care seeking for circumcision-related morbidities and acute illnesses unrelated to circumcision. RESULTS: Two hundred and thirty (8.1%) infants from the circumcision study had circumcision-related morbidities and 6265 (27.3%) infants from the Neovita study had acute illnesses unrelated to circumcision. A much lower proportion (35, 15.2%) of families of infants with circumcision-related morbidities sought healthcare compared with families of infants with acute illnesses in the Neovita study (5520, 88.1%). More families sought care from formal providers (24, 69%) compared with informal providers (11, 31%) for circumcision-related morbidities. There were no obvious determinants of care seeking for acute illnesses or circumcision-related morbidities in the population. CONCLUSIONS: Government and non-government organisations need to improve awareness about the complications and care seeking needed for circumcision-related morbidities. PMID- 28851803 TI - Mediating effects of self-stigma on the relationship between perceived stigma and psychosocial outcomes among psychiatric outpatients: findings from a cross sectional survey in Singapore. AB - OBJECTIVES: To examine whether self-stigma mediates the relationship between perceived stigma and quality of life, self-esteem and general functioning among outpatients with depression, schizophrenia, anxiety and obsessive-compulsive disorder (OCD). DESIGN: Cross-sectional survey. SETTING: Outpatient clinics at a tertiary psychiatric hospital in Singapore. PARTICIPANTS: 280 outpatients with a primary clinical diagnosis of either schizophrenia, depression, anxiety or OCD. METHODS: Data were collected in relation to self-stigma, perceived stigma, self esteem, functioning and quality of life. In order to examine the mediating role of self-stigma on the relationship between perceived stigma and psychosocial outcomes, bootstrapping mediation analyses were used. RESULTS: Mediation analyses revealed that the relationship between perceived stigma and psychosocial outcomes was subject to the effects of self-stigma among the overall sample. Separate mediation analyses were conducted by diagnoses and showed differences in the mediating effects of self-stigma. Among the whole sample and the subsample with OCD, self-stigma mediated the relationship between perceived stigma and all psychosocial outcomes. For those with anxiety, depression and schizophrenia, the mediating effects of self-stigma were present in all relationships except (1) perceived stigma with physical health in the anxiety sample, (2) perceived stigma with social relationships in the depression sample and (3) perceived stigma with physical health in the schizophrenia sample. CONCLUSIONS: The mediating effects of self-stigma on the relationship between perceived stigma and various psychosocial outcomes are evident and differ across diagnoses. Interventions to address and reduce the effects of self-stigma along with targeted treatments and psychoeducation to assist people with mental illness overcome or better manage self-stigma while providing them the skills to counteract public stigma are needed. PMID- 28851804 TI - Association of FK506 binding proteins with RyR channels - effect of CLIC2 binding on sub-conductance opening and FKBP binding. AB - Ryanodine receptor (RyR) Ca2+ channels are central to striated muscle function and influence signalling in neurons and other cell types. Beneficially low RyR activity and maximum conductance opening may be stabilised when RyRs bind to FK506 binding proteins (FKBPs) and destabilised by FKBP dissociation, with submaximal opening during RyR hyperactivity associated with myopathies and neurological disorders. However, the correlation with submaximal opening is debated and quantitative evidence is lacking. Here, we have measured altered FKBP binding to RyRs and submaximal activity with addition of wild-type (WT) CLIC2, an inhibitory RyR ligand, or its H101Q mutant that hyperactivates RyRs, which probably causes cardiac and intellectual abnormalities. The proportion of sub conductance opening increases with WT and H101Q CLIC2 and is correlated with reduced FKBP-RyR association. The sub-conductance opening reduces RyR currents in the presence of WT CLIC2. In contrast, sub-conductance openings contribute to excess RyR 'leak' with H101Q CLIC2. There are significant FKBP and RyR isoform specific actions of CLIC2, rapamycin and FK506 on FKBP-RyR association. The results show that FKBPs do influence RyR gating and would contribute to excess Ca2+ release in this CLIC2 RyR channelopathy. PMID- 28851805 TI - C-terminal motifs in promyelocytic leukemia protein isoforms critically regulate PML nuclear body formation. AB - Promyelocytic leukemia protein (PML) nuclear bodies (NBs), which are sub-nuclear protein structures, are involved in a variety of important cellular functions. PML-NBs are assembled by PML isoforms, and contact between small ubiquitin-like modifiers (SUMOs) with the SUMO interaction motif (SIM) are critically involved in this process. PML isoforms contain a common N-terminal region and a variable C terminus. However, the contribution of the C-terminal regions to PML-NB formation remains poorly defined. Here, using high-resolution microscopy, we show that mutation of the SIM distinctively influences the structure of NBs formed by each individual PML isoform, with that of PML-III and PML-V minimally changed, and PML I and PML-IV dramatically impaired. We further identify several C-terminal elements that are important in regulating NB structure and provide strong evidence to suggest that the 8b element in PML-IV possesses a strong ability to interact with SUMO-1 and SUMO-2, and critically participates in NB formation. Our findings highlight the importance of PML C-termini in NB assembly and function, and provide molecular insight into the PML-NB assembly of each distinctive isoform. PMID- 28851807 TI - Is it better to die than to be lonely? PMID- 28851809 TI - Postnatal Cardiac Gene Editing Using CRISPR/Cas9 With AAV9-Mediated Delivery of Short Guide RNAs Results in Mosaic Gene Disruption. AB - RATIONALE: CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9)-based DNA editing has rapidly evolved as an attractive tool to modify the genome. Although CRISPR/Cas9 has been extensively used to manipulate the germline in zygotes, its application in postnatal gene editing remains incompletely characterized. OBJECTIVE: To evaluate the feasibility of CRISPR/Cas9-based cardiac genome editing in vivo in postnatal mice. METHODS AND RESULTS: We generated cardiomyocyte-specific Cas9 mice and demonstrated that Cas9 expression does not affect cardiac function or gene expression. As a proof-of-concept, we delivered short guide RNAs targeting 3 genes critical for cardiac physiology, Myh6, Sav1, and Tbx20, using a cardiotropic adeno-associated viral vector 9. Despite a similar degree of DNA disruption and subsequent mRNA downregulation, only disruption of Myh6 was sufficient to induce a cardiac phenotype, irrespective of short guide RNA exposure or the level of Cas9 expression. DNA sequencing analysis revealed target dependent mutations that were highly reproducible across mice resulting in differential rates of in- and out-of-frame mutations. Finally, we applied a dual short guide RNA approach to effectively delete an important coding region of Sav1, which increased the editing efficiency. CONCLUSIONS: Our results indicate that the effect of postnatal CRISPR/Cas9-based cardiac gene editing using adeno associated virus serotype 9 to deliver a single short guide RNA is target dependent. We demonstrate a mosaic pattern of gene disruption, which hinders the application of the technology to study gene function. Further studies are required to expand the versatility of CRISPR/Cas9 as a robust tool to study novel cardiac gene functions in vivo. PMID- 28851806 TI - The deubiquitylase USP10 regulates integrin beta1 and beta5 and fibrotic wound healing. AB - Scarring and fibrotic disease result from the persistence of myofibroblasts characterized by high surface expression of alphav integrins and subsequent activation of the transforming growth factor beta (TGFbeta) proteins; however, the mechanism controlling their surface abundance is unknown. Genetic screening revealed that human primary stromal corneal myofibroblasts overexpress a subset of deubiquitylating enzymes (DUBs), which remove ubiquitin from proteins, preventing degradation. Silencing of the DUB USP10 induces a buildup of ubiquitin on integrins beta1 and beta5 in cell lysates, whereas recombinant USP10 removes ubiquitin from these integrin subunits. Correspondingly, the loss and gain of USP10 decreases and increases, respectively, alphav/beta1/beta5 protein levels, without altering gene expression. Consequently, endogenous TGFbeta is activated and the fibrotic markers alpha-smooth muscle actin (alpha-SMA) and cellular fibronectin (FN-EDA) are induced. Blocking either TGFbeta signaling or cell surface alphav integrins after USP10 overexpression prevents or reduces fibrotic marker expression. Finally, silencing of USP10 in an ex vivo cornea organ culture model prevents the induction of fibrotic markers and promotes regenerative healing. This novel mechanism puts DUB expression at the head of a cascade regulating integrin abundance and suggests USP10 as a novel antifibrotic target. PMID- 28851811 TI - The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation. AB - The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of transcription factors is emerging as global regulators of cancer cell survival and energy metabolism, both through the promotion of lysosomal genes as well as newly characterized targets, such as oxidative metabolism and the oxidative stress response. In addition, MiT/TFE factors can regulate lysosomal signaling, which includes the mTORC1 and Wnt/beta-catenin pathways, which are both substantial contributors to oncogenic signaling. This review describes recent discoveries in MiT/TFE research and how they impact multiple cancer subtypes. Furthermore, the literature relating to TFE-fusion proteins in cancers and the potential mechanisms through which these genomic rearrangements promote tumorigenesis is reviewed. Likewise, the emerging function of the Folliculin (FLCN) tumor suppressor in negatively regulating the MiT/TFE family and how loss of this pathway promotes cancer is examined. Recent reports are also presented that relate to the role of MiT/TFE driven lysosomal biogenesis in sustaining cancer cell metabolism and signaling in nutrient-limiting conditions. Finally, a discussion is provided on the future directions and unanswered questions in the field. In summary, the research surrounding the MiT/TFE family indicates that these transcription factors are promising therapeutic targets and biomarkers for cancers that thrive in stressful niches. Mol Cancer Res; 15(12); 1637-43. (c)2017 AACR. PMID- 28851810 TI - MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. AB - RATIONALE: Clinical benefits of reperfusion after myocardial infarction are offset by maladaptive innate immune cell function, and therapeutic interventions are lacking. OBJECTIVE: We sought to test the significance of phagocytic clearance by resident and recruited phagocytes after myocardial ischemia reperfusion. METHODS AND RESULTS: In humans, we discovered that clinical reperfusion after myocardial infarction led to significant elevation of the soluble form of MerTK (myeloid-epithelial-reproductive tyrosine kinase; ie, soluble MER), a critical biomarker of compromised phagocytosis by innate macrophages. In reperfused mice, macrophage Mertk deficiency led to decreased cardiac wound debridement, increased infarct size, and depressed cardiac function, newly implicating MerTK in cardiac repair after myocardial ischemia reperfusion. More notably, Mertk(CR) mice, which are resistant to cleavage, showed significantly reduced infarct sizes and improved systolic function. In contrast to other cardiac phagocyte subsets, resident cardiac MHCIILOCCR2- (major histocompatibility complex II/C-C motif chemokine receptor type 2) macrophages expressed higher levels of MerTK and, when exposed to apoptotic cells, secreted proreparative cytokines, including transforming growth factor-beta. Mertk deficiency compromised the accumulation of MHCIILO phagocytes, and this was rescued in Mertk(CR) mice. Interestingly, blockade of CCR2-dependent monocyte infiltration into the heart reduced soluble MER levels post-ischemia reperfusion. CONCLUSIONS: Our data implicate monocyte-induced MerTK cleavage on proreparative MHCIILO cardiac macrophages as a novel contributor and therapeutic target of reperfusion injury. PMID- 28851812 TI - A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer. AB - TWIST1, an epithelial-mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non-small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical-bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of TWIST1 by inducing oncogene induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC.Implications: TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. Mol Cancer Res; 15(12); 1764-76. (c)2017 AACR. PMID- 28851814 TI - Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes. AB - Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 (CDKN2A) locus and mutations in NF-kappaB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naive NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFbeta pathway activation signature.Implications: This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. Mol Cancer Res; 15(12); 1722-32. (c)2017 AACR. PMID- 28851813 TI - The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis. AB - Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733-40. (c)2017 AACR. PMID- 28851815 TI - EPAC-RAP1 Axis-Mediated Switch in the Response of Primary and Metastatic Melanoma to Cyclic AMP. AB - Cyclic AMP (cAMP) is an important second messenger that regulates a wide range of physiologic processes. In mammalian cutaneous melanocytes, cAMP-mediated signaling pathways activated by G-protein-coupled receptors (GPCR), like melanocortin 1 receptor (MC1R), play critical roles in melanocyte homeostasis including cell survival, proliferation, and pigment synthesis. Impaired cAMP signaling is associated with increased risk of cutaneous melanoma. Although mutations in MAPK pathway components are the most frequent oncogenic drivers of melanoma, the role of cAMP in melanoma is not well understood. Here, using the Braf(V600E)/Pten-null mouse model of melanoma, topical application of an adenylate cyclase agonist, forskolin (a cAMP inducer), accelerated melanoma tumor development in vivo and stimulated the proliferation of mouse and human primary melanoma cells, but not human metastatic melanoma cells in vitro The differential response of primary and metastatic melanoma cells was also evident upon pharmacologic inhibition of the cAMP effector protein kinase A. Pharmacologic inhibition and siRNA-mediated knockdown of other cAMP signaling pathway components showed that EPAC-RAP1 axis, an alternative cAMP signaling pathway, mediates the switch in response of primary and metastatic melanoma cells to cAMP. Evaluation of pERK levels revealed that this phenotypic switch was not correlated with changes in MAPK pathway activity. Although cAMP elevation did not alter the sensitivity of metastatic melanoma cells to BRAF(V600E) and MEK inhibitors, the EPAC-RAP1 axis appears to contribute to resistance to MAPK pathway inhibition. These data reveal a MAPK pathway-independent switch in response to cAMP signaling during melanoma progression.Implications: The prosurvival mechanism involving the cAMP-EPAC-RAP1 signaling pathway suggest the potential for new targeted therapies in melanoma. Mol Cancer Res; 15(12); 1792-802. (c)2017 AACR. PMID- 28851817 TI - Silencing and augmentation of IAG hormone transcripts in adult Macrobrachiumrosenbergii males affects morphotype transformation. AB - Morphotypic differentiation is the external manifestation of dominance hierarchy in Macrobrachium rosenbergii The intermediate morphotype orange claw (OC) male exhibits the highest growth rate and is subordinate in hierarchy to blue claw (BC) male while dominant on small male (SM). The present study was undertaken to examine the specific role of insulin-like androgenic gland (iag) hormone in morphotype differentiation of M. rosenbergii To achieve this, RNAi mediated knockdown as well as augmentation of iag transcripts were effected in ~60 g OC males using plasmid-based constructs pcD-IAG-lh and pcD-IAGorf, respectively. The treatments were administered to animals maintained in isolation as well as in community. The knockdown plasmid construct that expresses iag-specific long hairpin RNA caused 16-fold reduction of iag transcripts in the SSN1 cell line in vitro When injected into OC males living in a community, 2.3-fold iag knockdown was recorded, while in isolated OC males it was 4.2-fold initially, but returned to normal subsequently. Compared with the respective controls, OC to BC transformations in the iag silenced animals were significantly lower in the community-reared group, while no difference was observed in the isolated animals. It is reported here for the first time that iag augmentation in OC males resulted in significantly higher OC to BC transformations, when animals were reared in community. This plasmid-based IAG knockdown approach could be developed into a low stress, feed or immersion treatment for controlling heterogeneous individual growth of M. rosenbergii males in aquaculture. PMID- 28851816 TI - FOXD3 Regulates CSC Marker, DCLK1-S, and Invasive Potential: Prognostic Implications in Colon Cancer. AB - The 5' (alpha)-promoter of the human doublecortin-like kinase 1 (DCLK1) gene becomes epigenetically silenced during colon carcinogenesis, resulting in loss of expression of the canonical long(L)-isoform1 (DCLK1-L) in human colon adenocarcinomas (hCRCs). Instead, hCRCs express a short(S)-isoform2 (DCLK1-S) from an alternate (beta)-promoter of DCLK1. The current study, examined if the transcriptional activity of the (beta)-promoter is suppressed in normal versus cancerous cells. On the basis of in silico and molecular approaches, it was discovered that FOXD3 potently inhibits the transcriptional activity of the (beta)-promoter. FOXD3 becomes methylated in human colon cancer cells (hCCC), with loss of FOXD3 expression, allowing expression of the DCLK1(S) variant in hCCCs/hCRCs. Relative levels of FOXD3/DCLK1(S/L) were measured in a cohort of CRC patient specimens (n = 92), in relation to overall survival (OS). Patients expressing high DCLK1(S), with or without low FOXD3, had significantly worse OS compared with patients expressing low DCLK1(S). The relative levels of DCLK1-L did not correlate with OS. In a pilot retrospective study, colon adenomas from high-risk patients (who developed CRCs in <15 years) demonstrated significantly higher staining for DCLK1(S) + significantly lower staining for FOXD3, compared with adenomas from low-risk patients (who remained free of CRCs). Latter results strongly suggest a prognostic value of measuring DCLK1(S)/FOXD3 in adenomas. Overexpression of DCLK1(S), but not DCLK1(L), caused a significant increase in the invasive potential of hCCCs, which may explain worse outcomes for patients with high DCLK1-S-expressing tumors. On the basis of these data, FOXD3 is a potent repressor of DCLK1-S expression in normal cells; loss of FOXD3 in hCCCs/hCRCs allows upregulation of DCLK1-S, imparting a potent invasive potential to the cells. Mol Cancer Res; 15(12); 1678-91. (c)2017 AACR. PMID- 28851818 TI - Rapid expansion of pigmentation genes in penaeid shrimp with absolute preservation of function. AB - Crustaceans form their distinct patterns and colours through the interaction of the carotenoid astaxanthin with a protein called crustacyanin (CRCN). Presently, the expression of just two CRCN genes is thought to provide the protein subunits that combine to form the crustacyanin complex and associated carotenoid colour change from red to blue. This study aimed to explore the genetic complexity underlying the production of pigmentation and camouflage in penaeid shrimp. We isolated 35 new CRCN genes from 12 species, and their sequence analysis indicated that this gene family has undergone significant expansion and diversification in this lineage. Despite this duplication and sequence divergence, the structure of the CRCN proteins and their functional role in shrimp colour production has been strictly conserved. Using CRCN isoforms from Penaeus monodon as an example, we showed that isoforms were differentially expressed, and that subtle phenotypes were produced by the specific downregulation of individual isoforms. These findings demonstrate that our knowledge of the molecular basis of pigmentation in shrimp was overly simplistic, and suggests that multiple copies of the CRCN genes within species may be advantageous for colour production. This result is of interest for the origin and evolution of pigmentation in crustaceans, and the mechanisms by which gene function is maintained, diversified or sub functionalized. PMID- 28851819 TI - O2 binding and CO2 sensitivity in haemoglobins of subterranean African mole rats. AB - Inhabiting deep and sealed subterranean burrows, mole rats exhibit a remarkable suite of specializations, including eusociality (living in colonies with single breeding queens), extraordinary longevity, cancer immunity and poikilothermy, and extreme tolerance of hypoxia and hypercapnia. With little information available on adjustments in haemoglobin (Hb) function that may mitigate the impact of exogenous and endogenous constraints on the uptake and internal transport of O2, we measured haematological characteristics, as well as Hb-O2 binding affinity and sensitivity to pH (Bohr effect), CO2, temperature and 2,3-diphosphoglycerate (DPG, the major allosteric modulator of Hb-O2 affinity in red blood cells) in four social and two solitary species of African mole rats (family Bathyergidae) originating from different biomes and soil types across Central and Southern Africa. We found no consistent patterns in haematocrit (Hct) and blood and red cell DPG and Hb concentrations or in intrinsic Hb-O2 affinity and its sensitivity to pH and DPG that correlate with burrowing, sociality and soil type. However, the results reveal low specific (pH independent) effects of CO2 on Hb-O2 affinity compared with humans that predictably safeguard pulmonary loading under hypoxic and hypercapnic burrow conditions. The O2 binding characteristics are discussed in relation to available information on the primary structure of Hbs from adult and developmental stages of mammals subjected to hypoxia and hypercapnia and the molecular mechanisms underlying functional variation in rodent Hbs. PMID- 28851820 TI - Frequency organization of the Johnston's organ in male mosquitoes (Diptera, Culicidae). AB - The Johnston's organs (JO) of mosquitoes are the most complex mechanosensitive organs yet found in insects. Previous findings on the behavior of mosquitoes suggest that, together with exceptional sensitivity, their auditory system can discriminate frequencies. Analysis of compound responses of the JO did not provide unambiguous evidence of such discrimination, nor did it help to find its mechanism. Using the feedback stimulation method, we measured the tuning frequencies of the JO sensory neurons. Here we present electrophysiological evidence that male mosquitoes of Culex pipiens possess at least eight groups of auditory neurons that are distinct in their frequency tuning, with individual frequencies ranging from 85 to 470 Hz. Most of the neurons are tuned to 190-270 Hz, which corresponds to the difference between male and female flight tones. Axons of the JO sensory units propagate graded amplified receptor potentials rather than all-or-none action potentials, are grouped into pairs or triplets and often respond in anti-phase to each other. Some features of the mosquito auditory system suggest an analogy to the retinal mechanisms. Together with our previous findings on frequency tuning in female mosquitoes of different species, this study presents evidence in favor of sophisticated frequency analysis of sound in mosquitoes. PMID- 28851821 TI - Multimodal in situ datalogging quantifies inter-individual variation in thermal experience and persistent origin effects on gaping behavior among intertidal mussels (Mytilus californianus). AB - In complex habitats, environmental variation over small spatial scales can equal or exceed larger-scale gradients. This small-scale variation may allow motile organisms to mitigate stressful conditions by choosing benign microhabitats, whereas sessile organisms may rely on other behaviors to cope with environmental stresses in these variable environments. We developed a monitoring system to track body temperature, valve gaping behavior and posture of individual mussels (Mytilus californianus) in field conditions in the rocky intertidal zone. Neighboring mussels' body temperatures varied by up to 14 degrees C during low tides. Valve gaping during low tide and postural adjustments, which could theoretically lower body temperature, were not commonly observed. Rather, gaping behavior followed a tidal rhythm at a warm, high intertidal site; this rhythm shifted to a circadian period at a low intertidal site and for mussels continuously submerged in a tidepool. However, individuals within a site varied considerably in time spent gaping when submerged. This behavioral variation could be attributed in part to persistent effects of the mussels' developmental environment. Mussels originating from a wave-protected, warm site gaped more widely, and remained open for longer periods during high tide than mussels from a wave-exposed, cool site. Variation in behavior was modulated further by recent wave heights and body temperatures during the preceding low tide. These large ranges in body temperatures and durations of valve closure events - which coincide with anaerobic metabolism - support the conclusion that individuals experience 'homogeneous' aggregations such as mussel beds in dramatically different fashion, ultimately contributing to physiological variation among neighbors. PMID- 28851822 TI - Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a Ror2 signaling. AB - Cytoskeletal reorganization in osteoclasts to form actin rings is necessary for these cells to attach to bone and resorb bone matrices. We delineated the pathway through which Wnt5a signaling through receptor tyrosine kinase-like orphan receptor 2 (Ror2) promoted the bone-resorbing activity of osteoclasts. Wnt5a binding to Ror2 stimulated Rho, a small GTPase involved in cytoskeletal reorganization. Subsequently, the Rho effector kinase Pkn3 bound to and enhanced the activity of c-Src, a nonreceptor tyrosine kinase that is critical for actin ring formation. Mice with an osteoclast-specific deficiency in Ror2 (Ror2DeltaOcl/DeltaOcl) had increased bone mass. Osteoclasts derived from these mice exhibited impaired bone resorption and actin ring formation, defects that were rescued by overexpression of constitutively active RhoA. These osteoclasts also exhibited reduced interaction between c-Src and Pkn3 and reduced c-Src kinase activity. Similar to Ror2DeltaOcl/DeltaOcl mice, mice with a global deficiency of Pkn3 (Pkn3-/-) had increased bone mass. The proline-rich region and kinase domain of Pkn3 were required to restore the bone-resorbing activity of osteoclasts derived from Pkn3-/- mice. Thus, Pkn3 promotes bone resorption downstream of Wnt5a-Ror2-Rho signaling, and this pathway may be a therapeutic target for bone diseases such as osteoporosis, rheumatoid arthritis, and periodontal disease. PMID- 28851825 TI - Embryo biopsy and development: the known and the unknown. AB - Preimplantation genetic diagnosis (PGD) has been introduced in clinical practice as a tool for selecting 'healthy' embryos before their transfer in utero. PGD protocols include biopsy of cleaving embryos (blastomere biopsy (BB)) or blastocysts (trophectoderm biopsy (TB)), followed by genetic analysis to select 'healthy' embryos for transfer in utero. Currently, TB is replacing the use of BB in the clinical practice. However, based on the European Society of Human Reproduction and Embryology Preimplantation Genetic Diagnosis Consortium reports, BB has been used in >87% of PGD cycles for more than 10 years. An exhaustive evaluation of embryo biopsy (both BB and TB) risks and safety is still missing. The few epidemiological studies available are quite controversial and/or are limited to normalcy at birth or early childhood. On the other hand, studies on animals have shown that BB can be a risk factor for impaired development, during both pre- and postnatal life, while little is known on TB. Thus, there is an urgent need of focused researches on BB, as it has contributed to give birth to children for more than 10 years, and on TB, as its application is significantly growing in clinical practice. In this context, the aim of this review is to provide a complete overview of the current knowledge on the short-, medium- and long-term effects of embryo biopsy in the mouse model. PMID- 28851823 TI - Activation of master virulence regulator PhoP in acidic pH requires the Salmonella-specific protein UgtL. AB - Acidic conditions, such as those inside phagosomes, stimulate the intracellular pathogen Salmonella enterica to activate virulence genes. The sensor PhoQ responds to a mildly acidic pH by phosphorylating, and thereby activating, the virulence regulator PhoP. This PhoP/PhoQ two-component system is conserved in a subset of Gram-negative bacteria. PhoQ is thought to be sufficient to activate PhoP in mildly acidic pH. However, we found that the Salmonella-specific protein UgtL, which was horizontally acquired by Salmonella before the divergence of S. enterica and Salmonella bongori, was also necessary for PhoQ to activate PhoP under mildly acidic pH conditions but not for PhoQ to activate PhoP in response to low Mg2+ or the antimicrobial peptide C18G. UgtL increased the abundance of phosphorylated PhoP by stimulating autophosphorylation of PhoQ, thereby increasing the amount of the phosphodonor for PhoP. Deletion of ugtL attenuated Salmonella virulence and further reduced PhoP activation in a strain bearing a form of PhoQ that is not responsive to acidic pH. These data suggest that when Salmonella experiences mildly acidic pH, PhoP activation requires PhoQ to detect pH and UgtL to amplify the PhoQ response. Our findings reveal how acquisition of a foreign gene can strengthen signal responsiveness in an ancestral regulatory system. PMID- 28851824 TI - Blockade of surface-bound TGF-beta on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. AB - Regulatory T cells (Tregs) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8+ T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from Treg-depleted mice were cultured in this system. Experiments with neutralizing antibodies showed that blocking transforming growth factor-beta (TGF-beta) also prevented immunosuppression. Immunosuppression depended on cell-cell contact or cellular proximity because soluble factors from the collagen-fibrin gel cultures did not inhibit tumor cell killing by T cells. Moreover, intravital, two-photon microscopy showed that tumor-specific Pmel-1 effector T cells physically interacted with tumor-resident Tregs in mice. Tregs isolated from B16 tumors alone were sufficient to suppress CD8+ T cell-mediated killing, which depended on surface-bound TGF-beta on the Tregs Immunosuppression of CD8+ T cells correlated with a decrease in the abundance of the cytolytic protein granzyme B and an increase in the cell surface amount of the immune checkpoint receptor programmed cell death protein 1 (PD-1). These findings suggest that contact between Tregs and antitumor T cells in the tumor microenvironment inhibits antimelanoma immunity in a TGF-beta-dependent manner and highlight potential ways to inhibit intratumoral Tregs therapeutically. PMID- 28851826 TI - Protein phosphorylation in spermatozoa motility of Acipenser ruthenus and Cyprinus carpio. AB - Spermatozoa of externally fertilizing freshwater fish possess several different modes of motility activation. Spermatozoa of common carp (Cyprinus carpio L.) are activated by hypoosmolality, whereas spermatozoa of sterlet (Acipenser ruthenus) require Ca2+ and low concentration of K+ for motility activation. Intracellular signaling differs between these two species as well, particularly in terms of utilization of secondary messengers (cAMP and Ca2+), and kinase activities. The current study was performed in order to determine the importance of protein phosphorylation and protein kinases for activation of sperm motility in carp and sterlet. Treatment with kinase inhibitors indicates that protein kinases A and C (PKA and PKC) participate in spermatozoa motility of both species. Immunodetection of phospho-(Ser/Thr) PKA substrates shows that phosphorylated proteins are localized differently in spermatozoa of carp and sterlet. Strong phosphorylation of PKC substrate was observed in flagella of sterlet spermatozoa, whereas in carp sperm, PKC substrates were lightly phosphorylated in the midpiece and flagella. Motility activation induced either phosphorylation or dephosphorylation on serine, threonine and tyrosine residues of numerous proteins in carp and sterlet spermatozoa. Proteomic methods were used to identify proteins whose phosphorylation state changes upon the initiation of sperm motility. Numerous mitochondrial and glycolytic enzymes were identified in spermatozoa of both species, as well as axonemal proteins, heat shock proteins, septins and calcium-binding proteins. Our results contribute to an understanding of the roles of signaling molecules, protein kinases and protein phosphorylation in motility activation and regulation of two valuable fish species, C. carpio and A. ruthenus. PMID- 28851827 TI - [Mg2+]o/[Ca2+]o determines Ca2+ response at fertilization: tuning of adult phenotype? AB - Alteration of the postnatal phenotype has sparked great concern about the developmental impact of culture media used at fertilization. However, the mechanisms and compounds involved are yet to be determined. Here, we used the Ca2+ responses from mouse eggs fertilized by ICSI as a dynamic and quantitative marker to understand the role of compounds in egg functioning and establish possible correlations with adult phenotypes. We computed 134 Ca2+ responses from the first to the last oscillation in media with specific formulations. Analyses demonstrate that eggs generated two times as many Ca2+ oscillations in KSOM as in M16 media (18.8 +/- 7.0 vs 9.2 +/- 2.5). Moreover, the time increment of the delay between two consecutive oscillations, named TIbO, is the most sensitive coefficient characterizing the mechanism that paces Ca2+ oscillations once the egg has been fertilized. Neither doubling external free Ca2+ nor dispermic fertilization increased significantly the total number of Ca2+ oscillations. In contrast, removing Mg2+ from the M16 boosted Ca2+ oscillations to 54.0 +/- 35.2. Hence, [Mg2+]o/[Ca2+]o appears to determine the number, duration and frequency of the Ca2+ oscillations. These changes were correlated with long-term effects. The rate of female's growth was impacted with the 'KSOM' females having only half the fat deposit of 'M16' females. Moreover, adult animals issued from M16 had significantly smaller brain weight vs 'KSOM' and 'control' animals. TIbO is a new Ca2+ coefficient that gauges the very early functional impact of culture media. It offers the possibility of establishing correlations with postnatal consequences according to IVF medium formulation.Free French abstract: A French translation of this abstract is freely available at http://www.reproduction online.org/content/154/5/675/suppl/DC2. PMID- 28851828 TI - Evidence for complex life cycle constraints on salamander body form diversification. AB - Metazoans display a tremendous diversity of developmental patterns, including complex life cycles composed of morphologically disparate stages. In this regard, the evolution of life cycle complexity promotes phenotypic diversity. However, correlations between life cycle stages can constrain the evolution of some structures and functions. Despite the potential macroevolutionary consequences, few studies have tested the impacts of life cycle evolution on broad-scale patterns of trait diversification. Here we show that larval and adult salamanders with a simple, aquatic-only (paedomorphic) life cycle had an increased rate of vertebral column and body form diversification compared to lineages with a complex, aquatic-terrestrial (biphasic) life cycle. These differences in life cycle complexity explain the variations in vertebral number and adult body form better than larval ecology. In addition, we found that lineages with a simple terrestrial-only (direct developing) life cycle also had a higher rate of adult body form evolution than biphasic lineages, but still 10-fold lower than aquatic only lineages. Our analyses demonstrate that prominent shifts in phenotypic evolution can follow long-term transitions in life cycle complexity, which may reflect underlying stage-dependent constraints. PMID- 28851829 TI - Glucocorticoids promote Von Hippel Lindau degradation and Hif-1alpha stabilization. AB - Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src-mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL. PMID- 28851830 TI - Experimental and statistical reevaluation provides no evidence for Drosophila courtship song rhythms. AB - From 1980 to 1992, a series of influential papers reported on the discovery, genetics, and evolution of a periodic cycling of the interval between Drosophila male courtship song pulses. The molecular mechanisms underlying this periodicity were never described. To reinitiate investigation of this phenomenon, we previously performed automated segmentation of songs but failed to detect the proposed rhythm [Arthur BJ, et al. (2013) BMC Biol 11:11; Stern DL (2014) BMC Biol 12:38]. Kyriacou et al. [Kyriacou CP, et al. (2017) Proc Natl Acad Sci USA 114:1970-1975] report that we failed to detect song rhythms because (i) our flies did not sing enough and (ii) our segmenter did not identify many of the song pulses. Kyriacou et al. manually annotated a subset of our recordings and reported that two strains displayed rhythms with genotype-specific periodicity, in agreement with their original reports. We cannot replicate this finding and show that the manually annotated data, the original automatically segmented data, and a new dataset provide no evidence for either the existence of song rhythms or song periodicity differences between genotypes. Furthermore, we have reexamined our methods and analysis and find that our automated segmentation method was not biased to prevent detection of putative song periodicity. We conclude that there is no evidence for the existence of Drosophila courtship song rhythms. PMID- 28851832 TI - Shared sociogenetic basis of honey bee behavior and human risk for autism. PMID- 28851833 TI - Designed metalloenediyne warheads damage DNA and outpace DNA polymerase. PMID- 28851831 TI - TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER-Golgi intermediate compartments. AB - The conserved coat protein complex II (COPII) mediates the initial steps of secretory protein trafficking by assembling onto subdomains of the endoplasmic reticulum (ER) in two layers to generate cargo-laden transport carriers that ultimately fuse with an adjacent ER-Golgi intermediate compartment (ERGIC). Here, we demonstrate that Trk-fused gene (TFG) binds directly to the inner layer of the COPII coat. Specifically, the TFG C terminus interacts with Sec23 through a shared interface with the outer COPII coat and the cargo receptor Tango1/cTAGE5. Our findings indicate that TFG binding to Sec23 outcompetes these other associations in a concentration-dependent manner and ultimately promotes outer coat dissociation. Additionally, we demonstrate that TFG tethers vesicles harboring the inner COPII coat, which contributes to their clustering between the ER and ERGIC in cells. Together, our studies define a mechanism by which COPII transport carriers are retained locally at the ER/ERGIC interface after outer coat disassembly, which is a prerequisite for fusion with ERGIC membranes. PMID- 28851834 TI - Exploring regulation in tissues with eQTL networks. AB - Characterizing the collective regulatory impact of genetic variants on complex phenotypes is a major challenge in developing a genotype to phenotype map. Using expression quantitative trait locus (eQTL) analyses, we constructed bipartite networks in which edges represent significant associations between genetic variants and gene expression levels and found that the network structure informs regulatory function. We show, in 13 tissues, that these eQTL networks are organized into dense, highly modular communities grouping genes often involved in coherent biological processes. We find communities representing shared processes across tissues, as well as communities associated with tissue-specific processes that coalesce around variants in tissue-specific active chromatin regions. Node centrality is also highly informative, with the global and community hubs differing in regulatory potential and likelihood of being disease associated. PMID- 28851835 TI - Empathy and well-being correlate with centrality in different social networks. AB - Individuals benefit from occupying central roles in social networks, but little is known about the psychological traits that predict centrality. Across four college freshman dorms (n = 193), we characterized individuals with a battery of personality questionnaires and also asked them to nominate dorm members with whom they had different types of relationships. This revealed several social networks within dorm communities with differing characteristics. In particular, additional data showed that networks varied in the degree to which nominations depend on (i) trust and (ii) shared fun and excitement. Networks more dependent upon trust were further defined by fewer connections than those more dependent on fun. Crucially, network and personality features interacted to predict individuals' centrality: people high in well-being (i.e., life satisfaction and positive emotion) were central to networks characterized by fun, whereas people high in empathy were central to networks characterized by trust. Together, these findings provide network-based corroboration of psychological evidence that well-being is socially attractive, whereas empathy supports close relationships. More broadly, these data highlight how an individual's personality relates to the roles that they play in sustaining their community. PMID- 28851836 TI - Putting the network in network interventions. PMID- 28851837 TI - RNA structure inference through chemical mapping after accidental or intentional mutations. AB - Despite the critical roles RNA structures play in regulating gene expression, sequencing-based methods for experimentally determining RNA base pairs have remained inaccurate. Here, we describe a multidimensional chemical-mapping method called "mutate-and-map read out through next-generation sequencing" (M2-seq) that takes advantage of sparsely mutated nucleotides to induce structural perturbations at partner nucleotides and then detects these events through dimethyl sulfate (DMS) probing and mutational profiling. In special cases, fortuitous errors introduced during DNA template preparation and RNA transcription are sufficient to give M2-seq helix signatures; these signals were previously overlooked or mistaken for correlated double-DMS events. When mutations are enhanced through error-prone PCR, in vitro M2-seq experimentally resolves 33 of 68 helices in diverse structured RNAs including ribozyme domains, riboswitch aptamers, and viral RNA domains with a single false positive. These inferences do not require energy minimization algorithms and can be made by either direct visual inspection or by a neural-network-inspired algorithm called M2-net. Measurements on the P4-P6 domain of the Tetrahymena group I ribozyme embedded in Xenopus egg extract demonstrate the ability of M2-seq to detect RNA helices in a complex biological environment. PMID- 28851838 TI - Robust continuous clustering. AB - Clustering is a fundamental procedure in the analysis of scientific data. It is used ubiquitously across the sciences. Despite decades of research, existing clustering algorithms have limited effectiveness in high dimensions and often require tuning parameters for different domains and datasets. We present a clustering algorithm that achieves high accuracy across multiple domains and scales efficiently to high dimensions and large datasets. The presented algorithm optimizes a smooth continuous objective, which is based on robust statistics and allows heavily mixed clusters to be untangled. The continuous nature of the objective also allows clustering to be integrated as a module in end-to-end feature learning pipelines. We demonstrate this by extending the algorithm to perform joint clustering and dimensionality reduction by efficiently optimizing a continuous global objective. The presented approach is evaluated on large datasets of faces, hand-written digits, objects, newswire articles, sensor readings from the Space Shuttle, and protein expression levels. Our method achieves high accuracy across all datasets, outperforming the best prior algorithm by a factor of 3 in average rank. PMID- 28851839 TI - Inhibition of p110delta PI3K prevents inflammatory response and restenosis after artery injury. AB - Inflammatory cells play key roles in restenosis upon vascular surgical procedures such as bypass grafts, angioplasty and stent deployment but the molecular mechanisms by which these cells affect restenosis remain unclear. The p110delta isoform of phosphoinositide 3-kinase (PI3K) is mainly expressed in white blood cells. Here, we have investigated whether p110delta PI3K is involved in the pathogenesis of restenosis in a mouse model of carotid injury, which mimics the damage following arterial grafts. We used mice in which p110delta kinase activity has been disabled by a knockin (KI) point mutation in its ATP-binding site (p110deltaD910A/D910A PI3K mice). Wild-type (WT) and p110deltaD910A/D910A mice were subjected to longitudinal carotid injury. At 14 and 30 days after carotid injury, mice with inactive p110delta showed strongly decreased infiltration of inflammatory cells (including T lymphocytes and macrophages) and vascular smooth muscle cells (VSMCs), compared with WT mice. Likewise, PI-3065, a p110delta selective PI3K inhibitor, almost completely prevented restenosis after artery injury. Our data showed that p110delta PI3K plays a main role in promoting neointimal thickening and inflammatory processes during vascular stenosis, with its inhibition providing significant reduction in restenosis following carotid injury. p110delta-selective inhibitors, recently approved for the treatment of human B-cell malignancies, therefore, present a new therapeutic opportunity to prevent the restenosis upon artery injury. PMID- 28851841 TI - Backbone cyclization of analgesic conotoxin GeXIVA facilitates direct folding of the ribbon isomer. AB - Conotoxin GeXIVA inhibits the alpha9alpha10 nicotinic acetylcholine receptor (nAChR) and is analgesic in animal models of pain. alpha-Conotoxins have four cysteines that can have three possible disulfide connectivities: globular (CysI CysIII and CysII-CysIV), ribbon (CysI-CysIV and CysII-CysIII), or bead (CysI CysII and CysIII-CysIV). Native alpha-conotoxins preferably adopt the globular connectivity, and previous studies of alpha-conotoxins have focused on the globular isomers as the ribbon and bead isomers typically have lower potency at nAChRs than the globular form. A recent report showed that the bead and ribbon isomers of GeXIVA are more potent than the globular isomer, with low nanomolar half-maximal inhibitory concentrations (IC50). Despite this high potency, the therapeutic potential of GeXIVA is limited, because like most peptides, it is susceptible to proteolytic degradation and is challenging to synthesize in high yield. Here we used backbone cyclization as a strategy to improve the folding yield as well as increase the serum stability of ribbon GeXIVA while preserving activity at the alpha9alpha10 nAChR. Specifically, cyclization of ribbon GeXIVA with a two-residue linker maintained the biological activity at the human alpha9alpha10 nAChR and improved stability in human serum. Short linkers led to selective formation of the ribbon disulfide isomer without requiring orthogonal protection. Overall, this study highlights the value of backbone cyclization in directing folding, improving yields, and stabilizing conotoxins with therapeutic potential. PMID- 28851842 TI - A chemical compound inhibiting the Aha1-Hsp90 chaperone complex. AB - The eukaryotic Hsp90 chaperone machinery comprises many co-chaperones and regulates the conformation of hundreds of cytosolic client proteins. Therefore, it is not surprising that the Hsp90 machinery has become an attractive therapeutic target for diseases such as cancer. The compounds used so far to target this machinery affect the entire Hsp90 system. However, it would be desirable to achieve a more selective targeting of Hsp90-co-chaperone complexes. To test this concept, in this-proof-of-principle study, we screened for modulators of the interaction between Hsp90 and its co-chaperone Aha1, which accelerates the ATPase activity of Hsp90. A FRET-based assay that monitored Aha1 binding to Hsp90 enabled identification of several chemical compounds modulating the effect of Aha1 on Hsp90 activity. We found that one of these inhibitors can abrogate the Aha1-induced ATPase stimulation of Hsp90 without significantly affecting Hsp90 ATPase activity in the absence of Aha1. NMR spectroscopy revealed that this inhibitory compound binds the N-terminal domain of Hsp90 close to its ATP-binding site and overlapping with a transient Aha1-interaction site. We also noted that this inhibitor does not dissociate the Aha1-Hsp90 complex but prevents the specific interaction with the N-terminal domain of Hsp90 required for catalysis. In consequence, the inhibitor affected the activation and processing of Hsp90-Aha1-dependent client proteins in vivo We conclude that it is possible to abrogate a specific co-chaperone function of Hsp90 without inhibiting the entire Hsp90 machinery. This concept may also hold true for other co-chaperones of Hsp90. PMID- 28851843 TI - Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal fosA Gene. AB - Fosfomycin is a decades-old antibiotic which is being revisited because of its perceived activity against many extensively drug-resistant Gram-negative pathogens. FosA proteins are Mn2+ and K+-dependent glutathione S-transferases which confer fosfomycin resistance in Gram-negative bacteria by conjugation of glutathione to the antibiotic. Plasmid-borne fosA variants have been reported in fosfomycin-resistant Escherichia coli strains. However, the prevalence and distribution of fosA in other Gram-negative bacteria are not known. We systematically surveyed the presence of fosA in Gram-negative bacteria in over 18,000 published genomes from 18 Gram-negative species and investigated their contribution to fosfomycin resistance. We show that FosA homologues are present in the majority of genomes in some species (e.g., Klebsiella spp., Enterobacter spp., Serratia marcescens, and Pseudomonas aeruginosa), whereas they are largely absent in others (e.g., E. coli, Acinetobacter baumannii, and Burkholderia cepacia). FosA proteins in different bacterial pathogens are highly divergent, but key amino acid residues in the active site are conserved. Chromosomal fosA genes conferred high-level fosfomycin resistance when expressed in E. coli, and deletion of chromosomal fosA in S. marcescens eliminated fosfomycin resistance. Our results indicate that FosA is encoded by clinically relevant Gram-negative species and contributes to intrinsic fosfomycin resistance.IMPORTANCE There is a critical need to identify alternate approaches to treat infections caused by extensively drug-resistant (XDR) Gram-negative bacteria. Fosfomycin is an old antibiotic which is routinely used for the treatment of urinary tract infections, although there is substantial interest in expanding its use to systemic infections caused by XDR Gram-negative bacteria. In this study, we show that fosA genes, which encode dimeric Mn2+- and K+-dependent glutathione S-transferase, are widely distributed in the genomes of Gram-negative bacteria-particularly those belonging to the family Enterobacteriaceae-and confer fosfomycin resistance. This finding suggests that chromosomally located fosA genes represent a vast reservoir of fosfomycin resistance determinants that may be transferred to E. coli Furthermore, they suggest that inhibition of FosA activity may provide a viable strategy to potentiate the activity of fosfomycin against XDR Gram-negative bacteria. PMID- 28851844 TI - The New Xpert MTB/RIF Ultra: Improving Detection of Mycobacterium tuberculosis and Resistance to Rifampin in an Assay Suitable for Point-of-Care Testing. AB - The Xpert MTB/RIF assay (Xpert) is a rapid test for tuberculosis (TB) and rifampin resistance (RIF-R) suitable for point-of-care testing. However, it has decreased sensitivity in smear-negative sputum, and false identification of RIF-R occasionally occurs. We developed the Xpert MTB/RIF Ultra assay (Ultra) to improve performance. Ultra and Xpert limits of detection (LOD), dynamic ranges, and RIF-R rpoB mutation detection were tested on Mycobacterium tuberculosis DNA or sputum samples spiked with known numbers of M. tuberculosis H37Rv or Mycobacterium bovis BCG CFU. Frozen and prospectively collected clinical samples from patients suspected of having TB, with and without culture-confirmed TB, were also tested. For M. tuberculosis H37Rv, the LOD was 15.6 CFU/ml of sputum for Ultra versus 112.6 CFU/ml of sputum for Xpert, and for M. bovis BCG, it was 143.4 CFU/ml of sputum for Ultra versus 344 CFU/ml of sputum for Xpert. Ultra resulted in no false-positive RIF-R specimens, while Xpert resulted in two false-positive RIF-R specimens. All RIF-R-associated M. tuberculosis rpoB mutations tested were identified by Ultra. Testing on clinical sputum samples, Ultra versus Xpert, resulted in an overall sensitivity of 87.5% (95% confidence interval [CI], 82.1, 91.7) versus 81.0% (95% CI, 74.9, 86.2) and a sensitivity on sputum smear negative samples of 78.9% (95% CI, 70.0, 86.1) versus 66.1% (95% CI, 56.4, 74.9). Both tests had a specificity of 98.7% (95% CI, 93.0, 100), and both had comparable accuracies for detection of RIF-R in these samples. Ultra should significantly improve TB detection, especially in patients with paucibacillary disease, and may provide more-reliable RIF-R detection.IMPORTANCE The Xpert MTB/RIF assay (Xpert), the first point-of-care assay for tuberculosis (TB), was endorsed by the World Health Organization in December 2010. Since then, 23 million Xpert tests have been procured in 130 countries. Although Xpert showed high overall sensitivity and specificity with pulmonary samples, its sensitivity has been lower with smear-negative pulmonary samples and extrapulmonary samples. In addition, the prediction of rifampin resistance (RIF-R) in paucibacillary samples and for a few rpoB mutations has resulted in both false-positive and false-negative results. The present study is the first demonstration of the design features and operational characteristics of an improved Xpert Ultra assay. This study also shows that the Ultra format overcomes many of the known shortcomings of Xpert. The new assay should significantly improve TB detection, especially in patients with paucibacillary disease, and provide more-reliable detection of RIF-R. PMID- 28851845 TI - Inhibition of Amebic Lysosomal Acidification Blocks Amebic Trogocytosis and Cell Killing. AB - Entamoeba histolytica ingests fragments of live host cells in a nibbling-like process termed amebic trogocytosis. Amebic trogocytosis is required for cell killing and contributes to tissue invasion, which is a hallmark of invasive amebic colitis. Work done prior to the discovery of amebic trogocytosis showed that acid vesicles are required for amebic cytotoxicity. In the present study, we show that acidified lysosomes are required for amebic trogocytosis and cell killing. Interference with lysosome acidification using ammonium chloride, a weak base, or concanamycin A, a vacuolar H+ ATPase inhibitor, decreased amebic trogocytosis and amebic cytotoxicity. Our data suggest that the inhibitors do not impair the ingestion of an initial fragment but rather block continued trogocytosis and the ingestion of multiple fragments. The acidification inhibitors also decreased phagocytosis, but not fluid-phase endocytosis. These data suggest that amebic lysosomes play a crucial role in amebic trogocytosis, phagocytosis, and cell killing.IMPORTANCEE. histolytica is a protozoan parasite that is prevalent in low-income countries, where it causes potentially fatal diarrhea, dysentery, and liver abscesses. Tissue destruction is a hallmark of invasive E. histolytica infection. The parasite is highly cytotoxic to a wide range of human cells, and parasite cytotoxic activity is likely to drive tissue destruction. E. histolytica is able to kill human cells through amebic trogocytosis. This process also contributes to tissue invasion. Trogocytosis has been observed in other organisms; however, little is known about the mechanism in any system. We show that interference with lysosomal acidification impairs amebic trogocytosis, phagocytosis, and cell killing, indicating that amebic lysosomes are critically important for these processes. PMID- 28851846 TI - Cardiolipin Synthesis and Outer Membrane Localization Are Required for Shigella flexneri Virulence. AB - Cardiolipin, an anionic phospholipid that resides at the poles of the inner and outer membranes, is synthesized primarily by the putative cardiolipin synthase ClsA in Shigella flexneri An S. flexneri clsA mutant had no cardiolipin detected within its membrane, grew normally in vitro, and invaded cultured epithelial cells, but it failed to form plaques in epithelial cell monolayers, indicating that cardiolipin is required for virulence. The clsA mutant was initially motile within the host cell cytoplasm but formed filaments and lost motility during replication and failed to spread efficiently to neighboring cells. Mutation of pbgA, which encodes the transporter for cardiolipin from the inner membrane to the outer membrane, also resulted in loss of plaque formation. The S. flexneri pbgA mutant had normal levels of cardiolipin in the inner membrane, but no cardiolipin was detected in the outer membrane. The pbgA mutant invaded and replicated normally within cultured epithelial cells but failed to localize the actin polymerization protein IcsA properly on the bacterial surface and was unable to spread to neighboring cells. The clsA mutant, but not the pbgA mutant, had increased phosphatidylglycerol in the outer membrane. This appeared to compensate partially for the loss of cardiolipin in the outer membrane, allowing some IcsA localization in the outer membrane of the clsA mutant. We propose a dual function for cardiolipin in S. flexneri pathogenesis. In the inner membrane, cardiolipin is essential for proper cell division during intracellular growth. In the outer membrane, cardiolipin facilitates proper presentation of IcsA on the bacterial surface.IMPORTANCE The human pathogen Shigella flexneri causes bacterial dysentery by invading colonic epithelial cells, rapidly multiplying within their cytoplasm, and then spreading intercellularly to neighboring cells. Worldwide, Shigella spp. infect hundreds of millions of people annually, with fatality rates up to 15%. Antibiotic treatment of Shigella infections is compromised by increasing antibiotic resistance, and there is no approved vaccine to prevent future infections. This has created a growing need to understand Shigella pathogenesis and identify new targets for antimicrobial therapeutics. Here we show a previously unknown role of phospholipids in S. flexneri pathogenesis. We demonstrate that cardiolipin is required in the outer membrane for proper surface localization of IcsA and in the inner membrane for cell division during growth in the host cell cytoplasm. PMID- 28851847 TI - Rotavirus NSP1 Requires Casein Kinase II-Mediated Phosphorylation for Hijacking of Cullin-RING Ligases. AB - The rotavirus nonstructural protein NSP1 repurposes cullin-RING E3 ubiquitin ligases (CRLs) to antagonize innate immune responses. By functioning as substrate adaptors of hijacked CRLs, NSP1 causes ubiquitination and proteasomal degradation of host proteins that are essential for expression of interferon (IFN) and IFN stimulated gene products. The target of most human and porcine rotaviruses is the beta-transducin repeat-containing protein (beta-TrCP), a regulator of NF-kappaB activation. beta-TrCP recognizes a phosphorylated degron (DSGPhiXS) present in the inhibitor of NF-kappaB (IkappaB); phosphorylation of the IkappaB degron is mediated by IkappaB kinase (IKK). Because NSP1 contains a C-terminal IkappaB-like degron (ILD; DSGXS) that recruits beta-TrCP, we investigated whether the NSP1 ILD is similarly activated by phosphorylation and whether this modification is required to trigger the incorporation of NSP1 into CRLs. Based on mutagenesis and phosphatase treatment studies, we found that both serine residues of the NSP1 ILD are phosphorylated, a pattern mimicking phosphorylation of IkappaB. A three pronged approach using small-molecule inhibitors, small interfering RNAs, and mutagenesis demonstrated that NSP1 phosphorylation is mediated by the constitutively active casein kinase II (CKII), rather than IKK. In coimmunoprecipitation assays, we found that this modification was essential for NSP1 recruitment of beta-TrCP and induced changes involving the NSP1 N-terminal RING motif that allowed formation of Cul3-NSP1 complexes. Taken together, our results indicate a highly regulated stepwise process in the formation of NSP1 Cul3 CRLs that is initiated by CKII phosphorylation of NSP1, followed by NSP1 recruitment of beta-TrCP and ending with incorporation of the NSP1-beta-TrCP complex into the CRL via interactions dependent on the highly conserved NSP1 RING motif.IMPORTANCE Rotavirus is a segmented double-stranded RNA virus that causes severe diarrhea in young children. A primary mechanism used by the virus to inhibit host innate immune responses is to hijack cellular cullin-RING E3 ubiquitin ligases (CRLs) and redirect their targeting activity to the degradation of cellular proteins crucial for interferon expression. This task is accomplished through the rotavirus nonstructural protein NSP1, which incorporates itself into a CRL and serves as a substrate recognition subunit. The substrate recognized by the NSP1 of many human and porcine rotaviruses is beta-TrCP, a protein that regulates the transcription factor NF-kappaB. In this study, we show that formation of NSP1 CRLs is a highly regulated stepwise process initiated by CKII phosphorylation of the beta-TrCP recognition motif in NSP1. This modification triggers recruitment of the beta-TrCP substrate and induces subsequent changes in a highly conserved NSP1 RING domain that allow anchoring of the NSP1-beta-TrCP complex to a cullin scaffold. PMID- 28851848 TI - Genome-Wide Spectra of Transcription Insertions and Deletions Reveal That Slippage Depends on RNA:DNA Hybrid Complementarity. AB - Advances in sequencing technologies have enabled direct quantification of genome wide errors that occur during RNA transcription. These errors occur at rates that are orders of magnitude higher than rates during DNA replication, but due to technical difficulties such measurements have been limited to single-base substitutions and have not yet quantified the scope of transcription insertions and deletions. Previous reporter gene assay findings suggested that transcription indels are produced exclusively by elongation complex slippage at homopolymeric runs, so we enumerated indels across the protein-coding transcriptomes of Escherichia coli and Buchnera aphidicola, which differ widely in their genomic base compositions and incidence of repeat regions. As anticipated from prior assays, transcription insertions prevailed in homopolymeric runs of A and T; however, transcription deletions arose in much more complex sequences and were rarely associated with homopolymeric runs. By reconstructing the relocated positions of the elongation complex as inferred from the sequences inserted or deleted during transcription, we show that continuation of transcription after slippage hinges on the degree of nucleotide complementarity within the RNA:DNA hybrid at the new DNA template location.IMPORTANCE The high level of mistakes generated during transcription can result in the accumulation of malfunctioning and misfolded proteins which can alter global gene regulation and in the expenditure of energy to degrade these nonfunctional proteins. The transcriptome wide occurrence of base substitutions has been elucidated in bacteria, but information on transcription insertions and deletions-errors that potentially have more dire effects on protein function-is limited to reporter gene constructs. Here, we capture the transcriptome-wide spectrum of insertions and deletions in Escherichia coli and Buchnera aphidicola and show that they occur at rates approaching those of base substitutions. Knowledge of the full extent of sequences subject to transcription indels supports a new model of bacterial transcription slippage, one that relies on the number of complementary bases between the transcript and the DNA template to which it slipped. PMID- 28851849 TI - Functional Constraints on Replacing an Essential Gene with Its Ancient and Modern Homologs. AB - Genes encoding proteins that carry out essential informational tasks in the cell, in particular where multiple interaction partners are involved, are less likely to be transferable to a foreign organism. Here, we investigated the constraints on transfer of a gene encoding a highly conserved informational protein, translation elongation factor Tu (EF-Tu), by systematically replacing the endogenous tufA gene in the Escherichia coli genome with its extant and ancestral homologs. The extant homologs represented tuf variants from both near and distant homologous organisms. The ancestral homologs represented phylogenetically resurrected tuf sequences dating from 0.7 to 3.6 billion years ago (bya). Our results demonstrate that all of the foreign tuf genes are transferable to the E. coli genome, provided that an additional copy of the EF-Tu gene, tufB, remains present in the E. coli genome. However, when the tufB gene was removed, only the variants obtained from the gammaproteobacterial family (extant and ancestral) supported growth which demonstrates the limited functional interchangeability of E. coli tuf with its homologs. Relative bacterial fitness correlated with the evolutionary distance of the extant tuf homologs inserted into the E. coli genome. This reduced fitness was associated with reduced levels of EF-Tu and reduced rates of protein synthesis. Increasing the expression of tuf partially ameliorated these fitness costs. In summary, our analysis suggests that the functional conservation of protein activity, the amount of protein expressed, and its network connectivity act to constrain the successful transfer of this essential gene into foreign bacteria.IMPORTANCE Horizontal gene transfer (HGT) is a fundamental driving force in bacterial evolution. However, whether essential genes can be acquired by HGT and whether they can be acquired from distant organisms are very poorly understood. By systematically replacing tuf with ancestral homologs and homologs from distantly related organisms, we investigated the constraints on HGT of a highly conserved gene with multiple interaction partners. The ancestral homologs represented phylogenetically resurrected tuf sequences dating from 0.7 to 3.6 bya. Only variants obtained from the gammaproteobacterial family (extant and ancestral) supported growth, demonstrating the limited functional interchangeability of E. coli tuf with its homologs. Our analysis suggests that the functional conservation of protein activity, the amount of protein expressed, and its network connectivity act to constrain the successful transfer of this essential gene into foreign bacteria. PMID- 28851850 TI - Toxoplasma gondii Requires Glycogen Phosphorylase for Balancing Amylopectin Storage and for Efficient Production of Brain Cysts. AB - In immunocompromised hosts, latent infection with Toxoplasma gondii can reactivate from tissue cysts, leading to encephalitis. A characteristic of T. gondii bradyzoites in tissue cysts is the presence of amylopectin granules. The regulatory mechanisms and role of amylopectin accumulation in this organism are not fully understood. The T. gondii genome encodes a putative glycogen phosphorylase (TgGP), and mutants were constructed to manipulate the activity of TgGP and to evaluate the function of TgGP in amylopectin storage. Both a stop codon mutant (Pru/TgGPS25stop [expressing a Ser-to-stop codon change at position 25 in TgGP]) and a phosphorylation null mutant (Pru/TgGPS25A [expressing a Ser-to Ala change at position 25 in TgGp]) mutated at Ser25 displayed amylopectin accumulation, while the phosphorylation-mimetic mutant (Pru/TgGPS25E [expressing a Ser-to-Glu change at position 25 in TgGp]) had minimal amylopectin accumulation under both tachyzoite and bradyzoite growth conditions. The expression of active TgGPS25S or TgGPS25E restored amylopectin catabolism in Pru/TgGPS25A To understand the relation between GP and calcium-dependent protein kinase 2 (CDPK2), which was recently reported to regulate amylopectin consumption, we knocked out CDPK2 in these mutants. PruDeltacdpk2/TgGPS25E had minimal amylopectin accumulation, whereas the Deltacdpk2 phenotype in the other GP mutants and parental lines displayed amylopectin accumulation. Both the inactive S25A and hyperactive S25E mutant produced brain cysts in infected mice, but the numbers of cysts produced were significantly less than the number produced by the S25S wild-type GP parasite. Complementation that restored amylopectin regulation restored brain cyst production to the control levels seen in infected mice. These data suggest that T. gondii requires tight regulation of amylopectin expression for efficient production of cysts and persistent infections and that GP phosphorylation is a regulatory mechanism involved in amylopectin storage and utilization.IMPORTANCEToxoplasma gondii is an obligate intracellular parasite that causes disease in immune-suppressed individuals, as well as a fetopathy in pregnant women who acquire infection for the first time during pregnancy. This parasite can differentiate between tachyzoites (seen in acute infection) and bradyzoites (seen in latent infection), and this differentiation is associated with disease relapse. A characteristic of bradyzoites is that they contain cytoplasmic amylopectin granules. The regulatory mechanisms and the roles of amylopectin granules during latent infection remain to be elucidated. We have identified a role of T. gondii glycogen phosphorylase (TgGP) in the regulation of starch digestion and a role of posttranslational modification of TgGP, i.e., phosphorylation of Ser25, in the regulation of amylopectin digestion. By manipulating TgGP activity in the parasite with genome editing, we found that the digestion and storage of amylopectin due to TgGP activity are both important for latency in the brain. PMID- 28851851 TI - Multifunctional Involvement of a C2H2 Zinc Finger Protein (PbZfp) in Malaria Transmission, Histone Modification, and Susceptibility to DNA Damage Response. AB - In sexually reproducing organisms, meiosis is an essential step responsible for generation of haploid gametes from diploid somatic cells. The quest for understanding regulatory mechanisms of meiotic recombination in Plasmodium led to identification of a gene encoding a protein that contains 11 copies of C2H2 zinc fingers (ZnF). Reverse genetic approaches were used to create Plasmodium berghei parasites either lacking expression of full-length Plasmodium berghei zinc finger protein (PbZfp) (knockout [KO]) or expressing PbZfp lacking C-terminal zinc finger region (truncated [Trunc]). Mice infected with KO parasites survived two times longer (P < 0.0001) than mice infected with wild-type (WT) parasites. In mosquito transmission experiments, the infectivity of KO and Trunc parasites was severely compromised (>95% oocyst reduction). KO parasites revealed a total lack of trimethylation of histone 3 at several lysine residues (K4, K27, and K36) without any effect on acetylation patterns (H3K9, H3K14, and H4K16). Reduced DNA damage and reduced expression of topoisomerase-like Spo11 in the KO parasites with normal Rad51 expression further suggest a functional role for PbZfp during genetic recombination that involves DNA double-strand break (DSB) formation followed by DNA repair. These finding raise the possibility of some convergent similarities of PbZfp functions to functions of mammalian PRDM9, also a C2H2 ZnF protein with histone 3 lysine 4 (H3K4) methyltransferase activity. These functions include the major role played by the latter in binding recombination hotspots in the genome during meiosis and trimethylation of the associated histones and subsequent chromatin recruitment of topoisomerase-like Spo11 to catalyze DNA DSB formation and DMC1/Rad51-mediated DNA repair and homologous recombination.IMPORTANCE Malaria parasites are haploid throughout their life cycle except for a brief time period when zygotes are produced as a result of fertilization between male and female gametes during transmission through the mosquito vector. The reciprocal recombination events that follow zygote formation ensure orderly segregation of homologous chromosomes during meiosis, creating genetic diversity among offspring. Studies presented in the current manuscript identify a novel C2H2 ZnF-containing protein exhibiting multifunctional roles in parasite virulence, mosquito transmission, and homologous recombination during meiosis. Understanding the transmission biology of malaria will result in the identification of novel targets for transmission-blocking intervention approaches. PMID- 28851852 TI - Long Telomeres Do Not Affect Cellular Fitness in Yeast. AB - Telomeres, the ends of the eukaryotic chromosomes, help to maintain the genome's integrity and thus play important roles in aging and cancer. Telomere length is strictly controlled in all organisms. In humans, telomeres shorten with age, and it has been proposed that telomere shortening may play a causal role in aging. We took advantage of the availability of yeast strains with genetically or physiologically generated differences in telomere length to measure the effect that telomere length may have on cellular growth. By comparing the growth rates affecting telomere length of various yeast mutants we show that there is no correlation between their telomere length and cellular fitness. We also show that wild-type yeast cells carrying extremely long telomeres (~5 times longer than the average) showed no signs of mitotic or meiotic defects, and competition experiments found no differences in growth between strains with normal telomeres and strains with long telomeres. No advantage or disadvantage of cells with long telomeres was detected under stress conditions either. Finally, telomere length had no effect in a chronological life span assay, which measures survival of post mitotic-stage cells. We conclude that extreme telomere length has no effects (positive or negative) on the fitness of yeast cells.IMPORTANCE Telomeres protect the chromosomal ends from fusion, degradation, and unwanted repair. Therefore, telomeres preserve genome stability and cell viability. In humans, telomeres shorten with each cell duplication event and with age. It has thus been proposed that telomere shortening may be responsible for human aging and that elongation of telomeres may be a way to rejuvenate cells and to combat aging. However, it is difficult to prove this hypothesis in human cells. Yeasts are easy to manipulate and have telomeres whose length is strictly maintained. Here we show that yeast cells manipulated to have extremely long telomeres (~5-fold those of normal cells) did not show any improvement or reduction in fitness compared to otherwise identical cells with telomeres of normal length under all the conditions tested. Moreover, an assay that measures cell aging showed no effect of the presence of extremely long telomeres. We thus conclude that extreme telomere length, at least in yeast cells, does not affect cellular fitness, aging, or senescence. PMID- 28851854 TI - Characterization of gelatin and chitosan scaffolds cross-linked by dialdehyde starch addition. AB - In this study the influence of dialdehyde starch addition on the properties of scaffold based on gelatin and chitosan obtained by freeze-drying method was investigated. In addition, the adhesion and proliferation of human osteosarcoma SaOS-2 cells was examined on obtained scaffolds. Chitosan and gelatin were mixed in different weigh ratios (75/25, 50/50, 25/75) with 1, 2 and 5 wt% addition of dialdehyde starch. The obtained scaffolds were subjected to mechanical testing, infrared spectroscopy, swelling measurements, low-pressure porosimetry and zeta potential measurement. Internal material structures were observed by scanning electron microscopy. The results showed that the cross-linking process occurred after the addition of dialdehyde starch and resulted in increased mechanical strength, swelling properties, zeta potential and porosity of studied materials. Attachment of SaOS-2 cells to all modified materials was better compared to unmodified control and proliferation of these cells was markedly increased on modified scaffolds. PMID- 28851853 TI - Translational Repression of the RpoS Antiadapter IraD by CsrA Is Mediated via Translational Coupling to a Short Upstream Open Reading Frame. AB - CsrA is a global regulatory RNA binding protein that has important roles in regulating carbon metabolism, motility, biofilm formation, and numerous other cellular processes. IraD functions as an antiadapter protein that inhibits RssB mediated degradation of RpoS, the general stress response and stationary-phase sigma factor of Escherichia coli Here we identified a novel mechanism in which CsrA represses iraD translation via translational coupling. Expression studies with quantitative reverse transcriptase PCR, Western blotting, and lacZ fusions demonstrated that CsrA represses iraD expression. Gel mobility shift, footprint, and toeprint studies identified four CsrA binding sites in the iraD leader transcript, all of which are far upstream of the iraD ribosome binding site. Computational modeling and RNA structure mapping identified an RNA structure that sequesters the iraD Shine-Dalgarno (SD) sequence. Three open reading frames (ORFs), all of which are translated, were identified in the iraD leader region. Two of these ORFs do not affect iraD expression. However, the translation initiation region of the third ORF contains three of the CsrA binding sites, one of which overlaps its SD sequence. Furthermore, the ORF stop codon overlaps the iraD start codon, a sequence arrangement indicative of translational coupling. In vivo expression and in vitro translation studies with wild-type and mutant reporter fusions demonstrated that bound CsrA directly represses translation initiation of this ORF. We further established that CsrA-dependent repression of iraD translation occurs entirely via translational coupling with this ORF, leading to accelerated iraD mRNA decay.IMPORTANCE CsrA posttranscriptionally represses gene expression associated with stationary-phase bacterial growth, often in opposition to the transcriptional effects of the stationary-phase sigma factor RpoS. We show that CsrA employs a novel regulatory mechanism to repress translation of iraD, which encodes an antiadapter protein that protects RpoS against proteolysis. CsrA binds to four sites in the iraD leader transcript but does not directly occlude ribosome binding to the iraD SD sequence. Instead, CsrA represses translation of a short open reading frame encoded upstream of iraD, causing repression of iraD translation via translational coupling. This finding offers a novel mechanism of gene regulation by the global regulator CsrA, and since RpoS can activate csrA transcription, this also highlights a new negative feedback loop within the complex Csr and RpoS circuitry. PMID- 28851855 TI - Understanding molecular mechanism of improved proliferation and osteogenic potential of human mesenchymal stem cells grown on polyelectrolyte complex derived from non-mulberry silk fibroin and chitosan. AB - The development of engineered bone tissue, as a promising alternative to the conventional bone grafts, is not rewarding yet and remained challenging. Thus, attempts have been made in the present study to synthesize polyelectrolyte complex (PEC) scaffolds by blending of chitosan (CS) to silk fibroin (SF) derived from non-mulberry silkworm (Antheraea pernyi) at three different pH (5.0, 6.0, and 7.0), and characterize in terms of morphology, ultrastructure and mechanical properties with SEM, FTIR, XRD and tensile strength analyses. The prepared PEC scaffolds showed mean pore size of 130 um as revealed by SEM analysis and comparatively higher compressive strength. The findings of in vitro cytocompatibility, in vivo biocompatibility and osteogenic markers (genes/proteins) analysis suggested that the PECs blended at pH 7.0 showed greater stability and enhanced growth and osteogenic differentiation capability of human mesenchymal stem cells (MSCs). To aid our understanding of protein polyion binding mechanisms, we employed a molecular docking and simulation study of SF macrodomains and CS oligomer using Schrodinger 14 and GROMACS (GROningen Machine for Chemical Simulations) software. The study involved analytical techniques for macromolecular solution characterization and theoretical simulations based on molecular dynamics. The computational studies confirmed the presence of integral RGD sequence that played a vital role in superior cell attachment, proliferation and osteogenic differentiation of MSCs grown on the developed SF-CS PEC scaffolds. PMID- 28851856 TI - Tendon involvement in gout: utility of ultrasonography. PMID- 28851857 TI - Effect of Probiotic Lactobacilli on the Growth of Streptococcus Mutans and Multispecies Biofilms Isolated from Children with Active Caries. AB - BACKGROUND The purpose of this investigation was to evaluate the effect of probiotic lactobacilli on Streptococcus mutans (MS) and multispecies biofilms isolated from children with severe caries. MATERIAL AND METHODS Twenty children with active caries (DMFS >=6) were selected as the experimental group and Streptococcus mutans (MS) were isolated from their saliva. After identification the MS strains were mixed with lactobacilli at 37 degrees C, following which viable MS colonies were counted. At the same time dental plaques from the children were mixed with lactobacilli in vitro to form biofilms, and the population of nine common strains in the biofilms was enumerated after 24 hours of growth. RESULTS Lactobacillus casei Shirota, L. casei LC01, L. plantarum ST III and L. paracasei LPC37 all had strong inhibitory effects on the majority the MS isolated from children with active caries, with the inhibition rate reaching approximately 70-90% (p<0.05). L. casei Shirota, L. casei LC01, L. plantarum ST III, L. paracasei LPC37 also significantly reduced the numbers of MS, Streptococcus spp., S. sanguinis and total bacteria in mixed biofilms compared with the control group (p<0.05). CONCLUSIONS The four strains of lactobacilli were able to inhibit the growth of Streptococcus mutans and had effects on the composition of bacterial biofilms in vitro. Ingestion of probiotics may be a promising method of caries prevention. PMID- 28851858 TI - Matrix degradability controls multicellularity of 3D cell migration. AB - A major challenge in tissue engineering is the development of materials that can support angiogenesis, wherein endothelial cells from existing vasculature invade the surrounding matrix to form new vascular structures. To identify material properties that impact angiogenesis, here we have developed an in vitro model whereby molded tubular channels inside a synthetic hydrogel are seeded with endothelial cells and subjected to chemokine gradients within a microfluidic device. To accomplish precision molding of hydrogels and successful integration with microfluidics, we developed a class of hydrogels that could be macromolded and micromolded with high shape and size fidelity by eliminating swelling after polymerization. Using this material, we demonstrate that matrix degradability switches three-dimensional endothelial cell invasion between two distinct modes: single-cell migration and the multicellular, strand-like invasion required for angiogenesis. The ability to incorporate these tunable hydrogels into geometrically constrained settings will enable a wide range of previously inaccessible biomedical applications.The fabrication of vascularized 3D tissues requires an understanding of how material properties govern endothelial cell invasion into the surrounding matrix. Here the authors integrate a non-swelling synthetic hydrogel with a microfluidic device to study chemokine gradient-driven angiogenic sprouting and find that matrix degradability modulates the collectivity of cell migration. PMID- 28851859 TI - Regulation of Orai1/STIM1 mediated ICRAC by intracellular pH. AB - Ca2+ release activated Ca2+ (CRAC) channels composed of two cellular proteins, Ca2+-sensing stromal interaction molecule 1 (STIM1) and pore-forming Orai1, are the main mediators of the Ca2+ entry pathway activated in response to depletion of intracellular Ca2+ stores. Previously it has been shown that the amplitude of CRAC current (ICRAC) strongly depends on extracellular and intracellular pH. Here we investigate the intracellular pH (pHi) dependence of ICRAC mediated by Orai1 and STIM1ectopically expressed in HEK293 cells. The results indicate that pHi affects not only the amplitude of the current, but also Ca2+ dependent gating of CRAC channels. Intracellular acidification changes the kinetics of ICRAC, introducing prominent re-activation component in the currents recorded in response to voltage steps to strongly negative potentials. ICRAC with similar kinetics can be observed at normal pHi if the expression levels of Orai1 are increased, relative to the expression levels of STIM1. Mutations in the STIM1 inactivation domain significantly diminish the dependence of ICRAC kinetics on pHi, but have no effect on pHi dependence of ICRAC amplitude, implying that more than one mechanism is involved in CRAC channel regulation by intracellular pH. PMID- 28851860 TI - A qualitative study of GP, nurse and practice manager views on using targeted case-finding to identify patients with COPD in primary care. AB - : 'Finding the missing millions' with chronic obstructive pulmonary disease became part of the Department of Health strategy for England in 2010. Targeted case-finding within primary care is one potential pro-active strategy, but currently little is known about the views of healthcare professionals on this approach. In this study, 36 healthcare professionals (12 GPs, 14 nurses, and 10 practice managers) from 34 UK practices participated in semi-structured telephone interviews about targeted case-finding. Interviews followed an interview guide, were audio-recorded, transcribed verbatim, coded and analysed using 'Framework Approach'. Most of those interviewed practiced opportunistic case-finding. The main perceived barriers to wider case-finding programmes were the resource implications associated with running such programmes and identifying more chronic obstructive pulmonary disease patients. Financial incentives, support from specialist clinicians, and comprehensive guidance were viewed as facilitators. While targeted case-finding is conceptually accepted by primary care staff, scepticism surrounding (1) the value of identifying those with mild disease and (2) the availability of effective targeted case-finding methods, may lead some to favour an opportunistic approach. Key concerns were a lack of unequivocal evidence for the relative benefits vs. disadvantages of diagnosing patients earlier, and resource constraints in an already over-burdened system. Barriers to practical implementation of case-finding studies may be addressed with financial, human and educational resources, such as additional staff to undertake searches and perform spirometry tests, and practical and educational support from specialist teams. CHRONIC OBSTRUCTIVE PULMONARY DISEASE: SUPPORT NEEDED TO IDENTIFY THOSE UNDIAGNOSED: Additional staff and resources would facilitate targeted searches for patients showing symptoms of early-stage chronic lung disease. Chronic obstructive pulmonary disease (COPD) costs the UK economy billions of pounds each year, yet disparate symptoms mean patients aren't always diagnosed in the early, treatable stages of the disease. Recent guidelines suggest introducing 'targeted case-finding', where symptomatic patients with known risk factors are identified and approached for testing by doctors. Rachael Summers and colleagues at the University of Southampton analyzed the opinions of healthcare professionals on implementing targeted case-finding in primary care. While most of the 36 professionals interviewed agreed that diagnosing COPD earlier had clear benefits, concerns were raised regarding negative patient responses and increased stress for patients, alongside the added strain on already stretched resources. Employing independent staff and enhancing resources may facilitate such a program. PMID- 28851862 TI - Ultrafast carrier thermalization in lead iodide perovskite probed with two dimensional electronic spectroscopy. AB - In band-like semiconductors, charge carriers form a thermal energy distribution rapidly after optical excitation. In hybrid perovskites, the cooling of such thermal carrier distributions occurs on timescales of about 300 fs via carrier phonon scattering. However, the initial build-up of the thermal distribution proved difficult to resolve with pump-probe techniques due to the requirement of high resolution, both in time and pump energy. Here, we use two-dimensional electronic spectroscopy with sub-10 fs resolution to directly observe the carrier interactions that lead to a thermal carrier distribution. We find that thermalization occurs dominantly via carrier-carrier scattering under the investigated fluences and report the dependence of carrier scattering rates on excess energy and carrier density. We extract characteristic carrier thermalization times from below 10 to 85 fs. These values allow for mobilities of 500 cm2 V-1 s-1 at carrier densities lower than 2 * 1019 cm-3 and limit the time for carrier extraction in hot carrier solar cells.Carrier-carrier scattering rates determine the fundamental limits of carrier transport and electronic coherence. Using two-dimensional electronic spectroscopy with sub-10 fs resolution, Richter and Branchi et al. extract carrier thermalization times of 10 to 85 fs in hybrid perovskites. PMID- 28851861 TI - Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. AB - Emerging data demonstrate homologous recombination (HR) defects in castration resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP mediated repair pathways are upregulated in prostate cancer following androgen deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer. PMID- 28851863 TI - Probing the crystallographic orientation of two-dimensional atomic crystals with supramolecular self-assembly. AB - Probing the crystallographic orientation of two-dimensional (2D) materials is essential to understand and engineer their properties. However, the nondestructive identification of the lattice orientations of various 2D materials remains a challenge due to their very thin nature. Here, we identify the crystallographic structures of various 2D atomic crystals using molecules as probes by utilizing orientation-dependent molecule-substrate interactions. We discover that the periodic atomic packing of 2D materials guides oleamide molecules to assemble into quasi-one-dimensional nanoribbons with specific alignments which precisely indicate the lattice orientations of the underlying materials. Using oleamide molecules as probes, we successfully identify the crystallographic orientations of ~12 different 2D materials without degrading their intrinsic properties. Our findings allow for the nondestructive identification of the lattice structure of various 2D atomic crystals and shed light on the functionalization of these 2D materials with supramolecular assembly.Identifying the crystallographic orientations of 2D materials is important, but methods to do so are typically destructive. Here, the authors show that the orientational dependency of self-assembled nanoribbons of oleamide molecules can be used to non-invasively probe the lattice orientations of various 2D substrates. PMID- 28851864 TI - Improved split fluorescent proteins for endogenous protein labeling. AB - Self-complementing split fluorescent proteins (FPs) have been widely used for protein labeling, visualization of subcellular protein localization, and detection of cell-cell contact. To expand this toolset, we have developed a screening strategy for the direct engineering of self-complementing split FPs. Via this strategy, we have generated a yellow-green split-mNeonGreen21-10/11 that improves the ratio of complemented signal to the background of FP1-10-expressing cells compared to the commonly used split GFP1-10/11; as well as a 10-fold brighter red-colored split-sfCherry21-10/11. Based on split sfCherry2, we have engineered a photoactivatable variant that enables single-molecule localization based super-resolution microscopy. We have demonstrated dual-color endogenous protein tagging with sfCherry211 and GFP11, revealing that endoplasmic reticulum translocon complex Sec61B has reduced abundance in certain peripheral tubules. These new split FPs not only offer multiple colors for imaging interaction networks of endogenous proteins, but also hold the potential to provide orthogonal handles for biochemical isolation of native protein complexes.Split fluorescent proteins (FPs) have been widely used to visualise proteins in cells. Here the authors develop a screen for engineering new split FPs, and report a yellow-green split-mNeonGreen2 with reduced background, a red split-sfCherry2 for multicolour labeling, and its photoactivatable variant for super-resolution use. PMID- 28851865 TI - Comparative genomics of Australian and international isolates of Salmonella Typhimurium: correlation of core genome evolution with CRISPR and prophage profiles. AB - Salmonella enterica subsp enterica serovar Typhimurium (S. Typhimurium) is a serovar with broad host range. To determine the genomic diversity of S. Typhimurium, we sequenced 39 isolates (37 Australian and 2 UK isolates) representing 14 Repeats Groups (RGs) determined primarily by clustered regularly interspaced short palindromic repeats (CRISPR). Analysis of single nucleotide polymorphisms (SNPs) among the 39 isolates yielded an average of 1,232 SNPs per isolate, ranging from 128 SNPs to 11,339 SNPs relative to the reference strain LT2. Phylogenetic analysis of the 39 isolates together with 66 publicly available genomes divided the 105 isolates into five clades and 19 lineages, with the majority of the isolates belonging to clades I and II. The composition of CRISPR profiles correlated well with the lineages, showing progressive deletion and occasional duplication of spacers. Prophage genes contributed nearly a quarter of the S. Typhimurium accessory genome. Prophage profiles were found to be correlated with lineages and CRISPR profiles. Three new variants of HP2-like P2 prophage, several new variants of P22 prophage and a plasmid-like genomic island StmGI_0323 were found. This study presents evidence of horizontal transfer from other serovars or species and provides a broader understanding of the global genomic diversity of S. Typhimurium. PMID- 28851866 TI - Agricultural pesticide use and adverse birth outcomes in the San Joaquin Valley of California. AB - Virtually all agricultural communities worldwide are exposed to agricultural pesticides. Yet, the health consequences of such exposure are poorly understood, and the scientific literature remains ambiguous. Using individual birth and demographic characteristics for over 500 000 birth observations between 1997-2011 in the agriculturally dominated San Joaquin Valley, California, we statistically investigate if residential agricultural pesticide exposure during gestation, by trimester, and by toxicity influences birth weight, gestational length, or birth abnormalities. Overall, our analysis indicates that agricultural pesticide exposure increases adverse birth outcomes by 5-9%, but only among the population exposed to very high quantities of pesticides (e.g., top 5th percentile, i.e., ~4200 kg applied over gestation). Thus, policies and interventions targeting the extreme right tail of the pesticide distribution near human habitation could largely eliminate the adverse birth outcomes associated with agricultural pesticide exposure documented in this study.The health consequences of exposure to pesticides are uncertain and subject to much debate. Here, the effect of exposure during pregnancy is investigated in an agriculturally dominated residential area, showing that an increase in adverse birth outcomes is observed with very high levels of pesticide exposure. PMID- 28851867 TI - A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA (RTA-408) is protective against EAE. AB - Tolerogenic dendritic cells (DCs) have emerged as relevant clinical targets for the treatment of multiple sclerosis and other autoimmune disorders. However, the pathways essential for conferring the tolerizing DC phenotype and optimal methods for their induction remain an intense area of research. Triterpenoids are a class of small molecules with potent immunomodulatory activity linked to activation of Nrf2 target genes, and can also suppress the manifestations of experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that DCs are a principal target of the immune modulating activity of triterpenoids in the context of EAE. Exposure of DCs to the new class of triterpenoid CDDO-DFPA (RTA-408) results in the induction of HO-1, TGF-beta, and IL-10, as well as the repression of NF kappaB, EDN-1 and pro-inflammatory cytokines IL-6, IL-12, and TNFalpha. CDDO-DFPA exposed DCs retained expression of surface ligands and capacity for antigen uptake but were impaired to induce Th1 and Th17 cells. TGF-beta was identified as the factor mediating suppression of T cell proliferation by CDDO-DFPA pretreated DCs, which failed to passively induce EAE. These findings demonstrate the potential therapeutic utility of CDDO-DFPA in the treatment and prevention of autoimmune disorders, and its capacity to induce tolerance via modulation of the DC phenotype. PMID- 28851868 TI - An allosteric ligand-binding site in the extracellular cap of K2P channels. AB - Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are thus potential drug targets for treating diseases. Here, we identify N-(4 cholorphenyl)-N-(2-(3,4-dihydrosioquinolin-2(1H)-yl)-2 oxoethyl)methanesulfonamide (TKDC) as an inhibitor of the TREK subfamily, including TREK-1, TREK-2 and TRAAK channels. Using TKDC as a chemical probe, a study combining computations, mutagenesis and electrophysiology reveals a K2P allosteric ligand-binding site located in the extracellular cap of the channels. Molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway. Using virtual screening approach, we identify other inhibitors targeting the extracellular allosteric ligand-binding site of these channels. Overall, our results suggest that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins.TREKs are members of the two-pore domain potassium (K2P) channels, being important clinical targets. Here the authors identify inhibitors of K2P that bind to an allosteric site located in their extracellular cap, suggesting that it might be a promising drug target for these channels. PMID- 28851869 TI - Multifunctional quantum dot DNA hydrogels. AB - Biotemplated nanomaterials offer versatile functionality for multimodal imaging, biosensing, and drug delivery. There remains an unmet need for traceable and biocompatible nanomaterials that can be synthesized in a precisely controllable manner. Here, we report self-assembled quantum dot DNA hydrogels that exhibit both size and spectral tunability. We successfully incorporate DNA-templated quantum dots with high quantum yield, long-term photostability, and low cytotoxicity into a hydrogel network in a single step. By leveraging DNA-guided interactions, we introduce multifunctionality for a variety of applications, including enzyme-responsive drug delivery and cell-specific targeting. We report that quantum dot DNA hydrogels can be used for delivery of doxorubicin, an anticancer drug, to increase potency 9-fold against cancer cells. This approach also demonstrated high biocompatibility, trackability, and in vivo therapeutic efficacy in mice bearing xenografted breast cancer tumors. This work paves the way for the development of new tunable biotemplated nanomaterials with multiple synergistic functionalities for biomedical applications.The development of nanomaterials for imaging and drug delivery has been of great interest to the field. Here, the authors synthesized multifunctional enzyme-responsive hydrogels with self-assembling quantum dots for nucleic acid and drug delivery as well as having imaging capability. PMID- 28851871 TI - 2 + 1 dimensional de Sitter universe emerging from the gauge structure of a nonlinear quantum system. AB - Berry phases and gauge structures are fundamental quantum phenomena. In linear quantum mechanics the gauge field in parameter space presents monopole singularities where the energy levels become degenerate. In nonlinear quantum mechanics, which is an effective theory of interacting quantum systems, there can be phase transitions and hence critical surfaces in the parameter space. We find that these critical surfaces result in a new type of gauge field singularity, namely, a conic singularity that resembles the big bang of a 2 + 1 dimensional de Sitter universe, with the fundamental frequency of Bogoliubov excitations acting as the cosmic scale, and mode softening at the critical surface, where the fundamental frequency vanishes, causing a causal singularity. Such conic singularity may be observed in various systems such as Bose-Einstein condensates and molecular magnets. This finding offers a new approach to quantum simulation of fundamental physics. PMID- 28851870 TI - SDE5, a putative RNA export protein, participates in plant innate immunity through a flagellin-dependent signaling pathway in Arabidopsis. AB - In eukaryotes, RNA silencing, mediated by small interfering RNAs, is an evolutionarily widespread and versatile silencing mechanism that plays an important role in various biological processes. Increasing evidences suggest that various components of RNA silencing pathway are involved in plant defense machinery against microbial pathogens in Arabidopsis thaliana. Here, we show genetic and molecular evidence that Arabidopsis SDE5 is required to generate an effective resistance against the biotrophic bacteria Pseudomonas syringae pv. tomato DC3000 and for susceptibility to the necrotrophic bacteria Erwinia caratovora pv. caratovora. SDE5, encodes a putative mRNA export factor that is indispensable for transgene silencing and the production of trans-acting siRNAs. SDE5 expression is rapidly induced by exogenous application of phytohormone salicylic acid (SA), methyl jasmonate (MeJA), phytopathogenic bacteria, and flagellin. We further report that SDE5 is involved in basal plant defense and mRNA export. Our genetic data suggests that SDE5 and Nonexpressor of PR Gene1 (NPR1) may contribute to the same SA-signaling pathway. However, SDE5 over expressing transgenic plant exhibits reduced defense responsive phenotype after flagellin treatment. Taken together, these results support the conclusion that SDE5 contributes to plant innate immunity in Arabidopsis. PMID- 28851872 TI - Human eyes with dilated pupils induce pupillary contagion in infants. AB - Being sensitive and responsive to others' internal states is critical for social life. One reliable cue to what others might be feeling is pupil dilation because it is linked to increases in arousal. When adults view an individual with dilated pupils, their pupils dilate in response, suggesting not only sensitivity to pupil size, but a corresponding response as well. However, little is known about the origins or mechanism underlying this phenomenon of pupillary contagion. Here we show that 4- to 6-month-old infants show pupillary contagion when viewing photographs of eyes with varying pupil sizes: their pupils dilate in response to others' large, but not small or medium pupils. The results suggest that pupillary contagion is likely driven by a transfer of arousal and that it is present very early in life in human infants, supporting the view that it could be an adaptation fundamental for social and emotional development. PMID- 28851873 TI - Using ALoFT to determine the impact of putative loss-of-function variants in protein-coding genes. AB - Variants predicted to result in the loss of function of human genes have attracted interest because of their clinical impact and surprising prevalence in healthy individuals. Here, we present ALoFT (annotation of loss-of-function transcripts), a method to annotate and predict the disease-causing potential of loss-of-function variants. Using data from Mendelian disease-gene discovery projects, we show that ALoFT can distinguish between loss-of-function variants that are deleterious as heterozygotes and those causing disease only in the homozygous state. Investigation of variants discovered in healthy populations suggests that each individual carries at least two heterozygous premature stop alleles that could potentially lead to disease if present as homozygotes. When applied to de novo putative loss-of-function variants in autism-affected families, ALoFT distinguishes between deleterious variants in patients and benign variants in unaffected siblings. Finally, analysis of somatic variants in >6500 cancer exomes shows that putative loss-of-function variants predicted to be deleterious by ALoFT are enriched in known driver genes.Variants causing loss of function (LoF) of human genes have clinical implications. Here, the authors present a method to predict disease-causing potential of LoF variants, ALoFT (annotation of Loss-of-Function Transcripts) and show its application to interpreting LoF variants in different contexts. PMID- 28851874 TI - Dispersion engineering and frequency comb generation in thin silicon nitride concentric microresonators. AB - Kerr nonlinearity-based frequency combs and solitons have been generated from on chip microresonators. The initiation of the combs requires global or local anomalous dispersion which leads to many limitations, such as material choice, film thickness, and spectral ranges where combs can be generated, as well as fabrication challenges. Using a concentric racetrack-shaped resonator, we show that such constraints can be lifted and resonator dispersion can be engineered to be anomalous over moderately broad bandwidth. We demonstrate anomalous dispersion in a 300 nm thick silicon nitride film, suitable for semiconductor manufacturing but previously thought to result in waveguides with high normal dispersion. Together with a mode-selective, tapered coupling scheme, we generate coherent mode-locked frequency combs. Our method can realize anomalous dispersion for resonators at almost any wavelength and simultaneously achieve material and process compatibility with semiconductor manufacturing.Kerr frequency comb generation from microresonators requires anomalous dispersion, imposing restrictions on materials and resonator design. Here, Kim et al. propose a concentric racetrack-resonator design where the dispersion can be engineered to be anomalous via resonant mode coupling. PMID- 28851876 TI - The emergence of altruism as a social norm. AB - Expectations, exerting influence through social norms, are a very strong candidate to explain how complex societies function. In the Dictator game (DG), people expect generous behavior from others even if they cannot enforce any sharing of the pie. Here we assume that people donate following their expectations, and that they update their expectations after playing a DG by reinforcement learning to construct a model that explains the main experimental results in the DG. Full agreement with the experimental results is reached when some degree of mismatch between expectations and donations is added into the model. These results are robust against the presence of envious agents, but affected if we introduce selfish agents that do not update their expectations. Our results point to social norms being on the basis of the generous behavior observed in the DG and also to the wide applicability of reinforcement learning to explain many strategic interactions. PMID- 28851875 TI - Model-Based Therapy Planning Allows Prediction of Haemodynamic Outcome after Aortic Valve Replacement. AB - Optimizing treatment planning is essential for advances in patient care and outcomes. Precisely tailored therapy for each patient remains a yearned-for goal. Cardiovascular modelling has the potential to simulate and predict the functional response before the actual intervention is performed. The objective of this study was to proof the validity of model-based prediction of haemodynamic outcome after aortic valve replacement. In a prospective study design virtual (model-based) treatment of the valve and the surrounding vasculature were performed alongside the actual surgical procedure (control group). The resulting predictions of anatomic and haemodynamic outcome based on information from magnetic resonance imaging before the procedure were compared to post-operative imaging assessment of the surgical control group in ten patients. Predicted vs. post-operative peak velocities across the valve were comparable (2.97 +/- 1.12 vs. 2.68 +/- 0.67 m/s; p = 0.362). In wall shear stress (17.3 +/- 12.3 Pa vs. 16.7 +/- 16.84 Pa; p = 0.803) and secondary flow degree (0.44 +/- 0.32 vs. 0.49 +/- 0.23; p = 0.277) significant linear correlations (p < 0.001) were found between predicted and post operative outcomes. Between groups blood flow patterns showed good agreement (helicity p = 0.852, vorticity p = 0.185, eccentricity p = 0.333). Model-based therapy planning is able to accurately predict post-operative haemodynamics after aortic valve replacement. These validated virtual treatment procedures open up promising opportunities for individually targeted interventions. PMID- 28851877 TI - VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis. AB - Release of promoter-proximally paused RNA polymerase II (RNAPII) is a recently recognized transcriptional regulatory checkpoint. The biological roles of RNAPII pause release and the mechanisms by which extracellular signals control it are incompletely understood. Here we show that VEGF stimulates RNAPII pause release by stimulating acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells, ETS1 binds transcribed gene promoters and stimulates their expression by broadly increasing RNAPII pause release. 34 VEGF enhances ETS1 chromatin occupancy and increases ETS1 acetylation, enhancing its binding to BRD4, which recruits the pause release machinery and increases RNAPII pause release. Endothelial cell angiogenic responses in vitro and in vivo require ETS1-mediated transduction of VEGF signaling to release paused RNAPII. Our results define an angiogenic pathway in which VEGF enhances ETS1-BRD4 interaction to broadly promote RNAPII pause release and drive angiogenesis.Promoter proximal RNAPII pausing is a rate-limiting transcriptional mechanism. Chen et al. show that this process is essential in angiogenesis by demonstrating that the endothelial master transcription factor ETS1 promotes global RNAPII pause release, and that this process is governed by VEGF. PMID- 28851878 TI - Taxonomic and functional shifts in the beech rhizosphere microbiome across a natural soil toposequence. AB - It has been rarely questioned as to whether the enrichment of specific bacterial taxa found in the rhizosphere of a given plant species changes with different soil types under field conditions and under similar climatic conditions. Understanding tree microbiome interactions is essential because, in contrast to annual plants, tree species require decades to grow and strongly depend on the nutritive resources of the soil. In this context, we tested using a natural toposequence the hypothesis that beech trees select specific taxa and functions in their rhizosphere based on the soil conditions and their nutritive requirements. Our 16S rRNA gene pyrosequencing analyses revealed that the soil type determines the taxa colonizing the beech rhizosphere. A rhizosphere effect was observed in each soil type, but a stronger effect was observed in the nutrient-poor soils. Although the communities varied significantly across the toposequence, we identified a core beech rhizosphere microbiome. Functionally, GeoChip analyses showed a functional redundancy across the toposequence, with genes related to nutrient cycling and to the bacterial immune system being significantly enriched in the rhizosphere. Altogether, the data suggest that, regardless of the soil conditions, trees enrich variable bacterial communities to maintain the functions necessary for their nutrition. PMID- 28851879 TI - Accessibility explains preferred thiol-disulfide isomerization in a protein domain. AB - Disulfide bonds are key stabilizing and yet potentially labile cross-links in proteins. While spontaneous disulfide rearrangement through thiol-disulfide exchange is increasingly recognized to play an important physiological role, its molecular determinants are still largely unknown. Here, we used a novel hybrid Monte Carlo and Molecular Dynamics scheme to elucidate the molecular principles of thiol-disulfide exchange in proteins, for a mutated immunoglobulin domain as a model system. Unexpectedly, using simple proximity as the criterion for thiol disulfide exchange, our method correctly predicts the experimentally observed regiospecificity and selectivity of the cysteine-rich protein. While redox reactivity has been examined primarily on the level of transition states and activation barriers, our results argue for accessibility of the disulfide by the attacking thiol given the highly dynamic and sterically demanding protein as a major bottleneck of thiol-disulfide exchange. This scenario may be similarly at play in other proteins with or without an evolutionarily designed active site. PMID- 28851880 TI - Low-dose cryo electron ptychography via non-convex Bayesian optimization. AB - Electron ptychography has seen a recent surge of interest for phase sensitive imaging at atomic or near-atomic resolution. However, applications are so far mainly limited to radiation-hard samples, because the required doses are too high for imaging biological samples at high resolution. We propose the use of non convex Bayesian optimization to overcome this problem, and show via numerical simulations that the dose required for successful reconstruction can be reduced by two orders of magnitude compared to previous experiments. As an important application we suggest to use this method for imaging single biological macromolecules at cryogenic temperatures and demonstrate 2D single-particle reconstructions from simulated data with a resolution up to 5.4 A at a dose of 20e - /A2. When averaging over only 30 low-dose datasets, a 2D resolution around 3.5 A is possible for macromolecular complexes even below 100 kDa. With its independence from the microscope transfer function, direct recovery of phase contrast, and better scaling of signal-to-noise ratio, low-dose cryo electron ptychography may become a promising alternative to Zernike phase-contrast microscopy. PMID- 28851881 TI - The increased risk of sarcopenia in patients with cardiovascular risk factors in Suburb-Dwelling older Chinese using the AWGS definition. AB - The aim of the present study is to investigate the relationship between sarcopenia and cardiovascular risk factors (CVRF) in the Chinese elderly. A total of 1611 elderly individuals aged >=60 years were enrolled in this study. The well established CVRF of diabetes, hypertensions, and dyslipidemia were assessed. Sarcopenia was defined according to the recommended algorithm of the Asian Working Group for Sarcopenia (AWGS). Multiple logistic regression analyses and the linear regressions were used to evaluate the components of CVRF and the number of CVRF of elderly patients with sarcopenia. After adjusting for potential confounders, CVRF was associated with a high prevalence of sarcopenia in elderly Chinese populations. Furthermore, diabetes and hypertension, but not dyslipidemia, were found to be significantly associated with sarcopenia. The OR and 95% CI for sarcopenia of the participants with 1, 2, and 3 features of CVRF were 2.27(1.14-4.48), 4.13(1.80-9.46), and 4.90(1.01-23.81), respectively. A linear increase in the prevalence of sarcopenia was found to be associated with the number of CVRF components in the elderly population (P values for the trends < 0.001). Knowledge of known CVRF, particularly diabetes and hypertension, may help predict the risk for sarcopenia in the elderly. PMID- 28851883 TI - Manipulating the adhesion of electroless nickel-phosphorus film on silicon wafers by silane compound modification and rapid thermal annealing. AB - In this study, the effect of 3-2-(2-aminoethylamino) ethylamino propyl trimethoxysilane (ETAS) modification and post rapid thermal annealing (RTA) treatment on the adhesion of electroless plated nickel-phosphorus (ELP Ni-P) film on polyvinyl alcohol-capped palladium nanoclusters (PVA-Pd) catalyzed silicon wafers is systematically investigated. Characterized by pull-off adhesion, atomic force microscopy, X-ray spectroscopy and water contact angle, a time-dependent, three-staged ETAS grafting mechanism including islandish grafting, a self assembly monolayer (SAM) and multi-layer grafting is proposed and this mechanism is well correlated to the pull-off adhesion of ELP Ni-P film. In the absence of RTA, the highest ELP Ni-P film adhesion occurs when ETAS modification approaches SAM, where insufficient or multi-layer ETAS grafting fails to provide satisfactory results. On the other hand, if RTA is applied, the best ELP Ni-P film adhesion happens when ETAS modification is islandish owing to the formation of nickel silicide, where SAM or multi-layer ETAS modification cannot provide satisfactory adhesion because the interaction between ETAS and PVA-Pd has been sabotaged during RTA. Evidenced by microstructural images, we also confirmed that ETAS can act as an efficient barrier layer for nickel diffusion to bulk silicon. PMID- 28851882 TI - Poliovirus intrahost evolution is required to overcome tissue-specific innate immune responses. AB - RNA viruses, such as poliovirus, have a great evolutionary capacity, allowing them to quickly adapt and overcome challenges encountered during infection. Here we show that poliovirus infection in immune-competent mice requires adaptation to tissue-specific innate immune microenvironments. The ability of the virus to establish robust infection and virulence correlates with its evolutionary capacity. We further identify a region in the multi-functional poliovirus protein 2B as a hotspot for the accumulation of minor alleles that facilitate a more effective suppression of the interferon response. We propose that population genetic dynamics enables poliovirus spread between tissues through optimization of the genetic composition of low frequency variants, which together cooperate to circumvent tissue-specific challenges. Thus, intrahost virus evolution determines pathogenesis, allowing a dynamic regulation of viral functions required to overcome barriers to infection.RNA viruses, such as polioviruses, have a great evolutionary capacity and can adapt quickly during infection. Here, the authors show that poliovirus infection in mice requires adaptation to innate immune microenvironments encountered in different tissues. PMID- 28851884 TI - Cu-chitosan nanoparticle boost defense responses and plant growth in maize (Zea mays L.). AB - In agriculture, search for biopolymer derived materials are in high demand to replace the synthetic agrochemicals. In the present investigation, the efficacy of Cu-chitosan nanoparticles (NPs) to boost defense responses against Curvularia leaf spot (CLS) disease of maize and plant growth promotry activity were evaluated. Cu-chitosan NPs treated plants showed significant defense response through higher activities of antioxidant (superoxide dismutase and peroxidase) and defense enzymes (polyphenol oxidase and phenylalanine ammonia-lyase). Significant control of CLS disease of maize was recorded at 0.04 to 0.16% of Cu chitosan NPs treatments in pot and 0.12 to 0.16% of NPs treatments in field condition. Further, NPs treatments exhibited growth promotry effect in terms of plant height, stem diameter, root length, root number and chlorophyll content in pot experiments. In field experiment, plant height, ear length, ear weight/plot, grain yield/plot and 100 grain weight were enhanced in NPs treatments. Disease control and enhancement of plant growth was further enlightened through Cu release profile of Cu-chitosan NPs. This is an important development in agriculture nanomaterial research where biodegradable Cu-chitosan NPs are better compatible with biological control as NPs "mimic" the natural elicitation of the plant defense and antioxidant system for disease protection and sustainable growth. PMID- 28851885 TI - Large marine protected areas represent biodiversity now and under climate change. AB - Large marine protected areas (>30,000 km2) have a high profile in marine conservation, yet their contribution to conservation is contested. Assessing the overlap of large marine protected areas with 14,172 species, we found large marine protected areas cover 4.4% of the ocean and at least some portion of the range of 83.3% of the species assessed. Of all species within large marine protected areas, 26.9% had at least 10% of their range represented, and this was projected to increase to 40.1% in 2100. Cumulative impacts were significantly higher within large marine protected areas than outside, refuting the critique that they only occur in pristine areas. We recommend future large marine protected areas be sited based on systematic conservation planning practices where possible and include areas beyond national jurisdiction, and provide five key recommendations to improve the long-term representation of all species to meet critical global policy goals (e.g., Convention on Biological Diversity's Aichi Targets). PMID- 28851886 TI - Inference on Paleoclimate Change Using Microbial Habitat Preference in Arctic Holocene Sediments. AB - The present study combines data of microbial assemblages with high-resolution paleoceanographic records from Core GC1 recovered in the Chukchi Sea. For the first time, we have demonstrated that microbial habitat preferences are closely linked to Holocene paleoclimate records, and found geological, geochemical, and microbiological evidence for the inference of the sulphate-methane transition zone (SMTZ) in the Chukchi Sea. In Core GC1, the layer of maximum crenarchaeol concentration was localized surrounding the SMTZ. The vertically distributed predominant populations of Gammaproteobacteria and Marine Group II Euryarchaeota (MG-II) were consistent with patterns of the known global SMTZs. MG-II was the most prominent archaeal group, even within the layer of elevated concentrations of crenarchaeol, an archaeal lipid biomarker most commonly used for Marine Group I Thaumarchaeota (MG-I). The distribution of MG-I and MG-II in Core GC1, as opposed to the potential contribution of MG-I to the marine tetraether lipid pool, suggests that the application of glycerol dibiphytanyl glycerol tetraethers (GDGT)-based proxies needs to be carefully considered in the subsurface sediments owing to the many unknowns of crenarchaeol. In conclusion, microbiological profiles integrated with geological records seem to be useful for tracking microbial habitat preference, which reflect climate-triggered changes from the paleodepositional environment. PMID- 28851887 TI - Multiple electron transporting layers and their excellent properties based on organic solar cell. AB - To improve the performance of inverted polymer solar cells based on a ternary blend of polymerthieno [3,4-b] thiophene/benzodithiophene (PTB7), [6,6]-phenyl C71-butyric acid methyl ester (PC71BM) and indene-C60-bisadduct (ICBA), a two layer structure of zinc oxide (ZnO) and Al-doped zinc oxide (AZO) nanoperticles is used to improve electron extraction. Comparing to ZnO, AZO has lower work function and thus provides larger built-in potential across the organic heterojunction, resulting in more efficient photo-current extraction and larger open circuit voltages. Optimum devices with ZnO/AZO nanoparticles show enhancement of both short circuit current and open circuit voltage, leading to a power conversion efficiency (PCE) of 8.85%. The argument of energy level buffering and surface morphology is discussed in the paper. Finally, using a trilayer electron transporting unit of ZnO/AZO/PFN, the interface dipole between the organic active layer and AZO is introduced. The PCE is further enhanced to 9.17%. PMID- 28851888 TI - The Prognostic 97 Chemoresponse Gene Signature in Ovarian Cancer. AB - Patient diagnosis and care would be significantly improved by understanding the mechanisms underlying platinum and taxane resistance in ovarian cancer. Here, we aim to establish a gene signature that can identify molecular pathways/transcription factors involved in ovarian cancer progression, poor clinical outcome, and chemotherapy resistance. To validate the robustness of the gene signature, a meta-analysis approach was applied to 1,020 patients from 7 datasets. A 97-gene signature was identified as an independent predictor of patient survival in association with other clinicopathological factors in univariate [hazard ratio (HR): 3.0, 95% Confidence Interval (CI) 1.66-5.44, p = 2.7E-4] and multivariate [HR: 2.88, 95% CI 1.57-5.2, p = 0.001] analyses. Subset analyses demonstrated that the signature could predict patients who would attain complete or partial remission or no-response to first-line chemotherapy. Pathway analyses revealed that the signature was regulated by HIF1alpha and TP53 and included nine HIF1alpha-regulated genes, which were highly expressed in non responders and partial remission patients than in complete remission patients. We present the 97-gene signature as an accurate prognostic predictor of overall survival and chemoresponse. Our signature also provides information on potential candidate target genes for future treatment efforts in ovarian cancer. PMID- 28851889 TI - Hand Posture Modulates Perceived Tactile Distance. AB - A growing literature shows that body posture modulates the perception of touch, as well as somatosensory processing more widely. In this study, I investigated the effects of changes in the internal postural configuration of the hand on the perceived distance between touches. In two experiments participants positioned their hand in two postures, with the fingers splayed (Apart posture) or pressed together (Together posture). In Experiment 1, participants made forced-choice judgments of which of two tactile distances felt bigger, one oriented with the proximal-distal hand axis (Along orientation) and one oriented with the medio lateral hand axis (Across orientation). In Experiment 2, participants made verbal estimates of the absolute distance between a single pair of touches, in one of the two orientations. Consistent with previous results, there was a clear bias to perceive distances in the across orientation as larger than those in the along orientation. Perceived tactile distance was also modulated by posture, with increased judgments in both orientations when the fingers were splayed. These results show that changes in the internal posture of the hand modulate the perceived distance between touches on the hand, and add to a growing literature showing postural modulation of touch. PMID- 28851890 TI - Effect of fluoride treatment on gene expression in tea plant (Camellia sinensis). AB - Tea plant is a typical fluorine (F) accumulator. F concentration in mature tea leaves is several hundred times higher than that in normal field crops. Long-term consumption of teas with high level F will increase the risks of dental and skeletal fluorosis. The mechanism of F accumulation in tea stands unclear. RNA Seq and digital gene expression (DGE) techniques were used to investigate the effect of F on the differential expressions of transcriptome in tea plant. The results showed that F content in mature tea leaves was increased with increase in F concentration of cultural solution and duration of F treatment time. Based on comparison with data of GO, COG, KEGG and Nr databases, 144 differentially expressed unigenes with definite annotation were identified. Real-time reverse transcription PCR (qRT-PCR) was used to validate the effect of F on expression of 5 unigenes screened from the 144 unigenes. F treatment induced the expression of defense genes such as receptor-like kinases (RLKs) and U-box domain-containing protein. Based on the present study, F uptake is considered to be related to calcium-transporting ATPase, especially autoinhibited Ca2+ ATPase (ACAs) which was activated by the RLKs and worked as a carrier in uptake of F by tea plant. PMID- 28851891 TI - Segregating Top-Down Selective Attention from Response Inhibition in a Spatial Cueing Go/NoGo Task: An ERP and Source Localization Study. AB - Successfully inhibiting a prepotent response tendency requires the attentional detection of signals which cue response cancellation. Although neuroimaging studies have identified important roles of stimulus-driven processing in the attentional detection, the effects of top-down control were scarcely investigated. In this study, scalp EEG was recorded from thirty-two participants during a modified Go/NoGo task, in which a spatial-cueing approach was implemented to manipulate top-down selective attention. We observed classical event-related potential components, including N2 and P3, in the attended condition of response inhibition. While in the ignored condition of response inhibition, a smaller P3 was observed and N2 was absent. The correlation between P3 and CNV during the foreperiod suggested an inhibitory role of P3 in both conditions. Furthermore, source analysis suggested that P3 generation was mainly localized to the midcingulate cortex, and the attended condition showed increased activation relative to the ignored condition in several regions, including inferior frontal gyrus, middle frontal gyrus, precentral gyrus, insula and uncus, suggesting that these regions were involved in top-down attentional control rather than inhibitory processing. Taken together, by segregating electrophysiological correlates of top-down selective attention from those of response inhibition, our findings provide new insights in understanding the neural mechanisms of response inhibition. PMID- 28851892 TI - Determining the geographical origin of common buckwheat from China by multivariate analysis based on mineral elements, amino acids and vitamins. AB - This study aimed to establish a method for distinguishing the geographical origin of common buckwheat from Inner Mongolia, Shanxi and Shaanxi Provinces in China. Three chemical families including mineral elements, vitamins and amino acids of 48 samples from different geographical origins were analyzed by principal component analysis (PCA), cluster analysis (CA) and linear discriminate analysis (LDA) for this purpose. LDA clearly discriminated the geographical origin of common buckwheat samples grown in three regions, and gave a high correct classification rate of 95.8% and satisfactory cross-validation rate of 91.7%. Some variables (Mn, VPP, Se, Gly, Cu, Asp, Fe, and Ala) significantly contributed to the ability to discriminate the geographical origin of the common buckwheat. These results demonstrated that the proposed method is a powerful tool for controlling the geographical origin of common buckwheat by governmental administration and protecting consumers from improper domestic labeling. However, the discriminant method still needs to be further validated using more reliable data. PMID- 28851893 TI - The FER rs4957796 TT genotype is associated with unfavorable 90-day survival in Caucasian patients with severe ARDS due to pneumonia. AB - A recent genome-wide association study showed that a genetic variant within the FER gene is associated with survival in patients with sepsis due to pneumonia. Because severe pneumonia is the main cause of acute respiratory distress syndrome (ARDS), we aimed to investigate the effect of the FER polymorphism rs4957796 on the 90-day survival in patients with ARDS due to pneumonia. An assessment of a prospectively collected cohort of 441 patients with ARDS admitted to three intensive care units at the University Medical Centre identified 274 patients with ARDS due to pneumonia. The 90-day mortality risk was recorded as the primary outcome parameter. Sepsis-related organ failure assessment (SOFA) scores and organ support-free days were used as the secondary variables. FER rs4957796 TT homozygous patients were compared with C-allele carriers. The survival analysis revealed a higher 90-day mortality risk among T homozygotes than among C-allele carriers (p = 0.0144) exclusively in patients with severe ARDS due to pneumonia. The FER rs4957796 TT genotype remained a significant covariate for the 90-day mortality risk in the multivariate analysis (hazard ratio, 4.62; 95% CI, 1.58 13.50; p = 0.0050). In conclusion, FER rs4957796 might act as a prognostic variable for survival in patients with severe ARDS due to pneumonia. PMID- 28851895 TI - Optical Pump Rectification Emission: Route to Terahertz Free-Standing Surface Potential Diagnostics. AB - We introduce a method for diagnosing the electric surface potential of a semiconductor based on THz surface generation. In our scheme, that we name Optical Pump Rectification Emission, a THz field is generated directly on the surface via surface optical rectification of an ultrashort pulse after which the DC surface potential is screened with a second optical pump pulse. As the THz generation directly relates to the surface potential arising from the surface states, we can then observe the temporal dynamics of the static surface field induced by the screening effect of the photo-carriers. Such an approach is potentially insensitive to bulk carrier dynamics and does not require special illumination geometries. PMID- 28851894 TI - Activated Mesenchymal Stem Cells Interact with Antibiotics and Host Innate Immune Responses to Control Chronic Bacterial Infections. AB - Chronic bacterial infections associated with biofilm formation are often difficult to resolve without extended courses of antibiotic therapy. Mesenchymal stem cells (MSC) exert antibacterial activity in vitro and in acute bacterial infection models, but their activity in chronic infection with biofilm models has not been previously investigated. Therefore, we studied the effects of MSC administration in mouse and dog models of chronic infections associated with biofilms. Mice with chronic Staphylococcus aureus implant infections were treated by i.v. administration of activated or non-activated MSC, with or without antibiotic therapy. The most effective treatment protocol was identified as activated MSC co-administered with antibiotic therapy. Activated MSC were found to accumulate in the wound margins several days after i.v. administration. Macrophages in infected tissues assumed an M2 phenotype, compared to untreated infections which contained predominately M1 macrophages. Bacterial killing by MSC was found to be mediated in part by secretion of cathelicidin and was significantly increased by antibiotics. Studies in pet dogs with spontaneous chronic multi drug-resistant wound infections demonstrated clearance of bacteria and wound healing following repeated i.v. administration of activated allogeneic canine MSC. Thus, systemic therapy with activated MSC may be an effective new, non-antimicrobial approach to treatment of chronic, drug-resistant infections. PMID- 28851896 TI - Effects of alcohol drinking and smoking on pancreatic ductal adenocarcinoma mortality: A retrospective cohort study consisting of 1783 patients. AB - The effects of alcohol drinking and smoking on pancreatic ductal adenocarcinoma (PDAC) mortality are contradictory. Individuals who were diagnosed as PDAC and hospitalized at the China National Cancer Center between January 1999 and January 2016 were identified and included in the study. Ultimately, 1783 consecutive patients were included in the study. Patients were categorized as never, ex drinkers/smokers or current drinkers/smokers. Hazard ratios (HRs) of all-cause mortality and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Compared with never drinkers, the HRs were 1.25 for ever drinkers, 1.24 for current drinkers, and 1.33 for ex-drinkers (trend P = 0.031). Heavy drinking and smoking period of 30 or more years were positive prognostic factors for PDAC. For different smoking and alcohol drinking status, only subjects who are both current smokers and current drinkers (HR, 1.45; 95% CI, 1.03-2.05) were associated with reduced survival after PDAC compared to those who were never smokers and never drinkers. Patients who are alcohol drinkers and long-term smokers before diagnosis have a significantly higher risk of PDAC mortality. Compared to those who neither smoker nor drink, only patients who both smokers and drinkers were associated with reduced survival from PDAC. PMID- 28851897 TI - Microbial communities with distinct denitrification potential in spruce and beech soils differing in nitrate leaching. AB - Nitrogen leaching owing to elevated acid deposition remains the main ecosystem threat worldwide. We aimed to contribute to the understanding of the highly variable nitrate losses observed in Europe after acid deposition retreat. Our study proceeded in adjacent beech and spruce forests undergoing acidification recovery and differing in nitrate leaching. We reconstructed soil microbial functional characteristics connected with nitrogen and carbon cycling based on community composition. Our results showed that in the more acidic spruce soil with high carbon content, where Acidobacteria and Actinobacteria were abundant (Proteo:Acido = 1.3), the potential for nitrate reduction and loss via denitrification was high (denitrification: dissimilative nitrogen reduction to ammonium (DNRA) = 3). In the less acidic beech stand with low carbon content, but high nitrogen availability, Proteobacteria were more abundant (Proteo:Acido = 1.6). Proportionally less nitrate could be denitrified there (denitrification:DNRA = 1), possibly increasing its availability. Among 10 potential keystone species, microbes capable of DNRA were identified in the beech soil while instead denitrifiers dominated in the spruce soil. In spite of the former acid deposition impact, distinct microbial functional guilds developed under different vegetational dominance, resulting in different N immobilization potentials, possibly influencing the ecosystem's nitrogen retention ability. PMID- 28851898 TI - Surface PD-L1, E-cadherin, CD24, and VEGFR2 as markers of epithelial cancer stem cells associated with rapid tumorigenesis. AB - Cancer cells require both migratory and tumorigenic property to establish metastatic tumors outside the primary microenvironment. Identifying the characteristic features of migratory cancer stem cells with tumorigenic property is important to predict patient prognosis and combat metastasis. Here we established one epithelial and two mesenchymal cell lines from ascites of a bladder cancer patient (i.e. cells already migrated outside primary tumor). Analyses of these cell lines demonstrated that the epithelial cells with surface expression of PD-L1, E-cadherin, CD24, and VEGFR2 rapidly formed tumors outside the primary tumor microenvironment in nude mice, exhibited signatures of immune evasion, increased stemness, increased calcium signaling, transformation, and novel E-cadherin-RalBP1 interaction. The mesenchymal cells on the other hand, exhibited constitutive TGF-beta signaling and were less tumorigenic. Hence, targeting epithelial cancer stem cells with rapid tumorigenesis signatures in future might help to combat metastasis. PMID- 28851899 TI - The diagnostic and prognostic value of interleukin-6 in patients with soft tissue sarcomas. AB - The presence of systemic inflammation has been reported to be associated with poor prognosis in patients with soft tissue sarcoma (STS). The cytokine interleukin-6 (IL-6) has pleiotropic effects on various cell types in the tumor microenvironment. The aim of the present study was to determine whether serum IL 6 levels could be useful to assume the differentiation of benign soft tissue tumors from STS and to investigate the possible value of IL-6 for survival and oncological events in patients with STS. The medical records of 99 patients who underwent surgical resection were retrospectively reviewed. Serum IL-6 levels (median: 9.04 pg/ml) in patients with STS were statistically higher than those (3.31 pg/ml) in patients with benign soft tissue tumors. Our analyses confirmed that tumor size and IL-6 level were significant predictors of STS diagnosis. Next, we examined the relationship between IL-6 levels and survival in the 59 patients with STS. C-reactive protein levels, hemoglobin levels, and tumor grade were strongly correlated with IL-6 levels. Tumor grade and IL-6 level remained significant factors for survival and event-free survival. We suggest that measurement of IL-6 levels may be a useful method for identifying patients who are at a high risk of STS and tumor-related death. PMID- 28851900 TI - Cell-permeable capsids as universal antigen carrier for the induction of an antigen-specific CD8+ T-cell response. AB - Vaccine platforms that can be flexibly loaded with antigens can contribute to decrease response time to emerging infections. For many pathogens and chronic infections, induction of a robust cytotoxic T lymphocytes-mediated response is desirable to control infection. Antigen delivery into the cytoplasm of antigen presenting cells favors induction of cytotoxic T cells. By fusion of the cell permeable translocation motif (TLM)-peptide to the capsid-forming core protein of hepatitis B virus, and by insertion of the strep-tag in the spike tip (a domain that protrudes from the surface of the capsid), cell-permeable carrier capsids were generated that can be flexibly loaded with various antigens. Loading with antigens was demonstrated by electron microscopy, density gradient centrifugation and surface plasmon resonance spectroscopy. Confocal immunofluorescence microscopy showed that cell-permeable carrier capsids mediate transfer of cargo antigen into the cytoplasm. Using cell-permeable carrier capsids loaded with ovalbumin as model antigen, activation of antigen presenting cells and ovalbumin specific CD8+ T-cells, which correlates with enhanced specific killing activity, was found. This demonstrates the capacity of TLM-carrier-capsids to serve as universal antigen carrier to deliver antigens into the cytoplasm of antigen presenting cells, which leads to enhanced MHC class I-mediated presentation and induction of antigen-specific cytotoxic T lymphocytes response. PMID- 28851901 TI - Investigating the Association between Alcohol and Risk of Head and Neck Cancer in Taiwan. AB - Although alcohol is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature in several aspects. We analyzed detailed alcohol consumption data (amount and type of alcoholic beverage) of 811 HNC patients and 940 controls to evaluate the association between alcohol and HNC by HNC sites and by genotypes of ADH1B and ALDH2. Alcohol was associated with an increased HNC risk in a dose-response relationship, with the highest risk observed for hypopharyngeal cancer, followed by oropharyngeal and laryngeal cancers. Liquor showed a stronger positive association with HNC than beer and wine. The highest HNC risk occurred in individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. In our study population, 21.8% of HNCs, 55.7% of oropharyngeal cancers, and 89.1% of hypopharyngeal cancers could be attributed to alcohol. Alcohol accounted for 47.3% of HNCs among individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. The HNC risk associated with alcohol became comparable to that of never/occasional drinkers after ten or more years of cessation from regular alcohol drinking. In conclusion, alcohol use is associated with an increased HNC risk, particularly for individuals with slow ethanol metabolism. HNC incidence may be reduced by alcohol cessation. PMID- 28851902 TI - Fluoroquinolone structure and translocation flux across bacterial membrane. AB - Bacterial multidrug resistance is a worrying health issue. In Gram-negative antibacterial research, the challenge is to define the antibiotic permeation across the membranes. Passing through the membrane barrier to reach the inhibitory concentration inside the bacterium is a pivotal step for antibacterial molecules. A spectrofluorimetric methodology has been developed to detect fluoroquinolones in bacterial population and inside individual Gram-negative bacterial cells. In this work, we studied the antibiotic accumulation in cells expressing various levels of efflux pumps. The assays allow us to determine the intracellular concentration of the fluoroquinolones to study the relationships between the level of efflux activity and the antibiotic accumulation, and finally to evaluate the impact of fluoroquinolone structures in this process. This represents the first protocol to identify some structural parameters involved in antibiotic translocation and accumulation, and to illustrate the recently proposed "Structure Intracellular Concentration Activity Relationship" (SICAR) concept. PMID- 28851903 TI - Prion protein facilitates retinal iron uptake and is cleaved at the beta-site: Implications for retinal iron homeostasis in prion disorders. AB - Prion disease-associated retinal degeneration is attributed to PrP-scrapie (PrPSc), a misfolded isoform of prion protein (PrPC) that accumulates in the neuroretina. However, a lack of temporal and spatial correlation between PrPSc and cytotoxicity suggests the contribution of host factors. We report retinal iron dyshomeostasis as one such factor. PrPC is expressed on the basolateral membrane of retinal-pigment-epithelial (RPE) cells, where it mediates uptake of iron by the neuroretina. Accordingly, the neuroretina of PrP-knock-out mice is iron-deficient. In RPE19 cells, silencing of PrPC decreases ferritin while over expression upregulates ferritin and divalent-metal-transporter-1 (DMT-1), indicating PrPC-mediated iron uptake through DMT-1. Polarization of RPE19 cells results in upregulation of ferritin by ~10-fold and beta-cleavage of PrPC, the latter likely to block further uptake of iron due to cleavage of the ferrireductase domain. A similar beta-cleavage of PrPC is observed in mouse retinal lysates. Scrapie infection causes PrPSc accumulation and microglial activation, and surprisingly, upregulation of transferrin despite increased levels of ferritin. Notably, detergent-insoluble ferritin accumulates in RPE cells and correlates temporally with microglial activation, not PrPSc accumulation, suggesting that impaired uptake of iron by PrPSc combined with inflammation results in retinal iron-dyshomeostasis, a potentially toxic host response contributing to prion disease-associated pathology. PMID- 28851904 TI - Templating synthesis of Fe2O3 hollow spheres modified with Ag nanoparticles as superior anode for lithium ion batteries. AB - Ag-Fe2O3 hollow spheres are synthesized by using Ag@C core-shell matrix as sacrificial templates. The morphologies and structures of the as-prepared samples are characterized by scanning electron microscopy, X-ray powder diffraction energy dispersive, transmission electron microscopy and high resolution transmission electron microscopy. In contrast to Fe2O3 hollow spheres, Ag-Fe2O3 hollow spheres exhibit much higher electrochemical performances. The Ag-Fe2O3 composites exhibit an initial discharge capacity of 1030.9 mA h g-1 and retain a high capacity of 953.2 mA h g-1 at a current density of 100 mA g-1 after 200 cycles. Furthermore, Ag-Fe2O3 electrode can maintain a stable capacity of 678 mA h g-1 at 1 A g-1 after 250 cycles. Rate performance of Ag-Fe2O3 electrode exhibits a high capacity of 650.8 mA h g-1 even at 5 A g-1. These excellent performances can be attributed to the decoration of Ag particles which will enhance conductivity and accelerate electrochemical reaction kinetics. Moreover, the hollow structure and the constructing particles with nanosize will benefit to accommodate huge volume change and stabilize the structure. PMID- 28851905 TI - Honey-based hydrogel: In vitro and comparative In vivo evaluation for burn wound healing. AB - Honey was used to treat wounds since ancient times till nowadays. The present study aimed at preparing a honey-based hydrogel and assay its antimicrobial properties and wound healing activity; in-vitro and in-vivo. Topical honey hydrogel formulations were prepared using three honey concentrations with gelling agents; chitosan and carbopol 934. The prepared formulae were evaluated for pH, spreadability, swelling index, in-vitro release and antimicrobial activity. The pH and spreadability were in the range of 4.3-6.8 and 5.7-8.6 cm, respectively. Chitosan-based hydrogel showed higher in-vitro honey release with diffusional exponent 'n <= 0.5 indicates Fickian diffusion mechanism. Hydrogel formulae were assessed for in-vitro antimicrobial activity using Disc Diffusion antibiotic sensitivity test against common burn infections bacteria; Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia and Streptococcus pyogenes. The 75% honey-chitosan hydrogel showed highest antimicrobial activity. This formula was tested for in-vivo burn healing using burn-induced wounds in mice. The formula was evaluated for burn healing and antibacterial activities compared to commercial product. 75% honey-chitosan hydrogel was found to possess highest healing rate of burns. The present study concludes that 75% honey-chitosan hydrogel possesses greater wound healing activity compared to commercial preparation and could be safely used as an effective natural topical wound healing treatment. PMID- 28851907 TI - Electron work function - a probe for interfacial diagnosis. AB - A poor interface or defected interfacial segment may trigger interfacial cracking, loss of physical and mechanical functions, and eventual failure of entire material system. Here we show a novel method to diagnose local interphase boundary based on interfacial electron work function (EWF) and its gradient across the interface, which can be analyzed using a nano-Kelvin probe with atomic force microscope. It is demonstrated that a strong interface has its electron work function gradually changed across the interface, while a weaker one shows a steeper change in EWF across the interface. Both experimental and theoretical analyses show that the interfacial work function gradient is a measure of the interaction between two sides of the interface. The effectiveness of this method is demonstrated by analyzing sample metal-metal and metal-ceramic interfaces. PMID- 28851906 TI - A Total-variation Constrained Permutation Model for Revealing Common Copy Number Patterns. AB - Variations in DNA copy number carry important information on genome evolution and regulation of DNA replication in cancer cells. The rapid development of single cell sequencing technology enables exploration of gene-expression heterogeneity among single cells, providing important information on cell evolution. Evolutionary relationships in accumulated sequence data can be visualized by adjacent positioning of similar cells so that similar copy-number profiles are shown by block patterns. However, single-cell DNA sequencing data usually have low amount of starting genome, which requires an extra step of amplification to accumulate sufficient samples, introducing noise and making regular pattern finding challenging. In this paper, we will propose to tackle this issue of recovering the hidden blocks within single-cell DNA-sequencing data through continuous sample permutations such that similar samples are positioned adjacently. The permutation is guided by the total variational norm of the recovered copy number profiles, and is continued until the total variational norm is minimized when similar samples are stacked together to reveal block patterns. An efficient numerical scheme for finding this permutation is designed, tailored from the alternating direction method of multipliers. Application of this method to both simulated and real data demonstrates its ability to recover the hidden structures of single-cell DNA sequences. PMID- 28851908 TI - Arctic Ocean sea ice cover during the penultimate glacial and the last interglacial. AB - Coinciding with global warming, Arctic sea ice has rapidly decreased during the last four decades and climate scenarios suggest that sea ice may completely disappear during summer within the next about 50-100 years. Here we produce Arctic sea ice biomarker proxy records for the penultimate glacial (Marine Isotope Stage 6) and the subsequent last interglacial (Marine Isotope Stage 5e). The latter is a time interval when the high latitudes were significantly warmer than today. We document that even under such warmer climate conditions, sea ice existed in the central Arctic Ocean during summer, whereas sea ice was significantly reduced along the Barents Sea continental margin influenced by Atlantic Water inflow. Our proxy reconstruction of the last interglacial sea ice cover is supported by climate simulations, although some proxy data/model inconsistencies still exist. During late Marine Isotope Stage 6, polynya-type conditions occurred off the major ice sheets along the northern Barents and East Siberian continental margins, contradicting a giant Marine Isotope Stage 6 ice shelf that covered the entire Arctic Ocean.Coinciding with global warming, Arctic sea ice has rapidly decreased during the last four decades. Here, using biomarker records, the authors show that permanent sea ice was still present in the central Arctic Ocean during the last interglacial, when high latitudes were warmer than present. PMID- 28851909 TI - Towards Noise Simulation in Interacting Nonequilibrium Systems Strongly Coupled to Baths. AB - Progress in experimental techniques at nanoscale makes measurements of noise in molecular junctions possible. These data are important source of information not accessible through average flux measurements. The emergence of optoelectronics, the recently shown possibility of strong light-matter couplings, and developments in the field of quantum thermodynamics are making measurements of transport statistics even more important. Theoretical methods for noise evaluation in first principles simulations can be roughly divided into approaches for weak intra system interactions, and those treating strong interactions for systems weakly coupled to baths. We argue that due to structure of its diagrammatic expansion, and the use of many-body states as a basis of its formulation, the recently introduced nonequilibrium diagrammatic technique for Hubbard Green functions is a relatively inexpensive method suitable for evaluation of noise characteristics in first principles simulations over a wide range of parameters. We illustrate viability of the approach by simulations of noise and noise spectrum within generic models for non-, weakly and strongly interacting systems. Results of the simulations are compared to exact data (where available) and to simulations performed within approaches best suited for each of the three parameter regimes. PMID- 28851910 TI - Modelling of growth kinetics of Vibrio cholerae in presence of gold nanoparticles: effect of size and morphology. AB - Emergence of multiple drug resistant strains of pathogenic bacteria calls for new initiatives to combat infectious diseases. Gold nanoparticles (AuNPs), because of their non-toxic nature and size/shape dependent optical properties, offer interesting possibility. Here we report the antibacterial efficacy of AuNPs of different size and shape (AuNS10, AuNS100 and AuNR10; the number indicating the diameter in nm; S stands for sphere and R for rod) against the classical (O395) and El Tor (N16961) biotypes of Vibrio cholerae, the etiological agent responsible for cholera. Growth kinetics was monitored by measuring optical density at different time intervals and fitted by non-linear regression of modified Buchanan model. Sigmoidal growth curve for VcO395 indicated the existence of single phenotype population and was affected by AuNR10 only, implying the importance of morphology of AuNP. Growth of VcN16961 was affected by all three AuNPs indicating the vulnerability of El Tor biotype. Interestingly, VcN16961 exhibited the occurrence of two phenotypic subpopulations - one with shorter (vulnerable Type 1) and the other with extended (tolerant Type 2) lag phase. Various assays were conducted to probe the impact of AuNPs on bacterial cells. Apart from AuNR10, antimicrobial efficacy of AuNS10 was better compared to AuNS100. PMID- 28851911 TI - Graphene/h-BN Heterostructures for Vertical Architecture of RRAM Design. AB - The development of RRAM is one of the mainstreams for next generation non volatile memories to replace the conventional charge-based flash memory. More importantly, the simpler structure of RRAM makes it feasible to be integrated into a passive crossbar array for high-density memory applications. By stacking up the crossbar arrays, the ultra-high density of 3D horizontal RRAM (3D-HRAM) can be realized. However, 3D-HRAM requires critical lithography and other process for every stacked layer, and this fabrication cost overhead increases linearly with the number of stacks. Here, it is demonstrated that the 2D material-based vertical RRAM structure composed of graphene plane electrode/multilayer h-BN insulating dielectric stacked layers, AlOx/TiOx resistive switching layer and ITO pillar electrode exhibits reliable device performance including forming-free, low power consumption (Pset = ~2 MUW and Preset = ~0.2 MUW), and large memory window (>300). The scanning transmission electron microscopy indicates that the thickness of multilayer h-BN is around 2 nm. Due to the ultrathin-insulating dielectric and naturally high thermal conductivity characteristics of h-BN, the vertical structure combining the graphene plane electrode with multilayer h-BN insulating dielectric can pave the way toward a new area of ultra high-density memory integration in the future. PMID- 28851912 TI - Association of monoamine oxidase-A genetic variants and amygdala morphology in violent offenders with antisocial personality disorder and high psychopathic traits. AB - Violent offending is elevated among individuals with antisocial personality disorder (ASPD) and high psychopathic traits (PP). Morphological abnormalities of the amygdala and orbitofrontal cortex (OFC) are present in violent offenders, which may relate to the violence enacted by ASPD + PP. Among healthy males, monoamine oxidase-A (MAO-A) genetic variants linked to low in vitro transcription (MAOA-L) are associated with structural abnormalities of the amygdala and OFC. However, it is currently unknown whether amygdala and OFC morphology in ASPD relate to MAO-A genetic polymorphisms. We studied 18 ASPD males with a history of violent offending and 20 healthy male controls. Genomic DNA was extracted from peripheral leukocytes to determine MAO-A genetic polymorphisms. Subjects underwent a T1-weighted MRI anatomical brain scan that provided vertex-wise measures of amygdala shape and surface area and OFC cortical thickness. We found that ASPD + PP subjects with MAOA-L exhibited decreased surface area in the right basolateral amygdala nucleus and increased surface area in the right anterior cortical amygdaloid nucleus versus healthy MAOA-L carriers. This study is the first to describe genotype-related morphological differences of the amygdala in a population marked by high aggression. Deficits in emotional regulation that contribute to the violence of ASPD + PP may relate to morphological changes of the amygdala under genetic control. PMID- 28851913 TI - A study of size-dependent properties of MoS2 monolayer nanoflakes using density functional theory. AB - Novel physical phenomena emerge in ultra-small sized nanomaterials. We study the limiting small-size-dependent properties of MoS2 monolayer rhombic nanoflakes using density-functional theory on structures of size up to Mo35S70 (1.74 nm). We investigate the structural and electronic properties as functions of the lateral size of the nanoflakes, finding zigzag is the most stable edge configuration, and that increasing size is accompanied by greater stability. We also investigate passivation of the structures to explore realistic settings, finding increased HOMO-LUMO gaps and energetic stability. Understanding the size-dependent properties will inform efforts to engineer electronic structures at the nano scale. PMID- 28851914 TI - Simulated forward and backward self motion, based on realistic parameters, causes motion induced blindness. AB - Motion Induced Blindness (MIB) is a well-established visual phenomenon whereby highly salient targets disappear when viewed against a moving background mask. No research has yet explored whether contracting and expanding optic flow can also trigger target disappearance. We explored MIB using mask speeds corresponding to driving at 35, 50, 65 and 80 km/h in simulated forward (expansion) and backward (contraction) motion as well as 2-D radial movement, random, and static mask motion types. Participants (n = 18) viewed MIB targets against masks with different movement types, speed, and target locations. To understand the relationship between saccades, pupil response and perceptual disappearance, we ran two additional eye-tracking experiments (n = 19). Target disappearance increased significantly with faster mask speeds and upper visual field target presentation. Simulated optic flow and 2-D radial movement caused comparable disappearance, and all moving masks caused significantly more disappearance than a static mask. Saccades could not entirely account for differences between conditions, suggesting that self-motion optic flow does cause MIB in an artificial setting. Pupil analyses implied that MIB disappearance induced by optic flow is not subjectively salient, potentially explaining why MIB is not noticed during driving. Potential implications of MIB for driving safety and Head Up-Display (HUD) technologies are discussed. PMID- 28851915 TI - Poisson Plus Quantification for Digital PCR Systems. AB - Digital PCR, a state-of-the-art nucleic acid quantification technique, works by spreading the target material across a large number of partitions. The average number of molecules per partition is estimated using Poisson statistics, and then converted into concentration by dividing by partition volume. In this standard approach, identical partition sizing is assumed. Violations of this assumption result in underestimation of target quantity, when using Poisson modeling, especially at higher concentrations. The Poisson-Plus Model accommodates for this underestimation, if statistics of the volume variation are well characterized. The volume variation was measured on the chip array based QuantStudio 3D Digital PCR System using the ROX fluorescence level as a proxy for effective load volume per through-hole. Monte Carlo simulations demonstrate the efficacy of the proposed correction. Empirical measurement of model parameters characterizing the effective load volume on QuantStudio 3D Digital PCR chips is presented. The model was used to analyze digital PCR experiments and showed improved accuracy in quantification. At the higher concentrations, the modeling must take effective fill volume variation into account to produce accurate estimates. The extent of the difference from the standard to the new modeling is positively correlated to the extent of fill volume variation in the effective load of your reactions. PMID- 28851916 TI - A novel three-dimensional culture system maintaining the physiological extracellular matrix of fibrotic model livers accelerates progression of hepatocellular carcinoma cells. AB - Liver fibrosis is characterized by the progressive accumulation of extracellular matrix (ECM) and is a strong predictor of hepatocellular carcinoma (HCC) development and progression. However, the effect of ECM in fibrotic livers on HCC cells is poorly understood. The aims of this study were to create a new culture system that retained the natural ECM of fibrotic model livers and to establish whether natural ECM regulated the characteristics of HCC cells. Using an organ decellularization technique, we created a new culture system that preserved the tissue-specific ECM of fibrotic model livers from CCl4-treated rats. The content of ECM in fibrotic model liver scaffolds was increased and the ECM microstructure was distorted. Quantitative polymerase chain reaction and immunofluorescence assays of HCC cells cultured in fibrotic model liver scaffolds for 7 days showed an epithelial-mesenchymal transition phenotype. Moreover, the ECM of fibrotic model livers promoted proliferation and chemoresistance of HCC cells. These results showed a novel effect of natural ECM in fibrotic model livers on the malignant behaviour of HCC cells. This new culture system will be useful for both understanding the cell biology of fibrotic livers and developing novel anti cancer drugs. PMID- 28851917 TI - Nanoscale insights into doping behavior, particle size and surface effects in trivalent metal doped SnO2. AB - Despite considerable research, the location of an aliovalent dopant into SnO2 nanoparticles is far to be clarified. The aim of the present study on trivalent lanthanide doped SnO2 is to differentiate between substitutional versus interstitial and surface versus bulk doping, delineate the bulk and surface defects induced by doping and establish an intrinsic dopant distribution. We evidence for the first time a complex distribution of intrinsic nature composed of substitutional isolated, substitutional associates with defects as well as surface centers. Such multi-modal distribution is revealed for Eu and Sm, while Pr, Tb and Dy appear to be distributed mostly on the SnO2 surface. Like the previously reported case of Eu, Sm displays a long-lived luminescence decaying in the hundreds of ms scale which is likely related to a selective interaction between the traps and the substitutional isolated center. Analyzing the time gated luminescence, we conclude that the local lattice environment of the lattice Sn is not affected by the particle size, being remarkably similar in the ~2 and 20 nm particles. The photocatalytic measurements employed as a probe tool confirm the conclusions from the luminescence measurements concerning the nature of defects and the temperature induced migration of lanthanide dopants. PMID- 28851918 TI - Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies. AB - ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety. PMID- 28851919 TI - Human antigen R-regulated CCL20 contributes to osteolytic breast cancer bone metastasis. AB - Breast cancer mainly spreads to bone, causing decreased survival of patient. Human antigen R (HuR) and chemokines are important molecules associated with mRNA stability and cell-cell interaction in cancer biology. Here, HuR knockdown inhibited bone metastasis and osteolysis of metastatic breast cancer cells in mice and HuR expression promoted the metastatic ability of cancer cells via CCL20 and GM-CSF. In contrast with the findings for GM-CSF, ELAVL1 and CCL20 expressions were markedly increased in breast tumor tissues and ELAVL1 expression showed a strong positive correlation with CCL20 expression in breast cancer subtypes, particularly the basal-like subtype. Metastasis-free survival and overall survival were decreased in the breast cancer patients with high CCL20 expression. We further confirmed the role of CCL20 in breast cancer bone metastasis. Intraperitoneal administration of anti-CCL20 antibodies inhibited osteolytic breast cancer bone metastasis in mice. Treatment with CCL20 noticeably promoted cell invasion and the secretion of MMP-2/9 in the basal-like triple negative breast cancer cell lines, not the luminal. Moreover, CCL20 elevated the receptor activator of nuclear factors kappa-B ligand/osteoprotegerin ratio in breast cancer and osteoblastic cells and mediated the crosstalk between these cells. Collectively, HuR-regulated CCL20 may be an attractive therapeutic target for breast cancer bone metastasis. PMID- 28851920 TI - Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug. AB - Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia. PMID- 28851921 TI - The Multi Domain Caldicellulosiruptor bescii CelA Cellulase Excels at the Hydrolysis of Crystalline Cellulose. AB - The crystalline nature of cellulose microfibrils is one of the key factors influencing biomass recalcitrance which is a key technical and economic barrier to overcome to make cellulosic biofuels a commercial reality. To date, all known fungal enzymes tested have great difficulty degrading highly crystalline cellulosic substrates. We have demonstrated that the CelA cellulase from Caldicellulosiruptor bescii degrades highly crystalline cellulose as well as low crystallinity substrates making it the only known cellulase to function well on highly crystalline cellulose. Unlike the secretomes of cellulolytic fungi, which typically comprise multiple, single catalytic domain enzymes for biomass degradation, some bacterial systems employ an alternative strategy that utilizes multi-catalytic domain cellulases. Additionally, CelA is extremely thermostable and highly active at elevated temperatures, unlike commercial fungal cellulases. Furthermore we have determined that the factors negatively affecting digestion of lignocellulosic materials by C. bescii enzyme cocktails containing CelA appear to be significantly different from the performance barriers affecting fungal cellulases. Here, we explore the activity and degradation mechanism of CelA on a variety of pretreated substrates to better understand how the different bulk components of biomass, such as xylan and lignin, impact its performance. PMID- 28851922 TI - A Physics-Inspired Mechanistic Model of Migratory Movement Patterns in Birds. AB - In this paper, we introduce a mechanistic model of migratory movement patterns in birds, inspired by ideas and methods from physics. Previous studies have shed light on the factors influencing bird migration but have mainly relied on statistical correlative analysis of tracking data. Our novel method offers a bottom up explanation of population-level migratory movement patterns. It differs from previous mechanistic models of animal migration and enables predictions of pathways and destinations from a given starting location. We define an environmental potential landscape from environmental data and simulate bird movement within this landscape based on simple decision rules drawn from statistical mechanics. We explore the capacity of the model by qualitatively comparing simulation results to the non-breeding migration patterns of a seabird species, the Black-browed Albatross (Thalassarche melanophris). This minimal, two parameter model was able to capture remarkably well the previously documented migration patterns of the Black-browed Albatross, with the best combination of parameter values conserved across multiple geographically separate populations. Our physics-inspired mechanistic model could be applied to other bird and highly mobile species, improving our understanding of the relative importance of various factors driving migration and making predictions that could be useful for conservation. PMID- 28851923 TI - Response to Alternating Electric Fields of Tubulin Dimers and Microtubule Ensembles in Electrolytic Solutions. AB - Microtubules (MTs), which are cylindrical protein filaments that play crucial roles in eukaryotic cell functions, have been implicated in electrical signalling as biological nanowires. We report on the small-signal AC ("alternating current") conductance of electrolytic solutions containing MTs and tubulin dimers, using a microelectrode system. We find that MTs (212 nM tubulin) in a 20-fold diluted BRB80 electrolyte increase solution conductance by 23% at 100 kHz, and this effect is directly proportional to the concentration of MTs in solution. The frequency response of MT-containing electrolytes exhibits a concentration independent peak in the conductance spectrum at 111 kHz (503 kHz FWHM that decreases linearly with MT concentration), which appears to be an intrinsic property of MT ensembles in aqueous environments. Conversely, tubulin dimers (42 nM) decrease solution conductance by 5% at 100 kHz under similar conditions. We attribute these effects primarily to changes in the mobility of ionic species due to counter-ion condensation effects, and changes in the solvent structure and solvation dynamics. These results provide insight into MTs' ability to modulate the conductance of aqueous electrolytes, which in turn, has significant implications for biological information processing, especially in neurons, and for intracellular electrical communication in general. PMID- 28851924 TI - Feeling stiffness in the back: a protective perceptual inference in chronic back pain. AB - Does feeling back stiffness actually reflect having a stiff back? This research interrogates the long-held question of what informs our subjective experiences of bodily state. We propose a new hypothesis: feelings of back stiffness are a protective perceptual construct, rather than reflecting biomechanical properties of the back. This has far-reaching implications for treatment of pain/stiffness but also for our understanding of bodily feelings. Over three experiments, we challenge the prevailing view by showing that feeling stiff does not relate to objective spinal measures of stiffness and objective back stiffness does not differ between those who report feeling stiff and those who do not. Rather, those who report feeling stiff exhibit self-protective responses: they significantly overestimate force applied to their spine, yet are better at detecting changes in this force than those who do not report feeling stiff. This perceptual error can be manipulated: providing auditory input in synchrony to forces applied to the spine modulates prediction accuracy in both groups, without altering actual stiffness, demonstrating that feeling stiff is a multisensory perceptual inference consistent with protection. Together, this presents a compelling argument against the prevailing view that feeling stiff is an isomorphic marker of the biomechanical characteristics of the back. PMID- 28851926 TI - Formation of Thermally Stable Bulk Heterojunction by Reducing the Polymer and Fullerene Intermixing. AB - A morphologically stable bulk heterojunction (BHJ) with a large heterojunction area is prepared by reducing the portion of the small band gap polymer (PTB7) and fullerene intermixture through a sequential deposition (SqD) of the nanostructured PTB7 and the fullerene layer. The nanostructured PTB7 layer is prepared using a ternary solvent composed of chlorobenzene, 1,8-diiodooctane (DIO) and 1-chloronaphthalene (1-CN). Adding DIO and 1-CN enhances the ordering of PTB7 chains and results in a nanostructured polymer surface. The grazing incidence X-ray diffraction results reveal that the SqD of the nanostructured PTB7 and fullerene layers forms the BHJ with little intermixing between the polymer and the fullerene domains compared to the BHJ formed by the deposition of the blended PTB7 and fullerene solution (BSD). The OPV utilizing the SqD processed BHJ (SqD-OPV) exhibits a power conversion efficiency (PCE) of 7.43%, which is similar to that when the BSD processed BHJ (BSD-OPV) is utilized. Furthermore, the SqD-OPV exhibits an excellent thermal stability. The SqD-OPV maintains its initial PCE even after thermal annealing at 140 degrees C for 10 days, whereas the BSD-OPV maintains 78% of its initial efficiency under the same condition. PMID- 28851925 TI - Genome-wide profiling of humoral immunity and pathogen genes under selection identifies immune evasion tactics of Chlamydia trachomatis during ocular infection. AB - The frequency and duration of Chlamydia trachomatis (Ct) ocular infections decrease with age, suggesting development of partial immunity. However, there is a lack of clear correlates of immunity to Ct infection in humans. We screened sera from a cohort of Gambian children followed for six-months against a Ct proteome microarray. At genome sequence level, we detected signatures of selection from a population of ocular Ct isolates from Guinea-Bissau. Together these approaches allowed us to highlight the focus of humoral responses and hypothesise new modes of pathogen immune evasion. Children who were susceptible to frequent and/or prolonged Ct infection had a less focussed antibody response, including preferential recognition of forty-two antigens. There was evidence of positive and purifying selection across the genome, but little balancing selection. In contrast, most antigens that were associated with susceptibility were under neutral selection. These data suggest an evasion strategy in which Ct presents a large panel of irrelevant antigens to the immune system to block or misdirect protective responses. Development of a focused immune response, possibly induced through vaccination, may be an effective strategy to promote protection to Ct infection. PMID- 28851927 TI - In-situ observation of ultrafast 90 degrees domain switching under application of an electric field in (100)/(001)-oriented tetragonal epitaxial Pb(Zr0.4Ti0.6)O3 thin films. AB - Ferroelastic domain switching significantly affects piezoelectric properties in ferroelectric materials. The ferroelastic domain switching and the lattice deformation of both a-domains and c-domains under an applied electric field were investigated using in-situ synchrotron X-ray diffraction in conjunction with a high-speed pulse generator set up for epitaxial (100)/(001)-oriented tetragonal Pb(Zr0.4Ti0.6)O3 (PZT) films grown on (100) c SrRuO3//(100)KTaO3 substrates. The 004 peak (c-domain) position shifts to a lower 2theta angle, which demonstrates the elongation of the c-axis lattice parameter of the c-domain under an applied electric field. In contrast, the 400 peak (a-domain) shifts in the opposite direction (higher angle), thus indicating a decrease in the a-axis lattice parameter of the a-domain. 90 degrees domain switching from (100) to (001) orientations (from a-domain to c-domain) was observed by a change in the intensities of the 400 and 004 diffraction peaks by applying a high-speed pulsed electric field 200 ns in width. This change also accompanied a tilt in the angles of each domain from the substrate surface normal direction. This behaviour proved that the 90 degrees domain switched within 40 ns under a high-speed pulsed electric field. Direct observation of such high-speed switching opens the way to design piezo-MEMS devices for high-frequency operation. PMID- 28851928 TI - Calorie restriction effects on circadian rhythms in gene expression are sex dependent. AB - The rhythms in the expression of circadian clock genes are affected by calorie restriction (CR), a dietary paradigm known to increase lifespan. Many physiological effects of CR differ between males and females; here we investigated if the sex of animals affects the CR induced changes in the circadian rhythms. The liver expression of some circadian clock genes such as Bmal1 and three Periods (Per1, Per2 and Per3) and the effect of CR on the expression of these genes were sex independent, while the expression of Rev-Erb alpha, Ror gamma and both Cryptochome (Cry1 and Cry2) genes was different between males and females. The effect of CR on Rev-Erb alpha, Ror gamma and Cry1 gene expression was sex dependent. The expression and the effects of CR were sex specific for several genes previously reported to be regulated by CR: Fmo3, Mup4, Serpina12 and Cyp4a12, while the expression of Cyp4a14a was sex independent. IGF signaling plays an important role in aging and CR effects. Igf-1 expression is regulated by CR and by the circadian clock, we found that rhythms in Igf-1 expression have sexual dimorphism. Our data provide molecular evidence that the sex of animals is an important modulator of circadian rhythms in gene expression and their response to CR. PMID- 28851929 TI - Aspergillus flavus infection triggered immune responses and host-pathogen cross talks in groundnut during in-vitro seed colonization. AB - Aflatoxin contamination, caused by fungal pathogen Aspergillus flavus, is a major quality and health problem delimiting the trade and consumption of groundnut (Arachis hypogaea L.) worldwide. RNA-seq approach was deployed to understand the host-pathogen interaction by identifying differentially expressed genes (DEGs) for resistance to in-vitro seed colonization (IVSC) at four critical stages after inoculation in J 11 (resistant) and JL 24 (susceptible) genotypes of groundnut. About 1,344.04 million sequencing reads have been generated from sixteen libraries representing four stages in control and infected conditions. About 64% and 67% of quality filtered reads (1,148.09 million) were mapped onto A (A. duranensis) and B (A. ipaensis) subgenomes of groundnut respectively. About 101 million unaligned reads each from J 11 and JL 24 were used to map onto A. flavus genome. As a result, 4,445 DEGs including defense-related genes like senescence associated proteins, resveratrol synthase, 9s-lipoxygenase, pathogenesis-related proteins were identified. In A. flavus, about 578 DEGs coding for growth and development of fungus, aflatoxin biosynthesis, binding, transport, and signaling were identified in compatible interaction. Besides identifying candidate genes for IVSC resistance in groundnut, the study identified the genes involved in host pathogen cross-talks and markers that can be used in breeding resistant varieties. PMID- 28851930 TI - Reproducibility and differences in area of foveal avascular zone measured by three different optical coherence tomographic angiography instruments. AB - This study was performed to compare the area of the foveal avascular zone (FAZ area) obtained by three optical coherence tomography angiography (OCTA) instruments. This was a cross-sectional, non-interventional study of twenty-seven healthy right eyes. The superficial and deep FAZ-area was measured manually with three OCTA instruments: Triton (Topcon), RS3000 (Nidek), and CIRRUS (Zeiss). The intra-rater, inter-rater, and inter-instrument correlation coefficients (CC) were assessed. The intra-rater and inter-rater CC were significantly high for the superficial and deep FAZ-areas (P < 0.001). The inter-instrument CC (95% confidence interval) for the superficial FAZ-area was 0.920 (0.803-0.965) for Triton vs RS3000, 0.899 (0.575-0.965) for RS3000 vs CIRRUS, and was 0.963 (0.913 0.983) for CIRRUS vs Triton (P < 0.001). For the deep FAZ-area, the inter instrument CC was 0.813 (0.633-0.910) for Triton vs RS3000, 0.694 (0.369-0.857) for RS3000 vs CIRRUS, and 0.679 (0.153-0.872) for CIRRUS vs Triton (P < 0.001). The superficial FAZ-area (mm2) was 0.264 +/- 0.071 with Triton, 0.278 +/- 0.072 with RS3000 and 0.257 +/- 0.066 with CIRRUS. For deep FAZ-area, it was 0.617 +/- 0.175 with Triton, 0.646 +/- 0.178 with RS3000 and 0.719 +/- 0.175 with CIRRUS. The FAZ-area from these instruments was clinically interchangeable. However, the absolute values of FAZ-area are significantly different among them. These differences must be considered in comparing the FAZ-areas from different OCTA instruments. PMID- 28851931 TI - Dietary glycemic index, glycemic load, and cancer risk: results from the EPIC Italy study. AB - Factors linked to glucose metabolism are involved in the etiology of several cancers. High glycemic index (GI) or high glycemic load (GL) diets, which chronically raise postprandial blood glucose, may increase cancer risk by affecting insulin-like growth factor. We prospectively investigated cancer risk and dietary GI/GL in the EPIC-Italy cohort. After a median 14.9 years, 5112 incident cancers and 2460 deaths were identified among 45,148 recruited adults. High GI was associated with increased risk of colon and bladder cancer. High GL was associated with: increased risk of colon cancer; increased risk of diabetes related cancers; and decreased risk of rectal cancer. High intake of carbohydrate from high GI foods was significantly associated with increased risk of colon and diabetes-related cancers, but decreased risk of stomach cancer; whereas high intake of carbohydrates from low GI foods was associated with reduced colon cancer risk. In a Mediterranean population with high and varied carbohydrate intake, carbohydrates that strongly raise postprandial blood glucose may increase colon and bladder cancer risk, while the quantity of carbohydrate consumed may be involved in diabetes-related cancers. Further studies are needed to confirm the opposing effects of high dietary GL on risks of colon and rectal cancers. PMID- 28851932 TI - Genomic plasticity and rapid host switching can promote the evolution of generalism: a case study in the zoonotic pathogen Campylobacter. AB - Horizontal gene transfer accelerates bacterial adaptation to novel environments, allowing selection to act on genes that have evolved in multiple genetic backgrounds. This can lead to ecological specialization. However, little is known about how zoonotic bacteria maintain the ability to colonize multiple hosts whilst competing with specialists in the same niche. Here we develop a stochastic evolutionary model and show how genetic transfer of host segregating alleles, distributed as predicted for niche specifying genes, and the opportunity for host transition could interact to promote the emergence of host generalist lineages of the zoonotic bacterium Campylobacter. Using a modelling approach we show that increasing levels of homologous recombination enhance the efficiency with which selection can fix combinations of beneficial alleles, speeding adaptation. We then show how these predictions change in a multi-host system, with low levels of recombination, consistent with real r/m estimates, increasing the standing variation in the population, allowing a more effective response to changes in the selective landscape. Our analysis explains how observed gradients of host specialism and generalism can evolve in a multihost system through the transfer of ecologically important loci among coexisting strains. PMID- 28851934 TI - Modeling Oil Recovery for Mixed Macro- and Micro-Pore Carbonate Grainstones. AB - In general, modeling oil-recovery is a challenging problem involving detailed fluid flow calculations with required structural details that challenge current experimental resolution. Recent laboratory experiments on mixed micro- and macro pore suggest that there is a systematic relationship between remaining oil saturation (ROS) and the fraction of micro-pores. Working with experimental measurements of the pores obtained from X-ray tomography and mercury intrusion capillary pressure porosimetry, we define a digital rock model exemplifying the key structural elements of these carbonate grainstones. We then test two fluid flow models: invasion percolation model and effective medium model. Although invasion percolation identifies the important impact of macro-pore percolation on permeability, it does not describe the dependence of ROS on micro-pore percentage. We thus modified the effective medium model by introducing a single parameter descriptor, reff. Oil from pores r >= reff is fully removed, while for the remaining pores with r < reff, their contribution is scaled by (r/reff)2. Applying this straightforward physics to pore size distributions for the mixed pore grainstones reproduces the experimental ROS dependence. PMID- 28851933 TI - Intravenous Fluid Challenge Decreases Intracellular Volume: A Bioimpedance Spectroscopy-Based Crossover Study in Healthy Volunteers. AB - The effects of intravenous fluid therapy on fluid compartments and hemodynamics of the human body remain enigmatic. We therefore tested the efficacy of bioimpedance spectroscopy in a crossover study, where 15 males received 0.5 ml/kg/min ELO-MEL-isoton (osmolarity = 302 mosmol/l) during 60 minutes, or nothing at all. In group "Fluid", fluid load increased from -0.2 +/- 1.0 l extracellular volume at baseline to its maximum of 1.0 +/- 0.9 l in minute 70, and remained continuously elevated throughout minute 300. In group "Zero", fluid load decreased from 0.5 +/- 1.1 l at baseline to its minimum of -1.1 +/- 1.1 l in minute 300. In group "Fluid", intracellular volume decreased from 26.8 +/- 3.9 l at baseline to its minimum of 26.0 +/- 3.9 l in minute 70, and remained continuously decreased throughout minute 300. In group "Zero", intracellular volume increased from 26.5 +/- 3.8 l at baseline to its maximum of 27.1 +/- 3.9 l in minute 120, and decreased thereafter. In group "Fluid" compared to "Zero", systolic blood pressure was significantly higher, from minute 50-90. In conclusion, intravenous fluid therapy caused a clinically meaningful, sustained increase in fluid load, and a decrease in intracellular volume. These data raise interest in studying fluid administration by the gastrointestinal route, perhaps even when managing critical illness. PMID- 28851935 TI - Bacteria as Bio-Template for 3D Carbon Nanotube Architectures. AB - It is one of the most important needs to develop renewable, scalable and multifunctional methods for the fabrication of 3D carbon architectures. Even though a lot of methods have been developed to create porous and mechanically stable 3D scaffolds, the fabrication and control over the synthesis of such architectures still remain a challenge. Here, we used Magnetospirillum magneticum (AMB-1) bacteria as a bio-template to fabricate light-weight 3D solid structure of carbon nanotubes (CNTs) with interconnected porosity. The resulting porous scaffold showed good mechanical stability and large surface area because of the excellent pore interconnection and high porosity. Steered molecular dynamics simulations were used to quantify the interactions between nanotubes and AMB-1 via the cell surface protein MSP-1 and flagellin. The 3D CNTs-AMB1 nanocomposite scaffold is further demonstrated as a potential substrate for electrodes in supercapacitor applications. PMID- 28851936 TI - Putrescine independent wound response phenotype is produced by ODC-like RNAi in planarians. AB - Despite increasing evidence indicates polyamines as a convergence point for signaling pathways, including cell growth and differentiation, a unifying concept to interpret their role is still missing. The activity of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, is tightly regulated by a complex molecular machinery, and the demonstration of the existence of multiple ODC paralogs, lacking decarboxylation activity, suggests additional layers of complexity to the intricate ODC regulatory pathway. Because of their extraordinary regenerative abilities and abundance of stem cells, planarians have potential to contribute to our understanding of polyamine function in an in vivo context. We undertook a study on ODC function in planarians and we found six planarian ODCs (ODC1-6). Five out of six ODC homologs carry substitutions of key aminoacids for enzymatic activity, which makes them theoretically unable to decarboxylate ornithine. Silencing of ODC5 and 6 produced a complex phenotype, by prompting animals to an aberrant response, following chronic injury without tissue removal. Phenotype is neither rescued by putrescine, nor mimicked by difluoromethylornithine treatment. Moreover, the co-silencing of other genes of the ODC regulatory pathway did not modulate phenotype outcome or severity, thus suggesting that the function/s of these ODC-like proteins might be unrelated to decarboxylase activity and putrescine production. PMID- 28851937 TI - Serelaxin improves cardiac and renal function in DOCA-salt hypertensive rats. AB - Serelaxin, a recombinant form of the naturally occurring peptide hormone relaxin 2, is a pleiotropic vasodilating hormone that has been studied in patients with acute heart failure. In this study, the effects of serelaxin on cardiac and renal function, fibrosis, inflammation and lipid accumulation were studied in DOCA-salt treated rats. Uninephrectomized rats were assigned to two groups: controls provided with normal drinking water and DOCA provided with DOCA pellets and sodium chloride drinking water. After 4 weeks, the DOCA-salt rats were randomly selected and implanted with osmotic minipumps delivering vehicle or serelaxin for another 4 weeks. Treatment with serelaxin prevented cardiac and renal dysfunction in DOCA-salt rats. Serelaxin prevented cardiac and renal fibrosis, as determined by Picrosirius Red staining and Second Harmonic Generation (SHG) Microscopy. Treatment of DOCA-salt rats with serelaxin decreased renal inflammation, including the expression of TGF-beta, NFkappaB, MCP-1, IL-1, IL-6, ICAM-1, VCAM-1 and CD68 macrophages. Serelaxin also decreased lipid accumulation in kidney in part by decreasing SREBP-1c, SREBP-2, ChREBP, FATP1, HMGCoAR, and LDL receptor, and increasing Acox1 and ABCA1. In summary, serelaxin reversed DOCA-salt induced cardiac and renal dysfunction. PMID- 28851938 TI - Prevalence of Rare Genetic Variations and Their Implications in NGS-data Interpretation. AB - Next-generation sequencing (NGS) technology has improved enough to discover mutations associated with genetic diseases. Our study evaluated the feasibility of targeted NGS as a primary screening tool to detect causal variants and subsequently predict genetic diseases. We performed parallel computations on 3.7 megabase-targeted regions to detect disease-causing mutations in 103 participants consisting of 81 patients and 22 controls. Data analysis of the participants took about 6 hours using local databases and 200 nodes of a supercomputer. All variants in the selected genes led on average to 3.6 putative diseases for each patient while variants restricted to disease-causing genes identified the correct disease. Notably, only 12% of predicted causal variants were recorded as causal mutations in public databases: 88% had no or insufficient records. In this study, most genetic diseases were caused by rare mutations and public records were inadequate. Most rare variants, however, were not associated with genetic diseases. These data implied that novel, rare variants should not be ignored but interpreted in conjunction with additional clinical data. This step is needed so appropriate advice can be given to primary doctors and parents, thus fulfilling the purpose of this method as a primary screen for rare genetic diseases. PMID- 28851939 TI - Evaluating the role of coherent delocalized phonon-like modes in DNA cyclization. AB - The innate flexibility of a DNA sequence is quantified by the Jacobson Stockmayer's J-factor, which measures the propensity for DNA loop formation. Recent studies of ultra-short DNA sequences revealed a discrepancy of up to six orders of magnitude between experimentally measured and theoretically predicted J factors. These large differences suggest that, in addition to the elastic moduli of the double helix, other factors contribute to loop formation. Here, we develop a new theoretical model that explores how coherent delocalized phonon-like modes in DNA provide single-stranded "flexible hinges" to assist in loop formation. We combine the Czapla-Swigon-Olson structural model of DNA with our extended Peyrard Bishop-Dauxois model and, without changing any of the parameters of the two models, apply this new computational framework to 86 experimentally characterized DNA sequences. Our results demonstrate that the new computational framework can predict J-factors within an order of magnitude of experimental measurements for most ultra-short DNA sequences, while continuing to accurately describe the J factors of longer sequences. Further, we demonstrate that our computational framework can be used to describe the cyclization of DNA sequences that contain a base pair mismatch. Overall, our results support the conclusion that coherent delocalized phonon-like modes play an important role in DNA cyclization. PMID- 28851940 TI - Homogeneity evaluation of mesenchymal stem cells based on electrotaxis analysis. AB - Stem cell therapy that can restore function to damaged tissue, avoid host rejection and reduce inflammation throughout body without use of immunosuppressive drugs. The established methods were used to identify and to isolate specific stem cell markers by FACS or by immunomagnetic cell separation. The procedures for distinguishing population of stem cells took a time and needed many preparations. Here we suggest an electrotaxis analysis as a new method to evaluate the homogeneity of mesenchymal stem cells which can observe the stem cell population in culture condition and wide use to various types of stem cells. Human mesenchymal stem cell, adipose derived stem cell, tonsil derived stem cell and osteogenic differentiated cells migrated toward anode but the migration speed of differentiated cells was significantly decreased versus that of stem cells. In mixture of stem cells and differentiated cells condition, we identified that the ratio of stem cell versus differentiated cell was matched with the homogeneity evaluation data of stem cells based on electrotaxis analysis. As a result, our evaluation tool has the possibility of the wide use to stem cell homogeneity evaluation and might be used as the stem cell quality control during stem cell culture without any additional antibodies. PMID- 28851941 TI - An informatics guided classification of miscible and immiscible binary alloy systems. AB - The classification of miscible and immiscible systems of binary alloys plays a critical role in the design of multicomponent alloys. By mining data from hundreds of experimental phase diagrams, and thousands of thermodynamic data sets from experiments and high-throughput first-principles (HTFP) calculations, we have obtained a comprehensive classification of alloying behavior for 813 binary alloy systems consisting of transition and lanthanide metals. Among several physics-based descriptors, the slightly modified Pettifor chemical scale provides a unique two-dimensional map that divides the miscible and immiscible systems into distinctly clustered regions. Based on an artificial neural network algorithm and elemental similarity, the miscibility of the unknown systems is further predicted and a complete miscibility map is thus obtained. Impressively, the classification by the miscibility map yields a robust validation on the capability of the well-known Miedema's theory (95% agreement) and shows good agreement with the HTFP method (90% agreement). Our results demonstrate that a state-of-the-art physics-guided data mining can provide an efficient pathway for knowledge discovery in the next generation of materials design. PMID- 28851942 TI - A Combination of Species Identification and STR Profiling Identifies Cross contaminated Cells from 482 Human Tumor Cell Lines. AB - Human tumor cell lines are extremely important tools for cancer research, but a significant percentage is cross-contaminated with other cells. Short tandem repeat (STR) profiling is the prevailing standard for authenticating cell lines that originate from human tissues. Based on the analysis of 482 different human tumor cell lines used in China by STR, up to 96 cell lines were misidentified. More importantly, the study has found that STR profiling alone is insufficient to exclude inter-species cross-contamination of human cell lines. Among the 386 cell lines which had a correct STR profile, 3 of them were inter-species cross contaminated. Careful microscopic examination may be helpful in some cases to detect changes in morphology but additional testing is needed. Additionally, species verification by PCR could easily identify the contaminants, even with a low percentage of contaminating cells. Combining STR profiling with species identification by PCR, more than 20.5% (99/482) of tumor cell lines were revealed as having been incorrectly identified, including intra-species (14.5%), inter species (4.4%) cross-contamination and contaminating cell lines (1.7%). Therefore, quality control of cell lines is a systemic issue. Each cell line should undergo a full QA (Quality Assurance) assessment before it is used for research. PMID- 28851943 TI - Trace metals and magnetic particles in PM2.5: Magnetic identification and its implications. AB - Magnetic measurement was combined with geochemical analysis to investigate the trace metal pollution of PM2.5. The study was carried out in Nanjing, China, where the average PM2.5 concentrations in summer and winter in 2013-2014 were 66.37 and 96.92 MUg/m3, respectively. The dominant magnetic mineral in PM2.5 had a low-coercivity pseudo-single domain and consisted of magnetite and hematite. Iron-oxide magnetic particles comprised spherical as well as angular particles. Stable Pb isotopic ratio determinations showed that Pb in summer samples derived from coal emissions while the main sources of winter samples were smelting industry and coal emissions. The magnetic properties of the particles correlated strongly with trace metals derived from anthropogenic activities, such as industrial emission, coal combustion, and traffic vehicle activities, but poorly with those derived from natural sources. In the multiple linear regression analysis, Cr and Fe had higher correlation coefficients (training R > 0.7) in contrast to the low training R of As, Cd, Ni, Sr, and Ti (<0.5) determined using the PM2.5 concentrations and magnetic parameter values as the decision variables. Our results support the use of environmental magnetism determinations as a simple and fast method to assess trace metals in urban particulate matter. PMID- 28851944 TI - Therapeutic effect of human adipose-derived stem cells and their secretome in experimental diabetic pain. AB - Painful neuropathy is one of the complications of diabetes mellitus that adversely affects patients'quality of life. Pharmacological treatments are not fully satisfactory, and novel approaches needed. In a preclinical mouse model of diabetes the effect of both human mesenchymal stromal cells from adipose tissue (hASC) and their conditioned medium (hASC-CM) was evaluated. Diabetes was induced by streptozotocin. After neuropathic hypersensitivity was established, mice were intravenously injected with either 1 * 106 hASC or with CM derived from 2 * 106 hASC. Both hASC and CM (secretome) reversed mechanical, thermal allodynia and thermal hyperalgesia, with a rapid and long lasting effect, maintained up to 12 weeks after treatments. In nerves, dorsal root ganglia and spinal cord of neuropathic mice we determined high IL-1beta, IL-6 and TNF-alpha and low IL-10 levels. Both treatments restored a correct pro/antinflammatory cytokine balance and prevented skin innervation loss. In spleens of streptozotocin-mice, both hASC and hASC-CM re-established Th1/Th2 balance that was shifted to Th1 during diabetes. Blood glucose levels were unaffected although diabetic animals regained weight, and kidney morphology was recovered by treatments. Our data show that hASC and hASC-CM treatments may be promising approaches for diabetic neuropathic pain, and suggest that cell effect is likely mediated by their secretome. PMID- 28851945 TI - Delayed APC/C activation extends the first mitosis of mouse embryos. AB - The correct temporal regulation of mitosis underpins genomic stability because it ensures the alignment of chromosomes on the mitotic spindle that is required for their proper segregation to the two daughter cells. Crucially, sister chromatid separation must be delayed until all the chromosomes have attached to the spindle; this is achieved by the Spindle Assembly Checkpoint (SAC) that inhibits the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase. In many species the first embryonic M-phase is significantly prolonged compared to the subsequent divisions, but the reason behind this has remained unclear. Here, we show that the first M-phase in the mouse embryo is significantly extended due to a delay in APC/C activation. Unlike in somatic cells, where the APC/C first targets cyclin A2 for degradation at nuclear envelope breakdown (NEBD), we find that in zygotes cyclin A2 remains stable for a significant period of time after NEBD. Our findings that the SAC prevents cyclin A2 degradation, whereas over expressed Plk1 stimulates it, support our conclusion that the delay in cyclin A2 degradation is caused by low APC/C activity. As a consequence of delayed APC/C activation cyclin B1 stability in the first mitosis is also prolonged, leading to the unusual length of the first M-phase. PMID- 28851946 TI - Large and accessible conductivity of charged domain walls in lithium niobate. AB - Ferroelectric domain walls are interfaces between areas of a material that exhibits different directions of spontaneous polarization. The properties of domain walls can be very different from those of the undisturbed material. Metallic-like conductivity of charged domain walls (CDWs) in nominally insulating ferroelectrics was predicted in 1973 and detected recently. This important effect is still in its infancy: The electric currents are still smaller than expected, the access to the conductivity at CDWs is hampered by contact barriers, and stability is low because of sophisticated domain structures or proximity of the Curie point. Here, we report on large, accessible, and stable conductivity at CDWs in lithium niobate (LN) crystals - a vital material for photonics. Our results mark a breakthrough: Increase of conductivity at CDWs by more than 13 orders of magnitude compared to that of the bulk, access to the effect via ohmic and diode-like contacts, and high stability for temperatures T <= 70 degrees C are demonstrated. A promising and now realistic prospect is to combine CDW functionalities with linear and nonlinear optical phenomena. Our findings allow new generations of adaptive-optical elements, of electrically controlled integrated-optical chips for quantum photonics, and of advanced LN-semiconductor hybrid optoelectronic devices. PMID- 28851947 TI - Observation of Third-order Nonlinearities in Graphene Oxide Film at Telecommunication Wavelengths. AB - All-optical switches have been considered as a promising solution to overcome the fundamental speed limit of the current electronic switches. However, the lack of a suitable third-order nonlinear material greatly hinders the development of this technology. Here we report the observation of ultrahigh third-order nonlinearity about 0.45 cm2/GW in graphene oxide thin films at the telecommunication wavelength region, which is four orders of magnitude higher than that of single crystalline silicon. Besides, graphene oxide is water soluble and thus easy to process due to the existence of oxygen containing groups. These unique properties can potentially significantly advance the performance of all-optical switches. PMID- 28851948 TI - Significant association of the CHRNB3-CHRNA6 gene cluster with nicotine dependence in the Chinese Han population. AB - Although numerous studies have revealed significant associations between variants in the nicotinic acetylcholine receptors (nAChR) subunits and nicotine dependence (ND), only few studies were performed in Chinese subjects. Here, we performed association and interaction analysis for 20 single nucleotide polymorphisms (SNPs) in the CHRNB3-CHRNA6 gene cluster with ND in a Chinese Han population (N = 5,055). We found nominally significant associations for all tested SNPs with ND measured by the Fagerstrom Test for Nicotine Dependence score; of these, 11 SNPs remained significant after Bonferroni correction for multiple tests (p = 9 * 10 4~2 * 10-3). Further conditional analysis indicated that no other SNP was significantly associated with ND independent of the most-highly significant SNP, rs6474414. Also, our haplotype-based association analysis indicated that each haplotype block was significantly associated with ND (p < 0.01). Further, we provide the first evidence of the genetic interaction of these two genes in affecting ND in this sample with an empirical p-value of 0.0015. Finally, our meta-analysis of samples with Asian and European origins for five SNPs in CHRNB3 showed significant associations with ND, with p-values ranging from 6.86 * 10-14 for rs13280604 to 6.50 * 10-8 for rs4950. This represents the first study showing that CHRNB3/A6 are highly associated with ND in a large Chinese Han sample. PMID- 28851949 TI - Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors. AB - Anthracycline-based chemotherapy is associated with dose-dependent, irreversible damage to the heart. Childhood cancer survivors with hypertension after anthracycline exposure are at increased risk of cardiotoxicity, leading to the hypothesis that genetic susceptibility loci for hypertension may serve as predictors for development of late cardiotoxicity. Therefore, we determined the association between 12 GWAS-identified hypertension-susceptibility loci and cardiotoxicity in a cohort of long-term childhood cancer survivors (N = 108) who received anthracyclines and were screened for cardiac function via echocardiograms. Hypertension-susceptibility alleles of PLCE1:rs9327264 and ATP2B1:rs17249754 were significantly associated with cardiotoxicity risk conferring a protective effect with a 64% (95% CI: 0.18-0.76, P = 0.0068) and 74% (95% CI: 0.07-0.96, P = 0.040) reduction in risk, respectively. In RNAseq experiments of human induced pluripotent stem cell (iPSC) derived cardiomyocytes treated with doxorubicin, both PLCE1 and ATP2B1 displayed anthracycline-dependent gene expression profiles. In silico functional assessment further supported this relationship - rs9327264 in PLCE1 (P = 0.0080) and ATP2B1 expression (P = 0.0079) were both significantly associated with daunorubicin IC50 values in a panel of lymphoblastoid cell lines. Our findings demonstrate that the hypertension susceptibility variants in PLCE1 and ATP2B1 confer a protective effect on risk of developing anthracycline-related cardiotoxicity, and functional analyses suggest that these genes are influenced by exposure to anthracyclines. PMID- 28851950 TI - Biomechanical properties of predator-induced body armour in the freshwater crustacean Daphnia. AB - The freshwater crustacean Daphnia is known for its ability to develop inducible morphological defences that thwart predators. These defences are developed only in the presence of predators and are realized as morphological shape alterations e.g. 'neckteeth' in D. pulex and 'crests' in D. longicephala. Both are discussed to hamper capture, handling or consumption by interfering with the predator's prey capture devices. Additionally, D. pulex and some other daphniids were found to armour-up and develop structural alterations resulting in increased carapace stiffness. We used scanning transmission electron microscopy (STEM) and confocal laser scanning microscopy (CLSM) to identify predator-induced structural and shape alterations. We found species specific structural changes accompanying the known shape alterations. The cuticle becomes highly laminated (i.e. an increased number of layers) in both species during predator exposure. Using nano- and micro indentation as well as finite element analysis (FEA) we determined both: the structure's and shape's contribution to the carapace's mechanical resistance. From our results we conclude that only structural alterations are responsible for increased carapace stiffness, whereas shape alterations appear to pose handling difficulties during prey capture. Therefore, these defences act independently at different stages during predation. PMID- 28851951 TI - One-reactor plasma assisted fabrication of ZnO@TiO 2 multishell nanotubes: assessing the impact of a full coverage on the photovoltaic performance. AB - This paper addresses the fabrication of vertically aligned ZnO@TiO2 multishell nanotubes by a combined full vacuum-plasma approach at mild temperatures. The growth is carried out within the premises of a one-reactor approach, i.e. minimizing the number of vacuum chambers and sample transferences. In this way, the interface between ZnO and TiO2 is fully preserved from humidity thus increasing ZnO durability and stability. These nanostructures are studied by scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy in STEM (EDX-STEM). High density one-dimensional arrays of these nanotubes formed on FTO substrates are applied as photoanode in a dye-sensitized solar cell (DSC). The evolution of the dye adsorption capacity and solar cells parameters are explored as a function of the crystallinity and thickness of the TiO2 shell. The results show the critical effect of a full coverage by TiO2 of ZnO core to explain the mixed results found in the literature. PMID- 28851952 TI - Conservation priorities for endangered Indian tigers through a genomic lens. AB - Tigers have lost 93% of their historical range worldwide. India plays a vital role in the conservation of tigers since nearly 60% of all wild tigers are currently found here. However, as protected areas are small (<300 km2 on average), with only a few individuals in each, many of them may not be independently viable. It is thus important to identify and conserve genetically connected populations, as well as to maintain connectivity within them. We collected samples from wild tigers (Panthera tigris tigris) across India and used genome-wide SNPs to infer genetic connectivity. We genotyped 10,184 SNPs from 38 individuals across 17 protected areas and identified three genetically distinct clusters (corresponding to northwest, southern and central India). The northwest cluster was isolated with low variation and high relatedness. The geographically large central cluster included tigers from central, northeastern and northern India, and had the highest variation. Most genetic diversity (62%) was shared among clusters, while unique variation was highest in the central cluster (8.5%) and lowest in the northwestern one (2%). We did not detect signatures of differential selection or local adaptation. We highlight that the northwest population requires conservation attention to ensure persistence of these tigers. PMID- 28851953 TI - Embodiment in a Child-Like Talking Virtual Body Influences Object Size Perception, Self-Identification, and Subsequent Real Speaking. AB - People's mental representations of their own body are malleable and continuously updated through sensory cues. Altering one's body-representation can lead to changes in object perception and implicit attitudes. Virtual reality has been used to embody adults in the body of a 4-year-old child or a scaled-down adult body. Child embodiment was found to cause an overestimation of object sizes, approximately double that during adult embodiment, and identification of the self with child-like attributes. Here we tested the contribution of auditory cues related to one's own voice to these visually-driven effects. In a 2 * 2 factorial design, visual and auditory feedback on one's own body were varied across conditions, which included embodiment in a child or scaled-down adult body, and real (undistorted) or child-like voice feedback. The results replicated, in an older population, previous findings regarding size estimations and implicit attitudes. Further, although auditory cues were not found to enhance these effects, we show that the strength of the embodiment illusion depends on the child-like voice feedback being congruent or incongruent with the age of the virtual body. Results also showed the positive emotional impact of the illusion of owning a child's body, opening up possibilities for health applications. PMID- 28851954 TI - Interleukin-6, tumor necrosis factor-alpha and receptor activator of nuclear factor kappa ligand are elevated in hypertrophic gastric mucosa of pachydermoperiostosis. AB - Pachydermoperiostosis (PDP) is a rare inherited multisystem disease characterized with digital clubbing, pachydermia and periostosis. Variants in either HPGD or SLCO2A1 that interrupt the prostaglandin E2 (PGE2) pathway have been shown to be involved in PDP. Here, in addition to six confirmed variants in HPGD or SLCO2A1, we identified four novel SLCO2A1 variants in eight PDP patients from seven Chinese Han families. In addition, gastric mucosa hyperplasia was observed in all affected individuals and interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha) and receptor activator of nuclear factor kappa ligand (RANKL) expression were elevated in hypertrophic gastric mucosa. Two of eight patients who had severe arthralgia were treated with celecoxib. After three months, their arthralgia was partly relieved and IL-6, TNFalpha and RANKL expression were decreased in accordance with their relieved hypertrophic gastric mucosa. Our study broadens the variation spectrum of SLCO2A1 and suggests that the gastric mucosa hyperplasia might be a common characteristic of PDP. Moreover, celecoxib would be a considerable choice for PDP patients. We also revealed that IL-6, TNFalpha and RANKL may play important roles in the molecular mechanisms of gastric mucosa hyperplasia in PDP for the first time. PMID- 28851955 TI - Circulating endothelial cell-derived extracellular vesicles mediate the acute phase response and sickness behaviour associated with CNS inflammation. AB - Brain injury elicits a systemic acute-phase response (APR), which is responsible for co-ordinating the peripheral immunological response to injury. To date, the mechanisms responsible for signalling the presence of injury or disease to selectively activate responses in distant organs were unclear. Circulating endogenous extracellular vesicles (EVs) are increased after brain injury and have the potential to carry targeted injury signals around the body. Here, we examined the potential of EVs, isolated from rats after focal inflammatory brain lesions using IL-1beta, to activate a systemic APR in recipient naive rats, as well as the behavioural consequences of EV transfer. Focal brain lesions increased EV release, and, following isolation and transfer, the EVs were sequestered by the liver where they initiated an APR. Transfer of blood-borne EVs from brain-injured animals was also enough to suppress exploratory behaviours in recipient naive animals. EVs derived from brain endothelial cell cultures treated with IL-1beta also activated an APR and altered behaviour in recipient animals. These experiments reveal that inflammation-induced circulating EVs derived from endothelial cells are able to initiate the APR to brain injury and are sufficient to generate the associated sickness behaviours, and are the first demonstration that EVs are capable of modifying behavioural responses. PMID- 28851956 TI - A Plasmodium plasma membrane reporter reveals membrane dynamics by live-cell microscopy. AB - During asexual replication within the Anopheles mosquito and their vertebrate host, Plasmodium parasites depend on the generation of a massive amount of new plasma membrane to produce thousands of daughter parasites. How the parasite plasma membrane (PPM) is formed has mostly been studied by electron microscopy, which does not allow an insight into the dynamics of this process. We generated a Plasmodium berghei reporter parasite line by GFP-tagging of a non-essential PPM localized protein, and followed plasma membrane development in living parasites through the entire Plasmodium life cycle. By generating double-fluorescent parasites in which the PPM is visualized in combination with the parasite endoplasmic reticulum, we show that membrane contact sites are formed between both membrane systems during oocyst and liver stage development that might be used to deliver lipids to the dramatically expanding PPM. In conclusion, we have established a powerful tool to follow PPM development in living parasites, which promises to greatly expand our knowledge of membrane biology in the Plasmodium parasite. PMID- 28851957 TI - Tripolar mitosis and partitioning of the genome arrests human preimplantation development in vitro. AB - Following in vitro fertilisation (IVF), only about half of normally fertilised human embryos develop beyond cleavage and morula stages to form a blastocyst in vitro. Although many human embryos are aneuploid and genomically imbalanced, often as a result of meiotic errors inherited in the oocyte, these aneuploidies persist at the blastocyst stage and the reasons for the high incidence of developmental arrest remain unknown. Here we use genome-wide SNP genotyping and meiomapping of both polar bodies to identify maternal meiotic errors and karyomapping to fingerprint the parental chromosomes in single cells from disaggregated arrested embryos and excluded cells from blastocysts. Combined with time lapse imaging of development in culture, we demonstrate that tripolar mitoses in early cleavage cause chromosome dispersal to clones of cells with identical or closely related sub-diploid chromosome profiles resulting in intercellular partitioning of the genome. We hypothesise that following zygotic genome activation (ZGA), the combination of genomic imbalance and partial genome loss disrupts the normal pattern of embryonic gene expression blocking development at the morula-blastocyst transition. Failure to coordinate the cell cycle in early cleavage and regulate centrosome duplication is therefore a major cause of human preimplantation developmental arrest in vitro. PMID- 28851958 TI - Predictive Value of Serum Gamma-glutamyltranspeptidase for Future Cardiometabolic Dysregulation in Adolescents- a 10-year longitudinal study. AB - Serum gamma-glutamyltransferase (gamma-GT) is implicated in the pathogenesis of atherosclerosis and metabolic syndrome (MetS) in adults. The relationships between gamma-GT and cardiometabolic dysregulation remains unclear in adolescents. We enrolled 7,072 Taiwanese adolescents and followed them for a median of 6.8 years. The optimal cut-off values (CoVs) of baseline gamma-GT to predict future MetS, hypertension (HTN), and type 2 diabetes (T2DM) were determined by receiving operating characteristic (ROC) curve. Using these CoVs, the participants were divided into normal- and high-level groups. Cox proportional hazard analysis was used to calculate hazard ratios (HRs) for the subjects with a high level of gamma-GT for the risk of future cardiometabolic dysregulation. Serum gamma-GT was significantly higher in the subjects with MetS than in those without MetS at baseline (p < 0.001). The optimal CoVs of gamma-GT were 12 U/L for boys and 11 U/L for girls. In multivariate Cox regression analysis, a higher serum gamma-GT level increased the risk of future MetS (HRs 1.98 and 2.85 for boys and girls, respectively, both p < 0.001), but not new onset HTN and T2DM. In conclusion, serum gamma-GT levels not only demonstrated an excellent correlation with the presence of MetS and also in predicting future MetS in adolescents. PMID- 28851959 TI - Enhanced Fluorine-19 MRI Sensitivity using a Cryogenic Radiofrequency Probe: Technical Developments and Ex Vivo Demonstration in a Mouse Model of Neuroinflammation. AB - Neuroinflammation can be monitored using fluorine-19 (19F)-containing nanoparticles and 19F MRI. Previously we studied neuroinflammation in experimental autoimmune encephalomyelitis (EAE) using room temperature (RT) 19F radiofrequency (RF) coils and low spatial resolution 19F MRI to overcome constraints in signal-to-noise ratio (SNR). This yielded an approximate localization of inflammatory lesions. Here we used a new 19F transceive cryogenic quadrature RF probe ( 19 F-CRP) that provides the SNR necessary to acquire superior spatially-resolved 19F MRI. First we characterized the signal transmission profile of the 19 F-CRP. The 19 F-CRP was then benchmarked against a RT 19F/1H RF coil. For SNR comparison we used reference compounds including 19F nanoparticles and ex vivo brains from EAE mice administered with 19F nanoparticles. The transmit/receive profile of the 19 F-CRP diminished with increasing distance from the surface. This was counterbalanced by a substantial SNR gain compared to the RT coil. Intraparenchymal inflammation in the ex vivo EAE brains was more sharply defined when using 150 MUm isotropic resolution with the 19 F-CRP, and reflected the known distribution of EAE histopathology. At this spatial resolution, most 19F signals were undetectable using the RT coil. The 19 F-CRP is a valuable tool that will allow us to study neuroinflammation with greater detail in future in vivo studies. PMID- 28851960 TI - Fundamental and experimental aspects of diffraction for characterizing dislocations by electron channeling contrast imaging in scanning electron microscope. AB - Nowadays Field Emission Gun-Scanning Electron Microscopes provide detailed crystallographic information with high spatial and angular resolutions, and allow direct observation of crystalline defects, such as dislocations, through an attractive technique called Electron Channeling Contrast Imaging (ECCI). Dislocations play a crucial role in the properties of materials and ECCI has naturally emerged as an adapted tool for characterizing defects in bulk specimen. Nevertheless, fine control of the channeling conditions is absolutely required to get strong dislocation contrast for achieving comprehensive analysis. In this work, experiment-assisted fundamental aspects of the origin of dislocation contrast are studied. Experimentally, the potential of ECCI is explored in several dislocation configurations in Interstitial-Free steel (Fe - 1% Si) used as a model material. Full interpretations of dislocation contrast in (g, -g) and its evolution along the Kikuchi band are shown. Furthermore, a dislocation dipole is observed and fully characterized for the first time in an SEM. PMID- 28851961 TI - Acupuncture for behavioral changes of experimental depressive disorder: a systematic review and meta-analysis. AB - Acupuncture is considered to be a promising alternative therapy for depression. Nevertheless, up to now, it remains controversial on the effects exerted by acupuncture on behavioral changes in depression models. Consequently, it's necessary to develop a systematic review and meta-analysis to assess the effect of acupuncture for model rats of depression. Ultimately, 90 studies involving 1861 models were identified. Behavioral indicators including the number of crossings (NC) and the number of rearings (NR) in open field test (OFT), the capacity of sucrose intake (CSI) and the rate of sucrose intake (RSI) in sucrose intake test (SIT), final weight (FW) and gain weight (GW) were employed as main outcomes in depression model rats. The pooled results showed that acupuncture had not less effect than western medicine on improving NC, NR, FW, GW, RSI (P > 0.05). However, the CSI improvement was poorer compared with west medicine (P < 0.05). In conclusion, acupuncture has not less effect on behavior changes than western medicine, including improving NC, NR, RSI, FW and GW in depression models. PMID- 28851962 TI - Neural glycoprotein M6a is released in extracellular vesicles and modulated by chronic stressors in blood. AB - Membrane neuronal glycoprotein M6a is highly expressed in the brain and contributes to neural plasticity promoting neurite growth and spine and synapse formation. We have previously showed that chronic stressors alter hippocampal M6a mRNA levels in rodents and tree shrews. We now show that M6a glycoprotein can be detected in mouse blood. M6a is a transmembrane glycoprotein and, as such, unlikely to be free in blood. Here we demonstrate that, in blood, M6a is transported in extracellular vesicles (EVs). It is also shown that M6a-containing EVs are delivered from cultured primary neurons as well as from M6a-transfected COS-7 cells. Released EVs containing M6a can be incorporated into COS-7 cells changing its phenotype through formation of membrane protrusions. Thus, M6a containing EVs might contribute to maintain cellular plasticity. M6a presence in blood was used to monitor stress effects. Chronic restraint stress modulated M6a protein level in a sex dependent manner. Analysis of individual animals indicated that M6a level variations depend on the stressor applied. The response to stressors in blood makes M6a amenable to further studies in the stress disorder field. PMID- 28851963 TI - Bridging the Gap: Rewritable Electronics Using Real-Time Light-Induced Dielectrophoresis on Lithium Niobate. AB - In the context of micro-electronics, the real-time manipulation and placement of components using optics alone promises a route towards increasingly dynamic systems, where the geometry and function of the device is not fixed at the point of fabrication. Here, we demonstrate physically reconfigurable circuitry through light-induced dielectrophoresis on lithium niobate. Using virtual electrodes, patterned by light, to trap, move, and chain individual micro-solder-beads in real-time via dielectrophoresis, we demonstrate rewritable electrical contacts which can make electrical connections between surface-bound components. The completed micro-solder-bead bridges were found to have relatively low resistances that were not solely dominated by the number of interfaces, or the number of discrete beads, in the connection. Significantly, these connections are formed without any melting/fusing of the beads, a key feature of this technique that enables reconfigurability. Requiring only a low-power (~3.5 mW) laser source to activate, and without the need for external power supply or signal generation, the all-optical simplicity of virtual-electrodes may prove significant for the future development of reconfigurable electronic systems. PMID- 28851964 TI - A heart-coronary arteries structure of carbon nanofibers/graphene/silicon composite anode for high performance lithium ion batteries. AB - In an animal body, coronary arteries cover around the whole heart and supply the necessary oxygen and nutrition so that the heart muscle can survive as well as can pump blood in and out very efficiently. Inspired by this, we have designed a novel heart-coronary arteries structured electrode by electrospinning carbon nanofibers to cover active anode graphene/silicon particles. Electrospun high conductive nanofibers serve as veins and arteries to enhance the electron transportation and improve the electrochemical properties of the active "heart" particles. This flexible binder free carbon nanofibers/graphene/silicon electrode consists of millions of heart-coronary arteries cells. Besides, in the graphene/silicon "hearts", graphene network improves the electrical conductivity of silicon nanopaticles, buffers the volume change of silicon, and prevents them from directly contacting with electrolyte. As expected, this novel composite electrode demonstrates excellent lithium storage performance with a 86.5% capacity retention after 200 cycles, along with a high rate performance with a 543 mAh g-1 capacity at the rate of 1000 mA g-1. PMID- 28851965 TI - Comparison of Continuous Glucose Monitoring between Dexcom G4 Platinum and HD-XG Systems in Nonhuman Primates (Macaca Fascicularis). AB - Timely knowing glucose level helps diabetic patients to manage the disease, including decisions about food, physical activity and medication. This study compared two continuous glucose monitoring systems in conscious and moving-free nonhuman primates (NHPs, Macaca fascicularis). Each normoglycemic or diabetic monkey was implanted with one Dexcom G4 Platinum subcutaneously or one HD-XG glucose sensor arterially for glucose monitoring. The glucose levels measured by both telemetry devices significantly correlated with the glucometer readings. The data of oral glucose tolerance test (oGTT) showed that the glucose levels measured by either Dexcom G4 Platinum or HD-XG transmitter were very similar to glucometer readings. However, compared to HD-XG transmitter or glucometer, Dexcom G4 Platinum detected a decreased glucose peak of ivGTT with approximately 10 min delay due to interstitial glucose far behind blood glucose change. Our data showed the advantages of the telemetry systems are: (1) consecutive data collection (day and night); (2) no bleeding; (3) no anesthesia (moving freely); (4) recording natural response without physical restriction and stress; (5) less labor intensity during ivGTT and other tests; (6) quick outcomes without lab tests. This article summarized and compared the differences of the general characteristics of two continuous glucose monitoring systems in diabetic research. PMID- 28851966 TI - AhR-deficiency as a cause of demyelinating disease and inflammation. AB - The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases. PMID- 28851968 TI - Volumetric Optoacoustic Temperature Mapping in Photothermal Therapy. AB - Photothermal therapy and ablation are commonplace medical procedures employed for treatment of tumors, vascular and brain abnormalities as well as other disorders that require selective destruction of tissues. Yet, accurate mapping of the dynamic temperature field distribution in the treated region represents an unmet clinical need, strongly affecting the clinical outcome of these interventions. We introduce a fast three-dimensional temperature mapping method based on real-time optoacoustic sensing of the treated region coupled with a thermal-diffusion-based model of heat distribution in tissues. Deviations of the optoacoustic temperature readings provided at 40 ms intervals remained below 10% in tissue-mimicking phantom experiments for temperature elevations above 3 degrees C, as validated by simultaneous thermocouple measurements. Performance of the new method to dynamically estimate the volumetric temperature distribution was further showcased in post-mortem mouse imaging experiments. The newly discovered capacity to non-invasively measure the temperature map in an entire treated volume with both high spatial and temporal resolutions holds potential for improving safety and efficacy of light-based therapeutic interventions. PMID- 28851967 TI - Generation of a new infectious recombinant prion: a model to understand Gerstmann Straussler-Scheinker syndrome. AB - Human transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of fatal neurodegenerative disorders that include Kuru, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia. GSS is a genetically determined TSE caused by a range of mutations within the prion protein (PrP) gene. Several animal models, based on the expression of PrPs carrying mutations analogous to human heritable prion diseases, support that mutations might predispose PrP to spontaneously misfold. An adapted Protein Misfolding Cyclic Amplification methodology based on the use of human recombinant PrP (recPMCA) generated different self-propagating misfolded proteins spontaneously. These were characterized biochemically and structurally, and the one partially sharing some of the GSS PrPSc molecular features was inoculated into different animal models showing high infectivity. This constitutes an infectious recombinant prion which could be an invaluable model for understanding GSS. Moreover, this study proves the possibility to generate recombinant versions of other human prion diseases that could provide a further understanding on the molecular features of these devastating disorders. PMID- 28851969 TI - Graphene oxide papers with high water adsorption capacity for air dehumidification. AB - Graphene oxide (GO) has shown a high potential to adsorb and store water molecules due to the oxygen-containing functional groups on its hydrophilic surface. In this study, we characterized the water absorbing properties of graphene oxide in the form of papers. We fabricated three kinds of graphene oxide papers, two with rich oxygen functional groups and one with partial chemical reduction, to vary the oxygen/carbon ratio and found that the paper with high oxygen content has higher moisture adsorption capability. For the GO paper with reduction, the overall moisture absorbance was reduced. However, the absorbance at high humidity was significantly improved due to direct formation of multilayer water vapor in the system, which derived from the weak interaction between the adsorbent and the adsorbate. To demonstrate one application of GO papers as a desiccant, we tested grape fruits with and without GO paper. The fruits with a GO paper exhibited longer-term preservation with delayed mold gathering because of desiccation effect from the paper. Our results suggest that GO will find numerous practical applications as a desiccant and is a promising material for moisture desiccation and food preservation. PMID- 28851970 TI - Topographical interrogation of the living cell surface reveals its role in rapid cell shape changes during phagocytosis and spreading. AB - Dramatic and rapid changes in cell shape are perhaps best exemplified by phagocytes, such as neutrophils. These cells complete the processes of spreading onto surfaces, and phagocytosis within 100 s of stimulation. Although these cell shape changes are accompanied by an apparent large increase in cell surface area, the nature of the membrane "reservoir" for the additional area is unclear. One proposal is that the wrinkled cell surface topography (which forms micro-ridges on the neutrophil surface) provides the resource for neutrophils to expand their available surface area. However, it has been problematic to test this proposal in living cells because these surface structures are sub-light microscopic. In this paper, we report the development of a novel approach, a variant of FRAP (fluorescent recovery after photo-bleaching) modified to interrogate the diffusion path-lengths of membrane associated molecules. This approach provides clear evidence that the cell surface topography changes dramatically during neutrophil shape change (both locally and globally) and can be triggered by elevating cytosolic Ca2+. PMID- 28851971 TI - A broad range quorum sensing inhibitor working through sRNA inhibition. AB - For the last decade, chemical control of bacterial virulence has received considerable attention. Ajoene, a sulfur-rich molecule from garlic has been shown to reduce expression of key quorum sensing regulated virulence factors in the opportunistic pathogen Pseudomonas aeruginosa. Here we show that the repressing effect of ajoene on quorum sensing occurs by inhibition of small regulatory RNAs (sRNA) in P. aeruginosa as well as in Staphylococcus aureus, another important human pathogen that employs quorum sensing to control virulence gene expression. Using various reporter constructs, we found that ajoene lowered expression of the sRNAs RsmY and RsmZ in P. aeruginosa and the small dual-function regulatory RNA, RNAIII in S. aureus, that controls expression of key virulence factors. We confirmed the modulation of RNAIII by RNA sequencing and found that the expression of many QS regulated genes encoding virulence factors such as hemolysins and proteases were lowered in the presence of ajoene in S. aureus. Importantly, our findings show that sRNAs across bacterial species potentially may qualify as targets of anti-virulence therapy and that ajoene could be a lead structure in search of broad-spectrum compounds transcending the Gram negative positive borderline. PMID- 28851972 TI - A new route to enhance the ferromagnetic transition temperature in diluted magnetic semiconductors. AB - We investigate the magnetic and the transport properties of diluted magnetic semiconductors using a spin-fermion Monte-Carlo method on a simple cubic lattice in the intermediate coupling regime. The ferromagnetic transition temperature T c shows an optimization behavior with respect to the absolute carrier density p abs and the magnetic impurity concentration x as seen in the experiments. Our calculations also show an insulator-metal-insulator transition across the optimum p abs where the T c is maximum. Remarkably, the optimum p abs values lie in a narrow range around 0.11 (holes/site) for all x values and the ferromagnetic T c increases with x. We explain our results using the polaron percolation mechanism and outline a new route to enhance the ferromagnetic transition temperature in experiments. PMID- 28851973 TI - Frequency-dependent drug screening using optogenetic stimulation of human iPSC derived cardiomyocytes. AB - Side effects on cardiac ion channels are one major reason for new drugs to fail during preclinical evaluation. Herein we propose a simple optogenetic screening tool measuring extracellular field potentials (FP) from paced cardiomyocytes to identify drug effects over the whole physiological heart range, which is essential given the rate-dependency of ion channel function and drug action. Human induced pluripotent stem cell-derived cardiomyocytes were transduced with an adeno-associated virus to express Channelrhodopsin2 and plated on micro electrode arrays. Global pulsed illumination (470 nm, 1 ms, 0.9 mW/mm2) was applied at frequencies from 1 to 2.5 Hz, which evoked FP simultaneously in all cardiomyocytes. This synchronized activation allowed averaging of FP from all electrodes resulting in one robust FP signal for analysis. Field potential duration (FPD) was ~25% shorter at 2.5 Hz compared to 1 Hz. Inhibition of hERG channels prolonged FPD only at low heart rates whereas Ca2+ channel block shortened FPD at all heart rates. Optogenetic pacing also allowed analysis of the maximum downstroke velocity of the FP to detect drug effects on Na+ channel availability. In principle, the presented method is well scalable for high content cardiac toxicity screening or personalized medicine for inherited cardiac channelopathies. PMID- 28851974 TI - Lipoxygenase in singlet oxygen generation as a response to wounding: in vivo imaging in Arabidopsis thaliana. AB - Wounding, one of the most intensive stresses influencing plants ontogeny and lifespan, can be induced by herbivory as well as by physical factors. Reactive oxygen species play indispensable role both in the local and systemic defense reactions which enable "reprogramming" of metabolic pathways to set new boundaries and physiological equilibrium suitable for survival. In our current study, we provide experimental evidence on the formation of singlet oxygen (1O2) after wounding of Arabidopsis leaves. It is shown that 1O2 is formed by triplet triplet energy transfer from triplet carbonyls to molecular oxygen. Using lipoxygenase inhibitor catechol, it is demonstrated that lipid peroxidation is initiated by lipoxygenase. Suppression of 1O2 formation in lox2 mutant which lacks chloroplast lipoxygenase indicates that lipoxygenase localized in chloroplast is predominantly responsible for 1O2 formation. Interestingly, 1O2 formation is solely restricted to chloroplasts localized at the wounding site. Data presented in this study might provide novel insight into wound-induced signaling in the local defense reaction. PMID- 28851975 TI - An efficient eco advanced oxidation process for phenol mineralization using a 2D/3D nanocomposite photocatalyst and visible light irradiations. AB - Nanocomposites (CNTi) with different mass ratios of carbon nitride (C3N4) and TiO2 nanoparticles were prepared hydrothermally. Different characterization techniques were used including X-ray diffraction (XRD), UV-Vis diffuse reflectance spectroscopy (DRS), X-ray photoelectron spectroscopy (XPS), transmission electron spectroscopy (TEM) and Brunauer-Emmett-Teller (BET). UV-Vis DRS demonstrated that the CNTi nanocomposites exhibited absorption in the visible light range. A sun light - simulated photoexcitation source was used to study the kinetics of phenol degradation and its intermediates in presence of the as prepared nanocomposite photocatalysts. These results were compared with studies when TiO2 nanoparticles were used in the presence and absence of H2O2 and/or O3. The photodegradation of phenol was evaluated spectrophotometrically and using the total organic carbon (TOC) measurements. It was observed that the photocatalytic activity of the CNTi nanocomposites was significantly higher than that of TiO2 nanoparticles. Additionally, spectrophotometry and TOC analyses confirmed that degraded phenol was completely mineralized to CO2 and H2O with the use of CNTi nanocomposites, which was not the case for TiO2 where several intermediates were formed. Furthermore, when H2O2 and O3 were simultaneously present, the 0.1% g C3N4/TiO2 nanocomposite showed the highest phenol degradation rate and the degradation percentage was greater than 91.4% within 30 min. PMID- 28851976 TI - Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-kappaB. AB - Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15 lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-alpha transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms. PMID- 28851977 TI - Atmospheric deposition, CO2, and change in the land carbon sink. AB - Concentrations of atmospheric carbon dioxide (CO2) have continued to increase whereas atmospheric deposition of sulphur and nitrogen has declined in Europe and the USA during recent decades. Using time series of flux observations from 23 forests distributed throughout Europe and the USA, and generalised mixed models, we found that forest-level net ecosystem production and gross primary production have increased by 1% annually from 1995 to 2011. Statistical models indicated that increasing atmospheric CO2 was the most important factor driving the increasing strength of carbon sinks in these forests. We also found that the reduction of sulphur deposition in Europe and the USA lead to higher recovery in ecosystem respiration than in gross primary production, thus limiting the increase of carbon sequestration. By contrast, trends in climate and nitrogen deposition did not significantly contribute to changing carbon fluxes during the studied period. Our findings support the hypothesis of a general CO2 fertilization effect on vegetation growth and suggest that, so far unknown, sulphur deposition plays a significant role in the carbon balance of forests in industrialized regions. Our results show the need to include the effects of changing atmospheric composition, beyond CO2, to assess future dynamics of carbon climate feedbacks not currently considered in earth system/climate modelling. PMID- 28851978 TI - Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock. AB - The early metabolic signatures associated with the progression of septic shock and with responsiveness to therapy can be useful for developing target therapy. The Sequential Organ Failure Assessment (SOFA) score is used for stratifying risk and predicting mortality. This study aimed to verify whether different responses to therapy, assessed as changes in SOFA score at admission (T1, acute phase) and 48 h later (T2, post-resuscitation), are associated with different metabolite patterns. We examined the plasma metabolome of 21 septic shock patients (pts) enrolled in the Shockomics clinical trial (NCT02141607). Patients for which SOFAT2 was >8 and Delta = SOFAT1 - SOFAT2 < 5, were classified as not responsive to therapy (NR, 7 pts), the remaining 14 as responsive (R). We combined untargeted and targeted mass spectrometry-based metabolomics strategies to cover the plasma metabolites repertoire as far as possible. Metabolite concentration changes from T1 to T2 (Delta = T2 - T1) were used to build classification models. Our results support the emerging evidence that lipidome alterations play an important role in individual patients' responses to infection. Furthermore, alanine indicates a possible alteration in the glucose-alanine cycle in the liver, providing a different picture of liver functionality from bilirubin. Understanding these metabolic disturbances is important for developing any effective tailored therapy for these patients. PMID- 28851979 TI - Super-Resolved Nuclear Magnetic Resonance Spectroscopy. AB - We present a novel method that breaks the resolution barrier in nuclear magnetic resonance (NMR) spectroscopy, allowing one to accurately estimate the chemical shift values of highly overlapping or broadened peaks. This problem is routinely encountered in NMR when peaks have large linewidths due to rapidly decaying signals, hindering its application. We address this problem based on the notion of finite-rate-of-innovation (FRI) sampling, which is based on the premise that signals such as the NMR signal, can be accurately reconstructed using fewer measurements than that required by existing approaches. The FRI approach leads to super-resolution, beyond the limits of contemporary NMR techniques. Using this method, we could measure for the first time small changes in chemical shifts during the formation of a Gold nanorod-protein complex, facilitating the quantification of the strength of such interactions. The method thus opens up new possibilities for the application and acceleration of multidimensional NMR spectroscopy across a wide range of systems. PMID- 28851982 TI - Microtubules Modulate F-actin Dynamics during Neuronal Polarization. AB - Neuronal polarization is reflected by different dynamics of microtubule and filamentous actin (F-actin). Axonal microtubules are more stable than those in the remaining neurites, while dynamics of F-actin in axonal growth cones clearly exceed those in their dendritic counterparts. However, whether a functional interplay exists between the microtubule network and F-actin dynamics in growing axons and whether this interplay is instrumental for breaking cellular symmetry is currently unknown. Here, we show that an increment on microtubule stability or number of microtubules is associated with increased F-actin dynamics. Moreover, we show that Drebrin E, an F-actin and microtubule plus-end binding protein, mediates this cross talk. Drebrin E segregates preferentially to growth cones with a higher F-actin treadmilling rate, where more microtubule plus-ends are found. Interruption of the interaction of Drebrin E with microtubules decreases F actin dynamics and arrests neuronal polarization. Collectively the data show that microtubules modulate F-actin dynamics for initial axon extension during neuronal development. PMID- 28851980 TI - Hypoxic Stress Decreases c-Myc Protein Stability in Cardiac Progenitor Cells Inducing Quiescence and Compromising Their Proliferative and Vasculogenic Potential. AB - Cardiac progenitor cells (CPCs) have been shown to promote cardiac regeneration and improve heart function. However, evidence suggests that their regenerative capacity may be limited in conditions of severe hypoxia. Elucidating the mechanisms involved in CPC protection against hypoxic stress is essential to maximize their cardioprotective and therapeutic potential. We investigated the effects of hypoxic stress on CPCs and found significant reduction in proliferation and impairment of vasculogenesis, which were associated with induction of quiescence, as indicated by accumulation of cells in the G0-phase of the cell cycle and growth recovery when cells were returned to normoxia. Induction of quiescence was associated with a decrease in the expression of c-Myc through mechanisms involving protein degradation and upregulation of p21. Inhibition of c-Myc mimicked the effects of severe hypoxia on CPC proliferation, also triggering quiescence. Surprisingly, these effects did not involve changes in p21 expression, indicating that other hypoxia-activated factors may induce p21 in CPCs. Our results suggest that hypoxic stress compromises CPC function by inducing quiescence in part through downregulation of c-Myc. In addition, we found that c-Myc is required to preserve CPC growth, suggesting that modulation of pathways downstream of it may re-activate CPC regenerative potential under ischemic conditions. PMID- 28851983 TI - New insights into tenocyte-immune cell interplay in an in vitro model of inflammation. AB - Inflammation plays an important role in the development and resolution of tendon diseases, but underlying mechanisms are poorly understood. We therefore aimed to analyze the response of human tenocytes to inflammatory stimuli and to uncover their interplay with macrophages in vitro. Tenocytes from human ruptured supraspinatus tendons (n = 10) were treated for three days with a stimulation mixture derived from activated mononuclear cells isolated from healthy human peripheral blood. Significantly increased expression levels of selected adhesion- and human leukocyte antigen (HLA)-molecules, and enhanced interleukin (IL)-6 release were detected by flow cytometry. Tenocyte stimulation with the pro inflammatory cytokines interferon gamma, tumor necrosis factor alpha and IL-1beta triggered similar changes in surface markers and enhanced the release of IL-6, IL 8 and monocyte chemoattractant protein 1 (MCP-1). In co-cultures of macrophages with pre-stimulated tenocytes, macrophages significantly increased CD80 expression, but simultaneously decreased HLA-DR-expression, which are both typical pro-inflammatory polarization markers. Co-cultures also released more IL 6, IL-8, MCP-1 than tenocyte-cultures alone. We demonstrate that tenocytes respond to inflammatory environments in vitro with altered surface marker and cytokine profiles and influence macrophage polarization. Importantly, all changes detected in direct co-cultures were also present in a transwell setting, implicating that communication between the cells involves soluble factors. PMID- 28851981 TI - Lipopolysaccharide-binding protein (LBP) reverses the amyloid state of fibrin seen in plasma of type 2 diabetics with cardiovascular co-morbidities. AB - Type 2 diabetes (T2D) has many cardiovascular complications, including a thrombotic propensity. Many such chronic, inflammatory diseases are accompanied (and may be exacerbated, and possibly even largely caused) by amyloid fibril formation. Recognising that there are few strong genetic associations underpinning T2D, but that amyloidogenesis of amylin is closely involved, we have been seeking to understand what might trigger the disease. Serum levels of bacterial lipopolysaccharide are raised in T2D, and we recently showed that fibrin(ogen) polymerisation during blood clotting can be affected strongly by LPS. The selectivity was indicated by the regularisation of clotting by lipopolysaccharide-binding protein (LBP). Since coagulopathies are a hallmark of T2D, we wondered whether they might too be caused by LPS (and reversed by LBP). We show here, using SEM and confocal microscopy, that platelet-poor-plasma from subjects with T2D had a much greater propensity for hypercoagulability and for amyloidogenesis, and that these could both be reversed by LBP. These data imply that coagulopathies are an important feature of T2D, and may be driven by 'hidden' LPS. Given the prevalence of amyloid formation in the sequelae of diabetes, this opens up novel strategies for both the prevention and treatment of T2D. PMID- 28851984 TI - Nano-topography Enhances Communication in Neural Cells Networks. AB - Neural cells are the smallest building blocks of the central and peripheral nervous systems. Information in neural networks and cell-substrate interactions have been heretofore studied separately. Understanding whether surface nano topography can direct nerve cells assembly into computational efficient networks may provide new tools and criteria for tissue engineering and regenerative medicine. In this work, we used information theory approaches and functional multi calcium imaging (fMCI) techniques to examine how information flows in neural networks cultured on surfaces with controlled topography. We found that substrate roughness S a affects networks topology. In the low nano-meter range, S a = 0-30 nm, information increases with S a . Moreover, we found that energy density of a network of cells correlates to the topology of that network. This reinforces the view that information, energy and surface nano-topography are tightly inter-connected and should not be neglected when studying cell-cell interaction in neural tissue repair and regeneration. PMID- 28851985 TI - Anosmia impairs homing orientation but not foraging behaviour in free-ranging shearwaters. AB - Shearwaters deprived of their olfactory sense before being displaced to distant sites have impaired homing ability but it is unknown what the role of olfaction is when birds navigate freely without their sense of smell. Furthermore, treatments used to induce anosmia and to disrupt magneto-reception in displacement experiments might influence non-specific factors not directly related to navigation and, as a consequence, the results of displacement experiments can have multiple interpretations. To address this, we GPS-tracked the free-ranging foraging trips of incubating Scopoli's shearwaters within the Mediterranean Sea. As in previous experiments, shearwaters were either made anosmic with 4% zinc sulphate solution, magnetically impaired by attachment of a strong neodymium magnet or were controls. We found that birds from all three treatments embarked on foraging trips, had indistinguishable at-sea schedules of behaviour and returned to the colony having gained mass. However, we found that in the pelagic return stage of their foraging trips, anosmic birds were not oriented towards the colony though coastal navigation was unaffected. These results support the case for zinc sulphate having a specific effect on the navigational ability of shearwaters and thus the view that seabirds consult an olfactory map to guide them across seascapes. PMID- 28851986 TI - Skeletal Site-specific Changes in Bone Mass in a Genetic Mouse Model for Human 15q11-13 Duplication Seen in Autism. AB - Children suffering from autism have been reported to have low bone mineral density and increased risk for fracture, yet the cellular origin of the bone phenotype remains unknown. Here we have utilized a mouse model of autism that duplicates 6.3 Mb region of chromosome 7 (Dp/+) corresponding to a region of chromosome 15q11-13, duplication of which is recurrent in humans to characterize the bone phenotype. Paternally inherited Dp/+ (patDp/+) mice showed expected increases in the gene expression in bone, normal postnatal growth and body weight acquisition compared to the littermate controls. Four weeks-old patDp/+ mice develop a low bone mass phenotype in the appendicular but not the axial skeleton compared to the littermate controls. This low bone mass in the mutant mice was secondary to a decrease in the number of osteoblasts and bone formation rate while the osteoclasts remained relatively unaffected. Further in vitro cell culture experiments and gene expression analysis revealed a major defect in the proliferation, differentiation and mineralization abilities of patDp/+ osteoblasts while osteoclast differentiation remained unchanged compared to controls. This study therefore characterizes the structural and cellular bone phenotype in a mouse model of autism that can be further utilized to investigate therapeutic avenues to treat bone fractures in children with autism. PMID- 28851987 TI - P53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression in response to thymidylate synthase (TS) targeting. AB - Nucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5 fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells. Consequently, decrease in Histone H3K9AC and increase in H3K27me3 marks at the DPYD promoter are observed concomitantly with reduced expression of DPYD mRNA and protein in a p53-dependent manner. Mechanistic studies reveal inhibition of DPYD expression by p53 is augmented following thymidylate synthase (TS) inhibition and DPYD repression by p53 is dependent on DNA-dependent protein kinase (DNA-PK) and Ataxia telangiectasia mutated (ATM) signaling. In-vivo, liver specific Tp53 loss increases the conversion of 5-FU to 5-FUH2 in plasma and elicits a diminished 5 FU therapeutic response in a syngeneic colorectal tumor model consistent with increased DPYD-activity. Our data suggest that p53 plays an important role in controlling pyrimidine catabolism through repression of DPYD expression, following metabolic stress imposed by nucleotide imbalance. These findings have implications for the toxicity and efficacy of the cancer therapeutic 5-FU. PMID- 28851988 TI - Nosocomial transmission of Clostridium difficile Genotype ST81 in a General Teaching Hospital in China traced by whole genome sequencing. AB - Clostridium difficile infection (CDI) is increasingly recognized globally as a cause of significant morbidity and mortality. This study aimed to provide insight into the various dynamics of C. difficile transmission and infection in the hospital. We monitored the toxin and resistance profiles as well as evolutionary relationships of C. difficile strains to determine the epidemiology over time in a teaching hospital in Shanghai, China between May 2014 and August 2015. The CDI incidence of inpatients and outpatients were 67.7 cases and 0.3 cases per 100,000 patient-days, with a nosocomial patient-environment-patient transmission in May and June 2015. C. difficile genotype ST81, a clone with tcdA-negative and tcdB positive, was not only the most common strain (30.8%, 28/91) but also had much higher resistance rates to clindamycin and moxifloxacin compared with non-ST81 genotypes. Hospitalized patients infected with ST81 genotypes were over 65 years of age and had more comorbidities, however patients infected with ST81 presented with less clinical symptoms than non-ST81 infected patients. This study provides initial epidemiological evidence that C. difficile ST81 is a successful epidemic genotype that deserves continuous surveillance in China. PMID- 28851989 TI - Delineation of Tumor Habitats based on Dynamic Contrast Enhanced MRI. AB - Tumor heterogeneity can be elucidated by mapping subregions of the lesion with differential imaging characteristics, called habitats. Dynamic Contrast Enhanced (DCE-)MRI can depict the tumor microenvironments by identifying areas with variable perfusion and vascular permeability, since individual tumor habitats vary in the rate and magnitude of the contrast uptake and washout. Of particular interest is identifying areas of hypoxia, characterized by inadequate perfusion and hyper-permeable vasculature. An automatic procedure for delineation of tumor habitats from DCE-MRI was developed as a two-part process involving: (1) statistical testing in order to determine the number of the underlying habitats; and (2) an unsupervised pattern recognition technique to recover the temporal contrast patterns and locations of the associated habitats. The technique is examined on simulated data and DCE-MRI, obtained from prostate and brain pre clinical cancer models, as well as clinical data from sarcoma and prostate cancer patients. The procedure successfully identified habitats previously associated with well-perfused, hypoxic and/or necrotic tumor compartments. Given the association of tumor hypoxia with more aggressive tumor phenotypes, the obtained in vivo information could impact management of cancer patients considerably. PMID- 28851990 TI - Klein tunneling near the Dirac points in metal-dielectric multilayer metamaterials. AB - The Klein tunneling of optical waves near the Dirac points in the metal dielectric multilayer metamaterials is theoretically investigated and demonstrated through the coupled-mode theory under the tight-binding approximation and the rigorous band structure analysis based on the transfer matrix method. The optical analogue of Klein tunneling for the relativistic electrons passing across a potential barrier is revealed by the iso-frequency contour analysis and numerical simulation to describe the optical beam propagation and refraction across the interface of two metal-dielectric multilayer metamaterial stacks. The transmission and reflection spectra of the Klein tunneling of optical waves are also explained by the coupled mode theory. PMID- 28851991 TI - Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats. AB - Patients with chronic pain easily accompany the negative mood symptoms such as depression and anxiety, and these disturbances in turn affect the aversive perception of pain. However, the underlying mechanisms are largely unknown. We hypothesized that the alteration of metabotropic glutamate receptor 5 (mGluR5) in the brain region underlies such a comorbidity of aversive states. We scanned the brain of chronic neuropathic pain model rats using positron emission tomography (PET) technique with an mGluR5-selective radiotracer [11C] ABP688 and found various brain regions with higher or lower level of mGluR5 compared to control rats. Among the brain areas, a prominent upregulation of mGluR5 was shown in the prelimbic region (PrL) of the medial prefrontal cortex (mPFC) of chronic neuropathic pain animals. A pharmacological blockade of upregulated mGluR5 in the PrL ameliorated the negative symptoms including tactile hypersensitivity and depressive-like behavior, which relieved the subjects from the unpleasant state of chronic neuropathic pain condition. Conversely, lentiviral overexpression of the mGluR5 in the PrL of naive rats successfully induced comorbid pain and negative moods. Our data provide deeper insight into the shared mechanism of pain perception and negative emotions, identifying a therapeutic target for the treatment of chronic pain and mood disorders. PMID- 28851993 TI - Differential changes in the adenoids and tonsils in Japanese children and teenagers: a cross-sectional study. AB - When adenoids (Ad) and tonsils (Tn) become hypertrophied, craniofacial and general body growth is affected. However, there are no objective explicit criteria for evaluating the size of the Ad and Tn, and their respective growth patterns remain unclear. This study determined the average proportions of the Ad and Tn sizes to the upper airway area at various developmental stages in Japanese individuals. Lateral cephalometric radiographs were obtained from 300 Japanese children and teenagers (150 boys and 150 girls, aged 6-20 years), and the respective proportions of Ad to the nasopharynx (Ad/Np) and Tn to the oropharynx (Tn/Op) in the upper airway were determined. Average and standard deviation (SD) were calculated for each of the 5 age groups: lower primary school, upper primary school, junior high school, senior high school, and young adults. We investigated the correlation between age and growth patterns of Ad and Tn, and determined the average Ad/Np and Tn/Op. There was an age-related decrease in Ad and Tn size, and a significant positive correlation between Ad/Np and Tn/Op values in the upper primary school group. Both Ad/Np and Tn/Op decrease as individuals approach adulthood. However, the growth patterns of the Ad/Np and Tn/Op differ from each other. PMID- 28851992 TI - Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration. AB - Type 2 diabetes (T2D) is a disease characterized by impaired insulin secretion. The Wnt signaling transcription factor Tcf7l2 is to date the T2D-associated gene with the largest effect on disease susceptibility. However, the mechanisms by which TCF7L2 variants affect insulin release from beta-cells are not yet fully understood. By taking advantage of a tcf7l2 zebrafish mutant line, we first show that these animals are characterized by hyperglycemia and impaired islet development. Moreover, we demonstrate that the zebrafish tcf7l2 gene is highly expressed in the exocrine pancreas, suggesting potential bystander effects on beta-cell growth, differentiation and regeneration. Finally, we describe a peculiar vascular phenotype in tcf7l2 mutant larvae, characterized by significant reduction in the average number and diameter of pancreatic islet capillaries. Overall, the zebrafish Tcf7l2 mutant, characterized by hyperglycemia, pancreatic and vascular defects, and reduced regeneration proves to be a suitable model to study the mechanism of action and the pleiotropic effects of Tcf7l2, the most relevant T2D GWAS hit in human populations. PMID- 28851994 TI - Desorption of hydrocarbon chains by association with ionic and nonionic surfactants under flow as a mechanism for enhanced oil recovery. AB - The need to extract oil from wells where it is embedded on the surfaces of rocks has led to the development of new and improved enhanced oil recovery techniques. One of those is the injection of surfactants with water vapor, which promotes desorption of oil that can then be extracted using pumps, as the surfactants encapsulate the oil in foams. However, the mechanisms that lead to the optimal desorption of oil and the best type of surfactants to carry out desorption are not well known yet, which warrants the need to carry out basic research on this topic. In this work, we report non equilibrium dissipative particle dynamics simulations of model surfactants and oil molecules adsorbed on surfaces, with the purpose of studying the efficiency of the surfactants to desorb hydrocarbon chains, that are found adsorbed over flat surfaces. The model surfactants studied correspond to nonionic and cationic surfactants, and the hydrocarbon desorption is studied as a function of surfactant concentration under increasing Poiseuille flow. We obtain various hydrocarbon desorption isotherms for every model of surfactant proposed, under flow. Nonionic surfactants are found to be the most effective to desorb oil and the mechanisms that lead to this phenomenon are presented and discussed. PMID- 28851995 TI - Melatonin ameliorates restraint stress-induced oxidative stress and apoptosis in testicular cells via NF-kappaB/iNOS and Nrf2/ HO-1 signaling pathway. AB - Decline in semen quality has become a global public health concern. Psychological stress is common in the current modern society and is associated with semen decline. Increasing evidence demonstrated that melatonin has anti-apoptotic and antioxidant functions. Whether melatonin can ameliorate the damage in testes induced by psychological stress has never been investigated. Here, a mouse model of restraint stress demonstrated that melatonin normalized the sperm density decline, testicular cells apoptosis, and testicular oxidative stress in stressed male mice. Melatonin decreased reactive oxygen species (ROS) level, increased superoxide dismutase (SOD) and glutathione (GSH) activities, and downregulated inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF alpha) activities in stressed mice testes. Furthermore, melatonin reduced the stress-induced activation of the NF-kappaB signaling pathway by decreasing the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IkappaBalpha) and p65 nuclear translocation. In addition, melatonin upregulated the expression of anti-oxidant proteins including nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Meanwhile, in vitro studies also demonstrated melatonin could reduce oxidative apoptosis of testicular cells. Collectively, melatonin mitigated psychological stress-induced spermatogenic damage, which provides evidence for melatonin as a therapy against sperm impairment associated with psychological stress. PMID- 28851997 TI - Light-sound interconversion in optomechanical Dirac materials. AB - Analyzing the scattering and conversion process between photons and phonons coupled via radiation pressure in a circular quantum dot on a honeycomb array of optomechanical cells, we demonstrate the emergence of optomechanical Dirac physics. Specifically we prove the formation of polaritonic quasi-bound states inside the dot, and angle-dependent Klein tunneling of light and emission of sound, depending on the energy of the incident photon, the photon-phonon interaction strength, and the radius of the dot. We furthermore demonstrate that forward scattering of light or sound can almost switched off by an optically tuned Fano resonance; thereby the system may act as an optomechanical translator in a future photon-phonon based circuitry. PMID- 28851996 TI - Uncovering the underlying mechanisms and whole-brain dynamics of deep brain stimulation for Parkinson's disease. AB - Deep brain stimulation (DBS) for Parkinson's disease is a highly effective treatment in controlling otherwise debilitating symptoms. Yet the underlying brain mechanisms are currently not well understood. Whole-brain computational modeling was used to disclose the effects of DBS during resting-state functional Magnetic Resonance Imaging in ten patients with Parkinson's disease. Specifically, we explored the local and global impact that DBS has in creating asynchronous, stable or critical oscillatory conditions using a supercritical bifurcation model. We found that DBS shifts global brain dynamics of patients towards a Healthy regime. This effect was more pronounced in very specific brain areas such as the thalamus, globus pallidus and orbitofrontal regions of the right hemisphere (with the left hemisphere not analyzed given artifacts arising from the electrode lead). Global aspects of integration and synchronization were also rebalanced. Empirically, we found higher communicability and coherence brain measures during DBS-ON compared to DBS-OFF. Finally, using our model as a framework, artificial in silico DBS was applied to find potential alternative target areas for stimulation and whole-brain rebalancing. These results offer important insights into the underlying large-scale effects of DBS as well as in finding novel stimulation targets, which may offer a route to more efficacious treatments. PMID- 28851998 TI - Proteomic and network analysis of human serum albuminome by integrated use of quick crosslinking and two-step precipitation. AB - Affinity- and chemical-based methods are usually employed to prepare human serum albuminome; however, these methods remain technically challenging. Herein, we report the development of a two-step precipitation (TSP) method by combined use of polyethylene glycol (PEG) and ethanol. PEG precipitation was newly applied to remove immunoglobulin G for albuminome preparation, which is simple, cost effective, efficient and compatible with downstream ethanol precipitation. Nonetheless, chemical extraction using TSP may disrupt weak and transient protein interactions with human serum albumin (HSA) leading to an incomplete albuminome. Accordingly, rapid fixation based on formaldehyde crosslinking (FC) was introduced into the TSP procedure. The developed FC-TSP method increased the number of identified proteins, probably by favouring real-time capture of weakly bound proteins in the albuminome. A total of 171 proteins excluding HSA were identified from the fraction obtained with FC-TSP. Further interaction network and cluster analyses revealed 125 HSA-interacting proteins and 14 highly connected clusters. Compared with five previous studies, 55 new potential albuminome proteins including five direct and 50 indirect binders were only identified by our strategy and 12 were detected as common low-abundance proteins. Thus, this new strategy has the potential to effectively survey the human albuminome, especially low-abundance proteins of clinical interest. PMID- 28851999 TI - Benzo[a]pyrene-induced metabolic shift from glycolysis to pentose phosphate pathway in the human bladder cancer cell line RT4. AB - Benzo[a]pyrene (B[a]P), a well-known polyaromatic hydrocarbon, is known for its lung carcinogenicity, however, its role in bladder cancer development is still discussed. Comparative two-dimensional blue native SDS-PAGE analysis of protein complexes isolated from subcellular fractions of 0.5 uM B[a]P-exposed cells indicated a differential regulation of proteins involved in carbohydrate, fatty acid, and nucleotide metabolism, suggesting a possible metabolic flux redistribution. It appeared that B[a]P exposure led to a repression of enzymes (fructose-bisphosphate aldolase A, glucose-6-phosphate isomerase, lactate dehydrogenase) involved in glycolysis, and an up-regulation of proteins (glucose 6-phosphate 1-dehydrogenase, 6-phosphogluconolactonase) catalyzing the pentose phosphate pathway and one carbon metabolism (10-formyltetrahydrofolate dehydrogenase, bifunctional purine biosynthesis protein). Untargeted metabolomics further supported the proteomic data, a lower concentration of glycolytic metabolite was observed as compared to glutamine, xylulose and fatty acids. The analysis of the glutathione and NADPH/NADP+ content of the cells revealed a significant increase of these cofactors. Concomitantly, we did not observe any detectable increase in the production of ROS. With the present work, we shed light on an early phase of the metabolic stress response in which the urothelial cells are capable of counteracting oxidative stress by redirecting the metabolic flux from glycolysis to pentose phosphate pathway. PMID- 28852000 TI - Drug-Delivery System Based on Salmon DNA Nano- and Micro-Scale Structures. AB - Microneedles, fabricated by nano-moulding technology show great promise in the field of drug delivery by enabling the painless self-administration of drugs in a patient-friendly manner. In this study, double-stranded salmon DNA (SDNA) was used as both a drug-delivery vehicle and structural material with a microneedle system. SDNA is non-toxic and demonstrates good mechanical robustness, mouldability, biocompatibility, bio-absorbability, and binding affinity with drug molecules for bio-functional applications. Benign fabrication conditions to protect temperature-sensitive biomolecules are used to produce SDNA structures of various sizes with a high aspect ratio (4: 1). Unlike existing dissolving microneedle structure materials, the special binding characteristics of doxorubicin hydrochloride, anti-cancer drug molecules, and SDNA demonstrate the stability of drug-molecule encapsulation via UV-absorption and photoluminescence analyses. Based on COMSOL simulation and in vitro analysis of the stratum corneum of porcine skin, the mechanical functionality of SDNA microneedles was evaluated in vitro by penetrating the stratum corneum of porcine skin. The SDNA microneedle dissolved and drug permeation was assessed using rhodamine, a drug surrogate. Owing to its many beneficial characteristics, we anticipate that the SDNA microneedle platform will serve as an effective alternative for drug delivery. PMID- 28852001 TI - Salt tolerance response revealed by RNA-Seq in a diploid halophytic wild relative of sweet potato. AB - Crop wild relatives harbor exotic and novel genetic resources, which hold great potential for crop improvement. Ipomoea imperati is a wild diploid relative of sweet potato with the capability of high salinity tolerance. We compared the transcriptomes of I. imperati under salt stress vs. control to identify candidate genes and pathways involved in salt response. De novo assembly produced 67,911 transcripts with a high depth of coverage. A total of 39,902 putative genes were assigned annotations, and 936 and 220 genes involved in salt response in roots and leaves, respectively. Functional analysis indicated a whole system response during salt stress in I. imperati, which included four metabolic processes: sensory initiation, transcriptional reprogramming, cellular protein component change, and cellular homeostasis regulation. We identified a number of candidate genes involved in the ABA signaling pathway, as well as transcription factors, transporters, antioxidant enzymes, and enzymes associated with metabolism of synthesis and catalysis. Furthermore, two membrane transporter genes, including vacuole cation/proton exchanger and inositol transporter, were considered to play important roles in salt tolerance. This study provided valuable information not only for understanding the genetic basis of ecological adaptation but also for future application in sweet potato and other crop improvements. PMID- 28852002 TI - A rumor spreading model based on information entropy. AB - Rumor spreading can have a significant impact on people's lives, distorting scientific facts and influencing political opinions. With technologies that have democratized the production and reproduction of information, the rate at which misinformation can spread has increased significantly, leading many to describe contemporary times as a 'post-truth era'. Research into rumor spreading has primarily been based on either model of social and biological contagion, or upon models of opinion dynamics. Here we present a comprehensive model that is based on information entropy, which allows for the incorporation of considerations like the role of memory, conformity effects, differences in the subjective propensity to produce distortions, and variations in the degree of trust that people place in each other. Variations in the degree of trust are controlled by a confidence factor beta, while the propensity to produce distortions is controlled by a conservation factor K. Simulations were performed using a Barabasi-Albert (BA) scale-free network seeded with a single piece of information. The influence of beta and K upon the temporal evolution of the system was subsequently analyzed regarding average information entropy, opinion fragmentation, and the range of rumor spread. These results can aid in decision-making to limit the spread of rumors. PMID- 28852003 TI - Evidence for deficient motor planning in ADHD. AB - We compare motor planning mechanisms of ADHD and control subjects based on their effect on later observed kinematic characteristics. We monitor hand movement following planning conditions that differ in preparation time, and evaluate the differences across conditions and participants with/without ADHD. Our findings show that when there is sufficient planning time, people without ADHD seem to have a motor plan ready, and immediately initiate a planned movement after a 'GO' cue, with a bell shaped velocity profile. When planning time is not sufficient, they start the movement in a delayed time, possibly indicating that they needed to complete a movement plan. However, people with ADHD, did not start movement immediately after the cue, even when provided with a long preparation time, possibly indicating that even for this planning interval they did not have a motion plan ready. The movement was not only delayed, its velocity profile was not bell shaped and had several peaks. We further found differences between control and ADHD participants in the velocity profile, variability and jitter of movements. Our results suggest that ADHD motion characteristics, are associated with an immature motor plan. Based on the results we propose a paradigm to evaluate deficiencies in motor planning. PMID- 28852004 TI - Orchestrated Domain Movement in Catalysis by Cytochrome P450 Reductase. AB - NADPH-cytochrome P450 reductase is a multi-domain redox enzyme which is a key component of the P450 mono-oxygenase drug-metabolizing system. We report studies of the conformational equilibrium of this enzyme using small-angle neutron scattering, under conditions where we are able to control the redox state of the enzyme precisely. Different redox states have a profound effect on domain orientation in the enzyme and we analyse the data in terms of a two-state equilibrium between compact and extended conformations. The effects of ionic strength show that the presence of a greater proportion of the extended form leads to an enhanced ability to transfer electrons to cytochrome c. Domain motion is intrinsically linked to the functionality of the enzyme, and we can define the position of the conformational equilibrium for individual steps in the catalytic cycle. PMID- 28852005 TI - Tolerant indirect reciprocity can boost social welfare through solidarity with unconditional cooperators in private monitoring. AB - Indirect reciprocity is an important mechanism for resolving social dilemmas. Previous studies explore several types of assessment rules that are evolutionarily stable for keeping cooperation regimes. However, little is known about the effects of private information on social systems. Most indirect reciprocity studies assume public monitoring in which individuals share a single assessment for each individual. Here, we consider a private monitoring system that loosens such an unnatural assumption. We explore the stable norms in the private system using an individual-based simulation. We have three main findings. First, narrow and unstable cooperation: cooperation in private monitoring becomes unstable and the restricted norms cannot maintain cooperative regimes while they can in public monitoring. Second, stable coexistence of discriminators and unconditional cooperators: under private monitoring, unconditional cooperation can play a role in keeping a high level of cooperation in tolerant norm situations. Finally, Pareto improvement: private monitoring can achieve a higher cooperation rate than does public monitoring. PMID- 28852006 TI - A rapid evaluation of acute hydrogen sulfide poisoning in blood based on DNA Cu/Ag nanocluster fluorescence probe. AB - Hydrogen sulfide (H2S) is a highly toxic gas as a cause of inhalational death. Accurate detection of H2S poisoning concentration is valuable and vital for forensic workers to estimate the cause of death. But so far, it is no uniform and reliable standard method to measure sulfide concentrations in H2S poisoning blood for forensic identification. This study introduces a fluorescence sensing technique into forensic research, in which a DNA-templated copper/silver nanocluster (DNA-Cu/AgNCs) fluorescence probe has been proposed to selective detection of S2-. Under an optimized condition, the proposed method can allow for determination of S2- in the concentration range of 10 pM to 1 mM with a linear equation: y = -0.432 lg[S2-] + 0.675 (R2 = 0.9844), with the limit of detection of 3.75 pM. Moreover, acute H2S poisoning mouse models were established by intraperitoneally injected different doses of Na2S, and the practical feasibility of the proposed fluorescence sensor has been demonstrated by 35 poisoning blood samples. This proposed method is proved to be quite simple and straightforward for the detection of H2S poisoning blood. Also it may provide a basis for sulfide metabolizing study in body , and it woul d be m eaningful to further pus h forensic toxicology identification and clinical laboratory research. PMID- 28852007 TI - Bragg Coherent Diffractive Imaging of Zinc Oxide Acoustic Phonons at Picosecond Timescales. AB - Mesoscale thermal transport is of fundamental interest and practical importance in materials such as thermoelectrics. Coherent lattice vibrations (acoustic phonons) govern thermal transport in crystalline solids and are affected by the shape, size, and defect density in nanoscale materials. The advent of hard x-ray free electron lasers (XFELs) capable of producing ultrafast x-ray pulses has significantly impacted the understanding of acoustic phonons by enabling their direct study with x-rays. However, previous studies have reported ensemble averaged results that cannot distinguish the impact of mesoscale heterogeneity on the phonon dynamics. Here we use Bragg coherent diffractive imaging (BCDI) to resolve the 4D evolution of the acoustic phonons in a single zinc oxide rod with a spatial resolution of 50 nm and a temporal resolution of 25 picoseconds. We observe homogeneous (lattice breathing/rotation) and inhomogeneous (shear) acoustic phonon modes, which are compared to finite element simulations. We investigate the possibility of changing phonon dynamics by altering the crystal through acid etching. We find that the acid heterogeneously dissolves the crystal volume, which will significantly impact the phonon dynamics. In general, our results represent the first step towards understanding the effect of structural properties at the individual crystal level on phonon dynamics. PMID- 28852009 TI - Work Function Modulation of Molybdenum Disulfide Nanosheets by Introducing Systematic Lattice Strain. AB - Tuning the surface electronic properties of 2D transition metal dichalcogenides such as Molebdenum disulfide (MoS2) nanosheets is worth exploring for their potential applications in strain sensitive flexible electronic devices. Here in, the correlation between tensile strain developed in MoS2 nanosheets during swift heavy ion irradiation and corresponding modifications in their surface electronic properties is investigated. With prior structural characterization by transmission electron microscopy, chemically exfoliated MoS2 nanosheets were exposed to 100 MeV Ag ion irradiation at varying fluence for creation of controlled defects. The presence of defect induced systematic tensile strain was verified by Raman spectroscopy and X-ray Diffraction analysis. The effect of ion irradiation on in-plane mode is observed to be significantly higher than that on out-of-plane mode. The contribution of irradiation induced in-plane strain on modification of the surface electronic properties of nanosheets was analyzed by work function measurement using scanning Kelvin probe microscopy. The work function value is observed to be linearly proportional to tensile strain along the basal plane indicating a systematic shifting of Fermi surface with fluence towards the valence band. PMID- 28852008 TI - Retrograde trafficking of beta-dystroglycan from the plasma membrane to the nucleus. AB - beta-Dystroglycan (beta-DG) is a transmembrane protein with critical roles in cell adhesion, cytoskeleton remodeling and nuclear architecture. This functional diversity is attributed to the ability of beta-DG to target to, and conform specific protein assemblies at the plasma membrane (PM) and nuclear envelope (NE). Although a classical NLS and importin alpha/beta mediated nuclear import pathway has already been described for beta-DG, the intracellular trafficking route by which beta-DG reaches the nucleus is unknown. In this study, we demonstrated that beta-DG undergoes retrograde intracellular trafficking from the PM to the nucleus via the endosome-ER network. Furthermore, we provided evidence indicating that the translocon complex Sec61 mediates the release of beta-DG from the ER membrane, making it accessible for importins and nuclear import. Finally, we show that phosphorylation of beta-DG at Tyr890 is a key stimulus for beta-DG nuclear translocation. Collectively our data describe the retrograde intracellular trafficking route that beta-DG follows from PM to the nucleus. This dual role for a cell adhesion receptor permits the cell to functionally connect the PM with the nucleus and represents to our knowledge the first example of a cell adhesion receptor exhibiting retrograde nuclear trafficking and having dual roles in PM and NE. PMID- 28852010 TI - Hospital-acquired Clostridium difficile infection in Mainland China: A seven-year (2009-2016) retrospective study in a large university hospital. AB - Clostridium difficile infection (CDI) is associated with risk for severe disease and high mortality. Little is known about the extent of hospital-acquired CDI in Mainland China. In this study, we aimed to investigate the annual CDI incidence, bacterial genotypes, risk factors for severe CDI and survival over a 7-year period. A total of 307 hospital-acquired CDI patients were enrolled, and 70.7% of these cases were male. CDI incidence was 3.4 per 10,000 admissions. Thirty-three different sequence types (STs) were identified, among which ST-54 (18.2%), ST-35 (16.6%) and ST-37 (12.1%) were the most prevalent. During the follow-up period, 66 (21.5%) patients developed severe CDI and 32 (10.4%) patients died in 30 days. Multivariate analysis revealed that bloodstream infection, pulmonary infection and C-reactive protein were significantly associated with severe CDI. After adjustment for potential confounders, old age, bloodstream infection, fever, mechanical ventilation, connective tissue disease, macrolide use and hypoalbuminaemia were independently associated with 30-day mortality in patients with CDI. The CDI prevalence has been low and stable in our center, and STs of Clostridium difficile were different from dominant STs in Western countries. Our data emphasize the need of continued education and surveillance of CDI to reduce the CDI burden in China. PMID- 28852012 TI - Enhanced spectral profile in the study of Doppler-broadened Rydberg ensembles. AB - Combination of the electromagnetically-induced-transparency (EIT) effect and Rydberg-state atoms has attracted great attention recently due to its potential application in the photon-photon interaction or qubit operation. In this work, we studied the Rydberg-EIT spectra with room-temperature 87Rb atoms. Spectroscopic data under various experimental parameters all showed that the contrast of EIT transparency as a function of the probe field intensity is initially enhanced, reaches a maximum value and then decays gradually. The contrast of spectral profile at the optimum probe field intensity is enhanced by 2-4 times as compared with that at weakest intensity. Moreover, the signal-to-noise ratio of the spectrum can potentially be improved by 1 to 2 orders of magnitude. We provided a theoretical model to explain this behavior and clarified its underlying mechanism. Our work overcomes the obstacle of weak signal in the Rydberg-EIT spectrum caused by an apparent relaxation rate of the Rydberg polariton and weak coupling transition strength, and provides the useful knowledge for the Rydberg EIT study. PMID- 28852011 TI - Genome-Wide Linkage-Disequilibrium Mapping to the Candidate Gene Level in Melon (Cucumis melo). AB - Cucumis melo is highly diverse for fruit traits providing wide breeding and genetic research opportunities, including genome-wide association (GWA) analysis. We used a collection of 177 accessions representing the two C. melo subspecies and 11 horticultural groups for detailed characterization of fruit traits variation and evaluation of the potential of GWA for trait mapping in melon. Through genotyping-by-sequencing, 23,931 informative SNPs were selected for genome-wide analyses. We found that linkage-disequilibrium decays at ~100 Kb in this collection and that population structure effect on association results varies between traits. We mapped several monogenic traits to narrow intervals overlapping with known causative genes, demonstrating the potential of diverse collections and GWA for mapping Mendelian traits to a candidate-gene level in melon. We further report on mapping of fruit shape quantitative trait loci (QTLs) and comparison with multiple previous QTL studies. Expansion of sample size and a more balanced representation of taxonomic groups might improve efficiency for simple traits dissection. But, as in other plant species, integrated linkage association multi-allelic approaches are likely to produce better combination of statistical power, diversity capture and mapping resolution in melon. Our data can be utilized for selection of the most appropriate accessions for such approaches. PMID- 28852013 TI - Nanoscale 2.5-dimensional surface patterning with plasmonic lithography. AB - We report an extension of plasmonic lithography to nanoscale 2.5-dimensional (2.5D) surface patterning. To obtain the impulse response of a plasmonic lithography system, we described the field distribution of a point dipole source generated by a metallic ridge aperture with a theoretical model using the concepts of quasi-spherical waves and surface plasmon-polaritons. We performed deconvolution to construct an exposure map of a target shape for patterning. For practical applications, we fabricated several nanoscale and microscale structures, such as a cone, microlens array, nanoneedle, and a multiscale structure using the plasmonic lithography system. We verified the possibility of applying plasmonic lithography to multiscale structuring from a few tens of nanometres to a few micrometres in the lateral dimension. We obtained a root-mean square error of 4.7 nm between the target shape and the patterned shape, and a surface roughness of 11.5 nm. PMID- 28852015 TI - Pitfalls of using confocal-microscopy based automated quantification of synaptic complexes in honeybee mushroom bodies (response to Peng and Yang 2016). AB - A recent study by Peng and Yang in Scientific Reports using confocal-microscopy based automated quantification of anti-synapsin labeled microglomeruli in the mushroom bodies of honeybee brains reports potentially incorrect numbers of microglomerular densities. Whereas several previous studies using visually supervised or automated counts from confocal images and analyses of serial 3D electron-microscopy data reported consistent numbers of synaptic complexes per volume, Peng and Yang revealed extremely low numbers differing by a factor of 18 or more from those obtained in visually supervised counts, and by a factor 22-180 from numbers in two other studies using automated counts. This extreme discrepancy is especially disturbing as close comparison of raw confocal images of anti-synapsin labeled whole-mount brain preparations are highly similar across these studies. We conclude that these discrepancies may reside in potential misapplication of confocal imaging followed by erroneous use of automated image analysis software. Consequently, the reported microglomerular densities during maturation and after manipulation by insecticides require validation by application of appropriate confocal imaging methods and analyses tools that rely on skilled observers. We suggest several improvements towards more reliable or standardized automated or semi-automated synapse counts in whole mount preparations of insect brains. PMID- 28852014 TI - Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction. AB - Anesthesia blocks consciousness and memory while sparing non-conscious brain activities. While the exact mechanisms of anesthetic action are unknown, the Meyer-Overton correlation provides a link between anesthetic potency and solubility in a lipid-like, non-polar medium. Anesthetic action is also related to an anesthetic's hydrophobicity, permanent dipole, and polarizability, and is accepted to occur in lipid-like, non-polar regions within brain proteins. Generally the protein target for anesthetics is assumed to be neuronal membrane receptors and ion channels, however new evidence points to critical effects on intra-neuronal microtubules, a target of interest due to their potential role in post-operative cognitive dysfunction (POCD). Here we use binding site predictions on tubulin, the protein subunit of microtubules, with molecular docking simulations, quantum chemistry calculations, and theoretical modeling of collective dipole interactions in tubulin to investigate the effect of a group of gases including anesthetics, non-anesthetics, and anesthetic/convulsants on tubulin dynamics. We found that these gases alter collective terahertz dipole oscillations in a manner that is correlated with their anesthetic potency. Understanding anesthetic action may help reveal brain mechanisms underlying consciousness, and minimize POCD in the choice and development of anesthetics used during surgeries for patients suffering from neurodegenerative conditions with compromised cytoskeletal microtubules. PMID- 28852016 TI - The histidine-rich peptide LAH4-L1 strongly promotes PAMAM-mediated transfection at low nitrogen to phosphorus ratios in the presence of serum. AB - Non-viral vectors are widely used and investigated for the delivery of genetic material into cells. However, gene delivery barriers like lysosomal degradation, serum inhibition and transient gene expression so far still limit their clinical applications. Aiming to overcome these limitations, a pH-sensitive hybrid gene vector (PSL complex) was designed by self-assembly of poly(amidoamine) (PAMAM) dendrimers, the histidine-rich peptide LAH4-L1 and the sleeping beauty transposon system (SB transposon system, a plasmid system capable of efficient and precise genomic insertion). Transfection studies revealed that PSL complexes achieved excellent efficiency in all investigated cell lines (higher than 90% in HeLa cells and over 30% in MDCK cells, a difficult-to-transfect cell line). Additionally, the PSL complexes showed high serum tolerance and exhibited outstanding transfection efficiency even in medium containing 50% serum (higher than 90% in HeLa cells). Moreover, a high level of long-term gene expression (over 30% in HeLa cells) was observed. Furthermore, PSL complexes not only resulted in high endocytosis, but also showed enhanced ability of endosomal escape compared to PAMAM/DNA complexes. These results demonstrate that simple association of PAMAM dendrimers, LAH4-L1 peptides and the SB transposon system by self-assembly is a general and promising strategy for efficient and safe gene delivery. PMID- 28852017 TI - Prognosis of HIV Patients Receiving Antiretroviral Therapy According to CD4 Counts: A Long-term Follow-up study in Yunnan, China. AB - We aim to evaluate the overall survival and associated risk factors for HIV infected Chinese patients on antiretroviral therapy (ART). 2517 patients receiving ART between 2006 and 2016 were prospectively enrolled in Yunnan province. Kaplan-Meier analyses and Cox proportional hazard regression analyses were performed. 216/2517 patients died during a median 17.5 (interquartile range [IQR] 6.8-33.2) months of follow-up. 82/216 occurred within 6 months of starting ART. Adjusted hazard ratios were10.69 (95%CI 2.38-48.02, p = 0.002) for old age, 1.94 (95%CI 1.40-2.69, p < 0.0001) for advanced WHO stage, and 0.42 (95%CI 0.27 0.63, p < 0.0001) for heterosexual transmission compared to injecting drug users. Surprisingly, adjusted hazard ratios comparing low CD4 counts group (<50 cells/ul) with high CD4 counts group (>=500 cells/ul) within six months after starting ART was 20.17 (95%CI 4.62-87.95, p < 0.0001) and it declined to 3.57 (95%CI 1.10-11.58, p = 0.034) afterwards. Age, WHO stage, transmission route are significantly independent risk factors for ART treated HIV patients. Importantly, baseline CD4 counts is strongly inversely associated with survival in the first six months; whereas it becomes a weak prognostic factor after six months of starting ART. PMID- 28852018 TI - Ape1 guides DNA repair pathway choice that is associated with drug tolerance in glioblastoma. AB - Ape1 is the major apurinic/apyrimidinic (AP) endonuclease activity in mammalian cells, and a key factor in base-excision repair of DNA. High expression or aberrant subcellular distribution of Ape1 has been detected in many cancer types, correlated with drug response, tumor prognosis, or patient survival. Here we present evidence that Ape1 facilitates BRCA1-mediated homologous recombination repair (HR), while counteracting error-prone non-homologous end joining of DNA double-strand breaks. Furthermore, Ape1, coordinated with checkpoint kinase Chk2, regulates drug response of glioblastoma cells. Suppression of Ape1/Chk2 signaling in glioblastoma cells facilitates alternative means of damage site recruitment of HR proteins as part of a genomic defense system. Through targeting "HR-addicted" temozolomide-resistant glioblastoma cells via a chemical inhibitor of Rad51, we demonstrated that targeting HR is a promising strategy for glioblastoma therapy. Our study uncovers a critical role for Ape1 in DNA repair pathway choice, and provides a mechanistic understanding of DNA repair-supported chemoresistance in glioblastoma cells. PMID- 28852019 TI - Reference-based RADseq resolves robust relationships among closely related species of lichen-forming fungi using metagenomic DNA. AB - Despite increasing availability of phylogenomic datasets, strategies to generate genome-scale data from organisms involved in symbiotic relationships remains challenging. Restriction site-associated DNA sequencing (RADseq) can effectively generated reduced representation genomic loci. However, when using metagenomic DNA from inseparable symbiotic organisms, RADseq loci may belong to any number of the organisms involved in these intimate associations. In this study, we explored the potential for a reference-based RADseq approach to generate data for lichen forming fungi from metagenomic DNA extracted from intact lichens. We simulated RAD data from draft genomes of closely related lichenized fungi to test if RADseq can reconstruct robust evolutionary relationships. Subsequently, we generated empirical RADseq data from metagenomic lichen DNA, with RADseq loci mapped back to a reference genome to exclude loci from other lichen symbionts that are represented in metagenomic libraries. In all cases, phylogenetic reconstructions using RADseq loci recovered diversification histories consistent with a previous study based on more comprehensive genome sampling. Furthermore, RADseq loci were found to resolve relationships among closely related species, which were otherwise indistinguishable using a phylogenetic species recognition criterion. Our studies revealed that a modified, reference-based RADseq approach can successfully be implemented to generate symbiont-specific phylogenomic data from metagenomic reads. PMID- 28852020 TI - Co-delivery of paclitaxel and cetuximab by nanodiamond enhances mitotic catastrophe and tumor inhibition. AB - The poor intracellular uptake and non-specific binding of anticancer drugs into cancer cells are the bottlenecks in cancer therapy. Nanocarrier platforms provide the opportunities to improve the drug efficacy. Here we show a carbon-based nanomaterial nanodiamond (ND) that carried paclitaxel (PTX), a microtubule inhibitor, and cetuximab (Cet), a specific monoclonal antibody against epidermal growth factor receptor (EGFR), inducing mitotic catastrophe and tumor inhibition in human colorectal cancer (CRC). ND-PTX blocked the mitotic progression, chromosomal separation, and induced apoptosis in the CRC cells; however, NDs did not induce these effects. Conjugation of ND-PTX with Cet (ND-PTX-Cet) was specifically binding to the EGFR-positive CRC cells and enhanced the mitotic catastrophe and apoptosis induction. Besides, ND-PTX-Cet markedly decreased tumor size in the xenograft EGFR-expressed human CRC tumors of nude mice. Moreover, ND PTX-Cet induced the mitotic marker protein phospho-histone 3 (Ser10) and apoptotic protein active-caspase 3 for mitotic catastrophe and apoptosis. Taken together, this study demonstrated that the co-delivery of PTX and Cet by ND enhanced the effects of mitotic catastrophe and apoptosis in vitro and in vivo, which may be applied in the human CRC therapy. PMID- 28852021 TI - Evolutionary conserved role of eukaryotic translation factor eIF5A in the regulation of actin-nucleating formins. AB - Elongation factor eIF5A is required for the translation of consecutive prolines, and was shown in yeast to translate polyproline-containing Bni1, an actin nucleating formin required for polarized growth during mating. Here we show that Drosophila eIF5A can functionally replace yeast eIF5A and is required for actin rich cable assembly during embryonic dorsal closure (DC). Furthermore, Diaphanous, the formin involved in actin dynamics during DC, is regulated by and mediates eIF5A effects. Finally, eIF5A controls cell migration and regulates Diaphanous levels also in mammalian cells. Our results uncover an evolutionary conserved role of eIF5A regulating cytoskeleton-dependent processes through translation of formins in eukaryotes. PMID- 28852022 TI - Multipoint Tissue Circulation Monitoring with a Flexible Optical Probe. AB - Compromised circulation is a potential complication during the postoperative period following tissue transplantation. The use of a monitoring device allows physicians to detect compromised circulation immediately. Such monitoring devices need to be continuously usable, wearable, and area-detectable. However, existing devices fail to satisfy all of these requirements simultaneously. We developed a wearable, multipoint pulse wave-monitoring device. An array of reflective optical sensors implemented on a thin film substrate was used as a lightweight and flexible probe. As a model of tissue transplantation, an inguinal flap in a Wistar rat was dissected and freed from all subcutaneous tissue. By ligating the artery or vein, ischemia or congestion was induced in the tissue. In a human study, ischemia or congestion was induced in the palm by pressing the feeding artery or cutaneous vein, respectively. The amplitude of the pulse wave was evaluated using the power spectrum of Fourier transformed signals. Pulse wave amplitude significantly decreased under compromised circulation in both animal and human models. Moreover, we accomplished 1 week of continuous wireless monitoring in healthy subjects. These results demonstrated the potential utility of the developed device in postoperative blood-flow monitoring to improve the rescue rate of transplanted tissue. PMID- 28852023 TI - The synergy between natural polyphenol-inspired catechol moieties and plant protein-derived bio-adhesive enhances the wet bonding strength. AB - Novel soybean meal-based biomimetic (STP) adhesives were fabricated via soybean meal (SM) and enhanced by tannic acid (TA) and polyetheylenimine (PEI) (TAPI) co crosslinking network based on natural polyphenol-inspired chemistry. The multiple physico-chemical interactions (including intermolecular H-bonding and covalent bonding) between the TAPI co-crosslinking system and SM matrices were examined by the Fourier transform infrared spectroscopy, solid-state 13C nuclear magnetic resonance, X-ray diffraction, thermogravimetric analysis, and scanning electron microscopy. The results showed that a dense, robust, and water-resistant adhesive layer was constructed between network-bound catechol moieties in the TAPI and SM system, endowing the STP adhesive with high wet bonding strength for plywood. As expected, TAPI-modified SM adhesives showed a 156.1% increase in wet bonding strength compared to the control SM adhesive. The adhesion meets standard requirements for interior-use plywood. Both the solid content and residual mass analysis also confirmed that the enhancement in the STP adhesive was attributable to the network crosslinking density and stiffness after integrating the TAPI system. Moreover, the thermal stability of the resultant STP adhesive exhibited a significant improvement. The proposed STP adhesive may be a promising cost effective and wet-resistant bio-adhesive for the application in the wood composites industry. PMID- 28852024 TI - A novel automatic quantification method for high-content screening analysis of DNA double strand-break response. AB - High-content screening is commonly used in studies of the DNA damage response. The double-strand break (DSB) is one of the most harmful types of DNA damage lesions. The conventional method used to quantify DSBs is gammaH2AX foci counting, which requires manual adjustment and preset parameters and is usually regarded as imprecise, time-consuming, poorly reproducible, and inaccurate. Therefore, a robust automatic alternative method is highly desired. In this manuscript, we present a new method for quantifying DSBs which involves automatic image cropping, automatic foci-segmentation and fluorescent intensity measurement. Furthermore, an additional function was added for standardizing the measurement of DSB response inhibition based on co-localization analysis. We tested the method with a well-known inhibitor of DSB response. The new method requires only one preset parameter, which effectively minimizes operator dependent variations. Compared with conventional methods, the new method detected a higher percentage difference of foci formation between different cells, which can improve measurement accuracy. The effects of the inhibitor on DSB response were successfully quantified with the new method (p = 0.000). The advantages of this method in terms of reliability, automation and simplicity show its potential in quantitative fluorescence imaging studies and high-content screening for compounds and factors involved in DSB response. PMID- 28852025 TI - Intravenous rAAV2/9 injection for murine cochlear gene delivery. AB - Gene therapy for genetic deafness is a promising approach by which to prevent hearing loss or to restore hearing after loss has occurred. Although a variety of direct approaches to introduce viral particles into the inner ear have been described, presumed physiological barriers have heretofore precluded investigation of systemic gene delivery to the cochlea. In this study, we sought to characterize systemic delivery of a rAAV2/9 vector as a non-invasive means of cochlear transduction. In wild-type neonatal mice (postnatal day 0-1), we show that intravenous injection of rAAV2/9 carrying an eGFP-reporter gene results in binaural transduction of inner hair cells, spiral ganglion neurons and vestibular hair cells. Transduction efficiency increases in a dose-dependent manner. Inner hair cells are transduced in an apex-to-base gradient, with transduction reaching 96% in the apical turn. Hearing acuity in treated animals is unaltered at postnatal day 30. Transduction is influenced by viral serotype and age at injection, with less efficient cochlear transduction observed with systemic delivery of rAAV2/1 and in juvenile mice with rAAV2/9. Collectively, these data validate intravenous delivery of rAAV2/9 as a novel and atraumatic technique for inner ear transgene delivery in early postnatal mice. PMID- 28852027 TI - Investigation of beam splitter in a zero-refractive-index photonic crystal at the frequency of Dirac-like point. AB - The Dirac-like cone dispersion of the photonic crystal induced by the three-fold accidental degeneracy at the Brillouin center is calculated in this paper. Such photonic crystals can be mapped to zero-refractive-index materials at the vicinity of the Dirac-like point frequency, and utilized to construct beam splitter of high transmission efficiency. The splitting ratio is studied as a function of the position of the input/output waveguides. Furthermore, variant beam splitters with asymmetric structures, bulk defects, and some certain bending angles are numerically simulated. Finally, we show that 1 * 2 to 1 * N beam splitting can be realized with high transmission efficiency in such a zero refractive-index photonic crystal at the frequency of Dirac-like point. The proposed structure could be a fundamental component of the high density photonic integrated circuit technique. PMID- 28852026 TI - A time series transcriptome analysis of cassava (Manihot esculenta Crantz) varieties challenged with Ugandan cassava brown streak virus. AB - A time-course transcriptome analysis of two cassava varieties that are either resistant or susceptible to cassava brown streak disease (CBSD) was conducted using RNASeq, after graft inoculation with Ugandan cassava brown streak virus (UCBSV). From approximately 1.92 billion short reads, the largest number of differentially expressed genes (DEGs) was obtained in the resistant (Namikonga) variety at 2 days after grafting (dag) (3887 DEGs) and 5 dag (4911 DEGs). At the same time points, several defense response genes (encoding LRR-containing, NBARC containing, pathogenesis-related, late embryogenesis abundant, selected transcription factors, chaperones, and heat shock proteins) were highly expressed in Namikonga. Also, defense-related GO terms of 'translational elongation', 'translation factor activity', 'ribosomal subunit' and 'phosphorelay signal transduction', were overrepresented in Namikonga at these time points. More reads corresponding to UCBSV sequences were recovered from the susceptible variety (Albert) (733 and 1660 read counts per million (cpm)) at 45 dag and 54 dag compared to Namikonga (10 and 117 cpm respectively). These findings suggest that Namikonga's resistance involves restriction of multiplication of UCBSV within the host. These findings can be used with other sources of evidence to identify candidate genes and biomarkers that would contribute substantially to knowledge based resistance breeding. PMID- 28852029 TI - Agile Blocker and Clock Jitter Tolerant Low-Power Frequency Selective Receiver with Energy Harvesting Capability. AB - In this article, a novel tunable, blocker and clock jitter tolerant, low power, quadrature phase shift frequency selective (QPS-FS) receiver with energy harvesting capability is proposed. The receiver's design embraces and integrates (i) the baseband to radio frequency (RF) impedance translation concept to improve selectivity over that of conventional homodyne receiver topologies and (ii) broadband quadrature phase shift circuitry in the RF path to remove an active multi-phase clock generation circuit in passive mixer (PM) receivers. The use of a single local oscillator clock signal with a passive clock division network improves the receiver's robustness against clock jitter and reduces the source clock frequency by a factor of N, compared to PM receivers using N switches (N>=4). As a consequence, the frequency coverage of the QPS-FS receiver is improved by a factor of N, given a clock source of maximum frequency; and, the power consumption of the whole receiver system can eventually be reduced. The tunable QPS-FS receiver separates the wanted RF band signal from the unwanted blockers/interferers. The desired RF signal is frequency down-converted to baseband, while the undesired blocker/interferer signals are reflected by the receiver, collected and could be energy recycled using an auxiliary energy harvesting device. PMID- 28852028 TI - Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults. AB - Growing evidence supports the hypothesis that type 2 diabetes (T2D) increases the risk of developing dementia. Experimental evidence from mouse models demonstrates that the induction of T2D/insulin resistance (IR) can promote the accumulation of Alzheimer's disease (AD) pathological features. However, the association of T2D with pathological and clinical phenotypes in humans is unclear. Here we investigate the relationship of indices of IR (HOMA-IR) and pancreatic beta-cell function (HOMA-B) with cognitive performance across several domains (Verbal/Visual Episodic Memory, Executive Function, Language and a measure of Global cognition) and AD biomarkers (CSF Abeta42, T-tau/P-tau, hippocampal volume and neocortical Abeta-amyloid burden). We reveal that HOMA-IR (p < 0.001) incrementally increases across diagnostic groups, becoming significantly elevated in the AD group compared with cognitively normal (CN) adults. In CN adults, higher HOMA-IR was associated with poorer performance on measures of verbal episodic memory (p = 0.010), executive function (p = 0.046) and global cognition (p = 0.007), as well as with higher CSF T-tau (p = 0.008) and P-tau (p = 0.014) levels. No association was observed with CSF Abeta or imaging modalities. Together our data suggest that IR may contribute to reduced cognitive performance and the accumulation of CSF tau biomarkers in cognitively normal adults. PMID- 28852031 TI - Infection with the Makona variant results in a delayed and distinct host immune response compared to previous Ebola virus variants. AB - Zaire Ebolavirus (ZEBOV) continues to pose a significant threat to human health as highlighted by the recent epidemic that originated in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. Although the ZEBOV variant responsible for this epidemic (Makona) shares significant genetic similarity with previously identified variants (Kikwit and Mayinga), recent reports suggest slower disease progression in nonhuman primates. However, the pathogenesis caused by the new variant is not fully understood. We present the first comprehensive approach in understanding ZEBOV-Makona pathogenesis in cynomolgus macaques by measuring changes in immune cell frequencies, plasma levels of immune mediators, and differentially expressed genes (DEGs) within whole blood (WB) and peripheral blood mononuclear cells (PBMC). Our combined approach revealed a link between: 1) increased interferon-stimulated gene expression, IFNalpha levels, and activated plasmacytoid dendritic cells; 2) higher proinflammatory gene expression, cytokine and chemokine levels, and non classical monocytes; 3) gene signature of leukocyte activation and increased granulocytes; and 4) decreased expression of lymphocyte related genes and lymphopenia. In addition, our data strongly indicate delayed disease progression as well as limited overlap (~30%) in host transcriptome changes following ZEBOV Makona infection compared to ZEBOV-Kikwit. These observations provide novel insight into the molecular mechanisms of ZEBOV-Makona pathogenesis. PMID- 28852030 TI - The association between substance P and white matter integrity in medication naive patients with major depressive disorder. AB - Substance P (SP) has been implicated in major depressive disorder (MDD), with SP antagonists being studied as potential antidepressants. Although impaired neural plasticity is considered a key mechanism in MDD pathophysiology, the association between SP and brain structural changes in depression has not been investigated. We investigated the correlations between SP levels and white matter (WM) integrity in 42 medication-naive patients with MDD and 57 healthy controls (HCs). Plasma levels of SP were determined, and diffusion tensor imaging (DTI) was performed to investigate microstructural changes in WM tracts. In patients, negative correlations between SP levels and fractional anisotropy (FA) values of the forceps minor of the corpus callosum, and positive correlations between SP levels and radial diffusivity (RD) and mean diffusivity (MD) values of the right corticospinal tract (CST) were observed, with no significant correlations in HCs. Linear regression analyses showed SP levels to significantly predict FA values of the forceps minor, and RD and MD values of the right CST in patients, but not in HCs. We consider our findings to contribute to the neurobiological evidence on the association between SP and brain structural changes in depression, which may be related with the pathophysiology and treatment of MDD. PMID- 28852032 TI - Orientation anisotropy of quantitative MRI relaxation parameters in ordered tissue. AB - In highly organized tissues, such as cartilage, tendons and white matter, several quantitative MRI parameters exhibit dependence on the orientation of the tissue constituents with respect to the main imaging magnetic field (B0). In this study, we investigated the dependence of multiple relaxation parameters on the orientation of articular cartilage specimens in the B0. Bovine patellar cartilage bone samples (n = 4) were investigated ex vivo at 9.4 Tesla at seven different orientations, and the MRI results were compared with polarized light microscopy findings on specimen structure. Dependences of T2 and continuous wave (CW)-T1rho relaxation times on cartilage orientation were confirmed. T2 (and T2*) had the highest sensitivity to orientation, followed by TRAFF2 and adiabatic T2rho. The highest dependence was seen in the highly organized deep cartilage and the smallest in the least organized transitional layer. Increasing spin-lock amplitude decreased the orientation dependence of CW-T1rho. T1 was found practically orientation-independent and was closely followed by adiabatic T1rho. The results suggest that T1 and adiabatic T1rho should be preferred for orientation-independent quantitative assessment of organized tissues such as articular cartilage. On the other hand, based on the literature, parameters with higher orientation anisotropy appear to be more sensitive to degenerative changes in cartilage. PMID- 28852033 TI - FISH-based mitotic and meiotic diakinesis karyotypes of Morus notabilis reveal a chromosomal fusion-fission cycle between mitotic and meiotic phases. AB - Mulberry (Morus spp.), in family Moraceae, is a plant with important economic value. Many polyploid levels of mulberry have been determined. In the present study, the fluorescence in situ hybridization (FISH) technique was applied in Morus notabilis, using four single-copy sequences, telomere repeats, and 5S and 25S rDNAs as probes. All the mitotic chromosomes were clearly identified and grouped into seven pairs of homologous chromosomes. Three dot chromosome pairs were distinguished by the FISH patterns of the 25S rDNA probe and a simple sequence repeat (SSR2524). According to the FISH signals, chromosome length and morphology, detailed meiotic diakinesis karyotype was constructed. Interestingly, only six bivalent chromosomes were observed in diakinesis cells. The 25S rDNA probe was used to illustrate chromosome alterations. The results indicated that mitotic chromosomes 5 and 7 fused into diakinesis chromosome 5 during the meiotic phase. In mitotic cells, the fused chromosome 5 broke into chromosomes 5 and 7. A chromosomal fusion-fission cycle between the meiotic and mitotic phases in the same individual is reported here for the first time. This finding will contribute to the understanding of karyotype evolution in plants. PMID- 28852034 TI - Association between selected antimicrobial resistance genes and antimicrobial exposure in Danish pig farms. AB - Bacterial antimicrobial resistance (AMR) in pigs is an important public health concern due to its possible transfer to humans. We aimed at quantifying the relationship between the lifetime exposure of antimicrobials and seven antimicrobial resistance genes in Danish slaughter pig farms. AMR gene levels were quantified by qPCR of total-community DNA in faecal samples obtained from 681 batches of slaughter pigs. The lifetime exposure to antimicrobials was estimated at batch level for the piglet, weaner, and finisher periods individually for the sampled batches. We showed that the effect of antimicrobial exposure on the levels of AMR genes was complex and unique for each individual gene. Several antimicrobial classes had both negative and positive correlations with the AMR genes. From 10-42% of the variation in AMR gene levels could be explained in the final regression models, indicating that antimicrobial exposure is not the only important determinant of the AMR gene levels. PMID- 28852035 TI - Effects of H2 High-pressure Annealing on HfO2/Al2O3/In0.53Ga0.47As Capacitors: Chemical Composition and Electrical Characteristics. AB - We studied the impact of H2 pressure during post-metallization annealing on the chemical composition of a HfO2/Al2O3 gate stack on a HCl wet-cleaned In0.53Ga0.47As substrate by comparing the forming gas annealing (at atmospheric pressure with a H2 partial pressure of 0.04 bar) and H2 high-pressure annealing (H2-HPA at 30 bar) methods. In addition, the effectiveness of H2-HPA on the passivation of the interface states was compared for both p- and n-type In0.53Ga0.47As substrates. The decomposition of the interface oxide and the subsequent out-diffusion of In and Ga atoms toward the high-k film became more significant with increasing H2 pressure. Moreover, the increase in the H2 pressure significantly improved the capacitance-voltage characteristics, and its effect was more pronounced on the p-type In0.53Ga0.47As substrate. However, the H2-HPA induced an increase in the leakage current, probably because of the out diffusion and incorporation of In/Ga atoms within the high-k stack. PMID- 28852036 TI - Pheromones modulate reward responsiveness and non-associative learning in honey bees. AB - Pheromones are chemical messengers that trigger stereotyped behaviors and/or physiological processes in individuals of the same species. Recent reports suggest that pheromones can modulate behaviors not directly related to the pheromonal message itself and contribute, in this way, to behavioral plasticity. We tested this hypothesis by studying the effect of pheromones on sucrose responsiveness and habituation in honey bees. We exposed workers to three pheromone components: geraniol, which in nature is used in an appetitive context, and isopentyl acetate (IPA) and 2-heptanone (2H), which signal aversive situations. Pheromones associated with an aversive context induced a significant decrease of sucrose responsiveness as 40% and 60% of bees exposed to IPA and 2H, respectively, did not respond to any sucrose concentration. In bees that responded to sucrose, geraniol enhanced sucrose responsiveness while 2H, but not IPA, had the opposite effect. Geraniol and IPA had no effect on habituation while 2H induced faster habituation than controls. Overall, our results demonstrate that pheromones modulate reward responsiveness and to a lower degree habituation. Through their effect on sucrose responsiveness they could also affect appetitive associative learning. Thus, besides conveying stereotyped messages, pheromones may contribute to individual and colony-level plasticity by modulating motivational state and learning performances. PMID- 28852038 TI - Artificial gravity effect on spin-polarized exciton-polaritons. AB - The pseudospin dynamics of long-living exciton-polaritons in a wedged 2D cavity has been studied theoretically accounting for the external magnetic field effect. The cavity width variation plays the role of the artificial gravitational force acting on a massive particle: exciton-polariton. A semi-classical model of the spin-polarization dynamics of ballistically propagating exciton-polaritons has been developed. It has been shown that for the specific choice of the magnetic field magnitude and the initial polariton wave vector the polariton polarization vector tends to an attractor on the Poincare sphere. Based on this effect, the switching of the polariton polarization in the ballistic regime has been demonstrated. The self-interference of the polariton field emitted by a point like source has been shown to induce the formation of interference patterns. PMID- 28852037 TI - The G6PD flow-cytometric assay is a reliable tool for diagnosis of G6PD deficiency in women and anaemic subjects. AB - Glucose-6-phosphate dehydrogenase (G6PD) activity is essential for redox equilibrium of red blood cells (RBCs) and, when compromised, the RBCs are more susceptible to haemolysis. 8-aminoquinolines (primaquine and tafenoquine) are used for the radical curative treatment of Plasmodium vivax malaria and can cause haemolysis in G6PD deficient subjects. Haemolytic risk is dependent on treatment dose and patient G6PD status but ultimately it correlates with the number of G6PD deficient RBCs. The G6PD spectrophotometric assay reliably identifies deficient subjects but is less reliable in heterozygous females, especially when other blood conditions are present. In this work we analysed samples with a range of G6PD phenotypes and haematologic conditions from 243 healthy volunteers of Asian or African-American heritage using both the spectrophotomeric assay and the G6PD flow-cytometric assay. Overall 18.5% of subjects (29.3% of Asian females) presented with anaemia, associated with decreased RBCs volume (MCV) and reticulocytosis; the flow-cytometric assay showed good correlation with the spectrophotometric assay (Pearson's r 0.918-0.957) and was less influenced by haemoglobin concentration, number of RBCs and number of reticulocytes. This resulted in more precise quantification of the number of G6PD deficient RBCs and presumably higher predictive power of drug induced haemolytic risk. PMID- 28852039 TI - Laser-assisted Rapid Mineralization of Human Tooth Enamel. AB - The human body has difficulty repairing damaged dental enamel, an acellular hard tissue. Researchers have sought feasible biomimicry strategies to repair enamel defects; however, few have been successfully translated to clinical applications. In this study, we propose a new method for achieving rapid enamel mineralization under a near-physiological environment. Through treatment with a laser and chelating agents, 15 MUm crystals could be grown compactly on an enamel substrate in less than 20 min. The compact crystal layer had similar structure as native enamel prisms and high elastic modulus. This layer also had the potential for further remineralization in saliva. The benefit of using laser can not only speed up the mineralization, but also control the crystal growth precisely where in need. A mechanism for how laser and chelating agents synergistically function is also proposed. This strategy offers a possibility for enamel-biomimicking repair in dental clinics. PMID- 28852040 TI - Engineering of versatile redox partner fusions that support monooxygenase activity of functionally diverse cytochrome P450s. AB - Most bacterial cytochrome P450 monooxygenases (P450s or CYPs) require two redox partner proteins for activity. To reduce complexity of the redox chain, the Bacillus subtilis flavodoxin YkuN (Y) was fused to the Escherichia coli flavodoxin reductase Fpr (R), and activity was tuned by placing flexible (GGGGS)n or rigid ([E/L]PPPP)n linkers (n = 1-5) in between. P-linker constructs typically outperformed their G-linker counterparts, with superior performance of YR-P5, which carries linker ([E/L]PPPP)5. Molecular dynamics simulations demonstrated that ([E/L]PPPP)n linkers are intrinsically rigid, whereas (GGGGS)n linkers are highly flexible and biochemical experiments suggest a higher degree of separation between the fusion partners in case of long rigid P-linkers. The catalytic properties of the individual redox partners were best preserved in the YR-P5 construct. In comparison to the separate redox partners, YR-P5 exhibited attenuated rates of NADPH oxidation and heme iron (III) reduction, while coupling efficiency was improved (28% vs. 49% coupling with B. subtilis CYP109B1, and 44% vs. 50% with Thermobifida fusca CYP154E1). In addition, YR-P5 supported monooxygenase activity of the CYP106A2 from Bacillus megaterium and bovine CYP21A2. The versatile YR-P5 may serve as a non-physiological electron transfer system for exploitation of the catalytic potential of other P450s. PMID- 28852041 TI - Sex-specific eNOS activity and function in human endothelial cells. AB - Clinical and epidemiological data show that biological sex is one of the major determinants for the development and progression of cardiovascular disease (CVD). Impaired endothelial function, characterized by an imbalance in endothelial Nitric Oxide Synthase (eNOS) activity, precedes and accelerates the development of CVD. However, whether there is any sexual dimorphism in eNOS activity and function in endothelial cells (ECs) is still unknown. Here, by independently studying human male and female ECs, we found that female ECs expressed higher eNOS mRNA and protein levels both in vitro and ex vivo. The increased eNOS expression was associated to higher enzymatic activity and nitric oxide production. Pharmacological and genetic inhibition of eNOS affected migratory properties only in female ECs. In vitro angiogenesis experiments confirmed that sprouting mostly relied on eNOS-dependent migration in female ECs. At variance, capillary outgrowth from male ECs was independent of eNOS activity but required cell proliferation. In this study, we found sex-specific differences in the EC expression, activity, and function of eNOS. This intrinsic sexual dimorphism of ECs should be further evaluated to achieve more effective and precise strategies for the prevention and therapy of diseases associated to an impaired endothelial function such as CVD and pathological angiogenesis. PMID- 28852042 TI - The MC4R genotype is associated with postpartum weight reduction and glycemic changes among women with prior gestational diabetes: longitudinal analysis. AB - The genetic variants near the Melanocortin-4 receptor gene (MC4R), a key protein regulating energy balance and adiposity, have been related to obesity and glucose metabolism. We aimed to assess whether the MC4R genotype affected longitudinal changes in body weight and glucose metabolism biomarkers among women with prior gestational diabetes mellitus (GDM). The MC4R genotype, postpartum weight reduction, and glycemic changes between after delivery and pregnancy were assessed in a cohort of 1208 Chinese women who had experienced GDM. The adiposity increasing allele (C) of the MC4R variant rs6567160 was associated with greater postpartum increase of HbA1c (beta = 0.08%; P = 0.03) and 2-hour OGTT glucose concentrations (beta = 0.25 mmol/L; P = 0.02). In addition, we found an interaction between the MC4R genotype and postpartum weight reduction on changes in fasting plasma glucose (P-interaction = 0.03). We found that the MC4R genotype was associated with postpartum glycemic changes; and the association with fasting glucose were significantly modified by postpartum weight reduction in women who had experienced GDM. PMID- 28852043 TI - Comparison of vaginal microbiota sampling techniques: cytobrush versus swab. AB - Evidence suggests the vaginal microbiota (VM) may influence risk of persistent Human Papillomavirus (HPV) infection and cervical carcinogenesis. Established cytology biobanks, typically collected with a cytobrush, constitute a unique resource to study such associations longitudinally. It is plausible that compared to rayon swabs; the most commonly used sampling devices, cytobrushes may disrupt biofilms leading to variation in VM composition. Cervico-vaginal samples were collected with cytobrush and rayon swabs from 30 women with high-grade cervical precancer. Quantitative PCR was used to compare bacterial load and Illumina MiSeq sequencing of the V1-V3 regions of the 16S rRNA gene used to compare VM composition. Cytobrushes collected a higher total bacterial load. Relative abundance of bacterial species was highly comparable between sampling devices (R2 = 0.993). However, in women with a Lactobacillus-depleted, high-diversity VM, significantly less correlation in relative species abundance was observed between devices when compared to those with a Lactobacillus species-dominant VM (p = 0.0049). Cytobrush and swab sampling provide a comparable VM composition. In a small proportion of cases the cytobrush was able to detect underlying high diversity community structure, not realized with swab sampling. This study highlights the need to consider sampling devices as potential confounders when comparing multiple studies and datasets. PMID- 28852044 TI - Electrically driven, highly efficient three-dimensional GaN-based light emitting diodes fabricated by self-aligned twofold epitaxial lateral overgrowth. AB - Improvements in the overall efficiency and significant reduction in the efficiency droop are observed in three-dimensional (3D) GaN truncated pyramid structures fabricated with air void and a SiO2 layer. This 3D structure was fabricated using a self-aligned twofold epitaxial lateral overgrowth technique, which improved both the internal quantum efficiency and the light extraction efficiency. In addition, a reduced leakage current was observed due to the effective suppression of threading dislocations. While this study focuses primarily on the blue emission wavelength region, this approach can also be applied to overcome the efficiency degradation problem in the ultraviolet, green, and red emission regions. PMID- 28852045 TI - Analysis of temporal expression profiles after sciatic nerve injury by bioinformatic method. AB - After Peripheral nerve injuries (PNI), many complicated pathophysiologic processes will happen. A global view of functional changes following PNI is essential for the looking for the adequate therapeutic approaches. In this study, we performed an in-depth analysis on the temporal expression profiles after sciatic nerve injury by bioinformatic methods, including (1) cluster analysis of the samples; (2) identification of gene co-expression modules(CEMs) correlated with the time points; (3) analysis of differentially expressed genes at each time point (DEGs-ET); (4) analysis of differentially expressed genes varying over time (DEGs-OT); (5) creating Pairwise Correlation Plot for the samples; (6) Time Series Regression Analysis; (7) Determining the pathway, GO (gene ontology) and drug by enrichment analysis. We found that at a 3 h "window period" some specific gene expression may exist after PNI, and responses to lipopolysaccharide (LPS) and TNF signaling pathway may play important roles, suggesting that the inflammatory microenvironment exists after PNI. We also found that troglitazone was closely associated with the change of gene expression after PNI. Therefore, the further evaluation of the precise mechanism of troglitazone on PNI is needed and it may contribute to the development of new drugs for patients with PNI. PMID- 28852046 TI - Fast free-of-acrylamide clearing tissue (FACT)-an optimized new protocol for rapid, high-resolution imaging of three-dimensional brain tissue. AB - Fast Free-of-Acrylamide Clearing Tissue (FACT) is a new sodium dodecyl sulfate (SDS)-based clearing protocol for the chemical clearing and imaging of brain tissue containing transgenic or immunolabeled fluorescent proteins. In the present study, we have developed this new method and optimized multiple dimensions of the workflow, including reduced clearing time, improved efficiency of fluorescent signals without the need for electrophoretic or complex instrumentations, preservation of cytoarchitectural details, optimized confocal microscopy, and accelerated data collection. We systematically compared seven clearing protocols with the FACT protocol, using transgenic mouse brains with fluorochrome expression in microglia. Only six days were required for detecting transgene-labeled markers in a 1-mm thick brain slice from adult mice, and 14 days were required for detecting antibody-labeled markers in the same-sized tissue. Preservation of fluorescent signal was achieved by decreasing clearing time, adjusting the pH of the SDS solution, and using the appropriate temperature for tissue clearing, all of which contributed to the superiority of our method. We conclude that the FACT protocol can be successfully applied to the fluorescent imaging of mouse brain tissue, and will facilitate structural analyses and connectomics of large assemblies of cells and their networks in the context of three-dimensional organ systems. PMID- 28852047 TI - TCA cycle rewiring fosters metabolic adaptation to oxygen restriction in skeletal muscle from rodents and humans. AB - In mammals, hypoxic stress management is under the control of the Hypoxia Inducible Factors, whose activity depends on the stabilization of their labile alpha subunit. In particular, the skeletal muscle appears to be able to react to changes in substrates and O2 delivery by tuning its metabolism. The present study provides a comprehensive overview of skeletal muscle metabolic adaptation to hypoxia in mice and in human subjects exposed for 7/9 and 19 days to high altitude levels. The investigation was carried out combining proteomics, qRT-PCR mRNA transcripts analysis, and enzyme activities assessment in rodents, and protein detection by antigen antibody reactions in humans and rodents. Results indicate that the skeletal muscle react to a decreased O2 delivery by rewiring the TCA cycle. The first TCA rewiring occurs in mice in 2-day hypoxia and is mediated by cytosolic malate whereas in 10-day hypoxia the rewiring is mediated by Idh1 and Fasn, supported by glutamine and HIF-2alpha increments. The combination of these specific anaplerotic steps can support energy demand despite HIFs degradation. These results were confirmed in human subjects, demonstrating that the TCA double rewiring represents an essential factor for the maintenance of muscle homeostasis during adaptation to hypoxia. PMID- 28852048 TI - Unawareness of Hepatitis B Virus Infection confers on Higher Rate of Metabolic Syndrome: A Community-based Study. AB - The objective of this study was to determine whether awareness of hepatitis B virus (HBV) serostatus was discordant with metabolic syndrome (MetS) among people with chronic HBV infection. We conducted a community-based study in four Taiwanese districts. A total of 3493 adult participants were recruited. Participants who were hepatitis B surface antigen (HBsAg) seropositive and had self-reported HBV infection were considered aware of hepatitis B (aHB); those who denied a history of HBV infection were considered unaware of hepatitis B (uaHB). Among the 454 participants who were HBsAg seropositive, 275 (60.6%) were aHB and 179 (39.3%) were uaHB. Hypertriglyceridemia showed significant inverse association with HBsAg seropositive, especially among those who were aHB. Insulin resistance was significantly, positively associated with HBsAg seropositive, especially among participants who were uaHB. Those who were uaHB had a higher risk of central obesity, hyperglycemia, insulin resistance, and MetS than those who were aHB (odds ratio = 2.33, 1.64, 2.15, 1.85, respectively, all p < 0.05). The association among the prevalence of MetS, its individual components and HBsAg seropositivity varies according to awareness of HBV infection. It is important to recognize an individual's risk for MetS, especially who were unaware of HBV infection. PMID- 28852049 TI - Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage. AB - This study evaluates the relationship between single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID) metabolism and related pathways and spontaneous abortion (SAB, gestation < 20 weeks) risk. Women were enrolled in Right from the Start (2004-2010) prospective cohort. Periconceptional NSAIDs reported through the sixth week of pregnancy were obtained from study interviews. We evaluated 201 SNPs in 600 European American women. Interaction analyses between NSAID use and SNPs were conducted using logistic regression, adjusted for confounders. We also evaluated prostaglandin E2 urinary metabolite (PGE-M) in an independent population for association with SNPs using linear regression. NSAID use was reported by 63% of cases and 62% controls. The most significant interaction was at prostacyclin synthase (PGIS) rs5602 (OR = 0.34, 95% CI 0.19-0.60, p = 2.45 * 10-4) and was significant after a Bonferroni correction. NSAID users were protected from SAB (OR = 0.78, 95% CI 0.56-1.10), while non-NSAID users were at increased risk (OR = 2.11, 95% CI 1.35-3.29) in rs5602 stratified analyses. rs5602 also associated with increased PGE-M levels (Beta = 0.09, 95% CI -0.002-0.19, p = 0.033). We identified an association between a PGIS variant and SAB risk that is modified by NSAIDs use during pregnancy and directly associated with increased levels of PGE metabolites. This suggests the potential use of genetic information to guide pharmaceutical intervention to prevent adverse pregnancy outcomes. PMID- 28852050 TI - Neurotransmitters and neuropeptides in gonadal steroid receptor-expressing cells in medial preoptic area subregions of the male mouse. AB - Testosterone is involved in male sexual, parental and aggressive behaviors through the androgen receptor (AR) and estrogen receptor (ER) alpha expressed in the brain. Although several studies have demonstrated that ERalpha and AR in the medial preoptic area (MPOA) are required for exhibiting sexual and aggressive behaviors of male mice, the molecular characteristics of ERalpha- and AR expressing cells in the mouse MPOA are largely unknown. Here, we performed in situ hybridization for neurotransmitters and neuropeptides, combined with immunohistochemistry for ERalpha and AR to quantitate and characterize gonadal steroid receptor-expressing cells in the MPOA subregions of male mice. Prodynorphin, preproenkephalin (Penk), cocaine- and amphetamine-related transcript, neurotensin, galanin, tachykinin (Tac)1, Tac2 and thyrotropin releasing hormone (Trh) have distinct expression patterns in the MPOA subregions. Gad67-expressing cells were the most dominant neuronal subtype among the ERalpha- and AR-expressing cells throughout the MPOA. The percentage of ERalpha- and AR immunoreactivities varied depending on the neuronal subtype. A substantial proportion of the neurotensin-, galanin-, Tac2- and Penk-expressing cells in the MPOA were positive for ERalpha and AR, whereas the vast majority of the Trh expressing cells were negative. These results suggest that testosterone exerts differential effects depending on both the neuronal subtypes and MPOA subregions. PMID- 28852051 TI - Effective method for drug injection into subcutaneous tissue. AB - Subcutaneous injection of drug solution is widely used for continuous and low dose drug treatment. Although the drug injections have been administered for a long time, challenges in the design of injection devices are still needed to minimize the variability, pain, or skin disorder by repeated drug injections. To avoid these adverse effects, systematic study on the effects of injection conditions should be conducted to improve the predictability of drug effect. Here, the effects of injection conditions on the drug permeation in tissues were investigated using X-ray imaging technique which provides real-time images of drug permeation with high spatial resolution. The shape and concentration distribution of the injected drug solution in the porcine subcutaneous and muscle tissues are visualized. Dynamic movements of the wetting front (WF) and temporal variations of water contents in the two tissues are quantitatively analyzed. Based on the quantitative analysis of the experimental data, the permeability of drug solution through the tissues are estimated according to permeation direction, injection speed, and tissue. The present results would be helpful for improving the performance of drug injection devices and for predicting the drug efficacy in tissues using biomedical simulation. PMID- 28852052 TI - TGF-beta participates choroid neovascularization through Smad2/3-VEGF/TNF-alpha signaling in mice with Laser-induced wet age-related macular degeneration. AB - Choroidal neovascularization(CNV) is the most severe complication in Age-related macular degeneration(AMD) and the most common cause of irreversible blindness in the elderly in developed world. The aim of this study was to identify the effect of transforming growth factor-beta(TGF-beta) and Smad2/3-VEGF/TNF-alpha signaling on CNV angiopoiesis, and to explore TGF-beta inhibitors on the development of CNV in a CNV mouse model. Fundus fluorescein angiography(FFA) was used to evaluate the laser-induced CNV formation. The histology of CNV lesions stained with hematoxylin-eosin(HE) was obtained. The immunofluorescent staining was performed to determine TGF-beta protein expression. The expressions of TGF-beta, phosphorylated Smad2/3, VEGF and TNF-alpha were determined by using Western blot analysis. The CNV areas were analyzed by using fluorescein stain on RPE/choroid sclera flat mounts. We found the levels of TGF-beta protein expression increasingly reached the peak till 3rd week during the CNV development. The protein levels of VEGF and TNF-alpha also increased significantly in CNV mice, which were inhibited by a synthetic TGF-beta inhibitor LY2157299 or a natural TGF beta inhibitor Decorin. The phosphorylated Smad2/3 levels increased significantly in CNV mice, but this response was profoundly suppressed by the TGF-beta inhibitors. Here we have demonstrated that TGF-beta/Smad signaling plays an important role in Laser-induced CNV formation through down-regulation of VEGF and TNF-alpha expressions, suggesting TGF-beta inhibitors may provide an alternative to traditional methods in wet AMD treatment. PMID- 28852053 TI - Opposite trends in the genus Monsonia (Geraniaceae): specialization in the African deserts and range expansions throughout eastern Africa. AB - The African Austro-temperate Flora stands out by its important species richness. A distinctive element of this flora is Monsonia (Geraniaceae), mostly found in the Namib-Karoo but also in the Natal-Drakensberg, the Somalian Zambezian and the Saharo-Arabian regions. Here, we reconstruct the evolution and biogeographic history of Monsonia based on nuclear and plastid markers, and examine the role of morphological and niche evolution in its diversification using species distribution modeling and macroevolutionary models. Our results indicate that Monsonia first diversified in the Early Miocene c.21 Ma, coinciding with the start of desertification in southwestern Africa. An important diversification occurred c. 4-6 Ma, after a general cooling trend in western South Africa and the rising of the Eastern African Mountains. The resulting two main lineages of Monsonia are constituted by: (1) Namib-Karoo succulents, and (2) herbs of the Natal-Drakensberg plus three species that further colonised steppes in north and eastern Africa. The highest diversity of Monsonia is found in the Namib-Karoo coastal belt, within a mosaic-like habitat structure. Diversification was likely driven by biome shifts and key innovations such as water-storing succulent stems and anemochorous fruits. In contrast, and unlike other arid-adapted taxa, all species of Monsonia share a C3 metabolism. PMID- 28852054 TI - Tunable odd-frequency triplet pairing states and skyrmion modes in chiral p-wave superconductor. AB - Bogliubov-de Gennes equations are solved self-consistently to investigate the properties of bound states in chiral p-wave superconductive disks. It shows that either an s-wave or the mixed d- and s-wave state with odd-frequency and spin triplet symmetry is induced at the vortex core, depending both on the chirality of the pairing states and on the vortex topology. It is also found that the odd frequency triplet even parity (OTE) bound state can be manipulated with a local non-magnetic potential. Interestingly, with an appropriate potential amplitude, the zero-energy OTE bound state can be stabilized at a distance from the vortex core and from the local potential. Possible existences of the Majorana fermion modes are expected if the particle-hole symmetry property is applied to the zero energy OTE bound state. Moreover, skyrmion modes with an integer topological charge have been found to exist. PMID- 28852055 TI - Maximizing energy coupling to complex plasmonic devices by injecting light into eigenchannels. AB - Surface plasmon polaritons have attracted broad attention in the optoelectronics field due to their ability to merge nanoscale electronics with high-speed optical communication. As the complexity of optoelectronic devices increases to meet various needs, this integration has been hampered by the low coupling efficiency of light to plasmonic modes. Here we present a method to maximize the coupling of far-field optical waves to plasmonic waves for arbitrarily complex devices. The method consists of experimentally identifying the eigenchannels of a given nanostructure and shaping the wavefront of incident light to a particular eigenchannel that maximizes the generation of plasmonic waves. Our proposed approach increases the coupling efficiency almost four-fold with respect to the uncontrolled input. Our study will help to facilitate the integration of electronics and photonics. PMID- 28852056 TI - Electronic properties of (Sb;Bi)2Te3 colloidal heterostructured nanoplates down to the single particle level. AB - We investigate the potential use of colloidal nanoplates of Sb2Te3 by conducting transport on single particle with in mind their potential use as 3D topological insulator material. We develop a synthetic procedure for the growth of plates with large lateral extension and probe their infrared optical and transport properties. These two properties are used as probe for the determination of the bulk carrier density and agree on a value in the 2-3 * 1019 cm-3 range. Such value is compatible with the metallic side of the Mott criterion which is also confirmed by the weak thermal dependence of the conductance. By investigating the transport at the single particle level we demonstrate that the hole mobility in this system is around 40 cm2V-1s-1. For the bulk material mixing n-type Bi2Te3 with the p-type Sb2Te3 has been a successful way to control the carrier density. Here we apply this approach to the case of colloidally obtained nanoplates by growing a core-shell heterostructure of Sb2Te3/Bi2Te3 and demonstrates a reduction of the carrier density by a factor 2.5. PMID- 28852057 TI - Placental Dysfunction Underlies Increased Risk of Fetal Growth Restriction and Stillbirth in Advanced Maternal Age Women. AB - Pregnancies in women of advanced maternal age (AMA) are susceptible to fetal growth restriction (FGR) and stillbirth. We hypothesised that maternal ageing is associated with utero-placental dysfunction, predisposing to adverse fetal outcomes. Women of AMA (>=35 years) and young controls (20-30 years) with uncomplicated pregnancies were studied. Placentas from AMA women exhibited increased syncytial nuclear aggregates and decreased proliferation, and had increased amino acid transporter activity. Chorionic plate and myometrial artery relaxation was increased compared to controls. AMA was associated with lower maternal serum PAPP-A and sFlt and a higher PlGF:sFlt ratio. AMA mice (38-41 weeks) at E17.5 had fewer pups, more late fetal deaths, reduced fetal weight, increased placental weight and reduced fetal:placental weight ratio compared to 8 12 week controls. Maternofetal clearance of 14C-MeAIB and 3H-taurine was reduced and uterine arteries showed increased relaxation. These studies identify reduced placental efficiency and altered placental function with AMA in women, with evidence of placental adaptations in normal pregnancies. The AMA mouse model complements the human studies, demonstrating high rates of adverse fetal outcomes and commonalities in placental phenotype. These findings highlight placental dysfunction as a potential mechanism for susceptibility to FGR and stillbirth with AMA. PMID- 28852058 TI - Key glycolytic branch influences mesocarp oil content in oil palm. AB - The fructose-1,6-bisphosphate aldolase catalyzed glycolysis branch that forms dihydroxyacetone phosphate and glyceraldehyde-3-phosphate was identified as a key driver of increased oil synthesis in oil palm and was validated in Saccharomyces cerevisiae. Reduction in triose phosphate isomerase (TPI) activity in a yeast knockdown mutant resulted in 19% increase in lipid content, while yeast strains overexpressing oil palm fructose-1,6-bisphosphate aldolase (EgFBA) and glycerol-3 phosphate dehydrogenase (EgG3PDH) showed increased lipid content by 16% and 21%, respectively. Genetic association analysis on oil palm SNPs of EgTPI SD_SNP_000035801 and EgGAPDH SD_SNP_000041011 showed that palms harboring homozygous GG in EgTPI and heterozygous AG in EgGAPDH exhibited higher mesocarp oil content based on dry weight. In addition, AG genotype of the SNP of EgG3PDH SD_SNP_000008411 was associated with higher mean mesocarp oil content, whereas GG genotype of the EgFBA SNP SD_SNP_000007765 was favourable. Additive effects were observed with a combination of favourable alleles in TPI and FBA in Nigerian x AVROS population (family F7) with highest allele frequency GG.GG being associated with a mean increase of 3.77% (p value = 2.3E-16) oil content over the Family 1. An analogous effect was observed in yeast, where overexpressed EgFBA in TPI - resulted in a 30% oil increment. These results provide insights into flux balances in glycolysis leading to higher yield in mesocarp oil-producing fruit. PMID- 28852059 TI - Comparative RNA-Seq Analysis Uncovers a Complex Regulatory Network for Soybean Cyst Nematode Resistance in Wild Soybean (Glycine soja). AB - Soybean cyst nematode (SCN) is the most damaging pest of soybean worldwide. The molecular mechanism of SCN resistance remains largely unknown. We conducted a global RNA-seq comparison between a resistant genotype (S54) and a susceptible genotype (S67) of Glycine soja, the wild progenitor of soybean, to understand its regulatory network in SCN defense. The number of differentially expressed genes (DEGs) in S54 (2,290) was much larger than that in S67 (555). A number of defense related genes/pathways were significantly induced only in S54, while photosynthesis and several metabolic pathways were affected in both genotypes with SCN infection. These defense-associated DEGs were involved in pathogen recognition, calcium/calmodulin-mediated defense signaling, jasmonic acid (JA)/ethylene (ET) and sialic acid (SA)-involved signaling, the MAPK signaling cascade, and WRKY-involved transcriptional regulation. Our results revealed a comprehensive regulatory network involved in SCN resistance and provided insights into the complex molecular mechanisms of SCN resistance in wild soybean. PMID- 28852060 TI - FMNL2 and -3 regulate Golgi architecture and anterograde transport downstream of Cdc42. AB - The Rho-family small GTPase Cdc42 localizes at plasma membrane and Golgi complex and aside from protrusion and migration operates in vesicle trafficking, endo- and exocytosis as well as establishment and/or maintenance of cell polarity. The formin family members FMNL2 and -3 are actin assembly factors established to regulate cell edge protrusion during migration and invasion. Here we report these formins to additionally accumulate and function at the Golgi apparatus. As opposed to lamellipodia, Golgi targeting of these proteins required both their N terminal myristoylation and the interaction with Cdc42. Moreover, Golgi association of FMNL2 or -3 induced a phalloidin-detectable actin meshwork around the Golgi. Importantly, functional interference with FMNL2/3 formins by RNAi or CRISPR/Cas9-mediated gene deletion invariably induced Golgi fragmentation in different cell lines. Furthermore, absence of these proteins led to enlargement of endosomes as well as defective maturation and/or sorting into late endosomes and lysosomes. In line with Cdc42 - recently established to regulate anterograde transport through the Golgi by cargo sorting and carrier formation - FMNL2/3 depletion also affected anterograde trafficking of VSV-G from the Golgi to the plasma membrane. Our data thus link FMNL2/3 formins to actin assembly-dependent functions of Cdc42 in anterograde transport through the Golgi apparatus. PMID- 28852061 TI - CD271 determines migratory properties of melanoma cells. AB - Melanoma cell expression of the nerve growth factor receptor CD271 is associated with stem-like properties. However, the contributing role of the receptor in melanoma cell migration is elusive. Here, we explored extracranial (skin, soft tissue, lymph node and liver, n = 13) and matched brain metastases (BM, n = 12) and observed a heterogeneous distribution of phenotypically distinct subsets of CD271+ cells. In addition, we observed that CD271 expression gradually rises along with melanoma progression and metastasis by exploration of publicly available expression data of nevi, primary melanoma (n = 31) and melanoma metastases (n = 54). Furthermore, we observed highest levels of CD271 in BM. Sub clustering identified 99 genes differentially expressed among CD271high and CD271low (p < 0.05) BM-subgroups. Comparative analysis of subsets revealed increased ( >= 1.5fold, log2) expression of migration-associated genes and enrichment of CD271-responsible genes involved in DNA-repair and stemness. Live cell-imaging based scratch-wound assays of melanoma cells with stable knock-down of CD271 revealed a significantly reduced cell migration (3.9fold, p = 1.2E-04) and a reduced expression of FGF13, CSPG4, HMGA2 and AKT3 major candidate regulatory genes of melanoma cell migration. In summary, we provide new insights in melanoma cell migration and suggest that CD271 serves as a candidate regulator, sufficient to determine cellular properties of melanoma brain metastatic cells. PMID- 28852062 TI - Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage. AB - Farnesoid X receptor (FXR) activation has been reported to reduce inflammation and oxidative stress. Because both inflammation and oxidative stress are critical for tissue destruction during kidney ischemia reperfusion (I/R) injury, we investigated the protective role of FXR against kidney damage induced by I/R in mice. Mice undergoing renal I/R developed the typical features of acute kidney injury (AKI): increased creatinine, albuminuria, tubular necrosis and apoptosis. Inflammatory cytokine production and oxidative stress were also markedly increased. In mice pretreated with 6-ethyl-chenodeoxycholic acid (6-ECDCA), a selective FXR agonist, I/R induced changes were prevented and renal function and structure were improved. Moreover, FXR activation also effectively prevented the subsequent progression of AKI to chronic kidney disease (CKD) by ameliorating glomerulosclerosis and interstitial fibrosis and by suppressing fibrogenic gene expression. FXR mRNA levels were inversely correlated with the progression to CKD in mice and with the degree of interstitial fibrosis in human biopsies. In further experiments administering 6-ECDCA to renal proximal tubular cells cultured under hypoxia, the renoprotective effects of FXR activation were associated with inhibition of oxidative and ER stress and with increased antioxidant activity. In conclusion, FXR agonists may have a therapeutic role in conditions associated with ischemic kidney damage. PMID- 28852063 TI - External validation of the NUn score for predicting anastomotic leakage after oesophageal resection. AB - Early detection of anastomotic leakage (AL) after oesophageal resection for malignancy is crucial. This retrospective study validates a risk score, predicting AL, which includes C-reactive protein, albumin and white cell count in patients undergoing oesophageal resection between 2003 and 2014. For validation of the NUn score a receiver operating characteristic (ROC) curve is estimated. Area under the ROC curve (AUC) is reported with 95% confidence interval (CI). Among 258 patients (79.5% male) 32 patients showed signs of anastomotic leakage (12.4%). NUn score in our data has a median of 9.3 (range 6.2-17.6). The odds ratio for AL was 1.31 (CI 1.03-1.67; p = 0.028). AUC for AL was 0.59 (CI 0.47 0.72). Using the original cutoff value of 10, the sensitivity was 45.2% an the specificity was 73.8%. This results in a positive predictive value of 19.4% and a negative predictive value of 90.6%. The proportion of variation in AL occurrence, which is explained by the NUn score, was 2.5% (PEV = 0.025). This study provides evidence for an external validation of a simple risk score for AL after oesophageal resection. In this cohort, the NUn score is not useful due to its poor discrimination. PMID- 28852064 TI - Comprehensive transcriptome analyses reveal tomato plant responses to tobacco rattle virus-based gene silencing vectors. AB - In plants, virus-induced gene silencing (VIGS) is a popular tool for functional genomic studies or rapidly assessing individual gene functions. However, molecular details regarding plant responses to viral vectors remain elusive, which may complicate experimental designs and data interpretation. To this end, we documented whole transcriptome changes of tomato elicited by the application of the most widely used tobacco rattle virus (TRV)-based vectors, using comprehensive genome-wide analyses. Our data illustrated multiple biological processes with functional implications, including (1) the enhanced activity of miR167 in guiding the cleavage of an auxin response factor; (2) reduced accumulation of phased secondary small interfering RNAs from two genomic loci; (3) altered expression of ~500 protein-coding transcripts; and (4) twenty long noncoding RNAs specifically responsive to TRV vectors. Importantly, we unraveled large-scale changes in mRNA alternative splicing patterns. These observations will facilitate future application of VIGS vectors for functional studies benefiting the plant research community and help deepen the understanding of plant-virus interactions. PMID- 28852065 TI - Perturbation of formate pathway and NADH pathway acting on the biohydrogen production. AB - The formate pathway and NADH pathway as two common hydrogen-producing metabolic pathways have been well characterized to understand and improve biohydrogen production. These two pathways have been thought to be separate and have been independently investigated. However, in this study, perturbation of genes (hycA, fdhF, fhlA, ldhA, nuoB, hybO, fdh1, narP, and ppk) in Enterobacter aerogenes related to the formate pathway or NADH pathway revealed that these two pathways affected each other. Further metabolic analysis suggested that a linear relationship existed between the relative change of hydrogen yield in the formate pathway or NADH pathway and the relative change of NADH yield or ATP yield. Thus, this finding provides new insight into the role of cellular reducing power and energy level in the hydrogen metabolism. It also establishes a rationale for improving hydrogen production from a global perspective. PMID- 28852066 TI - A novel enzyme-assisted approach for efficient extraction of Z-ligustilide from Angelica sinensis plants. AB - Endophytes coexist with plants, in part, due to cellulase that allow saccharification of plant cell walls. The cellulase enzymes found in naturally occurring endophytes may exhibit stronger activity and more specificity than commercially available cellulase for enzyme-assisted extraction of compounds from medicinal plant materials. In order to identify endophytes with high cellulase activity, we screened endophytes taken from different parts of Angelica sinensis using the Congo red staining method. We identified three strains with higher cellulase activity. Of the 3 strains identified, No.Lut1201 increased the yield of extracted Z-ligustilide 2 fold compared to commercially available cellulase (Ningxia Sunson) using a cellulase-assisted extraction method and traditional extraction methods. Scanning electron microscopy clearly demonstrated that the cellulase extracted from endophytes enhance cell wall polysaccharide degradation as well as Z-ligustilide extraction from Radix Angelica sinensis (RAS). The current study provides a new method and ideas of using cellulase of endophytes for improving the extraction of compounds from medicinal plants. PMID- 28852067 TI - Light-induced Conductance Switching in Photomechanically Active Carbon Nanotube Polymer Composites. AB - Novel, optically responsive devices with a host of potential applications have been demonstrated by coupling carbon nanomaterials with photochromic molecules. For light-induced conductance switching in particular, we have recently shown that carbon nanotube-polymer nanocomposites containing azobenzene are very attractive and provide stable and non-degradable changes in conductivity over time at standard laboratory conditions. In these composites, the photoswitching mechanisms are based on light-induced changes in electronic properties and related to the Pool-Frenkel conduction mechanism. However, no link between conductivity switching and the molecular motion of azobenzene chromophores could be found due to application of high elastic modulus polymer matrices. Here we report on single wall carbon nanotube-polymer nanocomposites with a soft polycaprolactone polymer host. Such a system clearly shows the transfer of light induced, nano-sized molecular motion to macroscopic thickness changes of the composite matrix. We demonstrate that these photomechanical effects can indeed overshadow the electronic effects in conductivity switching behavior and lead to a reversion of the conductivity switching direction near the percolation threshold. PMID- 28852069 TI - Radio frequency surface plasma oscillations: electrical excitation and detection by Ar/Ag(111). AB - We electrically excite surface plasma oscillations on a Ag(111) single crystal by alternating electric charging at radio frequency. The radio frequency signal energy of 2.2 MUeV, used to induce surface plasma oscillations, is about 5 to 6 orders of magnitude lower than the plasmon energies reachable by optical excitation or electron impact. The detection of the surface plasma oscillations is achieved by nano-fabricated 2D single-crystal sensor-islands of Ar atoms, which are shown by imaging with a scanning tunneling microscope to restructure in response to the radio frequency surface plasma oscillations, providing nanometer spatial resolution and a characteristic decay time of ~150 ns. PMID- 28852068 TI - Interaction of lipopolysaccharides at intermolecular sites of the periplasmic Lpt transport assembly. AB - Transport of lipopolysaccharides (LPS) to the surface of the outer membrane is essential for viability of Gram-negative bacteria. Periplasmic LptC and LptA proteins of the LPS transport system (Lpt) are responsible for LPS transfer between the Lpt inner and outer membrane complexes. Here, using a monomeric E. coli LptA mutant, we first show in vivo that a stable LptA oligomeric form is not strictly essential for bacteria. The LptC-LptA complex was characterized by a combination of SAXS and NMR methods and a low resolution model of the complex was determined. We were then able to observe interaction of LPS with LptC, the monomeric LptA mutant as well as with the LptC-LptA complex. A LptC-LPS complex was built based on NMR data in which the lipid moiety of the LPS is buried at the interface of the two beta-jellyrolls of the LptC dimer. The selectivity of LPS for this intermolecular surface and the observation of such cavities at homo- or heteromolecular interfaces in LptC and LptA suggests that intermolecular sites are essential for binding LPS during its transport. PMID- 28852070 TI - Overexpression of C-type Natriuretic Peptide in Endothelial Cells Protects against Insulin Resistance and Inflammation during Diet-induced Obesity. AB - The endogenous peptide C-type natriuretic peptide (CNP) binds its receptor, guanylyl cyclase B (GCB), and is expressed by endothelial cells in diverse tissues. Because the endothelial cells of visceral adipose tissue have recently been reported to play a role in lipid metabolism and inflammation, we investigated the effects of CNP on features of obesity by using transgenic (Tg) mice in which CNP was placed under the control of the Tie2 promoter and was thus overexpressed in endothelial cells (E-CNP). Here we show that increased brown adipose tissue thermogenesis in E-CNP Tg mice increased energy expenditure, decreased mesenteric white adipose tissue (MesWAT) fat weight and adipocyte hypertrophy, and prevented the development of fatty liver. Furthermore, CNP overexpression improved glucose tolerance, decreased insulin resistance, and inhibited macrophage infiltration in MesWAT, thus suppressing pro-inflammation during high-fat diet-induced obesity. Our findings indicate an important role for the CNP produced by the endothelial cells in the regulation of MesWAT hypertrophy, insulin resistance, and inflammation during high-fat diet-induced obesity. PMID- 28852071 TI - Sonic Hedgehog mimetic prevents leukocyte infiltration into the CNS during acute HIV infection. AB - Infiltration of infected leukocytes culminates in establishment of a brain niche for Human Immunodeficiency Virus (HIV) during acute phase of infection, initiating an ongoing cascade of persistent viral replication and inflammation, that causes irreversible neuronal injury and HIV associated neurocognitive disease (HAND). In this study, humanized mice were treated with Smoothened Agonist (SAG), a Sonic Hedgehog (Shh) mimetic in order to fortify blood brain barrier (BBB) and dampen leukocyte extravasation into CNS during AHI. Results indicate that SAG treatment reduced viral burden in the CNS immediately after HIV transmission, but also conferred extended neuroprotection via increased BBB integrity (elevated levels of tight-junction protein, Claudin 5, and reduced S100B levels in periphery). These mice also showed healthier neurons with thick, uniform dendrites and reduced numbers of activated astrocytes. Additional in vitro experiments suggested SAG treatment was not associated with the establishment or reversal of latency in the target cells. Altogether, these findings validate neuroprotective role of Shh signaling and highlight the therapeutic potential of Shh mimetics against CNS complications associated with HIV infection. Further our results strongly demonstrate that pharmacological interventions to reduce leukocyte mobilization during early HIV infection, can provide prolonged neuroprotection, which might significantly delay the onset of HAND. PMID- 28852072 TI - Synergistic impact of mutations in Hepatitis B Virus genome contribute to its occult phenotype in chronic Hepatitis C Virus carriers. AB - We characterized occult HBV (OHBV) from hepatitis B surface antigen (HBsAg) negative chronic HCV carriers of Eastern India to explore the impact of genomic variability of HBV in causing undetectability of HBsAg and low viremia that define the occult phenomenon. Screening of sera samples revealed the presence of OHBV in 17.8% of HCV-infected patients. Determination of full-length OHBV sequences and comparison with that from HBsAg-positive carriers led to the detection of distinct substitutions/mutations in PreS2, S, P and X ORFs and in X promoter and Enhancer-II of OHBV. These mutations were introduced in wild-type HBV and their effects were evaluated by transfection in Huh7 cells. In vitro assays demonstrated that S-substitutions resulted in antigenically modified HBsAg that escaped detection by immunoassays whereas those in ORF-P caused significant decline in viral replication. Impairment in Enhancer-II and X-promoter activities were noted due to occult-associated mutations that generated reduced pregenomic RNA and intracellular HBV-DNA. Additionally, Enhancer-II mutations altered the small to large surface protein ratio and diminished extracellular HBV-DNA and HBsAg secretion. Further, mutations in PreS2, X and enhancer-II increased Grp78 promoter activity, suggesting that OHBV could trigger endoplasmic reticulum stress. Thus viral mutations contribute synergistically towards the genesis of occult phenotype and disease progression. PMID- 28852073 TI - Sensitivity-controllable refractive index sensor based on reflective theta-shaped microfiber resonator cooperated with Vernier effect. AB - In this paper, we report a sensitivity-controllable refractive index (RI) sensor based on a reflective theta-shaped microfiber resonator cooperated with Vernier effect. The theta-shaped microfiber resonator is a reflective all-fiber device with comb spectrum under weak coupling condition. By cascading it with a fiber Fabry-Perot interferometer, Vernier effect is generated to demodulate surrounding RI with enhanced sensitivity. Theoretical analysis reveals that RI sensitivity of the combined structure with Vernier effect is m times higher than the sensitivity of singular theta-shaped microfiber resonator. Moreover, by adjusting cavity length of the theta-shaped microfiber resonator, magnification factor M = (m + 1) can be tuned which enables the RI sensitivity to be controlled. Experimental result demonstrates that the RI sensitivity can be widely tuned from 311.77 nm/RIU (Reflective index unit) to 2460.07 nm/RIU when the cavity length of the theta-shaped microfiber resonator is adjusted from 9.4 mm to 8.7 mm. The theta shaped microfiber resonator based all-fiber RI sensor featuring controllable sensitivity and compact size can be widely used for chemical and biological detections. The proposed scheme of generating Vernier effect also offers a universal idea to increase measurement sensitivity for optical fiber sensing structures with comb spectrum. PMID- 28852074 TI - Mapping White Matter Microstructure in the One Month Human Brain. AB - White matter microstructure, essential for efficient and coordinated transmission of neural communications, undergoes pronounced development during the first years of life, while deviations to this neurodevelopmental trajectory likely result in alterations of brain connectivity relevant to behavior. Hence, systematic evaluation of white matter microstructure in the normative brain is critical for a neuroscientific approach to both typical and atypical early behavioral development. However, few studies have examined the infant brain in detail, particularly in infants under 3 months of age. Here, we utilize quantitative techniques of diffusion tensor imaging and neurite orientation dispersion and density imaging to investigate neonatal white matter microstructure in 104 infants. An optimized multiple b-value diffusion protocol was developed to allow for successful acquisition during non-sedated sleep. Associations between white matter microstructure measures and gestation corrected age, regional asymmetries, infant sex, as well as newborn growth measures were assessed. Results highlight changes of white matter microstructure during the earliest periods of development and demonstrate differential timing of developing regions and regional asymmetries. Our results contribute to a growing body of research investigating the neurobiological changes associated with neurodevelopment and suggest that characteristics of white matter microstructure are already underway in the weeks immediately following birth. PMID- 28852075 TI - Localization and Orientation of Xanthophylls in a Lipid Bilayer. AB - Xanthophylls (polar carotenoids) play diverse biological roles, among which are modulation of the physical properties of lipid membranes and protection of biomembranes against oxidative damage. Molecular mechanisms underlying these functions are intimately related to the localization and orientation of xanthophyll molecules in lipid membranes. In the present work, we address the problem of localization and orientation of two xanthophylls present in the photosynthetic apparatus of plants and in the retina of the human eye, zeaxanthin and lutein, in a single lipid bilayer membrane formed with dimyristoylphosphatidylcholine. By using fluorescence microscopic analysis and Raman imaging of giant unilamellar vesicles, as well as molecular dynamics simulations, we show that lutein and zeaxanthin adopt a very similar transmembrane orientation within a lipid membrane. In experimental and computational approach, the average tilt angle of xanthophylls relative to the membrane normal is independently found to be ~40 deg, and results from hydrophobic mismatch between the membrane thickness and the distance between the terminal hydroxyl groups of the xanthophylls. Consequences of such a localization and orientation for biological activity of xanthophylls are discussed. PMID- 28852076 TI - A novel approach for the prediction of species-specific biotransformation of xenobiotic/drug molecules by the human gut microbiota. AB - The human gut microbiota is constituted of a diverse group of microbial species harbouring an enormous metabolic potential, which can alter the metabolism of orally administered drugs leading to individual/population-specific differences in drug responses. Considering the large heterogeneous pool of human gut bacteria and their metabolic enzymes, investigation of species-specific contribution to xenobiotic/drug metabolism by experimental studies is a challenging task. Therefore, we have developed a novel computational approach to predict the metabolic enzymes and gut bacterial species, which can potentially carry out the biotransformation of a xenobiotic/drug molecule. A substrate database was constructed for metabolic enzymes from 491 available human gut bacteria. The structural properties (fingerprints) from these substrates were extracted and used for the development of random forest models, which displayed average accuracies of up to 98.61% and 93.25% on cross-validation and blind set, respectively. After the prediction of EC subclass, the specific metabolic enzyme (EC) is identified using a molecular similarity search. The performance was further evaluated on an independent set of FDA-approved drugs and other clinically important molecules. To our knowledge, this is the only available approach implemented as 'DrugBug' tool for the prediction of xenobiotic/drug metabolism by metabolic enzymes of human gut microbiota. PMID- 28852077 TI - Stress Writing Textured Graphite Conducting Wires/Patterns in Insulating Amorphous Carbon Matrix as Interconnects. AB - This study reports a mechanical stress-based technique that involves scratching or imprinting to write textured graphite conducting wires/patterns in an insulating amorphous carbon matrix for potential use as interconnects in future carbonaceous circuits. With low-energy post-annealing below the temperature that is required for the thermal graphitization of amorphous carbon, the amorphous carbon phase only in the mechanically stressed regions transforms into a well aligned crystalline graphite structure with a low electrical resistivity of 420 MUOmega-cm, while the surrounding amorphous carbon matrix remains insulating. Micro-Raman spectra with obvious graphitic peaks and high-resolution transmission electron microscopic observations of clear graphitic lattice verified the localized phase transformation of amorphous carbon into textured graphite exactly in the stressed regions. The stress-induced reconstruction of carbon bonds to generate oriented graphitic nuclei is believed to assist in the pseudo-self formation of textured graphite during low-temperature post annealing. PMID- 28852078 TI - Graphene Klein tunnel transistors for high speed analog RF applications. AB - We propose Graphene Klein tunnel transistors (GKTFET) as a way to enforce current saturation while maintaining large mobility for high speed radio frequency (RF) applications. The GKTFET consists of a sequence of angled graphene p-n junctions (GPNJs). Klein tunneling creates a collimation of electrons across each GPNJ, so that the lack of substantial overlap between transmission lobes across successive junctions creates a gate-tunable transport gap without significantly compromising the on-current. Electron scattering at the device edge tends to bleed parasitic states into the gap, but the resulting pseudogap is still sufficient to create a saturated output (I D -V D ) characteristic and a high output resistance. The modulated density of states generates a higher transconductance (g m ) and unity current gain cut-off frequency (f T ) than GFETs. More significantly the high output resistance makes the unity power gain cut-off frequency (f max ) of GKTFETs considerably larger than GFETs, making analog GKTFET potentially useful for RF electronics. Our estimation shows the f T /f max of a GKTFET with 1 MUm channel reaches 33 GHz/17 GHz, and scale up to 350 GHz/53 GHz for 100 nm channel (assuming a single, scalable trapezoidal gate). The f max of a GKTFET is 10 times higher than a GFET with the same channel length. PMID- 28852079 TI - Cesarean section without medical indication and risks of childhood allergic disorder, attenuated by breastfeeding. AB - Caesarean section (CS) may increase the risk of asthma and allergic diseases in children, but previous studies could not preclude the potential confounding effect of underlying medical indications for CS. We aim to assess the association between CS itself (without indications) and risks of asthma and allergic rhinitis in children. The 2014 Shanghai Children's Health, Education and Lifestyle Evaluation was a large population-based survey with cluster random probability sampling in 26 primary schools in Shanghai, China, in 2014. The mode of delivery and child history of asthma and allergic rhinitis were reported by parents. We included 12639 children in our analysis. CS without medical indication was associated with an increased risk of childhood asthma. CS without medical indication and CS for fetal complications were associated with increased risks of childhood allergic rhinitis, respectively. In children fed by exclusive breastfeeding or mixed feeding in the first four months after birth, these risks were not significant. In contrast, in children fed by exclusive formula milk, CS was highly significantly associated with childhood asthma and allergic rhinitis. In conclusion, CS without medical indication was associated with increased risks of both childhood asthma and allergic rhinitis. Breastfeeding in early infancy may attenuate these risks. PMID- 28852080 TI - Influence of estrogen-related receptor gamma (ESRRG) rs1890552 A > G polymorphism on changes in fasting glucose and arterial stiffness. AB - To determine the effects of the estrogen-related receptor gamma (ESRRG) rs1890552 A > G polymorphism on dietary advice-mediated changes in fasting glucose and arterial stiffness, 374 subjects with normal fasting glucose (NFG; control group, no treatment) and 142 subjects with impaired fasting glucose (IFG group, dietary advice) were followed for 3.5 years. At follow-up, the GG subjects in the IFG group showed a significant reduction in fasting glucose, which was greater than in the AA subjects. A significant association was observed between ESRRG rs1890552 A > G polymorphism and changes in fasting glucose, brachial-ankle pulse wave velocity (ba-PWV), and 8-epi-prostaglandin F2alpha in the IFG subjects. At baseline, the GG subjects showed a higher ba-PWV than the AA subjects in the IFG group. At the 3.5-year follow-up, subjects with AA or AG showed significant increases in ba-PWV, whereas subjects with GG showed a decrease from baseline. This study suggests that the ESRRG rs1890552 A > G polymorphism may modulate interindividual differences in atrial stiffness, with a reduction in fasting glucose in response to dietary advice in subjects with IFG after a 3.5-year follow-up. PMID- 28852081 TI - Robust seismicity forecasting based on Bayesian parameter estimation for epidemiological spatio-temporal aftershock clustering models. AB - In the immediate aftermath of a strong earthquake and in the presence of an ongoing aftershock sequence, scientific advisories in terms of seismicity forecasts play quite a crucial role in emergency decision-making and risk mitigation. Epidemic Type Aftershock Sequence (ETAS) models are frequently used for forecasting the spatio-temporal evolution of seismicity in the short-term. We propose robust forecasting of seismicity based on ETAS model, by exploiting the link between Bayesian inference and Markov Chain Monte Carlo Simulation. The methodology considers the uncertainty not only in the model parameters, conditioned on the available catalogue of events occurred before the forecasting interval, but also the uncertainty in the sequence of events that are going to happen during the forecasting interval. We demonstrate the methodology by retrospective early forecasting of seismicity associated with the 2016 Amatrice seismic sequence activities in central Italy. We provide robust spatio-temporal short-term seismicity forecasts with various time intervals in the first few days elapsed after each of the three main events within the sequence, which can predict the seismicity within plus/minus two standard deviations from the mean estimate within the few hours elapsed after the main event. PMID- 28852082 TI - Sleep problems and injury risk among juveniles: A systematic review and meta analysis of observational studies. AB - Recent studies have reported inconsistent results regarding the association between sleep problems and injury risk among juveniles. Moreover, the extent of this risk remains largely unexplored. Thus, a systematic review and meta-analysis was conducted by our team to determine whether sleep problems increase the incidence of injuries among juveniles. PubMed, PsycINFO, Embase, and Cochrane Library databases were searched for relevant studies that explored the association between sleep problems and injury risk and have been published before July 2016. Multivariate adjusted odds ratio (OR) and associated 95% confidence intervals (CIs) were extracted and pooled using random-effects models. A total of 10 observational studies involving 73,418 participants were identified. Meta analysis findings suggested that juveniles with sleep problems held a 1.64 times higher risk of injury than that of juveniles without sleep problems (OR: 1.64, 95% CI: 1.44-1.85). This relationship was also supported by subgroup analyses, which were based on different countries and study designs. The current evidence indicates that sleep problems are significantly associated with injury risk among juveniles. Sleep problems are highly important for young people; hence, sleep researchers and occupational physicians should focus on this aspect. Nevertheless, high-quality and adequately powered observational studies are still needed. PMID- 28852084 TI - High-altitude wind resources in the Middle East. AB - In the Middle East, near-surface wind resources are intermittent. However, high altitude wind resources are abundant, persistent, and readily available and may provide alternative energy resources in this fossil-fuel-dependent region. Using wind field data from the Modern-Era Retrospective Analysis for Research and Applications Version 2 (MERRA-2), this study identifies areas favorable to the deployment of airborne wind energy (AWE) systems in the Middle East and computes the optimal heights at which such systems would best operate. AWE potential is estimated using realistic AWE system specifications and assumptions about deployment scenarios and is compared with the near-surface wind generation potential with respect to diurnal and seasonal variability. The results show the potential utility of AWE in areas in the Middle East where the energy demand is high. In particular, Oman and Saudi Arabia have a high level of the potential power generation with low annual variability. PMID- 28852083 TI - Cryoconite as a temporary sink for anthropogenic species stored in glaciers. AB - Cryoconite, the typical sediment found on the surface of glaciers, is mainly known in relation to its role in glacial microbiology and in altering the glacier albedo. But if these aspects are relatively well addressed, the same cannot be said about the geochemical properties of cryoconite and the possible interactions with glacial and peri-glacial environment. Current glacier retreat is responsible for the secondary emission of species deposited in high-altitude regions in the last decades. The role played by cryoconite in relation to such novel geochemical fluxes is largely unknown. Few and scarce observations suggest that it could interact with these processes, accumulating specific substances, but why, how and to what extent remain open questions. Through a multi-disciplinary approach we tried to shed lights. Results reveal that the peculiar composition of cryoconite is responsible for an extreme accumulation capability of this sediment, in particular for some, specific, anthropogenic substances. PMID- 28852085 TI - Nanoparticle Delivery of Fidgetin siRNA as a Microtubule-based Therapy to Augment Nerve Regeneration. AB - Microtubule-stabilizing drugs have gained popularity for treating injured adult axons, the rationale being that increased stabilization of microtubules will prevent the axon from retracting and fortify it to grow through inhibitory molecules associated with nerve injury. We have posited that a better approach would be not to stabilize the microtubules, but to increase labile microtubule mass to levels more conducive to axonal growth. Recent work on fetal neurons suggests this can be accomplished using RNA interference to reduce the levels of fidgetin, a microtubule-severing protein. Methods to introduce RNA interference into adult neurons, in vitro or in vivo, have been problematic and not translatable to human patients. Here we show that a novel nanoparticle approach, previously shown to deliver siRNA into tissues and organs, enables siRNA to gain entry into adult rat dorsal root ganglion neurons in culture. Knockdown of fidgetin is partial with this approach, but sufficient to increase the labile microtubule mass of the axon, thereby increasing axonal growth. The increase in axonal growth occurs on both a favorable substrate and a growth-inhibitory molecule associated with scar formation in injured spinal cord. The nanoparticles are readily translatable to in vivo studies on animals and ultimately to clinical applications. PMID- 28852086 TI - Gapless edge states in (C,O,H)-built molecular system with p-stacking and hydrogen bonds. AB - The gapless edge states have been found in a 2D molecular system built with light atoms: C,O,H. This prediction is done on the basis of combined density functional theory (DFT) and tight-binding calculations. The system does not exhibit any effect of the spin-orbit coupling (SOC), neither intrinsic nor Rashba type. The band structure and the edge states are tuned with a strength of the p-stacking and O...H interactions. The elementary cell of this noncovalent structure, does not have the 3D inversion or rotational symmetry. Instead, the system transforms via a superposition of two reflections: with respect to the xz and xy mirror planes, both containing the non-periodic direction. This superposition is equivalent to the inversion in the 2D subspace, in which the system is periodic. The energy gap obtained with the DFT method is 0.11 eV, and largely opens (above 1 eV) with the GW and hybrid-DFT approaches. The bands inversion is partial, i.e. the Bloch states are mixed, with the "swapping" and "non-swapping" atomic contributions. PMID- 28852088 TI - Quantitative proteome and phosphoproteome analyses highlight the adherent population during Trypanosoma cruzi metacyclogenesis. AB - Trypanosoma cruzi metacyclogenesis is a natural process that occurs inside the triatomine vector and corresponds to the differentiation of non-infective epimastigotes into infective metacyclic trypomastigotes. The biochemical alterations necessary for the differentiation process have been widely studied with a focus on adhesion and nutritional stress. Here, using a mass spectrometry approach, a large-scale phospho(proteome) study was performed with the aim of understanding the metacyclogenesis processes in a quantitative manner. The results indicate that major modulations in the phospho(proteome) occur under nutritional stress and after 12 and 24 h of adhesion. Significant changes involve key cellular processes, such as translation, oxidative stress, and the metabolism of macromolecules, including proteins, lipids, and carbohydrates. Analysis of the signalling triggered by kinases and phosphatases from 7,336 identified phosphorylation sites demonstrates that 260 of these sites are modulated throughout the differentiation process, and some of these modulated proteins have previously been identified as drug targets in trypanosomiasis treatment. To the best of our knowledge, this study provides the first quantitative results highlighting the modulation of phosphorylation sites during metacyclogenesis and the greater coverage of the proteome to the parasite during this process. The data are available via ProteomeXchange with identifier number PXD006171. PMID- 28852087 TI - Reduced expression of Paternally Expressed Gene-3 enhances somatic cell reprogramming through mitochondrial activity perturbation. AB - Imprinted genes control several cellular and metabolic processes in embryonic and adult tissues. In particular, paternally expressed gene-3 (Peg3) is active in the adult stem cell population and during muscle and neuronal lineage development. Here we have investigated the role of Peg3 in mouse embryonic stem cells (ESCs) and during the process of somatic cell reprogramming towards pluripotency. Our data show that Peg3 knockdown increases expression of pluripotency genes in ESCs and enhances reprogramming efficiency of both mouse embryonic fibroblasts and neural stem cells. Interestingly, we observed that altered activity of Peg3 correlates with major perturbations of mitochondrial gene expression and mitochondrial function, which drive metabolic changes during somatic cell reprogramming. Overall, our study shows that Peg3 is a regulator of pluripotent stem cells and somatic cell reprogramming. PMID- 28852089 TI - Reproductive benefits of no-take marine reserves vary with region for an exploited coral reef fish. AB - No-take marine reserves (NTMRs) are expected to benefit fisheries via the net export of eggs and larvae (recruitment subsidy) from reserves to adjacent fished areas. Quantifying egg production is the first step in evaluating recruitment subsidy potential. We calculated annual egg production per unit area (EPUA) from 2004 to 2013 for the commercially important common coral trout, Plectropomus leopardus, on fished and NTMR reefs throughout the Great Barrier Reef (GBR), Australia. Geographic region, NTMR status, fish size, and population density were all found to affect EPUA. The interactions among these factors were such that, EPUA on NTMR reefs compared to reefs open to fishing was 21% greater in the southern GBR, 152% greater in the central GBR, but 56% less in the northern GBR. The results show that while NTMRs can potentially provide a substantial recruitment subsidy (central GBR reefs), they may provide a far smaller subsidy (southern GBR), or serve as recruitment sinks (northern GBR) for the same species in nearby locations where demographic rates differ. This study highlights the importance of considering spatial variation in EPUA when assessing locations of NTMRs if recruitment subsidy is expected from them. PMID- 28852090 TI - Synthesis and Characterization of PtTe2 Multi-Crystallite Nanoparticles using Organotellurium Nanocomposites. AB - Herein, we report the synthesis of new PtTe2 multi-crystallite nanoparticles (NPs) in different sizes through an annealing process using new nanostructured Pt Te organometallic NPs as a single source precursor. This precursor was obtained in a single reaction step using Ph2Te2 and H2PtCl6 and could be successfully size controlled in the nanoscale range. The resulting organometallic composite precursor could be thermally decomposed in 1,5 pentanediol to yield the new PtTe2 multi-crystallite NPs. The final size of the multi-crystallite spheres was successfully controlled by selecting the nanoprecursor size. The sizes of the PtTe2 crystallites formed using the large spheres were estimated to be in the range of 2.5-6.5 nm. The results provide information relevant to understanding specific mechanistic aspects related to the synthesis of organometallic nanomaterials and nanocrystals based on platinum and tellurium. PMID- 28852091 TI - Nanostructural origin of blue fluorescence in the mineral karpatite. AB - The colour of crystals is a function of their atomic structure. In the case of organic crystals, it is the spatial relationships between molecules that determine the colour, so the same molecules in the same arrangement should produce crystals of the same colour, regardless of whether they arise geologically or synthetically. There is a naturally-occurring organic crystal known as karpatite which is prized for its beautiful blue fluorescence under ultra-violet illumination. When grown under laboratory conditions however, the crystals fluoresce with an intense green colour. For 20 years, this difference has been thought to be due to chemical impurities in the laboratory-grown material. Using electron microscopy coupled with fluorescence spectroscopy and X Ray diffraction, we report here that this disparity is instead due to differences in the structure of the crystals at the nanoscale. The results show that in nature, karpatite has a nanotexture that is not present in the synthetic crystals, which enables different photonic pathways and therefore a blue, rather than green colour whilst undergoing fluorescence. PMID- 28852092 TI - Change in sensitivity to visual error in superior colliculus during saccade adaptation. AB - Saccadic eye movements provide a valuable model to study the brain mechanisms underlying motor learning. If a target is displaced surreptitiously while a saccade is underway, the saccade appears to be in error. If the error persists gradual neuronal adjustments cause the eye movement again to land near the target. This saccade adaptation typically follows an exponential time course, i.e., adaptation speed slows as adaptation progresses, indicating that the sensitivity to error decreases during adaptation. Previous studies suggested that the superior colliculus (SC) sends error signals to drive saccade adaptation. The objective of this study is to test whether the SC error signal is related to the decrease in the error sensitivity during adaptation. We show here that the visual activity of SC neurons, which is induced by a constant visual error that drives adaptation, decreases during saccade adaptation. This decrease of sensitivity to visual error was not correlated with the changes of primary saccade amplitude. Therefore, a possible interpretation of this result is that the reduction of visual sensitivity of SC neurons contributes an error sensitivity signal that could help control the saccade adaptation process. PMID- 28852093 TI - Connecting individual to collective cell migration. AB - Collective cell migration plays a pivotal role in the formation of organs, tissue regeneration, wound healing and many disease processes, including cancer. Despite the considerable existing knowledge on the molecular control of cell movements, it is unclear how the different observed modes of collective migration, especially for small groups of cells, emerge from the known behaviors of individual cells. Here we derive a physical description of collective cellular movements from first principles, while accounting for known phenomenological cell behaviors, such as contact inhibition of locomotion and force-induced cell repolarization. We show that this theoretical description successfully describes the motion of groups of cells of arbitrary numbers, connecting single cell behaviors and parameters (e.g., adhesion and traction forces) to the collective migration of small groups of cells and the expansion of large cell colonies. Specifically, using a common framework, we explain how cells characterized by contact inhibition of locomotion can display coherent collective behavior when in groups, even in the absence of biochemical signaling. We find an optimal group size leading to maximal group persistence and show that cell proliferation prevents the buildup of intercellular forces within cell colonies, enabling their expansion. PMID- 28852094 TI - Unraveling the gut microbiome of the long-lived naked mole-rat. AB - The naked mole-rat (Heterocephalus glaber) is a subterranean mouse-sized African mammal that shows astonishingly few age-related degenerative changes and seems to not be affected by cancer. These features make this wild rodent an excellent model to study the biology of healthy aging and longevity. Here we characterize for the first time the intestinal microbial ecosystem of the naked mole-rat in comparison to humans and other mammals, highlighting peculiarities related to the specific living environment, such as the enrichment in bacteria able to utilize soil sulfate as a terminal electron acceptor to sustain an anaerobic oxidative metabolism. Interestingly, some compositional gut microbiota peculiarities were also shared with human gut microbial ecosystems of centenarians and Hadza hunter gatherers, considered as models of a healthy gut microbiome and of a homeostatic and highly adaptive gut microbiota-host relationship, respectively. In addition, we found an enrichment of short-chain fatty acids and carbohydrate degradation products in naked mole-rat compared to human samples. These data confirm the importance of the gut microbial ecosystem as an adaptive partner for the mammalian biology and health, independently of the host phylogeny. PMID- 28852095 TI - Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta. AB - Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPalpha) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer's disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Abeta) at the expense of sAPPalpha and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Abeta and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Abeta on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Abeta, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Abeta toxicity, since higher levels of endogenous Abeta in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of beta-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPalpha or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism. PMID- 28852096 TI - A multi-trap microfluidic chip enabling longitudinal studies of nerve regeneration in Caenorhabditis elegans. AB - Several sophisticated microfluidic devices have recently been proposed for femtosecond laser axotomy in the nematode C. elegans for immobilization of the animals for surgery to overcome time-consuming and labor-intensive manual processes. However, nerve regeneration studies require long-term recovery of the animals and multiple imaging sessions to observe the regeneration capabilities of their axons post-injury. Here we present a simple, multi-trap device, consisting of a single PDMS (polydimethylsiloxane) layer, which can immobilize up to 20 animals at the favorable orientation for optical access needed for precise laser surgery and high-resolution imaging. The new device, named "worm hospital" allows us to perform the entire nerve regeneration studies, including on-chip axotomy, post-surgery housing for recovery, and post-recovery imaging all on one microfluidic chip. Utilizing the worm hospital and analysis of mutants, we observed that most but not all neurodevelopmental genes in the Wnt/Frizzled pathway are important for regeneration of the two touch receptor neurons ALM and PLM. Using our new chip, we observed that the cwn-2 and cfz-2 mutations significantly reduced the reconnection possibilities of both neurons without any significant reduction in the regrowth lengths of the severed axons. We observed a similar regeneration phenotype with cwn-1 mutation in ALM neurons only. PMID- 28852097 TI - Enhanced Second Harmonic Generation by Mode Matching in Gain-assisted Double plasmonic Resonance Nanostructure. AB - We theoretically study the gain-assisted double plasmonic resonances to enhance second harmonic generation (SHG) in a centrosymmetric multilayered silver dielectric-gold-dielectric (SDGD) nanostructure. Introducing gain media into the dielectric layers can not only compensate the dissipation and lead to giant amplification of surface plasmons (SPs), but also excite local quadrupolar plasmon which can boost SHG by mode matching. Specifically, as the quadrupolar mode dominates SHG in our nanostructure, under the mode matching condition, the intensity of second harmonic near-field can be enhanced by 4.43 * 102 and 1.21 * 105 times when the super-resonance is matched only at the second harmonic (SH) frequency or fundamental frequency, respectively. Moreover, the intensity of SHG near-field is enhanced by as high as 6.55 * 107 times when the nanostructure is tuned to double super-resonances at both fundamental and SH frequencies. The findings in this work have potential applications in the design of nanosensors and nanolasers. PMID- 28852098 TI - Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin. AB - Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies having no effective treatment. Exportin-1 (XPO1) is the key mediator of nuclear export of many tumor suppressor proteins and is overexpressed in human cancers. In this study, we examined the therapeutic potential of selinexor (XPO1 inhibitor) against human ATC cells both in vitro and in vivo. Here, we showed that XPO1 is robustly expressed in primary ATC samples and human ATC cell lines. Silencing of XPO1 by either shRNA or selinexor significantly reduced cellular growth and induced cell cycle arrest, apoptosis of ATC cells by altering the protein expression of cancer-related genes. Moreover, selinexor significantly inhibited tumor growth of ATC xenografts. Microarray analysis showed enrichment of DNA replication, cell cycle, cell cycle checkpoint and TNF pathways in selinexor treated ATC cells. Importantly, selinexor decreased AXL and GAS6 levels in CAL62 and HTH83 cells and suppressed the phosphorylation of downstream targets of AXL signaling such as AKT and P70S6K. Finally, a combination of selinexor with doxorubicin demonstrated a synergistic decrease in the cellular proliferation of several ATC cells. These results provide a rationale for investigating the efficacy of combining selinexor and doxorubicin therapy to improve the outcome of ATC patients. PMID- 28852099 TI - Intermolecular base stacking mediates RNA-RNA interaction in a crystal structure of the RNA chaperone Hfq. AB - The RNA-chaperone Hfq catalyses the annealing of bacterial small RNAs (sRNAs) with target mRNAs to regulate gene expression in response to environmental stimuli. Hfq acts on a diverse set of sRNA-mRNA pairs using a variety of different molecular mechanisms. Here, we present an unusual crystal structure showing two Hfq-RNA complexes interacting via their bound RNA molecules. The structure contains two Hfq6:A18 RNA assemblies positioned face-to-face, with the RNA molecules turned towards each other and connected via interdigitating base stacking interactions at the center. Biochemical data further confirm the observed interaction, and indicate that RNA-mediated contacts occur between Hfq RNA complexes with various (ARN)X motif containing RNA sequences in vitro, including the stress response regulator OxyS and its target, fhlA. A systematic computational survey also shows that phylogenetically conserved (ARN)X motifs are present in a subset of sRNAs, some of which share similar modular architectures. We hypothesise that Hfq can co-opt RNA-RNA base stacking, an unanticipated structural trick, to promote the interaction of (ARN)X motif containing sRNAs with target mRNAs on a "speed-dating" fashion, thereby supporting their regulatory function. PMID- 28852101 TI - Direct physical vapor deposition and flexible photoelectrical properties of large area free-standing films of metal octaethylporphyrin on ionic liquid surface. AB - Free-standing films of metal octaethylporphyrins (MOEPs) were prepared for the first time by a physical vapor deposition on surface of an ionic liquid (IL). Different from those on solid surfaces, the as-obtained films were very compact and with plannar structure. The monitoring of time-dependent process indicated that the high surface energy of IL and the strong pi...pi interaction between MOEP molecules played key roles in forming such films. Furthermore, the as obtained film showed good transferability, which made it possible to be easily transferred to any substrates for further device application. More importantly, the prototype photodetectors based on free-standing films of MOEP showed ultra flexibility, mechanical stability, and durability. PMID- 28852100 TI - Mechanisms of stem cell based cardiac repair-gap junctional signaling promotes the cardiac lineage specification of mesenchymal stem cells. AB - Different subtypes of bone marrow-derived stem cells are characterized by varying functionality and activity after transplantation into the infarcted heart. Improvement of stem cell therapeutics requires deep knowledge about the mechanisms that mediate the benefits of stem cell treatment. Here, we demonstrated that co-transplantation of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) led to enhanced synergistic effects on cardiac remodeling. While HSCs were associated with blood vessel formation, MSCs were found to possess transdifferentiation capacity. This cardiomyogenic plasticity of MSCs was strongly promoted by a gap junction-dependent crosstalk between myocytes and stem cells. The inhibition of cell-cell coupling significantly reduced the expression of the cardiac specific transcription factors NKX2.5 and GATA4. Interestingly, we observed that small non-coding RNAs are exchanged between MSCs and cardiomyocytes in a GJ-dependent manner that might contribute to the transdifferentiation process of MSCs within a cardiac environment. Our results suggest that the predominant mechanism of HSCs contribution to cardiac regeneration is based on their ability to regulate angiogenesis. In contrast, transplanted MSCs have the capability for intercellular communication with surrounding cardiomyocytes, which triggers the intrinsic program of cardiogenic lineage specification of MSCs by providing cardiomyocyte-derived cues. PMID- 28852102 TI - Conditions for Barrel and Clam-Shell Liquid Drops to Move on Bio-inspired Conical Wires. AB - It has been reported that, in a foggy environment, water drops with either barrel or clam-shell shapes are capable of self-running on conical wire-like structures, such as cactus spines, spider silk, and water striders' legs. On the other hand, the corresponding moving mechanisms are still not quite understood. For instance, it is unclear under what conditions clam-shell drops would move from the tip towards the root on a conical wire. In this work, based on the balance of forces, we derive conditions for a drop to self-transport towards or away from the root. We find that, although barrel and clam-shell drops have different shapes, these conditions are applicable to both of them, which thus provide good guidelines for developing artificial fog collectors. Furthermore, based on the derived conditions, we interpret drop movements on both hydrophilic and hydrophobic wires, with the support of experimental results on cactus spines. Finally, our results indicate that not all the cacti are able to harvest water from fog. PMID- 28852103 TI - Seed-mediated synthesis and SERS performance of graphene oxide-wrapped Ag nanomushroom. AB - A facile seed-mediated method was developed to modify core-shell Ag nanosphere@PSPAA with another Ag layer for achieving an enhancement of their surface-enhanced Raman scattering (SERS) activity. Interestingly, an Ag bridge in the polymer shell connected the inner and outer Ag layers, resulting in a mushroom-like nanostructure. The outer Ag grew around the polymer shell to form the cap of the nanomushrooms (NMs) with the extension of the reaction time. The epitaxial growth mechanism of this novel nanostructure was investigated by tuning the type of seed from nanosphere to nanocube and nanorod. With the growth of the outer Ag cap, the SERS intensity of these Ag NMs increased significantly together with the red-shifting and broadening of their typical localized surface plasmon resonance band. Such a phenomenon can be attributed to the formation of SERS hotspots between the inner and outer Ag layers. The Ag NMs were then wrapped with a graphene oxide (GO) shell via static interactions. The GO-wrapped Ag NMs exhibited a further better SERS performance in terms of sensitivity, homogeneity and stability compared with non-wrapped ones, indicating that the heterostructure could be potentially useful for SERS-based immunoassay. PMID- 28852104 TI - Impact of transient currents caused by alternating drain stress in oxide semiconductors. AB - Reliability issues associated with driving metal-oxide semiconductor thin film transistors (TFTs), which may arise from various sequential drain/gate pulse voltage stresses and/or certain environmental parameters, have not received much attention due to the competing desire to characterise the shift in the transistor characteristics caused by gate charging. In this paper, we report on the reliability of these devices under AC bias stress conditions because this is one of the major sources of failure. In our analysis, we investigate the effects of the driving frequency, pulse shape, strength of the applied electric field, and channel current, and the results are compared with those from a general reliability test in which the devices were subjected to negative/positive bias, temperature, and illumination stresses, which are known to cause the most stress to oxide semiconductor TFTs. We also report on the key factors that affect the sub-gap defect states, and suggest a possible origin of the current degradation observed with an AC drive. Circuit designers should apply a similar discovery and analysis method to ensure the reliable design of integrated circuits with oxide semiconductor devices, such as the gate driver circuits used in display devices. PMID- 28852105 TI - Purification of Dye-stuff Contained Wastewater by a Hybrid Adsorption-Periphyton Reactor (HAPR): Performance and Mechanisms. AB - The aim of this study was to develop an environmental-benign bio-measure that could be used to purify dye-contaminated wastewater. Herein, a hybrid adsorption periphyton reactor (HAPR), combining a bioadsorbent based adsorption unit and a periphyton-based photo-bioreactor (PPBR), was built and applied for the first time. Firstly, an efficient bioadsorbent, i.e, microwave-activated swede rape hull (MSRH), was produced, characterized and applied in an adsorption column, to pretreat methylene blue (MB) wastewater with high concentration (~100 mg L-1 or higher). Thereafter, the effluent of adsorption column, with lower dye concentration (~0.5 mg L-1), was collected and further purified by PPBR. Results showed that dye removal efficiency by HAPR was 99.95% (from 200 mg L-1 to 0.1 mg L-1 or lower). Decolorization mechanisms by PPBR, included adsorption process by extracellular polymeric substances (EPS) on the surface of periphyton and degradation process. The study showed that HAPR was a novel, environmental friendly, efficient and promising dye-purification method and deserved further attention in future investigation. PMID- 28852106 TI - The Role of Na+/Ca2+ Exchanger 1 in Maintaining Ductus Arteriosus Patency. AB - Patency of the ductus arteriosus (DA) is crucial for both fetal circulation and patients with DA-dependent congenital heart diseases (CHD). The Na+/Ca2+ exchanger 1 (NCX1) protein has been shown to play a key role in the regulation of vascular tone and is elevated in DA-dependent CHD. This current study was conducted to investigate the mechanisms underpinning the role of NCX1 in DA patency. Our data showed NCX1 expression was up-regulated in the DA of fetal mice. Up-regulation of NCX1 expression resulted in a concomitant decrease in cytosolic Ca2+ levels in human DA smooth muscle cells (DASMCs) and an inhibition of the proliferation and migration capacities of human DASMCs. Furthermore, treatment of DASMCs with KB-R7943, which can reduce Ca2+ influx, resulted in the inhibition of both cell proliferation and migration. These findings indicate that NCX1 may play a role in maintaining patent DA not only by preventing DA functional closure through reducing cytosolic Ca2+ level in DASMC but also by delaying the anatomical closure process. The latter delay is facilitated by the down-regulation of human DASMC proliferation and migration. It is also likely that a reduction in cytosolic Ca2+ levels inhibits the proliferation and migration capacities of human DASMCs in vitro. PMID- 28852107 TI - A functional approach to the structural complexity of coral assemblages based on colony morphological features. AB - Colony morphological features is among the best predictor of the scleractinian coral's function in reef ecosystems. However, morphological traits are categorical and to convert this information into a quantitative value as well as estimate their influence on ecosystem process remain a challenge. Here, we propose a trait-based approach to quantify morphological diversity and assess the structural complexity of the habitat provided by corals. We used a previously published dataset that is related to a bleaching event that affected the coral reef off Tikus Island in Indonesia in 1983. We found clear signs of recovery of the coral assemblage's complexity toward pre El Nino conditions five years after the event. Independent of the change observed in species richness, this return in structural complexity was accompanied by a global decrease in species number associated with each particular morphological entity (Functional Redundancy) and an increase in the number of single-species entities (Functional Vulnerability). Together with species loss, we show an overall functional erosion of the coral assemblage and suggest that the role of the coral reef habitat could be strongly imperiled under repeated or synergistic disturbances. This approach offers an opportunity for a better understanding of coral responses to natural and anthropogenic disturbances. PMID- 28852109 TI - Label-free optical vibrational spectroscopy to detect the metabolic state of M. tuberculosis cells at the site of disease. AB - Tuberculosis relapse is a barrier to shorter treatment. It is thought that lipid rich cells, phenotypically resistant to antibiotics, may play a major role. Most studies investigating relapse use sputum samples although tissue bacteria may play an important role. We developed a non-destructive, label-free technique combining wavelength modulated Raman (WMR) spectroscopy and fluorescence detection (Nile Red staining) to interrogate Mycobacterium tuberculosis cell state. This approach could differentiate single "dormant" (lipid rich, LR) and "non-dormant" (lipid poor, LP) cells with high sensitivity and specificity. We applied this to experimentally infected guinea pig lung sections and were able to distinguish both cell types showing that the LR phenotype dominates in infected tissue. Both in-vitro and ex-vivo spectra correlated well, showing for the first time that Mycobacterium tuberculosis, likely to be phenotypically resistant to antibiotics, are present in large numbers in tissue. This is an important step in understanding the pathology of relapse supporting the idea that they may be caused by M. tuberculosis cells with lipid inclusions. PMID- 28852108 TI - Expression and characterisation of a Sarcoptes scabiei protein tyrosine kinase as a potential antigen for scabies diagnosis. AB - Scabies is a disease that harms humans and other animals that is caused by the itch mite Sarcoptes scabiei burrowing into the stratum corneum of the skin. In the early stages of scabies, symptoms are often subclinical and there are no effective diagnostic methods. Herein, we cloned, expressed and characterised an S. scabiei protein tyrosine kinase (SsPTK) and evaluated its diagnostic value as a recombinant antigen in rabbit during the early stages of Sarcoptes infestation. The SsPTK protein is ~30 kDa, lacks a signal peptide, and shares high homology with a PTK from the rabbit ear mite Psoroptes ovis cuniculi. The protein was widely distributed at the front end of mites, particularly in the chewing mouthparts and legs. Indirect ELISA using recombinant SsPTK showed good diagnostic value, with 95.2% (40/42) sensitivity and 94.1% (48/51) specificity for detecting anti-PTK antibody in serum samples from naturally-infested rabbits. More importantly, PTK ELISA could diagnose infection in the early stages (infestation for 1 week) with an accuracy of 100% (24/24). SsPTK therefore shows potential as a sensitive antigen for the early diagnosis of parasitic mite infestation. PMID- 28852110 TI - Global invasion network of the brown marmorated stink bug, Halyomorpha halys. AB - Human mediated transportation into novel habitats is a prerequisite for the establishment of non-native species that become invasive, so knowledge of common sources may allow prevention. The brown marmorated stink bug (BMSB, Halyomorpha halys) is an East Asian species now established across North America and Europe, that in the Eastern United States of America (US) and Italy is causing significant economic losses to agriculture. After US populations were shown to originate from Northern China, others have tried to source BMSB populations now in Canada, Switzerland, Italy, France, Greece, and Hungary. Due to selection of different molecular markers, however, integrating all the datasets to obtain a broader picture of BMSB's expansion has been difficult. To address this limitation we focused on a single locus, the barcode region in the cytochrome oxidase I mitochondrial gene, and analyzed representative BMSB samples from across its current global range using an Approximate Bayesian Computation approach. We found that China is the likely source of most non-native populations, with at least four separate introductions in North America and three in Europe. Additionally, we found evidence of one bridgehead event: a likely Eastern US source for the central Italy populations that interestingly share enhanced pest status. PMID- 28852111 TI - Development of an Affimer-antibody combined immunological diagnosis kit for glypican-3. AB - Glypican-3 (GPC3) is a promising new marker for hepatocellular carcinoma, but the reported values for serum GPC3 differ markedly between currently available kits. Here we isolated Affimer non-antibody binding proteins against GPC3 by phage display and developed a new sandwich chemiluminescence immunoassay (CLIA) combining an Affimer with a monoclonal antibody (Affimer-MAb CLIA). The proposed CLIA assay demonstrated a wide linear range 0.03-600 ng/mL) with a good linear correlation coefficient (0.9999), a high detection limitation (0.03 ng/mL) and specificity (0-0.002%) for detection of GPC3. The accuracy, hook effect and stability were demonstrated to be satisfactory. The mean level of GPC3 in serum was higher (>8.5 fold, P < 0.001) in hepatocellular carcinoma patients compared to healthy and other liver disease individuals. A poor correlation (correlation coefficients ranged from -0.286 to 0.478) was observed through pairwise comparison within different kits. However, only this newly developed CLIA test showed high specificity and correlated with the "gold standard" GPC3 immunohistochemistry. This study indicates that Affimer-MAb CLIA can be used to generate a sensitive immunodiagnostic kit, which offers the potential for a highly specific clinically-relevant detection system. PMID- 28852112 TI - Interactions of Boron Clusters and their Derivatives with Serum Albumin. AB - Boron clusters are polyhedral boron hydrides with unique properties, and they are becoming increasingly widely used in biology and medicine, including for boron neutron capture therapy (BNCT) of cancers and in the design of novel bioactive molecules and potential drugs. Among boron cluster types, icosahedral boranes, carboranes, and metallacarboranes are particularly interesting, and there is a need for basic studies on their interaction with biologically important molecules, such as proteins. Herein, we report studies on the interaction of selected boron clusters and their derivatives with serum albumin, the most abundant protein in mammalian blood. The interaction of boron clusters with albumin was examined by fluorescence quenching, circular dichroism, dynamic and static light scattering measurements and MALDI-TOF mass spectrometry. Our results showed that metallacarboranes have the strongest interaction with albumin among the tested clusters. The observed strength of boron cluster interactions with albumin decreases in order: metallacarboranes [M(C2B9H11)2]- > carboranes (C2B10H12) >> dodecaborate anion [B12H12]2-. Metallacarboranes first specifically interact with the binding cavity of albumin and then, with increasing compound concentrations, interact non-specifically with the protein surface. These findings can be of importance and are useful in the development of new bioactive compounds that contain boron clusters. PMID- 28852113 TI - Precipitation phenomena in Al-Zn-Mg alloy matrix composites reinforced with B4C particles. AB - To provide insight into precipitation phenomena in age-hardening Al-Zn-Mg(-Cu) matrix composites, an Al 7075 alloy composite reinforced with B4C particles was selected as a model system. The bulk composites were fabricated via plasma activated sintering and followed by a peak aged (T6) heat treatment. Two types of Al matrix zones were identified in the composite: (1) the regions in the vicinity of the matrix/reinforcement interface, defined as "matrix plastic zone" (MPZ) hereafter, and (2) the regions away from the matrix/reinforcement interface, simply defined as matrix hereafter. The precipitation behavior in the MPZ was characterized and compared to that in the matrix. The MPZ contained a high density of dislocations. The number density of GP zones in the MPZ is lower than that in the matrix while the average size of the GP zones in MPZ is coarser. In addition, semi-coherent platelet eta' precipitates were observed but only in the MPZ. The dislocations and the Al/B4C interfaces provide more heterogeneous nucleation sites for the eta' precipitates in the MPZ. The growth and coarsening of the eta' precipitates caused rapid depletion of Mg and Zn solute atoms in the MPZ. PMID- 28852114 TI - No effects of transcranial DLPFC stimulation on implicit task sequence learning and consolidation. AB - Neurostimulation of the dorsolateral prefrontal cortex (DLPFC) can modulate performance in cognitive tasks. In a recent study, however, transcranial direct current stimulation (tDCS) of the DLPFC did not affect implicit task sequence learning and consolidation in a paradigm that involved bimanual responses. Because bimanual performance increases the coupling between homologous cortical areas of the hemispheres and left and right DLPFC were stimulated separately the null findings may have been due to the bimanual setup. The aim of the present study was to test the effect of neuro-stimulation on sequence learning in a uni manual setup. For this purpose two experiments were conducted. In Experiment 1, the DLPFC was stimulated with tDCS. In Experiment 2 the DLPFC was stimulated with transcranial magnetic stimulation (TMS). In both experiments, consolidation was measured 24 hours later. The results showed that sequence learning was present in all conditions and sessions, but it was not influenced by stimulation. Likewise, consolidation of sequence learning was robust across sessions, but it was not influenced by stimulation. These results replicate and extend previous findings. They indicate that established tDCS and TMS protocols on the DLPFC do not influence implicit task sequence learning and consolidation. PMID- 28852115 TI - Biased visuospatial perception in complex regional pain syndrome. AB - Complex regional pain syndrome (CRPS) is a chronic pain condition associating sensory, motor, trophic and autonomic symptoms in one limb. Cognitive difficulties have also been reported, affecting the patients' ability to mentally represent, perceive and use their affected limb. However, the nature of these deficits is still a matter of debate. Recent studies suggest that cognitive deficits are limited to body-related information and body perception, while not extending to external space. Here we challenge that statement, by using temporal order judgment (TOJ) tasks with tactile (i.e. body) or visual (i.e. extra-body) stimuli in patients with upper-limb CRPS. TOJ tasks allow characterizing cognitive biases to the advantage of one of the two sides of space. While the tactile TOJ tasks did not show any significant results, significant cognitive biases were observed in the visual TOJ tasks, affecting mostly the perception of visual stimuli occurring in the immediate vicinity of the affected limb. Our results clearly demonstrate the presence of visuospatial deficits in CRPS, corroborating the cortical contribution to the CRPS pathophysiology, and supporting the utility of developing rehabilitation techniques modifying visuospatial abilities to treat chronic pain. PMID- 28852116 TI - Studies on the regulatory mechanism of isocitrate dehydrogenase 2 using acetylation mimics. AB - Mitochondrial isocitrate dehydrogenase 2 (IDH2) converts NADP+ to NADPH and promotes regeneration of reduced glutathione (GSH) by supplying NADPH to glutathione reductase or thioredoxin reductase. We have previously shown that under calorie restriction, mitochondrial deacetylase Sirt3 deacetylates and activates IDH2, thereby regulating the mitochondrial glutathione antioxidant defense system in mice. To investigate the regulatory mechanism of mIDH2 (mouse mitochondrial IDH2), we used lysine-to-glutamine (KQ) mutants to mimic acetylated lysines and screened 15 KQ mutants. Among these mutants, the activities of the K256Q and K413Q proteins were less than 50% of the wild-type value. We then solved the crystal structures of the wild-type mIDH2 and the K256Q mutant proteins, revealing conformational changes in the substrate-binding pocket. Structural data suggested that positively charged Lys256 was important in stabilizing the pocket because it repelled a lysine cluster on the other side. Glutamine (or acetylated lysine) was neutral and thus caused the pocket size to decrease, which might be the main reason for the lower activity of the K256Q mutant. Together, our data provide the first structure of an acetylation mimic of mIDH2 and new insights into the regulatory mechanism of acetylation of mIDH2. PMID- 28852118 TI - An Orbital Angular Momentum (OAM) Mode Reconfigurable Antenna for Channel Capacity Improvement and Digital Data Encoding. AB - For purpose of utilizing orbital angular momentum (OAM) mode diversity, multiple OAM beams should be generated preferably by a single antenna. In this paper, an OAM mode reconfigurable antenna is proposed. Different from the existed OAM antennas with multiple ports for multiple OAM modes transmitting, the proposed antenna with only a single port, but it can be used to transmit mode 1 or mode -1 OAM beams arbitrary by controlling the PIN diodes on the feeding network through a programmable microcontroller which control by a remote controller. Simulation and measurement results such as return loss, near-field and far-field radiation patterns of two operating states for mode 1 and mode -1, and OAM mode orthogonality are given. The proposed antenna can serve as a candidate for utilizing OAM diversity, namely phase diversity to increase channel capacity at 2.4 GHz. Moreover, an OAM-mode based encoding method is experimentally carried out by the proposed OAM mode reconfigurable antenna, the digital data are encoded and decoded by different OAM modes. At the transmitter, the proposed OAM mode reconfigurable antenna is used to encode the digital data, data symbol 0 and 1 are mapped to OAM mode 1 and mode -1, respectively. At the receiver, the data symbols are decoded by phase gradient method. PMID- 28852117 TI - Novel evidence for complement system activation in chick myopia and hyperopia models: a meta-analysis of transcriptome datasets. AB - Myopia (short-sightedness) and hyperopia (long-sightedness) occur when the eye grows too long or short, respectively, for its refractive power. There are currently approximately 1.45 billion myopes worldwide and prevalence is rising dramatically. Although high myopia significantly increases the risk of developing a range of sight-threatening disorders, the molecular mechanisms underlying ocular growth regulation and its relationship to these secondary complications remain poorly understood. Thus, this study meta-analyzed transcriptome datasets collected in the commonly used chick model of optically-induced refractive error. Fifteen datasets (collected across five previous studies) were obtained from GEO, preprocessed in Bioconductor, and divided into 4 conditions representing early (<=1 day) and late (>1 day) myopia and hyperopia induction. Differentially expressed genes in each condition were then identified using Rank Product meta analysis. The results provide novel evidence for transcriptional activation of the complement system during both myopia and hyperopia induction, and confirm existing literature implicating cell signaling, mitochondrial, and structural processes in refractive error. Further comparisons demonstrated that the meta analysis results also significantly improve concordance with broader omics data types (i.e., human genetic association and animal proteomics studies) relative to previous transcriptome studies, and show extensive similarities with the genes linked to age-related macular degeneration, choroidal neovascularization, and cataract. PMID- 28852119 TI - Automated Classification of Benign and Malignant Proliferative Breast Lesions. AB - Misclassification of breast lesions can result in either cancer progression or unnecessary chemotherapy. Automated classification tools are seen as promising second opinion providers in reducing such errors. We have developed predictive algorithms that automate the categorization of breast lesions as either benign usual ductal hyperplasia (UDH) or malignant ductal carcinoma in situ (DCIS). From diagnosed breast biopsy images from two hospitals, we obtained 392 biomarkers using Dong et al.'s (2014) computational tools for nuclei identification and feature extraction. We implemented six machine learning models and enhanced them by reducing prediction variance, extracting active features, and combining multiple algorithms. We used the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for performance evaluation. Our top performing model, a Combined model with Active Feature Extraction (CAFE) consisting of two logistic regression algorithms, obtained an AUC of 0.918 when trained on data from one hospital and tested on samples of the other, a statistically significant improvement over Dong et al.'s AUC of 0.858. Pathologists can substantially improve their diagnoses by using it as an unbiased validator. In the future, our work can also serve as a valuable methodology for differentiating between low-grade and high-grade DCIS. PMID- 28852121 TI - Templated Assembly of Collagen Fibers Directs Cell Growth in 2D and 3D. AB - Collagen is widely used in tissue engineering and regenerative medicine, with many examples of collagen-based biomaterials emerging in recent years. While there are numerous methods available for forming collagen scaffolds from isolated collagen, existing biomaterial processing techniques are unable to efficiently align collagen at the microstructural level, which is important for providing appropriate cell recognition and mechanical properties. Although some attention has shifted to development of fiber-based collagen biomaterials, existing techniques for producing and aligning collagen fibers are not appropriate for large-scale fiber manufacturing. Here, we report a novel biomaterial fabrication approach capable of efficiently generating collagen fibers of appropriate sizes using a viscous solution of dextran as a dissolvable template. We demonstrate that myoblasts readily attach and align along 2D collagen fiber networks created by this process. Furthermore, encapsulation of collagen fibers with myoblasts into non-cell-adherent hydrogels promotes aligned growth of cells and supports their differentiation. The ease-of-production and versatility of this technique will support future development of advanced in vitro tissue models and materials for regenerative medicine. PMID- 28852120 TI - Insight into the metabolic mechanism of Diterpene Ginkgolides on antidepressant effects for attenuating behavioural deficits compared with venlafaxine. AB - Depression is a severe and chronic mental disorder, affecting about 322 million individuals worldwide. A recent study showed that diterpene ginkgolides (DG) have antidepressant-like effects on baseline behaviours in mice. Here, we examined the effects of DG and venlafaxine (VLX) in a chronic social defeat stress model of depression. Both DG and VLX attenuated stress-induced social deficits, despair behaviour and exploratory behaviour. To elucidate the metabolic changes underlying the antidepressive effects of DG and VLX, we investigated candidate functional pathways in the prefrontal cortex using a GC-MS-based metabolomics approach. Metabolic functions and pathways analysis revealed that DG and VLX affect protein biosynthesis and nucleotide metabolism to enhance cell proliferation, with DG having a weaker impact than VLX. Glutamate and aspartate metabolism played important roles in the antidepressant effects of DG and VLX. Tyrosine degradation and cell-to-cell signaling and interaction helped discriminate the two antidepressants. L-glutamic acid was negatively correlated, while hypoxanthine was positively correlated, with the social interaction ratio. Understanding the metabolic changes produced by DG and VLX should provide insight into the mechanisms of action of these drugs and aid in the development of novel therapies for depression. PMID- 28852122 TI - Chemical synthesis of hierarchical NiCo2S4 nanosheets like nanostructure on flexible foil for a high performance supercapacitor. AB - In this study, hierarchical interconnected nickel cobalt sulfide (NiCo2S4) nanosheets were effectively deposited on a flexible stainless steel foil by the chemical bath deposition method (CBD) for high-performance supercapacitor applications. The resulting NiCo2S4 sample was characterized by X-ray powder diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM), and electrochemical measurements. XRD and X-ray photoelectron spectroscopy (XPS) results confirmed the formation of the ternary NiCo2S4 sample with a pure cubic phase. FE-SEM and HR-TEM revealed that the entire foil surface was fully covered with the interconnected nanosheets like surface morphology. The NiCo2S4 nanosheets demonstrated impressive electrochemical characteristics with a specific capacitance of 1155 F g-1 at 10 mV s-1 and superior cycling stability (95% capacity after 2000 cycles). These electrochemical characteristics could be attributed to the higher active area and higher conductivity of the sample. The results demonstrated that the interconnected NiCo2S4 nanosheets are promising as electrodes for supercapacitor and energy storage applications. PMID- 28852123 TI - The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is the most common adult renal neoplasm and its incidence continues to increase. Collagen is the most abundant extracellular matrix protein in stroma, and contributes to the development and progression of ccRCC. We examined the human collagen type XXIII alpha1 chain (COL23A1) expression in ccRCC and the relationship between COL23A1 and patients' survival. We found COL23A1 mRNA was elevated in tumor compared with adjacent normal tissues, which was further validated by TCGA cohort. IHC results from 151 ccRCC cases suggested that high COL23A1 expression correlated with larger tumor size (P = 0.017) and advanced T stage (P = 0.011). The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P = 0.002). In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P = 0.017). Furthermore, COL23A1 knockdown repressed proliferation of ccRCC cell lines by blocking cell cycle progression. Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1. Our data indicate that COL23A1 may be a novel prognostic indicator in ccRCC and might be a specific and accessible biomarker as well as a potential new target for clinical diagnosis of ccRCC. PMID- 28852124 TI - Oxidative Stress and Immune Responses During Hepatitis C Virus Infection in Tupaia belangeri. AB - Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. To address the molecular basis of HCV pathogenesis using tupaias (Tupaia belangeri), we characterized host responses upon HCV infection. Adult tupaias were infected with HCV genotypes 1a, 1b, 2a, or 4a. Viral RNA, alanine aminotransferase, anti-HCV core and anti-nonstructural protein NS3 antibody titres, reactive oxygen species (ROS), and anti-3beta-hydroxysterol Delta24reductase (DHCR24) antibody levels were measured at 2-week intervals from 0 to 41 weeks postinfection. All HCV genotypes established infections and showed intermittent HCV propagation. Moreover, all tupaias produced anti-core and anti NS3 antibodies. ROS levels in sera and livers were significantly increased, resulting in induction of DHCR24 antibody production. Similarly, lymphocytic infiltration, disturbance of hepatic cords, and initiation of fibrosis were observed in livers from HCV-infected tupaias. Intrahepatic levels of Toll-like receptors 3, 7, and 8 were significantly increased in all HCV-infected tupaias. However, interferon-beta was only significantly upregulated in HCV1a- and HCV2a infected tupaias, accompanied by downregulation of sodium taurocholate cotransporting polypeptide. Thus, our findings showed that humoral and innate immune responses to HCV infection, ROS induction, and subsequent increases in DHCR24 auto-antibody production occurred in our tupaia model, providing novel insights into understanding HCV pathogenesis. PMID- 28852125 TI - IRF2BP2-deficient microglia block the anxiolytic effect of enhanced postnatal care. AB - Enhanced postnatal care (EPC) increases resilience to adversity in adulthood. Since microglia participate in shaping neural circuits, we asked how ablation of an inflammation-suppressing factor IRF2BP2 (Interferon Regulatory Factor 2 Binding Protein 2) in microglia would affect the responses to EPC. Mice lacking IRF2BP2 in microglia (KO) and littermate controls (WT) were subjected to EPC during the first 3 weeks after birth. EPC reduced anxiety in WT but not KO mice. This was associated with reduced inflammatory cytokine expression in the hypothalamus. Whole genome RNAseq profiling of the hypothalamus identified 101 genes whose expression was altered by EPC: 95 in WT, 11 in KO, with 5 in common that changed in opposite directions. Proteoglycan 4 (Prg4), prostaglandin D2 synthase (Ptgds) and extracellular matrix protease inhibitor Itih2 were suppressed by EPC in WT but elevated in KO mice. On the other hand, the glutamate transporter VGLUT1 (Slc17a7) was increased by EPC in WT but not KO mice. Prostaglandin D2 (PGD2) is known to enhance microglial inflammation and promote Gfap expression. ELISA confirmed reduced PGD2 in the hypothalamus of WT mice after EPC, associated with reduced Gfap expression. Our study suggests that the anxiety-reducing effect of EPC operates by suppressing microglial inflammation, likely by reducing neuronal prostaglandin D2 production. PMID- 28852126 TI - Decrease of FSTL1-BMP4-Smad signaling predicts poor prognosis in lung adenocarcinoma but not in squamous cell carcinoma. AB - Follistatin-related protein 1 (FSTL1) plays a critical role in lung development through regulating BMP4-p-Smad1/5/8-Smad4 pathway. Regarding that many developmental pathways in embryogenesis are dysregulated in cancer, we aim to unravel the role of FSTL1-BMP4-Smad pathway in lung cancer. Our results showed low FSTL1 immunoexpression was significantly correlated with poor prognosis while patients with low BMP4 or low Smad4 immunoexpression showed a trend toward poor prognosis. When stratified by different histological types, low FSTL1, BMP4, and Smad4 expression retained their trends in predicting poor prognosis in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma (SCC). Low FSTL1, BMP4, and Smad4 expression were more frequently observed in LUAD patients with smoking history. To determine smoking effect on FSTL1, normal cell BEAS2B and lung cancer cell lines was treated with nicotine and the results showed nicotine increased the proliferation of these cells. Interestingly, FSTL1 attenuated nicotine-induced BEAS2B and lung cancer cell line proliferation. Altogether, low FSTL1, BMP4, and Smad4 expression significantly correlated with poor prognosis in LUAD but not in SCC. Frequent decrease of FSTL1 expression in smokers LUAD further indicates its importance and therapeutic potential for lung cancer patients with specific subtypes. FSTL1 may prevent nicotine-induced lung cancer cell proliferation. PMID- 28852127 TI - BBS4 regulates the expression and secretion of FSTL1, a protein that participates in ciliogenesis and the differentiation of 3T3-L1. AB - Bardet-Biedl syndrome is a model ciliopathy. Although the characterization of BBS proteins has evidenced their involvement in cilia, extraciliary functions for some of these proteins are also being recognized. Importantly, understanding both cilia and cilia-independent functions of the BBS proteins is key to fully dissect the cellular basis of the syndrome. Here we characterize a functional interaction between BBS4 and the secreted protein FSTL1, a protein linked to adipogenesis and inflammation among other functions. We show that BBS4 and cilia regulate FSTL1 mRNA levels, but BBS4 also modulates FSTL1 secretion. Moreover, we show that FSTL1 is a novel regulator of ciliogenesis thus underscoring a regulatory loop between FSTL1 and cilia. Finally, our data indicate that BBS4, cilia and FSTL1 are coordinated during the differentiation of 3T3-L1 cells and that FSTL1 plays a role in this process, at least in part, by modulating ciliogenesis. Therefore, our findings are relevant to fully understand the development of BBS-associated phenotypes such as obesity. PMID- 28852129 TI - A novel function of cIAP1 as a mediator of CHIP-driven eIF4E regulation. AB - eIF4E is an initiator protein in cap-dependent translation. Its overexpression is linked to tumorigenesis in various human cancers, suggesting that the levels of eIF4E must be under tight control in normal cells. Although several eIF4E regulatory mechanisms have been demonstrated, the intracellular mechanisms controlling eIF4E protein levels remain poorly understood. Here, we report that eIF4E is efficiently regulated by dual mechanisms, both involving human inhibitor of apoptosis family protein cIAP1. cIAP1 itself ubiquitinates eIF4E as an E3 ligase, and interestingly, cIAP1 also functions as a mediator to present eIF4E to another E3 ligase, CHIP. This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis. Our results provide the first evidence for a mediator function of cIAP1 and collaborative activity of cIAP1 and CHIP, suggesting that maintaining balanced levels of these E3 ligases might be beneficial for normal cell growth. PMID- 28852128 TI - Printable Fluorescent Hydrogels Based on Self-Assembling Peptides. AB - Fluorescent hydrogels (FH) have a variety of potential applications in the field of soft electronics. However, fabrication of mechanically stable and printable fluorescent hydrogels remains challenging. Here, we report a kind of fluorescent hydrogel based on the co-assembly of peptide motif and transition metal ions. The metal ions are captured in the hydrogel network at specific positions through covalently linked ligands on the peptide hydrogelators. This efficiently prevents the aggregation and self-quenching of organometallic chromophores. In addition, the formation of metal-ligand complexes introduces additional interactions to stabilize the hydrogel network, making the FH even more stable after the incorporation of metal ions. The FH is optically transparent but highly fluorescent. By using three different metal ions, the white light fluorescent supramolecular hydrogel has been achieved. As a proof-of-principle, we demonstrate the printability of the hydrogels to various patterns. We anticipate that with the improved fluorescent performance and stability, this kind of FH can find broad applications in extrusion-based 3D printing for the construction of soft electronics. PMID- 28852130 TI - An approximate analytical solution of the Bethe equation for charged particles in the radiotherapeutic energy range. AB - Charged particles such as protons and carbon ions are an increasingly important tool in radiotherapy. There are however unresolved physics issues impeding optimal implementation, including estimation of dose deposition in non homogeneous tissue, an essential aspect of treatment optimization. Monte Carlo (MC) methods can be employed to estimate radiation profile, and whilst powerful, these are computationally expensive, limiting practicality. In this work, we start from fundamental physics in the form of the Bethe equation to yield a novel approximate analytical solution for particle range, energy and linear energy transfer (LET). The solution is given in terms of the exponential integral function with relativistic co-ordinate transform, allowing application at radiotherapeutic energy levels (50-350 MeV protons, 100-600 Mev/a.m.u carbon ions). Model results agreed closely for protons and carbon-ions (mean error within ~1%) of literature values. Agreement was high along particle track, with some discrepancy manifesting at track-end. The model presented has applications within a charged particle radiotherapy optimization framework as a rapid method for dose and LET estimation, capable of accounting for heterogeneity in electron density and ionization potential. PMID- 28852131 TI - Raman spectroscopy uncovers biochemical tissue-related features of extracellular vesicles from mesenchymal stromal cells. AB - Extracellular vesicles (EVs) from mesenchymal stromal cells (MSC) are emerging as valuable therapeutic agents for tissue regeneration and immunomodulation, but their clinical applications have so far been limited by the technical restraints of current isolation and characterisation procedures. This study shows for the first time the successful application of Raman spectroscopy as label-free, sensitive and reproducible means of carrying out the routine bulk characterisation of MSC-derived vesicles before their use in vitro or in vivo, thus promoting the translation of EV research to clinical practice. The Raman spectra of the EVs of bone marrow and adipose tissue-derived MSCs were compared with human dermal fibroblast EVs in order to demonstrate the ability of the method to distinguish the vesicles of the three cytotypes automatically with an accuracy of 93.7%. Our data attribute a Raman fingerprint to EVs from undifferentiated and differentiated cells of diverse tissue origin, and provide insights into the biochemical characteristics of EVs from different sources and into the differential contribution of sphingomyelin, gangliosides and phosphatidilcholine to the Raman spectra themselves. PMID- 28852132 TI - Identification of the protective mechanisms of Lactoferrin in the irradiated salivary gland. AB - Radiotherapy is commonly used in patients with head and neck cancer, and usually results in irreversible salivary glands damage and hypofunction. It is therefore important to manage such irradiation to prevent damage to the salivary glands. A previous study showed that Lactoferrin (LF) has a radioprotective effect, but the mechanism was not determined in salivary glands. In the present study, we investigated the detailed radioprotective effect of LF using both ex vivo submandibular salivary gland organ culture and ICR male mice in vivo. We found that LF had effects on both cell proliferation and CyclinD1-mediated cell-cycle progression which were regulated via the ERK1/2 and AKT signal transduction pathways. In addition, LF affected acinar cell structure and function after irradiation. These findings suggest that LF may be a useful agent to prevent irradiation effects in salivary glands. PMID- 28852133 TI - A kinetic model of multiple phenotypic states for breast cancer cells. AB - Quantitative modeling of microscopic genes regulatory mechanisms in an individual cell is a crucial step towards understanding various macroscopic physiological phenomena of cell populations. Based on the regulatory mechanisms of genes zeb1 and cdh1 in the growth and development of breast cancer cells, we propose a kinetic model at the level of single cell. By constructing the effective landscape of underlying stationary probability for the genes expressions, it is found that (i) each breast cancer cell has three phenotypic states (i.e., the stem-like, basal, and luminal states) which correspond to three attractions of the probability landscape. (ii) The interconversions between phenotypic states can be induced by the noise intensity and the property of phenotypic switching is quantified by the mean first-passage time. (iii) Under certain conditions, the probabilities of each cancer cell appearing in the three states are consistent with the macroscopic phenotypic equilibrium proportions in the breast cancer SUM159 cell line. (iv) Our kinetic model involving the TGF-beta signal can also qualitatively explain several macroscopic physiological phenomena of breast cancer cells, such as the "TGF-beta paradox" in tumor therapy, the five clinical subtypes of breast cancer cells, and the effects of transient TGF-beta on breast cancer metastasis. PMID- 28852134 TI - Microbial communities in peatlands along a chronosequence on the Sanjiang Plain, China. AB - Microbial communities play crucial roles in the global carbon cycle, particularly in peatland ecosystems under climate change. The peatlands of the Sanjiang Plain could be highly vulnerable to global warming because they are mainly located at the southern limit of northern peatlands. In this study, the alpha diversity and composition of bacterial communities in three different minerotrophic fens along a chronosequence were investigated. We captured a rich microbial community that included many rare operational taxonomic units (OTUs) but was dominated by a few bacterial classes that have frequently been detected in other peatland ecosystems. Notably, a large diversity of methanotrophs affiliated with Alpha- and Gammaproteobacteria was also detected. Bacterial alpha diversity and composition varied as a function of peat depth and its associated physical chemical properties, such as total carbon, total nitrogen, pH and bulk density. We also found that bacterial community turnover (beta diversity) to be significantly correlated with soil age, whereas bacterial alpha diversity was not. PMID- 28852135 TI - Peptide SS-31 upregulates frataxin expression and improves the quality of mitochondria: implications in the treatment of Friedreich ataxia. AB - Friedreich ataxia is a progressive neurodegenerative disease caused by the expansion of GAA trinucleotide repeats within the first intron of the FXN gene, which encodes frataxin. The pathophysiology of the disease is thought to be derived from the decrease of Fe-S cluster biogenesis due to frataxin deficiency. There is currently no effective treatment for the disease. In our study, we demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients. Interestingly, SS-31 treatment translationally upregulated the protein level of frataxin in a dose-dependent manner. Furthermore, SS-31 treatment increased the enzymatic activities of the iron-sulphur enzymes, including aconitase and complex II and III of the respiratory chain. Further evaluation of the quality of mitochondria showed that mitochondrial membrane potential, ATP content, NAD+/NADH, and the morphology of mitochondria all improved. Our results suggest that SS-31 might potentially be a new drug for the early treatment of Friedreich ataxia. PMID- 28852136 TI - High predictive values of RBC membrane-based diagnostics by biophotonics in an integrated approach for Autism Spectrum Disorders. AB - Membranes attract attention in medicine, concerning lipidome composition and fatty acid correlation with neurological diseases. Hyperspectral dark field microscopy (HDFM), a biophotonic imaging using reflectance spectra, provides accurate characterization of healthy adult RBC identifying a library of 8 spectral end-members. Here we report hyperspectral RBC imaging in children affected by Autism Spectrum Disorder (ASD) (n = 21) compared to healthy age matched subjects (n = 20), investigating if statistically significant differences in their HDFM spectra exist, that can comprehensively map a membrane impairment involved in disease. A significant difference concerning one end-member (spectrum 4) was found (P value = 0.0021). A thorough statistical treatment evidenced: i) diagnostic performance by the receiving operators curve (ROC) analysis, with cut offs and very high predictive values (P value = 0.0008) of spectrum 4 for identifying disease; ii) significant correlations of spectrum 4 with clinical parameters and with the RBC membrane deficit of the omega-3 docosahexaenoic acid (DHA) in ASD patients; iii) by principal component analysis, very high affinity values of spectrum 4 to the factor that combines behavioural parameters and the variable "cc" discriminating cases and controls. These results foresee the use of biophotonic methodologies in ASD diagnostic panels combining with molecular elements for a correct neuronal growth. PMID- 28852137 TI - The role of Nasoalveolar molding: A 3D Prospective analysis. AB - Nasoalveolar molding (NAM) is commonly employed to reduce the alveolar segments into proper alignment and to improve nasal symmetry in patients with cleft lip and palate. This study examines the periodical progression of NAM treatment over time. 20 patients with complete unilateral cleft lip and palate were prospectively recruited. A 2 stage NAM treatment protocol was applied. Stage 1 involved adjustment of the alveolar segments (mean age 15.6 days), while Stage 2 added nasal stents and started average 43 days after stage 1. 3D images (n = 241) were obtained prior to NAM initiation and weekly until the end of treatment. The cleft lip area, bilateral nostril areas, and the nostril height and width were measured. Treatment was assessed in the Cleft (C) side and the Non-cleft (N). There was significant difference in the C/N ratio of the nostril area, width, and height at pre-treatment (0.9 +/- 0.3, 4.1 +/- 1.1, and 0.5 +/- 0.2), at the end of stage 1 (1.1 +/- 0.3, 2.2 +/- 0.6, and 0.8 +/- 0.2), and at the end of stage 2 treatment (1.8 +/- 0.3, 1.8 +/- 0.4, and 1.2 +/- 0.1); p < 0.05. Comparative 3D analysis with dense sampling offers a precise methodology for showing effects of NAM treatment. The morphological changes achieved with NAM therapy occur in early treatment phase. PMID- 28852139 TI - Giant THz surface plasmon polariton induced by high-index dielectric metasurface. AB - We use computational approaches to explore the role of a high-refractive-index dielectric TiO2 grating with deep subwavelength thickness on InSb as a tunable coupler for THz surface plasmons. We find a series of resonances as the grating couples a normally-incident THz wave to standing surface plasmon waves on both thin and thick InSb layers. In a marked contrast with previously-explored metallic gratings, we observe the emergence of a much stronger additional resonance. The mechanism of this giant plasmonic resonance is well interpreted by the dispersion of surface plasmon excited in the air?TiO2?InSb trilayer system. We demonstrate that both the frequency and the intensity of the giant resonance can be tuned by varying dielectric grating parameters, providing more flexible tunability than metallic gratings. The phase and amplitude of the normally incident THz wave are spatially modulated by the dielectric grating to optimize the surface plasmon excitation. The giant surface plasmon resonance gives rise to strong enhancement of the electric field above the grating structure, which can be useful in sensing and spectroscopy applications. PMID- 28852138 TI - Inhibition of GDF8 (Myostatin) accelerates bone regeneration in diabetes mellitus type 2. AB - Metabolic diseases like diabetes mellitus cause bone healing deficiencies. We found significant impairment of bone regeneration, osteogenic differentiation and proliferation in diabetic bone. Moreover recent studies suggest a highly underestimated importance of GDF8 (Myostatin) in bone metabolism. Our goal was to analyze the role of GDF8 as a regulator of osteogenic differentiation, proliferation and bone regeneration. We used a murine tibial defect model in diabetic (Leprdb-/-) mice. Myostatin-Inhibitor Follistatin was administered in tibial bony defects of diabetic mice. By means of histology, immunohistochemistry and QRT-PC osteogenesis, differentiation and proliferation were analyzed. Application of Myostatin-inhibitor showed a significant improvement in diabetic bone regeneration compared to the control group (6.5 fold, p < 0.001). Immunohistochemistry revealed a significantly higher proliferation (7.7 fold, p = 0.009), osteogenic differentiation (Runx-2: 3.7 fold, p = 0.011, ALP: 9.3 fold, p < 0.001) and calcification (4.9 fold, p = 0.024) in Follistatin treated diabetic animals. Therapeutical application of Follistatin, known for the importance in muscle diseases, plays an important role in bone metabolism. Diabetic bone revealed an overexpression of the catabolic protein Myostatin. Antagonization of Myostatin in diabetic animals leads to a restoration of the impaired bone regeneration and represents a promising therapeutic option. PMID- 28852140 TI - Contribution of birth weight and adult waist circumference to cardiovascular disease risk in a longitudinal study. AB - To determine the association of birth weight (BW) and waist circumference (WC) on cardiovascular disease (CVD). The longitudinal cohort study consisted of 745 participants who were able to provide their birth weight information and were followed from 2002 to 2014. During the follow-up, 83 events of CVD were confirmed. After adjusting for confounding factors, subjects with birth weight <2500 g were at a significantly increased CVD risk when compared to subjects with birth weight between 2500-3999 g (OR 2.47, 95%CI, 1.07-5.71). When high waist circumference (HWC), a measurement of adult obesity, was incorporated into stratifying factors according to presence or absence of low birth weight (LBW, birth weight <2500 g), adjusted CVD risk was significantly elevated in -LBW/+ HWC group (OR 1.94, 95%CI, 1.10-3.43) and marginally significantly increased in +LBW/ HWC group (OR 2.94, 95%CI, 1.00-8.64). CVD risk was highest in subjects with LBW and HWC (+LBW/+HWC), OR 4.74 (95%CI, 1.48-15.21). Higher waist circumference in adulthood is an especially strong risk factor for cardiovascular disease among those small at birth. In this cohort, birth size and adiposity in adulthood interact to predict events of cardiovascular disease. PMID- 28852141 TI - Nonlocal Effects and Slip Heat Flow in Nanolayers. AB - Guyer-Krumhansl (G-K) equation is a promising macroscopic model to explore heat transport in nanoscale. In the present work, a new nonlocal characteristic length is proposed by considering the effects of heat carriers-boundaries interactions to modify the nonlocal term in G-K equation, and a slip heat flux boundary condition is developed based on the local mean free path of heat carriers. Then an analytical solution for heat flux across 2-D nanolayers and an in-plane thermal conductivity model are obtained based on the modified G-K equation and the slip heat flux boundary. The predictions of the present work are in good agreement with our numerical results of direct simulation Monte Carlo (DSMC) for argon gas nanolayer and the available experimental data for silicon thin layers. The results of this work may provide theoretical support for actual applications of G-K equation in predicting the thermal transport properties of nanolayers. PMID- 28852142 TI - Non-invasive three-dimension control of light between turbid layers using a surface quasi-point light source for precorrection. AB - Manipulating light non-invasively through inhomogeneous media is an attractive goal in many disciplines. Wavefront shaping and optical phase conjugation can focus light to a point. Transmission matrix method can control light on multiple output modes simultaneously. Here we report a non-invasive approach which enables three-dimension (3D) light control between two turbid layers. A digital optical phase conjugation mirror measured and conjugated the diffused wavefront, which originated from a quasi-point source on the front turbid layer and passed through the back turbid layer. And then, because of memory effect, the phase-conjugated wavefront could be used as a carrier wave to transport a pre-calculated wavefront through the back turbid layer. The pre-calculated wavefront could project a desired 3D light field inside the sample, which, in our experiments, consisted of two 220-grid ground glass plates spaced by a 20 mm distance. The controllable range of light, according to the memory effect, was calculated to be 80 mrad in solid angle and 16 mm on z-axis. Due to the 3D light control ability, our approach may find applications in photodynamic therapy and optogenetics. Besides, our approach can also be combined with ghost imaging or compressed sensing to achieve 3D imaging between turbid layers. PMID- 28852143 TI - Microbial communities in marine sediments modify success of an invasive macrophyte. AB - Invasive plants have extensive impacts on ecosystem function and biodiversity globally. Our inability to manage invasive species stems in part from a lack of understanding of the processes that control their successful establishment and spread. To date, studies have largely considered how above-ground processes control native/invasive plant interactions. Emerging research from terrestrial and wetland ecosystems demonstrates that below-ground processes under microbial control can determine the outcome of interactions between native and invasive plants. Whether sediment microbes modify the success of invasive macrophytes in marine ecosystems is untested, despite marine sediment microbes controlling many ecological processes (e.g. nutrient cycling) comparable to those in terrestrial ecosystems. We first show that sediment bacterial communities differ between the native seagrass Zostera capricorni and the invasive alga Caulerpa taxifolia and that those differences relate to functional changes in sulfur cycling between the macrophytes. Second, by experimentally manipulating the microbial communities we show that intact microbial communities in Z. capricorni sediments provide biotic resistance by reducing C. taxifolia fragment growth 119% compared to when they are inactive, and intact microbial communities in C. taxifolia sediments have positive feedbacks by increasing fragment growth 200%. Thus, similar to terrestrial ecosystems, microorganisms appear to indirectly control the success of invasive macrophytes in marine ecosystems. PMID- 28852144 TI - Molecular hydrogen increases resilience to stress in mice. AB - The inability to successfully adapt to stress produces pathological changes that can lead to depression. Molecular hydrogen has anti-oxidative and anti inflammatory activities and neuroprotective effects. However, the potential role of molecular hydrogen in stress-related disorders is still poorly understood. The present study aims to investigate the effects of hydrogen gas on resilience to stress in mice. The results showed that repeated inhalation of hydrogen-oxygen mixed gas [67%:33% (V/V)] significantly decreased both the acute and chronic stress-induced depressive- and anxiety-like behaviors of mice, assessed by tail suspension test (TST), forced swimming test (FST), novelty suppressed feeding (NSF) test, and open field test (OFT). ELISA analyses showed that inhalation of hydrogen-oxygen mixed gas blocked CMS-induced increase in the serum levels of corticosterone, adrenocorticotropic hormone, interleukin-6, and tumor necrosis factor-alpha in mice exposed to chronic mild stress. Finally, inhalation of hydrogen gas in adolescence significantly increased the resilience to acute stress in early adulthood, which illustrates the long-lasting effects of hydrogen on stress resilience in mice. This was likely mediated by inhibiting the hypothalamic-pituitary-adrenal axis and inflammatory responses to stress. These results warrant further exploration for developing molecular hydrogen as a novel strategy to prevent the occurrence of stress-related disorders. PMID- 28852145 TI - The Impact of the Polymer Chain Length on the Catalytic Activity of Poly(N-vinyl 2-pyrrolidone)-supported Gold Nanoclusters. AB - Poly(N-vinyl-2-pyrrolidone) (PVP) of varying molecular weight (M w = 40-360 kDa) were employed to stabilize gold nanoclusters of varying size. The resulting Au:PVP clusters were subsequently used as catalysts for a kinetic study on the sized-dependent aerobic oxidation of 1-indanol, which was monitored by time resolved in situ infrared spectroscopy. The obtained results suggest that the catalytic behaviour is intimately correlated to the size of the clusters, which in turn depends on the molecular weight of the PVPs. The highest catalytic activity was observed for clusters with a core size of ~7 nm, and the size of the cluster should increase with the molecular weight of the polymer in order to maintain optimal catalytic activity. Studies on the electronic and colloid structure of these clusters revealed that the negative charge density on the cluster surface also strongly depends on the molecular weight of the stabilizing polymers. PMID- 28852146 TI - The extraordinary variation of the organellar genomes of the Aneura pinguis revealed advanced cryptic speciation of the early land plants. AB - Aneura pinguis is known as a species complex with several morphologically indiscernible species, which are often reproductively isolated from each other and show distinguishable genetic differences. Genetic dissimilarity of cryptic species may be detected by genomes comparison. This study presents the first complete sequences of chloroplast and mitochondrial genomes of six cryptic species of A. pinguis complex: A. pinguis A, B, C, E, F, J. These genomes have been compared to each other in order to reconstruct phylogenetic relationships and to gain better understanding of the evolutionary process of cryptic speciation in this complex. The chloroplast genome with the nucleotide diversity 0.05111 and 1537 indels is by far more variable than mitogenome with pi value 0.00233 and number of indels 1526. Tests of selection evidenced that on about 36% of chloroplast genes and on 10% of mitochondrial genes of A. pinguis acts positive selection. It suggests an advanced speciation of species. The phylogenetic analyses based on genomes show that A. pinguis is differentiated and forms three distinct clades. Moreover, on the cpDNA trees, Aneura mirabilis is nested among the cryptic species of A. pinguis. This indicates that the A. pinguis cryptic species do not derive directly from one common ancestor. PMID- 28852147 TI - Proteomics analysis to reveal biological pathways and predictive proteins in the survival of high-grade serous ovarian cancer. AB - High-grade serous ovarian cancer (HGSC) is an aggressive cancer with a worse clinical outcome. Therefore, studies about the prognosis of HGSC may provide therapeutic avenues to improve patient outcomes. Since genome alteration are manifested at the protein level, we integrated protein and mRNA data of ovarian cancer from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) and utilized the sparse overlapping group lasso (SOGL) method, a new mechanism-driven variable selection method, to select dysregulated pathways and crucial proteins related to the survival of HGSC. We found that biosynthesis of amino acids was the main biological pathway with the best predictive performance (AUC = 0.900). A panel of three proteins, namely EIF2B1, PRPS1L1 and MAPK13 were selected as potential predictive proteins and the risk score consisting of these three proteins has predictive performance for overall survival (OS) and progression free survival (PFS), with AUC of 0.976 and 0.932, respectively. Our study provides additional information for further mechanism and therapeutic avenues to improve patient outcomes in clinical practice. PMID- 28852149 TI - Role of ultrasonic treatment, inoculation and solute in the grain refinement of commercial purity aluminium. AB - The present study investigates the influence of ultrasonic treatment on the grain refinement of commercial purity aluminium with a range of Al3Ti1B master alloy additions. When the aluminium contains the smallest amount of added master alloy, ultrasonics caused significant additional grain refinement compared to that provided by the master alloy alone. However, the influence of ultrasonics on grain size reduces with increasing addition of the master alloy which adds additional TiB2 particles and Ti solute with each incremental addition. Applying the Interdependence model to analyse the experimentally measured grain sizes revealed that the results of this study and those from similar experiments on an Al-2Cu alloy were consistent when the alloy compositions are converted to their growth restriction factors (Q) and that increasing Q had a major effect on reducing grain size and increasing grain number density. Compared with the application of ultrasonic treatment where an order of magnitude increase in the grain number density is achieved, an increase in the Ti content over the range of master alloy additions, causes the grain number density to increase by approximately three times. PMID- 28852148 TI - Semi-synthetic vNAR libraries screened against therapeutic antibodies primarily deliver anti-idiotypic binders. AB - Anti-idiotypic binders which specifically recognize the variable region of monoclonal antibodies have proven to be robust tools for pharmacokinetic studies of antibody therapeutics and for the development of cancer vaccines. In the present investigation, we focused on the identification of anti-idiotypic, shark derived IgNAR antibody variable domains (vNARs) targeting the therapeutic antibodies matuzumab and cetuximab for the purpose of developing specific capturing ligands. Using yeast surface display and semi-synthetic, CDR3 randomized libraries, we identified several highly specific binders targeting both therapeutic antibodies in their corresponding variable region, without applying any counter selections during screening. Importantly, anti-idiotypic vNAR binders were not cross-reactive towards cetuximab or matuzumab, respectively, and comprised good target recognition in the presence of human and mouse serum. When coupled to magnetic beads, anti-idiotypic vNAR variants could be used as efficient capturing tools. Moreover, a two-step procedure involving vNAR-functionalized beads was employed for the enrichment of potentially bispecific cetuximab * matuzumab antibody constructs. In conclusion, semi synthetic and CDR3-randomized vNAR libraries in combination with yeast display enable the fast and facile identification of anti-idiotypic vNAR domains targeting monoclonal antibodies primarily in an anti-idiotypic manner. PMID- 28852150 TI - Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat. AB - In this study we uncovered, through targeted ablation, a potential role for corticospinal, cerebello-rubro-spinal, and hypothalamic A11 dopaminergic systems in the development of restless legs syndrome (RLS)-like movements during sleep. Targeted lesions in select basal ganglia (BG) structures also revealed a major role for nigrostriatal dopamine, the striatum, and the external globus pallidus (GPe) in regulating RLS-like movements, in particular pallidocortical projections from the GPe to the motor cortex. We further showed that pramipexiole, a dopamine agonist used to treat human RLS, reduced RLS-like movements. Taken together, our data show that BG-cortico-spinal, cerebello-rubro-spinal and A11 descending projections all contribute to the suppression of motor activity during sleep and sleep-wake transitions, and that disruption of these circuit nodes produces RLS like movements. Taken together with findings from recent genomic studies in humans, our findings provide additional support for the concept that the anatomic and genetic etiological bases of RLS are diverse. PMID- 28852151 TI - Hypnotic analgesia reduces brain responses to pain seen in others. AB - Brain responses to pain experienced by oneself or seen in other people show consistent overlap in the pain processing network, particularly anterior insula, supporting the view that pain empathy partly relies on neural processes engaged by self-nociception. However, it remains unresolved whether changes in one's own pain sensation may affect empathic responding to others' pain. Here we show that inducing analgesia through hypnosis leads to decreased responses to both self and vicarious experience of pain. Activations in the right anterior insula and amygdala were markedly reduced when participants received painful thermal stimuli following hypnotic analgesia on their own hand, but also when they viewed pictures of others' hand in pain. Functional connectivity analysis indicated that this hypnotic modulation of pain responses was associated with differential recruitment of right prefrontal regions implicated in selective attention and inhibitory control. Our results provide novel support to the view that self nociception is involved during empathy for pain, and demonstrate the possibility to use hypnotic procedures to modulate higher-level emotional and social processes. PMID- 28852152 TI - Functional and effective whole brain connectivity using magnetoencephalography to identify monozygotic twin pairs. AB - Resting-state functional connectivity patterns are highly stable over time within subjects. This suggests that such 'functional fingerprints' may have strong genetic component. We investigated whether the functional (FC) or effective (EC) connectivity patterns of one monozygotic twin could be used to identify the co twin among a larger sample and determined the overlap in functional fingerprints within monozygotic (MZ) twin pairs using resting state magnetoencephalography (MEG). We included 32 cognitively normal MZ twin pairs from the Netherlands Twin Register who participate in the EMIF-AD preclinAD study (average age 68 years). Combining EC information across multiple frequency bands we obtained an identification rate over 75%. Since MZ twin pairs are genetically identical these results suggest a high genetic contribution to MEG-based EC patterns, leading to large similarities in brain connectivity patterns between two individuals even after 60 years of life or more. PMID- 28852153 TI - Ethyl Acetate Extract Components of Bushen-Yizhi Formula Provides Neuroprotection against Scopolamine-induced Cognitive Impairment. AB - Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and there is no effective cure for this devastating disease to date. Bushen Yizhi Formula (BSYZ-F), a Chinese herbal compound, has proved to be effective for AD. In this study, we further investigate the effective part of BSYZ-F, ethyl acetate extract components of BSYZ-F (BSYZ-E), protects scopolamine (SCOP)-induced cognitive impairment, which shows a similar effect to BSYZ-F. We also find that BSYZ-E could protect against SCOP-induced cholinergic system dysfunction. In neuron function level, BSYZ-E remarkably elevates protein levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). BSYZ-E also significantly mitigates SCOP-induced apoptosis, oxidative stress and nitrosative stress. Conclusively, BSYZ-E, the effective part of BSYZ-F, can provide neuroprotection against SCOP-induced cognitive impairment through a multifunctional strategy. These findings suggest that BSYZ-E might be developed as a therapeutic drug for AD by targeting multiple pathways of the pathogenesis. PMID- 28852154 TI - The naphthalene catabolic protein NahG plays a key role in hexavalent chromium reduction in Pseudomonas brassicacearum LZ-4. AB - Soil contamination by PAH and heavy metals is a growing problem. Here, we showed that a new isolate, Pseudomonas brassicacearum strain LZ-4, can simultaneously degrade 98% of 6 mM naphthalene and reduce 92.4% of 500 MUM hexavalent chromium [Cr (VI)] within 68 h. A draft genome sequence of strain LZ-4 (6,219,082 bp) revealed all the genes in the naphthalene catabolic pathway and some known Cr (VI) reductases. Interestingly, genes encoding naphthalene pathway components were upregulated in the presence of Cr (VI), and Cr (VI) reduction was elevated in the presence of naphthalene. We cloned and expressed these naphthalene catabolic genes and tested for Cr (VI) reduction, and found that NahG reduced 79% of 100 MUM Cr (VI) in 5 minutes. Additionally, an nahG deletion mutant lost 52% of its Cr (VI) reduction ability compared to that of the wild-type strain. As nahG encodes a salicylate hydroxylase with flavin adenine dinucleotide (FAD) as a cofactor for electron transfer, Cr (VI) could obtain electrons from NADH through NahG-associated FAD. To the best of our knowledge, this is the first report of a protein involved in a PAH-degradation pathway that can reduce heavy metals, which provides new insights into heavy metal-PAH contamination remediation. PMID- 28852155 TI - Three novel obese indicators perform better in monitoring management of metabolic syndrome in type 2 diabetes. AB - The present study evaluated the performance of three novel obese indicators, visceral adiposity index (VAI), lipid accumulation product (LAP) and waist circumference-triglyceride index (WTI), for identifying metabolic syndrome(MetS) in type 2 diabetes. A cross-sectional study was conducted on 711 type 2 diabetes in Qinhuangdao. The MetS was defined as the definition of Chinese Diabetes Society. Receiver operating characteristic curve analyses were performed to assess the accuracy of three obese indicators as diagnostic tests for MetS. The prevalence of MetS was 71.3%. In men, among all three obese indicators, the LAP had the highest area under curve (AUC) value (AUC = 0.894), followed by VAI (AUC = 0.860) and WTI (AUC = 0.855). In women, among all three obese indicators, the LAP had the highest AUC value (AUC = 0.906), followed by WTI (AUC = 0.887) and VAI (AUC = 0.881). However. there was no significant difference between the three obese indicators(P > 0.05). Three obese indicators were effective indicators for the screening of MetS, LAP and WTI are more simple. PMID- 28852156 TI - The neural mechanism underpinning balance calibration between action inhibition and activation initiated by reward motivation. AB - In everyday life, it is often the case that in some situations we are motivated and want not only to speed up our actions but also to avoid mistakes-for example, ballgames. How our brain works at that moment to resolve the situations and react properly has created an active research field. Previous findings indicated that maintaining a balance between withholding and executing an action are highly dynamic and involve many executive control processes. This fMRI study was set up to investigate how motivation affects these balancing processes. With manipulation of prospective rewards in a stop-signal task where both the proactive and reactive control were equally emphasized, our behavioral results replicated previous findings. The fMRI findings backed up the behavioral results. We found motivation effects in the anterior caudate and pre-SMA for action inhibition. The former works to register motivation status, the latter works to transform motivation into action inhibition control. Together with the results of connectivity analysis, our study also suggests a hierarchical relationship between functional roles of pre-SMA and right inferior frontal gyrus during action inhibition. While the pre-SMA acts to accommodate higher-order factors, such as motivation, for action control, the right inferior frontal cortex acts to participate in the execution of action inhibition. This study pinned down a neural mechanism that integrates reward motivation into action inhibition control. PMID- 28852157 TI - Dissecting the Molecular Mechanism of the Subcellular Localization and Cell-to cell Movement of the Sugarcane mosaic virus P3N-PIPO. AB - The coding sequence of P3N-PIPO was cloned by fusion PCR from Sugarcane mosaic virus (SCMV), a main causal agent of sugarcane (Saccharum spp. hybrid) mosaic disease. SCMV P3N-PIPO preferentially localized to the plasma membrane (PM) compared with the plasmodesmata (PD), as demonstrated by transient expression and plasmolysis assays in the leaf epidermal cells of Nicotiana benthamiana. The subcellular localization of the P3N-PIPO mutants P3N-PIPOT1 and P3N-PIPOT2 with 29 and 63 amino acids deleted from the C-terminus of PIPO, respectively, revealed that the 19 amino acids at the N-terminus of PIPO contributed to the PD localization. Interaction assays showed that the 63 amino acids at the C-terminus of PIPO determined the P3N-PIPO interaction with PM-associated Ca2+-binding protein 1, ScPCaP1, which was isolated from the SCMV-susceptible sugarcane cultivar Badila. Like wild-type P3N-PIPO, P3N-PIPOT1 and P3N-PIPOT2 could translocate to neighbouring cells and recruit the SCMV cylindrical inclusion protein to the PM. Thus, interactions with ScPCaP1 may contribute to, but not determine, SCMV Pm3N-PIPO's localization to the PM or PD. These results also imply the existence of truncated P3N-PIPO in nature. PMID- 28852158 TI - Investigation of a Canine Parvovirus Outbreak using Next Generation Sequencing. AB - Canine parvovirus (CPV) outbreaks can have a devastating effect in communities with dense dog populations. The interior region of Alaska experienced a CPV outbreak in the winter of 2016 leading to the further investigation of the virus due to reports of increased morbidity and mortality occurring at dog mushing kennels in the area. Twelve rectal-swab specimens from dogs displaying clinical signs consistent with parvoviral-associated disease were processed using next generation sequencing (NGS) methodologies by targeting RNA transcripts, and therefore detecting only replicating virus. All twelve specimens demonstrated the presence of the CPV transcriptome, with read depths ranging from 2.2X - 12,381X, genome coverage ranging from 44.8-96.5%, and representation of CPV sequencing reads to those of the metagenome background ranging from 0.0015-6.7%. Using the data generated by NGS, the presence of newly evolved, yet known, strains of both CPV-2a and CPV-2b were identified and grouped geographically. Deep-sequencing data provided additional diagnostic information in terms of investigating novel CPV in this outbreak. NGS data in addition to limited serological data provided strong diagnostic evidence that this outbreak most likely arose from unvaccinated or under-vaccinated canines, not from a novel CPV strain incapable of being neutralized by current vaccination efforts. PMID- 28852160 TI - Creating the Functional Single-Ring GroEL-GroES Chaperonin Systems via Modulating GroEL-GroES Interaction. AB - Chaperonin and cochaperonin, represented by E. coli GroEL and GroES, are essential molecular chaperones for protein folding. The double-ring assembly of GroEL is required to function with GroES, and a single-ring GroEL variant GroELSR forms a stable complex with GroES, arresting the chaperoning reaction cycle. GroES I25 interacts with GroEL; however, mutations of I25 abolish GroES-GroEL interaction due to the seven-fold mutational amplification in heptameric GroES. To weaken GroELSR-GroES interaction in a controlled manner, we used groES 7, a gene linking seven copies of groES, to incorporate I25 mutations in selected GroES modules in GroES7. We generated GroES7 variants with different numbers of GroESI25A or GroESI25D modules and different arrangements of the mutated modules, and biochemically characterized their interactions with GroELSR. GroES7 variants with two mutated modules participated in GroELSR-mediated protein folding in vitro. GroES7 variants with two or three mutated modules collaborated with GroELSR to perform chaperone function in vivo: three GroES7 variants functioned with GroELSR under both normal and heat-shock conditions. Our studies on functional single-ring bacterial chaperonin systems are informative to the single ring human mitochondrial chaperonin mtHsp60-mtHsp10, and will provide insights into how the double-ring bacterial system has evolved to the single-ring mtHsp60 mtHsp10. PMID- 28852159 TI - Loss of the podocyte glucocorticoid receptor exacerbates proteinuria after injury. AB - Nephrotic syndrome is a common disorder in adults and children whose etiology is largely unknown. Glucocorticoids remain the mainstay of therapy in most cases, though their mechanism of action remains poorly understood. Emerging evidence suggests that immunomodulatory therapies used in nephrotic syndrome directly target the podocytes. To study how steroids directly affect the podocytes in the treatment of proteinuria, we created a mouse model with podocyte-specific deletion of the glucocorticoid receptor. The podocyte-specific glucocorticoid receptor (GR) knockout mice had similar renal function and protein excretion compared to wild type. However, after glomerular injury induced by either LPS or nephrotoxic serum, the podocyte GR knockout mice demonstrated worsened proteinuria compared to wild type. Ultrastructural examination of podocytes confirmed more robust foot process effacement in the knockout animals. Expression of several key slit diaphragm protein was down regulated in pGR KO mice. Primary podocytes isolated from wild type and podocyte GR knockout mice showed similar actin stress fiber staining patterns in unstimulated conditions. Yet, when exposed to LPS, GR knockout podocytes demonstrated fewer stress fibers and impaired migration compared to wild type podocytes. We conclude that the podocyte glucocorticoid receptor is important for limiting proteinuria in settings of podocyte injury. PMID- 28852162 TI - Phase-change devices for simultaneous optical-electrical applications. AB - We present a viable pathway to the design and characterization of phase-change devices operating in a mixed-mode optical-electrical, or optoelectronic, manner. Such devices have potential applications ranging from novel displays to optically gated switches to reconfigurable metamaterials-based devices. With this in mind, a purpose-built optoelectronics probe station capable of simultaneous optical electrical excitation and simultaneous optical-electrical response measurement has been designed and constructed. Two prototype phase-change devices that might exploit simultaneous optical and electrical effects and/or require simultaneous optical and electrical characterisation, namely a mixed-mode cross-bar type structure and a microheater-based structure, have been designed, fabricated and characterized. The microheater-based approach was shown to be capable of successful thermally-induced cycling, between amorphous and crystalline states, of large-area phase-change devices, making it attractive for practicable pixel fabrication in phase-change display applications. PMID- 28852161 TI - Probe-based confocal laser endomicroscopy for in vivo evaluation of the tumor vasculature in gastric and rectal carcinomas. AB - Probe-based Confocal Laser Endomicroscopy (pCLE) is a powerful imaging technique that allows to perform gastrointestinal endomicroscopy at subcellular resolution. The aim of this study was to assess the use of pCLE to evaluate tumor angiogenesis in rectal and gastric cancers. A total of 35 consecutive patients with gastric and 91 with rectal carcinomas underwent endoscopy and pCLE during the same examination. Vascular assessment was based on vessel shape and size, vessel permeability and blood flow, and allowed the creation of an angiogenic score ranging from 0, for normal vasculature, to 4, for aberrant vasculature. A significant difference for the presence of vessels with large diameter and defective blood flow was found between rectal and gastric cancers. Overall, rectal cancers displayed a higher angiogenic score compared to gastric cancers. Conventional therapy induced a striking reduction in the angiogenic score only in rectal cancer patients. Taken together, our findings suggest that the pCLE technology is suitable for the evaluation of the tumor microvasculature abnormalities. Therefore, the real-time assessment of the vasculature status may represent a promising approach to predict the efficacy of the treatments and improve the clinical management of patients with gastric or rectal carcinomas. PMID- 28852163 TI - Expression and Purification of the Pain Receptor TRPV1 for Spectroscopic Analysis. AB - The transient receptor potential vanilloid 1 (TRPV1) channel is an essential component of the cellular mechanism through which noxious stimuli evoke pain. Functional and structural characterizations of TRPV1 shed light on vanilloid activation, yet the mechanisms for temperature and proton gating remain largely unknown. Spectroscopic approaches are needed to understand the mechanisms by which TRPV1 translates diverse stimuli into channel opening. Here, we have engineered a minimal cysteine-less rat TRPV1 construct (eTRPV1) that can be stably purified and reconstituted for spectroscopic studies. Biophysical analyses of TRPV1 constructs reveal that the S5-pore helix loop influences protein stability and vanilloid and proton responses, but not thermal sensitivity. Cysteine mutants retain function and stability for double electron-electron resonance (DEER) and electron paramagnetic resonance (EPR) spectroscopies. DEER measurements in the closed state demonstrate that eTRPV1 reports distances in the extracellular vestibule, equivalent to those observed in the apo TRPV1 structure. EPR measurements show a distinct pattern of mobilities and spectral features, in detergent and liposomes, for residues at the pore domain that agree with their location in the TRPV1 structure. Our results set the stage for a systematic characterization of TRPV1 using spectroscopic approaches to reveal conformational changes compatible with thermal- and ligand-dependent gating. PMID- 28852165 TI - Point defect formation in M2AlC (M = Zr,Cr) MAX phases and their tendency to disorder and amorphize. AB - First principles calculations are performed on Zr2AlC and Cr2AlC MAX phases to compare their ability to accommodate point defects under irradiation. Interatomic bonding is stronger in Cr2AlC than Zr2AlC but contrary to expectation Zr2AlC exhibits higher vacancy and antisite pair formation energies. However, interstitials and Frenkel defects are generally more difficult to form in Cr2AlC. The results are attributed to the mixed covalent/ionic/metallic nature of the bonding. Detailed comparison of all the energies suggests that the preferred defects in Zr2AlC and Cr2AlC are the VAl+Ali Frenkel and CrAl+AlCr antisite respectively. Thus the potential response of the two phases to irradiation is different and taking account of other competing defects it is suggested that Zr2AlC is less susceptible to amorphization. PMID- 28852166 TI - A Dynamic Metabolic Flux Analysis of Myeloid-Derived Suppressor Cells Confirms Immunosuppression-Related Metabolic Plasticity. AB - Recent years have witnessed an increasing interest at understanding the role of myeloid-derived suppressor cells (MDSCs) in cancer-induced immunosuppression, with efforts to inhibit their maturation and/or their activity. We have thus modelled MDSCs central carbon metabolism and bioenergetics dynamic, calibrating the model using experimental data on in vitro matured mice bone marrow cells into MDSCs. The model was then used to probe the cells metabolic state and dynamics, performing a dynamic metabolic flux analysis (dMFA) study. Indeed, MDSCs maturation correlates with a high glycolytic flux contributing to up to 95% of the global ATP turnover rate, while most of the glucose-derived carbon enters the TCA cycle. Model simulations also reveal that pentose phosphate pathway and oxidative phosphorylation activities were kept at minimal levels to ensure NADPH production and anabolic precursors synthesis. Surprisingly, MDSCs immunosuppressive activity, i.e. L-arginine uptake, metabolism and endogenous synthesis, only consumes sparse quantities of energy-rich nucleotides (ATP and NADPH). Therefore, model simulations suggest that MDSCs exhibit a heterogeous metabolic profile similar to tumour cells. This behavior is probably an indirect immunosuppressive mechanism where MDSCs reduce the availability of carbon sources in the tumour periphery microenvironment, which could explain the dysfuntion and death of immune effector cells. PMID- 28852164 TI - Genome-wide DNA methylation and transcriptome analyses reveal genes involved in immune responses of pig peripheral blood mononuclear cells to poly I:C. AB - DNA methylation changes play essential roles in regulating the activities of genes involved in immune responses. Understanding of variable DNA methylation linked to immune responses may contribute to identifying biologically promising epigenetic markers for pathogenesis of diseases. Here, we generated genome-wide DNA methylation and transcriptomic profiles of six pairs of polyinosinic polycytidylic acid-treated pig peripheral blood mononuclear cell (PBMC) samples and corresponding controls using methylated DNA immunoprecipitation sequencing and RNA sequencing. Comparative methylome analyses identified 5,827 differentially methylated regions and 615 genes showing differential expression between the two groups. Integrative analyses revealed inverse associations between DNA methylation around transcriptional start site and gene expression levels. Furthermore, 70 differentially methylated and expressed genes were identified such as TNFRSF9, IDO1 and EBI3. Functional annotation revealed the enriched categories including positive regulation of immune system process and regulation of leukocyte activation. These findings demonstrated DNA methylation changes occurring in immune responses of PBMCs to poly I:C stimulation and a subset of genes potentially regulated by DNA methylation in the immune responses. The PBMC DNA methylome provides an epigenetic overview of this physiological system in response to viral infection, and we expect it to constitute a valuable resource for future epigenetic epidemiology studies in pigs. PMID- 28852167 TI - Identification of butenolide regulatory system controlling secondary metabolism in Streptomyces albus J1074. AB - A large majority of genome-encrypted chemical diversity in actinobacteria remains to be discovered, which is related to the low level of secondary metabolism genes expression. Here, we report the application of a reporter-guided screening strategy to activate cryptic polycyclic tetramate macrolactam gene clusters in Streptomyces albus J1074. The analysis of the S. albus transcriptome revealed an overall low level of secondary metabolism genes transcription. Combined with transposon mutagenesis, reporter-guided screening resulted in the selection of two S. albus strains with altered secondary metabolites production. Transposon insertion in the most prominent strain, S. albus ATGSal2P2::TN14, was mapped to the XNR_3174 gene encoding an unclassified transcriptional regulator. The mutant strain was found to produce the avenolide-like compound butenolide 4. The deletion of the gene encoding a putative acyl-CoA oxidase, an orthologue of the Streptomyces avermitilis avenolide biosynthesis enzyme, in the S. albus XNR_3174 mutant caused silencing of secondary metabolism. The homologues of XNR_3174 and the butenolide biosynthesis genes were found in the genomes of multiple Streptomyces species. This result leads us to believe that the discovered regulatory elements comprise a new condition-dependent system that controls secondary metabolism in actinobacteria and can be manipulated to activate cryptic biosynthetic pathways. PMID- 28852168 TI - Hydrogen enhances strength and ductility of an equiatomic high-entropy alloy. AB - Metals are key materials for modern manufacturing and infrastructures as well as transpot and energy solutions owing to their strength and formability. These properties can severely deteriorate when they contain hydrogen, leading to unpredictable failure, an effect called hydrogen embrittlement. Here we report that hydrogen in an equiatomic CoCrFeMnNi high-entropy alloy (HEA) leads not to catastrophic weakening, but instead increases both, its strength and ductility. While HEAs originally aimed at entropy-driven phase stabilization, hydrogen blending acts opposite as it reduces phase stability. This effect, quantified by the alloy's stacking fault energy, enables nanotwinning which increases the material's work-hardening. These results turn a bane into a boon: hydrogen does not generally act as a harmful impurity, but can be utilized for tuning beneficial hardening mechanisms. This opens new pathways for the design of strong, ductile, and hydrogen tolerant materials. PMID- 28852169 TI - White Light Emission from Fluorescent SiC with Porous Surface. AB - ABSTARCT: We report for the first time a NUV light to white light conversion in a N-B co-doped 6H-SiC (fluorescent SiC) layer containing a hybrid structure. The surface of fluorescent SiC sample contains porous structures fabricated by anodic oxidation method. After passivation by 20 nm thick Al2O3, the photoluminescence intensity from the porous layer was significant enhanced by a factor of more than 12. Using a porous layer of moderate thickness (~10 um), high-quality white light emission was realized by combining the independent emissions of blue-green emission from the porous layer and yellow emission from the bulk fluorescent SiC layer. A high color rendering index of 81.1 has been achieved. Photoluminescence spectra in porous layers fabricated in both commercial n-type and lab grown N-B co-doped 6H-SiC show two emission peaks centered approximately at 460 nm and 530 nm. Such blue-green emission phenomenon can be attributed to neutral oxygen vacancies and interface C-related surface defects generated dring anodic oxidation process. Porous fluorescent SiC can offer a great flexibility in color rendering by changing the thickness of porous layer and bulk fluorescent layer. Such a novel approach opens a new perspective for the development of high performance and rare-earth element free white light emitting materials. PMID- 28852170 TI - Health risk assessment of rare earth elements in cereals from mining area in Shandong, China. AB - To investigate the concentrations of rare earth elements in cereals and assess human health risk through cereal consumption, a total of 327 cereal samples were collected from rare earth mining area and control area in Shandong, China. The contents of 14 rare earth elements were determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The medians of total rare earth elements in cereals from mining and control areas were 74.22 MUg/kg and 47.83 MUg/kg, respectively, and the difference was statistically significant (P < 0.05). The wheat had the highest rare earth elements concentrations (109.39 MUg/kg and 77.96 MUg/kg for mining and control areas, respectively) and maize had the lowest rare earth elements concentrations (42.88 MUg/kg and 30.25 MUg/kg for mining and control areas, respectively). The rare earth elements distribution patterns for both areas were characterized by enrichment of light rare earth elements. The health risk assessment demonstrated that the estimated daily intakes of rare earth elements through cereal consumption were considerably lower than the acceptable daily intake (70 MUg/kg bw). The damage to adults can be neglected, but more attention should be paid to the effects of continuous exposure to rare earth elements on children. PMID- 28852171 TI - Integrative Approach with Electrophysiological and Theoretical Methods Reveals a New Role of S4 Positively Charged Residues in PKD2L1 Channel Voltage-Sensing. AB - Numerical model-based simulations provide important insights into ion channel gating when experimental limitations exist. Here, a novel strategy combining numerical simulations with patch clamp experiments was used to investigate the net positive charges in the putative transmembrane segment 4 (S4) of the atypical, positively-shifted voltage-dependence of polycystic kidney disease 2 like 1 (PKD2L1) channel. Charge-neutralising mutations (K452Q, K455Q and K461Q) in S4 reduced gating charges, positively shifted the Boltzmann-type activation curve [i.e., open probability (P open)-V curve] and altered the time-courses of activation/deactivation of PKD2L1, indicating that this region constitutes part of a voltage sensor. Numerical reconstruction of wild-type (WT) and mutant PKD2L1 mediated currents necessitated, besides their voltage-dependent gating parameters, a scaling factor that describes the voltage-dependence of maximal conductance, G max. Subsequent single-channel conductance (gamma) measurements revealed that voltage-dependence of G max in WT can be explained by the inward rectifying property of gamma, which is greatly changed in PKD2L1 mutants. Homology modelling based on PKD2 and NaVAb structures suggest that such voltage dependence of P open and gamma in PKD2L1 could both reflect the charged state of the S4 domain. The present conjunctive experimental and theoretical approaches provide a framework to explore the undetermined mechanism(s) regulating TRP channels that possess non-classical voltage-dependent properties. PMID- 28852172 TI - Toward new gas-analytical multisensor chips based on titanium oxide nanotube array. AB - Reliable environmental monitoring requires cost effective but highly sensitive and selective gas sensors. While the sensitivity of the sensors is improved by reducing the characteristic dimensions of the gas-sensing material, the selectivity is often approached by combining the sensors into multisensor arrays. The development of scalable methods to manufacture such arrays based on low dimensional structures offers new perspectives for gas sensing applications. Here we examine an approach to produce multisensor array chips based on the TiOx nanotube layers segmented by multiple Pt strip electrodes. We study the sensitivity and selectivity of the developed chip at operating temperatures up to 400 degrees C towards organic vapors in the ppm range. The results indicate that the titania nanotubes are a promising material platform for novel cost-effective and powerful gas-analytical multisensor units. PMID- 28852173 TI - Chitin-deacetylase activity induces appressorium differentiation in the rice blast fungus Magnaporthe oryzae. AB - The rice blast fungus Magnaporthe oryzae differentiates a specialized infection structure called an appressorium to invade rice cells. In this report, we show that CBP1, which encodes a chitin-deacetylase, is involved in the induction phase of appressorium differentiation. We demonstrate that the enzymatic activity of Cbp1 is critical for appressorium formation. M. oryzae has six CDA homologues in addition to Cbp1, but none of these are indispensable for appressorium formation. We observed chitosan localization at the fungal cell wall using OGA488. This observation suggests that Cbp1-catalysed conversion of chitin into chitosan occurs at the cell wall of germ tubes during appressorium differentiation by M. oryzae. Taken together, our results provide evidence that the chitin deacetylase activity of Cbp1 is necessary for appressorium formation. PMID- 28852174 TI - Activation of invariant natural killer T cells stimulated with microbial alpha mannosyl glycolipids. AB - Some synthetic and bacterial glycolipids presented by CD1d specifically activate invariant NKT (iNKT) cells bearing an invariant Valpha14-Jalpha18 (mouse) or Valpha24-Jalpha18 (human) TCR. The antigenic glycolipids identified to date consist of two hydrophobic chains and an alpha-glycoside in which the 2'-OH group is in the cis orientation toward the anomeric group, namely, either an alpha galactoside or an alpha-glucoside. Several microbial alpha-mannosyl glycolipids, in which the 2'-OH group is in the trans orientation, were herein examined to establish whether they have potential to activate iNKT cells. We found that alpha mannnosyl1-3 (6'-O-acyl alpha-mannosyl)-1-1 monoacylglycerol and cholesteryl 6'-O acyl alpha-mannoside, found in Saccharopolyspora and Candida albicans, respectively, induced the activation of iNKT cells, dependent on CD1d. In contrast, alpha-mannosyldiacylglycerol found in Streptococcus suis or alpha mannosylceramide demonstrated markedly less antigenicity for iNKT cells. The potentially antigenic alpha-mannosyl glycolipids contributed to the protection of mice against infection with S. pneumoniae in which iNKT cells have previously been found to participate. Furthermore, these glycolipids induced the production of proinflammatory cytokines by macrophages, thereby suggesting their recognition by specific pattern recognition receptors (PRRs). Collectively, these results suggest that these microbial alpha-mannosyl glycolipids are capable of being recognized by both the invariant TCR and PRRs and inducing immune responses. PMID- 28852175 TI - Risk factors for postoperative surgical site infections in patients with Crohn's disease receiving definitive bowel resection. AB - Surgical site infection presents as a significant problem that limits the potential benefits of surgical interventions. This study is to investigate risk factors for postoperative SSI in patients with Crohn's disease receiving definitive bowel resection. A case-control study including 49 patients with SSI and 105 patients without SSI was performed. Demographics, clinical characteristics, laboratory information, medical and surgical data were compared between groups. Significant elements were subsequently brought into logistic regression analysis for further identification. Patients with SSI exhibited higher tobacco usage rate (p = 0.03), lower preoperative hemoglobin (p = 0.02) and pre-albumin level (p = 0.02). Bowel penetration instead of stricture was more frequent in patients with SSI (p = 0.04). Longer duration of operation (p = 0.03) and higher intraoperative lactate level (p = 0.02) were observed in patients with SSI. Logistic analysis identified that preoperative pre-albumin (95% CI: 0.2~0.7; OR = 0.5; p = 0.03), duration of operation (95% CI: 2.3~9.5; OR = 3.8; p = 0.03) and intraoperative lactate level (95% CI: 1.7~7.2; OR = 3.4; p = 0.04) were associated with postoperative surgical site outcome. Our data has identified that lower preoperative pre-albumin, longer duration of operation and higher intraoperative lactate level are risk factors for SSI in patients with Crohn's disease receiving definitive bowel resection. PMID- 28852177 TI - Highly tunable time-reversal-invariant topological superconductivity in topological insulator thin films. AB - We study time-reversal-invariant topological superconductivity in topological insulator (TI) thin films including both intra- and inter-surface pairing. We find a nontrivial topology for multiple different configurations. For intra surface pairing a pi-phase difference between the intra-surface pairing states is required. We show that in this case the resulting topological phase is highly tunable by both an applied electric field and varied chemical potential. For spin singlet inter-surface pairing, a sign-changing tunnel coupling present in many TI thin films is needed, and again, the topology can be tuned by electric field or doping. Notably, we find that the required inter-surface pairing strength for achieving nontrivial topology can still be subdominant compared to the intra surface pairing. Finally, for spin-triplet inter-surface pairing we prove that the superconducting state is always topological nontrivial. We show that thin films of Cu-doped Bi2Se3 will likely host such spin-triplet inter-surface pairing. Taken together, these results show that time-reversal-invariant topological superconductivity is common in superconducting TI thin films and that the topological phase and its Kramers pair of Majorana edge modes is highly tunable with an applied electric field and varied chemical potential. PMID- 28852176 TI - A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up regulation in gastric cancer cells. AB - A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer. PMID- 28852178 TI - Novel approaches for identification of anti-tumor drugs and new bioactive compounds. AB - Thanks to the pioneering work done by Professor Hamao Umezawa, bioactive compounds have been used in treatment of several diseases including cancer. In this review, we discuss our work, which focuses on developing new candidates for anti-tumor drugs by screening for bioactive natural compounds in microbial cultures using unique experimental systems. We summarize our recent progress including the following: (1) small-molecule modulators of tumor-stromal cell interactions, (2) inhibitors of three-dimensional spheroid formation of cancer cells, (3) multi-cancer cell panel screening and (4) new experimental animal models for cancer metastasis.The Journal of Antibiotics advance online publication, 30 August 2017; doi:10.1038/ja.2017.97. PMID- 28852179 TI - Total synthesis of architecturally complex indole terpenoids: strategic and tactical evolution. AB - Indole terpenes have attracted the interests of synthetic chemists due to their complex architectures and potent biological activities. Examples of total syntheses of several indole terpenes were reviewed in this article to honor Professor KC Nicolaou. PMID- 28852180 TI - Pathway-based expression profiling of benign prostatic hyperplasia and prostate cancer delineates an immunophilin molecule associated with cancer progression. AB - Aberrant restoration of AR activity is linked with prostate tumor growth, therapeutic failures and development of castrate-resistant prostate cancer. Understanding the processes leading to AR-reactivation should provide the foundation for novel avenues of drug discovery. A differential gene expression study was conducted using biopsies from CaP and BPH patients to identify the components putatively responsible for reinstating AR activity in CaP. From the set of genes upregulated in CaP, FKBP52, an AR co-chaperone, was selected for further analysis. Expression of FKBP52 was positively correlated with that of c Myc. The functional cross-talk between c-Myc and FKBP52 was established using c Myc specific-siRNA to LNCaP cells that resulted in reduction of FKBP52. A non canonical E-box sequence housing a putative c-Myc binding site was detected on the FKBP4 promoter using in silico search. LNCaP cells transfected with the FKBP52 promoter cloned in pGL3 basic showed increased luciferase activity which declined considerably when the promoter-construct was co-transfected with c-Myc specific-siRNA. ChIP-PCR confirmed the binding of c-Myc with the conserved E-box located in the FKBP52 promoter. c-Myc downregulation concomitantly affected expression of FGF8. Since expression of FGF8 is controlled by AR, our study unveiled a novel functional axis between c-Myc, AR and FGF8 operating through FKBP52. PMID- 28852181 TI - Enrichment of Viral Nucleic Acids by Solution Hybrid Selection with Genus Specific Oligonucleotides. AB - Despite recent advances, our knowledge of potential and rare human pathogens is far from exhaustive. Current molecular diagnostic tools mainly rely on the specific amplification of marker sequences and may overlook infections caused by unknown and rare pathogens. Using high-throughput sequencing (HTS) can solve this problem; but, due to the extremely low fraction of pathogen genetic material in clinical samples, its application is only cost-effective in special, rather than routine, cases. In this study, we present a method for the semi-specific enrichment of viral conservative sequences in a HTS library by hybridization in solution with genus-specific degenerate biotinylated oligonucleotides. Nucleic acids of the test viruses (yellow fever virus and Japanese encephalitis virus) were enriched by solution hybrid selection using pan-flavivirus oligonucleotides. Moreover, enterovirus (family: Picornaviridae, genus: Enterovirus) sequences were successfully enriched using foot-and-mouth disease virus (family: Picornaviridae, genus: Aphthovirus) oligonucleotide. The enrichment factor relative to the background nucleic acid was about 1,000-fold. As hybridization has less stringent oligonucleotide match requirements than PCR, few oligonucleotides are sufficient to cover the potential sequence variation in the whole genus and may even enrich nucleic acids of viruses of other related genera. Efficient enrichment of viral sequences makes its use in diagnostics cost-efficient. PMID- 28852182 TI - Unveiling the gut microbiota composition and functionality associated with constipation through metagenomic analyses. AB - Functional constipation (FC) is a gastrointestinal disorder with a high prevalence among the general population. The precise causes of FC are still unknown and are most likely multifactorial. Growing evidence indicates that alterations of gut microbiota composition contribute to constipation symptoms. Nevertheless, many discrepancies exist in literature and no clear link between FC and gut microbiota composition has as yet been identified. In this study, we performed 16 S rRNA-based microbial profiling analysis of 147 stool samples from 68 FC individuals and compared their microbial profiles with those of 79 healthy subjects (HS). Notably, the gut microbiota of FC individuals was shown to be depleted of members belonging to Bacteroides, Roseburia and Coprococcus 3. Furthermore, the metabolic capabilities of the gut microbiomes of five FC and five HS individuals were evaluated through shotgun metagenomics using a MiSeq platform, indicating that HS are enriched in pathways involved in carbohydrate, fatty acid and lipid metabolism as compared to FC. In contrast, the microbiomes corresponding to FC were shown to exhibit high abundance of genes involved in hydrogen production, methanogenesis and glycerol degradation. The identified differences in bacterial composition and metabolic capabilities may play an important role in development of FC symptoms. PMID- 28852183 TI - Temperature and pressure limits of guanosine monophosphate self-assemblies. AB - Guanosine monophosphate, among the nucleotides, has the unique property to self associate and form nanoscale cylinders consisting of hydrogen-bonded G-quartet disks, which are stacked on top of one another. Such self-assemblies describe not only the basic structural motif of G-quadruplexes formed by, e.g., telomeric DNA sequences, but are also interesting targets for supramolecular chemistry and nanotechnology. The G-quartet stacks serve as an excellent model to understand the fundamentals of their molecular self-association and to unveil their application spectrum. However, the thermodynamic stability of such self assemblies over an extended temperature and pressure range is largely unexplored. Here, we report a combined FTIR and NMR study on the temperature and pressure stability of G-quartet stacks formed by disodium guanosine 5'-monophosphate (Na25'-GMP). We found that under abyssal conditions, where temperatures as low as 5 degrees C and pressures up to 1 kbar are reached, the self-association of Na25'-GMP is most favoured. Beyond those conditions, the G-quartet stacks dissociate laterally into monomer stacks without significantly changing the longitudinal dimension. Among the tested alkali cations, K+ is the most efficient one to elevate the temperature as well as the pressure limits of GMP self assembly. PMID- 28852184 TI - Water-assisted and controllable synthesis of core/shell/shell structured carbon based nanohybrids, and their magnetic and microwave absorption properties. AB - By controlling the pyrolysis temperature, core/shell/shell structured Fe/Fe5C2/carbon nanotube bundles (Fe/Fe5C2/CNTBs), Fe/Fe3C/helical carbon nanotubes (Fe/Fe3C/HCNTs) and Fe/Fe3C/chain-like carbon nanospheres (Fe/Fe3C/CCNSs) with high encapsulation efficiency could be selectively synthesized in large-scale by water-assisted chemical vapor deposition method. Water vapor was proved to play an important role in the growth process. Because of alpha-Fe nanoparticles tightly wrapped by two layers, the obtained core/shell/shell structured nanohybrids showed high stabilities and good magnetic properties. The minimum reflection loss values of the as-prepared nanohybrids reached approximately -15.0, -46.3 and -37.1 dB, respectively. The excellent microwave absorption properties of the as-prepared core/shell/shell structured nanohybrids were considered to the quarter-wavelength matching model. Moreover, the possible enhanced microwave absorption mechanism of the as-prepared Fe/Fe3C/HCNTs and Fe/Fe3C/CCNSs were discussed in details. Therefore, we proposed a simple, inexpensive and environment-benign strategy for the synthesis of core/shell/shell structured carbon-based nanohybrids, exhibiting a promising prospect as high performance microwave absorbing materials. PMID- 28852185 TI - Low Carbon sink capacity of Red Sea mangroves. AB - Mangroves forests of Avicennia marina occupy about 135 km2 in the Red Sea and represent one of the most important vegetated communities in this otherwise arid and oligotrophic region. We assessed the soil organic carbon (Corg) stocks, soil accretion rates (SAR; mm y-1) and soil Corg sequestration rates (g Corg m-2 yr-1) in 10 mangrove sites within four locations along the Saudi coast of the Central Red Sea. Soil Corg density and stock in Red Sea mangroves were among the lowest reported globally, with an average of 4 +/- 0.3 mg Corg cm-3 and 43 +/- 5 Mg Corg ha-1 (in 1 m-thick soils), respectively. Sequestration rates of Corg, estimated at 3 +/- 1 and 15 +/- 1 g Corg m-2 yr-1 for the long (millennia) and short (last century) temporal scales, respectively, were also relatively low compared to mangrove habitats from more humid bioregions. In contrast, the accretion rates of Central Red Sea mangroves soils were within the range reported for global mangrove forests. The relatively low Corg sink capacity of Red Sea mangroves could be due to the extreme environmental conditions such as low rainfall, nutrient limitation and high temperature, reducing the growth rates of the mangroves and increasing soil respiration rates. PMID- 28852186 TI - Species composition and richness of aphid parasitoid wasps in cotton fields in northern China. AB - The cotton aphid, Aphis gossypii (Hemiptera: Aphididae), is a serious pest of cotton across the globe, particularly in the cotton agroecosystems of northern China. Parasitic wasps are deemed to be important natural enemies of A. gossypii, but limited information exists about their species composition, richness and seasonal dynamics in northern China. In this study, we combine sampling over a broad geographical area with intensive field trials over the course of three cropping seasons to describe parasitoid-hyperparasitoid communities in cotton crops. We delineate a speciose complex of primary parasitoids and hyperparasitoids associated with A. gossypii. Over 90% of the primary parasitoids were Binodoxys communis. Syrphophagus sp. and Pachyneuron aphidis made up most of the hyperparasitoids. Parasitism rates changed in a similar way following the fluctuation of the aphid population. Early in the growing period, there were more hyperparasitoids, while later, the primary parasitoids provided control of A. gossypii. The first systematic report of this cotton aphid parasitoid complex and their population dynamics in association with their hosts presented a comprehensive assessment of cotton parasitoid species and provided important information for the establishment and promotion of their biological control of cotton aphids. PMID- 28852187 TI - In vivo Confocal Microscopy of Posner-Schlossman Syndrome: Comparison with herpes simplex keratitis, HLA-B27 anterior uveitis and acute attack of primary angle closure. AB - To investigate in vivo confocal microscopy (IVCM) findings in patients with Posner-Schlossman Syndrome (PSS), we compared the IVCM findings from the eyes of patients with: PSS (44 eyes); herpes simplex keratitis (HSK) (45 eyes); HLA-B27 anterior uveitis (B27AU) (45 eyes); and with acute attack of primary angle closure (aPAC) (43 eyes). The central Langerhans cells (LCs) grade at the level of corneal basal epithelial cells of the PSS group (2.33 +/- 0.55) was similar to that of the HSK group (2.63 +/- 0.67) (chi2 = -1.435, P = 0.174) but was significantly higher than those of the B27AU group (1.80 +/- 0.79) (chi2 = 2.311, P = 0.023) and the aPAC group (1.75 +/- 0.46) (chi2 = 2.701, P = 0.022). The keratocyte activation grade of the PSS group (1.55 +/- 0.76) was similar to that of the HSK group (1.65 +/- 0.81) (chi2 = 1.104, P = 0.675) but was significantly higher than those of the B27AU group (1.00 +/- 0.71) (chi2 = 2.364, P = 0.025) and aPAC group (1.75 +/- 0.46) (chi2 = 2.532, P = 0.027). The LCs and keratocyte activation grades observed by IVCM in patients with PSS were higher than those in patients with B27AU and with aPAC, but they were similar to those in patients with HSK. This implies that PSS might be related to viral infection. PMID- 28852188 TI - Lipidomic Signatures of Nonhuman Primates with Radiation-Induced Hematopoietic Syndrome. AB - Concern over potential exposures of ionizing radiation (IR) to large populations has emphasized the need for rapid and reliable methods of biodosimetry to determine absorbed dose and required triage. Lipidomics has emerged as a powerful technique for large-scale lipid identification and quantification. Indirect effects from IR exposure generate reactive oxygen species (ROS) through water hydrolysis and may subsequently damage cellular lipids. Thus, rapid identification of specific affected lipid molecules represents possible targets for biodosimetry. The current study addresses temporal changes in the serum lipidome from 4 h to 28 d in nonhuman primates (NHPs) with radiation-induced hematopoietic syndrome (6.5 Gy exposure, LD50/30). Statistical analyses revealed a highly dynamic temporal response in the serum lipidome after IR exposure. Marked lipidomic perturbations occurred within 24 h post-irradiation along with increases in cytokine levels and C-reactive protein. Decreases were observed in di- and triacylglycerides, sphingomyelins (SMs), lysophosphatidylcholines (LysoPCs), and esterified sterols. Conversely, free fatty acids and monoacylglycerides significantly increased. Decreased levels of SMs and increased levels of LysoPCs may be important markers for biodosimetry ~2 d-3 d post irradiation. The biphasic and dynamic response to the serum lipidome post irradiation emphasize the importance of determining the temporal long-term response of possible radiation markers. PMID- 28852189 TI - Production of Monoclonal Antibodies to Pathologic beta-sheet Oligomeric Conformers in Neurodegenerative Diseases. AB - We describe a novel approach to produce conformational monoclonal antibodies selected to specifically react with the beta-sheet secondary structure of pathological oligomeric conformers, characteristic of many neurodegenerative diseases. Contrary to past and current efforts, we utilize a mammalian non-self antigen as an immunogen. The small, non-self peptide selected was covalently polymerized with glutaraldehyde until it reached a high beta-sheet secondary structure content, and species between 10-100kDa that are immunogenic, stable and soluble (p13Bri). Inoculation of p13Bri in mice elicited antibodies to the peptide and the beta-sheet secondary structure conformation. Hybridomas were produced and clones selected for their reactivity with at least two different oligomeric conformers from Alzheimer's, Parkinson and/or Prion diseases. The resulting conformational monoclonals are able to detect pathological oligomeric forms in different human neurodegenerative diseases by ELISA, immunohistochemistry and immunoblots. This technological approach may be useful to develop tools for detection, monitoring and treatment of multiple misfolding disorders. PMID- 28852190 TI - Mutational heterogeneity in non-serous ovarian cancers. AB - Epithelial ovarian cancer is a leading cause of death in gynecological cancers. While several systematic studies have revealed the mutation landscape of serous epithelial ovarian cancer, other non-serous subtypes of the disease have not been explored as extensively. Here we conduct exome sequencing of nine non-serous epithelial ovarian tumors (six endometrioid and three mucinous) and their corresponding normal DNA as well as a tumor-only granulosa cell sample. We integrated the exome data with targeted gene sequencing for 1,321 genes selected for their involvement in cancer from additional 28 non-serous ovarian tumors and compared our results to TCGA ovarian serous cystadenocarcinoma and uterine corpus endometrial carcinomas. Prevalence of TP53 mutations in non-serous was much lower than in serous epithelial OC, whereas the prevalence of PIK3CA, PIK3R1, PTEN, CTNNB1, ARID1A, and KRAS was higher. We confirmed the high prevalence of FOXL2 and KRAS mutations in granulosa cell tumors and in mucinous tumors, respectively. We also identified POLE proofreading domain mutations in three endometrioid ovarian tumors. These results highlight mutational differences between serous and non-serous ovarian cancers, and further distinguish different non-serous subtypes. PMID- 28852191 TI - Alpha-Glucan, Water Dikinase 1 Affects Starch Metabolism and Storage Root Growth in Cassava (Manihot esculenta Crantz). AB - ABSTARCT: Regulation of storage root development by source strength remains largely unknown. The cassava storage root delay (srd) T-DNA mutant postpones storage root development but manifests normal foliage growth as wild-type plants. The SRD gene was identified as an orthologue of alpha-glucan, water dikinase 1 (GWD1), whose expression is regulated under conditions of light/dark cycles in leaves and is associated with storage root development. The GWD1-RNAi cassava plants showed both retarded plant and storage root growth, as a result of starch excess phenotypes with reduced photosynthetic capacity and decreased levels of soluble saccharides in their leaves. These leaves contained starch granules having greatly increased amylose content and type C semi-crystalline structures with increased short chains that suggested storage starch. In storage roots of GWD1-RNAi lines, maltose content was dramatically decreased and starches with much lower phosphorylation levels showed a drastically reduced beta-amylolytic rate. These results suggested that GWD1 regulates transient starch morphogenesis and storage root growth by decreasing photo-assimilation partitioning from the source to the sink and by starch mobilization in root crops. PMID- 28852192 TI - The cross-sectional and longitudinal effect of hyperlipidemia on knee osteoarthritis: Results from the Dongfeng-Tongji cohort in China. AB - To quantify the cross-sectional and longitudinal effects of hyperlipidemia on knee osteoarthritis (KOA), we studied 13,906 middle-aged or older participants from the Dongfeng-Tongji cohort. Physical examinations were performed at baseline and follow-up. Knee pain was diagnosed by self-reported pain or stiffness. Clinical KOA was diagnosed from knee pain complains and clinical X-ray radiographs. The prevalence of knee pain and clinical KOA was 39.0% and 6.7% at baseline, respectively. Hyperlipidemia was associated with knee pain (OR 1.34, 1.23-1.45) and clinical KOA (1.34, 1.15-1.55). Compared with the participants without hyperlipidemia or use of lipid-lowering drugs, those with hyperlipidemia but no use of lipid-lowering drugs had higher risks of knee pain (1.28, 1.15 1.43) and clinical KOA (1.20, 0.97-1.48), those with hyperlipidemia and use of lipid-lowering drugs had the highest risks of knee pain (1.40, 1.26-1.56) and clinical KOA (1.45, 1.21-1.75). The risks were not elevated among participants without hyperlipidemia but using lipid-lowering drugs for prevention of other diseases. Furthermore, each 1-unit increase in triglyceride was associated with 9% and 5% increases in the risk of clinical KOA prevalence and clinical KOA onset, respectively. In conclusion, hyperlipidemia is associated with elevated risks of knee pain and clinical KOA among middle-aged or older adults. PMID- 28852193 TI - An enhanced C. elegans based platform for toxicity assessment. AB - There is a well-defined regulatory framework governing the approval of chemicals for use as pharmaceuticals or release into the environment. Toxicity assessment is thus a major hurdle in the compound discovery pipeline, currently involving large scale animal testing. The search for alternative testing platforms is therefore an important priority. We have developed a convenient, low cost assay utilising the nematode Caenorhabditis elegans, to rapidly assess both acute toxicity and developmental and reproductive toxicity (DART). However the worm is protected by a robust cuticle that forms a barrier to chemical uptake. We assessed mutants with altered cuticle properties to identify sensitized strains optimized for toxicity assays. Evaluating the trade-off between increased permeability and reduced fitness identifies bus-5(br19) as the most suitable strain for chemical exposure. We demonstrate the applicability of this assay for a range of chemicals with differing properties, including a modified exposure protocol for volatile or less soluble compounds. This work enhances the effectiveness of C. elegans for convenient toxicity assessment, which could contribute to a reduction in the use of vertebrates particularly at the crucial early stages of product development. Strains identified in this work will also enhance the sensitivity of C. elegans based drug discovery platforms. PMID- 28852194 TI - The relationship between scleral staphyloma and choroidal thinning in highly myopic eyes: The Beijing Eye Study. AB - Based on the Beijing Eye Study 2011, a detailed ophthalmic examination was performed including spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging for measurement of subfoveal choroidal thickness (SFCT) and relative height of posterior scleral staphyloma. OCT images were obtained in 103 highly myopic eyes (<=-6.00 diopters) and 227 normal eyes. The mean SFCT in highly myopic eyes was 110.6 +/- 85.2 MUm (range, 3 to 395 MUm). The SFCT of high myopia without posterior scleral staphyloma(55 eyes) was 157.79 +/- 85.18 MUm, which was significantly greater than that (54.94 +/- 49.96 MUm) of high myopia with posterior scleral staphyloma (48 eyes) (P < 0.001). In multivariate analysis, posterior scleral staphyloma was the most important factor of choroidal thinning in high myopia (F = 22.63; P < 0.001), then age (F = 19.14; P < 0.001), axial length (F = 17.37; P < 0.001) and gender (F = 17.31; P < 0.001). The SFCT in highly myopic eyes is very thin and undergoes further thinning with increasing age and axial length (refractive error). Posterior staphyloma formation was a key factor in choroidal thinning in highly myopic eyes and to be a good indicator for risk management of choroidal thinning. Abnormalities of the choroid may play a role in the pathogenesis of myopic degeneration. PMID- 28852195 TI - Temporal Stability and Composition of the Ocular Surface Microbiome. AB - To determine if there is a core ocular surface microbiome and whether there are microbial community changes over time, the conjunctiva of 45 healthy subjects were sampled at three time points over three months and processed using culture dependent and -independent methods. Contaminant taxa were removed using a linear regression model using taxa abundances in negative controls as predictor of taxa abundances in subject samples. Both cultured cell counts and sequencing indicated low microbial biomass on the ocular surface. No cultured species was found in all subjects at all times or in all subjects at any one time. After removal of contaminant taxa identified in negative controls using a statistical model, the most commonly detected taxon was Corynebacterium (11.1%). No taxa were found in all subjects at all times or in all subjects in any one time, but there were 26 taxa present in at least one or more subjects at all times including Corynebacterium and Streptococcus. The ocular surface contains a low diversity of microorganisms. Using culture dependent and independent methods, the ocular surface does not appear to support a substantial core microbiome. However, consistently present taxa could be observed within individuals suggesting the possibility of individual-specific core microbiomes. PMID- 28852196 TI - ADAM12-L confers acquired 5-fluorouracil resistance in breast cancer cells. AB - 5-FU-based combinatory chemotherapeutic regimens have been routinely used for many years for the treatment of breast cancer patients. Recurrence and chemotherapeutic drug resistance are two of the most prominent factors that underpin the high mortality rates associated with most breast cancers (BC). Increasing evidence indicates that overexpression of ADAMs could correlate with cancer progression. However, the role of ADAMs in the chemoresistance of cancer cells has rarely been reported. In this study, we observed that 5-FU induces expression of the ADAM12 isoform ADAM12-L but not ADAM12-S in BC cells and in recurrent BC tissues. The overexpression of ADAM12-L in BC cells following 5-FU treatment results in the acquisition of resistance to 5-FU. ADAM12-L overexoression also resulted in increased levels of p-Akt but not p-ERK. These alterations enhanced BC cell growth and invasive abilities. Conversely, ADAM12 knockdown attenuated the levels of p-Akt and restored 5-FU sensitivity in 5-FU resistant BC cells. ADAM12 knockdown also reduced BC cell survival and invasive abilities. These findings suggest that ADAM12-L mediates chemoresistance to 5-FU and 5-FU-induced recurrence of BC by enhancing PI3K/Akt signaling. The results of this study suggest that specific ADAM12-L inhibition could optimize 5-FU-based chemotherapy of BC, thereby preventing BC recurrence in patients. PMID- 28852197 TI - Comprehensive in situ co-detection of aneuploid circulating endothelial and tumor cells. AB - Conventional circulating tumor cell (CTC) detection strategies rely on cell surface marker EpCAM and intracellular cytokeratins (CKs) for isolation and identification, respectively. Application of such methods is considerably limited by inherent heterogeneous and dynamic expression or absence of EpCAM and/or CKs in CTCs. Here, we report a novel strategy, integrating antigen-independent subtraction enrichment and immunostaining-FISH (SE-iFISH), to detect a variety of aneuploid circulating rare cells (CRCs), including CTCs and circulating tumor endothelial cells (CECs). Enriched CRCs, maintained at high viability and suitable for primary tumor cell culture, are comprehensively characterized by in situ co-examination of chromosome aneuploidy by FISH and immunostaining of multiple biomarkers displayed in diverse fluorescence channels. We described and quantified for the first time the existence of individual aneuploid CD31+ CECs and co-existence of "fusion clusters" of endothelial-epithelial aneuploid tumor cells among enriched non-hematopoietic CRCs. Hence, SE-iFISH is feasible for efficient co-detection and in situ phenotypic and karyotypic characterization as well as quantification of various CRCs, allowing for their classification into diverse subtypes upon biomarker expression and chromosome ploidy. Enhanced SE iFISH technology, assisted by the Metafer-iFISH automated CRC imaging system, provides a platform for the analysis of potential contributions of each subtype of CRCs to distinct clinical outcome. PMID- 28852198 TI - Extracellular vesicles as potential biomarkers of acute graft-vs-host disease. AB - Acute graft-vs-host disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on extracellular vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow cytometry using a panel of 13 antibodies against specific membrane proteins that were reported to be predictive of acute GVHD. We observed a correlation between three potential biomarkers expressed on EV surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model. In our study, CD146 (MCAM-1) was correlated with an increased risk-by almost 60%-of developing GVHD, whereas CD31 and CD140 alpha (PECAM-1 and PDGFR-alpha) with a decreased risk-by almost 40 and 60%, respectively. These biomarkers also showed a significant change in signal level from baseline to the onset of acute GVHD. Our novel study encourages future investigations into the potential correlation between EVs and acute GVHD. Larger prospective multicenter studies are currently in progress. PMID- 28852199 TI - Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia. AB - Mutations in the interleukin-7 receptor (IL7R) or the Janus kinase 3 (JAK3) kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib. Comprehensive network interrogation using the phosphoproteomic signatures identified significant changes in pathways regulating cell cycle, translation initiation, mitogen-activated protein kinase and phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)/AKT signaling, RNA metabolism, as well as epigenetic and apoptotic processes. Key regulatory proteins within pathways that showed altered phosphorylation following JAK inhibition were targeted using selumetinib and trametinib (MEK), buparlisib (PI3K) and ABT-199 (BCL2), and found to be synergistic in combination with JAK kinase inhibitors in primary T-ALL samples harboring JAK3 mutations. These data provide the first detailed molecular characterization of the downstream signaling pathways regulated by JAK3 mutations and provide further understanding into the oncogenic processes regulated by constitutive kinase activation aiding in the development of improved combinatorial treatment regimens. PMID- 28852200 TI - Early gestational maternal low-protein diet diminishes hepatic response to fasting in young adult male mice. AB - Maternal low-protein (MLP) diet can lead to hepatic steatosis, which only develops with ageing. It is still unclear whether the young offspring show any signs of past exposure to prenatal adverse conditions. We hypothesized that early nutritional insult would first affect the dynamic responsiveness to nutritional challenges rather than the static state. We analyzed the transcriptome and metabolome profiles of the hepatic response to fasting/refeeding in young male mice offspring to identify changes induced by early gestational MLP diet. Restricted MLP exposure strictly to early gestation was achieved by the embryo transfer method. As a result, the fasting-induced upregulation of genes related to long-chain fatty acid metabolism and of stress response genes related to protein folding were significantly diminished in MLP pups. Lipid profiling after fasting showed that the hepatic signature of triacylglycerols was shifted to longer acyl-chains and higher saturation by the MLP diet. Bioinformatic analyses suggested that these phenomenological changes may be partially linked to the peroxisome proliferator activated receptor alpha (PPARalpha) pathway. Taken together, early gestational MLP diet affected the hepatic dynamic response to nutritional stress in seemingly healthy young offspring, accompanied with partial deterioration of PPARalpha action. PMID- 28852201 TI - Increased expression of latent TGF-beta-binding protein 4 affects the fibrotic process in scleroderma by TGF-beta/SMAD signaling. AB - This corrects the article DOI: 10.1038/labinvest.2017.20. PMID- 28852203 TI - Presence of obesity is associated with lower mortality in elderly patients with implantable cardioverter defibrillator. AB - BACKGROUND: Higher body mass index (BMI) is associated with greater prevalence of cardiovascular risk factors, yet an inverse relationship between obesity and survival after cardiovascular events has been described. It is unclear whether a similar relationship exists for patients with implantable cardioverter defibrillators (ICDs) at high risk for mortality. We aimed to assess the impact of BMI on mortality and cardiovascular hospitalization in patients with ICD. METHODS: Patients who underwent ICD implantation in 2010-2011 were divided into normal (<25 kg m-2), overweight (25-29.9 kg m-2) and obese (?30 kg m-2) groups based on BMI. Clinical parameters were compared and long-term outcomes were determined using chi2 test, Wilcoxon's rank-sum test, logistic regression models and Kaplan-Meier curves. RESULTS: Of 904 patients (mean age 67+/-13 years), 26% had normal BMI, 32% were overweight and 42% were obese. No significant baseline differences in ventricular ejection fraction, ICD for primary or secondary prevention, history of heart failure, syncope or cardiac arrest existed. Despite a greater prevalence of diabetes, hypertension and prior myocardial infarction, the obese and overweight groups had lower mortality (10.1% and 7.9%, respectively) than the normal group (22.9%, P<0.001). On multivariate logistic regression, BMI in the obese and overweight range (odds ratio (OR): 0.35; 95% confidence interval (CI): 0.21-0.58 and OR: 0.25; 95% CI: 0.13-0.40, respectively) was protective against mortality, whereas history of diabetes (OR: 2.01; 95% CI: 1.30-3.09), myocardial infarction (OR: 1.76; 95% CI: 1.11-2.80), heart failure (OR: 3.88; 95% CI: 1.56-9.66), stroke (OR: 3.19; 95% CI: 1.63-6.23) and history of cardiac arrest (OR: 2.65; 95% CI: 1.37-5.15) were independent risk factors for higher mortality. CONCLUSIONS: A paradoxical relationship between BMI and mortality risk is present in elderly patients with ICD at high risk of sudden death with a lower mortality in obese or overweight patients than in those with normal BMI. PMID- 28852204 TI - TUB gene expression in hypothalamus and adipose tissue and its association with obesity in humans. AB - BACKGROUND/OBJECTIVES: Mutations in the Tubby gene (TUB) cause late-onset obesity and insulin resistance in mice and syndromic obesity in humans. Although TUB gene function has not yet been fully elucidated, studies in rodents indicate that TUB is involved in the hypothalamic pathways regulating food intake and adiposity. Aside from the function in central nervous system, TUB has also been implicated in energy metabolism in adipose tissue in rodents. We aimed to determine the expression and distribution patterns of TUB in man as well as its potential association with obesity. SUBJECTS/METHODS: In situ hybridization was used to localize the hypothalamic regions and cells expressing TUB mRNA. Using RT-PCR, we determined the mRNA expression level of the two TUB gene alternative splicing isoforms, the short and the long transcript variants, in the hypothalami of 12 obese and 12 normal-weight subjects, and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissues from 53 severely obese and 24 non-obese control subjects, and correlated TUB expression with parameters of obesity and metabolic health. RESULTS: Expression of both TUB transcripts was detected in the hypothalamus, whereas only the short TUB isoform was found in both VAT and SAT. TUB mRNA was detected in several hypothalamic regions involved in body weight regulation, including the nucleus basalis of Meynert and the paraventricular, supraoptic and tuberomammillary nuclei. We found no difference in the hypothalamic TUB expression between obese and control groups, whereas the level of TUB mRNA was significantly lower in adipose tissue of obese subjects as compared to controls. Also, TUB expression was negatively correlated with indices of body weight and obesity in a fat-depot-specific manner. CONCLUSIONS: Our results indicate high expression of TUB in the hypothalamus, especially in areas involved in body weight regulation, and the correlation between TUB expression in adipose tissue and obesity. These findings suggest a role for TUB in human obesity. PMID- 28852205 TI - Probiotics administration following sleeve gastrectomy surgery: a randomized double-blind trial. AB - BACKGROUND: Probiotics are commonly used after bariatric surgery; however, uncertainty remains regarding their efficacy. Our aim was to compare the effect of probiotics vs placebo on hepatic, inflammatory and clinical outcomes following laparoscopic sleeve gastrectomy (LSG). METHODS: This randomized, double-blind, placebo-controlled, trial of 6-month treatment with probiotics (Bio-25; Supherb) vs placebo and 6 months of additional follow-up was conducted among 100 morbidly obese nonalcoholic fatty liver disease (NAFLD) patients who underwent LSG surgery. The primary outcome was a reduction in liver fat content, measured by abdominal ultrasound, and secondary outcomes were improvement of fibrosis, measured by shear-wave elastography, metabolic and inflammatory parameters, anthropometrics and quality of life (QOL). Fecal samples were collected and analyzed for microbial composition. RESULTS: One hundred patients (60% women, mean age of 41.9+/-9.8 years and body mass index of 42.3+/-4.7 kg m-2) were randomized, 80% attended the 6-month visit and 77% completed the 12-month follow up. Fat content and NAFLD remission rate were similarly reduced in the probiotics and placebo groups at 6 months postsurgery (-0.9+/-0.5 vs -0.7+/-0.4 score; P=0.059 and 52.5 vs 40%; P=0.262, respectively) and at 12 months postsurgery. Fibrosis, liver-enzymes, C-reactive protein (CRP), leptin and cytokeratin-18 levels were significantly reduced and QOL significantly improved within groups (P?0.014 for all), but not between groups (P?0.173 for all) at 6 and 12 months postsurgery. Within-sample microbiota diversity (alpha-diversity) increased at 6 month postsurgery compared with baseline in both study arms (P?0.008) and decreased again at 12 months postsurgery compared with 6 months postsurgery (P?0.004) but did not reach baseline values. CONCLUSIONS: Probiotics administration does not improve hepatic, inflammatory and clinical outcomes 6- and 12 months post-LSG. PMID- 28852206 TI - Do gender and ethnic differences in fasting leptin in Indians and Creoles of Mauritius persist beyond differences in adiposity? AB - Recent body composition studies on the island of Mauritius in young adults belonging to the two main ethnicities-Indians (South Asian descent) and Creoles (African/Malagasy descent)-have shown gender-specific ethnic differences in their body mass index (BMI)-Fat% relationships. We investigated here whether potential gender and ethnic differences in blood leptin would persist beyond that explained by differences in body composition. In healthy young adult Mauritian Indians and Creoles (79 men and 80 women; BMI range: 15-41 kg m-2), we investigated the relationships between fasted serum leptin with BMI, waist circumference (WC), total fat% assessed by deuterium oxide dilution technique and central adiposity (trunk fat%) assessed by abdominal bioimpedance analysis. The results indicate that the greater elevations in leptin-BMI and leptin-WC regression lines in women compared with men, as well as in Indian men compared with Creole men, are abolished when BMI and WC are replaced by total body fat% and trunk fat%, respectively. In women, no significant between-ethnic difference is observed in total body fat%, trunk fat% and serum leptin. Thus, in young adult Mauritians, a population at high risk for later cardiometabolic diseases, the differences in body fat% entirely accounted for the observed gender and ethnic differences in serum leptin. PMID- 28852207 TI - IgG is elevated in obese white adipose tissue but does not induce glucose intolerance via Fcgamma-receptor or complement. AB - BACKGROUND/OBJECTIVES: In obesity, B cells accumulate in white adipose tissue (WAT) and produce IgG, which may contribute to the development of glucose intolerance. IgG signals by binding to Fcgamma receptors (FcgammaR) and by activating the complement system. The aim of our study was to investigate whether activation of FcgammaR and/or complement C3 mediates the development of high-fat diet-induced glucose intolerance. METHODS: We studied mice lacking all four FcgammaRs (FcgammaRI/II/III/IV-/-), only the inhibitory FcgammaRIIb (FcgammaRIIb /-), only the central component of the complement system C3 (C3-/-), and mice lacking both FcgammaRs and C3 (FcgammaRI/II/III/IV/C3-/-). All mouse models and wild-type controls were fed a high-fat diet (HFD) for 15 weeks to induce obesity. Glucose metabolism was assessed and adipose tissue was characterized for inflammation and adipocyte functionality. RESULTS: In obese WAT of wild-type mice, B cells (+142%, P<0.01) and IgG (+128% P<0.01) were increased compared to lean WAT. Macrophages of FcgammaRI/II/III/IV-/-mice released lower levels of cytokines compared to wild-type mice upon IgG stimulation. Only C3-/- mice showed reduced HFD-induced weight gain as compared to controls (-18%, P<0.01). Surprisingly, FcgammaRI/II/III/IV-/- mice had deteriorated glucose tolerance (AUC +125%, P<0.001) despite reduced leukocyte number (-30%, P<0.05) in gonadal WAT (gWAT), whereas glucose tolerance and leukocytes within gWAT in the other models were unaffected compared to controls. Although IgG in gWAT was increased (+44 to +174%, P<0.05) in all mouse models lacking FcgammaRIIb, only FcgammaRI/II/III/IV/C3-/- mice exhibited appreciable alterations in immune cells in gWAT, for example, increased macrophages (+36%, P<0.001). CONCLUSIONS: Lack of FcgammaRs reduces the activity of macrophages upon IgG stimulation, but neither FcgammaR nor C3 deficiency protects against HFD-induced glucose intolerance or reduces adipose tissue inflammation. This indicates that if obesity-induced IgG contributes to the development of glucose intolerance, this is not mediated by FcgammaR or complement activation. PMID- 28852208 TI - Assessing genetic and environmental influences on epicardial and abdominal adipose tissue quantities: a classical twin study. AB - BACKGROUND/OBJECTIVES: Various adipose tissue compartments play an important role in the development of cardiometabolic diseases. The quantity of different fat compartments is influenced by genetic and environmental factors. The aim of our study was to evaluate the magnitude of genetic and environmental effects on epicardial, subcutaneous and visceral adipose tissue (EAT, SAT and VAT) quantities in a cohort of adult twin pairs. SUBJECTS/METHODS: In this cross sectional study we investigated adult twins (57 monozygotic (MZ) and 33 dizygotic (DZ) same-gender twin pairs; 180 twin subjects). We measured EAT volume using electrocardiogram-gated native computed tomography (CT) scan of the heart, and abdominal SAT and VAT areas were quantified between the third and fourth lumbar vertebra on native CT images. We calculated genetic and environmental impact on the size of various adipose tissue compartments by analyzing co-twin correlations in MZ and DZ pairs separately, and furthermore by using genetic structural equation models. RESULTS: In co-twin analysis, MZ twins had stronger correlations than DZ twins for EAT (rMZ=0.81, rDZ=0.32), similar to SAT and VAT quantities (rMZ=0.80, rDZ=0.68 and rMZ=0.79, rDZ=0.48, respectively). In multi-trait model fitting analysis, the overall contribution of genetic factors to EAT, SAT and VAT volumes were 80%, 78% and 70%, whereas environmental factors were 20%, 22% and 30%, respectively. Common pathway model analyses indicated that none of the EAT, SAT and VAT phenotypes was independent of the other two. CONCLUSIONS: Genetic factors have substantial influence, while environmental factors have only a modest impact on EAT volume, abdominal SAT and VAT quantities. There is a considerable amount of common genetic background influencing the quantities of all three adipose tissue compartments. PMID- 28852210 TI - Immunology: The renal sodium gradient in antimicrobial defence. PMID- 28852209 TI - Numerical simulation of seasonality in the distribution and fate of pyrene in multimedia aquatic environments with Markov chains. AB - This case study investigated the distribution and fate of organic pollutants in aquatic environments based on laboratory experiments and modeling. Pyrene (Pyr) is a hydrocarbon pollutant with adverse effects on aquatic ecosystems and human health, and was thus selected for this case study. The movement of Pyr was primarily influenced by its sorption from water onto sediment, and its desorption from sediment into water. Its elimination was mainly via biodegradation by microorganisms in sediment and by volatilization from water into air. The transport and elimination rates for Pyr were considerably influenced by temperature and moisture. Results of modeling with Markov chains revealed that the elimination of Pyr from water/sediment systems was the most rapid under wet conditions. Under average conditions, a Pyr concentration of 100 MUg/L of in water in such a system declined to a negligible level over 250 h. Under wet conditions, this decrease occurred over 120 h. Finally, under dry conditions, it took 550 h to achieve the same degree of elimination. PMID- 28852213 TI - Bacterial ecology: Cheaters take advantage. PMID- 28852211 TI - Mapping architectural and transcriptional alterations in non-lesional and lesional epidermis in vitiligo. AB - In vitiligo, chronic loss of melanocytes and consequent absence of melanin from the epidermis presents a challenge for long-term tissue maintenance. The stable vitiligo patches are known to attain an irreversible depigmented state. However, the molecular and cellular processes resulting in this remodeled tissue homeostasis is unclear. To investigate the complex interplay of inductive signals and cell intrinsic factors that support the new acquired state, we compared the matched lesional and non-lesional epidermis obtained from stable non-segmental vitiligo subjects. Hierarchical clustering of genome-wide expression of transcripts surprisingly segregated lesional and non-lesional samples in two distinct clades, despite the apparent heterogeneity in the lesions of different vitiligo subjects. Pathway enrichment showed the expected downregulation of melanogenic pathway and a significant downregulation of cornification and keratinocyte differentiation processes. These perturbations could indeed be recapitulated in the lesional epidermal tissue, including blunting of rete ridges, thickening of stratum corneum and increase in the size of corneocytes. In addition, we identify marked increase in the putrescine levels due to the elevated expression of spermine/spermidine acetyl transferase. Our study provides insights into the intrinsic self-renewing ability of damaged lesional tissue to restore epidermal functionality in vitiligo. PMID- 28852212 TI - Phosphatidylinositol-3 Kinase Inhibitors, Buparlisib and Alpelisib, Sensitize Estrogen Receptor-positive Breast Cancer Cells to Tamoxifen. AB - Tamoxifen is the standard first-line hormonal therapy for premenopausal women with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the crucial mechanisms underlying hormonal therapy resistance is the collateral activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of tamoxifen against ER-positive BC cells. We have observed a synergism between alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell lines harboring different PI3K alterations. Immunoblotting analysis showed alpelisib, buparlisib, or either drug in combination with tamoxifen downregulated the PI3K downstream targets in the MCF-7 and ZR75-1 cells. In the MCF-7 cells transfected with a constitutive active (myristoylated) AKT1 construct or mutant ER, the synergistic effect between alpelisib and tamoxifen was markedly attenuated, indicating that synergism depends on AKT inhibition or normally functioning ER. Combining alpelisib or buparlisib with tamoxifen also attenuated MCF-7 tumor growth in Balb/c nude mice. Our data suggest that additional PI3K blockade might be effective in enhancing the therapeutic effect of tamoxifen in ER-positive BC and support the rationale combination in clinical trials. PMID- 28852215 TI - Bacterial evolution: Historical influences on antibiotic resistance. PMID- 28852214 TI - Illuminating microbial diversity. PMID- 28852216 TI - Archaeal genetics: Structural insights into archaeal chromatin. PMID- 28852217 TI - Parasite development: RBP10 is key for parasite development in the blood. PMID- 28852219 TI - A reverse micelle strategy for fabricating magnetic lipase-immobilized nanoparticles with robust enzymatic activity. AB - Enzyme-immobilized nanoparticles that are both catalysis effective and recyclable would have wide applications ranging from bioengineering and food industry to environmental fields; however, creating such materials has proven extremely challenging. Herein, we present a scalable methodology to create Candida rugosa lipase-immobilized magnetic nanoparticles (L-MNPs) by the combination of nonionic reverse micelle method and Fe3O4 nanoparticles. Our approach causes the naturally abundant and sustainable Candida rugose lipase to ordered-assemble into nanoparticles with high catalytic activity and durability. The resultant L-MNPs exhibit the integrated properties of high porosity, large surface area, fractal dimension, robust enzymatic activity, good durability, and high magnetic saturation (59 emu g-1), which can effectively catalyze pentyl valerate esterification and be easily separated by an external magnet in 60 second. The fabrication of such fascinating L-MNPs may provide new insights for developing functional enzyme-immobilized materials towards various applications. PMID- 28852218 TI - A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling. AB - BPIFB4 is associated with exceptional longevity: four single-nucleotide polymorphisms distinguish the wild-type form from a longevity-associated variant conferring positive effects on blood pressure. The effect of a rare variant (RV; allele frequency, 4%) on blood pressure is unknown. Here, we show that overexpression of RV-BPIFB4 in ex-vivo mouse vessels impairs phosphorylation of endothelial nitric oxide synthase (eNOS), blunting acetylcholine-evoked vasorelaxation; in vivo, virally mediated overexpression of RV-BPIFB4 increases blood pressure, an action absent in eNOS-deficient mice. In humans, we found RV carriers to have increased diastolic blood pressure, a finding that was more marked in subjects on anti-hypertensive medication; moreover, recombinant RV BPIFB4 protein impaired eNOS function in ex-vivo human vessels. Thus, RV-BPIFB4 acts directly on blood pressure homeostasis and may represent a novel biomarker of vascular dysfunction and hypertension. PMID- 28852221 TI - Cytosolic lipolysis and lipophagy: two sides of the same coin. AB - Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases. PMID- 28852220 TI - Regulation of heat shock transcription factors and their roles in physiology and disease. AB - The heat shock transcription factors (HSFs) were discovered over 30 years ago as direct transcriptional activators of genes regulated by thermal stress, encoding heat shock proteins. The accepted paradigm posited that HSFs exclusively activate the expression of protein chaperones in response to conditions that cause protein misfolding by recognizing a simple promoter binding site referred to as a heat shock element. However, we now realize that the mammalian family of HSFs comprises proteins that independently or in concert drive combinatorial gene regulation events that activate or repress transcription in different contexts. Advances in our understanding of HSF structure, post-translational modifications and the breadth of HSF-regulated target genes have revealed exciting new mechanisms that modulate HSFs and shed new light on their roles in physiology and pathology. For example, the ability of HSF1 to protect cells from proteotoxicity and cell death is impaired in neurodegenerative diseases but can be exploited by cancer cells to support their growth, survival and metastasis. These new insights into HSF structure, function and regulation should facilitate the development tof new disease therapeutics to manipulate this transcription factor family. PMID- 28852222 TI - Chromosome biology: Different turfs for cohesin and condensin. PMID- 28852224 TI - Genetic engineering: Pigs without PERVs. PMID- 28852225 TI - Model organisms: New tools, new insights - probing social behaviour in ants. PMID- 28852223 TI - Beyond editing to writing large genomes. AB - Recent exponential advances in genome sequencing and engineering technologies have enabled an unprecedented level of interrogation into the impact of DNA variation (genotype) on cellular function (phenotype). Furthermore, these advances have also prompted realistic discussion of writing and radically re writing complex genomes. In this Perspective, we detail the motivation for large scale engineering, discuss the progress made from such projects in bacteria and yeast and describe how various genome-engineering technologies will contribute to this effort. Finally, we describe the features of an ideal platform and provide a roadmap to facilitate the efficient writing of large genomes. PMID- 28852226 TI - Emission enhancement through Nd3+-Yb3+ energy transfer in multifunctional NaGdF4 nanocrystals. AB - The growing need for biomedical contrast agents has led to the current development of multi-functional materials such as lanthanide-based nanoparticles (NPs). The optical and magnetic properties these nanoparticles (NPs) possess are important to enhance current biomedical imaging techniques. To increase the optical emissions of the nanoparticles, neodymium (Nd3+) and ytterbium (Yb3+) were introduced into a magnetic host of NaGdF4. The energy transfer between Nd3+ and the Yb3+ was then investigated at multiple concentrations to determine the optimal dopant levels. The NaGdF4:Nd3+,Yb3+ nanoparticles were synthesized through a modified solvothermal method, resulting in rectangular structures, with an average side length of 17.87 +/- 4.38 nm. A double dopant concentration of 10% Nd3+ and 4% Yb3+ was found to be optimal, increasing the emission intensity by 71.5% when compared to the widely used Nd3+ single dopant. Decay measurements confirm energy transfer from Nd3+ to Yb3+, with a lifetime shortening from Nd3+ 1064 nm emission and a calculated lifetime of 12.72 ms with 98% efficiency. Despite NaGdF4:Nd3+,Yb3+ NPs showing a slight decrease in their magnetic response at the expense of optimizing optical emission, as it is directly dependent on the Gd3+ concentration, a strong paramagnetic behavior was still observed. These results corroborate that NaGdF4:Nd3+,Yb3+ NPs are viable candidates for multimodal imaging. PMID- 28852227 TI - Bipolar Disorder: Clinical Conundrums 1. PMID- 28852228 TI - Interrelations of Level of Urinary Cotinine and Score for Fagerstrom Test for Nicotine Dependence among Beedi Smokers, and Smokeless Tobacco Users in India. AB - BACKGROUND: Tobacco related diseases is largely preventable and can stop pre mature death. According to World Health Organization (WHO), the prevalence rate of smoking is 28.6% (40% among males and 18.2% among females).[1] Beedismoking and tobacco chewing are the commonest forms of tobacco habits in India, and strongly associated with oral cancer in India.[2] There are methods to estimation of severity of tobacco dependency, of them FTND is identified. The score for FTND is used for cigarette smoking, but we do not know the FTND score of ST users and Beedi smokers in India. Therefore, keeping the study in plan, we aim a systemic review with the following objective. OBJECTIVES: 1. To pursue a review of published researches on interrelations between Beedi smoking and FTND score. 2. To pursue a review of published researches on interrelations between consumption of ST and FTND score. MATERIALS AND METHODS: A systematic search of published papers were examined from three different electronic databases namely Pubmed, Cochrane library, and ProQuest. The inclusion criteria and exclusion criteria was set based on commonality of the studies which was looked through the objectives. Total of four papers of its category were found, and those met the criteria for inclusion factors. RESULTS: Seventy-one articles were screened initially and forty-three articles were excluded and twenty-eight articles were screened, out of which twenty articles were excluded based on inclusion criteria. The abstracts of remaining eight articles were reviewed and four were removed because of duplication of the data. Finally, four articles were included for review after three stages of screening. Review results revealed that out of four selected reviews, one research study finding was interrelated with FTND score and Beedi and ST users. This study results also revealed that there is not a set of research carried out on FTND score for Beedi smokers and ST users. PMID- 28852229 TI - Cognitive Behavior Therapy for Medically Unexplained Symptoms: A Systematic Review and Meta-analysis of Published Controlled Trials. AB - Medically unexplained symptoms (MUS) commonly present across the board in medical specialties and are often challenging to treat. Our objective was to assess the efficacy for cognitive-behavior therapy (CBT) in MUS. Electronic search of databases was carried out for published controlled trials in English language peer-reviewed journals from inception till August 2016. Effect sizes for the trials were computed using standardized mean difference, and I2 test was used to assess sample heterogeneity. Pooled mean effect sizes were derived using a random effects model. Critical appraisal of studies was done using the Cochrane risk of bias assessment tool. A total of 11 trials involving 1235 subjects were included in the study. Ten trials used standard CBT techniques while one studied the efficacy of mindfulness-based CBT technique. The control arms were treatment as usual in five trials, augmented care in four and waitlisted controls in two trials. The pooled mean effect size for CBT was 0.388 (range 0.055-0.806, 95% confidence intervals 0.316-0.461). The I2 value was 0 using a random effects model indicating low heterogeneity among studies. Risk of bias was noted in many included studies. Egger plot intercept indicated potential publication bias. CBT was superior to the waiting list, treatment as usual or enhanced usual care with moderate effect sizes in the treatment of MUS. These findings are impacted by the limited number of studies in this area and questionable methodological rigor of included studies. PMID- 28852230 TI - Sleep Pattern and Sleep Hygiene Practices among Nigerian Schooling Adolescents. AB - BACKGROUND: Sleep problems, especially in the adolescent stage of development, may be associated with excessive daytime sleepiness, impaired neurocognitive function, and a host of others leading to suboptimal performance. OBJECTIVES: To determine the pattern of sleep problems in school-going adolescents based on the bedtime problems; excessive daytime sleepiness; awakenings during the night and problems falling back asleep; regularity and duration of sleep; sleep-disordered breathing (BEARS) sleep screening algorithm. MATERIALS AND METHODS: This is a cross-sectional descriptive study involving 353 secondary school-going adolescents in Kano metropolis. Subjects were selected for the study using multistage sampling technique. The study lasted from March 2015 to July 2015. Sleep problems were screened for using the BEARS sleep screening algorithm. Tables were used to present the qualitative data. The various BEARS sleep patterns were assessed, and comparison between stages of adolescence was done using Chi-square test (and Fisher's exact test where necessary). A significant association was considered at P < 0.05. RESULTS: Of the 353 adolescents studied, 61.8% were males while 38.2% were females with male, female ratio of 1.6:1. Early, middle, and late adolescents constituted 13.9%, 39.9%, 46.2% respectively. BEARS sleep screening revealed awakenings during the night (34.6%) as the most common sleep-related problem reported, and this was followed by excessive daytime sleepiness (21.0%). Age-group dependent sleep duration was 7.19 +/- 1.26, 7.13 +/ 1.13, 7.16 +/- 1.28, with P > 0.05. Although 62.9% of all the adolescents watched TV/play video games until 1 h before going to bed and this was highest in late adolescence, it was not statistically significantly associated with any of the sleep problems. CONCLUSION: Both the quality and quantity of sleep in Nigerian adolescents in Kano is suboptimal. Adolescent and sleep medicine should receive more attention in our environment. PMID- 28852231 TI - Cardiovascular Response to Mental Stress Tests and the Prediction of Blood Pressure. AB - BACKGROUND: It has been proposed that increased physiological responses (i.e., cardiovascular reactivity) to a stressor or stressors may increase the risk of developing cardiovascular disease (CVD) including increased blood pressure (BP) or hypertension. However, many prospective studies have examined the hemodynamic reactions to laboratory stress tests and CVD in Western countries and only a few studies have examined with varying durations of follow-up in the same sample studies. In addition, still relatively little is known about cardiovascular reactivity in Asian populations. Therefore, the aim of this study was to examine whether cardiovascular responses to psychological stressors remained a significant predictor of 40-month follow-up among initially normotensive participants in Thailand, Asia. MATERIALS AND METHODS: Hemodynamic parameter was measured at rest, during, and after mental arithmetic, a speech task, and a cold pressor task. Ninety-five healthy normotensive male and female participants were reevaluated BP at 40 months later. RESULTS: Regression analyses indicated that after adjustment for baseline BP, initial age, sex, body mass index, and family history of CVD, heightened systolic BP (SBP) responses to mental arithmetic was associated with increased future SBP (DeltaR2 = 0.04, P = 0.023). CONCLUSIONS: Therefore, these findings suggest that cardiovascular reactivity remains a prediction of future BP and may play a role in the development of hypertension and CVD. PMID- 28852232 TI - Characteristics of Patients with High Lie Scores in a Personality Test. AB - BACKGROUND: It is reported that persons with high Lie score (L score) of a personality test are aggressively self-confident and are also related to depression or schizophrenia In this study, we examined the characteristics of patients with high L scores on the Maudsley Personality Inventory (MPI) and examined the significance of the L score. MATERIALS AND METHODS: We collected the data of 10789 subjects and examined the relationship between L score or the number of characteristic biased persons and the parameters of age, sex, education level, occupation, and degree of pain. Furthermore, we examined the changes in extraversion-introversion (E score), neuroticism (N score), and L scores at approximately 1 year after surgery in 1711 patients who underwent surgery at our university hospital or affiliated hospitals. RESULTS: L score was significantly higher among persons with a high degree of pain, and ratio of the characteristic biased persons in L score was significantly high among persons in their 40s to 60s, healthcare professionals and those with a high degree of pain. Moreover, L score scarcely changed between before and after surgery when compared with E score and N score. CONCLUSION: L score is not greatly influenced by an individual's state of mind or situation at different times, and may indicate the personality traits proper to the person. It is shown that L score may indicate the personality trait characteristics of persons who want to make themselves look good in the eyes of other. PMID- 28852233 TI - Internet Addiction among Junior Doctors: A Cross-sectional Study. AB - BACKGROUND: The number of Internet users in India crossed 205 million in October 2013. Excessive internet use has been attributed to socio-occupational dysfunction, and this study is targeting the junior doctors on whom not many studies have been done till date. OBJECTIVE: The objective of this study was to analyze the proportion of junior doctors with internet addiction and whether there is any relation between increased internet use and psychological distress, assessed using General Health Questionnaire (GHQ). MATERIALS AND METHODS: One hundred postgraduate students and house surgeons were requested to fill out the specially prepared pro forma, Internet Addiction Test Questionnaire and GHQ, and the data were analyzed. P < 0.05 was considered statistically significant. RESULTS: Among the 100 study participants, 13% were found to have moderate addiction and none were in severe addiction range. Internet addiction was more common among those from urban areas (P = 0.011). A significant association was found between GHQ score and internet addiction test score (P = 0.031). CONCLUSION: The Internet is a double-edged social revolution. Further studies are required to delineate the specific effects on human behavior. PMID- 28852234 TI - Relationship of Anger with Alcohol use Treatment Outcome: Follow-up Study. AB - BACKGROUND: Anger is seen as comorbid condition in psychiatric conditions. It has an impact on one's quality of life. It leads to variation in the treatment outcome. The present study is going to explore the relationship of anger with treatment outcome among alcohol users after 1 year of treatment. The data for the present study were taken from the project work on correlates of anger among alcohol users, funded by center for addiction medicine, NIMHANS, Bengaluru, Karnataka, India. MATERIALS AND METHODS: A total of 100 males (50 alcohol dependent and 50 abstainers) in the age range of 20-45 years with a primary diagnosis of alcohol dependence were taken for the study. They were administered a semi-structured interview schedule to obtain information about sociodemographic details, information about alcohol use, its relationship with anger and its effects on anger control and the State-Trait Anger Expression Inventory. RESULTS: 68% of the dependent and abstainers perceived anger as negative emotion and 76% in control perceived it as negative. The presence of significant difference was seen for relapsers group in relation to trait anger and state anger. The group who remained abstinent from the intake to follow-up differs significantly from the dependent group in relation to state anger and anger control out. Mean score was higher on trait anger for the dependent group. CONCLUSIONS: It has implication for anger management intervention/matching of treatment with users attributes and helping the users to develop the behavioral repertoires to manage anger. PMID- 28852235 TI - Group Work Intervention for the Parents of Children with Mental Health Issues Admitted in the Tertiary Care Center. AB - OBJECTIVES: The objective of this study was to develop a structured curriculum for a group-based parenting program for parents/caregivers of children or adolescents treated in the inpatient child and adolescent mental health unit of a national health institute. METHODS: Data from group session reports of 3 years of conducting group-based parenting programs in the same setting were analyzed and prominent themes of discussions were shortlisted before finally arriving at a six session group parenting program module. RESULTS: A six-session intervention module was designed by psychiatric social workers experienced in group work. The content followed combination of various theoretical approaches and methodologies ultimately aiming in improving the overall knowledge and understanding of parents or caregivers on various child and adolescent mental health issues, and enhancing their skills and competence in dealing with various emotional and behavioral problems in children. CONCLUSION: Group-based parenting programs are found to be effective in improving the over psychosocial health of parents and the emotional and behavioral problems of children and adolescents as a result of better parenting. Development and standardization of culture appropriate group intervention curriculums would help in the development of this cost effective method as a medium of change. PMID- 28852236 TI - Felt Need and Treatment-seeking Barriers among Substance Abusers in Urban Slum Area in Central India. AB - INTRODUCTION: Substance abuse is known public health problem in the world. Felt need of treatment and barriers in seeking treatment are important for successful treatment of addictions. Therefore, this study was designed to understand the pattern (type) of substance abuse among residents of urban slum and to study the felt need and barriers for the treatment of substance abuse among substance abusers in urban slum areas of the central India. MATERIALS AND METHODS: A community-based cross-sectional study was conducted in slum area in central India. RESULTS: The smokeless tobacco (92.5%) and alcohol (70.35%) were the most common substances used in the study population. More than half (60.4%) of study participants were felt the need of de-addiction but in reality very few approached for treatment for their addiction. The most common barriers were unawareness about place of availability of treatment, absence of any health problem and the confidence of handling their own drug problem, and dependency on substance. CONCLUSIONS: There was huge gap in the felt need and actual treatment seeking practice due to treatment barriers in the treatment of substance abuse. PMID- 28852237 TI - A Study of Patterns of Platelet Counts in Alcohol Withdrawal. AB - AIMS: This study aimed to evaluate the patterns of platelet counts during the course of alcohol withdrawal and its relationship if any with liver enzymes. METHODOLOGY: Forty consecutive patients, with alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-fourth edition, Text Revision criteria, willing for a 10-day inpatient detoxification program and presenting within 12 h of the last consumption of alcohol were recruited in the study. Details about the diagnosis and alcohol consumption patterns were assessed with a detailed psychiatric interview. After admission, routine investigations (complete blood counts [CBCs] and liver function tests) were sent and records were kept. CBC was sent for platelet counts on the 2nd, 4th, 6th, 8th, and the 10th day of alcohol withdrawal. RESULTS: Nearly 40% of the patients developed delirium tremens (DT group) and rest had an uncomplicated alcohol withdrawal (ND group). Platelet counts at baseline and all the 4 days of collection were significantly lower in DT group than the ND group. Platelet counts increased gradually from baseline till 10th day of alcohol withdrawal, mean increase in platelet counts being 88.61 +/- 11.60% (median: 61.11%, range [23.41-391.23%]). Platelet counts in 63% of the patients showed a drop on the 4th day of withdrawal before rising till the 10th day of alcohol withdrawal. Platelet counts were not affected by liver enzymes or other alcohol consumption patterns. CONCLUSIONS: Transient thrombocytopenia and reverse thrombocytosis during alcohol withdrawal are associated with an initial drop in platelet counts. The synchrony between the drop and the onset of DT needs to be evaluated. PMID- 28852238 TI - Anxiety Treatment of Opioid Dependent Patients with Buprenorphine: A Randomized, Double-blind, Clinical Trial. AB - OBJECTIVE: The objective of this study is to examine the impact of vary doses of buprenorphine on anxiety symptoms in opioid-dependent inpatients over a 7 days period, using a randomized controlled trial design. DESIGN: Patients were randomized to three groups. PATIENTS AND METHODS: Fourteen men who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for both opioid use disorder and generalized anxiety disorder and were seeking for treatment. INTERVENTION: Patients obtain dosages of 32 mg or 64 mg or 96 mg of buprenorphine as a single dose only and were treated in a psychiatric inpatient unit. Of 14 subjects; 5 (35.7%) obtained 32 mg, 4 (28.6%) obtained 64 mg, and 5 (35.7%) obtained 96 mg of buprenorphine. MEASUREMENTS: Administering daily Hamilton Anxiety Rating Scale and interview. RESULTS: All the patients ended the 7-day treatment time. The results showed a significant reduction in anxiety symptoms within each of the three groups (P = 0.00), but no difference in outcome between the groups (P = 0.605). CONCLUSIONS: The outcome suggests a single high dose of buprenorphine can supply a speedy, safe, simple, and suitable means of anxiety treatment. The single high dose of buprenorphine could be a novel mechanism medication that provides a rapid and sustained improvement for generalized anxiety disorder in opioid dependent patients. Placebo-controlled trials of longer duration are needed to evaluate ability, safety, and psychological and physiological influence of extended exposure to this medication. PMID- 28852239 TI - Physical Comorbidity and its Impact on Symptom Profile of Depression among Elderly Patients Attending Psychiatry Services of a Tertiary Care Hospital. AB - AIM: This study aimed to evaluate the prevalence of physical comorbidities among elderly patients with depression attending psychiatric services and the secondary aim of the study was to evaluate the influence of physical comorbidities on symptom profile of depression. METHODOLOGY: 140 patients with a diagnosis of depression as per the International Classification of Diseases-10 criteria were evaluated on Geriatric Depression Scale (GDS) and a physical comorbidity checklist. RESULTS: More than two-third (72.1%) of the patients had at least one physical illness. Out of those with physical comorbidity, more than half (57 out of 101) had at least 2 physical illnesses. The most commonly involved systems were cardiovascular system (n = 68; 48.6%), followed by endocrinological system (27.1%) and ophthalmological system (26.4%). Most common physical comorbidity was hypertension (47.14%), followed by cataract (25.7%) and diabetes mellitus (25%). The presence of any physical comorbidity, presence of hypertension or presence of diabetes mellitus did not influence the manifestations of depression as assessed by GDS-30. CONCLUSION: Elderly patients with depression have high rates of physical comorbidities. Clinicians managing elderly patients with depression must get their patient thoroughly evaluated for the presence of various physical comorbidities. PMID- 28852240 TI - Effects of Family Structure on Mental Health of Children: A Preliminary Study. AB - BACKGROUND: To find any association between family structure and rates of hospitalization as an indicator for behavior problems in children. METHODS: Retrospective chart review of 154 patients who were admitted to the preadolescent unit at Lincoln Prairie Behavioral Health Center between July and December 2012. RESULTS: We found that only 11% of children came from intact families living with biological parents while 89% had some kind of disruption in their family structure. Two-third of the children in the study population had been exposed to trauma with physical abuse seen in 36% of cases. Seventy-one percent had reported either a parent or a sibling with a psychiatric disorder. Children coming from biologically family were less likely to have been exposed to trauma. Children coming from single/divorced families were less likely to have been exposed to sexual abuse but more likely to have a diagnosis of attention deficit hyperactivity disorder (ADHD) compared to other types of families. Strong association was found between exposure to trauma and certain diagnoses in respect to hospitalization. ADHD predicted a 4 times likelihood of having more than one previous hospitalization, with mood disorder, oppositional defiant disorder, and physical abuse increasing the risk by more than twice. CONCLUSIONS: Significant differences in family structure were demonstrated in our study of children being admitted to inpatient psychiatric hospitalization. The presence of trauma and family psychiatric history predicted higher rates of readmission. Our study highlighted the role of psychosocial factors, namely, family structure and its adverse effects on the mental well-being of children. PMID- 28852242 TI - Evaluation of Dried Urine Spot Method to Screen Cotinine among Tobacco Dependents: An Exploratory Study. AB - BACKGROUND AND OBJECTIVES: Assessment of cotinine, a metabolite of nicotine in body fluids, is an important approach for validating the self-report among tobacco users. Adaptation of assays on dried urine spots (DUSs) has advantages of ease of collection, transportation, minimal invasiveness, and requirement of small volume. The aim of the present study was to develop an efficient method for testing cotinine in DUSs and evaluating its clinical applicability. METHODS: This involved optimization of conditions for detection, recovery, and stability of cotinine from dried urine, spotted on filter paper. Enzyme-linked immunosorbent assay was used for screening, whereas confirmation was done by gas chromatography. For clinical applicability, urine samples of tobacco users were tested. RESULTS AND INTERPRETATION: Water was found to be a suitable extracting solvent as compared to carbonate-bicarbonate buffer (pH 9.2) and saline. Screening was achieved by two punches taken from a 20 MUl (diameter 1.3 cm) spotted urine samples, and confirmation was achieved by five complete circles each of 20 MUl sample volume. The recovery was found to be 97% in water. Limit of detection for the method was found to be 100 ng/ml. No signs of significant degradation were found under all storage conditions. All the urine samples of tobacco users were found to be positive by a conventional method as well as DUSs, and the method proved to be efficient. CONCLUSIONS: DUS samples are a useful alternative for biological monitoring of recent nicotine use, especially in developing countries where sample logistics could be an important concern. PMID- 28852241 TI - Predictors of Inpatient Treatment Completion among Females with Opioid Use Disorder: Findings from a Tertiary Care Drug Dependence Treatment Centre of India. AB - INTRODUCTION: Studies have reported that females who drop out prematurely from inpatient treatment have poor treatment outcome. However, literature from India is limited in this regard. METHODS: We reviewed case records of female patients admitted with opioid use disorder at NDDTC, Ghaziabad between January 1, 2008 and December 31, 2012 to study the predictors of inpatient treatment completion among female patients with opioid use disorder in relation to their sociodemographic and clinical profile. RESULTS: Over the 5 years, 72 female patients were admitted with opioid dependence. During the study period, out of 72 patients, 44 (61.1%) were inpatient treatment completers and 28 (38.9%) were noncompleters. Mean length of ward stay was 5.1 +/- 3.8 days and 16.2 +/- 11.8 days for inpatient treatment noncompleters and completers, respectively, the difference being statistically significant (t = 4.845, P < 0.001). The multivariable analysis (adjusted for selected demographic characteristics as marital status, education, and employment) revealed that most women taking drug for relief from pain, having medical morbidity, and onset of opioids at age 25 years or more had a significantly greater likelihood for being treatment completers. CONCLUSION: Certain factors can help in identification of women opioid users who are at risk of leaving the treatment. PMID- 28852243 TI - Genealogy Study of Three Generations of Patients with Bipolar Mood Disorder Type I. AB - INTRODUCTION: The purpose of this research is genealogy examination of three generation of bipolar mood disorder Type I patients. METHODS: Patients selected using Poisson sampling method from 100 patients with bipolar mood disorder Type I, referring to a psychiatric center of Amir Kabir Hospital of Arak, Iran. Examine issues such as physical ailments, psychological review of living and deceased family members of each patient, drawn family pedigree using pedigree chart, check the relationship of the different pattern of the autosomal dominant and recessive disease, sex-linked dominant and recessive and linked to Y chromosome have been performed on patients. Different methods used in this study are pedigree chart and young mania rating scale and SPSS and Pearson's correlation test for analyzing the data collected. RESULTS: Among the studied inheritance patterns, the most common inheritance pattern was autosomal recessive. There was a significant relationship between age, number of generation, and inheritance patterns with physical ailments in families of patients with bipolar mood disorder (P < 0.05), but there was no significant association with mental illness (P > 0.05). Furthermore, there was a significant relation between generation and skin, gastrointestinal, ovarian, lung, coronary heart disease, diabetes mellitus, hypertension, Cerebrovascular accident (CVA), hyperlipidemia, cardiomyopathy, hypothyroidism, and kidney disease in patients with bipolar affective disorder Type I (P < 0.05). CONCLUSION: The results showed that autosomal recessive was the most pattern of inheritance and there is a significant relationship between generation and some physical disorders in patients with bipolar mood disorder Type I. PMID- 28852244 TI - Value of Ethyl Glucuronide and Ethyl Sulfate in Serum as Biomarkers of Alcohol Consumption. AB - BACKGROUND: Urinary Ethyl glucuronide (EtG) and Ethyl sulfate (EtS) are established markers of alcohol conumption. Measurement of these markers in serum offers certain advantages. This outpatient department based study evaluated performance of serum Ethyl glucuronide (EtG) and Ethyl sulphate (EtS) as biomarkers of recent alcohol consumption in alcohol dependent subjects. It also evaluated effect of alcohol dose and time since consumption on serum EtG and EtS concentration. METHODS: Information regarding alcohol intake was collected using Time line follow back calendar method from 152 subjects. Blood samples were collected to determine serum EtG and EtS concentration. RESULTS: The results revealed that serum EtG (at a threshold of 45 ng/mL) could detect recent moderate to heavy alcohol consumption with 85 percent sensitivity and 89 percent specificity. The results also show that simultaneous measurement of EtS does not increase test accuracy. We found that dose of alcohol and time since alcohol consumption explain 68 and 62 percent variance in serum EtG and EtS levels. CONCLUSION: EtG testing in blood was found useful as a way to detect recent drinking. This sensitive and specific short-term biomarker provides valuable information about recent alcohol consumption. PMID- 28852245 TI - Resolution of Cognitive Adverse Effects of Electroconvulsive Therapy in Persons with Schizophrenia: A Prospective Study. AB - BACKGROUND: Cognitive impairments are among the most important adverse effects of electroconvulsive therapy (ECT). Although much is known about them in patients with depression, there is very little information about these in persons with schizophrenia. METHODS: In this study, we examined the persistence of cognitive impairments in a subsample of patients (n = 49) with schizophrenia who had earlier participated in a clinical trial comparing the therapeutic and cognitive efficacy of bifrontal ECT (BFECT; n = 23) and bitemporal ECT (BTECT; n = 29) electrode placements. Total scores on Hindi Mental State Examination, processing speed, working memory, and verbal fluency were assessed in these patients at two points: first, at the end of their respective ECT course and at the follow-up (mean [standard deviation] = 98.7 [38.3] days). The course of cognitive impairments was assessed in all patients (n = 49) as a single group. Further, BFECT and BTECT patients were also compared with one another. RESULTS: ECT induced acute cognitive impairments in patients with schizophrenia had normalized by the end of 3 months' follow-up post-ECT. All the tested parameters in the realm of Hindi Mental Status Examination, speed of processing, sequencing, spatial and working memory and verbal fluency showed recovery. Further, across all tests, BFECT and BTECT ultimately had similar scores at the follow-up though BFECT performed relatively better with regards to the acute effects. In fact, worst performing BTECT group caught up to recover to comparable levels of performance by the end of follow-up. CONCLUSIONS: In patients with schizophrenia, most of acute ECT-induced cognitive impairments recover by the end of 3 months' post-ECT. Further, different electrode placements do not seem to make any difference regarding ultimate recovery of cognitive deficits. Future prospective studies are needed that could address the limitations of this study. PMID- 28852246 TI - Technology Addiction Survey: An Emerging Concern for Raising Awareness and Promotion of Healthy Use of Technology. AB - BACKGROUND: Technology use has shown an impact of users' lifestyle. The use has been attributed to psychosocial reasons. This usage manifests as excessive to addictive use of technology. There is a need to explore its addictive potential on large sample study as well as its association with psychosocial variables. It is one of its kind study on wider age group. The present work assessed the magnitude, burden, and sociodemographic correlates of technology addiction in an urban community. MATERIALS AND METHODS: A total of 2755 individuals (1392 males and 1363 females) in the age group of 18-65 years were approached for screening internet addiction and mobile overuse, using house-to-house survey methodology. RESULTS: The survey indicated the presence of addiction for 1.3% for internet (2% males and 0.6% females) and mobile phone overuse (4.1%-2.5% males and 1.5% females). It was more common among males. Significant differences were observed in relation to family status for internet and mobile phone use more commonly among single/nuclear families. Technology addictions were found to be more common among single families and lesser in nuclear and joint families. Mobile phone users had psychiatric distress in comparison to users with internet addiction. The study showed negative correlation of age, years of marriage, and numbers of family members with internet addiction and mobile overuse. CONCLUSIONS: It has implication for raising awareness about addictive potential of technology and its impact on one's lifestyle. PMID- 28852247 TI - Somatoform Pain Disorder Presenting as "Atypical Facial Pain:" A Rare Presentation in a 13-year-old. AB - Children and adolescents often present to physicians and pediatricians with a range of medically unexplained symptoms, most common being headache, abdominal, and bone pains. These symptoms can be a manifestation of underlying depressive, anxiety or somatoform disorders, and sometimes the only symptom. Hence, it is important to recognize and manage these symptoms. Atypical facial pain (AFP) or atypical trigeminal neuralgia that has variably been described to be of psychological origin is considered to be rare in children. We describe the case of a 13-year-old adolescent girl who presented with AFP, who was finally diagnosed to have a somatoform disorder. We discuss the characteristics of AFP in the index case that justify the diagnosis. We also attempt to describe psychosocial factors related to such a presentation. PMID- 28852248 TI - Pathological Laughter in a Female with Multiple Episodes of Stroke and Subdural Hematoma. AB - Various brain areas in both cortical as well as subcortical locations are involved in pathological laughter. Pathological laughter may be seen as a prodromal symptom or acute manifestation or late sequel of stroke. Various other neuropsychiatric conditions attribute to stroke. It is often difficult to ascertain the cause of pathological laughter in the presence of multiple brain pathologies. Here, we highlight a case of a 55-year-old female, who had multiple episodes of stroke and subdural hematoma, presented with pathological laughter and other behavioral abnormalities. PMID- 28852249 TI - Where Lies the Fault in Diagnosing Dhat Syndrome among Females? Understanding through a Case Study. AB - Dhat syndrome is a culture-bound syndrome of South-East Asia, common in young men. However, similar entity has also been described in female patients who attribute their symptoms to nonpathological or physiological vaginal discharge. The current diagnostic system for psychiatric illnesses does not encompass Dhat syndrome in females, and so these group of patients receive alternative diagnoses such as somatoform disorder or depression. As a result of which the focus of unique Dhat syndrome-centered management gets weakened, affecting the clinical outcome. This case study focuses on the diagnostic dilemmas related to Dhat syndrome in females and pitfalls in the current diagnostic system. PMID- 28852250 TI - Delusion of Triplet Pregnancy in Abdominal Cavity: A Case Report with a Review of Literature. AB - The two terms, pseudocyesis and delusion of pregnancy, were frequently used for pseudopregnancy. Delusion of pregnancy is a special form of hypochondriacal/somatic delusion reported in various psychiatric and organic disorders. The origin of the delusion of pregnancy in schizophrenia has often been explained by psycho-analytic interpretations attributing wish fulfilling, protective role to false beliefs, and mother establishes an undisturbed union with her fetus during pregnancy, which eliminate loneliness and helplessness. The current case is a 49-year-old married female with an illness of total duration of 10 years. Initial symptoms were delusion of infidelity and persecution and 2nd and 3rd person auditory hallucination; however, the patient started reporting around 2 years back that she was pregnant and there were three female children inside her abdominal cavity rather than in uterus. She was firm on this belief and was not convinced by family members even giving evidence contrary to her belief like showing ultrasonography report. She firmly believed that these are gift of God, and they are special children who would be delivered through special procedure. Blood investigation revealed raised prolactin level, blood sugar and ultra sonography suggestive of cholelithisis. Patient's psychiatric symptoms including delusion of pregnancy were significantly improved with treatment, and medical and surgical comorbidities were managed with appropriate consultations. PMID- 28852252 TI - Psychosis Following Carbimazole-induced Acute Alteration of Hyperthyroid Status. AB - Abrupt normalization of hyperthyroid state with antithyroid drugs is reported to precipitate psychosis. We report the development of acute psychosis in a 20-year old woman, following 30 days use of tablet carbimazole 10 mg for hyperthyroidism due to the multinodular goiter. At the time of presentation, she was euthyroid with a resolution of hyperthyroid status both clinically and biochemically. After 20 days treatment with tablet olanzapine 10 mg/day and stoppage of carbimazole, psychotic symptoms remitted completely and she has since remained in a euthyroid state and free from psychotic symptoms. This case highlights the development of psychosis in individuals, following rapid restoration to normal serum thyroid hormone levels in hyperthyroid individuals with carbimazole. PMID- 28852251 TI - Cyclical Vomiting Syndrome: Psychiatrist's View Point. AB - Cyclical vomiting syndrome (CVS) is an idiopathic functional disorder characterized by recurrent episodes of nausea and vomiting separated by symptom free intervals. Even though initially described in children, it is seen in all age groups. Exact etiology is not known. Various physical, infectious, and psychosocial stressors have been implicated for CVS. High incidence of psychiatric comorbidities such as panic attacks, anxiety disorder, and depression is seen in CVS. Most children outgrow CVS with time though some may transition to migraine or continue to have CVS as adults. Frequent misdiagnosis, delay in diagnosis, or inadequate treatment often lead to years of recurrent vomiting. This case report highlights the importance of the management of CVS by a multidisciplinary team including a psychiatrist in addressing the various physical and psychological factors effectively and that would result in faster and prolonged recovery. PMID- 28852253 TI - Very Early-onset Schizophrenia with Secondary Onset Tic Disorder. AB - Very early-onset schizophrenia (defined as an onset of psychosis before 13 years of age) is a rare and severe form of the disorder which is clinically and neurobiologically continuous with the adult-onset disorder. It is rarely reported <12 years of age in Indian literature. Here, we present a 15-year-old boy who developed psychosis at 9 years of age and during illness developed tic disorder. PMID- 28852254 TI - Efficacy of Danger Ideation Reduction Therapy in Obsessive-Compulsive Disorder Washer with Poor Insight: A Case Study and Literature Review. AB - Obsessive-compulsive disorder (OCD) is characterized by obsessions and compulsions. Treatment usually consists of serotonergic medications along with exposure therapies. Danger ideation reduction therapy (DIRT) is an alternative therapy predominantly for washing compulsions and focuses on reduction of danger ideations. DIRT was tried on Ms. S. with a history of OCD for 15 years and improvement was noticed on Yale-Brown Obsessive Compulsive Scale, Padua Inventory, Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale after 15 sessions of DIRT though she was not fully symptom-free. Thus, DIRT was found to improve OCD symptoms and improved her insight into illness. PMID- 28852255 TI - Temporal Lobe Seizures Presenting as Abrupt Clinging Behavior in a Child. AB - True and psychogenic nonepileptic seizures (PNES) go hand in hand. One colors the picture of other. Although it is thought that children carry lower risk for PNES than adults, this may represent the under-diagnosis of this condition in childhood due to few studies on this specific topic. Again, true seizure can be misdiagnosed by dramatic and varied manifestations appearing as psychological phenomena. We report a case of a 9-year-old boy presenting with sudden onset, short lasting, off and on different "melodramatic" episodic behavioral problems with La-Belle' indifference without loss of consciousness, appearing to be of psychogenic origin but finally ended with a diagnosis of temporal lobe epilepsy and responded dramatically with antiepileptics. The goal of this case report is to alert the reader to be cautious about rarer presentations of epilepsy and see each case holistically which may be misguided as PNES. PMID- 28852256 TI - Successful Long-term Management of a Child with Kleine-Levin Syndrome with Low dose Lithium. AB - Kleine-Levin syndrome (KLS) is a rare disorder characterized by episodic hypersomnia along with cognitive and behavioral disturbances (i.e., hyperphagia and hypersexuality). It is commonly seen in a young male. Not much is known about its long-term management; however, many reports suggest the usefulness of anticonvulsants and lithium for the same. We hereby report a case of childhood KLS from India who was successfully treated with low-dose lithium and discuss the relevant literature. PMID- 28852257 TI - Subacute Sclerosing Panencephalitis Presenting with Isolated Positive Psychotic and Catatonic Symptoms. AB - Subacute sclerosing panencephalitis (SSPE) is a rare slowly progressing neurological illness. Although patients with SSPE initially present with symptoms such as myoclonic jerks, cognitive decline, and personality/behavioral changes usually, rarely pure psychiatric symptoms (e.g., mania, psychosis, and catatonia) have also been reported during the initial course of the illness. We report an unusual case of an adolescent with SSPE presenting with prominent positive psychotic and catatonic symptoms with the absence of classical symptoms of SSPE in initial course of illness and further discussed the relevant literature. PMID- 28852258 TI - Olanzapine-induced Skin Eruptions. AB - Adverse cutaneous reactions are known to occur with psychotropic medications, which may lead to poor drug compliance. As compared to other group of psychotropics, there is relatively scarce literature on olanzapine-induced skin eruptions. We present a case of a 39-year-old man diagnosed with first episode mania and alcohol dependence syndrome who was started on tablet olanzapine which leads to fixed drug eruptions. Exhaustive investigations were done, all of which came out within normal limits. A diagnosis of fixed drug eruptions was made by the dermatologist. The skin eruptions subsided after stopping olanzapine. It has, thus, been emphasized that clinicians should be aware of the potential cutaneous eruptions associated with olanzapine. Early detection of the same would lead to timely management and hence better compliance with the psychotropic treatment. PMID- 28852259 TI - Chlorpromazine as Prophylaxis for Bipolar Disorder with Treatment- and Electroconvulsive Therapy-Refractory Mania: Old Horse, New Trick. AB - A 22-year-old male diagnosed with bipolar affective disorder presented to us with a 3rd episode mania resistant to both olanzapine and haloperidol as well as electroconvulsive therapy. He, however, responded to chlorpromazine (CPZ) which was also effective as a mood stabilizer. The patient had a relapse of his illness when CPZ was stopped and responded again when it was started. The case demonstrates that CPZ may have a role in as both an anti-manic agent and for the maintenance for bipolar disorders. The possible underlying mechanism for this role is also discussed. PMID- 28852260 TI - "The Barking Girl": A Case Report of Psychogenic Cough in a Child with a Review of Literature. AB - A 9-year-old girl presented with 2-month history of continuous coughing; despite detailed evaluation, no organic cause was found. Considering the provisional diagnosis of a psychogenic cough, she was advised for psychiatry consultation. After a psychological assessment, she was found to have comorbid anxiety (Screen for Child Anxiety Related Disorders score- 25) along with punitive parenting and sibling rivalry issues. She was initially treated with parental psychoeducation, play therapy, and behavior therapy. Since she did not show expected progress with the treatment, low-dose escitalopram was started along with the ongoing therapy, considering her anxiety. There was a significant improvement in her symptoms in 1 month follow-up. She maintained improvement during further follow-ups. This case illustrates the need to identify and treat comorbid psychiatric issues in the management of a psychogenic cough. PMID- 28852261 TI - Mental Health of Zika Virus-infected Mother and Mother of Newborn with Microcephaly. PMID- 28852262 TI - Benzodiazepines in Schizophrenia: Nemesis or Nirvana? PMID- 28852263 TI - Need to Develop a Home-based Intervention for Specific Learning Disorder in Indian setting. PMID- 28852264 TI - Sex Chromosomes: Does it Affect the Way You Think? PMID- 28852265 TI - Clozapine-induced Tardive Dyskinesia. PMID- 28852267 TI - Fabrication and Postmodification of Nanoporous Liquid Crystalline Networks via Dynamic Covalent Chemistry. PMID- 28852266 TI - Serum Autoantibodies against STIP1 as a Potential Biomarker in the Diagnosis of Esophageal Squamous Cell Carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) remains one of the leading causes of cancer-related mortality around the world. The identification of novel serum biomarkers is required for early detection of ESCC. This study was designed to elucidate whether autoantibodies against STIP1 could be a diagnostic biomarker in ESCC. An enzyme-linked immunosorbent assay was performed to detect serum levels of STIP1 autoantibodies in a training cohort (148 ESCC patients and 111 controls) and a validation cohort (60 ESCC patients and 40 controls). Mann-Whitney's U test showed that ESCC patients in two cohorts have higher levels of autoantibodies against STIP1 when compared to controls (P < 0.001). According to receiver operating characteristic analysis, the sensitivity, specificity, and area under the curve (AUC) of autoantibodies against STIP1 in ESCC were 41.9%, 90.1%, and 0.682 in the training cohort and 40.0%, 92.5%, and 0.710 in the validation cohort, respectively. Moreover, detection of autoantibodies against STIP1 could discriminate early-stage ESCC patients from controls, with sensitivity, specificity, and AUC of 35.7%, 90.1%, and 0.684 in the training cohort and 38.5%, 92.5%, and 0.756 in the validation cohort, respectively. Our findings indicated that autoantibodies against STIP1 might be a useful biomarker for early-stage ESCC detection. PMID- 28852268 TI - Mycobacterium tuberculosis Multidrug-Resistant Strain M Induces Low IL-8 and Inhibits TNF-alpha Secretion by Bronchial Epithelial Cells Altering Neutrophil Effector Functions. AB - M strain, the most prevalent multidrug-resistant strain of Mycobacterium tuberculosis (Mtb) in Argentina, has mounted mechanisms to evade innate immune response. The role of human bronchial epithelium in Mtb infection remains unknown as well as its crosstalk with neutrophils (PMN). In this work, we evaluate whether M and H37Rv strains invade and replicate within bronchial epithelial cell line Calu-6 and how conditioned media (CM) derived from infected cells alter PMN responses. We demonstrated that M infects and survives within Calu-6 without promoting death. CM from M-infected Calu-6 (M-CM) did not attract PMN in correlation with its low IL-8 content compared to H37Rv-CM. Also, PMN activation and ROS production in response to irradiated H37Rv were impaired after treatment with M-CM due to the lack of TNF-alpha. Interestingly, M-CM increased H37Rv replication in PMN which would allow the spreading of mycobacteria upon PMN death and sustain IL-8 release. Thus, our results indicate that even at low invasion/replication rate within Calu-6, M induces the secretion of factors altering the crosstalk between these nonphagocytic cells and PMN, representing an evasion mechanism developed by M strain to persist in the host. These data provide new insights on the role of bronchial epithelium upon M infection. PMID- 28852269 TI - Cannabinoid Receptor 2 Modulates Neutrophil Recruitment in a Murine Model of Endotoxemia. AB - The endocannabinoid system consists of endogenous lipid mediators and cannabinoid receptors (CB) 1 and 2. It has previously been demonstrated that activation of the leukocyte-expressed CB2 has anti-inflammatory effects in vivo. Here, we report its role under baseline conditions and in a model of low-dose endotoxemia by comparing CB2 knockout to littermate control mice. CB2-deficient mice displayed significantly more neutrophils and fewer monocytes in the bone marrow under steady state. In initial validation experiments, administration of 1 mg/kg LPS to male C57BL/6J mice was shown to transiently upregulate systemic proinflammatory mediators (peaked at 2 hours) and mobilise bone marrow neutrophils and monocytes into circulation. In CB2 knockout mice, the level of the metalloproteinase MMP-9 was significantly elevated by 2 hours and we also observed augmented recruitment of neutrophils to the spleen in addition to increased levels of Ccl2, Ccl3, Cxcl10, and Il6. Collectively, our data show that the absence of CB2 receptor increases the levels of innate immune cell populations in the bone marrow under steady state. Furthermore, during an acute systemic inflammatory insult, we observe a highly reproducible and site-specific increase in neutrophil recruitment and proinflammatory chemokine expression in the spleen of CB2 knockout mice. PMID- 28852270 TI - The Role of Proinflammatory Pathways in the Pathogenesis of Colitis-Associated Colorectal Cancer. AB - Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC). The risk factors of CRC in IBD patients include long disease duration, extensive colitis, severe histological inflammation, and coexistence with primary sclerosing cholangitis (PSC). Several molecular pathways that contribute to sporadic CRC are also involved in the pathogenesis of colitis-associated CRC. It is well established that long-standing chronic inflammation is a key predisposing factor of CRC in IBD. Proinflammatory pathways, including nuclear factor kappa B (NF-kappaB), IL-6/STAT3, cyclooxygenase-2 (COX-2)/PGE2, and IL-23/Th17, promote tumorigenesis by inducing the production of inflammatory mediators, upregulating the expression of antiapoptotic genes, and stimulating cell proliferation as well as angiogenesis. Better understanding of the underlying mechanisms may provide some promising targets for prevention and therapy. This review aims to elucidate the role of these signaling pathways in the pathogenesis of colitis-associated CRC using evidence-based approaches. PMID- 28852272 TI - Teaching/Training and Practice of Public Health/PSM/Community Medicine. PMID- 28852271 TI - Potential Biomarkers for NSAID-Exacerbated Respiratory Disease. AB - Asthma is a common chronic disease with several variant phenotypes and endotypes. NSAID-exacerbated respiratory disease (NERD) is one such endotype characterized by asthma, chronic rhinosinusitis (CRS) with nasal polyps, and hypersensitivity to aspirin/cyclooxygenase-1 inhibitors. NERD is more associated with severe asthma than other asthma phenotypes. Regarding diagnosis, aspirin challenge tests via the oral or bronchial route are a standard diagnostic method; reliable in vitro diagnostic tests are not available. Recent studies have reported various biomarkers of phenotype, diagnosis, and prognosis. In this review, we summarized the known potential biomarkers of NERD that are distinct from those of aspirin tolerant asthma. We also provided an overview of the different NERD subgroups. PMID- 28852273 TI - Clinical Practice in Community Medicine: Challenges and Opportunities. AB - Clinical practice with community health perspective makes community medicine a unique specialty. In their health centers, community physicians not only implement disease prevention programs, assess community health needs, manage healthcare teams and advocate for health promoting policies but also diagnose and treat diseases. However, participation of community medicine faculty in the delivery of clinical care varies from place to place due to administrative constraints. Health centers attached with medical college are not dependent on community medicine faculty for clinical service as these centers have their own medical and paramedical staff; whereas, other clinical departments in medical colleges depend on their faculty for delivery of clinical care in the hospital. Consequently, a perception is gaining ground that community medicine is a para clinical specialty. Strategies for a fixed tenured rotation of faculty in the health centers should be evolved. All faculty members of community medicine must also provide clinical care in the health centers and the quantum of clinical services provided by each one of them should be reported widely to all stakeholders. Community medicine residency programs must ensure that trainee community physicians acquire competency to deliver comprehensive primary health care (promotive, preventive, curative, and rehabilitative) in a health center. PMID- 28852274 TI - Structural Violence on Women: An Impediment to Women Empowerment. AB - Violence on women has been present in our society since times immemorial. The ethics, the values, the morals, the culture of the society has been framed in such a way or we can say structured in such a way so as to promote exploitation of this segment which is in reality the root of the society. The concept of STRUCTURAL VIOLENCE was introduced by Johan Galtung in 1969. It refers to a form of violence wherein some http://www.studylecturenotes.com/social sciences/sociology/370-social-institution-definitions-a-structure-of-social institution social institution may harm people by preventing them from meeting their basic needs. Violence against women has taken the form of a global epidemic which has taken its toll on the physical, psychological, sexual and economic life of the female. Johan Galtung in "Violence, Peace and Peace Studies", 1969 has rightly remarked "when one husband beats his wife, there is a clear case of personal violence, but when one million husbands keep one million wives in ignorance, there is structural violence". India has been slow in its pace for action against violence on women, but the brutal gang- rape of a 23 year old Delhi girl on December 2012 aroused the Indians from their deep slumber on this issue. Structural violence is a demon against women that is devouring the society. The combined efforts of Government NGO's and most important, the sufferers of this violence, the women have to take a major step to fight this dragon. PMID- 28852275 TI - Factors Responsible for Disclosure of HIV Seropositivity among Residents of Cross River State, Nigeria. AB - CONTEXT: Disclosure of HIV-positive status to sex partners is viewed as a preventive measure and as a social and legal responsibility for HIV-infected individuals. AIMS: The aim of this study is to determine the proportions and factors responsible for disclosure of HIV seropositivity among residents of Cross River State, Nigeria. SETTINGS AND DESIGN: This was a cross-sectional comparative study. SUBJECTS AND METHODS: It involved 320 HIV-positive individuals equally selected from the urban and rural settings of Cross River State and use questionnaires. STATISTICAL ANALYSIS USED: Data analysis used SPSS version 20.0. Chi-square test and logistic regression were used to identify determinants of HIV status disclosure. RESULTS: Among urban respondents, 93.8% had disclosed compared with 79.4% among rural respondents, the difference was statistically significant (P < 0.001). There was a statistically significant association between HIV status disclosure and age (P = 0.008), marital status (P = 0.027), number of nonspousal sexual partner (P = 0.006), and area of residence (P < 0.001). There was no statistically significant association between HIV status disclosure and gender (P = 0.622), between occupation (P = 0.495) or income (P = 0.351 and head of household (P = 0.241). There was statistically significant association between HIV status disclosure and level of education (P = 0.015), house ownership (P = 0.008), time from diagnosis (P = 0.003), and duration of treatment (P = 0.002). CONCLUSIONS: This study has shown that HIV seropositive status disclosure was higher when compared with other local studies, and age, marital status, and area of residence were factors associated with HIV seropositive status disclosure. PMID- 28852276 TI - An Informal School-based, Peer-led Intervention for Prevention of Tobacco Consumption in Adolescence: A Cluster Randomized Trial in Rural Gandhinagar. AB - BACKGROUND: Tobacco use among adolescence is one of the important preventable causes of death as well as a leading public health problem all over the world. The present study was conducted with the objective of studying the effect of peer led interventions on tobacco use among adolescents. MATERIALS AND METHODS: Twenty schools were randomly selected and ten schools each were identified as cluster for intervention and control groups. A total of 402 students in intervention group and 422 in control group were studied. RESULTS: About 48% and 41% of adolescents were consuming smokeless tobacco in any form in the intervention and control groups, respectively. Prevalence of consumption of smokeless tobacco was significantly high among boys as compared to girls. Pan masala was the most common form of consumption. After conducting A Stop Smoking in School Trial-like peer-led intervention, a significant reduction in tobacco consumption of any form was observed in the intervention group (48%-36%) during the follow-up (Z = 3.2, P < 0.01). A significant reduction in exposure to passive smoking in the intervention group (32%-29%) was also observed. All the students smoking initially had stopped smoking at the end of the follow-up in both the groups. CONCLUSION: It was found that peer-led intervention was effective in reducing the consumption of smokeless tobacco in any form. The rate of reduction was more in the first follow-up as compared to the end of the intervention. Sustained intervention in the form of retraining is needed for the long-term effect. PMID- 28852277 TI - Violence against Educated Women by Intimate Partners in Urban Karnataka, India. AB - BACKGROUND: Initially viewed as a human rights issue, partner violence is increasingly seen as an important public health problem of international concern. OBJECTIVES: To assess the extent of physical, sexual, psychological, and controlling behavior of intimate partners against women in an educated society and find the association with age, age of marriage, married years, educational status of the women and that of partner. MATERIALS AND METHODS: A prevalence of 15% was taken and final sample was 200, after considering loss of follow-up. STATISTICAL METHODS: Proportion, Z-test, Chi-square test. RESULTS: The prevalence of violence against intimate partner in educated society was found to be 40.5% in a South Indian city. Physical assault was high in 30-50 years and increased with duration of marriage from 5.5% at 5 years to 33.3% in 10-20 years of married life. Sexual and psychological assault also increased in <5 years of married life to 35% and 47.6% in 10-20 years duration of marriage, which was statistically significant. Sexual and psychological assault showed a bimodal presentation. Less educated women and their partners were found to report more violence, which was statistically significant. CONCLUSION: Violence against women is not uncommon in the educated society. PMID- 28852278 TI - Developing Domains to Assess Understanding Regarding Sexually Transmitted Infections among Sexually Transmitted Infection Clinic Attendees: A Qualitative Study. AB - OBJECTIVE: To develop and validate domains to assess attendee's gain at sexually transmitted infection (STI) clinic and their understanding after utilizing services at STI Clinic. METHODS: Study was done in two phases. In-depth interviews were conducted to explore attendee's perception. Domains generated through the first phase were validated by conducting another 50 structured interviews. RESULTS: Major domains developed were perceptions on STI, the source of information, treatment seeking behavior, understanding of treatment, laboratory test, and follow-up. Friends and counselor played an important role as the source of right information, while elder family female played a role in delayed seeking care. CONCLUSION: Developed domains can be used to assess STI clinic attendee's perspective on STI. Poor understanding of STI care component especially prevention, partner treatment, and referral was noted after the clinic visit. PMID- 28852279 TI - Elevated Blood Pressure and Its Associated Risk Factors among Adolescents of a North Indian City - A Cross-sectional Study. AB - CONTEXT: Amidst the uncertainty in childhood blood pressure (BP) thresholds, besides the ambiguity in levels and duration of BP elevation causing organ damage, hypertension is present in substantial number of asymptomatic children and adolescents with only a few studies disclosing the setup. With projection of deaths due to noncommunicable diseases in 2030 rising to 52 million, it is necessary to know about the knowledge of present adolescents about BP and its modifiable risk factors. AIMS: (1) To assess the prevalence of elevated BP among adolescents and to ascertain the associated risk factors. (2) To assess adolescent's knowledge about BP and its modifiable factors. SETTINGS AND DESIGN: A community-based cross-sectional study was conducted on school going adolescents of Lucknow, from September 2014 to August 2015. SUBJECTS AND METHODS: BP, height, and weight were measured following standard protocols, Centers for Disease Control and Prevention charts for finding respective cut-off values and oral questionnaire for assessing lifestyle risk factors were used. STATISTICAL ANALYSIS: Chi-square, unpaired t-test, and logistic regression were used. RESULTS: Of the 1041 participants, elevated BP (BP percentile >=90) was prevalent in 24.2%. On regression, factors such as obesity (adjusted odds ratio [aOR] = 5.8, 95% confidence interval [CI] = 3.6-9.4), low fruit diet (aOR = 3.3, 95% CI = 2.1-5.4), and frequent junk food consumption (aOR = 1.9, 95% CI = 1.3-2.8) raised the odds of elevated BP while it was lowered by being physically active (aOR = 0.67, 95% CI = 0.46-0.97). Of 86.3% of children (n = 898) who were fathomed of BP, only less than third (33% and 21.9%) acquainted of BP raising and lowering practices, respectively. CONCLUSIONS: Prevalence of high BP is colossal with only a few children knowing its amendable nature. Strenuous efforts targeting detrimental behaviors and imparting the sense of healthy lifestyle enhancing practices are vital to control this epidemic. PMID- 28852280 TI - Utilization of Antenatal HealthCare Services among Fishermen Population in Kanchipuram District, Tamil Nadu: A Cross-sectional Study. AB - BACKGROUND: Considering the global and national level commitments in improving the maternal health as well as reducing the maternal mortality, assessment of factors influencing the delivery of antenatal healthcare services becomes essential. OBJECTIVES: The aim is to assess the utilization of antenatal health services and to identify the factors influencing their utilization among women of fishermen population in Kanchipuram district, Tamil Nadu. MATERIALS AND METHODS: The cross-sectional study was carried out among the mothers in Kovalam area of Kanchipuram district. Details were collected using a pretested questionnaire and analyzed using statistical software. RESULTS: The study included 284 mothers, of which 35% were illiterates. Nearly 60.21% have got registered with the Government sector, 59.51% of the mothers had three or more antenatal visits, 64.08% have received two doses of tetanus toxoid, and 73.24% have taken iron and folic acid tablets. Factors which were identified to have statistically significant association with better utilization of antenatal health services were age >30 years, higher educational status, skilled workers, those having their first child, and higher socioeconomic class. CONCLUSION: This study has reported the fact that antenatal healthcare services were not utilized fully by the community and the fishermen population being a special group has to be given the needed attention from the healthcare delivery system. PMID- 28852281 TI - Scorecard - An Innovative Simplified Tool to Supplement the Existing Monitoring Mechanism to Assess and Improve Performance of Antiretroviral Treatment Centers. AB - INTRODUCTION: All 26 antiretroviral treatment (ART) centers of Gujarat were monitored by Gujarat State AIDS Control Society under the National AIDS Control Program. A comprehensive tool is needed to identify gap in service delivery and to prioritize monitoring visits. OBJECTIVES: To supplement the existing monitoring system, identify strengths/weakness of ART centers, and give recommendations. METHODOLOGY: Scorecard was developed in spreadsheet format with 17 scoring indicators on monthly base from March 2014 onward. The centers were classified in three color zones: green (score >=80%), yellow (score <80% and >=50%), and red (score <50%). Visits were prioritized at centers with more indicators in yellow/red zone. The performance of centers was compared for March 2014 and March 2015. RESULTS: The statistically significant improvement was observed in indicator "ART initiation within 2 months of eligibility," while after removing red zone from analysis, four more indicators named "eligible patients transferred out before ART initiation, general clients started on ART, antenatal women started on ART, and pre-ART follow-up CD4 done" reflect statistically significant improvement. Quadrant analysis was done for some indicators, which provide insight that less number of eligible patients may be a reason for low initiation of ART at one center, and at four other centers, the possible reasons for low retention are high death rate and high lost to follow-up rate. Based on these findings, the recommendations were made to regular mentoring centers, improve coordination between ART center and care and support centers (CSCs), and conduct verbal autopsy. CONCLUSION: Scorecard is a simple and cost effective tool for monitoring, and by highlighting low-performing indicators, it helps in improving quality of services provided at ART centers. PMID- 28852282 TI - The Bone Pain Crisis of Sickle Cell Disease and Malaria: Observations from Gujarat, India. AB - BACKGROUND: Sickle cell disease is a common problem across central India, but its clinical features may differ from that in African populations. There is a need to define the features of sickle cell disease in India, and the current study addresses some features of the bone pain crisis. OBJECTIVES: The objective of the study was to describe the epidemiology of the bone pain crisis of sickle cell disease in Gujarat and explore the relationship with infection by Plasmodium vivax. MATERIALS AND METHODS: This was a prospective review of all admissions in patients with sickle cell disease to a private pediatric institution in Bardoli, Gujarat, in the year 2015. Hemoglobin electrophoresis of all patients was consistent with homozygous sickle cell disease, but family studies indicated that at least seven cases had the severe sickle cell-beta + thalassemia presumed to be the common IVS1-5G>C mutation. Clinical, hematological, and parasitological features were recorded. RESULTS: There were 914 admissions among 654 patients who had between one and seven admissions. The bone pain crisis accounted for 763 (83%) of admissions and increased between July and October coinciding with the monsoon period. Blood smears were examined for malarial parasites in 811 admissions and were positive for P. vivax in 73% patients. There was no evidence that P. vivax infections varied with the cause of admission or increased during the monsoon period. CONCLUSIONS: There was a high prevalence of P. vivax infection in hospital admissions of sickle cell patients, but the data did not support an etiological role in the bone pain crisis. A trial of malarial prophylaxis might determine its effect on the clinical features and outcome of sickle cell disease. PMID- 28852283 TI - Feasibility of Telecardiology Solution to Connect Rural Health Clinics to a Teaching Hospital. AB - BACKGROUND: In spite of enormous progress in cardiac care in India, rural communities lack access to even basic cardiac care. One possible solution to this problem is to employ telecardiology. OBJECTIVES: To demonstrate feasibility of telecardiology system to link rural clinics to a teaching hospital. METHODS: Five rural clinics were linked to a teaching hospital, using an inexpensive system of cardiographs and tablet PCs to transmit ECGs to hospital and have them interpreted by cardiologist. RESULTS: Three hundred eighty ECGs were acquired at clinics with 98.9% of them noise-free and transmitted to the hospital with 99.7% success on first attempt. Interpretation of ECG was provided to primary care physician at the clinic on the same day for 95.3% of ECGs. Abnormal ECG findings were seen on 22.6% of these ECGs. CONCLUSION: This system performed well with high success rate of acquisition and transmission. Staff at rural clinics successfully acquired quality ECGs and transmitted them and the staff at the hospital were able to provide timely interpretation of ECGs and advice to patients. PMID- 28852284 TI - Epidemiological Perspective of National Leprosy Eradication Programme in Maharashtra: Focusing on "Tribal Hot-spot" of Tribal District. AB - BACKGROUND: Leprosy or Hansen's disease, a chronic infectious disease caused by Mycobacterium leprae is a serious public health concern because of associated case load, morbidity and stigma attached to it. India achieved elimination of leprosy as a public health problem (prevalence rate [PR]<1 case/10,000 population) at the national level on January 1, 2006, still 19% districts in the country report PR more than one. In Maharashtra, it is found that very few districts within the state or very few pockets within the district are actually having leprosy burden. OBJECTIVES: (1) Identification of region-wise actual "hot spot" districts/pockets within state of Maharashtra.(2) Further drop-down below the district and block to tribal belt for understanding the actual high risk area/belt within the tribal districts. METHODS: Secondary data analysis of leprosy patients registered in the State during the period 2008-2015. RESULTS: PR per 10,000 was found more in Vidharbha region followed by rest of Maharashtra and then Marathwada. Analysis showed that, there are tribal districts and tribal area within tribal districts which are having higher leprosy burden as compared to the all other districts indicating need of allocation of programme funds and facilities to these tribal belts for the effective control and elimination of leprosy. CONCLUSION: National Leprosy Eradication Programme should focus on tribal belt for effective control. Without giving extra attention to these tribal areas within high risk district/pockets efforts of eradication of leprosy by 2018 would be unrealistic and impractical. PMID- 28852285 TI - Knowledge and Perception Regarding Autism among Primary School Teachers: A Cross sectional Survey from Pakistan, South Asia. AB - BACKGROUND: Early detection and intervention seem to improve development in autistic children, and teachers form an important part of their early social environment. OBJECTIVES: The objective of this study was to assess baseline knowledge and misconceptions regarding autism among school teachers and evaluate factors influencing their knowledge. MATERIALS AND METHODS: This is a cross sectional survey enrolling primary school teachers using a self-administered questionnaire. RESULTS: Seventy-three teachers (mean age of 34 years, 66% females) responded. Gaps in awareness and knowledge were found. About 52 (71.2%) teachers identified themselves as having some knowledge about autism, with 23 (44.2%) among this group understanding autism as a neurological/mental disorder. The majority (73.1%) believe that special education is a helpful intervention. The only significant factor that influenced knowledge among teachers was attendance of behavioral classes (P = 0.01). CONCLUSION: Results suggest that teachers have an inadequate understanding of autism due to several misconceptions. This calls for increased education of teachers with regard to autism and other childhood disorders. PMID- 28852286 TI - Sputum Conversion and Treatment Success among Tuberculosis Patients with Diabetes Treated under the Tuberculosis Control Programme in an Urban Setting in South India. AB - BACKGROUND: Studies from India on sputum conversion and tuberculosis (TB) treatment outcomes among TB patients with diabetes are limited. OBJECTIVE: The objective of this study is to estimate the proportion of sputum smear conversion and successful treatment outcomes among diabetic-TB patients treated under Revised National TB Control Programme (RNTCP). METHODOLOGY: Information on TB disease, diabetes, sputum conversion, and treatment outcomes were collected from treatment cards of adult TB patients (age >18 years) treated in the District TB Centre TB Unit, Tiruchirapalli, Tamil Nadu from July 1, 2014, to October 31, 2015. RESULTS: Diabetes was documented in 163 (14%) of 1131 TB patients. Sputum conversion was in 107 (94%) of 114 smear positive-TB patients. Successful TB treatment outcome was in 116 (85%) of 136 patients and 107 (86%) of 124 new TB patients. CONCLUSION: Sputum conversion was as per RNTCP target while treatment success rate among the new TB patients with diabetes was suboptimal. PMID- 28852287 TI - Data Envelopment Analysis of Components of Comprehensive Index for Community Health Assessment of Maharashtra. PMID- 28852288 TI - Evaluation of Antenatal Care Services Affecting Neonatal Health. PMID- 28852289 TI - Good Bye, Thank You, Ethics and Other Things.... PMID- 28852290 TI - The Science and Art of Eyebrow Transplantation by Follicular Unit Extraction. AB - Eyebrows constitute a very important and prominent feature of the face. With growing information, eyebrow transplant has become a popular procedure. However, though it is a small area it requires a lot of precision and knowledge regarding anatomy, designing of brows, extraction and implantation technique. This article gives a comprehensive view regarding eyebrow transplant with special emphasis on follicular unit extraction technique, which has become the most popular technique. PMID- 28852291 TI - Effectiveness of Fibrin Glue in Adherence of Skin Graft. AB - BACKGROUND: Graft fixation is important for graft take. Fibrin glue has been proposed as an ideal material, because of its human origin and it provides firm adhesion in seconds or minutes. OBJECTIVE: To evaluate the efficiency of fibrin glue, in increasing the take of skin graft. Assessment includes surgical time taken for graft fixation, haematoma/seroma formation, engraftment and wound closure by day 14. METHODS: The study is an observational prospective study conducted in the Department of Plastic Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, from January 2016 to June 2016. Sixteen patients who underwent split skin grafting were assessed during the study period. Fibrin glue was used on the recipient bed before grafting. RESULTS: Better haemostasis and graft adhesion, with a significant reduction of surgical time, were noted. CONCLUSION: The safety profile of fibrin glue was excellent as indicated by the lack of any related serious adverse experiences. These findings demonstrate that it is safe and effective for attachment of skin grafts, with outcomes at least as good as conventional methods. PMID- 28852292 TI - Fractional Carbon Dioxide, Long Pulse Nd:YAG and Pulsed Dye Laser in the Management of Keloids. AB - BACKGROUND: Keloids are abnormal wound responses characterised by excessive deposition of collagen and glycoprotein. They are both aesthetically and symptomatically distressing for most of the patients. There are reports of keloid management with pulsed dye laser (PDL), fractional carbon dioxide (CO2) laser and neodymium-doped yttrium aluminium garnet (Nd:YAG) laser individually and also in combination of CO2 with PDL and CO2 with Nd:YAG. Here, we discuss a combination of all the 3 lasers as a therapy for keloids. AIM: This study aims to assess the efficacy of fractional CO2 laser, long pulse Nd:YAG laser and PDL in the management of keloids. MATERIALS AND METHODS: Fifteen patients with keloids were treated by fractional CO2 laser, followed by PDL and long pulse Nd:YAG laser at monthly intervals. Four patients discontinued the study and were lost for follow up. Photographs were taken at the beginning of the treatment and at the end of five sessions. Clinical improvement was analysed based on a visual analogue scale graded by three blinded observers after assessing the clinical photographs for the improvement in size, colour and aesthetic impression. RESULTS: Of the 11 patients, one patient had excellent improvement, one patient had good improvement, four patients had moderate improvement, two patients had mild improvement and three had no improvement. CONCLUSION: Lasers may have a synergistic effect when combined with other modalities of treatment but cannot be used as monotherapy in the treatment of keloids. PMID- 28852293 TI - Simplified Non-cultured Non-trypsinised Epidermal Cell Graft Technique Followed by Psoralen and Ultraviolet A Light Therapy for Stable Vitiligo. AB - BACKGROUND AND AIMS: Stable vitiligo can be treated by various surgical procedures. Non-cultured melanocyte grafting techniques were developed to overcome the time-consuming process of culture while at the same time providing acceptable results. All the techniques using non-cultured melanocyte transfer involve trypsinisation as an integral step. Jodhpur technique used by the author is autologous, non-cultured, non-trypsinised, epidermal cell grafting. SETTINGS AND DESIGN: The study was conducted on patients visiting the dermatology outpatient department of a tertiary health centre in Western Rajasthan. MATERIALS AND METHODS: At the donor site, mupirocin ointment was applied and dermabrasion was done with the help of micromotor dermabrader till pinpoint bleeding was seen. The paste-like material obtained by this procedure containing melanocytes and keratinocytes admixed with the ointment base was harvested with spatula and was subsequently spread over the recipient area. Recipient site was prepared in the same manner by dermabrasion. After 10 days, dressing at both sites was removed taking utmost care at the recipient site as there was a theoretical risk of dislodging epidermal cells. RESULTS: In a study of 437 vitiligo patches, more than 75% re-pigmentation (excellent improvement) was seen in 41% of the patches. Lesions on thigh (100%), face (75%) and trunk (50%) showed maximal excellent improvement, whereas patches on joints and acral areas did not show much improvement. CONCLUSIONS: This technique is a simplified, cost effective, less time-consuming alternative to other techniques which involve tryspsinisation of melanocytes and at the same time provides satisfactory uniform pigmentation. PMID- 28852294 TI - A Spilt Head Study of Efficacy of Placebo versus Platelet-rich Plasma Injections in the Treatment of Androgenic Alopecia. AB - BACKGROUND: Platelet-rich plasma (PRP) is an autologous concentration of human platelets contained in a small volume of plasma with haemostatic and tissue repairing effects. Being enriched by various growth factors, PRP has become the focus of attention in numerous fields of medicine. Androgenic alopecia (AGA) is a common chronic hair loss disorder, characterised by progressive hair loss. Despite the therapeutic options available, there is low patient compliance and satisfaction rate. The topical and often systemic adverse effects of therapy has lead to the search of new treatment options for AGA. Recently, PRP has received growing attention as a potential therapeutic tool for hair loss. AIM: To compare the efficacy of placebo versus PRP injections in the treatment of male AGA. PATIENTS AND METHODS: Fifty male patients with AGA (Grade III to VI) were enrolled in the study. PRP was prepared using the double-spin method and injected in the androgen-related areas of scalp on the left side. Normal saline was injected on the right side in a similar fashion. Treatment sessions were performed with an interval of 21 days, and six sittings were completed for every patient. RESULTS: Hair loss reduced with evidence of new hair growth. Digital image analysis showed an overall improvement in hair density and quality as lanugo-like hair became thicker, normal hair. An improvement in hair density, quality and thickness on trichoscopy was noted. CONCLUSION: Our data suggest that PRP injections have therapeutic effect on male pattern hair loss with no major side effects and high patient satisfaction overall. PMID- 28852295 TI - Safety and Efficacy of Intralesional Vitamin D3 in Cutaneous Warts: An Open Uncontrolled Trial. AB - BACKGROUND: Cutaneous warts are treated primarily with destructive methods such as cryotherapy or electrocautery. These modalities of treatment are time consuming and may be associated with scarring in multiple warts. Immunotherapy is emerging as a new modality of treatment which acts on enhancing cell-mediated immunity against human papillomavirus for clearance of both treated and distant warts. AIMS: This study aims to evaluate the safety and efficacy of intralesional Vitamin D3 for the treatment of cutaneous warts. MATERIALS AND METHODS: Patients with multiple warts were selected for immunotherapy. Vitamin D3 (0.2 ml, 15 mg/ml) was injected to the base of warts after injecting with lignocaine (0.2 ml, 20 mg/ml). The injections were repeated 2 weeks apart for a maximum of 4 sessions or until complete clearance, whichever was earlier. A maximum of 2 warts were treated per session and patients were followed up for 6 months after the last injection. RESULTS: Forty-two patients with multiple warts were recruited for the study who completed the 6-month follow-up period and were available for analysis. Of these, 23 had palmoplantar warts, 18 had verruca vulgaris and 1 patient had filiform wart. In total, 33 of 42 patients (78.57%) showed complete response, 6 patients (14.28%) showed moderate response and three patients (7.14%) showed mild response. Recurrence was observed in one patient with the palmoplantar wart. No serious adverse effects were reported. LIMITATIONS: Lack of control group was the main drawback in our study. CONCLUSION: Intralesional Vitamin D3 is safe and effective for treatment of multiple cutaneous warts. PMID- 28852296 TI - The Clinical Pattern of Axillary Hidradenitis Suppurativa among Saudi Arabians: Mode of Presentation and Treatment Challenges. AB - BACKGROUND: Hidradenitis suppurativa is a chronic follicular occlusive disease affecting the folliculopilosebaceous unit. The clinical course is variable, ranging from mild to severe cases. Definitive evidence-based guidelines for the management are lacking. In addition, the multifaceted clinical features and the unpredictable course of the disease make a uniform approach to treatment impractical. As a result, there are multiple therapeutic approaches. Therefore, in this study, we aim to analyze the results of management of axillary hidradenitis suppurativa among the local community in Saudi Arabia. MATERIALS AND METHODS: A retrospective cohort database analysis of 1369 patients diagnosed and treated for axillary hidradenitis suppurativa between January 2004 and December 2013 was done. Seven hundred and forty-one (54.12%) were females and 628 (45.87%) were males. All patients with Stage I disease favored the conservative method while all patients with Stage II chose the surgical approach. RESULTS: The mean age was 25.5 years. Nine hundred and seventy-four (71.15%) patients were treated conservatively; the mean healing time was 5.5 weeks. Three hundred and ninety five (28.85%) patients were treated surgically. One hundred and fourteen (28.9%) had incision and drainage, 281 (71.1%) had complete excision; all wounds eventually healed without significant scarring. The recurrence rate was 12.5% (122 patients) in the conservative method group and zero (0%) in the surgical method group. CONCLUSIONS: Hidradenitis suppurativa remains a challenging clinical condition for patients and physicians. Further studies need to focus not only on the etiology of this disease but also on the optimal treatment regimen. Public awareness programs are necessary to avoid late presentation and complications. PMID- 28852297 TI - Assessment of the Efficacy and Safety of Hyaluronic Acid Gel Injection in the Restoration of Fullness of the Upper Lips. AB - BACKGROUND AND AIM: Lips have a significant role in face aesthetic perception, and lip augmentation is one of the most commonly requested aesthetic procedures. Non-permanent dermal fillers, such as hyaluronic acid (HA), are used for augmenting the lips. This article presents the results of Phase II, before - after designed study, assessing the safety and efficacy of a soft tissue HA filler, for upper lip augmentation. MATERIALS AND METHODS: Investigators treated 10 healthy adult women 28-45 years old, using a single injection of Hyamax Kiss soft tissue HA filler (a product from Hyamed Laboratories, Switzerland) for upper lip augmentation. The primary efficacy endpoint was an increase in lip fullness at least one grade on Medicis Lip Fullness Scale at 2, 12 and 24 weeks post treatment. Furthermore, the effectiveness and durability of filler were assessed using a 5-point Investigator's Global Assessment (IGA). Adverse events and volunteers' satisfaction were reported using visual analog scale. RESULTS: Response to treatment (as defined above) after 2, 12 and 24 weeks were observed in 80%, 70% and 80% of patients, respectively. No statistical difference was found in response to treatment rate between follow-up visits (P = 0.83). The mean value of IGA score in weeks 2, 12 and 24 were 3.4 +/- 0.96, 3.3 +/- 0.67 and 3.3 +/- 0.67, respectively. The study subjects were almost all satisfied with their lip improvement. Reported adverse effects were temporary and mostly mild in severity. CONCLUSION: Soft tissue HA filler tested in this study was well tolerated, efficient and durable when used for upper lip augmentation. PMID- 28852298 TI - Reconstructions of Small Scalp Defects with Step Flap. AB - INTRODUCTION: Defects of the scalp arise from several aetiologies including trauma, burn, injury, infection, radiation and surgical excision of tumours. Multiple options for reconstruction of scalp defects exist that included primary closure, skin grafts, local flaps, regional and distal free flaps. PATIENTS AND METHODS: This was a prospective case-series study, which was carried out in the Department of Plastic Surgery of our Hospital. Step flap was used for small (2.5 cm * 2.5 cm) scalp skin defects reconstructions after skin tumour ablations. In this 2 years study, 15 patients (7 female , 8 male), ranging from 40 to 72 years (mean, 53 years), underwent an operation with local step flap for reconstruction of scalp defects caused by basal cell carcinoma or squamous cell carcinoma excision. RESULTS: The patients who present with small scalp malignant tumours need complete resection and perfect reconstruction. This study showed that step flap with sufficient releasing was an effective method for reconstruction of small scalp defects due to skin malignancies. We had no case of flap complications such as ischaemia or necrosis. CONCLUSION: We recommend this local flap (z-flap) as a new approach for small scalp defect reconstruction in all areas of hair-bearing scalp. PMID- 28852299 TI - A Simplified Reconstructive Technique for Full-thickness Central Defects of the Auricle with the Use of a Post-auricular Folded Flap. AB - BACKGROUND: Post-auricular flaps have proved very effective in the reconstruction of most types of partial auricular defects. However, few reports exist regarding the reconstruction of centrally located perforating defects of the auricle. OBJECTIVES: This paper aimed to describe a one-stage technique including a post auricular folded flap (PAFF) for reconstruction of full-thickness defects of central auricular sites. PATIENTS AND METHODS: Between March 2010 and November 2014, five male patients were treated with this reconstructive technique under local anaesthesia. At the time of surgery, patients' age ranged from 76 to 86 years (mean age, 79.8). The patients suffered from a central and full-thickness defect owing to surgical excision of a skin malignancy or failed reconstruction procedures secondary to surgical excision of a skin malignancy. RESULTS: Healing was uneventful for all the included patients, without signs of dehiscence, necrosis, hematoma and infection. The defects were completely repaired, without the need of further operations. During the follow-up period, all the patients remained satisfied with the aesthetic outcome. CONCLUSIONS: This technique constitutes an immediate, effective and low-morbidity procedure to repair full thickness central defects of the auricle. Since PAFF requires only one surgical operation under local anaesthesia, patients with burdened medical history may profit from this technique. PMID- 28852300 TI - Giant Pedunculated Tumour on the Finger. PMID- 28852301 TI - Glomus Tumour with Intramedullary Bone Cyst: A Rare Presentation. PMID- 28852302 TI - Successful Management of Angiolymphoid Hyperplasia with Eosinophilia by Radiofrequency. PMID- 28852303 TI - Aesthetic Correction of Smoker's Lip Using 1064 nm Q-switched Neodymium-doped Yttrium Aluminium Garnet Laser. PMID- 28852304 TI - Wilson's disease: Prospective developments towards new therapies. AB - Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism, caused by mutations in the ATP7B gene. A clear demand for novel WD treatment strategies has emerged. Although therapies using zinc salts and copper chelators can effectively cure WD, these drugs exhibit limitations in a substantial pool of WD patients who develop intolerance and/or severe side effects. Several lines of research have indicated intriguing potential for novel strategies and targets for development of new therapies. Here, we review these new approaches, which comprise correction of ATP7B mutants and discovery of new compounds that circumvent ATP7B-deficiency, as well as cell and gene therapies. We also discuss whether and when these new therapeutic strategies will be translated into clinical use, according to the key requirements for clinical trials that remain to be met. Finally, we discuss the hope for the current rapidly developing research on molecular mechanisms underlying WD pathogenesis and for the related potential therapeutic targets to provide a solid foundation for the next generation of WD therapies that may lead to an effective, tolerable and safe cure. PMID- 28852305 TI - Are our endoscopy patients at risk for pyogenic liver abscess? AB - This is an editorial comment on a recent publication reporting an increased rate of pyogenic liver abscesses (PLAs) after upper gastrointestinal panendoscopy. Its aim is to critically highlight the findings, limitations and potential clinical implications of this study. Issues of the mucosal barrier, the microbial flora, administration of antibiotics and underlying diseases are discussed. The probability of PLAs after endoscopies is not exactly known and the length of the "incubation period" remains unclear, but a possible causality should already suffice to make us think how to avoid them. Especially in patients with risk factors such as diabetes mellitus, end-stage renal disease, liver cirrhosis, biliary tract infection, and malignancies, the potential risk for PLAs should be considered. Unnecessary insufflation during endoscopy (causing mucosal stretching and microscopic tears) as well as mucosal damage (by direct abrasion with the scope) should be avoided in order to limit the invasiveness of the procedure as much as possible. And, in everyday routine, it should be kept in mind that in patients after endoscopy, especially in those with a breach of the mucosal barrier and significant comorbidities, PLAs can potentially develop and require timely administration of antibiotics as well as further diagnostic and therapeutic steps. PMID- 28852306 TI - Pancreatitis: Preventing catastrophic haemorrhage. AB - Pancreatitis represents nearly 3% of acute admissions to general surgery in United Kingdom hospitals and has a mortality of around 1%-7% which increases to around 10%-18% in patients with severe pancreatitis. Patients at greatest risk were those identified to have infected pancreatic necrosis and/or organ failure. This review seeks to highlight the potential vascular complications associated with pancreatitis that despite being relatively uncommon are associated with mortality in the region of 34%-52%. We examine the current evidence base to determine the most appropriate method by which to image and treat pseudo aneurysms that arise as the result of acute and chronic inflammation of pancreas. We identify how early recognition of the presence of a pseudo-aneurysm can facilitate expedited care in an expert centre of a complex pathology that may require angiographic, percutaneous, endoscopic or surgical intervention to prevent catastrophic haemorrhage. PMID- 28852307 TI - Treating children with inflammatory bowel disease: Current and new perspectives. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gut characterised by alternating periods of remission and relapse. Whilst the mechanism underlying this disease is yet to be fully understood, old and newer generation treatments can only target selected pathways of this complex inflammatory process. This narrative review aims to provide an update on the most recent advances in treatment of paediatric IBD. A MEDLINE search was conducted using "paediatric inflammatory bowel disease", "paediatric Crohn's disease", "paediatric ulcerative colitis", "treatment", "therapy", "immunosuppressant", "biologic", "monitoring" and "biomarkers" as key words. Clinical trials, systematic reviews, and meta-analyses published between 2014 and 2016 were selected. Studies referring to earlier periods were also considered in case the data was relevant to our scope. Major advances have been achieved in monitoring the individual metabolism, toxicity and response to relevant medications in IBD including thiopurines and biologics. New biologics acting on novel mechanisms such as selective interference with lymphocyte trafficking are emerging treatment options. Current research is investing in the development of reliable prognostic biomarkers, aiming to move towards personalised treatments targeted to individual patients. PMID- 28852308 TI - Influence of gut microbiota on neuropsychiatric disorders. AB - The last decade has witnessed a growing appreciation of the fundamental role played by an early assembly of a diverse and balanced gut microbiota and its subsequent maintenance for future health of the host. Gut microbiota is currently viewed as a key regulator of a fluent bidirectional dialogue between the gut and the brain (gut-brain axis). A number of preclinical studies have suggested that the microbiota and its genome (microbiome) may play a key role in neurodevelopmental and neurodegenerative disorders. Furthermore, alterations in the gut microbiota composition in humans have also been linked to a variety of neuropsychiatric conditions, including depression, autism and Parkinson's disease. However, it is not yet clear whether these changes in the microbiome are causally related to such diseases or are secondary effects thereof. In this respect, recent studies in animals have indicated that gut microbiota transplantation can transfer a behavioral phenotype, suggesting that the gut microbiota may be a modifiable factor modulating the development or pathogenesis of neuropsychiatric conditions. Further studies are warranted to establish whether or not the findings of preclinical animal experiments can be generalized to humans. Moreover, although different communication routes between the microbiota and brain have been identified, further studies must elucidate all the underlying mechanisms involved. Such research is expected to contribute to the design of strategies to modulate the gut microbiota and its functions with a view to improving mental health, and thus provide opportunities to improve the management of psychiatric diseases. Here, we review the evidence supporting a role of the gut microbiota in neuropsychiatric disorders and the state of the art regarding the mechanisms underlying its contribution to mental illness and health. We also consider the stages of life where the gut microbiota is more susceptible to the effects of environmental stressors, and the possible microbiota-targeted intervention strategies that could improve health status and prevent psychiatric disorders in the near future. PMID- 28852309 TI - Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver disease. AB - AIM: To develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly. METHODS: Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls (n = 14), lanreotide (LAN: 3 mg/kg per 2 wk) (n = 10) or everolimus (EVR: 1 mg/kg per day) (n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene (quantitative RT-PCR) and protein expression (by Western blot) of the PI3K/AkT/mTOR signaling pathway was investigated. RESULTS: LV determination by MRI correlated excellent with the ex vivo measurements (r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were: (controls) +31.8%; (LAN) +5.1% and (EVR) +8.8%, indicating a significantly halt of LV progression compared with controls (respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis (P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt (Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/AkT/mTOR signaling cascade but acting at different molecular levels. CONCLUSION: Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR inhibition should be further explored in PCLD patients especially those that need immunosuppression. PMID- 28852310 TI - MicroRNA profile in neosquamous esophageal mucosa following ablation of Barrett's esophagus. AB - AIM: To investigate the microRNA expression profile in esophageal neosquamous epithelium from patients who had undergone ablation of Barrett's esophagus. METHODS: High throughput screening using TaqMan(r) Array Human MicroRNA quantitative PCR was used to determine expression levels of 754 microRNAs in distal esophageal mucosa (1 cm above the gastro-esophageal junction) from 16 patients who had undergone ablation of non-dysplastic Barrett's esophagus using argon plasma coagulation vs pretreatment mucosa, post-treatment proximal normal non-treated esophageal mucosa, and esophageal mucosal biopsies from 10 controls without Barrett's esophagus. Biopsies of squamous mucosa were also taken from 5 cm above the pre-ablation squamo-columnar junction. Predicted mRNA target pathway analysis was used to investigate the functional involvement of differentially expressed microRNAs. RESULTS: Forty-four microRNAs were differentially expressed between control squamous mucosa vs post-ablation neosquamous mucosa. Nineteen microRNAs were differentially expressed between post-ablation neosquamous and post-ablation squamous mucosa obtained from the more proximal non-treated esophageal segment. Twelve microRNAs were differentially expressed in both neosquamous vs matched proximal squamous mucosa and neosquamous vs squamous mucosa from healthy patients. Nine microRNAs (miR-424-5p, miR-127-3p, miR-98-5p, miR-187-3p, miR-495-3p, miR-34c-5p, miR-223-5p, miR-539-5p, miR-376a-3p, miR-409 3p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa. These microRNAs were also more highly expressed in Barrett's esophagus mucosa than matched proximal squamous and squamous mucosa from controls. Target prediction and pathway analysis suggests that these microRNAs may be involved in the regulation of cell survival signalling pathways. Three microRNAs (miR-187-3p, miR-135b-5p and miR-31 5p) were expressed at higher levels in post-ablation neosquamous mucosa than in matched proximal squamous and healthy squamous mucosa. These miRNAs were expressed at similar levels in pre-ablation Barrett's esophagus mucosa, matched proximal squamous and squamous mucosa from controls. Target prediction and pathway analysis suggests that these microRNAs may be involved in regulating the expression of proteins that contribute to barrier function. CONCLUSION: Neosquamous mucosa arising after ablation of Barrett's esophagus expresses microRNAs that may contribute to decreased barrier function and microRNAs that may be involved in the regulation of survival signaling pathways. PMID- 28852311 TI - Expression of Interleukin-26 is upregulated in inflammatory bowel disease. AB - AIM: To investigate interleukin (IL)-26 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and the function of IL-26. METHODS: Human colonic subepithelial myofibroblasts (SEMFs) were isolated from colon tissue surgically resected. The expression of IL-26 protein and its receptor complex was analyzed by immunohistochemistry. The gene expression induced by IL-26 was evaluated by real-time polymerase chain reaction. Intracellular signaling pathways were evaluated by immunoblotting and specific small interfering (si) RNA transfection. RESULTS: The mRNA and protein expression of IL-26 were significantly enhanced in the inflamed mucosa of patients with IBD. IL-26 receptor complex was expressed in colonic SEMFs in vivo and in vitro. IL-26 stimulated the mRNA expression of IL-6 and IL-8 in colonic SEMFs. The inhibitors of mitogen-activated protein kinases and phosphoinositide 3-kinase, and siRNAs for signal transducers and activator of transcription 1/3, nuclear factor-kappa B and activator protein-1 significantly reduced the mRNA expression of IL-6 and IL 8 induced by IL-26. CONCLUSION: These results suggest that IL-26 plays a role in the pathophysiology of IBD through induction of inflammatory mediators. PMID- 28852312 TI - Autophagic cell death induced by reactive oxygen species is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells. AB - AIM: To investigate whether autophagic cell death is involved in hyperthermic sensitization to ionizing radiation in human hepatocellular carcinoma cells, and to explore the underlying mechanism. METHODS: Human hepatocellular carcinoma cells were treated with hyperthermia and ionizing radiation. MTT and clonogenic assays were performed to determine cell survival. Cell autophagy was detected using acridine orange staining and flow cytometric analysis, and the expression of autophagy-associated proteins, LC3 and p62, was determined by Western blot analysis. Intracellular reactive oxygen species (ROS) were quantified using the fluorescent probe DCFH-DA. RESULTS: Treatment with hyperthermia and ionizing radiation significantly decreased cell viability and surviving fraction as compared with hyperthermia or ionizing radiation alone. Cell autophagy was significantly increased after ionizing radiation combined with hyperthermia treatment, as evidenced by increased formation of acidic vesicular organelles, increased expression of LC3II and decreased expression of p62. Intracellular ROS were also increased after combined treatment with hyperthermia and ionizing radiation. Pretreatment with N-acetylcysteine, an ROS scavenger, markedly inhibited the cytotoxicity and cell autophagy induced by hyperthermia and ionizing radiation. CONCLUSION: Autophagic cell death is involved in hyperthermic sensitization of cancer cells to ionizing radiation, and its induction may be due to the increased intracellular ROS. PMID- 28852313 TI - Yangzheng Sanjie decoction regulates proliferation and apoptosis of gastric cancer cells by enhancing let-7a expression. AB - AIM: To explore the let-7a-mediated anti-cancer effect of Yangzheng Sanjie decoction (YZSJD) in gastric cancer (GC) cells. METHODS: YZSJD-containing serum (YCS) was prepared using traditional Chinese medicine serum pharmacology methods. After YCS treatment, cell proliferation and apoptosis were assessed by cell counting kit-8 assay and flow cytometry, respectively, and miRNA expression profiles were determined using qPCR arrays. Let-7a expression was examined by in situ hybridization in GC tissues and by qPCR in GC cells. c-Myc protein expression was detected by immunohistochemistry in GC tissues, and by Western blot in cell lines. RESULTS: YZSJD significantly inhibited proliferation and induced apoptosis in AGS and HS-746T GC cells. After treatment with YCS, the miRNA expression profiles were altered and the reduced let-7a levels in both cell lines were up-regulated, accompanied by a decrease in c-Myc expression. Moreover, decreased let-7a expression and increased c-Myc expression were observed during the progression of gastric mucosa cancerization. CONCLUSION: YZSJD inhibits proliferation and induces apoptosis of GC cells by restoring the aberrant expression of let-7a and c-Myc. PMID- 28852314 TI - Crohn's disease environmental factors in the developing world: A case-control study in a statewide catchment area in Brazil. AB - AIM: To identify environmental risk factors associated with the development of Crohn's disease (CD) in order to re-assess the hygiene hypothesis. METHODS: A hospital-based, case-control study was carried out with CD patients (n = 145) and controls (n = 163) representing a socioeconomically diverse statewide catchment area in Brazil. Controls were recruited from caregivers of patients seen in different outpatient clinics at the same hospital. A multi-item survey with 94 questions regarding family history of CD, perinatal and childhood circumstances, living conditions, tobacco use and familial socioeconomic status was carried out by interviewers. RESULTS: On the univariate analysis, predictive variables for CD included being male, under age of 40, a high education level, urban dweller, smaller family size, exposure to enteric pathogens and user of treated water (P < 0.005). On the multivariate analysis, variables significantly associated with CD were male gender (OR = 2.09), under age 40 (OR = 3.10), white (OR = 2.32), from a small family in childhood (OR = 2.34) and adulthood (OR = 3.02), absence of viral infections in childhood (OR = 2.23), exposure to enteric pathogens (OR = 2.41), having had an appendectomy (OR = 2.47) and prior or current smoker (OR = 2.83/1.12). CONCLUSION: Most variables supporting the "hygiene hypothesis" are associated with the development of CD but are not independent predictors of the diagnosis. PMID- 28852315 TI - Postoperative bleeding in patients on antithrombotic therapy after gastric endoscopic submucosal dissection. AB - AIM: To investigated the relationship between postoperative bleeding following gastric endoscopic submucosal dissection (ESD) and individual antithrombotic agents. METHODS: A total of 2488 gastric neoplasms in 2148 consecutive patients treated between May 2001 and June 2016 were studied. The antithrombotic agents were categorized into antiplatelet agents, anticoagulants, and other antithrombotic agents, and we included combination therapies [e.g., dual antiplatelet therapy (DAPT)]. The risk factors associated with post-ESD bleeding, namely, antithrombotic agents overall, individual antithrombotic agents, withdrawal or continuation of antithrombotic agents, and bleeding onset period (during the first six days or thereafter), were analyzed using univariate and multivariate analyses. RESULTS: The en bloc resection and complete curative resection rates were 99.2% and 91.9%, respectively. Postoperative bleeding occurred in 5.1% cases. Bleeding occurred in 10.3% of the patients administered antithrombotic agents. Being male (P = 0.007), specimen size (P < 0.001), and antithrombotic agent used (P < 0.001) were independent risk factors for postoperative bleeding. Heparin bridging therapy (HBT) (P = 0.002) and DAPT/multidrug combinations (P < 0.001) were independent risk factors associated with postoperative bleeding. The bleeding rate of the antithrombotic agent continuation group was significantly higher than that of the withdrawal group (P < 0.01). Bleeding within postoperative day (POD) 6 was significantly higher in warfarin (P = 0.015), and bleeding after POD 7 was significantly higher in DAPT/multidrug combinations (P = 0.007). No thromboembolic events were reported. CONCLUSION: We must closely monitor patients administered HBT and DAPT/multidrug combinations after gastric ESD, particularly those administered multidrug combinations after discharge. PMID- 28852316 TI - Serous pancreatic neoplasia, data and review. AB - AIM: To describe the imaging features of serous neoplasms of the pancreas using ultrasound, endoscopic ultrasound, computed tomography and magnetic resonance imaging. METHODS: This multicenter international collaboration enhances a literature review to date, reporting features of 287 histologically confirmed cases of serous pancreatic cystic neoplasms (SPNs). RESULTS: Female predominance is seen with most SPNs presenting asymptomatically in the 5th through 7th decade. Mean lesion size was 38.7 mm, 98% were single, 44.2% cystic, 46% mixed cystic and solid, and 94% hypoechoic on B-mode ultrasound. Vascular patterns and contrast enhancement profiles are described as hypervascular and hyperenhancing. CONCLUSION: The described ultrasound features can aid differentiation of SPN from other neoplastic lesions under most circumstances. PMID- 28852317 TI - Pancreaticoduodenectomy for duodenal papilla carcinoma: A single-centre 9-year retrospective study of 112 patients with long-term follow-up. AB - AIM: To retrospectively evaluate the factors that influence long-term outcomes of duodenal papilla carcinoma (DPC) after standard pancreaticoduodenectomy (SPD). METHODS: This is a single-centre, retrospective study including 112 DPC patients who had a SPD between 2006 and 2015. Associations between serum levels of CA19-9 and CEA and various clinical characteristics of 112 patients with DPC were evaluated by the chi2 test and Fisher's exact test. The patients were followed-up every 3 mo in the first two years and at least every 6 mo afterwards, with a median follow-up of 60 mo (ranging from 4 mo to 168 mo). Survival analysis was conducted using the Kaplan-Meier survival and Cox proportional hazards model analysis. The difference in survival curves was evaluated with a log-rank test. RESULTS: In 112 patients undergoing SPD, serum levels of CA19-9 was associated with serum levels of CEA and drainage mode (the P values were 0.000 and 0.033, respectively); While serum levels of CEA was associated with serum levels of CA19 9 and differentiation of the tumour (the P values were 0.000 and 0.033, respectively). The serum levels of CA19-9 and CEA were closely correlated (chi2 = 13.277, r = 0.344, P = 0.000). The overall 5-year survival was 50.00% for 112 patients undergoing SPD. The Kaplan-Meier survival analysis showed that increased serum levels of CA19-9, CEA, and total bilirubin were correlated with a poor prognosis, as well as a senior grade of infiltration depth, lymph node metastases, and TNM stage(the P values were 0.033, 0.018, 0.015, 0.000, 0.000 and 0.000, respectively). Only the senior grade of infiltration depth and TNM stage retained their significance when adjustments were made for other known prognostic factors in Cox multivariate analysis (RR = 2.211, P = 0.022 and RR = 2.109, P = 0.047). CONCLUSION: For patients with DPC, the serum levels of CA19-9 and CEA were closely correlated, and play an important role in poor survival. Increased serum levels of total bilirubin and lymph node metastases were also correlated with a poor prognosis. The senior grade of infiltration depth and TNM stage can serve as independent prognosis indexes in the evaluation of patients with DPC after SPD. PMID- 28852318 TI - Efficacy and safety of Xiangsha Liujunzi granules for functional dyspepsia: A multi-center randomized double-blind placebo-controlled clinical study. AB - AIM: To assess the efficacy and safety of a Chinese herbal medicine (CHM), Xiangsha Liujunzi granules, in the treatment of patients with functional dyspepsia (FD). METHODS: We performed a randomized, double-blind, placebo controlled trial with patients from three centers. Two hundred and sixteen subjects diagnosed with FD according to ROME III criteria and confirmed by upper gastrointestinal endoscopy and spleen-deficiency and Qi-stagnation syndrome were selected to receive Xiangsha Liujunzi granules or placebo for 4 wk in a 2:1 ratio by blocked randomization. The subjects also received follow-up after the 4-wk intervention. Herbal or placebo granules were dissolved in 300 mL of water. Participants in both groups were administered 130 mL (45 degrees C) three times a day. Participants were evaluated prior to and following 4 wk of the intervention in terms of changes in the postprandial discomfort severity scale (PDSS) score, clinical global impression (CGI) scale score, hospital anxiety and depression scale (HADS) score, traditional Chinese medicine symptoms score (SS), scores of various domains of the 36-item short form health survey (SF-36), gastric emptying (GE) and any observed adverse effects. RESULTS: Compared with the placebo group, patients in the CHM group showed significant improvements in the scores of PDSS, HADS, SS, SF-36 and CGI scale (P < 0.05 or P < 0.01). They also showed the amelioration in the GE rates of the proximal stomach and distal stomach (P < 0.05 or P < 0.01). CONCLUSION: Xiangsha Liujunzi granules offered significant symptomatic improvement in patients with FD. PMID- 28852319 TI - Combination of acoustic radiation force impulse imaging, serological indexes and contrast-enhanced ultrasound for diagnosis of liver lesions. AB - AIM: To assess the value of combined acoustic radiation force impulse (ARFI) imaging, serological indexes and contrast-enhanced ultrasound (CEUS) in distinguishing between benign and malignant liver lesions. METHODS: Patients with liver lesions treated at our hospital were included in this study. The lesions were divided into either a malignant tumor group or a benign tumor group according to pathological or radiological findings. ARFI quantitative detection, serological testing and CEUS quantitative detection were performed and compared. A comparative analysis of the measured indexes was performed between these groups. Receiver operating characteristic (ROC) curves were constructed to compare the diagnostic accuracy of ARFI imaging, serological indexes and CEUS, alone or in different combinations, in identifying benign and malignant liver lesions. RESULTS: A total of 112 liver lesions in 43 patients were included, of which 78 were malignant and 34 were benign. Shear wave velocity (SWV) value, serum alpha-fetoprotein (AFP) content and enhancement rate were significantly higher in the malignant tumor group than in the benign tumor group (2.39 +/- 1.20 m/s vs 1.50 +/- 0.49 m/s, 18.02 +/- 5.01 ng/mL vs 15.96 +/- 4.33 ng/mL, 2.14 +/- 0.21 dB/s vs 2.01 +/- 0.31 dB/s; P < 0.05). The ROC curve analysis revealed that the areas under the curves (AUCs) of SWV value alone, AFP content alone, enhancement rate alone, SWV value + AFP content, SWV value + enhancement rate, AFP content + enhancement rate and SWV value + AFP content + enhancement rate were 85.1%, 72.1%, 74.5%, 88.3%, 90.4%, 82.0% and 92.3%, respectively. The AUC of SWV value + AFP content + enhancement rate was higher than those of SWV value + AFP content and SWV value + enhancement rate, and significantly higher than those of any single parameter or the combination of any two of parameters. CONCLUSION: The combination of SWV, AFP and enhancement rate had better diagnostic performance in distinguishing between benign and malignant liver lesions than the use of any single parameter or the combination of any two of parameters. It is expected that this would provide a tool for the differential diagnosis of benign and malignant liver lesions. PMID- 28852320 TI - Incidents and adverse events of endoscopic ultrasound-guided fine-needle aspiration for pancreatic cystic lesions. AB - AIM: To evaluate the diagnostic value and safety mainly regarding incidents of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for pancreatic cystic lesions (PCLs). METHODS: A total of 150 consecutive patients with suspected PCLs were prospectively enrolled from April 2015 to November 2016. We finally enrolled 140 patients undergoing EUS-FNA. We compared the diagnostic accuracy of EUS-FNA and pathological diagnosis, which is regarded as the gold standard, for PCLs. Patients undergoing EUS-FNA at least 1 wk preoperatively were monitored for incidents and adverse events to evaluate its safety. RESULTS: There were 88 (62.9%) women and 52 (37.1%) men among 140 patients, with a mean age of 50.1 (+/- 15.4) years. There were 67 cysts located in the head/uncinate of the pancreas and 67 in the body/tail, and 6 patients had at least 1 cyst in the pancreas. There were 75 patients undergoing surgery and 55 undergoing EUS-FNA with interval at least 1 wk before other operations, with 3 patients undergoing the procedure twice. The accuracy of EUS-FNA in differentiating benign and malignant lesions was 97.3% (73/75), while the accuracy of characterizing PCL subtype was 84.0% (63/75). The incident rate was 37.9% (22/58), whereas only 1 AE was observed in 58 cases. CONCLUSION: EUS-FNA is effective and safe for diagnosis of PCLs, however procedure-related incidents are common. Caution should be taken in patients undergoing EUS-FNA. PMID- 28852321 TI - Systematic review of giant gastric lipomas reported since 1980 and report of two new cases in a review of 117110 esophagogastroduodenoscopies. AB - AIM: To systematically review the syndrome of giant gastric lipomas, report 2 new illustrative cases. METHODS: Literature systematically reviewed using PubMed for publications since 1980 with following medical subject heading/keywords: ("giant lipoma") AND ("gastric") OR [("lipoma") and ("gastric") and ("bleeding")]. Two authors independently reviewed literature, and decided by consensus which articles to incorporate. Computerized review of pathology/endoscopy records at William Beaumont Hospitals, Royal Oak and Troy, Michigan, January 2005-December 2015, revealed 2 giant gastric lipomas among 117110 consecutive esophagogastroduodenoscopies (EGDs), which were thoroughly reviewed, including re review of original endoscopic photographs, radiologic images, and pathologic slides. RESULTS: Giant gastric lipomas are extremely rare: 32 cases reported since 1980, and 2 diagnosed among 117110 consecutive EGDs. Average patient age = 54.5 +/- 17.0 years old (males = 22, females = 10). Maximal lipoma dimension averaged 7.9 cm +/- 4.1 cm. Ulcerated mass occurred in 21 patients. Lipoma locations: antrum-17, body-and-antrum-4, antrum-intussuscepting-into-small intestine-3, body-2, fundus-1, and unspecified-5. Intramural locations included submucosal-22, subserosal-2, and unspecified-8. Presentations included: acute upper gastrointestinal (UGI) bleeding-19, abdominal pain-5, nausea/vomiting-5, and asymptomatic-3. Symptoms among patients with UGI bleeding included: weakness/fatigue-6, abdominal pain-4, nausea/vomiting-4, early-satiety-3, dizziness-2, and other-1. Their hemoglobin on admission averaged 7.5 g/dL +/- 2.8 g/dL. Patients with GI bleeding had significantly more frequently ulcers than other patients. EGD was extremely helpful diagnostically (n = 31 patients), based on characteristic endoscopic findings, including yellowish hue, well-demarcated margins, smooth overlying mucosa, and endoscopic cushion, tenting, or naked-fat signs. However, endoscopic mucosal biopsies were mostly non-diagnostic (11 of 12 non-diagnostic). Twenty (95%) of 21 abdominal CTs demonstrated characteristic findings of lipomas, including: well-circumscribed, submucosal, and homogeneous mass with attenuation of fat. Endoscopic-ultrasound showed characteristic findings in 4 (80%) of 5 cases: hyperechoic, well-localized, mass in gastric-wall layer-3. Transabdominal ultrasound and UGI series were generally less helpful. All 32 patients underwent successful therapy without major complications or mortality, including: laparotomy and full-thickness gastric wall resection of tumor using various surgical reconstructions-26; laparotomy-and-enucleation-2; laparoscopic-transgastric-resection-2; endoscopic-mucosal-resection-1, and other 1. Two new illustrative patients are reported who presented with severe UGI bleeding from giant, ulcerated, gastric lipomas. CONCLUSION: This systematic review may help standardize the endoscopic and radiologic evaluation and therapy of patients with this syndrome. PMID- 28852323 TI - Close congruence between Barcode Index Numbers (bins) and species boundaries in the Erebidae (Lepidoptera: Noctuoidea) of the Iberian Peninsula. AB - The DNA barcode reference library for Lepidoptera holds much promise as a tool for taxonomic research and for providing the reliable identifications needed for conservation assessment programs. We gathered sequences for the barcode region of the mitochondrial cytochrome c oxidase subunit I gene from 160 of the 176 nominal species of Erebidae moths (Insecta: Lepidoptera) known from the Iberian Peninsula. These results arise from a research project which constructing a DNA barcode library for the insect species of Spain. New records for 271 specimens (122 species) are coupled with preexisting data for 38 species from the Iberian fauna. Mean interspecific distance was 12.1%, while the mean nearest neighbour divergence was 6.4%. All 160 species possessed diagnostic barcode sequences, but one pair of congeneric taxa (Eublemma rosea and Eublemma rietzi) were assigned to the same BIN. As well, intraspecific sequence divergences higher than 1.5% were detected in four species which likely represent species complexes. This study reinforces the effectiveness of DNA barcoding as a tool for monitoring biodiversity in particular geographical areas and the strong correspondence between sequence clusters delineated by BINs and species recognized through detailed taxonomic analysis. PMID- 28852324 TI - The use of dielectric blood coagulometry in the evaluation of coagulability in patients with peripheral arterial disease. AB - BACKGROUND: Platelets and coagulation proteins contribute to the development of peripheral arterial disease, especially atherosclerotic disease. Several experimental studies have proven a significant correlation between hypercoagulability and atherosclerosis. We used dielectric blood coagulometry, which was initially designed to evaluate the coagulable status, to examine the coagulability of peripheral arterial disease patients, and investigated the factors that were significantly correlated with the results. METHODS: We performed dielectric blood coagulometry in 49 peripheral arterial disease patients. In addition, we recorded the patients' demographic information, including the presence of comorbidities, hemodynamic status, and laboratory findings. To investigate coagulability, we calculated the Tmax value, which indicates the time from recalcification to maximum normalized permittivity. RESULTS: The Tmax values of diabetes mellitus patients were significantly lower than those of non-diabetic patients (1 MHz, P = 0.010; 10 MHz, 0.011). Furthermore, the Tmax value was statistically correlated with the activated partial thromboplastin time (1 MHz, rho = 0.286, P = 0.048; 10 MHz, rho = 0.301, P = 0.037). CONCLUSIONS: Dielectric blood coagulometry detected the hypercoagulable status in diabetes mellitus patients, and reflected their level of coagulability, which was also evaluated by the activated partial thromboplastin time. PMID- 28852322 TI - Acute colonic pseudo-obstruction: A systematic review of aetiology and mechanisms. AB - AIM: To critically review the literature addressing the definition, epidemiology, aetiology and pathophysiology of acute colonic pseudo-obstruction (ACPO). METHODS: A systematic search was performed to identify articles investigating the aetiology and pathophysiology of ACPO. A narrative synthesis of the evidence was undertaken. RESULTS: No consistent approach to the definition or reporting of ACPO has been developed, which has led to overlapping investigation with other conditions. A vast array of risk factors has been identified, supporting a multifactorial aetiology. The pathophysiological mechanisms remain unclear, but are likely related to altered autonomic regulation of colonic motility, in the setting of other predisposing factors. CONCLUSION: Future research should aim to establish a clear and consistent definition of ACPO, and elucidate the pathophysiological mechanisms leading to altered colonic function. An improved understanding of the aetiology of ACPO may facilitate the development of targeted strategies for its prevention and treatment. PMID- 28852325 TI - Primary ovarian angiosarcoma in a 12- year -old girl: a case report of an exceptional localization in a context of limited resources country. AB - BACKGROUND: Ovarian sarcomas represent less than 1% of all ovary cancers and usually are frequent in adults. Primary angiosarcomas are exceptional in the ovaries within children. CASE PRESENTATION: We reported a case of primary ovarian angiosarcoma in a 12-year-old girl in a resource-constrained context. Immunohistochemistry study showed the positivity of CD34, CD31, factor VIII, while S100 was negative. The diagnosis of primary non-metastatic angiosarcoma was retained. She was unable to undergo the CWS-2002P chemotherapy since her parents could not afford it. CONCLUSION: This case report described a rare type of a primary ovarian angiosarcoma within a child, diagnosed in a low-income country in a laboratory with limited resources. PMID- 28852326 TI - Cost-effectiveness analysis of a universal mass vaccination program with a PHiD CV 2+1 schedule in Malaysia. AB - BACKGROUND: Currently, two pediatric pneumococcal conjugate vaccines are available in the private market of Malaysia-13-valent pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide and non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV). This study aimed to evaluate the cost-effectiveness of a universal mass vaccination program with a PHiD-CV 2+1 schedule versus no vaccination or with a PCV13 2+1 schedule in Malaysia. METHODS: A published Markov cohort model was adapted to evaluate the epidemiological and economic consequences of programs with no vaccination, a PHiD-CV 2+1 schedule or a PCV13 2+1 schedule over a 10-year time horizon. Disease cases, deaths, direct medical costs, quality-adjusted life-years (QALYs) and incremental cost effectiveness ratios (ICERs) were estimated. Locally published epidemiology and cost data were used whenever possible. Vaccine effectiveness and disutility data were based on the best available published data. All data inputs and assumptions were validated by local clinical and health economics experts. Analyses were conducted from the perspective of the Malaysian government for a birth cohort of 508,774. Costs and QALYs were discounted at 3% per annum. One-way and probabilistic sensitivity analyses were performed. RESULTS: Compared with no vaccination, a PHiD-CV 2+1 program was projected to prevent 1109 invasive pneumococcal disease (IPD), 24,679 pneumonia and 72,940 acute otitis media (AOM) cases and 103 IPD/pneumonia deaths over 10 years, with additional costs and QALYs of United States dollars (USD) 30.9 million and 1084 QALYs, respectively, at an ICER of USD 28,497/QALY. Compared with a PCV13 2+1 program, PHiD-CV 2+1 was projected to result in similar reductions in IPD cases (40 cases more) but significantly fewer AOM cases (30,001 cases less), with cost savings and additional QALYs gained of USD 5.2 million and 116 QALYs, respectively, demonstrating dominance over PCV13. Results were robust to variations in one-way and probabilistic sensitivity analyses. CONCLUSIONS: A PHiD-CV 2+1 universal mass vaccination program could substantially reduce pneumococcal disease burden versus no vaccination, and was expected to be cost-effective in Malaysia. A PHiD-CV 2+1 program was also expected to be a dominant choice over a PCV13 2+1 program in Malaysia. PMID- 28852327 TI - Dynamic Fixation of Humeral Shaft Fractures Using Active Locking Plates: A Prospective Observational Study. AB - BACKGROUND: Rigid locked plating constructs can suppress fracture healing by inhibiting interfragmentary motion required to stimulate natural bone healing by callus formation. Dynamic fixation with active locking plates reduces construct stiffness, enables controlled interfragmentary motion, and has been shown to induce faster and stronger bone healing in vivo compared to rigid locking plates. This prospective observational study represents the first clinical use of active locking plates. It documents our early clinical experience with active plates for stabilization of humeral shaft fractures to assess their durability and understand potential complications. METHODS: Eleven consecutive patients with humeral shaft fractures (AO/OTA types 12 A-C) were prospectively enrolled at a level I and a level II trauma center. Fractures were stabilized by using active locking plates without supplemental bone graft or bone morphogenic proteins. The screw holes of active locking plates are elastically suspended in elastomer envelopes inside the plate, enabling up to 1.5 mm of controlled interfragmentary motion. Progression of fracture healing and integrity of implant fixation was assessed radiographically at 3, 6, 12, and 24 weeks post surgery. Patient reported functional outcome measures were obtained at 6, 12, and 24 weeks post surgery. The primary endpoint of this study was plate durability in absence of plate bending or breakage, or failure of the elastically suspended locking hole mechanism. Secondary endpoints included fracture healing, complications requiring revision surgery, and functional outcome scores. RESULTS: The eleven patients had six simple AO/ OTA type 12A fractures, three wedge type 12B fractures, and two comminuted type 12C fracture, including one open fracture. All active locking plates endured the 6-month loading period without any signs of fatigue or failure. Ten of eleven fractures healed at 10.9 +/- 5.2 weeks, as evident by bridging callus and pain-free function. One fracture required revision surgery 37 weeks post surgery due to late fixation failure at the screwbone interface in the presence of a atrophic delayed union. The average Disability of the Arm, Shoulder and Hand (DASH) score improved from 31 +/- 22 at week 6 to 13 +/- 15 by week 24, approaching that of the normal, healthy population (DASH = 10.1). By week 12, the difference between Constant shoulder scores, expressed as the difference between the affected and contralateral arm (8 +/- 8), was considered excellent. By week 24, the SF-12 physical health score (44 +/- 9) and mental health score (48 +/- 11) approached the mean value of 50 that represents the norm for the general U.S. population. CONCLUSION: Absence of failure of the plate and locking holes suggests that dynamic fixation of humeral shaft fractures with active plates provides safe and effective fixation. Moreover, early callus bridging and excellent functional outcome scores suggest that dynamic fixation with active locking plates may promote increased fracture healing over standard locked plating. PMID- 28852328 TI - Optimizing Hybrid Plate Fixation with a Locked, Oblique End Screw in Osteoporotic Fractures. AB - BACKGROUND: The end screw in a fracture plate creates the greatest resistance to bending. For osteoporotic fractures treated with plates, there is some question as to the optimal screw insertion technique for the screw farthest from the fracture. A locked, oblique end screw was previously shown to increase resistance to periprosthetic fracture. It is unknown, however, how this end screw configuration would resist pullout when subjected to bending. METHODS: Narrow, low contact 3.5 mm locking compression plates with 6 and 12 holes were anchored to simulated bone material with material properties representing osteoporotic bone. Four configurations were evaluated for the end screw: perpendicular and angulated 30 degrees away from the fracture for both non-locked and locked screws (n=6 per group). The constructs were subjected to 3 point bending until the peak load and finally total construct failure was achieved. RESULTS: Peak force, stiffness, energy to peak load, and the failure mode of each construct were determined. All four 12-hole construct groups failed by gross plastic bending deformation of the plate at the fulcrum past a previously established clinically relevant limit for failure (15 degrees ). All 12-hole plate constructs failed at statistically higher loads and energy than any of the 6-hole plate constructs, with the exception of the 6-hole locked, oblique construct. CONCLUSION: The locked, oblique end screw provides equivalent pull out strength for 3.5 mm low contact plates regardless of plate length. Combined with its resistance to periprosthetic fracture, this end screw configuration appears to be the best option for the construct integrity of hybrid plating for osteoporotic fractures. CLINICAL RELEVANCE: Osteoporotic fractures are challenging to treat. The current study and the existing literature show that resistance to both bending loads and refracture at the end of a plate are minimized with a locked screw angled away from the fracture. PMID- 28852329 TI - Fascia Iliaca Block for Reduction of Anterior Native Hip Dislocation: a Case Report. AB - Native hip dislocations require urgent reduction in a setting where adequate sedation and analgesia is essential. We have recently implemented the use of fascia iliaca blocks at our institution for preoperative pain management for patients with proximal femur fractures. In the setting of limited resources, alternate modalities for sedation and analgesia may need to be implemented to obtain a timely reduction for hip dislocations. We present a case report where of the use of a fascia iliaca block along with light sedation to obtain a successful, atraumatic reduction of an anterior dislocation of a native hip joint. While many hip dislocations may require a deeper level of sedation and muscle relaxation for successful reduction, the current report suggests that fascia iliaca blocks provide adequate analgesia for the procedure and may be helpful in the setting of limited resources. PMID- 28852330 TI - Femoral Iatrogenic Subtrochanteric Fatigue Fracture Risk is not Increased by Placing Drill Holes Below the Level of the Lesser Trochanter. AB - BACKGROUND: Iatrogenic subtrochanteric fractures of the femur can occur postoperatively following placement of screws in the lateral femoral cortex. Drilling holes below the lesser trochanter is generally avoided to prevent fatigue failure; however, there is little biomechanical evidence to support this recommendation. We hypothesized that hole placement below the level of the lesser trochanter will not accelerate fatigue failure compared to holes at the level of the lesser trochanter. METHODS: Twelve matched-pairs of male fresh-frozen cadaveric femurs were used for biomechanical testing. A single screw hole was drilled through the lateral femoral cortex either at the level of the lesser trochanter (proximal-hole group) or below the lesser trochanter (distal-hole group). Each femur was cycled to failure using a physiologically-relevant loading model. Paired t-test was used to evaluate for a difference in cycles to failure between groups. RESULTS: There was no statistical difference in cycles to failure between the groups with the hole drilled at or below the lesser trochanter. CONCLUSIONS: The traditional recommendation to avoid drilling holes below the level of the lesser trochanter is based mainly on experience and case reports in the literature. The results of this study indicate that placing holes below the level of the lesser trochanter, in and of itself, may not pose any additional risk of fracture. Other important factors need to be considered, such as tapering of the lateral femoral cortex. CLINICAL RELEVANCE: There are often situations where the patient's anatomy and facture pattern is more conducive to placing a screw distal to the lesser trochanter. This study may allow surgeons greater flexibility in placing screws more distally in the lateral femoral cortex by demonstrating the safety of doing so, at least in the population studied. PMID- 28852331 TI - Conversion Total Hip Arthroplasty After Failed Basicervical Hip Fracture Fixation: A Case Report and Review of Literature. AB - Proximal femur fractures are a common orthopedic injury, and it is estimated that their prevalence will continue to increase over the next twenty years. There has been much debate over the optimal management of basicervical fractures, which can be difficult to identify radiographically. There is also a role for conversion total hip arthroplasty in patients where fracture fixation fails. We present a case report of a proximal femur fracture managed as a basicervical fracture, and subsequently needing a conversion arthroplasty and revision surgery. We also review the literature to identify the complexities of basicervical fractures and conversion arthroplasty. PMID- 28852332 TI - Radiographic Risk Factors For Interprosthetic Femur Fractures. AB - PURPOSE: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are among the most common orthopaedic procedures performed in the United States annually. As the number of patients undergoing these procedures increases so too does the incidence of periprosthetic femur fractures. A number of these periprosthetic fractures occur between two ipsilateral implants, so-called interprosthetic fractures. Recent biomechanical data has challenged the importance of these interprosthetic distances, relating that cortical width and osteoporotic bone are more closely correlated with fracture than interprosthetic distance. The purpose of the current study is to further define the presence of osteoporosis, cortical width (CW) and medullary diameter (MD) as potential predictive factors for interprosthetic femur fractures. METHODS: Current Procedural Terminology (CPT) codes were used to identify a cohort of patients undergoing operative treatment for periprosthetic femur fractures. A review of the medical records identified 23 patients (5 male / 18 female) with a femur fracture between two intramedullary implants. CPT codes were also used to identify a second cohort of 25 patients (8 male / 17 female) having undergone ipsilateral THA and TKA. The intact femoral isthmus was identified radiographically and the MD and CW (mm) were measured. A ratio of MD to CW was also determined. Chart review was undertaken and any diagnosis of osteoporosis was recorded. An independent sample T-test was performed comparing the mean MD, CW, and the ratio of MD:CW for these groups. Significance was set at p. PMID- 28852333 TI - Perioperative Considerations When Treating Isolated Periprosthetic Distal Femur Fractures. AB - BACKGROUND: Periprosthetic distal femur (PPDF) fractures occur most frequently via low energy mechanisms in elderly patients. This population is often frail and ill-suited to the physiologic burden of trauma and surgery. Here, we describe the perioperative and early hospital course for patients with PPDF fractures, and identify risk factors for poor outcomes. METHODS: Consecutive patients with isolated PPDF fractures from 2005 - 2015 were treated operatively at a Level I trauma center. Perioperative records were reviewed. Complications included wound complications, cardiac complications, pneumonia, thromboembolic events, urinary tract infections (UTIs), sepsis, multiple organ failure, death, and 90-day readmissions. RESULTS: Thirty-nine patients were treated operatively for isolated PPDF fractures. Mean age was 75.1 years old, 87.2% were women, and 92.3% occurred after falls from standing. Average American Society of Anesthesiologists score was 3.0. Thirty-six patients underwent open reduction and internal fixation with a mean operative time of 108 minutes. Excluding outliers, mean LOS was 4.6 days. Patients admitted to the ICU had longer LOS (p=0.03). Complications occurred in 17.9% of patients, including cardiac events (12.8%) and (5.1%) deaths. CONCLUSIONS: Patients with PPDF fractures frequently have underlying medical comorbidities. A complicated and/or protracted hospital course is not uncommon. Further study to optimize treatment appears warranted. Level of evidence: Prognostic, level 4. PMID- 28852334 TI - Should All Shoulder Dislocations be Closed Reduced? Assessment of Risk of Iatrogenic Injury in 150 Patients. AB - AIMS: The purpose of this study was to determine if there was an association between iatrogenic fractures and closed reduction of shoulder dislocations. PATIENTS AND METHODS: In a retrospective case series, 150 consecutive patients with acute first time shoulder dislocations were evaluated. Patient demographics, direction of dislocation, associated injuries, reduction methods, number of attempts, and type of anesthesia/analgesia were determined. Pre- and post reduction radiographs and medical record were reviewed to identify the presence of proximal humerus fractures. RESULTS: There were thirty nine fracture dislocations (26%) of the proximal humerus. Eight patients (5%) failed reduction on initial attempt. Four of these (3%) were unable to be reduced in the emergency room and were taken to OR for reduction. There was no statistically significant difference in reduction maneuver or type of anesthesia/analgesia used when comparing fracture-dislocations to dislocations only (p<0.05). No new fractures after reduction were identified. CONCLUSION: Iatrogenic fractures of the proximal humerus due to reduction of a shoulder dislocation are extremely rare. None were identified in this review of 150 patients. We believe that closed reduction is safe even in the setting of fracture dislocations. PMID- 28852335 TI - Proximal Humerus Fracture-Dislocation with Laceration of the Axillary Artery: A Case Report. AB - BACKGROUND: Proximal humerus fractures account for approximately 4-6% of all fractures. While the majority of these fractures are treated non-operatively, the amount of fracture displacement, concomitant injuries, and patient factors often result in the need for surgical stabilization. Although concomitant neurovascular injury in the setting of low-energy trauma is rare, injury to the surrounding neurovascular structures have previously been reported. METHODS: We report a case of a 79-year-old male who sustained a low energy fall resulting in a two-part fracture dislocation of the proximal humerus with an associated brachial plexopathy and axillary artery laceration. The patient underwent emergent open reduction internal fixation of his fracture in addition to an axillary-brachial artery bypass using a reverse-saphenous vein graft. The current article reports the presentation, management and prognosis of this rare injury. RESULTS: At 6 months, the patient demonstrated limited active shoulder abduction with no observed motor function at this elbow, wrist or hand. Radiographic follow up demonstrated a reduced glenohumeral joint with evidence avascular necrosis of the humeral head. CONCLUSION: Fracture-dislocations of the proximal humerus may be associated with significant neurovascular injury in the setting of low energy trauma. Despite early treatment, the prognosis of patients with this constellation of injuries is guarded. PMID- 28852336 TI - Tibial Plateau Fractures: A New Rank Ordering Method For Determining To What Degree Injury Severity Or Quality Of Reduction Correlate With Clinical Outcome. AB - BACKGROUND: Injury severity may be the most important factor in determining outcome after articular fractures, but there is a surprising paucity of clinical evidence to support this assertion. The purpose of this study was to utilize a new method for rank ordering a group of patient radiographs to assess the effect of injury severity and quality of reduction on patient outcomes after tibial plateau fractures. METHODS: Tibial plateau fractures in 64 patients were treated operatively or non-operatively based on physician preference from standard of care techniques. Fracture severity and reduction quality were stratified from radiographs by four expert clinicians using an iTunes-based rank ordering methodology. The images were distributed electronically, and the ranks were performed on local computers at three different institutions. Clinical outcomes were measured with the SF-12 health questionnaire and the Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: There was excellent or very good agreement between raters for injury severity ranking (correlation 0.77-0.91) and quality of reduction (correlation 0.66-0.82). There was no correlation between the injury severity nor quality of reduction and general or joint-specific clinical outcomes. CONCLUSIONS: Expert orthopaedic traumatologists strongly agree on how to rank order tibial plateau fractures based both on injury severity and quality of reduction. The novel electronic interface utilized allows an ever expanding series of cases to be ranked quickly, conveniently, and across multiple centers. This interface holds great promise for establishing prospective, continuously expanding rank orders of various fracture types, which may have great value for clinical research, education about fracture severity, and for prognosis and treatment decisions. In the present study, neither injury severity nor quality of reduction correlated with the clinical outcomes. Other patient- and injury-related factors may be more important in determining clinical outcome of tibial plateau fractures than the appearances of the radiographs at the time of injury or after reduction. Level of Evidence: level III evidence. PMID- 28852337 TI - Injuries in Collegiate Wrestlers at an Elite Division I NCAA Wrestling Program: An Epidemiological Study. AB - BACKGROUND: Injury is common in the sport of wrestling. More than 6000 athletes compete in NCAA wrestling yearly. Despite this popularity, little is known about the epidemiology of wrestlers' injuries and factors affecting return to competition. We hypothesized that patterns of injury and associated factors influence return to participation. METHODS: Retrospective database review of one Division I NCAA wrestling program over nine seasons (2002 to 2011). RESULTS: From 2002 to 2011, 125 wrestlers were varsity participants at a single NCAA Division I program. Among these wrestlers, there were 4275 exposures per year on average. We identified 1034 musculoskeletal injuries, skin injuries, and concussions in 120 athletes (96% of participants). Eighty-two percent of athletes missed at least one day secondary to these injuries, while 69% were unable to compete in at least one match. The injury rate was estimated at 19.6 (SD 16.5) per 1000 exposures. The rate of injuries requiring surgery was estimated at 1.4 (SD 2.1) per 1000 exposures. Weight class, record, age at injury, and eligibility status did not affect the rate or type of injury. A significant difference was noted in the athletes who returned to competition following surgery. Athletes who returned to competition after surgical treatment for an injury ultimately competed in more matches (62.4 vs 18.2, p < 0.001), had more wins (45.2 vs 12.1, p<0.001) and a higher win percentage (67.5 vs 51.2 p < 0.01) than those who did not return following surgery. CONCLUSION: Return to competition in collegiate wrestling is dependent on many factors in addition to severity of injury and surgery type. There is a positive association between return to sport and success as a collegiate wrestler. Our findings will be helpful to wrestlers and coaches in guiding expectations after injury. Level of Evidence: Level 4 diagnostic. PMID- 28852338 TI - Evaluating Different Clinical Diagnosis of Anterior Cruciate Ligament Ruptures In Providers with Different Training Backgrounds. AB - INTRODUCTION: Previous studies have shown that provider training and the tests performed play a role in the accuracy of diagnosis of anterior cruciate ligament (ACL) injuries. The specific aim of the current study is to determine the examiner proficiency and accuracy in performing the different proactive tests of ACL rupture before and after the induction of anesthesia prior to a definitive surgical procedure. MATERIALS AND METHODS: A case series was performed from January of 2015 through July of 2015. Two examiners were included (an experienced orthopaedic sports surgeon with more than 16 years in practice and an experienced orthopaedic physician assistant with 6 years of clinical experience in orthopaedic sports medicine). Three different physical examination tests were used before and after the induction of anesthesia to the patient: 1) Lachman test, 2) pivot shift test, and 3) Lelli test. Relevant patient demographic information such as BMI, thigh girth, and calf girth were recorded. Diagnosis of ACL rupture had been established pre-operatively. RESULTS: Thirty three patients met the inclusion criteria (males: 21 (64%), female: 12 (36%)). High percent of false negative was found with pivot shift test for both before and after anesthesia when compared to the other two tests. The Lelli test seemed to be most favorable to both the surgeon and the physician assistant with at least 67% favorable, while the pivot shift was least often felt to be the most useful test. No relationship was found for either patients' thigh or patients' calf girths with the physical examination test results for both examiners for any of the three tests (p = 0.110). CONCLUSION: The diagnostic accuracy and limitations of the various tests for ACL injury need to be understood. Clinically, it is recommended performing at least two different examinations, as each test has its own specific limitations. Level of Evidence: III- Prospective Cohort Study without blinding. PMID- 28852339 TI - Case Report: Snapping Biceps Femoris Tendon Due to Abnormal Fibular Morphology. AB - BACKGROUND: Several cases of snapping biceps femoris tendons have been reported with anomalous insertions of the distal tendon insertion or in the context of trauma. There are only three published cases due to abnormal fibular head morphology. METHODS/RESULTS: We present a case of unilateral snapping of the biceps femoris tendon in a 19 year old. We decided to proceed with surgery after the patient failed a trial of non-operative treatment and had significant functional limitations. Surgical exploration of the posterolateral knee showed a prominent ridge on the posterior aspect of the fibular head over which the biceps femoris tendon was snapping with deep knee flexion. The bony ridge was resected, leaving surrounding structures intact, including the insertion of the biceps femoris tendon. The patient experienced resolution of snapping symptoms and associated pain. CONCLUSIONS: Although rare, snapping of the biceps femoris tendon can cause pain and functional limitation. In this case, resection of a prominent ridge on the fibular head resolved snapping and pain. Level of evidence: Level five. PMID- 28852340 TI - Thickness of the Rotator Cuff Tendons at the Articular Margin: An Anatomic Cadaveric Study. AB - BACKGROUND: With a substantial portion of the population experiencing rotator cuff pathology, the importance of understanding mechanisms of rotator cuff disease remains critical. Current research aimed at understanding relationships between shoulder movement and cuff injuries has been hindered by our limited knowledge of the thickness of soft tissue structures within the shoulder. Therefore, the purpose of this study is to measure the thicknesses of all four rotator cuff tendons at the articular margin. METHODS: An anatomic study of 21 cadaveric shoulders was conducted. The thicknesses of the four rotator cuff tendon insertions were measured by caliper at the articular margin. RESULTS: The mean thickness of the supraspinatus at the articular margin was 4.9 mm +/- 2.1 (median: 4.2 mm, range: 2.9-12.7 mm). The mean thickness of the infraspinatus tendon was 4.9 mm +/- 1.3 (median: 4.8 mm, range: 3.0-7.2 mm). The mean thickness of the teres minor tendon was 3.20 mm +/- 1.14 (median: 2.9 mm, range: 1.7-5.7 mm). Finally, the mean thickness of the subscapularis tendon at the articular margin was 5.5 mm +/- 1.3 (median: 5.5 mm, range: 3.5-9.3 mm). CONCLUSIONS: This current study provides needed objective data about the thickness of the rotator cuff tendons at the articular margin. Data regarding the infraspinatus, teres minor and teres major, which have been largely understudied, are particularly important. In addition, the current study demonstrates that rotator cuff thicknesses can vary substantially between individuals. There are likely natural age related changes as well as changes from etiologies that are not yet elucidated. Clinical Relevance: Data from this study will allow for improved modelling accuracy of soft tissue structures specific to the shoulder. Eventually knowledge gained through study of shoulder mechanics can be used to pursue prevention of rotator cuff tears and improve targeted treatment planning. PMID- 28852341 TI - Age Differences in the Prevalence of Isolated Medial and Lateral Meniscal Tears in Surgically Treated Patients. AB - PURPOSE: To compare the prevalence of isolated lateral and medial meniscal tears in different aged populations. METHODS: A five-year retrospective review for meniscal procedures performed on a total of 782 patients. Each chart was reviewed to document the prevalence of medial or lateral meniscal injuries. Inclusion criteria were patients found to have documented evidence of meniscal tear, either lateral or medial, without any concomitant injuries and/or any other procedures performed. Patients excluded from the study were those with concomitant pathologies, such as chondromalacia, malalignment or ligamentous injuries. Patients were classified by age into three groups: < 20 years, 20-30 years and > 30 years old. RESULTS: 68.7% of patients had medial meniscal tears, (average age 37.6 years), 17.1% of these were isolated medial meniscus injuries (average 31.9 years). 31.3% had lateral meniscal injuries (average 27.7 years). Of these, 18.8 % had isolated lateral meniscal injuries (average 22.8 years). All remaining patients had additional diagnoses/procedures. Isolated medial meniscal injuries were more common in older patients as 48 of the 92 isolated medial tears (52.2%) were found in patients > 30 years of age (p <0.001). Isolated lateral meniscal injuries, on the other hand, were more common in younger patients. 29 of the 46 isolated lateral tears (63%) occurred in patients under 20 years (p = 0.002). Only seven (15.2%) isolated lateral tears were shown in patients older than 30 years. CONCLUSION: Isolated lateral meniscal tears are more common in patients < 20 years, and decrease with age, while the prevalence of medial meniscal tears increase with age. PMID- 28852342 TI - Strength of Resistance to "Flip" the Tightened Half-Hitches of an Arthroscopic Knot. AB - PURPOSE: The purpose of this study was to biomechanically determine the minimum strength required to "flip" a seated and tightened half-hitch in a knot of different braided polyblend sutures. METHODS: ForceFiber, FiberWire, Orthocord, and Ultrabraid were evaluated. All knot tying processes began by advancing an initial base knot down to a standardized rod. All half-hitches were tied using a single-hole knot pusher in a dry environment, and were tightened with 45N by using past-pointing maneuver. A tension was then deliberately applied to the wrapping suture limb until a "flip" occurred, and the amount of tension was measured by the load cell. Three trials for each half-hitch and 3 half-hitches for each arthroscopic knot with 12 knots of each material were tied. All respective tension loads were collected through the digital video recordings (knot closeup view and load cell reading). RESULTS: Orthocord was the easiest to "flip" a seated and tightened half-hitch (average: 10+/-3N), whereas Ultrabraid was hardest to "flip" (average: 23+/-7N). ForceFiber and FiberWire were about 49% and 15% more resistance to "flip" when compared to Orthocord. After each trial of flipping the half-hitch back and re-tightened, there was a significant reduction in strength required to "flip" the tightened half-hitch. CONCLUSION: 1) The unintentional minimum tensile strength greater than 10N applied to the wrapping suture limb on the seated and tightened half-hitch could potentially "flip" the half-hitch in a knot during arthroscopic procedures, and 2) different braided suture material has an affect on the tensile strength to "flip" a seated and tightened half-hitch in an arthroscopic knot. CLINICAL RELEVANCE: The findings of this study indicated that even a seated and tightened half-hitch in an arthroscopic knot could easily be "flipped" if an unintentional tension was applied to the wrapping suture limb, and thereby reduced the knot security strength. In addition different suture materials could have an effect on the strength needed to "flip" the tightened half-hitch. PMID- 28852343 TI - Finite Element Analysis of Patella Alta: A Patellofemoral Instability Model. AB - BACKGROUND: This study aims to provide biomechanical data on the effect of patella height in the setting of medial patellofemoral ligament (MPFL) reconstruction using finite element analysis. The study will also examine patellofemoral joint biomechanics using variable femoral insertion sites for MPFL reconstruction. METHODS: A previously validated finite element knee model was modified to study patella alta and baja by translating the patella a given distance to achieve each patella height ratio. Additionally, the models were modified to study various femoral insertion sites of the MPFL (anatomic, anterior, proximal, and distal) for each patella height model, resulting in 32 unique scenarios available for investigation. RESULTS: In the setting of patella alta, the patellofemoral contact area decreased, resulting in a subsequent increase in maximum patellofemoral contact pressures as compared to the scenarios with normal patellar height. Additionally, patella alta resulted in decreased lateral restraining forces in the native knee scenario as well as following MPFL reconstruction. Changing femoral insertion sites had a variable effect on patellofemoral contact pressures; however, distal and anterior femoral tunnel malpositioning in the setting of patella alta resulted in grossly elevated maximum patellofemoral contact pressures as compared to other scenarios. CONCLUSIONS: Patella alta after MPFL reconstruction results in decreased lateral restraining forces and patellofemoral contact area and increased maximum patellofemoral contact pressures. When the femoral MPFL tunnel is malpositioned anteriorly or distally on the femur, the maximum patellofemoral contact pressures increase with severity of patella alta. CLINICAL RELEVANCE: When evaluating patients with patellofemoral instability, it is important to recognize patella alta as a potential aggravating factor. Failure to address patella alta in the setting of MPFL femoral tunnel malposition may result in even further increases in patellofemoral contact pressures, making it essential to optimize intraoperative techniques to confirm anatomic MPFL femoral tunnel positioning. PMID- 28852344 TI - Total Shoulder Arthroplasty: Is Less Time in the Hospital Better? AB - BACKGROUND: The incidence of total shoulder arthroplasty (TSA) has increased significantly over the last decade. Short-stay protocols for other highvolume procedures have been shown to be safe and effective but have yet to be fully explored for TSA. Our purpose in comparing short-stay and inpatient TSA was to determine: (1) patient demographics and comorbidities, (2) 30-day morbidity, mortality, and readmissions using a matched analysis, and (3) independent predictors of 30-day complications. METHODS: The American College of Surgeons National Surgical Quality Improvement (ACS NSQIP) database was queried and all patients undergoing elective, primary TSA between 2006 and 2013 were identified. Patients were categorized as short-stay or inpatient based on day of discharge. Propensity score matching was used to adjust for selection bias. Univariate and multivariate statistical analysis was used to compare 30-day morbidity and mortality between the two cohorts. RESULTS: Overall, 4,619 cases were available, with inpatient admission occurring in 65.7% of patients. Prior to propensity score matching, short-stay patients were significantly younger, more frequently male, with fewer comorbid conditions. After matching, inpatient admission was associated with increased rates of urinary tract infection (1.1% vs. 0.1%; p = 0.001), blood transfusion (5.3% vs. 0.8%; p < 0.001), and total complications (4.7% vs. 1.8%; p < 0.001). Multivariate analysis identified inpatient admission as an independent risk factor for 30-day complication following TSA. CONCLUSIONS: Short-stay TSA is a safe option for the appropriately selected patient. Inpatient admission was an independent risk factor for complication following TSA. Level of Evidence: III. PMID- 28852345 TI - Outside-In vs. Anteromedial Portal Drilling During Primary ACL Reconstruction: Comparison at Two Years. AB - BACKGROUND: Anteromedial (AM) and outside-in (OI) are two commonly used techniques for drilling the femoral tunnel during anterior cruciate ligament reconstruction (ACLR). The purpose of this study was to compare clinical and radiographic outcomes of patients undergoing primary ACLR using either AM or OI femoral drilling with minimum two year follow-up. METHODS: Overall, 138 prospectively enrolled patients undergoing primary ACLR underwent AM or OI femoral drilling. Patients were categorized by femoral drilling technique and were evaluated pre-operatively as well as at six weeks and two years post operatively. Outcomes scores were collected at each visit using SF-36 PCS and MCS components, KOOS, and the Knee Activity Rating Scale. Complications, including graft failure, stiffness requiring manipulation under anesthesia, and revision surgery were also collected. RESULTS: Overall, 47 (34.1%) patients underwent AM femoral drilling and 91 (65.9%) patients underwent OI femoral drilling. Univariate analysis revealed no difference in pre-operative outcomes with the exception of the AM group having higher KOOS Knee Pain (p=0.023) and WOMAC Pain (p=0.036) scores. Postoperatively, OI femoral tunnels had a higher radiographic coronal angle (68.8 degrees +/-8.6 degrees vs 51.4 degrees +/-11.3 degrees ; p<0.001) and knee extension (1.2 degrees +/-2.7 vs 2.9 degrees +/-4.0 degrees ; p=0.010). There were no differences in knee flexion, complications, or graft failure. Postoperatively, the AM group had higher KOOS ADL and WOMAC Functional (85 vs. 79 ,p=0.030) scores at the six week mark, although these differences did not meet the minimal clinically importance difference1. Graft failure at two years were similar in the AM and OI groups (8.5% vs. 6.6%, p=0.735). Multivariate analysis showed no clinical outcome differences between AM and OI techniques. CONCLUSIONS: ACL reconstruction using the AM technique yielded lower radiographic coronal tunnel angle and slightly decreased knee extension. The theoretical risk of graft failure secondary to higher coronal angle of the graft as it passes around a sharper femoral tunnel aperture was not observed. Additionally, differences in pre-operative KOOS Knee pain existed but these differences were not significant postoperatively. We conclude no clinically relevant differences by two years in patients undergoing primary ACL reconstruction using either AM or OI femoral drilling techniques. Level of Evidence: Level II Prospective Comparative Study. PMID- 28852346 TI - Medial Meniscus Root Tear in the Middle Aged Patient: A Case Based Review. AB - Biomechanical studies have shown that medial meniscal root tears result in meniscal extrusion and increased tibiofemoral joint contact pressures, which can accelerate the progression of arthritis. Repair is generally recommended for acute injuries in the young, active patient population. The far more common presentation however, is a subacute root tear with medial meniscal extrusion in a middle aged patient. Coexisting arthritis is common in this population and complicates decision making. Treatment should be based on the severity of the underlying arthritis. In cases of early or minimal arthritis, root repair is ideal to improve symptoms and restore meniscal function. In patients with moderate or severe medial compartment arthritis, medial unloader bracing or injections can be tried initially. When non-operative treatment fails, high tibial osteotomy or arthroplasty is recommended. Long term clinical studies are needed to determine the natural history of medial meniscal root tears in middle aged patients and the best surgical option. PMID- 28852347 TI - Marjolin's Ulcer of the Tibia With Pelvic Lymph Node Metastasis. AB - Marjolin's ulcer, a form of squamous cell carcinoma, is a rare complication of a chronic wound infection. To date, there have not been any detailed reports of lymphatic spread of Marjolin's ulcer from an extremity. This report describes a 44-year old male with a history of an open tibia fracture at age 15, who presented with chronic osteomyelitis, increasing bloody wound drainage, and an enlarging vascular exophytic masses in the region of drainage. Biopsy of the mass showed squamous cell carcinoma. Initial staging with computed tomography (CT) was negative for metastatic disease. Six months after undergoing a below-knee amputation (BKA), the patient developed an enlarged lymph node in the left inguinal area. His re-staging CT and biopsy of inguinal node confirmed the presence of metastatic squamous cell carcinoma. The patient was subsequently treated with inguinal node dissection and adjuvant radiation therapy. At 2.5 years follow-up, the patient remains disease-free. Our case illustrates the importance suspecting squamous cell carcinoma in patients with chronic infections and diligent follow up for patients with Marjolin's ulcers. PMID- 28852348 TI - Lessons and Advice From Our Patients: A Focus Group of Sarcoma Survivors. AB - BACKGROUND: Sarcomas are a rare, encompassing a heterogeneous group of malignancies. Success treatment often requires a combination of surgical resection, chemotherapy, and/or radiation. These life-altering interventions can have lasting impact on function and quality-of-life. There is little known about treatment outcomes from the perspective of sarcoma patients. PURPOSE: The initial goal of this investigation was to determine the sources and categories of information patients sought at various time points in their care. In addition, we investigated how participants coped with physical and psychological issues that accompany treatment. Finally, we elicited advice on what the care team did well, and could have been done differently, during their diagnosis and recovery. METHODS: A qualitative, focus group research method was utilized. A purposive sample of participants with a diagnosis of a sarcoma was identified. Three focus groups (20 total participants) were formed and audio/video recorded. The transcripts were analyzed to identify common themes and a scissor-and-sort technique was used to attribute participant comments to the identified themes. RESULTS: Themes were identified and categorized into four major areas: 1) Information at diagnosis, 2) Relationship with care team, 3) Social support, and 4) Restoration to "normal." CONCLUSION: We identified several areas that can be addressed to enhance patient counseling, emotional understanding, and expectations of treatment. These can serve as a guide for future research endeavors and program development. PMID- 28852349 TI - An Osteological Study on the Prevalence of Osteochondromas. AB - BACKGROUND: Osteochondromas are frequently reported to be the most common benign tumor of bone. However, there is not definitive data on their prevalence rate as they are often clinically silent, with previous studies estimating 1-3%. METHODS: We examined a large osteologic collection of 2954 skeletons to identify likely osteochondromas. One author examined all bones excluding the skull in each skeleton for atypical cortical projections. These candidates were then evaluated by an orthopedic resident and then a fellowship trained pediatric orthopedic surgeon for final inclusion using strict criteria. RESULTS: 13 cases of osteochondroma were identified from 2954 skeletons to yield a prevalence of 0.44% (95% confidence interval 0.20% - 0.68%) in the study population. All were located on long bones: three in the humerus, six in the femur and four in the tibia. CONCLUSIONS: We found a prevalence of 0.44% for osteochondromas, which is approximately half the lowest value reported in previous literature. PMID- 28852350 TI - Significance Of Pirani Score at Bracing-Implications for Recognizing A Corrected Clubfoot. AB - BACKGROUND: The aim of clubfoot treatment by Ponseti method is to achieve a corrected foot, with at least 15 degrees dorsiflexion and 70 degrees abduction, and fit comfortably into a brace at the recommended setting. This study aimed to acknowledge the validity and reliability of the Pirani scoring system, while investigating if a corrected clubfoot has a Pirani score of zero. The study hypothesized that a corrected clubfoot may or may not have a Pirani score of zero. METHODS: 706 patients with clubfoot were treated by Ponseti's method of weekly manipulations and casting, from November 2011 to May 2016, at a tertiary care hospital, making a total of 1055 feet. All data was entered into the International Clubfoot Network Database, along with Pirani scoring. Tenotomy was performed in eligible patients. RESULTS: The mean Pirani score at the end of treatment phase of casting and initiation of the maintenance phase of bracing for the right foot was 1.1 (SD=0.55) and left foot was 1.2 (SD=0.58). These feet not only fit the criteria of a corrected clubfoot, 70 degrees abduction and 15 degrees dorsiflexion, but also fit well in a foot abduction brace. Of the 1055 diagnosed Clubfeet, 643 required tenotomy (60.9%). CONCLUSION: The study shows that the affected foot does not need to have a Pirani score of zero to be considered a corrected foot. Pirani score is an excellent tool used over the years to evaluate clubfoot. Pirani score does not assess adequately the transition from the treatment phase of casting to the maintenance phase of bracing. The use of the International Clubfoot Database-Treatment visit form, including all components of clubfoot and the Pirani score, provides a clear understanding of whether the patient has achieved foot correction or not. Level of Evidence: Level IV. PMID- 28852351 TI - Rapid Prototyping 3D Model in Treatment of Pediatric Hip Dysplasia: A Case Report. AB - BACKGROUND: Rapid prototyping is an emerging technology that integrates common medical imaging with specialized production mechanisms to create detailed anatomic replicas. 3D-printed models of musculoskeletal anatomy have already proven useful in orthopedics and their applications continue to expand. CASE DESCRIPTION: We present the case of a 10 year-old female with Down syndrome and left acetabular dysplasia and chronic hip instability who underwent periacetabular osteotomy. A rapid prototyping 3D model was created to better understand the anatomy, counsel the family about the problem and the surgical procedure, as well as guide surgical technique. The intricate detail and size match of the model with the patient's anatomy offered unparalleled, hands-on experience with the patient's anatomy pre-operatively and improved surgical precision. CONCLUSIONS: Our experience with rapid prototyping confirmed its ability to enhance orthopedic care by improving the surgeon's ability to understand complex anatomy. Additionally, we report a new application utilizing intraoperative fluoroscopic comparison of the model and patient to ensure surgical precision and minimize the risk of complications. This technique could be used in other challenging cases. The increasing availability of rapid prototyping welcomes further use in all areas of orthopedics. PMID- 28852352 TI - Closed and Open Reduction of Displaced Pediatric Lateral Condyle Humeral Fractures, a Study of Short-Term Complications and Postoperative Protocols. AB - BACKGROUND: Displaced lateral condyle humeral fractures in children are treated operatively to maximize function and growth of the elbow. Traditionally an open approach is used for reduction of the fracture, but recent series have shown promising results with closed reduction. Percutaneous pins are typically used for fixation, no matter the reduction method. This retrospective review compares our experience with early complications after open and closed reduction of these fractures. METHODS: We retrospectively reviewed charts and radiographs of operatively treated lateral condyle fractures. The Song and Jakob classification systems were utilized to determine fracture severity. High-grade displacement was defined as Song stage 4 and 5, or Jakob type 3. Data was analyzed by fracture type (high-grade or low-grade) and by treatment method to look for differences in complication rates and treatment differences. Complications were defined as delayed union and infection. RESULTS: 172 fractures were analyzed, 141 were treated open, and 31 were treated closed. There were no statistically significant differences in pin duration, total cast time, additional procedures, or short term complications between the open and closed treatment groups, or the high and low-grade fracture groups. High-grade fractures were more likely to be treated with open reduction (p<0.0001). Pin duration prior to removal was not associated with increased incidence of infection or delayed union. CONCLUSIONS: Closed reduction and percutaneous pinning of lateral condyle fractures amenable to this treatment does not seem to require any changes in postoperative treatment or alter the incidence of early complications when compared to open procedures. LEVEL OF EVIDENCE: IV. PMID- 28852353 TI - Management of Painful Patellar Clunk and Crepitance: Results at a Mean Follow-Up of Five Years. AB - INTRODUCTION: Painful patellar clunk and crepitance (PCC) is a known complication of total knee arthroplasty (TKA) with posterior-stabilized designs. Arthroscopic management of PCC has been proposed as a treatment option for PCC. METHODS: We reviewed all cases of PCC from a consecutive single-surgeon series using a specific posterior stabilized (PS) design treated with arthroscopy for PCC. In a series of 1,488 TKA cases, forty-six patients (3.1%) were identified to have clinical signs and symptoms of PCC during post-operative clinic follow-up. RESULTS: Patients elected for arthroscopic excision of the supra-patellar lesion in eighteen of the forty-six cases (39%), after failing conservative management, for a 1.2% incidence of arthroscopic excision for PCC in the TKA cohort. All cases were followed for a minimum of two years. Three of the cases had recurrence of PCC after arthroscopy (16.7%), and each of these patients was successfully treated with a second arthroscopic excision procedure. Patient satisfaction after arthroscopic excision was rated extremely satisfied or very satisfied in 79% of patients and moderately satisfied in 21% of patients. Several radiographic measurements were considered in the PCC cohort, and only increased posterior tibial slope was associated with the need for arthroscopic excision. At final followup, the mean knee society score was 92.4, the mean WOMAC score was 82.9, and mean range of motion was 0-119.7 degrees. DISCUSSION: The incidence of PCC requiring arthroscopic excision with the Sigma PS design was relatively low, at 1.2% of patient. Patients who underwent arthroscopic excision for PCC had high patient satisfaction and low recurrence rates. In recurrent cases, repeat excision also resolved symptoms. Thus, arthroscopic excision is an effective treatment option for PCC in symptomatic patients. PMID- 28852354 TI - Popliteal (Baker's) Cysts in the Setting of Primary Knee Arthroplasty. AB - BACKGROUND: Popliteal (Baker's) Cysts are rare complications of knee arthroplasty. Enlargement, irritation, or rupture of the cyst can lead to significant pain, tightness, and tenderness. The literature regarding popliteal cysts occurring following knee arthroplasty is limited and does not report prevalence, natural history, and treatment of popliteal cyst in the setting of knee arthroplasty. METHODS: Following Institutional Review Board approval, 2,025 primary total and partial knee arthroplasties by four surgeons at one institution from 2011-2016 were reviewed for occurrence of popliteal cysts. Twelve cases occurring after arthroplasty were identified, including four unicompartmental knee arthroplasties and eight total knee arthroplasties. Demographic data were evaluated and symptoms, time of onset following arthroplasty, attempted treatment strategies, and success or failure of attempted treatments or interventions were recorded. RESULTS: The mean age of patients that presented with a popliteal cyst was 63.6 years old (range = 45 - 78 years). There were 5 males and 7 females. The mean BMI was 26.32 (range = 19.0 - 35.0). In 2,205 primary knee arthroplasties performed from 2011-2016 (including 175 partial and 1850 total), the prevalence of popliteal cysts following surgery was 0.6% (n=12). All popliteal cysts were discovered between six weeks and two years following surgery, with the majority occurring during the first year. Twenty-five percent (3/12) of patients presented with minimal symptoms. These were managed expectantly. Seventy-five percent (9/12) were symptomatic. One patient had only a diagnostic ultrasound, two patients underwent ultrasound-guided aspiration and steroid injection, three underwent simple aspiration. Two underwent surgical excision. One cyst ruptured. All cases went on to symptomatic resolution. There was no association with diabetes, smoking, or body mass index. A disproportionately high number (25% or 4/12) occurred in partial knee arthroplasty. CONCLUSION: While popliteal cysts following primary total knee arthroplasty are rare, they can become a persistent and even disabling problem for arthroplasty patients. Given the lack of formalized recommendations in the existing literature, we propose a treatment algorithm that has been successful in our clinic, including observation initially, ultrasound-guided injection/aspiration if symptomatic, and surgical excision as a last resort. LEVEL OF EVIDENCE: Level IV. PMID- 28852355 TI - How Reliable is the Acetabular Cup Position Assessment from Routine Radiographs? AB - BACKGROUND: Cup position is crucial for optimal outcomes in total hip arthroplasty. Radiographic assessment of component position is routinely performed in the early postoperative period. AIMS: The aims of this study were to determine in a controlled environment if routine radiographic methods accurately and reliably assess the acetabular cup position and to assess if there is a statistical difference related to the rater's level of training. METHODS: A pelvic model was mounted in a spatial frame. An acetabular cup was fixed in different degrees of version and inclination. Standardized radiographs were obtained. Ten observers including five fellowship-trained orthopaedic surgeons and five orthopaedic residents performed a blind assessment of cup position. Inclination was assessed from anteroposterior radiographs of the pelvis and version from cross-table lateral radiographs of the hip. RESULTS: The radiographic methods used showed to be imprecise specially when the cup was positioned at the extremes of version and inclination. An excellent inter observer reliability (Intra-class coefficient > 0,9) was evidenced. There were no differences related to the level of training of the raters. CONCLUSIONS: These widely used radiographic methods should be interpreted cautiously and computed tomography should be utilized in cases when further intervention is contemplated. PMID- 28852356 TI - Detection of Retained Foreign Objects in Upper Extremity Surgical Procedures With Incisions of Two Centimeters or Smaller. AB - BACKGROUND: While the true incidence of retained foreign bodies after surgery is unknown, it has been approximated at 1:5,500 operations overall, with substantially less frequency in hand and upper extremity procedures. Despite the rarity of foreign body retention in hand and upper extremity surgery, universal radiofrequency scanning for electronically-tagged sponges and automatic radiographic evaluation for incorrect sponge counts are employed for all surgical procedures at our institution. We demonstrate the infeasibility of retaining an operative sponge of a standard size in commonly performed hand and upper extremity procedures with incision sizes of two centimeters or less, and establish that visual detection of sponges in these cases is adequate. METHODS: Eighteen trigger finger releases, five carpal tunnel releases, three trigger thumb releases, and three de Quervain's tenosynovitis releases were successfully performed upon five cadaveric specimens by residents under supervision of fellowship-trained hand surgeons for a total of 29 two-centimeter or smaller incisions. Randomized surgical sponge placement was evaluated by a blinded observer at two distances and incision sizes were quantified. Kappa values were calculated to determine the acuity of visual detection versus the actual presence of a sponge. RESULTS: The maximum length of the standard surgical sponge that could be contained within an incision was three centimeters. When compared with the gold standard (whether the sponge had been placed or not by the operating resident), the placement of a standard surgical sponge could be detected correctly in 100% of cases at both "across the room" and "at the table" distances, for kappa values of 1.0 and 1.0 respectively. This did not vary with incision size or surgical procedure. CONCLUSIONS: The added cost and time from radiofrequency detection of retained sponges and radiographic evaluation in the event of incorrect sponge counts can be safely eliminated if sponges can be reliably visually detected. CLINICAL RELEVANCE: This cadaveric study informs patient safety practices by demonstrating that visual detection of surgical sponges is adequate for certain upper extremity procedures. PMID- 28852357 TI - Influence of 45S5 Bioactive Glass in A Standard Calcium Phosphate Collagen Bone Graft Substitute on the Posterolateral Fusion of Rabbit Spine. AB - INTRODUCTION: Spinal fusion surgery is an effective but costly treatment for select spinal pathology. Historically iliac crest bone graft (ICBG) has remained the gold standard for achieving successful arthrodesis. Given well-established morbidity autograft harvest, multiple bone graft replacements, void fillers, and extenders have been developed. The objective of this study was to evaluate the in vivo efficacy and safety of two mineralized collagen bone void filler materials similar in composition. Both bone void fillers were composed of hydroxyapatite (HA), tricalcium phosphate (TCP) and bovine collagen. The first test article (Bi Ostetic bioactive glass foam or "45S5") also contained 45S5 bioactive glass particles while the second test article (Formagraft or "FG") did not. 45S5 and FG were combined with bone marrow aspirate and iliac crest autograft and compared to ICBG in an established posterolateral spine fusion rabbit model. MATERIALS AND METHODS: Sixty-nine mature New Zealand White rabbits were divided into 3 test cohorts: ICBG, 45S5, and FG. A Posterolateral fusion model previous validated was utilized to assess fusion efficacy. The test groups were evaluated for spine fusion rate, new bone formation, graft resorption and inflammatory response using radiographic, MUCT, biomechanical and histological endpoints at 4, 8 and 12 weeks following implantation. RESULTS: There were 4 clinical complications unrelated to the graft materials and were evenly split between groups (ICBG graft harvest complications; hind limb mobility, chronic pain) and were euthanized. These omissions did not affect the overall outcome of the study. Radiographic scoring of the fusion sites indicated a normal healing response in all test groups, with no adverse reactions and similar progressions of new bone formation observed over time. All groups demonstrated significantly less range of motion in both flexion/extension and lateral bending compared to normal not-fused controls, which supports fusion results observed in the other endpoints. Fusion occurred earlier in the 45S5 group: ICBG 0%, FG 0%, and 45S5 20% at 4 weeks; ICBG 43%, FG 38%, and 45S5 50% at 8 weeks; and ICBG 50%, FG 56%, and 45S5 56% at 12 weeks. Histopathology analysis of the fusion masses, from each test article and time point, indicated an expected normal response for resorbable calcium phosphate (HA/TCP) and collagen graft material. Mild inflammation with macrophage and multinucleated giant cell response to the graft material was evident in all test groups. DISCUSSION: This study has confirmed the biocompatibility, safety, efficacy and bone healing characteristics of the HA-TCP collagen (with or without 45S5 bioactive glass) composites. The results show that the 3 test groups had equivalent long-term fusion performance and outcome at 12 weeks. However, the presence of 45S5 bioactive glass seemed to accelerate the fusion process as evidenced by the higher fusion rates at 4 and 8 weeks for the HA-TCP-collagen composite containing bioactive glass particles. The results also demonstrate that the HA-TCP-45S5 bioactive glass-collagen composite used as an extender closely mirrors the healing characteristics (i.e. amount and quality of bone) of the 100% autograft group. PMID- 28852358 TI - The Surgical Incidence to Publication (SIP) Index: A Novel Equation Used to Focus Future Research Efforts AB - BACKGROUND: With increased publication rates across all fields of medicine, some research topics become heavily weighted in the literature while other, equally important topics do not receive the same exposure. The purpose of this study is to present a simple equation which can be used to measure the current level of research interest on any particular surgical procedure or medical diagnosis. METHODS: The SIP Index (surgical incidence/ publications) is calculated as shown below, [Formula: see text]where X can be any particular surgical procedure. The numerator, utilized as a surrogate for the actual number of a particular case performed in a given time period, was estimated by the total number of cases presented during Part-II of the American Board of Orthopaedic Surgery (ABOS) certification examination from 1999-2003. The denominator was taken from a PubMed search for several of the most common orthopaedic procedures submitted to ABOS from 1999-2003. RESULTS: Based on the SIP Index, subacromial decompression and arthroscopic knee chondroplasty were found to be significantly under-researched procedures, while rotator cuff repair and total hip and knee arthroplasty were significantly over-researched during the study period. CONCLUSIONS: The SIP Index can be used to assess national or worldwide research efforts on any particular surgical procedure or medical diagnosis. This study provides an example of how this equation can be applied to a set of incidence data on common orthopaedic surgical procedures. When used in this way, the SIP Index can provide some insight into which procedures are relatively over- or under-researched. PMID- 28852359 TI - Have Residents Produced More Research Since the Inception of the 80-Hour Workweek? AB - BACKGROUND: This study hypothesizes that resident involvement in research has increased since institution of the maximum 80-hour workweek in 2002. METHODS: All 571 papers published in the Journal of Bone and Joint Surgery (JBJS) in 1997 and 2007 (five years before and after the start of the 80-hour workweek) were reviewed. To identify resident authors, a search was performed in the American Board of Orthopaedic Surgery (ABOS) database for any U.S. author with a medical doctorate (MD). Any authors who were board-certified more than two years after the publication date were identified as "residents." Two-tailed Fisher's exact tests were used to assess proportional changes over time. RESULTS: Between 1997 and 2007, the percentage of U.S. MD authors who were orthopaedic residents increased significantly from 12% to 18% (p = 0.01). U.S. publications with a resident first-author increased from 17% to 27% (p = 0.02), and contributions from foreign nations also increased significantly (p < 0.001). The number of total authors per paper increased (p < 0.001), but linear regression showed that this had no particular association with the proportion of residents (p = 0.20). The relative proportions of MD and non-MD authors did not change between years. The LOE of resident-authored papers improved significantly over time (p = 0.005), while that of international papers did not. CONCLUSIONS: Proportional resident authorship has increased significantly in one of the highest-impact, peer reviewed orthopaedic journals. LOE of resident-authored papers has improved, and basic science papers are more likely to have a resident first author. LEVEL OF EVIDENCE: III, retrospective cohort study. PMID- 28852360 TI - Eponymous Instruments in Orthopaedic Surgery. AB - Every day surgeons call for instruments devised by surgeon trailblazers. This article aims to give an account of commonly used eponymous instruments in orthopaedic surgery, focusing on the original intent of their designers in order to inform how we use them today. We searched PubMed, the archives of longstanding medical journals, Google, the Internet Archive, and the HathiTrust Digital Library for information regarding the inventors and the developments of 7 instruments: the Steinmann pin, Bovie electrocautery, Metzenbaum scissors, Freer elevator, Cobb periosteal elevator, Kocher clamp, and Verbrugge bone holding forceps. A combination of ingenuity, necessity, circumstance and collaboration produced the inventions of the surgical tools numbered in our review. In some cases, surgical instruments were improvements of already existing technologies. The indications and applications of the orthopaedic devices have changed little. Meanwhile, instruments originally developed for other specialties have been adapted for our use. Although some argue for a transition from eponymous to descriptive terms in medicine, there is value in recognizing those who revolutionized surgical techniques and instrumentation. Through history, we have an opportunity to be inspired and to better understand our tools. PMID- 28852361 TI - The Scarcity of Orthopaedic Physician Scientists. AB - Breakthrough advances in medicine almost uniformly result from the translation of new basic scientific knowledge into clinical practice, rather than from assessment, modification or refinement of current methods of diagnosis and treatment. However, as is intuitively understood, those most responsible for scientific conception and creation-scientists - are generally not the ones applying these advances at the patient's bedside or the operating room, and vice versa. Recognition of the scarcity of clinicians with a background that prepares them to develop new basic knowledge, and to critically evaluate the underlying scientific basis of methods of diagnosis and treatment, has led to initiatives including federally funded Physician-Scientist programs, whereby young, motivated scholars begin a rigorous training, which encompasses education and mentorship within both medical and scientific fields, culminating in the conferment of both MD and PhD degrees. Graduates have demonstrated success in integrating science into their academic medical careers. However, for unknown reasons, orthopaedic surgery, more than other specialties, has struggled to recruit and retain physician-scientists, who possess a skill set evermore rare in today's increasingly complicated medical and scientific landscape. While the reasons for this shortfall have yet to be completely elucidated, one thing is clear: If orthopaedics is to make significant advances in the diagnosis and treatment of musculoskeletal diseases and injuries, recruitment of the very best and brightest physician-scientists to orthopaedics must become a priority. This commentary explores potential explanations for current low-recruitment success regarding future orthopaedic surgeon-scientists, and discusses avenues for resolution. PMID- 28852364 TI - 2017 IOJ Editors' Note. PMID- 28852362 TI - Visual Interpretation of Plain Radiographs in Orthopaedics Using Eye-Tracking Technology. AB - BACKGROUND: Despite the importance of radiographic interpretation in orthopaedics, there not a clear understanding of the specific visual strategies used while analyzing a plain film. Eyetracking technology allows for the objective study of eye movements while performing a dynamic task, such as reading X-rays. Our study looks to elucidate objective differences in image interpretation between novice and experienced orthopaedic trainees using this novel technology. METHODS: Novice and experienced orthopaedic trainees (N=23) were asked to interpret AP pelvis films, searching for unilateral acetabular fractures while eye-movements were assessed for pattern of gaze, fixation on regions of interest, and time of fixation at regions of interest. Participants were asked to label radiographs as "fractured" or "not fractured." If "fractured", the participant was asked to determine the fracture pattern. A control condition employed Ekman faces and participants judged gender and facial emotion. Data were analyzed for variation in eye movements between participants, accuracy of responses, and response time. RESULTS: Accuracy: There was no significant difference by level of training for accurately identifing fracture images (p=0.3255). There was a significant association between higher level of training and correctly identifying non-fractured images (p=0.0155); greater training was also associated with more success in identifying the correct Judet Letournel classification (p=0.0029). Response Time: Greater training was associated with faster response times (p=0.0009 for fracture images and 0.0012 for non-fractured images). Fixation Duration: There was no correlation of average fixation duration with experience (p=0.9632). Regions of Interest (ROIs): More experience was associated with an average of two fewer fixated ROIs (p=0.0047). Number of Fixations: Increased experience was associated with fewer fixations overall (p=0.0007). CONCLUSIONS: Experience has a significant impact on both accuracy and efficiency in interpreting plain films. Greater training is associated with a shift toward a more efficient and thorough assessment of plain radiographs. Eyetracking is a useful descriptive tool in the setting of plain film interpretation. CLINICAL RELEVANCE: We propose further assessment of eye movements in larger populations of orthopaedic surgeons, including staff orthopaedists. Describing the differences between novice and expert interpretation may provide insight into ways to accelerate the learning process in young orthopaedists. PMID- 28852366 TI - 2017 Iowa Orthopedic Journal Dedication: Dr. Ernest "Ernie" Found. PMID- 28852363 TI - Patient Factors Systematically Influence Hospital Length of Stay in Common Orthopaedic Procedures. AB - INTRODUCTION: As the United States healthcare system evolves towards improved value delivery, patient outcomes and healthcare costs are increasingly used to evaluate physicians and provider organizations. One such metric is hospital length of stay, which has the potential to be influenced by a variety of patient characteristics and comorbidities. Determining factors influencing length of stay represents an opportunity to increase value in healthcare delivery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database (2006-2012) was utilized to identify a cohort of 92,266 patients having one of 14 common orthopaedic procedures. A generalized linear model was utilized to identify patient factors that increase hospital length of stay. RESULTS: During the six-year study period, length of stay decreased significantly in the total joint arthroplasty population. Nine variables were independently associated with increased length of stay. Congestive heart failure and underweight status increased length of stay the most, at 1.46 and 1.01 days, respectively. Other factors increasing length of stay include: non-white race (0.69 days), chronic obstructive pulmonary disease (0.50 days), diabetes mellitus (0.25 days), morbid obesity (0.23 days), hypertension (0.10 days), and patient age (0.02 days for each additional year). DISCUSSION: In conclusion, congestive heart failure and underweight status are the greatest predictors of increased length of stay. COPD, diabetes, morbid obesity, and hypertension represent other modifiable risk factors that increase length of stay. This data can be used to counsel patients and their families regarding anticipated duration of hospitalization. Systematic targeting of patient factors known to increase length of stay represents an opportunity for cost reduction and improved value delivery. When utilizing hospital length of stay as a metric for evaluation, it is important to incorporate the factors that increase length of stay, so that orthopaedic surgeons and provider organizations can be evaluated based on representative patient population characteristics. PMID- 28852371 TI - The 2017 Michael Bonfiglio Award for Student Research in Orthopaedic Surgery: The 2017 Iowa Orthopaedic Society Medical Student Research Award for Musculoskeletal Research. PMID- 28852372 TI - Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? AB - The branched chain amino acids (BCAAs) are leucine, valine and isoleucine. A multi-million dollar industry of nutritional supplements has grown around the concept that dietary supplements of BCAAs alone produce an anabolic response in humans driven by a stimulation of muscle protein synthesis. In this brief review the theoretical and empirical bases for that claim are discussed. Theoretically, the maximal stimulation of muscle protein synthesis in the post-absorptive state in response to BCAAs alone is the difference between muscle protein breakdown and muscle protein synthesis (about 30% greater than synthesis), because the other EAAs required for synthesis of new protein can only be derived from muscle protein breakdown. Realistically, a maximal increase in muscle protein synthesis of 30% is an over-estimate because the obligatory oxidation of EAAs can never be completely suppressed. An extensive search of the literature has revealed no studies in human subjects in which the response of muscle protein synthesis to orally-ingested BCAAs alone was quantified, and only two studies in which the effect of intravenously infused BCAAs alone was assessed. Both of these intravenous infusion studies found that BCAAs decreased muscle protein synthesis as well as protein breakdown, meaning a decrease in muscle protein turnover. The catabolic state in which the rate of muscle protein breakdown exceeded the rate of muscle protein synthesis persisted during BCAA infusion. We conclude that the claim that consumption of dietary BCAAs stimulates muscle protein synthesis or produces an anabolic response in human subjects is unwarranted. PMID- 28852373 TI - Advances in the Treatment of Hepatitis B and Hepatitis C Nonresponders: A Report of Symposia Presented at the 15th Conference of the Asian Pacific Association for the Study of the LiverAugust 18-21, 2005Bali, Indonesia. PMID- 28852374 TI - Smokefree signage at children's playgrounds: Field observations and comparison with Google Street View. AB - BACKGROUND: Although there is global growth in outdoor smokefree areas, little is known about the associated smokefree signage. We aimed to study smokefree signage at playgrounds and to compare field observations with images from Google Street View (GSV). METHODS: We randomly selected playgrounds in 21 contiguous local government areas in the lower North Island of New Zealand, all of which had smokefree playground policies. Field data were collected on smokefree signage along with dog control signage to allow for comparisons. The sensitivity and specificity of using GSV for data collection were calculated. RESULTS: Out of the 63 playgrounds studied, only 44% (95% CI: 33%-57%) had any smokefree signage within 10 m of the playground equipment. The mean number of such signs was 0.8 per playground (range: 0 to 6). Sign size varied greatly from 42 cm2 up to 2880 cm2; but was typically fairly small (median = 600 cm2; ie, as per a 20 * 30 cm rectangle). Qualitatively the dog signs appeared to use clearer images and were less wordy than the smokefree signs. Most playground equipment (82%), could be seen on GSV, but for these settings the sensitivity for identifying smokefree signs was poor at 16%. Yet specificity was reasonable at 96%. CONCLUSIONS: The presence and quality of smokefree signage was poor in this sample of children's playgrounds in this developed country setting. There appears to be value in comparing smokefree signage with other types of signage (eg, dog control signage). Google Street View was not a sensitive tool for studying such signage. PMID- 28852376 TI - BDNF pro-peptide: a novel synaptic modulator generated as an N-terminal fragment from the BDNF precursor by proteolytic processing. AB - Most growth factors are initially synthesized as precursors and it was cleaved into bioactive mature domain and pro-domain. However, compared with the expression and function of bioactive mature domain, the biological role of the pro-domain is poorly understood. Unexpectedly, we found that the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which is well-known neurotrophic factor in brain, has a potential ability to facilitate hippocampal long-term depression. Furthermore, a BDNF polymorphism Val66Met, which substitute valine into methionine at 66 amino acid, impacted the biological activity of the BDNF pro-peptide. We lastly discuss the possible roles of BDNF and its pro peptide in the generation of neural stem cells and progress of ischemia. PMID- 28852375 TI - Schwann cell development, maturation and regeneration: a focus on classic and emerging intracellular signaling pathways. AB - The development, maturation and regeneration of Schwann cells (SCs), the main glial cells of the peripheral nervous system, require the coordinate and complementary interaction among several factors, signals and intracellular pathways. These regulatory molecules consist of integrins, neuregulins, growth factors, hormones, neurotransmitters, as well as entire intracellular pathways including protein-kinase A, C, Akt, Erk/MAPK, Hippo, mTOR, etc. For instance, Hippo pathway is overall involved in proliferation, apoptosis, regeneration and organ size control, being crucial in cancer proliferation process. In SCs, Hippo is linked to merlin and YAP/TAZ signaling and it seems to respond to mechanic/physical challenges. Recently, among factors regulating SCs, also the signaling intermediates Src tyrosine kinase and focal adhesion kinase (FAK) proved relevant for SC fate, participating in the regulation of adhesion, motility, migration and in vitro myelination. In SCs, the factors Src and FAK are regulated by the neuroactive steroid allopregnanolone, thus corroborating the importance of this steroid in the control of SC maturation. In this review, we illustrate some old and novel signaling pathways modulating SC biology and functions during the different developmental, mature and regenerative states. PMID- 28852377 TI - Impact of glucocorticoid on neurogenesis. AB - Neurogenesis is currently an area of great interest in neuroscience. It is closely linked to brain diseases, including mental disorders and neurodevelopmental disease. Both embryonic and adult neurogeneses are influenced by glucocorticoids secreted from the adrenal glands in response to a variety of stressors. Moreover, proliferation/differentiation of the neural stem/progenitor cells (NSPCs) is affected by glucocorticoids through intracellular signaling pathways such as phosphoinositide 3-kinase (PI3K)/Akt, hedgehog, and Wnt. Our review presents recent evidence of the impact of glucocorticoids on NSPC behaviors and the underlying molecular mechanisms; this provides important information for understanding the pathological role of glucocorticoids on neurogenesis-associated brain diseases. PMID- 28852378 TI - RACK1 regulates neural development. AB - Receptor for activated C kinase 1 (RACK1) is an evolutionarily conserved scaffolding protein within the tryptophan-aspartate (WD) repeat family of proteins. RACK1 can bind multiple signaling molecules concurrently, as well as stabilize and anchor proteins. RACK1 also plays an important role at focal adhesions, where it acts to regulate cell migration. In addition, RACK1 is a ribosomal binding protein and thus, regulates translation. Despite these numerous functions, little is known about how RACK1 regulates nervous system development. Here, we review three studies that examine the role of RACK1 in neural development. In brief, these papers demonstrate that (1) RACK-1, the C. elegans homolog of mammalian RACK1, is required for axon guidance; (2) RACK1 is required for neurite extension of neuronally differentiated rat PC12 cells; and (3) RACK1 is required for axon outgrowth of primary mouse cortical neurons. Thus, it is evident that RACK1 is critical for appropriate neural development in a wide range of species, and future discoveries could reveal whether RACK1 and its signaling partners are potential targets for treatment of neurodevelopmental disorders or a therapeutic approach for axonal regeneration. PMID- 28852379 TI - Targeting 14-3-3 adaptor protein-protein interactions to stimulate central nervous system repair. AB - The goal of developing treatments for central nervous system (CNS) injuries is becoming more attainable with the recent identification of various drugs that can repair damaged axons. These discoveries have stemmed from screening efforts, large expression datasets and an improved understanding of the cellular and molecular biology underlying axon growth. It will be important to continue searching for new compounds that can induce axon repair. Here we describe how a family of adaptor proteins called 14-3-3s can be targeted using small molecule drugs to enhance axon outgrowth and regeneration. 14-3-3s bind to many functionally diverse client proteins to regulate their functions. We highlight the recent discovery of the axon-growth promoting activity of fusicoccin-A, a fungus-derived small molecule that stabilizes 14-3-3 interactions with their client proteins. Here we discuss how fusicoccin-A could serve as a starting point for the development of drugs to induce CNS repair. PMID- 28852380 TI - Spinal cord injury drives chronic brain changes. AB - Only a few studies have considered changes in brain structures other than sensory and motor cortex after spinal cord injury, although cognitive impairments have been reported in these patients. Spinal cord injury results in chronic brain neuroinflammation with consequent neurodegeneration and cognitive decline in rodents. Regarding the hippocampus, neurogenesis is reduced and reactive gliosis increased. These long-term abnormalities could explain behavioral impairments exhibited in humans patients suffering from spinal cord trauma. PMID- 28852381 TI - SoxC transcription factors in retinal development and regeneration. AB - Glaucoma and other optic neuropathies result in optic nerve degeneration and the loss of retinal ganglion cells (RGCs) through complex signaling pathways. Although the mechanisms that regulate RGC development remain unclear, uncovering novel developmental pathways may support new strategies to regenerate the optic nerve or replace RGCs. Here we review recent studies that provide strong evidence that the Sry-related high-mobility-group C (SoxC) subfamily of transcription factors (TFs) are necessary and sufficient for axon guidance and RGC fate specification. These findings also uncover novel SoxC-dependent mechanisms that serve as master regulators during important steps of RGC development. For example, we review work showing that SoxC TFs regulate RGC axon guidance and direction through the optic chiasm towards their appropriate targets in the brain. We also review work demonstrating that Sox11 subcellular localization is, in part, controlled through small ubiquitin-like post-translational modifier (SUMO) and suggest compensatory cross-talk between Sox4 and Sox11. Furthermore, Sox4 overexpression is shown to positively drive RGC differentiation in human induced pluripotent stem cells (hiPSCs). Finally, we discuss how these findings may contribute to the advancement of regenerative and cell-based therapies to treat glaucoma and other optic nerve neuropathies. PMID- 28852383 TI - Using induced pluripotent stem cells derived neurons to model brain diseases. AB - The ability to use induced pluripotent stem cells (iPSC) to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders. Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology. iPSC derived neurons, or other neural cell types, provide the ability to access pathology in cells derived directly from a patient's blood sample or skin biopsy where availability of brain tissue is limiting. Thus, utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future. Many brain diseases across the spectrum of neurodevelopment, neurodegenerative and neuropsychiatric are being approached by iPSC models. The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells. In this mini review, the importance of iPSC cell models validated for pluripotency, germline competency and function assessments is discussed. Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed. PMID- 28852384 TI - Exploring pre-degenerative alterations in humans using induced pluripotent stem cell-derived dopaminergic neurons. PMID- 28852382 TI - Mitochondrial quality control in amyotrophic lateral sclerosis: towards a common pathway? AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons. Different mechanisms contribute to the disease initiation and progression, including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis. Indeed, while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants, it is now well established that mitochondria become also dysfunctional in other ALS conditions. In such context, the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death, by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy. Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system. This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS. PMID- 28852386 TI - Neuroregeneration using in vivo cellular reprogramming. PMID- 28852385 TI - The impact of graphene on neural regenerative medicine. PMID- 28852387 TI - Impact of dietary supplementation of one-carbon metabolism on neural recovery. PMID- 28852388 TI - Evidence for using a dual COX 1/2 and 5-LOX inhibitor in neurodegenerative diseases. PMID- 28852389 TI - Dual face of axonal inhibitory inputs in the modulation of neuronal excitability in cortical pyramidal neurons. AB - Limited by the tiny structure of axons, the effects of these axonal hyperpolarizing inputs on neuronal activity have not been directly elucidated. Here, we imitated these processes by simultaneously recording the activities of the somas and proximal axons of cortical pyramidal neurons. We found that spikes and subthreshold potentials propagate between somas and axons with high fidelity. Furthermore, inhibitory inputs on axons have opposite effects on neuronal activity according to their temporal integration with upstream signals. Concurrent with somatic depolarization, inhibitory inputs on axons decrease neuronal excitability and impede spike generation. In addition, following action potentials, inhibitory inputs on an axon increase neuronal spike capacity and improve spike precision. These results indicate that inhibitory inputs on proximal axons have dual regulatory functions in neuronal activity (suppression or facilitation) according to neuronal network patterns. PMID- 28852390 TI - Putative adult neurogenesis in two domestic pigeon breeds (Columba livia domestica): racing homer versus utility carneau pigeons. AB - Generation of neurons in the brains of adult birds has been studied extensively in the telencephalon of song birds and few studies are reported on the distribution of PCNA and DCX in the telencephalon of adult non-song learning birds. We report here on adult neurogenesis throughout the brains of two breeds of adult domestic pigeons (Columba livia domestica), the racing homer and utility carneau using endogenous immunohistochemical markers proliferating cell nuclear antigen (PCNA) for proliferating cells and doublecortin (DCX) for immature and migrating neurons. The distribution of PCNA and DCX immunoreactivity was very similar in both pigeon breeds with only a few minor differences. In both pigeons, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, walls of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and cerebellum. Generally, the olfactory bulbs and telencephalon had more PCNA and DCX cells than other regions. Two proliferative hotspots were evident in the dorsal and ventral poles of the lateral ventricles. PCNA- and DCX-immunoreactive cells migrated radially from the walls of the lateral ventricle into the parenchyma. In most telencephalic regions, the density of PCNA- and DCX-immunoreactive cells increased from rostral to caudal, except in the mesopallium where the density decreased from rostral to middle levels and then increased caudally. DCX immunoreactivity was more intense in fibres than in cell bodies and DCX-immunoreactive cells included small granular cells, fusiform bipolar cells, large round and or polygonal multipolar cells. The similarity in the distribution of proliferating cells and new neurons in the telencephalon of the two breeds of pigeons may suggest that adult neurogenesis is a conserved trait as an ecological adaptation irrespective of body size. PMID- 28852391 TI - Serum prealbumin as an effective prognostic indicator for determining clinical status and prognosis in patients with hemorrhagic stroke. AB - Serum prealbumin is a recognized marker of malnutrition, but its prognostic role in patients with hemorrhagic stroke remains unclear. In this study, we retrospectively reviewed the records of 105 patients with hemorrhagic stroke admitted to Renmin Hospital of Wuhan University, China, from January to December 2015. We collected demographic and radiological data, and recorded serum prealbumin levels at admission and on days 1, 3, 6, 9, and 14-21. The existence of infections and gastrointestinal hemorrhage, and clinical condition at discharge were also recorded. Serum prealbumin levels during hospitalization were significantly lower in patients with infections compared with those without infections, and also significantly lower in patients with gastrointestinal hemorrhage compared with those without. Serum prealbumin levels at discharge were significantly higher in patients with good recovery than in those with poor recovery. We conclude that regular serum prealbumin measurements in patients with hemorrhagic stroke may be a useful indicator for determining clinical status and prognosis, which may therefore help to guide clinical decision-making. PMID- 28852392 TI - Neural differentiation of human Wharton's jelly-derived mesenchymal stem cells improves the recovery of neurological function after transplantation in ischemic stroke rats. AB - Human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) have excellent proliferative ability, differentiation ability, low immunogenicity, and can be easily obtained. However, there are few studies on their application in the treatment of ischemic stroke, therefore their therapeutic effect requires further verification. In this study, hWJ-MSCs were transplanted into an ischemic stroke rat model via the tail vein 48 hours after transient middle cerebral artery occlusion. After 4 weeks, neurological functions of the rats implanted with hWJ MSCs were significantly recovered. Furthermore, many hWJ-MSCs homed to the ischemic frontal cortex whereby they differentiated into neuron-like cells at this region. These results confirm that hWJ-MSCs transplanted into the ischemic stroke rat can differentiate into neuron-like cells to improve rat neurological function and behavior. PMID- 28852393 TI - Adult neural stem cell dysfunction in the subventricular zone of the lateral ventricle leads to diabetic olfactory defects. AB - Sensitive smell discrimination is based on structural plasticity of the olfactory bulb, which depends on migration and integration of newborn neurons from the subventricular zone. In this study, we examined the relationship between neural stem cell status in the subventricular zone and olfactory function in rats with diabetes mellitus. Streptozotocin was injected through the femoral vein to induce type 1 diabetes mellitus in Sprague-Dawley rats. Two months after injection, olfactory sensitivity was decreased in diabetic rats. Meanwhile, the number of BrdU-positive and BrdU+/DCX+ double-labeled cells was lower in the subventricular zone of diabetic rats compared with age-matched normal rats. Western blot results revealed downregulated expression of insulin receptor beta, phosphorylated glycogen synthase kinase 3beta, and beta-catenin in the subventricular zone of diabetic rats. Altogether, these results indicate that diabetes mellitus causes insulin deficiency, which negatively regulates glycogen synthase kinase 3beta and enhances beta-catenin degradation, with these changes inhibiting neural stem cell proliferation. Further, these signaling pathways affect proliferation and differentiation of neural stem cells in the subventricular zone. Dysfunction of subventricular zone neural stem cells causes a decline in olfactory bulb structural plasticity and impairs olfactory sensitivity in diabetic rats. PMID- 28852394 TI - Effects of visual information regarding tactile stimulation on the somatosensory cortical activation: a functional MRI study. AB - Many studies have investigated the evidence for tactile and visual interactive responses to activation of various brain regions. However, few studies have reported on the effects of visuo-tactile multisensory integration on the amount of brain activation on the somatosensory cortical regions. The aim of this study was to examine whether coincidental information obtained by tactile stimulation can affect the somatosensory cortical activation using functional MRI. Ten right handed healthy subjects were recruited for this study. Two tasks (tactile stimulation and visuotactile stimulation) were performed using a block paradigm during fMRI scanning. In the tactile stimulation task, in subjects with eyes closed, tactile stimulation was applied on the dorsum of the right hand, corresponding to the proximal to distal directions, using a rubber brush. In the visuotactile stimulation task, tactile stimulation was applied to observe the attached mirror in the MRI chamber reflecting their hands being touched with the brush. In the result of SPM group analysis, we found brain activation on the somatosensory cortical area. Tactile stimulation task induced brain activations in the left primary sensory-motor cortex (SM1) and secondary somatosensory cortex (S2). In the visuo-tactile stimulation task, brain activations were observed in the both SM1, both S2, and right posterior parietal cortex. In all tasks, the peak activation was detected in the contralateral SM1. We examined the effects of visuo-tactile multisensory integration on the SM1 and found that visual information during tactile stimulation could enhance activations on SM1 compared to the tactile unisensory stimulation. PMID- 28852395 TI - Diffusion-weighted magnetic resonance imaging reflects activation of signal transducer and activator of transcription 3 during focal cerebral ischemia/reperfusion. AB - Signal transducer and activator of transcription (STAT) is a unique protein family that binds to DNA, coupled with tyrosine phosphorylation signaling pathways, acting as a transcriptional regulator to mediate a variety of biological effects. Cerebral ischemia and reperfusion can activate STATs signaling pathway, but no studies have confirmed whether STAT activation can be verified by diffusion-weighted magnetic resonance imaging (DWI) in rats after cerebral ischemia/reperfusion. Here, we established a rat model of focal cerebral ischemia injury using the modified Longa method. DWI revealed hyperintensity in parts of the left hemisphere before reperfusion and a low apparent diffusion coefficient. STAT3 protein expression showed no significant change after reperfusion, but phosphorylated STAT3 expression began to increase after 30 minutes of reperfusion and peaked at 24 hours. Pearson correlation analysis showed that STAT3 activation was correlated positively with the relative apparent diffusion coefficient and negatively with the DWI abnormal signal area. These results indicate that DWI is a reliable representation of the infarct area and reflects STAT phosphorylation in rat brain following focal cerebral ischemia/reperfusion. PMID- 28852396 TI - Protective effects of Dendrobium nobile Lindl. alkaloids on amyloid beta (25-35) induced neuronal injury. AB - Dendrobium nobile Lindl. alkaloids (DNLA), the active ingredients of a traditional Chinese medicine Dendrobium, have been shown to have anti-oxidative effects, anti-inflammatory action, and protective effect on neurons against oxygen-glucose deprivation. However, it is not clear whether DNLA reduces amyloid beta (Abeta)-induced neuronal injury. In this study, cortical neurons were treated with DNLA at different concentrations (0.025, 0.25, and 2.5 mg/L) for 24 hours, followed by administration of Abeta25-35 (10 MUM). Abeta25-35 treatments increased cell injury as determined by the leakage of lactate dehydrogenase, which was accompanied by chromatin condensation and mitochondrial tumefaction. The damage caused by Abeta25-35 on these cellular properties was markedly attenuated when cells were pretreated with DNLA. Treatment with Abeta25-35 down regulated the expressions of postsynaptic density-95 mRNA and decreased the protein expression of synaptophysin and postsynaptic density-95, all changes were significantly reduced by pretreatment of cells with DNLA. These findings suggest that DNLA reduces the cytotoxicity induced by Abeta25-35 in rat primary cultured neurons. The protective mechanism that DNLA confers on the synaptic integrity of cultured neurons might be mediated, at least in part, through the upregulation of neurogenesis related proteins synaptophysin and postsynaptic density-95. PMID- 28852397 TI - Neuroprotective potential of Quercetin in combination with piperine against 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. AB - 1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that selectively damages dopaminergic neurons in the substantia nigra pars compacta and induces Parkinson's like symptoms in rodents. Quercetin (QC) is a natural polyphenolic bioflavonoid with potent antioxidant and anti-inflammatory properties but lacks of clinical attraction due to low oral bioavailability. Piperine is a well established bioavailability enhancer used pre-clinically to improve the bioavailability of antioxidants (e.g., Quercetin). Therefore, the present study was designed to evaluate the neuroprotective potential of QC together with piperine against MPTP-induced neurotoxicity in rats. MPTP (100 MUg/MUL/rat, bilaterally) was injected intranigrally on days 1, 4 and 7 using a digital stereotaxic apparatus. QC (25 and 50 mg/kg, intragastrically) and QC (25 mg/kg, intragastrically) in combination with piperine (2.5 mg/kg, intragastrically) were administered daily for 14 days starting from day 8 after the 3rd injection of MPTP. On day 22, animals were sacrificed and the striatum was isolated for oxidative stress parameter (thiobarbituric acid reactive substances, nitrite and glutathione), neuroinflammatory cytokine (interleukin 1beta, interleukin-6, and tumor necrosis factor-alpha) and neurotransmitter (dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, glutamate, 3,4 dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid) evaluations. Bilateral infusion of MPTP into substantia nigra pars compacta led to significant motor deficits as evidenced by impairments in locomotor activity and rotarod performance in open field test and grip strength and narrow beam walk performance. Both QC (25 and 50 mg/kg) and QC (25 mg/kg) in combination with piperine (2.5 mg/kg), in particular the combination therapy, significantly improved MPTP-induced behavioral abnormalities in rats, reversed the abnormal alterations of neurotransmitters in the striatum, and alleviated oxidative stress and inflammatory response in the striatum. These findings indicate that piperine can enhance the antioxidant and anti-inflammatory properties of QC, and QC in combination with piperine exhibits strong neuroprotective effects against MPTP induced neurotoxicity. PMID- 28852398 TI - How does conserved dopamine neurotrophic factor protect against and rescue neurodegeneration of PC12 cells? AB - Conserved dopamine neurotrophic factor protects and rescues dopaminergic neurodegeneration induced by 6-hydroxydopamine in vivo, but its potential value in treating Parkinson's disease remains controversial. Here, we used the proteasome inhibitors lactacystin and MG132 to induce neurodegeneration of PC12 cells. Afterwards, conserved dopamine neurotrophic factor was administrated as a therapeutic factor, both pretreatment and posttreatment. Our results showed that (1) conserved dopamine neurotrophic factor enhanced lactacystin/MG132-induced cell viability and morphology, and attenuated alpha-synuclein accumulation in differentiated PC12 cells. (2) Enzyme linked immunosorbent assay showed up regulated 26S proteasomal activity in MG132-induced PC12 cells after pre- and posttreatment with conserved dopamine neurotrophic factor. Similarly, 26S proteasome activity was upregulated in lactacystin-induced PC12 cells pretreated with conserved dopamine neurotrophic factor. (3) With regard proteolytic enzymes (specifically, glutamyl peptide hydrolase, chymotrypsin, and trypsin), glutamyl peptide hydrolase activity was up-regulated in lactacystin/MG132-administered PC12 cells after pre- and posttreatment with conserved dopamine neurotrophic factor. However, upregulation of chymotrypsin activity was only observed in MG132 administered PC12 cells pretreated with conserved dopamine neurotrophic factor. There was no change in trypsin expression. We conclude that conserved dopamine neurotrophic factor develops its neurotrophic effects by modulating proteasomal activities, and thereby protects and rescues PC12 cells against neurodegeneration. PMID- 28852399 TI - Effect of glycosides of Cistanche on the expression of mitochondrial precursor protein and keratin type II cytoskeletal 6A in a rat model of vascular dementia. AB - Glycosides of Cistanche (GC) is a preparation used extensively for its neuroprotective effect against neurological diseases, but its mechanisms of action remains incompletely understood. Here, we established a bilateral common carotid artery occlusion model of vascular dementia in rats and injected the model rats with a suspension of GC (10 mg/kg/day, intraperitoneally) for 14 consecutive days. Immunohistochemistry showed that GC significantly reduced p-tau and amyloid beta (Abeta) immunoreactivity in the hippocampus of the model rats. Proteomic analysis demonstrated upregulation of mitochondrial precursor protein and downregulation of keratin type II cytoskeletal 6A after GC treatment compared with model rats that had received saline. Western blot assay confirmed these findings. Our results suggest that the neuroprotective effect of GC in vascular dementia occurs via the promotion of neuronal cytoskeleton regeneration. PMID- 28852400 TI - Long-term acupuncture treatment has a multi-targeting regulation on multiple brain regions in rats with Alzheimer's disease: a positron emission tomography study. AB - The acute effect of acupuncture on Alzheimer's disease, i.e., on brain activation during treatment, has been reported. However, the effect of long-term acupuncture on brain activation in Alzheimer's disease is unclear. Therefore, in this study, we performed long-term needling at Zusanli (ST36) or a sham point (1.5 mm lateral to ST36) in a rat Alzheimer's disease model, for 30 minutes, once per day, for 30 days. The rats underwent 18F-fluorodeoxyglucose positron emission tomography scanning. Positron emission tomography images were processed with SPM2. The brain areas activated after needling at ST36 included the left hippocampus, the left orbital cortex, the left infralimbic cortex, the left olfactory cortex, the left cerebellum and the left pons. In the sham-point group, the activated regions were similar to those in the ST36 group. However, the ST36 group showed greater activation in the cerebellum and pons than the sham-point group. These findings suggest that long-term acupuncture treatment has targeted regulatory effects on multiple brain regions in rats with Alzheimer's disease. PMID- 28852401 TI - Aldehyde dehydrogenase 2 overexpression inhibits neuronal apoptosis after spinal cord ischemia/reperfusion injury. AB - Aldehyde dehydrogenase 2 (ALDH2) is an important factor in inhibiting oxidative stress and has been shown to protect against renal ischemia/reperfusion injury. Therefore, we hypothesized that ALDH2 could reduce spinal cord ischemia/reperfusion injury. Spinal cord ischemia/reperfusion injury was induced in rats using the modified Zivin's method of clamping the abdominal aorta. After successful model establishment, the agonist group was administered a daily consumption of 2.5% alcohol. At 7 days post-surgery, the Basso, Beattie, and Bresnahan score significantly increased in the agonist group compared with the spinal cord ischemia/reperfusion injury group. ALDH2 expression also significantly increased and the number of apoptotic cells significantly decreased in the agonist group than in the spinal cord ischemia/reperfusion injury group. Correlation analysis revealed that ALDH2 expression negatively correlated with the percentage of TUNEL-positive cells (r = -0.485, P < 0.01). In summary, increased ALDH2 expression protected the rat spinal cord against ischemia/reperfusion injury by inhibiting apoptosis. PMID- 28852402 TI - Short-term observations of the regenerative potential of injured proximal sensory nerves crossed with distal motor nerves. AB - Motor nerves and sensory nerves conduct signals in different directions and function in different ways. In the surgical treatment of peripheral nerve injuries, the best prognosis is obtained by keeping the motor and sensory nerves separated and repairing the nerves using the suture method. However, the clinical consequences of connections between sensory and motor nerves currently remain unknown. In this study, we analyzed the anatomical structure of the rat femoral nerve, and observed the motor and sensory branches of the femoral nerve in the quadriceps femoris. After ligation of the nerves, the proximal end of the sensory nerve was connected with the distal end of the motor nerve, followed by observation of the changes in the newly-formed regenerated nerve fibers. Acetylcholinesterase staining was used to distinguish between the myelinated and unmyelinated motor and sensory nerves. Denervated muscle and newly formed nerves were compared in terms of morphology, electrophysiology and histochemistry. At 8 weeks after connection, no motor nerve fibers were observed on either side of the nerve conduit and the number of nerve fibers increased at the proximal end. The proportion of newly-formed motor and sensory fibers was different on both sides of the conduit. The area occupied by autonomic nerves in the proximal regenerative nerve was limited, but no distinct myelin sheath was visible in the distal nerve. These results confirm that sensory and motor nerves cannot be effectively connected. Moreover, the change of target organ at the distal end affects the type of nerves at the proximal end. PMID- 28852403 TI - Recovery of sympathetic nerve function after lumbar sympathectomy is slower in the hind limbs than in the torso. AB - Local sympathetic denervation by surgical sympathectomy is used in the treatment of lower limb ulcers and ischemia, but the restoration of cutaneous sympathetic nerve functions is less clear. This study aims to explore the recovery of cutaneous sympathetic functions after bilateral L2-4 sympathectomy. The skin temperature of the left feet, using a point monitoring thermometer, increased intraoperatively after sympathectomy. The cytoplasm of sympathetic neurons contained tyrosine hydroxylase and dopamine beta-hydroxylase, visualized by immunofluorescence, indicated the accuracy of sympathectomy. Iodine starch test results suggested that the sweating function of the hind feet plantar skin decreased 2 and 7 weeks after lumbar sympathectomy but had recovered by 3 months. Immunofluorescence and western blot assay results revealed that norepinephrine and dopamine beta-hydroxylase expression in the skin from the sacrococcygeal region and hind feet decreased in the sympathectomized group at 2 weeks. Transmission electron microscopy results showed that perinuclear space and axon demyelination in sympathetic cells in the L5 sympathetic trunks were found in the sympathectomized group 3 months after sympathectomy. Although sympathetic denervation occurred in the sacrococcygeal region and hind feet skin 2 weeks after lumbar sympathectomy, the skin functions recovered gradually over 7 weeks to 3 months. In conclusion, sympathetic functional recovery may account for the recurrence of hyperhidrosis after sympathectomy and the normalization of sympathetic nerve trunks after incomplete injury. The recovery of sympathetic nerve function was slower in the limbs than in the torso after bilateral L2-4 sympathectomy. PMID- 28852405 TI - Predictive determinants of scorpion stings in a tropical zone of south Iran: use of mixed seasonal autoregressive moving average model. AB - BACKGROUND: More than 1.2 million scorpion stings occur annually worldwide, particularly in tropical regions. In the absence of proper medical care, mortality due to venomous scorpion stings is an important public health issue. The aim of the present study is to explore the temporal trend of scorpionism with time series models and determine the effective factors on this event using regression models. METHODS: A retrospective cross sectional study was conducted on 853 scorpion stung patients. They were referred to Haji-Abad Hospital of Hormozgan University of Medical Sciences (HUMS), south Iran, from May 2012 to July 2016. A linear model to describe and predict the monthly trend of scorpion sting cases is fit with autoregressive moving average (ARMA) model. RESULTS: Of 853 victims, 384 (45%) patients were female and 30.2% of them lived in urban areas. The mean (+/- SD) age of patients was 30.1 (+/- 19.6) years and the most affected age group was 20-29 years (21.8%). Most victims were unemployed people and farmers (54.7%) followed by housewives (30.2%). The majority of the stings occurred indoors (53.7%), between midnight and 6 a.m. (29.2%), in the summer (44.2%), and the most affected limbs were hands and legs (81.2%). Patient genders and occasions of being stung by scorpions were significantly different between outdoors and indoors (p < 0.001). Scorpion stings due to Odontobuthus doriae were significantly higher than due to other species in urban and rural patients (p = 0.04). Mixed seasonal ARMA at lag 12, ARMA (1, 1) * (0, 1), was selected as the best process for monthly trend of data. Regression results indicated that significant climate factors associated with scorpion stings are temperature (p < 0.001) and relative humidity (p = 0.002). CONCLUSIONS: Scorpion stings have a noticeable effect on tropical rural populations, mainly farmers. Two effective climate factors associated positively and negatively with scorpion sting cases are temperature and relative humidity, respectively. The results of time series and regression models to predict the trends and determinants of scorpion stings are almost the same. PMID- 28852404 TI - Umbilical cord: an unlimited source of cells differentiable towards dopaminergic neurons. AB - Cell replacement therapy utilizing mesenchymal stem cells as its main resource holds great promise for ultimate treatment of human neurological disorders. Parkinson's disease (PD) is a common, chronic neurodegenerative disorder hallmarked by localized degeneration of a specific set of dopaminergic neurons within a midbrain sub-region. The specific cell type and confined location of degenerating neurons make cell replacement therapy ideal for PD treatment since it mainly requires replenishment of lost dopaminergic neurons with fresh and functional ones. Endogenous as well as exogenous cell sources have been identified as candidate targets for cell replacement therapy in PD. In this review, umbilical cord mesenchymal stem cells (UCMSCs) are discussed as they provide an inexpensive unlimited reservoir differentiable towards functional dopaminergic neurons that potentially lead to long-lasting behavioral recovery in PD patients. We also present miRNAs-mediated neuronal differentiation of UCMSCs. The UCMSCs bear a number of outstanding characteristics including their non tumorigenic, low-immunogenic properties that make them ideal for cell replacement therapy purposes. Nevertheless, more investigations as well as controlled clinical trials are required to thoroughly confirm the efficacy of UCMSCs for therapeutic medical-grade applications in PD. PMID- 28852406 TI - Regulation of Corticosteroidogenic Genes by MicroRNAs. AB - The loss of normal regulation of corticosteroid secretion is important in the development of cardiovascular disease. We previously showed that microRNAs regulate the terminal stages of corticosteroid biosynthesis. Here, we assess microRNA regulation across the whole corticosteroid pathway. Knockdown of microRNA using Dicer1 siRNA in H295R adrenocortical cells increased levels of CYP11A1, CYP21A1, and CYP17A1 mRNA and the secretion of cortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycorticosterone, and aldosterone. Bioinformatic analysis of genes involved in corticosteroid biosynthesis or metabolism identified many putative microRNA-binding sites, and some were selected for further study. Manipulation of individual microRNA levels demonstrated a direct effect of miR-125a-5p and miR-125b-5p on CYP11B2 and of miR-320a-3p levels on CYP11A1 and CYP17A1 mRNA. Finally, comparison of microRNA expression profiles from human aldosterone-producing adenoma and normal adrenal tissue showed levels of various microRNAs, including miR-125a-5p to be significantly different. This study demonstrates that corticosteroidogenesis is regulated at multiple points by several microRNAs and that certain of these microRNAs are differentially expressed in tumorous adrenal tissue, which may contribute to dysregulation of corticosteroid secretion. These findings provide new insights into the regulation of corticosteroid production and have implications for understanding the pathology of disease states where abnormal hormone secretion is a feature. PMID- 28852407 TI - The Association between Bone Quality and Atherosclerosis: Results from Two Large Population-Based Studies. AB - OBJECTIVE: It is highly debated whether associations between osteoporosis and atherosclerosis are independent of cardiovascular risk factors. We aimed to explore the associations between quantitative ultrasound (QUS) parameters at the heel with the carotid artery intima-media thickness (IMT), the presence of carotid artery plaques, and the ankle-brachial index (ABI). METHODS: The study population comprised 5680 men and women aged 20-93 years from two population based cohort studies: Study of Health in Pomerania (SHIP) and SHIP-Trend. QUS measurements were performed at the heel. The extracranial carotid arteries were examined with B-mode ultrasonography. ABI was measured in a subgroup of 3853 participants. Analyses of variance and linear and logistic regression models were calculated and adjusted for major cardiovascular risk factors. RESULTS: Men but not women had significantly increased odds for carotid artery plaques with decreasing QUS parameters independent of diabetes mellitus, dyslipidemia, and hypertension. Beyond this, the QUS parameters were not significantly associated with IMT or ABI in fully adjusted models. CONCLUSIONS: Our data argue against an independent role of bone metabolism in atherosclerotic changes in women. Yet, in men, associations with advanced atherosclerosis, exist. Thus, men presenting with clinical signs of osteoporosis may be at increased risk for atherosclerotic disease. PMID- 28852408 TI - Prevalence of Rhinitis in Athletes: Systematic Review. AB - BACKGROUND: Prevalence of rhinitis in athletes has frequently been studied and varies widely from 27% to 74%. The aim of this systematic review was to examine the prevalence of rhinitis in athletes, to specifically compare the evidence of rhinitis in land-based and aquatic athletes. METHODS: Systematic search of MEDLINE, EMBASE, and the non-MEDLINE subset of PubMed was performed from inception to March 8, 2016, to identify studies on rhinitis in athletes. RESULTS: Of the 373 identified unique articles, a total of 13 studies satisfied the criteria for this review. The final group contained 9 cohort and 4 case-control studies. We found 10 studies that reported the prevalence of allergic rhinitis (21%-56.5%). In contrast, nonallergic rhinitis was identified by only 1 author (6%). We have also evaluated the prevalence of rhinitis in the separate subgroups (land, water, and cold air) where swimmers seem to be the most affected (40% 74%), followed by cross-country skiers (46%) and track and field athletes (21 to 49%). CONCLUSION: We did not reveal any convincing trend of a higher prevalence in land-based athletes compared to general population. By contrast, aquatic and cold air athletes demonstrate increased prevalence reflecting the irritant effects of their environment on the nasal mucosa. PMID- 28852409 TI - Traumatic Brain Injury and Stem Cell: Pathophysiology and Update on Recent Treatment Modalities. AB - Traumatic brain injury (TBI) is a complex condition that presents with a wide spectrum of clinical symptoms caused by an initial insult to the brain through an external mechanical force to the skull. In the United States alone, TBI accounts for more than 50,000 deaths per year and is one of the leading causes of mortality among young adults in the developed world. Pathophysiology of TBI is complex and consists of acute and delayed injury. In the acute phase, brain tissue destroyed upon impact includes neurons, glia, and endothelial cells, the latter of which makes up the blood-brain barrier. In the delayed phase, "toxins" released from damaged cells set off cascades in neighboring cells eventually leading to exacerbation of primary injury. As researches further explore pathophysiology and molecular mechanisms underlying this debilitating condition, numerous potential therapeutic strategies, especially those involving stem cells, are emerging to improve recovery and possibly reverse damage. In addition to elucidating the most recent advances in the understanding of TBI pathophysiology, this review explores two primary pathways currently under investigation and are thought to yield the most viable therapeutic approach for treatment of TBI: manipulation of endogenous neural cell response and administration of exogenous stem cell therapy. PMID- 28852410 TI - Management of chronic spontaneous urticaria (CSU): a treat to target approach using a patient reported outcome. AB - BACKGROUND: Treat-to-target therapy approaches are established for chronic diseases such as diabetes, hypertension, and more recently rheumatoid arthritis, resulting in improved patient outcomes. These approaches do not use patient reported outcomes (PRO) as targets of therapy. Chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria (CIU), is defined as recurrent urticaria of known and unknown cause, lasting more than 6 weeks. Treatment of CSU can be challenging. However, with the advent of proven therapies and validated instruments for measuring disease activity, the concept of treat-to-target (T2T) can be successfully applied to CSU. Herein, we propose a potential PRO therapeutic target and suggest a T2T approach for the management of patients with CSU. METHODS: Principles and recommendations for a treat-to-target approach in CSU (T2T/CSU) were developed by a Canadian task force, consisting of dermatologists, immunologists, and allergists. The task force formulated recommendations for therapeutic targets in CSU on the basis of a systematic literature review and expert opinion. RESULTS: The key features of these T2T/CSU recommendations are the use of a PRO as the principal target, with symptom control as measured by Urticaria Activity Score 7 (UAS7 <= 6), targeting symptom remission (UAS7 = 0). CONCLUSION: Treatment targets such as UAS7 <= 6 and UAS7 = 0 provide a benchmark for success in the care of patients with CSU, and will permit the evaluation of a PRO-based T2T approach in the care of these patients and the effect of this approach on improved patient care as seen in other chronic diseases. PMID- 28852411 TI - Prevalence, Etiology, and Risk Factors of Tinea Pedis and Tinea Unguium in Tunisia. AB - BACKGROUND: Foot mycoses are a frequent disease that represents a public health problem worldwide. OBJECTIVES: This study aims to evaluate the epidemiology of foot mycoses among Tunisian patients, in order to determine the fungal etiological agents and to identify possible risk factors. PATIENTS AND METHODS: A prospective study of three hundred and ninety-two patients was undertaken during one year (2013-2014). All subjects were asked to collect demographic data related to the risk factors of foot mycoses. A complete mycological diagnosis was carried out on all patients. RESULTS: A total of 485 samples were collected; tinea pedis and tinea unguium were confirmed in 88.2% of cases. Dermatophytes were isolated in 70.5% and the most frequent pathogen was Trichophyton rubrum (98.1%), followed by yeasts (17.7%) commonly Candida parapsilosis. Non-dermatophyte molds (NDMs) were observed in 8.02% cases and Fusarium sp. was the frequent genus (29.1%). The main predisposing factors of fungal foot infections were practicing ritual washing (56.6%) and frequentation of communal showers (50.5%). CONCLUSION: This is a recent survey of foot mycoses in Tunisia. Epidemiological studies can be useful to eradicate these infections and to provide further measures of hygiene and education. PMID- 28852412 TI - Platonia insignis Mart., a Brazilian Amazonian Plant: The Stem Barks Extract and Its Main Constituent Lupeol Exert Antileishmanial Effects Involving Macrophages Activation. AB - Platonia insignis Mart., popularly known as "bacurizeiro," is used in traditional medical practices based on its diverse biological properties. This study was aimed at evaluating the antileishmanial effects of the ethanol extract (EtOH Ext), hexane fraction (Hex-F), and its main isolated Lupeol obtained from stem barks of P. insignis against Leishmania (Leishmania) amazonensis, as well as their cytotoxicity and possible mechanisms of action. The EtOH-Ext, Hex-F, and Lupeol inhibited the growth of L. amazonensis promastigote forms at IC50 of 174.24, 45.23, and 39.06 ug/mL, respectively, as well as L. amazonensis axenic amastigote forms at IC50 of 40.58, 35.87, and 44.10 ug/mL, respectively. The mean cytotoxic concentrations for macrophages (CC50) were higher than those for amastigotes (341.95, 71.65, and 144.0 ug/mL, resp.), indicating a selective cytotoxicity towards the parasite rather than the macrophages. Interestingly, all treatments promoted antileishmanial effect against macrophage-internalized amastigotes at concentrations lower than CC50. Furthermore, increases of lysosomal volume of macrophages treated with EtOH-Ext, Hex-F, and Lupeol were observed. On the other hand, only Lupeol stimulated increase of phagocytic capability of macrophages, suggesting this compound might be characterized as the biomarker for the antileishmanial effect of P. insignis stem bark, as well as the involvement of immunomodulatory mechanisms in this effect. PMID- 28852413 TI - Zanthoxylum heitzii Modulates Ferric Nitrilotriacetate-Dependent Oxidative Alterations in Four Vital Organs: An In Vitro Organoprotective Model. AB - Ferric nitrilotriacetate (Fe-NTA) is a highly reactive compound used to induce degenerative disorders through oxidative stress (OS). Zanthoxylum heitzii (Z. heitzii) is a spice used as a medicinal plant to treat a variety of illnesses. This study investigated the ability of extracts from the leaves, fruits, roots, and barks of Z. Heitzii to inhibit Fe-NTA mediated oxidative damage in rats. The supernatant of rat liver homogenates was pretreated with the extracts for one hour before the induction of oxidative damage using a solution of Fe-NTA (400 mM). The activities of superoxide dismutase (SOD), catalase, and peroxidases were measured together with the marker of lipid peroxidation and the level of glutathione. The pretreated groups showed a significant increase in the activity of SOD, catalase, and peroxidases. The methanolic extract from the leaves of Z. heitzii (36.78 +/- 3.30) and aqueous extract from the fruits (37.01 +/- 2.52) showed the highest activities of SOD in the liver. The lowest concentration of MDA was found in the liver, and the glutathione was greater in the brain. Conclusively, these results suggest that Z. heitzii might be a chemoprotector which may be used in for prevention of distinct types of diseases induced by oxidative stress. PMID- 28852414 TI - Systematic Review on Acupuncture for Treatment of Dysphagia after Stroke. AB - OBJECTIVE: To assess the therapeutic efficacy of acupuncture for dysphagia after stroke. METHODS: Seven electronic databases were searched from their inception until 31 September 2016. All randomized controlled trials (RCTs) incorporating acupuncture or acupuncture combined with other interventions for treatment of dysphagia after stroke were enrolled. Then they were extracted and assessed by two independent evaluators. Direct comparisons were conducted in RevMan 5.3.0 software. RESULTS: 6010 patients of 71 papers were included. The pooled analysis of efficacy rate of 58 studies indicated that acupuncture group was superior to the control group with moderate heterogeneity (RR = 1.17, 95% CI: 1.13 1.21, Z = 9.08, and P < 0.00001); meta-analysis of the studies using blind method showed that the efficacy rate of acupuncture group was 3.01 times that of control group with no heterogeneity (RR = 3.01, 95% CI: 1.95 4.65, Z = 4.97, and P < 0.00001). Only 13 studies mentioned the safety evaluation. CONCLUSION: The result showed that the acupuncture group was better than control group in terms of efficacy rate of dysphagia after stroke. And the combining result of those researches using blind method was more strong in proof. Strict evaluation standard and high quality RCT design are necessary for further exploration. PMID- 28852415 TI - Model checking in multiple imputation: an overview and case study. AB - BACKGROUND: Multiple imputation has become very popular as a general-purpose method for handling missing data. The validity of multiple-imputation-based analyses relies on the use of an appropriate model to impute the missing values. Despite the widespread use of multiple imputation, there are few guidelines available for checking imputation models. ANALYSIS: In this paper, we provide an overview of currently available methods for checking imputation models. These include graphical checks and numerical summaries, as well as simulation-based methods such as posterior predictive checking. These model checking techniques are illustrated using an analysis affected by missing data from the Longitudinal Study of Australian Children. CONCLUSIONS: As multiple imputation becomes further established as a standard approach for handling missing data, it will become increasingly important that researchers employ appropriate model checking approaches to ensure that reliable results are obtained when using this method. PMID- 28852416 TI - Effectiveness of experiential learning with empowerment strategies and social support from grandmothers on breastfeeding among Thai adolescent mothers. AB - BACKGROUND: Grandmothers are important to successful breastfeeding because their knowledge, attitudes and experiences influence adolescent mothers' decision to initiate and to continue breastfeeding. The purpose of this study was to assess the effectiveness of an experiential learning with empowerment strategies and social support (ELESSS) programme for grandmothers according to improvements in the rate and duration of exclusive breastfeeding (EBF); knowledge and attitude (KA) regarding breastfeeding; and perceived social support among adolescent mothers. METHODS: A quasi-experimental study was conducted in two hospitals, Banmi as an intervention hospital and Inburi as a control hospital, between May 2015 and March 2016. Forty-two pairs of adolescent mothers and grandmothers were recruited from each hospital. At the baseline, grandmothers in the intervention group attended 2 days of an ELESSS programme, and they attended a refresher course 2 and 4 months after delivery. The grandmothers in the control group and adolescent mothers in both groups received the routine programme. Participants were assessed at the baseline and at two and 6 months after delivery to determine the rate and duration of EBF, KA regarding breastfeeding and perceived social support. RESULTS: Adolescent mothers in the intervention group had the EBF rate at 6 months of around 29%, whereas the control group had the EBF rate at 6 months of about 5%, and the proportion of EBF in the intervention group was six times that of the control group. The median EBF duration in the intervention group was 90 days, while the control group was 0 day. A repeated measure ANOVA analysis showed that the intervention group's participants had significantly better knowledge and attitudes towards breastfeeding, while the adolescent mothers in the intervention group had a significantly higher perceived level of social support. CONCLUSION: The ELESSS programme proved to be effective in increasing the rate and duration of EBF in adolescent mothers. Grandmothers are key to promoting, protecting and supporting breastfeeding. TRIAL REGISTRATION: ClinicalTrials.in.th: TCTR20161001002. PMID- 28852417 TI - Partially local three-way alignments and the sequence signatures of mitochondrial genome rearrangements. AB - BACKGROUND: Genomic DNA frequently undergoes rearrangement of the gene order that can be localized by comparing the two DNA sequences. In mitochondrial genomes different mechanisms are likely at work, at least some of which involve the duplication of sequence around the location of the apparent breakpoints. We hypothesize that these different mechanisms of genome rearrangement leave distinctive sequence footprints. In order to study such effects it is important to locate the breakpoint positions with precision. RESULTS: We define a partially local sequence alignment problem that assumes that following a rearrangement of a sequence F, two fragments L, and R are produced that may exactly fit together to match F, leave a gap of deleted DNA between L and R, or overlap with each other. We show that this alignment problem can be solved by dynamic programming in cubic space and time. We apply the new method to evaluate rearrangements of animal mitogenomes and find that a surprisingly large fraction of these events involved local sequence duplications. CONCLUSIONS: The partially local sequence alignment method is an effective way to investigate the mechanism of genomic rearrangement events. While applied here only to mitogenomes there is no reason why the method could not be used to also consider rearrangements in nuclear genomes. PMID- 28852418 TI - Danggui Buxue Tang, a simple Chinese formula containing Astragali Radix and Angelicae Sinensis Radix, stimulates the expressions of neurotrophic factors in cultured SH-SY5Y cells. AB - BACKGROUND: Danggui Buxue Tang (DBT), a phytoestrogen-enriched Chinese herbal formula, serves as dietary supplement in stimulating the "Blood" functions of menopausal women. In traditional Chinese medicine (TCM) theory, "Blood" has a strong relationship with brain activities. Previous studies supported that some ingredients of DBT possessed neuronal beneficial functions. Therefore, the neurotrophic function and the mechanistic action of DBT were systematically evaluated in cultured human neuroblastoma SH-SY5Y cells. METHODS: The DBT triggered protein expressions were analyzed by western blotting, while the transcriptional activities of promoters coding for related genes were revealed by luciferase assays. For mechanistic analysis of DBT, Erk1/2 and its inhibitor U0126 were analyzed. RESULTS: The application of DBT in cultured neuroblastoma cells showed the efficacies in: (1) up-regulation of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF); (2) activation of transcriptional activities of promoters coding for NGF, BDNF, GDNF; (3) activation of Erk1/2 and CREB; and (4) attenuation of the neurotrophic factor expression by the treatment of an Erk1/2 inhibitor. CONCLUSIONS: Our study supports that MAPK/Erk pathway acts as fundamental role in monitoring DBT-induced expression of neurotrophic factors in cultured human neuroblastoma cell. These results shed light in developing the working mechanism of this ancient herbal decoction for its neuronal function. PMID- 28852419 TI - Diagnostic value of prothrombin induced by the absence of vitamin K or antagonist II (PIVKA-II) for early stage HBV related hepatocellular carcinoma. AB - BACKGROUND: To evaluate the diagnostic efficacy of prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) for early stage hepatitis virus B (HBV) related hepatocellular carcinoma (HCC). METHODS: Serums levels of PIVKA II and a-Fetoprotein (AFP) was detected and compared in 113 patients with clinical confirmed Barcelona Clinic Liver Cancer (BCLC) stage 0-A HBV-related HCC and 161 chronic hepatitis B (CHB) patients. Diagnostic efficiencies as well as cut-off values of PIVKA-II, AFP and combination of the two markers were calculated using receiver operator curve (ROC) analysis. RESULTS: The mean level of PIVKA-II among HCC patients were 79.64 +/- 149.88, significantly higher than control group (P < 0.001). ROC results showed that among those AFP-negative HCC patients, the area under ROC curve (AUROC) of PIVKA-II was 0.73 (95%CI 0.640 0.815, P < 0.001). Among HCC patients diagnosed with small HCC (tumor size <=2 cm), the AUROC of PIVKA- II was 0.692 (95%CI 0.597-0.788, P < 0.001). To evaluate the diagnostic value of PIVKA-II in HCC patient, all CHB cases were pooled together as control for analysis. The AUROC of PIVKA-II was 0.756 (95%CI 0.698 0.814, P < 0.001), and the optimal cutoff value of PIVKA-II was 32.09 mAU/ml with sensitivity of 52.21% and specificity of 81.49%. When serum levels of PIVKA-II and AFP were combined to obtain a new marker for HCC diagnosis, PIVKA-II + AFP further increased diagnostic efficiency, with AUROC of 0.868 (95%CI 0.822-0.913), higher than that of AFP (P < 0.01) or PIVKA-II (P < 0.001) alone. In addition, we found that HCC patients in poorly differentiated- undifferentiated group and in microvascular invasion group had higher levels of PIVKA-II. Multivariate analysis showed that high serum PIVKA-II level (OR = 1.003, 95%CI 1.001-1.007, P = 0.047) was an independent risk factor for microvascular invasion in HCC patients. CONCLUSION: Serum PIVKA-II level is a potential marker for early diagnosis of HCC and microvascular invasion. The use of PIVKA-II may improve assessment of tumor prognosis and guide development of therapeutic strategy. PMID- 28852420 TI - Co-rumination buffers the link between social anxiety and depressive symptoms in early adolescence. AB - OBJECTIVES: We examined whether co-rumination with online friends buffered the link between social anxiety and depressive symptoms over time in a community sample. METHODS: In a sample of 526 participants (358 girls; Mage = 14.05) followed at three time points, we conducted a latent cross-lagged model with social anxiety, depressive symptoms, and co-rumination, controlling for friendship stability and friendship quality, and adding a latent interaction between social anxiety and co-rumination predicting depressive symptoms. RESULTS: Social anxiety predicted depressive symptoms, but no direct links between social anxiety and co-rumination emerged. Instead, co-rumination buffered the link between social anxiety and depressive symptoms for adolescents with higher but not lower levels of social anxiety. CONCLUSIONS: These findings indicate that co rumination exerted a positive influence on interpersonal relationships by diminishing the influence from social anxiety on depressive symptoms over time. PMID- 28852421 TI - Metagenomic mining pectinolytic microbes and enzymes from an apple pomace-adapted compost microbial community. AB - BACKGROUND: Degradation of pectin in lignocellulosic materials is one of the key steps for biofuel production. Biological hydrolysis of pectin, i.e., degradation by pectinolytic microbes and enzymes, is an attractive paradigm because of its obvious advantages, such as environmentally friendly procedures, low in energy demand for lignin removal, and the possibility to be integrated in consolidated process. In this study, a metagenomics sequence-guided strategy coupled with enrichment culture technique was used to facilitate targeted discovery of pectinolytic microbes and enzymes. An apple pomace-adapted compost (APAC) habitat was constructed to boost the enrichment of pectinolytic microorganisms. RESULTS: Analyses of 16S rDNA high-throughput sequencing revealed that microbial communities changed dramatically during composting with some bacterial populations being greatly enriched. Metagenomics data showed that apple pomace adapted compost microbial community (APACMC) was dominated by Proteobacteria and Bacteroidetes. Functional analysis and carbohydrate-active enzyme profiles confirmed that APACMC had been successfully enriched for the targeted functions. Among the 1756 putative genes encoding pectinolytic enzymes, 129 were predicted as novel (with an identity <30% to any CAZy database entry) and only 1.92% were more than 75% identical with proteins in NCBI environmental database, demonstrating that they have not been observed in previous metagenome projects. Phylogenetic analysis showed that APACMC harbored a broad range of pectinolytic bacteria and many of them were previously unrecognized. CONCLUSIONS: The immensely diverse pectinolytic microbes and enzymes found in our study will expand the arsenal of proficient degraders and enzymes for lignocellulosic biofuel production. Our study provides a powerful approach for targeted mining microbes and enzymes in numerous industries. PMID- 28852422 TI - Enhanced polyhydroxyalkanoate (PHA) production from the organic fraction of municipal solid waste by using mixed microbial culture. AB - BACKGROUND: In Europe, almost 87.6 million tonnes of food waste are produced. Despite the high biological value of food waste, traditional management solutions do not consider it as a precious resource. Many studies have reported the use of food waste for the production of high added value molecules. Polyhydroxyalkanoates (PHAs) represent a class of interesting bio-polyesters accumulated by different bacterial cells, and has been proposed for production from the organic fraction of municipal solid waste (OFMSW). Nevertheless, until now, no attention has been paid to the entire biological process leading to the transformation of food waste to organic acids (OA) and then to PHA, getting high PHA yield per food waste unit. In particular, the acid-generating process needs to be optimized, maximizing OA production from OFMSW. To do so, a pilot-scale Anaerobic Percolation Biocell Reactor (100 L in volume) was used to produce an OA rich percolate from OFMSW which was used subsequently to produce PHA. RESULTS: The optimized acidogenic process resulted in an OA production of 151 g kg-1 from fresh OFMSW. The subsequent optimization of PHA production from OA gave a PHA production, on average, of 223 +/- 28 g kg-1 total OA fed. Total mass balance indicated, for the best case studied, a PHA production per OFMSW weight unit of 33.22 +/- 4.2 g kg-1 from fresh OFMSW, corresponding to 114.4 +/- 14.5 g kg-1 of total solids from OFMSW. PHA composition revealed a hydroxybutyrate/hydroxyvalerate (%) ratio of 53/47 and Mw of 8?105 kDa with a low polydispersity index, i.e. 1.4. CONCLUSIONS: This work showed how by optimizing acidic fermentation it could be possible to get a large amount of OA from OFMSW to be then transformed into PHA. This step is important as it greatly affects the total final PHA yield. Data obtained in this work can be useful as the starting point for considering the economic feasibility of PHA production from OFMSW by using mixed culture. PMID- 28852423 TI - Single cell oil production by Trichosporon cutaneum from steam-exploded corn stover and its upgradation for production of long-chain alpha,omega-dicarboxylic acids. AB - BACKGROUND: Single cell oil (SCO) production from lignocelluloses by oleaginous microorganisms is still high in production cost, making the subsequent production of biofuels inviable economically in such an era of low oil prices. Therefore, how to upgrade the final products of lignocellulose-based bioprocess to more valuable ones is becoming a more and more important issue. RESULTS: Differently sourced cellulases were compared in the enzymatic hydrolysis of the steam exploded corn stover (SECS) and the cellulase from the mixed culture of Trichoderma reesei and Aspergillus niger was found to have the highest enzymatic hydrolysis yield 86.67 +/- 4.06%. Three-stage enzymatic hydrolysis could greatly improve the efficiency of the enzymatic hydrolysis of SECS, achieving a yield of 74.24 +/- 2.69% within 30 h. Different bioprocesses from SECS to SCO were compared and the bioprocess C with the three-stage enzymatic hydrolysis was the most efficient, producing 57.15 g dry cell biomass containing 31.80 g SCO from 327.63 g SECS. An efficient and comprehensive process from corn stover to long chain alpha,omega-dicarboxylic acids (DCAs) was established by employing self metathesis, capable of producing 6.02 g long-chain DCAs from 409.54 g corn stover and 6.02 g alkenes as byproducts. CONCLUSIONS: On-site cellulase production by the mixed culture of T. reesei and A. niger is proven the most efficient in providing cellulase to the lignocellulose-based bioprocess. Three-stage enzymatic hydrolysis was found to have very good application value in SCO production by Trichosporon cutaneum from SECS. A whole process from corn stover to long-chain DCAs via a combination of biological and chemical approaches was successfully established and it is an enlightening example of the comprehensive utilization of agricultural wastes. PMID- 28852425 TI - Evaluation of three read-depth based CNV detection tools using whole-exome sequencing data. AB - BACKGROUND: Whole exome sequencing (WES) has been widely accepted as a robust and cost-effective approach for clinical genetic testing of small sequence variants. Detection of copy number variants (CNV) within WES data have become possible through the development of various algorithms and software programs that utilize read-depth as the main information. The aim of this study was to evaluate three commonly used, WES read-depth based CNV detection programs using high-resolution chromosomal microarray analysis (CMA) as a standard. METHODS: Paired CMA and WES data were acquired for 45 samples. A total of 219 CNVs (size ranged from 2.3 kb - 35 mb) identified on three CMA platforms (Affymetrix, Agilent and Illumina) were used as standards. CNVs were called from WES data using XHMM, CoNIFER, and CNVnator with modified settings. RESULTS: All three software packages detected an elevated proportion of small variants (< 20 kb) compared to CMA. XHMM and CoNIFER had poor detection sensitivity (22.2 and 14.6%), which correlated with the number of capturing probes involved. CNVnator detected most variants and had better sensitivity (87.7%); however, suffered from an overwhelming detection of small CNVs below 20 kb, which required further confirmation. Size estimation of variants was exaggerated by CNVnator and understated by XHMM and CoNIFER. CONCLUSION: Low concordances of CNV, detected by three different read-depth based programs, indicate the immature status of WES-based CNV detection. Low sensitivity and uncertain specificity of WES-based CNV detection in comparison with CMA based CNV detection suggests that CMA will continue to play an important role in detecting clinical grade CNV in the NGS era, which is largely based on WES. PMID- 28852424 TI - Screening and evolution of a novel protist xylose isomerase from the termite Reticulitermes speratus for efficient xylose fermentation in Saccharomyces cerevisiae. AB - BACKGROUND: The yeast Saccharomyces cerevisiae, a promising host for lignocellulosic bioethanol production, is unable to metabolize xylose. In attempts to confer xylose utilization ability in S. cerevisiae, a number of xylose isomerase (XI) genes have been expressed heterologously in this yeast. Although several of these XI encoding genes were functionally expressed in S. cerevisiae, the need still exists for a S. cerevisiae strain with improved xylose utilization ability for use in the commercial production of bioethanol. Although currently much effort has been devoted to achieve the objective, one of the solutions is to search for a new XI gene that would confer superior xylose utilization in S. cerevisiae. Here, we searched for novel XI genes from the protists residing in the hindgut of the termite Reticulitermes speratus. RESULTS: Eight novel XI genes were obtained from a cDNA library, prepared from the protists of the R. speratus hindgut, by PCR amplification using degenerated primers based on highly conserved regions of amino acid sequences of different XIs. Phylogenetic analysis classified these cloned XIs into two groups, one showed relatively high similarities to Bacteroidetes and the other was comparatively similar to Firmicutes. The growth rate and the xylose consumption rate of the S. cerevisiae strain expressing the novel XI, which exhibited highest XI activity among the eight XIs, were superior to those exhibited by the strain expressing the XI gene from Piromyces sp. E2. Substitution of the asparagine residue at position 337 of the novel XI with a cysteine further improved the xylose utilization ability of the yeast strain. Interestingly, introducing point mutations in the corresponding asparagine residues in XIs originated from other organisms, such as Piromyces sp. E2 or Clostridium phytofermentans, similarly improved xylose utilization in S. cerevisiae. CONCLUSIONS: A novel XI gene conferring superior xylose utilization in S. cerevisiae was successfully isolated from the protists in the termite hindgut. Isolation of this XI gene and identification of the point mutation described in this study might contribute to improving the productivity of industrial bioethanol. PMID- 28852426 TI - Cross-cultural adaptation and validation of Spanish version of The Foot and Ankle Ability Measures (FAAM-Sp). AB - BACKGROUND: The Foot and Ankle Ability Measure (FAAM) is a Patient Reported Outcome (PRO) commonly used to determine the effectiveness of therapeutic interventions for patients with foot and ankle pathologies and associated impairments of body function and structure, activity limitations, and participation restrictions. The aim of this study was to cross-culturally adapt the FAAM into Spanish. METHODS: Cross-cultural adaptation was performed according to the international guidelines of the International Society for Pharmacoeconomics and Outcomes Research. Cronbach's alpha, test re-test reliability, and item-total and inter-item correlations were analyzed. Confirmatory factor analysis (CFA) was carried out to test construct validity. Pearson correlations were calculated to assess the convergent validity between FAAM and EuroQol-5. RESULTS: Spanish data set comprised 194 patients, with a mean age of 38.45 (16.04) and 130 (67.1%) were female, seeing a podiatrist with a wide variety of foot and ankle related disorders. CFA was carried out to test structure matrix (which has three factors). The test-retest reliability was high with global ICC of 0.95 (95% CI: 0.93 to 0.98). A 15 items version of the FAAM-Sp Activities of Daily Living (ADL) obtained the best fit: relative chi-square (x2/df) of 2.46, GFI 0.90 CFI 0.95, NFI 0.93, and RMSEA 0.08 (90% CI 0.04 to 0.09). For exploratory factor analysis for the FAAM-Sp Sport, a one factor solution was obtained, which explained 76.70% of total variance. CFA corroborated this model with an excellent goodness of fit:: relative chi-square (x2/df) of 0.80, GFI 0.99 CFI 1.00, NFI 0.99, and RMSEA 0.00 (90% CI 0.00 to 0.75). CONCLUSIONS: This study validated a new 15-item FAAM-Sp ADL and FAAM-Sp Sport subscales, which can be used as a self-reported outcome measure in clinical practice and research for patients resident in Spain whose main language is Spanish. PMID- 28852428 TI - Compartmentalized embryoid body culture for induction of spatially patterned differentiation. AB - We developed a compartmentalized culture system of single embryoid bodies (EBs) utilizing a through-hole on a membrane to induce spatially patterned differentiation. An EB derived from mouse pluripotent stem cells was immobilized on the through-hole. By introducing a stem cell maintenance medium and a differentiation medium into upper and lower culture compartments, respectively, a localized differentiated state was achieved only in the lower part of EB, which is exposed to the medium in the lower compartment. This system may enable us to reconstruct complex tissues and to recapitulate developmental processes using EBs. PMID- 28852427 TI - Seven-CpG-based prognostic signature coupled with gene expression predicts survival of oral squamous cell carcinoma. AB - BACKGROUND: DNA methylation has started a recent revolution in genomics biology by identifying key biomarkers for multiple cancers, including oral squamous cell carcinoma (OSCC), the most common head and neck squamous cell carcinoma. METHODS: A multi-stage screening strategy was used to identify DNA-methylation-based signatures for OSCC prognosis. We used The Cancer Genome Atlas (TCGA) data as training set which were validated in two independent datasets from Gene Expression Omnibus (GEO). The correlation between DNA methylation and corresponding gene expression and the prognostic value of the gene expression were explored as well. RESULTS: The seven DNA methylation CpG sites were identified which were significantly associated with OSCC overall survival. Prognostic signature, a weighted linear combination of the seven CpG sites, successfully distinguished the overall survival of OSCC patients and had a moderate predictive ability for survival [training set: hazard ratio (HR) = 3.23, P = 5.52 * 10-10, area under the curve (AUC) = 0.76; validation set 1: HR = 2.79, P = 0.010, AUC = 0.67; validation set 2: HR = 3.69, P = 0.011, AUC = 0.66]. Stratification analysis by human papillomavirus status, clinical stage, age, gender, smoking status, and grade retained statistical significance. Expression of genes corresponding to candidate CpG sites (AJAP1, SHANK2, FOXA2, MT1A, ZNF570, HOXC4, and HOXB4) was also significantly associated with patient's survival. Signature integrating of DNA methylation, gene expression, and clinical information showed a superior ability for prognostic prediction (AUC = 0.78). CONCLUSION: Prognostic signature integrated of DNA methylation, gene expression, and clinical information provides a better prognostic prediction value for OSCC patients than that with clinical information only. PMID- 28852429 TI - Bioprinted 3D vascularized tissue model for drug toxicity analysis. AB - To develop biomimetic three-dimensional (3D) tissue constructs for drug screening and biological studies, engineered blood vessels should be integrated into the constructs to mimic the drug administration process in vivo. The development of perfusable vascularized 3D tissue constructs for studying the drug administration process through an engineered endothelial layer remains an area of intensive research. Here, we report the development of a simple 3D vascularized liver tissue model to study drug toxicity through the incorporation of an engineered endothelial layer. Using a sacrificial bioprinting technique, a hollow microchannel was successfully fabricated in the 3D liver tissue construct created with HepG2/C3A cells encapsulated in a gelatin methacryloyl hydrogel. After seeding human umbilical vein endothelial cells (HUVECs) into the microchannel, we obtained a vascularized tissue construct containing a uniformly coated HUVEC layer within the hollow microchannel. The inclusion of the HUVEC layer into the scaffold resulted in delayed permeability of biomolecules into the 3D liver construct. In addition, the vascularized construct containing the HUVEC layer showed an increased viability of the HepG2/C3A cells within the 3D scaffold compared to that of the 3D liver constructs without the HUVEC layer, demonstrating a protective role of the introduced endothelial cell layer. The 3D vascularized liver model presented in this study is anticipated to provide a better and more accurate in vitro liver model system for future drug toxicity testing. PMID- 28852430 TI - Porous monolith microfluidics for bacterial cell-to-cell communication assays. AB - Genetically engineered bacteria can be used for a wide range of applications, from monitoring environmental toxins to studying complex communication networks in the human digestive system. Although great strides have been made in studying single strains of bacteria in well-controlled microfluidic environments, there remains a need for tools to reliably control and measure communication between multiple discrete bacterial populations. Stable long-term experiments (e.g., days) with controlled population sizes and regulated input (e.g., concentration) and output measurements can reveal fundamental limits of cell-to-cell communication. In this work, we developed a microfluidic platform that utilizes a porous monolith to reliably and stably partition adjacent strains of bacteria while allowing molecular communication between them for several days. We measured small molecule production by the bacterial populations in response to stimuli using analytical chemistry methods and measured fluorescent output. The results are compared with communication and diffusion delay models. This porous monolith microfluidic system enables bacterial cell-to-cell communication assays with dynamic control of inputs, relatively long-term experimentation with no cross contamination, and stable bacterial population size. This system can serve as a valuable tool in understanding bacterial communication and improving biosensor design capabilities. PMID- 28852431 TI - Generating 2-dimensional concentration gradients of biomolecules using a simple microfluidic design. AB - This study reports a microfluidic device for generating 2-dimensional concentration gradients of biomolecules along the width and length of a chamber and conventional 1-dimensional gradients along the width of its lateral parallel channels. The gradient profile can be precisely controlled by the applied flow rate. The proposed design is simple and straightforward, has a small footprint size compared to previously reported devices such as tree-shape designs, and for the first time, provides capability of generating desired 2D and 1D gradients, simultaneously. The finite element simulation analysis proves the feasibility of the microfluidic device, and the fluorescently labelled IgG antibody is used to demonstrate generated chemical gradients. This simple microfluidic device can be implemented for a wide range of high-throughput concentration gradient applications such as chemotaxis, drug screening, and organs-on-chips. PMID- 28852432 TI - On the kinematics-wave motion of living particles in suspension. AB - This work presents theoretical and experimental analyses on the kinematics-wave motion of suspended active particles in a biological fluid. The fluid is an active suspension of nematodes immersed in a gel-like biological structure, moving at a low Reynolds number. The nematode chosen for the study is Caenorhabditis elegans. Its motion is subjected to the time reversibility of creeping flows. We investigate how this worm reacts to this reversibility condition in order to break the flow symmetry and move in the surrounding fluid. We show that the relationship between the length of an individual nematode and the wavelength of its motion is linear and can be fitted by a theoretical prediction proposed in this work. We provide a deep discussion regarding the propulsion mechanics based on a scaling analysis that identifies three major forces acting on an individual nematode. These forces are a viscous force, a yield stress force due to gelification of agar molecules in the gel-like medium, and a bending force associated with the muscular tension imposed by the nematodes in the medium. By the scalings, we identify the most relevant physical parameters of the nematode's motion. In order to examine and quantify the motion, dynamical system tools such as FFT are used in the present analysis. The motion characterization is performed by examining (or studying) two different populations: (i) in the absence of food with starving nematodes and (ii) with well-fed nematodes. In addition, several kinematic quantities of the head, center of mass, and tail for a sample of nematodes are also investigated: their slip velocities, wavelengths, trajectories, frequency spectra, and mean curvatures. The main findings of this work are the confirmation of a linear relationship between the nematode's physical length and its motion wavelength, the identification of secondary movements in high frequencies that helps breaking the time-reversibility in which the worms are bonded, and the observation and interpretation of a systematic difference between the individual motion of well fed and starving nematodes. PMID- 28852433 TI - Cytokines Genotype-Phenotype Correlation in Nonalcoholic Steatohepatitis. AB - NASH consists in lipid accumulation in hepatocytes that trigger oxidative stress, secretion of proinflammatory cytokines leading to steatohepatitis (NASH). The study aimed to investigate the levels of proinflammatory (TNF-alpha and IL-6) along with anti-inflammatory cytokine IL-10 in patients with NASH and to correlate the cytokines' level with their polymorphism. Sixty-six patients with NASH and 30 healthy volunteers were included in the study. The plasmatic level of IL-6, IL-10, and TNF-alpha were determined by ELISA. IL-10 -1082 G/A, IL-6 -174 G/C, and TNF-alpha -308 G/A polymorphisms were determined using the PCR-RFLP technique. IL-6, TNF-alpha, and CRP levels were significantly higher in patients with NASH. There was a positive correlation between proinflammatory cytokines and a negative correlation between IL-10 and proinflammatory markers. The G allele and GG genotype of IL-6 -174 G/C polymorphism were more frequently noticed in NASH patients. Regarding IL-10 -1082 G/A polymorphism, the AA genotype was correlated with NASH and with a low plasmatic level of IL-10. The A allele in position 308 of the TNF-alpha gene was associated with high level of cytokine. In conclusion, there was an imbalance between pro- and anti-inflammatory cytokines in NASH patients. IL-10 -1082 G/A and TNF-alpha -308 G/A genotypes were correlated with the plasmatic levels of cytokines. PMID- 28852434 TI - A New Natural Antioxidant Mixture Protects against Oxidative and DNA Damage in Endothelial Cell Exposed to Low-Dose Irradiation. AB - Exposure to ionizing radiation during diagnostic procedures increases systemic oxidative stress and predisposes to higher risk of cancer and cardiovascular disease development. Many studies indicated that antioxidants protect against radiation-induced damage and have high efficacy and lack of toxicity in preventing radiation exposure damages. The purpose of this study was to investigate the in vitro protective effect of a new antioxidant mixture, named RiduROS, on oxidative stress generation and DNA double-strand breaks (DSBs) induced by low doses of X-rays in endothelial cells. Human umbilical vein endothelial cells (HUVEC) were treated with RiduROS mixture 24 h before a single exposure to X-rays at an absorbed dose of 0.25 Gy. The production of reactive oxygen species (ROS) was evaluated by fluorescent dye staining and nitric oxide (NO) by the Griess reaction, and DSBs were evaluated as number of gamma-H2AX foci. We demonstrated that antioxidant mixture reduced oxidative stress induced by low dose of X-ray irradiation and that RiduROS pretreatment is more effective in protecting against radiation-induced oxidative stress than single antioxidants. Moreover, RiduROS mixture is able to reduce gamma-H2AX foci formation after low-dose X-ray exposure. The texted mixture of antioxidants significantly reduced oxidative stress and gamma-H2AX foci formation in endothelial cells exposed to low-dose irradiation. These results suggest that RiduROS could have a role as an effective radioprotectant against low-dose damaging effects. PMID- 28852436 TI - Feasibility and toxicity of hematopoietic stem cell transplant in multiple sclerosis. AB - Multiple sclerosis is a debilitating disease of the central nervous system. It affects people of all ages but is more prevalent among 20-40 year olds. Patients with MS can be presented with potentially any neurological symptom depending on the location of the lesion. A quarter of patients with MS suffer from bilateral lower limb spasticity among other symptoms. These devastating effects can be detrimental to the patient's quality of life. Hematopoietic stem cells (HSCs) have been used as a treatment for MS over the past 2 decades but their safety and efficacy has are undetermined. The objective of this study is to evaluate the feasibility and toxicity of autologous HSCs transplantation in MS. A literature search was done from 1997 to 2016 using different keywords. A total of 9 articles, which met the inclusion and exclusion criteria, were included in this review. The type of conditioning regimen and technique of stem cell mobilization are summarized and compared in this study. All studies reported high-dose immunosuppressive therapy with autologous HSCs transplantation being an effective treatment option for severe cases of multiple sclerosis. Fever, sepsis, and immunosuppression side effects were the most observed adverse effects that were reported in the selected studies. HSCs is a feasible treatment for patients with MS; nevertheless the safety is still a concern due to chemo toxicity. PMID- 28852435 TI - Complete Genome sequence of the nematicidal Bacillus thuringiensis MYBT18246. AB - 10.1601/nm.5000 is a rod-shaped facultative anaerobic spore forming bacterium of the genus 10.1601/nm.4857. The defining feature of the species is the ability to produce parasporal crystal inclusion bodies, consisting of delta-endotoxins, encoded by cry-genes. Here we present the complete annotated genome sequence of the nematicidal 10.1601/nm.5000 strain MYBT18246. The genome comprises one 5,867,749 bp chromosome and 11 plasmids which vary in size from 6330 bp to 150,790 bp. The chromosome contains 6092 protein-coding and 150 RNA genes, including 36 rRNA genes. The plasmids encode 997 proteins and 4 t-RNA's. Analysis of the genome revealed a large number of mobile elements involved in genome plasticity including 11 plasmids and 16 chromosomal prophages. Three different nematicidal toxin genes were identified and classified according to the Cry toxin naming committee as cry13Aa2, cry13Ba1, and cry13Ab1. Strikingly, these genes are located on the chromosome in close proximity to three separate prophages. Moreover, four putative toxin genes of different toxin classes were identified on the plasmids p120510 (Vip-like toxin), p120416 (Cry-like toxin) and p109822 (two Bin-like toxins). A comparative genome analysis of 10.1601/nm.5000 MYBT18246 with three closely related 10.1601/nm.5000 strains enabled determination of the pan genome of 10.1601/nm.5000 MYBT18246, revealing a large number of singletons, mostly represented by phage genes, morons and cryptic genes. PMID- 28852437 TI - A novel treatment approach for retinoblastoma by targeting epithelial growth factor receptor expression with a shRNA lentiviral system. AB - OBJECTIVES: Non-invasive treatment options for retinoblastoma (RB), the most common malignant eye tumor among children, are lacking. Epithelial growth factor receptor (EGFR) accelerates cell proliferation, survival, and invasion of many tumors including RB. However, RB treatment by targeting EGFR has not yet been researched. In the current study, we investigated the effect of EGFR down regulation on RB progression using shRNA lentiviral vectors. MATERIALS AND METHODS: EGFR expression in Weri-Rb-1 cells was down-regulated by EGFR shRNA bearing lentiviral vectors. Cell death, proliferation, cell cycle as well as invasion after EGFR down-regulation were determined. Further signaling pathway analysis was done by Western blot. RESULTS: Our results revealed that EGFR shRNA could specifically down-regulate EGFR expression and down-regulation of this protein promoted cell death. Further analysis on cell cycle demonstrated that EGFR down-regulation also suppressed cell proliferation by arresting cells at G1 phase. Invasion analysis showed that EGFR down-regulation suppressed cell invasion and was correlated with alteration in the expression of matrix metalloproteinases 2 and 9. Further signaling pathway analysis revealed that EGFR down-regulation mediated RB progression was through PI3K/AKT/mTOR signaling pathway. CONCLUSION: Our study revealed that EGFR down-regulation, through the PI3K/AKT/mTOR signaling pathway, could inhibit RB progression by promoting cell death while suppressing cell proliferation and invasion. The findings of our study indicated that down-regulation of EGFR using shRNA lentiviral vectors may offer a novel non-invasive treatment for RB. PMID- 28852438 TI - Effect of eugenol on lithium-pilocarpine model of epilepsy: behavioral, histological, and molecular changes. AB - OBJECTIVES: Epilepsy establishment gives rise to biochemical and morphological changes in the hippocampus. Oxidative stress, morphological changes, and mossy fiber sprouting (MFS) in the hippocampus underpin the epilepsy establishment. Eugenol is the main component of the essential oil extracted from cloves with the potential to modulate neuronal excitability. Therefore, we investigated the effect of eugenol on convulsive behavior, oxidative stress, and histological changes of the hippocampus in lithium-pilocarpine model of epilepsy. MATERIALS AND METHODS: Male Wistar rats weighing 220-250 g were divided into 4 groups; Control, Pilocarpine, Eugenol-Pilocarpine, and Eugenol. Oxidative stress markers were assayed by a biochemical method. Nissl and Timm staining were used to show neuronal survival and MFS, respectively. Behavioral convulsions were evaluated using the modified Racine scale. RESULTS: Eugenol decreased seizure stage and duration as well as mortality. Neuronal numbers were preserved by eugenol treatment in epileptic animals, while eugenol alone reduced the number by itself in all hippocampal sub-regions including DG, CA3, and CA1. Furthermore, eugenol alone increased MDA, GPx and SOD markers, while it increased MDA not only in combined treatment with pilocarpine but also in pilocarpine-treated animals. In contrast to MFS enhancement in naive animals, eugenol partially reversed the MFS enhancement induced by pilocarpine. CONCLUSION: Eugenol could prevent behavioral convulsions and show neuroprotective effects through increasing neuronal survival probably by decreasing MFS and increasing the GPx antioxidant marker. PMID- 28852439 TI - Crocin has anti-inflammatory and protective effects in ischemia-reperfusion induced renal injuries. AB - OBJECTIVES: Crocus sativus (saffron) has been widely used in traditional medicine. It has also been found to possess many beneficial properties in modern medicine. The most important ingredients of saffron are crocin, crocetin, safranal, and picrocrocin. This study evaluated the protective effects of crocin against the inflammation, oxidative stress, and functional disturbances of the kidney induced by renal ischemia/reperfusion (I/R). MATERIALS AND METHODS: Different doses of crocin (0, 100, 200, and 400 mg/kg) were administered intraperitoneally 30 min before I/R. The rats of the sham group were also injected with normal saline before the sham surgery. For induction of I/R, both renal artery and vein clamped for 30 min, bilaterally. The I/R-induced renal injuries were assessed by measuring leukocyte infiltration, intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor-alpha (TNF-alpha) mRNA expression levels, malondialdehyde (MDA) and ferric reducing/antioxidant power (FRAP) levels in the kidney tissue, and plasma creatinine and urea-nitrogen concentrations. RESULTS: Except for the tissue level of FRAP which decreased, all other measured parameters increased following I/R induction. Pretreatment with all doses of crocin significantly reduced the severity of these disturbances (P<0.05 to P<0.001). In fact, while there was no significant differences between MDA and FRAP levels, plasma creatinine and urea-nitrogen concentrations of the crocin-treated animals and the sham group, crocin administration reduced leukocyte infiltration and ICAM-1 and TNF-alpha mRNA expression levels in a dose dependent manner. CONCLUSION: The present study clearly demonstrated the anti inflammatory, antioxidant, and protective effects of crocin, a main constituent of saffron, against renal damages resulted from I/R in rats. PMID- 28852440 TI - The cardioprotective effect of vanillic acid on hemodynamic parameters, malondialdehyde, and infarct size in ischemia-reperfusion isolated rat heart exposed to PM10. AB - OBJECTIVES: Particulate matter (PM) exposure can promote cardiac ischemia and myocardial damage. The effects of PM10 on hemodynamic parameters, lipid peroxidation, and infarct size induced by ischemia-reperfusion injury and the protective effects of vanillic acid (VA) in isolated rat heart were investigated. MATERIALS AND METHODS: Eighty male Wistar rats (250-300 g) were divided into 8 groups (n=10): Control, Sham, VAc, VA, PMa (0.5 mg/kg PM, intratracheal instillation), PMb (2.5 mg/kg PM, intratracheal instillation), PMc (5 mg/kg PM, intratracheal instillation), and PMc + VA (5 mg/kg PM, intratracheal instillation; and 10 mg/kg vanillic acid, gavage for 10 days). PM10 was instilled into the trachea in two stages, within 48 hr. After isolating the hearts and transfer to a Langendorff apparatus, hearts were subjected to 30 min ischemia and 60 min reperfusion. Hemodynamic parameters (+/-dp/dt, LVSP, LVDP, and RPP), production of lipid peroxidation (MDA), and infarct size were assessed. RESULTS: A significant decrease in +/-dp/dt, LVSP, LVDP and RPP occurred in PM groups. A significant increase in MDA and myocardial infarct size occurred in PM groups. A significant increase in LVDP, LVSP, +/-dp/dt, RPP and decrease in infarct size, MDA, and myocardial dysfunction was observed in groups that received vanillic acid after ischemia-reperfusion. CONCLUSION: It was demonstrated that PM10 increases MDA, as well as the percentage of cardiac infarct size, and has negative effects on hemodynamic parameters. This study suggests that vanillic acid may serve as an adjunctive treatment in delaying the progression of ischemic heart disease. PMID- 28852441 TI - Expression of pro-inflammatory genes in lesions, spleens and blood neutrophils after burn injuries in mice treated with silver sulfodiazine. AB - OBJECTIVES: It is now supposed that cytokines released during the burn injuries have a great impact on the immunological and pathological responses after the burn. The main objective of this study was to investigate the expression of some pro-inflammatory genes in the wound, spleen and blood neutrophils during the healing process of burn wounds in a murine model. MATERIALS AND METHODS: The expression of ten pro-inflammatory genes were examined in wounds, spleens and blood neutrophils of mice with burn injuries treated with either silver sulfodiazine or phosphate-buffered saline (PBS) using RT-PCR at the end of the first and second weeks after injuries. RESULTS: None of the pro-inflammatory genes were expressed in the skin, spleen and blood neutrophils of healthy mice. In the group control, IL-12P35, IL-12P40, CCR5, IL-1beta and IFN-gamma were expressed in the spleen and blood neutrophils in the first week. Instead, CCL5, CCR5, IL-1beta and IFN-gamma were expressed in the wound, but in the second week, the expression of the genes became similar. In the test group, in the first week, TNF-alpha, IL-12P35, IL-12P40 and IL-1beta were expressed in the lesions, CCL4, IL-1alpha, IL-12P35, IL-12P40, CCR5 and IFN-gamma were expressed in the spleen and no pro-inflammatory gene expression was detected in blood neutrophils. CONCLUSION: IL-1beta and IFN-gamma are expressed in wound, spleen and neutrophils of untreated mice, but not in silver sulfodiazine treated mice. Hence, treatment with silver sulfodiazine suppressed the expression of pro-inflammatory genes in some stages of healing. PMID- 28852442 TI - Cardiovascular effects of nitrergic system of the pedunculopontine tegmental nucleus in anesthetized rats. AB - OBJECTIVES: Nitric oxide (NO) is an important neurotransmitter in central nervous system involved in central cardiovascular regulation. The presence of NO in the pedunculopontine tegmental (PPT) nucleus has been shown, but its cardiovascular effect has not been determined. In the present study, the cardiovascular effect of NO in the PPT nucleus was evaluated. MATERIALS AND METHODS: After induction of anesthesia, a polyethylene catheter (PE-50) filled with heparinized saline inserted into the femoral artery, and the blood pressure (BP) and heart rate (HR) were continuously recorded. Animals were then placed in a stereotaxic apparatus and maximum changes of mean arterial pressure (?MAP) and heart rate (?HR) after microinjection of two doses of NG-nitro-L-arginine methyl ester (L-NAME, 30 and 90 nmol), L-arginine (L-Arg 10 and 50 nmol) and sodium nitroprusside (SNP, 9 and 27 nmol) into the PPT were provided and compared with control group (One-way ANOVA). RESULTS: Both doses of L-NAME significantly increased ?MAP compared to control (P<0.05 and P<0.01, respectively). ?HR only in higher dose (90 nmol) significantly increased compared to control (P<0.05). Two doses of L-Arg (10 and 50 nmol/150 nl) had no significant effect on ?MAP or ?HR. Higher dose of SNP (27 nmol) significantly decreased ?MAP (P<0.05) and its both doses significantly decreased ?HR compared to control (P<0.05 and P<0.001, respectively). Effect of higher dose on ?HR was significantly higher than the lower dose (P<0.05). CONCLUSION: Our results show an inhibitory effect of the nitrergic system of the PPT on central cardiovascular system. PMID- 28852443 TI - miR-92a promotes hepatocellular carcinoma cells proliferation and invasion by FOXA2 targeting. AB - OBJECTIVES: MicroRNAs (miRNAs) are considered as powerful, post-transcriptional regulators of gene expression in hepatocellular carcinoma cells (HCC). However, the function of miR-92a is still unclear in HCC. MATERIALS AND METHODS: Expression of miR-92a in human HCC cell lines was evaluated using qRT-PCR. MTT assay and transwell assay were used to examine the function of miR-92a in HepG2 and Huh7 cells. Bioinformatic analyses and luciferase reporter assays were used to validate FOXA2 as a direct target gene of miR-92a. Consistently, the biological outcome of miR-92a on regulating FOXA2 was examined by proliferation and invasion analysis in vitro. RESULTS: Here, we detected the higher expression of miR-92a in human HCC cell lines, such as HepG2, Huh7 and Hep3B, compared with the normal human hepatocyte L02 cells. Overexpression of miR-92a significantly increased cell growth and invasion ability, while the knockdown of miR-92a could remarkably inhibit the growth and invasion possibility. We identified that miR 92a has specific targeting sites in the 3'-UTR of the FOXA2. By overexpressing miR-92a in HepG2 cells or Huh7 cells, the expression of FOXA2 was remarkably repressed. CONCLUSION: We demonstrated that miR-92a may play a critical role in HCC proliferation and invasion and may serve as a novel therapeutic target by the repression of FOXA2. PMID- 28852444 TI - Heterologous expression of a truncated form of human recombinant vascular endothelial growth factor-A and its biological activity in wound healing. AB - OBJECTIVES: Vascular endothelial growth factor (VEGF) is one of the most effective proteins in angiogenesis, mesenchymal stem cells (MSCs) differentiation and wound healing. These abilities are therapeutic potential of VEGF in diabetic retinopathy, nephropathy and other tissue damage circumstances. In this study, recombinant VEGF was produced in Escherichia coli (E. coli) system and then biological activity of this protein was evaluated in animal wound healing. MATERIALS AND METHODS: E. coli BL21 (DE3) competent cells were transformed with pET32a-VEGF clone and induced by isopropyl-beta-D-thio-galactoside (IPTG). The recombinant protein was purified by affinity chromatography. Recombinant VEGF-A based ointment (VEGF/Vaseline 0.8 mg/100 w/w) was used for external wound (25*15mm thickness) healing in animal model. In vivo activity of ointment was evaluated by clinical evidences and cytological microscopic assessment. RESULTS: The recombinant protein with molecular weight of 45 kilodaltons (kDa) and concentration of 0.8 mg/ml was produced. Immunoblotting data showed that the antigenic region of VEGF can be expressed in E. coli and the recombinant protein has similar epitopes with close antigenic properties to the natural form. Macroscopic findings and microscopic data showed that the recombinant VEGF-A ointment was effective on excisional wound healing. CONCLUSION: Recombinant VEGF A produced by pET32a in E. coli, possesses acceptable structure and has wound healing capability. PMID- 28852445 TI - Evaluation of phytochemicals, antioxidant and burn wound healing activities of Cucurbita moschata Duchesne fruit peel. AB - OBJECTIVES: Cucurbita moschata Duchesne (pumpkin) is a well-known plant with several pharmacological effects. The aim of the present study was to assess burn wound healing activity of C. moschata peel extract (CE). Also, standardized CE was assessed for antioxidant activity and antibacterial effects against major pathogens of burns. MATERIALS AND METHODS: Healing properties of topical preparation of 10% and 20% concentrations of CE were assessed on second degree burn in rats during a 14-day period as well as histological studies, total antioxidant power, lipid peroxidation and total thiol content of skin tissue samples. RESULTS: Radical scavenging IC50 and ferric-reducing antioxidant power value were 4.015+/-0.20 mg/ml and 142.63+/-2.65 mmol Fe2+/g, respectively. Total mucilage content was 13.8%. The optimal results were obtained by 20% CE that showed 90.80+/-5.86 % wound closure and tissue repair as well as significant reduction of tissue oxidative stress biomarkers. Histological analyses confirmed wound healing activity of pumpkin peel extract. CONCLUSION: Considering the high mucilage content of the plant, providing a moist environment for wound, C. moschata peel extract could be a natural remedy for treatment of burns. Further clinical studies are suggested to confirm C. moschata peel extract as a wound healing agent. PMID- 28852446 TI - Effect of chondroitinase ABC on inflammatory and oxidative response following spinal cord injury. AB - OBJECTIVES: Chondroitinase ABC (cABC) treatment improves functional recovery following spinal cord injury (SCI) through degrading inhibitory molecules to axon growth. However, cABC involvement in other pathological processes contributing to SCI remains to be investigated. Here, we studied the effect of cABC I on oxidative stress and inflammation developed in a rat model of SCI. MATERIALS AND METHODS: Male rats (220-250 g) were divided into three groups (n=28) including rats that underwent SCI (SCI group), rats subjected to SCI and received an intrathecal injection of phosphate buffer saline (SCI+PBS group), and rats that underwent SCI and received cABC intrathecally (SCI+E group). Then, the level of TNF-alpha, Il-1beta, malondialdehyde, nitric oxide, and myeloperoxidase in injured tissues, as well as hindlimb motor function, were measured at 4 hr, 1, 3 and 7 days post-SCI. RESULTS: Our data showed that cABC treatment reduced the development of inflammation and oxidative stress associated with SCI at all-time points. In addition, functional recovery was improved in rats that received cABC at 7 days post-SCI. CONCLUSION: The present findings indicate that cABC treatment can exert its neuroprotective effect through modulation of post-traumatic inflammatory and oxidative response. PMID- 28852447 TI - Naringin attenuates diabetic retinopathy by inhibiting inflammation, oxidative stress and NF-kappaB activation in vivo and in vitro. AB - OBJECTIVES: Naringin, an essential flavonoid, inhibits inflammatory response and oxidative stress in diabetes. However, whether naringin has beneficial effects on diabetic retinopathy (DR) remains unknown. MATERIALS AND METHODS: Streptozotocin (STZ, 65 mg/kg) was intraperitoneally injected into male rats (8 weeks old weighting 200-250 g) to establish diabetic model, then naringin (20, 40 or 80 mg/kg/day) was intraperitoneally injected into the diabetic rats for twelve weeks. Glial fibrillary acidic protein (GFAP) level, thickness of ganglion cell layer (GCL) and ganglion cell counts were assessed in diabetic retina in vivo. Naringin (50 MUM) that significantly inhibited high glucose (HG, 25 mM)-induced cell proliferation was used to treat rat Muller cell line (rMC1) in vitro. Inflammatory response, oxidative stress and activation of nuclear factor kappa B (NF-kappaB) p65 were evaluated in retina in vivo and in rMC1 cells in vitro. RESULTS: Naringin alleviated DR symptoms as evidenced by the increased retinal ganglion cells and decreased GFAP level in rat retina. Naringin exhibited anti inflammatory and antioxidative effects as confirmed by the down-regulated pro inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and interleukin-6 (IL-6), and the up-regulated antioxidants, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in DR rats. Moreover, we found that naringin inhibited HG-induced proliferation, abnormal inflammatory response and oxidative stress in rMC1 cells. In addition, the enhanced nuclear translocation of NF-kappaB p65 in diabetic rat retina and HG induced rMC1 cells was suppressed by naringin. CONCLUSION: Naringin attenuates inflammatory response, oxidative stress and NF-kappaB activation in experimental models of DR. PMID- 28852448 TI - GABAB receptors within the central nucleus of amygdala may involve in the morphine-induced incentive tolerance in female rats. AB - OBJECTIVES: Central nucleus of amygdala (CeA) is the most important region for morphine-induced reward, and GABAergic system plays an important role on morphine reinforcement. The influence of CeA administration of GABAB receptor agonist and antagonist on the expression and acquisition of morphine-induced incentive tolerance using conditioned place preference (CPP) paradigm was investigated in the present study. Our purpose was to evaluate the role of CeA GABAB receptors in morphine tolerance. MATERIALS AND METHODS: Seven days after surgery and cannulation, the experiments were begun. Subcutaneous (SC) injections of morphine induced CPP. Administration of one daily dose of morphine (12.5 mg/kg) for 3 days in order to develop tolerance to the drug reduced the conditioning induced by morphine (7.5 mg/kg, SC). GABAB receptor agonist, baclofen (1.5, 6 and 12 ug/rat) or GABAB receptor antagonist, CGP35348 (1.5, 6 and 12 ug/rat) were injected into the CeA 5 min before the experiments in the test day (expression of tolerance) or 5 min before each injection of morphine (12.5 mg/kg) (acquisition of tolerance). RESULTS: It was shown that injections of baclofen (1.5 and 12 ug/rat) reduced acquisition, whereas the dose of 6 ug/rat of the drug exacerbated the acquisition of morphine tolerance. Baclofen at all doses significantly increased the expression of tolerance to morphine. Administration of CGP35348 (1.5, 6 and 12 ug/rat) reduced the acquisition and expression of morphine tolerance. CONCLUSION: These results confirmed the importance of GABAB receptors with in the CeA in morphine tolerance in female rats. PMID- 28852449 TI - Umbelliprenin induced both anti-inflammatory and regulatory cytokines in C57/BL6 mice. AB - OBJECTIVES: Umbelliprenin is a prenyloxy-coumarin with pharmacologically polyvalent activity. Several studies have shown Several studies have been shown its anti-inflammatory, anti-tumor, antioxidant, and antigenotoxic activities. However, the exact mechanism of action of this compound on the immune response has not yet been shown. Here, we investigated umbelliprenin effects on the predominance of Th1 and Th2 responses in normal C57/BL6 mice. MATERIALS AND METHODS: Umbelliprenin (2.5 mg/200 ul IP) were administered to six C57/BL6 mice every other day for 8 days. Paraffin and PBS-injected mice were enrolled as solvent and control groups, respectively (n=6 mice/group). IL-10, IFN-gamma, and IL-4 levels were determined in sera and also in splenocytes culture supernatants in the presence of Con A (3 ug/ml) after 72 hr. H&E staining of paraffin embedded blocks was performed for lung and liver tissues of mice. RESULTS: Umbelliprenin could significantly increase the secretion of IFN-gamma and IL-4 in sera and IL 10 in splenocytes cultures. Comparison of IFN-gamma/IL-4 in the sera and splenocytes culture supernatants showed lower ratios in umbelliprenin treated mice than in solvent and untreated groups. CONCLUSION: The in vivo study showed that umbelliprenin could induce anti-inflammatory responses via the predominance of Th2 cells and some regulatory responses in C57/BL6 mice. PMID- 28852450 TI - Staging of colorectal cancer using serum metabolomics with 1HNMR Spectroscopy. AB - OBJECTIVES: Determination of stages of colon cancer is done by biopsy usually after surgery. Metabolomics is the study of all the metabolites using LC-MS and 1HNMR spectroscopy with chemometric techniques. The stages of colon cancer were detected from patients' sera using 1HNMR. MATERIALS AND METHODS: Five ml blood was collected from 16 confirmed patients referred for colonoscopy. One group of eight patients were diagnosed with stage 0 to I colon cancer and the second group of 8 patients with II-IV stage colon cancer. Sera were sent for 1HNMR. The differentiating metabolites were identified using HMDB and the metabolic cycles from Metaboanalyst. RESULTS: Six metabolites of which pyridoxine levels lowered, and glycine, cholesterol, taurocholic acid, cholesteryl ester and deoxyinosine increased. CONCLUSION: The different stages of cancer were identified by the main metabolic cycles such as primary bile acid biosynthesis, purine and vitamin B metabolic pathways and the glutathione cycle. PMID- 28852451 TI - Neurofibromatosis type 1 and male breast cancer: emerging risk factor? AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by the appearance of cafe au lait spots, neurofibromas and Lisch nodules. There is an established link between NF1 and the development of breast cancer in women; however, due to the rarity of both NF1 and male breast cancer, the same link has yet to be elucidated in men. The concurrent presentation of NF1 and male breast cancer is a very rare phenomenon with only a handful of case descriptions in the literature. To the best of our knowledge, there have only been four other reported cases of NF1 and male breast cancer before ours. We present one such case of a 56-year-old male with a four generation history of NF1 and a personal history of NF1 who presented with invasive ductal carcinoma of the right breast. PMID- 28852452 TI - Adrenal incidentaloma in a patient with HIV/AIDS. AB - Human immunodeficiency virus (HIV) is well known to be associated with various neoplasms and opportunistic infections. Kaposi sarcoma (KS), associated with human herpes virus 8 (HHV8) infection, is the most common tumour in HIV positive patients and is also an acquired immune deficiency syndrome (AIDS) defining illness. Cutaneous manifestations are the most common presenting symptom; however, visceral involvement is also recognized. We present the case of a 55 year-old male who was diagnosed with AIDS-related KS, who was referred to our surgical unit with an indeterminate left adrenal lesion. He subsequently started antiretroviral therapy and given the indeterminate nature of his adrenal lesion, we performed a laparoscopic left adrenalectomy, with KS of the adrenal gland confirmed on histology. PMID- 28852453 TI - Myomectomies for massive hemoperitoneum from spontaneous bleeding of a uterine myoma. AB - Massive hemoperitoneum from spontaneous bleeding of uterine myoma is an extremely rare condition, that needs urgent surgical exploration. We report a 40-year-old woman, admitted for acute onset of abdominal pain. Physical examination revealed hypovolemic shock. The hemoglobin level was of 5 g/dL. Ultrasonography revealed hemoperitoneum. Emergency surgical exploration was planned. There was hemoperitoneum of 3 L, uterine myomas with multiple subserous myomas, bleeding from superficial ruptured varice overlying the most largest subserous myoma, which measured 15 cm. Glove adapted as a tourniquet, was applied at the base of the uterus, and myomectomies were performed with removal of around twenty myomas. The postoperative course was uneventful. Myomectomies can be safely and effectively performed by using a tourniquet, for massive hemoperitoneum with precarious hemodynamic status due to subserous myoma bleeding, despite the number and the size of myomas. PMID- 28852454 TI - Minimally invasive management of traumatic lung herniation. AB - Post-traumatic pulmonary hernia can occur immediately after thoracic trauma or it may also appear months or even years after the onset. We report a case of a seventeen year-old male patient with thoracic blunt trauma secondary to high energy bicycle accident. Chest CT shows moderate hemothorax and pneumothorax, displaced fracture of the fifth left rib, and protusion of pulmonary tissue through a chest wall defect. In the Emergency Room the patient presents with chest pain (7/10 in Visual Analog Scale) and respiratory distress. Video-assisted thoracic surgery approach was chosen. Hernia reduction, non-anatomic lingular resection and rib fracture external fixation using a titanium plate was performed. Traumatic pulmonary hernia is an uncommon complication of thoracic trauma which may constitute an emergency for the trauma or thoracic surgeon. The early management of this injury can be developed by minimally invasive approach with excellent results. PMID- 28852455 TI - Eccrine angiokeratomatous hamartoma: case report of a 1.5-year girl. AB - Eccrine angiokeratomatous hamartoma is a rare newly defined vascular lesion of the skin, the first case of which was reported in 2006 (Kanitakis J, Ly A, Claudy A. Eccrine angiokeratomatous hamartoma: a new variant of eccrine hamartoma with angiokeratoma. J Am Acad Dermatol 2006; 55: S104-6). On web Literature Search, Only three previously documented cases of the lesions were found. A 1.5-year-old female child presented with a painless lesion on her right leg since birth which has been gradually increasing in size and recently developed central ulceration. Histological examination of the excised lesion confirmed the diagnosis. This is the first of the cases to be reported in paediatric age-group (<2 years). PMID- 28852456 TI - A rare diaphragmatic hernia with a delayed presentation of intestinal symptoms following spleno-distal pancreatectomy: a case report. AB - Acquired diaphragmatic hernia, non-related to trauma, is a very rare condition. It can constitute a therapeutic problem and the surgical solution is not always immediately clear. We report the case of a 73-year-old woman with a history of spleno-distal pancreatectomy for a neuroendocrine tumour performed in 2009, who came back to Emergency Room 2 years later, complaining of abdominal pain. Chest radiography and computed tomography were performed; they showed a diaphragmatic hernia with visceral migration into the thorax. The diaphragmatic defect was surgically repaired and the patient had an uneventful post-operative recovery. PMID- 28852457 TI - Syndrome of inappropriate antidiuretic hormone associated with rectal small cell neuroendocrine carcinoma: a case report. AB - Neuroendocrine tumors can arise from any portion of the gastrointestinal tract including the colon and rectum. In the scope of all colon and rectal malignancies, they are a rare cause of colorectal carcinoma. Relating to their pluripotent neuroendocrine cellular origins these carcinomas can produce a variety of biologically active peptides with several resultant paraneoplastic syndromes. One of these paraneoplastic syndromes is the syndrome of inappropriate antidiuretic hormone (SIADH). In the SIADH, supraphysiologic levels of vasopressin (antidiuretic hormone, AVP) precipitates exorbitant free water retention and resultant electrolyte abnormalities, most notably hyponatremia. Herein we report a rare case of paraneoplastic SIADH from rectal small cell neuroendocrine carcinoma. To our knowledge, SIADH from rectal small cell neuroendocrine carcinoma has been reported only three times. PMID- 28852458 TI - A long-term survival case after surgical resection of skeletal muscle metastasis following esophagectomy for squamous cell carcinoma of the esophagus. AB - Cases of skeletal muscle metastasis of esophageal carcinoma are very rare, with few reports of long-term survival. We report a case of long-term survival after surgical resection of skeletal muscle metastasis. A 56-year-old man with advanced esophageal cancer and early gastric cancer underwent thoracoscopic esophagectomy, 2-field lymph node dissection, partial gastrectomy and gastric tube reconstruction. Six months later, cervical lymph node metastasis and mediastinal lymph node recurrence were found. Therefore, the patient underwent cervical lymph node dissection and adjuvant chemoradiotherapy. Two years and 3 months after the esophagectomy, a muscle metastasis was found in the left shoulder, and he underwent tumor dissection, followed by adjuvant chemotherapy for a year. There has been no sign of recurrence since, even 13 years after the esophagectomy. We believe our aggressive surgical treatment might have led to long-term survival. PMID- 28852459 TI - Multifocal rib osteomyelitis in children: a case report and literature review. AB - Rib osteomyelitis is a rare disease, occurring in ~1% or less of all cases of haematogenous osteomyelitis. During the last century, 58 cases of rib osteomyelitis were reported in the literature, of which, multiple ribs were involved in only five patients. Because of its rarity and non-specific clinical signs, diagnostic of rib osteomyelitis may be delayed. We report a case of multifocal rib osteomyelitis revealed by a dorsal mass in a healthy 13-year-old female child. PMID- 28852460 TI - Ureterovaginal fistula following spontaneous vaginal delivery, repaired by vaginal ureteroneocystostomy in a low resource setting. AB - Ureterovaginal fistula commonly follows ureteric injury during pelvic surgery, and presents with continuous urinary incontinence in spite of normal micturition. Continuous urinary incontinence has significant impact on quality of life, thus requiring effective surgical intervention in order to restore health. We found no reported case of ureterovaginal fistula following spontaneous vaginal delivery with prolonged obstructed labour. Relevant history and simple diagnostic procedures were used for diagnosis and the patient had successful vaginal ureteroneocystostomy. This could be the first reported ureterovaginal fistula following spontaneous vaginal delivery with prolonged obstructed labour. Vaginal ureteroneocystostomy though scarcely reported, is feasible in selected cases. PMID- 28852461 TI - Case report: an atypical presentation of Eagle syndrome. AB - Elongation of the styloid process occurs in 4-7% of individuals. In the majority this elongation is asymptomatic. Presence of oropharyngeal pain and dysphagia with such elongation is known as Eagle syndrome. The aetiology of Eagle syndrome is believed to be a reactive osseus hyperplasia of the styloid process in response to pharyngeal trauma or surgical intervention, such as tonsillectomy. We present a case of a 72-year-old lady with a twelve month history of left sided oropharyngeal pain and worsening dysphagia, presenting with a long, slender, bony intraoral projection found to be an elongated styloid process. She previously underwent tonsillectomy and radiotherapy on the left side for a tonsillar carcinoma. Surgical reduction of the elongated styloid process via intraoral approach led to immediate post-operative pain relief and normal swallowing. We conclude that this atypical presentation of Eagle syndrome was caused by the patient's prior treatment for tonsillar carcinoma. PMID- 28852462 TI - Non-curative surgery for aortoenteric fistula. AB - Graft infection with secondary aortic fistula is a rare complication following implantation of aortic prostheses, frequently occurring after emergency procedures and reoperations. The condition is associated with considerable morbidity and mortality. Curative treatment consists of explantation of the infected graft followed by fistula revision and implantation of a new graft in combination with antimicrobial therapy. Non-curative treatment with aortic stentgraft and long-term substitution treatment with antibiotics may be an option in cases where graft explantation is deemed too risky. We present an elderly patient with aortoenteric fistula following surgery for ruptured abdominal aortic aneurysm. Implantation of an aortic stentgraft and fistula revision was performed but the original aortic prosthesis was not explanted. The aortoenteric fistula recurred twice, but the patient has survived more than 12 years following non curative surgery with good quality of life. PMID- 28852463 TI - Laparoscopic splenic cyst fenestration-a viable spleen preserving option. AB - Cystic lesions of the spleen are a rare encounter in surgical practice and are broadly split into two categories: true and false, depending upon the presence of a defined epithelial lining. True cysts can further be broken down into parasitic and non-parasitic origins while false or pseudocysts tend to develop commonly after a traumatic event. We present here a 23-year-old female who came to the clinic with symptoms of abdominal fullness, early satiety and left flank pain which was diagnosed as a large splenic cyst after radiology confirmation. The patient was prepared and underwent laparoscopic splenic cyst fenestration successfully without any complications. Laparoscopic fenestration for benign uncomplicated splenic cysts is a viable alternative to splenectomy with low rates of recurrence and less patient morbidity along with the advantage of preservation of splenic function. PMID- 28852464 TI - Missed diagnosis of a large, right-sided diaphragmatic rupture with herniated liver and concomitant liver laceration after blunt trauma: consequences for delayed surgical repair. AB - Diaphragmatic injuries are relatively rare and as such frequently missed, particularly if they occur as a rare event on the right-sided dome. Even if detected in the early phase, the concomitant injury of other organs may delay the time to repair. The delay in surgical correction may aggravate additional adherences between thoracic and abdominal organs and cause the diaphragmatic muscle to retract, causing a larger tissue defect that may prevent primary suture repair. This should be taken into consideration when choosing access to repair (thoracic, abdominal or both cavities), mode (open or laparoscopic) and type of repair (primary suture or use of mesh material to close the defect). Here we present a case of delayed right-sided, blunt diaphragmatic injury with herniation of liver. Repair was performed in a delayed manner with an initial laparoscopic exploration converted to open abdominal repair with closing of defect with Gore tex mesh material. PMID- 28852465 TI - Gallbladder bleeding associated with microscopic polyangiitis: a case report. AB - A 71-year-old male who had a 6 years history of microscopic polyangiitis (MPA) was admitted to our hospital with a chief complaint of upper abdominal pain and nausea. Abdominal contrast-enhanced CT revealed extravasation of contrast medium in the gallbladder, and the patient was diagnosed with gallbladder bleeding. Although we started conservative treatment, anemia, hypotension and tachycardia had progressed gradually. Therefore, we performed emergent laparoscopic cholecystectomy on the following day. Intraoperative findings showed a remarkably distended gallbladder due to interior clots; however, the cholecystitis itself was not significant. Histopathological findings showed infiltrations of inflammatory cells around the blood vessels and vascular rupture. The postoperative course was uneventful. MPA is a type of ANCA-associated vasculitis. To the best of our knowledge, this is the first report of gallbladder bleeding associated with MPA. Spontaneous hemostasis cannot be expected, instead, surgical treatment must be performed promptly. PMID- 28852466 TI - An omental fibroma resembling a testicular tumour but presented as an irreducible inguinal hernia. AB - We present a case of omental fibroma, which posed a surgical diagnostic dilemma. Primary tumours of the omentum are uncommon, and omental fibromas account for 2% of these. The rarity of omental fibroma and paucity of available information hamper an accurate diagnosis. In this particular case, the diagnostic process was misleading. The history was classical of an irreducible inguinal hernia, but the physical examination and imaging studies were suggestive of a testicular tumour. However, intraoperatively, an omental tumour and a normal testicle were found in the scrotum. Histopathological examination proved the tumour to be a fibroma. The presentation of an omental fibroma in an inguinal hernia sac had never been reported in literature. Due to the rarity of such cases, a thorough history, detailed examination, and objective investigation are the pillars to attain the correct diagnosis. PMID- 28852467 TI - Activity of anthracycline- and ifosfamide-based chemotherapy in a series of patients affected by advanced myxofibrosarcoma. AB - BACKGROUND: We report on the activity of anthracycline-based and high-dose prolonged-infusion ifosfamide chemotherapy in a retrospective series of patients affected by advanced myxofibrosarcoma treated at Istituto Nazionale Tumori in Milan, Italy, and within the Italian Rare Cancer Network (RTR). METHODS: Advanced myxofibrosarcoma patients treated with anthracycline + ifosfamide and high-dose prolonged-infusion ifosfamide as a single agent from November 2001 to December 2016 were retrospectively reviewed. All pathological diagnosis were centrally reviewed by at least two expert pathologists. Response was evaluated by RECIST, and survival functions were computed. RESULTS: Among 34 advanced myxofibrosarcoma patients, 13 were treated with front-line anthracycline + ifosfamide chemotherapy (male/female = 6/7, median age 54 years, range 33-72). Overall best response was: 4 partial responses, 3 stable diseases and 6 progressive diseases, with a median progression-free survival of 4 months. Twenty-eight patients received second/further line high-dose prolonged-infusion ifosfamide (male/female = 17/11, median age 55 years, range 27-75 years). We observed 10 partial responses, 4 stable diseases and 14 progressive diseases, with a median progression-free survival of 4 months. Median overall survival was 12 months. CONCLUSIONS: This retrospective analysis suggests that the combination of anthracyclines and ifosfamide is active in myxofibrosarcoma. In patients already treated with a combination of anthracyclines and ifosfamide, high-dose prolonged-infusion ifosfamide showed activity as well. PMID- 28852468 TI - Phosphorylation of astrocytic connexin43 by ERK1/2 impairs blood-brain barrier in acute cerebral ischemia. AB - BACKGROUND: Connexins are a family of transmembrane proteins that form gap junctions, which are important for diffusion of cytosolic factors such as ions and second messenger signaling molecules. Our previous study has shown that Connexin40 (Cx40), one dominant connexin expressed in brain, was involved in brain injury. In this study, Cx43, another dominant connexin in brain, was investigated. Using bilateral common carotid artery occlusion-induced ischemia rat model, we tested the expression and phosphorylation level of Cx43 as well as heteromeric Cx40/Cx43 complex formation in brain after ischemia induction. We screened total 16 kinase inhibitors to identify the kinase for Cx43 phosphorylation and confirmed the result using siRNA targeting the specific kinase. Finally, we explored the role of the identified kinase in brain damage using in vivo rat model. RESULTS: We discovered that phosphorylation of Cx43 increased after ischemia. The formation of Cx40/Cx43 heteromeric complex on membrane also increased. Inhibition of ERK activity resulted in inhibition of Cx43 phosphorylation on astrocytes. In in vivo model, application of ERK inhibitor and siRNA prevented brain damage and protected blood-brain barrier integrity in rat. CONCLUSION: Our study provides evidence that Cx43 phosphorylation by ERK is implicated in ischemia induced brain damage. PMID- 28852469 TI - Ginkgetin aglycone ameliorates LPS-induced acute kidney injury by activating SIRT1 via inhibiting the NF-kappaB signaling pathway. AB - BACKGROUND: Ginkgetin aglycone (GA), a novel Ginkgo biloba extract (GBE) by acid hydrolysis and recrystallization, is characterized by higher liposolubility and antioxidation than classical GBEs. There is no study depicting the functional role of GA in acute kidney injury (AKI). Here, we firstly reported the protective effect of GA on lipopolysaccharide (LPS)-induced AKI and its underlying mechanism. METHODS: ELISA analysis was applied to measure plasma level of TNF alpha and IL-6, and NF-kappaB activity in kidney homogenate. Renal function analysis was performed by detecting serum concentration of Kim-1 and urine level of BUN. Cell apoptosis in kidney tissues was detected by TUNEL assay and caspase 3 activity assay. qRT-PCR was conducted to determine mRNA expression of TNF alpha, IL-6 and IkappaBalpha. Western blot was carried out to confirm expression of p-IkappaBalpha, SIRT1, and iNOS. RESULTS: GA administration protected mice from LPS-induced AKI by attenuating inflammatory response, renal injury, as well as tubular apoptosis both in vivo. GA suppressed inflammatory response induced by LPS in HK-2 cells. Moreover, GA upregulated SIRT1 expression and blocked the NF kappaB signaling pathway in LPS-induced AKT in vivo and vitro. Furthermore, suppression of SIRT1 abated the inhibitory effect of GA on LPS-induced inflammatory response and renal injury. CONCLUSIONS: GA prevented LPS-induced AKI by activating SIRT1 via inhibiting the NF-kappaB signaling pathway, providing new insights into the function and molecular mechanism of GA in AKI. Therefore, GA may be a promising therapeutic agent for the treatment of septic AKI. PMID- 28852470 TI - Investigation of host-pathogen interaction between Burkholderia pseudomallei and autophagy-related protein LC3 using hydrophobic chromatography-based technique. AB - BACKGROUND: Burkholderia pseudomallei is an intracellular bacteria causing Melioidosis, the disease widely disseminates in Southeast Asia and Northern Australia. B. pseudomallei has ability to invade various types of host cell and to interfere with host defense mechanisms, such as nitric oxide (NO). Due to the cross-talk among alternative killing mechanisms in host immune response against invading microbes, autophagy is the molecular mechanism belonging to intracellular elimination of eukaryotic cells that has been widely discussed. However, bacterial evasion strategy of B. pseudomallei and host-bacterial protein protein interaction within autophagic machinery remain unknown. METHODS: Here, we demonstrated the protein-protein interaction study between different strains of B. pseudomallei, including wild type PP844 and rpoS mutant, with autophagy related protein LC3 that has been constructed, using the modified immunoaffinity hydrophobic chromatography based-technique. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis was utilized for identifying the eluted proteins obtained from the established column. In addition, the expression level of gene encoding candidate protein was predicted prior to verification using real-time quantitative reverse transcription PCR assay (RT-qPCR). RESULTS: LC3 recombinant proteins could be entrapped inside the column before encountering their bacterial interacting partners. Based on affinity interaction, the binding capacity of LC3 with antibody displayed over 50% readily for hydrophobically binding with bacterial proteins. Following protein identification, bacterial ATP-binding cassette (ABC) transporter periplasmic substrate-binding protein (BPSL2203) was identified as a candidate LC3-interacting protein, which was found only in B. pseudomallei wild type. Gene expression analysis and bioinformatics of BPSL2203 were validated the proteomic result which are suggesting the role of RpoS dependent gene regulation. CONCLUSIONS: Remarkably, utilization of the modified immunoaffinity hydrophobic chromatography with LC-MS/MS is a convenient and reliable approach to a study in B. pseudomallei-LC3 protein-protein interaction. PMID- 28852471 TI - Enhancing antitumor immunogenicity of HPV16-E7 DNA vaccine by fusing DNA encoding E7-antigenic peptide to DNA encoding capsid protein L1 of Bovine papillomavirus. AB - BACKGROUND: Human papillomavirus (HPV) has been identified as the primary etiologic factor of cervical cancer, the fourth leading cause of cancer death in females worldwide. We have previously shown that coadministration of DNA encoding L1 capsid protein of Bovine papillomavirus (BPV) can enhance the antigen-specific immune response elicited by a therapeutic HPV16-E7 DNA vaccination. In this study, we sought to generate and evaluate the immunogenicity of a therapeutic HPV16-E7 DNA vaccine that encodes the fusion construct of HPV16-E7 and BPV-L1. RESULTS: We generated a therapeutic HPV16-E7 DNA vaccine construct, pcDNA3-BPVL1 E7(49-57), encoding the fusion sequence of full-length BPVL1 protein and a murine E7 antigenic epitope, aa49-57. Transfecting 293-Db cells with pcDNA3-BPVL1-E7(49 57) demonstrated that this DNA construct can effectively lead to the presentation of E7 epitope for the activation of E7-specific CD8+ T cells in vitro. Intramuscular vaccination of pcDNA3-BPVL1-E7(49-57) with electroporation generated a stronger E7-specific CD8+ T cell-mediated immune response than coadministration of pcDNA3-BPVL1 and pcDNA3-E7(49-57) in C57BL/6 mice. Furthermore, we observed that the strong E7-specific CD8+ T cell response elicited by pcDNA3-BPVL1-E7(49-57) vaccination translated into potent protective and therapeutic antitumor effects in C57BL/6 mice against HPV16-E7 expressing TC 1 tumor cells. Finally, using antibody depletion experiment, we showed that the antitumor immune response generated by pcDNA3-BPVL1-E7(49-57) is CD8+ T cell dependent, and CD4+ T cell and NK cell independent. CONCLUSION: Treatment with fusion construct of BPV-L1 and HPV16-E7 epitope can elicit effective E7-specific antitumor immune response in mice. Due to the potential ability of the fusion DNA construct to also trigger immune responses specific to the L1 protein, the current study serves to support future design of HPV DNA vaccines encoding fusion HPVL1-E6/E7 constructs for the generation of both T cell and B cell mediated immune responses against HPV infections and associated diseases. PMID- 28852472 TI - Better recognition, diagnosis and management of non-IgE-mediated cow's milk allergy in infancy: iMAP-an international interpretation of the MAP (Milk Allergy in Primary Care) guideline. AB - Cow's milk allergy (CMA) is one of the most common presentations of food allergy seen in early childhood. It is also one of the most complex food allergies, being implicated in IgE-mediated food allergy as well as diverse manifestations of non IgE-mediated food allergy. For example, gastrointestinal CMA may present as food protein induced enteropathy, enterocolitis or proctocolitis. Concerns regarding the early and timely diagnosis of CMA have been highlighted over the years. In response to these, guideline papers from the United Kingdom (UK), Australia, Europe, the Americas and the World Allergy Organisation have been published. The UK guideline, 'Diagnosis and management of non-IgE-mediated cow's milk allergy in infancy-a UK primary care practical guide' was published in this journal in 2013. This Milk Allergy in Primary Care (MAP) guideline outlines in simple algorithmic form, both the varying presentations of cow's milk allergy and also focuses on the practical management of the most common presentation, namely mild-to-moderate non-IgE-mediated allergy. Based on the international uptake of the MAP guideline, it became clear that there was a need for practical guidance beyond the UK. Consequently, this paper presents an international interpretation of the MAP guideline to help practitioners in primary care settings around the world. It incorporates further published UK guidance, feedback from UK healthcare professionals and affected families and, importantly, also international guidance and expertise. PMID- 28852473 TI - Evaluation of operating room reverse Trendelenburg positioning and its effect on postoperative hypoxemia, aspiration, and length of stay: a retrospective study of consecutive patients. AB - BACKGROUND: In 2014, this group published an investigation of surgical patients from 2012 who had substantial rates of postoperative hypoxemia (POH) and perioperative pulmonary aspiration (POPA). Therefore, we investigated whether intraoperative reverse Trendelenburg positioning (RTP) decreases POH and POPA rates. METHODS: Consecutive ASA I-IV surgical patients who had preoperative pulmonary stability requiring general anesthesia with endotracheal intubation were evaluated. Using pulse oximetry, hypoxemia was documented intraoperatively and during the 48 h following PACU discharge. POPA was the presence of a pulmonary infiltrate with hypoxemia. In early 2015, a multifaceted effort was undertaken to enhance anesthesiologist and operating nurse awareness of RTP to potentially decrease POH and POPA rates. Analyses included (1) combining 2012 and 2015 cohorts to assess risk conditions, (2) comparing post-campaign 2015 (increased RTP) and 2012 cohorts, and (3) comparing 2015 patients with audit documented RTP during surgery to the other 2015 patients. RESULTS: Combining the 500 patients in 2012 with the 1000 in 2015 showed that POH had increased mortality (2.3%), compared to no POH (0.2%; p = 0.0004). POH had increased postoperative length of stay (LOS) (4.6 days), compared to no POH (2.0 days; p < 0.0001). POPA had increased mortality (7.7%) and LOS (8.8 days), compared to no POPA (0.4%; p = 0.0004; 2.3 days; p < 0.0001). Open aortic, cranial, laparotomy, and neck procedures had greater POH (41.3%) and LOS (4.0 days), compared to other procedures (16.3%; p < 0.0001; 2.2 days; p < 0.0001). Glycopyrrolate on induction had lower POH (17.4%) and LOS (1.9 days), compared to no glycopyrrolate (21.6%; p = 0.0849; 2.7 days; p < 0.0001). POH was lower (18.1%) in 2015, than in 2012 (25.6%; p = 0.0007). POPA was lower with RTP in 2015 (0.6%), than in 2012 (4.8%; p = 0.0088). For the 2015 patients, LOS was lower with audit-documented RTP (2.2 days), compared to other patients (2.7 days; p = 0.0246). CONCLUSIONS: These findings are only hypothesis-generating. A randomized clinical trial is needed to confirm whether RTP has an inverse association with POH and POPA, and if RTP and glycopyrrolate are associated with improved outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02984657. PMID- 28852474 TI - The prevalence of pulmonary complications after thoracic and abdominal surgery and associated risk factors in patients admitted at a government hospital in Harare, Zimbabwe-a retrospective study. AB - BACKGROUND: The burden of HIV/AIDS in Sub-Saharan Africa has presented unusual and challenging acute surgical problems across all specialties. Thoraco-abdominal surgery cuts through muscle and thereby disrupts the normal anatomy and activity of the respiratory muscles leading to reduced lung volumes and putting the patients at greater risk of developing post-operative pulmonary complications (PPCs). PPCs remain an important cause of post-operative morbidity, mortality, and impacts on the long-term outcomes of patients post hospital discharge. The objective of the study was to determine the pulmonary complications developing after abdominal and thoracic surgery and the associated risks factors. METHODS: A retrospective records review of all abdominal and thoracic surgery patients admitted at a central hospital from January 2014 to October 2014 was done. Data collected included demographic data, surgical history, comorbidities and the PPCs present. RESULTS: Out of the 92 patients whose records were reviewed, 55 (59.8%) were males and 84 (91.3%) had abdominal surgery. The mean age of the patients was 42.6 years (SD = 18.4). The common comorbidities were HIV infection noted in 14(15.2%) of the patients and hypertension in 10 (13.0%). Thirty nine (42.4%) developed PPCs and the most common complications were nosocomial pneumonia in 21 (22.8%) patients, ventilator associated pneumonia in 11 (12.0%), and atelectasis in 6 (6.5%) patients. Logistic regression showed that a history of alcohol consumption, prolonged surgery, prolonged stay in hospital or critical care unit, incision type, and comorbidities were significant risk factors for PPCs (p < 0.05). The mortality rate was 10.9%. CONCLUSION: PPCs like nosocomial and ventilator associated pneumonia were common and were associated with increased morbidity and adversely affected clinical outcomes of patients. HIV and hypertension presented significant comorbidities which the health team needed to recognize and address. Strategies to reduce the occurrence of PPCs have to be implemented through coordinated efforts by the health practitioners as a team during the entire perioperative period. PMID- 28852475 TI - Genetic characterization of novel class 1 Integrons In0, In1069 and In1287 to In1290, and the inference of In1069-associated integron evolution in Enterobacteriaceae. AB - BACKGROUND: This study aims to characterize genetically related class 1 integrons In1069, In893 and In1287 to In1290, and to further propose a scheme of stepwise integration or excision of individual gene cassettes (GCs) to generation of these integron variations. METHODS: Six of 139 non-redundant Enterobacteriaceae strains were studied by bacterial antimicrobial susceptibility testing, detection of carbapenemase activity, and integron sequencing and sequence comparison. RESULTS: Six novel class 1 integrons, In0, In1069, and In1287 to In1290, together with the previously characterized In893, were determined from the above strains. An unusual blaKPC-2-carrying In0 and the blaIMP-30-carrying In1069 coexists in a single isolate of Escherichia coli. In0 contains a PcH1 promoter and a truncated aacA4'-3 gene cassette (GCaacA4'-3), as well as a blaKPC-2-containing region of Tn6296 integrated between PcH1 and GCaacA4'-3. In1069 carries GCblaIMP-30 and GCaacA4'-3 in this order. The other five integrons, In893 and In1287 to In1290, are genetically related to In1069, and all possess a core GCaacA4'-3. The integration or excision of one or more individual gene cassettes, such as GCblaIMP-30, GCaadA16, GCcatB3, GCarr3 and GCdfrA27, upstream or downstream of GCaacA4'-3 generates various gene cassettes arrays among these five integrons. CONCLUSIONS: These findings provide the insight into stepwise and parallel evolution of In1069-associated integron variations likely under antibiotic selection pressure in clinical settings. PMID- 28852476 TI - Resistance of Staphylococcus aureus to antimicrobial agents in Ethiopia: a meta analysis. AB - BACKGROUND: Emergence of antimicrobial resistance by Staphylococcus aureus has limited treatment options against its infections. The purpose of this study was to determine the pooled prevalence of resistance to different antimicrobial agents by S. aureus in Ethiopia. METHODS: Web-based search was conducted in the databases of PubMed, Google Scholar, Hinari, Scopus and the Directory of Open Access Journals (DOAJ) to identify potentially eligible published studies. Required data were extracted and entered into Excel spread sheet. Statistical analyses were performed using Stata version 13.0. The metaprop Stata command was used to pool prevalence values. Twenty-one separate meta-analysis were done to estimate the pooled prevalence of the resistance of S. aureus to twenty-one different antimicrobial agents. Heterogeneity among the studies was assessed using the I2 statistic and chi-square test. Publication bias was assessed using Egger's test. Because of significant heterogeneity amongst the studies, the random effects model was used to pool prevalence values. RESULTS: The electronic database search yielded 1317 studies among which 45 studies met our inclusion criteria. Our analyses demonstrated very high level of resistance to amoxicillin (77% [95% confidence interval (CI): 68%, 0.85%]), penicillin (76% [95% CI: 67%, 84%]), ampicillin (75% [95% CI: 65%, 85%]), tetracycline (62% [95% CI: 55%, 68%]), methicillin (47% [95% CI: 33%, 61%]), cotrimoxaziole (47% [95% CI: 40%, 55%]), doxycycline (43% [95% CI: 26%, 60%]), and erythromycin (41% [95% CI: 29%, 54%]). Relatively low prevalence of resistance was observed with kanamycin (14% [95% CI: 5%, 25%]) and ciprofloxacin (19% [95% CI: 13%, 26%]). The resistance level to vancomycin is 11% 995% CI: (4%, 20%). High heterogeneity was observed for each of the meta-analysis performed (I2 ranging from 79.36% to 95.93%; all p values <=0.01). Eggers' test did not show a significant publication bias for all antimicrobial agents except for erythromycin and ampicillin. CONCLUSIONS: S. aureus in Ethiopia has gotten notoriously resistant to almost to all of antimicrobial agents in use including, penicillin, cephalosporins, tetracyclines, chloramphenicol, methicillin, vancomycin and sulphonamides. The resistance level to vancomycin is bothersome and requires a due attention. Continued and multidimensional efforts of antimicrobial stewardship program promoting rational use of antibiotics, infection prevention and containment of AMR are urgently needed. PMID- 28852478 TI - An end-of-life practice survey among clinical nephrologists associated with a single nephrology fellowship training program. AB - BACKGROUND: Our nephrology fellowship requires specific training in recognition and referral of end-stage renal disease patients likely to benefit from palliative and hospice care. METHODS: To identify end-of-life (EOL) referral barriers that require greater training emphasis, we performed a cross-sectional, 17-item anonymous online survey (August-October 2015) of 93 nephrologists associated with the program since 1987. RESULTS: There was a 61% response rate (57/93 surveys). Ninety-five percent practiced clinical nephrology (54/57). Of these, 51 completed the survey (55% completion rate), and their responses were analyzed. Sixty-four percent were in practice >10 years; 65% resided in the Southern USA. Ninety-two percent felt comfortable discussing EOL care, with no significant difference between those with <=10 versus >10 years of practice experience (P = 0.28). Thirty-one percent reported referring patients to EOL care 'somewhat' or 'much less often' than indicated. The most frequent referral barriers were: time-consuming nature of EOL discussions (27%); difficulty in accurately determining prognosis for <6-month survival (35%); patient (63%) and family (71%) unwillingness; and patient (69%) and family (73%) misconceptions. Fifty-seven percent would refer more patients if dialysis or ultrafiltration could be performed in hospice. Some reported that local palliative care resources (12%) and hospice resources (6%) were insufficient. CONCLUSIONS: The clinical nephrologists surveyed were comfortable with EOL care discussion and referral. Patient, family, prognostic and system barriers exist, and many reported lower than indicated referral rates. Additional efforts, including, but not limited to, EOL training during fellowship, are needed to overcome familial and structural barriers to facilitate nephrologist referral for EOL care. PMID- 28852477 TI - Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases. AB - Endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic "network structure" that facilitates the formation of inter organellar connections. As a result, mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis. Importantly, emerging evidence suggests that the abnormality and dysfunction of MAMs have been involved in various neurodegenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. This review will focus on the architecture and function of MAMs and its involvement in the neurodegenerative diseases. PMID- 28852479 TI - Collapsing glomerulopathy: a 30-year perspective and single, large center experience. AB - Collapsing glomerulopathy (CGP) is a pattern of kidney injury seen on renal biopsy with multiple associations and etiologies. It is most commonly described in African-Americans and others with recent African ancestry. The disease is rapidly progressive and often presents with abrupt onset of renal failure and nephrotic-range proteinuria. Since its description 30 years ago, this entity has transformed from a morphologic diagnosis typically seen in the setting of HIV infection to a complicated diagnosis with numerous etiologies, many of which are associated with underlying apolipoprotein L1 (APOL1)-risk variants or other genetic disorders. We review the evolution of CGP, and its history and proposed pathomechanisms. We also present the disease spectrum from our experience with emphasis on recognizing the lesion, distinguishing from mimics and linking the histopathological pattern to a specific cause. Our understanding continues to evolve as clinicians and scientists work toward a more complete understanding of the molecular pathways of injury in this disease and how these might be disrupted for therapeutic purposes. Much still remains to be discovered in CGP as the molecular underpinnings leading to disease are still not completely understood and no effective treatment exists despite the high morbidity. Based on this rapid evolution, CGP is a modern template of how we diagnose and think about kidney disease. The story of CGP represents the current shift in nephrology and nephropathology from morphology-alone-based diagnosis to a comprehensive approach including molecular diagnostics. We believe this new, holistic approach will lead to pathogenesis-centered diagnoses that will help to individualize risk stratification and treatment protocols. PMID- 28852480 TI - Intravenous cyclophosphamide and oral prednisolone is a safe and effective treatment option for idiopathic membranous nephropathy. AB - BACKGROUND: Idiopathic membranous nephropathy (IMN) is one of the most common causes of nephrotic syndrome in adults. A proportion of patients will experience spontaneous remission and the decision to offer immunosuppression is guided by the presence of adverse prognostic features. Data relating to the efficacy of different immunosuppressive protocols is lacking, in particular there are little data available on the efficacy or benefits of an intravenous (IV) cyclophosphamide-based regimen. Since 2010, our unit has been using a treatment regimen based on IV cyclophosphamide and oral prednisolone for patients with IMN associated with adverse prognostic features. The outcomes of these patients were compared with a historic cohort of similar patients who did not receive immunosuppressive therapy. METHODS: Between January 2010 and 2014, a total of 41 patients were treated with pulse IV cyclophosphamide and oral prednisolone. The historical comparator group included 47 similar patients diagnosed between 2006 and 2010 who did not receive immunosuppression. Two-year follow-up data were collected. The primary outcome measure was time to remission of nephrotic syndrome (defined as normalization of serum albumin). Secondary outcomes included rate of progression of kidney disease as well as incidence of treatment-related adverse events. RESULTS: As compared with supportive care alone, treatment with IV cyclophosphamide and oral prednisolone was associated with a significantly higher number of patients achieving remission. Within 18 months of therapy, 74% of treated patients had achieved a normal serum albumin level. Though there was a trend towards a more rapid decline in estimated glomerular filtration rate in the untreated cohort, this did not reach statistical significance. The IV cyclophosphamide-based regimen was well tolerated, with few significant treatment associated side effects. CONCLUSION: IV cyclophosphamide is a safe and effective treatment for IMN. PMID- 28852481 TI - Infectious complications of rituximab therapy in renal disease. AB - Rituximab, an anti-CD20 monoclonal antibody, was originally used to treat B-cell malignancies. Its use has significantly increased in recent years, as it is now also used to treat a variety of autoimmune diseases including rheumatoid arthritis and ANCA-associated vasculitis (AAV). Initial studies suggested that the adverse effects of rituximab were minimal. Though the risk of malignancy with rituximab-based immunosuppressive regimens appears similar to that of the general population, there are now concerns regarding the risk of infectious complications. Rituximab has been associated with serious infections, including Pneumocystis jiroveci pneumonia (PJP) and the reactivation of hepatitis B virus (HBV) and tuberculosis (TB). The risk of infection appears to be the result of a variety of mechanisms, including prolonged B-cell depletion, B-cell-T-cell crosstalk, panhypogammaglobulinaemia, late-onset neutropenia and blunting of the immune response after vaccination. Importantly, the risk of infectious complications is also related to individual patient characteristics and the indication for rituximab. Individualization of treatment is, therefore, crucial. Particular attention should be given to strategies to minimize the risk of infectious complications, including vaccinating against bacterial and viral pathogens, monitoring white cell count and immunoglobulin levels, prophylaxis against PJP and screening for HBV and TB. PMID- 28852482 TI - Infectious complications of a rituximab-based immunosuppressive regimen in patients with glomerular disease. AB - BACKGROUND: Recent years have seen increasing use of rituximab (RTX) for various types of primary and secondary glomerulopathies. However, there are no studies that specifically address the risk of infection related to this agent in patients with these conditions. METHODS: We reviewed the outcomes of all patients who received RTX therapy for glomerular disease between June 2000 and October 2011 in eight French nephrology departments. Each case was analysed for survival, cause of death if a non-survivor and/or the presence of infectious complications, including severe or opportunistic infection occurring within the 12 months following RTX infusion. RESULTS: Among 98 patients treated with RTX, 25 presented with at least one infection. We report an infection rate of 21.6 per 100 patient years. Five patients died within 12 months following an RTX infusion, of whom four also presented with an infection. The median interval between the last RTX infusion and the first infectious episode was 2.1 months (interquartile range 0.5 5.1). Most infections were bacterial (79%) and pneumonia was the most frequent infection reported (27%). The presence of diabetes mellitus (P = 0.006), the cumulative RTX dose (P = 0.01) and the concomitant use of azathioprine (P = 0.03) were identified as independent risk factors. Renal failure was significantly associated with an increased infection risk by bivariate analysis (P = 0.03) and was almost significant by multivariate analysis (P = 0.05). Nephrotic syndrome did not further increase the risk of infection and/or death. CONCLUSION: The risk of infection after RTX-based immunosuppression among patients with glomerulopathy must be considered and patients should receive close monitoring and appropriate infection prophylaxis, especially in those with diabetes and high-dose RTX regimens. PMID- 28852483 TI - Immunoglobulin levels and infection risk with rituximab induction for anti neutrophil cytoplasmic antibody-associated vasculitis. AB - BACKGROUND: Rituximab (RTX), a B cell-depleting anti-CD20 monoclonal antibody, is approved for treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Low immunoglobulin (Ig) levels have been observed surrounding RTX treatment. The association between the degree of Ig deficiency and infection risk is unclear in AAV patients. METHODS: AAV patients treated with RTX for remission induction at a single center (2005-15) with serum Ig measurements were included. Patient characteristics; serum IgG, IgM and IgA levels and occurrence of infections were collected retrospectively. Low IgG was defined as mild (376 749 mg/dL) or severe (>375 mg/dL). Logistic regression models were adjusted for age at RTX administration, estimated glomerular filtration rate (eGFR) and race to examine the association of degree and type of Ig deficiency and infection risk. RESULTS: Our cohort of 30 patients had a mean age of 63 (SD 7) years, 23 were women, 16 had granulomatosis with polyangiitis and 13 were PR3 ANCA positive. Nine patients received concomitant cyclophosphamide. The mean IgG level was 625 mg/dL (SD 289), mean IgM level was 55 mg/dL (SD 41) and mean IgA level was 133 mg/dL (SD 79). In this cohort, 20 patients had low serum IgG levels (<750 mg/dL) following RTX treatment. During the follow-up period, four individuals developed infections requiring hospitalization. In unadjusted logistic regression analysis, an IgG level <= 375 mg/dL was associated with 23 times higher odds of hospitalized infection [95% confidence interval (CI) 1.8-298.4; P = 0.02]. After adjustment for age, race and eGFR, results were similar [odds ratio (OR) 21.1 (95% CI 1.1-404.1) P = 0.04]. Low IgA was also associated with an increased risk of infections requiring hospitalization after adjusting for age, race and eGFR [OR 24.6 (95% CI 1.5-799.5) P = 0.03]. Low IgM was not associated with a higher risk of infections requiring hospitalization. CONCLUSIONS: Severe hypogammaglobulinemia was associated with increased odds of infection requiring hospitalization in this cohort. Further investigation is warranted given our study is limited by small sample size, concomitant cyclophosphamide use and variable timing of Ig measurement. PMID- 28852484 TI - Sickle cell disease and albuminuria: recent advances in our understanding of sickle cell nephropathy. AB - Albuminuria is considered to be a relevant biomarker for the detection of early glomerular damage in patients with sickle cell disease (SCD). Improvements in our understanding of the pathophysiological processes and molecular mechanisms underlying albuminuria are required, because increasing numbers of patients with SCD are developing chronic kidney disease. The early recognition of sickle cell nephropathy (SCN) and studies of the natural course of this emerging renal disease are therefore crucial, together with identification of the associated clinical and biological risk factors, to make it possible to initiate kidney protective therapy at early stages of renal impairment. The pathophysiological process underlying SCN remains hypothetical, but chronic haemolysis-related endothelial dysfunction and the relative renal hypoxia triggered by repeated vaso occlusive crises have been identified as two potential key factors. The optimal preventive and curative management of albuminuria in the context of SCD is yet to be established, but recent studies have suggested that hydroxyurea therapy, the cornerstone of SCD treatment, could play a key role in reducing albuminuria. The place of conventional kidney-protecting measures, such as renin-angiotensin system inhibitors, in the treatment of SCD patients also remains to be determined. PMID- 28852485 TI - Prevalence and determinants of microalbuminuria in children suffering from sickle cell anemia in steady state. AB - BACKGROUND: Sickle cell anemia (SCA) is considered a major risk factor for renal complications. The main goal of this study was to determine the frequency of macroalbuminuria and microalbuminuria in Congolese children <18 years of age suffering from Sickle cell anemia and to identify associated factors. METHODS: The cross-sectional study was completed in 150 hemoglobin-SS children (77 boys and 73 girls). Microalbuminuria was defined by a urine albumin:creatinine ratio of 30-299 mg/g. RESULTS: The mean age of this group was 8.8 +/- 4.3 years (range 2-18). Microalbuminuria was found in 27 children (18%). In multivariate logistic regression, only age emerged as a determinant of microalbuminuria odds ratio 1.11 (95% confidence interval 1.00-1.22); P = 0.042]. CONCLUSIONS: In our series, only age was a major determinant of the occurrence of microalbuminuria. These results confirm the need for early screening of microalbuminuria in Congolese children suffering from Sickle cell anemia in a context where access to renal and bone marrow transplant is nonexistent. PMID- 28852486 TI - Diabetes, deafness and renal disease. AB - Deafness, kidney disease and diabetes are not a usual association, neither is a family history of these diseases. We present the case of a 47-year-old woman with non-nephrotic proteinuria, no haematuria, normal renal function, sensorineural hearing loss, recently diagnosed diabetes and maculopathy. There was a maternal family history of deafness, diabetes and renal disease. Renal biopsy revealed focal and segmental glomerulosclerosis (FSGS), leading to the pursuit of an m.3243A > G mitochondrial mutation and diagnosis of maternally inherited diabetes and deafness. The association of FSGS with mitochondrial diseases is not well known among nephrologists. Its timely diagnosis is important to avoid exposure to ineffective and unnecessary immunosuppression. PMID- 28852487 TI - Rare genetic variants in Shiga toxin-associated haemolytic uraemic syndrome: genetic analysis prior to transplantation is essential. AB - We present a case of haemolytic uraemic syndrome (HUS) in a 16-year-old female with serological evidence of acute Escherichia coli O157:H7 infection. She progressed to established renal failure and received a deceased donor kidney transplant. Shiga toxin-associated HUS (STEC-HUS) does not recur following renal transplantation, but unexpectedly this patient did experience rapid and severe HUS recurrence. She responded to treatment with the terminal complement inhibitor eculizumab and subsequent genetic analysis revealed a rare variant in a complement gene. This highlights the importance of genetic analysis in patients with STEC-HUS prior to renal transplantation so that management can be individualized. PMID- 28852488 TI - Revisiting angioplasty for renovascular hypertension. AB - Following contemporary trends in arterial endovascular therapy of the lower extremities, recent major trials in anti-hypertensive renovascular revascularization have focused on outcomes after primary stenting of the renal artery. Angioplasty-only therapy has not been studied in a major trial since the year 2000. As such, the current study by Saeed et al. presents an updated data set on the technique with one unique aspect: patients underwent post-procedural physiologic scintigraphy to document the effects of unilateral intervention in patients with two kidneys. Although these physiologic changes should not supersede the clinically relevant outcome of blood pressure reduction (which was also accomplished in this study albeit to a modest but statistically significant degree), the physiologic consequences of unilateral intervention are elegantly presented in this short-term follow-up study. Furthermore, while current renovascular intervention is trending towards treatment of global renal ischemia (i.e. bilateral renal artery stenosis or renal artery stenosis in a congenitally or acquired solitary functional kidney scenario), the current study provides a useful data set for reference in guiding future renovascular revascularization studies and treatment algorithms. PMID- 28852489 TI - Split renal function in patients with unilateral atherosclerotic renal artery stenosis-effect of renal angioplasty. AB - OBJECTIVE: To evaluate the effect of percutaneous transluminal renal angioplasty (PTRA) on split renal function (SRF) in patients with unilateral atherosclerotic renal artery stenosis (ARAS). METHODS: We performed a retrospective analysis of all consecutively examined patients at our centre with significant ARAS undergoing PTRA during 2002-07. A significant ARAS was defined as a lesion with a trans-stenotic mean arterial pressure gradient of at least 10 mmHg or a diameter stenosis >50% on angiography. Ambulatory (24 h) systolic and diastolic blood pressure (ASBP and ADBP, respectively) and calculated SRF using 99mTc-DTPA renal scintigraphy were evaluated before (baseline) and 4 weeks after PTRA. RESULTS: ASBP and ADBP were significantly lower 4 weeks after PTRA compared with baseline levels. Although total estimated glomerular filtration rate (eGFR; four-variable Modification of Diet in Renal Disease equation) had not changed by PTRA, analysis of SRF showed significantly increased eGFR in stenotic kidneys and a comparable reduction in eGFR in non-stenotic kidneys 4 weeks after PTRA. CONCLUSIONS: In patients with unilateral ARAS, PTRA significantly improved eGFR in stenotic kidneys and decreased filtration in contralateral, non-stenotic kidneys. These potentially beneficial effects may not be apparent when total renal function remains stable. The clinical significance of these findings needs to be evaluated further. PMID- 28852491 TI - Captivating a captive audience: a quality improvement project increasing participation in intradialytic exercise across five renal dialysis units. AB - BACKGROUND: Benefits of exercise on dialysis (EOD) are well established, however, uptake in our local satellite haemodialysis units is low. The implications of the status quo are risks to treatment efficiency, equity and patient centredness in managing personal health risks. The current study aimed to identify and address barriers to exercise participation while on dialysis by substantiating local EOD risks, assigning context, implementing changes and evaluating their impact. Our primary objective was to increase the uptake of EOD across our five dialysis units. METHODS: Semi-structured interview and questionnaire data from patients and nursing staff were used to inform a root-cause analysis of barriers to exercise participation while on dialysis. Intervention was subsequently designed and implemented by a senior physiotherapist. It consisted of patient and nursing staff education, equipment modification and introduction of patient motivation schemes. RESULTS: Staff knowledge, patient motivation and equipment problems were the main barriers to EOD. A significant increase in the uptake of EOD from 23.3% pre-intervention to 74.3% post-intervention was achieved [chi2 (1, N = 174) = 44.18, P < 0.001]. CONCLUSIONS: Barriers to EOD are challenging, but there is evidence that patients wish to participate and would benefit from doing so. The input of a physiotherapist in the dialysis units had a significant positive effect on the uptake of EOD. National guidelines should encourage dialysis units to include professional exercise provision in future service planning. PMID- 28852490 TI - The importance of accurate measurement of aortic stiffness in patients with chronic kidney disease and end-stage renal disease. AB - Cardiovascular (CV) disease is the leading cause of death in chronic kidney disease (CKD) and end-stage renal disease (ESRD). A key driver in this pathology is increased aortic stiffness, which is a strong, independent predictor of CV mortality in this population. Aortic stiffening is a potentially modifiable biomarker of CV dysfunction and in risk stratification for patients with CKD and ESRD. Previous work has suggested that therapeutic modification of aortic stiffness may ameliorate CV mortality. Nevertheless, future clinical implementation relies on the ability to accurately and reliably quantify stiffness in renal disease. Pulse wave velocity (PWV) is an indirect measure of stiffness and is the accepted standard for non-invasive assessment of aortic stiffness. It has typically been measured using techniques such as applanation tonometry, which is easy to use but hindered by issues such as the inability to visualize the aorta. Advances in cardiac magnetic resonance imaging now allow direct measurement of stiffness, using aortic distensibility, in addition to PWV. These techniques allow measurement of aortic stiffness locally and are obtainable as part of a comprehensive, multiparametric CV assessment. The evidence cannot yet provide a definitive answer regarding which technique or parameter can be considered superior. This review discusses the advantages and limitations of non invasive methods that have been used to assess aortic stiffness, the key studies that have assessed aortic stiffness in patients with renal disease and why these tools should be standardized for use in clinical trial work. PMID- 28852493 TI - Gastrointestinal complications induced by sevelamer crystals. AB - BACKGROUND: Sevelamer is a phosphate binder widely used in chronic kidney disease (CKD) patients. Sevelamer, as well as other resin-based binders, can crystallize leading to the formation of concretions. Sevelamer crystals (SC) have been associated with gastrointestinal (GI) mucosal injury. We describe three new cases of GI lesions associated with SC and review previously reported cases. METHODS: We describe three new cases of GI lesions associated with SC and review previously reported cases. RESULTS: We found 16 previously reported cases of SC induced GI lesions. The mean patient age was 61 years (interquartile range 51.5 71.75), 62.5% were females and 10 patients were diabetic. In 13 cases, SC was found inside the GI mucosa. Six patients had history of major abdominal surgery. GI bleeding was the most common clinical symptom (n = 7), with three patients presenting with acute abdomen requiring surgical intervention. Although, SC induced lesions were observed in all GI segments, intestine was involved in 81% of the cases. Endoscopic examination revealed mainly erosions and ulcerations (n = 7) and pseudoinflammatory polyps (n = 5). No association between sevelamer doses and the severity of GI lesions was found. However, diabetics patients seemed to develop GI lesions with smaller doses of sevelamer as compared with non diabetic patients, in spite of their fewer GI comorbidities. CONCLUSIONS: SC induced GI lesions should be considered in CKD patients treated with sevelamer who present GI symptoms, especially lower GI bleeding, once other causes have been ruled out. Diabetics seem more prone to develop SC- associated GI lesions. Sevelamer therapy should be avoided if possible in patients with a history of major abdominal surgery or chronic constipation, because of the high risk of serious GI complications. PMID- 28852492 TI - High-density lipoprotein particle pattern and overall lipid responses to a short term moderate-intensity aerobic exercise training intervention in patients with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with abnormal lipid profiles and altered high-density lipoprotein (HDL) particle size patterns. Lower levels of the larger, cardioprotective HDL particles found in CKD may play a role in the increased risk for cardiovascular disease in these patients. The current study was designed to assess the effects of short-term moderate-intensity aerobic exercise training on the HDL particle pattern and overall lipid profiles in stage 3 CKD patients. METHODS: Forty-six men and women with stage 3 CKD were randomized to either exercise (EX, n = 25) or control (CON, n = 21). Those in the EX group completed 16 weeks of supervised moderate-intensity aerobic exercise three times per week. Serum total cholesterol, HDL cholesterol (HDL-C), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), HDL particle size, estimated glomerular filtration rate (eGFR), body composition and peak oxygen uptake (VO2peak) were assessed at baseline and week 16. RESULTS: The rate of compliance in the EX group was 97 +/- 7.2%. No change was observed in eGFR over time in either group. There was an 8.2% improvement in VO2peak in the EX group (P = 0.05), while VO2peak decreased in the CON group. HDL-C, TGs, HDL particle size and body composition remained unchanged in both groups. A trend was found for lower total cholesterol (TC) (P = 0.051) and LDL-C (P = 0.07) in the CON group. CONCLUSION: Our findings indicate that a short-term aerobic exercise training intervention in stage 3 CKD patients does not induce changes in HDL particle size or favorable lipid profile modifications. PMID- 28852494 TI - Age-dependent reference intervals for estimated and measured glomerular filtration rate. AB - BACKGROUND: Defining mean and reference intervals for glomerular filtration rate (GFR) has been the subject of only a limited number of studies and review articles, with contradicting statements about the mean. Normal measured GFR (mGFR) values of ~120-130 mL/min/1.73 m2 have long been the referenced values for young adults but seem to be too high according to recent studies. Reference intervals are difficult to define because of the age decline of GFR, which is also observed in healthy subjects. Little data are available for subjects >70 years of age. METHODS: Based on the reference intervals for serum creatinine (SCr) and the recently published full-age spectrum (FAS) equation, we define simple age-dependent equations for the reference limits of GFR. The mGFR of 633 living potential kidney donors was used to validate the new formulae that define the reference interval. RESULTS: The reference limits for estimated GFR (eGFR), calculated by entering the reference limits for SCr into the FAS equation closely correspond with published reference limits for mGFR. Of the mGFRs of potential living kidney donors, 97.2% lie between the newly defined reference limits for GFR. CONCLUSION: SCr reference limits may serve to define age-dependent reference limits for eGFR and mGFR. PMID- 28852495 TI - Reasons for admission and predictors of national 30-day readmission rates in patients with end-stage renal disease on peritoneal dialysis. AB - BACKGROUND: The number of patients with end-stage renal disease (ESRD) on peritoneal dialysis (PD) has increased by over 30% between 2007 and 2014. The Centers for Medicare and Medicaid has identified readmissions in ESRD patients to be a quality measure; however, there is a paucity of studies examining readmissions in PD patients. METHODS: Utilizing the National Readmission Database for the year 2013, we aimed to determine reasons for admission, the associated rates of unplanned readmission and independent predictors of readmissions in PD patients. RESULTS: The top 10 reasons for initial hospitalization were implant/PD catheter complications (23.22%), hypertension (5.47%), septicemia (5.18%), diabetes mellitus (DM) (5.12%), complications of surgical procedures/medical care (3.50%), fluid and electrolyte disorders (4.29%), peritonitis (3.76%), congestive heart failure (3.25%), pneumonia (2.90%) and acute myocardial infarction (AMI) (2.01%). The overall 30-day readmission rate was 14.6%, with the highest rates for AMI (21.8%), complications of surgical procedure/medical care (19.6%) and DM (18.4%). Concordance among the top 10 reasons for index admission and readmission was 22.6% and varied by admission diagnosis. Independent predictors of readmissions included age 35-49 years compared with 18-34 years [adjusted odds ratio (aOR) 1.35; 95% confidence interval (CI) 1.09-1.68; P = 0.006], female gender (aOR 1.27; 95% CI 1.12-1.44; P < 0.001), and comorbidities including liver disease (aOR 1.39; 95% CI 1.07-1.81; P = 0.01), peripheral vascular disease (aOR 1.33; 95% CI 1.14-1.56; P < 0.001) and depression (aOR 1.22; 95% CI 1.00-1.48; P = 0.04). CONCLUSIONS: This study demonstrates the most common reasons for admission and readmissions in PD patients and several comorbidities that are predictive of readmissions. Targeted interventions towards these patients may be of benefit in reducing readmission in this growing population. PMID- 28852496 TI - Effect of kidney donor hepatitis C virus serostatus on renal transplant recipient and allograft outcomes. AB - BACKGROUND: Hepatitis C virus (HCV) infection is common in dialysis patients and renal transplant recipients and has been associated with diminished patient and allograft survival. HCV-positive (HCV+) kidneys have been used in HCV-positive (HCV+) recipients as a means of facilitating transplantation and expanding the organ donor pool; however, the effect of donor HCV serostatus in the modern era is unknown. METHODS: Using national transplant registry data, we created a propensity score-matched cohort of HCV+ recipients who received HCV-positive donor kidneys compared to those transplanted with HCV-negative kidneys. RESULTS: Transplantation with an HCV+ kidney was associated with an increased risk of death {hazard ratio [HR] 1.43 [95% confidence interval (CI) 1.18-1.76]; P < 0.001} and allograft loss [HR 1.39 (95% CI 1.16-1.67); P < 0.001] compared with their propensity score-matched counterparts. However, HCV+ kidneys were not associated with an increased risk of acute rejection [odds ratio 1.16 (95% CI 0.84-1.61); P = 0.35]. CONCLUSIONS: While use of HCV+ donor kidneys can shorten the wait for renal transplantation and maximize organ utility for all candidates on the waiting list, potential recipients should be counseled about the increased risks associated with HCV+ kidney. PMID- 28852497 TI - Risk factors for bleeding complications after nephrologist-performed native renal biopsy. AB - BACKGROUND: Bleeding is a recognized complication of native percutaneous renal biopsy. This study aimed to describe the incidence of major bleeding after biopsy in a single centre over a 15-year period and examine factors associated with major bleeding. METHODS: We identified consecutive adult patients undergoing ultrasound-guided native renal biopsy in the Glasgow Renal and Transplant Unit from 2000 to 2014. From the electronic patient record, we collected data pertaining to biopsy indication, pre- and post-biopsy laboratory measurements, prescribed medication and diagnosis. Aspirin was routinely continued. We defined major bleeding post-biopsy as the need for blood transfusion, surgical or radiological intervention or death. Binary logistic regression analysis was used to assess factors associated with increased risk of major bleeding. RESULTS: There were 2563 patients who underwent native renal biopsy (1499 elective, 1064 emergency). The average age of patients was 57 (SD 17) years and 57.4% were male. Overall, the rate of major bleeding was 2.2%. In all, 46 patients required transfusion (1.8%), 9 patients underwent embolization (0.4%), no patient required nephrectomy and 1 patient died as a result of a significant late retroperitoneal bleed. Major bleeding was more common in those undergoing emergency compared with elective renal biopsy (3.4 versus 1.1%; P < 0.001). Aspirin was being taken at the time of biopsy in 327 of 1509 patients, with no significant increase in the risk of major bleeding (P = 0.93). Body mass index (BMI) data were available for 546 patients, with no increased risk of major bleeding in 207 patients classified as obese (BMI >30). CONCLUSIONS: The risk of major bleeding following native renal biopsy in the modern era is low. Complications are more common when biopsy is conducted as an emergency, which has implications for obtaining informed consent. Our data support the strategy of not stopping aspirin before renal biopsy. PMID- 28852498 TI - Serum microRNAs are altered in various stages of chronic kidney disease: a preliminary study. AB - [This retracts the article DOI: 10.1093/ckj/sfw060.]. PMID- 28852501 TI - Is any job better than no job at all? Studying the relations between employment types, unemployment and subjective health in Belgium. AB - BACKGROUND: This study focuses on the health impact of the labour market position, since recent research indicates that exposure to both unemployment and precarious employment causes serious harm to people's health and well-being. An overview of general and mental health associations of different labour market positions in Belgium is provided. A distinction is made between employment and unemployment and in addition between different types of jobs among the employed, taking into account the quality of employment. Given the fact that precarious labour market positions tend to coincide with a precarious social environment, the latter is taken into consideration by including the composition and material living conditions of the household and the presence of social support. METHODS: Belgian data from the 1st Generations and Gender Survey are used. A Latent Class Cluster Analysis is performed to construct a typology of labour market positions that includes four different types of waged employment: standard jobs, instrumental jobs, precarious jobs and portfolio jobs, as well as self-employment and unemployment. Then, binary logistic regression analyses are performed in order to relate this typology to health, controlling for household situation and social support. Two health outcomes are included: self-perceived general health (good versus fair/bad) and self-rated mental health (good versus bad, based on 7 items from the Center for Epidemiologic Studies Depression Scale). RESULTS: Two labour market positions are consistently related to poor general and mental health in Belgium: unemployment and the precarious job type. The rather small gap in general and mental health between both labour market positions emphasises the importance of employment quality for the health and well-being of individuals in waged employment. Controlling for the household level context and social support illustrates that part of the reported health associations can be explained by the precarious social environment of individuals in unfavourable labour market positions. CONCLUSIONS: The results from this study confirm that the labour market position and social environment of individuals are important health determinants in Belgium. PMID- 28852499 TI - Candidate genes for male and female reproductive traits in Canchim beef cattle. AB - BACKGROUND: Beef cattle breeding programs in Brazil have placed greater emphasis on the genomic study of reproductive traits of males and females due to their economic importance. In this study, genome-wide associations were assessed for scrotal circumference at 210 d of age, scrotal circumference at 420 d of age, age at first calving, and age at second calving, in Canchim beef cattle. Data quality control was conducted resulting in 672,778 SNPs and 392 animals. RESULTS: Associated SNPs were observed for scrotal circumference at 420 d of age (435 SNPs), followed by scrotal circumference at 210 d of age (12 SNPs), age at first calving (six SNPs), and age at second calving (four SNPs). We investigated whether significant SNPs were within genic or surrounding regions. Biological processes of genes were associated with immune system, multicellular organismal process, response to stimulus, apoptotic process, cellular component organization or biogenesis, biological adhesion, and reproduction. CONCLUSIONS: Few associations were observed for scrotal circumference at 210 d of age, age at first calving, and age at second calving, reinforcing their polygenic inheritance and the complexity of understanding the genetic architecture of reproductive traits. Finding many associations for scrotal circumference at 420 d of age in various regions of the Canchim genome also reveals the difficulty of targeting specific candidate genes that could act on fertility; nonetheless, the high linkage disequilibrium between loci herein estimated could aid to overcome this issue. Therefore, all relevant information about genomic regions influencing reproductive traits may contribute to target candidate genes for further investigation of causal mutations and aid in future genomic studies in Canchim cattle to improve the breeding program. PMID- 28852502 TI - The stigma of clean dieting and orthorexia nervosa. AB - BACKGROUND: Although the stigma of eating disorders such as anorexia has been well established, little is known about the social consequences of "clean dieting" and orthorexia nervosa. In two studies, we examined the social stigma of clean dieting and orthorexia. METHOD: In Study 1, participants read a vignette describing a woman following a "clean" diet, a woman with anorexia, or a control target (minimal information about the individual). In Study 2, participants read a vignette describing a woman with orthorexia, a woman displaying identical orthorexic behaviors but without the orthorexia label, a woman with anorexia, or a control target. Participants then rated the target individual on a range of measures assessing stereotypes, emotions, and behavioral intentions toward the target. RESULTS: Study 1 found that the clean-dieting target was evaluated more negatively than the control target on some dimensions, but less negatively than the target with anorexia nervosa. Study 2 found that evaluations of the targets with orthorexia nervosa were more negative than evaluations of a control target, but did not differ from evaluations of the target with anorexia nervosa. Perceptions of the target's control over her behavior were associated with more positive evaluations (Studies 1 and 2), whereas perceptions of blame and responsibility for the condition were associated with more negative evaluations (Study 2). CONCLUSIONS: Overall, these findings highlight the potential negative social consequences of clean dieting and orthorexia nervosa, and point to perceptions of control and blame as potential mechanisms underlying the stigma of these conditions. PMID- 28852500 TI - Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities. AB - BACKGROUND: Among breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities. METHODS: We quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects. RESULTS: TNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases. CONCLUSIONS: Similar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients. PMID- 28852503 TI - Lower incidence of respiratory infections among iron-deficient children in Kilimanjaro, Tanzania. AB - Objective: We posited a trade-off in iron nutrition, with iron deficiency decreasing risk for infection by depriving infectious agents of iron while increasing risk for infection by compromising immune protection. We described associations between iron deficiency and prevalent and incident infectious disease episodes and cell-mediated immunity (CMI) among 283 children in Kilimanjaro, Tanzania. Methodology: Whole blood specimens were evaluated for hemoglobin and dried blood spots (DBS) were evaluated for biomarkers of iron deficiency (transferrin receptor) and inflammation (C-reactive protein and alpha1 acid glycoprotein). Prevalent and incident infectious disease episodes were identified by physician's diagnosis. CMI was evaluated as delayed-type hypersensitivity to Candida albicans (DTH-Candida). Associations between iron status and elevated inflammation, prevalent infectious disease episodes and DTH Candida were described with logistic regression models; associations between iron status and incident infectious disease episodes were described with Cox proportional hazards models. Results: Elevated inflammation and diagnosed infectious diseases were more common among children with iron-deficiency anemia (IDA, severe iron deficiency), but not significantly so. The incidence of infectious disease was lowest among children with moderate iron deficiency (iron deficient erythropoiesis, IDE); this pattern was most apparent for respiratory infections (aHR: 0.24; p: 0.030). DTH-Candida was not compromised among children with any degree of iron deficiency. Conclusions and implications: We observed no adverse effect of iron deficiency on CMI, but did observe patterns consistent with the hypothesis that moderate iron deficiency protects against respiratory infections and may represent a nutritional adaptation to infectious disease. This suggests that interventions targeting iron deficiency should be coupled with effective infectious disease control measures. PMID- 28852504 TI - Intrinsic and extrinsic influences on standard metabolic rates of three species of Australian otariid. AB - The study of marine mammal energetics can shed light on how these animals might adapt to changing environments. Their physiological potential to adapt will be influenced by extrinsic factors, such as temperature, and by intrinsic factors, such as sex and reproduction. We measured the standard metabolic rate (SMR) of males and females of three Australian otariid species (two Australian fur seals, three New Zealand fur seals and seven Australian sea lions). Mean SMR ranged from 0.47 to 1.05 l O2 min-1, which when adjusted for mass was from 5.33 to 7.44 ml O2 min-1 kg-1. We found that Australian sea lion mass-specific SMR (sSMR; in millilitres of oxygen per minute per kilogram) varied little in response to time of year or moult, but was significantly influenced by sex and water temperature. Likewise, sSMR of Australian and New Zealand fur seals was also influenced by sex and water temperature, but also by time of year (pre-moult, moult or post-moult). During the moult, fur seals had significantly higher sSMR than at other times of the year, whereas there was no discernible effect of moult for sea lions. For both groups, females had higher sSMR than males, but sea lions and fur seals showed different responses to changes in water temperature. The sSMR of fur seals increased with increasing water temperature, whereas sSMR of sea lions decreased with increasing water temperature. There were no species differences when comparing animals of the same sex. Our study suggests that fur seals have more flexibility in their physiology than sea lions, perhaps implying that they will be more resilient in a changing environment. PMID- 28852505 TI - Non-invasive endocrine monitoring indicates seasonal variations in gonadal hormone metabolites in dholes (Cuon alpinus). AB - To date, there is no information on reproductive endocrinology of dholes (Cuon alpinus). The objectives of the present study were as follows: (i) to characterize longitudinal profiles of gonadal steroids; and (ii) to examine the relationship between gonadal hormones and sexual behaviours in dholes. Three breeding pairs and two bachelor males were included in the study. Among these, four animals (2 males and 2 females; 4 years old) were imported from The Netherlands to Thailand 3 months before the study onset; the remaining individuals (3 males and 1 female; 5-7 years old) were native born. Faecal samples were collected 3-7 days/week for 12 months, extracted and assessed for gonadal hormone metabolites using a validated enzyme immunoassay. Observations of behaviour were conducted in 30 min sessions, 3-5 days/week. For the three breeding males, testosterone was elevated (P < 0.05) from October to January in the two imported males, whereas the concentration of steroid metabolites was high from April to June and from September to November in the native male. However, there was no clear seasonal pattern of reproductive hormone in the bachelor group. Oestrogen metabolite level of imported females was elevated for 9-12 days in January, followed by a rise in progestagen concentration. For native females, oestrogen metabolites were above the basal values in April and September, each of which was followed by a rise in progestagen concentration that remained elevated for 77 and 112 days, respectively. Sexual behaviours, including solicitation, mounting and copulations, were observed during the oestrogen peak in all females. Our findings indicate that reproductive seasonality of dholes may depend on the animals' origin and social group. PMID- 28852506 TI - Energy metabolism in mobile, wild-sampled sharks inferred by plasma lipids. AB - Evaluating how predators metabolize energy is increasingly useful for conservation physiology, as it can provide information on their current nutritional condition. However, obtaining metabolic information from mobile marine predators is inherently challenging owing to their relative rarity, cryptic nature and often wide-ranging underwater movements. Here, we investigate aspects of energy metabolism in four free-ranging shark species (n = 281; blacktip, bull, nurse, and tiger) by measuring three metabolic parameters [plasma triglycerides (TAG), free fatty acids (FFA) and cholesterol (CHOL)] via non lethal biopsy sampling. Plasma TAG, FFA and total CHOL concentrations (in millimoles per litre) varied inter-specifically and with season, year, and shark length varied within a species. The TAG were highest in the plasma of less active species (nurse and tiger sharks), whereas FFA were highest among species with relatively high energetic demands (blacktip and bull sharks), and CHOL concentrations were highest in bull sharks. Although temporal patterns in all metabolites were varied among species, there appeared to be peaks in the spring and summer, with ratios of TAG/CHOL (a proxy for condition) in all species displaying a notable peak in summer. These results provide baseline information of energy metabolism in large sharks and are an important step in understanding how the metabolic parameters can be assessed through non-lethal sampling in the future. In particular, this study emphasizes the importance of accounting for intra-specific and temporal variability in sampling designs seeking to monitor the nutritional condition and metabolic responses of shark populations. PMID- 28852507 TI - Conservation physiology and the quest for a 'good' Anthropocene. AB - It has been proposed that we are now living in a new geological epoch known as the Anthropocene, which is specifically defined by the impacts that humans are having on the Earth's biological diversity and geology. Although the proposal of this term was borne out of an acknowledgement of the negative changes we are imparting on the globe (e.g. climate change, pollution, coastal erosion, species extinctions), there has recently been action amongst a variety of disciplines aimed at achieving a 'good Anthropocene' that strives to balance societal needs and the preservation of the natural world. Here, we outline ways that the discipline of conservation physiology can help to delineate a hopeful, progressive and productive path for conservation in the Anthropocene and, specifically, achieve that vision. We focus on four primary ways that conservation physiology can contribute, as follows: (i) building a proactive approach to conservation; (ii) encouraging a pragmatic perspective; (iii) establishing an appreciation for environmental resilience; and (iv) informing and engaging the public and political arenas. As a collection of passionate individuals combining theory, technological advances, public engagement and a dedication to achieving conservation success, conservation physiologists are poised to make meaningful contributions to the productive, motivational and positive way forward that is necessary to curb and reverse negative human impact on the environment. PMID- 28852508 TI - Physiology can contribute to better understanding, management, and conservation of coral reef fishes. AB - Coral reef fishes, like many other marine organisms, are affected by anthropogenic stressors such as fishing and pollution and, owing to climate change, are experiencing increasing water temperatures and ocean acidification. Against the backdrop of these various stressors, a mechanistic understanding of processes governing individual organismal performance is the first step for identifying drivers of coral reef fish population dynamics. In fact, physiological measurements can help to reveal potential cause-and-effect relationships and enable physiologists to advise conservation management by upscaling results from cellular and individual organismal levels to population levels. Here, we highlight studies that include physiological measurements of coral reef fishes and those that give advice for their conservation. A literature search using combined physiological, conservation and coral reef fish key words resulted in ~1900 studies, of which only 99 matched predefined requirements. We observed that, over the last 20 years, the combination of physiological and conservation aspects in studies on coral reef fishes has received increased attention. Most of the selected studies made their physiological observations at the whole organism level and used their findings to give conservation advice on population dynamics, habitat use or the potential effects of climate change. The precision of the recommendations differed greatly and, not surprisingly, was least concrete when studies examined the effects of projected climate change scenarios. Although more and more physiological studies on coral reef fishes include conservation aspects, there is still a lack of concrete advice for conservation managers, with only very few published examples of physiological findings leading to improved management practices. We conclude with a call to action to foster better knowledge exchange between natural scientists and conservation managers to translate physiological findings more effectively in order to obtain evidence-based and adaptive management strategies for the conservation of coral reef fishes. PMID- 28852509 TI - A right whale pootree: classification trees of faecal hormones identify reproductive states in North Atlantic right whales (Eubalaena glacialis). AB - Immunoassay of hormone metabolites extracted from faecal samples of free-ranging large whales can provide biologically relevant information on reproductive state and stress responses. North Atlantic right whales (Eubalaena glacialis Muller 1776) are an ideal model for testing the conservation value of faecal metabolites. Almost all North Atlantic right whales are individually identified, most of the population is sighted each year, and systematic survey effort extends back to 1986. North Atlantic right whales number <500 individuals and are subject to anthropogenic mortality, morbidity and other stressors, and scientific data to inform conservation planning are recognized as important. Here, we describe the use of classification trees as an alternative method of analysing multiple hormone data sets, building on univariate models that have previously been used to describe hormone profiles of individual North Atlantic right whales of known reproductive state. Our tree correctly classified the age class, sex and reproductive state of 83% of 112 faecal samples from known individual whales. Pregnant females, lactating females and both mature and immature males were classified reliably using our model. Non-reproductive [i.e. 'resting' (not pregnant and not lactating) and immature] females proved the most unreliable to distinguish. There were three individual males that, given their age, would traditionally be considered immature but that our tree classed as mature males, possibly calling for a re-evaluation of their reproductive status. Our analysis reiterates the importance of considering the reproductive state of whales when assessing the relationship between cortisol concentrations and stress. Overall, these results confirm findings from previous univariate statistical analyses, but with a more robust multivariate approach that may prove useful for the multiple analyte data sets that are increasingly used by conservation physiologists. PMID- 28852511 TI - What if you can't sense your enemy... and your enemy is an invasive predator? PMID- 28852510 TI - Conservation at a slow pace: terrestrial gastropods facing fast-changing climate. AB - The climate is changing rapidly, and terrestrial ectotherms are expected to be particularly vulnerable to changes in temperature and water regime, but also to an increase in extreme weather events in temperate regions. Physiological responses of terrestrial gastropods to climate change are poorly studied. This is surprising, because they are of biodiversity significance among litter-dwelling species, playing important roles in ecosystem function, with numerous species being listed as endangered and requiring efficient conservation management. Through a summary of our ecophysiological work on snail and slug species, we gained some insights into physiological and behavioural responses to climate change that we can organize into the following four threat categories. (i) Winter temperature and snow cover. Terrestrial gastropods use different strategies to survive sub-zero temperatures in buffered refuges, such as the litter or the soil. Absence of the insulating snow cover exposes species to high variability in temperature. The extent of specific cold tolerance might influence the potential of local extinction, but also of invasion. (ii) Drought and high temperature. Physiological responses involve high-cost processes that protect against heat and dehydration. Some species decrease activity periods, thereby reducing foraging and reproduction time. Related costs and physiological limits are expected to increase mortality. (iii) Extreme events. Although some terrestrial gastropod communities can have a good resilience to fire, storms and flooding, an increase in the frequency of those events might lead to community impoverishment. (iv) Habitat loss and fragmentation. Given that terrestrial gastropods are poorly mobile, landscape alteration generally results in an increased risk of local extinction, but responses are highly variable between species, requiring studies at the population level. There is a great need for studies involving non-invasive methods on the plasticity of physiological and behavioural responses and the ability for local adaptation, considering the spatiotemporally heterogeneous climatic landscape, to allow efficient management of ecosystems and conservation of biodiversity. PMID- 28852512 TI - Down the rabbit hole: how complex do eco-physiological models need to be? PMID- 28852513 TI - Can local adaptation explain varying patterns of herbivory tolerance in a recently introduced woody plant in North America? AB - Patterns of woody-plant mortality have been linked to global-scale environmental changes, such as extreme drought, heat stress, more frequent and intense fires, and episodic outbreaks of insects and pathogens. Although many studies have focussed on survival and mortality in response to specific physiological stresses, little attention has been paid to the role of genetic heritability of traits and local adaptation in influencing patterns of plant mortality, especially in non-native species. Tamarix spp. is a dominant, non-native riparian tree in western North America that is experiencing dieback in some areas of its range due to episodic herbivory by the recently introduced northern tamarisk leaf beetle (Diorhabda carinulata). We propose that genotype * environment interactions largely underpin current and future patterns of Tamarix mortality. We anticipate that (i) despite its recent introduction, and the potential for significant gene flow, Tamarix in western North America is generally adapted to local environmental conditions across its current range in part due to hybridization of two species; (ii) local adaptation to specific climate, soil and resource availability will yield predictable responses to episodic herbivory; and (iii) the ability to cope with a combination of episodic herbivory and increased aridity associated with climate change will be largely based on functional tradeoffs in resource allocation. This review focusses on the potential heritability of plant carbon allocation patterns in Tamarix, focussing on the relative contribution of acquired carbon to non-structural carbohydrate (NSC) pools versus other sinks as the basis for surviving episodic disturbance. Where high aridity and/or poor edaphic position lead to chronic stress, NSC pools may fall below a minimum threshold because of an imbalance between the supply of carbon and its demand by various sinks. Identifying patterns of local adaptation of traits related to resource allocation will improve forecasting of Tamarix population susceptibility to episodic herbivory. PMID- 28852514 TI - Capture severity, infectious disease processes and sex influence post-release mortality of sockeye salmon bycatch. AB - Bycatch is a common occurrence in heavily fished areas such as the Fraser River, British Columbia, where fisheries target returning adult Pacific salmon (Oncorhynchus spp.) en route to spawning grounds. The extent to which these encounters reduce fish survival through injury and physiological impairment depends on multiple factors including capture severity, river temperature and infectious agents. In an effort to characterize the mechanisms of post-release mortality and address fishery and managerial concerns regarding specific regulations, wild-caught Early Stuart sockeye salmon (Oncorhynchus nerka) were exposed to either mild (20 s) or severe (20 min) gillnet entanglement and then held at ecologically relevant temperatures throughout their period of river migration (mid-late July) and spawning (early August). Individuals were biopsy sampled immediately after entanglement and at death to measure indicators of stress and immunity, and the infection intensity of 44 potential pathogens. Biopsy alone increased mortality (males: 33%, females: 60%) when compared with non-biopsied controls (males: 7%, females: 15%), indicating high sensitivity to any handling during river migration, especially among females. Mortality did not occur until 5-10 days after entanglement, with severe entanglement resulting in the greatest mortality (males: 62%, females: 90%), followed by mild entanglement (males: 44%, females: 70%). Infection intensities of Flavobacterium psychrophilum and Ceratonova shasta measured at death were greater in fish that died sooner. Physiological indicators of host stress and immunity also differed depending on longevity, and indicated anaerobic metabolism, osmoregulatory failure and altered immune gene regulation in premature mortalities. Together, these results implicate latent effects of entanglement, especially among females, resulting in mortality days or weeks after release. Although any entanglement is potentially detrimental, reducing entanglement durations can improve post-release survival. PMID- 28852515 TI - The effects of elevated temperature and ocean acidification on the metabolic pathways of notothenioid fish. AB - The adaptations used by notothenioid fish to combat extreme cold may have left these fish poorly poised to deal with a changing environment. As such, the expected environmental perturbations brought on by global climate change have the potential to significantly affect the energetic demands and subsequent cellular processes necessary for survival. Despite recent lines of evidence demonstrating that notothenioid fish retain the ability to acclimate to elevated temperatures, the underlying mechanisms responsible for temperature acclimation in these fish remain largely unknown. Furthermore, little information exists on the capacity of Antarctic fish to respond to changes in multiple environmental variables. We have examined the effects of increased temperature and pCO2 on the rate of oxygen consumption in three notothenioid species, Trematomus bernacchii, Pagothenia borchgrevinki, and Trematomus newnesi. We combined these measurements with analysis of changes in aerobic and anaerobic capacity, lipid reserves, fish condition, and growth rates to gain insight into the metabolic cost associated with acclimation to this dual stress. Our findings indicated that temperature is the major driver of the metabolic responses observed in these fish and that increased pCO2 plays a small, contributing role to the energetic costs of the acclimation response. All three species displayed varying levels of energetic compensation in response to the combination of elevated temperature and pCO2. While P. borchgrevinki showed nearly complete compensation of whole animal oxygen consumption rates and aerobic capacity, T. newnesi and T. bernacchii displayed only partial compensation in these metrics, suggesting that at least some notothenioids may require physiological trade-offs to fully offset the energetic costs of long-term acclimation to climate change related stressors. PMID- 28852517 TI - The costs of being big in a warmer world. PMID- 28852516 TI - Compatibility of preparatory procedures for the analysis of cortisol concentrations and stable isotope (delta13C, delta15N) ratios: a test on brown bear hair. AB - The measurement of naturally occurring glucocorticoids and stable isotopes of several elements has gained importance in wildlife studies in recent decades and opened a myriad of ecological applications. Cortisol and stable isotopes equilibrate in animal tissues over periods of integration related to the growth rate of the tissue, providing information reflecting systemic cortisol secretion and dietary intake. Sample preparation shares the common step of first cleaning the sample of external contamination. However, it is not well understood how different solvents used in sample preparation affect isotopic and cortisol values, and whether it is safe to follow the same procedures for both measures to optimize analyses of the same sample. We conducted an experiment to compare different preparation protocols for the analysis of cortisol concentrations and stable carbon (delta13C) and nitrogen (delta15N) isotope ratios in hair. Hair samples from 12 brown bears (Ursus arctos) were each divided into five aliquots; two aliquots were rinsed with a 2:1 chloroform:methanol (v/v) mixture with one aliquot ground prior to cortisol analysis and the other left intact for stable isotope analyses; two aliquots were washed with methanol with one aliquot ground prior to cortisol analysis and the other left intact for stable isotope analyses; and one aliquot washed with methanol and ground prior to stable isotope analyses. The cortisol, delta13C and delta15N values remained consistent following all treatments. Our results indicate that hair samples rinsed with a 2:1 chloroform:methanol mixture or washed with methanol can be used for both types of analyses. Further, hair that has been ground in a standard hair cortisol procedure can also be used for stable isotope analysis. This information is important for improving laboratory efficiency and compatibility of procedures used for wildlife physiological ecology studies where concurrent measurements of cortisol and stable isotopes in hair are required. PMID- 28852518 TI - Erratum: Heavy with child? Pregnancy status and stable isotope ratios as determined from biopsies of humpback whales. AB - [This corrects the article DOI: 10.1093/conphys/cow050.]. PMID- 28852519 TI - Fatal diffuse alveolar haemorrhage mimicking acute exacerbation in idiopathic pulmonary fibrosis treated with nintedanib. AB - A 75-year-old man was referred to our hospital with a 1-year history of persistent dry cough and progressive dyspnoea on exertion. He was treated with aspirin due to thrombosis of internal carotid artery. He was diagnosed with idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), and started on inhaled N-acetylcysteine therapy and pirfenidone. Since his clinical condition progressively deteriorated after 6 months, he was switched from pirfenidone to nintedanib. As a result, his general condition worsened rapidly. He was diagnosed with acute exacerbation (AE) of IPF, and was treated with methylprednisolone pulse and recombinant human soluble thrombomodulin. Despite the administration of these treatments, he died of severe haemoptysis four days after the onset of AE. Autopsied lungs revealed significantly dark red-brown appearance corresponding to diffuse alveolar haemorrhage (DAH) histopathogically with a background pattern of UIP with fibrotic change. Notably, there was no evidence of diffuse alveolar damage suggesting IPF-AE. PMID- 28852520 TI - Variations of emotion dysregulation in borderline personality disorder: a latent profile analysis approach with adult psychiatric inpatients. AB - BACKGROUND: The purpose of the present study was to identify variations in emotional dysregulation patterns among adults diagnosed with borderline personality disorder (BPD), with an eye toward implications for treatment. METHODS: Latent profile analysis (LPA) was utilized to classify 156 inpatients with BPD, based on patterns of Difficulties in Emotion Regulation Scale (DERS; Gratz and Roemer, J Psychopathol Behav Assess 26: 41-54, 2004) subscale scores. RESULTS: Results revealed that a three class solution best fit the sample (Low Impairment, Global Dysregulation, and Emotionally Aware). Further analysis of the classes at admission revealed that the Global Dysregulation group reported significantly higher suicidal ideation than either the Low Impairment or Emotionally Aware groups, and that the Global Dysregulation group reported significantly higher functional impairment than the Low Impairment group. CONCLUSIONS: All three groups improved greatly over the course of hospital treatment, although they remained distinguishable at discharge, retaining their positions symptomatically relative to one another. Limitations, implications, and future directions are discussed. PMID- 28852522 TI - Systematic review of mixed cryoglobulinemia associated with hepatitis E virus infection: association or causation? AB - Background and aim: Mixed cryoglobulinemia (MC) has been associated with several viral infections, and chronic hepatitis C is recognized as a major cause. MC associated with hepatitis E virus (HEV) has been described and little is known about this rare association. The aim of this study is to perform a systematic review of MC associated with HEV, and examine the presence of a causal relationship. Methods: An experienced librarian conducted a search of databases from each database's inception to 12 December 2016 based on a priori criteria. The risk of bias was assessed, and Hill's criteria were applied to determine causality. Results: Five publications met inclusion criteria, with a total of 15 cases. Three studies had low, one low to moderate and one moderate risk of bias. Median age was 43 years, and all patients came from Western Europe. Two patients were immunocompetent, while 13 were immunosuppressed, post solid organ transplant and had chronic hepatitis E. Renal involvement was observed in seven patients, mild to moderately severe cryoglobulinemic disease in one patient and severe cryoglobulinemic disease in three patients. One patient improved spontaneously, and another was treated with immunosuppressant reduction leading to viral clearance. Ten patients treated with peg-interferon or ribavirin for 3 months achieved loss of cryoglobulinemia and end-of-treatment response, but sustained virologic response was reported and achieved in two. Immunosuppressant achieved loss of cryoglobulinemia in three patients. One case of chronic renal failure, three cases of end-stage renal disease and one death were observed. Five of the nine Hill's criteria were fulfilled. Conclusion: MC has been described with HEV infection. A causal relationship between HEV infection and cryoglobulinemia is highly probable. PMID- 28852521 TI - Perioperative use of immunosuppressive medications in patients with Crohn's disease in the new "biological era". AB - Crohn's disease (CD) is characterized by transmural inflammation of the gastrointestinal tract leading to inflammatory, stricturing and/or and fistulizing disease. Once a patient develops medically refractory disease, mechanical obstruction, fistulizing disease or perforation, surgery is indicated. Unfortunately, surgery is not curative in most cases, underscoring the importance of bowel preservation and adequate perioperative medical management. As many of the medications used to treat CD are immunosuppressive, the concern for postoperative infectious complications and anastomotic healing are particularly concerning; these concerns have to be balanced with preventing and treating residual or recurrent disease. We herein review the available literature and make recommendations regarding the preoperative, perioperative and postoperative administration of immunosuppressive medications in the current era of biological therapy for CD. Standardized algorithms for perioperative medical management would greatly assist future research for optimizing surgical outcomes and preventing disease recurrence in the future. PMID- 28852523 TI - Variceal bleeding in cirrhotic patients. AB - Variceal bleeding is one of the major causes of death in cirrhotic patients. The management during the acute phase and the secondary prophylaxis is well defined. Recent recommendations (2015 Baveno VI expert consensus) are available and should be followed for an optimal management, which must be performed as an emergency in a liver or general intensive-care unit. It is based on the early administration of a vasoactive drug (before endoscopy), an antibiotic prophylaxis and a restrictive transfusion strategy (hemoglobin target of 7 g/dL). The endoscopic treatment is based on band ligations. Sclerotherapy should be abandoned. In the most severe patients (Child Pugh C or B with active bleeding during initial endoscopy), transjugular intrahepatic portosystemic shunt (TIPS) should be performed within 72 hours after admission to minimize the risk of rebleeding. Secondary prophylaxis is based on the association of non-selective beta-blockers (NSBBs) and repeated band ligations. TIPS should be considered when bleeding reoccurs in spite of a well-conducted secondary prophylaxis or when NSBBs are poorly tolerated. It should also be considered when bleeding is refractory. Liver transplantation should be discussed when bleeding is not controlled after TIPS insertion and in all cases when liver function is deteriorated. PMID- 28852524 TI - Fecal microbiota transplantation for Clostridium difficile infection in patients with ileal pouches. AB - Background:Clostridium difficile infection (CDI) in patients with ileal pouch anal anastomosis (IPAA) has been increasingly recognized. The aim of this study was to evaluate the outcome of fecal microbiota transplantation (FMT) in patients with pouch and CDI. Methods: All consecutive patients that underwent FMT for CDI from 2012 to 2016 were extracted from our IRB-approved, prospectively maintained Registry of Pouch Disorders. The primary outcome was negative stool tests for Clostridium difficile after FMT and the secondary outcomes were symptomatic and endoscopic responses. Results: A total of 13 patients were included in this study, with 10 being Caucasian males (76.9%). All patients had underlying ulcerative colitis for J pouch surgery. After a mean of 2.8+/-0.8 courses of antibiotic treatments was given and failed, 22 sessions of FMT were administered with an average of 1.7+/-1.1 sessions each. Within the 22 sessions, 16 were given via pouchoscopy, 4 via esophagogastroduodenoscopy and 2 via enemas. All patients tested negative on C. difficile polymerase chain reaction (PCR) after the initial FMT with a total of 7/12 (58.3%) documented patients showed symptomatic improvements and 3/11 (27.3%) patients showed endoscopic improvement according to the modified Pouchitis Disease Activity Index. During the follow-up of 1.2+/-1.1 years, there were a total of five patients (38.5%) that had recurrence after the successful initial treatment and four of them were successfully treated again with FMT. Conclusions: FMT appeared to be effective in eradication of CDI in patients with ileal pouches. However, FMT had a modest impact on endoscopic inflammation and recurrence after FMT and recurrence was common. PMID- 28852525 TI - Real world experience with pegylated interferon and ribavirin in hepatitis C genotype 1 population with favourable IL28B polymorphism. AB - Background and aim: Conventional hepatitis C treatment using pegylated interferon (PEG-IFN) and ribavirin is associated with significant side effects. IL28B polymorphism can predict response to treatment, with CC genotype having a better response. ITPA gene deficiency protects against clinically significant anaemia induced by treatment. The purpose of this study was to determine IL28B polymorphism and ITPA variation among hepatitis C genotype 1 patients who have undergone therapy with PEG-IFN and ribavirin and their association with sustained viral response (SVR). Methods: All hepatitis C genotype 1 patients who had been treated with PEG-IFN and ribavirin over the past 10 years were identified by available medical records and were contacted by letter of invitation to participate in the study. Blood samples for IL28B and ITPA genotyping were obtained. Medical records were reviewed for verification of treatment response, development of anaemia and if treatment reduction was required during the treatment. Results: A total of 61 patients with hepatitis C genotype 1 were treated with PEG-IFN and ribavirin, of whom 42 agreed to participate in the study. Mean age was 45.6+/-12.9 years at time of treatment, and 83.3% of patients were males. Thirty-three (78.6%) had IL28B CC genotype, of whom 25 (75.8%) obtained SVR compared with only 3 of 9 (33.3%) non C/C genotype patients who achieved SVR (P=0.041). Eleven (26.1%) patients had ITPA AC genotype, and 30 (71.4%) had CC genotype. There was no statistically significant difference between ITPA AC and CC genotypes in predicting clinically significant anaemia (45.5% vs 63.3%, P=0.302). Even among patients who developed anaemia, 70.8% still managed to achieve SVR. Treatment reduction also had no impact on SVR. Conclusion: Hepatitis C genotype 1 patients should be informed of the response rate for treatment with PEG-IFN and ribavirin in a population with favourable IL28B genotype before consideration of newer therapeutic options. PMID- 28852526 TI - Identification of the distinguishing features of Crohn's disease and ischemic colitis using computed tomographic enterography. AB - Background and aims: The differential diagnosis between Crohn's disease (CD) and ischemic colitis (ISC) is important as their clinical management is different. ISC can easily be misdiagnosed as CD, especially in elderly populations. The distinctive radiographic features of the two disease entities have not been investigated. The aim of this study is to assess the utility of computed tomographic enterography (CTE) in the differential diagnosis between CD and ISC. Methods: Patients with confirmed CD and ISC were identified through an electronic medical record search of the Cleveland Clinic Foundation. Patients who had undergone CTE, with or without concurrent colonoscopy and histopathological specimens, were included in this study. CTE images were blindly re-reviewed by an expert gastrointestinal radiologist. The sensitivities, specificities, accuracies and positive and negative predictive values for each of the CTE findings in differentiating CD from ISC were estimated. Kappa coefficients (kappa) were calculated to measure diagnosis agreement between CTE and the reference standard. Results: A total of 34 eligible patients were included in this study with 17 having CD and 17 having ISC. In differentiating CD from ISC, the presence of mucosal hyperenhancement and absence of the "target sign" on CTE showed a sensitivity of 100% each for CD, while the two radiographic features yielded a low specificity of 35.3% and 76.5%, respectively. The presence of stricture had a lower sensitivity of 64.7% for the detection of CD but had a high specificity of 100%. In distinguishing CD from ISC, the accuracy of presence of mucosal hyperenhancement, stricture and absence of target sign were 67.7%, 82.4% and 88.2%, respectively. The combination of the presence of mucosal hyperenhancement and the absence of the target sign achieved an accuracy of 100% for distinguishing CD from ISC. There was a good correlation between CTE and the reference standard for distinguishing CD from ISC (kappa = 0.882). Conclusions: CTE appeared to be clinically useful in distinguishing CD from ISC. PMID- 28852528 TI - An outline of anemia among adolescent girls in Bangladesh: findings from a cross sectional study. AB - BACKGROUND: Anemia is a significant wide spread public health threat especially among the adolescent girls who are more vulnerable towards low level of hemoglobin particularly of low and middle income countries (LMICs). We investigated the prevalence of anemia among the adolescent girls (10-19 years) in Bangladesh and its socio-demographics distribution. METHODS: We collected data digitally in ODK platform from a sub-sample of a nationwide cross-sectional survey of 1314 adolescent girls in 2015. Capillary blood hemoglobin level was estimated using HemoCue(r); anthropometric measurements through standardized procedure and details socio-demographic information were captured and analyzed. Malnutrition was defined as BMI-for-age Z-score below -2SD (BAZ < -2SD), measured in WHO-AnthroPlus. Univariate analysis followed by multiple logistic regression were performed to examine the association between socio-demographic variables and anemia, while controlling the effect of potential confounding variables. RESULTS: Overall, 51.6% girls were suffering from any form of anemia (non-pregnant-Hb < 12 g/dl; pregnant-Hb < 11 g/dl) while 46% were mildly (non-pregnant-Hb: 10-11.9 g/dl; pregnant-Hb: 10-10.9 g/dl) and 5.4% were moderately (Hb: 7-9.9 g/dl) anemic while only 0.2% were severely anemic. After controlling for relevant covariates in multiple logistic regression model, malnutrition (AOR: 1.42, 95% CI = 1.0 2.10, p-value = 0.083), non-pregnancy (AOR: 6.10, 95% CI = 2.70-13.78, p-value < 0.001), and households with bottom wealth quintile (AOR: 1.54, 95% CI = 1.03 2.30, p-value = 0.037) were identified as significant risk factors of anemia among adolescent girls of Bangladesh. CONCLUSIONS: Higher number of adolescent girls are still suffering from anemia in Bangladesh and non-pregnant adolescent girls contributed the most. Immediate, long term and sustainable public health intervention would require to combat the situation. PMID- 28852529 TI - Evaluating insulin information provided on discharge summaries in a secondary care hospital in the United Kingdom. AB - BACKGROUND: Prescribing errors at the time of hospital discharge are common and could potentially lead to avoidable patient harm, especially when they involve insulin, a high-risk medicine widely used for the treatment of diabetes mellitus. When information regarding insulin therapy is not sufficiently communicated to a patient's primary care provider, continuity of care for patients with diabetes may be compromised. The objectives of this study were to investigate the nature and prevalence of insulin-related medication discrepancies contained in hospital discharge summaries for patients with diabetes. A further objective was to examine the timeliness and completeness of relevant information regarding insulin therapy provided on discharge summaries. METHODS: The study was undertaken at a large foundation trust hospital in the North of England, UK. A retrospective analysis of discharge summaries of all patients who were being treated with insulin and were included in the 2016 National Inpatient Diabetes Audit was conducted. Insulin regimen information provided on discharge summaries was scrutinised in light of available medical records pertaining to the admission and current national recommendations. RESULTS: Thirty-three (79%) out of the 42 patients included in the study had changes made to their insulin regimen during hospital admission. Eighteen (43%) patients were identified as having an error or discrepancy relating to insulin on their discharge summary. A total of 27 insulin errors or discrepancies were identified on discharge, most commonly involving non communication of an insulin dose change (n = 8) and wrong insulin device (n = 7). Seventeen issues relating to completeness of insulin information were identified, including the omission of the prescribed time of insulin administration (n = 10) and unexplained insulin dose change (n = 4). Two patients who had insulin-related errors identified on their discharge summaries were readmitted to hospital within 30 days of discharge due to poor diabetic control. CONCLUSIONS: This small-scale study demonstrates that errors and discrepancies regarding insulin therapy on discharge persist despite current insulin safety initiatives. Poorly communicated information regarding insulin therapy may jeopardise optimal glycaemic control and continuity of patient care. Insulin-related information should be comprehensively documented at the point of discharge. This is to improve communication across the interface and to minimise risks to patient safety. PMID- 28852530 TI - Multidisciplinary approach to manage antenatally suspected placenta percreta: updated algorithm and patient outcomes. AB - BACKGROUND: Due to the significant morbidity and mortality associated with placenta percreta, alternative management options are needed. Beginning in 2005, our institution implemented a multidisciplinary strategy to patients with suspected placenta percreta. The purpose of this study is to present our current strategy, maternal morbidity and outcomes of patients treated by our approach. METHODS: From 2005 to 2014, a retrospective cohort study of patients with suspected placenta percreta at an academic tertiary care institution was performed. Treatment modalities included immediate hysterectomy at the time of cesarean section (CHYS), planned delayed hysterectomy (interval hysterectomy 6 weeks after delivery) (DH), and fertility sparing (uterine conservation) (FS). Prognostic factors of maternal morbidity were identified from medical records. Complications directly related to interventional procedures and DH was recorded. Descriptive statistics were utilized. RESULTS: Of the 21 patients with suspected placenta percreta, 7 underwent CHYS, 13 underwent DH, and 1 had FS with uterine preservation. Of the 20 cases that underwent hysterectomy, final pathology showed 11 increta, 7 percreta, and 2 inconclusive. 19/20 cases underwent interventional radiology (IR) procedures. Selective embolization was utilized in 14 cases (2/7 CHYS; 12/13 DH). The median time from cesarean section (CS) to DH was 41 [26-68] days. There were no cases of emergent hysterectomy, delayed hemorrhage, or sepsis in the DH group. Both estimated blood loss and number of packed red blood cell transfusions were significantly higher in the CHYS group. 3/21 cases required massive transfusion (2 CHYS, 1 FS) with median total blood product transfusion of 13 units [12-15]. The four IR-related complications occurred in the DH group. Incidence of postoperative complications was similar between both groups. Median hospital length of stay (LOS) after CHYS was 4 days [3-8] compared to DH cohort: 7 days [3-33] after CS and 4 days [1 -10] after DH. The DH cohort had a higher rate of hospital readmission of 54% (7/13) compared to 14% (1/7) CHYS, most commonly due to pain. There were no maternal deaths. CONCLUSION: This multidisciplinary strategy may appear feasible; however, further investigation is warranted to evaluate the effectiveness of alternative approaches to cesarean hysterectomy in cases of morbidly adherent placenta. PMID- 28852531 TI - Transversus abdominis plane block with liposomal bupivacaine compared to oral opioids alone for acute postoperative pain after laparoscopic hysterectomy for early endometrial cancer: a cost-effectiveness analysis. AB - BACKGROUND: To determine the cost-effectiveness of transversus abdominis plane block with liposomal bupivacaine (TAP) compared to oral opioids alone for acute postoperative pain after laparoscopic hysterectomy for early endometrial cancer. METHODS: A cost-effectiveness analysis using a decision tree structure with a 30.5 day time-horizon was used to calculate incremental cost-effectiveness ratio (ICER) values per quality-adjusted life-year (QALY). Base-case costs, probabilities, and QALY values were identified from recently published all-payer national database studies, 2017 Medicare fee-schedules, randomized trials, institutional case series, or assumed, when published values were not available. One-way, two-way and multiple probabilistic sensitivity analyses were performed. RESULTS: The TAP strategy dominated the oral opioid-only strategy, with decreased costs and increased effectiveness. Specifically, the TAP strategy saved $235.90 under the base-case assumptions. Threshold analyses demonstrated that if the relative same-day discharge probability was >= 12% higher in the TAP group, then TAP was cost-saving over oral opioids-alone. Similarly, TAP was cost-saving whenever the costs saved by same-day discharge compared to admission were >= $1115.22. Cost-effectiveness of the TAP strategy was highly robust of a variety of sensitivity analyses. CONCLUSIONS: TAP with liposomal bupivacaine was robustly cost-effective at conventional willingness-to-pay thresholds. Further, TAP was cost-saving compared to opioids-only when the same-day discharge rate among TAP users was greater than among opioid-only users. PMID- 28852532 TI - An unusual neck tumor in a young pregnant woman: challenge diagnosis and response to treatment. AB - We report the case of a 19-year-old woman 33 weeks pregnant who presented a painful mass of progressive growth in the neck, having also dysphonia and dyspnea. Physical examination revealed a primary laryngeal tumor. A neuroendocrine small-cell carcinoma was diagnosed after histopathology, immunohistochemistry and genetic studies. Chemo-radiotherapy with a cisplatin etoposide schedule was administered. Despite obtaining a complete response, the patient relapsed and finally survived 35 months with successive cisplatin-based treatments. Small-cell neuroendocrine carcinoma of the larynx is an uncommon entity, differential diagnosis can be problematic and treatment is challenging. PMID- 28852534 TI - Editorial. PMID- 28852533 TI - Huge teratoma in a teenager. AB - Mature cystic teratoma is the most common ovarian tumor in young females. We are presenting a 13-year-old African-American female with abdominal distension. Computed tomography of the abdomen showed midline cystic mass. Diagnosis was confirmed after laparoscopic left salpingo-oophorectomy. Malignant transformation of mature cystic teratoma is rare. PMID- 28852535 TI - Public attitudes toward legally coerced biological treatments of criminals. AB - How does the public view the offer of a biological treatment in lieu of prison for criminal offenders? Using the contrastive vignette technique, we explored this issue, using mixed-methods analysis to measure concerns regarding changing the criminal's personality, the coercive nature of the offer, and the safety of the proposed treatment. Overall, we found that of the three variables, the safety of the pill had the strongest effect on public acceptance of a biological intervention. Indeed, it was notable that the public was relatively sanguine about coercive offers of biological agents, as well as changing the personality of criminals. While respondents did not fully endorse such coercive offers, neither were they outraged by the use of biological treatments of criminals in lieu of incarceration. These results are discussed in the context of the retributive and rehabilitative sentiments of the public, and legal jurisprudence in the arena of human rights law. PMID- 28852536 TI - Sperm donor anonymity and compensation: an experiment with American sperm donors. AB - Most sperm donation that occurs in the USA proceeds through anonymous donation. While some clinics make the identity of the sperm donor available to a donor conceived child at age 18 as part of 'open identification' or 'identity release programs,' no US law requires clinics to do so, and the majority of individuals do not use these programs. By contrast, in many parts of the world, there have been significant legislative initiatives requiring that sperm donor identities be made available to children after a certain age (typically when the child turns 18). One major concern with prohibiting anonymous sperm donation has been that the number of willing sperm donors will decrease leading to shortages, as have been experienced in some of the countries that have prohibited sperm donor anonymity. One possible solution, suggested by prior work, would be to pay current anonymous sperm donors more per donation to continue to donate when their anonymity is removed. Using a unique sample of current anonymous and open identity sperm donors from a large sperm bank in the USA, we test that approach. As far as we know, this is the first attempt to examine what would happen if the USA adopted a prohibition on anonymous sperm donation that used the most ecologically valid population, current sperm donors. We find that 29% of current anonymous sperm donors in the sample would refuse to donate if the law changed such that they were required to put their names in a registry available to donor conceived children at age 18. When we look at the remaining sperm donors who would be willing to participate, we find that they would demand an additional $60 per donation (using our preferred specification). We also discuss the ramifications for the industry. PMID- 28852537 TI - EBOLA and FDA: reviewing the response to the 2014 outbreak, to find lessons for the future. AB - In 2014, West Africa confronted the most severe outbreak of Ebola virus disease (EVD) in history. At the onset of the outbreak-as now-there were no therapies approved by the U.S. Food and Drug Administration (FDA) for prevention of, post exposure prophylaxis against, or treatment of EVD. As a result, the outbreak spurred interest in developing novel treatments, sparked calls to use experimental interventions in the field, and highlighted challenges to the standard approach to FDA approval of new drugs. Although the outbreak was geographically centered in West Africa, it showcased FDA's global role in drug development, approval, and access. FDA's response to EVD highlights the panoply of agency powers and demonstrates the flexibility of FDA's regulatory framework. This paper evaluates the strengths and weaknesses of FDA's response and makes policy recommendations regarding how FDA should respond to new and re-emerging public health threats. In particular, it argues that greater emphasis should be placed on drug development in interoutbreak periods and on assuring access to approved products. The current pandemic of Zika virus infection is but one example of an emerging health threat that will require FDA involvement in order to achieve a successful response. PMID- 28852539 TI - Postnatal human genetic enhancement and the parens patriae doctrine. AB - This paper explores the role of the state, acting as parens patriae, with respect to the future-looking technology of postnatal human genetic enhancement (PoGE), applied to minors by their parents or the state. Considering postnatal rather than prenatal genetic enhancement (PGE) allows us to explore the putative obligations of the state with respect to actual persons, in contrast to future persons the subjects of speculative investigation in the traditionally studied case of PGE. Part I features PoGE, mostly by analogy to PGE and other (non genetic) postnatal enhancements. Part II examines the nature and scope of the parens patriae doctrine, distinguishing between its protective and substitutive facets. I conclude, drawing on contemporary legal constructions, that: a) the state's interference in parental genetic enhancement (GE) discretion, under its protective role, should generally be minimal, reserved to extreme cases where grave harm to the child has been caused or is reasonably foreseeable; and b) since we cannot readily find parents obligated to genetically enhance their offspring, the state as parens patriae, under its substitutive role, will be respectively exempt from such duty towards state-dependent-children, save for certain GEs considered a sine qua non necessity, equally obligating parents and state to provide children with. PMID- 28852538 TI - Forensic bitemark identification: weak foundations, exaggerated claims. AB - Several forensic sciences, especially of the pattern-matching kind, are increasingly seen to lack the scientific foundation needed to justify continuing admission as trial evidence. Indeed, several have been abolished in the recent past. A likely next candidate for elimination is bitemark identification. A number of DNA exonerations have occurred in recent years for individuals convicted based on erroneous bitemark identifications. Intense scientific and legal scrutiny has resulted. An important National Academies review found little scientific support for the field. The Texas Forensic Science Commission recently recommended a moratorium on the admission of bitemark expert testimony. The California Supreme Court has a case before it that could start a national dismantling of forensic odontology. This article describes the (legal) basis for the rise of bitemark identification and the (scientific) basis for its impending fall. The article explains the general logic of forensic identification, the claims of bitemark identification, and reviews relevant empirical research on bitemark identification-highlighting both the lack of research and the lack of support provided by what research does exist. The rise and possible fall of bitemark identification evidence has broader implications-highlighting the weak scientific culture of forensic science and the law's difficulty in evaluating and responding to unreliable and unscientific evidence. PMID- 28852540 TI - Redefining responsible research and innovation for the advancement of biobanking and biomedical research. AB - One of the core objectives of responsible research and innovation (RRI) is to maximize the value of publicly funded research so that it may be returned to benefit society. However, while RRI encourages innovation through societal engagement, it can give rise to complex and previously untested issues that challenge the existing legal frameworks on intellectual property (IP) and public entitlement to benefits of research. In the case of biobanking, the personal nature of human biological materials and often altruistic intention of participants to donate samples intensifies the need to adhere to RRI principles with respect to the research, development, and commercialization of innovations derived from biobanks. However, stakeholders participate and collaborate with others in the innovation process to fulfill their own agenda. Without IP to safeguard investments in R&D, stakeholders may hesitate to contribute to the translation of discoveries into innovations. To realize the public benefit objective, RRI principles must protect the interests of stakeholders involved in the translation and commercialization of knowledge. This article explores the seemingly contradictory and competing objectives of open science and commercialization and proposes a holistic innovation framework directed at improving RRI practice for positive impact on obtaining the optimal social and economic values from research. PMID- 28852541 TI - Uterus transplantation: does procreative liberty encompass a right to gestate? PMID- 28852542 TI - The off-label use, utility and potential value of tDCS in the clinical care of particular neuropsychiatric conditions. PMID- 28852543 TI - Universalizing anonymity anxiety. PMID- 28852544 TI - Drinking from the Data Well: Response to Gamete donor anonymity and limits on numbers of offspring: the views of three stakeholders. PMID- 28852545 TI - Anonymity in third party reproduction: an old dilemma in new packaging? PMID- 28852546 TI - Third-party reproductive practices: legislative inertia and the need for nuanced empirical data. PMID- 28852547 TI - Peer commentary: in vitro gametogenesis: just another way to have a baby. PMID- 28852548 TI - Modernizing biomedical regulation: foresight and values in the promotion of responsible research and innovation. PMID- 28852549 TI - Alice and 'something more': the drift towards European patent jurisprudence. PMID- 28852550 TI - Beyond abstraction: applying the brakes to runaway patent ineligibility. PMID- 28852552 TI - Mitochondrial replacement therapy: the UK and US regulatory landscapes. PMID- 28852551 TI - As anonymity disappears the focus becomes limits on donor offspring. PMID- 28852553 TI - Strange bedfellows: anti-abortion and disability rights advocacy. PMID- 28852554 TI - Definitions of death: brain death and what matters in a person. PMID- 28852555 TI - Editorial. PMID- 28852556 TI - Promoting healthcare innovation on the demand side. AB - Innovation policy often focuses on fortifying the incentives of firms that develop and sell new products by offering them lucrative rights to exclude competitors from the market. Regulators also rely on these same firms-and on similar incentives-to develop information about the effects of their products in patients, despite their obvious conflict of interest. The result may be a distorted understanding that leads to overuse of expensive new medical technologies. Recent technological advances have put healthcare payers in an excellent position to play a larger role in future innovation to improve healthcare and reduce its costs. Insurance companies and integrated healthcare providers have custody of treasure troves of data about healthcare provision and outcomes that can yield valuable insights about the effects of medical treatment without the need to conduct costly clinical trials. Some integrated healthcare systems have seized upon this advantage to make notable discoveries about the effects of particular products that have changed the standard of care. Moreover, to the extent that healthcare payers can profit from reducing costs, they will seek to avoid inappropriate use of costly technologies. Greater involvement of payers in healthcare innovation thus offers a potential counterweight to the incentives of product sellers to promote excessive use of costly new products. In recent years, the federal government has sought to promote innovation through analysis of healthcare records in a series of initiatives; some picture insurers as passive data repositories, while others provide opportunities for insurers to take a more active role in innovation. In this paper, we examine the role of health insurers in developing new knowledge about the provision and effects of healthcare-what we call 'demand-side innovation'. We address the contours of this underexplored area of innovation and describe the behavior of participating firms. We examine the effects of current legal rules on demand-side innovation, including insurance regulation, intellectual property rules, privacy protections, and FDA regulation of new healthcare technologies. Throughout, we highlight many policy tools that government can use and is using to facilitate payer innovation outside the traditional toolkit of patents and exclusive rights. PMID- 28852557 TI - Mitochondrial replacement techniques and Mexico's rule of law: on the legality of the first maternal spindle transfer case. AB - News about the first baby born after a mitochondrial replacement technique (MRT; specifically maternal spindle transfer) broke on September 27, 2016 and, in a matter of hours, went global. Of special interest was the fact that the mitochondrial replacement procedure happened in Mexico. One of the scientists behind this world first was quoted as having said that he and his team went to Mexico to carry out the procedure because, in Mexico, there are no rules. In this paper, we explore Mexico's rule of law in relation to mitochondrial replacement techniques and show that, in fact, certain instances of MRTs are prohibited at the federal level and others are prohibited at the state level. According to our interpretation of the law, the scientists behind this first successful MRT procedure broke federal regulations regarding assisted fertilization research. PMID- 28852558 TI - Reflecting the 'human nature' of IVF embryos: disappearing women in ethics, law, and fertility practice. AB - Many laws and ethical documents instruct us that disembodied embryos created through IVF processes are not mere tissue; they are 'widely regarded' as unique objects of serious moral consideration. Even in jurisdictions which disavow any overt characterization of embryonic personhood, the embryo, by virtue of its uniqueness and orientation toward future development, is said to have a 'special status' or command 'respect'. The woman whose desire for a child or children created this embryo, and who inhabits the body to whom it may one day be returned, is an omission or at best an afterthought in such frameworks. This paper engages in an historical analysis of this conundrum in the Australian context. It argues that the institutional structure of foundational ethics bodies (made up of a mandated mix of scientific and religious representation, in practice dominated by men, and absent any requirement of the participation of women patients) has produced the embryo as an object of ideological compromise: 'not mere cells' and 'not life', but a poorly bounded and endlessly contested something-in-between. The paper then turns to engage with the narratives of a selection of women patients about their sense of connectedness to their stored or discarded embryos, drawn from a larger study on decision making concerning patient's experience of decision making about IVF embryos. I draw on these narratives to ask how we could reorient law and policy toward the concerns, needs and desires of such women. PMID- 28852559 TI - Clinical genomics, big data, and electronic medical records: reconciling patient rights with research when privacy and science collide. AB - Widespread use of medical records for research, without consent, attracts little scrutiny compared to biospecimen research, where concerns about genomic privacy prompted recent federal proposals to mandate consent. This paper explores an important consequence of the proliferation of electronic health records (EHRs) in this permissive atmosphere: with the advent of clinical gene sequencing, EHR based secondary research poses genetic privacy risks akin to those of biospecimen research, yet regulators still permit researchers to call gene sequence data 'de identified', removing such data from the protection of the federal Privacy Rule and federal human subjects regulations. Medical centers and other providers seeking to offer genomic 'personalized medicine' now confront the problem of governing the secondary use of clinical genomic data as privacy risks escalate. We argue that regulators should no longer permit HIPAA-covered entities to treat dense genomic data as de-identified health information. Even with this step, the Privacy Rule would still permit disclosure of clinical genomic data for research, without consent, under a data use agreement, so we also urge that providers give patients specific notice before disclosing clinical genomic data for research, permitting (where possible) some degree of choice and control. To aid providers who offer clinical gene sequencing, we suggest both general approaches and specific actions to reconcile patients' rights and interests with genomic research. PMID- 28852560 TI - Substitute consent to data sharing: a way forward for international dementia research? AB - A deluge of genetic and health-related data is being generated about patients with dementia. International sharing of these data accelerates dementia research. Seeking consent to data sharing is a challenge for dementia research where patients have lost or risk losing legal capacity. The laws of most countries enable substitute decision makers (SDMs) to consent on behalf of incapable adults to research participation. We compare regulatory frameworks governing capacity, research, and personal data protection across eight countries to determine when SDMs can consent to data sharing. In most countries, an SDM can consent to data sharing in the incapable adult's best interests. Best interests typically include consideration of the individual's previously expressed wishes, values and beliefs; well-being; and inclusion in decision making. Countries differ in how these considerations are balanced. A clear previous consent or refusal to share data typically binds the discretion of an SDM. Though generally permissive, National patchworks of laws and guidelines cause confusion. Clarity on the applicable law and processes to enhance ethical decision making are needed to facilitate substitute consent. Researchers can encourage patients to communicate their research preferences before a loss of capacity, and educate SDMs about their ethical and legal duties. The research community must also continue to promote the importance of data sharing in dementia. PMID- 28852561 TI - Barred from better medicine? Reexamining regulatory barriers to the inclusion of prisoners in research. AB - In 2015, President Obama announced plans for the Precision Medicine Initiative(r) (PMI), an ambitious longitudinal project aimed at revolutionizing medicine. Integral to this Initiative is the recruitment of over one million Americans into a volunteer research cohort, the All of UsSM Research Program. The announcement has generated much excitement but absent is a discussion of how the All of Us Research Program-to be implemented within the context of social realities of mass incarcerations and racial disparities in criminal justice and healthcare-might excaberate health disparities. We examine how attainment of Initiative's stated goals of reflecting the diversity of the American population and including all who are interested in participating might be impeded by regulatory and administrative barriers to the involvement of participants who become incarcerated during longitudinal studies. Changes have been proposed to the federal policy for human subjects research protections, but current regulations and administrative policies-developed under a protectionist paradigm in response to scandalous research practices with confined populations-dramatically limit research involving prisoners. Our review provides rationale for the development of Initiative policies that anticipate recruitment and retention obstacles that might frustrate inclusivity and exacerbate health disparities. Furthermore, we question the effective ban on biomedical and behavioral research involving prisoners and advocate for regulatory reforms that restore participatory research rights of prisoners. Disparities in health and justice are intertwined, and without regulatory reforms to facilitate participatory research rights of prisoners and careful planning of viable and responsible recruitment, engagement, and retention strategies, Initiative could miss discovery opportunities, exacerbate health disparities, and increase levels of distrust in science. PMID- 28852562 TI - Disappearing women, vanishing ladies and property in embryos. PMID- 28852563 TI - The testosterone rule-constructing fairness in professional sport. PMID- 28852564 TI - Fee-for-value in the pharmaceutical industry: a policy framework applying data science to negotiate drug prices. PMID- 28852565 TI - Designing a standard of proof: the case for professional standards in next generation sequencing laboratory-developed tests. PMID- 28852566 TI - Erratum: Patenting nature or protecting culture? Ethnopharmacology and indigenous intellectual property rights. AB - [This corrects the article DOI: 10.1093/jlb/lsw003.]. PMID- 28852567 TI - A Computerized Cognitive behavioral therapy Randomized, Controlled, pilot trial for insomnia in Parkinson Disease (ACCORD-PD). AB - BACKGROUND: Parkinson disease (PD) is associated with a high prevalence of insomnia, affecting up to 88% of patients. Pharmacotherapy studies in the literature addressing insomnia in PD reveal disappointing and inconsistent results. Cognitive behavioral therapy (CBT) is a novel treatment option with durable effects shown in primary insomnia. However, the lack of accessibility and expense can be limiting. For these reasons, computerized CBT for insomnia (CCBT I) has been developed. The CCBT-I program is a 6-week web-based course consisting of daily "lessons" providing learnable skills and appropriate recommendations to help patients improve their sleep habits and patterns. METHODS: We conducted a single-center, pilot, randomized controlled trial comparing CCBT-I versus standardized sleep hygiene instructions to treat insomnia in PD. Twenty-eight subjects with PD experiencing insomnia, with a score > 11 on the Insomnia Severity Index (ISI) were recruited. Based on a 6-point improvement in ISI in treatment group when compared to controls and an alpha = 0.05 and beta of 0.1 (power = 90%) a sample size of 11 patients (on active treatment) were required to detect this treatment effect using a dependent sample t-test. RESULTS: In total, 8/14 (57%) subjects randomized to CCBT-I versus 13/14 (93%) subjects randomized to standard education completed the study. Among completers, the improvement in ISI scores was greater with CCBT-I as compared to standard education (-7.9 vs 3.5; p = 0.03). However, in an intention-to-treat analysis, where all enrolled subjects were included, the change in ISI between groups was not significant ( .4.5 vs -3.3; p = 0.48), likely due to the high dropout rate in the CCBT-I group (43%). CONCLUSION: This pilot study suggests that CCBT-I can be an effective treatment option for PD patients with insomnia when the course is thoroughly completed. High drop-out rate in our study shows that although effective, it may not be a generalizable option; however, larger studies are needed for further evaluation. PMID- 28852568 TI - Etiology of acute respiratory disease in fattening pigs in Finland. AB - BACKGROUND: The objective of our study was to clinically and etiologically investigate acute outbreaks of respiratory disease in Finland. Our study also aimed to evaluate the clinical use of various methods in diagnosing respiratory infections under field conditions and to describe the antimicrobial resistance profile of the main bacterial pathogen(s) found during the study. METHODS: A total of 20 case herds having finishing pigs showing acute respiratory symptoms and eight control herds showing no clinical signs suggesting of respiratory problems were enrolled in the study. Researchers visited each herd twice, examining and bleeding 20 pigs per herd. In addition, nasal swab samples were taken from 20 pigs and three pigs per case herd were necropsied during the first visit. Serology was used to detect Actinobacillus pleuropneumoniae (APP), swine influenza virus (SIV), porcine reproductive and respiratory syndrome virus (PRRSV), porcine respiratory coronavirus (PRCV) and Mycoplasma hyopneumoniae antibodies. Polymerase chain reaction (PCR) was used to investigate the presence of porcine circovirus type 2 (PCV2) in serum and SIV in the nasal and lung samples. Pathology and bacteriology, including antimicrobial resistance determination, were performed on lung samples obtained from the field necropsies. RESULTS: According to the pathology and bacteriology of the lung samples, APP and Ascaris suum were the main causes of respiratory outbreaks in 14 and three herds respectively, while the clinical signs in three other herds had a miscellaneous etiology. SIV, APP and PCV2 caused concurrent infections in certain herds but they were detected serologically or with PCR also in control herds, suggesting possible subclinical infections. APP was isolated from 16 (80%) case herds. Marked resistance was observed against tetracycline for APP, some resistance was detected against trimethoprim/sulfamethoxazole, ampicillin and penicillin, and no resistance against florfenicol, enrofloxacin, tulathromycin or tiamulin was found. Serology, even from paired serum samples, gave inconclusive results for acute APP infection diagnosis. CONCLUSIONS: APP was the most common cause for acute respiratory outbreaks in our study. SIV, A. suum, PCV2 and certain opportunistic bacteria were also detected during the outbreaks; however, viral pathogens appeared less important than bacteria. Necropsies supplemented with microbiology were the most efficient diagnostic methods in characterizing the studied outbreaks. PMID- 28852569 TI - Survey on Mycoplasma hyopneumoniae gilt acclimation practices in Europe. AB - Gilts are considered to play a key role in Mycoplasma hyopneumoniae (M. hyopneumoniae) transmission and control. An effective gilt acclimation program should ideally reduce M. hyopneumoniae shedding at first farrowing, decreasing pre-weaning colonization prevalence and potential respiratory problems in fatteners. However, information on gilt acclimation practices is scarce in Europe. The aim of this study was to identify current acclimation strategies for M. hyopneumoniae in Europe using a questionnaire designed to assess 15 questions focused on gilt replacement status, acclimation strategies and methods used to ascertain its effect. A total of 321 questionnaires (representing 321 farms) were voluntarily completed by 108 veterinarians (from 18 European countries). From these farms, 280 out of 321 (87.2%) were aware of the health status of gilts on arrival. From these 280 farms, 161 (57.5%) introduced M. hyopneumoniae positive replacements. In addition, 249 out of 321 (77.6%) farms applied an acclimation process using different strategies, being M. hyopneumoniae vaccination (145 out of 249, 58.2%) and the combination of vaccine and exposure to sows selected for slaughter (53 out of 249, 21.3%) the most commonly used. Notwithstanding, only 53 out of 224 (23.6%) farms, knowing the M. hyopneumoniae initial status and performing acclimation strategies against it, verified the effect of the acclimation by ELISA (22 out of 53, 41.5%), PCR (4 out of 53, 7.5%) or both (27 out of 53, 50.9%). This study showed that three fourths of the farms represented in this European survey have M. hyopneumoniae acclimation strategies for gilts, and one fifth of them verify to some extent the effect of the process. Taking into account that the assessment of acclimation efficacy could help in optimizing replacement gilt introduction into the breeding herd, it seems these practices for M. hyopneumoniae are still poorly developed in Europe. PMID- 28852570 TI - Internal validation of an automated system for brachial and femoral flow mediated dilation. AB - BACKGROUND: Flow Mediated Dilation (FMD) has immense potential to become a clinical, non-invasive biomarker of endothelial function and nitric oxide bioavailability, which regulate vasomotor activity. Unfortunately, FMD analysis techniques could deviate significantly in different laboratories if a validation process is not involved. The purpose of this study was to provide validation to the assessment of FMD analysis in our laboratory and to standardize this process before reporting results of FMD. METHODS: Brachial and femoral arteries FMD were performed on 28 apparently healthy participants (15 male and 13 female, ages 18 35 years). For the intratester reliability study, nine subjects were asked to come to the lab for a second brachial FMD within 48 h. All FMD procedures were performed by the same investigator, while the FMD analyses were performed by 2 independent testers who were blind to each other's analyses. FMD analyses included baseline artery diameter measurements, peak artery diameter after 5 min of ischemia, and FMD. Analysis was completed via an automated edge detection system by both testers after training of the methodical process of analysis to minimize variability. Intratester and intertester reliability were determined by using coefficient of variation (CV) between first and second visit (intratester) and between results obtained by both testers (intertester). RESULTS: The intratester CVs for tester 1 and 2 were 3.28 and 2.62%, 3.74 and 3.27%, and 4.95 and 2.38% for brachial baseline artery diameter, brachial peak artery dilation, and brachial FMD, respectively. In the intertester CVs were 2.40, 3.16, and 3.37% for brachial baseline artery diameter, peak artery dilation, and FMD, respectively and 4.52, 5.50, and 3.46% for femoral baseline artery diameter, peak artery dilation, and FMD, respectively. CONCLUSION: All CVs were under or around 5%, confirming a strong reliability of the method. Our laboratory has shown that the FMD protocol is reproducible due to the significantly low coefficient of variation. This is one step closer to use FMD as a biomarker for endothelial function in our laboratory. PMID- 28852571 TI - Glycerol kinase-like proteins cooperate with Pld6 in regulating sperm mitochondrial sheath formation and male fertility. AB - Spermatids undergo the final steps of maturation during spermiogenesis, a process that necessitates extensive rearrangement of organelles such as the mitochondria. Male infertility has been linked to mitochondrial disorder, for example, hypospermatogenesis and asthenozoospermia. However, the mechanisms that regulate mitochondrial dynamics during spermiogenesis remain largely unknown. We found the glycerol kinase (Gyk)-like proteins glycerol kinase-like 1 (Gykl1) and glycerol kinase 2 (Gk2) were specifically localized to the mitochondria in spermatids. Male mice deficient in either Gykl1 or Gk2 were infertile due to dysfunctional spermatozoa, which exhibited unregulated ATP production, disordered mitochondrial sheath formation, abnormal mitochondrial morphology, and defective sperm tail. We demonstrated that the unique C-terminal sequences found in Gykl1 and Gk2 mediated their targeting to the mitochondrial outer membrane. Furthermore, both Gykl1 and Gk2 could interact with Pld6 (MitoPLD) and induce Pld6 and phosphatidic acid (PA) dependent mitochondrial clustering in cells. Taken together, our study has revealed previously unsuspected functions of Gyk-like proteins in spermiogenesis, providing new insight into the potential mechanisms that lead to spermatozoa dysfunction and male infertility. PMID- 28852572 TI - Adaptive HIV-1 evolutionary trajectories are constrained by protein stability. AB - Despite the use of combination antiretroviral drugs for the treatment of HIV-1 infection, the emergence of drug resistance remains a problem. Resistance may be conferred either by a single mutation or a concerted set of mutations. The involvement of multiple mutations can arise due to interactions between sites in the amino acid sequence as a consequence of the need to maintain protein structure. To better understand the nature of such epistatic interactions, we reconstructed the ancestral sequences of HIV-1's Pol protein, and traced the evolutionary trajectories leading to mutations associated with drug resistance. Using contemporary and ancestral sequences we modelled the effects of mutations (i.e. amino acid replacements) on protein structure to understand the functional effects of residue changes. Although the majority of resistance-associated sequences tend to destabilise the protein structure, we find there is a general tendency for protein stability to decrease across HIV-1's evolutionary history. That a similar pattern is observed in the non-drug resistance lineages indicates that non-resistant mutations, for example, associated with escape from the immune response, also impacts on protein stability. Maintenance of optimal protein structure therefore represents a major constraining factor to the evolution of HIV-1. PMID- 28852573 TI - Biased phylodynamic inferences from analysing clusters of viral sequences. AB - Phylogenetic methods are being increasingly used to help understand the transmission dynamics of measurably evolving viruses, including HIV. Clusters of highly similar sequences are often observed, which appear to follow a 'power law' behaviour, with a small number of very large clusters. These clusters may help to identify subpopulations in an epidemic, and inform where intervention strategies should be implemented. However, clustering of samples does not necessarily imply the presence of a subpopulation with high transmission rates, as groups of closely related viruses can also occur due to non-epidemiological effects such as over-sampling. It is important to ensure that observed phylogenetic clustering reflects true heterogeneity in the transmitting population, and is not being driven by non-epidemiological effects. We qualify the effect of using a falsely identified 'transmission cluster' of sequences to estimate phylodynamic parameters including the effective population size and exponential growth rate under several demographic scenarios. Our simulation studies show that taking the maximum size cluster to re-estimate parameters from trees simulated under a randomly mixing, constant population size coalescent process systematically underestimates the overall effective population size. In addition, the transmission cluster wrongly resembles an exponential or logistic growth model 99% of the time. We also illustrate the consequences of false clusters in exponentially growing coalescent and birth-death trees, where again, the growth rate is skewed upwards. This has clear implications for identifying clusters in large viral databases, where a false cluster could result in wasted intervention resources. PMID- 28852574 TI - Spatially induced nestedness in a neutral model of phage-bacteria networks. AB - Ecological networks, both displaying mutualistic or antagonistic interactions, seem to share common structural traits: the presence of nestedness and modularity. A variety of model approaches and hypothesis have been formulated concerning the significance and implications of these properties. In phage bacteria bipartite infection networks, nestedness seems to be the rule in many different contexts. Modeling the coevolution of a diverse virus-host ensemble is a difficult task, given the dimensionality and multi parametric nature of a standard continuous approximation. Here, we take a different approach, by using a neutral, toy model of host-phage interactions on a spatial lattice. Each individual is represented by a bit string (a digital genome) but all strings in each class (i.e. hosts or phages) share the same sets of parameters. A matching allele model of phage-virus recognition rule is enough to generate a complex, diverse ecosystem with heterogeneous patterns of interaction and nestedness, provided that interactions take place under a spatially constrained setting. It is found that nestedness seems to be an emergent property of the co-evolutionary dynamics. Our results indicate that the enhanced diversity resulting from localized interactions strongly promotes the presence of nested infection matrices. PMID- 28852575 TI - A Protocol for Diagnosis and Management of Aortic Atherosclerosis in Cardiac Surgery Patients. AB - In patients undergoing cardiac surgery, use of perioperative screening for aortic atherosclerosis with modified TEE (A-View method) was associated with lower postoperative mortality, but not stroke, as compared to patients operated on without such screening. At the time of clinical implementation and validation, we did not yet standardize the indications for modified TEE and the changes in patient management in the presence of aortic atherosclerosis. Therefore, we designed a protocol, which combined the diagnosis of atherosclerosis of thoracic aorta and the subsequent considerations with respect to the intraoperative management and provides a systematic approach to reduce the risk of cerebral complications. PMID- 28852576 TI - Recent Advances in Hydrogel-Based Drug Delivery for Melanoma Cancer Therapy: A Mini Review. AB - The purpose of this study is to describe some of the latest advances in using hydrogels for cancer melanoma therapy. Hydrogel formulations of polymeric material from natural or synthetic sources combined with therapeutic agents have gained great attention in the recent years for treating various maladies. These formulations can be categorized according to the strategies that induce cancer cell death in melanoma. First of all, we should note that these formulations can only play a supporting role that releases bioactive agents against cancer cells rather than the main role. This strategy involves delivering the drug via transdermal pathways, resulting in the death of cancerous cells. Another strategy utilizes magnetic gel composites to combat melanoma via hyperthermia therapy. This review discusses both transdermal and hyperthermia therapies and the recent advances that have occurred in the field. PMID- 28852577 TI - Sequential Venous Percutaneous Transluminal Angioplasty and Balloon Dilatation of the Interatrial Septum during Percutaneous Edge-to-Edge Mitral Valve Repair. AB - Percutaneous edge-to-edge mitral valve repair (PMVR) is widely used for selected, high-risk patients with severe mitral valve regurgitation (MR). This report describes a case of 81-year-old woman presenting with severe and highly symptomatic mitral valve regurgitation (MR) caused by a flail of the posterior mitral valve leaflet (PML). PMVR turned out to be challenging in this patient because of a stenosis and tortuosity of both iliac veins as well as sclerosis of the interatrial septum, precluding the vascular and left atrial access by standard methods, respectively. We managed to achieve atrial access by venous percutaneous transluminal angioplasty (PTA) and balloon dilatation of the interatrial septum. Subsequently, we could advance the MitraClip(r) system to the left atrium, and deployment of the clip in the central segment of the mitral valve leaflets (A2/P2) resulted in a significant reduction of MR. PMID- 28852578 TI - Calciphylaxis of the Postmenopausal Female Breast: An Uncommonly Encountered Mimic of Carcinoma. AB - Calciphylaxis is a serious medical condition that is typically associated with end-stage renal disease and presents as the sequelae of calcifications in arterioles with subsequent ischemia of affected tissues. Classically, calciphylaxis produces ulcerated and necrotic skin lesions. These may be biopsied to aid in confirmation of the diagnosis. Herein we report a case of a large necrotic breast lesion in the clinical setting of calciphylaxis, and we emphasize that a multidisciplinary approach to diagnosis and management is important to avoid unnecessary oncological resection. PMID- 28852580 TI - Incidental Finding of Dual Ectopic Thyroid on Computed Tomography Angiography. AB - The presence of simultaneous two ectopic foci of thyroid tissue (dual ectopic thyroid) is rare, and few cases have been reported in the literature. The ectopic thyroid tissue is an extremely uncommon embryological aberration due to the alterations occurring during the embryological development with incomplete migration of thyroid precursors. Commonly ectopic thyroid tissue is a midline structures, but the lateral location is possible but very rare. Ectopic thyroid is common in women and can vary in size from a microscopic focus to a few centimeters. The normal process of migration of the thyroid can be interrupted at various levels determining a lingual ectopy, a sublingual ectopic, prelaryngeal ectopy, or mediastinic ectopy. Intrathoracic and subdiaphragmatic organs are other sites where the ectopic thyroid tissue may be present. In most of the cases, ectopic tissue is a lingual thyroid and this condition can be totally asymptomatic, discovered incidentally, or occurs with symptoms such as dysphonia, dysphagia, dyspnea, and hemoptysis. Sublingual or suprahyoid ectopia is rare and even rarer are the cases of two foci of ectopic thyroid tissue simultaneously present. On imaging, the ectopic tissue shows the same characteristics of orthotopic thyroid tissue and similarly can undergo goiterous and cancerous transformation. We report a case of incidental dual ectopic thyroid in lingual and suprahyoid level in a 72-year-old female patient, asymptomatic and with normal thyroid function, who underwent computed tomography (CT) angiography before vascular surgery for the treatment of carotid stenosis. The presence of a lingual thyroid can lead to a difficult and dangerous intubation, with possible fatal consequences. For this reason, the discovery of these abnormalities has totally changed the patient management who has been subjected to endovascular treatment, instead to the classical surgery. PMID- 28852579 TI - Predictors of Functional and Quality of Life Outcomes following Deep Brain Stimulation Surgery in Parkinson's Disease Patients: Disease, Patient, and Surgical Factors. AB - OBJECTIVE: The primary objective was to evaluate predictors of quality of life (QOL) and functional outcomes following deep brain stimulation (DBS) in Parkinson's disease (PD) patients. The secondary objective was to identify predictors of global improvement. METHODS: PD patients who underwent DBS at our Center from 2006 to 2011 were evaluated by chart review and email/phone survey. Postoperative UPDRS II and EQ-5D were analyzed using simple linear regression adjusting for preoperative score. For global outcomes, we utilized the Patient Global Impression of Change Scale (PGIS) and the Clinician Global Impression of Change Scale (CGIS). RESULTS: There were 130 patients in the dataset. Preoperative and postoperative UPDRS II and EQ-5D were available for 45 patients, PGIS for 67 patients, and CGIS for 116 patients. Patients with falls/postural instability had 6-month functional scores and 1-year QOL scores that were significantly worse than patients without falls/postural instability. For every 1 point increase in preoperative UPDRS III and for every 1-unit increase in body mass index (BMI), the 6-month functional scores significantly worsened. Patients with tremors, without dyskinesia, and without gait-freezing were more likely to have "much" or "very much" improved CGIS. CONCLUSIONS: Presence of postural instability, high BMI, and worse baseline motor scores were the greatest predictors of poorer functional and QOL outcomes after DBS. PMID- 28852581 TI - One Year Primary Patency of Infrapopliteal Angioplasty Using Drug- Eluting Balloons: Single Center Experience at King Hussein Medical Center. AB - OBJECTIVE: Conventional percutaneous transluminal angioplasty (PTA) for long lesions in the below-the-knee (BTK) arteries in patients presenting with critical limb ischemia (CLI) has high restenosis rates at 1 year. Our goal is to evaluate whether paclitaxel drug-eluting balloons (DEB) have higher 1 year primary patency rates compared to conventional PTA. METHODS: This is a single-center, prospective, randomized trial that was conducted from June 2013 to December 2015. The aim of the study was to compare 1 year primary patency rates of DEB and PTA in BTK arteries in CLI patients. Inclusion criteria were patients presenting with CLI (Rutherford class 4 or greater), stenosis or occlusion >=30 mm of at least one tibial artery, and agreement to 12-month evaluation. Exclusion criteria were life expectancy <1 year, allergy to paclitaxel, and contraindication to combined antiplatelet treatment. Follow-up was performed by clinical assessment, ankle brachial pressure index, Doppler ultrasound imaging, and conventional angiogram if indicated. Primary end point was 1 year primary patency, and secondary end points were target lesion revascularization (TLR) and major amputation. Statistical analysis was performed using Fischer's exact test. RESULTS: Ninety three patients with 106 lesions in the BTK arteries were enrolled in this study. One year primary patency was achieved in 26 (65%) and seven (17%) in the DEB and PTA groups (P = 0.006), respectively. TLR was performed in nine lesions (23%) and 29 lesions (71%) in DEB and PTA groups (P = 0.009), respectively. Major amputations occurred in one limb (2%) and two limbs (4%) in DEB and PTA groups (P = 0.6), respectively. CONCLUSION: Paclitaxel DEB has significantly higher 1 year primary patency rate associated with significantly less TLR than conventional PTA, following endovascular recanalization of BTK arteries in patients presenting with CLI. PMID- 28852582 TI - Term Neonate with Atypical Hypoxic-Ischemic Encephalopathy Presentation: A Case Report. AB - We describe a case of atypical hypoxic-ischemic encephalopathy (HIE) in a neonate following a normal pregnancy and delivery who was found to have an umbilical vein thrombosis. The infant arrived to our center with continuous bicycling movement of her lower extremities. She had a continuous electroencephalogram that showed burst suppression and magnetic resonance imaging of the brain showed diffusely abnormal cerebral cortical/subcortical diffusion restriction which may be secondary hypoxic-ischemic injury. Interestingly, a pathology report noted a focal umbilical vein thrombosis appearing to have compressed an umbilical artery with associated arterial dissection and hematoma. Our case illustrates how umbilical venous or arterial thrombosis may be associated with HIE and refractory seizures. PMID- 28852583 TI - Comparative molecular analyses of select pH- and osmoregulatory genes in three freshwater crayfish Cherax quadricarinatus, C. destructor and C. cainii. AB - Systemic acid-base balance and osmotic/ionic regulation in decapod crustaceans are in part maintained by a set of transport-related enzymes such as carbonic anhydrase (CA), Na+/K+-ATPase (NKA), H+-ATPase (HAT), Na+/K+/2Cl- cotransporter (NKCC), Na+/Cl-/HCO[Formula: see text] cotransporter (NBC), Na+/H+ exchanger (NHE), Arginine kinase (AK), Sarcoplasmic Ca+2-ATPase (SERCA) and Calreticulin (CRT). We carried out a comparative molecular analysis of these genes in three commercially important yet eco-physiologically distinct freshwater crayfish, Cherax quadricarinatus, C. destructor and C. cainii, with the aim to identify mutations in these genes and determine if observed patterns of mutations were consistent with the action of natural selection. We also conducted a tissue specific expression analysis of these genes across seven different organs, including gills, hepatopancreas, heart, kidney, liver, nerve and testes using NGS transcriptome data. The molecular analysis of the candidate genes revealed a high level of sequence conservation across the three Cherax sp. Hyphy analysis revealed that all candidate genes showed patterns of molecular variation consistent with neutral evolution. The tissue-specific expression analysis showed that 46% of candidate genes were expressed in all tissue types examined, while approximately 10% of candidate genes were only expressed in a single tissue type. The largest number of genes was observed in nerve (84%) and gills (78%) and the lowest in testes (66%). The tissue-specific expression analysis also revealed that most of the master genes regulating pH and osmoregulation (CA, NKA, HAT, NKCC, NBC, NHE) were expressed in all tissue types indicating an important physiological role for these genes outside of osmoregulation in other tissue types. The high level of sequence conservation observed in the candidate genes may be explained by the important role of these genes as well as potentially having a number of other basic physiological functions in different tissue types. PMID- 28852584 TI - The extracellular vesicles secreted by lung cancer cells in radiation therapy promote endothelial cell angiogenesis by transferring miR-23a. AB - Angiogenesis is an important factor contributing to the radioresistance of lung cancer. However, the associated mechanisms underlying radiotherapy-induced pro angiogenesis are unclear. Here, we demonstrated that Extracellular vesicles (EVs) derived from cultured cells in vitro enhanced HUVEC proliferation and migration, and the enhancement effect became more obvious when HUVECs were treated with EV derived from A549 or H1299, two lung cancer cell lines. Additionally, the pro angiogenesis effect induced by EV could be strengthened when the lung cancer cells were exposed to X-ray irradiation. Furthermore, we verified that the downregulation of PTEN plays a vital role in this process. By evaluating the changes in the levels of microRNAs(miRNAs) targeting PTEN in EV, we found that miR-23a was significantly upregulated and mediated a decrease in PTEN. A luciferase reporter gene transfer experiment demonstrated that PTEN was the direct target of miR-23a, and the kinetics of PTEN expression were opposite to those of miR-23a. Our results show that the miR-23a/PTEN pathway plays an important role in EV-induced angiogenesis. These findings implicate the miR 23a/PTEN axis as a novel therapeutic target for lung cancer radiotherapy. PMID- 28852585 TI - Implications of nutritional stress as nestling or fledgling on subsequent attractiveness and fecundity in zebra finches (Taeniopygia guttata). AB - The conditions an organism experiences during early development can have profound and long lasting effects on its subsequent behavior, attractiveness, and life history decisions. Most previous studies have exposed individuals to different conditions throughout development until nutritional independence. Yet under natural conditions, individuals may experience limitations for much shorter periods due to transient environmental fluctuations. Here, we used zebra finches (Taeniopygia guttata) in captivity to determine if conditions experienced during distinctly different early developmental phases contribute differently to male and female attractiveness and subsequent reproduction. We conducted a breeding experiment in which offspring were exposed to food regimes with (a) low quality food provided only during the nestling period, (b) low quality food provided only during the fledgling period, or (c) high quality food throughout early development. We show that despite short-term effects on biometry and physiology, there were no effects on either male or female attractiveness, as tested in two way mate choice free-flight aviary experiments. In a subsequent breeding experiment, the offspring from the initial experiment were allowed to breed themselves. The next generation offspring from mothers raised under lower quality nutrition as either nestling or fledging were lighter at hatching compared to offspring from mothers raised under higher quality nutrition whereas paternal early nutrition had no such effects. The lack of early developmental limitations on attractiveness suggests that attractiveness traits were not affected or that birds compensated for any such effects. Furthermore, maternal trans-generational effects of dietary restrictions emphasize the importance of role of limited periods of early developmental stress in the expression of environmentally determined fitness components. PMID- 28852586 TI - RNA-seq reveals more consistent reference genes for gene expression studies in human non-melanoma skin cancers. AB - Identification of appropriate reference genes (RGs) is critical to accurate data interpretation in quantitative real-time PCR (qPCR) experiments. In this study, we have utilised next generation RNA sequencing (RNA-seq) to analyse the transcriptome of a panel of non-melanoma skin cancer lesions, identifying genes that are consistently expressed across all samples. Genes encoding ribosomal proteins were amongst the most stable in this dataset. Validation of this RNA-seq data was examined using qPCR to confirm the suitability of a set of highly stable genes for use as qPCR RGs. These genes will provide a valuable resource for the normalisation of qPCR data for the analysis of non-melanoma skin cancer. PMID- 28852587 TI - A systematic review of differential rate of use of the word "evolve" across fields. AB - BACKGROUND: Although evolution is the driving force behind many of today's major public health and agriculture issues, both journalists and scientific researchers often do not use the term "evolve" in discussions of these topics. METHODS: In a total of 1,066 articles and 716 papers selected from 25 US newspapers and 34 scientific journals, we assess usage of the word "evolve" and its substitute words in the contexts of cancer tumor drug resistance, HIV drug resistance, mosquito insecticide resistance, and weed pesticide resistance. RESULTS: We find significant differences in the use of "evolve" among fields and sources. "Evolve" is used most when discussing weed pesticide resistance (25.9% in newspapers, 52.4% in journals) and least when discussing cancer tumor drug resistance (3.9% in newspapers, 9.8% in journals). On average, scientific journals use "evolve" more often (22.2%) than newspapers (7.8%). Different types of journals (general science, general clinical, cancer specific, and drug resistance specific) show significantly different "evolve" usages when discussing cancer tumor drug resistance. DISCUSSION: We examine potential explanations of these findings, such as the relatively recent framing of cancer in evolutionary terms, before looking at consequences of low "evolve" usage and of differential "evolve" usage across fields. Use of the word "evolve" may not reflect current understanding of the problems we examine. However, given that our ability to tackle resistance issues relies upon accurate understandings of what causes and exacerbates resistance, use of the word "evolve" when called for may help us confront these issues in the future. PMID- 28852588 TI - Expression differences in Aphidius ervi (Hymenoptera: Braconidae) females reared on different aphid host species. AB - The molecular mechanisms that allow generalist parasitoids to exploit many, often very distinct hosts are practically unknown. The wasp Aphidius ervi, a generalist koinobiont parasitoid of aphids, was introduced from Europe into Chile in the late 1970s to control agriculturally important aphid species. A recent study showed significant differences in host preference and host acceptance (infectivity) depending on the host A. ervi were reared on. In contrast, no genetic differentiation between A. ervi populations parasitizing different aphid species and aphids of the same species reared on different host plants was found in Chile. Additionally, the same study did not find any fitness effects in A. ervi if offspring were reared on a different host as their mothers. Here, we determined the effect of aphid host species (Sitobion avenae versus Acyrthosiphon pisum reared on two different host plants alfalfa and pea) on the transcriptome of adult A. ervi females. We found a large number of differentially expressed genes (between host species: head: 2,765; body: 1,216; within the same aphid host species reared on different host plants: alfalfa versus pea: head 593; body 222). As expected, the transcriptomes from parasitoids reared on the same host species (pea aphid) but originating from different host plants (pea versus alfalfa) were more similar to each other than the transcriptomes of parasitoids reared on a different aphid host and host plant (head: 648 and 1,524 transcripts; body: 566 and 428 transcripts). We found several differentially expressed odorant binding proteins and olfactory receptor proteins in particular, when we compared parasitoids from different host species. Additionally, we found differentially expressed genes involved in neuronal growth and development as well as signaling pathways. These results point towards a significant rewiring of the transcriptome of A. ervi depending on aphid-plant complex where parasitoids develop, even if different biotypes of a certain aphid host species (A. pisum) are reared on the same host plant. This difference seems to persist even after the different wasp populations were reared on the same aphid host in the laboratory for more than 50 generations. This indicates that either the imprinting process is very persistent or there is enough genetic/allelic variation between A. ervi populations. The role of distinct molecular mechanisms is discussed in terms of the formation of host fidelity. PMID- 28852589 TI - Assessing the utility of urinary and fecal cortisol as an indicator of stress in golden snub-nosed monkeys (Rhinopithecus roxellana). AB - Cortisol concentration (CC) is often used as a stress indicator in animals, as high CC is associated with elevated stress levels. During field research, non invasive methods of measuring CC, such as collection of urine and feces, are superior to using blood samples when monitoring free-ranging animals' stress levels. However, due to different metabolic pathways, whether CC can be detected in urine and feces to reliably assess stress varies across species. Therefore, it is important to ascertain whether urine and fecal samples are a reliable source for determining CCs and to determine a suitable sampling regime. In this study, we subjected three captive adult golden snub-nosed monkeys (Rhinopithecus roxellana) to a high-stress situation (capture and injection). Urine and feces were collected for four days before and for four days after the manipulations for laboratory analysis. Immunoreactive CC was detected with a commercial enzyme immunoassay (EIA) kit and showed distinct rises. Peak CC values in urine were detected within 5 h, while peak fecal CC ranged between 5 and 24 hours post interference. These results provide evidence that CC in urine and feces can be used to assess stress levels in the golden snub-nosed monkey. The optimal time frame to collect urinary and fecal samples for CC analysis is within one day of a potential stressful event. PMID- 28852590 TI - Population structure of Bathymodiolus manusensis, a deep-sea hydrothermal vent dependent mussel from Manus Basin, Papua New Guinea. AB - Deep-sea hydrothermal vents in the western Pacific are increasingly being assessed for their potential mineral wealth. To anticipate the potential impacts on biodiversity and connectivity among populations at these vents, environmental baselines need to be established. Bathymodiolus manusensis is a deep-sea mussel found in close association with hydrothermal vents in Manus Basin, Papua New Guinea. Using multiple genetic markers (cytochrome C-oxidase subunit-1 sequencing and eight microsatellite markers), we examined population structure at two sites in Manus Basin separated by 40 km and near a potential mining prospect, where the species has not been observed. No population structure was detected in mussels sampled from these two sites. We also compared a subset of samples with B. manusensis from previous studies to infer broader population trends. The genetic diversity observed can be used as a baseline against which changes in genetic diversity within the population may be assessed following the proposed mining event. PMID- 28852591 TI - The effects of allogenic stem cells in a murine model of hind limb diabetic ischemic tissue. AB - BACKGROUND: Diabetes is one of the major risk factors for peripheral arterial disease. In patients in whom surgery cannot be performed, cell therapy may be an alternative treatment. Since time is crucial for these patients, we propose the use of allogenic mesenchymal cells. METHODS: We obtained mesenchymal cells derived from the fat tissue of a healthy Sprague-Dawley rat. Previous diabetic induction with streptozotocin in 40 male Sprague-Dawley rats, ligation plus left iliac and femoral artery sections were performed as a previously described model of ischemia. After 10 days of follow-up, macroscopic and histo-pathological analysis was performed to evaluate angiogenic and inflammatory parameters in the repair of the injured limb. All samples were evaluated by the same blind researcher. Statistical analysis was performed using the SPSS v.11.5 program (P < 0.05). RESULTS: Seventy percent of the rats treated with streptozotocin met the criteria for diabetes. Macroscopically, cell-treated rats presented better general and lower ischemic clinical status, and histologically, a better trend towards angiogenesis, greater infiltration of type 2 macrophages and a shortening of the inflammatory process. However, only the inflammatory variables were statistically significant. No immunological reaction was observed with the use of allogeneic cells. DISCUSSION: The application of allogeneic ASCs in a hind limb ischemic model in diabetic animals shows no rejection reactions and a reduction in inflammatory parameters in favor of better repair of damaged tissue. These results are consistent with other lines of research in allogeneic cell therapy. This approach might be a safe, effective treatment option that makes it feasible to avoid the time involved in the process of isolation, expansion and production of the use of autologous cells. PMID- 28852592 TI - Comparison of chemical compounds associated with sclerites from healthy and diseased sea fan corals (Gorgonia ventalina). AB - BACKGROUND: The roles of gorgonian sclerites as structural components and predator deterrents have been widely studied. Yet their role as barriers against microbes has only recently been investigated, and even less is known about the diversity and roles of the chemical compounds associated with sclerites. METHODS: Here, we examine the semi-volatile organic compound fraction (SVOCs) associated with sclerites from healthy and diseased Gorgonia ventalina sea fan corals to understand their possible role as a stress response or in defense of infection. We also measured the oxidative potential of compounds from diseased and healthy G. ventalina colonies. RESULTS: The results showed that sclerites harbor a great diversity of SVOCs. Overall, 70 compounds were identified, the majority of which are novel with unknown biological roles. The majority of SVOCs identified exhibit multiple immune-related roles including antimicrobial and radical scavenging functions. The free radical activity assays further confirmed the anti-oxidative potential of some these compounds. The anti-oxidative activity was, nonetheless, similar across sclerites regardless of the health condition of the colony, although sclerites from diseased sea fans display slightly higher anti-oxidative activity than the healthy ones. DISCUSSION: Sclerites harbor great SVOCs diversity, the majority of which are novel to sea fans or any other corals. Yet the scientific literature consulted showed that the roles of compounds found in sclerites vary from antioxidant to antimicrobial compounds. However, this study fell short in determine the origin of the SVOCs identified, undermining our capacity to determine the biological roles of the SVOCs on sclerites and sea fans. PMID- 28852593 TI - Defensive behaviors of the Oriental armyworm Mythimna separata in response to different parasitoid species (Hymenoptera: Braconidae). AB - This study examined defensive behaviors of Mythimna separata (Lepidoptera: Noctuidae) larvae varying in body size in response to two parasitoids varying in oviposition behavior; Microplitis mediator females sting the host with the ovipositor after climbing onto it while Meteorus pulchricornis females make the sting by standing at a close distance from the host. Mythimna separata larvae exhibited evasive (escaping and dropping) and aggressive (thrashing) behaviors to defend themselves against parasitoids M. mediator and M. pulchricornis. Escaping and dropping did not change in probability with host body size or parasitoid species. Thrashing did not vary in frequency with host body size, yet performed more frequently in response to M. mediator than to M. pulchricornis. Parasitoid handling time and stinging likelihood varied depending not only on host body size but also on parasitoid species. Parasitoid handling time increased with host thrashing frequency, similar in slope for both parasitoids yet on a higher intercept for M. mediator than for M. pulchricornis. Handling time decreased with host size for M. pulchricornis but not for M. mediator. The likelihood of realizing an ovipositor sting decreased with thrashing frequency of both small and large hosts for M. pulchricornis, while this was true only for large hosts for M. mediator. Our results suggest that the thrashing behavior of M. separata larvae has a defensive effect on parasitism, depending on host body size and parasitoid species with different oviposition behaviors. PMID- 28852594 TI - Fluctuating selection across years and phenotypic variation in food-deceptive orchids. AB - Nectarless flowers that deceive pollinators offer an opportunity to study asymmetric plant-insect interactions. Orchids are a widely used model for studying these interactions because they encompass several thousand species adopting deceptive pollination systems. High levels of intra-specific phenotypic variation have been reported in deceptive orchids, suggesting a reduced consistency of pollinator-mediated selection on their floral traits. Nevertheless, several studies report on widespread directional selection mediated by pollinators even in these deceptive orchids. In this study we test the hypothesis that the observed selection can fluctuate across years in strength and direction thus likely contributing to the phenotypic variability of this orchid group. We performed a three-year study estimating selection differentials and selection gradients for nine phenotypic traits involved in insect attraction in two Mediterranean orchid species, namely Orchis mascula and O. pauciflora, both relying on a well-described food-deceptive pollination strategy. We found weak directional selection and marginally significant selection gradients in the two investigated species with significant intra-specific differences in selection differentials across years. Our data do not link this variation with a specific environmental cause, but our results suggest that pollinator-mediated selection in food-deceptive orchids can change in strength and in direction over time. In perennial plants, such as orchids, different selection differentials in the same populations in different flowering seasons can contribute to the maintenance of phenotypic variation often reported in deceptive orchids. PMID- 28852595 TI - Characterization of the Polish Primitive Horse (Konik) maternal lines using mitochondrial D-loop sequence variation. AB - The Polish Primitive Horse (PPH, Konik) is a Polish native horse breed managed through a conservation program mainly due to its characteristic phenotype of a primitive horse. One of the most important goals of PPH breeding strategy is the preservation and equal development of all existing maternal lines. However, until now there was no investigation into the real genetic diversity of 16 recognized PPH dam lines using mtDNA sequence variation. Herein, we describe the phylogenetic relationships between the PPH maternal lines based upon partial mtDNA D-loop sequencing of 173 individuals. Altogether, 19 mtDNA haplotypes were detected in the PPH population. Five haplotypes were putatively novel while the remaining 14 showed the 100% homology with sequences deposited in the GenBank database, represented by both modern and primitive horse breeds. Generally, comparisons found the haplotypes conformed to 10 different recognized mtDNA haplogroups (A, B, E, G, J, M, N, P, Q and R). A multi-breed analysis has indicated the phylogenetic similarity of PPH and other indigenous horse breeds derived from various geographical regions (e.g., Iberian Peninsula, Eastern Europe and Siberia) which may support the hypothesis that within the PPH breed numerous ancestral haplotypes (found all over the world) are still present. Only in the case of five maternal lines (Bona, Dzina I, Geneza, Popielica and Zaza) was the segregation of one specific mtDNA haplotype observed. The 11 remaining lines showed a higher degree of mtDNA haplotype variability (2-5 haplotypes segregating in each line). This study has revealed relatively high maternal genetic diversity in the small, indigenous PPH breed (19 haplotypes, overall HapD = 0.92). However, only some traditionally distinguished maternal lines can be treated as genetically pure. The rest show evidence of numerous mistakes recorded in the official PPH pedigrees. This study has proved the importance of maternal genetic diversity monitoring based upon the application of molecular mtDNA markers and can be useful for proper management of the PPH conservation program in the future. PMID- 28852596 TI - Chloroplast genome expansion by intron multiplication in the basal psychrophilic euglenoid Eutreptiella pomquetensis. AB - BACKGROUND: Over the last few years multiple studies have been published showing a great diversity in size of chloroplast genomes (cpGenomes), and in the arrangement of gene clusters, in the Euglenales. However, while these genomes provided important insights into the evolution of cpGenomes across the Euglenales and within their genera, only two genomes were analyzed in regard to genomic variability between and within Euglenales and Eutreptiales. To better understand the dynamics of chloroplast genome evolution in early evolving Eutreptiales, this study focused on the cpGenome of Eutreptiella pomquetensis, and the spread and peculiarities of introns. METHODS: The Etl. pomquetensis cpGenome was sequenced, annotated and afterwards examined in structure, size, gene order and intron content. These features were compared with other euglenoid cpGenomes as well as those of prasinophyte green algae, including Pyramimonas parkeae. RESULTS AND DISCUSSION: With about 130,561 bp the chloroplast genome of Etl. pomquetensis, a basal taxon in the phototrophic euglenoids, was considerably larger than the two other Eutreptiales cpGenomes sequenced so far. Although the detected quadripartite structure resembled most green algae and plant chloroplast genomes, the gene content of the single copy regions in Etl. pomquetensis was completely different from those observed in green algae and plants. The gene composition of Etl. pomquetensis was extensively changed and turned out to be almost identical to other Eutreptiales and Euglenales, and not to P. parkeae. Furthermore, the cpGenome of Etl. pomquetensis was unexpectedly permeated by a high number of introns, which led to a substantially larger genome. The 51 identified introns of Etl. pomquetensis showed two major unique features: (i) more than half of the introns displayed a high level of pairwise identities; (ii) no group III introns could be identified in the protein coding genes. These findings support the hypothesis that group III introns are degenerated group II introns and evolved later. PMID- 28852597 TI - Allele specific expression analysis identifies regulatory variation associated with stress-related genes in the Mexican highland maize landrace Palomero Toluqueno. AB - BACKGROUND: Gene regulatory variation has been proposed to play an important role in the adaptation of plants to environmental stress. In the central highlands of Mexico, farmer selection has generated a unique group of maize landraces adapted to the challenges of the highland niche. In this study, gene expression in Mexican highland maize and a reference maize breeding line were compared to identify evidence of regulatory variation in stress-related genes. It was hypothesised that local adaptation in Mexican highland maize would be associated with a transcriptional signature observable even under benign conditions. METHODS: Allele specific expression analysis was performed using the seedling leaf transcriptome of an F1 individual generated from the cross between the highland adapted Mexican landrace Palomero Toluqueno and the reference line B73, grown under benign conditions. Results were compared with a published dataset describing the transcriptional response of B73 seedlings to cold, heat, salt and UV treatments. RESULTS: A total of 2,386 genes were identified to show allele specific expression. Of these, 277 showed an expression difference between Palomero Toluqueno and B73 alleles under benign conditions that anticipated the response of B73 cold, heat, salt and/or UV treatments, and, as such, were considered to display a prior stress response. Prior stress response candidates included genes associated with plant hormone signaling and a number of transcription factors. Construction of a gene co-expression network revealed further signaling and stress-related genes to be among the potential targets of the transcription factors candidates. DISCUSSION: Prior activation of responses may represent the best strategy when stresses are severe but predictable. Expression differences observed here between Palomero Toluqueno and B73 alleles indicate the presence of cis-acting regulatory variation linked to stress-related genes in Palomero Toluqueno. Considered alongside gene annotation and population data, allele specific expression analysis of plants grown under benign conditions provides an attractive strategy to identify functional variation potentially linked to local adaptation. PMID- 28852599 TI - Impressive Response to Concomitant Platinum-based Chemotherapy and Yttrium-90 in a Patient with Heavily Pretreated Triple-negative Breast Cancer Widely Metastasized to the Liver. AB - Metastatic triple-negative breast cancer (TNBC) constitutes a heterogeneous group of diseases with systemic treatment options limited to cytotoxic chemotherapy at the time being. The disease tends to affect visceral organs more frequently when compared to hormone receptor-positive breast cancer. The prognoses of patients with heavily pretreated disease affecting the liver are very dismal. We present the response to radioembolization and systemic chemotherapy in a seriously ill patient who had undergone previous lines of chemotherapy for TNBC with extensive liver metastases. PMID- 28852598 TI - Gene expression profiling and functional analysis reveals that p53 pathway related gene expression is highly activated in cancer cells treated by cold atmospheric plasma-activated medium. AB - BACKGROUND: Cold atmospheric-pressure plasma (CAP) has been considered a promising strategy for anti-cancer treatment. Traditionally, CAP was employed to kill cancer cells or tumor tissues by direct irradiation. However, CAP has some disadvantages such as infiltration capacity and storage convenience. Recently, plasma-activated medium (PAM) was used as an alternative strategy to treat cancer cells or tumors. The novel PAM approach has potential as an anti-cancer therapy. OBJECTIVE: To reveal the global activation of signaling pathways in oral cancer cells induced by PAM. METHODS: Oral squamous cell line SCC15 were treated by PAM and gene expression profiles were evaluated by using RNA-seq. Functional analyses were employed to reveal the global responses of SCC15 cells with PAM stimulation. QRT-PCR and Western blot were carried out to validate the expression levels of selected genes. RESULTS: More than 6G clean data per sample were obtained in PAM treated SCC15 cells. A total of 934 differentially expressed genes (DEGs) were identified and GO analysis implicated the deep involvement of biological process. KEGG mapping further clustered 40 pathways, revealing that "p53 pathway" was significantly enriched. SCC15 cells were commonly used as a p53-null cell line. Therefore, the enriched p53 pathway-related genes in our analysis might be activated by other stimulators, in a p53-independent manner. Gene set enrichment analysis (GSEA) was also performed to evaluate changes at the gene-sets level. The results demonstrated not only the high engagement of "p53 pathway" but also the involvement of novel pathways such as hypoxia pathway. CONCLUSIONS: The present study elucidates the transcriptomic changes of PAM treated SCC15 cells, containing highly enriched DEGs involved in "p53 pathway". Our analysis in this work not only provides genomic resources for future studies but also gives novel insights to uncover the molecular mechanism of PAM stimulation. PMID- 28852600 TI - A Review on Antibiotic Resistance: Alarm Bells are Ringing. AB - Antibiotics are the 'wonder drugs' to combat microbes. For decades, multiple varieties of antibiotics have not only been used for therapeutic purposes but practiced prophylactically across other industries such as agriculture and animal husbandry. Uncertainty has arisen, as microbes have become resistant to common antibiotics while the host remains unaware that antibiotic resistance has emerged. The aim of this review is to explore the origin, development, and the current state of antibiotic resistance, regulation, and challenges by examining available literature. We found that antibiotic resistance is increasing at an alarming rate. A growing list of infections i.e., pneumonia, tuberculosis, and gonorrhea are becoming harder and at times impossible to treat while antibiotics are becoming less effective. Antibiotic-resistant infections correlate with the level of antibiotic consumption. Non-judicial use of antibiotics is mostly responsible for making the microbes resistant. The antibiotic treatment repertoire for existing or emerging hard-to-treat multidrug-resistant bacterial infections is limited, resulting in high morbidity and mortality report. This review article reiterates the optimal use of antimicrobial medicines in human and animal health to reduce antibiotic resistance. Evidence from the literature suggests that the knowledge regarding antibiotic resistance in the population is still scarce. Therefore, the need of educating patients and the public is essential to fight against the antimicrobial resistance battle. PMID- 28852601 TI - Solitary Orbital Metastasis 35 Years after a Diagnosis of Lobular Carcinoma in Situ. AB - This report describes a solitary orbital metastasis of lobular carcinoma in a woman 35 years after diagnosis of right breast lobular carcinoma in situ (LCIS). After partial response to anastrozole, the patient was treated with proton radiotherapy to 45 cobalt gray equivalents (CGE) with an excellent response. We additionally discuss treatment strategies for this rare metastatic site. PMID- 28852602 TI - The Importance of a Complete Differential: Case Report of a Tuberculoma in a Patient without Pulmonary Involvement. AB - Patients with a tuberculoma typically present with pulmonary involvement of tuberculosis and have risk factors for tuberculosis (TB). The risk factors for tuberculosis include bacillary load, proximity to infectious case, immunosuppressive conditions, malnutrition, young age, diabetes mellitus, working in healthcare, recent incarceration, alcohol use, and tobacco use. Although rare, it is possible for a patient to present with a tuberculoma despite the absence of risk factors for tuberculosis other than diabetes and without pulmonary involvement. PMID- 28852603 TI - Palliative Radiation Therapy for Symptom Control in an Advanced Case of Pseudomyxoma Peritonei. AB - Pseudomyxoma peritonei (PP) is a rare clinical condition characterized by progressive mucinous ascites, which is typically caused by a mucin-producing neoplasm. Reports of radiation therapy (RT) in the management of PP are limited. We report a unique case of a 62-year-old woman with severe, end-stage, recurrent PP and a large, mucin-secreting mass protruding through her abdominal wall. Low dose, hypofractionated palliative RT was administered for symptom control with the hope of improving her quality of life. We suggest that radiation therapy be considered in the comprehensive palliative management of patients with PP. PMID- 28852604 TI - Rapid Glycopeptide Enrichment Using Cellulose Hydrophilic Interaction/Reversed Phase StageTips. AB - Because the ionization efficiency for glycopeptides is lower than that of peptides in electrospray ionization, it is frequently necessary to enrich them prior to their analysis using liquid chromatography coupled with tandem mass spectrometry. Although some methods for selectively enriching glycopeptides (e.g., lectin, agarose, and cellulose methods) have been reported, they are time consuming (procedures that require several hours) and may not be applicable to submicrogram-sized samples. Here, we report on a rapid, simple method for enriching glycopeptides in small sample amounts using cellulose hydrophilic interaction (cellulose HILIC)/reversed-phase (RP) stop-and-go extraction tips (StageTips). Using the cellulose HILIC/RP StageTips, glycopeptide-selective enrichment can be achieved at the nanogram level within a few minutes. PMID- 28852605 TI - Towards Practical Endoscopic Mass Spectrometry. AB - In this paper, we briefly review the remote mass spectrometric techniques that are viable to perform "endoscopic mass spectrometry," i.e., in-situ and in-vivo MS analysis inside the cavity of human or animal body. We also report our experience with a moving string sampling probe for the remote sample collection and the transportation of adhered sample to an ion source near the mass spectrometer. With a miniaturization of the probe, the method described here has the potential to be fit directly into a medical endoscope. PMID- 28852606 TI - Delayed Brain Edema and Swelling following Craniectomy for Evacuation of an Epidural Abscess that Improved by Cranioplasty: Case Report. AB - We report a unique case of delayed brain swelling following craniectomy that improved rapidly after cranioplasty, and discuss the potential mechanism underlying this delayed and reversible brain swelling. A 22-year-old woman developed surgical site infection after removal of a convexity meningioma. Magnetic resonance imaging revealed an epidural abscess around the surgical site. Subsequently, the abscess was evacuated, and the bone flap was removed. Later, brain edema around the skull defect emerged and progressed gradually, despite resolution of the infection. The edematous brain developed focal swelling outward through the bone defect without ventricle dilatation. Because we suspected that the edema and swelling were caused by the state of the bone defect, we performed a cranioplasty 10 weeks after the bone flap removal, and brain edema improved rapidly. We hypothesized that the brain edema was initially caused by surgical stress and inflammation, followed by compression of cortical veins between the dural edge and brain tissue, leading to disruption of venous return and exacerbation of brain edema. When delayed focal brain edema and external swelling progress gradually after bone flap removal, after excluding other pathological conditions, cranioplasty should be considered to improve cortical venous congestion caused by postsurgical adhesion. PMID- 28852607 TI - Recent Breakthroughs in Supercapacitors Boosted by Nitrogen-Rich Porous Carbon Materials. AB - Featured with unique mechanical, electronic and chemical properties, nitrogen doped carbon materials have become the research hotspot of energy storage. As electrode materials in supercapacitors (SCs), N-doped carbons have demonstrated intriguing flexibility and superb performances in a wide electrochemical window, equipped with versatile properties as both cathodes and anodes for constructing high voltage devices. Compared with limited doping level, N-rich and porous carbon materials (NPCs) are of great desire to release the restricted properties of N species and obtain high specific capacitances (>600 F g-1), pushing the energy density towards the battery level without scarifying the capacitor-level power ability. In this Research News we firstly discuss the key factors influencing the performance of NPC electrodes to disclose related charge storage mechanisms. In addition, the trade-off among N-content, porous structure and electrical conductivity is involved as well as electrochemical behaviors in different electrolytes. Also, various progressive developments are highlighted systematically ranging from asymmetric to symmetric and hybrid configurations, covering both aqueous and non-aqueous systems. Finally, some stubborn and unsolved problems are summarized, with prospective research guidelines on NPC based SCs. PMID- 28852608 TI - Plasmonics of 2D Nanomaterials: Properties and Applications. AB - Plasmonics has developed for decades in the field of condensed matter physics and optics. Based on the classical Maxwell theory, collective excitations exhibit profound light-matter interaction properties beyond classical physics in lots of material systems. With the development of nanofabrication and characterization technology, ultra-thin two-dimensional (2D) nanomaterials attract tremendous interest and show exceptional plasmonic properties. Here, we elaborate the advanced optical properties of 2D materials especially graphene and monolayer molybdenum disulfide (MoS2), review the plasmonic properties of graphene, and discuss the coupling effect in hybrid 2D nanomaterials. Then, the plasmonic tuning methods of 2D nanomaterials are presented from theoretical models to experimental investigations. Furthermore, we reveal the potential applications in photocatalysis, photovoltaics and photodetections, based on the development of 2D nanomaterials, we make a prospect for the future theoretical physics and practical applications. PMID- 28852609 TI - Black Phosphorus Quantum Dots with Tunable Memory Properties and Multilevel Resistive Switching Characteristics. AB - Solution-processed black phosphorus quantum-dot-based resistive random access memory is demonstrated with tunable characteristics, multilevel data storage, and ultrahigh ON/OFF ratio. Effects of the black phosphorous quantum dots layer thickness and the compliance current setting on resistive switching behavior are systematically studied. Our devices can yield a series of SET voltages and current levels, hence having the potential for practical applications in the flexible electronics industry. PMID- 28852610 TI - Graphene Nanoribbon Based Thermoelectrics: Controllable Self- Doping and Long Range Disorder. AB - Control of both the regularity of a material ensemble and nanoscale architecture provides unique opportunities to develop novel thermoelectric applications based on 2D materials. As an example, the authors explore the electronic and thermal properties of functionalized graphene nanoribbons (GNRs) in the single-sheet and helical architectures using multiscale simulations. The results suggest that appropriate functionalization enables precise tuning of the doping density in a planar donor/acceptor GNR ensemble without the need to introduce an explicit dopant, which is critical to the optimization of power factor. In addition, the self-interaction between turns of a GNR may induce long-range disorder along the helical axis, which suppresses the thermal contribution from phonons with long wavelengths, leading to anomalous length independent phonon thermal transport in the quasi-1D system. PMID- 28852611 TI - A 3D-Engineered Conformal Implant Releases DNA Nanocomplexs for Eradicating the Postsurgery Residual Glioblastoma. AB - Gene therapy has great promise for glioblastoma treatment; however, it remains a great challenge to efficiently deliver genes to the brain. The incomplete resection of glioblastoma always leads to poor prognosis. Here, a 3D-engineered conformal implant for eradicating the postsurgery residual glioblastoma is designed. This implant is constructed by 3D-printing technology to match the tumor cavity and release an oncolytic virus-inspired DNA nanocomplex to kill glioblastoma cells through apoptosis induction. Meanwhile, a 3D-engineered subcutaneous glioblastoma xenograft is built to mimic the resection tumor cavity in mice. Insertion of the implant into the glioblastoma resection cavity efficiently delays tumor recurrence and significantly prolongs overall survival. This study provides a proof-of-concept of glioblastoma therapy using a conformal implant that releases oncolytic DNA nanocomplexs. This strategy can lead to the development of future precision therapy for eradicating postsurgery residual tumors. PMID- 28852612 TI - Bisphenol A Impairs Synaptic Plasticity by Both Pre- and Postsynaptic Mechanisms. AB - Bisphenol A (BPA), an environmental xenoestrogen, has been reported to induce learning and memory impairments in rodent animals. However, effects of BPA exposure on synaptic plasticity and the underlying physiological mechanisms remain elusive. Our behavioral and electrophysiological analyses show that BPA obviously perturbs hippocampal spatial memory of juvenile Sprague-Dawley rats after four weeks exposure, with significantly impaired long-term potentiation (LTP) in the hippocampus. These effects involve decreased spine density of pyramidal neurons, especially the apical dendritic spine. Further presynaptic findings show an overt inhibition of pulse-paired facilitation during electrophysiological recording, which suggest the decrease of presynaptic transmitter release and is consistent with reduced production of presynaptic glutamate after BPA exposure. Meanwhile, LTP-related glutamate receptors, NMDA receptor 2A (NR2A) and AMPA receptor 1 (GluR1), are significantly downregulated in BPA-exposed rats. Excitatory postsynaptic currents (EPSCs) results also show that EPSCNMDA, but not EPSCAMPA, is declined by 40% compared to the baseline in BPA-perfused brain slices. Taken together, these findings reveal that juvenile BPA exposure has negative effects on synaptic plasticity, which result from decreases in dendritic spine density and excitatory synaptic transmission. Importantly, this study also provides new insights into the dynamics of BPA induced memory deterioration during the whole life of rats. PMID- 28852613 TI - An Alternative Host Material for Long-Lifespan Blue Organic Light-Emitting Diodes Using Thermally Activated Delayed Fluorescence. AB - It has been challenging to find stable blue organic light emitting diodes (OLEDs) that rely on thermally activated delayed fluorescence (TADF). Lack of stable host materials well-fitted to the TADF emitters is one of the critical reasons. The most popular host for blue TADF, bis[2-(diphenylphosphino)phenyl] ether oxide (DPEPO), leads to unrealistically high maximum external quantum efficiency. DPEPO is however an unstable material and has a poor charge transporting ability, which in turn induces an intrinsic short OLED operating lifespan. Here, an alternative host material is introduced which educes the potential efficiency and device lifespan of given TADF emitters with the appropriateness of replacing the most popular host material, DPEPO, in developing blue TADF emitters. It simultaneously provides much longer device lifespan and higher external quantum efficiency at a practical brightness due to its high material stability and electron-transport type character well-fitted for hole-transport-type TADF emitters. PMID- 28852614 TI - Strategies Based on Nitride Materials Chemistry to Stabilize Li Metal Anode. AB - Lithium metal battery is a promising candidate for high-energy-density energy storage. Unfortunately, the strongly reducing nature of lithium metal has been an outstanding challenge causing poor stability and low coulombic efficiency in lithium batteries. For decades, there are significant research efforts to stabilize lithium metal anode. However, such efforts are greatly impeded by the lack of knowledge about lithium-stable materials chemistry. So far, only a few materials are known to be stable against Li metal. To resolve this outstanding challenge, lithium-stable materials have been uncovered out of chemistry across the periodic table using first-principles calculations based on large materials database. It is found that most oxides, sulfides, and halides, commonly studied as protection materials, are reduced by lithium metal due to the reduction of metal cations. It is discovered that nitride anion chemistry exhibits unique stability against Li metal, which is either thermodynamically intrinsic or a result of stable passivation. The results here establish essential guidelines for selecting, designing, and discovering materials for lithium metal protection, and propose multiple novel strategies of using nitride materials and high nitrogen doping to form stable solid-electrolyte-interphase for lithium metal anode, paving the way for high-energy rechargeable lithium batteries. PMID- 28852615 TI - Bubbled RNA-Based Cargo for Boosting RNA Interference. AB - As ribonucleic acid (RNA) nanotechnology has advanced, it has been applied widely in RNA-based therapeutics. Among the range of approaches, enzymatically synthesized RNA structures for inducing RNA interference in cancer cells have potential for silencing genes in a target-specific manner. On the other hand, the efficiency of gene silencing needs to be improved to utilize the RNA-based system for RNAi therapeutics. This paper introduces a new approach for efficient generation of siRNA from bubbled RNA-based cargo (BRC). The presence of bubbles in between to avoid nonfunctional short dsRNAs allows the RNA-based cargoes to contain multiple Dicer-cleavage sites to release the functional siRNAs when introduced to cells. BRCs can be synthesized easily in a one-pot process and be purified by simple centrifugation. Furthermore, efficient target gene silencing by the bubbled structure is confirmed both in vitro and in vivo. Therefore, this bubbled RNA cargo system can be utilized for target-specific RNAi therapeutics with high efficiency in the generation of functional siRNAs in the target cells. PMID- 28852616 TI - Synthesis and Optimization of MoS2@Fe3O4-ICG/Pt(IV) Nanoflowers for MR/IR/PA Bioimaging and Combined PTT/PDT/Chemotherapy Triggered by 808 nm Laser. AB - Elaborately designed biocompatible nanoplatforms simultaneously achieving multimodal bioimaging and therapeutic functions are highly desirable for modern biomedical applications. Herein, uniform MoS2 nanoflowers with a broad size range of 80-180 nm have been synthesized through a facile, controllable, and scalable hydrothermal method. The strong absorbance of MoS2 nanoflowers at 808 nm imparts them with high efficiency and stability of photothermal conversion. Then a novel multifunctional composite of MoS2@Fe3O4-ICG/Pt(IV) (labeled as Mo@Fe-ICG/Pt) is designed by covalently grafting Fe3O4 nanoparticles with polyethylenimine (PEI) functionalized MoS2, and then loading indocyanine green molecules (ICG, photosensitizers) and platinum (IV) prodrugs (labeled as Pt(IV) prodrugs) on the surface of MoS2@Fe3O4. The resulting Mo@Fe-ICG/Pt nanocomposites can achieve excellent magnetic resonance/infrared thermal/photoacoustic trimodal biomaging as well as remarkably enhanced antitumor efficacy of combined photothermal therapy, photodynamic therapy, and chemotherapy triggered by a single 808 nm NIR laser, thus leading to an ideal nanoplatform for cancer diagnosis and treatment in future. PMID- 28852617 TI - A General Electrode Design Strategy for Flexible Fiber Micro-Pseudocapacitors Combining Ultrahigh Energy and Power Delivery. AB - Herein, a general strategy is proposed to boost the energy storage capability of pseudocapacitive materials (i.e., MnO2) to their theoretical limits in unconventional 1D fiber configuration by rationally designing bicontinuous porous Ni skeleton@metal wire "sheath-core" metallic scaffold as a versatile host. As a proof of concept, the 1D metallic scaffold supported-MnO2 fiber electrode is demonstrated. The proposed "sheath" design not only affords large electrode surface area with ordered macropores for large electrolyte-ion accessibility and high electroactive material loading, but also renders interconnected porous metallic skeleton for efficient electronic and ionic transport, while the metallic "core" functions as an extra current collector to promote long-distance electron transport and electron collection. Benefiting from all these merits, the optimized fiber electrode yields unprecedented specific areal capacitance of 1303.6 mF cm-2 (1278 F g-1 based on MnO2, approaching the theoretical value of 1370 F g-1) in liquid KOH and 847.22 mF cm-2 in polyvinyl alcohol (PVA)/KOH gel electrolyte, 2-350 times of previously reported fiber electrodes. The solid-state fiber micro-pseudocapacitors simultaneously achieve remarkable areal energy and power densities of 18.83 uWh cm-2 and 16.33 mW cm-2, greatly exceeding the existing symmetric fiber supercapacitors, together with long cycle life and high rate capability. PMID- 28852618 TI - Furan Is Superior to Thiophene: A Furan-Cored AIEgen with Remarkable Chromism and OLED Performance. AB - Furan-cored AIEgen namely tetraphenylethylene-furan (TPE-F) is developed by diyne cyclization and its fluorescent and chemical properties are investigated and compared with its thiophene analogue. Results show that furan is superior to thiophene in terms of fluorescence, chromism, and charge transport. The mechanism of chromism of TPE-F is investigated and its efficient solid-state photoluminescence and good charge-transporting property enable it to serve as light-emitting material for the construction of electroluminescence devices with excellent performance. This work not only demonstrates an efficient strategy for constructing furan-cored AIEgens but also indicates that they are promising as advanced optoelectronic materials. PMID- 28852619 TI - High-Performance Nonvolatile Organic Field-Effect Transistor Memory Based on Organic Semiconductor Heterostructures of Pentacene/P13/Pentacene as Both Charge Transport and Trapping Layers. AB - Nonvolatile organic field-effect transistor (OFET) memory devices based on pentacene/N,N'-ditridecylperylene-3,4,9,10-tetracarboxylic diimide (P13)/pentacene trilayer organic heterostructures have been proposed. The discontinuous n-type P13 embedded in p-type pentacene layers can not only provide electrons in the semiconductor layer that facilitates electron trapping process; it also works as charge trapping sites, which is attributed to the quantum well like pentacene/P13/pentacene organic heterostructures. The synergistic effects of charge trapping in the discontinuous P13 and the charge-trapping property of the poly(4-vinylphenol) (PVP) layer remarkably improve the memory performance. In addition, the trilayer organic heterostructures have also been successfully applied to multilevel and flexible nonvolatile memory devices. The results provide a novel design strategy to achieve high-performance nonvolatile OFET memory devices and allow potential applications for different combinations of various organic semiconductor materials in OFET memory. PMID- 28852620 TI - Self-Organized Fullerene Interfacial Layer for Efficient and Low-Temperature Processed Planar Perovskite Solar Cells with High UV-Light Stability. AB - In this Communication, a self-organization method of [6,6]-phenyl-C61-butyric acid 2-((2-(dimethylamino)-ethyl) (methyl)amino)ethyl ester (PCBDAN) interlayer in between 6,6-phenyl C61-butyric acid methyl ester (PCBM) and indium tin oxide (ITO) has been proposed to improve the performance of N-I-P perovskite solar cells (PSCs). The introduction of self-organized PCBDAN interlayer can effectively reduce the work function of ITO and therefore eliminate the interface barrier between electron transport layer and electrode. It is beneficial for enhancing the charge extraction and decreasing the recombination loss at the interface. By employing this strategy, a highest power conversion efficiency of 18.1% has been obtained with almost free hysteresis. Furthermore, the N-I-P PSCs have excellent stability under UV-light soaking, which can maintain 85% of its original highest value after 240 h accelerated UV aging. This self-organization method for the formation of interlayer can not only simplify the fabrication process of low-cost PSCs, but also be compatible with the roll-to-roll device processing on flexible substrates. PMID- 28852621 TI - Research Progress towards Understanding the Unique Interfaces between Concentrated Electrolytes and Electrodes for Energy Storage Applications. AB - The electrolyte is an indispensable component in all electrochemical energy storage and conversion devices with batteries being a prime example. While most research efforts have been pursued on the materials side, the progress for the electrolyte is slow due to the decomposition of salts and solvents at low potentials, not to mention their complicated interactions with the electrode materials. The general properties of bulk electrolytes such as ionic conductivity, viscosity, and stability all affect the cell performance. However, for a specific electrochemical cell in which the cathode, anode, and electrolyte are optimized, it is the interface between the solid electrode and the liquid electrolyte, generally referred to as the solid electrolyte interphase (SEI), that dictates the rate of ion flow in the system. The commonly used electrolyte is within the range of 1-1.2 m based on the prior optimization experience, leaving the high concentration region insufficiently recognized. Recently, electrolytes with increased concentration (>1.0 m) have received intensive attention due to quite a few interesting discoveries in cells containing concentrated electrolytes. The formation mechanism and the nature of the SEI layers derived from concentrated electrolytes could be fundamentally distinct from those of the traditional SEI and thus enable unusual functions that cannot be realized using regular electrolytes. In this article, we provide an overview on the recent progress of high concentration electrolytes in different battery chemistries. The experimentally observed phenomena and their underlying fundamental mechanisms are discussed. New insights and perspectives are proposed to inspire more revolutionary solutions to address the interfacial challenges. PMID- 28852622 TI - Kinetically Controlled Fabrication of Single-Crystalline TiO2 Nanobrush Architectures with High Energy {001} Facets. AB - This study demonstrates that precise control of nonequilibrium growth conditions during pulsed laser deposition (PLD) can be exploited to produce single crystalline anatase TiO2 nanobrush architectures with large surface areas terminated with high energy {001} facets. The data indicate that the key to nanobrush formation is controlling the atomic surface transport processes to balance defect aggregation and surface-smoothing processes. High-resolution scanning transmission electron microscopy data reveal that defect-mediated aggregation is the key to TiO2 nanobrush formation. The large concentration of defects present at the intersection of domain boundaries promotes aggregation of PLD growth species, resulting in the growth of the single-crystalline nanobrush architecture. This study proposes a model for the relationship between defect creation and growth mode in nonequilibrium environments, which enables application of this growth method to novel nanostructure design in a broad range of materials. PMID- 28852623 TI - Diketopyrrolopyrrole-Based Conjugated Polymer Entailing Triethylene Glycols as Side Chains with High Thin-Film Charge Mobility without Post-Treatments. AB - Side chain engineering of conjugated donor-acceptor polymers is a new way to manipulate their optoelectronic properties. Two new diketopyrrolopyrrole (DPP) terthiophene-based conjugated polymers PDPP3T-1 and PDPP3T-2, with both hydrophilic triethylene glycol (TEG) and hydrophobic alkyl chains, are reported. It is demonstrated that the incorporation of TEG chains has a significant effect on the interchain packing and thin-film morphology with noticeable effect on charge transport. Polymer chains of PDPP3T-1 in which TEG chains are uniformly distributed can self-assemble spontaneously into a more ordered thin film. As a result, the thin film of PDPP3T-1 exhibits high saturated hole mobility up to 2.6 cm2 V-1 s-1 without any post-treatment. This is superior to those of PDPP3T with just alkyl chains and PDPP3T-2. Moreover, the respective field effect transistors made of PDPP3T-1 can be utilized for sensing ethanol vapor with high sensitivity (down to 100 ppb) and good selectivity. PMID- 28852624 TI - Regular Organic Solar Cells with Efficiency over 10% and Promoted Stability by Ligand- and Thermal Annealing-Free Al-Doped ZnO Cathode Interlayer. AB - Landmark power conversion efficiency (PCE) over 10% has been accomplished in the past year for single-junction organic solar cell (OSCs), suggesting a promising potential application of this technology. However, most of the high efficient OSCs are based on inverted configuration. Regular structure OSCs with both high efficiency and good stability are still rarely reported to date. In this work, by utilizing a new designed ligand-free and non-thermal-annealing-treated Al-doped ZnO cathode interlayer, high efficiency and greatly improved stability are simultaneously realized in regular OSCs. The highest PCE of 10.14% is accomplished for single-junction regular OSCs with active blend of poly [[2,6' 4,8-di(5-ethylhexylthienyl)benzo[1,2-b;3,3-b]dithiophene][3-fluoro-2[(2 ethylhexyl)carbonyl]thieno [3,4-b]thiophenediyl]] (PTB7-Th):[6,6]-phenyl C71 butyric acid methyl ester (PC71BM). Excellent device stability is confirmed as well, by keeping 90% of its initial PCE value after 135 d in N2, and 80% of its initial PCE value after 15 d in ambient air, respectively. Furthermore, the applicability of the designed interlayer in regular OSCs is demonstrated by other active blend systems, including the nonfullerene material. This work highlights that high efficiency and good stability can be realized simultaneously in regular OSCs as well, and will provide referential strategy and methodology for this target. PMID- 28852625 TI - Efficient Storing Energy Harvested by Triboelectric Nanogenerators Using a Safe and Durable All-Solid-State Sodium-Ion Battery. AB - Storing energy harvested by triboelectric nanogenerators (TENGs) from ambient mechanical motion is still a great challenge for achieving low-cost and environmental benign power sources. Here, an all-solid-state Na-ion battery with safe and durable performance used for efficient storing pulsed energy harvested by the TENG is demonstrated. The solid-state sodium-ion batteries are charged by galvanostatic mode and pulse mode with the TENG, respectively. The all-solid state sodium-ion battery displays excellent cyclic performance up to 1000 cycles with a capacity retention of about 85% even at a high charge and discharge current density of 48 mA g-1. When charged by the TENG, an energy conversion efficiency of 62.3% is demonstrated. The integration of TENGs with the safe and durable all-solid-state sodium-ion batteries is potential for providing more stable power output for self-powered systems. PMID- 28852626 TI - Facile and Scalable Synthesis of Robust Ni(OH)2 Nanoplate Arrays on NiAl Foil as Hierarchical Active Scaffold for Highly Efficient Overall Water Splitting. AB - Developing highly efficient low-cost electrocatalysts for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in alkaline electrolyte is essential to advance water electrolysis technology. Herein, Ni(OH)2 nanoplates aligned on NiAl foil (Ni(OH)2/NiAl) are developed by simply dealloying NiAl foil in KOH, which exhibits high electrocatalytic activity for OER with a small overpotential of 289 mV to achieve 10 mA cm-2 and outstanding durability with no detectable degradation during long-term operation. Furthermore, such Ni(OH)2/NiAl can effectively act as an active and robust hierarchical scaffold to simply electrodeposit other catalysts with intrinsically higher activity such as NiMo and NiFe nanoparticles for highly efficient HER and OER, respectively. The prepared NiFe/Ni(OH)2/NiAl displays superior OER catalytic activity with overpotentials of 246, 315, and 374 mV at 10, 100, and 500 mA cm-2, respectively. While NiMo/Ni(OH)2/NiAl catalyst exhibits remarkable HER performance with a small overpotential of 78 mV to deliver 10 mA cm-2. Consequently, the electrolysis device composed of the above two electrocatalysts demonstrates superb water splitting performance with a cell voltage of 1.59 V at 10 mA cm-2. These results open up opportunities to explore and optimize low-cost advanced catalysts for energy applications. PMID- 28852627 TI - A Conjugated Microporous Polymer for Palladium-Free, Visible Light-Promoted Photocatalytic Stille-Type Coupling Reactions. AB - The Stille coupling reaction is a versatile method to mainly form aromatic C-C bonds. However, up to now, the use of palladium catalysts is necessary. Here, a palladium-free and photocatalytic Stille-type coupling reaction of aryl iodides and aryl stannanes catalyzing a conjugated microporous polymer-based phototcatalyst under visible light irradiation at room temperature is reported. The novel coupling reaction mechanism occurs between the photogenerated aryl radical under oxidative destannylation of the aryl stannane, and the electron activated aryl iodide, resulting into the aromatic C-C bond formation reaction. The visible light-promoted Stille-type coupling reaction using the polymer-based pure organic photocatalyst offers a simple, sustainable, and more economic synthetic pathway toward palladium-free aromatic C-C bond formation. PMID- 28852628 TI - Self-Healing and Shape Memory Effects in Gold Microparticles through the Defects Mediated Diffusion. AB - Some metal alloys subjected to irreversible plastic deformation can repair the inflicted damage and/or recover their original shape upon heating. The conventional shape memory effect in metallic alloys relies on collective, or "military" phase transformations. This work demonstrates a new and fundamentally different type of self-healing and shape memory in single crystalline faceted nano and microparticles of pure gold, which are plastically deformed with an atomic force microscope tip. It is shown that annealing of the deformed particles at elevated temperatures leads to nearly full recovery of their initial asymmetric polyhedral shape, which does not correspond to global energy minimum shape. The atomistic molecular dynamic simulations demonstrate that the shape recovery of the particles is controlled by the self-diffusion of gold atoms along the terrace ledges formed during the particles indentation. This ledge-guided diffusion leads to shape recovery by the irreversible diffusion process. A semiquantitative model of healing developed in this work demonstrates a good agreement with the experimental data. PMID- 28852629 TI - Essential Medicine Utilization and Situation in Selected Ten Developing Countries: A Compendious Audit. AB - Medicine improves the quality of life and increases mean age of human beings as it fights against diseases. Accessibility to medicines is the fundamental right of every person. The principle of the essential medicines (EMs) is that a limited number of availability of medicine will promote to a better supply chain and rational prescribing to the rural and remote health centers for any developing countries. Furthermore, it was also expected that this concept will also ensure better procurement policy at lower costs, more in amount, with easier storage. Thereby, EMs will safeguard and improve distribution and dispensing of medicine. Correspondingly, motivational and dedicated training program regarding drug information and adverse drug reactions will boost up access to medicine and health-care. In addition, the selection of medicine from EM is the first step in the direction of the rational use of medicine and progress and ensuring the quality of health care. Thereafter, selection needs to be followed by appropriate use. Everyone should receive the right medicine, in an adequate dose for an adequate duration, with appropriate information and follow-up treatment, and at an affordable cost. The acceptance and implementation of World Health Organization-promoted EM policies in deferent countries have improved quality use of medicine in terms of accessibility and affordability, predominantly in developing countries. The corporations and teamwork among various participants of health care are instantly obligatory to progress equitable access to medicines in low- and middle-income countries. PMID- 28852630 TI - Awareness, Attitude, and Knowledge of Basic Life Support among Medical, Dental, and Nursing Faculties and Students in the University Hospital. AB - OBJECTIVE: To assess the awareness, attitude, and knowledge about basic life support (BLS) among medical, dental, and nursing students and faculties and the proposal of BLS skills in the academic curriculum of undergraduate (UG) course. Recognition, prevention, and effective management of life-threatening emergencies are the responsibility of health-care professionals. These situations can be successfully managed by proper knowledge and training of the BLS skills. These life-saving maneuvers can be given through the structured resuscitation programs, which are lacking in the academic curriculum. MATERIALS AND METHODS: A questionnaire study consisting of 20 questions was conducted among 659 participants in the Kalinga Institute of Dental Sciences, Kalinga Institute of Medical Sciences, KIIT University. Medical junior residents, BDS faculties, interns, nursing faculties, and 3rd-year and final-year UG students from both medical and dental colleges were chosen. The statistical analysis was carried out using SPSS software version 20.0 (Armonk, NY:IBM Corp). RESULTS: After collecting the data, the values were statistically analyzed and tabulated. Statistical analysis was performed using Mann-Whitney U-test. The results with P < 0.05 were considered statistically significant. Our participants were aware of BLS, showed positive attitude toward it, whereas the knowledge about BLS was lacking, with the statistically significant P value. CONCLUSION: By introducing BLS regularly in the academic curriculum and by routine hands on workshops, all the health-care providers should be well versed with the BLS skills for effectively managing the life-threatening emergencies. PMID- 28852631 TI - Comparison of Efficacy of Manual and Powered Toothbrushes in Plaque Control and Gingival Inflammation: A Clinical Study among the Population of East Indian Region. AB - AIM AND OBJECTIVE: To figure out, analyze and assess the effectiveness of powered toothbrush (Braun/Oral-B two-dimensional) and manual toothbrush (Oral-B40 Regular Advantage Plus) on supragingival plaque and gingival health. MATERIALS AND METHODS: The efficacy of powered toothbrush to that of manual one was compared by using a randomized clinical trial over a 4 weeks period in controlling plaque and gingivitis using gingival index, plaque index (PI), and oral hygiene index. A total of 45 patients with age group from 19 to 23 years were included in the study. Collected data were analyzed, and different subgroups were compared using Student's t-test, Levene's test, and Chi-square test. RESULTS: In both groups whether using powered or manual toothbrush, there was marked decrease in PI scores and gingival health improvement. However, there was better reduction in PI scores and improvement in gingival health in powered toothbrush group. CONCLUSION: All individuals with both groups showed reduction in PI and hygiene index, but when it was assessed on the 4th week, individuals using powered toothbrush showed better results when compared to the individuals using manual toothbrush. PMID- 28852632 TI - Incidence of Endodontic Flare-ups and Its Related Factors: A Retrospective Study. AB - AIMS AND OBJECTIVES: The aim and objective of the study were to determine the incidence of flare-ups during endodontic treatment and to identify the risk factors associated with flare-ups. SUBJECTS AND METHODS: A total of 1725 patients who were treated during the time period of 2009-2014 by the same endodontist were reviewed. Incidence of flare-up, patients' age, gender, status of pulp, tooth position, number of roots, and treatment provided were taken from their dental records. Relationship between these factors and flare-ups was examined. Statistical analysis was done using Pearson Chi-square test and Fisher's exact test. RESULTS: A total of 2% incidence of endodontic flare-ups was seen out of 1725 cases. Patient's age, gender, and diagnosis had a significant effect on the development of flare-ups (P < 0.05). Tooth type, position of tooth, number of root canals, number of visits, and treatment modality had no significant effect on flare-up incidence. CONCLUSIONS: Diagnosis plays an important role in predicting the incidence of flare-ups. Patients in the age group of 40-60 years had a higher risk of developing flare-ups. Women compared to men are more prone to flare-ups. PMID- 28852633 TI - Antibacterial Effects of Different Concentrations of Althaea officinalis Root Extract versus 0.2% Chlorhexidine and Penicillin on Streptococcus mutans and Lactobacillus (In vitro). AB - AIMS AND OBJECTIVES: The aims of the present study were to determine and compare the effects of different concentrations of Althaea officinalis extract, 0.2% chlorhexidine (CHX), and penicillin on Streptococcus mutans and Lactobacillus acidophilus in vitro. MATERIALS AND METHODS: The laboratory study was done, for a period of 8 weeks. Minimum inhibitory concentration (MIC) in the test tube, minimum bactericidal concentration (MBC) in a plate culture medium, and growth inhibition zone diameter methods were used to compare the antibacterial effects of 0.2% CHX, penicillin, and different concentrations of A. officinalis root extract. The data were analyzed by SPSS version 24 using ANOVA and t-test analysis. RESULTS: The results showed A. officinalis root extract had antibacterial effect, but significant differences were in MIC and MBC against L. acidophilus and S. mutans with penicillin and 0.2% CHX mouthwash. In addition, the mean growth inhibition zones of all the concentrations of the plant extract were less than that of the positive control group (P = 0.001). However, the difference in the maximum growth inhibition zone from that with the negative control group was significant. In addition, the antibacterial effect of the extract increased with an increase in its concentration. The extract exerted a greater antibacterial effect on S. mutans than on L. acidophilus. The plant polyphenols content is 3.7% which is equivalent to 29.93 g/ml. CONCLUSION: The root extract of A. officinalis exhibited antibacterial effects on S. mutans and L. acidophilus, but this effect was less than those of CHX mouthwash and penicillin. The antibacterial effect increased with an increase in the concentration of the extract. PMID- 28852634 TI - Association between Tooth Loss and Opium Addiction: Results of a Community-Based Study on 5900 Adult Individuals in South East of Iran in 2015. AB - BACKGROUND: Like any other drug abuse, opium use is known to have detrimental effects on oral health. Oral hygiene neglect in opium users can lead to tooth loss resulting in further functional, esthetic, and dieting problems. Therefore, the aim of this study was to assess the association between tooth loss and opium addiction in a large-scale population. MATERIALS AND METHODS: This study was part of an extensive study related to the risk factors of cardiovascular disease and conducted by the center for physiological research during 2012-2015 in Kerman. A total of 5900, 15-75-year-old individuals, were recruited by a single-stage random cluster sampling method. Factors including opium and smoking consumption, factors related to oral health, hygiene, and the number of missing teeth were examined. Data were collected through questionnaires, interviews, and physical examination. RESULTS: Of 5900 individuals, 2662 (45.1%) were men and the rest were women, which 1011 individuals (17.1%) consumed opium. The prevalence of opium abuse was significantly higher in men. Regarding the oral dental indicators, the numbers of missing teeth (P < 0.001), decayed (P = 0.01), and the total index of decayed, missing, and filled teeth (P < 0.001) were significantly higher in addicts as compared to nonaddicts. The gingival index and community periodontal index scores were significantly lower in addicts. Addicted women had a higher prevalence of tooth loss. CONCLUSIONS: Opium addiction is associated with higher tooth loss, especially, in women opium users. Dental practitioners and health politicians should pay special attention to the oral health of addicts before tooth loss occurs. PMID- 28852635 TI - Parental Perception of Oral Health-related Quality of Life of Syrian Refugee Children. AB - AIMS AND OBJECTIVES: The conflict in Syria has resulted in the displacement of over 5 million people, many of whom intend to return home at the cessation of hostilities. Oral health plays a critical role in early childhood and this study aimed to qualitatively and quantitatively assess the oral health-related quality of life (OHRQoL) of these children. MATERIALS AND METHODS: The quantitative assessment of OHRQoL was done using a validated Arabic version of the short-form Parental-Caregiver Perceptions Questionnaire-8 (P-CPQ-8). The P-CPQ-8 was administered to 22 sets of parents of children in a community center catering to urban refugees. A focus group interview and thematic analysis of nine mothers were used to gain a qualitative insight into the problems that could affect the OHRQoL of their children. RESULTS: The P-CPQ-8 revealed that oral symptoms were the greatest concern of the parents with dental pain being the most commonly reported condition. Although mothers reported higher P-CPQ-8 scores among all domains than fathers, there were no significant differences in the concerns of the fathers and the mothers. The focus group interview raised three major themes (1) access to dental care, (2) pain felt by the child, and (3) oral hygiene of the child. CONCLUSION: The parents interviewed in this study were aware of the importance of oral hygiene but reported being unable to look after their children's teeth. Children who are refugees from the Syrian conflict face significant OHRQoL challenges. PMID- 28852637 TI - An In vitro Study to Evaluate the Effect of Eugenol-free and Eugenol-containing Temporary Cements on the Bond Strength of Resin Cement and Considering Time as a Factor. AB - AIMS AND OBJECTIVES: The aim of this study was to assess the outcome of eugenol free and eugenol-containing cements on the bond strength of resin cement. MATERIALS AND METHODS: Dentin was exposed in five groups of extracted teeth (20 specimens each). In Group 1, specimens were not given temporary cementation. In Groups 2 and 3, specimens were given temporary restoration fixed with eugenol free temporary cement for 7 and 14 days, respectively. In Groups 4 and 5, specimens were given temporary restoration fixed with eugenol-containing temporary cement for 7 and 14 days, respectively. Permanent cementation was done for all groups after specified period of time. Shear bond strength testing of specimens was carried under universal testing machine. The data were analyzed by SPSS for Windows (version 14) statistical package (SPSS Inc., Chicago, IL, USA). RESULTS: One-way analysis of variance test revealed that Group 1 specimens produced higher shear bond strength than Groups 2, 3, 4, 5 and the difference was statistically significant (P < 0.001). In Groups 2, 3, 4, and 5, no significant difference in shear bond strength was observed between provisional restoration with eugenol-containing zinc oxide cement and provisional restoration with eugenol-free zinc oxide cement (P = 0.095). CONCLUSION: The findings of this in vitro experiment lend no support to the common opinion that eugenol-containing cements should be avoided as temporary cement. PMID- 28852636 TI - Isolation and Identification of Nonoral Pathogenic Bacteria in the Oral Cavity of Patients with Removable Dentures. AB - AIMS AND OBJECTIVES: Dentures in the oral cavity may act as a reservoir of microorganisms, which may be related to systemic infections. The aim of this study was to investigate the nonoral pathogenic bacteria in the oral cavity of patients with removable dentures in Shiraz, Southern Iran. MATERIALS AND METHODS: The bacterial flora of saliva samples from 50 men and 50 women with removable dentures and 100 age- and sex-matched controls with normal dentate were compared using culture, Gram staining, and API20E Kit methods. All data were analyzed using SPSS software. RESULTS: Except for Enterobacter cloacae isolate (P = 0.03), there was no significant difference between both groups for the presence of Escherichia coli, Klebsiella pneumoniae, nonfermenting Gram-negative bacilli, Raoultella ornithinolytica, Raoultella planticola, Kluyvera spp., and Enterobacter aerogenes. No significant correlation was noticed between age and presence of bacteria in the oral cavity. The Gram-negative rod bacteria were more in males, but the difference was not significant. When a total of Gram-negative rods were considered, there was a significant difference between case and control groups (P = 0.004). CONCLUSIONS: Based on our findings that nonoral pathogenic bacteria are detected from the saliva of the denture wearers, general and oral health measures in patients with removable dentures should be adopted to decrease the risk of cross infection. PMID- 28852638 TI - Repetition of Examination Due to Motion Artifacts in Horizontal Cone Beam CT: Comparison among Three Different Kinds of Head Support. AB - AIMS AND OBJECTIVES: The aim of this study was to evaluate the repetition rate of examination due to motion artifacts in horizontal cone beam computed tomography, using three different kinds of head support, with reference to the patient's age. Further purpose was to evaluate how comfortable head supports were. MATERIALS AND METHODS: Seven hundred and fifty patients underwent a maxillofacial/dental arches volumetric imaging scan. They were divided into three groups depending on the head support used: foam headrest, foam headrest with head strap, and head restraint helmet. Each group was subdivided into three age groups: <=18-year-old, 19-65-year-old, and >=66-year-old patients. A severity index of motion artifacts, divided into four tiers from absence to remarkable artifacts, was adopted. Finally, each patient gave their judgment about the head support comfort by a questionnaire including ten yes/no questions. A three-score scale (insufficient, sufficient, and good) was used to judge the comfort. Collected data were analyzed using the SPSS(r) version 23.0 statistical analysis software. RESULTS: Forty-one patients (5.4%) repeated the examination. In 16 (2.1%), 15 (2.0%), and 10 (1.3%) of them, foam headrest, foam headrest with head strap, and head restraint helmet were used, respectively. Examination was repeated in 5.3%, 3.8%, and 10.6% in <=18-year-old, 19-65-year-old, and >=66-year-old patients, respectively. Patients almost always judged good the comfort for each kind of support. The lowest percentage of satisfaction was observed for the headrest with head strap and was judged good in 78% of the cases. CONCLUSIONS: The repetition rate of examination showed similar values among the foam headrest, foam headrest with head strap, and head restraint helmet in under 66-year-old patients. In over 65-year-old patients, the head restraint helmet obviously decreased the repetition rate of examination. All three head supports were good comfort, especially the foam headrest. PMID- 28852639 TI - A Comparative Evaluation of Mixed Dentition Analysis on Reliability of Cone Beam Computed Tomography Image Compared to Plaster Model. AB - AIMS AND OBJECTIVE: The aim of the study was to evaluate the reliability of cone beam computed tomography (CBCT) obtained image over plaster model for the assessment of mixed dentition analysis. MATERIALS AND METHODS: Thirty CBCT derived images and thirty plaster models were derived from the dental archives, and Moyer's and Tanaka-Johnston analyses were performed. The data obtained were interpreted and analyzed statistically using SPSS 10.0/PC (SPSS Inc., Chicago, IL, USA). Descriptive and analytical analysis along with Student's t-test was performed to qualitatively evaluate the data and P < 0.05 was considered statistically significant. RESULTS: Statistically, significant results were obtained on data comparison between CBCT-derived images and plaster model; the mean for Moyer's analysis in the left and right lower arch for CBCT and plaster model was 21.2 mm, 21.1 mm and 22.5 mm, 22.5 mm, respectively. CONCLUSION: CBCT derived images were less reliable as compared to data obtained directly from plaster model for mixed dentition analysis. PMID- 28852640 TI - Modified Revascularization in Human Teeth Using an Intracanal Formation of Treated Dentin Matrix: A Report of Two Cases. AB - Ethylenediaminetetraacetic acid (EDTA)-treated dentin matrix (TDM) is an enriched source of bioactive molecules. Therefore, it was hypothesized that fabrication of autogenous TDM on root dentinal walls of necrotic immature permanent teeth may allow more predictable outcome of revascularization treatments. Two young patients with permanent nonvital immature teeth were chosen for revascularization treatment. After appropriate disinfection of root canal system, TDM was fabricated on root dentinal walls using different dilutions of EDTA. Then, bleeding was induced in canals and calcium-enriched mixture (CEM) cement was placed over the blood clots. In all follow-up periods, both cases were asymptomatic and radiographic findings have shown a continued root development. Revascularization is a valuable treatment for nonvital immature teeth, allows continuation of root development. Modification of root regeneration through a TDM protocol may seem more predictable treatment and improve maturogenesis than traditional therapy. PMID- 28852641 TI - Is there any link between tumor-induced osteomalacia and psoriasis? A case report. AB - BACKGROUND: Tumor-induced osteomalacia is an uncommon paraneoplastic syndrome caused by Fibroblast growth factor-23-secreting tumors. It is characterized by phosphaturia, hypophosphatemia, and a high plasma level of alkaline phosphatase. CASE PRESENTATION: We report a young patient with psoriasis who had suffered from bone pain and muscle weakness for more than 6.5 years. He was finally diagnosed with tumor-induced osteomalacia. However, mistakenly attributing the patient's signs and symptoms to psoriatic arthritis for a long time had resulted in multiple complications for the patient. Finally, the tumor was localized and surgically resected. This resulted in clinical improvements and the resolution of all biochemical abnormalities. CONCLUSION: To our knowledge, this is the second case of tumor-induced osteomalacia accompanied by psoriasis. There is growing evidence to suggest that Fibroblast growth factor-23 has a role in regulating immune function while an increased level of it may play a role in the pathogenesis of psoriasis. As a result, tumor-induced osteomalacia may affect the psoriasis clinical course by secreting a high amount of Fibroblast growth factor 23. On the other hand, several studies have showed an increased risk of malignancy among patients with psoriasis. Consequently, long-term psoriasis may predispose patients to Fibroblast growth factor-23-secreting tumors. Finally, as psoriasis is a common disease, this presentation may simply be a coincidence. PMID- 28852642 TI - Cardiovascular risk assessment by FRS and SCORE in Iranian adult population. AB - BACKGROUND: Handling the growing epidemic of coronary heart disease in developing nations hinges on primary prevention, which logistically requires directing preventive interventions to those at the highest risk. Therefore, implementing cardiovascular risk assessment profiles is crucial to distinguish high risk groups who truly need extensive preventive measures. We aimed to draw a picture of the cardiovascular risk profiles in the Iranian adult population for the first time. METHODS: Demographic, anthropometric, and laboratory data as well as blood pressure and smoking status of 3944 subjects participating in the 2011 national surveillance of risk factors for non-communicable diseases were used to calculate the mean estimated risk of coronary artery disease and the relative frequency of low-, medium- and high-risk subjects based on FRS and SCORE indices in general population as well as different age, sex, and residence subgroups. RESULTS: The average 10-year risk of coronary artery disease (FRS) and 10-year risk of fatal coronary and cerebrovascular accidents (SCORE) in the 25 to 64 year-old population was 13.82 and 0.72 respectively. The relative frequency of the intermediate- and high- risk subjects was 25.8 and 22.6% based on FRS and 9.2 and 1.8% based on SCORE respectively. Average FRS and SCORE were significantly higher among men than women, but were not significantly different among urban and rural residents. CONCLUSIONS: A significant proportion of the Iranian population, based on FRS model, will be at moderate to high risk of coronary events in the next 10 years. Urgent preventive plans are needed at the national level. PMID- 28852643 TI - Concealed use of herbal and dietary supplements among Thai patients with type 2 diabetes mellitus. AB - BACKGROUND: Diabetes mellitus (DM) has been one of the most common chronic diseases that create great impacts on both morbidities and mortalities. Many patients who suffering from this disease seek for complementary and alternative medicine. The aim of this study was to determine the prevalence and related factors of herbal and dietary supplement (HDS) use in patients with DM type 2 at a single university hospital in Thailand. METHODS: A cross-sectional study was performed in 200 type 2 DM patients via face-to-face structured interviews using developed questionnaires comprised of demographic data, diabetes-specific information, details on HDS use, and medical adherence. RESULTS: From the endocrinology clinic, 61% of total patients reported HDS exposure and 28% were currently consuming. More than two-thirds of HDS users did not notify their physicians, mainly because of a lack of doctor concern; 73% of cases had no awareness of potential drug-herb interaction. The use of drumstick tree, turmeric and bitter gourd and holy mushroom were most frequently reported. The main reasons for HDS use were friend and relative suggestions and social media. Comparisons of demographic characteristics, medical adherence, and hemoglobin A1c among these non-HDS users, as well as current and former users, were not statistically significantly different. CONCLUSIONS: This study revealed a great number of DM patients interested in HDS use. The use of HDS for glycemic control is an emerging public health concern given the potential adverse effects, drug interactions and benefits associated with its use. Health care professionals should aware of HDS use and hence incorporate this aspect into the clinical practice. PMID- 28852645 TI - Weight gain during acute treatment of an initial pulmonary exacerbation is associated with a longer interval to the next exacerbation in adults with cystic fibrosis. AB - Weight gain during treatment for a cystic fibrosis exacerbation http://ow.ly/f1zl30dU9AO. PMID- 28852644 TI - Asbestos-related diseases in mineworkers: a clinicopathological study. AB - The accurate diagnosis of asbestos-related diseases is important because of past and current asbestos exposures. This study evaluated the reliability of clinical diagnoses of asbestos-related diseases in former mineworkers using autopsies as the reference standard. Sensitivity, specificity, positive predictive value and negative predictive value were calculated. The 149 cases identified had clinical examinations 0.3-7.4 years before death. More asbestos-related diseases were diagnosed at autopsy rather than clinically: 77 versus 52 for asbestosis, 27 versus 14 for mesothelioma and 22 versus 3 for lung cancer. Sensitivity and specificity values for clinical diagnoses were 50.6% and 81.9% for asbestosis, 40.7% and 97.5% for mesothelioma, and 13.6% and 100.0% for lung cancer. False negative diagnoses of asbestosis were more likely using radiographs of acceptable (versus good) quality and in cases with pulmonary tuberculosis at autopsy. The low sensitivity values are indicative of the high proportion of false-negative diagnoses. It is unlikely that these were the result of disease manifestation between the last clinical assessment and autopsy. Where clinical features suggest asbestos-related diseases but the chest radiograph is negative, more sophisticated imaging techniques or immunohistochemistry for asbestos-related cancers should be used. Autopsies are useful for the detection of previously undiagnosed and misdiagnosed asbestos-related diseases, and for monitoring clinical practice and delivery of compensation. PMID- 28852646 TI - The Role of Hysteroscopy in the Diagnosis and Treatment of Adenomyosis. AB - Uterine adenomyosis is a common gynecologic disorder in women of reproductive age, characterized by the presence of ectopic endometrial glands and stroma within the myometrium. Dysmenorrhea, abnormal uterine bleeding, chronic pelvic pain, and deep dyspareunia are common symptoms of this pathological condition. However, adenomyosis is often an incidental finding in specimens obtained from hysterectomy or uterine biopsies. The recent evolution of diagnostic imaging techniques, such as transvaginal sonography, hysterosalpingography, and magnetic resonance imaging, has contributed to improving accuracy in the identification of this pathology. Hysteroscopy offers the advantage of direct visualization of the uterine cavity while giving the option of collecting histological biopsy samples under visual control. Hysteroscopy is not a first-line treatment approach for adenomyosis and it represents a viable option only in selected cases of focal or diffuse "superficial" forms. During office hysteroscopy, it is possible to enucleate superficial focal adenomyomas or to evacuate cystic haemorrhagic lesions of less than 1.5 cm in diameter. Instead, resectoscopic treatment is indicated in cases of superficial adenomyotic nodules > 1.5 cm in size and for diffuse superficial adenomyosis. Finally, endometrial ablation may be performed with the additional removal of the underlying myometrium. PMID- 28852647 TI - Predictive Value of CTA Spot Sign on Hematoma Expansion in Intracerebral Hemorrhage Patients. AB - Hematoma expansion (HE) occurs in approximately one-third of patients with intracerebral hemorrhage and leads to high rates of mortality and morbidity. Currently, contrast extravasation within hematoma, termed the spot sign on computed tomography angiography (CTA), has been identified as a strong independent predictor of early hematoma expansion. Past studies indicate that the spot sign is a dynamic entity and is indicative of active hemorrhage. Furthermore, to enhance the spot sign's accuracy of predicting HE, spot parameters observed on CTA or dynamic CTA were used for its quantification. In addition, spot signs detected on multiphase CTA and dynamic CTA are shown to have higher sensitivity and specificity when compared with simple standardized spot sign detection in recent studies. Based on the spot sign, novel methods such as leakage sign and rate of contrast extravasation were explored to redefine HE prediction in combination with clinical characteristics and spot sign on CTA to assist clinical judgment. The spot sign is an accepted independent predictor of active hemorrhage and is used in both secondary intracerebral hemorrhage and the process of surgical assessment for hemorrhagic risk in patients with ischemic stroke. Spot sign predicts patients at high risk for hematoma expansion. PMID- 28852648 TI - Hepatic Immune Microenvironment in Alcoholic and Nonalcoholic Liver Disease. AB - Many types of innate (natural killer cells, natural killer T cells, and Kupffer cells/macrophages) and adaptive (T cells and B cells) immune cells are enriched within the liver and function in liver physiology and pathology. Liver pathology is generally induced by two types of immunologic insults: failure to eliminate antigens derived from the gastrointestinal tract which are important for host defense and an impaired tissue protective tolerance mechanism that helps reduce the negative outcomes of immunopathology. Accumulating evidence from the last several decades suggests that hepatic immune cells play an important role in the pathogenesis of alcoholic and nonalcoholic liver injury and inflammation in humans and mice. Here, we focus on the roles of innate and adaptive immune cells in the development and maintenance of alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Additionally, the pathogenesis of liver disease and new therapeutic targets for preventing and treating alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis are discussed. PMID- 28852649 TI - The Role of Three-Dimensional Scaffolds in Treating Long Bone Defects: Evidence from Preclinical and Clinical Literature-A Systematic Review. AB - Long bone defects represent a clinical challenge. Bone tissue engineering (BTE) has been developed to overcome problems associated with conventional methods. The aim of this study was to assess the BTE strategies available in preclinical and clinical settings and the current evidence supporting this approach. A systematic literature screening was performed on PubMed database, searching for both preclinical (only on large animals) and clinical studies. The following string was used: "(Scaffold OR Implant) AND (Long bone defect OR segmental bone defect OR large bone defect OR bone loss defect)." The search retrieved a total of 1573 articles: 51 preclinical and 4 clinical studies were included. The great amount of preclinical papers published over the past few years showed promising findings in terms of radiological and histological evidence. Unfortunately, this in vivo situation is not reflected by a corresponding clinical impact, with few published papers, highly heterogeneous and with small patient populations. Several aspects should be further investigated to translate positive preclinical findings into clinical protocols: the identification of the best biomaterial, with both biological and biomechanical suitable properties, and the selection of the best choice between cells, GFs, or their combination through standardized models to be validated by randomized trials. PMID- 28852650 TI - Metabolic Tumor Volume by 18F-FDG PET/CT Can Predict the Clinical Outcome of Primary Malignant Spine/Spinal Tumors. AB - BACKGROUND AND PURPOSE: Primary malignant spine/spinal tumors (PMSTs) are rare and life-threatening diseases. In this study, we demonstrated the advantage of volume-based 18F-FDG PET/CT metabolic parameter, metabolic tumor volume (MTV), for assessing the aggressiveness of PMSTs. MATERIALS AND METHODS: We retrospectively reviewed 27 patients with PMSTs and calculated SUVmax, MTV, and total lesion glycolysis (TLG) to compare their accuracy in predicting progression free survival (PFS) and overall survival (OS) by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate analyses were used to compare the reliability of the metabolic parameters and various clinical factors. RESULTS: MTV exhibited greater accuracy than SUVmax or TLG. The cut-off values for PFS and OS derived from the AUC data were MTV 45 ml and 83 ml and TLG 250 SUV*ml and 257 SUV*ml, respectively. MTV above cut-off value, but not TLG, was identified as significant prognostic factor for PFS by log-lank test (p = 0.04). In addition, MTV was the only significant predictive factors for PFS and OS in the multivariate analysis. CONCLUSIONS: MTV was a more accurate predictor of PFS and OS in PMSTs compared to TLG or SUVmax and helped decision-making for guiding rational treatment options. PMID- 28852651 TI - The Effect of Adherence to Dietary Tracking on Weight Loss: Using HLM to Model Weight Loss over Time. AB - The role of dietary tracking on weight loss remains unexplored despite being part of multiple diabetes and weight management programs. Hence, participants of the Diabetes Prevention and Management (DPM) program (12 months, 22 sessions) tracked their food intake for the duration of the study. A scatterplot of days tracked versus total weight loss revealed a nonlinear relationship. Hence, the number of possible tracking days was divided to create the 3 groups of participants: rare trackers (<33% total days tracked), inconsistent trackers (33-66% total days tracked), and consistent trackers (>66% total days tracked). After controlling for initial body mass index, hemoglobin A1c, and gender, only consistent trackers had significant weight loss (-9.99 pounds), following a linear relationship with consistent loss throughout the year. In addition, the weight loss trend for the rare and inconsistent trackers followed a nonlinear path, with the holidays slowing weight loss and the onset of summer increasing weight loss. These results show the importance of frequent dietary tracking for consistent long-term weight loss success. PMID- 28852653 TI - Effectiveness of Quercus brantii hydroalcoholic extract on dyspepsia: A randomized, double blind clinical trial. AB - CONTEXT AND AIMS: We aimed to evaluate the effectiveness of hydroalcoholic extract of Quercus brantii's nut on clinical, endoscopic, and pathological findings of patients with dyspepsia. PATIENTS AND METHODS: In this randomized, double-blind clinical trial, patients with symptomatic dyspepsia who had an endoscopic evaluation for dyspepsia were included and randomized into two groups. One Group (A) received drug extract with a dose of 100 mg twice a day for 10 days. Group B, as a control group, received placebo. Immediately and 2 months after intervention, the patients were followed up, and the characteristics of their dyspepsia (severity and frequency), endoscopic and pathologic findings were reevaluated and compared. RESULTS: In this trial, 13 and ten patients participated in the study in Groups A and B, respectively. Two months after intervention, ten (76.9%) and six (60%) participants referred for follow-up and endoscopic evaluation. There were no significant changes in clinical presentations after intervention (P > 0.05). Two months after intervention, clinical presentations including severity and frequency of epigastric pain had significant decrease in Group A and endoscopic evaluation indicated significant improvement in Group A (P < 0.05). Pathologic findings were similar and not significantly different in two studied groups after intervention (P > 0.05). CONCLUSIONS: The findings of this trial indicated that hydroalcoholic extract of Q. brantii's nut could have delayed significant proper effect on clinical and endoscopic presentations of patients with dyspepsia. We recommend that this study should be considered as pilot one in this field. The results could be used as baseline data for more interventional studies. More surveys are needed to investigate the mechanism of extract action at molecular basis. PMID- 28852652 TI - Postpartum depression risk factors: A narrative review. AB - Postpartum depression is a debilitating mental disorder with a high prevalence. The aim of this study was review of the related studies. In this narrative review, we report studies that investigated risk factors of postpartum depression by searching the database, Scopus, PubMed, ScienceDirect, Uptodate, Proquest in the period 2000-2015 published articles about the factors associated with postpartum depression were assessed in Farsi and English. The search strategy included a combination of keywords include postpartum depression and risk factors or obstetrical history, social factors, or biological factors. Literature review showed that risk factors for postpartum depression in the area of economic and social factors, obstetrical history, and biological factors, lifestyle and history of mental illness detected. Data from this study can use for designing a screening tools for high-risk pregnant women and for designing a prevention programs. PMID- 28852654 TI - Assessing the effect of an educational intervention program based on Health Belief Model on preventive behaviors of internet addiction. AB - INTRODUCTION: Internet addiction refers to the excessive use of the internet that causes mental, social, and physical problems. According to the high prevalence of internet addiction among university students, this study aimed to determine the effect of an educational intervention on preventive behaviors of internet addiction among Tehran University of Medical Sciences students. MATERIALS AND METHODS: This study was a quasi-experimental study conducted among female college students who live in the dormitories of Tehran University of Medical Sciences. Two-stage cluster sampling was used for selection of eighty participants in each study groups; data were collected using "Young's Internet Addiction" and unstructured questionnaire. Validity and reliability of unstructured questionnaire were evaluated by expert panel and were reported as Cronbach's alpha. Information of study groups before and 4 months after the intervention was compared using statistical methods by SPSS 16. RESULTS: After the intervention, the mean scores of internet addiction, perceived barriers construct, and the prevalence of internet addiction significantly decreased in the intervention group than that in the control group and the mean scores of knowledge and Health Belief Model (HBM) constructs (susceptibility, severity, benefits, self-efficacy) significantly increased. CONCLUSIONS: Education based on the HBM was effective on the reduction and prevention of internet addiction among female college students, and educational interventions in this field are highly recommended. PMID- 28852655 TI - Four components of pain management in Iranian neonatal Intensive Care Units: The nurses' and physicians' viewpoint. AB - BACKGROUND: As an important right and a treatment priority, pain management and alleviation can prevent harmful consequences and sever effects to the infant. The aim of this study was to determine the nurses and physicians' viewpoints about assessment, intervention, and evaluation of pain in the infants in the neonatal Intensive Care Units (NICUs). METHODS: The cross-sectional study was performed in census method in the NICUs of educational hospitals with participation of 157 staff in 2015 in Iran. Data collection tool was a questioner that was designed to assess the four components of pain management namely assessment, pharmacological intervention, nonpharmacological intervention, and evaluation. The collected data were analyzed in a descriptive and inferential statistics by means of the SPSS software, version 16. RESULTS: The findings of study indicated the total average scores of pain management from nurses and physicians' viewpoint 66.7 and 65.5, respectively that were at the moderate level. The average score of nonpharmacological interventions from nurses' viewpoint (69.4) was meaningfully higher than that of the physicians'. A significant relationship was noticed between the respondents' viewpoint on the nonpharmacological interventions and their NICU background (r = 0.18, P = 0.03). A meaningful relation was found between participation in continuing education and scores of pain management. CONCLUSIONS: The results of this study showed that the nurses and physicians' viewpoint about pain management was at a moderate level. The effect of work experience and continuing education on pain management is proved in the study. Researchers suggest that both experienced staff employment and education continuation must be incorporated in pain management in NICUs. PMID- 28852656 TI - Preconception care in therapeutic abortion applicants. AB - BACKGROUND: Some risk factors that would lead to therapeutic abortion do even exist before pregnancy and could be resolved or corrected through appropriate interventions. The present study was conducted to evaluate the condition of preconception care among therapeutic abortion applicants. MATERIALS AND METHODS: This research was a descriptive, cross-sectional study that was conducted on 200 applicants for therapeutic abortion at the Forensics Medicine Center of Isfahan (Iran) who were selected convenience sampling from October 2014 to March 2015. Data were gathered using a researcher made checklist. Data were analyzed using SPSS version 16 through descriptive statistics and Chi-square and independent t test. RESULTS: Eighty-five percent of the participants were applicants for therapeutic abortion due to fetal problems, and the other 15% were due to maternal issues. About 41.7% of participants with fetal problems and all of the participants with maternal issues had not received preconception care. In 93.3% of the applicants with maternal issues, the disease existed before the pregnancy. About 48.2% of participants needed genetic counseling, but 28.6% had not received any. CONCLUSIONS: Results showed that in most of the participants, the risk factor for therapeutic abortion existed before the pregnancy. Providing preconception care along with the elimination of risk factors before the pregnancy could prevent some of the pregnancies with the indication of therapeutic abortion. PMID- 28852657 TI - A content analysis of pediatric information in widely circulated newspapers in Iran. AB - BACKGROUND: Newspapers play an important role in improving public health literacy. This study analysis the content of pediatric information in widely circulated Iranian newspapers in 2014. MATERIALS AND METHODS: This is an applied survey performed using content analysis method. The data gathering tool was a checklist designed by the researcher. The sample size was determined using nonprobability sampling to be 426 articles with pediatric-related topics of five Iranian newspapers. RESULTS: The results showed that the most popular topics included "psychological disorders" (19.6%) and "nutrition" (19.27%). The null areas include "physiopathology of body fluids and fluid therapy" and "gynecological problems in childhood" (0%). CONCLUSION: The messages identified were more in line with needs of Iranian society which shows a need to pay more attention to international standards by both journalists and pediatricians. PMID- 28852658 TI - The effect of happiness training on self-esteem in the mothers of children with cleft lip and palate in Isfahan 2015. AB - BACKGROUND: Birth of a child with cleft lip and palate, as a crisis, can affect family relationships and interactions seriously and hence self-esteem in family members. The present study was conducted to investigate the effect of a happiness training program on self-esteem in the mothers of children with cleft lip and palate. MATERIALS AND METHODS: In this quasi-experimental study, 64 mothers of children with cleft lip and palate referring to health-care team in the Isfahan University Medical Sciences were enrolled by convenience random sampling. Then, the program of happiness training was implemented within 10 sessions, and a questionnaire of demographic characteristics and Coopersmith Self-Esteem Inventory was filled out before and 2 months after the last session. The data were analyzed by descriptive and analytical statistics (paired t-test, independent t-test, Chi-square, and Mann-Whitney) in SPSS 20 (SPSS Inc: Chicago). RESULTS: The mean age of the mothers in intervention and control groups was 33.3 +/- 6.3 and 33.5 +/- 5.8 years, respectively. The mean age of the children in the intervention and control groups was 6.34 +/- 3.37 and 5.03 +/- 3.36 years. Independent t-test indicated a significant difference in self-esteem mean score after training in the intervention and control groups. Moreover, paired t-test indicated a significant difference in self-esteem mean score between before and after training in the intervention group. CONCLUSION: In the light of the effect of happiness training on the promotion of self-esteem in children with cleft lip and palate, this program can be used as a care intervention to reduce psychological and mental problems and to enhance adjustment in parents. PMID- 28852659 TI - Evaluation of the disruptive behaviors among treatment teams and its reflection on the therapy process of patients in the operating room: The impact of personal conflicts. AB - INTRODUCTION: Understanding the development and distribution of disruptive behaviour among members of a health-care team is critical to the safety and quality of patient care in high-risk environments such as operating rooms. The present study identified disruptive behaviour and its effect on the treatment of patients in the operating room environment. SUBJECTS AND METHODS: This cross sectional study used the convenience sampling method to select 144 operating room physicians and nurses (91 women and 53 men). The study was conducted in the operating rooms of four academic hospitals with different specialties in North Khorasan province in Iran from December 2013 to September 2014. The data were collected using a translated, modified, and validated questionnaire to investigate the prevalence and consequences of disruptive behaviour, the response of the health care system to the behaviour, factors affecting the creation of conflict and the spread of disruptive behaviour. Statistical analysis of the data was performed using SPSS 18. RESULTS: Disruptive behaviour was reported by 82.95% physicians and nurses. On average, 39% of physicians and 21% of operating room nurses exhibited disruptive behaviour. Disruptive behaviour is associated with psychological and clinical consequences. Factors such as fear of retaliation (8%), lack of change (43.8%), lack of security (18.1%) and attitude of the organization (14.6%) are significant reasons for the failure to report these behaviours. CONCLUSIONS: The findings suggest that disruptive behaviour occurs and affects treatment and workflow of treatment teams in the operating room. Interpersonal conflict contributes to the growth of such behaviour; thus, more research should focus on this subject in the future. PMID- 28852660 TI - Comparing the effect of group-based and compact disk-based training on midwives' knowledge and attitude toward domestic violence in women of reproductive age. AB - BACKGROUND: Training the health personnel about domestic violence would cause them to investigate and evaluate this issue more than before. Considering the new educational approaches for transferring knowledge, the goal of this research was to compare the effect of group-based and compact disk (CD)-based training on midwives' knowledge and attitude toward domestic violence. METHODS: In this clinical experiment, seventy midwives working at health centers and hospitals of Isfahan were randomly allocated into two classes of group-based and CD-based trainings and were trained in the fields of recognition, prevention, and management of domestic violence. Data were collected by questionnaires which were completed by the midwives for evaluation of their knowledge and attitude. RESULTS: The mean score of midwives' knowledge and attitude toward domestic violence had a meaningful increase after the training (16.1, 46.9) compared to the score of before the training (12.1, 39.1) in both of the classes (group-based training: 17.7, 45.4) (CD-based training: 11.7, 38.6). No meaningful difference was observed between the two groups regarding midwives' attitude toward domestic violence after the intervention; however, regarding their knowledge level, the difference was statistically meaningful (P = 0.001), and this knowledge increase was more in the CD-based training group. CONCLUSIONS: In spite of the effectiveness of both of the training methods in promoting midwives' knowledge and attitude about domestic violence, training with CD was more effective in increasing their knowledge; as a result, considering the benefits of CD-based training such as cost-effectiveness and possibility of use at any time, it is advised to be used in training programs for the health personnel. PMID- 28852661 TI - Nursing students' viewpoints toward two methods of clinical conference and clinical nursing round. AB - BACKGROUND: Clinical education provides a chance to combine theoretical knowledge and clinical skills. Students are the key elements in the evaluation of clinical education efficacy. The present study was aimed to define nursing students' viewpoints concerning conformity to the characteristics of clinical conference and clinical round. METHODS: This descriptive analytical study was conducted on the bachelor's students of the 4th-6th semester of nursing. Sampling was conducted using census sampling method during the 2nd semester of 2014-2015 school year. Data collection tool was a three-section researcher-made questionnaire containing demographic, nursing round, and clinical conference characteristics. Descriptive and inferential statistical tests (independent t test, ANOVA, and Spearman and Pearson correlation coefficients) were used for data analysis. RESULTS: Participants were 134 bachelor's students of the 4th-6th semester of nursing. According to half of the participants, conformity to the characteristics of clinical conference (45.5%, 53%) and clinical round (44%, 51.5%) were poor and medium, respectively. Paired t-test showed a significant difference between students' viewpoints toward the planning of clinical conference and clinical nursing round (P = 0.006, t = 2.77). CONCLUSIONS: According to the results of the present study on students' viewpoints, clinical education faces a serious challenge with regard to clinical education methods. Considering the necessity and importance of clinical education, more investigation should be conducted to detect its relevant factors and plan for its improvement. PMID- 28852662 TI - Challenges of teacher-based clinical evaluation from nursing students' point of view: Qualitative content analysis. AB - INTRODUCTION: Clinical evaluation is very important in the educational system of nursing. One of the most common methods of clinical evaluation is evaluation by the teacher, but the challenges that students would face in this evaluation method, have not been mentioned. Thus, this study aimed to explore the experiences and views of nursing students about the challenges of teacher-based clinical evaluation. METHODS: This study was a descriptive qualitative study with a qualitative content analysis approach. Data were gathered through semi structured focused group sessions with undergraduate nursing students who were passing their 8th semester at Rafsanjan University of Medical Sciences. Date were analyzed using Graneheim and Lundman's proposed method. Data collection and analysis were concurrent. RESULTS: According to the findings, "factitious evaluation" was the main theme of study that consisted of three categories: "Personal preferences," "unfairness" and "shirking responsibility." These categories are explained using quotes derived from the data. CONCLUSION: According to the results of this study, teacher-based clinical evaluation would lead to factitious evaluation. Thus, changing this approach of evaluation toward modern methods of evaluation is suggested. The finding can help nursing instructors to get a better understanding of the nursing students' point of view toward this evaluation approach and as a result could be planning for changing of this approach. PMID- 28852663 TI - Does maternal and fetal health locus of control predict self-care behaviors among women with gestational diabetes? AB - INTRODUCTION: Gestational diabetes is the most common metabolic disorder in pregnancy, and lack of self-care is the most important reason for mortality in diabetic patients. Since the glycemic control is associated with physiological and psychological mechanisms, variables such as health locus of control can play a role in health behaviors of diabetic patients. Therefore, this study was aimed to predict self-care behaviors among women with gestational diabetes based on maternal health locus of control (MHLC) and fetal health locus of control (FHLC). METHODS: This study is a descriptive, predictive correlational study that it is conducted on over 400 women with gestational diabetes attending the health centers and clinic of hospitals affiliated to Mashhad University of Medical Sciences in 2015. Data were collected using individual questionnaire, self-care derived from the summary of diabetes self-care activities, MHLC, and FHLC scale. The data were analyzed using Spearman's correlation coefficient test, linear regressions model, and multiple regression in SPSS software version 16. P < 0.05 was considered statistically significant. RESULTS: Results of Spearman's correlation coefficient test showed a significant direct linear relationship between self-care and internal MHLC (P = 0.027) and internal dimensions (P < 0.0001) and powerful others (P = 0.012) of FHLC. According to linear regressions model, internal MHLC (P = 0.027), internal dimensions (P < 0.0001), and powerful others (P = 0.012) of FHLC are considered as predictor variables of self-care. CONCLUSION: Midwives should perform interventions to increase internal locus of control and encourage more responsibility among women with gestational diabetes to achieve better self-care. PMID- 28852664 TI - Nurses' experiences from pain management in children in Iranian culture: A phenomenology study. AB - BACKGROUND: Management pain in hospitalized children is challenging for the health-care professionals. Nurses have the most interactions with children who need to assess and manage for their pain. Therefore, the aim was to describe nurses' experiences from pain management among hospitalized children from Iranian culture in this study. METHODS: A phenomenological study was conducted in which 23 nurses working in an educational hospital in Isfahan-Iran. The nurses participated in interviews based on a purposeful sampling method. RESULTS: Participants' experiences were categorized into three major themes and twelve subthemes including the nurses' ability of detection of the pain nature, reaction to pain management and belief in pain relief. CONCLUSIONS: The research showed that the nurses have valuable experiences in pain management in their workplaces. Their descriptions were based on the use of three domains that consist of knowledge, belief, and practice. Therefore, it is vital to focus on the subject of pain in nursing curriculum and guidelines in hospitals. A more extensive research is needed to demonstrate perceived barriers to pain management. PMID- 28852665 TI - Promotion of higher order of cognition in undergraduate medical students using case-based approach. AB - BACKGROUND: The curriculum of pathology is conventionally "taught" in a series of didactic lectures, which promotes learning by rote. In this study, case-based learning (CBL) was introduced to assess its effect on higher order cognition and problem-solving skills in undergraduate medical students. SUBJECTS AND METHODS: The prescribed syllabus of hepatobiliary system was delivered to the undergraduate medical students of the fourth semester by conventional didactic lectures. A pretest, which contained questions designed to test both analysis and recall, was administered, followed by CBL sessions, in the presence of a facilitator, encouraging active discussion among students. Students were then assessed using a similar posttest. The perceptions of the students and the faculty were gathered by means of feedback questionnaires. The scores obtained by the students in the pre- and post-test were compared by paired t-test. RESULTS: Eighty-one students participated in CBL sessions, with 95.06% expressing a desire for more such sessions, preferably in all the topics. The faculty members also felt that CBL would be beneficial for the students but opined that it should be restricted to some topics. CBL was found to cause a highly significant (P < 0.0001) improvement in the students' higher levels of cognition, whereas the lower orders of cognition remained unaffected (P = 0.2048). CONCLUSIONS: CBL promotes active learning and helps in the development of critical thinking and analysis in undergraduate medical students. Although it is resource-intensive, an attempt should be made to incorporate it along with lectures in clinically important topics. PMID- 28852666 TI - Designing a model of patient tracking system for natural disaster in Iran. AB - CONTEXT: Disaster patient tracking consists of identifying and registering patients, recording data on their medical conditions, settings priorities for evacuation of scene, locating the patients from scene to health care centers and then till completion of treatment and discharge. AIM: The aim of this study was to design a model of patient tracking system for natural disaster in Iran. MATERIALS AND METHODS: This applied study was conducted in two steps in 2016. First, data on disaster patient tracking systems used in selected countries were collected from library-printed and electronic references and then compared. Next, a preliminary model of disaster patient tracking system was provided using these systems and validated by Delphi technique and focus group. The data of the first step were analyzed by content analysis and those of the second step by descriptive statistics. RESULTS: Analysis of the comments of key information persons in three Delphi rounds, consisting of national experts, yielded three themes, i.e., content, function, and technology, ten subthemes, and 127 components, with consensus rate of over 75%, to provide a disaster patient tracking system for Iran. CONCLUSION: In Iran, there is no comprehensive process to manage the data on disaster patients. Offering a patient tracking system can be considered a humanitarian and effective measure to promote the process of identifying, caring for, evacuating, and transferring patients as well as documenting and following up their medical and location conditions from scene till completion of the treatment. PMID- 28852667 TI - Long-lasting chondromyxoid fibroma of the zygoma: A rare case report and review of literature. AB - Chondromyxoid fibroma (CMF) is a benign tumor which usually occurs in skeletal long bones. Its presence in zygoma is extremely rare. The patient was a 47-year old female, with chief complaint of painful swelling in the left side of zygoma since 1 month ago after a long-lasting painless swelling for about 15 years. Computed tomography scan showed an osteolytic lesion, in the body of left zygomatic bone with lobulated and well-demarcated margins. During surgery, the mass was completely excised and the histological feature of the tumor was in favor of CMF. CMF is benign tumor and complete resection is the treatment of choice. PMID- 28852668 TI - Erratum: Assessing the presence of Chlamydia trachomatis genome in pregnant women with spontaneous abortion using polymerase chain reaction method in Yasuj: First report from Southwest of Iran. AB - [This corrects the article on p. 45 in vol. 6, PMID: 28616412.]. PMID- 28852669 TI - Decreasing Incidence of Skin and Soft Tissue Infections With a Seasonal Pattern at an Academic Medical Center, 2006-2014. AB - Background. The incidence of skin and soft tissue infections (SSTIs) in the United States increased sharply after 2000 with the emergence of USA300 methicillin-resistant Staphylococcus aureus. We examined trends in SSTI incidence in 2006-2014 at the University of Chicago Medicine (UCM). Methods. Data were obtained for patient encounters at UCM with an International Classification of Diseases, Ninth Revision-coded SSTI diagnosis between January 1, 2006 and March 31, 2014. Incidence density was calculated per 1000 encounters by quarter and year. Encounters were stratified by inpatient, outpatient clinic and emergency department (ED) encounters and by age group, gender, and race. Poisson regression was used to assess change over time. Results. In 2006-2014, data were collected for 38 201 SSTI-associated encounters among 31 869 subjects. Among all patients treated at UCM, there was a decrease of 1% per year in the incidence of SSTIs during 2006-2013, with an overall decrease of 16%. There was a significant decrease in SSTI-related encounters among inpatients (rate ratio [RR] = 0.97; 95% confidence interval [CI], .96-.98), ED patients (RR = 0.98; 95% CI, .97-.98), adults (RR = 0.98; 95% CI, .97-.98), children (RR = 0.96; 95% CI, .95-.97), and African Americans (RR = 0.99; 95% CI, .98-.99). There was an annual seasonal trend, with the peak incidence occurring during the late summer. Conclusions. The incidence of SSTIs at UCM decreased in children and adults with seasonal variation, peaking during the summer months. This suggests a reversal of the massive increase in SSTI incidence in the United States after 2000. PMID- 28852670 TI - Decreased Microvascular Function in Tanzanian Children With Severe and Uncomplicated Falciparum Malaria. AB - Microvascular function and oxygen consumption affect oxygen homeostasis but have not been assessed in African children with malaria. Microvascular function in Tanzanian children with severe malaria (SM) or uncomplicated malaria were 39% and 72%, respectively, of controls (P < .001). Uncomplicated malaria (P = .04), not SM (P = .06), children had increased oxygen consumption compared with controls. PMID- 28852671 TI - Corynebacterium kroppenstedtii Is an Emerging Cause of Mastitis Especially in Patients With Psychiatric Illness on Antipsychotic Medication. AB - This retrospective study of patients with Corynebacterium kroppenstedtii infections revealed a predominance of mastitis and a potential association with psychiatric illnesses. At least one third of our patients with C kroppenstedtii mastitis had psychiatric illness, and >92% received antipsychotic medications. Drug-induced hyperprolactinemia may be an important modifiable risk factor in these patients. PMID- 28852672 TI - Bundle in the Bronx: Impact of a Transition-of-Care Outpatient Parenteral Antibiotic Therapy Bundle on All-Cause 30-Day Hospital Readmissions. AB - BACKGROUND: A streamlined transition from inpatient to outpatient care can decrease 30-day readmissions. Outpatient parenteral antibiotic therapy (OPAT) programs have not reduced readmissions; an OPAT bundle has been suggested to improve outcomes. We implemented a transition-of-care (TOC) OPAT bundle and assessed the effects on all-cause, 30-day hospital readmission. METHODS: Retrospectively, patients receiving postdischarge intravenous antibiotics were evaluated before and after implementation of a TOC-OPAT program in Bronx, New York, between July, 2015 and February, 2016. Pearson's chi2 test was used to compare 30-day readmissions between groups, and logistic regression was used to adjust for covariates. Time from discharge to readmission was analyzed to assess readmission risk, using log-rank test to compare survival curves and Cox proportional hazards model to adjust for covariates. Secondary outcomes, 30-day emergency department (ED) visits, and mortality were analyzed similarly. RESULTS: Compared with previous standard care (n = 184), the TOC-OPAT group (n = 146) had significantly lower 30-day readmissions before (13.0% vs 26.1%, P < .01) and after adjustment for covariates (odds ratio [OR] = 0.51; 95% confidence interval [CI], 0.27-0.94; P = .03). In time-dependent analyses, TOC-OPAT patients were at significantly lower risk for readmission (log-rank test, P < .01; hazard ratio = 0.56; 95% CI, 0.32-0.97; P = .04). Propensity-matched sensitivity analysis showed lower readmissions in the TOC-OPAT group (13.6% vs 24.6%, P = .04), which was attenuated after adjustment (OR = 0.51; 95% CI, 0.25-1.05; P = .07). Mortality and ED visits were similar in both groups. CONCLUSIONS: Our TOC-OPAT patients had reduced 30-day readmissions compared with the previous standard of care. An effective TOC-OPAT bundle can successfully improve patient outcomes in an economically disadvantaged area. PMID- 28852673 TI - "Tweak Your Order Set!" Implementation of Modified Laboratory Order Set Improves Hepatitis C Virus Screening Rates in People Living With Human Immunodeficiency Virus. AB - There are several barriers to annual hepatitis C virus antibody (HCVAb) testing, including lack of provider knowledge of the changing HCV epidemic and provider underestimation of a patient's risk. We identified low rates of testing for HCVAb in people living with human immunodeficiency virus (HIV) in our outpatient HIV Infectious Diseases clinic, and we developed a quality improvement project to increase rates of HCVAb screening. PMID- 28852674 TI - A Review of Clinical Influenza A and B Infections With Reduced Susceptibility to Both Oseltamivir and Zanamivir. AB - Anti-influenza drugs play major roles in the management of severe influenza infections. Neuraminidase inhibitors (NAIs), which are active against all influenza A subtypes and the 2 major influenza B lineages, constitute the only class of antivirals recommended for the control of influenza epidemics and eventual pandemics. Thus, the emergence of NAI resistance could be a major clinical concern. Although most currently circulating influenza A and B strains are susceptible to NAIs, clinical cases of influenza viruses harboring single or multiple NA substitutions or deletions conferring a cross-resistance phenotype to the 2 main NAIs (oseltamivir and zanamivir) have been reported, mostly in immunocompromised individuals. Moreover, such events seem to be more frequent in A(H1N1)pdm09 viruses containing the H274Y substitution together with other NA changes (I222R, E119D/G). This review summarizes the therapeutic regimens leading to the emergence of NAI cross-resistant influenza A and B viruses as well as the virologic properties of such variants. PMID- 28852675 TI - Live-Attenuated Influenza Vaccine Effectiveness in Children From 2009 to 2015 2016: A Systematic Review and Meta-Analysis. AB - BACKGROUND: This systematic review and meta-analysis describes and consolidates findings from all studies that assessed the effectiveness of live-attenuated influenza vaccine (LAIV) against laboratory-confirmed influenza since the 2009 pandemic in children and young adults. METHODS: A MEDLINE search was conducted for articles published from January 1, 2010 to November 30, 2016. All original publications reporting an effectiveness estimate of LAIV against cases of influenza confirmed by reverse-transcription polymerase chain reaction or culture were retained for analysis. Effectiveness estimates were categorized by LAIV formulation (monovalent, trivalent, and quadrivalent) and strain (any influenza strain, A(H1N1)pdm09, A(H3N2), and B strains). Consolidated estimates were obtained with a random-effects model. RESULTS: A total of 24 publications presenting 29 observational studies were retained for meta-analysis. Live attenuated influenza vaccine was not shown to be effective against A(H1N1)pdm09 strains as a monovalent formulation in 2009-2010 or as a trivalent formulation from 2010-2011 to 2013-2014, but consolidated sample sizes were small. It was effective as a quadrivalent formulation but less effective than inactivated influenza vaccine (IIV). Live-attenuated influenza vaccine was consistently effective against B strains and matched A(H3N2) strains but was not shown to provide significant protection against mismatched A(H3N2) strains in 2014-2015. CONCLUSIONS: These findings confirm that effectiveness of LAIV against A(H1N1)pdm09 strains has been lower than IIV. A systematic investigation has been initiated to determine the root cause of the difference in effectiveness between pre- and postpandemic A(H1N1) vaccine strains and to identify a more consistently effective A(H1N1)pdm09 vaccine strain. PMID- 28852676 TI - The Burden and Clinical Presentation of Pulmonary Tuberculosis in Adults With Severe Respiratory Illness in a High Human Immunodeficiency Virus Prevalence Setting, 2012-2014. AB - BACKGROUND: Understanding the burden and clinical presentation of tuberculosis in patients with severe respiratory illness (SRI) has important implications for anticipating treatment requirements. METHODS: Hospitalized patients aged >=15 years with SRI at 2 public teaching hospitals in periurban areas in 2 provinces (Edendale Hospital in Pietermaritzburg, KwaZulu-Natal Province and Tshepong Hospital in Klerksdorp, North West Province) were enrolled prospectively from 2012 to 2014. Tuberculosis testing included smear microscopy, culture, or Xpert MTB/Rif. RESULTS: We enrolled 2486 individuals with SRI. Of these, 2097 (84%) were tested for tuberculosis, 593 (28%) were positive. Tuberculosis detection rate was 18% (133 of 729) in individuals with acute (<=14 days) presentation and 34% (460 of 1368) in those with chronic (>14 days) presentation. Among laboratory confirmed tuberculosis cases, those with acute presentation were less likely to present with cough (88% [117 of 133] vs 97% [447 of 460]; ajusted odds ratio [aOR] = 0.2, 95% confidence interval [CI] = 0.1-0.5), night sweats (57% [75 of 132] vs 73% [337 of 459]; aOR = 0.4, 95% CI = 0.3-0.7), or be started on tuberculosis treatment on admission (63% [78 of 124] vs 81% [344 of 423]; aOR = 0.4, 95% CI = 0.3-0.7), but they were more likely to be coinfected with pneumococcus (13% [16 of 124] vs 6% [26 of 411]; aOR 2.3, 95% CI 1.3-5.3) than patients with chronic presentation. Annual incidence of acute and chronic tuberculosis-associated SRI per 100000 population was 28 (95% CI = 22-39) and 116 (95% CI = 104-128), respectively. CONCLUSIONS: In this setting, tuberculosis, including acute presentation, is common in patients hospitalized with SRI. PMID- 28852677 TI - The Effect of Smallpox and Bacillus Calmette-Guerin Vaccination on the Risk of Human Immunodeficiency Virus-1 Infection in Guinea-Bissau and Denmark. AB - BACKGROUND: The live smallpox and Bacillus Calmette-Guerin (BCG) vaccinations have been associated with better adult survival in both Guinea-Bissau and Denmark. In Guinea-Bissau, human immunodeficiency virus (HIV)-1 became an important cause of death after smallpox vaccination was phased out globally in 1980. We hypothesised that smallpox and BCG vaccinations were associated with a lower prevalence of HIV-1 infection, and we tested this hypothesis in both Guinea Bissau and Denmark. METHODS: We conducted 2 studies: (1) a cross-sectional study of HIV infection and vaccination scars in Guinea-Bissau including 1751 individuals and (2) a case-base study with a background population of 46239 individuals in Denmark. In Guinea-Bissau, HIV-1 transmission was almost exclusively sexually transmitted. In Denmark, we excluded intravenous drug users. Data were analyzed using logistic regression. RESULTS: Bacillus Calmette-Guerin and/or smallpox vaccination compared with neither of these vaccines was associated with an adjusted odds ratio (aOR) for HIV-1 of 0.62 (95% confidence interval [CI], 0.36-1.07) in Guinea-Bissau and 0.70 (95% CI, 0.43-1.15) in Denmark. We combined the results from both settings in a meta-analysis (aOR = 0.66; 95% CI, 0.46-0.96). Data from Guinea-Bissau indicated a stronger effect of multiple smallpox vaccination scars (aOR = 0.27; 95% CI, 0.10-0.75) as follows: women, aOR = 0.18 (95% CI, 0.05-0.64); men, aOR = 0.52 (95% CI, 0.12-2.33); sex differential effect, P = .29. CONCLUSIONS: The studies from Guinea-Bissau and Denmark, 2 very different settings, both suggest that the BCG and smallpox vaccines could be associated with a decreased risk of sexually transmitted HIV-1. It might be informative to pursue this observation and explore possible protective mechanisms as part of the search for an HIV-1 vaccine. PMID- 28852678 TI - The Risk of Cardiac Device-Related Infection in Bacteremic Patients Is Species Specific: Results of a 12-Year Prospective Cohort. AB - BACKGROUND: The species-specific risk of cardiac device-related infection (CDRI) among bacteremic patients is incompletely understood. METHODS: We conducted a prospective cohort study of hospitalized patients from October 2002 to December 2014 with a cardiac device (CD) and either Staphylococcus aureus bacteremia (SAB) or Gram-negative bacteremia (GNB). Cardiac devices were defined as either prosthetic heart valves (PHVs), including valvular support rings, permanent pacemakers (PPMs)/automatic implantable cardioverter defibrillators (AICDs), or left ventricular assist devices (LVADs). RESULTS: During the study period, a total of 284 patients with >=1 CD developed either SAB (n = 152 patients) or GNB (n = 132 patients). Among the 284 patients, 150 (52.8%) had PPMs/AICDs, 72 (25.4%) had PHVs, 4 (1.4%) had LVADs, and 58 (20.4%) had >1 device present. Overall, 54.6% of patients with SAB and 16.7% of patients with GNB met criteria for definite CDRI (P < .0001). Multivariable logistic regression analysis revealed that 3 bacterial species were associated with an increased risk for CDRI: Staphylococcus aureus (odds ratio [OR] = 5.57; 95% confidence interval [CI], 2.16-14.36), Pseudomonas aeruginosa (OR = 50.28; 95% CI, 4.16-606.93), and Serratia marcescens (OR = 7.75; 95% CI, 1.48-40.48). CONCLUSIONS: Risk of CDRI among patients with bacteremia varies by species. Cardiac device-related infection risk is highest in patients with bacteremia due to S aureus, P aeruginosa, or S marcescens. By contrast, it is lower in patients with bacteremia due to other species of Gram-negative bacilli. Patients with a CD who develop bacteremia due to either P aeruginosa or S marcescens should be considered for diagnostic imaging to evaluate for the presence of CDRI. PMID- 28852679 TI - Diagnosis of Extrapulmonary Legionellosis in Allogeneic Hematopoietic Cell Transplant Recipients by Direct 16S Ribosomal Ribonucleic Acid Sequencing and Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. AB - Identifying extrapulmonary legionellosis is difficult due to the lack of clinical suspicion and limitations of conventional microbiologic methods. We present a case series of hematopoietic cell transplant recipients with extrapulmonary legionellosis diagnosed via molecular diagnostics: 16S ribosomal ribonucleic acid gene Sanger sequencing and matrix-assisted laser desorption/ionization time-of flight mass spectrometry. PMID- 28852680 TI - Feasibility of Treating Hepatitis C in a Transient Jail Population. AB - Jails represent a critical component of the public health response to HCV elimination. We report on outcomes of 104 patients receiving HCV treatment from January 1, 2014 to June 30, 2016 in a large urban jail setting. Our data demonstrate that treatment in jails is feasible, but many barriers remain. PMID- 28852681 TI - Comparison of Standardized Cytomegalovirus (CMV) Viral Load Thresholds in Whole Blood and Plasma of Solid Organ and Hematopoietic Stem Cell Transplant Recipients with CMV Infection and Disease. AB - BACKGROUND: Quantification of cytomegalovirus (CMV) deoxyribonucleic acid (DNA) has important diagnostic, prognostic, and therapeutic implications in the management of transplant recipients. We aimed to assess a viral load in plasma and whole blood that distinguishes CMV disease from asymptomatic infection in a cohort of solid organ and hematopoietic stem cell transplantation. METHODS: We prospectively measured and compared CMV viral load in paired plasma and whole blood samples collected from transplant recipients with CMV infection and disease. Cytomegalovirus viral loads were determined by a commercially available US Food and Drug Administration-approved quantitative assay (COBAS AmpliPrep/COBAS TaqMan CMV Test [CAP/CTM CMV]) calibrated to the first World Health Organization International Standard for CMV DNA quantification. RESULTS: Moderate agreement of CMV viral load was observed between plasma and whole blood, with 31% of samples having discordant findings, particularly among samples with low DNA levels. Among the subset of samples where both paired samples had quantifiable levels, we observed a systematic bias that reflected higher viral load in whole blood compared with plasma. Based on receiver operating curve analysis, an initial plasma CMV viral load threshold of 1700 IU/mL in solid organ transplant recipients (sensitivity 80%, specificity 74%) and 1350 IU/mL in allogeneic hematopoietic stem cell transplant recipients (sensitivity 87%, specificity 87%) distinguished CMV disease and asymptomatic infection. CONCLUSIONS: This study identifies standardized viral load thresholds that distinguish CMV disease from asymptomatic infection using CAP/CTM CMV assay. We propose these thresholds as potential triggers to be evaluated in prospective studies of preemptive therapy. Plasma was better than whole blood for measuring viral load using the CAP/CTM CMV assay. PMID- 28852683 TI - Successful Treatment of Influenza-Associated Acute Necrotizing Encephalitis in an Adult Using High-Dose Oseltamivir and Methylprednisolone: Case Report and Literature Review. AB - A case of influenza-associated acute necrotizing encephalitis (ANE) is described in an otherwise healthy adult. The patient was treated successfully with a combination of high-dose methylprednisolone and high-dose oseltamivir. The patient relapsed after discontinuing 150 mg twice daily oseltamivir but quickly improved and eventually recovered after reinitiation of high-dose oseltamivir for an additional 2 weeks. The clinical presentation, pathogenesis, and treatment of influenza-associated ANE is reviewed. The use of high-dose oseltamivir in combination with methylprednisolone may offer additional therapeutic benefit for this rare and poorly understood complication of influenza infection. PMID- 28852682 TI - The Intestinal Microbiome in Infectious Diseases: The Clinical Relevance of a Rapidly Emerging Field. AB - The field of infectious disease is undergoing a paradigm shift as the intestinal microbiome is becoming understood. The aim of this review is to inform infectious disease physicians of the potential relevance of the intestinal microbiome to their practice. We searched Medline using both index and text words relating to infectious diseases, microbiome, and probiotics. Relevant articles published up through 2017 were reviewed within Rayyan. The review illustrates pathophysiologic concepts linking the microbiome and infectious diseases; specifically, the intestinal microbiome's relevance to early immune development, the microbiome and enteric infections, the microbiome's relevance in compromised hosts, and antimicrobial resistance. Within each subject, there are specific examples of diseases and at-risk patient populations where a role for the microbiome has been strongly established. This provides an overview of the significance of the intestinal microbiome to microbiology, pediatric and adult infectious diseases with an underpinning of concepts useful for the practicing clinician. PMID- 28852684 TI - Preface to Special Topic: Ultrafast Structural Dynamics-A Tribute to Ahmed H. Zewail. PMID- 28852685 TI - Ultrafast atomic-scale visualization of acoustic phonons generated by optically excited quantum dots. AB - Understanding the dynamics of atomic vibrations confined in quasi-zero dimensional systems is crucial from both a fundamental point-of-view and a technological perspective. Using ultrafast electron diffraction, we monitored the lattice dynamics of GaAs quantum dots-grown by Droplet Epitaxy on AlGaAs-with sub picosecond and sub-picometer resolutions. An ultrafast laser pulse nearly resonantly excites a confined exciton, which efficiently couples to high-energy acoustic phonons through the deformation potential mechanism. The transient behavior of the measured diffraction pattern reveals the nonequilibrium phonon dynamics both within the dots and in the region surrounding them. The experimental results are interpreted within the theoretical framework of a non Markovian decoherence, according to which the optical excitation creates a localized polaron within the dot and a travelling phonon wavepacket that leaves the dot at the speed of sound. These findings indicate that integration of a phononic emitter in opto-electronic devices based on quantum dots for controlled communication processes can be fundamentally feasible. PMID- 28852686 TI - Solving the jitter problem in microwave compressed ultrafast electron diffraction instruments: Robust sub-50 fs cavity-laser phase stabilization. AB - We demonstrate the compression of electron pulses in a high-brightness ultrafast electron diffraction instrument using phase-locked microwave signals directly generated from a mode-locked femtosecond oscillator. Additionally, a continuous wave phase stabilization system that accurately corrects for phase fluctuations arising in the compression cavity from both power amplification and thermal drift induced detuning was designed and implemented. An improvement in the microwave timing stability from 100 fs to 5 fs RMS is measured electronically, and the long term arrival time stability ([Formula: see text]10 h) of the electron pulses improves to below our measurement resolution of 50 fs. These results demonstrate sub-relativistic ultrafast electron diffraction with compressed pulses that is no longer limited by laser-microwave synchronization. PMID- 28852687 TI - Heterodyne x-ray diffuse scattering from coherent phonons. AB - Here, we report Fourier-transform inelastic x-ray scattering measurements of photoexcited GaAs with embedded ErAs nanoparticles. We observe temporal oscillations in the x-ray scattering intensity, which we attribute to inelastic scattering from coherent acoustic phonons. Unlike in thermal equilibrium, where inelastic x-ray scattering is proportional to the phonon occupation, we show that the scattering is proportional to the phonon amplitude for coherent states. The wavevectors of the observed phonons extend beyond the excitation wavevector. The nanoparticles break the discrete translational symmetry of the lattice, enabling the generation of large wavevector coherent phonons. Elastic scattering of x-ray photons from the nanoparticles provides a reference for heterodyne mixing, yielding signals proportional to the phonon amplitude. PMID- 28852688 TI - EUV stimulated emission from MgO pumped by FEL pulses. AB - Stimulated emission is a fundamental process in nature that deserves to be investigated and understood in the extreme ultra-violet (EUV) and x-ray regimes. Today, this is definitely possible through high energy density free electron laser (FEL) beams. In this context, we give evidence for soft-x-ray stimulated emission from a magnesium oxide solid target pumped by EUV FEL pulses formed in the regime of travelling-wave amplified spontaneous emission in backward geometry. Our results combine two effects separately reported in previous works: emission in a privileged direction and existence of a material-dependent threshold for the stimulated emission. We develop a novel theoretical framework, based on coupled rate and transport equations taking into account the solid density plasma state of the target. Our model accounts for both observed mechanisms that are the privileged direction for the stimulated emission of the Mg L2,3 characteristic emission and the pumping threshold. PMID- 28852691 TI - A Conversation with Jose Almirall. PMID- 28852689 TI - Time-resolved soft X-ray absorption spectroscopy in transmission mode on liquids at MHz repetition rates. AB - We present a setup combining a liquid flatjet sample delivery and a MHz laser system for time-resolved soft X-ray absorption measurements of liquid samples at the high brilliance undulator beamline UE52-SGM at Bessy II yielding unprecedented statistics in this spectral range. We demonstrate that the efficient detection of transient absorption changes in transmission mode enables the identification of photoexcited species in dilute samples. With iron(II) trisbipyridine in aqueous solution as a benchmark system, we present absorption measurements at various edges in the soft X-ray regime. In combination with the wavelength tunability of the laser system, the set-up opens up opportunities to study the photochemistry of many systems at low concentrations, relevant to materials sciences, chemistry, and biology. PMID- 28852690 TI - Understanding anti-IgLON5 disease. PMID- 28852692 TI - Seeking Key Materials for Quantum Communications. PMID- 28852693 TI - Thermally Switching On/Off the Hardening of Soaked Nanocomposite Materials. PMID- 28852694 TI - Building a Better Magnetic Resonance Imaging Contrast Agent Using Macromolecular Architecture. PMID- 28852695 TI - Are We Approaching a Speed Limit for the Chromatographic Separation of Enantiomers? AB - As the speed of chromatographic enantioseparations advances to the point where the enantiomers of most chiral compounds can be resolved in less than a minute, some in less than a second, we pose the question of how this field is likely to develop over the next few years. Are we approaching a fundamental speed limit, or will further technological advances continue to deliver faster and faster separations? Are faster separations even needed for chemical research, and if so, how will they help? We herein examine this trend, investigating the barriers that currently limit speed and offering some insights into the continued evolution of fast chromatographic enantioseparations. PMID- 28852696 TI - The Proteasome in Modern Drug Discovery: Second Life of a Highly Valuable Drug Target. AB - As the central figure of the cellular protein degradation machinery, the proteasome is critical for cell survival. Having been extensively targeted for inhibition, the constitutive proteasome has proven its role as a highly valuable drug target. However, recent advances in the protein homeostasis field suggest that additional chapters can be added to this successful story. For example, selective immunoproteasome inhibition promises high clinical efficacy for autoimmune disorders and inflammation, and proteasome inhibitors might serve as novel therapeutics for malaria or other microorganisms. Furthermore, utilizing the destructive force of the proteasome for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Thus, the field of proteasome drug discovery still holds exciting questions to be answered and does not simply end with inhibiting the constitutive proteasome. PMID- 28852697 TI - Facile Synthesis of Uniform Virus-like Mesoporous Silica Nanoparticles for Enhanced Cellular Internalization. AB - The low-efficiency cellular uptake property of current nanoparticles greatly restricts their application in the biomedical field. Herein, we demonstrate that novel virus-like mesoporous silica nanoparticles can easily be synthesized, showing greatly superior cellular uptake property. The unique virus-like mesoporous silica nanoparticles with a spiky tubular rough surface have been successfully synthesized via a novel single-micelle epitaxial growth approach in a low-concentration-surfactant oil/water biphase system. The virus-like nanoparticles' rough surface morphology results mainly from the mesoporous silica nanotubes spontaneously grown via an epitaxial growth process. The obtained nanoparticles show uniform particle size and excellent monodispersity. The structural parameters of the nanoparticles can be well tuned with controllable core diameter (~60-160 nm), tubular length (~6-70 nm), and outer diameter (~6-10 nm). Thanks to the biomimetic morphology, the virus-like nanoparticles show greatly superior cellular uptake property (invading living cells in large quantities within few minutes, <5 min), unique internalization pathways, and extended blood circulation duration (t1/2 = 2.16 h), which is much longer than that of conventional mesoporous silica nanoparticles (0.45 h). Furthermore, our epitaxial growth strategy can be applied to fabricate various virus-like mesoporous core-shell structures, paving the way toward designed synthesis of virus-like nanocomposites for biomedicine applications. PMID- 28852698 TI - Electroreduction of CO2 Catalyzed by a Heterogenized Zn-Porphyrin Complex with a Redox-Innocent Metal Center. AB - Transition-metal-based molecular complexes are a class of catalyst materials for electrochemical CO2 reduction to CO that can be rationally designed to deliver high catalytic performance. One common mechanistic feature of these electrocatalysts developed thus far is an electrogenerated reduced metal center associated with catalytic CO2 reduction. Here we report a heterogenized zinc porphyrin complex (zinc(II) 5,10,15,20-tetramesitylporphyrin) as an electrocatalyst that delivers a turnover frequency as high as 14.4 site-1 s-1 and a Faradaic efficiency as high as 95% for CO2 electroreduction to CO at -1.7 V vs the standard hydrogen electrode in an organic/water mixed electrolyte. While the Zn center is critical to the observed catalysis, in situ and operando X-ray absorption spectroscopic studies reveal that it is redox-innocent throughout the potential range. Cyclic voltammetry indicates that the porphyrin ligand may act as a redox mediator. Chemical reduction of the zinc-porphyrin complex further confirms that the reduction is ligand-based and the reduced species can react with CO2. This represents the first example of a transition-metal complex for CO2 electroreduction catalysis with its metal center being redox-innocent under working conditions. PMID- 28852699 TI - CO2 Reduction Selective for C>=2 Products on Polycrystalline Copper with N Substituted Pyridinium Additives. AB - Electrocatalytic CO2 reduction to generate multicarbon products is of interest for applications in artificial photosynthetic schemes. This is a particularly attractive goal for CO2 reduction by copper electrodes, where a broad range of hydrocarbon products can be generated but where selectivity for C-C coupled products relative to CH4 and H2 remains an impediment. Herein we report a simple yet highly selective catalytic system for CO2 reduction to C>=2 hydrocarbons on a polycrystalline Cu electrode in bicarbonate aqueous solution that uses N substituted pyridinium additives. Selectivities of 70-80% for C2 and C3 products with a hydrocarbon ratio of C>=2/CH4 significantly greater than 100 have been observed with several additives. 13C-labeling studies verify CO2 to be the sole carbon source in the C>=2 hydrocarbons produced. Upon electroreduction, the N substituted pyridinium additives lead to film deposition on the Cu electrode, identified in one case as the reductive coupling product of N-arylpyridinium. Product selectivity can also be tuned from C>=2 species to H2 (~90%) while suppressing methane with certain N-heterocyclic additives. PMID- 28852700 TI - Hierarchical Self-Organization of AB n Dendron-like Molecules into a Supramolecular Lattice Sequence. AB - To understand the hierarchical self-organization behaviors of soft materials as well as their dependence on molecular geometry, a series of AB n dendron-like molecules based on polyhedral oligomeric silsesquioxane (POSS) nanoparticles were designed and synthesized. The apex of these molecules is a hydrophilic POSS cage with 14 hydroxyl groups (denoted DPOSS). At its periphery, there are different numbers (n = 1-8) of hydrophobic POSS cages with seven isobutyl groups (denoted BPOSS), connected to the apical DPOSS via flexible dendron type linker(s). By varying the BPOSS number from one to seven, a supramolecular lattice formation sequence ranging from lamella (DPOSS-BPOSS), double gyroid (space group of Ia3d, DPOSS-BPOSS2), hexagonal cylinder (plane group of P6mm, DPOSS-BPOSS3), Frank Kasper A15 (space group of Pm3n, DPOSS-BPOSS4, DPOSS-BPOSS5, and DPOSS-BPOSS6), to Frank-Kasper sigma (space group of P42/mnm, DPOSS-BPOSS7) phases can be observed. The nanostructure formations in this series of AB n dendron-like molecules are mainly directed by the molecular geometric shapes. Furthermore, within each spherical motif, the spherical core consists hydrophilic DPOSS cages with flexible linkages, while the hydrophobic BPOSS cages form the relative rigid shell, and contact with neighbors to provide decreased interfaces among the spherical motifs for constructing final polyhedral motifs in these Frank-Kasper lattices. This study provides the design principle of molecules with specific geometric shapes and functional groups to achieve anticipated structures and macroscopic properties. PMID- 28852701 TI - Membrane Binding of Recoverin: From Mechanistic Understanding to Biological Functionality. AB - Recoverin is a neuronal calcium sensor involved in vision adaptation that reversibly associates with cellular membranes via its calcium-activated myristoyl switch. While experimental evidence shows that the myristoyl group significantly enhances membrane affinity of this protein, molecular details of the binding process are still under debate. Here, we present results of extensive molecular dynamics simulations of recoverin in the proximity of a phospholipid bilayer. We capture multiple events of spontaneous membrane insertion of the myristoyl moiety and confirm its critical role in the membrane binding. Moreover, we observe that the binding strongly depends on the conformation of the N-terminal domain. We propose that a suitable conformation of the N-terminal domain can be stabilized by the disordered C-terminal segment or by binding of the target enzyme, i.e., rhodopsin kinase. Finally, we find that the presence of negatively charged lipids in the bilayer stabilizes a physiologically functional orientation of the membrane-bound recoverin. PMID- 28852702 TI - A Nano-In-Micro System for Enhanced Stem Cell Therapy of Ischemic Diseases. AB - Stem cell therapy holds great potential for treating ischemic diseases. However, contemporary methods for local stem cell delivery suffer from poor cell survival/retention after injection. We developed a unique multiscale delivery system by encapsulating therapeutic agent-laden nanoparticles in alginate hydrogel microcapsules and further coentrapping the nano-in-micro capsules with stem cells in collagen hydrogel. The multiscale system exhibits significantly higher mechanical strength and stability than pure collagen hydrogel. Moreover, unlike nanoparticles, the nano-in-micro capsules do not move with surrounding body fluid and are not taken up by the cells. This allows a sustained and localized release of extracellular epidermal growth factor (EGF), a substance that could significantly enhance the proliferation of mesenchymal stem cells while maintaining their multilineage differentiation potential via binding with its receptors on the stem cell surface. As a result, the multiscale system significantly improves the stem cell survival at 8 days after implantation to ~70% from ~4-7% for the conventional system with nanoparticle-encapsulated EGF or free EGF in collagen hydrogel. After injecting into the ischemic limbs of mice, stem cells in the multiscale system facilitate tissue regeneration to effectively restore ~100% blood perfusion in 4 weeks without evident side effects. PMID- 28852703 TI - Biomimetic Reversible Heat-Stiffening Polymer Nanocomposites. AB - Inspired by the ability of the sea cucumber to (reversibly) increase the stiffness of its dermis upon exposure to a stimulus, we herein report a stimuli responsive nanocomposite that can reversibly increase its stiffness upon exposure to warm water. Nanocomposites composed of cellulose nanocrystals (CNCs) that are grafted with a lower critical solution temperature (LCST) polymer embedded within a poly(vinyl acetate) (PVAc) matrix show a dramatic increase in modulus, for example, from 1 to 350 MPa upon exposure to warm water, the hypothesis being that grafting the polymers from the CNCs disrupts the interactions between the nanofibers and minimizes the mechanical reinforcement of the film. However, exposure to water above the LCST leads to the collapse of the polymer chains and subsequent stiffening of the nanocomposite as a result of the enhanced CNC interactions. Backing up this hypothesis are energy conserving dissipative particle dynamics (EDPD) simulations which show that the attractive interactions between CNCs are switched on upon the temperature-induced collapse of the grafted polymer chains, resulting in the formation of a percolating reinforcing network. PMID- 28852704 TI - Catalytic Hydroxylation of Polyethylenes. AB - Polyolefins account for 60% of global plastic consumption, but many potential applications of polyolefins require that their properties, such as compatibility with polar polymers, adhesion, gas permeability, and surface wetting, be improved. A strategy to overcome these deficiencies would involve the introduction of polar functionalities onto the polymer chain. Here, we describe the Ni-catalyzed hydroxylation of polyethylenes (LDPE, HDPE, and LLDPE) in the presence of m CPBA as an oxidant. Studies with cycloalkanes and pure, long-chain alkanes were conducted to assess precisely the selectivity of the reaction and the degree to which potential C-C bond cleavage of a radical intermediate occurs. Among the nickel catalysts we tested, [Ni(Me4Phen)3](BPh4)2 (Me4Phen = 3,4,7,8, tetramethyl-1,10-phenanthroline) reacted with the highest turnover number (TON) for hydroxylation of cyclohexane and the highest selectivity for the formation of cyclohexanol over cyclohexanone (TON, 5560; cyclohexanol/(cyclohexanone + epsilon caprolactone) ratio, 10.5). The oxidation of n-octadecane occurred at the secondary C-H bonds with 15.5:1 selectivity for formation of an alcohol over a ketone and 660 TON. Consistent with these data, the hydroxylation of various polyethylene materials by the combination of [Ni(Me4Phen)3](BPh4)2 and m CPBA led to the introduction of 2.0 to 5.5 functional groups (alcohol, ketone, alkyl chloride) per 100 monomer units with up to 88% selectivity for formation of alcohols over ketones or chloride. In contrast to more classical radical functionalizations of polyethylene, this catalytic process occurred without significant modification of the molecular weight of the polymer that would result from chain cleavage or cross-linking. Thus, the resulting materials are new compositions in which hydroxyl groups are located along the main chain of commercial, high molecular weight LDPE, HDPE, and LLDPE materials. These hydroxylated polyethylenes have improved wetting properties and serve as macroinitiators to synthesize graft polycaprolactones that compatibilize polyethylene-polycaprolactone blends. PMID- 28852705 TI - The Sweat Metabolome of Screen-Positive Cystic Fibrosis Infants: Revealing Mechanisms beyond Impaired Chloride Transport. AB - The sweat chloride test remains the gold standard for confirmatory diagnosis of cystic fibrosis (CF) in support of universal newborn screening programs. However, it provides ambiguous results for intermediate sweat chloride cases while not reflecting disease progression when classifying the complex CF disease spectrum given the pleiotropic effects of gene modifiers and environment. Herein we report the first characterization of the sweat metabolome from screen-positive CF infants and identify metabolites associated with disease status that complement sweat chloride testing. Pilocarpine-stimulated sweat specimens were collected independently from two CF clinics, including 50 unaffected infants (e.g., carriers) and 18 confirmed CF cases. Nontargeted metabolite profiling was performed using multisegment injection-capillary electrophoresis-mass spectrometry as a high throughput platform for analysis of polar/ionic metabolites in volume-restricted sweat samples. Amino acids, organic acids, amino acid derivatives, dipeptides, purine derivatives, and unknown exogenous compounds were identified in sweat when using high resolution tandem mass spectrometry, including metabolites associated with affected yet asymptomatic CF infants, such as asparagine and glutamine. Unexpectedly, a metabolite of pilocarpine, used to stimulate sweat secretion, pilocarpic acid, and a plasticizer metabolite from environmental exposure, mono(2-ethylhexyl)phthalic acid, were secreted in the sweat of CF infants at significantly lower concentrations relative to unaffected CF screen-positive controls. These results indicated a deficiency in human paraoxonase, an enzyme unrelated to mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) and impaired chloride transport, which is a nonspecific arylesterase/lactonase known to mediate inflammation, bacterial biofilm formation, and recurrent lung infections in affected CF children later in life. This work sheds new light into the underlying mechanisms of CF pathophysiology as required for new advances in precision medicine of orphan diseases that benefit from early detection and intervention, including new molecular targets for therapeutic intervention. PMID- 28852706 TI - Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease. AB - OBJECTIVE: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families. METHODS: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE epsilon4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia. RESULTS: Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes. CONCLUSIONS: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers. PMID- 28852708 TI - A novel intronic mutation in MTM1 detected by RNA analysis in a case of X-linked myotubular myopathy. PMID- 28852707 TI - Design and rationale for examining neuroimaging genetics in ischemic stroke: The MRI-GENIE study. AB - OBJECTIVE: To describe the design and rationale for the genetic analysis of acute and chronic cerebrovascular neuroimaging phenotypes detected on clinical MRI in patients with acute ischemic stroke (AIS) within the scope of the MRI-GENetics Interface Exploration (MRI-GENIE) study. METHODS: MRI-GENIE capitalizes on the existing infrastructure of the Stroke Genetics Network (SiGN). In total, 12 international SiGN sites contributed MRIs of 3,301 patients with AIS. Detailed clinical phenotyping with the web-based Causative Classification of Stroke (CCS) system and genome-wide genotyping data were available for all participants. Neuroimaging analyses include the manual and automated assessments of established MRI markers. A high-throughput MRI analysis pipeline for the automated assessment of cerebrovascular lesions on clinical scans will be developed in a subset of scans for both acute and chronic lesions, validated against gold standard, and applied to all available scans. The extracted neuroimaging phenotypes will improve characterization of acute and chronic cerebrovascular lesions in ischemic stroke, including CCS subtypes, and their effect on functional outcomes after stroke. Moreover, genetic testing will uncover variants associated with acute and chronic MRI manifestations of cerebrovascular disease. CONCLUSIONS: The MRI-GENIE study aims to develop, validate, and distribute the MRI analysis platform for scans acquired as part of clinical care for patients with AIS, which will lead to (1) novel genetic discoveries in ischemic stroke, (2) strategies for personalized stroke risk assessment, and (3) personalized stroke outcome assessment. PMID- 28852709 TI - Ataxia-pancytopenia syndrome with SAMD9L mutations. AB - OBJECTIVE: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia pancytopenia (ATXPC) syndrome and SAMD9L mutations. METHODS: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed. RESULTS: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC. CONCLUSIONS: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial. PMID- 28852710 TI - Vapour-Deposited Cesium Lead Iodide Perovskites: Microsecond Charge Carrier Lifetimes and Enhanced Photovoltaic Performance. AB - Metal halide perovskites such as methylammonium lead iodide (MAPbI3) are highly promising materials for photovoltaics. However, the relationship between the organic nature of the cation and the optoelectronic quality remains debated. In this work, we investigate the optoelectronic properties of fully inorganic vapour deposited and spin-coated black-phase CsPbI3 thin films. Using the time-resolved microwave conductivity technique, we measure charge carrier mobilities up to 25 cm2/(V s) and impressively long charge carrier lifetimes exceeding 10 MUs for vapour-deposited CsPbI3, while the carrier lifetime reaches less than 0.2 MUs in the spin-coated samples. Finally, we show that these improved lifetimes result in enhanced device performance with power conversion efficiencies close to 9%. Altogether, these results suggest that the charge carrier mobility and recombination lifetime are mainly dictated by the inorganic framework rather than the organic nature of the cation. PMID- 28852711 TI - Enterovirus D68 in Viet Nam (2009-2015). AB - BACKGROUND: Since 1962, enterovirus D68 (EV-D68) has been implicated in multiple outbreaks and sporadic cases of respiratory infection worldwide, but especially in the USA and Europe with an increasing frequency between 2010 and 2014. We describe the detection, associated clinical features and molecular characterization of EV-D68 in central and southern Viet Nam between 2009 and 2015. METHODS: Enterovirus/rhinovirus PCR positive respiratory or CSF samples taken from children and adults with respiratory/central nervous system infections in Viet Nam were tested by an EV-D68 specific PCR. The included samples were derived from 3 different observational studies conducted at referral hospitals across central and southern Viet Nam between 2009 and 2015. Whole-genome sequencing was carried out using a MiSeq based approach. Phylogenetic reconstruction and estimation of evolutionary rate and recombination were carried out in BEAST and Recombination Detection Program, respectively. RESULTS: EV-D68 was detected in 21/625 (3.4%) enterovirus/rhinovirus PCR positive respiratory samples but in none of the 15 CSF. All the EV-D68 patients were young children (age range: 11.8 - 24.5 months) and had moderate respiratory infections. Phylogenetic analysis suggested that the Vietnamese sequences clustered with those from Asian countries, of which 9 fell in the B1 clade, and the remaining sequence was identified within the A2 clade. One intra sub-clade recombination event was detected, representing the second reported recombination within EV-D68. The evolutionary rate of EV-D68 was estimated to be 5.12E -3 substitutions/site/year. Phylogenetic analysis indicated that the virus was imported into Viet Nam in 2008. CONCLUSIONS: We have demonstrated for the first time EV-D68 has been circulating at low levels in Viet Nam since 2008, associated with moderate acute respiratory infection in children. EV-D68 in Viet Nam is most closely related to Asian viruses, and clusters separately from recent US and European viruses that were suggested to be associated with acute flaccid paralysis. PMID- 28852712 TI - Further investigations of the W-test for pairwise epistasis testing. AB - Background: In a recent paper, a novel W-test for pairwise epistasis testing was proposed that appeared, in computer simulations, to have higher power than competing alternatives. Application to genome-wide bipolar data detected significant epistasis between SNPs in genes of relevant biological function. Network analysis indicated that the implicated genes formed two separate interaction networks, each containing genes highly related to autism and neurodegenerative disorders. Methods: Here we investigate further the properties and performance of the W-test via theoretical evaluation, computer simulations and application to real data. Results: We demonstrate that, for common variants, the W-test is closely related to several existing tests of association allowing for interaction, including logistic regression on 8 degrees of freedom, although logistic regression can show inflated type I error for low minor allele frequencies, whereas the W-test shows good/conservative type I error control. Although in some situations the W-test can show higher power, logistic regression is not limited to tests on 8 degrees of freedom but can instead be tailored to impose greater structure on the assumed alternative hypothesis, offering a power advantage when the imposed structure matches the true structure. Conclusions: The W-test is a potentially useful method for testing for association - without necessarily implying interaction - between genetic variants disease, particularly when one or more of the genetic variants are rare. For common variants, the advantages of the W-test are less clear, and, indeed, there are situations where existing methods perform better. In our investigations, we further uncover a number of problems with the practical implementation and application of the W test (to bipolar disorder) previously described, apparently due to inadequate use of standard data quality-control procedures. This observation leads us to urge caution in interpretation of the previously-presented results, most of which we consider are highly likely to be artefacts. PMID- 28852713 TI - ANXIOLYTIC - LIKE PROPERTIES OF Hallea ciliata IN MICE. AB - BACKGROUND: The aim of the present study was to evaluate the anxiolytic properties of the decoction of stem bark of Hallea ciliate in mice. The decoction of Hallea ciliata is used in traditional medicine in Cameroon to treat diseases like anxiety disorders, fever, infantile convulsions and malaria. MATERIALS AND METHODS: Stress induced hyperthermia, elevated plus maze, open field and hole board tests were used. Four different doses of the decoction were administered to mice and their effects were compared to the effects of diazepam and vehicle. Phytochemical characterization of the decoction revealed the presence of alkaloids, flavonoids, tannins and saponins. RESULTS: Administration of Hallea ciliata resulted in a significant decrease of stress induced hyperthermia in mice at the doses of 29.5, 59 and 118 mg/kg. In the elevated plus maze test, Hallea ciliata increased the number of entries and the percentages of entries and time into the open arms, and reduced the number of entries and the percentages of entries and time into the closed arms. In the hole-board test, Hallea ciliata increased the number of both head-dipping and crossing and decreased the latency to the first head-dips and rearing. The decoction of Hallea ciliata and diazepam increased locomotion in the open field test. CONCLUSION: The number of rearing and the mass of fecal boli produced were decreased in mice treated with decoction and diazepam. In conclusion, the results indicated that decoction of Hallea ciliata has anxiolytic-like properties in mice and could potentially be used for anxiety treatment. PMID- 28852714 TI - THE EFFECTS OF Syzygium aromaticum-DERIVED TRITERPENES ON GASTROINTESTINAL GHRELIN EXPRESSION IN STREPTOZOTOCIN-INDUCED DIABETIC RATS. AB - BACKGROUND: Diabetic polyphagia has been associated with elevated plasma ghrelin levels in experimental type 1 diabetes. This increase in food consumption contributes to chronic hyperglycaemia in diabetes thus contributing to the development of micro- and macrovascular complications. We have reported that plant-derived oleanolic acid (OA) and maslinic acid (MA) reduce blood glucose levels, in part, through the inhibition of intestinal carbohydrate hydrolyzing enzymes and glucose transporters. However, their effects on food intake and plasma ghrelin concentrations are unclear. Accordingly, we investigated the effects of these triterpenes on food intake and ghrelin expression in streptozotocin-induced diabetic rats. MATERIAL: The effects of OA and MA on blood glucose concentration; food and water intake were monitored over five weeks after which plasma ghrelin concentrations were measured. Additionally, the expression of ghrelin in the various sections of the GIT was determined using Western blot analysis. RESULTS: Ghrelin concentrations in untreated STZ-induced diabetic rats were significantly higher in comparison to the non-diabetic control. Interestingly, the administration of OA and MA reduced food intake, blood glucose levels and plasma ghrelin levels in STZ-induced diabetic rats. This was further complemented by significant reductions in the gastrointestinal expression of ghrelin suggesting that the anti-diabetic properties of these triterpenes are mediated, in part, through the reduction of food intake and the modulation of ghrelin expression. CONCLUSION: The findings of the study suggest that the control of food intake through the reduction of ghrelin expression by plant derived OA and MA may constitute an avenue of glycaemic control in diabetes mellitus. PMID- 28852715 TI - PRELIMINARY STUDIES ON THE BEHAVIOURAL EFFECTS OF THE METHANOL EXTRACT OF LEONOTIS NEPETIFOLIA LINN STEM IN MICE. AB - BACKGROUND: Leonotis nepetifolia Linn (Lamiaceae) is used in traditional medicine for its calming (tranquilizing) effects. The aim of this study was to determine whether there is any scientific justification for this use. To achieve this purpose, we investigated the behavioural effects of the methanol extract of Leonotis nepetifolia stem (37.5, 75 and 150 mg/kg) in mice. METHODS: Acute toxicity studies were carried out on the methanol stem extract of Leonotis nepetifolia to determine the LD50. The behavioural tests employed were diazepam induced sleep onset and duration, hole board assay for exploratory activity, mouse beam walk assay for motor coordination, and the staircase test for the detection of anxiolytic compounds. Preliminary phytochemical screening was also carried out on the extract. RESULTS: The intraperitoneal LD50 value was found to be 3.8 g/kg. The results showed that the extract significantly prolonged the duration of diazepam-induced sleep at the highest dose (150 mg/kg). There was no observable effect on exploratory activity and motor coordination at the doses tested (37.5, 75 and 150 mg/kg). The extract, however, at 150 mg/kg elicited a significant decrease in the number of rearings in the staircase test, an effect also observed in the group of mice injected with an anxiolytic dose of diazepam. The preliminary phytochemical screening revealed the presence of alkaloids, saponins, glycosides and triterpenoids. CONCLUSION: The results obtained suggest that the crude methanol extract of Leonotis nepetifolia stem possesses some biologically active constituents with potential anxiolytic activity and thus may justify its traditional use as a tranquilizer. PMID- 28852716 TI - DRY CUPPING IN CHILDREN WITH FUNCTIONAL CONSTIPATION: A RANDOMIZED OPEN LABEL CLINICAL TRIAL. AB - BACKGROUND: As a common disease in pediatrics, constipation poses a high burden to the community. In this study, we aimed to investigate the efficacy of dry cupping therapy (an Eastern traditional manipulative therapy) in children with functional constipation. MATERIALS AND METHODS: One hundred and twenty children (4-18 years old) diagnosed as functional constipation according to ROME III criteria were assigned to receive a traditional dry cupping protocol on the abdominal wall for 8 minutes every other day or standard laxative therapy (Polyethylene glycol (PEG) 40% solution without electrolyte), 0.4 g/kg once daily) for 4 weeks, in an open label randomized controlled clinical trial using a parallel design with a 1:1 allocation ratio. Patients were evaluated prior to and following 2, 4, 8 and 12 weeks of the intervention commencement in terms of the ROME III criteria for functional constipation. RESULTS: There were no significant differences between the two arms regarding demographic and clinical basic characteristics. After two weeks of the intervention, there was a significant better result in most of the items of ROME III criteria of patients in PEG group. In contrast, after four weeks of the intervention, the result was significantly better in the cupping group. There was no significant difference in the number of patients with constipation after 4 and 8 weeks of the follow-up period. CONCLUSION: This study showed that dry cupping of the abdominal wall, as a traditional manipulative therapy, can be as effective as standard laxative therapy in children with functional constipation. PMID- 28852717 TI - EFFECTS OF L-ASCORBIC ACID AND ALPHA-TOCOPHEROL ON BIOCHEMICAL PARAMETERS OF SWIMMING-INDUCED OXIDATIVE STRESS IN SERUM OF GUINEA PIGS. AB - BACKGROUND: The purpose of this study is to determine the effect of L-ascorbic acid and alpha-tocopherol as well as combination of these vitamins with or without exposure to physical exercise on intensity of lipid peroxidation, activity of xanthine oxidase, activity of total antioxidative system, concentration of glutathione, and activity of catalase in the serum of guinea pigs. MATERIALS AND METHODS: The experimental measurements of intensity of lipid peroxidation, activity of xanthine oxidase, activity of total antioxidative system, concentration of glutathione, and activity of catalase were done in the serum of guinea pigs. The animals were exposed to the test load to achieve exhaustion and the test was terminated when the animal for the third time to sink into the water. RESULTS: The results of this study demonstrated that endurance exercise of guinea pigs induced oxidative stress response in terms of increased lipid peroxidation and activity of xanthine oxidase in the serum of experimental animals. Our study investigated the antioxidant activity of L-ascorbic acid and alpha-tocopherol also measuring three protective markers in the serum: total antioxidant activity, content of glutathione and activity of catalase. The results obtained show that the vitamins influence the concentrations of above mentioned biochemical parameters, which points out their protective effect of swimming-induced oxidative stress. CONCLUSION: Single or combined administration of L-ascorbic acid and alpha-tocopherol caused significant inhibition of these markers indicating the important antioxidant activity of the vitamins. Results lead to conclude that the combined treatments with vitamins with or without exposure to physical exercise showed the clear synergistic effect.. PMID- 28852718 TI - THE EFFECTS OF OXIDATIVE STRESS ON PHENOLIC COMPOSITION AND ANTIOXIDANT METABOLISM IN CALLUS CULTURE OF COMMON DAISY. AB - BACKGROUND: Exogenous pretreatment of oxidative stress on callus cultures of Bellis perennis L. (common daisy) induced catalase (CAT), superoxide dismutase (SOD), total phenolic, total flavonoid, total protein and selected commercial phenolic compounds production and accumulation. MATERIALS AND METHODS: The callus culture obtained from B. perennis pedicel explants was incubated on Murashige and Skoog medium (MS) containing 10 mM H2O2 or 0 mM H2O2 (for control group) for 10 hours. Twenty phenolic compounds (apigenin, caffeic acid, p-coumaric acid, gallic acid, genistein, kaempferol, luteolin, myricetin, procyanidin-C1, quercetin, rutin hydrate, vanillic acid, ferulic acid, salicylic acid, sinapic acid, chlorogenic acid, hesperedin, naringenin, rosmarinic acid and isorhamnetin) were detected by LC-ESI-MS/MS analysis in methanolic extracts of 10 mM H2O2 and control treatments. RESULTS: A predominant phenolic compound was chlorogenic acid followed by rutin hydrate, caffeic acid, luteoline, isorhamnetin, quercetin, myricetin, apigenin, p-coumaric acid and kaempferol. No gallic acid, genistein, procyanidin-C1, vanillic acid, sinapic acid, hesperidin and naringenin were detected in H2O2 treatment and control groups of B. perennis. The total phenolic contents estimated were in the order of H2O2 treatment (285.36 MUg/g dw) and control (220.79 MUg/g dw) groups. The biosynthesis and accumulation of kaempferol, myricetin, quercetin and isorhamnetin were only determined in H2O2 treatment callus materials. The H2O2 pretreatment clearly showed in a raise in enzymatic and non-enzymatic antioxidant activities. Finally, a significant positive correlation between phenolic accumulation and comprehensive activities of CAT, SOD, total phenolic, total flavonoid and proline was accessible. CONCLUSION: The present results suggest that using H2O2 as an elicitor or a stimulant plays a significant enhancement role in special phenolic molecules biosynthesis and activation of antioxidant metabolism on callus cultures of B. perennis. PMID- 28852719 TI - IN VITRO ANTIMICROBIAL ACTIVITY SCREENING OF XYLARIA HYPOXYLON. AB - BACKGROUND: Fungi have a potential of using both as nutritive and medicinal food stuff. Because of containing several therapeutic agents, they are reported to be used for hundreds of years to treat several diseases caused by bacteria, fungi, viruses and parasites. The aim of this study is to determine the in vitro antimicrobial activity of Xylaria hypoxylon, which were collected from Yomra, Trabzon, Turkey. MATERIALS AND METHODS: X. hypoxylon samples were air dried and extracted by using ethanol. Antimicrobial activity of X. hypoxylon ethanol extracts were investigated against 21 bacterial and 2 fungal strains, namely, Bacillus subtilis DSMZ 1971, Bacillus subtilis ATCC 6633, Candida albicans ATCC 10231, Candida albicans DSMZ 1386, Enterobacter aerogenes ATCC 13048, Enterococcus durans, Enterococcus faecalis ATCC 29212, Enterococcus faecium, Escherichia coli ATCC 25922, Escherichia coli CFAI, Klebsiella pneumoniae, Listeria innocula, Listeria monocytogenes ATCC 7644, Pseudomonas aeruginosa DSMZ 50071, Pseudomonas fluorescence P1, Salmonella enteritidis ATCC 13075, Salmonella infantis, Salmonella kentucky, Salmonella typhimurium SL 1344, Staphylococcus aureus ATCC 25923, Staphylococcus carnosus MC1.B, Staphylococcus epidermidis DSMZ 20044 and Streptococcus agalactiae DSMZ 6784 by using the disk diffusion method. RESULTS: It is observed that ethanol extracts of X. hypoxylon has antimicrobial activity against several Gram positive and Gram negative microorganisms tested. As a result of the study, an antimicrobial activity of X. hypoxylon found against most of strains used in the study. CONCLUSION: The results of our study clearly puts forward that X. hypoxylon could have a possible medicinal use. PMID- 28852720 TI - ANTIMICROBIAL ACTIVITY OF GYMNOSPERMA GLUTINOSUM (SPRENG.) LESS. (ASTERACEAE) METHANOL EXTRACTS AGAINST HELICOBACTER PYLORI. AB - BACKGROUND: Prolonged use of antibiotics may lead to the selection of drug resistant bacteria; as a result, efforts are being made to identify new and effective antimicrobial agents, particularly, from medicinal plants, against bacterial infections. Antimicrobial activity of Gymnosperma glutinosum against Helicobacter pylori has not yet been reported. MATERIALS AND METHODS: The antibacterial in vitro effect of Gymnosperma glutinosum methanol leaf extracts against Helicobacter pylori (ATCC 43504) was evaluated in liquid medium by the colorimetric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay and in solid medium by the colony forming units (CFU) method. RESULTS: Methanol extracts significantly (p<0.05) inhibited in vitro H. pylori growth in liquid medium from 24% to 82% at concentrations ranging from 31.25 mg/ml to 500 mg/ml, respectively, and in solid medium the extracts caused significant (p<0.05) 52% and 100% bacterial growth inhibition at concentrations of 250 MUg/mL and 500 MUg/mL, respectively, as compared with untreated control. Methanol vehicle did not affect H. pylori growth. CONCLUSION: The observed antibacterial effect of G. glutinosum extracts may be of benefit as an adjuvant treatment of diseases caused by H. pylori. PMID- 28852721 TI - IN VIVO AND IN VITRO IMMUNOMODULATORY AND ANTI-INFLAMMATORY EFFECTS OF TOTAL FLAVONOIDS OF ASTRAGALUS. AB - BACKGROUND: Astragali Radix has long been used to improve immune function in traditional Chinese medicine. However, its main active components and potential immunomodulatory or anti-inflammatory activities have not been elucidated. In the present study, the immunomodulatory and anti-inflammatory activities of total flavonoids of Astragalus (TFA) isolated from Astragali Radix were evaluated by using in vivo animal models and in vitro cell models. MATERIALS AND METHODS: The in vivo Immunomodulatory and anti-inflammatory activities of TFA were assessed by measuring macrophage phagocytic index, delayed type hypersensitivity, serum hemolysin level and immune organ index in mice, ear edema test in mice, paw edema test in rats, vascular permeability test in mice and granuloma test in rats. The in vitro Immunomodulatory and anti-inflammatory activities of TFA were assessed by examining its effect on cytokine and mediator production in un-stimulated and LPS-stimulated murine RAW 264.7 macrophages. RESULTS: The results of in vivo experiments showed that TFA enhanced macrophage phagocytic index, delayed type hypersensitivity, serum hemolysin level and immune organ index in mice, and attenuated mouse ear edema, rat paw edema, mouse vascular permeability and rat granuloma formation. The results of in vitro experiments showed that TFA stimulated the production of NO and cytokine TNF-alpha, IL-Iotabeta, IL-6 and IFN gamma in un-stimulated RAW 264.7 macrophages, and inhibited the overproduction of these inflammatory mediators in LPS-stimulated RAW 264.7 macrophages in a dose dependent manner without exerting cytotoxicity. CONCLUSION: These results of this study indicate that TFA have potential immunostimulatory and anti-inflammatory effects. PMID- 28852722 TI - PHYTOCHEMICAL, ELEMENTAL AND BIOTECHNOLOGICAL STUDY OF CRYPTOCARYA LATIFOLIA. AB - BACKGROUND: Existing populations of Cryptocarya latifolia (Lauraceae) are rapidly declining as a consequence of their substitutive use for Ocotea bullata. The uncontrolled and excessive removal of the bark and roots of this species has led to the death of many of these plants and may eventually result in its depletion in the natural habitat. MATERIALS AND METHODS: The secondary metabolites from the leaves and fruits of C. latifolia were extracted using solvents of various polarities, isolated using column chromatography and identified using spectroscopic techniques. The in vitro free radical scavenging activity (antioxidant capacity) of selected phytocompounds at varied concentrations was determined by the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. A propagation study of the species was also conducted. RESULTS: The compounds isolated from the plant were the novel compound, alpha-pyrone (5-hexyltetrahydro-2H-pyran-2-one) and known compounds quercetin-3-O-rhamnoside, beta-sitosterol, copaene and nerolidol. The radical scavenging activity of the isolated compounds indicated moderate to good anti-oxidant activity. Treatment of explants with BAP: NAA at 1.0:0.01 mg L-1 produced the highest percentage of shoots (94%) and longest shoot length (8.06 mm). CONCLUSION: This study validates the ethno-medicinal use of the plant and supports the replacement of bark and roots by leaves and fruits for the management and conservation of this declining plant species. The benefits of consuming the fruits are two-fold as they can also contribute to the recommended dietary allowances of most essential elements for the majority of individuals. PMID- 28852723 TI - EVALUATION THE EXPRESSION OF THREE GENES TO EPITHELIAL OVARIAN CANCER RISK IN CHINESE POPULATION. AB - BACKGROUND: Ovarian cancer is associated with poor survival, because patients are diagnosed at an advanced stage of the disease, and in addition, tumors develop chemoresistance, which carries a poor prognosis for the patient. MATERIAL AND METHODS: We hypothesize that high expression of SDF-1, survivin and smac is associated with ovarian cancers development and could be used as a biomarker to identify this disease. The expressions of SDF-1, survivin and smac in normal ovarian (NO) tissue, benign tumor (BT) tissue and epithelial ovarian cancer (EOC) tissue were immunohistochemically analysed. RESULTS: Positive expressions of SDF 1, survivin and smac were significantly higher in EOC tissue than those in NO and BT tissues. SDF-1 expressions were significantly more weaker in advanced ovarian carcinomas (FIGO stage III-IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and SDF-1 positivity (P < 0.05). Survivin expressions were significantly more stronger in advanced ovarian carcinomas (FIGO stage III-IV), and in high grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and surviving positivity (P < 0.05). Smac expressions were significantly more stronger in advanced ovarian carcinomas (FIGO stage III-IV), and in high-grade carcinomas. There was a positive correlation between EOC patients with lymph node metastasis and with ascites and smac positivity (P < 0.05). CONCLUSION: These results indicate that SDF-1, surviving and smac are closely associated with EOC metastasis. PMID- 28852724 TI - ETHNOBOTANICAL AND BIOLOGICAL ACTIVITIES OF Leptadenia pyrotechnica (Forssk.) Decne.: A REVIEW. AB - BACKGROUND: Leptadenia pyrotechnica is traditionally used for treating various diseases. This species holds variety of bioactive constituents that trigger healing properties. The present review was aimed to analyze nutritional, phytochemical and pharmacological activities of L. pyrotechnica. MATERIALS AND METHODS: The present review regarding Leptadenia pyrotechnica (Forssk.) Decne. Is the compilation of data from the previous research works conducted by various scientists across the world. Various published papers, medicinal plant databases, etc were utilized to compile the information. RESULTS: L. pyrotechnica is a wonderful desert plant belongs to the family Asclepiadaceae This plant possesses antifungal, antibacterial, anticancer, antioxidant, wound healing, anthelmintic, antiatheroscloretic, hypolipidemic, antdiabetic and hepatoprotective activities coupled with other multifarious uses. Almost all plant parts are used in the traditional medicinal system to treat various disorders. CONCLUSION: This review includes the substance of different ethnobotanical uses, phytochemistry and exclusive capability of this plant in the field of anti-microbial and human disease activities. PMID- 28852725 TI - SUSTAINABLE DEVELOPMENT OF AMOMUM VILLOSUM: A SYSTEMATIC INVESTIGATION ON THREE DIFFERENT PRODUCTION MODES. AB - BACKGROUND: Amomum Villosum (A. Villosum), called Chunsharen in Chinese, is widely used in treating gastrointestinal disease. Its clinical benefits have been confirmed by both in vitro and in vivo studies. Facing the shortage of wild A. Villosum, artificial cultivating and natural fostering have been practiced in recent years. Therefore, it would be wondered whether the three different types of A. Villosum are comparable or not, particularly the herbal qualities, technological challenges, ecological impacts and economic benefits. MATERIAL AND METHODS: In this study, we combined quality research by using GC-MS, and field investigation to provide a systematic assessment about the three types of A. Villosum from these four aspects. RESULTS: It found that the wild type had low output and was in an endangered situation. The artificial cultivation had larger agriculturing area with higher productivity, but faced the ecological challenges. Lastly, the natural fostering type generated the highest economic benefit and relatively low ecological impact. In addition, the natural fostering type had relatively better quality than the other types. CONCLUSION: Therefore, it suggests that natural fostering can be applied for long-term sustainable development of A. Villosum. PMID- 28852726 TI - PHYTOCHEMISTRY, CYTOTOXICITY AND APOPTOSIS STUDIES OF B-SITOSTEROL-3-O-GLUCOSIDE AND Beta -AMYRIN FROM PRUNUS AFRICANA. AB - BACKGROUND: Prunus africana is used traditionally in many countries for the treatment of cancer and benign prostate hyperplasia. MATERIALS AND METHODS: In this study, compounds from the leaves and bark of this plant were isolated and tested for their cytotoxicity and apoptosis induction in two human cancer cell lines (hepatocellular carcinoma (HepG2) and colorectal carcinoma (Caco-2)) and a non-cancer cell line (embryonic kidney (HEK293)). GC-MS profiling of the extract was also conducted. RESULTS: Three compounds (beta-sitosterol, beta-amyrin and beta-sitosterol-3-O-glucoside) were isolated and the cytotoxic activity of beta amyrin and beta-sitosterol-3-O-glucoside on the HepG2, Caco-2 and HEK293 was determined using the MTT cell viability assay. Both compounds had significant cytotoxic activity towards the Caco-2 cell line with IC50 values of 81 MUg mL-1 and 54 MUg mL-1 for beta-amyrin and beta-sitosterol-3-O-glucoside, respectively while low cytotoxicity was observed on HepG2 cell lines with IC50 values of 206 MUg mL-1 and 251 MUg mL-1 for beta-amyrin and beta-sitosterol-3-O-glucoside, respectively. Apoptosis induction in cells was studied using acridine orange/ethidium bromide dual staining. In both cases, the compounds tested demonstrated selective cytotoxicity towards cancer cells with high apoptosis indices in cells exposed to beta-amyrin. Low IC50 values of 156 MUg mL-1 and 937 MUg mL-1 for beta-amyrin and beta-sitosterol-3-O-glucoside, respectively, were observed in the HEK293 cell line. CONCLUSION: This study reveals that the plant is rich biologically active compounds thereby validating its ethno-medicinal use. PMID- 28852727 TI - METABOLIC EFFECTS OF TULBAGHIA VIOLACEA HARV. IN A DIABETIC MODEL. AB - BACKGROUND: Diabetes mellitus (DM) is a cluster of metabolic diseases with chronic hyperglycemia as a defining feature, associated with long-term organ damage and dysfunction. In this study we examined the effect of Tulbaghia violacea rhizome methanolic extract on blood glucose and lipids in normal and streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Male Wistar rats (250-300g) were injected intraperitoneally (i.p.) with streptozotocin (60mg/kg body weight) to induce diabetes; or provided with distilled water for the control (CON) (3 ml/kg/b.w.) animals and treatment with TVL (60mg/kg.b.w). The rats were divided into 5 groups of 6 animals per group as follows: Non-diabetic control (NDC)-received distilled water (3ml/kg.b.w), Non-diabetic TVL (ND+TVL)-received TVL (60mh/kg b.w), Diabetic control (DC)-received distilled water (3ml/kg.b.w), Diabetic experimental (D+TVL)-received TVL (60mg/kg.b.w), Diabetic experimental (D+M)-received Metformin (250 mg/kg.b.w). All doses were administered daily via oral gavage. RESULTS: TVL-treated animals showed reduced blood glucose, increased plasma insulin, reduced plasma TG, TC, VLDL and increased HDL. Furthermore we found decreased thiobarbituric acid reactive substances (TBARS) and increased superoxide dismutase (SOD) activity and nitric oxide significantly. Regarding renal parameters we found increased blood urea nitrogen (BUN), and improved renal morphology in TVL-treated animals. CONCLUSION: Tulbaghia violacea has a hypoglycaemic effect which could due to its effects on multiple pathways of the hyperglycemic process. Further work is needed to identify the mechanism of its antidiabetic effect. PMID- 28852728 TI - MEDICINAL HERBS USED BY HIV-POSITIVE PEOPLE IN LESOTHO. AB - BACKGROUND: The use of medicinal herbs whose efficacy and toxicities are not known by HIV-positive people in Lesotho is a threat to the effectiveness of antiretroviral treatment. This study explored some medicinal herbs used by HIV positive people in Lesotho and the reasons for their use. METHODS: This was a cross sectional study based on a questionnaire distributed to purposively-sampled HIV-positive people in Leribe and Maseru districts of Lesotho. The participants' socio-demographic and clinical variables were summarized using frequency tables in Stata version 13 statistical software. Data variables for medicinal herbs used, frequency of use, uses by the participants and in the literature, parts of plants used and the method of preparation were also explored. RESULTS: Out of 400 questionnaires distributed to the participants, 389 were returned with data acceptable for analysis. Ages of the participants ranged from 18 to 75 years (Mean=43 + 11.6). Out of the 272 (69.9%) participants who conceded that they had used medicinal herbs at least once, 30 (7.7%) participants used medicinal herbs frequently while 242 (62.2 %) rarely used the herbs. At least 20 plant species belonging to 16 families were reportedly used by the participants. Asteraceae was the most common plant family reportedly used by the participants. Allium sativum and Dicoma anomala, reportedly used by 21.0% and 14.3% respectively, were the most commonly used medicinal herbs in this population. In addition, boosting the immune system and treating gastrointestinal ailments, apparently cited by 32% and 28% participants respectively, were the most commonly reported reasons for using medicinal herbs. CONCLUSION: A considerable proportion (69.9%) of HIV-positive people use medicinal herbs in this population, and 7.7% use them frequently. At least 20 plant species belonging to 16 families were reportedly used by the participants. HIV counselling protocols in Lesotho should emphasize the dangers of using medicinal herbs whose safety and compatibility with antiretroviral drugs is not known. The efficacy and toxicity profiles of the medicinal plants identified in this study need to be investigated. Furthermore, the effects of these plants on antiretroviral treatment outcomes including herb-drug interactions need to be explored. PMID- 28852729 TI - HEXANE EXTRACT OF Dacryodes edulis FRUITS POSSESSES ANTI-DIABETIC AND HYPOLIPIDAEMIC POTENTIALS IN ALLOXAN DIABETES OF RATS. AB - BACKGROUND: The fruit extract of Dacryodes edulis (D. edulis), the African pear or plum, a tree indigenous to the humid tropics has been used for managing wounds, skin diseases, sickle cell anaemia, dysentery and fever in some African nations. In South Eastern Nigeria, 'herbal doctors' include its marshed fruit in decoctions administered to diabetic patients. However no scientific substantiation of their claim and use exist in literature. Hence, the need to evaluate the antidiabetic and hypolipidaemic activity of hexane extracts of D. edulis fruit in alloxanised animal model. MATERIALS AND METHODS: Sub-toxic doses between 400 and 1600mg/kg were orally administered sub-chronically to alloxan induced diabetic rats for 15 days and compared to glibenclamide (2.5mg/kg). The glycaemia levels, body weights, lipid profile, blood urea, creatinine and liver enzyme levels were measured. Basic histology of the pancreatic tissue was also performed to examine the effects on the pancreas as possible mechanistic lead. RESULTS: Oral acute dosing of D. edulis hexane extract decreased blood glucose levels, while sub-chronic treatment of the extract down-regulated significantly hyperglycaemia, total cholesterol, triglycerides, LDL-C, ALT and ALP levels. However, the HDL-C levels increased significantly. Histopathological examination of the pancreatic tissues after sub-chronic treatment showed that glibenclamide and the highest dose of the extract 1600mg/kg restored the afore-damaged pancreatic beta-cell architecture. CONCLUSION: Our findings portend that D. edulis hexane fruit extract possesses hypoglycaemic and hypolipidaemic activities as well as restoration of the pancreatic architecture without any obvious untoward hepatic damages, suggesting that its use in the management of the diabetes may be valid. List of Non-standard abbreviations:D. edulis = dacryode edulis, DEnH = Dacryodes edulis n-hexane fruit extract, B.wt. = Body weight, Per os = Oral administration, NC = normal control, DC =Diabetic control, SC = Standard control, LDL-C = low density lipoprotein cholesterol, HDL-C = High density lipoprotein cholesterol, TG = Triglyceride, TC = Total cholesterol. PMID- 28852730 TI - DIFFERENT CONCENTRATIONS OF SIJUNZI DECOCTION INHIBIT PROLIFERATION AND INDUCE APOPTOSIS OF HUMAN GASTRIC CANCER SGC-7901 SIDE POPULATION. AB - BACKGROUND: Sijunzi Decoction (SD) is a traditional Chinese medicine which is composed of Ginseng, Atractylodes, Poria and Licorice. It is one of the commonly used Chinese traditional medicines that showed anti-gastric cancer activity in clinical studies. Previous evidence demonstrated SD parties (Ginseng, Atractylodes, Poria, Licorice) can inhibit proliferation and induced apoptosis for gastric cancer cell. In order to further investigate the anticancer effect of SD in gastric cancer, we observed the effects of different concentrations of SD on proliferation and apoptosis of Side Population Cells (SP) of human gastric cancer SGC-7901. MATERIALS AND METHODS: SGC-7901 SP and Non- Side Population Cells (NSP) were sorted through flow cytometry; to detect the changes of proliferation of SP and NSP before and after the intervention of serum containing different concentrations of SD using cck-8 method; to detect the changes of cell cycle and apoptosis of SP and NSP before and after the intervention of serum containing different concentrations of SD through flow cytometry; to detect the effects of serum containing different concentrations of SD on apoptosis-related proteins Bax and Bcl-2 of SP and NSP before and after the intervention by western blot. RESULTS: It was found that different concentrations of SD serum treatments inhibited cell proliferation in a time-dependent and concentration-dependent manner. Compared with the control group (normal saline serum treatment), there were increase in G1/G0 phase population of SP and NSP, and decrease in G2/M and S phase population (P<0.05). Meanwhile, we found G1/G0 arrest induced by different concentrations of SD serum which was followed by apoptosis in a time-dependent and concentration-dependent manner. The apoptosis rate of SD serum treatment group was higher than the control group (P<0.05), the apoptosis rate of 48 h treatment was higher than 24 h treatment (P<0.05), and as the SD serum concentration increases, apoptosis rate is higher and higher (P<0.05). The expression of Bax protein of SP and NSP was higher than the control group in a time-dependent and concentration dependent manner. The expression of Bcl-2 protein of SP and NSP was lower than the control group in a time-dependent and concentration- dependent manner. CONCLUSION: With the increase of SD serum concentrations, SD can gradually inhibits the proliferation of SP of SGC-7901 cell lines through G1/G0 phase arrest and followed by apoptosis which involves the up-regulation of Bax and the down-regulation of Bcl-2. List of Abbreviations: (SD) Sijunzi Decoction, (SP) side population, (NSP) non-side population, (Control) normal saline serum group, (L) low concentration SD serum group, (N) normal concentration SD serum group, (H) high concentration SD serum group, (ABCG 2) Adenosine triphosphate Binding Cassette super family G member-2 of transport protein, (Bcl-2) B-cell lymphoma 2, (BAX) Bcl-2 Associated X Protein, (FBS) Fetal bovine serum, (PBS) Phosphate buffer solution, (CCK-8) Cell Counting Kit-8 reagent, (AV) Annexin V-FITC, (PI) Propidium iodide, (EDTA) Ethylene Diamine Tetraacetic Acid, (PMSF) Phenylmethanesulfonyl fluoride, (RIPA) Radio Immunoprecipitation Assay, (PVDF) Poly (vinylidene fluoride), (TBST) Tris buffered saline containing Tween-20. PMID- 28852731 TI - SALVIANOLIC ACID B ALLEVIATING MYOCARDIUM INJURY IN ISCHEMIA REPERFUSION RATS. AB - BACKGROUND: Salvia miltiorrhiza (SM) Bunge is one of the widely-used Chinese medicinal herbs. Salvianolic acid B (Sal B), a bioactive compound isolated from the Chinese herb Radix Salviae Miltiorrhizae, has been reported to exhibit anti inflammatory and anti-oxidantive effects. MATERIAL AND METHOD: To study the cardioprotective effects of salvianolic acid B (Sal B) on acute myocardial ischemia reperfusion (MIR) injury rats, on the basis of this investigation, the possible mechanism of salvianolic acid B was elucidated. Male Sprague- Dawley rats (200-220 g) were randomly divided into five groups: sham-operated, MIR, MIR + Sal B (10 mg/kg/day, orally), MIR + Sal B (20 mg/kg/ day, orally) and MIR + Sal B (30 mg/kg/ day, orally). Before operation, the foregoing groups were pretreated with homologous drug once a day for 7 days, respectively. After twelve hours in MIR, the cardioprotective effects of SPJ were evaluated by infarct size, biochemical values, and the antioxidative and antiapoptotic relative gene expressions. RESULTS: Sal B significantly improved heart function and decreased infarct size; remarkably decreased levels of serum TNF-alpha and IL-Iotabeta levels, increased contents of myocardium antioxidant enzymes activities; western blot results showed that Sal B ameliorate the increased Bax and caspase-3 protins expressions and decreased Bcl-2 proteins expression and ratios of Bcl-2 to Bax. CONCLUSION: In ischemic myocardium, oxidative stress caused the overgeneration and accumulation of reactive oxygen species (ROS), which was central of cardiac ischemic injury. Sal B exerted beneficially cardioprotective effects on myocardial ischemia injury rats, mainly scavenging oxidative stress-triggered overgeneration and accumulation of ROS, alleviating myocardial ischemia injury and cardiac cell death. List of abbreviations: salvianolic acid B (Sal B); myocardial ischemia reperfusion (MIR); reactive oxygen species (ROS); Left ventricular end-diastolic pressure (LVEDP); left ventricular end-diastolic volume (LVEDV); Malondialdehyde (MDA); superoxide dismutase (SOD); catalase (CAT); Glutathione peroxidase (GSH-Px); glutathione reductase (GR). PMID- 28852732 TI - ANTIPROTOZOAL ACTIVITY OF EXTRACTS OF ELAEODENDRON TRICHOTOMUM (CELASTRACEAE). AB - BACKGROUND: Chagas disease, amebiasis, giardiasis and trichomoniasis represent a serious health problem in Latin America. The drugs employed to treat these illnesses produce important side effects and resistant strains have appeared. The present study was aimed to evaluate the antiprotozoal activity of leaves, stem bark and root bark of Elaeodendron trichotomum, a celastraceus, that is used in Mexico as an anti-infective in febrile-type diseases. MATERIALS AND METHODS: Dichloromethane and methanol extracts of leaves, bark and roots of Elaeodendron trichotomum were tested against Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, and Trypanosoma cruzi. A quantitative HPLC analysis of pristimerin and tingenone was performed. RESULTS: The dichloromethane extract of roots was active against E. histolytica, G. lamblia, T. vaginalis, and T. cruzi, at IC50's of 0.80, 0.44, 0.46, and 2.68 MUg/mL, respectively. The HPLC analysis revealed the presence of tingenone (3.84%) and pristimerin (0.14%). CONCLUSIONS: The dichloromethane extract of the roots bark showed significant activity against all screened protozoa. PMID- 28852733 TI - ETHNOBIOLOGICAL SURVEY OF PLANTS AND ANIMALS USED FOR THE TREATMENT OF ACUTE RESPIRATORY INFECTIONS IN CHILDREN OF A TRADITIONAL COMMUNITY IN THE MUNICIPALITY OF BARBALHA, CEARA, BRAZIL. AB - BACKGROUND: The use of natural resources for the treatment of acute respiratory infections in children is a widespread practice within traditional communities, especially by women by being the primary caregivers. This study aimed to perform ethnobiological survey of plants and animals used for the treatment of acute respiratory infections in children of a traditional community in the municipality of Barbalha, Ceara, Brazil. METHODS: It is a descriptive exploratory study with a quantitative approach, developed in Sitio Santo Antonio, in the municipality of Barbalha, Ceara, Brazil. As a tool for data collection, was applied a questionnaire and a semi-structured interview. Data analysis used descriptive statistics (simple and percentage rate) and the Relative Frequency of Citation. RESULTS: The research included a total of 54 informants. In total, there were 38 species cited. According to the Relative Frequency of Citation the following species were the most cited: Ocimum basilicum L. (0.59), Eucalyptus globulus Labili (0.59), Plectranthus amboinicus (L.) Spreng (0.42), Hyptis suaveolens (L.) Poit. (0.24), Allium aescalonicum L. (0.22) and Mentha arvensis L. (0.18). Among the symptoms mentioned by the research subjects to treat the acute respiratory infections in childhood, there were: fever; cough; coughing with secretions; sore throat; hoarseness; tiredness; nasal congestion. CONCLUSIONS: It is important the knowledge about the usefulness of natural resources as alternative practices in diseases treatment, seeking to rescue popular knowledge used in the traditional community and fomenting the need to consider cultural aspects in the full practice to children's health care. PMID- 28852734 TI - ANTI-INFLAMMATORY ACTIVITY OF PLATYCODIN D ON ALCOHOL-INDUCED FATTY LIVER RATS VIA TLR4-MYD88-NF-kappaB SIGNAL PATH. AB - BACKGROUND: The current study was designed to evaluate the effect of Platycodin D (PD), triterpenoid saponins extracted from the roots of Platycodon grandiflorum (PG) on alcohol-induced fatty liver (AFL) and investigate the possible mechanism. METHODS AND MATERIALS: A rat model was set up by feeding ethanol and fish oil to experimental rats, which then were treated with PD of 10, 20, 30 mg/kg body weight/day for 4 weeks, respectively, whereafter, liver function enzymes, endotoxin of serum and liver lipid were assayed by biochemical methods, cytokines, histochemistry of hepatic tissue, the protein expression of CD14 and TLR4, the mRNA expression of MD-2, MyD 88 and TRAF-6 were assayed. RESULTS: Treatment with PD on AFL rats significantly decreased the levels of serum ALT, AST and TBIL, coefficient of liver index and the hepatic tissue contents of TG, additionally and dramatically decreased serum endotoxin levels, down-regulated MD 2 and CD14 levels, as well as the mRNA expression of TLR4, MyD88 and TRAF-6, accordingly suppressed NF-kappaB: p65 as well as endotoxin-mediated inflammatory factors such as TNF-alpha and IL-6. CONCLUSIONS: Treatment with PD effectively protects against AFL through anti-inflammatory and anti-endotoxic process, and the confirmed mechanism is that PD treatment ameliorate alcoholic-induced liver injury mainly via TLR4-MyD88-NF-K: B signal path in AFL rat. List of Abbreviations: AFL: alcoholic-induced fatty liver, CD14: cluster of differentiation 14, LPS: lipopolysaccharide, LBP: lipopolysaccharide-binding protein, TLR4: toll-like receptor 4, MD-2: molecule myeloid differential protein 2, MyD 88: myeloid differentiation primary response protein 88, TRAF-6: TNF receptor associated factor-6, NF-kappaB: nuclear transcription factor kappa B, IL 6: interleukin-6, TNF-alpha: tumor necrosis factor-alpha, PG: Platycodon grandiflorum, PD: Platycodin D. PMID- 28852736 TI - EFFECT OF HARVEST DATE AND STALK SECTION ON SELECTED STRENGTH CHARACTERISTICS OF TURKISH OREGANO (Origanum onites L). AB - BACKGROUND: The time required to harvest plant crops is important to the plant properties. It is affected by design of the harvest equipment and the desire for high-quality products with low energy usage. MATERIALS AND METHODS: Strength characteristics of Origanum onites L., an important medicinal aromatic plant, harvested on 2, 9, 16 and 23 July, 2012-2014 (H1, H2, H3 and H4, respectively) were measured at the bottom and top sections of the stalk. Measurements included maximum force, bio-yield force, shearing force, bending stress, shearing stress, shearing energy, and shearing deformation. RESULTS: The highest maximum force (35.17 N) was at H4 on the bottom section, and the lowest was at H1 on the top. Maximum values for bio-yield force, shearing force, and bending stress were at H4 on the bottom section, and corresponding minimum values were at H1 on the top section. Shearing stress decreased at successive harvest dates for both stalk sections. The minimum shearing energy was at H4, (0.13 J and 0.06 J for bottom and top, respectively). Strength measurements for bottom sections of the stalk were greater than those for top sections. CONCLUSION: When reduced harvesting force is needed because of harvester design or harvest procedures, harvesting near the top of the stalk is recommended. PMID- 28852735 TI - INHIBITORY EFFECT OF LYCOPENE AGAINST THE GROWTH OF HUMAN GASTRIC CANCER CELLS. AB - BACKGROUND: The aim of this study was to investigate the anti-proliferative effect of Lycopene on HGC-27 cells. MATERIALS AND METHODS: HGC-27 cells were treated with varying concentration lycopene for 24, 48, 72 h. The cell growth inhibition was analyzed by MTT. Western blotting was used to indicate changes in the levels of LC3-I, LC3-II, ERK (extracellular signal-regulated protein kinase) and phosphorylation-ERK (p-ERK). RESULTS: Lycopene displayed antiproliferative activity in HGC-27 cell lines. Western blotting showed that Lycopene significantly enhanced LC3-I, p-ERK proteins expression. In gastric cancer nude mice model, lycopene treatment significantly decreased tumour weight. These findings indicated that lycopene treatment induces the anti-proliferation of HGC 27 cells. CONCLUSION: Lycopene treatment inhibited HGC-27 cells growth by activating ERK. PMID- 28852737 TI - PROTECTIVE EFFECTS OF ETHYL ACETATE EXTRACTION FROM GASTRODIA ELATA BLUME ON BLOOD-BRAIN BARRIER IN FOCAL CEREBRAL ISCHEMIA REPERFUSION. AB - BACKGROUND: Damage of the blood brain barrier (BBB) during the process of cerebral ischemic injury is a key factor which influences the therapeutic efficacy to the cerebral ischemic injury. The present study was designed to verify the mechanisms underlying the protective effects of the ethyl acetate (EtOAc) extraction from Gastrodia elata Blume (GEB) on the BBB by developing a model of cerebral ischemia-reperfusion in rats. MATERIAL AND METHODS: MCAO/R model in rats was developed through a thread embolism method. The neurological scales, the moisture and the evans blue (EB) contents of brains were detected. Meanwhile, the release of nitric oxide (NO) and activities of NO synthase (NOS) in brain tissues were measured. Western blotting analyses were also performed to assess the protein expressions of AQP-4, Occludin and Claudin-5 in brain tissue. RESULTS: After rats were pretreated with different concentrations of EtOAc extractions from GEB, the neurologic scores, the EB contents in the brain tissues and the moisture of the brains were significantly decreased. Meanwhile, the release of NO, the activities of nNOS and iNOS were notably inhibited. Furthemore, the protein expression of AQP-4 was markedly decreased, but the protein expressions of -5 and Occludin were significantly increased. CONCLUSION: the EtOAc extracts of GEB may decrease the permeability of BBB when focal cerebral ischemia occurs. The inhibition of the NOS pathways, the attenuation of the protein expression of AQP-4 and the enhancement of the expressions of the tight junction proteins may contribute to the protective effects of the EtOAc extracts from GEB on BBB. PMID- 28852738 TI - KAEMPFEROL, A FLAVONOID COMPOUND FROM GYNURA MEDICA INDUCED APOPTOSIS AND GROWTH INHIBITION IN MCF-7 BREAST CANCER CELL. AB - BACKGROUND: Kaempferol, a natural flavonoid, has been shown to induce cancer cell apoptosis and cell growth inhibition in several tumors. Previously we have conducted a full investigation on the chemical constituents of Gynura medica, kaempferol and its glycosides are the major constituents of G. medica. Here we investigated the growth inhibition and apoptosis induction effect of kaempferol extracted from G. medica. MATERIALS AND METHODS: The inhibition effects of kaempferol were evaluated by MTS assay and soft agar colony formation assay. Fluorescence staining and western blotting were be used to study the apoptosis. The structure was identified by 1H- NMR), 13C-NMR and ESI-MS analyses. RESULTS: Our results showed that kaempferol's inhibition of MCF-7 breast cancer cell growth may through inducing apoptosis and downregulation of Bcl2 expression. CONCLUSION: Kaempferol is a promising cancer preventive and therapeutic agent for breast cancer. List of non-standard abbreviations: MTS: 3-(4,5-dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, HPLC: High performance liquid chromatography, NMR: Nuclear Magnetic Resonance, ESI-MS Electrospray Ionization Mass Spectral, PARP: Poly ADP-ribose polymerase. PMID- 28852739 TI - ANTIOXIDANT AND ANTIFUNGAL ACTIVITY OF SELECTED MEDICINAL PLANT EXTRACTS AGAINST PHYTOPATHOGENIC FUNGI. AB - BACKGROUND: Medicinal plants are used by many ethnic groups as a source of medicine for the treatment of various ailments in both humans and domestic animals. These plants produce secondary metabolites that have antimicrobial properties, thus screening of medicinal plants provide another alternative for producing chemical fungicides that are relatively non-toxic and cost-effective. MATERIALS AND METHODS: Leaf extracts of selected South African plant species (Bucida buceras, Breonadia salicina, Harpephyllum caffrum, Olinia ventosa, Vangueria infausta and Xylotheca kraussiana) were investigated for activity against selected phytopathogenic fungi (Aspergillus niger, Aspergillus parasiticus, Colletotricum gloeosporioides, Penicillium janthinellum, P. expansum, Trichoderma harzianum and Fusarium oxysporum). These plant fungal pathogens causes major economic losses in fruit industry such as blue rot on nectaries and postharvest disease in citrus. Plant species were selected from 600 evaluated inter alia, against two animal fungal pathogens (Candida albicans and Cryptococcus neoformans). Antioxidant activity of the selected plant extracts were investigated using a qualitative assay (2, 2-diphenyl-1-picrylhydrazyl (DPPH)). Bioautography assay was used to determine the number of antifungal compounds in plant extracts. RESULTS: All plant extracts were active against the selected plant phytopathogenic fungi. Moreover, Bucida buceras had the best antifungal activity against four of the fungi, with minimum inhibitory concentration (MIC) values as low as 0.02 mg/ml and 0.08 mg/ml against P. expansum, P. janthinellum, T. harzianum and F. oxysporum. The plant extracts of five plant species did not possess strong antioxidant activity. However, methanol extract of X. kraussiana was the most active radical scavenger in the DPPH assay amongst the six medicinal plants screened. No antifungal compounds were observed in some of the plant extracts with good antifungal activity as shown in the microdilution assay, indicating possible synergism between the separated metabolites. CONCLUSION: The results showed that acetone was the best extractant. Furthermore, our findings also confirm the traditional use of Breonadia salicina and demonstrate the potential value of developing biopesticides from plants. PMID- 28852741 TI - Editorial: Come back when you've finished your homework! PMID- 28852740 TI - INVASIVE ALIEN PLANT SPECIES USED FOR THE TREATMENT OF VARIOUS DISEASES IN LIMPOPO PROVINCE, SOUTH AFRICA. AB - BACKGROUND: Invasive alien plant species (IAPs) are plants that have migrated from one geographical region to non-native region either intentional or unintentional. The general view of IAPs in environment is regarded as destructive to the ecosystem and they pose threat to native vegetation and species. However, some of these IAPS are utilized by local inhabitants as a substitute for scarce indigenous plants. The aim of the study is to conduct ethnobotanical survey on medicinal usage of invasive plant species in Waterberg District, Limpopo Province, South Africa. MATERIALS AND METHODS: An ethnobotanical survey on invasive plant species was conducted to distinguish species used for the treatment of various ailments in the Waterberg, District in the area dominated by Bapedi traditional healers. About thirty Bapedi traditional healers (30) were randomly selected via the snowball method. A guided field work by traditional healers and a semi-structured questionnaire was used to gather information from the traditional healers. The questionnaire was designed to gather information on the local name of plants, plant parts used and methods of preparation which is administered by the traditional healers. RESULTS: The study revealed that Schinus molle L., Catharanthus roseus (L.), Datura stramonium L., Opuntia stricta (Haw.) Haw., Opuntia ficus- indica, Sambucus canadensis L., Ricinus communis L., Melia azedarch L., Argemone ochroleuca and Eriobotrya japonica are used for treatment of various diseases such as chest complaint, blood purification, asthma, hypertension and infertility. The most plant parts that were used are 57.6% leaves, followed by 33.3% roots, and whole plant, seeds and bark at 3% each. Noticeably, most of these plants are cultivated (38%), followed by 28% that are common to the study area, 20% abundant, 12% wild, and 3% occasionally. Schinus molle is the most frequently used plant species for the treatment of various ailments in the study area. National Environmental Management Biodiversity Act (NEMBA) (10/2004) and Conservation of Agricultural Resource Act (CARA) were consulted to confirm the invaders status. Only eight plants (60%) are regulated by CARA (10/2004). Of 10 IAPs, 80% (8 species) are listed in both NEMBA and CARA legislation. Only 20% (2 species) are listed in NEMBA alone. CONCLUSION: Invasive alien plants are utilized by communities to combat various ailments in humans and these plants can help to reduce pressure on heavily harvested indigenous plant. PMID- 28852742 TI - Attachment and growth of human osteoblasts on different biomaterial surfaces. AB - OBJECTIVES: To prove the biocompatibility of biomaterials applied in biomedical devices, in vitro testing is crucial to render a material fit for medical application. The material of choice for dental implants is commercially pure titanium (cp-Ti), while other materials such as zirconia and polyetheretherketone (PEEK) are considered highly promising due to their functional and esthetic properties. The aim of this study was to determine whether PEEK with defined mean surface roughness and composition could achieve results equal to titanium or zirconia. MATERIALS AND METHODS: Disks measuring 14 mm in diameter and 1 mm in thickness made from cp-Ti, yttria-stabilized zirconia (Y-TZP), and filled PEEK with a smooth surface finish were used for cell culture experiments. Human fetal osteoblasts (hFOB) were cultured in vitro on each material to observe changes after 1, 3, and 7 days regarding cell viability and lactate dehydrogenase (LDH) release. Additionally, mRNA expression of proliferative factors PCNA and Ki67 and cellular adhesion (vinculin mRNA expression and immunofluorescence staining) were analyzed after 3 days in the culture. RESULTS: In hFOB cultures, adhesion and viability were decreased on PEEK platelets, while LDH release remained stable. No significant difference was observed in cp-Ti and Y-TZP when compared to the control. CONCLUSIONS: The performance of cp-Ti and Y-TZP was equal to the control in all tests. It seems that highly polished PEEK in this particular composition cannot be recommended for osseointegrated implant applications due to decreased osteoblast attachment. Further investigations are recommended, especially in surface structures optimized for osseointegration. PMID- 28852743 TI - Load bearing capacity, fracture mode, and wear performance of digitally veneered full-ceramic single crowns. AB - OBJECTIVES: Computer-aided technologies can help to minimize clinical complications of zirconia-based restorations such as veneering porcelain fractures. The aim of this study was to evaluate different veneering approaches for zirconia single crowns regarding contact wear, fracture strength, and failure mode. METHODS: Six different types of computer-aided design (CAD) crowns were manufactured and conventionally cemented on 10 metal dies each: three groups with a zirconia framework and a CAD/CAM-fabricated veneering cap ("digital veneering system": DVS, CAD-on, Infix CAD), zirconia-based crowns with pressed veneering caps (Infix Press), zirconia framework containing the dentin layer with only the incisal enamel material added (dentin-core), and conventional substructure with powder buildup veneering porcelain (layering technique). All specimens were submitted to artificial aging (120,000 mechanical cycles, 50 N load, 0.7-mm sliding movement, 320 thermocycles). After contact wear was measured with a laser scanning system, fracture resistance and failure mode were examined using a universal testing machine and a scanning electron microscope. Statistical analysis was performed at a significance level of 5%. RESULTS: No statistical difference was revealed regarding the contact wear of the restorations (P = 0.171; ANOVA). No significant difference was found regarding the fracture resistance of the crowns (P = 0.112; ANOVA). Failure analysis revealed three different failure patterns: cohesive veneering fracture, adhesive delamination, and total fracture, with a characteristic distribution between the groups. SIGNIFICANCE: All tested specimens survived artificial aging and exhibited clinically acceptable wear resistance and fracture resistance. Digital veneering techniques offer a promising, time- and cost-effective manufacturing process for all-ceramic restorations and may usefully complement the digital workflow. PMID- 28852744 TI - Antagonist wear by polished zirconia crowns. AB - AIM: The aim of this in vivo study was to measure antagonist wear caused by polished monolithic posterior zirconia crowns over a 24-month period using the intraoral digital impression (IDI) technique. MATERIALS AND METHODS: Thirteen zirconia crowns were placed in nine patients. The crowns and adjacent teeth were captured using an intraoral scanner (Lava C.O.S.). The corresponding antagonist teeth and the respective neighboring teeth were also scanned. Scanning was performed immediately after the restoration (baseline) as well as 12 and 24 months after crown placement. Geomagic Qualify software was used to superimpose the follow-up data sets onto the corresponding baseline data set, identify wear sites, and measure maximum vertical height loss in each individual wear site. Overall antagonist wear was then determined as the mean of wear rates measured in all of the individual antagonist units. In addition, wear rates in enamel and ceramic antagonists were analyzed as part of the scope of this study. RESULTS: The maximum mean wear with standard deviation (SD) in the overall sample with a total of nine patients, 13 antagonist units, and 98 evaluable wear sites was 86 +/- 23 um at 12 months, and 103 +/- 39 um at 24 months. The maximum mean wear in the enamel antagonist subgroup was 87 +/- 41 um at 12 months, and 115 +/- 71 um at 24 months; and in the ceramic antagonist subgroup 107 +/- 22 um at 12 months, and 120 +/- 27 um at 24 months. CONCLUSIONS: The wear rates determined in this study are comparable to those of existing studies. The IDI technique of wear analysis can be carried out in a practical manner and produces useful results. PMID- 28852745 TI - The importance of the cement spacer for proper crown seating Erratum. AB - Marginal integrity is important for the longevity of a restoration. An increase in the marginal discrepancy after cementation contributes adversely to the longevity of a restoration. In the past, the preferred method to overcome this discrepancy was to create internal space for the cement by using a number of coats of a die-spacing material. In the digital age, however, this method is no longer the only option. Currently, an amount of die spacer is engineered into the computer program and forms part of the milling process. The present study attempted to identify the optimal setting of the Spacer parameter that a) is necessary for the complete cementation of a Cerec milled all-ceramic crown, and b) does not compromise the strength of the crown postcementation. PMID- 28852746 TI - Fracture resistance of single-rooted pulpless teeth using hybrid CAD/CAM blocks for post and core restoration. AB - PURPOSE: The purpose of this study was to determine whether there is a significant difference in the fracture strengths of hybrid computer-aided design/computer-aided manufacturing (CAD/CAM) blocks and fiber posts for post and core restorations in both ferrule and nonferrule pulpless mandibular canines. MATERIALS AND METHOD: Forty extracted human mandibular canines were divided into ferrule and nonferrule groups and restored with hybrid CAD/CAM blocks using either the CAD/CAM system or fiber posts (control). Thus, there were four subgroups of ten specimens each. A 45-degree oblique load was applied with a crosshead of 0.5 mm/min, and the fracture loads were recorded. The mode of fracture was evaluated using an optical microscope at 3* magnification, and the data were tabulated and statistically analyzed using the Mann-Whitney U test and the t test, respectively, for the existence of significant difference at a 0.05 significance level. RESULTS: No statistically significant difference was found between the fracture strength under oblique loading when using hybrid CAD/CAM blocks and fiber posts in both ferrule and nonferrule groups. The failure mode distribution of the nonferrule group presented no unfavorable failures, whereas failures in the ferrule groups were spread out between the Favorable and Unfavorable groups. CONCLUSIONS: The results show that hybrid CAD/CAM blocks can be considered as an alternative restorative system in post and core restorations. Further basic and clinical research should be conducted to support the improvement of this system. PMID- 28852747 TI - Establishing a suitable surface roughness for lithium disilicate implant abutments under laboratory conditions: a morphologic SEM and profilometric pilot study. AB - The increasing use of dental implants rather than fixed cantilever bridges for standard dental restorations has led to the development of multiple materials in this field. The goal in modern dentistry in recent years has been to achieve results in implantology that match the natural dentition in esthetics and function. Constant efforts have been made to achieve a perfect emergence profile, and to individualize the surrounding periimplant soft tissue. Powder-free digital scanning is now possible, which allows for the computer-assisted design/computer assisted manufacturing (CAD/CAM) of ready-to-fit customized immediate implant abutments in various appropriate materials. Since lithium disilicate can be used as a hybrid abutment for restorations, many patients today can more easily afford a customized solution. Apart from the esthetic advantages in the transition area of the crown, the microscopic characterization of the emergence profile is also relevant. Numerous research studies have shown that the optimal surface of titanium abutments is neither too rough nor too smooth. Following these studies, various methods have been used to establish the same proven roughness for zirconia and lithium disilicate surfaces. The present study looks at different polishing methods and glaze firing processes. PMID- 28852748 TI - Up to 27-years clinical long-term results of chairside Cerec 1 CAD/CAM inlays and onlays. AB - The objective of this follow-up study was to examine the performance of Cerec 1 inlays and onlays in terms of clinical quality over a mean functional period of 25 years. Out of 200 Cerec 1 inlays and onlays placed consecutively in 108 patients in a private practice between 1989 and early 1991, 141 restorations could be reevaluated in 65 patients after up to 26 years and 10 months. All ceramic inlays and onlays had been generated chairside using the Cerec 1 method, and had been seated adhesively using bonding composite. At follow-up examinations, the restorations were classified based on modified United States Public Health Service (USPHS) criteria. According to the Kaplan-Meier analysis, the success rate of Cerec 1 inlays and onlays dropped to 87.5% after up to 27 years. In 19 patients, a total of 23 failures were found. Of these failures, 78% were caused by either ceramic fractures (65%) or tooth fractures (13%). The reasons for the remaining failures were caries (18%), and endodontic problems (4%). Three-surface restorations had a significantly higher failure risk (P < 0.05) than one-, two-, and four-surface restorations, and restorations in premolars presented a lower failure risk than those in molars. The survival probability of 87.5% after up to 27 years of clinical service of Cerec 1 computer assisted design/computer-assisted manufacturing (CAD/CAM) restorations made of Vita Mark I feldspathic ceramic proved to be highly acceptable in private practice. PMID- 28852749 TI - Static and dynamic magnetic properties of the ferromagnetic coordination polymer [Co(NCS)2(py)2]n. AB - [Co(NCS)2(py)2]n (py = pyridine) is composed of ferromagnetic chains of Co(ii) cations connected by double NCS bridges. The chains are irregular because of two crystallographically inequivalent Co(ii) cations. The coordination polyhedron of the Co(ii) cations is a distorted octahedron built from two N and two S atoms of four equatorial NCS anions and two apical N atoms of the pyridine ligands. Magnetic and specific heat studies show that the compound undergoes a phase transition at 3.7 K to a ferromagnetic state. The determined magnetic interactions, intrachain (J/kB = 28 K) and interchain (zJ'/kB = 0.5 K), confirm the quasi 1D Ising magnetic character of [Co(NCS)2(py)2]n. Using AC magnetic susceptibility measurements the energy barriers for magnetization reversal of different relaxation processes were determined including those of the individual chains. By means of high field-high frequency ESR study the magnetic excitations were observed and explained in the frame of the Ising model in agreement with the results of the magnetic study. Ab initio calculations confirm the high magnetic anisotropy of the system and allow determination of the direction of the easy axis. The broken symmetry DFT calculations support the ferromagnetic intrachain interactions. The energetic relations relevant for relaxations are discussed. It is concluded that the magnetic model of [Co(NCS)2(py)2]n is not a pure Ising but the transversal exchange plays a role. PMID- 28852750 TI - Nucleophilicity and electrophilicity of the C(sp3)-H bond: methane and ethane binary complexes with iodine. AB - The occurrence of stable van der Waals complexes of small saturated hydrocarbons with molecular iodine is assessed in order to investigate the ability of sp3 hybridized carbon atoms to act as either electron donors or electron acceptors depending on the ligand orientation. Systematic ab initio potential energy surface exploration of methane-I2 and ethane-I2 model dimers was followed by thorough characterization. Despite modest evidence of whole-adduct polarization, the resulting interactions feature a dominant dispersive character. The noncovalent interaction descriptors employed comprise NBO, AIM, NCI, and source function analyses. The relevance of bonding C-H orbitals in donor-acceptor interactions involving saturated hydrocarbons is highlighted. The results here presented corroborate existing literature regarding the electrophilicity of the aliphatic C-H group, and also indicate that the nucleophilic character of C(sp3) shares a dependence on electron withdrawing/donating substituents similar to that extensively documented for sigma-holes. Indeed, the sole difference between the two, aside from the nucleophilicity/electrophilicity switch, seems to lie in their directionality. Nucleophilic sites on C(sp3) are not limited to the outermost region of C along a covalent bond axis, but can also engage electrophiles via the bifurcation plane of a CH2 unit. Since valence electrons on these carbon atoms are engaged in covalent bonds, they can only interact with polarizing ligands via the electron density accumulation/depletion in the four corresponding sigma orbitals. These, however, do not seem to interact individually with the accompanying electrophile. Source function and NCI results suggest instead that nucleophilic carbon centres participate in the noncovalent bond themselves by drawing electron density from their shared electron pairs. PMID- 28852751 TI - Sensing the framework state and guest molecules in MIL-53(Al) via the electron paramagnetic resonance spectrum of VIV dopant ions. AB - X-ray diffraction (XRD) and electron paramagnetic resonance spectroscopy (EPR) were combined to study the structural transformations induced by temperature, pressure and air humidity of the "breathing" metal-organic framework (MOF) MIL 53(Al), doped with paramagnetic VIV ions, after activation. The correlation between in situ XRD and thermogravimetric analysis measurements showed that upon heating this MOF in air, starting from ambient temperature and pressure, the narrow pore framework first dehydrates and after that makes the transition to a large pore state (lp). The EPR spectra of VIV[double bond, length as m-dash]O molecular ions, replacing Al-OH in the structure, also allow to distinguish the as synthesized, hydrated (np-h) and dehydrated narrow pore (np-d), and lp states of MIL-53(Al). A careful analysis of EPR spectra recorded at microwave frequencies between 9.5 and 275 GHz demonstrates that all VIV[double bond, length as m-dash]O in the np-d and lp states are equivalent, whereas in the np-h state (at least two) slightly different VIV[double bond, length as m-dash]O sites exist. Moreover, the lp MIL-53(Al) framework is accessible to oxygen, leading to a notable broadening of the VIV[double bond, length as m-dash]O EPR spectrum at pressures of a few mbar, while such effect is absent for the np-h and np-d states for pressures up to 1 bar. PMID- 28852752 TI - Cross-sectional structures of a molecular monolayer nanotube explored with SAXS: evidence for the parallel orientation of the headgroups in asymmetric bolaamphiphiles. AB - We investigated the cross-sectional structure of a molecular monolayer nanotube self-assembled from asymmetric bolaamphiphiles having two different hydrophilic headgroups. Small-angle X-ray scattering measurements clarified that the glucose and amino headgroups form the exterior and interior surfaces of the nanotube, respectively. PMID- 28852753 TI - An unsymmetrical non-fullerene acceptor: synthesis via direct heteroarylation, self-assembly, and utility as a low energy absorber in organic photovoltaic cells. AB - This study reports on the design and synthesis of an unsymmetrical pi-conjugated organic molecule composed of perylene diimide, thienyl diketopyrrolopyrrole, and indoloquinoxaline pieced together using direct heteroarylation. This material demonstrates unprecedented response in the thin-film upon post-deposition solvent vapor annealing, resulting in dramatic red-shifts in optical absorption. Such changes were utilized to enhance photocurrent generation in P3HT based organic solar cells. PMID- 28852754 TI - Reversible structural switching of a metal-organic framework by photoirradiation. AB - A photoresponsive metal organic framework material undergoes switching of its pore volume and sorption capacity. UV irradiation of the crystals causes cyclisation within the bis-thienylcyclopentene bridging ligands, thereby altering the node positions relative to one another along the Zn-L-Zn linkages. Incorporation of conformational flexibility into the dicarboxylic acid co-ligands facilitates the change in the framework geometry enforced by photocyclisation. PMID- 28852755 TI - Intelligent identification of multi-level nanopore signatures for accurate detection of cancer biomarkers. AB - To achieve accurate detection of cancer biomarkers with nanopore sensors, the precise recognition of multi-level current blockage events (signature) is a pivotal problem. However, it remains rather a challenge to identify the multi level current blockages of target biomarkers in nanopore experiments, especially for the nanopore analysis of serum samples. In this work, we combined a modified DBSCAN (Density-Based Spatial Clustering of Applications with Noise) algorithm with the Viterbi training algorithm of the hidden Markov model (HMM) to achieve intelligent retrieval of multi-level current signatures from microRNA in serum samples. The results showed that the developed intelligent data analysis method is highly efficient for processing the large-scale nanopore data, which facilitates future application of nanopores to the clinical detection of cancer biomarkers. PMID- 28852756 TI - Inhomogeneous-collapse driven micelle-vesicle transition of amphiphilic block copolymers. AB - Understanding the morphological transition dynamics related to the hydrophilic hydrophobic interface has been a challenge due to the lack of an effective evaluation method. Herein, nuclear magnetic resonance spectroscopy was employed to study the morphological transition related chain collapse of poly(N,N' diethylaminoethylmethacrylate)-b-poly(N-isopropylacrylamide) (PDEAEMA133-b PNIPA322) and poly(N,N'-dimethylaminoethylmethacrylate)-b-poly(N isopropylacrylamide) (PDMAEMA95-b-PNIPA228) and was proved to be a powerful technique in morphological transition mechanism studies once combined with dynamic light scattering and transmission electron microscopy. Unlike the cooperative coil collapse of two blocks in the PDMAEMA95-b-PNIPA228 alkaline solution upon heating which induces the assembly of a nanostructure (~200 nm) with a hydrophobic core containing both collapsed PDMAEMA and PNIPA segments and a hydrophilic surface part consisting of un-shrunk PDMAEMA and PNIPA segments, PDEAEMA133-b-PNIPA322 with a low-temperature core-shell micelle structure showed a micelle-vesicle transition due to temperature-induced inhomogeneous-collapse of PNIPA. The PNIPA segments in the shell sequentially collapse outside (starting at the core-shell interface), accompanied by a gradual decrease in micelle size. Above the critical temperature, the residual hydrophilic PNIPA segments become too short to stabilize the micelle structure, the micelles then transform into vesicles of a slightly larger size, instead of micelle aggregation and precipitation as normally expected. PMID- 28852757 TI - Nickel-catalyzed methylation of aryl halides/tosylates with methyl tosylate. AB - This work describes the cross-electrophile methylation of aryl bromides and aryl tosylates with methyl tosylate. The mild reaction conditions allow effective methylation of a wide set of heteroaryl electrophiles and dimethylation of dibromoarenes. PMID- 28852758 TI - Robust synthesis of green fuels from biomass-derived ethyl esters over a hierarchically core/shell-structured ZSM-5@(Co/SiO2) catalyst. AB - A novel bifunctional ZSM-5@(Co/SiO2) material with a hierarchical core/shell structure was successfully prepared through a simple chemoselective interaction between the crystal surface silica species of zeolite and the external Co2+ source in basic media, which served as an excellent catalyst in the synthesis of green fuels from biomass-derived ethyl esters. PMID- 28852759 TI - Confined methanol within InOF-1: CO2 capture enhancement. AB - The CO2 capture performance of InOF-1 was optimised by confining small amounts of MeOH within its micropores (MeOH@InOF-1). In comparison with fully activated InOF 1, MeOH@InOF-1 shows a 1.30 and 4.88-fold increase in CO2 capture capacity for kinetic and static isothermal CO2 adsorption experiments respectively. Density functional theory calculations coupled with forcefield based-Monte Carlo simulations revealed that such an enhancement is assigned to an increase of the degree of confinement felt by the CO2 molecules resulting from the formation of a lump at the vicinity of the MU2-OH groups since MeOH strongly interacts with these adsorption sites and is thus highly localized in this region. PMID- 28852760 TI - An Aptamer Bio-barCode (ABC) assay using SPR, RNase H, and probes with RNA and gold-nanorods for anti-cancer drug screening. AB - With modifications to an ultra-sensitive bio-barcode (BBC) assay, we have developed a next generation aptamer-based bio-barcode (ABC) assay to detect cytochrome-c (Cyto-c), a cell death marker released from cancer cells, for anti cancer drug screening. An aptamer is a short single-stranded DNA selected from a synthetic DNA library that is capable of binding to its target with high affinity and specificity based on its unique DNA sequence and 3D structure after folding. Similar to the BBC assay, Cyto-c is captured by a micro-magnetic particle (MMP) coated with capturing antibodies (Ab) and an aptamer specifically against Cyto-c to form sandwich structures ([MMP-Ab]-[Cyto-c]-[Aptamer]). After washing and melting, our aptamers, acting as a DNA bio-barcode, are released from the sandwiches and hybridized with the probes specially designed for RNase H for surface plasmon resonance (SPR) sensing. In an aptamer-probe duplex, RNase H digests the RNA in the probe and releases the intact aptamer for another round of hybridization and digestion. With signal enhancement effects from gold-nanorods (Au-NRs) on probes for SPR sensing, the detection limit was found to be 1 nM for the aptamer and 80 pM for Cyto-c. Without the time-consuming DNA amplification steps by PCR, the detection process of this new ABC assay can be completed within three hours. As a proof-of-concept, phenylarsine oxide was found to be a potent agent to kill liver cancer cells with multi-drug resistance at the nano-molar level. This approach thus provides a fast, sensitive and robust tool for anti cancer drug screening. PMID- 28852761 TI - Controlling ligand binding for tunable and switchable catalysis: cation-modulated hemilability in pincer-crown ether ligands. AB - Methods for in situ reversible control over ligand binding processes at transition metal complexes can enable advances in switchable and tunable catalysis. After a brief overview of different approaches to controlling ligand binding, this Perspective details the development of "pincer-crown ether" ligands that contain a rigid pincer backbone and a hemilabile aza-crown ether unit that enables cation-modulated hemilability. Applications of pincer-crown ether complexes in small molecule activation and catalysis are discussed, culminating in a set of design principles for ligands capable of cation-modulated ligand binding. PMID- 28852762 TI - Sibling rivalry: intrinsic luminescence from two xanthene dye monoanions, resorufin and fluorescein, provides evidence for excited-state proton transfer in the latter. AB - While the emission spectrum of fluorescein monoanions isolated in vacuo displays a broad and featureless band, that of resorufin, also belonging to the xanthene family, has a sharp band maximum, clear vibronic structure, and experiences a small Stokes shift. Excited-state proton transfer in fluorescein can account for the differences. PMID- 28852763 TI - [The R1 resection in visceral oncological surgery]. PMID- 28852764 TI - Erratum to: Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy. PMID- 28852765 TI - ESNR 2017. PMID- 28852766 TI - [Erratum to: Methamphetamine : Epidemiology, clinical importance and sequelae of abuse]. PMID- 28852770 TI - Slowly growing mass on the left shoulder. Pilomatricoma. PMID- 28852767 TI - European Society of Paediatric Radiology abdominal imaging task force recommendations in paediatric uroradiology, part IX: Imaging in anorectal and cloacal malformation, imaging in childhood ovarian torsion, and efforts in standardising paediatric uroradiology terminology. AB - At the occasion of the European Society of Paediatric Radiology (ESPR) annual meeting 2015 in Graz, Austria, the newly termed ESPR abdominal (gastrointestinal and genitourinary) imaging task force set out to complete the suggestions for paediatric urogenital imaging and procedural recommendations. Some of the last missing topics were addressed and proposals on imaging of children with anorectal and cloacal malformations and suspected ovarian torsion were issued after intense discussions and a consensus finding process that considered all evidence. Additionally, the terminology was adapted to fit new developments introducing the term pelvicalyceal dilatation/distension (PCD) instead of the sometimes misunderstood hydronephrosis. The present state of paediatric urogenital radiology was discussed in a dedicated minisymposium, including an attempt to adapt terminology to create a standardised glossary. PMID- 28852771 TI - Early severe anemia as the first sign of cystic fibrosis. PMID- 28852772 TI - [Telemedicine-requirements and concepts for change]. PMID- 28852773 TI - [Cardiac arrest in a fitness trainer with apical hypertrophic cardiomyopathy associated with cor triatriatum sinister]. AB - We report on a 49-year-old fitness trainer, who was admitted to our hospital after cardiac arrest due to ventricular fibrillation. Return of spontaneous circulation was achieved after immediate cardiopulmonary resuscitation. Coronary angiography could exclude coronary artery disease. Echocardiography demonstrated the presence of apical hypertrophic cardiomyopathy, associated with cor triatriatum sinister. Cardiac magnetic resonance imaging additionally showed marked myocardial fibrosis. The patient underwent placement of an implantable cardioverter-defibrillator and was subsequently discharged for rehabilitation in good condition. PMID- 28852775 TI - Natural Agents-Mediated Targeting of Histone Deacetylases. AB - In the past few years, basic and clinical scientists have witnessed landmark achievements in many research projects, such as those conducted by the US National Institutes of Health Roadmap Epigenomics Mapping Consortium, the International Human Epigenome Consortium, The Cancer Genome Atlas Network and the International Cancer Genome Consortium, which have provided near-complete resolution of epigenetic landscape in different diseases. Furthermore, genome sequencing of tumors has provided compelling evidence related to frequent existence of mutations in readers, erasers and writers of epigenome in different cancers. Histone acetylation is an intricate mechanism modulated by two opposing sets of enzymes and deeply studied as a key biological phenomenon in 1964 by Vincent Allfrey and colleagues. The research group suggested that this protein modification contributed substantially in transcriptional regulation. Subsequently, histone deacetylases (HDACs), histone acetyltransferases and acetyl Lys-binding proteins were identified as transcriptional mediators, which further deepened our comprehension regarding biochemical modifications. Overwhelmingly increasing high-impact research is improving our understanding of this molecularly controlled mechanism; moreover, quantification and identification of lysine acetylation by mass spectrometry has added new layers of information. We partition this multi-component review into how both activity and expression of HDAC are targeted using natural agents. We also set spotlight on how oncogenic fusion proteins tactfully utilize HDAC-associated nano-machinery to modulate expression of different genes and how HDAC inhibitors regulate TRAIL-induced apoptosis in cancer cells. HDAC inhibitors have been reported to upregulate expression of TRAIL receptors and protect TRAIL from proteasomal degradation. Deeper understanding of HDAC biology will be useful for stratification and selection of patients who are responders, non-responders and poor-responders for HDACi therapy, and for the rational design of combination studies using HDACi. PMID- 28852774 TI - Mechanisms of ciliary targeting: entering importins and Rabs. AB - Primary cilium is a rod-like plasma membrane protrusion that plays important roles in sensing the cellular environment and initiating corresponding signaling pathways. The sensory functions of the cilium critically depend on the unique enrichment of ciliary residents, which is maintained by the ciliary diffusion barrier. It is still unclear how ciliary cargoes specifically enter the diffusion barrier and accumulate within the cilium. In this review, the organization and trafficking mechanism of the cilium are compared to those of the nucleus, which are much better understood at the moment. Though the cilium differs significantly from the nucleus in terms of molecular and cellular functions, analogous themes and principles in the membrane organization and cargo trafficking are notable between them. Therefore, knowledge in the nuclear trafficking can likely shed light on our understanding of the ciliary trafficking. Here, with a focus on membrane cargoes in mammalian cells, we briefly review various ciliary trafficking pathways from the Golgi to the periciliary membrane. Models for the subsequent import translocation across the diffusion barrier and the enrichment of cargoes within the ciliary membrane are discussed in detail. Based on recent discoveries, we propose a Rab-importin-based model in an attempt to accommodate various observations on ciliary targeting. PMID- 28852777 TI - [Clostridium difficile-associated deaths from 2013-2016 in Munich and Nuremberg : Reporting behavior and patient characteristics]. AB - BACKGROUND: A number of risk factors for C. difficile infection (CDI) are described in the literature, in particular an antibiotic therapy 4-6 weeks before disease, an age of >65 years, immunosuppression and living in a long-term care facility. Increasing incidence rates have been reported for Germany. CDI is the fourth most common nosocomial infection with 6.4%. AIM: Due to the amendment of the Infection Protection Act of 01.05.2016, the proportion of all deaths that are C. difficile-associated deaths should be investigated to determine the extent to which the obligation to report is fulfilled in the case of a severe CDI. The epidemiological situation in Munich and Nuremberg should also be investigated and the characteristics of the deceased should be analyzed. MATERIAL AND METHODS: A review of all death certificates for the period from 1 January 2013 to 30 June 2016 was carried out according to defined inclusion criteria for clostridia infection. All data were anonymized, standardized and statistically evaluated. RESULTS: Almost every hundredth death is associated with C. difficile. Medical and outbreak reports are very poor and do not reflect the real situation. The age of the deceased and increased factors for the acquisition of a CDI correspond to the literature. The collected data from both cities show a good congruence. CONCLUSION: For the first time, data from the health authorities can be submitted on the proportion of all deaths that are C. difficile-associated deaths, reporting behavior and patient characteristics in cases of severe CDI. This is a serious disease, especially for older people with regard to the existence of risk factors, and its frequency and effects are significantly underestimated. PMID- 28852776 TI - Malvidin attenuates pain and inflammation in rats with osteoarthritis by suppressing NF-kappaB signaling pathway. AB - OBJECTIVE: Malvidin is one of the most widespread anthocyanidins which exhibits significant antioxidant and anti-inflammatory activity. The aim of this paper is to investigate the effects of Malvidin on osteoarthritis (OA). MATERIALS AND METHODS: We created an animal model of OA using Wistar rats administered by monosodium iodoacetate (MIA). Effects of Malvidin on hyperalgesia were evaluated by paw pressure tests and compression threshold test. Articular chondrocytes were isolated from the OA rats to detect the apoptotic chondrocytes using senescence associated beta-galactosidase (SA-beta-gal) staining kit. The expression levels of pro-inflammatory cytokines and matrix metalloproteinase (MMPs) were assessed by western blot and qPCR. Luciferase assay was used to determine the impact of Malvidin on nuclear factor-kappa B (NF-kappaB) pathway. RESULTS: Malvidin treatment exhibited significant pain-relieving effects in OA rats and decreased the expression level of apoptotic marker SA-beta-gal in chondrocytes. We found that the upregulated expressions of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), and MMPs induced by MIA in cartilage tissues were significantly reversed by Malvidin. Furthermore, Malvidin inhibited NF-kappaB pathway via an NF-kappaB inhibitor (IkappaBalpha)-independent manner through suppressing p65 nuclear transportation in vitro. CONCLUSIONS: Our findings suggest that Malvidin significantly attenuates the OA-induced pain and inflammation by inhibiting NF-kappaB signaling pathway and suppressing pro inflammatory cytokine expression and chondrocyte apoptosis. PMID- 28852780 TI - Optimization of total vaporization solid-phase microextraction (TV-SPME) for the determination of lipid profiles of Phormia regina, a forensically important blow fly species. AB - A new method has been developed for the determination of fatty acids, sterols, and other lipids which naturally occur within pupae of the blow fly Phormia regina. The method relies upon liquid extraction in non-polar solvent, followed by derivatization using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) w/ 1% trimethylchlorsilane (TMCS) carried out inside the sample vial. The analysis is facilitated by total vaporization solid-phase microextraction (TV-SPME), with gas chromatography-mass spectrometry (GC-MS) serving as the instrumentation for analysis. The TV-SPME delivery technique is approximately a factor of five more sensitive than traditional liquid injection, which may alleviate the need for rotary evaporation, reconstitution, collection of high performance liquid chromatography fractions, and many of the other pre-concentration steps that are commonplace in the current literature. Furthermore, the ability to derivatize the liquid extract in a single easy step while increasing sensitivity represents an improvement over current derivatization methods. The most common lipids identified in fly pupae were various saturated and unsaturated fatty acids ranging from lauric acid (12:0) to arachinoic acid (20:4), as well as cholesterol. The concentrations of myristic acid (14:0), palmitelaidic acid (16:2), and palmitoleic acid (16:1) were the most reliable indicators of the age of the pupae. Graphical abstract Blow fly pupae were extracted prior to emerging as adults. The extracts were analyzed via total vaporization solid-phase microextraction (TV-SPME), revealing a complex mixture of lipids that could be associated with the age of the insect. This information may assist in determining a post-mortum interval (PMI) in a death investigation. PMID- 28852778 TI - Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that have common molecular and pathogenic characteristics, such as aberrant accumulation and ubiquitylation of TDP-43; however, the mechanisms that drive this process remain poorly understood. We have recently identified CCNF mutations in familial and sporadic ALS and FTD patients. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase (SCFcyclin F) complex that is responsible for ubiquitylating proteins for degradation by the ubiquitin-proteasome system. In this study, we examined the ALS/FTD-causing p.Ser621Gly (p.S621G) mutation in cyclin F and its effect upon downstream Lys48 specific ubiquitylation in transfected Neuro-2A and SH-SY5Y cells. Expression of mutant cyclin FS621G caused increased Lys48-specific ubiquitylation of proteins in neuronal cells compared to cyclin FWT. Proteomic analysis of immunoprecipitated Lys48-ubiquitylated proteins from mutant cyclin FS621G expressing cells identified proteins that clustered within the autophagy pathway, including sequestosome-1 (p62/SQSTM1), heat shock proteins, and chaperonin complex components. Examination of autophagy markers p62, LC3, and lysosome associated membrane protein 2 (Lamp2) in cells expressing mutant cyclin FS621G revealed defects in the autophagy pathway specifically resulting in impairment in autophagosomal-lysosome fusion. This finding highlights a potential mechanism by which cyclin F interacts with p62, the receptor responsible for transporting ubiquitylated substrates for autophagic degradation. These findings demonstrate that ALS/FTD-causing mutant cyclin FS621G disrupts Lys48-specific ubiquitylation, leading to accumulation of substrates and defects in the autophagic machinery. This study also demonstrates that a single missense mutation in cyclin F causes hyper-ubiquitylation of proteins that can indirectly impair the autophagy degradation pathway, which is implicated in ALS pathogenesis. PMID- 28852781 TI - Spectroscopic imaging of biomaterials and biological systems with FTIR microscopy or with quantum cascade lasers. AB - Spectroscopic imaging of biomaterials and biological systems has received increased interest within the last decade because of its potential to aid in the detection of disease using biomaterials/biopsy samples and to probe the states of live cells in a label-free manner. The factors behind this increased attention include the availability of improved infrared microscopes and systems that do not require the use of a synchrotron as a light source, as well as the decreasing costs of these systems. This article highlights the current technical challenges and future directions of mid-infrared spectroscopic imaging within this field. Specifically, these are improvements in spatial resolution and spectral quality through the use of novel added lenses and computational algorithms, as well as quantum cascade laser imaging systems, which offer advantages over traditional Fourier transform infrared systems with respect to the speed of acquisition and field of view. Overcoming these challenges will push forward spectroscopic imaging as a viable tool for disease diagnostics and medical research. Graphical abstract Absorbance images of a biopsy obtained using an FTIR imaging microscope with and without an added lens, and also using a QCL microscope with high-NA objective. PMID- 28852782 TI - Ultrasensitive SERS immunoassay based on diatom biosilica for detection of interleukins in blood plasma. AB - An ultrasensitive surface-enhanced Raman scattering (SERS) immunoassay based on diatom biosilica with integrated gold nanoparticles (AuNPs) for the detection of interleukin 8 (IL-8) in blood plasma has been developed. The SERS sensing originates from unique features of the diatom frustules, which are capable of enhancing the localized surface-plasmon resonance of metal nanostructures. The SERS immune tags ware fabricated by functionalizing 70-nm Au nanoparticles with DTNB (i.e., 5,5'-dithiobis(2-nitrobenzoic acid)), which acted as a Raman reporter molecule, as well as the specific antibodies. These DTNB-labeled immune-AuNPs can form a sandwich structure with IL-8 antigens (infection marker) and the antibodies immobilized on the biosilica material. Our method showed an improved IL-8 detection limit in comparison to standard ELISA methods. The current detection limit for IL-8 using a conventional ELISA test is about 15.6 pg mL-1. The lower detection limit for IL-8 in blood plasma was estimated to be 6.2 pg mL 1. To the best of our knowledge, this is the first report on the recognition of IL-8 in human samples using a SERS-based method. This method clearly possesses high sensitivity to clinically relevant interleukin concentrations in body fluids. The average relative standard deviation of this method is less than 8%, which is sufficient for analytical analysis and comparable to those of classical ELISA methods. This SERS immunoassay also exhibits high biological specificity for the detection of IL-8 antigens. The established SERS immunoassay offers a valuable platform for the ultrasensitive and highly specific detection of immune biomarkers in a clinical setting for medical diagnostics. Graphical Abstract The SERS-based immunoassay based on naturally generated photonic biosilica for the detection of interleukin 8 (IL-8) in human plasma samples. PMID- 28852783 TI - Determination of fluoroquinolones in fish tissues, biological fluids, and environmental waters by liquid chromatography tandem mass spectrometry. AB - This work describes the optimization, validation, and application in real samples of accurate and precise analytical methods to determine ten fluoroquinolones (FQs) (norfloxacin, enoxacin, pefloxacin, ofloxacin, levofloxacin, ciprofloxacin, danofloxacin, lomefloxacin, enrofloxacin, and sparfloxacin) in different environmental matrices, such as water (estuarine, seawater, and wastewater treatment plant effluent), fish tissues (muscle and liver), and fish biofluids (plasma and bile). The analysis step performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was fully optimized to improve the separation and detection steps. The extraction of analytes from fish tissues was accomplished using focused ultrasound solid-liquid extraction using methanol/acetic acid (95:5 v/v) as extractant. The preconcentration and clean-up steps were optimized in terms of extraction efficiency and cleanliness and the best strategy for each matrix was selected: (i) Oasis HLB for seawater and muscle, (ii) liquid-liquid extraction combined with Oasis HLB for the lipid-rich liver, (iii) the combination of Evolute-WAX and Oasis HLB for estuarine water and wastewater treatment plant effluent, and (iv) molecular imprinted polymers for biofluids. The methods afforded satisfactory apparent recoveries (80-126%) and repeatability (RSD < 15%), except for sparfloxacin, which showed a lack of correction with the available isotopically labeled surrogates ([2H8]-ciprofloxacin and [2H5] enrofloxacin). Ciprofloxacin, norfloxacin, and ofloxacin were detected in both water and fish liver samples from the Biscay Coast at concentrations up to 278 ng/L and 4 ng/g, respectively. To the best of our knowledge, this work is one of the few analyzing up to ten FQs and in so many fish tissues and biofluids. Graphical abstract Determination of fluoroquinolones in different environmental matrices, such as water (estuarine, seawater, and wastewater treatment plant effluent), fish tissues (muscle and liver), and fish biofluids (plasma and bile). PMID- 28852784 TI - [Orthopedic surgery with limited resources after mass disasters and during armed conflicts : First international guidelines for the management of limb injuries and the experience of Doctors Without Borders]. AB - Disasters and armed conflicts are often the unfortunate basis for aid projects run by Doctors Without Borders/Medecins Sans Frontieres (MSF). The nature of war and disasters means that surgery is an integral part of this medical emergency aid. In these situations, resources are usually limited. As a result, surgical work in these contexts differs significantly from the daily routine of a surgeon working in a highly resourced hospital. The principles of surgery do not change but surgeons must adapt their tactical approach to the changed context otherwise there is a high risk of failing to improve the health of patients and potentially jeopardizing their prospects for recovery. Every experienced war surgeon has learned new skills the hard way. The Field Guide to Manage Limb Injury in Disaster and Conflict has been written to help new surgeons who may face the challenges of disaster and war surgery and to avoid unnecessary suffering for patients ( https://icrc.aoeducation.org ). Under the guidance of the International Committee of the Red Cross (ICRC), with participation of the World Health Organization (WHO), financed by the AO Foundation, and featuring the experiences of experts from different organizations (amongst them MSF), the book details techniques and guidelines for surgery in low resource settings. The following article provides a short summary of some of the surgical challenges when working with limited resources and reflects on a few specific recommendations for so-called war surgery. PMID- 28852786 TI - [The scaphoid fracture : Between pseudoarthrosis and possible anatomical variance]. AB - The diagnosis of a scaphoid fracture, especially in the differentiation of a fresh fracture, the nonunion or a possible anatomical norm variant, can be difficult. We report on two patients who presented with stress-related, radiocarpal pain in our department. In both cases, radiological abnormalities were observed in the scaphoideal area, with a scaphoideum bipartitum on both sides, as well as an approximately 25-year-old scaphoid pseudarthrosis. PMID- 28852785 TI - Management of oral bisphosphonates treatment by rheumatologists and determinants of therapeutic changes: a case-vignette-based study. AB - : Using case vignette methodology, this study shows that only 4% of patients are maintained on oral bisphosphonates over 5 years, and prescribers switch or stop the treatment in 20-30% of cases at each visit. There are few determinants of these changes. More information on appropriate follow-up could help in patients' management. INTRODUCTION: Persistence to oral bisphosphonates, the most commonly prescribed anti-osteoporotic treatments, is low. The aim of this study was to evaluate the role of rheumatologists on the treatment patterns, and to assess the determinants of treatment changes. METHODS: We used the methodology of case vignettes with the participation of 142 rheumatologists. Three baseline clinical vignettes were presented: (1) the physician was asked to indicate the most appropriate period to schedule the next visit over 5 years, (2) the physician was tested about parameters for follow-up (including traps), and (3) various results (both clinical, biological, densitometric, and radiological) were given by random and analyzed as determinants of treatment changes. RESULTS: The study allowed assessment of 426 virtual clinical cases. Clinical examinations, patient's height, inquiries about falls, and adherence to treatment were deemed necessary in > 90% of cases. Bone mineral density was measured in 22, 40, and 71% of cases at 2, 3, and 5 years, respectively. Dental follow-up was recommended in less than 25% of cases. Only 4.2% of patients were maintained on the same treatment at 5 years, and a change of treatment (stop or switch) occurs in 20-30% of cases at each visit. Significant determinants were adherence to treatment, serum C terminal crosslinking telopeptide of type 1 collagen (CTX) value, change in patient's height, and the occurrence of an incident vertebral fracture. CONCLUSION: Our study shows that maintenance of oral bisphosphonate in postmenopausal women managed by rheumatologists is low; there are few determinants of these changes and more information on appropriate follow-up could help in patients' management. PMID- 28852787 TI - Exploring the binding of two potent anticancer drugs bosutinib and imatinib mesylate with bovine serum albumin: spectroscopic and molecular dynamic simulation studies. AB - Bosutinib (BST) and imatinib mesylate (IMT) are tyrosine kinase inhibitors (TKIs). In view of the importance of these inhibitors in cancer treatment, we investigated the mechanism of interaction between BST/IMT and bovine serum albumin (BSA) using various spectroscopic and molecular docking methods. Fluorescence studies indicated that BST/IMT interacted with BSA without affecting the microenvironment around the residue Trp213 of BSA. The quenching mechanism associated with the BST-BSA and IMT-BSA interactions was determined by performing fluorescence measurements at different temperatures. These results suggested that BST and IMT quenched the fluorescence intensity of BSA through static and dynamic processes, respectively, which was confirmed by time-resolved fluorescence measurements. Evaluation of the thermodynamic parameters ?H degrees , ?S degrees , and ?G degrees suggested that hydrophobic and electrostatic interactions played significant roles in the BST-BSA interaction, while IMT-BSA was stabilized by hydrophobic forces. Competitive experimental results revealed that the primary binding sites for BST and IMT on BSA were sites II and I, respectively. This was supported by the results of molecular docking and dynamic simulation studies. The change in the secondary structure of BSA upon binding with BST/IMT was investigated by 3D fluorescence, absorption, and CD spectroscopic studies. In addition, the influences of beta-cyclodextrin and metal ions (Cu2+ and Zn2+) on the binding affinities of BST and IMT to BSA were examined. Graphical abstract Binding of BST and IMT in BSA at site II and site I respectively. PMID- 28852788 TI - Development and application of a sampling method for the determination of reactive halogen species in volcanic gas emissions. AB - Volcanoes release large amounts of reactive trace gases including sulfur and halogen-containing species into the atmosphere. The knowledge of halogen chemistry in volcanic plumes can deliver information about subsurface processes and is relevant for the understanding of the impact of volcanoes on atmospheric chemistry. In this study, a gas diffusion denuder sampling method using 1,3,5 trimethoxybenzene (1,3,5-TMB)-coated glass tubes for the in situ derivatization of reactive halogen species (RHS) was characterized by a series of laboratory experiments. The coating proved to be applicable to collect selectively gaseous bromine species with oxidation states (OS) of +1 or 0 (such as Br2, BrCl, HOBr, BrO, and BrONO2) while being unreactive to HBr (OS -1). The reaction of 1,3,5-TMB with reactive bromine species forms 1-bromo-2,4,6-TMB-other halogens give corresponding derivatives. Solvent elution of the derivatives followed by analysis with GC-MS results in absolute detection limits of a few nanograms for Br2, Cl2, and I2. In 2015, the technique was applied on volcanic gas plumes at Mt. Etna (Italy) measuring reactive bromine mixing ratios between 0.8 and 7.0 ppbv. Total bromine mixing ratios between 4.7 and 27.5 ppbv were derived from alkaline trap samples, simultaneously taken by a Raschig tube and analyzed with IC and ICP-MS. This leads to the first results of the reactive bromine contribution to total bromine in volcanic emissions, spanning over a range between 12% (+/-1) and 36% (+/-2). Our finding is in an agreement with previous model studies, which imply values <44% for plume ages <1 min, which is consistent with the assumed plume age at the sampling sites. Graphical abstract Illustration of the measurement procedure for the determination of reactive halogen species in volcanic plumes. PMID- 28852789 TI - A multi-center prospective cohort study of patient transfers from the intensive care unit to the hospital ward. AB - PURPOSE: To provide a 360-degree description of ICU-to-ward transfers. METHODS: Prospective cohort study of 451 adults transferred from a medical-surgical ICU to a hospital ward in 10 Canadian hospitals July 2014-January 2016. Transfer processes documented in the medical record. Patient (or delegate) and provider (ICU/ward physician/nurse) perspectives solicited by survey 24-72 h after transfer. RESULTS: Medical records (100%) and survey responses (ICU physicians 80%, ICU nurses-80%, ward physicians-46%, ward nurses-64%, patients-74%) were available for most transfers. The median time from initiation to completion of transfer was 25 h (IQR 6-52). ICU physicians and nurses reported communicating with counterparts via telephone (78 and 75%) when transfer was requested (82 and 24%) or accepted (31 and 59%) and providing more elements of clinical information than ward physicians (mean 4.7 vs. 3.9, p < 0.001) and nurses (5.0 vs. 4.4, p < 0.001) reported receiving. Patients were more likely to report satisfaction with the transfer when they received more information (OR 1.32, 95% CI 1.18-1.48), had their questions addressed (OR 3.96, 95% CI 1.33-11.84), met the ward physician prior to transfer (OR 4.61, 95% CI 2.90-7.33), and were assessed by a nurse within 1 h of ward arrival (OR 4.70, 95% CI 2.29-9.66). Recommendations for improvement included having a documented care plan travel with the patient (all stakeholders), standardized face-to-face handover (physicians), avoiding transfers at shift change (nurses) and informing patients about pending transfers in advance (patients). CONCLUSIONS: ICU-to-ward transfers are characterized by failures of patient flow and communication; experienced differently by patients, ICU/ward physicians and nurses, with distinct suggestions for improvement. PMID- 28852790 TI - Informed consent checklists for midurethral slings: a common-sense approach. AB - INTRODUCTION AND HYPOTHESIS: Following the US Food and Drug Administration's (FDA's) warning about the use of transvaginal mesh to treat pelvic organ prolapse (POP) and the use of single-incision slings to treat incontinence, the number of lawsuits for medical negligence regarding the use of any polypropylene mesh in the vagina has increased tremendously. METHODS: This same FDA document did not question the use of polypropylene midurethral slings and polypropylene for sacrocolpopexies. Surprisingly, despite all the evidence and recommendations from respected international scientific societies, we are constantly being called upon by our patients to defend the use of midurethral slings. The most common reasons for the new rash of medicolegal proceedings involving midurethral slings has to do with "breach of duties" resulting from undisclosed postoperative complications on the consent form and/or the lack of information in the medical records confirming that all possible alternative treatment options were presented to and discussed with the patient. RESULTS: One response to these lawsuits involves the addition of preoperative checklists when performing informed consent with patients electing surgical correction of stress urinary incontinence (SUI). CONCLUSIONS: This clinical opinion provides an expert clinician's perspectives and legal point of view on this controversial topic and discusses the role of a preoperative checklist supplementary to the standard informed consent form. PMID- 28852791 TI - Hamstring autografts are associated with a high rate of contamination in anterior cruciate ligament reconstruction. AB - PURPOSE: To quantitatively evaluate the rate, type, and level of contamination of anterior cruciate ligament (ACL) hamstring autografts after harvesting and preparation or dropping onto the operating room (OR) floor. METHODS: Two hamstring autograft specimens were prospectively retrieved from each graft in a consecutive series of 50 patients undergoing primary isolated ACL reconstruction (100 specimens total). One specimen was retrieved immediately after harvesting and dropped onto the OR floor (dropped group). The other was retrieved just after graft implantation and before fixation (control group). Each specimen was incubated for aerobic and anaerobic growth, and the number of colony-forming units (CFU)/g was measured. Patients' clinical course was monitored for signs of surgical site infection (SSI). RESULTS: The control and dropped groups had positive culture rates of 11/50 (22%) and 16/50 (32%), respectively, with no significant difference between groups (n.s.). The most common organism in the control group was Staphylococcus epidermidis (45.5%) followed by S. aureus (36.4%). In the dropped group, the most common organism was S. epidermidis (31.3%) followed by Bacillus species (25%). The median (range) CFU/g among positive specimens in the dropped and control groups was 65 (8-150) and 10 (2 60), respectively (P = 0.0003). No patient developed postoperative SSI. CONCLUSION: Intraoperative hamstring autograft contamination rates were high. Hence, routine prophylactic decontamination of all hamstring autografts after harvesting and preparation and before implantation is recommended. LEVEL OF EVIDENCE: Controlled laboratory study. PMID- 28852793 TI - [Cartilage repair of the knee joint]. AB - BACKGROUND: Cartilage defects around the knee joint frequently occur in the region of the medial femoral condyle and the retropatellar cartilage surface. The distinction between local cartilage defects and large area degenerative cartilage lesions is very important for both prognosis and surgical therapy. The size and position of the lesion, the underlying pathomechanism and the age of the patient are very important factors which should be considered in the therapy algorithm for optimal cartilage defect restoration. Important cofactors such as stability, long leg axis and muscle balance should be taken into account. AIM: Current procedures for cartilage repair of the knee joint and their results are summarized in this article. In addition, the necessity of precise and comprehensive preoperative clinical and radiological diagnostics is displayed to be able to treat co-pathologies in order to enable a successful repair of the cartilage defect. RESULTS AND CONCLUSIONS: Preoperative planning of cartilage repair techniques usually includes x-ray images and a magnetic resonance imaging (MRI) examination. If MRI is not available, an arthro-computed tomography could be an alternative. Modern and routinely used procedures for cartilage repair at the knee joint are microfracture, autologous matrix-induced chondrogenesis, autologous chondrocyte transplantation, matrix-induced autologous chondrocyte implantation and osteochondral transplantation. Successful surgical cartilage repair surgeries require a correct and individualized indication, addressing of copathologies and a standardized rehabilitation that is adapted to the surgical procedure. Evidence-based criteria for an exact time point for the return to sports according to individually operative cartilage repair techniques currently do not exist. PMID- 28852792 TI - Human pancreatic neuro-insular network in health and fatty infiltration. AB - AIMS/HYPOTHESIS: Identification of a pancreatic neuro-insular network in mice suggests that a similar integration of islets and nerves may be present in the human pancreas. To characterise the neuro-insular network and the intra pancreatic ganglia in a clinically related setting, we examined human pancreases in health and with fatty infiltration via 3-dimensional (3D) histology and compared the human pancreatic microenvironment with its counterpart in mice. METHODS: Human pancreatic specimens from individuals with normal BMI, high BMI (>= 25) and type 2 diabetes were used to investigate the neuro-insular network. Transparent specimens were prepared by tissue clearing for transmitted light and deep-tissue fluorescence imaging to simultaneously visualise infiltrated adipocytes, islets and neurovascular networks. RESULTS: High-definition images of human islets reveal that both the sympathetic and parasympathetic nerves enter the islet core and reside in the immediate microenvironment of islet cells. Around the islets, the neuro-insular network is visualised with 3D histology to identify the intra-pancreatic ganglia (peri-lobular and intra-parenchymal ganglia) and the islet-ganglionic association. In humans, but not in mice, pancreatic fatty infiltration (BMI dependent) features adipocytes infiltrating into the parenchyma and accumulating in the peri-lobular space, in which the peri lobular ganglia also reside. We identified the formation of adipose-ganglionic complexes in the peri-lobular space and enlargement of ganglia around adipocytes. In the specimen from the individual with type 2 diabetes, an increase in the number of nerve projections from the intra-parenchymal ganglia is associated with severe fatty infiltration. CONCLUSIONS/INTERPRETATION: We present new perspectives of human pancreas and islet innervation via 3D histology. Our results strongly suggest that fatty infiltration in the human pancreas creates a neurotrophic microenvironment and promotes remodelling of pancreatic innervation. PMID- 28852794 TI - Microbiology neutralization of zearalenone using Lactococcus lactis and Bifidobacterium sp. AB - The aim of the study was to neutralize zearalenone by lactic acid bacteria (LAB) such as Lactococcus lactis and Bifidobacterium sp. and investigate the mechanism of zearalenone (ZEA) binding. Neutralization of ZEA by LAB was confirmed by identification of binding kinetics and spectroscopic studies such as Fourier transform infrared spectroscopy (FT-IR) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The obtained results showed that the kinetic process of zearalenone binding to L. lactis is not homogeneous but is expressed with an initial rapid stage with about 90% of ZEA biosorption and with a much slower second step. In case of Bifidobacterium sp., the neutralization process is homogeneous; the main stage can be described with about 88% of ZEA biosorption. MALDI-TOF-MS measurements and FTIR analysis confirmed the uptake of zearalenone molecules by bacterial species. Moreover, the assessment of dead and live lactic acid bacteria cells after zearalenone treatment was performed using fluorescence microscopy. Graphical abstract Microbiology neutralization of zearalenone using Lactococcus lactis and Bifidobacterium sp. was confirmed by identification of binding kinetics and spectroscopic studies such as FT-IR spectroscopy and MALDI-TOF-MS spectrometry. The mechanism of ZEA binding was also investigated. PMID- 28852795 TI - [Meniscal lesion. A pre-osteoarthritic condition of the knee joint]. AB - BACKGROUND: A close relationship between meniscal damage and articular cartilage exist. Likewise, (partial) meniscectomy may lead to the development of osteoarthritis (OA). OBJECTIVES: With a special emphasis on therapeutic consequences for orthopaedic surgeons, the structural and functional relationship between meniscal tears/extrusion and cartilage loss, and/or the effect of meniscectomy or meniscal repair on the development of OA, are emphasized. MATERIALS AND METHODS: A selective literature review with implementation of own research findings. RESULTS: The close topographical and functional interplay between the menisci and the tibiofemoral cartilage is the basis for the clinically important relationship between meniscal damage and cartilage degeneration. In particular, due to its close connection to tibiofemoral OA, a degenerative meniscal lesion represents a pre-osteoarthritic condition. Meniscus extrusion is also often associated with tibiofemoral OA. Even large cartilage defects can cause meniscus lesions. Partial meniscectomy is strongly associated with the incidence and risk of progression of OA. Clinical results are particularly problematic after partial resection of the lateral meniscus. Although the use of arthroscopic partial resection for degenerative meniscal lesions has been controversially discussed, no long-term studies are available. A large number of studies emphasize the medium-term value of meniscus reconstruction compared to partial meniscus resection. Combined meniscus and cartilage damage are complex cases, and the value of a simultaneous therapy remains unclear. CONCLUSIONS: Preserving the meniscus is the first step towards cartilage repair. Randomized and controlled studies will provide better information on the long-term outcomes of meniscal resection and repair with regard to OA development. PMID- 28852796 TI - Phthalocyanine-BODIPY dye: synthesis, characterization, and utilization for pattern recognition of CYFRA 21-1 in whole blood samples. AB - Phthalocyanine-BODIPY dye (BODIPY = boron dipyrromethene) was synthesized, fully characterized, and used for molecular recognition of CYFRA 21-1, a lung cancer biomarker, from whole blood samples. Thin films of three magnesium oxides ((MgO) n , where n = 8, 9, or 10)) were deposited on a paper substrate, and they were immersed in a solution of phthalocyanine-BODIPY dye (1.17 * 10-3 mol/L) for the design of stochastic sensors. Limits of determination of picograms per milliliter magnitude order were recorded for the proposed stochastic sensors. CYFRA 21-1 was reliably identified and determined with recoveries higher than 95% and RSD lower than 1% in whole blood samples. PMID- 28852797 TI - Biomarkers in acute kidney injury: that's all the story? : Discussion on "Have biomarkers failed in acute kidney injury?" PMID- 28852798 TI - Enantioselective separation and determination of miconazole in rat plasma by chiral LC-MS/MS: application in a stereoselective pharmacokinetic study. AB - Miconazole has one chiral center, and consists of two enantiomers. In this study, a novel chiral liquid chromatography-tandem mass spectrometry method was developed for enantioselective separation and determination of miconazole in rat plasma. For the first time, the enantioselective pharmacokinetics of miconazole was investigated by the current method. Firstly, attempts were made to separate the enantiomers in reversed-phase mode with a mobile phase that was mass spectrometry compatible. Baseline separation was achieved on a Chiralpak IC column with a mobile phase composed of acetonitrile and aqueous ammonium hydrogen carbonate (5 mM; 80:20, v/v). Data were acquired in multiple reaction monitoring mode with positive electrospray ionization by triple-quadrupole mass spectrometry. Then, overall method validation regarding the linearity, accuracy, precision, extraction recovery, matrix effect, and stability of each enantiomer was performed, and acceptable results were obtained for all of these. Finally, the method developed was applied in an enantioselective pharmacokinetic study of miconazole enantiomers in rats after oral administration of racemic miconazole at doses of 5 and 10 mg/kg. The results demonstrated that (-)-(R)-miconazole had a higher concentration than (+)-(S)-miconazole in plasma, with a ratio of 1.3-1.7 for both doses. This is the first experimental evidence of enantioselective behavior of miconazole in vivo, and provides a reference for clinical practice and encourages further research into miconazole enantioselective metabolism and drug interactions. Graphical Abstract A stereoselective pharmacokinetic study of the miconazole enantiomers was investigated using a novel chiral liquid chromatography-tandem mass spectrometry method. Baseline separation was achieved on Chiralpak IC column, and Chiralcel OJ column was used to collect single enantiomer. A significant difference between the two enantiomers was observed in view of the plasma concentration. PMID- 28852799 TI - Selection for water-soluble carbohydrate accumulation and investigation of genetic * environment interactions in an elite wheat breeding population. AB - KEY MESSAGE: Water-soluble carbohydrate accumulation can be selected in wheat breeding programs with consideration of genetic * environmental interactions and relationships with other important characteristics such as relative maturity and nitrogen concentration, although the correlation between WSC traits and grain yield is low and inconsistent. The potential to increase the genetic capacity for water-soluble carbohydrate (WSC) accumulation is an opportunity to improve the drought tolerance capability of rainfed wheat varieties, particularly in environments where terminal drought is a significant constraint to wheat production. A population of elite breeding germplasm was characterized to investigate the potential for selection of improved WSC concentration and total amount in water deficit and well-watered environments. Accumulation of WSC involves complex interactions with other traits and the environment. For both WSC concentration (WSCC) and total WSC per area (WSCA), strong genotype * environment interactions were reflected in the clear grouping of experiments into well watered and water deficit environment clusters. Genetic correlations between experiments were high within clusters. Heritability for WSCC was larger than for WSCA, and significant associations were observed in both well-watered and water deficit experiment clusters between the WSC traits and nitrogen concentration, tillering, grains per m2, and grain size. However, correlations between grain yield and WSCC or WSCA were weak and variable, suggesting that selection for these traits is not a better strategy for improving yield under drought than direct selection for yield. PMID- 28852800 TI - [Myoclonus as a movement disorder]. AB - Myoclonus is often a diagnostic and therapeutic challenge due to its broad phenomenological variability and limited therapeutic options. This article gives a short survey and characterizes in detail two common types of myoclonus, cortical myoclonus and reticular reflex myoclonus. Clinical testing and electrophysiological investigations provide relevant local diagnostic indications for the generating structure(s). Such indications would influence not only the strategies of neuroimaging and laboratory investigations aimed at clarifying the underlying cause but also the selection of drugs to suppress myoclonus. PMID- 28852801 TI - A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity. PMID- 28852802 TI - An ultra-dense integrated linkage map for hexaploid chrysanthemum enables multi allelic QTL analysis. AB - KEY MESSAGE: We constructed the first integrated genetic linkage map in a polysomic hexaploid. This enabled us to estimate inheritance of parental haplotypes in the offspring and detect multi-allelic QTL. Construction and use of linkage maps are challenging in hexaploids with polysomic inheritance. Full map integration requires calculations of recombination frequency between markers with complex segregation types. In addition, detection of QTL in hexaploids requires information on all six alleles at one locus for each individual. We describe a method that we used to construct a fully integrated linkage map for chrysanthemum (Chrysanthemum * morifolium, 2n = 6x = 54). A bi-parental F1 population of 406 individuals was genotyped with an 183,000 SNP genotyping array. The resulting linkage map consisted of 30,312 segregating SNP markers of all possible marker dosage types, representing nine chromosomal linkage groups and 107 out of 108 expected homologues. Synteny with lettuce (Lactuca sativa) showed local colinearity. Overall, it was high enough to number the chrysanthemum chromosomal linkage groups according to those in lettuce. We used the integrated and phased linkage map to reconstruct inheritance of parental haplotypes in the F1 population. Estimated probabilities for the parental haplotypes were used for multi-allelic QTL analyses on four traits with different underlying genetic architectures. This resulted in the identification of major QTL that were affected by multiple alleles having a differential effect on the phenotype. The presented linkage map sets a standard for future genetic mapping analyses in chrysanthemum and closely related species. Moreover, the described methods are a major step forward for linkage mapping and QTL analysis in hexaploids. PMID- 28852803 TI - The hypertrehalosemic neuropeptides of cicadas are structural isomers-evidence by ion mobility mass spectrometry. AB - It has been known for more than 20 years that the neurosecretory glands of the cicadas, the corpora cardiaca, synthesize two isobaric peptides with hypertrehalosemic activity. Both decapeptides have exactly the same amino acid sequence (pGlu-Val-Asn-Phe-Ser-Pro-Ser-Trp-Gly-Asn-NH2) and mass but differ in their retention time in reversed-phase liquid chromatography. A synthetic peptide with the same sequence elutes together with the second more hydrophobic peptide peak of the natural cicada extract. It is not clear what modification is causing the described observations. Therefore, in the current study, ion mobility separation in conjunction with high-resolution mass spectrometry was used to investigate this phenomenon as it was sensitive to changes in conformation. It detected different drift times in buffer gas for both the intact peptides and some of their fragment ions. Based on the ion mobility and fragment ion intensity of the corresponding ions, it is concluded that the region Pro6-Ser7-Trp8 contains a structural feature differing from the L-amino acids present in the known peptide. Whether the conformer is the result of racemization or other biochemical processes needs to be further investigated. PMID- 28852805 TI - [Double fracture of the clavicle : A critical incident report]. PMID- 28852806 TI - Biofluid pretreatment using gradient insulator-based dielectrophoresis: separating cells from biomarkers. AB - Blood is one of the most important biofluids used for clinical diagnostics. Cells and proteins in the blood can provide a rich source of information for the evaluation of human health. Efficient separation of blood components is a necessary process in order to minimize the interference of unwanted components during sensing, separation, and detection. In this paper, an insulator-based gradient dielectrophoretic device has been applied to separate red blood cells from model protein biomarkers for myocardial infarction in buffer. Within one min, red blood cells are largely depleted regardless of the minimum adherence on the channel wall. Considering the adhered red blood cells will not be transported further, a purified protein solution can be delivered for potential downstream processing or detection. Graphical Abstract ?. PMID- 28852804 TI - Prolonged exposure of mouse and human podocytes to insulin induces insulin resistance through lysosomal and proteasomal degradation of the insulin receptor. AB - AIMS/HYPOTHESIS: Podocytes are insulin-responsive cells of the glomerular filtration barrier and are key in preventing albuminuria, a hallmark feature of diabetic nephropathy. While there is evidence that a loss of insulin signalling to podocytes is detrimental, the molecular mechanisms underpinning the development of podocyte insulin resistance in diabetes remain unclear. Thus, we aimed to further investigate podocyte insulin responses early in the context of diabetic nephropathy. METHODS: Conditionally immortalised human and mouse podocyte cell lines and glomeruli isolated from db/db DBA/2J mice were studied. Podocyte insulin responses were investigated with western blotting, cellular glucose uptake assays and automated fluorescent imaging of the actin cytoskeleton. Quantitative (q)RT-PCR was employed to investigate changes in mRNA. Human cell lines stably overproducing the insulin receptor (IR) and nephrin were also generated, using lentiviral constructs. RESULTS: Podocytes exposed to a diabetic environment (high glucose, high insulin and the proinflammatory cytokines TNF-alpha and IL-6) become insulin resistant with respect to glucose uptake and activation of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling. These podocytes lose expression of the IR as a direct consequence of prolonged exposure to high insulin concentrations, which causes an increase in IR protein degradation via a proteasome-dependent and bafilomycin-sensitive pathway. Reintroducing the IR into insulin-resistant human podocytes rescues upstream phosphorylation events, but not glucose uptake. Stable expression of nephrin is also required for the insulin-stimulated glucose uptake response in podocytes and for efficient insulin-stimulated remodelling of the actin cytoskeleton. CONCLUSIONS/INTERPRETATION: Together, these results suggest that IR degradation, caused by high levels of insulin, drives early podocyte insulin resistance, and that both the IR and nephrin are required for full insulin sensitivity of this cell. This could be highly relevant for the development of nephropathy in individuals with type 2 diabetes, who are commonly hyperinsulinaemic in the early phases of their disease. PMID- 28852807 TI - Construction of a highly sensitive signal-on aptasensor based on gold nanoparticles/functionalized silica nanoparticles for selective detection of tryptophan. AB - In this work, a highly sensitive, low-cost, and label-free aptasensor based on signal-on mechanisms of response was developed by immobilizing the aptamer on gold nanoparticles (AuNPs)/amine-functionalized silica nanoparticle (FSN)/screen printed electrode (SPE) surface for highly selective electrochemical detection of tryptophan (Trp). The hemin (Hem), which interacted with the guanine bases of the aptamer, worked as a redox indicator to generate a readable electrochemical signal. The changes in the charge transfer resistance have been monitored using the voltammetry and electrochemical impedance spectroscopic (EIS) techniques. The peak current of Hem linearly increased with increasing concentration of Trp, in differential pulse voltammetry, from 0.06 to 250 nM with a detection limit of 0.026 nM. Also, the results obtained from EIS studies showed that the Trp was detected sensitively with the fabricated aptasensor in the range of 0.06-250 nM. The detection limit is 0.01 nM, much lower than that obtained by most of the reported electrochemical methods. The usage of aptamer as a recognition layer led to a sensor with high affinity for Trp, compared with control amino acids of tyrosine, histidine, arginine, lysine, valine, and methionine. The usability of the aptasensor was successfully evaluated by the determination of Trp in a human blood serum sample. Thus, the sensor could provide a promising plan for the construction of aptasensors. Graphical abstract Schematic outline the principle for tryptophan aptasensing. PMID- 28852808 TI - Technical aspects of mediastinal ultrasound for pediatric pulmonary tuberculosis. AB - Diagnosing childhood pulmonary tuberculosis (TB) may be challenging due to difficulties in obtaining adequate sputum samples, paucibacillary disease and the low sensitivity of diagnostic tests. Chest radiography is an important diagnostic tool for pulmonary TB, but it involves radiation exposure, requires facilities that can house X-ray equipment and has poor inter-reader agreement. The cardinal radiologic finding of mediastinal lymphadenopathy may be detected using mediastinal ultrasound (US). We describe technical aspects of performing mediastinal US, which may assist diagnosis of paediatric pulmonary TB. PMID- 28852810 TI - Label-free peptide aptamer based impedimetric biosensor for highly sensitive detection of TNT with a ternary assembly layer. AB - We report a label-free peptide aptamer based biosensor for highly sensitive detection of TNT which was designed with a ternary assembly layer consisting of anti-TNT peptide aptamer (peptamer), dithiothreitol (DTT), and 6-mercaptohexanol (MCH), forming Au/peptamer-DTT/MCH. A linear relationship between the change in electron transfer resistance and the logarithm of the TNT concentration from 0.44 to 18.92 pM, with a detection limit of 0.15 pM, was obtained. In comparison, the detection limit of the aptasensor with a common binary assembly layer (Au/peptamer/MCH) was 0.15 nM. The remarkable improvement in the detection limit could be ascribed to the crucial role of the ternary assembly layer, providing an OH-richer hydrophilic environment and a highly compact surface layer with minimal surface defects, reducing the non-covalent binding (physisorption) of the peptamer and non-specific adsorption of TNT onto the electrode surface, leading to high sensitivity, and which can serve as a general sensing platform for the fabrication of other biosensors. PMID- 28852809 TI - The fate of radiology report recommendations at a pediatric medical center. AB - BACKGROUND: The American College of Radiology (ACR) practice parameters for communication dictate that follow-up recommendations be suggested when appropriate. Radiologists assume that referring physicians read their reports and heed their advice. In reality, recommendations might not be carried out or even acknowledged. OBJECTIVE: We aimed to determine the proportion of imaging recommendations that are acknowledged and acted upon. MATERIALS AND METHODS: We conducted a retrospective review of all consecutive radiology reports containing "recommend" in the impression at a single academic children's hospital over a 1 month period. We documented point of care (emergency department, inpatient, outpatient), study type, recommendation wording, and communication method (report only or direct verbal). We reviewed medical records to ascertain whether the recommendations were acknowledged or executed. We used chi-square tests to evaluate associations between variables. P<0.05 was considered significant. RESULTS: We reviewed 526 reports and excluded 73. We included the remaining 453 reports, from 370 unique patients (201 male, 169 female). Inpatients comprised most reports (n=223), followed by emergency department (ED) patients (n=118) and outpatients (n=112). Among these reports, 69% (n=313) of recommendations were executed. Of the 140 recommendations not carried out, 14% were acknowledged in clinical notes. Compliance correlated with point of care (ED>inpatient>outpatient; P=0.001) but not with additional verbal communication (P=0.33), study type (radiograph vs. other; P=0.35) or type of follow-up recommendation (follow-up imaging vs. other; P=0.99). CONCLUSION: Nearly one third of radiology report follow-up recommendations are not executed. Recommendations are most commonly neglected for outpatient imaging reports. The radiology community should take steps to improve recommendation adherence. PMID- 28852811 TI - Determination of fluorine in herbs and water samples by molecular absorption spectrometry after preconcentration on nano-TiO2 using ultrasound-assisted dispersive micro solid phase extraction. AB - This work presents ultrasound-assisted dispersive micro solid phase extraction (USA DMSPE) for preconcentration of fluorine (F) in water and herb samples. TiO2 nanoparticles (NPs) were used as an adsorbent. The determination with slurry sampling was performed via molecular absorption of calcium monofluoride (CaF) at 606.440 nm using a high-resolution continuum source electrothermal absorption spectrometry (HR-CS ET MAS). Several factors influencing the efficiency of the preconcentration technique, such as the amount of TiO2, pH of sample solution, ultrasonication and centrifugation time and TiO2 slurry solution preparation before injection to HR-CS ET MAS, were investigated in detail. The conditions of detection step (wavelength, calcium amount, pyrolysis and molecule-forming temperatures) were also studied. After extraction, adsorbent with the analyte was mixed with 200 MUL of H2O to prepare a slurry solution. The concentration limit of detection was 0.13 ng mL-1. The achieved preconcentration factor was 7. The relative standard deviations (RSDs, %) for F in real samples were 3-15%. The accuracy of this method was evaluated by analyses of certified reference materials after spiking: INCT-MPH-2 (Mixed Polish Herbs), INCT-SBF-4 (Soya Bean Flour), ERM-CAO11b (Hard Drinking Water) and TMDA-54.5 (Lake Ontario Water). The measured F contents in reference materials were in satisfactory agreement with the added amounts, and the recoveries were found to be 97-109%. Under the developed extraction conditions, the proposed method has been successfully applied for the determination of F in real water samples (lake, sea, tap water) and herbs. PMID- 28852812 TI - Pediatric providers and radiology examinations: knowledge and comfort levels regarding ionizing radiation and potential complications of imaging. AB - BACKGROUND: Pediatric providers should understand the basic risks of the diagnostic imaging tests they order and comfortably discuss those risks with parents. Appreciating providers' level of understanding is important to guide discussions and enhance relationships between radiologists and pediatric referrers. OBJECTIVE: To assess pediatric provider knowledge of diagnostic imaging modalities that use ionizing radiation and to understand provider concerns about risks of imaging. MATERIALS AND METHODS: A 6-question survey was sent via email to 390 pediatric providers (faculty, trainees and midlevel providers) from a single academic institution. A knowledge-based question asked providers to identify which radiology modalities use ionizing radiation. Subjective questions asked providers about discussions with parents, consultations with radiologists, and complications of imaging studies. RESULTS: One hundred sixty-nine pediatric providers (43.3% response rate) completed the survey. Greater than 90% of responding providers correctly identified computed tomography (CT), fluoroscopy and radiography as modalities that use ionizing radiation, and ultrasound and magnetic resonance imaging (MRI) as modalities that do not. Fewer (66.9% correct, P<0.001) knew that nuclear medicine utilizes ionizing radiation. A majority of providers (82.2%) believed that discussions with radiologists regarding ionizing radiation were helpful, but 39.6% said they rarely had time to do so. Providers were more concerned with complications of sedation and cost than they were with radiation-induced cancer, renal failure or anaphylaxis. CONCLUSION: Providers at our academic referral center have a high level of basic knowledge regarding modalities that use ionizing radiation, but they are less aware of ionizing radiation use in nuclear medicine studies. They find discussions with radiologists helpful and are concerned about complications of sedation and cost. PMID- 28852813 TI - Thermodynamics and molecular insight in guest-host complexes of fluoroquinolones with beta-cyclodextrin derivatives, as revealed by ATR-FTIR spectroscopy and molecular modeling experiments. AB - beta-Syclodextrin (CD) is a perspective class of excipients used in pharmaceutical formulations to enhance solubility, bioavailability, and pharmacokinetics of various poorly soluble drugs, forming a non-covalent guest host complex. However, the development of such formulations is usually a very laborious and time-consuming process due to lack of appropriate analytical tools to directly track and study the detailed molecular mechanism of such complex formation. Here, using guest-host complexes of fluoroquinolones (FQ) with CDs, as an example, we demonstrate the utility of ATR-FTIR to determine the thermodynamic stability, as well as structural features associated with complex formation, including involvement of certain functional groups. Furthermore, varying the CD's side groups, we were able to tailor the CD's geometry and binding surface to make FQ-CD interactions strong enough to potentially affect its pharmacokinetics and justify development of a new sustained-release drug formulation (dissociation constant decreased from 5 * 10-3 M to 10-5 M). 3D molecular modeling with energy optimization supports the findings and conclusions made on the basis of ATR-FTIR data analysis and explains the observed difference in dissociation constants. PMID- 28852814 TI - Identification of Resveratrol, an Herbal Compound, as an Activator of the Calcium Activated Chloride Channel, TMEM16A. AB - Calcium-activated chloride channels (CaCCs) play vital roles in a variety of physiological processes. Dysfunction of the CaCCs is implicated in many diseases. Drug discovery targeting at CaCCs has recently become possible with the determination that TMEM16A is the molecular identity of CaCCs. In this study, we demonstrated that resveratrol (RES), a Chinese traditional medicine compound, is a novel activator of TMEM16A. The yellow fluorescence protein quenching assay and measurement of intracellular calcium fluorescence intensity show that RES activates TMEM16A channels in an intracellular Ca2+-independent way. The data of inside-out patch clamp revealed that RES dose-dependently activates TMEM16A (EC50 = 47.92 +/- 9.35 MUM). Furthermore, RES enhanced the contractions of the ileum of guinea pigs by activating the TMEM16A channel, which indicated that RES might be a promising drug for the treatment of gastrointestinal hypomotility. As RES was able to induce TMEM16A channel activation, TMEM16A can be added to the list of RES drug targets. PMID- 28852816 TI - IR-MALDESI method optimization based on time-resolved measurement of ion yields. AB - In the field of mass spectrometry imaging, typical experiments involve ionization directly from complex samples with no pre-ionization separation, relying on high resolving power mass analyzers to separate ions of interest. When an ion trapping step is involved in the analysis, the dynamic range of the analysis may be limited by the capacity of the ion trap, which is easily exceeded. To minimize collection of undesired ambient species while maximizing collection of analyte signal, accurate timing between ion generation and collection is a requirement. Here, a method for achieving synchronicity between infrared laser ablation and ion collection on a Q Exactive Plus mass spectrometer is described and demonstrated through measurement of ion accumulation at fixed time points following a laser ablation event with electrospray post-ionization of ablated material. In a model imaging experiment using infrared matrix-assisted laser desorption electrospray ionization, fixing the injection time at the minimum duration required to capture all ions generated by the last laser pulse in a sequence is shown to maximize target ion abundances. Using optimized timing is shown to yield a doubling or better of useful signal compared to previously used parameters. Graphical abstract Illustration of the effects of signal optimization on data quality for a single lipid species (cholesterol) measured from mouse liver tissue. PMID- 28852815 TI - Mycobacterium tuberculosis Major Facilitator Superfamily Transporters. AB - The cell membrane or biofilm serve as permeable barrier for xenobiotics to maintain the homeostasis of cells or bacterial community. Transport systems are essential for the uptake of nutrients and substances necessary for biofilm formation, efflux of deleterious compounds, as well as communication between cells and environment. Major facilitator superfamily (MFS) represents the largest secondary transporter family and is responsible for the transport of a broad spectrum of substrates with diverse physiochemical properties by utilizing the energy stored in electrochemical gradient across the membrane. Importantly, multidrug efflux pumps belonging to the major facilitator superfamily are important contributing factors to drug resistance and biofilm formation in many clinical strains like Mycobacterium tuberculosis. This review summarized the structural properties and functions of M. tuberculosis MFS transporters, molecular mechanisms of substrates transfer, and efflux pump inhibitors for better control of biofilm-associated infections. PMID- 28852818 TI - Cerebral lupus presented with late postpartum eclampsia and atypical reversible leucoencephalopathy. PMID- 28852817 TI - Risk Factors for Heart Failure and Its Costs Among Children with Complex Congenital Heart Disease in a Medicaid Cohort. AB - Little research attention has been paid to the occurrence of heart failure (HF) in children with complex congenital heart diseases (CHDs). Herein, we describe the prevalence, risk factors, and costs associated with HF in complex CHD. Patients aged <=17 years and diagnosed with a complex CHD on multiple service visits over a 15-year period in the SC Medicaid dataset (1996-2010) were tracked and analyzed. The cohort included 2999 unduplicated patients; 51.0% were male; 34.4% were African American. HF was diagnosed in 7.6%. Single ventricle lesions, genetic syndromes, and ventricular arrhythmia were significantly associated with an increased likelihood of being diagnosed with HF, controlling for development of comorbid pulmonary hypertension. Patients with HF received significantly more subspecialty care, more surgeries, more hospitalizations, more total days of inpatient care, and more emergency department care than those without HF. Patients with significantly higher total care costs paid by Medicaid had HF, more cardiac surgeries, and more specialized mechanical or other support procedures, controlling for diagnosed single ventricle CHD, a genetic syndrome, and number of non-cardiac surgeries. Complex CHD patients with HF incur significantly higher care costs but require multifaceted, intensive supports for management of incident complications and comorbid conditions. PMID- 28852819 TI - Outcomes of surgery for acromioclavicular joint dislocation using different angled hook plates: a prospective study. AB - PURPOSE: Hook plate fixation is widely used to treat acromioclavicular joint dislocation. However, there are many post-operative complications affecting the effect of treatment. The aim of this study is to evaluate the efficacy of the clavicular hook plate with different hook angles as a method of treatment in AC joint dislocation, and to guide the clinical application of hook plate. METHODS: We prospectively analysed 54 patients who were diagnosed with AC joint dislocation and treated with hook plate fixation by different hook angles. The patients were randomised into three groups: the -20 degrees < AHP < 0 degrees group, the 20 degrees > AHP > 0 degrees group and the 40 degrees > AHP > 20 degrees group. All patients were required to conform to regular follow-up post operatively. Routine imaging to the shoulder was obtained to evaluate maintenance of the dislocation and the implant. Constant-Murley criteria were used to evaluate functional results. RESULTS: There were 19 patients in the -20 degrees < AHP < 0 degrees group, with one lost to follow-up, 22 patients in the 20 degrees > AHP > 0 degrees group, with two male patients lost to follow-up, and one female patient excluded because of no follow-up consent, and 19 patients in the 40 degrees > AHP > 20 degrees group, with one female and one male patient lost to follow-up. The Constant score was 61.8 +/- 12.8, 74.7 +/- 9.2 and 70.7 +/ 9.4 before implant removal, and 78.8 +/- 8.3, 87.1 +/- 6.4 and 85.0 +/- 6.1 after implant removal in the -20 degrees < AHP < 0 degrees , 20 degrees > AHP > 0 degrees and 40 degrees > AHP > 20 degrees groups, respectively. The functional results of the 20 degrees > AHP > 0 degrees and 40 degrees > AHP > 20 degrees groups were significantly better than the -20 degrees < AHP < 0 degrees group (P < 0.05), but the functional results of the 20 degrees > AHP > 0 degrees and 40 degrees > AHP > 20 degrees groups were not statistically significant. The CCD was 98.1 +/- 4.8%, 107.5 +/- 5.1% and 105.5 +/- 4.1% before implant removal, and 98.8 +/- 4.6%, 108.3 +/- 4.8% and 107.2 +/- 3.3% after implant removal in the three groups, respectively. The CCD of the 20 degrees > AHP > 0 degrees and 40 degrees > AHP > 20 degrees groups were statistically significantly different from the -20 degrees < AHP < 0 degrees group (P < 0.001). However, there was no statistical difference between the 20 degrees > AHP > 0 degrees group and the 40 degrees > AHP > 20 degrees group. Post operative persistent pain occurred in 18.5% of all patients, post-operative stiffness occurred in 25.9% of all patients and 24.0% of patients had subacromial erosion. CONCLUSIONS: Hook plate treatment for AC joint dislocation can achieve the desired results, but the efficacy was significantly different depending on the different angles of the hook plate. AHP should be controlled within the range of 0-40 degrees as much as possible when making clinical decisions. PMID- 28852820 TI - Assessment of simpler calibration models in the development and validation of a fast postmortem multi-analyte LC-QTOF quantitation method in whole blood with simultaneous screening capabilities using SWATH acquisition. AB - In postmortem toxicology, fast methods can provide a triage to avoid unnecessary autopsies. Usually, this requires multiple qualitative and quantitative analytical methods. The aim of the present study was to develop a postmortem LC QTOF method for simultaneous screening and quantitation using easy sample preparation and reduced alternative calibration models. Hence, a method for 24 highly relevant substances in forensic toxicology was fully validated using the following calibration models: one-point external, one-point internal via corresponding deuterated standards, multi-point external daily calibration, and multi-point external weekly calibration. Two hundred microliters of postmortem blood were spiked with internal deuterated standard mixture and extracted by acetonitrile protein precipitation. Analysis was performed on a Sciex 6600 QTOF instrument with ESI+ mode using data-independent acquisition (DIA) namely sequential window acquisition of all theoretical mass spectra (SWATH). Validation of the different calibration models included selectivity, autosampler stability, recovery, matrix effects, accuracy, and precision for 24 substances. In addition, corresponding deuterated analogs of 52 substances were included to the internal standard mix for semi-quantitative concentration assessment. The simple protein precipitation provided recoveries higher than 55 and 75% for all analytes at low and high concentrations, respectively. Accuracy and precision criteria (bias and imprecision +/- 15 and +/- 20% near the limit of quantitation) were fulfilled by the different calibration models for most analytes. The validated method was successfully applied to more than 100 authentic postmortem samples and 3 proficiency tests. Furthermore, the one-point internal calibration via corresponding deuterated standard proved to be a considerably time saving technique for 76 analytes. Graphical abstract One-point and multi-point calibration and the resulting beta-tolerance intervals from method validation. PMID- 28852821 TI - Conservatively treated knee injury is associated with knee cartilage matrix degeneration measured with MRI-based T2 relaxation times: data from the osteoarthritis initiative. AB - OBJECTIVE: To investigate the association of cartilage degeneration with previous knee injuries not undergoing surgery, determined by morphologic and quantitative 3-T magnetic resonance imaging (MRI). MATERIALS AND METHODS: We performed a nested cross-sectional study of right knee MRIs from participants in the Osteoarthritis Initiative (OAI) aged 45-79 with baseline Kellgren-Lawrence score of 0-2. Cases were 142 right knees of patients with self-reported history of injury limiting the ability to walk for at least 2 days. Controls were 426 right knees without history of injury, frequency-matched to cases on age, BMI, gender, KL scores and race (1:3 ratio). Cases and controls were compared using covariate adjusted linear regression analysis, with the outcomes of region-specific T2 mean, laminar analysis and heterogeneity measured by texture analysis to investigate early cartilage matrix abnormalities and the Whole-Organ Magnetic Resonance Imaging Score (WORMS) to investigate morphologic knee lesions. RESULTS: Compared to control subjects, we found significantly higher mean T2 values in the injury [lateral tibia (28.10 ms vs. 29.11 ms, p = 0.001), medial tibia (29.70 ms vs. 30.40 ms, p = 0.014) and global knee cartilage (32.73 ms vs. 33.29 ms, p = 0.005)]. Injury subjects also had more heterogeneous cartilage as measured by GLCM texture contrast, variance and entropy (p < 0.05 in 14 out of 18 texture parameters). WORMS gradings were not significantly different between the two groups (p > 0.05). CONCLUSION: A history of knee injury not treated surgically is associated with higher and more heterogeneous T2 values, but not with morphologic knee abnormalities. Our findings suggest that significant, conservatively treated knee injuries are associated with permanent cartilage matrix abnormalities. PMID- 28852822 TI - Incidence and risk factors for symptomatic spinal epidural haematoma following lumbar spinal surgery. AB - PURPOSE: Spinal epidural haematoma (SEH) is a common complication after lumbar spinal decompression surgery, and symptomatic SEH usually causes devastating neurological deficits. Although different risk factors for post-operative SEH have been reported, few studies focused on patients' laboratory tests. The purpose of this study was to analyze the incidence of symptomatic SEH following lumbar spinal surgery, as well as identify the risk factors for it. METHODS: Patients who underwent posterior lumbar spinal decompression surgery between January 2010 and August 2016 were included in this study and their medical records were retrospectively reviewed. Those who developed post-operative symptomatic SEH after the surgery were identified. The risk factors for SEH were analyzed by univariate and multivariate regression analysis. RESULTS: In total, 2715 patients were included in this study and 31 (1.14%) were identified with post-operative symptomatic SEH. Of these patients, 19 were males and 12 were females, with an average age of 59.39 +/- 11.66 years. After multivariate logistic regression analysis, low serum calcium level (P = 0.025), blood type A (P = 0.04), increased estimated blood loss (P = 0.032), prolonged surgical duration (P = 0.018), and decreased post-operative globulin (P = 0.016) were identified as the independent risk factors for post-operative SEH following lumbar spinal surgery. Furthermore, prolonged surgical duration (odds ratio = 3.105) was the strongest risk factor for SEH. CONCLUSION: Based on a large population investigation, the incidence of symptomatic SEH following lumbar spinal decompression surgery was 1.14%. Blood type A, increased estimated blood loss, and prolonged surgical duration were identified as the independent risk factors for post-operative SEH while two new risk factors, including low serum calcium level and decreased post-operative globulin, were firstly identified in this study. PMID- 28852823 TI - A proteomic portrait of dinoflagellate chromatin reveals abundant RNA-binding proteins. AB - Dinoflagellate chromatin is unique among eukaryotes, as the chromosomes are permanently condensed in a liquid crystal state instead of being packed in nucleosomes. However, how it is organized is still an unsolved mystery, in part due to the lack of a comprehensive catalog of dinoflagellate nuclear proteins. Here, we report the results of CHromatin Enrichment for Proteomics (CHEP) followed by shotgun mass spectrometry sequencing of the chromatin-associated proteins from the dinoflagellate Lingulodinum polyedra. Our analysis identified proteins involved in DNA replication and repair, transcription, and mRNA splicing, and showed a low level of contamination by proteins from other organelles. A limited number of proteins containing DNA-binding domains were found, consistent with the lack of diversity of these proteins in dinoflagellate transcriptomes. However, the number of proteins containing RNA-binding domains was unexpectedly high supporting a potential role for this type of protein in mediating gene expression and chromatin organization. We also identified a number of proteins involved in chromosome condensation and cell cycle progression as well as a single histone protein (H4). Our results provide the first detailed look at the nuclear proteins associated with the unusual chromatin structure of dinoflagellate nuclei and provide important insights into the biochemical basis of its structure and function. PMID- 28852824 TI - Influence of microbial community diversity and function on pollutant removal in ecological wastewater treatment. AB - Traditional wastewater treatments based on activated sludge often encounter the problems of bulking and foaming, as well as malodor. To solve these problems, new treatment technologies have emerged in recent decades, including the ecological wastewater treatment process, which introduces selected local plants into the treatment system. With a focus on the underlying mechanisms of the ecological treatment process, we explored the microbial community biomass, composition, and function in the treatment system to understand the microbial growth in this system and its role in pollutant removal. Flow cytometry analysis revealed that ecological treatment significantly decreased influent bacterial quantity, with around 80% removal. 16S rRNA gene sequencing showed that the ecological treatment also altered the bacterial community structure of the wastewater, leading to a significant change in Comamonadaceae in the effluent. In the internal ecological system, because most of microbes aggregate in the plant rhizosphere and the sludge under plant roots, we selected two plant species (Nerium oleander and Arundo donax) to study the characteristics of rhizosphere and sludge microbes. Metagenomic results showed that the microbial community composition and function differed between the two species, and the microbial communities of A. donax were more sensitive to seasonal effects. Combined with their greater biomass and abundance of metabolic genes, microbes associated with N. oleander showed a greater contribution to pollutant removal. Further, the biodegradation pathways of some micropollutants, e.g., atrazine, were estimated. PMID- 28852827 TI - The Utility of Transesophageal Echocardiogram and Transabdominal Ultrasound for Facilitation of Inferior Vena Cava and Right Atrial Thrombus Removal Using AngioVac System. PMID- 28852825 TI - Incarceration of the inferior oblique muscle branch of the oculomotor nerve in patients with orbital floor trapdoor fracture. AB - PURPOSE: To examine the clinical characteristics of patients with concomitant incarceration of the inferior oblique muscle branch of the oculomotor nerve who had suffered from an orbital floor trapdoor fracture with orbital fat incarceration. METHODS: Fifty-nine patients were retrospectively reviewed. Concomitant inferior oblique muscle branch incarceration was diagnosed by inferior oblique muscle underaction on the Hess chart and a missing inferior oblique muscle branch on computed tomographic images on baseline examination. RESULTS: Eleven patients (18.6%) were diagnosed with concomitant branch incarceration. The patients with branch incarceration were all under 19 years of age, and were younger than those without branch incarceration (P = 0.026). There were no significant differences between the groups in terms of cause of injury, presence of concomitant medial wall fracture, hypoesthesia of the cheek region, or ocular and periocular complications (P > 0.050). All patients with branch incarceration underwent surgical reduction, whereas 16 of 48 patients without branch incarceration were observed without surgery (P = 0.021). Although preoperative binocular single vision field was smaller in patients with branch incarceration (P = 0.026), it improved after surgery, comparable to that of patients without branch incarceration (P = 0.079). CONCLUSIONS: Concomitant incarceration of inferior oblique muscle branch of the oculomotor nerve occurred in 18.6% of patients who had suffered from an orbital floor trapdoor fracture with orbital fat incarceration. Patients with branch incarceration were all under 19 years of age. Branch incarceration resulted in a smaller binocular single vision field, which considerably improved after surgical reduction. PMID- 28852826 TI - Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - INTRODUCTION: In chronic obstructive pulmonary disease (COPD), there is an activation of the L-arginine nitric oxide pathway. Pulmonary obstruction causes to elevated nitric oxide (NO) levels, which lead to higher production of the NO inhibiting metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). METHODS: We investigated the association of L-arginine, ADMA, and SDMA with clinical outcomes in a well-defined observational cohort of 150 patients with acute exacerbation of COPD. We measured L-arginine, ADMA, and SDMA by mass spectrometry in patients with pneumonic or non-pneumonic exacerbation of COPD included in a Swiss multicenter trial. We used Cox regression models to investigate the associations between blood marker levels and disease severity as well as all-cause mortality over a follow-up of 6.1 years. RESULTS: Six-year all-cause mortality was 54%. Admission levels of ADMA and SDMA (MUmol L-1) were increased in 6-year non-survivors compared to survivors' median (0.60 vs. 0.46, p = 0.004; and 1.05 vs. 0.85, p = 0.012). In a multivariate Cox regression analysis, ADMA was associated with long-term mortality resulting in an age- and comorbidity-adjusted hazard ratio (HR) of 4.55 (95% confidence interval 1.02-20.43, p = 0.048). SDMA was only associated in univariate models and no association of L-arginine with outcome was found. CONCLUSION: ADMA was found to be an independent risk factor for long-term all-cause mortality in patients with acute exacerbation of COPD. Whether therapeutic modification of the L-arginine nitric oxide pathway has the potential to improve outcome should be evaluated in future interventional trials. PMID- 28852828 TI - Exercise-related sensations contribute to decrease power during repeated cycle sprints with limited influence on neural drive. AB - PURPOSES: We manipulated the inspired oxygen fraction (FiO2) to examine the effects of physiological perturbations on exercise-related sensations and the neural drive of the quadriceps during repeated, brief, maximal cycle sprints. METHODS: Nine active males completed a repeated sprint cycle protocol (10 * 4-s maximal sprints with 30 s of passive recovery) in normoxia (NM; FiO2 0.21) and severe normobaric hypoxia (HY; FiO2 0.13). Peak power, quadriceps Root Mean Squared electromyography (RMS EMG), physiological (heart rate, arterial oxygen saturation, blood lactate concentration) and perceptual responses were recorded. RESULTS: The 10 sprints in HY were associated with lower arterial oxygen saturation values compared to NM [80.7 +/- 0.9 vs. 95.6 +/- 0.6%; P < 0.001; effect size (ES) = 0.98], higher blood lactate values (11.9 +/- 0.4 vs. 9.9 +/- 0.9 mmol L-1; P = 0.05; ES = 0.36), and greater exercise-related sensations (~36%; P < 0.001; ES > 0.47). Mean power for sprints 1-10 were lower (-13 +/- 3%; P = 0.001; ES = 0.79), and sprint decrement was more pronounced in HY compared to NM (21.4 +/- 3.7 vs. 13.2 +/- 2.7%; P = 0.003). There was a 17% decrease in RMS EMG activity from the first to the last sprint (P < 0.001; ES = 0.65), independent of condition (P = 0.597; ES = 0.04). CONCLUSIONS: Despite severe hypoxia exacerbating both physiological and perceptual perturbations, the performance decrement observed during the repeated sprint protocol did not coincide with an accentuated decline in RMS EMG activity. These data suggest that higher-than-normal exercise-related sensations or perceptions coincide with fatigue during repeated sprinting, independent of changes in neural drive, when the task characteristics are known beforehand. PMID- 28852829 TI - PAL-12, a new anti-aging hexa-peptoid, inhibits UVB-induced photoaging in human dermal fibroblasts and 3D reconstructed human full skin model, Keraskin-FTTM. AB - Peptoids are a class of peptidomimetics whose pharmacological activities are widely investigated owing to their remarkable biological stability. However, the utilities of peptoids as cosmetic functional ingredients have not been fully explored. Here, we investigated anti-aging effects of PAL-12, a new hexa-peptoid, on UVB-induced photoaging in human dermal fibroblasts (HDFs) and a 3D reconstituted human full skin model, Keraskin-FTTM. PAL-12 suppressed matrix metalloproteinase-1 (MMP-1) expression induced by UVB irradiation along with the attenuation of MMP-1 secretion as determined by ELISA assay. Interestingly PAL-12 slightly enhanced the expression levels of collagen-1 and fibronectin-1 in HDFs or Keraskin-FTTM. In addition, PAL-12 prevented the decrease of cell viability following UVB irradiation. However, PAL-12 failed to affect ROS generation, cell necrosis and apoptosis significantly. Instead, PAL-12 suppressed UVB-induced activation of epidermal growth factor receptors (EGFR), extracellular signal regulated kinase (ERK) and c-Jun, which may resulted in the attenuation of AP-1 promoted MMP-1 expression. Collectively, these results suggest that PAL-12 might be a novel cosmetic ingredient effective against UVB-induced skin photoaging. PMID- 28852830 TI - Global hopf bifurcation of a delayed equation describing the lag effect of media impact on the spread of infectious disease. AB - We proposed a delay differential model, associated with the response time for individuals to the current infection, to examine the media impact on the transmission dynamics of infectious diseases. We investigated the global bifurcation by considering the delay as a bifurcation parameter and examined the onset and termination of Hopf bifurcations from a positive equilibrium. Numerical studies to identify ranges of parameters for coexisting multiple periodic solutions are guided by the bifurcation analysis and the Matlab package DDE BIFTOOL developed by Engelborghs et al. Further, we parameterized the proposed model on the basis of the 2009 A/H1N1 pandemic influenza data in Shaanxi province, China, and estimated the basic reproduction number to be 1.79 [95% CI (1.77-1.80)] and the time delay to be 2.94 days [95% CI (2.56-3.24)]. Our main results indicated that media impact with time delay significantly influenced the transmission dynamics of infectious diseases. PMID- 28852831 TI - Uterine intravascular lymphoma as a cause of fever of unknown origin. AB - Primary intravascular large B cell lymphoma (IVL) remains a diagnostic challenge because of non-specific clinical, laboratory and imaging findings. The aim of the study was to analyse the major characteristics of IVL with uterine involvement. We retrospectively collected features of IVL with uterine involvement that was proven histologically or demonstrated by significant 18FDG uptake on 18FDG PET/CT. Findings were compared to a comprehensive literature review. Five patients were identified. All of them were admitted for fever of unknown origin (FUO), with haemophagocytic lymphohistiocytosis in three cases. None had gynaecological symptom, contrasting with the literature data. Structural imaging (including whole-body CT scan and pelvic RMI) failed to yield any diagnosis. 18FDG-PET/CT showed intense uterine uptake in all cases. Endometrial biopsy was performed in three cases and was positive in one. Diagnosis was obtained from coelioscopic iliac adenopathy biopsy in one case and from total hysterectomy in another. Punch biopsy of skin lesions led to diagnosis in the two remaining cases. Bone marrow biopsy was normal in all cases. Clinicians should be aware of potential isolated uterine involvement in IVL, especially in elderly women with FUO. Normal structural imaging does not rule out the diagnosis and 18FDG-TEP/CT should be performed to guide high-yielding biopsy. PMID- 28852832 TI - Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review. AB - Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice. PMID- 28852833 TI - Mortality in bullous pemphigoid and prognostic factors in 1st and 3rd year of follow-up in specialized centre in Poland. AB - Bullous pemphigoid (BP) is associated with higher mortality and coexisting comorbidities, some of them affecting poor prognosis. The aim of the study was to identify prognostic factors causing greater mortality both in the 1st and 3rd year of follow-up and to determine the 1-, 2-, 3-year mortality rates, standardized mortality ratio (SMR) in Polish BP patients. All patients with BP (a cohort of 205 patients, mean age 76.2 years) diagnosed between 5 January 2000 and 10 December 2013 in a referral unit for autoimmune bullous diseases at the university hospital in Poland were included retrospectively. Mortality data were obtained from the Centre for Document Personalization at the Minister of Interior and Administration. Our original observation was that prednisone in moderate dose (0.5 mg kg-1) in monotherapy was an independent risk factor of fatal prognosis in the 1st year of follow-up, assessed using multivariate analysis. We confirmed the strong correlation between neurological diseases and greater mortality. Both in the 1st and 3rd year of follow-up, dementia and Parkinson disease resulted in increased mortality. We also found that arrhythmias significantly increased mortality in the 1st and 3rd year of follow-up. The prognostic factors in BP changed over time of follow-up. In the 3rd year of observation, the age above 77, longer hospitalization and BP severity were associated with greater mortality. We observed poorer prognosis in BP patients than age-matched general Polish population. The 1-, 2-, 3-year mortality rates were 22.4, 31.2, 39.5% and SMR was 3.8 (95% CI 3.4-3.7). PMID- 28852834 TI - [Legal considerations of telemedical care]. AB - Telemedical methods are on the rise in patient care. In addition to the actual changes for both sides in the physician-patient relationship, the use of information and communication technology also involves legal challenges. This article deals with the legal framework of telemedical care. Thereby the article discusses the prohibition of remote treatment (S 7 Abs. 4 MBO-A) and the question to what extent the omission of a telemedical method of treatment can fulfill a medical breach of duty. A distinction must be drawn between the question as to whether telemedical monitoring shall be executed and the question how to use telemedical systems, in order to mitigate liability risks for the physicians. The physician can for example violate his/her medical duties by not sufficiently informing the patient about all essential circumstances concerning the consent, by not adequately monitoring the functioning of the telemedical devices, or by not reacting fast enough to telemedical occurrence reports. All this may lead to a case of liability. PMID- 28852835 TI - Elemental fingerprinting of schizophrenia patient blood plasma before and after treatment with antipsychotics. AB - Antipsychotics are the main line of treatment for schizophrenia, a disorder that affects about 1% of the worldwide population. Considering the poor performance of antipsychotics on patients, this work aimed at detecting alterations in the elemental profile resulting from the use of this type of medication using an elemental fingerprinting strategy. We evaluated 56 plasma samples from schizophrenia patients by inductively coupled plasma mass spectrometry (ICP-MS) before (t0) and after 6 weeks (t6) of treatment. The level of response of the patients (good vs. poor responders) and the medications taken were considered. Zinc, aluminum, phosphorus, and iron levels were found to be increased, whereas sodium, potassium, calcium, and magnesium levels decreased after treatment. Aluminum presented a higher level in poor responders at t0 when compared to good responders. At t6, iron showed an increased level when compared to t0 for good responders; however, its level remained constant in poor responders. The results of this exploratory study provide clues for further investigations on the role of metal ions in the treatment of schizophrenia. PMID- 28852836 TI - Indications for surgical stabilization of rib fractures in patients without flail chest: surveyed opinions of members of the Chest Wall Injury Society. AB - PURPOSE: There are currently no evidence-based indications for surgical stabilization of rib fractures (SSRF) in patients without flail chest. The purpose of this survey was to identify patients for whom there is relative equipoise (operative vs. non-operative) in order to assist in designing a randomized clinical trial. METHODS: Members of the Chest Wall Injury Society were sent an online survey, in which 18 patient scenarios were presented. The baseline patient had >= three displaced, contiguous fractures and had no other contraindications for surgery. This default scenario was then varied based upon patient age, degree of traumatic brain injury (TBI), fracture series location, and number of abnormal pulmonary physiologic variables (oxygen requirement, respiratory rate, incentive spirometry ability, cough, and numeric pain score). RESULTS: Thirty respondents provided a total of 540 answers. Overall, the majority of responses were in favor of SSRF (n = 413, 84.1%). Furthermore, the vast majority of responses indicated that some degree of pulmonary compromise was necessary to recommend SSRF (n = 44, 90.4%), with >= two abnormal parameters being the most common threshold (n = 156, 31.8%). Decision to recommend SSRF varied significantly by number of abnormal clinical variables, age, and degree of TBI, but not by fracture series location. Patients aged 85 years old and those with moderate TBI were the least likely to be recommended for SSRF, regardless of abnormal pulmonary physiologic variables. The most appropriate cutoff for equipoise appeared to be a patient aged 21-79 years old, with no or mild TBI, >= two abnormal pulmonary parameters, and regardless of fracture location (44.8% consensus for SSRF). CONCLUSIONS: SSRF was recommended for most patients with non flail, displaced rib fractures. However, this recommendation was contingent upon patient age, degree of TBI, and pulmonary clinical status. Results of this survey may be used to inform inclusion criteria for a future randomized, clinical trial. PMID- 28852837 TI - Skeletal muscle metastasis from the most common carcinomas orthopedic surgeons deal with. A systematic review of the literature. AB - INTRODUCTION: There is scarce information in the literature dealing with the clinical presentation, management and oncologic outcomes of skeletal muscle metastases (SMM). We sought to perform a systematic review of the literature to investigate: (1) tumor characteristics of SMM, (2) therapeutic approach, and (3) oncological outcomes. METHODS: A systematic review of the literature was performed using PubMed and EMBASE search engines. A total of 3231 references were reviewed and 49 studies were included. Demographic data, presentation characteristics, and oncological outcomes were recorded. Statistical analysis was performed using SPSS 22.0 software (IBM; Armonk, New York) and Comprehensive Meta Analysis software version 3 (Biostat, Inc.), with p < 0.05 as statistically significant. RESULTS: A total of 231 patients were included. These tumors presented more commonly on males 58.4% (135/231), with a mean age of 60.08 +/- 10.6 years, and in the axial area 39.6% (88/222). The most common carcinoma type was lung 41.1% (95/231). Resection of a single metastases did not change survival significantly (p = 0.992). LRR was higher within the group of patients that underwent WLE compared with non-WLE [31.3% (23/74) vs. 8.7% (2/23), p <= 0.001]. Kaplan-Meier survival analysis for the entire cohort showed an estimate of 15.3 months [95% confidence interval (CI) 11.6-19; standard error (SE) 0.432], with lung carcinoma carrying the worst prognosis 6.7 months (95% CI 5.4-8.07; SE 0.68). Patients with a single SMM showed a worse estimate mean survival time compared to patients with multiple metastases limited to muscles [8.6 months (95% CI 4.7-12.5; SE 2.0) vs 25.4 months (95% CI 19.8-31.05; SE 2.8; p <= 0.001)]. CONCLUSIONS: Overall survival is poor and is driven mainly by the type of carcinoma. An Increased LRR might be present due to the systemic nature of the condition, and degree of control of the primary carcinoma. PMID- 28852838 TI - Prognostic factors indicating survival with native liver after Kasai procedure for biliary atresia. AB - BACKGROUND: The number of the bile ducts in the portal canal/measured surface area of the portal canal (BDP ratio) indicates prognosis in biliary atresia (BA), as does an elevated cytokeratin 7 positivity percentage (PCK7). We compared these two markers. METHODS: We reviewed 32 BA cases undergoing Kasai operation from 1976 to 2016 with >5 portal canals in biopsy samples. Group I required liver transplantation or died within a year of operation (n = 8). Group II survived with their native liver (n = 24). We determined the BDP ratio (102/mm2) and PCK7 (%), subdividing patients into three groups by their age at operation: Group A <=60 days (n = 6, 1 Group I), 60< Group B <=90days (n = 16, 5 Group I), Group C >90 days (n = 10, 2 Group I). RESULTS: PCK7 (%) was 2.71 +/- 1.87 in Group I and 4.25 +/- 2.56 in Group II (p = 0.13). BDP ratio (102/mm2) was 1.19 +/- 0.424 in Group I and 1.64 +/- 0.534 in Group II (p = 0.04). Both markers were higher in Group C than in Group A or B (p < 0.01). CONCLUSION: The BDP ratio is a better prognostic indicator than PCK7 in BA. PMID- 28852840 TI - Biomechanical study of novel unilateral C1 posterior arch screws and C2 laminar screws combined with an ipsilateral crossed C1-C2 pedicle screw-rod fixation for atlantoaxial instability. AB - INTRODUCTION: Current surgical methods to treat atlantoaxial instability pose potential risks to the surrounding blood vessels and nerves of operative approach. Therefore, more secure and highly effective methods are expected. This study sought to assess the biomechanical efficacy of a novel unilateral double screw-rod fixation system by comparing with traditional and emerging fixation methods in cadaveric models. MATERIALS AND METHODS: Ligamentous cervical spines (C0-C7) from ten fresh cadaveric specimens were used to complete range of motion (ROM) test in their intact condition (control group), destabilization, and stabilization after different fixations, including unilateral C1-C2 pedicle screws (PS) with a screw-rod system (Group A), bilateral C1-C2 PS with screw-rod systems (Group B), unilateral C1 posterior arch screws (PAS) and C2 laminar screws (LS) combined with an ipsilateral paralleled C1-C2 PS-rod (Group C), and unilateral C1 PAS and C2 LS combined with an ipsilateral crossed C1-C2 PS-rod (Group D). After that, pullout strength test was performed between PS and PAS using ten isolated atlas vertebras. RESULTS: All fixation groups reduced flexibility in all directions compared with both control group and destabilization group. Furthermore, comparisons among different fixation groups showed that bilateral C1-C2 PS-rod (Group B), unilateral C1 PAS + C2 LS combined with an ipsilateral paralleled C1-C2 PS-rod (Group C) and unilateral C1 PAS + C2 LS combined with an ipsilateral crossed C1-C2 PS-rod (Group D) could provide a better stability, respectively, in all directions than unilateral C1-C2 PS-rod (Group A). However, no statistical significance was observed among Groups B, C, and D. Data from pullout strength test showed that both C1 PS (585 +/- 53 N) and PAS (463 +/- 49 N) could provide high fixed strength, although PS was better (P = 0.009). CONCLUSION: The surgical technique of unilateral C1 PAS + C2 LS combined with a ipsilateral crossed C1-C2 PS-rod fixation could provide a better stability than the traditional unilateral PS-rod fixation and a same stability as bilateral PS-rod fixation, but with less risk of neurovascular injury. Therefore, this new technique may provide novel insight for an alternative of atlantoaxial instability treatment. PMID- 28852839 TI - Effect of eplerenone on extracellular cardiac matrix biomarkers in patients with acute ST-elevation myocardial infarction without heart failure: insights from the randomized double-blind REMINDER Study. AB - OBJECTIVE: Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with an acute myocardial infarction (MI). METHODS: The REMINDER trial assessed the effect of eplerenone in patients with an acute ST elevation Myocardial Infarction (STEMI) without known heart failure (HF), when initiated within 24 h of symptom onset. The primary outcome was almost totally (>90%) driven by natriuretic peptide (NP) thresholds after 1-month post-MI (it also included a composite of cardiovascular death or re-hospitalization or new onset HF or sustained ventricular tachycardia or fibrillation or LVEF <=40% after 1-month post-MI). This secondary analysis aims to assess the extracellular matrix marker (ECMM) levels with regards to: (1) patients' characteristics; (2) determinants; (3) and eplerenone effect. RESULTS: Serum levels of ECMM were measured in 526 (52%) of the 1012 patients enrolled in the REMINDER trial. Patients with procollagen type III N-terminal propeptide (PIIINP) above the median were older and had worse renal function (p < 0.05). Worse renal function was associated with increased levels of PIIINP (standardized beta ~ 0.20, p < 0.05). Eplerenone reduced PIIINP when the levels of this biomarker were above the median of 3.9 ng/mL (0.13 +/- 1.48 vs. -0.37 +/- 1.56 ng/mL, p = 0.008). Higher levels of PIIINP were independently associated with higher proportion of NP above the prespecified thresholds (HR = 1.95, 95% CI 1.16-3.29, p = 0.012). CONCLUSIONS: Eplerenone effectively reduces PIIINP levels when baseline values were above the median. Eplerenone may limit ECMM formation in post-MI without HF. PMID- 28852841 TI - Association of breathing sound spectra with glottal dimensions in exercise induced vocal cord dysfunction. AB - The objective of this study was to evaluate associations between the breathing sound spectra and glottal dimensions in exercise-induced vocal cord dysfunction (EIVCD) during a bicycle ergometry test. Nineteen subjects (mean age 21.8 years and range 13-39 years) with suspected EIVCD were studied. Vocal folds were continuously imaged with videolaryngoscopy and breathing sounds were recorded during the bicycle exercise test. Twelve subjects showed paradoxical movement of the vocal folds during inspiration by the end of the exercise. In seven subjects, no abnormal reactions in vocal folds were found; they served as control subjects. The glottal quotient (interarytenoid distance divided by the anteroposterior glottal distance) was calculated. From the same time period, the tracheal-vocal tract resonance peaks of the breathing sound spectra were analyzed, and stridor sounds were detected and measured. Subjects with EIVCD showed significantly higher resonance peaks during the inspiratory phase compared to the expiratory phase (p < 0.014). The glottal quotient decreased significantly in the EIVCD group (p < 0.001), but not in the control group. 8 out of 12 EIVCD patients (67%) showed stridor sounds, while none of the controls did. There was a significant inverse correlation between the frequencies of the breathing sound resonance peaks and the glottal quotient. The findings indicate that the typical EIVCD reaction of a paradoxical approximation of the vocal folds during inspiration, measured here as a decrease in the glottal quotient, is significantly associated with an increase in inspiratory resonance peaks. The findings are applicable in the documentation of EIVCD findings using videolaryngoscopy, in addition to giving clinicians tools for EIVCD recognition. However, the study is limited by the small number of subjects. PMID- 28852842 TI - The impact of combined nutraceutical supplementation on quality of life and metabolic changes during the menopausal transition: a pilot randomized trial. AB - PURPOSE: The aim of this study was to assess the efficacy of a combined nutraceutical supplement on symptoms and early metabolic alterations during the menopausal transition. This pilot randomized study was conducted at the service for menopause disorders of the Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy. METHODS: Ninety women in menopausal transition who attended our service with menopausal symptoms were enrolled in the study. Sixty patients, randomly assigned to the treatment group, were prescribed one daily tablet of a combined nutraceutical compound with phytoestrogen substances, vitamins, micronutrients and passion flower herbal medicine for 6 months. Thirty patients did not receive any treatment and comprised the control group. The intensity of perimenopausal symptoms was assessed by the modified Kuppermann Index (KI) at enrollment and at 3 and 6 months of treatment. At baseline and at the end of the study, patients underwent a clinical evaluation, a pelvic ultrasound and analysis of blood samples. RESULTS: In the nutraceutical supplemented group, a significant reduction in menopausal symptoms was demonstrated according to the KI after 3 and 6 months of supplementation (p < 0.01). The within-group analysis of different KI parameters in the treated group showed a significant improvement in hot flushes (p < 0.001), insomnia (p < 0.01), fatigue (p < 0.01) and irritability (p < 0.01). Metabolic parameters did not change significantly in the nutraceutical supplemented group. In the control group, total cholesterol level showed a significant increase (p < 0.05). CONCLUSIONS: Combined nutraceutical supplementation provides an effective and safe solution for early symptoms occurring during menopausal transition. PMID- 28852843 TI - Enhancing recovery after minimally invasive repair of pectus excavatum. AB - PURPOSE: There are variations in the perioperative management of patients who undergo minimally invasive repair of pectus excavatum (MIRPE). The purpose is to analyze the change in resource utilization after implementation of a standardized practice plan and describe an enhanced recovery pathway. METHODS: A standardized practice plan was implemented in 2013. A retrospective review of patients who underwent MIRPE from 2012 to 2015 was performed to evaluate the trends in resource utilization. A pain management protocol was implemented and a retrospective review was performed of patients who underwent repair before (2010 2012) and after (2014-2015) implementation. RESULTS: There were 71 patients included in the review of resource utilization. After implementation, there was a decrease in intensive care unit length of stay (LOS), and laboratory and radiologic studies ordered. There were 64 patients included in the pain protocol analysis. After implementation, postoperative morphine equivalents (3.3 +/- 1.4 vs 1.2 +/- 0.5 mg/kg, p < 0.01), urinary retention requiring catheterization (33 vs 14%, p = 0.07), and LOS (4 +/- 1 vs 2.8 +/- 0.8 days, p < 0.01) decreased. CONCLUSION: The implementation of an enhanced recovery pathway is a feasible and effective way to reduce resource utilization and improve outcomes in pediatric patients who undergo minimally invasive repair of pectus excavatum. PMID- 28852844 TI - Take time: odor coding capacity across sensory neurons increases over time in Drosophila. AB - Due to the highly efficient olfactory code, olfactory sensory systems are able to reliably encode enormous numbers of olfactory stimuli. The olfactory code consists of combinatorial activation patterns across sensory neurons, thus its capacity exceeds the number of involved classes of sensory neurons by a manifold. Activation patterns are not static but vary over time, caused by the temporally complex response dynamics of the individual sensory neuron responses. We systematically analyzed the temporal dynamics of olfactory sensory neuron responses to a diverse set of odorants. We find that response dynamics depend on the combination of sensory neuron and odorant and that information about odorant identity can be extracted from the time course of the response. We also show that new response dynamics can arise when mixing two odorants. Our data show that temporal dynamics of odorant responses are able to significantly enhance the coding capacity of olfactory sensory systems. PMID- 28852845 TI - Short-term peripheral sensitization by brief exposure to pheromone components in Spodoptera littoralis. AB - In insects, the olfactory system displays a high degree of plasticity. In Spodoptera littoralis, pre-exposure of males to the sex pheromone has been shown to increase the sensitivity of the olfactory sensory neurons at peripheral level. In this study, we have investigated this sensitization effect by recording the electroantennographic responses of male antennae to the major sex pheromone component (Z,E)-9,11-tetradecadienyl acetate and to the minor components (Z,E) 9,12-tetradecadienyl acetate and (Z)-9-tetradecenyl acetate. Responses to the conjugated diene acetate at 1 and 10 ug and to the unconjugated ester at 10 ug at three different times (11, 22 and 33 min) after pre-exposure (T = 0 min) were significantly higher than those at T = 0, whereas no increase of sensitivity to the pheromone was elicited by any dose of the minor monoene acetate. In addition, pre-exposed antennae to sub-threshold amounts (0.1, 1 and 10 ng) of the major pheromone component also induced an increased response to the chemical at different times (5 and 15 min) after exposure. Our results revealed that pre exposed isolated antennae display a short-term higher sensitivity at the peripheral level when compared to naive antennae. In addition, we provide evidence of a peripheral sensitization mediated not only by the major pheromone component, but also by the minor unconjugated diene acetate, and the induction of this sensitivity appears to be dependent on the pre-exposure dose and the time span between pre-exposure and subsequent recordings. Possible implications of the sensitization effect displayed by the minor component for a more effective discrimination of the pheromone bouquets of other closely related species are highlighted. PMID- 28852846 TI - Leveraging the electronic health record to improve quality and safety in rheumatology. AB - During the last two decades, improving the quality and safety of healthcare has become a focus in rheumatology. Widespread use of electronic health records (EHRs) and the availability of digital data have the potential to drive quality improvement, improve patient outcomes, and prevent adverse events. In the coming years, developing and leveraging tools within the EHR will be the key to making the next big strides in improving the health of patients with rheumatoid arthritis and other rheumatic diseases, including building EHR infrastructure to capture patient outcomes and developing automated methods to retrieve information from free text of clinical notes. PMID- 28852848 TI - Set size influences the relationship between ANS acuity and math performance: a result of different strategies? AB - Previous research has proposed that the approximate number system (ANS) constitutes a building block for later mathematical abilities. Therefore, numerous studies investigated the relationship between ANS acuity and mathematical performance, but results are inconsistent. Properties of the experimental design have been discussed as a potential explanation of these inconsistencies. In the present study, we investigated the influence of set size and presentation duration on the association between non-symbolic magnitude comparison and math performance. Moreover, we focused on strategies reported as an explanation for these inconsistencies. In particular, we employed a non symbolic magnitude comparison task and asked participants how they solved the task. We observed that set size was a significant moderator of the relationship between non-symbolic magnitude comparison and math performance, whereas presentation duration of the stimuli did not moderate this relationship. This supports the notion that specific design characteristics contribute to the inconsistent results. Moreover, participants reported different strategies including numerosity-based, visual, counting, calculation-based, and subitizing strategies. Frequencies of these strategies differed between different set sizes and presentation durations. However, we found no specific strategy, which alone predicted arithmetic performance, but when considering the frequency of all reported strategies, arithmetic performance could be predicted. Visual strategies made the largest contribution to this prediction. To conclude, the present findings suggest that different design characteristics contribute to the inconsistent findings regarding the relationship between non-symbolic magnitude comparison and mathematical performance by inducing different strategies and additional processes. PMID- 28852847 TI - Distinct molecular profile of diffuse cerebellar gliomas. AB - Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs. PMID- 28852849 TI - The serine protease inhibitor of Kazal-type 7 (SPINK7) is expressed in human skin. AB - Proteases and their inhibitors play an important role in epidermal homeostasis. Their imbalance contributes to severe skin diseases. SPINK7 is a member of the SPINK protease inhibitor family and has been described so far as a cancer-related gene in the esophagus. Herein, we describe for the first time its expression in healthy human skin. Moreover, SPINK7 is up-regulated in inflammatory skin diseases like psoriasis and eczema as demonstrated by immunohistochemistry, though real-time PCR analyses revealed no significant up-regulation. In cultured keratinocytes, SPINK7 mRNA expression was up-regulated by IL-17A together with IFNgamma. Our observation points to a role of SPINK7 in skin homeostasis and its involvement in inflammatory skin diseases. PMID- 28852850 TI - Antimicrobial Mechanism of Oleanolic and Ursolic Acids on Streptococcus mutans UA159. AB - Triterpenoid saponin derivatives oleanolic acid (OA) and ursolic acid (UA), but not betulinic acid (BA), were previously found to have strong antimicrobial activity against Streptococcus mutans. OA and UA inhibited the transcription of genes related to peptidoglycan biosynthesis, thereby preventing bacterial growth. However, it is not clear whether this is the only pathway involved in the antimicrobial activity of these compounds against S. mutans. Therefore, we used quantitative real-time PCR (qPCR) and microarray analyses to examine the expression of genes related to essential metabolic pathways in S. mutans UA159 following incubation with OA, UA, or BA. An oligonucleotide array consisting of 5363 probes was designed to survey 1928 of the 1963 genes in the genome of S. mutans UA159. Genes that showed >2-fold changes in expression in response to the treatment conditions were annotated, and selected target genes involved in central metabolism were analyzed by qPCR. Microarray analysis confirmed that the gene expression patterns of the OA- and UA-treated cells differed from that of the BA-treated culture, indicating differences in the antimicrobial mechanism. In particular, the expression of pfk and pykF, coding for glycolysis regulatory proteins phosphofructokinase and pyruvate kinase, respectively, were significantly decreased in the OA and UA groups (P < 0.05), as were genes involved in fatty acid and amino acid synthesis. In addition, the microarray analysis confirmed previous qPCR results showing that peptidoglycan synthesis is down-regulated in the OA- and UA-treated groups. OA and UA also appear to decrease the generation of organic acids by S. mutans UA159, which would have an anticaries effect. Overall, these findings suggest that OA and UA affect multiple genes involved in the central metabolism of S. mutans, with inhibition of glycolysis, fatty acid synthesis, amino acid synthesis, and peptidoglycan synthesis, all contributing to their antimicrobial activity. PMID- 28852851 TI - IL-36 cytokines are increased in acne and hidradenitis suppurativa. AB - Interleukin (IL)-36 cytokines are new members of the IL-1 family, which include pro-inflammatory factors, IL-36alpha, IL-36beta and IL-36gamma, and a natural receptor antagonist IL-36Ra. Over recent years, much has been learned on their important functions in the regulation of immune response and, especially, on their role in many inflammatory skin diseases. However, to date, no data have been reported on their possible involvement in acne and hidradenitis suppurativa (HS). Here, we have shown that IL-36alpha, IL-36beta, and IL-36gamma are increased in lesional skin of acne and HS, highlighting their possible pathogenetic contribution to these two skin conditions. In contrast, IL-36Ra (the anti-inflammatory member of IL-36 sub-family) was increased just in psoriasis, suggesting that an imbalance in IL-36/IL36Ra functions could play a role in the phenotype of skin damage. One of the consequences of this imbalance may be the increased induction of IL-8 that we found higher in acne, HS, and ACD respect to psoriasis. PMID- 28852852 TI - Hemophilic pseudotumor of the mandible in a patient with hemophilia B. AB - INTRODUCTION: Hemophilic pseudotumor is a rare complication occurring in patients with hemophilia, frequently seen in the femur, tibia, pelvic bones, iliac bones, or rarely in the maxillofacial region. CASE REPORT: A 7-year-old male reported with a spontaneous extra-oral swelling that was managed with pre-operative transfusion of factor IX along with curettage of the lesion. Our report presents only the fourth case in literature wherein this tumor presented in a patient with hemophilia B. FINDING: Hemophilic pseudotumor is a rare entity in the maxillofacial region. High degree of suspicion is required for diagnosis, and close coordination between the medical and surgical teams aids in management. PMID- 28852853 TI - Predicting symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage with an artificial neural network in a pediatric population. AB - PURPOSE: Artificial neural networks (ANN) are increasingly applied to complex medical problem solving algorithms because their outcome prediction performance is superior to existing multiple regression models. ANN can successfully identify symptomatic cerebral vasospasm (SCV) in adults presenting after aneurysmal subarachnoid hemorrhage (aSAH). Although SCV is unusual in children with aSAH, the clinical consequences are severe. Consequently, reliable tools to predict patients at greatest risk for SCV may have significant value. We applied ANN modeling to a consecutive cohort of pediatric aSAH cases to assess its ability to predict SCV. METHODS: A retrospective chart review was conducted to identify patients < 21 years of age who presented with spontaneously ruptured, non traumatic, non-mycotic, non-flow-related intracranial arterial aneurysms to our institution between January 2002 and January 2015. Demographics, clinical, radiographic, and outcome data were analyzed using an adapted ANN model using learned value nodes from the adult aneurysmal SAH dataset previously reported. The strength of the ANN prediction was measured between - 1 and 1 with - 1 representing no likelihood of SCV and 1 representing high likelihood of SCV. RESULTS: Sixteen patients met study inclusion criteria. The median age for aSAH patients was 15 years. Ten underwent surgical clipping and 6 underwent endovascular coiling for definitive treatment. One patient experienced SCV and 15 did not. The ANN applied here was able to accurately predict all 16 outcomes. The mean strength of prediction for those who did not exhibit SCV was - 0.86. The strength for the one patient who did exhibit SCV was 0.93. CONCLUSIONS: Adult derived aneurysmal SAH value nodes can be applied to a simple AAN model to accurately predict SCV in children presenting with aSAH. Further work is needed to determine if ANN models can prospectively predict SCV in the pediatric aSAH population in toto; adapted to include mycotic, traumatic, and flow-related origins as well. PMID- 28852854 TI - Comparative study of chemical neuroanatomy of the olfactory neuropil in mouse, honey bee, and human. AB - Despite divergent evolutionary origins, the organization of olfactory systems is remarkably similar across phyla. In both insects and mammals, sensory input from receptor cells is initially processed in synaptically dense regions of neuropil called glomeruli, where neural activity is shaped by local inhibition and centrifugal neuromodulation prior to being sent to higher-order brain areas by projection neurons. Here we review both similarities and several key differences in the neuroanatomy of the olfactory system in honey bees, mice, and humans, using a combination of literature review and new primary data. We have focused on the chemical identity and the innervation patterns of neuromodulatory inputs in the primary olfactory system. Our findings show that serotonergic fibers are similarly distributed across glomeruli in all three species. Octopaminergic/tyraminergic fibers in the honey bee also have a similar distribution, and possibly a similar function, to noradrenergic fibers in the mammalian OBs. However, preliminary evidence suggests that human OB may be relatively less organized than its counterparts in honey bee and mouse. PMID- 28852856 TI - Chronic stress targets adult neurogenesis preferentially in the suprapyramidal blade of the rat dorsal dentate gyrus. AB - The continuous generation of new neurons and glial cells in the adult hippocampal dentate gyrus (DG) represents an important form of adult neuroplasticity, involved in normal brain function and behavior but also associated with the etiopathogenesis and treatment of psychiatric disorders. Despite the large number of studies addressing cell genesis along the septotemporal axis, data on the anatomical gradients of cytogenesis along the DG transverse axis is scarce, especially after exposure to stress. As such, in this study we characterized both basal proliferation and survival of adult-born neural cells along the transverse axis of the rat dorsal DG, and after stress exposure. In basal conditions, both proliferating cells and newborn neurons and glial cells were preferentially located at the subgranular zone and suprapyramidal blade. Exposure to chronic stress induced an overall decrease in the generation of adult-born neural cells and, more specifically, produced a regional-specific decrease in the survival of adult-born neurons at the suprapyramidal blade. No particular region-specific alterations were observed on surviving adult-born glial cells. This work reveals, for the first time, a distinct survival profile of adult-born neural cells, neurons and glial cells, among the transverse axis of the DG, in both basal and stress conditions. Our results unveil that adult-born neurons are preferentially located in the suprapyramidal blade and suggest a regional-specific impact of chronic stress in this blade with potential repercussions for its functional significance. PMID- 28852857 TI - Efficacy of laparoscopic herniorrhaphy for treating incarcerated pediatric inguinal hernia. AB - PURPOSE: Inguinal hernia repair is one of the most common elective surgeries. Most patients present with reducible inguinal bulging; however, in cases of incarcerated inguinal hernia (IIH), an emergency surgery is required. Here, we report the surgical outcomes of a laparoscopic approach for IIH. METHODS: Laparoscopic herniorrhaphy was performed in 4782 pediatric patients from September 2012 to December 2016 at Damsoyu Hospital, Seoul, Korea. Among them, the surgical outcomes of 164 IIH patients were retrospectively analyzed. RESULTS: Incarcerated organs comprised 51 ovaries, 103 intestines, and 10 omentums. The ovary (51/66) and intestine (88/98) were the most common incarcerated organs in females and males, respectively. The intestines, ovaries, and omentums were preserved in most cases. An oophorectomy was performed in one female patient with an unrecovered ischemic ovary, and an orchiectomy was performed in a male patient with ischemic testis because of cord vessel compression caused by intestine incarceration. In male pediatric patients, an age of <12 months and symptom duration of >1 week were risk factors for IIH, whereas in female pediatric patients, an age of <12 months and symptom duration of <=1 week were risk factors for IIH. CONCLUSIONS: The intestines and ovaries were the most commonly herniated organs in male and female pediatric patients, respectively. Intracorporeal organ reduction was easily performed with a laparoscopic instrument. PMID- 28852855 TI - How does the stimulus define exocytosis in adrenal chromaffin cells? AB - The extent and type of hormones and active peptides secreted by the chromaffin cells of the adrenal medulla have to be adjusted to physiological requirements. The chromaffin cell secretory activity is controlled by the splanchnic nerve firing frequency, which goes from approximately 0.5 Hz in basal conditions to more than 15 Hz in stress. Thus, these neuroendocrine cells maintain a tonic release of catecholamines under resting conditions, massively discharge intravesicular transmitters in response to stress, or adequately respond to moderate stimuli. In order to adjust the secretory response to the stimulus, the adrenal chromaffin cells have an appropriate organization of Ca2+ channels, secretory granules pools, and sets of proteins dedicated to selectively control different steps of the secretion process, such as the traffic, docking, priming and fusion of the chromaffin granules. Among the molecules implicated in such events are the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, Ca2+ sensors like Munc13 and synaptotagmin-1, chaperon proteins such as Munc18, and the actomyosin complex. In the present review, we discuss how these different actors contribute to the extent and maintenance of the stimulus-dependent exocytosis in the adrenal chromaffin cells. PMID- 28852858 TI - Wallemia peruviensis sp. nov., a new xerophilic fungus from an agricultural setting in South America. AB - We obtained four isolates of the xerophilic genus Wallemia from the rooftop of a house made of red brick and cement in an agronomic field planted with common beans and maize in Pachacamac, Lima, Peru. Bayesian phylogenetic analysis with rDNA gene sequences showed these Wallemia isolates form a distinct and strongly supported clade closely related to W. hederae. We examined the macro and micromorphology, growth rate and production of exudates of isolates on media containing different amounts of glucose and NaCl (water activity from 0.9993 to 0.8480). Their chaotropic and kosmotropic tolerance were tested on media with multiple molar concentrations of MgCl2 and MgSO4 (water activity from 0.9880 to 0.7877). Isolates are xerophilic and halotolerant, growing on 17% NaCl supplemented media (water activity = 0.8480). Maximum concentrations of MgCl2 and MgSO4 at which growth was observed were 1.7 and 3.5 M, respectively. Isolates were shown to represent a novel species, described as Wallemia peruviensis sp. nov. In contrast to W. hederae, W. peruviensis does not produce exudates on malt extract agar + 17% NaCl media. An updated dichotomous key to Wallemia species is provided. This is the first new species of Wallemia described from South America and the first association of a Wallemia species with an agricultural environment on this continent. PMID- 28852859 TI - Neuronal connections of the central amygdalar nucleus with refeeding-activated brain areas in rats. AB - Following fasting, satiety is accompanied by neuronal activation in brain areas including the central amygdalar nucleus (CEA). Since CEA is known to inhibit food intake, we hypothesized that CEA contributes to the termination of meal during refeeding. To better understand the organization of this satiety-related circuit, the interconnections of the CEA with refeeding-activated neuronal groups were elucidated using retrograde (cholera toxin-beta subunit, CTB) and anterograde (phaseolus vulgaris leucoagglutinin, PHA-L) tracers in male rats. C-Fos immunoreactivity was used as marker of neuronal activation. The refeeding activated input of the CEA primarily originated from the paraventricular thalamic, parasubthalamic and parabrachial nuclei. Few CTB-c-Fos double-labeled neurons were detected in the prefrontal cortex, lateral hypothalamic area, nucleus of the solitary tract (NTS) and the bed nuclei of the stria terminalis (BNST). Only few refeeding-activated proopiomelanocortin-producing neurons of the arcuate nucleus projected to the CEA. Anterograde tract tracing revealed a high density of PHAL-labeled axons contacted with refeeding-activated neurons in the BNST, lateral hypothalamic area, parasubthalamic, paraventricular thalamic and parabrachial nuclei and NTS; a low density of labeled axons was found in the paraventricular hypothalamic nucleus. Chemogenetic activation of the medial CEA (CEAm) inhibited food intake during the first hour of refeeding, while activation of lateral CEA had no effect. These data demonstrate the existence of reciprocal connections between the CEA and distinct refeeding-activated hypothalamic, thalamic and brainstem nuclei, suggesting the importance of short feedback loops in the regulation of satiety and importance of the CEAm in the regulation of food intake during refeeding. PMID- 28852860 TI - Bilateral endoscopic totally extraperitoneal (TEP) inguinal hernia repair does not impair male fertility. AB - PURPOSE: Endoscopic totally extraperitoneal (TEP) hernia repair with polypropylene mesh has become a well-established technique. However, since the mesh is placed in close contact with the spermatic cord, mesh-induced inflammation may affect its structures, possibly resulting in impaired fertility. The aim of this observational prospective cohort study was to assess fertility after bilateral endoscopic TEP inguinal hernia repair in male patients. METHODS: Fifty-seven male patients (22-60 years old) with primary, reducible, bilateral inguinal hernias underwent elective bilateral endoscopic TEP hernia repair with use of polypropylene mesh. The primary outcome was testicular perfusion; secondary outcomes were testicular volume, endocrinological status, and semen quality. All patients were assessed preoperatively and 6 months postoperatively. RESULTS: Follow-up was completed in 44 patients. No statistically significant differences in measurements of testicular blood flow parameters or testicular volume were found. Postoperative LH levels were significantly higher [preoperative median 4.3 IU/L (IQR 3.4-5.3) versus postoperative median 5.0 IU/L (IQR 3.6-6.5), p = 0.03]. Levels of inhibin B were significantly lower postoperatively [preoperative median 139.0 ng/L (IQR 106.5-183.0) versus postoperative median 27.0 ng/L (IQR 88.3-170.9), p = 0.01]. No significant changes in FSH or testosterone levels were observed. There were no differences in semen quality. CONCLUSIONS: Our data suggest that bilateral endoscopic TEP hernia repair with polypropylene mesh does not impair fertility, as no differences in testicular blood flow, testicular volume, or semen quality were observed. Postoperative levels of LH and inhibin B differed significantly from preoperative measurements, yet no clinical relevance could be ascribed to these findings. PMID- 28852861 TI - Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease. AB - BACKGROUND: The mucosa-associated gut microbiota directly modulates epithelial and mucosal function. In this study, we investigated the mucosa-associated microbial community in patients with inflammatory bowel disease (IBD), using endoscopic brush samples. METHODS: A total of 174 mucus samples from 43 patients with ulcerative colitis (UC), 26 with Crohn's disease (CD) and 14 non-IBD controls were obtained by gentle brushing of mucosal surfaces using endoscopic cytology brushes. The gut microbiome was analyzed using 16S rRNA gene sequencing. RESULTS: There were no significant differences in microbial structure among different anatomical sites (the ileum, cecum and sigmoid colon) within individuals. There was, however, a significant difference in microbial structure between CD, UC and non-IBD controls. The difference between CD and non-IBD controls was more marked than that between UC patients and non-IBD controls. alpha-Diversity was significantly lower in UC and CD patients than non-IBD controls. When comparing CD patients with non-IBD controls, the phylum Proteobacteria was significantly increased and the phyla Firmicutes and Bacteroidetes were significantly reduced. These included a significant increase in the genera Escherichia, Ruminococcus (R. gnavus), Cetobacterium, Actinobacillus and Enterococcus, and a significant decrease in the genera Faecalibacterium, Coprococcus, Prevotella and Roseburia. Comparisons between CD and UC patients revealed a greater abundance of the genera Escherichia, Ruminococcus (R. gnavus), Clostridium, Cetobacterium, Peptostreptococcus in CD patients, and the genera Faecalibacterium, Blautia, Bifidobacterium, Roseburia and Citrobacter in UC patients. CONCLUSIONS: Mucosa-associated dysbiosis was identified in IBD patients. CD and UC may be distinguishable from the mucosa associated microbial community structure. PMID- 28852863 TI - Self-care, quality of life and clinical outcomes of type 2 diabetes patients: an observational cross-sectional study. AB - AIMS: To describe self-care of T2DM patients and to evaluate outcomes associated with self-care in T2DM patients. METHODS: A multicentre cross-sectional study was conducted on a sample of 302 randomly selected T2DM patients. Clinical and socio demographic data were collected by medical records. The Summary of Diabetes Self care Activities was used to measure self-care about diet, blood testing, exercise and foot care. The EQ-5D was used to measure perceived quality of life. Multiple regression models were used to evaluate the associations between self-care and body mass index (BMI), glycated haemoglobin (HbA1c), presence of diabetes complications and quality of life (QoL). RESULTS: Self-care was lower about exercise (median = 2.0) and foot care (median = 3.5) than about diet (median = 5.2) and blood testing (median = 4.5). HbA1c was associated with diet (p = 0.025), exercise (p = 0.017) and blood testing (p = 0.034). BMI was associated with exercise (p = 0.0071). Diabetes complications were associated with exercise (p = 0.031) and blood testing (p < 0.009). QoL was associated with exercise (p < 0.0001), blood testing (p = 0.032) and foot care (p = 0.013). CONCLUSIONS: Self care influences both clinical outcomes and quality of life of T2DM patients. Although exercise is more frequently associated with positive outcomes, it is particularly poor in T2DM population. Blood testing and foot care should be performed to prevent complications and not only when a health problem is already occurred. Interventions aimed to improve exercise are recommended. Further research is needed to explore barriers to exercise. PMID- 28852862 TI - Connections between the zona incerta and superior colliculus in the monkey and squirrel. AB - The zona incerta contains GABAergic neurons that project to the superior colliculus in the cat and rat, suggesting that it plays a role in gaze changes. However, whether this incertal connection represents a general mammalian pattern remains to be determined. We used neuronal tracers to examine the zona incerta connections with the midbrain tectum in the gray squirrel and macaque monkey. Collicular injections in both species revealed that most incertotectal neurons lay in the ventral layer, but anterogradely labeled tectoincertal terminals were found in both the dorsal and ventral layers. In the monkey, injections of the pretectum also produced retrograde labeling, but mainly in the dorsal layer. The dendritic fields of incertotectal and incertopretectal cells were generally contained within the layer inhabited by their somata. The macaque, but not the squirrel, zona incerta extended dorsolaterally, within the external medullary lamina. Zona incerta injections produced retrogradely labeled neurons in the superior colliculus of both species. In the squirrel, most cells inhabited the lower sublamina of the intermediate gray layer, but in the monkey, they were scattered throughout the deeper layers. Labeled cells were present among the pretectal nuclei in both species. Labeled terminals were concentrated in the lower sublamina of the intermediate gray layer of both species, but were dispersed among the pretectal nuclei. In summary, an incertal projection that is concentrated on the collicular motor output layers and that originates in the ventral layer of the ipsilateral zona incerta is a common mammalian feature, suggesting an important role in collicular function. PMID- 28852865 TI - Microalgal cultivation and hydrodynamic characterization using a novel tubular photobioreactor with helical blade rotors. AB - Industrial-scale microalgal cultivation for food, feedstocks and biofuel production is limited by several engineering factors, such as cultivation systems. As a closed microalgal growth system, tubular photobioreactors are the most preferred ones in the mass algae production. In this work, microalgal cultivation and hydrodynamic characterization using a novel tubular photobioreactor equipped with helical blade rotors (HBRs) were investigated, with the aid of computational fluid dynamics and cultivation experiments to evaluate the effect of HBRs on the performance of tubular photobioreactor and growth of the Chlorella sp. The results showed that the use of HBRs in tubular photobioreactors would result in swirl flow and increase of radial velocity and circumferential velocity; it also indicated that the HBRs would enable microalgal cells to move forward helically and to be shuttled alternatively between the light zone and the dark zone. This has led to the faster growth rate of Chlorella sp. and no attachment on the tube surface in the tubular photobioreactor during the whole cultivation cycle. In conclusion, the HBRs could improve the performance of tubular photobioreactors and thus impact positively on the cultivation of microalgae cells for biotechnological industry. PMID- 28852864 TI - Epidemiological factors related to hospitalization due to influenza in children below 6 months of age. AB - : The aim of this study was to address the epidemiological factors associated to hospital admissions due to influenza in infants younger than 6 months. A case control study was performed in a tertiary hospital in Spain. Cases were infants under 6 months of age without comorbidities who were admitted due to influenza between October 2010 and March 2015. Controls were healthy infants younger than 6 months who were hospitalized due to non-respiratory illness or non-infectious diseases (urinary tract infection was included as controls). Data were retrospectively collected from medical records and phone interviews. A total of 88 cases and 122 controls we included. From univariate analysis, differences were found in relation to maternal age (43.1 +/- 4.95 vs 32 +/- 5.3), paternal age (37 +/- 6.4 vs 34.5 +/- 6.1), having siblings (79 vs 24%), siblings below 4 years old (54 vs 15%), and having vaccinated grandparents (18 vs 39%) (p < 0.05). After logistic regression, having vaccinated grandparents was an independent protective factor (OR 0.22 [CI95%; 0.05-0.91]), while having siblings was a risk factor (OR 15.8 [CI95% 3.15-79.5]). Vaccination during pregnancy was highly uncommon (3.5 vs 8.3%; p = 0.3). CONCLUSION: This study underlines the importance of increasing influenza immunization among household contacts of infants below 6 months to prevent their influenza admission. What is Known: * Infants younger than 6 months old are considered a high-risk population. * Vaccination against influenza is not licensed in infants below 6 months. What is New: * Increasing vaccination coverage in elderly people could reduce infants' hospitalization rates. * Cocoon immunization strategy may reduce the admission of infants. PMID- 28852866 TI - Distance- and density-dependent leaf dynamics of seedlings of a tropical rainforest tree. AB - Parental distance and plant density dependence of seedling leaf turnover and survival was examined to investigate predictions of the Janzen-Connell hypothesis. The focal study species, Shorea macroptera is a canopy tree species in a lowland rain forest in peninsular Malaysia. We found that the peak of the distribution of plants shifted from 3-6 m to 6-9 m during the course of the change from seedling to sapling stage. The leaf demography of the seedlings was influenced by their distance from the adult tree and also by the seedling density. Although significant density- and distance dependence in leaf production was not detected, seedling leaf loss decreased with distance from the parent tree and with seedling density. Similarly, leaf damage was not found to be distance- or density-dependent, but net leaf gain of seedlings increased with distance from the parent tree. Although no significant distance- or density-dependence was evident in terms of leaf damage, significant distance dependence of the net leaf gain was found. Thus, we concluded that positive distance dependence in the leaf turnover of seedlings may gradually contribute to a shift in the distribution pattern of the progeny through reductions in growth and survivorship. PMID- 28852867 TI - No evidence of task co-representation in a joint Stroop task. AB - People working together on a task must often represent the goals and salient items of their partner. The aim of the present study was to study the influence of joint task representations in an interference task in which the congruency relies on semantic identity. If task representations are shared between partners in a joint Stroop task (co-representation account), we hypothesized that items in the response set of one partner might influence performance of the other. In Experiment 1, pairs of participants sat side by side. Each participant was instructed to press one of two buttons to indicate which of two colors assigned to them was present, ignoring the text and responding only to the pixel color. There were three types of incongruent distractor words: names of colors from their own response set, names of colors from the other partner's response set, and neutral words for colors not used as font colors. The results of Experiment 1 showed that when people were doing this task together, distractor words from the partner's response set interfered more than neutral words and just as much as the words from their own response color set. However, in three follow-up experiments (Experiments 2a, 2b, and 2c), we found an elevated interference for the other response-set words even though no co-actor was present. The overall pattern of results across our study suggests that an alternative response set, regardless of whether it belonged to a co-actor or to a non-social no-go condition, evoked equal amounts of interference comparable to those of the own response set. Our findings are in line with a theory of common coding, in which all events irrespective of their social nature-are represented and can influence behavior. PMID- 28852869 TI - Bismuth adjuvant and adverse effects of chemotherapy: issues with statistical analyses. PMID- 28852868 TI - Prevalence and predictors of anxiety disorders amongst low-income pregnant women in urban South Africa: a cross-sectional study. AB - Anxiety is highly prevalent in many populations; however, the burden of anxiety disorders amongst pregnant women in low-resource settings is not well documented. We investigated the prevalence and predictors of antenatal anxiety disorders amongst low-income women living with psychosocial adversity. Pregnant women were recruited from an urban, primary level clinic in Cape Town, South Africa. The Mini-International Neuropsychiatric Interview diagnostic interview assessed prevalence of anxiety disorders. Four self-report questionnaires measured psychosocial characteristics. Logistic regression models explored demographic and socioeconomic characteristics, psychosocial risk factors and psychiatric comorbidity as predictors for anxiety disorders. Amongst 376 participants, the prevalence of any anxiety disorder was 23%. Although 11% of all women had post traumatic stress disorder, 18% of the total sample was diagnosed with other anxiety disorders. Multivariable analysis revealed several predictors for anxiety including a history of mental health problems (adjusted odds ratio [AOR] 4.11; 95% confidence interval (CI) 2.03-8.32), Major depressive episode (MDE) diagnosis (AOR 3.83; CI 1.99-7.31), multigravidity (AOR 2.87; CI 1.17-7.07), food insecurity (AOR 2.57; CI 1.48-4.46), unplanned and unwanted pregnancy (AOR 2.14; CI 1.11-4.15), pregnancy loss (AOR 2.10; CI 1.19-3.75) and experience of threatening life events (AOR 1.30; CI 1.04-1.57). Increased perceived social support appeared to reduce the risk for antenatal anxiety (AOR 0.95; CI 0.91 0.99). A range of antenatal anxiety disorders are prevalent amongst pregnant women living in low-resource settings. Women who experience psychosocial adversity may be exposed to multiple risk factors, which render them vulnerable to developing antenatal anxiety disorders. PMID- 28852870 TI - Top-down effects of an invasive omnivore: detection in long-term monitoring of large-river reservoir chlorophyll-a. AB - Invasive species are capable of altering ecosystems through the consumption of basal resources. However, quantifying the effects of invasive species in large ecosystems is challenging. Measuring changes in basal resources (i.e., phytoplankton) at an ecosystem scale is an important and potentially translatable response vital to the understanding of how introduced species influence ecosystems. In this study, we analyzed patterns of early summer chlorophyll-a in a large-river reservoir in response to invasion of silver carp (Hypophthalmichthys molitrix). We used 25 years of ecological data from a 30-km reach of Kentucky Lake collected before and after silver carp establishment. We found significant decreases in chlorophyll-a within certain reservoir habitats since establishment of silver carp. Additionally, environmental and biological drivers of phytoplankton production showed no significant differences before and after invasion. These results suggest seasonal, and habitat-specific consumptive effects of invasive silver carp on an important basal food web resource. Further, our results convey the utility of long-term quantitative biological and physiochemical data in understanding ecosystem responses to elements of global change (i.e., species invasions). Importantly, the observed changes in the basal food web resource of Kentucky Lake may apply to other ecosystems facing invasion by silver carp (e.g., Laurentian Great Lakes). Our study offers insight into the mechanisms by which silver carp may influence ecosystems and furthers our understanding of invasive omnivores. PMID- 28852872 TI - Amino acids are major energy substrates for tissues of hybrid striped bass and zebrafish. AB - Fish generally have much higher requirements for dietary protein than mammals, and this long-standing puzzle remains unsolved. The present study was conducted with zebrafish (omnivores) and hybrid striped bass (HSB, carnivores) to test the hypothesis that AAs are oxidized at a higher rate than carbohydrates (e.g., glucose) and fatty acids (e.g., palmitate) to provide ATP for their tissues. Liver, proximal intestine, kidney, and skeletal muscle isolated from zebrafish and HSB were incubated at 28.5 degrees C (zebrafish) or 26 degrees C (HSB) for 2 h in oxygenated Krebs-Henseleit bicarbonate buffer (pH 7.4, with 5 mM D glucose) containing 2 mM L-[U-14C]glutamine, L-[U-14C]glutamate, L-[U 14C]leucine, or L-[U-14C]palmitate, or a trace amount of D-[U-14C]glucose. In parallel experiments, tissues were incubated with a tracer and a mixture of unlabeled substrates [glutamine, glutamate, leucine, and palmitate (2 mM each) plus 5 mM D-glucose]. 14CO2 was collected to calculate the rates of substrate oxidation. In the presence of glucose or a mixture of substrates, the rates of oxidation of glutamate and ATP production from this AA by the proximal intestine, liver, and kidney of HSB were much higher than those for glucose and palmitate. This was also true for glutamate in the skeletal muscle and glutamine in the liver of both species, glutamine in the HSB kidney, and leucine in the zebrafish muscle, in the presence of a mixture of substrates. We conclude that glutamate plus glutamine plus leucine contribute to ~80% of ATP production in the liver, proximal intestine, kidney, and skeletal muscle of zebrafish and HSB. Our findings provide the first direct evidence that the major tissues of fish use AAs (mainly glutamate and glutamine) as primary energy sources instead of carbohydrates or lipids. PMID- 28852873 TI - Barriers and enablers to implementing scalp cooling in Australia: a qualitative study of health professionals' attitudes to and experience with scalp cooling. AB - BACKGROUND: Chemotherapy-induced alopecia is a common and distressing adverse event for patients. Scalp cooling to reduce this alopecia has been available in Europe for more than a decade, but only recently introduced in Australia. The aim of this study was to qualitatively explore health professionals' perceptions of the barriers and enablers to the implementation of scalp cooling in Australian cancer centres. METHODS: Using a qualitative methodology, telephone interviews were conducted with 21 health professionals working in a tumour stream where chemotherapy-induced alopecia is an adverse event of treatment. Participants were recruited from five centres in Australia where scalp cooling is currently available and one centre without access to the technology. RESULTS: Four interrelated themes were identified: (1) health professional attitudes, (2) concerns for patient equity, (3) logistical considerations and (4) organisational support. CONCLUSIONS: This qualitative study provides the first methodological exploration of Australian health professionals' perceptions of barriers and enablers to scalp cooling uptake. The results highlighted health professional support drives the introduction of scalp cooling. Integration of the technology requires adjustments to nursing practice to manage the increased time, workload and change in patient flow. Strategies to manage the change in practice and organisational support for change in work flow are essential for successful implementation into routine care. PMID- 28852874 TI - Body mass and wing shape explain variability in broad-scale bird species distributions of migratory passerines along an ecological barrier during stopover. AB - Migrating birds are under selective pressure to complete long-distance flights quickly and efficiently. Wing morphology and body mass influence energy expenditure of flight, such that certain characteristics may confer a greater relative advantage when making long crossings over ecological barriers by modifying the flight range or speed. We explored the possibility, among light (mass <50 g) migrating passerines, that species with relatively poorer flight performance related to wing shape and/or body mass have a lower margin for error in dealing with the exigencies of a long water crossing across the Gulf of Mexico and consequently minimize their travel time or distance. We found that species mean fat-free body mass and wing tip pointedness independently explained variability among species distributions within ~50 km from the northern coast. In both spring and autumn, lighter (i.e., slower flying) species and species with more rounded wings were concentrated nearest the coastline. Our results support the idea that morphology helps to shape broad-scale bird distributions along an ecological barrier and that migration exerts some selective force on passerine morphology. Furthermore, smaller species with less-efficient flight appear constrained to stopping over in close proximity to ecological barriers, illustrating the importance of coastal habitats for small passerine migrants. PMID- 28852875 TI - Commentary on: undertreatment trend in elderly lung cancer patients in Brazil. PMID- 28852871 TI - SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities. AB - Low levels of the survival of motor neuron (SMN) protein cause the neurodegenerative disease spinal muscular atrophy (SMA). SMA is a pediatric disease characterized by spinal motor neuron degeneration. SMA exhibits several levels of severity ranging from early antenatal fatality to only mild muscular weakness, and disease prognosis is related directly to the amount of functional SMN protein that a patient is able to express. Current therapies are being developed to increase the production of functional SMN protein; however, understanding the effect that natural stresses have on the production and function of SMN is of critical importance to ensuring that these therapies will have the greatest possible effect for patients. Research has shown that SMN, both on the mRNA and protein level, is highly affected by cellular stress. In this review we will summarize the research that highlights the roles of SMN in the disease process and the response of SMN to various environmental stresses. PMID- 28852877 TI - First report of postoperative intracranial Weeksella virosa infection. AB - A 49-year-old female underwent multiple craniotomies for resection of recurrent malignant meningiomata (WHO grade III). She re-presented with sepsis due to a ventricular empyema. The craniotomy wound was urgently debrided, and isolates of the gram-negative rod, Weeksella virosa, were identified on 16S PCR. This species is most commonly found as a genitourinary commensal. We present the first documented intracranial infection by Weeksella virosa and its successful treatment with oral beta-lactam antibiotics. PMID- 28852876 TI - A possible mechanism of inhibition of U87MG and SH-SY5Y cancer cell proliferation by diallyl trisulfide and other aspects of its activity. AB - The study was conducted to elucidate the mechanism of antiproliferative and antioxidative action of diallyl trisulfide (DATS), a garlic-derived organosulfur compound. Changes in the L-cysteine desulfuration, and the levels of cystathionine and non-protein thiols in DATS-treated human glioblastoma (U87MG) and neuroblastoma (SH-SY5Y) cells were investigated. The inhibition of proliferation of the investigated cells by DATS was correlated with an increase in the inactivated form of Bcl-2. In U87MG cells, an increased level of sulfane sulfur and an increased activity of 3-mercaptopyruvate sulfurtransferase (MPST) and rhodanese, the enzymes involved in sulfane sulfur generation and transfer, suggest that DATS can function as a donor of sulfane sulfur atom, transferred by sulfurtransferases, to sulfhydryl groups of cysteine residues of Bcl-2 and in this way lower the level of active form of Bcl-2 by S-sulfuration. Diallyl trisulfide antioxidative effects result from an increased level of cystathionine, a precursor of cysteine, and an increased glutathione level. MPST and rhodanese, the level of which is increased in the presence of DATS, can serve as antioxidant proteins. PMID- 28852878 TI - Compensating for cross-reactions using avidity and computation in a suspension multiplex immunoassay for serotyping of Zika versus other flavivirus infections. AB - The recent spread of Zika virus (ZIKV) in the Americas and Asia necessitates an increased preparedness for improved maternal and perinatal health and blood safety. However, serological cross-reactions, especially to Dengue virus (DENV), complicate ZIKV antibody serodiagnosis. A novel "pan-Flavi" suspension multiplex immunoassay (PFSMIA) using 25 antigens, whole virus (WV), non-structural protein 1 (NS1), and envelope (E) proteins, from 7 zoonotic flaviviruses for specific detection of ZIKV and DENV IgM and IgG was developed. Patterns of antibody cross reactivity, avidity, and kinetics were established in 104 sera from returning travelers with known ZIKV and DENV infections. PFSMIA gave IgM- and IgG sensitivities for both viruses of 96-100%, compared to an immunofluorescence assay. Main IgM cross-reactions were to NS1, for IgG to the E and WV antigens. Infecting virus yielded reactivity to several antigens of the homologous virus, while cross-reactions tended to occur only to a single antigen from heterologous virus(es). A specificity-enhancing computer procedure took into account antibody isotype, number of antibody-reactive antigens per virus, avidity, average degree of cross-reactivity to heterologous flavivirus antigens, and reactivity changes in serial sera. It classified all 50 cases correctly. Applied to sera from 200 pregnant women and 173 blood donors from Sweden, one blood donor was found ZIKV NS1 IgM positive, and another as ZIKV NS1 IgG positive. These samples did not react with other ZIKV antigens and were thereby judged as false-positives. PFSMIA provided sensitive and specific ZIKV and DENV serology, warranting high throughput serological surveillance and a minimized need for laborious and expensive virus neutralization assays. PMID- 28852879 TI - Using fluorescence lymphangiography to define the ileocolic mesentery: proof of concept for the watershed area using real-time imaging. AB - Recent advances in mesenteric science have demonstrated that the mesentery is a continuous structure with a 'watershed' area at the mesenteric apex between the right colon and terminal ileum, where lymphatic flow can proceed either proximally or distally. With this new understanding of the anatomy, functional features are emerging, which can have an impact on surgical management. Fluorescence lymphangiography or lymphoscintigraphy with indocyanine green allows real-time visualization of lymphatic channels, which highlights sentinel lymph nodes and may facilitate identification of the ideal margins for mesenteric lymphadenectomy during bowel resection for colon cancer. By using this novel technology, it is possible to demonstrate a watershed area in the ileocolic region and may facilitate more precise mesenteric dissection. In the present study, we provide proof of concept for the ileocolic watershed area using fluorescence lymphangiography. PMID- 28852880 TI - A systematic review and meta-analysis of the direct anterior approach for hemiarthroplasty for femoral neck fracture. AB - BACKGROUND: We performed a systematic review and meta-analysis to assess whether the direct anterior approach (DAA) is associated with improved functional and clinical outcomes compared to other surgical approaches for hemiarthroplasty for displaced femoral neck fractures. MATERIALS AND METHODS: Randomized trials and cohort studies of hemiarthroplasty performed via DAA versus another surgical approach (anterolateral, lateral, posterolateral, posterior) were included. Our primary outcome was postoperative functional mobility. Secondary outcomes included overall complication rate, dislocation rate, perioperative fracture, infection rate, re-operation rate, overall mortality, operative time, pain, intra operative blood loss, and length of stay. RESULTS: Nine studies met inclusion criteria, comprising a total of 698 hips (330 direct anterior, 57 anterolateral, 89 lateral, 114 posterolateral, 108 posterior approach). With regard to functional mobility, DAA was favored in 4 studies, and no study favored another approach over DAA. DAA had a significantly lower dislocation rate compared to posterior capsular approaches. Analysis of other secondary outcomes did not identify statistically significant differences. CONCLUSION: This is the first systematic review and meta-analysis of the DAA for hemiarthroplasty. Available evidence suggests superior early functional mobility with the DAA. The DAA is associated with a significantly lower dislocation rate compared to posterior capsular approaches for hemiarthroplasty. PMID- 28852881 TI - iTRAQ-based proteomics monitors the withering dynamics in postharvest leaves of tea plant (Camellia sinensis). AB - Tea plant [Camellia sinensis (L.) O. Kuntze] is a typical leaf-type beverage crop. Many secondary metabolites, such as tea polyphenols, theanine, and caffeine that accumulated in tea leaves are beneficial to human health. The fresh leaves of tea plant are harvested and timely processed into tea products with different flavors. The withering of fresh tea leaves is the first step in tea processing and directly affects tea color, taste, and fragrance. To understand the molecular mechanism that influences tea quality during withering, we investigated the dynamic changes in the proteome of postharvest tea leaves in four withering stages (0, 1, 4, and 12 h treatments). A total of 863 unique differentially expressed proteins (DEPs) were identified by iTRAQ. The up- and down-regulated DEPs and the protein-protein interaction networks in different samples presented dynamic changes in their characteristics. The results of the functional annotation revealed that the molecular characteristics of tea withering are similar to leaf senescence. The biosynthesis of main tea-specific compounds that constitute tea color, taste, and fragrance of tea is restricted during withering. The substance transformation and degradation may have positive contributions to tea quality in withering technology. The proteome dynamics can be a useful aid for understanding the withering mechanisms and providing available information for functional discovery of proteins in the future. PMID- 28852883 TI - The effects of hot nights on mortality in Barcelona, Spain. AB - Heat-related effects on mortality have been widely analyzed using maximum and minimum temperatures as exposure variables. Nevertheless, the main focus is usually on the former with the minimum temperature being limited in use as far as human health effects are concerned. Therefore, new thermal indices were used in this research to describe the duration of night hours with air temperatures higher than the 95% percentile of the minimum temperature (hot night hours) and intensity as the summation of these air temperatures in degrees (hot night degrees). An exposure-response relationship between mortality due to natural, respiratory, and cardiovascular causes and summer night temperatures was assessed using data from the Barcelona region between 2003 and 2013. The non-linear relationship between the exposure and response variables was modeled using a distributed lag non-linear model. The estimated associations for both exposure variables and mortality shows a relationship with high and medium values that persist significantly up to a lag of 1-2 days. In mortality due to natural causes, an increase of 1.1% per 10% (CI95% 0.6-1.5) for hot night hours and 5.8% per each 10 degrees (CI95% 3.5-8.2%) for hot night degrees is observed. The effects of hot night hours reach their maximum with 100% and lead to an increase by 9.2% (CI95% 5.3-13.1%). The hourly description of night heat effects reduced to a single indicator in duration and intensity is a new approach and shows a different perspective and significant heat-related effects on human health. PMID- 28852882 TI - In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual color in situ hybridization in a large cohort of gastric cancer patients. AB - BACKGROUND: Fibroblast growth factor receptor (FGFR2) has been proposed as a target in gastric cancer. However, appropriate methods to select patients for anti-FGFR2 therapies have not yet been established. METHODS: We used in situ techniques to investigate FGFR2 mRNA expression and gene amplification in a large cohort of 1036 Japanese gastric cancer patients. FGFR2 mRNA expression was determined by RNAscope. FGFR2 gene amplification was determined by dual-color in situ hybridization (DISH). RESULTS: We successfully analyzed 578 and 718 samples by DISH and RNAscope, respectively; 2% (12/578) showed strong FGFR2 gene amplification (FGFR2:CEN10 >10); moderate FGFR2 gene amplification (FGFR2:CEN10 <10; >=2) was detected in 8% (47/578); and high FGFR2 mRNA expression of score 4 (>10 dots/cell and >10% of positive cells with dot clusters under a 20* objective) was seen in 4% (29/718). For 468 samples, both mRNA and DISH data were available. FGFR2 mRNA expression levels were associated with gene amplification; FGFR2 mRNA levels were highest in the highly amplified samples (n = 12). All highly amplified samples showed very strong FGFR2 mRNA expression (dense clusters of the signal visible under a 1* objective). Patients with very strong FGFR2 mRNA expression showed more homogeneous FGFR2 mRNA expression compared to patients with lower FGFGR2 mRNA expression. Gastric cancer patients with tumors that had an FGFR2 mRNA expression score of 4 had shorter RFS compared with score 0-3 patients. CONCLUSION: RNAscope and DISH are suitable methods to evaluate FGFR2 status in gastric cancer. Formalin-fixed paraffin-embedded (FFPE) tissue slides allowed evaluation of the intratumor heterogeneity of these FGFR2 biomarkers. PMID- 28852885 TI - Assessment of releases of translocated and rehabilitated Yucatan black howler monkeys (Alouatta pigra) in Belize to determine factors influencing survivorship. AB - Rehabilitation and reintroduction have become important to the management and welfare of primates worldwide. However, the suitability and success of these practices must be evaluated to determine their effectiveness as well as to improve programs and methods, as little is known about the factors influencing survival of released individuals. Between 2011 and 2014, 28 howler monkeys, Alouatta pigra, were released at Fireburn Reserve, northern Belize by the Primate Rehabilitation Centre of Belize: Wildtracks. From March to August 2015, field trips were made to determine the number and identity of surviving individuals to assess whether differences in individual outcomes (survived or disappeared) could be associated with specific characteristics or backgrounds of the monkeys. Fourteen of the twenty rehabilitated monkeys and seven of the eight translocated monkeys were found alive. The proportion of surviving individuals was not significantly different between rehabilitants and translocated animals, males and females, former pets and wild animals, short- and long-term rehabilitants, or different ages at release or intake. As mortality was low and none of the general factors analyzed influenced survivorship, it is suggested that chance or individual traits may be important in the outcomes of releases. This study provides an example of successful population reintroduction from both rehabilitation and translocation programs, and the first analyses of characteristics impacting the success of releases of howler monkeys. PMID- 28852884 TI - Clinicopathological and long-term prognostic features of membranous nephropathy with crescents: a Japanese single-center experience. AB - BACKGROUND: Three recent studies from the United States and China reported the clinicopathological features and short-term prognosis in patients with membranous nephropathy (MN) and crescents in the absence of secondary MN, anti-glomerular basement membrane (GBM) antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We compared clinicopathological and prognostic features in 16 MN patients with crescents (crescent group) and 38 MN patients without crescents (control group), in the absence of secondary MN, anti-GBM antibodies, and ANCA. Median follow-up periods in the crescent and control groups were 79 and 50 months, respectively. RESULTS: Decreased estimated glomerular filtration rates (<50 mL/min/1.73 m2), glomerulosclerosis, and moderate-to-severe interstitial fibrosis were more frequently observed in the crescent group than in the control group (P = 0.043, P = 0.004, and P = 0.035, respectively). Positive staining rates for glomerular IgG2 and IgG4 were significantly different between the 2 groups (P = 0.032, P = 0.006, respectively). Doubling of serum creatinine during follow-up was more frequently observed in the crescent group than in the control group (P = 0.002), although approximately two-thirds of patients in the crescent group were treated with immunosuppressive therapy. Crescent formation and interstitial fibrosis were risks for doubling of serum creatinine [hazard ratio (HR) = 10.506, P = 0.012; HR = 1.140, P = 0.009, respectively]. CONCLUSIONS: This is the first Japanese study demonstrating significant differences in clinicopathological and prognostic features between the 2 groups. Most patients in the crescent group may develop a long-term decline in renal function despite immunosuppressive therapy. PMID- 28852886 TI - Relationships Between Illness Perception and Post-traumatic Growth Among Newly Diagnosed HIV-Positive Men Who have Sex with Men in China. AB - Newly diagnosed HIV-positive men who have sex with men (NHMSM) are at high risk of mental health problems but may also develop post-traumatic growth (PTG). According to the Common Sense Model, illness perception (including both cognitive representation and emotional representation) affects coping and health-related outcomes. A cross-sectional survey was conducted to examine the associations between illness perception and PTG among 225 NHMSM in Chengdu, China. Linear regression analyses indicated that the constructs of emotional representation subscale (beta = -0.49) and five cognitive representation subscales (timeline, consequence, identity, attribution to god's punishment/will, and attribution to chance/luck) (beta = -0.13 to -0.37) were negative correlates of PTG, while four other constructs of cognitive representation (coherence, treatment control, personal control, and attribution to carelessness) were positive correlates (beta = 0.15 to 0.51). No moderating effects were observed. The associations between five cognitive representation subscales and PTG were fully-mediated via emotional representation. The results indicate that interventions promoting PTG among NHMSM are warranted and should alter illness perception, emotional representation in particular. Future studies should clarify relationships between cognitive representation and emotional representation, and extend similar research to other health-related outcomes and HIV-positive populations. PMID- 28852887 TI - Nanostructured cinnamon oil has the potential to control Rhipicephalus microplus ticks on cattle. AB - The aim of this study was to evaluate the capacity of pure and nanostructured cinnamon oil to control the infestation and reproductive efficiency of Rhipicephalus microplus on dairy cows. In vitro (stage I)-engorged female ticks were immersed in concentrations of 1.0, 5.0 and 10% of cinnamon oil on its pure form, and 0.5, 1.0, and 5.0% of the nanostructured form. 10% cinnamon oil (pure form) showed 100% efficacy, whereas concentrations of 1 and 5% were 62 and 97% efficacious, respectively. Nanocapsules and nanoemulsions containing cinnamon oil at 5% showed 95 and 97% efficacy, respectively. In vivo (stage II)-16 naturally tick-infested cows were divided into four groups of four animals each: Group A was composed of dairy cows sprayed with Triton (control); Group B was composed of dairy cows sprayed with cinnamon oil in its pure form (5%), whereas groups C and D were composed of dairy cows sprayed with nanocapsules and nanoemulsions, respectively, containing cinnamon oil at 0.5%. The ticks on each animal were counted on days 0, 1, 4 and 20 after spraying. Animals sprayed with pure and nanoencapsulated cinnamon oil carried significantly fewer ticks on days 1 and 4 post-treatment and were free of ticks on day 20 post-treatment. Ticks collected from these dairy cows (24 h after application) had impaired oviposition and larval inhibition, resulting in 90.5 and 100% efficacy when using pure and nanocapsules, respectively. In conclusion, the pure and nanostructured forms of cinnamon oil interfered with tick reproduction, whereas a significant acaricidal effect was found when applied onto cattle. PMID- 28852888 TI - Peer-Assisted Social Learning for Diverse and Low-Income Youth: Infusing Mental Health Promotion Into Urban After-School Programs. AB - Community-based after-school programs (ASPs) can promote social competence by infusing evidence-based practice into recreation. Through collaborative partnership, we developed and implemented a peer-assisted social learning (PASL) model to leverage natural opportunities for peer-mediated problem-solving. ASP Staff (n = 5) led elementary-school youth (n = 30) through 21 activities that partnered socially-skilled and less-skilled children; outcomes were compared to children (n = 31) at another site, via quasi-experimental design. Findings were mixed, including strong evidence for fidelity (adherence) and feasibility (attendance, participation, enthusiasm) of implementation. Relative to Comparison children, PASL children demonstrated improved social skills and behavior, but no changes in problem-solving, peer likability, or social network status. PMID- 28852889 TI - Objective Assessment of Bradykinesia Estimated from the Wrist Extension in Older Adults and Patients with Parkinson's Disease. AB - Parkinson's disease (PD) presents several motor signs, including tremor and bradykinesia. However, these signs can also be found in other motor disorders and in neurologically healthy older adults. The incidence of bradykinesia in PD is relatively high in all stages of the disorder, even when compared to tremor. Thus, this research proposes an objective assessment of bradykinesia in patients with PD (G PD: 15 older adults with Parkinson's disease, 65.3 +/- 9.1 years) and older adults (G HV: 12 healthy older adults, 60.1 +/- 6.1 years). The severity of bradykinesia in the participants of G PD was assessed using the Unified Parkinson's Disease Rating Scale. Movement and muscular activity were detected by means of inertial (accelerometer, gyroscope, magnetometer) and electromyographic sensors while the participants performed wrist extension against gravity with the forearm on pronation. Mean and standard error of inertial and electromyographic signal parameters could discriminate PD patients from healthy older adults (p value <0.05). In discriminating patients with PD from healthy older adults, the mean sensitivity and specificity were respectively 86.67 and 83.33%. The discrimination between the groups, based on the objective evaluation of bradykinesia, may contribute to the accurate diagnosis of PD and to the monitoring of therapies to control parkinsonian bradykinesia, and opens the possibility for further comparative studies considering individuals suffering from other motor disorders. PMID- 28852890 TI - Body representation in patients after vascular brain injuries. AB - Neuropsychological literature suggests that body representation is a multidimensional concept consisting of various types of representations. Previous studies have demonstrated dissociations between three types of body representation specified by the kind of data and processes, i.e. body schema, body structural description, and body semantics. The aim of the study was to describe the state of body representation in patients after vascular brain injuries and to provide evidence for the different types of body representation. The question about correlations between body representation deficits and neuropsychological dysfunctions was also investigated. Fifty patients after strokes and 50 control individuals participated in the study. They were examined with tasks referring to dynamic representation of body parts positions, topological body map, and lexical and semantic knowledge about the body. Data analysis showed that vascular brain injuries result in deficits of body representation, which may co-occur with cognitive dysfunctions, but the latter are a possible risk factor for body representation deficits rather than sufficient or imperative requisites for them. The study suggests that types of body representation may be separated on the basis not only of their content, but also of their relation with self. Principal component analysis revealed three factors, which explained over 66% of results variance. The factors, which may be interpreted as types or dimensions of mental model of a body, represent different degrees of connection with self. The results indicate another possibility of body representation types classification, which should be verified in future research. PMID- 28852891 TI - Altered Ethanol Consumption in Osteocalcin Null Mutant Mice. AB - Osteocalcin (OC) is an abundant extracellular calcium-binding protein synthesized by osteoblasts. Although most OC is bound to hydroxyapatite mineral during bone formation, a consistent amount is released directly to circulation. Plasma OC (pOC) levels are highly sensitive to stressful stimuli that alter stress responsive hormones, such as glucocorticoids (cortisol or corticosterone) and the catecholamines norepinephrine and epinephrine. To gain a better understanding of the apparent relationship of OC to the effects of ethanol (EtOH) and the stress responses, we compared mice that have OC (WT [OC+/+] and HET [OC+/-]) with OC null mutants (KO [OC-/-]), which have no OC in either plasma or in bone. One experiment included chronic unpredictable stress, a second was conducted in the absence of any known stressors other than EtOH, while a third imposed a more severe acute immobilization stress in addition to EtOH consumption. The data obtained confirmed significant differences in EtOH consumption in mice that previously experienced various stressful stimuli. We also determined that adrenal tyrosine-hydroxylase expression was inversely proportional to EtOH consumption and tended to be lower in KO than in WT. Data suggest that OC possesses the ability to modulate the adrenal gene expression of the catecholamine synthetic pathway. This modulation may be responsible for differences in EtOH consumption under stress. PMID- 28852892 TI - Recombinant neuritin affects the senescence, apoptosis, proliferation, and migration of rat bone marrow-derived mesenchymal stem cells. AB - OBJECTIVE: To study the effects of recombinant neuritin expressed by Pichia pastoris GS115 on the senescence, apoptosis, proliferation, and migration associated with rat bone marrow-derived mesenchymal stem cells (BMSCs). RESULTS: Recombinant neuritin was purified by Ni-affinity chromatography and identified by western blot and MALDI-TOF spectrometry. The effects of recombinant neuritin on senescence, apoptosis, proliferation, and migration of rat BMSCs WERE investigated. beta-Galactosidase staining indicated that recombinant neuritin administration significantly inhibited BMSCs senescence at 1 MUg neuritin/ml. Additionally, recombinant neuritin reduced the number of apoptotic cells at the early stage according to Annexin V/propidium iodide staining and inhibited cell proliferation according to MTT assay results. Moreover wound healing assay results showed that recombinant neuritin promoted BMSCs migration in the neuritin treatment group. CONCLUSION: Recombinant neuritin affects the senescence, apoptosis, proliferation, migration of rat BMSCs. Our findings offer insight into neuritin function outside of the nervous system. PMID- 28852893 TI - Correlates of Unknown HIV Status Among MSM Participating in the 2014 American Men's Internet Survey (AMIS). AB - Increasing serostatus awareness is a key HIV prevention strategy. Despite expanded testing efforts, some men who have sex with men (MSM) remain unaware of their HIV status. This study explored demographic characteristics, sexual identity, sexual role, and behavioral factors associated with unknown HIV status among MSM in the United States. Data from 9170 MSM in the 2014 American Men's Internet Survey were analyzed using logistic regression to identify correlates of unknown HIV status. Young age, race, low education, rural residence, and lack of recent healthcare visits were significantly associated with unknown HIV status. In addition, nondisclosure of one's sexual orientation (OR = 3.70, 95% CI 2.99 4.59) and a self-identified sexual role as "bottom" (OR = 1.45, 95% CI 1.24-1.70) were predictors of unknown HIV status. Post-hoc analysis showed HIV-negative MSM not tested in the last year had fewer self-reported risk behaviors than recent testers, suggesting that repeat testing among MSM may be aligned with individual risk. PMID- 28852894 TI - Impact and ecosystem service of forest and sacred grove as saviour of water quantity and quality in Garhwal Himalaya, India. AB - The present study was conducted in environs of the sacred grove of Garhwal Himalaya, India, with a view to assess the impacts of sacred groves and forests on the quality and quantity of water and also to assess the effect of seasonality on perennial stream quality. Water samples were collected from three randomly selected stream spots of both the sacred grove dominated by deodar (Cedrus deodara) and the non-sacred patch dominated by oak (Quercus leucotrichophora). Water samples from both patches were within the World Health Organization (WHO) standard limits. Based on an already established water quality index, water quality of both patches was safe for domestic and irrigation purposes but needs treatment for drinking purposes. Results of the present study also showed a very prominent impact of forest type as well as management condition on water quality and quantity. The water discharge from an oak forest shows more consistency than the discharge from a deodar forest. Due to the presence of the sacred grove, the area has become the source of good quality water supply during lean season for the surrounding villages. Water quality and quantity differed along with the change in season. The sacred grove and the existing forest leave a great impression on local dwellers, as due to its presence, local dwellers never run out of water supply during the dry season. As a result, the villagers sincerely want to protect the area for the sake of their own well-being. PMID- 28852895 TI - Basolateral pressure challenges mammary epithelial cell monolayer integrity, in vitro. AB - Mammary gland epithelium is physiologically exposed to variations of hydrostatic pressure due to accumulation of milk and removal by suckling and mechanical milking. Integrity of the mammary gland epithelium primarily relies on the tight junction. To analyze pressure-induced effects on the tight junction, we established a modified Ussing chamber and tested the hypothesis if hydrostatic pressure on the basal side of the epithelium is able to affect barrier properties in a mammary epithelial cell model, in vitro. Therefore, a conventional Ussing chamber was modified by an additional tube system to apply hydrostatic pressure. Monolayers of the mammary epithelial cell line HC11 were mounted in the modified Ussing chambers and incubated with increasing basal hydrostatic pressure. Transepithelial resistance and short circuit current were recorded and compared to controls. Hydrostatic pressure was stably applied and incubation steps of 30 min were technically feasible, leading to a decrease of transepithelial resistance and an increase of short circuit current in all monolayers. In a series of experiments simulating the physiological exposure time by short intervals of 5 min, these electrophysiological findings were also observed, and monolayer integrity was not significantly perturbed as analyzed by fluorescence immunohistochemistry selectively staining tight junction proteins. Moreover, electrophysiology demonstrated reversibility of effects. In conclusion, the modified Ussing chamber is an adequate method to analyze the effects of hydrostatic pressure on epithelial cell monolayers, in vitro. Both, the reduction of transepithelial resistance and the increase of short circuit current may be interpreted as protective reactions. PMID- 28852896 TI - Retinal toxicity related to hydroxychloroquine in patients with systemic lupus erythematosus and rheumatoid arthritis. AB - PURPOSE: To compare the retinal toxicity due to hydroxychloroquine (HCQ) use in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) using multifocal electroretinography (mfERG), fundus autofluorescence (FAF) and optical coherence tomography (OCT). METHODS: Patients who were using HCQ due to SLE and RA, and healthy subjects evaluated in this study. Central foveal thickness (CFT), inner-outer segment (IS-OS) junction irregularity, retinal nerve fiber layer thickness, mfERG and FAF measurements were performed to evaluate retinal toxicity. RESULTS: Study included 35 eyes of 35 SLE patients, 40 eyes of 40 RA patients and 20 eyes of 20 healthy subjects. In SLE group, retinal abnormality was found in three eyes with mfERG, in one eye with FAF and in four eyes with OCT. In RA group, retinal abnormality was found in 10 eyes with mfERG, in five eyes with FAF and in nine eyes with OCT. A statistically significant difference was found with respect to mfERG between "eyes with abnormal responses and without abnormal responses" and "eyes with abnormal responses and controls" (p < 0.05). A statistically significant difference was found with respect to CFT between "eyes with IS-OS junction irregularities and without IS-OS junction irregularities" and "eyes with/without IS-OS junction irregularities and controls" (p < 0.05). CONCLUSIONS: The use of HCQ seems to cause retinal toxicity more often in RA patients compared to SLE patients. For the early detection of retinal changes, OCT and mfERG can be used as screening tools due to their higher sensitivity rates compared to other tests. PMID- 28852897 TI - Effect of berberine on lipopolysaccharide-induced monocyte chemotactic protein-1 and interleukin-8 expression in a human retinal pigment epithelial cell line. AB - PURPOSE: In this study, we elucidated the effects of berberine, a major alkaloid component contained in medicinal herbs, such as Phellodendri Cortex and Coptidis Rhizoma, on expression of monocyte chemotactic protein-1 (MCP-1) and interleukin 8 (IL-8) in a human retinal pigment epithelial cell line (ARPE-19) caused by lipopolysaccharide (LPS) stimulation. METHODS: ARPE-19 cells were cultured to confluence. Berberine and LPS were added to the medium. MCP-1 and IL-8 mRNA were measured by real-time polymerase chain reaction. MCP-1 and IL-8 protein concentrations in the media were measured using enzyme-linked immunosorbent assay. RESULTS: After stimulation with LPS, MCP-1 and IL-8 mRNA in ARPE-19 cells reached maximum levels at 3 h, and MCP-1 and IL-8 protein in the culture media reached maximum levels at 24 h. Berberine dose-dependently inhibited MCP-1 and IL 8 mRNA expression of the cells and protein levels in the media stimulated with LPS. CONCLUSIONS: These findings indicate that berberine inhibited the expression of MCP-1 and IL-8 induced by LPS. PMID- 28852898 TI - Anti-hyperalgesic activity of the aqueous and methanol extracts of the leaves of Pittosporum mannii Hook on CFA-induced persistent inflammatory pain. AB - BACKGROUND: Previous study showed that aqueous (AEPM) and methanol (MEPM) extracts from the leaves of Pittosporum mannii have analgesic effects in acute pain models. The present study evaluates the acute and chronic anti hypernociceptive and anti-inflammatory effects of AEPM and MEPM in a model of persistent inflammatory pain. METHODS: The third day after induction of inflammatory pain by subplantar injection of 100 uL of CFA in Wistar rats, AEPM and MEPM were administered orally (75, 150 and 300 mg/kg/day) and their anti hyperalgesic and anti-inflammatory effects were follow in acute (1-24 h) and chronic (for 14 days) treatments. At the end of the chronic treatment, oxidative stress and liver parameters were assessed. Effects of plant extracts were also evaluated on nociception induced by Phorbol 12-Myristate 13-Acetate (PMA) and 8 bromo 3',5'-cAMP (8-Br-cAMP) in mice. RESULTS: AEPM and MEPM significantly reversed the mechanical hyperalgesia caused by CFA in acute and chronic treatment. Moreover, AEPM and MEPM also significantly reduced the nociception caused by PMA (60%) and 8-Br-cAMP (87%). Nevertheless, AEPM and MEPM failed to inhibit the paw edema caused by CFA. Plant extracts significantly reduced the nitric oxide content in the spinal cord and the plasmatic concentration of alanine aminotransferase. MEPM also significantly increased the glutathione content in the spinal cord. CONCLUSION: AEPM and MEPM given orally are effective in inhibiting mechanical hyperalgesia in persistent inflammatory pain caused by CFA. Their mechanisms of action seem to involve an interaction with PKC, PKA and nitric oxide pathways. These extracts might be devoid of hepatotoxic effects. PMID- 28852899 TI - Dissipation behavior and risk assessment of butralin in soybean and soil under field conditions. AB - Dissipation behavior, final residue, and risk assessment of butralin in soybean, green soybean, plant, and soil were investigated. Butralin residues were extracted with acetonitrile and then soybean samples were detected with gas chromatography-mass spectrometer (GC-MS) and soil samples were determined with GC with nitrogen phosphorous detector (GC-NPD). The limit of quantification (LOQ) of the method was 0.01 mg/kg for soybean, green soybean, plant, and soil. Average recoveries ranged from 90.4 ~ 98.2% for green soybean, 86.2 ~ 86.6% for soybean, 86.0 ~ 98.8% for plant, and 85.0 ~ 106.8% for soil. The relative standard deviations (RSDs) were 2.0 ~ 7.2% for green soybean, 2.0 ~ 3.0% for soybean, 3.1 ~ 8.1% for plant, and 1.8 ~ 6.6% for soil. Half-lives of butralin in soil samples varied in the range of 11-22 days. At harvest time, final residues of butralin in soybean and green soybean were lower than LOQ. Risk assessment demonstrated that, at recommended dosage and frequency, butralin would not induce significant harm on humans. The study could be used as a quantitative basis for application of butralin on soybean. PMID- 28852900 TI - Building Employer Capacity to Support Meaningful Employment for Persons with Developmental Disabilities: A Grounded Theory Study of Employment Support Perspectives. AB - To explore strategies to build employer capacity to support people with DD in meaningful employment from perspective of employment support workers. A grounded theory study was conducted with 34 employment support individuals. A theoretical sampling approach was used to identify and recruit participants from multiple sites in Ontario and Alberta. Three main themes, with seven sub-themes, emerged: (1) experiences of supporting employment finding for people with DD, (2) institutional influences on employee experiences, and (3) attitudes, assumptions and stigma. Several recommendations related to building employer capacity were offered. Our findings provide insight on specific elements and strategies that can support building employer capacity for persons with DD. PMID- 28852901 TI - Self-Competence and Depressive Symptom Trajectories during Adolescence. AB - The purpose of this study was to examine the relationship between self-competence and subsequent depressive symptom trajectories, by gender, in a community sample of adolescents (N = 753; 53% female; 65% non-Hispanic White). Data were collected annually for three years beginning when adolescents were in the 10th and 11th grades (Age: M = 16.09, SD = 0.72 years). Adolescents provided self-reports of self-competence at baseline and depressive symptoms every year. In latent growth curve models examining the overall trajectory of depressive symptoms, higher global self-worth and self-competence in close friendships were significantly associated with greater decreases in depressive symptoms (ps < 0.05). In contrast, higher academic self-competence was associated with more attenuated decreases in depressive symptoms (p = 0.001). When examining subgroups of latent depressive symptom trajectories within the context of growth mixture modeling, higher self-competence in physical appearance was associated with a decreased likelihood of membership in trajectory classes characterized by high initial, then decreasing depressive symptoms or and low initial, then increasing depressive symptoms (ps < 0.01). Among girls, higher global self-worth and self competence in close friendship and academic domains were associated with membership in a trajectory class distinguished by high stable depressive symptoms (ps < 0.01); these associations were not observed among boys (ps > 0.05). Findings suggest that the competence-based model of depression is valid and applicable during middle-to-late adolescence, and emphasize the importance of considering gender and individual differences in the developmental course of depressive symptoms to gain a more nuanced understanding of the role of self competence in depressive symptom trajectories. PMID- 28852902 TI - A new method to evaluate anti-allergic effect of food component by measuring leukotriene B4 from a mouse mast cell line. AB - Leukotrienes (LTs), chemical mediators produced by mast cells, play an important role in allergic symptoms such as food allergies and hay fever. We tried to construct an evaluation method for the anti-LTB4 activity of chemical substances using a mast cell line, PB-3c. PB-3c pre-cultured with or without arachidonic acid (AA) was stimulated by calcium ionophore (A23187) for 20 min, and LTB4 production by the cells was determined by HPLC with UV detection. LTB4 was not detected when PB-3c was pre-cultured without AA. On the other hand, LTB4 production by PB-3c pre-cultured with AA was detectable by HPLC, and the optimal conditions of PB-3c for LTB4 detection were to utilize the cells pre-cultured with 50 uM AA for 48 h. MK-886 (5-lipoxygenase inhibitor) completely inhibited LTB4 production, but AACOCF3 (phospholipase A2 inhibitor) slightly increased LTB4 production, suggesting that LTB4 was generated from exogenous free AA through 5 lipoxygenase pathway. We applied this technique to the evaluation of the anti LTB4 activity of food components. PB-3c pre-cultured with 50 uM AA for 48 h was stimulated with A23187 in the presence of 50 uM soybean isoflavones (daidzin, genistin, daidzein, and genistein), equol, quercetin, or kaempferol. Genistein, equol, quercetin, and kaempferol strongly inhibited LTB4 production without cytotoxicity. These results suggest that a new assay system using PB-3c is convenient to evaluate LTB4 inhibition activity by food components. This method could be utilized for elucidation of the mechanisms of LTB4 release suppression by food components such as flavonoids and the structure-activity relationship. PMID- 28852903 TI - Contextual Factors Related to Conventional and Traditional Tobacco Use Among California Asian Indian Immigrants. AB - California's tobacco control program contracted for tobacco use surveillance of Asian Indian Americans to address the paucity of information about tobacco use in this community, given their growing proportion of California's population. This study examined correlates of conventional (CTU) and Asian Indian traditional tobacco use (TTU) in a population-based sample of predominantly immigrant Asian Indian adults residing in California (N = 3228). The analytic sample (n = 2140) was limited to self-identified immigrants from India. Descriptive statistics, bivariate analyses, and multivariate logistic regressions were conducted to examine correlates of tobacco use among Asian Indian immigrants related to their acculturation and religious affiliation. While 65% of the sample had ever used traditional tobacco products (paan masala, gutka, bidis), only 25% had ever used conventional tobacco (cigarettes, cigar, pipe, chewing tobacco, snuff). Less than 5% reported tobacco use in the past 30 days. Rates of ever TTU and CTU were higher among men than women. Ethnic enclave residence was not associated with tobacco use. Impaired mental health was associated with CTU, and number of years spent in the U.S. was positively associated with both CTU and TTU. Individuals affiliated with Sikhism were less likely to use tobacco than individuals affiliated with Hinduism. Few population-based studies in the U.S. address both CTU and TTU use among Asian Indian immigrants. Tobacco use in Asian Indian immigrants may be seriously underestimated if surveillance is limited to conventional tobacco products. Interventions to reduce tobacco use should address mental health issues and consider religious affiliation. PMID- 28852904 TI - "What should I inject next?" Challenging treatment decisions in the multiple anti VEGF: a review of publications exploring anti-VEGF switching for nAMD. AB - PURPOSE: The purpose of our work was to collate information from studies published to date focusing on switching in anti-VEGF therapy and describe the currently available data on anti-VEGF switching in nAMD. METHODS: A PubMed search of published articles from January 2010 to January 2017 was conducted. Published studies were compared in parameters of sample size, reason for switch, duration of follow-up, and switch outcome (functional and anatomical). RESULTS: Our search revealed 31 relevant publications. Switching from bevacizumab to ranibizumab mostly resulted in improvement in visual acuity (VA) and anatomical outcomes (CMT, CRT; 7/8 and 6/8 studies, respectively), whereas switching from ranibizumab to bevacizumab was less effective (no VA or anatomical improvement in 2/4 studies). Switching from either agent to aflibercept resulted mostly in improvement of anatomical outcomes (19/21 studies), but rarely in VA improvement (6/21 studies). Not all results were statistically significant, likely due to small sample sizes. CONCLUSION: Switching anti-VEGF therapy from bevacizumab to ranibizumab might be of benefit (functionally and anatomically) for patients who failed to improve with intravitreal bevacizumab injections, whereas switching from either agent to aflibercept resulted mostly in reduced macular thickness only. PMID- 28852905 TI - The evaluation of the risk factors for capsular complications in phacoemulsification. AB - PURPOSE: To determine and quantify the risk factors for disruption of lens capsule integrity during phacoemulsification. METHODS: The medical records of the patients who had undergone phacoemulsification cataract surgery and had a complication associated with lens capsule were reviewed. Consecutive cases were also reviewed in reverse chronological order as a control group. The exclusion criteria were pediatric cataracts, traumatic cataracts and lens dislocation. As a result, 403 uncomplicated and 83 complicated eyes were analyzed. The differences between the complication group and the group without complications regarding the risk factors were shown by employing the Chi-square test and Fischer's exact test. The variables having the level of significance (p < 0.25) after the Chi square test and Fischer's exact test were enrolled into the multiple stepwise logistic regression analysis. RESULTS: Age (60-69/<=80) (p = 0.017), male gender (p = 0.006), pupil size <=3 mm (p = <0.001), mature-brunescent cataract (p = <0.001), anterior chamber depth <2.5 mm (p = 0.001), posterior polar cataract (p = 0.006), diabetic retinopathy(p = <0.001), coronary artery disease (p = 0.098) and surgeon factor (junior resident/senior resident, p = 0.015; senior resident/specialist in ophthalmology, p = 0.026; junior resident/specialist in ophthalmology, p = 0.020) were among the factors significantly related to a capsule complication. An Excel program has been developed according to these results to predict the probability of capsule complication. CONCLUSIONS: Higher risk cases can be predicted preoperatively, thus allowing surgeons to take appropriate precautions, better informing the patient and better selecting the cases especially for trainee surgeons. PMID- 28852906 TI - Descriptive Epidemiology for Community-wide Naloxone Administration by Police Officers and Firefighters Responding to Opioid Overdose. AB - Recently implemented New York State policy allows police and fire to administer intranasal naloxone when responding to opioid overdoses. This work describes the geographic distribution of naloxone administration (NlxnA) by police and fire when responding to opioid overdoses in Erie County, NY, an area of approximately 920,000 people including the City of Buffalo. Data are from opioid overdose reports (N = 800) filed with the Erie County Department of Health (July 2014-June 2016) by police/fire and include the overdose ZIP code, reported drug(s) used, and NlxnA. ZIP code data were geocoded and mapped to examine spatial patterns of NlxnA. The highest NlxnA rates (range: 0.01-84.3 per 10,000 population) were concentrated within the city and first-ring suburbs. Within 3 min 27.3% responded to NlxnA and 81.6% survived the overdose. The average individual was male (70.3%) and 31.4 years old (SD = 10.3). Further work is needed to better understand NlxnA and overdose, including exploring how the neighborhood environment creates a context for drug use, and how this context influences naloxone use and overdose experiences. PMID- 28852908 TI - Suitability of selected bioindicators of atmospheric pollution in the industrialised region of Ostrava, Upper Silesia, Czech Republic. AB - This study is a continuation of our preceding research identifying suitable environmental samples for the tracing of atmospheric pollution in industrial areas. Three additional types of environmental samples were used to characterise contamination sources in the industrial area of Ostrava city, Czech Republic. The region is known for its extensive metallurgical and mining activities. Fingerprinting of stable Pb isotopes was applied to distinguish individual sources of anthropogenic Pb. A wide range of 206Pb/207Pb ratios was observed in the investigated samples: 206Pb/207Pb = 1.168-1.198 in mosses; 206Pb/207Pb = 1.167-1.215 in soils and 206Pb/207Pb = 1.158-1.184 in tree cores. Black and brown coal combustion, as well as metallurgical activities, is the two main sources of pollution in the area. Fossil fuel burning in industry and households seems to be a stronger source of Pb emissions than from the metallurgical industry. Concentration analyses of tree rings showed that a significant increase in As concentrations occurred between 1999 and 2016 (from 0.38 mg kg-1 to 13.8 mg kg 1). This shift corresponds to the use of brown coal from Bilina, Czech Republic, with an increased As concentration. The burning of low-quality fuels in households remains a problem in the area, as small ground sources have a greater influence on the air quality than do industrial sources. PMID- 28852907 TI - Functional Role of SUV39H1 in Human Renal Tubular Epithelial Cells Under High glucose Ambiance. AB - SUV39H1, the histone methyltransferase (HMTase) of histone H3 lysine 9 trimethylation (H3K9me3), is a known transcriptional repressor of inflammatory genes. The effect of SUV39H1 on inflammatory gene promoters under high-glucose stimulation in vascular smooth muscle cells (VSMCs), macrophages, and cardiomyocytes has been studied, but how SUV39H1 functions in renal tubules under diabetic conditions is unclear. Renal biopsy specimens of ten diabetic nephropathy (DN) subjects and seven non-DN minimal change diseases (MCD) subjects were collected. SUV39H1, IL-6, and MCP-1 expression in renal tissues were measured using immunohistochemical, while SUV39H1, H3K9me3, IL-6, and MCP-1 in human proximal tubular epithelial cells (HK-2) under varying glucose conditions were assayed by Western blot and ELISA. SUV39H1 was overexpressed in HK-2 cells; the regulation of SUV39H1 and H3K9me3 on NF-kappaB, IL-6, MCP-1, caspase 3, and apoptosis was measured. SUV39H1 was expressed more in diabetic human renal tubules. HK-2 cells with high glucose up-regulated IL-6 and MCP-1 in a dose- and time-dependent manner, and SUV39H1 expression was reduced with greater glucose and prolonged stimulation. Expression of H3K9me3 was synchronized with SUV39H1. Moreover, overexpression of SUV39H1 in high glucose environment was accompanied with increased H3K9me3 and decreased inflammation and apoptosis. SUV39H1 dysregulation may be involved in DN progression. Overexpression of SUV39H1 may reduce renal inflammation and apoptosis via epigenetic modulation, thus plays a protective role in DN. PMID- 28852909 TI - Effects of rifampin, itraconazole and esomeprazole on the pharmacokinetics of alisertib, an investigational aurora a kinase inhibitor in patients with advanced malignancies. AB - Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD). Blood samples for alisertib and 2 major metabolites were collected up to 72 h (Study 1) and 96 h (Study 2) postdose. Area under the curve from time zero extrapolated to infinity (AUC0-inf) and maximum concentrations (Cmax) were calculated and compared using analysis of variance to estimate least squares (LS) mean ratios and 90% confidence intervals (CIs). Results The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of esomeprazole were 1.28 (1.07, 1.53) and 1.14 (0.97, 1.35), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of rifampin were 0.53 (0.41, 0.70) and 1.03 (0.84, 1.26), respectively. The LS mean ratios (90% CIs) for alisertib AUC0-inf and Cmax in the presence compared to the absence of itraconazole were 1.39 (0.99, 1.95) and 0.98 (0.82, 1.19), respectively. Conclusions The use of gastric acid reducing agents, strong CYP3A inhibitors or strong metabolic enzyme inducers should be avoided in patients receiving alisertib. PMID- 28852912 TI - A Content Analysis of Hospitals' Community Health Needs Assessments in the Most Violent U.S. Cities. AB - The emergence of evidence-supported interventions allows hospitals the opportunity to reduce future reinjury among patients who are violently injured. However, hospital knowledge of these interventions and their perceived role in violence prevention is unknown. The Patient Protection and Affordable Care Act created new legal requirements for non-profit hospitals to conduct community health needs assessments (CHNA) every three years to maintain not-for-profit status. In turn, this allows an empiric evaluation of hospital recognition and response to community violence. To do so, this study performed a content analysis of hospital CHNAs from the 20 U.S. cities with the highest violent crime rates. A total of 77 CHNAs were examined for specific violence-related keywords as well as whether violence prevention was listed as a priority community need. Overall, 74% of CHNAs mentioned violence-related terms and only 32% designated violence prevention as a priority need. When discussed, 88% of CHNAs referenced community violence, 42% intimate partner or sexual violence, and 22% child abuse. This study suggests that hospitals may lack awareness of violence as an actionable, preventable public health issue. Further, evidence-based program models are available to hospitals that can reduce the recurrence of assaultive injuries. PMID- 28852910 TI - Pediatric keratoconus: a review of the literature. AB - PURPOSE: To describe the epidemiology and prevalence, rates of progression, difference between adult and pediatric populations, and therapeutic approaches to pediatric keratoconus from documented literature. METHODS: A literature search was done on PubMed using key words including pediatric keratoconus, children with keratoconus, adult keratoconus, penetrating keratoplasty, corneal cross-linking and intracorneal ring segments. The literature was reviewed and reported to explore the key epidemiological differences between the pediatric and adult population with regards to presentation and treatment options. RESULTS: Pediatric keratoconus is more aggressive than adult keratoconus, which has been explained by structural differences in the cornea between both populations. High rates of progression were documented in pediatric populations. While corneal collagen cross-linking, intracorneal ring segments and penetrating keratoplasties have been used as therapies in the pediatric population, the literature overwhelmingly shows higher rates of failure and progression despite these measures as compared to adults. CONCLUSION: Pediatric keratoconus is more aggressive than adult keratoconus, and current therapies used in adults may not be sufficient for the pediatric population. PMID- 28852911 TI - Compositional Changes in Foliage Phenolics with Plant Age, a Natural Experiment in Boreal Forests. AB - The composition of plant secondary metabolites (PSMs) extensively impacts ecosystem functioning. It is vital that we understand temporal patterns in the plants' allocation of resources to PSMs, particularly those influenced by human activity. Existing data are insufficient in the long-term perspective of perennial plants (age or ontogeny). We analysed phenolic concentrations in foliage from birch (Betula pubescens Ehr.) considered to be undamaged and growing on 5, 10 and 15 years old clear-cuts in two boreal forest landscapes in Norway, sampled at the peak of the growing season. In sum, low molecular weight phenolic concentrations decreased with age. Apart from one apigenin glycoside, the low molecular weight phenolics co-varied similarly at all ages, suggesting a lack of temporal compound-specific prioritisation of this group. In contrast, the concentration of MeOH-soluble condensed tannins increased with age. The compositional shift fits well with several hypotheses that may provide proximate explanations for age patterns in PSM allocations, including both resource constraints and external pressures. Regardless of these explanations, our study adds an important perennial perspective (plant age) to temporal PSM patterns already well-known in boreal plant phenology (foliage age). PMID- 28852913 TI - Cancer patients' intentions towards receiving unsolicited genetic information obtained using next-generation sequencing. AB - Next-generation sequencing (NGS) can be used to generate information about a patient's tumour and personal genome. This powerful diagnostic tool provides solicited and unsolicited hereditary genetic (risk) information that could have consequences for cancer patients and their quality of life. A well-defined approach for returning appropriate genetic risk information is needed in personalized cancer care. A qualitative design with semi-structured interviews was used. We conducted interviews with 24 Dutch patients with different types of cancer, both NGS-experienced and NGS-inexperienced, to learn their intentions, needs and preferences towards receiving unsolicited genetic information obtained using NGS. Almost all participants had a positive attitude towards receiving unsolicited findings. After receiving comprehensive background information on NGS, including a binning model of four categories of unsolicited findings, most participants preferred to receive only subsets of genetic information. Their main concern was their own and others' (including family members) ability to cope with (the increased risk of having) a genetic disorder. Providing background information gave cancer patients the opportunity to select subsets of findings and increased their ability to make an informed choice. Special attention is needed for social and emotional factors to support the patients themselves and when communicating test results with their family members. PMID- 28852915 TI - Evaluation of Pharmacist-Initiated Interventions on Vaccination Rates in Patients with Asthma or COPD. AB - To determine if pharmacy-initiated interventions improved the rate of influenza and pneumococcal vaccinations in adult patients with asthma and/or chronic obstructive pulmonary disease (COPD). Adult patients who filled prescriptions at one of three community pharmacies, who had a dispensing history indicative of an asthma and/or COPD diagnosis were randomized to receive a personal phone call or standardized mailed letter recommending influenza and pneumococcal vaccinations, or control with no vaccination information. The rate of influenza and pneumococcal vaccinations was measured for each group and measured using Chi square. Of 831 eligible participants, 210 patients completed the study, and self reported a diagnosis of asthma and/or COPD. The influenza vaccine was administered to 56 (72.7%), 55 (87.3%), and 62 (88.6%) patients (p = 0.019); pneumococcal vaccine was administered to 46 (59.7%), 39 (61.9%), and 39 (55.7%) patients in the phone call, letter, and control groups, respectively. While the control group had significantly more influenza vaccinations, between the interventions the letter showed a higher rate of influenza vaccination over the phone call. Reviewing patients under age 65, the letter had a significantly higher rate of influenza vaccination than the phone call (p = 0.021). No significant improvement was found for the pneumococcal vaccination. Patients under age 65 who received a mailed letter had a significantly higher rate of influenza vaccination than those who received a phone call, and had a higher rate of pneumococcal vaccination. A standardized, mailed letter may help community pharmacists improve vaccination rates in patients with asthma and/or COPD. PMID- 28852914 TI - Induction of Metallothionein in Rat Liver by Zinc Exposure: A Dose and Time Dependent Study. AB - Metallothioneins (MTs) are low molecular weight ubiquitous metalloproteins with high cysteine (thiol) content. The intracellular concentration of zinc (Zn) is tightly regulated and MT plays a crucial role in it. The present study investigates the relationship between the Zn status (as a function of Zn concentration and time) in the rat liver and the occurrence of hepatic MT. For dose dependent study, four experimental groups, one control and three receiving different levels of metal supplementation, were chosen [Group 1 control and Group 2, Group 3, Group 4 receiving subcutaneous dose of 10, 50 and 100 mg of Zn/kg body weight (in the form of ZnSO4.7H2O), respectively]. For the time dependent expression of MT, again four experimental groups, i.e. Group 5 control and Group 6, Group 7, Group 8 receiving 50 mg of Zn/kg body weight (in the form of ZnSO4.7H2O) subcutaneously and sacrificed at different time intervals after last injection i.e. 6, 18, 48 h, respectively were chosen. Isolation of MT was done by using combination of gel filtration and ion exchange chromatography while characterization of MT fraction was carried in the wavelength range 200-400 nm. Expression of MT was studied by using Western blot analysis. The results revealed that the MT expression increases with increasing the dose of Zn administered and maximum at 18 h after last Zn injection. Accumulation of MT with increase dose would help in maintaining the intracellular Zn concentration by its sequestration which further reduces the possibility of undesirable binding of Zn to other proteins significantly and maintains Zn homeostasis. The maximum expression of MT at 18 h is indicative of its half life. PMID- 28852916 TI - Vinblastine and antihelmintic mebendazole potentiate temozolomide in resistant gliomas. AB - Glioblastoma (GBM) is a very aggressive tumor that has not had substantial therapeutic improvement since the introduction of temozolomide (TMZ) in combination with radiotherapy. Combining TMZ with other chemotherapeutic agents is a strategy that could be further explored for GBM. To search for molecular predictors of TMZ resistance, the TCGA (The Cancer Genome Atlas) database was utilized to assess the impact of specific genes on TMZ response. Patients whose tumors expressed low levels of FGFR3 and AKT2 responded poorly to TMZ. Combination treatment of vinblastine (VBL) plus mebendazole (MBZ) with TMZ was more effective in reducing cell number in most cultures when compared to TMZ alone, especially in cells with low expression levels of FGFR3 and AKT2. Cell cycle distribution and nuclear morphometric analysis indicated that the triple combination of TMZ, VBL and MBZ (TVM) was able to induce polyploidy and senescence, in addition to increasing the Notch3 RNA level in patient-derived gliomas. Thus, this set of data suggests that the triple combination of TMZ, VBL and MBZ may be a considerable therapeutic alternative for the TMZ-tolerant gliomas that harbor low expression of FGFR3/AKT2. PMID- 28852917 TI - Perceptual Training of Second-Language Vowels: Does Musical Ability Play a Role? AB - The present study attempts to extend the research on the effects of phonetic training on the production and perception of second-language (L2) vowels. We also examined whether success in learning L2 vowels through high-variability intensive phonetic training is related to the learners' general musical abilities. Forty Azerbaijani learners of Standard Southern British English participated in a pre test/training/post-test setting. Discrimination and production tests were used in pre- and post-tests. The participants' musical ability was evaluated through three musical aptitude tests. Results revealed a significant improvement in the discrimination and production of L2 vowels after training. However, the lack of a one-to-one relationship between production and perception gains suggests distinct representations underlying L2 speech perception and production. There was no significant correlation between overall musical ability scores and L2 vowel learning, however, results revealed a correlation between discrimination improvements and tonal memory. This suggests tonal memory facilitates the perceptual learning of the novel phonological structure of L2. PMID- 28852918 TI - All that Glitters is not Gold: Six Steps Before Selecting and Prioritizing e Health Services. AB - Since the market for e-health applications is constantly growing, it is getting an ever more complex endeavor to select and prioritize the right service offering given a particular situation. In examining the extant literature, it was revealed that little emphasis is actually placed on how to analyze contextual or environmental factors prior to the selection and prioritization of e-health services. With this paper, we therefore propose a formative framework consisting of six fundamental yet very pragmatic steps that may support decision makers in identifying the most important contextual pre-requisites that e-health services need to fulfill in order to be considered as effective for their environment to be implemented. PMID- 28852919 TI - Impact of Length of Residence in the United States on Risk of Diabetes and Hypertension in Resettled Refugees. AB - The relationship between resettlement and development of chronic disease has yet to be elucidated in refugees. We aimed to assess the relationship between length of residence in the US and development of diabetes and hypertension utilizing multivariable logistic regression models in a sample of former refugee patients seeking primary care services. Multivariable logistic regression models adjusting for age, gender, and country of origin showed significantly increasing odds of type 2 diabetes (OR 1.12, 95% CI 1.03-1.22, p < 0.01) and hypertension (OR 1.07, 95% CI 1.00-1.14) with increasing length of stay in the US for resettled refugee adults. A significant proportion of diabetes (26.7%) and hypertension (36.9%) diagnoses were made within one year of arrival, highlighting the critical role of focusing diagnosis and prevention of chronic disease in newly resettled refugees, and continuing this focus throughout follow-up as these patients acculturate to their new homeland. PMID- 28852921 TI - Primary Care Providers' Perceptions of Young Cambodian American Female Patients. AB - There are significant health disparities among Southeast Asian Americans. As an initial step toward understanding the psychosocial factors associated with these disparities, the present study examined primary care providers' perspectives of health status, healthcare utilization, health-related behaviors, and stressors among one subset of Southeast Asian Americans-Cambodian American women between the ages of 18 and 24 years. Interviews with five primary care providers indicated that cultural, historical, psychological and social issues were associated with health outcomes and health behaviors. Results also pointed to clinical considerations and research directions that would improve treatment and understanding of health problems among young Cambodian American women. PMID- 28852922 TI - Insight into muscle physiology through understanding mechanisms of muscle pathology. PMID- 28852920 TI - The significance of aryl acylamidase activity of acetylcholinesterase in osteoblast differentiation and mineralization. AB - Osteoblast differentiation is an essential event in the developmental process, which is favoured by the production of extra cellular matrix proteins and various enzymes including discrete ones like acetylcholinesterase (AChE). Despite the fact that AChE facilitates osteoblast differentiation, the significance of its catalytic functions [esterase and aryl acylamidase (AAA) activities] in the process is yet to be ascertained. In this context, SaOS-2 cell line was used in the present study to implicate the catalytic activities of AChE in process of osteoblast differentiation and mineralization. During differentiation, it was found that the activity of both esterase and AAA increased 1.13 and 1.46 folds respectively, signifying the involvement of catalytic activities of AChE in the process. Inhibition of both the catalytic activities of AChE with edrophonium significantly reduced the amount of mineralization by decreasing the alkaline phosphatase (ALP) activity and expression of differentiation-related genes such as RUNX-2, COL1A, ALP, OC, and OP significantly (p < 0.05). Inhibition of esterase activity without altering the AAA activity using gallamine significantly increased the level ALP activity and expression of differentiation-associated genes (p < 0.05), thus favouring mineralization. Therefore, this study concludes and confirms that the AAA activity of AChE is actively involved in the process of osteoblast differentiation and mineralization. PMID- 28852923 TI - Total glycosides of Paeony shows Neuroprotective effects against Semen Strychni induced neurotoxicity by recovering secretion of hormones and improving brain energy metabolism. AB - In this study, we investigated the protective effect of total glycosides of paeony against Semen Strychni-induced neurotoxicity and discussed some probably mechanisms. Levels of estrone, estradiol, estriol and growth hormone in male rats' serum were determined by ELISA, levels of ATP and substances associated with energy metabolism in rats' brain were determined by HPLC and levels of progesterone was determined by a UPLC-MS/MS method. The results showed that neurotoxicity induced by Semen Strychni could cause a significant decrease (p < 0.05, compare to the blank group) in secretion of estrogens and GH and disorder brain energy metabolism at the same time. While, rats with total glycosides of paeony pre-protection (orally administrated with total glycosides of paeony for 15 days before administrating Semen Strychni extract) showed a much better condition in the secretion of hormones and brain energy metabolism, and showed no significant changes in most of those associated substances when comparing to the blank group. Our study indicated that total glycosides of paeony have neuroprotective effects on Semen Strychni-induced neurotoxicity. It could recover the disordered hormone secretion and improve the brain energy metabolism. Total glycosides of paeony is potential to be further used in clinic to protect against neurotoxicity induced by other reasons. PMID- 28852924 TI - USP10 inhibits lung cancer cell growth and invasion by upregulating PTEN. AB - To determine the potential tumor suppressor functions of ubiquitin-specific protease 10 (USP10) in lung cancer and elucidate underlying molecular mechanism. The relative expression of USP10 was determined by real-time PCR and immunoblotting. The inhibitory effect of USP10 on tumor growth was demonstrated on allograft mice with Lewis carcinoma cell inoculation. The relative cell proliferation was measured with Cell Counting Kit-8 (CCK-8). The invasive capacity was evaluated by transwell assay. The interaction between USP10 and Phosphatase And Tensin Homolog (PTEN) was examined by co-immunoprecipitation. Ubiquitination/deubiquitination was analyzed by immunoprecipitation followed by immunoblotting. USP10 was down-regulated in lung cancer. Knockdown of USP10 promotes tumor growth and invasion both in vitro and in vivo. We further demonstrated that USP10 directly interacted with and stabilized PTEN via deubiquitination. The pro-cancerous effect of USP10 deficiency was abolished by re-introduction of PTEN. We suggested a tumor suppressor function of USP10 in lung cancer via deubiquitinating and stabilizing PTEN. PMID- 28852925 TI - Against the integrative turn in bioethics: burdens of understanding. AB - The advocates of Integrative Bioethics have insisted that this recently emerging project aspires to become a new stage of bioethical development, surpassing both biomedically oriented bioethics and global bioethics. We claim in this paper that if the project wants to successfully replace the two existing paradigms, it at least needs to properly address and surmount the lack of common moral vocabulary problem. This problem points to a semantic incommensurability due to cross language communication in moral terms. This paper proceeds as follows. In the first part, we provide an overview of Integrative Bioethics and its conceptual building blocks: mutlidisciplinarity, interdisciplinarity, and transdisciplinarity. In the second part, we disclose the problem of semantic incommensurability. The third part gives an overview of various positions on the understanding of interdisciplinarity and integration in interdisciplinary communication, and corresponding attempts at solving the lack of common moral vocabulary problem. Here we lean mostly on Holbrook's three theses regarding the character of interdisciplinary communication. Finally, in the fourth part, we discuss a particular bioethical case-that of euthanasia-to demonstrate the challenge semantic incommensurability poses to dialogues in Integrative Bioethics. We conclude that Integrative Bioethics does not offer a methodological toolset that would warrant optimism in its advocates' predictions of surpassing current modes of doing bioethics. Since Integrative Bioethics leaves controversial methodological questions unresolved on almost all counts and shows no attempts at overcoming the critical stumbling points, we argue for its rejection. PMID- 28852926 TI - Potential molecular mechanisms mediating the protective effects of tetrahydroxystilbene glucoside on MPP+-induced PC12 cell apoptosis. AB - Our previous work demonstrated that tetrahydroxystilbene glucoside (TSG) was able to effectively attenuate 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in PC12 cells partially via inhibiting reactive oxygen species (ROS) generation. However, the precise molecular mechanisms of TSG responsible for suppressing neuronal apoptosis have not been fully elucidated. To investigate the possible mechanism, we studied the neuroprotective effects of TSG on MPP+-induced PC12 cells apoptosis and explored the molecular mechanisms that mediated the effects of TSG. Our results showed that treatment with TSG prior to MPP+ exposure effectively attenuated the cell viability decrease in PC12 cells, reversed the cell apoptosis, and further restored the mitochondria membrane potential (MMP). In addition, TSG remarkably enhanced the anti-oxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and efficiently reduced the malondialdehyde (MDA) content in the PC12 cells. Meanwhile, TSG markedly upregulated the Bcl-2/Bax ratio, reversed release of Cytochrome c, and inhibited the activation of caspase-3 induced by MPP+. Furthermore, TSG significantly inhibited the activation of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway, while extracellular signal-regulated protein kinases (ERK) phosphorylation was not affected. Together, these findings provide the basis for TSG clinical application as a new therapeutic strategy in the treatment of neurodegenerative diseases. PMID- 28852927 TI - Phenolic Acids Profiles and Cellular Antioxidant Activity in Tortillas Produced from Mexican Maize Landrace Processed by Nixtamalization and Lime Extrusion Cooking. AB - Phenolic acids profiles, chemical antioxidant activities (ABTS and ORAC), as well as cellular antioxidant activity (CAA) of tortilla of Mexican native maize landraces elaborated from nixtamalization and lime cooking extrusion processes were studied. Both cooking procedures decreased total phenolics, chemicals antioxidant activity when compared to raw grains. Extruded tortillas retained 79.6-83.5%, 74.1-77.6% and 79.8-80.5% of total phenolics, ABTS and ORAC values, respectively, compared to 47.8-49.8%, 41.3-42.3% and 43.7-44.4% assayed in traditional tortillas, respectively. Approximately 72.5-88.2% of ferulic acid in raw grains and their tortillas were in the bound form. Regarding of the CAA initially found in raw grains, the retained percentage for traditional and extruded tortillas ranged from 47.4 to 48.7% and 72.8 to 77.5%, respectively. These results suggest that Mexican maize landrace used in this study could be considered for the elaboration of nixtamalized and extruded food products with nutraceutical potential. PMID- 28852928 TI - Laparoscopic ureteral reimplantation with extracorporeal tailoring and direct nipple ureteroneocystostomy for adult obstructive megaureter: long-term outcomes and comparison to open procedure. AB - PURPOSE: To evaluate the long-term outcomes of laparoscopic ureteral reimplantation with extracorporeal tailoring and direct nipple ureteroneocystostomy for adult obstructive megaureter and compare the results with the open procedure. METHODS: From January 2007 to July 2013, 22 patients underwent laparoscopic and 28 patients underwent open ureteral reimplantation for adult obstructive megaureter. For laparoscopic group, the dilated ureter was delivered out of through a 12-mm port and the distal end was tailored and formed into an antireflux nipple extracorporeally. The ureteral nipple was intracorporeally reimplanted into the posterolateral wall of the bladder. Demographics, complications and follow-up data were analyzed and compared retrospectively between the groups. RESULTS: Baseline characteristics including age, gender, body mass index, affected side, age at diagnosis and follow-up time were statistically similar for the groups. All of the surgeries were performed successfully, and no major complications occurred. Comparing with the open group, the use of our novel laparoscopic procedure resulted in less estimated blood loss (50.0 vs. 71.0 ml; P = 0.001), less narcotic analgesic (3.0 vs. 18.0 mg; P = 0.01) and shorter hospital stay (5.1 vs. 7.9 days; P < 0.001). Long-term outcomes including rates of recurrent ureteral stricture (4.5 vs. 0%; P = 0.25), rates of vesicoureteral reflux (9.1 vs. 3.6%, P = 0.42) and success rates (86.4 vs. 96.9%; P = 0.45) did not significantly differ between the two groups. CONCLUSION: Laparoscopic ureteral reimplantation with extracorporeal tailoring and direct nipple ureteroneocystostomy is a safe and equally effective as the open surgery for the long-term outcomes of adult obstructive megaureter. PMID- 28852929 TI - Npro His49 and Erns Lys412 mutations in pig bovine viral diarrhea virus type 2 synergistically enhance the cellular antiviral response. AB - Type I interferons are major components of the innate immune response of hosts, and accordingly, many viruses have evolved mechanisms to modulate the host response during infection. Bovine viral diarrhea virus (BVDV) nonstructural protein Npro and structural protein Erns play important roles in inhibiting type I interferon. The aim of this study was to explore the epistatic effects of amino acid mutations in Npro and Erns in porcine ST cells to characterize the immune response induced by BVDV-2. Plasmids with mutant amino acids His49 (H49), Glu22 (E22) in Npro, and His300 (H300), Lys412 (K412) in Erns which had been changed to Alanine (A) had similar effects on type I interferon production in MDBK and ST cells, but resulted in much greater ISG15, OAS, and Mx production in ST cells. The rescued vASH/NproH49ErnsK412 virus showed the best efficiency with respect to modulating antiviral cytokines, indicating that the amino acids Npro H49 and Erns K412 had highly synergistic effects in abolishing the ability to inhibit type I interferon. These findings have importance practical implications owing to the increasing prevalence of BVDV infections, including persistent infections, in domestic pigs. PMID- 28852930 TI - Role of SH3b binding domain in a natural deletion mutant of Kayvirus endolysin LysF1 with a broad range of lytic activity. AB - The spontaneous host-range mutants 812F1 and K1/420 are derived from polyvalent phage 812 that is almost identical to phage K, belonging to family Myoviridae and genus Kayvirus. Phage K1/420 is used for the phage therapy of staphylococcal infections. Endolysin of these mutants designated LysF1, consisting of an N terminal cysteine-histidine-dependent aminohydrolase/peptidase (CHAP) domain and C-terminal SH3b cell wall-binding domain, has deleted middle amidase domain compared to wild-type endolysin. In this work, LysF1 and both its domains were prepared as recombinant proteins and their function was analyzed. LysF1 had an antimicrobial effect on 31 Staphylococcus species of the 43 tested. SH3b domain influenced antimicrobial activity of LysF1, since the lytic activity of the truncated variant containing the CHAP domain alone was decreased. The results of a co-sedimentation assay of SH3b domain showed that it was able to bind to three types of purified staphylococcal peptidoglycan 11.2, 11.3, and 11.8 that differ in their peptide bridge, but also to the peptidoglycan type 11.5 of Streptococcus uberis, and this capability was verified in vivo using the fusion protein with GFP and fluorescence microscopy. Using several different approaches, including NMR, we have not confirmed the previously proposed interaction of the SH3b domain with the pentaglycine bridge in the bacterial cell wall. The new naturally raised deletion mutant endolysin LysF1 is smaller than LysK, has a broad lytic spectrum, and therefore is an appropriate enzyme for practical use. The binding spectrum of SH3b domain covering all known staphylococcal peptidoglycan types is a promising feature for creating new chimeolysins by combining it with more effective catalytic domains. PMID- 28852931 TI - Comorbidity assessment as predictor of short and long-term mortality in elderly patients with hemodynamically stable acute pulmonary embolism. AB - Elderly patients presenting with acute pulmonary embolism (PE) frequently have significant underlying comorbidities which may condition the prognosis. The current study aimed to determine the ability of Charlson comorbidity index (CCI) score to predict short and long-term mortality in elderly patients with hemodynamically stable acute PE. All hemodynamically stable patients aged >65 years with acute PE, evaluated in the Emergency Department since 2010 through 2014, were included in this retrospective cohort study. CCI, simplified pulmonary embolism severity index (sPESI) scores and vital status were recorded. Were included 162 patients with confirmed PE, out of 657 suspected cases (24.7%). Median age: 79.2 years, 74.1% presented an sPESI > 1 and 61.1% a CCI > 1. The overall 30, 90-day and 2-year mortality was 11.7% (95%CI 6.6-16.6), 19.8% (95%CI 13.4-25.7) and 31.8% (95%CI 24.1-38.8). For 30-day mortality sPESI showed an AUC 0.642 (95%CI 0.511-0.772) and adding CCI as covariate did not increase its prognostic performance. For 90-day mortality, in an adjusted model including sPESI and CCI, CCI showed a HR 1.282 (95%CI 1.151-1.429, p-value < 0.001), and sPESI a HR = NS(p-value = 0.267). For 2-year mortality, in an adjusted model including sPESI and CCI, CCI showed a HR 1.295 (95%CI 1.180-1.421, p-value < 0.001) and sPESI a HR = NS(p-value = 0.353). In elderly patients with hemodynamically stable PE, the CCI score was found to be an independent predictor of mortality. CCI shows a significantly better ability to predict 90-day and 2 year mortality than sPESI. The assessment of comorbidity burden by using the CCI score may be proposed as an useful tool to predict mortality in these patients. PMID- 28852932 TI - Bioenergetic variation is related to autism symptomatology. AB - Autism spectrum disorder (ASD) has been associated with mitochondrial dysfunction but few studies have examined the relationship between mitochondrial function and ASD symptoms. We measured Complex I and IV and citrate synthase activities in 76 children with ASD who were not receiving vitamin supplementation or medication. We also measured language using the Preschool Language Scales or Clinical Evaluation of Language Fundamentals, adaptive behavior using the Vineland Adaptive Behavioral Scale, social function using the Social Responsiveness Scale and behavior using Aberrant Behavior Checklist, Childhood Behavior Checklist and the Ohio Autism Clinical Impression Scale. Children with ASD demonstrated significantly greater variation in mitochondrial activity compared to controls with more than expected ASD children having enzyme activity outside of the normal range for Citrate Synthase (24%), Complex I (39%) and Complex IV (11%). Poorer adaptive skills were associated with Complex IV activity lower or higher than average and lower Complex I activity. Poorer social function and behavior was associated with relatively higher Citrate Synthase activity. Similar to previous studies we find both mitochondrial underactivity and overactivity in ASD. This study confirms an expanded variation in mitochondrial activity in ASD and demonstrates, for the first time, that such variations are related to ASD symptoms. PMID- 28852933 TI - Extracellular Cytosolic Aspartate Aminotransferase Promotes Axonal Growth and Object Recognition Memory. AB - Previous proteome analysis studies from other groups have shown that cAST might be secreted from neurons and that cAST was detected in human cerebrospinal fluid. However, none of these studies focused on its role or significance. We therefore investigated the role of extracellular cAST for neurons. cAST was detected in conditioned medium from cultured cortical neurons, but not in fresh medium. Recombinant cAST treatment of cortical neurons significantly extended axonal length. Continuous intracerebroventricular administration of recombinant cAST in normal mice for 14 days significantly enhanced object recognition ability. In the brains of those mice, axonal densities and c-Fos expression levels were enhanced, especially in the perirhinal cortex, which mainly relates to object recognition memory. The present study found, for the first time, that extracellular cAST promoted axonal growth function in neurons and activated memory function. These findings indicate a new function of extracellular cAST and may drive the establishment of new therapeutic strategies for cognitive dysfunction. The present study found, for the first time, that extracellular cAST promotes axonal growth in neurons. PMID- 28852934 TI - Anti-glioma Activity of Dapsone and Its Enhancement by Synthetic Chemical Modification. AB - The sulfone dapsone is an old antibiotic used for the treatment of mycobacterial and protozoal infections. We postulated before that dapsone might possess biological activity exceeding its anti-infectious properties and that it could potentially be repurposed for the treatment of glioma. To test this hypothesis, we treated established and primary cultured glioma cells with dapsone or several dapsone analogues which we previously synthesized (D2-D5) and determined effects on proliferation, anchorage-independent growth and migration. While dapsone and its synthetic analogues D2-D5 displayed only modest anti-proliferative activity, important neoplastic features such as anchorage-independent growth, clonogenic survival and directed migration were significantly inhibited by dapsone treatment. Moreover, dapsone analogues D3, D4 and D5 yielded even enhanced anti glioma activity against different pro-neoplastic features. Overall these data suggest that dapsone provides activity against glioma which can be further enhanced by molecular modifications. These compounds could potentially serve as a therapeutic adjunct to the treatment of gliomas in a repurposing approach. PMID- 28852936 TI - Down-regulation of PAX2 promotes in vitro differentiation of podocytes from human CD34+ cells. AB - Podocytes are major kidney cells that help in glomerular filtration and any damage or loss is a major event in the progression of kidney diseases. Understanding podocytes development will help in designing therapeutic strategies against these renal diseases. Therefore, in vitro generation of podocytes from adult hematopoietic CD34+ stem cells is explored in the present study. Apheretically, isolated human HSCs from peripheral blood showed the presence of CD34 surface glycoprotein through immunocytochemistry (ICC) and flowcytometry. Initially, these HSCs were induced with activin-A (10 ng/ml), retinoic acid (RA) (10 ng/ml) and bone morphogenic protein (BMP-7) (2.5 ng/ml) for 5 days. Transdifferentiation of HSCs to podocytes through intermediate mesoderm was studied with positive selection of Osr1+ cells. Subsequently, thus-obtained Osr1+ cells were induced further with activin-A (10 ng/ml), RA (10 ng/ml), BMP-7 (2.5 ng/ml), EGF (30 ng/ml) and bFGF (30 ng/ml) for 9 days. Distinct cobblestone morphological changes were observed on staining with Leishman's stain. Consequently, differentiated cells were immunopositive for anti-podocin, anti synaptopodin and anti-GLEPP1 monoclonal antibodies. These cells showed expression of early podocyte markers PAX2 and Wt1 at day 3 followed by day 6 and mature podocyte markers NPHS1, SULT1B1, NPHS2 and Synaptopodin at day 9. Interestingly, on day 9, diminished expression of PAX2 was noted. Differentiated cells showed high tyrosine kinase activity signifying that phosphorylation controls slit diaphragm proteins. Synaptopodin regulates the integrity of cytoskeleton and cell motility of podocytes and this phenomenon was confirmed through scratch assay using agarose molds that showed high cell mobility and migration. These findings establish HSCs as ideal candidates for regenerative therapies of damaged podocytes. PMID- 28852935 TI - SHP2 regulates proliferation and tumorigenicity of glioma stem cells. AB - SHP2 is a cytoplasmic protein tyrosine phosphatase (PTPase) involved in multiple signaling pathways and was the first identified proto-oncogene PTPase. Previous work in glioblastoma (GBM) has demonstrated the role of SHP2 PTPase activity in modulating the oncogenic phenotype of adherent GBM cell lines. Mutations in PTPN11, the gene encoding SHP2, have been identified with increasing frequency in GBM. Given the importance of SHP2 in developing neural stem cells, and the importance of glioma stem cells (GSCs) in GBM oncogenesis, we explored the functional role of SHP2 in GSCs. Using paired differentiated and stem cell primary cultures, we investigated the association of SHP2 expression with the tumor stem cell compartment. Proliferation and soft agar assays were used to demonstrate the functional contribution of SHP2 to cell growth and transformation. SHP2 expression correlated with SOX2 expression in GSC lines and was decreased in differentiated cells. Forced differentiation of GSCs by removal of growth factors, as confirmed by loss of SOX2 expression, also resulted in decreased SHP2 expression. Lentiviral-mediated knockdown of SHP2 inhibited proliferation. Finally, growth in soft-agar was similarly inhibited by loss of SHP2 expression. Our results show that SHP2 function is required for cell growth and transformation of the GSC compartment in GBM. PMID- 28852937 TI - Surgeon preference of surgical approach for partial nephrectomy in patients with baseline chronic kidney disease: a nationwide population-based analysis in the USA. AB - PURPOSE: To examine trends in utilization of open, laparoscopic and robot assisted surgical approaches for treatment of patients with chronic kidney disease (CKD) undergoing partial nephrectomy (PN) within the USA. METHODS: We analyzed a weighted sample of 112,117 patients from the Premier administrative dataset who underwent PN for renal mass between 2003 and 2015. Proportions of surgical approach utilization were evaluated by CKD status and further stratified by surgery year and surgeon volume. A multivariate logistic regression model was created to predict receipt of minimally invasive PN. RESULTS: Seven thousand five hundred and sixty-five (6.7%) patients with CKD were identified. The proportion of CKD patients receiving open PN decreased from 72.4% in 2003-2007 to 36.1% in 2012-2015 (p < 0.001). Although the robot-assisted PN was the dominant surgical approach for both patients with and without CKD in 2012-2015, the proportion receiving open PN was higher in patients with CKD compared to those without CKD (p = 0.018). Multivariate analysis showed that the presence of CKD was independently associated with lower odds of receiving a minimally invasive approach (OR 0.47 for the entire study cohort, OR 0.27 for high volume robot assisted PN surgeons, and OR 0.51 for recent years, all p < 0.001). These trends remained when CKD stages were evaluated individually. CONCLUSION: Patients with CKD undergoing PN were preferentially treated with open surgery despite an overall increase in robot-assisted PN use over the past 13 years. Further studies evaluating surgical outcomes in this population are warranted for determination of optimal approach and construction of evidence-based guidelines. PMID- 28852938 TI - Medicalising short children with growth hormone? Ethical considerations of the underlying sociocultural aspects. AB - In 2003, the Food and Drug Administration approved the use of growth hormone treatment for idiopathic short stature children, i.e. children shorter than average due to an unknown medical cause. Given the absence of any pathological conditions, this decision has been contested as a case of medicalisation. The aim of this paper is to broaden the debate over the reasons for and against the treatment, to include considerations of the sociocultural phenomenon of the medicalisation of short stature, by means of a critical understanding of the concept of medicalisation. After defining my understanding of medicalisation and describing both the treatment and the condition of idiopathic short stature, I will problematise two fundamental issues: the medical/non-medical distinction and the debate about the goals of medicine. I will analyse them, combining perspectives of bioethics, medical sociology, philosophy of medicine and medical literature, and I will suggest that there are different levels of normativity of medicalisation. Ultimately, this study shows that: (1) the definition of idiopathic short stature, focusing only on actual height measurement, does not provide enough information to assess the need for treatment or not; (2) the analysis of the goals of medicine should be broadened to include justifications for the treatment; (3) the use of growth hormone for idiopathic short stature involves strong interests from different stakeholders. While the treatment might be beneficial for some children, it is necessary to be vigilant about possible misconduct at different levels of medicalisation. PMID- 28852939 TI - Health-related quality of life after gastrectomy, esophagectomy, and combined esophagogastrectomy for gastroesophageal junction adenocarcinoma. AB - BACKGROUND: The postoperative health-related quality of life (HRQOL) outcomes in patients with gastroesophageal junction (GEJ) adenocarcinoma after gastrectomy and esophagectomy are unclear. The aim was to evaluate HRQOL outcomes 6 months after extended total gastrectomy, subtotal esophagectomy, and combined esophagogastrectomy. METHODS: Patients who underwent surgery for GEJ adenocarcinoma of Siewert type 2 or 3 in 2001-2005 were identified from a nationwide Swedish prospective and population-based cohort. Three surgical strategies, i.e., gastrectomy, esophagectomy, or esophagogastrectomy, were analyzed in relationship to HRQOL measured at 6 months after surgery (main outcome). HRQOL was assessed using well-validated questionnaires for general (EORTC QLQ-C30) and esophageal cancer-specific (EORTC QLQ-OES18) symptoms. Mean score differences (MSD) and 95% confidence intervals (CI) were analyzed using ANCOVA and adjusted for age, sex, tumor stage, comorbidity, education level, hospital volume, and postoperative complications. MSDs > 10 were regarded as clinically relevant. RESULTS: Among 176 patients with complete information on HRQOL and covariates, none of the MSDs for HRQOL among the three surgery groups were clinically and statistically significant. MSDs comparing esophagectomy and gastrectomy showed no major differences in global quality of life (MSD, +8, 95% CI, 0 to +16), physical function (MSD, +2, 95% CI, -5 to +9), pain (MSD, -3, 95% CI, -12 to +7), or reflux (MSD, +5, 95% CI, -4 to +14). Also, complication rates and 5-year survival rates were similar comparing esophagectomy and gastrectomy. CONCLUSIONS: Extended total gastrectomy, subtotal esophagectomy, and combined esophagogastrectomy seemed to yield similar 6-month postoperative HRQOL outcomes for patients with GEJ adenocarcinoma. PMID- 28852940 TI - Antioxidative and Anti-Apoptotic Roles of Silibinin in Reversing Learning and Memory Deficits in APP/PS1 Mice. AB - Silibinin has been widely used to treat liver diseases due to its antioxidant activity. However, the effects of silibinin on the central nervous system have not been thoroughly investigated. The pathological hallmarks of Alzheimer's disease are the accumulation of amyloid beta protein, development of neurofibrillary tangles and increased oxidative stress, which ultimately lead to irreversible neuronal loss and cognitive impairment. Our findings show that silibinin ameliorated memory impairments in APP/PS1 mice in the Morris water maze via suppression of oxidative stress and inhibition of apoptosis. Treatment with silibinin reduced malondialdehyde content level and increased glutathione and superoxide dismutase activity in APP/PS1 mice. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay revealed an anti-apoptotic effect of silibinin. Silibinin suppressed the activation of caspase-3 by inhibiting Jun N terminal kinase phosphorylation and the downstream hippocampal Bax/Bcl-2 ratio. Silibinin treatment significantly increased levels of synaptophysin and PSD95 in APP/PS1 transgenic mice. These results suggest that silibinin could be a potential therapeutic agent for the treatment of Alzheimer's disease. PMID- 28852941 TI - Monitoring of Cardiac Remodeling in a Mouse Model of Pressure-Overload Left Ventricular Hypertrophy with [18F]FDG MicroPET. AB - PURPOSE: This study aims to analyze the left ventricular function parameters, scar load, and hypertrophy in a mouse model of pressure-overload left ventricular (LV) hypertrophy over the course of 8 weeks using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) micro-positron emission tomography (microPET) imaging. PROCEDURES: LV hypertrophy was induced in C57BL/6 mice by transverse aortic constriction (TAC). Myocardial hypertrophy developed after 2-4 weeks. ECG-gated microPET scans with [18F]FDG were performed 4 and 8 weeks after surgery. The extent of fibrosis was measured by histopathologic analysis. LV function parameters and scar load were calculated using QGS(r)/QPS(r). LV metabolic volume (LVMV) and percentage injected dose per gram were estimated by threshold-based analysis. RESULTS: The fibrotic tissue volume increased significantly from 4 to 8 weeks after TAC (1.67 vs. 3.91 mm3; P = 0.044). There was a significant increase of the EDV (4 weeks: 54 +/- 15 MUl, 8 weeks: 79 +/- 32 MUl, P < 0.01) and LVMV (4 weeks: 222 +/- 24 MUl, 8 weeks: 276 +/- 52 MUl, P < 0.01) as well as a significant decrease of the LVEF (4 weeks: 56 +/- 17 %, 8 weeks: 44 +/- 20 %, P < 0.01). The increase of LVMV had a high predictive value regarding the amount of ex vivo measured fibrotic tissue (R = 0.905, P < 0.001). The myocardial metabolic defects increased within 4 weeks (P = 0.055) but only moderately correlated with the fibrosis volume (R = 0.502, P = 0.021). The increase in end-diastolic volume showed a positive correlation with the fibrosis at 8 weeks (R = 0.763, P = 0.017). CONCLUSIONS: [18F]FDG-PET is applicable for serial in vivo monitoring of the TAC mouse model. Myocardial hypertrophy, the dilation of the left ventricle, and the decrease in LVEF could be reliably quantified over time, as well as the developing localized scar. The increase in volume over time is predictive of a high fibrosis load. PMID- 28852942 TI - Sublethal Effects of Neonicotinoid Insecticide on Calling Behavior and Pheromone Production of Tortricid Moths. AB - In moths, sexual behavior combines female sex pheromone production and calling behavior. The normal functioning of these periodic events requires an intact nervous system. Neurotoxic insecticide residues in the agroecosystem could impact the normal functioning of pheromone communication through alteration of the nervous system. In this study we assess whether sublethal concentrations of the neonicotinoid insecticide thiacloprid, that competitively modulates nicotinic acetylcholine receptors at the dendrite, affect pheromone production and calling behavior in adults of three economically important tortricid moth pests; Cydia pomonella (L.), Grapholita molesta (Busck), and Lobesia botrana (Denis & Schiffermuller). Thiacloprid significantly reduced the amount of calling in C. pomonella females at LC0.001 (a lethal concentration that kills only 1 in 105 individuals), and altered its calling period at LC1, and in both cases the effect was dose-dependent. In the other two species the effect was similar but started at higher LCs, and the effect was relatively small in L. botrana. Pheromone production was altered only in C. pomonella, with a reduction of the major compound, codlemone, and one minor component, starting at LC10. Since sex pheromones and neonicotinoids are used together in the management of these three species, our results could have implications regarding the interaction between these two pest control methods. PMID- 28852943 TI - Comparative stylostome ultrastructure of Hirsutiella zachvatkini (Trombiculidae) and Trombidium holosericeum (Trombidiidae) larvae. AB - Stylostomes (feeding tubes) of Hirsutiella zachvatkini (Schluger) (Trombiculidae), feeding on bank voles [Myodes glareolus (Schreber)], and of Trombidium holosericeum (L.) (Trombidiidae), feeding on larvae of Stenodemini sp. (Heteroptera, Miridae), were studied by TEM methods and on semi-thin sections. The stylostome of H. zachvatkini is a homogeneous structure of low electron density and without strict margins. It extends within the concave host epidermis, undergoing hyperplasia and hyperkeratosis. TEM does not reveal any obvious stratification in the stylostome walls. The cheliceral movable digits are moved apart by 5-6 um and tightly applied/adhered to the stylostome substance. A local area beneath the open end of the stylostome canal is not empty but contains a nearly homogeneous substrate, which can pass into the central stylostome canal. The latter is mostly free of contents. In contrast to H. zachvatkini, larvae of T. holosericeum form a root-like stylostome chaotically branching within the clear space underneath the host cuticle free of tissue elements. Tubules of the distal stylostome branches become progressively thinner and disappear blindly. As in H. zachvatkini, the stylostome walls of T. holosericeum are devoid of stratification but show moderate to high electron density. The cheliceral movable digits are moved apart by the same distance, as in H. zachvatkini, and tightly applied to the stylostome substance. The lumen of the central canal is either electron lucent, in the distal portions, or filled with a fine granular or homogeneous substrate of low electron density in the proximal portions forming a type of ampoule. This study shows that Trombiculidae and Trombidiidae share similar initial stages of stylostome formation but the resultant stylostome of each family is distinctly different. PMID- 28852944 TI - Bayes Factor Covariance Testing in Item Response Models. AB - Two marginal one-parameter item response theory models are introduced, by integrating out the latent variable or random item parameter. It is shown that both marginal response models are multivariate (probit) models with a compound symmetry covariance structure. Several common hypotheses concerning the underlying covariance structure are evaluated using (fractional) Bayes factor tests. The support for a unidimensional factor (i.e., assumption of local independence) and differential item functioning are evaluated by testing the covariance components. The posterior distribution of common covariance components is obtained in closed form by transforming latent responses with an orthogonal (Helmert) matrix. This posterior distribution is defined as a shifted-inverse gamma, thereby introducing a default prior and a balanced prior distribution. Based on that, an MCMC algorithm is described to estimate all model parameters and to compute (fractional) Bayes factor tests. Simulation studies are used to show that the (fractional) Bayes factor tests have good properties for testing the underlying covariance structure of binary response data. The method is illustrated with two real data studies. PMID- 28852945 TI - Positional therapy in the management of positional obstructive sleep apnea-a review of the current literature. AB - More than 50% of obstructive sleep apnea (OSA) patients have worsening of their OSA in the supine position (positional obstructive sleep apnea [POSA], commonly defined as supine to non-supine apnea hypopnea index (AHI) ratio of >= 2). Positional therapy (PT) aims to prevent patients from sleeping in the supine position. One of the major limiting factors to the routine use of PT in clinical practice is the lack of validated tools to measure compliance objectively. Furthermore, there are no universal guidelines to determine if PT will be effective as standalone or as adjunctive therapy. This paper assesses recent literature on PT demonstrating its effectiveness in management of POSA. It also outlines the proposed subclassification systems for POSA. Electronic literature review was done on EMBASE. Since the last review of PT by Ravesloot et al. (2012), ten studies were identified which demonstrate effectiveness of PT in POSA. We found three publications proposing different subclassification systems for POSA. There were three studies validating different compliance monitoring tools for PT. One study showed the cost benefits of incorporating PT into OSA management. Positional therapy is an effective treatment for POSA and progress has been made in development of tools for measuring compliance. Creating a subclassification of POSA may help develop targeted therapy for patients and determine its use as standalone or adjunct therapy. The integration of PT into POSA management may be cost-effective when compared to the use of CPAP alone. PMID- 28852946 TI - Clinical pattern of primary systemic therapy and outcomes of estrogen receptor positive, HER2-negative metastatic breast cancer: a review of a single institution. AB - PURPOSE: In the management of estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer (ER+HER2-MBC) patients, endocrine therapy (ET) is preferred to chemotherapy (CT) as a primary systemic therapy (PST) when tumor burden is not high. However, there are no definite criteria for choosing a PST, transitioning from ET to CT or using maintenance ET subsequent to CT. METHODS: We reviewed the medical records of 311 ER+HER2-MBC patients who underwent CT from September 2002 to December 2016 and assessed their outcomes. RESULTS: Of the 311 patients, 178 (57%) received ET as a PST (ET-first group), and 133 (43%) received CT prior to ET (CT-first group). The ET-first group showed a median overall survival (OS) from the diagnosis of MBC (OSMBC) of 1593 days, and the median OS from the initiation of CT (OSCT) was 938 days. Patients with visceral involvement, liver metastasis, soft tissue metastasis, >=3 organ involvement, or primary advanced BC at the MBC diagnosis showed a significantly higher tendency to be assigned to the CT-first group (P < 0.01 for any visceral involvement, P < 0.05 for all others). Maintenance ET was available in 74 (55.6%) patients in the CT-first group, who showed a significantly better OSMBC and OSCT than patients without maintenance ET (median OSMBC 1423 and 867 days, respectively, P < 0.0001; median OSCT 1350 and 637 days, respectively, P < 0.0001). CONCLUSION: Our findings suggest the possibility for changing the treatment paradigm of patients with ER+HER2-MBC, so a randomized prospective study is warranted to determine the optimum sequence of systemic therapies. PMID- 28852947 TI - Modeling of the metabolic energy dissipation for restricted tumor growth. AB - Energy dissipation mostly represents unwanted outcome but in the biochemical processes it may alter the biochemical pathways. However, it is rarely considered in the literature although energy dissipation and its alteration due to the changes in cell microenvironment may improve methods for guiding chemical and biochemical processes in the desired directions. Deeper insight into the changes of metabolic activity of tumor cells exposed to osmotic stress or irradiation may offer the possibility of tumor growth reduction. In this work effects of the osmotic stress and irradiation on the thermodynamical affinity of tumor cells and their damping effects on metabolic energy dissipation were investigated and modeled. Although many various models were applied to consider the tumor restrictive growth they have not considered the metabolic energy dissipation. In this work a pseudo rheological model in the form of "the metabolic spring-pot element" is formulated to describe theoretically the metabolic susceptibility of tumor spheroid. This analog model relates the thermodynamical affinity of cell growth with the volume expansion of tumor spheroid under isotropic loading conditions. Spheroid relaxation induces anomalous nature of the metabolic energy dissipation which causes the damping effects on cell growth. The proposed model can be used for determining the metabolic energy "structure" in the context of restrictive cell growth as well as for predicting optimal doses for cancer curing in order to tailor the clinical treatment for each person and each type of cancer. PMID- 28852948 TI - The Association Between Acculturation and Cardiovascular Disease Risk in Ghanaian and Nigerian-born African Immigrants in the United States: The Afro-Cardiac Study. AB - The burden of cardiovascular disease (CVD) risk in ethnic minorities in the United States (US) is high. Acculturation may worsen or improve cardiovascular health in immigrants. We sought to examine the association between acculturation and elevated cardiovascular disease risk in African immigrants, a growing immigrant population in the US. We conducted a cross-sectional study of Ghanaian and Nigerian born-African immigrants in the US. To determine whether acculturation was associated with having elevated CVD risk (defined as >=3 CVD risk factors or Pooled Cohort Equations score >=7.5%), we performed unadjusted and adjusted logistic regression analyses. For both outcomes, sex-specific models were fitted. Participants (N = 253) were aged 35-74 years and resided in Baltimore-Washington-D.C. The mean age (SD) was 49.5 (9.2) years and 58% were female. Residing in the US for >=10 years was associated with an almost fourfold (95% CI 1.05-14.35) and eightfold (95% CI 2.09-30.80) greater odds of overweight/obesity and elevated CVD risk respectively in males. Females residing in the US for >=10 years had 2.60 times (95% CI 1.04-6.551) greater odds of hypertension than newer residents. Participants were classified according to acculturation strategies: Integrationists, 166 (66%); Traditionalists, 80 (32%); Marginalists, 5 (2%); and Assimilationists, 2 (1%). Integrationists had a 0.46 (95% CI 0.24-0.87) lower odds of having >=3 CVD risk factors and 0.38 (95% CI 0.18-0.78) lower odds of having elevated CVD risk (Pooled Cohort Equations score >=7.5%) than Traditionalists. Although longer length of stay was associated with CVD risk, Integrationists had lower CVD risk than Traditionalists. Our results suggest that coordinated public health responses to the epidemic of CVD risk factors in the US should target this understudied population. Acculturation should be considered as a meaningful contributor of increased CVD risk and acculturation strategies may be used to tailor interventions in African immigrants. Promoting successful integration may reduce immigrants' CVD risk. PMID- 28852949 TI - Risk assessment and interpretation of heavy metal contaminated soils on an urban brownfield site in New York metropolitan area. AB - In this study, soil samples were collected at 22 sites in Liberty State Park, New Jersey, in 2005, for metal enrichment and potential ecological risk assessment. The geoaccumulation index (I geo) showed that enrichment levels of trace metals followed an order of Cu > Pb > Zn > As > Cr > Hg while the potential ecological risk factor ([Formula: see text]) indicated that the potential ecological risk of the metals was in the order of Cu > Pb > As > Hg > Zn > Cr. Among these 22 sites, this investigation identified 9 sites at moderate ecological risk, 3 sites at considerable ecological risk, and 4 sites at high ecological risk according to the potential ecological risk index (RI). Hierarchical cluster analysis (CA) of soil metal concentrations separated the study sites into four groups, which are supported by the significant difference in RI values. Geographically, three regions in the Liberty State Park brownfield site were determined based on the CA results and RI values. Subarea 1 had low ecological risk while subareas 2 and 3 had a greater potential for ecological risk. Significant correlations of Pb with Cr and Zn were observed in subareas 2 and 3, respectively. This study shows that statistical approaches coupled with a risk assessment index provide a more comprehensive interpretation of land contamination than a single approach in support of planning land redevelopment. PMID- 28852950 TI - Are Tumor Cell Lineages Solely Shaped by Mechanical Forces? AB - This paper investigates cell proliferation dynamics in small tumor cell aggregates using an individual-based model (IBM). The simulation model is designed to study the morphology of the cell population and of the cell lineages as well as the impact of the orientation of the division plane on this morphology. Our IBM model is based on the hypothesis that cells are incompressible objects that grow in size and divide once a threshold size is reached, and that newly born cell adhere to the existing cell cluster. We performed comparisons between the simulation model and experimental data by using several statistical indicators. The results suggest that the emergence of particular morphologies can be explained by simple mechanical interactions. PMID- 28852951 TI - Effects of golpar (Heracleum persicum Desf.) and probiotics in drinking water on performance, carcass characteristics, organ weights, blood plasma constituents, and immunity of broilers. AB - Increasing levels of Heracleum persicum (golpar) in drinking water were studied in broilers. Two hundred and forty-one-day-old male chickens were allocated to one of six treatments: control, without added phytogenics nor probiotics in drinking water, and probiotics at recommended manufacturer's level (P) or 1.0, 1.5, 2.0, and 2.5 ml/l of golpar extract solution (G1, G1.5, G2, and G2.5 treatments, respectively) in drinking water. As a result of this study, no linear or quadratic trends in the feed intake (FI) and feed conversion rate (FCR) due to golpar supplementation were found. Body weight gain, final body weight, and relative carcass weight showed a positive linear response with increasing levels of golpar supplementation. Neither golpar nor probiotics had effects on the percentages of edible parts of the carcass. Golpar supplementation levels caused a linear negative response of the albumin content in blood plasma, whereas both abdominal fat as percentage of carcass weight and uric acid levels in blood plasma linearly increased. The effects on Ig responses were only observed at 42 days of age and were similar in probiotics and the highest level of golpar supplementation. Based on our results, both probiotics and golpar supplementation could improve broiler performance and immune function. PMID- 28852952 TI - Atlas-Based Segmentation of Temporal Bone Anatomy. AB - PURPOSE: To develop a time-efficient automated segmentation approach that could identify critical structures in the temporal bone for visual enhancement and use in surgical simulation software. METHODS: An atlas-based segmentation approach was developed to segment the cochlea, ossicles, semicircular canals (SCCs), and facial nerve in normal temporal bone CT images. This approach was tested in images of 26 cadaver bones (13 left, 13 right). The results of the automated segmentation were compared to manual segmentation visually and using DICE metric, average Hausdorff distance, and volume similarity. RESULTS: The DICE metrics were greater than 0.8 for the cochlea, malleus, incus, and the SCCs combined. It was slightly lower for the facial nerve. The average Hausdorff distance was less than one voxel for all structures, and the volume similarity was 0.86 or greater for all structures except the stapes. CONCLUSIONS: The atlas-based approach with rigid body registration of the otic capsule was successful in segmenting critical structures of temporal bone anatomy for use in surgical simulation software. PMID- 28852953 TI - Modeling the Transfer of Drug Resistance in Solid Tumors. AB - ABC efflux transporters are a key factor leading to multidrug resistance in cancer. Overexpression of these transporters significantly decreases the efficacy of anti-cancer drugs. Along with selection and induction, drug resistance may be transferred between cells, which is the focus of this paper. Specifically, we consider the intercellular transfer of P-glycoprotein (P-gp), a well-known ABC transporter that was shown to confer resistance to many common chemotherapeutic drugs. In a recent paper, Duran et al. (Bull Math Biol 78(6):1218-1237, 2016) studied the dynamics of mixed cultures of resistant and sensitive NCI-H460 (human non-small lung cancer) cell lines. As expected, the experimental data showed a gradual increase in the percentage of resistance cells and a decrease in the percentage of sensitive cells. The experimental work was accompanied with a mathematical model that assumed P-gp transfer from resistant cells to sensitive cells, rendering them temporarily resistant. The mathematical model provided a reasonable fit to the experimental data. In this paper, we develop a new mathematical model for the transfer of drug resistance between cancer cells. Our model is based on incorporating a resistance phenotype into a model of cancer growth (Greene et al. in J Theor Biol 367:262-277, 2015). The resulting model for P-gp transfer, written as a system of integro-differential equations, follows the dynamics of proliferating, quiescent, and apoptotic cells, with a varying resistance phenotype. We show that this model provides a good match to the dynamics of the experimental data of Duran et al. (2016). The mathematical model shows a better fit when resistant cancer cells have a slower division rate than the sensitive cells. PMID- 28852954 TI - Pressure ulcers are associated with 6-month mortality in elderly patients with hip fracture managed in orthogeriatric care pathway. AB - : Despite orthogeriatric management, 12% of the elderly experienced PUs after hip fracture surgery. PUs were significantly associated with a low albumin level, history of atrial fibrillation coronary artery disease, and diabetes. The risk ratio of death at 6 months associated with pressure ulcer was 2.38 (95% CI 1.31 4.32%, p = 0.044). INTRODUCTION: Pressure ulcers in hip fracture patients are frequent and associated with a poor outcome. An orthogeriatric management, recommended by international guidelines in hip fracture patients and including pressure ulcer prevention and treatment, could influence causes and consequences of pressure ulcer. However, remaining factors associated with pressure ulcer occurrence and prognostic value of pressure ulcer in hip fracture patients managed in an orthogeriatric care pathway remain unknown. METHODS: From June 2009 to April 2015, all consecutive patients with hip fracture admitted to a unit for Post-operative geriatric care were evaluated for eligibility. Patients were included if their primary presentation was due to hip fracture and if they were >= 70 years of age. Patients were excluded in the presence of pathological fracture or if they were already hospitalized at the time of the fracture. In our unit, orthogeriatric principles are implemented, including a multi-component intervention to improve pressure ulcer prevention and management. Patients were followed-up until 6 months after discharge. RESULTS: Five hundred sixty-seven patients were included, with an overall 14.4% 6-month mortality (95% CI 11.6 17.8%). Of these, 67 patients (12%) experienced at least one pressure ulcer. Despite orthogeriatric management, pressure ulcers were significantly associated with a low albumin level (RR 0.90, 95% CI 0.84-0.96; p = 0.003) and history of atrial fibrillation (RR 1.91, 95% CI 1.05-3.46; p = 0.033), coronary artery disease (RR 2.16, 95% CI 1.17-3.99; p = 0.014), and diabetes (RR 2.33, 95% CI 1.14-4.75; p = 0.02). A pressure ulcer was associated with 6-month mortality (RR 2.38, 95% CI 1.31-4.32, p = 0.044). CONCLUSION: In elderly patients with hip fracture managed in an orthogeriatric care pathway, pressure ulcer remained associated with poorly modifiable risk factors and long-term mortality. PMID- 28852955 TI - Increased Metabolic Benefit for Obese, Elderly Patients Undergoing Roux-en-Y Gastric Bypass vs Sleeve Gastrectomy. AB - PURPOSE: We sought to assess outcomes of laparoscopic sleeve gastrectomy (LSG) vs laparoscopic Roux-en-Y gastric bypass (LRYGB) in a cohort of morbidly obese, elderly patients. MATERIALS AND METHODS: Retrospective review was conducted of all patients age 60 years or greater undergoing LSG or LRYGB at our institution between 2007 and 2014. RESULTS: A total of 134 patients who underwent LSG (n = 65) or LRYGB (n = 69) were identified. Groups were similar with respect to age (64 years, range 60-75 years), BMI (44.0 +/- 6.1), and ASA score (91% >= ASA 3). There were no differences in major post-operative complications (3, 4.7% LSG vs 4, 5.8% LRYGB, p = 0.75). Median follow-up was 39 months (IQR 14-64 months) with no patients lost to follow-up. Patients undergoing LRYGB had improvement in each of diabetes mellitus 2 (DM2), hypertension (HTN), hyperlipidemia (HL), and gastroesophageal reflux disease (GERD) as well as a significant decrease in insulin use (16/47, 34.0% pre-operatively vs 7/47, 15.2% post-operatively; p = 0.03). Patients undergoing LSG had improvement in DM2 and HTN but not in HL or GERD; there was no reduction in insulin dependence. Weight loss was not significantly different between groups; mean percent total weight loss at 36 months was 26.9 +/- 9.0% in the LSG group and 23.9 +/- 9.3% in the LRYGB group, p = 0.24. CONCLUSIONS: Both LSG and RYGB can be safely performed on morbidly obese, elderly adults. At intermediate follow-up, there is an increased metabolic benefit for elderly patients undergoing LRYGB over LSG. PMID- 28852956 TI - Dissipation of spiromesifen and spiromesifen-enol on tomato fruit, tomato leaf, and soil under field and controlled environmental conditions. AB - Dissipation of spiromesifen and its metabolite, spiromesifen-enol, on tomato fruit, tomato leaf, and soil was studied in the open field and controlled environmental conditions. Sample preparation was carried out by QuEChERS method and analysis using LC-MS/MS. Method validation for analysis of the compounds was carried out as per "single laboratory method validation guidelines." Method validation studies gave satisfactory recoveries for spiromesifen and spiromesifen enol (71.59-105.3%) with relative standard deviation (RSD) < 20%. LOD and LOQ of the method were 0.0015 MUg mL-1 and 0.005 mg kg-1, respectively. Spiromesifen residues on tomato fruits were 0.855 and 1.545 mg kg-1 in open field and 0.976 and 1.670 mg kg-1 under polyhouse condition, from treatments at the standard and double doses of 125 and 250 g a.i. ha-1, respectively. On tomato leaves, the residues were 5.64 and 8.226 mg kg-1 in open field and 6.874 and 10.187 mg kg-1 in the polyhouse. In soil, the residues were 0.532 and 1.032 mg kg-1 and 0.486 and 0.925 mg kg-1 under open field and polyhouse conditions, respectively. The half-life of degradation of spiromesifen on tomato fruit was 6-6.5 days in the open field and 8.1-9.3 days in the polyhouse. On tomato leaves, it was 7-7.6 and 17.6-18.4 days and in soil 5.6-7.4 and 8.4-9.5 days, respectively. Metabolite, spiromesifen-enol, was not detected in any of the sample throughout the study period. Photodegradation could be the major route for dissipation of spiromesifen in the tomato leaves, whereas in the fruits, it may be the combination of photodegradation and dilution due to fruit growth. The results of the study can be utilized for application of spiromesifen in plant protection of tomato crop under protected environmental conditions. PMID- 28852957 TI - A 12-Month Review of Revisional Single Anastomosis Gastric Bypass for Complicated Laparoscopic Adjustable Gastric Banding for Body Mass Index over 35. AB - BACKGROUND: In many countries, laparoscopic adjustable gastric banding (LAGB) was previously the most commonly performed bariatric procedure due to its operative safety and early efficacy. This procedure is now superseded because of doubtful long-term results and late complications. Many people eventually required revisional bariatric surgery such as conversion to single anastomosis gastric bypass (SAGB). This study aims to assess the safety and durability of single stage conversion from LAGB to SAGB in patients who are intolerant to LAGB and who also fail to lose weight, or re-gain weight. METHODS: Seventy-four patients with BMI > 35 kg m-2 were selected from a prospective bariatric database between July 2012 and December 2015 for revisional laparoscopic SAGB surgery and were followed up at 6 weeks, 3, 6 and 12 months after their operation. RESULTS: The mean BMI at 6 weeks, then 3, 6 and 12 months were 41.6 +/- 7.66, 38.8 +/- 7.54, 35.4 +/- 7.10 and 33.2 +/- 7.34 kg m-2, respectively. The mean percentage EWL at 6 weeks then 3, 6 and 12 months were 21.0 +/- 9.12, 37.8 +/- 12.5, 55.1 +/- 15.8 and 67.0 +/- 19.6%, respectively. Postoperative follow-up at these times were 97, 85, 69 and 46%, respectively. Early (< 30 day) morbidity was 20.3% with major complications of CD grade 3a or more of 13.5%. CONCLUSIONS: This study demonstrates that single stage revisional SAGB after a failed LAGB achieved good short-term weight loss and low 30-day morbidity. PMID- 28852959 TI - How should we manage type B aortic dissections? AB - Dissection of the descending aorta is a serious and potentially lethal event. Treatment options consist of medical therapy, open surgical replacement of the affected aorta and thoracic endovascular repair. In acute cases, medical treatment is started initially. When complicated, endovascular repair is generally considered as first choice treatment, except for connective tissue disorders where open surgery remains the standard. In stable, uncomplicated patients with risk factors for future aortic growth pre-emptive endovascular repair should be considered in the sub-acute phase of the dissection. The treatment strategy in chronic dissections is somewhat debated. Long-term results and aortic remodeling of endovascular repair are disappointing and open surgery remains the standard. PMID- 28852958 TI - Clinical benefit of antiangiogenic therapy in advanced and metastatic chondrosarcoma. AB - Chondrosarcoma is the most common bone sarcoma in adults. Conventional chondrosarcoma, the commonest histological subtype, is largely resistant to anthracycline-based chemotherapy. There have been anecdotal reports of durable clinical benefit with antiangiogenic agents in this disease. A retrospective search of patients treated at three sarcoma referral centers was performed to identify patients with advanced chondrosarcoma treated with antiangiogenic agents. The aim of this study was to evaluate the efficacy and safety of antiangiogenic agents in advanced chondrosarcoma. Ten patients were identified; seven with conventional, one each with clear cell, extraskeletal mesenchymal chondrosarcoma and extraskeletal myxoid chondrosarcoma. The median progression free survival for patients with conventional and clear cell sarcoma was 22.6 months. Median overall survival has not been met. Antiangiogenic therapy was well tolerated in this series of patients. Our retrospective data suggest that antiangiogenic therapy can provide prolonged clinical benefit in advanced chondrosarcoma patients. Further prospective trials are required to precisely define the role of this class of agent in advanced chondrosarcoma. PMID- 28852960 TI - Long-term cardiovascular complications in stage I seminoma patients. AB - PURPOSE: The cure rate of stage I seminoma patients is close to 100% and so the recent focus of clinical research has shifted onto the prevention of treatment related complications. We assessed long-term cardiovascular complications and identified risk factors for cardiovascular events (CVEs) in stage I seminoma patients. METHODS: This retrospective cohort study included 406 consecutive stage I seminoma patients. Primary endpoint was CVE rate. RESULTS: During a median follow-up of 8.6 years, we observed 23 CVEs in 406 patients [10-year CVE risk 5.6% (95% CI 3.2 to 8.8)]. In univariable competing risk analysis, higher age, positive smoking status, history of diabetes and hypertension were significantly associated with the occurrence of CVE. In multi-state analysis, new onset of diabetes, hypertension and hyperlipidemia during follow-up predicted for an excessively increased CVE risk. In multivariable analysis adjusting for age and smoking, the development of hypertension and hyperlipidemia after tumor-specific treatment prevailed as risk factors for CVE. Regarding adjuvant treatment modalities, patients receiving adjuvant radiotherapy had a significantly higher probability of CVE than patients receiving adjuvant carboplatin [16% vs. 0%; risk difference (RD) = 16%, 95% CI 6 to 25%, p = 0.001]. This difference prevailed after adjusting for age, follow-up-time, diabetes, hypertension and smoking (RD = 11%, 95% CI 1 to 20%, p = 0.025). CONCLUSION: We identified a panel of baseline risk factors and dynamically, occurring predictors of CVE in stage I seminoma patients. This information may be used for targeting comorbidity management in these patients. The observed association of adjuvant radiotherapy with higher CVE risk warrants further investigation. PMID- 28852961 TI - Late anastomotic breakdown with bevacizumab in colorectal cancers, a case-based review. AB - BACKGROUND: Bevacizumab is the first angiogenesis inhibitor to be approved for metastatic colorectal cancer. Unfortunately, bevacizumab treatment has been associated with a variety of complications including haemorrhage, poor wound healing and gastrointestinal perforation. Late anastomotic breakdown related to bevacizumab therapy however has rarely been described. CASE REPORT: Here, we present the case of a 56-year-old woman who had a bevacizumab-related anastomotic breakdown 17 months following her primary anastomosis. She initially underwent an emergency Hartmann's procedure and two further laparotomies for significant intra abdominal haemorrhage. Despite the best efforts of the surgical and intensive care teams, ultimately, the patient passed away. DISCUSSION: There is a small but growing body of literature relating to bevacizumab use and late anastomotic breakdown. It would seem prudent to take extra caution when using bevacizumab in those patients with previous pelvic irradiation, who have a rectal site of anastomosis or have experienced a previous anastomotic leak. PMID- 28852962 TI - Effect of solution pH on aging dynamics and surface structural evolution of mZVI particles: H2 production and spectroscopic/microscopic evidence. AB - A microscale zero-valent iron (mZVI)-based in situ reactive zone is a promising technology for contaminated groundwater remediation. Estimation of mZVI aging behavior after its injection into the subsurface is essential for efficiency and longevity assessments. In this study, batch tests were conducted to investigate the effect of initial pH on mZVI aging dynamics, as well as the formation and evolution of aging products over 112 days. Results indicated that mZVI aging accelerated with decreasing initial pH. Corrosion rates of mZVI particles under pH 6.0 and 7.5 were approximately two orders of magnitude higher than those observed at pH 9.0. The morphological, structural, and compositional evolution of mZVI particles in three systems (pH = 6.0, 7.5, and 9.0) were investigated using scanning electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. In acidic and neutral solutions, a thick passivation layer with loosely and unevenly distributed aging precipitates was observed, and Fe3O4 was the final aging precipitate. Nevertheless, in alkaline solutions, minute aging precipitates were detected on the mZVI surface at 112 day. Characterization results suggested that mZVI was oxidized via the Fe0-Fe(OH)2-Fe3O4 route. These findings shed new light on mZVI aging mechanisms, particularly its physicochemical characteristics and the structural evolution of mZVI in field scale groundwater remediation applications. PMID- 28852963 TI - Minimal Residual Disease Eradication in CML: Does It Really Matter? AB - BCR-ABL1 tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic phase chronic myeloid leukemia (CP-CML) to an extent that survival is largely determined by non-CML mortality. Monitoring for minimal residual disease by measuring BCR-ABL1 messenger RNA is a key component of CML management. CP-CML patients who achieve a stable deep molecular response may discontinue (TKIs) with an ~ 50% chance of entering treatment-free remission (TFR). So far discontinuation of TKIs has largely been limited to clinical trials, but is on the verge of becoming a part of wider clinical practice. Careful patient selection, dense molecular monitoring, and prompt reinstitution of treatment in the event of relapse are all vital to reproduce the same level of success. Much effort has been dedicated to identifying therapeutic strategies to eliminate CML stem cells and enable to TFR in more patients. Unfortunately, despite promising preclinical data, as yet, none of the various approaches have entered clinical practice. PMID- 28852964 TI - PPAR-gamma and Akt regulate GLUT1 and GLUT3 surface localization during Mycobacterium tuberculosis infection. AB - The success of Mycobacterium tuberculosis (Mtb) as a pathogen stems from its ability to manipulate the host macrophage towards increased lipid biogenesis and lipolysis inhibition. Inhibition of lipolysis requires augmented uptake of glucose into the host cell causing an upregulation of the glucose transporters GLUT1 and GLUT3 on the cell surface. Mechanism behind this upregulation of the GLUT proteins during Mtb infection is hitherto unknown and demands intensive investigation in order to understand the pathways linked with governing them. Our endeavor to investigate some of the key proteins that have been found to be affected during Mtb infection led us to investigate host molecular pathways such as Akt and PPAR-gamma that remain closely associated with the survival of the bacilli by modulating the localization of glucose transporters GLUT1 and GLUT3. PMID- 28852965 TI - Traumatic Stress and Accelerated Cellular Aging: From Epigenetics to Cardiometabolic Disease. AB - PURPOSE OF REVIEW: The aim of this paper is to review the recent literature on traumatic stress-related accelerated aging, including a focus on cellular mechanisms and biomarkers of cellular aging and on the clinical manifestations of accelerated biological aging. RECENT FINDINGS: Multiple lines of research converge to suggest that PTSD is associated with accelerated aging in the epigenome, and the immune and inflammation systems, and this may be reflected in premature onset of cardiometabolic and cardiovascular disease. The current state of research paves the way for future work focused on identifying the peripheral and central biological mechanisms linking traumatic stress to accelerated biological aging and medical morbidity, with an emphasis on processes involved in inflammation, immune functioning, oxidative stress, autonomic arousal, and stress response. Ultimately, such work could help reduce the pace of biological aging and improve health and wellness. PMID- 28852966 TI - Characterization of the fungal flora of dolo, a traditional fermented beverage of Burkina Faso, using MALDI-TOF mass spectrometry. AB - A cross-sectional study was conducted in Bobo-Dioulasso, Burkina Faso, to identify the yeast diversity associated with the manufacture of dolo, a traditional fermented beverage of Burkina Faso. From sixty specimens spread onto chromogenic medium plates, sixty-two strains were isolated then identified using MALDI-TOF analysis. Seven yeast species were identified, Saccharomyces cerevisiae (39%) followed by Pichia manshurica (18%) being the most frequent. Forty-three percent of the samples contained Candida species, notably Candida albicans. In conclusion, the combined use of a chromogenic medium and MALDI-TOF analysis reveals a higher diversity in yeast species present in the dolo than previously thought. PMID- 28852967 TI - Recent Advances in Pancreatic Cancer Surgery. AB - OPINION STATEMENT: Pancreatic cancer surgery is a continuously evolving field. Despite tremendous advances in perioperative outcomes, pancreatic resection is still associated with substantial morbidity, and mortality is not nil. Institutional caseload is a well-established determinant of patient outcomes, and centralization to experienced centers is essential to the safety and oncological appropriateness of the resection. Minimally invasive approaches are increasingly applied for pancreatic resection, even in cancer patients. Nevertheless, the level of evidence in this field remains low. Minimally invasive distal pancreatectomy appears potentially beneficial towards some perioperative outcomes, although its oncological results remain incompletely studied. Data regarding perioperative and oncologic outcomes for minimally invasive pancreaticoduodenectomy (Whipple's resection) is even less mature, but suggest that similar results as the open approach can be achieved in selected, high volume centers. Conversely, its indiscriminate adoption by inexperienced surgeons and institutions has potential deleterious effects given its steep learning curve. Newer neoadjuvant treatment protocols display enhanced ability to downstage advanced tumors, increasing candidates for potentially curative surgery. Conversely, putative benefits of neoadjuvant treatment in patients with technically resectable tumors have not been reliably demonstrated and its optimal indications remain highly controversial. PMID- 28852968 TI - The Pyrazole Derivative BTP2 Attenuates IgG Immune Complex-induced Inflammation. AB - Store-operated calcium entry (SOCE) is the most common mode of calcium influx in non-excitable cells, including immune cells. The two STIM isoforms mediate SOCE as well as Fc receptor (FcR)-downstream activation of macrophages and mast cells which appears to be relevant in vivo, in models of antibody-dependent tissue injury and allergy. Hence, the pathway of SOCE may be a therapeutic target for treatment of immune complex (IC)-mediated autoimmunity and allergic asthma. The pyrazole derivative, BTP2 is an efficient inhibitor of SOCE, which has already been shown to attenuate allergic inflammation. However, its effect on Fc gamma receptor (FcgammaR) signaling and IC-induced tissue injury had not yet been studied. Here, we show that BTP2 is a potent inhibitor of SOCE in primary macrophages, blocking FcgammaR-mediated responses. To investigate the effect of inhibition of SOCE in IC-mediated tissue injury, we induced reverse passive Arthus reaction to IgG immune complexes in the skin and lungs of BTP2- or control treated mice. Treatment with BTP2 resulted in markedly attenuated inflammation in both the skin and the lungs. Our findings indicate the involvement of SOCE in FcgammaR-mediated responses in vitro and in vivo and suggest that BTP2-mediated inhibition of SOCE may have a therapeutic potential on IC-mediated autoimmunity. PMID- 28852969 TI - Recovery from very long aortic cross-clamping in redo complex aortic surgery. AB - A 68-year-old man had undergone ascending aortic replacement for acute type A aortic dissection. Three months later, he had a new aortic dissection with an ulcer-like projection located in the aortic arch with suspected graft infection. An emergent redo total aortic arch and root replacement was performed because of the coexistence of a fragile aortic root wall. The extensive redo procedure necessitated a very long aortic cross-clamping time (516 min). After 25 min of assisted circulation, he was easily weaned from the cardiopulmonary bypass. Finally, an omental flap was harvested to cover the graft. Postoperative ECG and CK-MB examinations showed no significant myocardial injury. He had no symptoms of heart failure and was discharged after a month of antibiotic therapy. One-year follow-up UCG study revealed no abnormal findings except for signs of pericardial adhesion. PMID- 28852970 TI - Exploring barriers to the receipt of necessary medical care among cancer survivors under age 65 years. AB - PURPOSE: With increasing cancer care costs and greater patient cost-sharing in the USA, understanding access to medical care among cancer survivors is imperative. This study aims to identify financial, psychosocial, and cancer related barriers to the receipt of medical care, tests, or treatments deemed necessary by the doctor or patient for cancer among cancer survivors age < 65 years. METHODS: We used data on 4321 cancer survivors aged 18-64 years who completed the 2012 LIVESTRONG Survey. Multivariable logistic regression was used to identify risk factors associated with the receipt of necessary medical care, including sociodemographic, financial hardship, debt amount, caregiver status, and cancer-related variables. RESULTS: Approximately 28% of cancer survivors were within 1 year, and 43% between 1 and 5 years, since their last treatment at the time of survey. Nearly 9% of cancer survivors reported not receiving necessary medical care. Compared to survivors without financial hardship, the likelihood of not receiving necessary medical care significantly increased as the amount of debt increased among those with financial hardship (RRFinancial hardship w/< $10,000 debt = 1.94, 95% CI 1.55-2.42, and RR RRFinancial hardship w/>= $10,000 debt = 3.41, 95% CI 2.69-4.33, p < 0.001). Survivors who reported lack of a caregiver, being uninsured, and not receiving help understanding medical bills were significantly more likely to not receive necessary medical care. CONCLUSION: We identified key financial and insurance risk factors that may serve as significant barriers to the receipt of necessary medical care among cancer survivors age < 65 in the USA IMPLICATIONS FOR CANCER SURVIVORS: The majority of cancer survivors reported receiving medical care either they or their doctors deemed necessary. However, identifying potentially modifiable barriers to receipt of necessary medical cancer care among cancer survivors age < 65 is imperative for developing interventions to ensure equitable access to care and reducing cancer disparities. PMID- 28852971 TI - Identification of Phytochemicals Targeting c-Met Kinase Domain using Consensus Docking and Molecular Dynamics Simulation Studies. AB - c-Met receptor tyrosine kinase is a proto-oncogene whose aberrant activation is attributed to a lower rate of survival in most cancers. Natural product-derived inhibitors known as "fourth generation inhibitors" constitute more than 60% of anticancer drugs. Furthermore, consensus docking approach has recently been introduced to augment docking accuracy and reduce false positives during a virtual screening. In order to obtain novel small-molecule Met inhibitors, consensus docking approach was performed using Autodock Vina and Autodock 4.2 to virtual screen Naturally Occurring Plant-based Anti-cancer Compound-Activity Target database against active and inactive conformation of c-Met kinase domain structure. Two hit molecules that were in line with drug-likeness criteria, desired docking score, and binding pose were subjected to molecular dynamics simulations to elucidate intermolecular contacts in protein-ligand complexes. Analysis of molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area studies showed that ZINC08234189 is a plausible inhibitor for the active state of c-Met, whereas ZINC03871891 may be more effective toward active c-Met kinase domain compared to the inactive form due to higher binding energy. Our analysis showed that both the hit molecules formed hydrogen bonds with key residues of the hinge region (P1158, M1160) in the active form, which is a hallmark of kinase domain inhibitors. Considering the pivotal role of HGF/c-Met signaling in carcinogenesis, our results propose ZINC08234189 and ZINC03871891 as the therapeutic options to surmount Met-dependent cancers. PMID- 28852972 TI - Double-Stranded RNA-Mediated Suppression of Trypsin-Like Serine Protease (t-SP) Triggers Over-Expression of Another t-SP Isoform in Helicoverpa armigera. AB - High diversity of digestive proteases is considered to be the key factor in the evolution of polyphagy in Helicoverpa armigera. Serine proteases (SPs) contribute ~85% of the dietary protein digestion in H. armigera. We investigated the dynamics of SP regulation in the polyphagous pest, H. armigera using RNA interference (RNAi). HaTry1, an isoform of SP, expressed irrespective of the composition of the diet, and its expression levels were directly proportional to the larval growth rate. Therefore, HaTry1 was silenced by delivering 10 and 20 MUg concentrations of double-stranded RNA through semi-synthetic diet. This led to a drastic reduction in the target gene transcript levels that manifested in a significant reduction in the larval weight initially, but the larvae recovered in later stages despite continuous dsRNA treatment. This was probably due to the compensatory effect by over-expression of HaTry13 (31-folds), another isoform of SP. Phylogenetic analysis of H. armigera SPs revealed that the over-expressed isoform was closely related to the target gene as compared to the other tested isoforms. Further, silencing of both the isoforms (HaTry1 and HaTry13) caused the highest reduction in the larval weight and there was no larval growth recovery. These findings provide a new evidence of the existence of compensatory effect to overcome the effect of silencing individual gene with RNAi. Hence, the study emphasizes the need for simultaneous silencing of multiple isoforms. PMID- 28852973 TI - Child with Headache. AB - Headache is a common complaint for which parents seek pediatrician's consult. Headaches are seen in increasing frequency from 3 y of age onwards with peaks in older children and adolescents. In children, secondary headaches due to underlying etiologies are far more common than primary headaches due to migraine. Recognition of temporal pattern of headache along with focused neurological examination will help in narrowing down the etiology. The key goal in urgent care assessment is to identify children with underlying serious illnesses that require stabilization and urgent referral. For benign causes, symptomatic treatment with analgesics like paracetamol or ibuprofen would suffice initially, while identification of the underlying condition would lead to further appropriate management, particularly in primary headaches. PMID- 28852974 TI - Low dose versus standard dose of corticosteroids in the management of adverse events of special interest from abiraterone acetate: data from a literature-based meta-analysis. AB - Abiraterone acetate is a CYP-17 inhibitor approved for the treatment of prostate cancer. Abiraterone acetate (AA) therapy is associated with toxicities, including hypokalemia, hypertension, liver function test abnormalities and cardiac events. These adverse events are traditionally managed with a standard dose of corticosteroids. However, preliminary data are available on the use of a lower dose of corticosteroids. The aim of this report is to perform a pooled analysis evaluating the risk ratio (RR) of AA-related adverse events of special interest associated with low or standard dose of corticosteroids. A total of 5374 cases from 4 randomized clinical trials were included. Subgroup analysis according to corticosteroids dosage revealed a higher RR of adverse events associated with a dose of 5 mg, compared to 10 mg. In particular, there was a statistically significant higher RR of hypokalemia and ALT/AST increase, and only a modest risk increase for cardiac disorders and hypertension. In conclusion, given the limitations of a literature-based study, in comparison with a meta-analysis based on individual patients' data, our study identified a relatively small increase in RR for hypertension and cardiac disorders and a bigger increase of RR for hypokalemia and ALT/AST toxicity when 5 mg, rather than 10 mg of corticosteroids were administered to manage adverse events of special interest from AA. Further studies with specified end-points are awaited to confirm these results. PMID- 28852975 TI - Enhanced adsorption of hexavalent chromium by a biochar derived from ramie biomass (Boehmeria nivea (L.) Gaud.) modified with beta-cyclodextrin/poly(L glutamic acid). AB - This paper explored biochar modification to enhance biochar's ability to adsorb hexavalent chromium from aqueous solution. The ramie stem biomass was pyrolyzed and then treated by beta-cyclodextrin/poly(L-glutamic acid) which contained plentiful functional groups. The pristine and modified biochar were characterized by FTIR, X-ray photoelectron spectroscopy, specific surface area, and zeta potential measurement. Results indicated that the beta-cyclodextrin/poly(L glutamic acid) was successfully bound to the biochar surface. Batch experiments were conducted to investigate the kinetics, isotherm, thermodynamics, and adsorption/desorption of Cr(VI). Adsorption capacities of CGA-biochar were significantly higher than that of the untreated biochar, and its maximum adsorption capacity could reach up to 197.21 mg/g at pH 2.0. Results also illustrated that sorption performance depended on initial solution pH; in addition, acidic condition was beneficial to the Cr(VI) uptake. Furthermore, the Cr(VI) uptake was significantly affected by the ion strength and cation species. This study demonstrated that CGA-biochar could be a potential adsorbent for Cr(VI) pollution control. PMID- 28852976 TI - Experimental Study of Right Ventricular Hemodynamics After Tricuspid Valve Replacement Therapies to Treat Tricuspid Regurgitation. AB - The increased understanding of right heart diseases has led to more aggressive interventions to manage functional tricuspid regurgitation (FTR). In some cases of FTR, prosthetic valve replacement is typically considered when concomitant organic components or significant geometrical distortions are involved in the pathology of the tricuspid valve. However, little is known of the performance of current devices in the right heart circulation. In this study, a novel in vitro mock circulatory system that incorporated a realistic tricuspid valve apparatus in a patient-specific silicon right ventricle (RV) was designed and fabricated. The system was calibrated to emulate severe FTR, enabling the investigation of RV hemodynamics in pre- and post-implantation of tri-leaflet tissue implant and bi leaflet mechanical implant. 2D particle imaging velocimetry was performed to visualize flow and quantify relevant hemodynamic parameters. While our results showed all prosthetic implants improved cardiac output, these implants also subjected the RV to increased turbulence level. Our study also revealed that the implants did not create the optimal behavior of fluid transfer in the RV as we expected. Among the implants tested, tissue implant created the most dominant vortices, which persisted throughout diastole; its observed strong negative vortex could lead to increase energy expenditure due to undesired fluid direction. In contrast, both native valve and mechanical implant had both weaker vortex formation as well as more significant vortex dissipation. Interestingly, the vortex dissipation of native valve was associated with streamlined flow pattern that tended towards the pulmonary outlet, while the mechanical implant generated more regions of flow stagnation within the RV. These findings heighten the imperative to improve designs of current heart valves to be used in the right circulation. PMID- 28852977 TI - Histologic Review of Sarcoidosis in a Neck Lymph Node. AB - Sarcoidosis is a multisystem granulomatous disease of unknown etiology. It may occur at any age, but is most commonly seen in young to middle age adults. Sarcoidosis remains more common in women regardless of geographic or racial boundaries. Although the etiology remains unclear, the most common explanation is that sarcoidosis is a disease of immunologic dysregulation triggered by an as yet unidentified environmental or microbial antigen in genetically susceptible persons. We review a case of sarcoidosis with was initially diagnosed in a neck lymph node that was removed for evaluation of metastatic squamous cell carcinoma with a discussion on the clinical and histologic characteristic of the disease. PMID- 28852979 TI - Estimation of effective brain connectivity with dual Kalman filter and EEG source localization methods. AB - Effective connectivity is one of the most important considerations in brain functional mapping via EEG. It demonstrates the effects of a particular active brain region on others. In this paper, a new method is proposed which is based on dual Kalman filter. In this method, firstly by using a brain active localization method (standardized low resolution brain electromagnetic tomography) and applying it to EEG signal, active regions are extracted, and appropriate time model (multivariate autoregressive model) is fitted to extracted brain active sources for evaluating the activity and time dependence between sources. Then, dual Kalman filter is used to estimate model parameters or effective connectivity between active regions. The advantage of this method is the estimation of different brain parts activity simultaneously with the calculation of effective connectivity between active regions. By combining dual Kalman filter with brain source localization methods, in addition to the connectivity estimation between parts, source activity is updated during the time. The proposed method performance has been evaluated firstly by applying it to simulated EEG signals with interacting connectivity simulation between active parts. Noisy simulated signals with different signal to noise ratios are used for evaluating method sensitivity to noise and comparing proposed method performance with other methods. Then the method is applied to real signals and the estimation error during a sweeping window is calculated. By comparing proposed method results in different simulation (simulated and real signals), proposed method gives acceptable results with least mean square error in noisy or real conditions. PMID- 28852978 TI - Unmet Needs in IBD: the Case of Fatigue. AB - Fatigue is a highly prevalent but relatively ignored problem in IBD patients. It is one of the most burdensome symptoms to the patient with an important impact on the quality of life. Therefore, fatigue is a highly relevant patient-reported outcome that should be included not only in disease activity measurement but also in the endpoints of clinical trials in IBD. However, most of the currently available scoring systems to quantify fatigue are not specifically designed for patients with IBD and none of them has undergone a complete validation process for IBD-related fatigue. Fatigue is more prevalent in patients with active disease and may improve or disappear when remission is reached. Far more complex is the persistence or onset of fatigue in quiescent IBD which presents in up to 40% of the patients. In this subgroup of patients, fatigue can be related to smoldering systemic inflammation, a poor sleep quality, anemia, nutritional deficiencies, or comorbidities. In most cases, however, no direct cause can be identified. The lack of knowledge on the mechanisms that drive fatigue in IBD hamper the development of specific drugs to treat the condition and only psychological support can be offered to the patient. Rodent models are indispensable to increase our understanding of the molecular pathways that lead to fatigue in chronic intestinal inflammation, and to develop novel therapies. PMID- 28852980 TI - Effect of processing method on platycodin D content in Platycodon grandiflorum roots. AB - Platycodon grandiflorum root is a traditional medicine and food material rich in triterpenoid saponins. Its major constituent, platycodin D (PD), is known to have various pharmacological properties, but processing methods may influence the PD content. In this study, a fully validated HPLC-ELSD method was developed for the quantification of PD in various states of 73 P. grandiflorum root samples from East Asia, and it exhibited a marked variation of the content. Furthermore, the effects of processing procedures such as peeling and drying temperature on the PD content were investigated using UPLC-ELSD analysis, and as a result, a significant influence of processing methods such as peeling and heating of samples on the content was confirmed. Specifically, unpeeled samples that were dried at 40 degrees C showed the greatest PD content. The obtained results could facilitate the reliable standardization of P. grandiflorum for precise authentication and efficacious applications. PMID- 28852981 TI - 1916-2016: a centenary of publications. AB - Last year, the centenary of the 1916 Easter rising in Ireland was marked by a commemorative programme organised by the Irish government including both historical and cultural events. The main themes of these events were remembering the past, celebrating Irish achievements and imagining our future. Reviewing the medical literature offers an insight into a century of achievement and change in Irish medicine, captured from the unique perspective of Ireland's oldest medical journal. This manuscript examines papers published during the last 100 years of the Irish Journal of Medical Science, specifically examining the most cited paper from each year. The majority of top cited papers originate in Ireland (77%) with Trinity College Dublin the commonest institution (n = 12) and obstetrics the most common specialty (n = 9). The average number of citations per article was 20.56 (SD +/- 22.36; range 1-118) and the article with most citations was 'Coagulative properties of cancers' published in 1958 by O'Meara et al. The mean number of citations for the top cited publication each year has increased over time. The journal continued to publish even amidst backgrounds of war and civil unrest and represents an important cultural artefact that deserves our ongoing support. PMID- 28852982 TI - Toxicological effects of chemical constituents from Piper against the environmental burden Aedes aegypti Liston and their impact on non-target toxicity evaluation against biomonitoring aquatic insects. AB - Dengue is the most rapidly spreading mosquito-borne viral disease in the world. The mosquito, Aedes aegypti, also spreads Yellow fever, Chikungunya, and Zika virus. As the primary vector for dengue, Ae. aegypti now occurs in over 20 countries and is a serious concern with reports of increasing insecticide resistance. Developing new treatments to manage mosquitoes are needed. Formulation of crude volatile oil from Piper betle leaves (Pb-CVO) was evaluated as a potential treatment which showed larvicidal, ovipositional, and repellency effects. Gut-histology and enzyme profiles were analyzed post treatment under in vitro conditions. The Pb-CVO from leaves of field collected plants was obtained by steam distillation and separated through rotary evaporation. The Pb-CVO were evaluated for chemical constituents through GC-MS analyses revealed 20 vital compounds. The peak area was establish to be superior in Eudesm-7(11)-en-4-ol (14.95%). Pb-CVO were determined and tested as four different concentrations (0.25, 0.5, 1.0, and 1.5 mg/L) of Pb-CVO towards Ae. aegypti. The larvicidal effects exhibited dose dependent mortality being greatest at 1.5 mg Pb-CVO/10 g leaves. The LC50 occurred at 0.63 mg Pb-CVO/L. Larva of Ae. aegypti exposed to Pb CVO showed significantly reduced digestive enzyme actions of alpha- and beta carboxylesterases. In contrast, GST and CYP450 enzyme levels increased significantly as concentration increased. Correspondingly, oviposition deterrence index and egg hatch of Ae. aegypti exposed to sub-lethal doses of Pb-CVO demonstrated a strong effect suitable for population suppression. Repellency at 0.6 mg Pb-CVO applied as oil had a protection time of 15-210 min. Mid-gut histological of Ae. aegypti larvae showed severe damage when treated with 0.6 mg of Pb-CVO treatment compared to the control. Non-toxic effects against aquatic beneficial insects, such as Anisops bouvieri and Toxorhynchites splendens, were observed at the highest concentrations, exposed for 3 h. These results suggest that the Pb-CVO may contain effective constituents suitable for development of new vector control agents against Ae. aegypti. PMID- 28852983 TI - Myocarditis with high 18F-FDG uptake and no 18F-FLT uptake. AB - We present a case of myocarditis with increased 18F-FDG uptake and no 18F fluorothymidine (FLT) uptake. PMID- 28852984 TI - Counting ions and other nucleophiles at surfaces by chemical trapping. AB - The interfaces of membranes and other aggregates are determined by the polarity, electrical charge, molecular volume, degrees of motional freedom and packing density of the head groups of the amphiphiles. These properties also determine the type of bound ion (ion selectivity) and its local density, i.e. concentration defined by choosing an appropriate volume element at the aggregate interface. Bulk and local ion concentrations can differ by orders of magnitude. The relationships between ion (or other compound) concentrations in the bulk solvent and in the interface are complex but, in some cases, well established. As the local ion concentration, rather than that in the bulk, controls a variety of properties of membranes, micelles, vesicles and other objects of theoretical and applied interests, measurement of local (interfacial, bound) ion concentrations is of relevance for understanding and characterizing such aggregates. Many experimental methods for estimating ion distributions between the bulk solution and the interface provide indirect estimates because they are based on concentration-dependent properties, rather than concentration measurements. Dediazoniation, i.e. the loss of N2, of a substituted diazophenyl derivative provides a tool for determining the number of nucleophiles (including neutral or negatively charged ions) surrounding the diazophenyl derivative prior to the dediazoniation event. This reaction, defined as chemical trapping, and the appropriate reference points obtained in bulk solution allow direct measurements of local concentrations of a variety of nucleophiles at the surface of membranes and other aggregates. Here we review our contributions of our research group to the use, and understanding, of this method and applications of chemical trapping to the description of local concentrations of ions and other nucleophiles in micelles, reverse micelles, vesicles and solvent mixtures. Among other results, we have shown that interfacial water determines micellar shape, zwitterionic vesicle-forming amphiphiles display ion selectivity and urea does not accumulate at micellar interfaces. We have also shown that reaction products can be predicted from the composition of the initial state, even in non-ideal solvent mixtures, supporting the usefulness of chemical trapping as a method to determine local concentrations. In addition, we have analysed the mechanism of dediazoniation, both on theoretical and experimental basis, and concluded that the formation of a free phenyl cation is not a necessary part of the reaction pathway. PMID- 28852985 TI - Comparison of Acyclovir and Multistrain Lactobacillus brevis in Women with Recurrent Genital Herpes Infections: a Double-Blind, Randomized, Controlled Study. AB - We performed a randomized double-blind controlled trial to compare the efficacy and safety of multistrain probiotic and acyclovir in women patients with recurrent genital herpes simplex virus type 2 (HSV-2) infections. Eighty-one patients enrolled in the study were being treated with multistrain Lactobacillus brevis one vaginal capsule every 12 h and oral acyclovir 400 mg twice daily for 6 months. Of 53 patients who completed both treatment courses, no important differences were identified between acyclovir and probiotic for the primary and secondary efficacy endpoint, resolution of episode (hazard ratio, 0.60; 95% CI, 0.3429 to 1.0663; P = 0.08), lesion healing time (hazard ratio, 0.57; 95% CI, 0.3034 to 1.0717, P = 0.08), viral shedding (hazard ratio, 0.54; 95% CI, 0.3027 to 0.9750, P = 0.04), and percentage of pain (hazard ratio, 0.48; 95% CI, 0.2708 to 0.8545, P = 0.01). The median time to first and second recurrence after treatment were 43 and 121 days in patients receiving acyclovir and 33 and 118 days in patients receiving probiotic (HR 2.61; 95% CI, 1.4427 to 4.7546, P = 0.001, and HR 0.62; 95% CI, 0.3500 to 1.1133, P = 0.1, respectively). No clinically important effects happened during the probiotic treatment but some of adverse events reported in patients taking acyclovir. Easy availability, low cost, and no side effect of L. brevis are valuable properties of probiotic therapy compared with acyclovir. Therefore, we concluded that multistrain L. brevis could play an important role in suppression of recurrent genital herpes simplex virus infection. PMID- 28852986 TI - A simulator for advanced analysis of a 5-DOF EM tracking systems in use for image guided surgery. AB - PURPOSE: To assess the accuracy of medical electromagnetic tracking systems, reference positioning systems are generally required. Errors are unavoidable in such systems, and despite how tiny they may be, prevent the ground truth from being known. In this work, a simulator was developed and used to analyze the theoretical system performances in electromagnetic tracking. METHODS: To simulate the entire tracking process, the magnetic dipole model, Faraday's law, and a mathematical optimization algorithm are applied. With the simulator, we optimized the spatial placement of the transmitter coils, analyzed the tracking accuracy by applying stochastic and optimized coil placement. Additionally, the performance of the calibration of transmitter coils' measurement error and Kalman filtering was tested. RESULTS: The results show that, after optimizing the spatial arrangement of the transmitter coils, the tracking accuracy is significantly improved to a much higher level compared with applying statistical arrangement. The measurement errors of the transmitter coils' positions and orientations can be totally rectified by the developed calibration algorithm when no noises are introduced. The Kalman filter reduces the sensor jitter errors caused by noise, which potentially allows the EM tracking system to reach a larger volume of interest. CONCLUSIONS: We proposed a simulator for advanced analysis in electromagnetic tracking without hardware requirements. Grounded on this, we performed an optimization of the spatial arrangement of the transmitter coils to improve the tracking accuracy further. The performances of the calibration algorithm and Kalman filtering were also evaluated. The developed simulator can also be applied for other analysis in electromagnetic tracking. PMID- 28852987 TI - Drosophila suzukii in Southern Neotropical Region: Current Status and Future Perspectives. AB - Non-native insect pests are often responsible for important damage to native and agricultural plant hosts. Since Drosophila suzukii Matsumura (Diptera: Drosophilidae) has become an important pest in North America and Europe (i.e., in 2008), the global production of soft thin-skinned fruits has faced severe production losses. In the southern Neotropical region, however, the first record of D. suzukii occurred in 2013 in the south of Brazil. It has also been recorded in Uruguay, Argentina, and Chile. Despite its recent occurrence in the southern Neotropical region, the fast dispersion of D. suzukii has inspired local research efforts in an attempt to mitigate the consequences of this insect pest invasion. In this forum, we explore the current status of D. suzukii in southern Neotropical regions, discussing its future perspectives. Additionally, we attempt to draft activities and a research agenda that may help to mitigate the losses caused by D. suzukii in native and commercial soft-skinned fruits produced in this region. Currently, D. suzukii appears to be well established in the south of Brazil, but considering the entire southern Neotropical region, the invasion panorama is still underinvestigated. The lack of studies and regulatory actions against D. suzukii has contributed to the invasion success of this species in this region. Considering several peculiarities of both the pest biology and the environmental of this region, the authors advocate for the need of intensive and integrative studies toward the development and implementation of area-wide integrated pest management programs against D. suzukii in the southern Neotropical region. PMID- 28852988 TI - Best of both worlds. PMID- 28852990 TI - Detection of the Cyanotoxins L-BMAA Uptake and Accumulation in Primary Neurons and Astrocytes. AB - We show for the first time that a newly developed polyclonal antibody (pAb) can specifically target the cyanotoxin beta-methylamino-L-alanine (BMAA) and can be used to enable direct visualization of BMAA entry and accumulation in primary brain cells. We used this pAb to investigate the effect of acute and chronic accumulation, and toxicity of both BMAA and its natural isomer 2,4-diaminobutyric acid (DAB), separately or in combination, on primary cultures of rat neurons. We further present evidence that co-treatment with BMAA and DAB increased neuronal death, as measured by MAP2 fluorescence level, and appeared to reduce BMAA accumulation. DAB is likely to be acting synergistically with BMAA resulting in higher level of cellular toxicity. We also found that glial cells such as microglia and astrocytes are also able to directly uptake BMAA indicating that additional brain cell types are affected by BMAA-induced toxicity. Therefore, BMAA clearly acts at multiple cellular levels to possibly increase the risk of developing neurodegenerative diseases, including neuro- and gliotoxicity and synergetic exacerbation with other cyanotoxins. PMID- 28852989 TI - Biophysical aspects of biomineralization. AB - During the process of endochondral bone formation, chondrocytes and osteoblasts mineralize their extracellular matrix (ECM) by promoting the synthesis of hydroxyapatite (HA) seed crystals in the sheltered interior of membrane-limited matrix vesicles (MVs). Several lipid and proteins present in the membrane of the MVs mediate the interactions of MVs with the ECM and regulate the initial mineral deposition and posterior propagation. Among the proteins of MV membranes, ion transporters control the availability of phosphate and calcium needed for initial HA deposition. Phosphatases (orphan phosphatase 1, ectonucleotide pyrophosphatase/phosphodiesterase 1 and tissue-nonspecific alkaline phosphatase) play a crucial role in controlling the inorganic pyrophosphate/inorganic phosphate ratio that allows MV-mediated initiation of mineralization. The lipidic microenvironment can help in the nucleation process of first crystals and also plays a crucial physiological role in the function of MV-associated enzymes and transporters (type III sodium-dependent phosphate transporters, annexins and Na+/K+ ATPase). The whole process is mediated and regulated by the action of several molecules and steps, which make the process complex and highly regulated. Liposomes and proteoliposomes, as models of biological membranes, facilitate the understanding of lipid-protein interactions with emphasis on the properties of physicochemical and biochemical processes. In this review, we discuss the use of proteoliposomes as multiple protein carrier systems intended to mimic the various functions of MVs during the initiation and propagation of mineral growth in the course of biomineralization. We focus on studies applying biophysical tools to characterize the biomimetic models in order to gain an understanding of the importance of lipid-protein and lipid-lipid interfaces throughout the process. PMID- 28852991 TI - Is feedback to medical learners associated with characteristics of improved patient care? AB - PURPOSE: To investigate the association of medical learner feedback with patient management and outcomes. METHODS: The authors investigated 27 articles that utilized patient data or chart reviews as a subset of a prior feedback scoping review. Data extraction was completed by two authors and all authors reviewed the descriptive data analysis. RESULTS: The studies were predominantly short-term investigations conducted in the US at academic teaching hospitals (89%) with one medical discipline (78%), most commonly internal medicine (56%). Patient-related outcomes primarily involved improved documentation (26%) and adherence to practice guidelines (19%) and were mostly measured through chart reviews (56%) or direct observation (15%). The primary method of feedback delivery involved a written format (30%). The majority of the studies showed a positive effect of feedback on the patient-oriented study outcomes (82%), although most involved a non-rigorous study design. CONCLUSIONS: Published studies focusing on the relationship between medical learner feedback and patient care are sparse. Most involve a single discipline at a single institution and are of a non-rigorous design. Measurements of improved patient outcomes are restricted to changes in management, procedures and documentation. Well-designed studies that directly link learner feedback to patient outcomes may help to support the use of feedback in teaching clinical outcomes improvement in alignment with competency-based milestones. PMID- 28852992 TI - Foster and Adoptive Parent Perspectives on Needs and Services: a Mixed Methods Study. AB - Caring for children with complex needs severely stresses foster and adoptive parents, but few studies have examined their perspectives on needs and services. To examine parental views, the authors analyzed four focus groups (n = 27 participants) and one state-wide survey (n = 512 respondents, 42% of 1206 contacted) of foster and adoptive parents in one state. Results highlighted inadequate communication between providers and families, cultural and legal barriers, needs for parent training and preparation, the importance of several types of parent supports, and needs for specialized mental health treatment for the children. Surveyed parents identified children's behavior problems as their top challenge, and over half rated the availability of mental health providers who treat attachment and family as insufficient. The findings suggest specific areas in which state leaders could enhance training and supports for child welfare staff and foster and adoptive parents and improve mental health services for children in foster and adoptive care. PMID- 28852993 TI - STAT4 Polymorphisms are Associated with Neuromyelitis Optica Spectrum Disorders. AB - STAT4 plays a crucial role in the functioning of the innate and adaptive immune cells and has been identified as a susceptibility gene in numerous autoimmune disorders. However, its association with neuromyelitis optica spectrum disorders (NMOSD) remains uncertain. Here, we performed a case-control study to determine whether STAT4 contributed to the risk of NMOSD. We tested five STAT4 SNPs in 233 patients with established NMOSD and 492 healthy controls. Chi-square tests and logistic regression analyses were performed with four genetic models, including allelic, additive, dominant, and recessive models, to identify associations with NMOSD. The results of multiple test comparisons were corrected using the Benjamini and Hochberg false discovery rate (FDR-BH). After correcting for multiple test comparisons, the minor alleles of four STAT4 SNPs exhibited significant association with increased risk of NMOSD (rs7574865 T, odds ratio [OR] = 1.66, 95% confidence interval [CI] 1.32-2.08, P corr = 0.000; rs10181656 G, OR = 1.62, 95% CI 1.29-2.03, P corr = 0.000; rs10168266 T, OR = 1.59, 95% CI 1.27-2.00, P corr = 0.001; and rs13426947 A, OR = 1.51, 95% CI 1.21-1.90, P corr = 0.004). Identical results were observed in the dominant, recessive, and additive models. In contrast, the G allele of rs7601754 displayed a protective effect against NMOSD (OR = 0.53, 95% CI 0.36-0.76, P corr = 0.006). Our study indicates that STAT4 polymorphisms are associated with the risk of NMOSD, which provides novel insights into the underlying mechanisms of this disease. PMID- 28852994 TI - Laser Desorption Ionization of As2Ch3 (Ch = S, Se, and Te) Chalcogenides Using Quadrupole Ion Trap Time-of-Flight Mass Spectrometry: A Comparative Study. AB - Laser desorption ionization using time-of-flight mass spectrometer afforded with quadrupole ion trap was used to study As2Ch3 (Ch = S, Se, and Te) bulk chalcogenide materials. The main goal of the study is the identification of species present in the plasma originating from the interaction of laser pulses with solid state material. The generated clusters in both positive and negative ion mode are identified as 10 unary (S p+/- and As m+/- ) and 34 binary (As m S p+/- ) species for As2S3 glass, 2 unary (Se q+/- ) and 26 binary (As m Se q+/- ) species for As2Se3 glass, 7 unary (Te r+/- ) and 23 binary (As m Te r+/- ) species for As2Te3 material. The fragmentation of chalcogenide materials was diminished using some polymers and in this way 45 new, higher mass clusters have been detected. This novel approach opens a new possibility for laser desorption ionization mass spectrometry analysis of chalcogenides as well as other materials. Graphical abstract ?. PMID- 28852995 TI - [Key-topics in Austrian Child and Adolescent Psychiatry 2007-2017]. AB - The medical speciality "Child and Adolescent Psychiatry" exists since 2007. 2015 a new training regulation defined an increment to "Child and Adolescent Psychiatry and Psychotherapeutic Medicine". To document the achievements in research within the last 10 years for the first time, all papers listed in Pubmed and all books published by the member of the OGKJP were summarized. Additionally, the clinical/scientific key aspects of all large teaching centres were documented.All members of the OGKJP are scientifically active in various areas of child psychiatry. Most of the 284 publications (n = 115; 41%) were published on 5 topics: eating disorders, forensic psychiatry, neuropediatrics, psychoses and prodromal states, suicidality. Thirteen of the papers have already been awared prices because of their high quality. All departments define clinical/scientific key areas - beside a time-consuming clinical work load - and offer specialized care. Further development of research competence should take place and should also have high priority in health politics. PMID- 28852996 TI - Prostatic Urethral Lift Versus Transurethral Resection of the Prostate (TURP). AB - Lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE) represent one of the most common bothersome conditions impairing quality of life in men. Its management comprises conservative treatment, pharmacotherapy, and various surgical techniques. Medication and surgical procedures provide meaningful relief of LUTS, but their therapeutic efficacy has to be counterbalanced against the associated adverse events and morbidity. With the advent of novel minimally invasive treatment options, the surgical standards are challenged for at least equally effective approaches with a much more favorable safety profile. Clinical randomized controlled trials confirmed that PUL is able to provide rapid and durable relief of LUTS without compromising sexual function. However, in order to define the value and true benefit of a novel technique among established surgical procedures, the direct comparison with the reference method TURP is necessary. This was the main objective of the BPH6 study, which evaluated symptom relief, recovery experience, sexual function, urinary continence, and safety of PUL compared to TURP. Over a 2-year follow-up, no relevant negative impact on erectile function, urinary continence, and treatment-related safety was observed for both procedures. Improvement of LUTS was better after TURP, whereas PUL turned out to be superior in terms of quality of recovery, ejaculatory function, and quality of sleep. PUL can be considered in selected patients with bothersome LUTS, with special interest in the complete preservation of sexual function and a rapid and smooth return to daily activity. PMID- 28852998 TI - ? PMID- 28852997 TI - The Regulatory Role of IFN-gamma on the Proliferation and Differentiation of Hematopoietic Stem and Progenitor Cells. AB - The replenishment of all blood cell lineages is hierarchically organized by the process of hematopoiesis, which is based on the differentiation pathways of hematopoietic stem and progenitor cells (HSPCs). Due to the ability to balance between self-renewal and differentiation, hematopoietic stem cells (HSCs) can generate the appropriate cell type that is required by the immune system and peripheral blood in response to physiological or pathological conditions. Numerous studies have shown that some proinflammatory cytokines contribute to the regulation of the various hematopoietic compartments. Of these, IFN-gamma is a type II interferon primarily produced by T cells and natural killer cells, and plays a major role in the defense against invading pathogens and transformed cancer cells; moreover, a growing amount of research indicates that it exerts negative or positive regulatory effect on hematopoiesis. Although IFN-gamma is a widely regarded negative regulator of HSC proliferation, it also participates in some chronic infections or hematological malignancies that induce bone marrow failure. Recent studies have demonstrated unexpected effects of IFN-gamma, including the promotion of HSC formation and the stimulation of myelopoiesis. Here, we review the direct and indirect effects of IFN-gamma on hematopoiesis, as well as the underlying signaling mechanisms of how IFN-gamma modulates the self renewal, cell cycle entry, and proliferation of HSCs. Next, we describe how IFN gamma affects different stages of the lineage differentiation from HSCs. Finally, we discuss the relationship between IFN-gamma and compensatory extramedullary hematopoiesis, as well as some related clinical diseases. PMID- 28852999 TI - Sex and Cardiovascular Involvement in Inflammatory Joint Diseases. AB - The term inflammatory joint disease (IJD) encompasses a group of chronic conditions with predominant joint involvement. They share an increased risk of cardiovascular (CV) complications. However, the implication of the sex in the risk of CV disease in IJD has not been specifically addressed. The aim of this work is to assess the influence of sex on the clinical expression of CV manifestations associated to IJD. With this objective, an update of the current knowledge of the sex influence on CV disease in patients with IJD was conducted. A PubMed database search of the most relevant literature on this topic was performed mainly based on studies published in English over the last 10 years. Although most studies on IJD were not specifically designed to address sex differences regarding CV complications, it seems that men with rheumatoid arthritis (RA) are at higher risk of pericarditis, ischemic heart disease, heart failure (HF) with reduced ejection fraction (EF), and CV mortality than women with RA. In contrast, HF with preserved EF and diastolic dysfunction is more frequent in women with RA. Men with ankylosing spondylitis present more frequently disorders of the conduction system and aortic valvulopathy than women. A limited number of studies addressed CV differences according to sex in psoriatic arthritis. Although there are some differences according to sex in the clinical expression of CV complications in patients with IJD, much research is still needed to better identify the implication of sex in the risk of CV disease in these patients. PMID- 28853000 TI - Discontinuation of Preventive Medicines in Older People with Limited Life Expectancy: A Systematic Review. AB - BACKGROUND: In the presence of multimorbidity and limited life expectancy (LLE), the need for continued use of preventive medicines becomes uncertain as they may neither improve health nor confer continued health benefits. OBJECTIVE: Our objective was to systematically review the literature to examine the discontinuation of preventive medicines in older people with LLE. METHODS: A systematic literature search was conducted using the Ovid MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Central Register databases. Studies investigating discontinuation of preventive medicines in older individuals (mean age >=65 years) with LLE (<=12 months) published between 1 January 1997 and 28 February 2017 were included. The Cochrane risk-of-bias assessment criteria and the Newcastle-Ottawa Scale were used to assess the quality of the studies. RESULTS: Ten studies-a randomized controlled trial (RCT), two case-control studies, and seven cohort studies-involving 26,854 participants with a mean age ranging from 66.0 to 85.0 years were included in this review. The studies were primarily conducted in palliative care (n = 3), residential facility (n = 2), and community (n = 1) settings, and the remainder were pharmacoepidemiological studies (n = 4). The most common life-limiting illnesses were cancer (n = 5), followed by other unspecified illnesses (n = 4) and advanced dementia (n = 1). The most common preventive medicine discontinued was statins, followed by warfarin and aspirin. LLE potentially prompted discontinuation; however, some individuals continued to receive preventive medicines until they died. CONCLUSIONS: The review found that withdrawal of preventive medicines at the end of life is challenging. Decisions about the discontinuation of preventive medicines for individuals approaching the end of life are increasingly complicated by the lack of clear deprescribing guidelines for these medicines. PMID- 28853001 TI - Sphenoid sinus microbiota in pituitary apoplexy: a preliminary study. AB - PURPOSE: There is a high incidence of abnormal sphenoid sinus changes in patients with pituitary apoplexy (PA). Their pathophysiology is currently unexplored and may reflect an inflammatory or infective process. In this preliminary study, we characterised the microbiota of sphenoid sinus mucosa in patients with PA and compared findings to a control group of surgically treated non-functioning pituitary adenomas (NFPAs). METHODS: In this prospective observational study of patients undergoing trans-sphenoidal surgery for PA or NFPA, sphenoid sinus mucosal specimens were microbiologically profiled through PCR-cloning of the 16S rRNA gene. RESULTS: Ten patients (five with PA and five with NFPAs) with a mean age of 51 years (range 23-71) were included. Differences in the sphenoid sinus microbiota of the PA and NFPA groups were observed. Four PA patients harboured Enterobacteriaceae (Enterobacter spp., N = 3; Escherichia coli, N = 1). In contrast, patients with NFPAs had a sinus microbiota more representative of health, including Staphylococcus epidermidis (N = 2) or Corynebacterium spp. (N = 2). CONCLUSIONS: PA may be associated with an abnormal sphenoid sinus microbiota that is similar to that seen in patients with sphenoid sinusitis. PMID- 28853003 TI - [Preventive human rights monitoring in child and adolescent psychiatry and welfare institutions]. AB - Since 1 July 2012 the Austrian Ombudsman Board (AOB) together with its six regional expert commissions form the so called "National Prevention Mechanism" implementing the UN Optional Protocol to the Convention against Torture and other Cruel, Inhuman or Degrading Treatment or Punishment (OPCAT). The commissions are mandated to conduct regular, unrestricted and unannounced visits to all types of places in which there is or can be a deprivation or restriction of personal liberty, such as prisons, police stations, but also psychiatric hospitals or residential homes/groups for children and juveniles supervised by youth welfare services. 20 monitoring visits have been held in departments for Child- and Adolescent Psychiatry between 2012 and 2016. In the field of residential groups for young people 40 visiting protocols (out of a total of 176 between 2015 and 2016) have been chosen for this analysis. The following article overviews the legal sources and key issues of the monitoring process in this field as well as the commissions' findings and recommendations. PMID- 28853002 TI - The Serrated Polyp Pathway: Is It Time to Alter Surveillance Guidelines? AB - PURPOSE OF REVIEW: In this manuscript, we review current surveillance guidelines for serrated polyps (SPs) and discuss how recent studies inform the selection of appropriate surveillance intervals for patients with SPs. RECENT FINDINGS: Large and/or proximal SPs, particularly sessile serrated polyps (SSPs), are associated with increased risk of both synchronous and metachronous neoplasia, including advanced adenomas and colorectal cancer (CRC). Persons harboring multiple SSPs or dysplastic SSPs are at the highest risk. Moreover, a high percentage of large and/or proximal SPs are reclassified as SSPs when read by trained gastrointestinal pathologists, even if they were originally reported as hyperplastic polyps. These findings support the adoption of surveillance guidelines that prescribe closer surveillance of large and/or proximal SPs, regardless of subtype. SSPs remain a challenge to reliably identify, resect, and diagnose via histology. The increased risk of future neoplasia in patients with SSPs is likely driven by a combination of underdetection, inadequate removal, misclassification, and biology. Until further evidence emerges, we support guidelines that recommend close surveillance of patients with a history of large and/or proximal SPs and SSPs specifically in order to mitigate the threat of interval CRC. PMID- 28853004 TI - Sex-specific issues in eating disorders: a clinical and psychopathological investigation. AB - OBJECTIVE: To highlight the characteristics of eating disorders (ED) in males, with particular attention to sex-related clinical features and psychiatric co morbidities. METHOD: Out of 280 persons, referred to our outpatients ED clinic between January 2011 and June 2014, 267 with complete information were included in this retrospective observational study. RESULTS: The men/women ratio was one to five (male 16.5% vs female 83.5%) with an increasing proportion of male patients over the years. The most frequent ED in males was binge eating disorder, whereas in females anorexia nervosa and bulimia nervosa prevailed. Excessive exercising and fasting were the most common compensation behaviours in males; while self-induced vomiting and laxative-diuretic abuse were more typical in females. Among women, the most represented psychiatric co-morbidities were mood and somatoform disorders, whereas among men, anxiety and psychosis spectrum disorders were the most frequent ones. Borderline and histrionic personality disorders were prevalent in female ED, while narcissistic and antisocial personality disorders prevailed in males. DISCUSSION: ED in men is a growing phenomenon. Male ED, compared to female ED, show differences in clinical presentation, symptoms and co-morbidities. Despite the use of clinical and psychometric evaluating tools targeting female patients, sex differences do exist and additional studies are required to investigate male specific issues in ED. Level of Evidence Level V, cross-sectional descriptive study. PMID- 28853005 TI - Unmet Needs in the Pathogenesis and Treatment of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease with a prevalence of approximately 1 in 1000. Over the last 30 years, advances in treatment such as use of corticosteroids and immunosuppressants have improved life expectancy and quality of life for patients with lupus and the key unmet needs have therefore changed. With the reduced mortality from disease activity, development of cardiovascular disease (CVD) has become an increasingly important cause of death in patients with SLE. The increased CVD risk in these patients is partly, but not fully explained by standard risk factors, and abnormalities in the immune response to lipids may play a role. Invariant natural killer T cells, which are triggered specifically by lipid antigens, may protect against progression of subclinical atherosclerosis. However, currently our recommendation is that clinicians should focus on optimal management of standard CVD risk factors such as smoking, blood pressure and lipid levels. Fatigue is one of the most common and most limiting symptoms suffered by patients with SLE. The cause of fatigue is multifactorial and disease activity does not explain this symptom. Consequently, therapies directed towards reducing inflammation and disease activity do not reliably reduce fatigue and new approaches are needed. Currently, we recommend asking about sleep pattern, optimising pain relief and excluding other causes of fatigue such as anaemia and metabolic disturbances. For the subgroup of patients whose disease activity is not fully controlled by standard treatment regimes, a range of different biologic agents have been proposed and subjected to clinical trials. Many of these trials have given disappointing results, though belimumab, which targets B lymphocytes, did meet its primary endpoint. New biologics targeting B cells, T cells or cytokines (especially interferon) are still going through trials raising the hope that novel therapies for patients with refractory SLE may be available soon. PMID- 28853006 TI - Are the Current Guidelines on Caffeine Use in Sport Optimal for Everyone? Inter individual Variation in Caffeine Ergogenicity, and a Move Towards Personalised Sports Nutrition. AB - Caffeine use is widespread in sport, with a strong evidence base demonstrating its ergogenic effect. Based on existing research, current guidelines recommend ingestion of 3-9 mg/kg approximately 60 min prior to exercise. However, the magnitude of performance enhancement following caffeine ingestion differs substantially between individuals, with the spectrum of responses ranging between highly ergogenic to ergolytic. These extensive inter-individual response distinctions are mediated by variation in individual genotype, environmental factors, and the legacy of prior experiences partially mediated via epigenetic mechanisms. Here, we briefly review the drivers of this inter-individual variation in caffeine response, focusing on the impact of common polymorphisms within two genes, CYP1A2 and ADORA2A. Contemporary evidence suggests current standardised guidelines are optimal for only a sub-set of the athlete population. Clearer understanding of the factors underpinning inter-individual variation potentially facilitates a more nuanced, and individually and context-specific customisation of caffeine ingestion guidelines, specific to an individual's biology, history, and competitive situation. Finally, we identify current knowledge deficits in this area, along with future associated research questions. PMID- 28853008 TI - Monoclonal Antibodies for Atopic Dermatitis: Progress and Potential. AB - Atopic dermatitis (AD) is a complex and heterogeneous inflammatory skin disorder with a profound symptom and lesional burden. Moderate-to-severe AD is particularly challenging to manage, as topical treatments are often inadequate and the systemic immunosuppressants are limited by concerns of toxicity and tolerability. Recent AD research has elucidated the mechanisms and immunologic factors involved in AD pathogenesis. These breakthroughs have led to the development of multiple therapeutic monoclonal antibodies that are directed against specific immunologic targets. This review provides an overview on the pathogenesis of AD as well as the rationale for the targets of various monoclonal antibodies. Additionally, this review explores the efficacy and safety of use for various monoclonal antibodies in the management of AD, as well as the potential role of these agents in the treatment of AD. PMID- 28853007 TI - Lipid-packing perturbation of model membranes by pH-responsive antimicrobial peptides. AB - The indiscriminate use of conventional antibiotics is leading to an increase in the number of resistant bacterial strains, motivating the search for new compounds to overcome this challenging problem. Antimicrobial peptides, acting only in the lipid phase of membranes without requiring specific membrane receptors as do conventional antibiotics, have shown great potential as possible substituents of these drugs. These peptides are in general rich in basic and hydrophobic residues forming an amphipathic structure when in contact with membranes. The outer leaflet of the prokaryotic cell membrane is rich in anionic lipids, while the surface of the eukaryotic cell is zwitterionic. Due to their positive net charge, many of these peptides are selective to the prokaryotic membrane. Notwithstanding this preference for anionic membranes, some of them can also act on neutral ones, hampering their therapeutic use. In addition to the electrostatic interaction driving peptide adsorption by the membrane, the ability of the peptide to perturb lipid packing is of paramount importance in their capacity to induce cell lysis, which is strongly dependent on electrostatic and hydrophobic interactions. In the present research, we revised the adsorption of antimicrobial peptides by model membranes as well as the perturbation that they induce in lipid packing. In particular, we focused on some peptides that have simultaneously acidic and basic residues. The net charges of these peptides are modulated by pH changes and the lipid composition of model membranes. We discuss the experimental approaches used to explore these aspects of lipid membranes using lipid vesicles and lipid monolayer as model membranes. PMID- 28853009 TI - Adaptation of Lactobacillus acidophilus to Thermal Stress Yields a Thermotolerant Variant Which Also Exhibits Improved Survival at pH 2. AB - Loss in probiotic viability upon exposure to stressful storage and transport conditions has plagued the probiotic market worldwide. Lactobacillus acidophilus is an important probiotic that is added to various functional foods. It is known to be fairly labile and susceptible to temperature variations that it encounters during processing and storage which increases production cost. It has been repeatedly demonstrated that pre-exposure to sub-lethal doses of stress, particularly, temperature and pH, leads to improved survival of various probiotics when they subsequently encounter the same stress of a much greater magnitude. Attempts to adapt L. acidophilus to temperatures as high as 65 degrees C to arrive at a thermotolerant variant have not been reported previously. To improve viability at elevated temperatures, we gradually adapted the L. acidophilus NCFM strain to survival at 65 degrees C for 40 min. Following adaptation, the variant showed a 2-log greater survival compared to wild-type at 65 degrees C. Interestingly, this thermotolerant variant also demonstrated a 2 log greater stability compared to wild-type at pH 2.0. The improved pH and temperature stress tolerance exhibited by this variant remained unaltered even when the strain was lyophilized. Moreover, the thermotolerant variant demonstrated improved stability compared to wild-type when stored for up to a week at 37 and 42 degrees C. Probiotic properties of the variant such as adherence to epithelial cells and antibacterial activity remained unaltered. This strain can potentially help address the issue of significant loss in viable cell counts of L. acidophilus which is typically encountered during probiotic manufacture and storage. PMID- 28853011 TI - Selective introduction of Cu impurity into fine-dispersed ZnS obtained during the process of one-stage synthesis. AB - Fine ZnS:Cu, obtained by method of self-propagating high-temperature synthesis was investigated. As flux in the mixture NaCl was used, Zn and S were taken in stoichiometric ratio; Cu concentration in charge consisted ~1.5 wt.%. Using SEM data, it was established that obtained ZnS:Cu consists from two fractions-first with particles sizes ~10 MUm and more, and other with sizes 50-500 nm. It was established that composition of ZnS:Cu fractions was essentially different. According to EDS data, Cu concentration in particles of fraction with 50-500 nm sizes consists ~2 wt.%, and in particles with sizes ~10 MUm and more the presence of Cu was not detected. The reasons that lead to the selective doping of particles in dependence on their size and also the role of NaCl in processes undergoing during synthesis of material are discussed. PMID- 28853010 TI - Coagulation after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a retrospective cohort analysis. AB - PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) benefit patients with peritoneal carcinomatosis. Nevertheless, this therapy is associated with considerable postoperative pain due to the extensive abdominal incision. While epidural analgesia offers efficacious pain control, CRS and HIPEC therapy is associated with perioperative coagulopathy that may impact its use. The purpose of this retrospective study is to characterize the postoperative coagulopathy in this patient subset and to develop a model that will help predict those at risk. METHODS: Our database of patients treated with CRS and HIPEC (n = 171) was reviewed to assess perioperative changes in platelet count, international normalized ratio (INR), and partial thromboplastin time (PTT). Abnormal coagulation was defined by platelet count < 100 * 10-9.L-1, INR >= 1.5, or PTT >= 45 sec. Severe abnormality in coagulation was defined by platelet count < 50 *10-9.L-1, INR > 2.0, and/or PTT > 60 sec. A logistic regression model was developed to determine if patient, disease, and/or surgical factor(s) were associated with the development of postoperative coagulopathy. Epidural catheter management in this patient population was also reviewed. RESULTS: Significant differences (adjusted P < 0.007) were noted between median preoperative and postoperative platelet and INR values on postoperative days (POD) 0 through 6 and days 0 through 3, respectively. Highest observed median differences between preoperative and postoperative values showed a decrease in platelet count of 94 * 10-9.L-1 (POD 2 and POD 3), an increase in INR of 0.2 (POD 0 to POD 2), and a decrease in PTT of 3.1 sec (POD 5). Coagulopathy and severe coagulopathy occurred in 38% and 4.7% of patients, respectively. Predictors of coagulopathy included intraoperative transfusion of packed red blood cells (PRBCs) and perhaps the peritoneal carcinomatosis index (PCI). Epidural catheters were inserted in 26 patients for a median [IQR] duration of 7.0 [5.0-7.0] days without complication. At the time of their removal, no blood products were required to correct abnormal coagulation values. CONCLUSIONS: Altered coagulation may appear during the postoperative period in approximately 40% of our patients treated with CRS and HIPEC. Intraoperative transfusion of RBCs and possibly increased PCI are associated with abnormal postoperative coagulation. Close monitoring of coagulation parameters is required to help ensure safe removal of an epidural catheter. PMID- 28853012 TI - Fluorine-18 fluorodeoxyglucose positron emission tomography for cardiac sarcoidosis-is it time to consider a new radiotracer? PMID- 28853014 TI - From the Editor. PMID- 28853015 TI - Boat Building in Maine. PMID- 28853013 TI - Effects of Bariatric Surgery on Change of Brown Adipocyte Tissue and Energy Metabolism in Obese Mice. AB - BACKGROUND: Bariatric surgery is an effective treatment for obesity causing changes in energy expenditure. Brown adipose tissue (BAT) is an energy-related organ, and the potential effects of bariatric surgery are yet to be investigated. We aimed to study the effects of different bariatric surgeries on growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, brown adipocyte differentiation, and energy metabolism in obese mice and explore the underlying mechanisms. METHODS: Mice were fed a high-fat diet for 12 weeks and subjected to different bariatric procedures: adjustable gastric band (AGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and sham operation (SO). Pre- and postoperative weight, a metabolic index, content, and metabolic activity of BAT was recorded by micro-positron emission tomography/computed tomography (micro PET/CT). Altered energy metabolism was estimated by metabolic cage technology. Serum GH/IGF-1 level and the brown adipose cell differentiation-related gene expression were estimated. RESULTS: By postoperative week 4, serum GH and IGF-1 levels, as well as the content and metabolic activity of BAT increased postoperatively. The differentiation factors of the brown adipose cell were significantly stronger, energy consumption increased, and respiratory exchange frequency decreased postoperative. The effect was predominant in RYGB; SG demonstrated superior result to ABG. With weight regain 8-week postoperation, these parameters deteriorated in the operation groups, significantly in the GB group; the RYGB group seemed superior to the SG group. CONCLUSIONS: Bariatric surgery elevated the GH/IGF-1 levels and increased BAT volume and activity, meanwhile decreasing the respiratory exchange frequency. This may help us better understand the mechanisms of bariatric surgery. PMID- 28853016 TI - Don't be the "Fifth Guy": Risk, Responsibility, and the Rhetoric of Handwashing Campaigns. AB - In recent years, outbreaks such as H1N1 have prompted heightened efforts to manage the risk of infection. These efforts often involve the endorsement of personal responsibility for infection risk, thus reinforcing an individualistic model of public health. Some scholars-for example, Peterson and Lupton (1996) term this model the "new public health." In this essay, I describe how the focus on personal responsibility for infection risk shapes the promotion of hand hygiene and other forms of illness etiquette. My analysis underscores the use of constitutive and stigmatizing rhetoric to depict individual bodies, rather than environments, as prime sources of infection. Common among workplaces, this rhetoric provides the impetus for encouraging individual behavior change as a hedge against infection risk. I argue, though, that the mandating of personal responsibility for infection risk galvanizes a culture of stigma and blame that may work against the aims of public health. PMID- 28853017 TI - [Child and adolescent psychiatry - a panorama]. AB - The child- and adolescent psychiatry has emancipated itself 10 years ago from an additional specialist physician's area to a separate specialist medical domain with a specific curriculum. Associated with this is an irreconcilable interlacing with the psychotherapy of childhood and adolescence. Even if childhood and juvenile psychiatry is always settled within the framework of a biopsychosocial model, psychotherapy is of particular importance. In the following, the psychotherapeutic requirements and ethical issues of the human being are to be formulated according to a view on the new morbidity and the Zeitgeist in which we are working. A scientific legitimation leads to the demarcation of esoteric endeavors and the view into practice leads us from nosology to functionality in the consideration of mental disorders in children and adolescents. PMID- 28853018 TI - Improvement of the pharmacological activity of menthol via enzymatic beta-anomer selective glycosylation. AB - Menthol has a considerable cooling effect, but the use range of menthol is limited because of its extremely low solubility in water and inherent flavor. (-) Menthol beta-glucoside was determined to be more soluble in water (>27 times) than (-)-menthol alpha-glucoside; hence, beta-anomer-selective glucosylation of menthol is necessary. The in vitro glycosylation of (-)-menthol by uridine diphosphate glycosyltransferase (BLC) from Bacillus licheniformis generated (-) menthol beta-glucoside and new (-)-menthol beta-galactoside and (-)-menthol N acetylglucosamine. The maximum conversion rate of menthol to (-)-menthol beta-D glucoside by BLC was found to be 58.9%. Importantly, (-)-menthol beta-D-glucoside had a higher cooling effect and no flavor compared with menthol. In addition, (-) menthol beta-D-glucoside was determined to be a non-sensitizer in a skin allergy test in the human cell line activation test, whereas menthol was a sensitizer. PMID- 28853019 TI - High-Order Dielectric Metasurfaces for High-Efficiency Polarization Beam Splitters and Optical Vortex Generators. AB - In this paper, a high-order dielectric metasurface based on silicon nanobrick array is proposed and investigated. By controlling the length and width of the nanobricks, the metasurfaces could supply two different incremental transmission phases for the X-linear-polarized (XLP) and Y-linear-polarized (YLP) light with extremely high efficiency over 88%. Based on the designed metasurface, two polarization beam splitters working in high-order diffraction modes have been designed successfully, which demonstrated a high transmitted efficiency. In addition, we have also designed two vortex-beam generators working in high-order diffraction modes to create vortex beams with the topological charges of 2 and 3. The employment of dielectric metasurfaces operating in high-order diffraction modes could pave the way for a variety of new ultra-efficient optical devices. PMID- 28853020 TI - Illicit Drug Use Among Gym-Goers: a Cross-sectional Study of Gym-Goers in Sweden. AB - BACKGROUND: The use of anabolic-androgenic steroids has increased among gym goers, and it has been proposed that this may be part of a polysubstance use pattern that includes the use of illicit drugs. Still, epidemiological data on illicit drug use among gym-goers of both genders are meager. The aim of the present study was thus to examine the use of illicit drugs and its correlates in a large sample of men and women who engaged in weight training at gyms across Sweden. METHODS: In this cross-sectional study, a total of 1969 gym-goers who engaged in weight training in 54 gyms across Sweden were invited to fill in a questionnaire. The questionnaire included 25 items on background variables, weight training frequency, use of illicit drugs and doping substances, and non medical use of benzodiazepines. RESULTS: Of the gym-goers, 19.6% reported having ever used illicit drugs, 6.5% reported use during the past 12 months, and 2.1% during the past 30 days. The most commonly used drug was cannabis, followed by cocaine, amphetamine, and ecstasy. Almost 40% of those who reported drug use had used more than one drug. Male participants and participants between 20 and 39 years of age made up the majority of users. Furthermore, 5.1% of the reported drug users had ever used a doping substance. There was an almost threefold higher odds (OR = 2.99, 95% CI = 1.16-7.66, p < 0.023) of doping use among people who had reported drug use as compared to non-users. CONCLUSIONS: Training at gyms is typically considered a health-promoting behavior. However, our results revealed a slightly higher prevalence of illicit drug use among gym attendees as compared to the general population. Our findings may have captured an underrecognized group of young adult males who engage in weightlifting and use illicit drugs recreationally and/or as training aids. Developing knowledge is imperative in orientating preventive efforts among at-risk gym-goers. TRIAL REGISTRATION: ISRCTN11655041. PMID- 28853021 TI - First-Principles Study on the Stability and STM Image of Borophene. AB - Very recently, borophene (atomic-thin two-dimensional boron sheet) has been successfully synthesized on the Ag(111) surface by deposition. Two kinds of structures were found. However, the identification of the monolayer boron sheets grown on the metal substrate, as well as the stability of different 2D boron sheets, is controversial. By performing the first-principles calculations, present study investigates the atomic structure, stability, and electronic properties of the most possible boron sheets grown on metal surface, namely, buckled triangular, beta12, and chi3 types of crystal lattice. Our result shows that all the three freestanding sheets are thermodynamically unstable and all are metallic. On the other hand, our result indicates the Ag(111) substrate stabilize these sheets. Additionally, our simulated STM images of these monoatomic-thin boron sheets on Ag(111) surface reproduce the experiment observations well and clearly identify the as-grown boron sheets. PMID- 28853022 TI - Single-Leg Assessment of Postural Stability After Anterior Cruciate Ligament Injury: a Systematic Review and Meta-Analysis. AB - BACKGROUND: Previous reports of single-leg assessment demonstrated functional deficits in postural stability following anterior cruciate ligament (ACL) injury. However, quantified measures describing postural stability vary among investigations and results seem not to be clear. The first aim of this systematic review was to quantify postural deficits in eyes open single-leg stance in patients after ACL injury. Moreover, the second aim was to examine the potential of traditional center of pressure (CoP) measures in order to distinguish postural stability between ACL patients and healthy controls. METHODS: A systematic literature search in the databases PubMed and Scopus was conducted from their inception to December 2016 to identify relevant articles. Eligibility criteria were limited to controlled trials of eyes open static single-leg stance on a force or pressure plate recording CoP measures in patients after ACL injury. RESULTS: Eleven studies were included, involving a total of 329 ACL-injured and 265 control subjects. Random-effects meta-analysis showed significantly increased sway magnitudes (SMDwm = 0.94, p = 0.003) and velocities (SMDwm = 0.66, p = 0.0002) in the ACL group compared to the healthy controls. Sway magnitude in anteroposterior (SMDwm = 0.58, p = 0.02) and mediolateral (SMDwm = 1.15, p = 0.02) direction were significantly increased in ACL patients. No differences were found for the non-injured side. Similarly, no differences have been observed among ACL patients between the injured and non-injured side for sway velocity, while sway magnitude significantly differed (SMDwm = 0.58, p = 0.05). CONCLUSIONS: The findings of this systematic review and meta-analysis demonstrated decreased postural stability in individuals with ACL injury. Sway magnitude and velocity were significantly increased in the ACL group compared to the healthy controls. Although the included research still exhibited considerable heterogeneity, it may be proposed that fundamental CoP measures are suitable to differentiate patients after ACL injury and healthy controls with respect to postural stability in eyes open single-leg stance. PMID- 28853023 TI - Automatic change detection in vision: Adaptation, memory mismatch, or both? II: Oddball and adaptation effects on event-related potentials. AB - In this study we compared the event-related potentials (ERPs) obtained in two different paradigms: a passive visual oddball paradigm and an adaptation paradigm. The aim of the study was to investigate the relation between the effects of activity decrease following an adaptor (stimulus-specific adaptation) and the effects of an infrequent stimulus within sequences of frequent ones. In Experiment 1, participants were presented with different line textures. The frequent (standard) and rare (deviant) texture elements differed in their orientation. In Experiment 2, windmill pattern stimuli were presented in which the number of vanes differentiated the deviant and standard stimuli. In Experiment 1 the ERP differences elicited between the oddball deviant and the standard were similar to the differences between the ERPs to the nonadapted and adapted stimuli in the adaptation paradigm. In both paradigms the differences appeared as a posterior negativity with the latency of 120-140 ms. This finding demonstrates that the representation of a sequential rule (successive presentation of the standard) and the violation of this rule are not necessary for deviancy effects to emerge. In Experiment 2 (windmill pattern), in the oddball paradigm the difference potentials appeared as a long-lasting negativity. In the adaptation condition, the later part of this negativity (after 200 ms) was absent. We identified the later part of the oddball difference potential as the genuine visual mismatch negativity-that is, an ERP correlate of sequence violations. The latencies of the difference potentials (deviant minus standard) and the endogenous components (P1 and N1) diverged; therefore, the adaptation of these particular ERP components cannot explain the deviancy effect. Accordingly, the sources contributing to the standard-versus-deviant modulations differed from those related to visual adaptation; that is, they generated distinct ERP components. PMID- 28853024 TI - Does experience matter? A meta-analysis of physician rating websites of Orthopaedic Surgeons. AB - PURPOSE: To perform a systematic review evaluating online ratings of Orthopaedic Surgeons to determine: (1) the number of reviews per surgeon by website, (2) whether the number of reviews and rate of review acquisition correlated with years in practice, and (3) whether the use of ratings websites varied based on the surgeons' geographic region of practice. METHODS: The USA was divided into nine geographic regions, and the most populous city in each region was selected. HealthGrades and the American Board of Orthopaedic Surgery (ABOS) database were used to identify and screen (respectively) all Orthopaedic Surgeons within each of these nine cities. These surgeons were divided into three "age" groups by years since board certification (0-10, 10-20, and 20-30 years were assigned as Groups 1, 2, and 3, respectively). An equal number of surgeons were randomly selected from each region for final analysis. The online profiles for each surgeon were reviewed on four online physician rating websites (PRW, i.e. HealthGrades, Vitals, RateMDs, Yelp) for the number of available patient reviews. Descriptive statistics, analysis of variance (ANOVA), and Pearson correlations were used. RESULTS: Using HealthGrades, 2802 "Orthopaedic Surgeons" were identified in nine cities. However, 1271 (45%) of these were not found in the ABOS board certification database. After randomization, a total of 351 surgeons were included in the final analysis. For these 351 surgeons, the mean number of reviews per surgeon found on all four websites was 9.0 +/- 14.8 (range 0-184). The mean number of reviews did not differ between the three age groups (p > 0.05) with 8.7 +/- 14.4, (2) 10.3 +/- 18.3, and (3) 8.0 +/- 10.8 for Groups 1, 2, and 3, respectively. However, the rate that reviews were obtained (i.e. reviews per surgeon per year) was significantly higher (p < 0.001) in Group 1 (2.6 +/- 7.7 reviews per year) compared to Group 2 (1.4 +/- 2.4) and Group 3 (1.1 +/- 1.4). There was no correlation between the number of reviews and years in practice (R < 0.001), and there was a poor correlation between number of reviews and regional population (R = 0.199). CONCLUSIONS: The number of reviews per surgeon did not differ significantly between the three defined age groups based on years in practice. However, surgeons with less than 10 years in practice were accumulating reviews at a significantly higher rate. Interestingly nearly half of "Orthopaedic Surgeons" listed were not found to be ABOS-certified Orthopaedic Surgeons. PMID- 28853025 TI - Is There a Place for Ozone Therapy in Patients with Heart Failure? PMID- 28853026 TI - Folate Receptor-targeted Bioflavonoid Genistein-loaded Chitosan Nanoparticles for Enhanced Anticancer Effect in Cervical Cancers. AB - In this study, novel folic acid-conjugated chitosan nanoparticle was formulated for specific delivery of bioflavonoid, Genistein (GEN), to the cervical cancer cells. The prepared GEN-loaded chitosan nanoparticles (GCN) and folic acid conjugated GCN (FGCN) showed smaller size with a controlled drug release profile. FGCN exhibited enhanced internalization potential in HeLa cells than that of GCN. The specific internalization of FGCN was mainly due to the affinity of folic acid (FA) with FRs-alpha which is present in large numbers in HeLa cells. The results revealed that FGCN has a specific affinity towards HeLa cells that will contribute to the better treatment. Folic acid-tagged nanoformulations exhibited a superior cytotoxic effect compared to that of non-targeted formulations. Consistently, IC50 value of GEN decreased from 33.8 to 14.6 MUg/ml when treated with FGCN after 24 h incubation. The apoptosis studies indicated that the FGCN nanoparticles were then either GCN or free GEN in terms of anticancer activity. Overall, results revealed that folate conjugation to the delivery system might have great effect on the survival of cervical cancers that will be beneficial for overall cancer treatment. PMID- 28853027 TI - [Ten years of child and adolescent psychiatry in Austria: a new medical speciality within the structures of public health services]. AB - We discuss the comprehensive work for the development of child and adolescent psychiatry in Austria, summarize the current status of care in various settings and focus on further developments. Intramural care offers about 50% of the places needed and is heterogeneously distributed over the country, extramural care offers already around one quarter of care in need. We calculated a fully developed extramural care system from about 2033. Further development of the Austrian care system in child and adolescent psychiatry needs collaborative efforts of all responsible players. PMID- 28853028 TI - Erratum to: Exploring the Interplay between Rescue Drugs, Data Imputation, and Study Outcomes: Conceptual Review and Qualitative Analysis of an Acute Pain Data Set. PMID- 28853029 TI - Effect of High-Intensity Interval Training on Fitness, Fat Mass and Cardiometabolic Biomarkers in Children with Obesity: A Randomised Controlled Trial. AB - BACKGROUND: Paediatric obesity significantly increases the risk of developing cardiometabolic diseases across the lifespan. Increasing cardiorespiratory fitness (CRF) could mitigate this risk. High-intensity interval training (HIIT) improves CRF in clinical adult populations but the evidence in paediatric obesity is inconsistent. OBJECTIVES: The objectives of this study were to determine the efficacy of a 12-week, HIIT intervention for increasing CRF and reducing adiposity in children with obesity. METHODS: Children with obesity (n = 99, 7-16 years old) were randomised into a 12-week intervention as follows: (1) HIIT [n = 33, 4 * 4-min bouts at 85-95% maximum heart rate (HRmax), interspersed with 3 min of active recovery at 50-70% HRmax, 3 times/week] and nutrition advice; (2) moderate-intensity continuous training (MICT) [n = 32, 44 min at 60-70% HRmax, 3 times/week] and nutrition advice; and (3) nutrition advice only (nutrition) [n = 34]. CRF was quantified through a maximal exercise test ([Formula: see text]) while adiposity was assessed using magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry (DXA) and air-displacement plethysmography. RESULTS: HIIT stimulated significant increases in relative [Formula: see text] compared with MICT (+3.6 mL/kg/min, 95% CI 1.1-6.0, P = 0.004) and the nutrition intervention (+5.4 mL/kg/min, 95% CI 2.9-7.9, P = 0.001). However, the intervention had no significant effect on visceral and subcutaneous adipose tissue, whole body composition or cardiometabolic biomarkers (P > 0.05). CONCLUSION: A 12-week, HIIT intervention was highly effective in increasing cardiorespiratory fitness when compared with MICT and nutrition interventions. While there were no concomitant reductions in adiposity or blood biomarkers, the cardiometabolic health benefit conferred through increased CRF should be noted. CLINICAL TRIALS REGISTRATION NUMBER: Clinicaltrials.gov; NCT01991106. PMID- 28853031 TI - Deiodinases and stem cells: an intimate relationship. AB - Thyroid hormone is a major determinant of tissue functions in vivo. The deiodinase family controls the tissue-specific activation or inactivation of intracellular thyroid hormones. Precise control of the T3-dependent transcriptional program is required by multiple cell systems, including the stem cell. In this context, the identification of a close connection between thyroid hormones and different signal pathways involved in the control of stem cell functions suggested that the deiodinases may play a role in the definition of stem cell biology and physiology. Stem cells have an unlimited self-renewal capacity and the potential to differentiate into different types of mature cells. Deciphering how all these events are achieved, how the T3 signal is controlled and integrated in stem cells and their niches, and how it can impact on them is essentially unknown and represents a challenge for coming years. In this review, I will explore the role played by the deiodinases in the modulation of the TH signal in stem cells of adult tissues, namely muscle and intestine, and how their actions control the delicate balance among self-renewal, proliferation and differentiation. Elucidation of the molecular mechanisms presiding thyroid hormone action in stem cells may reveal therapeutic potential, for example in the fields of regenerative diseases and cancer. PMID- 28853030 TI - Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer's disease. AB - Hypertension in the elderly substantially increases both the risk of vascular cognitive impairment (VCI) and Alzheimer's disease (AD); however, the underlying mechanisms are not completely understood. This review discusses the effects of hypertension on structural and functional integrity of cerebral microcirculation, including hypertension-induced alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage (capillary rarefaction, blood-brain barrier disruption), and the genesis of cerebral microhemorrhages and their potential role in exacerbation of cognitive decline associated with AD. Understanding and targeting the hypertension-induced cerebromicrovascular alterations that are involved in the onset and progression of AD and contribute to cognitive impairment are expected to have a major role in preserving brain health in high-risk older individuals. PMID- 28853032 TI - [The epidemiology of mental disorders in youth : A narrative review including Austrian data]. AB - For decades, epidemiological studies have consistently and impressively demonstrated the frequency of mental illness in childhood and adolescence. Mental health disorders are among the most common causes of diminished quality of life among young people, sometimes casting long shadows into adulthood. This narrative review looks at this phenomenon using a selection of research findings dealing with overall prevalence figures, with the prevalence of individual disorders, and with the progression of mental illness from childhood and adolescence to adulthood. Austrian epidemiological studies supplementing these findings are also presented. PMID- 28853033 TI - Dual Antiplatelet Therapy Duration: Reconciling the Inconsistencies. AB - Dual antiplatelet therapy (DAPT) prevents recurrent ischemic events after an acute coronary syndrome (ACS) as well as stent thrombosis (ST) in patients with prior stent implantation. Nevertheless, these benefits are counterbalanced by a significant bleeding hazard, which is directly related to the treatment duration. Although DAPT has been extensively studied in numerous clinical trials, optimal treatment duration is still debated, mostly because of apparent inconsistencies among studies. Shortened treatment duration of 6 or 3 months was shown to mitigate bleeding risk compared with consensus-grounded 12-month standard duration, without any apparent excess of ischemic events. However, recent trials showed that a >12-month course of treatment reduces ischemic events but increases bleeding compared with 12 months. The inconsistent benefit of a longer DAPT course compared with shorter treatment durations is puzzling, and requires a careful appraisal of between-studies differences. We sought to summarize the existing evidence aiming at reconciling apparent inconsistencies among these studies, as well as thoroughly discuss the possible increased risk of fatal events associated with long-term DAPT. Benefits and risks of prolonging or shortening DAPT duration will be discussed, with a focus on treatment individualization. Finally, we will provide an outlook for possible future directions in the field. PMID- 28853035 TI - Expanding Antimicrobial Stewardship to Urgent Care Centers Through a Pharmacist Led Culture Follow-up Program. AB - INTRODUCTION: Urgent care centers represent a high-volume outpatient setting where antibiotics are prescribed frequently but resources for antimicrobial stewardship may be scarce. In 2015, our pharmacist-led Emergency Department (ED) culture follow-up program was expanded to include two urgent care (UC) sites within the same health system. The UC program is conducted by ED and infectious diseases clinical pharmacists as well as PGY1 pharmacy residents using a collaborative practice agreement (CPA). The purpose of this study was to describe the pharmacist-led UC culture follow-up program and its impact on pharmacist workload. METHODS: This retrospective, descriptive study included all patients discharged to home from UC with a positive culture from any site resulting between 1 January and 31 December 2016. Data collected included the culture type, presence of intervention, and proportion of interventions made under the CPA. Additionally, pharmacist workload was reported as the number of call attempts made, new prescriptions written, and median time to complete follow-up per patient. Data were reported using descriptive statistics. RESULTS: A total of 1461 positive cultures were reviewed for antibiotic appropriateness as part of the UC culture follow-up program, with 320 (22%) requiring follow-up intervention. Culture types most commonly requiring intervention were urine cultures (25%) and sexually transmitted diseases (25%). A median of 15 min was spent per intervention, with a median of one call (range 1-6 calls) needed to reach each patient. Less than half of patients required a new antimicrobial prescription at follow-up. CONCLUSION: A pharmacist-led culture follow-up program conducted using a CPA was able to be expanded to UC sites within the same health system using existing clinical pharmacy staff along with PGY1 pharmacy residents. Service expansion resulted in minimal increase in pharmacist workload. Adding UC culture follow-up services to an existing ED program can allow health systems to expand antimicrobial stewardship initiatives to satellite locations. PMID- 28853034 TI - Biophysical and biochemical strategies to understand membrane binding and pore formation by sticholysins, pore-forming proteins from a sea anemone. AB - Actinoporins constitute a unique class of pore-forming toxins found in sea anemones that are able to bind and oligomerize in membranes, leading to cell swelling, impairment of ionic gradients and, eventually, to cell death. In this review we summarize the knowledge generated from the combination of biochemical and biophysical approaches to the study of sticholysins I and II (Sts, StI/II), two actinoporins largely characterized by the Center of Protein Studies at the University of Havana during the last 20 years. These approaches include strategies for understanding the toxin structure-function relationship, the protein-membrane association process leading to pore formation and the interaction of toxin with cells. The rational combination of experimental and theoretical tools have allowed unraveling, at least partially, of the complex mechanisms involved in toxin-membrane interaction and of the molecular pathways triggered upon this interaction. The study of actinoporins is important not only to gain an understanding of their biological roles in anemone venom but also to investigate basic molecular mechanisms of protein insertion into membranes, protein-lipid interactions and the modulation of protein conformation by lipid binding. A deeper knowledge of the basic molecular mechanisms involved in Sts cell interaction, as described in this review, will support the current investigations conducted by our group which focus on the design of immunotoxins against tumor cells and antigen-releasing systems to cell cytosol as Sts-based vaccine platforms. PMID- 28853036 TI - Successful conversion surgery for gastric cancer with multiple liver metastases treated after S-1 plus cisplatin combination chemotherapy: a case report. AB - BACKGROUND: Gastric cancer with multiple liver metastases have poor prognosis. Recently, stage IV gastric cancer patients who respond well to systemic chemotherapy can be treated by gastrectomy. We herein report a case of advanced gastric cancer with liver metastases who was successfully downstaged by systemic chemotherapy and underwent conversion surgery. CASE PRESENTATION: A 60-year-old male patient was diagnosed with gastric cancer with multiple liver metastases [cT3N3M1, stage IV]. After 18 courses of S-1 plus cisplatin combination chemotherapy (S-1 administered orally (80 mg/m2/day) twice a day for 21 consecutive days and cisplatin (60 mg/m2) infused on day 8), marked regression of liver metastasis was achieved, and we performed open total gastrectomy with D2 lymph node dissection. The patient was discharged from the hospital 10 days after the operation. Histopathological examination revealed no malignant cells in the lymph nodes [ypT1bN0M0, stage IA]. S-1 as the adjuvant chemotherapy was administered for 12 months, and the patient is alive without a recurrence for 33 months after surgery. CONCLUSIONS: Conversion surgery may improve the poor prognosis of gastric cancer. PMID- 28853037 TI - Does visuomotor adaptation contribute to illusion-resistant grasping? AB - Do illusory distortions of perceived object size influence how wide the hand is opened during a grasping movement? Many studies on this question have reported illusion-resistant grasping, but this finding has been contradicted by other studies showing that grasping movements and perceptual judgments are equally susceptible. One largely unexplored explanation for these contradictions is that illusion effects on grasping can be reduced with repeated movements. Using a visuomotor adaptation paradigm, we investigated whether an adaptation model could predict the time course of Ponzo illusion effects on grasping. Participants performed a series of trials in which they viewed a thin wooden target, manually reported an estimate of the target's length, then reached to grasp the target. Manual size estimates (MSEs) were clearly biased by the illusion, but maximum grip apertures (MGAs) of grasping movements were consistently accurate. Illusion resistant MGAs were observed immediately upon presentation of the illusion, so there was no decrement in susceptibility for the adaptation model to explain. To determine whether online corrections based on visual feedback could have produced illusion-resistant MGAs, we performed an exploratory post hoc analysis of movement trajectories. Early portions of the illusion effect profile evolved as if they were biased by the illusion to the same magnitude as the perceptual responses (MSEs), but this bias was attenuated prior to the MGA. Overall, this preregistered study demonstrated that visuomotor adaptation of grasping is not the primary source of illusion resistance in closed-loop grasping. PMID- 28853038 TI - Drug-Induced QT Prolongation and Torsades de Pointes: An All-Exclusive Relationship or Time for an Amicable Separation? AB - QT prolongation was perceived as a major antiarrhythmic mechanism, but soon became a surrogate for torsades de pointes (TdP) instead. Drugs that prolong the QT interval range from having potent torsadogenic activity to no proarrhythmic action and even antiarrhythmic effects. Blockade of hERG channels is the primary cause of TdP, but blockade/activation of other channels can also be torsadogenic. TdP is primarily caused by disturbances of TRIaD, but disturbance of wavelength can also contribute to TdP (where TRIaD is triangulation, reverse use dependence, instability and dispersion, and wavelength equals conduction velocity times effective refractory period). The above proarrhythmic parameters do not only result in TdP, but can also lead to ventricular tachycardia (VT) and ventricular fibrillation (VF). Note that QT prolongation (not listed as a causal factor) yields many false positives (potentially depriving patients from much needed drugs) and false negatives (potentially exposing patients to lethal arrhythmias). Thus, drug-induced QT prolongation is a bad surrogate for TdP, VT or VF; it is high time to move away from an oversimplified and erroneous surrogate. PMID- 28853039 TI - Erratum to: Assessment of the Validity and Reproducibility of a Novel Standardized Test Meal for the Study of Postprandial Triacylglycerol Concentrations. PMID- 28853041 TI - The Effect of Metabolic and Bariatric Surgery on DNA Methylation Patterns. AB - PURPOSE OF REVIEW: Metabolic and bariatric surgery (MBS) is considered to be the most effective treatment for obesity. Not only due to the significant weight reduction but also because of the many health benefits associated with it. In the last 5 years, several studies have suggested that epigenetic modifications could be involved in the mechanisms underlying the response to bariatric surgery. In this review, we will compile the different studies (2012-2017) concerning the effect of this surgical procedure on DNA methylation patterns (the most studied epigenetic marker) and its association with metabolic improvement. This is an emerging area, and currently, there are not many studies in the literature. The aim is to show what has been done so far and what the future direction in this emerging area might be. RECENT FINDINGS: Recent findings have shown how metabolic and bariatric surgery modifies the DNA methylation profile of the specific genes associated with the pathophysiology of the disease. The studies were performed in morbidly obese subjects, mainly in women, with the aim of reducing weight and improving the obesity-associated comorbidities. DNA methylation has been measured both in specific tissue and in peripheral blood samples. In general, studies about site-specific DNA methylation have shown a change in the methylation profile after surgery, whereas the studies analyzing global DNA methylation are not so conclusive. Summing up, metabolic and bariatric surgery can modify the DNA methylation profile of different genes and contributes to the metabolic health benefits that are often seen after metabolic and bariatric surgery. Although there are still many issues to be resolved, the capacity to revert the DNA methylation profile of specific sites opens a window for searching for target markers to treat obesity-related comorbidities. PMID- 28853042 TI - [Future development of child and adolescent psychiatry in Austria]. AB - Anniversaries are turningpoints for reflexions of the past and planing for the future. In conclusion of all papers in this actual issue one can say tha CAP has reached a respected place in the medical landscape. Also internationally, the work of Austrian child and adolescent psychiatrist is recognised and respected. CAP is cooperating as an respected discipline with adjacent specialties as pediatrics and psychiatry as well as with external partners as Kinder- und Jugendhilfe (social child welfare).Anyway, the actual situation shows several deficits concerning patient care on all levels of the health system as well as in education and training of sufficient numbers of child and adolescent psychiatrists. PMID- 28853040 TI - State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease. AB - Acute vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Multiple complex pathophysiological processes can result in pain during a VOC. Despite significant improvements in the understanding and management of SCD, little progress has been made in the management of pain in SCD, although new treatments are being explored. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment of VOC pain, but new classes of drugs are being tested to prevent and treat acute pain. Advancements in the understanding of the pathophysiology of SCD and pain and the pharmacogenomics of opioids have yet to be effectively utilized in the management of VOC. Opioid tolerance and opioid-induced hyperalgesia are significant problems associated with the long-term use of opioids, and better strategies for chronic pain therapy are needed. This report reviews the mechanisms of pain associated with acute VOC, describes the current management of VOC, and describes some of the new therapies under evaluation for the management of acute VOC in SCD. PMID- 28853043 TI - Comparative evaluation of 18F-FLT and 18F-FDG for detecting cardiac and extra cardiac thoracic involvement in patients with newly diagnosed sarcoidosis. AB - BACKGROUND: 18F-FDG PET has been used in sarcoidosis for diagnosis and determination of the extent of the disease. However, assessing inflammatory lesions in cardiac sarcoidosis using 18F-FDG can be challenging because it accumulates physiologically in normal myocardium. Another radiotracer, 3'-deoxy 3'-18F-fluorothymidine (18F-FLT), has been investigated as a promising PET tracer for evaluating tumor proliferative activity. In contrast to 18F-FDG, 18F-FLT uptake in the normal myocardium is low. The purpose of this retrospective study was to compare the uptake of 18F-FLT and 18F-FDG in the evaluation of cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis. Data for 20 patients with newly diagnosed sarcoidosis were examined. 18F-FLT and 18F-FDG PET/CT studies had been performed at 1 h after each radiotracer injection. The patients had fasted for at least 18 h before 18F-FDG PET/CT but were given no special dietary instructions regarding the period before 18F-FLT PET/CT. Uptake of 18F-FLT and 18F-FDG was examined visually and semiquantitatively using maximal standardized uptake value (SUVmax). RESULTS: Two patients had cardiac sarcoidosis, 7 had extra-cardiac thoracic sarcoidosis, and 11 had both cardiac and extra-cardiac thoracic sarcoidosis. On visual analysis for diagnosis of cardiac sarcoidosis, 4/20 18F-FDG scans were rated as inconclusive because the 18F-FDG pattern was diffuse, whereas no FLT scans were rated as inconclusive. The sensitivity of 18F-FDG PET/CT for detection of cardiac sarcoidosis was 85%; specificity, 100%; and accuracy, 90%. The corresponding values for 18F-FLT PET/CT were 92, 100, and 95%, respectively. Using semiquantitative analysis of cardiac sarcoidosis, the mean 18F-FDG SUVmax was significantly higher than the mean 18F-FLT SUVmax (P < 0.005). Both 18F-FDG and 18F-FLT PET/CT studies detected all 24 extra-cardiac lesions. Using semiquantitative analysis of extra-cardiac sarcoidosis, the mean 18F-FDG SUVmax was significantly higher than the mean 18F-FLT SUVmax (P < 0.001). CONCLUSIONS: The results of this preliminary study suggest that 18F-FLT PET/CT can detect cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis as well as 18F-FDG PET/CT, although uptake of 18F-FLT in lesions was significantly lower than that of 18F-FDG. However, 18F-FLT PET/CT may be easier to perform since it requires neither prolonged fasting nor a special diet prior to imaging. PMID- 28853045 TI - [The history of child and adolescent psychiatry in Austria : Essay about a long development]. AB - The history of child and adolescent psychiatry in Austria is very short - it was established first in 1975, finally it achieved the status of a seperate specialisation in 2007. In earlier years the name of this specialty was used under the guise of scientific interest for malpractice and child abuse or child murder during the times of the 2nd World War.But also, the development after 1945 showed how long abviant ideas could survive. During the last decade CAP showed a formidable development, quality and support of patient care improved significantly. Also the scientific development and education in CAP improved. The Austrian Society for CAP developed - although exclusively privately run - into a professional and scientific society, which ist respected by politicians and society. PMID- 28853044 TI - Consensus Statement for Clinical Pathway Development for Perioperative Pain Management and Care Transitions. AB - The perioperative surgical home (PSH) model has been created with the intention to reduce costs and to improve efficiency of care and patient experience in the perioperative period. The PSH is a comprehensive model of care that is team-based and patient-centric. The team in each facility should be multidisciplinary and include the input of perioperative services leadership, surgical services, and support personnel in order to provide seamless care for the patient from the preoperative period when decision to undergo surgery is initially made to discharge and, if needed after discharge from the hospital, until full recovery is achieved. PSH is discussed in this consensus article with the emphasis on perioperative care coordination of patients with chronic pain conditions. Preoperative optimization can be successfully undertaken through patient evaluation, screening, and education. Many important positive implications in the PSH model, in particular for those patients with increased potential morbidity, mortality, and high-risk populations, including those with a history of substance abuse or anxiety, reflect a more modern approach to health care. Newer strategies, such as preemptive and multimodal analgesic techniques, have been demonstrated to reduce opioid consumption and to improve pain relief. Continuous catheters, ketamine, methadone, buprenorphine, and other modalities can be best delivered with the expertise of an anesthesiologist and a support team, such as an acute pain care coordinator. A physician-led PSH is a model of care that is patient-centered with the integration of care from multiple disciplines and is ideally suited for leadership from the anesthesia team. Optimum pain control will have a significant positive impact on the measures of the PSH, including lowering of complication rates, lowering of readmissions, improved patient satisfaction, reduced morbidity and mortality, and shortening of hospital stays. All stakeholders should work together and consider the PSH model to ensure the best quality of health care for patients undergoing surgery in the future. The pain management physician's role in the postoperative period should be focused on providing optimal analgesia associated with improved patient satisfaction and outcomes that result in reduced health care costs. PMID- 28853046 TI - Effect of Confinement on Photophysical Properties of P3HT Chains in PMMA Matrix. AB - The influence of arrangement of poly(3-hexylthiophene) (P3HT) chains embedded into poly(methyl methacrylate) (PMMA) matrix on photophysical properties, such as electronic absorption spectrum, band gap, and photoluminescence quantum yield, of the formed P3HT aggregates have been studied. It has been found that variation of P3HT fraction in PMMA matrix from 25 to 2 wt% is accompanied with the increasing quantum yield of photoluminescence, red shift of the band gap, and structural change of P3HT crystallites. The above changes are accompanied with disruption of the continuous network of P3HT fraction into smaller P3HT particles with size ranged from several microns to several tens of nanometers. The results are interpreted in terms of the changing intermolecular packing and reduced intramolecular torsional disorder. It is discussed that the most contribution to the above changes comes from P3HT molecules at the interface of P3HT cluster and PMMA environment. PMID- 28853048 TI - Dissecting combining ability effect in a rice NCII-III population provides insights into heterosis in indica-japonica cross. AB - BACKGROUND: Combining ability is a measure for selecting elite parents that make the highest contributions to hybrid performance. However, the genetic bases of combining ability and how they contributed to heterosis is seldomly known. RESULTS: We constructed a both NCII and NCIII population derived from an indica japonica cross to study the relationship among parental performance, combining ability and hybrid performance of 11 agronomic traits. Among them, specific combining ability is more important to grain yield than parental performance and general combining ability. We performed linkage analyses to phenotypic values and combining ability of all 11 traits in Doubled haploid lines and its two backcross populations and identified 108 QTLs in total. Among these QTLs, four known loci, Sd1, Ghd7, Ghd8 and DEP1 contribute a lot to GCA effects of agronomic traits except grain yield and seed setting rate. Three QTLs, Ghd8, S5 and qS12, contribute a lot to SCA effects of grain yield and present overdominace. CONCLUSIONS: Our study provides insights into the genetic bases of combining ability and heterosis and will promote the improvements of indica-japonica hybrid breeding. PMID- 28853049 TI - Erratum to: Implementation Science and Employer Disability Practices: Embedding Implementation Factors in Research Designs. PMID- 28853050 TI - Clinical Pharmacokinetics and Pharmacodynamics of the Epidermal Growth Factor Receptor Inhibitor Panitumumab in the Treatment of Colorectal Cancer. AB - Despite progress in the treatment of metastatic colorectal cancer (mCRC) in the last 15 years, it is still a condition with a relatively low 5-year survival rate. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is able to prolong survival in patients with mCRC. Panitumumab is used in different lines of therapy in combination with chemotherapy, and as monotherapy for the treatment of wild-type (WT) RAS mCRC. It is administered as an intravenous infusion of 6 mg/kg every 2 weeks and has a t 1/2 of approximately 7.5 days. Elimination takes place via two different mechanisms, and immunogenicity rates are low. Only RAS mutations have been confirmed as a negative predictor of efficacy with anti-EGFR antibodies. Panitumumab is generally well tolerated and has a manageable toxicity profile, despite a very high prevalence of dermatologic side effects. This article presents an overview of the clinical pharmacokinetics and pharmacodynamics of panitumumab, including a description of the studies that led to its approval in the different lines of therapy of mCRC. PMID- 28853051 TI - Patient predictors of weight loss following a behavioral weight management intervention among US Veterans with severe obesity. AB - PURPOSE: Identification of patient characteristics that are associated with behavioral weight loss success among bariatric surgery candidates could inform selection of optimal bariatric surgery candidates. We examined the associations between psychosocial characteristics and weight loss in a group of Veterans with severe obesity who participated in a behavioral weight loss intervention. METHODS: The MAINTAIN trial involved a 16-week weight loss program followed by randomization among participants losing at least 4 kg to a maintenance intervention or usual care. This secondary analysis was performed on Veterans who participated in the 16-week weight loss program and met NIH criteria for bariatric surgery (body mass index [BMI] 35.0-39.9 with at least 1 obesity related comorbidity or BMI >= 40). Unadjusted and adjusted associations between baseline patient characteristics and weight loss during the 16-week induction phase were evaluated with linear regression. Missing weight measurements were multiply imputed, and results combined across ten imputations. RESULTS: Among the 206 patients who met inclusion criteria, mean initial BMI was 40.8 kg/m2 (SD 6.0), and mean age was 59.2 years (SD 9.4). Approximately 20% of participants were female, 51.5% were Black, and 44.7% were White. Estimated mean 16-week weight loss was 5.16 kg (SD 4.31). In adjusted analyses, greater social support and older age were associated with greater weight loss (p < 0.05). None of the nine psychosocial characteristics we examined were associated with greater weight loss. CONCLUSIONS: Understanding and strengthening the level of social support for bariatric surgery candidates may be important given that it appears to be strongly correlated with behavioral weight loss success. LEVEL OF EVIDENCE: Level II, Evidence obtained from well-designed controlled trials without randomization. TRIAL REGISTRATION: ClinicalTrials.gov NCT01357551 http://clinicaltrials.gov/show/NCT01357551 . PMID- 28853053 TI - Erratum to: The Brand's PREACH Survey: A Capacity Assessment Tool for Predicting Readiness to Engage African American Churches in Health. PMID- 28853054 TI - Erratum to: The Burden of Chronic Urticaria from Brazilian Patients' Perspective. PMID- 28853052 TI - Thyroid diseases and bone health. AB - Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor alpha (TRalpha). Discovery of this rare condition recapitulated animal studies demonstrating that TRalpha mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength. PMID- 28853055 TI - Quantification of the Pharmacodynamic Interaction of Morphine and Gabapentin Using a Response Surface Approach. AB - The combination of morphine and gabapentin has shown to be promising for managing postoperative pain but finding the right dose for the combination has proven to be a challenge. The purpose of this study was to quantitatively characterize the pharmacodynamic interaction between the two drugs and to identify the optimal concentration-effect relationship of the combination. Information regarding plasma concentrations and von Frey withdrawal thresholds following incisional surgery on Sprague Dawley rats, after administration of morphine, gabapentin, or their combination was available from published studies. The combined pharmacodynamic effect of morphine and gabapentin was analyzed and linked to drug plasma concentrations via a response surface approach using non-linear mixed effect modeling. Full reversal of withdrawal thresholds for the pain stimulation to presurgery values was estimated at morphine plasma concentration of 435.1 ng/mL. Co-administration of up to 40 MUg/mL of gabapentin led to a reduction of the needed morphine concentration down to 307.5 ng/mL (~ 29% reduction). Combination of concentration ranges of gabapentin between 20 and 40 MUg/mL with any morphine concentrations between 100 and 600 ng/mL were found to lead up to 50% increased effect relatively to the effect attained by morphine alone. This study highlights the importance of finding the right combination in multimodal analgesia and demonstrates the usefulness of the response surface approach for the study of pharmacodynamic interactions. The proposed pharmacokinetic pharmacodynamic model may provide the basis for a rational clinical trial design with the aim to identify the optimal dose combination ratios in humans. PMID- 28853056 TI - Effect of Gold Nanoparticle Distribution in TiO2 on the Optical and Electrical Characteristics of Dye-Sensitized Solar Cells. AB - Photoanodes comprising Au nanoparticles (GNPs) and thin TiO2 layers with a stacked structure were fabricated by repeating the application of TiO2 paste and GNP solutions on conductive glass to vary the distribution of GNPs in the TiO2 layer. The plasmon-enhanced characteristics of dye-sensitized solar cells (DSSCs) with such photoanodes were investigated. Both the absorption of the TiO2 layer and the performance of the DSSC are found to be most increased by plasmonic enhancement when GNPs are concentrated near the position in the TiO2 layer, which is the penetration depth of the incident light of wavelength corresponding to the maximum absorption of the N719 dye (~ 520 nm). When a GNP layer with a relatively high density of 1.3 MUg/cm2 density was formed at its position, and two GNP layers with a relatively low density of 0.65 MUg/cm2 were formed near the front side of the incident light, the short-circuit current density (Jsc) and energy conversion efficiency (eta) of the DSSC were found to be 10.8 mA/cm2 and 5.0%, increases of 15 and 11%, respectively, compared with those of the DSSC without GNPs. Our work suggests that optimization of the distribution of GNPs in the TiO2 layer is very important for improving the performance of DSSCs fabricated by utilizing GNPs. PMID- 28853057 TI - Erratum to: Updates in Cardiac Resynchronization Therapy for Chronic Heart Failure: Review of Multisite Pacing. PMID- 28853059 TI - Synaptobrevin-2 facilitates the trafficking and function of atrial SK2 channel. PMID- 28853058 TI - Pharmacological Management of Chronic Rhinosinusitis: Current and Evolving Treatments. AB - Chronic rhinosinusitis (CRS) is an inflammatory sinonasal condition with multiple etiologic factors that is associated with a vast economic cost. Treatment is most frequently pharmacologic and has centered on agents that ameliorate inflammation, decrease bacterial or pathogen load, and facilitate egress of mucus or purulence from the sinonasal cavity. Nasal saline irrigations, topical nasal steroids, certain antibiotics, and systemic steroids have shown some efficacy in the management of CRS. Recently, biologic therapeutics that target specific inflammatory pathways associated with subsets of CRS have been developed and evaluated. Early data evaluating these biologic treatments suggest a potential role in treating a subset of CRS with refractory, poorly controlled disease. Additional studies are necessary to identify which patients would benefit most from biologic therapies and to assess the cost of these therapies compared with the benefit they provide. This review describes the pathophysiology of CRS and summarizes both established and novel biologic pharmacologic treatments. PMID- 28853060 TI - Metabolic liver function in humans measured by 2-18F-fluoro-2-deoxy-D-galactose PET/CT-reproducibility and clinical potential. AB - BACKGROUND: PET/CT with the radioactively labelled galactose analogue 2-18F fluoro-2-deoxy-D-galactose (18F-FDGal) can be used to quantify the hepatic metabolic function and visualise regional metabolic heterogeneity. We determined the day-to-day variation in humans with and without liver disease. Furthermore, we examined whether the standardised uptake value (SUV) of 18F-FDGal from static scans can substitute the hepatic systemic clearance of 18F-FDGal (K met, mL blood/min/mL liver tissue/) quantified from dynamic scans as measure of metabolic function. Four patients with cirrhosis and six healthy subjects underwent two 18F FDGal PET/CT scans within a median interval of 15 days for determination of day to-day variation. The correlation between K met and SUV was examined using scan data and measured arterial blood concentrations of 18F-FDGal (blood samples) from 14 subjects from previous studies. Regional and whole-liver values of K met and SUV along with total metabolic liver volume and total metabolic liver function (total SUV, average SUV multiplied by total metabolic liver volume) were calculated. RESULTS: No significant day-to-day differences were found for K met or SUV. SUV had higher intraclass correlation coefficients than K met (0.92-0.97 vs. 0.49-0.78). The relationship between K met and SUV was linear. Total metabolic liver volume had non-significant day-to-day variation (median difference 50 mL liver tissue; P = 0.6). Mean total SUV in healthy subjects was 23,840 (95% CI, 21,609; 26,070), significantly higher than in the patients (P < 0.001). CONCLUSIONS: The reproducibility of 18F-FDGal PET/CT was good and SUV can substitute K met for quantification of hepatic metabolic function. Total SUV of 18F-FDGal is a promising tool for quantification of metabolic liver function in pre-treatment evaluation of individual patients. PMID- 28853061 TI - Counting does not improve the accuracy of long time productions. AB - It is common to use counting strategies to produce time intervals accurately. Does counting improve the accuracy (deviation of produced duration from veridical duration) and precision (variability of produced duration) of time productions in the range of seconds to minutes? In a series of experiments, we compared chronometric counting to intuitive timing (no counting) and to attentional control (simultaneously performing mental arithmetic). In a field experiment, participants had to produce time intervals of 60-s duration in a classroom setting. Relative to intuitive timing, counting did not improve the accuracy (absolute error) of time productions but led to overproduction of duration (larger constant error). In four laboratory experiments, we tested the effects of counting on time production of 10-, 30-, 45-, 60-, and 90-s intervals. Consistently, counting did not improve the accuracy of time production. The relative overproduction due to counting was replicated for long intervals (60 and 90 s) but disappeared at shorter intervals. However, across all intervals tested, counting had positive effects on the precision of time production. As expected, mental arithmetic impaired accuracy and precision and led to overproduction of duration, indicating that participants followed instructions. Based on the experimental data, the overproduction of longer intervals due to counting can neither be explained in terms of attentional processes nor by means of a word length effect when counting multisyllabic numbers or when participants switch their pace of counting from mono- to multisyllables. PMID- 28853062 TI - Adjusting health spending for the presence of comorbidities: an application to United States national inpatient data. AB - BACKGROUND: One of the major challenges in estimating health care spending spent on each cause of illness is allocating spending for a health care event to a single cause of illness in the presence of comorbidities. Comorbidities, the secondary diagnoses, are common across many causes of illness and often correlate with worse health outcomes and more expensive health care. In this study, we propose a method for measuring the average spending for each cause of illness with and without comorbidities. METHODS: Our strategy for measuring cause of illness-specific spending and adjusting for the presence of comorbidities uses a regression-based framework to estimate excess spending due to comorbidities. We consider multiple causes simultaneously, allowing causes of illness to appear as either a primary diagnosis or a comorbidity. Our adjustment method distributes excess spending away from primary diagnoses (outflows), exaggerated due to the presence of comorbidities, and allocates that spending towards causes of illness that appear as comorbidities (inflows). We apply this framework for spending adjustment to the National Inpatient Survey data in the United States for years 1996-2012 to generate comorbidity-adjusted health care spending estimates for 154 causes of illness by age and sex. RESULTS: The primary diagnoses with the greatest number of comorbidities in the NIS dataset were acute renal failure, septicemia, and endocarditis. Hypertension, diabetes, and ischemic heart disease were the most common comorbidities across all age groups. After adjusting for comorbidities, chronic kidney diseases, atrial fibrillation and flutter, and chronic obstructive pulmonary disease increased by 74.1%, 40.9%, and 21.0%, respectively, while pancreatitis, lower respiratory infections, and septicemia decreased by 21.3%, 17.2%, and 16.0%. For many diseases, comorbidity adjustments had varying effects on spending for different age groups. CONCLUSIONS: Our methodology takes a unified approach to account for excess spending caused by the presence of comorbidities. Adjusting for comorbidities provides a substantially altered, more accurate estimate of the spending attributed to specific cause of illness. Making these adjustments supports improved resource tracking, accountability, and planning for future resource allocation. PMID- 28853063 TI - Free Immunoglobulin Light Chains as Criteria of Extracorporeal Hemocorrection in Patients with Monoclonal Gammopathies. AB - Elimination of free immunoglobulin light chains with the use of EMic2 selective filters was carried out in 12 patients with monoclonal gammopathies and high production of free immunoglobulin light chains. We showed that extracorporeal detoxification for direct removal of excessive free immunoglobulin light chains from the circulation is advisable for these patients, irrespective of the presence and severity of renal insufficiency. Rapid reduction or elimination of free light chains of immunoglobulins in the course of selective extracorporeal elimination helps to prevent the development of irreversible renal failure and to perform adequate antitumor therapy. PMID- 28853064 TI - Receptor Activator of Nuclear Transcription Factor NF-kappaB (RANK), Its Ligand RANKL, and Natural Inhibitor of RANKL Osteoprotegerin (OPG) in the Blood Serum of Patients with Primary Bone Tumors. AB - The content of components of the RANK/RANKL/OPG system, the key regulator of homeostasis in the bone tissue, in blood serum samples from 199 patients with primary bone neoplasms and 131 practically healthy volunteers was measured by ELISA. Borderline giantcell tumor of the bone with high osteoclastogenic and osteolytic activity is characterized by an increase in the level of all components of this system and highest ratio of sRANKL/OPG in the blood serum. Study indexes in patients with various benign neoplasms and tumor-like bone lesions were lower than in patients with giant-cell tumor. The patients with malignant bone tumors could be divided into 2 subgroups with opposite indexes of the RANK/RANKL/OPG system. The patients with osteosarcoma and Ewing sarcoma had a low level of sRANK, but a high level of sRANKL. The patients with chondrosarcoma and chordoma had a high level of sRANK, but a low level of sRANKL. PMID- 28853065 TI - Target Cell Glycosylation Determines the Biodistribution of Plant Lectin Viscumin. AB - We studied the possibility of using viscumin lectin (MLI) for targeted delivery of antitumor drugs. Affinity of MLI for more than 600 oligosaccharide structures was determined and the glycosylation profiles of cell surface in various mouse tissues were analyzed. It was found that biodistribution of MLI was determined by not only expression of oligosaccharides specifically recognized by the lectin in tissue cells, but also by the structure of glycan in general. PMID- 28853066 TI - Phenotypical Characteristics of Chemically Induced Mammary Tumor. AB - The histological and immunohistochemical type of chemically induced (injection of N-methyl-N-nitrosourea into the mammary gland) breast tumor was studied in Wistar females. The tumor induced by N-methyl-N-nitrosourea was moderately differentiated adenocarcinoma with infiltrative growth lacking estrogen-alpha and human epidermal growth factor receptors, and expressing progesterone receptors; tumor cells were characterized by high proliferative activity. This variant of chemically induced breast tumor corresponds to human breast cancer luminal type B. PMID- 28853067 TI - Changes in the Activity of Proteasomes and Calpains in Metastases of Human Lung Cancer and Breast Cancer. AB - In patients with breast cancer and lung cancer, chymotrypsin-like and caspase like activities of proteasomes and total activity of calpains in the primary tumor nodes and lymphogenic metastasis are elevated in comparison with the corresponding normal tissues. The development of lymphogenic metastases of breast cancer and lung cancer was associated with opposite change in caspase-like activity of proteasomes. These results can be useful for the development of methods for evaluation of aggressiveness of breast and lung cancer. PMID- 28853068 TI - Immunohistochemical Study of the Expression of Vascular Endothelial Growth Factor Receptor-2 (KDR/Flk-1) during Myocardial Infarction. AB - Immunohistochemical study showed that vascular endothelial growth factor receptor 2 (KDR/Flk-1) is expressed in the cytoplasm of viable cardiomyocytes, mononuclear cells of the granulation tissue, and smooth muscle cells of intramural arteries at all terms of postinfarction reparative regeneration. Cardiomyocytes were highly heterogeneous by the intensity of staining. This feature was typical of cardiomyocytes in the ischemic area (no staining), as well as within various muscle bundles and one muscle bundle. KDR/Flk-1 expression was revealed in mononuclear cells of the necrotic area (macrophages and fibroblast cells). The distribution of KDR/Flk-1 remained practically unchanged with lengthening of the postinfarction period (more than 7 days). The increase in the heterogeneity of cardiomyocyte staining under these conditions illustrates variations in the intensity of cytoprotective processes during ischemia. KDR/Flk-1 expression in smooth muscle cells of intramural arteries was shown to increase in a later period of observations. PMID- 28853069 TI - Peculiarities in Interaction of Independent Components of Resting-State fMRI Signal in Patients with Mild Depressions. AB - Some aspects of resting-state fMRI signal can be the key markers of depression. fMRI was recoded over 4 min in evidently healthy persons (N=21) and in patients with mild depression (N=21). The data were separated into the independent spatial components, and the strength of their association with established brain networks was analyzed. The patients with mild depression were characterized with greater correlations between the components representing the ventral and dorsal subdivisions of default mode network (DMN), whereas correlations between the components relating to cerebellum and to the left hemisphere language system were less pronounced. The data revealed a significant role of DMN in the development of affective abnormalities and importance of its functional state as a probable marker of mild depression. PMID- 28853070 TI - Activation of Microglyocytes in the Anterior Horns of Rat Spinal Cord after Administration of Bacterial Lipopolysaccharide. AB - We studied the reaction of the microglia of the anterior horns of the rat spinal cord to intraperitoneal administration of bacterial LPS. Immunohistochemical analysis showed that acute systemic inflammation leads to activation of more than half of microglial cells as soon as in 24 h after LPS injection, while the total number of microglial cells does not change significantly. It was hypothesized that activated microglial cells are involved in the reorganization of synaptic connections, but do not have a neurotoxic effect. PMID- 28853071 TI - Patterns of Cell-Matrix Interactions during Formation the Distraction Bone Regenerates. AB - Multiple-day distraction regenerate contains a number of foci or zones merging into one another with different structural organization of the fibrocellular basis that reflects successive stages of reparative regeneration. At the moment of the last traction, the central part of the regenerate represents a zone of fibrogenesis (growth zone), which is common for the proximal and distal parts of the distraction regenerate. The other zones are paired and symmetrical: zones of angiogenesis, fibrous osteogenesis (primary), and osteogenesis (secondary). The latter include subzones of resorption, secondary osteogenesis, and functional remodeling. PMID- 28853072 TI - Immunohistochemical Parameters of Musashi-1 in Nodular and Diffuse Adenomyosis. AB - Comparative immunohistochemical analysis of the expression of somatic stem cells marker Musashi-1 in the endometrium was performed during various phases of menstrual cycle and in patients with nodular and diffuse adenomyosis. The expression of Musashi-1 reflecting proliferative potential of epithelial and stromal cells was quantitatively analyzed by the optical density in the nuclei and cytoplasm of epithelial and stromal cells of the eutopic endometrium and adenomyosis foci. In the eutopic endometrium, the immunohistochemical reaction was more intensive during proliferation phase in comparison with secretion phase. Enhanced expression of Musashi-1 was observed in adenomyosis foci in comparison with endometrial cells. The most intensive staining was found in nodular adenomyosis, especially in epithelial cells during the secretion phase. These data attest to the role of somatic stem cells in the development and progression of various forms of adenomyosis. PMID- 28853073 TI - Human Umbilical Cord Mesenchymal Stromal Cells Support Viability of Umbilical Cord Blood Hematopoietic Stem Cells but not the "Stemness" of Their Progeny in Co Culture. AB - Cell-cell interactions and the ability of mesenchymal stromal cells to support the expansion of hematopoietic progenitor cells were studied in co-culture of human umbilical cord tissue-derived mesenchymal stromal cells and nucleated umbilical cord blood cells. It was found that hematopoietic stem cells from the umbilical cord blood are capable to adhere to mesenchymal stromal cells and proliferate during 3-4 weeks in co-culture. However, despite the formation of hematopoietic foci and accumulation of CD34+ and CD133+ cells in the adherent cell fraction, the ability of newly generated blood cells to form colonies in semi-solid culture medium was appreciably reduced. These findings suggest that human umbilical cord tissue-derived mesenchymal stromal cells display a weak capability to support the "stemness" of hematopoietic stem cell progeny despite long-term maintenance of their viability and proliferation. PMID- 28853074 TI - The Influence of Proinflammatory Factors on the Neuroprotective Efficiency of Multipotent Mesenchymal Stromal Cells in Traumatic Brain Injury. AB - We studied the neuroprotective potential of multipotent mesenchymal stromal cells in traumatic brain injury and the effect of inflammatory preconditioning on neuroprotective properties of stem cells under in vitro conditions. To this end, the effects of cell incubation with LPS or their co-culturing with leukocytes on production of cytokines IL-1alpha, IL-6, TNFalpha, and MMP-2 and MMP-9 by these cells were evaluated. Culturing under conditions simulating inflammation increased the production of all these factors by multipotent mesenchymal stromal cells. However, acquisition of the inflammatory phenotype by stromal cells did not reduce their therapeutic effectiveness in traumatic brain injury. Moreover, in some variants of inflammatory preconditioning, multipotent mesenchymal stromal cells exhibited more pronounced neuroprotective properties reducing the volume of brain lesion and promoting recovery of neurological functions after traumatic brain injury. PMID- 28853075 TI - Assessment of Erythroid and Granulocytic Hematopoietic Lineages in Patients with Non-Small-Cell Lung Carcinoma. AB - The toxic effects of combined cisplatin/docetaxel therapy cycles on erythroid and granulocytic hematopoietic lineages as well as their intercycle recovery were examined in patients with stage III-IV non-small-cell lung carcinoma. Responsiveness of the blood system to this therapy remained at a high level. Combined therapy pronouncedly activated the key elements of the erythroid and granulocytic hematopoietic lineages leading to accumulation of immature and mature myelokaryocytes in the bone marrow, enlargement of the medullary pool of mature neutrophils, and increase in the count of medullary erythroid and granulocytic precursor cells under conditions of their accelerated maturation. PMID- 28853076 TI - Plasma Level of hsa-miR-619-5p microRNA Is Associated with Prostatic Cancer Dissemination beyond the Capsule. AB - Profiles of circulating microRNA in the plasma of patients with prostate cancer with pathomorphological stages pT2, pT3, and pT4 are analyzed. The level of circulating microRNA hsa-miR-619-5p is elevated in patients with extracapsular spreading of the tumor, increasing significantly from stage pT2 to stage pT4. PMID- 28853077 TI - Modification of the Method of Receiving of Insertion Mutants with the EZ::TN5 System. AB - We demonstrated the possibility of obtaining insertion mutants by a modified technique using EZ::TN5 system during culturing of the recipient strain on a dense nutrient medium and exclusion of the centrifugation stage. The frequency of transposon mutants of E. coli 10979/EZ::TN5 was 2*10-6. Genetically modified strains were characterized by kanamycin resistance, inability to L-malate assimilation, changes in the expression of individual proteins of protein mass spectra (5096.3, 6252.9, and 9067.7 Da), and the presence of fragments in genomic DNA amplified by specific forward and reverse primers that were homologous to Tn5 transposon insertion sites. The modified procedure for obtaining insertion mutants by using EZ::TN5 system was not inferior by the efficiency to the standard procedure, but shortens experiment duration, simplifies it, and reduces the risks related to working with group 2 pathogenicity microorganisms. PMID- 28853078 TI - 3111T/C Clock Gene Polymorphism in Women with Insomnia. AB - Comparative analysis of the frequency distributions of genotypes and alleles of 3111T/C Clock gene polymorphism was carried out in climacteric Caucasian women with and without insomnia. Genotype TT is more incident in women with insomnia (55.5% vs. 42.6% in the control). Allele T predominated in the control and study group and its frequency is higher in women with insomnia. The OR for the risk of insomnia realization is 1.78 (95%CI 1.16-2.75). No association between genotypes and complaints of patients with insomnia is detected. PMID- 28853079 TI - Specific Localization of Missense Mutations in the VHL Gene in Clear Cell Renal Cell Carcinoma. AB - Missense mutations in the VHL gene during sporadic clear cell renal cell carcinoma were studied to evaluate their localization in relation to functionally important motifs of the VHL protein. Somatic mutations were identified in 124 of 307 samples. All missense mutations in the alpha-domain were localized in the binding site for elongin C. Substitutions in the beta-domain (77%) were found in the HIF-binding site. Five missense mutations were absent in these sites, which illustrates their role in VHL protein formation or suppressor function of other protein cofactors. Mutation c.392A->T (p.N131I) was identified for the first time. Our results hold much promise to estimate the boundaries of functionally important sites in the VHL suppressor gene and contribute to the interpretation of a pathogenic role of mutations in direct DNA diagnostics. PMID- 28853080 TI - Selective Cytotoxicity of Manganese Nanoparticles against Human Glioblastoma Cells. AB - Toxicity of different types of manganese nanoparticles against glioblastoma U 87MG and U-251 cells and normal human cells was studied using MTT test. The selectivity of the toxic effect of nanoparticles was evaluated as the ratio of 50% cytotoxic concentration (SS50) for human embryos fibroblasts (FECh-15) to their SS50 for tumor cells. Five of 6 samples of tested nanoparticles demonstrated selective toxic effect in vitro. Manganese oxide nanoparticles were characterized by maximum selectivity (SS50 6.9 nM and 2.1 nM for U-87MG and U-251 cells, respectively): selectivity index for glioblastoma U-87MG and U-251 cells was 29 and 95.2, respectively. Manganese oxide nanoparticles used for MRI detection of gliomas can be used for designing an oncolytic agent for the treatment of glial tumors in humans. PMID- 28853081 TI - Expression of Signal Molecules in Culture of Human Endothelial Cells in Atherosclerosis and Restenosis. AB - We compared the expression of signal molecules in the culture of human endothelial cells under normal conditions and in atherosclerosis and restenosis. Expression of connexin-37 and sirtuin-1 in atherosclerosis and restenosis surpassed the normal by 2 and 5 times, respectively, and expression of endothelin 1 3-fold surpassed the normal. In restenosis, changes in the expression connexin 37 and endothelin-1 became more pronounced in comparison with atherosclerosis. Connexin-37 and endothelin-1 can serve as predictive markers for prognosis of post-stenting complications in patients with atherosclerosis. PMID- 28853082 TI - Reprogramming of Human Retinal Pigment Epithelial Cells under the Effect of bFGF In Vitro. AB - We studied the effect of bFGF on human retinal pigment epithelial cells in vitro In ARPE-19 cells, enhanced expression of KLF4 mRNA and reduced expression of PAX6, MITF, and OTX2 mRNA specific for retinal pigment epithelium were observed after bFGF application. The expression of KLF4 mRNA peaked in 72 h after bFGF application and then sharply decreased, which was accompanied by a 3-fold increase in TUBB3 mRNA expression (neuronal marker). Immunocytochemical analysis showed that in the presence of bFGF, some cells retained epithelial properties and showed positive staining for connexin-43, while others had long axon-like processes and demonstrated positive staining for betaIII-tubulin, which attests to their neuronal transdifferentiation. Despite the prevalence of the epithelial properties, ARPE-19 cells under the influence of bFGF can show proneuronal properties. PMID- 28853083 TI - The level of Hydrogen Peroxide in HeLa Cells in an Ozonated Medium. AB - We studied the role of hydrogen peroxide in the response of tumor cells to treatment with ozonated culture medium. Changes of the level of hydrogen peroxide in tumor cells incubated in ozonated medium were detected by using fluorescence microscopy and genetically-encoded sensor HyPer2. Modifications of fluorescent properties of the sensor reflecting accumulation of hydrogen peroxide in the cell cytoplasm were detected within 70 min from the start of exposure. The concentration of hydrogen peroxide continued to increase until 375 min. The revealed changes support the involvement of hydrogen peroxide in the cell response to ozone treatment. PMID- 28853084 TI - Gene-Gene Interactions of Apolipoprotein Gene Polymorphic Variants in Adolescents with Essential Arterial Hypertension and Dyslipidemia. AB - Using MDR bioinformatic analysis we studied gene-gene interactions between apolipoprotein genes in adolescents with essential arterial hypertension and dyslipidemia against the background of essential arterial hypertension. Optimal models of gene-gene interactions were formed. The six-locus model was the most significant: (ApoA1(+83T), ApoA1(-75A), ApoB(Del), ApoC3(S2), ApoE(epsilon2), ApoE(epsilon4). The maximum synergism in both adolescent groups were shown for allele variants ApoA1(-75A), ApoB(Del), and ApoE(epsilon4). The maximum contribution to gene-gene interactions entropy was made by allelic polymorphisms ApoA1(-75A) and ApoE(epsilon4) and (in the comorbid pathology group) for ApoE(epsilon4)+ApoB(Del). PMID- 28853085 TI - Isolation of Induced Pluripotent Cells from Stromal Liver Cells of Patients with Alcoholic Cirrhosis. AB - Stromal liver cells obtained from liver biopsy specimens of a patient with alcoholic cirrhosis can proliferate for a long time in culture passing more than 30 passages. In the course of culturing from early to late passages, acceleration of cell proliferation, decrease of the expression of some markers, and loss of hepatogenic differentiation potential were observed. On passage 30, induced pluripotent stem cells were obtained from these cells and comparative analysis of adipogenic and hepatic differentiation potencies of these cells and original liver stromal cells was performed. Induced pluripotent stem cells differentiated into both directions more efficiently and more rapidly than initial cells. Under conditions of hepatic differentiation, liver stromal cells started to express markers of definitive endoderm, but not markers of immature/mature hepatocytes, whereas induced pluripotent stem cells consistently expressed markers of definitive endoderm, immature/mature hepatocytes. PMID- 28853086 TI - Proliferation of Peripheral Blood Lymphocytes and Mesenchymal Stromal Cells Derived from Wharton's Jelly in Mixed and Membrane-Separated Cultures. AB - We studied the effect of mesenchymal stromal cells on proliferation of CFSE stained T cells in mixed and membrane-separated (Transwell) cultures and in 3D culture of mesenchymal stromal cells from Wharton's jelly. The interaction of mesenchymal stromal cells with mitogen-activated peripheral blood lymphocytes from an allogeneic donor was followed by suppression of T-cell proliferation in a wide range of cell proportions. Culturing in the Transwell system showed the absence of suppression assessed by the fraction of proliferating cells and by the cell cycle analysis. In 3D cultures, contact interaction of mesenchymal stromal cells and lymphocytes was demonstrated that led to accumulation of G2/M phase lymphocytes and G0/G1 phase mesenchymal stromal cells. The suppressive effect of mesenchymal stromal cells from Wharton's jelly is mediated by two mechanisms. The effects are realized within 6 days, which suggests that the therapeutic effects of mesenchymal stromal cells persist until their complete elimination from the body. PMID- 28853087 TI - Tripeptides Restore the Number of Neuronal Spines under Conditions of In Vitro Modeled Alzheimer's Disease. AB - In primary culture of mouse hippocampal neurons, peptide EDR (200 ng/ml) under conditions of amyloid synaptotoxicity (a model of Alzheimer's disease) increased the number of mushroom spines by 71% and returned this parameter to the normal level. Under the same conditions, tripeptide KED (200 ng/ml) increased the number of mushroom spines in hippocampal neurons by 20%. Tripeptide EDR can be recommended for further experimental study as a candidate neuroprotective agent for prevention and treatment of Alzheimer's disease. PMID- 28853088 TI - Possibility of Aggravation of Tissue Sclerosis after Injection of Multipotent Mesenchymal Stromal Cells Near the Forming Cicatrix in the Experiment. AB - The peculiarities of tissue sclerosis after injection of autologous bone marrow multipotent mesenchymal stromal cells transfected with GFP gene and stained with Vybrant CM-Dil cell membrane dye were studied by light microscopy with luminescence. The surgical intervention consisting in ligation of the great vein was followed by tissue sclerotic transformation caused by direct damage and chronic inflammation caused by the presence of slowly resorbed ligature. Injection of stromal cells after this intervention led to formation of more extensive scar. This can attest to the possibility of stromal cells differentiation into connective tissue cells, fibroblasts, and stimulation of proliferation and collagen synthesis by host fibroblasts. A decrease in the volume of dense fibrous connective tissue due to scar reorganization at latter terms cannot not excluded. PMID- 28853089 TI - Role of JAK1, JAK2, and JAK3 in Functional Stimulation of Mesenchymal Precursor Cells by Alkaloid Songorine. AB - We studied the role of some JAK in the effect of diterpene alkaloid songorine on realization of the growth potential of mesenchymal precursor cells. The participation of JAK1, JAK2, and JAK3 in stimulation of proliferation of the precursor cells was demonstrated. Specific inhibitors of these JAK reduced the yield of fibroblast CFU and the rate of their division. Inhibition of JAK2 against the background of songorine treatment increased the rate of precursor differentiation. PMID- 28853090 TI - Effects of Miramistin and Phosprenil on Microbial Biofilms. AB - Effects of Miramistin and Phosprenil on biofilms of S. pyogenes, S. aureus, E. coli, L. acidophilus, and L. plantarum were studied. Significant differences in the effects of these substances on mature biofilms of microorganisms and the process of their formation were observed. Miramistin had significant inhibiting effects on the forming of biofilms and on the formed biofilms of all studied microorganisms. Treatment with Miramistin inhibited biofilm formation by 2-3 times compared to the control. This effect was found already after using of Miramistin in the low doses (3.12 MUg/ml). Inhibition of the growth of a formed biofilm was observed only after treatment with Miramistin in the high doses (25 50 MUg/ml). Phosprenil in the high doses (15-30 mg/ml) inhibited the forming of biofilms, especially the biofilms of S. pyogenes and L. plantarum (by 3-4.5 times). Treatment of formed biofilms with the agent in doses of 6.0 and 0.6 mg/ml was associated with pronounced stimulation of its growth in S. pyogenes, S. aureus, and L. acidophilus. PMID- 28853091 TI - Biodistribution of Viscumin after Subcutaneous Injection to Mice and In Vitro Modeling of Endoplasmic Reticulum Stress. AB - Viscumin (mistletoe lectin I, MLI) in concentrations of 10-11-10-7 M causes endoplasmic reticulum stress and triggers unfolded protein response, a modulator of antitumor immunity, in target cells. PMID- 28853092 TI - Involvement of Semaphorin (Sema4D) in T-Dependent Activation of B Cells. AB - The involvement of endogenous semaphorin (Sema4D) into the key stage of T dependent differentiation of B cells, formation of plasmoblasts, was demonstrated in vitro in T/B cell co-culture under conditions of polyclonal activation of T cells. The effect of semaphorin was not associated with activation of high affinity Sema4D receptor plexin B1, but involves lowaffinity receptor CD72. These data indicate that Sema4D-dependent signal regulates not only the initial stage of B-cell activation, proliferative response to the antigen, but also further differentiation of B cells into plasma cells. PMID- 28853093 TI - Effect of Pectin Gel Particles on Endotoxemia Induced by Restraint Stress in Mice. AB - We studied the effect of pectin gel particles on endotoxemia in mice induced by restraint stress. It was shown that the concentration of LPS in mouse blood increased during restraint stress, which was associated with memory impairment. Pectin gel particles prevented the development of stress-induced endotoxemia and memory impairment in mice. PMID- 28853094 TI - Effect of Prenatal and Postnatal Exposure to Low Doses of DDT on Catecholamine Secretion in Rats in Different Period of Ontogeny. AB - We studied the effects of prenatal and postnatal exposure to low doses of DDT on secretion of basic catecholamines epinephrine and norepinephrine in pubertal and adult rats. It was found that the endocrine-disrupting chemical under study led to a progressive decrease in the content of epinephrine and especially norepinephrine in systemic circulation, which indicated their disturbed secretion by the adrenal medulla and sympathetic nervous system cells. In animals exposed to low doses of DDT in both pre- and postnatal periods, the decrease in catecholamine secretion after puberty was less pronounced than in animals exposed only during the postnatal period, which can indicate the development of compensatory processes. PMID- 28853095 TI - Study of Endothelial Protective Activity of Phenol-Derived Thrombin and Arginase 2 Inhibitors KUD-259 and KUD-974. AB - We performed correction of endothelial dysfunction with phenol derivatives KUD 259 and KUD-974 containing heteroatomic and heterocyclic structures. Pharmacological activity of KUD-259 and KUD-974 surpassed that of L-norvaline, a non-selective arginase inhibitor. PMID- 28853096 TI - Induced Aneugenic Effects in Mouse Oocytes In Vivo. AB - Aneugenic effects of the chemicals with antitumor activity were studied in mouse oocytes in vivo by cytogenetic analysis. In control mice, no oocytes with numerical chromosome aberrations were found. Colchicine (0.2-4 mg/kg), paclitaxel (2.5-7.5 mg/kg), and etoposide (10-60 mg/kg) produced a significant dose dependent aneugenic effects (induction of up to 25% aneuploid oocytes) and increased the yield of oocytes arrested in the meiotic MI stage and with premature separation of sister chromatid. Paclitaxel induced up to 20% polyploid chromosomes. Doxorubicin (2.5 mg/kg), melphalan (10 mg/kg), and cisplatin (5-10 mg/kg) exhibited weak aneugenic activity (induction of up to 5% aneuploid oocytes). Cyclophosphamide (10-80 mg/kg) had minor effect on the studied parameters. Methotrexate (25-200 mg/kg) exhibited no aneugenic activity, but significantly increased the level of polyploid cells. The observed aneugenic effects included hypo- and hyperploidy in various proportions or hypoploidy, but no solely hyperhaploidy. PMID- 28853097 TI - Application of Tetrameric Recombinant Human Butyrylcholinesterase as a Biopharmaceutical for Amelioration of Symptoms of Acute Organophosphate Poisoning. AB - We present a procedure for optimizing the expression of recombinant tetrameric butyrylcholinesterase that enables large-scale production with the yield >30 mg/liter (>90 mg/roller bottle). Intravenous injection of the preparation significantly increased survival and decreased the severity of symptoms of poisoning with paraoxon, an organophosphorus toxin. PMID- 28853098 TI - p38 MARK is Involved in Regulation of Epigenetic Mechanisms of Food Aversion Learning. AB - Consolidation of the conditioned food aversion response in Helix lucorum was associated with induction of histone H3 acetylation and methylation. We hypothesized that not only activatory, but also inhibitory p38 MARK-mediated pathways are involved in these processes. To assess the contribution of p38 MAPK to epigenetic processes, we studied the effect p38 MAPK inhibitor SB203580 on acetylation of histone H3 during training of Helix lucorum. Administration of SB203580 decreased learning-induced enhancement of histone H3 acetylation in the CNS of Helix lucorum, which was accompanied by long-term memory impairment. Thus, p38 MAPK is involved in the regulation of epigenetic mechanisms of long-term memory. PMID- 28853099 TI - Effects of Chronic Exposure to Ultrasound of Alternating Frequencies on the Levels of Aggression and Anxiety in CBA and BALB/c mice. AB - Stress-induced changes in the behavior of CBA and BALB/c mice were studied after 3-week ultrasound exposure (22-45 kHz). The mice of both lines demonstrated increased aggression in the resident-intruder and social interest paradigms and reduced number of social interactions in the social interest test. Elevated plus maze test showed a decrease in anxiety level in CBA mice and an increase in this parameter in BALB/c mice. Chronic exposure to ultrasound induced an increase in aggression level in mice of both lines that was not directly related to changes in anxiety level. PMID- 28853100 TI - Effect of Selank on Functional State of Rat Hepatocytes under Conditions of Restraint Stress. AB - We studied the effect of Selank administered intraperitoneally in doses of 100, 300, and 1000 MUg/kg to male Wistar rats 15 min prior to restraint stress on the content of aminotransferases and total protein concentration in blood serum and intensity of free radical oxidation in the liver. Under conditions of acute restraint stress, Selank in doses of 100 and 300 MUg/kg decreased catalase and superoxide dismutase activities and malondialdehyde concentration and increased total antioxidant activity in the liver homogenate. Administration of Selank in a dose of 1000 MUg/kg reduced the content of aminotransferases in blood serum, decreased superoxide dismutase activity in the liver, and increased total antioxidant activity. Under conditions of chronic stress, Selank in all doses produced similar effects: reduced superoxide dismutase activity and malondialdehyde concentration in the liver tissue and AST activity in the serum. The other parameters remained unchanged. PMID- 28853101 TI - The Effect of Folate and Folate Plus Zinc Supplementation on Endocrine Parameters and Sperm Characteristics in Sub-Fertile Men: A Systematic Review and Meta Analysis. AB - PURPOSE: To evaluate the effect of folate and folate plus zinc supplementation on endocrine parameters and sperm characteristics in sub fertile men. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis. Electronic databases of Medline, Scopus , Google scholar and Persian databases (SID, Iran medex, Magiran, Medlib, Iran doc) were searched from 1966 to December 2016 using a set of relevant keywords including "folate or folic acid AND (infertility, infertile, sterility)".All available randomized controlled trials (RCTs), conducted on a sample of sub fertile men with semen analyses, who took oral folic acid or folate plus zinc, were included. Data collected included endocrine parameters and sperm characteristics. Statistical analyses were done by Comprehensive Meta-analysis Version 2. RESULTS: In total, seven studies were included. Six studies had sufficient data for meta-analysis. "Sperm concentration was statistically higher in men supplemented with folate than with placebo (P < .001)". However, folate supplementation alone did not seem to be more effective than the placebo on the morphology (P = .056) and motility of the sperms (P = .652). Folate plus zinc supplementation did not show any statistically different effect on serum testosterone (P = .86), inhibin B (P = .84), FSH (P = .054), and sperm motility (P = .169) as compared to the placebo. Yet, folate plus zinc showed statistically higher effect on the sperm concentration (P < .001), morphology (P < .001), and serum folate level (P < .001) as compared to placebo. CONCLUSION: Folate plus zinc supplementation has a positive effect on sperm characteristics in sub fertile men. However, these results should be interpreted with caution due to the important heterogeneity of the studies included in this meta-analysis. Further trials are still needed to confirm the current findings. PMID- 28853102 TI - An Up-to-date Meta-analysis of Coffee Consumption and Risk of Prostate Cancer. AB - PURPOSE: Results of the association between coffee consumption (CC) and the risk of prostate cancer (PC) are still controversy. Based on published relevant studies, we conducted an up-to-date meta-analysis to investigatethis issue. MATERIALS AND METHODS: The protocol used in this article is in accordance with the PRISMA checklist. Eligible studies were screened and retrieved by using PUBMED and EMBASE as well as manual review of references up to July 2016. We calculated the pooled relative risk (RR) with 95% confidence interval (CI) with random effect models. The dose-response relationship was assessed by generalized least-squares trend estimation analysis. RESULTS: Totally, we included twenty eight studies (14 case-control and 14 cohort studies) on CC with 42399 PC patients for the final meta-analysis. No significant association of PC was found for high versus non/lowestCC, with RR = 1.07 (95% CI: 0.96-1.18). In subgroup meta-analysis by study design, there were no significant positive associations between CC and PC in case-control studies (RR = 1.19, 95% CI: 1.05-1.35) or in the cohort studies (RR = 0.97, 95% CI: 0.84-1.12). Additionally, RR with different quality of studies were respectively 1.15 (95% CI: 0.99-1.34) and 1.28 (95% CI: 1.03-1.58) for high and low quality in the case-control studies; while were respectively 1.02 (95% CI: 0.88-1.20) and 0.81 (95% CI: 0.57-1.14) in the cohort studies. When analyzed by geographic area, we found no association between CC and PC, with RR = 1.06 (95% CI: 0.86-1.30) for 10 studies from Europe, 1.06 (95% CI: 0.94-1.20) for 13 studies conducted in America; 1.12 (95% CI: 0.70-1.79) for 4 studiesfrom Asia. However, in subgroup analysis by subtype of the disease, there was a significant negative (beneficial) association in the localized PC (RR = 0.90, 95% CI: 0.84-0.97), but not for the advanced PC (RR = 0.90, 95%CI: 0.70 1.16). Additionally, RR = 0.99 (95% CI: 0.98-0.99) for an increment of one cup per day of coffee intake shows significant association with the localized PC. CONCLUSION: Our results indicate that CC has no harmful effect on PC. On the contrary, it has an effect on reducing the localized PC risk. Further prospective cohort studies of high quality are required to clarify this relationship. PMID- 28853103 TI - Platelet-to-Lymphocyte Ratio: A New Factor for Predicting Systemic Inflammatory Response Syndrome after Percutaneous Nephrolithotomy. AB - PURPOSE: The first purpose of this study was to reveal factors affecting the postoperative development of systemic inflammatory response syndrome (SIRS) in patients undergoing standard percutaneous nephrolithotomy (PNL) for renal stones. The second purpose was to determine the role of the preoperative platelet-to lymphocyte ratio (PLR) and the neutrophil-to-lymphocyte ratio (NLR) in the prediction of SIRS.Matarials and Methods: In total, 192 patients who had undergone conventional PNL for renal stones from 2013 to 2015 were included in the study. SIRS developed postoperatively in 41 (21.3%) patients. The patients were divided into SIRS and non-SIRS groups, and the effects of the PLR, NLR, and other demographic and operative data were investigated to predict the development of SIRS. Variables significant in the univariate analysis were evaluated using a multiple logistic regression model to determine the independent risk factors for developing SIRS after PNL. RESULTS: Univariate analysis revealed significant differences in the preoperative PLR (P < .001), preoperative NLR (P = .018), number of access sites (P < .001), mean renal parenchymal thickness (P = .02), operative time (P < .001), decrease in hemoglobin (P = .016), length of hospital stay (P < .001), stone-free status (P = .023), and complication rate between the two groups of patients. However, multivariate analysis showed that only the PLR and the number of access sites were independent factors affecting the development of SIRS. When the PLR cut-off value was 114.1, development of SIRS was predicted with 80.4% sensitivity and 60.2% specificity. CONCLUSION: The preoperative PLR is an effective and inexpensive biomarker with which to predict SIRS after PNL. In particular, we recommend close monitoring of patients with a PLR of >114.1 because of the possibledevelopment of serious complications. PMID- 28853104 TI - The Association of Household Food Insecurity and the Risk of Calcium Oxalate Stones. AB - PURPOSE: Food insecurity has been defined as 'limited or uncertain availability of nutritionally adequate and safe foods', which associated with adverse health consequences in human. Another alarming condition, which is related to several comorbidities is kidney stone. This study aimed to determine the association of household food insecurity and developing kidney stones (calcium oxalate) in adults referred to medical centers of Babol. MATERIALS AND METHODS: This case control study included 200 participants 18-65 years of ages (100 cases, 100 controls). An 18-items food insecurity questionnaire (USDA), a valid and reliable 147-item food frequency questionnaire (FFQ) and demographic characteristics were obtained via interviewing. RESULTS: Sixty eight percent of cases and 40% of controls were food insecure, respectively. Food insecurity was significantly associated with the risk of kidney stone (P < .05). Furthermore, body mass index (BMI) and family history of kidney stone were significantly associated with the risk of kidney stones (P < .05). CONCLUSION: Food insecurity and BMI were significantly associated with the kidney stone, which shows the importance of availability of nutritionally adequate and safe foods in prevention of the kidney stone. PMID- 28853105 TI - Different Approaches to Detect "Nanobacteria" in Patients with Kidney Stones: an Infectious Cause or a Subset of Life? AB - PURPOSE: This research focused on the detection of nanobacteria in kidney stones of 30 Iranian patients without adding fetal bovine serum (FBS) to the culture media. MATERIALS AND METHODS: Nanobacteria were isolated from a nephro ureterolithiasis extract of the urinary tract and kidney of patients and were cultured in the laboratory. The growth of nanobacteria was monitored using a spectrophotometer, and with inverted microscopy technique, their crystallization was analyzed after two days. The images from atomic force microscopy (AFM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM) indicated the morphology and demonstrated the size of the cultured nanobacteria which is between 60 and 160 nm. Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) were used to study the chemical composition, surface functional groups and crystal structure of the igloo-like nanobacteria shell. FTIR spectra in theregion of 1000 to 1200 cm-1 and the XRD peaks provided evidence that the main components of the nanobacteria shell were apatite-based compounds. RESULTS: Nanobacteria infected all the 27 patients with apatite kidney stone, and none of the three patients who had uric acid kidney stone were infected as confirmed by the cultivation of the stones samples. The results showed that nanobacteria might play a fundamental role in the formation of apatite-based kidney stones. CONCLUSION: The biomineralization ability of nanobacteria may lead to calcification of the soft tissues, which in turn may result in other diseases. It is also suggested that nanobacteria may be a factor in calcification-related diseases and disorders with poorly characterized etiologies. This research with its different approaches, clarified significant doubts that nanobacteria act as contaminant, warranting continued investigation of its role in other diseases. PMID- 28853107 TI - A Comparative Study on the Clinical Efficacy of Two Different Disposable Circumcision Suture Devices in Adult Males. AB - PURPOSE: We evaluated the safety and efficacy of two different kinds of disposable circumcision suture devices in adult men. MATERIALS AND METHODS: Adult male patients (n = 179; mean age: 23.7 years) with redundant prepuce and/or phimosis were included in a clinical trial from July 2015 to August 2016. Patients were divided into 2 groups: group A using the Langhe disposable circumcision suture device (n = 89), and group B using the Daming disposable circumcision suture device (n = 94). RESULTS: Intraoperative and postoperative bleeding were more serious in the group A of disposable circumcision suture device compared with the group B of disposable circumcision suture device (4.21 +/- 1.31 ml) versus (2.56 +/- 1.45 ml). Patients in the group B of disposable circumcision suture device had a longer swelling time (group A versus group B: 11.7 +/- 0.9 days versus 14.5 +/- 1.4 days), the postoperative pain score in the 7 days after surgery (group A versus group B: 2.9 +/- 0.9 versus 3.8 +/- 1.5), and higher postoperative infection rate (group A versus group B: 4.7% versus 13.8%), the differences were statistically significant (p < 0.05). CONCLUSION: postoperative complications of the two kinds of disposable circumcision suture devices are different. We should pay attention to the risk of postoperative bleeding when the patients use the Langhe disposable circumcision suture device, while the patients who use the Langhe disposable circumcision suture device will have a longer healing time, and postoperative pain and the risk of infection cannot be ignored after the surgery. PMID- 28853106 TI - Prognostic Role of Lymphovascular Invasion in Patients with Urothelial Carcinoma of the Upper Urinary Tract. AB - PURPOSE: To evaluate the impact of lymphovascular invasion on the prognosis of patients treated for upper urinary tract urothelial carcinomas. MATERIALS AND METHODS: Clinical records of 49 patients treated surgically at our institute for upper urinary tract urothelial carcinomas were reviewed retrospectively. LVI was defined as the presence of cancer cells within an endotheluim-lined space without underlying muscular walls. Actuarial survival curves were analysed by Kaplan Meier method. Multivariate analysis was performed using Cox's proportional hazard model. RESULTS: Median follow-up was 32 months. Lymphovascular invasion was present in 26 (53%) patients. Lymphovascular invasion was associated with higher pathological tumor stage (pT) and higher tumor grade. The disease-free and overall survival rates of the patients with lymphovascular invasion were significantly worse than those of the patients without lymphovascular invasion (p < 0.001 and p = 0.027 respectively). Multivariate analysis revealed that lymphovascular invasion as well as tumor grade and pathological tumor stage were significant prognosticfactors for disease-free and overall survival. CONCLUSION: The presence of lymphovascular invasion was a strong predictor of a poor outcome for UTUC. This finding could help identify patients at greater risk for disease recurrence who would benefit from close follow-up and early adjuvant therapy. PMID- 28853108 TI - Differences in Poly(ADP-ribose) Polymerase1- (PARP1-) and Proliferative Cell Nuclear Antigen (PCNA) Immunoreactivity in Patients Who Experienced Successful and Unsuccessful Microdissection Testicular Sperm Extraction Procedures. AB - PURPOSE: The aim of this study is to evaluate expression of deoxyribonucleic acid (DNA) synthesis and repair markers in testicular tissues of azoospermic men in whom sperm retrieval could and could not be achieved as a result of microdissection testicular sperm extraction (micro-TESE) procedure. MATERIALS AND METHODS: In this prospective cohort study, testicular tissues were retrieved from 60 Non-obstructive Azoospermia (NOA) patients who underwent micro-TESE procedure. These patients were divided into twogroups: micro-TESE positive group, which included 30 NOA patients from whom sperm could be extracted via micro-TESE procedure; and micro-TESE negative group, which included 30 NOA patients from whom sperm retrieval could not be achieved via micro-TESE procedure. Expression and distribution patterns of poly(ADP-ribose) polymerase-1 (PARP-1) and proliferative cell nuclear antigen (PCNA) in extracted tissues were assessedby immunohistochemical staining to reveal any differences in DNA synthesis and repair between the two groups. RESULTS: Micro-TESE positive group exhibited significantly stronger immunoreactivity for both PCNA and PARP-1 (P = .001 and P = .001 respectively). The results of this study reveal that both DNA synthesis and repair markers were expressed strongly in patients who experienced successful micro-TESE procedure. CONCLUSION: Although further studies are needed to support these findings, PARP-1 and PCNA expression in testicular tissues of NOA patients could be promising predictive factors for micro-TESE procedure success. PMID- 28853109 TI - Impact of Four Week Swimming Exercise with Alpha-Tocopherol Supplementation on Fertility Potential in Healthy Rats. AB - PURPOSE: The aim of this study was to evaluate the effect of 4 week intensive swimming exercise and alpha-tocopherol supplementation on testicular oxidative stress and spermatogenesis in rats. MATERIALS AND METHODS: 40 male rats were randomly assigned to Control (C), Sham (S), Exercise (E) and Exercise + supplement (ES) groups. Exercise training performed for 4 weeks (1session/day, 6days/week). Each session included 180 minutes of swimming. In ES group, alpha ocopherol was injected at a dose of 50 mg/kg/day. 48 hours after last training session, all rats were killed and gonads of them were removed from their body for histological and biochemical assays. All statistical analysis was performed by SPSS 16. P values less than 0.05 were considered as statistically significant. RESULTS: Total testicular antioxidant capacity increased significantly in E (P = .003) and ES groups (P = .001) whereas there was no significant difference between C and E group in testicle Malondialdehyde (a lipid peroxidation marker) level (P = .999) and spermatogenesis quality (P = .381). Testicle Malondialdehyde level decreased (P = .009) and spermatogenesis quality was improved significantly in ES group (P = .001). CONCLUSION: Alpha-tocopherol supplementation is effective in order to improve spermatogenesis process in athletes who exercise with high intensity. PMID- 28853110 TI - Retained Surgical Gauze Presenting With Gross Hematuria: A Case Report. AB - Gossipyboma is a mass which is made around a cotton sponge or abdominal compress retained in a patient during surgery accidentally. Patients manifest with either acute or chronic symptoms due to complications. Here in wereported an 89-year-old man case of transvesical migration of gossipyboma who presented with gross hematuria with a history of transvesical prostatectomy 6 years ago. Patient underwent exploratory laparotomy with repairing of the bladder and peritoneum. He had no complications during surgery and was subsequently discharged. PMID- 28853111 TI - Staged Bilateral Laparoscopic Adrenalectomy for Infantile ACTH-independent Cushing's Syndrome (Bilateral Micronodular Non-pigmented Adrenal Hyperplasia): A Case Report. AB - ACTH-independent Cushing's syndrome is an uncommon disorder in children. While laparoscopic adrenalectomy is well-established in adults, it is rarely used in infants and is associated with some concerns. A seven-month infant was referred to our hospital due to progressive signs and symptoms of Cushing's syndrome. Laboratory data confirmed ACTH-independent hypercortisolism. No history of exogenous corticosteroid contact was observed. The patient underwent left transperitoneal laparoscopic adrenalectomy when she was 7 months old, nevertheless,complete response was not seen. The patient underwent right laparoscopic adrenalectomy (contra-lateral adrenal gland) when she was 20 months old. The signs and symptoms of Cushing's syndrome began to resolve and serum and urine cortisol levels became normal 3 months after the second surgery. laparoscopic adrenalectomy is safe and feasible in infants, and in this case, relieved patient of the symptoms and saved her life. PMID- 28853113 TI - A retrospective analysis: do bacterial culture and sensitivity data support empiric use of piperacillin-tazobactam and antipseudomonal fluoroquinolones in hospitalized patients? PMID- 28853112 TI - Outcomes of a military regional multispecialty synchronous telehealth platform and the importance of the dedicated patient presenter. AB - : Implementing a successful multispecialty synchronous telehealth program requires identifying and overcoming numerous barriers. One key aspect of synchronous telehealth involves the telehealth presenter; however, the impact that a dedicated patient presenter has supporting routine multispecialty synchronous telehealth is unknown. METHODS: We conducted a retrospective review of telehealth encounters conducted from a single regional medical center over a two-year period to 12 outlying health clinics which provided one of 3 levels of patient presenter support: category 1 locations had a dedicated telehealth registered nurse, category 2 locations had a nondedicated registered nurse or licensed vocational nurse, and category 3 locations were supported by an Army medic (military occupational specialty 68W). RESULTS: A total of 4,032 telehealth encounters occurred from January 2014 to December 2015 involving 26 distinct specialties located within a single regional medical center and 12 outlying health clinics which supported 60,232 beneficiaries. The 3 category 1 locations (3/12, 25%) supported the most telehealth encounters per month compared to either category 2 or category 3 locations (P<.0001). Category 1 and category 2 locations averaged a 239% and 122% year-to-year growth, respectively. Category 3 locations averaged a year-to-year decline of 11.7%. COMMENT: This is the first study of which we are aware that has compared different patient presenter levels and evaluated its effect on telehealth activity. Regional medical centers initiating a multispecialty synchronous telehealth program should strongly consider hiring, educating, and placing dedicated presenters at patient originating sites. PMID- 28853116 TI - Resilience-enhancing relationships: what we can learn from those with a history of adverse childhood experiences. PMID- 28853114 TI - Low Prevalence of carbapenem-resistant Enterobacteriaceae among wounded military personnel. AB - Multidrug-resistant organisms (MDROs) are a global health problem that affect both civilian and military populations. Among wounded warriors, MDROs further complicate the care of trauma-related infections, resulting in extended duration of hospitalization, as well as increased morbidity and mortality. During the wars in Iraq and Afghanistan, extended spectrum beta-lactamase-producing Enterobacteriaceae were frequently isolated from wounded warriors. The potential emergence of difficult-to-treat carbapenem-resistant Enterobacteriaceae represented a serious challenge for clinicians. We examined carbapenem-resistant Enterobacteriaceae prevalence among wounded military personnel over a 6-year period (2009-2015). Among 4090 Enterobacteriaceae isolates collected, 16 (0.4%) were carbapenem-resistant, of which the majority was Enterobacter aerogenes (44%) followed by Klebsiella pneumoniae (37%), and Escherichia coli (19%). Five isolates (31%) collected from 2 patients were carbapenemase-producers with one associated with an infection. All 5 carbapenemase-producing isolates were resistant to all tested carbapenems and each carried one carbapenemase gene (4 with blaKPC-3 and 1 with blaNDM-1). Overall, although a large number of Enterobacteriaceae isolates were collected, only a small proportion was carbapenem-resistant and data indicate a lack of a cluster. Due to these limited numbers, it is difficult to make any conclusions regarding the association between carbapenem resistance, antibiotic exposure, and clinical outcomes. PMID- 28853115 TI - Effects of mandatory screening labs in directing the disposition of the apparently healthy psychiatric patient in the emergency department. AB - OBJECTIVE: To determine whether mandatory psychiatric admission laboratory tests yield results that change the disposition of a patient with primary psychiatric complaint from admission to a psychiatric service to admission to a medical service. METHODS: This was a single center retrospective cohort chart review study approved by the facility Institutional Review Board in which we used a records database maintained by the emergency department's social workers to access the records of every patient that presented to our emergency department with a psychiatric chief complaint between the dates of December 1, 2011, and December 1, 2013. We focused on those that were admitted to either a psychiatric service or a medical service after a thorough evaluation by the department of social work and an emergency provider. We applied our inclusion and exclusion criteria and reviewed the results of the mandatory psychiatric laboratory tests (complete blood count, comprehensive metabolic panel, thyroid stimulating hormone, acetaminophen, aspirin, blood alcohol level, urinalysis, urine pregnancy test, urine drug screen) required for admission. Our independent variables were the compulsory psychiatric admission laboratory tests and our dependent variable was the admission to a medical service. RESULTS: Of 5,606 laboratory tests that were ordered and produced results for the 682 patients enrolled in our study, 51 results were considered clinically significant abnormal results, or results requiring treatment prior to psychiatric service admission, by the 2 reviewing emergency physicians. Only one of 682 psychiatric patients received a final disposition to a medical service based upon abnormal laboratory studies. That patient presented without any medical complaints but a chief complaint of "suicidal ideation," and was found to have diabetic ketoacidosis. Based on our data, the probability that an abnormal laboratory test will result in a change in disposition is 1/682=0.1% (95% CI: 0.0% to 0.9%). CONCLUSION: Patients presenting to the emergency department with a psychiatric chief complaint and no physical complaints, abnormal vital signs, or abnormal physical exam findings have less than 1% probability that an abnormal laboratory study will change their disposition from a psychiatric admission to a medical admission. PMID- 28853117 TI - A randomized comparison between neurostimulation and ultrasound-guided lateral femoral cutaneous nerve block. AB - BACKGROUND: This prospective, randomized trial compared neurostimulation (NS) and ultrasound (US) guided lateral femoral cutaneous nerve (LFCN) block. We hypothesized that US would result in a shorter total anesthesia-related time (sum of performance and onset times). METHODS: Twenty-one volunteers were enrolled. The right lower limb was randomized to an NS- or US-guided LFCN block. The alternate technique was employed for the left lower limb. With NS, paresthesias were sought in the lateral thigh at a stimulatory threshold of 0.6 mA (pulse width=0.3 ms; frequency=2 Hz) or lower. With US, local anesthetic was deposited under the inguinal ligament, ventral to the iliopsoas muscle. In both groups, 5 mL of lidocaine 2% were used to anesthetize the nerve. During the procedure of the block, the performance time and number of needle passes were recorded. Subsequently, a blinded observer assessed sensory block in the lateral thigh every minute until 20 minutes. Success was defined as loss of pinprick sensation at a point midway between the anterior superior iliac spine and the lateral knee line. The blinded observer also assessed the areas of sensory block in the anterior, medial, lateral, and posterior aspects of the thigh and mapped this distribution onto a corresponding grid. RESULTS: Both modalities provided comparable success rates (76.2%-95.2%), performance times (162.1 to 231.3 seconds), onset times (300.0 to 307.5 seconds) and total anesthesia related-times (480.1 to 554.0 seconds). However US required fewer needle passes (3.2+/-2.9 vs 9.5+/-12.2; P=.009). There were no intergroup differences in terms of the distribution of the anesthetized cutaneous areas. However considerable variability was encountered between individuals and between the 2 sides of a same subject. The most common areas of sensory loss included the central lateral two eighths anteriorly and the central antero-inferior three-eighths laterally. CONCLUSION: Ultrasound guidance and NS provide similar success rates and total anesthesia-related times for LFCN block. The territory of the LFCN displays wide inter- and intra-individual variability. PMID- 28853118 TI - Occlusion training: pilot study for postoperative lower extremity rehabilitation following primary total knee arthroplasty. AB - With continued emphasis on the value of healthcare, factors such as quality of life and patient reported outcomes are critical in evaluating high-demand procedures such as knee replacement surgery. Equally important to the surgery itself is maximizing the effectiveness and efficiency of the treatment, both preoperatively and postoperatively, which can have a significant effect the final outcome. Technical outcomes of total knee replacement are generally considered excellent; however, many patients continue to have postoperative pain, functional limitations, and low treatment satisfaction. The recovery process can be difficult and is often prolonged in older patient populations. Blood flow restriction (BFR) training is a resistance exercise performed with a venous tourniquet that stimulates local changes in muscle at low resistance. Herein we report on 3 patients who participated in BFR exercises as an adjunct to their normal physical therapy following total knee arthroplasty. PMID- 28853119 TI - Martial arts-based high intensity interval training as a component of warfighter rehabilitation and tactical athlete fitness. PMID- 28853120 TI - Martial arts-based high intensity interval training in the rehabilitation of combat amputees. PMID- 28853121 TI - Characteristics of US combat veterans (2001-2011) who remain on active duty after upper extremity amputations. AB - OBJECTIVES: Return to duty following traumatic amputations has been extensively studied in those with lower extremity amputation. As upper extremity amputations occur less frequently, the issue of return to duty for those with upper extremity amputations has received relatively little research. The purpose of this study was to determine the rate at which service members remain on active duty at least one year after having sustained traumatic upper extremity amputations during Operation Iraqi Freedom, Operation Enduring Freedom, and other overseas contingency operations of the Global War on Terrorism. DESIGN: Retrospective. SETTING: Military, Academic Level 1 trauma center. PATIENTS: One hundred eighteen patients who sustained combat-related upper extremity amputations between October 2001 and December 2011. INTERVENTION: Data was obtained from the medical record for these 118 patients. MAIN OUTCOME MEASUREMENTS: Percentage of service member remaining on active duty one year following an upper extremity amputation, and evaluation of demographic and injury related factors associated with retention. RESULTS: The overall rate for the upper extremity amputees studied at one year from injury who remained on active duty was 47%. Officers were more likely to remain on active duty than their enlisted counterparts (P=.021) and patients who sustained burns were also more likely to remain on active duty than patients with similar amputation types without concomitant burn injuries (P=.039). CONCLUSIONS: The rate of service members with traumatic upper extremity amputations who were still on active duty status 1-year postinjury was 47%. The presence of burns and rank were significant factors when examining retention on active duty. Further study on war casualties who sustain upper-extremity traumatic amputations with and without burns is required to optimize outcomes in this population. PMID- 28853122 TI - Temporospatial angiogenesis-associated gene expression profiles in rat ischemic skin flaps. AB - OBJECTIVES: Emerging therapies designed to improve soft tissue flap survival include the use of angiogenic factors. However, endogenous expression patterns for these factors have not been characterized. The purpose of this study was to identify spatial and temporal variations in expression patterns of angiogenesis associated genes in ischemic rat skin flaps. STUDY DESIGN: This is an observational animal study characterizing spatial and temporal angiogenesis associated gene expression patterns in rat ischemic skin flaps. METHODS: Dorsal skin flaps were created on 15 male Sprague-Dawley rats. The flap tissue was harvested and sectioned at 1, 3, or 7 days postsurgery. Total RNA was isolated, amplified, labeled with biotin, and hybridized to microarrays containing probes for 113 angiogenesis-associated genes. Microarray analysis revealed unique spatial and temporal patterns with statistically significant gene modulation over the length of the flap (P<.05). RESULTS: The molecular analysis performed in this study correlates with the hemodynamic profile previously published. Expression patterns associated with blood flow were markedly different from patterns associated with stasis and avascularity. CONCLUSIONS: To our knowledge, this study is the first to characterize endogenous spatial and temporal angiogenesis associated gene expression in rat ischemic skin flaps. Further characterization of expression patterns may allow clinicians to differentiate ischemic tissue that may be rescued via pharmacological or surgical intervention from tissue destined to succumb. Additionally, comparison of the expression profiles observed in this study with profiles generated from pharmacologically treated rats may suggest mechanisms for enhanced healing. PMID- 28853123 TI - Resistance to abrasion of extrinsic porcelain esthetic characterization techniques. AB - STATEMENT OF PROBLEM: A novel esthetic porcelain characterization technique involves mixing an appropriate amount of ceramic colorants with clear, low-fusing porcelain (LFP), applying the mixture on the external surfaces, and firing the combined components onto the surface of restorations in a porcelain oven. This method may provide better esthetic qualities and toothbrush abrasion resistance compared to the conventional techniques of applying color-corrective porcelain colorants alone, or applying a clear glaze layer over the colorants. However, there is no scientific literature to support this claim. PURPOSE: This research evaluated toothbrush abrasion resistance of a novel porcelain esthetic characterization technique by subjecting specimens to various durations of simulated toothbrush abrasion. The results were compared to those obtained using the conventional characterization techniques of colorant application only or colorant followed by placement of a clear over-glaze. METHOD AND MATERIALS: Four experimental groups, all of which were a leucite reinforced ceramic of E TC1 (Vita A1) shade, were prepared and fired in a porcelain oven according to the manufacturer's instructions. Group S (stain only) was characterized by application of surface colorants to provide a definitive shade of Vita A3.5. Group GS (glaze over stain) was characterized by application of a layer of glaze over the existing colorant layer as used for Group S. Group SL (stain+LFP) was characterized by application of a mixture of colorants and clear low-fusing add on porcelain to provide a definitive shade of Vita A3.5. Group C (Control) was used as a control without any surface characterization. The 4 groups were subjected to mechanical toothbrushing using a 1:1 water-to-toothpaste solution for a simulated duration of 32 years of clinical use. The amount of wear was measured at time intervals simulating every 4 years of toothbrushing. These parameters were evaluated longitudinally for all groups as well as compared at similar time points among groups. RESULTS: In this study, the novel external characterization technique (stain+LFP: Group SL) did not significantly enhance the wear resistance against toothbrush abrasion. Instead, the average wear of the applied extrinsic porcelain was 2 to 3 times more than Group S (stain only) and Group GS (glaze over stain). Application of a glaze layer over the colorants (Group GS) showed a significant improvement on wear resistance. Despite its superior physical properties, the leucite reinforced ceramic core (Group C) showed 2 to 4 times more wear when compared with other test groups. CONCLUSION: A conventional external esthetic characterization technique of applying a glaze layer over the colorants (Group GS) significantly enhanced the surface wear resistance to toothbrush abrasion when compared with other techniques involving application of colorants only (Group S) or mixture of colorant and LFP (Group SL). The underlying core ceramic had significantly less wear resistance compared with all externally characterized specimens. The novel esthetic characterization technique showed more wear and less color stability, and is thus not advocated as the "best" method for surface characterization. CLINICAL IMPLICATIONS: Application of a glaze layer provides a more wear-resistant surface from toothbrush abrasion when adjusting or extrinsically characterizing leucite reinforced ceramic restorations. Without the glaze layer, the restoration is subjected to a 2 to 4 times faster rate and amount of wear leading to possible shade mismatch. PMID- 28853124 TI - Effect of smokeless tobacco on surface roughness of dental restorations. AB - CLINICAL RELEVANCE: Surface alterations of dental restorations can result in increased plaque biofilm. This leads to increased risk of premature restoration failure. Smokeless tobacco, in common use by some US military personnel, represents a potential source for surface alteration. If smokeless tobacco causes an untoward effect, selection of a more resistant restorative material could increase restoration longevity, thus minimizing lost work time and costs associated with replacement of failed restorations. PURPOSE: Comparatively assess the effect of smokeless tobacco/salivary substitute mixture on altering surface roughness of amalgam, composite resin, and resin modified glass ionomer (RMGI) restorations. MATERIALS AND METHODS: Sixty cubic restorations (3 groups of 20) were fabricated using a 4 mm by 3 mm Teflon mold. One examiner assessed the restorations at time points representing zero days, one day, one week, 2 weeks, one month, and 3 months. The data obtained were collected using a surface profilometer, measured in micrometers. Data were statistically analyzed using 2 way analysis of variance (ANOVA) test. A difference was significant if P< .05. RESULTS: Confidence levels with a 95% overall rating received a clinically acceptable classification. The 2-way ANOVA test detected significant differences between baseline, one day, one week, 2 weeks, one month, and 3-month data for surface roughness (P<.05). With respect to time and restoration type, results proved statistically significant with P<.0001. All restorations were statistically significant with respect to change in surface roughness with RMGIs showing the greatest surface roughness alteration. CONCLUSION: Smokeless tobacco mixed with a salivary substitute altered restoration surface roughness over time. Resin-modified glass isonomer restorations demonstrate the greatest alteration of surface roughness, with amalgam restorations showing the least. Amalgam remains the preferential restorative material in patients who use smokeless tobacco. PMID- 28853125 TI - Placement and replacement rates of amalgam and composite restorations on posterior teeth in a military population. AB - OBJECTIVE: Replacement rates of direct dental restorations have been reported to be 37% to 70%, occupying a large proportion of a general dentist's time. Variations in the rate of initial placement and replacement of direct dental restorations may be associated with material placed (amalgam or composite), age, caries risk of the patient, and other factors. The purpose of this research was to clarify where the majority of patient care time is spent as a restorative Army dentist regarding either the initial placement or replacement of failed restorations; and how the location, caries risk, and material used (amalgam or composite) affects replacement rates. METHODS: This retrospective cross-sectional study gathered data from 600 randomly selected military patient dental records. All paper records were reviewed and cross checked with the digital record and digital x-ray databases. Record review was limited to all direct dental restorations placed in the posterior dentition within the past 2 years (March 2011 to March 2013). Statistical analysis was accomplished using chi-square tests and logistic regression analyses. RESULTS: Of the 600 charts reviewed, 525 were male, 75 were female, with an average age of 26 years (SD=6), ranging from 17 to 54 years. A third of the patients were classified as high, moderate, and low caries risk, respectively. The total number of posterior direct dental restorations placed was 2,117. Initial restorations totaled 1,429 (67.5%), and replacement restorations placed totaled 688 (32.5%). Four hundred forty-one of the 688 direct dental restorations replaced were amalgam (64%), the 247 remaining direct restorations replaced were composite (36%). Mandibular first molar dental restorations were replaced the most often (23.1%) while mandibular first premolar restorations were replaced the least often (0.9%). Older patients were more likely to have replacement of an existing restoration. CONCLUSIONS: Military dentists spend about one-third (32.5%) of their time replacing existing direct dental restorations. The majority of direct dental restorations placed and replaced were amalgam. No significant difference was found between composite and amalgam restorations. Location was shown to be significant with first molars and second molar restorations failing with the highest frequency. There was no significant difference found between male and female patients. As patient's age increased, the number of replacement restorations also increased. PMID- 28853126 TI - Improving coding accuracy in an academic practice. AB - : Practice management has become an increasingly important component of graduate medical education. This applies to every practice environment; private, academic, and military. One of the most critical aspects of practice management is documentation and coding for physician services, as they directly affect the financial success of any practice. Our quality improvement project aimed to implement a new and innovative method for teaching billing and coding in a longitudinal fashion in a family medicine residency. We hypothesized that implementation of a new teaching strategy would increase coding accuracy rates among residents and faculty. METHODS: Design: single group, pretest-posttest. SETTING: military family medicine residency clinic. Study populations: 7 faculty physicians and 18 resident physicians participated as learners in the project. Educational intervention: monthly structured coding learning sessions in the academic curriculum that involved learner-presented cases, small group case review, and large group discussion. MAIN OUTCOME MEASURES: overall coding accuracy (compliance) percentage and coding accuracy per year group for the subjects that were able to participate longitudinally. Statistical tests used: average coding accuracy for population; paired t test to assess improvement between 2 intervention periods, both aggregate and by year group. RESULTS: Overall coding accuracy rates remained stable over the course of time regardless of the modality of the educational intervention. A paired t test was conducted to compare coding accuracy rates at baseline (mean (M)=26.4%, SD=10%) to accuracy rates after all educational interventions were complete (M=26.8%, SD=12%); t24= 0.127, P=.90. CONCLUSIONS: Didactic teaching and small group discussion sessions did not improve overall coding accuracy in a residency practice. Future interventions could focus on educating providers at the individual level. PMID- 28853127 TI - Winging of the scapula diagnosed as Parsonage-Turner syndrome: a case report. AB - A 24-year-old active duty female Soldier complained of right shoulder burning, stinging, electrical shock-like pain with radiation to the right hand after completing a ruck march. She also complained of swelling and feelings of her cold right hand. Examination showed a deficit in the deltoid, upper trapezius, supraspinatus, and also right winging of the scapula. She also exhibited weakness to right arm, weak right hand grip, and decreased sensation over the dorsal right hand. The right hand was also noticed to be colder to touch than the left one. She had tenderness to palpation over right paracervical muscles from C3 to C7. A previous magnetic resonance arthrogram of the right shoulder revealed no findings. The cervical magnetic resonance imagery showed mild disc protrusion at C5-C6 without spinal cord impingement. Based on the history and the physical findings, the patient was diagnosed with Parsonage-Turner syndrome. PMID- 28853128 TI - Eliminating hepatitis from the Eastern Mediterranean Region. PMID- 28853129 TI - Patients' attitudes and perceptions regarding research and their rights: a pilot survey study from the Middle East. AB - Ethical and regulatory oversight of research may be suboptimal in low- and middle income countries. To determine patients' attitudes and perceptions toward research participation and perceptions of their rights, we recruited 202 participants from hospitals in Egypt, Lebanon, Saudi Arabia and Sudan and asked them to complete a questionnaire assessing attitudes and perceptions. Around 20% believed that doctors sometimes perform research on patients without their knowledge and 35% believed that if participants withdrew from the research they would not receive good medical care. Over 85% believed that they should have rights regarding confidentiality of data, free medical care if injured during the research and asking questions. Almost half believed they have a right to withdraw without penalty and around 75% believed they could make complaints without fear of harm. Those who were illiterate or unemployed were less likely to appreciate their rights compared with their counterparts. PMID- 28853130 TI - Urbanization and noncommunicable disease (NCD) risk factors: WHO STEPwise Iranian NCD risk factors surveillance in 2011. AB - This study was conducted to examine the relationship between urbanization and risk factors of noncommunicable diseases (NCDs) according to the World Health Organization stepwise approach to surveillance of NCDs. This study is part of a NCD risk factor surveillance of 10 069 individuals in all provinces of the Islamic Republic of Iran, aged over 20 years, during 2011. By utilizing 2011 census data, urbanization levels were determined in all provinces and logistics regression was used to examine the relationship between urbanization and risk factors. Among males, urbanization had a positive correlation with low physical activity (OR=1.7; 95% CI: 1.42-2.09), low fruit and vegetable consumption (OR=1.8; 95% CI: 1.09-2.96), and high BMI (OR=1.4; 95% CI: 1.20-1.70). Among females there was a positive and significant correlation with low physical activity (OR=1.2; 95% CI: 1.08-1.49), low fruit and vegetable consumption (OR=1.22; 95% CI: 0.78-1.91) and high BMI (OR=1.3; 95% CI: 1.14-1.53). Thus, urbanization has a significant correlation with increases in NCD factors in the Islamic Republic of Iran. PMID- 28853131 TI - Implementation of a peer-mediated health education model in the United Arab Emirates: addressing risky behaviours among expatriate adolescents. AB - Tobacco use among young people is increasing in the United Arab Emirates, and the country is ranked 15th in the world for prevalence of type II diabetes. Expatriates comprise a majority of the population, making them an important subset to study. We aimed to test whether an educational intervention would be effective in this cultural setting. We designed 2 peer-to-peer health workshops: tobacco use and nutrition/physical activity. One workshop was randomly assigned to 18 classrooms in private schools in Abu Dhabi. Surveys were administered before and after the workshops to assess intervention effectiveness. The tobacco workshop significantly improved responses (P < 0.05). The nutrition and physical activity workshop resulted in decreased satisfaction with personal activity levels. This study provides evidence to support the national adoption of a peer to-peer health education model as an intervention for tobacco use but not for nutrition and physical activity choices. PMID- 28853132 TI - Prevalence of attention deficit hyperactivity disorder among school-aged children in Jordan. AB - The purpose of this study was to determine the prevalence of attention deficit hyperactivity disorder (ADHD) symptoms among school children in Jordan and the probable associated risk factors. This was a crosssectional descriptive study and simple random sampling was used to select 480 students, aged 6-12 years, from government primary schools in Mafraq City, Jordan. Data were collected using the modified Arabic version of the Attention Deficit Disorder Evaluation Scale (ADDES) school version and parental questionnaire. Prevalence rates within the inattentive, hyperactive-impulsive and combined subtypes were 10.83, 9.58 and 20.21%, respectively. Increased family size and being male were both associated with increased prevalence of ADHD symptoms. The study revealed that ADHD is common among Jordanian school children. The government should establish education programmes to increase awareness of ADHD. PMID- 28853133 TI - Prevalence and preventability of sentinel events in Saudi Arabia: analysis of reports from 2012 to 2015. AB - This study aimed to assess the pattern of sentinel events reported to Ministry of Health of Saudi Arabia from January 2012 to June 2015. Sentinel event reports were examined for patient characteristics, type of event, outcome, cause and preventability. There were 433 sentinel events: 58.2% were deaths, 14.8% were unexpected loss of a limb or a function, 7.4% major medication errors and 7.4% retained instruments or sponges. Among the reported events, 44% were associated with surgical interventions and most were classified as preventable (91.6%). Age 19-64 years was significantly associated with death as an outcome (P = 0.02). Non preventable sentinel events were significantly more likely among women than men (P = 0.01). Unavailability of policy and procedures and/ or failure to implement them (55%), and lack of proper communication (35%) and training (33%) were the main causes for the adverse events. Efforts should focus on enhancing the National Sentinel Events Reporting System, adopting criteria for effective reporting and ensuring availability and implementation of policies and procedures. PMID- 28853134 TI - Health-related quality of life of patients with asthma: a cross-sectional study in Semnan, Islamic Republic of Iran. AB - Asthma can profoundly affect the quality of life of individuals with the disease. There are limited data on the quality of life of people with asthma in the Islamic Republic of Iran. This cross-sectional study aimed to evaluate quality of life in adults with asthma in Semnan using the 36-item short form health survey (SF-36). The effect of sociodemographic characteristics on quality of life scores was examined. The study included a convenience sample of 385 outpatients with asthma attending a pulmonary clinic from June to December 2013. The mean physical and mental component scores were 58.8 (SD 18.3) and 57.3 (SD 17.0) respectively. The study sample had lower quality of life scores in all the fields than the reference population (P < 0.05). Patients with lower education, urban residents, widowed/divorced patients and manual workers had lower quality of life scores (P < 0.05). Efforts are needed to improve the quality of life of people with asthma in parallel with precise management plans. PMID- 28853135 TI - Epidemiological characteristics and trends in the incidence of animal bites in Maku County, Islamic Republic of Iran, 2003-2012. AB - This study examined the epidemiological characteristics and incidence over time of animal bites in Maku County. Data were obtained from health centre records of animal bites from 2003 to 2012. Information on demographic characteristics and bite-related factors were recorded. A total of 2232 people were bitten; the frequency of bites was highest among males (75.4%), rural residents (72.3%) and those < 20 years (47.3%). Most bites were to the legs and feet (65%) and dogs were responsible for 92% of bites. Over 25% of those bitten delayed seeking care for more than a day, particularly rural residents. The mean incidence was 250 per 100 000 population and there was a statistically significant increasing linear trend over the 10-year period. There is a need to raise public awareness, especially among rural residents, of the importance of early treatment. Given the increasing trend in animal bites, a health policy to tackle this problem is needed. PMID- 28853136 TI - Reprocessing practices for gastrointestinal endoscopes: a multicentre study in Egyptian university hospitals. AB - The aim of this study was to assess the practices of health care workers during gasterointestinal endoscope reprocessing, evaluate their knowledge about reprocessing, and verify their compliance with laboratory and microbiological tests in endoscopy units at Zagazig University and Fayoum University hospitals. All nursing staff on duty from 10 endoscopy units, with 16 flexible endoscopes, were included. Knowledge and practice were assessed by a questionnaire and a checklist. The mean knowledge score was 7.5 (SD 1.9), which was poor. Compliance was 90% for disinfection and 74% for endoscope processing after disinfection. Before reuse after cleaning, no organisms were detected in 5 endoscopes, while 8 colony forming units were found in 2. Pseudomonas aeruginosa was the most common organism isolated. Strict implementation of the reprocessing guidelines are needed, especially the pre-cleaning stage and leak testing. Repeating high level disinfection after storage and before use must be followed. PMID- 28853137 TI - Water Table Uncertainties due to Uncertainties in Structure and Properties of an Unconfined Aquifer. AB - We consider two sources of geology-related uncertainty in making predictions of the steady-state water table elevation for an unconfined aquifer. That is the uncertainty in the depth to base of the aquifer and in the hydraulic conductivity distribution within the aquifer. Stochastic approaches to hydrological modeling commonly use geostatistical techniques to account for hydraulic conductivity uncertainty within the aquifer. In the absence of well data allowing derivation of a relationship between geophysical and hydrological parameters, the use of geophysical data is often limited to constraining the structural boundaries. If we recover the base of an unconfined aquifer from an analysis of geophysical data, then the associated uncertainties are a consequence of the geophysical inversion process. In this study, we illustrate this by quantifying water table uncertainties for the unconfined aquifer formed by the paleochannel network around the Kintyre Uranium deposit in Western Australia. The focus of the Bayesian parametric bootstrap approach employed for the inversion of the available airborne electromagnetic data is the recovery of the base of the paleochannel network and the associated uncertainties. This allows us to then quantify the associated influences on the water table in a conceptualized groundwater usage scenario and compare the resulting uncertainties with uncertainties due to an uncertain hydraulic conductivity distribution within the aquifer. Our modeling shows that neither uncertainties in the depth to the base of the aquifer nor hydraulic conductivity uncertainties alone can capture the patterns of uncertainty in the water table that emerge when the two are combined. PMID- 28853138 TI - Eigenvalue significance testing for genetic association. AB - Genotype eigenvectors are widely used as covariates for control of spurious stratification in genetic association. Significance testing for the accompanying eigenvalues has typically been based on a standard Tracy-Widom limiting distribution for the largest eigenvalue, derived under white-noise assumptions. It is known that even modest local correlation among markers inflates the largest eigenvalues, even in the absence of true stratification. In addition, a few sample eigenvalues may be extreme, creating further complications in accurate testing. We explore several methods to identify appropriate null eigenvalue thresholds, while remaining sensitive to eigenvalues corresponding to population stratification. We introduce a novel block permutation approach, designed to produce an appropriate null eigenvalue distribution by eliminating long-range genomic correlation while preserving local correlation. We also propose a fast approach based on eigenvalue distribution modeling, using a simple fit criterion and the general Marcenko-Pastur equation under a simple discrete eigenvalue model. Block permutation and the model-based approach work well for pure simulations and for data resampled from the 1000 Genomes project. In contrast, we find that the standard approach of computing an "effective" number of markers does not perform well. The performance of the methods is also demonstrated for a motivating example from the International Cystic Fibrosis Consortium. PMID- 28853139 TI - Studying the human oral microbiome: challenges and the evolution of solutions. AB - Since the pioneering work of van Leeuwenhoek in 1684, subsequently built upon by other renowned microbiologists Robert Koch, Willoughby Miller and GV Black, oral microbiology has developed innovative techniques to study the oral microflora (now termed the 'oral microbiome'). The advent of molecular techniques such as DNA-DNA hybridization, polymerase chain reaction and DNA sequencing has created an array of opportunities to construct a comprehensive picture of the diversity and composition of the oral microbiome. Approximately 700 oral bacterial species have been identified, of which 50% have yet to be cultivated, and some of these are known only by their signature DNA sequences. The synergism of ever-evolving culture-based and state-of-the-art culture-independent molecular techniques has facilitated in-depth understanding of the dynamics, acquisition and transfer of oral bacteria, along with their role in oral and general health and disease. Further research is needed to not only analyse but also to make sense of the ever increasing volumes of data which these molecular techniques (especially high throughput DNA sequencing) are generating, as well as why particular bacteria are present and what they are 'actually doing' there. This review presents a comprehensive literature search of oral microbiology-related methods currently used to study the oral microbiome. PMID- 28853140 TI - Groundwater Modeling with Stakeholders: Finding the Complexity that Matters. PMID- 28853141 TI - Influence of tumor response and treatment schedule on the distribution of tumor recurrence in esophageal cancer patients treated with neoadjuvant chemoradiotherapy. AB - BACKGROUND AND OBJECTIVES: The impact of different neoadjuvant chemoradiotherapy (nCRT) schedules and pathologic complete response (pCR) on the distribution of recurrence is unclear in esophageal cancer (EC). We assessed the effect of pCR and nCRT schedule in EC. METHODS: Patients with T1N+/T2-4aN0-3/M0 EC treated in different centers, with either carboplatin/paclitaxel/41.4 Gy (CROSS: n = 134) or Cisplatin/5-fluorouracil/45-50.4 Gy (Cis/5FU: n = 88) followed by surgery were included. The effect of pCR on distribution and site-specific recurrence was determined for the CROSS group. After propensity score matching we compared the impact of both schedules (n = 63 each) on the recurrence pattern. RESULTS: Overall (P = 0.005) and disease-free survival (P = 0.002) were significantly longer after pCR (n = 24). The pattern of recurrence differed between pCR and non pCR group (P = 0.001) for locoregional (0 vs 7; 6.4%), distant (5; 20.8% vs 36; 32.7%), and combined local and distant (0 vs 21; 19.1%), respectively. After pCR, less local and distant recurrences were seen (P = 0.008). With equal median time to recurrence, the distribution of metastases only differed for lung metastases (P = 0.029), with 15 (23.8%) in the CROSS group versus 6 (9.5%) following Cis/5FU. CONCLUSIONS: Patients with pCR have less local and distant recurrence. The nCRT regime had a minor influence on the site-specific distribution of recurrence. PMID- 28853142 TI - 'Blowing the whistle': the ethical, professional and legal implications of raising concerns and self-regulation within dentistry. AB - 'Whistle-blowers' are a necessary part of any system; dentistry is no different. The role of whistle-blowers in dentistry has been enshrined in Australian law since 2010. Raising concerns has become a legal duty as well as an ethical and professional obligation. It is important that these different aspects of raising concerns are explored as each adds another layer of consideration to the issue. The health professional's duty to whistle-blow could be viewed as problematic; the observance of this duty is associated with being 'trapped between a rock and a hard place' where any decision to engage or not may have negative consequences. For the obligation of raising concerns to gain acceptability within the dental profession, the concept requires reframing as being necessary for the profession's continued success. The stigma of mandatory reporting needs to be removed to allow this essential process to occur. This article will discuss the ethical, professional and legal imperatives for the dental profession to engage with whistle-blowing and the likely challenges that are likely to be met in doing so. PMID- 28853143 TI - Description of Triplophysa luochengensis sp. nov. (Teleostei: Nemacheilidae) from a karst cave in Guangxi, China. AB - A new cave-dwelling fish Triplophysa luochengensis is described based on specimens collected from a karst cave in Guangxi Zhuang Autonomous Region, China, that is interconnected to the Hongshui River drainage. The species can be distinguished from its congeners by a combination of characters: eyes degenerated, anal fin with six branched rays, caudal fin with 16-17 branched rays, pectoral-fin length 72.4-95.8% of the distance between pectoral-fin origin and pelvic-fin origin, lateral head length 26.2-28.2% of standard length (LS ), eye diameter 7.5-8.6 of LS , body covered by sparse scales, lateral line complete and 7-8 pre-operculo-mandibular pores. Dark pigments irregularly present on dorsum of head, dorsum and flank. PMID- 28853144 TI - Prosthodontic management of maxillofacial cases: a case series. AB - Maxillofacial prosthetics is an important and recognized sub-discipline of prosthodontics that forms a key component of postgraduate training programmes. General dentists have a role to play in the management of maxillofacial defect patients even though treatment usually requires a multidisciplinary approach in an institutional environment. Maxillofacial prosthetic cases frequently present with complex histories but simple patient goals. The conservatively managed implant-retained auricular prosthesis, speech aid prosthesis and orbital prosthesis cases described in this report were completed in a postgraduate clinical residency program and highlight the intrinsic complexities, challenges and ultimately satisfaction related to cases of this nature. PMID- 28853145 TI - Effect of hydrocolloids on the physico-chemical and rheological properties of reconstituted sweetened yoghurt powder. AB - BACKGROUND: The consistency of sweetened yoghurt (misti dahi) is a desired characteristic which is attributed to the casein protein network formation during fermentation. Unfortunately, this property is lost in reconstituted sweetened yoghurt (RSY) due to the irreversible nature of protein denaturation during spray drying. Therefore, this study aimed to increase the consistency of RSY using different hydrocolloids. RESULTS: The effects addition of guar gum, pectin, kappa carrageenan and gelatin (0.1%w/v each) on the physico-chemical, microbial, rheological and sensory properties of RSY were investigated. RSY with 40% total solids demonstrated the rheological properties which are very similar to those of fresh sweetened yoghurt. RSY containing different hydrocolloids further increased the rheological properties. The dynamic rheological study revealed that the magnitude of storage modulus (G'), loss modulus (G"), and loss tangent (tan delta) were significantly influenced by the addition of hydrocolloids and gelatin exhibited highest dynamic moduli in RSY. However, kappa-carrageenan added RSY was preferred sensorially as the rheological properties were very close to gelatin added RSY. Addition of hydrocolloids significantly increased the starter bacteria count and pH and reduced water expulsion rate (P < 0.05). CONCLUSION: Addition of hydrocolloids can improve the rheological properties of reconstituted yoghurt. The study concluded that the addition of kappa-carrageenan showed better results in terms of rheological and sensory properties of RSY. (c) 2017 Society of Chemical Industry. PMID- 28853146 TI - Computer-based versus in-person interventions for preventing and reducing stress in workers. AB - BACKGROUND: Chronic exposure to stress has been linked to several negative physiological and psychological health outcomes. Among employees, stress and its associated effects can also result in productivity losses and higher healthcare costs. In-person (face-to-face) and computer-based (web- and mobile-based) stress management interventions have been shown to be effective in reducing stress in employees compared to no intervention. However, it is unclear if one form of intervention delivery is more effective than the other. It is conceivable that computer-based interventions are more accessible, convenient, and cost-effective. OBJECTIVES: To compare the effects of computer-based interventions versus in person interventions for preventing and reducing stress in workers. SEARCH METHODS: We searched CENTRAL, MEDLINE, PubMed, Embase, PsycINFO, NIOSHTIC, NIOSHTIC-2, HSELINE, CISDOC, and two trials registers up to February 2017. SELECTION CRITERIA: We included randomised controlled studies that compared the effectiveness of a computer-based stress management intervention (using any technique) with a face-to-face intervention that had the same content. We included studies that measured stress or burnout as an outcome, and used workers from any occupation as participants. DATA COLLECTION AND ANALYSIS: Three authors independently screened and selected 75 unique studies for full-text review from 3431 unique reports identified from the search. We excluded 73 studies based on full-text assessment. We included two studies. Two review authors independently extracted stress outcome data from the two included studies. We contacted study authors to gather additional data. We used standardised mean differences (SMDs) with 95% confidence intervals (CIs) to report study results. We did not perform meta-analyses due to variability in the primary outcome and considerable statistical heterogeneity. We used the GRADE approach to rate the quality of the evidence. MAIN RESULTS: Two studies met the inclusion criteria, including a total of 159 participants in the included arms of the studies (67 participants completed computer-based interventions; 92 participants completed in-person interventions). Workers were primarily white, Caucasian, middle-aged, and college educated. Both studies delivered education about stress, its causes, and strategies to reduce stress (e.g. relaxation or mindfulness) via a computer in the computer-based arm, and via small group sessions in the in-person arm. Both studies measured stress using different scales at short-term follow-up only (less than one month). Due to considerable heterogeneity in the results, we could not pool the data, and we analysed the results of the studies separately. The SMD of stress levels in the computer-based intervention group was 0.81 standard deviations higher (95% CI 0.21 to 1.41) than the in-person group in one study, and 0.35 standard deviations lower (95% CI -0.76 to 0.05) than the in-person group in another study. We judged both studies as having a high risk of bias. AUTHORS' CONCLUSIONS: We found very low-quality evidence with conflicting results, when comparing the effectiveness of computer-based stress management interventions with in-person stress management interventions in employees. We could include only two studies with small sample sizes. We have very little confidence in the effect estimates. It is very likely that future studies will change these conclusions. PMID- 28853147 TI - Neonicotinoid insecticides differently modulate acetycholine-induced currents on mammalian alpha7 nicotinic acetylcholine receptors. AB - BACKGROUND AND PURPOSE: Neonicotinoid insecticides are described as poor agonists of mammalian nicotinic ACh receptors. In this paper, we show that their effects on mammalian nicotinic receptors differ between compounds. EXPERIMENTAL APPROACH: Two-electrode voltage-clamp electrophysiology was used to characterize the pharmacology of three neonicotinoid insecticides on nicotinic alpha7 receptors expressed in Xenopus oocytes. Single and combined application of clothianidin, acetamiprid and thiamethoxam were tested. RESULTS: Two neonicotinoid insecticides, clothianidin and acetamiprid, were partial agonists of mammalian neuronal alpha7 nicotinic receptors, whereas another neonicotinoid insecticide, thiamethoxam, which is converted to clothianidin in insect and plant tissues, had no effect. Pretreatment with clothianidin and acetamiprid (10 MUM) ACh significantly enhanced the subsequent currents evoked by ACh (100 MUM ) whereas pretreatment with thiamethoxam (10 MUM) reduced ACh-induced current amplitudes.A combination of the three neonicotinoids decreased the ACh-evoked currents. CONCLUSIONS AND IMPLICATIONS: The present findings suggest that neonicotinoid insecticides differ markedly in their direct effects on mammalian alpha7 nicotinic ACh receptors and can also modulate ACh-induced currents. Furthermore, our data indicate a previously unknown modulation of mammalian alpha7 nicotinic receptors by a combination of clothianidin, acetamiprid and thiamethoxam. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 28853148 TI - Rumen microbial protein synthesis and nitrogen efficiency as affected by tanniferous and non-tanniferous forage legumes incubated individually or together in Rumen Simulation Technique. AB - BACKGROUND: A limited availability of microbial protein can impair productivity in ruminants. Ruminal nitrogen efficiency might be optimised by combining high quality forage legumes such as red clover (RC), which has unfavourably high ruminal protein degradability, with tanniferous legumes like sainfoin (SF) and birdsfoot trefoil (BT). Silages from SF and from BT cultivars [Bull (BB) and Polom (BP)] were incubated singly or in combination with RC using the Rumen Simulation Technique (n = 6). RESULTS: The tanniferous legumes, when compared to RC, changed the total short-chain fatty acid profile by increasing propionate proportions at the expense of butyrate. Silage from SF contained the most condensed tannins (CTs) (136 g CT kg-1 dry matter) and clearly differed in various traits from the BT and RC silages. The apparent nutrient degradability (small with SF), microbial protein synthesis, and calculated content of potentially utilisable crude protein (large with SF) indicated that SF had the greatest efficiency in ruminal protein synthesis. The effects of combining SF with RC were mostly linear. CONCLUSION: The potential of sainfoin to improve protein supply, demonstrated either individually or in combination with a high performance forage legume, indicates its potential usefulness in complementing protein-deficient ruminant diets and high-quality forages rich in rumen degradable protein. (c) 2017 Society of Chemical Industry. PMID- 28853149 TI - Assessing Methane in Shallow Groundwater in Unconventional Oil and Gas Play Areas, Eastern Kentucky. AB - The expanding use of horizontal drilling and hydraulic fracturing technology to produce oil and gas from tight rock formations has increased public concern about potential impacts on the environment, especially on shallow drinking water aquifers. In eastern Kentucky, horizontal drilling and hydraulic fracturing have been used to develop the Berea Sandstone and the Rogersville Shale. To assess baseline groundwater chemistry and evaluate methane detected in groundwater overlying the Berea and Rogersville plays, we sampled 51 water wells and analyzed the samples for concentrations of major cations and anions, metals, dissolved methane, and other light hydrocarbon gases. In addition, the stable carbon and hydrogen isotopic composition of methane (delta13 C-CH4 and delta2 H-CH4 ) was analyzed for samples with methane concentration exceeding 1 mg/L. Our study indicates that methane is a relatively common constituent in shallow groundwater in eastern Kentucky, where methane was detected in 78% of the sampled wells (40 of 51 wells) with 51% of wells (26 of 51 wells) exhibiting methane concentrations above 1 mg/L. The delta13 C-CH4 and delta2 H-CH4 ranged from -84.00/00 to 58.30/00 and from -246.50/00 to -146.00/00, respectively. Isotopic analysis indicated that dissolved methane was primarily microbial in origin formed through CO2 reduction pathway. Results from this study provide a first assessment of methane in the shallow aquifers in the Berea and Rogersville play areas and can be used as a reference to evaluate potential impacts of future horizontal drilling and hydraulic fracturing activities on groundwater quality in the region. PMID- 28853150 TI - Data-Driven Approach for Analyzing Hydrogeology and Groundwater Quality Across Multiple Scales. AB - Recent trends of assimilating water well records into statewide databases provide a new opportunity for evaluating spatial dynamics of groundwater quality and quantity. However, these datasets are scarcely rigorously analyzed to address larger scientific problems because they are of lower quality and massive. We develop an approach for utilizing well databases to analyze physical and geochemical aspects of groundwater systems, and apply it to a multiscale investigation of the sources and dynamics of chloride (Cl- ) in the near-surface groundwater of the Lower Peninsula of Michigan. Nearly 500,000 static water levels (SWLs) were critically evaluated, extracted, and analyzed to delineate long-term, average groundwater flow patterns using a nonstationary kriging technique at the basin-scale (i.e., across the entire peninsula). Two regions identified as major basin-scale discharge zones-the Michigan and Saginaw Lowlands were further analyzed with regional- and local-scale SWL models. Groundwater valleys ("discharge" zones) and mounds ("recharge" zones) were identified for all models, and the proportions of wells with elevated Cl- concentrations in each zone were calculated, visualized, and compared. Concentrations in discharge zones, where groundwater is expected to flow primarily upwards, are consistently and significantly higher than those in recharge zones. A synoptic sampling campaign in the Michigan Lowlands revealed concentrations generally increase with depth, a trend noted in previous studies of the Saginaw Lowlands. These strong, consistent SWL and Cl- distribution patterns across multiple scales suggest that a deep source (i.e., Michigan brines) is the primary cause for the elevated chloride concentrations observed in discharge areas across the peninsula. PMID- 28853151 TI - A preliminary assessment of a new dedicated endodontic software for use with CBCT images to evaluate the canal complexity of mandibular molars. AB - AIM: To investigate in vivo the complexity of canals within mesial roots of mandibular molars using 3D EndoTM software linked to CBCT images. METHODOLOGY: The CBCT images of 100 mandibular first molars were analysed using the 3D EndoTM software. The number of canals in the mesial roots, the presence of apical confluences, the canal lengths and the canal configurations using Vertucci's classification were evaluated in buccolingual (BL) and mesiodistal (MD) views. The software allowed the visualization of canal trajectories in three dimensions using a coloured outline, which was used to develop a new objective scoring system to provide an overall assessment of canal complexity. Data were analysed statistically using anova and t-tests with the significance set at P < 0.05. RESULTS: Vertucci type IV canals were found in 44% of the cases, whilst 54% were type II. The mean distance from the apical foramen to the orifice was 13.15 mm (+/-1.21) and that between a confluence and the foramen, 2.81 mm (+/-1.13). The number of curvatures and the canal complexity scores in the MD view were significantly higher than in the BL view (P < 0.05). The scores were not directly correlated to the canal (MB versus ML), to the canal length or to the presence of confluences. CONCLUSIONS: 3D Endo software features the automatic detection and measurement of several anatomical canal parameters, and is a promising tool for the study of canal complexity in vivo. The unpredictable anatomy of the mesial roots of mandibular molars highlights the value of a three-dimensional preoperative evaluation of each case. The proposed scoring system aims to provide the clinician with an overall assessment of canal complexity. PMID- 28853152 TI - Neutrophilic dermatosis of hands preceding extensive small cell lung cancer. PMID- 28853153 TI - Treatment of cutaneous iatrogenic Kaposi sarcoma with topical timolol. PMID- 28853154 TI - Oral health of community-dwelling older Australian men: the Concord Health and Ageing in Men Project (CHAMP). AB - BACKGROUND: The Concord Health and Ageing in Men Project (CHAMP) is a cohort study of the health of a representative sample of Australian men aged 70 years and older. The aim of this report is to describe the oral health of these men. METHODS: Oral health was assessed when the men were all aged 78 years or older. Two calibrated examiners conducted a standardized intraoral assessment. Descriptive data were analysed by statistical association tests. Participants were excluded from the collection of some periodontal assessments if they had a medical contraindication. RESULTS: Dental assessments of 614 participants revealed 90 (14.6%) were edentate. Men had a mean of 13.8 missing teeth and 10.3 filled teeth. Dentate participants had a mean of 1.1 teeth with active coronal decay. Those in the low-income group had a higher rate of decayed teeth and lower rate of filled teeth. Thirty-four participants (5.5%) had one or more dental implants, and 66.3% relied on substitute natural teeth for functional occlusion. Of those with full periodontal assessments; 90.9% had sites with pocket depths of 3 mm or more, 96.6% had sites with CAL of 5 mm or more, and 79.7% had three or more sites with GI scores of 2 or more. CONCLUSIONS: There was a high prevalence of periodontal diseases and restorative burden of dentitions, which suggests that greater attention needs to be given to prevention and health maintenance in older Australian men. PMID- 28853155 TI - A dynamic metabolic flux analysis of ABE (acetone-butanol-ethanol) fermentation by Clostridium acetobutylicum ATCC 824, with riboflavin as a by-product. AB - The present study reveals that supplementing sodium acetate (NaAc) strongly stimulates riboflavin production in acetone-butanol-ethanol (ABE) fermentation by Clostridium acetobutylicum ATCC 824 with xylose as carbon source. Riboflavin production increased from undetectable concentrations to ~0.2 g L-1 (0.53 mM) when supplementing 60 mM NaAc. Of interest, solvents production and biomass yield were also promoted with fivefold acetone, 2.6-fold butanol, and 2.4-fold biomass adding NaAc. A kinetic metabolic model, developed to simulate ABE biosystem, with riboflavin production, revealed from a dynamic metabolic flux analysis (dMFA) simultaneous increase of riboflavin (ribA) and GTP (precursor of riboflavin) (PurM) synthesis flux rates under NaAc supplementation. The model includes 23 fluxes, 24 metabolites, and 72 kinetic parameters. It also suggested that NaAc condition has first stimulated the accumulation of intracellular metabolite intermediates during the acidogenic phase, which have then fed the solventogenic phase leading to increased ABE production. In addition, NaAc resulted in higher intracellular levels of NADH during the whole culture. Moreover, lower GTP-to adenosine phosphates (ATP, ADP, AMP) ratio under NaAc supplemented condition suggests that GTP may have a minor role in the cell energetic metabolism compared to its contribution to riboflavin synthesis. PMID- 28853156 TI - Characterisation and prediction of carbohydrate content in zucchini fruit using near infrared spectroscopy. AB - BACKGROUND: Zucchini fruit plays an important part in healthy nutrition due to its high content of carbohydrates. Recent studies have demonstrated the feasibility of visible-NIRS to predict quality profile. However, this procedure has not been applied to determine carbohydrates. RESULTS: Visible-NIR and wet chemical methods were used to determine individual sugars and starch in zucchini fruits. By applying a principal component analysis (PCA) with NIR spectral data a differentiation between the less sweet versus the sweetest zucchini accessions could be found. For the determination of carbohydrate content effective prediction models for individual sugars such as glucose, fructose, sucrose and starch by using partial least squares (PLS) regression have been developed. CONCLUSION: The coefficients of determination in the external validation (R2 VAL) ranged from 0.66 to 0.85. The standard deviation (SD) to standard error of prediction ratio (RPD) and SD to range (RER) were variable for different quality compounds and showed values that were characteristic of equations suitable for screening purposes. From the study of the MPLS loadings of the first three terms of the different equations for sugars and starch, it can be concluded that some major cell components such as pigments, cellulose, organic acids highly participated in modelling the equations for carbohydrates. (c) 2017 Society of Chemical Industry. PMID- 28853157 TI - The preoperative globulin-to-albumin ratio, a novel inflammation-based prognostic system, predicts survival after potentially curative liver resection for patients with hepatocellular carcinoma. AB - BACKGROUND AND OBJECTIVES: Although the globulin-to-albumin ratio (GAR) is useful for prognostication of patients with various cancers, its relationship with hepatocellular carcinoma (HCC) remains unclear. The study aims to investigate the relationship between GAR and postoperative survival among patients with HCC undergoing potentially curative liver resection (LR). METHODS: We retrospectively reviewed 368 patients with newly diagnosed HCC who underwent initial and potentially curative LR. Univariate and multivariate analyses using the Cox proportional hazard model were performed to detect clinical characteristics that correlated with overall survival (OS). Kaplan-Meier analysis and log-rank test were used to compare OS and disease-free survival (DFS). RESULTS: The result of multivariate analysis using 25 clinical characteristics selected by univariate analysis revealed that the GAR (>=0.918/<0.918) was significantly associated with OS (hazard ratio [HR], 2.398; 95% confidence interval [CI], 1.012-5.683; P = 0.047), as well as platelet count (<14/>=14, *104 /mm3 ) and portal vein invasion (presence/absence). Kaplan-Meier analysis and log-rank test demonstrated that the OS and DFS of patients with a high GAR (>0.918) were significantly worse than that of patients with a low GAR (<=0.918). CONCLUSIONS: The GAR is a useful predictor of postoperative survival among patients with HCC undergoing potentially curative LR. PMID- 28853158 TI - A pairwise likelihood augmented Cox estimator for left-truncated data. AB - Survival data collected from a prevalent cohort are subject to left truncation and the analysis is challenging. Conditional approaches for left-truncated data could be inefficient as they ignore the information in the marginal likelihood of the truncation times. Length-biased sampling methods may improve the estimation efficiency but only when the underlying truncation time is uniform; otherwise, they may generate biased estimates. We propose a semiparametric method for left truncated data under the Cox model with no parametric distributional assumption about the truncation times. Our approach is to make inference based on the conditional likelihood augmented with a pairwise likelihood, which eliminates the truncation distribution, yet retains the information about the regression coefficients and the baseline hazard function in the marginal likelihood. An iterative algorithm is provided to solve for the regression coefficients and the baseline hazard function simultaneously. By empirical process and U-process theories, it has been shown that the proposed estimator is consistent and asymptotically normal with a closed-form consistent variance estimator. Simulation studies show substantial efficiency gain of our estimator in both the regression coefficients and the cumulative baseline hazard function over the conditional approach estimator. When the uniform truncation assumption holds, our estimator enjoys smaller biases and efficiency comparable to that of the full maximum likelihood estimator. An application to the analysis of a chronic kidney disease cohort study illustrates the utility of the method. PMID- 28853160 TI - A new classification system for the restoration of root filled teeth. AB - The aim of this report is to (i) review the current literature on the status of root filled teeth, (ii) analyse the most important factors in decision-making, (iii) discuss the current restorative concepts, and (iv) classify both the evidence and clinical practice in a way that seeks to be clear, understandable and helpful for clinicians. Restoration of root filled teeth represents a challenge for the clinician and remains a controversial subject. The guidelines describe a new classification that is drawn from evidence presented in the literature and also from clinical expertise-based reviews. It describes five categories of teeth. PMID- 28853159 TI - Tetrahydrocannabinolic acid is a potent PPARgamma agonist with neuroprotective activity. AB - BACKGROUND AND PURPOSE: Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as Delta9 tetrahydrocannabinol have been extensively investigated, the bioactivity of Delta9 -tetahydrocannabinol acid (Delta9 -THCA) is largely unknown, despite its occurrence in different Cannabis preparations. Here we have assessed possible neuroprotective actions of Delta9 -THCA through modulation of PPARgamma pathways. EXPERIMENTAL APPROACH: The effects of six phytocannabinoids on PPARgamma binding and transcriptional activity were investigated. The effect of Delta9 -THCA on mitochondrial biogenesis and PPARgamma coactivator 1-alpha expression was investigated in Neuro-2a (N2a) cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). The in vivo neuroprotective activity of Delta9 -THCA was investigated in mice intoxicated with the mitochondrial toxin 3 nitropropionic acid (3-NPA). KEY RESULTS: Cannabinoid acids bind and activate PPARgamma with higher potency than their decarboxylated products. Delta9 -THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells and by mutHtt q94 in N2a cells. Delta9 -THCA, through a PPARgamma-dependent pathway, was neuroprotective in mice treated with 3-NPA, improving motor deficits and preventing striatal degeneration. In addition, Delta9 -THCA attenuated microgliosis, astrogliosis and up-regulation of proinflammatory markers induced by 3-NPA. CONCLUSIONS AND IMPLICATIONS: Delta9 -THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases. PMID- 28853161 TI - Jaw sensorimotor control in healthy adults and effects of ageing. AB - The oro-facial sensorimotor system is a unique system significantly distinguished from the spinal sensorimotor system. The jaw muscles are involved in mastication, swallowing and articulatory speech movements and their integration with respiration. These sensorimotor functions are vital for sustaining life and necessitate complex neuromuscular processing to provide for exquisite sensorimotor control of numerous oro-facial muscles. The function of the jaw muscles in relation to sensorimotor control of these movements may be subject to ageing-related declines. This review will focus on peripheral, brainstem and higher brain centre mechanisms involved in reflex regulation and sensorimotor coordination and control of jaw muscles in healthy adults. It will outline the limited literature bearing on age-related declines in jaw sensorimotor functions and control including reduced biting forces and increased risk of impaired chewing, speaking and swallowing. The mechanisms underlying these alterations include age-related degenerative changes within the peripheral neuromuscular system and in brain regions involved in the generation and control of jaw movements. In the light of the vital role of jaw sensorimotor functions in sustaining life, normal ageing involves compensatory mechanisms that utilise the neuroplastic capacity of the brain and the recruitment of additional brain regions involved in sensorimotor performance and closely associated functions (e.g. cognition and memory). However, these regions are themselves susceptible to detrimental age-related changes. Thus, better understanding of the peripheral and central mechanisms underlying age-related sensorimotor impairment is crucial for developing improved treatment approaches to prevent or cure impaired jaw sensorimotor functions and to thereby improve health and quality of life. PMID- 28853163 TI - Effects of Acknowledging Uncertainty about Earthquake Risk Estimates on San Francisco Bay Area Residents' Beliefs, Attitudes, and Intentions. AB - We test here the risk communication proposition that explicit expert acknowledgment of uncertainty in risk estimates can enhance trust and other reactions. We manipulated such a scientific uncertainty message, accompanied by probabilities (20%, 70%, implicit ["will occur"] 100%) and time periods (10 or 30 years) in major (>=magnitude 8) earthquake risk estimates to test potential effects on residents potentially affected by seismic activity on the San Andreas fault in the San Francisco Bay Area (n = 750). The uncertainty acknowledgment increased belief that these specific experts were more honest and open, and led to statistically (but not substantively) significant increases in trust in seismic experts generally only for the 20% probability (vs. certainty) and shorter versus longer time period. The acknowledgment did not change judged risk, preparedness intentions, or mitigation policy support. Probability effects independent of the explicit admission of expert uncertainty were also insignificant except for judged risk, which rose or fell slightly depending upon the measure of judged risk used. Overall, both qualitative expressions of uncertainty and quantitative probabilities had limited effects on public reaction. These results imply that both theoretical arguments for positive effects, and practitioners' potential concerns for negative effects, of uncertainty expression may have been overblown. There may be good reasons to still acknowledge experts' uncertainties, but those merit separate justification and their own empirical tests. PMID- 28853162 TI - Depressive symptoms account for differences between self-reported versus polysomnographic assessment of sleep quality in women with myofascial TMD. AB - Patients with temporomandibular disorder (TMD) report poor sleep quality on the Pittsburgh Sleep Quality Index (PSQI). However, polysomnographic (PSG) studies show meagre evidence of sleep disturbance on standard physiological measures. The present aim was to analyse self-reported sleep quality in TMD as a function of myofascial pain, PSG parameters and depressive symptomatology. PSQI scores from 124 women with myofascial TMD and 46 matched controls were hierarchically regressed onto TMD presence, ratings of pain intensity and pain-related disability, in-laboratory PSG variables and depressive symptoms (Symptoms Checklist-90). Relative to controls, TMD cases had higher PSQI scores, representing poorer subjective sleep and more depressive symptoms (both P < 0.001). Higher PSQI scores were strongly predicted by more depressive symptoms (P < 0.001, R2 = 26%). Of 19 PSG variables, two had modest contributions to higher PSQI scores: longer rapid eye movement latency in TMD cases (P = 0.01, R2 = 3%) and more awakenings in all participants (P = 0.03, R2 = 2%). After accounting for these factors, TMD presence and pain ratings were not significantly related to PSQI scores. These results show that reported poor sleep quality in TMD is better explained by depressive symptoms than by PSG-assessed sleep disturbances or myofascial pain. As TMD cases lacked typical PSG features of clinical depression, the results suggest a negative cognitive bias in TMD and caution against interpreting self-report sleep measures as accurate indicators of PSG sleep disturbance. Future investigations should take account of depressive symptomatology when interpreting reports of poor sleep. PMID- 28853164 TI - Two-stage designs versus European scaled average designs in bioequivalence studies for highly variable drugs: Which to choose? AB - The usual approach to determine bioequivalence for highly variable drugs is scaled average bioequivalence, which is based on expanding the limits as a function of the within-subject variability in the reference formulation. This requires separately estimating this variability and thus using replicated or semireplicated crossover designs. On the other hand, regulations also allow using common 2 * 2 crossover designs based on two-stage adaptive approaches with sample size reestimation at an interim analysis. The choice between scaled or two-stage designs is crucial and must be fully described in the protocol. Using Monte Carlo simulations, we show that both methodologies achieve comparable statistical power, though the scaled method usually requires less sample size, but at the expense of each subject being exposed more times to the treatments. With an adequate initial sample size (not too low, eg, 24 subjects), two-stage methods are a flexible and efficient option to consider: They have enough power (eg, 80%) at the first stage for non-highly variable drugs, and, if otherwise, they provide the opportunity to step up to a second stage that includes additional subjects. PMID- 28853165 TI - Changes in psychological health, subjective food intake ability and oral health related quality of life during orthodontic treatment. AB - Assessing changes in patient's psychological health and oral health-related quality of life (OHRQoL) over time during orthodontic treatment may help clinicians to treat patients more carefully. To evaluate changes in mental health, self-reported masticatory ability and OHRQoL during orthodontic treatment in adults, this prospective study included 66 adults (30 men, 36 women; mean age, 24.2 +/- 5.2 years). Each patient completed the Korean versions of the State Trait Anxiety Inventory, Zung Self-Rating Depression Scale, Rosenberg self-esteem scale, key subjective food intake ability (KFIA) test for five key foods and Oral Health Impact Profile-14 (OHIP-14K) at baseline (T0), 12 months after treatment initiation (T1) and debonding (T2). All variables changed with time. Self-esteem and the total OHIP-14K score significantly decreased and increased, respectively, at T1, with a particular increase in the psychological and social disabilities scores. There were no significant differences in any questionnaire scores before and after treatment. The total OHIP-14K score was positively correlated with trait anxiety and depression, and negatively correlated with self-esteem and KFIA at T0, regardless of the treatment duration. Older patients showed a significant increase in the total OHIP-14K score at T1 and T2. OHRQoL worsened with an increase in the treatment duration. Our results suggest that OHRQoL temporarily deteriorates, with the development of psychological and social disabilities, during orthodontic treatment. This is related to the baseline age, psychological health and self-reported masticatory function. However, patients recover once the treatment is complete. PMID- 28853166 TI - Masticatory performance-related factors in preschool children: establishing a method to assess masticatory performance in preschool children using colour changeable chewing gum. AB - A knowledge gap regarding masticatory performance in preschool children exists, which in turn delays intervention for preventive care; therefore, a method to easily assess performance is needed. The purpose of this study is to investigate the feasibility of assessing masticatory performance using colour-changeable chewing gum and to investigate masticatory performance-related factors in preschool children. This cross-sectional survey was conducted in two childcare facilities and our laboratory. First, a one-third quantity of colour-changeable chewing gum was masticated by six adults to assess the nature and progression of colour changes in this quantity. Then, masticatory performance in 370 children 4 6 years of age was assessed using the same quantity of colour-changeable chewing gum (60 chew strokes). The maximum bite force, body height, weight, age and number of healthy teeth were recorded. A t-test was performed to determine whether gum-chewing experience or lack thereof produced a significant difference in masticatory performance. The Spearman's rank correlation coefficient was then determined for masticatory performance assessment values and other factors solely for children with gum-chewing experience. Measurements from 259 children were obtained. Children with gum-chewing experience demons trated significantly higher assessment values and were deemed to have been correctly assessed. A very weak but significant positive correlation was observed only between masticatory performance and the number of healthy teeth. The masticatory performance of preschool children was easily assessed using colour-changeable chewing gum. The assessment values demonstrated significant correlation with the number of healthy teeth, but not with maximum bite force, body height, weight or age. PMID- 28853167 TI - A urinary biomarker-based risk score correlates with multiparametric MRI for prostate cancer detection. AB - BACKGROUND: Prostate cancer (PCa) diagnostics would greatly benefit from more accurate, non-invasive techniques for the detection of clinically significant disease, leading to a reduction of over-diagnosis and over-treatment. The aim of this study was to determine the association between a novel urinary biomarker based risk score (SelectMDx), multiparametric MRI (mpMRI) outcomes, and biopsy results for PCa detection. METHODS: This retrospective observational study used data from the validation study of the SelectMDx score, in which urine was collected after digital rectal examination from men undergoing prostate biopsies. A subset of these patients also underwent a mpMRI scan of the prostate. The indications for performing mpMRI were based on persistent clinical suspicion of PCa or local staging after PCa was found upon biopsy. All mpMRI images were centrally reviewed in 2016 by an experienced radiologist blinded for the urine test results and biopsy outcome. The PI-RADS version 2 was used. RESULTS: In total, 172 patients were included for analysis. Hundred (58%) patients had PCa detected upon prostate biopsy, of which 52 (52%) had high-grade disease correlated with a significantly higher SelectMDx score (P < 0.01). The median SelectMDx score was significantly higher in patients with a suspicious significant lesion on mpMRI compared to no suspicion of significant PCa (P < 0.01). For the prediction of mpMRI outcome, the area-under-the-curve of SelectMDx was 0.83 compared to 0.66 for PSA and 0.65 for PCA3. There was a positive association between SelectMDx score and the final PI-RADS grade. There was a statistically significant difference in SelectMDx score between PI-RADS 3 and 4 (P < 0.01) and between PI-RADS 4 and 5 (P < 0.01). CONCLUSIONS: The novel urinary biomarker-based SelectMDx score is a promising tool in PCa detection. This study showed promising results regarding the correlation between the SelectMDx score and mpMRI outcomes, outperforming PCA3. Our results suggest that this risk score could guide clinicians in identifying patients at risk for significant PCa and selecting patients for further radiological diagnostics to reduce unnecessary procedures. PMID- 28853168 TI - A Novel Three-Compartmental Model for Artificial Pancreas: Development and Validation. AB - Closed-loop insulin delivery system, also known as artificial pancreas (AP), provides the blood glucose control in diabetic patients, enabling the automatic blood-sugar management and reducing the risks and improving the lives of people with diabetes. A new three-compartmental model of glucose-insulin interaction for AP is presented and tested in this paper. The glucose and insulin "spaces" are split into a plasma compartment and interstitial fluids compartment, respectively. The model includes an additional subcutaneous compartment and provides three explicit delays and three parameters influencing the regulatory system and correlating with the physiopathology of the patients. Two delays are related with hepatic glucose production and insulin secretion; the third delay represents the lag time in the absorption of exogenous insulin in subcutaneous tissue. The parameters regulate the system dynamics acting on the glucose utilization and the insulin secretion. The clinical data (including information on food ingestion and exogenous insulin injection) from five case studies of Type 1 diabetics are presented and used to validate the mathematical model. After training the parameters for each case study, the model well simulates the glucose level during a 4-day test. The estimated values are physiologically meaningful and provide a further insight on the subject's dysfunctions and on the state of the disease. The results have been also compared with a parallel simulation carried out by implementing a previous two-compartmental model. The proposed algorithm produces a lower sum of the squared error between the simulated and the measured glucose concentrations over time. PMID- 28853169 TI - Effect of body posture on chewing behaviours in healthy volunteers. AB - Mastication is essential to the eating process and forms an important part of feeding behaviour. Many factors related to the food bolus, such as bolus texture and size, are known to influence mastication. The aim of this study was to determine the effects of body posture on (i) chewing duration prior to the first swallow and (ii) patterns of mastication-related EMG activity. We asked 10 healthy adults to chew 8 g of steamed rice with barium sulphate while we recorded masseter, suprahyoid and infrahyoid muscle activity and simultaneously collected videofluorographic images. Participants chewed in either an upright or reclining position. Chewing duration, which was defined as the time from the start of mastication to the first swallow, was not different between the positions. However, the variability of chewing duration was larger in the upright versus reclining position, and the chewing duration in the reclining position was distributed around 15 s. Masseter activity gradually decreased in a time dependent manner and was significantly larger at the early versus late stage of mastication. Suprahyoid activity was significantly larger at the early versus middle stage of mastication in the upright position only. Finally, masseter activity per second was negatively correlated with changes in chewing duration, that is, the larger the increase in chewing duration in the reclining position, the more the decrease in masseter activity per second. These results suggest that position-dependent changes in chewing behaviours, as described by chewing duration and EMG activity, may vary among participants. PMID- 28853170 TI - First-generation annotations for the fathead minnow (Pimephales promelas) genome. AB - Ab initio gene prediction and evidence alignment were used to produce the first annotations for the fathead minnow (Pimephales promelas) genome. We also describe a genome browser, hosted by the Society of Environmental Toxicology and Chemistry, that provides simplified access to the annotation data in context with the genomic sequence. The present study extends the utility of the fathead minnow genome and supports the continued development of this species as a model organism for predictive toxicology. Environ Toxicol Chem 2017;36:3436-3442. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28853171 TI - Relationship between morphological abnormalities in commercial bull frozen semen doses and conception rate. AB - Commercial doses of frozen bull semen for artificial insemination may have a certain percentage of morphological defects, despite being subject to prior selection. The aims of this study were to determine the prevalence of morphological abnormalities in commercial doses (n = 55, r = 2) of dairy and beef bulls, from AI Centers and to determine the possible existence of differences between them, regarding the percentage of abnormal spermatozoa. At least 200 spermatozoa per sample were evaluated using Bengal Rose stain (3% m/v) and light microscopy (*1000 magnification). The mean percentage of abnormal sperm samples from dairy breeds was 7.19% +/- 4.91% and from beef breeds was 15.83% +/- 9.28%. Significant differences between biotypes were found in the proportion of abnormal spermatozoa, abnormal heads and abnormal midpieces; it could be due to different selection pressure. It was observed that the percentage of abnormal spermatozoa was not a good fertility level predictor for the commercial samples of frozen bovine semen used in this study. In both biotypes, the midpiece abnormalities were the most frequent, mainly its distal flexion (compensable defect). This could be as a result of the effects of freezing and thawing on spermatozoa. PMID- 28853172 TI - When doctors deny drugs: Sexism and contraception access in the medical field. AB - Politicians, employers, courts, and health insurance companies are often discussed as problematically preventing access to birth control. However, doctors have more direct control over women's health and quietly have been much more effective at preventing patients' access to contraception. Obstetrician/Gynecologists routinely deny their patients access to contraception ostensibly in the name of health by withholding birth control until patients undergo yearly pap smears. I argue that those in the medical field are motivated by similarly sexist concerns as those in other major institutions in the United States, but that they are often overlooked in discussions of biomedical ethics. After providing background, I argue that using birth control as a bargaining chip to control patients is morally impermissible, is paternalistic, and is contrary to consent. I next argue that sexism explains, though does not justify, this practice. I discuss the medical harms of routine pap smears and withholding birth control. These claims make medical malpractice likely. Withholding birth control to coerce individuals seeking medical care is medical malpractice, paternalistic, violates autonomy, and is contrary to consent. PMID- 28853173 TI - Pharmacological inhibition of S6K1 impairs self-renewal and osteogenic differentiation of bone marrow stromal cells. AB - mTORC1 signaling not only plays important physiological roles in the regulation of proliferation and osteogenic differentiation of BMSCs, but also mediates exogenous Wnt-induced protein anabolism and osteoblast differentiation. However, the downstream effectors of the mTORC1 signaling in the above processes are still poorly understood. In this study, we explored the specific role of S6K1, one of the major targets of the mTORC1 pathway, in BMSCs self-renewal and osteogenic differentiation. We first found that S6K1 was active in primary mouse bone marrow stromal cells, and further activated upon osteogenic induction. We then determined the effects of S6K1 inhibition by LY2584702 Tosylate, a selective inhibitor of S6K1 (hereafter S6KI), using both primary mouse bone marrow stromal cells and ST2 cells. Colony-Forming Unit-Fibroblast (CFU-F) assays showed that S6KI dramatically reduced the total number of colonies formed in primary BMSCs cultures. Under the basal osteogenic culture condition, S6KI significantly inhibited mRNA expression of osteoblast marker genes (Sp7, Bglap, Ibsp, and Col1a1), ALP activity and matrix mineralization. Upon Wnt3a treatments, S6KI inhibited Wnt3a-induced osteoblast differentiation and expression of protein anabolism genes in ST2 cells, but to a much lesser degree than rapamycin (a specific inhibitor of mTORC1 signaling). Collectively, our findings have demonstrated that pharmacological inhibition of S6K1 impaired self-renewal and osteogenic differentiation of BMSCs, but only partially suppressed exogenous Wnt3a-induced osteoblast differentiation and protein anabolism. PMID- 28853174 TI - Blockade of 5-HT3 receptors with granisetron does not affect trigeminothalamic nociceptive transmission in rats: Implication for migraine. AB - One way to expand the existing range of anti-migraine drugs seems to be the search for pharmacological agents with anti-cephalalgic properties among medicines approved for clinical indications other than migraine. Numerous experimental and clinical data imply that selective serotonin 5-HT3 receptor antagonists can be considered as potential anti-migraine agents. Therefore, the objective of our work was to examine the impact of selective 5-HT3 receptor blockade with granisetron on migraine-related nociceptive transmission within the spinal trigeminal nucleus (STN) and the ventroposteromedial nucleus of the thalamus (VPM). Using an electrophysiological model of trigemino-durovascular nociception in anaesthetised male Wistar rats, we evaluated the effects of intravenous administration of granisetron on ongoing firing and dural electrical stimulation-evoked responses of the spinal trigeminal and thalamic cells. Granisetron did not substantially affect responses of the STN and VPM neurons to electrical stimulation of the dura mater as well as did not cause steady changes in ongoing firing of the spinal trigeminal cells. The results obtained argue against the use of 5-HT3 receptor antagonists for treating migraine. These data also lead to the conclusion that in the absence of sustained sensitisation of neurons along the trigemino-thalamo-cortical pathway the role of 5-HT3 receptor dependent mechanisms in serotonergic modulation of trigeminovascular nociceptive transmission can hardly be considered crucial. PMID- 28853175 TI - Safety of non-ablative fractional laser for acne scars within 1 month after treatment with oral isotretinoin: A randomized split-face controlled trial. AB - BACKGROUND AND OBJECTIVE: Based on reports of poor wound healing and scarring, it is currently recommended that patients wait 6 months after completion of oral isotretinoin therapy before the safe initiation of laser treatment. Our aim was to evaluate the safety of non-ablative fractional laser (NAFL) treatment for acne scars within 1 month after isotretinoin therapy. STUDY DESIGN/METHODS: This was a randomized split-face controlled trial involving 10 patients with acne scars who had completed isotretinoin treatment. All patients received three treatments each spaced 4 weeks apart with an erbium-doped 1550 nm NAFL on one side of the face within 1 month after isotretinoin therapy. The untreated side acted as a control. Wound healing and adverse effects as well as acne scar improvement were evaluated by two blinded dermatologists. RESULTS: All patients demonstrated normal wound healing post NAFL treatments, and neither hypertrophic scars nor keloids were observed. Acne scar improvement was satisfactory. CONCLUSION: NAFL treatment for acne scarring appears to be well tolerated within 1 month of completing isotretinoin treatment. Dermatologists should reevaluate the current recommendation to wait 6 months after isotretinoin treatment for acne scar revision with lasers. Other larger studies are necessary to further challenge this dogma. Lasers Surg. Med. 49:886-890, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28853176 TI - Optimal Mission Abort Policy for Systems Operating in a Random Environment. AB - Many real-world critical systems, e.g., aircrafts, manned space flight systems, and submarines, utilize mission aborts to enhance their survivability. Specifically, a mission can be aborted when a certain malfunction condition is met and a rescue or recovery procedure is then initiated. For systems exposed to external impacts, the malfunctions are often caused by the consequences of these impacts. Traditional system reliability models typically cannot address a possibility of mission aborts. Therefore, in this article, we first develop the corresponding methodology for modeling and evaluation of the mission success probability and survivability of systems experiencing both internal failures and external shocks. We consider a policy when a mission is aborted and a rescue procedure is activated upon occurrence of the mth shock. We demonstrate the tradeoff between the system survivability and the mission success probability that should be balanced by the proper choice of the decision variable m. A detailed illustrative example of a mission performed by an unmanned aerial vehicle is presented. PMID- 28853177 TI - Recent advances in CE and microchip-CE in clinical applications: 2014 to mid 2017. AB - CE and microchip CE (ME) are powerful tools for the analysis of a number of different analytes and have been applied to a variety of clinical fields and human samples. This review will present an overview of the most recent applications of these techniques to different areas of clinical medicine during the period of 2014 to mid-2017. CE and ME have been applied to clinical chemistry, drug detection and monitoring, hematology, infectious diseases, oncology, endocrinology, neonatology, nephrology, and genetic screening. Samples examined range from serum, plasma, and urine to lest utilized materials such as tears, cerebral spinal fluid, sweat, saliva, condensed breath, single cells, and biopsy tissue. Examples of clinical applications will be given along with the various detection systems employed. PMID- 28853178 TI - The AB Portable Driver Generates Higher Drive-Line Pressures Possibly Leading to Accelerated Hemolysis. AB - The AB5000 Circulatory Support System is paracorporeal pulsatile ventricular assist device. The AB Portable Driver is a portable console for this system. We experienced two cases with accelerated hemolysis while receiving support by the AB Portable Driver. The purpose of this study was to clarify the mechanical differences associated with the hemolysis between the AB5000 console and the AB Portable Driver. The mock circulatory system modeled by an AB5000 ventricle and a blood sampling bag of vinyl chloride was run with an AB5000 console or AB Portable Driver. The peak drive-line pressure, the mean arterial cannula pressure and the pumping rate of the VAD were recorded. The AB5000 console generated a peak drive-line pressure of 280-300 mm Hg in LVAD mode and 210-220 mm Hg in RVAD mode, approximately 100 mm Hg lower than officially documented. In contrast, the AB Portable Driver generated pressures of 310-330 mm Hg in LVAD mode and 230-250 mm Hg in RVAD mode, 65-95 mm Hg higher than officially documented. The AB Portable Driver console generates higher drive-line pressures than the AB5000 console, possibly explaining the accelerated hemolysis. PMID- 28853180 TI - Di(hydroperoxy)alkane Adducts of Phosphine Oxides: Safe, Solid, Stoichiometric, and Soluble Oxidizing Agents. AB - The di(hydroperoxy)alkane adducts of phosphine oxides 1-9, Ph3 PO?(HOO)2 CMe2 , Cy3 PO?(HOO)2 CMe2 , Ph3 PO? (HOO)2 CMeEt, Cy3 PO?(HOO)2 CMeEt, Cy3 PO?(HOO)2 CEt2 , Cy3 PO? (HOO)2 C(CH2 )5 , Cy3 PO?(HOO)2 CMePh, (Ph2 P(O)CH2 CH2 P(O)Ph2 )? ((HOO)2 CEt2 )2 , and Ph2 P(O)CH2 P(O)Ph2 ?(HOO)2 CMe2 , respectively, are synthesized and fully characterized by 1 H, 13 C, and 31 P NMR, and IR spectroscopies. Single crystal X-ray structures are reported for 3-9. Different one-pot synthetic pathways, starting from R3 P, R3 PO, R3 PO?H2 O, and R3 PO?H2 O2 are explored and discussed and a mechanism for the formation of the di(hydroperoxy)alkane adducts of phosphine oxides is suggested. The longevity of the adducts is tested by monitoring the oxidation of Ph3 P with quantitative NMR. The solubilities of the adducts in organic solvents are presented, and their applicability as stoichiometric oxidizing agents for the selective oxidation of sulfides to sulfoxides is reported. PMID- 28853179 TI - Hyperosmolarity induces notochordal cell differentiation with aquaporin3 upregulation and reduced N-cadherin expression. AB - The nucleus pulposus (NP) of intervertebral discs (IVD) undergoes dramatic changes with aging including loss of its gelatinous structure and large, vacuolated notochordal cells (NCs) in favor of a matrix-rich structure populated by small NP cells (sNPCs). NP maturation also involves a loading-pattern shift from pressurization to matrix deformations, and these events are thought to predispose to degeneration. Little is known of the triggering events and cellular alterations involved with NP maturation, which remains a fundamental open spinal mechanobiology question. A mouse IVD organ culture model was used to test the hypotheses that hyperosmotic overloading will induce NP maturation with transition of NCs to sNPCs while also increasing matrix accumulation and altering osmoregulatory and mechanotransductive proteins. Results indicated that static hyperosmolarity, as might occur during growth, caused maturation of NCs to sNPCs and involved a cellular differentiation process since known NC markers (cytokeratin-8, -19, and sonic hedgehog) persisted without increased cell apoptosis. Osmosensitive channels Aquaporin 3 (Aqp3) and transient receptor potential vanilloid-4 (TRPV4) expression were both modified with altered osmolarity, but increased Aqp3 with hyperosmolarity was associated with NC to sNPC differentiation. NC to sNPC differentiation was accompanied by a shift in cellular mechanotransduction proteins with decreased N-cadherin adhesions and increased Connexin 43 connexons. We conclude that hyperosmotic overloading can promote NC differentiation into sNPCs. This study identified osmolarity as a triggering mechanism for notochordal cell differentiation with associated shifts in osmoregulatory and mechanotransductive proteins that are likely to play important roles in intervertebral disc aging. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:788-798, 2018. PMID- 28853181 TI - Solvent-Sensitive Emitting Urea-Bridged bis-BODIPYs: Ready Access by a One-Pot Tandem Staudinger/Aza-Wittig Ureation. AB - Herein we describe the synthesis, and computationally aided photophysical characterization of a new set of urea-bridged bis-BODIPY derivatives. These new dyads are efficiently obtained by a one-pot tandem Staudinger/aza-Wittig ureation protocol, from easily accessible meso-phenyl ortho-azidomethyl BODIPYs. These symmetric bis-BODIPYs outstand by a high absorption probability and excellent fluorescence and laser emission in less polar media. Nevertheless, this emission ability decreases in more polar media, which is ascribed to a light-induced charge-transfer from the urea spacer to the dipyrrin core, a process that can be modulated by appropriate changes in the substitution pattern of the BODIPY core. Furthermore, this ureation protocol can also be employed for the direct conjugation of our BODIPY-azides to amine-containing compounds, thus providing access to fluorescent non-symmetric ureas. PMID- 28853182 TI - Extracorporeal photopheresis for the management of lung allograft rejection. PMID- 28853183 TI - Differentiation of Folate-Receptor-Positive and -Negative Cells Using a Substrate Mimicking Fluorescent Probe. AB - Diagnosis and therapy exploiting overexpressed receptors on the cell surface is one important strategy in medicine. Determination of the over expression level of a particular receptor is prerequisite for it to be of clinical use. Differentiation between FR-positive (FR=folate receptor) and -negative cells via fluorescence microscopy using a substrate mimetic fluorophore is presented in this work. The strategy adopted here is not the classical FA-conjugated (FA=folic acid) fluorescent probe but a small and environment-sensitive pterin-based (pterin is part of folate, i.e., vitamin B9) fluorescent probe. Electronically diverse pterin-based fluorescent probes have been designed and synthesized to understand the effect of the binding environment on the receptor-substrate interactions. By utilizing steady-state UV/Vis and fluorescence along with time resolved fluorescence spectroscopy, the effects on the electronic and acid-base properties of the substrate were investigated. Evidently, one synthesized probe showed FA-mimicking behavior with strong binding interaction with FR. PMID- 28853184 TI - NCN-Coordinating Ligands based on Pyrene Structure with Potential Application in Organic Electronics. AB - Five novel derivatives of pyrene, substituted at positions 1,3,6,8 with 4-(2,2 dimethylpropyloxy)pyridine (P1), 4-decyloxypyridine (P2), 4-pentylpyridine (P3), 1-decyl-1,2,3-triazole (P4), and 1-benzyl-1,2,3-triazole (P5), are obtained through a Suzuki-Miyaura cross-coupling reaction or CuI -catalyzed 1,3-dipolar cycloaddition reaction, respectively, and characterized thoroughly. TGA measurements reveal the high thermal stability of the compounds. Pyrene derivatives P1-P5 all show photoluminescence (PL) quantum yields (Phi) of approximately 75 % in solution. Solid-state photo- and electroluminescence characteristics of selected compounds as organic light-emitting diodes are tested. In the guest-host configuration, two matrixes, that is, poly(N vinylcarbazole) (PVK) and a binary matrix consisting of PVK and 2-tert butylphenyl-5-biphenyl-1,3,4-oxadiazole (PBD) (50:50 wt %), are applied. The diodes show red, green, or blue electroluminescence, depending on both the compound chemical structure and the actual device architecture. In addition, theoretical studies (DFT and TD-DFT) provide a deeper understanding of the experimental results. PMID- 28853185 TI - A camelid nanobody against EGFR was easily obtained through refolding of inclusion body expressed in Escherichia coli. AB - Using anti-EGFR (epidermal growth factor receptor) nanobody is a good choice for diagnoses and therapeutics for high EGFR expression diseases. In the present study, the percentage composition of anti-EGFR nanobody attained 25% of the total cell protein expressed in Escherichia coli BL21 (DE3). However, almost all nanobodies were expressed as inclusion bodies. To acquire active nanobodies, a series of dilution refolding procedures were optimized after inclusion bodies were dissolved into 6 M urea and purified with immobilized metal affinity chromatography. The results showed the refolding rate of the anti-EGFR nanobodies attained to 73%, and about 100 mg nanobodies were refolded from 1 L cells under the conditions that the initial nanobody concentration was 0.3 mg/mL, the dilution speed was 2.5 mL/Min, the dilution buffer was Tris-HCl at pH 8.0, the additives were 0.2 M Arg, 5 mM reduced glutathione (GSH), and 1 mM oxidized glutathione (GSSG). Then the activity of the refolded nanobodies was confirmed. The results showed that the refolded anti-EGFR nanobodies, in a dose-dependent manner, bounded to the tumor cell surface of A431 and MCF-7 and significantly inhibited the proliferation of A431 caused by the epidermal growth factor. Our study provides a facile method to rapidly, efficiently, and massively prepare anti-EGFR antibodies and promotes anti-EGFR-based recognition in cancer diagnoses and therapeutics. PMID- 28853186 TI - Coordinatively Labile 18-Electron Arene Ruthenium Iminophosphonamide Complexes. AB - The thermodynamics of chloride dissociation from the 18e arene ruthenium iminophosphonamides [(eta6 -arene)RuCl{(R'N)2 PR2 }] (1 a-d) [previously known with arene=C6 Me6 , R=Ph, R'=p-Tol (a); R=Et, R'=p-Tol (b); R=Ph, R'=Me (c); and new with arene=p-cymene, R=Ph, R'=p-Tol (d)] was assessed in both polar and apolar solvents by variable-temperature UV/Vis, NMR, and 2D EXSY 1 H NMR methods, which highlighted the influence of the NPN ligand on the equilibrium parameters. The dissociation enthalpy DeltaHd decreases with increasing electron-donating ability of the N- and P-substituents (1 a, 1 d>1 b>1 c) and solvent polarity, and this results in exothermic spontaneous dissociation of 1 c in polar solvents. The coordination of neutral ligands (MeCN, pyridine, CO) to the corresponding 16e complexes [(eta6 -arene)Ru{(R'N)2 PR2 }]+ PF6- (2 a-d) is reversible; the stability of the 2?L adducts depends on the pi-accepting ability of L. Carbonylation of 2 a and 2 d resulted in rare examples of cationic arene ruthenium carbonyl complexes (3 a, 3 d), while the monocarbonyl adduct derived from 2 c reacts further with a second equivalent of CO with conversion to carbonyl-carbamoyl complex 3 c, in which one CO molecule is inserted into the Ru N bond. The new complexes 1 d, 2 d, 3 a, 3 c, and 3 d were isolated and structurally characterized. PMID- 28853187 TI - Time motion analysis of nursing work in ICU, telemetry and medical-surgical units. AB - AIM: This study examined nurses' work, comparing nursing interventions and locations across three units in a United States hospital using Omaha System standardized terminology as the organizing framework. BACKGROUND: The differences in nurses' acute-care work across unit types are not well understood. Prior investigators have used time-motion methodologies; few have compared differences across units, nor used standardized terminology. METHODS: Nurse-observers recorded locations and interventions of nurses on three acute-care units using hand-held devices and web-based TimeCaTTM software. Nursing interventions were mapped to Omaha System terms. Unit-differences were analysed. RESULTS: Nurses changed locations approximately every 2 min, and averaged approximately one intervention/minute. Unit differences were found in both the interventions performed and the locations. Most interventions were case-management related, demonstrating the nurses' patient management/coordination role. CONCLUSIONS: Unit differences in nursing interventions and location were found among three unit types. Omaha System terminology, as well as the observational method used, were found to be feasible and practical. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing work varies by unit, yet managers have not been armed with empirical data with which to make more informed decisions about nurses' work priorities, clinical outcomes, patient satisfaction, staff satisfaction and cost. The results from this study will help them to do so. PMID- 28853188 TI - Alkyl Triarylstannanecarbodithioates: Synthesis, Crystal Structures, and Efficiency in RAFT Polymerization. AB - Eight alkyl triarylstannanecarbodithioates were synthesized starting from the corresponding triarylstannyl chlorides. They were fully characterized by IR and 1 H, 13 C, and 119 Sn NMR spectroscopy and mass spectrometry. Their solid-state structures and geometric parameters were determined and compared to those of other classes of thiocarbonylthio compounds. These new organotin derivatives are efficient reversible chain-transfer agents for reversible addition-fragmentation chain transfer (RAFT) polymerization of styrene (St) and n-butyl acrylate (BA), with controlled number-average molecular weights and narrow dispersities (D<1.3). In some cases, loss of control of the polymerization was evidenced and supported by the observation of side products by 119 Sn NMR spectroscopy. This phenomenon was attributed to the thermal instability of the Sn-RAFT terminal group. PMID- 28853189 TI - Clinical and angiographic outcome of a single center, real world population treated with a dedicated technique of implantation for bioresorbable vascular scaffolds. The FAtebenefratelli Bioresorbable Vascular Scaffold (FABS) registry. AB - OBJECTIVES: With this prospective study we aim at investigating the long-term outcome of a consecutive cohort of patients successfully treated with bioresorbable scaffold (BVS) implantation. BACKGROUND: It is not clearly understood if there is a relation between the technique of BVS implantation and the outcome. METHODS: Between December 2012 and December 2014, all consecutive patients treated with BVS were included in this registry and received an angiographic follow-up. After a run-in phase, all BVS were implanted using a specific technique consisting of aggressive predilation, correct scaffold sizing, visually determined, and high-pressure post-dilation with a noncompliance balloon. Primary endpoint was late lumen loss (LLL) at 1-year angiographic follow up and ischemia-driven target-lesion revascularization (ID-TLR) at 2-year clinical follow-up. Secondary endpoints were the occurrence of binary restenosis, major adverse cardiac events (MACE), and every single component of MACE (cardiac death, myocardial infarction, TLR) at 2 years. RESULTS: A total of 144 lesions in 122 patients treated consecutively with BVS, were enrolled. Diabetics were 29.5% and acute coronary syndrome at presentation occurred in 29.5% of patients. At the angiographic follow-up LLL was 0.38 +/- 0.9. At 2-year clinical follow-up, ID-TLR occurred in eight patients (5.6%). We observed two cases of scaffold thrombosis (1.38%, one early and one very late). At multivariate statistical analysis, STEMI presentation remained a significant predictor for TLR. CONCLUSIONS: In a complex, all-comers real world population, BVS implantation with a specific, and standardized technique showed to be feasible, with acceptable mid-term angiographic and long-term clinical outcome. PMID- 28853190 TI - Diagnostic accuracy of instantaneous wave free-ratio in clinical practice. AB - AIMS: To evaluate the correlation between iFR and FFR in real-world clinical practice. METHODS AND RESULTS: Retrospective, single-centre study of 229 consecutive pressure-wire studies (np = 158). Real-time iFR and FFR measurements were performed for angiographically borderline stenoses. Functionally significant stenoses were defined as iFR <0.86 or FFR <=0.80. An iFR between 0.86 and 0.93 was considered within the grey zone (Hybrid approach). Median iFR and FFR (IQR) were 0.92 (0.87-0.95) and 0.83 (0.76-0.89), respectively. Pearson's correlation coefficient was 0.75 (P < 0.001). Bland-Altman plot showed a mean difference between iFR and FFR that remained consistent throughout the range of values. The optimal iFR cutoff was 0.91-sensitivity 80%, specificity 82% with ROC area under curve of 89%. Using the Hybrid iFR-FFR strategy, we demonstrated high accuracy of iFR results-sensitivity 95%, specificity 96%, PPV 95%, and NPV 96%. In addition, this method would have avoided adenosine in 56% of patients. Mean follow-up period was 17.2 (+/-3.4) months. All-cause mortality was 3.2% (np = 5) and repeat intervention was required in six lesions (2.6%). CONCLUSIONS: This study demonstrates that iFR is a valuable adjunct to FFR using the Hybrid iFR-FFR strategy in a real-world population. The use of adenosine may be avoided in about half the cases. PMID- 28853191 TI - A national survey of nurse training: Confidence and competence in educating patients commencing methotrexate therapy. AB - INTRODUCTION: Methotrexate is routinely used to treat active disease in inflammatory arthritis. There have previously been patient safety concerns associated with methotrexate usage in practice. Most patients commencing methotrexate treatment are seen by the rheumatology nurse, to receive education (often referred to as drug counselling) on this agent prior to starting treatment. Yet, there are no recommended criteria regarding education or experience to ensure minimum competence of the rheumatology nurse. The objectives of the present survey were, firstly, to identify the relevant training experience of rheumatology nurses who provide methotrexate education and, secondly, to explore their confidence and competence in undertaking this role. METHOD: A national electronic survey of rheumatology nurses, identified via the Royal College of Nursing Rheumatology Forum, national meetings and personal contacts, in order to access nurses who counsel patients on methotrexate, was carried out. RESULTS: A total of 104 nurses completed the survey. Reported training was highly variable, ranging from very little to having undertaken MSc courses. Knowledge of the drug was rated as the most important requirement. Confidence was largely very good and was reported to develop with experience, with 80% of participants reporting being confident after 1 year in the role. A small number of participants (four) indicated that they were 'not at all confident'. Aspects of competence and knowledge were assessed using questions on clinical situations; knowledge appeared to be good, with the exception of a question on shingles. Confidence correlated with knowledge (r = 0.21; p = 0.05), amount of training (r = 0.24; p = 0.03) and most strongly with time in the role (r = 0.74; p = 0.00001). The amount of training correlated with confidence but not with knowledge. All participants used written information, often using more than one source, with 87% of participants favouring the Arthritis Research UK information leaflet on methotrexate. CONCLUSIONS: There was a wide variety of training for this role. Confidence seemed to come with experience, training and knowledge, and took many months to develop. A training package in this area may be helpful. Reassuringly, confidence and knowledge were related. PMID- 28853192 TI - Resection accuracy of patient-specific cutting guides in total knee replacement. AB - BACKGROUND: Patient-specific guides (PSGs) have been thoroughly investigated with regards to reconstitution of mechanical alignment in total knee arthroplasty (TKA). The ability to replicate the preoperative surgical plan is essential for optimal outcomes but intraoperative measurements to confirm accurate progression through the operation are limited. This leads to our clinical question: can PSGs replicate the planned bone resection depth during TKA? METHODS: This is a prospective case series of 118 patients who underwent TKA using magnetic resonance imaging-based patient-specific cutting guides. Intraoperative bone resection thickness was measured and compared with the preoperative planned bone resections as a primary outcome. Secondary outcomes included the need for additional bone resections, the number of cases for which the PSG technique was abandoned, final component sizes and mechanical alignment. RESULTS: PSGs could not accurately recreate preoperative plan. PSGs resulted in over-resection in all bone cuts compared with the preoperative surgical resection plan. Secondary osteotomies were required in 37% of patients. PSGs had to be abandoned in 10.5% of cases, mostly due to suboptimal fit of the femoral block. The tibial component size was altered more frequently than the femoral. CONCLUSION: Intraoperatively, PSGs could not accurately recreate the preoperative plan. PSGs are marketed as user-friendly tools to simplify TKA but our research demonstrates the need for surgeons to monitor surgical progression and compensate for errors occurring during the use of PSGs. PMID- 28853193 TI - Peroxidyme-Amplified Radical Chain Reaction (PARCR): Visible Detection of a Catalytic Reporter. AB - Peroxidyme Amplified Radical Chain Reaction (PARCR), a novel enzyme-free system that achieves exponential amplification of a visible signal, is presented. Typical enzyme-free amplification systems that produce a visible readout suffer from long reaction times, low sensitivity, and narrow dynamic range. PARCR employs photocatalyzed nonlinear signal generation, enabling unprecedented one pot, naked-eye detection of a catalytic reporter from 1 MUm down to 100 pm. In this reaction, hemin-binding peroxidase-mimicking DNAzymes ("peroxidymes") mediate the NADH-driven oxidation of a colorless, nonfluorescent phenoxazine dye (Amplex Red) to a brightly colored, strongly fluorescent product (resorufin); illumination with green light initiates multiple radical-forming positive feedback loops, rapidly producing visible levels of resorufin. Collectively, these results demonstrate the potential of PARCR as an easy-to-use readout for a range of detection schemes, including aptamer labels, hybridization assays, and nucleic acid amplification. PMID- 28853194 TI - Lysine-Targeting Covalent Inhibitors. AB - Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small-molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding-site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the epsilon-amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples, and present recent developments that demonstrate the potential of lysine targeting for future drug discovery. PMID- 28853195 TI - Location of white matter changes and response to donepezil in patients with Alzheimer's disease: A retrospective and observational study. AB - AIM: The response to donepezil in patients with Alzheimer's disease varies, and it is important to identify the potential responder before therapy. Cerebral white matter changes (WMC) are frequently observed in older patients, and the effect of WMC on therapeutic response remains controversial. The present study aimed to investigate the relationships between the location of WMC, severe WMC and the response to donepezil. METHODS: Among 418 patients with Alzheimer's disease receiving donepezil, 196 patients were eligible for analysis. Five brain areas on each side were analyzed using computed tomography scans and the Age Related White Matter Changes Rating Scale before therapy. The Cognitive Abilities Screening Instrument was used annually. Patients were defined as responders if their baseline Cognitive Abilities Screening Instrument score minus their follow up Cognitive Abilities Screening Instrument score was <=0. RESULTS: There was no significant difference in demographic data between responder and non-responder groups. Patients in the responder group had significantly less involvement of WMC in the frontal area (P = 0.0213) and nearly a trend for less involvement of WMC in the basal ganglia (P = 0.1103). After adjustment for age, sex, education, polymorphism of apolipoprotein E, hypertension and diabetes, WMC in the frontal area (OR 0.446, P = 0.0139) and basal ganglia (OR 0.243, P = 0.0380) were significantly associated with a reduced therapeutic response. CONCLUSIONS: Patients with WMC in the frontal area and basal ganglia had significant decreases in their therapeutic response to donepezil. The location of WMC, independent of their severity, might be associated with the therapeutic response in patient with Alzheimer's disease. Geriatr Gerontol Int 2018; 18: 123-129. PMID- 28853196 TI - A new screening strategy for varices by liver and spleen stiffness measurement (LSSM) in cirrhotic patients: A randomized trial. AB - BACKGROUND: Variceal bleeding is a common and life-threatening complication in patients with cirrhosis. Screening with upper endoscopy is recommended but is uncomfortable to patients. Non-invasive assessment with transient elastography for liver/spleen stiffness measurement (LSM and SSM) is accurate in detecting varices. AIMS: To test the hypothesis that a new screening strategy for varices guided by LSM/SSM results (LSSM-guided) is non-inferior to universal endoscopic screening in detecting clinically significant varices in patients with cirrhosis. METHODS: This was a non-inferiority, open-label, randomized controlled trial. Adult patients with known chronic liver diseases, radiological evidence of cirrhosis and compensated liver function. The primary outcome was clinically significant varix diagnosed with upper endoscopy. RESULTS: Between October 2013 and June 2016, 548 patients were randomized to LSSM arm (n = 274) and conventional arm (n = 274) which formed the intention-to-test (ITT) population. Patients in both study arms were predominantly middle-aged men with viral hepatitis-related cirrhosis in 85% of the cases. In the ITT analysis, 11/274 participants in the LSSM arm (4.0%) and 16/274 in the conventional arm (5.8%) were found to have clinically significant varices. The difference between two groups was -1.8% (90% CI, -4.9% to -1.2%, P < .001). The absolute difference in the number of patients with clinically significant varices detected was 5/16 (31.3%) fewer in the LSSM arm. CONCLUSIONS: Non-inferiority of the LSSM-guided screening strategy to the convention approach cannot be excluded by this RCT. This approach should be further evaluated in a cohort of larger sample size with more clinically significant varices. PMID- 28853197 TI - Two cases of musical hallucination successfully treated with quetiapine. PMID- 28853198 TI - Soil fertility shapes belowground food webs across a regional climate gradient. AB - Changes in soil fertility during pedogenesis affect the quantity and quality of resources entering the belowground subsystem. Climate governs pedogenesis, yet how climate modulates responses of soil food webs to soil ageing remains unexplored because of the paucity of appropriate model systems. We characterised soil food webs along each of four retrogressive soil chronosequences situated across a strong regional climate gradient to show that belowground communities are predominantly shaped by changes in fertility rather than climate. Basal consumers showed hump-shaped responses to soil ageing, which were propagated to higher-order consumers. There was a shift in dominance from bacterial to fungal energy channels with increasing soil age, while the root energy channel was most important in intermediate-aged soils. Our study highlights the overarching importance of soil fertility in regulating soil food webs, and indicates that belowground food webs will respond more strongly to shifts in soil resources than climate change. PMID- 28853199 TI - Bacterial infection-triggered acute-on-chronic liver failure is associated with increased mortality. AB - BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by an acute deterioration of liver function in patients with cirrhosis in combination with recently defined organ failures. Our aim was to independently validate the prognostic value of the recently established EASL-CLIF-Consortium definition of ACLF and to identify new predictors of short-term mortality. METHODS: Patients with cirrhosis and the International Classification of Diseases, Tenth Revision diagnosis of (sub)acute liver failure were retrospectively categorized according to the EASL-CLIF-Consortium definition. Logistic regression analyses were performed to identify clinical and epidemiological predictors of 30- and 90-day mortality. RESULTS: From 2008 to 2015, 257 patients were included. Overall, 173 (67%) patients met the EASL criteria for ACLF (grade 1: n = 43 [25%], grade 2: n = 52 [30%], grade 3: n = 79 [45%]). Mortality within 30 days in patients without ACLF was 3.6%, and 18.6%, 37.3% and 62.0% in patients with ACLF grades 1, 2 and 3 respectively. Outcome of patients with bacterial infection-triggered ACLF was distinct from non-infection-triggered ACLF (71.6% vs 33.8% 30-day survival, P < .001), and infection-triggered ACLF was independently associated with increased mortality (odds ratio [OR] = 4.28, P < .001). Pneumonia was a particularly frequent infection and burdened with high mortality. In addition, infections with multidrug-resistant organisms were frequent and independently associated with mortality (P = .030, OR = 4.41), as was glycopeptide antibiotic therapy as initial empirical antibiotic therapy (P = .005). CONCLUSIONS: This study confirmed the EASL-CLIF-Consortium definition of ACLF as strong predictor of mortality in patients with acute decompensation of cirrhosis. However, we have observed a remarkably higher mortality in infection-triggered ACLF compared to other precipitating events. PMID- 28853200 TI - The 2017 Academic Emergency Medicine Consensus Conference: Catalyzing System Change Through Healthcare Simulation: Systems, Competency, and Outcomes. AB - Over the past decade, emergency medicine (EM) took a lead role in healthcare simulation in part due to its demands for successful interprofessional and multidisciplinary collaboration, along with educational needs in a diverse array of cognitive and procedural skills. Simulation-based methodologies have the capacity to support training and research platforms that model micro-, meso-, and macrosystems of healthcare. To fully capitalize on the potential of simulation based research to improve emergency healthcare delivery will require the application of rigorous methods from engineering, social science, and basic science disciplines. The Academic Emergency Medicine (AEM) Consensus Conference "Catalyzing System Change Through Healthcare Simulation: Systems, Competency, and Outcome" was conceived to foster discussion among experts in EM, engineering, and social sciences, focusing on key barriers and opportunities in simulation-based research. This executive summary describes the overall rationale for the conference, conference planning, and consensus-building approaches and outlines the focus of the eight breakout sessions. The consensus outcomes from each breakout session are summarized in proceedings papers published in this issue of Academic Emergency Medicine. Each paper provides an overview of methodologic and knowledge gaps in simulation research and identifies future research targets aimed at improving the safety and quality of healthcare. PMID- 28853201 TI - Response to Cytoplasmic rods and rings in ribavirin and Cytoplasmic rods and rings in mycophenolic acid treatment. PMID- 28853202 TI - Ursodeoxycholic acid: Effects on hepatic unfolded protein response, apoptosis and oxidative stress in morbidly obese patients. AB - BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is a secondary hydrophilic bile acid (BA) used as therapy for a range of hepatobiliary diseases. Its efficacy in non-alcoholic fatty liver disease (NAFLD) is still under debate. Here, we aimed to decipher molecular mechanisms of UDCA in regulating endoplasmic reticulum (ER) homeostasis, apoptosis and oxidative stress in morbidly obese patients. METHODS: In this randomized controlled pharmacodynamic study, liver and serum samples from 40 well-matched morbidly obese NAFLD-patients were analysed. Patients received UDCA (20 mg/kg/d) or no treatment 3 weeks before samples were obtained during bariatric surgery. RESULTS: Patients treated with UDCA displayed higher scoring of steatosis (S), activity (A) and fibrosis (F), the so called SAF-scoring. UDCA partially disrupted ER homeostasis by inducing the expression of the ER stress markers CHOP and GRP78. However, ERDJ4 and sXBP1 levels were unaffected. Enhanced CHOP expression, a suggested pro-apoptotic trigger, failed to induce apoptosis via BAK and BAX in the UDCA treated group. Potentially pro-apoptotic miR-34a was reduced in the vesicle-free fraction in serum but not in liver after UDCA treatment. Thiobarbituric acid reactive substances, 4-hydroxynonenal and mRNA levels of several oxidative stress indicators remained unchanged after UDCA treatment. CONCLUSION: Our data suggest that UDCA treatment has ambivalent effects in NAFLD patients. While increased SAF-scores and elevated CHOP levels may be disadvantageous in the UDCA treated cohort, UDCA's cytoprotective properties potentially changed the apoptotic threshold as reflected by absent induction of pro-apoptotic triggers. UDCA treatment failed to improve the oxidative stress status in NAFLD patients. PMID- 28853203 TI - Transcrestal sinus floor augmentation with immediate implant placement applied in three types of fresh extraction sockets: A clinical prospective study with 1-year follow-up. AB - BACKGROUND: Immediate implant insertion and transcrestal sinus augmentation both can provide a lot of advantages for patients and clinicians. OBJECTIVE: This prospective study aims to verify the use of a modified technique for immediate implant insertion simultaneously with sinus augmentation in different types of sockets. MATERIALS AND METHODS: Thirty-seven patients were recruited for the clinical study and were divided into 3 groups according to the relationship of their maxillary molar roots and sinus floor: group 1 with none of the teeth roots contacts sinus floor; group 2 as at least 1 teeth root contacting sinus floor, but no root is observed penetrating into sinus cavity; group 3 with at least 1 teeth root penetrating into sinus cavity. Implants were inserted after transcrestal sinus floor augmentation and immediately after tooth extraction. The change of mucosa thickness, diagnosis of rhinosinusitis, marginal bone loss (MBL), pocket depth (PD), and sulcus bleeding index were examined through radiographic measurement or clinical monitoring. RESULT: During the study period, no implants failed. The relationship of the root of maxillary molars and sinus floor may have an effect on the bone height of the interradicular crest. Sinus mucosa was observed thicker after surgery. After healing period, sinus mucosa returned as thin as presurgery. At the time of 1-year follow-up, MBL was measured on X-ray (group 1: mesial: 0.63 +/- 0.20 mm, distal: 0.70 +/- 0.14 mm; group 2: mesial: 0.67 +/- 0.21, distal: 0.65 +/- 0.22 mm; group 3: mesial: 0.70 +/- 0.15 mm, distal: 0.73 +/- 0.19 mm). No statistical difference was found in MBL and PD as well as bleeding index among 3 groups. CONCLUSION: In consideration of the advantages of sinus floor augmentation and immediate implant placement, our clinical result confirms that it is promising to combine the 2 techniques for replacing maxillary molars especially when using residual roots as implant orientation and taking full advantage of the interradicular crest bone. PMID- 28853204 TI - Test methods for estimating the efficacy of the fast-acting disinfectant peracetic acid on surfaces of personal protective equipment. AB - AIMS: The work aimed at developing and evaluating practically relevant methods for testing of disinfectants on contaminated personal protective equipment (PPE). METHODS AND RESULTS: Carriers were prepared from PPE fabrics and contaminated with Bacillus subtilis spores. Peracetic acid (PAA) was applied as a suitable disinfectant. In method 1, the contaminated carrier was submerged in PAA solution; in method 2, the contaminated area was covered with PAA; and in method 3, PAA, preferentially combined with a surfactant, was dispersed as a thin layer. In each method, 0.5-1% PAA reduced the viability of spores by a factor of >=6 log10 within 3 min. The technique of the most realistic method 3 proved to be effective at low temperatures and also with a high organic load. Vaccinia virus and Adenovirus were inactivated with 0.05-0.1% PAA by up to >=6 log10 within 1 min. The cytotoxicity of ricin was considerably reduced by 2% PAA within 15 min of exposure. CONCLUSIONS: PAA/detergent mixture enabled to cover hydrophobic PPE surfaces with a thin and yet effective disinfectant layer. SIGNIFICANCE AND IMPACT OF THE STUDY: The test methods are objective tools for estimating the biocidal efficacy of disinfectants on hydrophobic flexible surfaces. PMID- 28853205 TI - Tree-Bark-Shaped N-Doped Porous Carbon Anode for Hydrazine Fuel Cells. AB - Metal-free N-doped porous carbon has great potential as a catalyst for hydrazine oxidation in direct hydrazine fuel cells (DHFCs). However, previous studies have reported only half-cell characterization, and the effect of the pore size distribution has not been intensively investigated. Herein, we report the synthesis of highly active, metal-free N-doped carbon (NDC) by controlling the pore size distribution, and for the first time, the effect of the pore size distribution on the anode performance in a DHFC is investigated. As a result, tree-bark-shaped NDC with meso/macroporous (>10 nm) structures exhibit a remarkable power density of 127.5 mW cm-2 in a DHFC. PMID- 28853206 TI - Assessment of schistosomiasis and soil-transmitted helminths prevalence in school aged children and opportunities for integration of control in local health services in Kwilu Province, the Democratic Republic of the Congo. AB - OBJECTIVE: To determine the prevalence of schistosomiasis (SCH) and soil transmitted helminths (STH) in the Democratic Republic of Congo, and to assess the capacity of the local health centres for diagnosis and treatment. METHODS: Cross-sectional school-based survey in two health districts in the Province of Kwilu. We collected a stool and a urine sample for parasitological examination. Urine filtration and duplicate Kato-Katz thick smears were used for the diagnosis of SCH. Health centres were evaluated using a structured questionnaire. RESULTS: In total, 526 children participated in the study and the overall prevalence of Schistosoma mansoni infection was 8.9% (95% CI: 3.5-13.2) in both districts. The prevalence was higher in Mosango (11.7%; 95% CI: 8.9-14.8) than Yasa Bonga district (6.2%; 95% CI: 1.1-11.4). Urine filtration showed that Schistosoma haematobium infection was not present. The combined STH infection prevalence was 58.1% in both districts; hookworm infection was the most common STH found in 52.9% (95% CI: 29.3-62.4) of subjects, followed by Ascaris lumbricoides 9.3% (95% CI: 5.8-15.5) and Trichuris trichiura 2.1% (95% CI: 0.9-4.9). Mixed STH infections were observed as well as SCH-STH coinfection. CONCLUSION: Further mapping of both SCH and STH burden is needed, and coverage of preventive chemotherapy in school-aged children should be increased. PMID- 28853207 TI - Curcumin ameliorates severe influenza pneumonia via attenuating lung injury and regulating macrophage cytokines production. AB - Curcumin, an active phenolic agent extract from the Curcuma longa, exhibits excellent anti-cancer, anti-inflammation, and neuroprotective effects. We aimed to investigate the anti-influenza role of curcumin in vitro and in vivo. The effect of curcumin on replication of influenza A virus (IAV) was examined in human lung cancer cell line A549, as well as in a mouse model. Curcumin could inhibit IAV in vitro and alleviate the severity of the disease in the mouse after infection with IAV. The results also indicated that curcumin could trigger expression of Heme oxygenase-1 in vivo and attenuate IAV-induced injury to the lung tissue. Furthermore, curcumin could regulate immune response following IAV infection through inhibiting production of local inflammatory cytokines. In addition, curcumin was found to inhibit NF-kappaB signalling in macrophages, as well as the subsequent production of cytokines/chemokines responding to IAV infection, by enhancing IkappaBalpha and AMPK. Our current study supports the potential of curcumin as a promising treatment against IAV infection, whose effect may be mediated by regulating immune response to prevent injury to the lung tissue. PMID- 28853208 TI - Clinical outcomes and toxicity following palliative radiotherapy for childhood cancers. AB - BACKGROUND: Few reports of palliative radiotherapy (RT) for pedialltric malignancies have been published. We described clinical indications, outcomes, and toxicities for children who received palliative RT. PROCEDURE: Pediatric patients (age <=18 years) treated with palliative RT for incurable cancer from January 1 2008 to February 26, 2014 were included. Diagnosis, details of RT, treatment response, toxicity, and survival were retrospectively reviewed. RESULTS: Forty-six patients received 76 RT courses. Fifteen patients (33%) had >=2 courses. Median age at palliative RT was 10.3 years; 54% were male. The most common diagnoses were neuroblastoma (20%) and diffuse intrinsic pontine glioma (17%). The most common indications for RT were oligometastatic disease in asymptomatic patients (39%) and pain (25%). The most common treatment sites were brain (32%) and bone (29%). Median RT dose was 30 Gy. Median number of RT fractions was 12. Sixty-five treatment courses (86%) were delivered with fraction sizes >=2.5 Gy. Twenty-seven treatment courses (36%) were given under general anesthesia. Median follow-up was 3.9 months. Grade 1-2 RT-related toxicity occurred in 21% of treatment courses and 4-8% up to 12 months after RT. Two patients had Grade 3 toxicity during RT (esophagitis). Of symptomatic patients, 91%, 73%, 58%, and 43% had improved or stable symptoms during RT and 0-3, 3-6, and 6-12 months afterwards, respectively. Median survival after palliative RT was 4.2 months. Four of 21 surviving patients (19%) had hospice care at last follow up. CONCLUSIONS: Palliative RT was well tolerated in children with incurable malignancies, with most cases associated with acceptable toxicity, and improved or stable symptoms. PMID- 28853209 TI - Inferior vena cava atresia predisposing to acute lower extremity deep vein thrombosis in children: A descriptive dual-center study. AB - PURPOSE: Thrombosis in the healthy pediatric population is a rare occurrence. Little is known about the optimal treatment or outcomes of children with unprovoked acute lower extremity (LE) deep vein thrombosis (DVT) associated with atresia of the inferior vena cava (IVC). METHODS: We retrospectively analyzed the records of patients with acute LE DVT subsequently found to have IVC atresia who presented to two tertiary pediatric institutions between 2008 and 2016. Data were reviewed for thrombophilia risk factors, treatment, and outcomes. RESULTS: Eighteen patients, aged 13-18 years (median: 16 years), presenting with acute LE DVT were found to have IVC atresia. Three patients also presented with pulmonary embolism. Fourteen patients underwent site-directed thrombolysis in addition to anticoagulation. Five patients (28%) had confirmed or suspected recurrent thrombosis. Thirteen patients (72%) had no identified provocation for DVT. Ten patients (56%) had post-thrombotic syndrome, and 17 of 18 patients remain on indefinite anticoagulation. CONCLUSION: This study suggests that IVC atresia is a risk factor for LE DVT and pulmonary embolism in otherwise healthy children and highlights the importance of dedicated imaging of the IVC in young patients with unprovoked LE DVT. Indefinite anticoagulation may be considered in pediatric patients presenting with unprovoked thrombosis secondary to an atretic IVC. PMID- 28853210 TI - Modulation of Starch Digestibility in Breakfast Cereals Consumed by Subjects with Metabolic Risk: Impact on Markers of Oxidative Stress and Inflammation during Fasting and the Postprandial Period. AB - SCOPE: Decreasing postprandial glycaemic excursions may have a beneficial effect on inflammatory and oxidative stress profiles. In this study, we investigated the impact of carbohydrate digestibility modulation per se, as a means of reducing the glycaemic response, on metabolic and inflammatory responses in subjects with metabolic risk factors. METHODS AND RESULTS: Twenty healthy subjects with metabolic risk consumed a cereal product either high in Slowly Digestible Starch (HSDS) or low in SDS (LSDS) at breakfast daily for 3 weeks, in a cross-over design. Following each 3-week session, postprandial glycaemia, insulinaemia, the lipid profile, inflammation and oxidative stress markers were assessed and compared to those induced by ingestion of a glucose solution (as a reference). The 2-h glycaemic and insulinaemic responses were significantly lower following the HSDS breakfast compared with the LSDS breakfast or glucose. No significant differences between the products were observed in terms of the lipid profile, C reactive protein, IL-6 and tumour necrosis factor alpha. We observed a slight increase in fasting lipid peroxidation markers, including an increase in plasma malondialdehyde (MDA) and a decrease in whole blood glutathione (GSH), without significant alteration of urinary F2-isoprostanes or plasma glutathione peroxidase (GPx) activity. CONCLUSION: Consumption of HSDS products for 3 weeks significantly altered both postprandial glycaemia and insulinaemia, but was not sufficient to modify the inflammatory profile. Consumption of both cereal products was associated with a slightly higher fasting oxidative stress profile. PMID- 28853211 TI - Synthesis of 8-Substituted 2'-Deoxyisoguanosines via Unprotected 8-Brominated 2 Amino-2'-deoxyadenosine. AB - A variety of applications of 8-alkynylated nucleosides has prompted the synthesis of new purine analogues. Bromination of unprotected 2-amino-2'-deoxyadenosine with Br2 /AcOH/AcONa gives 2-amino-8-bromo-2'-deoxyadenosine (87%). The brominated derivative is converted to 8-alkynylated 2-amino-2'-deoxyadenosines by palladium-catalyzed Sonogashira cross-coupling reaction via microwave assistance (81 - 95%). The resulting compounds are further transformed to 8-alkynylated 2' deoxyisoguanosines (52 - 70%). The physical properties of new compounds are investigated. PMID- 28853213 TI - Advances and challenges in the detection of transcriptome-wide protein-RNA interactions. AB - RNA binding proteins (RBPs) play key roles in determining cellular behavior by manipulating the processing of target RNAs. Robust methods are required to detect the numerous binding sites of RBPs across the transcriptome. RNA immunoprecipitation followed by sequencing (RIP-seq) and crosslinking followed by immunoprecipitation and sequencing (CLIP-seq) are state-of-the-art methods used to identify the RNA targets and specific binding sites of RBPs. Historically, CLIP methods have been confounded with challenges such as the requirement for tens of millions of cells per experiment, low RNA yields resulting in libraries that contain a high number of polymerase chain reaction duplicated reads, and technical inconveniences such as radioactive labeling of RNAs. However, recent improvements in the recovery of bound RNAs and the efficiency of converting isolated RNAs into a library for sequencing have enhanced our ability to perform the experiment at scale, from less starting material than has previously been possible, and resulting in high quality datasets for the confident identification of protein binding sites. These, along with additional improvements to protein capture, removal of nonspecific signals, and methods to isolate noncanonical RBP targets have revolutionized the study of RNA processing regulation, and reveal a promising future for mapping the human protein-RNA regulatory network. WIREs RNA 2018, 9:e1436. doi: 10.1002/wrna.1436 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Methods > RNA Analyses in Cells. PMID- 28853212 TI - Tissue glycomics distinguish tumour sites in women with advanced serous adenocarcinoma. AB - In the era of precision medicine, the tailoring of cancer treatment is increasingly important as we transition from organ-based diagnosis towards a more comprehensive and patient-centric molecular diagnosis. This is particularly the case for high-grade serous adenocarcinomas of the ovary and peritoneum, which are commonly diagnosed at an advanced stage, and collectively treated and managed similarly. We characterized the N- and O-glycome of serous ovarian (OC) and peritoneal cancer (PC) tissues using PGC-LC-ESI-IT-MS/MS profiling and validated the discriminatory glycans and their corresponding glyco-gene expression levels using cell lines and transcriptomic data from 232 patients. Overall, the N- and O glycan repertoires of both cancer types were found to comprise mostly of alpha2,6 sialylated glycan structures, with the majority of N-glycans displaying the biantennary mono- and disialylation as well as bisecting-type biantennary glycans. The MS profiling by PGC-LC also revealed several glycan structural isomers that corresponded to LacdiNAc-type (GalNAcbeta1-4GlcNAc) motifs that were unique to the serous ovarian cancers and that correlated with elevated gene expression of B4GALNT3 and B4GALNT4 in patients with serous cancer. Statistical evaluation of the discriminatory glycans also revealed 13 N- and 3 O-glycans (P < 0.05) that significantly discriminated tumour-sampling sites, with LacdiNAc-type N-glycans (m/z 1205.02- and m/z 1059.42- ) being associated with ovarian-derived cancer tissue and bisecting GlcNAc-type (m/z 994.92- ) and branched N-glycans (m/z 1294.02- and m/z 1148.42- ) upregulated at the metastatic sites. Hence, we demonstrate for the first time that OC and PC display distinct molecular signatures at both their glycomic and transcriptomic levels. These signatures may have potential utility for the development of accurate diagnosis and personalized treatments. PMID- 28853214 TI - Long-term evaluation of osteotome sinus floor elevation and simultaneous placement of implants without bone grafts: 10-Year radiographic and clinical follow-up. AB - BACKGROUND: Insertion of an implant in the edentulous posterior maxilla is a challenging procedure because of poor bone quality and increased pneumatization of the maxillary sinus after tooth extraction. To increase the amount of bone, several surgical bone grafting techniques have been used-with considerable morbidity for patients. Osteotome sinus floor elevation (OSFE) is a less invasive technique. The clinical and radiographic outcome of 53 implants placed with this technique without bone graft has been reported previously. PURPOSE: Here we report the clinical and radiographic findings after 10 years of implant load bearing. MATERIAL AND METHODS: In a retrospective study, 34 Astra implants in 25 patients were subjected to 10-year follow-up radiologically and clinically. Each patient received 1 or 2 conical Astra implants. The level of the marginal bone and the height of the residual peri-implant alveolar bone (RPAB) for each implant were measured from digital intra-oral radiographs. RESULTS: Two implants in edentulous patients were lost at the 1-year follow-up, and 1 more at the 3-year examination. There was no loss between 3-year and 10-year follow-up. At 10-year follow-up 36 implants were included. Implants used in single-tooth replacements and in partially edentulous cases had a 100% survival rate. The mean marginal bone loss was 0.6 +/- 0.8 mm. The bone height at the time of implant insertion ranged from 1.8 to 6.9 mm, with a mean value of 4.3 +/- 1.0 mm. At 10-year follow up the mean gain in bone at the implant sites for all implants was 2.6 +/- 1.2 mm. CONCLUSIONS: The OSFE technique is a reliable method for rehabilitation of patients with atrophied posterior maxilla. However, the success of this method is associated with the amount of the residual bone. In the present study, this surgical approach without bone graft showed reliable long-term results with Astra implants. PMID- 28853215 TI - Survival rate of titanium-zirconium narrow diameter dental implants versus commercially pure titanium narrow diameter dental implants: A systematic review. AB - BACKGROUND: Despite the existence of several studies validating the use of narrow diameter implants, most of them are based on pure Ti alloys. There is few clinical evidence of the success of TiZr narrow diameter implants (TiZr NDIs) regarding survival rate (SR) and marginal bone loss (MLB). PURPOSE: The aim of this review was to systematically assess SR, as well as MBL of TiZr NDIs compared to commercially pure titanium narrow diameter implants (cpTi NDIs). MATERIAL AND METHODS: The search was conducted in Medline/PubMed, Cochrane, Scopus, and Embase databases (year 2000 to November 2016). Cohort studies and randomized trials were included. RESULTS: Six clinical studies from the 3453 articles initially identified met the inclusion criteria. There were no statistically significant differences in SR when TiZr NDIs and cpTi NDIs were compared in the 1-year follow up (P = .5), or when comparing TiZr NDIs placed in posterior and anterior regions. There was no difference between groups regarding 1-year SR: -0.01 (95% CI, -0.05-0.03) and MLB: -0.01 mm (95% CI: -0.14-0.12). CONCLUSION: It can be concluded that TiZr NDIs present similar success rates and peri-implant bone resorption to cpTi NDIs. PMID- 28853216 TI - Central nervous system disease in pediatric acute myeloid leukemia. PMID- 28853217 TI - Cytolytic virus activation therapy and treatment monitoring for Epstein-Barr virus associated nasopharyngeal carcinoma in a mouse tumor model. AB - Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein Barr virus (EBV). Expression of viral proteins in the tumor cells is highly restricted. EBV reactivation by CytoLytic Virus Activation (CLVA) therapy triggers de novo expression of early viral kinases (PK and TK) and uses antiviral treatment to kill activated cells. The mechanism of tumor elimination by CLVA was analyzed in NPC mouse model using C666.1 cells. Valproic acid (VPA) was combined with gemcitabine (GCb) to stimulate EBV reactivation, followed by antiviral treatment with ganciclovir (GCV). A single cycle of CLVA treatment resulted in specific tumor cell killing as indicated by reduced tumor volume, loss of EBV positive cells in situ, and paralleled by decreased EBV DNA levels in circulation, which was more pronounced than treatment with GCb alone. In vivo reactivation was confirmed by presence of lytic gene transcripts and proteins in tumors 6 days after GCb/VPA treatment. Virus reactivation was visualized by [124 I]-FIAU accumulation in tumors using PET-scan. This studied showed that CLVA therapy is a potent EBV-specific targeting approach for killing tumor cells. The [124 I]-FIAU appears valuable as PET tracer for studies on CLVA drug dosage and kinetics in vivo, and may find clinical application in treatment monitoring. PMID- 28853218 TI - Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B-precursor acute lymphoblastic leukemia. AB - BACKGROUND: We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians. PROCEDURE: Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346). RESULTS: The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02). CONCLUSIONS: Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B precursor ALL. PMID- 28853219 TI - Numerical activities of daily living in adults with neurofibromatosis type 1. AB - BACKGROUND: This study aimed to identify the mathematical domains affected in adults with neurofibromatosis 1 (NF1) and the impact of the numerical difficulties on the patients' activities of daily living. METHODS: We assessed 28 adult patients with NF1 and 28 healthy control participants. All participants completed the standardised battery of numerical activities of daily living along with clinical batteries of cognitive (Mini-Mental State Examination) and daily functioning (instrumental activities of daily living). The group comparisons of the performance on numerical activities of daily living were carried out using t test correcting for multiple comparisons. RESULTS: The results showed that the NF1 group performed worse than controls in written subtractions, written multiplication, multiplication principles and digit comprehension (dot counting) tasks. Importantly, no significant differences in numerical ecological tasks were found between patients and controls, suggesting a possible use of compensatory strategies in daily living abilities in spite of calculation deficits. CONCLUSION: The findings indicate that NF1 affects calculation but not the basic comprehension or representation of numbers in adult patients. These data have important implications for designing cognitive interventions tailored to the cognitive profile of individuals with NF1. PMID- 28853221 TI - Male urinary paracetamol and semen quality. AB - The endocrine-disrupting properties of paracetamol have been previously demonstrated in rodent studies of abnormal sperm morphology and diminished testosterone production, in addition to epidemiologic studies of diminished couple fecundity. In this study, we examined the relationship between paracetamol and its metabolite p-aminophenol quantified in a single spot urine and semen quality among 501 male partners of couples planning for pregnancy. Men provided a urine specimen and two fresh semen samples collected approximately one month apart and underwent 24-h analysis for 35 semen quality parameters. Paracetamol and p-aminophenol were quantified in urine by ultra-high-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry. The relationship between natural-log-transformed urinary paracetamol and p aminophenol rescaled by their standard deviation and 21 Box-Cox-transformed, 14 non-transformed semen parameters was assessed using linear mixed-effects models. The median concentrations (IQR) of urinary paracetamol and p-aminophenol were 15.5 ng/mL (5.44, 73.5) and 978 ng/mL (500, 1596), respectively. Following adjustment for creatinine and age, a 1-standard deviation increase in log transformed urinary paracetamol was associated with a reduction in beat cross frequency and an increase in DNA fragmentation [beta (95% CI): -0.59 Hz (-1.16, 0.03) and 0.05% (0.01, 0.09), respectively]. These findings were corroborated in models of categorical chemical concentrations; higher concentrations of paracetamol remained associated with reduced beat cross-frequency and increased DNA fragmentation. A 1-standard deviation increase in log-transformed urinary p aminophenol was associated with a reduction in sperm head area [beta (95% CI): 0.1 MUm2 (-0.18, -0.02) and width -0.02 MUm (-0.04, -0.01)]. However, only the association with sperm head area remained statistically significant in models of p-aminophenol quartiles. Our findings suggest that adult male urinary paracetamol is associated with sperm motility and DNA fragmentation, while the metabolite, p aminophenol, is predominantly associated with sperm head morphometry. PMID- 28853220 TI - Hemodynamic Evaluation of a Biological and Mechanical Aortic Valve Prosthesis Using Patient-Specific MRI-Based CFD. AB - Modeling different treatment options before a procedure is performed is a promising approach for surgical decision making and patient care in heart valve disease. This study investigated the hemodynamic impact of different prostheses through patient-specific MRI-based CFD simulations. Ten time-resolved MRI data sets with and without velocity encoding were obtained to reconstruct the aorta and set hemodynamic boundary conditions for simulations. Aortic hemodynamics after virtual valve replacement with a biological and mechanical valve prosthesis were investigated. Wall shear stress (WSS), secondary flow degree (SFD), transvalvular pressure drop (TPD), turbulent kinetic energy (TKE), and normalized flow displacement (NFD) were evaluated to characterize valve-induced hemodynamics. The biological prostheses induced significantly higher WSS (medians: 9.3 vs. 8.6 Pa, P = 0.027) and SFD (means: 0.78 vs. 0.49, P = 0.002) in the ascending aorta, TPD (medians: 11.4 vs. 2.7 mm Hg, P = 0.002), TKE (means: 400 vs. 283 cm2 /s2 , P = 0.037), and NFD (means: 0.0994 vs. 0.0607, P = 0.020) than the mechanical prostheses. The differences between the prosthesis types showed great inter-patient variability, however. Given this variability, a patient-specific evaluation is warranted. In conclusion, MRI-based CFD offers an opportunity to assess the interactions between prosthesis and patient-specific boundary conditions, which may help in optimizing surgical decision making and providing additional guidance to clinicians. PMID- 28853222 TI - Methotrexate still works: comment on the articles by Rohr et al and Hirata et al. PMID- 28853223 TI - Prediabetes awareness among Southeastern European physicians. AB - AIMS/INTRODUCTION: Prediabetes (PD) represents a transitional state where the glucose levels are higher than normal, but not enough for diabetes mellitus diagnosis. As there is a growing number of the population with PD, its early detection and treatment could prevent the development of diabetes mellitus and its complications. We aimed to assess the overall knowledge of PD among medical professionals of different varieties. MATERIALS AND METHODS: A questionnaire based study addressing PD and type 2 diabetes mellitus knowledge among Southeastern European general practitioners, postgraduates, physicians and superior specialists was carried out. RESULTS: A total of 397 physicians completed the questionnaire. The total rate of correct answers from diabetologists, non-diabetologist internists, residents and general practitioners was 69, 56.1, 54 and 53%, respectively. Questions related to the PD definition achieved a total of 46.6% correct answers. Correct responses considering the numerical definition of impaired fasting glucose and impaired glucose tolerance were 46.3 and 46.8%, respectively. Younger physicians had better knowledge of numerical values regarding PD and type 2 diabetes mellitus criteria (P < 0.001). CONCLUSIONS: The present results show that overall knowledge of PD is poor among Southeastern European physicians, which necessitates adequate educational programs on PD in this region. PMID- 28853224 TI - Response to: Letter to the Editor regarding "Changing the surgical dogma in frontal sinus trauma: transnasal endoscopic repair". PMID- 28853225 TI - Regional differences between perisynovial and infrapatellar adipose tissue depots and their response to class II and III obesity in patients with osteoarthritis: comment on the article by Harasymowicz et al. PMID- 28853226 TI - Muscle ultrasonography is a potential tool for detecting fasciitis in dermatomyositis and polymyositis: comment on the article by Yoshida et al. PMID- 28853227 TI - Chlorination-promoted Transformation of Isolated Pentagon Rule C78 into Fused pentagons- and Heptagons-containing Fullerenes. AB - Cage transformations in fullerenes are rare phenomena which are still not fully understood. We report the first skeletal transformation of an Isolated-Pentagon Rule (IPR) isomer of C78 fullerene upon high-temperature chlorination which proceeds by six-step Stone-Wales rearrangements affording non-IPR, non-classical (NC) C78 (NC2)Cl24 with two cage heptagons, six pairs of fused pentagons, and an unprecedented loop-like chlorination pattern. The following loss of a C2 unit results in C76 (NC3)Cl24 containing three cage heptagons. PMID- 28853228 TI - Comparison of effects of anagliptin and alogliptin on serum lipid profile in type 2 diabetes mellitus patients. AB - INTRODUCTION: Anagliptin (ANA) improves dyslipidemia in addition to blood glucose levels. However, there are no comparative studies on the effects of ANA and other dipeptidyl peptidase-4 inhibitors on serum lipid profile. We compared the effects of ANA on serum lipid profile with those of alogliptin (ALO) in type 2 diabetes mellitus outpatients. MATERIALS AND METHODS: The study participants were 87 type 2 diabetes mellitus patients who had been treated with dipeptidyl peptidase-4 inhibitors for >=8 weeks and had a low-density lipoprotein cholesterol (LDL-C) level of >=120 mg/dL. Participants were switched to either 200 mg/day ANA or 25 mg/day ALO for 24 weeks. RESULTS: There was no significant difference in percentage change in LDL-C level at 24 weeks between the ANA and ALO groups. Treatment with ANA for 12 weeks significantly decreased LDL-C levels, one of the secondary end-points. Treatment with ANA for 24 weeks significantly improved apolipoprotein B-100 levels, and the percentage change in LDL-C levels at 24 weeks correlated significantly with the percentage change in apolipoprotein B-100 levels in the ANA group. CONCLUSIONS: The LDL-C-lowering effects of ANA and ALO at 24 weeks were almost similar in patients with type 2 diabetes mellitus. However, the results showed a tendency for a decrease in LDL-C level at 24 weeks in the ANA group, and that such improvement was mediated, at least in part, through the suppression of apolipoprotein B-100 synthesis. PMID- 28853230 TI - Risk factors for multidrug-resistant Gram-negative infection in burn patients. AB - BACKGROUND: Infection with multidrug-resistant (MDR) Gram-negative organisms leads to poorer outcomes in the critically ill burn patient. The aim of this study was to identify the risk factors for MDR Gram-negative pathogen infection in critically ill burn patients admitted to a major tertiary referral intensive care unit (ICU) in Australia. METHODS: A retrospective case-control study of all adult burn patients admitted over a 7-year period was conducted. Twenty-one cases that cultured an MDR Gram-negative organism were matched with 21 controls of similar age, gender, burn size and ICU stay. Multivariable conditional logistic regression was used to individually assess risk factors after adjusting for Acute Burn Severity Index. Adjusted odds ratios (ORs) were reported. P-values < 0.25 were considered as potentially important risk factors. RESULTS: Factors increasing the risk of MDR Gram-negative infection included superficial partial thickness burn size (OR: 1.08; 95% confidence interval (CI): 1.01-1.16; P-value: 0.034), prior meropenem exposure (OR: 10.39; 95% CI: 0.96-112.00; P-value: 0.054), Gram-negative colonization on admission (OR: 9.23; 95% CI: 0.65-130.15; P value: 0.10) and escharotomy (OR: 2.66; 95% CI: 0.52-13.65; P-value: 0.24). For cases, mean age was 41 (SD: 13) years, mean total body surface area burned was 47% (SD: 18) and mean days in ICU until MDR specimen collection was 17 (SD: 10) days. CONCLUSION: Prior meropenem exposure, Gram-negative colonization on admission, escharotomy and superficial partial thickness burn size may be potentially important factors for increasing the risk of MDR Gram-negative infection in the critically ill burn patient. PMID- 28853229 TI - Average spectral power changes at the hippocampal electroencephalogram in schizophrenia model induced by ketamine. AB - The use of ketamine (Ket) as a pharmacological model of schizophrenia is an important tool for understanding the main mechanisms of glutamatergic regulated neural oscillations. Thus, the aim of the current study was to evaluate Ket induced changes in the average spectral power using the hippocampal quantitative electroencephalography (QEEG). To this end, male Wistar rats were submitted to a stereotactic surgery for the implantation of an electrode in the right hippocampus. After three days, the animals were divided into four groups that were treated for 10 consecutive days with Ket (10, 50, or 100 mg/kg). Brainwaves were captured on the 1st or 10th day, respectively, to acute or repeated treatments. The administration of Ket (10, 50, or 100 mg/kg), compared with controls, induced changes in the hippocampal average spectral power of delta, theta, alpha, gamma low or high waves, after acute or repeated treatments. Therefore, based on the alterations in the average spectral power of hippocampal waves induced by Ket, our findings might provide a basis for the use of hippocampal QEEG in animal models of schizophrenia. PMID- 28853231 TI - Treatment at a high-volume centre is associated with improved survival among patients with non-metastatic hepatocellular carcinoma. AB - BACKGROUND & AIMS: The association between case volume and outcomes is well documented for several cancer types. However, it is unknown if patients with hepatocellular carcinoma treated at high-volume centres have improved overall survival. METHODS: About 135 442 patients diagnosed with hepatocellular carcinoma between 2004-2014 were identified in the Commission on Cancer's National Cancer Database and 53 795 patients were excluded for metastatic or node-positive disease. Average annual case volume was calculated as the total number of cases treated per centre from 2004-2014 and dividing by 10. Receiver operating characteristic curves showed the most significant case number threshold between high-volume centres and remaining centres. Univariate and multivariate analyses were performed using Cox regression analysis to determine factors associated with improved survival. Kaplan-Meier curves and log-rank tests were used for overall survival estimates. RESULTS: A total of 81 647 patients with stage I-III hepatocellular carcinoma were treated at a total of 1218 centres. The median [range] case volume per year averaged over the 10-year study period was 48.6 [0.1 205.5]. High-volume centres treated >114 cases of hepatocellular carcinoma annually while remaining centre treated <=114 cases. Median survival for patients treated in high-volume centres and remaining centres were 31.9 and 16.6 months respectively (Log Rank P < .001). On multivariate analysis, average annual case volume was significantly associated with improved survival. CONCLUSIONS: Receiving treatment at a high-volume centre is significantly associated with survival for patients with non-metastatic disease. Improved survival at high volume centres may be related to access to a variety of treatment modalities, multidisciplinary evaluation, and/or subspecialty expertise. PMID- 28853232 TI - Rate Control With Beta-blockers Versus Calcium Channel Blockers in the Emergency Setting: Predictors of Medication Class Choice and Associated Hospitalization. AB - OBJECTIVES: Rate control is an important component of the management of patients with atrial fibrillation (AF). Previous studies of emergency department (ED) rate control have been limited by relatively small sample sizes. We examined the use of beta-blockers (BBs) versus nondihydropyridine calcium channel blockers (CCBs) in ED patients from 24 sites and the associated hospital admission rates. METHODS: In this preplanned substudy, we examined chart data on AF patients who visited one of 24 hospital EDs in Ontario, Canada, between April 2008 and March 2009. We describe the proportion of patients who received either a BB or a CCB, had a heart rate < 110 beats/min 2 hours later, and had any complications. We used hierarchical logistic regression modeling to determine the predictors of BB versus CCB use and to assess the between-hospital variation in use of BBs versus CCBs. Solely in patients who had no rhythm control attempts, we examined the difference in the probability of hospital admission after propensity score matching patients by medication class. RESULTS: Of the 1,639 patients who received either a BB (n = 429) or a CCB (n = 1,210), 70.9% of the patients who received a BB had successful rate control versus 66.1% for a CCB. Complications were rare (2.4%), and the large majority were hypotension (2.0%). In adjusted analyses, predictors of receiving a BB (compared to a CCB) included already being on a BB, being sent in from a doctor's office, or being seen at a teaching hospital. In contrast, patients with evidence of heart failure, prior use of a CCB, a higher presenting heart rate, or a successful pharmacologic cardioversion (vs. no attempt) or who were seen at the highest AF volume EDs were significantly less likely to receive a BB, compared to a CCB. Systematic between-hospital differences accounted for 8% of the variation in BB versus CCB use. Hospital characteristics accounted for the large majority of that variation: after accounting for patient characteristics the between-hospital variation decreased by a relative 2.8%. By further adjusting for hospital characteristics, it decreased by a relative 74.7%. Among propensity score-matched patients with no rhythm control attempts, more CCB patients were admitted (51.6%) compared to BB patients (40.0%; difference of 11.6%; 95% confidence interval = 7.9%-16.2%). CONCLUSIONS: In this study of 24 EDs, CCBs were used more frequently for rate control than BBs, and complications were rare and easily managed using both agents. Variation between hospitals in BB versus CCB use was predominantly due to hospital characteristics such as teaching status and AF volumes, rather than different case mix. Among patients who did not receive attempts at rhythm control, use of a BB for rate control was associated with a lower rate of hospitalization. PMID- 28853233 TI - Terbium (III) coordination polymer-copper (II) compound as fluorescent probe for time-resolved fluorescence 'turn-on' detection of hydrogen sulfide. AB - With recognition of the biological importance of hydrogen sulfide (H2 S), we present a simple and effective fluorescent probe for H2 S using a Tb3+ coordination polymer-Cu2+ compound (DPA/Tb/G-Cu2+ ). Dipicolinic acid (DPA) and guanosine (G) can coordinate with Tb3+ to form a macromolecular coordination polymer (DPA/Tb/G). DPA/Tb/G specifically binds to Cu2+ in the presence of coexisting cations, and obvious fluorescence quenching is observed. The quenched fluorescence can be exclusively recovered upon the addition of sulfide, which is measured in the mode of time-resolved fluorescence. The fluorescence intensities of the DPA/Tb/G-Cu2+ compound enhance linearly with increasing sulfide concentrations from 1 to 30 MUM. The detection limit for sulfide in aqueous solution is estimated to be 0.3 MUM (at 3sigma). The DPA/Tb/G-Cu2+ compound was successfully applied to sense H2 S in human serum samples and exhibited a satisfactory result. It displays some desirable properties, such as fast detection procedure, high selectivity and excellent sensitivity. This method is very promising to be utilized for practical detection of H2 S in biological and environmental samples. PMID- 28853234 TI - Cross-Coupling of alpha-Carbonyl Sulfoxonium Ylides with C-H Bonds. AB - The functionalization of carbon-hydrogen bonds in non-nucleophilic substrates using alpha-carbonyl sulfoxonium ylides has not been so far investigated, despite the potential safety advantages that such reagents would provide over either diazo compounds or their in situ precursors. Described herein are the cross coupling reactions of sulfoxonium ylides with C(sp2 )-H bonds of arenes and heteroarenes in the presence of a rhodium catalyst. The reaction proceeds by a succession of C-H activation, migratory insertion of the ylide into the carbon metal bond, and protodemetalation, the last step being turnover-limiting. The method is applied to the synthesis of benz[c]acridines when allied to an iridium catalyzed dehydrative cyclization. PMID- 28853236 TI - The Language of Data Program: Use of Gaming to Promote Critical Appraisal Skills. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning and implementation of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 28853235 TI - Efficiency of different storage media for avulsed teeth in animal models: a systematic review. AB - BACKGROUND/AIMS: Tooth avulsion consists of the complete displacement of a tooth from the alveolar socket. When immediate replantation is not possible, the avulsed tooth should be kept in a storage medium capable of maintaining the viability of periodontal ligament (PDL) cells on the root surface. However, there is no consensus on the best storage medium able to prevent sequels such as ankylosis and tooth resorption. The aim of this study was to perform a systematic review to evaluate the in vivo effectiveness of different storage media for avulsed teeth. METHODS: Two reviewers performed a database search for studies published between January 1950 and December 2015 which were indexed in the PubMed, Scopus, Web of Science, and Bireme databases. An additional manual search was performed. Studies with animal models that evaluated tooth avulsion, storage media, and replantation were included. After full-text analysis of the potentially relevant studies, the selected studies were included in the systematic review. RESULTS: The database search found 157 distinct studies evaluating avulsed teeth storage media. However, only six studies met the selection criteria and were included in the review. There was a high variability in the study estimates for the parameters analyzed. When assessing the quality and level of evidence of each study, one study was rated as having a very low level of evidence, four studies had low levels of evidence, and one had a moderate level of evidence. CONCLUSION: As a result of data heterogeneity and limitations of the studies, there was insufficient evidence to determine the most effective storage medium for avulsed teeth. PMID- 28853237 TI - Pixel classification method in optical coherence tomography for tumor segmentation and its complementary usage with OCT microangiography. AB - A novel machine-learning method to distinguish between tumor and normal tissue in optical coherence tomography (OCT) has been developed. Pre-clinical murine ear model implanted with mouse colon carcinoma CT-26 was used. Structural-image-based feature sets were defined for each pixel and machine learning classifiers were trained using "ground truth" OCT images manually segmented by comparison with histology. The accuracy of the OCT tumor segmentation method was then quantified by comparing with fluorescence imaging of tumors expressing genetically encoded fluorescent protein KillerRed that clearly delineates tumor borders. Because the resultant 3D tumor/normal structural maps are inherently co-registered with OCT derived maps of tissue microvasculature, the latter can be color coded as belonging to either tumor or normal tissue. Applications to radiomics-based multimodal OCT analysis are envisioned. PMID- 28853239 TI - Editorial: Anti-Citrullinated Protein Antibody, Anti-Carbamylated Protein Antibody, and Rheumatoid Arthritis: Azurophilic Granules Sing the Blues. PMID- 28853238 TI - Herpes Zoster as a Risk Factor for Incident Giant Cell Arteritis. AB - OBJECTIVE: Histopathologic studies have implicated herpes zoster (HZ) as a causative organism of giant cell arteritis (GCA). The purpose of this study was to assess the epidemiologic association of HZ events with incident GCA. METHODS: We performed a retrospective cohort study in 2 large independent US administrative data sets: Medicare 5% and Truven Health Analytics MarketScan. Eligible subjects had 12 months of continuous coverage, were >50 years old, and had no history of GCA or polymyalgia rheumatica. HZ events (complicated and uncomplicated) and GCA were identified by the presence of International Classification of Diseases, Ninth Revision, Clinical Modification codes from physician visit or hospital discharge records. Antiviral therapies and vaccinations were identified from prescription claims and drug codes. Risk of incident GCA was calculated using multivariable Cox proportional hazards regression. RESULTS: Among 16,686,345 subjects, a total of 5,942 GCA cases occurred, with 3.1% (MarketScan) and 6.0% (Medicare) having preceding HZ events. Unadjusted GCA incidence rates were highest in the groups with complicated and uncomplicated HZ. After multivariable adjustment, complicated HZ was associated with an increased risk of GCA (hazard ratio [HR] 1.99 [95% confidence interval (95% CI) 1.32-3.02] in the Medicare cohort and 2.16 [95% CI 1.46-3.18] in the MarketScan cohort), as was uncomplicated HZ (HR 1.42 [95% CI 1.02-1.99] and HR 1.45 [95% CI 1.05-2.01] in the respective cohorts). Vaccination and antiviral treatment were not consistently associated with GCA risk, although antiviral treatment was marginally associated with a decreased risk of GCA in the Medicare cohort (HR 0.67 [95% CI 0.46-0.99]). CONCLUSION: HZ is associated with an increased risk of GCA. The infrequency of HZ in GCA patients suggests that it is only one potential trigger for GCA. Antivirals and vaccination did not consistently mitigate this risk. PMID- 28853240 TI - Association of the Presence of Anti-Carbamylated Protein Antibodies in Early Arthritis With a Poorer Clinical and Radiologic Outcome: Data From the French ESPOIR Cohort. AB - OBJECTIVE: To assess the prevalence of anti-carbamylated protein (anti-CarP) antibodies in a French cohort of patients with early arthritis and to investigate their association with clinical features, final diagnosis, prognosis, and comorbidities. METHODS: The presence of anti-CarP antibodies among patients with early arthritis in the French Etude et Suivi des Polyarthrites Indifferenciees Recentes (ESPOIR) cohort (n = 720) was determined using enzyme-linked immunosorbent assay. We investigated the prevalence of anti-CarP antibodies in different patient subgroups stratified according to anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) status. Diagnostic and prognostic values of the test were evaluated in this population. RESULTS: Anti-CarP antibodies were present in approximately one-third of the patients (32.6%) and in 23.6% of the patients who were seronegative for both RF and ACPA. Anti-CarP positivity was associated with a more active disease status at baseline and over time. Anti-CarP-positive patients had a significantly higher Disease Activity Score in 28 joints using the erythrocyte sedimentation rate at month 36 than anti CarP-negative patients (3.1 +/- 0.11 versus 2.8 +/- 0.06; P = 0.03). Anti-CarP positive early arthritis was associated with a higher risk of developing erosions after 96 months of follow-up (55.6% of anti-CarP-positive patients versus 37.3% of anti-CarP-negative patients) (odds ratio 2.1 [95% CI 1.2-3.6]; P = 0.009). This association was particularly true when anti-CarP was associated with ACPA positivity. Moreover, ACPA positivity alone in early arthritis was not associated with a higher risk of erosive evolution. CONCLUSION: Our findings indicate that anti-CarP antibodies are present in one-third of patients with early arthritis and in one-fourth of the RF-negative and ACPA-negative patients. They are particularly associated with a more severe radiographic outcome. Anti-CarP antibody positivity may help to accurately identify those at risk of erosive evolution in an early arthritis population. PMID- 28853241 TI - Metabolic compensation constrains the temperature dependence of gross primary production. AB - Gross primary production (GPP) is the largest flux in the carbon cycle, yet its response to global warming is highly uncertain. The temperature dependence of GPP is directly linked to photosynthetic physiology, but the response of GPP to warming over longer timescales could also be shaped by ecological and evolutionary processes that drive variation in community structure and functional trait distributions. Here, we show that selection on photosynthetic traits within and across taxa dampens the effects of temperature on GPP across a catchment of geothermally heated streams. Autotrophs from cold streams had higher photosynthetic rates and after accounting for differences in biomass among sites, biomass-specific GPP was independent of temperature in spite of a 20 degrees C thermal gradient. Our results suggest that temperature compensation of photosynthetic rates constrains the long-term temperature dependence of GPP, and highlights the importance of considering physiological, ecological and evolutionary mechanisms when predicting how ecosystem-level processes respond to warming. PMID- 28853242 TI - Resilience to suicide ideation: A cross-cultural test of the buffering hypothesis. AB - Depression and suicide ideation are common in student populations across the world. The present study investigated factors buffering the association between depression and suicide ideation. A total of 2,687 Chinese students and 601 German students took part in the investigation. Social support, satisfaction with life, self-efficacy, psychosocial stress resistance, and positive mental health were considered as resilience factors moderating the association between depressive symptoms and suicide ideation within both samples. Positive mental health moderated the impact of depressive symptoms on suicide ideation in German and Chinese students. Life satisfaction moderated the impact of depressive symptoms on suicide ideation in German students. Social support moderated the impact of depressive symptoms on suicide ideation in Chinese students. No interaction effects were found for self-efficacy and psychosocial stress resistance. Positive mental health, satisfaction with life, and perceived social support seem to confer resilience and should be taken into account, when assessing individuals for suicide risk. PMID- 28853243 TI - Retrospective evaluation of the effectiveness of xylazine for inducing emesis in cats: 48 cats (2011-2015). AB - OBJECTIVE: To determine the effectiveness of xylazine for the induction of emesis in cats that were suspected of ingesting potentially toxic substances or foreign objects. DESIGN: Retrospective study. SETTING: Private emergency and specialty referral hospital. ANIMALS: Forty-eight client-owned cats that were administered xylazine to induce emesis for decontamination of a toxic substance or expulsion of an ingested foreign object. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The medical records of 48 cats presenting for known or suspected ingestion of foreign material that underwent decontamination with xylazine were reviewed. Signalment, material ingested, dose and route of xylazine administration, success of emesis and recovery of foreign material ingested, use of a reversal agent, and adverse effects were noted. The induction of emesis was successful in 29/48 (60%) of cats. Sedation was the most common adverse effect and was noted in 15/48 (31%) of patients. CONCLUSIONS: Xylazine is safe and reasonably effective at inducing emesis in cats. PMID- 28853244 TI - Optical coherence tomography image denoising using Gaussianization transform. AB - We demonstrate the power of the Gaussianization transform (GT) for modeling image content by applying GT for optical coherence tomography (OCT) denoising. The proposed method is a developed version of the spatially constrained Gaussian mixture model (SC-GMM) method, which assumes that each cluster of similar patches in an image has a Gaussian distribution. SC-GMM tries to find some clusters of similar patches in the image using a spatially constrained patch clustering and then denoise each cluster by the Wiener filter. Although in this method GMM distribution is assumed for the noisy image, holding this assumption on a dataset is not investigated. We illustrate that making a Gaussian assumption on a noisy dataset has a significant effect on denoising results. For this purpose, a suitable distribution for OCT images is first obtained and then GT is employed to map this original distribution of OCT images to a GMM distribution. Then, this Gaussianized image is used as the input of the SC-GMM algorithm. This method, which is a combination of GT and SC-GMM, remarkably improves the results of OCT denoising compared with earlier version of SC-GMM and even produces better visual and numerical results than the state-of-the art works in this field. Indeed, the main advantage of the proposed OCT despeckling method is texture preservation, which is important for main image processing tasks like OCT inter- and intraretinal layer analysis. Thus, to prove the efficacy of the proposed method for this analysis, an improvement in the segmentation of intraretinal layers using the proposed method as a preprocessing step is investigated. Furthermore, the proposed method can achieve the best expert ranking between other contending methods, and the results show the helpfulness and usefulness of the proposed method in clinical applications. PMID- 28853245 TI - Treatment of peripheral vestibular dysfunction using photobiomodulation. AB - Gentamicin, which is still used in modern medicine, is a known vestibular toxic agent, and various degrees of balance problems have been observed after exposure to this pharmacologic agent. Photobiomodulation is a candidate therapy for vertigo due to its ability to reach deep inner ear organs such as the cochlea. Previous reports have suggested that photobiomodulation can improve hearing and cochlea function. However, few studies have examined the effect of photobiomodulation on balance dysfunction. We used a rat model to mimic human vestibulopathy resulting from gentamicin treatment and evaluated the effect of photobiomodulation on vestibular toxicity. Slow harmonic acceleration (SHA) rotating platform testing was used for functional evaluation and both qualitative and quantitative epifluorescence analyses of cupula histopathology were performed. Animals were divided into gentamicin only and gentamicin plus laser treatment groups. Laser treatment was applied to one ear, and function and histopathology were evaluated in both ears. Decreased function was observed in both ears after gentamicin treatment, demonstrated by low gain and no SHA asymmetry. Laser treatment minimized the damage resulting from gentamicin treatment as shown by SHA asymmetry and recovered gain in the treated ear. Histology results reflected the functional results, showing increased hair cell density and epifluorescence intensity in laser-treated cupulae. PMID- 28853247 TI - Activatable clinical fluorophore-quencher antibody pairs as dual molecular probes for the enhanced specificity of image-guided surgery. AB - The emergence of fluorescently labeled therapeutic antibodies has given rise to molecular probes for image-guided surgery. However, the extraneous interstitial presence of an unbound and nonspecifically accumulated probe gives rise to false positive detection of tumor tissue and margins. Thus, the concept of tumor-cell activation of smart probes provides a potentially superior mechanism of delineating tumor margins as well as small tumor deposits. The combination of molecular targeting with intracellular activation circumvents the presence of extracellular, nonspecific signals of targeted probe accumulation. Here, we present a demonstration of the clinical antibodies cetuximab (cet, anti-EGFR mAb) and trastuzumab (trast, anti-HER-2 mAb) conjugated to Alexa Fluor molecules and IRDye QC-1 quencher optimized at the ratio of 1?2?6 to provide the greatest degree of proteolytic fluorescence activation, synonymous with intracellular lysosomal degradation. The cet-AF-Q-C1 conjugate (1?2?6) provides up to 9.8-fold proteolytic fluorescence activation. By preparing a spectrally distinct, irrelevant sham IgG-AF-QC-1 conjugate, a dual-activatable probe approach is shown to enhance the specificity of imaging within an orthotopic AsPC-1 pancreatic cancer xenograft model. The dual-activatable approach warrants expedited clinical translation to improve the specificity of image-guided surgery by spectrally decomposing specific from nonspecific probe accumulation, binding, and internalization. PMID- 28853248 TI - [Preface for special issue on veterinary biotechnology (2017)]. AB - Veterinary biotechnologies that represent the applications of biotechnologies in veterinary science are advancing rapidly in the last decade in spite of relatively late kickoff. This special issue consists of four sections, reviews, new technologies, new methods and others, presenting the recent progress in diagnostic assays, vaccines and others of emerging and reemerging animal infectious diseases. PMID- 28853246 TI - Use of Mueller matrix polarimetry and optical coherence tomography in the characterization of cervical collagen anisotropy. AB - Preterm birth (PTB) presents a serious medical health concern throughout the world. There is a high incidence of PTB in both developed and developing countries ranging from 11% to 15%, respectively. Recent research has shown that cervical collagen orientation and distribution changes during pregnancy may be useful in predicting PTB. Polarization imaging is an effective means to measure optical anisotropy in birefringent materials, such as the cervix's extracellular matrix. Noninvasive, full-field Mueller matrix polarimetry (MMP) imaging methodologies, and optical coherence tomography (OCT) imaging were used to assess cervical collagen content and structure in nonpregnant porcine cervices. We demonstrate that the highly ordered structure of the nonpregnant porcine cervix can be observed with MMP. Furthermore, when utilized ex vivo, OCT and MMP yield very similar results with a mean error of 3.46% between the two modalities. PMID- 28853249 TI - [Strategies for producing high-yield viral vaccine antigens]. AB - Vaccination is an important strategy to prevent infectious diseases. However, low antigen yield of vaccine producing strains may lead to high cost of vaccines, low antigen production and vaccine failure. In recent years, many efforts have been made to improve the antigen yield of many vaccines. This mini-review summarizes various methods for increasing the antigen yield for vaccine production, including genetic modification of viruses, improvement of the adaptation of viruses to cells, and optimization of antigen expression systems and manufacturing procedures. Furthermore, we discuss the advantages and the problems of current strategies, as well as indicate the perspectives. PMID- 28853250 TI - [RS-1 enhanced the efficiency of CRISPR-Cas9 mediated knock-in of human lactoferrin]. AB - This study aims to knock out the goat beta-lactoglobulin (BLG) gene using CRISPR Cas9 system and knock in human lactoferrin (hLF) at the BLG locus, and further study the effect of RAD51 stimulatory compound (RS-1) on homologous recombination efficiency. First, we designed an sgRNA targeting the first exon of goat BLG gene and constructed a co-expression vector pCas9-sgBLG. This sgRNA vector was then transfected into goat ear fibroblasts (GEFs), and the target region was examined by T7EN1 assay and sequencing. Second, we constructed a targeting vector pBHA-hLF NIE including NEO and EGFP genes based on BLG gene locus. This targeting vector together with pCas9-sgBLG expression vector was co-transfected into GEFs. Transfected cells were then treated with 0, 5, 10 and 20 MUmol/L RS-1 for 72 h to analyse the EGFP expression efficiency. Next, we used 800 MUg/mL G418 to screen G418-resistent cell clones, and studied hLF site-specific knock-in cell clones by PCR and sequencing. The editing efficiency of sgBLG was between 25% and 31%. The EGFP expression efficiency indicated that the gene knock-in efficiency was improved by RS-1 in a dose-dependent manner, which could reach 3.5-fold compared to the control group. The percentage of positive cells with hLF knock-in was increased to 32.61% when 10 MUmol/L RS-1 was used. However, when the concentration of RS-1 increased to 20 MUmol/L, the percentage of positive cells decreased to 22.22% and resulted in an increase of senescent cell clone number. These results suggested that hLF knock-in and BLG knock-out in GEFs were achieved by using CRISPR/Cas9 system, and optimum concentration of RS-1 could improve knock-in efficiency, which provides a reference for efficiently obtaining gene knock-in cells using CRISPR/Cas9 in the future. PMID- 28853251 TI - [Expression and antiviral activity of a chimeric porcinized monoclonal antibody (cHQ06) against E2 protein of classical swine fever virus]. AB - Classical swine fever (CSF), one of OIE-listed diseases, is a highly contagious and economically important disease of pigs. Classical swine fever virus (CSFV) is the causative agent of CSF. The capsid (C) protein and the glycoproteins Erns, E1 and E2, are structural components of the virus. E2 is the most immunogenic protein of the CSFV glycoproteins, inducing neutralizing antibodies that provide protection against lethal CSFV challenge. In a previous study, we developed a murine MAb HQ06 against the E2 protein of CSFV. In this study, the variable region genes from HQ06 and constant regions gene of swine antibody are fused and cloned into the eukaryotic expression vectors to establish a cell line which can stably express a chimeric porcinized MAb (cHQ06) against E2 in CHO cell. The purified cHQ06 antibody protein was determined to be successfully generated, which exhibited high reactivity between cHQ06 and the E2 protein of CSFV by enzyme-linked immunosorbent assay (ELISA) and Western blotting. More importantly, we investigated the neutralizing activity of cHQ06 against CSFV. In conclusion, this study generated cHQ06 for efficient and stable production which can be used against to develop novel diagnostic assays, investigate the structure and function of the E2 protein and generate novel preparations of diagnosis and treatment. PMID- 28853252 TI - [Identification of epitope recognized by a monoclonal antibody against VP2 protein of bluetongue virus serotype 8]. AB - To confirm the B cell epitope recognized by monoclonal antibody (MAb) 3G11 of bluetongue virus type 8 (BTV-8) VP2 protein prepared in our laboratory, antigen epitopes recognized by 3G11 were screened and identified by phage display technology. KLLAT sequence was found by sequencing of blue spot after four rounds panning and 283LL284 of common short peptide sequence was obtained after comparison to amino acid sequence of BTV-8 VP2 protein. The peptide sequences KLLAA, KALAT, KLAAT and KLLAT were synthesized and identified by indirect ELISA. KLLAA and KLLAT bound strongly with supernatant and as cites of 3G11 cells and reacted specifically with BTV-8 positive standard sera. Further sequence analysis showed that amino acid sequence 283LL284 was conserved among different serotypes of BTV-8 strains, and283LL284 was the key amino acids of antigen epitopes recognized by 3G11. This study laid the foundation to establish type 8 BTV specific immunological detection methods. PMID- 28853253 TI - [Establishment of a high sensitive indirect ELISA for detecting specific antibodies against H9 subtype avian influenza virus]. AB - H9 subtype avian influenza virus causes worldwide epidemic, resulting in enormous economic losses of poultry production. In the present study, an indirect ELISA method was established for more accurate and specific detection. The recombinant protein of the globular head domain of HA of H9 subtype avian influenza virus was used as antigen. Specific blocking buffers and dilution buffers were determined to increase the sensitivity and specificity. The sensitivity of ELISA was higher than that of hemagglutination inhibition (HI) test. The coating antigen is very specific and no cross-reactivity with positive serum against H3N2, H5N2 and H7N9 subtype influenza viruses, Newcastle disease virus, avian infectious bronchitis virus, avian infectious disease virus, and egg drop syndrome virus. Two hundred of clinical sera samples were examined. The results indicate the coincidence rate between ELISA and HI test reached 97%. In addition, there was a positive correlation between OD450 values and the logarithm of HI titer to the base 2 of an individual serum sample (R2=0.981 1). PMID- 28853254 TI - [Development and application of real-time RT-PCR and S1 protein-based indirect ELISA for porcine deltacoronavirus]. AB - Porcine deltacoronavirus (PDCoV) has been recently recognized as an emerging viral pathogen that causes diarrhea in newborn piglets. A total of 254 small intestinal or fecal samples collected from 10 provinces including Henan, Hunan, Zhejiang, Jiangxi, Anhui, Hebei, Heilongjiang, Jiangsu, Shandong and Shanghai between 2014 and 2015, were screened by quantitative RT-PCR targeting the viral M gene. Eleven PDCoV positive samples were identified with a total positive rate of 4.33%. An indirect enzyme-linked immunosorbent assay (ELISA) was developed based on the recombinant S1 protein of PDCoV. This assay was used to test 609 serum samples of pigs with diarrhea symptoms collected from 10 provinces between 2015 and 2016. The positive rate of PDCoV antibody was 44.17% (269/609). The two methods can be used to monitor the PDCoV epidemiology in the levels of PDCoV specific RNA or antibody, helping better prevent and control PDCoV. PMID- 28853255 TI - [Preparation and identification of polyclonal antibodies specific for nsp4 protein of porcine reproductive and respiratory syndrome virus]. AB - To obtain specific antibodies against nsp4 protein of porcine reproductive and respiratory syndrome virus (PRRSV), nsp4 gene was amplified by RT-PCR and cloned into pET-28a(+) vector, designated pET28a-nsp4. pET28a-nsp4 was transformed into Escherichia coli Trasseta (DE3) cells and expressed after induction of IPTG. SDS PAGE analysis showed that the recombinant protein was expressed in soluble form with the molecular weight of 26 kDa. The soluble fusion protein in the supernatant was purified using Ni+-NTA affinity chromatography. New Zealand rabbits were immunized by the purified nsp4 and anti-sera against nsp4 were obtained. The titer of polyclonal antibodies was about 106 and showed good specificity and sensitivity in the immunofluorescence assay and Western blotting analysis. The polyclonal antibodies also recognized native nsp4 form PRRSV infected Marc-145 cells, providing a useful tool in PRRSV replication mechanism study. PMID- 28853256 TI - [Establishment of two competitive ELISAs for specific detection of bluetongue virus serotype 4]. AB - To develop a clinical diagnosis technique for bluetongue virus infection, we established serotype-specific methods to detect serotype 4 of bluetongue virus (BTV-4). Two monoclonal antibodies (mAbs) against VP2 protein of BTV-4, named 4A 1G7 and 4B-1B6, were used as competitive antibodies in the competitive enzyme linked immunosorbent assays (C-ELISA). We detected 50 negative serum samples from sheep, goats and cattle by C-ELISA. The cut-off values of 4A-1G7 and 4B-1B6 mAbs were 49% and 40%, respectively. The results of the sensitivity, specificity and repeatability by detecting standard positive serum, were consistent with the general standard of Office International Des Epizooties. Furthermore, serum samples of BTV-4, BTV-18 and BTV-20 infection could be screened out through the combined C-ELISAs by 4A-1G7 and 4B-1B6 mAbs. Thus, this technique may diagnose BTV-4, BTV-18 and BTV-20 infections. PMID- 28853257 TI - [Clinical detection of seven porcine diarrhea-associated viruses and evolution analysis of porcine kobuvirus]. AB - In this study, a multiplex RT-PCR method was developed for detection of seven diarrhea-associated porcine viruses, including porcine teschovirus (PTV), porcine sapovirus (PSV), porcine deltacornavirus (PDCoV), porcine kobuvirus (PKV), porcine sapovirus (PSaV), porcine astrovirus (PAstV) and porcine torovirus (PToV). A total of 419 samples were screened by this method and results showed that PKV had the highest positive rate of 26.98%?45.79% and its mixed infection rate reached 9.52%-18.54%. On account of high positive rate of PKV and its important role in diarrhea disease, complete genomic sequences of three PKV positive samples were further sequenced. Three PKV labeled as PD-PKV, JS-PKV and CM-PKV were classified into porcine kobuvirus genus and had far genetic distance with other kobuviruses. The complete genome homologies among them were 88.1% 89.1%. CM-PKV had the highest identity with the Chinese strain JS-02a-CHN/2013 reported in 2013 while JS-PKV and PD-PKV were most closed to the K-30 HUN/2008/HUN strain reported in Hungary in 2008. This illustrates the significant genetic differences of the different PKV isolates in Shanghai while its relationship with the viral pathogenicity still needs to be explored. This research provides references for further understanding the prevalence of PKV and its role in swine diarrhea. PMID- 28853258 TI - [Expression of Laminin gene family in porcine pluripotent stem cells]. AB - Laminin (LN) proteins are important components of extracellular matrix. These proteins regulate cell proliferation, differentiation, migration, and tissue repair. The LN family has 12 genes that encode 5 alpha, 4 beta, and 3 gamma proteins. LamininA5 (LAMA5) as an important gene can support pluripotent cell growth and have been widely studied. However, porcine LAMA5 is absent in all tested porcine genomic databases so far. In this study, we confirmed for the first time the existence of porcine LAMA5 through bioinformatics analysis, and verified this result by cDNA cloning and sequencing. To reveal the expression pattern of Laminin gene family, we detected the expression of Laminin genes in porcine tissues, somatic cells, and porcine induced pluripotent stem cells (piPSCs). The results showed that an alternative splicing variant of Laminin B1 (LAMB1-a) was found exclusively in all tested piPSCs. The expression of this alternative splicing variant is positively correlated with the pluripotent state of piPSCs. The above findings provide evidences and foundations for the father use of LN as extracellular matrix to facilitate the derivation and culture of porcine pluripotent stem cells. PMID- 28853259 TI - [Nuclease activity of the recombinant plancitoxin-1-like proteins with mutations in the active site from Trichinella spiralis]. AB - Although there are 125 predicted DNase II-like family genes in the Trichinella spiralis genome, plancitoxin-1-like (Ts-Pt) contains the HKD motif, a typical conserved region of DNase II, in N- and C-terminal. It is generally believed that histidine is the active site in DNase II. To study the nuclease activity of recombinant Ts-Pt with mutations in the active site from T. spiralis, different fragments of the mutated Ts-Pt genes were cloned using overlap PCR technique and inserted into the expressing vector pET-28a(+), and transformed into Escherichia coli Rosseta (DE3). The fusion proteins were purified by Ni-NTA affinity chromatography and SDS-PAGE. Nuclease activity of the recombinant proteins was detected by agarose gel electrophoresis and nuclease-zymography. The recombinant plasmids harboring the mutated Ts-Pt genes were constructed and expressed as inclusive body in a prokaryotic expression system. After renaturation in vitro, the recombinant proteins had no nuclease activity according to agarose gel electrophoresis. However, the expressed proteins as inclusive body displayed the ability to degrade DNA after renaturation in gel. And the nuclease activity was not affected after subjected to mutation of active site in N- and C-termini of Ts Pt. These results provide the basis to study the relationship between DNase II like protein family and infection of T. spiralis. PMID- 28853260 TI - [Effect of porcine epidemic diarrhea virus nsp1 on type I interferon response]. AB - Porcine epidemic diarrhea virus (PEDV) inhibits the host typeIinterferon and cellular antiviral response, but its inhibition mechanism is unclear, and the roles of PEDV nonstructural proteins in regulating typeIinterferon responses have been seldom studied. To study the effect of nsp1 on typeIinterferon response, nsp1 gene was cloned into a eukaryotic expression vector pCAGGS. The expression of nsp1 in transfected cells was determined by Western blot and indirect immunofluorescence assay. The effects of nsp1 on the induction of typeIinterferon were evaluated by dual luciferase reporter gene assay, ELISA and VSV bioassay. Western blot and indirect immunofluorescence assay showed that nsp1 was highly expressed in transfected cells and PEDV-infected cells. Dual luciferase reporter gene assay results indicated that nsp1 strongly inhibited the IFN-beta promoter activity, and the inhibitory effect was nsp1 dose-dependent. ELISA results showed that nsp1 significantly inhibited the expression of IFN-beta in protein level. And VSV replication-inhibition bioassay revealed that nsp1 significantly inhibited typeIIFN antiviral activities induced by poly(I:C). Our results implied that nsp1 was a highly conserved protein of PEDV and exhibited antagonistic function on interferon promoter activity. The results have laid a foundation for further understanding the immune evasion mechanism of PEDV and for developing new effective vaccine against PEDV. PMID- 28853261 TI - [Expression and assembly of chimeric flagellins in Escherichia coli BL21(DE3) and Salmonella]. AB - Flagellin can be expressed in monomeric or polymeric form based on assembly. The difference of these two forms of flagellin is less studied. In this experiment, recombinant plasmid pET-fliC/M2e2 was transferred into Escherichia coli BL21(DE3) and Salmonella SL5928 to express chimeric flagellin, mfliC/M and pfliC/M, respectively, and then their assembly characteristics were analyzed. Sodium dodecyl sulfate polyacrylamide gel electrophoresis results indicated that the two recombinant bacteria could successfully express chimeric flagellin. The transmission electronic microscope observation showed that no flagella were found on the surface of recombinant E. coli, whereas it was found for recombinant Salmonella. After purification, distinct circular dichroism spectra between them were found and pfliC/M showed the similar structure as wild-type flagellin, but not for mfliC/M. The dynamic light scattering assay also indicated that the polymerization of mfliC/M was much lower than that for pfliC/M. Three hours after transfection into mouse peritoneal macrophages, both could induce interleukin 1beta secretion, but mfliC/M is stronger than pfliC/M. These data will be helpful for the selection of expression form of flagellin. PMID- 28853262 TI - [New methods for cloning large gene clusters based on CRISPR/cas9]. AB - Cloning of large genomic sequences is an enabling technology in synthetic biology. To obtain large gene fragments, traditional cloning methods are faced with various defects, for instance, random library cloning relies always on high throughput screening. It is difficult to get gene fragments more than 10 kb by PCR amplification. Assembly of small fragments is labor intensive with high mutation rates. It is difficult to find suitable cleavage sites on the fragment ends by restriction endonuclease. Recently genome-wide editing creates a new high performance large fragments cloning methods. For example, CRISPR/cas9 system can identify and cut 20 bp nucleic acid sequences recognition sites used to obtain any desired gene fragments; if combined with Gibson or transformation associated recombination (TAR) assembly technology, these methods can efficiently clone large fragments. This article introduces large fragments cloning technology by classification, then proposes the choice criteria of methods for cloning gene fragments of different sizes. PMID- 28853263 TI - [Plant active LTR retrotransposons: a review]. AB - Long terminal repeat (LTR) retrotransposons are mobile DNA sequences that ubiquitously exist in eukaryotic genomes. They replicate themselves in the genome by copy-paste mechanism with RNA as medium. In higher plants, many active LTR retrotransposons have been applied to analyze molecular marker technology, genetic tagging, insertion mutation and gene function. Here, we systematically review the characteristics of plant active LTR retrotransposons, including their structures, copy numbers and distributions. We further analyzed the gag (group specific antigen) and pol (polymerase) sequence features of different plants active LTR retrotransposons and the distribution patterns of the cis-acting elements in LTR regions. The results show that autonomous active LTR retrotransposons must contain LTR regions and code Gag, Pr, Int, Rt, Rh proteins. Both LTR regions are highly homologous with each other and contain many cis regulatory elements; RVT and RNase_H1_RT domain are essential for Rt and Rh protein respectively. These results provide the basis for subsequent identification of plant active LTR retrotransposons and their functional analysis. PMID- 28853264 TI - [Advances in protein cyclization]. AB - Proteins, which exist mainly in linear form in vivo, are easily affected by the change of ambient temperature and pH. The application of proteins (enzymes) in the fields of industrial catalyzing, food manufacturing and medicine are restricted due to their properties. The cyclic structure of natural cyclic peptides confers high thermal stability on itself; such mechanism can be referred to in further enhancement of the thermal stability and transformation of the structure of enzymes. This article reviewed the latest progress in the domestic and international studies on protein cyclization and summarized the traditional methods (such as protein trans-splicing, expressed protein ligation and sortase catalyzed transpeptidation) in protein cyclization. A novel method based on SpyTag/SpyCather-mediated enzyme cyclization was discussed in more detail. PMID- 28853265 TI - [A nonsurgical embryo transfer technique in mice]. AB - Although efficient nonsurgical transfer of embryos in mice would provide many advantages over a surgical method, the low success rate of nonsurgical transfer has hampered its acceptance and use. Here, a plastic catheter was used to mimic embryo transfer process and then the transfer efficiency was evaluated by intrauterine trypan blue dye dispersion. Also 3.5-day blastocysts from natural pregnant mice were transferred through cervix into uterine horns. The results show that 70.9% of CD-1 mouse 3.5-day blastocysts transferred into unilateral uterine horns of pseudopregnant 2.5-day recipients can be developed to live newborns, and an efficient mouse nonsurgical embryo transfer technique was established. The technique was simple, rapid, inexpensive, unlikely to get contaminated, ethical and do not need specialized apparatus, and can completely replace surgical embryo transfer techniques. Moreover, the mouse nonsurgical embryo transfer technique provides a research model for human and other large animal embryo transfer. PMID- 28853266 TI - [Effects of temperature and pH on the growth of H1N1 subtype of influenza A virus by surface-enhanced Raman spectroscopy]. AB - Surface enhanced Raman spectroscopy technology (SERS), using gold nanoparticles as a base, was developed for rapid and sensitive detection of virus strains. SERS can be used as a rapid and reliable method to distinguish the titers of viral replication. In the present study, we characterized H1N1 subtypes of influenza A virus strains in different conditions of pH or temperatures, while we analyzed data from SERS technology using gold nanoparticles as a base and cell cultures were employed to further confirm the data from virus strains. Origin8.0 was used to collect Raman spectra, smooth and homogenize data, and to contrast spectra. Our results indicated that the peaks of different virus strains in optimal environmental conditions (T=37 C/pH=7.2) reached >=3 000. This criterion was verified by subsequent virological method. The present data indicate that the established SERS protocol can be used as a rapid and reliable method to distinguish the replication rate of virus, which can be further used in clinical samples. PMID- 28853267 TI - [Effect of ensilage on bioconversion of switchgrass to ethanol based on liquid hot water pretreatment]. AB - Ensilage is a traditional way of preserving fresh biomass. However, in order to apply ensilage to the ethanol biorefinery, two parameters need to be evaluated: quantity and quality changes of the biomass; and its effects on bioconversion process. To study these two aspects, switchgrass harvested on three different time points (Early, mid and late fall) were used as feedstock. The early fall harvested biomass was ensiled at 5 moisture levels ranging from 30% to 70%. Silage of 40% moisture and 3 other raw switchgrass were pretreated with liquid hot water, followed by enzymatic hydrolysis as well as simultaneous saccharification and fermentation. After 21 days storage pH values of all silages decreased below 4.0 and the dry matter losses were less than 2.0%, and structural sugars contents did not change dramatically. Liquid hot water caused more hemicellulose dissolution in the silage than in unensiled switchgrass. However, ensilage also increased the risk of releasing more sugar degradation products; After enzymatic hydrolysis, silage obtained higher total glucose, xylose and galactose yields than raw materials; After simultaneous saccharification and fermentation, ethanol concentration in silage was 12.1 g/L, higher than the unensiled switchgrass (10.3 g/L, 9.7 g/L and 10.6 g/L for early, mid and late fall respectively). Our results suggest that ensilage helps increase pretreatment efficiency and sugar yield, which increases final ethanol production. PMID- 28853268 TI - [Construction and characterization of Escherichia coli D-3-phosphoglycerate dehydrogenase mutants with feedback-inhibition relief]. AB - 3-Phosphoglycerate dehydrogenase (PGDH, EC 1.1.1.95) is the key enzyme in L serine biosynthesis and its coding gene is serA. PGDH is feedback inhibited by L serine. In order to relieve the feedback-inhibition of PGDH by L-serine, H344 or D346 or D364 were chosen for site directed mutagenesis. The mutants were generated by the standard QuikChange mutagenesis, further subcloned into expression vector pT7-7 and transformed into Escherichia coli BL21 (DE3) cells. The recombinant cells were collected after cultured in LB media post induced by isopropyl beta-Dthiogalactopyranoside. The enzymes were purified by anion exchange chromatography, and SDS-PAGE showed that the purified enzymes were homogenous. Enzyme characterization indicated that the mutant enzyme showed similar activity, optimal temperature, and optimal pH as that of the wild-type enzyme. Moreover, feedback inhibition study showed that the activity of the double mutant (N346A/H344A) could remain 96% in the presence of serine up to 160 mmol/L, whereas the activity of the wild-type enzyme remains only 50% in the presents of serine of 7 MUmol/L, thus successfully relieving the feedback inhibition of PGDH with its activity remained. PMID- 28853269 TI - [One-step fermentation for producing simvastatin via RNAi silencing of lovF gene in Aspergillus terreus]. AB - Simvastatin is one of the important prescription drugs for hypercholesterolemia. Monacolin J is a key intermediate during simvastatin synthesis, and also an intermediate of lovastatin biosynthesis. In this work, we construct a monacolin J producing strain via RNA interference to achieve one-step fermentation to obtain simvastatin. The lovF gene silencing plasmid pMHJ137 was constructed and transformed into Aspergillus terreus by Agrobacterium tumefaciens mediated transformation method. Precursor DMB-S-MMP was supplied during the fermentation to screen positive strains of transformants; which also further confirmed the simvastatin producing capability of MJ1-24 by one-step fermentation. Strain MJ1 24 produced monacolin J rather than lovastatin, and the feeding of DMB-S-MMP resulted in the generation of simvastatin. This study suggested that RNAi can efficiently silence the lovF gene of A. terreus and promote the simvastatin production by one-step fermentation. PMID- 28853270 TI - [Gene cloning and expression characteristics of vacuolar-type ATPase subunit B in Bombyx mori]. AB - Vacuolar-type ATPase (V-ATPase), located in the membrane and organelle membrane, is one of important H+-transporting proteins. It keeps the proton balance by transporting H+ into vacuole, vesicle, or extracellular using the energy from ATP hydrolysis. The subunit B of the vacuolar-type ATPase (BmV-ATPase B) contains the ATP catalytic site, and plays an important role in this process. To study the function of V-ATPase B in Bombyx mori (BmV-ATPase B), we cloned its coding gene from the midgut of the 5th instar silkworm larvae. Then we constructed prokaryotic expression vector and produced the recombinant protein in E. coli. The recombinant protein was identified as BmV-ATPase B by mass spectrometry and purified using Ni-NTA affinity chromatography. This purified protein was used to immunize rabbit to generate polyclonal antibodies of BmV-ATPase B. Finally, the expression patterns of BmV-ATPase B in the silk gland were analyzed by western blotting and immunofluorescence. The full length CDS sequence of BmV-ATPase B was 1 473 bp. BmV-ATPase B was 55 kDa with a PI of 5.3. We analyzed the expression patterns of BmV-ATPase B in different sections of silk gland from the silkworm on the 3rd day of 5th instar and 1st day of wander stage by western blotting. BmV ATPase B was expressed in all sections of the silk gland and it was abundant in the anterior silk gland (ASG) both in these two developmental stages. Furthermore, immunofluorescence indicated that BmV-ATPase B was located in the silk gland cells. Laser confocal scanning microscopy analysis revealed that BmV ATPase B was mainly expressed in the cytomembrane of silk gland cells. These data elucidated the expression patterns of BmV-ATPase B in the silk gland of silkworm, which provides a good basis for further studies on the function of V-ATPase B in silk fiber formation. PMID- 28853271 TI - [Structural characterization and analysis of Omalizumab and its biosimilar CMAB007 by LC-MS]. AB - We compared the similarity of Omalizumab (Xolair; a humanized anti-immunoglobulin E monoclonal antibody) and it's biosimilar CMAB007. An in depth characterization of a candidate biosimilar was carried out using a systematic approach, the approach provides a set of routine tools that combine accurate intact mass measurement, peptide mapping, and released glycan profiling. CMAB007 and Omalizumab had the same primary structure and exhibited almost the same content of C-terminal lysine variants. The types of detected free oligosaccharides were very similar, such as sialylation, fucosylation and high mannose types. CMAB007 could be considered as a highly similar molecular to Omalizumab and expected to be the first humanized anti-immunoglobulin E monoclonal antibody drug in China. PMID- 28853272 TI - [Eukaryotic expression of human NOVA1 protein and identification of its anti hypoxia activity]. AB - The aim of this study was to construct the eukaryotic expression vector of pCMV Myc-NOVA1 based on NOVA1 gene, and to screen the optimum expression condition after transfecting to PC12 cells, and further to explore the distribution of NOVA1 protein in PC12 cells using cell immunohistochemistry, and to identifyits anti-hypoxia activity. According to the NOVA1 gene sequence of NCBI database, we designed the upstream and downstream primers, and performed polymerase chain reaction (PCR) to amplify the full length cDNA coding sequence using pCR4-TOPO NOVA1 as a template. The products were digested by restriction endonuclease SalIand XhoI, and conjugated to the eukaryotic expression vector ofpCMV-Myc followed by validating by digestion and direct sequencing. Subsequently, the validated pCMV-Myc-NOVA1 was transfected to PC12 cells followed by optimizing of transfection ratio and transfection time, and identified by qPCR, Western blotting and cell immunohistochemistry respectively. After validation by digestion and direct sequencing, the eukaryotic expression vector of pCMV-Myc NOVA1 was correctly constructed. The optimum transfection ratio of plasmid to Lipo 2000 was 1:2.5, and the optimum transfection time was 72 h. At the optimum transfection condition, the expression level of NOVA1 mRNA and protein significantly increased, and after transfection of pCMV-Myc-NOVA1, NOVA1 protein mainly distributed in cell nucleus and cytoplasm. After 6 h hypoxia, the cell proliferation activity was significantly increased compared to that of the control and pCMV-Myc group. Our findings provided a reference for exploring the mechanism of NOVA1, and also a technical support for potential drug development of NOVA1. PMID- 28853273 TI - [The expression of phenylalanine hydroxylase in the brain of ragworm Neanthes japonica (Polychaeta, Annelida)]. AB - Phenylalanine hydroxylase (PAH) is a member of aromatic amino acid hydroxylase (AAAHs) family, and catalyze phenylalanine (Phe) into tyrosine (Tyr). Using immunological and RT-PCR methods to prove the existence of phenylalanine hydroxylase (PAH) gene in the brain of Neanthes japonica in protein and nucleic acid level. Using Western blotting to detect the pah immunogenicity of Neanthes japonica. Making paraffin sections and using immunohistochemical technique to identify the presence and distribution of the phenylalanine hydroxylase gene in the brain of Neanthes japonica. Clone pah gene from the brain of Neanthes japonica by RT-PCR, constructing plasmid and transferring into E. coli to amplification, picking a single homogeneous colony, double digesting then making sequence and comparing homology. Western blotting results showed that the expression of the protein is present in Neanthes japonica brain, immunohistochemistry technique results showed that phenylalanine hydroxylase mainly expressed in abdominal of forebrain, dorsal and sides of midbrain. RT-PCR technique results showed that the phenylalanine hydroxylase exist in the brain of Neanthes japonica and has a high homology with others animals. PAH is present in the lower organisms Neanthes japonica, in protein and nucleic acid level. Which provide the foundation for further study the evolution of aromatic amino acid hydroxylase genes in invertebrate. PMID- 28853274 TI - [Heterologous expression and characterization of Klebsiella oxytoca lysine decarboxylase]. AB - Cadaverine is a biogenic amine that has the potential to become an important platform chemical for the production of industrial polymers, such as polyamides and polyurethanes. We reported here a lysine decarboxylase from Klebsiella oxytoca. The lysine decarboxylase from Klebsiella oxytoca was cloned to Escherichia coli to get the strain LN18. The specific activity of the crude protein from LN18 reached 30 000 U. The molecular weight was about 80 kDa. The optimum temperature and pH of the crude protein were 55 C and 5.5 respectively. The specific activity could keep over 30% at pH 8.0 compared the one at pH 5.5, much difference from Escherichia coli lysine decarboxylase CadA. Mg2+ was positive to the specific activity, whereas Fe2+, Zn2+ and Ca2+ were negative. PMID- 28853275 TI - Magnetic and Photoluminescent Coupling in SrTi0.87Fe0.13O3-delta/ZnO Vertical Nanocomposite Films. AB - Self-assembled growth of SrTi0.87Fe0.13O3-delta (STF)/ZnO vertical nanocomposite films by combinatorial pulsed laser deposition is described. The nanocomposite films form vertically aligned columnar epitaxial nanostructures on SrTiO3 substrates, in which the STF shows room-temperature magnetism. The magnetic properties are discussed in terms of strain states, oxygen vacancies, and microstructures. The nanocomposites exhibit magneto-photoluminescent coupling behavior that the near-band-edge emission of ZnO is shifted as a function of magnetic field. PMID- 28853276 TI - Light-Converting Polymer/Si Nanocrystal Composites with Stable 60-70% Quantum Efficiency and Their Glass Laminates. AB - Thiol-ene polymer/Si nanocrystal bulk hybrids were synthesized from alkyl passivated Si nanocrystal (Si NC) toluene solutions. Radicals in the polymer provided a copassivation of "dark" Si NCs, making them optically active and leading to a substantial ensemble quantum yield increase. Optical stability over several months was confirmed. The presented materials exhibit the highest photoluminescence quantum yield (~65%) of any solid-state Si NC hybrid reported to date. The broad tunability of thiol-ene polymer reactivity provides facile glass integration, as demonstrated by a laminated structure. This, together with extremely fast polymerization, makes the demonstrated hybrid material a promising candidate for light converting applications. PMID- 28853277 TI - Ambipolar Graphene-Quantum Dot Hybrid Vertical Photodetector with a Graphene Electrode. AB - A strategy to fabricate an ambipolar near-infrared vertical photodetector (VPD) by sandwiching a photoactive material as a channel film between the bottom graphene and top metal electrodes was developed. The channel length in the vertical architecture was determined by the channel layer thickness, which can provide an ultrashort channel length without the need for a high-precision manufacturing process. The performance of VPDs with two types of semiconductor layers, a graphene-PbS quantum dot hybrid (GQDH) and PbS quantum dots (QDs), was measured. The GQDH VPD showed better photoelectric properties than the QD VPD because of the high mobility of graphene doped in the channel. The GQDH VPD exhibited excellent photoresponse properties with a responsivity of 1.6 * 104 A/W in the p-type regime and a fast response speed with a rise time of 8 ms. The simple manufacture and the promising photoresponse of the GQDH VPDs reveal that an easy and effective way to fabricate high-performance ambipolar photodetectors was developed. PMID- 28853278 TI - Elucidating the Key Role of a Lewis Base Solvent in the Formation of Perovskite Films Fabricated from the Lewis Adduct Approach. AB - High-quality perovskite films can be fabricated from Lewis acid-base adducts through molecule exchange. Substantial work is needed to fully understand the formation mechanism of the perovskite films, which helps to further improve their quality. Here, we study the formation of CH3NH3PbI3 perovskite films by introducing some dimethylacetamide into the PbI2/N,N-dimethylformamide solution. We reveal that there are three key processes during the formation of perovskite films through the Lewis acid-base adduct approach: molecule intercalation of solvent into the PbI2 lattice, molecule exchange between the solvent and CH3NH3I, and dissolution-recrystallization of the perovskite grains during annealing. The Lewis base solvents play multiple functions in the above processes. The properties of the solvent, including Lewis basicity and boiling point, play key roles in forming smooth perovskite films with large grains. We also provide some rules for choosing Lewis base additives to prepare high-quality perovskite films through the Lewis adduct approach. PMID- 28853279 TI - Transforming Commercial Textiles and Threads into Sewable and Weavable Electric Heaters. AB - We describe a process to transform commercial textiles and threads into electric heaters that can be cut/sewn or woven to fashion lightweight fabric heaters for local climate control and personal thermal management. Off-the-shelf fabrics are coated with a 1.5 MUm thick film of a conducting polymer, poly(3,4 ethylenedioxythiophene), using an improved reactive vapor deposition method. Changes in the hand feel, weight, and breathability of the textiles after the coating process are imperceptible. The resulting fabric electrodes possess competitively low sheet resistances-44 Omega/? measured for coated bast fiber textiles and 61 Omega/? measured for coated cotton textiles-and act as low-power consuming Joule heating elements. The electrothermal response of the textile electrodes remain unaffected after cutting and sewing due to the robustness of the conductive coating. Coated, conductive cotton yarns can also be plain-woven into a monolithic fabric heater. A demonstrative circuit design for a soft, lightweight, and breathable thermal glove is provided. PMID- 28853280 TI - Highly Sensitive Flexible Photodetectors Based on Self-Assembled Tin Monosulfide Nanoflakes with Graphene Electrodes. AB - Tin monosulfide (SnS) nanostructures have attracted huge attention recently because of their high absorption coefficient, high photoconversion efficiencies, low energy cost, ease of deposition, and so on. Here, in this paper, we report on the low-cost hydrothermal synthesis of the self-assembled SnS nanoflake-like structures in terms of performance for the photodetectors. High-performance photodetectors were fabricated using SnS nanoflakes as active layers and graphene as the lateral electrodes. The SnS photodetectors exhibited excellent photoresponse properties with a high responsivity of 1.7 * 104 A/W and have fast response and recovery times. In addition, the photodetectors exhibited long-term stability and strong dependence of photocurrent on light intensity. These excellent characteristics were attributed to the larger surface-to-volume ratio of the self-assembled SnS nanoflakes and the effective separation of the photogenerated carriers at graphene/SnS interfaces. Additionally, a flexible photodetector based on SnS nanoflakes was also fabricated on a flexible substrate that demonstrated similar photosensitive properties. Furthermore, this study also demonstrates the potential of hydrothermal-processed SnS nanoflakes for high performance photodetectors and their application in flexible low-cost optoelectronic devices. PMID- 28853281 TI - Regulating Molecular Aggregations of Polymers via Ternary Copolymerization Strategy for Efficient Solar Cells. AB - For many high-performance photovoltaic materials in polymer solar cells (PSCs), the active layers usually need to be spin-coated at high temperature due to the strong intermolecular aggregation of donor polymers, which is unfavorable in device repeatability and large-scale PSC printing. In this work, we adopted a ternary copolymerization strategy to regulate polymer solubility and molecular aggregation. A series of D-A1-D-A2 random polymers based on different acceptors, strong electron-withdrawing unit ester substituted thieno[3,4-b]thiophene (TT-E), and highly planar dithiazole linked TT-E (DTzTT) were constructed to realize the regulation of molecular aggregation and simplification of device fabrication. The results showed that as the relative proportion of TT-E segment in the backbone increased, the absorption evidently red-shifted with a gradually decreased aggregation in solution, eventually leading to the active layers that can be fabricated at low temperature. Furthermore, due to the excellent phase separation and low recombination, the optimized solar cells based on the terpolymer P1 containing 30% of TT-E segment exhibit high power conversion efficiency (PCE) of 9.09% with a significantly enhanced fill factor up to 72.86%. Encouragingly, the photovoltaic performance is insensitive to the fabrication temperature of the active layer, and it still could maintain high PCE of 8.82%, even at room temperature. This work not only develops the highly efficient photovoltaic materials for low temperature processed PSCs through ternary copolymerization strategy but also preliminarily constructs the relationship between aggregation and photovoltaic performance. PMID- 28853282 TI - Silicon Nanoparticles: Stability in Aqueous Slurries and the Optimization of the Oxide Layer Thickness for Optimal Electrochemical Performance. AB - In this study, silicon nanoparticles are oxidized in a controlled manner to obtain different thicknesses of SiO2 layers. Their stability in aqueous slurries as well as the effect of oxide layer thickness on the electrochemical performance of the silicon anodes is evaluated. Our results show that slightly increasing the oxide layer of silicon nanoparticles significantly improves the stability of the nanoparticles in aqueous slurries and does not compromise the initial electrochemical performance of the electrodes. A careful comparison of the rate and cycle performance between 400 degrees C treated Si nanoparticles and pristine Si nanoparticles shows that by treating the silicon nanoparticles in air for slightly increasing the oxide layer, improvement in both rate and cycle performance can be achieved. PMID- 28853283 TI - Direct, Label-Free, and Rapid Transistor-Based Immunodetection in Whole Serum. AB - Transistor-based biosensors fulfill many requirements posed upon transducers for future point-of-care diagnostic devices such as scalable fabrication and label free and real-time quantification of chemical and biological species with high sensitivity. However, the short Debye screening length in physiological samples (<1 nm) has been a major drawback so far, preventing direct measurements in serum. In this work, we demonstrate how tailoring the sensing surface with short specific biological receptors and a polymer polyethylene glycol (PEG) can strongly enhance the sensor response. In addition, the sensor performance can be dramatically improved if the measurements are performed at elevated temperatures (37 degrees C instead of 21 degrees C). With this novel approach, highly sensitive and selective detection of a representative immunosensing parameter human thyroid-stimulating hormone-is shown over a wide measuring range with subpicomolar detection limits in whole serum. To the best of our knowledge, this is the first demonstration of direct immunodetection in whole serum using transistor-based biosensors, without the need for sample pretreatment, labeling, or washing steps. The presented sensor is low-cost, can be easily integrated into portable diagnostics devices, and offers a competitive performance compared to state-of-the-art central laboratory analyzers. PMID- 28853284 TI - Polyamidoamine-Decorated Nanodiamonds as a Hybrid Gene Delivery Vector and siRNA Structural Characterization at the Charged Interfaces. AB - Nanodiamonds have been discovered as a new exogenous material source in biomedical applications. As a new potent form of nanodiamond (ND), polyamidoamine decorated nanodiamonds (PAMAM-NDs) were prepared for E7 or E6 oncoprotein suppressing siRNA gene delivery for high risk human papillomavirus-induced cervical cancer, such as types 16 and 18. It is critical to understand the physicochemical properties of siRNA complexes immobilized on cationic solid ND surfaces in the aspect of biomolecular structural and conformational changes, as the new inert carbon material can be extended into the application of a gene delivery vector. A spectral study of siRNA/PAMAM-ND complexes using differential scanning calorimetry and circular dichroism spectroscopy proved that the hydrogen bonding and electrostatic interactions between siRNA and PAMAM-NDs decreased endothermic heat capacity. Moreover, siRNA/PAMAM-ND complexes showed low cell cytotoxicity and significant suppressing effects for forward target E6 and E7 oncogenic genes, proving functional and therapeutic efficacy. The cellular uptake of siRNA/PAMAM-ND complexes at 8 h was visualized by macropinocytes and direct endosomal escape of the siRNA/PAMAM-ND complexes. It is presumed that PAMAM-NDs provided a buffering cushion to adjust the pH and hard mechanical stress to escape endosomes. siRNA/PAMAM-ND complexes provide a potential organic/inorganic hybrid material source for gene delivery carriers. PMID- 28853285 TI - Electronic pi-Delocalization Boosts Catalytic Water Oxidation by Cu(II) Molecular Catalysts Heterogenized on Graphene Sheets. AB - A molecular water oxidation catalyst based on the copper complex of general formula [(Lpy)CuII]2-, 22-, (Lpy is 4-pyrenyl-1,2-phenylenebis(oxamidate) ligand) has been rationally designed and prepared to support a more extended pi conjugation through its structure in contrast with its homologue, the [(L)CuII]2- water oxidation catalyst, 12- (L is o-phenylenebis(oxamidate)). The catalytic performance of both catalysts has been comparatively studied in homogeneous phase and in heterogeneous phase by pi-stacking anchorage to graphene-based electrodes. In the homogeneous system, the electronic perturbation provided by the pyrene functionality translates into a 150 mV lower overpotential for 22- with respect to 12- and an impressive increase in the kcat from 6 to 128 s-1. Upon anchorage, pi-stacking interactions with the graphene sheets provide further pi delocalization that improves the catalytic performance of both catalysts. In this sense, 22- turned out to be the most active catalyst due to the double influence of both the pyrene and the graphene, displaying an overpotential of 538 mV, a kcat of 540 s-1 and producing more than 5300 TONs. PMID- 28853287 TI - Stress Propagation through Biological Lipid Bilayers in Silico. AB - Membrane tension plays various critical roles in the cell. We here asked how fast and how far localized pulses of mechanical stress dynamically propagate through biological lipid bilayers. In both coarse-grained and all-atom molecular dynamics simulations of a dipalmitoylphosphatidylcholine lipid bilayer, we observed nanometer-wide stress pulses, propagating very efficiently longitudinally at a velocity of approximately 1.4 +/- 0.5 nm/ps (km/s), in close agreement with the expected speed of sound from experiments. Remarkably, the predicted characteristic attenuation time of the pulses was in the order of tens of picoseconds, implying longitudinal stress propagation over length scales up to several tens of nanometers before damping. Furthermore, the computed dispersion relation leading to such damping was consistent with proposed continuum viscoelastic models of propagation. We suggest this mode of stress propagation as a potential ultrafast mechanism of signaling that may quickly couple mechanosensitive elements in crowded biological membranes. PMID- 28853286 TI - Y Chromosome Missing Protein, TBL1Y, May Play an Important Role in Cardiac Differentiation. AB - Despite evidence for sex-specific cardiovascular physiology and pathophysiology, the biological basis for this dimorphism remains to be explored. Apart from hormonal factors, gender-related characteristics may reside in the function of sex chromosomes during cardiac development. In this study, we investigated the differential expression of the male-specific region of the Y chromosome (MSY) genes and their X counterparts during cardiac differentiation of human embryonic stem cells (hESC). We observed alterations in mRNA and protein levels of TBL1Y, PCDH11Y, ZFY, KDM5D, USP9Y, RPS4Y1, DDX3Y, PRY, XKRY, BCORP1, RBMY, HSFY, and UTY, which accompanied changes in intracellular localization. Of them, the abundance of a Y chromosome missing protein, TBL1Y, showed a significant increase during differentiation while the expression level of its X counterpart decreased. Consistently, reducing TBL1Y cellular level using siRNA approach influenced cardiac differentiation by reducing its efficacy as well as increasing the probability of impaired contractions. TBL1Y knockdown may have negatively impacted cardiogenesis by CtBP stabilization. Furthermore, we presented compelling experimental evidence to distinguish TBL1Y from TBL1X, its highly similar X chromosome homologue, and proposed reclassification of TBL1Y as "found missing protein" (PE1). Our results demonstrated that MSY proteins may play an important role in cardiac development. PMID- 28853288 TI - Intrinsic Defect Physics in Indium-based Lead-free Halide Double Perovskites. AB - Lead-free halide double perovskites (HDPs) are expected to be promising photovoltaic (PV) materials beyond organic-inorganic halide perovskite, which is hindered by its structural instability and toxicity. The defect- and stability related properties of HDPs are critical for the use of HDPs as important PV absorbers, yet their reliability is still unclear. Taking Cs2AgInBr6 as a representative, we have systemically investigated the defect properties of HDPs by theoretical calculations. First, we have determined the stable chemical potential regions to grow stoichiometric Cs2AgInBr6 without structural decomposition. Second, we reveal that Ag-rich and Br-poor are the ideal chemical potential conditions to grow n-type Cs2AgInBr6 with shallow defect levels. Third, we find the conductivity of Cs2AgInBr6 can change from good n-type, to poorer n type, to intrinsic semiconducting depending on the growth conditions. Our studies provided important guidance for experiments to fabricate Pb-free perovskite-based solar cell devices with superior PV performances. PMID- 28853289 TI - Characterization and Control of Nanoparticle Emission during 3D Printing. AB - This study aimed to evaluate particle emission characteristics and to evaluate several control methods used to reduce particle emissions during three dimensional (3D) printing. Experiments for particle characterization were conducted to measure particle number concentrations, emission rates, morphology, and chemical compositions under manufacturer-recommended and consistent temperature conditions with seven different thermoplastic materials in an exposure chamber. Eight different combinations of the different control methods were tested, including an enclosure, an extruder suction fan, an enclosure ventilation fan, and several types of filter media. We classified the thermoplastic materials as high emitter (>1011 #/min), medium emitters (109 #/min -1011 #/min), and low emitters (<109 #/min) based on nanoparticle emissions. The nanoparticle emission rate was at least 1 order of magnitude higher for all seven filaments at the higher consistent extruder temperature than at the lower manufacturer-recommended temperature. Among the eight control methods tested, the enclosure with a high-efficiency particulate air (HEPA) filter had the highest removal effectiveness (99.95%) of nanoparticles. Our recommendations for reducing particle emissions include applying a low temperature, using low-emitting materials, and instituting control measures like using an enclosure around the printer in conjunction with an appropriate filter (e.g., HEPA filter) during 3D printing. PMID- 28853290 TI - Modulating Hole Transport in Multilayered Photocathodes with Derivatized p-Type Nickel Oxide and Molecular Assemblies for Solar-Driven Water Splitting. AB - For solar water splitting, dye-sensitized NiO photocathodes have been a primary target. Despite marginal improvement in performance, limitations remain arising from the intrinsic disadvantages of NiO and insufficient catalysis. We report here a new approach to modifying NiO photocathodes with doped NiO bilayers and an additional layer of macro-mesoporous ITO. The trilayered electrode is functionalized with a surface-attached ruthenium polypyridyl dye and a covalently bridged nickel-based hydrogen evolution catalyst. The NiO film, containing a 2% K+-doped NiO inner layer and a 2% Cu2+-doped NiO outer layer, provides sufficient driving force for hole transport following hole injection by the molecular assembly. Upon light irradiation, the resulting photocathode generates hydrogen from water sustainably with enhanced photocurrents and a Faradaic efficiency of ~90%. This approach highlights the value of modifying both the internal and surface structure of NiO and provides insights into a new generation of dye sensitized photocathodes for solar-driven water splitting cells. PMID- 28853291 TI - Fishmeal Application Induces Antibiotic Resistance Gene Propagation in Mariculture Sediment. AB - Antibiotic resistance genes (ARGs) are globally prevalent in mariculture sediment, and their presence is an issue of concern in the context of antibiotic use. Although large amounts of fishmeal have been released into the sediment, the role of fishmeal in ARG dissemination remains unclear. In this study, high throughput ARG profiles in representative fishmeal products and the impact of fishmeal on the sediment resistome were investigated. A total of 132 unique ARGs and 4 mobile genetic elements (MGEs) were detected in five fishmeal products. ARG abundance and diversity in the mariculture microcosm sediment were significantly increased by the addition of fishmeal, and trends in ARG patterns correlated with the resident bacterial community in sediment (P < 0.05). After DNase treatment of fishmeal removed 84.3% of total ARGs, the remaining nutrients in fishmeal increased the relative abundance but not the diversity of ARGs in microcosm sediment. Our study has revealed for the first time that fishmeal itself is a major reservoir for ARGs, and the shift in the bacterial community induced by the nutrients in fishmeal is the main driver shaping the resistome in mariculture microcosm sediment. Our findings caution against the previously unperceived risk of ARG propagation in fishmeal-receiving ecosystems. PMID- 28853292 TI - Prediction of high-stage liver fibrosis using ADC value on diffusion-weighted imaging and quantitative enhancement ratio at the hepatobiliary phase of Gd-EOB DTPA-enhanced MRI at 1.5 T. AB - Background Recently, diffusion-weighted imaging (DWI) and quantitative enhancement ratio measured at the hepatobiliary phase (HBP) of Gd-EOB-DTPA enhanced magnetic resonance imaging (MRI) has been established as an effective method for evaluating liver fibrosis. Purpose To evaluate which is a more favorable surrogate marker in predicting high-stage liver fibrosis, apparently diffusion coefficient (ADC) value or quantitative enhancement ratio measured on HBP. Material and Methods Eighty-three patients with 99 surgically resected hepatic lesions were enrolled in this study. DWI was performed with b-values of 100 and 800 s/mm2. Regions of interest were set on ADC map, and the HBP of Gd-EOB DTPA-enhanced MRI, to calculate ADC value, liver-to-muscle ratio (LMR), liver-to spleen ratio (LSR), and contrast enhancement index (CEI) of liver. We compared these parameters between low-stage fibrosis (F0, F1, and F2) and high-stage fibrosis (F3 and F4). Receiver operating characteristic analysis was performed to compare the diagnostic performance when distinguishing low-stage fibrosis from high-stage fibrosis. Results LMR and CEI were significantly lower at high-stage fibrosis than at the low stage ( P < 0.01 and P = 0.04, respectively), whereas LSR did not show a significant difference ( P = 0.053). No significant difference was observed in diagnostic performance between LMR and CEI ( P = 0.185). The best sensitivity and specificity, when an LMR of 2.80 or higher was considered to be low-stage fibrosis, were 82.4% and 75.6%, respectively. ADC value showed no significant differences among fibrosis grades ( P = 0.320). Conclusion LMR and CEI were both adequate surrogate parameters to distinguish high-stage fibrosis from low-stage fibrosis. PMID- 28853293 TI - Predictors of Vasopressin Responsiveness in Critically Ill Adults. AB - BACKGROUND: Vasopressin is commonly used as an adjunct vasopressor in shock. However, response to vasopressin varies among critically ill patients. OBJECTIVE: To identify patient-specific factors that are associated with vasopressin responsiveness in critically ill adults. METHODS: This retrospective, multicenter study included adult patients who were admitted to an intensive care unit (ICU) and received vasopressin for shock. Patients were excluded if they received vasopressin for less than 30 minutes, if vasopressin was initiated prior to ICU arrival, or if an additional vasopressor was initiated within 30 minutes of starting vasopressin. Responsiveness was defined as an increase in mean arterial pressure of >=10 mm Hg or the ability to taper a concurrent catecholamine vasopressor. Patient-specific factors evaluated in a multivariate analysis included age, gender, ethnicity, body mass index, type of shock, serum pH, Sequential Organ Failure Assessment (SOFA) score, and use of stress-dose steroids. These variables were also evaluated in a subgroup analysis of patients with septic shock. RESULTS: Of 1619 patients screened, 400 patients were included, with 231 identified as vasopressin responsive and 169 as nonresponsive. Vasopressin used as an adjunct vasopressor, as opposed to first line, during shock was the only variable associated with vasopressin responsiveness (odds ratio [OR] = 1.71; 95% CI = 1.10 to 2.65). Among the subgroup of patients with septic shock, female patients had a higher odds of responding than male patients (OR = 2.10; 95% CI = 1.12 to 3.95). CONCLUSIONS: Vasopressin initiated as an adjunct vasopressor, as opposed to first-line therapy, was associated with response. PMID- 28853294 TI - Suboptimal rise in awakening-induced cortisol is an accurate marker of cortisol insufficiency in patients with normal renal function (eGFR >60 mL/min). AB - Background The insulin tolerance test is the gold standard for diagnosis of cortisol insufficiency. However, it is cumbersome, invasive, requires supervised hospital facilities and has unpleasant side-effects. A non-invasive outpatient based test will be useful. We hypothesized that free cortisol concentrations in multiple spot urine samples can be used to diagnose cortisol insufficiency in patients with normal renal function (eGFR > 60 mL/min). Method Patients and controls provided urine samples at bedtime (S1), and first (S2) and second (S3) void the next day. Cortisol and creatinine were measured in all three samples, and cortisol:creatinine ratio (S1, S2 and S3) was used for further analysis. The sum of S1 + S2 + S3 was used to calculate total cortisol secretion (T). Variation (V) in cortisol secretion in response to circadian rhythm was calculated as the modulus of the difference between S1 and S2 and S2 and S3. Results Samples were collected from 96 controls and 11 patients. S1 was significantly lower vs . S2 and S3 in controls ( P < 0.0001) but not in patients. S2, S3, T and V were significantly lower in patients vs . controls ( P < 0.0001). ROC curve analysis using insulin tolerance test as gold standard showed that S2, S3, T and V were all equally accurate diagnostic markers for cortisol insufficiency (AUC: 0.87, NPV: 100%). The best balance of sensitivity and specificity was achieved using T (sensitivity: 100%, specificity: 58%). Conclusion Multiple spot urine samples test is an accurate, relatively inexpensive, non-invasive, convenient outpatient based screening test for exclusion of cortisol insufficiency. PMID- 28853295 TI - Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients. AB - Background Oral prochlorperazine, a dopamine D2 receptor antagonist, is largely metabolized to sulphoxide, 7-hydroxylate and N-desmethylate by cytochrome P450s (CYPs). This study evaluated the influence of CYP genotype on the plasma dispositions of prochlorperazine and its metabolites and their relationships with antiemetic efficacy and prolactin elevation in cancer patients. Methods Forty eight cancer patients treated with oral prochlorperazine were enrolled. Plasma prochlorperazine and its metabolites concentrations and serum prolactin concentration were determined at 12 h after the evening dosing. The genotypes of CYP2C19, CYP2D6 and CYP3A5 and the incidences of nausea and vomiting were investigated. Results The plasma concentrations of the prochlorperazine metabolites were weakly correlated with that of the parent drug. The CYP genotypes did not affect the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine and its metabolites were not associated with the incidences of nausea and vomiting. The incidence of vomiting was significantly higher in females than in males. The serum prolactin concentration was weakly correlated with the plasma concentrations of prochlorperazine and its metabolites. The plasma concentrations of prochlorperazine metabolites rather than the parent drug had a weaker relation to serum prolactin concentration. Conclusions The CYP genotypes did not affect the plasma dispositions of prochlorperazine and its metabolites. The prochlorperazine metabolites did not have a strong effect on antiemetic efficacy, while they were slightly associated with prolactin secretion in cancer patients. PMID- 28853296 TI - Art participation for psychosocial wellbeing during stroke rehabilitation: a feasibility randomised controlled trial. AB - PURPOSE: To examine the feasibility of undertaking a pragmatic single-blind randomised controlled trial (RCT) of a visual arts participation programme to evaluate effects on survivor wellbeing within stroke rehabilitation. METHODS: Stroke survivors receiving in-patient rehabilitation were randomised to receive eight art participation sessions (n = 41) or usual care (n = 40). Recruitment, retention, preference for art participation and change in selected outcomes were evaluated at end of intervention outcome assessment and three-month follow-up. RESULTS: Of 315 potentially eligible participants 81 (29%) were recruited. 88% (n = 71) completed outcome and 77% (n = 62) follow-up assessments. Of eight intervention group non-completers, six had no preference for art participation. Outcome completion varied between 97% and 77%. Running groups was difficult because of randomisation timing. Effectiveness cannot be determined from this feasibility study but effects sizes suggested art participation may benefit emotional wellbeing, measured on the positive and negative affect schedule, and self-efficacy for Art (d = 0.24-0.42). CONCLUSIONS: Undertaking a RCT of art participation within stroke rehabilitation was feasible. Art participation may enhance self-efficacy and positively influence emotional wellbeing. These should be outcomes in a future definitive trial. A cluster RCT would ensure art groups could be reliably convened. Fewer measures, and better retention strategies are required. Implications for Rehabilitation This feasibility randomised controlled trial (RCT) showed that recruiting and retaining stroke survivors in an RCT of a visual arts participation intervention within stroke rehabilitation was feasible. Preference to participate in art activities may influence recruitment and drop out rates, and should be addressed and evaluated fully. Art participation as part of rehabilitation may improve some aspects of post-stroke wellbeing, including positive affect and self-efficacy for art. A future definitive cluster RCT would facilitate full evaluation of the value art participation can add to rehabilitation. PMID- 28853297 TI - Mindfulness-based Intervention in Elementary School Students With Anxiety and Depression: A Series of n-of-1 Trials on Effects and Feasibility. AB - Mindfulness-based interventions constitute a promising option to address anxiety and depression in elementary school students. This study evaluated the effect of a mindfulness-based intervention on anxiety and depression in elementary school students with a diagnosis of anxiety or depression disorder. A single-subject experimental A-B-A design was used. Participants were three elementary school students from grades three and four, along with their teacher. Anxiety and depression were measured on 10 occasions at baseline, during the intervention, and at follow-up. Primary hypotheses were tested using a univariate single case multilevel modeling strategy and visual analysis. Following intervention, 2 participants reported improvements on anxiety and depression, while their teachers reported deteriorating scores on these variables. Results from this n-of 1 trial design is consistent with other work suggesting caution with regard to the overall impact and efficacy of mindfulness-based interventions as a universal treatment option for youth. Future research is warranted. PMID- 28853298 TI - Analyses of hair and salivary cortisol for evaluating hypothalamic-pituitary adrenal axis activation in patients with autoimmune disease. AB - Although many studies have shown that patients with autoimmune disease present a hypoactive hypothalamic-pituitary-adrenal axis (HPA), controversial results have been described. Our objective was to study HPA axis activity in women with autoimmune disease compared to healthy women. Therefore, we analyzed salivary cortisol over the course of a day, and hair cortisol concentrations from the three preceding months, from 65 women divided into two groups: healthy women (n = 30), with a mean age of 44.70 +/- 11.65 years; and women with autoimmune disease (n = 35), with a mean age of 48.26 +/- 9.04 years. The latter group comprises women with systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), and systemic sclerosis (SSc). Perceived stress and psychopathological symptomatology were also evaluated. Autoimmune disease group scored higher on the somatization subscale SCL-90-R and lower on the anxiety subscale than the control group. Regarding HPA axis activation, the area under curve for cortisol levels during the day was higher for the autoimmune disease group. In addition, higher cortisol levels in hair were found in the group with autoimmune disease. Our findings show greater short and long-term HPA axis activity in women with autoimmune disease than in healthy women. PMID- 28853299 TI - The osteoimmunomodulatory properties of MBG scaffold coated with amino functional groups. AB - Mesoporous bioactive glass (MBG) is a good scaffold for bone regeneration. In this study, amino functionalized MBG (N-MBG) was used as a model scaffold to examine the effect of the scaffold to bone marrow stromal cells (BMSCs) and macrophages. The MTT results revealed that the proliferation of BMSCs from ovariectomized rabbits was enhanced by N-MBG. Compared to the control group, the expression of osteogenic genes was significantly enhanced by N-MBG, which was related to CaSR pathway. Meanwhile, the anti-inflammatory cytokines (interleukin 10 and arginase-1) were also upregulated by N-MBG stimulation compared with MBG. Furthermore, the amino functionalization of MBG resulted in an increase in the pH value of the material extract. Interestingly, the formation of TRAP+ multinuclear cells was inhibited by the slightly alkaline extract to a certain extent, which reasonably explained the increase in TRAP+ multinuclear cells after adjusting the pH value of N-MBG extract. In vivo, the areas of new bone formation in the maxillary sinus floor elevation were increased in the N-MBG/BMSCs group with less TRAP+ multinuclear cells compared with the MBG/BMSCs group. These findings provided valuable insight that the osteogenic ability of MBG scaffold could be enhanced by amino functionalization due to coordinate BMSCs and macrophages differentiation. PMID- 28853301 TI - Total parathyroidectomy versus total parathyroidectomy with autotransplantation for secondary hyperparathyroidism: systematic review and meta-analysis. AB - BACKGROUND: Total parathyroidectomy (tPTX) and total parathyroidectomy with autotransplantation (tPTX + AT) are effective and inexpensive treatments for secondary hyperparathyroidism (sHPT), but we do not know which one is the optimal approach. Therefore, we undertook a meta-analysis to compare the safety and efficacy of these two surgical procedures. METHODOLOGY: Studies published in English on PubMed, Embase and the Cochrane Library from inception to 27 September 2016 were searched systematically. Eligible studies comparing tPTX with tPTX + AT for sHPT were included and Review Manager v5.3 was used. RESULTS: Eleven studies were included in this meta-analysis. Ten cohort studies and one randomized controlled trial (RCT) involving 1108 patients with sHPT were identified. There was no significant difference in the prevalence of surgical complications (relative risk [RR], 1.71; 95% confidence interval [CI], 0.77-3.79; p = .19), all cause mortality (RR, 0.68; 95% CI, 0.33-1.39; p = .29), sHPT persistence (RR, 3.81; 95% CI, 0.56-25.95; p = .17) or symptomatic improvement (RR, 1.02; 95% CI, 0.91-1.13; p = .79). tPTX could reduce the risk of sHPT recurrence (RR, 0.19; 95% CI, 0.09-0.41; p < .0001) and reoperation because of recurrence or persistence of sHPT (RR, 0.46; 95% CI 0.24-0.86; p = .01) compared with tPTX + AT. Simultaneously, tPTX increased the risk of hypoparathyroidism (RR, 2.63; 95% CI, 1.06-6.51; p = .04). CONCLUSIONS: We found tPTX and tPTX + AT to be useful methods for sHPT treatment. tPTX was superior for reducing the risk of sHPT recurrence and reoperation than tPTX + AT but, due to a lack of high statistical power RCTs, comparative studies will be needed in the future. PMID- 28853300 TI - Enteroendocrine, Musashi 1 and neurogenin 3 cells in the large intestine of Thai and Norwegian patients with irritable bowel syndrome. AB - OBJECTIVES: The prevalence, gender distribution and clinical presentation of IBS differ between Asian and Western countries. This study aimed at studying and comparing enteroendocrine, Musashi 1 (Msi 1) and neurogenin 3 (neurog 3) cells in Thai and Norwegian IBS patients. MATERIAL AND METHODS: Thirty Thai and 61 Norwegian IBS patients as well as 20 Thai and 24 Norwegian controls were included. Biopsy samples were taken from each of the sigmoid colon and the rectum during a standard colonoscopy. The samples were immunostained for serotonin, peptide YY, oxyntomodulin, pancreatic polypeptide, somatostatin, Msi 1 and neurog 3. The densities of immunoreactive cells were determined with computerized image analysis. RESULTS: The densities of several enteroendocrine cell types were altered in both the colon and rectum of both Thai and Norwegian IBS patients. Some of these changes were similar in Thai and Norwegian IBS patients, while others differed. CONCLUSIONS: The findings of abnormal densities of the enteroendocrine cells in Thai patients support the notion that enteroendocrine cells are involved in the pathophysiology of IBS. The present observations highlight that IBS differs in Asian and Western countries, and show that the changes in large-intestine enteroendocrine cells in Thai and Norwegian IBS patients might be caused by different mechanisms. PMID- 28853302 TI - Novel approach of laparoscopic and endoscopic cooperative surgery (LECS) for cholecystectomy. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) techniques, such as generating an artificial space between digestive tract layers for safer dissection, were thought to be safer for the resection of organs in cholecystectomy. We investigated whether combinations of endoscopic techniques and laparoscopic techniques could be performed more safely and rapidly. MATERIAL AND METHODS: Laparoscopic and endoscopic cooperative-cholecystectomy (LEC-chole) and conventional laparoscopic cholecystectomy (Lapa-chole) were performed in six dogs. Operation time was defined as the time from the creation of the first port to the retrieval of the resected gallbladder (GB); and GB bed dissection time was the time from local injection of natural saline to the clipping of the cystic duct. The main roles of the endoscope in LEC-chole were to obtain a sufficient cutting space via local injection of natural saline to the GB bed and to monitor the operative view without laparoscopic camera, thus omitting the umbilical port. RESULTS: The operation times were 60 +/- 18.3 minutes for LEC-chole and 95 +/- 7.0 for Lapa-chole (p = .036). The GB bed dissection times were 31 +/- 8.54 minutes in LEC-chole and 50.6 +/- 7.37 minutes in Lapa-chole (p = 0.048). There were significant differences in liver damage and bleeding (p = 0.116), but there were no significant differences in one-month survival. CONCLUSIONS: The application of LEC-chole may be expanded to cholecystectomy. PMID- 28853304 TI - Interim PET in lymphoma: from Deauville to Peking criteria. On the road, again.... PMID- 28853303 TI - Hypertension Prevalence, Health Service Utilization, and Participant Satisfaction: Findings From a Pilot Randomized Controlled Trial in Aged Chinese Canadians. AB - Responding to high prevalence of hypertension and patients' preference of integrating traditional Chinese medicine for blood pressure control, the Dietary Approach to Stop Hypertension With Sodium Reduction for Chinese Canadian (DASHNa CC) intervention was newly designed as a culturally sensitive dietary educational intervention to facilitate middle-aged and senior Chinese Canadians' blood pressure control in community. The aim of this study was to report the hypertension prevalence rate according to the data from blood pressure screening events, to describe the characteristics of health service utilization among aged Chinese Canadians, and to report the evaluation of participant satisfaction to the DASHNa-CC intervention. This study was designed as a pilot randomized controlled trial with a sample size of 60. Among 618 Chinese Canadians participated in blood pressure screening events, 54.5% (n = 337) having various levels of hypertension. Across 2 months, 38 (63.3%) participants made a total of 47 visits to see their family physicians; 20 (33.3%) participants consulted their family members 224 times for lifestyle modifications and hypertension self management. Various forms of Chinese media were frequently used as sources of health care information, and English media were rarely accessed. Participants highly satisfied with the contents, delivery approaches, and integration of traditional Chinese medicine in the intervention. Results indicated that middle aged and senior Chinese Canadians have high hypertension prevalence and specific characteristics of health service utilization. It is important to implement interventions, which are culturally tailored, language appropriate, using proper technology and incorporating traditional Chinese medicine, in Chinese Canadian community for hypertension control. PMID- 28853305 TI - Freestanding Emergency Departments Are Associated With Higher Medicare Costs: A Longitudinal Panel Data Analysis. AB - The number of freestanding emergency departments (FSEDs) is growing rapidly in the United States. Proponents of FSEDs cite potential benefits of FSEDs including lower waiting time and reduced travel distance for needed emergency care. Others have suggested that increased access to emergency care may lead to an increase in the use of emergency departments for lower acuity patients, resulting in higher overall health care expenditures. We examined the relationship between the number of FSEDs in each county and total Medicare expenditures between 2003 and 2009. Our results show that each additional FSED in a county is associated with an expenditure increase of $55 per Medicare beneficiary. This finding suggests that even if FSEDs may increase access to emergency care, it may result in higher overall Medicare expenditures. PMID- 28853306 TI - Aftermarket Performance of Health Care and Biopharmaceutical IPOs: Evidence From ASEAN Countries. AB - We examine the evidence from the long-run abnormal returns using data for 76 health care and biopharmaceutical initial public offerings (IPOs) listed in a 29 year period between 1986 and 2014 in the Association of Southeast Asian Nations (ASEAN) countries such as Indonesia, Malaysia, Singapore, Thailand, the Philippines, Vietnam, Myanmar, and Laos. Based on the event-time approach, the 3 year stock returns of the IPOs are investigated using cumulative abnormal return (CAR) and buy-and-hold abnormal return (BHAR). As a robustness check, the calendar-time approach, related to the market model as well as Fama-French and Carhart models, was applied for verifying long-run abnormal returns. We found evidence that the health care IPOs overperform in the long-run, irrespective of the alternative benchmarks and methods. In addition, when we divide our sample into 5 groups by listing countries, our results show that the health care stock prices of the Singaporean firms behaved differently from those of most of the other firms in ASEAN. The Singaporean IPOs are characterized by a worse post offering performance, whereas the IPOs of Malaysian and Thai health care companies performed better in the long-run. PMID- 28853307 TI - Genetic testing in women with breast cancer: implications for treatment. AB - INTRODUCTION: Mutations in either the BRCA1 or BRCA2 genes are responsible for approximately 42,000 cases of breast cancer annually. Identifying these germline mutations in a woman with breast cancer is important because it can influence her immediate and long-term management and has important implications for other family members. Areas covered: This review highlights how treatment-focussed genetic testing for BRCA1 and BRCA2 mutations can potentially influence cancer treatment and secondary prevention decisions in women with breast cancer. Expert commentary: Testing women with breast cancer for BRCA1 and BRCA2 germline mutations has the potential to decrease cancer burden and improve cancer outcomes. It can help optimise surgical and systemic therapy approaches. Clinicians should actively consider whether genetic testing is appropriate for each woman with breast cancer, and if so should instigate it early in the treatment trajectory when it can most influence cancer care. PMID- 28853308 TI - Insulin suppresses MPP+-induced neurotoxicity by targeting integrins and syndecans in C6 astrocytes. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease in the elderly. In central nervous system, astrocytes regulates neuronal function via the modulation of synaptic transmission and plasticity, secretion of growth factors, uptake of neurotransmitters and regulation of extracellular ion concentrations and metabolic support of neurons. Therefore, C6 astroglial cells have been used to study the in vitro PD model induced by 1-methyl-4-phenyl pyridinium (MPP+). In this study, pre-treatment of insulin inhibited MPP+-induced cell membrane damages on LDH and NO releases, which also inhibited the iNOS and Cox-2 levels. Insulin also up-regulated the PI3K and p-GSK-3beta protein expressions in C6 cells. In addition, MPP+ and/or insulin enhanced the autophagy by increasing LC3-I to LC3-II conversion. Furthermore, MPP+-induced toxicity diminished the integrin beta3, alphaV, syndecan-1 and -3. Insulin pre-treatment enhanced the phosphorylation of integrin-linked kinase and further induced the integrin and syndecan molecules. These findings suggest that insulin prevents MPP+-induced toxicity through activation of PI3K, p-GSK-3beta, autophagy, integrins and syndecans pathways in C6 glial cells. PMID- 28853309 TI - The Current Studies of Education for a Traditional and Complementary Medicine in Malaysia. AB - The aim of this study is to understand the current tradition and complementary medicine (T&CM) education in Malaysia. We referred to literature regarding to traditional medicine education in Malaysia, and collected the information via website or interview with faculty of T&CM in universities/colleges and Division of T&CM, Ministry of Health, Malaysia. T&CM education in Malaysia has been following China's T&CM systems for 50 years. Currently, Division of T&CM, Ministry of Health; and Ministry of Higher Education has approved 11 institutions to offer T&CM education. Students may major in Chinese herbal medicine, acupuncture, or other T&CM subjects. Generally, clinical training programs in China, Taiwan, or Australia include substantial proportion of clinical training. We report on the general information of T&CM education in Malaysia. This result would be the first-stage information for the establishment of a strategy regarding the enhancement of T&CM education in Malaysia. PMID- 28853310 TI - Responses to romidepsin in patients with cutaneous T-cell lymphoma and prior treatment with systemic chemotherapy. AB - Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had >=1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to romidepsin, and response rates were similar to those in patients who were chemotherapy naive. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy. PMID- 28853311 TI - Spatial and temporal variation of H and O isotopic compositions of the Xijiang River system, Southwest China. AB - Ratios of stable isotopes of hydrogen and oxygen (2H/1H and 18O/16O) in river waters were measured to investigate the hydrological pathway of the Xijiang River, Southwest China. The delta2H and delta18O values of river waters exhibit significant spatial and temporal variations and the isotopic compositions vary with elevation, temperature and precipitation of the recharge area. Spatially, delta18O values of river waters from high mountain areas are lower than those from the lower reaches of the Xijiang River due to lower temperature and higher elevation for the recharge area. However, both 2H and 18O are enriched differently in river waters from the middle reaches during the high flow season, depending on the season and degree of anthropogenic disturbances (e.g. water impoundments). In contrast, deuterium excess (d-excess) values of waters from the middle reaches are substantially lower than those from the upper and lower reaches, suggesting that river waters may be resided in the reservoir and evaporation increases in the middle reaches of the Xijiang River. PMID- 28853312 TI - (Unpacking) father involvement in the context of childhood neurodisability research: a scoping review. AB - BACKGROUND: In the past thirty years, theoretical and empirical scholarship on father involvement has emerged and firmly established itself. Efforts to define, measure, and explore outcomes related to father involvement in the context of childhood neurodisability are evident but less well established. The purpose of this study was to systematically map empirical studies on father involvement in the context of childhood neurodisability in order to delineate the current state of research and to highlight profitable directions for future research. METHODS: A rigorous scoping review method was used to select and analyze empirical studies published between the years 1988 and 2016 in order to systematically map research findings about fathers' affective, behavioral, and cognitive involvement. RESULTS: Fifty-four (n = 54) studies (quantitative n = 47 and qualitative n = 7) met inclusion criteria associated with three levels of review. Four main trends emerged: (a) paternal "stress" is a main concept of interest; (b) comparison of mothers and fathers on affective and cognitive involvement; (c) lack of a focus on fathers' behavioral involvement, and (d) the absence of research designs that allow for examination of fathers' unique perspectives. CONCLUSIONS: Fathers are generally underrepresented in research in the context of childhood neurodisability. While there is a lack of depth in this area of research, granular analyses revealed important and unique differences about fathers' parenting experiences. Recommendations for research and practice are provided. Implications for rehabilitation Fathers are underrepresented in the parenting in childhood neurodisability literature. Fathers who report feeling competent in parenting and connected to their child also report less parenting distress and more satisfaction in their couple relationship and family environment. Rehabilitation and allied health professionals should include fathers in parenting/family assessments. Manifestation of distress may differ among family members. Rehabilitation and allied health professionals should offer individualized care that is attuned to the needs of all family members. PMID- 28853313 TI - Immunomodulatory effects of heat-killed Mycobacterium obuense on human blood dendritic cells. AB - Heat-killed (HK) Mycobacterium obuense is a novel immunomodulator, currently undergoing clinical evaluation as an immunotherapeutic agent in the treatment of cancer. Here, we examined the effect of in vitro exposure to HK M. obuense on the expression of different categories of surface receptors on human blood myeloid (m) and plasmacytoid (p) DCs. Moreover, we have characterized the cytokine and chemokine secretion patterns of purified total blood DCs stimulated with HK M. obuense. HK M. obuense significantly up-regulated the expression of CD11c, CD80, CD83, CD86, CD274 and MHC class II in whole-blood mDCs and CD80, CD123 and MHC class II in whole-blood pDCs. Down-regulation of CD195 expression in both DC subpopulations was also noted. Further analysis showed that HK M. obuense up regulated the expression of CD80, CD83 and MHC class II on purified blood DC subpopulations. TLR2 and TLR1 were also identified to be engaged in mediating the HK M. obuense-induced up-regulation of surface receptor expression on whole blood mDCs. In addition, our data demonstrated that HK M. obuense augmented the secretion of CCL4, CCL5, CCL22, CXCL8, IL-6, IL-12p40 and TNF-alpha by purified total blood DCs. Taken together, our data suggest that HK M. obuense exerts potent differential immunomodulatory effects on human DC subpopulations. PMID- 28853314 TI - Stakeholders' Perspectives on Strategies for the Recruitment and Retention of Primary Health Care Employees in Qatar: A Qualitative Approach. AB - This study explores the recruitment and retention conditions influencing primary health care (PHC) human resources for health (HRH) in Qatar and suggests strategies for their improvement. A qualitative design employing semistructured key informant interviews with PHC stakeholders in Qatar was utilized. Key interviewees were originally recognized, and snowball sampling was used to identify additional interviewees until reaching saturation point. Interview scripts were transcribed and then analyzed thematically using the Nvivo software package. Thematic analysis precipitated a number of themes. Under recruitment, the centrality of enhancing collaboration with academic institutions, enhancing extrinsic benefits, and strengthening human resources recruitment and management practices. Dedicated support needs to be provided to expatriate HRH especially in regard to housing services, children schooling, and streamlining administrative processes for relocation. Findings revealed that job security, continuous professional development, objective performance appraisal systems, enhanced job transparency, and remuneration are key retention concerns. The study provides a number of recommendations for the proper recruitment and retention of HRH. Health planners and decision makers must take these recommendations into consideration to ensure the presence of a competent and sustainable HRH in the PHC sector in the future. PMID- 28853315 TI - A phase I study of lenalidomide in patients with chronic myelomonocytic leukemia (CMML) - AGMT_CMML-1. AB - According to former classification systems chronic myelomonocytic leukemia (CMML) is listed within myelodysplastic syndromes (MDS). Therefore data regarding treatment of CMML is largely derived from MDS trials. Two published studies suggest efficacy of lenalidomide in a proportion of patients with CMML, but the number of patients included was very low. We initiated this phase I trial with lenalidomide in patients with CMML. Primary objective of the current study was to determine the maximum tolerated dose (MTD). Secondary objectives were safety, tolerability and response. Twenty patients were enrolled and received lenalidomide using a classical 3 + 3 design. Lenalidomide 5 mg daily was confirmed as MTD. Best response achieved was partial remission in one patient and stable disease in nine patients. Lack of response with primary progressive disease was seen in three patients. Lenalidomide had a good toxicity profile in this study with thrombocytopenia being the main toxicity observed. Efficacy needs to be confirmed in further trials. PMID- 28853316 TI - Effect of electromagnetic field accompanying the magnetic resonance imaging on human heart rate variability - a pilot study. AB - The effect of electromagnetic field on cardiovascular system in the literature is defined in ambiguous way. The aim of this study was to evaluate the effect of electromagnetic field on the heart rate variability (HRV) during the examination with magnetic resonance. Forty-two patients underwent Holter ECG heart monitoring for 30 minutes twice: immediately before and after the examination with magnetic resonance imaging (MRI). HRV was analysed by assessing a few selected time and spectral parameters. Is has been shown that standard deviation of NN intervals (SDNN) and very low frequency rates increased, whereas the low frequency:high frequency parameter significantly decreased following the MRI examination. These results show that MRI may affect the HRV most likely by changing the sympathetic parasympathetic balance. PMID- 28853317 TI - Shoe drop reduction influences the lower limb biomechanics of children tennis players during an open stance forehand: A longitudinal study. AB - Compared to traditional tennis shoes, using 0-drop shoes was shown to induce an immediate switch from rear- to forefoot strike pattern to perform an open stance tennis forehand for 30% of children tennis players. The purpose of the study was to examine the long-term effects of a gradual reduction in the shoe drop on the biomechanics of children tennis players performing open stance forehands. Thirty children tennis players participated in 2 laboratory biomechanical test sessions (intermediate: +4 months and final: +8 months) after an inclusion visit where they were randomly assigned to control (CON) or experimental (EXP) group. CON received 12-mm-drop shoes twice, whereas EXP received 8 mm then 4-mm-drop shoes. Strike index indicated that all CON were rearfoot strikers in intermediate and final test sessions. All EXP were rearfoot strikers in intermediate test session, but half the group switched towards a forefoot strike pattern in final test session. This switch resulted in a decreased loading rate of the ground reaction force (-73%, p = .005) but increased peak ankle plantarflexors moment (+47%, p = .050) and peak ankle power absorption (+107%, p = .005) for these participants compared with CON. Biomechanical changes associated with the long-term use of partial minimalist shoes suggest a reduction in heel compressive forces but an increase in Achilles tendon tensile forces. PMID- 28853318 TI - Corrigendum. PMID- 28853319 TI - Fabrication and characterization of phlorotannins/poly (vinyl alcohol) hydrogel for wound healing application. AB - Phlorotannins (PH) derived from brown algae have been shown to have biological effects. However, the application of PH in biomedical materials has not been investigated. Here, we investigated the effects of PH on normal human dermal fibroblast (NHDF) proliferation and fabricated a composite hydrogel consisting PH and poly (vinyl alcohol) (PVA) (PVA/PH) by a freezing-thawing method for wound healing applications. Cell proliferation was significantly higher in the PH treated (0.01 and 0.02%) cells than in non-treated cells. Based on the mechanical properties, the PVA/PH hydrogel had a significantly increased swelling ratio and ultimate strain compared to the PVA hydrogel, but the ultimate tensile strength and tensile modulus were decreased. Additionally, cell attachment and proliferation on the composites were evaluated using NHDFs. The results showed that after 1 and 5 days, cell attachment and proliferation were significantly increased on the PVA/PH hydrogel compared with that on the PVA hydrogel. The findings from this study suggest that the PVA/PH hydrogel may be a candidate biomedical material for wound healing applications. PMID- 28853320 TI - Description of the Nicotiana benthamiana-Cercospora nicotianae Pathosystem. AB - Nicotiana benthamiana is a valuable model organism in plant biology research. This report describes its extended applicability in the field of molecular plant pathology by introducing a nonbiotrophic fungal pathogen Cercospora nicotianae that can be conveniently used under laboratory conditions, consistently induces a necrotic leaf spot disease on Nicotiana benthamiana, and is specialized on solanaceous plants. Our inoculation studies showed that C. nicotianae more effectively colonizes N. benthamiana than its conventional host, N. tabacum. The functions of two critical regulators of host immunity, coronatine-insensitive 1 (COI1) and ethylene-insensitive 2 (EIN2), were studied in N. benthamiana using Tobacco rattle virus-based virus-induced gene silencing (VIGS). Perturbation of jasmonic acid or ethylene signaling by VIGS of either COI1 or EIN2, respectively, resulted in markedly increased Cercospora leaf spot symptoms on N. benthamiana plants. These results suggest that the N. benthamiana-C. nicotianae host-pathogen interaction is a prospective but hitherto unutilized pathosystem for studying gene functions in diseased plants. PMID- 28853321 TI - Investigation of contributing factors to extremely severe traffic crashes using survival theory. AB - This study aimed to investigate the contributing factors to serious casualty crashes in China. Crashes with deaths greater than 10 people are defined as serious casualty crashes in China. The serious casualty crash data were collected from 2009 to 2014. The random forest analysis was first conducted to select the candidate variables that affect the risks of serious casualty crashes. The Bayesian random parameters accelerated failure time (AFT) model was then developed to link the probability of the serious casualty crash with road geometric conditions, pavement conditions, environmental characteristics, collision characteristics, vehicle conditions, and driver characteristics. The AFT model estimation results indicate that overload driving, country road, northwest china region, turnover crash, private car, snowy or icy road surface and sight distance conditions have significant fixed effects on the likelihood of serious casualty crashes. In addition to these fixed-parameter variables, freeway, clear weather conditions, coach drivers, and upgrade horizontal curve affect the likelihood of serious casualty crashes with varying magnitude across observations. One of the important findings is that the serious casualty crash likelihood does not always decrease with an increase in the driving experience (number of years driven). Before the inflection point of 7 years, the serious casualty crash likelihood increases as the driving experience grows. The results of this study can help to develop effective countermeasures and policy initiatives for the prevention of serious casualty crashes. PMID- 28853322 TI - Moving From Knowledge to Action in Partnership: A Case Study on Program Adaptation to Support Optimal Aging in the Context of Migration. AB - This case study explored how a researcher-community partnership contributed to program adaptations when implementing person-centered group-based health promotion services to older people who have migrated to Sweden. The study was conducted over 3 years and various data sources were used: focus groups, individual interviews, documents, and archive material. Findings from different data sources and partners' perspectives were triangulated to an overall case description using an iterative process. Adaptations were shaped through a dynamic process, negotiating toward suitable solutions that culminated in actions taken to adapt or inhibit adaptations. The negotiations were driven by the interplay within and between three reasons to adapt. The partners' opportunities to influence the negotiation process depended on establishing common ground to shape adaptations. Practical implications are provided on how to move from knowledge to action when implementing person-centered group-based health promotion to support optimal aging in the context of migration. PMID- 28853323 TI - "The individual at the centre" - a grounded theory explaining how sport clubs retain young adults. AB - PURPOSE: There is still a lack of knowledge regarding which social processes occur in sport clubs and what factors influence young adults to want to remain in a sport club context. Thus, the purpose of this study was to construct a grounded theory (GT) explaining how sport clubs can retain their young adults. METHOD: The study uses an intersectional approach. In line with constructivist GT methodology, data from 14 focus-group interviews (27 coaches and 28 young adults) were collected and analysed using a constant comparative method. RESULTS: The core category, "The individual at the centre of a community", summarizes a process, whereby the generated GT contains three main categories, namely (1) "Participation and influence", (2) "Social connectedness" and (3) "Good conditions". CONCLUSIONS: The coaches put the individual at the centre of a community and pay attention to the needs and interests of all the young adults, regardless of their background, ambitions, and skills. However, while the idea of a moral imperative to provide for diversity was not directly absent in the discussions with both the coaches and young adults, most of the diversity approaches seemed to be based on ambition and skills, gender, age and sexuality. PMID- 28853324 TI - A Case of Juvenile Onset Neuronal Intranuclear Inclusion Disease With a Negative Antemortem Skin Biopsy. AB - Neuronal intranuclear (hyaline) inclusion disease (NIID) is a rare neurodegenerative disorder with a variable clinical presentation and multiple subtypes. We present the clinicopathologic details of a patient with juvenile onset NIID and discuss the pathogenesis. We also discuss the utility of antemortem skin biopsy which was negative in our case. PMID- 28853325 TI - Factors preventing early case detection for women affected by leprosy: a review of the literature. AB - BACKGROUND: Although leprosy can affect both sexes equally, it is globally reported that men are affected, or simply report, more often than females at the average ratio of 2:1. If cases are simply not being reported, women may be suffering in silence more often than men, and, therefore, understanding the social reasons for this in a number of countries could support the prevention of long-term disabilities caused as a result of leprosy. OBJECTIVES: The objective of this review is to recognise the current academic literature surrounding the potential factors for late diagnosis of women affected by leprosy, giving possible explanations for the 2:1 gender disparity observed in case detection globally. It is hoped that health practitioners will become more equipped to recognise these barriers and ensure they are doing whatever possible to encourage women to report the early symptoms of leprosy. METHODS: The review used a systematic search process in order to identify gender-related publications using robust research, useful for gleaning a cross-cultural perception of issues women may confront on the prospect of a diagnosis of leprosy. RESULTS: Identifying 12 publications from just five countries, the review found there to be four overarching areas which may be considered barriers more often faced by women: societal stigma; women's dependence and low status; self-stigmatising attitudes; and the gender insensitivity of leprosy services. CONCLUSION: Stigma surrounding leprosy experienced from these four overarching areas can all be attributed to the later diagnosis of women affected by leprosy, in relation to their male counterparts. The need for future research surrounding the specific experience of women affected by leprosy is pressing. PMID- 28853326 TI - Which set of factors contribute to increase the likelihood of pedestrian fatality in road crashes? AB - This study aimed to explore the combination of factors and circumstances that could increase the likelihood of a pedestrian crash to be fatal. Six pedestrian crash clusters identified in our previous study on 34,178 crashes occurred in Iran, were employed in the current work and the association rules technique was used as the analysis tool. Based on the results, jaywalking or waiting beside the road on poorly illuminated locations of those segments of rural roads that pass through residential/agricultural districts substantially increased the fatality risk of pedestrian (Lift = 3.4). Therefore, appropriately illuminated locations need to be designed on these segments of rural roads for pedestrians to wait beside or cross the road safely. In case of motorcycle-pedestrian crashes, inattention to yield sign, especially in residential areas, might significantly increase the fatality risk of pedestrian (by a factor of 8.1). Also, in those crashes where the motorcyclist is under 19 years old (i.e. unlicensed) and the pedestrian is over 60, the crash could be 5.3 times more likely to be fatal. More strict law enforcement over unlicensed motorcyclists is required as they were found to involve in more severe pedestrian crashes. The combined use of clustering analysis and association rules discovery should not be considered as an alternative to other modelling techniques, but as a complementary descriptive method to be used in road safety research. PMID- 28853328 TI - The Feasibility, Effectiveness, and Process of Change of Mindfulness-Based Cognitive Therapy for Adults With ADHD: A Mixed-Method Pilot Study. AB - OBJECTIVE: Mindfulness-Based Cognitive Therapy (MBCT) is a promising psychosocial intervention for adult ADHD. The feasibility and effectiveness of an adapted MBCT program is explored, together with the possible process of change. METHOD: Mixed method study with 31 ADHD patients participating in an adapted MBCT program. Self report questionnaires on ADHD symptoms, executive functioning, mindfulness skills, self-compassion, patient functioning, and health status were administered before and after MBCT. Semi-structured interviews were conducted with 24 patients. RESULTS: A modest drop-out of n = 5 (16%) was found. MBCT resulted in a significant reduction of ADHD symptoms and improvements of executive functioning, self-compassion, and mental health. Qualitative analysis provided insight in facilitators and barriers participants experienced, and their process of change. CONCLUSION: The adapted MBCT program seemed to be feasible for adults with ADHD and preliminary evidence for the effectiveness is shown. An adequately powered Randomized Controlled Trial (RCT) is needed to further examine the effectiveness of MBCT for ADHD. PMID- 28853327 TI - Medical students' perception of lesbian, gay, bisexual, and transgender (LGBT) discrimination in their learning environment and their self-reported comfort level for caring for LGBT patients: a survey study. AB - BACKGROUND: Historically, medical students who are lesbian, gay, bisexual or transgendered (LGBT) report higher rates of social stress, depression, and anxiety, while LGBT patients have reported discrimination and poorer access to healthcare. OBJECTIVE: The objectives of this study were: (1) to assess if medical students have perceived discrimination in their learning environment and; (2) to determine self-reported comfort level for caring for LGBT patients. DESIGN: Medical students at the University of Ottawa (N = 671) were contacted via email and invited to complete a confidential web-based survey. RESULTS: Response rate was 15.4% (103/671). This included 66 cis-gender heterosexuals (64.1%) and 37 LGBT students (35.9%). Anti-LGBT discrimination had been witnessed by 14.6% and heterosexism by 31.1% of respondents. Anti-LGBT discrimination most often originated from fellow medical students. Respondents who self-identified as LGBT were more likely to have perceived heterosexism (favoring opposite-sex relationships) (OR = 8.2, p < 0.001) or anti-LGBT discrimination (OR = 6.6, p = 0.002). While half of LGBT students shared their status with all classmates (51.4%), they were more likely to conceal this from staff physicians (OR = 27.2, p = 0.002). Almost half of medical students (41.7%) reported anti-LGBT jokes, rumors, and/or bullying by fellow medical students and/or other members of the healthcare team. Still, most respondents indicated that they felt comfortable with and capable of providing medical care to LGBT patients (>=83.5%), and were interested in further education around LGBT health issues (84.5%). CONCLUSION: Anti-LGBT discrimination and heterosexism are noted by medical students, indicating a suboptimal learning environment for LGBT students. Nonetheless, students report a high level of comfort and confidence providing health care to LGBT patients. PMID- 28853329 TI - Artificial biomembrane morphology: a dissipative particle dynamics study. AB - Artificial membranes mimicking biological structures are rapidly breaking new ground in the areas of medicine and soft-matter physics. In this endeavor, we use dissipative particle dynamics simulation to investigate the morphology and behavior of lipid-based biomembranes under conditions of varied lipid density and self-interaction. Our results show that a less-than-normal initial lipid density does not create the traditional membrane; but instead results in the formation of a 'net', or at very low densities, a series of disparate 'clumps' similar to the micelles formed by lipids in nature. When the initial lipid density is high, a membrane forms, but due to the large number of lipids, the naturally formed membrane would be larger than the simulation box, leading to 'rippling' behavior as the excess repulsive force of the membrane interior overcomes the bending energy of the membrane. Once the density reaches a certain point however, 'bubbles' appear inside the membrane, reducing the rippling behavior and eventually generating a relatively flat, but thick, structure with micelles of water inside the membrane itself. Our simulations also demonstrate that the interaction parameter between individual lipids plays a significant role in the formation and behavior of lipid membrane assemblies, creating similar structures as the initial lipid density distribution. This work provides a comprehensive approach to the intricacies of lipid membranes, and offers a guideline to design biological or polymeric membranes through self-assembly processes as well as develop novel cellular manipulation and destruction techniques. PMID- 28853330 TI - Activity of the antioxidant enzyme paraoxonase in Argentinean children living at high altitude. AB - BACKGROUND: Children living at high altitude in San Antonio de los Cobres (SAC), Argentina, were shown to have lower high-density lipoprotein cholesterol (HDL-C) levels than Buenos Aires (BA) children. HDL antioxidant capacity is mainly attributed to paraoxonase1 (PON1). OBJECTIVE: To compare PON1 activity in indigenous SAC vs. BA children. METHODS: A cross-sectional study compared 158 SAC vs. 97 BA children (6-16 years). Anthropometric data and lipoprotein profile were measured. PON1 was evaluated employing paraoxon (PON) and phenylacetate (ARE) activity. RESULTS: The prevalence of overweight/obesity was lower in SAC than in BA children (18.3 vs. 30.9%). Triglycerides (1.34 vs. 0.90 mmol/l), apo B (0.84 vs.0.72 g/l), apo A-I (1.33 vs. 1.27 g/l), and ARE activity (100 vs. 90 umol/ml/min) were higher, while HDL-C (1.16 vs. 1.32 mmol/l) and PON activity (170 vs. 203 nmol/ml/min) were lower in SAC than in BA. Separate multiple linear regression analyses showed that SAC children had significantly higher triglyceride (Beta -0.38), apo B (Beta -0.34), and ARE (Beta -0.36) plus lower HDL-C (Beta 0.33) and PON (Beta 0.25) compared with BA; adjusted for age, gender, and BMI. CONCLUSION: SAC showed an unfavorable lipoprotein profile, lower PON and higher ARE activities compared with BA children, suggesting the presence of altered HDL metabolism and antioxidant capacity. PMID- 28853331 TI - The effects of varying levels of hemispheric activation on episodic memory. AB - Bilateral saccadic eye movements enhance episodic memory retrieval; however, this usually only occurs for consistent-handed, not inconsistent-handed, individuals. It was hypothesized that inconsistent-handers begin closer to the peak of a Yerkes-Dodson-type inverted-U curve and increasing activation pushes them along the curve eventually decreasing performance, while consistent-handers start at a lower baseline and therefore increasing activation increases their performance. The current study tested this hypothesis by using hand clenching (grip strength) to increase activation at 5 different levels for both consistent- and inconsistent-handers. A total of 316 participants were presented with a list of 36 words after which they squeezed a hand dynamometer to induce cortical activation, and then recalled as many of the words as they could. Results showed that, as predicted, both inconsistent- and consistent-handers demonstrated an inverted-U pattern of memory performance as the strength of squeeze increased with inconsistent-handers peaking at a lower level of grip strength than consistent-handers. These results may help explain past findings, not only with episodic memory but also a variety of other cognitive tasks. They may also have interesting theoretical and real-world implications, which are discussed. PMID- 28853332 TI - Cognitive functioning in schizotypy through the lens of the accessibility model. AB - INTRODUCTION: Individuals with schizotypy self-report subjective cognitive complaints commensurate with deficits reported by individuals with schizophrenia. In contrast to schizophrenia, objective deficits in memory are modest in individuals with schizotypy, as compared to their self-reported cognitive complaints. It has been proposed that abnormalities in semantic memory systems may underlie this dysjunction. METHODS: This study employed a modified verbal memory paradigm in a sample of 87 individuals with psychometrically defined schizotypy. Appraisals of memory performance were evaluated across global (i.e. drawing on semantic memory systems and assessing perceived typical performance) and situation-specific (i.e. drawing on episodic memory systems) epochs. Objective memory performance was assessed using a verbal recall paradigm. RESULTS: Individuals with schizotypy did not differ in situation-specific appraisals or in objective memory performance. Global appraisals of memory performance predicted negative and disorganised schizotypy scores. No other measure of memory performance predicted any facet of schizotypy. Individuals with schizotypy appraised their global memory performance higher than controls at a medium effect. CONCLUSIONS: Higher order global appraisals of cognitive performance, subsumed within semantic networks, may be important in the subjective-objective paradox in schizotypy, suggesting the importance of considering demand characteristics when assessing measures of neurocognitive performance in individuals with schizotypy. PMID- 28853334 TI - Identification of novel PPARalpha/gamma dual agonists by virtual screening, ADMET prediction and molecular dynamics simulations. AB - PPARalpha and PPARgamma have been the most widely studied Peroxisome proliferator activated receptor (PPAR) subtypes due to their important roles in regulating glucose, lipids, and cholesterol metabolism. By combining the lowering serum triglyceride levels benefit of PPARalpha agonists (such as fibrates) with the glycemic advantages of the PPARgamma agonists (such as TZD), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence, has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of virtual screening, ADMET prediction and molecular dynamics (MD) simulations techniques, one compound-ASN15761007 with high binding score, low toxicity were gained. It was observed by MD simulations that ASN15761007 not only possessed the same function as AZ242 did in activating PPARalpha and BRL did in activating PPARgamma, but also had more favorable conformation for binding to the two receptors. Our results provided an approach to rapidly produce novel PPARalpha/gamma dual agonists which might be a potential lead compound to develop against insulin resistance and hyperlipidemia. PMID- 28853335 TI - Correction to: Carvalho et al., Prevalence of iron deficiency anemia and iron deficiency in a pediatric population with inflammatory bowel disease. PMID- 28853333 TI - Under-reporting of major birth defects in Northwest Russia: a registry-based study. AB - : The objective was to assess the prevalence of selected major birth defects, based on data from two medical registries in Murmansk County, and compare the observed rates with those available for Norway and Arkhangelsk County, Northwest Russia. It included all newborns (>=22 completed weeks of gestation) registered in the Murmansk County Birth Registry (MCBR) and born between 1 January 2006 and 31 December 2009 (n=35,417). The infants were followed-up post-partum for 2 years through direct linkage to the Murmansk Regional Congenital Defects Registry (MRCDR). Birth defects identified and confirmed in both registries constituted the "cases" and corresponded to one or more of the 21 birth defect types reportable to health authorities in Moscow. The overall prevalence of major birth defects recorded in the MRCDR was 50/10,000 before linkage and 77/10,000 after linkage with the MCBR. Routine under-reporting to the MRCDR of 40% cases was evident. This study demonstrates that birth registry data improved case ascertainment and official prevalence assessments and reduced the potential of under-reporting by physicians. The direct linkage of the two registries revealed that hypospadias cases were the most prevalent among the major birth defects in Murmansk County. ABBREVIATIONS: ICD-10, International Classification of Diseases, 10th revision; MCBR, Murmansk County Birth Registry; MRCDR, Murmansk Regional Congenital Defects Registry; MGC, Murmansk Genetics Center. PMID- 28853337 TI - Increased monocyte-to-HDL cholesterol ratio is related to cardiac syndrome X. AB - OBJECTIVE: Cardiac syndrome X (CSX) is typically identified with ischaemia in treadmill exercise test or stress myocardial perfusion scintigraphy as well as angina-like chest pain without stenosis in coronary angiography. The purpose of the present study is to investigate the association between cardiac syndrome X and monocyte-to-HDL cholesterol ratio (MHR) which is a new marker associated with inflammation. PATIENTS AND METHODS: A total of 230 patients (105 patients with cardiac syndrome X and 125 normal controls) were included in the study. Peripheral venous blood samples were drawn from all study population before coronary angiography for measuring MHR and other haematological parameters. RESULTS: The patients with cardiac syndrome X were more likely to have higher platelet counts, plateletcrit (PCT), monocyte count and MHR values. Monocyte count and MHR of the CSX group were significantly higher than the control group [0.53 (0.35-1) vs. 0.49 (0.23-0.96); p = .002, .011 (0.006-0.038) vs. 0.010 (0.004-0.034); p < .001, respectively]. HDL-cholesterol levels of the CSX group were significantly lower than the control groups (46.3 +/- 10.1 vs. 49.6 +/- 11.6; p = .021). Higher MHR and PCT values were found to be associated with the presence of CSX by multivariate logistic regression analysis. CONCLUSIONS: Elevated MHR level independently was found in association with the presence of CSX. The value of MHR appears additive to conventional expensive methods commonly used in CSX prediction. PMID- 28853336 TI - The percutaneous absorption of soman in a damaged skin porcine model and the evaluation of WoundStatTM as a topical decontaminant. AB - PURPOSE: The aim of this study was to evaluate a candidate haemostat (WoundStatTM), down-selected from previous in vitro studies, for efficacy as a potential skin decontaminant against the chemical warfare agent pinacoyl methylfluorophosphonate (Soman, GD) using an in vivo pig model. MATERIALS AND METHODS: An area of approximately 3 cm2 was dermatomed from the dorsal ear skin to a nominal depth of 100 um. A discrete droplet of 14C-GD (300 ug kg-1) was applied directly onto the surface of the damaged skin at the centre of the dosing site. Animals assigned to the treatment group were given a 2 g application of WoundStatTM 30 s after GD challenge. The decontamination efficacy of WoundStatTM against GD was measured by the direct quantification of the distribution of 14C GD, as well as routine determination of whole blood cholinesterase and physiological measurements. RESULTS: WoundStatTM sequestered approximately 70% of the applied 14C-GD. Internal radiolabel recovery from treated animals was approximately 1% of the initially applied dose. Whole blood cholinesterase levels decreased to less than 10% of the original value by 15 min post WoundStatTM treatment and gradually decreased until the onset of apnoea or until euthanasia. All treated animals showed signs of GD intoxication that could be grouped into early (mastication, fasciculations and tremor), intermediate (miosis, salivation and nasal secretions) and late onset (lacrimation, body spasm and apnoea) effects. Two of the six WoundStatTM treated animals survived the study duration. CONCLUSIONS: The current study has shown that the use of WoundStatTM as a decontaminant on damaged pig ear skin was unable to fully protect against GD toxicity. Importantly, the findings indicate that the use of WoundStatTM in GD contaminated wounds would not exacerbate GD toxicity. These data suggest that absorbent haemostatic products may offer some limited functionality as wound decontaminants. PMID- 28853338 TI - Future Costs of Long-term Care in Japan and Sweden. AB - Population aging is expected to increase long-term care (LTC) costs in both Japan and Sweden. This study projected LTC costs for 2010 through 2040 for different assumptions of population change, LTC need by age group and gender, and LTC provided per level of need and cost in Japan and Sweden. Population data were taken from the official national forecasts. Needs projections were based on epidemiological data from the Nihon University Japanese Longitudinal Study of Aging and the Swedish Survey of Living Conditions. Data on LTC provision by need and cost were taken from nine Japanese municipalities collected by assessments in the LTC insurance system and from surveys in eight Swedish municipalities. Total initial costs were calibrated to official national figures. Two projections based on two different scenarios were made for each country from 2010 to 2040. The first scenario assumed a constant level of need for LTC by age group and gender, and the other assumed a continuation of the present LTC need trends until 2025. For Japan, this resulted in a projected cost increase of 93% for the one and 80% for the other; for Sweden it was 52% and 24%, respectively. The results reflected differences in population aging and health development. PMID- 28853339 TI - TDQ-60 - a color picture-naming test for adults and elderly people: validation and normalization data. AB - Word-finding difficulties are usually assessed with picture-naming tests. In this article, we present the TDQ-60, a new test designed to assess acquired lexical access deficits, taking into account semantics and psycholinguistic variables. The article includes three studies. Study 1 describes the development phase of the TDQ-60. In study 2, healthy control participants and individuals with a diagnosis of the semantic variant of primary progressive aphasia were assessed to establish the convergent and discriminant validity of the TDQ-60. Finally, in Study 3, a group of 305 young and elderly French-speaking adults from Quebec were assessed in order to provide normative data. The results demonstrate that the TDQ 60 has good convergent validity and good discriminant validity. This study also provides normative data in which were considered the effect of age and education.The TDQ-60 is a new valid picture-naming test, controlled for psycholinguistic variables and designed to identify the influence of semantics on lexical access in spoken production. PMID- 28853341 TI - My daughter's nurse gave our family truly personalised, kind care. AB - Jo O'Toole was the specialist respiratory nurse for our daughter Amelie, who has CHARGE syndrome, for several years. She gave us truly personalised and kind care. PMID- 28853342 TI - Strong nurse leadership still undermined by high turnover. AB - An effective, well-led health and social care system is dependent on having strong clinical leadership at board level. Not my words, but those of Christine McKenzie, lead of the RCN's executive nurse network, in response to the latest findings of Nursing Standard's annual survey of turnover among directors of nursing. PMID- 28853340 TI - Variability in Affect and Willingness to Take Medication. AB - OBJECTIVE: To determine if 1) patients have distinct affective reaction patterns to medication information, and 2) whether there is an association between affective reaction patterns and willingness to take medication. METHODS: We measured affect in real time as subjects listened to a description of benefits and side effects for a hypothetical new medication. Subjects moved a dial on a handheld response system to indicate how they were feeling from "Very Good" to "Very Bad". Patterns of reactions were identified using a cluster-analytic statistical approach for multiple time series. Subjects subsequently rated their willingness to take the medication on a 7-point Likert scale. Associations between subjects' willingness ratings and affect patterns were analyzed. Additional analyses were performed to explore the role of race/ethnicity regarding these associations. RESULTS: Clusters of affective reactions emerged that could be classified into 4 patterns: "Moderate" positive reactions to benefits and negative reactions to side effects ( n = 186), "Pronounced" positive reactions to benefits and negative reactions to side effects ( n = 110), feeling consistently "Good" ( n = 58), and feeling consistently close to "Neutral" ( n = 33). Mean (standard error) willingness to take the medication was greater among subjects feeling consistently Good 4.72 (0.20) compared with those in the Moderate 3.76 (0.11), Pronounced 3.68 (0.14), and Neutral 3.62 (0.26) groups. Black subjects with a Pronounced pattern were less willing to take the medication compared with both Hispanic ( P = 0.0270) and White subjects ( P = 0.0001) with a Pronounced pattern. CONCLUSION: Patients' affective reactions to information were clustered into specific patterns. Reactions varied by race/ethnicity and were associated with treatment willingness. Ultimately, a better understanding of how patients react to information may help providers develop improved methods of communication. PMID- 28853345 TI - Ensuring dignity in death. AB - Homeless people are dying in unsupported and unacceptable situations with inadequate access to palliative care, a recent study found. PMID- 28853349 TI - Student life - Off on a placement in Zambia. AB - Recent outbreaks of disease, including Ebola, Zika and Middle East Respiratory Syndrome, have shown the need for a collaborative and co-ordinated response to global health issues. PMID- 28853352 TI - Think before you accept or reject a job. AB - The stress and excitement of applying for a job has three obvious outcomes. PMID- 28853354 TI - 'FIT TO SIT' in the emergency department. AB - A campaign to get patients out of bed and wearing their day clothes instead of pyjamas has caught the imagination of nurses and other healthcare staff across the country. But staff at Nottingham University Hospitals Trust have taken the #EndPJparalysis campaign a step further, with a 'fit to sit' initiative that starts as soon as patients come into the emergency department. PMID- 28853358 TI - When can I say no? AB - If the professional relationship between a nurse and a patient has broken down through no fault of either party, it is often more appropriate for the patient's care and treatment to be provided by another nurse. This could be initiated by the nurse or the patient. PMID- 28853359 TI - The way nurses are treated is a national tragedy. AB - Nurses are an invaluable resource. We look after the sick and care for the dying, often with little thanks. PMID- 28853360 TI - Positive practice: the use of restrictive interventions. AB - A rights-based approach, placing the person at the centre of all we do, is essential to modern healthcare. PMID- 28853361 TI - 'Short shelf life' remains a problem in senior posts. AB - Nursing Standard research reveals half of chief nurses in the UK have been in post for three years or less, prompting further concern about high turnover in senior roles. More than a third (36%) took up their positions in the past two years, while 17% started in the past eight months. PMID- 28853363 TI - 10,000 more training places isn't enough. AB - News that the Department of Health intends to fund an additional 10,000 training places for nurses and allied health professionals is obviously welcome. But how many of these places will be for nursing students, and how will they be split across the four fields of nursing, given the government's recent announcement on bolstering mental health services? PMID- 28853364 TI - Advice for new nursing students. AB - As a nurse who trained in the 60s and worked for almost 45 years in a variety of disciplines, my advice to new nursing students is: one, get enough sleep; two, play hard; three, study hard; four, turn up on time for your shift (remember that you are replacing someone who wants to go home); five, don't let anyone intimidate you; six: join a union. PMID- 28853368 TI - 'Vaccination can protect everyone'. AB - Leony Davies qualified as an RGN from the University Hospital of Wales, Cardiff, in 1994. She then qualified as a registered sick children's nurse (RSCN) and specialist community public health nurse while working as a children's nurse and school nurse. Since 2010, she has been employed by Public Health Wales as a specialist nurse in immunisation with the Vaccine Preventable Disease Programme, and is studying for her master's degree in public health and health promotion at Swansea University. PMID- 28853369 TI - X-rays: what the nurse needs to know. AB - Rationale and key points X-ray imaging is a form of electromagnetic radiation that is able to pass through the human body producing an image of the internal structures. X-rays are one of the main investigations for confirming a suspected diagnosis. Developing an understanding of the underlying mechanism and the rationale for requesting an X-ray will increase nurses' understanding of the process and enable improved patient preparation through explanation and reassurance. This article provides an overview of the fundamental principles underlying the process of obtaining an X-ray. " X-ray imaging is a common diagnostic tool that nurses will encounter on a regular basis. " Several factors affect the production of a clear X-ray image, including patient movement. " Radiation safety and avoidance of unnecessary exposure are paramount. " Co operation and communication by the multidisciplinary team are vital to ensure that X-ray imaging can be requested, performed, interpreted and acted on, and the findings communicated to the patient. PMID- 28853371 TI - Remember their names with pride. AB - When Barbara Hallows watched television footage of the service to mark the centenary of the Battle of Passchendaele, something really hit home for her - the value of a name. PMID- 28853372 TI - Improving nurses' level of reflection. AB - Reflecting on practice is an important aspect of nursing. There is widespread acknowledgement of the value of reflective practice and it has a significant role in coursework assessment and revalidation requirements. However, less attention has been given to the various levels of reflection and what constitutes a higher or lower level of reflection. This article aims to assist nurses to understand how identifying the various levels of reflection can improve their practice. A case study example is used to demonstrate how mentors might support nurses in incorporating reflection into their practice. PMID- 28853373 TI - Using bibliometrics to support revalidation requirements. AB - Bibliometrics is a method of statistically analysing written works, including books and journal articles. It can be used to measure an academic article's value, the importance of individual authors or academic research, and the productivity of authors, institutions or departments. Aim To explore how bibliometrics can assist nurse academics in providing documented evidence to meet the Nursing and Midwifery Council's (NMC's) revalidation requirements. Method The author's publication history was used to demonstrate how nurse academics can use bibliometrics to provide evidence of their continuing professional development (CPD). A standard search using bibliographic software provided data on the author's h-index, a summary of his year-by-year citations and details of the journals where his work was published. Data were subjected to a co-word and multidimensional scaling and cluster analysis. Results Data were identified on the number of articles, the journals in which they were published, and the thematic focus of the author's academic work. Four themes were identified from the co-word analysis: nursing and health policy; global influence and change; regulatory research; and leadership and social network analysis. Comparing these results with the revalidation requirements set by the NMC demonstrated the potential for using bibliometrics as a source of CPD evidence. Conclusion Bibliometrics is compatible with the NMC's revalidation requirements and provides a valid means of assisting nurse academics to complete their revalidation portfolios. PMID- 28853375 TI - Supporting children after a traumatic event. AB - Essential facts More than two thirds of children will have experienced at least one traumatic event by the age of 16. Traumatic events are direct or indirect experiences that put a person or someone close to them at risk of serious harm or death. They include road accidents, experiencing or witnessing violence or abuse, serious illnesses and fires. Rare examples include natural disasters, terrorist attacks or conditions of war. PMID- 28853377 TI - Readers' panel - Are stressed healthcare staff in danger of forgetting the lessons of Mid Staffs? AB - Our experts consider a hot topic of the day. PMID- 28853378 TI - Keep your carrots, just give us a pay rise. AB - Golden hellos? I must be dreaming. Employers across the country are offering financial inducements as carrots to entice nurses to work for them. PMID- 28853386 TI - Gaining insight into obesity. AB - In my second year of training I was working with an obese patient, who I will call Mark. PMID- 28853387 TI - Managing resources. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article provided information about managing resources and reducing waste in healthcare settings. It has been reported that healthcare organisations in the UK are under significant financial pressure. Therefore, it is important consider ways to reduce costs and waste. PMID- 28853388 TI - We all have a role to play in ending domestic abuse. AB - An RCN position statement issued this month confirms the college's ongoing commitment to supporting nurses, midwives and healthcare workers to better understand the complexities that surround domestic abuse. PMID- 28853389 TI - Dementia care mapping in nursing homes: effects on caregiver attitudes, job satisfaction, and burnout. A quasi-experimental trial. AB - BACKGROUND: The Dementia Care Mapping (DCM) method is an internationally recognized complex intervention in dementia research and care for implementing person-centered care. The Leben-QD II trial aimed to evaluate the effectiveness of DCM with regard to caregivers. METHODS: The nine participating nursing home units were allocated to three groups: (1) DCM method experienced >= 1 year, (2) DCM newly introduced during this trial, and (3) regular rating of residents' quality of life (control group). Linear mixed models were fit to cluster aggregated data after 0, 6, and 18 months, adjusting for repeated measurements and confounders. The primary outcome was the Approaches to Dementia Questionnaire (ADQ) score; the secondary outcomes were the Copenhagen Psychosocial Questionnaire (COPSOQ) and the Copenhagen Burnout Inventory (CBI). RESULTS: The analysis included 201 caregivers with 290 completed questionnaires (all three data collection time points). The ADQ showed a significant time and time*intervention effect. At baseline, the estimated least-square means for the ADQ were 71.98 (group A), 72.46 (group B), and 71.15 (group C). The non-linear follow-up of group A indicated an estimated-least square means of 69.71 (T 1) and 68.97 (T 2); for group B, 72.80 (T 1) and 72.29 (T 2); and for group C, 66.43 (T 1) and 70.62 (T 2). CONCLUSIONS: The DCM method showed a tendency toward negatively affecting the primary and secondary outcomes; this finding could be explained by the substantial deviation in adherence to the intervention protocol. PMID- 28853390 TI - National Survey of Environmental Cleaning and Disinfection in Hospitals in Thailand. AB - More than 90% of Thai hospitals surveyed reported implementing environmental cleaning and disinfection (ECD) protocols. Hospital epidemiologist presence was associated with the existence of an ECD checklist (P=.01) and of ECD auditing (P=.001), while good and excellent hospital administrative support were associated with better adherence to ECD protocols (P<.001) and ECD checklists (P=.005). Infect Control Hosp Epidemiol 2017;38:1250-1253. PMID- 28853391 TI - Trends in the burden of varicella in UK general practice. AB - Childhood varicella vaccination has not yet been introduced in the UK. To inform decision-making about future vaccine programmes, data on the burden of varicella in general practice over a 10-year period (01/01/2005-31/12/2014) was calculated by age and ethnicity, using anonymised data from >8 million individuals in the Clinical Practice Research Datalink. Varicella consultations peaked at 20 603 in 2007, then decreased annually in all age groups to 11 243 in 2014. Each year, consultation rates were common among infants, were highest among 1-3 year olds (61.2 consultations/1000 person-years in 2007, 39.7/1000 person-years in 2014) and then fell with increasing age to <1.0/1000 person-years at ages ?20 years. Varicella acquisition appeared to be delayed in some ethnic groups, with lower consultation rates for children aged <3 years but increased rates for older children and adults aged ?40 years among those of black African, Afro-Caribbean, South Asian or other Asian ethnicity. Decreasing general practice consultation rates over time could reflect changes in healthcare utilisation, with patients seeking care in alternative settings such as Accident and Emergency Departments, although current data prevent full assessment of this. Availability of data on varicella diagnoses across all health settings would enable estimation of the total healthcare burden due to varicella and the cost-effectiveness of introducing varicella vaccination. PMID- 28853392 TI - Pilot of a randomised controlled trial of the selective serotonin reuptake inhibitor sertraline versus cognitive behavioural therapy for anxiety symptoms in people with generalised anxiety disorder who have failed to respond to low intensity psychological treatments as defined by the National Institute for Health and Care Excellence guidelines. AB - BACKGROUND: Generalised anxiety disorder (GAD) is common, causing unpleasant symptoms and impaired functioning. The National Institute for Health and Care Excellence (NICE) guidelines have established good evidence for low-intensity psychological interventions, but a significant number of patients will not respond and require more intensive step 3 interventions, recommended as either high-intensity cognitive behavioural therapy (CBT) or a pharmacological treatment such as sertraline. However, there are no head-to-head comparisons evaluating which is more clinically effective and cost-effective, and current guidelines suggest that treatment choice at step 3 is based mainly on patient preference. OBJECTIVES: To assess clinical effectiveness and cost-effectiveness at 12 months of treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline compared with CBT for patients with persistent GAD not improved with NICE-defined low-intensity psychological interventions. DESIGN: Participant randomised trial comparing treatment with sertraline with high-intensity CBT for patients with GAD who had not responded to low-intensity psychological interventions. SETTING: Community-based recruitment from local Improving Access to Psychological Therapies (IAPT) services. Four pilot services located in urban, suburban and semirural settings. PARTICIPANTS: People considered likely to have GAD and not responding to low-intensity psychological interventions identified at review by IAPT psychological well-being practitioners (PWPs). Those scoring >= 10 on the Generalised Anxiety Disorder-7 (GAD-7) anxiety measure were asked to consider involvement in the trial. INCLUSION CRITERIA: Aged >= 18 years, a score of >= 10 on the GAD-7, a primary diagnosis of GAD diagnosed on the Mini International Neuropsychiatric Interview questionnaire and failure to respond to NICE-defined low-intensity interventions. EXCLUSION CRITERIA: Inability to participate because of insufficient English or cognitive impairment, current major depression, comorbid anxiety disorder(s) causing greater distress than GAD, significant dependence on alcohol or illicit drugs, comorbid psychotic disorder, received antidepressants in past 8 weeks or high-intensity psychological therapy in previous 6 months and any contraindications to treatment with sertraline. RANDOMISATION: Consenting eligible participants randomised via an independent, web-based, computerised system. INTERVENTIONS: (1) The SSRI sertraline prescribed in therapeutic doses by the patient's general practitioner for 12 months and (2) 14 (+/- 2) CBT sessions delivered by high-intensity IAPT psychological therapists in accordance with a standardised manual designed for GAD. MAIN OUTCOME MEASURES: The primary outcome was the Hospital Anxiety and Depression Scale - Anxiety component at 12 months. Secondary outcomes included measures of depression, social functioning, comorbid anxiety disorders, patient satisfaction and economic evaluation, collected by postal self-completion questionnaires. RESULTS: Only seven internal pilot participants were recruited against a target of 40 participants at 7 months. Far fewer potential participants were identified than anticipated from IAPT services, probably because PWPs rarely considered GAD the main treatment priority. Of those identified, three-quarters declined participation; the majority (30/45) were reluctant to consider the possibility of randomisation to medication. LIMITATIONS: Poor recruitment was the main limiting factor, and the trial closed prematurely. CONCLUSIONS: It is unclear how much of the recruitment difficulty was a result of conducting the trial within a psychological therapy service and how much was possibly a result of difficulty identifying participants with primary GAD. FUTURE WORK: It may be easier to answer this important question by recruiting people from primary care rather than from those already engaged in a psychological treatment service. TRIAL REGISTRATION: Current Controlled Trials ISCRTN14845583. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 45. See the NIHR Journals Library website for further project information. PMID- 28853393 TI - Parallel Activin and BMP signaling coordinates R7/R8 photoreceptor subtype pairing in the stochastic Drosophila retina. AB - Drosophila color vision is achieved by comparing outputs from two types of color sensitive photoreceptors, R7 and R8. Ommatidia (unit eyes) are classified into two subtypes, known as 'pale' or 'yellow', depending on Rhodopsin expression in R7 and R8. Subtype specification is controlled by a stochastic decision in R7 and instructed to the underlying R8. We find that the Activin receptor Baboon is required in R8 to receive non-redundant signaling from the three Activin ligands, activating the transcription factor dSmad2. Concomitantly, two BMP ligands activate their receptor, Thickveins, and the transcriptional effector, Mad. The Amon TGFbeta processing factor appears to regulate components of the TGFbeta pathway specifically in pale R7. Mad and dSmad2 cooperate to modulate the Hippo pathway kinase Warts and the growth regulator Melted; two opposing factors of a bi-stable loop regulating R8 Rhodopsin expression. Therefore, TGFbeta and growth pathways interact in postmitotic cells to precisely coordinate cell-specific output. PMID- 28853397 TI - The pressing problem of Indonesia's forest fires. PMID- 28853394 TI - Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila. AB - Apoptosis and its molecular mediators, the caspases, have long been regarded as tumor suppressors and one hallmark of cancer is 'Evading Apoptosis'. However, recent work has suggested that apoptotic caspases can also promote proliferation and tumor growth under certain conditions. How caspases promote proliferation and how cells are protected from the potentially harmful action of apoptotic caspases is largely unknown. Here, we show that although caspases are activated in a well studied neoplastic tumor model in Drosophila, oncogenic mutations of the proto oncogene Ras (RasV12) maintain tumorous cells in an 'undead'-like condition and transform caspases from tumor suppressors into tumor promotors. Instead of killing cells, caspases now promote the generation of intra- and extracellular reactive oxygen species (ROS). One function of the ROS is the recruitment and activation of macrophage-like immune cells which in turn signal back to tumorous epithelial cells to activate oncogenic JNK signaling. JNK further promotes and amplifies caspase activity, thereby constituting a feedback amplification loop. Interfering with the amplification loop strongly reduces the neoplastic behavior of these cells and significantly improves organismal survival. In conclusion, RasV12-modified caspases initiate a feedback amplification loop involving tumorous epithelial cells and macrophage-like immune cells that is necessary for uncontrolled tumor growth and invasive behavior. PMID- 28853396 TI - Clinical trial research in focus: ensuring new cystic fibrosis drugs fulfil their potential. PMID- 28853398 TI - Around the world: preschool wheeze. PMID- 28853395 TI - Polo-like kinase Cdc5 regulates Spc72 recruitment to spindle pole body in the methylotrophic yeast Ogataea polymorpha. AB - Cytoplasmic microtubules (cMT) control mitotic spindle positioning in many organisms, and are therefore pivotal for successful cell division. Despite its importance, the temporal control of cMT formation remains poorly understood. Here we show that unlike the best-studied yeast Saccharomyces cerevisiae, position of pre-anaphase nucleus is not strongly biased toward bud neck in Ogataea polymorpha and the regulation of spindle positioning becomes active only shortly before anaphase. This is likely due to the unstable property of cMTs compared to those in S. cerevisiae. Furthermore, we show that cMT nucleation/anchoring is restricted at the level of recruitment of the gamma-tubulin complex receptor, Spc72, to spindle pole body (SPB), which is regulated by the polo-like kinase Cdc5. Additionally, electron microscopy revealed that the cytoplasmic side of SPB is structurally different between G1 and anaphase. Thus, polo-like kinase dependent recruitment of gamma-tubulin receptor to SPBs determines the timing of spindle orientation in O. polymorpha. PMID- 28853399 TI - A rigid solution to a relapsing problem. PMID- 28853400 TI - Susceptibility to exacerbation in COPD. PMID- 28853401 TI - Glasgow, Scotland: tackling injection of drugs in public spaces through introduction of safer facilities. PMID- 28853402 TI - Money, money, money. PMID- 28853403 TI - Architecture of change: rethinking child and adolescent mental health. PMID- 28853404 TI - Regulatory meta-analyses for the evaluation of psychotropic medicines. PMID- 28853405 TI - Ketamine-ECT Study - Author's reply. PMID- 28853406 TI - Use of lithium in patients with unipolar depression. PMID- 28853407 TI - Ketamine-ECT Study. PMID- 28853408 TI - Is excessive sexual behaviour an addictive disorder? PMID- 28853409 TI - Use of lithium in patients with unipolar depression - Author's reply. PMID- 28853412 TI - WPA elections. PMID- 28853410 TI - A proposal to introduce formal recording of psychosocial adversities associated with mental health using ICD-10 codes. PMID- 28853413 TI - Corrections. PMID- 28853414 TI - Architecture and functioning of child and adolescent mental health services: a reply from Slovenia - Authors' reply. PMID- 28853415 TI - Architecture and functioning of child and adolescent mental health services: a reply from Slovenia. PMID- 28853416 TI - "Bright flashes in the dark": a close time-locked relationship between posterior lateralized periodic discharges and visual flashes. PMID- 28853417 TI - Recommendations for cerebrospinal fluid examination in acute leukemia. AB - Cytological identification of blasts in cerebrospinal fluid in acute leukemia, lymphoid or myeloid, in adult and child, at diagnosis or during follow up lead to the diagnosis of leukemic meningitidis. Suitable CNS therapy based on a defined "CNS status" following an international standardized classification, lead to decrease cerebrospinal relapses. Established in 1993, this classification allows to treat patients based on their CNS status. Based on the red blood cells count, nucleated cells count and presence of blasts, it requires a standard technical procedure that guarantees the comparability of results coming from different medical laboratory. To improve the quality of cerebrospinal fluid analysis, in acute leukemias, preanalytical guidelines (turn around time), analytical guidelines (cytocentrifugation, adding serum protein, speed and duration of cytocentrifugation) and postanalytical guidelines (duration of conservation) are set by the Groupe francophone d'hematologie cellulaire. PMID- 28853418 TI - Executive Function and Academic Outcomes in Children Who Were Extremely Preterm. AB - OBJECTIVES: Cognitive and behavioral impairments of children born extremely preterm (EP) (<28 weeks' gestation) and extremely low birth weight (ELBW) (<1000 g) may change with age. We assessed the individual stability of behavioral executive function (EF) from 8 to 18 years of age in children born EP or ELBW and their academic outcomes. METHODS: Participants comprised 180 children born EP or ELBW from a large geographic cohort. We investigated the frequency of 4 developmental groups (persistent, remitting, late-onset, and typical development) on the basis of dichotomized scores (typical versus elevated) at ages 8 and 18 years in 2 indices (the Behavioral Regulation Index [BRI] and the Metacognition Index [MCI]) of the parental form of the Behavior Rating Inventory of Executive Function. Adolescent academic outcomes were measured by using the word reading, spelling, and math computation subtests of the Wide Range Achievement Test, Fourth Edition. RESULTS: Most participants had a typical EF (BRI 61%, MCI 53%), followed by persistent (BRI 15%, MCI 16%), late-onset (BRI 12%, MCI 19%), or remitting (BRI 12%, MCI 13%) executive difficulties. Groups with executive impairments at age 18 years (persistent and late onset) had poorer academic outcomes than the typical and remitting groups. Shifting impairment categories between 8 and 18 years old was relevant to later academic outcomes. CONCLUSIONS: Most children showed stable and age-appropriate EF, although persistent and transient difficulties were observed and related to uneven academic outcomes. Studying the origins and consequences of the developmental stability of EF may contribute to the development of interventions to decrease the adverse neurodevelopmental outcomes of preterm birth. PMID- 28853419 TI - Repeal of the Affordable Care Act Will Negatively Impact Children at End of Life. PMID- 28853420 TI - Decoding natural reach-and-grasp actions from human EEG. AB - OBJECTIVE: Despite the high number of degrees of freedom of the human hand, most actions of daily life can be executed incorporating only palmar, pincer and lateral grasp. In this study we attempt to discriminate these three different executed reach-and-grasp actions utilizing their EEG neural correlates. APPROACH: In a cue-guided experiment, 15 healthy individuals were asked to perform these actions using daily life objects. We recorded 72 trials for each reach-and-grasp condition and from a no-movement condition. MAIN RESULTS: Using low-frequency time domain features from 0.3 to 3 Hz, we achieved binary classification accuracies of 72.4%, STD +/- 5.8% between grasp types, for grasps versus no movement condition peak performances of 93.5%, STD +/- 4.6% could be reached. In an offline multiclass classification scenario which incorporated not only all reach-and-grasp actions but also the no-movement condition, the highest performance could be reached using a window of 1000 ms for feature extraction. Classification performance peaked at 65.9%, STD +/- 8.1%. Underlying neural correlates of the reach-and-grasp actions, investigated over the primary motor cortex, showed significant differences starting from approximately 800 ms to 1200 ms after the movement onset which is also the same time frame where classification performance reached its maximum. SIGNIFICANCE: We could show that it is possible to discriminate three executed reach-and-grasp actions prominent in people's everyday use from non-invasive EEG. Underlying neural correlates showed significant differences between all tested conditions. These findings will eventually contribute to our attempt of controlling a neuroprosthesis in a natural and intuitive way, which could ultimately benefit motor impaired end users in their daily life actions. PMID- 28853421 TI - Obstructive Sleep Apnea Syndrome (OSAS): Occupational Health and other medical disciplines facing the problem. AB - Obstructive Sleep Apnea Syndrome (OSAS) is one of the most common causes of excessive daytime sleepiness, therefore an important determinant of road and work accidents, as well as being associated with multiple chronic-degenerative diseases. The recent transposition of the European Commission Directive 2014/85/EU on driver licensing highlighted the need to tackle the problem appropriately, not only for its high prevalence in the general population, but also for its significant impact on occupational safety and health, and related social costs. The Occupational Health Physician is required to play a strategic role in this regard, not just for early diagnosis, but also for monitoring the therapeutic efficacy in maintaining or reintegrating workers into specific jobs. The effectiveness of his/her work will depend primarily on the level of interaction he/she will be able to establish with the different specialists who are in charge of the diagnostic and therapeutic process, in order to maintain a satisfactory work performance and to prevent possible deleterious effects on health in the medium and long-term period. The logic of this multidisciplinary approach has led nineteen scientific Societies and Associations to establish a Joint Technical Committee and to address the problem in the light of effectiveness and efficiency criteria in the interest of the individual and the community. PMID- 28853422 TI - The obstructive sleep apnea syndrome (OSAS): implications for work and Occupational Health. AB - Commission Directive 2104/85/EU on driving licenses highlighted significant issues related to the Obstructive Sleep Apnea Syndrome (OSAS). Due to the high incidence of this syndrome in the general population, it is important to precisely assess its impact on work and driving performance, in terms of employee and third-party safety, general health and related social costs (errors, accidents, absenteeism, presenteism, treatments). As occupational health physicians regularly check the workers in the age group in which the incidence of OSAS is higher, they are called upon to play a strategic role in the early detection of the disease and the prescription of an appropriate therapy, as well as in monitoring the treatment effectiveness in order to assess fitness to work and/or drive. The soundness and effectiveness of the occupational health physicians' work depend not only on their knowledge of and attention to the problem, but above all on the interaction with specialists from other disciplines, essential to arrive at a correct diagnosis and an effective treatment. Main goals of this activity are to maintain a satisfactory operating performance and to prevent possible deleterious health effects in the medium and long-term period. PMID- 28853423 TI - Daytime sleepiness: more than just Obstructive Sleep Apnea (OSA). AB - Excessive Daytime Sleepiness (EDS) is a common condition with a significant impact on quality of life and general health. A mild form of sleepiness can be associated with reduced reactivity and modest distractibility symptoms, but more severe symptomatic forms are characterized by an overwhelming and uncontrollable need to sleep, causing sudden sleep attacks, amnesia and automatic behaviors. The prevalence in the general population is between 10 and 25%. Furthermore, EDS has been considered a core symptom of obstructive sleep apnea (OSA), as well as being the main symptom of primary hypersomnias such as narcolepsy types 1 and 2, and idiopathic hypersomnia. Moreover, it can be considered secondary to other sleep disorders (Restless Legs Syndrome, Chronic insomnia, Periodic Limb Movements), psychiatric conditions (Depression, Bipolar Disorder) or a consequence of the intake/abuse of drugs and/or substances. An accurate medical history cannot be sufficient for the differential diagnosis, therefore instrumental recordings by means of polysomnography and the Multiple Sleep Latency Test (MSLT) are mandatory for a correct diagnosis and treatment of the underlying cause of EDS. PMID- 28853424 TI - The clinical diagnosis of Obstructive Sleep Apnea Syndrome (OSAS). AB - Obstructive Sleep Apnea Syndrome (OSAS) is the most frequent sleep breathing disorder in the general population. To reach a correct diagnosis, the clinical work-up requires the association of comprehensive clinical evaluation (anamnesis, physical examination) and nocturnal polysomnography. Polysomnographic recordings may differ by number of bio-parameters recorded and setting (in laboratory or at home), and allow the identification of other sleep disorders in addition to the diagnosis of OSAS. Excessive daytime sleepiness (EDS) is the most frequent daytime complaint of OSAS patients. Its evaluation is fundamental in subjects with suspected OSAS and concomitant high risk of sleep-related accidents due to work-related factors (e.g. professional drivers). To test EDS, physicians may use subjective (questionnaires) and/or objective (polysomnografic or performance tests) measures. Objective tests are more advisable, but to date they are time consuming and expensive. Objective tests less time-consuming and easily applicable to clinic practice are being evaluated. PMID- 28853425 TI - Obstructive Sleep Apnea Syndrome (OSAS) and Cardiovascular System. AB - There is increasing evidence of a relationship between Obstructive Sleep Apnea (OSA) and cardiovascular diseases. The strong association between OSA and arterial hypertension, in particular in patients with resistant hypertension and/or a non-dipping profile, has been extensively reported. The relationship between OSA and high blood pressure (BP) has been found independent from a number of confounders, but several factors may affect this relationship, including age and sex. It is thus important to better assess pathophysiologic and clinical interactions between OSA and arterial hypertension, also aimed at optimizing treatment approaches in OSA and hypertensive patients with co-morbidities. Among possible mechanisms, cardiovascular autonomic control alterations, altered mechanics of ventilation, inflammation, endothelial dysfunction, and renin angiotensin-aldosterone system should be considered with particular attention. Additionally, available studies also support the occurrence of a bidirectional association between OSA and cardiovascular alterations, in particular heart failure, stroke and cardiac arrhythmias, emphasizing that greater attention is needed to both identify and treat sleep apneas in patients with cardiovascular diseases. However, a number of aspects of such a relationship are still to be clarified, in particular with regard to gender differences, effect of sleep related breathing disorders in childhood, and influence of OSA treatment on cardiovascular risk, and they may represent important targets for future studies. PMID- 28853426 TI - Obstructive Sleep Apnea Syndrome (OSAS): Continuous Positive Airway Pressure (CPAP) therapy and other positive-pressure devices. AB - The Obstructive Sleep Apnea Syndrome (OSAS) consists of recurring episodes of complete or partial obstruction of the pharynx. The application of a continuous positive pressure in the airways (CPAP) is the first therapeutic option that is found to ensure complete patency of the pharynx during sleep, avoiding apneas and hypopneas with resolution of the symptoms. More recently, other devices have been proposed as OSAS treatment. The auto-CPAP has a role in finding the therapeutic value of the CPAP pressure rather than in OSAS therapy. When apnea/hypopnea events are associated with other and/or predominant respiratory disorders like hypoventilation or Cheyne-Stokes breathing, the treatment of choice is the noninvasive ventilation with a double level of pressure support. Although it was proposed 35 years ago, the CPAP still represents the only effective therapy regardless of OSAS severity, as well as the treatment with the greatest evidence in terms of long-term benefits. PMID- 28853427 TI - Ear nose and throat (ENT) aspects of Obstructive Sleep Apnea Syndrome (OSAS) diagnosis and therapy. AB - : This article analyzes the role played by the ear, nose and throat (ENT) specialist in the diagnosis and treatment of the Obstructive Sleep Apnea Syndrome (OSAS). DIAGNOSIS: The instrumental methods of investigation of otolaryngology expertise are fiberoptic rhinolaryngoscopy and sleep endoscopy. To better define and treat OSAS it is essential to define location, extension and degree of obstruction. The major limitation of rhinolaryngoscopy is that it is conducted while the patient is awake. Sleep endoscopy was introduced to address this issue: it is an endoscopic examination conducted during pharmacologically induced sleep (midazolam, propofol). Surgical treatment: The applicability of surgical treatment is limited: it is not efficient for every patient and not to the same extent. Surgical therapy is based on the detection and correction of the site of obstruction, although in most cases the obstruction sites are located at different levels. The surgical approach usually follows a path characterized by "subsequent steps". According to Stanford University Powell-Riley Protocol the first phase includes: nasal surgery, palate surgery (UPPP, LAUP Laser Assisted uvulopalatoplasty, UvuloPalatalFlap UPF) and tongue base surgery (tongue suspension, genioglossus advancement, hyoid suspension) that could either be executed individually or associated. Four-six months after surgery a physical and polysomnography examination should be performed. In case of symptoms persistence, the surgeon could move on to phase II surgery as recovery therapy. The phase II surgery includes: maxillo-mandibular advancement, tongue base resection and tracheotomy. In selected cases a Phase II surgery could be planned at the beginning of treatment. PMID- 28853428 TI - Obstructive Sleep Apnea Syndrome (OSAS): evaluation and treatment of odontostomatological problems. AB - The Obstructive Sleep Apnea Syndrome (OSAS) is a breathing disorder characterized by repeated episodes of apnea/hypopnea occurring during sleep and caused by the obstruction of the upper airway. As OSAS can have a significant impact on quality of life, an early diagnosis and a multi-specialized recognition become important. Therapeutic proposals include the Mandibular Advancement Devices (MADs), intraoral devices that induce a mandibular advancement during the night to eliminate snoring and apnea. Italian guidelines on dental aspects of OSAS in adults and children focus primarily on anamnestic and clinical methods by which the dentist, in a role of epidemiological sentinel, can first identify a patient with OSAS and then participate in the therapeutic process using specific orthodontic intraoral devices. PMID- 28853429 TI - Obstructive sleep apnea (OSA) and driving safety. AB - Intermittent hypoxia and sleep fragmentation cause excessive daytime sleepiness (EDS) and cognitive impairment in obstructive sleep apnoea (OSA); neuroimaging and neurophysiological studies in patients with OSA have delineated a putative regional "fingerprint" of OSA-induced brain injury: a disconnection of the fronto parietal regions and a disruption of the thalamocortical oscillator, with involvement of the hippocampal formation with impaired attention, awareness, working memory, time reaction, visuoconstructive and executive functions. For these reasons OSA is the main medical cause of EDS and is also associated with an increased risk of motor vehicle accidents (MVAs). About 7% of MVAs for a population of male drivers involved in MVAs are attributable to OSA. Subjects with OSA have nearly twofold increased odds of work accidents. Professional drivers add fatigue to sleep deprivation. A higher risk of MVAs cannot be adequately explained by OSA and sleep deprivation (SD), and EDS is a further, independent risk factor like the other two. There is an association between the amount of hours of sleep per night and MVA or near miss accidents (NMA) rates with an inverse linear correlation. When OSA, SD or EDS are present, the risk of MVAs or NMAs in truck drivers is severely increased. Taking a rest break or a nap appear to be protective against MVAs e NMAs and they should be considered a primary prevention strategy together with screening for OSA, EDS, and SD. PMID- 28853430 TI - Assessing fitness for professional and non-professional drivers: legislation and medico-legal issues. AB - For a long time, European legislation has not considered the Obstructive Sleep Apnea Syndrome (OSAS) a relevant factor for road safety. In Italy, in 2010 the Scientific Society of Legal Medicine COMLAS published Guidelines for the assessment of fitness to drive. An entire chapter, written in collaboration with the Commission "Sleepiness, Safety and Transportation" of the Italian Association of Sleep Medicine (AIMS), is dedicated to the criteria for assessing fitness to drive of people with OSAS or narcolepsy. Only in 2016, following the adoption of European Commission Directive 2014/85/EU, Italian law recognized OSAS as a condition to be considered in the assessment of fitness to drive. The author discusses the ascertainment criteria and the medico-legal implications regarding information to patients and reporting duty. PMID- 28853431 TI - Obstructive sleep apnea (OSA): healthcare and social costs. AB - Obstructive sleep apnea (OSA) syndrome is an underdiagnosed widespread chronic disease involving both sexes and all ages. Undiagnosed and untreated OSA is associated with workplace productivity losses and significant direct and indirect medical costs. A cost analysis of OSA was carried out in Italy ten years ago. Overall OSA medical costs, largely due to treatment of comorbidity, amounted to ? 2,9 billion or 55% of total medical costs. Direct medical costs, due to diagnosis and treatment of OSA, were 6% of overall OSA costs, while medical costs due to the absence of diagnosis and of prevention of comorbidities represented 49% of the overall cost. Non-medical costs made up for the remaining 45%. ? 1.5 billion could be saved by promoting screening campaigns aimed at detecting OSA that would otherwise remain undiagnosed and by improving adherence to treatment. Bearing in mind the increasing OSA prevalence and the recent quantification of avoidable OSA related road accidents, the real cost of OSA is higher than estimated up to now. PMID- 28853432 TI - The Disabilities of the Arm, Shoulder and Hand scale in the evaluation of disability - A literature review. AB - : Work-related musculoskeletal disorders (WRMDs) interfere with workers' productivity and quality of life. Thus, early detection of disabilities caused by WRMDs is vital for preventing the aggravation of symptoms. Early detection aids and is aided by educational and preventive programs. WRMDs can be detected using the Disabilities of the Arm, Shoulder and Hand (DASH) Scale. OBJECTIVES: The present study aimed to review the literature on the application of the DASH Scale through a consideration of the cultural adaptation process and an evaluation of the scale's psychometric properties. METHODS: The literature review was conducted using the terms "disabilities", "musculoskeletal disorders", "DASH" "questionnaire" and "upper limbs". RESULTS: Forty-eight articles were collected, and these included only articles available in English which contained the full version of the DASH Scale and which focused on the evaluation of its psychometric properties (n=25). CONCLUSION: Most of the studies partially evaluated the psychometric properties of the DASH instrument; however, these properties were typically evaluated using only a correlation analysis involving other instruments. PMID- 28853433 TI - Corrigendum: Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling. AB - This corrects the article DOI: 10.1038/ncomms14095. PMID- 28853434 TI - Corrigendum: 14-3-3zeta regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function. AB - This corrects the article DOI: 10.1038/ncomms12862. PMID- 28853435 TI - Corrigendum: Isotope analysis in the transmission electron microscope. AB - This corrects the article DOI: 10.1038/ncomms13040. PMID- 28853436 TI - Small nucleoli are a cellular hallmark of longevity. AB - Animal lifespan is regulated by conserved metabolic signalling pathways and specific transcription factors, but whether these pathways affect common downstream mechanisms remains largely elusive. Here we show that NCL-1/TRIM2/Brat tumour suppressor extends lifespan and limits nucleolar size in the major C. elegans longevity pathways, as part of a convergent mechanism focused on the nucleolus. Long-lived animals representing distinct longevity pathways exhibit small nucleoli, and decreased expression of rRNA, ribosomal proteins, and the nucleolar protein fibrillarin, dependent on NCL-1. Knockdown of fibrillarin also reduces nucleolar size and extends lifespan. Among wildtype C. elegans, individual nucleolar size varies, but is highly predictive for longevity. Long lived dietary restricted fruit flies and insulin-like-peptide mutants exhibit small nucleoli and fibrillarin expression, as do long-lived dietary restricted and IRS1 knockout mice. Furthermore, human muscle biopsies from individuals who underwent modest dietary restriction coupled with exercise also display small nucleoli. We suggest that small nucleoli are a cellular hallmark of longevity and metabolic health conserved across taxa. PMID- 28853437 TI - Corrigendum: In situ targeted MRI detection of Helicobacter pylori with stable magnetic graphitic nanocapsules. AB - This corrects the article DOI: 10.1038/ncomms15653. PMID- 28853438 TI - Periaqueductal Gray Glutamatergic Transmission Governs Chronic Stress-Induced Depression. AB - The mechanisms underlying chronic stress-induced dysfunction of glutamatergic transmission that contribute to helplessness-associated depressive disorder are unknown. We investigated the relationship of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors and stress, and the neuroplastic changes of stress-induced depression-like behavior in the ventrolateral periaqueductal gray (vlPAG). We conducted whole-cell patch-clamp electrophysiological recordings in the vlPAG neurons. Depression-like behavior was assayed using tail suspension test and sucrose preference test. Surface and cytosolic glutamate receptor 1 (GluR1) AMPA receptor expression was analyzed using western blotting. Phosphorylated GluR1 expression was quantified using western blotting and immunohistochemical analysis. Unpredictable inescapable foot shock stress caused reduction in glutamatergic transmission originating from both presynaptic and postsynaptic loci in the vlPAG that was associated with behavioral despair and anhedonia in chronic stress-induced depression. Pharmacological inhibition of GluR1 function in the vlPAG caused depression-like behavior. Diminished glutamatergic transmission was due to reduced glutamate release presynaptically and enhanced GluR1-endocytosis from the cell surface postsynaptically. Chronic stress-induced neuroplastic changes and maladaptive behavior were reversed and mimicked by administration of glucocorticoid receptor (GR) antagonist and agonist, respectively. However, chronic stress did not affect gamma-aminobutyric acid (GABA)-mediated inhibitory synaptic transmission in the vlPAG. These results demonstrate that depression-like behavior is associated with remarkable reduction in glutamatergic, but not GABAergic, transmission in the vlPAG. These neuroplastic changes and maladaptive behavior are attributed to GR-dependent mechanisms. As reduced GluR1-associated responses in the vlPAG contribute to chronic stress-induced neuroplastic changes, this cellular mechanism may be a critical component in the pathogenesis of stress-associated neuropsychiatric disorders. PMID- 28853440 TI - Airway T cells protect against RSV infection in the absence of antibody. AB - This corrects the article DOI: 10.1038/mi.2017.46. PMID- 28853439 TI - US Epidemiology of Cannabis Use and Associated Problems. AB - This review provides an overview of the changing US epidemiology of cannabis use and associated problems. Adults and adolescents increasingly view cannabis as harmless, and some can use cannabis without harm. However, potential problems include harms from prenatal exposure and unintentional childhood exposure; decline in educational or occupational functioning after early adolescent use, and in adulthood, impaired driving and vehicle crashes; cannabis use disorders (CUD), cannabis withdrawal, and psychiatric comorbidity. Evidence suggests national increases in cannabis potency, prenatal and unintentional childhood exposure; and in adults, increased use, CUD, cannabis-related emergency room visits, and fatal vehicle crashes. Twenty-nine states have medical marijuana laws (MMLs) and of these, 8 have recreational marijuana laws (RMLs). Many studies indicate that MMLs or their specific provisions did not increase adolescent cannabis use. However, the more limited literature suggests that MMLs have led to increased cannabis potency, unintentional childhood exposures, adult cannabis use, and adult CUD. Ecological-level studies suggest that MMLs have led to substitution of cannabis for opioids, and also possibly for psychiatric medications. Much remains to be determined about cannabis trends and the role of MMLs and RMLs in these trends. The public, health professionals, and policy makers would benefit from education about the risks of cannabis use, the increases in such risks, and the role of marijuana laws in these increases. PMID- 28853442 TI - PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+ T cell transcriptomal molecular signatures. AB - Protective efficacy of Bacillus Calmette-Guerin (BCG) may be affected by the methods and routes of vaccine administration. We have studied the safety and immunogenicity of oral (PO) and/or intradermal (ID) administration of BCG in healthy human subjects. No major safety concerns were detected in the 68 healthy adults vaccinated with PO and/or ID BCG. Although both PO and ID BCG could induce systemic Th1 responses capable of IFN-gamma production, ID BCG more strongly induced systemic Th1 responses. In contrast, stronger mucosal responses (TB specific secretory IgA and bronchoalveolar lavage T cells) were induced by PO BCG vaccination. To generate preliminary data comparing the early gene signatures induced by mucosal and systemic BCG vaccination, CD4+ memory T cells were isolated from subsets of BCG vaccinated subjects pre- (Day 0) and post vaccination (Days 7 and 56), rested or stimulated with BCG infected dendritic cells, and then studied by Illumina BeadArray transcriptomal analysis. Notably, distinct gene expression profiles were identified both on Day 7 and Day 56 comparing the PO and ID BCG vaccinated groups by GSEA analysis. Future correlation analyses between specific gene expression patterns and distinct mucosal and systemic immune responses induced will be highly informative for TB vaccine development. PMID- 28853445 TI - Tumour immunology: Cell cycle inhibitors boost tumour immunogenicity. PMID- 28853444 TI - Synthetic immune niches for cancer immunotherapy. AB - Cancer immunotherapy can successfully promote long-term anticancer immune responses, although there is still only a limited number of patients who benefit from such treatment, and it can sometimes have severe treatment-associated adverse events. Compared with systemic immunomodulation, local immunomodulation may enable more effective treatment at lower doses and, at the same time, prevent systemic toxicity. Local delivery of engineered three-dimensional scaffolds may fulfil this role by acting as synthetic immune niches that boost anticancer immunity. In this Opinion article, we highlight the potential of scaffold-based adoptive cell transfer and scaffold-based cancer vaccines that, although applied locally, can promote systemic antitumour immunity. Furthermore, we discuss how scaffold-based cancer immunotherapy may contribute to the development of the next generation of cancer treatments. PMID- 28853441 TI - Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity. AB - The intestinal epithelium must balance efficient absorption of nutrients with partitioning commensals and pathogens from the bodies' largest immune system. If this crucial barrier fails, inappropriate immune responses can result in inflammatory bowel disease or chronic infection. Enteroendocrine cells represent 1% of this epithelium and have classically been studied for their detection of nutrients and release of peptide hormones to mediate digestion. Intriguingly, enteroendocrine cells are the key sensors of microbial metabolites, can release cytokines in response to pathogen associated molecules and peptide hormone receptors are expressed on numerous intestinal immune cells; thus enteroendocrine cells are uniquely equipped to be crucial and novel orchestrators of intestinal inflammation. In this review, we introduce enteroendocrine chemosensory roles, summarize studies correlating enteroendocrine perturbations with intestinal inflammation and describe the mechanistic interactions by which enteroendocrine and mucosal immune cells interact during disease; highlighting this immunoendocrine axis as a key aspect of innate immunity. PMID- 28853443 TI - Type 2 immunity in tissue repair and fibrosis. AB - Type 2 immunity is characterized by the production of IL-4, IL-5, IL-9 and IL-13, and this immune response is commonly observed in tissues during allergic inflammation or infection with helminth parasites. However, many of the key cell types associated with type 2 immune responses - including T helper 2 cells, eosinophils, mast cells, basophils, type 2 innate lymphoid cells and IL-4- and IL 13-activated macrophages - also regulate tissue repair following injury. Indeed, these cell populations engage in crucial protective activity by reducing tissue inflammation and activating important tissue-regenerative mechanisms. Nevertheless, when type 2 cytokine-mediated repair processes become chronic, over exuberant or dysregulated, they can also contribute to the development of pathological fibrosis in many different organ systems. In this Review, we discuss the mechanisms by which type 2 immunity contributes to tissue regeneration and fibrosis following injury. PMID- 28853449 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000450872.]. PMID- 28853447 TI - Work and family conflicts in employees with spinal cord injury and their caregiving partners. AB - STUDY DESIGN: Cross-sectional, observational. OBJECTIVES: To investigate the association of conflicts between work and family life with indicators of health and to examine the antecedents of those conflicts in employees with spinal cord injury (SCI) and their caregiving partners. SETTING: Community, Switzerland. METHODS: Data from employed persons with SCI (n=79) and caregiving partners (n=93) who participated in the pro-WELL study were used. Logistic and tobit regressions were performed to assess the association of work-family and family work conflicts with health indicators, namely mental health (36-item Short Form Health Survey (SF-36)), vitality (SF-36), well-being (WHOQoL BREF) and positive and negative affect (Positive and Negative Affect Scale short form (PANAS-S)). Own and partners' engagement in productive activities and socioeconomic circumstances were evaluated as potential antecedents of work-family and family work conflicts using logistic regression. RESULTS: Work-family conflicts were related to reduced mental health (caregiving partners only), vitality and well being. Family-work conflicts were linked to reduced mental health, vitality, well being and positive affect in SCI and to reduced vitality in caregiving partners. Persons with lower income (SCI only) and lower subjective social position reported more conflicts than persons with higher income and higher subjective position. Higher workload increased work-family conflicts in caregiving partners and decreased family-work conflicts in SCI. Education, amount of caregiving, care receiving and partners' employment status were not associated with the occurrence of conflicts. CONCLUSION: The optimal balance between work and family life is important to promote mental health, vitality and well-being in employees with SCI and their caregiving partners. This is especially true in employees perceiving their social position as low and in caregivers with a high workload. PMID- 28853448 TI - Use of medicines, adherence and attitudes to medicines among persons with chronic spinal cord injury. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVES: To describe the use of medicines and adherence among persons with spinal cord injury (SCI). Further, to examine the influence of pain, spasms and beliefs about medicines on adherence. SETTING: Sunnaas Rehabilitation Hospital, Norway. METHODS: Persons (?18 years) with chronic SCI (more than 1-year post injury), using at least one drug regularly, and admitted for a follow-up stay at Sunnaas Rehabilitation Hospital were included. Participants were interviewed about their drug regimen and filled out validated self-report questionnaires: Morisky Medication Adherence Scale (MMAS-8), beliefs about medicines questionnaire (BMQ), visual analogue scale (VAS) for pain and modified Penn spasm frequency scale (mPSFS). RESULTS: The 105 participants used in average 4.2 drugs regularly (range, 1-15), and 70% reported high or moderate adherence to their treatment. Of the 39 participants using oral spasmolytics, 74% reported high or moderate adherence to these drugs. A total of 97% of the participants reported high perceptions of necessity to their treatment and 54% reported a high level of concern. CONCLUSION: The persons with SCI included in this study used in average the same number of regular drugs compared to persons with other chronic conditions. Regardless of high overall adherence, the participants were more concerned about their medicines compared to other patient groups. Further studies are required for understanding adherence and attitudes toward medicines in this population, especially to help the persons with chronic SCI feel safe about their drug regimen. PMID- 28853450 TI - Erratum: Erratum: Efficacy of Formoterol Fumarate Delivered by Metered Dose Inhaler Using Co-SuspensionTM Delivery Technology Versus Foradil(r) Aerolizer(r) in Moderate-To-Severe COPD: A Randomized, Dose-Ranging Study. AB - [This corrects the article DOI: 10.15326/jcopdf.4.1.2016.0158.]. PMID- 28853446 TI - Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD. AB - Tissue hypoxia occurs when local oxygen demand exceeds oxygen supply. In chronic inflammatory conditions such as IBD, the increased oxygen demand by resident and gut-infiltrating immune cells coupled with vascular dysfunction brings about a marked reduction in mucosal oxygen concentrations. To counter the hypoxic challenge and ensure their survival, mucosal cells induce adaptive responses, including the activation of hypoxia-inducible factors (HIFs) and modulation of nuclear factor-kappaB (NF-kappaB). Both pathways are tightly regulated by oxygen sensitive prolyl hydroxylases (PHDs), which therefore represent promising therapeutic targets for IBD. In this Review, we discuss the involvement of mucosal hypoxia and hypoxia-induced signalling in the pathogenesis of IBD and elaborate in detail on the role of HIFs, NF-kappaB and PHDs in different cell types during intestinal inflammation. We also provide an update on the development of PHD inhibitors and discuss their therapeutic potential in IBD. PMID- 28853451 TI - Ultraclean pure shift NMR. AB - "Pure shift" methods can greatly improve the resolution of proton NMR spectra. However, current pure shift spectra show small periodic artefacts that prevent their use for studying dilute mixture components. A new technique, compatible with all current pure shift methods, is presented that suppresses such sidebands to arbitrary order, allowing ultraclean spectra to be obtained. PMID- 28853452 TI - Strategies for large-scale analysis of non-histone protein methylation by LC MS/MS. AB - Protein methylation is an important post-translational modification (PTM) that plays crucial roles in the regulation of diverse biological processes. Though many efforts have been devoted to the investigation of protein methylation, the analysis of non-histone methylation at the proteome level is still a great challenge. The alteration of the protein/peptide physicochemical properties caused by methylation is very small, thus it is difficult to develop highly efficient enrichment approaches to separate methylated peptides from a pool of diverse background peptides. The mass shifts caused by methylations are identical to the substitutions of some amino acids, thus it is difficult to confidently identify methylated peptides. In this review, we report on recent advances in the development of methods for large-scale analysis of non-histone protein methylation. Especially the methods for efficient enrichment and the approaches for controlling identification confidence have been covered. PMID- 28853453 TI - Thiophene bridged hydrocyanine - a new fluorogenic ROS probe. AB - Hydrocyanines are a class of commonly used reactive oxygen species (ROS) fluorescent imaging probes, which can image ROS in cell culture, organ culture, and in vivo. However, despite their widespread use, hydrocyanines have several drawbacks that limit their effectiveness, such as a high rate of auto-oxidation, a small Stokes shift, and poor water solubility. In addition, the hydrocyanines oxidize into cyanine dyes, which themselves decompose in the presence of ROS, and this further lowers their sensitivity towards detecting ROS. In this report, we present a new hydrocyanine analog, termed as thiophene-bridged hydrocyanine (TBHC), which has its double bonds replaced with a bisthiophene. TBHC is 8.06 fold more stable to auto-oxidation than the hydrocyanine hydro-Cy5 and is significantly better at imaging ROS in cell culture. PMID- 28853454 TI - Ability of the Poisson-Boltzmann equation to capture molecular dynamics predicted ion distribution around polyelectrolytes. AB - Here, we examine polyelectrolyte (PE) and ion chemistry specificity in ion condensation via all-atom molecular dynamics (MD) simulations and assess the ability of the Poisson-Boltzmann (PB) equation to describe the ion distribution predicted by the MD simulations. The PB model enables the extraction of parameters characterizing ion condensation. We find that the modified PB equation which contains the effective PE radius and the energy of the ion-specific interaction as empirical fitting parameters describes ion distribution accurately at large distances but close to the PE, especially when strongly localized charge or specific ion binding sites are present, the mean field description of PB fails. However, the PB model captures the MD predicted ion condensation in terms of the Manning radius and fraction of condensed counterions for all the examined PEs and ion species. We show that the condensed ion layer thickness in our MD simulations collapses on a single master curve for all the examined simple, monovalent ions (Na+, Br+, Cs+, Cl-, and Br-) and PEs when plotted against the Manning parameter (and consequently the PE line charge density). The significance of this finding is that, contrary to the Manning radius extracted from the mean field PB model, the condensed layer thickness in the all atom detail MD modelling does not depend on the PE chemistry or counterion type. Furthermore, the fraction of condensed counterions in the MD simulations exceeds the PB theory prediction. The findings contribute toward understanding and modelling ion distribution around PEs and other charged macromolecules in aqueous solutions, such as DNA, functionalized nanotubes, and viruses. PMID- 28853455 TI - Retraction: Multifunctional tin dioxide materials: advances in preparation strategies, microstructure, and performance. AB - Retraction of 'Multifunctional tin dioxide materials: advances in preparation strategies, microstructure, and performance' by Zhiwen Chen et al., Chem. Commun., 2015, 51, 1175-1184. PMID- 28853456 TI - Theoretical insights into the effect of a conjugated core on the hole transport properties of hole-transporting materials for perovskite solar cells. AB - Conjugated bifluorenylidene and naphthalene central cores are introduced into hole-transporting materials DT1 and DT2 to replace the spiro-core of the reported, highly efficient FDT. The effects of the conjugated core on the geometrics, electronic properties and hole transport properties are investigated by using density functional theory coupled with Marcus theory and the Einstein relation. The calculated results show that DT1 (-5.21 eV) and DT2 (-5.23 eV) have lower HOMO levels than FDT (-5.15 eV), which indicates that the perovskite solar cells with conjugated hole-transporting materials can have higher open-circuit voltages. The introduction of the conjugated core is beneficial to the more efficient face-to-face packing pattern of the dimer, resulting in a larger intermolecular electronic coupling. Importantly, it is found that DT1 (1.6 * 10-3 cm2 V-1 s-1) and DT2 (2.7 * 10-2 cm2 V-1 s-1) exhibit relatively higher hole mobilities than FDT (1.3 * 10-4 cm2 V-1 s-1) owing to the larger electronic coupling. Therefore, enhanced hole transport ability can be achieved by switching from the spiro-core to the conjugated core. The present work provides a new strategy to improve the hole transport properties of hole-transporting materials, which will contribute to the development of conjugated small molecules as hole transporting materials in efficient perovskite solar cells. PMID- 28853457 TI - Endohedral gas adsorption by cucurbit[7]uril: a theoretical study. AB - The selectivity of cucurbit[7]uril (CB[7]) towards adsorbing a series of 14 molecules encompassing four hydrocarbons (C2H2, C2H4, C2H6, and CH4), diatomic molecules of halogens (F2 and Cl2), nitrogen oxides (NO2 and NO), carbon oxides (CO2 and CO), SO2, H2S, N2, and H2 is explored via a density functional theory based study. CB[7] is noted to have high selectivity towards adsorbing SO2 over the other considered molecules, highlighting its probable utility to separate SO2 from flue gas or other gas mixtures containing these molecules. The nature of bonding is deciphered via the computations of non-covalent interaction indices and energy decomposition analysis. Although in all cases the dispersion interaction turns out to be the most dominating contributor in stabilizing these complexes, the electrostatic contribution is also considerable. In fact, the combined effect of these two energy terms in SO2@CB[7] is responsible for the obtained selectivity. PMID- 28853458 TI - Transition-metal doping induces the transition of electronic and magnetic properties in armchair MoS2 nanoribbons. AB - The electronic structure, magnetic properties and stability of transition-metal (TM) doped armchair MoS2 nanoribbons (AMoS2NRs) with full hydrogen passivation have been investigated using density functional theory. The hydrogen passivated AMoS2NRs are non-magnetic semiconductors, but TM doping can make the AMoS2NRs display diverse characteristics (such as non-magnetic metal, magnetic semiconductor, non-magnetic semiconductor and semi-metal properties), in which a transition of the electronic and magnetic properties is observed. Electronic structure analysis shows that the magnetism of the TM-doped AMoS2NRs is concentrated on the TM dopant and the edge Mo atoms, which mainly comes from the competition between the exchange splitting and crystal-field splitting. More importantly, Mn-doped AMoS2NRs may be good candidates for spintronic devices due to their good ferromagnetism with long-range FM magnetic coupling, reliable Curie temperature and high stability. These interesting findings on AMoS2NRs may open the possibility of their application in nanodevices and spintronic devices based on low-dimensional nanostructures. PMID- 28853459 TI - Potential color tunable Sr3LaNa(PO4)3F:Eu2+/Tb3+/Mn2+ phosphor induced by Eu2+ -> Tb3+ and Tb3+ -> Mn2+ energy transfer for WLEDs. AB - Color tunable Sr3LaNa(PO4)3F:Eu2+,Tb3+ and Sr3LaNa(PO4)3F:Tb3+,Mn2+ phosphors were prepared by a high temperature solid state reaction. The crystal structure, luminescence properties, and energy transfer mechanism of the samples were investigated in detail. The Eu2+ doped phosphors can be efficiently excited in the range from 250 to 410 nm, which matches well with the commercial n-UV LED chips. Utilizing the energy transfer from Eu2+ to Tb3+ ions, tunable colors from blue to green were obtained under the irradiation of 405 nm. The mechanism of the Eu2+ -> Tb3+ energy transfer was demonstrated to be a dipole-quadrupole interaction in terms of the experimental results and analysis of the photoluminescence spectra and decay curves of the phosphors. Moreover, the thermal stability and quantum efficiency of the Eu2+ and Tb3+ co-doped phosphors were studied. For the Sr3LaNa(PO4)3F:Tb3+,Mn2+ samples, tunable green-orange emissions were obtained by changing the relative ratio of Tb3+ and Mn2+ ions under 230 nm irradiation. The investigation results suggest that color tunable phosphors with potential for WLEDs were obtained utilizing the energy transfer process. PMID- 28853460 TI - Retraction: Facile synthesis of hierarchical Mn3O4 superstructures and efficient catalytic performance. AB - Retraction of 'Facile synthesis of hierarchical Mn3O4 superstructures and efficient catalytic performance' by Zhixiang Hu et al., Phys. Chem. Chem. Phys., 2016, 18, 26602-26608. PMID- 28853461 TI - The pKa value of the proximal water molecule trans to a high-valent MnV[double bond, length as m-dash]O porphyrin: towards the control of reactivity by pH. AB - The high-valent manganese-oxo species of Mn-TMPyP4 porphyrin interacts in the minor grooves of AT-rich regions of DNA and mediates hydroxylation of C-H bonds of deoxyribose leading to DNA break. The reaction was observed at different pHs. It is shown that the hydroxylation was not efficient at low pH (pH 6) while it worked well at higher pH (pH 8). Deprotonation of the coordinated water molecule, trans to the manganese-oxo entity, into a hydroxide anion drives high-valent manganese-oxo porphyrin toward hydroxylation at pH > 7. PMID- 28853462 TI - Onsite cavity enhanced Raman spectrometry for the investigation of gas exchange processes in the Earth's critical zone. AB - Raman gas spectrometry is introduced as a robust, versatile method for onsite, battery-powered field measurements of gases in the unsaturated and saturated critical zone. In this study, depth-profiles of the concentrations of oxygen and carbon dioxide were simultaneously monitored down to ~70 meters depth in the subsurface via a transect of drilling holes located in the Hainich Critical Zone Exploratory in central Germany. A special multichannel monitoring system was designed to access and analyze these gases non-consumptively onsite in a closed loop measurement cycle. During the timeframe of six months, seasonal changes in groundwater levels and microbial activity were related to changes observed in gas concentrations. High oxygen concentrations were found in the depths surrounding a karstified aquifer complex, while low oxygen concentrations were found in a fractured aquifer complex. Raman gas depth-profiles complement standard dissolved oxygen measurements as they also deliver oxygen concentrations in the unsaturated zone. The measured depth-profiles of the gas concentrations indicated that regions of anoxia can exist between the aquifer complexes. Lateral transport of O2 in the deeper aquifer complex provides a local source of O2 that can influence metabolism. Correlations were found between the observed CO2 concentrations and pH-values, indicating strong control of carbonate equilibria. The concentrations of O2 and CO2 were largely decoupled, thus simultaneous measurements of O2 soil effluxes give additional insights into biotic and abiotic processes in the Hainich CZE. These results illustrate the versatility of robust onsite Raman multigas measurements of the soil atmosphere and how they can contribute to the analysis of complex processes in previous uncharacterized environments in the critical zone. PMID- 28853463 TI - Systematic size mediated trapping of anions of varied dimensionality within a dimeric capsular assembly of a flexible neutral bis-urea platform. AB - A rationally designed ortho-phenylenediamine based trifluoromethyl meta disubstituted bis-urea receptor (L) exhibits effective, consistent and systematic binding in its neutral form towards smaller spherical halides (fluoride, chloride, bromide and iodide), and relatively larger planar carbonate and tetrahedral sulphate oxyanions. All the complexes are well characterized both in the solid-state and solution phase. In the presence of excess fluoride anions, the receptor L encapsulates a hydrated cyclic fluoride-water [F2(H2O)2]2- tetramer inside the n-TBA cation sealed dimeric complementary cavity (complex 1). Whereas excess n-TBA/TEA salts of chloride, bromide and iodide result in unusual (Cl-)2, (Br-)2, and (I-)2 doubly encapsulated 2 : 2 dimeric host-guest complexes (2a, 2b, 3 and 4). Two receptor units encapsulate a carbonate ion, via hydroxide induced aerial CO2 fixation (complex 5), and a sulphate anion (complex 6), respectively, in the presence of excess tetrabutylammonium hydroxide and bisulphate salt. 1H NMR titration and 2D NOESY experiments corroborate the solution-state binding and encapsulation of hydrated/non-hydrated halides and oxyanions via N-HA hydrogen bonding. PMID- 28853464 TI - Retraction: Graphene-SnO2 nanocomposites decorated with quantum tunneling junctions: preparation strategies, microstructures and formation mechanism. AB - Retraction of 'Graphene-SnO2 nanocomposites decorated with quantum tunneling junctions: preparation strategies, microstructures and formation mechanism' by Qingxiu Wang et al., Phys. Chem. Chem. Phys., 2014, 16, 19351-19357. PMID- 28853465 TI - Reduction of carbon dioxide with a superalkali. AB - The ability of the superalkali Li3F2 to reduce (electron transfer) carbon dioxide (CO2) is presented. The CBS-QB3 composite method is employed to obtain reliable information on the geometries and energetics of the investigated species. Transition states and minima were located by scanning the potential energy surface for CO2 addition to the Li3F2 superalkali. The stability of Li3F2/CO2 is explained by high binding energy, charge flows, and the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap. The selectivity of Li3F2 towards CO2 has also been computed by performing the same calculations for the most abundant atmospheric gas molecule N2. These results show a very small chemical affinity of Li3F2 for N2. PMID- 28853466 TI - Retraction: Two-dimensional nanosheets associated with one-dimensional single crystalline nanorods self-assembled into three-dimensional flower-like Mn3O4 hierarchical architectures. AB - Retraction of 'Two-dimensional nanosheets associated with one-dimensional single crystalline nanorods self-assembled into three-dimensional flower-like Mn3O4 hierarchical architectures' by Mei Wang et al., Phys. Chem. Chem. Phys., 2014, 16, 21742-21746. PMID- 28853467 TI - H/D scrambling in a chromium-catalyzed dehydrocoupling reaction of a borane dimethylamine adduct. AB - H/D scrambling took place in a chromium-catalyzed dehydrocoupling reaction of a deuterium-labeled borane-dimethylamine adduct. In the hydrogen elimination of BH3.NDMe2 (1a-dN), H2, HD and D2 were generated in 65 : 30 : 5 ratio, and 62% of deuterium atoms were incorporated into the major product, the dimethylaminoborane dimer. Proton and deuteron nuclei were thus concentrated into the evolved dihydrogen and aminoborane dimer, respectively. The mechanism of H/D scrambling is understood based on the reaction pathway of the dehydrocoupling of 1a, which was previously proposed based on DFT calculations. The H/D distribution in the products is explained by the energy difference according to the deuterated position in an intermediate of the dehydrocoupling reaction. PMID- 28853468 TI - Direct transformation of 2-acetylpyridine oxime esters into alpha-oxygenated imines in an Ir(iii) complex. AB - 2-Acetylpyridine oxime esters are transformed into the corresponding alpha oxygenated imines in an Ir(iii) complex under mild conditions, where the selective metal coordination of the imino group effectively promotes tautomerization of the oxime esters into the N-oxyenamines and the subsequent rearrangement. PMID- 28853469 TI - Construction of CuO/In2S3/ZnO heterostructure arrays for enhanced photocatalytic efficiency. AB - Novel one-dimensional (1D) heterostructure arrays composed of CuO nanowire cores, intermediate In2S3 nanostructures, and ZnO nanorod sheaths (i.e. CuO/In2S3/ZnO heterostructure arrays) have been successfully synthesized by a multi-step process. First, single-crystalline CuO nanowires were directly grown on flexible Cu mesh substrates using a one-step annealing process under ambient conditions. Second, In2S3 nanostructures and ZnO nanorods were sequentially grown on the CuO nanowires by a two-step hydrothermal method at low reaction temperature. The morphology, crystal structures, and optical properties of the CuO/In2S3/ZnO heterostructure arrays were studied by scanning electron microscopy, X-ray diffraction, transmission electron microscopy, energy-dispersive spectroscopy, and photoluminescence spectroscopy. The resultant ternary CuO/In2S3/ZnO heterostructure arrays exhibit excellent photocatalytic activity in the photodegradation of rhodamine 6G (R6G) under 10 W UV light irradiation, which is much higher than that of single-component (CuO nanowire arrays) or two-component systems (CuO/In2S3 heterostructure arrays). Furthermore, the reusability test demonstrates that the CuO/In2S3/ZnO heterostructure arrays on the Cu mesh still maintain high photocatalytic activity in the degradation of three kinds of organic pollutants even after five cycles, without any significant decline. These findings provide an insight into the design and synthesis of new CuO-based composites to effectively improve their photocatalytic performance. PMID- 28853470 TI - Selective lysine modification of native peptides via aza-Michael addition. AB - A series of vinylsulfonamides were synthesized and screened for site-selective modification of the epsilon-amino group of lysine-bearing free alpha-amine residues. N-Methyl-N-phenylethenesulfonamide has emerged as an applicable reagent and has been developed for efficient and highly selective modification of the lysine residue of native peptides in the presence of a free N-terminus via aza Michael addition. We demonstrated that functional N-phenylvinylsulfonamide derivatives with a fluorescent moiety or drug could also be conjugated to the lysine residue of octreotide and insulin with high specificity, without modifying the N-terminus. Our method provides a promising strategy for site-selective lysine functionalization in native peptides with a free N-terminus. PMID- 28853471 TI - Hybrid nanomaterials of WS2 or MoS2 nanosheets with liposomes: biointerfaces and multiplexed drug delivery. AB - Lipid containing hybrid materials are of significant interest for biointerface research and drug delivery applications, and a large number of previous studies have focused on graphene oxide (GO). In this work, novel hybrid materials made of transition metal dichalcogenides (TMDCs) and phosphocholine (DOPC) liposomes were prepared and compared with GO. All these inorganic materials are 2D nanosheets. DOPC liposomes are adsorbed by tungsten disulfide (WS2) as intact liposomes as indicated by cryo-TEM and liposome leakage assays. WS2 likely uses van der Waals forces for liposome adsorption as determined from urea, salt, and surfactant washing experiments. In addition, WS2 adsorbed doxorubicin (DOX) and DOPC liposomes synergistically. The adsorption capacity of DOPC on bare WS2 was 22.5% of the weight of WS2. After adsorbing DOX on WS2, the liposome adsorption capacity increased to ~110%. Hydrogen bonding also contributed to liposome adsorption on DOX-loaded WS2. Confocal fluorescence microscopy confirmed the uptake of the DOPC/WS2 hybrid material by HeLa cells, and the co-delivery of DOX and calcein was achieved by loading calcein inside the liposomes. This study provides fundamental insights into the interaction between PC liposomes and WS2. Furthermore, preliminary biomedical applications of this hybrid material were explored. PMID- 28853472 TI - Exfoliated BN shell-based high-frequency magnetic core-shell materials. AB - The miniaturization of electric machines demands high frequency magnetic materials with large magnetic-flux density and low energy loss to achieve a decreased dimension of high rotational speed motors. Herein, we report a solution processed high frequency magnetic composite (containing a nanometal FeCo core and a boron nitride (BN) shell) that simultaneously exhibits high electrical resistivity and magnetic permeability. The frequency dependent complex initial permeability and the mechanical robustness of nanocomposites are intensely dependent on the content of BN insulating phase. The results shown here suggest that insulating magnetic nanocomposites have potential for application in next generation high-frequency electric machines with large electrical resistivity and permeability. PMID- 28853473 TI - Silicon-based nanotheranostics. AB - With the rapid expansion of nanoscience and nanotechnology in interdisciplinary fields, multifunctional nanomaterials have attracted particular attention. Recent advances in nanotherapeutics for cancer applications provided diverse groups of synthetic particles with defined cellular and biological functions. The advance of nanotechnology significantly increased the number of possibilities for the construction of diverse biological tools. Such materials are destined to be of great importance because of the opportunity to combine the biotechnological potential of nanoparticles together with the recognition, sensitivity and modulation of cellular pathways or genes when applied to living organisms. In this mini review three main types of Si-based nanomaterials are highlighted in the area of their application for therapy and imaging: porous silicon nanoparticles (pSiNPs), mesoporous silica nanoparticles (MSNs), focusing on their nanoconstructs containing coordination compounds, and periodic mesoporous silica nanoparticles (PMONPs). Moreover, a critical discussion on the research efforts in the construction of nanotheranostics is presented. PMID- 28853476 TI - Synthesis and evaluation of selenium-containing indole chalcone and diarylketone derivatives as tubulin polymerization inhibition agents. AB - Sixteen new selenium-containing indole chalcone and diarylketone derivatives were synthesized and evaluated as tubulin polymerization inhibitors. Among them, compound 25b exhibited the most potent antiproliferative activities against six human cancer cell lines with IC50 values of 0.004-0.022 MUM. A microtubule dynamics assay and an immunofluorescence assay confirmed that 25b could effectively inhibit tubulin polymerization (IC50 = 2.1 +/- 0.27 MUM). Further cellular mechanism studies revealed that 25b induced G2/M phase arrest, which was further evidenced by the decrease in the mitochondrial membrane potential (MMP). PMID- 28853475 TI - Deep Fano resonance with strong polarization dependence in gold nanoplate nanosphere heterodimers. AB - Plasmonic Fano resonance arises from the destructive interference between a superradiant and a subradiant plasmon mode that overlap spectrally with each other. Because of its importance in revealing many physical phenomena and its applications in sensing, metamaterials, photoswitching and spectroscopy, a variety of metal nanostructures have been fabricated to generate Fano resonance. However, few metal nanostructures can support deep Fano resonance with strong polarization dependence. Herein, we report on the observation of deep Fano resonance with strong polarization dependence in Au nanoplate-nanosphere heterodimers. Experiments and simulations reveal that the presence of a nanosphere at one side edge or one vertex of the nanoplate causes distinct Fano resonance. With increasing nanosphere sizes, the shape of the scattering spectrum becomes more asymmetric, with the Fano dip getting deeper correspondingly. When the nanosphere diameter reaches 68 nm, the Fano dip almost reaches the spectral background. Moreover, the heterodimers with the nanosphere attached to one vertex of the nanoplate exhibit Fano resonance with strong polarization dependence. Such heterodimers are very attractive for constructing polarization-controlled plasmonic Fano switches. PMID- 28853477 TI - Rotational superstructure in van der Waals heterostructure of self-assembled C60 monolayer on the WSe2 surface. AB - Hybrid van der Waals (vdW) heterostructures composed of two-dimensional (2D) layered materials and self-assembled organic molecules are promising systems for electronic and optoelectronic applications with enhanced properties and performance. Control of molecular assembly is therefore paramount to fundamentally understand the nucleation, ordering, alignment, and electronic interaction of organic molecules with 2D materials. Here, we report the formation and detailed study of highly ordered, crystalline monolayers of C60 molecules self-assembled on the surface of WSe2 in well-ordered arrays with large grain sizes (~5 MUm). Using high-resolution scanning tunneling microscopy (STM), we observe a periodic 2 * 2 superstructure in the C60 monolayer and identify four distinct molecular appearances. Using vdW-corrected ab initio density functional theory (DFT) simulations, we determine that the interplay between vdW and Coulomb interactions as well as adsorbate-adsorbate and adsorbate-substrate interactions results in specific rotational arrangements of the molecules forming the superstructure. The orbital ordering through the relative positions of bonds in adjacent molecules creates a charge redistribution that links the molecule units in a long-range network. This rotational superstructure extends throughout the self-assembled monolayer and opens a pathway towards engineering aligned hybrid organic/inorganic vdW heterostructures with 2D layered materials in a precise and controlled way. PMID- 28853474 TI - Molecular simulations of peptide amphiphiles. AB - This review describes recent progress in the area of molecular simulations of peptide assemblies, including peptide-amphiphiles and drug-amphiphiles. The ability to predict the structure and stability of peptide self-assemblies from the molecular level up is vital to the field of nanobiotechnology. Computational methods such as molecular dynamics offer the opportunity to characterize intermolecular forces between peptide-amphiphiles that are critical to the self assembly process. Furthermore, these computational methods provide the ability to computationally probe the structure of these supramolecular assemblies at the molecular level, which is a challenge experimentally. Herein, we briefly highlight progress in the areas of all-atomistic and coarse-grained simulation studies investigating the self-assembly process of short peptides and peptide amphiphiles. We also discuss recent all-atomistic and coarse-grained simulations of the self-assembly of a drug-amphiphile into elongated filaments. Next, we discuss how these computational methods can provide further insight into the pathway of cylindrical nanofiber formation and predict their biocompatibility by studying the interaction of these peptide-amphiphile nanostructures with model cell membranes. PMID- 28853478 TI - Scalable synthesis of organic-soluble carbon quantum dots: superior optical properties in solvents, solids, and LEDs. AB - Carbon quantum dots (CQDs) have attracted much attention owing to their unique optical properties and a wide range of applications. The fabrication and control of CQDs with organic solubility and long-wavelength emission are still urgent issues to be addressed for their practical use in LEDs. Here, organic-soluble CQDs were produced at a high yield of ~90% by a facile solvent engineering treatment of 1,3,6-trinitropyrene, which were simultaneously used as the nitrogen and carbon sources. The optical properties of the organic-soluble CQDs (o-CQDs) were investigated in nonpolar and polar solvents, films, and LED devices. The CQDs have a narrow size distribution around 2.66 nm, and can be dispersed in different organic solvents. Significantly, the as-prepared CQDs present an excitation-independent emission at 607 nm with fluorescence quantum yields (QYs) up to 65.93% in toluene solution. A pronounced solvent effect was observed and their strong absorption bands can be tuned in the whole visible region (400-750 nm) by changing the solvent. The CQDs in various solvents can emit bright, excitation-independent, long-wavelength fluorescence (orange to red). Furthermore, benefiting from the unique oil-solution properties, the as-prepared CQDs can be processed in thin film and device forms to meet the requirements of various applications, such as phosphor-based white-light LEDs. The color coordinate for these CQD modified LEDs is realized at (0.32, 0.31), which is close to pure white light (0.33, 0.33). PMID- 28853479 TI - Dual active nitrogen doped hierarchical porous hollow carbon nanospheres as an oxygen reduction electrocatalyst for zinc-air batteries. AB - Developing non-platinum catalysts for the oxygen reduction reaction (ORR) has become urgent for electrochemical energy devices. Herein, we synthesize N-doped hollow carbon nanospheres (N-HCNs) which only contain active pyridinic-N and graphitic-N by using polystyrene spheres and aniline as the corresponding template and precursor. The electrochemical measurements show that N-HCNs possess superior ORR electrocatalytic activity (half-wave potential is 15 mV higher than that of the precious Pt/C electrocatalyst), durability and anti-toxicity to Pt/C in alkaline media. Simultaneously, N-HCNs also reveal comparable ORR activity and superior stability to Pt/C in acidic media. Such high ORR performance can be ascribed to their hierarchical porous structure, ultra-high specific surface area, plenty of edge defects and high contents of active N atoms. It is noteworthy that when used as the catalyst for the air electrode of zinc-air batteries, N-HCNs present a higher power density and a larger operating voltage than Pt/C at the same discharge current density. PMID- 28853480 TI - Retraction: Insights from investigations of tin dioxide and its composites: electron-beam irradiation, fractal assessment, and mechanism. AB - Retraction of 'Insights from investigations of tin dioxide and its composites: electron-beam irradiation, fractal assessment, and mechanism' by Zhiwen Chen et al., Nanoscale, 2015, 7, 15532-15552. PMID- 28853481 TI - Formation of hydrazones and stabilized boron-nitrogen heterocycles in aqueous solution from carbohydrazides and ortho-formylphenylboronic acids. AB - A recent addition to the suite of fast bioorthogonal reactions combines hydrazines and hydroxylamines with ortho-carbonyl substituted phenylboronic acids. Carbohydrazides are easily incorporated into biomolecules, making them appealing substrates in these reactions. Here we show that simple alkyl carbohydrazides form a single product with ortho-formylphenylboronic acid in an organic solvent and in the solid state. The solution structures of the products formed from the carbohydrazides in buffered aqueous solution, however, are markedly different from those identified in the organic solvent and solid state. The reactants form a mixture of hydrazone and heterocyclic products, the relative composition of which varies with pH. The observed reversibility of bioconjugates using carbohydrazide can thus be explained by the reversibility of the boron nitrogen bond in the heterocycle. In contrast, the inclusion of an alpha-amine into the carbohydrazide substrate yields a single product in which both nitrogens are bonded to boron. These tricyclic structures are the same in organic solvent, solid state and aqueous solution from pH 4 to pH 9. Bioconjugates formed with alpha-amino carbohydrazides are stable to SDS-PAGE, while those formed with simple alkyl carbohydrazides are not. We propose that the inclusion of an intramolecular stabilizing ligand into a carbohydrazide substrate is a generally applicable principle that may be exploited to form boronic acid-based bioconjugates with a defined structure and resistance to hydrolysis. PMID- 28853482 TI - Fluorescent sensing arrays for cations and anions. AB - Array-based sensing methods can be used to distinguish sets of similar analytes, by using a number of non-specific or cross-reactive probes. Following subsequent statistical analysis, patterns or components can be isolated that can be used to unambiguously identify the specific analyte(s) present. Over the past two decades, various arrays for the identification of cations and anions have been reported. These often employ fluorescence methods, owing to good sensitivity and a versatile, easy to read output. The past few years have seen an increase in the number of such studies reported in the literature. This critical review will summarise this recent work, and identify the criteria required for a successful array system. In particular, it will focus on the different types of molecular structures that can be used, the breadth of ions that can be distinguished in a single array, the sensitivity and dynamic range to which they can be identified, and how successfully these aims have been met. PMID- 28853483 TI - Superior lithium-ion insertion/extraction properties of a novel LiFePO4/C/graphene material used as a cathode in aqueous solution. AB - Herein, olivine LiFePO4 covered with graphene and carbon layers is prepared via a sol-gel method, followed by calcination, and the resultant composite is used as a cathode material in aqueous rechargeable lithium-ion batteries (ARLBs). The phase structure and morphology of the composite are characterized via X-ray diffraction (XRD), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM) and specific surface area analysis (BET). The ARLB system is fabricated using LiFePO4/C/graphene as the cathode and a zinc anode in 1 mol L-1 ZnSO4.7H2O and saturated LiNO3 aqueous solution without dissolved oxygen, which delivers a capacity of 153 mA h g-1 at 0.5C rate. Even at a 50C rate, it maintains a capacity of 95 mA h g-1 after 200 cycles. The excellent rate capabilities show that this cathode material exhibits good electrochemical performance and this novel ARLB has great potential in the fields of energy storage and high power sources. PMID- 28853484 TI - Integrating multiple fitting regression and Bayes decision for cancer diagnosis with transcriptomic data from tumor-educated blood platelets. AB - The application of machine learning in cancer diagnostics has shown great promise and is of importance in clinic settings. Here we consider applying machine learning methods to transcriptomic data derived from tumor-educated platelets (TEPs) from individuals with different types of cancer. We aim to define a reliability measure for diagnostic purposes to increase the potential for facilitating personalized treatments. To this end, we present a novel classification method called MFRB (for Multiple Fitting Regression and Bayes decision), which integrates the process of multiple fitting regression (MFR) with Bayes decision theory. MFR is first used to map multidimensional features of the transcriptomic data into a one-dimensional feature. The probability density function of each class in the mapped space is then adjusted using the Gaussian probability density function. Finally, the Bayes decision theory is used to build a probabilistic classifier with the estimated probability density functions. The output of MFRB can be used to determine which class a sample belongs to, as well as to assign a reliability measure for a given class. The classical support vector machine (SVM) and probabilistic SVM (PSVM) are used to evaluate the performance of the proposed method with simulated and real TEP datasets. Our results indicate that the proposed MFRB method achieves the best performance compared to SVM and PSVM, mainly due to its strong generalization ability for limited, imbalanced, and noisy data. PMID- 28853485 TI - Controlled core-to-core photo-polymerisation - fabrication of an optical fibre based pH sensor. AB - The fabrication of fluorescence-based pH sensors, embedded into etched pits of an optical fibre via highly controllable and spatially selective photo polymerisation is described and the sensors validated. PMID- 28853486 TI - Evaluation of drug combination for glioblastoma based on an intestine-liver metabolic model on microchip. AB - An intestine-liver-glioblastoma biomimetic system was developed to evaluate the drug combination therapy for glioblastoma. A hollow fiber (HF) was embedded into the upper layer of the microfluidic chip for culturing Caco-2 cells to mimic drug delivery as an artificial intestine. HepG2 cells cultured in the bottom chamber of the chip acted as an artificial liver for metabolizing the drugs. The dual drug combination to glioblastoma U251 cells was evaluated based on the intestine liver metabolic model. The drugs, irinotecan (CPT-11), temozolomide (TMZ) and cyclophosphamide (CP), were used to dynamically stimulate the cells by continuous infusion into the intestine unit. After intestine absorption and liver metabolism, the prodrugs were transformed to active metabolites, which induced glioblastoma cells apoptosis. The anticancer activity of the CPT-11 and TMZ combination is significantly enhanced compared to that of the single drug treatments. Combination index (CI) values of the combination groups, CPT-11 and TMZ, CPT-11 and CP, and TMZ and CP, at half maximal inhibitory concentration were 0.137, 0.288, and 0.482, respectively. The results indicated that the CPT-11 and TMZ combination was superior to the CPT-11 and CP group as well as the TMZ and CP group towards the U251 cells. The metabolism mechanism of CPT-11 and TMZ was further studied by coupling with mass spectrometric analysis. The biomimetic model enables the performance of long-term cell co-culture, drug delivery, metabolism and real-time analysis of drug effects, promising systematic in vitro mimicking of physiological and pharmacological processes. PMID- 28853487 TI - Oxygen defect engineering by the current effect assisted with temperature cycling in a perovskite-type La0.7Sr0.3CoO3 film. AB - Introducing and modulating the oxygen deficiency concentration have been received as an effective way to obtain high catalytic activity in perovskite oxides. However, it is difficult to control the oxygen vacancy in conventional oxygen defect engineering due to harsh reaction conditions at elevated temperatures and the reducing atmosphere, which make it impractical for many technological applications. Herein, we report a new approach to oxygen defect engineering based on the combination of the current effect and temperature cycling at low temperature. Our investigations revealed that the electrical conductivity of the (011)-La0.7Sr0.3CoO3/PMN-PT film changes continuously from metallicity to insulativity under repeated transport measurements below room temperature, which indicates the transformation of the Co4+ state to Co3+ in the film. Further experiments and analysis revealed that oxygen vacancies can be well regulated by the combined current effect and temperature cycling in repeated measurements, which results in a decrease of Co4+/Co3+ and thus the remarkable variation of conductive properties of the film. Our work provides a simple and highly efficient method to engineer oxygen vacancies in perovskite-type oxides and brings new opportunities in designing high-efficiency oxidation catalysts. PMID- 28853488 TI - Nickel-catalysed direct C2-arylation of N-heterocyclic carbenes. AB - A highly efficient nickel catalysed method for the direct C2-arylation of N heterocyclic carbenes (NHCs) is reported. This protocol enables a facile access to C2-arylated imidazolium salts (NHC-Ar)X (X = Cl, Br, I or OTf). Experimental and theoretical studies suggest the viability of a Ni(i)/Ni(ii) catalytic pathway in which the dinuclear Ni(i) species [(NHC)NiX]2 plays a key role. PMID- 28853489 TI - Quintuple super bonding between the superatoms of metallic clusters. AB - The synthesis of a stable compound with Cr-Cr quintuple bonding (sigma, 2pi, 2delta) opened the door to a new field of chemistry (T. Nguyen, A. D. Sutton, M. Brynda, J. C. Fettinger, G. J. Long and P. P. Power, Science, 2005, 310, 844). Looking back to the mass experiments on sodium clusters (W. D. Knight, K. Clemenger, W. A. de Heer, W. A. Saunders, M. Y. Chou and M. L. Cohen, Phys. Rev. Lett., 1984, 52, 2141), this work tells some new stories about the experimentally viewed magic numbers 26e and 30e. By unbiased global search, the 26e Li20Mg3 cluster has a perfect double-icosahedral motif with a large HOMO-LUMO energy gap (1.44 eV). We theoretically found that each icosahedron is an independent superatom and molecule-like electronic shell-closure is achieved via quintuple super bonding between two superatoms: [8e](1D2S)5-(1D2S)5[8e]. Similar quintuple bonding also exists in the 30e double-icosahedral Li18Mg3Al2 cluster: [8e](1D2S)7 (1D2S)7[8e]. The 26e/30e quintuple bonding was verified by the beautiful analogies in molecular orbital diagrams and chemical bonding patterns with V2/Re2 molecules. Such a quintuple super bonding makes a bridge between the jellium model and chemical bonding, which further expands the community of chemical bonds. PMID- 28853490 TI - Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines. AB - Interleukin (IL)-26 is abundant in human airways and this cytokine is involved in the local immune response to a bacterial stimulus in vivo. Specifically, local exposure to the toll-like receptor (TLR) 4 agonist endotoxin does increase IL-26 in human airways and this cytokine potentiates chemotactic responses in human neutrophils. In addition to T-helper (Th) 17 cells, alveolar macrophages can produce IL-26, but it remains unknown whether this cytokine can also be produced in the airway mucosa per se in response to a viral stimulus. Here, we evaluated whether this is the case using primary bronchial epithelial cells from the airway epithelium in vitro, and exploring the signaling mechanisms involved, including the modulatory effects of additional Th17 cytokines. Finally, we assessed IL-26 and its archetype signaling responses in healthy human airways in vivo. We found increased transcription and release of IL-26 protein after stimulation with the viral-related double stranded (ds) RNA polyinosinic-polycytidylic acid (poly-IC) and showed that this IL-26 release involved mitogen-activated protein (MAP) kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB). The release of IL-26 in response to a viral stimulus was modulated by additional Th17 cytokines. Moreover, there was transcription of IL26 mRNA and expression of the protein in epithelial cells of bronchial brush and tissue biopsies respectively after harvest in vivo. In addition, the extracellular IL-26 protein concentrations in bronchoalveolar lavage (BAL) samples did correlate with increased epithelial cell transcription of an archetype intracellular signaling molecule downstream of the IL-26-receptor complex, STAT1, in the bronchial brush biopsies. Thus, our study suggests that viral stimulation causes the production of IL-26 in lining epithelial cells of human airway structural cells that constitute a critical immune barrier and that this production is modulated by Th17 cytokines. PMID- 28853491 TI - Eczema in Psoriatico: An Important Differential Diagnosis Between Chronic Allergic Contact Dermatitis and Psoriasis in Palmoplantar Localization. AB - Differential diagnosis of palmoplantar non-pustular psoriasis and chronic allergic contact dermatitis (ACD) and the combination of these conditions, termed "eczema in psoriatico" (EIP), is difficult, especially in cases of isolated involvement. A blind re-evaluation of 63 archived formalin-fixed palmoplantar samples, previously diagnosed clinically as either psoriasis or chronic ACD, was performed. Samples were allocated to histopathological diagnoses of psoriasis, contact dermatitis or EIP. Immunohistological stainings were performed for better characterization. Immunochemistry of EIP revealed features that overlapped contemporarily with psoriasis (cytokeratin 17 (CK17), Ki67, interleukin (IL)-8, IL-17, IL-23) and with ACD (CD1a, major histocompatibility complex (MHC) class I, MHC class II, epidermal T-cell subsets). Surprisingly, a significantly much higher number of dermal CD8+ T cells was found in EIP than in ACD and psoriasis. In conclusion, this study provides insight into the immunohistological differentiation of palmoplantar psoriasis, chronic ACD and EIP. PMID- 28853492 TI - Role of Substance P and Its Receptor Neurokinin 1 in Chronic Prurigo: A Randomized, Proof-of-Concept, Controlled Trial with Topical Aprepitant. AB - Substance P (SP) and its receptor neurokinin 1 (NK1R) are thought to be involved in the pathogenesis of chronic prurigo. Here, we assessed SP serum levels, cutaneous NK1R expression, and the effects of topical aprepitant, an NK1R antagonist, in patients with chronic prurigo. SP and NK1R were increased, compared with controls, in the serum and in lesional vs. non-lesional skin of the patients, respectively. Aprepitant, in a randomized, placebo-controlled, split sided, doubleblind trial, reduced the intensity of pruritus as assessed by visual analogue scale by >50% from baseline to day 28 (-35.2), but so did placebo vehicle (-38.1, p= 0.76). Overall clinical scores improved significantly by day 28 in both treatment groups, with no significant difference between the 2 groups (p=0.32). Our findings imply that both SP and NK1R are involved in the pathogenesis of chronic prurigo. Parallel groupdesigned trials are needed to assess the efficacy of topical aprepitant treatment in this condition. PMID- 28853493 TI - Staphylococcal Scalded Skin Syndrome Caused by a Rare Variant of Exfoliative toxin-A+ S. aureus in an Adult Immunocompromised Woman. PMID- 28853494 TI - Assessment of Quality of Life in Chronic Pruritus: Relationship Between ItchyQoL and Dermatological Life Quality Index in 1,150 Patients. PMID- 28853495 TI - Epidemiology and Outcome of Squamous Cell Carcinoma in Epidermolysis Bullosa in Australia and New Zealand. AB - We investigate the epidemiology and outcomes of squamous cell carcinoma (SCC) in recessive dystrophic epidermolysis bullosa (RDEB) from the Australasian EB registry cohort. Seventeen out of 49 (34.6%) RDEB patients developed at least one SCC. Data detailing SCC was obtainable from 16/17 RDEB-SCC patients. A total number of 161 primary SCCs occurred in 16 RDEB-SCC patients with a mean of 10 SCCs per person. The earliest age of first SCC development was 16 years. Eleven out of 16 RDEB-SCC patients eventually developed metastatic SCCs. The majority of the tumours were well and moderately differentiated. The cumulative risk of SCC development by age 35 was 76.1% for RDEB-Generalized Severe (RDEB-GS) and 10% for RDEB-Generalized Intermediate (RDEB-GI). Amongst those who developed SCCs, their median time to death after first SCC was 5 years for RDEB-GI and 4 years for RDEB GS. This is the first retrospective study of RDEB-SCC in Australasia. PMID- 28853496 TI - Incidence and Regression of Actinic Keratoses in Organ Transplant Recipients. AB - Actinic keratoses (AKs) are highly dynamic lesions and AK activity has been shown to be associated with squamous cell carcinoma (SCC). We sought to explore risk factors which may affect the 12-month turnover of AKs in organ transplant recipients (OTRs). The number of incident AKs, regressed AKs and net change in AK counts were calculated. Negative binomial regression and Poisson regression models were used to estimate rate ratios (RR) for these 3 outcomes. Among 150 renal and 89 liver OTRs, those who spent > 50% of a typical weekday in the sun had a lower rate of AK regression than those who spent minimal time in the sun during a typical weekday. Age, parents' country of origin, hair colour, skin cancer history and recent AK treatment were all significantly associated with AK turnover. Clinically, these risk factors may be used to monitor OTRs at increased risk of SCC. PMID- 28853497 TI - [Vital pulp therapy of damaged dental pulp]. AB - The development of an expert consensus on vital pulp therapy can provide practical guidance for the improvement of pulp damage care in China. Dental pulp disease is a major type of illness that adversely affects human oral health. Pulp capping and pulpotomy are currently the main methods for vital pulp therapy. Along with the development of minimal invasion cosmetic dentistry, using different treatment technologies and materials reasonably, preserving healthy tooth tissue, and extending tooth save time have become urgent problems that call for immediate solution in dental clinics. This paper summarizes the experiences and knowledge of endodontic experts. We develop a clinical path of vital pulp therapy for clinical work by utilizing the nature, approach, and degree of pulp damage as references, defense and self-repairing ability of pulp as guidance, and modern technologies of diagnosis and treatment as means. PMID- 28853498 TI - [Criterion of dental treatment for the disabled]. AB - The number of disabled persons increases in the course of human life and in the aging population. The high prevalence, low treatment rate, long therapy period, and sophisticated procedures prevent most of disabled individuals from availing dental services. Moreover, special dental institutions for the disabled are insufficient, and a certain treatment standard is commonly not complied. This study performed analysis and evaluation, including treatment features, pretreatment procedures, patient communication, treatment factors, and treatment standards to provide a targeted solution for the special requirements of the oral therapy for disabled patients. PMID- 28853499 TI - [Clinical application and material selection of provisional restorations]. AB - Provisional restorations are beneficial to final restorations. However, the importance of provisional restorations is often overlooked because they are designed to function for a limited period. This article summarizes the clinical values and two common materials of provisional restorations. PMID- 28853500 TI - [Effect of different oxygen tension on the cytoskeleton remodeling of goat temporomandibular joint disc cells]. AB - Objective The effect of different oxygen tensions on the cytoskeleton remodeling of goat temporomandibular joint (TMJ) disc cells were investigated. Methods Goat TMJ disc cells were cultured under normoxia (21% O2) and hypoxia (2%, 4%, and 8% O2). Toluidine blue, picrosirius red, and type I collagen immunocytochemical staining were performed to observe the changes in cell phenotype under different oxygen levels. Immunofluorescent staining and real-time reverse transcription polymerase chain reaction analysis were then performed to identify actin, tubulin, and vimentin in the cultured disc cells. Results TMJ disc cells still displayed fibroblast characteristics under different oxygen levels and their cytoskeletons had regular arrangement. The fluorescence intensities of actin and vimentin were lowest at 4% O2(P<0.05), whereas that of tubulin was highest at 2% O2 (P<0.05). No significant difference among the other groups was observed (P>0.05). Actin mRNA levels were considerably decreased at 2% O2 and 4% O2 in hypoxic conditions, while actin mRNA expression was highest in 21% O2. Tubulin mRNA levels considerably increased at 2% O2, while tubulin mRNA expression was lowest in 8% O2 (P<0.05). Vimentin mRNA expression was lowest at 4% O2 and highest at 21% O2, and significant differences were observed between vimentin mRNA expression levels among these oxygen levels (P<0.05). Conclusion Cytoskeletons were reconstructed in different oxygen tensions, and 2% O2 may be the optimal oxygen level required to proliferate TMJ disc cells. PMID- 28853501 TI - [The effect of Toll-like receptor 4 in nicotine suppressing the osteogenic potential of periodontal ligament stem cells]. AB - Objective To explore the impact of nicotine on proliferation and osteogenic capability of periodontal ligament stem cells (PDLSCs), and the role of Toll-like receptor 4 (TLR4) in nicotine, suppressing the osteogenic capability of PDLSCs. Methods PDLSCs were cultured in vitro, and the flow cytometer was used to identify the surface antigen markers of PDLSCs. WST-1 was used to detect the proliferation ability of PDLSCs, which were stimulated by different concentrations of nicotine. Alizarin red staining was used to observe the formation of mineralized nodules after PDLSCs stimulation with different concentrations of nicotine. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to detect the change in osteogenic potential of PDLSCs stimulated by nicotine, after TAK-242, and with the inhibitor of TLR4. Results PDLSCs expressed mesenchymal stem cell-associated markers CD90 and CD105. When the concentration of nicotine was 10-4 mol.L-1, the PDLSC proliferation could be suppressed after 3 d compared with the control group (P<0.05). The amount of mineralized nodules reduced after osteogenic differentiation at 21 d by alizarin red staining. RT-PCR and Western blot showed the expression levels of alkaline phosphatase (ALP), and osteocalcin (OCN), and the Runt-related transcription factor-2 (Runx-2) were lower than in the control group when nicotine suppressed the PDLSCs (P<0.05). This effect was attenuated after TAK-242 was added. Conclusion Nicotine suppresses the proliferation and osteogenic capability of PDLSCs, which may be regulated by TLR4. PMID- 28853503 TI - [Brushing abrasion of the enamel surface after erosion]. AB - Objective A study was conducted to compare the effect of different enamel remineralization periods after erosion on the depth of brushing abrasion. Methods Ten volunteers were selected for a 4-day experiment. A total of 60 enamels were randomly assigned into six groups (A-F) and placed in intraoral palatal devices. On the first day, the palatal devices were placed in oral cavity (24 h) . On the following three days, brushing experiments were performed extraorally, two times per day. The specific experimental method of brushing follows these next steps. First, the group F specimens were covered with a film of wax, and then acid etched for 2 min. Subsequently, the film of wax was detached. The groups from A to D were brushed after remineralization at the following time intervals: group A, 0 min; group B, 20 min; group C, 40 min; group D, 60 min. Erosion and remineralization were performed on group E, but without brushing. Remineralization was performed on group F, but without acid etching and brushing. The depth of enamel abrasion was determined by a mechanical profilometer. The surface morphology of the enamel blocks was observed using a scanning electron microscope. Results 1) The depth of abrasion was different in varied enamel remineralization time after acid etching. The statistical significant differences between groups were as follows. 2) When the time of enamel remineralization after acid etching was short, the surface depression in the electron microscope was deep, and the surface morphology was rough. Conclusion Brushing immediately after acid etching would cause much serious abrasion to the enamel surface. Brushing after 60 min can effectively reduce the abrasion of acid etching enamel. PMID- 28853502 TI - [Effects of geranylgeranyltransferaseIsilencing on the proliferation of tongue squamous cancer cells]. AB - Objective This study aims to investigate the effect of geranylgeranyltransferaseI (GGTase-I) on the proliferation and growth of tongue squamous cancer cells. Methods Three small interfering RNAs (siRNAs) were designed on the basis of the GGTase-I sequence in GeneBank. These siRNAs were then transfected into tongue squamous cancer cells Cal-27. The mRNA and protein expression of GGTase-I and RhoA were examined by real-time quantitative polymerase chain reaction and Western blotting, respectively. The expression of Cyclin D1 and p21 were examined by Western blotting. The proliferation and growth ability were analyzed by cell counting kit-8 assay and flow cytometry. Results The mRNA and protein expression of GGTase-I in Cal-27 was reduced significantly after the GGTase-I siRNAs were transfected (P<0.05). No significant difference in RhoA mRNA and protein expression was detected (P>0.05). Cyclin D1 expression decreased, whereas p21 expression increased significantly. The cell cycle was altered, and the growth proliferative activity was inhibited (P<0.05). Conclusion GGTase-I siRNA can inhibit the expression of GGTase-I and the proliferative activity of tongue squamous cancer cells. GGTase-I may be a potential target for gene therapy in tongue squamous cell cancer. PMID- 28853504 TI - [Clinical application of cone beam computed tomography combined with micro ultrasound technique in treating three mesial canals in mandibular first molars]. AB - Objective The aim of this study is to investigate the influence of cone beam computed tomography (CBCT) and micro-ultrasound technique for the treatment of three mesial canals in mandibular first molars. The three mesial canals according to Pomeranz's classification were characterized. Methods A total of 75 permanent mandibular first molars for root canal treatment were randomly selected from patients belonging to the age group of 14-60 years. After preparing the access cavity and locating the main canals, the middle mesial canal orifices in all teeth were determined with an endodontic explorer under direct vision (StageI), under magnification with the aid of micro-ultrasound (Stage II), and with the combined use of CBCT and micro-ultrasound to remove the dentin wall and calcifications (Stage III). Results Middle mesial canals were detected in 4.0%, 18.7%, and 22.7% of the teeth in StagesI-III, respectively. Statistical analysis showed significant differences (P<0.05) between StagesIand II with regard to middle mesial canal detection. The number of Stage III was more than that of Stage II. The difference between the two stages was no significant. Among the 17 middle mesial canals, "confluent", "fin" and "independent" anatomies were 52.9%, 35.3%, and 11.8%. Conclusion When used with adjunctive aids, including CBCT, micro-ultrasound facilitates dental clinicians in the location and treatment of middle mesial canals. PMID- 28853505 TI - [Effect of repeated sintering and variations in thickness on the color and microstructure of dental lithium disilicate-based glass ceramic veneers]. AB - Objective The aim of this study is to evaluate the effect of repeated sintering and variation in thickness on the color and microstructure of dental lithium disilicate-based glass ceramic veneers. Methods A total of 24 computer aided design and computer aided manufacturing (CAD/CAM) veneers was fabricated using the IPS e.max-CAD LS2 and then randomly divided into four groups (S0, S1, S2, S3; n=6). Each group was sintered 0, 1, 2, 3 times individually according to the manufacturer's recommendation. The color parameters (L, C, H, a, b values) of all the specimens were measured by a Vita easyshade dental colorimeter. The results were statistically analyzed using the SAS 9.1.3 software for MANOVA and LSD. Subsequently, the microstructures of the intersecting surfaces of the specimens were observed by scanning electron microscopy (SEM). Results After repeated sintering, the L value significantly decreased (P<0.05). For the C and b values, statistical differences were observed among the groups except between S2 and S3. SEM results showed that the interlocking microstructures of rod-shaped Li2Si2O5 crystals became more compact when the number of sintering times was increased. Conclusion Repeated sintering exhibited significant influence on the color of the IPS e.max-CAD LS2 veneers. PMID- 28853506 TI - [Measurements of mechanical properties and morphology of root canal in maxillary primary anterior teeth]. AB - Objective This study aimed to measure the taper and diameter of root canal, as well as the elastic modulus and hardness in the root dentin of maxillary primary anterior teeth. Methods Patients under general anesthesia who needed root canal therapy in the maxillary primary anterior teeth were selected. Silicone impression material was used to take impressions. The impressions were scanned, and the taper and diameter of root canal were measured. Maxillary primary anterior teeth were collected in vitro. The elastic modulus and hardness of root dentin was tested. Results A total of 74 silicone impressions were obtained. The mean tapers of primary incisor teeth, primary lateral incisor teeth, and primary canine teeth were 0.106, 0.185, and 0.098, respectively. The mean diameters of the root canal 5 mm below the cementum-enamel junction (CEJ) were 1.267, 0.860, and 1.429 mm, respectively. The elastic modulus and hardness of root dentin were measured in 10 primary anterior teeth in vitro. The range of elastic modulus was 19.919-25.017 GPa. The range of hardness was 0.867-1.082 GPa. Conclusion The root canal post used in primary anterior teeth can be produced by the following data: taper of primary incisor teeth and primary canine teeth, 0.1; diameters of their tips, 1.2 mm and 1.4 mm, respectively; taper of primary lateral incisor teeth, 0.2; diameter of their tips, 0.8 mm; range of elastic modulus, 20-25 GPa; and range of hardness, 0.87-1.08 GPa. PMID- 28853507 TI - [Application of single-retainer all-ceramic resin-bonded fixed partial denture in replacing single anterior tooth]. AB - Objective In this study, we aimed to evaluate the clinical effect of single retainer all-ceramic resin-bonded fixed partial denture (RBFPD) on the single anterior tooth loss patients. Methods A total of 20 single-retainer all-ceramic RBFPD?were fabricated and evaluated in a two-year follow-up observation. The restorations were examined on the basis of the American Public Health Association (APHA) criteria. Results A total of 20 single-retainer all-ceramic RBFPD achieved class A evaluation after a six-month follow-up observation. One single-retainer all-ceramic RBFPD was classified as class B for secondary caries after a one-year follow-up observation. After a two-year follow-up observation, one single retainer all-ceramic RBFPD was classified as class B because of secondary caries, and one single-retainer all-ceramic RBFPD was classified as class B because of fracture. Conclusion Single-retainer all-ceramic RBFPD is a promising and optional method in replacing single anterior tooth. PMID- 28853508 TI - [Characteristics of mandible and mandibular dentition in patients with near normal occlusion and different vertical facial skeletal types]. AB - Objective The aim of our work is to characterize individual normal occlusions to establish appropriate treatment standards for different vertical facial types. Methods A total of 30 patients with near-normal occlusion were grouped into high angle group (eight cases), medium-angle group (12 cases), and low-angle group (10 cases) according to vertical facial skeletal type. Invivo5 software was used and digital imaging and communications in medicine data were rebuilt to measure the ?L1/MP, ?L6/MP, axis corner of L6, cant of occlusion plane, Balkwill angle, and Bonwill triangle of each group. Results Among the groups, the low-angle group had the smallest ?L6/MP (P<0.05) and largest cant of occlusion. No significant difference was observed among the three groups with regard to the other parameters (P>0.05). Conclusion Patients with low-angle vertical facial skeletal type requires a modified treatment standard. In this group, the treatment standard must ensure that the cant of occlusion plane is more parallel to the Frankfurt horizontal plane compared with those of the other groups, and the axis of L6 is tilted distally relative to the mandibular plane. PMID- 28853509 TI - [Comparison between propofol and propofol-remifentanil sedation under target controlled infusion for impacted supernumerary teeth extraction surgery for children]. AB - Objective The aim of this study is to compare sedation titrated under target controlled infusion of propofol and propofol-remifentanil for impacted supernumerary teeth extraction surgery for children. Methods A total of 60 children with anterior maxillary region impacted supernumerary teeth extraction surgery were divided randomly into two groups, namely, propofol group (group P, n=30) and propofol-remifentanil group (group PR, n=30). In group P, a titrated infusion of propofol was started until the modified observer's assessment of alertness/sedation (OAA/S) scale reached level 3 before the actual surgery. In group PR, a remifentanil infusion with a target plasma concentration of 1 ng.mL-1 was started until the operation was finished. A titrated infusion of propofol was also started until the modified OAA/S score reached level 3 before the actual surgery. The Houpt behavior scale was adopted to evaluate the cooperation of each patient in both groups. The heart rate, blood pressure, respiratory rate, oxyhemoglobin saturation, and Narcotrend index, complications, adverse reactions and propofol infusion of all patients were recorded during the operation. Results The Houpt behavior scales in group PR were better than those in group P (P<0.05). The oxyhemoglobin saturation and respiratory rate in group PR were lower than that in group P (P<0.05). The heart rate, blood pressure and NI in two groups were no significant difference (P>0.05). The incidence of respiratory depression and anterograde amnesia in group PR were higher than that in group P (P<0.05). Conclusion Sedation titrated under the target-controlled infusion of propofol and that titrated under propofol-remifentanil for impacted supernumerary teeth extraction surgery for children are safe. The sedation titrated under target controlled infusion of propofol-remifentanil is better than sedation by propofol when inhaling oxygen. PMID- 28853510 TI - [Single-photon emission computed tomography for the diagnosis of mandibular invasion caused by oral cancers: a systematic review and Meta-analysis]. AB - Objective This review aimed at assessing the diagnostic efficacy of contrast enhanced single-photon emission computed tomography (SPECT) in the diagnosis of mandibular invasion by oral cancers. Methods Five databases were searched electronically on August 5, 2016. The reference lists of included studies were hand searched. Quality assessment was performed by two reviewers in duplicate with tools suggested by Cochrane's handbook. Furthermore, the data extraction of included studies was delivered. Meta-analysis was performed using STATA 11.0. Results Ten studies with 460 participants were included. One study had a low risk of bias, and two studies had a high risk of bias. The remaining seven studies had an unclear risk of bias. Meta-analysis results showed that SPECT had a pooled sensitivity of 0.99 [95% confidence interval=0.87-?1.00]. Sensitivity was 0.99 on Q* point. The specificity of 0.61 and the area under summary receiver operating characteristic curve (SROC) were 0.93 [95% confidence interval=0.90-?0.95]. The pooled positive likelihood ratio was 2.555. The negative likelihood ratio was 0.015. The diagnostic odd ratio was 5.115. Conclusion SPECT had high sensitivity, which became suitable for excluding bone invasion by oral cancers. However, its specificity was relatively low, indicating its limited capability in confirming diagnosis. Therefore, surgeons should perform this method under certain conditions. PMID- 28853511 TI - [Association between chronic periodontitis and hyperlipidemia: a Meta-analysis based on observational studies]. AB - Objective The aim of this study is to evaluate the relationship between periodontitis and hyperlipidemia risks through Meta-analysis. Methods Two researchers conducted an electronic search on PubMed, Cochrane Library, Embase, CBM, CNKI, Wanfang and VIP databases established until July 2016 for observational studies on the association between periodontitis and hyperlipidemia. The language used was limited to Chinese and English. After data extraction and quality evaluation of included trials, Meta-analysis was conducted using the RevMan 5.3 software. The GRADE 3.6 software was used to evaluate the quality level of the evidence. Results Six case-control studies and one cohort study were included. The results of Meta-analysis showed that serum triglyceride (TG) in patients with periodontitis was significantly higher than that of the periodontal health group (MD=50.50, 95% confidence interval=39.57-61.42, P<0.000 01), as well as serum total cholesterol (TC) (MD=17.54, 95% confidence interval=10.91-24.18, P<0.000 01). Furthermore, the risks of TG and TC in the serum of patients with chronic periodontitis were 4.73 times (OR=4.73, 95% confidence interval=2.74-8.17, P<0.000 01) and 3.62 times (OR=3.62, 95% confidence interval=2.18-6.03, P<0.000 01) of that of periodontal healthy patients. No significant difference was observed between the group with high density lipoprotein cholesterol (HDL-C) and that with low density lipoprotein cholesterol (LDL-C). Conclusion Current evidence indicates that a correlation exists between chronic periodontitis and hyperlipidemia, and chronic periodontitis is an independent risk factor for hyperlipidemia, especially for TC and TG in serum. PMID- 28853512 TI - [Advances in macrophage function and its anti-inflammatory and proresolving activity and role in periodontitis development]. AB - Macrophage plays an important role in human innate immune system. It has powerful functions, such as recognition, phagocytosis, and bacteria and foreign body removal. Periodontitis, which is a chronic infectious disease characterized by gum inflammation and bone loss, is a major cause of tooth loss in adults. Several studies demonstrated that periodontal tissue destruction is caused by the host immune response defending against infections. As an important part of host immune response, macrophage is also involved in periodontitis pathogenesis. Recently, anti-inflammatory and proresolving activities of macrophage was discovered. Thus, the complex function of macrophage in the occurrence, development, and resolution of inflammation and its potential role in periodontitis were reviewed. PMID- 28853513 TI - [Current therapy of atrophic edentulous mandibular fractures among elderly people]. AB - The cases of mandible fractures among elderly people, especially those with atrophic mandibles, are increasing. Atrophic mandibular fractures among elderly people require specific treatment because of the differences between the anatomicophysiologies of elderly people and those of normal adults. This paper serves as a literature review on the characteristics, selection of the treatment method, and complication of atrophic edentulous mandibular fractures among elderly people. PMID- 28853514 TI - [Effect of maternal health and prenatal environmental exposure factors on tooth development]. AB - Odontogenesis is a consequence of a complex series of reciprocal signal interactions between odontogenic epithelium and neural crest-derived odontotgenic mesenchyme. These interactions result from a complex interplay of genetic and environmental factors. Given that a fetus develops in the mother, maternal health and environmental exposures have a great influence on tooth development. In this review, we focused on the key issues in the developmental defects of teeth induced by various types of maternal environmental factors, including environmental endocrine disruptors, joint action of two or more chemical exposures, and maternal health status. This review also discussed the adverse effects of maternal environmental factors on tooth development. These effects include enamel developmental defects, molar incisor hypomineralization, dental fluorosis, hyperdontia and hypodontia. Overall, this review provides a theoretical basis for the prevention of tooth defects in early life, assessment of risks from developmental tooth defects, and advancement of pediatric oral health management. PMID- 28853515 TI - [Clinical application of mandibular overdenture supported by a two-implant and interforaminal bar in an edentulous atrophic mandible]. AB - Implant-overdenture supported by an interforaminal bar provides stability and is effective in an edentulous atrophic mandible. However, using this attachment requires precise planning from the restorative and surgical aspects to ensure a satisfying outcome. Consdering the feature and space requirements for bar attachment, this article establishes a clinical protocol for a two-implant retained overdenture on the mandible. In this study, a case of mandibular edentulism was considered to illustrate this protocol and provide a reference for clinical practice. PMID- 28853516 TI - [Intentional replantation for the treatment of palatal radicular groove with endo periodontal lesion in the maxillary lateral incisor: a case report]. AB - Palatal radicular groove leads to severe endo-periodontal lesion in lateral incisors. The groove occurs on the labial and lingual root surfaces, while the localized periodontal pocket develops along the lingual groove length. The complicated root canal system, extensively destroyed bone lamella, and persistent fistula pose a challenge for root canal therapy, tooth retention, and thorough infection control inside and outside of the root canal. Combining microscopic root canal therapy with intentional replantation and nano-biomaterial application facilitates infection control, tooth retention, and formation of newly periodontal attachment. PMID- 28853517 TI - HIV, violence, blame and shame: pathways of risk to internalized HIV stigma among South African adolescents living with HIV. AB - INTRODUCTION: Internalized HIV stigma is a key risk factor for negative outcomes amongst adolescents living with HIV (ALHIV), including non-adherence to anti retroviral treatment, loss-to-follow-up and morbidity. This study tested a theoretical model of multi-level risk pathways to internalized HIV stigma among South African ALHIV. METHODS: From 2013 to 2015, a survey using total population sampling of ALHIV who had ever initiated anti-retroviral treatment (ART) in 53 public health facilities in the Eastern Cape, South Africa was conducted. Community-tracing ensured inclusion of ALHIV who were defaulting from ART or lost to follow-up. 90.1% of eligible ALHIV were interviewed (n = 1060, 55% female, mean age = 13.8, 21% living in rural locations). HIV stigma mechanisms (internalized, enacted, and anticipated), HIV-related disability, violence victimization (physical, emotional, sexual abuse, bullying victimization) were assessed using well-validated self-report measures. Structural equation modelling was used to test a theoretically informed model of risk pathways from HIV-related disability to internalized HIV stigma. The model controlled for age, gender and urban/rural address. RESULTS: Prevalence of internalized HIV stigma was 26.5%. As hypothesized, significant associations between internalized stigma and anticipated stigma, as well as depression were obtained. Unexpectedly, HIV related disability, victimization, and enacted stigma were not directly associated with internalized stigma. Instead significant pathways were identified via anticipated HIV stigma and depression. The model fitted the data well (RMSEA = .023; CFI = .94; TLI = .95; WRMR = 1.070). CONCLUSIONS: These findings highlight the complicated nature of internalized HIV stigma. Whilst it is seemingly a psychological process, indirect pathways suggest multi-level mechanisms leading to internalized HIV stigma. Findings suggest that protection from violence within homes, communities and schools may interrupt risk pathways from HIV-related health problems to psychological distress and internalized HIV stigma. This highlights the potential for interventions that do not explicitly target adolescents living with HIV but are sensitive to their needs. PMID- 28853519 TI - Corrigendum. PMID- 28853518 TI - Early virological response to HIV treatment: can we predict who is likely to experience subsequent treatment failure? Results from an observational cohort study, London, UK. AB - INTRODUCTION: For people living with HIV, the first antiretroviral treatment (ART) regimen offers the best chance for a good virological response. Early identification of those unlikely to respond to first-line ART could enable timely intervention and increase chances of a good initial treatment response. In this study we assess the extent to which the HIV RNA viral load (VL) at 1 and 3 months is predictive of first-line treatment outcome at 6 months. Methods All previously ART-naive individuals starting ART at two London centres since 2000 with baseline (-180 to 3 days) VL >500 c/mL had a VL measurement between 6 and 12 months after starting ART, and at least one at month 1 (4-60 days) or month 3 (61-120 days) were included. Lack of treatment response was defined as (i) VL >200 copies/mL at 6 months or (ii) VL >200 copies/mL at 6 months or simultaneous switch in drugs from at least two different drug classes before 6 months. The association with VL measurements at 1 and 3 months post-ART; change from pre-ART in these values; and CD4 count measurements at 1 and 3 months were assessed using logistic regression models. The relative fit of the models was compared using the Akaike information criterion (AIC). RESULTS: A total of 198 out of 3258 individuals (6%) experienced lack of treatment response at 6 months (definition i), increasing to 511 (16%) for definition (ii). Those with a 1-month (day 4-60 window) VL of <1000, 1000 9999, 10,000-99,999 and >100,000 copies/ml had a 4%, 8%, 23% and 24% chance, respectively, of subsequently experiencing treatment non-response at 6 months (definition (i)). When considering the 3-month (day 61-120 window) VL, the chances of subsequently experiencing treatment non-response were, respectively, 3%, 25%, 67% and 75%. Results were similar for definition (ii). CONCLUSIONS: Whilst 3-month VL provides good discrimination between low and high risk of treatment failure, 1-month VL does not. Presence of a VL >10,000 copies/ml after 3 months of ART is a cutoff above which individuals are at a sufficiently higher risk of non-response that they may be considered for intervention. PMID- 28853520 TI - [ANTI-N-METHYL-D-ASPARTATE (NMDA) ENCEPHALITIS: THE ISRAELI PEDIATRIC MULTI CENTER EXPERIENCE]. AB - INTRODUCTION: Anti-N-methyl-D-aspartate (NMDA) encephalitis is a disorder characterized by acute neuro-psychiatric symptoms, appearing mostly after a recent febrile disease, with a gradual progressive course, associated with laboratory or radiologic evidence of active inflammation. Many of the patients will present with a continuous neuro-cognitive disorder which could lead to major morbidity and even mortality. It was recently reported that this disorder can present at childhood as a primary disease or as a secondary complication of herpes simplex infection. Early diagnosis and treatment have significantly improved the patients' prognosis and prevented chronic complications. We will present six pediatric patients at ages 1-14 years, followed from 2011-2014 in Schneider Children's Medical Center and Assaf Harofeh Medical Center due to acute encephalitis, with a clinical course under suspicion for anti-NMDA encephalitis. The article will review the clinical and diagnostic dilemmas and suggested guidelines. Pediatricians should be aware of this new emerging syndrome. PMID- 28853521 TI - [HEMISPHEROTOMY FOR TREATMENT OF REFRACTORY EPILEPSY IN CHILDREN]. AB - INTRODUCTION: Hemispherotomies are an extreme treatment for epilepsy. As opposed to focal resections, in hemispherotomies the entire hemisphere is disconnected from the remaining nervous system, including functional regions and fibers. Despite this, hemispherotomy is recommended for certain indications, with good epilepsy and functional outcomes. AIMS: To summarize the experience of hemispherotomy performed at a tertiary national center. METHODS: A retrospective study was conducted including all patients operated on between 2001 and 2014. Patients were 10 months to 18 years old at the time of surgery, and all underwent hemispherotomy for treatment of refractory epilepsy. RESULTS: A total of 14 children were included in the study. The main etiology for epilepsy included Rasmussen encephalitis (5), hemispheral cortical dysplasia (3), and ischemic stroke (2). Six children had previous surgeries. All children underwent peri insular hemispherotomy. One child lives abroad and was lost to follow-up. Of the remaining 13: 9 are seizure-free since surgery, 3 have rare seizures and 1 has frequent seizures (however, less than preoperatively). The average number of antiepileptic drugs was reduced by about 50%. All children had neurological deficits similar to their preoperative status, or had gradual improvement in motor and cognitive/linguistic skills. There was one complication - an infection that had no neurological impact, but necessitated surgical wound revision. CONCLUSIONS: Hemispherotomy changes the natural history of refractory hemispheric epilepsy. The epilepsy and functional outcomes are good. DISCUSSION: Hemispherotomy surgery is part of the treatment options for children with refractory hemispheric epilepsy. Despite the hemispheric disconnection, functional outcome is encouraging. The degree of functional outcome depends on preoperative neurological injury, thus it is important not to delay surgery if indicated. PMID- 28853522 TI - [THE EFFECT OF VITAMIN D ON THE EXPRESSION OF ADAMTS13 IN CULTURED ENDOTHELIAL CELLS EXPOSED TO A DIABETIC-LIKE ENVIRONMENT]. AB - BACKGROUND: Diabetes mellitus (DM) is the leading cause of end-stage kidney disease. Inflammation, fibrosis, coagulability and oxidative stress exacerbate kidney disease. The glycoprotein, Von Willebrand Factor (VWF) has a crucial role in platelet thrombus formation. The enzyme ADAMTS13 is responsible for VWF cleavage. Both are important in the interface between diabetic nephropathy, hypercoagulability and atherosclerotic cardiovascular disease. Vitamin D inhibits endothelial proliferation, blunts angiogenesis and is a cardioprotective agent. This study evaluated the role of vitamin D on ADAMTS13 activity in human umbilical vein endothelial cells (HUVEC) exposed to a diabetic-like environment. METHODS: HUVEC were stimulated with 200ug/ul AGE-HSA, 250mg/dl glucose, and 10 10mol/l vitamin D for 24 hours. Western blot and ELISA techniques were used to determine ADAMTS13 protein expression and IL6 and IL8 protein secretion. RESULTS: ADAMTS13 protein expression decreased and IL6 and IL8 protein secretion increased in HUVEC exposed to a diabetic-like environment. The addition of vitamin D significantly down-regulated IL6 and IL8 secretion and up-regulated ADAMST13 expression. CONCLUSIONS: Decreased ADAMTS13 expression in HUVEC exposed to a diabetic-like environment may contribute to the pathogenesis of hypercoagulability observed in DM. Normalization of ADAMTS13 by vitamin D may contribute to improvement in hypercoagulability. PMID- 28853523 TI - [NON-VALVULAR ATRIAL FIBRILLATION AT THE DEPARTMENT OF INTERNAL MEDICINE]. AB - BACKGROUND: Most of the data on atrial fibrillation is known from registries including mostly ambulatory patients. Less is known about atrial fibrillation among patients hospitalized at departments of medicine. OBJECTIVES: To explore the characteristics of atrial fibrillation in patients hospitalized at the departments of medicine, and their management during hospitalization, focusing on anticoagulation treatment. METHODS: A retrospective study was conducted based on reviewing patient charts at the departments of medicine of a tertiary medical center. Inclusion criteria: patients with non-valvular atrial fibrillation hospitalized during a period of 3 months. The following parameters were collected: age, gender, co-morbidities, cause of index admission, mean hemoglobin, platelets and creatinine levels, CHA2DS2-VASc and HAS-BLED scores and INR levels; rhythm/rate control strategy, anticoagulation and anti-platelets treatments were documented at admission and discharge. RESULTS: The study group consisted of 404 subjects, who had 735 admissions. Mean age was 76+/-12 years, half were male. The most common co-morbidity was hypertension (73%). Most patients (90%) were diagnosed with atrial fibrillation previous to current admissions, and were at high risk for embolization (CHA2DS2-Vasc >=3 - 86%) and bleeding (HASBLED >= 3 -79%). On admission, in three quarters of the cases patients with established atrial fibrillation were treated by rate control, 45% were not treated by anticoagulants. The therapeutic strategy of rate control or anticoagulation treatment did not change significantly during hospitalization. The rate of anticoagulation treatment did not differ significantly between CHA2DS2-VASc levels. The most predictive parameter for anticoagulants treatment at discharge was previous anticoagulation treatment. CONCLUSIONS: The effect of hospitalization on atrial fibrillation treatment policy is poor. Future registries of hospitalized patients with atrial fibrillation, as well as therapeutic interventions are needed. PMID- 28853524 TI - [CEREBRAL PALSY AT THE AGE OF MODERN OBSTETRICS: ANCIENT BELIEFS VERSUS SOLID FACTS]. AB - INTRODUCTION: For many decades the conventional wisdom was that the sole etiology for cerebral palsy is difficult delivery. The adverse outcome associated with cerebral palsy was intuitively related to complications during labor. The blame, unjustifiably and recklessly, was placed on devoted physicians and midwifes. This wrongful accusation, that one may describe as "scientific blood libel" is unprecedented in medicine. In his article, Professor Blickstein scrupulously revises the scientific evidence connecting birth asphyxia and cerebral palsy and refutes the common belief that the only cause for cerebral palsy is complicated delivery. Indeed, meticulous review of the scientific data suggest that the overwhelming majority of cerebral palsy cases has nothing to do with the process of labor. PMID- 28853525 TI - [PRINCIPLES OF CAUSALITY BETWEEN PERIPARTUM EVENTS AND CEREBRAL PALSY]. AB - INTRODUCTION: Understanding the intrapartum development of cerebral palsy (CP) may improve obstetrical management, would decrease the incidence of CP, and would help the court in judging whether CP is a result of negligence. In 1999, the Australian task force, and in 2003 the American task force, published their consensus regarding the criteria to establish intrapartum development of CP (recently reaffirmed by the American task force). The rationale is that CP is the end product of a continuum starting with an intrapartum hypoxic event that continues with the birth of an asphyxiated neonate, that exhibit specific neurological manifestations, and ends with a specific type of CP. The more studies that are performed over time on the consensus criteria, the more valid they appear to be. PMID- 28853526 TI - [DO WE HAVE MEDICAL MEASURES THAT ATTEST TO THE EFFECT OF SPIRITUAL CARE IN TIME OF ILLNESS?] AB - INTRODUCTION: Everyone has spiritual resources that generally serve them well, and in times of struggle, part of people's suffering is spiritual. Tending to patients' "whole pain" must include their spiritual pain. Studies from Israel and worldwide found that approximately one-third of advanced cancer patients suffer spiritual distress. In addition, over half of cancer patients attach great importance to feeling hopeful, coping peacefully, and finding meaning in times of illness. Studies found a significant predictive correlation among advanced cancer patients between spiritual wellbeing and despair, desire to die, and suicidal ideation, and a longitudinal connection among patients with heart disease between survival rates and spiritual wellbeing. Spiritual care is provided in thousands of hospitals worldwide, and in limited fashion in over ten hospitals in Israel. By the nature of spiritual care, it is difficult to clinically measure its full impact on and contribution to patients and family members. Nonetheless, studies have found a correlation between a hospital's providing spiritual care, lowered mortality rates in the hospital and increased use of hospice care. Receipt of spiritual care correlated with higher quality of life at the end of life. When the staff, including the spiritual care provider, attends to patients' spirituality, studies find a substantial reduction in aggressive medical interventions at the end of life. In recent years, the Ministry of Health has further emphasized the need to develop hospital-based palliative care teams. As part of this effort, we must consider the integration of spiritual care providers as full members of that team. PMID- 28853527 TI - [LOW GRADE OVARIAN CANCER]. AB - INTRODUCTION: According to the new and reproducible grading system of the MD Anderson Cancer Center (MDACC), low grade serous cancer (LGSC) differs greatly from the commonly known high grade serous cancer (HGSC). Pathology speaking, LGSC has less mitotic index; the grade of nuclear atypia is low to intermediate. Genetically speaking, these tumors tend to show mutation in the mitogen-activated protein kinase (MAPK) pathway, mainly in the KRAS and BRAF genes, resulting in uncontrolled proliferation; however, it seems that the presence of this mutation might be related to a better prognosis compared to their absence. The presenting symptoms and spread is similar to HGSC, such as the elevated Ca-125 and the advanced stage at the presentation. The rate of proliferation, on one hand affects the prognosis and therefore, although it tends to present in advanced stages such as HGSC, the prognosis is better. On the other hand, low proliferation might be the reason for the relative decrease in the sensitivity to the common chemotherapy given in HGSC. Treatment strategy, as well. is similar to HGSC consisting of debulking surgery followed by or after chemotherapy. Molecular and pathology studies confirm borderline tumor might be a precursor of some of LGSC, since it shares similar mutation pathways seen in LGSC. Those pathways are targets for newer chemotherapy agents, currently under phase II and III promising trials. PMID- 28853528 TI - [NEURO-ONCOLOGY A NEW FIELD IN DAVIDOFF CANCER CENTER AT RABIN MEDICAL CENTER]. AB - INTRODUCTION: Neuro-oncology is a subspecialty attracting physicians from medical disciplines such as neurology, neurosurgery, pediatrics, oncology, and radiotherapy. It deals with diagnosis and management of primary brain tumors, as well as metastatic and non-metastatic neurological manifestations that frequently affect cancer patients including brain metastases, paraneoplastic syndromes and neurological complications of cancer treatment. A neuro-oncology unit was established in Davidoff Cancer Center at Rabin Medical Center. It provides a multidisciplinary team approach for management of brain tumors and services, such as expert outpatient clinics and inpatient consultations for the departments of oncology, hematology, bone marrow transplantation and other departments in the Rabin Medical Center. In addition, expert consultation is frequently provided to other hospitals that treat cancer patients with neurological manifestations. The medical disciplines that closely collaborate for the daily management of neuro oncology patients include radiotherapy, hematology, oncology, neuro-surgery, neuro-radiology and neuro-pathology. The neuro-oncology center is also involved in clinical and laboratory research conducted in collaboration with researchers in Israel and abroad. The new service contributes substantially to the improved care of cancer patients and to the advance of research topics in the field of neuro-oncology. PMID- 28853529 TI - [ARTIFICIAL STONE SILICOSIS: THE ISRAEL EPIDEMIC, CURRENT VIEW]. AB - INTRODUCTION: Silicosis is a fibrotic occupational pulmonary disease that results from over-exposure to crystalline silica-containing dust. Silicosis is a progressive disease which can often lead to advanced respiratory failure, the need for lung transplantation or death. There are a number of silicosis associated diseases which constitute diagnostic challenges, as well as contribute to further morbidity. Although preventable through appropriate workplace precautions, silicosis not only remains an endemic disease worldwide, it has also manifested a resurgence of epidemic disease in recent years, as seen in the inclining prevalence of disease in Israel. This review aims to present the silicosis epidemic in Israel, its causes and the ways to prevent further outbreaks of disease. We describe clinical and radiological imaging features, associated diseases and differential diagnosis for the purpose of raising awareness of the disease among medical professionals thus promoting early detection and diagnosis. PMID- 28853530 TI - [NOVELTIES IN PERICARDIAL DISEASES: A FOCUSED REVIEW OF THE LATEST EUROPEAN GUIDELINES]. AB - INTRODUCTION: More than a decade has elapsed since the first international guidelines on the diagnosis and management of pericardial diseases were issued by the European Society of Cardiology (ESC) in 2004. Since then, significant advances have been made in this field due to several randomized double blinded controlled trials and also retrospective, as well as prospective, cohort studies that were conducted during this time frame. However, despite the amount of knowledge that has been accumulated, only Spanish and Brazilian national societies of cardiology have so far published national guidelines on the management of pericardial diseases. No official guidelines were issued by the American College of Cardiology/American Heart Association. Therefore, a demand for an updated document has become inevitable in order to summarize all new data and translate them into a set of recommendations which could be implemented in clinical practice. For this purpose, the new guidelines, focused on the clinical management of patients with pericardial diseases were issued by the ESC in 2015. The full text of the 2015 guidelines reflects the progress that has been made so far: the manuscript contains 9 sections (excluding appendix and references), nearly 30 second-level subsections and covers 44 pages. Several new chapters are introduced for the first time in the current guidelines, as compared with the previous version. Therefore, the aim of this review is to summarize and emphasize the most clinically relevant new aspects of the current guidelines as compared with its previous version published in 2004. PMID- 28853531 TI - [SOCIAL MEDIA USE AND THE DOCTOR-PATIENT RELATIONSHIP - IS PROGRESSION REALLY LEADING US FORWARD?] AB - INTRODUCTION: Lately, social media have become a pivotal aspect in our communication with the world around us. It seems that it is only a matter of time until it will take a major role in the communication with our patients. Before we hand ourselves over to this new technology, it is necessary to examine the consequences that this media will have on this interaction and the changes that follow the utilization of this tool. This paper deals with the basic conflict that stands between the principles of medical practice and the nature of social media, focusing on the importance of boundaries, empathy and physical contact in the doctor-patient interaction. Different aspects of social media in the doctor patient relationship are discussed, raising the question of whether this progress in technology really leads to a better therapeutic interaction. PMID- 28853532 TI - [NOTES FROM A SIX MONTHS VOLUNTEER MISSION AS MEDICAL STAFF IN A DISTRICT HOSPITAL IN UGANDA]. AB - INTRODUCTION: In December 2014 my husband and I flew for a stay of six months in Uganda. We went there in order to volunteer in the district hospital of Kiboga, one of the most impoverished districts of this poverty stricken country. A district in which over 60% of the population lives off less than a dollar and twenty five cents a day, in which the average life expectancy is 46.7 years (9.1 years lower than the national average expectancy). Kiboga's district hospital serves the 300,000 residents of the district, of whom 20,000 live in the district capital, while the rest are mainly farmers and cattle keepers, scattered in small villages that have limited and weather-dependent access. The hospital houses 120 beds, which are divided into four wards (maternity, pediatric, male and female), and is manned routinely by one on-call local physician, who (when present) is almost exclusively occupied by emergency cesarean sections. Therefore, the majority of hospitalized patients are not inspected by a doctor at any point of their stay. The hospital functions with no running water and in the absence of a reliable power supply. The nursing staff, composed largely of people with limited or no training, is always desperately understaffed, and many of the means needed for a patient's stay (starting with a bed pan and linens and ending with many of the medications prescribed) are not supplied by the hospital. Perhaps it would have been appropriate to continue by describing unsettling data about the health infrastructure in Kiboga (such as the fact that infant mortality rate is a staggering 15%, or that nearly 10% of the districts population have HIV), however, it appears to me that it would be more educating to learn from the story of the patients we encountered. PMID- 28853533 TI - [THE IMPORTANCE OF LEAD AVR IN THE EVALUATION OF AN ECG STRIP]. AB - INTRODUCTION: Over the years, the aVR lead has been overlooked by clinicians while observing a normal 12-lead ECG (electrocardiogram). A positive P-QRS complex in the aVR lead should raise prompt suspicion for either a congenital heart malrotation or a lead misplacement. In this article we present a case of an asymptomatic patient and a pathological ECG strip displaying ST elevations and a positive QRS in the aVR lead. A follow-up ECG was performed in the emergency department, and revealed a normal sinus rhythm with no abnormalities indicating acute ischemia. Through this case, we demonstrated the importance of proper examination of the aVR lead and its role in preventing unnecessary treatments. PMID- 28853534 TI - [Cataract and glaucoma: what is the appropriate terminology in Hebrew?] PMID- 28853537 TI - Is digital technology sufficient to counteract sedentary behavior? PMID- 28853538 TI - Poly High Internal Phase Emulsion for the Immobilization of Chemical Warfare Agents. AB - We report a facile method for the absorption (characterized by the weight/weight swelling degree, Q) of a variety of chemical warfare agents (CWAs); including sulfur mustard (HD) (Q = 40) and V-series (VM, VX, i-Bu-VX, n-Bu-VX) of nerve agents (Q >= 45) and a simulant, methyl benzoate (Q = 55), through the use of a poly(styrene-co-vinyl benzyl chloride-co-divinylbenzene) lightly cross-linked poly high internal phase emulsion (polyHIPE). By varying the vinyl benzyl chloride (VBC) content and the volume of the internal phase of the precursor emulsion it is demonstrated that absorption is facilitated both by the swelling of the polymer and the uptake of liquid in the pores. In particular the sample prepared from a 95% internal emulsion water content showed rapid swelling (<5 min to total absorption) and the ability to swell both from a monolithic state and from a compressed state, making these systems ideal practical candidates for the rapid immobilization of CWAs. PMID- 28853539 TI - Immuno-Matrix-Assisted Laser Desorption/Ionization Assays for Quantifying AKT1 and AKT2 in Breast and Colorectal Cancer Cell Lines and Tumors. AB - The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway is one of the most commonly dysregulated signaling pathways that is linked to cancer development and progression, and its quantitative protein analysis holds the promise to facilitate patient stratification for targeted therapies. Whereas immunohistochemistry (IHC) and immunoassays are routinely used for clinical analysis of signaling pathways, mass spectrometry-based approaches such as liquid chromatography/electrospray ionization multiple reaction monitoring mass spectrometry (LC/ESI-MRM-MS) are more commonly used in clinical research. Both technologies have certain disadvantages, namely, the nonspecificity of IHC and immunoassays, and potentially long analysis times per sample of LC/ESI-MRM-MS. To create a robust, fast, and sensitive protein quantification tool, we developed immuno-matrix assisted laser desorption/ionization (iMALDI) assays with automated liquid handling. The assays are able to quantify AKT1 and AKT2 from breast cancer and colon cancer cell lines and flash-frozen tumor lysates with a linear range of 0.05-2.0 fmol/MUg of total lysate protein and with coefficients of variation < 15%. Compared to other mass spectrometric methods, the developed assays require less sample per analysis-only 25 MUg of total protein-and are therefore suitable for analysis of needle biopsies. Furthermore, the presented iMALDI technique is the first MS-based method for absolute quantitation of AKT peptides from cancer tissues. This study demonstrates the suitability of iMALDI for low limit-of detection and reproducible quantitation of signaling pathway members using a benchtop MALDI mass spectrometer within approximately 6-7 h. PMID- 28853540 TI - Size-Controllable Gold Nanopores with High SERS Activity. AB - Nanopore structures have been successfully employed in next-generation DNA sequencing. For more complicated protein which normally contains 20 different amino acids, identifying the fluctuation of ionic current caused by different amino acids appears inadequate for protein sequencing. Therefore, it is highly desirable to develop size-controllable nanopores with optical activity that can provide additional structural information. Herein, we discovered the novel nanopore properties of the self-assembled ultramicroelectrodes originally developed by Bard and co-workers. Using a slightly modified method, the self assembly of 7 +/- 1 nm gold nanoparticles (AuNPs) can be precisely controlled to form a gold nanoporous sphere (GPS) on the tip of a glass capillary. Different dithiol linker molecules (1,3-propanedithiol, C3; 1,6-hexanedithiol, C6; and 1,9 nonanedithiol, C9) reproducibly led to rather similar nanopore sizes (5.07 +/- 0.02, 5.13 +/- 0.02, and 5.25 +/- 0.01 nm), respectively. The GPS nanostructures were found to exhibit high ionic current rectification as well as surface enhanced Raman scattering (SERS) activity due to the presence of nanopores and numerous "hot spots" among the cross-linked AuNPs on the surface of GPS. The rectification effect of the small nanopores was observed even under high concentration of electrolyte (290 mM), along with SERS enhancement factors well above 1 * 105. The GPS nanostructures were successfully applied for SERS-based detection of glutathione from a single HeLa cell. PMID- 28853541 TI - Highly Catalytic Pt Nanoparticles Grown in Two-Dimensional Conducting Polymers at the Air-Water Interface. AB - We report a new approach to the synthesis of uniform, high areal density Pt nanocrystals supported by conducting polymers. The key strategy is the use of ice templated, two-dimensional polyaniline nanosheets at the air-water interface as a platform for expediting Pt nucleation. Highly crystalline Pt nanoparticles with a narrow size distribution of 2.7 +/- 0.3 nm and a high electrochemically active surface area of 94.57 m2 g-1 were obtained. Pt NPs were strongly anchored to the polyaniline nanosheets, and demonstrated high current densities, good durability for the methanol oxidation reaction, and excellent carbon monoxide tolerance, all of which are unprecedented. The idea established in this study could be applied to the production of a wide range of other catalysts with enhanced activities. PMID- 28853542 TI - 1D-Reactor Decentralized MDA for Uniform and Accurate Whole Genome Amplification. AB - Multiple displacement amplification (MDA), a most popular isothermal whole genome amplification (WGA) method, suffers the major hurdle of highly uneven amplification, thus, leading to many problems in approaching biological applications related to copy-number assessment. In addition to the optimization of reagents and conditions, complete physical separation of the entire reaction system into numerous tiny chambers or droplets using microfluidic devices, has been proven efficient to mitigate this amplifying bias in recent works. Here, we present another MDA advance, microchannel MDA (MUcMDA), which decentralizes MDA reagents throughout a one-dimensional slender tube. Due to the double effect from soft partition of high molecular-weight DNA molecules and less-limited diffusion of small particles, MUcMDA is shown to be significantly effective at improving the amplification uniformity, which enables us to accurately detect single nucleotide variants (SNVs) with higher efficiency and sensitivity. More importantly, this straightforward method requires neither customized instruments nor complicated operations, making it a ready-to-use technique in almost all biological laboratories. PMID- 28853543 TI - A Sandwiched/Cracked Flexible Film for Multithermal Monitoring and Switching Devices. AB - Polydimethylsiloxane (PDMS)-based flexible films have substantiated advantages in various sensing applications. Here, we demonstrate the highly sensitive and programmable thermal-sensing capability (thermal index, B, up to 126 * 103 K) of flexible films with tunable sandwiched microstructures (PDMS/cracked single walled carbon nanotube (SWCNT) film/PDMS) when a thermal stimulus is applied. We found that this excellent performance results from the following features of the film's structural and material design: (1) the sandwiched structure allows the film to switch from a three-dimensional to a two-dimensional in-plane deformation and (2) the stiffness of the SWCNT film is decreased by introducing microcracks that make deformation easy and that promote the macroscopic piezoresistive behavior of SWCNT crack islands and the microscopic piezoresistive behavior of SWCNT bundles. The PDMS layer is characterized by a high coefficient of thermal expansion (alpha = 310 * 10-6 K-1) and low stiffness (~2 MPa) that allow for greater flexibility and higher temperature sensitivity. We determined the efficacy of our sandwiched, cracked, flexible films in monitoring and switching flexible devices when subjected to various stimuli, including thermal conduction, thermal radiation, and light radiation. PMID- 28853544 TI - Tuning Antibacterial Activity of Cyclodextrin-Attached Cationic Ammonium Surfactants by a Supramolecular Approach. AB - Two beta-cyclodextrin-attached cationic ammonium surfactants bearing a dodecyl chain (APDB) and a hexadecyl chain (APCB) were synthesized to reduce the cytotoxicity of cationic surfactants to mammalian cells and endow the surfactants with host-guest recognition sites, and three kinds of guest molecules were utilized to improve the antibacterial ability of APDB and APCB via host-guest interaction by regulating the electrostatic or hydrophobic interaction of APDB or APCB with bacteria. The guest molecules include AD-NH3+ carrying one positive charge, DB with a benzene ring group and a dodecyl chain, and single chain cationic ammonium surfactant DTAB or CTAB. Either AD-NH3+ or DB increases the killing efficacy of APCB against S. aureus at 50 MUM from 59% to about 75%, while DTAB or CTAB improves the killing efficacy of APCB to more than 90%. In particular, only a very small amount CTAB can improve the antibacterial activity of APCB to a very high level, but keeps very low cytotoxicity. However, the mixtures of the guest molecules with APDB are devoid of any activity against S. aureus. This is mainly attributed to the fact that APCB and its mixtures with the guest molecules form 100-200 nm spherical aggregates, while the mixtures of APDB with the guest molecules cannot form aggregates at lower concentration. It is revealed that the three kinds of guest molecules trapped in the APCB spherical aggregates lead to diverse interaction modes of the APCB spherical aggregates with S. aureus, accounting for the different killing efficacy of the APCB/guest molecule mixtures. This supramolecular strategy provides an effective approach for the construction of highly efficient antibacterial agents with low cytotoxicity. PMID- 28853545 TI - Ratiometric Luminescent Detection of Organic Amines Due to the Induced Lactam Lactim Tautomerization of Organic Linker in a Metal-Organic Framework. AB - Here we demonstrate that a fluorescent benzothiadiazole (BTD)-conjugated terphenyldicarboxylate (TPDC) linker (denoted as H2-ostpdc) has been hybridized by a quinoxaline-2,3-(1H,4H)-dione (QD) moiety possessing lactam-lactim tautomerism, which was further integrated into a robust and porous UiO-68 type zirconium metal-organic framework (MOF UiO-68-osdm) by utilizing the mixed two dicarboxylate struts with the same ligand lengths. The resultant MOF UiO-68-osdm can work as a ratiometric luminescent sensor for visual and selective detection of alkyl amines. Furthermore, it can discriminate secondary alkylamines from other type amine species. PMID- 28853546 TI - Highly Sensitive, Uniform, and Reproducible Surface-Enhanced Raman Spectroscopy Substrate with Nanometer-Scale Quasi-periodic Nanostructures. AB - We introduce a simple and cost-effective approach for fabrication of effective surface-enhanced Raman spectroscopy (SERS) substrates. It is shown that the as fabricated substrates show excellent SERS effects in various probe molecules with high sensitivity, that is, picomolar level detection, and also good reliability. With a SERS enhancement factor beyond 108 and excellent reproducibility (deviation less than 5%) of signal intensity, the fabrication of the SERS substrate is realized on a four-inch wafer and proven to be effective in pesticide residue detection. The SERS substrate is realized first through the fabrication of quasi-periodic nanostructured silicon with dimension features in tens of nanometers using superaligned carbon nanotubes networks as an etching mask, after which a large amount of hot spots with nanometer gaps are formed through deposition of a gold film. With rigorous nanostructure design, the enhanced performance of electromagnetic field distribution for nanostructures is optimized. With the advantage of cost-effective large-area preparation, it is believed that the as-fabricated SERS substrate could be used in a wide variety of actual applications where detection of trace amounts is necessary. PMID- 28853547 TI - A Supramolecular Nanofiber-Based Passive Memory Device for Remembering Past Humidity. AB - Memorizing the magnitude of a physical parameter such as relative humidity in a consignment may be useful for maintaining recommended conditions over a period of time. In relation to cost and energy considerations, it is important that the memorizing device works in the unpowered passive state. In this article, we report the fabrication of a humidity-responsive device that can memorize the humidity condition it had experienced while being unpowered. The device makes use of supramolecular nanofibers obtained from the self-assembly of donor-acceptor (D A) molecules, coronene tetracarboxylate salt (CS) and dodecyl methyl viologen (DMV), respectively, from aqueous medium. The fibers, while being highly sensitive to humidity, tend to develop electrically induced disorder under constant voltage, leading to increased resistance with time. The conducting state can be regained via self-assembly by exposing the device to humidity in the absence of applied voltage, the extent of recovery depending on the magnitude of the humidity applied under no bias. This nature of the fibers has been exploited in reading the humidity memory state, which interestingly is independent of the lapsed time since the humidity exposure as well as the duration of exposure. Importantly, the device is capable of differentiating the profiles of varying humidity conditions from its memory. The device finds use in applications requiring stringent condition monitoring. PMID- 28853548 TI - Facile Construction of Robust Multilayered PEG Films on Polydopamine-Coated Solid Substrates for Marine Antifouling Applications. AB - We report an effective and versatile approach to control marine fouling on artificial surfaces based on specific chemical interactions found in marine mussels. The approach consists of mussel-inspired polydopamine coating, spin coating-assisted deposition of poly(ethylene glycol) (PEG) catechols, and their cross-linking via catechol-Fe3+-catechol interactions. Using this approach, multilayered PEG films that were highly resistant to marine diatom adhesion were successfully constructed on various substrates, such as stainless steel, nylon, titanium oxide, and silicon oxide. We believe that our results will provide a basis for the construction of a marine antifouling agent that can be applied by a large variety of industries owing to its applicability to different types of substrates and stability under marine environments. PMID- 28853550 TI - One-Pot Aqueous Synthesis of Nucleoside-Templated Fluorescent Copper Nanoclusters and Their Application for Discrimination of Nucleosides. AB - A facile, one-pot synthetic method has been proposed to prepare water-soluble fluorescent copper nanoclusters (CuNCs) templated by nucleosides. The nucleoside templated fluorescent CuNCs were further characterized by using various analytical techniques, such as transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and fluorescence spectroscopy. The role of various reactants such as ascorbic acid, nucleoside, and citrate buffer in the synthesis process of fluorescent CuNCs was explored. The results showed that nucleoside and ascorbic acid were very likey to respectively act as a stabilizer and a reductant to form nanoclusters, and citrate buffer acted as both pH regulator solution and a reducing agent. The fluorescence spectra of various nucleoside-templated CuNCs were finally combined with multivariate chemometrics analysis for discrimination of different nucleosides. PMID- 28853549 TI - Ionic Strength Sensing in Living Cells. AB - Knowledge of the ionic strength in cells is required to understand the in vivo biochemistry of the charged biomacromolecules. Here, we present the first sensors to determine the ionic strength in living cells, by designing protein probes based on Forster resonance energy transfer (FRET). These probes allow observation of spatiotemporal changes in the ionic strength on the single-cell level. PMID- 28853551 TI - Noticeable Role of TFSI- Anion in the Carbon Cathode Degradation of Li-O2 Cells. AB - In this work we address the phenomena at the basis of the performance loss in a Li-O2 cell operating in the presence of a lithium bis(trifluoromethanesulfonyl)imide (LiTFSI)/tetraethylene glycol dimethyl ether (TEGDME) salt/solvent couple and a porous carbonaceous cathode. The cell was discharged/charged applying both voltage and capacity limits, and the effects of repeated galvanostatic cycling were addressed. The ex situ characterization of carbonaceous cathodes corresponding to different cutoff voltages was based on vibrational spectroscopies, transmission electron microscopy, and X-ray photoelectron spectroscopy. The reversible precipitation/decomposition of undesired products deriving from degradation of both carbon cathode and ethereal solvent is pointed out within a single voltage limited (2.0-4.6 V) discharge/charge cycle, whereas their irreversible accumulation on the surface of the electrode results after 100 capacity limited cycles. At the same time, the presence of polar degradation products (carbonates and carboxylates) at the cathode surface is accompanied by the buildup of a surface electric potential gradient, as revealed by differential binding energy shifts resulting from C 1s photoelectron spectra. This effect, seldom reported for Li-ion batteries, is for the first time put in evidence for a Li-O2 cell. Furthermore, the use of TFSI- anion is shown to lead to carbonate-based degradation products not involving the formation of Li2CO3. The peculiar occurrence of such degradation phenomena are attributed to the intrinsic low-donor number characteristic of the TFSI- anion. PMID- 28853552 TI - Nanoscale Chemical Characterization of Solid-State Microbattery Stacks by Means of Auger Spectroscopy and Ion-Milling Cross Section Preparation. AB - The current sustained demand for "smart" and connected devices has created a need for more miniaturized power sources, hence for microbatteries. Lithium-ion or "lithium-free" all-solid-state thin-film batteries are adapted solutions to this issue. The capability to carry out spatially resolved chemical analysis is fundamental for the understanding of the operation in an all-solid-state microbattery. Classically cumbersome and not straightforward techniques as TEM/STEM/EELS and FIB preparation methods could be used to address this issue. The challenge in this work is to make the characterization of Li-based material possible by coupling ion-milling cross section preparation method and AES techniques to characterize the behavior of a LiCoO2 positive electrode in an all solid state microbattery. The surface chemistry of LiCoO2 has been studied before and after LiPON deposition. Modifications of the chemical environments characteristic of the positive electrode have been reported at different steps of the electrochemical process. An original qualitative and a semiquantitative analysis has been used in this work with the peak deconvolution method based on real, certified reference spectra to better understand the lithiation/delithiation process. This original coupling has demonstrated that a full study of the pristine, cycled, and post mortem positive electrode in a microbattery is also possible. The ion-milling preparation method allows access to a large area, and the resolution of Auger analysis is highly resolved in energy to separate the lithium and the cobalt signals in an accurate way. PMID- 28853553 TI - Highly Functionalized Tricyclic Oxazinanones via Pairwise Oxidative Dearomatization and N-Hydroxycarbamate Dehydrogenation: Molecular Diversity Inspired by Tetrodotoxin. AB - Benzenoids in principle represent attractive and abundant starting materials for the preparation of substituted cyclohexanes; however, the synthetic tools available for overcoming the considerable aromatic energies inherent to these building blocks limit the available product types. In this paper, we demonstrate access to heretofore unknown heterotricyclic structures by leveraging oxidative dearomatization of 2-hydroxymethyl phenols with concurrent N-hydroxycarbamate dehydrogenation using a common oxidant. The pairwise-generated, mutually reactive species then participate in a second stage acylnitroso Diels-Alder cycloaddition. The reaction chemistry of the derived [2.2.2]-oxazabicycles, bearing four orthogonal functional groups and three stereogenic centers, is shown to yield considerable diversity in downstream products. The methodology allows for the expeditious synthesis of a functionalized intermediate bearing structural and stereochemical features in common with the complex alkaloid tetrodotoxin. PMID- 28853554 TI - Endocannabinoid Interaction with Human FABP1: Impact of the T94A Variant. AB - Using recombinant human wild-type fatty acid binding protein 1 (WT FABP1 T94T) and a variant (FABP1 T94A) protein, fluorescence binding assays, and circular dichroism, it was shown for the first time that WT FABP1 and the T94A variant each have a single, relatively hydrophobic site for binding fluorescent NBD labeled analogues of N-arachidonoylethanolamide and 2-arachidonoylglycerol with high affinity. Most native N-acylethanolamides (NAEs) but only one 2 monoacylglycerol [i.e., 2-arachidonoylglycerol (2-AG)] displaced WT FABP1-bound fluorescently labeled endocannabinoids (ECs). While the T94A variant did not differ in affinity for AEA and most other NAEs, it exhibited a modestly higher affinity for OEA, as well as a higher affinity for 2-AG. Binding of AEA and 2-AG altered WT FABP1's secondary structure more extensively than any other previously examined ligand did. The T94A variant without a ligand was more susceptible to temperature-induced unfolding. While the T94A variant was much less sensitive to ligand (i.e., AEA or 2-AG)-induced conformational change, nevertheless binding of AEA and 2-AG significantly stabilized the T94A structure to thermal unfolding. These data provide the first evidence that ECs not only bind to but also alter the secondary structure of the human FABP1, with the latter markedly impacted by the T94A substitution, a variant strongly associated with hepatic accumulation of lipids and non-alcoholic fatty liver disease (NAFLD). Importantly, NAFLD has been associated with elevated hepatic levels of ECs and FABP1. PMID- 28853555 TI - Transmembrane Proteins: Amyloids Hidden in Plain Sight? PMID- 28853556 TI - Axial Ligand Field in D4d Coordination Symmetry: Magnetic Relaxation of Dy SMMs Perturbed by Counteranions. AB - A series of mononuclear DyIII complexes with the general formula [DyLz2(salicylaldehyde)2].X.solvent (Lz = 6-pyridin-2-yl[1,3,5]triazine-2,4 diamine; X = OH- (1.OH), Cl- (2.Cl), Br- (3.Br)) have been synthesized using mixed salicylaldehyde/pyridinyl-triazine ligands and discriminative counteranions. The DyIII ion in these three complexes resides in a similar D4d coordination geometry with counteranions perturbing the coordination environment and bond lengths and angles in the lattice. Magnetostructural studies reveal that the asymmetric distribution of salicylaldehyde/pyridinyl-triazine ligands and the presence of discriminative counteranions result in the coexistence of large anisotropy and quantum tunneling of magnetization. The magnetic anisotropy is dominated by the axial ligand field with short Dy-Osali distances and large ?Osali-Dy-Osali angles, while the quantum tunneling relaxation is probably dictated by the pi-pi stacking of the Lz ligands, which induces an axial constriction of the coordinating plane. Ab initio calculations substantiate the diversity of the magnetic behaviors in these complexes and highlight the importance of axial ligand field with short Dy-Osali distances, large ?Osali-Dy Osali angles and less ligand stacking in these pseudo-D4d-symmetrical single molecule magnets. PMID- 28853557 TI - Enhanced Photocatalytic Reaction at Air-Liquid-Solid Joint Interfaces. AB - Semiconductor photocatalysis has long been considered as a promising approach for water pollution remediation. However, limited by the recombination of electrons and holes, low kinetics of photocatalysts and slow reaction rate impede large scale applications. Herein, we addressed this limitation by developing a triphase photocatalytic system in which a photocatalytic reaction is carried out at air liquid-solid joint interfaces. Such a triphase system allows the rapid delivery of oxygen, a natural electron scavenger, from air to the reaction interface. This enables the efficient removal of photogenerated electrons from the photocatalyst surface and minimization of electron-hole recombination even at high light intensities, thereby resulting in an approximate 10-fold enhancement in the photocatalytic reaction rate as compared to a conventional liquid/solid diphase system. The triphase system appears an enabling platform for understanding and maximizing photocatalyst kinetics, aiding in the application of semiconductor photocatalysis. PMID- 28853558 TI - Mn3 Single-Molecule Magnets and Mn6/Mn9 Clusters from the Use of Methyl 2-Pyridyl Ketone Oxime in Manganese Phosphinate and Phosphonate Chemistry. AB - The syntheses, structures, and magnetochemical properties are reported for five new Mn clusters: [MnIII3O(O2PPh2)3(mpko)3](ClO4) (1), [MnIII3O(O2PPh2)3(ppko)3](ClO4) (2) [MnIII6O2(OMe)4(O2PPh2)4(mpko)4](ClO4)2 (3), [MnIII8MnIIO6(O2CMe)7(O3PPh)2(mpko)3(H2O)] (4), and [MnIII2MnIIO(mpko)3(H2O)4(ClO4)2](ClO4) (5), where mpko- (or ppko-) is the anion of methyl (or phenyl) 2-pyridyl ketone oxime. 1 was obtained by carboxylate substitution on [MnIII3O(O2CMe)3(mpko)3](ClO4) by treatment with diphenylphosphinic acid (Ph2PO2H). The comproportionation reaction between Mn(ClO4)2 and NBun4MnO4 in the presence of Ph2PO2H and ppkoH in EtOH, or mpkoH in MeOH, led to 2 and 3, respectively. 4 was obtained as was 3, but with phenylphosphonic acid (PhPO3H2) instead of Ph2PO2H. 5 was obtained by aerial oxidation of Mn(ClO4)2 in the presence of mpkoH. 1 and 2 contain a triangular Mn3 core, 3 comprises the fusion of two Mn3 units of 1 by MeO- bridges, and 4 has a cagelike structure. 5 is similar to 1 in possessing a triangular core. Variable temperature, solid-state direct-current (dc) and alternating-current (ac) magnetic data were collected on 1-5: 1 and 2 exhibit ferromagnetic Mn....Mn exchange interactions, S = 6 ground states, and are new single-molecule magnets (SMMs). 3-5 possess S = 4, 5/2, and 5/2 ground states, respectively, from dominant antiferromagnetic interactions. Fits of dc magnetization data in the 1.8 10.0 K and 10-70 kG ranges gave D and g values of: -0.29(2) cm-1 and 1.94(1) for 1, -0.38(2) cm-1 and 1.99(1) for 2, -0.29(2) cm-1 and 1.96(1) for 3, -1.26(4) cm 1 and 1.99(2) for 4, -1.41(4) cm-1 and 1.98(2) for 5, where D is the axial zero field splitting parameter. PMID- 28853559 TI - Hydrothermal Conversion of Layered Niobate K4Nb6O17.3H2O to Rare Microporous Niobate K6Nb10.8O30. AB - We report a new facile route to synthesizing K6Nb10.8O30, a rare microporous niobate. When hydrothermally treated under alkali conditions, a layered niobate, K4Nb6O17.3H2O, was converted to K6Nb10.8O30. This product had a much smaller particle size than K6Nb10.8O30, prepared by a conventional solid-state reaction, and showed enhanced adsorption properties. PMID- 28853560 TI - Strengthening the Study on the Behavior and Transformation of Medium-Chain Chlorinated Paraffins in the Environment. PMID- 28853561 TI - Simultaneous Electrochemical Speciation of Oxidized and Reduced Glutathione. Redox Profiling of Oxidative Stress in Biological Fluids with a Modified Carbon Electrode. AB - The simultaneous electrochemical quantification of oxidized (GSSG) and reduced glutathione (GSH), biomarkers of oxidative stress, is demonstrated in biological fluids. The detection was accomplished by the development of a modified carbon electrode and was applied to the analysis of biological fluids of model organisms under oxidative stress caused by lead intoxication. Nanocomposite molecular material based on cobalt phthalocyanine (CoPc) and multiwalled carbon nanotubes functionalized with carboxyl groups (MWCNTf) was developed to modify glassy carbon electrodes (GCE) for the detection of reduced and oxidized glutathione. The morphology of the nanocomposite film was characterized by scanning electron microscopy (SEM) and profilometry. The electrochemical behavior of the modified electrode was assessed by cyclic voltammetry (CV) to determine the surface coverage (Gamma) by CoPc. The electrocatalytic behavior of the modified electrode toward reduced (GSH) and oxidized (GSSG) forms of glutathione was assessed by CV studies at physiological pH. The obtained results show that the combined use of CoPc and MWCNTf results in an electrocatalytic activity for GSH oxidation and GSSG reduction, enabling the simultaneous detection of both species. Differential pulse voltammetry reveals detection limits of 100 MUM for GSH and 8.3 MUM for GSSG, respectively. The potential interference from ascorbic acid, cysteine, glutamic acid, and glucose was also studied, and the obtained results show limited effects from these species. Finally, the hybrid electrode was used for the determination of GSH and GSSG in rat urine and plasma samples, intoxicated or not by lead. Both glutathione forms were detected in these complex biological matrixes without any pretreatment. Our results portray the role of GSH and GSSG as markers of oxidative stress in live organisms under lead intoxication. PMID- 28853562 TI - High-Pressure and High-Temperature Synthesis and Pressure-Induced Simultaneous Optimization of the Electrical and Thermal Transport Properties of Nonstoichiometric TiO1.80. AB - We developed suitable high-pressure and high-temperature (HPHT) conditions for improvement of the thermoelectric properties of nonstoichiometric TiO1.80. X-ray diffraction, scanning transmission microscopy, transmission electron microscopy, and ultraviolet spectral measurements demonstrate that the crystal structures and microstructures are strongly modulated by our HPHT. The electrical properties and thermal conductivity are improved simultaneously by raising the reactive sintering pressure. The band gap was narrowed, contributing to the increase of the electrical properties with the pressure. In addition, relatively low thermal conductivities were obtained here as a result of a full spectrum of phonon scattering, benefiting from our deliberately engineered microstructures via HPHT. As a consequence, a high dimensionless figure of merit (zT) of 0.36 was obtained at 700 degrees C in the sample fabricated at 5 GPa. As far as we know, this is higher than all of the results of nonstoichiometric titanium oxide by other means and an enhancement of 57% of the best ever result. HPHT offers us a promising alternative for optimization of the thermoelectric properties, and it is worthwhile to popularize it. PMID- 28853563 TI - Substitution of Cytosine with Guanylurea Decreases the Stability of i-Motif DNA. AB - Both 5-aza-2'-deoxycytidine (decitabine) and its primary breakdown product, 2' deoxyriboguanylurea (GuaUre-dR), have been shown to act as mutagens and epimutagens that cause replication stress and alter both DNA methylation and gene expression patterns. As cytosine analogues, both are expected to be preferentially incorporated into regions of GC skew where runs of cytosine residues are sequestered on one strand and guanine residues on the other. Given that such regions have been identified as sites with the potential for effects on gene expression and replication stress linked to formation of alternative DNA secondary structures, it is of interest to determine the influence that these base analogues might have on the stability of structures of this kind. Here we report that incorporation of GuaUre-dR into an i-motif-forming sequence decreases both the thermal and pH stability of an i-motif despite the apparent ability of GuaUre-dR to base pair with cytosine. PMID- 28853564 TI - Organometallic Neptunium Chemistry. AB - Fifty years have passed since the foundation of organometallic neptunium chemistry, and yet only a handful of complexes have been reported, and even fewer have been fully characterized. Yet, increasingly, combined synthetic/spectroscopic/computational studies are demonstrating how covalently bonding, soft, carbocyclic organometallic ligands provide an excellent platform for advancing the fundamental understanding of the differences in orbital contributions and covalency in f-block metal-ligand bonding. Understanding the subtleties is the key to the safe handling and separations of the highly radioactive nuclei. This review describes the complexes that have been synthesized to date and presents a critical assessment of the successes and difficulties in their analysis and the bonding information they have provided. Because of increasing recent efforts to start new Np-capable air-sensitive inorganic chemistry laboratories, the importance of radioactivity, the basics of Np decay and its ramifications (including the radiochemical synthesis of one organometallic compound), and the available anhydrous starting materials are also surveyed. The review also highlights a range of instances in which important differences in the chemical behavior between Np and its closest neighbors, uranium and plutonium, are found. PMID- 28853565 TI - "Two-Story" Calix[6]arene-Based Zinc and Copper Complexes: Structure, Properties, and O2 Binding. AB - A new "two-story" calix[6]arene-based ligand was synthesized, and its coordination chemistry was explored. It presents a tren cap connected to the calixarene small rim through three amido spacers. X-ray diffraction studies of its metal complexes revealed a six-coordinate ZnII complex with all of the carbonyl groups of the amido arms bound and a five-coordinate CuII complex with only one amido arm bound. These dicationic complexes were poorly responsive toward exogenous neutral donors, but the amido arms were readily displaced by small anions or deprotonated with a base to give the corresponding monocationic complexes. Cyclic voltammetry in various solvents showed a reversible wave for the CuII/CuI couple at very negative potentials, denoting an electron-rich environment. The reversibility of the system was attributed to the amido arms, which can coordinate the metal center in both its +II and +I redox states. The reversibility was lost upon anion binding to Cu. Upon exposure of the CuI complex to O2 at low temperature, a green species was obtained with a UV-vis signature typical of an end-on superoxide CuII complex. Such a species was proposed to be responsible for oxygen insertion reactions onto the ligand according to the unusual and selective four-electron oxidative pathway previously described with a "one-story" calix[6]tren ligand. PMID- 28853566 TI - Tunicate-Inspired Gallol Polymers for Underwater Adhesive: A Comparative Study of Catechol and Gallol. AB - Man-made glues often fail to stick in wet environments because of hydration induced softening and dissolution. The wound healing process of a tunicate inspired the synthesis of gallol-functionalized copolymers as underwater adhesive. Copolymers bearing three types of phenolic groups, namely, phenol, catechol, and gallol, were synthesized via the methoxymethyl protection/deprotection route. Surprisingly, the newly synthesized copolymers bearing gallol groups exhibited stronger adhesive performances (typically 7* stronger in water) than the widely used catechol-functionalized copolymers under all tested conditions (in air, water, seawater, or phosphate-buffered saline solution). The higher binding strength was ascribed to the tridentate-related interfacial interaction and chemical cross-linking. Moreover, gallol functionalized copolymers adhered to all tested surfaces including plastic, glass, metal, and biological material. In seawater, the performance of gallol functionalized copolymer even exceeds the commercially available isocyanate-based glue. The insights from this study are expected to help in the design of biomimetic materials containing gallol groups that may be utilized as potential bioadhesives and for other applications. The results from such a kind of comparable study among phenol, catechol, and gallol suggests that tridentate structure should be better than bidentate structure for bonding to the surface. PMID- 28853567 TI - Presence of Emerging Per- and Polyfluoroalkyl Substances (PFASs) in River and Drinking Water near a Fluorochemical Production Plant in the Netherlands. AB - The present study investigated the presence of legacy and emerging per- and polyfluoroalkyl substances (PFASs) in river water collected in 2016 up- and downstream from a fluorochemical production plant, as well as in river water from control sites, in The Netherlands. Additionally, drinking water samples were collected from municipalities in the vicinity from the production plant, as well as in other regions in The Netherlands. The PFOA replacement chemical GenX was detected at all downstream river sampling sites with the highest concentration (812 ng/L) at the first sampling location downstream from the production plant, which was 13 times higher than concentrations of sum perfluoroalkylcarboxylic acids and perfluoroalkanesulfonates (?PFCA+?PFSA). Using high resolution mass spectrometry, 11 polyfluoroalkyl acids belonging to the C2nH2nF2nO2, C2nH2n+2F2nSO4 or C2n+1H2nF2n+4SO4 homologue series were detected, but only in downstream water samples. These emerging PFASs followed a similar distribution as GenX among the downstream sampling sites, suggesting the production plant as the source. Polyfluoroalkyl sulfonates (C2nH2F4nSO3) were detected in all collected river water samples, and therefore appear to be ubiquitous contaminants in Dutch rivers. GenX was also detected in drinking water collected from 3 out of 4 municipalities in the vicinity of the production plant, with highest concentration at 11 ng/L. Drinking water containing the highest level of GenX also contained two C2nH2nF2nO2 homologues. PMID- 28853568 TI - Experimental Study and Modeling of the UV-Vis and Infrared Spectra of the [VO(O2)Hheida]- Complex Dissolved in Water. AB - Combined theoretical and experimental studies of the [VO(O2)Hheida]- anion dissolved in water that may serve as a functional model for vanadium haloperoxidase enzymes have been performed. The geometrical structure and absorption and vibrational spectra of this system have been evaluated within the framework of density functional theory (DFT). The obtained theoretical results on the equilibrium structure and optical spectra are in quite good agreement with the experimental data. With the aid of the combination of UV-visible spectroscopy and electronic structure calculations, it has been revealed that, in the apparent absorption spectra of the [VO(O2)Hheida]- anion, the highest in energy band corresponds to a ligand to metal electron excitation, while the band with a maximum at 430 nm arises from the peroxo group. The calculations also reproduce quite well the positions, intensities and the grouping of frequencies in the near infrared (NIR) spectra. The visualization of the calculated vibrations in the energy range of 400-1100 cm-1 has been presented. PMID- 28853569 TI - Copper-Catalyzed N-Arylation of Nitroenamines with Diaryliodonium Salts. AB - A novel synthetic methodology was developed for the N-arylation of nitroenamine derivatives utilizing diaryliodonium triflates and copper(I) chloride as a catalyst. The procedure enables the easy aryl transfer from the hypervalent species under mild catalytic conditions with unusual heteroatom preference and high efficiency. PMID- 28853570 TI - Synthesis of 2D Imine-Linked Covalent Organic Frameworks through Formal Transimination Reactions. AB - Covalent organic frameworks (COFs) are crystalline, permanently porous, two dimensional or three-dimensional polymers with tunable topology and functionality. COFs linked with imines or beta-ketoenamines are more chemically stable than their boron-linked counterparts, making them more promising for a broad range of applications, including energy storage devices, proton-conductive membranes, and catalyst supports. We report a general and scalable method for synthesizing imine- and beta-ketoenamine-linked COFs based on the formal transimination of N-aryl benzophenone imines. These substrates are often the synthetic precursors of traditional polyfunctional aryl amine monomers and are more stable, soluble, and easy to handle and purify. The imine- and beta ketoenamine-linked COFs obtained from this approach show excellent materials quality, as characterized by X-ray diffraction and surface area analysis. The most optimized COF exhibited a Brunauer-Emmett-Teller surface area (>2600 m2/g) very close to its theoretical value (2830 m2/g). This method is amenable to both conventional solvothermal conditions and microwave heating, providing similar or even improved materials quality with shorter reaction times. The high materials quality, scalability, and availability of benzophenone imine monomers are all attractive features of this approach. PMID- 28853571 TI - Electrochemical Decarboxylative Sulfonylation of Cinnamic Acids with Aromatic Sulfonylhydrazides to Vinyl Sulfones. AB - A stereoselective synthesis of (E)-vinyl sulfones has been developed via electrochemical oxidative N-S bond cleavage of aromatic sulfonylhydrazides, followed by cross-coupling reactions with cinnamic acids to form the C-S bond. The protocol proceeded smoothly to afford (E)-vinyl sulfones in good yields with wide substrate scope under metal-free and halogen-free conditions. PMID- 28853572 TI - Insights into the Reaction Mechanism of Criegee Intermediate CH2OO with Methane and Implications for the Formation of Methanol. AB - Criegee intermediates (CIs) play a key role in controlling the atmospheric budget of hydroxyl radical, organic acids, and secondary organic aerosols. In this study, the detailed reaction mechanisms of the simplest Criegee intermediate CH2OO and its derivatives with methane (CH4) have been systematically investigated theoretically. Two pathways A and B have been identified for the title reaction. In pathway A, CIs can act as an oxygen donor by inserting its terminal oxygen atom into the C-H bond of alkanes, resulting in the formation of alcohol species. The corresponding energy barriers ranging from 6.5 to 24.1 kcal/mol are associated with the O-O bond strength of CIs. Meanwhile, this pathway is more favorable thermodynamically, where the free energy changes (enthalpy changes) range from -81.1 (-78.3) to -110.9 (-109.0) kcal/mol, respectively. In pathway B, an addition reaction to produce the hydroperoxides occurs, accompanying the hydrogen transfer from the alkanes to the terminal oxygen atom of CIs. The corresponding energy barriers ranging from 17.3 to 30.9 kcal/mol are higher than those in pathway A. Further calculations of the rate constants suggest that pathway A is the most favorable reaction channel and the rate constant exhibits a positive temperature dependence. In addition, the conformation-dependent reactivity for the title reaction has been observed. The present findings can enable us to better understand the potential reactivity of CIs in the presence of the alkane species. PMID- 28853573 TI - Macroscopic Wires from Fluorophore-Quencher Dyads with Long-Lived Blue Emission. AB - We report the formation of macroscopic wires up to centimeters in length from a series of structurally flexible, covalently tethered small-molecular fluorophore quencher dyads (FQDs, average MW = 425 Da), comprised of carbazole, melatonin, and cyanobenzoate moieties. These FQDs are nonemissive in organic solutions but become moderately to highly luminescent (PhiF = 0.037-0.39) upon formation of wires with emission maxima in the blue region (446-483 nm). The blue photoluminescence (PL) is ascribed to a combination of singlet charge transfer, localized triplet state, and possibly delayed fluorescence emissions with intrinsic luminescence lifetimes ranging from 0.228 to 21333 MUs, based on luminescence, transient absorption measurements, X-ray diffraction, and calculations. PMID- 28853574 TI - Light-Induced Surface Reactions at the Bismuth Vanadate/Potassium Phosphate Interface. AB - Bismuth vanadate has recently drawn significant research attention as a light absorbing photoanode due to its performance for photoelectrochemical water splitting. In this study, we use in situ ambient pressure X-ray photoelectron spectroscopy with "tender" X-rays (4.0 keV) to investigate a polycrystalline bismuth vanadate (BiVO4) electrode in contact with an aqueous potassium phosphate (KPi) solution at open circuit potential under both dark and light conditions. This is facilitated by the creation of a 25 to 30 nm thick electrolyte layer using the "dip-and-pull" method. We observe that under illumination bismuth phosphate forms on the BiVO4 surface leading to an increase of the surface negative charge. The bismuth phosphate layer may act to passivate surface states observed in photoelectrochemical measurements. The repulsive interaction between the negatively charged surface under illumination and the phosphate ions in solution causes a shift in the distribution of ions in the thin aqueous electrolyte film, which is observed as an increase in their photoelectron signals. Interestingly, we find that such changes at the BiVO4/KPi electrolyte interface are reversible upon returning to dark conditions. By measuring the oxygen 1s photoelectron peak intensities from the phosphate ions and liquid water as a function of time under dark and light conditions, we determine the time scales for the forward and reverse reactions. Our results provide direct evidence for light-induced chemical modification of the BiVO4/KPi electrolyte interface. PMID- 28853575 TI - Structure-Guided Development of Covalent and Mutant-Selective Pyrazolopyrimidines to Target T790M Drug Resistance in Epidermal Growth Factor Receptor. AB - Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug-resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPK parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile. PMID- 28853576 TI - Data Resources for the Computer-Guided Discovery of Bioactive Natural Products. AB - Natural products from plants, animals, marine life, fungi, bacteria, and other organisms are an important resource for modern drug discovery. Their biological relevance and structural diversity make natural products good starting points for drug design. Natural product-based drug discovery can benefit greatly from computational approaches, which are a valuable precursor or supplementary method to in vitro testing. We present an overview of 25 virtual and 31 physical natural product libraries that are useful for applications in cheminformatics, in particular virtual screening. The overview includes detailed information about each library, the extent of its structural information, and the overlap between different sources of natural products. In terms of chemical structures, there is a large overlap between freely available and commercial virtual natural product libraries. Of particular interest for drug discovery is that at least ten percent of known natural products are readily purchasable and many more natural products and derivatives are available through on-demand sourcing, extraction and synthesis services. Many of the readily purchasable natural products are of small size and hence of relevance to fragment-based drug discovery. There are also an increasing number of macrocyclic natural products and derivatives becoming available for screening. PMID- 28853577 TI - Diffusiophoresis in Ionic Surfactant Gradients. AB - Surfactants play a ubiquitous role in many areas of science and technology, and gradients often form-either spontaneously or intentionally-in a variety of nonequilibrium situations and processes. We visualize and measure the diffusiophoretic migration of latex colloids in response to gradients of cationic and anionic surfactants, both below and above the critical micelle concentration (cmc). Below the cmc, colloidal migration can be described using classic theories for diffusiophoresis under electrolyte gradients, although subtleties and distinctions do appear. Cationic surfactants adsorb onto anionic colloids, changing the surface charge and thus reversing the direction of diffusiophoretic migration. Above the cmc, diffusiophoretic mobilties decrease by orders of magnitude. We argue this to occur because charged monomers (rather than micelles) dominate colloidal diffusiophoresis. Because monomer concentrations remain essentially constant above the cmc, surfactant gradients imposed above the cmc result in very small monomer gradients-and, therefore, very weak diffusiophoresis. Our findings suggest conceptual strategies to understand diffusiophoresis in the presence of surfactants, as well as strategies to predict and design systems that harness them. PMID- 28853578 TI - Copper- or Nickel-Enabled Oxidative Cross-Coupling of Unreactive C(sp3)-H Bonds with Azole C(sp2)-H Bonds: Rapid Access to beta-Azolyl Propanoic Acid Derivatives. AB - beta-Azolyl propanoic acid derivatives are frequently found in biologically active molecules and pharmaceuticals. Here, we report the oxidative heteroarylation of unactivated C(sp3)-H bonds with azole C(sp2)-H bonds via copper or nickel catalysis with the aid of removable bidentate auxiliary, which provides a rapid pathway to beta-azolyl propanoic acid derivatives. A variety of azoles such as oxazole, benzoxazole, thiazole, benzothiazoles, benzimidazole, purine, and even [1,2,4]triazolo[1,5-a]pyrimidine could be engaged in this protocol. PMID- 28853579 TI - Rhodium(III)-Catalyzed Oxidative Cross-Coupling of Unreactive C(sp3)-H Bonds with C(sp2)-H Bonds. AB - The development of the oxidative cross-coupling of unreactive C(sp3)-H bonds with (hetero)arene C(sp2)-H bonds is considerably appealing, yet conceptually and practically challenging. Here, we disclose the rhodium-catalyzed oxidative heteroarylation of unactivated C(sp3)-H bonds with heteroarene C(sp2)-H bonds. This method provides a step-economic route to beta-heteroarylated 2-ethylpyridine derivatives, which exhibits relatively broad substrate scope, high tolerance level of sensitive functional groups, and high selectivity. The protocol can also be extended to the coupling reaction between 8-methylquinoline derivatives and heteroarenes. PMID- 28853580 TI - Formyloxyacetoxyphenylmethane as an N-Formylating Reagent for Amines, Amino Acids, and Peptides. AB - Formyloxyacetoxyphenylmethane is a stable, water-tolerant, N-formylating reagent for primary and secondary amines that can be used under solvent-free conditions at room temperature to prepare a range of N-formamides, N-formylanilines, N formyl-alpha-amino acids, N-formylpeptides, and an isocyanide. PMID- 28853581 TI - Formation of Colloidal Nanocellulose Glasses and Gels. AB - Nanocellulose (NC) suspensions can form rigid volume-spanning arrested states (VASs) at very low volume fractions. The transition from a free-flowing dispersion to a VAS can be the result of either an increase in particle concentration or a reduction in interparticle repulsion. In this work, the concentration-induced transition has been studied with a special focus on the influence of the particle aspect ratio and surface charge density, and an attempt is made to classify these VASs. The results show that for these types of systems two general states can be identified: glasses and gels. These NC suspensions had threshold concentrations inversely proportional to the particle aspect ratio. This dependence indicates that the main reason for the transition is a mobility constraint that, together with the reversibility of the transition, classifies the VASs as colloidal glasses. If the interparticle repulsion is reduced, then the glasses can transform into gels. Thus, depending on the preparation route, either soft and reversible glasses or stiff and irreversible gels can be formed. PMID- 28853582 TI - Fine Tuning of Retinal Photoinduced Decay in Solution. AB - Single methylation at position C10 of the all-trans retinal protonated Schiff base switches its excited-state decay in methanol from a slower picosecond into an ultrafast, protein-like subpicosecond process. QM/MM modeling in conjunction with on-the-fly excited-state dynamics provides fundamental understanding of the fine-tuning mechanics that "catalyzes" the photoinduced decay of solvated retinals. Methylation alters the interplay between the ionic S1 and covalent S2 states, reducing the excited-state lifetime by favoring the formation of a S1 transient fluorescent state with fully inverted bond lengths that accounts for the recorded transient spectroscopy and from which a space-saving conical intersection seam is quickly (<1 ps) reached. Minimal and apparently innocent chemical modifications thus affect the characteristic intramolecular charge transfer of the S1 state as well as the interaction with the covalent S2 excited state, eventually providing the high tunability of retinal photophysics and photochemistry and delivering a new concept for the rational design of retinal based photoactive molecular devices. PMID- 28853583 TI - Cisplatin-Mediated Formation of Polyampholytic Chitosan Nanoparticles with Attenuated Viscosity and pH-Sensitive Drug Release. AB - Chitosan is a biocompatible natural polysaccharide, which has been employed as a polymeric scaffold for versatile, systemic delivery platforms and for locally injectable gels with temperature-sensitive viscosity modulation. Despite the extensive investigation on the chemical modification strategies, however, most of the chitosan-based delivery platforms have been focused on the encapsulation of hydrophobic drugs, which can be simply adsorbed on the chitosan scaffolds by hydrophobic interaction via the postparticle-formation drug-loading process. Herein, we present the facile formation of a cisplatin-coordinated chitosan nanoplatform by exploiting the divalent metal (PtII)-mediated conformational changes of chitosan chains, which allows for the simultaneous drug-loading and nanoparticle formation. To this end, the native chitosan has been chemically modified with short polyethylene glycol and malonic acid as a colloidal stabilizer and a bidentate chelating ligand for PtII coordination, respectively. The resulting PtII-modified polyampholytic chitosan (PtII-MPC) has been self associated in aqueous media by hydrophobic segregation into a compact nanostructure, which exhibited an attenuated viscosity and pH-sensitive release of PtII compounds. Once the cationic drug molecules have been released under mild acidic conditions, the neutralized PtII-free MPC undergoes interchain flocculation near the isoelectric point because of the polyampholytic property, possibly allowing for the facilitated endosomal escape during the cellular endocytosis by the known membrane perturbation property of chitosan. PMID- 28853584 TI - Opening Remarks from Karen S. Pence, Second Lady of the United States. PMID- 28853585 TI - The effect of systematic factors on the outcome of trauma laparotomy at a major trauma centre in South Africa. AB - Introduction The aim of this study was to examine and interrogate outcomes in trauma laparotomy in a South African trauma centre to determine whether systematic factors were associated with any discrepancies in outcome. Methods This was a retrospective review of a prospectively entered trauma registry undertaken at the Pietermaritzburg Metropolitan Trauma Service, Pietermaritzburg, South Africa. The service has developed a hybrid electronic medical record system (HEMR) where clinical data were captured in real time, which were incorporated this into a database. Results During the period from December 2012 to July 2016, 562 patients underwent emergency laparotomy for trauma and the time and date of surgery was recorded in the HEMR. The mean age of all patients was 29.5 years. There were 256 operations during the weekend or over a public holiday, with a mortality of 8% (n = 21) compared with 306 during the week (mortality of 10%, n = 31). This difference was not statistically significant (P = 0.237). A total of 327 operations were performed at night (18:00 - 08:00) and 235 operations were performed during the day (08:00-18:00 Hours). This was a significant difference in mortality (10% (33) vs 7 % (16), P=0.013) These differences persisted if weekends and public holidays were separated out from normal working days. A total of 188 operations were performed on a week night, with a mortality of 11% (n = 20) and 121 operations were performed during a week day, with a mortality of 8% (n = 10). There were 139 operations on a weekend or public holiday night, with a mortality of 9% (n = 13). A total of 114 operations were performed on a weekend or public holiday day with a mortality of 7% (n = 8). A total of 208 procedures were performed with an consultant present. Of these, 32 patients (15%) died. A total of 368 procedures were performed without a consultant present and 8 (2%) died. Conclusions This study demonstrated a discrepancy in outcome for trauma laparotomy, depending on whether the operation was performed at night or during the day. The reasons for this are unclear, although the lack of consultant presence at night in comparison to during the day appears to be implicated. PMID- 28853586 TI - Positioning tips for distal fibula ankle fracture fixation. PMID- 28853587 TI - An efficient method of soft tissue preparation of amputated digits for replantation. PMID- 28853588 TI - Malignant bone tumours of the foot. AB - Introduction Malignant osseous foot tumours are uncommon. Their oncological outcomes have been poorly documented in the literature so far. The aim of this study was to establish the incidence and to evaluate the oncological outcomes of such patients. Methods Our large orthopaedic oncology database was used to review 70 malignant osseous foot tumour patients. Results The age at diagnosis of malignant osseous foot tumours demonstrated a bimodal distribution peaking in the second and eighth decades of life. Overall, 55 primary malignant bone tumours of the foot (79%) were identified. The median duration from onset of symptoms to diagnosis was 52 weeks (interquartile range [IQR]: 17-104). Eight primary tumours (15%) underwent an accidental excision (ie intralesional excision of a malignant bone tumour where some of the tumour has been left behind, also known as a 'whoops procedure') prior to referral to our unit. Forty-six patients (84%) underwent surgery overall and thirteen of these developed recurrence or metastases. Seven of eight patients with a previous accidental excision underwent amputation. Fifteen osseous metastatic foot lesions were identified. The median length of foot symptoms to diagnosis was 24 weeks (IQR: 20-36 weeks). The median time to death following diagnosis of osseous foot metastases was 20.1 months (IQR: 11.3-27.8 months). Conclusions A high index of suspicion and awareness of clinical features of malignant osseous foot tumours are both essential to avoid diagnostic delays. Amputation is associated with a respectable outcome for patients who have undergone previous accidental excisions. PMID- 28853589 TI - Positioning of bilateral midshaft femur fractures. PMID- 28853590 TI - Pedunculated, well differentiated liposarcoma of the oesophagus mimicking giant fibrovascular polyp. AB - We present a rare case of a big oesophageal liposarcoma causing dysphagia and weight loss in a 75-year-old patient. Endoscopically, a pedunculated lesion with subtotal obstruction of the oesophageal lumen had been detected and thoracoabdominal oesophageal resection with gastric sleeve reconstruction was performed. Surprisingly, a liposarcoma of the oesophagus was revealed on histopathological analysis, showing MDM2 overexpression. Oncological follow-up has been uneventful and the patient remains in good clinical shape at 15 months after surgery. PMID- 28853591 TI - Introduction of antibiotic-loaded cement during hip hemiarthroplasty washout to reduce the need for full revision surgery. PMID- 28853592 TI - Diaphragmatic eventration presenting as a recurrent diaphragmatic hernia. AB - Diaphragmatic eventration is an uncommon condition, usually discovered incidentally in asymptomatic patients. Even in symptomatic patients, the diagnosis can be challenging and should be considered among the differential diagnoses of diaphragmatic hernia. The correct diagnosis can often only be made in surgery. We describe the case of a 31-year-old patient with diaphragmatic eventration that was misdiagnosed as a recurrent congenital diaphragmatic hernia and review the corresponding literature. PMID- 28853593 TI - Changes in bone turnover markers in primary hyperparathyroidism and response to surgery. AB - Introduction Involvement of the bone is common in primary hyperparathyroidism. The aim of the study was to assess bone turnover markers in response to surgery for primary hyperparathyroidism. Methods This was a retrospective study of patients diagnosed and treated for parathyroid disease between 2005 and 2012. Interventions studied were surgery and medical treatment. The main outcome measures studied were serum levels of calcium, intact parathyroid hormone (iPTH), bone-specific alkaline phosphatase, N-terminal cross-linking propeptide of type 1 procollagen (P1NP) and C-terminal cross-linking telopeptides of type I collagen (CTX), both pre- and postoperatively at 6 months and 1 year; bone mineral density (at the spine and hip assessed by dual-energy x-ray absorptiometry after 1 year of treatment. Results A total of 122 (110 female, 12 male) patients (age range 25 91 years) underwent treatment for parathyroid disease during the study period; 30 patients were treated conservatively and 92 proceeded to surgery following localisation studies. Following surgical intervention, P1NP dropped significantly from a mean of 64.68 ng/ml (standard deviation, SD +/- 68.07 ng/ml) preoperatively to 26.37 ng/ml (SD +/- 20.94 ng/ml) and CTX from 0.69 pg/ml (SD +/ 0.44 pg/ml) to 0.15 pg/ml (SD +/- 0.16 pg/ml) at 6-12 months (P < 0.0001). This change was reflected in improvement in bone mineral density (T scores) of the hip and spine by 43% (P < 0.03) and 38% (P < 0.01), respectively, following surgery. In patients treated conservatively (n = 30), there was no improvement either in the bone turnover markers or bone densitometry scans. Conclusions Surgery improves bone density in patients with parathyroid disease. Improvement in serum bone turnover markers is seen following parathyroidectomy. The association with bone density needs further evaluation in larger studies. PMID- 28853594 TI - Bone metastases of the hand. AB - Introduction The aim of this study was to identify patients with malignant hand lesions, establish the proportions of those that were metastases and review their clinical course. Methods A retrospective search of a prospective tumour database was carried out to identify all patients treated at our unit with hand metastases. Patient demographics were recorded including site of primary malignancy, region of the hand involved, management of their metastasis and clinical outcome. Results Overall, 149 patients were identified with a malignant tumour of the hand. Ten had a metastatic lesion. There were 3 women and 7 men with a median age of 68 years (range: 28-91 years) at presentation. All presented with non-mechanical hand pain while four had pain and swelling. The median interval from symptom onset to diagnosis was eight weeks. The minimum follow-up duration was four months. Three patients had no history of malignancy. Of the remaining seven patients, three had other known metastases. Six patients underwent solely palliative radiotherapy. Three patients had amputation. One was treated with surgical excision and radiotherapy. One had an amputation and axillary node clearance. All but one patient had died by the time of the latest follow-up appointment. The median time to death following identification of acrometastases was 18 months. Sites of primary disease were skin (n=4), lung (n=3), kidney (n=2) and neuroendocrine system (n=1). The thumb was the most commonly affected location. Conclusions This study demonstrates that patients presenting with non-mechanical hand pain should be considered to have a malignant process until proved otherwise, particularly in patients with thumb symptoms and a history of prior malignancy. PMID- 28853595 TI - Staple line oversewing during laparoscopic sleeve gastrectomy. AB - Introduction This meta-analysis was performed to assess the possible benefits of staple line oversewing during laparoscopic sleeve gastrectomy. Methods A comprehensive search up to February 2017 was conducted on PubMed, the Web of ScienceTM and EmbaseTM. All eligible studies were included, and the outcomes of staple line bleeding and leak, overall complications and operative time were pooled. Results A total of 7 randomised controlled trials involving 845 patients (428 cases and 417 controls) were analysed. There was no significant difference in staple line bleeding (relative risk [RR]: 0.858, 95% confidence interval [CI]: 0.343-2.143, p=0.742), leak (RR: 0.650, 95% CI: 0.257-1.644, p=0.363) or overall complications (RR: 0.913, 95% CI: 0.621-1.342, p=0.644) between the oversewing group and the patients who did not have oversewing. Oversewing of the staple line was associated with a longer operative time (weighted mean difference: 14.400, 95% CI: 7.198-21.602, p=0.000). Conclusions Oversewing the staple line during laparoscopic sleeve gastrectomy does not decrease the risk of staple line bleeding, leakage or overall complications but it does prolong the operative time. PMID- 28853596 TI - A novel technique to reduce proximal junctional kyphosis in adults. PMID- 28853597 TI - Safety and effectiveness of antireflux surgery in obese patients. AB - Introduction The incidence of gastro-oesophageal reflux disease and obesity has increased significantly in recent years. The number of antireflux procedures being carried out on people with a higher body mass index (BMI) has been rising. Evidence is conflicting for outcomes of antireflux surgery in obese patients in terms of its safety and efficacy. Given the contradictory reports, this meta analysis was undertaken to establish the outcomes of antireflux surgery (ARS) in obese patients and its associated safety. Methods A systematic electronic search was conducted using the PubMed, MEDLINE(r), Ovid(r), Cochrane Library and Google ScholarTM databases to identify studies that analysed the effect of BMI on the outcomes of ARS. A meta-analysis was performed using the random effects model. The intraoperative and postoperative outcomes that were examined included operative time, conversion to an open procedure, mean length of hospital stay, recurrence of acid reflux requiring reoperation and wrap migration. Results A total of 3,772 patients were included in 13 studies. There was no significant difference in procedure conversion rate, recurrence of reflux requiring reoperation or wrap migration between obese and non-obese patients. However, both the mean operative time and mean length of stay were longer for obese patients. Conclusions ARS in obese patients with gastro-oesophageal reflux disease is safe and outcomes are comparable with those in patients with a BMI in the normal range. A high BMI should therefore not be a deterrent to considering ARS for appropriate patients. PMID- 28853598 TI - Incidental finding of a persistent median artery (palmar type) during a routine carpal tunnel decompression: a case report. AB - Carpal tunnel syndrome is characterised by compression of the median nerve. The mainstay of treatment is surgical decompression. This case report highlights the occurrence of a persistent median artery, which could complicate surgery. A 55 year-old woman underwent carpal tunnel decompression. An incidental finding of a large-calibre persistent median artery, which was superficial to the flexor sheath, could have been damaged. This was carefully retracted and the procedure was completed, without any complications. Several studies have shown the prevalence of persistent median artery to range from 1.1-27.1%. It is usually found deep to the flexor retinaculum but in this case it was found to be just beneath the palmar fascia. There is increased chance of iatrogenic injury with this particular variant. Surgeons performing the procedure should be mindful of this variation, because accidental damage could result in devastating consequences to the hand. PMID- 28853599 TI - Pyomyositis of the pectineus muscle in an adolescent male. AB - The 'irritable hip' continues to pose a challenge for clinicians. Even with predictive clinical algorithms, decision making can be difficult. Emergency treatment is required if septic arthritis is suspected. Other differential diagnoses such as transient synovitis, pyomyositis of the pelvic girdle muscles and osteomyelitis must be considered in order to help guide appropriate investigations and allow early treatment. We report the case of a 13-year-old boy presenting to our institution with an acutely painful left hip but still able to weight bear. Despite a fever and raised inflammatory markers, the clinical examination did not correspond to that of an infected hip joint. Urgent magnetic resonance imaging (MRI) confirmed pyomyositis of the pectineus muscle. To our knowledge, this is the first reported case in the literature. The child was treated with seven days of intravenous antibiotics. There was a good clinical response as well as normalisation of the C-reactive protein level and white cell count. The patient was discharged home with a further week of oral antibiotics. Follow-up MRI at two weeks demonstrated a dramatic reduction in the inflammation of the pectineus. At the clinic follow-up appointment, the child was asymptomatic and back to normal function. Pyomyositis is typically found in tropical areas but its rates in temperate climates have been rising. It usually affects large groups of muscles such as the quadriceps and gluteal muscles. MRI is the gold standard investigation. If diagnosed early, the condition can be treated successfully with intravenous antibiotics alone. Given the widespread availability of MRI, we recommend its increased use to distinguish between pyomyositis and other paediatric hip pathologies. PMID- 28853601 TI - Rotator cuff surgery in patients with rheumatoid arthritis: clinical outcome comparable to age, sex and tear size matched non-rheumatoid patients. AB - Aims This study aimed to compare the clinical outcomes of rotator cuff repair in patients with rheumatoid arthritis with those of patients who have no known history of the disease. We hypothesised that the functional outcomes are comparable between patients and without rheumatoid arthritis and may be affected by the level of disease activity, as assessed from C-reactive protein (CRP) level and history of systemic steroid intake. Patients and methods We conducted a retrospective review of the institutional surgical database from May 1995 to April 2012. Twenty-nine patients with rheumatoid arthritis who had rotator cuff repair were enrolled as the study group. Age, sex, and tear size matched patients with no disease who were selected as the control group. The mean duration of follow-up was 46 months (range 24-92 months). Clinical outcomes were assessed with the American Shoulder and Elbow Surgeons (ASES) questionnaire, Constant score and visual analogue scale (VAS). All data were recorded preoperatively and at regular postoperative follow-up visits. CRP was measured preoperatively as the disease activity marker for rheumatoid arthritis. Medication history was thoroughly reviewed in the study group. Results In patients with rheumatoid arthritis, all shoulder functional scores improved after surgery (ASES 56.1-78.1, Constant 50.8-70.5 and VAS 5.2-2.5; P < 0.001). The functional outcome of surgery in patients with rheumatoid arthritis was comparable to that of the control group (difference with control: ASES 78.1 vs. 85.5, P = 0.093; Constant 70.5 vs. 75.9, P = 0.366; VAS 2.5 vs. 1.8, P = 0.108). Patients with rheumatoid arthritis who had an elevated CRP level (> 1 mg/dl) showed inferior clinical outcomes than those with normal CRP levels. Patients with a history of systemic steroid intake showed inferior functional outcomes than those who had not taken steroids. Conclusions Surgical intervention for rotator cuff tear in patients with rheumatoid arthritis improved the shoulder functional outcome comparable to that in matched patients without rheumatoid arthritis. Elevated preoperative CRP level and history of systemic steroid intake portend inferior functional outcome in patients with rheumatoid arthritis. PMID- 28853602 TI - Management of choledocholithiasis after previous gastrectomy. AB - Common bile duct stones in patients with a previous gastrectomy can be a technical challenge because of the altered anatomy. This paper presents the successful management of two such patients using non-traditional techniques as conventional endoscopic retrograde cholangiopancreatography was not possible. PMID- 28853603 TI - The BeSMART (Best Supportive Management for Adults Referred with Tonsillopharyngitis) multicentre observational study. AB - Introduction Tonsillopharyngitis is the most common ear, nose and throat emergency admission, with 80,000 episodes recorded in England in 2015-2016. Despite this, there is a paucity of evidence addressing the supportive management of tonsillopharyngitis in inpatients. The aim of this retrospective multicentre observational study was to consider the Best Supportive Management for Adults Referred with Tonsillopharyngitis (BeSMART) in the inpatient setting, and to establish any associations between practice and outcomes. Methods Seven hospitals in North West England and North East Scotland participated in the study. Overall, 236 adult patients admitted with tonsillopharyngitis were included. The main outcome measures were interval to return to soft diet, length of stay (LOS), pain scores and readmissions. Results Women were more likely to seek professional help before presenting to secondary care (p=0.04). Patients admitted at the weekend were more likely to have a shorter LOS (p=0.03). There was no relationship between day of admission and seniority or specialty of the doctor initially seen. Prescription of corticosteroid, analgesia and a higher initial intravenous fluid infusion rate were not related to a shorter LOS. Conclusions This study is the first to yield valuable insights into the inpatient management of tonsillopharyngitis. This work represents part of an ongoing project to establish the evidence for common medical interventions for sore throat. Patient and professional surveys as well as a prospective interventional study are planned for the future. PMID- 28853604 TI - A fatal case of amphetamine induced ischaemic colitis. AB - Amphetamine induced ischaemic colitis is an exceedingly rare presentation of amphetamine toxicity. The cases reported in the literature have described mild or transient disease. We present a fatal case of ischaemic colitis induced by amphetamine use in a 44-year-old woman who presented in extremis after a cardiac arrest en route to the emergency department. A short history of headache, abdominal pain, vomiting and agitation preceded her admission. Imaging revealed changes consistent with ischaemic colitis. Emergency laparotomy revealed widespread colonic necrosis necessitating a subtotal colectomy. Despite aggressive resuscitation and inotropic support from arrival, the patient deteriorated intraoperatively and died in the immediate postoperative period. Histology showed arterial type ischaemia/reperfusion injury of the area supplied by the superior mesenteric artery. The patient's serum amphetamine level was 0.52mg/l (peak therapeutic levels <0.2mg/l). The postmortem examination concluded that amphetamines were the likely cause of the vasospasm, leading to profound colonic ischaemia. PMID- 28853605 TI - Current assessment of choledochoduodenostomy: 130 consecutive series. AB - Introduction Cholelithiasis usually can be managed successfully by endoscopic sphincterotomy. Choledochoduodenostomy (CDD) is one of the surgical treatment options but its acceptance remains debated because of the risk of reflux cholangitis and sump syndrome. The aim of this study was to assess the current features and outcomes of patient undergoing CDD. Patients and methods We retrospectively analysed the surgical results of consecutive 130 patients treated by CDD between 1991 and 2013 and excluded five cases with a malignant disorder. Indications for surgery included endoscopic management where stones were difficult or failed to pass and primary common bile duct stones with choledochal dilatation. Incidences of reflux cholangitis, stone recurrence, pancreatitis or sump syndrome were investigated and the data between end-to-side and side-to-side CDD were compared. Results Reflux cholangitis and stone recurrence was 1.6% (2/125) and 0% (0/125) of cases by CDD. There is no therapeutic-related pancreatitis in CDD. Sump syndrome was not also observed in side-to-side CDD. Conclusions This study is a first comparative study between end-to-side and side to-side CDD. The surgical outcomes for CDD treatment of choledocholithiasis were acceptable. The incidence of reflux cholangitis, stone recurrence, pancreatitis and sump syndrome was very low. PMID- 28853606 TI - Impact of the quantity of intradiscal cement leak on the progression of intervertebral disc degeneration. AB - Introduction We aim to assess the impact of the quantity of intradiscal cement leak during kyphoplasty on the rate of progression of degenerative changes in the affected disc. Methods Of 316 kyphoplasty procedures, we identified 32 episodes of intradiscal cement leak in 26 patients. The quantity of cement leaked was graded from I to IV. Disc degenerative changes were assessed at presentation and follow-up using radiographical scoring and magnetic resonance imaging (MRI) grading systems. Data for low-grade leaks (grade I) were compared with the medium and high-grade leaks (grades II-IV) using a chi-squared test. Results Median follow-up radiographic and MRI assessments were made at 18 and 21 months, respectively. Medium- and high-grade leaks were associated with a significantly higher radiographic disc degeneration scores compared with low-grade leaks (P = 0.04295) but no difference was found in MRI disc degeneration grades and in adjacent vertebral fracture rates. Conclusions Our findings indicate that the quantity of cement leaking into the disc space significantly influences the rate of progression of disc degeneration. PMID- 28853607 TI - Ringing the changes. PMID- 28853608 TI - Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation. AB - RATIONALE: Mesenchymal stem/stromal cell (MSC) therapies have shown promise in preclinical models of pathologies relevant to newborn medicine, such as bronchopulmonary dysplasia (BPD). We have reported that the therapeutic capacity of MSCs is comprised in their secretome, and demonstrated that the therapeutic vectors are exosomes produced by MSCs (MSC-exos). OBJECTIVES: To assess efficacy of MSC-exo treatment in a preclinical model of BPD and to investigate mechanisms underlying MSC-exo therapeutic action. METHODS: Exosomes were isolated from media conditioned by human MSC cultures. Newborn mice were exposed to hyperoxia (HYRX; 75% O2), treated with exosomes on Postnatal Day (PN) 4 and returned to room air on PN7. Treated animals and appropriate controls were harvested on PN7, -14, or 42 for assessment of pulmonary parameters. MEASUREMENTS AND MAIN RESULTS: HYRX exposed mice presented with pronounced alveolar simplification, fibrosis, and pulmonary vascular remodeling, which was effectively ameliorated by MSC-exo treatment. Pulmonary function tests and assessment of pulmonary hypertension showed functional improvements after MSC-exo treatment. Lung mRNA sequencing demonstrated that MSC-exo treatment induced pleiotropic effects on gene expression associated with HYRX-induced inflammation and immune responses. MSC exos modulate the macrophage phenotype fulcrum, suppressing the proinflammatory "M1" state and augmenting an antiinflammatory "M2-like" state, both in vitro and in vivo. CONCLUSIONS: MSC-exo treatment blunts HYRX-associated inflammation and alters the hyperoxic lung transcriptome. This results in alleviation of HYRX induced BPD, improvement of lung function, decrease in fibrosis and pulmonary vascular remodeling, and amelioration of pulmonary hypertension. The MSC-exo mechanism of action is associated with modulation of lung macrophage phenotype. PMID- 28853609 TI - Featured Article: In vitro development of personalized cartilage microtissues uncovers an individualized differentiation capacity of human chondrocytes. AB - Personalized features in the treatment of knee injuries and articular replacement therapies play an important role in modern life with increasing demand. Therefore, cell-based therapeutic approaches for the regeneration of traumatic defects of cartilage tissue were developed. However, great variations in the quality of repair tissue or therapeutic outcome were observed. The aim of the study was to capture and visualize individual differentiation capacities of chondrocytes derived from different donors with regard to a possible personal regeneration capacity using a cell-based therapy. The redifferentiation potential of monolayer cultured cells was analyzed in a scaffold-free three-dimensional tissue model. Furthermore, stimulating options using cartilage maturation factors such as L-ascorbic acid and transforming growth factor beta 2 (TGF-beta2) on this process were of special interest. Cells and tissues were analyzed via histological and immunohistochemical methods. Gene expression was measured by quantitative real-time polymerase chain reaction. In monolayer culture, cells from all donors showed an almost identical differentiation profile. In contrast, the differentiation state of cartilage-like three-dimensional microtissues revealed clear differences with respect to individual donors. Analyses at the protein and mRNA levels showed high variations regarding cartilage-typical matrix components (e.g. proteoglycans, collagen type II) and intracellular proteins (e.g. S100). Interestingly, only donor chondrocytes with a basic tendency to re differentiate in a three-dimensional environment were able to increase this tissue-specific maturation when exposed to L-ascorbic acid and/or TGF-beta2. Our approach revealed clear-cut possibilities for classification of individual donors into responders or non-responders. On the basis of these results an in vitro platform could be designed to discriminate responders from non-responders. This in vitro three-dimensional test system may be a suitable basis to establish a "personalized diagnostic tool" with the opportunity to assess the capacity of expanded chondrocytes to respond to an autologous cell-based therapy. Impact statement A challenge in cell-based cartilage regeneration therapies is the identification of a "personalized diagnostic tool" to predict the chondrogenic potency of cells from patients who are going to be treated with autologous cells. Comparing the phenotype of isolated chondrocytes from different donors in vitro revealed an individual cartilage-specific differentiation capacity. These personalized features are not detectable in vitro until the monolayer cells have the possibility to rearrange in 3D tissues. Cells from articular cartilage in monolayer culture may not be a suitable basis to discriminate responders from non responders with respect to a personalized cell-based therapy to treat cartilage defects. A more physiological 3D (micro-)environment enable the cells to present their individual differentiation capacity. The here described microtissue model might be the basis for an in vitro platform to predict the therapeutic outcome of autologous cell-based cartilage repair and/or a suitable tool to identify early biomarkers to classify the patients. PMID- 28853610 TI - White matter hyperintensities in migraine: Clinical significance and central pulsatile hemodynamic correlates. AB - Background The role of central pulsatile hemodynamics in the pathogenesis of white matter hyperintensities in migraine patients has not been clarified. Methods Sixty patients with migraine (20-50 years old; women, 68%) without overt vascular risk factors and 30 demographically-matched healthy controls were recruited prospectively. Cerebral white matter hyperintensities volume was determined by T1-weighted magnetic resonance imaging with CUBE-fluid-attenuated inversion-recovery sequences. Central systolic blood pressure, carotid-femoral pulse wave velocity, and carotid augmentation index were measured by applanation tonometry. Carotid pulsatility index was derived from Doppler ultrasound carotid artery flow analysis. Results Compared to the controls, the migraine patients had higher white matter hyperintensities frequency (odds ratio, 2.75; p = 0.04) and greater mean white matter hyperintensities volume (0.174 vs. 0.049, cm3, p = 0.04). Multivariable regression analysis showed that white matter hyperintensities volume in migraine patients was positively associated with central systolic blood pressure ( p = 0.04) and carotid-femoral pulse wave velocity ( p < 0.001), but negatively associated with carotid pulsatility index ( p = 0.04) after controlling for potential confounding factors. The interaction effects observed indicated that the influence of carotid-femoral pulse wave velocity ( p = 0.004) and central systolic blood pressure ( p = 0.03) on white matter hyperintensities formation was greater for the lower-carotid pulsatility index subgroup of migraine patients. White matter hyperintensities volume in migraine patients increased with decreasing carotid pulsatility index and with increasing central systolic blood pressure or carotid-femoral pulse wave velocity. Conclusions White matter hyperintensities are more common in patients with migraine than in healthy controls. Increased aortic stiffness or central systolic blood pressure in the presence of low intracranial artery resistance may predispose patients with migraine to white matter hyperintensities formation. PMID- 28853611 TI - Altered thalamic connectivity during spontaneous attacks of migraine without aura: A resting-state fMRI study. AB - Background Functional connectivity of brain networks may be altered in migraine without aura patients. Functional magnetic resonance imaging (fMRI) studies have demonstrated changed activity in the thalamus, pons and cerebellum in migraineurs. Here, we investigated the thalamic, pontine and cerebellar network connectivity during spontaneous migraine attacks. Methods Seventeen patients with episodic migraine without aura underwent resting-state fMRI scan during and outside of a spontaneous migraine attack. Primary endpoint was a difference in functional connectivity between the attack and the headache-free days. Functional connectivity was assessed in four different networks using seed-based analysis. The chosen seeds were in the thalamus (MNI coordinates x,y,z: right, 22,-24,0 and left, -22,-28,6), pons (right, 8,-24,-32 and left, -8,-24,-32), cerebellum crus I (right, 46,-58,-30 and left, -46,-58,-30) and cerebellum lobule VI (right, 34, 42,-36 and left, -32,-42,-36). Results We found increased functional connectivity between the right thalamus and several contralateral brain regions (superior parietal lobule, insular cortex, primary motor cortex, supplementary motor area and orbitofrontal cortex). There was decreased functional connectivity between the right thalamus and three ipsilateral brain areas (primary somatosensory cortex and premotor cortex). We found no change in functional connectivity in the pontine or the cerebellar networks. Conclusions The study indicates that network connectivity between thalamus and pain modulating as well as pain encoding cortical areas are affected during spontaneous migraine attacks. PMID- 28853612 TI - Foot Problems in Older Adults Associations with Incident Falls, Frailty Syndrome, and Sensor-Derived Gait, Balance, and Physical Activity Measures. AB - BACKGROUND: Research on foot problems and frailty is sparse and could advance using wearable sensor-based measures of gait, balance, and physical activity (PA). This study examined the effect of foot problems on the likelihood of falls, frailty syndrome, motor performance, and PA in community-dwelling older adults. METHODS: Arizona Frailty Cohort Study participants (community-dwelling adults aged >=65 years without baseline cognitive deficit, severe movement disorders, or recent stroke) underwent Fried frailty and foot assessment. Gait, balance (bipedal eyes open and eyes closed), and spontaneous PA over 48 hours were measured using validated wearable sensor technologies. RESULTS: Of 117 participants, 41 (35%) were nonfrail, 56 (48%) prefrail, and 20 (17%) frail. Prevalence of foot problems (pain, peripheral neuropathy, or deformity) increased significantly as frailty category worsened (any problem: 63% in nonfrail, 80% in prefrail [odds ratio (OR) = 2.0], and 95% in frail [OR = 8.3]; P = .03 for trend) due to associations between foot problems and both weakness and exhaustion. Foot problems were associated with fear of falling but not with fall history or incident falls over 6 months. Foot pain and peripheral neuropathy were associated with lower gait speed and stride length; increased double support time; increased mediolateral sway of center of mass during walking, age adjusted; decreased eyes open sway of center of mass and ankle during quiet standing, age adjusted; and lower percentage walking, percentage standing, and total steps per day. CONCLUSIONS: Foot problems were associated with frailty level and decreased motor performance and PA. Wearable technology is a practical way to screen for deterioration in gait, balance, and PA that may be associated with foot problems. Routine assessment and management of foot problems could promote earlier intervention to retain motor performance and manage fear of falling in older adults, which may ultimately improve healthy aging and reduce risk of frailty. PMID- 28853614 TI - Refeeding after caloric restriction reverses altered liver glucose release. AB - CONTEXT: Caloric restriction increases liver glucose release (LGR), but it is not known if this is a permanent condition. OBJECTIVE: To investigate if refeeding after caloric restriction reverses the high LGR. MATERIALS AND METHODS: Rats were organised in six-pups litters (GC); 12-pups litters with either 50% caloric restriction from 21 to 80 days of age (GR) or fed at will from 50 to 80 days of age (GRL). Liver perfusion was made at the age of 80 days. RESULTS: LGR was higher in the GR both during basal and adrenaline-stimulated conditions. Refeeding after caloric restriction decreased it to values close to those of GC rats. DISCUSSION: The altered LGR of GR rats was reversed by refeeding (group GRL). The influence of hypothalamic neuropetides on these hepatic changes is suggested. CONCLUSIONS: Enhanced LGR under caloric restriction is not programmed by early feeding; instead, it is determined by the current nutritional conditions. PMID- 28853615 TI - Radical cystectomy or bladder preservation with radiochemotherapy in elderly patients with muscle-invasive bladder cancer: Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators. AB - BACKGROUND: Radical cystectomy (RC) and radiochemotherapy (RCT) are curative options for muscle-invasive bladder cancer (MIBC). Optimal treatment strategy remains unclear in elderly patients. MATERIAL AND METHODS: Patients aged 80 years old and above with T2-T4aN0-2M0-Mx MIBC were identified in the Retrospective International Study of Cancers of the Urothelial Tract (RISC) database. Patients treated with RC were compared with those treated with RCT. The impact of surgery on overall survival (OS) was assessed using a Cox proportional hazard model. Progression included locoregional and metastatic relapse and was considered a time-dependent variable. RESULTS: Between 1988 and 2015, 92 patients underwent RC and 72 patients had RCT. Median age was 82.5 years (range 80-100) and median follow-up was 2.90 years (range 0.04-11.10). Median OS was 1.99 years (95%CI 1.17 2.76) after RC and 1.97 years (95%CI 1.35-2.64) after RCT (p = .73). Median progression-free survival (PFS) after RC and RCT were 1.25 years (95%CI 0.80 1.75) and 1.52 years (95%CI 1.01-2.04), respectively (p = .54). In multivariate analyses, only disease progression was significantly associated with worse OS (HR = 10.27 (95%CI 6.63-15.91), p < .0001). Treatment modality was not a prognostic factor. CONCLUSIONS: RCT offers survival rates comparable to those observed with RC for patients aged >=80 years. PMID- 28853613 TI - Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis. AB - RATIONALE: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. METHODS: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. MEASUREMENTS AND MAIN RESULTS: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3 kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. CONCLUSIONS: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis. PMID- 28853616 TI - Low cost assistive technology to support educational activities for adolescents with cerebral palsy. AB - INTRODUCTION: The concept of assistive technology covers several areas of action; one of them is communication with the elaboration of accessible solutions to overcome daily difficulties. It contributes to the resumption of functional abilities, expanding and facilitating inclusion and independent living. OBJECTIVE: To analyze the usability of a low cost prototype device to support educational activities of adolescents with cerebral palsy. METHODS: A descriptive observational study. The evaluation of a prototype device was made through a validated questionnaire, Quest Version 2.0, on the level of the user's satisfaction with an assistive technology, composed of 12 evaluation items. The questionnaire was filled out by the educator based on the observation of four wheelchair-bound participants diagnosed with cerebral palsy according to the international classification of diseases and health-related problems, ICD-10, who attend a coexistence and teaching institution in the state of Sao Paulo, Brazil. RESULTS: The device developed was considered an assistive technology, which provided an experience with a positive level of satisfaction for the participants. CONCLUSION: The tested prototype contributes to communication and interaction allowing adolescents with cerebral palsy to participate in educational activities. Implications for Rehabilitation The device assists the individual in the educational activities and can positively influence their development, observe the individual number 5, who has an important limitation in coordination and fine movements, placing the role of the task in the vertical position offers a new perspective to perform the task, this stimulates him to try to perform the work, so the challenge was adjusted to the demands of each individual which can contribute to its neuromotor development, the amplitude of the distal movements and the manual ability, since it must look for alternatives to complete the task requested. PMID- 28853617 TI - Prognostic value of pre-transplant PET/CT in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation. AB - Pre-transplant PET/CT may be prognostic in diffuse large B-cell lymphoma (DLBCL) patients undergoing autologous stem cell transplantation (ASCT). We reviewed relapsed and pre-transplant PET/CT scans of 32 patients with DLBCL treated with ASCT to determine the Deauville score and the maximum standardized uptake value (SUVmax). Patients with a Deauville score of 4 had a significantly inferior prognosis. The 3-year progression-free survival (PFS) for patients with Deauville 1-3 score was 64%, compared to 0% for Deauville 4, while the 3-year overall survival (OS) was 84% and 25%, respectively (p < .001, p = .002). The change in the SUVmax (>66 versus <=66%) was not predictive of PFS or OS, but a high pre transplant SUVmax (>6) demonstrated a trend towards an inferior PFS. Pre transplant PET/CT is a tool for identifying DLBCL patients at high risk for treatment failure with ASCT and could be used to risk-stratify patients in prospective clinical trials of novel transplant strategies. PMID- 28853618 TI - Burdens experienced and perceived needs of relatives of persons with SMI - a systematic meta-synthesis. AB - BACKGROUND: Close relatives of people with severe mental illness (SMI) experience problems known as family burdens. In addition, they may have their own needs for support, something often overlooked by the healthcare system. Meta-syntheses in this area may help explore the meaning of the experience of living with someone who has a SMI. AIM: Our aim was to describe the burdens experienced and needs perceived on a daily basis by relatives to someone who has a SMI. METHODS: The databases PubMed, CINAHL, and PsychInfo were searched using a systematic search strategy. Studies were screened for relevance and quality was appraised. A meta synthesis of nine qualitative studies was then conducted. RESULTS: The nine studies discerned the following themes. Burden themes; Forced to carry a sometimes unbearable burden; Burdened by own ill-health and disrupted relationships; Distressed and stigmatized by society. Needs themes; strengthening protective factors; Skills and practical support greatly appreciated. CONCLUSIONS: The burdens and needs of relatives of persons with SMI strongly influence their lives. They require relief from both practical and emotional burdens. Family interventions and other programs to support relatives should be encouraged with this knowledge in mind. PMID- 28853619 TI - Grip strength feigning is hard to detect: an exploratory study. AB - : Detecting submaximal effort when testing grip strength is difficult. Research so far has focused on the discrimination between sincere and feigning healthy participants, whereas the clinically relevant distinction is between injured patients and feigning participants. The aim of our study was to compare rapid exchange grip and isometric grip strength testing in 41 participants feigning weakness with 39 patients with decreased hand function. Various parameters that describe grip strength were recorded and tested for differences between the groups. Only the maximum grip strength during rapid exchange grip was found to be significantly higher in feigning participants compared with patients, but this cannot be used for decision-making on an individual basis. We found no parameters that are useful for the detection of feigned weakness in an individual case. LEVEL OF EVIDENCE: III. PMID- 28853620 TI - Prevalence of cold sensitivity in upper extremity nerve compression syndromes. AB - : This prospective observational study assessed the prevalence of cold sensitivity in patients with nerve compression using the Cold Intolerance Symptom Severity (CISS) questionnaire. One hundred patients (72 women, 28 men; mean age 59 years) with carpal tunnel syndrome ( n = 95) or cubital tunnel syndrome ( n = 5) were studied. Fifty-two patients reported symptoms of cold sensitivity with a mean CISS score of 50. Overall, significantly more women (58% vs. 36%) reported cold sensitivity with significantly worse CISS scores than men. LEVEL OF EVIDENCE: IV. PMID- 28853621 TI - Does power mobility training impact a child's mastery motivation and spectrum of EEG activity? An exploratory project. AB - PURPOSE: The purposes of this exploratory project were: (1) to evaluate the impact of power mobility training with a child who has multiple, severe impairments and (2) to determine if the child's spectrum of electroencephalography (EEG) activity changed during power mobility training. STUDY DESIGN: A single-subject A-B-A-B research design was conducted with a four week duration for each phase. Two target behaviours were explored: (1) mastery motivation assessed via the dimensions of mastery questionnaire (DMQ) and (2) EEG data collected under various conditions. Power mobility skills were also assessed. METHODS: The participant was a three-year, two-month-old girl with spastic quadriplegic cerebral palsy, gross motor function classification system level V. Each target behaviour was measured weekly. During intervention phases, power mobility training was provided. RESULTS: Improvements were noted in subscale scores of the DMQ. Short-term and long-term EEG changes were also noted. Improvements were noted in power mobility skills. CONCLUSIONS: The participant in this exploratory project demonstrated improvements in power mobility skill and function. EEG data collection procedures and variability in an individual's EEG activity make it difficult to determine if the participant's spectrum of EEG activity actually changed in response to power mobility training. Additional studies are needed to investigate the impact of power mobility training on the spectrum of EEG activity in children who have multiple, severe impairments. Implications for Rehabilitation Power mobility training appeared to be beneficial for a child with multiple, severe impairments though the child may never become an independent, community-based power wheelchair user. Electroencephalography may be a valuable addition to the study of power mobility use in children with multiple, severe impairments. Power mobility training appeared to impact mastery motivation (the internal drive to solve complex problems and master new skills) in a child who has multiple, severe impairments. PMID- 28853622 TI - Military veteran engagement with mental health and well-being services: a qualitative study of the role of the peer support worker. AB - BACKGROUND: Many UK military veterans experiencing mental health and well-being difficulties do not engage with support services to get the help they need. Some mental health clinics employ Peer Support Workers (PSWs) to help veteran patients engage, however it is not known how the role influences UK veteran engagement. AIMS: To gain insight into the role of peer support in UK veteran engagement with mental health and well-being services. METHOD: A qualitative study based on 18 semi-structured interviews with veterans, PSWs and mental health clinicians at a specialist veteran mental health and well-being clinic in Scotland. RESULTS: Four themes of the PSW role as positive first impression, understanding professional friend, helpful and supportive connector, and an open door were identified across all participants. The PSWs' military connection, social and well-being support and role in providing veterans with an easily accessible route to dis-engage and re-engage with the service over multiple engagement attempts were particularly crucial. CONCLUSIONS: The Peer Support role enhanced veteran engagement in the majority of instances. Study findings mirrored existing peer support literature, provided new evidence in relation to engaging UK veterans, and made recommendations for future veteran research and service provision. PMID- 28853623 TI - Predischarge Predictors of Readmissions and Postdischarge Complications in Robot Assisted Radical Prostatectomy. AB - BACKGROUND AND OBJECTIVE: Robot-assisted radical prostatectomy (RARP) has become the preferred surgical treatment for localized prostate cancer in the United States. Little is reported about the association between predischarge outcomes and postdischarge outcomes following RARP. The objective of this study was to explore the predischarge predictors of readmissions and postdischarge complications in RARP. MATERIALS AND METHODS: The National Surgery Quality Improvement Program (NSQIP) database was used to identify prostate cancer patients who underwent elective RARP from 2012 to 2014. Multivariable logistic regression was performed to assess potential predischarge predictors of readmissions and NSQIP-defined postdischarge complications within 30 days of RARP. To test the robustness of primary analysis, a secondary multivariable logistic regression was performed in the cohort of patients without any NSQIP defined predischarge complications. RESULTS: A total of 9975 patients were included. The readmission rate in the cohort was 3.3% (n = 332), and 4.4% (n = 441) had at least one complication. Multivariable logistic regression showed that American Society of Anesthesiologists (ASA) score of 3-4 (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.00-1.62, p = 0.050), increasing operative time (OT, per minute) (OR = 1.002, 95% CI = 1.000-1.003, p = 0.012), increasing length of hospital stay (LOS, per day) (OR = 1.36, 95% CI = 1.23-1.49, p < 0.001), and predischarge complication (OR = 2.15, 95% CI = 1.27-3.65, p = 0.004) were associated with readmission. Increasing OT (OR = 1.002, 95% CI = 1.001-1.004, p = 0.002) and increasing LOS (OR = 1.16, 95% CI = 1.02-1.30, p = 0.020) were associated with postdischarge complications. Logistic regression in patients without predischarge complications (n = 9804) confirmed that ASA score of 3-4 (OR = 1.37, 95% CI = 1.07-1.75, p = 0.013), increasing OT (OR = 1.002, 95% CI = 1.000 1.003, p = 0.022), and increasing LOS (OR = 1.34, 95% CI = 1.21-1.49, p < 0.001) were associated with readmissions. Secondary analyses also confirmed that increasing OT (OR = 1.002, 95% CI = 1.001-1.004, p = 0.002) and increasing LOS (OR = 1.18, 95% CI = 1.04-1.34, p = 0.011) were associated with postdischarge complications. CONCLUSIONS: Predischarge complications, OT, and LOS are associated with readmissions and postdischarge complications after RARP. It may be possible to identify patients at a higher risk of postdischarge adverse events to direct prevention interventions. Further prospective studies are needed to validate our findings. PMID- 28853624 TI - Prevention of recurrent lower urinary tract infections in postmenopausal women with genitourinary syndrome: outcome after 6 months of treatment with ospemifene. AB - Aim of this study was to evaluate the efficacy of ospemifene in the prevention of recurrent lower urinary tract infections in postmenopausal women with vulvovaginal atrophy. The study have a retrospective design. Thirty-nine patients were enrolled. Patients underwent clinical examination and urine culture. The urinary symptoms and the quality of life were evaluated with UTISA score, PUF and SF-36 questionnaires before and after treatment. All 39 patients received ospemifene 60 mg one tablet/daily for 6 months. Adverse effects and complications were assessed. Thirty-nine patients were enrolled in the study. Two patients experienced one new UTI episode and the mean number of positive urine culture decreased significantly after 6 months (3.65 +/- 2.12 vs 0.25 +/- 0.17, p < .0001). The mean number of urinary infection symptoms decreased significantly after treatment; dysuria reduced (4.76 +/- 2.45 vs 0.89 +/- 1.12). PUF score and SF-36 showed a statistically significant change (22.43 +/- 5.89 vs 12.14 +/- 3.21) and (52.86 +/- 9.21 vs 83.43 +/- 10.76). No adverse effects were reported and the total success rate was the 92.3% after 6 months at PGI-I. Ospemifene is a valid alternative with excellent tolerability for the UTIS prevention in postmenopausal patients. PMID- 28853625 TI - Screening of Lactic Acid Bacteria for Anti-Fusarium Activity and Optimization of Incubation Conditions. AB - Anti-Fusarium activities of lactic acid bacteria (LAB) Lactobacillus plantarum 299V, L. plantarum NRRL-4496, and Lactobacillus rhamnosus VT1 were determined by a microdilution assay developed in this study against Fusarium graminearum 08/RG/BF/51. A cell-free Lactobacillus culture supernatant (CFLCS) of L. rhamnosus VT1 had the highest anti-Fusarium activity. Response surface methodology was used to optimize the incubation conditions for production of CFLCS. A Box-Behnken factorial design was used to investigate the effects of incubation time, shaking speed, and incubation temperature on the inhibition rate of CFLCS. A model equation was generated to predict the inhibition rate of CFLCS under various incubation conditions. A low probability value (0.0012) and associated F value of 25.10 suggested that the model was highly significant. A high R2 value (0.978) indicated a very satisfactory model performance. Response surface methodology analysis suggested that an incubation temperature at 34 degrees C, a shaking speed at 170 rpm, and an incubation time of 55 h were the best combination for production of CFLCS from L. rhamnosus VT1. Under these incubation conditions, a 10% L. rhamnosus VT1 CFLCS solution was predicted to inhibit the growth of F. graminearum by 75.6% in vitro and inhibited 83.7% of the growth in the validation experiment. Thus, the CFLCS of L. rhamnosus VT1 was an effective anti-Fusarium mixture. PMID- 28853626 TI - Profile of the Illegal Import of Products of Animal Origin to Brazilian Cities at the Border with Argentina and Uruguay. AB - International food transit is a risk to public and animal health when not subject to legal importation sanitation procedures. Due to the extensive border area, illegal food import in Brazil is a common practice, especially in Rio Grande do Sul (RS), a state that borders with Argentina and Uruguay. The objective of this study was to evaluate the profile of Brazilians living in cities in RS that border with Argentina (BR-AR) or Uruguay (BR-UR) regarding the practice of illegal import of products of animal origin and to determine associations between the population characteristics and illegal import. A questionnaire with information related to the personal profile, habits of acquisition of imported food, and knowledge of health risks deriving from the consumption of the imported products was elaborated. The questionnaire was administered in six cities in RS (three cities bordering Argentina and three cities bordering Uruguay) and responses were obtained from 744 individuals. The variables city, sex, level of education, and knowledge were subjected to the chi-square test to verify the association between these variables and food import. Part of the interviewees admitted to illegally importing products of animal origin at both BR-AR (65.17%) and BR-UR (76.28%) borders. Dairy products were the main imported goods, followed by raw and processed meat. The study revealed that illegal import is common at the frontier region of RS, especially that of products of animal origin, dairy, and raw and processed meat. Although illegal importation occurs at all the cities under study, it was higher at the BR-UR border. Also, knowledge of the health risks influences the decision to import food or not. PMID- 28853627 TI - Reduction of Ochratoxin A in Oat Flakes by Twin-Screw Extrusion Processing. AB - Ochratoxin A (OTA) is one of the most important mycotoxins owing to its widespread occurrence and toxicity, including nephrotoxicity and potential carcinogenicity to humans. OTA has been detected in a wide range of agricultural commodities, including cereal grains and their processed products. In particular, oat-based products show a higher incidence and level of contamination. Extrusion cooking is widely used in the manufacturing of breakfast cereals and snacks and may reduce mycotoxins to varying degrees. Hence, the effects of extrusion cooking on the stability of OTA in spiked (100 MUg/kg) oat flake was investigated by using a laboratory-scale twin-screw extruder with a central composite design. Factors examined were moisture content (20, 25, and 30% dry weight basis), temperature (140, 160, and 180 degrees C), screw speed (150, 200, and 250 rpm), and die size (1.5, 2, and 3 mm). Both nonextruded and extruded samples were analyzed for reductions of OTA by high-performance liquid chromatography, coupled with fluorescence detection. The percentage of reductions in OTA in the contaminated oat flakes upon extrusion processing were in the range of 0 to 28%. OTA was partially stable during extrusion, with only screw speed and die size having significant effect on reduction (P < 0.005). The highest reduction of 28% was achieved at 180 degrees C, 20% moisture, 250 rpm screw speed, and a 3-mm die with 193 kJ/kg specific mechanical energy. According to the central composite design analyses, up to 28% of OTA can be reduced by a combination of 162 degrees C, 30% moisture, and 221 rpm, with a 3-mm die. PMID- 28853628 TI - Inactivation of Escherichia coli O157:H7 in Minute Steaks Cooked under Selected Conditions. AB - A national survey was conducted in Canada to determine consumer cooking practices for minute steaks (thin, mechanically tenderized beef cutlets). Results indicate that most Canadians prefer cooking minute steaks by pan frying and to a medium level of doneness. To identify safe cooking conditions, retail minute steaks (~125 g), inoculated at three sites per steak with a five-strain cocktail of nontoxigenic Escherichia coli O157:H7 (6.1 log CFU per site), were cooked on a hot plate (200 degrees C), mimicking a pan-frying scenario. The steaks (n = 5) were cooked for 4, 6, 8, or 10 min with turning over (flipping) up to four times at equal time intervals; or to 63 or 71 degrees C at the thickest area with or without a tinfoil lid. When cooked for 4 min, E. coli O157:H7 was recovered from all inoculation sites, and the mean reductions at various sites (1.2 to 3.4 log CFU per site) were not different (P > 0.05), irrespective of the flipping frequency. When cooked for 6 min with flipping once or twice, or for 8 min with flipping once, E. coli O157:H7 was recovered from most sites; the mean reductions (3.8 to 5.3 log CFU per site) were not different (P > 0.05), but they were higher (P < 0.05) than those for steaks cooked for 4 min. When cooked for 10, 8, or 6 min with flipping once, twice, or three times, respectively, E. coli O157:H7 was eliminated from most sites, but sites with <5-log reductions were found. Reductions of E. coli O157:H7 by >5 log at all inoculation sites were attained when the steaks were cooked for 10 or 8 min with two or more or three or more flippings, respectively, or for 6 min with four flippings. When flipped twice during cooking to 63 or 71 degrees C, E. coli O157:H7 was recovered from three or fewer sites; however, >5-log reductions throughout the steaks were only attained for the latter temperature, irrespective of whether the hot plate was covered with the tinfoil lid. Thus, turning over minute steaks twice during cooking to 71 degrees C or flipping two, three, or four times with a cooking time of 10, 8, or 6 min could achieve 5-log reductions throughout the steaks. PMID- 28853629 TI - Impact of the Global Food Safety Initiative on Food Safety Worldwide: Statistical Analysis of a Survey of International Food Processors. AB - In 2000, the Consumer Goods Forum established the Global Food Safety Initiative (GFSI) to increase the safety of the world's food supply and to harmonize food safety regulations worldwide. In 2013, a university research team in conjunction with Diversey Consulting (Sealed Air), the Consumer Goods Forum, and officers of GFSI solicited input from more than 15,000 GFSI-certified food producers worldwide to determine whether GFSI certification had lived up to these expectations. A total of 828 usable questionnaires were analyzed, representing about 2,300 food manufacturing facilities and food suppliers in 21 countries, mainly across Western Europe, Australia, New Zealand, and North America. Nearly 90% of these certified suppliers perceived GFSI as being beneficial for addressing their food safety concerns, and respondents were eight times more likely to repeat the certification process knowing what it entailed. Nearly three quarters (74%) of these food manufacturers would choose to go through the certification process again even if certification were not required by one of their current retail customers. Important drivers for becoming GFSI certified included continuing to do business with an existing customer, starting to do business with new customer, reducing the number of third-party food safety audits, and continuing improvement of their food safety program. Although 50% or fewer respondents stated that they saw actual increases in sales, customers, suppliers, or employees, significantly more companies agreed than disagreed that there was an increase in these key performance indicators in the year following GFSI certification. A majority of respondents (81%) agreed that there was a substantial investment in staff time since certification, and 50% agreed there was a significant capital investment. This survey is the largest and most representative of global food manufacturers conducted to date. PMID- 28853630 TI - Prevalence and Antimicrobial Resistance of Salmonella Isolates Recovered from Retail Pork in Major Village Markets in Tai'an Region, China. AB - The current study was undertaken to evaluate Salmonella contamination in retail pork at major village markets of the Tai'an region, China. In total, 200 retail pork samples were collected from four village markets between June 2015 and February 2016, of which 69 samples (34.5%) were determined to be positive for Salmonella. Eleven serotypes were identified from the 69 Salmonella isolates, and Salmonella Derby was the most common (18 of 69, 26.1%), followed by Typhimurium (17 of 69, 24.6%) and Meleagridis (11 of 69, 15.9%). Antimicrobial susceptibility testing showed that antimicrobial resistance against tetracycline was the most prevalent (42 of 69, 60.9%), but antimicrobial resistance against both ceftriaxone and cefotaxime was 1.4% (1 of 69) and 2.9% (2 of 69), respectively. Multilocus sequence typing revealed that the 69 Salmonella isolates were divided into 11 sequence types (STs), among which ST40 (18 of 69, 26.1%) was the most common, followed by ST34 (15 of 69, 21.7%) and ST64 (13 of 69, 18.8%). Collectively, retail pork at village markets in the Tai'an region has a high Salmonella contamination rate, and these isolates exhibit broad-spectrum antimicrobial resistance. However, the absence of a dominant ST demonstrates that the Salmonella isolates from retail pork may be of diverse origins. PMID- 28853631 TI - Approaches toward Identification of Surrogates To Validate Antimicrobial Washes as Preventive Controls for Fresh-Cut Leafy Greens. AB - In fresh-cut produce production, antimicrobials may be used during washing to control the risk of cross-contamination by microbial hazards. Surrogate microorganisms have long been used to validate processes, but none have been identified for validating the efficacy of antimicrobial washing of fresh-cut produce. The objective of this study was to develop procedures by which surrogates may be identified for use in validating the control of cross contamination for fresh-cut lettuce operations. Four microbial characteristics, which may be important factors in cross-contamination events, were quantitatively evaluated in potential surrogate microorganisms for comparison to a reasonably foreseeable hazard, Escherichia coli O157:H7: sensitivity to chlorine in solution, sensitivity to chlorine on lettuce leaf surfaces, shedding from contaminated lettuce leaves into the water during washing, and cross contamination from inoculated to uninoculated lettuce leaves during chorine washing. A procedure of practical quantitative experiments for comparing the characteristics reduced the original pool of 80 potential strains, which consisted of lactic acid bacteria, probiotics, and isolates obtained from lettuce enrichment cultures, to five strains: Lactobacillus plantarum, Pediococcus pentosaceus, probiotic 22C, and two lettuce enrichment isolates. These strains may be evaluated in additional studies involving comparisons to other reasonably foreseeable hazards and including other potential process variables that should be understood and controlled to prevent cross-contamination in fresh-cut lettuce operations. PMID- 28853632 TI - Isolation and Identification of Campylobacter spp. from Poultry and Poultry By Products in Tunisia by Conventional Culture Method and Multiplex Real-Time PCR. AB - Thermophilic Campylobacter spp. are one of the primary causes of bacterial human diarrhea. The consumption of poultry meats, by-products, or both is suspected to be a major cause of human campylobacteriosis. The aims of this study were to determine the prevalence of thermophilic Campylobacter spp. in fresh poultry meat and poultry by-products by conventional culture methods and to confirm Campylobacter jejuni and Campylobacter coli isolates by using the multiplex PCR assay. Two hundred fifty fresh poultry samples were collected from a variety of supermarkets and slaughterhouses located in Sfax, Tunisia, including chicken (n =149) and turkey (n =101). The samples were analyzed using conventional microbiological examinations according to the 2006 International Organization for Standardization method (ISO 10272-1) for Campylobacter spp. Concurrently, a real time PCR was used for identification of C. jejuni and C. coli . Of the 250 samples of poultry meat and poultry by-products, 25.6% (n = 64) were contaminated with Campylobacter spp. The highest prevalence of Campylobacter spp. was found in chicken meat (26.8%) followed by turkey meat (23.7%). Among the different products, poultry breasts showed the highest contamination (36.6%) followed by poultry by-products (30%), poultry wings (28%) and poultry legs (26%) showed the lowest contamination, and no contamination was found on neck skin. Of the 64 thermophilic Campylobacter isolates, C. jejuni (59.7%) was the most frequently isolated species and 10.9% of the isolates were identified as C. coli . All of the 64 Campylobacter isolates identified by the conventional culture methods were further confirmed by PCR. The seasonal peak of Campylobacter spp. contamination was in the warm seasons (spring and summer). The study concluded that high proportions of poultry meat and poultry by-products marketed in Tunisia are contaminated by Campylobacter spp. Furthermore, to ensure food safety, poultry meats must be properly cooked before consuming. PMID- 28853633 TI - Treatment gaps in Parkinson's disease care in the Philippines. AB - Neurological services and resources are scarce in low-income and developing countries, such as the Philippines. We looked into the treatment gaps in Parkinson's disease (PD) care in the Philippines in the following areas: epidemiology, healthcare, financial coverage, pharmacotherapy, surgical treatment and manpower. We collected relevant data on the above-mentioned areas. There is no available Philippine data on PD prevalence. Philippine healthcare is paid through user fees at the point of service. The average consultation fee in Manila ranges from US$10.57-31.74. The average minimum daily wage is US$9.39-10.17. Philippine healthcare is devolved to the local government units. Deep brain stimulation surgery is only available in Manila. Most PD medications are available in the Philippines. There are only nine movement disorder specialists for a population of 100.98 million. Gaps and challenges in PD care in the Philippines still exist. PMID- 28853634 TI - Impaired bed mobility: quantitative torque analysis with axial inertial sensors. AB - : Difficulty in turning in bed is rated as the most troublesome night-time symptom among Parkinson's disease (PD) patients. AIM: To develop a practical objective method for home assessment of a patient's ability to turn in bed. METHODS: Nocturnal parameters and torque of self-turning in bed from 17 PD couples were assessed and compared using a wearable axial sensor for two nights in their homes. RESULTS: The torque of axial rotation which indicates the ability of PD patients to turn in bed was significantly less than their spouses (p < 0.001). Significant correlations were observed between the torque of turning in bed and total unified Parkinson's Disease Rating Scale score (r = 0.71; p = 0.001), and total Nocturnal Akinesia Dystonia and Cramp score (r = 0.634; p = 0.006). CONCLUSION: Our study confirms a decreased ability in turning in PD. PMID- 28853635 TI - In this issue of Neurodegenerative Disease Management. PMID- 28853636 TI - Moyamoya disease: A rare case with an unusual presentation. PMID- 28853637 TI - Promoting smoking cessation in China: a foot-in-the-door approach to tobacco control advocacy. AB - INTRODUCTION: The Chinese government's implementation of the MPOWER policies and compliance with the WHO Framework Convention on Tobacco Control requirements has been slow. We used the 'foot-in-the-door' approach to promote tobacco control advocacy through capacity building of healthcare leaders, and establishment of smoking cessation clinics in Guangzhou and Beijing (two of the largest cities in China). METHODS: This collaborative pilot project involved the University of Hong Kong and three major hospitals in Guangzhou and Beijing. A steering committee conducted the smoking cessation training workshops starting from April 2006, and set up three smoking cessation model clinics during August 2006 to October 2008. We followed up the trained health care professionals (HCPs) in 2014 and 2015 to assess their impacts on tobacco control beyond smoking cessation. RESULTS: We emphasized the importance of the general tobacco control atmosphere during smoking cessation training of 139 HCPs to motivate them to engage in tobacco control advocacy. In addition to enhancing their knowledge and skills in cessation, the HCPs were then involved in the establishment of three in-hospital smoking cessation clinics and served as smoking cessation counselors since June 2008. Moreover, they ventured outside the clinics and the community to publicize smoking cessation. Their effort has contributed to smoke-free legislation, better surveillance on smoking and media advocacy on tobacco control in China. CONCLUSIONS: The training and establishment of smoking cessation clinics could serve as a means to motivate and empower HCPs who could contribute to broaden tobacco control policy in China. PMID- 28853638 TI - Self-assembled nanoparticles made from a new PEGylated poly(aspartic acid) graft copolymer for intravaginal delivery of poorly water-soluble drugs. AB - New amphiphilic PEGylated poly(aspartic acid) graft copolymer (PASP-PEG-Ph) was synthesized as a nanocarrier for intravaginal drug delivery of poorly water soluble drugs. PASP-PEG-Ph self-assembled into negatively charged spherically shaped nanoparticles in the presence of pH 4.5 and pH 7.0 vaginal fluid simulants with a diameter of approximately 200 nm as evidenced by Zeta-potentiometer, scanning electron microscope (SEM), dynamic light scattering (DLS) analysis. A significant number of stable NPs could be maintained at pH 4.5, 37 degrees C for 13 days. The PASP-PEG-Ph NP showed no significant cytotoxicity toward the T-cell line SupT1 and human vaginal epithelial cell line Vk2/E6E7 up to 1 mg/mL. The highest encapsulation efficiency of the model drug coumarin 6 (C6) by PASP-PEG-Ph was 92.0 +/- 5.7%. The sustained release profile of the encapsulated C6 was demonstrated by an in vitro release study. An in vitro cellular uptake study revealed strong cellular uptake of the C6 loaded NP by SupT1 cells within 2 h. PMID- 28853639 TI - Acute vision loss in systemic lupus erythematosus: bilateral combined retinal artery and vein occlusion as a catastrophic form of clinical flare. AB - Presentation of a combination of branch retinal artery occlusion (BRAO)/central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) in systemic lupus erythematosus (SLE) is extremely rare. Herein, we have presented the case of a 29-year-old female with SLE, who simultaneously developed bilateral CRVO and BRAO/CRAO in the absence of antiphospholipid syndrome (APS) as a catastrophic form of clinical flare. A combinatorial diagnosis of CRVO and BRAO/CRAO should be considered during clinical flare-up in a patient with SLE who presents with rapidly progressive visual loss. PMID- 28853640 TI - Health system redesign using Collective Impact: implementation of the Behavioural Supports Ontario initiative in Southwest Ontario. AB - This paper describes how the Collective Impact framework facilitated the design, implementation and development of a quality improvement initiative aimed at changing the way healthcare is provided to older adults living with mental health, addictions, neurocognitive and behavioral issues in southwestern Ontario. By promoting a common agenda, shared measurement systems, mutually reinforcing activities, continuous communication and with leadership from a backbone organization, system-wide change occurred. Outcomes, operational/strategic, clinical, capacity enhancement and community support structures as well as challenges are discussed. Improved coordination with primary care will further support enhanced clinical activities and capacity development strategies. Large scale, multisectoral change is possible when aligned with a collaborative, problem-solving framework that promotes the commitment of many service providers/agencies to a common agenda. PMID- 28853641 TI - Management of the symptoms of multiple sclerosis using functional electrical stimulation and exercise. AB - Previously, it was believed that exercise-related activity was likely to lead to the symptoms of multiple sclerosis (MS) becoming worse. More recently, it has been acknowledged that the consequences of not exercising are detrimental and may exacerbate symptoms of MS. In addition, it has been recognized that some of the disability that occurs after MS is likely to be due to deconditioning from a reduction in physical activity. The current paper will explore the potential role of functional electrical stimulation of the peroneal nerve, for facilitating neurorehabilitation, through increasing mobility and overcoming barriers to accessing exercise. The paper will also examine the impact of using exercise related activity to manage the symptoms of MS along with the potential neuroprotective effects. PMID- 28853643 TI - Scars of disengagement: perspectives on community leadership and youth engagement in rural South Africa. AB - Given the emerging global youth disengagement epidemic, anticipated population growth, and the threat of continued rural-urban migration among young adults, recent research has focused on community leadership practice and the factors that influence youth engagement at the local level. Studying these practices and factors can elicit interventions that can improve youth engagement and youth health. This study engaged South African rural community leaders in interviews to collect perceptions and experiences on community leadership and factors that influence youth engagement and their health behaviors. Content analysis was used to analyze the data. Emergent themes are categorized into four domains: conceptualizations of leadership, current youth behaviors, barriers to youth engagement, and youth leadership opportunities and potential solutions. Findings demonstrate a clear grasp of the concept of community leadership among community leaders, and an awareness of the complex interplay of social, economic and environmental factors on youth disengagement and the potential interventions to promote more youth participation. PMID- 28853642 TI - The Ribosomal Protein RplY Is Required for Pectobacterium carotovorum Virulence and Is Induced by Zantedeschia elliotiana Extract. AB - Pectobacterium carotovorum subsp. carotovorum strain PccS1, a bacterial pathogen causing soft rot disease of Zantedeschia elliotiana (colored calla), was investigated for virulence genes induced by the host plant. Using a promoter-trap transposon (mariner), we obtained 500 transposon mutants showing kanamycin resistance dependent on extract of Z. elliotiana. One of these mutants, PM86, exhibited attenuated virulence on both Z. elliotiana and Brassica rapa subsp. pekinensis. The growth of PM86 was also reduced in minimal medium (MM), and the reduction was restored by adding plant extract to the MM. The gene containing the insertion site was identified as rplY. The deletion mutant DeltarplY, exhibited reduced virulence, motility and plant cell wall-degrading enzyme production but not biofilm formation. Analysis of gene expression and reporter fusions revealed that the rplY gene in PccS1 is up-regulated at both the transcriptional and the translational levels in the presence of plant extract. Our results suggest that rplY is induced by Z. elliotiana extract and is crucial for virulence in P. carotovorum subsp. carotovorum. PMID- 28853644 TI - Effectiveness of the conservative therapy for spontaneous isolated iliac artery dissection: Preliminary results. AB - Purpose To investigate the effectiveness of conservative therapy for spontaneous isolated iliac artery dissection (SIIAD). Methods From February 2006 to May 2016, all patients with SIIAD were included and analyzed. The diagnosis of SIIAD was made based on contrast-enhanced computed tomography. The imaging morphologic characteristics, treatments, and outcomes for each patient were analyzed. Results A total of 11 patients (10 male and 1 female, age 71.1 +/- 7.8 years) were included in this study. Of the 11 patients, 8 patients were asymptomatic and the SIIADs were discovered during the course of computed tomography for other diseases, and 3 patients were symptomatic. Initial computed tomography findings: iliac arterial calcification ( n = 7); compression of the true lumen ( n = 6), with stenosis of the true lumen from 25% to 50% ( n = 3) and >= 50% ( n = 3); thrombosed false lumen partially ( n = 4), and no thrombosis in false lumen ( n = 7); dissecting aneurysm ( n = 11); entry points ( n = 11); re-entry points ( n = 1); no dissection extended to the internal iliac or common femoral artery. Conservative treatment was performed in six patients, and the remaining five patients need no treatment. During 23.3 +/- 14.2 months follow-up, none recurred symptoms and signs of symptomatic SIIAD; partial remodeling of SIIAD was achieved in four patients, and the remaining seven patients with no change of SIIAD. There was no presence of new false lumen enhancement on contrast-enhanced computed tomography during follow-up. Conclusions SIIAD without arterial rupture or lower limb necrosis can be safely treated with conservative therapy. PMID- 28853645 TI - Is Romantic Desire Predictable? Machine Learning Applied to Initial Romantic Attraction. AB - Matchmaking companies and theoretical perspectives on close relationships suggest that initial attraction is, to some extent, a product of two people's self reported traits and preferences. We used machine learning to test how well such measures predict people's overall tendencies to romantically desire other people (actor variance) and to be desired by other people (partner variance), as well as people's desire for specific partners above and beyond actor and partner variance (relationship variance). In two speed-dating studies, romantically unattached individuals completed more than 100 self-report measures about traits and preferences that past researchers have identified as being relevant to mate selection. Each participant met each opposite-sex participant attending a speed dating event for a 4-min speed date. Random forests models predicted 4% to 18% of actor variance and 7% to 27% of partner variance; crucially, however, they were unable to predict relationship variance using any combination of traits and preferences reported before the dates. These results suggest that compatibility elements of human mating are challenging to predict before two people meet. PMID- 28853648 TI - Healthcare staff urged to contribute to 'radical overhaul of nursing education'. AB - Front-line nurses are being urged to use their experience to help shape a 'radical overhaul' of nursing education. PMID- 28853646 TI - Opportunities for change: the United Nations Working for Health and Growth report. AB - The United Nations High-Level Commission on Health Employment and Economic Growth recently published a report that makes ten recommendations and four calls for immediate action. Analysis of the report, Working for Health and Growth: Investing in the Health Workforce, highlights several opportunities for nursing to contribute to a wide-based agenda while positioning the profession to gain wider influence. The report, when analysed through the lens of regulation, professional practice and socio-economic welfare, offers opportunities for nurses in different sectors to work collaboratively to further the recommendations. Importantly, the report seeks to reframe how money spent on healthcare provision is viewed. In particular, it suggests that such funding should be regarded as an investment rather than a cost, and one that delivers up to ninefold returns. The report is supported by several technical evidence-based documents, and features contributions from a range of intergovernmental agencies, such as the World Health Organization, the Organisation for Economic Cooperation and Development and the International Labour Organization. This article argues that nurses can, and should, make a significant contribution to this agenda and, in so doing, position the profession for the future. PMID- 28853649 TI - Fungus from Japan infects UK hospitals. AB - More than 200 people have been contaminated or infected with a potentially deadly strain of drug-resistant fungus during outbreaks at UK hospitals. PMID- 28853650 TI - Nurses' lifestyle resource launched. AB - An interactive resource has been launched to help nurses maintain lifestyles as healthy as those they want for their patients. PMID- 28853651 TI - Summer of protest message is getting through. AB - Nursing Management subscribers are receiving print copies of the September issue just days before the RCN's latest move in its Scrap the Cap pay campaign, its 'biggest ever UK rally', in London on Wednesday 6 September. According to general secretary Janet Davies, the 'summer of protest' message is getting through. PMID- 28853652 TI - Compassion is a vital element of care. AB - The NHS was founded 69 years ago on the principles of compassion and commitment to providing free healthcare to those who require it, regardless of age, gender, ethnicity, economic status or any other characteristic. PMID- 28853653 TI - Exploring the development and identity of advanced practice nursing in the UK. AB - The development of advanced nurse practice in the UK has been slow compared to some parts of the world. This article explores the history of advanced level nursing, the drivers for advanced nurse practice in the context of contemporary nursing and clinical leadership, the identity of advanced practice nursing roles, and the importance of advanced nurse practice in the UK. PMID- 28853654 TI - Nurses' and midwives' revalidation preparation experiences at one NHS trust. AB - Since 1 April 2016, UK nurses and midwives have been required to undertake revalidation to maintain their registration with the Nursing and Midwifery Council. This article reports the results of a service evaluation to identify the revalidation preparation experiences of nurses and midwives at University College London Hospitals NHS Foundation Trust (UCLH). Findings suggest that the revalidation preparation process at UCLH supports staff to seek opportunities continually for practice feedback, reflect on their everyday experiences and link their learning to ongoing professional development. PMID- 28853655 TI - Towards a smoke-free generation. AB - Essential facts Currently just over 15% of adults in the UK smoke, the lowest level since records began. However, smoking remains the single biggest cause of preventable deaths, with more than 200 every day. PMID- 28853656 TI - Nurses cannot always be bystanders. AB - Sometimes we tell stories about situations in which we were unhappy, but where we could not have stepped in to ensure different outcomes. PMID- 28853657 TI - New campaign to promote nursing. AB - Nurses are too often 'invisible, taken for granted and prevented from being as effective as they could be', according to a former health minister and NHS leader. PMID- 28853658 TI - A logic model approach to the development of an educational app. AB - Technological educational resources require planning and structure to ensure successful implementation. This article describes the development, and evolution of, an online educational training package for third-year undergraduate nursing students. It explains how a 'logic model' was used as a framework to help develop and implement an online clinical supervision supervisee-training programme, and describes evolution of the framework to an app for mobile devices. PMID- 28853659 TI - RCN warns nine in ten largest NHS hospitals short of nurses. AB - Nine in ten of England's 50 largest NHS hospital trusts are not staffed with nurses to the level planned by their own management, the RCN says. PMID- 28853660 TI - Clinical Leadership in Nursing and Healthcare: Values into Action Stanley David Clinical Leadership in Nursing and Healthcare: Values into Action 392pp L34.99 Wiley Blackwell 9781119253761 1119253764 [Formula: see text]. AB - This book, now in its second edition, explores new ways of evaluating leadership in nursing and focuses on the importance of clinical leadership under the heading 'congruent leadership'. PMID- 28853661 TI - Recording and measuring public health effect. AB - It is important to record and measure public health impact, not least because they highlight the work of healthcare professionals, encourage continued investment in public health and demonstrate the value of public health services to commissioners. PMID- 28853662 TI - 'Courage of conviction with compassion'. AB - What is your job? I am chief executive officer (CEO) of Woking and Sam Beare Hospices, Surrey. The charity delivers specialist palliative care services to more than 1,400 patients and their families across six boroughs, and has recently moved into a brand new state-of-the-art hospice. My role includes the financial and business running of the hospice, along with fundraising, retail, governance and clinical services. PMID- 28853663 TI - Knowledge and confidence in medication management. AB - The most common intervention in clinical practice is medication, yet medication errors account for between 10% and 20% of all adverse events, and one quarter of litigation claims, in the NHS. PMID- 28853666 TI - Take charge and change our healthcare system. AB - It is often said that no two days in nursing are the same. This means staff nurses and nurse managers understand how to work with unknowns. Nurses often make the best of any situation, calmly delivering measured care while advocating for what they know to be the best for their patients and staff. PMID- 28853665 TI - Rights for carers. AB - In April 2018, the Carers' Act comes into force in Scotland to ensure the rights of adult and young carers are recognised and upheld, and that they receive consistent and appropriate support to continue their caring role. PMID- 28853664 TI - Information governance laws and principles. AB - The Health Quality Improvement Partnership has launched a guide on how information governance laws and principles apply to the use of personal data in local or regional multi-agency healthcare quality improvement studies, such as clinical audits, productivity reviews, intervention testing and service evaluation. PMID- 28853667 TI - Trainee healthcare support workers. AB - The new nursing associate role will sit alongside those of other healthcare support workers, including registered nurses, in the delivery of hands-on patient care. A second wave of around 2,000 nursing associates is being trained by providers across England, and Health Education England has filmed videos of trainees explaining their aspirations and their experience of training so far. PMID- 28853668 TI - Quality and Safety in Nursing: A Competency Approach to Improving Outcomes Sherwood Gwen Barnsteiner Jane Quality and Safety in Nursing: A Competency Approach to Improving Outcomes 424pp L45.99 Wiley Blackwell 9781119151678 1119151678 [Formula: see text]. AB - Two of the most vital features of high-standard, patient-focused care are quality and safety. This publication, now in its second edition, begins by identifying the driving forces of excellent care and the complexities of adopting a competency approach to improve outcomes. PMID- 28853670 TI - Around the world. AB - 1. 19th International Conference on Nursing Leadership and Management 18-19 September, Rome, Italy tinyurl.com/nursing-leadership-italy. PMID- 28853669 TI - Future of nursing in Scotland. AB - There is much to like in Scotland's Nursing 2030 Vision, but its success will depend on its implementation. As the name suggests, the document, published in July, sets out a strategy for what nursing in Scotland should look like in 2030. It considers what is done well and what should change, and how to deal with future demands, such as the ageing population and workforce. PMID- 28853671 TI - Noticeboard. AB - Courses, events, grants, and awards to progress your career. PMID- 28853672 TI - There's more to staff recruitment than pay: NHS Improvement. AB - Retaining staff remains a major problem for the NHS. Over the past six years the proportion of nurses leaving the health service has risen by one quarter, to top 10% in 2016. PMID- 28853673 TI - Differentiation of Hepatocellular Carcinoma from Other Hepatic Malignancies in Patients at Risk: Diagnostic Performance of the Liver Imaging Reporting and Data System Version 2014. AB - Purpose To evaluate the diagnostic performance and interrater reliability of the Liver Imaging Reporting and Data System (LI-RADS) version 2014 in differentiating hepatocellular carcinoma (HCC) from non-HCC malignancy in a population of patients at risk for HCC. Materials and Methods This retrospective HIPAA compliant institutional review board-approved study was exempt from informed consent. A total of 178 pathology-proven malignant liver masses were identified in 178 patients at risk for HCC but without established extrahepatic malignancy from August 2012 through August 2015. Two readers blinded to pathology findings and clinical follow-up data independently evaluated a liver protocol magnetic resonance or computed tomography study for each lesion and assigned LI-RADS categories, scoring all major and most ancillary features. Statistical analyses included the independent samples t test, x2 test, Fisher exact test, and Cohen k. Results This study included 136 HCCs and 42 non-HCC malignancies. Specificity and positive predictive value of an HCC imaging diagnosis (LR-5 or LR-5V) were 69.0% and 90.5%, respectively, for reader 1 (R1) and 88.3% and 95.5%, respectively, for reader 2 (R2). Tumor in vein was a common finding in patients with non-HCC malignancies (R1, 10 of 42 [23.8%]; R2, five of 42 [11.9%]). Exclusion of the LR 5V pathway improved specificity and positive predictive value for HCC to 83.3% and 92.9%, respectively, for R1 (six fewer false-positive findings) and 92.3% and 96.4%, respectively, for R2 (one fewer false-positive finding). Among masses with arterial phase hyperenhancement, the rim pattern was more common among non-HCC malignancies than among HCCs for both readers (R1: 24 of 36 [66.7%] vs 13 of 124, [10.5%], P < .001; R2: 27 of 35 [77.1%] vs 21 of 123 [17.1%], P < .001) (k = 0.76). Exclusion of rim arterial phase hyperenhancement as a means of satisfying LR-5 criteria also improved specificity and positive predictive value for HCC (R1, two fewer false-positive findings). Conclusion Modification of the algorithmic role of tumor in vein and rim arterial phase hyperenhancement improves the diagnostic performance of LI-RADS version 2014 in differentiating HCC from non-HCC malignancy. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28853675 TI - "San Junipero," Black Mirror Season 3, Episode 4. PMID- 28853674 TI - MR Imaging-based Multimodal Autoidentification of Perivascular Spaces (mMAPS): Automated Morphologic Segmentation of Enlarged Perivascular Spaces at Clinical Field Strength. AB - Purpose To describe a fully automated segmentation method that yields object based morphologic estimates of enlarged perivascular spaces (ePVSs) in clinical field-strength (3.0-T) magnetic resonance (MR) imaging data. Materials and Methods In this HIPAA-compliant study, MR imaging data were obtained with a 3.0-T MR imager in research participants without dementia (mean age, 85.3 years; range, 70.4-101.2 years) who had given written informed consent. This method is built on (a) relative normalized white matter, ventricular and cortical signal intensities within T1-weighted, fluid-attenuated inversion recovery, T2-weighted, and proton density data and (b) morphologic (width, volume, linearity) characterization of each resultant cluster. Visual rating was performed by three raters, including one neuroradiologist, after established single-section guidelines. Correlations between visual counts and automated counts, as well session-to-session correlation of counts within each participant, were assessed with the Pearson correlation coefficient r. Results There was a significant correlation between counts by visual raters and automated detection of ePVSs in the same section (r = 0.65, P < .001; r = 0.69, P < .001; and r = 0.54, P < .01 for raters 1, 2, and 3, respectively). With regard to visual ratings and whole-brain count consistency, average visual rating scores were highly correlated with automated detection of total burden volume (r = 0.58, P < .01) and total ePVS number (r = 0.76, P < .01). Morphology of clusters across 28 data sets was consistent with published radiographic estimates of ePVS; mean width of clusters segmented was 3.12 mm (range, 1.7-13.5 mm). Conclusion This MR imaging-based method for multimodal autoidentification of perivascular spaces yields individual whole-brain morphologic characterization of ePVS in clinical MR imaging data and is an important tool in the detailed assessment of these features. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28853677 TI - Reasons for switching ART: Comparison of data collected in 2012-2013 and 2014 2015 in Florence, Italy. AB - Persons living with HIV should remain on antiretroviral therapy (ART) indefinitely; however, a switch in the drug regimen is often necessary. In order to investigate if reasons for switching ART changed over time, we retrospectively analyzed reasons for switching and characteristics of switches among patients at Santa Maria Annunziata Hospital (OSMA), Florence area, Tuscany, Italy, over two periods (November 2012-October 2013 and November 2014-October 2015). The reasons for switching were classified as: simplification; virologic failure; occurrence of co-morbidities; and drug tolerability/toxicity issues. In period 1 (2012 2013), 18% patients changed their regimen vs. 13.5% in period 2 (2014-2015) (p = 0.019). Among reasons for switching, switches for simplification significantly increased from 41% in period 1 to 53% in period 2 (p = 0.004), with an increasing use of single tablet regimens (p = 0.002); no other statistically significant differences were found in other reasons for switching in periods 1 and 2. Characteristics of patients and of switches were analyzed and described. According to our data, the main reason for switching is now simplification, reflecting the recent changes in recommendations aimed to enhance adherence and quality of life, and to minimize, at the same time, drug toxicity and side effects. PMID- 28853676 TI - HIV/AIDS conspiracy beliefs and intention to adopt preexposure prophylaxis among black men who have sex with men in Los Angeles. AB - In the United States, black men who have sex with men (MSM) are the group most affected by the HIV/AIDS epidemic. Pre-exposure prophylaxis (PrEP) is an important new HIV prevention strategy that may help reduce new HIV infections among black MSM. This analysis examined the association between HIV/AIDS conspiracy beliefs and intentions to adopt PrEP among 224 black MSM. The likelihood of adopting PrEP was assessed and more than half (60%) of the study population indicated a high intention to adopt PrEP. HIV/AIDS genocidal and treatment-related conspiracies were assessed using scales previously validated with black MSM. Almost two-thirds (63%) endorsed at least one of eight HIV/AIDS conspiracy beliefs presented. In multivariable analyses, black MSM who agreed with the genocidal or treatment-related conspiracy beliefs scales had a lower intention to adopt PrEP (Adjusted Odds Ratio [AOR] = 0.73, 95% CI = 0.54, 0.99 and AOR = 0.36, 95% CI = 0.23, 0.55, respectively). Our findings indicate that preexisting HIV/AIDS conspiracy beliefs may deter some black MSM from adopting PrEP. We suggest strategies PrEP implementers may want to employ to address the influence that HIV/AIDS conspiracy beliefs may have on the adoption of PrEP among black MSM, a population disproportionately affected by HIV/AIDS. PMID- 28853678 TI - HPV-related squamous cell carcinoma in a neovagina after male-to-female gender confirmation surgery. AB - Vaginoplasty by penile and scrotal skin inversion is a well-established technique for male-to-female gender confirmation surgery. In this setting, chronic inflammation and lacerations associated with history of human papillomavirus (HPV) infection may induce a high risk of malignant degeneration in the long term. A 78-year-old transgender woman was admitted with genital discomfort and neovaginal discharge. The patient's history revealed male-to-female gender confirmation surgery with construction of a neovagina by penile and scrotal skin inversion at 33 years of age. Physical examination of the genitalia revealed presence of fecal material, suggestive of recto-neovaginal fistula. A biopsy specimen was positive for well-differentiated HPV-related squamous cell carcinoma. Magnetic resonance imaging (MRI) showed a bulky mass in the posterior wall of the neovagina that infiltrated the urethra, prostatic gland and the anterior rectal wall. Following a multidisciplinary evaluation, we performed a definitive sigmoid colostomy and administered chemotherapy. Long-term follow-up seems advisable in patients after vaginoplasty due to the possibility of delayed development of cancer. Following biopsy, we consider MRI as the modality of choice to identify possible infiltration of the adjacent structures. As data regarding these lesions are scarce and management is complex, a multidisciplinary approach is recommended. PMID- 28853679 TI - Massilia phosphatilytica sp. nov., a phosphate solubilizing bacteria isolated from a long-term fertilized soil. AB - A Gram-stain-negative and rod-shaped bacterial strain, 12-OD1T, with rock phosphate solubilizing ability was isolated from agricultural soil in Hailun, Heilongjiang, PR China. The isolate was affiliated to the genus Massilia, based on 16S rRNA gene sequence alignments, having the highest similarities with Massilia putida6 NM-7T (98.67 %), Massilia kyonggiensis TSA1T (98.28 %), and Massilia norwichensis NS9T (98.07 %), respectively. The DNA G+C content was 67.72 mol% and DNA-DNA hybridization showed low relatedness values (less than 47 %) between strain 12-OD1T and other phylogenetically related species of the genus Massilia. The predominant isoprenoid quinone was Q-8 and the polar lipid profile comprised diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The major fatty acids were C17 : 0 cyclo (25.4 %), C16 : 0 (23.4 %) and summed feature 3 (C16 : 1omega7c and/or C16 : 1 omega6c) (22.5 %), which differentiates it from close relatives within the genus Massilia. Combined genetic, physiological and biochemical properties indicate that strain 12-OD1T is a novel species of the genus Massilia, for which the name Massilia phosphatilytica sp. nov., is proposed, with the type strain 12-OD1T (=CCTCC AB 2016251T=LMG 29956T=KCTC 52513T). PMID- 28853680 TI - Pseudonocardia thailandensis sp. nov., an actinomycete isolated from a subterranean termite nest. AB - A novel Gram-stain-positive bacterium designated CMU-NKS-70T was isolated from a subterranean termite nest and characterized using a polyphasic approach. The strain exhibited branching, pinkish-cream aerial mycelium and cream-brown substrate mycelium, and formed chains of rod-like spores. The 16S rRNA gene sequence analyses indicated that strain CMU-NKS-70T belonged to the genus Pseudonocardia, showing high similarity with Pseudonocardia oroxyli D10T (98.9 % 16S rRNA gene sequence similarity), Pseudonocardia xishanensis YIM 63638T (98.9 %) and Pseudonocardia kujensis A4038T (98.5 %). However, DNA-DNA relatedness values between strains CMU-NKS-70T and the closest phylogenetically related species ranged from 40.5+/-2.9 to 48.6+/-0.7 %. Whole-cell hydrolysates of strain CMU-NKS-70T consisted of meso-diaminopimelic acid, glucose, galactose, arabinose, mannose, ribose and rhamnose. The predominant menaquinone was MK-8(H4). The major cellular fatty acids (>10 %) were iso-C16 : 0, C16 : 0, C16 : 1omega7c and/or iso C15 : 0 2-OH and 10-methyl C16 : 0. The polar lipids detected were phosphatidylethanolamine, phosphatidylmethylethanolamine, hydroxyphosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, three unidentified glycolipids and two unidentified phospholipids. The G+C content of genomic DNA was 71.9 mol%. The physiological and biochemical properties also supported the phenotypic distinction of strain CMU-NKS-70T from its closely related species. On the basis of evidence from this study using a polyphasic approach, strain CMU-NKS-70T represents a novel species of the genus Pseudonocardia for which the name Pseudonocardia thailandensis sp. nov. is proposed. The type strain is CMU-NKS-70T (=JCM 31292T=TBRC 2000T). PMID- 28853681 TI - Proposal for the reclassification of obligately purine-fermenting bacteria Clostridium acidurici (Barker 1938) and Clostridium purinilyticum (Durre et al. 1981) as Gottschalkia acidurici gen. nov. comb. nov. and Gottschalkiapurinilytica comb. nov. and of Eubacterium angustum (Beuscher and Andreesen 1985) as Andreesenia angusta gen. nov. comb. nov. in the family Gottschalkiaceae fam. nov. AB - Several strictly anaerobic bacteria that are Gram-stain-positive have the ability to use uric acid as the sole source of carbon and energy. The phylogeny of three such species, Clostridium acidurici, Clostridium purinilyticum, and Eubacterium angustum, members of the Clostridium cluster XII that ferment purines, but not most amino acids or carbohydrates, has been re-examined, taking advantage of their recently sequenced genomes. Phylogenetic analyses, based on 16S rRNA gene sequences, protein sequences of RpoB and GyrB, and on a concatenated alignment of 50 ribosomal proteins, revealed tight clustering of C. acidurici and C. purinilyticum. Eubacterium angustum showed consistent association with C. acidurici and C. purinilyticum , but differed from these two in terms of the genome size, G+C content of its chromosomal DNA and its inability to form spores. We propose reassigning C. acidurici and C. purinilyticum to the novel genus Gottschalkia as Gottschalkia acidurici gen. nov. comb. nov. (the type species of the genus) and Gottschalkia purinilytica comb. nov., respectively. Eubacterium angustum is proposed to be reclassified as Andreesenia angusta gen. nov. comb. nov. Furthermore, based on the phylogenetic data and similar metabolic properties, we propose assigning genera Gottschalkia and Andreesenia to the novel family Gottschalkiaceae. Metagenomic sequencing data indicate the widespread distibution of organisms falling within the radiation of the proposed family Gottschalkiaceae in terrestrial and aquatic habitats from upstate New York to Antarctica, most likely due to their ability to metabolize avian-produced uric acid. PMID- 28853682 TI - Thermus caldifontis sp. nov., a thermophilic bacterium isolated from a hot spring. AB - A thermophilic bacterial strain, designated YIM 73026T was isolated from a sediment sample collected from a hot spring in Tibet, PR China. The taxonomic position of the novel isolate was investigated by a polyphasic approach. The novel isolate was Gram-stain-negative, aerobic and rod-shaped. Colonies were circular, convex, opaque and yellow. The strain grew at 50-70 degrees C (optimum, 60 degrees C), pH 6.0-8.0 (optimum, pH 7.0) and in the presence of up to 1.0 % NaCl (w/v). Comparison of the 16S rRNA gene sequences of YIM 73026T and those of other members of the genus Thermus showed sequence similarities ranging from 91.2 to 97.5 %, with YIM 73026T showing closest sequence similarity to Thermus scotoductus SE-1T (97.5 %). DNA-DNA hybridization results, however, revealed that DNA-DNA reassociation values between YIM 73026T and T. scotoductus DSM 8553T (37.6 %), Thermusamyloliquefaciens YIM 77409T (34.5 %), Thermusantranikianii DSM 12462T (30.3 %), Thermuscaliditerrae YIM 77925T (28.6 %) and Thermustengchongensis YIM 77924T (27.3 %) were well below the 70 % limit for species identification. YIM 73026T contained MK-8 as the respiratory quinone, and iso-C15 : 0, iso-C16 : 0, iso-C17 : 0 and anteiso-C15 : 0 as the major cellular fatty acids (>10 %). The polar lipids consisted of one aminophospholipid, one phospholipid and two glycolipids. The genomic DNA G+C content of YIM 73026T was 65.4 mol%. On the basis of morphological, chemotaxonomic and genotypic characteristics, it is proposed that the isolate represents a novel species of the genus Thermus, for which the name Thermus caldifontis sp. nov. is proposed. The type strain is YIM 73026T (=NBRC 112415T=CCTCC AB 2016305T). PMID- 28853683 TI - Nocardioides thalensis sp. nov., isolated from a desert. AB - A novel actinobacterial strain, designated NCCP-696T, was isolated from the Thal desert in Punjab, Pakistan, and characterized by using a polyphasic taxonomy approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain NCCP-696T belongs to the genus Nocardioides and showed the highest level of sequence similarity with respect to Nocardioides panacisoliGsoil 346T (98.2 %) and less than 96.4 % to the strains of other species of the genus Nocardioides. Cells of strain NCCP-696T were Gram-positive, aerobic, non-motile rods and formed cream-coloured colonies. The strain was positive for oxidase and catalase. Growth occurred at 20-42 degrees C (optimum 30-37 degrees C) at pH 5.5-9.0 (optimum pH 7.0) and with 0-4 % NaCl (optimum 0-2 %, w/v). Strain NCCP-696T contained Iso-C16 : 0, C18 : 1omega9c, C17 : 1omega8c and C17 : 0 as the predominant fatty acids and was found to have LL-2,6-diaminopimelic acid in the cell-wall peptidoglycan. The polar lipid profile consisted of phosphatidylinositol, phosphatidylglycerol and one unknown phospholipid. The major menaquinone was MK-8(H4) (98.7 %) while a minor amount (1.3 %) of MK-9(H2) was also detected. The DNA G+C content of the genomic DNA was 71.6 mol%. The DNA-DNA hybridization value of the isolate against the closely related type strain Nocardioides panacisoliGsoil 346T was 56.3+/-1.4. On the basis of the phylogenetic inference, chemotaxonomic characteristics and phenotypic data, strain NCCP-696T should be classified as a novel species, for which the name Nocardioides thalensis sp. nov. is proposed. The type strain is NCCP-696T (=DSM 103833T=CCTCC AB 2016296T). PMID- 28853684 TI - Micrococcoides hystricis gen. nov., sp. nov., a novel member of the family Micrococcaceae, phylum Actinobacteria. AB - A Gram-stain-positive bacterium, designated TSL3T, was isolated from faeces of a porcupine, Hystrix indica, from the Budapest Zoo and Botanical Garden, Hungary. On the basis of 16S rRNA gene sequence analysis, the strain is phylogenetically related to the family Micrococcaceae. The highest 16S rRNA gene sequence similarity was found with Micrococcus terreus V3M1T (96.50 %) followed by Arthrobacter humicola KV-653T (96.43 %). Cells of strain TSL3T were aerobic, non motile and coccoid-shaped. The main fatty acids were anteiso-C15 : 0 (54.4 %), iso-C16 : 0 (18.2 %) and iso C15 : 0 (9.7 %). The major menaquinone was MK-7, and the polar lipid profile included phosphatidylglycerol, diphosphatidylglycerol, dimannosylglyceride, trimannosyldiacylglycerol, phosphatidylinositol, three unknown phospholipids and two unknown glycolipids. Strain TSL3T showed the peptidoglycan structure A4alpha l-Lys - Gly - l-Glu. The DNA G+C content of strain TSL3T was 58.4 mol%. Phenotypic and genotypic characterisation clearly showed that strain TSL3T could be differerentiated from the members of other genera in the family Micrococcaceae. According to these results, strain TSL3T represents a novel genus and species, for which the name Micrococcoides hystricis gen. nov., sp. nov. is proposed. The type strain is TSL3T (=DSM 29785T=NCAIM B. 02604T). PMID- 28853686 TI - Serratia oryzae sp. nov., isolated from rice stems. AB - A novel endophytic bacterium, strain J11-6T, was isolated from rice stems. Its taxonomic position was investigated using a polyphasic approach. The novel strain was Gram-staining-negative, facultatively anaerobic, motile and rod-shaped. Although the results of phylogenetic analysis based on 16S rRNA gene sequences indicated that J11-6T represented a member of the genus Rahnella, multilocus sequence analysis (MLSA) on the basis of concatenated partial atpD, gyrB, rpoB and infB gene sequences showed a clear distinction of J11-6T from the type strains of species of the genus Rahnella but indicated that it lay within the clade of the genus Serratia. The phylogenetically closest species were Serratia fonticola and Serratia aquatilis on the basis of the results of the MLSA phylogenetic analysis. The predominant cellular fatty acids were C16 : 1omega7c (38.7 %) and C16 : 0 (25.0 %). The DNA G+C content was 53.2 mol%. The DNA-DNA relatedness was 17.4 % between J11-6T and Rahnella aquatilis CIP 78.65T, and 29.2 % between J11-6T and S. fonticola LMG 7882T which indicates that this strain represents a novel species of the genus Serratia. Characterization by genotypic and phenotypic analysis indicated that J11-6T (=ACCC 19934T=KCTC 52529T) represents a novel species of the genus Serratia, for which the name Serratia oryzae sp. nov. is proposed. PMID- 28853685 TI - Arenimonas soli sp. nov., isolated from saline-alkaline soil. AB - A Gram-staining-negative, non-motile, aerobic bacterial strain, designated Y3L17T, was isolated from the saline-alkaline soil of a farmland, Hangjin Banner, Inner Mongolia, northern China. Y3L17T could grow at 15-45 degrees C (optimum 35 degrees C), pH 6.0-10.0 (optimum pH 8.0) and with 0-4 % (w/v) NaCl (optimum 0 %). The results of phylogenetic analysis based on the 16S rRNA gene and gyrB gene sequences revealed that Y3L17T tightly clustered with strains of members of the genus Arenimonas, sharing the highest 16S rRNA gene similarities with Arenimonas aestuarii S2-21T (99.5 %) and Arenimonas donghaensis HO3-R19T (98.2 %), and lower similarities (<97 %) with all the other type strains of species of this genus. However, Y3L17T shared only 92.62 % gyrB gene similarities with A. aestuarii S2 21T. The DNA-DNA hybridization values of Y3L17T with A. aestuariiS2-21T and A. donghaensis HO3-R19T were 20.1+/-2.5 and 18.2+/-3.2 %, respectively. Y3L17T contained phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, five unknown phospholipids and one unknown lipid as the major polar lipids. Ubiquinone-8 (Q-8) was the predominant respiratory quinone, while iso-C15 : 0, iso-C17 : 0omega9c and iso-C11 : 0 3-OH were the major cellular fatty acids. Its genomic DNA G+C content was 65.4 mol%. On the basis of its phenotypic, phylogenetic and genotypic characteristics, Y3L17T represents a novel species within the genus Arenimonas, for which the name Arenimonas soli sp. nov. is proposed, the type strain is Y3L17T (=CGMCC 1.15905T =KCTC 52420T). PMID- 28853687 TI - Nonomuraea stahlianthi sp. nov., an endophytic actinomycete isolated from the stem of Stahlianthus campanulatus. AB - A novel endophytic actinomycete, designated strain SC1-1T, was isolated from sterilized stem tissue from Stahlianthus campanulatus collected in Udon Thani province, Thailand. The isolate formed short chains of spores on aerial mycelium and presented meso-diaminopimelic acid in the cell wall peptidoglycan. Glucose, madurose, mannose, rhamnose and ribose were observed as sugars in the cells. The cell membrane phospholipids were phosphatidylethanolamine, phosphatidylmethylethanolamine, hydroxy-phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and ninhydrin-positive phosphoglycolipids. The major menaquinones were MK-9(H4) and MK-9(H2). The main cellular fatty acids were iso-C16:0, 10-methyl C17 : 0 and C17 : 1omega6c. A high G+C content (70.7 mol%) was present in the genomic DNA. The taxonomic position based on the 16S rRNA gene sequence analysis revealed that strain SC1-1T belonged to the genus Nonomuraea and shared the highest 16S rRNA gene sequence similarity value with Nonomuraea dietziae DSM 44320T (98.82 %), followed by Nonomuraea africana IFO 14745T (98.58 %), Nonomuraea jabiensis A4036T (98.43 %), Nonomuraea endophytica YIM 65601T (98.36 %), Nonomuraea purpurea 1SM4 01T (98.34 %), Nonomuraea angiospora IFO 13155T (98.29 %), Nonomuraea roseola IFO 14685T (98.23 %) and Nonomuraea recticatena IFO 14525T (98.23 %). On the basis of the DNA-DNA hybridization relatedness and including the physiological and biochemical characteristics, strain SC1-1T should be judged as a novel species of the genus Nonomuraea, for which the name Nonomuraea stahlianthi sp. nov. is proposed. The type strain is strain SC1-1T (=BCC 66361T=NBRC 110006T). PMID- 28853688 TI - Corrigendum: Actinomyces vulturis sp. nov., isolated from Gyps himalayensis. PMID- 28853689 TI - Sphingomonas silvisoli sp. nov., isolated from forest soil. AB - A novel Gram-stain-negative, aerobic, non-motile and short-rod-shaped bacterium, designated RP18T, was isolated from forest soil in Gwang-ju, Republic of Korea. Growth occurred at 15-30 degrees C (optimum 30 degrees C), pH 6.0-7.0 (optimum pH 7.0), and was inhibited in the presence of normal saline. According to the 16S rRNA gene sequence, strain RP18T showed the highest sequence similarity to Sphingomonas kyeonggiensis THG-DT81T (96.0 %), followed by Sphingomonas pituitosa EDIVT (95.4 %) and Sphingomonas dokdonensis DS-4T (95.2 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain RP18T was clustered with Sphingomonas gimensis 9PNM-6T and Sphingomonas jejuensis MS-31T under the genus Sphingomonas. The G+C content of the genomic DNA of strain RP18T was 61.5 mol%. The major cellular fatty acids (>6 % of the total) were C16 : 0, C14 : 0 2-OH, C17 : 1omega6s, summed feature 3 (C16 : 1omega7s and/or C16 : 1omega6s) and summed feature 8 (C18 : 1omega7s and/or C18 : 1omega6s). Ubiquinone-10 (Q-10) and sym-homospermidine were detected as the predominant respiratory quinone and major compound in the polyamine pattern, respectively. The major polar lipids of the isolate consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phospholipid and sphingoglycolipid. Based on phylogenetic analysis and physiological and biochemical characterization, strain RP18T represents a novel species of the genus Sphingomonas, for which the name Sphingomonas silvisoli sp. nov. is proposed. The type strain is RP18T (=KACC 18914T=JCM 31801T). PMID- 28853690 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 67, part 5, of the IJSEM. PMID- 28853691 TI - Corrigendum: Paraliobacillus sediminis sp. nov., isolated from East China sea sediment. PMID- 28853692 TI - Altererythrobacter halimionae sp. nov. and Altererythrobacter endophyticus sp. nov., two endophytes from the salt marsh plant Halimione portulacoides. AB - Two Gram-negative, rod-shaped, motile bacterial strains, named CPA5T and BR75T, were isolated from the halophyte Halimione portulacoides. Both presented optimum growth at 30 degrees C, pH 7.0-7.5 and 1-2 % NaCl (w/v) for strain CPA5T, and pH 7.5-8.0 and 2 % NaCl (w/v) for strain BR75T. Phylogenetic analyses based on 16S rRNA gene sequences affiliated both strains to the genus Altererythrobacter. CPA5T presented highest 16S rRNA gene sequence similarity with Altererythrobacter aestuarii KYW147T (96.5 %), followed by Altererythrobacter namhicola KYW48T (95.9 %), Novosphingobium indicum H25T (95.6 %) and Altererythrobacter oceanensis Y2T (95.5 %). BR75T displayed highest similarity with Altererythrobacter marensis MSW 14T (96.5 %), followed by Altererythrobacter xinjiangensis S3-63T, Altererythrobacter luteolus SW-109T and Altererythrobacter indicus MSSRF26T (96.1 %). Neither strain contained Bacteriochlorophyll a. The main fatty acids observed for CPA5T were C17 : 1omega6c and summed features 3 (C16 : 1omega7c and/or iso C15 : 0 2-OH) and 8 (C18 : 1 omega7c and/or C18 : 1omega6c). The latter summed feature was the dominant fatty acid observed for strain BR75T as well. The major polar lipids were phosphatidylethanolamine, unidentified phospholipids and unidentified glycolipids for both strains. The predominant ubiquinone was Q-10 for both strains, and the DNA G+C contents were 63.4 mol% and 58.3 mol% for CPA5T and BR75T, respectively. Based on phenotypic and genotypic results, both strains represent novel species belonging to the genus Altererythrobacter for which the names Altererythrobacter halimionae sp. nov. (type strain CPA5T=CECT 9130T=LMG 29519T) and Altererythrobacter endophyticus sp. nov (type strain BR75T=CECT 9129T=LMG 29518T) are proposed. PMID- 28853693 TI - Mesorhizobium oceanicum sp. nov., isolated from deep seawater. AB - A novel Gram-staining-negative, oval-shaped (0.4-0.6*0.8-1.0 um), non-motile strain without flagella, designated B7T, was isolated from deep seawater in the South China Sea. Strain B7T was able to grow at 25-40 degrees C (optimum 35 degrees C), at pH 5.5-9.0 (optimum pH 7.0) and with 0-8 % (w/v) NaCl (optimum 3 %). Chemotaxonomic analysis showed that the predominant isoprenoid quinone was Q 10 and the dominant fatty acids were C19 : 0 cyclo 8c and summed feature 8 (C18 : 1omega7c/C18 : 1omega6c). The polar lipids of strain B7T were diphosphatidyglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, one unknown aminophospholipid, one unknown glycolipid and three unknown lipids. The DNA G+C content of the genomic DNA was 65.1 mol%. Phylogenetic analysis of 16S rRNA gene sequences showed that strain B7T belongs to the genus Mesorhizobium with similarities ranging from 96.2 to 97.5 %. Phylogenetic analyses of housekeeping genes recA, atpD and glnII indicated that strain B7T represented a distinct evolutionary lineage with the genus Mesorhizobium. OrthoANI values between strain B7T and related strains of the genus Mesorhizobium (<80 %) were lower than the threshold value of 95 % ANI relatedness for species demarcation. Therefore, strain B7T is concluded to represent a novel species of the genus Mesorhizobium, for which the name Mesorhizobium oceanicumsp. nov. is proposed. The type strain is B7T (=KCTC 42783T=MCCC 1K02305T). PMID- 28853694 TI - Zunongwangia endophytica sp. nov., an endophyte isolated from the salt marsh plant, Halimione portulacoides, and emended description of the genus Zunongwangia. AB - Taxonomical analyses were performed on strain CPA58T, a novel isolate obtained from surface-sterilized aboveground tissues of the halophyte Halimione portulacoides, collected from a salt marsh in Ria de Aveiro, Portugal. The strain was Gram-stain-negative, rod-shaped, oxidase-negative and catalase-positive. Optimal growth was observed at 26 degrees C, at pH 6-8 and in the presence of 2 to 3 % (w/v) NaCl. Phylogenetic analyses, based on the 16S rRNA gene sequence, showed that strain CPA58T belongs to the genus Zunongwangia, with highest sequence similarities to both Zunongwangia profunda SM-A87T and Zunongwangia mangrovi P2E16T (96.5 %), followed by Zunongwangia atlantica 22II14-10F7T (95.9 %). The principal fatty acids were iso-C15 : 0, summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH) and iso-C17 : 0 3-OH. The major respiratory quinone was MK-6 and the DNA G+C content was 35.1 mol%. Phylogenetic and chemotaxonomic analyses clearly placed strain CPA58T in the genus Zunongwangia. However, 16S rRNA gene sequence analysis showed that the threshold for same species relatedness was not surpassed, and biochemical tests revealed diagnostic characteristics that differentiated this strain from other type strains of species of the genus Zunongwangia. Overall, the analyses showed that strain CPA58T represents a novel species within the genus Zunongwangia, for which the name Zunongwangia endophytica sp. nov. is proposed, with the type strain CPA58T (=CECT 9128T=LMG 29517T). PMID- 28853695 TI - Paradoxical results obtained with Ki67-labeling and PHH3-mitosis index in glial tumors: a literature analysis. AB - Precise tiered tumor grading is essential for predicting prognosis, selecting different treatment options and for follow-up of brain tumor patients. Ki67 labeling index (LI) is widely employed in assessing aggressiveness of glial brain tumors. However, Ki67 is subject to interlaboratory variability, and its antigen is expressed on all cell cycle phases except G0, which hinders its usage as a precise criterion for assessing cell proliferation. Indeed, there exist peculiar observations pertinent to increases of Ki67 index in glial tumors following radiotherapy or treatment with tyrosine kinase inhibitors. Moreover, we have witnessed a reduced Ki67 labeling in a gemistocytic glioma during its rapid recurrence under temozolomide treatment. Therefore, we reviewed pitfalls in employing Ki67 indices for predicting glial tumor biology and tried to answer whether the mitotic marker PHH3 (phosphorylated histone H3) could provide additional information in predicting glial tumor biology. PHH3-based assessment of proliferating cell fraction provides novel potentials, but it has also its own weaknesses. It has not yet been determined whether it would be more advantageous to report: a mitotic count (MC) per unit-area (e.g., 10 high power fields (HPF)) or a mitotic index (MI) (per 1,000 tumor cells). Further, there exist peculiarities in terms of unexpectedly low or high PHH3 values in pilocytic astrocytomas and angiocentric gliomas, respectively. Indeed, we encountered almost no staining with PHH3 in our unique gemistocytic astrocytoma case. Hence, at least in some glial malignancies, PHH3 may not be necessary for cell proliferation. Awareness of the weaknesses of proliferation markers in brain tumors may improve patient monitoring and treatment.?. PMID- 28853696 TI - Amelanotic melanocytoma of the sella mimicking pituitary adenoma. AB - We describe a 50-year-old man with a well-demarcated intra- and extrasellar lesion and clinical signs of a non-functioning pituitary adenoma. Neuropathological examination revealed tumor composed of non-pigmented spindle cells arranged in tightly packed nests separated by delicate vascular septae. There was no significant cellular atypia or mitotic activity, and Ki67-positive nuclei were present in less than 1% of cells. The neoplastic cells were positive for S-100 and vimentin, and negative for numerous cellular markers including HMB45, anti-melanoma cocktail antibodies, and Masson melanin stain. Electron microscopy revealed scattered cells with small numbers of premelanosomes, aiding in the correct diagnosis of an amelanotic melanocytoma. This is the first case report of entirely amelanotic melanocytoma of meninges, and in a very unique location. BRAF was negative supporting the diagnosis of intracranial origin of the tumor. Approximately 2 years after subtotal resection and stereotactic radiosurgery the patient is alive and well with a non-progressive residual tumor.?. PMID- 28853697 TI - Analysis of inappropriate medication use and drug interactions in older people in South Korea?. AB - OBJECTIVES: Medication use in older people has been increasing as the incidence of chronic diseases increases worldwide. The objective of this study was to assess potentially inappropriate medications (PIMs) and potential drug-drug interactions (pDDIs) to improve the rational use of medications in this population. MATERIALS AND METHODS: In this large, cross-sectional study, data on older people from a regional community obtained during health examinations in 2013 - 2014 were analyzed. Demographic and medication information were collected. We evaluated PIM use in older people by analyzing medication data. The most common PIMs and pDDIs are presented. RESULTS: Among 864 older people, 145 (16.8%) had at least 1 PIM. 41 patients (4.7%) were prescribed more than 2 PIMs, with a mean PIM number of 1.34 per patient. The most commonly prescribed PIMs were alprazolam (12.6%), followed by diazepam (9.4%), amitriptyline (7.9%), meloxicam (7.3%), and nabumetone (5.2%). There were a total of 2,469 cases of pDDIs, with 236 cases (9.6%) of risk categories X and D. The most common pDDI was atorvastatin and diltiazem. CONCLUSION: Our findings demonstrated that PIM use and pDDIs were common in older people in the community setting, suggesting that optimal medication use and supportive interventions are necessary in this population. PMID- 28853698 TI - Prioritization of diseases for the development of a pharmaceutical care service model in South Korea using the analytic hierarchy process?. AB - OBJECTIVE: Drug therapy plays a critical role in most chronic diseases. Effectiveness of pharmaceutical care services in the improvement of clinical, social, or economic outcomes has been scientifically proven through numerous studies. In South Korea, to optimize and standardize pharmaceutical care for patients with chronic metabolic diseases, the development of a pharmaceutical care service model is needed. MATERIALS: To determine the priority of diseases in developing pharmaceutical care service models, analytic hierarchny process (AHP)analysis was used. A survey questionnaire standardized with detailed evaluation areas and an index, to ensure sufficient understanding and identical standards of evaluators, was designed. It was prepared for pair-wise comparisons of individual criteria of candidate diseases. METHODS: Medical specialists and pharmacists who have clinical experience and expertise in chronic metabolic diseases or at least 10 years of experience in pharmacy practice were recruited. They responded to a survey consisting of nine sections by using the pair-wise comparison method. RESULTS: A total of seven candidate diseases were selected for prioritization. Diabetes mellitus was given the highest score of 0.2695, cardiovascular disease (0.2598) being the next, followed by chronic kidney disease (0.2000), and cerebrovascular diseases (0.1087). The criteria were weighted as follows: disease characteristics (0.4964), patient-oriented care (0.3649), and improvement in services (0.1386). CONCLUSION: Diabetes, cardiovascular diseases, and chronic kidney disease were found to have high priority in developing a pharmaceutical care service model in South Korea. In the future, further research for the development and application of pharmaceutical care services models for different types of diseases is required.?. PMID- 28853699 TI - Successful therapy with mycophenolic acid in a membranous glomerulonephritis due to Kimura disease?. AB - Kimura disease (KD) is a rare inflammatory soft tissue disorder of unknown origin most frequent in Asians, the prevalence of which is growing in Western countries. Painless papules and/or nodules with a predilection for the head and the neck region, lymphadenopathies, parotid gland involvement, eosinophilia, and raised IgE levels are parts of its presentation. Renal involvement with various forms of glomerulonephritis, including membranous nephropathy (MN), can occur and is generally associated with a proteinuria that encompasses nephrotic syndrome. Corticosteroids are the mainstay of treatment of KD-associated glomerulonephritis, but steroids withdrawal is often followed by relapsing nephrotic syndrome. Various immunosuppressive agents have been tested to prolong the remission of KD-associated nephrotic syndrome while tapering steroids, but they are only partly effective or associated with significant complications. To the best of our knowledge, we describe here the first case of KD-related membranous glomerulonephritis with a favorable evolution and a sustained remission of 4 years under prolonged therapy with mycophenolic acid (MPA). MPA and its active metabolite, mycophenolate mofetil (MMF), treatments as supportive therapies to corticosteroids and ACE inhibitors should be further investigated in KD-related membranous nephropathies.?. PMID- 28853700 TI - Comparison of hemodialysis with medium cut-off dialyzer and on-line hemodiafiltration on the removal of small and middle-sized molecules?. AB - BACKGROUND: Recent data suggest that the use of medium cut-off (MCO) dialyzers in hemodialysis (HD) promotes greater clearance and reduction ratio (RR) for myoglobin and other large-sized molecules than on-line hemodiafiltration (ol HDF), but its effects on beta2-microglobulin are not clear. We compared RR and clearances of small and middle-sized molecules between high-flux ol-HDF and MCO (Theranova) dialyzer in HD (MCO-HD) as well as nutritional parameters. MATERIALS AND METHODS: We retrospectively analyzed 10 patients treated first with ol-HDF who were thereafter switched to MCO-HD over a 1-year period. Three dialysis sessions in each 6-month period were examined. We calculated RR and clearance of small and middle-sized molecules. RESULTS: There was no significant difference between ol-HDF and MCO-HD for median serum albumin and prealbumin level, mean KT/V, mean urea and creatinine RR, mean beta2-microglobulin (81 +/- 5 vs. 81 +/- 6%, p = 0.72) and myoglobin (60 +/- 9% vs. 61 +/- 7%, p = 0.59), RR or clearances. CONCLUSION: The use of MCO (Theranova) dialyzer in HD produces similar removal of urea, creatinine, beta2-microglobulin and myoglobin as does ol HDF, with good tolerance profile and without modification of nutritional status.?. PMID- 28853701 TI - The prevalence and risk factors of abnormal circadian blood pressure in patients with IgA nephropathy?. AB - AIMS: To investigate the prevalence and risk factors of abnormal circadian blood pressure (BP) rhythm among IgA nephropathy (IgAN) patients. MATERIALS AND METHODS: 375 Chinese IgAN patients with biopsy-proven primary IgAN were recruited from June 2013 to December 2014 and divided into four groups based on circadian BP rhythm (dippers, non-dippers, reversed dippers, and extreme dippers) measured by 24-hour ambulatory BP monitoring. Demographic and clinicopathologic data were collected and analyzed. RESULTS: The prevalence of abnormal circadian BP was 84% (315/375) in all the participants, accounting for 82.4% of the normotensive patients and 86.1% of the hypertensive patients. The prevalence increased with the decline of estimated glomerular filtration rate (eGFR) in IgAN patients. The non-dipper pattern was most frequent (63.8%, 201/315) in this population, followed by the reversed-dipper (27.3%, 86/315), and then the extreme-dipper pattern (8.9%, 28/315). Multivariate logistic regression analysis revealed that the eGFR (odds ratio (OR) = 0.64, 95% conficence interval (CI): 0.45 - 0.93, p = 0.037), serum uric acid (OR = 1.60, 95% CI: 1.01 - 2.54, p = 0.014), and small vessel hyalinosis (OR = 2.17, 95% CI: 1.14 - 4.11, p = 0.044) were independently associated with abnormal circadian BP rhythm. CONCLUSION: Abnormal circadian BP rhythm was common in IgAN patients and occurred in the early stages of chronic kidney disease. Low eGFR, high serum uric acid, and small vessel hyalinosis increased risk of abnormal BP rhythm in IgAN patients.?. PMID- 28853702 TI - Familial antiglomerular basement membrane disease in zero human leukocyte antigen mismatch siblings?. AB - Reported cases of familial Antiglomerular basement membrane (anti-GBM) disease are extremely rare. The single gene mutations that may play a role in the development of familial anti-GBM disease are currently unidentified. While human leukocyte antigen (HLA)-DR15 is known to be associated with an increased risk of anti-GBM disease, HLA types in patients with familial anti-GBM disease have never been reported. We present a case of a 65-year-old woman with rapidly-progressive glomerulonephritis and pulmonary involvement, consistent with Goodpasture's syndrome. Two of her 15 siblings also had a history of anti-GBM disease during adolescence and both received a kidney transplant. Our patient and her siblings were smokers and had also had exposure to kerosene, a low-viscosity hydrocarbon. HLA testing was performed and showed identical HLA typing (0 of 6 HLA mismatch) as one of her brothers with anti-GBM disease. Interestingly, they both had HLA DR15. Despite severe acute kidney injury requiring hemodialysis, the patient responded well to the standard therapy with cyclophosphamide, plasmapheresis, and systemic corticosteroids. At her 3-month follow-up visit, the patient's kidney functions had recovered, and hemodialysis was discontinued. Concluding, we illustrate an extremely rare familial anti-GBM disease involving 3 siblings with potential links of HLA-DR15 and environmental triggers with the development of familial anti-GBM disease.?. PMID- 28853703 TI - Potential pitfalls in estimating renal injury by KDIGO, overcome by measuring creatinine clearance in acute kidney injury?. AB - Acute kidney injury (AKI) is a common and serious condition frequently encountered in hospitalized patients. The severity of kidney injury is defined by the KDIGO criteria which attempt to establish the degree of renal impairment. These criteria do not measure actual creatinine clearance (K) but rather represents static measures of a dynamic process in AKI and are fraught with potential for false positives and negatives results. This paper, presented in an educational format, uses a new, unique, simple, and accurate method for estimating actual K in AKI utilizing urine creatinine excretion over an established time interval. Patient examples are provided to highlight the use of this method and its advantage over KDIGO, which has inherent shortcomings, while often incorrectly classifying the extent of renal injury in the patient with AKI. These cases highlight where KDIGO staging may over- or underestimate the actual degree of renal injury in patients with AKI. The present paper provides the practitioner with a useful tool to estimate real-time K in AKI with enough precision to predict the severity of the renal injury. It is the author's belief that this simple method, or others like it, improve on KDIGO for estimating the degree of renal impairment in AKI, and allow a more accurate estimate of K. Methods to measure creatinine clearance in AKI have the potential to improve care for patients with this condition. PMID- 28853704 TI - Comparison of hypoalbuminemia-corrected serum calcium using BCP albumin assay to ionized calcium and impact on prescribing in hemodialysis patients?. AB - BACKGROUND: Albumin-corrected calcium (cCa) is recommended over ionized calcium (iCa) in hemodialysis (HD) patients per the Kidney Disease: Improving Global Outcomes position statements due to cost and feasibility. Two common albumin assays, bromocresol green (BCG) and bromocresol purple (BCP), produce differing results in uremic patients. All previous studies compared iCa to cCa from a BCG assay. This study, using the BCP assay, aimed to compare cCa and total calcium, respectively, to iCa. We also sought to assess phosphate binders and dialysis prescribing patterns following abnormal calcium measurements. MATERIALS AND METHODS: Retrospective review of 122 stable chronic HD patients with iCa, serum calcium, and albumin measured together throughout 6 blood work periods for a total of 338 sets of comparison values. Payne and Jain calcium correction equations were used. Prescription changes within 2 weeks of abnormal iCa values were recorded. RESULTS: Mean iCa, cCa, and total calcium were 1.17 +/- 0.08, 2.37 +/- 0.16, and 2.28 +/- 0.15 mmol/L, respectively. Total calcium and cCa compared to iCa had kappa-coefficients of 0.19 and 0.08, respectively, for hypocalcemia, 0.19 and -0.02 for normocalcemia and 0.59 and 0.46 for hypercalcemia. 21 interventions were made in hypocalcemic patients using iCa as reference; however, if total or corrected calcium values were used, only 8 and 5 interventions, respectively, would result. CONCLUSION: When BCP assay is used, conventional correction equations should not be utilized in hemodialysis patients; uncorrected serum calcium has a better predictive value.?. PMID- 28853705 TI - Urinary creatinine excretion in AKI - just another look. PMID- 28853707 TI - Physics of SrTiO3-based heterostructures and nanostructures: a review. AB - 1 Overview 1 1.1 Introduction 1 1.1.1 Oxide growth techniques are rooted in search for high-Tc superconductors 2 1.1.2 First reports of interface conductivity 2 1.2 2D physics 2 1.3 Emergent properties of oxide heterostructures and nanostructures 3 1.4 Outline 3 2 Relevant properties of SrTiO3 3 2.1 Structural properties and transitions 3 2.2 Ferroelectricity, Paraelectricity and Quantum Paraelectricity 4 2.3 Electronic structure 5 2.4 Defects 6 2.4.1 Oxygen vacancies 6 2.4.2 Terraces 7 2.5 Superconductivity 7 3 SrTiO3-based heterostructures and nanostructures 8 3.1 Varieties of heterostructures 8 3.1.1 SrTiO3 only 9 3.1.2 LaAlO3/SrTiO3 9 3.1.3 Other heterostructures formed with SrTiO3 10 3.2 Thin-film growth 10 3.2.1 Substrates 10 3.2.2 SrTiO3 surface treatment 11 3.2.3 Pulsed Laser Deposition 11 3.2.4 Atomic Layer Deposition 13 3.2.5 Molecular Beam Epitaxy 14 3.2.6 Sputtering 15 3.3 Device Fabrication 15 3.3.1 "Conventional" photolithography - Thickness Modulation, hard masks, etc. 15 3.3.2 Ion beam irradiation 16 3.3.3 Conductive-AFM lithography 16 4 Properties and phase diagram of LaAlO3/SrTiO3 16 4.1 Insulating state 16 4.2 Conducting state 17 4.2.1 Confinement thickness (the depth profile of the 2DEG) 17 4.3 Metal-insulator transition and critical thickness 18 4.3.1 Polar catastrophe (? electronic reconstruction) 18 4.3.2 Oxygen Vacancies 19 4.3.3 Interdiffusion 20 4.3.4 Polar Interdiffusion + oxygen vacancies + antisite pairs 20 4.3.5 Role of surface adsorbates 21 4.3.6 Hidden FE like distortion - Strain induced instability 21 4.4 Structural properties and transitions 21 4.5 Electronic band structure 22 4.5.1 Theory 22 4.5.2 Experiment 23 4.5.3 Lifshitz transition 24 4.6 Defects, doping, and compensation 25 4.7 Magnetism 25 4.7.1 Experimental evidence 25 4.7.2 Two types of magnetism 27 4.7.3 Ferromagnetism 27 4.7.4 Metamagnetism 28 4.8 Superconductivity 28 4.9 Optical properties 29 4.9.1 Photoluminesce experiments 29 4.9.2 Second Harmonic Generation 29 4.10 Coexistence of superconductivity and magnetism 30 4.11 Magnetic and conducting phases 30 5 Quantum transport in LaAlO3/SrTiO3 heterostructures and microstructures 31 5.1 2D transport 31 5.2 Inhomogeneous Transport 31 5.3 Anisotropic Magnetoresistance 32 5.4 Spin-orbit coupling 32 5.5 Anomalous Hall Effect 34 5.6 Shubnikov-de Haas (SdH) Oscillation 35 5.7 Quantum Hall Effect 37 5.8 Spintronic Effects 38 6 Quantum transport in LaAlO3/SrTiO3 nanostructures 39 6.1 Quasi-1D Superconductivity 39 6.2 Universal conductance fluctuations 40 6.3 Dissipationless Electronic Waveguides 40 6.4 Superconducting Quantum Interference Devices (SQUID) 41 6.5 Electron pairing without superconductivity 41 6.6 Tunable Electron-Electron Interaction 42 7 Outlook 43 7.1 Outstanding physics questions 43 7.1.1 Polar catastrophe (not) 43 7.1.2 Coexistence of phases 43 7.1.3 Novel superconducting states (e.g., FFLO, other pairing symmetries) 43 7.1.4 Magnetism mechanism 43 7.1.5 Exotic phases (eg. Majorana physics) 43 7.1.6 Luttinger liquids 44 7.2 Future applications 44 7.2.1 Spintronics 44 7.2.2 Quantum simulation 44 7.2.3 Qubits/quantum computing 44 7.2.4 Sensing 44 8 Figures 45 9 Reference 6. PMID- 28853708 TI - Water-resistant, monodispersed and stably luminescent CsPbBr3/CsPb2Br5 core-shell like structure lead halide perovskite nanocrystals. AB - Lead halide perovskite materials are thriving in optoelectronic applications due to their excellent properties, while their instability due to the fact that they are easily hydrolyzed is still a bottleneck for their potential application. In this work, water-resistant, monodispersed and stably luminescent cesium lead bromine perovskite nanocrystals coated with CsPb2Br5 were obtained using a modified non-stoichiometric solution-phase method. CsPb2Br5 2D layers were coated on the surface of CsPbBr3 nanocrystals and formed a core-shell-like structure in the synthetic processes. The stability of the luminescence of the CsPbBr3 nanocrystals in water and ethanol atmosphere was greatly enhanced by the photoluminescence-inactive CsPb2Br5 coating with a wide bandgap. The water-stable enhanced nanocrystals are suitable for long-term stable optoelectronic applications in the atmosphere. PMID- 28853709 TI - Quantum many-body simulation using monolayer exciton-polaritons in coupled cavities. AB - Quantum simulation is a promising approach to understanding complex strongly correlated many-body systems using relatively simple and tractable systems. Photon-based quantum simulators have great advantages due to the possibility of direct measurements of multi-particle correlations and ease of simulating non equilibrium physics. However, interparticle interaction in existing photonic systems is often too weak, limiting the potential for quantum simulation. Here we propose an approach to enhance the interparticle interaction using exciton polaritons in MoS2 monolayer quantum dots embedded in 2D photonic crystal microcavities. Realistic calculation yields optimal repulsive interaction in the range of 1-10 meV-more than an order of magnitude greater than the state-of-the art value. Such strong repulsive interaction is found to emerge neither in the photon-blockade regime for small quantum dot nor in the polariton-blockade regime for large quantum dot, but in the crossover between the two regimes with a moderate quantum-dot radius around 20 nm. The optimal repulsive interaction is found to be largest in MoS2 among commonly used optoelectronic materials. Quantum simulation of strongly correlated many-body systems in a finite chain of coupled cavities and its experimental signature are studied via the exact diagonalization of the many-body Hamiltonian. A method to simulate 1D superlattices for interacting exciton-polariton gases in serially coupled cavities is also proposed. Realistic considerations on experimental realizations reveal advantages of transition metal dichalcogenide monolayer quantum dots over conventional semiconductor quantum emitters. PMID- 28853706 TI - Evolutionary routes to biochemical innovation revealed by integrative analysis of a plant-defense related specialized metabolic pathway. AB - The diversity of life on Earth is a result of continual innovations in molecular networks influencing morphology and physiology. Plant specialized metabolism produces hundreds of thousands of compounds, offering striking examples of these innovations. To understand how this novelty is generated, we investigated the evolution of the Solanaceae family-specific, trichome-localized acylsugar biosynthetic pathway using a combination of mass spectrometry, RNA-seq, enzyme assays, RNAi and phylogenomics in different non-model species. Our results reveal hundreds of acylsugars produced across the Solanaceae family and even within a single plant, built on simple sugar cores. The relatively short biosynthetic pathway experienced repeated cycles of innovation over the last 100 million years that include gene duplication and divergence, gene loss, evolution of substrate preference and promiscuity. This study provides mechanistic insights into the emergence of plant chemical novelty, and offers a template for investigating the ~300,000 non-model plant species that remain underexplored. PMID- 28853710 TI - Large patternable metal nanoparticle sheets by photo/e-beam lithography. AB - Techniques for micro/nano-scale patterning of large metal nanoparticle sheets can potentially be used to realize high-performance photoelectronic devices because the sheets provide greatly enhanced electrical fields around the nanoparticles due to localized surface plasmon resonances. However, no single metal nanoparticle sheet currently exists with sufficient durability for conventional lithographical processes. Here, we report large photo and/or e-beam lithographic patternable metal nanoparticle sheets with improved durability by incorporating molecular cross-linked structures between nanoparticles. The cross-linked structures were easily formed by a one-step chemical reaction; immersing a single nanoparticle sheet consisting of core metals, to which capping molecules ionically bond, in a dithiol ethanol solution. The ligand exchange reaction processes were discussed in detail, and we demonstrated 20 MUm wide line and space patterns, and a 170 nm wide line of the silver nanoparticle sheets. PMID- 28853711 TI - Extracting the interfacial free energy and anisotropy from a smooth fluctuating dividing surface. AB - Interfaces between different materials and phases play a crucial role in many physical and chemical phenomena. When performing simulations of matter at the atomic scale, however, it is often not trivial to characterize these interfaces, particularly when they are rough or diffuse. Here we discuss a generalization of a construction, due to Willard and Chandler, that allows one to obtain a smooth dividing surface that follows the irregular, ever changing shape of these fluctuating interfaces. We show how this construction can be used to study the surface that separates a solid material from its melt and how analyses of the Fourier modes for the capillary fluctuations of this instantaneous dividing surface can be performed. This particular analysis is useful as one can compute the specific free energy excess of the interface, and its dependence on orientation relative to the bulk phases, from the average amplitude of the Fourier modes. We therefore discuss the efficiency of this approach, both in terms of system size and statistical sampling. PMID- 28853712 TI - RKKY interaction of magnetic impurities in multi-Weyl semimetals. AB - We have systematically investigated the Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction between two magnetic impurities in Weyl semimetals with arbitrary monopole charge Q. We find that the RKKY interaction becomes intrinsically anisotropic for [Formula: see text], and its dependence on Fermi energy and impurity separation is directly controlled by the monopole charge. With the increase of Q, the RKKY interaction becomes more long-ranged and more anisotropic, which makes interesting magnetic orders easier to form and thus may have important applications in spintronics. PMID- 28853713 TI - Effects of the Hubbard U on density functional-based predictions of BiFeO3 properties. AB - First principles studies of multiferroic materials, such as bismuth ferrite (BFO), require methods that extend beyond standard density functional theory (DFT). The DFT + U method is one such extension that is widely used in the study of BFO. We present a systematic study of the effects of the U parameter on the structural, ferroelectric and electronic properties of BFO. We find that the structural and ferroelectric properties change negligibly in the range of U typically considered for BFO (3-5 eV). In contrast, the electronic structure varies significantly with U. In particular, we see large changes to the character and curvature of the valence band maximum and conduction band minimum, in addition to the expected increase in band gap, as U increases. Most significantly, we find that the [Formula: see text]/[Formula: see text] ordering at the conduction band minimum inverts for U values larger than 4 eV. We therefore recommend a U value of at most 4 eV to be applied to the Fe d orbitals in BFO. More generally, this study emphasises the need for systematic investigations of the effects of the U parameter not merely on band gaps but on the electronic structure as a whole, especially for strongly correlated materials. PMID- 28853714 TI - Anisotropic lattice thermal conductivity in three-fold degeneracy topological semimetal MoP: a first-principles study. AB - Recently, three-component new fermions in topological semimetal MoP are experimentally observed (2017 Nature 546 627), which may have potential applications like topological qubits, low-power electronics and spintronics. These are closely related to thermal transport properties of MoP. In this work, the phonon transport of MoP is investigated by solving the linearized phonon Boltzmann equation within the single-mode relaxation time approximation (RTA). The calculated room-temperature lattice thermal conductivity is 18.41 [Formula: see text] and 34.71 [Formula: see text] along the in- and cross-plane directions, exhibiting very strong anisotropy. The isotope and size effects on the lattice thermal conductivity are also considered. It is found that isotope scattering produces little effect, and phonon has little contribution to the lattice thermal conductivity, when phonon mean free path (MFP) is larger than 0.15 [Formula: see text] at 300 K. It is noted that average room-temperature lattice thermal conductivity of MoP is lower than that of representative Weyl semimetal TaAs, which is due to smaller group velocities and larger Gruneisen parameters. Our works provide valuable informations for the thermal management of MoP-based nano electronics devices, and motivate further experimental works to study thermal transport of MoP. PMID- 28853715 TI - Aptasensor based optical detection of glycated albumin for diabetes mellitus diagnosis. AB - Glycated albumin (GA) has been reported as an important biomarker for diabetes mellitus. This study investigates an optical sensor comprised of deoxyribonucleic acid (DNA) aptamer, semiconductor quantum dot and gold (Au) nanoparticle for the detection of GA. The system functions as a 'turn on' sensor because an increase in photoluminescence intensity is observed upon the addition of GA to the sensor. This is possibly because of the structure of the DNA aptamer, which folds to form a large hairpin loop before the addition of the analyte and is assumed to open up after the addition of target to the sensor in order to bind to GA. This pushes the quantum dot and the Au nanoparticle away causing an increase in photoluminescence. A linear increase in photoluminescence intensity and quenching efficiency of the sensor is observed as the GA concentration is varied between 0 14 500 nM. Time based photoluminescence studies with the sensor show the decrease in binding rate of the aptamer to the target within a specific time period. The sensor was found to have a higher selectivity towards GA than other control proteins. Further investigation of this simple sensor with greater number of clinical samples can open up avenues for an efficient diagnosis and monitoring of diabetes mellitus when used in conjunction with the traditional method of glucose level monitoring. PMID- 28853716 TI - Estimating pairwise relatedness in a small sample of individuals. AB - The genetic relatedness between individuals because of their recent common ancestry is now routinely estimated from marker genotype data in molecular ecology, evolutionary biology and conservation studies. The estimators developed for this purpose assume that marker allele freque218 in a population are known without errors. Unfortunately, however, these frequencies, upon which both the definition and the estimation of relatedness are based, are rarely known in reality. Frequently, the only data available in a relatedness analysis are a sample of multilocus genotypes from which both allele frequencies and relatedness must be deduced. Furthermore, because of various constraints, sample sizes of individuals can be quite small (say <50 individuals) in practice. This study shows, for the first time, that the widely used relatedness estimators become severely biased when they use allele frequencies calculated from an extremely small sample (say <10 individuals). The extent of bias depends on the sample size, the (unknown) population allele frequencies, the actual relatedness and the estimators. It also shows that relatedness estimators become even more biased when they use allele frequencies calculated from a sample by omitting a focal pair of individuals whose relatedness is being estimated. This study modifies two estimators to suit small samples and shows, both analytically and by analysing simulated and empirical data, that the two modified estimators are much less biased, more precise and more accurate than the original estimators. These performance advantages of the modified estimators are shown to increase with a decreasing sample size of individuals and with an increasing value of actual relatedness. PMID- 28853717 TI - In utero delivery of rAAV2/9 induces neuronal expression of the transgene in the brain: towards new models of Parkinson's disease. AB - Animal models are essential tools for basic pathophysiological research as well as validation of therapeutic strategies for curing human diseases. However, technical difficulties associated with classical transgenesis approaches in rodent species higher than Mus musculus have prevented this long-awaited development. The availability of viral-mediated gene delivery systems in the past few years has stimulated the production of viruses with unique characteristics. For example, the recombinant adeno-associated virus serotype 9 (rAAV2/9) crosses the blood-brain barrier, is capable of transducing developing cells and neurons after intravenous injection and mediates long-term transduction. Whilst post natal delivery is technically straightforward, in utero delivery bears the potential of achieving gene transduction in neurons at embryonic stages during which the target area is undergoing development. To test this possibility, we injected rAAV2/9 carrying either A53T mutant human alpha-synuclein or green fluorescent protein, intracerebroventricularly in rats at embryonic day 16.5. We observed neuronal transgene expression in most regions of the brain at 1 and 3 months after birth. This proof-of-concept experiment introduces a new opportunity to model brain diseases in rats. PMID- 28853719 TI - Viewing the male-specific chromosome Y in a new light. PMID- 28853720 TI - The Y chromosome: a blueprint for men's health? AB - The Y chromosome has long been considered a 'genetic wasteland' on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men's susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome. PMID- 28853721 TI - The wide spectrum of POT1 gene variants correlates with multiple cancer types. AB - The POT1 protein binds and protects telomeres. Germline variants in the POT1 gene have recently been shown to be associated with risk of developing tumors in different tissues such as familial chronic lymphocytic leukemia, colorectal, glioma and melanoma tumors. Recently, we uncovered a variant in the POT1 gene (p.R117C) as causative of familial cardiac angiosarcomas (CAS) in Li-Fraumeni like (LFL) syndrome families. Our in silico studies predicted that this protein had lost the ability to interact with TPP1 and single-stranded DNA. In vitro studies corroborated this prediction and showed that this lack of function leads to abnormally long telomeres. To better understand the POT1 gene and its role with tumorigenesis, we extended the study to LFL (with and without members affected with angiosarcomas (AS)) and sporadic AS and cardiac sarcomas. We found POT1 variants in the 20% of the families with members affected with AS and 10% of sporadic AS and sarcomas. In silico studies predicted that these new variants were damaging in the same manner as previously described for the POT1 p.R117C variants. The wide spectrum of variants in the POT1 gene leading to tumorigenesis in different tissues demonstrates its general importance. Study of the POT1 gene should be considered as routine diagnostic in these cancers. PMID- 28853718 TI - Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis. AB - Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14 1.21), P=1.8 * 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 * 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG. PMID- 28853722 TI - Propionic acidemia as a cause of adult-onset dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is extremely heterogeneous with a large proportion due to dominantly inherited disease-causing variants in sarcomeric genes. Recessive metabolic diseases may cause DCM, usually with onset in childhood, and in the context of systemic disease. Whether metabolic defects can also cause adult-onset DCM is currently unknown. Therefore, we performed an extensive metabolic screening in 36 consecutive adult-onset DCM patients. Diagnoses were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Measurement of propionyl-CoA carboxylase (PCC) activity was done in fibroblasts. Whole exome sequencing (WES) data of 157 additional DCM patients were analyzed for genetic defects. We found a metabolic profile characteristic for propionic acidemia in a patient with severe DCM from 55 years of age. Genetic analysis demonstrated compound heterozygous variants in PCCA. Enzymatic activity of PCC in fibroblasts was markedly reduced. A targeted analysis of the PCCA and PCCB genes using available WES data from 157 further DCM patients subsequently identified another patient with propionic acidemia. This patient had compound heterozygous variants in PCCB, and developed severe DCM from 42 years of age. Adult-onset DCM can be caused by propionic acidemia, an autosomal recessive inheritable metabolic disorder usually presenting as neonatal or childhood disease. Current guidelines advise a low-protein diet to ameliorate or prevent detrimental aspects of the disease. Long-term follow-up of a larger group of patients may show whether this diet would also ameliorate DCM. Our results suggest that diagnostic metabolic screening to identify propionic acidemia and related disorders in DCM patients is justified. PMID- 28853723 TI - NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect. AB - Mitochondrial respiratory chain complex I consists of 44 different subunits and can be subgrouped into three functional modules: the Q-, the P- and the N-module. NDUFAF4 (C6ORF66) is an assembly factor of complex I that associates with assembly intermediates of the Q-module. Via exome sequencing, we identified a homozygous missense variant in a complex I-deficient patient with Leigh syndrome. Supercomplex analysis in patient fibroblasts revealed specifically altered stoichiometry. Detailed assembly analysis of complex I, indicative of all of its assembly routes, showed an accumulation of parts of the P- and the N-module but not the Q-module. Lentiviral complementation of patient fibroblasts with wild type NDUFAF4 rescued complex I deficiency and the assembly defect, confirming the causal role of the variant. Our report on the second family affected by an NDUFAF4 variant further characterizes the phenotypic spectrum and sheds light into the role of NDUFAF4 in mitochondrial complex I biogenesis. PMID- 28853724 TI - Executive function and extremely preterm children. PMID- 28853725 TI - The triglycerides and glucose index is associated with cardiovascular risk factors in normal-weight children and adolescents. AB - BackgroundGiven the usefulness of the product of triglycerides and glucose (TyG) to recognize individuals at high risk for developing cardiovascular events, the aim of this study was to determine whether the TyG index is associated with the presence of cardiovascular risk factors in apparently healthy normal-weight children and adolescents.MethodsApparently healthy children and adolescents with normal weight, aged 6-15 years, were enrolled in a population-based cross sectional study. The children were allocated into groups with and without cardiovascular risk factors. Cardiovascular risk factors were considered as the occurrence of at least one of the following: elevated blood pressure, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), or hyperglycemia.ResultsA total of 2,117 children and adolescents were enrolled in the study; of them, 1,078 (50.9%) participants exhibited cardiovascular risk. The adjusted logistic regression analysis showed that elevated TyG index was significantly associated with hypertriglyceridemia (odds ratio (OR)=96.45, 95% confidence interval (CI): 48.44-192.04), low HDL-C (OR=2.07, 95% CI: 1.46-2.92), and hyperglycemia (OR=3.11, 95% CI: 2.05-4.72), but not with elevated blood pressure (OR=1.39, 95% CI: 0.89-2.16).ConclusionThe elevated TyG index is associated with the presence of cardiovascular risk factors in healthy normal weight children and adolescents. PMID- 28853726 TI - Enhancing clinical trial development for pediatric kidney diseases. AB - The conduct of clinical trials in small pediatric subspecialties such as pediatric nephrology is hampered by both clinical demands on the pediatric nephrologist and the small number of appropriate patients available for such studies. The American Society of Pediatric Nephrology Therapeutics Development Committee (TDC) was established to (1) identify the various stakeholders with interests and/or expertise related to clinical trials in children with kidney disease and (2) develop more effective partnerships among all parties regarding strategies for successful clinical trial development and execution. This article discusses the rationale, structure, and function of the TDC, the status of progress toward its goals, and the insights gained to date that may be useful for other subspecialties that face similar challenges. PMID- 28853727 TI - Evaluation of Gastrointestinal Patient Reported Outcomes Measurement Information System (GI-PROMIS) Symptom Scales in Subjects With Inflammatory Bowel Diseases. AB - OBJECTIVES: Patient reported outcomes (PROs) are important treatment endpoints in inflammatory bowel diseases (IBD). We evaluated the gastrointestinal (GI) PRO Measurement Information System (PROMIS) in IBD subjects. METHODS: Crohn's and Colitis Foundation of America's Partners is an Internet-based cohort of IBD subjects. Participants complete surveys, including demographics, disease characteristics, PROMIS domains, disease activity (short Crohn's disease activity index or simple clinical colitis activity index) and quality of life (QoL) indices. In a nested cross-sectional study, we used univariate and bivariate analyses to assess associations between 8 GI-PROMIS domains (reflux, swallowing, diarrhea, nausea, belly pain, gas, incontinence, and constipation) and QoL and disease activity indices. RESULTS: The study included 2,378 Crohn's Disease (CD) and 1,455 ulcerative colitis (UC) respondents with a median age of 41 years. Median disease duration was 11 years for CD subjects and 8 years for UC subjects; 57% of CD subjects and 42% of UC subjects were in remission. Among symptomatic CD subjects, those with active CD reported significantly worse symptoms on all 8 domains than those in remission. The same was observed for UC subjects with the exception of disrupted swallowing. IBD subjects with worse QoL reported significantly worse symptoms on all 8 domains compared to those with better QoL. CONCLUSIONS: In IBD subjects experiencing GI symptoms, GI-PROMIS domains were strongly associated with disease activity and QoL indices. GI-PROMIS holds potential as PRO measures in IBD and correlates with other validated indices in this population. PMID- 28853728 TI - Fibrosis-4 Index Helps Identify HBV Carriers With the Lowest Risk of Hepatocellular Carcinoma. AB - OBJECTIVES: Several viral and host risk factors have been used to predict risks of hepatocellular carcinoma (HCC) in patients with chronic infection of hepatitis B virus (HBV). However, little is known whether fibrosis-4 (FIB-4) index, a liver fibrosis biomarker, helps identify non-cirrhotic patients with the lowest HCC risk. METHODS: A total of 2075 treatment-naive Taiwanese patients with chronic HBV infection were followed for an average period of 16.02 years. None of them had liver cirrhosis at baseline. We explored whether a low FIB-4 index complements the favourable predictors to defines patients with the lowest HCC risk. The finding was validated in 532 non-cirrhotic patients receiving long-term nucleos(t)ide analogue (NUC) treatment with suppressed viral replication. RESULTS: A total of 137 treatment-naive and 10 NUC-treated patients developed HCC, respectively. We found that HCC risk started to increase when baseline FIB-4 index >1.29 in the treatment-naive cohort. Patients with FIB-4 >1.29, compared to those with FIB-4 <1.29, were associated with a higher risk of HCC with hazards ratio of 5.56 (95% confidence interval: 3.93-7.86). More importantly, among patients with low viral load (HBV DNA level <2,000 IU/ml), baseline FIB-4 index helped stratify different HCC risks such that none of 326 HBeAg-negative patients with FIB-4 index <1.29, ALT level <40 U/l, and HBsAg level <1,000 IU/ml developed HCC. In addition, the patients with the FIB-4 index <1.29 consistently had the lowest HCC risks in the validation cohort receiving long-term NUC treatment. CONCLUSIONS: In non-cirrhotic patients with chronic HBV infection, FIB-4 index <1.29 complements the existing clinical profile to define patients with the lowest HCC risk. PMID- 28853730 TI - Antibacterials: PUMmeling RNAP. PMID- 28853731 TI - Biocatalysis: Achieving aminase activity. PMID- 28853729 TI - Predictors of Early Readmission in Patients With Cirrhosis After the Resolution of Bacterial Infections. AB - OBJECTIVES: In patients with cirrhosis, infections represent a frequent trigger for complications, increasing frequency of hospitalizations and mortality rate. This study aimed to identify predictors of early readmission (30 days) and of mid term mortality (6 months) in patients with liver cirrhosis discharged after a hospitalization for bacterial and/or fungal infection. METHODS: A total of 199 patients with cirrhosis discharged after an admission for a bacterial and/or fungal infection were included in the study and followed up for a least 6 months. RESULTS: During follow-up, 69 patients (35%) were readmitted within 30 days from discharge. C-reactive protein (CRP) value at discharge (odds ratio (OR)=1.91; P=0.022), diagnosis of acute-on-chronic liver failure during the hospital stay (OR=2.48; P=0.008), and the hospitalization in the last 30 days previous to the admission/inclusion in the study (OR=1.50; P=0.042) were found to be independent predictors of readmission. During the 6-month follow-up, 47 patients (23%) died. Age (hazard ratio (HR)=1.05; P=0.001), model of end-stage liver disease (MELD) score (HR=1.13; P<0.001), CRP (HR=1.85; P=0.001), refractory ascites (HR=2.22; P=0.007), and diabetes (HR=2.41; P=0.010) were found to be independent predictors of 6-month mortality. Patients with a CRP >10 mg/l at discharge had a significantly higher probability of being readmitted within 30 days (44% vs. 24%; P=0.007) and a significantly lower probability of 6-month survival (62% vs. 88%; P<0.001) than those with a CRP <=10 mg/l. CONCLUSIONS: CRP showed to be a strong predictor of early hospital readmission and 6-month mortality in patients with cirrhosis after hospitalization for bacterial and/or fungal infection. CRP values could be used both in the stewardship of antibiotic treatment and to identify fragile patients who deserve a strict surveillance program. PMID- 28853732 TI - Hints of hidden chemistry. PMID- 28853734 TI - Redox regulation: Scaffolding H2O2 signaling. PMID- 28853735 TI - Enzymology: Tracking off-targets. PMID- 28853733 TI - Harnessing yeast organelles for metabolic engineering. AB - Each subcellular compartment in yeast offers a unique physiochemical environment and metabolite, enzyme, and cofactor composition. While yeast metabolic engineering has focused on assembling pathways in the cell cytosol, there is growing interest in embracing subcellular compartmentalization. Beyond harnessing distinct organelle properties, physical separation of organelles from the cytosol has the potential to eliminate metabolic crosstalk and enhance compartmentalized pathway efficiency. In this Perspective we review the state of the art in yeast subcellular engineering, highlighting the benefits of targeting biosynthetic pathways to subcellular compartments, including mitochondria, peroxisomes, the ER and/or Golgi, vacuoles, and the cell wall, in different yeast species. We compare the performances of strains developed with subcellular engineering to those of native producers or yeast strains previously engineered with cytosolic pathways. We also identify important challenges that lie ahead, which need to be addressed for organelle engineering to become as mainstream as cytosolic engineering in academia and industry. PMID- 28853736 TI - Biosynthesis: Methylating mushrooms. PMID- 28853737 TI - Neurodegenerative disease: Not stuck on repeat. PMID- 28853738 TI - Erratum: The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. PMID- 28853739 TI - Structural biology: Full monty of family B GPCRs. PMID- 28853740 TI - Erratum: Structural and conformational determinants of macrocycle cell permeability. PMID- 28853741 TI - A compositional data perspective on studying the associations between macronutrient balances and diseases. PMID- 28853742 TI - Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. AB - BACKGROUND/OBJECTIVES: Glutathione (GSH) is the most abundant endogenous antioxidant and a critical regulator of oxidative stress. Maintenance of optimal tissues for GSH levels may be an important strategy for the prevention of oxidative stress-related diseases. We investigated if oral administration of liposomal GSH is effective at enhancing GSH levels in vivo. SUBJECTS/METHODS: A 1 month pilot clinical study of oral liposomal GSH administration at two doses (500 and 1000 mg of GSH per day) was conducted in healthy adults. GSH levels in whole blood, erythrocytes, plasma and peripheral blood mononuclear cells (PBMCs) were assessed in 12 subjects at the baseline and after 1, 2 and 4 weeks of GSH administration. RESULTS: GSH levels were elevated after 1 week with maximum increases of 40% in whole blood, 25% in erythrocytes, 28% in plasma and 100% in PBMCs occurring after 2 weeks (P<0.05). GSH increases were accompanied by reductions in oxidative stress biomarkers, including decreases of 35% in plasma 8 isoprostane and 20% in oxidized:reduced GSH ratios (P<0.05). Enhancements in immune function markers were observed with liposomal GSH administration including Natural killer (NK) cell cytotoxicity, which was elevated by up to 400% by 2 weeks (P<0.05), and lymphocyte proliferation, which was elevated by up to 60% after 2 weeks (P<0.05). Overall, there were no differences observed between dose groups, but statistical power was limited due to the small sample size in this study. CONCLUSIONS: Collectively, these preliminary findings support the effectiveness of daily liposomal GSH administration at elevating stores of GSH and impacting the immune function and levels of oxidative stress. PMID- 28853744 TI - Imaging on-surface hierarchical assembly of chiral supramolecular networks. AB - The bottom-up assembly of chiral structures usually relies on a cascade of molecular recognition interactions. A thorough description of these complex stereochemical mechanisms requires the capability of imaging multilevel coordination in real-time. Here we report the first direct observation of hierarchical expression of supramolecular chirality at work, for 10,10'-dibromo 9,9'-bianthryl (DBBA) on Cu(111). Molecular recognition first steers the growth of chiral organometallic chains and then leads to the formation of enantiopure islands. The structure of the networks was determined by noncontact atomic force microscopy (nc-AFM), while high-speed scanning tunnelling microscopy (STM) revealed details of the assembly mechanisms at the ms time-scale. The direct observation of the chirality transfer pathways allowed us to evaluate the enantioselectivity of the interchain coupling. PMID- 28853743 TI - Evaluation and review of body fluids saliva, sweat and tear compared to biochemical hydration assessment markers within blood and urine. AB - Evaluating and testing hydration status is increasingly requested by rehabilitation, sport, military and performance-related activities. Besides commonly used biochemical hydration assessment markers within blood and urine, which have their advantages and limitations in collection and evaluating hydration status, there are other potential markers present within saliva, sweat or tear. This literature review focuses on body fluids saliva, sweat and tear compared to blood and urine regarding practicality and hydration status influenced by fluid restriction and/or physical activity. The selected articles included healthy subjects, biochemical hydration assessment markers and a well described (de)hydration procedure. The included studies (n=16) revealed that the setting and the method of collecting respectively accessing body fluids are particularly important aspects to choose the optimal hydration marker. To obtain a sample of saliva is one of the simplest ways to collect body fluids. During exercise and heat exposures, saliva composition might be an effective index but seems to be highly variable. The collection of sweat is a more extensive and time consuming technique making it more difficult to evaluate dehydration and to make a statement about the hydration status at a particular time. The collection procedure of tear fluid is easy to access and causes very little discomfort to the subject. Tear osmolarity increases with dehydration in parallel to alterations in plasma osmolality and urine-specific gravity. But at the individual level, its sensitivity has to be further determined. PMID- 28853745 TI - Understanding the metal mediated assembly and hydrogel formation of a beta hairpin peptide. AB - We report the design and characterization of a peptide that assembles as beta hairpins and forms hydrogels under physiological conditions. These hydrogels formed both in the absence and presence of several metal ions and displayed characteristic sheer-thinning properties. In particular, in the presence of Zn2+, we observed a novel hydrogel that proceeded via an intermolecular metal coordination mechanism - intermolecular assembly that was previously reported instead to promote amyloid type aggregates. PMID- 28853746 TI - Stabilization of ultra-small [Ag2]2+ and [Agm]n+ nano-clusters through negatively charged tetrahedrons in oxyfluoride glass networks: To largely enhance the luminescence quantum yields. AB - Herein, three different silver species were stably formed in SiO2-Al2O3-B2O3-Na2O ZnF2-CaF2 glasses and were identified by their characteristic luminescence bands: violet blue luminescence (Ag+: 4d95s1 -> 4d10), green white molecular fluorescence (molecule-like [Agm]n+, named ML-Ag) and orange molecular fluorescence ([Ag2]2+ pairs). Due to the relatively low aggregation degrees of [Agm]n+ and [Ag2]2+, non-radiative transitions were highly suppressed, and the PL quantum yields (QYs) of ML-Ag and [Ag2]2+ pairs reached 73.7% and 89.7%, respectively. The substitution of 0.5B2O3-0.5Na2O with SiO2 promoted the partial reduction of Ag+ to Ag0 and the subsequent aggregation of Ag+ and Ag0 to form [Agm]n+ (ML-Ag). The absence of Na2O also resulted in an increasing amount of Ag+ Ag+ pairs with closing interionic distance to form [Ag2]2+ in glass. According to the X-ray photoelectron spectra (XPS) and magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra, a solubility strategy and a charge compensation model were proposed to describe the transformations between different silver species. The formation of ML-Ag was further controlled via the solubility of Ag+ in glass, whereas [Ag2]2+ centers could be effectively produced by lowering the total amount of other competitive charge compensators, such as Na+, or by introducing negatively charged [BO4]-, [AlO4]-, and [ZnO4]2- tetrahedrons into the glass matrix. PMID- 28853748 TI - A route to robust thioether-functionalized MOF solid materials displaying heavy metal uptake and the ability to be further oxidized. AB - Here we developed a facile solvent-assisted ligand exchange method for synthesizing thioether-containing hybrid metal-organic frameworks (MOFs) that cannot be made using direct synthesis. Such a tailored approach provides an alternative method to achieve thioether-based MOFs and its oxidation-decorated materials. These materials showed the ability to take up heavy metals from solution and the ability to capture CO2. PMID- 28853751 TI - H4octapa: synthesis, solution equilibria and complexes with useful radiopharmaceutical metal ions. AB - H4octapa is an extremely versatile acyclic chelator for a wide variety of medicinally relevant metal ions, forming complexes of both high thermodynamic and kinetic stability. This work reports a significantly simplified 3 step high yield straightforward synthesis of H4octapa directly from EDDA. Crystals of the octa protonated form of the ligand [H8octapa]4+ as its tetrachloride salt, and of the mixed lanthanum-sodium salt of [La(octapa)]- were isolated and characterized by X ray diffraction. All eight protonation constants for the ligand were determined through combined potentiometric-spectrophotometric titrations and in batch experiments using UV spectrophotometry and 1H NMR spectroscopy. Synthesis, characterisation and solution equilibria studies are presented for complexes [Ln(octapa)]- (Ln = lanthanide element) with Sm(iii), Dy(iii), and Yb(iii) (each of which have radiopharmaceutical applications). Complex formation equilibria studies provided evidence of Ln(Hoctapa), [Ln(octapa)]- and [Ln(octapa)(OH)]2- species in solution, and their stability constants were evaluated by pH potentiometric competition titrations using [ttha]6- as a competing ligand, and by UV-vis spectrophotometric measurements. The high stability constants of the [Ln(octapa)]- complexes with Sm(iii), Dy(iii), and Yb(iii) (log KSmL = 20.10(2), log KDyL = 20.14(3) and log KYbL = 19.90(1)) are similar to the published values for other lanthanides and consequently these initial investigations confirm H4octapa as a valuable ligand for Sm(iii), Dy(iii), Yb(iii) and other Ln for application in diagnostic and therapeutic nuclear medicine. PMID- 28853753 TI - A multiscale study of the role of dynamin in the regulation of glucose uptake. AB - Glucose uptake in muscle cells in response to insulin is a fundamental mechanism for metabolism. The inability of cells to mobilize the specific glucose transporter GLUT4 is believed to be at least partially accountable for diseases, like diabetes, where cells do not respond to an insulin stimulus. In this work, a microchip is used to detect electrochemically glucose uptake from C2C12 myoblasts cultured on a patch of paper upon exposure to insulin. More importantly, the data suggest a new role for dynamin, a molecular motor which would be involved in GLUT4 translocation by facilitating exocytosis. It is also shown in vivo that dynamin is involved in the response to glucose in a completely distinct organism, namely the nematode Caenorhabditis elegans. The new mechanism for dynamin could therefore be more generally relevant in vivo and may play a role in insulin resistance. PMID- 28853755 TI - Catalytic macrolactonizations for natural product synthesis. AB - Covering: 2000 to 2017Macrolactones are privileged structural motifs in many functional molecules, particularly natural products and pharmaceutical molecules. They are commonly synthesized from the corresponding seco acids with various stoichiometric activating reagents to promote the formation of the macrocycle. Advances in new methods and strategies for synthesizing macrolactones have been made over the years to improve the overall synthetic efficiency and economy. This highlight focuses on the recent developments of catalytic macrolactonization methods and strategies without the use of seco acids and their applications in natural product total synthesis. In particular, catalytic C-H macrolactonization, enantioselective Rh-catalyzed redox-neutral allene-acid cyclization, catalytic carbonylative macrolactonization, and NHC-catalyzed oxidative macrolactonization are highlighted. PMID- 28853756 TI - Structural variations in (CuL)2Ln complexes of a series of lanthanide ions with a salen-type unsymmetrical Schiff base(H2L): Dy and Tb derivatives as potential single-molecule magnets. AB - A new series of heterometallic trinuclear Cu2Ln complexes [lanthanide ions Ln = Gd (1), Tb (2), Dy (3), Ho (4) and Er (5)] has been synthesized using a Cu(ii) metalloligand derived from a N2O2 donor unsymmetrical Schiff base, H2L (where H2L = N-alpha-methylsalicylidene-N'-salicylidene-1,3-propanediamine), and structurally characterized. Among these complexes, [(CuL)2Gd(NO3)3(CH3CN)2] (1), [(CuL)2Tb(NO3)3(CH3CN)2] (2) and [(CuL)2Dy(NO3)3(CH3CN)2] (3) are isomorphic and isostructural. In these complexes two metalloligands coordinate to the central Ln(iii) (Ln = Gd, Tb and Dy respectively) ion in a transoid fashion viaMU2 phenoxido oxygen atoms. The Ln(iii) ions are deca-coordinated with a distorted tetradecahedron geometry. The two terminal Cu(ii) ions of the complexes possess a hexa-coordinated distorted octahedral geometry. In contrast, in complexes [(CuL)2Ho(NO3)3(CH3CN)], (4) and [(CuL)2Er(NO3)3(CH3CN)].0.5(CH3CN) (5), the two metalloligands coordinated to the Ln(iii) ions in a cisoid fashion. The Ho(iii) ion in 4 is nona-coordinated with a distorted tricapped trigonal prismatic geometry and the Er(iii) ion in 5 is octa-coordinated with a distorted square antiprismatic geometry. The two terminal Cu(ii) ions in complexes 4 and 5 are penta-coordinated with a distorted square-pyramidal geometry. The dc magnetic susceptibilities and field dependent magnetization measurement of complex 1 reveal the occurrence of ferromagnetic interactions between Cu(ii) and Gd(iii) ions as well as intermolecular antiferromagnetic interactions. Both complexes 2 and 3 show ferromagnetic interactions between Cu(ii) and Ln(iii) ions. The ac magnetic susceptibilities of all the complexes were also recorded and it was found that only complexes 2 and 3 exhibit slow relaxation of magnetization reorientation below 10 K at 2000 Oe applied dc field, this being characteristic of single molecule magnets. PMID- 28853757 TI - Novel pyrrolobenzodiazepine and pyrroloquinazoline scaffolds synthesized by a simple and highly selective Ugi/cyclization sequence. AB - Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) and other benzo-fused N-heterocycles constitute privileged structures found in numerous bioactive compounds. Thus, developing simple and selective syntheses to furnish these derivatives from easily accessible starting materials is an important and challenging goal. In this work, novel pyrrolobenzodiazepine and pyrroloquinazoline derivatives have been synthesized following a common two step synthetic strategy. This strategy involves a one-pot Ugi/cyclization sequence followed by a reduction with spontaneous thermocontrolled cyclization. The control of the temperature in this second step allows fully selective access to either pyrrolo[2,1 c][1,4]benzodiazepine-3-ones 6 or pyrrolo[2,1-b]quinazolines 7. Density functional theory (DFT) calculations have been carried out to rationalize this reactivity, identifying the kinetic and thermodynamic reaction products and offering insights into the cyclization pathways. These synthetic methodologies show the versatility of the Ugi reaction as a tool in the synthesis of heterocyclic compounds with a pseudopeptidic skeleton. PMID- 28853765 TI - Pulmonary embolism four days after interruption of therapy with rivaroxaban. AB - Thrombosis after cessation of anticoagulation, also named rebound thrombosis, is a matter of concern and controversy. There are only few published data about occurrence of rebound thrombosis associated with non-vitamin K-antagonist oral anticoagulant drugs (NOACs). We report on a 58-year-old male with paroxysmal atrial fibrillation (AF) with a CHA2DS2VASC score of 4 who developed central pulmonary embolism four days after interruption of rivaroxaban because of parotid surgery. He had received 40 mg enoxaparin/d. The parotid gland was partially resected within 6 hours without blood loss. Pulmonary embolism and AF occurred on the first postoperative day. He recovered with low-molecular-weight heparin in therapeutic dosages and amiodarone and was discharged with phenprocoumon. The relevance of a rivaroxaban rebound phenomenon, manifesting as arterial embolism, stroke or venous thromboembolism should be clarified. It should be assessed if rebound-phenomena also exist for the NOACs dabigatran, apixaban and edoxaban. Thus, the randomized trials and registries investigating patients with AF or venous thromboembolism should be re-analysed and, based on these data, recommendations should be developed for situations in which NOAC-therapy has to be interrupted or ceased. PMID- 28853764 TI - Exploring Vital Sign Data Quality in Electronic Health Records with Focus on Emergency Care Warning Scores. AB - BACKGROUND: Computerized clinical decision support and automation of warnings have been advocated to assist clinicians in detecting patients at risk of physiological instability. To provide reliable support such systems are dependent on high-quality vital sign data. Data quality depends on how, when and why the data is captured and/or documented. OBJECTIVES: This study aims to describe the effects on data quality of vital signs by three different types of documentation practices in five Swedish emergency hospitals, and to assess data fitness for calculating warning and triage scores. The study also provides reference data on triage vital signs in Swedish emergency care. METHODS: We extracted a dataset including vital signs, demographic and administrative data from emergency care visits (n=335027) at five Swedish emergency hospitals during 2013 using either completely paper-based, completely electronic or mixed documentation practices. Descriptive statistics were used to assess fitness for use in emergency care decision support systems aiming to calculate warning and triage scores, and data quality was described in three categories: currency, completeness and correctness. To estimate correctness, two further categories - plausibility and concordance - were used. RESULTS: The study showed an acceptable correctness of the registered vital signs irrespectively of the type of documentation practice. Completeness was high in sites where registrations were routinely entered into the Electronic Health Record (EHR). The currency was only acceptable in sites with a completely electronic documentation practice. CONCLUSION: Although vital signs that were recorded in completely electronic documentation practices showed plausible results regarding correctness, completeness and currency, the study concludes that vital signs documented in Swedish emergency care EHRs cannot generally be considered fit for use for calculation of triage and warning scores. Low completeness and currency were found if the documentation was not completely electronic. PMID- 28853766 TI - Enhancing Patient Safety Event Reporting. A Systematic Review of System Design Features. AB - OBJECTIVES: Electronic patient safety event reporting (e-reporting) is an effective mechanism to learn from errors and enhance patient safety. Unfortunately, the value of e-reporting system (a software or web server based platform) in patient safety research is greatly overshadowed by low quality reporting. This paper aims at revealing the current status of system features, detecting potential gaps in system design, and accordingly proposing suggestions for future design and implementation of the system. METHODS: Three literature databases were searched for publications that contain informative descriptions of e-reporting systems. In addition, both online publicly accessible reporting forms and systems were investigated. RESULTS: 48 systems were identified and reviewed. 11 system design features and their frequencies of occurrence (Top 5: widgets (41), anonymity or confidentiality (29), hierarchy (20), validator (17), review notification (15)) were identified and summarized into a system hierarchical model. CONCLUSIONS: The model indicated the current e-reporting systems are at an immature stage in their development, and discussed their future development direction toward efficient and effective systems to improve patient safety. PMID- 28853767 TI - A large animal model for a failed two-stage revision of intramedullary nail related infection by methicillin-resistant Staphylococcus aureus. AB - The treatment of chronic orthopaedic device-associated infection (ODRI) often requires multiple surgeries and prolonged antibiotic therapy. Despite this extensive treatment protocol, the procedure is associated with significant failure rates. Currently, no large animal model is available that recapitulates a failed revision. Therefore, our aim was to establish a large animal model for failed treatment of an ODRI in order to serve as a testbed for future interventional strategies. Adult Swiss Alpine sheep received an intramedullary nail in the tibia and a localised inoculum of either a methicillin-sensitive or methicillin-resistant Staphylococcus aureus (MSSA, MRSA respectively). After 8 weeks, when chronic infection had been established, the animals underwent a staged revision with debridement and temporary placement of an antibiotic-loaded cement spacer. Antibiotics were delivered systemically in a standard or pathogen adapted manner. Debridement and implant exchange alone failed to treat the MSSA infection. Neither local therapy alone nor systemic therapy alone were effective in resolving infection with MSSA, but a combination of local and systemic therapy was effective against it. MRSA infection was not resolved by the combination of local and systemic antibiotics (standard or pathogen-adapted). A model for failed revision of MRSA infection is described despite the use of local and systemic antibiotics. Novel interventions may be assessed using this model, including antibiotic and non-antibiotic interventions. PMID- 28853768 TI - Systemic Treatment with a miR-146a Mimic Suppresses Endotoxin Sensitivity and Partially Protects Mice from the Progression of Acute Graft-versus-Host Disease. AB - Acute GVHD (aGVHD) is driven by interactions between the allogenic T cell response, inflammation, tissue injury and microbial products that enter the circulation when protective barriers such as the intestinal epithelium become compromised. Mice with aGVHD become hypersensitive to LPS, secreting large quantities of inflammatory mediators that exacerbate tissue injury. We hypothesized that microRNA (miR) modulators could be used in vivo to mitigate LPS hypersensitivity, altering the course of aGVHD. Using the C57BL/6 -> (C57BL/6 * DBA/2)F1 -hybrid model of aGVHD, we measured intestinal permeability over time and used a qPCR array to detect concomitant changes in the expression levels of certain microRNAs (miRs) in the intestine. Large increases in permeability were seen on day 15, when endotoxemia becomes detectable and GVHD-associated histopathological lesions develop. Amongst the miRs with altered expression levels were some that regulate sensitivity to endotoxin. We chose to focus on miR 146a and treated recipient mice systemically with a miR-146a mimic early in the GVH reaction. This led to a reduction in the burst of IFNgamma that likely plays a priming role in the mechanism underlying heightened sensitivity to endotoxin. LPS-induced TNFalpha release and GVHD-associated weight loss were also diminished and survival was prolonged. In summary, systemic treatment with a miR-146a mimic dampens the heightened sensitivity to LPS that occurs concomitantly with increased intestinal permeability and provides partial protection from the progression of acute GVHD. PMID- 28853769 TI - Modern Methods for Isolation, Purification, and Cultivation of Soil Cyanobacteria. AB - Up-to-date methods for isolation of cyanobacteria from soil samples, removal of accompanying microflora, obtaining axenic strains, and -conditions and media for subsequnt cultivation are reviewed. Char acterization of soil as a specific habitat for cyanobacteria is provided. Comparative analysis of pH and ele- mental composition of the liquid phase of most soil types with the media for cultivating cyanobacteria is car- ried out. The functional role of the major components required for the cultivation of cyanobacteria is de- scribed. The problems associated with isolation, purification, and cultivation of soil cyanobacteria, as well as the relevant solutions, are discussed. PMID- 28853770 TI - Hydrogenogenic and Sulfidogenic Growth of Thermococcus Archaea on Carbon Monoxide and Formate. AB - Enrichment and pure cultures of hyperthermophilic archaea capable of anaerobic growth on one- carbon compounds (CO and/or formate) were obtained from deep-sea sites of hydrothermal activity at the Mid-Atlantic Ridge, Lau Basin, and Guaymas Basin. All isolates belonged to the T barophilus-T paralvi- .nellae group within the genus Thermococcus. In all cases available for analysis, the genomes of Thermococcus strains capable of growth by hydrogenogenic utilization of CO and/or formate contained clusters of genes en- coding energy-converting hydrogenase and either CO dehydrogenase or formate dehydrogenase and formate transporter. Apart from the previously known processes of hydrogenogenic oxidation of CO and formate, the oxidation of these substrates coupled to sulfur reduction was observed, processes previously unknown among archaea. The capacities for hydrogenogenic or sulfidogenic oxidation of CO and formate occurred in the studied strains in all possible combinations, which could only in part be explained by peculiarities of organi- zation of genetic determinants revealed in the genomes. Investigation of CO and formate consumption kinet- ics revealed that T barophilus strain Ch5 was able to grow at concentrations close to the environmental ones. Thus, it was shown that hyperthermophilic archaea from deep sea hydrothermal vents are able to utilize one- carbon substrates of abiotic origin both in the presence of an electron acceptor (sulfur) and in its absence. These processes were probably of importance under the conditions of the early Earth biosphere. PMID- 28853771 TI - Characterization of Extracellular Yeast Peptide Factors and Their Stress Protective Effect on Probiotic Lactic Acid Bacteria. AB - Protective effect of the extracellular peptide fraction (reactivating factors, RF) produced by yeasts of various taxonomic groups (Saccharomyces cerevisiae, Kluyveromyces lactis, Candida utilis, and Yarrowia li- polytica) on probiotic lactic acid bacteria (LAB) Lactobacillus casei, L. acidophilus,'and L. reuteri under bile salt (BS)-induced stress was shown. RF of all yeasts were shown to be of peptide nature; the active component of the S. cerevisiae RF was identified as a combination of low-molecular polypeptides with molecular masses of 0.6 to 1.5 kDa. The protective and reactivating effects of the yeast factors were not species-specific and were similar to those of the Luteococcusjaponicus subsp. casei R. In BS-treated cells of the tester bacteria, a pro- tective effect was observed after 10-min preincubation of the LAB cell suspension with yeast RE: the number of surviving cells (CFU) was 2 to 4.5 times higher than in the control. The reactivating effect was observed when RF was added to LAB cell suspensions not later than 15 min after stress treatment. It was less pro- nounced than the protector effect, with the CFU number I to 3 times that of the control. Both the protector and the reactivating effects were most pronounced in the S. cerevisiae and decreased in the row: C. utilis > K. lactis > Y lipolytica. The efficiency of protective action of yeast RF was found to depend on the properties of recepient LAB cells, with the L. casei strain being most sensitive to BS treatment. In both variants, the highest protective effect of RF (increase in the CFU number) was observed for L. acidophilus, while the least pronounced one, for L. casei. The reasons for application of the LAB strains combining high stress resistance and high response to stress-protecting metabolites, including RF factors, as probiotics, is discussed. PMID- 28853772 TI - Effect of Illumination Intensity and Inhibition of Carotenoid Biosynthesis on Assembly of Peripheral Light-Gathering Complexes in Purple Sulfur Bacteria C Allochromatium vinosum ATCC 17899. AB - Effect of illumination intensity and inhibition of carotenoid biosynthesis on assemblage of different spectral types of LH2 complexes in a purple sulfur bacterium Allochromatium (Alc.) vinosum ATCC 17899 was studied. Under illumination of 1200 and 500 lx, the complexes B800-850 and B800-840 and B800-820 were assembled. While rhodopine was the major carotenoid in all spectral types of the LH2 complex, a certain- increase in the content of carotenoids with higher numbers of conjugated double bonds (anhydrorhodovibrin and didehydrorhodovibrin) was observed in the B800-820 complex. At 1200 lx, the cells grew slowly at diphe- nylamine (DPA) concentrations not exceeding 53 .iM, while at illumination intensity decreased to 500 Ix they could grow at 71 jiM DPA (DPA cells). Independent on illumination level, the inhibitor is supposed to impair the functioning of phytoine synthetase (resulting in a decrease in the total carotenoid content) and of phyto- ine desturase, which results in formation of neurosporene hydroxy derivatives and ;-carotene. In the cells grown at 500 lx, small amounts of spheroidene and.OH-spheroidene were detected. These carotenoids were originally found under conditions of carotenoid synthesis inhibition in bacteria with spirilloxanthin as the major carotenoid. Carotenoid content in the LH2 complexes isolated from the DPA cells was -15% of the control (without inhibition) for the B800-850 and -20%of the control for the B800-820 and B800-840 DPA complexes. Compared to the DPA pigment-containing membranes, the DPA complexes were enriched with -carotenoids due to- disintegration of some carotenoid-free complexes in the course of isolation. These results support the supposition that some of the B800-820, B800-840, and B800-850 complexes may be Assembled in the cells of Alc. vinosum ATCC 17899 without carotenoids. Comparison of the characteristics obtained for Alc. vinosum ATCC 17899 and the literature data on strain D of the same bacteria shows that they belong to two different strains, rather than to one as was previously supposed. PMID- 28853773 TI - Taxonomic Specificity of the Sensitivity to the Wickerhamomyces bovis Fungistatic Mycocin. AB - Wickerhamomyces bovis type strain was found to secret a mycocin with a fungistatic effect at pH from 3.5 to 6.0. The peak of its activity occurred at pH 5.0 in the presence of 3% NaCl. Yeast species sensitive to this mycocin belonged to phylogenetically related genera Ambrosiozyma, Nakazawaea, Ogataea, and Pet- erozyma within the family Wickerhamomycetaceae. PMID- 28853774 TI - A Novel Uncultured Bacterium of the Family Gallionellaceae: Description and Genome Reconstruction Based on the Metagenomic Analysis of Microbial Community in Acid Mine Drainage. AB - Drainage waters at the metal mining areas often have low pH and high content of dissolved metals due to oxidation of sulfide minerals. Extreme conditions limit microbial diversity in- such ecosystems. A drainage water microbial community (6.5'C, pH 2.65) in an open pit at the Sherlovaya Gora polymetallic open-cast mine (Transbaikal region, Eastern Siberia, Russia) was studied using metagenomic techniques. Metagenome sequencing provided information for taxonomic and functional characterization of the micro- bial community. The majority of microorganisms belonged to a single uncultured lineage representing a new Betaproteobacteria species of the genus Gallionella. While no.acidophiles are known among the cultured members of the family Gallionellaceae, similar 16S rRNA gene sequences were detected in acid mine drain- ages. Bacteria ofthe genera Thiobacillus, Acidobacterium, Acidisphaera, and Acidithiobacillus,-which are com- mon in acid mine drainage environments, were the minor components of the community. Metagenomic data were -used to determine the almost complete (-3.4 Mb) composite genome of the new bacterial. lineage desig- nated Candidatus Gallionella acididurans ShG14-8. Genome analysis revealed that Fe(II) oxidation probably involved the cytochromes localized on the outer membrane of the cell. The electron transport chain included NADH dehydrogenase, a cytochrome bc1 complex, an alternative complex III, and cytochrome oxidases of the bd, cbb3, and bo3 types. Oxidation of reduced sulfur compounds probably involved the Sox system, sul- fide-quinone oxidoreductase, adenyl sulfate reductase, and sulfate adenyltransferase. The genes required for autotrophic carbon assimilation via the Calvin cycle were present, while no pathway for nitrogen fixation was revealed. High numbers of RND metal transporters and P type ATPases were probably responsible for resis- tance to heavy metals. The new microorganism was an aerobic chemolithoautotroph of the group of psychrotolerant iron- and sulfur oxidizing acidophiles of the family Gallionellaceae, which are common in acid mine drainages. PMID- 28853775 TI - A New Bacillus licheniformis Mutant Strain Producing Serine Protease Efficient for Hvdrolvqis of Sov Meal Proteins. AB - Induced mutagenesis with y-irradiation of the industrial strain Bacillus licheniformis-60 VKM B-2366,D was used to obtain a new highly active producer of an extracellular serine protease, Bacillus licheni- formis7 145. Samples of dry.concentrated preparations of serine protease produced by the original and mutant strains were obtained, and identity of their protein composition was'established. Alkaline serine protease sub- tilisin DY was the main component of the preparations. The biochemical and physicochemical properties of the Protolkheterm-145 enzyme preparation obtained from the mutant strain were studied. It exhibited pro- teolytic activity (1.5 times higher than the preparation from the initial strain) within broad ranges of pH (5- 11) and temperature (30-70'C).-Efficient hydrolysis of extruded soy meal protein at high concentrations (2 to 50%) in-the reaction mixture was.the main advantage of the Protolikheterm 145 preparation. Compared to,. the preparation obtained using the initial strain, the new preparation with increased proteolytic-activity pro- vided for more complete hydrolysis of the main non-nutritious soy,proteins.(glycinin and 0-conglycinin) with the yield of soluble protein increased by 19-28%, which decreased the cost of bioconversion of the protein- aceous material and indicated promise of the new preparation in resource-saving technologies for processing soy meals and cakes. PMID- 28853776 TI - Sulfate Reduction and Inorganic Carbon Assimilation in Acidic Thermal Springs of the Kamchatka Peninsula. AB - Thermoacidophilic sulfate reduction remains a poorly studied process, which was investigated in the present work. Radioisotope analysis with 35S-Iabeled sulfate was used to determine the rates of dissimilatory sulfate reduction in acidic thermal springs of Kamchatka, Russia. Sulfate reduction rates were found to vary from 0.054 to 12.9 nmol S04/(cm3 day). The Neftyanaya ploshchadka spring (Uzon caldera, 60'C, pH 4.2) and Oreshek spring (Mutnovskii volcano, 91'C, pH 3.5) exhibited the highest activity of sulfate-reducing prokaryotes. Stable enrich- ment'cultures reducing sulfate at pH and temperature values close to'the environmental ones were obtained from these springs. Analysis of the 16S rRNA gene sequences revealed that'a chemolithoautotrophic bacterium Ther- modesufobium sp. 3127-1 was responsible for sulfate reduction in the enrichment from the Oil Site spring. A chemoorganoheterotrophic archaeon Vulcanisaeta sp. 3102-1 (phylum Crenarchaeota) was identified in the en- richment from Oreshek spring. Thus, dissimilatory sulfate reduction under thermoacidophilic conditions was demonstrated and the agents responsible for this process were revealed. PMID- 28853777 TI - Trophic Interactions of Proteolytic Bacteria Proteinivorax tanatarense in an Alkalinphilic Microbial Community. AB - Lythic action of an anaerobic proteolytic bacterium Proteinivorax tanatarense on organisms with different cell wall types was studied. In the absence of photosynthetic oxygen release, this proteolytic was able to grow on intact biomass of cyanobacteria belonging to various systematic groups. Itis probably their usual saprotrophic-satellite responsible for the regulation of abundance of primary producers during the dark phase. Growth also occurred on the biomass of a nonphototrophic gram-negative microorganism-Halomonas campisalis, a common component of alkaliphilic. microbial communities: Comparative analysis of the interaction of the proteolytic with.H. campisalis cells at different physiological states revealed the lytic action to be re- stricted to dead and/or weakened cells, rather than the actively dividing ones. Strict specificity of the action of the proteolytic bacterium on gram-negative microorganisms with no effect on gram-positive ones was shown. PMID- 28853778 TI - Yeasts in Hevea brasiliensis Latex. AB - Yeast abundance and species diversity in the latex of caoutchouc tree Hevea brasiliensis (Willd. ex Juss.) M611. Arg., on its green leaves, and in soil below the plant Was studied. The yeasts present in the fresh latex in concentrations of up to 5.5 log(CFU/g) were almost exclusively represented by the species Candida heveicola, which was previously isolated from Hevea latex in China. In the course of natural modification of the latex yeast diversity increased, while yeast abundance decreased. The yeasts of thickened and solidified latex were represented by typical epiphytic and ubiquitous species: Kodamea ohmeri, Debaryomyces hansenii, Rhodotorula mucilaginosa, and synanthropic species Candida parapsilosis and Cutaneotrichosporon arbori- formis. The role of yeasts in latex modification at the initial stages of succession and their probable role in de- velopment of antifungal activity in the latex are discussed. PMID- 28853779 TI - Broiler Cecal Microbiocenoses Depending on Mixed Fodder. AB - Molecular genetic techniques (NGS sequencing and quantitative PCR) were used to determine the composition of the cecal bacterial community of broiler chickens fed with different mixed fodder. The Cecal microbiome exhibited taxonomic diversity, with both typical inhabitants of avian intestine belonging to the families Clostridiaceae, Eubacteriaceae, and Lactobacillaceae and to the phylum Bacteroidetes, and new un- identified taxa, as well as bacteria of the families Lachnospiraceae and Ruminococcaceae, which were previ- ously considered restricted to the rumen microflora. Contrary to traditional concepts, enterococci and bi- fidobacteria were among the minor components of the community, lactate fermenting species were absent, and typical avian pathogens of the genus Staphylococcus were detected but seldom. Members of the family Suterellaceae and the genus Gallibacterium, which are responsible for avian respiratory infections, were also detected. Significant fluctuations of abundance and composition of microbial groups within the cecal com- munity and of the parameters of broiler productivity were found to occur depending on the feed allowance. Cellulose content in the feed had the most pronounced effect on the composition aid structure of bacterial communities. Decreased cellulose content resulted in a decrease of bacterial abundance by-aii order of mag- nitude and in increased ratios of members of the phylum Bacteroidetes and the family Clostridiaceae, which possess the enzymes degrading starch polysadcharides. Abundance of the normal inhabitants of avian intes- tine belonging to the genus Ldctobacillus and the order Bacillales decreased, while the share of Escherichia and members of the family Sutterellaceae increased, including some species capable of causing dysbiotic changes in avian intestine. No significant change in abundance of cellulolytics of the families Ruminococca- ceae, Lachnospiraceae, and Eubacteriaceae was observed. PMID- 28853780 TI - [In process]. PMID- 28853781 TI - [In process]. PMID- 28853782 TI - [In process]. PMID- 28853783 TI - Current status on the application of image processing of digital intraoral radiographs amongst general dental practitioners. AB - OBJECTIVES: The objectives of this study were to present the subjective knowledge level and the use of image processing on digital intraoral radiographs amongst general dental practitioners at Distriktstandvrden AB, Stockholm. MATERIAL AND METHODS: A questionnaire, consisting of12 questions, was sent to 12 dental prac- tices in Stockholm. Additionally, 2000 radiographs were randomly selected from these clinics for evaluation of applied image processing and its effect on image quality. Descriptive and analytical statistical methods were applied to present the current status of the use of image proces- sing alternatives for the dentists' daily clinical work. RESULTS: 50 out of 53 dentists participated in the survey.The survey showed that most of dentists in.this study had received education on image processing at some stage of their career. No correlations were found between application of image processing on one side and educa- tion received with regards to image processing, previous working experience, age and gender on the other. Image processing in terms of adjusting brightness and contrast was frequently used. Overall, in this study 24.5% of the 200 images were actually image processed in practice, in which 90% of the images were improved or maintained in image quality. CONCLUSIONS: According to our survey, image processing is experienced to be frequently used by the dentists at Distriktstandvaden AB for diagnosing anatomical and pathological changes using intraoral radiographs. 24.5% of the 200 images were actually image processed in terms of adjusting brightness and/or contrast. In the present study we did not found that the dentists' age, gender, previous working experience and education in image processing influence their viewpoint towards the application of image processing. PMID- 28853784 TI - Clinical and radiographic outcomes of lateral sinus floor elevation: a retrospective study. AB - The aim of this retrospective study was to evaluate the clinical and radiographic outcomes of lateral sinus floor elevation (LSFE). A total of 347 medium rough surface implants were placed in both xenogenic bone and natural bone in 103 patients. A two-stage surgical technique was performed with a lateral window approach followed by a healing period of 9 months prior to implant placement. Patients were analysed with regard to pre- and post-augmentation bone height data (Group A), levels of mar- ginal bone (Group B) and implant survival rates/complications. A total of 6 implants were lost in the present investigation, of which two were still osseoin- tegrated, albeit mechanically damaged.The implant survival rate was 99.0% considering those engaging BioOss, and the corresponding figure for implants placed in natural bone was 96.2%. The average follow-up time was 2.5 years.The mean preoperative bone height was 3.8 mm and the mean postoperative bone height was 13.7 mm. It may be advocated that preoperative bone heights exceeding 7 mm are not indicative of LSFE treatment and that preoperative bone heights of 4-7 mm may imply alternative treatment options. A group of subjects, corresponding to 16.5%- of the patient material, had some sort of postoperative complication. One may conclude that LSFE is a predictable and safe treatment procedure, with a high implant survival rate. LSFE resulted in gained bone height in the range of 10 mm. PMID- 28853785 TI - The association between root canal filling and treatment outcome. AB - The aim of the study was to evaluate the technical quality of endodontic treatment per- formed by postgraduate students in Karolinska Institutet, Stockholm, Sweden during the years (2008-2011) and to evaluate the treatment outcome. In addition, possible influencing factors to treatment outcome were analyzed. All maxillary first molars that received endo- dontic treatment between 2008 and 2011 were included in the study. Pre, post and follow up radiographs were collected.The apical status (PAI-score),the quality of the root canal treat- ment (RCT) and the treatment outcome were assessed. Analysis of the treatment outcome in relation to the quality of root canal treatment and other possible influencing variables was performed by Chi2 or Fisher's Exact test, and the statistical significance was set at P<0.05. A total of 73 teeth were included in the study. Out of these, sixty-three teeth (86,3 %) had periapical lesions at the time for RCT. An initial root canal treatment was performed in 46 teeth (63 %) and 27 teeth (37 %) were retreated.There was no significant as- sociation between the outcome and the type of treatment.The majority of the RCT's (58 %) had good seal and correct length. In total, the treatment outcome was successful in 59 (81 %) of the cases. The success rate was 88% in cases with high quality root fillings, compared to 71% in cases with less good quality.There was a non- significant trend (P =0.066) of an association between RCT quality and treatment outcome. In conclusion the association between the quality of the root filling and the treatment outcome was not verified with statistical significance, but the results indicate a trend that satisfactory root fillings are associated with a favorable outcome.This study was limited by its retrospective nature and a relatively small sample size. PMID- 28853786 TI - A randomized controlled cross-over study of the effect of alcohol-free chlorhexidine and essential oils on interleukin-1 levels in crevicular fluid. AB - Aim of the study was to determine the effect of an alcohol-free chlorhexidine mouth rinse and an essential oils containing mouth rinse on pro-inflammatory cytokine levels in gingival crevicularfluid in participants who continue to perform their regular mechanical oral hygiene regimes and normal dietary practice. Twenty adult volunteers (mean age: 59 years) participated in the double blind randomised controlled cross-over study.Three mouth rinses were used during 16-day periods as an adjunctiveto regular mechanical oral hygiene: a solution with alcohol-free chlorhexidine (CHX; Paroex), a solution with essential oils (EO; Listerine), and water (negative control).The mouth rinse periods were separated by 3-month washout periods. At days o (baseline) and 17 (end) of each mouth rinse period, gingival crevicular fluid (GCF) was collected at different tooth sites and analyzed with ELISA technique for IL-1alpha, IL-1beta and IL-ira levels. No significant correlations between clinical parameters (QHI and GI) and cytokine concentra- tions were observed, regardless of mouth rinse regimen.The generalized linear models revealed that none of the mouth rinses had a statistically significant impact on IL-1 concentrations in GCF. Large inter individual variations were observed for the levels of IL-ialpha, IL-1beta and IL ira. Also the changes in concentrations between day o and day 17fo r the mouthrinses showed large intra-individual variations. It can be concluded that neither the alcohol-free chlorhexidine nor the mouth rinse contain- ing essential oils reduced the levels of IL-ialpha, IL1beta and IL-ira in GCF. PMID- 28853787 TI - Oral condition and background factors in Somali immigrant children newly arrived in Sweden. AB - The aim of the present study was to obtain baseline information about oral health, oral health behaviours and knowledge about prevention of oral diseases in newly arrived Somali children. All 310 Somali children arriving in four municipalities in Kronoberg County, Sweden, during 2013 participated. We collected interview data (background factors related to oral health) and performed a clinical examination (oral hygiene, marginal bone loss, malocclusion, dental caries) within the first two months after arrival.The children were analysed in three age groups: 3-6 years (n=49), 7-11 years (n=125), and 12 17years (n=136). The interview revealed that 78-82% of the children in the three groups had never visited a dental clinic in Somalia. Toothache was reported by 18 28% of the children. In the youngest group,71% of the parents did not assist with tooth-cleaning and children commonly used a Miswak stick for cleaning. About half the children had poor oral hygiene while 25-33% repor- ted daily intake of sugary snacks. Malocclusion affected 40% of the 7-11-year-olds and 50% of the 12-17-year olds. Bone loss affected 13% of the 12-17-year-olds.The 3-6-year-olds had a high prevalence (37%) of missing primary, lower cuspids. Their mean number of decayed, extracted and filled primary teeth (deft) was 2.3, and 43% were free from caries. In the 7-11-year-olds, mean decayed and filled permanent teeth (DFT) was o.8, while in the 12--17-year-olds DFT was 2.2 with 40% caries-free. Comparison with resident children indicates substantially higher caries preva- lence among the Somali children. The study has shown that newly arrived Somali children often present with oral diseases and are in urgent need of treatment and have great need for oral health promotion. PMID- 28853788 TI - Swedish orthodontists' opinions and experiences regarding miniscrew implants. AB - Miniscrew implants (MSI) can be a useful tool when maximal anchorage is desired in ortho- dontic treatment.The aim of this study was to describe the opinions and experiences of mini- screw implants among orthodontists currently practising in Sweden. A web-based anonymous questionnaire containing 17 multiple choice questions was sent to 218 listed members of the Swedish Association of Orthodontists during fall 2012. Descriptive statistics were used for analysing the collected data set. In a total of 147 (67%) respondents 80 were women, 62 were men and five did not specify gender. MSI had been used by 78 (53%) respondents in orthodontic treatment.The majority of the respondents, 53 (70%), had used i-io MSI.The majority of MSI placements were made by orthodontists (84%) while 18 (9%) referred the procedure to an oral surgeon. The most common indications for MSI were space closure, intrusion, and bodily movements. The use of MSI enabled 61 (81%) of the respondents to set higher treatment objectives.The suc- cess frequency of the MSI was perceived as satisfactory by 48 (65%) of the respondents. PMID- 28853789 TI - Reporting dental caries disease in longitudinal studies - a suggestion. AB - In general, most infectious and/or lifestyle-related diseases are defined as being present when sufficient signs or symptoms occurs in an individual. The term "sufficient".is a relative concept and a disease can therefore be measured with different degrees of certainty.These symptoms are commonly defined in such a way that it is possible to determine the incidence and prevalence of the disease and also the proportion of individuals that are cured from the dis- ease. If dental caries is an individual disease which can be compared to other diseases regarding incidence and prevalence, it is important to determine for how long an individual must be free from new signs of the disease before being considered cured or free from the disease and to define the "sufficient" signs or symptoms needed for a diagnose. Based on these thoughts, the purpose of this study was to calculate caries incidence and prevalence in a group of adolescents from a definition of dental caries based on ICD-1o. This study included all12 year olds in 1990 who attended a clinical dental examination in 1990-1995 in Orebro County, Orebro, Sweden, yearly during these six years. Dental caries disease at the individual level was defined as K02.1 (dentinal caries) according to ICD-io while freedom of caries was defined as the absence of K02.1 during a three-year period. In this study the yearly prevalence was 12%, the three year cu- mulative incidence was 18% and the incidence rate 13%. Results of this study highlight the poor outcomes in curing caries disease in this age-group, according to the criteria in this study, as only 17% of the children with caries at the outset of the study were free from the disease three years later. Defining both a practical level to measure signs of dental caries, and the period an individual must be free from them to be classified as cured from the disease create new oppor- tunities to compare and communicate the disease of dental caries with other diseases.This way of registration is also of advantage for planning purposes as there the centre of interest must be the individual patient and not the tooth or surface. PMID- 28853790 TI - Dental nurses' experiences of performing a school-based fluoride varnish programme for children and adolescents in Sweden. AB - In many parts of Sweden today, school-based fluoride varnish programmes (FVP) are perfor- med by dental nurses. Studies have shown that the dental personnel are largely responsible for creating the atmosphere related to children's and adolescents'experiences of the program- mes. Knowledge of dental nurses'experiences of performing FVP is therefore crucial in order to develop and improve these programmes and the dental health of children and adolescents.The aim of this study was to describe dental nurses'experiences of performing FVP for children and adolescents in Sweden. Fifteen female dental nurses, strategically chosen, aged 40-63, from the Public Dental Service in the Vistra Gtaland Region, Sweden, were individually interviewed.The interviews were transcribed verbatim and analysed according to the phenomenographic ap- proach.Three themes with a total of 11 categories, all describing the dental nurses' conceptions of performing FVP, emerged in the analysis. The main conclusions were that in overall terms, performing an FVP was found to be a positive experience for the dental nurses, as it meant mee- ting children and adolescents in a context in which the children and adolescents are comforta- ble and relaxed.The opportunity to identify children and adolescents with poor dental health or poor health and to be able to offer them assistance was regarded as a major advantage. In addition,the participants described a feeling of professional development originatingfrom the challenges associated with working in an arena outside the dental clinic. PMID- 28853791 TI - Prevalence of dental caries among 16-year-olds in Troms County, Northern Norway. AB - The investigation documents caries prevalence and associated factors in a sample of16-year- olds from Troms County, Northern Norway. DMFT/S-values were 4.2/6.1, indicating dental health being similar to the south of Norway and the rest of Scandinavia. No ethnic differences were recorded. Out of a total of 22 tested variables, the following nine showed an independent strong association (p=0,001) with prevalence of dental caries: parental education, tooth brushing frequency, parental control of oral hygiene in young age, dental fear, self-rated dental health, BMI, self-rated general health, use of smokeless tobacco, and initial approximal caries. The final multivariate regression analysis indicated that use of smokeless tobacco, dental fear, self-rated dental health and initial approximal caries showed a strong independent association with prevalence of manifest dental caries. In addition, parental education and sugar consumption appeared to be of importance. Sedentary lifestyle with low level of physical activity or hours spent in front of a TV/computer screen did not show any correlation with prevalence of dental caries. Tooth brushing frequency, gingival bleeding, obesity and aspects of general health showed a strong bi-variate association that disappeared when controlling for other variables in a multivariate regression model.The results highlight the importance of including attitude and lifestyle modifiable factors in oral and general health education approaches. Additionally, focus should be set on the management of dental fear in the context of targeted oral health strategies. Fi- nally, it would be beneficial to include initial approximal caries, life style factors, and perception and attitudes to general as well as dental health in caries prediction models. PMID- 28853792 TI - Clinical performance of enamel-dentine bonded all-ceramic restorations: retrospective evaluation in a postgraduate clinic. AB - The aim of this retrospective study was to evaluate the clinical survival and success of five dif- ferent types of adhesive bonded all-ceramic restorations, in a postgraduate clinic. All ceramic enamel-dentin adhesive bonded restorations, either partial (n=94) or full coverage (n=145), were assessed by clinical examination using a modified Californian Dental Association (CDA) system for quality evaluation of dental care and a questionnaire assessing patient satis- faction (VAS) of 29 subjects with 239 restorations. The same 3-step adhesive bonding system in combination with dual-cured resin composite cement was used for all restorations Rubber dam was used for moisture control.The ceramics were evaluated with respect to patient satisfaction, esthetics, technical and biological complications. The reasons for treatment were mineralisation disorders (n=82), trauma (n=40), esthetic (n=57) and pathological tooth wear (n=60). Observation period for the restorations was up to 71 month (mean 33). All restorations were in place at the examinations (l00% survival rate). Number offractures and infractions were 28 and 20 respectively giving a 69% success rate. No significant difference was observed between full coverage and partial coverage restorations. Most of the fractures were small chippings of the veneering porcelain. From a biological point of view subgingival location of the restoration margin showed a significant correlation with bleeding on probing.The esthetic outcome seemed to depend on the ability of the selected veneering material to mask a severe tooth discoloration.The patients reported a high degree of satisfaction with both the esthetics and the function of their restorations. In conclusion all-ceramic enamel-dentin-bonded restorations demonstrated good short-term survival rate.The success rate was found to be lower. Both technical and biological complica- tions were present but mainly without any need of correction.The patients were in general very satisfied with the result of their dental treatment both esthetically and functionally. PMID- 28853793 TI - Non-specific chronic orofacial pain patients' experiences of everyday life situations: a qualitative study. AB - Chronic orofacial pain is a complex condition with consequences that affect daily living. The aim was to analyse nonspecific chronic orofacial pain patients'experiences of everyday life situations, using a qualitative approach. Eleven women and 3 men (21 to 77years) were selected through a purposive sampling among chronic orofacial pain patients referred to the Faculty of Odontology's orofacial pain unit at Malmo University, Malmo Sweden. All selected subjects agreed to participate. Data were obtained via two thematic in-depth interviews with each subject. Interviews were taped and transcribed verbatim.Text dealing with the subjects' daily experiences was identified in all interviews and analysed using qualitative content analysis that focused on manifest content. In everyday life situations, the analysis of nonspecific chronic orofacial pain patients' narrations exposed a fear of conflict, of personal weakness, and of the intangible; they also exposed self-blame and avoidance of fear-triggering situations. Eight of the 14 subjects did not spontaneously mention any situation in which they were content during daily living. When the patients spoke about everyday life experiences, the main finding was that unpleasant emotions dominated the subjects'experiences. In conclusion, the chronic orofacial pain condition cannot be understood as an isolated phenomenon; it must be considered in rela- tion to the person who is suffering from the condition. PMID- 28853794 TI - Caries treatment in Swedish adults: effectiveness, costs and equity. A 4-year follow-up study of data from the Swedish national dental health register. AB - At a national level, planning and management of dental services should be based on assess- ments of equity, effectiveness and costs. In Sweden, data for the adult population are now acces- sible through The Swedish dental health register, at The National Board of Health and Welfare. This study, on two large cohorts of Swedish adults, is based on longitudinal follow-up data, retrieved from the Swedish dental health register.The aims were twofold: to assess frequencies and costs of fillings and crowns, including subsequent repair; secondly to study the relationship between preventive and restorative dental treatment.The Swedish dental health register pro- vides data on the adult population which offers a new perspective on public health aspects of management of dental care at the national level. A longitudinal, prospective study model was used to follow-up two large cohorts for over four years. In the first cohort, data on 1,088,923 adult patients were analysed with reference to provision of single crowns and fillings over a period of 42 -48 months.The second cohort comprised 1,703,147 adult patients: the data were analysed with reference to preventive interventions over a period of 48 - 54 months. Frequencies of distribution of dental care by age group showed that the cohorts were representative for the whole patient group.With respect to equity, the average number of dentist appointments per i,ooo inhabitants for all 21 regions of Sweden was 140 to 160, despite major variations in geographic conditions and population densities. With respect to effectiveness, about 76% of the teeth with index interven- tions required no additional intervention over four consecutive years of follow-up. For the remain- ing 24% of the teeth 77% had only one additional intervention. When differences of case-mix were taken into account, the costs of repairs to earlier ihterventions were basically similar, regardless of age-group.There were no gender differences. However, there were pronounced differences, of up to three intact teeth, among patients from different regions of Sweden. Follow-up of effects of caries prevention showed no gender differences. However, costs for reparative interventions increased with higher costs for preventive treatment. Moreover, the longer the interval between preventive interventions, the lower the costs for reparative interventions.The national dental health register is a potentially valuable source of data for dental research. In this study, longitu- dinal registry data on restorative and preventive treatment were retrieved and analysed, with reference to efficacy, costs and equity. The results have potential application in improving mana- gement of public dental health. PMID- 28853795 TI - Diagnostic accuracy of carious lesions in digital radiographs at a public dental clinic - can it be improved by optimizing viewing conditions and further education?. AB - OBJECTIVE: This study investigated the diagnostic accuracy of digital dental radiograpny for detecting carious lesions on approximal surfaces before and after optimization of the environ- ment, and after joint training on evaluation and review of x-rays. A further aim was to evaluate differences in diagnostic accuracy between general dental practitioners (GDPs) and dental hygienists (DHs). MATERIALS AND METHODS: One hundred extracted teeth (premolars and molars) underwent standardized radiography. Eleven participants (seven GDPs and four DHs) evaluated digital images for approximal carious lesions in three sessions: (1) at current conditions with no optimization or further training, (2) under optimized viewing conditions, and (3) under optimized viewing conditions after a short educational session. Receiver operating characteristic curves were,used to evaluate the results. Histological evaluation was made and served as a cri- terion standard for differentiating sound teeth and teeth with carious lesions. Kappa statistics evaluated intra-observer agreement. RESULTS: Diagnostic accuracy in the GDP group differed sig- nificantlyfor all types of carious lesions between the first and third evaluations (p=0.002), and also between the second and third (p=0.015). Diagnostic accuracy also differed significantly for carious lesions into the dentin between the first and third evaluations (p=0.010) and between the second and third (p=0.015). CONCLUSION: Most of the staff had optimized the environment when evaluating digital radiographs. A short educational session highlighting the difficulty of caries diagnostics in digital dental radiography can increase diagnostic accuracy. Diagnostic accuracy in the detection of approximal carious lesions on digital radiographs did not differ between GDPs and DHs. PMID- 28853796 TI - Physician Burnout. PMID- 28853797 TI - Using Geographic Information Systems (GIS) to Characterize Pediatric Pedestrian Motor Vehicle Accidents in the State of Delaware. AB - BACKGROUND: Pediatric pedestrian motor vehicle-associated of injuries correlated with a particular census tract's trauma is a significant public health concern for children. demographic composition. GIS mapping software was used We aimed to use geographic information systems (GIS) to examine the relationship between motor vehicle pedestrian injuries in children and the demographics of the region in which they occurred for the state of Delaware. METHODS: This is a retrospective analysis of collected data from the Delaware State Trauma Registry form January 1, 2002, to December 31, 2012. The records of all patients younger than 18 years who went to one of the state's six trauma centers during the study were reviewed. For each injury event, patient demographic information was recorded, and latitude/longitude coordinates of the injury site were determined. Median income, minority population, education level, and percentage of males and children in the census tract were obtained from state census data. Analysis of variance was used to characterize how the frequency of injuries correlated with a particular census tract's demographic composition. GIS mapping software was used to identify specific "hot spots" throughout the state where the examine the relationship between motor vehicle pedestrian frequency of traffic crash events was the highest. RESULTS: Urban and poorer areas had tile highest number of injury events, with Wilmington having the highest frequency Methods: This is a retrospective analysis of collected data of injuries per capita. Census tracts with low median income, from the Delaware State Trauma Registry from January 1, lack of high school degree, and increased percentage of 2002, to December 31, 2012. The records of all patients African Americans and females had significantly higher injury younger than 18 years who went to one of the state's six counts compared with other census tracts. CONCLUSIONS: In the state of Delaware, children in urban and poor areas are disproportionately affected by motor vehicle associated pedestrian injuries. Specific risk factors for accidents in these areas need to be identified to facilitate the development of focused prevention strategies. PMID- 28853798 TI - Intubation Barotrauma and/or CPR Causing Tension Pneumoperitoneum. AB - BACKGROUND: Review the radiologic findings and clinical significance of tension pneumoperitoneum. CASE REPORT: Imaging case presented to radiology during patient's prolonged and complicated hospital stay. CONCLUSIONS: Tension pneumoperitoneum associated with barotrauma is a rare, but potentially life threatening complication of mechanical ventilation. The radiologist should be able to recognize the imaging findings associated with tension pneumoperitoneum in order to assist in diagnosis of this potentially reversible entity. PMID- 28853799 TI - ? PMID- 28853800 TI - [Bariatric surgery : complications and endoscopic treatment]. AB - Obesity is a major public health issue. Surgery is the most effective treatment to obtain weight loss, stabilize weight status and decrease comorbidities. Yet post-operative complications can be serious and their treatment can also be a real challenge. The low invasive nature of endoscopy makes it an alternative to surgery. It can be used to diagnose and treat digestive hemorrhage, ulcers, stenosis, anastomotic leakage or fistula. This article aims to review the different bariatric surgical techniques, complications and their specific endoscopic treatment options. PMID- 28853801 TI - [Hepatitis B: new guidelines of disease management]. AB - Hepatitis B virus (HBV) infection is a major public health concern associated with major clinical complications, notably chronic liver disease that can progress with time to cirrhosis or even to hepatocellular carcinoma. The management of HBV-infected patients is complex and requires the close collaboration between the general practitioner and the specialist. This review presents an overview of recently published guidelines, from the European Association for the Study of the Liver, and suggests strategies for initial management and referral of HBV-infected patients for the general practitioner. PMID- 28853802 TI - [Hepatopulmonary syndrome and portopulmonary hypertension]. AB - Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are two frequent pulmonary complications of liver disease. Portal hypertension is a key element in the pathogenesis of both disorders, which are however distinct in terms of pathogenesis, diagnosis and treatment. HPS corresponds to an abnormal arterial oxygenation in relation with the development of intrapulmonary vascular dilatations. POPH is a pulmonary arterial hypertension in the setting of portal hypertension and elevated pulmonary vascular resistance. As both diseases are associated with an increased risk of morbidity and mortality, it is important to screen and evaluate the severity of these two disorders particularly in liver transplant candidates. PMID- 28853803 TI - [Portal vein thrombosis in patients with cirrhosis]. AB - Portal vein thrombosis is frequently encountered in patients with cirrhosis. Increased indication for non-invasive imaging in patients with cirrhosis has dramatically increased the recognition of PVT. This has led to a large amount of studies on pathogenesis as well as the prognostic impact of portal vein thrombosis on natural history of cirrhosis. However, in clinical practice, several aspects of the management of portal vein thrombosis remain unclear. This practical review discusses the most recent data toward the management of portal vein thrombosis in cirrhosis, especially regarding : a) the value of etiological workup ; b) the impact of portal vein thrombosis on the natural history of cirrhosis, and c) the indications and modalities of anticoagulation therapy. PMID- 28853804 TI - [Benign focal liver lesions: a clinical, radiological and pathological review]. AB - Benign focal liver lesions are a heterogeneous group of tumors of different cellular origin. They might develop from mesenchymal cells, hepatocytes or cholangiocytes. They are more often detected due to the increasing number of imaging investigations and the excellent performance of the new ultrasound machines. The imaging findings have to be interpreted while bearing the patient's clinical context in mind. The aim of this review is to discuss the three most frequent benign focal hepatic lesions : hemangioma, focal nodular hyperplasia and hepatocellular adenoma. PMID- 28853805 TI - [Management of ulcerative colitis in 2017]. AB - Ulcerative colitis (UC) has a prevalence of 1 in 1000 inhabitants in Switzerland. The diagnosis of UC is based on a typical clinical presentation that involves bloody diarrhea, characteristic endoscopic features with continuous inflammation involving the rectum, and compatible histology. UC develops in genetically susceptible individuals with a dysregulated mucosal immune system. This article highlights latest insights into the pathogenesis, diagnosis, and therapy of UC. PMID- 28853806 TI - ? PMID- 28853807 TI - ? PMID- 28853808 TI - ? PMID- 28853809 TI - ? PMID- 28853810 TI - ? PMID- 28853811 TI - ? PMID- 28853812 TI - ? PMID- 28853813 TI - Police-community safety and trust. AB - (1)In 2017 alone, 46 states have enacted over 270 laws affecting policing. (2) At least six states have enacted laws to train the public on their rights and expectations during police interactions. (3) Police are increasingly partnering with health care professionals to more safely respond to mental health and substance use disorders. PMID- 28853814 TI - Magnetic resonance imaging and clinical findings in seminal vesicle pathologies. AB - PURPOSE: Congenital and acquired pathologies of the seminal vesicles (SV) are rare diseases. The diagnosis of SV anomalies is frequently delayed or wrong due to the rarity of these diseases and the lack of adequate evaluation of SV pathology. For this reason, we aimed to comprehensively evaluate SV pathologies and accompanying genitourinary system abnormalities. MATERIALS AND METHODS: Between March 2012 and December 2015, 1455 male patients with different provisional diagnosis underwent MRI. Congenital and acquired pathology of the SV was identified in 42 of these patients. The patients were categorized according to their SV pathologies. The patients were analyzed in terms of genitourinary system findings associated with SV pathologies. RESULTS: SV pathologies were accompanied by other genitourinary system findings. Congenital SV pathologies were bilateral or predominantly in the left SV. Patients with bilateral SV hypoplasia were diagnosed at an earlier age compared to patients with unilateral SV agenesis. There was a significant association between abnormal signal intensity in the SV and benign prostate hypertrophy (BPH) and patient age. CONCLUSION: SV pathologies are rare diseases of the genitourinary system. The association between seminal vesicle pathology and other genitourinary system diseases requires complete genitourinary system evaluation that includes the seminal vesicles. PMID- 28853815 TI - A Safe teaching protocol of LRP (laparoscopic radical prostatectomy). AB - PURPOSE: The LRP has a steep learning curve to obtain proficiency during which patient safety may be compromised. We present an adapted modular training system which purpose to optimize the learning curve and perform a safe surgery. MATERIALS AND METHODS: A retrospective analysis of the LRP safe learning protocol applied during a fellowship program over eight years (2008-2015). The surgery was divided in 12 steps and 5 levels of difficulty. A maximum time interval was stipulated in 240 minutes. After an adaptation, the fellows had 120 minutes to perform all the corresponding modules to its accumulated skill. The participants gradually and safely pass through the steps and difficulty levels. Surgeries performed by fellows were analyzed as a single group and compared to a prior series performed by tutor. RESULTS: In eight years, 250 LRP were performed (25 per apprentice) during fellowship program and 150 procedures after completion. The baseline characteristics were comparable. Most cases operated were of intermediate risk. Mean operative time was longer in the fellow group when compared to the tutor (150 min). Mean estimated blood loss were similar among the groups. Functional and oncological outcomes were better in the Tutor's group. No conversion to open surgery was performed. CONCLUSIONS: The LRP safe learning protocol proved to be an effective method to optimize the learning curve and perform safe surgery. However, the tutor's functional and oncological results were better, showing that this is a procedure with a steep learning curve and proficiency demands more than 25 cases. PMID- 28853816 TI - Re: Unusual intravesical foreign body in a young female migrated from the vagina due to autoerotism. PMID- 28853817 TI - Incidentally detected tuberculous prostatitis with microabscess. PMID- 28853818 TI - Spermatozoa retrieval for cryopreservation after death. AB - OBJECTIVES: To describe the retrieval spermatozoa technique for cryopreservation after death, including the proximal part of vas deferens. MATERIAL AND METHODS: A 28-years old man, with previous history of infertility, who died 12 hours ago, was submitted to spermatozoa retrieval for cryopreservation, with surgical bilateral resection in bloc of the proximal part of vas deferens, testicle and epididymis. At the laboratory, by milking the epididymis and vas deferens, the extracted fluid was collected; also, three samples of each testicle parenchyma were also harvested. RESULTS: The fluid from the vas deferens showed spermatozoa, mostly with in situ motility. Testicular fragments also presented spermatozoa, mostly with small tail movements or immobile. CONCLUSION: The inclusion of the proximal part of vas deferens during spermatozoa retrieval after death must be performed, since it contains high concentration of spermatozoa, and even in the presence of previous infertility, as was with this patient, it is possible to retrieve spermatozoa. PMID- 28853852 TI - Graphene Coating via Chemical Vapor Deposition for Improving Friction and Wear of Gray Cast Iron at Interfaces. AB - This study reports the influence of CVD-graphene on the tribological performance of gray cast iron (GCI) from the internal combustion engine (ICE) cylinder liners by performing a ball-on-disk friction tests. The graphene-coated specimen exhibited a significant reduction (~53%) of friction as compared to that of the uncoated specimen, whereas wear resistance increased by 2- and 5-fold regarding the wear of specimen and ball, respectively. Extremely low shear strength and highly lubricating nature of graphene contribute to the formation of a lubricative film between the sliding surfaces and decreases the interaction between surfaces in the dry environment. Under the applied load, a uniform film of iron oxides such as Fe2O3, Fe3O4, and FeOOH is found to be formed between the surfaces. It is proposed that the graphene encapsulation with the metal debris and oxides formed between the specimens increases the lubricity and decreases the shear force. The transformation of graphene/graphite into nanocrystalline graphites across the contact interfaces following the amorphization trajectory further increases the lubricity of the film that ultimately reduces friction and wear of the material. PMID- 28853819 TI - Risk factors for mortality in fournier's gangrene in a general hospital: use of simplified founier gangrene severe index score (SFGSI). AB - OBJECTIVE: To evaluate risk factors for mortality in patients with Fournier's gangrene (FG), with emphasis in the Simplified Fournier Gangrene Severe Index Score (SFGSI). MATERIALS AND METHODS: This was a cross-sectional study that was carried out from January 2010 to December 2014, with 124 patients treated for FG in a General Hospital. Several clinical and laboratory variables, including SFGSI, were evaluated and correlated with mortality through univariate analysis and logistic regression. RESULTS: Of the 124 patients, 99 were men (79.8%), the mean age was 50.8+/-19.5 years and the main comorbidity was diabetes mellitus (51.6%). The mortality rate was 25.8%. Variables that presented independent correlation with mortality were the extension of the lesion to the abdomen (OR=4.0, CI=1.10-14.68, p=0.03), hematocrit (OR=0.81, CI=0.73-0.90, p<0.0001), potassium (OR=2.41, CI=1.13-5.10, p=0.02) and creatinine (OR=2.15, CI=1.04-4.41, p=0.03). When hematocrit, potassium and creatinine were tested together, as part of the SFGSI, a >2 result was the largest of the independent predictors of mortality (OR=50.2; CI=13.18-191.47; p<0.0001). CONCLUSION: The SFGSI >2 presented a higher correlation with mortality than any variable tested alone. It seems to be a promising alternative to evaluate predictors of mortality in Fournier's gangrene. The main advantage is easy applicability because it contains only three parameters and can be used immediately after patient's admission. PMID- 28853854 TI - Scanning Probe Photonic Nanojet Lithography. AB - The use of nano/microspheres or beads for optical nanolithography is a consolidated technique for achieving subwavelength structures using a cost effective approach; this method exploits the capability of the beads to focus electromagnetic waves into subwavelength beams called photonic nanojets, which are used to expose the photoresist on which the beads are placed. However, this technique has only been used to produce regular patterns based on the spatial arrangement of the beads on the substrate, thus considerably limiting the pool of applications. Here, we present a novel microsphere-based optical lithography technique that offers high subwavelength resolution and the possibility of generating any arbitrary pattern. The presented method consists of a single microsphere embedded in an AFM cantilever, which can be controlled using the AFM motors to write arbitrary patterns with subwavelength resolution (down to 290 nm with a 405 nm laser). The performance of the proposed technique can compete with those of commercial high-resolution standard instruments, with the advantage of a one-order-of-magnitude reduction in costs. This approach paves the way for direct integration of cost-effective, high-resolution optical lithography capabilities into several existing AFM systems. PMID- 28853853 TI - BNANC Gapmers Revert Splicing and Reduce RNA Foci with Low Toxicity in Myotonic Dystrophy Cells. AB - Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by an expanded CTG repeat in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene. Short, DNA-based antisense oligonucleotides termed gapmers are a promising strategy to degrade toxic CUG expanded repeat (CUGexp) RNA. Nucleoside analogs are incorporated to increase gapmer affinity and stability; however, some analogs also exhibit toxicity. In this study, we demonstrate that the 2',4'-BNANC[NMe] (BNANC) modification is a promising nucleoside analog with high potency similar to 2',4'-LNA (LNA). BNANC gapmers targeting a nonrepetitive region of the DMPK 3' UTR show allele-specific knockdown of CUGexp RNA and revert characteristic DM1 molecular defects including mis-splicing and accumulation of RNA foci. Notably, the BNANC gapmers tested in this study did not induce caspase activation, in contrast to a sequence matched LNA gapmer. This study indicates that BNANC gapmers warrant further study as a promising RNA targeting therapeutic. PMID- 28853855 TI - Rapid and Efficient Self-Assembly of Au@ZnO Core-Shell Nanoparticle Arrays with an Enhanced and Tunable Plasmonic Absorption for Photoelectrochemical Hydrogen Generation. AB - High-quality Au@ZnO core-shell nanoparticle (NP) array films were easily and efficiently fabricated through an air/water interfacial self-assembly. These materials have remarkable visible light absorption capacity and fascinating performance in photoelectrochemical (PEC) water splitting with a photocurrent density of ~3.08 mA/cm2 at 0.4 V, which is superior to most ZnO-based photoelectrodes in studies. Additionally, the interesting PEC performance could be effectively adjusted by altering the thickness of the ZnO shell and/or the layer number of the array films. Results indicated that the bilayer film based on Au@ZnO NPs with 25 nm shell thickness displayed optimal behavior. The remarkable PEC capability could be ascribed to the enhanced light-harvesting ability of the Au@ZnO structured NPs by the SPR effect and the optimum film thickness. This work demonstrates a desirable paradigm for preparing photoelectrodes based on the synergistic effect of plasmatic NPs as the core and a visible optical absorbent and semiconductor as the shell. Moreover, this work provides a new approach for fabricating optoelectronic anode thin film devices through a self-assembly method. PMID- 28853856 TI - Highly Stretchable, Ultrasensitive, and Wearable Strain Sensors Based on Facilely Prepared Reduced Graphene Oxide Woven Fabrics in an Ethanol Flame. AB - The recent booming development of wearable electronics urgently calls for high performance flexible strain sensors. To date, it is still a challenge to manufacture flexible strain sensors with superb sensitivity and a large workable strain range simultaneously. Herein, a facile, quick, cost-effective, and scalable strategy is adopted to fabricate novel strain sensors based on reduced graphene oxide woven fabrics (GWF). By pyrolyzing commercial cotton bandages coated with graphene oxide (GO) sheets in an ethanol flame, the reduction of GO and the pyrolysis of the cotton bandage template can be synchronously completed in tens of seconds. Due to the unique hierarchical structure of the GWF, the strain sensor based on GWF exhibits large stretchability (57% strain) with high sensitivity, inconspicuous drift, and durability. The GWF strain sensor is successfully used to monitor full-range (both subtle and vigorous) human activities or physical vibrational signals of the local environment. The present work offers an effective strategy to rapidly prepare low-cost flexible strain sensors with potential applications in the fields of wearable electronics, artificial intelligence devices, and so forth. PMID- 28853857 TI - Biological Monitoring of Inhaled Nanoparticles in Patients: An Appealing Approach To Study Causal Link between Human Respiratory Pathology and Exposure to Nanoparticles. AB - Although necessary, in vitro and in vivo studies are not fully successful at predicting nanomaterials toxicity. We propose to associate such assays to the biological monitoring of nanoparticles in clinical samples to get more relevant data on the chemical and physical nature and dose of nanoparticles found in humans. The concept is to establish the load of nanoparticles in biological samples of patients. Then, by comparing samples from different patient groups, nanoparticles of interest could be identified and a potential link between a given nanoparticle type and toxicity could be suggested. It must be confirmed by investigating the biological effects induced by these nanoparticles using in vitro or in vivo models (mechanistic or dose-response studies). This translational approach from the bedside to the bench and vice versa could allow a better understanding of the nanoparticle effects and mechanisms of toxicity that can contribute, at least in part, to a disease. PMID- 28853859 TI - Metal Affinity-Enabled Capture and Release Antibody Reagents Generate a Multiplex Biomarker Enrichment System that Improves Detection Limits of Rapid Diagnostic Tests. AB - Multi-antigen rapid diagnostic tests (RDTs) are highly informative, simple, mobile, and inexpensive, making them valuable point-of-care (POC) diagnostic tools. However, these RDTs suffer from several technical limitations-the most significant being the failure to detect low levels of infection. To overcome this, we have developed a magnetic bead-based multiplex biomarker enrichment strategy that combines metal affinity and immunospecific capture to purify and enrich multiple target biomarkers. Modifying antibodies to contain histidine-rich peptides enables reversible loading onto immobilized metal affinity magnetic beads, generating a novel class of antibodies coined "Capture and Release" (CaR) antibody reagents. This approach extends the specificity of immunocapture to metal affinity magnetic beads while also maintaining a common trigger for releasing multiple biomarkers. Multiplex biomarker enrichment is accomplished by adding magnetic beads equipped with CaR antibody reagents to a large sample volume to capture biomarkers of interest. Once captured, these biomarkers are magnetically purified, concentrated, and released into a RDT-compatible volume. This system was tailored to enhance a popular dual-antigen lateral flow malaria RDT that targets Plasmodium falciparum histidine-rich protein-II (HRPII) and Plasmodium lactate dehydrogenase (pLDH). A suite of pLDH CaR antibody reagents were synthesized, characterized, and the optimal CaR antibody reagent was loaded onto magnetic beads to make a multiplex magnetic capture bead that simultaneously enriches pLDH and HRPII from Plasmodium falciparum parasitized blood samples. This system achieves a 17.5-fold improvement in the dual positive HRPII/pan-pLDH detection limits enabling visual detection of both antigens at levels correlating to 5 p/MUL. This front-end sample processing system serves as an efficient strategy to improve the sensitivity of RDTs without the need for modifications or remanufacturing. PMID- 28853858 TI - Enhanced Photobactericidal and Targeting Properties of a Cationic Porphyrin following the Attachment of Polymyxin B. AB - A novel compound consisting of a cationic porphyrin covalently attached to a derivative of polymyxin B has been synthesized and presents enhanced activity and targeting properties compared to the usual cationic porphyrins recognized as efficient photosensitizers in photodynamic antimicrobial chemotherapy (PACT). A synthesis pathway was established to preserve the bactericidal activity of the peptide. Accordingly, the N-terminal amino acid (l-2,4-diaminobutyric acid) of polymyxin B (PMB) was switched for a cysteine residue. Then, the resulting derivative of PMB was covalently bound to 5-(4-aminophenyl)-10,15,20-tri(4-N methylpyridyl)-21H,23H-porphyrin using a thiol-maleimide "click" coupling. The peptide-coupled photosensitizer has demonstrated an improved PACT efficiency compared to the cationic porphyrin alone. This enhancement has been observed against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli in particular. Flow cytometry analyses and confocal imaging microscopy demonstrated that the porphyrin-peptide conjugate selectively adhered to the cell walls of either Gram-positive or Gram-negative bacteria, thus justifying the damages induced by singlet oxygen production. PMID- 28853860 TI - Iron-Sulfur Cluster States of the Hydrogenase Maturase HydF. PMID- 28853862 TI - Accuracy and Mechanistic Details of Optical Printing of Single Au and Ag Nanoparticles. AB - Optical printing is a powerful all-optical method that allows the incorporation of colloidal nanoparticles (NPs) onto substrates with nanometric precision. Here, we present a systematic study of the accuracy of optical printing of Au and Ag NPs, using different laser powers and wavelengths. When using light of wavelength tuned to the localized surface plasmon resonance (LSPR) of the NPs, the accuracy improves as the laser power is reduced, whereas for wavelengths off the LSPR, the accuracy is independent of the laser power. Complementary studies of the printing times of the NPs reveal the roles of Brownian and deterministic motion. Calculated trajectories of the NPs, taking into account the interplay between optical forces, electrostatic forces, and Brownian motion, allowed us to rationalize the experimental results and gain a detailed insight into the mechanism of the printing process. A clear framework is laid out for future optimizations of optical printing and optical manipulation of NPs near substrates. PMID- 28853861 TI - Renal-Clearable Ultrasmall Coordination Polymer Nanodots for Chelator-Free 64Cu Labeling and Imaging-Guided Enhanced Radiotherapy of Cancer. AB - Developing tumor-homing nanoparticles with integrated diagnostic and therapeutic functions, and meanwhile could be rapidly excreted from the body, would be of great interest to realize imaging-guided precision treatment of cancer. In this study, an ultrasmall coordination polymer nanodot (CPN) based on the coordination between tungsten ions (WVI) and gallic acid (W-GA) was developed via a simple method. After polyethylene glycol (PEG) modification, PEGylated W-GA (W-GA-PEG) CPNs with an ultrasmall hydrodynamic diameter of 5 nm were rather stable in various physiological solutions. Without the need of chelator molecules, W-GA-PEG CPNs could be efficiently labeled with radioisotope 64Cu2+, enabling positron emission tomography (PET) imaging, which reveals efficient tumor accumulation and rapid renal clearance of W-GA-PEG CPNs upon intravenous injection. Utilizing the radio-sensitizing function of tungsten with strong X-ray absorption, such W-GA PEG CPNs were able to greatly enhance the efficacy of cancer radiotherapy in inhibiting the tumor growth. With fast clearance and little long-term body retention, those W-GA-PEG CPNs exhibited no appreciable in vivo toxicity. This study presents a type of CPNs with excellent imaging and therapeutic abilities as well as rapid renal clearance behavior, promising for further clinic translation. PMID- 28853864 TI - Core-Shell Fibers Electrospun from Phase-Separated Blend Solutions: Fiber Formation Mechanism and Unique Energy Dissipation for Synergistic Fiber Toughness. AB - Through single-tube electrospinning, the biodegradable core-shell fibers of poly(3-hydroxybutyrate) (PHB) and poly(d,l-lactic acid) (PDLLA) were obtained from blend solutions with different compositions at a total polymer concentration of 7 wt %. Regardless whether PHB is the major or minor component (PHB/PDLLA = 90/10, 75/25, 50/50, and 25/75 wt. ratio), these phase-separated solutions all yielded core-shell fibers with PHB as core and PDLLA as shell. A new scenario of core-shell fiber formation was proposed on the basis of the relative magnitude of the intrinsic relaxation rate of fluids and external extension rate during electrospinning. The effects of blend compositions on the morphologies of the Taylor cone, whipping jet, and as-spun fibers were investigated. The diameters of core-shell fibers can be tailored by simply varying the PHB/PDLLA ratios. Two scaling laws describing the apparent viscosity (etao) dependence of the outer fiber diameter (dfo) and core fiber diameter (dfc) were derived. That is, dfo ~ etao0.38 and dfc ~ etao0.86. The microstructures of the as-spun fibers were determined by differential scanning calorimetry, Fourier transform infrared spectroscopy, and synchrotron wide-angle and small-angle X-ray scatterings. Results showed that the PDLLA component was in the amorphous state, and the crystallizability of PHB component remained unchanged, except the amorphous 10/90 fibers electrospun from a miscible solution state. The synergistic mechanical properties of the core-shell fibers were obtained, along with the ductile PDLLA shell enclosing the brittle PHB core. The enhanced toughness was attributed to the fragmentation of the brittle PHB core and necking fracture of the ductile PDLLA shell, which served as an effective route for energy dissipation. Compared with the neat PHB fiber, the 90/10 and 75/25 core-shell fibers possessed larger elastic moduli, which was attributed to the high PHB crystal orientation in their core sections despite the reduced PHB crystallinity. By contrast, the crystal c axis of PHB in the 25/75 core-shell fibers was preferentially perpendicular to the fiber axis, suggesting the significant stretching of developing PHB crystals during electrospinning. PMID- 28853863 TI - Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. AB - Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs in the world. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunction. The aim of this study is to further investigate VPA-induced mechanisms of steatosis by analyzing changes in patterns of methylation in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, primary human hepatocytes (PHHs) were exposed to an incubation concentration of VPA that was shown to cause steatosis without inducing overt cytotoxicity. VPA was administered daily for 5 days, and this was followed by a 3 day washout (WO). Methylated DNA regions (DMRs) were identified by using the methylated DNA immunoprecipitation-sequencing (MeDIP-seq) method. The nDNA DMRs after VPA treatment could indeed be classified into oxidative stress- and steatosis-related pathways. In particular, networks of the steatosis-related gene EP300 provided novel insight into the mechanisms of toxicity induced by VPA treatment. Furthermore, we suggest that VPA induces a crosstalk between nDNA hypermethylation and mtDNA hypomethylation that plays a role in oxidative stress and steatosis development. Although most VPA-induced methylation patterns appeared reversible upon terminating VPA treatment, 31 nDNA DMRs (including 5 zinc finger protein genes) remained persistent after the WO period. Overall, we have shown that MeDIP-seq analysis is highly informative in disclosing novel mechanisms of VPA-induced toxicity in PHHs. Our results thus provide a prototype for the novel generation of interesting methylation biomarkers for repeated dose liver toxicity in vitro. PMID- 28853865 TI - Heteroleptic Fe(II) Complexes with N4S2 Coordination as a Platform for Designing Spin-Crossover Materials. AB - Heteroleptic complexes [Fe(bpte)(bim)]X2 and [Fe(bpte)(xbim)]X2 (bpte = S,S' bis(2-pyridylmethyl)-1,2-thioethane, bim = 2,2'-biimidazole, xbim = 1,1' (alpha,alpha'-o-xylyl)-2,2'-biimidazole, X = ClO4-, BF4-, OTf-) were prepared by reacting the corresponding Fe(II) salts with a 1:1 mixture of the ligands. All mononuclear complexes exhibit temperature-induced spin crossover (SCO) with the onset above room temperature. The SCO is rather gradual, due to low cooperativity of interactions between the cationic complexes, as revealed by crystal structure analyses. These complexes expand the range of the recently discovered Fe(II) SCO materials with {N4S2} coordination environment. PMID- 28853866 TI - Layered Double Hydroxides: Potential Release-on-Demand Fertilizers for Plant Zinc Nutrition. AB - A novel zinc (Zn) fertilizer concept based on Zn-doped layered double hydroxides (Zn-doped Mg-Fe-LDHs) has been investigated. Zn-doped Mg-Fe-LDHs were synthesized, their chemical composition was analyzed, and their nutrient release was studied in buffered solutions with different pH values. Uptake of Zn by barley (Hordeum vulgare cv. Antonia) was evaluated in short- (8 weeks), medium- (11 weeks), and long-term (28 weeks) experiments in quartz sand and in a calcareous soil enriched with Zn-doped Mg-Fe-LDHs. The Zn release rate of the Zn doped Mg-Fe-LDHs was described by a first-order kinetics equation showing maximum release at pH 5.2, reaching approximately 45% of the total Zn content. The Zn concentrations in the plants receiving the LDHs were between 2- and 9.5-fold higher than those in plants without Zn addition. A positive effect of the LDHs was also found in soil. This work documents the long-term Zn release capacity of LDHs complying with a release-on-demand behavior and serves as proof-of-concept that Zn-doped Mg-Fe-LDHs can be used as Zn fertilizers. PMID- 28853867 TI - Tryptorubin A: A Polycyclic Peptide from a Fungus-Derived Streptomycete. AB - Fungus-growing ants engage in complex symbiotic relationships with their fungal crop, specialized fungal pathogens, and bacteria that provide chemical defenses. In an effort to understand the evolutionary origins of this multilateral system, we investigated bacteria isolated from fungi. One bacterial strain (Streptomyces sp. CLI2509) from the bracket fungus Hymenochaete rubiginosa, produced an unusual peptide, tryptorubin A, which contains heteroaromatic links between side chains that give it a rigid polycyclic globular structure. The three-dimensional structure was determined by NMR and MS, including a 13C-13C COSY of isotopically enriched material, degradation, derivatives, and computer modeling. Whole genome sequencing identified a likely pair of biosynthetic genes responsible for tryptorubin A's linear hexapeptide backbone. The genome also revealed the close relationship between CLI2509 and Streptomyces sp. SPB78, which was previously implicated in an insect-bacterium symbiosis. PMID- 28853868 TI - Evaluation of Iodine Bioavailability in Seaweed Using in Vitro Methods. AB - Due to the high levels of iodine present in seaweed, the ingestion of a large amount of this type of food can produce excessive intake of iodine. However, the food after ingestion undergoes different chemistry and physical processes that can modify the amount of iodine that reaches the systemic circulation (bioavailability). Studies on the bioavailability of iodine from food are scarce and indicate that the bioavailable amount is generally lower than ingested. Iodine in vitro bioavailability estimation from different commercialized seaweed has been studied using different in vitro approaches (solubility, dialyzability, and transport and uptake by intestinal cells). Results indicate that iodine is available after gastrointestinal digestion for absorption (bioaccessibility: 49 82%), kombu being the seaweed with the highest bioaccessibility. The incorporation of dialysis cell cultures to elucidate bioavailability modifies the estimation of the amount of iodine that may reach the systemic circulation (dialysis, 5-28%; cell culture, <=3%). The paper discusses advantages and drawbacks of these methodologies for iodine bioavailability in seaweed. PMID- 28853869 TI - Redox-Based Photostabilizing Agents in Fluorescence Imaging: The Hidden Role of Intersystem Crossing in Geminate Radical Ion Pairs. AB - Here we report transient absorption studies on the ground-state recovery dynamics of the single-molecule fluorophore Cy3B in the presence of four different photostabilizing agents, namely beta-mercaptoethanol (beta-ME), Trolox (TX), n propyl gallate (n-PG), and ascorbic acid (AA). These are triplet-state quenchers that operate via photoinduced electron transfer (PeT). While quantitative geminate recombination was recorded following PeT for beta-ME (~100%), for Trolox, n-propyl gallate, and ascorbic acid the extent of geminate recombination was >48%, >27%, and >13%, respectively. The results are rationalized in terms of the rates of intersystem crossing (ISC) in the newly formed geminate radical ion pairs (GRIPs). Rapid spin relaxation in the radicals formed accounts for quantitative geminate recombination with beta-ME and efficient geminate recombination with TX. Our results illustrate how the interplay of PeT quenching efficiency and geminate recombination dynamics may lead to improved photostabilization strategies, critical for single-molecule fluorescence and super-resolution imaging. PMID- 28853870 TI - Electric-Magneto-Optical Kerr Effect in a Hybrid Organic-Inorganic Perovskite. AB - Hybrid organic-inorganic compounds attract a lot of interest for their flexible structures and multifunctional properties. For example, they can have coexisting magnetism and ferroelectricity whose possible coupling gives rise to magnetoelectricity. Here using first-principles computations, we show that, in a perovskite metal-organic framework (MOF), the magnetic and electric orders are further coupled to optical excitations, leading to an Electric tuning of the Magneto-Optical Kerr effect (EMOKE). Moreover, the Kerr angle can be switched by reversal of both ferroelectric and magnetic polarization only. The interplay between the Kerr angle and the organic-inorganic components of MOFs offers surprising unprecedented tools for engineering MOKE in complex compounds. Note that this work may be relevant to acentric magnetic systems in general, e.g., multiferroics. PMID- 28853871 TI - Digitizing Poly-l-lysine Dendrigrafts: From Experimental Data to Molecular Dynamics Simulations. AB - Despite the growing use of poly-l-lysine dendrigrafts in biomedical applications, a deeper understanding of the molecular level properties of these macromolecules is missing. Herein, we report a simple methodology for the construction of three dimensional structures of poly-l-lysine dendrigrafts and the subsequent investigation of their structural features using microsecond molecular dynamics simulations. This methodology relies on the encoding of the polymers' experimental characterizations (i.e., composition, degrees of polymerization, branching ratios, charges) into alphanumeric strings that are readable by the Amber simulation package. Such an original approach opens avenues toward the in silico exploration of dendrigrafts and hyperbranched polymers. PMID- 28853872 TI - Oryzanol Modifies High Fat Diet-Induced Obesity, Liver Gene Expression Profile, and Inflammation Response in Mice. AB - In Western countries and China, the dietary habit of high calories usually results in hyperlipidemia, which is closely associated with cardiovascular diseases. In the study, we investigated the antihyperlipidemic effect of oryzanol and its molecular mechanism in the high fat diet (HFD) mouse model. In total, 60 ICR mice were randomly divided into control group, HFD group, and HFD+Ory group. The mice from the HFD+Ory group were additionally fed with 100 mg/kg of oryzanol by intragastric administration. Our data indicated that oryzanol treatment for 10 weeks significantly reduced bodyweight, liver weight, and adipose tissues weight of the mice; lowered the contents of total cholesterol (TC), triglycerides (TG), and low density lipoprotein-cholesterol (LDL-C); and elevated high density lipoprotein-cholesterol (HDL-C) in the plasma of HFD mice. Compared with the HFD group, H&E staining showed that oryzanol treatment decreased the size of fat droplets of liver tissues and the size of adipocytes. Gene chip data found that oryzanol administration caused 32 genes to increase expressions while 60 genes had reduced expressions in the liver tissues of HFD mice. IPA software was used to analyze the protein interaction network and found that transcript factor NF kappaB located in the central role of network, meaning NF-kappaB may have important function in the lipid-lowering effect of oryzanol. Western blotting and RT-qPCR confirmed that lipid metabolism-related gene expressions were obviously regulated by oryzanol administration. Oryzanol also inhibited expressions of inflammatory factor in the liver tissues of HDF mice. Taken together, our data indicate that oryzanol treatment can regulate lipid metabolism-related gene expressions and inhibit HDF-caused obesity in mice. PMID- 28853873 TI - Bioaccumulation Behavior of Pharmaceuticals and Personal Care Products in Adult Zebrafish (Danio rerio): Influence of Physical-Chemical Properties and Biotransformation. AB - The factors influencing bioaccumulation of pharmaceuticals and personal care products (PPCPs) in aquatic organisms are not well understood. The present study involved a comprehensive laboratory investigation to assess the bioaccumulation behavior of several PPCPs in adult zebrafish (Danio rerio). The studied PPCPs included several ionogenic organic compounds (IOCs) such as weak acids and weak bases. Experiments involved two exposure groups (high and low) and a control group, with a 6 day aqueous exposure, followed by a 7 day depuration phase under flow-through conditions. Uptake rate constants (ku) ranged between 0.19 and 8610 L.kg-1.d-1, while depuration rate constants (kd) ranged between 0.14 and 5.14 d-1 in different fish tissues. Steady-state bioconcentration factor (BCFss) values varied widely among the studied PPCPs, ranging from 0.09 to 6,460. In many cases, BCFss values of individual PPCPs differed substantially among different fish tissues. Positive linear relationships were observed between log BCFss values and physical-chemical properties such as octanol-water distribution coefficients (log Dow), membrane-water distribution coefficients (log Dmw), albumin-water distribution coefficients (log DBSAw), and muscle protein-water distribution coefficients (log Dmpw), indicating the importance of lipid-, phospholipid-, and protein-water partitioning. The results also showed that for many PPCPs, the estimated whole-body metabolism rate constant (km) values were comparable to the observed depuration rate (kd), indicating that metabolism plays a major role in the overall elimination of these compounds in zebrafish. An exception was sertraline, which exhibited a kd value (0.4-0.5 d-1) that was much higher than the estimated whole-body km (0.03 d-1). Overall, the results help to better understand the influence of physical-chemical properties and biotransformation on bioaccumulation behavior of these contaminants of concern in aquatic organisms. PMID- 28853874 TI - Chloride Oxidation by Ruthenium Excited-States in Solution. AB - Photodriven HCl splitting to produce solar fuels is an important goal that requires strong photo-oxidants capable of chloride oxidation. In a molecular approach toward this goal, three ruthenium compounds with 2,2'-bipyrazine backbones were found to oxidize chloride ions in acetone solution. Nanosecond transient absorption measurements provide compelling evidence for excited-state electron transfer from chloride to the Ru metal center with rate constants in excess of 1010 M-1 s-1. The Cl atom product was trapped with an olefin. This reactivity was promoted through pre-organization of ground-state precursors in ion pairs. Chloride oxidation with a tetra-cationic ruthenium complex was most favorable, as the dicationic complexes were susceptible to photochemical ligand loss. Marcus analysis afforded an estimate of the chlorine formal reduction potential E degrees (Cl*/-) = 1.87 V vs NHE that is at least 300 meV more favorable than the accepted values in water. PMID- 28853875 TI - Small-Angle X-ray Scattering Data in Combination with RosettaDock Improves the Docking Energy Landscape. AB - We have performed a benchmark to evaluate the relative success of using small angle X-ray scattering (SAXS) data as constraints (hereafter termed SAXSconstrain) in the RosettaDock protocol (hereafter termed RosettaDockSAXS). For this purpose, we have chosen 38 protein complex structures, calculated the theoretical SAXS data for the protein complexes using the program CRYSOL, and then used the SAXS data as constraints. We further considered a few examples where crystal structures and experimental SAXS data are available. SAXSconstrain were added to the protocol in the initial, low-resolution docking step, allowing fast rejection of complexes that violate the shape restraints imposed by the SAXS data. Our results indicate that the implementation of SAXSconstrain in general reduces the sampling space of possible protein-protein complexes significantly and can indeed increase the probability of finding near-native protein complexes. The methodology used is based on rigid-body docking and works for cases where no or minor conformational changes occur upon binding of the docking partner. In a wider perspective, the strength of RosettaDockSAXS lies in the combination of low resolution structural information on protein complexes in solution from SAXS experiments with protein-protein interaction energies obtained from RosettaDock, which will allow the prediction of unknown three-dimensional atomic structures of protein-protein complexes. PMID- 28853876 TI - Biomimetic Synthesis of Lankacidin Antibiotics. AB - We devised short syntheses of lankacidinol and lankacyclinol that feature biomimetic Mannich macrocyclization. The modular construction of the carbon framework of these compounds is amenable to rapid structural diversification for the development of antibiotic and antitumor agents. PMID- 28853877 TI - Aggregation-Dependent Oxidation of Metal Nanoparticles. AB - Here we describe the effect of aggregation on the oxidation of citrate-stabilized Au nanoparticles (NPs) attached electrostatically to amine-functionalized glass/ITO electrodes. When the Au NPs are attached to the electrode from a solution with pH greater than ~3.0, they are well-separated on the electrode and oxidize in bromide-containing electrolyte at 0.698, 0.757, and 0.943 V (vs Ag/AgCl) for 4, 15, and 50 nm diameter Au NPs, respectively, in line with their size-dependent oxidation behavior. In solutions below pH 3.0, the Au NPs aggregate in solution and attach to the electrode in the aggregated form. The solution UV-vis spectra and scanning electron microscopy images of the electrodes show clear evidence of aggregation. The oxidation potential for aggregated 4 and 15 nm diameter Au NPs shifts positive by a maximum of 230 and 180 mV, respectively. The magnitude of the shift depends on the extent of aggregation, which was controlled by the solution pH and time. NP aggregation leads to a significant reduction in the surface area-to-volume ratio, which is likely responsible for the positive shift in the oxidation potential. The oxidation potential does not shift at all for aggregated 50 nm diameter Au NPs. PMID- 28853878 TI - Complexation and Redox Buffering of Iron(II) by Dissolved Organic Matter. AB - Iron (Fe) bioavailability depends upon its solubility and oxidation state, which are strongly influenced by complexation with natural organic matter (NOM). Despite observations of Fe(II)-NOM associations under conditions favorable for Fe oxidation, the molecular mechanisms by which NOM influences Fe(II) oxidation remain poorly understood. In this study, we used X-ray absorption spectroscopy to determine the coordination environment of Fe(II) associated with NOM (as-received and chemically reduced) at pH 7, and investigated the effect of NOM complexation on Fe(II) redox stability. Linear combination fitting of extended X-ray absorption fine structure (EXAFS) data using reference organic ligands demonstrated that Fe(II) was complexed primarily by carboxyl functional groups in reduced NOM. Functional groups more likely to preserve Fe(II) represent much smaller fractions of NOM-bound Fe(II). Fe(II) added to anoxic solutions of as received NOM oxidized to Fe(III) and remained organically complexed. Iron oxidation experiments revealed that the presence of reduced NOM limited Fe(II) oxidation, with over 50% of initial Fe(II) remaining after 4 h. These results suggest reduced NOM may preserve Fe(II) by functioning both as redox buffer and complexant, which may help explain the presence of Fe(II) in oxic circumneutral waters. PMID- 28853879 TI - Direct Probing of Criegee Intermediates from Gas-Phase Ozonolysis Using Chemical Ionization Mass Spectrometry. AB - Criegee intermediates (CIs), mainly formed from gas-phase ozonolysis of alkenes, are considered as atmospheric oxidants besides OH and NO3 radicals as well as ozone. Direct CI measurement techniques are inevitably needed for reliable assessment of CIs' role in atmospheric processes. We found that CIs from ozonolysis reactions can be directly probed by means of chemical ionization mass spectrometry with a detection limit of about 104-105 molecules cm-3. Results from quantum chemical calculations support the experimental findings. The simplest CI, CH2OO, is detectable as an adduct with protonated ethers, preferably with protonated tetrahydrofuran. Kinetic measurements yielded k(CH2OO + SO2) = (3.3 +/ 0.9) * 10-11 and k(CH2OO + acetic acid) = (1.25 +/- 0.30) * 10-10 cm3 molecule-1 s-1 at 295 +/- 2 K, in very good agreement with recent measurements using diiodomethane photolysis for CH2OO generation. CIs from the ozonolysis of cyclohexene, acting as surrogate for cyclic terpenes, are followed as protonated species (CI)H+ using protonated amines as reagent ions. Kinetic investigations indicate a different reactivity of cyclohexene-derived CIs compared with that of simple CIs, such as CH2OO. It is supposed that the aldehyde group significantly influences the CI reactivity of the cyclohexene-derived CIs. The direct CI detection method presented here should allow study of the formation and reactivity of a wide range of different CIs formed from atmospheric ozonolysis reactions. PMID- 28853880 TI - Near-Infrared Dioxetane Luminophores with Direct Chemiluminescence Emission Mode. AB - Chemiluminescent luminophores are considered as one of the most sensitive families of probes for detection and imaging applications. Due to their high signal-to-noise ratios, luminophores with near-infrared (NIR) emission are particularly important for in vivo use. In addition, light with such long wavelength has significantly greater capability for penetration through organic tissue. So far, only a few reports have described the use of chemiluminescence systems for in vivo imaging. Such systems are always based on an energy-transfer process from a chemiluminescent precursor to a nearby emissive fluorescent dye. Here, we describe the development of the first chemiluminescent luminophores with a direct mode of NIR light emission that are suitable for use under physiological conditions. Our strategy is based on incorporation of a substituent with an extended pi-electron system on the excited species obtained during the chemiexcitation pathway of Schaap's adamantylidene-dioxetane probe. In this manner, we designed and synthesized two new luminophores with direct light emission wavelength in the NIR region. Masking of the luminophores with analyte responsive groups has resulted in turn-ON probes for detection and imaging of beta-galactosidase and hydrogen peroxide. The probes' ability to image their corresponding analyte/enzyme was effectively demonstrated in vitro for beta galactosidase activity and in vivo in a mouse model of inflammation. We anticipate that our strategy for obtaining NIR luminophores will open new doors for further exploration of complex biomolecular systems using non-invasive intravital chemiluminescence imaging techniques. PMID- 28853881 TI - Ultrasensitivity of Water Exchange Kinetics to the Size of Metal Ion. AB - Metal ions play a vital role in many biological processes. An important factor in these processes is the dynamics of exchange between ion bound-water molecules and the bulk. Although structural and dynamical properties of labile waters bound to metal ions, such as Na+ and Ca2+, can be elucidated using molecular dynamics simulations, direct evaluation of rates of exchange of waters rigidly bound to high charge density Mg2+, has been elusive. Here, we report a universal relationship, allowing us to determine the water exchange time on metal ions as a function of valence and hydration radius. The proposed relationship, which covers times spanning 14 orders of magnitude, highlights the ultrasensitivity of water lifetime to the ion size, as exemplified by divalent ions, Ca2+ (~100 ps) and Mg2+ (~1.5 MUs). We show that even when structures, characterized by radial distributions are similar, a small difference in hydration radius leads to a qualitatively different (associative or dissociative) mechanism of water exchange. Our work provides a theoretical basis for determination of hydration radius, which is critical for accurately modeling the water dynamics around multivalent ions, and hence in describing all electrostatically driven events such as ribozyme folding and catalysis. PMID- 28853882 TI - Photoswitchable Dihydroazulene Macrocycles for Solar Energy Storage: The Effects of Ring Strain. AB - Efficient energy storage and release are two major challenges of solar energy harvesting technologies. The development of molecular solar thermal systems presents one approach to address these issues by tuning the isomerization reactions of photo/thermoswitches. Here we show that the incorporation of photoswitches into macrocyclic structures is a particularly attractive solution for increasing the storage time. We present the synthesis and properties of a series of macrocycles incorporating two dihydroazulene (DHA) photoswitching subunits, bridged by linkers of varying chain length. Independent of ring size, all macrocycles exhibit stepwise, light-induced, ring-opening reactions (DHA-DHA to DHA-VHF to VHF-VHF; VHF = vinylheptafulvene) with the first DHA undergoing isomerization with a similar efficiency as the uncyclized parent system while the second (DHA-VHF to VHF-VHF) is significantly slower. The energy-releasing, VHF-to DHA, ring closures also occur in a stepwise manner and are systematically found to proceed slower in the more strained (smaller) cycles, but in all cases with a remarkably slow conversion of the second VHF to DHA. We managed to increase the half-life of the second VHF-to-DHA conversion from 65 to 202 h at room temperature by simply decreasing the ring size. A computational study reveals the smallest macrocycle to have the most energetic VHF-VHF state and hence highest energy density. PMID- 28853883 TI - Characterization of the Degradation Profile of Umbelliprenin, a Bioactive Prenylated Coumarin of a Ferulago Species. AB - Umbelliprenin is a secondary plant metabolite that displays promising chemopreventive, anti-inflammatory, and antigenotoxic properties. It possesses potential for applications to human welfare notably to prevent the emergence of cancer. For this purpose, stability studies are needed to define proper storage conditions and adapted formulations for this drug candidate. The identification of degradative products is a major concern for the preclinical development of umbelliprenin, providing also interesting information related to potential original phytochemicals formed in plants exposed to stressors. The stability profile of umbelliprenin under various stress conditions including exposure to heat, light, oxidation, and hydrolytic medium was assessed via HPLC/UV data. The data support that umbelliprenin undergoes inter- and intramolecular [2+2] cycloaddition under light exposure, leading respectively to a cyclobutane umbelliprenin dimer and a 16-membered macrocycle. Their structures were characterized via MS and NMR data. It was shown that UV-A filters prevent this process, whereas UV-B filters and antioxidants are not or weakly effective. The study provides useful information for the preclinical development of umbelliprenin as an original chemopreventive agent. PMID- 28853884 TI - Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3 dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2 carboxamide (VH298). AB - The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated alpha subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-alpha protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1alpha intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs. PMID- 28853886 TI - Quantitative Determination of Ala-Ala Conformer Ratios in Solution by Decomposition of Raman Optical Activity Spectra. AB - Raman optical activity (ROA) spectroscopy combined with quantum-chemical simulations is a sensitive method to determine the absolute configuration and conformation of chiral molecules in solutions. However, the precision of this approach varies for different systems. In the present study, the reliability and numerical stability of decomposing experimental spectra into calculated subspectra is tested on the Ala-Ala dipeptide. Molecular dynamics (MD) snapshots of Ala-Ala/water clusters are averaged to account for solvent effects and molecular flexibility. Multiple experiments with protonated, zwitterionic, and deprotonated dipeptide forms and natural and d2- and d8-isotopically labeled dipeptides are used to verify the results and estimate the overall accuracy. Although the precision is still limited by experimental noise and computational error, a very close match between the observed and theoretical spectral shapes has been achieved. This enabled quantitative determination of conformer populations with a typical dispersion of 10%. The spectroscopy also demonstrated how the conformation depends on pH. The ROA results were more consistent than the Raman ones. Typically, the ROA analysis was more resistant to artifacts in the experiment, such as incomplete baseline subtraction. Conformer ratios predicted by MD agree fairly but not fully with the experimental ones. This indicates minor deficiencies in the Amber force field, particularly for the protonated dipeptide. Overall, the combination of ROA experiment and computational chemistry appears to be a robust tool providing deep insight into molecular structure. PMID- 28853885 TI - Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). AB - Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12. PMID- 28853888 TI - Water Evaporation from Acoustically Levitated Aqueous Solution Droplets. AB - We present a systematic study of the effect of solutes on the evaporation rate of acoustically levitated aqueous solution droplets by suspending individual droplets in a zero-relative humidity environment and measuring their size as a function of time. The ratios of the early time evaporation rates of six simple salts (NaCl, NaBr, NaNO3, KCl, MgCl2, CaCl2) and malonic acid to that of water are in excellent agreement with predictions made by modifying the Maxwell equation to include the time-dependent water activity of the evaporating aqueous salt solution droplets. However, the early time evaporation rates of three ammonium salt solutions (NH4Cl, NH4NO3, (NH4)2SO4) are not significantly different from the evaporation rate of pure water. This finding is in accord with a previous report that ammonium sulfate does not depress the evaporation rate of its solutions, despite reducing its water vapor pressure, perhaps due to specific surface effects. At longer evaporation times, as the droplets approach crystallization, all but one (MgCl2) of the solution evaporation rates are well described by the modified Maxwell equation. PMID- 28853887 TI - Characterization of Cladosporols from the Marine Algal-Derived Endophytic Fungus Cladosporium cladosporioides EN-399 and Configurational Revision of the Previously Reported Cladosporol Derivatives. AB - Four new cladosporol derivatives, cladosporols F-I (1-4), the known cladosporol C (5), and its new epimer, cladosporol J (6), were isolated and identified from the marine algal-derived endophytic fungus Cladosporium cladosporioides EN-399. Their structures were determined by detailed interpretation of NMR and MS data, and the absolute configurations were established on the basis of TDDFT-ECD and OR calculations. The configurational assignment of cladosporols F (1) and G (2) showed that the previously reported absolute configuration of cladosporol A and all the related cladosporols need to be revised from (4'R) to (4'S). Compounds 1 6 showed antibacterial activity against Escherichia coli, Micrococcus luteus, and Vibrio harveyi with MIC values ranging from 4 to 128 MUg/mL. Compound 3 showed significant cytotoxicity against A549, Huh7, and LM3 cell lines with IC50 values of 5.0, 1.0, and 4.1 MUM, respectively, and compound 5 showed activity against H446 cell line with IC50 value of 4.0 MUM. PMID- 28853889 TI - IR Spectroscopy of Protonated Acetylacetone and Its Water Clusters: Enol-Keto Tautomers and Ion->Solvent Proton Transfer. AB - Protonated ions of acetylacetone, H+(Hacac), and their argon-tagged analogues are produced via a pulsed discharge and cooled in a supersonic expansion. These ions are mass analyzed, selected in a time-of-flight spectrometer, and studied with infrared laser photodissociation spectroscopy using the method of rare-gas atom tagging. Computational studies at the DFT/B3LYP level are employed to elucidate the structures and spectra of these ions, which are expected to exist as either enol- or keto-based tautomers. The protonated acetylacetone ion is found to form a single enol-based isomer. Adding one or two water molecules to this ion, for example, H+(Hacac)(H2O)1,2, produces primarily enol-based structures, although a small concentration of keto structures also contribute to the spectra. The vibrational patterns resulting from hydrogen bonding in these systems are not well-described by theory. Addition of a third water molecule to form the H+(Hacac)(H2O)3 ion causes a significant change in the spectroscopy, attributed to proton transfer from the H+(Hacac) ion into the water solvent. PMID- 28853890 TI - Beyond Doping and Charge Balancing: How Polymer Acid Templates Impact the Properties of Conducting Polymer Complexes. AB - Polymer acids are increasingly used as dopants/counterions to access and stabilize the electrically conducting states of conducting polymers. Beyond doping and/or charge balancing, these polymer acids also serve as active components that impact the macroscopic properties of the conducting polymer complexes. Judicious selection of the polymer acid at the onset of synthesis or manipulation of the interactions between the polymer acid and the conducting polymer through processing significantly impacts the electrical conductivity, piezoresistivity, electrochromism, mechanical properties, and thermoelectric efficiency of conducting polymers. As polyelectrolytes, these polymer acids enable conducting polymer complexes to transport ions in addition to electrons/holes. Understanding the role of the polymer acid and its interactions with the conducting polymer generates processing-structure-function relationships for conducting polymer/polymer acid complexes, which can help overcome challenges that were associated with these materials, such as low electrical conductivity and sensitivity to humidity, and enable the design of conducting polymer complexes with desired functionalities. PMID- 28853891 TI - Investigation of the Iron(II) Release Mechanism of Human H-Ferritin as a Function of pH. AB - We investigated the kinetics of the release of iron(II) ions from the internal cavity of human H-ferritin as a function of pH. Extensive molecular dynamics simulations of the entire 24-mer ferritin provided atomic-level information on the release mechanism. Double protonation of His residues at pH 4 facilitates the removal of the iron ligands within the C3 channel through the formation of salt bridges, resulting in a significantly lower release energy barrier than pH 9. PMID- 28853892 TI - Ultrafast Microscopy: Imaging Light with Photoelectrons on the Nano-Femto Scale. AB - Experimental methods for ultrafast microscopy are advancing rapidly. Promising methods combine ultrafast laser excitation with electron-based imaging or rely on super-resolution optical techniques to enable probing of matter on the nano-femto scale. Among several actively developed methods, ultrafast time-resolved photoemission electron microscopy provides several advantages, among which the foremost are that time resolution is limited only by the laser source and it is immediately capable of probing of coherent phenomena in solid-state materials and surfaces. Here we present recent progress in interference imaging of plasmonic phenomena in metal nanostructures enabled by combining a broadly tunable femtosecond laser excitation source with a low-energy electron microscope. PMID- 28853893 TI - Photon Harvesting in Conjugated Polymer-Based Functional Nanoparticles. AB - The design of new generation light-harvesting systems based on conjugated polymer nanoparticles (PNPs) is an emerging field of research to convert solar energy into renewable energy. In this Perspective, we focus on the understanding of the light harvesting processes like exciton dynamics, energy transfer, antenna effect, charge carrier dynamics, and other related processes of conjugated polymer-based functional nanomaterials. Spectroscopic investigations unveil the rotational dynamics of the dye molecules inside of PNPs and exciton dynamics of the self-assembled structures. A detailed understanding of the cascade energy transfer for white light and singlet oxygen generation in multiple fluorophores containing a PNP system by time-resolved spectroscopy is highlighted. Finally, ultrafast spectroscopic investigations provide direct insight into the impacts of electron and hole transfer at the interface in the hybrid materials for photocatalysis and photocurrent generation to construct efficient light harvesting systems. PMID- 28853895 TI - Diagrammatic Exciton Basis Theory of the Photophysics of Pentacene Dimers. AB - Covalently linked acene dimers are of interest as candidates for intramolecular singlet fission. We report many-electron calculations of the energies and wave functions of the optical singlets, the lowest triplet exciton, and the triplet triplet biexciton, as well as the final states of excited state absorptions from these states in a family of phenyl-linked pentacene dimers. While it is difficult to distinguish the triplet and the triplet-triplet from their transient absorptions in the 500-600 nm region, by comparing theoretical transient absorption spectra against earlier and very recent experimental transient absorptions in the near- and mid-infrared, we conclude that the end product of photoexcitation in these particular bipentacenes is the bound triplet-triplet and not free triplets. We predict additional transient absorptions at even longer wavelengths, beyond 1500 nm, to the equivalent of the classic 21Ag- in linear polyenes. PMID- 28853894 TI - Chemodivergent, Tunable, and Selective Iodine(III)-Mediated Bromo Functionalizations of Polyprenoids. AB - Mild oxidation of bromides by iodine(III) reagents generated active electrophilic bromination species that were reacted with polyprenoids. By simple and minor variations of an I(III)/Br combination, the reactivity could be selectively steered toward dibromination, oxybromination, or bromocyclization, giving access to a wide array of brominated motifs. PMID- 28853896 TI - The Weak Link: Optimization of the Ligand-Nanoparticle Interface To Enhance Cancer Cell Targeting by Polymer Micelles. AB - Many promising targeting ligands are hydrophobic peptides, and these ligands often show limited accessibility to receptors, resulting in suboptimal targeting. A systematic study to elucidate the rules for the design of linkers that optimize their presentation on nanoparticles has not been carried out to date. In this study, we recombinantly synthesized an elastin-like polypeptide diblock copolymer (ELPBC) that self-assembles into monodisperse micelles. AHNP and EC1, two hydrophobic ErbB2-targeted peptide ligands, were incorporated at the C-terminus of the ELPBC with an intervening peptide linker. We tested more than 20 designs of peptide linkers, where the linker could be precisely engineered at the gene level to systematically investigate the molecular parameters-sequence, length, and charge-of the peptide linker that optimally assist ligands in targeting the ErbB2 receptor on cancer cells. We found that peptide linkers with a minimal length of 12 hydrophilic amino acids and an overall cationic charge-and that impart a zeta potential of the micelle that is close to neutral-were necessary to enhance the uptake of peptide-modified ELPBC micelles by cancer cells that overexpress the ErbB2 receptor. This work advances our understanding of the optimal presentation of hydrophobic ligands by nanoparticles and suggests design rules for peptide linkers for targeted delivery by polymer micelles, an emerging class of nanoparticle carriers for drugs and imaging agents. PMID- 28853897 TI - Progress on the HUPO Draft Human Proteome: 2017 Metrics of the Human Proteome Project. AB - The Human Proteome Organization (HUPO) Human Proteome Project (HPP) continues to make progress on its two overall goals: (1) completing the protein parts list, with an annual update of the HUPO draft human proteome, and (2) making proteomics an integrated complement to genomics and transcriptomics throughout biomedical and life sciences research. neXtProt version 2017-01-23 has 17 008 confident protein identifications (Protein Existence [PE] level 1) that are compliant with the HPP Guidelines v2.1 ( https://hupo.org/Guidelines ), up from 13 664 in 2012 12 and 16 518 in 2016-04. Remaining to be found by mass spectrometry and other methods are 2579 "missing proteins" (PE2+3+4), down from 2949 in 2016. PeptideAtlas 2017-01 has 15 173 canonical proteins, accounting for nearly all of the 15 290 PE1 proteins based on MS data. These resources have extensive data on PTMs, single amino acid variants, and splice isoforms. The Human Protein Atlas v16 has 10 492 highly curated protein entries with tissue and subcellular spatial localization of proteins and transcript expression. Organ-specific popular protein lists have been generated for broad use in quantitative targeted proteomics using SRM-MS or DIA-SWATH-MS studies of biology and disease. PMID- 28853899 TI - Refractory Plasmonics without Refractory Materials. AB - Refractory plasmonics deals with metallic nanostructures that can withstand high temperatures and intense laser pulses. The common belief was that refractory materials such as TiN are necessary for this purpose. Here we show that refractory plasmonics is possible without refractory materials. We demonstrate that gold nanostructures which are overcoated with 4 and 40 nm Al2O3 (alumina) by an atomic layer deposition process or by thick IC1-200 resist can withstand temperatures of over 800 degrees C at ambient atmospheric conditions. Furthermore, the alumina-coated structures can withstand intense laser radiation of over 10 GW/cm2 at ambient conditions without damage. Thus, it is possible to combine the excellent linear and nonlinear plasmonic properties of gold with material properties that were believed to be only possible with the lossier and less nonlinear refractory materials. PMID- 28853898 TI - Direct Observation of Insulin Association Dynamics with Time-Resolved X-ray Scattering. AB - Biological functions frequently require protein-protein interactions that involve secondary and tertiary structural perturbation. Here we study protein-protein dissociation and reassociation dynamics in insulin, a model system for protein oligomerization. Insulin dimer dissociation into monomers was induced by a nanosecond temperature-jump (T-jump) of ~8 degrees C in aqueous solution, and the resulting protein and solvent dynamics were tracked by time-resolved X-ray solution scattering (TRXSS) on time scales of 10 ns to 100 ms. The protein scattering signals revealed the formation of five distinguishable transient species during the association process that deviate from simple two-state kinetics. Our results show that the combination of T-jump pump coupled to TRXSS probe allows for direct tracking of structural dynamics in nonphotoactive proteins. PMID- 28853900 TI - Strain-Modulated Bandgap and Piezo-Resistive Effect in Black Phosphorus Field Effect Transistors. AB - Energy bandgap largely determines the optical and electronic properties of a semiconductor. Variable bandgap therefore makes versatile functionality possible in a single material. In layered material black phosphorus, the bandgap can be modulated by the number of layers; as a result, few-layer black phosphorus has discrete bandgap values that are relevant for optoelectronic applications in the spectral range from red, in monolayer, to mid-infrared in the bulk limit. Here, we further demonstrate continuous bandgap modulation by mechanical strain applied through flexible substrates. The strain-modulated bandgap significantly alters the density of thermally activated carriers; we for the first time observe a large piezo-resistive effect in black phosphorus field-effect transistors (FETs) at room temperature. The effect opens up opportunities for future development of electromechanical transducers based on black phosphorus, and we demonstrate an ultrasensitive strain gauge constructed from black phosphorus thin crystals. PMID- 28853901 TI - Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering. AB - In this study, we catalog structure activity relationships (SAR) of several short chain fatty acid (SCFA)-modified hexosamine analogues used in metabolic glycoengineering (MGE) by comparing in silico and experimental measurements of physiochemical properties important in drug design. We then describe the impact of these compounds on selected biological parameters that influence the pharmacological properties and safety of drug candidates by monitoring P glycoprotein (Pgp) efflux, inhibition of cytochrome P450 3A4 (CYP3A4), hERG channel inhibition, and cardiomyocyte cytotoxicity. These parameters are influenced by length of the SCFAs (e.g., acetate vs n-butyrate), which are added to MGE analogues to increase the efficiency of cellular uptake, the regioisomeric arrangement of the SCFAs on the core sugar, the structure of the core sugar itself, and by the type of N-acyl modification (e.g., N-acetyl vs N-azido). By cataloging the influence of these SAR on pharmacological properties of MGE analogues, this study outlines design considerations for tuning the pharmacological, physiochemical, and the toxicological parameters of this emerging class of small molecule drug candidates. PMID- 28853902 TI - Size-Dependent Conformational Features of Abeta17-42 Protofilaments from Molecular Simulation Studies. AB - Alzheimer's disease is caused due to aggregation of amyloid beta (Abeta) peptide into soluble oligomers and insoluble fibrils in the brain. In this study, we have performed room temperature molecular dynamics simulations to probe the size dependent conformational features and thermodynamic stabilities of five Abeta17 42 protofilaments, namely, O5 (pentamer), O8 (octamer), O10 (decamer), O12 (dodecamer), and O14 (tetradecamer). Analysis of the free energy profiles of the aggregates showed that the higher order protofilaments (O10, O12, and O14) undergo conformational transitions between two minimum energy states separated by small energy barriers, while the smaller aggregates (O5 and O8) remain in single deep minima surrounded by high barriers. Importantly, it is demonstrated that O10 is the crossover point for which the twisting of the protofilament is maximum, beyond which the monomers tend to rearrange themselves in an intermediate state and eventually transform into more stable conformations. Our results suggest that the addition of monomers along the axis of an existing protofilament with a critical size (O10 according to the present study) proceeds via an intermediate step with relatively less stable twisted structure that allows the additional monomers to bind and form stable larger protofilaments with minor rearrangements among themselves. More importantly, it is demonstrated that a combination of twist angle and end-to-end distance can be used as a suitable reaction coordinate to describe the growth mechanism of Abeta protofilaments in simulation studies. PMID- 28853903 TI - Electrolyte-induced Instability of Colloidal Dispersions in Nonpolar Solvents. AB - Dispersions of poly(methyl methacrylate) (PMMA) latexes were prepared in a low dielectric, nonpolar solvent (dodecane) both with and without the oil-soluble electrolyte, tetradodecylammonium-tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. For dispersions with a high concentration of background electrolyte, the latexes become colloidally unstable and sediment in a short period of time (<1 h). This is completely reversible upon dilution. Instability of the dispersions is due to an apparent attraction between the colloids, directly observed using optical tweezers by bringing optically trapped particles into close proximity. Simple explanations generally used by colloid scientists to explain loss of stability (charge screening or stabilizer collapse) are insufficient to explain this observation. This unexpected interaction seems, therefore, to be a consequence of the materials that can be dispersed in low dielectric media and is expected to have ramifications for studying colloids in such solvents. PMID- 28853904 TI - Right Heart Thrombi in Pulmonary Embolism, Association of Pulmonary Embolism with Acute Exacerbations of Chronic Obstructive Pulmonary Disease, and Catheter directed Therapies for Acute Pulmonary Embolism. PMID- 28853906 TI - Human Umbilical Cord Cells Express Neural Markers after Transplantation into Subventricular Zone of the DevelopingRat Brain. PMID- 28853907 TI - Elevation of Cytotoxic Lymphocyte Gene Expression is Predictive of Islet Allograft Rejection in Non-Human Primates. PMID- 28853905 TI - Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity. AB - RATIONALE: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known. OBJECTIVES: We sought to identify novel CF disease modifying mechanisms using an integrated approach based on analyzing "in vivo" CF airway epithelial gene expression complemented with genome-wide association study (GWAS) data. METHODS: Nasal mucosal RNA from 134 patients with CF was used for RNA sequencing. We tested for associations of transcriptomic (gene expression) data with a quantitative phenotype of CF lung disease severity. Pathway analysis of CF GWAS data (n = 5,659 patients) was performed to identify novel pathways and assess the concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested. MEASUREMENTS AND MAIN RESULTS: Significant evidence of heritable gene expression was identified. Gene expression pathways relevant to airway mucosal host defense were significantly associated with CF lung disease severity, including viral infection, inflammation/inflammatory signaling, lipid metabolism, apoptosis, ion transport, Phe508del CFTR processing, and innate immune responses, including HLA (human leukocyte antigen) genes. Ion transport and CFTR processing pathways, as well as HLA genes, were identified across differential gene expression and GWAS signals. CONCLUSIONS: Transcriptomic analyses of CF airway epithelia, coupled to genomic (GWAS) analyses, highlight the role of heritable host defense variation in determining the pathophysiology of CF lung disease. The identification of these pathways provides opportunities to pursue targeted interventions to improve CF lung health. PMID- 28853908 TI - Effect of pistachio on brachial artery diameter and flow-mediated dilatation: A systematic review and meta-analysis of randomized, controlled-feeding clinical studies. AB - BACKGROUND: Results of previous clinical trials evaluating the effect of pistachio supplementation on endothelial reactivity (ER) are controversial. AIMS: We aimed to assess the impact of pistachio on ER through systematic review of literature and meta-analysis of available randomized, controlled-feeding clinical studies (RCTs). METHODS: The literature search included SCOPUS, PubMed-Medline, ISI Web of Science and Google Scholar databases up to 1st August 2017 to identify RCTs investigating the impact of pistachio on ER. Two independent reviewers extracted data on study characteristics, methods and outcomes. Overall, the impact of pistachio on ER was reported in 4 trials. RESULTS: The meta-analysis did not suggest a significant change in brachial artery flow-mediated dilatation (FMD) (WMD: +0.28%; 95%CI: -0.58, 1.13; p = 0.525) while brachial artery diameter (BAD) improved (WMD: +0.04%; 95%CI: 0.03, 0.06; p<0.001) following pistachios consumption. CONCLUSION: The present meta-analysis suggests a significant effect of pistachios on ER, affecting BAD but not FMD. PMID- 28853909 TI - Postharvest processes of edible insects in Africa: A review of processing methods, and the implications for nutrition, safety and new products development. AB - In many African cultures, insects are part of the diet of humans and domesticated animals. Compared to conventional food and feed sources, insects have been associated with a low ecological foot print because fewer natural resources are required for their production. To this end, the Food and Agriculture Organization of the United Nations recognized the role that edible insects can play in improving global food and nutrition security; processing technologies, as well as packaging and storage techniques that improve shelf-life were identified as being crucial. However, knowledge of these aspects in light of nutritional value, safety, and functionality is fragmentary and needs to be consolidated. This review attempts to contribute to this effort by evaluating the available evidence on postharvest processes for edible insects in Africa, with the aim of identifying areas that need research impetus. It further draws attention to potential postharvest technology options for overcoming hurdles associated with utilization of insects for food and feed. A greater research thrust is needed in processing and this can build on traditional knowledge. The focus should be to establish optimal techniques that improve presentation, quality and safety of products, and open possibilities to diversify use of edible insects for other benefits. PMID- 28853910 TI - Coffee consumption and disease correlations. AB - Coffee is one of the most widely consumed beverages in the world. It has primarily consumed due to its stimulant effect and unique taste since the ancient times. Afterwards, its consumption has been historically associated with a lower risk of some diseases such as type 2 diabetes mellitus, obesity, cardiovascular disease and some type of cancer and thus it has also consumed due to health benefits. It contains many bioactive compounds such as caffeine, chlorogenic acids and diterpenoid alcohols which have so far been associated with many potential health benefits. For example, caffeine reduces risk of developing neurodegenerative disease and chlorogenic acids (CGA) and diterpene alcohols have many health benefits such as antioxidant and chemo-preventive. Coffee also have harmful effects. For example, diterpenoid alcohols increases serum homocysteine and cholesterol levels and thus it has adverse effects on cardiovascular system. Overall, the study that supports the health benefits of coffee is increasing. But, it is thought-provoking that the association with health benefits of coffee consumption and frequency at different levels in each study. For this reason, we aimed to examine the health effect of the coffee and how much consumption is to investigate whether it meets the claimed health benefits. PMID- 28853911 TI - A review on influencing factors on the minimum inhibitory concentration of essential oils. AB - With growing interest in essential oils as natural preservatives in the food industry, the literature is expanding enormously. To understand the antimicrobial activity of essential oils, the antimicrobial mechanism of individual essential oil (EO) compounds, and their minimum inhibitory concentrations (MICs), are interesting starting points for research. Therefore, and to get insight into the factors influencing their antimicrobial activities, the Web of Science was searched for MICs of EO compounds (1995-2016). Many MICs for individual EO compounds have already been reported in the literature, but there is large variability in these data, even for the MIC of the same compound against the same species. No correlation was found between the tested structural parameters of EO compounds (polarity, water solubility, dissociation constant, molecular weight and molecular complexity) and their MICs against all microorganisms, Gram negative bacteria, Gram-positive bacteria and fungi. Few clear differences in sensitivity between microorganisms could be found. Based on this review it is clear that different incubation conditions, culture media and the use of emulsifiers/solvents have an influence on the MIC, causing big variance. This review points out the need for a good international standard method to assess the antimicrobial activity of EO compounds for better comparability between studies. PMID- 28853912 TI - A Pilot Study of Pokemon Go and Players' Physical Activity. AB - OBJECTIVE: Pokemon Go is a mobile game released in 2016 that gained great popularity. The goals of this pilot study were to investigate player's game related behavior pattern, to evaluate Pokemon Go's impact on players' physical activity (PA) and game enjoyment, and to examine the influence of neighborhood environment on game behavior. MATERIALS AND METHODS: Forty-seven valid online surveys were collected. Participants were asked questions from five aspects regarding their (1) game status, (2) demographic background and pre-game physical activity, (3) game enjoyment and socializing motivations, (4) perceived game impact on their post-game physical activity, and (5) neighborhood environment's influence on their choice of game location. We examined the first four aspects through descriptive statistics and t-tests, and we investigated the neighborhood impact using logistic regression. RESULTS: Sixty-four percent of participants felt that Pokemon Go made them exercise more than before, about three more times, 3 additional hours, and 5.6 extra miles of PA in total per week. This impact did not vary by gender or body weight status. However, 78.7% participants started to quit or reduce game time by the time of the survey. We also found that players' choice of playing Pokemon Go in the neighborhood is positively associated with the perceived safety level and the walk score of their neighborhood, but negatively associated with the number of Pokestops near home. CONCLUSIONS: Pokemon Go as a location-based mobile game is a promising tool for promoting PA, but more research is needed to prolong its positive impact. PMID- 28853913 TI - Comparison of the Effects of Osteochondral Autograft Transplantation With Platelet-Rich Plasma or Platelet-Rich Fibrin on Osteochondral Defects in a Rabbit Model. AB - BACKGROUND: Although osteochondral autograft transplantation (OAT) provides satisfactory outcomes for osteochondral defects, for large defects OAT is often inadequate because of graft availability. Osteochondral allograft transplantation is an alternative treatment for large defects, but this approach is limited by graft storage constraints and carries disease transmission risks. Platelet-rich fibrin (PRF) is a second-generation platelet concentrate, and its positive effect on articular cartilage has been reported. However, the effect of PRF with OAT of osteochondral defects is unknown. PURPOSE: To compare the effects of OAT with platelet-rich plasma (PRP) and PRF on osteochondral defects in a rabbit model. STUDY DESIGN: Controlled laboratory study. METHODS: Forty-two juvenile rabbits were divided into control, PRP, and PRF groups. In the control and PRP groups, a cylindrical osteochondral defect (5 mm in diameter and 2 mm in depth) was created on the patellar groove, and an osteochondral graft (3.5 mm in diameter and 5 mm in length) harvested from the contralateral side was inserted into the distal portion of the defect. After wound closure, either normal saline or PRP was injected in the knee. In the PRF group, a PRF clot was placed in the defect before grafting. The surgical site was macroscopically and histologically assessed after 3 and 12 weeks. RESULTS: At 3 weeks, the PRF group (n = 8) was macroscopically healed compared with the other 2 groups (control, n = 7; PRP, n = 6) ( P < .005). Histologically, osteochondral graft cartilage of the PRF group had normal cellularity and higher amounts of safranin O staining relative to the other 2 groups ( P < .005). At 12 weeks, all 3 groups (n = 8 per group) were macroscopically healed with normal or nearly normal cartilage, and osteochondral graft cartilage was histologically hyaline cartilage. In contrast, the PRF group healed with hyaline-like cartilage at nongrafted defects, whereas the other 2 groups healed with fibrocartilage ( P < .001). CONCLUSION: OAT with PRF maintained hyaline cartilage, and the nongrafted defect healed with hyaline-like cartilage. CLINICAL RELEVANCE: PRF has the potential to improve clinical outcomes of OAT used to treat osteochondral lesions. PMID- 28853914 TI - A Novel Strategy Incorporated the Power of Mesenchymal Stem Cells to Allografts for Segmental Bone Tissue Engineering. AB - Mesenchymal stem cells (MSCs) hold great promise for bone regeneration. However, the power of mesenchymal stem cells has not been applied to structural bone allografts in clinical practice. This study designed a new strategy to enhance the efficiency of allografts for segmental bone regeneration. Isolated MSCs were cultured to form a cell sheet. The MSC sheet was then wrapped onto structural allografts. The assembled structures were cultured in vitro to evaluate the differentiation potential of MSC sheet. The assembled structures were implanted subcutaneously into nude mice as well as into the segmental radius defect of rabbits to investigate the efficiency of MSC sheets to repopulate allografts for bone repair. MSC sheets, upon assembling on bone grafts, showed similar differentiation properties to the in situ periosteum in vitro. After implantation the MSC sheets accelerated the repopulation of bone grafts in nude mice. Moreover, MSC sheets induced thicker cortical bone formation and more efficient graft-to-bone end fusion at the segmental bone defects in rabbits. This study thus presented a novel, more efficient, and practical strategy for large weight bearing bone reconstruction by using MSC sheets to deliver large number of MSCs to repopulate the bone allografts. PMID- 28853917 TI - Correction to: Reconfiguring diagnostic work in Danish general practice; regulation, triage and the secretaries as diagnostician. PMID- 28853915 TI - RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice. AB - A cardinal feature of asthma is airway hyperresponsiveness (AHR) to spasmogens, many of which activate G protein-coupled receptors (GPCRs) on airway smooth muscle (ASM) cells. Asthma subtypes associated with allergy are characterized by eosinophilic inflammation in the lung due to the type 2 immune response to allergens and proinflammatory mediators that promote AHR. The degree to which intrinsic abnormalities of ASM contribute to this phenotype remains unknown. The regulators of G protein signaling (RGS) proteins are a large group of intracellular proteins that inhibit GPCR signaling pathways. RGS2- and RGS5 deficient mice develop AHR spontaneously. Although RGS4 is upregulated in ASM from patients with severe asthma, the effects of increased RGS4 expression on AHR in vivo are unknown. Here, we examined the impact of forced RGS4 overexpression in lung on AHR using transgenic (Tg) mice. Tg RGS4 was expressed in bronchial epithelium and ASM in vivo, and protein expression in lung was increased at least 4-fold in Tg mice compared with wild-type (WT) mice. Lung slices from Tg mice contracted less in response to the m3 muscarinic receptor agonist methacholine compared with the WT, although airway resistance in live, unchallenged mice of both strains was similar. Tg mice were partially protected against AHR induced by fungal allergen challenge due to weakened contraction signaling in ASM and reduced type 2 cytokine (IL-5 and IL-13) levels in Tg mice compared with the WT. These results provide support for the hypothesis that increasing RGS4 expression and/or function could be a viable therapeutic strategy for asthma. PMID- 28853916 TI - Vascular endothelial growth factor: An important molecular target of curcumin. AB - The discovery of Vascular Endothelial Growth Factor (VEGF), the key modulator of angiogenesis, has triggered intensive research on anti-angiogenic therapeutic modalities. Although several clinical studies have validated anti-VEGF therapeutics, with few of them approved by the U.S. Food and Drug Administration (FDA), anti-angiogenic therapy is still in its infancy. Phytochemicals are compounds that have several metabolic and health benefits. Curcumin, the yellow pigment derived from turmeric (Curcuma longa L.) rhizomes, has a wide range of pharmaceutical properties. It has also been shown to inhibit VEGF by several studies. In this review, we elaborate the effect of curcumin on VEGF and angiogenesis and its therapeutic application. PMID- 28853918 TI - Human Bronchial Epithelial Cell-derived Factors from Severe Asthmatic Subjects Stimulate Eosinophil Differentiation. AB - Activated bronchial epithelial cells (BEC) release various alarmins, including thymic stromal lymphopoietin (TSLP), that drive type 2 inflammation. We hypothesize that BEC-derived factors promote in situ eosinophil differentiation and maturation, a process that is driven by an IL-5-rich microenvironment in asthmatic airways. To assess the eosinophilopoietic potential of epithelial derived factors, eosinophil/basophil colony forming units (Eo/B-CFU) were enumerated in 14-day methylcellulose cultures of blood-derived nonadherent mononuclear cells incubated with BEC supernatants (BECSN) from healthy nonatopic controls (n = 8), mild atopic asthmatics (n = 9), and severe asthmatics (n = 5). Receptor-blocking antibodies were used to evaluate the contribution of alarmins. Modulation of the mRNA expression of transcription factors that are crucial for eosinophil differentiation was evaluated. BECSN stimulated the clonogenic expansion of eosinophil progenitors in vitro. In the presence of IL-5, Eo/B-CFU numbers were significantly greater in cocultures of BESCN from severe asthmatics compared with other groups. This was attenuated in the presence of a TSLP (but not an IL-33) receptor-blocking antibody. Recombinant human TSLP (optimal at 100 pg/ml) stimulated Eo/B-CFU growth, which was significantly enhanced in the presence of IL-5 (1 ng/ml). Overnight culture of CD34+ cells with IL-5 and TSLP synergistically increased GATA-binding factor 2 and CCAAT/enhancer-binding protein alpha mRNA expression. The eosinophilopoietic potential of factors derived from BEC is increased in severe asthma. Our data suggest that TSLP is a key alarmin that is produced by BECs and promotes in situ eosinophilopoiesis in a type 2-rich microenvironment. PMID- 28853920 TI - Integration of Agrobacterium T-DNA into the Plant Genome. AB - Agrobacterium strains transfer a single-strand form of T-DNA (T-strands) and Virulence (Vir) effector proteins to plant cells. Following transfer, T-strands likely form complexes with Vir and plant proteins that traffic through the cytoplasm and enter the nucleus. T-strands may subsequently randomly integrate into plant chromosomes and permanently express encoded transgenes, a process known as stable transformation. The molecular processes by which T-strands integrate into the host genome remain unknown. Although integration resembles DNA repair processes, the requirement of known DNA repair pathways for integration is controversial. The configuration and genomic position of integrated T-DNA molecules likely affect transgene expression, and control of integration is consequently important for basic research and agricultural biotechnology applications. This article reviews our current knowledge of the process of T-DNA integration and proposes ways in which this knowledge may be manipulated for genome editing and synthetic biology purposes. PMID- 28853919 TI - Regeneration Genetics. AB - Understanding how and why animals regenerate complex tissues has the potential to transform regenerative medicine. Here we present an overview of genetic approaches that have recently been applied to dissect mechanisms of regeneration. We describe new advances that relate to central objectives of regeneration biologists researching different tissues and species, focusing mainly on vertebrates. These objectives include defining the cellular sources and key cell behaviors in regenerating tissue, elucidating molecular triggers and brakes for regeneration, and defining the earliest events that control the presence of these molecular factors. PMID- 28853922 TI - Origin and Evolution of the Universal Genetic Code. AB - The standard genetic code (SGC) is virtually universal among extant life forms. Although many deviations from the universal code exist, particularly in organelles and prokaryotes with small genomes, they are limited in scope and obviously secondary. The universality of the code likely results from the combination of a frozen accident, i.e., the deleterious effect of codon reassignment in the SGC, and the inhibitory effect of changes in the code on horizontal gene transfer. The structure of the SGC is nonrandom and ensures high robustness of the code to mutational and translational errors. However, this error minimization is most likely a by-product of the primordial code expansion driven by the diversification of the repertoire of protein amino acids, rather than a direct result of selection. Phylogenetic analysis of translation system components, in particular aminoacyl-tRNA synthetases, shows that, at a stage of evolution when the translation system had already attained high fidelity, the correspondence between amino acids and cognate codons was determined by recognition of amino acids by RNA molecules, i.e., proto-tRNAs. We propose an experimentally testable scenario for the evolution of the code that combines recognition of amino acids by unique sites on proto-tRNAs (distinct from the anticodons), expansion of the code via proto-tRNA duplication, and frozen accident. PMID- 28853923 TI - The Yeast Genomes in Three Dimensions: Mechanisms and Functions. AB - The three-dimensional (3D) genome structure is highly ordered by a hierarchy of organizing events ranging from enhancer-promoter or gene-gene contacts to chromosomal territorial arrangement. It is becoming clear that the cohesin and condensin complexes are key molecular machines that organize the 3D genome structure. These complexes are highly conserved from simple systems, e.g., yeast cells, to the much more complex human system. Therefore, knowledge from the budding and fission yeast systems illuminates highly conserved molecular mechanisms of how cohesin and condensin establish the functional 3D genome structures. Here I discuss how these complexes are recruited across the yeast genomes, mediate distinct genome-organizing events such as gene contacts and topological domain formation, and participate in important nuclear activities including transcriptional regulation and chromosomal dynamics. PMID- 28853924 TI - Regulation by 3'-Untranslated Regions. AB - 3'-untranslated regions (3'-UTRs) are the noncoding parts of mRNAs. Compared to yeast, in humans, median 3'-UTR length has expanded approximately tenfold alongside an increased generation of alternative 3'-UTR isoforms. In contrast, the number of coding genes, as well as coding region length, has remained similar. This suggests an important role for 3'-UTRs in the biology of higher organisms. 3'-UTRs are best known to regulate diverse fates of mRNAs, including degradation, translation, and localization, but they can also function like long noncoding or small RNAs, as has been shown for whole 3'-UTRs as well as for cleaved fragments. Furthermore, 3'-UTRs determine the fate of proteins through the regulation of protein-protein interactions. They facilitate cotranslational protein complex formation, which establishes a role for 3'-UTRs as evolved eukaryotic operons. Whereas bacterial operons promote the interaction of two subunits, 3'-UTRs enable the formation of protein complexes with diverse compositions. All of these 3'-UTR functions are accomplished by effector proteins that are recruited by RNA-binding proteins that bind to 3'-UTR cis-elements. In summary, 3'-UTRs seem to be major players in gene regulation that enable local functions, compartmentalization, and cooperativity, which makes them important tools for the regulation of phenotypic diversity of higher organisms. PMID- 28853925 TI - Sex Determination in the Mammalian Germline. AB - Sexual reproduction crucially depends on the production of sperm in males and oocytes in females. Both types of gamete arise from the same precursor, the germ cells. We review the events that characterize the development of germ cells during fetal life as they commit to, and prepare for, oogenesis or spermatogenesis. In females, fetal germ cells enter meiosis, whereas in males they delay meiosis and instead lose pluripotency, activate an irreversible program of prospermatogonial differentiation, and temporarily cease dividing. Both pathways involve sex-specific molecular signals from the somatic cells of the developing gonads and a suite of intrinsic receptors, signal transducers, transcription factors, RNA stability factors, and epigenetic modulators that act in complex, interconnected positive and negative regulatory networks. Understanding these networks is important in the contexts of the etiology, diagnosis, and treatment of infertility and gonadal cancers, and in efforts to augment human and animal fertility using stem cell approaches. PMID- 28853926 TI - Genetics and Evolution of Social Behavior in Insects. AB - The study of insect social behavior has offered tremendous insight into the molecular mechanisms mediating behavioral and phenotypic plasticity. Genomic applications to the study of eusocial insect species, in particular, have led to several hypotheses for the processes underlying the molecular evolution of behavior. Advances in understanding the genetic control of social organization have also been made, suggesting an important role for supergenes in the evolution of divergent behavioral phenotypes. Intensive study of social phenotypes across species has revealed that behavior and caste are controlled by an interaction between genetic and environmentally mediated effects and, further, that gene expression and regulation mediate plastic responses to environmental signals. However, several key methodological flaws that are hindering progress in the study of insect social behavior remain. After reviewing the current state of knowledge, we outline ongoing challenges in experimental design that remain to be overcome in order to advance the field. PMID- 28853921 TI - Human Genetic Determinants of Viral Diseases. AB - Much progress has been made in the identification of specific human gene variants that contribute to enhanced susceptibility or resistance to viral diseases. Herein we review multiple discoveries made with genome-wide or candidate gene approaches that have revealed significant insights into virus-host interactions. Genetic factors that have been identified include genes encoding virus receptors, receptor-modifying enzymes, and a wide variety of innate and adaptive immunity related proteins. We discuss a range of pathogenic viruses, including influenza virus, respiratory syncytial virus, human immunodeficiency virus, human T cell leukemia virus, human papilloma virus, hepatitis B and C viruses, herpes simplex virus, norovirus, rotavirus, parvovirus, and Epstein-Barr virus. Understanding the genetic underpinnings that affect infectious disease outcomes should allow tailored treatment and prevention approaches in the future. PMID- 28853927 TI - Emerging Strategies in Neural Transplantation and Repair: A Special Section Based on the INTR-8 Conference. PMID- 28853928 TI - The Noradrenergic System of Aged GDNF Heterozygous Mice. AB - Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor for noradrenergic (NE) neurons of the pontine nucleus locus coeruleus (LC). Decreased function of the LC-NE neurons has been found during normal aging and in neurodegenerative disorders. We have previously shown that GDNF participates in the differentiation of LC-NE neurons during development. However, the continued role of GDNF for LC-NE neurons during maturation and aging has not been addressed. We examined alterations in aged mice that were heterozygous for the GDNF gene (Gdnf+/-). Wild-type (Gdnf+/+) and Gdnf+/- mice (18 months old) were tested for locomotor activity and brain tissues were collected for measuring norepinephrine levels and uptake, as well as for morphological analysis. Spontaneous locomotion was reduced in Gdnf+/- mice in comparison with Gdnf+/+ mice. The reduced locomotor activity of Gdnf +/- mice was accompanied by reductions in NE transporter activity in the cerebellum and brain stem as well as decreased norepinephrine tissue levels in the LC. Tyrosine hydroxylase (TH) immunostaining demonstrated morphological alterations of LC-NE cell bodies and abnormal TH-positive fibers in the hippocampus, cerebellum, and frontal cortex of Gdnf+/- mice. These findings suggest that the LC-NE system of Gdnf+/- mice is impaired and suggest that GDNF plays an important role in continued maintenance of this neuronal system throughout life. PMID- 28853929 TI - 13th Meeting of the Network of European CNS Transplantation and Restoration (NECTAR). PMID- 28853930 TI - Japanese Society for Regenerative Medicine: Introduction. PMID- 28853931 TI - Assessment of Different Transfection Parameters in Efficiency Optimization. AB - Achieving optimal transfection efficiency is the most critical step in overcoming the primary obstacle to success in nonviral-mediated gene therapy. Several transfection parameters were being examined including the effects of different types of transfection media, glucose concentration, reporter DNA concentration, and incubation time in lipotransfectant. Efficiency of transfection obtained was highest for Opti-MEM I (29 +/- 2.28%; p = 0.001) followed by M199 (24 +/- 1.54%; p = 0.009), both of which performed significantly better than DMEM (14 +/- 0.28%) as a transfection medium. The rate of transfection was affected by glucose levels in only DMEM with higher efficiency achieved using low glucose containing DMEM (17 +/- 0.38%) than its counterpart. Furthermore, transfection rate and cell viability were severely hampered by lengthened exposure to transfection complexes, leading to an overall mean efficiency of 5 +/- 0.87%. However, doubling the DNA content in the transfection mixture did not significantly change the mean rate of transfection in M199 medium (24 +/- 1.54% to 27 +/- 1.54%; p = 0.273). The overall range of mean efficiency acquired with our protocol under different transfection conditions was between 14% and 29%. Hopefully results from this study will further potential success in nonviral-mediated gene transfer. PMID- 28853932 TI - Tissue-Engineered Grafts Matured in the Right Ventricular Outflow Tract. AB - Autologous smooth muscle cell (SMC)-seeded biodegradable scaffolds could be a suitable material to repair some pediatric right ventricular outflow tract (RVOT) cardiac anomalies. Adult syngenic Lewis rat SMCs (2 * 106) were seeded onto a new biodegradable copolymer sponge made of ?-caprolactone-co-L-lactide reinforced with poly-L-lactide fabric (PCLA). Two weeks after seeding, the patch was used to repair a surgically created RVOT defect in an adult rat. At 8 weeks after implantation the spongy copolymer component was biodegraded, and SM tissue and extracellular matrices containing elastin fibers were present in the scaffolds. By 22 weeks more fibroblasts and collagen were present (p < 0.05). The number of capillaries in the grafts also increased (p < 0.001) between 8 and 22 weeks. The fibrous poly-L-lactide component of the PCLA scaffold remained. The 22-week grafts maintained their thickness and surface area in the RVOT. The SMCs prior to implantation were in a synthetic phenotype and developed in vivo into a more contractile phenotype. By 8 weeks the patches were endothelialized on their endocardial surfaces. Future work to increase the SM tissue and elastin content in the patch will be necessary before implantation into a pediatric large-animal model is tested. PMID- 28853933 TI - Transplantation of Adipose Tissue-Derived Stromal Cells Increases Mass and Functional Capacity of Damaged Skeletal Muscle. AB - The regenerating skeletal muscle environment is capable of inducing uncommitted progenitors to terminally differentiate. The aim of this work was to determine whether adipose tissue-derived stromal cells were able to participate in muscle regeneration and to characterize the effect on muscle mass and functional capacities after transplantation of these cells. Adipose tissue stromal cells labeled with Adv cyto LacZ from 3-day-old primary cultures (SVF1) were autotransplanted into damaged tibialis anterior muscles. Fifteen days later, beta galactosidase staining of regenerated fibers was detected, showing participation of these cells in muscle regeneration. Two months after SVF1 cell transfer, muscles were heavier, showed a significantly larger fiber section area, and developed a significantly higher maximal force compared with damaged control muscles. These results are similar to those previously obtained after satellite cell transplantation. However, SVF1 transfer also generated a small amount of adipose tissue localized along the needle course. To minimize these adipose contaminants, we transferred cells from 7-day-old secondary cultures of the SVF1, containing only a small proportion of already engaged preadipocytes (SVF2). Under these conditions, no adipose tissue was observed in regenerated muscle but there was also no effect on muscle performances compared with damaged control muscles. This result provides further evidence for the existence of progenitor cells in the stromal fraction of freshly isolated adipose tissue cells, which, under our conditions, keep some of their pluripotent properties in primary cultures. PMID- 28853934 TI - Endogenous Pancreatic Enzyme Activity Levels Show no Significant Effect on Human Islet Isolation Yield. AB - Despite advances in human islet isolation, islet yield remains inconsistent and unreliable. In recent studies, it has been suggested that serine proteases, in particular trypsin, have been shown to have a damaging effect on islet yield. This study evaluated enzyme activity levels throughout 42 human islet isolation procedures. Trypsin, chymotrypsin, and elastase activity was determined spectrophotometrically using suitable chromophoric substrates. The results of the islet isolations were rated as successful (n = 19) or unsuccessful (n = 23) based on the islet yield and functionality. The enzyme activity profiles of the isolations were compared. No significant differences in donor-related variables were found in this study. However, in the successful isolations, a significantly greater amount (85.6 +/- 1.9%; p = 0.0017) of the pancreas was digested in a significantly shorter digestion time (19.7 +/- 0.6 min; p = 0.0054) compared with 74.8 +/- 2.5% of digested tissue in 22.6 +/- 0.7 min in the poor isolations. This study showed no significant effect of serine protease levels on the outcome of islet isolations, regardless of enzyme inhibitor supplementation. These data suggest that serine protease activity does not sufficiently affect islet yield. However, the data show that the most successful human islet isolations are achieved when the maximum amount of tissue is digested in the shortest amount of time. This suggests that further understanding of the isolation process should focus on the role of the collagenase digestion solution in the dissociation of the endocrine-exocrine tissue connection. PMID- 28853939 TI - Intramuscular Migration of Myoblasts Transplanted after Muscle Pretreatment with Metalloproteinases. AB - The effect of pretreatments of host muscles with metalloproteinases (MMPs) or with notexin on the migration of transplanted myoblasts was investigated. Transgenic TnILacZ mice in which the beta-galactosidase gene is under the control of a quail fast skeletal troponin I gene promoter were used as donors. A polyethylene microtube with four perforations was inserted in the tibialis anterior (TA) of CD1 mice. Both pretreatment substances and cells were slowly injected through that microtube. Muscles were pretreated 2 days before myoblast injection either with a mixture of collagenase, matrilysin, and notexin or with only collagenase and matrilysin or only notexin. As control for our experiments, TnILacZ and C2C12 myoblasts were also injected in TA muscles not pretreated. Comparison of short and long-term myoblast radial migration was performed using a dye (PKH26) and X-gal staining, respectively. The recipient mice were immunosuppressed with FK506. Two days after myoblast transplantation, the cell movement in muscles pretreated with collagenase, matrilysin, and notexin was slightly greater than in muscles pretreated only with collagenase and matrilysin but was about twice that observed in muscles treated with notexin alone. Almost no radial migration of TnILacZ myoblasts was observed in untreated muscles. The C2C12 myoblasts showed a four-to fivefold higher migration capacity than TnILacZ myoblasts. At 15 days after TnILacZ myoblast transplantation, the farthest positive beta-gal muscle fibers show a two- to threefold extension of the initial migration observed at 2 days, demonstrating the ability of myoblasts to continue the migration following all pretreatments and even in the untreated muscles. In addition, more muscle fibers expressed the beta-gal reporter gene in muscles pretreated only with MMPs. Our results clearly demonstrate that muscle pretreatments with MMPs increase myoblast migration and fusion with host muscle fibers after transplantation and that the C2C12 cell line producing MMPs has a higher migratory capacity. PMID- 28853943 TI - Japanese Society for Regenerative Medicine: Introduction. PMID- 28853944 TI - Promotion of Neurite Outgrowth from Fetal Hippocampal Cells by TNF-alpha Receptor 1-Derived Peptide. AB - Cytokines such as tumor necrosis factor-alpha (TNF-alpha), FasL, and TNF-related apoptosis-inducing ligand (TRAIL) induce apoptosis or inflammation through binding to their specific receptors, TNFR1, Fas, and DR5, respectively. We have previously reported ligand-binding and cell death-inhibiting synthetic peptides, which were designed based on the crystal structure of a ligand-receptor complex and the homology of the amino acid sequence among the death receptor family members. Here we show that, among these death receptor-derived peptides, the TNFR1-derived peptide specifically arrested cell proliferation and promoted cell adhesion of fetal rat (E16) hippocampal cells, and promoted neurite outgrowth from hippocampus-derived neurospheres cultured with the addition of the peptide or cultured on a peptide-coated surface. Furthermore, among these death receptor derived peptides, marked neurite outgrowth was observed only when the neurospheres were cultured on a TNFR1-derived peptide-conjugated covalently cross linked alginate gel. The neurites from the neurospheres positively immunostained with an antibody against neurofilaments. These results suggest that the TNFR1 derived peptide promotes neuronal differentiation of the hippocampal neural stem cells and the TNFR1-derived peptide-conjugated covalently cross-linked alginate gel may be a useful material for assisting neural stem cell transplantation. PMID- 28853945 TI - In Vitro Screening of Exogenous Factors for Human Neural Stem/Progenitor Cell Proliferation Using Measurement of Total ATP Content in Viable Cells. AB - One of the newest and most promising methods for treating intractable neuronal diseases and injures is the transplantation of ex vivo-expanded human neural stem/progenitor cells (NSPCs). Human NSPCs are selectively expanded as free floating neurospheres in serum-free culture medium containing fibroblast growth factor 2 (FGF2) and/or epidermal growth factor (EGF); however, the culture conditions still need to be optimized for performance and cost before the method is used clinically. Here, to improve the NSPC culture method for clinical use, we used an ATP assay to screen the effects of various reagents on human NSPC proliferation. Human NSPCs responded to EGF, FGF2, and leukemia inhibitory factor (LIF) in a dose-dependent manner, and the minimum concentrations eliciting maximum effects were 10 ng/ml EGF, 10 ng/ml FGF2, and 5 ng/ml LIF. EGF and LIF were stable in culture medium without NSPCs, although FGF2 was degraded. In the presence of human NSPCs, however, FGF2 and LIF were both degraded very rapidly, to below the estimated minimum concentration on day 3, but EGF remained above the minimum concentration for 5 days. Adding supplemental doses of each growth factor during the incubation promoted human NSPC proliferation. Among other supplements, insulin and transferrin promoted human NSPC growth, but progesterone, putrescine, selenite, D-glucose, and lactate were not effective and were cytotoxic at higher concentrations. Supplementing with conditioned medium from human NSPCs significantly increased human NSPC proliferation, but using a high percentage of the medium had a negative effect. These findings suggest that human NSPC culture is regulated by a balance in the culture medium between decreasing growth factor levels and increasing positive or negative factors derived from the NSPCs. Thus, in designing culture conditions for human NSPCs, it is useful to take the individual properties of each factor into consideration. PMID- 28853946 TI - Synergistic Effects of FGF-2 with Insulin or IGF-I on the Proliferation of Human Auricular Chondrocytes. AB - Chondrocyte preparation with the safety and efficiency is the first step in cartilage regenerative medicine. To prepare a chondrocyte proliferation medium that does not contain fetal bovine serum (FBS) and that provides more than a 1000 fold increase in cell numbers within approximately 1 month, we attempted to use the medium containing 5% human serum (HS), but it exerted no more than twofold increase in 2 weeks. To compensate for the limited proliferation ability in HS, we investigated the combinational effects of 12 factors [i.e., fibroblast growth factor(FGF)-2, insulin-like growth factor(IGF)-I, insulin, bone morphogenetic protein-2, parathyroid hormone, growth hormone, dexamethasone, 1alpha25-dihydroxy vitamin D3, L-3,3',5'-triodothyronine, interleukine-1 receptor antagonist, 17beta estradiol, and testosterone] on the proliferation of human auricular chondrocytes by analysis of variance in fractional factorial design. As a result, FGF-2, dexamethasone, insulin, and IGF-I possessed promotional effects on proliferation, while the combination of FGF-2 with insulin or IGF-I synergistically enhanced the proliferation. Actually, the chondrocytes increased 7.5-fold in number in 2 weeks in a medium containing 5% HS with 10 ng/ml FGF-2, while the cell number synergistically gained a 10-12-fold increase with 5 MUg/ml insulin or 100 ng/ml IGF-I in the same period. The proliferation effects were more enhanced at a concentration of 100 ng/ml for FGF-2, and especially for the combination of 100 ng/ml FGF-2 and 5 MUg/ml insulin (approximately 16-fold within 2 weeks). In the long-term culture with repeated passaging, this combination provided more than 10,000-fold within 8 weeks (i.e., passage 4). Thus, we concluded that such a combination of FGF-2 with insulin or IGF-I may be useful for promotion of auricular chondrocyte proliferation in a clinical application for cartilage regeneration. PMID- 28853947 TI - Article Commentary: Islet Xenotransplantation. PMID- 28853948 TI - Beneficial Effects of Hyperbaric Oxygen Therapy on Islet Transplantation. AB - We envisage that hyperbaric oxygen (HBO) would ameliorate islet anoxia, preventing early graft failure. Thus, treatment of HBO to diabetic recipients should improve the outcome of islet transplantation. We tested this hypothesis by syngeneically transplanting insufficient number of islets (150 islets) into streptozotocin-diabetic C57BL/6 mice, each followed by HBO (2.4 ATA, 100% O2) therapy for 1.5 h from day 0 to 28, once daily (group A) or twice daily (group B), or from day 5 to 28, once daily (group C) or twice daily (group D), 6 days/week. Recipients without HBO treatment served as controls. At day 28 after transplantation, groups B, C, and D gained weight and had lower blood glucose compared with their baseline values. In addition, groups B and D had higher insulin content of the graft than the controls. To determine the optimal timing of HBO therapy, groups B and D were compared with recipients treated with HBO twice daily, 6 days/week, from day -14 to 0 (group E) and from day -14 to 28 (group F). At day 28 after transplantation, groups B, D, E, and F had significantly lower blood glucose than their individual baseline values and higher insulin content of the graft than controls. But only group F had more beta cell mass of the graft than controls. These findings lend credence to the expectation that peritransplant application of adequate frequency of HBO to diabetic recipients would enhance the performance and growth of the islet graft, resulting in an improvement of the outcome of the transplantation. PMID- 28853949 TI - Changes in Mass and Performance in Rabbit Muscles after Muscle Damage with or without Transplantation of Primary Satellite Cells. AB - Changes in morphology, metabolism, myosin heavy chain gene expression, and functional performances in damaged rabbit muscles with or without transplantation of primary satellite cells were investigated. For this purpose, we damaged bilaterally the fast muscle tibialis anterior (TA) with either 1.5 or 2.6 ml cardiotoxin 10-5 M injections. Primary cultures of satellite cells were autotransplanted unilaterally 5 days after muscle degeneration. Two months postoperation, the masses of damaged TAs, with or without transplantation, were significantly larger than those of the controls. Furthermore, damaged transplanted muscles weighed significantly more than damaged muscles only. The increase in muscle mass was essentially due to increased fiber size. These results were independent of the quantity of cardiotoxin injected into the muscles. Maximal forces were similar in control and 2.6 ml damaged TAs with or without satellite cell transfer. In contrast, 1.5 ml damaged TAs showed a significant decrease in maximal forces that reached the level of controls after transplantation of satellite cells. Fatigue resistance was similar in control and 1.5 ml damaged TAs independently of satellite cell transfer. Fatigue index was significantly higher in 2.6 ml damaged muscles with or without cell transplantation. These changes could be explained in part by muscle metabolism, which shifted towards oxidative activities, and by gene expression of myosin heavy chain isoforms, which presented an increase in type IIa and a decrease in type I and IIb in all damaged muscles with or without cell transfer. Under our experimental conditions, these results show that muscle damage rather than satellite cell transplantation changes muscle metabolism, myosin heavy chain isoform gene expression, and, to a lesser extent, muscle contractile properties. In contrast, muscle weight and fiber size are increased both by muscle damage and by satellite cell transfer. PMID- 28853950 TI - Health Halo Effects from Product Titles and Nutrient Content Claims in the Context of "Protein" Bars. AB - Research on front-of-package (FOP) labeling demonstrates that nutrient content claims (e.g., "low fat") can lead consumers to perceive foods as healthier in general-effects that have been interpreted using halo effect theories of impression formation. Extending this work, the present study investigates whether these effects may depend on whether nutrient information comes in the form of a nutrient content claim ("good source of protein") or embedded within the product title itself ("protein" bar)-an important question given the popularity of energy/nutrition bars and ongoing policy debates over food-labeling regulation. Results from a between-subjects experiment (n = 274) revealed that although both conditions increased perceived protein content for a nutritional bar, only the product title condition increased overall perceptions of product healthfulness-an effect mediated by increased perceptions of additional non-claimed "healthy" nutrients (fiber, iron). Finally, although the presence of a traffic light warning label increased perceived sugar and calorie content, it did not counteract the effect of the product title on perceived healthfulness. We conclude with a discussion focused on implications for policy and health halo effects in the context of food labeling. PMID- 28853951 TI - Corrigenda. PMID- 28853952 TI - Perceptions of asthma and exercise in adolescents with and without asthma. AB - OBJECTIVE: To elicit the views of adolescents, with and without asthma, about exercise and asthma, and the perceived benefits of and barriers to participation. The adolescent views elicited would subsequently inform the design of a high intensity exercise intervention to improve asthma control. METHODS: Fifty-four adolescents (age 13.1 +/- 0.9 years; 26 with asthma) participated in twelve semi structured group interviews. Questions were structured around knowledge, attitudes and beliefs towards asthma and its impact on exercise participation and lifestyle. The interviews were transcribed verbatim, thematically analysed and presented via diagrams of emergent themes. Ethical approval was granted by the institutional research ethics committee. RESULTS: Fear of an asthma attack emerged as the main barrier to exercise, with many adolescents with asthma withdrawing from exercise as a coping strategy; many healthy adolescents perceived this withdrawal as laziness or an excuse. Despite this, the majority (81%) of adolescents with asthma reported exercise to be their most enjoyable activity. Adolescents suggested incorporating mixed activities, such as team games (e.g., rounders, football, netball), for future interventions to ensure adherence. CONCLUSIONS: Whilst exercise is important in the management of asthma, the tendency of those with asthma to withdraw from exercise to avoid adverse events could be addressed through a games-based high-intensity exercise intervention. Furthermore, educating all adolescents on asthma could simultaneously reduce stigmatisation and enhance exercise engagement. PMID- 28853953 TI - Toilet Talk: Eliminating Open Defecation and Improved Sanitation in Nepal. AB - Globally, 2.4 billion people lack adequate sanitation, and open defecation remains common. In this article, I present the qualitative findings from an evaluation of a water, sanitation, and hygiene intervention in remote, mid-West Nepal. The evaluation, conducted in 2014, involved villagers from eight wards in Kotgaun Village Development Committee. Drawing on the concept of the "toilet tripod," I argue as follows: multi-scalar political will provide an important foundation for construction and sustained use of toilets, proximate social pressures contributed significantly to toilet adoption and efforts to eliminate open defecation, and water insecurity constrained improved sanitation and hygiene. PMID- 28853954 TI - Correction to: Langer et al., Menopausal hormone therapy for primary prevention: why the USPSTF is wrong. PMID- 28853955 TI - Lexical tone and stuttering in Cantonese. AB - Cantonese is a tone language, in which the variation of the fundamental frequency contour of a syllable can change meaning. There are six different lexical tones in Cantonese. While research with Western languages has shown an association between stuttering and syllabic stress, nothing is known about whether stuttering in Cantonese speakers is associated with one or more of the six lexical tones. Such an association has been reported in conversational speech in Mandarin, which is also a tone language, but which varies markedly from Cantonese. Twenty-four native Cantonese-speaking adults who stutter participated in this study, ranging in age from 18-33 years. There were 18 men and 6 women. Participants read aloud 13 Cantonese syllables, each of which was produced with six contrastive lexical tones. All 78 syllables were embedded in the same carrier sentence, to reduce the influence of suprasegmental or linguistic stress, and were presented in random order. No significant differences were found for stuttering moments across the six lexical tones. It is suggested that this is because lexical tones, at least in Cantonese, do not place the task demands on the speech motor system that typify varying syllabic stress in Western languages: variations not only in fundamental frequency, but also in duration and intensity. The findings of this study suggest that treatments for adults who stutter in Western languages, such as speech restructuring, can be used with Cantonese speakers without undue attention to lexical tone. PMID- 28853956 TI - New and emerging targeted systemic therapies: a new era for atopic dermatitis. AB - PURPOSE: This is a review of emerging targeted, systemic therapies for atopic dermatitis (AD). The information presented aims to provide dermatologists with updated therapeutic options, stimulate academic interest, and spark future research. MATERIAL AND METHODS: Extensive search of ClinicalTrials.gov, the National Eczema Association, and PubMed was performed for clinical trials examining the effect of emerging targeted, systemic therapies in patients with AD. Results were included if they demonstrated efficacy in reversing AD symptoms. Studies that did not demonstrate clinical benefit were excluded. RESULTS: A number of emerging systemic agents targeting specific mediators involved in the pathogenesis of AD were found. These targets include IL-4, IL-13, IgE, B-cells, IL-5, IL-31, JAK-STAT, SYK, IL-6, PDE-4, IL-12, IL-17, IL-23, IL-22, H4R, NKR1, kappaOR, TSLP, PPAR-gamma, and DGLA. Treatment of AD patients with these therapies has, in many cases, led to statistically significant improvements in clinical severity scores and patient-reported outcomes. CONCLUSIONS: While multiple agents have demonstrated efficacy, only dupilumab is currently approved for adults with AD. Large-scale, randomized, placebo-controlled, double-blind trials, especially in children, are needed. As we enter the dawn of targeted therapy for AD, a comprehensive clinical trial registry is needed to facilitate data pooling and comparison among international registries. PMID- 28853957 TI - Reducing emergency department visits utilizing a primary care asthma specialty clinic in a high-risk patient population. AB - OBJECTIVE: Asthma is a leading cause of pediatric emergency department (ED) use. Optimizing asthma outcomes is a goal of Nationwide Children's Hospital (NCH) and its affiliated Accountable Care Organization. NCH's Primary Care Network, comprised of 12 offices serving a predominantly Medicaid population, sought to determine whether an Asthma Specialty Clinic (ASC) operated within a single primary care office could reduce ED asthma rates and improve quality measures, relative to all other network offices. METHODS: An ASC was piloted with four components: patient monitoring, provider continuity, standardized assessment, and multi-disciplinary education. A registry was established to contact patients at recommended intervals. At extended-length visits, a general pediatrician evaluated patients and a multi-disciplinary team provided education. Novel educational tools were utilized, guideline-based templates recorded and spirometry obtained. ED asthma rate, spirometry utilization, and controller fills by intervention office patients were compared to all other network offices before and after ASC initiation. RESULTS: At baseline, asthma ED visits by intervention and usual care populations were similar (p = 0.43). After, rates were significantly lower for intervention office patients versus usual care office patients (p < 0.001), declining in the intervention population by 26.2%, 25.2%, and 31.8% in 2013, 2014, and 2015, respectively, from 2012 baseline, versus increases of 3.8%, 16.2%, and 9.5% in the usual care population. Spirometry completion, controller fills, and patients with favorable Asthma Medication Ratios significantly increased for intervention office patient relative to the usual care population. CONCLUSIONS: A primary care-based asthma clinic was associated with a significant and sustainable reduction in ED utilization versus usual care. What's new: This study describes a comprehensive, multi-disciplinary, and innovative model for an asthma management program within the medical home that demonstrated a significant reduction in ED visits, an increase in spirometry utilization, and an increase in controller fills in a high-risk asthma population versus comparison group. PMID- 28853958 TI - Meditation for asthma: Systematic review and meta-analysis. AB - OBJECTIVE: To conduct a comprehensive review and meta-analysis of the effectiveness of meditation on a variety of asthma outcomes. METHODS: We searched MEDLINE, EMBASE, CINAHL, PsycINFO and AMED in June 2016 to identify randomized controlled trials (RCTs) investigating the effectiveness of meditation in adults with asthma. No restriction was put on language or year of publication. Study quality was assessed using The Cochrane Risk of Bias Assessment Tool. Meta analysis was carried out using RevMan 5.3. RESULTS: Four RCTs involving 201 patients met the inclusion criteria. Quality of studies was inconsistent with only one study reporting adequate allocation concealment. Disease-specific quality of life was assessed in two trials; a pooled result involving 62 intervention and 65 control participants indicated a significant improvement in quality of life in the meditation group compared to the control group (SMD 0.40, 95% CI 0.05-0.76). A pooled result from all four studies indicated the uncertain effect of meditation in forced expiratory volume in 1 s (FEV1) (SMD -0.67, 95% CI -2.17 to 0.82). Results from the individual trials suggest that meditation may be helpful in reducing perceived stress and the use of short-term rescue medication. CONCLUSION: Our review suggests that there is some evidence that meditation is beneficial in improving quality of life in asthma patients. As two out of four studies in our review were of poor quality, further trials with better methodological quality are needed to support or refute this finding. PMID- 28853959 TI - Association between asthma and falls: A nationwide population-based study. AB - OBJECTIVES: We evaluated the relationship between asthma and falls in Koreans using data from a large population-based cross-sectional survey. METHODS: Data were obtained from 228,642 participants, of whom 6,372 had asthma, who participated in the 2013 Korean Community Health Survey. We explored the risk of falls after adjusting for sociodemographic factors and comorbidities. Logistic regression was used to identify risk factors for falls in asthmatics. Patients with asthma who had been diagnosed by a physician were included after excluding those who did not respond to the self-reported questionnaire. RESULTS: In all, 1,733/6,372 (27.1%) asthma patients and 258/788 (32.7%) patients with uncontrolled asthma (who had visited the emergency room because of asthma exacerbation in the prior 12 months) reported histories of falls. In asthmatics, the crude odds ratio (OR) for falls was 1.57 (95% confidence interval [CI]: 1.48 1.67); the OR for falls in the group with uncontrolled asthma was 2.13 (95% CI: 1.83-2.47). The multivariate OR for falls in the asthma group (compared to the non-asthma group) was 1.27 (95% CI, 1.18-1.35) and the OR for falls in the uncontrolled asthma group (again compared to the non-asthma group) was 1.55 (95% CI, 1.32-1.82). Subgroup analysis of the adjusted ORs for falls in asthmatics by age group revealed a significant difference between the presence of asthma and uncontrolled asthma, and falls, in each age group, similar to the relationship evident in the total adult population. CONCLUSION: Asthma is associated with falls, even after adjusting for sociodemographic and comorbid variables. PMID- 28853960 TI - Skin hyperpigmentation treatment using herbs: A review of clinical evidences. AB - Hyperpigmentation of skin is caused by several factors. UV exposure, in addition to oxidative stress, elevates inflammatory mediators stimulating melanogenesis. Herbal-derived compounds for improving skin lightness are gaining interest as they are perceived to be milder, safer, and healthier than fully synthetic products. This review briefly addresses the causes of skin hyperpigmentation and extensively summarizes the status of herbs currently used in skin-lightening cosmetics. The properties of active compounds and their dose rate information are summarized where available, along with human or animal relevant models for activity testing. This review will be of value to cosmetic formulators and dermatologists who are searching for naturally derived ingredients for improving skin lightness, in line with consumer preference and expectations. PMID- 28853961 TI - Punctal Ectropion repair using the Raus-Garito clamp. AB - PURPOSE: To evaluate the results from the correction of ectropion of the punctum lacrimale in lower eyelids with a new surgical clamp. DESIGN: Prospective study. METHODS: Eighty eight eyelids in 55 patients with mild and moderate ectropion were included in the study. An excision of a diamond of tarso-conjunctiva with retractor reattachment and concomitant correction of horizontal lid laxity, if present, was performed. RESULTS: Resolution of tearing was obtained in 77 eyes. In 11 eyes, persistent tearing was reported. CONCLUSION: Conclusion:Conclusion: Repair of early to intermediate ectropion of the lacrimal punctum using the Raus Garito clamp is associated with a good functional and cosmetic outcome. PMID- 28853962 TI - Unlocking design potential: Design with people diagnosed with schizophrenia. AB - With the expansion of e-health systems to more diverse and heterogeneous contexts and user groups, it is increasingly important to include users in design. Designers recognize the benefits of user participation, but including users with lowered cognitive and social abilities can be difficult. This paper intends to answer how these users can participate in the design of e-health systems. We conducted a case study with stakeholder interviews and design workshops with users diagnosed with schizophrenia to identify and overcome the challenges for participation. From the stakeholder interviews, we identified challenges relating to social interaction, technical experience, cognitive ability, and loss of individuality. We designed workshops that addressed these challenges and identify five strategies for unlocking the design potential of the participants: (1) work together with concrete materials and examples; (2) maintain a positive focus; (3) accept all ideas; (4) maintain and require realism; and (5) use previous interaction. We conclude that, when supported appropriately, it is possible to involve people diagnosed with schizophrenia. We also highlight the difficulty for someone not self-experienced to understand contexts as challenging and sensitive as this, and thus the value of user participation. PMID- 28853963 TI - Time for new low density lipoprotein cholesterol (LDL-C) targets? PMID- 28853965 TI - Correction to: Andron, Hostovsky, Nair, Sagiv, Schiby, and Ben-Simon, The impact of IgG-4-ROD on the diagnosis of orbital tumors: A retrospective analysis. PMID- 28853964 TI - "The influence of orbital vector on involutional entropion and ectropion". AB - PURPOSE: This study aimed to evaluate the effect of orbital vector and other biometric parameters (i.e. axial globe length, axial globe projection) on the development of involutional entropion or ectropion. METHODS: In this cross sectional study, 167 eyes from 132 patients were included. Of these eyes, 128 had involutional entropion and 39 had involutional ectropion, all of lower lids. The axial globe projection was measured using Hertel exophthalmometry; axial globe length was assessed by A-mode ultrasound; and orbital vector was determined clinically. Patient-specific categorical variables and continuous variables were compared using the chi-square test and the two-sided t test, respectively. Correlations were derived using the Pearson correlation. RESULTS: The percentage of females was 59% and 33.3% in the entropion group and in the ectropion group, respectively. A significant association was found between the gender and type of eyelid malposition (p = 0.015). Exophthalmometry reading was greater in the ectropion group than in the entropion group (17.7 +/- 2.5 versus 10.8 +/- 3.7 mm, respectively; p < 0.001). There was no significant correlation between axial globe length and exophthalmometry reading. Positive orbital vectors were observed in 87.5% of eyelids with involutional entropion. Negative orbital vectors were observed in 92.3% of eyelids with involutional ectropion (p < 0.001). Patients with negative orbital vectors showed greater axial globe projection than patients with positive orbital vectors (18.0 +/- 2.1 versus 10.6 +/- 3.5 mm, respectively; p < 0.001). CONCLUSIONS: There is an association between orbital vector measurement and involutional entropion and ectropion. Measuring the orbital vector may help predict the development of these lid malpositions. PMID- 28853966 TI - What we can learn from naming errors of children with language impairment at preschool age. AB - Naming is a complex, multi-level process. It is composed of distinct semantic and phonological levels. Children with naming deficits produce different error types when failing to retrieve the target word. This study explored the error characteristics of children with language impairment compared to those with typical language development. 46 preschool children were tested on a naming test: 16 with language impairment and a naming deficit and 30 with typical language development. The analysis compared types of error in both groups. In a group level, children with language impairment produced different error patterns compared to the control group. Based on naming error analysis and performance on other language tests, two case studies of contrasting profiles suggest different sources for lexical retrieval difficulties in children. The findings reveal differences between the two groups in naming scores and naming errors, and support a qualitative impairment in early development of children with naming deficits. The differing profiles of naming deficits emphasise the importance of including error analysis in the diagnosis. PMID- 28853967 TI - Labial tissue rejuvenation and sexual function improvement using a novel noninvasive focused monopolar radio frequency device. AB - INTRODUCTION: With aging, the vulvar tissue loses its vitality and elasticity due to collagen fibers fatigue. Such changes and functional characteristics of the external genitalia often cause negative psychological effects resulting in impeded sexual function. The objective of this study is to evaluate the safety and efficacy of a radio frequency (RF) device when used for treating labial laxity and for improvement of female sexual fuction. MATERIALS AND METHODS: Using a monopolar RF device, 19 women received four once-a-week treatments. Images taken at the baseline and at the 1-month follow-up were evaluated for improvement in vulvar appearance on a scale of 0-3. The female sexual function index (FSFI) scores were calculated and compared between the baseline, the 1-month follow-up visit, and the 12-month follow-up visit. RESULTS: Average improvement in the vulvar appearance according to the patients and the physician was 2.00 +/- 0.58 and 1.79 +/- 0.54, respectively. Both values represent "moderate change" according to the applied scale. The average FSFI increased by 9.79 +/- 4.35 and 7.10 +/- 5.17 when comparing the baseline to the 1-month and the 12-month follow up, respectively. No adverse events were reported. DISCUSSION: Efficacy and safety of the investigated device were proven. Longevity of results was proven by the 12-month follow-up. PMID- 28853968 TI - Evaluation of autologous platelet-rich plasma plus ablative carbon dioxide fractional laser in the treatment of acne scars. AB - INTRODUCTION: Acne scar is a common distressing complication of acne vulgaris. CO2 laser resurfacing proved effective for the treatment of this problem, but the associated complications may limit its use. Platelet-rich plasma (PRP) may increase the chance of favorable outcome. AIM OF THE WORK: To evaluate the synergistic effects of autologous PRP with fractional CO2 laser resurfacing in the treatment of acne scars among Egyptian patients. PATIENTS AND METHOD: This study included 30 patients suffering from post-acne scars. CO2 laser treatment was applied to both sides of the face followed by PRP injection for the right side. Evaluation was carried out through operating physicians, two blinded physicians as well as through patient's satisfaction. RESULT: The right side of the face (PRP-treated side) achieved excellent improvement in 13.3% of the patients, while there was no excellent improvement on the left side. CONCLUSION: Combination of fractional CO2 laser resurfacing and intradermal PRP was superior to CO2 laser alone for acne scar treatment. PMID- 28853969 TI - The active engagement model of applied ethics as a structure for ethical reflection in the context of course-based service learning. AB - PURPOSE: The purpose of this case report is to explore the active engagement model as a tool to illuminate the ethical reflections of student physical therapists in the context of service learning in a developing country. METHODS: The study participants were a convenience sample of six students. The study design is a case report using a phenomenological perspective. Data were collected from students' narrative writing and semi-structured interviews. The steps of the active engagement model provided the structural framework for student responses. The analysis process included open coding, selective coding, and member checking. RESULTS: Results showed the emergence of two main themes: 1) gathering rich detail and 2) developing independent moral identity. Students' descriptions of their relationships were detailed and included explanations about the complexities of the sociocultural context. Independent and deliberate agency was evident by the students' preparedness to be collaborative, to raise ethical questions, to identify ethically important aspects of their practice and to describe their professional roles. The students noted that the use of the model increased their engagement in the ethical decision-making process and their recognition of ethical questions. CONCLUSIONS: This case report illustrates attributes of the active engagement model which have implications for teaching ethical reflection: scaffolding for ethical reflection, use of narrative for reflection, reflection in action, and illumination of relevant themes. Each of these attributes leads to the development of meaningful ethical reflection. The attributes of this model shown by this case report have potential applications to teaching ethical reflection. PMID- 28853970 TI - Primary Care Physicians' Views about Prescribing Methadone to Treat Opioid Use Disorder. AB - BACKGROUND: Methadone maintenance treatment is an effective way to reduce harms associated with opioid use disorder and, in several countries, is delivered in community-based primary care settings. Expanding methadone into primary care depends, in part, on physicians' willingness and readiness to integrate it into their practices. OBJECTIVES: This qualitative study explores factors that primary care physicians consider important when contemplating prescribing methadone to treat opioid use disorder. METHODS: In-depth interviews were conducted during 2015 with 20 primary care physicians in various sized communities throughout Nova Scotia, Canada. Participants shared their views and experiences related to prescribing methadone to treat opioid use disorder. Data were analyzed inductively using thematic analysis to identify predominant themes. RESULTS: Participants discussed an interplay of factors as they contemplated prescribing methadone to treat opioid use disorder in primary care. Physician-related factors included access to methadone expertise, support from allied professionals, suitability of skills, and personal experiences. Patient-related factors involved perceptions about methadone users as a difficult patient group with highly complex needs. Practice-related factors encompassed concerns about threats to physicians' careers, surveillance duties, unfair remuneration, safety risks, and practice disruptions. Contextual factors included knowledge deficits about substance use disorders, the generalist nature of primary care, methadone's socio political context, and opioid prescribing patterns in primary care. CONCLUSIONS: Understanding the perspectives of physicians is vital to expanding methadone into primary care. This study identifies factors that should be addressed to attract, support, and retain primary care physicians in prescribing methadone to treat opioid use disorder. PMID- 28853971 TI - Improved parental attitudes and beliefs through stepwise perinatal vaccination education. AB - This study examined the effects of providing vaccination education during the perinatal period on Japanese parents' knowledge, attitudes, and beliefs about childhood vaccination. A cluster-randomized controlled-trial method was used on a sample of 160 pregnant women recruited from 9 obstetrical sites in Niigata, Japan. The treatment group received a stepwise interactive education intervention, while the control group received a general vaccination leaflet. Changes in parental attitudes toward and beliefs about infant vaccination were assessed on the child's one-month and 6-month birthdays using paper questionnaires. Of the initial 188 participants, 160 (90.4%) completed the final post-survey questionnaire. Scores on injunctive social norms (a morally neutral perception of the behavior of the majority) and descriptive social norms (a moral perception of what individuals should do) significantly increased in the treatment group (p = .02 and p = .01, respectively). There was a significant difference between the 2 groups over time in terms of perceived benefit (efficacy of available preventive actions) (p = .03), but no significant differences in perceived severity (seriousness of a disease outcome), perceived susceptibility (likelihood of getting a disease), perceived benefits, perceived behavioral control, or descriptive social norms between the groups at any time point or in the patterns of change over time (p > .31). Thus, stepwise perinatal vaccination education was found to positively influence maternal attitudes and beliefs about infant vaccination. This study suggests the importance of vaccination education during the perinatal period. PMID- 28853972 TI - Programmed cell death 4 mechanism of action: The model to be updated? AB - Programmed cell death 4 (Pdcd4) is frequently suppressed in tumors of various origins and its suppression correlates with tumor progression. Pdcd4 inhibits cap dependent translation from mRNAs with highly structured 5'-regions through interaction with the eukaryotic translation initiation factor 4A (eIF4A) helicase and a target transcript. Decrease in Pdcd4 protein is believed to provide a relief of otherwise suppressed eIF4A-dependent translation of proteins facilitating tumor progression. However, it remains unknown if lowered Pdcd4 levels in cells suffices to cause a relief in translation inhibition through appearance of the Pdcd4-free translation-competent eIF4A protein, or more complex and selective mechanisms are involved. Here we showed that eIF4A1, the eIF4A isoform involved in translation, significantly over-represents Pdcd4 both in cancerous and normal cells. This observation excludes the possibility that cytoplasmic Pdcd4 can efficiently exert its translation suppression function owing to excess of eIF4A, with Pdcd4-free eIF4A being in excess over Pdcd4-bound translation-incompetent eIF4A, thus leaving translation from Pdcd4 mRNA targets unaffected. This contradiction is resumed in the proposed model, which supposes initial complexing between Pdcd4 and its target mRNAs in the nucleus, with subsequent transport of translation-incompetent, Pdcd4-bound target mRNAs into the cytoplasm. Noteworthy, loss of nuclear Pdcd4 in cancer cells was reported to correlate with tumor progression, which supports the proposed model of Pdcd4 functioning. PMID- 28853974 TI - The Impact of Individual-Level Social Capital in Non-Medical use of Pain Medications Among Individuals 50 Years or Older from Diverse Racial/Ethnic Backgrounds. AB - OBJECTIVES: In 2014, there were 21.5 million Americans (12 years old or older) that had a substance abuse disorder and almost 2 million of them had a substance use disorder involving prescription pain relievers (SAMHSA, 2014). The misuse of non-medical pain medication (NMPM) is a significant public health problem. This study examines the impact of individual-level social capital in non-medical use of pain medications (NMPM) among individuals 50 years or older. METHODS: Data from the 2003 National Survey on Drug Use and Health (n = 11,146) was analyzed using bivariate analysis and logistic regression analysis. RESULTS: Perception of social capital varied by race/ethnicity; White respondents reported the highest rates of non-medical use of pain medications (NMPM) in the past year and lifetime. Social capital was associated with a decrease in the likelihood of NMPM across the various groups in the sample. DISCUSSION: Features of social capital were associated with likelihood of non-medical use of pain medications. Future research should focus on understanding the mechanisms by which these features of social capital impact NMPM among diverse groups. PMID- 28853973 TI - Decoding telomere protein Rap1: Its telomeric and nontelomeric functions and potential implications in diabetic cardiomyopathy. AB - Mammalian Rap1, the most conserved telomere-interacting protein, beyond its role within nucleus for the maintenance of telomeric functions, is also well known for its pleiotropic functions in various physiological and pathological conditions associated with metabolism, inflammation and oxidative stress. For all these, nowadays Rap1 is the subject of critical investigations aimed to unveil its molecular signaling pathways and to scrutinize the applicability of its modulation as a promising therapeutic strategy with clinical relevance. However, the underlying intimate mechanisms of Rap1 are not extensively studied, but any modulation of this protein level has been associated with pathologies like inflammation, oxidative stress and deregulated metabolism. This is considerably important in light of the recent discovery of Rap1 modulation in diseases like cancer and cardiac metabolic disorders. In this review, we focus on both the telomeric and nontelomeric functions of Rap1 and its modulation in various health risks, especially on the heart. PMID- 28853975 TI - Impact of a website based educational program for increasing vaccination coverage among adolescents. AB - Data regarding the use of technology to improve adolescent knowledge on vaccines are scarce. The main aim of this study was to evaluate whether different web based educational programmes for adolescents might increase their vaccination coverage. Overall, 917 unvaccinated adolescents (389 males, 42.4%; mean age +/- standard deviation, 14.0 +/- 2.2 years) were randomized 1:1:1 into the following groups: no intervention (n = 334), website educational program only (n = 281), or website plus face to face lesson (n = 302) groups. The use of the website plus the lesson significantly increased the overall knowledge of various aspects of vaccine-preventable disease and reduced the fear of vaccines (p < 0.001). A significant increase in vaccination coverage was observed for tetanus, diphtheria, acellular pertussis and conjugated meningococcal ACYW vaccines in the 2 groups using the website (p < 0.001), and better results were observed in the group that had also received the lesson; in this last group, significant results were observed in the increase in vaccination coverage for meningococcal B vaccine (p < 0.001). Overall, the majority of the participants liked the experience of the website, although they considered it important to further discuss vaccines with parents, experts and teachers. This study is the first to evaluate website based education of adolescents while considering all of the vaccines recommended for this age group. Our results demonstrate the possibility of increasing vaccination coverage by using a website based educational program with tailored information. However, to be most effective, this program should be supplemented with face-to-face discussions of vaccines at school and at home. Thus, specific education should also include teachers and parents so that they will be prepared to discuss with adolescents what is true and false in the vaccination field. PMID- 28853976 TI - Generation of genome-modified Drosophila cell lines using SwAP. AB - The ease of generating genetically modified animals and cell lines has been markedly increased by the recent development of the versatile CRISPR/Cas9 tool. However, while the isolation of isogenic cell populations is usually straightforward for mammalian cell lines, the generation of clonal Drosophila cell lines has remained a longstanding challenge, hampered by the difficulty of getting Drosophila cells to grow at low densities. Here, we describe a highly efficient workflow to generate clonal Cas9-engineered Drosophila cell lines using a combination of cell pools, limiting dilution in conditioned medium and PCR with allele-specific primers, enabling the efficient selection of a clonal cell line with a suitable mutation profile. We validate the protocol by documenting the isolation, selection and verification of eight independently Cas9-edited armadillo mutant Drosophila cell lines. Our method provides a powerful and simple workflow that improves the utility of Drosophila cells for genetic studies with CRISPR/Cas9. PMID- 28853978 TI - Air Travel at the End of Life #338. PMID- 28853979 TI - The Effect of Atorvastatin on Vascular Function and Structure in Young Adult Survivors of Childhood Cancer: A Randomized, Placebo-Controlled Pilot Clinical Trial. AB - PURPOSE: Many adult survivors of childhood cancer are at high-risk of developing cardiovascular disease. Cancer therapy may cause damage to the vascular endothelium, thereby initiating atherosclerosis. Atorvastatin has been shown to improve endothelial function independent of reducing cholesterol, as well as reduce/slow arterial stiffness and thickening, yet has never been studied in childhood cancer survivors (CCS). METHODS: Twenty-seven young adult (age 26.8 +/- 6.2 years) survivors of childhood acute lymphoblastic leukemia or Non-Hodgkin's lymphoma were randomly assigned (1:1) 40 mg/day of atorvastatin or placebo for 6 months. Brachial artery flow-mediated dilation (FMD), small artery reactive hyperemia index (RHI), arterial stiffness, and carotid artery elasticity/thickness were assessed. RESULTS: Fifteen participants completed the trial. No significant treatment effect for any vascular outcomes was observed at 6 months; however, a significant decrease in peak FMD (-3.0 [95% confidence interval [CI]: -5.3, -0.7]) and a trending significant decrease in RHI (-0.3 [95% CI: -0.62, 0.01]) was observed in the placebo group, resulting in a trend toward a treatment effects (p < 0.10). No effect on arterial stiffness, carotid arterial elasticity, or thickness was observed. CONCLUSION: Six months of atorvastatin treatment did not improve endothelial function or arterial stiffness in young adult CCS. While a trend toward an improvement in endothelial function was present, findings should be interpreted with caution owing to the small number of evaluable participants and subsequent lack of sufficient power. Further research in a larger sample size is needed to fully elucidate the effects of atorvastatin on vascular function. Trial registered at clinicaltrials.gov as NCT01733953. PMID- 28853977 TI - Immunotherapy of house dust mite allergy. AB - House dust mite (HDM) is a predominant source of indoor aeroallergen worldwide, which induces allergic diseases including allergic rhinoconjunctivitis, allergic asthma, atopic eczema and other allergic skin diseases. Allergen specific immunotherapy (AIT) is the only potential disease-modifying treatment of HDM allergic subjects. However, AIT remains underused due to no universally accepted allergen standardization and a shortage of rigorous clinical studies to confirm safety and efficacy. With the effort of doctors and researchers in allergy field, efficacy, safety, standardization and strategy of AIT are being continuously developed. This review presents the updated research based on recently published trials and meta-analyses. PMID- 28853982 TI - Outcomes of two surgical techniques for major trichiasis treatment. AB - The purpose of this article is to analyze the outcomes of two surgical techniques to treat major trichiasis. A retrospective chart review of 67 patients (89 eyelids) with major trichiasis was performed who underwent surgical treatment using one of two techniques: intermarginal split lamella with graft (ISLG group) or lid lamella resection (LLR group). There were 30 lids in the ISLG group with mean patient age of 71.8 years and 63.3% were females. There were 59 lids in the LLR group with mean patient age of 72.5 years and 52.5% were female. The minimum postoperative follow up was six months. Statistical analysis included descriptive measures, Goodman association test for contrasts between and within multinomial populations and nonparametric Mann-Whitney test for comparison between groups. P < 0.05 was considered statistically significant. The underlying causes of trichiasis were blepharitis (37.07%), chronic meibomitis (21.3%), multiple causes (20.2%), ectropion (11.2%), actinic keratosis (6.7%), or prior ocular surgery (3.3%). Postoperatively, in the ISLG group, there were 20% lids with complete success, 50% underwent laser or electrolysis, 16.7% required further surgery, and 13.3% were unsuccessful. Postoperatively, in the LLR group, there were 47.5% eyelids with complete success, 46.7% underwent laser or electrolysis, 6.8% required further surgery, and 5.1% were unsuccessful. There was a higher statistical chance of complete success with LLR (P < 0.05). LLR is superior to ISLG surgery for the treatment of major trichiasis. There is a greater chance of success with LLR and it is technically simpler. PMID- 28853980 TI - Approaching a decade since HPV vaccine licensure: Racial and gender disparities in knowledge and awareness of HPV and HPV vaccine. AB - : Purpose: Gaps remain in the public's knowledge of the human papillomavirus (HPV). We assessed racial/ethnic and gender disparities in knowledge and awareness of HPV and the HPV vaccine among US adults. METHODS: Data from the Health Information National Trends Survey 4 Cycle 3 (September - December 2013) and Cycle 4 (August - November 2014) were analyzed for 6,862 respondents aged 18 years and older. Weighted multivariable logistic regression models were used to estimate racial/ethnic and gender disparities in HPV knowledge and HPV vaccination awareness. RESULTS: Sixty-six percent of respondents had heard of HPV and the HPV vaccine (57% of men vs. 75% of women). In multivariable analyses, compared with men, women were 225% (95% CI: 2.60 - 4.07) more likely to have heard of HPV, and 281% (95% CI: 3.06 - 4.74) more likely to have heard of the HPV vaccine. Non-Hispanic Blacks were 33% (95% CI: 0.47 - 0.96) and 44% (95% CI: 0.39 - 0.81) less likely than non-Hispanic Whites to have heard of HPV and the HPV vaccine, respectively. Hispanics were 27% (95% CI: 0.52 - 1.02) and 53% (95% CI: 0.34 - 0.64) less likely than non-Hispanic Whites to have heard of HPV and the HPV vaccine, respectively. CONCLUSIONS: There was evidence of disparities in HPV and HPV vaccine awareness among men compared with women and non-Hispanic Blacks and Hispanics compared with non-Hispanic Whites. To foster improvements in HPV vaccine uptake and reduce disparities in HPV associated cancers, future interventions must target men and minority populations, for whom knowledge gaps exist. PMID- 28853981 TI - Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway. AB - Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes. PMID- 28853983 TI - Identification of WEE1 as a target to make AKT inhibition more effective in melanoma. AB - AKT3 is one of the major therapeutic targets in melanoma but clinically targeting AKT3 alone seems to be an ineffective therapeutic approach. To identify unique strategies to enhance the efficacy of targeting AKT3, a screen was undertaken where AKT3 was co-targeted with a panel of kinases important in melanoma development. The screen identified WEE1 as the most potent target that when inhibited along with AKT3 would enhance the efficacy of targeting AKT3 in melanoma. RNAi mediated inhibition of AKT3 and WEE1 synergistically inhibited the viability of melanoma cells leading to a 65-75% decrease in tumor development. This approach was effective by mechanistically modulating pathways associated with the transcription factors p53 and FOXM1. Simultaneously regulating the activity of these two transcriptionally driven pathways, cooperatively deregulated cell cycle control and DNA damage repair to synergistically kill melanoma cells. This study uniquely identifies a potential approach to improve the efficacy of targeting AKT3 in melanoma. PMID- 28853986 TI - Erratum. PMID- 28853984 TI - Next generation immunotherapy for tree pollen allergies. AB - Tree pollen induced allergies are one of the major medical and public health burdens in the industrialized world. Allergen-Specific Immunotherapy (AIT) through subcutaneous injection or sublingual delivery is the only approved therapy with curative potential to pollen induced allergies. AIT often is associated with severe side effects and requires long-term treatment. Safer, more effective and convenient allergen specific immunotherapies remain an unmet need. In this review article, we discuss the current progress in applying protein and peptide-based approaches and DNA vaccines to the clinical challenges posed by tree pollen allergies through the lens of preclinical animal models and clinical trials, with an emphasis on the birch and Japanese red cedar pollen induced allergies. PMID- 28853985 TI - A Moraxella catarrhalis vaccine to protect against otitis media and exacerbations of COPD: An update on current progress and challenges. AB - Moraxella catarrhalis is a major cause of morbidity and mortality worldwide, especially causing otitis media in young children and exacerbations of chronic obstructive pulmonary disease in adults. This pathogen uses several virulence mechanisms to colonize and survive in its host, including adherence and invasion of host cells, formation of polymicrobial biofilms with other bacterial pathogens, and production of beta-lactamase. Given the global impact of otitis media and COPD, an effective vaccine to prevent M. catarrhalis infection would have a huge impact on the quality of life in both patient populations by preventing disease, thus reducing morbidity and health care costs. A number of promising vaccine antigens have been identified for M. catarrhalis. The development of improved animal models of M. catarrhalis disease and identification of a correlate of protection are needed to accelerate vaccine development. This review will discuss the current state of M. catarrhalis vaccine development, and the challenges that must be addressed to succeed. PMID- 28853988 TI - Family Consumer Behaviors, Adolescent Prediabetes and Diabetes in the National Health and Nutrition Examination Survey (2007-2010). AB - BACKGROUND: Prediabetes or diabetes (characterized by hemoglobin A1c [HbA1c] levels >= 5.7 gm%) has been associated with numerous long-term complications. Family consumer behaviors are important risk factors that lead to impaired glucose tolerance or diabetes. However, few studies have studied the association between the family consumer environment and prediabetes and diabetes in adolescents. OBJECTIVE: The aim of this study was to examine the association between family consumer behaviors (healthy food availability and supermarket spending) and adolescent prediabetes and diabetes (ClinicalTrials.gov identifier #NCT03136289.) Methods: Data from a nationwide survey conducted by the Centers for Disease Control and Prevention (National Health and Nutrition Examination Survey [NHANES] 2007-2010 data) were used for these analyses. Adolescents aged 12 19 years were selected for this study. Bivariate analyses and logistic regression models assessed the relationship between family consumer behaviors and the prevalence of adolescent prediabetes and diabetes. Multivariable models adjusted for age, gender, ethnicity, physical activity, education, income, and household size. RESULTS: A total of 2520 adolescents were eligible for this study. Adolescents with healthier household food availability had negative odds (odds ratio [OR] = 0.74, 95% confidence interval [CI], 0.55-1.00), as did higher log supermarket spending (OR = 0.69; 95% CI, 0.57-0.85). Interaction models demonstrated that adolescent females had more negative odds of prediabetes/diabetes for both healthier food availability (OR = 0.79, 95% CI, 0.39-1.29) and for greater log supermarket spending (OR = 0.69, 95% CI, 0.57 0.85). CONCLUSION: This study shows that both healthy food availability and an increase in supermarket spending were associated with a decreased adjusted prevalence of prediabetes and diabetes in adolescents, with a greater effect in females. These results suggest the need for policy and dietary interventions targeting the consumer environment. PMID- 28853989 TI - Genomic Analysis and Resistance Mechanisms in Shigella flexneri 2a Strain 301. AB - Shigella flexneri is one of the most prominent pathogenic bacteria in developing countries. In the battle against shigellosis and other bacterial diseases, antibiotic resistance has become an increasing global public health threat. Although the serious phenomenon of multidrug resistance (MDR) has been identified as one of the top three burdens on human health, resistance mechanisms are still poorly understood at the molecular level. In this study, we analyzed genomic data and the evolution of resistance in Shigella flexneri under sequential selection stress from three separate antibiotics: ciprofloxacin (CIP), ceftriaxone (CRO), and tetracycline. Through whole-genome sequencing, 82 chromosomal antibiotic resistance genes were identified. Re-sequencing of the evolved populations identified single nucleotide polymorphisms (SNPs) that contributed to MDR and SNPs that were specific to a single drug. A total of 40 SNPs in 8 genes and 3 intergenic regions, including mutations in metG (L582R) and 1538924, 1538924, and 1538924, appeared under each antibiotic. Several nonsynonymous mutations in gyrB (S464Y), ydgA (E378A), rob (R156H), and narX (K75E) were observed under selective pressure from CIP or CRO. Based on a bioinformatic analysis and previous reports, we discuss the contribution of these mutated genes to resistance. Therefore, more circumspect selection and use of antimicrobial drugs for treating shigellosis is necessary. PMID- 28853987 TI - Forced degradation of recombinant monoclonal antibodies: A practical guide. AB - Forced degradation studies have become integral to the development of recombinant monoclonal antibody therapeutics by serving a variety of objectives from early stage manufacturability evaluation to supporting comparability assessments both pre- and post- marketing approval. This review summarizes the regulatory guidance scattered throughout different documents to highlight the expectations from various agencies such as the Food and Drug Administration and European Medicines Agency. The various purposes for forced degradation studies, commonly used conditions and the major degradation pathways under each condition are also discussed. PMID- 28853990 TI - Sub1 and RNAPII, until termination does them part. AB - Sub1 was initially identified as a coactivator factor with a role during transcription initiation. However, over the last years, many evidences showed that it influences processes downstream during mRNA biogenesis, such as elongation, termination, and RNAPII phosphorylation. The recent discover that Sub1 directly interacts with the RNAPII stalk adds new insights into how it achieves all these tasks. PMID- 28853991 TI - Determining Barriers to Use of Edible School Gardens in Illinois. AB - OBJECTIVE: The objective of this study was to gather data regarding the awareness, perceived benefits, interest in, and barriers to establishment of edible school gardens in Illinois public schools. METHOD: Setting/Design: This study used an online survey design. PARTICIPANTS: Participants included Illinois public elementary school principals and superintendents. VARIABLES MEASURED: Region and community population, current edible garden use, perception (Likert scale) of garden benefits, interest in establishment of a school edible garden, and barriers to establishment of a school edible garden were the variables of interest. ANALYSES: Logit regression and Kruskal-Wallis with follow-up where p < 0.05 were performed. RESULTS: Elementary school principals and superintendents are aware of gardens and their potential benefits to students, but many barriers exist that make their use challenging. Funding, staff and volunteer support, and class time were identified as the major barriers. Region affected likelihood of garden use, and community population size also affected the odds of having an edible school garden. CONCLUSION AND IMPLICATIONS: Data suggest that edible garden use would increase with provision of resources and organization of dedicated supporters. PMID- 28853993 TI - Constraints on Generality (COG): A Proposed Addition to All Empirical Papers. AB - Psychological scientists draw inferences about populations based on samples-of people, situations, and stimuli-from those populations. Yet, few papers identify their target populations, and even fewer justify how or why the tested samples are representative of broader populations. A cumulative science depends on accurately characterizing the generality of findings, but current publishing standards do not require authors to constrain their inferences, leaving readers to assume the broadest possible generalizations. We propose that the discussion section of all primary research articles specify Constraints on Generality (i.e., a "COG" statement) that identify and justify target populations for the reported findings. Explicitly defining the target populations will help other researchers to sample from the same populations when conducting a direct replication, and it could encourage follow-up studies that test the boundary conditions of the original finding. Universal adoption of COG statements would change publishing incentives to favor a more cumulative science. PMID- 28853992 TI - Effect of Incorporating Bay Leaves in Cookies on Postprandial Glycemia, Appetite, Palatability, and Gastrointestinal Well-Being. AB - BACKGROUND: Previous studies of patients with type 2 diabetes showed that capsules containing 1, 2, and 3 g of bay leaves lower fasting blood glucose, triglycerides, low-density lipoprotein cholesterol, and total cholesterol concentrations after 30 days of treatment. However, the acute effect of bay leaves on postprandial glycemic and appetite responses has not yet been determined. OBJECTIVE: The objective of this study was to determine the effect of cookies containing different doses of bay leaves on postprandial glycemia, appetite, palatability, and gastrointestinal well-being in healthy subjects. METHODS: In a randomized crossover study, 20 subjects consumed 3 test foods each providing 50 g of available carbohydrates. The test foods were provided as breakfast, 1-2 weeks apart, and were control cookies (CC) made from 100% wheat flour, cookies containing 3% (w/w) bay leaf powder (B3), and cookies containing 6% (w/w) bay leaf powder (B6). Blood glucose, subjective appetite, and gastrointestinal well-being were assessed at fasting and postprandially for 2 hours. Palatability of the test cookies was measured using 9-point hedonic scale. RESULTS: There was a significant effect of time (p < 0.001), treatment (p = 0.033), and Time * Treatment interaction (p = 0.001) on postprandial blood glucose concentrations. Post hoc pairwise comparison showed that blood glucose concentration was significantly reduced by B6 compared to CC at 30 and 45 minutes (p = 0.014 and p = 0.010, respectively). However, there were no significant differences (p = 0.411) in blood glucose incremental areas under the curves (iAUCs) among the treatments. No significant effect on any of the appetite parameters was observed among the treatments. All of the cookies were rated as acceptable and subjects did not report any gastrointestinal discomfort. CONCLUSION: In conclusion, the results indicate that cookies containing bay leaf powder at 6% (w/w) incorporation level provides a palatable product that induces a reduced glycemic response. PMID- 28853994 TI - Whole Red Grape Juice Reduces Blood Pressure at Rest and Increases Post-exercise Hypotension. AB - OBJECTIVE: The objective of this study was to evaluate the effect of whole red grape juice (juice) on blood pressure (BP) at rest and on the magnitude of post exercise hypotension (PEH). METHODS: This double-blind, randomized controlled study was performed with 26 individuals with hypertension (40 to 59 years old) who were divided into experimental (n = 14) and control (n = 12) groups. Subsequently, the experimental group was subdivided according to the initial BP values. The subjects performed 2 sessions of aerobic exercise on a treadmill (60 minutes, 60%-85% maximum heart rate), separated by a 28-day period of supplementation with a daily dose of juice (150 ml for men and 100 ml for women) or a control drink. BP was measured before, during, and immediately after each exercise session as well as every 10 minutes during the 60-minute post-exercise recovery period. RESULTS: The BP at rest did not change in the experimental group, but when this group was subdivided by initial BP, the subjects with controlled initial BP (EGCP) achieved a significant reduction (133.3 +/- 5.6 to 114.6 +/- 12.2 mmHg, p = 0.02); in contrast, the experimental group with borderline hypertensive BP values (EGBP) did not. Intervention with juice did not modify PEH in the experimental group, but when this group was divided as a function of the initial BP, PEH was potentiated at some times in EGCP. CONCLUSIONS: We conclude that juice promotes a reduction in BP at rest and is also capable of improving PEH in individuals with hypertension, but these effects are dependent on the initial BP values. PMID- 28853996 TI - Effect of probiotic strain Lactobacillus acidophilus (LBKV-3) on fecal residual lactase activity in undernourished children below 10 years. AB - Clinically proven Lactobacillus acidophilus strain LBKV-3 intended as probiotic for humans was used to test its effect on fecal residual lactase activity in undernourished children below 10 years of age. The children were selected from malnutrition-declared area of Maharashtra (India). One of the major causes of malnutrition is lactose intolerance which leads to diarrhea. The basic consideration in selecting the probiotic strain of L. acidophilus (LBKV-3) in this investigation was the fact that the organism is isolated from human vaginal surface swab and it was found extensively studied for probiotic characteristic. LBKB3 is tested by several workers as probiotic for hypocholesterolemic activity, implantation ability, therapeutic effects on gastrointestinal (GI) and related ailments. The results of present investigation have shown that the fecal residual lactase activity significantly increased than its initial value (which was almost zero). It appeared that the fecal residual beta-galactosidase activity is an indication of positive implementation abilities of the cultures under investigation. These trends were compared with the control and blank group of children receiving Dahi and buffalo milk (BM). It was observed that both these products failed to exert any significant impact on increase in residual lactase activity. PMID- 28853995 TI - Hinge action versus grip in translocation by RNA polymerase. AB - Based on molecular dynamics simulations and functional studies, a conformational mechanism is posited for forward translocation by RNA polymerase (RNAP). In a simulation of a ternary elongation complex, the clamp and downstream cleft were observed to close. Hinges within the bridge helix and trigger loop supported generation of translocation force against the RNA-DNA hybrid resulting in opening of the furthest upstream i-8 RNA-DNA bp, establishing conditions for RNAP sliding. The beta flap tip helix and the most N-terminal beta' Zn finger engage the RNA, indicating a path of RNA threading out of the exit channel. Because the beta flap tip connects to the RNAP active site through the beta subunit double Psi-beta-barrel and the associated sandwich barrel hybrid motif (also called the flap domain), the RNAP active site is coupled to the RNA exit channel and to the translocation of RNA-DNA. Using an exonuclease III assay to monitor translocation of RNAP elongation complexes, we show that K+ and Mg2+ and also an RNA 3'-OH or a 3'-H2 affect RNAP sliding. Because RNAP grip to template suggests a sticky translocation mechanism, and because grip is enhanced by increasing K+ and Mg2+concentration, biochemical assays are consistent with a conformational change that drives forward translocation as observed in simulations. Mutational analysis of the bridge helix indicates that 778-GARKGL-783 (Escherichia coli numbering) is a homeostatic hinge that undergoes multiple bends to compensate for complex conformational dynamics during phosphodiester bond formation and translocation. PMID- 28853997 TI - Progress in Deciphering the Controls on the Geochemistry of Fluids in Seafloor Hydrothermal Systems. AB - Over the last four decades, more than 500 sites of seafloor hydrothermal venting have been identified in a range of tectonic environments. These vents represent the seafloor manifestation of hydrothermal convection of seawater through the permeable oceanic basement that is driven by a subsurface heat source. Hydrothermal circulation has fundamental effects on the transfer of heat and mass from the lithosphere to the hydrosphere, the composition of seawater, the physical and chemical properties of the oceanic basement, and vent ecosystems at and below the seafloor. In this review, we compare and contrast the vent fluid chemistry from hydrothermal fields in a range of tectonic settings to assess the relative roles of fluid-mineral equilibria, phase separation, magmatic input, seawater entrainment, and sediment cover in producing the observed range of fluid compositions. We focus particularly on hydrothermal activity in those tectonic environments (e.g., mid-ocean ridge detachment faults, back-arc basins, and island arc volcanoes) where significant progress has been made in the last decade in documenting the variations in vent fluid composition. PMID- 28853998 TI - Ecological Stoichiometry of Ocean Plankton. AB - Marine plankton elemental stoichiometric ratios can deviate from the Redfield ratio (106C:16N:1P); here, we examine physiological and biogeochemical mechanisms that lead to the observed variation across lineages, regions, and seasons. Many models of ecological stoichiometry blend together acclimative and adaptive responses to environmental conditions. These two pathways can have unique molecular mechanisms and stoichiometric outcomes, and we attempt to disentangle the two processes. We find that interactions between environmental conditions and cellular growth are key to understanding stoichiometric regulation, but the growth rates of most marine plankton populations are poorly constrained. We propose that specific physiological mechanisms have a strong impact on plankton and community stoichiometry in nutrient-rich environments, whereas biogeochemical interactions are important for the stoichiometry of the oligotrophic gyres. Finally, we outline key areas with missing information that is needed to advance understanding of the present and future ecological stoichiometry of ocean plankton. PMID- 28853999 TI - Effect of Green Tea on Plasma Adiponectin Levels: A Systematic Review and Meta analysis of Randomized Controlled Clinical Trials. AB - OBJECTIVE: Our objective was to perform a systematic review and meta-analysis on randomized controlled trials (RCTs) assessing the effect of green tea on serum adiponectin concentration. METHOD: We searched PubMed, ISI Web of Science, Scopus, and the Google Scholar databases up to November 2016. RCTs conducted among human adults studied the effects of green tea and green tea extract on serum adiponectin concentrations as an outcome variable was included. The weighted mean differences and standard deviations (SD) of change in serum adiponectin levels were calculated. The random effects model was used for deriving a summary of mean estimates with their corresponding SDs. The protocol was registered with PROSPERO (No. CRD42017057716). RESULT: Fourteen RCTs were eligible to be included in the systematic review and the meta-analysis. Our analysis showed that green tea did not significantly affect adiponectin concentrations in comparison with placebo (weighted mean difference = -0.02 ug/ml, 95% confidence interval [CI], -0.41, 0.38; p = 0.936). There was a substantial heterogeneity between studies (I2 = 91.7%; p < 0.0001). Subgroup analyses based on sex, type of intervention, continent, and body mass index (BMI) could not explain the sources of heterogeneity. Metaregression analyses revealed that the dose and duration of green tea ingestion did not have any effect on adiponectin concentrations. CONCLUSION: Green tea could not change the circulatory adiponectin levels. The dose and duration of green tea could not change the result. RCTs with longer follow-up periods and higher doses are needed to replicate our results. PMID- 28854000 TI - Multistable Perception and the Role of the Frontoparietal Cortex in Perceptual Inference. AB - A given pattern of optical stimulation can arise from countless possible real world sources, creating a dilemma for vision: What in the world actually gives rise to the current pattern? This dilemma was pointed out centuries ago by the astronomer and mathematician Ibn Al-Haytham and was forcefully restated 150 years ago when von Helmholtz characterized perception as unconscious inference. To buttress his contention, von Helmholtz cited multistable perception: recurring changes in perception despite unchanging sensory input. Recent neuroscientific studies have exploited multistable perception to identify brain areas uniquely activated in association with these perceptual changes, but the specific roles of those activations remain controversial. This article provides an overview of theoretical models of multistable perception, a review of recent neuroimaging and brain stimulation studies focused on mechanisms associated with these perceptual changes, and a synthesis of available evidence within the context of current notions about Bayesian inference that find their historical roots in von Helmholtz's work. PMID- 28854001 TI - The Properties and Antecedents of Hedonic Decline. AB - We review the phenomenon of hedonic decline, whereby repeated exposure to a stimulus typically reduces the hedonic response (e.g., enjoyment). We first discuss the typical trajectory of hedonic decline and the common research paradigms used to study it. We next discuss the most popular theories regarding general mechanisms widely believed to underlie hedonic decline. We then propose a taxonomy to organize these various general theories and to incorporate more recent work on top-down, self-reflective theories. This taxonomy identifies three general classes of antecedents to hedonic decline: physiological feedback, perceptual changes, and self-reflection. For each class, we review the supporting evidence for specifically identified antecedents and recent developments on how each antecedent influences hedonic decline. Our review focuses especially on more recent work in the growing area of self-reflection. PMID- 28854004 TI - Sleep Medicine. PMID- 28854002 TI - Efficacy of Folic Acid Therapy in Patients with Hyperhomocysteinemia. AB - BACKGROUND: Increased plasma homocysteine (Hcy) levels are a risk factor for stroke and can be reduced with folic acid therapy. Therefore, it is extremely important for patients with hyperhomocysteinemia (HHcy) to obtain the normal level of Hcy after folate intervention. Thus far, few studies have reported the effective rate defined as percentage of patients who achieved normal plasma Hcy levels after folic acid therapy. OBJECTIVES: The present study aimed to investigate the effective rate of folic acid for the treatment of HHcy and the impact of plasma baseline Hcy levels and the compliance of oral folic acid on the efficacy. METHODS: A total of 858 patients with HHcy were treated with oral folic acid (5 mg/d) for 3 months. Fasting blood samples collected at baseline and at the end of treatment were assayed for plasma Hcy levels. RESULTS: After 3 months of treatment, the plasma Hcy levels of 484 patients were reduced to below the normal levels (15 MUmol/L), corresponding to an effective rate of 56.41%. The average of Hcy levels decreased by 28.05%. The effective rates of folic acid therapy in a mild Hcy elevated group and an intermediate Hcy elevated group were 61.34% and 27.78%, respectively (p = 0.000). The effective rates among patients with good and poor compliance of oral folic acid were 65.29% and 35.18%, respectively (p = 0.000). CONCLUSIONS: More than 40% patients with HHcy failed to reach the normal range (5-15 MUmol/L) after 3 months of folic acid supplementation. Further prospective studies are warranted to explore the reasons for failure. PMID- 28854006 TI - Pediatric Otolaryngology. PMID- 28854005 TI - Rhinology/Allergy. PMID- 28854003 TI - Soluble F proteins exacerbate pulmonary histopathology after vaccination upon respiratory syncytial virus challenge but not when presented on virus-like particles. AB - Respiratory syncytial virus (RSV) fusion (F) protein is suggested to be a protective vaccine target although its efficacy and safety concerns remain not well understood. We investigated immunogenicity, efficacy, and safety of F proteins in a soluble form or on virus-like particle (F-VLP). F VLP preferentially elicited IgG2a antibody and T helper type 1 (Th1) immune responses whereas F protein induced IgG1 isotype and Th2 responses. Despite lung viral clearance after prime or prime-boost and then RSV challenge, F protein immune mice displayed weight loss and lung histopathology and high mucus production and eosinophils. In contrast, prime or prime-boost vaccination of F VLP induced effective protection, prevented infiltration of eosinophils and vaccine- enhanced disease after challenge. This study provides insight into developing an effective and safe RSV vaccine candidate. PMID- 28854007 TI - Patient Safety/Quality Improvement. PMID- 28854008 TI - Otolology/Neurotology. PMID- 28854009 TI - Laryngology/Broncho-Esophagology. PMID- 28854010 TI - Head and Neck Surgery. PMID- 28854011 TI - General Otolaryngology. PMID- 28854012 TI - 2017 Honor Award Recipients. PMID- 28854013 TI - Facial Plastic and Reconstructive Surgery. PMID- 28854015 TI - 2017 Distinguished Service Award Recipients. PMID- 28854014 TI - Endocrine Surgery. PMID- 28854018 TI - Accreditation Information. PMID- 28854016 TI - Honorary Guest Lectures 2017. PMID- 28854019 TI - Business of Medicine/Practice Management. PMID- 28854020 TI - 2017 President Gregory W. Randolph, MD. PMID- 28854021 TI - 2017 Annual Meeting Program Committee. PMID- 28854022 TI - 2017 Journal Star Reviewers. PMID- 28854023 TI - Sleep Medicine. PMID- 28854024 TI - Rhinology/Allergy. PMID- 28854025 TI - Pediatric Otolaryngology. PMID- 28854026 TI - Business of Medicine/Practice Management. PMID- 28854027 TI - Patient Safety/Quality Improvement. PMID- 28854028 TI - Business of Medicine/Practice Management. PMID- 28854030 TI - Laryngology/Broncho-Esophagology. PMID- 28854029 TI - Otology/Neurotology. PMID- 28854031 TI - Head and Neck Surgery. PMID- 28854032 TI - General Otolaryngology. PMID- 28854033 TI - Sleep Medicine. PMID- 28854034 TI - Facial Plastic and Reconstructive Surgery. PMID- 28854035 TI - Endocrine Surgery. PMID- 28854037 TI - Pediatric Otolaryngology. PMID- 28854036 TI - Rhinology/Allergy. PMID- 28854038 TI - Patient Safety/Quality Improvement. PMID- 28854039 TI - Otology/Neurotology. PMID- 28854040 TI - Laryngology/Broncho-Esophagology. PMID- 28854041 TI - Head and Neck Surgery. PMID- 28854043 TI - General Otolaryngology. PMID- 28854044 TI - Facial Plastic and Reconstructive Surgery. PMID- 28854045 TI - Endocrine Surgery. PMID- 28854046 TI - Gene Therapy for Alcoholism and Other Substance Use Disorders. PMID- 28854047 TI - Politics and palliative care: Togo. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 28854048 TI - Assessing student characteristics in palliative care education research: a literature review. AB - BACKGROUND: Assessing characteristics in educational research is important to describe a student sample. However, consistency in measuring student characteristics is lacking, particularly in palliative and end-of-life (PEOL) care education research. METHODS: A literature review was conducted to determine the primary characteristics to assess in PEOL education research, the corresponding level of measurement and associated statistical analyses to perform with the data. RESULTS: Key characteristics to measure include: age, previous PEOL healthcare experience, previous personal experience with death/loss, previous PEOL education, program of enrolment and religion. Gender, ethnicity/race and living situation/place of residence were not supported as key characteristics to assess. Best methods by which to measure characteristics remain unclear and the utilisation of characteristics in research is inconsistent. CONCLUSION: Identified characteristics should be measured in PEOL education research at the highest level of measurement. The influence of characteristics on outcomes should be considered in association with research questions. PMID- 28854049 TI - Feasibility of the Namaste Care Programme to enhance care for those with advanced dementia. AB - Many individuals approaching the end of life with advanced dementia will live in a care or residential home. A wide spectrum of care is required and physical and safety needs may be prioritised above all other requirements. The Namaste Care Programme is designed to provide a holistic approach to meeting the needs of those with advanced dementia. This paper will outline the process of introducing this programme into a care home and its impact upon those who were involved. With a small sample of residents (n=9) the programme ran for 4 weeks. Feedback was gathered at baseline and during the programme from family and staff. This service innovation offered useful insights and indicated that it has the potential to improve the experiences of those with dementia, their family members and staff. The learning gained will be valuable when developing this initiative at scale and for future robust evaluation. PMID- 28854050 TI - Forensic nursing and the palliative approach to care: an empirical nursing ethics analysis. AB - BACKGROUND: A movement is underway to promote a palliative approach to care in all contexts where people age and live with life-limiting conditions, including psychiatric settings. Forensic psychiatry nursing-a subfield of mental health nursing- focuses on individuals who are in conflict with the criminal justice system. We know little about the values of nurses working in forensic psychiatry, and how these values might influence a palliative approach to care for frail and aging patients. METHOD: Interviews with four nurses working on one of two forensic units of a university-affiliated mental health hospital in an urban area of eastern Canada. FINDINGS: Three specific values were found to guide forensic nurses in their care of aging patients that are commensurate with a palliative approach: hope, inclusivity, and quality of life. CONCLUSION: When we started this project, we wondered whether the culture of forensic nursing practice was antithetical to the values of a palliative approach. Instead, we found several parallels between forensic nurses' moral identities and palliative philosophy. These findings have implications for how we think about the palliative approach in contexts not typically associated with palliative care, but in which patients will increasingly age and die. PMID- 28854051 TI - The boundaries of end-of-life care. PMID- 28854052 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 28854053 TI - Independent non-medical prescribing in children's hospices in the UK: a practice snapshot. AB - BACKGROUND: Non-medical prescribing is well established within the British health service, with increasing numbers of nurses practicing within children's hospices. AIM: To identify the context of non-medical prescribing in children's hospices in the UK, focusing on the perceived benefits and challenges. METHOD: Internet-based questionnaires were sent to 55 UK children's hospices, exploring the practice and context of prescribing. RESULTS: Of the 55 invited, 20 children's hospices responded to the questionnaire, 14 of which employed a total of 39 non-medical prescribers (NMPs). Sixteen individual NMPs responded, of which half (50%) prescribed to enable the continuation of existing medicines, 37.5% prescribed independently surrounding symptom management and control and 31.3% in end-of-life care. Perceived benefits of prescribing included timely access to medicines, increased efficiency and accuracy in the admissions process and medicine reconciliation and the increased ability to offer choice in the place of palliative and hospice care. Perceived barriers to prescribing surrounded opportunities to develop confidence, defining the scope of practice and the time required to assess, diagnose and treat. CONCLUSION: NMPs are making a significant contribution to the prescribing workforce within hospices; however, a number of challenges need to be addressed to enable hospices to realise the benefits. PMID- 28854054 TI - e-Health in palliative care: review of literature, Google Play and App Store. AB - AIM: To analyse the use of e-Health technologies and mobile apps in palliative care (PC). METHODS: Search on PubMed, using 'telemedicine', 'ehealth', 'mobile health', 'telecare', 'health information systems' and 'palliative care'. Original Portuguese, Spanish, French and English papers were included. Google Play and App Store (iOS) were searched for mobile apps using 'palliative care', 'medical apps' and 'symptom management'. RESULTS: Twenty-five papers and forty mobile apps were analysed. Teleconsultation is the principal e-Health technology. Mobile apps focus on communication, drugs, tools/clinical guidelines, hospice, symptom management and PC information. CONCLUSIONS: e-Health is an emergent topic in PC. Teleconsultation enhances communication among patients, families and PC teams, reinforces partnership and decreases the burden on families and use of the emergency services. IMPLICATIONS FOR PRACTICE: e-Health technologies are a good strategy in PC but further research based on different methodological approaches is needed to promote evidence-based practice. PMID- 28854055 TI - Powdery mildew of Chrysanthemum * morifolium: phylogeny and taxonomy in the context of Golovinomyces species on Asteraceae hosts. AB - The taxonomic history of the common powdery mildew of Chrysanthemum * morifolium (chrysanthemum, florist's daisy), originally described in Germany as Oidium chrysanthemi, is discussed. The position of O. chrysanthemi was investigated on the basis of morphological traits and molecular phylogenetic analyses. Based on the results of this study, this species, which is closely related to Golovinomyces artemisae, was reassessed and reallocated to Golovinomyces. The phylogenetic analysis and taxonomic reassessment of the chrysanthemum powdery mildew is supplemented by a morphological description, a summary of its worldwide distribution data, and a brief discussion of the introduction of this fungus to North America. G. chrysanthemi differs from true G. artemisiae in that it has much longer conidiophores, is not constricted at the base, and has much larger and most importantly longer conidia. The close affinity of Golovinomyces to Artemisia and Chrysanthemum species signifies a coevolutionary event between the powdery mildews concerned and their host species in the subtribe Artemisiinae (Asteraceae tribe Anthemideae). This conclusion is fully supported by the current phylogeny and taxonomy of the host plant genera and the coevolution that occurred with the host and pathogen. The following powdery mildew species, which are associated with hosts belonging to the tribe Anthemideae of the Asteraceae, are epitypified: Alphitomorpha depressa beta artemisiae (= Alphitomorpha artemisiae), Erysiphe artemisiae, and Oidium chrysanthemi. Erysiphe macrocarpa is neotypified. Their sequences were retrieved from the epitype collections and have been added to the phylogenetic tree. Golovinomyces orontii, an additional powdery mildew species on Chrysanthemum *morifolium, is reported. This species is rarely found as a spontaneous infection and was obtained from inoculation experiments. PMID- 28854056 TI - BDSM Role Fluidity: A Mixed-Methods Approach to Investigating Switches Within Dominant/Submissive Binaries. AB - This mixed-methods study of BDSM investigates the nuances of BDSM participants' role identities, role frequencies, and role fluidities-shifts in identities and play across time, location, scene, and play partner. Data were gathered from 202 online surveys and 25 semistructured interviews about participants' roles given their gender and sexual identities. These data reveal that men tend to self identify as Dominant, Master, Top, or Sadist (DMTS) and always perform dominant roles, while women tend to self-identify as Submissive, Slave, Bottom, or Masochist (SSBM) and always perform submissive roles. Although this would seem to support the theory that BDSM reinforces gendered dominant/submissive binaries, further analyses indicate that women and queer/pansexual individuals disrupt this binary through their Switch identities and roles. Switching and queer identities, thus, offer the possibility for transforming dominant/submissive and other binaries. PMID- 28854057 TI - Impact of commercial cigarette smoke condensate on brain tissue co-cultured with astrocytes and blood-brain barrier endothelial cells. AB - The purpose of the current study was to investigate the effect of two commercial cigarette smoke condensates (CCSC) on oxidative stress and cell cytotoxicity in human brain (T98G) or astrocytes (U-373 MG) in the presence of human brain microvascular endothelial cells (HBMEC). Cell viability of mono-culture of T98G or U-373 MG was markedly decreased in a concentration-dependent manner, and T98G was more susceptible than U-373 MG to CCSC exposure. Cytotoxicity was less prominent when T98G was co-cultured with HBMEC than when T98G was co-cultured with U-373 MG. Significant reduction in trans-epithelial electric resistance (TEER), a biomarker of cellular integrity was noted in HBMEC co-cultured with T98G (HBMEC-T98G co-culture) and U-373 MG co-cultured with T98G (U-373 MG-T98G co culture) after 24 or 48 hr CCSC exposure, respectively. TEER value of U-373 MG co cultured with T98G (79-84%) was higher than HBMEC co-cultured with T98G (62-63%) within 120-hr incubation with CCSC. Reactive oxygen species (ROS) generated by CCSC in mono-culture of T98G and U-373 MG reached highest levels at 4 and 16 mg/ml, respectively. ROS production by T98G fell when co-cultured with HBMEC or U 373MG. These findings suggest that adverse consequences of CCSC treatment on brain cells may be protected by blood-brain barrier or astrocytes, but with chronic exposure toxicity may be worsened due to destruction of cellular integrity. PMID- 28854058 TI - Impact of mounting methods in computerized axiography on assessment of condylar inclination. AB - OBJECTIVE: Valid and reliable recording is a key requirement for accurately simulating individual jaw movements. METHODS: Horizontal condylar inclination (HCI) and Bennett's angle were measured using a digital jaw tracker (Cadiax(r) Compact 2) in 27 young adults. Three mounting methods (paraocclusal tray adapter, periocclusal tray adapter, and tray adapter with mandibular clamp) were tested. RESULTS: The mean values of the HCI differed by up to 10 degrees between the mounting methods; however, the values for Bennett's angle did not differ substantially. While the intersession reliability of the Bennett's angle assessment did not depend on the mounting method, the reliability of the HCI assessment was only fair to good for the paraocclusal mounting method but poor for both periocclusal mounting methods. DISCUSSION: For attaching the tracing bow of jaw trackers to the mandible, a paraocclusal tray adapter should be applied, to achieve the most reliable results. PMID- 28854059 TI - Surgical treatment of stage 2 medication-related osteonecrosis of the jaw compared to osteomyelitis. AB - OBJECTIVE: To compare the characteristics and outcomes of patients who underwent surgical treatment for stage 2 medication-related osteonecrosis of the jaw (MRONJ) versus osteomyelitis. METHODS: This retrospective study compared the following variables in 73 patients with stage 2 MRONJ versus 89 patients with osteomyelitis: impaired wound healing after surgery, sex, age, the presence of actinomycosis, location of the jaw lesion, and involvement of the inferior alveolar nerve (IAN). RESULTS: There were significant differences between the groups in age, sex, rates of impaired wound healing, actinomycosis, and the location (anterior/posterior) of the lesion. Impaired wound healing after surgical treatment in the stage 2 MRONJ group was associated with patient age. All patients with impaired wound healing after the initial surgery recovered fully after reoperation. CONCLUSIONS: These findings for surgical treatment of stage 2 MRONJ may help clinicians plan surgical treatment of MRONJ. PMID- 28854060 TI - Racial/Ethnic Differences in Prevalence Trends for Heroin use and Non-Medical use of Prescription Opioids Among Entrants to Opioid Treatment Programs, 2005-2016. AB - Recent data suggest an increase in use of heroin and non-medical use of prescription opioids (POs) in the United States, but it is unclear if these trends are consistent across racial/ethnic groups. In a nationwide prevalence study, 69,140 patients newly admitted to an opioid treatment program (OTP) completed a brief self-administered survey of past month heroin use and PO misuse from January 2005 through September 2016. We calculated heroin use and PO misuse prevalence rates, and prevalence rate ratios of Black and Latino OTP entrants compared to White entrants over time. Initially, Black and Latino respondents reported much higher prevalence of heroin use and much lower prevalence of PO misuse than White respondents. Heroin use increased among White respondents, while it decreased among Black respondents, resulting in rates that were no longer significantly different. PO misuse prevalence decreased among White respondents while it increased among Black respondents, but remained significantly higher among White respondents. Heroin use decreased and PO misuse increased among Latino respondents during the late 2000s, but these trends largely reversed in more recent years. Among OTP entrants, racially/ethnically disparate rates of heroin use, and to a lesser extent, of PO misuse have become more similar over time. These trends were stronger when analysis was restricted to OTP entrants who either had no previous OTP history or were younger. To understand potential impacts of interventions to deter PO misuse and to maximize the effectiveness of OTPs it is important to consider potential changes in opioid use across racial/ethnic groups. PMID- 28854061 TI - Lassoing Skill Through Learner Choice. AB - The authors examined several issues related to the motor learning benefits resulting from giving learners choices. In 2 experiments, participants practiced a novel task, throwing a lasso. In Experiment 1, giving learners a choice ostensibly irrelevant to performance (color of mat under target) resulted in enhanced learning relative to a control group. The choice group also reported more positive affect. Experiment 2 compared the effectiveness of task-irrelevant (mat color) versus task-relevant (video demonstrations of the skill) choices. In both choice groups, each participant was yoked to a participant in the other group, and each received the same mat color or saw the video demonstration, respectively, as chosen by their counterpart in the other group. In the control group, participants were yoked to their respective counterparts in each of the choice groups. On a retention test, the 2 choice groups did not differ from each other, but both outperformed the control group. The affective and learning effects seen when learners are given choices, and the fact that task-relevant and task-irrelevant choices resulted in similar learning benefits, are consistent with a content-neutral mechanism for the effects of choice on learning, as described in the OPTIMAL theory of motor learning (Wulf & Lewthwaite, 2016 ). PMID- 28854062 TI - The potential etiologic factors influencing tinnitus intensity in patients with temporomandibular disorders. AB - OBJECTIVES: To investigate the potential relationships between the intensity of tinnitus associated with temporomandibular disorders (TMD) and potential etiologic factors, including age, gender, freeway space, sleep bruxism (SB), joint clicking, and headache. METHODS: The sample was comprised of 90 patients without any hearing loss, as confirmed by otorhinolaryngology, who self-reported subjective tinnitus and simultaneous TMD, based on the Research Diagnostic Criteria for TMD (RDC/TMD). RESULTS: The results showed a positive, weak correlation between the intensity of tinnitus and age (r = 0.225, p = 0.033). The presence of SB and headache were seen in higher proportions in the present sample, at 75.5% (n = 68) and 66.6% (n = 60), respectively. CONCLUSIONS: In a population of patients with subjective tinnitus and TMD, no significant associations were found between tinnitus intensity and age, freeway space, SB, clicking presence, and headache, though gender did show a weak correlation with tinnitus intensity. PMID- 28854064 TI - MicroRNA-141 Is Involved in Ulcerative Colitis Pathogenesis via Aiming at CXCL5. AB - MicroRNAs (miRNAs) are gene expression's important posttranscriptional regulators. The precise function of miRNAs in ulcerative colitis (UC) is not entirely known. Our investigation's aim was to identify miRNAs induced in patients with active UC and to evaluate miR-141 influences on ameliorating intestinal inflammation. The miRNA expression profiles in patients suffering active UC (n = 15) and healthy individuals used as control (n = 13) were assessed adopting miRNA microarrays. Via quantitative real-time polymerase chain reaction, miR-141 expression was confirmed. Modulation of the objective gene CXCL5 expression through miR-141 was examined via luciferase reporter construct assays and miR-141 mimic or inhibitor transfections. The impacts of CXCL5 or miR-141 on AKT, MMP-2, and MMP-9 were examined via Western blot in HT29 cells. We found that in patients suffering active UC, miR-141 was substantially downregulated, and CXCL5 expression efficaciously increased. The results of luciferase reporter assays illustrated that miR-141 directly targeted CXCL5 and affected downstream expression of CXCL5 in HT29 cells. In addition, quiescent CXCL5 and the overexpression of miR-141 reduced levels of MMP-2 and MMP-9 in tumor necrosis factor-alpha-treated HT29 cells by means of repressing the inhibitory AKT. miR 141 seems to play a role in the bowel inflammation of individuals with active UC via downregulation of CXCL5 expression. This method may be related with the AKT activation signaling pathway. PMID- 28854063 TI - A Tale of Two Towns: A Comparative Study Exploring the Possibilities and Pitfalls of Social Capital among People Seeking Recovery from Substance Misuse. AB - BACKGROUND: Social capital has become an influential concept in debating and understanding the modern world. Within the drug and alcohol sector, the concept of 'recovery capital' has gained traction with researchers suggesting that people who have access to such capital are better placed to overcome their substance use related problems than those who do not (Cloud and Granfield, 2008), leading to requests for interventions that focus on building social capital networks (Neale & Stevenson, 2015). While accepting that the concept of social capital has enormous potential for addressing the problems associated with drug use, this paper also considers its 'dark side'. METHODS: Data were drawn from semi structured interviews with 180 participants including 135 people who use drugs and 45 people who formerly used drugs. RESULTS: High levels of trust, acquired through the establishment of dense social networks, are required to initiate recovery. However, these 'strong bonds' may also lead to the emergence of what is perceived by others as an exclusive social network that limits membership to those who qualify and abide by the 'rules' of the recovery community, particularly around continuous abstinence. CONCLUSIONS: Depending on the nature of the networks and the types of links participants have into them being socially connected can both inhibit and encourage recovery. Therefore, the successful application of social capital within the drugs and alcohol field requires a consideration of not only the presence or absence of social connections but their nature, the value they produce, and the social contexts within which they are developed. PMID- 28854065 TI - Efficacy of Thalidomide in Preventing Delayed Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy: A Randomized, Multicenter, Double-Blind, Placebo Controlled Phase III Trial (CLOG1302 study). AB - Purpose We examined the efficacy and safety of thalidomide (THD) for the prevention of delayed nausea and vomiting in patients who received highly emetogenic chemotherapy (HEC). Patients and Methods In a randomized, double blind, active-controlled, phase III trial, chemotherapy-naive patients with cancer who were scheduled to receive HEC that contained cisplatin or cyclophosphamide-doxorubicin/epirubincin >= 50 mg/m2 regimens were randomly assigned to a THD group (100 mg twice daily on days 1 to 5) or placebo group, both with palonosetron (0.25 mg on day 1) and dexamethasone (12 mg on day 1; 8 mg on days 2 to 4). Primary end point was complete response to vomiting-no emesis or use of rescue medication-in the delayed phase (25 to 120 h). Nausea and anorexia on days 1 to 5 were evaluated by the 4-point Likert scale (0, no symptoms; 3, severe). Quality of life was assessed by the European Organization for Research and Treatment of Cancer QLQ-C30 version 3 questionnaire on days -1 and 6. Results Of 656 patients, 638 were evaluable: 317 in the THD group and 321 in the control group. Compared with placebo, delayed and overall (0 to 120 h) complete response rates to vomiting were significantly higher with THD: 76.9% versus 61.7% ( P < .001) and 66.1% versus 53.3% ( P = .001), respectively. Rates of no nausea were also higher in the THD group (delayed: 47.3% v 33.3%; P < .001; overall: 41% v 29.6%; P = .003), and mean scores of anorexia were lower overall (0.44 +/- 0.717 v 0.64 +/- 0.844; P = .003). Adverse effects were mild to moderate. The THD group had increased sedation, dizziness, constipation, and dry mouth, but experienced better quality of life after chemotherapy. Conclusion Thalidomide combined with palonosetron and dexamethasone significantly improved HEC-induced delayed nausea and vomiting prevention in chemotherapy-naive patients. PMID- 28854066 TI - Activity of Eribulin in Patients With Advanced Liposarcoma Demonstrated in a Subgroup Analysis From a Randomized Phase III Study of Eribulin Versus Dacarbazine. AB - Purpose A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma showed a significant improvement in overall survival (OS) for the eribulin arm, with a manageable toxicity profile. We now report the histology-specific subgroup analysis of the efficacy and safety of eribulin compared with dacarbazine in patients with LPS, an independently randomized stratified subgroup of this phase III trial. Methods Patients >= 18 years with advanced or metastatic dedifferentiated, myxoid/round cell, or pleomorphic LPS incurable by surgery or radiotherapy were included. Patients with Eastern Cooperative Oncology Group performance status <= 2 and two or more prior systemic treatment regimens, including one with anthracycline, were randomly assigned 1:1 to receive eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850, 1,000, or 1,200 mg/m2 intravenously on day 1) every 21 days. OS, progression-free survival (PFS), and safety were analyzed. Results In the LPS subgroup, OS was significantly improved: 15.6 versus 8.4 months (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < .001) with eribulin versus dacarbazine, respectively. Longer OS with eribulin was observed in all LPS histologic subtypes and in all geographic regions evaluated. PFS was also improved with eribulin versus dacarbazine (2.9 v 1.7 months, respectively; hazard ratio, 0.52; 95% CI, 0.35 to 0.78; P = .0015). Adverse events were similar between arms. Conclusion In patients with previously treated LPS, eribulin was associated with significantly superior OS and PFS compared with dacarbazine. Eribulin represents an important treatment option for patients with LPS, a sarcoma subtype for which limited effective systemic treatments are available. Further studies are justified to explore the role of eribulin in earlier lines of therapy as well as in combination with other agents. PMID- 28854067 TI - Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. AB - Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naive squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population. PMID- 28854068 TI - Practice Makes Perfect: The Rest of the Story in Testicular Cancer as a Model Curable Neoplasm. PMID- 28854069 TI - Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography After Concurrent Chemoradiotherapy in Locally Advanced Head-and-Neck Squamous Cell Cancer: The ECLYPS Study. AB - Purpose To assess the standardized implementation and reporting of surveillance [18F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) scan of the neck in locoregionally advanced head-and-neck squamous cell carcinoma (LAHNSCC) after concurrent chemoradiotherapy (CCRT). Patients and Methods We performed a prospective multicenter study of FDG-PET/CT scanning 12 weeks after CCRT in newly diagnosed patients with LAHNSCC (stage IVa/b) that used standardized reconstruction and Hopkins reporting criteria. The reference standard was histology or > 12 months of clinical follow-up. The primary outcome measure was the negative predictive value (NPV) of FDG-PET/CT scans and other supporting diagnostic test characteristics, including time dependency with increasing follow-up time. Results Of 152 patients, 125 had adequate primary tumor control after CCRT and entered follow-up (median, 20.4 months). Twenty three (18.4%) had residual neck disease. Overall, NPV was 92.1% (95% CI, 86.9% to 95.3%; null hypothesis: NPV = 85%; P = .012) with sensitivity of 65.2% (95% CI, 44.9% to 81.2%), specificity of 91.2% (95% CI, 84.1% to 95.3%), positive predictive value of 62.5% (95% CI, 45.5% to 76.9%), and accuracy of 86.4% (95% CI, 79.3% to 91.3%). Sensitivity was time dependent and high for residual disease manifesting up to 9 months after imaging but lower (59.7%) for disease detected up to 12 months after imaging. Standardized reporting criteria reduced the number of equivocal reports (95% CI for the difference, 2.6% to 15.0%; P = .003). Test characteristics were not improved with the addition of lymph node CT morphology criteria. Conclusion FDG-PET/CT surveillance using Hopkins criteria 12 weeks after CCRT is reliable in LAHNSCC except for late manifesting residual disease, which may require an additional surveillance scan at 1 year after CCRT to be detected. PMID- 28854071 TI - Endoxifen: The End, or Are We at the Beginning? PMID- 28854070 TI - First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer. AB - Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity. PMID- 28854072 TI - Acclimating to the Increase in Statin Use in Accountable Care Organizations Based on Changes in Quality Measures: A Report from the Accountable Care Organization Research Network, Services, and Education. AB - : The Accountable Care Organization Research Network, Services, and Education (ACORN SEED), founded by faculty members at Nova Southeastern University College of Pharmacy, is a group of pharmacists that provides unique pharmacy services to accountable care organizations (ACOs), patient-centered medical homes, and management services organizations to help maximize shared savings and target medication-related issues, while promoting the pharmacy profession and unique learning experiences for pharmacy students within these settings. In this report, ACORN SEED investigators provide a brief overview of the ACO benchmark measures in relation to statin use. Historically, hyperlipidemia treatment was tailored to meet certain cholesterol levels as a surrogate marker in preventing major adverse cardiovascular events, specifically a low-density lipoprotein cholesterol (LDL-C) level less than 100 mg/dL as a target goal. In addition, Medicare assessed a health care provider's performance based on this target goal in specific populations (i.e., diabetes and ischemic vascular disease). In 2013, the American College of Cardiology and American Heart Association published updated recommendations removing these LDL-C treatment goals. Rather than treating with cholesterol-lowering medications in an effort to reduce cholesterol levels, patients are now being evaluated for statin therapy use based on 4 benefit groups that focus on the risk of atherosclerotic cardiovascular disease. In 2015, Medicare's shared savings program removed the previous LDL-C goals from its quality measures and now assesses positive performance from the updated guidelines. Currently, under ACO benchmark measure #42, health care providers are being rewarded for prescribing statin therapy for the prevention and treatment of cardiovascular disease, which reflects updated evidence-based recommendations. With the increase in statin use, randomized controlled trials or ACO validation studies are important in determining future implications on cardiovascular outcomes. DISCLOSURES: No funding was involved in the preparation of this report. The authors have no conflicts of interest to declare. Both authors contributed equally to data collection, analysis, and manuscript preparation. PMID- 28854073 TI - Major Bleeding Risk During Anticoagulation with Warfarin, Dabigatran, Apixaban, or Rivaroxaban in Patients with Nonvalvular Atrial Fibrillation. AB - BACKGROUND: The use of non-vitamin K oral anticoagulants (NOACs) has increased steadily following marketing approval; however, their relative safety in nonvalvular atrial fibrillation (NVAF) patients in real-world clinical practice remains unclear. OBJECTIVE: To compare the risk of major bleeding during anticoagulation therapy between warfarin and NOACs. METHODS: This retrospective cohort study analyzed administrative claims data on new NVAF users of warfarin, dabigatran, apixaban, or rivaroxaban in routine clinical care from November 2010 to February 2015 in a commercially insured population in the United States. The primary outcome was time to first major bleeding event requiring hospitalization. Patients were followed until discontinuation or switch of anticoagulants, health plan disenrollment, death, or end of study. All patient characteristics were balanced after propensity score inverse probability of treatment (IPT) weighting. Event rates by type of anticoagulant exposure were compared using IPT-weighted Cox proportional hazards models. RESULTS: The study cohort comprised 44,057 patients who used warfarin (n = 23,431), dabigatran (n = 8,539), apixaban (n = 3,689), and rivaroxaban (n = 8,398). Overall mean (SD) age was 70 (12) years, and 41% of the patients were women. A total of 2,337 major bleeding events occurred during 36,636.2 person-years of follow-up. The unadjusted rate of major bleeding with warfarin was 6.0 per 100 person-years versus 2.8 with dabigatran, 3.3 with apixban, and 5.0 with rivaroxaban. Relative to warfarin, major bleeding risk was lower with dabigatran (HR = 0.67, 95% CI = 0.60-0.76) and apixaban (HR = 0.52, 95% CI = 0.41-0.67). Compared with rivaroxaban, major bleeding risk was also lower with dabigatran (HR = 0.67, 95% CI = 0.58-0.78) and apixaban (HR = 0.52, 95% CI = 0.40-0.68). Major bleeding risk was similar for rivaroxaban and warfarin. Relative to apixaban, dabigatran was associated with a significantly higher risk of major gastrointestinal bleeding (HR = 1.43, 95% CI = 1.09-1.88). CONCLUSIONS: Study results were consistent with safety findings from pivotal clinical trials comparing NOACs with warfarin and added the perspective of a large real-world observational study that compared bleeding risks associated with NOACs during anticoagulation therapy. Apixaban and dabigatran were associated with lower major bleeding risk compared with warfarin or rivaroxaban; however, apixaban had a lower risk of major gastrointestinal bleeding than dabigatran. These findings can help inform the choice of an optimal agent, which must balance effectiveness and bleeding risk in complex patients. DISCLOSURES: This study was funded by Anthem. Adeboyeje, Sylwestrzak, and Barron are employees of HealthCore, a wholly owned and independently operated subsidiary of Anthem. White, Rosenberg, Abarca, and Crawford are employees of Anthem. Study concept and design were primarily contributed by Adeboyeje and Sylwestrzak, along with the other authors. Adeboyeje took the lead in data collection, along with Sylwestrzak and Barron. Data interpretation was performed primarily by Rosenberg, Crawford, and Redberg, with assistance from the other authors. The manuscript was written by all the authors and revised primarily by White, Abarca, and Redberg, along with the other authors. PMID- 28854074 TI - Implementation of a New Clinic-Based, Pharmacist-Managed PCSK9 Inhibitor Consultation Service. AB - BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab were approved by the FDA in 2015. In anticipation of provider interest and a potential increase in referrals to the on-site specialty pharmacy, we created a pharmacist-managed consultation service. PROGRAM DESCRIPTION: The development of a clinic-based pharmacist-managed consultation service for the management of the PCSK9 inhibitor agents alirocumab and evolocumab is described. Key implementation steps included (a) creation of a pharmacy team and collaboration with cardiology; (b) completion of a needs assessment; (c) service creation; (d) collaboration with the on-site specialty pharmacy; (e) development of an electronic consult order and consult pool; (f) personnel training; and (g) service approval and marketing. The service development occurred over 9 months (July 2015-April 2016) and was implemented hospital-wide in May 2016. OBSERVATIONS: The University of Illinois Hospital and Health Sciences System PCSK9 inhibitor consultation service successfully integrated the benefits of a clinical review process, information technology capabilities of an electronic medical record system, and collaboration with the on-site specialty pharmacy to provide a comprehensive service that aimed to facilitate appropriate medication management from prescribing to patient administration and provide monitoring for this class of specialty medications. IMPLICATIONS/RECOMMENDATIONS: The PCSK9 pharmacist-managed consultation service provides a method for complex therapies to be managed comprehensively through the collaboration of ambulatory care clinics and outpatient specialty pharmacies. DISCLOSURES: No outside funding supported this study. Groo reports speaker bureau fees from Pfizer and Bristol-Myers Squibb. The other authors have nothing to disclose. All the authors contributed to study concept and design. Atande took the lead in data collection, and data interpretation was performed by Groo and Atanda. The manuscript was written by Atanda and revised by all the authors. PMID- 28854075 TI - Adherence to Rivaroxaban Compared with Other Oral Anticoagulant Agents Among Patients with Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Adherence to oral anticoagulant (OAC) agents is important for patients with nonvalvular atrial fibrillation (NVAF) to prevent potentially severe adverse events. OBJECTIVE: To compare real-world adherence rates and time to discontinuation for rivaroxaban versus other OACs (apixaban, dabigatran, and warfarin) among patients with NVAF using claims-based data. METHODS: Health care claims from the IMS Health Real-World Data Adjudicated Claims database (July 2012 June 2015) were analyzed. Adherence rate was defined as the percentage of patients with proportion of days covered (PDC) >= 0.80 and >= 0.90. Discontinuation was defined as a gap of more than 30 days between the end of a dispensing days of supply and the start date of the next fill, if any. Patients were included if they had >= 2 dispensings of rivaroxaban, apixaban, dabigatran, or warfarin at least 180 days apart (the first was considered the index date), had > 60 days of supply, had >= 6 months of pre-index eligibility, had >= 1 atrial fibrillation (AF) diagnosis pre-index or at index date, and had no valvular involvement. A logistic regression model was used to evaluate adherence to OAC therapy, while a Cox model was used to compare time to discontinuation; both models adjusted for baseline confounders. RESULTS: A total of 13,645 rivaroxaban, 6,304 apixaban, 3,360 dabigatran, and 13,366 warfarin patients were identified. A significantly higher proportion of rivaroxaban users (80.1%) was adherent to therapy (PDC >= 0.80 at 6 months) versus apixaban (75.8%), dabigatran (69.2%), and warfarin users (64.5%). After adjustment, the proportion of patients adherent to therapy remained significantly higher for rivaroxaban users versus apixaban (absolute difference [AD] = 5.8%), dabigatran (AD = 9.5%), and warfarin users (AD = 13.6%; all P < 0.001). More pronounced differences were found with a PDC >=0.90. In addition, rivaroxaban users were significantly less likely to discontinue therapy compared with other OACs after adjustments (all P < 0.05). CONCLUSIONS: Among NVAF patients, rivaroxaban was associated with significantly higher adherence rates relative to other OACs whether using either a PDC of > 0.80 or > 0.90. Such differences in adherence could translate into improved patient outcomes and lower health care costs. DISCLOSURES: This research was funded by Janssen Scientific Affairs. Ashton, Crivera, and Schein are employees and stockholders of Janssen Scientific Affairs. Laliberte, Germain, Wynant, and Lefebvre are employees of Analysis Group, a consulting company that received research grants from Janssen Scientific Affairs in connection with this study. McHorney is an employee of Evidera, a consulting company that received research grants from Janssen Scientific Affairs in connection with this study. Peterson received research grants from Janssen Scientific Affairs in connection with this study. All authors contributed to concept and design. The data were collected by Germain, Wynant, Laliberte, and Lefebvre and interpreted primarily by McHorney and Peterson, with the assistance of Lefebvre, Laliberte, Ashton, Crivera, and Schein. The manuscript was written primarily by Laliberte, Germain, and Lefebvre, with the assistance of Wynant. Revisions were made primarily by Ashton, Crivera, McHorney, Schein, and Peterson. PMID- 28854076 TI - Estimation of Missed Statin Prescription Use in an Administrative Claims Dataset. AB - BACKGROUND: Nonadherence to statin medications is associated with increased risk of cardiovascular disease and poses a challenge to lipid management in patients who are at risk for atherosclerotic cardiovascular disease. Numerous studies have examined statin adherence based on administrative claims data; however, these data may underestimate statin use in patients who participate in generic drug discount programs or who have alternative coverage. OBJECTIVE: To estimate the proportion of patients with missing statin claims in a claims database and determine how missing claims affect commonly used utilization metrics. METHODS: This retrospective cohort study used pharmacy data from the PharMetrics Plus (P+) claims dataset linked to the IMS longitudinal pharmacy point-of-sale prescription database (LRx) from January 1, 2012, through December 31, 2014. Eligible patients were represented in the P+ and LRx datasets, had >=1 claim for a statin (index claim) in either database, and had >= 24 months of continuous enrollment in P+. Patients were linked between P+ and LRx using a deterministic method. Duplicate claims between LRx and P+ were removed to produce a new dataset comprised of P+ claims augmented with LRx claims. Statin use was then compared between P+ and the augmented P+ dataset. Utilization metrics that were evaluated included percentage of patients with >= 1 missing statin claim over 12 months in P+; the number of patients misclassified as new users in P+; the number of patients misclassified as nonstatin users in P+; the change in 12-month medication possession ratio (MPR) and proportion of days covered (PDC) in P+; the comparison between P+ and LRx of classifications of statin treatment patterns (statin intensity and patients with treatment modifications); and the payment status for missing statin claims. RESULTS: Data from 965,785 patients with statin claims in P+ were analyzed (mean age 56.6 years; 57% male). In P+, 20.1% had >= 1 missing statin claim post-index; 13.7% were misclassified as nonstatin users; and 14.9% were misclassified as new statin users. MPR was higher in the augmented P+ dataset versus the P+ dataset alone for all patients (79.4% vs. 76.7%, P < 0.001) and new users (61.4% vs. 58.7%, P < 0.001). Similarly, mean PDC was higher in the P+ dataset augmented with LRx versus the P+ dataset alone for all patients (76.0% vs. 74.0%, P < 0.001) and new users (58.5% vs. 56.5%, P < 0.001). Most patients received moderate-intensity statins; few changes in dose, intensity, or discontinuation of statins were observed when the P+ dataset was augmented. The most common reasons for missing data were payment by an alternate third-party program (66.3%) and use of cash, coupon, or discount cards (18.7%). CONCLUSIONS: Augmenting commercial claims data with point-of-sale data provides a more accurate assessment of statin use than claims data alone. DISCLOSURES: This study was funded by Amgen, which contributed to data interpretation and manuscript preparation. Wade, Hill, and De are employees of QuintilesIMS, which received funding from Amgen for work on this study. Patel and Harrison are employees of Amgen and own Amgen stock/stock options. Study concept and design were contributed by Wade, Hill, Patel, and Harrison. De took the lead in data collection, along with the other authors, and all authors contributed to data analysis. The manuscript was written and revised by all the authors. PMID- 28854077 TI - Adherence to Rivaroxaban, Dabigatran, and Apixaban for Stroke Prevention for Newly Diagnosed and Treatment-Naive Atrial Fibrillation Patients: An Update Using 2013-2014 Data. AB - BACKGROUND: Few studies have assessed adherence to non-vitamin K antagonist oral anticoagulants (NOACs), especially using contemporary data now that multiple NOACs are available. OBJECTIVE: To compare adherence and treatment patterns among NOACs for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Incident and treatment-naive NVAF patients were identified during 2013-2014 from a large claims database in this retrospective cohort study. Patients were included who initiated rivaroxaban, dabigatran, or apixaban within 30 days after diagnosis. Adherence to the index medication and adherence to any oral anticoagulant was assessed using the proportion of days covered (PDC) at 3, 6, and 9 months. The number of switches and gaps in therapy were also evaluated. Analyses were stratified by stroke risk scores, and a logistic regression model was used to control for factors that may predict high adherence. RESULTS: Dabigatran had lower adherence (PDC = 0.76, 0.64, 0.57) compared with rivaroxaban (PDC = 0.83, 0.73, 0.66; P < 0.001) and apixaban (PDC = 0.82, 0.72, 0.66; P < 0.001) at 3, 6, and 9 months of follow-up and twice the number of switches to either other anticoagulants or antiplatelet therapy. Adherence was higher overall as stroke risk increased, and dabigatran had consistently lower adherence compared with the other NOACs. Multivariable logistic regression predicting PDC >= 0.80 showed rivaroxaban users with higher odds of high adherence compared with dabigatran or rivaroxaban across all time periods. Adjusted analyses showed that increasing age and comorbid hypertension and diabetes were associated with higher adherence. CONCLUSIONS: In this real-world analysis of adherence to NOACs, rivaroxaban and apixaban had favorable unadjusted adherence profiles compared with dabigatran, while rivaroxaban users had higher odds of high adherence (PDC >= 0.80) among the NOACs in adjusted analyses. Clinicians and managed care organizations should consider the implications of lower adherence on clinical outcomes and quality assessment. DISCLOSURES: This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors have nothing to disclose. Study concept and design were contributed by Brown and Shewale. Brown and Talbert collected the data, and data analysis was performed primarily by Brown, along with Shewale and Talbert. The manuscript was written primarily by Brown, along with Shewale, and revised by all the authors. PMID- 28854078 TI - Changes in Treatment Patterns and Incremental Health Care Utilization Due to P2Y12-Associated Complications in Patients with Acute Coronary Syndrome. AB - BACKGROUND: P2Y12 antiplatelet therapy (APT) is highly efficacious in reducing the incidence of ischemic events in patients with acute coronary syndrome (ACS); however, it is associated with several adverse complications. Data on P2Y12 associated complications and adherence to APT are sparse. OBJECTIVE: To describe the characteristics, frequency of P2Y12-associated complications, adherence and persistence to P2Y12 APT, and health care utilization among ACS patients on P2Y12 APT. METHODS: This retrospective observational study of the MarketScan Commercial Claims and Encounters Database identified patients aged >= 18 years who were discharged from an ACS hospitalization in 2012-2014 and initiated P2Y12 APT (ticagrelor, prasugrel, or clopidogrel). The proportion of patients within each treatment group who experienced P2Y12-associated complications within 1 year and who were adherent to APT were determined. Frequencies of all-cause health care utilization (i.e., hospitalization, length of stay, emergency room [ER] visits, outpatient visits, cardiac events, and transfusions) were evaluated for each treatment group. Poisson regressions were conducted to evaluate the association between nonad-herence with P2Y12 APT and health care utilization, after adjusting for demographics (age and gender), health insurance type, and comorbidities. RESULTS: Among 11,629 ACS patients, most were male; 44.6% had hypertension; 20.6% had diabetes; and 53.4% had hyperlipidemia. Clopidogrel use was common (62.6%), with ticagrelor use less common (9.0%). Among all groups, approximately one third experienced P2Y12-associated complications. One-year adherence to APT was suboptimal (68% overall), with 73.3% adherence among prasugrel users, followed by 71.4% adherence among ticagrelor users and 65.6% adherence among clopidogrel users. Switching was most common with ticagrelor users. Inpatient hospitalizations, cardiac events, and transfusions were more common in clopidogrel users compared with prasugrel and ticagrelor users. Nonadherent patients experienced significantly more hospitalizations, ER visits, and transfusions (1.34, 1.09, and 1.85 [P < 0.05], respectively) compared with adherent patients. These trends of association remained consistent across all treatment groups. Also, patients not adherent to ticagrelor experienced 1.9 times as many cardiac events as adherent patients. However, this association was not significant for clopidogrel and prasugrel users. Patients not adherent to P2Y12 APT experienced significantly lower outpatient visits compared with adherent patients. CONCLUSIONS: Complications associated with P2Y12 in ACS patients treated with P2Y12 APT were common, with dyspnea, heart block, and major or life threatening bleeding as the most common. Adherence was significantly associated with lower health care utilization. Increased adherence to secondary prevention therapy among these very high-risk patients is crucial. Disease management strategies to improve adherence and reduce treatment-associated adverse events through individualized patient care, alternative secondary treatment options, and physician awareness should be designed, implemented, and sustained. DISCLOSURES: Data analysis was conducted by Merck & Co., the manufacturer of vorapaxar (ZONTIVITY). At the time of this study, Vyas was an employee of Rutgers University, which received grant funding from Merck & Co. for this study, and is now employed with the University of Rhode Island. Patel was employed by Symphony Solutions and the University of North Carolina during the drafting and revising of the manuscript. Bash is employed by Merck & Co. Simpson received consulting fees from Merck & Co. for work on this study and has received fees for research from Amgen and Pfizer. Study concept and design were contributed by Vyas, Bash, Patel, and Simpson. Patel took the lead in data collection, assisted by the other authors. All the authors contributed equally to data analysis and manuscript preparation. The abstract for this study was presented as a poster at the American Heart Association Scientific Sessions 2016; November 12-16, 2016; New Orleans, Louisiana. PMID- 28854079 TI - Identification of Patients with Statin Intolerance in a Managed Care Plan: A Comparison of 2 Claims-Based Algorithms. AB - BACKGROUND: While statins are safe and efficacious, some patients may experience statin intolerance or treatment-limiting adverse events. Identifying patients with statin intolerance may allow optimal management of cardiovascular event risk through other strategies. Recently, an administrative claims data (ACD) algorithm was developed to identify patients with statin intolerance and validated against electronic medical records. However, how this algorithm compared with perceptions of statin intolerance by integrated delivery networks remains largely unknown. OBJECTIVE: To determine the concurrent validity of an algorithm developed by a regional integrated delivery network multidisciplinary panel (MP) and a published ACD algorithm in identifying patients with statin intolerance. METHODS: The MP consisted of 3 physicians and 2 pharmacists with expertise in cardiology, internal medicine, and formulary management. The MP algorithm used pharmacy and medical claims to identify patients with statin intolerance, classifying them as having statin intolerance if they met any of the following criteria: (a) medical claim for rhabdomyolysis, (b) medical claim for muscle weakness, (c) an outpatient medical claim for creatinine kinase assay, (d) fills for >= 2 different statins excluding dose increases, (e) decrease in statin dose, or (f) discontinuation of a statin with a subsequent fill for a nonstatin lipid-lowering therapy. The validated ACD algorithm identified statin intolerance as absolute intolerance with rhabdomyolysis; absolute intolerance without rhabdomyolysis (i.e., other adverse events); or as dose titration intolerance. Adult patients (aged >= 18 years) from the integrated delivery network with at least 1 prescription fill for a statin between January 1, 2011, and December 31, 2012 (first fill defined the index date) were identified. Patients with >= 1 year pre- and >= 2 years post-index continuous enrollment and no statin prescription fills in the pre-index period were included. The MP and ACD algorithms were applied to the population, and concordance was examined using individual (i.e., sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) and overall performance measures (i.e., accuracy, Cohen's kappa coefficient, balanced accuracy, F-1 score, and phi coefficient). RESULTS: After applying the inclusion criteria, 7,490 patients were evaluated for statin intolerance. The mean (SD) age of the population was 51.1 (8.5) years, and 55.7% were male. The MP and ACD algorithms classified 11.3% and 5.4% of patients as having statin intolerance, respectively. The concordance of the MP algorithm was mixed, with negative classification of statin intolerance measures having high concordance (specificity 0.91, NPV 0.97) and positive classification of statin intolerance measures having poor concordance (sensitivity 0.45, PPV 0.21). Overall performance measures showed mixed agreement between the algorithms. CONCLUSIONS: Both algorithms used a mix of pharmacy and medical claims and may be useful for organizations interested in identifying patients with statin intolerance. By identifying patients with statin intolerance, organizations may consider a variety of options, including using nonstatin lipid-lowering therapies, to manage cardiovascular event risk in these patients. DISCLOSURES: This study was funded by Regeneron Pharmaceuticals and Sanofi US. Boklage is employed by, and owns stock in, Regeneron, and Charland is employed by Sanofi. Bellows has received fees from Avenir for advisory board membership and grants from Myriad Genetics, Biogen, Janssen, and National Institutes of Health. Brixner reports advisory board and consultancy fees and grants from Sanofi. Mitchell reports consultancy fees from Sanofi. Study concept and design were contributed by Bellows, Boklage, Charland, and Brixner. Bellows, Sainski-Nguyen, and Olsen took the lead in data collection, along with Mitchell. Data interpretation was performed by Mitchell, along with the other authors. The manuscript was written by Bellows, Sainski-Nguyen, and Olsen and revised by all the authors. PMID- 28854080 TI - Biological events and molecular signaling following MLKL activation during necroptosis. AB - Necroptosis is a form of programmed necrotic cell death mediated by the kinase RIPK3 and its substrate MLKL. MLKL, which displays plasma membrane (PM) pore forming activity upon phosphorylation, functions as the executioner during necroptosis. Thus, it was previously assumed that MLKL phosphorylation is the endpoint of the necroptotic signaling pathway. Here, we summarize several events that characterize the dying necroptotic cells after MLKL phosphorylation, including Ca2+ influx, phosphatidylserine (PS) externalization, PM repair by ESCRT-III activation, and the final compromise of PM integrity. These processes add several unexpected regulatory events downstream of MLKL signaling. We have also observed that CoCl2, which may mimic hypoxia, can induce necroptosis, which suggests that in vivo triggers of necroptosis might include a transient lack of O2. PMID- 28854081 TI - Treatment of axillary web syndrome using instrument assisted soft tissue mobilization and thoracic manipulation for associated thoracic rotation dysfunction. AB - PURPOSE: There is a paucity of research that investigates physical therapy management for patients with axillary web syndrome (AWS) and thoracic rotation dysfunction. The purpose of this case report is to describe the management of a patient with AWS and thoracic rotation dysfunction using an impairment-based approach that includes instrument assisted soft tissue mobilization (IASTM), thoracic manipulation, and stretching. CASE DESCRIPTION: The patient was a 48 year-old female with a past medical history of bilateral breast cancer with a bilateral latissimus dorsi flap reconstruction. The patient was referred to physical therapy with chief complaints of right shoulder pain with reaching and an inability to resume running due to right shoulder and scapula pain. The patient was seen in outpatient physical therapy for four visits over four weeks. Treatment consisted of IASTM, thoracic manipulation, stretching exercises, and home exercise program instruction. OUTCOMES: Upon discharge, the patient had improved right shoulder and thoracic range of motion, decreased pain, and improved function on the patient specific functional scale (PSFS). CONCLUSION: Utilization of an impairment-based physical therapy approach to treat a patient with AWS and thoracic dysfunction yielded positive outcomes. Further research on the efficacy of IASTM and physical therapy management of AWS is warranted. PMID- 28854083 TI - Eosinophilic Bronchitis. PMID- 28854082 TI - Protein engineering to increase the potential of a therapeutic antibody Fab for long-acting delivery to the eye. AB - To date, ocular antibody therapies for the treatment of retinal diseases rely on injection of the drug into the vitreous chamber of the eye. Given the burden for patients undergoing this procedure, less frequent dosing through the use of long acting delivery (LAD) technologies is highly desirable. These technologies usually require a highly concentrated formulation and the antibody must be stable against extended exposure to physiological conditions. Here we have increased the potential of a therapeutic antibody antigen-binding fragment (Fab) for LAD by using protein engineering to enhance the chemical and physical stability of the molecule. Structure-guided amino acid substitutions in a negatively charged complementarity determining region (CDR-L1) of an anti-factor D (AFD) Fab resulted in increased chemical stability and solubility. A variant of AFD (AFD.v8), which combines light chain substitutions (VL-D28S:D30E:D31S) with a substitution (VH-D61E) to stabilize a heavy chain isomerization site, retained complement factor D binding and inhibition potency and has properties suitable for LAD. This variant was amenable to high protein concentration (>250 mg/mL), low ionic strength formulation suitable for intravitreal injection. AFD.v8 had acceptable pharmacokinetic (PK) properties upon intravitreal injection in rabbits, and improved stability under both formulation and physiological conditions. Simulations of expected human PK behavior indicated greater exposure with a 25-mg dose enabled by the increased solubility of AFD.v8. PMID- 28854084 TI - Abandonment. PMID- 28854086 TI - Myeloproliferative Neoplasms. PMID- 28854087 TI - Myeloproliferative Neoplasms. PMID- 28854088 TI - Precision Diagnosis and Treatment for Advanced Non-Small-Cell Lung Cancer. PMID- 28854090 TI - Interprofessional Education - A Foundation for a New Approach to Health Care. PMID- 28854089 TI - Case 27-2017. A 32-Year-Old Man with Acute Chest Pain. PMID- 28854091 TI - Medical Assistance in Dying. PMID- 28854092 TI - Medical Assistance in Dying. PMID- 28854093 TI - Sturge-Weber Syndrome. PMID- 28854094 TI - A Tale of Two Epidemics - HCV Treatment among Native Americans and Veterans. PMID- 28854095 TI - Porphyria. PMID- 28854097 TI - A New Chapter for Diabetic Kidney Disease. PMID- 28854096 TI - Targeting the Colorectal Cancer Stem Cell. PMID- 28854098 TI - Lithium Use in Pregnancy and the Risk of Cardiac Malformations. PMID- 28854099 TI - Melanoma Sentinel-Node Metastasis. PMID- 28854100 TI - Melanoma Sentinel-Node Metastasis. PMID- 28854101 TI - Analyses of long non-coding RNA and mRNA profiles in the spinal cord of rats using RNA sequencing during the progression of neuropathic pain in an SNI model. AB - The pathogenesis of neuropathic pain (NP) is characterized by an increased responsiveness of nociceptive neurons in the nervous system. However, the molecular mechanisms underpinning the NP still remain elusive. Recent data suggest that long non-coding RNAs (lncRNAs) regulate expression of NP-associated genes. Herein, we analyzed lncRNAs and mRNA profiles in the spinal cord of rats by RNA sequencing during the progression of NP in a spared nerve injury (SNI) model. Sprague-Dawley (SD) rats were employed for the establishment of the SNI models, and nociceptive responses to mechanical and thermal stimuli were measured 3 hours prior to surgery and on postoperative days 1, 3, 7 and 14, with L4-5 spinal cords extracted from three SD rats under deep anesthesia at each time point after behavioral test. SNI rats exhibited higher sensitivity to mechanical stimuli from days 1 to 14. Mechanical hyperalgesia reached a steady peak at day14 after surgery, whereas thermal allodynia did not develop. The results of second generation sequencing suggested that the expression profiles of lncRNAs and mRNAs were significantly altered in spinal cords of SNI rats versus the control rats at different stages during NP. Differentially expressed (DE) lncRNAs and mRNAs were demonstrated at each stage during the NP course using Volcano Plot, Venn and Hcluster heatmap analyses. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses were performed to predict the functionalities of differentially expressed lncRNAs and target genes. Protein interaction networks were constructed based on the correlation analyses of DE lncRNA target proteins at 7 and 14 days after SNI, respectively. Taken together, our results revealed the profiles of lncRNAs and mRNAs in the rat spinal cord under an NP condition. These lncRNAs and mRNAs may represent new therapeutic targets for the treatment of NP. PMID- 28854102 TI - Seroprevalence of hepatitis B and delta viruses among HIV-infected population attending anti-retroviral clinic in selected health facilities in Abuja, Nigeria. AB - INTRODUCTION: Triple infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis D virus (HDV) is rare. There is limited data on the seroprevalence of HIV/HBV/HDV tri-infection especially in Nigeria. The aim of this study was to determine the seroprevalences of HBsAg and HDV among HIV infected individuals attending anti-retroviral (ARV) clinics in Abuja, Nigeria. METHODS: In this cohort study, blood samples were collected from 1102 (male = 450; female = 652), with age range <20 to >=51 years (mean age = 34.0; SD = 11.5), consenting HIV-infected population attending ARV clinics at selected health facilities in Abuja, Nigeria, between April and October 2016. A well structured questionnaire was used to capture demographic information from the respondents. Enzyme-linked immunosorbent assay (ELISA) was used to determine the seroprevalence of hepatitis B surface antigen and anti-HDV. The result was interpreted according to manufacturer's instruction. Statistical data were analyzed using SPSS software version 21, and chi-square (chi2) test was used to determine association with P < 0.05 considered significant. RESULTS: Overall seroprevalences of 10.3%, 7.1%, and 0.7% for HBV, HBV/HDV, and HIV/HBV/HDV, respectively, were found among the study population. The infection rate (13.3%) peaked at age range of 31-40 years for HBV (P = 0.002), 50% at <20 years for HBV/HDV (P = 0.049), and 1.5% at 31-40 years for HIV/HBV/HDV (P = 0.202). By gender, the rate was higher in males (10.9%, 10.2%, 1.1%) than females (9.8%, 4.9%, 0.5%) for HBV, HBV/HDV, and HIV/HBV/HDV infections, respectively. However, there was no significant association between infection rate and gender. CONCLUSION: This study has established that HBV and HDV prevalence is still high in the population studied and that the rate of triple infection is low. We advocate for more robust control measures for HBV which should be extended to HDV in HIV population through screening and vaccination. PMID- 28854104 TI - La Crosse Virus Vectors Are Host-Seeking and Ovipositing After 1700 H in Eastern Tennessee. AB - La Crosse virus (LACV) is transmitted via the bites of infected Aedes mosquitoes (Ae. triseriatus, Ae. albopictus, and Ae. japonicus) and causes La Crosse encephalitis, which is the most commonly diagnosed arbovirus in eastern Tennessee children. This study identified host-seeking and oviposition activity of LACV vectors over a diel period, as it relates to traditional working hours. Nineteen sites in Knox County, TN, were monitored with host-seeking (Centers for Disease Control and Prevention [CDC] miniature light traps) and oviposition traps (CDC gravid traps) during 2 diel periods (0900-1700 h and 1700-900 h). We collected 2,444 adult mosquitoes, comprising 19 different species of which 1,337 (54.7%) were LACV vectors: Ae. albopictus (1,207 specimens), Ae. triseriatus (85 specimens), and Ae. japonicus (45 specimens). These species were active throughout the sampling period, but significantly more were collected from 1700 0900 h. The CDC gravid trap was the most effective method for monitoring Ae. japonicus; there were no trap effects or trap * time interactive effects for Ae. albopictus or Ae. triseriatus. Overall, significantly more LACV vectors were collected from 1700-0900 h compared to 0900-1700 h. Information gathered in this study improves vector surveillance, helps communities control mosquito populations, and minimizes nontarget effects. PMID- 28854105 TI - Evaluating the Vector Control Potential of the In2Care(r) Mosquito Trap Against Aedes aegypti and Aedes albopictus Under Semifield Conditions in Manatee County, Florida. AB - Successful integrated vector management programs may need new strategies in addition to conventional larviciding and adulticiding strategies to target Aedes aegypti and Ae. albopictus, which can develop in small, often cryptic, artificial and natural containers. The In2Care(r) mosquito trap was recently developed to target and kill larval and adult stages of these invasive container-inhabiting Aedes mosquitoes by utilizing autodissemination. Gravid females that visit the trap pick up pyriproxyfen (PPF) that they later transfer to nearby larval habitats as well as Beauveria bassiana spores that slowly kill them. We assessed the efficacy of the In2Care mosquito trap in a semifield setting against locally sourced strains of Ae. aegypti and Ae. albopictus. We found that the In2Care mosquito trap is attractive to gravid Ae. aegypti and Ae. albopictus females and serves as an egg sink, preventing any adult emergence from the trap (P = 0.0053 for both species). Adult females successfully autodisseminated PPF to surrounding water-filled containers, leading to a statistically significant reduction in new mosquito emergence (P <= 0.0002 for both species). Additionally, we found effective contamination with Beauveria bassiana spores, which significantly reduced the survivorship of exposed Ae. aegypti and Ae. albopictus (P <= 0.008 for both species in all experimental setups). In summary, the In2Care mosquito trap successfully killed multiple life stages of 2 main mosquito vector species found in Florida under semifield conditions. PMID- 28854106 TI - Mosquito Vector Biology and Control in Latin America-A 27th Symposium. AB - The 27th Annual Latin American Symposium presented by the American Mosquito Control Association (AMCA) was held as part of the 83rd Annual Meeting of the AMCA in San Diego, CA, in February 2017. The Latin American Symposia promote the participation of vector control specialists, public health workers, and academicians from Latin America and the sharing of data between continents. Generally, presentations are in Spanish and simultaneously translated in English, although the majority of PowerPoint slides are in English so all meeting attendees can understand the content. This publication includes summaries of 23 oral presentations by participants from Brazil, Colombia, Mexico, Puerto Rico, and the USA. Topics addressed in the symposium included surveillance, operations and response thresholds/planning, mosquito ecology, insecticide resistance, and population control via chemicals, natural products, and biological control. Sterile insect technique protocols were explored regarding larval rearing diets and the use of microRNAs. Presentations were related to vectors including Aedes, Culex, and Anopheles mosquitoes, which can transmit malaria, dengue, chikungunya, and Zika, and Lutzomyia phlebotomine sand flies, the key vectors of leishmaniasis. PMID- 28854107 TI - Effect of Nozzle Orientation on Dispersion of Aqualuer 20-20 Sprayed by a Truck Mounted Ultra-Low Volume Sprayer Against Caged Aedes aegypti. AB - Inconsistencies in efficacy of ultra-low volume (ULV) ground applications in the literature are linked to the lack of adjustments in sprayer parameters. To investigate the effect of nozzle orientation of a truck-mounted ULV sprayer on application efficacy, a study was conducted at St. Johns County Fairground, Elkton, FL, during the summer of 2014. The efficacy was assessed by mortality of caged adult Aedes aegypti, spray deposition, and droplet size spectrum up to 122 m from the spray line. Aqualuer 20-20 (20.6% permethrin active ingredient [AI] and 20% piperonyl butoxide [PBO]) was applied at the maximum label rate with the nozzle pointed 45 degrees upward, horizontal (0 degrees ), or 30 degrees downward. Mortality was recorded after 24 h, deposition was determined with fluorometry, and droplets were measured with DropVision. Overall, horizontal nozzle angle spraying Aqualuer 20-20 achieved the highest efficacy followed by a 30 degrees downward angle, while a 45 degrees angle showed the least efficacy in open field tests. The mortality data showed complete mortality from a 0 degrees nozzle up to 122 m from the spray line except for 1 location at 122 m in 1 replication. The mortality from a 30 degrees downward orientation was lower beyond 30 m from the spray line, while the mortality from a 45 degrees upward orientation was low close to the spray line and beyond 30 m. Horizontal orientation had higher deposition than other orientations, but the differences were not significant. There was also no significant difference in droplet spectrum from all orientations. PMID- 28854108 TI - Citizen Science as a Tool for Mosquito Control. AB - In this paper, we share our findings from a 2-year citizen science program called Mosquito Stoppers. This pest-oriented citizen science project is part of a larger coupled natural-human systems project seeking to understand the fundamental drivers of mosquito population density and spatial variability in potential exposure to mosquito-borne pathogens in a matrix of human construction, urban renewal, and individual behaviors. Focusing on residents in West Baltimore, participants were recruited through neighborhood workshops and festivals. Citizen scientists participated in yard surveys of potential mosquito habitat and in evaluating mosquito nuisance. We found that citizen scientists, with minimal education and training, were able to accurately collect data that reflect trends found in a comparable researcher-generated database. PMID- 28854109 TI - VectorTestTM West Nile Virus Antigen Assay in an Inhibition Platform as Field Screening Tool for Flavivirus Group-Specific Antibodies in Brazilian Equines. AB - Current methods for detecting Flavivirus antibodies are enzyme-linked immunosorbent assays (ELISAs) and neutralization tests, both of which require laboratories and trained staff. We evaluated the VectorTestTM West Nile Virus Antigen Assay in an inhibition platform (VecTest-inhibition assay [VIA]) as a simpler screening method for detecting antibodies for a variety of flaviviruses among a population of equines from Brazil. We found that the VIA is a field deployable rapid method with 100% sensitivity and 64% specificity compared with blocking ELISA for the detection of group-specific Flavivirus antibodies in equine serum samples. The VIA is a potentially useful field test for rapid field based Flavivirus antibody detection in equine serum samples. PMID- 28854110 TI - First Record of Culex Coronator in Virginia, with Notes on Its Rapid Dispersal, Trapping Methods, and Biology. AB - Culex coronator is a Neotropical mosquito species that was first described in Trinidad in the early 20th century. Since then, the species has been discovered from Patagonia to the southern USA. A single adult female Cx. coronator was collected on November 1, 2016, in Suffolk, VA, in a BG-Sentinel 2(r) trap during routine mosquito surveillance. This represents the 1st record of this species in the state of Virginia and the northernmost record in the USA. Based on male specimens examined from Texas and Mississippi, Cx. coronator sensu stricto seems to be the only species from the complex expanding into the southeastern USA. A comprehensive review of the available literature from the southern and southeastern USA is provided describing trapping methods, ecological, and biological information. PMID- 28854111 TI - Adulticidal Susceptibility Evaluation of Aedes albopictus Using New Diagnostic Doses in Penang Island, Malaysia. AB - Insecticide-based vector control approaches are facing challenges due to the development of resistance in vector mosquitoes. Therefore, a proper resistance surveillance program using baseline lethal concentrations is crucial for resistance management strategies. Currently, the World Health Organization's (WHO) diagnostic doses established for Aedes aegypti and Anopheles species are being used to study the resistance status of Aedes albopictus. In this study, we established the diagnostic doses for permethrin, deltamethrin, and malathion using a known susceptible reference strain. Five field-collected populations were screened against these doses, following the WHO protocol. This study established the diagnostic dose of malathion at 2.4%, permethrin at 0.95%, and deltamethrin at 0.28%, which differ from the WHO doses for Aedes aegypti and Anopheles spp. Among the insecticides tested on the 5 wild populations, only deltamethrin showed high effectiveness. Different susceptibility and resistance patterns were observed with permethrin, malathion, and dichloro-diphenyl-trichloroethane (DDT) at 4%. This study may assist the health authorities to improve future chemical based vector control operations in dengue-endemic areas. PMID- 28854112 TI - Characterization of Tolypocladium cylindrosporum (Hypocreales: Ophiocordycipitaceae) and Its Impact Against Aedes aegypti and Aedes albopictus Eggs at Low Temperature. AB - We examined the growth characteristics of Tolypocladium cylindrosporum IBT 41712 and its potential to infect eggs of Aedes aegypti and Ae. albopictus at a low temperature (15 degrees C). When grown on Sabouraud dextrose agar supplemented with yeast extract, the IBT 41712 formed white colonies turning to a slightly darker, off-white color when mature. The mycelia bore swollen conidiophores producing smooth-walled, oblong to cylindrical conidia with varying sizes, ranging from 1.5 to 3.5 MUm long. To determine the optimum temperature for the fungus, we cultured the fungus at eight temperatures (4 degrees C, 12 degrees C, 15 degrees C, 21 degrees C, 28 degrees C, 33 degrees C, 37 degrees C, and 40 degrees C) and measured the diametric growth. The optimum temperature for growth was 28 degrees C since it had the highest diametric growth rate (2.1 +/- 0.05 mm/day) and the fastest sporulation period (within 8-10 days of incubation). There was no fungal growth at the 3 highest temperatures (33 degrees C, 37 degrees C, and 40 degrees C) but plates incubated at 33 degrees C, when shifted to optimal temperature (28 degrees C), showed visible growth indicating that following incubation at 33 degrees C, the fungus remained viable. The IBT 41712 successfully infected mosquito eggs at 15 degrees C. Fungal treatment induced egg hatch on moist seed-germination paper and this effect was more pronounced in Ae. aegypti compared to Ae. albopictus. When treated eggs were immersed in dH2O 21 days posttreatment, larval hatch of both Ae. aegypti (control = 91%, 1 * 107 conidia/ml, fungal treatment = 0%) and Ae. albopictus (control = 85%, fungal treatment = 28%) was significantly lower in fungal treatment compared to the controls. The ability of the strain to grow in a wide temperature range, and effectively infect mosquito eggs and induce egg hatch at a low temperature warrants further investigation for its potential as a mosquito control agent targeting eggs that overwinter or undergo long diapause. PMID- 28854113 TI - A Statewide Survey for Container-Breeding Mosquitoes in Mississippi. AB - Container-breeding mosquitoes are important in public health due to outbreaks of Zika, chikungunya, and dengue viruses. This paper documents the distribution of container-breeding mosquito species in Mississippi, with special emphasis on the genus Aedes. Five sites in each of the 82 Mississippi counties were sampled monthly between May 1 and August 31, 2016, and 50,109 mosquitoes in 14 species were collected. The most prevalent and widely distributed species found was Ae. albopictus, being found in all 82 counties, especially during July. A recent invasive, Ae. japonicus, seems to be spreading rapidly in Mississippi since first being discovered in the state in 2011. The most abundant Culex species collected were Cx. quinquefasciatus (found statewide), Cx. salinarius (almost exclusively in the southern portion of the state), and Cx. restuans (mostly central and southern Mississippi). Another relatively recent invasive species, Cx. coronator, was found in 20 counties, predominantly in the southern one-third of the state during late summer. Co-occurrence data of mosquito species found in the artificial containers were also documented and analyzed. Lastly, even though we sampled extensively in 410 sites across Mississippi, no larval Ae. aegypti were found. These data represent the first modern statewide survey of container species in Mississippi, and as such, allows for better public health readiness for emerging diseases and design of more effective vector control programs. PMID- 28854114 TI - Evidence for Sticky-Trap Avoidance by Stable Fly, Stomoxys calcitrans (Diptera: Muscidae), in Response to Trapped Flies. AB - Populations of stable flies, Stomoxys calcitrans, and other filth flies are often sampled using sticky traps. We wanted to know whether flies already caught on sticky traps might inhibit to some extent subsequent flies from being caught. To test this, we recorded the number of stable flies landing on white plastic corrugated panels (Coroplast(r)), which were prepared according to 4 treatments: 12 live stable flies glued to the surface, 12 live house flies (Musca domestica) glued to the surface, 12 black dots, and no treatment. From 160 observations, we found that fewer stable flies landed on panels with either attached stable flies (129) or house flies (133) compared with the number landing on panels with black dots (259) and/or with no treatment (210). This apparent inhibitory effect of trapped flies may explain published trap-catch patterns from field studies. PMID- 28854116 TI - First Data on Resistance to Pyrethroids in Wild Populations of Aedes albopictus from Spain. AB - The invasive mosquito, Aedes albopictus, found in Spain since 2004, is a competent vector of yellow fever, Zika, dengue, and chikungunya viruses among other diseases. Although controversial, the use of adulticiding is a relevant tool for vector control and could be crucial for the management of any possible outbreak of imported diseases. We present the 1st study in Spain on the susceptibility of field populations from Barcelona, Peniscola, Castellon, and Mallorca of Ae. albopictus to several pyrethroids using either bioassays under the World Health Organization methodology and biochemical tests. In the bioassays, the discriminating concentrations were calculated using a local, susceptible laboratory strain. Different susceptibility levels were found for some combinations of populations and products. The biochemical tests carried out by enzymatic analysis supported these results, showing an overexpression of glutathione S-transferase activity in 1 population. PMID- 28854115 TI - Sugar and Multivitamin Diet Effects on The Longevity and Mating Capacity of Laboratory-Reared Male Anopheline Mosquitoes. AB - Successful mating by male mosquitoes is dependent on several factors, with sugar feeding being particularly important. The effect of ingested vitamins on adult male mosquitoes is poorly understood. This laboratory study used 3 anopheline species, Anopheles campestris, An. dirus, and An. sawadwongporni, to study the effect of sugar and vitamins on male longevity, copulation, and fecundity. Males were fed 1 of 5 diets containing different combinations of sugar and vitamins: 10% glucose, 10% sucrose, 10% multivitamin syrup, 10% multivitamin syrup + 10% glucose, and 10% multivitamin syrup + 10% sucrose. The longevity of males was measured for a period of 15 days. Forced mating was used to simulate copulation, and fecundity was measured by counting the number of eggs oviposited and the hatch rate of larvae. The longevity of An. campestris and An. dirus was greatest when fed a diet of 10% multivitamin syrup + 10% glucose, and the longevity of An. sawadwongporni was greatest when fed a diet of 10% multivitamin syrup + 10% sucrose. The 1st mating routinely produced the most viable eggs when males were mated with several females. The diet of 10% multivitamin syrup + 10% sucrose produced numerically greater egg production and larval emergence for all 3 species, although this was not always statistically significant due to variability and small sample size. These results indicate that the addition of multivitamin syrup to sucrose may produce healthier and more fit male anophelines. This has potential implications for increasing insectary operations and improving the fitness of laboratory-reared male mosquitoes that will be released for mosquito and disease-pathogen control studies. PMID- 28854118 TI - Antibacterial, tyrosinase, and DNA photocleavage studies of some triazolylnucleosides. AB - In order to explore the biological potential, some synthesized triazolylnucleosides were evaluated for their antibacterial, tyrosinase and DNA photocleavage activities. Triazolylnucleosides (5-12) were screened against Staphylococcus aureus (ATCC 6538), gram-positive and Escherichia coli (ATCC 10536), gram-negative bacterial strains. Among the series, compound 9 exhibited a significant level of antibacterial activity against both strains at higher concentration in reference to the standard drug, Levofloxacin. Tyrosinase activity and inhibition of these compounds were also studied, and it has been found that compounds 8 and 11 displayed more than 50% inhibitory activity. In addition, six compounds (7-12) were evaluated for their DNA photocleavage activity. The compounds 8 and 12 exhibited excellent DNA photocleavage activity at a concentration of 10 MUg and may be used as template for antitumor drugs in the future. PMID- 28854119 TI - New tricks for an old dog: Brf2-dependent RNA Polymerase III transcription in oxidative stress and cancer. AB - Here, we discuss the role of Brf2, an RNA Polymerase III core transcription factor, as a master switch of the oxidative stress response. We highlight the interplay of Brf2 with the Nrf2/Keap1 pathway, as well as the role of Brf2 in cancer and other possible regulations. PMID- 28854120 TI - Antibody immunoprophylaxis and immunotherapy for influenza virus infection: Utilization of monoclonal or polyclonal antibodies? AB - Control programs for emerging influenza are in urgent need of novel therapeutic strategies to mitigate potentially devastating threats from pathogenic strains with pandemic potential. Current vaccines and antivirals have inherent limitations in efficacy, especially with rapid evolutionary changes of influenza viruses. Antibody-based antiviral protection harnesses the natural power of the immune system. Antibodies present prophylactic and therapeutic intervention options for prevention and control of influenza, especially for at-risk populations. Specific monoclonal antibodies are well defined in purity and initial efficacy but polyclonal antibodies are easier to scale-up and cost effective with long-term efficacy, using batches with broadly neutralizing properties against influenza variants. This review presents the pros and cons of monoclonal versus polyclonal antibody therapy for influenza. PMID- 28854121 TI - Entyloma helianthi: identification and characterization of the causal agent of sunflower white leaf smut. AB - White leaf smut is a minor foliar disease of sunflower (Helianthus annuus) in the United States. The disease occurs primarily in greenhouse-grown sunflowers in California and causes leaf spot, defoliation, and a reduction in yield and crop value. Historically, many Entyloma specimens with similar morphological characters, but infecting diverse plant genera including Helianthus, were called Entyloma polysporum. Recent comparative morphological and molecular work has shown that Entyloma species infect hosts within a single genus or species, suggesting that the sunflower Entyloma species may not be E. polysporum. In 2015, sunflower leaf smut material was collected from ornamental sunflowers in a greenhouse in Santa Barbara County, California. Morphologically, this species differed from E. polysporum in having smaller, more regular-shaped teliospores and prominently developed conidiophores with cylindrical conidia. The rDNA ITS1 5.8S-ITS2 (internal transcribed spacer [ITS]) region of the sunflower leaf smut was phylogenetically distinct from all previously sequenced Entyloma species and found only on H. annuus. This study confirms that the sunflower leaf smut pathogen represents a novel species, Entyloma helianthi. Possible misidentification of the anamorphic stage of Entyloma helianthi as another leaf spot pathogen, Ramularia helianthi, is also discussed. PMID- 28854122 TI - The Differentiating Role of State and Trait Hopelessness in Suicidal Ideation and Suicide Attempt. AB - With suicide being a leading cause of death in the United States, research must aim to increase efficacious prevention methods. The purpose of the present study was to gain greater understanding of the difference between suicidal ideation and suicide attempt. Previous research emphasizes the role of hopelessness in attempts and ideation (Bagge, Lamis, Nadorff, & Osman, 2014 ). Yet while hopelessness offers predictive value to suicide attempt, it fails in discriminating between suicide attempters and suicide ideators. Thus the goal was to examine the possible influence of different types of hopelessness on suicidal ideation and attempt. The experience of hopelessness as a temporary feeling, or state, versus as an enduring emotion, or trait, was examined in this study. The State-Trait Hopelessness Scale and 4 suicidal thought and suicidal behavior questions were assessed. Results of logistic regression analysis supported the hypothesis that state and trait hopelessness were differentially associated with ideation and attempt. While trait hopelessness was significantly positively associated with responses to all 4 suicidality questions (p's < 0.001), state hopelessness was only positively related to responses to 1 ideation question (p < 0.01). In all, these results point to the importance of understanding the role of different types of hopelessness in differentiating suicidal ideation and attempt. PMID- 28854123 TI - Performance of Faller and Nonfaller Older Adults on a Motor-Motor Interference Task. AB - Typically, falls in older adults occur when 2 tasks are performed simultaneously, due to the increased motor demand required to maintain stability and attention to perform the other task. The authors' purpose was to investigate walking while grasping, transporting, and placing a dowel on a predetermined target while manipulating difficulty levels of the manual task. Faller and nonfaller older adults performed a walking block (manual tasks combined with gait) and a stationary block (upright stance combined with manual tasks). The manual task involved grasping, transporting, and placing the dowel over a target. The results showed that fallers underperformed when compared with nonfallers in the task of placing the dowel over the target. The main difference observed between the groups was found in the condition that required allocation of attention between tasks and greater accuracy in the final placement of the object. Fallers showed gait stability similar to the nonfallers, but fallers were less accurate than nonfallers in the object placement task, especially for the highest level of difficulty. Thus, fallers seem to use a stability-first strategy. Fallers had problems in executing the manual tasks, which suggests a more global change in motor behavior rather than specific changes to balance control. PMID- 28854124 TI - "I Believe What I See": College Students' Use of Media, Issue Engagement, and Perceived Responsibility Regarding Campus Sexual Assault. AB - The topic of campus sexual assault has received much media attention recently, prompting scholars to examine media effects on students' attitudes and behaviors. A survey of 567 American college students examined how their media exposure is related to issue engagement, perceived responsibility, and acceptance of rape myths. Results indicated that reading newspaper stories about campus sexual assault might contribute to college students' victim blaming. Among other media channels examined, social media were found to be highly correlated with students' engagement with the issue. We also found that victim blaming and acceptance of rape myths could be reduced by raising students' perceived importance of the issue. Theoretical and practical implications are discussed in detail. PMID- 28854125 TI - The design of an environmentally relevant mixture of persistent organic pollutants for use in in vivo and in vitro studies. AB - Amongst the substances listed as persistent organic pollutants (POP) under the Stockholm Convention on Persistent Organic Pollutants (SCPOP) are chlorinated, brominated, and fluorinated compounds. Most experimental studies investigating effects of POP employ single compounds. Studies focusing on effects of POP mixtures are limited, and often conducted using extracts from collected specimens. Confounding effects of unmeasured substances in such extracts may bias the estimates of presumed causal relationships being examined. The aim of this investigation was to design a model of an environmentally relevant mixture of POP for use in experimental studies, containing 29 different chlorinated, brominated, and perfluorinated compounds. POP listed under the SCPOP and reported to occur at the highest levels in Scandinavian food, blood, or breast milk prior to 2012 were selected, and two different mixtures representing varying exposure scenarios constructed. The in vivo mixture contained POP concentrations based upon human estimated daily intakes (EDIs), whereas the in vitro mixture was based upon levels in human blood. In addition to total in vitro mixture, 6 submixtures containing the same concentration of chlorinated + brominated, chlorinated + perfluorinated, brominated + perfluorinated, or chlorinated, brominated or perfluorinated compounds only were constructed. Using submixtures enables investigating the effect of adding or removing one or more chemical groups. Concentrations of compounds included in feed and in vitro mixtures were verified by chemical analysis. It is suggested that this method may be utilized to construct realistic mixtures of environmental contaminants for toxicity studies based upon the relative levels of POP to which individuals are exposed. PMID- 28854126 TI - The Influence of Guided Error-Based Learning on Motor Skills Self-Efficacy and Achievement. AB - The authors investigated the role of errors in motor skills teaching, specifically the influence of errors on skills self-efficacy and achievement. The participants were 75 undergraduate students enrolled in petanque courses. The experimental group (guided error-based learning, n = 37) received a 6-week period of instruction based on the students' errors, whereas the control group (correct motion instruction, n = 38) received a 6-week period of instruction emphasizing correct motor skills. The experimental group had significantly higher scores in motor skills self-efficacy and outcomes than did the control group. Novices' errors reflect their schema in motor skills learning, which provides a basis for instructors to implement student-centered instruction and to facilitate the learning process. Guided error-based learning can effectively enhance beginners' skills self-efficacy and achievement in precision sports such as petanque. PMID- 28854127 TI - Adding Insult to Injury: Sex, Sexual Orientation, and Juror Decision-Making in a Case of Intimate Partner Violence. AB - Societal definitions of intimate partner violence (IPV) are highly gendered and heteronormative, resulting in dissonance regarding cases of same-sex IPV. This study explored perceptions of IPV when the context of the case is inconsistent with societal norms regarding sex and sexuality. Mock jurors read a vignette describing a case of alleged IPV in which the sex and sexual orientation of the defendant were manipulated. Participants (N = 415) rendered a verdict and provided ratings of the defendant, victim, and case. Results suggest participants were more confident in a guilty verdict when the defendant was male, compared to female. Further, male defendants were perceived as more morally responsible, but only when the victim was female. Perceptions regarding the crime suggest violence perpetrated by a man against a woman is viewed more adversely than any other condition. Data are discussed in terms of implications for legal decision-makers and public policy. PMID- 28854128 TI - Digital Health Communication and Global Public Influence: A Study of the Ebola Epidemic. AB - Scientists and health communication professionals expressed frustration over the relationship between misinformation circulating on the Internet and global public perceptions of and responses to the Ebola epidemic originating in West Africa. Using the big data platform Media Cloud, we analyzed all English-language stories about keyword "Ebola" published from 1 July 2014 to 17 November 2014 from the media sets U.S. Mainstream Media, U.S. Regional Media, U.S. Political Blogs, U.S. Popular Blogs, Europe Media Monitor, and Global Voices to understand how social network theory and models of the networked global public may have contributed to health communication efforts. 109,400 stories met our inclusion criteria. The CDC and WHO were the two media sources with the most inlinks (hyperlinks directed to their sites). Twitter was fourth Significantly more public engagement on social media globally was directed toward stories about risks of U.S. domestic Ebola infections than toward stories focused on Ebola infections in West Africa or on science-based information. Corresponding public sentiments about Ebola were reflected in the policy responses of the international community, including violations of the International Health Regulations and the treatment of potentially exposed individuals. The digitally networked global public may have influenced the discourse, sentiment, and response to the Ebola epidemic. PMID- 28854129 TI - The Opposite of Denial: Social Learning at the Onset of the Ebola Emergency in Liberia. AB - This study analyzes findings from a rapid-response community-based qualitative research initiative to study the content of Ebola-related communications and the transmission of Ebola-related behaviors and practices through mass media communications and social learning in Monrovia, Liberia during August-September 2014. Thirteen neighborhoods in the common Monrovia media market were studied to appraise the reach of health communications and outreach regarding Ebola prevention and response measures. A World Health Organization (WHO) research team collected data on social learning and Ebola knowledge, attitudes, and practices through focus group-based discussions and key informant interviews over a 14-day period to assess the spread of information during a period of rapidly escalating crisis. Findings show that during a 2-week period, Monrovia neighborhood residents demonstrated rapid changes in beliefs about the source of Ebola, modes of contagion, and infection prevention and control (IPC) practices, discarding incorrect information. Changes in practices tended to lag behind the acquisition of learning. Findings also show that many continued to support conspiracy theories even as correct information was acquired. The implications for community engagement are substantial: (1) Under conditions of accelerating mortality, communities rapidly assimilate health information and abandon incorrect information; (2) Behavior change is likely to lag behind changes in beliefs due to local physical, structural, sociocultural, and institutional constraints; (3) Reports of "resistance" in Monrovia during the Ebola response were overstated and based on a limited number of incidents, and failed to account for specific local conditions and constraints. PMID- 28854130 TI - Facilitators and Barriers to Community Acceptance of Safe, Dignified Medical Burials in the Context of an Ebola Epidemic, Sierra Leone, 2014. AB - Sierra Leone was heavily affected by the Ebola epidemic, with over 14,000 total cases. Given that corpses of people who have died from Ebola are highly infectious and given the extremely high risk of Ebola transmission associated with direct contact with bodies of people who have died of Ebola, community acceptance of safe, dignified medical burials was one of the important components of efforts to stop the Ebola epidemic in Sierra Leone. Information on barriers and facilitators for community acceptance of safe, dignified medical burials is limited. A rapid qualitative assessment using focus group discussions (FGDs) explored community knowledge, attitudes, and practices towards safe and dignified burials in seven chiefdoms in Bo District, Sierra Leone. In total, 63 FGDs were conducted among three groups: women >25 years of age, men >25 years of age, and young adults 19-25 years of age. In addition to concerns about breaking cultural traditions, barriers to safe burial acceptance included concerns by family members about being able to view the burial, perceptions that bodies were improperly handled, and fear that stigma may occur if a family member receives a safe, dignified medical burial. Participants suggested that providing opportunities for community members to participate in safe and dignified burials would improve community acceptance. PMID- 28854131 TI - Including Communities in Public Health Action: Harnessing Best Practices. PMID- 28854132 TI - Use of SMS-Based Surveys in the Rapid Response to the Ebola Outbreak in Liberia: Opening Community Dialogue. AB - During an emerging health crisis like the 2014 Ebola outbreak in West Africa, communicating with communities to learn from them and to provide timely information can be a challenge. Insight into community thinking, however, is crucial for developing appropriate communication content and strategies and for monitoring the progress of the emergency response. In November 2014, the Health Communication Capacity Collaborative partnered with GeoPoll to implement a Short Message Service (SMS)-based survey that could create a link with affected communities and help guide the communication response to Ebola. The ideation metatheory of communication and behavior change guided the design of the survey questionnaire, which produced critical insights into trusted sources of information, knowledge of transmission modes, and perceived risks-all factors relevant to the design of an effective communication response that further catalyzed ongoing community actions. The use of GeoPoll's infrastructure for data collection proved a crucial source of almost-real-time data. It allowed for rapid data collection and processing under chaotic field conditions. Though not a replacement for standard survey methodologies, SMS surveys can provide quick answers within a larger research process to decide on immediate steps for communication strategies when the demand for speedy emergency response is high. They can also help frame additional research as the response evolves and overall monitor the pulse of the situation at any point in time. PMID- 28854133 TI - Community Engagement and the Communication Response to Ebola. PMID- 28854134 TI - Barriers and Enablers to Treatment-Seeking Behavior and Causes of High-Risk Practices in Ebola: A Case Study From Sierra Leone. AB - Nine months after the start of the Ebola outbreak in Sierra Leone in May 2014, communities in Port Loko continued to engage in high-risk practices; many remained unwilling to seek treatment. In the face of such behaviors, Oxfam Community Outreach teams conducted qualitative research using in-depth interviews, focus groups, and questionnaires to better understand the barriers and enablers affecting treatment-seeking behavior. Analysis of their results highlights 3 primary barriers to treatment seeking: fear and limited information, concern about unknown outsiders, and the often prohibitive distance and limited accessibility of treatment. Communities were asked to provide suggestions on how to address these barriers. Their recommendations fell into 4 main categories: providing information and better communication, including community members in decisions, providing closer treatment facilities with opportunities to learn how they operate, and using survivors to inspire hope for other sufferers. This research highlights the need for social mobilization programs to invest early in understanding the underlying causes of risky behaviors in order to develop programs that address them. PMID- 28854135 TI - Community-Led Total Sanitation, Open Defecation Free Status, and Ebola Virus Disease in Lofa County, Liberia. AB - The Ebola virus disease (EVD) epidemic entered Liberia through Lofa County in February 2014 and spread to two health districts where the nongovernmental organization Global Communities had been implementing community-led total sanitation (CLTS) since 2012. By December 2014 the county had 928 Ebola cases (422 of them confirmed) and 648 deaths. Before the epidemic, CLTS was triggered in 155 communities, and 98 communities were certified as Open Defecation Free (ODF). Using mixed quantitative and qualitative methods, we determined that no cases of EVD were found in ODF communities and in only one CLTS community that had not reached ODF status. No differences were found between EVD and non-EVD communities in tribe, religion, ethnic group, or major sources of Ebola information. Radio was the most common source of information for all communities, but health workers were the most trusted information sources. CLTS ODF communities attributed their avoidance of EVD to Water, Sanitation, and Hygiene behaviors, especially hand washing with soap and disposal of feces that they learned from CLTS prior to the epidemic. Communities that got EVD blamed their strong initial resistance to Ebola response messages on their distrust that Ebola was real and their reliance on friends and family for advice. A strong inverse correlation between EVD and CLTS with or without ODF emerged from the regression analysis (R = -.6). PMID- 28854136 TI - A Theory-Based Socioecological Model of Communication and Behavior for the Containment of the Ebola Epidemic in Liberia. AB - The Ebola virus disease that emerged in the West African countries of Liberia, Sierra Leone, and Guinea in 2014 created an unprecedented public health emergency that caught national and international organizations off guard. Despite available guidelines to respond to public health emergencies, coordinated action to control the disease only came almost 6 months after what is now considered the first human contact with the virus. Theory-based frameworks, like the ideation model and the pathways framework, are important tools for guiding research and the design of communication activities and strategies to effectively impact on the more likely determinants of the intended behavior. By using theory, these frameworks increase the chances that localized research and communication interventions can effectively change desired behaviors and their behavioral determinants. In an outbreak situation such frameworks are all the more important, when time is of the essence and lives are on the line. PMID- 28854137 TI - The Development of Standard Operating Procedures for Social Mobilization and Community Engagement in Sierra Leone During the West Africa Ebola Outbreak of 2014-2015. AB - This article describes the development of standard operating procedures (SOPs) for social mobilization and community engagement (SM/CE) in Sierra Leone during the Ebola outbreak of 2014-2015. It aims to (a) explain the rationale for a standardized approach, (b) describe the methodology used to develop the resulting SOPs, and (c) discuss the implications of the SOPs for future outbreak responses. Mixed methodologies were applied, including analysis of data on Ebola-related knowledge, attitudes, and practices; consultation through a national forum; and a series of workshops with more than 250 participants active in SM/CE in seven districts with recent confirmed cases. Specific challenges, best practices, and operational models were identified in relation to (a) the quality of SM/CE approaches; (b) coordination and operational structures; and (c) integration with Ebola services, including case management, burials, quarantine, and surveillance. This information was synthesized and codified into the SOPs, which include principles, roles, and actions for partners engaging in SM/CE as part of the Ebola response. This experience points to the need for a set of global principles and standards for meaningful SM/CE that can be rapidly adapted as a high-priority response component at the outset of future health and humanitarian crises. PMID- 28854138 TI - Health Communication in the Time of Ebola: A Culture-Centered Interrogation. AB - This brief essay is a commentary on how critical health communication theory can contribute to an understanding of the cultural dynamics of infectious disease pandemics. In particular, we focus on a specific trajectory of health communication theorizing-the culture-centered approach-and its heuristic and pragmatic utility in enhancing knowledge about public health crises like infectious disease outbreaks. In the backdrop of the mobilizations against the 2014 Ebola virus disease epidemic in the 3 West African nations of Guinea, Sierra Leone, and Liberia, indigenous cultural practices were construed as pathogenic and local agency of affected communities disregarded, even as the global risks of the epidemic were highlighted. In contrast to this interventionist notion of culture, the culture-centered approach offers a heuristic rubric through which to scrutinize the dialectical interrelationship between indigenous cultural practices, structural determinants of health, and the everyday agency of individuals of affected communities. We argue that such a listening-based paradigm of communication theorizing is instrumental in developing authentic, ethical, and effective health communication practice in public health crises. PMID- 28854139 TI - Treatment Seeking and Ebola Community Care Centers in Sierra Leone: A Qualitative Study. AB - Ebola Treatment Units were able to provide only 60% of necessary treatment beds in Sierra Leone. As a result, the Government of Sierra Leone decided to construct Community Care Centers. These were intended to increase treatment-seeking behavior and reduce the community-level spread of Ebola by facilitating access to care closer to communities. Through qualitative data collection in 3 districts, this study seeks to understand the perceived impact that proximity to such Centers had on treatment-seeking behavior. Feedback from community members and Community Health Volunteers indicates that proximity to treatment reduced fears, especially those arising from the use of ambulances, lack of familiarity with medical Centers, and loss of contact with family members taken for treatment. Participants report that having a Center close to their home enables them to walk to treatment and witness survivors being discharged. Living close to Centers also enables communities to be involved in their design and daily operation, helping to build trust in them as acceptable treatment facilities. Further research is required to understand the appropriate design, operation, and epidemiological impact of Centers. Further investigation should incorporate the effect of an outbreak's severity and the stage (duration) of the outbreak on potential acceptance of Centers. PMID- 28854140 TI - Community Engagement in Liberia: Routine Immunization Post-Ebola. AB - A national integrated polio, measles, and deworming campaign was implemented across Liberia May 8-14, 2015. The community engagement and social mobilization component of the campaign was based on structures that had been invested in during the Ebola response. This article provides an overview of the community engagement and social mobilization activities that were conducted and reports the key findings of a rapid qualitative assessment conducted immediately after the campaign that focused on community perceptions of routine immunization in the post-Ebola context. Focus group discussions and interviews were conducted across four counties in Liberia (Montserrado, Nimba, Bong, and Margibi). Thematic analysis identified the barriers preventing and drivers leading to the utilization of routine immunization. Community members also made recommendations and forwarded community-based solutions to encourage engagement with future health interventions, including uptake in vaccination campaigns. These should be incorporated in the development and implementation of future interventions and programs. PMID- 28854143 TI - Biases in Individualized Cost-effectiveness Analysis: Influence of Choices in Modeling Short-Term, Trial-Based, Mortality Risk Reduction and Post-Trial Life Expectancy. AB - BACKGROUND: The benefits and costs of a treatment are typically heterogeneous across individual patients. Randomized clinical trials permit the examination of individualized treatment benefits over the trial horizon but extrapolation to lifetime horizon usually involves combining trial-based individualized estimates of short-term risk reduction with less detailed (less granular) population life tables. However, the underlying assumption of equal post-trial life expectancy for low- and high-risk patients of the same sex and age is unrealistic. We aimed to study the influence of unequal granularity between models of short-term risk reduction and life expectancy on individualized estimates of cost-effectiveness of aggressive thrombolysis for patients with an acute myocardial infarction. METHODS: To estimate life years gained, we multiplied individualized estimates of short-term risk reduction either with less granular and with equally granular post-trial life expectancy estimates. Estimates of short-term risk reduction were obtained from GUSTO trial data (30,510 patients) using logistic regression analysis with treatment, sex, and age as predictor variables. Life expectancy estimates were derived from sex- and age-specific US life tables. RESULTS: Based on sex- and age-specific, short-term risk reductions but average population life expectancy (less granularity), we found that aggressive thrombolysis was cost effective (incremental cost-effectiveness ratio below $50,000) for women above age 49 y and men above age 53 y (92% and 69% of the population, respectively). Considering sex- and age-specific short-term mortality risk reduction and correspondingly sex- and age-specific life expectancy (equal granularity), aggressive thrombolysis was cost-effective for men above age 45 y and women above age 50 y (95% and 76% of the population, respectively). CONCLUSIONS: Failure to model short-term risk reduction and life expectancy at an equal level of granularity may bias our estimates of individualized cost-effectiveness and misallocate resources. PMID- 28854145 TI - Strategy instruction for middle and secondary students with mild disabilities: Creating independent learners. PMID- 28854144 TI - A Queer Theorist's Critique of Online Domestic Violence Advocacy: Critically Responding to the National Coalition Against Domestic Violence Web Site. AB - Since the foundations of the contemporary anti-violence movement in the 1960s and 1970s, advocates have sought to establish a critical understanding of domestic violence that we can use to direct our efforts for social change. Yet many advocates and advocacy organizations continue to rely on a problematic narrative of sameness that marginalizes and erases diverse victims' experiences and needs. In this article, I conduct a critical discourse analysis of the National Coalition Against Domestic Violence Web site to identify outcomes of this narrative for the inclusivity of advocacy efforts. I argue that despite the organization's numerous claims to represent diverse victims' experiences, Web site content reveals that its purportedly general account of domestic violence normalizes the experiences of a small group of victims-namely, heterosexual, cisgender women. Further, the Web site's content greatly limits the potential for thinking about and discussing violence across difference. I conclude with recommendations for changes in advocacy practices. PMID- 28854146 TI - Evaluation of the carcinogenic risks at the influence of POPs. AB - INTRODUCTION: Kazakhstan is included in the list of environmentally vulnerable countries and Kyzylorda oblast in particular. This is due to its geographical, spatial and temporal and socioeconomic features. MATERIALS AND METHODS: As part of the program "Integrated approaches in the management of public health in the Aral region", we have carried out an expertise on many samples of natural environments and products. Samples were selected in accordance with sampling procedures according to regulatory documents by specialists of the Pesticide Toxicology Laboratory. It is accredited by the State Standard of the Republic of Kazakhstan, for compliance with ST RK ISO/IEC 17025-2007 "General requirements for the competence of test and calibration laboratories". Gas chromatograph was used for the determination of residues of organochlorine pesticides. For the determination of dioxins, polychlorinated biphenyl was conducted on the gas chromatomass spectrometer with quadruple detector produce by Agilent Company, USA. To assess the risk, we carried out the mathematical calculations according to the risk of chemicals polluting (No P 2.1.10.1920-04, Russia). Calculation of the carcinogenic risk was carried out with the use of data on the size of the exposure and meanings of carcinogenic potential factors (slope factor and unit risk). RESULTS AND DISCUSSION: The evaluation of persistent organic pollutants (POPs), based on the previous results of the research concerning water, soil and food products, was held in five population settlements in Kyzylorda oblast villages: Ayteke bi, Zhalagash, Zhosaly, Shieli and Aralsk town. Pollution with the POPs in the environmental objects by means of exposition and evaluation of the carcinogenic risk to human health is confirmed by the data of the statistical reporting about some morbidity in Kyzylorda oblast, such as skin diseases and subcutaneous tissue, endocrine system diseases, pregnancy complications etc. CONCLUSION: The received levels of carcinogenic risks, which were first carried out in the Republic of Kazakhstan in the village of Shieli, meet the third-risk range, which is not acceptable to the life of the population that again shows the problem of the Aral Sea, called the zone of ecological disaster. PMID- 28854147 TI - Novel therapies for multiple myeloma. PMID- 28854148 TI - A new opportunity for MEMRI. PMID- 28854149 TI - Chronic exercise reduces hypothalamic transforming growth factor-beta1 in middle aged obese mice. AB - Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-beta (TGF-beta1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-beta1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF beta1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-beta1 expression and IkB-alpha ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-beta1/IkB-alpha axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging. PMID- 28854150 TI - Anti-aging effects of coffee. PMID- 28854152 TI - Novel nanofluidic chemical cells based on self-assembled solid-state SiO2 nanotubes. AB - Novel nanofluidic chemical cells based on self-assembled solid-state SiO2 nanotubes on silicon-on-insulator (SOI) substrate have been successfully fabricated and characterized. The vertical SiO2 nanotubes with a smooth cavity are built from Si nanowires which were epitaxially grown on the SOI substrate. The nanotubes have rigid, dry-oxidized SiO2 walls with precisely controlled nanotube inner diameter, which is very attractive for chemical-/bio-sensing applications. No dispersion/aligning procedures were involved in the nanotube fabrication and integration by using this technology, enabling a clean and smooth chemical cell. Such a robust and well-controlled nanotube is an excellent case of developing functional nanomaterials by leveraging the strength of top-down lithography and the unique advantage of bottom-up growth. These solid, smooth, clean SiO2 nanotubes and nanofluidic devices are very encouraging and attractive in future bio-medical applications, such as single molecule sensing and DNA sequencing. PMID- 28854153 TI - Report on the accident at Windscale No. 1 Pile on 10 October 1957. AB - A serious fire developed in the core of a nuclear reactor at Windscale Works, Sellafield, northwest England, which led to the release of significant quantities of radioactive material into the environment during 10-11th October, 1957. In 1957, Windscale Works was operated by the United Kingdom Atomic Energy Authority (UKAEA), and on 15th October it was announced by the Chairman of the UKAEA that a Committee of Inquiry had been established under the chairmanship of Sir William Penney to conduct an investigation into the accident. The Committee sat at Windscale Works during 17-25th October, interviewed 37 people (some more than once), and examined 73 technical exhibits. The Committee reported to the Chairman of the UKAEA on 26th October. The Report of the Committee formed the technical basis of a UK Government White Paper (Cmnd. 302) published on 8th November, 1957, but the Penney Report itself was not published, and was only made public (at what is now The National Archives, TNA, Kew) in January, 1988. The original Report of the Committee of Inquiry is reproduced here from a copy of the Report supplied by TNA from TNA File AB 86/25. PMID- 28854154 TI - Point spread function based image reconstruction in optical projection tomography. AB - As a result of the shallow depth of focus of the optical imaging system, the use of standard filtered back projection in optical projection tomography causes space-variant tangential blurring that increases with the distance to the rotation axis. We present a novel optical tomographic image reconstruction technique that incorporates the point spread function of the imaging lens in an iterative reconstruction. The technique is demonstrated using numerical simulations, tested on experimental optical projection tomography data of single fluorescent beads, and applied to high-resolution emission optical projection tomography imaging of an entire zebrafish larva. Compared to filtered back projection our results show greatly reduced radial and tangential blurring over the entire [Formula: see text] mm2 field of view, and a significantly improved signal to noise ratio. PMID- 28854151 TI - Aging effects on intestinal homeostasis associated with expansion and dysfunction of intestinal epithelial stem cells. AB - Intestinal epithelial stem cells (IESCs) are critical to maintain intestinal epithelial function and homeostasis. We tested the hypothesis that aging promotes IESC dysfunction using old (18-22 months) and young (2-4 month) Sox9-EGFP IESC reporter mice. Different levels of Sox9-EGFP permit analyses of active IESC (Sox9 EGFPLow), activatable reserve IESC and enteroendocrine cells (Sox9-EGFPHigh), Sox9-EGFPSublow progenitors, and Sox9-EGFPNegative differentiated lineages. Crypt villus morphology, cellular composition and apoptosis were measured by histology. IESC function was assessed by crypt culture, and proliferation by flow cytometry and histology. Main findings were confirmed in Lgr5-EGFP and Lgr5-LacZ mice. Aging-associated gene expression changes were analyzed by Fluidigm mRNA profiling. Crypts culture from old mice yielded fewer and less complex enteroids. Histology revealed increased villus height and Paneth cells per crypt in old mice. Old mice showed increased numbers and hyperproliferation of Sox9-EGFPLow IESC and Sox9-EGFPHigh cells. Cleaved caspase-3 staining demonstrated increased apoptotic cells in crypts and villi of old mice. Gene expression profiling revealed aging-associated changes in mRNAs associated with cell cycle, oxidative stress and apoptosis specifically in IESC. These findings provide new, direct evidence for aging associated IESC dysfunction, and define potential biomarkers and targets for translational studies to assess and maintain IESC function during aging. PMID- 28854155 TI - Synthesis of 3D-MoO2 microspheres supported MoSe2 as an Efficient Electrocatalyst for Hydrogen Evolution Reaction. AB - Many efforts have been devoted to explore non-noble metal electrocatalysts for hydrogen evolution reaction (HER) in recent years. Here, we developed a 3D-MoO2 microspheres supported MoSe2 via a facile hydrothermal approach followed by selenylation treatment for HER. The loosely stacked MoSe2 layer were formed on the conductive MoO2 surface and acted as active sites for HER. Meanwhile, metallic inner MoO2 facilitates to electron transport for proton reduction. In addition, the MoSe2 could protect the inner MoO2 from the acidic electrolyte in the HER precess. Significantly, the as-synthesized MoO2/MoSe2 exhibits excellent catalytic activity for HER featured by a low onset potential of -101 mV vs reversible hydrogen electrode, a small overpotential of 167 mV at a current density of 10 mA cm-2 along with Tafel slope values of 68 mV dec-1 as well as outstanding stability in 0.5 mol L-1 H2SO4. PMID- 28854156 TI - Graphene supercapacitor with both high power and energy density. AB - Supercapacitors, based on fast ion transportation, are specialized to provide high power, long stability, and efficient energy storage using highly porous electrode materials. However, their low energy density excludes them from many potential applications that require both high energy density and high power density performances. Using a scalable nanoporous graphene synthesis method involving an annealing process in hydrogen, here we show supercapacitors with highly porous graphene electrodes capable of achieving not only a high power density of 41 kW kg-1 and a Coulombic efficiency of 97.5%, but also a high energy density of 148.75 Wh kg-1. A high specific gravimetric and volumetric capacitance (306.03 F g-1 and 64.27 F cm-3) are demonstrated. The devices can retain almost 100% capacitance after 7000 charging/discharging cycles at a current density of 8 A g-1. The superior performance of supercapacitors is attributed to their ideal pore size, pore uniformity, and good ion accessibility of the synthesized graphene. PMID- 28854157 TI - Real-time monitoring of 2D semiconductor film growth with optical spectroscopy. AB - Real-time monitoring of the growth is essential for synthesizing high quality two dimensional (2D) transition-metal dichalcogenides with precisely controlled thickness. Here, we report the first real time in situ optical spectroscopic study on the molecular beam epitaxy of atomically thin molybdenum diselenide (MoSe2) films on sapphire substrates using differential reflectance spectroscopy. The characteristic optical spectrum of MoSe2 monolayer is clearly distinct from that of bilayer allowing a precise control of the film thickness during the growth. Furthermore, the evolution of the characteristic differential reflectance spectrum of the MoSe2 thin film as a function of the thickness sheds light on the details of the growth process. Our result demonstrates the importance and the great potential of the real time in situ optical spectroscopy for the realization of controlled growth of 2D semiconductor materials. PMID- 28854158 TI - Laser additive manufacturing bulk graphene-copper nanocomposites. AB - The exceptional mechanical properties of graphene make it an ideal nanofiller for reinforcing metal matrix composites (MMCs). In this work, graphene-copper (Gr-Cu) nanocomposites have been fabricated by a laser additive manufacturing process. Transmission electron microscopy (TEM), x-ray diffraction (XRD) and Raman spectroscopy were utilized to characterize the fabricated nanocomposites. The XRD, Raman spectroscopy, energy dispersive spectroscopy and TEM results demonstrated the feasibility of laser additive manufacturing of Gr-Cu nanocomposites. The microstructures were characterized by high resolution TEM and the results further revealed the interface between the copper matrix and graphene. With the addition of graphene, the mechanical properties of the composites were enhanced significantly. Nanoindentation tests showed that the average modulus value and hardness of the composites were 118.9 GPa and 3 GPa respectively; 17.6% and 50% increases were achieved compared with pure copper, respectively. This work demonstrates a new way to manufacture graphene copper nanocomposites with ultra-strong mechanical properties and provides alternatives for applications in electrical and thermal conductors. PMID- 28854159 TI - On the use of multi-dimensional scaling and electromagnetic tracking in high dose rate brachytherapy. AB - High dose rate brachytherapy affords a frequent reassurance of the precise dwell positions of the radiation source. The current investigation proposes a multi dimensional scaling transformation of both data sets to estimate dwell positions without any external reference. Furthermore, the related distributions of dwell positions are characterized by uni-or bi-modal heavy-tailed distributions. The latter are well represented by alpha-stable distributions. The newly proposed data analysis provides dwell position deviations with high accuracy, and, furthermore, offers a convenient visualization of the actual shapes of the catheters which guide the radiation source during the treatment. PMID- 28854160 TI - Falls requiring visit to emergency room in a population-based cohort of diabetic patients in Italy. AB - BACKGROUND: The aims were to assess the frequency of falls among the diabetic adult population of the Italian Northeastern region Friuli Venezia Giulia and to identify risk factors. METHODS: This was a population-based retrospective cohort study using administrative data of the regional health information system as the source of information. In a cohort of diabetics 18 years of age or more, living in the region on December 31, 2014, the occurrence of falls requiring a visit to the regional Emergency Rooms was assessed. Multivariate logistic regression was used to identify factors associated with increased risk of falling. RESULTS: Of 80,162 cohort subjects, 2967 (3.7%) had at least one fall requiring a visit to ER. Factors associated with increased risk of falling were female sex, older age, prescription of a thiazolidinedione as the last antidiabetic medication in 2014, increasing number of active principles prescribed in 2014, longer diabetes duration, and prescription of certain classes of medications other than antidiabetics in 2014. CONCLUSIONS: In Friuli Venezia Giulia, injurious falls are a complication of diabetes relevant from the public health viewpoint. Efforts are needed to screen diabetic patients, review their prescriptions, provide appropriate care, and implement targeted interventions to minimize the individual risk of falls. PMID- 28854161 TI - A search for a safer bucket to prevent children drowning at home. AB - BACKGROUND: Unintentional drowning is the leading cause of death for children younger than 5 years old. A bucket is one of the most common water container in which children can drown. The objective of this work was to evaluate the base diameter of a bucket and the necessary force to shed it. METHODS: This was an experimental study. We used six galvanized buckets of different diameters. Each selected bucket was pulled using a pulley with other buckets full of water until the water spilled out. The statistical analysis was done by linear regression with p less than 0.05 as statistically significant. RESULTS: This research shows a direct relation between the wide base diameter (in a bucket 23 cm high, 25 cm rim, with a 20 cm water depth) and the strength required to spill the liquid contents (beta= 1.21; x= diameter of the base in centimeters; alpha= 14.59; r= 0.99 and p less than 0.001). CONCLUSIONS: We conclude that the bucket structure could determine the risk of child drowning. The risk could increase directly as its base width increases. PMID- 28854162 TI - Elimination of violence against women and girls as a global action agenda. AB - This article outlines the goals and targets of Sustainable Development Goals (SDGs) related to elimination of violence against women and girls (VAWG) and to explain the framework to target these goals. Prevention of VAWG has been identified as one of the key agents for sustainable development. SDGs gave enough importance and called for the elimination of "all forms of violence against all women and girls everywhere". It identified different social and political enablers of reducing violence which are targeted under different SDGs. This acknowledges tacitly that VAWG is preventable and it is set to prevent and eliminate it. Evidences show that preventing VAWG is possible through multi sectorial programs. The United Nations committed to revitalized global partnership to mobilize resources for implementing the agenda. Hence, designing and implementing interventions and subsequently scaling-up and intensifying these interventions are required to end VAWG. PMID- 28854163 TI - Decreasing Eukaryotic Initiation Factor 3C (EIF3C) Suppresses Proliferation and Stimulates Apoptosis in Breast Cancer Cell Lines Through Mammalian Target of Rapamycin (mTOR) Pathway. AB - BACKGROUND Translation initiation is the rate limiting step of protein synthesis and is highly regulated. Eukaryotic initiation factor 3C (EIF3C), an oncogene overexpressed in several human cancers, plays an important role in tumorigenesis and cell proliferation. MATERIAL AND METHODS Immunohistochemistry was used to determine the expression of EIF3C in breast cancer tissues from 42 patients. We investigated whether EIF3C silencing decreases breast cancer cell proliferation as assessed by colony formation assay, and whether EIF3C gene knockdown induces apoptosis as assessed by flow cytometry analysis. We utilized the stress and apoptosis signaling antibody array kit, while p-ERK1/2, p-Akt, p-Smad2, p-p38 MAPK, cleaved caspase-3, and cleaved caspase-7 were explored between EIF3C-siRNA and controls. Furthermore, the effects of EIF3C gene knockdown in mTOR pathway were analyzed by western blotting for different cell lines. RESULTS In EIF3C positive tumors, 32 out of 42 showed significantly higher frequencies of high grade group by immunoreactivity (p=0.0016). BrdU incorporation after four days of cell plating was significantly suppressed in MDA-MB-231 cells by EIF3C knockdown compared with controls, with average changes of 7.8-fold (p<0.01). Clone number was significantly suppressed in MDA-MB-231 cells by EIF3C knockdown compared with controls (p<0.05). Cell apoptosis was significantly increased in the EIF3C-siRNA group when compared with the cells that were transfected with scrambled siRNA (3.51+/-0.0842 versus 13.24+/-0.2307, p<0.01). The mTOR signaling pathway was involved in decreasing EIF3C translational efficiency. CONCLUSIONS Unveiling the mechanisms of EIF3 action in tumorigenesis may help identify attractive targets for cancer therapy. PMID- 28854165 TI - Cancer models: The next best thing. PMID- 28854164 TI - Island biogeography of marine organisms. AB - Studies on the distribution and evolution of organisms on oceanic islands have advanced towards a dynamic perspective, where terrestrial endemicity results from island geographical aspects and geological history intertwined with sea-level fluctuations. Diversification on these islands may follow neutral models, decreasing over time as niches are filled, or disequilibrium states and progression rules, where richness and endemism rise with the age of the archipelago owing to the splitting of ancestral lineages (cladogenesis). However, marine organisms have received comparatively little scientific attention. Therefore, island and seamount evolutionary processes in the aquatic environment remain unclear. Here we analyse the evolutionary history of reef fishes that are endemic to a volcanic ridge of seamounts and islands to understand their relations to island evolution and sea-level fluctuations. We also test how this evolutionary history fits island biogeography theory. We found that most endemic species have evolved recently (Pleistocene epoch), during a period of recurrent sea-level changes and intermittent connectivity caused by repeated aerial exposure of seamounts, a finding that is consistent with an ephemeral ecological speciation process. Similar to findings for terrestrial biodiversity, our data suggest that the marine speciation rate on islands is negatively correlated with immigration rate. However, because marine species disperse better than terrestrial species, most niches are filled by immigration: speciation increases with the random accumulation of species with low dispersal ability, with few opportunities for in situ cladogenesis and adaptive radiation. Moreover, we confirm that sea-level fluctuations and seamount location play a critical role in marine evolution, mainly by intermittently providing stepping stones for island colonization. PMID- 28854166 TI - Metallic molybdenum disulfide nanosheet-based electrochemical actuators. AB - Actuators that convert electrical energy to mechanical energy are useful in a wide variety of electromechanical systems and in robotics, with applications such as steerable catheters, adaptive wings for aircraft and drag-reducing wind turbines. Actuation systems can be based on various stimuli, such as heat, solvent adsorption/desorption, or electrochemical action (in systems such as carbon nanotube electrodes, graphite electrodes, polymer electrodes and metals). Here we demonstrate that the dynamic expansion and contraction of electrode films formed by restacking chemically exfoliated nanosheets of two-dimensional metallic molybdenum disulfide (MoS2) on thin plastic substrates can generate substantial mechanical forces. These films are capable of lifting masses that are more than 150 times that of the electrode over several millimetres and for hundreds of cycles. Specifically, the MoS2 films are able to generate mechanical stresses of about 17 megapascals-higher than mammalian muscle (about 0.3 megapascals) and comparable to ceramic piezoelectric actuators (about 40 megapascals)-and strains of about 0.6 per cent, operating at frequencies up to 1 hertz. The actuation performance is attributed to the high electrical conductivity of the metallic 1T phase of MoS2 nanosheets, the elastic modulus of restacked MoS2 layers (2 to 4 gigapascals) and fast proton diffusion between the nanosheets. These results could lead to new electrochemical actuators for high-strain and high-frequency applications. PMID- 28854167 TI - Cancer: Division hierarchy leads to cell heterogeneity. PMID- 28854168 TI - Commensal bacteria make GPCR ligands that mimic human signalling molecules. AB - Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome biosynthetic gene therapy). PMID- 28854169 TI - A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. AB - The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late onset neurodegenerative disorder. This is associated with accumulation of ERK activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases. PMID- 28854170 TI - Neuroscience: From embryo mutation to adult degeneration. PMID- 28854085 TI - Liraglutide and Renal Outcomes in Type 2 Diabetes. AB - BACKGROUND: In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown. METHODS: We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. RESULTS: A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively). CONCLUSIONS: This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .). PMID- 28854171 TI - Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy. AB - Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy. PMID- 28854177 TI - Uncertainties in tumor allele frequencies limit power to infer evolutionary pressures. PMID- 28854173 TI - Early members of 'living fossil' lineage imply later origin of modern ray-finned fishes. AB - Modern ray-finned fishes (Actinopterygii) comprise half of extant vertebrate species and are widely thought to have originated before or near the end of the Middle Devonian epoch (around 385 million years ago). Polypterids (bichirs and ropefish) represent the earliest-diverging lineage of living actinopterygians, with almost all Palaeozoic taxa interpreted as more closely related to other extant actinopterygians than to polypterids. By contrast, the earliest material assigned to the polypterid lineage is mid-Cretaceous in age (around 100 million years old), implying a quarter-of-a-billion-year palaeontological gap. Here we show that scanilepiforms, a widely distributed radiation from the Triassic period (around 252-201 million years ago), are stem polypterids. Importantly, these fossils break the long polypterid branch and expose many supposedly primitive features of extant polypterids as reversals. This shifts numerous Palaeozoic ray fins to the actinopterygian stem, reducing the minimum age for the crown lineage by roughly 45 million years. Recalibration of molecular clocks to exclude phylogenetically reassigned Palaeozoic taxa results in estimates that the actinopterygian crown lineage is about 20-40 million years younger than was indicated by previous molecular analyses. These new dates are broadly consistent with our revised palaeontological timescale and coincident with an interval of conspicuous morphological and taxonomic diversification among ray-fins centred on the Devonian-Carboniferous boundary. A shifting timescale, combined with ambiguity in the relationships of late Palaeozoic actinopterygians, highlights this part of the fossil record as a major frontier in understanding the evolutionary assembly of modern vertebrate diversity. PMID- 28854178 TI - Genetic insights into mammalian heart regeneration. AB - Genetic and functional analyses of 120 mouse strains have identified a heart regeneration candidate gene that modulates the contractile sarcomeric apparatus. This gene, Tnni3k, controls the frequency of the mononuclear, diploid cardiomyocyte population, which affects cardiomyocyte proliferative potential after injury. PMID- 28854175 TI - Multiplexed quantification of proteins and transcripts in single cells. AB - We present a tool to measure gene and protein expression levels in single cells with DNA-labeled antibodies and droplet microfluidics. Using the RNA expression and protein sequencing assay (REAP-seq), we quantified proteins with 82 barcoded antibodies and >20,000 genes in a single workflow. We used REAP-seq to assess the costimulatory effects of a CD27 agonist on human CD8+ lymphocytes and to identify and characterize an unknown cell type. PMID- 28854180 TI - Reply: Uncertainties in tumor allele frequencies limit power to infer evolutionary pressures. PMID- 28854174 TI - Orthotopic patient-derived xenografts of paediatric solid tumours. AB - Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo. PMID- 28854176 TI - Concepts, estimation and interpretation of SNP-based heritability. AB - Narrow-sense heritability (h2) is an important genetic parameter that quantifies the proportion of phenotypic variance in a trait attributable to the additive genetic variation generated by all causal variants. Estimation of h2 previously relied on closely related individuals, but recent developments allow estimation of the variance explained by all SNPs used in a genome-wide association study (GWAS) in conventionally unrelated individuals, that is, the SNP-based heritability (). In this Perspective, we discuss recently developed methods to estimate for a complex trait (and genetic correlation between traits) using individual-level or summary GWAS data. We discuss issues that could influence the accuracy of , definitions, assumptions and interpretations of the models, and pitfalls of misusing the methods and misinterpreting the models and results. PMID- 28854172 TI - Discovery of stimulation-responsive immune enhancers with CRISPR activation. AB - The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues. Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption, but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA. We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (TH17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs. PMID- 28854181 TI - Reaching for the next branch on the biobank tree of knowledge. AB - An innovative study analyzing genetic association across tree-structured routine healthcare data in the UK Biobank represents a new branch on a tree that is poised to grow rapidly and offer new kinds of insights on how genome variation relates to human health and disease. Indeed, this tree is likely to offer new kinds of insights into the very nature of human disease. PMID- 28854179 TI - Genomic prediction unifies animal and plant breeding programs to form platforms for biological discovery. AB - The rate of annual yield increases for major staple crops must more than double relative to current levels in order to feed a predicted global population of 9 billion by 2050. Controlled hybridization and selective breeding have been used for centuries to adapt plant and animal species for human use. However, achieving higher, sustainable rates of improvement in yields in various species will require renewed genetic interventions and dramatic improvement of agricultural practices. Genomic prediction of breeding values has the potential to improve selection, reduce costs and provide a platform that unifies breeding approaches, biological discovery, and tools and methods. Here we compare and contrast some animal and plant breeding approaches to make a case for bringing the two together through the application of genomic selection. We propose a strategy for the use of genomic selection as a unifying approach to deliver innovative 'step changes' in the rate of genetic gain at scale. PMID- 28854182 TI - Expanding the effects of ERG on chromatin landscapes and dysregulated transcription in prostate cancer. AB - ERG overexpression in prostate cancers promotes the development of widespread changes in gene expression and chromatin landscapes, leading to redistribution of key transcription factors in prostate cancers positive for the TMPRSS2-ERG fusion gene. The overexpression of ERG is further assisted by the development of a super enhancer in the ERG locus. PMID- 28854183 TI - Ancestry-inspired genomic health. PMID- 28854184 TI - Exploring virulence and immunogenicity in the emerging pathogen Sporothrix brasiliensis. AB - Sporotrichosis is a polymorphic chronic infection of humans and animals classically acquired after traumatic inoculation with soil and plant material contaminated with Sporothrix spp. propagules. An alternative and successful route of transmission is bites and scratches from diseased cats, through which Sporothrix yeasts are inoculated into mammalian tissue. The development of a murine model of subcutaneous sporotrichosis mimicking the alternative route of transmission is essential to understanding disease pathogenesis and the development of novel therapeutic strategies. To explore the impact of horizontal transmission in animals (e.g., cat-cat) and zoonotic transmission on Sporothrix fitness, the left hind footpads of BALB/c mice were inoculated with 5*106 yeasts (n = 11 S. brasiliensis, n = 2 S. schenckii, or n = 1 S. globosa). Twenty days post-infection, our model reproduced both the pathophysiology and symptomology of sporotrichosis with suppurating subcutaneous nodules that progressed proximally along lymphatic channels. Across the main pathogenic members of the S. schenckii clade, S. brasiliensis was usually more virulent than S. schenckii and S. globosa. However, the virulence in S. brasiliensis was strain-dependent, and we demonstrated that highly virulent isolates disseminate from the left hind footpad to the liver, spleen, kidneys, lungs, heart, and brain of infected animals, inducing significant and chronic weight loss (losing up to 15% of their body weight). The weight loss correlated with host death between 2 and 16 weeks post infection. Histopathological features included necrosis, suppurative inflammation, and polymorphonuclear and mononuclear inflammatory infiltrates. Immunoblot using specific antisera and homologous exoantigen investigated the humoral response. Antigenic profiles were isolate-specific, supporting the hypothesis that different Sporothrix species can elicit a heterogeneous humoral response over time, but cross reaction was observed between S. brasiliensis and S. schenckii proteomes. Despite great diversity in the immunoblot profiles, antibodies were mainly derived against 3-carboxymuconate cyclase, a glycoprotein oscillating between 60 and 70 kDa (gp60-gp70) and a 100-kDa molecule in nearly 100% of the assays. Thus, our data broaden the current view of virulence and immunogenicity in the Sporothrix-sporotrichosis system, substantially expanding the possibilities for comparative genomic with isolates bearing divergent virulence traits and helping uncover the molecular mechanisms and evolutionary pressures underpinning the emergence of Sporothrix virulence. PMID- 28854185 TI - Relationships between aquatic vegetation and water turbidity: A field survey across seasons and spatial scales. AB - Field surveys often show that high water turbidity limits cover of aquatic vegetation, while many small-scale experiments show that vegetation can reduce turbidity by decreasing water flow, stabilizing sediments, and competing with phytoplankton for nutrients. Here we bridged these two views by exploring the direction and strength of causal relationships between aquatic vegetation and turbidity across seasons (spring and late summer) and spatial scales (local and regional), using causal modeling based on data from a field survey along the central Swedish Baltic Sea coast. The two best-fitting regional-scale models both suggested that in spring, high cover of vegetation reduces water turbidity. In summer, the relationships differed between the two models; in the first model high vegetation cover reduced turbidity; while in the second model reduction of summer turbidity by high vegetation cover in spring had a positive effect on summer vegetation which suggests a positive feedback of vegetation on itself. Nitrogen load had a positive effect on turbidity in both seasons, which was comparable in strength to the effect of vegetation on turbidity. To assess whether the effect of vegetation was primarily caused by sediment stabilization or a reduction of phytoplankton, we also tested models where turbidity was replaced by phytoplankton fluorescence or sediment-driven turbidity. The best fitting regional-scale models suggested that high sediment-driven turbidity in spring reduces vegetation cover in summer, which in turn has a negative effect on sediment-driven turbidity in summer, indicating a potential positive feedback of sediment-driven turbidity on itself. Using data at the local scale, few relationships were significant, likely due to the influence of unmeasured variables and/or spatial heterogeneity. In summary, causal modeling based on data from a large-scale field survey suggested that aquatic vegetation can reduce turbidity at regional scales, and that high vegetation cover vs. high sediment driven turbidity may represent two self-enhancing, alternative states of shallow bay ecosystems. PMID- 28854186 TI - Meloidogyne aberrans sp. nov. (Nematoda: Meloidogynidae), a new root-knot nematode parasitizing kiwifruit in China. AB - High infection rates of roots of wild kiwifruit (Actinidia chinensis Planch) and soil infestation by a root-knot nematode were found in Anshun, GuiZhou Province, China. Morphology, esterase phenotype and molecular analyses confirmed that this nematode was different from previously described root-knot nematodes. In this report, the species is described, illustrated and named Meloidogyne aberrans sp. nov. The new species has a unique combination of characters. A prominent posterior protuberance, round and faint perineal pattern and a medium-length stylet (13.6-15.5 MUm) characterized the females. Second-stage juveniles (J2) were characterized by a smooth lip region with distinctly protruded medial lips and a depression in outline at the oral aperture, a relatively long stylet (15.9 16.8 MUm), four incisures in the lateral field and a very short, even poorly defined, hyaline tail terminus (2.2-5.5 MUm). More incisures (11-15) existed in the lateral field of males, and the stylet and spicules of males were 18.2-19.6 MUm and 22.7-36.8 MUm long respectively. Egg masses were typically produced within the roots of kiwifruit. The new species had a rare Est phenotype, S2. Phylogenetic trees inferred from SSU, LSU D2D3, ITS, and partial coxII-16S rRNA revealed that M. aberrans sp. nov. was within the Meloidogyne clade and was distinguished from all described root-knot nematodes. Moreover, from histopathological observations, M. aberrans sp. nov. induced the formation of multinucleate giant cells. PMID- 28854188 TI - Correction: Germline and reproductive tract effects intensify in male mice with successive generations of estrogenic exposure. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006885.]. PMID- 28854187 TI - Decoding the similarities and differences among mycobacterial species. AB - Mycobacteriaceae comprises pathogenic species such as Mycobacterium tuberculosis, M. leprae and M. abscessus, as well as non-pathogenic species, for example, M. smegmatis and M. thermoresistibile. Genome comparison and annotation studies provide insights into genome evolutionary relatedness, identify unique and pathogenicity-related genes in each species, and explore new targets that could be used for developing new diagnostics and therapeutics. Here, we present a comparative analysis of ten-mycobacterial genomes with the objective of identifying similarities and differences between pathogenic and non-pathogenic species. We identified 1080 core orthologous clusters that were enriched in proteins involved in amino acid and purine/pyrimidine biosynthetic pathways, DNA related processes (replication, transcription, recombination and repair), RNA methylation and modification, and cell-wall polysaccharide biosynthetic pathways. For their pathogenicity and survival in the host cell, pathogenic species have gained specific sets of genes involved in repair and protection of their genomic DNA. M. leprae is of special interest owing to its smallest genome (1600 genes and ~1300 psuedogenes), yet poor genome annotation. More than 75% of the pseudogenes were found to have a functional ortholog in the other mycobacterial genomes and belong to protein families such as transferases, oxidoreductases and hydrolases. PMID- 28854189 TI - A dynamic model for estimating adult female mortality from ovarian dissection data for the tsetse fly Glossina pallidipes Austen sampled in Zimbabwe. AB - Human and animal trypanosomiasis, spread by tsetse flies (Glossina spp), is a major public health concern in much of sub-Saharan Africa. The basic reproduction number of vector-borne diseases, such as trypanosomiasis, is a function of vector mortality rate. Robust methods for estimating tsetse mortality are thus of interest for understanding population and disease dynamics and for optimal control. Existing methods for estimating mortality in adult tsetse, from ovarian dissection data, often use invalid assumptions of the existence of a stable age distribution, and age-invariant mortality and capture probability. We develop a dynamic model to estimate tsetse mortality from ovarian dissection data in populations where the age distribution is not necessarily stable. The models correspond to several hypotheses about how temperature affects mortality: no temperature dependence (model 1), identical temperature dependence for mature adults and immature stages, i.e., pupae and newly emerged adults (model 2), and differential temperature dependence for mature adults and immature stages (model 3). We fit our models to ovarian dissection data for G. pallidipes collected at Rekomitjie Research Station in the Zambezi Valley in Zimbabwe. We compare model fits to determine the most probable model, given the data, by calculating the Akaike Information Criterion (AIC) for each model. The model that allows for a differential dependence of temperature on mortality for immature stages and mature adults (model 3) performs significantly better than models 1 and 2. All models produce mortality estimates, for mature adults, of approximately 3% per day for mean daily temperatures below 25 degrees C, consistent with those of mark recapture studies performed in other settings. For temperatures greater than 25 degrees C, mortality among immature classes of tsetse increases substantially, whereas mortality remains roughly constant for mature adults. As a sensitivity analysis, model 3 was simultaneously fit to both the ovarian dissection and trap data; while this fit also produces comparable mortality at temperatures below 25 degrees C, it is not possible to obtain good fits to both data sources simultaneously, highlighting the uncertain correspondence between trap catches and population levels and/or the need for further improvements to our model. The modelling approach employed here could be applied to any substantial time series of age distribution data. PMID- 28854190 TI - Population structure and molecular genetic characterization of clinical Candida tropicalis isolates from a tertiary-care hospital in Kuwait reveal infections with unique strains. AB - Candida tropicalis is a frequently isolated yeast species causing bloodstream, urinary tract and other infections particularly in patients admitted to intensive care units (ICUs) and those requiring prolonged urinary catheterization (UC) or receiving broad-spectrum antibiotics (BSA). This study investigated clinical characteristics and genetic relatedness among C. tropicalis strains isolated from patients at Al-Amiri Hospital in Kuwait. C. tropicalis strains (n = 63) isolated from blood, genito-urinary, respiratory (RT) and digestive (GIT) tracts and wound sites from 54 patients were used. All isolates were phenotypically identified and tested against six antifungal drugs by using Vitek 2 system. Molecular identification was performed by PCR amplification of rDNA. Fingerprinting was achieved by 6-loci-based multilocus sequence typing (MLST) and data were analyzed by BioNumerics software for phylogenetic relationships. Patients mean age was >65 years and >20% patients were hospitalized in ICUs. Most patients had underlying conditions that included UC, BSA, diabetes and RT/GIT abnormalities. Most candiduria cases had UC, ureteric stent or suprapubic catheters. All isolates were identified as C. tropicalis by Vitek 2 and by species-specific PCR. Sixty two isolates were susceptible to all tested antifungal drugs. MLST identified 59 diploid sequence types (DSTs) including 54 newly-identified DSTs. C. tropicalis isolates from multiple sites of same patient usually belonged to different DSTs. Interestingly, 56 of 57 isolates from 48 patients belonged to unique genotypes. Only six isolates from six patients belonged to three DSTs (clusters), however, C. tropicalis strains in each cluster were isolated >3 months apart. Our data show diverse origins of C. tropicalis infections in Kuwait as most isolates were unique strains. There was no obvious correlation between cluster isolates with time of isolation and/or hospital ward of their origin. This study presents the first MLST analysis of C. tropicalis isolates from Middle East and may be useful for studying genetic relationships among global C. tropicalis strains. PMID- 28854191 TI - Use of noninvasive 'bug-eggs' to enable comparative inferences on genetic mating system with and without parental information: A study in a cattle egret colony. AB - Colonial waterbirds such as herons, egrets and spoonbills exhibit ecological characteristics that could have promoted the evolution of conspecific brood parasitism and extra-pair copulation. However, an adequate characterization of the genetic mating systems of this avian group has been hindered by the lack of samples of elusive candidate parents which precluded conducting conventional parentage allocation tests. Here, we investigate the genetic mating system of the invasive cattle egret using hematophagous insects contained in fake eggs to collect blood from incubating adults in a wild breeding colony. We tested a protocol with a previously unused Neotropical Triatominae, Panstrongylus megistus, obtained blood samples from males and females in 31 nests built on trees, drew blood from 89 nestlings at those nests, and genotyped all samples at 14 microsatellite loci, including six new species-specific loci. We comparatively addressed the performance of parentage allocation versus kinship classification of nestlings to infer the genetic mating system of cattle egrets. In line with previous behavioral observations, we found evidence in support of a non monogamous genetic mating system, including extra-pair paternity (EPP) and conspecific brood parasitism (CBP). Parentage allocation tests detected a higher percentage of nests with alternative reproductive tactics (EPP: 61.7%; CBP: 64.5%) than the kinship classification method (EPP: 50.0%; CBP: 43.3%). Overall, these results indicate that rates of alternative reproductive tactics inferred in the absence of parental genetic information could be underestimated and should be interpreted with caution. This study highlights the importance of incorporating samples from candidate parents to adequately determine the genetic mating system of a species. We expand knowledge on the reproductive tactics of colonial waterbirds, contributing novel data on the genetic mating system of the cattle egret, valuable for the design of management strategies for this invasive bird. PMID- 28854192 TI - Essential metrics for assessing sex & gender integration in health research proposals involving human participants. AB - Integrating sex and gender in health research is essential to produce the best possible evidence to inform health care. Comprehensive integration of sex and gender requires considering these variables from the very beginning of the research process, starting at the proposal stage. To promote excellence in sex and gender integration, we have developed a set of metrics to assess the quality of sex and gender integration in research proposals. These metrics are designed to assist both researchers in developing proposals and reviewers in making funding decisions. We developed this tool through an iterative three-stage method involving 1) review of existing sex and gender integration resources and initial metrics design, 2) expert review and feedback via anonymous online survey (Likert scale and open-ended questions), and 3) analysis of feedback data and collective revision of the metrics. We received feedback on the initial metrics draft from 20 reviewers with expertise in conducting sex- and/or gender-based health research. The majority of reviewers responded positively to questions regarding the utility, clarity and completeness of the metrics, and all reviewers provided responses to open-ended questions about suggestions for improvements. Coding and analysis of responses identified three domains for improvement: clarifying terminology, refining content, and broadening applicability. Based on this analysis we revised the metrics into the Essential Metrics for Assessing Sex and Gender Integration in Health Research Proposals Involving Human Participants, which outlines criteria for excellence within each proposal component and provides illustrative examples to support implementation. By enhancing the quality of sex and gender integration in proposals, the metrics will help to foster comprehensive, meaningful integration of sex and gender throughout each stage of the research process, resulting in better quality evidence to inform health care for all. PMID- 28854193 TI - Study on molecular mechanism of ANOS1 promoting development of colorectal cancer. AB - Our main aim was to elucidate the molecular mechanism responsible for the development and metastasis of colorectal cancer. Furthermore, we also identified the key genes participating in this molecular mechanism and stimulating the progression of colorectal cancer. In our experiment, the ANOS1 gene showed up regulated expression levels continuously, whereas the methylation level showed downregulated levels when the colorectal cancer progressed through the four clinical stages of development and metastasis. We obtained this information by analyzing the expression profile data and methylation data of ANOS1 gene in colorectal cancer. This phenomenon indicates that ANOS1 gene shows continuous activation during the progression of colorectal cancer. According to the results of survival analysis, the expression of ANOS1 gene is closely related to the overall survival rate of patients (p = 0.003); moreover, the expression of ANOS1 gene is also strongly associated with the disease-specific survival rate (p = 0.001). When the expression of ANOS1 gene is high, the survival rate is low in patients. When the expression of ANOS1 gene is low, the survival rate of patients is high. To elucidate the possible molecular mechanism of ANOS1, we performed GSEA enrichment analysis based on the expression value of ANOS1 gene. We found that gene with an up-regulated expression was mainly involved in Wnt signaling pathway; these up-regulated genes were present in the group of high ANOS1 expression. Although several genes were involved in Wnt signaling pathway, CTHRC1 gene was of higher occurrence frequency. By co-expression analysis, we found that both expression value and expression extent of CTHRC1 were associated with ANOS1. All these results indicate that ANOS1 possibly promotes the activation of Wnt signaling pathway with its co-expression partner CTHRC1. Thus, ANOS1 and CTHRC1 genes promote the development and metastasis of colorectal cancer. PMID- 28854194 TI - The earliest settlers of Mesoamerica date back to the late Pleistocene. AB - Preceramic human skeletal remains preserved in submerged caves near Tulum in the Mexican state of Quintana Roo, Mexico, reveal conflicting results regarding 14C dating. Here we use U-series techniques for dating a stalagmite overgrowing the pelvis of a human skeleton discovered in the submerged Chan Hol cave. The oldest closed system U/Th age comes from around 21 mm above the pelvis defining the terminus ante quem for the pelvis to 11311+/-370 y BP. However, the skeleton might be considerable older, probably as old as 13 ky BP as indicated by the speleothem stable isotope data. The Chan Hol individual confirms a late Pleistocene settling of Mesoamerica and represents one of the oldest human osteological remains in America. PMID- 28854195 TI - Link prediction based on non-negative matrix factorization. AB - With the rapid expansion of internet, the complex networks has become high dimensional, sparse and redundant. Besides, the problem of link prediction in such networks has also obatined increasingly attention from different types of domains like information science, anthropology, sociology and computer sciences. It makes requirements for effective link prediction techniques to extract the most essential and relevant information for online users in internet. Therefore, this paper attempts to put forward a link prediction algorithm based on non negative matrix factorization. In the algorithm, we reconstruct the correlation between different types of matrix through the projection of high-dimensional vector space to a low-dimensional one, and then use the similarity between the column vectors of the weight matrix as the scoring matrix. The experiment results demonstrate that the algorithm not only reduces data storage space but also effectively makes the improvements of the prediction performance during the process of sustaining a low time complexity. PMID- 28854197 TI - Environmental disturbance increases social connectivity in a passerine bird. AB - Individual level response to natural and anthropogenic disturbance represents an increasingly important, but as yet little understood, component of animal behavior. Disturbance events often alter habitat, which in turn can modify behaviors of individuals in affected areas, including changes in habitat use and associated changes in social structure. To better understand these relationships, we investigated aspects of habitat selection and social connectivity of a small passerine bird, the red-backed fairywren (Malurus melanocephalus), before vs. after naturally occurring fire disturbance in Northern Territory, Australia. We utilized a social network framework to evaluate changes in social dynamics pre- vs. post-fire. Our study covered the non-breeding season in two consecutive years in which fires occurred, and individuals whose habitat was affected and those that were not affected by fire. Individuals in habitat affected by fires had stronger social ties (i.e. higher weighted degree) after fires, while those that were in areas that were not affected by fire actually had lower weighted degree. We suggest that this change in social connections may be linked to habitat. Before fires, fairywrens used habitat that had similar grass cover to available habitat plots randomly generated within our study site. Fire caused a reduction in grass cover, and fairywrens responded by selecting habitat with higher grass cover relative to random plots. This study demonstrates how changes in habitat and/or resource availability caused by disturbance can lead to substantive changes in the social environment that individuals experience. PMID- 28854196 TI - Home food preparation practices, experiences and perceptions: A qualitative interview study with photo-elicitation. AB - Food-related choices have an important impact on health. Food preparation methods may be linked to diet and health benefits. However, the factors influencing people's food choices, and how they are shaped by food preparation experiences, are still not fully understood. We aimed to study home food preparation practices, experiences and perceptions amongst adults in North East England. A matrix was used to purposively sample participants with diverse socio-demographic characteristics. Participants developed photographic food diaries that were used as prompts during semi-structured interviews. Data were analysed using the Framework Method. Interviews were conducted with 18 adults (five men and 13 women), aged approximately 20 to 80 years, to reach data saturation. Participants' practices varied widely, from reliance on pre-prepared foods, to preparing complex meals entirely from basic ingredients. Key themes emerged regarding the cook (identity), the task (process of cooking), and the context (situational drivers). Resources, in terms of time, money and facilities, were also underpinning influences on food preparation. Participants' practices were determined by both personal motivations to cook, and the influence of others, and generally reflected compromises between varied competing demands and challenges in life. Most people appeared to be overall content with their food preparation behaviour, though ideally aspired to cook more frequently, using basic ingredients. This often seemed to be driven by social desirability. Home food preparation is complex, with heterogeneous practices, experiences and perceptions both between individuals and within the same individual over time, according to shifting priorities and circumstances. Generalisability of these findings may be limited by the regional participant sample; however the results support and build upon previous research. Focussing interventions on life transition points at which priorities and circumstances change, with careful targeting to stimulate personal motivation and social norms, may prove effective in encouraging home food preparation. PMID- 28854198 TI - Consequences and coping strategies six years after a subarachnoid hemorrhage - A qualitative study. AB - BACKGROUND: After a subarachnoid haemorrhage (SAH), continuing impairment is common and may impact the person's life. There is a lack of knowledge regarding long-term consequences experienced. PURPOSE: To explore experiences of the care and rehabilitation as well as the consequences and strategies used to cope with everyday life six years post SAH. METHODS: An explorative interview study with a qualitative design. Individual interviews, with open ended questions, using an interview guide were performed with sixteen participants (mean age 63, 8 men, 8 women) six years post SAH. Data was analyzed according to a descriptive thematic analysis, and themes were discovered inductively. RESULTS: Two major themes from the analysis, both including four sub-themes, were identified; these themes were consequences of the SAH and coping strategies. Participants were grateful to have survived the SAH and most were satisfied with their acute medical care. If discharged directly from the neurosurgical unit participants can feel abandoned. In contrast, participants who were referred to a rehabilitation clinic felt supported and informed. Cognitive problems, such as impaired memory and mental fatigue, were reported as still present six years post SAH. Coping strategies were; receiving support from family, society, employers, or technical equipment. At work, talking to colleagues and to taking breaks were common. Participants described hiding their symptoms from employers and friends, as well as trying to continue doing tasks in the same manner as prior to the SAH. If this was not possible, some refrained from doing these tasks. They went through a mourning process, fear, and worries. CONCLUSIONS: Participants reported several long-term consequences which impacted on their daily lives post SAH, and different coping strategies were used to cope with these problems. Participants reported lack of awareness regarding the consequences of SAH and stressed the importance of structured multidisciplinary follow-ups, which mostly is missing. PMID- 28854200 TI - Sanitation facilities, hygienic conditions, and prevalence of acute diarrhea among under-five children in slums of Addis Ababa, Ethiopia: Baseline survey of a longitudinal study. AB - BACKGROUND: In developing countries, children under the age of five years who live in slums are highly vulnerable to diarrhea. However, there is a paucity of information on the relationship between sanitation facilities and hygienic conditions to acute diarrhea among under-five children in slum areas of Addis Ababa, Ethiopia. Therefore, this study examines the sanitation facilities and hygienic conditions in the slums of Addis Ababa and identifies the main factors significantly associated with acute diarrhea among children aged 0-50 months in those slums. METHODS: A community-based cross-sectional household survey was carried out between September and November 2014, that then served as the baseline survey of a longitudinal study. For this survey, 697 children aged 0-50 months were recruited from two slum districts in Addis Ababa. A pre-tested structured questionnaire and an observational checklist were used for data collection. Multivariable logistic regression analysis was used to identify sanitation facilities and hygiene-related factors that were significantly associated with acute diarrhea by controlling potential confounding effects of selected socio demographic factors. Adjusted odds ratio (AOR) with corresponding 95% confidence interval (CI) was used to quantify the strength of association. MAIN FINDINGS: The prevalence of acute diarrhea among children aged 0-50 months in the study area was 11.9% and 94.6% of the sanitation facilities were unimproved. Sharing of a sanitation facility by six or more households (AOR = 4.7; 95% CI: 2.4-9.4), proximity of sanitation facilities within 15 meters of homes (AOR = 6.6; 95% CI: 2.5-17.0), presence of feces (AOR = 3.9; 95% CI: 1.5-10.3) and flies (AOR = 2.5; 95% CI: 1.3-5.0) on the floor of and/or around sanitation facilities, and presence of uncollected garbage inside house compounds (AOR = 3.2; 95% CI: 1.2 8.4) were significantly associated with acute diarrhea. CONCLUSION: This study reveals the slum environment to be high risk for diarrhea due to close proximity of sanitation facilities to homes, sharing of sanitation facilities, and poor hygiene of the sanitation facilities and housing compounds. We recommend the development of a comprehensive diarrheal disease prevention program that focuses on improving the cleanliness of the sanitation facilities and housing compounds. Increasing the number of improved sanitation facilities at an appropriate distance from houses is also essential in order to reduce the number of households that share one latrine. PMID- 28854201 TI - Association of whale sharks (Rhincodon typus) with thermo-biological frontal systems of the eastern tropical Pacific. AB - Satellite tracking of 27 whale sharks in the eastern tropical Pacific, examined in relation to environmental data, indicates preferential occupancy of thermo biological frontal systems. In these systems, thermal gradients are caused by wind-forced circulation and mixing, and biological gradients are caused by associated nutrient enrichment and enhanced primary productivity. Two of the frontal systems result from upwelling, driven by divergence in the current systems along the equator and the west coast of South America; the third results from wind jet dynamics off Central America. All whale sharks were tagged near Darwin Island, Galapagos, within the equatorial Pacific upwelling system. Occupancy of frontal habitat is pronounced in synoptic patterns of shark locations in relation to serpentine, temporally varying thermal fronts across a zonal expanse > 4000 km. 80% of shark positions in northern equatorial upwelling habitat and 100% of positions in eastern boundary upwelling habitat were located within the upwelling front. Analysis of equatorial shark locations relative to thermal gradients reveals occupancy of a transition point in environmental stability. Equatorial subsurface tag data show residence in shallow, warm (>22 degrees C) water 94% of the time. Surface zonal current speeds for all equatorial tracking explain only 16% of the variance in shark zonal movement speeds, indicating that passive drifting is not a primary determinant of movement patterns. Movement from equatorial to eastern boundary frontal zones occurred during boreal winter, when equatorial upwelling weakens seasonally. Off Peru sharks tracked upwelling frontal positions within ~100-350 km from the coast. Off Central America, the largest tagged shark (12.8 m TL) occupied an oceanic front along the periphery of the Panama wind jet. Seasonal movement from waning equatorial upwelling to productive eastern boundary habitat is consistent with underlying trophic dynamics. Persistent shallow residence in thermo-biological frontal zones suggests the role of physical-biological interactions that concentrate food resources. PMID- 28854199 TI - Ultrasound 2D strain measurement for arm lymphedema using deformable registration: A feasibility study. AB - PURPOSE: Lymphedema, a swelling of the extremity, is a debilitating morbidity of cancer treatment. Current clinical evaluation of lymphedema is often based on medical history and physical examinations, which is subjective. In this paper, the authors report an objective, quantitative 2D strain imaging approach using a hybrid deformable registration to measure soft-tissue stiffness and assess the severity of lymphedema. METHODS: The authors have developed a new 2D strain imaging method using registration of pre- and post-compression ultrasound B-mode images, which combines the statistical intensity- and structure-based similarity measures using normalized mutual information (NMI) metric and normalized sum-of squared-differences (NSSD), with an affine-based global and B-spline-based local transformation model. This 2D strain method was tested through a series of experiments using elastography phantom under various pressures. Clinical feasibility was tested with four participants: two patients with arm lymphedema following breast-cancer radiotherapy and two healthy volunteers. RESULTS: The phantom experiments have shown that the proposed registration-based strain method significantly increased the signal-to-noise and contrast-to-noise ratio under various pressures as compared with the commonly used cross-correlation-based elastography method. In the pilot study, the strain images were successfully generated for all participants. The averaged strain values of the lymphedema affected arms were much higher than those of the normal arms. CONCLUSIONS: The authors have developed a deformable registration-based 2D strain method for the evaluation of arm lymphedema. The initial findings are encouraging and a large clinical study is warranted to further evaluate this 2D ultrasound strain imaging technology. PMID- 28854202 TI - Formation of homophily in academic performance: Students change their friends rather than performance. AB - Homophily, the tendency of individuals to associate with others who share similar traits, has been identified as a major driving force in the formation and evolution of social ties. In many cases, it is not clear if homophily is the result of a socialization process, where individuals change their traits according to the dominance of that trait in their local social networks, or if it results from a selection process, in which individuals reshape their social networks so that their traits match those in the new environment. Here we demonstrate the detailed temporal formation of strong homophily in academic achievements of high school and university students. We analyze a unique dataset that contains information about the detailed time evolution of a friendship network of 6,000 students across 42 months. Combining the evolving social network data with the time series of the academic performance (GPA) of individual students, we show that academic homophily is a result of selection: students prefer to gradually reorganize their social networks according to their performance levels, rather than adapting their performance to the level of their local group. We find no signs for a pull effect, where a social environment of good performers motivates bad students to improve their performance. We are able to understand the underlying dynamics of grades and networks with a simple model. The lack of a social pull effect in classical educational settings could have important implications for the understanding of the observed persistence of segregation, inequality and social immobility in societies. PMID- 28854203 TI - Signage as a tool for behavioral change: Direct and indirect routes to understanding the meaning of a sign. AB - Signs, prompts, and symbols are a common means to change behavior in our society. Understanding the psychological mechanisms by which signage influences behavior is a critical first step to achieve the desired outcome. In the current research, we propose a theoretical model of sign-to-behavior process. The model suggests that when one encounters a sign, it is encoded to construct an action representation (comprehension process), which is then acted on unless its enactment is inhibited (decision process). We test the implications of the model in two studies. In support of our hypothesis, for unfamiliar signs, clarity of purpose predicts perceived effectiveness of a sign; however, for familiar signs, clarity of purpose does not matter. Insights gained from the studies will help to design effective signs. Practical implications of the model are discussed, and future research directions are outlined. PMID- 28854204 TI - Impact of the two-dose rubella vaccination regimen on incidence of rubella seronegativity in gravidae aged 25 years and younger. AB - OBJECTIVE: This study compared the incidence of rubella seronegativity among gravidae of 25 year-old and younger, between those born in Hong Kong after 1983 when the two-dose rubella vaccination was implemented, versus gravidae born before, to examine the impact of the two-dose regimen. METHODS: In this retrospective cohort study, the incidence of antenatal rubella seronegativity in our parturients managed in1997-2015 was analysed by their age from <=16 to 25 years, and the effect of year of birth was determined adjusting for confounding factors including teenage status, obstetric history, anthropometric factors, and health parameters including anaemia, thalassaemia trait and hepatitis B carrier status. RESULTS: Among the 12743 gravidae, the 6103 gravidae born after 1983 had overall higher rubella seronegativity (9.1% versus 4.4%, OR 2.061, 95% CI 1.797 2.364), with significant difference (p = 0.006) and inverse correlation (p<0.001) with age, in contrast to the 6640 gravidae born in/before 1983 whom there was significant difference (p = 0.027) but a positive correlation (p = 0.008) with age. For each year of age, the former had significantly higher incidence of rubella seronegativity except for those of <=16 years. Regression analysis confirmed that birth after 1983 was independently associated with rubella seronegativity (aOR 2.207, 95% CI 1.902-2.562). CONCLUSION: There was a significant trend between rubella seronegativity with age in young gravidae, but the pattern was opposite between gravidae born after versus in/before 1983, with the former having a higher incidence of seronegativity at all ages. Young women covered by the two-dose rubella immunisation programme have a paradoxically higher incidence of rubella seronegativity. PMID- 28854205 TI - The more total cognitive load is reduced by cues, the better retention and transfer of multimedia learning: A meta-analysis and two meta-regression analyses. AB - Cueing facilitates retention and transfer of multimedia learning. From the perspective of cognitive load theory (CLT), cueing has a positive effect on learning outcomes because of the reduction in total cognitive load and avoidance of cognitive overload. However, this has not been systematically evaluated. Moreover, what remains ambiguous is the direct relationship between the cue related cognitive load and learning outcomes. A meta-analysis and two subsequent meta-regression analyses were conducted to explore these issues. Subjective total cognitive load (SCL) and scores on a retention test and transfer test were selected as dependent variables. Through a systematic literature search, 32 eligible articles encompassing 3,597 participants were included in the SCL related meta-analysis. Among them, 25 articles containing 2,910 participants were included in the retention-related meta-analysis and the following retention related meta-regression, while there were 29 articles containing 3,204 participants included in the transfer-related meta-analysis and the transfer related meta-regression. The meta-analysis revealed a statistically significant cueing effect on subjective ratings of cognitive load (d = -0.11, 95% CI = [ 0.19, -0.02], p < 0.05), retention performance (d = 0.27, 95% CI = [0.08, 0.46], p < 0.01), and transfer performance (d = 0.34, 95% CI = [0.12, 0.56], p < 0.01). The subsequent meta-regression analyses showed that dSCL for cueing significantly predicted dretention for cueing (beta = -0.70, 95% CI = [-1.02, -0.38], p < 0.001), as well as dtransfer for cueing (beta = -0.60, 95% CI = [-0.92, -0.28], p < 0.001). Thus in line with CLT, adding cues in multimedia materials can indeed reduce SCL and promote learning outcomes, and the more SCL is reduced by cues, the better retention and transfer of multimedia learning. PMID- 28854206 TI - Increased rates of Guillain-Barre syndrome associated with Zika virus outbreak in the Salvador metropolitan area, Brazil. AB - In mid-2015, Salvador, Brazil, reported an outbreak of Guillain-Barre syndrome (GBS), coinciding with the introduction and spread of Zika virus (ZIKV). We found that GBS incidence during April-July 2015 among those >=12 years of age was 5.6 cases/100,000 population/year and increased markedly with increasing age to 14.7 among those >=60 years of age. We conducted interviews with 41 case-patients and 85 neighborhood controls and found no differences in demographics or exposures prior to GBS-symptom onset. A higher proportion of case-patients (83%) compared to controls (21%) reported an antecedent illness (OR 18.1, CI 6.9-47.5), most commonly characterized by rash, headache, fever, and myalgias, within a median of 8 days prior to GBS onset. Our investigation confirmed an outbreak of GBS, particularly in older adults, that was strongly associated with Zika-like illness and geo-temporally associated with ZIKV transmission, suggesting that ZIKV may result in severe neurologic complications. PMID- 28854207 TI - First evidence of dengue infection in domestic dogs living in different ecological settings in Thailand. AB - BACKGROUND: Dengue is a vector-borne disease transmitted by Aedes mosquitoes. It is considered an important public health problem in many countries worldwide. However, only a few studies have been conducted on primates and domestic animals that could potentially be a reservoir of dengue viruses. Since domestic dogs share both habitats and vectors with humans, this study aimed to investigate whether domestic dogs living in different ecological settings in dengue endemic areas in Thailand could be naturally infected with dengue viruses. METHODOLOGY/PRINCIPAL FINDINGS: Serum samples were collected from domestic dogs in three different ecological settings of Thailand: urban dengue endemic areas of Nakhon Sawan Province; rubber plantation areas of Rayong Province; and Koh Chang, an island tourist spot of Trat Province. These samples were screened for dengue viral genome by using semi-nested RT-PCR. Positive samples were then inoculated in mosquito and dog cell lines for virus isolation. Supernatant collected from cell culture was tested for the presence of dengue viral genome by semi-nested RT PCR, then double-strand DNA products were double-pass custom-sequenced. Partial nucleotide sequences were aligned with the sequences already recorded in GenBank, and a phylogenetic tree was constructed. In the urban setting, 632 domestic dog serum samples were screened for dengue virus genome by RT-PCR, and six samples (0.95%) tested positive for dengue virus. Four out of six dengue viruses from positive samples were successfully isolated. Dengue virus serotype 2 and serotype 3 were found to have circulated in domestic dog populations. One of 153 samples (0.65%) collected from the rubber plantation area showed a PCR-positive result, and dengue serotype 3 was successfully isolated. Partial gene phylogeny revealed that the isolated dengue viruses were closely related to those strains circulating in human populations. None of the 71 samples collected from the island tourist spot showed a positive result. CONCLUSIONS/SIGNIFICANCE: We concluded that domestic dogs can be infected with dengue virus strains circulating in dengue endemic areas. The role of domestic dogs in dengue transmission needs to be further investigated, i.e., whether they are potential reservoirs or incidental hosts of dengue viruses. PMID- 28854208 TI - Delaying the start of iron until 28 days after antimalarial treatment is associated with lower incidence of subsequent illness in children with malaria and iron deficiency. AB - We evaluated the incidence of all-cause and malaria-specific clinic visits during follow-up of a recent trial of iron therapy. In the main trial, Ugandan children 6-59 months with smear-confirmed malaria and iron deficiency [zinc protoporphyrin (ZPP > = 80 MUmol/mol heme)] were treated for malaria and randomized to start a 27-day course of oral iron concurrently with (immediate group) or 28 days after (delayed group) antimalarial treatment. All children were followed for the same 56-day period starting at the time of antimalarial treatment (Day 0) and underwent passive and active surveillance for malaria and other morbidity for the entire follow-up period. All ill children were examined and treated by the study physician. In this secondary analysis of morbidity data from the main trial, we report that although the incidence of malaria-specific visits did not differ between the groups, children in the immediate group had a higher incidence rate ratio of all-cause sick-child visits to the clinic during the follow-up period (Incidence Rate Ratio (IRR) immediate/delayed = 1.76; 95%CI: 1.05-3.03, p = 0.033). Although these findings need to be tested in a larger trial powered for malaria-specific morbidity, these preliminary results suggest that delaying iron by 28 days in children with coexisting malaria and iron deficiency is associated with a reduced risk of subsequent all-cause illness. PMID- 28854210 TI - Honey bee foraging ecology: Season but not landscape diversity shapes the amount and diversity of collected pollen. AB - The availability of pollen in agricultural landscapes is essential for the successful growth and reproduction of honey bee colonies (Apis mellifera L.). The quantity and diversity of collected pollen can influence the growth and health of honey bee colonies, but little is known about the influence of landscape structure on pollen diet. In a field experiment, we rotated 16 honey bee colonies across 16 agricultural landscapes, used traps to collect samples of collected pollen and observed intra-colonial dance communication to gain information about foraging distances. DNA metabarcoding was applied to analyze mixed pollen samples. Neither the amount of collected pollen nor pollen diversity was related to landscape diversity. However, we found a strong seasonal variation in the amount and diversity of collected pollen in all sites independent of landscape diversity. The observed increase in foraging distances with decreasing landscape diversity suggests that honey bees compensated for lower landscape diversity by increasing their pollen foraging range in order to maintain pollen amount and diversity. Our results underscore the importance of a diverse pollen diet for honey bee colonies. Agri-environmental schemes aiming to support pollinators should focus on possible spatial and temporal gaps in pollen availability and diversity in agricultural landscapes. PMID- 28854209 TI - Identification of a serum-induced transcriptional signature associated with metastatic cervical cancer. AB - OBJECTIVE: Tumor cells that escape local tissue control can convert inflammatory cells from tumor suppressors to tumor promoters. Moreover, soluble immune modulating factors secreted from the tumor environment can be difficult to identify in patient serum due to their low abundance. We used an alternative strategy to infer a metastatic signature induced by sera of cervical cancer patients. METHODS: Sera from patients with local and metastatic cervical cancer were used to induce a disease-specific transcriptional signature in cultured, healthy peripheral blood mononuclear cells (PBMCs). An empirical Bayesian method, EBarrays, was used to identify differentially expressed (DE) genes with a target false discovery rate of <5%. Ingenuity Pathway Analysis (IPA) software was used to detect the top molecular and cellular functions associated with the DE genes. IPA and in silco analysis was used to pinpoint candidate upstream regulators, including cancer-related microRNAs (miRNAs). RESULTS: We identified enriched pathways in the metastatic cervical group related to immune surveillance functions, such as downregulation of engulfment, accumulation, and phagocytosis of hematopoietic cells. The predicted top upstream genes were IL-10 and immunoglobulins. In silco analysis identified miRNAs predicted to drive the transcriptional signature. Two of the 4 miRNAs (miR-23a-3p and miR-944) were validated in a cohort of women with local and metastatic cervical cancer. CONCLUSIONS: This study supports the use of a cell-based assay that uses PBMC "reporters" to predict biologically relevant factors in patient serum. Further, disease-specific transcriptional signatures induced by patient sera have the potential to differentiate patients with local versus metastatic disease. PMID- 28854211 TI - Identification of metal ion binding sites based on amino acid sequences. AB - The identification of metal ion binding sites is important for protein function annotation and the design of new drug molecules. This study presents an effective method of analyzing and identifying the binding residues of metal ions based solely on sequence information. Ten metal ions were extracted from the BioLip database: Zn2+, Cu2+, Fe2+, Fe3+, Ca2+, Mg2+, Mn2+, Na+, K+ and Co2+. The analysis showed that Zn2+, Cu2+, Fe2+, Fe3+, and Co2+ were sensitive to the conservation of amino acids at binding sites, and promising results can be achieved using the Position Weight Scoring Matrix algorithm, with an accuracy of over 79.9% and a Matthews correlation coefficient of over 0.6. The binding sites of other metals can also be accurately identified using the Support Vector Machine algorithm with multifeature parameters as input. In addition, we found that Ca2+ was insensitive to hydrophobicity and hydrophilicity information and Mn2+ was insensitive to polarization charge information. An online server was constructed based on the framework of the proposed method and is freely available at http://60.31.198.140:8081/metal/HomePage/HomePage.html. PMID- 28854212 TI - Condensation patterns of prophase/prometaphase chromosome are correlated with H4K5 histone acetylation and genomic DNA contents in plants. AB - Mitotic prophase chromosome condensation plays an essential role in nuclear division being therefore regulated by highly conserved mechanisms. However, degrees of chromatin condensation in prophase-prometaphase cells may vary along the chromosomes resulting in specific condensation patterns. We examined different condensation patterns (CPs) of prophase and prometaphase chromosomes and investigated their relationship with genome size and distribution of histone H4 acetylated at lysine 5 (H4K5ac) in 17 plant species. Our results showed that most species with small genomes (2C < 5 pg) (Arachis pusilla, Bixa orellana, Costus spiralis, Eleutherine bulbosa, Indigofera campestris, Phaseolus lunatus, P. vulgaris, Poncirus trifoliata, and Solanum lycopersicum) displayed prophase chromosomes with late condensing terminal regions that were highly enriched in H4K5ac, and early condensing regions with apparently non-acetylated proximal chromatin. The species with large genomes (Allium cepa, Callisia repens, Araucaria angustifolia and Nothoscordum pulchellum) displayed uniformly condensed and acetylated prophase/prometaphase chromosomes. Three species with small genomes (Eleocharis geniculata, Rhynchospora pubera, and R. tenuis) displayed CP and H4K5ac labeling patterns similar to species with large genomes, whereas a forth species (Emilia sonchifolia) exhibited a gradual chromosome labeling, being more acetylated in the terminal regions and less acetylated in the proximal ones. The nucleolus organizer chromatin was the only chromosomal region that in prometaphase or metaphase could be hyperacetylated, hypoacetylated or non acetylated, depending on the species. Our data indicate that the CP of a plant chromosome complement is influenced but not exclusively determined by nuclear and chromosomal DNA contents, whereas the CP of individual chromosomes is clearly correlated with H4K5ac distribution. PMID- 28854213 TI - Evaluation of average travel delay caused by moving bottlenecks on highways. AB - This paper presents a modelling framework to evaluate travel delay of all vehicles influenced by moving bottlenecks on highways. During the derivation of analytical formulas, the arrival of slow vehicles was approximated by a Poisson process based on the assumption that they occupied a constant low proportion of the traffic stream. The mathematical analysis process was developed from moving bottlenecks with the same velocity to those with multiple different velocities, and the closed-form expression of expected average travel delay was obtained by utilizing kinematic-wave moving bottleneck theory, gap acceptance theory, probability theory and renewal theory. Model validation and parameters sensitive analysis were conducted by simulation relying on the open source database of US highway 10. The maximum passing rate and the macroscopic parameters of initial traffic state with maximum delay could be found by means of approximate formulas. The proposed modeling framework can be applied for evaluating impacts of slow vehicles on highway operation quantifiably, based on which traffic managements like truck prohibited period decision and speed or lane restriction could be made more scientifically. PMID- 28854214 TI - Litopenaeus vannamei hemocyanin exhibits antitumor activity in S180 mouse model in vivo. AB - Hemocyanin is a multifunctional glycoprotein, which also plays multiple roles in immune defense. While it has been demonstrated that hemocyanin from some mollusks can induce potent immune response and is therefore undergoing clinical trials to be used in anti-tumor immunotherapy, little is currently known about how hemocyanin from arthropods affect tumors. In this study we investigated the anti tumor activity of hemocyanin from Litopenaeus vannamei on Sarcoma-180 (S180) tumor-bearing mice model. Eight days treatment with 4mg/kg bodyweight of hemocyanin significantly inhibited the growth of S180 up to 49% as compared to untreated. Similarly, histopathology analysis showed a significant decrease in tumor cell number and density in the tissues of treated mice. Moreover, there was a significant increase in immune organs index, lymphocyte proliferation, NK cell cytotoxic activity and serum TNF-alpha level, suggesting that hemocyanin could improve the immunity of the S180 tumor-bearing mice. Additionally, there was a significant increase in superoxide dismutase (SOD) activity and a decrease in the level of malondialdehyde (MDA) in serum and liver, which further suggest that hemocyanin improved the anti-oxidant ability of the S180 tumor-bearing mice. Collectively, our data demonstrated that L. vannamei hemocyanin had a significant antitumor activity in mice. PMID- 28854215 TI - High PROX1 expression in gastric cancer predicts better survival. AB - BACKGROUND: PROX1 is a transcription factor involved in the development of various organs. It has also an important function in colorectal cancer progression. The aim of this study was to investigate the prognostic role of PROX1 expression in gastric cancer. METHODS: We evaluated PROX1 expression in gastric cancer by immunohistochemistry of tumor-tissue microarrays including tumor specimens from 283 patients who underwent surgery at Helsinki University Hospital. We investigated the association of PROX1 expression with clinicopathologic variables and patient survival. RESULTS: Cytoplasmic PROX1 reactivity was high in 56 (20.5%) and low in 217 (79.5%) cases. Low PROX1 immunostaining associated with diffuse cancer type (p = 0.002). In subgroup analysis, PROX1 was a significant marker of better prognosis in patients aged under 66 (p = 0.007), in those with intestinal cancer (p = 0.025), among men (p = 0.019), and in tumors of less than 5 cm diameter (p = 0.030). Patients with high PROX1 expression had a cancer-specific 5-year survival of 65.6% (95% CI 52.7 78.5), compared to 37.1% (95% CI 30.2-44.0) for those with low expression (p = 0.004, log-rank test). This result remained significant in multivariable analysis (HR = 0.56; 95% CI 0.35-0.90; p = 0.017). CONCLUSION: In gastric cancer, high cytoplasmic PROX1 expression is an independent marker of better prognosis. PMID- 28854216 TI - QuantiFERON(r)-TB Gold In-Tube for contact screening in BCG-vaccinated adults: A longitudinal cohort study. AB - OBJECTIVE: To assess the utility of QuantiFERON(r)-TB Gold In-tube (QFT-GIT) for targeting preventive therapy in BCG-vaccinated contacts of tuberculosis (TB), based on its high specificity and negative predictive value for development of TB. METHODS: We compared two screening strategies for TB contact tracing in two consecutive periods: the tuberculin skin test (TST) period, when all contacts were screened with the TST alone; and the QFT-GIT period, when BCG-vaccinated contacts underwent TST and QFT-GIT. Diagnosis of TB infection among BCG vaccinated contacts relied on TST >=5 mm in the TST period, while in the QFT-GIT period either a positive QFT-GIT or a TST >=15 mm was required. MEASUREMENTS AND MAIN RESULTS: Six hundred and sixty-one contacts were compared. In the QFT-GIT period there was a reduction in diagnoses of TB infection (77.4% vs. 51.2%; p <0.01) and preventive therapy prescribed (62.1% vs. 48.2%; p = 0.02) among the 290 BCG-vaccinated contacts. After a median follow-up of 5 years, cumulative incidences of TB were 0.62 and 0.29 in the TST and QFT-GIT periods respectively (p = 0.59). CONCLUSIONS: In BCG-vaccinated TB contacts, the addition of QFT-GIT safely reduced TB diagnosis and treatment rates without increasing the risk of subsequent active TB. PMID- 28854217 TI - Perception of recovery of households affected by 2008 Wenchuan earthquake: A structural equation model. AB - Much of the literature on recovery focuses on the economy, the physical environment and infrastructure at a macro level, which may ignore the personal experiences of affected individuals during recovery. This paper combines internal factors at a micro level and external factors at a macro level to model for understanding perception of recovery (PoR). This study focuses on areas devastated by the 2008 Wenchuan earthquake in China. With respect to three recovery-related aspects (house recovery condition (HRC), family recovery power (FRP) and reconstruction investment (RI)), structural equation modeling (SEM) was applied. It was found that the three aspects (FRP, HRC and RI) effectively explain how earthquake affected households perceive recovery. Internal factors associated with FRP contributed the most to favourable PoR, followed by external factors associated with HRC. Findings identified that for PoR the importance of active recovery within households outweighed an advantageous house recovery condition. At the same time, households trapped in unfavourable external conditions would invest more in housing recovery, which result in wealth accumulation and improved quality of life leading to a high level of PoR. In addition, schooling in households showed a negative effect on improving PoR. This research contributes to current debates around post-disaster permanent housing policy. It is implied that a one-size-fits-all policy in disaster recovery may not be effective and more specific assistance should be provided to those people in need. PMID- 28854218 TI - Honokiol induces superoxide production by targeting mitochondrial respiratory chain complex I in Candida albicans. AB - BACKGROUND: Honokiol, a compound extracted from Magnolia officinalis, has antifungal activities by inducing mitochondrial dysfunction and triggering apoptosis in Candida albicans. However, the mechanism of honokiol-induced oxidative stress is poorly understood. The present investigation was designed to determine the specific mitochondrial reactive oxygen species (ROS)-generation component. METHODS/RESULTS: We found that honokiol induced mitochondrial ROS accumulation, mainly superoxide anions (O2*-) measured by fluorescent staining method. The mitochondrial respiratory chain complex I (C I) inhibitor rotenone completely blocked O2*- production and provided the protection from the killing action of honokiol. Moreover, respiratory activity and the C I enzyme activity was significantly reduced after honokiol treatment. The differential gene expression profile also showed that genes involved in oxidoreductase activity, electron transport, and oxidative phosphorylation were upregulated. CONCLUSIONS: The present work shows that honokiol may bind to mitochondrial respiratory chain C I, leading to mitochondrial dysfunction, accompanied by increased cellular superoxide anion and oxidative stress. GENERAL SIGNIFICANCE: This work not only provides insights on the mechanism by which honokiol interferes with fungal cell, demonstrating previously unknown effects on mitochondrial physiology, but also raises a note of caution on the use of M. officinalis as a Chinese medicine due to the toxic for mitochondria and suggests the possibility of using honokiol as chemosensitizer. PMID- 28854219 TI - Molecular characterization of vancomycin-resistant Staphylococcus aureus strains isolated from clinical samples: A three year study in Tehran, Iran. AB - INTRODUCTION: Emergence of vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant S. aureus (VRSA) strains has led to great concern in global public health in both developing and developed countries. This study investigated distribution and molecular characterization of VRSA strains in Tehran's hospitals using a combination of molecular typing methods. MATERIALS AND METHODS: A total of 1789 S. aureus isolates obtained between 2014 and 2017 and were characterized using antibiogram, SCCmec typing, spa typing, and multilocus sequence typing. Resistance to vancomycin was determined by E-test method. After confirmation of the isolated VRSA strain, genetic analysis was performed by evaluating vanA and vanB genes presence.The presence of resistance (ermA, ermB, ermC, mupA, msrA, msrB, tetM, ant (4?)-Ia, aac (6?)-Ie/aph (2"), aph (3?)-IIIa) and toxin (etb, eta, pvl, tst) encoding genes was investigated by the polymerase chain reaction (PCR) technique. RESULTS: Of all S. aureus tested isolates, four isolates were confirmed as VRSA isolates and two isolates confirmed as VISA isolates. ST5- SCCmec II/t002 and ST239-SCCmec III/t037 strains had MIC values of 512MUg/ml, ST239-SCCmec III/t037 and ST8-SCCmecIV/t008 strains had MIC values of 64MUg/ml and ST22-SCCmec IV/t790 and ST239-SCCmec III/t030 strains had MIC values >= 8 MUg/ml. pvl-encoding gene was confirmed in ST8-SCCmecIV/t008 and ST22-SCCmec IV/t790 strains. The isolates differed in the carriage of resistance and toxin encoding genes. CONCLUSIONS: The study revealed the existence of VRSA strains in capital of Iran, Tehran. To our knowledge, this is the first report of ST239 SCCmec III/t037 as VRSA strain. These findings support the need for future surveillance studies on VRSA strains to keep the emergence and transmission of these isolates to a minimum. PMID- 28854220 TI - Automated diagnosis of myositis from muscle ultrasound: Exploring the use of machine learning and deep learning methods. AB - OBJECTIVE: To evaluate the use of ultrasound coupled with machine learning (ML) and deep learning (DL) techniques for automated or semi-automated classification of myositis. METHODS: Eighty subjects comprised of 19 with inclusion body myositis (IBM), 14 with polymyositis (PM), 14 with dermatomyositis (DM), and 33 normal (N) subjects were included in this study, where 3214 muscle ultrasound images of 7 muscles (observed bilaterally) were acquired. We considered three problems of classification including (A) normal vs. affected (DM, PM, IBM); (B) normal vs. IBM patients; and (C) IBM vs. other types of myositis (DM or PM). We studied the use of an automated DL method using deep convolutional neural networks (DL-DCNNs) for diagnostic classification and compared it with a semi automated conventional ML method based on random forests (ML-RF) and "engineered" features. We used the known clinical diagnosis as the gold standard for evaluating performance of muscle classification. RESULTS: The performance of the DL-DCNN method resulted in accuracies +/- standard deviation of 76.2% +/- 3.1% for problem (A), 86.6% +/- 2.4% for (B) and 74.8% +/- 3.9% for (C), while the ML RF method led to accuracies of 72.3% +/- 3.3% for problem (A), 84.3% +/- 2.3% for (B) and 68.9% +/- 2.5% for (C). CONCLUSIONS: This study demonstrates the application of machine learning methods for automatically or semi-automatically classifying inflammatory muscle disease using muscle ultrasound. Compared to the conventional random forest machine learning method used here, which has the drawback of requiring manual delineation of muscle/fat boundaries, DCNN-based classification by and large improved the accuracies in all classification problems while providing a fully automated approach to classification. PMID- 28854221 TI - Collective movements of pedestrians: How we can learn from simple experiments with non-human (ant) crowds. AB - INTRODUCTION: Understanding collective behavior of moving organisms and how interactions between individuals govern their collective motion has triggered a growing number of studies. Similarities have been observed between the scale-free behavioral aspects of various systems (i.e. groups of fish, ants, and mammals). Investigation of such connections between the collective motion of non-human organisms and that of humans however, has been relatively scarce. The problem demands for particular attention in the context of emergency escape motion for which innovative experimentation with panicking ants has been recently employed as a relatively inexpensive and non-invasive approach. However, little empirical evidence has been provided as to the relevance and reliability of this approach as a model of human behaviour. METHODS: This study explores pioneer experiments of emergency escape to tackle this question and to connect two forms of experimental observations that investigate the collective movement at macroscopic level. A large number of experiments with human and panicking ants are conducted representing the escape behavior of these systems in crowded spaces. The experiments share similar architectural structures in which two streams of crowd flow merge with one another. Measures such as discharge flow rates and the probability distribution of passage headways are extracted and compared between the two systems. FINDINGS: Our findings displayed an unexpected degree of similarity between the collective patterns emerged from both observation types, particularly based on aggregate measures. Experiments with ants and humans commonly indicated how significantly the efficiency of motion and the rate of discharge depend on the architectural design of the movement environment. PRACTICAL APPLICATIONS: Our findings contribute to the accumulation of evidence needed to identify the boarders of applicability of experimentation with crowds of non-human entities as models of human collective motion as well as the level of measurements (i.e. macroscopic or microscopic) and the type of contexts at which reliable inferences can be drawn. This particularly has implications in the context of experimenting evacuation behaviour for which recruiting human subjects may face ethical restrictions. The findings, at minimum, offer promise as to the potential benefit of piloting such experiments with non-human crowds, thereby forming better-informed hypotheses. PMID- 28854222 TI - rahu is a mutant allele of Dnmt3c, encoding a DNA methyltransferase homolog required for meiosis and transposon repression in the mouse male germline. AB - Transcriptional silencing by heritable cytosine-5 methylation is an ancient strategy to repress transposable elements. It was previously thought that mammals possess four DNA methyltransferase paralogs-Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l-that establish and maintain cytosine-5 methylation. Here we identify a fifth paralog, Dnmt3c, that is essential for retrotransposon methylation and repression in the mouse male germline. From a phenotype-based forward genetics screen, we isolated a mutant mouse called 'rahu', which displays severe defects in double-strand break repair and homologous chromosome synapsis during male meiosis, resulting in sterility. rahu is an allele of a transcription unit (Gm14490, renamed Dnmt3c) that was previously mis-annotated as a Dnmt3-family pseudogene. Dnmt3c encodes a cytosine methyltransferase homolog, and Dnmt3crahu mutants harbor a non synonymous mutation of a conserved residue within one of its cytosine methyltransferase motifs, similar to a mutation in human DNMT3B observed in patients with immunodeficiency, centromeric instability and facial anomalies syndrome. The rahu mutation lies at a potential dimerization interface and near the potential DNA binding interface, suggesting that it compromises protein protein and/or protein-DNA interactions required for normal DNMT3C function. Dnmt3crahu mutant males fail to establish normal methylation within LINE and LTR retrotransposon sequences in the germline and accumulate higher levels of transposon-derived transcripts and proteins, particularly from distinct L1 and ERVK retrotransposon families. Phylogenetic analysis indicates that Dnmt3c arose during rodent evolution by tandem duplication of Dnmt3b, after the divergence of the Dipodoidea and Muroidea superfamilies. These findings provide insight into the evolutionary dynamics and functional specialization of the transposon suppression machinery critical for mammalian sexual reproduction and epigenetic regulation. PMID- 28854223 TI - Therapeutic potential of tonsil-derived mesenchymal stem cells in dextran sulfate sodium-induced experimental murine colitis. AB - The therapeutic potential of tonsil-derived mesenchymal stem cells (TMSC) prepared from human tonsillar tissue has been studied in animal models for several diseases such as hepatic injury, hypoparathyroidism, diabetes and muscle dystrophy. In this study, we examined the therapeutic effects of TMSC in a dextran sulfate sodium (DSS)-induced colitis model. TMSC were injected in DSS induced colitis mice via intraperitoneal injection twice (TMSC[x2]) or four times (TMSC[x4]). Control mice were injected with either phosphate-buffered saline or human embryonic kidney 293 cells. Body weight, stool condition and disease activity index (DAI) were examined daily. Colon length, histologic grading, and mRNA expression of pro-inflammatory cytokines, interleukin 1beta (IL-1beta), IL 6, IL-17 and tumor necrosis factor alpha, and anti-inflammatory cytokines, IL-10, IL-11 and IL-13, were also measured. Our results showed a significant improvement in survival rates and body weight gain in colitis mice injected with TMSC[x2] or TMSC[x4]. Injection with TMSC also significantly decreased DAI scores throughout the experimental period; at the end of experiment, almost complete reversal of DAI scores to normal was found in colitis mice treated with TMSC[x4]. Colon length was also significantly recovered in colitis mice treated with TMSC[x4]. However, histopathological alterations induced by DSS treatment were not apparently improved by injection with TMSC. Finally, treatment with TMSC[x4] significantly reversed the mRNA levels of IL-1beta and IL-6, although expression of all pro-inflammatory cytokines tested was induced in colitis mice. Under our experimental conditions, however, no apparent alterations in the mRNA levels of all the anti-inflammatory cytokines tested were found. In conclusion, our findings demonstrate that multiple injections with TMSC produced a therapeutic effect in a mouse model of DSS-induced colitis. PMID- 28854224 TI - The 5'-poly(A) leader of poxvirus mRNA confers a translational advantage that can be achieved in cells with impaired cap-dependent translation. AB - The poly(A) leader at the 5'-untranslated region (5'-UTR) is an unusually striking feature of all poxvirus mRNAs transcribed after viral DNA replication (post-replicative mRNAs). These poly(A) leaders are non-templated and of heterogeneous lengths; and their function during poxvirus infection remains a long-standing question. Here, we discovered that a 5'-poly(A) leader conferred a selective translational advantage to mRNA in poxvirus-infected cells. A constitutive and uninterrupted 5'-poly(A) leader with 12 residues was optimal. Because the most frequent lengths of the 5'-poly(A) leaders are 8-12 residues, the result suggests that the poly(A) leader has been evolutionarily optimized to boost poxvirus protein production. A 5'-poly(A) leader also could increase protein production in the bacteriophage T7 promoter-based expression system of vaccinia virus, the prototypic member of poxviruses. Interestingly, although vaccinia virus post-replicative mRNAs do have 5'- methylated guanosine caps and can use cap-dependent translation, in vaccinia virus-infected cells, mRNA with a 5'-poly(A) leader could also be efficiently translated in cells with impaired cap dependent translation. However, the translation was not mediated through an internal ribosome entry site (IRES). These results point to a fundamental mechanism poxvirus uses to efficiently translate its post-replicative mRNAs. PMID- 28854226 TI - Socioeconomic position and health services use in Germany and Spain during the Great Recession. AB - OBJECTIVE: The relationship of socioeconomic position with the use of health services may have changed with the emergence of the economic crisis. This study shows that relationship before and during the economic crisis, in Germany and in Spain. METHODS: Data from the 2006 and 2011 Socio-Economic Panel carried out in Germany, and from the 2006 and 2011 National Health Surveys carried out in Spain were used. The health services investigated were physician consultations and hospitalization. The measures of socioeconomic position used were education and household income. The magnitude of the relationship between socioeconomic position and the use of each health services was estimated by calculating the percentage ratio by binary regression. RESULTS: In Germany, in both periods, after adjusting for age, sex, type of health insurance and need for care, subjects belonging to the lower educational categories had a lower frequency of physician consultations, while those belonging to the lower income categories had a higher frequency of hospitalization. In the model comparing the two lower socioeconomic categories to the two higher categories, the percentage ratio for physician consultation by education was 0.97 (95%CI 0.96-0.98) in 2006 and 0.96 (95%CI 0.95-0.97) in 2011, and the percentage ratio for hospitalization by income was 1.14 (95%CI 1.05-1.25) in 2006 and 1.12 (95%CI 1.03-1.21) in 2011. In Spain, no significant socioeconomic differences were observed in either period in the frequency of use of these health services in the fully adjusted model. CONCLUSION: The results suggest that the economic crisis did not alter accessibility to the health system in either country, given that the socioeconomic pattern in the use of these health services was similar before and during the crisis in both countries. PMID- 28854225 TI - Enteric viruses in HIV-1 seropositive and HIV-1 seronegative children with diarrheal diseases in Brazil. AB - Diarrheal diseases (DD) have distinct etiological profiles in immune-deficient and immune-competent patients. This study compares detection rates, genotype distribution and viral loads of different enteric viral agents in HIV-1 seropositive (n = 200) and HIV-1 seronegative (n = 125) children hospitalized with DD in Rio de Janeiro, Brazil. Except for group A rotavirus (RVA), which were detected through enzyme immunoassay, the other enteric viruses (norovirus [NoV], astrovirus [HAstV], adenovirus [HAdV] and bocavirus [HBoV]) were detected through PCR or RT-PCR. A quantitative PCR was performed for RVA, NoV, HAstV, HAdV and HBoV. Infections with NoV (19% vs. 9.6%; p<0.001), HBoV (14% vs. 7.2%; p = 0.042) and HAdV (30.5% vs. 14.4%; p<0.001) were significantly more frequent among HIV-1 seropositive children. RVA was significantly less frequent among HIV-1 seropositive patients (6.5% vs. 20%; p<0.001). Similarly, frequency of infection with HAstV was lower among HIV-1 seropositive children (5.5% vs. 12.8%; p = 0.018). Among HIV-1 seropositive children 33 (16.5%) had co-infections, including three enteric viruses, such as NoV, HBoV and HAdV (n = 2) and NoV, HAstV and HAdV (n = 2). The frequency of infection with more than one virus was 17 (13.6%) in the HIV-1 negative group, triple infection (NoV + HAstV + HBoV) being observed in only one patient. The median viral load of HAstV in feces was significantly higher among HIV-1 positive children compared to HIV-1 negative children. Concerning children infected with RVA, NoV, HBoV and HAdV, no statistically significant differences were observed in the medians of viral loads in feces, comparing HIV-1 seropositive and HIV-1 seronegative children. Similar detection rates were observed for RVA, HAstV and HAdV, whilst NoV and HBoV were significantly more prevalent among children with CD4+ T lymphocyte count below 200 cells/mm3. Enteric viruses should be considered an important cause of DD in HIV-1 seropositive children, along with pathogens more classically associated with intestinal infections in immunocompromised hosts. PMID- 28854227 TI - Relational values resonate broadly and differently than intrinsic or instrumental values, or the New Ecological Paradigm. AB - Value orientations used to explain or justify conservation have been rooted in arguments about how much and in what context to emphasize the intrinsic versus instrumental value of nature. Equally prominent are characterizations of beliefs known as the New Ecological Paradigm (NEP), often used to help explain pro environmental behaviour. A recent alternative to these positions has been identified as 'relational value'-broadly, values linking people and ecosystems via tangible and intangible relationships to nature as well as the principles, virtues and notions of a good life that may accompany these. This paper examines whether relational values are distinct from other value orientation and have potential to alleviate the intrinsic-instrumental debate. To test this possibility, we sought to operationalize the construct-relational values-by developing six relational statements. We ask: 1) Do the individual statements used to characterize relational values demonstrate internal coherence as either a single or multi-dimensional construct? 2) Do relational value statements (including those strongly stated) resonate with diverse populations? 3) Do people respond to relational value statements in a consistently different way than NEP scale statements? Data for this work is drawn from an online panel of residents of northeastern US (n = 400), as well as a sample of Costa Rican farmers (n = 253) and tourists in Costa Rica (n = 260). Results indicate relational values are distinct as a construct when compared to the NEP. PMID- 28854228 TI - Sensitivity of self-reported opioid use in case-control studies: Healthy individuals versus hospitalized patients. AB - BACKGROUND: Several case-control studies have shown associations between the risk of different cancers and self-reported opium use. Inquiring into relatively sensitive issues, such as the history of drug use, is usually prone to information bias. However, in order to justify the findings of these types of studies, we have to quantify the level of such a negative bias. In current study, we aimed to evaluate sensitivity of self-reported opioid use and suggest suitable types of control groups for case-control studies on opioid use and the risk of cancer. METHODS: In order to compare the validity of the self-reported opioid use, we cross-validated the response of two groups of subjects 1) 178 hospitalized patients and 2) 186 healthy individuals with the results of their tests using urine rapid drug screen (URDS) and thin layer chromatography (TLC). The questioners were asked by trained interviewers to maximize the validity of responses; healthy individuals were selected from the companions of patients in hospitals. RESULTS: Self-reported regular opioid use was 36.5% in hospitalized patients 19.3% in healthy individuals (p-value> 0.001).The reported frequencies of opioid use in the past 72 hours were 21.4% and 11.8% in hospitalized patients and healthy individuals respectively. Comparing their responses with the results of urine tests showed a sensitivity of 77% and 69% among hospitalized patients and healthy individuals for self-reports (p-value = 0.4). Having corrected based on the mentioned sensitivities; the frequency of opioid regular use was 47% and 28% in hospitalized patients and healthy individuals, respectively. Regular opioid use among hospitalized patients was significantly higher than in healthy individuals (p-value> 0.001). CONCLUSION: Our findings showed that the level of opioid use under-reporting in hospitalized patients and healthy individuals was considerable but comparable. In addition, the frequency of regular opioid use among hospitalized patients was significantly higher than that in the general population. Altogether, it seems that, without corrections for these differences and biases, the results of many studies including case-control studies on opioid use might distort findings substantially. PMID- 28854229 TI - Urbanization-induced habitat fragmentation erodes multiple components of temporal diversity in a Southern California native bee assemblage. AB - Despite a large number of ecological studies that document diversity loss resulting from anthropogenic disturbance, surprisingly few consider how disturbance affects temporal patterns of diversity that result from seasonal turnover of species. Temporal dynamics can play an important role in the structure and function of biological assemblages. Here, we investigate the temporal diversity patterns of bee faunas in Southern California coastal sage scrub ecosystems that have been extensively fragmented by urbanization. Using a two-year dataset of 235 bee species (n = 12,036 specimens), we compared 1-ha plots in scrub fragments and scrub reserves with respect to three components of temporal diversity: overall plot-level diversity pooled over time (temporal gamma diversity), diversity at discrete points in time (temporal alpha diversity), and seasonal turnover in assemblage composition (temporal beta diversity). Compared to reserves, fragments harbored bee assemblages with lower species richness and assemblage evenness both when summed across temporal samples (i.e., lower temporal gamma diversity) and at single points in time (i.e., lower temporal alpha diversity). Bee assemblages in fragments also exhibited reduced seasonal turnover (i.e., lower temporal beta diversity). While fragments and reserves did not differ in overall bee abundance, bee abundance in fragments peaked later in the season compared to that in reserves. Our results argue for an increased awareness of temporal diversity patterns, as information about the distinct components of temporal diversity is essential both for characterizing the assemblage dynamics of seasonal organisms and for identifying potential impacts of anthropogenic disturbance on ecosystem function through its effects on assemblage dynamics. PMID- 28854231 TI - Marine protected areas increase temporal stability of community structure, but not density or diversity, of tropical seagrass fish communities. AB - Marine protected areas (MPAs) have been shown to increase long-term temporal stability of fish communities and enhance ecosystem resilience to anthropogenic disturbance. Yet, the potential ability of MPAs to buffer effects of environmental variability at shorter time scales remains widely unknown. In the tropics, the yearly monsoon cycle is a major natural force affecting marine organisms in tropical regions, and its timing and severity are predicted to change over the coming century, with potentially severe effects on marine organisms, ecosystems and ecosystem services. Here, we assessed the ability of MPAs to buffer effects of monsoon seasonality on seagrass-associated fish communities, using a field survey in two MPAs (no-take zones) and two unprotected (open-access) sites around Zanzibar (Tanzania). We assessed the temporal stability of fish density and community structure within and outside MPAs during three monsoon seasons in 2014-2015, and investigated several possible mechanisms that could regulate temporal stability. Our results show that MPAs did not affect fish density and diversity, but that juvenile fish densities were temporally more stable within MPAs. Second, fish community structure was more stable within MPAs for juvenile and adult fish, but not for subadult fish or the total fish community. Third, the observed effects may be due to a combination of direct and indirect (seagrass-mediated) effects of seasonality and, potentially, fluctuating fishing pressure outside MPAs. In summary, these MPAs may not have the ability to enhance fish density and diversity and to buffer effects of monsoon seasonality on the whole fish community. However, they may increase the temporal stability of certain groups, such as juvenile fish. Consequently, our results question whether MPAs play a general role in the maintenance of biodiversity and ecosystem functioning under changing environmental conditions in tropical seagrass fish communities. PMID- 28854230 TI - Heterologous expression of anti-apoptotic human 14-3-3beta/alpha enhances iron mediated programmed cell death in yeast. AB - The induction of Programmed Cell Death (PCD) requires the activation of complex responses involving the interplay of a variety of different cellular proteins, pathways, and processes. Uncovering the mechanisms regulating PCD requires an understanding of the different processes that both positively and negatively regulate cell death. Here we have examined the response of normal as well as PCD resistant yeast cells to different PCD inducing stresses. As expected cells expressing the pro-survival human 14-3-3beta/alpha sequence show increased resistance to numerous stresses including copper and rapamycin. In contrast, other stresses including iron were more lethal in PCD resistant 14-3-3beta/alpha expressing cells. The increased sensitivity to PCD was not iron and 14-3 3beta/alpha specific since it was also observed with other stresses (hydroxyurea and zinc) and other pro-survival sequences (human TC-1 and H-ferritin). Although microscopical examination revealed little differences in morphology with iron or copper stresses, cells undergoing PCD in response to high levels of prolonged copper treatment were reduced in size. This supports the interaction some forms of PCD have with the mechanisms regulating cell growth. Analysis of iron-mediated effects in yeast mutant strains lacking key regulators suggests that a functional vacuole is required to mediate the synergistic effects of iron and 14-3 3beta/alpha on yeast PCD. Finally, mild sub-lethal levels of copper were found to attenuate the observed inhibitory effects of iron. Taken together, we propose a model in which a subset of stresses like iron induces a complex process that requires the cross-talk of two different PCD inducing pathways. PMID- 28854232 TI - Role of the aphid species and their feeding locations in parasitization behavior of Aphelinus abdominalis, a parasitoid of the lettuce aphid Nasonovia ribisnigri. AB - Aphid species feeding on lettuce occupy distinct feeding sites: the lettuce aphid Nasonovia ribisnigri prefers to feed on heart leaves, whereas the potato aphid Macrosiphum euphorbiae feeds only on outer leaves. The aphid parasitoid Aphelinus abdominalis, known to be able to regulate M. euphorbiae on many crops, has recently been indicated as a promising biocontrol candidate also for use against N. ribisnigri, a major pest of lettuce. This study therefore examined A. abdominalis parasitization preference between N. ribisnigri and M. euphorbiae and its ability to parasitize aphids feeding on different parts of lettuce plants. In addition, life history traits of A. abdominalis on these aphid species were investigated. In no-choice laboratory experiments on leaf discs and 24 h exposure, A. abdominalis successfully parasitized 54% and 60% of the offered N. ribisnigri and M. euphorbiae, respectively, with no significant difference. In the corresponding choice experiment, however, A. abdominalis had a tendency for a significantly higher preference for M. euphorbiae (38%) compared to N. ribisnigri (30%). Growth chamber experiments on whole plants demonstrated that A. abdominalis was able to parasitize aphids, regardless of their feeding locations on lettuce plants. However, aphid feeding behavior had a significant effect on the parasitization rate. A. abdominalis parasitized significantly higher percentages of M. euphorbiae or N. ribisnigri when aphids were exposed separately to parasitoids on whole lettuce plants as compared with N. ribisnigri exposed only on heart leaf. A significant preference of A. abdominalis for M. euphorbiae compared to N. ribisnigri was also observed in the growth chamber choice experiment. A high percentage of adult emergence (> 84%) and female-biased sex ratio (> 83%) were found irrespective of the aphid species. PMID- 28854234 TI - Temporal variability in shell mound formation at Albatross Bay, northern Australia. AB - We report the results of 212 radiocarbon determinations from the archaeological excavation of 70 shell mound deposits in the Wathayn region of Albatross Bay, Australia. This is an intensive study of a closely co-located group of mounds within a geographically restricted area in a wider region where many more shell mounds have been reported. Valves from the bivalve Tegillarca granosa (Linnaeus, 1758) were dated. The dates obtained are used to calculate rates of accumulation for the shell mound deposits. These demonstrate highly variable rates of accumulation both within and between mounds. We assess these results in relation to likely mechanisms of shell deposition and show that rates of deposition are affected by time-dependent processes both during the accumulation of shell deposits and during their subsequent deformation. This complicates the interpretation of the rates at which shell mound deposits appear to have accumulated. At Wathayn, there is little temporal or spatial consistency in the rates at which mounds accumulated. Comparisons between the Wathayn results and those obtained from shell deposits elsewhere, both in the wider Albatross Bay region and worldwide, suggest the need for caution when deriving behavioural inferences from shell mound deposition rates, and the need for more comprehensive sampling of individual mounds and groups of mounds. PMID- 28854235 TI - Brain MR image segmentation based on an improved active contour model. AB - It is often a difficult task to accurately segment brain magnetic resonance (MR) images with intensity in-homogeneity and noise. This paper introduces a novel level set method for simultaneous brain MR image segmentation and intensity inhomogeneity correction. To reduce the effect of noise, novel anisotropic spatial information, which can preserve more details of edges and corners, is proposed by incorporating the inner relationships among the neighbor pixels. Then the proposed energy function uses the multivariate Student's t-distribution to fit the distribution of the intensities of each tissue. Furthermore, the proposed model utilizes Hidden Markov random fields to model the spatial correlation between neigh-boring pixels/voxels. The means of the multivariate Student's t distribution can be adaptively estimated by multiplying a bias field to reduce the effect of intensity inhomogeneity. In the end, we reconstructed the energy function to be convex and calculated it by using the Split Bregman method, which allows our framework for random initialization, thereby allowing fully automated applications. Our method can obtain the final result in less than 1 second for 2D image with size 256 * 256 and less than 300 seconds for 3D image with size 256 * 256 * 171. The proposed method was compared to other state-of-the-art segmentation methods using both synthetic and clinical brain MR images and increased the accuracies of the results more than 3%. PMID- 28854233 TI - Protective capacity of neutralizing and non-neutralizing antibodies against glycoprotein B of cytomegalovirus. AB - Human cytomegalovirus (HCMV) is an important, ubiquitous pathogen that causes severe clinical disease in immunocompromised individuals, such as organ transplant recipients and infants infected in utero. Antiviral chemotherapy remains problematic due to toxicity of the available compounds and the emergence of viruses resistant to available antiviral therapies. Antiviral antibodies could represent a valuable alternative strategy to limit the clinical consequences of viral disease in patients. The envelope glycoprotein B (gB) of HCMV is a major antigen for the induction of virus neutralizing antibodies. However, the role of anti-gB antibodies in the course of the infection in-vivo remains unknown. We have used a murine CMV (MCMV) model to generate and study a number of anti-gB monoclonal antibodies (mAbs) with differing virus-neutralizing capacities. The mAbs were found to bind to similar antigenic structures on MCMV gB that are represented in HCMV gB. When mAbs were used in immunodeficient RAG-/- hosts to limit an ongoing infection we observed a reduction in viral load both with mAbs having potent neutralizing capacity in-vitro as well as mAbs classified as non neutralizing. In a therapeutic setting, neutralizing mAbs showed a greater capacity to reduce the viral burden compared to non-neutralizing antibodies. Efficacy was correlated with sustained concentration of virus neutralizing mAbs in-vivo rather than their in-vitro neutralizing capacity. Combinations of neutralizing mAbs further augmented the antiviral effect and were found to be as potent in protection as polyvalent serum from immune animals. Prophylactic administration of mAbs before infection was also protective and both neutralizing and non-neutralizing mAbs were equally effective in preventing lethal infection of immunodeficient mice. In summary, our data argue that therapeutic application of potently neutralizing mAbs against gB represent a strategy to modify the outcome of CMV infection in immunodeficient hosts. When present before infection, both neutralizing and non-neutralizing anti-gB exhibited protective capacity. PMID- 28854236 TI - Generation and evaluation of an indicator of the health system's performance in maternal and reproductive health in Colombia: An ecological study. AB - OBJECTIVE: To generate and evaluate an indicator of the health system's performance in the area of maternal and reproductive health in Colombia. MATERIALS AND METHODS: An indicator was constructed based on variables related to the coverage and utilization of healthcare services for pregnant and reproductive age women. A factor analysis was performed using a polychoric correlation matrix and the states were classified according to the indicator's score. A path analysis was used to evaluate the relationship between the indicator and social determinants, with the maternal mortality ratio as the response variable. RESULTS: The factor analysis indicates that only one principal factor exists, namely "coverage and utilization of maternal healthcare services" (eigenvalue 4.35). The indicator performed best in the states of Atlantic, Bogota, Boyaca, Cundinamarca, Huila, Risaralda and Santander (Q4). The poorest performance (Q1) occurred in Caqueta, Choco, La Guajira, Vichada, Guainia, Amazonas and Vaupes. The indicator's behavior was found to have an association with the unsatisfied basic needs index and women's education (beta = -0.021; 95%CI -0031 to -0.01 and beta 0.554; 95%CI 0.39 to 0.72, respectively). According to the path analysis, an inverse relationship exists between the proposed indicator and the behavior of the maternal mortality ratio (beta = -49.34; 95%CI -77.7 to -20.9); performance was a mediating variable. DISCUSSION: The performance of the health system with respect to its management of access and coverage for maternal and reproductive health appears to function as a mediating variable between social determinants and maternal mortality in Colombia. PMID- 28854237 TI - Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. AB - Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease. PMID- 28854238 TI - Elastic network model of learned maintained contacts to predict protein motion. AB - We present a novel elastic network model, lmcENM, to determine protein motion even for localized functional motions that involve substantial changes in the protein's contact topology. Existing elastic network models assume that the contact topology remains unchanged throughout the motion and are thus most appropriate to simulate highly collective function-related movements. lmcENM uses machine learning to differentiate breaking from maintained contacts. We show that lmcENM accurately captures functional transitions unexplained by the classical ENM and three reference ENM variants, while preserving the simplicity of classical ENM. We demonstrate the effectiveness of our approach on a large set of proteins covering different motion types. Our results suggest that accurately predicting a "deformation-invariant" contact topology offers a promising route to increase the general applicability of ENMs. We also find that to correctly predict this contact topology a combination of several features seems to be relevant which may vary slightly depending on the protein. Additionally, we present case studies of two biologically interesting systems, Ferric Citrate membrane transporter FecA and Arachidonate 15-Lipoxygenase. PMID- 28854239 TI - Helicobacter pylori sabA gene is associated with iron deficiency anemia in childhood and adolescence. AB - BACKGROUND: Gastric Helicobacter pylori colonization leads to iron deficiency anemia (IDA), especially in children and adolescents. However the pathogenesis is poorly understood. OBJECTIVE: We sought to identify specific H. pylori genes involved in IDA development, by comparing bacterial genome-wide expression profiling in patients affected or not. METHODS: H. pylori were isolated from four children with IDA and four from matched controls without IDA. Based on these isolates, cDNA microarrays under iron-replete or depleted conditions were systematically performed to compare gene expression profiles at the whole genome level. Real-time reverse-transcription (RT-) PCR and protein assays were performed for further assessing the profile differentiation of the identified H. pylori IDA-associated genes. RESULTS: We identified 29 and 11 genes with significantly higher or lower expression in the IDA isolates compared to non-IDA isolates, respectively. Especially notable were higher expression of sabA gene encoding sialic acid-binding adhesin in the IDA isolates, which was confirmed by real-time RT-PCR study. Moreover, iron-depletion in vitro led to up-regulation of fecA1 and frpB1 genes and down-regulation of pfr, as predicted. Known iron regulated genes such as fur, pfr, fecA, and feoB did not significantly differ between both groups. The IDA isolates had significantly higher expression of vacuolating cytotoxin gene vacA than non-IDA isolates, consistent with the results of VacA protein assays. There were no significant differences in bacterial growth value between IDA and non-IDA isolates. CONCLUSIONS: It is likely that H. pylori carrying high expression of sabA causes IDA, especially in children and adolescents who have increased daily iron demand. In addition, it is possible that several host-interactive genes, including vacA, may play a synergistic role for sabA in IDA development. PMID- 28854240 TI - The activity of phenoloxidase in haemolymph plasma is not a predictor of Lymantria dispar resistance to its baculovirus. AB - Host innate immunity is one of the factors that determines the resistance of insects to their entomopathogens. In the research reported here we studied whether or not phenoloxidase (PO), a key enzyme in the melanogenesis component of humoral immunity of insects, plays a role in the protection of Lymantria dispar larvae from infection by L. dispar multiple nucleopolyhedrovirus. We studied two types of viral infection: overt and covert. The following lines of investigation were tested: i) the intravital individual estimation of baseline PO activity in haemolymph plasma followed by virus challenging; ii) the specific inhibition of PO activity in vivo by peroral treatment of infected larvae with phenylthiourea (PTU), a competitive inhibitor of PO; iii) the evaluation of PO activity in the haemolymph plasma after larval starvation. Starvation is a stress that activates the covert infection to an overt form. All of these experiments did not show a relationship between PO activity in haemolymph plasma of L. dispar larvae and larval susceptibility to baculovirus. Moreover, starvation-induced activation of covert viral infection to an overt form occurred in 70 percent of virus-carrying larvae against the background of a dramatic increase of PO activity in haemolymph plasma in the insects studied. Our conclusion is that in L. dispar larvae PO activity is not a predictor of host resistance to baculovirus. PMID- 28854241 TI - 2D Ti3C2Tx (MXene)-reinforced polyvinyl alcohol (PVA) nanofibers with enhanced mechanical and electrical properties. AB - Novel 2D Ti3C2Tx (MXene)-reinforced polyvinyl alcohol (PVA) nanofibers have been successfully fabricated by an electrospinning technique. The high aspect ratio, hydrophilic surfaces, and metallic conductivity of delaminated MXene nanosheet render it promising nanofiller for high performance nanocomposites. Cellulose nanocrystals (CNC) were used to improve the mechanical properties of the nanofibers. The obtained electrospun nanofibers had diameter from 174 to 194 nm depending on ratio between PVA, CNC and MXene. Dynamic mechanical analysis demonstrated an increase in the elastic modulus from 392 MPa for neat PVA fibers to 855 MPa for fibers containing CNC and MXene at 25 degrees C. Moreover, PVA nanofibers containing 0.14 wt. % Ti3C2Tx exhibited dc conductivity of 0.8 mS/cm conductivity which is superior compared to similar composites prepared using methods other than electrospinning. Improved mechanical and electrical characteristics of the Ti3C2Tx /CNC/PVA composites make them viable materials for high performance energy applications. PMID- 28854242 TI - Evolution and functional characterization of CAZymes belonging to subfamily 10 of glycoside hydrolase family 5 (GH5_10) in two species of phytophagous beetles. AB - Hemicelluloses, such as xyloglucan, xylan and mannans, consist of a heterogeneous array of plant-derived polysaccharides that form the plant cell wall. These polysaccharides differ from each other in their structure and physiochemical properties, but they share a beta-(1,4)-linked sugar backbone. Hemicelluloses can be hydrolyzed by plant-cell-wall-degrading enzymes (PCWDEs), which are widely distributed in phytopathogenic microbes. Recently, it has become apparent that phytophagous beetles also produce their own PCWDEs. Our previous work identified genes encoding putative mannanases belonging to the subfamily 10 of glycoside hydrolase (GH) family 5 (GH5_10) in the genomes of the leaf beetle, Gastrophysa viridula (Chrysomelidae, Chrysomelinae; one gene), and of the bean beetle, Callosobruchus maculatus (Chrysomelidae, Bruchinae; four genes). In contrast to proteins from other GH5 subfamilies, GH5_10 proteins are patchily distributed within the tree of life and have so far hardly been investigated. We addressed the following questions: Are beetle-derived GH5_10s active PCWDEs? How did they evolve? What is their physiological function? Using heterologous protein expression and enzymatic assays, we show that the G. viridula GH5_10 protein is an endo-beta-1,4-mannanase. We also demonstrate that only one out of four C. maculatus GH5_10 proteins is an endo-beta-1,4-mannanase, which has additional activity on carboxymethyl cellulose. Unexpectedly, another C. maculatus GH5_10 protein has evolved to use xylan instead of mannans as a substrate. RNAi experiments in G. viridula indicate (i) that the sole GH5_10 protein is responsible for breaking down mannans in the gut and (ii) that this breakdown may rather be accessory and may facilitate access to plant cell content, which is rich in nitrogen and simple sugars. Phylogenetic analyses indicate that coleopteran-derived GH5_10 proteins cluster together with Chelicerata-derived ones. Interestingly, other insect-derived GH5_10 proteins cluster elsewhere, suggesting insects have several independent evolutionary origins. PMID- 28854243 TI - Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP treated marmosets. AB - OBJECTIVE: Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD). BACKGROUND: In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications. METHODS: Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD. RESULTS: When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects. CONCLUSION: We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic. PMID- 28854244 TI - Equalizing access to pandemic influenza vaccines through optimal allocation to public health distribution points. AB - Vaccines are arguably the most important means of pandemic influenza mitigation. However, as during the 2009 H1N1 pandemic, mass immunization with an effective vaccine may not begin until a pandemic is well underway. In the U.S., state-level public health agencies are responsible for quickly and fairly allocating vaccines as they become available to populations prioritized to receive vaccines. Allocation decisions can be ethically and logistically complex, given several vaccine types in limited and uncertain supply and given competing priority groups with distinct risk profiles and vaccine acceptabilities. We introduce a model for optimizing statewide allocation of multiple vaccine types to multiple priority groups, maximizing equal access. We assume a large fraction of available vaccines are distributed to healthcare providers based on their requests, and then optimize county-level allocation of the remaining doses to achieve equity. We have applied the model to the state of Texas, and incorporated it in a Web-based decision-support tool for the Texas Department of State Health Services (DSHS). Based on vaccine quantities delivered to registered healthcare providers in response to their requests during the 2009 H1N1 pandemic, we find that a relatively small cache of discretionary doses (DSHS reserved 6.8% in 2009) suffices to achieve equity across all counties in Texas. PMID- 28854245 TI - miR-625-3p is upregulated in CD8+ T cells during early immune reconstitution after allogeneic stem cell transplantation. AB - Alloreactive CD8+ T-cells mediate the curative graft-versus-leukaemia effect, the anti-viral immunity and graft-versus-host-disease (GvHD) after allogeneic stem cell transplantation (SCT). Thus, immune reconstitution with CD8+ T-cells is critical for the outcome of patients after allogeneic SCT. Certain miRNAs such as miR-146a or miR-155 play an important role in the regulation of post-transplant immunity in mice. While some miRNAs e.g. miR-423 or miR-155 are regulated in plasma or full blood during acute GvHD also in man, the relevance and expression profile of miRNAs in T-cells after allogeneic SCT is unknown. miR-625-3p has recently been described to be overexpressed in colorectal malignancies where it promotes migration, invasion and apoptosis resistance. Since similar regulative functions in cancer and T-cells have been described for an increasing number of miRNAs, we assumed a role for the cancer-related miR-625-3p also in T-cells. Here, we studied miR-625-3p expression selectively in CD8+ T-cells both in vitro and during immune reconstitution after allogeneic SCT in man. T-cell receptor stimulation lead to miR-625-3p upregulation in human CD8+ T-cells in vitro. Maintenance of elevated miR-625-3p expression levels was dependent on ongoing T cell proliferation and was abrogated by withdrawal of interleukin 2 or the mTOR inhibitor rapamycin. Finally, miR-625-3p expression was analyzed in human CD8+ T cells purified from 137 peripheral blood samples longitudinally collected from 74 patients after allogeneic SCT. miR-625-3p expression was upregulated on day 25 and on day 45, i.e. during the early phase of CD8+ T-cell reconstitution after allogeneic SCT and subsequently declined with completion of CD8+ T-cell reconstitution until day 150. In conclusion, this study has shown for the first time that miR-625-3p is regulated in CD8+ T-cells during proliferation in vitro and during early immune reconstitution after allogeneic SCT in vivo. These results warrant further studies to identify the targets and function of miR-625 3p in CD8+ T-cells and to analyze its predictive value for an effective immune reconstitution. PMID- 28854246 TI - Non-alcoholic fatty liver disease as a risk factor for female sexual dysfunction in premenopausal women. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) has become a common and important chronic liver disease worldwide. Previous studies have indicated that NAFLD has an adverse effect on the quality of life, but information is lacking about the impact of NAFLD on female sexual dysfunction. The aim of this study was to determine the association between NAFLD and female sexual dysfunction in premenopausal women. METHODS: This retrospective study consisted of premenopausal women who were sexually active and visited the outpatient clinic for a routine health check-up between January 2010 and December 2011. Based on the examination of the liver ultrasound scan, the study population was divided into 2 groups: cases with NAFLD and normal controls (cases without NAFLD). The female sexual function was compared between the two groups of cases. For the assessment of sexual function, a female sexual function index (FSFI) questionnaire was used. RESULTS: Four hundred seventy women were included, and the prevalence of NAFLD and female sexual dysfunction were 67/470 (14.3%) and 238/470 (50.6%), respectively. Cases with NAFLD had a lower total FSFI score and higher rate of female sexual dysfunction than the normal control [median score of total FSFI (interquartile range): 24.7 (21.9-27.8) in NAFLD vs. 26.7 (23.7-29.8) in normal control, p<0.005; the female sexual dysfunction: 64.2% in NAFLD vs. 48.4% in normal control, p<0.05]. This difference in female sexual dysfunction between the two groups remained significant after adjustment. CONCLUSION: NAFLD is associated with female sexual dysfunction in premenopausal women. PMID- 28854247 TI - Living on the edge: Daily, seasonal and annual body temperature patterns of Arabian oryx in Saudi Arabia. AB - Heterothermy, the ability to allow body temperature (Tb) to fluctuate, has been proposed as an adaptive mechanism that enables large ungulates to cope with the high environmental temperatures and lack of free water experienced in arid environments. By storing heat during the daytime and dissipating it during the night, arid-adapted ungulates may reduce evaporative water loss and conserve water. Adaptive heterothermy in large ungulates should be particularly pronounced in hot environments with severely limited access to free water. In the current study we investigated the effects of environmental temperature (ambient, Ta and soil, Ts) and water stress on the Tb of wild, free-ranging Arabian oryx (Oryx leucoryx) in two different sites in Saudi Arabia, Mahazat as-Sayd (MS) and Uruq Bani Ma'arid (UBM). Using implanted data loggers wet took continuous Tb readings every 10 minutes for an entire calendar year and determined the Tb amplitude as well as the heterothermy index (HI). Both differed significantly between sites but contrary to our expectations they were greater in MS despite its lower environmental temperatures and higher rainfall. This may be partially attributable to a higher activity in an unfamiliar environment for translocated animals in UBM. As expected Tb amplitude and HI were greatest during summer. Only minor sex differences were apparent that may be attributable to sex-specific investment into reproduction (e.g. male-male competition) during rut. Our results suggest that the degree of heterothermy is not only driven by extrinsic factors (e.g. environmental temperatures and water availability), but may also be affected by intrinsic factors (e.g. sex and/or behaviour). PMID- 28854248 TI - Maternal health care initiatives: Causes of morbidities and mortalities in two rural districts of Upper West Region, Ghana. AB - BACKGROUND: Maternal and neonatal morbidities and mortalities have received much attention over the years in sub-Saharan Africa; yet addressing them remains a profound challenge, no more so than in the nation of Ghana. This study focuses on finding explanations to the conditions which lead to maternal and neonatal morbidities and mortalities in rural Ghana, particularly the Upper West Region. METHOD: Mixed methods approach was adopted to investigate the medical and non medical causes of maternal and neonatal morbidities and mortalities in two rural districts of the Upper West Region of Ghana. Survey questionnaires, in-depth interviews and focus group discussions were employed to collect data from: a) 80 expectant mothers (who were in their second and third trimesters, excluding those in their ninth month), b) 240 community residents and c) 13 healthcare providers (2 district directors of health services, 8 heads of health facilities and 3 nurses). RESULT: Morbidity and mortality during pregnancy is attributed to direct causes such urinary tract infection (48%), hypertensive disorders (4%), mental health conditions (7%), nausea (4%) and indirect related sicknesses such as anaemia (11%), malaria, HIV/AIDS, oedema and hepatitis B (26%). Socioeconomic and cultural factors are identified as significant underlying causes of these complications and to morbidity and mortality during labour and the postnatal period. Birth asphyxia and traditional beliefs and practices were major causes of neonatal deaths. CONCLUSION: These findings provide focused targets and open a window of opportunity for the community-based health services run by Ghana Health Service to intensify health education and promotion programmes directed at reducing risky economic activities and other cultural beliefs and practices affecting maternal and neonatal morbidity and mortality. PMID- 28854250 TI - Direct and Inverted Repeat stimulated excision (DIRex): Simple, single-step, and scar-free mutagenesis of bacterial genes. AB - The need for generating precisely designed mutations is common in genetics, biochemistry, and molecular biology. Here, I describe a new lambda Red recombineering method (Direct and Inverted Repeat stimulated excision; DIRex) for fast and easy generation of single point mutations, small insertions or replacements as well as deletions of any size, in bacterial genes. The method does not leave any resistance marker or scar sequence and requires only one transformation to generate a semi-stable intermediate insertion mutant. Spontaneous excision of the intermediate efficiently and accurately generates the final mutant. In addition, the intermediate is transferable between strains by generalized transductions, enabling transfer of the mutation into multiple strains without repeating the recombineering step. Existing methods that can be used to accomplish similar results are either (i) more complicated to design, (ii) more limited in what mutation types can be made, or (iii) require expression of extrinsic factors in addition to lambda Red. I demonstrate the utility of the method by generating several deletions, small insertions/replacements, and single nucleotide exchanges in Escherichia coli and Salmonella enterica. Furthermore, the design parameters that influence the excision frequency and the success rate of generating desired point mutations have been examined to determine design guidelines for optimal efficiency. PMID- 28854249 TI - Deregulation of KSHV latency conformation by ER-stress and caspase-dependent RAD21-cleavage. AB - Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a human gammaherpesvirus recognized as the principal causative agent of KS and primary effusion lymphoma (PEL). KSHV establishes persistent latent infection in B lymphocytes where viral gene expression is restricted, in part, by a cohesin-dependent chromosome conformation. Here, we show that endoplasmic reticulum (ER) stress induces a rapid, caspase-dependent cleavage of cohesin subunit RAD21. ER stress-induced cleavage of RAD21 correlated with a rapid and strong viral lytic transcriptional activation. This effect was observed in several KSHV positive PEL cells, but not in other B-cells or non-B-cell models of KSHV latency. The cleaved-RAD21 does not dissociate from viral genomes, nor disassemble from other components of the cohesin complex. However, RAD21 cleavage correlated with the disruption of the latency genome conformation as revealed by chromosome conformation capture (3C). Ectopic expression of C-terminal RAD21 cleaved form could partially induce KSHV lytic genes transcription in BCBLI cells, suggesting that ER-stress induced RAD21 cleavage was sufficient to induce KSHV reactivation from latency in PEL cells. Taken together our results reveal a novel aspect for control and maintenance of KSHV genome latency conformation mediated by stress-induced RAD21 cleavage. Our studies also suggest that RAD21 cleavage may be a general regulatory mechanism for rapid alteration of cellular chromosome conformation and cohesin-dependent transcription regulation. PMID- 28854251 TI - Facilitatory and inhibitory pain mechanisms are altered in patients with carpal tunnel syndrome. AB - Preliminary evidence from studies using quantitative sensory testing suggests the presence of central mechanisms in patients with carpal tunnel syndrome (CTS) as apparent by widespread hyperalgesia. Hallmarks of central mechanisms after nerve injuries include nociceptive facilitation and reduced endogenous pain inhibition. Methods to study nociceptive facilitation in CTS so far have been limited to quantitative sensory testing and the integrity of endogenous inhibition remains unexamined. The aim of this study was therefore to investigate changes in facilitatory and inhibitory processing in patients with CTS by studying hypersensitivity following experimentally induced pain (facilitatory mechanisms) and the efficacy of conditioned pain modulation (CPM, inhibitory mechanisms). Twenty-five patients with mild to moderate CTS and 25 age and sex matched control participants without CTS were recruited. Increased pain facilitation was evaluated via injection of hypertonic saline into the upper trapezius. Altered pain inhibition through CPM was investigated through cold water immersion of the foot as the conditioning stimulus and pressure pain threshold over the thenar and hypothenar eminence bilaterally as the test stimulus. The results demonstrated that patients with CTS showed a greater duration (p = 0.047), intensity (p = 0.044) and area (p = 0.012) of pain in response to experimentally induced pain in the upper trapezius and impaired CPM compared to the control participants (p = 0.006). Although typically considered to be driven by peripheral mechanisms, these findings indicate that CTS demonstrates characteristics of altered central processing with increased pain facilitation and reduced endogenous pain inhibition. PMID- 28854252 TI - Molecular markers in keratins from Mysticeti whales for species identification of baleen in museum and archaeological collections. AB - Baleen has been harvested by indigenous people for thousands of years, as well as collected by whalers as an additional product of commercial whaling in modern times. Baleen refers to the food-filtering system of Mysticeti whales; a full baleen rack consists of dozens of plates of a tough and flexible keratinous material that terminate in bristles. Due to its properties, baleen was a valuable raw material used in a wide range of artefacts, from implements to clothing. Baleen is not widely used today, however, analyses of this biomolecular tissue have the potential to contribute to conservation efforts, studies of genetic diversity and a better understanding of the exploitation and use of Mysticeti whales in past and recent times. Fortunately, baleen is present in abundance in museum natural history collections. However, it is often difficult or impossible to make a species identification of manufactured or old baleen. Here, we propose a new tool for biomolecular identification of baleen based on its main structural component alpha-keratin (the same protein that makes up hair and fingernails). With the exception of minke whales, alpha-keratin sequences are not yet known for baleen whales. We therefore used peptide mass fingerprinting to determine peptidic profiles in well documented baleen and evaluated the possibility of using this technique to differentiate species in baleen samples that are not adequately identified or are unidentified. We examined baleen from ten different species of whales and determined molecular markers for each species, including species-specific markers. In the case of the Bryde's whales, differences between specimens suggest distinct species or sub-species, consistent with the complex phylogeny of the species. Finally, the methodology was applied to 29 fragments of baleen excavated from archaeological sites in Labrador, Canada (representing 1500 years of whale use by prehistoric people), demonstrating a dominance of bowhead whale (Balaena mysticetus) in the archaeological assemblage and the successful application of the peptide mass fingerprinting technique to identify the species of whale in unidentified and partially degraded samples. PMID- 28854253 TI - Effects of traffic noise on the calling behavior of two Neotropical hylid frogs. AB - Anthropogenic disturbance has been pointed to as one of the major causes of the world's biodiversity crisis. Among them, noise pollution is a potential underestimated threat, projected to increase in the next decades accompanying urban expansion. Rising levels of noise pollution may result in negative impacts on species highly dependent on acoustic communication. Amphibians have long served as model organisms for investigating animal acoustic communication because their reproduction depends on transmitting and receiving acoustic signals. A few studies have investigated the effects of anthropogenic noise on anurans, but there is still limited knowledge on how it affects them. In this study, we test the effect of two intensities of traffic noise on calling males of two Neotropical treefrogs species. We expect to record more changes in call parameters, to avoid masking effect, at higher intensity noise treatments, and in the species with higher call/noise frequency overlap. We performed a set of field playback experiments exposing male frogs to road noise at two different intensities (65dB and 75dB). Focal species are Boana bischoffi (high call/noise frequency overlap) and B. leptolineata (low call/noise frequency overlap). Both species changed acoustic parameters during or after the exposure to traffic noise. Advertisement call rate of B. bischoffi decreased during road noise, and dominant frequency decreased over time. Call length of B. leptolineata increased or decreased, depending on the order of noise intensity. We also observed spatial displacement in both species, which moved away from the noise source. Our results provide evidence that traffic noise affects anuran calling behavior, and noise intensity is an important factor affecting how species respond. PMID- 28854254 TI - Using tsunami deposits to determine the maximum depth of benthic burrowing. AB - The maximum depth of sediment biomixing is directly related to the vertical extent of post-depositional environmental alteration in the sediment; consequently, it is important to determine the maximum burrowing depth. This study examined the maximum depth of bioturbation in a natural marine environment in Funakoshi Bay, northeastern Japan, using observations of bioturbation structures developed in an event layer (tsunami deposits of the 2011 Tohoku-Oki earthquake) and measurements of the radioactive cesium concentrations in this layer. The observations revealed that the depth of bioturbation (i.e., the thickness of the biomixing layer) ranged between 11 and 22 cm, and varied among the sampling sites. In contrast, the radioactive cesium concentrations showed that the processing of radioactive cesium in coastal environments may include other pathways in addition to bioturbation. The data also revealed the nature of the bioturbation by the heart urchin Echinocardium cordatum (Echinoidea: Loveniidae), which is one of the important ecosystem engineers in seafloor environments. The maximum burrowing depth of E. cordatum in Funakoshi Bay was 22 cm from the seafloor surface. PMID- 28854255 TI - Protein abundances can distinguish between naturally-occurring and laboratory strains of Yersinia pestis, the causative agent of plague. AB - The rapid pace of bacterial evolution enables organisms to adapt to the laboratory environment with repeated passage and thus diverge from naturally occurring environmental ("wild") strains. Distinguishing wild and laboratory strains is clearly important for biodefense and bioforensics; however, DNA sequence data alone has thus far not provided a clear signature, perhaps due to lack of understanding of how diverse genome changes lead to convergent phenotypes, difficulty in detecting certain types of mutations, or perhaps because some adaptive modifications are epigenetic. Monitoring protein abundance, a molecular measure of phenotype, can overcome some of these difficulties. We have assembled a collection of Yersinia pestis proteomics datasets from our own published and unpublished work, and from a proteomics data archive, and demonstrated that protein abundance data can clearly distinguish laboratory adapted from wild. We developed a lasso logistic regression classifier that uses binary (presence/absence) or quantitative protein abundance measures to predict whether a sample is laboratory-adapted or wild that proved to be ~98% accurate, as judged by replicated 10-fold cross-validation. Protein features selected by the classifier accord well with our previous study of laboratory adaptation in Y. pestis. The input data was derived from a variety of unrelated experiments and contained significant confounding variables. We show that the classifier is robust with respect to these variables. The methodology is able to discover signatures for laboratory facility and culture medium that are largely independent of the signature of laboratory adaptation. Going beyond our previous laboratory evolution study, this work suggests that proteomic differences between laboratory-adapted and wild Y. pestis are general, potentially pointing to a process that could apply to other species as well. Additionally, we show that proteomics datasets (even archived data collected for different purposes) contain the information necessary to distinguish wild and laboratory samples. This work has clear applications in biomarker detection as well as biodefense. PMID- 28854256 TI - Peripheral denervation participates in heterotopic ossification in a spinal cord injury model. AB - We previously reported the development of a new acquired neurogenic HO (NHO) mouse model, combining spinal cord transection (SCI) and chemical muscle injury. Pathological mechanisms responsible for ectopic osteogenesis after central neurological damage are still to be elucidated. In this study, we first hypothesized that peripheral nervous system (PNS) might convey pathological signals from injured spinal cord to muscles in NHO mouse model. Secondly, we sought to determine whether SCI could lead to intramuscular modifications of BMP2 signaling pathways. Twenty one C57Bl6 mice were included in this protocol. Bilateral cardiotoxin (CTX) injection in hamstring muscles was associated with a two-stage surgical procedure, combining thoracic SCI with unilateral peripheral denervation. Volumes of HO (Bone Volume, BV) were measured 28 days after surgery using micro-computed tomography imaging techniques and histological analyses were made to confirm intramuscular osteogenesis. Volume comparisons were conducted between right and left hind limb of each animal, using a Wilcoxon signed rank test. Quantitative polymerase chain reaction (qPCR) was performed to explore intra muscular expression of BMP2, Alk3 and Id1. Nineteen mice survive the complete SCI and peripheral denervation procedure. When CTX injections were done right after surgery (n = 7), bilateral HO were detected in all animals after 28 days. Micro-CT measurements showed significantly increased BV in denervated paws (1.47 mm3 +/- 0.5) compared to contralateral sides (0.56 mm3 +/-0.4), p = 0.03. When peripheral denervation and CTX injections were performed after sham SCI surgery (n = 6), bilateral HO were present in three mice at day 28. Quantitative PCR analyses showed no changes in intra muscular BMP2 expression after SCI as compared to control mice (shamSCI). Peripheral denervation can be reliably added to spinal cord transection in NHO mouse model. This new experimental design confirms that neuro inflammatory mechanisms induced by central or peripheral nervous system injury plays a key role in triggering ectopic osteogenesis. PMID- 28854258 TI - Temporal variation in black-caiman-nest predation in varzea of central Brazilian amazonia. AB - On the Amazon floodplain, the main predators of black caiman (Melanosuchus niger) eggs are jaguars (Panthera onca), tegu lizards (Tupinambis teguixim), capuchin monkeys (Sapajus macrocephalus) and humans (Homo sapiens). In this study, we investigated the relationship between predator attacks on nests and incubation period, and evaluated the influence of initial predation on subsequent predation in the Mamiraua Sustainable Development Reserve. We also evaluated the influence of presence of females near the nests and manipulation of nests on the occurrence of attacks. We compared results from data obtained with camera traps and vestiges left by predators on estimates of rates of predation by different predators. Egg predation was recorded in 32% of the 658 black caiman nests monitored during two years. Our results suggest that the probability of predation on black caiman eggs is relatively constant throughout the incubation period and that predation on eggs was lower when adults, presumably females, were present. Careful opening of nests and handling of eggs did not increase the number of attacks on black caiman nests. Nest opening by a predator appeared to increase the chances of a subsequent attack because most of the attacks on nests occurred soon after a predator first opened the nest. However, attacks by another species of predator do not appear to be necessary to initiate attacks by any other species of predator. Results based on camera traps and vestiges differed, but use of vestiges was adequate for identifying the principal predators on eggs in black caiman nests and, in many circumstances, the vestiges may be better for estimating predation by humans. In this study, opening nests and handling eggs did not increase the number of attacks on black caiman nests. PMID- 28854257 TI - HRS plays an important role for TLR7 signaling to orchestrate inflammation and innate immunity upon EV71 infection. AB - Enterovirus 71 (EV71) is an RNA virus that causes hand-foot-mouth disease (HFMD), and even fatal encephalitis in children. Although EV71 pathogenesis remains largely obscure, host immune responses may play important roles in the development of diseases. Recognition of pathogens mediated by Toll-like receptors (TLRs) induces host immune and inflammatory responses. Intracellular TLRs must traffic from the endoplasmic reticulum (ER) to the endolysosomal network from where they initiate complete signaling, leading to inflammatory response. This study reveals a novel mechanism underlying the regulation of TLR7 signaling during EV71 infection. Initially, we show that multiple cytokines are differentially expressed during viral infection and demonstrate that EV71 infection induces the production of proinflammatory cytokines through regulating TLR7-mediated p38 MAPK, and NF-kappaB signaling pathways. Further studies reveal that the expression of the endosome-associated protein hepatocyte growth factor regulated tyrosine kinase substrate (HRS) is upregulated and highly correlated with the expression of TLR7 in EV71 infected patients, mice, and cultured cells. Virus-induced HRS subsequently enhances TLR7 complex formation in early- and late endosome by interacting with TLR7 and TAB1. Moreover, HRS is involved in the regulation of the TLR7/NF-kappaB/p38 MAPK and the TLR7/NF-kappaB/IRF3 signaling pathways to induce proinflammatory cytokines and interferons, respectively, resulting in the orchestration of inflammatory and immune responses to the EV71 infection. Therefore, this study demonstrates that HRS acts as a key component of TLR7 signaling to orchestrate immune and inflammatory responses during EV71 infection, and provides new insights into the mechanisms underlying the regulation of host inflammation and innate immunity during EV71 infection. PMID- 28854259 TI - Arizona bark scorpion venom resistance in the pallid bat, Antrozous pallidus. AB - The pallid bat (Antrozous pallidus), a gleaning bat found in the western United States and Mexico, hunts a wide variety of ground-dwelling prey, including scorpions. Anecdotal evidence suggests that the pallid bat is resistant to scorpion venom, but no systematic study has been performed. Here we show with behavioral measures and direct injection of venom that the pallid bat is resistant to venom of the Arizona bark scorpion, Centruroides sculpturatus. Our results show that the pallid bat is stung multiple times during a hunt without any noticeable effect on behavior. In addition, direct injection of venom at mouse LD50 concentrations (1.5 mg/kg) has no effect on bat behavior. At the highest concentration tested (10 mg/kg), three out of four bats showed no effects. One of the four bats showed a transient effect suggesting that additional studies are required to identify potential regional variation in venom tolerance. Scorpion venom is a cocktail of toxins, some of which activate voltage gated sodium ion channels, causing intense pain. Dorsal root ganglia (DRG) contain nociceptive neurons and are principal targets of scorpion venom toxins. To understand if mutations in specific ion channels contribute to venom resistance, a pallid bat DRG transcriptome was generated. As sodium channels are a major target of scorpion venom, we identified amino acid substitutions present in the pallid bat that may lead to venom resistance. Some of these substitutions are similar to corresponding amino acids in sodium channel isoforms responsible for reduced venom binding activity. The substitution found previously in the grasshopper mouse providing venom resistance to the bark scorpion is not present in the pallid bat, indicating a potentially novel mechanism for venom resistance in the bat that remains to be identified. Taken together, these results indicate that the pallid bat is resistant to venom of the bark scorpion and altered sodium ion channel function may partly underlie such resistance. PMID- 28854260 TI - Particle shape impacts export and fate in the ocean through interactions with the globally abundant appendicularian Oikopleura dioica. AB - Marine microbes exhibit highly varied, often non-spherical shapes that have functional significance for essential processes, including nutrient acquisition and sinking rates. There is a surprising absence of data, however, on how cell shape affects grazing, which is crucial for predicting the fate of oceanic carbon. We used synthetic spherical and prolate spheroid microbeads to isolate the effect of particle length-to-width ratios on grazing and fate in the ocean. Here we show that the shape of microbe-sized particles affects predation by the appendicularian Oikopleura dioica, a globally abundant marine grazer. Using incubation experiments, we demonstrate that shape affects how particles are retained in the house and that the minimum particle diameter is the key variable determining how particles are ingested. High-speed videography revealed the mechanism behind these results: microbe-sized spheroids oriented with the long axis parallel to fluid streamlines, matching the speed and tortuosity of spheres of equivalent width. Our results suggest that the minimum particle diameter determines how elongated prey interact with the feeding-filters of appendicularians, which may help to explain the prevalence of ellipsoidal cells in the ocean, since a cell's increased surface-to-volume ratio does not always increase predation. We provide the first evidence that grazing by appendicularians can cause non-uniform export of different shaped particles, thereby influencing particle fate. PMID- 28854262 TI - Accurate measurement of chest compression depth using impulse-radio ultra wideband sensor on a mattress. AB - OBJECTIVE: We developed a new chest compression depth (CCD) measuring technology using radar and impulse-radio ultra-wideband (IR-UWB) sensor. This study was performed to determine its accuracy on a soft surface. METHODS: Four trials, trial 1: chest compressions on the floor using an accelerometer device; trial 2: chest compressions on the floor using an IR-UWB sensor; trial 3: chest compressions on a foam mattress using an accelerometer device; trial 4: chest compressions on a foam mattress using an IR-UWB sensor, were performed in a random order. In all the trials, a cardiopulmonary resuscitation provider delivered 50 uninterrupted chest compressions to a manikin. RESULTS: The CCD measured by the manikin and the device were as follows: 57.42 +/- 2.23 and 53.92 +/- 2.92 mm, respectively in trial 1 (p < 0.001); 56.29 +/- 1.96 and 54.16 +/- 3.90 mm, respectively in trial 2 (p < 0.001); 55.61 +/- 1.57 and 103.48 +/- 10.48 mm, respectively in trial 3 (p < 0.001); 57.14 +/- 3.99 and 55.51 +/- 3.39 mm, respectively in trial 4 (p = 0.012). The gaps between the CCD measured by the manikin and the devices (accelerometer device vs. IR-UWB sensor) on the floor were not different (3.50 +/- 2.08 mm vs. 3.15 +/- 2.27 mm, respectively, p = 0.136). However, the gaps were significantly different on the foam mattress (48.53 +/- 5.65 mm vs. 4.10 +/- 2.47 mm, p < 0.001). CONCLUSION: The IR-UWB sensor could measure the CCD accurately both on the floor and on the foam mattress. PMID- 28854261 TI - Gemcitabine treatment induces endoplasmic reticular (ER) stress and subsequently upregulates urokinase plasminogen activator (uPA) to block mitochondrial dependent apoptosis in Panc-1 cancer stem-like cells (CSCs). AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates. The presence of cancer stem-like cells (CSCs) is believed to be among the underlying reasons for the aggressiveness of PDAC, which contributes to chemoresistance and recurrence. However, the mechanisms that induce chemoresistance and inhibit apoptosis remain largely unknown. METHODS: We used serum-free medium to enrich CSCs from panc-1 human pancreatic cancer cells and performed sphere formation testing, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and semi-quantitative western blotting to confirm the stemness of panc-1 CSCs. Hallmarks of endoplasmic reticulum (ER) stress, including IRE1, PERK, ATF4, ATF6alpha, GRP78 and uPA expression, were detected after gemcitabine treatment. Effects of gemcitabine induced uPA expression on cell invasion, sphere formation, colony formation and gemcitabine sensitivity were detected. Electrophoretic mobility shift assays (EMSAs) and RNA-immunoprecipitation (RIP) were performed to detect interaction between the uPA mRNA 3'-UTR and mutant p53-R273H expressed by panc-1 CSCs. The effects of upregulated uPA by gemcitabine on apoptosis were detected by Annexin V FITC/PI staining, and the impact of uPA on small molecule CP-31398-restored mutant p53 transcriptional activity was measured by a luciferase reporter assay. RESULTS: Enriched panc-1 CSCs expressing high levels of CD44 and CD133 also produced significantly higher amounts of Oct4 and Nanog. Compared with panc-1 cells, panc-1 CSCs presented chemoresistance to gemcitabine. ER stress gene detections demonstrated effects of gemcitabine-induced ER stress on both the pro apoptotic and pro-survival branches. ER stress-induced ATF6alpha upregulated level of uPA by transcriptionally activating GRP78. Gemcitabine-induced uPA promoted invasion, sphere formation and colony formation and attenuated apoptosis induced by gemcitabine in panc-1 CSCs, depending on interaction with mutant p53 R273H. Upregulation of uPA abolished CP-31398-mediated restoration of mutant p53 transcriptional activity in panc-1 CSCs. CONCLUSION: Gemcitabine treatment induced ER stress and promoted mutant p53-R273H stabilization via transcriptionally activated uPA which may contribute to chemoresistance to gemcitabine. Notably, upregulation of uPA by gemcitabine treatment may lead to the failure of CP-31398; thus, a novel strategy for modulating mutant p53 function needs to be developed. PMID- 28854263 TI - Assessment of metabolic and mitochondrial dynamics in CD4+ and CD8+ T cells in virologically suppressed HIV-positive individuals on combination antiretroviral therapy. AB - Metabolism plays a fundamental role in supporting the growth, proliferation and effector functions of T cells. We investigated the impact of HIV infection on key processes that regulate glucose uptake and mitochondrial biogenesis in subpopulations of CD4+ and CD8+ T cells from 18 virologically-suppressed HIV positive individuals on combination antiretroviral therapy (cART; median CD4+ cell count: 728 cells/MUl) and 13 HIV seronegative controls. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) production were also analysed in total CD4+ and CD8+ T cells. Among HIV+/cART individuals, expression of glucose transporter (Glut1) and mitochondrial density were highest within central memory and naive CD4+ T cells, and lowest among effector memory and transitional memory T cells, with similar trends in HIV-negative controls. Compared to HIV-negative controls, there was a trend towards higher percentage of circulating CD4+Glut1+ T cells in HIV+/cART participants. There were no significant differences in mitochondrial dynamics between subject groups. Glut1 expression was positively correlated with mitochondrial density and MMP in total CD4+ T cells, while MMP was also positively correlated with ROS production in both CD4+ and CD8+ T cells. Our study characterizes specific metabolic features of CD4+ and CD8+ T cells in HIV-negative and HIV+/cART individuals and will invite future studies to explore the immunometabolic consequences of HIV infection. PMID- 28854264 TI - Oral glucose tolerance test predicts increased carotid plaque burden in patients with acute coronary syndrome. AB - BACKGROUND: Type 2 diabetes and prediabetes are established risk factors for atherosclerosis. The aim of this study was to evaluate the atherosclerotic plaque burden in the carotid arteries of patients with acute coronary syndrome according to their glycemic status. METHODS: Patients with acute coronary syndrome and no previous history of type 2 diabetes were consecutively included in the study. Glucose metabolism was evaluated with fasting glucose in plasma, HbA1c and a standard two-hour oral glucose tolerance test. Atherosclerotic plaque in the carotid arteries was evaluated with a standardized ultrasound examination where total plaque area was measured and patients classified as having no plaque or a significant plaque formation. RESULTS: A total of 245 acute coronary syndrome patients (male 78%, 64 years (SD: 10.9)) were included. The proportion diagnosed with normal glucose metabolism, prediabetes and type 2 diabetes was 28.6%, 64.1% and 7.3%, respectively. A significant atherosclerotic plaque was found in 48.5%, 66.9% and 72.2% of patients with normal glucose metabolism, prediabetes and type 2 diabetes, respectively. An incremental increase in total plaque area was found from normal glucose metabolism to prediabetes (25.5%) and from normal glucose metabolism to type 2 diabetes (35.9%) (p = 0.04). When adjusted for conventional cardiovascular risk factors the OR of having significant atherosclerotic plaque in the carotid arteries was 2.17 (95% CI 1.15-4.15) for patients with newly diagnosed dysglycemia compared to patients with normal glucose metabolism. When additionally adjusted for the 2-hour plasma glucose after glucose loading (2hPG) the OR attenuated to 1.77 (95% CI 0.83-3.84). CONCLUSION: Newly detected dysglycemia is an independent predictor of significant atherosclerotic plaque in the carotid arteries with oral glucose tolerance test as a major determinant of carotid plaque burden in this group of individuals with acute coronary syndrome. PMID- 28854265 TI - Zinc transporter ZIP13 suppresses beige adipocyte biogenesis and energy expenditure by regulating C/EBP-beta expression. AB - Given the relevance of beige adipocytes in adult humans, a better understanding of the molecular circuits involved in beige adipocyte biogenesis has provided new insight into human brown adipocyte biology. Genetic mutations in SLC39A13/ZIP13, a member of zinc transporter family, are known to reduce adipose tissue mass in humans; however, the underlying mechanisms remains unknown. Here, we demonstrate that the Zip13-deficient mouse shows enhanced beige adipocyte biogenesis and energy expenditure, and shows ameliorated diet-induced obesity and insulin resistance. Both gain- and loss-of-function studies showed that an accumulation of the CCAAT/enhancer binding protein-beta (C/EBP-beta) protein, which cooperates with dominant transcriptional co-regulator PR domain containing 16 (PRDM16) to determine brown/beige adipocyte lineage, is essential for the enhanced adipocyte browning caused by the loss of ZIP13. Furthermore, ZIP13-mediated zinc transport is a prerequisite for degrading the C/EBP-beta protein to inhibit adipocyte browning. Thus, our data reveal an unexpected association between zinc homeostasis and beige adipocyte biogenesis, which may contribute significantly to the development of new therapies for obesity and metabolic syndrome. PMID- 28854266 TI - Female sex is not a risk factor for post procedural mortality in coronary bypass surgery in the elderly: A secondary analysis of the GOPCABE trial. AB - OBJECTIVE: Female sex is considered a significant risk in cardiac surgery and is included in the majority of scores for risk assessment. However, the evidence is controversial and older women undergoing cardiac surgery have not specifically been investigated. We assessed the influence of female sex on surgical risk (30 day mortality) in a secondary analysis of the GOPCABE trial (German Off-Pump Coronary Artery Bypass grafting in the Elderly (GOPCABE) trial, comparing on- to off-pump) and also evaluated its impact on risk prediction from commonly used risk scores. METHODS: We performed logistic regression analyses on the GOPCABE trial population, where patients were randomized to either on- or off-pump CABG. The study was performed in 12 cardiac surgery centers in Germany and analyzed 2394 patients having undergone CABG at age >=75 years (1187 on-pump, 1207 off pump). Of the 2394 patients, 755 (32%) were women. The logistic EuroSCORE and the German KCH score were calculated as expected (E) mortality and values were compared to observed (O) 30-day mortality (O/E ratio). RESULTS: There was no difference in mortality or major cardiovascular adverse events after 30 days between men and women for both on- and off-pump CABG (men: on- vs. off-pump OR = 0.90, 95%-CI: [0.63;1.27]; women: on- vs. off-pump OR = 1.07, 95%-CI: [0.62;1.87]). Therefore, groups were combined for further analyses. Both men and women had considerable and similar comorbidities. Expected mortality was significantly higher for women than for men (logistic EuroSCORE: 8.88+/-6.71% vs. 7.99+/-6.69%, p = 0.003; KCH score: 4.42+/-3.97% vs. 3.57+/-3.65%, p = 0.001). However, observed mortality rates (O) tended to be even lower in women (2.1% vs. 3.0%). The O/E ratio was closer to 1 in men than in women (0.84 vs. 0.47). Excluding female sex from the risk models increased O/E ratio to 0.69. CONCLUSIONS: Female sex is not a risk factor in coronary bypass surgery in the GOPCABE population. The result is the same for on- and off-pump surgery. Since female sex is a component of most risk scores, the findings may identify a potential inaccuracy in current surgical risk assessment, specifically for elderly women. TRIAL REGISTRATION: Clinicaltrials.gov GOPCABE trial No. NCT00719667. PMID- 28854268 TI - Apparent climate-mediated loss and fragmentation of core habitat of the American pika in the Northern Sierra Nevada, California, USA. AB - Contemporary climate change has been widely documented as the apparent cause of range contraction at the edge of many species distributions but documentation of climate change as a cause of extirpation and fragmentation of the interior of a species' core habitat has been lacking. Here, we report the extirpation of the American pika (Ochotona princeps), a temperature-sensitive small mammal, from a 165-km2 area located within its core habitat in California's Sierra Nevada mountains. While sites surrounding the area still maintain pikas, radiocarbon analyses of pika fecal pellets recovered within this area indicate that former patch occupancy ranges from before 1955, the beginning of the atmospheric spike in radiocarbon associated with above ground atomic bomb testing, to c. 1991. Despite an abundance of suitable rocky habitat climate warming appears to have precipitated their demise. Weather station data reveal a 1.9 degrees C rise in local temperature and a significant decline in snowpack over the period of record, 1910-2015, pushing pika habitat into increasingly tenuous climate conditions during the period of extirpation. This is among the first accounts of an apparently climate-mediated, modern extirpation of a species from an interior portion of its geographic distribution, resulting in habitat fragmentation, and is the largest area yet reported for a modern-era pika extirpation. Our finding provides empirical support to model projections, indicating that even core areas of species habitat are vulnerable to climate change within a timeframe of decades. PMID- 28854267 TI - Aggressiveness as a latent personality trait of domestic dogs: Testing local independence and measurement invariance. AB - Studies of animal personality attempt to uncover underlying or "latent" personality traits that explain broad patterns of behaviour, often by applying latent variable statistical models (e.g., factor analysis) to multivariate data sets. Two integral, but infrequently confirmed, assumptions of latent variable models in animal personality are: i) behavioural variables are independent (i.e., uncorrelated) conditional on the latent personality traits they reflect (local independence), and ii) personality traits are associated with behavioural variables in the same way across individuals or groups of individuals (measurement invariance). We tested these assumptions using observations of aggression in four age classes (4-10 months, 10 months-3 years, 3-6 years, over 6 years) of male and female shelter dogs (N = 4,743) in 11 different contexts. A structural equation model supported the hypothesis of two positively correlated personality traits underlying aggression across contexts: aggressiveness towards people and aggressiveness towards dogs (comparative fit index: 0.96; Tucker-Lewis index: 0.95; root mean square error of approximation: 0.03). Aggression across contexts was moderately repeatable (towards people: intraclass correlation coefficient (ICC) = 0.479; towards dogs: ICC = 0.303). However, certain contexts related to aggressiveness towards people (but not dogs) shared significant residual relationships unaccounted for by latent levels of aggressiveness. Furthermore, aggressiveness towards people and dogs in different contexts interacted with sex and age. Thus, sex and age differences in displays of aggression were not simple functions of underlying aggressiveness. Our results illustrate that the robustness of traits in latent variable models must be critically assessed before making conclusions about the effects of, or factors influencing, animal personality. Our findings are of concern because inaccurate "aggressive personality" trait attributions can be costly to dogs, recipients of aggression and society in general. PMID- 28854269 TI - Six-year changes in refraction and related ocular biometric factors in an adult Chinese population. AB - PURPOSE: To investigate longitudinal changes in refraction and biometry in Chinese adults. DESIGN: Population-based prospective cohort study. METHODS: 1817 subjects aged >= 35 years were randomly recruited from Yuexiu district, Guangzhou, China in 2008. Of which 1595 (87.8%) were reexamined in 2010 and 1427 (78.5%) were reexamined in 2014. Non-cycloplegic automated refraction and visual acuity test were performed at baseline and the 6-year follow-up examination for all participants. In addition, 50% of the participants were randomly selected for axial length (AL), anterior chamber depth (ACD) and lens thickness (LT) measurements using non-contact partial coherence laser interferometry. Lens power (LP) was calculated with the Bennett's equation. RESULTS: A total of 1300 participants were included in current analysis (2008 mean [SD] age, 51.4 [10.6] years; 54.5% women). Mean change in spherical equivalence (SE) was +0.24 (95% confidence interval [CI], +0.19 to +0.30), +0.51 (95% CI, +0.46 to +0.57), +0.26 (95% CI, +0.15 to +0.38) and -0.05 (95% CI, -0.21 to +0.10) diopters (D) for individuals in the age groups of 35 to 44, 45 to 54, 55 to 64 and 65+ years at baseline, respectively. Corneal power, AL and LT increased while ACD and LP decreased during the follow-up. Baseline SE and changes in biometric factors could explain 97.2% of the variance in longitudinal SE change while LP solely could explain 65.2%. Six-year mean change in cylinder power was -0.16 (95% CI, 0.19 to -0.13) D, the axis of astigmatism changed from "with-the-rule" to "against-the-rule" in 16.4% of the participants and to "oblique" in 0.9%. CONCLUSIONS: This study confirms a hyperopic shift in the elderly before 65 years old and a myopic shift thereafter. Longitudinal refraction change could be well explained by corresponding biometry changes, especially LP. There is also a shift to "against-the-rule" astigmatism for the adult population. PMID- 28854270 TI - Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals. AB - Imprinted genes show parent-specific activity (functional haploidy), which makes them particularly vulnerable to epigenetic dysregulation. Here we studied the methylation profiles of oppositely imprinted genes at single DNA molecule resolution by two independent parental allele-specific deep bisulfite sequencing (DBS) techniques. Using Roche (GSJunior) next generation sequencing technology, we analyzed the maternally imprinted MEST promoter and the paternally imprinted MEG3 intergenic (IG) differentially methylated region (DMR) in fetal cord blood, adult blood, and visceral adipose tissue. Epimutations were defined as paternal or maternal alleles with >50% aberrantly (de)methylated CpG sites, showing the wrong methylation imprint. The epimutation rates (range 2-66%) of the paternal MEST and the maternal MEG3 IG DMR allele, which should be completely unmethylated, were significantly higher than those (0-15%) of the maternal MEST and paternal MEG3 alleles, which are expected to be fully methylated. This hypermethylation of the non-imprinted allele (HNA) was independent of parental origin. Very low epimutation rates in sperm suggest that HNA occurred after fertilization. DBS with Illumina (MiSeq) technology confirmed HNA for the MEST promoter and the MEG3 IG DMR, and to a lesser extent, for the paternally imprinted secondary MEG3 promoter and the maternally imprinted PEG3 promoter. HNA leads to biallelic methylation of imprinted genes in a considerable proportion of normal body cells (somatic mosaicism) and is highly variable between individuals. We propose that during development and differentiation maintenance of differential methylation at most imprinting control regions may become to some extent redundant. The accumulation of stochastic and environmentally-induced methylation errors on the non-imprinted allele may increase epigenetic diversity between cells and individuals. PMID- 28854271 TI - Identification of novel genetic loci for osteoporosis and/or rheumatoid arthritis using cFDR approach. AB - There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients. PMID- 28854273 TI - High resolution imaging of the mitral valve in the natural state with 7 Tesla MRI. AB - Imaging techniques of the mitral valve have improved tremendously during the last decade, but challenges persist. The delicate changes in annulus shape and papillary muscle position throughout the cardiac cycle have significant impact on the stress distribution in the leaflets and chords, thus preservation of anatomically accurate positioning is critical. The aim of this study was to develop an in vitro method and apparatus for obtaining high-resolution 3D MRI images of porcine mitral valves in both the diastolic and systolic configurations with physiologically appropriate annular shape, papillary muscle positions and orientations, specific to the heart from which the valve was harvested. Positioning and mounting was achieved through novel, customized mounting hardware consisting of papillary muscle and annulus holders with geometries determined via pre-mortem ultrasonic intra-valve measurements. A semi-automatic process was developed and employed to tailor Computer Aided Design models of the holders used to mount the valve. All valve mounting hardware was 3D printed using a stereolithographic printer, and the material of all fasteners used were brass for MRI compatibility. The mounted valves were placed within a clear acrylic case, capable of holding a zero-pressure and pressurized liquid bath of a MRI compatible fluid. Obtaining images from the valve submerged in liquid fluid mimics the natural environment surrounding the valve, avoiding artefacts due to tissue surface tension mismatch and gravitational impact on tissue shape when not neutrally buoyant. Fluid pressure was supplied by reservoirs held at differing elevations and monitored and controlled to within +/-1mmHg to ensure that the valves remained steady. The valves were scanned in a 7 Tesla MRI system providing a voxel resolution of at least 80MUm. The systematic approach produced 3D datasets of high quality which, when combined with physiologically accurate positioning by the apparatus, can serve as an important input for validated computational models. PMID- 28854272 TI - Overall survival in EGFR mutated non-small-cell lung cancer patients treated with afatinib after EGFR TKI and resistant mechanisms upon disease progression. AB - PURPOSE: To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors. METHODS: Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre- and post-afatinib tumor biopsies and normal tissue. RESULTS: A total of 38 patients were treated with afatinib. T790M mutations were identified in 22/29 (76%) pre-afatinib treatment tumor samples. No difference in median progression-free-survival (2.8 months (95% CI 2.3-3.3) and 2.7 months (95% CI 0.9-4.6), p = 0.55) and median overall-survival (8.8 months (95% CI 4.2-13.4) and 3.6 months (95% CI 2.3-5.0), p = 0.14) were observed in T790M+ patients compared to T790M- mutations. Somatic mutations in TP53, ADAMTS2, CNN2 and multiple genes in the Wnt and PI3K-AKT pathway were observed in post afatinib tumors of six afatinib-responding and in one non-responding patient. No new EGFR mutations were found in the post-afatinib samples of the six responding patients. Further analyses of post-afatinib progressive tumors revealed 28 resistant specific mutations in six genes (HLA-DRB1, AQP7, FAM198A, SEC31A, CNTLN, and ESX1) in three afatinib responding patients. No known EGFR-TKI resistant-associated copy number gains were acquired in the post-afatinib samples. CONCLUSION: No differences in survival were observed in patients with EGFR-T790M treated with afatinib compared to those without T790M. Tumors from patients who had progressive disease during afatinib treatment were enriched for mutations in genes involved in Wnt and PI3K-AKT pathways. PMID- 28854275 TI - Correction: The Influence of Programmed Cell Death in Myeloid Cells on Host Resilience to Infection with Legionella pneumophila or Streptococcus pyogenes. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006032.]. PMID- 28854274 TI - Enhancing antibacterial effect of sodium hypochlorite by low electric current assisted sonic agitation. AB - BACKGROUND: This research focused on the effects of low electric current (MUE) assisted sonic agitation of sodium hypochlorite on Enterococcus faecalis infected human root dentin. METHODS: Extracted human canine roots were instrumented, sterilized, and experimentally contaminated with E. faecalis. After incubation for 21 days, the presence of the biofilm was confirmed by scanning electron microscopy (n = 3). Roots were randomly divided into seven groups according to decontamination procedures: G1: no treatment; G2: sterile saline; G3: 5.25% sodium hypochlorite; G4: passive ultrasonic irrigation; G5: EndoActivator (Dentsply Tulsa Dental Specialties, Tulsa, OK) agitation (EA); G6: MUE agitation; and G7: MUE-assisted sonic agitation. Fixed MUE amperage and intensities were applied in G6 and G7. Following microbial sampling, bacterial colonies were counted using the direct plating method. RESULTS: Biofilm was not eradicated in any sample. The MUE-assisted sonic agitation of sodium hypochlorite revealed the lowest cfu values (p<0.05), whereas there were no significant differences among the passive ultrasonic irrigation, EndoActivator and MUE agitation alone (p>0.05). CONCLUSIONS: Based on available evidence, the following conclusions were drawn: The MUE-assisted sonic agitation increased the antibiofilm efficiency of sodium hypochlorite than passive ultrasonic irrigation and EndoActivator. The MUE-assisted sonic agitation on 5.25% sodium hypochlorite is not capable to eradicate biofilms at 10mA energy level in 60s. PMID- 28854276 TI - A significant increase in the pepsinogen I/II ratio is a reliable biomarker for successful Helicobacter pylori eradication. AB - BACKGROUND: Helicobacter pylori (H. pylori) eradication is usually assessed using the 13C-urea breath test (UBT), anti-H. pylori antibody and the H. pylori stool antigen test. However, a few reports have used pepsinogen (PG), in particular, the percentage change in the PG I/II ratio. Here, we evaluated the usefulness of the percentage changes in serum PG I/II ratios for determining the success of eradication therapy for H. pylori. MATERIALS AND METHODS: In total, 650 patients received eradication therapy from October 2008 to March 2013 in our Cancer Institute Hospital. We evaluated the relationship between H. pylori eradication and percentage changes in serum PG I/II ratios before and 3 months after treatment with CLEIA(r) (FUJIREBIO Inc, Tokyo, Japan). The gold standard of H. pylori eradication was defined as negative by the UBT performed 3 months after completion of eradication treatment. Cut-off values for percentage changes in serum PG I/II ratios were set as +40, +25 and +10% when the serum PG I/II ratio before treatment was below 3.0, above 3.0 but below 5.0 and 5.0 or above, respectively. RESULTS: Serum PG I and PG II levels were measured in 562 patients with H. pylori infection before and after eradication therapy. Eradication of H. pylori was achieved in 433 patients studied (77.0%). The ratios of first, second, third-line and penicillin allergy eradication treatment were 73.8% (317/429), 88.3% (99/112), 75% (12/16) and 100% (5/5), respectively. An increasing percentage in the serum levels of the PG I/II ratios after treatment compared with the values before treatment clearly distinguished success from failure of eradication (108.2+/-57.2 vs. 6.8+/-30.7, p<0.05). Using the above cut-off values, the sensitivity, specificity and validity for determination of H. pylori were 93.1, 93.8 and 93.2%, respectively. CONCLUSION: In conclusion, the percentage changes in serum PG I/II ratios are useful as evaluation criteria for assessing the success of eradication therapy for H. pylori. PMID- 28854277 TI - Ethnic and gender discrimination in the private rental housing market in Finland: A field experiment. AB - Ethnic and gender discrimination in a variety of markets has been documented in several populations. We conducted an online field experiment to examine ethnic and gender discrimination in the private rental housing market in Finland. We sent 1459 inquiries regarding 800 apartments. We compared responses to standardized apartment inquiries including fictive Arabic-sounding, Finnish sounding or Swedish-sounding female or male names. We found evidence of discrimination against Arabic-sounding names and male names. Inquiries including Arabic-sounding male names had the lowest probability of receiving a response, receiving a response to about 16% of the inquiries made, while Finnish-sounding female names received a response to 42% of the inquires. We did not find any evidence of the landlord's gender being associated with the discrimination pattern. The findings suggest that both ethnic and gender discrimination occur in the private rental housing market in Finland. PMID- 28854278 TI - Interaction of the cyclic-di-GMP binding protein FimX and the Type 4 pilus assembly ATPase promotes pilus assembly. AB - Type IVa pili (T4P) are bacterial surface structures that enable motility, adhesion, biofilm formation and virulence. T4P are assembled by nanomachines that span the bacterial cell envelope. Cycles of T4P assembly and retraction, powered by the ATPases PilB and PilT, allow bacteria to attach to and pull themselves along surfaces, so-called "twitching motility". These opposing ATPase activities must be coordinated and T4P assembly limited to one pole for bacteria to show directional movement. How this occurs is still incompletely understood. Herein, we show that the c-di-GMP binding protein FimX, which is required for T4P assembly in Pseudomonas aeruginosa, localizes to the leading pole of twitching bacteria. Polar FimX localization requires both the presence of T4P assembly machine proteins and the assembly ATPase PilB. PilB itself loses its polar localization pattern when FimX is absent. We use two different approaches to confirm that FimX and PilB interact in vivo and in vitro, and further show that point mutant alleles of FimX that do not bind c-di-GMP also do not interact with PilB. Lastly, we demonstrate that FimX positively regulates T4P assembly and twitching motility by promoting the activity of the PilB ATPase, and not by stabilizing assembled pili or by preventing PilT-mediated retraction. Mutated alleles of FimX that no longer bind c-di-GMP do not allow rapid T4P assembly in these assays. We propose that by virtue of its high-affinity for c-di-GMP, FimX can promote T4P assembly when intracellular levels of this cyclic nucleotide are low. As P. aeruginosa PilB is not itself a high-affinity c-di-GMP receptor, unlike many other assembly ATPases, FimX may play a key role in coupling T4P mediated motility and adhesion to levels of this second messenger. PMID- 28854280 TI - Joint modelling of potentially avoidable hospitalisation for five diseases accounting for spatiotemporal effects: A case study in New South Wales, Australia. AB - BACKGROUND: Three variant formulations of a spatiotemporal shared component model are proposed that allow examination of changes in shared underlying factors over time. METHODS: Models are evaluated within the context of a case study examining hospitalisation rates for five chronic diseases for residents of a regional area in New South Wales: type II diabetes mellitus (DMII), chronic obstructive pulmonary disease (COPD), coronary arterial disease (CAD), hypertension (HT) and congestive heart failure (CHF) between 2001-2006. These represent ambulatory care sensitive (ACS) conditions, often used as a proxy for avoidable hospitalisations. Using a selected model, the effects of socio-economic status (SES) as a shared component are estimated and temporal patterns in the influence of the residual shared spatial component are examined. RESULTS: Choice of model depends upon the application. In the featured application, a model allowing for changing influence of the shared spatial component over time was found to have the best fit and was selected for further analyses. Hospitalisation rates were found to be increasing for COPD and DMII, decreasing for CHF and stable for CAD and HT. SES was substantively associated with hospitalisation rates, with differing degrees of influence for each disease. In general, most of the spatial variation in hospitalisation rates was explained by disease-specific spatial components, followed by the residual shared spatial component. CONCLUSION: Appropriate selection of a joint disease model allows for the examination of temporal patterns of disease outcomes and shared underlying spatial factors, and distinction between different shared spatial factors. PMID- 28854279 TI - Transfer of in vitro-expanded naive T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells. AB - The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naive T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naive T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naive T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL 23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo-expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo-expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects. PMID- 28854281 TI - Education of staff in preschool aged classrooms in child care centers and child outcomes: A meta-analysis and systematic review. AB - Staff education is considered key to quality of early childhood education and care (ECEC) programs. However, findings about associations between staff education and children's outcomes have been inconsistent. We conducted a systematic review and meta-analysis of associations between ECEC staff education and child outcomes. Searches of Medline, PsycINFO, and ERIC, websites of large datasets and reference sections of all retrieved articles were conducted. Eligible studies provided a statistical link between staff education and child outcomes for preschool-aged children in ECEC programs. Titles, abstracts and paper reviews as well as all data extraction were conducted by two independent raters. Of the 823 studies reviewed for eligibility, 39 met our inclusion criteria. Research in this area is observational in nature and subject to the inherent biases of that research design. Results from our systematic review were hampered by heterogeneity in how staff education was defined, variability in whose education was measured and the child outcomes that were assessed. However, overall the qualitative summary indicates that associations between staff education and childhood outcomes are non-existent to very borderline positive. In our meta-analysis of more homogeneous studies we identified certain positive, albeit very weak, associations between staff education and children's language outcomes (specifically, vocabulary and letter word identification) and no significant association with a mathematics outcome (WJ Applied Problems). Thus, our findings suggest that within the range of education levels found in the existing literature, education is not a key driver of child outcomes. However, since we only explored levels of education that were reported in the literature, our findings cannot be used to argue for lowering education standards in ECEC settings. PMID- 28854282 TI - Endothelial-derived extracellular matrix ameliorate the stemness deprivation during ex vivo expansion of mouse bone marrow-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) hold great potential in cell therapies by virtue of the regenerative effects and immunomodulatory properties, but the scarce nature of MSCs makes ex vivo expansion indispensable prior to transplantation purposes. However, potential loss of stemness ensuing culture expansion has hindered the advancements in MSCs-based treatments. In principle, stemness could be preserved by reconstructing the stem cell niche. To test whether the endothelial cells (ECs) participate in the constitution of the stem cell niche for mesenchymal stem cells (MSCs), ECs derivatives including extracellular matrix (ECM) and conditioned medium (CM) prepared from aortic endothelial cells (AECs) and Mile Sven 1 endothelial cell line (MS1) were investigated for the potential to maintain MSCs stemness. MSCs expanded on endothelial ECMs, especially on MS1-ECM, possessed a more juvenile morphology and showed delayed proliferation, when compared with untreated MSCs and MSCs on MSC-ECM and in CMs. Once induced, MS1 ECM group showed better tri-lineage differentiations indicating that MS1-ECM could better preserve MSC stemness. MSCs on MS1-ECM showed stronger immune modulatory potential and had significantly higher H3K27me3 with lower Kdm6b expression. Taken together, MS1-ECM shapes an inhibitory chromatin signature and retains MSCs stemness. Our work provided supportive evidence that MSCs can reside in a perivascular niche, and a feasible novel approach for MSCs expansion. PMID- 28854283 TI - Transdermal rivastigmine for HIV-associated cognitive impairment: A randomized pilot study. AB - OBJECTIVE: To assess the efficacy and safety of transdermal rivastigmine for the treatment of HIV-associated cognitive impairment. METHODS: We recruited HIV infected patients with cognitive impairment on stable antiretroviral therapy in a randomized controlled pilot trial with a 48-week follow-up. An additional assessment was held at 12 weeks. Participants received transdermal rivastigmine (9.5 mg daily), lithium (400 mg twice daily, titrated progressively), or remained in a control group (no new medication). The primary efficacy endpoint was change in a global cognitive score (NPZ-7). Secondary endpoints included change in specific cognitive measures, domains, and functional parameters. Safety covered the frequency of adverse events and changes in laboratory results. RESULTS: Seventy-six subjects were screened, and 29 were finally enrolled. Better cognitive outcomes were observed in all groups, although there were no significant differences between the arms (mean NPZ-7 change [SD]): rivastigmine, 0.35 (0.14); lithium, 0.25 (0.40); control, 0.20 (0.44) (p = 0.78). The rivastigmine group showed the highest positive trend (mean NPZ-7 [SD], baseline vs week 48): rivastigmine, -0.47 (0.22) vs -0.11 (0.29), p = 0.06; lithium, -0.50 (0.40) vs -0.26 (0.21), p = 0.22; control, -0.52 (0.34) vs -0.32 (0.52), p = 0.44. The cognitive domains with the highest positive trends were information processing speed at week 12 and executive function at week 48 (rivastigmine vs control): information processing speed, 0.35 (0.64) vs -0.13 (0.25), p = 0.17, d = 0.96; and executive functioning, 0.73 (0.33) vs 0.03 (0.74), p = 0.09, d = 1.18. No relevant changes were observed regarding functional outcomes. A total of 12 (41%) individuals dropped out of the study: 2 (20%) were due to medication related effects in the rivastigmine group and 4 (36%) in the lithium group. No severe adverse events were reported. CONCLUSIONS: The results from this small randomized trial indicate that transdermal rivastigmine did not provide significant cognitive benefits in people with HAND on stable antiretroviral therapy, even though positive trends were found in specific cognitive domains. Relevant tolerability issues were not observed. PMID- 28854284 TI - D-galactose-induced brain ageing model: A systematic review and meta-analysis on cognitive outcomes and oxidative stress indices. AB - Animal models are commonly used in brain ageing research. Amongst these, models where rodents are exposed to d-galactose are held to recapitulate a number of features of ageing including neurobehavioral and neurochemical changes. However, results from animal studies are often inconsistent. To better understand the characteristics of the model and effects of d-galactose on neurobehavioral and neurochemical outcomes in rodents we performed a systematic review and meta analysis. We applied random-effects meta-analysis to evaluate the effect of study features. Our results give an overview of the characteristics of the d-galactose rodent ageing model, including neurobehavioral and neurochemical outcomes. We found that few studies took measures to reduce risks of bias, and substantial heterogeneity in the reported effects of d-galactose in included studies. This highlights the need for improvements in the use of the d-galactose rodent ageing model if it is to provide useful in the development of drugs to treat human ageing. PMID- 28854287 TI - Risk of Superinfection in Peri-implantitis After Systemic Broad Spectrum Antibiotics. AB - Peri-implant disease has developed over the last few years as a complication that is often difficult to resolve. The disease process is mainly attributed to bacterial infection. Proposed combined therapies use broad-spectrum antibiotics to halt its progression. A major associated risk is the undetected development of superinfections that are difficult to eradicate. A group of healthy individuals with advanced peri-implantitis (PI) were referred for evaluation due to severe, rapidly progressive bone loss. Previous nonsurgical and empiric antibiotic therapy had been rendered. Culture and polymerase chain reaction-based identification were performed for PI lesions, healthy implants, and saliva. Clinical and radiographic examinations revealed peri-implant bleeding on probing, deep pockets, and severe radiographic bone loss with absence of lamina dura. A number of superinfecting agents were identified, such as Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Candida albicans, and Epstein-Barr virus (EBV). EBV is significantly more prevalent at peri-implantitis sites than at healthy implants and in saliva. Specific systemic antimicrobial therapy and nonsurgical or surgical debridement may eradicate some opportunistic pathogens, but follow-up tests should be performed to identify potential emerging pathogenic microbiota, such as C albicans and enteric rods, at peri-implant sites. Antifungal and antiviral therapy may be needed. Due to the extent and severity of tissue loss, some implants were removed. Peri-implant superinfections are a major risk associated with broad-spectrum antibiotics in immunocompetent individuals. Lack of follow-up and antibiotic susceptibility testing and indiscriminate empiric treatment regimens may lead to ongoing microbial challenge that exacerbates and maintains the disease progression. Personalized periodontal supportive therapy could prevent risks by sustaining a healthy microbial ecologic balance, reducing specific pathogen proportions, maintaining optimal plaque control, and detecting early signs of inflammation. PMID- 28854285 TI - Population genetic analysis of a global collection of Fragaria vesca using microsatellite markers. AB - The woodland strawberry, Fragaria vesca, holds great promise as a model organism. It not only represents the important Rosaceae family that includes economically important species such as apples, pears, peaches and roses, but it also complements the well-known model organism Arabidopsis thaliana in key areas such as perennial life cycle and the development of fleshy fruit. Analysis of wild populations of A. thaliana has shed light on several important developmental pathways controlling, for example, flowering time and plant growth, suggesting that a similar approach using F. vesca might add to our understanding on the development of rosaceous species and perennials in general. As a first step, 298 F. vesca plants were analyzed using microsatellite markers with the primary aim of analyzing population structure and distribution of genetic diversity. Of the 68 markers tested, 56 were polymorphic, with an average of 4.46 alleles per locus. Our analysis partly confirms previous classification of F. vesca subspecies in North America and suggests two groups within the subsp. bracteata. In addition, F. vesca subsp. vesca forms a single global population with evidence that the Icelandic group is a separate cluster from the main Eurasian population. PMID- 28854286 TI - Therapeutic time window for conivaptan treatment against stroke-evoked brain edema and blood-brain barrier disruption in mice. AB - BACKGROUND: Ischemic stroke is often complicated by brain edema, disruption of blood-brain barrier (BBB), and uncontrolled release of arginine-vasopressin (AVP). Conivaptan, a V1a and V2 receptor antagonist, reduces brain edema and minimizes damage to the blood-brain barrier after stroke. Most stroke patients do not receive treatment immediately after the onset of brain ischemia. Delays in therapy initiation may worsen stroke outcomes. Therefore, we designed a translational study to explore the therapeutic time window for conivaptan administration. METHODS: Mice were treated with conivaptan beginning 3, 5, or 20 hours after 60-minute focal middle cerebral artery occlusion. Treatments were administered by continuous IV infusion for a total of 48 hours. Brain edema and blood-brain barrier (BBB) disruption were evaluated at endpoint. RESULTS: Conivaptan therapy initiated at 3 hours following ischemia reduced edema in the ipsilateral hemisphere, which corresponded with improvements in neurological deficits. Stroke-triggered BBB disruption was also reduced in mice when conivaptan treatments were initiated at 3 hours of reperfusion. However, 5 and 20 hour delays of conivaptan administration failed to reduce edema or protect BBB. CONCLUSION: Timing of conivaptan administration is important for successful reduction of brain edema and BBB disruption. Our experimental data open new possibilities to repurpose conivaptan, and make an important "bench-to-bedside translation" of the results into clinical practice. PMID- 28854288 TI - Use of Bone Morphogenetic Protein-2 in Molar Extraction Sockets for Immediate Implant Placement: A Prospective Case Series. AB - This prospective case series enrolled consecutively qualifying patients that required immediate dental implant placement in large, uncontained, fresh molar extraction sites using recombinant human bone morphogentic protein-2/absorbable collagen sponge (rhBMP-2/ACS) combined with mineralized bone allograft. A total of 11 patients with 15 extraction sites missing bony walls were enrolled for treatment in this prospective case series. The clinical and radiographic effectiveness of rhBMP-2/ACS combined with mineralized bone allograft supported healing of immediately placed implants. Implants were uncovered at 4 to 6 months and were clinically and radiographically evaluated for ridge preservation and implant integration. All extraction sites exhibited ridge preservation and implant integration 1 year following restoration. PMID- 28854293 TI - Uniform Nomenclature to Describe Clinical Features of Pigmented Lesions. PMID- 28854294 TI - Incorrectly Reported Request for Reply. PMID- 28854295 TI - Could Tranexamic Acid Bias the Optimal Ratio of Fresh Frozen Plasma to Red Blood Cells During Massive Transfusion? PMID- 28854297 TI - Attitudes Toward Morbidity and Mortality Conferences Among Medical and Surgical Pediatric Specialists in Armenia. PMID- 28854298 TI - The Utility of Microbiological Studies in Diagnosis and Management of Suspected Dermatological Infection. PMID- 28854296 TI - Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents: A Systematic Review and Meta-analysis. AB - Importance: Depressive disorders (DDs), anxiety disorders (ADs), obsessive compulsive disorder (OCD), and posttraumatic stress disorder (PTSD) are common mental disorders in children and adolescents. Objective: To examine the relative efficacy and safety of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and placebo for the treatment of DD, AD, OCD, and PTSD in children and adolescents. Data Sources: PubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Database from inception through August 7, 2016. Study Selection: Published and unpublished randomized clinical trials of SSRIs or SNRIs in youths with DD, AD, OCD, or PTSD were included. Trials using other antidepressants (eg, tricyclic antidepressants, monoamine oxidase inhibitors) were excluded. Data Extraction and Synthesis: Effect sizes, calculated as standardized mean differences (Hedges g) and risk ratios (RRs) for adverse events, were assessed in a random-effects model. Main Outcomes and Measures: Primary outcomes, as defined by authors on preintervention and postintervention data, mean change data, and adverse event data, were extracted independently by multiple observers following PRISMA guidelines. Results: Thirty six trials were eligible, including 6778 participants (3484 [51.4%] female; mean [SD] age, 12.9 [5.1] years); 17 studies for DD, 10 for AD, 8 for OCD, and 1 for PTSD. Analysis showed that SSRIs and SNRIs were significantly more beneficial compared with placebo, yielding a small effect size (g = 0.32; 95% CI, 0.25-0.40; P < .001). Anxiety disorder (g = 0.56; 95% CI, 0.40-0.72; P < .001) showed significantly larger between-group effect sizes than DD (g = 0.20; 95% CI, 0.13 0.27; P < .001). This difference was driven primarily by the placebo response: patients with DD exhibited significantly larger placebo responses (g = 1.57; 95% CI, 1.36-1.78; P < .001) compared with those with AD (g = 1.03; 95% CI, 0.84 1.21; P < .001). The SSRIs produced a relatively large effect size for ADs (g = 0.71; 95% CI, 0.45-0.97; P < .001). Compared with participants receiving placebo, patients receiving an antidepressant reported significantly more treatment emergent adverse events (RR, 1.07; 95% CI, 1.01-1.12; P = .01 or RR, 1.49; 95% CI, 1.22-1.82; P < .001, depending on the reporting method), severe adverse events (RR, 1.76; 95% CI, 1.34-2.32; P < .001), and study discontinuation due to adverse events (RR, 1.79; 95% CI, 1.38-2.32; P < .001). Conclusions and Relevance: Compared with placebo, SSRIs and SNRIs are more beneficial than placebo in children and adolescents; however, the benefit is small and disorder specific, yielding a larger drug-placebo difference for AD than for other conditions. Response to placebo is large, especially in DD. Severe adverse events are significantly more common with SSRIs and SNRIs than placebo. PMID- 28854300 TI - Effectiveness and Safety of Antidepressants for Children and Adolescents: Implications for Clinical Practice. PMID- 28854299 TI - Response to Laser Treatment of Cafe au Lait Macules Based on Morphologic Features. AB - Importance: Response to laser treatment for cafe au lait macules (CALMs) is inconsistent and difficult to predict. Objective: To test the hypothesis that irregularly bordered CALMs of the "coast of Maine" subtype respond better to treatment than those of the smooth-bordered "coast of California" subtype. Design, Setting, and Participants: This retrospective case series included patients from 2 multiple-clinician US practices treated from 2005 through 2016. All patients had a clinical diagnosis of CALM and were treated with a Q-switched or picosecond laser. A total of 51 consecutive patients were eligible, 6 of whom were excluded owing to ambiguous lesion subtype. Observers were blinded to final patient groupings. Exposures: Treatment with 755-nm alexandrite picosecond laser, Q-switched ruby laser, Q-switched alexandrite laser, or Q-switched 1064-nm Nd:YAG laser. Main Outcomes and Measures: Main outcome was grade in a visual analog scale (VAS) consisting of 4 levels of treatment response: poor (grade 1, 0%-25% improvement), fair (grade 2, 26%-50% improvement), good (grade 3, 51%-75% improvement), and excellent (grade 4, 76%-100% improvement). Results: Forty-five patients were included in the series, 19 with smooth-bordered lesions and 26 with irregularly bordered lesions. Thirty-four (76%) of the participants were female; 33 (73%) were white; and the mean age at the time of laser treatment was 14.5 years (range, 0-44 years). Smooth-bordered lesions received a mean VAS score of 1.76, corresponding to a fair response on average (26%-50% pigmentary clearance). Irregularly bordered lesions received a mean VAS score of 3.67, corresponding to an excellent response on average (76%-100% clearance) (P < .001). Conclusions and Relevance: CALMs with jagged or ill-defined borders of the coast of Maine subtype tend to respond well to laser treatment, whereas those with smooth and well defined borders of the coast of California subtype tend to have poor response. Clinicians using Q-switched or picosecond lasers to treat CALMs can use morphologic characteristics to help predict response and more effectively manage patient expectations. PMID- 28854301 TI - Understanding Hearing and Hearing Loss in Children With Down Syndrome. AB - Purpose: This study evaluated the prevalence of permanent and transient hearing loss, the use of hearing aids as a recommendation, and middle ear dysfunction in children with Down syndrome (DS) through a large multiage and ethnically diverse sample, using current audiologic testing practices. Method: Retrospective analysis of data collected on 308 children with DS (168 boys, 140 girls; average age = 5.99 +/- 4.88 years) who received an audiological evaluation during 2013 as part of their medical care at a large pediatric hospital. Results: Permanent hearing loss was identified in 24.9% of the children, among whom bilateral (75.4%) and conductive (33.3%) hearing losses occurred most often. Of children with DS, 22%-30% experienced a transient hearing loss, with a high incidence of middle ear pathologies from infancy until early adulthood. There were no statistical differences between ethnicity and permanent/transient hearing loss diagnosis. Twenty-three percent were current hearing aid users or had them recommended in a treatment plan. Conclusions: The prevalence of hearing loss and abnormal middle ear status is high in the pediatric population with DS. Audiologic evaluations should follow the American Academy of Pediatrics practice guidelines to monitor this high-risk population, and amplification should be considered as an appropriate intervention option if repeated audiologic examinations reveal hearing loss. PMID- 28854304 TI - Medical Students Fall Short on Blood Pressure Check Challenge. PMID- 28854302 TI - Association Between Psychotic Experiences and Subsequent Suicidal Thoughts and Behaviors: A Cross-National Analysis From the World Health Organization World Mental Health Surveys. AB - Importance: Community-based studies have linked psychotic experiences (PEs) with increased risks of suicidal thoughts and behaviors (STBs). However, it is not known if these associations vary across the life course or if mental disorders contribute to these associations. Objective: To examine the temporal association between PEs and subsequent STBs across the life span as well as the influence of mental disorders (antecedent to the STBs) on these associations. Design, Setting, and Participants: A total of 33 370 adult respondents across 19 countries from the World Health Organization World Mental Health Surveys were assessed for PEs, STBs (ie, ideation, plans, and attempts), and 21 DSM-IV mental disorders. Discrete-time survival analysis was used to investigate the associations of PEs with subsequent onset of STBs. Main Outcomes and Measures: Prevalence and frequency of STBs with PEs, and odds ratios and 95% CIs. Results: Of 33 370 included participants, among those with PEs (n = 2488), the lifetime prevalence (SE) of suicidal ideation, plans, and attempts was 28.5% (1.3), 10.8% (0.7), and 10.2% (0.7), respectively. Respondents with 1 or more PEs had 2-fold increased odds of subsequent STBs after adjusting for antecedent or intervening mental disorders (suicidal ideation: odds ratio, 2.2; 95% CI, 1.8-2.6; suicide plans: odds ratio, 2.1; 95% CI, 1.7-2.6; and suicide attempts: odds ratio, 1.9; 95% CI, 1.5-2.5). There were significant dose-response relationships of number of PE types with subsequent STBs that persisted after adjustment for mental disorders. Although PEs were significant predictors of subsequent STB onset across all life stages, associations were strongest in individuals 12 years and younger. After adjustment for antecedent mental disorders, the overall population attributable risk proportions for lifetime suicidal ideation, plans, and attempts associated with temporally prior PEs were 5.3%, 5.7%, and 4.8%, respectively. Conclusions and Relevance: Psychotic experiences are associated with elevated odds of subsequent STBs across the life course that cannot be explained by antecedent mental disorders. These results highlight the importance of including information about PEs in screening instruments designed to predict STBs. PMID- 28854306 TI - The Spot on My Wrist. PMID- 28854303 TI - Medical Malpractice Lawsuits Involving Surgical Residents. AB - Importance: Medical malpractice litigation against surgical residents is rarely discussed owing to assumed legal doctrine of respondeat superior, or "let the master answer." Objective: To better understand lawsuits targeting surgical trainees to prevent future litigation. Design, Setting, and Participants: Westlaw, an online legal research database containing legal records from across the United States, was retrospectively reviewed for malpractice cases involving surgical interns, residents, or fellows from January 1, 2005, to January 1, 2015. Infant-related obstetric and ophthalmologic procedures were excluded. Exposures: Involvement in a medical malpractice case. Main Outcomes and Measures: Data were collected on patient demographics, case characteristics, and outcomes and were analyzed using descriptive statistics. Results: During a 10-year period, 87 malpractice cases involving surgical trainees were identified. A total of 50 patients were female (57%), and 79 were 18 years of age or older (91%), with a median patient age of 44.5 years (interquartile range, 45-56 years). A total of 67 cases (77%) resulted in death or permanent disability. Most cases involved elective surgery (61 [70%]) and named a junior resident as a defendant (24 of 35 [69%]). Cases more often questioned the perioperative medical knowledge, decision making errors, and injuries (53 [61%]: preoperative, 19 of 53 [36%]) and postoperative, 34 of 53 [64%]) than intraoperative errors and injuries (43 [49%]). Junior residents were involved primarily with lawsuits related to medical decision making (21 of 24 [87%]). Residents' failure to evaluate the patient was cited in 10 cases (12%) and lack of direct supervision by attending physicians was cited in 48 cases (55%). A total of 42 cases (48%) resulted in a jury verdict or settlement in favor of the plaintiff, with a median payout of $900 000 (range, $1852 to $32 million). Conclusions and Relevance: This review of malpractice cases involving surgical residents highlights the importance of perioperative management, particularly among junior residents, and the importance of appropriate supervision by attending physicians as targets for education on litigation prevention. PMID- 28854305 TI - Could Tranexamic Acid Bias the Optimal Ratio of Fresh Frozen Plasma to Red Blood Cells During Massive Transfusion?-Reply. PMID- 28854307 TI - Vitamin D Supplementation and Cardiovascular Disease Risk-Reply. PMID- 28854310 TI - Vitamin D Supplementation and Cardiovascular Disease Risk. PMID- 28854308 TI - Association of Neighborhood Demographics With Out-of-Hospital Cardiac Arrest Treatment and Outcomes: Where You Live May Matter. AB - Importance: We examined whether resuscitation care and outcomes vary by the racial composition of the neighborhood where out-of-hospital cardiac arrests (OHCAs) occur. Objective: To evaluate the association between bystander treatments (cardiopulmonary resuscitation and automatic external defibrillation) and timing of emergency medical services personnel on OHCA outcomes according to the racial composition of the neighborhood where the OHCA event occurred. Design, Setting, and Participants: This retrospective observational cohort study examined patients with OHCA from January 1, 2008, to December 31, 2011, using data from the Resuscitation Outcomes Consortium. Neighborhoods where OHCA occurred were classified by census tract, based on percentage of black residents: less than 25%, 25% to 50%, 51% to 75%, or more than 75%. Multilevel mixed-effects logistic regression modeling examined the association between racial composition of neighborhoods and OHCA survival, adjusting for patient, neighborhood, and treatment characteristics. Main Outcomes and Measures: Survival to discharge, return of spontaneous circulation on emergency department arrival, and favorable neurologic status at discharge. Results: We examined 22 816 adult patients with nontraumatic OHCA at Resuscitation Outcomes Consortium sites in the United States. The median age of patients with OHCA was 64 years (interquartile range [IQR], 51-78). Compared with patients who experienced OHCA in neighborhoods with a lower proportion of black residents, those in neighborhoods with more than 75% black residents were slightly younger, were more frequently women, had lower rates of initial shockable rhythm, and less frequently experienced OHCA in a public location. The percentage of patients with OHCA receiving bystander cardiopulmonary resuscitation or a lay automatic external defibrillation was inversely associated with the percentage of black residents in neighborhoods. Compared with OHCA in predominantly white neighborhoods (<25% black), those with OHCA in mixed to majority black neighborhoods had lower adjusted survival rates to hospital discharge (25%-50% black: odds ratio, 0.76; 95% CI, 0.61-0.93; 51% 75% black: odds ratio, 0.67; 95% CI, 0.49-0.90; >75% black: odds ratio, 0.63; 95% CI, 0.50-0.79; P < .001). There was similar mortality risk for black and white patients with OHCA in each neighborhood racial quantile. When the primary model included geographic site, there was an attenuated nonsignificant association between racial composition in a neighborhood and survival. Conclusions and Relevance: Those with OHCA in predominantly black neighborhoods had the lowest rates of bystander cardiopulmonary resuscitation and automatic external defibrillation use and significantly lower likelihood for survival compared with predominantly white neighborhoods. Improving bystander treatments in these neighborhoods may improve cardiac arrest survival. PMID- 28854311 TI - Types of Shade Vary in Protection Just Like Sunscreens-Reply. PMID- 28854312 TI - Vitamin D Supplementation and Cardiovascular Disease Risk. PMID- 28854309 TI - Determining the Incidence of Pneumocystis Pneumonia in Patients With Autoimmune Blistering Diseases Not Receiving Routine Prophylaxis. AB - Importance: Pneumocystis pneumonia (PCP) is a potentially lethal opportunistic infection that primary prophylaxis can help prevent. The risk of prophylactic therapy must be weighed against the incidence of PCP in the patient population. Prophylaxis most frequently involves trimethoprim-sulfamethoxazole, with second line therapies, including atovaquone, dapsone, and pentamide. The indication for prophylaxis in immunocompromised patients without HIV is less well defined. Previously, an incidence of at least 3.5% has been proposed as a cutoff to justify prophylaxis. Objective: To assess the incidence of PCP in patients with autoimmune blistering diseases receiving no routine prophylaxis. Design, Setting, and Participants: This was a retrospective analysis of patient medical records to determine the incidence of PCP infections. The multicenter study was performed at tertiary care centers that provide care for patients with autoimmune blistering disease in Germany, Italy, Singapore, Israel, and the Netherlands. Patients had a confirmed diagnosis of pemphigus vulgaris/foliaceus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid/cicatricial pemphigoid, or anti-p200 pemphigoid. Main Outcomes and Measures: To determine the incidence of PCP defined as patients with the International Classification of Diseases, Ninth Revision (ICD-9), code 136.3, for PCP, or free text documentation of PCP occurring based on characteristic radiographic findings with elevated lactate dehydrogenase, or hospitalization for pneumonia with bronchioalveolar lavage demonstrating Pneumocystis jiroveci on confirmatory stains. Results: A total of 801 patients with autoimmune blistering diseases were included in this study; their mean (SD) age was 66.5 (17.6) years, and a total of 465 (58%) were female. Only 1 patient developed PCP, resulting in an incidence rate of 0.1%. This incidence significantly fell below the recommended threshold of 3.5% (0.1% vs 3.5%, chi21 = 27.0; P < .001). This incidence was significantly lower than the previously reported incidence of PCP in all immunosuppressed dermatologic patients (0.1% vs 1.3%; chi21 = 8.2; P = .004). Conclusions and Relevance: Routine Pneumocystis prophylaxis for patients with autoimmune blistering diseases does not seem to be warranted. Patients with autoimmune blistering disease seem to have a lower risk of PCP than the general population of immunosuppressed dermatology patients. Risks of routine prophylaxis include hyperkalemia, hypoglycemia, photosensitivity, thrombocytopenia, and more rare adverse reactions. PMID- 28854314 TI - Neighborhood-Level Disparities in Resuscitation and the Potential of Connected Health. PMID- 28854313 TI - Training Peer Partners to Use a Speech-Generating Device With Classmates With Autism Spectrum Disorder: Exploring Communication Outcomes Across Preschool Contexts. AB - Purpose: This study examined effects of a peer-mediated intervention that provided training on the use of a speech-generating device for preschoolers with severe autism spectrum disorder (ASD) and peer partners. Method: Effects were examined using a multiple probe design across 3 children with ASD and limited to no verbal skills. Three peers without disabilities were taught to Stay, Play, and Talk using a GoTalk 4+ (Attainment Company) and were then paired up with a classmate with ASD in classroom social activities. Measures included rates of communication acts, communication mode and function, reciprocity, and engagement with peers. Results: Following peer training, intervention effects were replicated across 3 peers, who all demonstrated an increased level and upward trend in communication acts to their classmates with ASD. Outcomes also revealed moderate intervention effects and increased levels of peer-directed communication for 3 children with ASD in classroom centers. Additional analyses revealed higher rates of communication in the added context of preferred toys and snack. The children with ASD also demonstrated improved communication reciprocity and peer engagement. Conclusions: Results provide preliminary evidence on the benefits of combining peer-mediated and speech-generating device interventions to improve children's communication. Furthermore, it appears that preferred contexts are likely to facilitate greater communication and social engagement with peers. PMID- 28854315 TI - Distributed Training Enhances Implicit Sequence Acquisition in Children With Specific Language Impairment. AB - Purpose: This study explored the effects of 2 different training structures on the implicit acquisition of a sequence in a serial reaction time (SRT) task in children with and without specific language impairment (SLI). Method: All of the children underwent 3 training sessions, followed by a retention session 2 weeks after the last session. In the massed-training condition, the 3 training sessions were in immediate succession on 1 day, whereas in the distributed-training condition, the 3 training sessions were spread over a 1-week period in an expanding schedule format. Results: Statistical analyses showed that the children with normal language were unaffected by the training conditions, performing the SRT task similarly in both training conditions. The children with SLI, however, were affected by the training structure, performing the SRT task better when the training sessions were spaced over time rather than clustered on 1 day. Conclusion: This study demonstrated that although intensive training does not increase learning in children with SLI, distributing training sessions over time does increase learning. The implications of these results on the learning abilities of children with SLI are discussed, as are the mechanisms involved in massed versus distributed learning. PMID- 28854317 TI - Canakinumab for Severe Hidradenitis Suppurativa: Preliminary Experience in 2 Cases. PMID- 28854316 TI - Remnant Liver Ischemia as a Prognostic Factor for Cancer-Specific Survival After Resection of Colorectal Liver Metastases. AB - Importance: Ischemia-reperfusion injury during hepatic resection has been shown to accelerate progression of liver cancer. However, the prognostic relevance of remnant liver ischemia (RLI) after resection of colorectal liver metastases (CLMs) is unknown to date. Objectives: To assess the prognostic influence of RLI after resection of CLMs and to identify correlates of greater extent of RLI. Design, Setting, and Participants: This study was a retrospective analysis at The University of Texas MD Anderson Cancer Center based on prospectively collected data. The study identified 202 patients who underwent curative resection of CLMs between January 1, 2008, and December 31, 2014, and had enhanced computed tomographic images obtained within 30 days after surgery. Main Outcomes and Measures: Remnant liver ischemia was defined as reduced or absent contrast enhancement during the portal phase. Postoperative RLI was classified as grade 0 (none), 1 (marginal), 2 (partial), 3 (segmental), or 4 (necrotic) as previously defined. Experienced members of the surgical team retrospectively performed imaging assessments. Team members were masked to the postoperative outcomes. Survival after resection was stratified by RLI grade. Predictors of RLI grade 2 or higher and survival were identified. Results: Among 202 patients (median [range] age, 56 [27-87] years; 84 female), the RLI grades were as follows: grade 0 (105 patients), grade 1 (47 patients), grade 2 (45 patients), grade 3 (5 patients), and grade 4 (0 patients). Recurrence-free survival (RFS) and cancer specific survival (CSS) rates after hepatic resection were worse in patients with RLI grade 2 or higher vs grade 1 or lower (RFS at 3 years, 6.4% [3 of 50] vs 39.2% [60 of 152]; P < .001 and CSS at 5 years, 20.7% [10 of 50] vs 63.7% [97 of 152]; P < .001). A largest metastasis at least 3 cm (OR, 2.74; 95% CI, 1.35-5.70; P = .005), multiple CLMs (OR, 2.51; 95% CI, 1.25-5.24; P = .009), and nonanatomic resection (odds ratio [OR], 3.29; 95% CI, 1.52-7.63; P = .002) were associated with RLI grade 2 or higher. A largest metastasis at least 3 cm (hazard ratio [HR], 1.70; 95% CI, 1.01-2.88; P = .045), mutant RAS (HR, 2.15; 95% CI, 1.27 3.64; P = .005), and RLI grade 2 or higher (HR, 2.90; 95% CI, 1.69-4.84; P < .001) were associated with worse CSS. Conclusions and Relevance: In this study, remnant liver ischemia grade 2 or higher was associated with worse CSS after resection of CLMs. High-quality anatomic surgery to minimize RLI after resection is essential. PMID- 28854318 TI - Tying Reimbursement to Outcomes Is an Ideal Strategy for PCSK9 Inhibitors. PMID- 28854319 TI - Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. AB - BACKGROUND: Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of NEC. However, slow feed advancement may delay establishment of full enteral feeding and may be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition. OBJECTIVES: To determine effects of slow rates of enteral feed advancement on the incidence of NEC, mortality, and other morbidities in very preterm or VLBW infants. SEARCH METHODS: We used the standard Cochrane Neonatal search strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 5), MEDLINE via PubMed (1966 to June 2017), Embase (1980 to June 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2017). We searched clinical trials databases, conference proceedings, previous reviews, and reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed effects of slow (up to 24 mL/kg/d) versus faster rates of advancement of enteral feed volumes upon the incidence of NEC in very preterm or VLBW infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) and risk difference (RD) for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model for meta-analyses and explored potential causes of heterogeneity via sensitivity analyses. We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified 10 RCTs in which a total of 3753 infants participated (2804 infants participated in one large trial). Most participants were stable very preterm infants of birth weight appropriate for gestation. About one-third of all participants were extremely preterm or extremely low birth weight (ELBW), and about one-fifth were small for gestational age (SGA), growth-restricted, or compromised in utero, as indicated by absent or reversed end-diastolic flow velocity (AREDFV) in the fetal umbilical artery. Trials typically defined slow advancement as daily increments of 15 to 20 mL/kg, and faster advancement as daily increments of 30 to 40 mL/kg. Trials generally were of good methodological quality, although none was blinded.Meta-analyses did not show effects on risk of NEC (typical RR 1.07, 95% CI 0.83 to 1.39; RD 0.0, 95% CI -0.01 to 0.02) or all-cause mortality (typical RR 1.15, 95% CI 0.93 to 1.42; typical RD 0.01, 95% CI -0.01 to 0.03). Subgroup analyses of extremely preterm or ELBW infants, or of SGA or growth-restricted or growth-compromised infants, showed no evidence of an effect on risk of NEC or death. Slow feed advancement delayed establishment of full enteral nutrition by between about one and five days. Meta-analysis showed borderline increased risk of invasive infection (typical RR 1.15, 95% CI 1.00 to 1.32; typical RD 0.03, 95% CI 0.00 to 0.05). The GRADE quality of evidence for primary outcomes was "moderate", downgraded from "high" because of lack of blinding in the included trials. AUTHORS' CONCLUSIONS: Available trial data do not provide evidence that advancing enteral feed volumes at daily increments of 15 to 20 mL/kg (compared with 30 to 40 mL/kg) reduces the risk of NEC or death in very preterm or VLBW infants, extremely preterm or ELBW infants, SGA or growth-restricted infants, or infants with antenatal AREDFV. Advancing the volume of enteral feeds at a slow rate results in several days of delay in establishing full enteral feeds and may increase the risk of invasive infection. PMID- 28854320 TI - [[Abortion: An Unforgivable Sin?].] AB - Abortion has become something to hide, something you can't tell other people, something you have to expiate forever. Besides, abortion is more and more difficult to achieve because of the raising average of consciencious objection (from 70 to 90% of health care providers are conscientious objectors, 2014 data, Ministero della Salute) and illegal abortion is "coming back"from the 70s, when abortion was a crime (Italian law n. 194/1978). Abortion is often blamed as a murder, an unforgivenable sin, even as genocide. Silence against shouting "killers!" to women who are going to have an abortion: this is a common actual scenario. Why is it so difficult to discuss and even to mention abortion? PMID- 28854321 TI - [[Abortive Pollution in the Sacred Laws of Cyrene and Kos].] AB - In the society of the ancient Greece sacred laws on the abortion are a typical example of a mixture between the temple wisdom tradition and the medical tugvr. The epigraphic discoveries made between the end of the nineteenth century and the beginning of the twentieth century in Cos and Cyrene offered meaningfid evidences of the cooperation between priests and physicians to evaluate each single case of abortion and impose the right atonement. This contribution aims at showing how firm the line of continuity between medicine as wisdom and medicine as T Xvn was in the ancient Greece, focusing on the hot topic of the abortion. The question will be analyzed from a multidisciplinary approach which includes history of language, history of medicine and history of religion as the nature of the topic and of the evidences reauires. PMID- 28854322 TI - [[ABORTION BETWEEN CRIME AND CARE (ITALY, 1889-1943)].] AB - Perception of guilt and remorse is tied to the complicated question of what is an abortion. There is no doubt that abortion practices have had a long and complex history. Abortion is, in fact, a 'mobile' category, whose definition and identification depends on several factors and is related to the context and - not least - the complex question of identifying the actual voluntariness of the act. The frequency of spontaneous abortions, due to -excessive force or working conditions, and the inevitability of the appeal to the interruption of pregnancy in the absence of other means of fertility control methods, allowed a widespread lack of guilt, testified also by language even in the mid-twenties, when the fascist regime begins to structure a policy that culminates, during the thirties, in unprecedented emphasis on the role and the female body in an exclusively procreative function and configuration of maternity as a patriotic duty particularly enshrined in the new Penal code of 1930. PMID- 28854323 TI - [[Medical Abortion and Surgical Abortion: What Changes?].] AB - After an analysis of the history of the introduction of the so called "abortion pill" in various countries included Italy, it is analyzed the substantial differences between the two procedures of medical abortion comparing with surgical abortion. PMID- 28854324 TI - [[The Obstacles to the Application of the Law 194].] AB - Law 194 was introduced in Italy in 1978, following a campaign by women's groups, but alsofollowing the rise in illegal abortions and related deaths; after quite 40 years, we are now assisting to the dangerous return to illegality, related with the obstacles to the application of the law. The main causes of this phenomena are: the conscientious objection, the non- compliance of the law and the providers' "burn-out". The law permits to medical and non medical personnel to refuse to carry out abortions on conscientious groumds, but this right is greatly abused, with harmfil consequences on women's health. Another huge obstacle is represented by the non-compliance of the law: the hospital's "objection", the scarce accessibility to medical abortion, the lack of scientific, practical and ethic formation of the providers. The provider's "burn out" is the last obstacle, a hidden but not secondary factor. A new, really non religious thought, becomes thus a necessity for our life and for women's health. PMID- 28854325 TI - [["Conflicting Right": A "Bottom-up" Approach to Map the Problem of Abortion].] AB - The paper examines the particular nature of the rights involved in disciplines related to the termination of pregnancy. It focuses on the ways by which these rights must be appropriately balanced with constitutional rights and values. It also stresses the need of a "botton-up" approach rather than a more restrictive and dangerous "top-down" approach. Only in this way it seems possible to tackle and appreciate the problem in all its actual complexity. PMID- 28854326 TI - [[Getting Free from One's Own Nature? An Insight on Abortion as a Constitutional Issue].] AB - The right to abortion was the forerunner of a new idea of liberty, the liberty from gender roles which 'naturalize' oppressive social constructs. In Italy, in the Seventies of the 20th Century, some feminist opinions objected, in the name offemale liberty, to the battle for the right to abortion and against gender roles. This, they .argued, could cost women to disclaim their sex as a resource for self-identification and social change. Actually, forty years after its legalisation, abortion remains controversial, nor tells it much about female liberty. As a matter of fact, it did not create a principle of liberty in reproductive choices, and it is regarded as an unwanted and embarassing relative by supporters of LGTB's rights. Does this reveal that there is something flawed in the idea offreedom on which the right to abortion is built? PMID- 28854327 TI - [['Love them Both': Abortion in a Globalized World].] AB - This article explores the origins and the development of women-protective anti abortion arguments in a globalized world. Unlike fetus-base pro- life arguments, women protective ones focus on gender stereotypes and on the theory of gender complementarity. The article traces the influence of US conservative groups in spreading such arguments beyond the US borders, so that in today's globalized world, womnen-protective arguments have become central in abortion and contraception related legislation and litigation in the US, Europe and Russia. The article points to the dangers of the women-protective anti-abortion strategy, which aims at disempowering women, by denying them agency and control over reproduction, resulting in a direct challenge to gender equality. PMID- 28854328 TI - [[The Devil in the Details: Women's Right to Abortion and Health Organization].] AB - Often a woman's right to terminate a pregnancy for health reasons is considered as achieved by simply performing the intervention. But today isn't in doubt that the effective protection of health requires that health organizations carrying out performance which also affect other aspects: taking charge of women, information on services, respect for the dignity and autonomy of women, etc ... You could say that these are details, compared to the final performance. But, as we know, often the devil is in the details. PMID- 28854329 TI - [[Italian 194 Law, Conscientious Objection and the European Disapproval].] AB - This essay aims at delving into the issues raised by the application of the Law No. 194/1978 in the matter of the voluntary termination of pregnancy, taking into account the constitutional principles, the judgments of the Italian Constitutional Court and the recent decision on the merit of the Collective Complaint No. 87/2012 (International Planned Parenthood Federation European Network v. Italy) adopted by the European Committee of Social Rights. PMID- 28854330 TI - [[Abortion, Stigma and Conscientious Objection: Experiences and Opinions of Gynecologists in Italy and Catalonia].] AB - This article discusses the issue of abortion stigma and conscientious objection based on the main results of a qualitative study carried out in hospitals providing abortion care in Italy and Spain (Catalunya). This study was aimed at examining obstetricians-gynaecologists' experiences and attitudes to abortion, or voluntary interruption of pregnancy. The abortion law is relatively liberal in these two Catholic countries (much more liberal in Spain than in Italy). However, abortion still is strongly stigmatized in the public debate on human and reproductive rights, whose focus has shifted, over the last decade, from women's rights to the "rights of the conceived". Based on a study carried out in Italy in 2011-2012 and in Spain in 2013- 2015, this article discusses the impact of the stigmatization of abortion on the quality of obstetricians-gynaecologists' training and on their professional choices concerning conscientious objection and shows how physicians contribute to reproduce abortion stigma in the two countries. PMID- 28854331 TI - [The Ram's Heads on the Pompejan Quadri Valve Speculum (Bljouiez. Jackson 291: Naples Arch. Mus. 113264)1]. AB - This article discusses the hypothesis that the ram's heads on the speculum recovered in Pompeii in 1881-82 had some symbolic significance - on the basis of the connection between the ram and the human reproductive organs, well testified in Egyptian mythology. Infact, there is ample evidence of Egyptian influence in Pompeii, particularly nearby the houses where we presume the discovery of the speculum was made. PMID- 28854332 TI - [[General Practitioners and Public Health in Italy: Medical Office of Doctor Sgandurra from Farindola (Abruzzi, Central Italy)].] AB - Until the so-called sanitary reform (1978), which introduced a Beveridge' system, in Italy existed a peculiar kind of general practitioner, paid by municipalities, who ensured healthcare to those not covered by social insurance. In small towns those physicians also carried out the finction of Health Officers, performing Public Health duties. We had the possibility to study the very large archive of one of them, doctor Sgandurrafrom Farindola, a village in the Abruzzi Region (central Italy): in the paper we briefly analyse six public health acts that he issued in the first half of the 1950s. PMID- 28854333 TI - Combining CRISPR and CRISPRi Systems for Metabolic Engineering of E. coli and 1,4 BDO Biosynthesis. AB - Biosynthesis of 1,4-butanediol (1,4-BDO) in E. coli requires an artificial pathway that involves six genes and time-consuming, iterative genome engineering. CRISPR is an effective gene editing tool, while CRISPR interference (CRISPRi) is repurposed for programmable gene suppression. This study aimed to combine both CRISPR and CRISPRi for metabolic engineering of E. coli and 1,4-BDO production. We first exploited CRISPR to perform point mutation of gltA, replacement of native lpdA with heterologous lpdA, knockout of sad and knock-in of two large (6.0 and 6.3 kb in length) gene cassettes encoding the six genes (cat1, sucD, 4hbd, cat2, bld, bdh) in the 1,4-BDO biosynthesis pathway. The successive E. coli engineering enabled production of 1,4-BDO to a titer of 0.9 g/L in 48 h. By combining the CRISPRi system to simultaneously suppress competing genes that divert the flux from the 1,4-BDO biosynthesis pathway (gabD, ybgC and tesB) for >85%, we further enhanced the 1,4-BDO titer for 100% to 1.8 g/L while reducing the titers of byproducts gamma-butyrolactone and succinate for 55% and 83%, respectively. These data demonstrate the potential of combining CRISPR and CRISPRi for genome engineering and metabolic flux regulation in microorganisms such as E. coli and production of chemicals (e.g., 1,4-BDO). PMID- 28854335 TI - NOO Peroxy Isomer Exposed with Velocity-Map Imaging. AB - The chemistry of NO2, a key atmospheric trace gas, has historically been interpreted in terms of the C2v isomer ONO, with the peroxy isomer NOO only postulated to be stable. In this work, a velocity-map-imaged photoelectron spectrum of the nitrite anion, NO2-, reveals energetic-electron structure that may only occur by photodetachment from the NOO-(X1A') isomer. This measurement defines NOO(X2A') bond frequencies and an electron affinity of only 335(30) cm-1, which, supported by ab initio calculations, confirm the first observation of this important reactive species. PMID- 28854334 TI - Factors Influencing Water System Functionality in Nigeria and Tanzania: A Regression and Bayesian Network Analysis. AB - Sufficient, safe, and continuously available water services are important for human development and health yet many water systems in low- and middle-income countries are nonfunctional. Monitoring data were analyzed using regression and Bayesian networks (BNs) to explore factors influencing the functionality of 82 503 water systems in Nigeria and Tanzania. Functionality varied by system type. In Tanzania, Nira handpumps were more functional than Afridev and India Mark II handpumps. Higher functionality was associated with fee collection in Nigeria. In Tanzania, functionality was higher if fees were collected monthly rather than in response to system breakdown. Systems in Nigeria were more likely to be functional if they were used for both human and livestock consumption. In Tanzania, systems managed by private operators were more functional than community-managed systems. The BNs found strong dependencies between functionality and system type and administrative unit (e.g., district). The BNs predicted functionality increased from 68% to 89% in Nigeria and from 53% to 68% in Tanzania when best observed conditions were in place. Improvements to water system monitoring and analysis of monitoring data with different modeling techniques may be useful for identifying water service improvement opportunities and informing evidence-based decision-making for better management, policy, programming, and practice. PMID- 28854336 TI - In Vitro Anti-Inflammatory Activity of Ilex cornuta Extract Mediated by Inhibition of Extracellular Signal-Regulated Kinase Phosphorylation. AB - Ilex cornuta, commonly known as Chinese holly, is an evergreen shrub from the family Aquifoliaceae, and it is widely distributed in Korea and China. In folk medicine, the leaves of I. cornuta are used for treatment of several disorders, including weakness of the waist and knees, arthrodynia, headache, acute conjunctivitis, toothache, urticaria, rheumatic arthralgia, and cardiovascular diseases. In this study, we investigated the anti-inflammatory effects of an I. cornuta leaf ethanol extract (ILE) and its underlying mechanisms of action. The anti-inflammatory activities of ILE were evaluated in murine RAW 264.7 macrophages, using lipopolysaccharide (LPS) stimulation. ILE treatment-related changes in the production of nitric oxide (NO), prostaglandin E2 (PGE2), and proinflammatory cytokines were also measured. Finally, the expression of signaling molecules involved in inflammatory reactions was also assessed. Pretreatment of macrophages with ILE attenuated the expression of inducible NO synthase and cyclooxygenase-2, resulting in a decrease in NO and PGE2 production. The secretion of proinflammatory cytokines such as interleukin (IL)-6 and IL 1beta was also reduced. Furthermore, ILE reduced extracellular signal-regulated kinases (ERK) phosphorylation, without affecting the inhibitor of kappa Balpha and other mitogen-activated protein kinases. Liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) demonstrated that 1 g of ILE contains 27 mg of kaempferol, 0.3 mg of vanillic acid, and 21 mg of combined amount of isoquercetin and hyperin, among which isoquercetin and kaempferol significantly suppressed IL 6, IL-1beta, and PGE2 production. Our results demonstrated that ILE possesses anti-inflammatory effects mediated through inhibition of ERK phosphorylation. PMID- 28854337 TI - Exercise training with concomitant nitric oxide synthase inhibition improved anxiogenic behavior, spatial cognition, and BDNF/P70S6 kinase activation in 20 month-old rats. AB - This study aimed to investigate the effect of exercise and nitric oxide synthase (NOS) inhibition on memory, anxiety, and protein levels of brain-derived neurotrophic factor (BDNF) and P70S6 kinase (P70S6K). Twenty-month-old rats were divided into 6 groups: a control group, 2 groups treated with l-nitro-arginine methyl ester (L-NAME) (25 or 100 mg/kg) for 63 days, 2 groups treated with L-NAME (25 or 100 mg/kg) for 63 days plus 2 months of exercise, and 1 group treated with exercise. Behavioral tests were conducted to determine the anxiolytic and memory improving role of exercise and NOS inhibition. BDNF, P70S6K, and cleaved caspase 3 protein levels in the hippocampus and prefrontal cortex were evaluated by Western blotting. Exercise and L-NAME (25 mg/kg) or their combination had an anxiolytic effect and improved spatial memory in old rats compared with the control or exercised group, respectively. Exercise and treatment with a low dose of L-NAME (25 mg/kg) each increased BDNF and P70S6K in the hippocampus and prefrontal cortex compared with levels in control rats. In comparison with exercise alone, co-treatment with exercise and a low dose of L-NAME (25 mg/kg) also increased BDNF and P70S6K in the hippocampus. The neuronal level of cleaved caspase-3 was reduced in the L-NAME (25 mg/kg) + exercise group compared with the exercised group. The L-NAME (100 mg/kg) + exercise treatment had no positive behavioral or molecular effects compared with exercise alone. The protective role of NOS inhibition and aerobic exercise against aging is probably modulated via BDNF and P70S6K in the brain. PMID- 28854338 TI - Effects of ovariectomy on antioxidant defence systems in the right ventricle of female rats with pulmonary arterial hypertension induced by monocrotaline. AB - The aim of this study was to evaluate the impact of ovariectomy on oxidative stress in the right ventricle (RV) of female rats with pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). Rats were divided into 4 groups (n = 6 per group): sham (S), sham + MCT (SM), ovariectomized (O), and ovariectomized + MCT (OM). MCT (60 mg.kg-1 i.p.) was injected 1 week after ovariectomy or sham surgery. Three weeks later, echocardiographic analysis and RV catheterisation were performed. RV morphometric, biochemical, and protein expression analysis through Western blotting were done. MCT promoted a slight increase in pulmonary artery pressure, without differences between the SM and OM groups, but did not induce RV hypertrophy. RV hydrogen peroxide increased in the MCT groups, but SOD, CAT, and GPx activities were also enhanced. Non-classical antioxidant defenses diminished in ovariectomized groups, probably due to a decrease in the nuclear factor Nrf2. Hemoxygenase-1 and thioredoxin-1 protein expression was increased in the OM group compared with SM, being accompanied by an elevation in the estrogen receptor beta (ER-beta). Hemoxygenase-1 and thioredoxin-1 may be involved in the modulation of oxidative stress in the OM group, and this could be responsible for attenuation of PAH and RV remodeling. PMID- 28854339 TI - Improving the Safety and Functionality of an Artificial Pancreas System for Use in Younger Children: Input from Parents and Physicians. AB - BACKGROUND: Artificial pancreas (AP) systems have initially been designed for and tested in teens and adults, but there is evidence that an AP system with additional support and safety systems could greatly benefit younger children with type 1 diabetes (T1D). SUBJECTS AND METHODS: Five pediatric endocrinologists and 15 parents of children aged 5-8 years with T1D participated in a total of four focus groups. Focus groups investigated current diabetes technology use and acceptance, as well as possible modifications to the current adult AP system, which would allow for safe and successful use in younger children. Modifications discussed include child-specific functionality for input tasks, safety features, and monitoring capabilities. RESULTS: Participant suggestions included the following: passcodes for differential access to AP features by parents, ancillary caregivers, and the child; preset early, intermediate, and advanced child access categories; maximal customization for general and alarm settings; simplified meal screens utilizing the AP' corrective blood glucose (BG) ability; automated exercise mode; spoken and dictated messaging capabilities; emergency contacts; treatment instructions for the child and caregiver; remote monitoring website and application; animated continuous glucose monitor BG trace; gamification, such as rewarding diabetes-friendly behaviors; and comprehensive training of all individuals involved in the child's diabetes care. CONCLUSION: Parents and physicians were eager for AP applications to be available for younger children, but stressed that a modified system could better serve this group's needs for safety and improved diabetes-related communication. The diverse and emerging needs of 5-8-year olds require flexible and customizable systems for T1D management. PMID- 28854340 TI - Sequential analysis and staging of a diethylnitrosamine-induced hepatocellular carcinoma in male Wistar albino rat model. AB - Hepatocellular carcinoma (HCC) is one of the most life-threatening cancers. The present study was designed to chronologically analyze the HCC chemically induced by diethylnitrosamine (DEN) in male Wistar rats during a 27-week period. DEN was given to rats in drinking water (100 mg/L) to induce HCC. In the present study, the DEN-administered groups recorded dramatic results in the tumor markers, oxidative stress, lipid profile, liver function, and hematological parameters at all intervals when compared with their corresponding values in the control groups. In addition, the morphometric analysis of livers of the DEN-administered groups (from 9 to 27 weeks) showed gradual enlargement and several grayish white nodules and foci on the peripheral surface of the liver as the features of HCC. In conclusion, the present sequential model chronologically analyzes all steps of hepatocarcinogenesis and presents a new staging system for classification of HCC that may be valuable for investigating the effects of anticarcinogenic compounds at varying stages of hepatocarcinogenesis in vivo. PMID- 28854341 TI - The protease inhibitor E64d improves ox-LDL-induced endothelial dysfunction in human aortic endothelial cells. AB - Oxidized low-density lipoprotein (ox-LDL)-induced endothelial dysfunction in human vascular endothelial cells contributes to the development of atherosclerosis. E64d, a cysteine protease inhibitor, blocks the elastolytic activity of cathepsin essential for vascular matrix remodeling and reduces neurovascular endothelial apoptosis. The objective of this study was to investigate the effects and the underling mechanisms of E64d on ox-LDL-induced endothelial dysfunction in human aortic endothelial cells (HAECs). HAECs were treated with various concentrations of ox-LDL (0-200 mg/L) for 24 h with or without E64d. The results showed that E64d attenuated ox-LDL-induced increase in soluble intercellular adhesion molecule-1 (sICAM-1) concentration and reduction in endothelial nitric oxide synthase (eNOS) expression, prevented ox-LDL-induced reduction in cell viability and migration ability of HAECs. E64d decreased the protein expression of cathepsin B (CTSB), Beclin 1, and microtubule-associated protein light chain 3 (LC3)-II, but not p62. LC3 puncta and autophagosome formation were also reduced by E64d in HAECs. Moreover, E64d decreased the production of MDA and increased the activity of SOD. The results showed that E64d ameliorated ox-LDL-induced endothelial dysfunction in HAECs. PMID- 28854342 TI - Short-term effects of hemodiafiltration versus conventional hemodialysis on erythrocyte performance. AB - Hemodiafiltration (HDF) is a renal replacement therapy that is based on the principles of diffusion and convection for the elimination of uremic toxins. A significant and increasing number of end-stage renal disease (ESRD) patients are treated with HDF, even in the absence of definite and conclusive survival and anemia treatment data. However, its effects on red blood cell (RBC) physiological features have not been examined in depth. In this study, ESRD patients under regular HDF or conventional hemodialysis (cHD) treatment were examined for RBC related parameters, including anemia, hemolysis, cell shape, redox status, removal signaling, membrane protein composition, and microvesiculation, in repeated paired measurements accomplished before and right after each dialysis session. The HDF group was characterized by better redox potential and suppressed exovesiculation of blood cells compared with the cHD group pre-dialysis. However, HDF was associated with a temporary but acute, oxidative-stress-driven increase in hemolysis, RBC removal signaling, and stomatocytosis, probably associated with the effective clearance of dialyzable natural antioxidant components, including uric acid, from the uremic plasma. The nature of these adverse short-term effects of HDF on post-dialysis plasma and RBCs strongly suggests the use of a parallel antioxidant therapy during the HDF session. PMID- 28854343 TI - Updates on Immunohistochemical and Molecular Markers in Selected Head and Neck Diagnostic Problems. AB - CONTEXT: - The head and neck regions have complex anatomic structures. They are not exempted from the rare occurrences of highly unusual, diagnostically challenging malignant neoplasms and mimickers. OBJECTIVE: - To review and update the utility of immunohistochemistry and molecular biomarkers and to pursue diagnostic accuracy on selected rare neoplasms, especially some poorly differentiated malignancies. DATA SOURCES: - Personal experience and information from the literature. CONCLUSIONS: - Head and neck tumors include neoplasms originating from heterogeneous tissue. Using the selected clinical cases, this review illustrates a continuous development of emerging molecular-genetic techniques to assist in the interpretation of uncommon, often poorly differentiated, highly malignant neoplasms. The diagnostic results are appropriately transmitted to the oncologists, radiation oncologists, and surgeons to create a coordinated plan of care for patients with these unusual disorders affecting the head and neck. PMID- 28854345 TI - Abstracts and Case Studies From the College of American Pathologists 2017 Annual Meeting (CAP17). PMID- 28854344 TI - Giant Cell Arteritis of the Breast. AB - Giant cell arteritis is an inflammatory lesion of the large- and medium-sized arteries, usually involving the temporal arteries of older women. Rarely, the breast has been reported as the primary site of involvement. Patients usually present with breast masses that are tender or painful in most reported cases. The disease may be associated with constitutional symptoms that resemble polymyalgia rheumatica, but most reported cases do not have an established diagnosis of autoimmune disease. Clinically, giant cell arteritis of the breast may mimic breast carcinoma. Establishing the diagnosis is important because most patients achieve remission of symptoms after treatment with prednisone. PMID- 28854346 TI - Abstract/Case Study Review Committee for the College of American Pathologists 2017 Annual Meeting (CAP17). AB - The Archives of Pathology & Laboratory Medicine acknowledges the following individuals for volunteering to review abstract and case study submissions for the CAP17 meeting. PMID- 28854347 TI - Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas. AB - CONTEXT: - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES: - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES: - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS: - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care. PMID- 28854348 TI - Changing Initial Glaucoma Medical Therapy Increases Healthcare Resource Utilization. AB - PURPOSE: To determine the frequency and economic impact of changing initial glaucoma therapy for patients with newly diagnosed open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: This retrospective longitudinal cohort study identified individuals within a large managed care network in the United States, who were newly diagnosed with OAG or OHT from 2001 to 2012 and were prescribed either a topical beta blocker (BB) or a prostaglandin analog (PGA). Claims data were analyzed over the 12-month period following their index prescription to determine physician prescribing habits, healthcare resource utilization patterns, and sociodemographic factors which may have contributed to changing the initial treatment strategy. RESULTS: A total of 15,019 beneficiaries were identified with newly diagnosed OAG or OHT and whose index therapy was either a topical BB or PGA. Among these enrollees 80.9% were started on PGAs, while 19.1% were started on BBs. Of these beneficiaries, 29.2% of those started on PGAs and 39.5% of those started on BBs underwent a change in therapy within 12 months of their index prescription. Those in the topical BB treatment group had a 38% increased odds of changing glaucoma therapy relative to those started on PGAs (odds ratio [OR] 0.61, 95% CI:0.56-0.68). Patients who changed therapy required more frequent office visits (P < 0.0001) and incurred higher median eye care related charges (P < 0.0001) compared to those who remained on the index therapy unchanged. CONCLUSIONS: Changing initial ocular hypotensive therapy is common. Individuals who undergo a change in therapy required more frequent face-to-face monitoring and incurred higher healthcare related costs. Identifying strategies capable of optimizing the process of initiating ocular hypotensive therapy are appealing and possess the potential to improve patient outcomes and reduce healthcare costs. PMID- 28854350 TI - Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma. PMID- 28854349 TI - Ranking States on Coverage of Cancer-Preventing Vaccines Among Adolescents: The Influence of Imprecision. AB - OBJECTIVES: Identifying the best and worst states for coverage of cancer preventing vaccines (hepatitis B [HepB] and human papillomavirus [HPV]) may guide public health officials in developing programs, such as promotion campaigns. However, acknowledging the imprecision of coverage and ranks is important for avoiding overinterpretation. The objective of this study was to examine states' vaccination coverage and ranks, as well as the imprecision of these estimates, to inform public health decision making. METHODS: We used data on coverage of HepB and HPV vaccines among adolescents aged 13-17 from the 2011-2015 National Immunization Survey-Teen (n = 103 729 from 50 US states and Washington, DC). We calculated coverage, 95% confidence intervals (CIs), and ranks for vaccination coverage in each state, and we generated simultaneous 95% CIs for ranks using a Monte Carlo method with 100 000 simulations. RESULTS: Across years, HepB vaccination coverage was 92.2% (95% CI, 91.8%-92.5%; states' range, 84.3% in West Virginia to 97.0% in Connecticut). HPV vaccination coverage was 57.4% (95% CI, 56.6%-58.2%; range, 41.8% in Kansas to 78.0% in Rhode Island) for girls and 31.0% (95% CI, 30.3%-31.8%; range, 19.0% in Utah to 59.3% in Rhode Island) for boys. States with the highest and lowest ranks generally had narrow 95% CIs; for example, Rhode Island was ranked first (95% CI, 1-1) and Kansas was ranked 51st (95% CI, 49-51) for girls' HPV vaccination. However, states with intermediate ranks had wider and more imprecise 95% CIs; for example, New York was 26th for girls' HPV vaccination coverage, but its 95% CI included ranks 18-35. CONCLUSIONS: States' ranks of coverage of cancer-preventing vaccines were imprecise, especially for states in the middle of the range; thus, performance rankings presented without measures of imprecision could be overinterpreted. However, ranks can highlight high-performing and low-performing states to target for further research and vaccination promotion programming. PMID- 28854351 TI - FcgammaRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis. PMID- 28854352 TI - Screening of "spice" herbal mixtures: From high-field to low-field proton NMR. AB - Forty one samples of herbal spices intended to be introduced into the European market and seized by the French customs were analysed with high-field 1H NMR. Nine synthetic cannabinoids (MAM-2201, JWH-073, JWH-210, JWH-122, JWH-081, JWH 250, UR-144, XLR-11 and AKB-48-5F) were detected and quantified. The ability of a compact benchtop low-field NMR spectrometer for a rapid screening of the content of herbal blends was then successfully explored for the first time. Even if low field 1H NMR spectra are much less resolved than high-field spectra, we demonstrate that they provide valuable clues on the chemical structures of synthetic cannabinoids with the detection of some typical signals. PMID- 28854353 TI - Feeling Stressed under the Sun? RPA1 Acetylation to the Rescue. AB - Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV induced DNA damage response. PMID- 28854354 TI - PCAF/GCN5-Mediated Acetylation of RPA1 Promotes Nucleotide Excision Repair. AB - The RPA complex can integrate multiple stress signals into diverse responses by activating distinct DNA repair pathways. However, it remains unclear how RPA1 elects to activate a specific repair pathway during different types of DNA damage. Here, we report that PCAF/GCN5-mediated K163 acetylation of RPA1 is crucial for nucleotide excision repair (NER) but is dispensable for other DNA repair pathways. Mechanistically, we demonstrate that the acetylation of RPA1 is critical for the steady accumulation of XPA at damaged DNA sites and preferentially activates the NER pathway. DNA-PK phosphorylates and activates PCAF upon UV damage and consequently promotes the acetylation of RPA1. Moreover, the acetylation of RPA1 is tightly regulated by HDAC6 and SIRT1. Together, our results demonstrate that the K163 acetylation of RPA1 plays a key role in the repair of UV-induced DNA damage and reveal how the specific RPA1 modification modulates the choice of distinct DNA repair pathways. PMID- 28854355 TI - UV-Induced RPA1 Acetylation Promotes Nucleotide Excision Repair. AB - Replication protein A (RPA) is a multifunctional, single-stranded DNA-binding protein complex and plays a critical role in DNA replication and damage response. Herein, we show that the 70-kDa subunit of RPA (RPA1) is acetylated on lysine 163 by the acetyltransferases GCN5 and PCAF and that such acetylation is reversed principally via the action of the deacetylase HDAC6. UV irradiation promotes cytoplasmic translocation of HDAC6, thereby disrupting the interaction of HDAC6 with RPA1 and increasing RPA1 acetylation. Mutation of the acetylation site of RPA1 specifically impairs the ability of the protein to interact with the key nucleotide excision repair (NER) protein XPA, reduces XPA retention at sites of DNA damage caused by UV, compromises NER, and renders the cell hypersensitive to UV irradiation. Our data suggest that the acetylation status of RPA1 played a crucial role in repair of DNA damage via NER. PMID- 28854356 TI - Multilayered Reprogramming in Response to Persistent DNA Damage in C. elegans. AB - DNA damage causally contributes to aging and age-related diseases. Mutations in nucleotide excision repair (NER) genes cause highly complex congenital syndromes characterized by growth retardation, cancer susceptibility, and accelerated aging in humans. Orthologous mutations in Caenorhabditis elegans lead to growth delay, genome instability, and accelerated functional decline, thus allowing investigation of the consequences of persistent DNA damage during development and aging in a simple metazoan model. Here, we conducted proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment to gain comprehensive insights into the full range of physiological adaptations to unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated proteostatic response. We assign central roles for the insulin-, EGF-, and AMPK-like signaling pathways in orchestrating the adaptive response to DNA damage. Our results provide insights into the DNA damage responses in the organismal context. PMID- 28854357 TI - NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis. AB - Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence independent manner. Moreover, NEIL3 is recruited to telomeres through its interaction with TRF1, and this interaction enhances the enzymatic activity of purified NEIL3. Finally, we show that NEIL3 interacts with AP Endonuclease 1 (APE1) and the long-patch base excision repair proteins PCNA and FEN1. Taken together, we propose that NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase. PMID- 28854358 TI - SMC Progressively Aligns Chromosomal Arms in Caulobacter crescentus but Is Antagonized by Convergent Transcription. AB - The structural maintenance of chromosomes (SMC) complex plays an important role in chromosome organization and segregation in most living organisms. In Caulobacter crescentus, SMC is required to align the left and the right arms of the chromosome that run in parallel down the long axis of the cell. However, the mechanism of SMC-mediated alignment of chromosomal arms remains elusive. Here, using genome-wide methods and microscopy of single cells, we show that Caulobacter SMC is recruited to the centromeric parS site and that SMC-mediated arm alignment depends on the chromosome-partitioning protein ParB. We provide evidence that SMC likely tethers the parS-proximal regions of the chromosomal arms together, promoting arm alignment. Furthermore, we show that highly transcribed genes near parS that are oriented against SMC translocation disrupt arm alignment, suggesting that head-on transcription interferes with SMC translocation. Our results demonstrate a tight interdependence of bacterial chromosome organization and global patterns of transcription. PMID- 28854359 TI - Lysophosphatidic Acid Receptor 4 Activation Augments Drug Delivery in Tumors by Tightening Endothelial Cell-Cell Contact. AB - Vascular normalization in tumors may improve drug delivery and anti-tumor immunity. Angiogenesis inhibitors induce hypoxia, which may facilitate malignant progression; therefore, we investigated other methods to promote vascular maturation. Here, we show that lysophosphatidic acid (LPA) enhances blood flow by promoting fine vascular networks, thereby improving vascular permeability and suppressing tumor growth when combined with anti-cancer drug treatment. Six different G protein-coupled receptors have been identified as LPA receptors (LPA1 6). In studies using mutant mice, we found that LPA4 is involved in vascular network formation. LPA4 activation induces circumferential actin bundling beneath the cell membrane and enhances linear adherens junction formation by VE-cadherin in endothelial cells. Therefore, we conclude that activation of LPA4 is a promising approach for vascular regulation. PMID- 28854360 TI - Spatiotemporal Control of Lipid Conversion, Actin-Based Mechanical Forces, and Curvature Sensors during Clathrin/AP-1-Coated Vesicle Biogenesis. AB - Clathrin/adaptor protein-1-coated carriers connect the secretory and the endocytic pathways. Carrier biogenesis relies on distinct protein networks changing membrane shape at the trans-Golgi network, each regulating coat assembly, F-actin-based mechanical forces, or the biophysical properties of lipid bilayers. How these different hubs are spatiotemporally coordinated remains largely unknown. Using in vitro reconstitution systems, quantitative proteomics, and lipidomics, as well as in vivo cell-based assays, we characterize the protein networks controlling membrane lipid composition, membrane shape, and carrier scission. These include PIP5K1A and phospholipase C-beta 3 controlling the conversion of PI[4]P into diacylglycerol. PIP5K1A binding to RAC1 provides a link to F-actin-based mechanical forces needed to tubulate membranes. Tubular membranes then recruit the BAR-domain-containing arfaptin-1/2 guiding carrier scission. These findings provide a framework for synchronizing the chemical/biophysical properties of lipid bilayers, F-actin-based mechanical forces, and the activity of proteins sensing membrane shape during clathrin/adaptor protein-1-coated carrier biogenesis. PMID- 28854361 TI - Aberrant Compartment Formation by HSPB2 Mislocalizes Lamin A and Compromises Nuclear Integrity and Function. AB - Small heat shock proteins (HSPBs) contain intrinsically disordered regions (IDRs), but the functions of these IDRs are still unknown. Here, we report that, in mammalian cells, HSPB2 phase separates to form nuclear compartments with liquid-like properties. We show that phase separation requires the disordered C terminal domain of HSPB2. We further demonstrate that, in differentiating myoblasts, nuclear HSPB2 compartments sequester lamin A. Increasing the nuclear concentration of HSPB2 causes the formation of aberrant nuclear compartments that mislocalize lamin A and chromatin, with detrimental consequences for nuclear function and integrity. Importantly, phase separation of HSPB2 is regulated by HSPB3, but this ability is lost in two identified HSPB3 mutants that are associated with myopathy. Our results suggest that HSPB2 phase separation is involved in reorganizing the nucleoplasm during myoblast differentiation. Furthermore, these findings support the idea that aberrant HSPB2 phase separation, due to HSPB3 loss-of-function mutations, contributes to myopathy. PMID- 28854362 TI - Loss of Apela Peptide in Mice Causes Low Penetrance Embryonic Lethality and Defects in Early Mesodermal Derivatives. AB - Apela (also known as Elabela, Ende, and Toddler) is a small signaling peptide that activates the G-protein-coupled receptor Aplnr to stimulate cell migration during zebrafish gastrulation. Here, using CRISPR/Cas9 to generate a null, reporter-expressing allele, we study the role of Apela in the developing mouse embryo. We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. Three-dimensional micro computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. Transcriptomics at late gastrulation identified aberrant upregulation of erythroid and myeloid markers in mutant embryos prior to the appearance of physical malformations. Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr expressing mesodermal populations independently of the alternative ligand Apelin, leading to lethal cardiac defects in some Apela null embryos. PMID- 28854363 TI - Folding of the Cerebral Cortex Requires Cdk5 in Upper-Layer Neurons in Gyrencephalic Mammals. AB - Folds in the cerebral cortex in mammals are believed to be key structures for accommodating increased cortical neurons in the cranial cavity. However, the mechanisms underlying cortical folding remain largely unknown, mainly because genetic manipulations for the gyrencephalic brain have been unavailable. By combining in utero electroporation and the CRISPR/Cas9 system, we succeeded in efficient gene knockout of Cdk5, which is mutated in some patients with classical lissencephaly, in the gyrencephalic brains of ferrets. We show that Cdk5 knockout in the ferret cerebral cortex markedly impaired cortical folding. Furthermore, the results obtained from the introduction of dominant-negative Cdk5 into specific cortical layers suggest that Cdk5 function in upper-layer neurons is more important for cortical folding than that in lower-layer neurons. Cdk5 inhibition induced severe migration defects in cortical neurons. Taken together, our findings suggest that the appropriate positioning of upper-layer neurons is critical for cortical folding. PMID- 28854364 TI - A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity. AB - Hippocampal neurogenesis is important for certain forms of cognition, and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. Here, we show that the rate of fatty acid oxidation (FAO) regulates the activity of NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity. PMID- 28854365 TI - Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition. AB - Although Netos are considered auxiliary subunits critical for kainate receptor (KAR) function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM)-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1)-, and parvalbumin (PV)-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals. PMID- 28854366 TI - The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology. AB - The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD. PMID- 28854369 TI - The Functional Impact of Alternative Splicing in Cancer. AB - Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers). PMID- 28854368 TI - Genomic Determinants of Protein Abundance Variation in Colorectal Cancer Cells. AB - Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells. PMID- 28854370 TI - Generation of Mouse Haploid Somatic Cells by Small Molecules for Genome-wide Genetic Screening. AB - The recent success of derivation of mammalian haploid embryonic stem cells (haESCs) has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn2+-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance. PMID- 28854367 TI - Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death. AB - Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate limiting enzyme of the mammalian NAD+ biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD+ biosynthesis pathway is a potential therapeutic target for degenerative MN diseases. PMID- 28854371 TI - Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation. AB - Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future. PMID- 28854372 TI - Systems Vaccinology Identifies an Early Innate Immune Signature as a Correlate of Antibody Responses to the Ebola Vaccine rVSV-ZEBOV. AB - Predicting vaccine efficacy remains a challenge. We used a systems vaccinology approach to identify early innate immune correlates of antibody induction in humans receiving the Ebola vaccine rVSV-ZEBOV. Blood samples from days 0, 1, 3, 7, and 14 were analyzed for changes in cytokine levels, innate immune cell subsets, and gene expression. Integrative statistical analyses with cross validation identified a signature of 5 early innate markers correlating with antibody titers on day 28 and beyond. Among those, IP-10 on day 3 and MFI of CXCR6 on NK cells on day 1 were independent correlates. Consistently, we found an early gene expression signature linked to IP-10. This comprehensive characterization of early innate immune responses to the rVSV-ZEBOV vaccine in humans revealed immune signatures linked to IP-10. These results suggest correlates of vaccine-induced antibody induction and provide a rationale to explore strategies for augmenting the effectiveness of vaccines through manipulation of IP-10. PMID- 28854374 TI - Phospho-Rasputin Stabilization by Sec16 Is Required for Stress Granule Formation upon Amino Acid Starvation. PMID- 28854375 TI - Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function. PMID- 28854373 TI - Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs. AB - N6-methyladenosine (m6A) is the most abundant internal modification of mRNAs and is implicated in all aspects of post-transcriptional RNA metabolism. However, little is known about m6A modifications to circular (circ) RNAs. We developed a computational pipeline (AutoCirc) that, together with depletion of ribosomal RNA and m6A immunoprecipitation, defined thousands of m6A circRNAs with cell-type specific expression. The presence of m6A circRNAs is corroborated by interaction between circRNAs and YTHDF1/YTHDF2, proteins that read m6A sites in mRNAs, and by reduced m6A levels upon depletion of METTL3, the m6A writer. Despite sharing m6A readers and writers, m6A circRNAs are frequently derived from exons that are not methylated in mRNAs, whereas mRNAs that are methylated on the same exons that compose m6A circRNAs exhibit less stability in a process regulated by YTHDF2. These results expand our understanding of the breadth of m6A modifications and uncover regulation of circRNAs through m6A modification. PMID- 28854376 TI - Effect of ambient light on the time needed to complete a fetal biophysical profile: A randomized controlled trial. AB - OBJECTIVE: The objective of this study is to determine whether ambient light serves as a fetal stimulus to decrease the amount of time needed to complete a biophysical profile. STUDY DESIGN: This is a randomized controlled trial of singleton gestations undergoing a biophysical profile. Patients were randomized to either ambient light or a darkened room. The primary outcome was the time needed to complete the biophysical profile. Secondary outcomes included total and individual component biophysical profile scores and scores less than 8. A subgroup analysis of different maternal body mass indices was also performed. RESULTS: 357 biophysical profile studies were analyzed. 182 studies were performed with ambient light and 175 were performed in a darkened room. There was no difference in the median time needed to complete the biophysical profile based on exposure to ambient light (6.1min in darkened room versus 6.6min with ambient light; P=0.73). No difference was found in total or individual component biophysical profile scores. Subgroup analysis by maternal body mass index did not demonstrate shorter study times with ambient light exposure in women who were normal weight, overweight or obese. CONCLUSION: Ambient light exposure did not decrease the time needed to complete the biophysical profile. There was no evidence that ambient light altered fetal behavior observed during the biophysical profile. PMID- 28854377 TI - Embryonic survival, development and cryoinjury of repeatedly vitrified mouse preimplantation embryos. AB - OBJECTIVE: The aim of this study is to investigate the embryonic survival, development, and expressions of cryoinjury- or antioxidant-related genes in once, twice, or three-time vitrified mouse preimplantation embryos. Study desisgn: Six hundred 8-cell stage embryos were obtained from 60 female mice and randomly assigned to control and three experimental groups. Embryos were vitrified by indirect methods The developmental outcomes such as survival rate, blastocyst forming rate, and the percentage of hatching/hatched blastocyst were assessed. The cell numbers of hatching/hatched blastocyst were counted after nuclear staining. From hatching/hatched blastocysts, the mRNA expressions for Cirbp, Casp3, Sod1, Gpx3, and Cat were quantified by real-time quantitative RT-PCR. RESULTS: In once, twice, or three-time vitrified mouse 8-cell stage embryos, survival rates, blastocyst-forming rates, the percentages of hatching/hatched blastocyst, and the cell counts were all similar when compared with non-vitrified control group. The mRNA expression levels of Cirbp, Casp3, Sod1, Gpx3 and Cat were not affected. CONCLUSION: Repeatedly vitrified mouse 8-cell stage embryos well developed up to blastocyst stage without cryoinjury and without decrease of antioxidant-related genes. PMID- 28854378 TI - Detection of bisphenol A, cumylphenol and parabens in surface waters of Greater Poland Voivodeship. AB - Amounts of bisphenol A (BPA), 4-cumylphenol (CP) and 5 parabens - methylparaben (MP), ethylparaben (EP), propylparaben (PP), butylparaben (BP) and benzylparaben (BzP) in Greater Poland Voivodeship's surface waters are reported. The water samples were collected from selected 15 locations in 2015-2016 at seven different time points: in March, June, August, and October 2015 and March, June, and September 2016. MP was found in every tested sample with typical concentration at several dozen nanograms per liter and the highest level almost 1600 ng L-1 in a sample collected from the Warta River in October 2015. The other four parabens were determined at considerably lower concentrations than MP at levels not exceeding 100 ng L-1 with PP found at the highest and BzP at the lowest levels. BPA was determined at similar concentration level to parabens - between 5 ng L-1 and 95 ng L-1 and CP was found only in a limited number of samples. Noticeable seasonal changes of paraben concentrations were found showing that for these compounds the pollutant release factor dominates both the biodegradation factor and the water volume factor. These seasonal changes were not observed for BPA and CP. Out of all determined parabens only MP was found at considerably higher concentrations than BPA. However, MP's endocrine properties are much lower than those of BPA posing a lower environmental impact potential than BPA. Influence of other (more endocrine disrupting) parabens is also relatively weak in comparison to BPA due to their considerably lower concentrations in the environment. PMID- 28854379 TI - Element-specific behaviour and sediment properties modulate transfer and bioaccumulation of trace elements in a highly-contaminated area (Augusta Bay, Central Mediterranean Sea). AB - High sediment contamination in the coastal area of Priolo Bay, adjacent to the highly-polluted Augusta Harbour, poses serious risks for the benthic communities inhabiting the area. Nevertheless, the transfer of trace elements and consequent bioaccumulation in the biota is an overlooked issue. This study aimed to assess the transfer and bioaccumulation patterns of As, Cd, Ni and Hg to the dominant macroalgae and benthic invertebrates of Priolo Bay. Results revealed different patterns among trace elements (TEs), not driven by sediment contamination but rather by element-specific behaviour coupled with sediment physicochemical properties. Specifically, As accumulated in macroalgae but not in invertebrates, indicating bioavailability of dissolved As only, and a lack of effective trophic transfer. Ni was confined to surface sediment and transfer to biota was not highlighted. Cd and Hg showed the highest concentrations in invertebrates and bioaccumulated especially in filter feeders and carnivores, revealing the importance of suspended particulate and diet as transfer pathways. Total organic carbon (TOC), fine-grained sediments and redox potential were the most important sediment features in shaping the sediment contamination spatial patterns as well as those of TE transfer and bioaccumulation. In particular, As and Cd transfer to macroalgae, and especially Hg bioaccumulation in benthic invertebrates was controlled by sediment properties, resulting in limited transfer and accumulation in the most contaminated stations. PMID- 28854380 TI - The role of antioxidants in attenuation of Caenorhabditis elegans lethality on exposure to TiO2 and ZnO nanoparticles. AB - The exponential increase in the usage of engineered nanoparticles (ENPs) has raised global concerns due to their potential toxicity and environmental impacts. Nano-TiO2 and nano-ZnO have been extensively used in various applications. Thus, there is a need for determining the toxic potentials of ENPs as well as, to develop the possible attenuation method for ENPs toxicity. Both in the in vitro and in vivo systems, exposure to the majority of ENPs have shown Reactive Oxygen Species (ROS) generation, which leads to oxidative stress mediated inflammation, genotoxicity, and cytotoxicity. Hence, with the rationale of determining easy and economical protection against ENPs exposure, the amelioration effect of the antioxidants (curcumin and vitamin-C) against the nano-TiO2 and nano-ZnO induced ROS and lethality were investigated in Caenorhabditis elegans. We not only employed pre-treatment and along with treatment approach, but also determined the effect of antioxidants at different time points of treatment. Our study revealed that both the antioxidants efficiently ameliorate nanoparticles induced ROS as well as lethality in worms. Further, the pretreatment approach was more effective than the along with treatment. Therefore, our study indicates the possibility of evading the nanotoxicity by incorporating curcumin and vitamin-C in everyday diet. PMID- 28854381 TI - Degradation of acrylamide by the UV/chlorine advanced oxidation process. AB - The degradation of acrylamide (AA) during UV/chlorine advanced oxidation process (AOP) was investigated in this study. The degradation of AA was negligible during UV irradiation alone. However, AA could be effectively degraded and mineralized during UV/chlorination due to the generation of hydroxyl radicals (OH). The degradation kinetics of AA during UV/chlorination fitted the pseudo-first order kinetics with the rate constant between AA and OH radicals being determined as 2.11 * 109 M-1 s-1. The degradation rate and mineralization of AA during UV/chlorination were significantly promoted at acidic conditions as well as increasing chlorine dosage. The volatile degradation products of AA during UV/chlorination were identified using gas chromatography-mass spectrometry and the degradation pathways were then proposed accordingly. The formation of disinfection by-products (DBPs) in Milli-Q water and tap water during UV/chlorination of AA was also investigated. The DBPs included chloroform, dichloroacetonitrile, trichloroacetonitrile, 2,2-dichloroacetamide and 2,2,2 trichloroacetamide. Furthermore, the variations of AA degradation during UV/chlorination in different real water samples were evaluated. PMID- 28854382 TI - Smart Kd-values, their uncertainties and sensitivities - Applying a new approach for realistic distribution coefficients in geochemical modeling of complex systems. AB - One natural retardation process to be considered in risk assessment for contaminants in the environment is sorption on mineral surfaces. A realistic geochemical modeling is of high relevance in many application areas such as groundwater protection, environmental remediation, or disposal of hazardous waste. Most often concepts with constant distribution coefficients (Kd-values) are applied in geochemical modeling with the advantage to be simple and computationally fast, but not reflecting changes in geochemical conditions. In this paper, we describe an innovative and efficient method, where the smart Kd concept, a mechanistic approach mainly based on surface complexation modeling, is used (and modified for complex geochemical models) to calculate and apply realistic distribution coefficients. Using the geochemical speciation code PHREEQC, multidimensional smart Kd-matrices are computed as a function of varying (or uncertain) environmental conditions. On the one hand, sensitivity and uncertainty statements for the distribution coefficients can be derived. On the other hand, smart Kd-matrices can be used in reactive transport (or migration) codes (not shown here). This strategy has various benefits: (1) rapid computation of Kd-values for large numbers of environmental parameter combinations; (2) variable geochemistry is taken into account more realistically; (3) efficiency in computing time is ensured, and (4) uncertainty and sensitivity analysis are accessible. Results are presented exemplarily for the sorption of uranium(VI) onto a natural sandy aquifer material and are compared to results based on the conventional Kd-concept. In general, the sorption behavior of U(VI) in dependence of changing geochemical conditions is described quite well. PMID- 28854383 TI - The agricultural contaminant 17beta-trenbolone disrupts male-male competition in the guppy (Poecilia reticulata). AB - Despite a growing literature highlighting the potential impact of human-induced environmental change on mechanisms of sexual selection, relatively little is known about the effects of chemical pollutants on male-male competition. One class of environmental pollutant likely to impact male competitive interactions is the endocrine-disrupting chemicals (EDCs), a large and heterogeneous group of chemical contaminants with the potential to influence morphology, physiology and behaviour at minute concentrations. One EDC of increasing concern is the synthetic, androgenic steroid 17beta-trenbolone, which is used globally to promote growth in beef cattle. Although 17beta-trenbolone has been found to cause severe morphological and behavioural abnormalities in fish, its potential impact on male-male competition has yet to be investigated. To address this, we exposed wild male guppies (Poecilia reticulata) to an environmentally realistic concentration of 17beta-trenbolone (average measured concentration: 8 ng/L) for 21 days using a flow-through system. We found that, in the presence of a competitor, 17beta-trenbolone-exposed males carried out more frequent aggressive behaviours towards rival males than did unexposed males, as well as performing less courting behaviour and more sneak (i.e., coercive) mating attempts towards females. Considering that, by influencing mating outcomes, male-male competition has important consequences for population dynamics and broader evolutionary processes, this study highlights the need for greater understanding of the potential impact of EDCs on the mechanisms of sexual selection. PMID- 28854384 TI - Pb concentrations and isotopic record preserved in northwest Greenland snow. AB - We present high-resolution lead (Pb) concentrations and isotopic ratios from a northwest Greenland snow pit covering a six-year period between 2003 and 2009. Pb concentrations ranged widely from 2.7 pg g-1 to 97.3 pg g-1, with a mean concentration of 21.6 pg g-1. These values are higher than those recorded for the pre-industrial period. Pb concentrations exhibit seasonal spikes in winter-spring layers. Crustal Pb enrichment factors (EF) suggest that the northwest Greenland snow pit is highly enriched with Pb of predominantly anthropogenic origin. The 206Pb/207Pb ratios ranged from 1.144 to 1.169 with a mean value of 1.156, which fall between less radiogenic Eurasian-type and more radiogenic Canadian-type signatures. This result suggests that several potential source areas of Pb impact on northwest Greenland. Abrupt changes in Pb concentrations and Pb isotope ratios were observed and related to seasonal shifts in source regions of aerosol transport. The 206Pb/207Pb isotope ratio increased gradually between 2003 and 2009. The similarity of the three-isotope plot (206Pb/207Pb versus 208Pb/207Pb) between some of our samples and Chinese urban aerosols suggests a steadily increasing contribution of Chinese Pb to northwest Greenland snow. PMID- 28854385 TI - Performance evaluation of a smart buffer control at a wastewater treatment plant. AB - Real time control (RTC) is increasingly seen as a viable method to optimise the functioning of wastewater systems. Model exercises and case studies reported in literature claim a positive impact of RTC based on results without uncertainty analysis and flawed evaluation periods. This paper describes two integrated RTC strategies at the wastewater treatment plant (WWTP) Eindhoven, the Netherlands, that aim to improve the use of the available tanks at the WWTP and storage in the contributing catchments to reduce the impact on the receiving water. For the first time it is demonstrated that a significant improvement can be achieved through the application of RTC in practice. The Storm Tank Control is evaluated based on measurements and reduces the number of storm water settling tank discharges by 44% and the discharged volume by an estimated 33%, decreasing dissolved oxygen depletion in the river. The Primary Clarifier Control is evaluated based on model simulations. The maximum event NH4 concentration in the effluent reduced on average 19% for large events, while the load reduced 20%. For all 31 events the reductions are 11 and 4% respectively. Reductions are significant taking uncertainties into account, while using representative evaluation periods. PMID- 28854386 TI - First principles computational study on hydrolysis of hazardous chemicals phosphorus trichloride and oxychloride (PCl3 and POCl3) catalyzed by molecular water clusters. AB - Using first principles calculations we unveil fundamental mechanism of hydrolysis reactions of two hazardous chemicals PCl3 and POCl3 with explicit molecular water clusters nearby. It is found that the water molecules play a key role as a catalyst significantly lowing activation barrier of the hydrolysis via transferring its protons to reaction intermediates. Interestingly, torsional angle of the molecular complex at transition state is identified as a vital descriptor on the reaction rate. Analysis of charge distribution over the complex further reinforces the finding with atomic level correlation between the torsional angle and variation of the orbital hybridization state of phosphorus (P) in the complex. Electronic charge separation (or polarization) enhances thermodynamic stability of the activated complex and reduces the activation energy through hydrogen bonding network with water molecules nearby. Calculated potential energy surfaces (PES) for the hydrolysis of PCl3 and POCl3 depict their two contrastingly different profiles of double- and triple-depth wells, respectively. It is ascribed to the unique double-bonding O=P in the POCl3. Our results on the activation free energy show well agreements with previous experimental data within 7kcalmol-1 deviation. PMID- 28854387 TI - Biogeochemical controls on the speciation and aquatic toxicity of vanadium and other metals in sediments from a river reservoir. AB - Effects of hydrologic variability on reservoir biogeochemistry are relatively unknown, particularly for less studied metals like vanadium (V). Further, few studies have investigated the fate and effects of sediment-associated V to aquatic organisms in hydrologically variable systems. Our primary objective was to assess effects of hydrologic manipulation on speciation and toxicity of V (range: 635 to 1620mgkg-1) and other metals to Hyalella azteca and Daphnia magna. Sediments were collected from a reservoir located in a former mining area and microcosm experiments were conducted to emulate 7-day drying and inundation periods. Despite high sediment concentrations, V bioavailability remained low with no significant effects to organism survival, growth, or reproduction. The lack of V toxicity was attributed to reduced speciation (III, IV), non-labile complexation, and sorption to Al/Fe/Mn-oxyhydroxides. Zinc (Zn) increased in surface and porewater with inundation, for some sediments exceeding the U.S. EPA threshold for chronic toxicity. While no effects of Zn to organism survival or growth were observed, Zn body concentrations were negatively correlated with H. azteca growth. Results from this study indicate that V bioavailability and environmental risk is dependent on V-speciation, and V is less influenced by hydrologic variability than more labile metals such as Zn. PMID- 28854388 TI - Effect-based approach for screening of chemical mixtures in whole blood of green turtles from the Great Barrier Reef. AB - Organisms are exposed to mixtures of both known and unknown chemicals which are diverse and variable, and thus difficult and costly to characterise and monitor using traditional target analyses. The objective of this study was to validate and apply in vitro effect-based methods by which whole blood can be used to screen internal exposure to such complex chemical mixtures. For this study, we used whole blood of green sea turtles (Chelonia mydas). To ensure the chemical mixture in blood is transferred with minimal losses or bias, we tested a modified QuEChERS extraction method specifically developed for multi- and non-target instrument analysis. The extracts were dosed to a battery of in vitro bioassays (AhR-CAFLUX, AREc32, NFkappaB-bla, VM7Luc4E2, Microtox), each with a different mode of action (e.g., AhR receptor mediated xenobiotics, NrF2-mediated oxidative stress, NFkappaB mediated response to inflammation, estrogen activity and baseline toxicity oxidative stress, respectively) in order to cover a wide spectrum of chemicals. Results confirmed the absence of interferences of the blood extract with the responses of the different assays, thus indicating the methods' compatibility with effect-based screening approaches. To apply this approach, whole blood samples were collected from green turtles foraging in agricultural, urban and remote areas of the Australian Great Barrier Reef. The effect-based screening revealed significant differences in exposure, with higher induction of AhR-CAFLUX, AREc32 and Microtox assays in turtles from the agricultural foraging ground. Overall, these results corroborated with concurrent health, target and non-target analyses in the same animals performed as part of a larger program. This study provides evidence that the proposed effect-based approach is suitable for screening and evaluating internal exposure of organisms to chemical mixtures. The approach could be valuable for advancing understanding on multiple levels ranging from identification of priority chemicals in effect directed investigations to exploring relationships between exposure and disease, not only in sea turtles, but in any organism. PMID- 28854389 TI - Assessing on toxic potency of PM2.5-bound polycyclic aromatic hydrocarbons at a national atmospheric background site in North China. AB - A total of 76PM2.5 samples collected at Tuoji Island from November 2011 to January 2013 were used to analyze 15 congeners of polycyclic aromatic hydrocarbons (?15PAHs) and assess their toxic potency. The average ?15PAHs was 15.34+/-8.87ngm-3, ranging from 4.24 to 40.62ngm-3 over the sampling period. BkF, BbF, Phe and BaP were dominant PAH congeners, contributing together 60.64% of the ?15PAH concentration. The highest monthly ?15PAHs concentration was in January 2012, followed by the next January, which was closely four times greater than the lowest level occurred in July 2012. Wheat straw burning was responsible for the high PAH concentrations in June 2012. The averaged BaP toxicity equivalent (TEQ BaP) concentration was 2.70+/-1.88ngm-3 over the sampling period. BaP and DaA were the largest contributors, which contributed 58.5% and 14.7% of totals, respectively. The high TEQ-BaP and TEQ-BaP value per unit of ?15PAHs concentration (TEQ-BaP(U)) values occurred in the cold season and the low levels presented in the warm period. The heaviest monthly TEQ-BaP was 5.28+/-2.84ngm-3, which appeared in January 2012; the lowest value was 0.86+/-0.33ngm-3, which occurred in July 2012. The potential source contribution function (PSCF) showed the occurrence of the high health risk associated with PAHs in the middle of Liaoning and the south of Shandong Peninsula. PMID- 28854390 TI - Particle deposition in tracheobronchial airways of an infant, child and adult. AB - BACKGROUND: Particle deposition in human airways is important for assessing both health effects of inhaled particles and therapeutic efficacy of inhaled drug aerosols, but is not well understood for infants and children. OBJECTIVE: We investigate particle deposition in infants and children by using computational fluid dynamics (CFD), and compare this with particle deposition in adults. METHODS: We chose three population age groups: 7-month infant, 4-year old child, and 20-year old adult. Both airway structures and breathing conditions are considered to vary as a human grows from infancy to adulthood. We investigated deposition of micron-size particles (1-10MUm) in both the upper (G3-G6) and lower (G9-G12) tracheobronchial (TB) airways under sedentary conditions. RESULTS: We found that particle deposition in both upper and lower airways is the highest in an infant, next in a child, and lowest in an adult. As age increases, particle deposition decreases in the upper airways but increases in the lower. For infants, inertial impaction is the dominant deposition mechanism, thus particles are deposited more in the upper airways than in the lower. However, particles are deposited more in the lower airways than in the upper in adults, as gravitational sedimentation is the dominant deposition mechanism. CONCLUSION: Given the differences in the airway structure and particle deposition mechanisms, particle deposition in infants and children differs from that in adults, not only in the efficiency of deposition but also in the site. Our findings provide evidence that "children are not small adults". PMID- 28854391 TI - Monitoring tylosin and sulfamethazine in a tile-drained agricultural watershed using polar organic chemical integrative sampler (POCIS). AB - This study evaluated the influence of temporal variation on the occurrence, fate, and transport of tylosin (TYL) and sulfamethazine (SMZ); antibiotics commonly used in swine production. Atrazine (ATZ) was used as a reference analyte to indicate the agricultural origin of the antibiotics. We also assessed the impact of season and hydrology on antibiotic concentrations. A reconnaissance study of the South Fork watershed of the Iowa River (SFIR), was conducted from 2013 to 2015. Tile drain effluent and surface water were monitored using polar organic integrative sampler (POCIS) technology. Approximately 169 animal feeding operations (AFOs) exist in SFIR, with 153 of them being swine facilities. All analytes were detected, and detection frequencies ranged from 69 to 100% showing the persistence in the watershed. Antibiotics were detected at a higher frequency using POCIS compared to grab samples. We observed statistically significant seasonal trends for SMZ and ATZ concentrations during growing and harvest seasons. Time weighted average (TWA) concentrations quantified from the POCIS were 1.87ngL-1 (SMZ), 0.30ngL-1 (TYL), and 754.2ngL-1 (ATZ) in the watershed. SMZ and TYL concentrations were lower than the minimum inhibitory concentrations (MIC) for E. coli. All analytes were detected in tile drain effluent, confirming tile drainage as a pathway for antibiotic transport. Our results identify the episodic occurrence of antibiotics, and highlights the importance identifying seasonal fate and occurrence of these analytes. PMID- 28854392 TI - Transport of pharmaceuticals and their metabolites between water and sediments as a further potential exposure for aquatic organisms. AB - Although pharmaceuticals are frequently studied contaminants, their fate in the environment is still not completely clear. During a one year study, a complex approach including water, sediment and fish sampling was used to describe the behaviour of pharmaceuticals and their metabolites (PTMs) in the environment. Eighteen pharmaceuticals and seven of their metabolites were determined in a pond used for the tertiary treatment of wastewater effluent. A liquid chromatography tandem mass spectrometry method was applied to determine the PTMs concentrations in all matrices. Seasonal variations in concentrations were evaluated. The partitioning of contaminants between pond compartments was estimated by means of solid water distribution coefficients (Kd) and bioaccumulation factors (BAF) for the livers of fish. Kd values were almost stable throughout the year, which may be a sign of the continuous transport of PTMs between water and sediment under the experimental conditions. Almost all of the studied compounds, with exception of sertraline (BAF of 6200), were found to not be bioaccumulative in fish livers. The pond removal efficiency was calculated for all PTMs, and favourable conditions for natural pharmaceutical removal were proposed. Further aspects regarding fish pharmaceutical exposure need to be studied. PMID- 28854393 TI - Actinobacteria consortium as an efficient biotechnological tool for mixed polluted soil reclamation: Experimental factorial design for bioremediation process optimization. AB - The objective of the present work was to establish optimal biological and physicochemical parameters in order to remove simultaneously lindane and Cr(VI) at high and/or low pollutants concentrations from the soil by an actinobacteria consortium formed by Streptomyces sp. M7, MC1, A5, and Amycolatopsis tucumanensis AB0. Also, the final aim was to treat real soils contaminated with Cr(VI) and/or lindane from the Northwest of Argentina employing the optimal biological and physicochemical conditions. In this sense, after determining the optimal inoculum concentration (2gkg-1), an experimental design model with four factors (temperature, moisture, initial concentration of Cr(VI) and lindane) was employed for predicting the system behavior during bioremediation process. According to response optimizer, the optimal moisture level was 30% for all bioremediation processes. However, the optimal temperature was different for each situation: for low initial concentrations of both pollutants, the optimal temperature was 25 degrees C; for low initial concentrations of Cr(VI) and high initial concentrations of lindane, the optimal temperature was 30 degrees C; and for high initial concentrations of Cr(VI), the optimal temperature was 35 degrees C. In order to confirm the model adequacy and the validity of the optimization procedure, experiments were performed in six real contaminated soils samples. The defined actinobacteria consortium reduced the contaminants concentrations in five of the six samples, by working at laboratory scale and employing the optimal conditions obtained through the factorial design. PMID- 28854394 TI - A method for simulating the release of natural gas from the rupture of high pressure pipelines in any terrain. AB - The rupture of a high-pressure natural gas pipeline can pose a serious threat to human life and environment. In this research, a method has been proposed to simulate the release of natural gas from the rupture of high-pressure pipelines in any terrain. The process of gas releases from the rupture of a high-pressure pipeline is divided into three stages, namely the discharge, jet, and dispersion stages. Firstly, a discharge model is established to calculate the release rate of the orifice. Secondly, an improved jet model is proposed to obtain the parameters of the pseudo source. Thirdly, a fast-modeling method applicable to any terrain is introduced. Finally, based upon these three steps, a dispersion model, which can take any terrain into account, is established. Then, the dispersion scenarios of released gas in four different terrains are studied. Moreover, the effects of pipeline pressure, pipeline diameter, wind speed and concentration of hydrogen sulfide on the dispersion scenario in real terrain are systematically analyzed. The results provide significant guidance for risk assessment and contingency planning of a ruptured natural gas pipeline. PMID- 28854395 TI - Sentinel node biopsy in early breast cancer. A review on recent and ongoing randomized trials. AB - INTRODUCTION: Sentinel Lymph Node Biopsy (SLNB) is regarded as the standard procedure for nodal staging in patients with early breast cancer. In the last decade several randomized trials have been evaluating its role and indications. MATERIALS AND METHODS: This article reviews recent and ongoing randomized trials on SLNB. RESULTS: Four randomized controlled trials have recently shown evidence that SLNB either alone or followed by radiation therapy is effective for the management in patients with low axillary tumor burden in early breast cancer. Nine randomized controlled trials on SLNB are ongoing: four assessing its role in case of positive sentinel node, three evaluating whether SLNB itself can be omitted when the preoperative nodal imaging is negative, two are studying SLNB in the neoadjuvant setting. DISCUSSION AND CONCLUSION: SLNB either alone or with axillary radiotherapy has been shown to be non-inferior to complete axillary dissection in terms of local recurrence, disease-free survival and overall survival in early breast cancer with minimally metastatic axilla. So far, results from ongoing trials are going to confirm the appropriate treatment in patients with limited axillary nodal involvement, the role and the timing of SLNB within the neoadjuvant setting and to define whether surgery can be avoided in the axilla in early stage breast cancer patients with negative preoperative imaging. PMID- 28854396 TI - Effect of resistance training on headache symptoms in adults: Secondary analysis of a RCT. AB - BACKGROUND: While strength training for the neck and shoulder muscles may be effective in reducing headache, the optimal combination of exercise frequency and duration is unknown. This study investigates the effect of different time-wise combinations of one weekly hour of strength training for the neck and shoulder muscles on headache frequency, intensity, and use of analgesics. METHODS: A total of 573 office workers were randomly allocated at the cluster-level to five groups; 3 * 20 min a week of minimally supervised (3MS), 1 * 60 (1WS), 3 * 20 (3WS) or 9 * 7 (9WS) min a week of supervised high-intensity strength training for 20 weeks, or to a reference group without training (REF). Headache frequency, intensity, and use of analgesics in relation to headache were determined by questionnaire at baseline and follow-up. RESULTS: The intention-to-treat analysis showed reduced headache frequency and intensity of approximately 50% in all training groups compared with REF at 20-week follow-up (P < 0.001). Use of analgesics was lower in the supervised training groups (1WS, 3WS and 9WS), but not in the group with minimal training supervision (3MS), compared with REF at follow-up. CONCLUSION: One hour of specific strength training - regardless of the distribution during the week - effectively reduced both headache frequency and intensity in office workers. Thus, a large time-wise flexibility exists when implementing specific strength training at the workplace. However, only supervised training led to a reduction in use of analgesics for headache. PMID- 28854397 TI - Functions of ABC transporters in plant growth and development. AB - ABC transporters are essential for plant development, playing roles in processes such as gametogenesis, seed development, seed germination, organ formation, and secondary growth. ABC transporters are directly energized by ATP and can transport complex organic materials against concentration gradients; thus, they are uniquely suited to provide the complex building blocks required for the development of specialized plant cells. We review recent progress in our understanding of the contribution ABC transporters make to the growth and development of plants, including their roles in protective layer formation and in transporting phytohormones. PMID- 28854398 TI - Epigenetic discrimination of identical twins from blood under the forensic scenario. AB - Monozygotic (MZ) twins share the same STR profile, demonstrating a practical problem in forensic casework. DNA methylation has provided a suitable resource for MZ twin differentiation; however, studies addressing the forensic feasibility are lacking. Here, we investigated epigenetic MZ twin differentiation from blood under the forensic scenario comprising i) the discovery of candidate markers in reference-type blood DNA via genome-wide analysis, ii) the technical validation of candidate markers in reference-type blood DNA using a suitable targeted method, and iii) the analysis of the validated markers in trace-type DNA. Genome wide methylation analysis in blood DNA from 10 MZ twin pairs resulted in 19-111 twin-differentially methylated sites (tDMSs) per pair with >0.3 twin-to-twin differences. Considering all top three candidate tDMSs across all pairs in the technical validation based on methylation-specific qPCR, 67.85% generated >0.1 twin-to-twin differences. Of the validated tDMSs, 68.4% showed >0.1 twin-to-twin differences with qPCR in trace-type DNA across 8 pairs. Using an updated marker selection strategy, 8 additional candidate tDMSs were obtained for an example MZ pair, of which 7 showed >0.1 twin-to-twin differences in both reference- and trace-type DNA. Lastly, we introduce a high-resolution melting curve analysis of the entire fragment that can complement the proposed approach. Overall, our study demonstrates the general feasibility of epigenetic twin differentiation in the forensic context and highlights that the number of informative tDMSs in the final trace DNA analysis is crucial, as some candidate markers identified in reference DNA were shown not informative in the trace DNA due to various, including technical, reasons. Future studies will need to address the optimal number of epigenetic markers required for reliable identification of MZ twin individuals including statistical considerations. PMID- 28854399 TI - Detection and evaluation of DNA methylation markers found at SCGN and KLF14 loci to estimate human age. AB - Recent developments in the analysis of epigenetic DNA methylation patterns have demonstrated that certain genetic loci show a linear correlation with chronological age. It is the goal of this study to identify a new set of epigenetic methylation markers for the forensic estimation of human age. A total number of 27 CpG sites at three genetic loci, SCGN, DLX5 and KLF14, were examined to evaluate the correlation of their methylation status with age. These sites were evaluated using 72 blood samples and 91 saliva samples collected from volunteers with ages ranging from 5 to 73 years. DNA was bisulfite modified followed by PCR amplification and pyrosequencing to determine the level of DNA methylation at each CpG site. In this study, certain CpG sites in SCGN and KLF14 loci showed methylation levels that were correlated with chronological age, however, the tested CpG sites in DLX5 did not show a correlation with age. Using a 52-saliva sample training set, two age-predictor models were developed by means of a multivariate linear regression analysis for age prediction. The two models performed similarly with a single-locus model explaining 85% of the age variance at a mean absolute deviation of 5.8 years and a dual-locus model explaining 84% of the age variance with a mean absolute deviation of 6.2 years. In the validation set, the mean absolute deviation was measured to be 8.0 years and 7.1 years for the single- and dual-locus model, respectively. Another age predictor model was also developed using a 40-blood sample training set that accounted for 71% of the age variance. This model gave a mean absolute deviation of 6.6 years for the training set and 10.3years for the validation set. The results indicate that specific CpGs in SCGN and KLF14 can be used as potential epigenetic markers to estimate age using saliva and blood specimens. These epigenetic markers could provide important information in cases where the determination of a suspect's age is critical in developing investigative leads. PMID- 28854400 TI - Association between strained capacity and mortality among patients admitted to intensive care: A path-analysis modeling strategy. AB - PURPOSE: To evaluate the associations between strained ICU capacity and patient outcomes. METHODS: Multi-center population-based cohort study of nine integrated ICUs in Alberta, Canada. Path-analysis modeling was adopted to investigate direct and indirect associations between strain (available beds <=1; occupancy >=95%) and outcomes. Mixed-effects multivariate regression was used to measure the association between strain and acuity (APACHE II score), and both acuity and strain measures on ICU mortality and length of stay. RESULTS: 12,265 admissions comprise the study cohort. Available beds <=1 and occupancy >=95% occurred for 22.3% and 17.0% of admissions. Lower bed availability was associated with higher APACHE II score (p<0.0001). The direct effect of <=1 available beds at ICU admission on ICU mortality was 11.6% (OR 1.116; 95% CI, 0.995-1.252). Integrating direct and indirect effects resulted in a 16.5% increased risk of ICU mortality (OR 1.165; 95% CI, 1.036-1.310), which exceeded the direct effect by 4.9%. Findings were similar with strain defined as occupancy >=95%. Strain was associated with shorter ICU stay, primarily mediated by greater acuity. CONCLUSIONS: Strained capacity was associated with increased ICU mortality, partly mediated through greater illness acuity. Future work should consider both the direct and indirect relationships of strain on outcomes. PMID- 28854401 TI - Post-ICU psychological morbidity in very long ICU stay patients with ARDS and delirium. AB - PURPOSE: We investigated the impact of delirium on illness severity, psychological state, and memory in acute respiratory distress syndrome patients with very long ICU stay. MATERIALS AND METHODS: Prospective cohort study in the medical-surgical ICUs of 2 teaching hospitals. Very long ICU stay (>75days) and prolonged delirium (>=40days) thresholds were determined by ROC analysis. Subjects were >=18years, full-code, and provided informed consent. Illness severity was assessed using Acute Physiology and Chronic Health Evaluation IV, Simplified Acute Physiology Score-3, and Sequential Organ Failure Assessment scores. Psychological impact was assessed using the Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised, and the 14-question Post Traumatic Stress Syndrome (PTSS-14). Memory was assessed using the ICU Memory Tool survey. RESULTS: 181 subjects were included. Illness severity did not correlate with delirium duration. On logistic regression, only PTSS-14<49 correlated with delirium (p=0.001; 95% CI 1.011, 1.041). 49% remembered their ICU stay clearly. 47% had delusional memories, 50% reported intrusive memories, and 44% reported unexplained feelings of panic or apprehension. CONCLUSION: Delirium was associated with memory impairment and PTSS-14 scores suggestive of PTSD, but not illness severity. PMID- 28854402 TI - Evaluation of the absolute affinity of neuraminidase inhibitor using steered molecular dynamics simulations. AB - The absolute free energy difference of binding (DeltaG) between neuraminidase and its inhibitor was evaluated using fast pulling of ligand (FPL) method over steered molecular dynamics (SMD) simulations. The metric was computed through linear interaction approximation. Binding nature was described by free energy differences of electrostatic and van der Waals (vdW) interactions. The finding indicates that vdW metric is dominant over electrostatics in binding process. The computed values are in good agreement with experimental data with a correlation coefficient of R=0.82 and error of sigmaDeltaGexp=2.2kcal/mol. The results were observed using Amber99SB-ILDN force field in comparison with CHARMM27 and GROMOS96 43a1 force fields. Obtained results may stimulate the search for an Influenza therapy. PMID- 28854403 TI - An HPLC-MS/MS method for quantitation of Gly-MCA in mouse plasma: Application to a pharmacokinetic study. AB - A simple, sensitive and rapid method using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was developed and validated for quantification of glycine-beta-muricholic acid (Gly-MCA) in mouse plasma for the first time. Plasma samples were pretreated with protein precipitation. The analyte and internal standard were separated on a Shimadzu Shim-pack XR-ODS column (4.6*50mm, 2.2MUm) using 0.1% formic acid-water-methanol as mobile phase, with a runtime of 5min. Detection was performed using negative ion electrospray tandem mass spectrometry via multiple reaction monitoring (MRM) scan mode. The linear range was 5ng-2MUg/ml (correlation coefficient >0.995) for Gly-MCA with a lower limit of quantitation of 5ng/ml. The intra-day and inter-day precision were less than 9.2% for the analyte and accuracy was from 0.4% to 7.0%. This analytical method was then successfully applied to a pharmacokinetic study of Gly MCA following oral administration and intraperitoneal injection in mice. PMID- 28854404 TI - Separation and characterization of chemical constituents in Ginkgo biloba extract by off-line hydrophilic interaction*reversed-phase two-dimensional liquid chromatography coupled with quadrupole-time of flight mass spectrometry. AB - Ginkgo biloba extract (GBE), derived from the leaves of Ginkgo biloba L., is one of the most widely used traditional Chinese medicines worldwide. Due to high structural diversity and low abundance of chemical constituents in GBE, conventional reversed-phase liquid chromatography has limited power to meet the needs of its quality control. In this study, an off-line hydrophilic interaction*reversed-phase two-dimensional liquid chromatography (HILIC*RP 2D-LC) system coupled with diode array detection (DAD) and quadrupole time-of-flight mass spectrometry (qTOF-MS) was established to comprehensively analyze the chemical constituents of GBE. After optimizing the chromatographic columns and mobile phase of 2D-LC, a Waters XBridge Amide column using acetonitrile/water/formic acid as the mobile phase was selected as the first dimension to fractionate GBE, and the obtained fractions were further separated on an Agilent Zorbax XDB-C18 column with methanol/water/formic acid as the mobile phase. As a result, a total of 125 compounds were detected in GBE. The orthogonality of the 2D-LC system was 69.5%, and the practical peak capacity was 3864 and 2994, respectively, calculated by two different methods. The structures of 104 compounds were tentatively characterized by qTOF-MS analysis, and 21 of them were further confirmed by comparing with reference standards. This established HILIC*RP 2D-LC-qTOF/MS system can greatly improve the separation and characterization of natural products in GBE or other complicated herbal extracts. PMID- 28854405 TI - Newer antiepileptic drugs compared to levetiracetam as adjunctive treatments for uncontrolled focal epilepsy: An indirect comparison. AB - PURPOSE: Newer antiepileptic drugs (AEDs), such as Eslicarbazepine (ESL), Lacosamide (LAC), Perampanel (PER) and Brivaracetam (BRV), have been marketed as adjunctive treatments for partial-onset seizures. Our aim was to compare the efficacy and tolerability of newer AEDs with Levetiracetam (LEV), when used as add-on treatments for uncontrolled focal epilepsy. METHOD: We conducted an online database search on PubMed, Embase, Cochrane Online Library and Clinicaltrials.gov for all available randomized controlled trials (RCTs) investigating the therapeutic effects of newer AEDs or LEV vs placebo. Indirect comparisons for clinical efficacy and tolerability at different doses between the newer AEDs and LEV were then performed using Indirect Treatment Comparison (ITC) software. RESULTS: Twenty-four RCTs with a total of 8540 patients were included. Compared to LEV, ESL, LAC and BRV did not showed significant difference in efficacy at all dose level. PER showed lower 50% response rates and seizure-free rates at the highest effective recommended dosages. Treatment-emergent adverse events (TEAEs) and withdrawal rates due to adverse events (AEs) of LAC and PER were higher than LEV at the highest effective recommended dosages, and overall AE rates from ESL were higher than LEV. CONCLUSIONS: Indirect comparisons suggested that ESL, LAC and BRV were not inferior to LEV in efficacy. ESL, LAC and PER may have a possible worse tolerability profile compared to LEV at high dose. But BRV may exhibit a similar tolerability to LEV. Newer AEDs cannot exceed the LEV on efficacy and tolerability. PMID- 28854406 TI - Laparoscopic extraction of a giant peritoneal loose body: Case report and review of literature. AB - INTRODUCTION: A peritoneal loose body is a rare finding and is sometimes founded incidentally during laparotomy or autopsy. A giant peritoneal loose body, measuring more than 50mm, is very rare, and only a few cases of laparoscopic extraction of these giant bodies have been reported in the literature. PRESENTATION OF CASE: A 70-year-old man presented for evaluation of urinary frequency. He had no history of previous abdominal surgery or trauma. Computed tomography of the abdomen and pelvis showed a giant oval-shaped mass with calcification of the luminal core, measuring 58mm in diameter. Magnetic resonance imaging revealed a lesion with low intensity in T1-/T2-weighted images. Exploratory laparoscopy was performed. During the procedure, a yellow-white, oval shaped mass with a "Boiled egg" appearance was discovered in front of the rectum. The mass was freely floating in the peritoneal cavity, without attachment to any intraperitoneal organs. The giant peritoneal loose body was extracted through a small incision, using an enlarged trocar site. DISCUSSION: Most peritoneal loose bodies are small, not exceeding 2cm in diameter, and are asymptomatic. Only a few cases of giant peritoneal loose bodies exceeding 5cm have been reported. CONCLUSION: A giant peritoneal loose body is very rare and laparoscopic extraction was a useful technique. We report a case of a giant peritoneal loose body and review previously published series. PMID- 28854407 TI - A large benign phyllodes tumour of the breast: A case report and literature review. AB - INTRODUCTION: Phyllodes tumours are uncommon fibroepithelial lesions that typically grow up to 4cm in size but 10cm tumours known as giant phyllodes tumours have been described. We present a case report of a 20cm benign phyllodes tumour and a literature review. PRESENTATION OF CASE: A 54 years old lady with an enlarging left breast mass measuring 20cm of 6 months duration presented to our outpatient breast clinic. She also had an incidental right parotid lump. Core biopsy of the left breast mass returned as a cellular fibroepithelial lesion. A mastectomy and axillary lymph node sampling were done and skin cover was obtained from a split skin graft from the thigh. Final histology returned as a benign phyllodes tumour. Her post-operative recovery was uneventful. DISCUSSION: Phyllodes tumours are suspected in middle age women with rapidly enlarging painless breast masses. Though there are some suggestive features on ultrasound and MRI, the key to diagnosis is still histopathology. However, a pre-operative diagnosis may not always be possible as the interpretation of stromal cellularity and degree of atypia needed to differentiate cellular fibroadenoma from a phyllodes tumour is subjective. When a phyllodes tumour is suspected, adequate margins should be taken for optimal outcome. CONCLUSION: Successful management of phyllodes tumour involves obtaining a pre-operative diagnosis via a core biopsy when possible and planning for adequate margins. PMID- 28854408 TI - Wound dehiscence after total knee arthroplasty. AB - INTRODUCTION: Wound dehiscence is one of the most common complications of surgical ulcer, involving the breaking open of the surgical incision along the stitch. This condition is a severe complication of total knee arthroplasty. PRESENTATION OF CASE: We report a case of a 59-year-old female patient with diabetes who underwent a total knee arthroplasty in which all layers of wounds were dehiscence and prosthetic was exposed. DISCUSSION: Wound dehiscence is a complication after total knee arthroplasty especially in diabetic patient. So, patients with diabetes more susceptible to development of wound dehiscence following total knee arthroplasty and should be followed particularly postoperatively care. CONCLUSION: Postoperative care after knee replacement should be more considered in diabetic patients. Finally the patient was successfully treated with irrigation and debridement (I&D) and polyethylene insert exchange. PMID- 28854409 TI - Spontaneous regression of anterior mediastinal seminoma with normalization of beta-human chorionic gonadotropin levels. AB - INTRODUCTION: Although spontaneous regression (SR) of anterior mediastinal seminoma is very rare with normalization of beta-human chorionic gonadotropin (beta-hCG) level, video-assisted thoracic surgery (VATS) is the most effective solution for definite diagnosis of indeterminate anterior mediastinal masses. DIAGNOSIS, THERAPEUTIC INTERVENTIONS, AND OUTCOMES: A rare case of an asymptomatic 37-year-old man with an anterior mediastinal mass that was detected on a routine chest X-ray is presented. Computed tomography (CT) showed a large anterior mediastinal tumor with superior vena cava invasion and SR before VATS for definitive diagnosis. On pathology, the definitive diagnosis was seminoma. Microscopic examination showed abundant apoptotic cells within the tumor. Chemotherapy (bleomycin 30mg/day, etoposide 200mg/day, cisplatin 40mg/day) was given to this patient, and the tumor showed high sensitivity. CONCLUSION: Anterior mediastinal seminoma showing SR induced by spontaneous apoptosis of tumor cells may have good sensitivity to chemotherapy, and a good clinical outcome may be achieved in these patients. This case also highlights that VATS is the most effective solution for definite diagnosis of indeterminate anterior mediastinal masses. PMID- 28854410 TI - Mixed adenoneuroendocrine carcinoma of the distal bile duct: A case report. AB - INTRODUCTION: Mixed adenoneuroendocrine carcinomas (MANECs) of the distal bile duct are extremely rare, and only a few cases have been reported in the English literature. PRESENTATION OF CASE: An 82-year-old man was referred to our hospital for increasing biliary enzymes. Abdominal computed tomography (CT) showed enlargement of the intrahepatic bile ducts and stenosis of the distal bile duct. Endoscopic retrograde cholangiopancreatography showed stenosis of the distal bile duct and a high-density signal at the same site on diffusion weighted imaging. PET-CT showed increased FDG accumulation (SUVmax: 4.5) at the distal bile duct stenosis. Biopsy specimens obtained by endoscopic ultrasonography-guided fine needle aspiration revealed adenocarcinoma. The patient was diagnosed with adenocarcinoma of the distal bile duct and underwent subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection. The resected distal bile duct tumor was 18*14*12mm in diameter. Hematoxylin and eosin staining revealed a composite carcinoma with adenocarcinoma and non-adenocarcinoma elements. The non-adenocarcinoma component stained positive for synaptophysin and chromogranin A. The Ki-67 labeling index was 37%. The non-adenocarcinoma component was therefore diagnosed as a neuroendocrine carcinoma. The two composite carcinoma was diagnosed as MANEC of the distal bile duct. The patient was treated with surgery alone and he remained disease-free for 7 months after the surgery. DISCUSSION: The treatment of MANECs of the bile duct remains controversial and the prognosis is poor. CONCLUSIONS: There is no standard treatment for MANECs of the bile duct. Larger studies are required to establish standard treatment regimens. PMID- 28854411 TI - An isolated intestinal duplication cyst masquerading as a mucinous cystic neoplasm of the pancreas: A case report and review of the literature. AB - INTRODUCTION: Enteric duplication cysts presenting in adulthood are rare. Isolated enteric duplication cysts, which lack a connection to the GI tract or the adjacent mesenteric vasculature, have only been cited in six previous case reports. CASE PRESENTATION: A 48-year-old female presented with a four-year history of intermittent nausea, vomiting and abdominal pain. Computed tomography (CT) scan of the abdomen revealed a 7cm multi-lobular, calcified, cystic lesion intimately involved with the pancreas. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) was non-diagnostic; however, the cyst fluid Carcinoembryonic Antigen (CEA) level was significantly elevated leading to a presumed diagnosis of a mucinous cystic neoplasm (MCN) of the pancreas. Intraoperatively, the cystic mass was identified and notably did not have any true attachments to the neighboring pancreas, gastrointestinal tract or vasculature. Final pathology demonstrated an isolated small bowel duplication cyst. DISCUSSION: In this case a patient presented with a clinical picture consistent with an MCN of the pancreas. However, intraoperatively and on final pathology the mass was found to be an isolated enteric duplication cyst. This represents only the seventh such case report in an adult. CONCLUSION: Although rare, isolated enteric duplication cysts can be considered in a patient presenting with chronic abdominal pain and an abdominal mass on imaging. In this case we demonstrate that an isolated enteric duplication cyst can clinically mimic an MCN of the pancreas. PMID- 28854412 TI - Wide-spread cone-shaped epiphyses in two Saudi siblings with Ellis-van Creveld syndrome. AB - INTRODUCTION: Ellis-van Creveld (EVC) syndrome is one of the rarest ciliopathy syndromes. It is caused by mutations of the EVC and EVC2 genes which encode the EVC proteins present in the basal body of the primary cilium. PRESENTATION OF CASES: We report on a Saudi family with two affected children. Gene analysis revealed a homozygous c.2T >A in exon 1 of the EVC gene. The most interesting finding in our patients was the wide - spread cone-shaped epiphyses in the hands and feet. DISCUSSION: Although cone-shaped epiphyses is a known feature of EVC syndrome, it usually limited to the middle or proximal phalanges. The wide-spread cone-shaped epiphyses seen in our patients have not been previously reported. CONCLUSION: EVC syndrome is very rare in the Middle East. We report on the first Saudi family with EVC syndrome confirmed by gene analysis. The most unique finding in our patients was the wide-spread cone-shaped epiphyses in the hands and feet. The abnormality is probably related to abnormal Indian hedgehog signaling in the primary cilium. PMID- 28854413 TI - Fattigation-platform nanoparticles using apo-transferrin stearic acid as a core for receptor-oriented cancer targeting. AB - A major hurdle in cancer treatment is the precise targeting of drugs to the cancer site. As many cancer cells overexpress the transferrin receptor (TfR), the transferrin (Tf)-TfR interaction is widely exploited to target cancer cells. In this study, novel amphiphilic apo-Tf stearic acid (TfS) conjugates were prepared and characterized by Fourier transform infrared (FTIR) spectroscopy, matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, and trinitrobenzenesulfonic acid (TNBS) assay. The prepared TfS conjugates were readily self-assembled in water to form nanoparticles (NPs), consisting of TfS as a core of NPs, whose sizes and zeta potentials were determined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and a particle size analyzer. Hydrophilic water-soluble doxorubicin (DOX) was chosen as a model drug. DOX-loaded TfS NPs (NP+DOX), prepared by the adsorption of DOX on the NP surface via the incubation method, were analyzed for their cell targeting and killing efficiencies in TfR overexpressing A549 and HCT116 cell lines by MTT assay, confocal microscopy, and fluorescence assisted cell sorting (flow cytometry). The data showed that NP+DOX exhibited improved cancer cell targeting and killing properties compared to that reported for free DOX. Further, the cytotoxic efficiency of NP+DOX was comparable to that of PEGylated liposomal product, Doxil(r), while its cellular uptake was higher than that of Doxil(r). Thus, this novel receptor-based TfS NP drug delivery system has great potential to target TfR-overexpressing cancer cells without off-target effects. PMID- 28854414 TI - Chitosan-modified cholesterol-free liposomes for improving the oral bioavailability of progesterone. AB - Based on the structurally similar properties of progesterone and cholesterol, chitosan-coated cholesterol-free liposomes (CS-Lipo/Prog) were formulated. CS Lipo/Prog are spherical and uniform in size (662.1+/-19.3nm) with positive potential (28.19+/-1.97mV). The average drug entrapment efficiency (EE) is approximately 80%. The in vitro release profile of CS-Lipo/Prog shows sustained release. The in vitro stability evaluation demonstrated that CS-Lipo/Prog can efficiently shield Prog from degradation in the gastrointestinal tract. CS Lipo/Prog showed a longer MRT and higher AUC0-infinite after oral administration to mice than in the control group (progesterone-free). The relative bioavailability of CS-Lipo/Prog was higher than that of progesterone soft capsules (QINING(r)) and Lipo/Prog. Collectively, these findings suggest that cholesterol-free chitosan-coated liposomes are a promising alternative for improving the oral bioavailability of progesterone. PMID- 28854416 TI - New Advanced Biomaterials for Tissue and Organ Regeneration/Repair. PMID- 28854415 TI - Dual delivery nanosystem for biomolecules. Formulation, characterization, and in vitro release. AB - Because of the biocompatible and biodegradable properties of poly (lactic-co glycolic acid) (PLGA), nanoparticles (NPs) based on this polymer have been widely studied for drug/biomolecule delivery and long-term sustained-release. In this work, two different formulation methods for lysozyme-loaded PLGA NPs have been developed and optimized based on the double-emulsion (water/oil/water, W/O/W) solvent evaporation technique. They differ mainly in the phase in which the surfactant (Pluronic(r) F68) is added: water (W-F68) and oil (O-F68). The colloidal properties of these systems (morphology by SEM and STEM, hydrodynamic size by DLS and NTA, electrophoretic mobility, temporal stability in different media, protein encapsulation, release, and bioactivity) have been analyzed. The interaction surfactant-protein depending on the formulation procedure has been characterized by surface tension and dilatational rheology. Finally, cellular uptake by human mesenchymal stromal cells and cytotoxicity for both systems have been analyzed. Spherical hard NPs are made by the two methods However, in one case, they are monodisperse with diameters of around 120nm (O-F68), and in the other case, a polydisperse system of NPs with diameters between 100 and 500nm is found (W-F68). Protein encapsulation efficiency, release and bioactivity are maintained better by the W-F68 formulation method. This multimodal system is found to be a promising "dual delivery" system for encapsulating hydrophilic proteins with strong biological activity at the cell-surface and cytoplasmic levels. PMID- 28854417 TI - Effects of Blue Light Emitting Diode Irradiation On the Proliferation, Apoptosis and Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells. AB - BACKGROUND/AIMS: Blue light emitting diodes (LEDs) have been proven to affect the growth of several types of cells. The effects of blue LEDs have not been tested on bone marrow-derived mesenchymal stem cells (BMSCs), which are important for cell-based therapy in various medical fields. Therefore, the aim of this study was to determine the effects of blue LED on the proliferation, apoptosis and osteogenic differentiation of BMSCs. METHODS: BMSCs were irradiated with a blue LED light at 470 nm for 1 min, 5 min, 10 min, 30 min and 60 min or not irradiated. Cell proliferation was measured by performing cell counting and EdU staining assays. Cell apoptosis was detected by TUNEL staining. Osteogenic differentiation was evaluated by ALP and ARS staining. DCFH-DA staining and gamma H2A.X immunostaining were used to measure intracellular levels of ROS production and DNA damage. RESULTS: Both cell counting and EdU staining assays showed that cell proliferation of BMSCs was significantly reduced upon blue LED irradiation. Furthermore, treatment of BMSCs with LED irradiation was followed by a remarkable increase in apoptosis, indicating that blue LED light induced toxic effects on BMSCs. Likewise, BMSC osteogenic differentiation was inhibited after exposure to blue LED irradiation. Further, blue LED irradiation was followed by the accumulation of ROS production and DNA damage. CONCLUSIONS: Taken together, our study demonstrated that blue LED light inhibited cell proliferation, inhibited osteogenic differentiation, and induced apoptosis in BMSCs, which are associated with increased ROS production and DNA damage. These findings may provide important insights for the application of LEDs in future BMSC-based therapies. PMID- 28854418 TI - A Comparative Proteomic Analysis of Erinacine A's Inhibition of Gastric Cancer Cell Viability and Invasiveness. AB - : Background / Aims: Erinacine A, isolated from the ethanol extract of the Hericium erinaceus mycelium, has been demonstrated as a new alternative anticancer medicine. Drawing upon current research, this study presents an investigation of the molecular mechanism of erinacine A inhibition associated with gastric cancer cell growth. METHODS: Cell viability was determined by Annexin V-FITC/propidium iodide staining and migration using a Boyden chamber assay to determine the effects of erinacine A treatment on the proliferation capacity and invasiveness of gastric cancer cells. A proteomic assay provided information that was used to identify the differentially-expressed proteins following erinacine A treatment, as well as the mechanism of its targets in the apoptotic induction of erinacine A. RESULTS: Our results demonstrate that erinacine A treatment of TSGH 9201 cells increased cytotoxicity and the generation of reactive oxygen species (ROS), as well as decreased the invasiveness. Treatment of TSGH 9201 cells with erinacine A resulted in the activation of caspases and the expression of TRAIL. Erinacine A induction of apoptosis was accompanied by sustained phosphorylation of FAK/AKT/p70S6K and the PAK1 pathways, as well as the generation of ROS. Furthermore, the induction of apoptosis and anti-invasion properties by erinacine A could involve the differential expression of the 14-3-3 sigma protein (1433S) and microtubule associated tumor suppressor candidate 2 (MTUS2), with the activation of the FAK/AKT/p70S6K and PAK1 signaling pathways. CONCLUSIONS: These results lead us to speculate that erinacine A may generate an apoptotic cascade in TSGH 9201 cells by activating the FAK/AKT/p70S6K/PAK1 pathway and upregulating proteins 1433S and MTUS2, providing a new mechanism underlying the anti-cancer effects of erinacine A in human gastric cancer cells. PMID- 28854419 TI - Non-Genomic Action of Androgens is Mediated by Rapid Phosphorylation and Regulation of Androgen Receptor Trafficking. AB - BACKGROUND: Testosterone is critical for maintaining spermatogenesis and male fertility. The accomplishment of these processes requires the synergistic actions of the classical and non-classical signaling pathways of androgens. METHODS: A murine testicular Sertoli cell line, TM4 cell was used to examine androgen actions in Sertoli cells. Western blot analysis and immunofluorescence assay were employed to study the testosterone-induced Androgen receptor (AR) translocation. Protein phosphorylation antibody array was applied to identify the phosphorylation sites under testosterone treatment, and these findings were verified by Western blot analysis. RESULTS: We found that a physiological dose of testosterone induced fast membrane association of AR. By using a phosphorylation antibody array, several phosphorylation sites, such as MEK1/2 (Ser217/221), Akt (Ser473), and Erk1/2 (Thr202/Tyr204) were rapidly phosphorylated within 5 min of testosterone treatment. Inhibition of the MEK and Akt signaling pathways prevented AR trafficking. Blocking of AR by flutamide eliminated the stimulation effect of testosterone on kinase phosphorylation. Testosterone induced kinase Src phosphorylation, and inhibition of Src restricted AR translocation to the membrane and the nucleus. CONCLUSION: Findings suggested that the membrane association of AR was mediated by the MEK and Akt phosphorylation signaling pathways, which resulted in Src activation and was initiated by testosterone binding to the membrane-localized AR. This study provides new insights into the testosterone signaling pathway in Sertoli cells, which mediate spermatogenesis. In addition, the study can be used in the diagnosis and treatment of male infertility caused by disorders in spermatogenesis. PMID- 28854420 TI - Tetrahydroxystilbene Glycoside Improves Microvascular Endothelial Dysfunction and Ameliorates Obesity-Associated Hypertension in Obese ZDF Rats Via Inhibition of Endothelial Autophagy. AB - AIMS: Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension. METHODS: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP-RFP-LC3. RESULTS: Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins. CONCLUSION: Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy. PMID- 28854422 TI - Effects of the Long Non-Coding RNA HOST2 On the Proliferation, Migration, Invasion and Apoptosis of Human Osteosarcoma Cells. AB - BACKGROUND/AIMS: This study aimed to explore the effects of the long non-coding RNA HOST2 (lnc-HOST2) on the proliferation, migration, invasion and apoptosis of osteosarcoma cells. METHODS: Osteosarcoma tissues and adjacent normal tissues from 52 patients were selected. Human osteosarcoma cell lines (SaOS2, HOS, U2OS and MG-63) were collected and cultured; MG-63 cells had the highest lnc-HOST2 expression and thus were used in subsequent experiments. Then, MG-63 cells were transfected and divided into the blank (no transfection), si-CON (transfected with negative control siRNA) and si-lnc-HOST2 (transfected with small interference lnc-HOST2 siRNA) groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of lnc-HOST2 in primary tissues and cells. Cell growth was detected using the CCK-8 and colony formation assays. Cell doubling time was detected. Cell migration and invasion were observed using the scratch test and Transwell assays. Cell apoptosis and cell cycle progression of osteosarcoma cells were detected using flow cytometry with annexin V/PI double staining and PI staining, respectively. RESULTS: The level of lnc-HOST2 expression in the si-lnc-HOST2 group was significantly decreased compared to that in the blank and si-CON groups. The OD values in the si-lnc HOST2 group were significantly lower than those in the blank and si-CON groups. Compared to the blank and si-CON groups, the si-lnc-HOST2 group presented significant decreases in the colony number and healing rates after scratching. The number of invasive cells in the si-lnc-HOST2 group was significantly less than that in the blank and si-CON groups. In the si-lnc-HOST2 group, the cell cycle was mainly halted in the G1 phase, and the apoptosis rate and doubling time in this group were significantly higher than those in the blank group and si-CON group. CONCLUSIONS: Inhibition of lnc-HOST2 could suppress the proliferation, migration, and invasion and promote the apoptosis of osteosarcoma cells. PMID- 28854421 TI - Long Noncoding RNA FAL1 Promotes Cell Proliferation, Invasion and Epithelial Mesenchymal Transition Through the PTEN/AKT Signaling Axis in Non-Small Cell Lung Cancer. AB - BACKGROUND/AIMS: Recently, long non-coding RNAs (lncRNAs) have been found to have many biological effects in different cancer stages. Several studies have revealed that focally amplified lncRNA on chromosome 1 (FAL1) regulates cancer progression via p21. However, the expression and mechanism of FAL1 in non-small cell lung cancer (NSCLC) still remain unclear. METHODS: We detected the FAL1 level in NSCLC tissues and in established cell lines using quantitative real-time PCR and evaluated the clinical significance. FAL1 was silenced or overexpressed using siRNA or lentivirus to study whether FAL1 affected cell proliferation, invasion and migration. Xenograft growth and pulmonary metastasis were observed using nude mouse models. The mechanisms were explored with western blotting and immunohistochemistry. RESULTS: FAL1 was significantly overexpressed in NSCLC compared with adjacent normal tissues, and a high level of FAL1 correlated with poor histological grade, increased lymph node metastasis and advanced TNM stage. Loss- and gain-of-function experiments in vitro verified that knockdown of FAL1 inhibited cell proliferation, invasion, migration and EMT via the PTEN/AKT pathway. Furthermore, an in vivo assay confirmed that overexpression of FAL1 facilitated tumor growth and metastasis. CONCLUSION: FAL1 may promote tumorigenesis and progression of NSCLC through the PTEN/AKT axis, which could lead to lncRNA-related diagnostics and therapeutics in NSCLC. PMID- 28854423 TI - Nonampullary Duodenal Adenomas Rarely Recur after Complete Endoscopic Resection: A Swiss Experience Including a Literature Review. AB - INTRODUCTION: Duodenal polyps and especially duodenal adenomas are a rare and mostly coincidental finding in patients undergoing upper gastrointestinal endoscopy. Due to their malignant potential, duodenal adenomas should be removed upon diagnosis. So far, the limited available data on the performance of endoscopic polypectomy show conflicting results with regard to adverse events and the adenoma recurrence rate. PATIENTS AND METHODS: After summarizing the currently available data, we retrospectively analyzed all patients undergoing endoscopic resection of nonampullary duodenal adenomas (NAD) at our institution between 2006 and 2016. RESULTS: A total of 78 patients underwent endoscopic polypectomy for NAD adenoma. End-of-treatment success with complete resection requiring a mean of 1.2 interventions was achieved in 91% (n = 71). Procedural hemorrhage occurred in 12.8% (n = 10), whereas delayed bleeding was noted in 9% (n = 7). Duodenal perforation was registered and successfully treated in 2 cases (2.6%). No adenoma recurrence was noted following primary complete adenoma resection after a mean follow-up time of 33 months. Acute post-polypectomy bleeding was statistically significantly associated with large polyp size (p = 0.003) and lack of endoscopic prophylaxis (p = 0.0008). Delayed post-polypectomy bleeding showed a trend in the occurrence of large polyps (p = 0.064), and was statistically significantly associated with familial cancer syndrome (p = 0.019) and advanced histopathology (p = 0.013). CONCLUSION: Our data suggest that endoscopic polypectomy of NAD is well feasible with high success rates. Procedural and delayed hemorrhage seems to be the primary issue rather than adenoma recurrence. We therefore advocate referral of patients with large NAD to experienced centers for endoscopic resection. PMID- 28854424 TI - Poly (Ethylene Glycol)-Block-Brush Poly (L-Lysine) Copolymer as an Efficient Nanocarrier for Human Hepatocyte Growth Factor with Enhanced Bioavailability and Anti-Ischemia Reperfusion Injury Efficacy. AB - BACKGROUND/AIMS: The aim of this study was to assess the effect of human hepatocyte growth factor (hHGF)-loaded poly (ethylene glycol)-b-brush poly (l lysine) (PEG-b-P(ELG-g-PLL)) copolymer on ischemia/reperfusion (I/R) injury to different organs. METHODS: The isoelectric point (pI) of hHGF is 5.5, and hHGF combined with PEG-b-P(ELG-g-PLL) copolymer via electrostatic interactions at pH 7.4. The synthesized PEG-b-P(ELG-g-PLL) copolymer was analyzed using 1H nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). The hHGF/PEG b-P(ELG-g-PLL) complex was evaluated using a nanoparticle size instrument and transmission electron microscopy (TEM). In addition, vivo performance of hHGF/PEG b-P(ELG-g-PLL) complex was evaluated using plasma hHGF concentration and different organs ischemia reperfusion injury in rats. RESULTS: An in vitro investigation showed that PEG-b-P(ELG-g-PLL) could serve as a potential hHGF nanocarrier with efficient encapsulation and sustained release. An additional in vivo investigation revealed that the hHGF/PEG-b-P(ELG-g-PLL) complex could prolong increases in plasma hHGF concentration and protect different organs (the brain, heart and kidney) against I/R injury. CONCLUSION: Poly (ethylene glycol) block-brush poly (l-lysine) copolymer as an efficient nanocarrier for human hepatocyte growth factor with enhanced bioavailability and anti-ischemia reperfusion injury efficacy. PMID- 28854425 TI - Hydrogen Sulfide-Preconditioning of Human Endothelial Progenitor Cells Transplantation Improves Re-Endothelialization in Nude Mice with Carotid Artery Injury. AB - BACKGROUND/AIMS: The aim of present study was to test the hypothesis that preconditioning with sodium hydrosulfide (NaHS) could enhance the capacity of migration, adhesion and proliferation of endothelial progenitor cells (EPCs) in vitro, and also could improve the efficacy of EPCs transplantation for re endothelialization in nude mice with carotid artery injury. The paper further addressed the underlying mechanisms. METHODS: EPCs were isolated from peripheral blood mononuclear cells of healthy male volunteers and the markers of EPCs were analyzed by flow cytometry. Thereafter, different concentrations of NaHS (25, 50, 100, 200 and 500 uM) were used for preconditioning EPCs. In vitro and in vivo migration, adhesion and proliferation as well as nitric oxide (NO) production of EPCs were evaluated. Carotid artery injury model was produced in nude mice and thereafter, NaHS-preconditioned EPCs were transplanted in order to evaluate their capacity of re-endothelialization. RESULTS: Cellular immuno-staining showed that isolated cells expressed the key markers of EPCs. In vitro, EPCs proliferation rates and NO production were gradually increased in a NaHS-concentration dependent manner, while these benefits were blocked at a concentration of 500 uM NaHS. Similarly, the migration and adhesion rates of EPCs were also increased the most prominently at a concentration of 200 uM NaHS. In vivo, compared to the control group, treatment with NaHS-preconditioned EPCs significantly enhanced the capacity of re-endothelialization of EPCs. Fluorescent microscope revealed that there were more EPCs homing to the injury vessels in the NaHS-preconditioned EPCs group than the non-preconditioned group. With the administration of AMPK or eNOS inhibitors respectively, the above benefits of NaHS-preconditioning were abrogated. CONCLUSION: These results suggested that NaHS-preconditioning enhanced the biological function and re-endothelialization of EPCs through the AMPK/eNOS signaling pathway. PMID- 28854426 TI - Autophagy Inhibition Contributes to ROS-Producing NLRP3-Dependent Inflammasome Activation and Cytokine Secretion in High Glucose-Induced Macrophages. AB - BACKGROUND: Type 2 diabetes is a persistent inflammatory response that impairs the healing process. We hypothesized that stimulation with high glucose following a pro-inflammatory signal would lead to autophagy inhibition, reactive oxygen species (ROS) production and eventually to the activation of the Nod-like receptor protein (NLRP) -3. METHODS: Macrophages were isolated from human diabetic wound. We measured the expression of NLRP3, caspase1 and interleukin-1 beta (IL-1beta) by western blot and real-time PCR, and the surface markers on cells by flow cytometry. THP-1-derived macrophages exposed to high glucose were applied to study the link between autophagy, ROS and NLRP3 activation. LC3-II, P62, NLRP3 inflammation and IL-1beta expression were measured by western blot and real-time PCR. ROS production was measured with a Cellular Reactive Oxygen Species Detection Assay Kit. RESULTS: Macrophages isolated from diabetic wounds exhibited a pro-inflammatory phenotype, including sustained NLRP3 inflammasome activity associated with IL-1beta secretion. Our data showed that high glucose inhibited autophagy, induced ROS production, and activated NLRP3 inflammasome and cytokine secretion in THP-1-derived macrophages. To study high glucose-induced NLRP3 inflammasome signalling, we performed studies using an autophagy inducer, a ROS inhibitor and a NLRP3 inhibitor and found that all reduced the NLRP3 inflammasome activation and cytokine secretion. CONCLUSION: Sustained NLRP3 inflammasome activity in wound-derived macrophages contributes to the hyper inflammation in human diabetic wounds. Autophagy inhibition and ROS generation play an essential role in high glucose-induced NLRP3 inflammasome activation and cytokine secretion in macrophages. PMID- 28854427 TI - Structural Diversity of the Extensor Digitorum Profundus Muscle Complex in Platyrrhini. AB - Separate extension of fingers in the hand of primates is performed by 3 muscles: m. extensor pollicis longus, m. extensor digiti secundi, and m. extensor digitorum lateralis. Here it is proposed to consider them as parts of the extensor digitorum profundus muscular complex. The diversity in structure of these muscles in primates is examined based both on original anatomical study of New World monkeys and analysis of extensive published data on primates from different taxonomic groups. It is shown that in these muscles there are 2 main types of structure variations - the division of the muscle belly into several heads which give rise to separate tendons, and the split of the single terminal tendon into several branches. The first type of modification ensures the possibility of a separate management of the fingers, and the second, on the contrary, ensures the coupled control of extension of fingers. A scheme of evolutionary transformations of muscles belonging to the complex of the deep extensors of fingers is proposed. PMID- 28854429 TI - A Personal Tribute to Frank A. Gotch and Lee W. Henderson, Giants in Dialysis and in Life. PMID- 28854428 TI - MicroRNA-222 Promotes the Proliferation of Pulmonary Arterial Smooth Muscle Cells by Targeting P27 and TIMP3. AB - BACKGROUND/AIMS: Aberrant vascular smooth muscle cell (VSMC) proliferation plays an important role in the development of pulmonary artery hypertension (PAH). Dysregulated microRNAs (miRNAs, miRs) have been implicated in the progression of PAH. miR-222 has a pro-proliferation effect on VSMCs while it has an anti proliferation effect on vascular endothelial cells (ECs). As the biological function of a single miRNA could be cell-type specific, the role of miR-222 in pulmonary artery smooth muscle cell (PASMC) proliferation is not clear and deserves to be explored. METHODS: PASMCs were transfected with miR-222 mimic or inhibitor and PASMC proliferation was determined by Western blot for PCNA, Ki-67 and EdU staining, and cell number counting. The target genes of miR-222 including P27 and TIMP3 were determined by luciferase assay and Western blot. In addition, the functional rescue experiments were performed based on miR-222 inhibitor and siRNAs to target genes. RESULTS: miR-222 mimic promoted PASMC proliferation while miR-222 inhibitor decreased that. TIMP3 was identified to be a direct target gene of miR-222 based on luciferase assay. Meanwhile, P27 and TIMP3 were up-regulated by miR-222 inhibitor and down-regulated by miR-222 mimic. Moreover, P27 siRNA and TIMP3 siRNA could both attenuate the anti-proliferation effect of miR-222 inhibitor in PASMCs, supporting that P27 and TIMP3 are at least partially responsible for the regulatory effect of miR-222 in PASMCs. CONCLUSION: miR-222 promotes PASMC proliferation at least partially through targeting P27 and TIMP3. PMID- 28854430 TI - Genomic and Cytogenetic Characterization of a Balanced Translocation Disrupting NUP98. AB - A 41-year-old Asian woman with bilateral renal angiomyolipomas (AML) was incidentally identified to have a balanced translocation, 46,XX,t(11;12)(p15.4;q15). She had no other features or family history to suggest a diagnosis of tuberous sclerosis. Her healthy daughter had the same translocation and no renal AML at the age of 3 years. Whole-genome sequencing was performed on genomic maternal DNA isolated from blood. A targeted de novo assembly was then conducted with ABySS for chromosomes 11 and 12. Sanger sequencing was used to validate the translocation breakpoints. As a result, genomic characterization of chromosomes 11 and 12 revealed that the 11p breakpoint disrupted the NUP98 gene in intron 1, causing a separation of the promoter and transcription start site from the rest of the gene. The translocation breakpoint on chromosome 12q was located in a gene desert. NUP98 has not yet been associated with renal AML pathogenesis, but somatic NUP98 alterations are recurrently implicated in hematological malignancies, most often following a gene fusion event. We also found evidence for complex structural events involving chromosome 12, which appear to disrupt the TDG gene. We identified a TDGP1 partially processed pseudogene at 12p12.1, which adds complexity to the de novo assembly. In conclusion, this is the first report of a germline constitutional structural chromosome rearrangement disrupting NUP98 that occurred in a generally healthy woman with bilateral renal AML. PMID- 28854431 TI - Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury. AB - BACKGROUND: Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. METHODS: We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. RESULTS: Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1beta and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. CONCLUSION: S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target. PMID- 28854432 TI - Ursolic Acid Improves Liver Transplantation and Inhibits Apoptosis in Miniature Pigs Using Donation After Cardiac Death. AB - BACKGROUND: Ursolic acid (UA) possesses extensive pharmacological activities, including anti-oxidation, anti-infection, anti-inflammation, anti-tumor, liver protection. This study was designed to investigate the effect of UA on liver transplantation after liver transplantation using donation after cardiac death (DCD), and to assess the mechanisms. METHODS: 24 healthy experimental pigs were randomly divided into control and experimental groups. Each group received six DCD liver transplantations. In the experimental group, the recipient pigs received 120 mg/kg UA 4 h before surgery by intraperitoneal injection. The liver tissues and vein blood were collected 0 h, 1 h, 3 h, 6 h, 12 h and 24 h after transplantation. Morphological change, malondialdehyde (MDA) level, protein kinase-like ER kinase (PERK)-CHOP signaling pathway and apoptosis in liver tissue and serum aminotransferase (ALT) level were assessed. RESULTS: Compared with control group, ALT level was significantly decreased (P<0.05) and pathological changes in liver were ameliorated in experimental group. UA treatment also decreased MDA level in liver tissue and attenuated the apoptosis. Compared with control group, Bax decreased and Bcl-2 increased in UA-treated group. Importantly, UA decreased p-PERK, PERK, p-eIF2alpha, eIF2alpha, ATF4 and CHOP levels compared with control group. CONCLUSION: Our results showed that UA treatment could improve the DCD liver transplantation likely through inhibiting apoptosis and PERK-CHOP pathway. PMID- 28854433 TI - Cytokine Release and Focal Adhesion Proteins in Normal Thyroid Cells Cultured on the Random Positioning Machine. AB - BACKGROUND/AIMS: Spaceflight impacts on the function of the thyroid gland in vivo. In vitro normal and malignant thyrocytes assemble in part to multicellular spheroids (MCS) after exposure to the random positioning machine (RPM), while a number of cells remain adherent (AD). We aim to elucidate possible differences between AD and MCS cells compared to 1g-controls of normal human thyroid cells. METHODS: Cells of the human follicular epithelial thyroid cell line Nthy-ori 3-1 were incubated for up to 72 h on the RPM. Afterwards, they were investigated by phase-contrast microscopy, quantitative real-time PCR and by determination of cytokines released in their supernatants. RESULTS: A significant up-regulation of IL6, IL8 and CCL2 gene expression was found after a 4h RPM-exposure, when the whole population was still growing adherently. MCS and AD cells were detected after 24 h on the RPM. At this time, a significantly reduced gene expression in MCS compared to 1g-controls was visible for IL6, IL8, FN1, ITGB1, LAMA1, CCL2, and TLN1. After a 72 h RPM-exposure, IL-6, IL-8, and TIMP-1 secretion rates were increased significantly. CONCLUSION: Normal thyrocytes form MCS within 24 h. Cytokines seem to be involved in the initiation of MCS formation via focal adhesion proteins. PMID- 28854434 TI - Reply concerning Statistical Comments on "Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder". PMID- 28854435 TI - N-Terminal Prosomatostatin and Risk of Vascular Dementia. AB - BACKGROUND: Increased somatostatin plasma concentration has been found in patients with vascular dementia. However, it is unknown whether or not somatostatin levels may predict dementia development in the general population. To this end, we sought to assess the association of circulating N-terminal prosomatostatin (NT-proSST) with incident dementia among community-dwelling older adults. METHODS: In the prospective population-based Malmo Preventive Project, 5,347 study participants (mean age: 69 +/- 6years; 70% men) provided plasma for the determination of NT-proSST concentration. Of these, 373 participants (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) during a follow-up period of 4.6 +/- 1.3 years. The association of NT-proSST with the risk of dementia and its subtypes was studied using multivariable-adjusted Cox regression models controlling for age, gender, body mass index, systolic blood pressure, antihypertensive treatment, smoking, diabetes, lipid levels and prevalent stroke. RESULTS: Higher levels of NT-proSST were significantly associated with an increased risk of vascular dementia (hazard ratio [HR] per 1 SD: 1.29; 95% CI 1.05-1.59; p = 0.016), whereas no association was observed with Alzheimer's disease (HR per 1 SD: 0.99; 95% CI 0.81-1.20; p = 0.91), all-cause dementia (HR per 1 SD: 1.04; 95% CI 0.94-1.16; p = 0.44), and mixed dementia (HR per 1 SD: 0.98; 95% CI 0.79-1.21; p = 0.84). Levels of NT proSST above 563 pmol/L (highest quartile) conferred distinctly increased risk of vascular dementia (HR 1.66; 95% CI 1.05-2.63; p = 0.029) compared with lower values. CONCLUSIONS: Higher levels of circulating N-terminal-prosomatostatin are associated with increased incidence of vascular dementia. Our findings might be of importance for the understanding of dementia development in older adults. PMID- 28854436 TI - Pregnancy-Associated Plasma Protein A2 in Hemodialysis Patients: Significance for Prognosis. AB - BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A) is associated with adverse outcome of long-term hemodialysis patients (HD). The aim of the study was to test whether its homolog pregnancy-associated plasma protein A2 (PAPP-A2) can be detected in serum of HD patients and to define its significance. METHODS: The studied group consisted of 102 long-term HD patients and 25 healthy controls. HD patients were prospectively followed up for five years (2009-2014). PAPP-A2 was measured by surface plasmon resonance biosensor, PAPP-A by time resolved amplified cryptate emission. RESULTS: PAPP-A2, similarly as PAPP-A, was significantly increased in HD patients (median (interquartile range)) PAPP-A2: 6.2 (2.6-10.8) ng/mL, vs. 3.0 (0.7-5.9) ng/mL, p=0.006; PAPP-A: 18.9 (14.3-23.4) mIU/L, vs. 9.5 (8.4-10.5) mIU/L, p<0.001). In HD patients, PAPP-A2 correlated weakly but significantly with PAPP-A (tau=0.193, p=0.004). Unlike PAPP-A, PAPP-A2 was not significant for prognosis of HD patients when tested alone. There was a significant interaction between PAPP-A and PAPP-A2 on the mortality due to infection of HD patients (p=0.008). If PAPP-A was below median, mortality due to infection was significantly higher for patients with PAPP-A2 values above median than for patients with low PAPP-A2 levels (p=0.011). CONCLUSION: PAPP-A2 is increased in HD patients and interacts with PAPP-A on patients' prognosis. PMID- 28854437 TI - The Ameliorative Effect of Pectin-Insulin Patch On Renal Injury in Streptozotocin Induced Diabetic Rats. AB - BACKGROUND/AIMS: Renal damage and dysfunction is attributed to sustained hyperglycaemia in overt diabetes. Subcutaneous insulin injections are beneficial in delaying the progression of renal dysfunction and damage in diabetics. However, the current mode of administration is associated with severe undesirable effects. In this study, we evaluated the ameliorative effects of pectin-insulin dermal patches on renal dysfunction in diabetes. METHODS: Pectin-insulin patches (20.0, 40.8 and 82.9 ug/kg) were applied on the skin of streptozotocin-induced diabetic rats, thrice daily for 5 weeks. Blood glucose concentration, blood pressure and urine output volume were recorded on week 5 after which the animals were sacrificed after which the kidneys and plasma were collected. Kidney nephrin expression and urinary nephrin concentration, albumin excretion rate (AER), creatinine clearance (CC) and albumin creatinine ratio (ACR) were assessed. RESULTS: Patch application resulted in reduced blood glucose concentration and blood pressure. Furthermore, pectin-insulin patch treatment resulted in increased kidney nephrin expression and reduced urinary nephrin concentration. AER, CC ACR were also reduced post patch application. CONCLUSIONS: The application of pectin insulin patch limited diabetes associated kidney damaged and improved kidney function. These observations suggest that pectin-insulin patches may ameliorate kidney dysfunction that is associated with chronic subcutaneous insulin administration. PMID- 28854438 TI - Down-Regulation of Lncrna MALAT1 Attenuates Neuronal Cell Death Through Suppressing Beclin1-Dependent Autophagy by Regulating Mir-30a in Cerebral Ischemic Stroke. AB - BACKGROUND/AIMS: LncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was reported to be highly expressed in an in vitro mimic of ischemic stroke conditions. However, the exact biological role of MALAT1 and its underlying mechanism in ischemic stroke remain to be elucidated. METHODS: The roles of MALAT1 and miR-30a on cell death and infarct volume and autophagy were evaluated in experimental ischemic stroke. The relationships between miR-30a and MALAT1, Beclin1 were confirmed by luciferase reporter assay. The autophagy inhibitor 3-methyadenine (3-MA) was used to examine the impact of autophagy on ischemic injury. RESULTS: We found that MALAT1, along with the levels of conversion from autophagy-related protein microtubule-associated protein light chain 3-I (LC3-I) to LC3-phosphatidylethanolamine conjugate (LC3-II), as well as Beclin1 were up-regulated and miR-30a was down-regulated in cerebral cortex neurons after oxygen-glucose deprivation (OGD) and mouse brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Down-regulation of MALAT1 suppressed ischemic injury and autophagy in vitro and in vivo. Furthermore, MALAT1 may serve as a molecular sponge for miR-30a and negatively regulate its expression. In addition, MALAT1 overturned the inhibitory effect of miR-30a on ischemic injury and autophagy in vitro and in vivo, which might be involved in the derepression of Beclin1, a direct target of miR-30a. Mechanistic analyses further revealed that autophagy inhibitor 3-methyadenine (3-MA) markedly suppressed OGD-induced neuronal cell death and MCAO-induced ischemic brain infarction. CONCLUSION: Taken together, our study first revealed that down regulation of MALAT1 attenuated neuronal cell death through suppressing Beclin1 dependent autophagy by regulating miR-30a expression in cerebral ischemic stroke. Besides, our study demonstrated a novel lncRNA-miRNA-mRNA regulatory network that is MALAT1-miR-30a-Beclin1 in ischemic stroke, contributing to a better understanding the pathogenesis and progression of ischemic stroke. PMID- 28854440 TI - The Nrf2/HO-1 Pathway Mediates the Antagonist Effect of L-Arginine On Renal Ischemia/Reperfusion Injury in Rats. AB - BACKGROUND/AIMS: Ischemia/reperfusion (I/R) is the most common cause of acute renal injury. I/R-induced oxidative stress is involved in the development of acute renal injury, which can be reversed by supplementation with L-arginine, a precursor of nitric oxide (NO). This study was conducted to evaluate alterations in the expression of transcription factors [nuclear factor kappa B (NF-kappaB), nuclear factor-E2-related factor-2 (Nrf2), and heme oxygenase 1 (HO-1)] and heat shock protein 70 (HSP70) in the kidney of I/R-induced injury rats. METHODS: Sprague-Dawley (SD) rats were subjected to bilateral renal ischemia for 45 min followed by reperfusion for 24 h. Group 1, Sham; group 2, I/R; group 3, L arginine; and group 4, L-arginine+zinc protoporphyrin (ZnPP). The levels of serum creatinine (Scr), blood urea nitrogen (BUN), serum nitric oxide (NO), histic malondialdehyde (MDA) and reactive oxygen species (ROS) and superoxide dismutase (SOD) activity were determined, and the expression levels of Nrf2, HO-1, NF kappaB, and HSP70 were evaluated. RESULTS: The treatment of rats with L-arginine produced a significant reduction in the levels of BUN, Scr, MDA and a significant enhancement in the level of NO and in the activity of SOD compared to renal I/R groups. The expression levels of Nrf2, HO-1, and HSP70 were strongly increased, and the expression of NF-kappaB and production of ROS were significantly decreased in the L-arginine group compared to that of the I/R group. ZnPP increased renal damage and displayed effects opposite to those of L-arginine. CONCLUSION: These findings suggested that L-arginine/NO reduces renal dysfunction associated with I/R of the kidney and may act as a trigger to regulate the NF kappaB, HSP70 and Nrf2/HO-1 signaling cascades. PMID- 28854439 TI - mPGES-1-Derived PGE2 Contributes to Indoxyl Sulfate-Induced Mesangial Cell Proliferation. AB - BACKGROUND/AIMS: We previously reported that indoxyl sulfate (IS) could cause mesangial cell (MC) proliferation via a cyclooxygenase (COX)-2-dependent mechanism. However, the specific prostaglandin contributing to COX-2 effect on IS induced MC proliferation remained unknown. Thus, the present study was undertaken to examine the role of microsomal prostaglandin E synthase-1 (mPGES-1)-derived Prostaglandin E2 (PGE2) in IS-induced MC proliferation. METHODS: IS was administered to the MCs with or without mPGES-1 siRNA pretreatment to induce the MC proliferation which was determined by cell cycle analysis, DNA synthesis, and the expressions of cyclins. In another experimental setting, PGE2 was applied to the MCs to examine its direct effect on MC proliferation, as well as the regulation of prostaglandin E receptors (EPs) by qRT-PCR. RESULTS: With the administration of IS, mPGES-1(not mPGES-2 and cytosolic PGES) was significantly upregulated at both protein and mRNA levels in line with a promoted MC proliferation. Interestingly, silencing mPGES-1 reduced cell number in S and G2 phases and blocked the upregulation of cyclin A2 and cyclin D1 in parallel with blunted PGE2 release after IS treatment, indicating that mPGES-1-derived PGE2 could contribute to MC proliferation. Furthermore, we confirmed that exogenous PGE2 could directly trigger the proliferative response in MCs. Lastly, we observed a selective upregulation of EP2 after PGE2 treatment and enhanced phosphorylation of NF-kappaB following IS administration in MCs, suggesting the potential involvements of EP2 and NF-kappaB in this pathological process. CONCLUSION: mPGES-1-derived PGE2 contributed to IS-induced mesangial cell proliferation. PMID- 28854443 TI - Osteotomies around the Knee-Part II. PMID- 28854442 TI - Statistical Comments on "Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder". PMID- 28854444 TI - Total Knee Arthroplasty in Combination with Osteotomies around the Knee. PMID- 28854441 TI - Increased Retinal Thinning after Combination of Internal Limiting Membrane Peeling and Silicone Oil Endotamponade in Proliferative Diabetic Retinopathy. AB - BACKGROUND: The aim of this study was to examine the change in retinal thickness after vitrectomy with internal limiting membrane (ILM) peeling and/or silicone oil (SO) endotamponade in proliferative diabetic retinopathy (PDR). METHODS: The actual amount and ratio of changes in the retinal thickness were calculated. RESULTS: Compared to control eyes in the ILM peeling (-)/SO (-) group, the central, superior inner, and temporal inner retina in the ILM peeling (+)/SO (-) group, the central and superior inner retina in the ILM peeling (-)/SO (+) group, and the central, inferior inner, temporal inner, and nasal inner retina in the ILM peeling (+)/SO (+) group showed a significant reduction of the retinal thickness. The central, superior inner, and temporal inner retina in the ILM peeling (+)/SO (-) group, the central and superior inner retina in the ILM peeling (-)/SO (+) group, and the central, superior inner, inferior inner, and temporal inner retina in the ILM peeling (+)/SO (+) group showed a significantly increased reduction rate of the retinal thickness compared to the control group. CONCLUSIONS: Macular retinal thinning in PDR was observed after ILM peeling and SO endotamponade, and it was increased by the combination of these 2 factors. PMID- 28854445 TI - [Testing the Psychometric Properties of the Helping Alliance Questionnaire (HAQ) in Different Health Care Settings]. AB - Introduction The Helping Alliance Questionnaire developed by Luborsky was psychometricly examined for the first time and translated into German by Bassler et al. in the mid-1990s. It consists of 11 Items, which are summarized to the scales "relation to the therapist" and "satisfaction with therapeutic outcome". HAQ is now one of the most used instruments to measure therapeutic alliance. The goal of this study was to test the psychometric properties based on three large patient samples in different treatment settings. Material and methods Analyses were conducted based on 2 samples of patients in inpatient psychosomatic/psychotherapeutic rehabilitation (n=655, n=2494) and one sample in outpatient psychotherapy (n=1477). Exploratory factor analyses and for verification confirmatory factor analyses were applied. Furthermore reliability and validity analysis were conducted. Results The 2-factorial structure found in literature was replicated with an increasing stability at the end of treatment. Item 2 and 3 had inconsistent factor loadings at different points of measurement and study. Reliability and validity indices were satisfying to good. The fit of the model, on the other hand, was less satisfying and suggests a solution without Item 2 and 3. For reasons of content as well as for reasons of dissemination, it is pleaded for the maintenance of the existing item assignments in the HAQ for the present. PMID- 28854446 TI - The Hemodynamics of Labor in Women Undergoing Vaginal and Cesarean Deliveries as Determined by Whole Body Bioimpedance. AB - OBJECTIVE: The objective of this study was to assess the hemodynamics of labor, delivery, and 48 hours postpartum in women undergoing vaginal and cesarean deliveries by utilizing a whole body bioimpedance-based device. MATERIALS AND METHODS: A prospective longitudinal single-center observational study was performed between September 2014 and September 2015. The hemodynamics of low-risk women undergoing spontaneous vaginal delivery were compared with those undergoing elective cesarean sections. Cardiac index (CI), stroke index, total peripheral resistance index (TPRI), and mean arterial pressure (MAP) were assessed at different time points during delivery and in the immediate postpartum period (1, 24, and 48 hours postpartum). RESULTS: Eighty-seven women were evaluated, 63 parturients in the vaginal delivery group and 24 in the cesarean delivery group. Normal vaginal delivery was characterized by a reduction in MAP and CI after epidural anesthesia, whereas elective cesarean sections were characterized by a rise in MAP and CI after spinal anesthesia. As labor progressed, CI increased reaching its peak during the second stage. Immediately following delivery, TPRI declined to its nadir with no significant change in CI. As opposed to vaginal delivery, in cesarean delivery, TPRI peaked within 1-hour postpartum resulting in a significant decline in CI. CONCLUSION: Whole body bioimpedance can be used effectively to assess the hemodynamics of vaginal and cesarean deliveries. PMID- 28854447 TI - Prenatal Therapy with Magnesium Sulfate and Its Correlation with Neonatal Serum Magnesium Concentration. AB - INTRODUCTION: Antenatal magnesium sulfate (MgSO4) administration has shown to be effective in minimizing cerebral palsy and severe motor dysfunction at the age of 2 years. The aim of this study is to determine the relationship between the magnesium dose delivered to the mother and the magnesium concentration in the neonates. MATERIALS AND METHODS: A prospective cohort study was conducted on neonates of less than 32 weeks' gestation admitted to the neonatal intensive care unit of University Hospital Complex of Vigo from December 2012 to July 2015. Comparative analysis of magnesium levels between the groups of neonates exposed to MgSO4 and the control group. RESULTS: A total of 118 neonates were included in the study. The mothers of 62 of them had received MgSO4 as a neuroprotective agent. There was a significant correlation between the full dose of MgSO4 received by the mother and the levels of magnesium in the neonate in the first 24 hours of life (r2 = 0.397; p < 0.001). CONCLUSION: The MgSO4 dose received by the mother has a linear relationship with the magnesium levels obtained in neonates. PMID- 28854448 TI - Erratum: Primary versus Staged Closure of Exomphalos Major: Cardiac Anomalies Do Not Affect Outcome. PMID- 28854450 TI - ? PMID- 28854449 TI - Editorial Compilation IV. PMID- 28854451 TI - ? PMID- 28854452 TI - ? PMID- 28854453 TI - ? PMID- 28854454 TI - ? PMID- 28854455 TI - ? PMID- 28854457 TI - ? PMID- 28854456 TI - ? PMID- 28854458 TI - ? PMID- 28854459 TI - ? PMID- 28854460 TI - ? PMID- 28854461 TI - ? PMID- 28854462 TI - ? PMID- 28854463 TI - ? PMID- 28854464 TI - ? PMID- 28854465 TI - ? PMID- 28854466 TI - ? PMID- 28854467 TI - ? PMID- 28854468 TI - ? PMID- 28854469 TI - ? PMID- 28854470 TI - ? PMID- 28854471 TI - ? PMID- 28854472 TI - ? PMID- 28854473 TI - ? PMID- 28854474 TI - ? PMID- 28854475 TI - ? PMID- 28854476 TI - ? PMID- 28854477 TI - ? PMID- 28854478 TI - ? PMID- 28854479 TI - [Special urological traumatology in children and adolescents]. AB - Isolated injuries of the genitourinary tract are rare, with the kidney being the most frequently affected organ, especially in situations of polytrauma. Overall, the genitourinary tract is involved in approximately 3 % of all children suffering polytrauma accidents. The literature and international guidelines provide clear therapeutic concepts with a consensus on the diagnosis and treatment of renal trauma, both for the treatment of adults and for children and adolescents. However, the most common injuries to the external genitalia in children and adolescents are caused by blunt trauma, abrasion, bruising, and piling. For these forms of injuries there are no general recommendations in literature and guidelines regarding diagnostic or therapeutic procedures, which may be due to the wide variety of origins of the injuries. Consequently, as shown in our sequence of case reports, each type of injury to the external genitourinary system requires an individual evaluation and therapeutic approach. PMID- 28854480 TI - ? PMID- 28854481 TI - ? PMID- 28854482 TI - Applying high-frequency surrogate measurements and a wavelet-ANN model to provide early warnings of rapid surface water quality anomalies. AB - It is critical for surface water management systems to provide early warnings of abrupt, large variations in water quality, which likely indicate the occurrence of spill incidents. In this study, a combined approach integrating a wavelet artificial neural network (wavelet-ANN) model and high-frequency surrogate measurements is proposed as a method of water quality anomaly detection and warning provision. High-frequency time series of major water quality indexes (TN, TP, COD, etc.) were produced via a regression-based surrogate model. After wavelet decomposition and denoising, a low-frequency signal was imported into a back-propagation neural network for one-step prediction to identify the major features of water quality variations. The precisely trained site-specific wavelet ANN outputs the time series of residual errors. A warning is triggered when the actual residual error exceeds a given threshold, i.e., baseline pattern, estimated based on long-term water quality variations. A case study based on the monitoring program applied to the Potomac River Basin in Virginia, USA, was conducted. The integrated approach successfully identified two anomaly events of TP variations at a 15-minute scale from high-frequency online sensors. A storm event and point source inputs likely accounted for these events. The results show that the wavelet-ANN model is slightly more accurate than the ANN for high frequency surface water quality prediction, and it meets the requirements of anomaly detection. Analyses of the performance at different stations and over different periods illustrated the stability of the proposed method. By combining monitoring instruments and surrogate measures, the presented approach can support timely anomaly identification and be applied to urban aquatic environments for watershed management. PMID- 28854483 TI - Land use and wind direction drive hybridization between cultivated poplar and native species in a Mediterranean floodplain environment. AB - Deforestation and intensive land use management with plantations of fast-growing tree species, like Populus spp., may endanger native trees not only by eliminating or reducing their habitats, but also by diminishing their species integrity via hybridization and introgression. The genus Populus has persistent natural hybrids because clonal and sexual reproduction is common. The objective of this study was to assess the effect of land use management of poplar plantations on the spatial genetic structure and species composition in poplar stands. Specifically, we studied the potential breeding between natural and cultivated poplar populations in the Mediterranean environment to gain insight into spontaneous hybridization events between exotic and native poplars; we also used a GIS-based model to evaluate the potential threats related to an intensive land use management. Two study areas, both near to poplar plantations (P.*euramericana), were designated in the native mixed stands of P. alba, P. nigra and P.*canescens within protected areas. We found that the spatial genetic structure differed between the two stands and their differences depended on their environmental features. We detected a hybridization event with P.*canescens that was made possible by the synchrony of flowering between the poplar plantation and P.*canescens and facilitated by the wind intensity and direction favoring the spread of pollen. Taken together, our results indicate that natural and artificial barriers are crucial to mitigate the threats, and so they should be explicitly considered in land use planning. For example, our results suggest the importance of conserving rows of trees and shrubs along rivers and in agricultural landscapes. In sum, it is necessary to understand, evaluate, and monitor the spread of exotic species and genetic material to ensure effective land use management and mitigation of their impact on native tree populations. PMID- 28854484 TI - Oncogenic papillomavirus and polyomavirus in urban sewage in Egypt. AB - Recently, the occurrence of oncogenic viruses in contaminated water and their potential for waterborne transmission has been reported. We addressed an environmental surveillance of both HPyVs (JCPyV and BKPyV) and HPVs in three wastewater treatment plants in Egypt. A high level of dissemination was found for both viruses. HPyVs (JCPyV and BKPyV) were found in ~73% of examined samples, while HPVs were detected in 30.5%. Sequence analysis of HPV positive samples revealed a wide variety of circulating genotypes representing both anogenital (HPV-6, HPV-16, HPV-53, HPV-44, HPV-31, HPV-43) and cutaneous (HPV-37, HPV-21, HPV-120, HPV-111, HPV-5) types. In addition, two unclassified sequences were identified, suggesting putative types. The median concentrations of HPyVs in inflow samples were 3.03*1005, 3.9*1005, and 1.44*1005GC/l in the three WWTPs, respectively. Whereas, the viral concentration in outflow reduced by one order of magnitude in WWTP-A and WWTP-C and two orders of magnitude in WWTP-B. On the other hand, the mean concentration of the quantified HPVs positive samples was 1.68*1003GC/l for inflow and a quite similar pattern in the outflow as well. These data provide an evidence about the actual circulation pattern of both viruses in the population. Also, the high abundance of HPyVs supports its potential as a possible fecal indicator. However, further investigations are required for both viruses to elucidate the potential health risk via contaminated water. PMID- 28854485 TI - Erythritol production by Yarrowia lipolytica from okara pretreated with the in house enzyme pools of fungi. AB - Okara (soybean residue) is an ideal erythritol feedstock due to its low price and high-nutrient content. Fungal-fermentations were carried out in okara using in house enzyme pools generated by Mucor flavus or Trichoderma reesei to make okara more accessibility in the subsequent erythritol production using Yarrowia lipolytica. Mucor-fermented okara produced a high erythritol yield because of its special component and micromorphology. Five days is the optimal period for Mucor fermentation. Different fermentation modes were compared in terms of erythritol production and yield. The concentration of Mucor-fermented okara in erythritol fermentation medium was optimal at 30.0g/L. Moreover, 40.0g/L NaCl was added as the osmotic regulator. No extra ingredient was needed during this process. Results of 5-L fermentations showed that an erythritol titer of 14.7g/L, with a yield of 0.49g/g okara was obtained. These findings indicated that Mucor fermented okara was an economically alternative feedstock for low-cost erythritol production. PMID- 28854486 TI - Analysis of patient-detected breast cancer recurrence. AB - BACKGROUND: After primary surgical resection, breast cancer survivors regularly undergo surveillance using multiple modalities to detect recurrences. OBJECTIVE: The goal of this study was to determine how breast cancer recurrences were detected in our sample population of breast cancer survivors. We hypothesize that the majority of recurrences are patient-detected. METHODS: This was a retrospective observational study evaluating patients with a detected breast cancer recurrence between 2010 and 2015. Patients were analyzed by initial detection modality (patient versus clinician versus imaging). Other variables of interest included insurance status, ambulation capability, living situation, age at diagnosis and recurrence, and time to recurrence. Statistical methods included chi-square tests, log-rank tests, and analysis of variance. RESULTS: 115 patients were identified with a recurrence (mean age 61 years). 88 (77%) recurrences were patient-detected, 14 (12%) were detected by imaging, and 13 (11%) were clinician detected (chi-square goodness of fit test p < 0.001). Median time to recurrence was 4 years in the patient-detection group compared to 3 for the clinician group and 2 for imaging detection (log-rank test p = 0.01). CONCLUSION: While the majority of recurrences were patient-detected, these were detected later and at a more advanced clinical stage. This could represent an opportunity to enhance outcomes by empowering patient detection strategies. PMID- 28854487 TI - The study of stresses characteristic of contact mechanism in total knee replacement using two-dimensional finite element analysis. AB - The knee joint is one of the more important parts in the human body. Its continuous involvement in the human movement makes it prone to breakage. Due to small contact area, the contact pressure is quite large in this joint. Therefore, the understanding of stresses behavior in knee joint contact is a necessity. In this study, we investigated the stresses behavior in the tibial insert by FEA. A two-dimensional FE model representing the knee joint contact mechanism was created. In the elastic simulation, the contact pressure dropped by 0.2% when the coefficient of friction (CoF) was added. While in the plastic simulation it rose by 12.06%. The average contact pressure fell by 36.42% of the inclusion of plasticity. The CoF lowered the Tresca stress by 0.16% and 12.37% in the elastic and plastic simulation, respectively. Meanwhile, the inclusion of plasticity decreased the average Tresca stress by 74.25%. The CoF, in the elastic simulation, decreased the compressive and tensile stress by 3.29% and 12.46%, respectively. Conversely, in the plastic simulation the compressive stress and tensile rose by 12.01% and 8.20%, respectively. Meanwhile, the inclusion of plasticity caused the compressive stress to decrease by 70.50% and tensile stress to increase by 72.06%. PMID- 28854488 TI - Histological and biomechanical characterization of decellularized porcine pericardium as a potential scaffold for tissue engineering applications. AB - BACKGROUND: Each year, more than 800,000 vascular and cardiac surgeries are performed therefore, there is a great need for suitable material for bioprosthetic operations. Porcine pericardium is a double-walled sac that covers the heart and can be used in vascular and cardiac thoracic surgery. OBJECTIVE: The aim of the present study was to evaluate the decellularization process and biomechanical properties in porcine pericardial tissue after the decellularization treatment. METHODS: A detergent based protocol was used for the decellularization of porcine pericardium. Histological analysis and contact cytotoxicity assay were performed. Additionally, biomechanical testing and in vivo biocompatibility by implantation into Wistar Rats were performed. RESULTS: The histological analysis showed the preservation of the extracellular matrix, without any observable cellular remnants. No toxic effects were noticed when contact cytotoxicity assay performed. The decellularized tissues, after implantation in Wistar Rats, remained for up to 12 weeks without being rejected. Finally, the biomechanical testing showed no significant differences between native and decellularized tissues. CONCLUSION: In this study, the decellularization of the porcine pericardium produced a non toxic scaffold, free of any cellular remnants, thus serving as an alternative material for tissue engineering applications including heart valve and vascular patch development. PMID- 28854489 TI - Modulating the release of proteins from a loaded carrier of alginate/gelatin porous spheres immersed in different solutions. AB - BACKGROUND: A biodegradable porous particle for the controlled biofactor delivery which assembly of pores in scaffolds can improve the permeation and diffusion of drugs or growth factors. OBJECTIVE: Porous-spheres in millimeter scale were prepared by mixing sodium alginate and gelatin interpenetrating networks with cross-linkers; interconnected open pores were fabricated through solvent casting and particulate leaching. METHODS: Morphological characteristics, degradation, and bovine serum albumin (BSA) release rates of the porous-spheres immersed in three different solutions, namely, deionized distilled water, simulated body fluid (SBF), and phosphate-buffered saline (PBS), were detected. RESULTS: Porous spheres with a large amount of gelatin exhibited an increase in water absorption rates without affecting scaffold strength and no cytotoxicity was elicited. Highly interconnected pores with a diameter of 100-200 um were uniformly distributed in scaffolds. The weight loss in PBS was faster than that in other solutions; the highest release rate of BSA in SBF was observed for 2 h. The release rates also exhibited linear patterns from 2 h to 24 h in all of the groups. CONCLUSIONS: After 1 d of immersion in solutions, BSA release rates in scaffolds logarithmically decreased for 14 d. The degradation of porous-spheres also showed an inverse pattern. PMID- 28854490 TI - A numerical study on the effect of geometrical parameters and loading profile on the expansion of stent. AB - BACKGROUND: Stenting has been proposed as an effective treatment to restore blood flow in obstructed arteries by plaques. Although several modified designs for stents have been suggested, most designs have the risk of disturbing blood flow. OBJECTIVE: The main objective is to propose a stent design to attain a uniform lumen section after stent deployment. METHODS: Mechanical response of five different designs of J & J Palmaz-Schatz stent with the presence of plaque and artery are investigated; four stents have variable strut thickness of different magnitudes and the rest one is a uniform-strut-thickness stent. Nonlinear finite element is employed to simulate the expansion procedure of the intended designs using ABAQUS explicit. RESULTS: The stent design whose first cell thickness linearly increases by 35 percent, exhibits the best performance, that is it has the lowest recoiling and stress induced in the intima for a given lumen gain. It also enjoys the minimal discrepancy between the final at the distal and proximal ends. CONCLUSIONS: A uniform widened artery can be achieved by using the stent design with 35 percent increase in its first cell, which provides the possibility to prevent from disturbing blood flow and consequently post-operation complications. PMID- 28854491 TI - In vitro evaluation of collagen immobilization on polytetrafluoroethylene through NH3 plasma treatment to enhance endothelial cell adhesion and growth. AB - BACKGROUND: Polytetrafluoroethylene (PTFE) is poorly biocompatible due to its low surface energy and hydrophobicity, which cause weak cell attachment and proliferation and complicate its use in implants. OBJECTIVE: NH3 plasma was used for surface modification and binding of amine groups on the PTFE surface. Collagen was immobilized on the plasma-treated PTFE in order to enable it to support enhanced cell adhesion and growth. METHODS: PTFE was exposed to NH3 plasma and collagen was immobilized on the NH3 plasma-treated surface. ATR-IR, SEM, EDXA and contact angle were conducted to determine the composition, microstructure and wettability of samples. The cytocompatibility of the samples was assessed via the growth HUVEC cells using MTT assay. RESULTS: Plasma treatment resulted in an incorporation of functional groups, containing N2 and O2 that caused the PTFE surface to become hydrophilic with contact angle 68 degrees . Also, a reduction in F/C ratio was observed after collagen immobilization that indicates the presence of collagen. Cells proliferated in greater numbers on the collagen immobilized-PTFE as compared to the plasma-treated one. CONCLUSIONS: Plasma treatment incorporates functional polar moieties on the PTFE surface, causing enhanced wettability, collagen immobilization and cell viability. Collagen-immobilized PTFE may offer a valuable solution in biomedical applications such as vessel grafts. PMID- 28854492 TI - Effect of different post-treatments on the bioactivity of alkali-treated Ti-5Si alloy. AB - BACKGROUND: As titanium (Ti) alloys are bioinert, various chemically-modified Ti surface has been developed to promote bioactivity and bone ingrowth. OBJECTIVE: In this study, various post treatments (water aging, hydrothermal, and heat treatments) were applied to NaOH-treated Ti-5Si to improve its bioactivity. METHODS: The bioactivity of surface-modified Ti-5Si was access by using the apatite formation ability of Ti-5Si surfaces soaking in a simulated body fluid (SBF). RESULTS: The results showed that the NaOH-treated surface formed a porous network structure composed of sodium titanate hydrogel, which was changed to sodium titanate after subsequent post treatments, whereas sodium titanate, anatase and rutile phases were found on the Ti-5Si surfaces after heat treatment. After immersion in SBF for 14 days, compact apatite layers were observed on the surfaces of all the Ti-5Si tested. The results of XRD and FTIR indicated that the apatite deposited on the Ti-5Si substrate with various surface modified conditions was carbonate-substituted hydroxyapatite. CONCLUSIONS: The apatite forming ability of the surface of the Ti-5Si was excellent, even though Ti-5Si was not subjected to surface modifications. As a result, the bioactivity of Ti 5Si alloy was verified by the apatite-forming ability, making it suitable for use in orthopedic and dental implants. PMID- 28854493 TI - Triton X-100 combines with chymotrypsin: A more promising protocol to prepare decellularized porcine carotid arteries. AB - BACKGROUND: Morbidity and mortality of cardiovascular diseases are increasing in recent years. To solve these problems, vascular transplantation has become a common approach. Decellularization has been a hot spot of tissue engineering to prepare vessel substitutes for vascular transplantation. However, there is no established canonical protocol for decellularization thus far. OBJECTIVE: To further understand the decellularization effect of decellularization protocols and the causal relationship between decellularization and mechanical properties. METHODS: Three decellularization protocols including two chemical protocols based on SDS and Trypsin respectively and a combination of Triton X-100 with chymotrypsin were adopted to obtain decellularized porcine carotid arteries in our study. After decellularization, histological analysis, scanning electron microscopy and mechanical tests were performed to evaluate their efficiency on removing of cellular components, retention of extracellular matrix and influence on mechanical properties. RESULTS: All these decellularization protocols used in our study were efficient to remove cellular components. However, SDS and trypsin performed more disruptive effect on ECM structure and mechanical properties of native arteries while Triton X-100 combines with chymotrypsin had no significant disruptive effect. CONCLUSIONS: Compared with decellularization protocols based on SDS and trypsin, Triton X-100 combines with chymotrypsin used in our study may be a more promising protocol to prepare decellularized porcine carotid arteries for vascular tissue engineering applications. PMID- 28854494 TI - Comparative studies of physical properties of kinesiotapes. AB - BACKGROUND: Nowadays we observe growing popularity of kinesiotaping as a supportive method in physiotherapy. In documents available on kinesiotaping we can find that mechanical properties of tapes are similar to the ones of a human skin, but usually there is hardly any numerical data characterizing these properties. OBJECTIVE: Therefore, testing and comparing physical properties of commercially available kinesiotapes seems to be important. METHODS: Physical properties of five commercially available kinesiotapes were examined. Strain vs. stress data was collected up to 15 N. Program Origin 9.0 was used for data analysis. RESULTS: The obtained results show that up to about 2 N the strain vs. stress characteristics of the tested tapes are similar while for greater stress they differ essentially. CONCLUSIONS: An alternative, to commonly used, way of defining relative strain is proposed. This definition could be more suitable in those cases when desired tape tensions are higher than 50% i.e. in ligament and tendon techniques. PMID- 28854495 TI - Computational simulation of biomolecules transport with multi-physics near microchannel surface for development of biomolecules-detection devices. AB - BACKGROUND: The quantitative evaluation of the biomolecules transport with multi physics in nano/micro scale is demanded in order to optimize the design of microfluidics device for the biomolecules detection with high detection sensitivity and rapid diagnosis. OBJECTIVE: This paper aimed to investigate the effectivity of the computational simulation using the numerical model of the biomolecules transport with multi-physics near a microchannel surface on the development of biomolecules-detection devices. METHODS: The biomolecules transport with fluid drag force, electric double layer (EDL) force, and van der Waals force was modeled by Newtonian Equation of motion. The model validity was verified in the influence of ion strength and flow velocity on biomolecules distribution near the surface compared with experimental results of previous studies. The influence of acting forces on its distribution near the surface was investigated by the simulation. RESULTS: The trend of its distribution to ion strength and flow velocity was agreement with the experimental result by the combination of all acting forces. Furthermore, EDL force dominantly influenced its distribution near its surface compared with fluid drag force except for the case of high velocity and low ion strength. CONCLUSIONS: The knowledges from the simulation might be useful for the design of biomolecules-detection devices and the simulation can be expected to be applied on its development as the design tool for high detection sensitivity and rapid diagnosis in the future. PMID- 28854496 TI - The efficacy and safety of combination therapy of low-intensity pulsed ultrasound stimulation in the treatment of unstable both radius and ulna fractures in children. AB - BACKGROUND: There are few reports of Low-intensity pulsed ultrasound (LIPUS) treatment for fresh forearm fractures in children. OBJECTIVES: LIPUS stimulation was applied after surgery of forearm fractures in children and the efficacy and safety of combination therapy of LIPUS treatment were evaluated. PATIENTS AND METHODS: Children with both radius and ulna fracture, twenty-five diaphysis (mid R&U) and nineteen metaphysis (dist-R&U) fractures, were treated with intramedullary nailing followed by cast and splint mobilization. Thirteen patients in the mid-R&U fracture group and eight patients in the dist-R&U fracture group were combined with LIPUS stimulation postoperatively. RESULTS: Periosteal callus appeared significantly earlier after surgery in the LIPUS treated groups than in the groups without LIPUS treatment. The duration of external fixation was significantly shorter in the dist-R&U fracture group treated with LIPUS stimulation compared with that in the mid-R&U fracture group without LIPUS treatment. Furthermore, the time span needed for bone union in the groups with LIPUS stimulation was significantly shorter than in the groups without LIPUS stimulation. CONCLUSIONS: It is suggested that LIPUS stimulation can lead to a reduction of treatment periods of unstable forearm fractures safely after operation even in children. PMID- 28854497 TI - Influence of spine surgery on the ability to perform an emergency stop while driving a car. AB - BACKGROUND: Spinal surgeries have strongly increased in number over the past decade. The question of when it is safe to resume driving is thereby one the most frequently asked questions that patients ask of their treating physician. OBJECTIVE: The aim of this study was to assess braking performance before and after spine surgery. METHODS: Reaction time, foot transfer time (together brake response time [BRT]), and brake force (BF) were evaluated in a drive simulator. A longitudinal patient cohort (n= 27) was tested preoperatively and at the first follow-up. A cross-sectional cohort (n= 27) was tested at > 1 year postoperatively. The values from these groups were compared with a healthy age matched control group of 24 volunteers. RESULTS: No significant improvement in BRT was seen in lumbar fusion three months postoperatively (p= 0.597); BF was even weaker than it was preoperatively (p= 0.044). In comparison to the control group (median BRT 479 ms), preoperative BRT was already impaired in lumbar fusion patients (median 560 ms), representing an increased braking distance of 2.25 m at 100 km/h. CONCLUSION: Although most patients performed adequately, about one third presented critical braking performance. Risk factors for impaired braking may include scheduled multisegmental fusion surgery, female sex, and pain. PMID- 28854498 TI - Dorsal scapular nerve injury after trigger point injection into the rhomboid major muscle: A case report. AB - BACKGROUND AND OBJECTIVE: We report the case of a patient who presented with right dorsal scapular neuropathy after a trigger point injection into the right rhomboid major muscle. Through a nerve conduction study and electromyography, we demonstrated dorsal scapular nerve injury in this patient. CASE REPORT: A 38-year old man complained that his right shoulder functioned less optimally during push up exercises after a trigger point injection 4 weeks prior. Physical examination revealed mildly reduced right shoulder retractor muscle strength compared with the left side. We performed a nerve conduction velocity test and electromyography 5 weeks after the injection. The compound muscle action potential of the right dorsal scapular nerve showed low amplitude (left vs. right side: 5.2 vs. 1.6 mV) and delayed latency (left vs. right side: 4.9 vs. 6.8 ms). Positive sharp wave (1+) and mildly reduced recruitment were seen on electromyography of the rhomboid major muscle. The findings of the nerve conduction velocity test and electromyography indicated partial right dorsal scapular neuropathy. The nerve injury seemed to have been caused by the needle inserted during trigger point injection. CONCLUSION: Clinicians should pay attention to the occurrence of dorsal scapular nerve injury when performing trigger point injection into the rhomboid muscle. PMID- 28854499 TI - Persian adaptation of Quality of Life Profile for Spinal Deformities questionnaire. AB - BACKGROUND: The Quality of Life Profile for Spinal Deformities (QLPSD) is the first specific questionnaire to evaluate health-related quality-of-life (HRQoL) in adolescents with spinal deformities. Measuring HRQoL is important because spinal deformities and their management may negatively affect quality of life (QoL), thereby importantly affecting treatment effectiveness. OBJECTIVE: This study aimed to examine the validity and reliability of a Persian version of the QLPSD through patients with adolescent idiopathic scoliosis and Scheuermann's kyphosis. METHODS: A cross-sectional design was used to determine the validity and reliability of the Persian version of the QLPSD based on the IQOLA protocols. RESULTS: The QLPSD was successfully culturally adapted, showing acceptable internal consistency (cronbach's alpha= 0.88) and intraclass correlation coefficients (ICC = 0.91). Concurrent validity was supported by comparing scores on corresponding dimensions of the Persian versions of QLPSD and the Scoliosis Research Society-22r (SRS-22r) questionnaires (function, pain, and body-image). Discriminant validity was supported though observation of significant differences between participants who had different clinical characteristics (p< 0.05). CONCLUSIONS: The Persian QLPSD is valid and reliably measures QoL among adolescents with spinal deformities; it may be used in clinical evaluations and future research. PMID- 28854500 TI - Efficacy of high intensity laser therapy in treatment of patients with lumbar disc protrusion: A randomized controlled trial. AB - OBJECTIVE: This study aims to evaluate the effect of high intensity laser therapy (HILT) in patients with lumbar disc protrusion (LDP). METHODS: This study included 63 patients suffering from protrusion of lumbar intervertebral disc; they were divided into Groups 1 (n= 32) and 2 (n= 31). Group 1 was treated with HILT and spinal decompression system (SDS). Patients in Group 2 received SDS alone. Evaluations were conducted on oswestry disability index (ODI), lumbosacral portion pain, and lower limb radiation pain with visual analogue scale (VAS) of two patient groups before treatment, two weeks after treatment, and 1 month after follow-up visit. Lumbar flexion range and angle of straight leg raising before treatment and 2 weeks after treatment. RESULTS: After two weeks of treatment of two patient groups, ODI, VAS, lumbar flexion range and angle of straight leg raising significantly improved compared with their conditions before treatment (P< 0.01). A significant difference was noted in ODI, lumbar flexion range, and angle of straight leg raising between groups after two weeks of treatment (P< 0.05). Non-statistical significant difference was observed in lumbosacral portion pain and lower limb radiation pain with VAS (P> 0.05). However, difference in was VAS smaller in Group 1. All groups showed significantly different results in terms of ODI, lumbosacral portion pain, and lower limb radiation pain with VAS. CONCLUSION: As one of available treatments for LDP, HILT can speed up improvement in lumbar segment motion, angle of straight leg raising, and overall function and allow early return of patients to their family and society. Treatment effect is long-lasting and can be widely promoted and applied clinically. PMID- 28854501 TI - Clinical predictors of the medical interventions provided to patients with low back pain in the emergency department. AB - BACKGROUND: Low back pain is a common complaint in emergency departments (ED), where deviations from standard of care have been noted. OBJECTIVE: To relate the ordering of advanced imaging and opioid prescriptions with the presentation of low back pain in ED. METHODS: Six hundred adults with low back pain from three centers were prospectively analyzed for history, examination, diagnosis, and the ordering of tests and treatments. RESULTS: Of 559 cases the onset of pain was less than one week in 79.2%; however, most had prior low back pain, 63.5% having warning signs of a potential serious condition, and 83.9% had psychosocial risk factors. Computer tomography (CT) or magnetic resonance imaging (MRI) were ordered in 16.6%, opioids were prescribed in 52.6%, and hospital admission in 4.5%. A one-year follow-up of 158 patients found 40.8% received subsequent spine care and 5.1% had a medically serious condition. Caucasian race, age 50 years or older, warning signs, and radicular findings were associated with advanced imaging. Severe pain and psychosocial factors were associated with opioid prescribing. CONCLUSIONS: Most patients present to the ED with acute exacerbations of chronic low back pain. Risk factors for a serious condition are common, but rarely do they develop. Racial disparities and psychosocial factors had concerning relationships with clinical decision-making. PMID- 28854502 TI - Prognostic role of BiP/GRP78 expression as ER stress in patients with gastric adenocarcinoma. AB - PURPOSE: The glucose-regulated protein 78 (GRP78), also referred to as immunoglobulin heavy chain binding protein (BiP) (BiP/GRP78), is a major molecular chaperone in the endoplasmic reticulum (ER) and is extensively expressed in human neoplasms. Although the enhanced expression of BiP/GRP78 has been described to be associated with poor prognosis in gastric cancer (GC), details regarding its prognostic significance remain unclear. The aim of this study was to elucidate the prognostic role of BiP/GRP78 in patients with GC. METHODS: Study subjects included 328 patients who underwent surgical resection. Tumor specimens of primary tumors underwent immunohistochemical staining for BiP/GRP78. RESULTS: BiP/GRP78 was highly expressed in 57% (188/328) of patients. High expression of BiP/GRP78 was significantly associated with older age, male, disease staging, T factor, lymph node metastases, differentiation, lymphatic permeation, and vascular invasion. According to univariate analysis, age, disease staging, T factor, N factor, lymphatic permeation, vascular invasion, and BiP/GRP78 expression were significant prognostic factors for OS. In particular, high BiP/GRP78 expression was proven to be a significant predictor of prognosis in patients with older age, female sex, early disease stage, T1-2 factor, well or moderately differentiated tumors, and negative vascular invasion. CONCLUSION: BiP/GRP78 is significantly associated with tumor aggressiveness and progression. The increased expression of BiP/GRP78 was identified as an independent factor for predicting poor OS in patients with early stage of disease, especially T1-2 factor. PMID- 28854503 TI - The Utility of the Cognitive Function Instrument (CFI) to Detect Cognitive Decline in Non-Demented Older Adults. AB - BACKGROUND: Subjective cognitive complaint is a sensitive marker of decline. OBJECTIVE: This study aimed to (1) examine reliability of subjective cognitive complaint using the Cognitive Function Instrument (CFI), and (2) assess the utility of the CFI to detect cognitive decline in non-demented elders. METHODS: Data from a four-year longitudinal study at multiple Alzheimer's Disease Cooperative Study (ADCS) sites were extracted (n = 644). Of these, 497 had Clinical Dementia Rating (CDR) global scores of 0 and 147 had a CDR of 0.5. Mean age and education were 79.5+/-3.6 and 15.0+/-3.1 years, respectively. All participants and their study partners completed the subject and study partner CFI yearly. Modified Mini-Mental State Exam (mMMSE) and Free and Cued Selective Reminding Test (FCSRT) were administered. Scores below the predetermined cut-off scores on either measure at annual visit were triggers for a full diagnostic evaluation. Cognitive decline was defined by the absence/presence of the trigger. RESULTS: Three-month test retest reliability showed that inter-class coefficients for subject and study partner CFI were 0.76 and 0.78, respectively. Generalized estimating equation method revealed that both subject and study partner CFI change scores and scores from previous year were sensitive to cognitive decline in the CDR 0 group (p < 0.05). In the CDR 0.5 group, only the study partner CFI change score predicted cognitive decline (p < 0.05). CONCLUSION: Cognitive decline was predicted differentially by CDR level with subject CFI scores providing the best prediction for those with CDR 0 while study partner CFI predicted best for those at CDR 0.5. PMID- 28854504 TI - The Natural Product Curcumin as a Potential Coadjuvant in Alzheimer's Treatment. AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive impairment of patients, affecting around 12% of people older than 65 years old. WHO estimated that over 48.6 million all over the world suffer this disease. On the basis of cumulative results on our research, we have postulated the neuroimmunomodulation hypothesis that appears to provide a reasonable explanation of both the preclinical and clinical observations. In this context, the long-term activation of the innate immune system triggers an anomalous cascade of molecular signals, finally leading to tau oligomerization in the pathway to neuronal degeneration. In the present scenario of the failure of many anti-AD drugs, nutraceutical compounds provide an avenue for AD prevention and possibly as coadjuvants in the treatment of this disease. Recent discoveries point to the relevance of curcumin, a natural anti-inflammatory agent, in controlling oxidative stress and improving cholinergic function in the brain, even though the mechanisms underlying these actions are unknown. We investigated the effects of curcumin in cultures of neuronal cells. For this study, we exposed cells to prooxidant conditions, both in the presence and absence of curcumin. Our data reveal that curcumin exert a strong neuroprotective effect in N2a cells, thus preventing toxicity by oxidative agents H2O2 and Fe+3. This is supported by results that indicate that curcumin control the neurodegenerative effects of both oxidative agents, relieving cells from the loss of neuritogenic processes induced by prooxidants. In addition, curcumin was able to slow down the tau aggregation curve and disassemble tau pathological oligomeric structures. Data suggest that curcumin could be a potential compound for prevention of cognitive disorders associated with AD. PMID- 28854505 TI - Impact of prenatal diagnosis of fetus-in-fetu. AB - Fetus in fetu (FIF) is an extremely rare condition (1/500,000 live births) in which a fetiform structure is incorporated into the body of its twin. FIF can be a diagnostic dilemma due to its similarity to a teratoma, but identification of FIF is important for subsequent medical and surgical management. We compare two cases of fetal masses diagnosed on prenatal imaging that were later identified as FIF through further radiological, surgical, and pathologic evaluation. We use these cases to illustrate key pre- and postnatal features of FIF and highlight the benefits of prenatal detection and follow-up for postnatal management. PMID- 28854506 TI - Transfusion-related acute lung injury following PDA ligation in a preterm neonate. AB - Transfusion-related acute lung injury (TRALI) is a life-threatening complication of blood product transfusion characterized by sudden onset hypoxemic respiratory failure with bilateral lung infiltrates and non-cardiogenic pulmonary edema developing within 6 hours of transfusion. It is believed to be under-recognized, particularly among preterm neonates in whom co-existing developmental lung disease adds diagnostic complexity. Here we report the case of a preterm neonate who developed TRALI during a blood transfusion following PDA ligation. PMID- 28854507 TI - Improving handover between the transport team and neonatal intensive care unit staff in neonatal transports using the plan-do-study-act tool. AB - OBJECTIVES: The aim was to achieve 100% effective handover from the critical care transport team to the neonatal intensive care unit (NICU) medical team. STUDY DESIGN: All patients transferred from referring hospitals by the critical care transport team to the Level IV NICU were included. Data for each infant was collected prospectively. The percentage of transported patients for which medical team and nursing handover occurred was recorded. A quality improvement project was launched using the Plan-Do-Study-Act (PDSA) tool. We implemented several processes including call from the transport team before arrival and the completion of a transfer of care form on arrival to the NICU. The process measures and the outcome measure of completion of handover were monitored. Run charts of process measures and the outcome measure were analyzed. RESULTS: Completion of medical handover increased from 95% (baseline) to 100% after 3 PDSA cycles and this has been maintained for 18 consecutive months. CONCLUSION: Medical handover from the critical care transport team to the NICU medical staff has been achieved and sustained for all neonatal transports. PMID- 28854508 TI - The influence of the built environment on adverse birth outcomes. AB - Adverse birth outcomes are associated with neonatal morbidity and mortality, and higher risk for coronary heart disease, non-insulin-dependent diabetes and hypertension in adulthood. Although there has been considerable research investigating the association between maternal and environmental factors on adverse birth outcomes, one risk factor, not fully understood, is the influence of the built environment. A search of MEDLINE, Scopus, and Cochrane was conducted to find articles assessing the influence of the built environment on preterm birth (PTB), low birth weight (LBW), and small-for-gestational-age (SGA). In total, 41 studies met our inclusion criteria, and were organized into nine categories: Roadways, Greenness, Power Plants, Gas Stations/Wells, Waste Management, Power Lines, Neighborhood Conditions, Food Environment, and Industry. The most common built environmental variable was roads/traffic, encompassing 17/41 (41%) of the articles reviewed, of which 12/17 (71%) found a significant small to moderate association between high traffic exposure and adverse birth outcomes. PMID- 28854509 TI - Hemorrhagic cystitis in pregnancy: Case report and review of the literature. AB - Hemorrhagic cystitis is generally a benign self-limited disorder, however there are some severe cases which are associated to a significant blood loss. The etiology may be either bacterial, viral or chemical in origin; though the cause is not identified in most of the cases. Immunocompromised patients or patients who have undergone chemotherapy or radiation constitute the highest risk group. There are only a few articles about hemorrhagic cystitis in pregnancy, frequently associated with preterm labor. We describe, for the first time in literature, one patient with a clinical status of hematuria in two consequent pregnancies, without any identified cause and a medical history negative for recurrent or hemorrhagic cystitis and we report an overview of literature concerning this topic. PMID- 28854510 TI - Troponin-T as a biomarker in neonates with perinatal asphyxia. AB - BACKGROUND: Troponin-T is a commonly used cardiac biomarker, which could be useful in perinatal asphyxia. We aimed to analyze troponin-T concentrations in asphyxiated neonates and to correlate the concentrations with clinical outcomes. METHODS: Data were collected from electronic medical records of neonates diagnosed with perinatal asphyxia over a period of four years. RESULTS: There were 63 neonates with moderate to severe encephalopathy, in whom serial troponin T concentrations had been done on days 1, 3, and 7. 53 (84%) asphyxiated infants had troponin-T concentration >100 pg/ml at 2-4 h of life.The difference in troponin-T concentrations between moderate and severe encephalopathy was not statistically significant (173 vs. 263 pg/ml, p value 0.40). The difference in the concentrations at 72 hours between cooled and non-cooled neonates was not significant (48.5 vs. 62.5 pg/ml, p value 0.22). Troponin-T concentration was significantly higher in babies with hypotensive shock and hepatic injury, but not acute kidney injury. There was no significant correlation between troponin-T and the extent of resuscitation needed.Troponin-T concentration on day 1 of life was significantly higher in babies who died than who survived (407 vs. 168 pg/ml, p value 0.03). ROC curve for troponin-T to predict mortality had an area under the curve (AUC) of 0.803; the best cut-off value (190 pg/ml) had 82% sensitivity and 80% specificity. CONCLUSION: There was no significant difference in troponin-T concentrations between cooled and non-cooled neonates. Troponin-T concentration had a good predictive accuracy for mortality before discharge. PMID- 28854511 TI - Neonatal complex arrhythmias possibly related to a TTN mutation. AB - We describe a neonate born with complex arrhythmias that included concurrent atrial and ventricular tachycardias. Genetic testing demonstrated a mutation in the TTN gene, which codes for titin, a large protein found in striated muscle sarcomeres. The complex arrhythmias were successfully treated with amiodarone and flecainide. The patient remains asymptomatic with normal biventricular function. We speculate that the complex arrhythmias and TTN gene mutation may be related. PMID- 28854512 TI - Cerebral oxygenation and desaturations in preterm infants - a longitudinal data analysis. AB - OBJECTIVE: Hypoxemic episodes commonly occur in very preterm infants and may be associated with several adverse effects. Cerebral tissue oxygen saturation (StO2) as measured by near infrared spectroscopy (NIRS) may be a useful measure to assess brain oxygenation. However, knowledge on variability of StO2 is limited in preterm infants at this time, so StO2 dependency on arterial oxygenation (SpO2) and heart rate (HR) was assessed in preterm infants using statistical methods of time series analysis. STUDY DESIGN: StO2, SpO2, and HR were recorded from 15 preterm infants every 2 seconds for six hours. Statistical methods of time series and longitudinal data analysis were applied to the data. RESULT: The mean StO2 level was found as 72% (95% confidence interval (CI) 55.5% -85.5%) based on a moving average process with a 5 minute order. Accordingly, longitudinal SpO2 measurements showed a mean level of 91% (95% CI 69% -98%). Generally, compensation strategies to cope with both StO2 and SpO2 desaturations were observed in the studied patients. SpO2 had a significant effect on cerebral oxygenation (p < 0.001), but HR did not, which led to inconclusive results considering different time intervals. CONCLUSION: In infants with intermittent hypoxemia and bradycardia, we found a mean StO2 level of 72% and a strong correlation with SpO2. We observed large differences between individuals in the ability to maintain StO2 at a stable level. PMID- 28854513 TI - Preoperative metabolic acidosis in infants with gastroschisis. AB - INTRODUCTION: There is little in literature regarding preoperative management of infants with gastroschisis. It is unclear if these infants develop metabolic acidosis as a consequence of prolonged intrauterine gut compromise or dehydration secondary to increased fluid loss. AIM: To assess the frequency of preoperative metabolic acidosis in infants with gastroschisis and investigate whether this acidosis reflects degree of gut compromise. METHODS: All infants with gastroschisis born between May 2005 and April 2013 in a single tertiary care center were reviewed. Metabolic acidosis was defined by the presence of pH <7.26 and serum bicarbonate <18.5 or base excess < -8.5 mmol/l. Infants with significant birth depression were excluded. Maternal and neonatal data were collected. Frequency of preoperative metabolic acidosis and its association with gastroschisis prognostic score (GPS), time to first and time to reach full feeds were investigated. RESULTS: Sixty infants were identified, 11 were excluded (birth depression/lack of preoperative blood gases). Median preoperative total fluid intake was 130 ml/kg/d. Nine infants (18%) had metabolic acidosis at a median age of 1.2 hours. No association was found between metabolic acidosis or serum lactate and GPS, age at first feed or age at full feeds. CONCLUSION: Preoperative metabolic acidosis was identified in a significant number of patients with gastroschisis despite high fluid intake. It does not appear to be associated with the degree of gut compromise. Using metabolic acidosis as an indication of dehydration in these patients needs more investigation. PMID- 28854514 TI - Reduction in necrotizing enterocolitis and improved outcomes in preterm infants following routine supplementation with Lactobacillus GG in combination with bovine lactoferrin. AB - BACKGROUND: Preterm infants remain at high risk of adverse outcomes following necrotizing enterocolitis (NEC) and late onset sepsis (LOS). Meta-analysis of randomized trials has indicated a reduction in severe NEC following use of probiotics and bovine lactoferrin (LF). Overall, however, uncertainty remains over which probiotic, or combination to use. The aim of this study was to compare the incidence of severe NEC and LOS before and after routine supplementation with Lactobacillus GG (LGG) and LF. METHODS: In this retrospective cohort study, infants <32 weeks or <1500 g routinely received LGG and 100 mg lactoferrin daily from 2011 -2015 were compared with similar infants born from 2004-2008. Cases of NEC were Bell stage 2 or greater and LOS was blood or spinal fluid culture positive after 48 hrs of age. RESULTS: We noted a marked decline in the incidence of NEC from 3% to 1% with a RR of 0.29 (CI 0.1-0.9) and a number needed to benefit of 50. The cost of preventing one case of NEC was estimated to be NZ $2800, considerably lower than the cost of treatment. LOS rates were not significantly different. There was a decrease in retinopathy treatment rates. During the period there was one case of LGG sepsis in a 23 week gestation infant with abdominal pathology and one infant developed NEC after stopping prophylaxis. CONCLUSION: The rates of severe NEC was markedly reduced following prophylaxis. The case of LGG sepsis indicates caution is required in extremely preterm infants. PMID- 28854515 TI - Intravenous immunoglobulin in the management of a rare cause of hemolytic disease of the newborn: Anti-SARA antibodies. AB - Hemolytic disease of newborn (HDN) is a condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta and attack the fetal red blood cells. HDN can occur due to Rh and ABO incompatibilities between the mother and the fetus as well as due to other allo-immune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNS (M, N, S, and s) systems. Role of intravenous immunoglobulin in management of HDN is not clear.SARA red blood cell antigen, first discovered in 1990 is a low frequency antigen. We report, a multiparous female whose pregnancy was complicated by HDN due to anti-SARA antibodies requiring both exchange transfusion and intravenous immunoglobulin. The response was sustained after intravenous immunoglobulin (IVIG) rather than after exchange transfusion. PMID- 28854516 TI - Risk of morbidity following catheter removal among neonates with catheter associated bloodstream infection. AB - OBJECTIVE: We hypothesized that infectious morbidities following percutaneously inserted central venous catheter (PICC) removal would be greater among neonates with central-line associated bloodstream infection (CLBASI). STUDY DESIGN: This retrospective cohort study, included all neonates who required a PICC over a ten year period. Outcomes assessed following PICC removal included: late bloodstream infection, rule-out sepsis workups, need for a subsequent PICC and antibiotic days and PICC days after PICC removal. Odds ratios (OR) and 95% confidence intervals (CI) were determined for outcomes. Regression analyses were used to control for confounders. RESULTS: Two-thousand nine hundred and thirteen neonates required at least one PICC during the study period. After adjusting for confounders neonates with CLABSI were 3.4 (95% confidence interval (CI) 2.5, 4.6) and 2.2 (95% CI 1.2, 4.0) times more likely respectively to require a subsequent PICC or develop a late bloodstream infection after PICC removal. Neonates with CLABSI required 1.33 (95% CI 0.77, 1.89) more days of antibiotic treatment and 6.85 (95% CI 5.34, 8.37) more PICC days following PICC removal than neonates without a CLABSI. CONCLUSIONS: Neonates with CLABSI are at risk for additional infectious morbidities after PICC removal. Future intervention studies aimed at reducing CLABSI should evaluate whether morbidities following catheterization are also reduced. PMID- 28854518 TI - Intestinal perforation in the premature infant. AB - OBJECTIVE: To compare demographic data, prenatal and postnatal characteristics, laboratory data, and outcomes in a cohort of premature infants with spontaneous ileal perforation (SIP), surgical necrotizing enterocolitis (sNEC) and matched controls. METHODS: A retrospective case-control study of infants with intestinal perforation with a birth weight (BW) less than 2,000 grams and gestational age (GA) less than 34 weeks and infants without perforation matched for BW (+/-150 grams) and GA (+/-1week). RESULTS: 130 premature infants were included, 30 infants with SIP, 35 infants with sNEC and 65 control infants. The median age of onset was 5 days postnatal age in SIP versus 25 days in sNEC (p < 0.001) and the peak onset was at 26 weeks corrected GA for SIP and 30 weeks corrected GA for sNEC. Infants with perforation had significantly higher rates of mortality (p < 0.001) and common morbidities associated with prematurity. Administration of corticosteroids and indomethacin did not differ among groups. SIP was more common among infants born to young mothers (p = 0.04) and less common in infants receiving caffeine (p = 0.02). sNEC was less common among infants receiving early red cell transfusion (p = 0.01). Perforation and sNEC trended towards less common in infants receiving inhaled nitric oxide. CONCLUSION: SIP and sNEC are distinct clinical entities. Potential protective effects of caffeine, inhaled nitric oxide, and early transfusion should be further studied. PMID- 28854517 TI - The effect of meconium exposure on the expression and differentiation of amniotic fluid mesenchymal stem cells. AB - BACKGROUND: The goal of this study was to determine if exposure to meconium would alter the phenotype of amniotic fluid mesenchymal stem cells (AF-MSCs) and the ability of these cells to be differentiated into distal airway type cells. METHODS: Meconium was collected, lyophilized and resuspended in PBS at 3 different concentrations (high, medium, and low). AF-MSCs were cultured in the presence of this meconium suspension for 8 hours and then analyzed for changes in gene expression. Additionally, AF-MSCs exposed to meconium were differentiated for 14 days using modified small airway growth medium (mSAGM) and gene expression was determined. As a spontaneous differentiation control, meconium exposed AF MSCs were cultured in amniotic fluid stem cell medium (AF medium). RESULTS: After 8 hours of exposure in culture, AF-MSCs had increased expression of distal airway genes aquaporin 5 (AQP5) and surfactant protein c (SPC) when cultured in AF medium containing meconium. These gene expression levels were similar to that of AF-MSCs that were differentiated in mSAGM for 14 days. Furthermore, there was an up regulation of pluripotency genes NANOG and OCT4 in response to low meconium concentration for 8 hours. Following 14 days of culture in mSAGM, there was an upregulation of TTF1, SPC and AQP5 expression in the control, as well as in the low and medium meconium exposed groups indicating that these cells were still able to be differentiated. High meconium concentration did, however, appear to influence the level of distal airway gene expression after 14 days in mSAGM. After 14 days in AF medium, there was significant downregulation in pluripotency and mesenchymal markers as well as distal airway gene expression in all groups. CONCLUSION: The phenotype of AF-MSCs is modulated by meconium exposure; however, the cells were still able to differentiate into distal airway gene and protein expression. This result supports the hypothesis that progenitor cells exist in the amniotic fluid and the presence of meconium may affect their initial phenotype. However, these cells were still able to be differentiated to a distal lung phenotype. PMID- 28854519 TI - Isolated neonatal MRI punctate white matter lesions in very preterm neonates and quality of life at school age. AB - OBJECTIVE: To study the quality of life at school age of very preterm infants presenting isolated punctate periventricular white matter lesions (IPWL) on late preterm or term magnetic resonance imaging (MRI). METHODS: In 1996-2000, 16 of the 131 very preterm neonates explored by MRI were found to have IPWL. At the age of 9-14, 12 children from the IPWL group were compared with 54 children born preterm but with a normal MRI (no lesion). Quality of life (Health Status Classification System Pre School questionnaire), school performance, and motor outcome were investigated. RESULTS: Overall quality of life did not differ between the groups (classified as perfect in 2/12 of the IPWL vs 20/54 in the no lesion). The sub-items mobility and dexterity differed significantly between the two groups, with impairment in the IPWL group (p < 0.001 and p < 0.05). This group also displayed higher levels of motor impairment: they began walking later [20(4) vs. 15(3) months), p < 0.01], had higher frequencies of cerebral palsy (6/12 vs. 2/54, p < 0.05), and dyspraxia (4/12 vs. 0/54, p < 0.001). The rate of grade retention did not differ between the groups (3/12 in the IPWL group vs. 17/54 in the no-lesions group) but, as expected, was higher than that of the French general population (17.4%) during the study period. CONCLUSION: This long term follow-up study detected no increase in the risk of subsequent cognitive impairment in very preterm infants with IPWL, but suggests that these children may have a significantly higher risk of dyspraxia, and motor impairment. PMID- 28854520 TI - Neuroplasticity and behavioral effects of fluoxetine after experimental stroke. AB - The brain can undergo self-repair and has the ability to compensate for functions lost after a stroke. The plasticity of the ischemic brain is influenced by several factors including aging and pharmacotherapy. Fluoxetine is an antidepressant which enhances serotonergic neurotransmission through selective inhibition of neuronal reuptake of serotonin. In clinical practice, fluoxetine alleviates the symptoms of post-stroke depression (PSD), helps motor recovery in stroke patients. In animal experiments, chronic administration of fluoxetine induces increased excitability of mature granule cells (GCs), enhancing axonal and dendritic reorganization, as well as promoting neurogenesis or angiogenesis in the dentate gurus (DG), but the effect of fluoxetine in the subventricular zone (SVZ) remains controversial. Meanwhile, chronic treatment with fluoxetine did not reverse age-dependent suppression of proliferation cells in the DG. Interestingly, although fluoxetine has been found to enhance neurogenesis in the DG in stroke rats, this property is not consistent with the behavioral recovery. More studies into this issue will be required to reveal how to translate enhanced neuronal plasticity into behavioral benefits. This review provides an update of the current knowledge about the neurogenesis and the fate of the newly generated cells after the use of fluoxetine, as well as its ability to promote a behavioral recovery after stroke in clinical and experimental results and attempts to define the therapeutic properties of fluoxetine in regenerative neuroscience. PMID- 28854521 TI - Substitution-rate based screening model to assess stenosis progression in experimental stenotic arteriovenous grafts. AB - An arteriovenous graft (AVG) has a higher patency rate in stenosis progression at the venous anastomosis site, which causes coexisting inflow and outflow stenoses. This leads to increases in blood pressure, flow velocity, and flow resistance, resulting in hemodialysis (HD) vascular access dysfunction from early clots and thrombosis to the progression of coexisting stenoses. To prevent vascular access complications such as inflow or outflow stenoses, this study proposes a novel examination method in an experimental AVG system using a substitution-rate based screening model. In our practical measurements, we found that inflow and outflow channeled through a narrowed access indicated both pressure and resistance differences as the degree of stenosis (DOS) gradually increased. A substitution rate matrix was conducted to replace bilateral pressure variations, while a transition probability matrix was calculated. Differences in transition probabilities were then used to distinguish between normal conditions and flow instabilities using the distance estimation method. The joint probability decayed from < 0.81 to 0.00 could be specified to identify the progression in stenosis levels from a DOS% = 50.0-95.0%. Average joint probabilities were found to be inversely related with the DOS using a non-linear regression (R>2 0.90). Hence, the joint probability could be specified as a critical threshold, < 0.81, to identify the severity stenosis level, DOS% ? 70%, in the assessment of coexisting inflow and outflow stenoses. Experimental results suggest that the proposed model is superior to hemodynamic analysis and traditional intelligent method, and can be used for dysfunction screening during HD treatment. PMID- 28854522 TI - An investigation on effects of amputee's physiological parameters on maximum pressure developed at the prosthetic socket interface using artificial neural network. AB - Technological advances in prosthetics have attracted the curiosity of researchers in monitoring design and developments of the sockets to sustain maximum pressure without any soft tissue damage, skin breakdown, and painful sores. Numerous studies have been reported in the area of pressure measurement at the limb/socket interface, though, the relation between amputee's physiological parameters and the pressure developed at the limb/socket interface is still not studied. Therefore, the purpose of this work is to investigate the effects of patient specific physiological parameters viz. height, weight, and stump length on the pressure development at the transtibial prosthetic limb/socket interface. Initially, the pressure values at the limb/socket interface were clinically measured during stance and walking conditions for different patients using strain gauges placed at critical locations of the stump. The measured maximum pressure data related to patient's physiological parameters was used to develop an artificial neural network (ANN) model. The effects of physiological parameters on the pressure development at the limb/socket interface were examined using the ANN model. The analyzed results indicated that the weight and stump length significantly affects the maximum pressure values. The outcomes of this work could be an important platform for the design and development of patient-specific prosthetic socket which can endure the maximum pressure conditions at stance and ambulation conditions. PMID- 28854523 TI - Modeling of sectionally continuous communication channel with inhomogeneously distributed tissues. AB - BACKGROUND: This study aimed to investigate effects on the transmission channel caused by heterogeneous distribution in tissues and joint characteristics. METHOD: Human arm section scans were taken using CT technology, and zoned, following which, a circumference measurement experiment was performed to analyze the effect of inhomogeneous distribution of tissues. In order to analyze the arm joint's effect on channel transmission, we proposed a piecewise modeling method in combination with connection conditions. CONCLUSIONS: It can be seen from the experiment that, in the quasi-static mode, the communication channel error caused by the inhomogeneous distribution of tissues is small enough to be negligible. The error between calculated and experimental results is reduced by 3.93 dB in this experiment relative to models that did not include joint characteristics, and the average error is lowered by 0.73 dB. The variation curve fit to experimental data is also improved in this method. As such, it can be quantitatively determined that a channel model with joint characteristics is superior to models excluding joint characteristics. PMID- 28854524 TI - School sport-associated injuries in adolescents: A single center experience. AB - BACKGROUND: Each year, on average 1.26 million students face physical injuries at German schools and universities. Implementation of systematic prevention programs against school-associated injuries in adolescents is poor. Part of the reason might be a lack of data on nature and frequency of common school-associated injuries. OBJECTIVE: The aim of this study was to obtain qualitative and quantitative data that might help to develop prevention or protection strategies against sport-associated injuries at school. METHODS: A retrospective analysis was conducted on all patients between the ages of 10 and 16 years admitted from January 1st, 2009 to December 31st, 2013 to the emergency room of an academic teaching hospital for school-associated injuries (n= 901). For injuries associated with school sports, time of injury, type of sports and injured body region were analyzed. RESULTS: A significant part of school-associated injuries occurred in school sports (55.7%). The frequency of school sport-associated injuries per school day did not differ between months or seasons of the school year. Most injuries occurred between the ages of thirteen to fifteen. Ball sports were associated with 41% of all sport-associated injuries, particularly with soccer (22%). Distal extremities like hands (38.4%) and feet/ankle (30.3%) were predominantly injured, but only 5% of cases needed surgery. CONCLUSIONS: Most school-associated injuries occur in school sport, particularly with ball sports. Mostly, distal extremities were injured. Implementation of systematic prevention strategies for a reduction in finger injuries should be subject of future research. PMID- 28854525 TI - Clinical study on minimally invasive liquefaction and drainage of intracerebral hematoma in the treatment of hypertensive putamen hemorrhage. AB - OBJECTIVE: This study aims to compare the curative effect of different treatment methods of hypertensive putamen hemorrhage, in order to determine an ideal method of treatment; and to explore the curative effect of the application of soft channel technology-minimally invasive liquefaction and drainage of intracerebral hematoma in the treatment of hypertensive putamen hemorrhage. METHODS: Patients with hypertensive cerebral hemorrhage, who were treated in our hospital from January 2015 to January 2016, were included into this study. Patients were divided into three groups: minimally invasive drainage group, internal medical treatment group and craniotomy group. In the minimally invasive drainage group, puncture aspiration and drainage were performed according to different hematoma conditions detected in brain CT, the frontal approach was selected for putamen and intracerebral hemorrhage, and drainage was reserved until the hematoma disappeared in CT detection. Drug therapy was dominated in the internal medical treatment group, while surgery under general anesthesia was performed to remove the hematoma in the craniotomy group. RESULTS: Post-treatment neurological function defect scores in minimally invasive drainage group and internal medical group were 16.14 +/- 11.27 and 31.43 +/- 10.42, respectively; and the difference was remarkably significant (P< 0.01). Post-treatment neurological function defect scores in the minimally invasive drainage group and craniotomy group were 16.14 +/- 11.27 and 24.20 +/- 12.23, respectively; and the difference was statistically significant (P< 0.05). There was a remarkable significant difference in ADL1-2 level during followed-up in survival patients between the minimally invasive drainage group and internal medical treatment group (P< 0.01), and there was a significant difference in followed-up mortality between these two groups (P< 0.01). CONCLUSION: Clinical observation and following-up results revealed that minimally invasive drainage treatment was superior to internal medical treatment and craniotomy. PMID- 28854526 TI - A comparative study of three different gene expression analysis methods. AB - BACKGROUND: TNF-alpha regulates immune cells and acts as an endogenous pyrogen. Reverse transcription polymerase chain reaction (RT-PCR) is one of the most commonly used methods for gene expression analysis. Among the alternatives to PCR, loop-mediated isothermal amplification (LAMP) shows good potential in terms of specificity and sensitivity. OBJECTIVE: However, few studies have compared RT PCR and LAMP for human gene expression analysis. Therefore, in the present study, we compared one-step RT-PCR, two-step RT-LAMP and one-step RT-LAMP for human gene expression analysis. METHODS: We compared three gene expression analysis methods using the human TNF-alpha gene as a biomarker from peripheral blood cells. Total RNA from the three selected febrile patients were subjected to the three different methods of gene expression analysis. RESULTS: In the comparison of three gene expression analysis methods, the detection limit of both one-step RT PCR and one-step RT-LAMP were the same, while that of two-step RT-LAMP was inferior. One-step RT-LAMP takes less time, and the experimental result is easy to determine. CONCLUSIONS: One-step RT-LAMP is a potentially useful and complementary tool that is fast and reasonably sensitive. In addition, one-step RT-LAMP could be useful in environments lacking specialized equipment or expertise. PMID- 28854527 TI - 3D-Imaging evaluation of double aortic arch with MSCTA: A case report and mini review. AB - Double aortic arch (DAA) is a rare congenital anomaly associated with the formation of a vascular ring. Patients with DAA commonly suffer from complications caused by intracardiac and extracardiac malformations and different degrees of airway stenosis. Multislice computed tomographic angiography (MSCTA) is an intuitive and effective medical imaging technique in clinical diagnosis of DAA. MSCTA can accurately manifest the aortic arch and the course of the descending aorta and airway stenosis in three-dimension (3D). It is important to diagnose and make an operative plan for DAA. In this paper, we present a case of DAA diagnosed by MSCTA with 3D-static images and rotated reconstruction images and performed a mini-review. PMID- 28854528 TI - Combine TV-L1 model with guided image filtering for wide and faint ring artifacts correction of in-line x-ray phase contrast computed tomography. AB - In practice, mis-calibrated detector pixels give rise to wide and faint ring artifacts in the reconstruction image of the In-line phase-contrast computed tomography (IL-PC-CT). Ring artifacts correction is essential in IL-PC-CT. In this study, a novel method of wide and faint ring artifacts correction was presented based on combining TV-L1 model with guided image filtering (GIF) in the reconstruction image domain. The new correction method includes two main steps namely, the GIF step and the TV-L1 step. To validate the performance of this method, simulation data and real experimental synchrotron data are provided. The results demonstrate that TV-L1 model with GIF step can effectively correct the wide and faint ring artifacts for IL-PC-CT. PMID- 28854529 TI - A mathematical model to characterize the degree of coalification based on the low angle region of the X-ray diffractogram. AB - Based on X-ray diffraction (XRD) pattern of coal, an empirical model for judging the coalification degree is used to calculate the ratio of the 002 peak height to the Full width at half maximum (FWHM). However, the existing models are often simpler and more suitable for judgment of the medium and low rank coal, while are not feasible in determination of high rank coal. In order to address this issue, the objective of this study is to establish a new modified mathematical model based on optimization of the existing empirical models. Through the calculation of Bragg equation, it demonstrates that the low-angle region (2theta= 3-10 degrees ) in the XRD pattern reflects the information of micropore in coal with a diameter of (0.884-2.94) nm. Accordingly, its diffraction intensity corresponds to the porosity rate in coal. As a result, the modified mathematical model has been established for characterizing the coalification degree by introducing the variation of porosity rate with the coal ranks creatively. The synergistic effects of the change regulation of organic matter peak and the porosity rate with coal rank ensure the accuracy of the model. Furthermore, the good stability and high reliability of new model are verified through the recalculation of a total of 14 coal samples. Study results demonstrated that the new method enabled to determine coal rank more conveniently and accurately in the industrial production. PMID- 28854530 TI - Intelligent dynamic clinical checklists improved checklist compliance in the intensive care unit. AB - Background: Checklists can reduce medical errors. However, the effectiveness of checklists is hampered by lack of acceptance and compliance. Recently, a new type of checklist with dynamic properties has been created to provide more specific checklist items for each individual patient. Our purpose in this simulation-based study was to investigate a newly developed intelligent dynamic clinical checklist (DCC) for the intensive care unit (ICU) ward round. Methods: Eligible clinicians were invited to participate as volunteers. Highest achievable scores were established for six typical ICU scenarios to determine which items must be checked. The participants compared the DCC with the local standard of care. The primary outcomes were the caregiver satisfaction score and the percentages of checked items overall and of critical items requiring a direct intervention. Results: In total, 20 participants were included, who performed 116 scenarios. The median percentage of checked items was 100.0% with the DCC and 73.6% for the scenarios completed with local standard of care ( P <0.001). Critical items remained unchecked in 23.1% of the scenarios performed with local standard of care and 0.0% of the scenarios where the DCC was available ( P <0.001). The mean satisfaction score of the DCC was 4.13 out of 5. Conclusions: This simulation study indicates that an intelligent DCC significantly increases compliance with best practice by reducing the percentage of unchecked items during ICU ward rounds, while the user satisfaction rate remains high. Real-life clinical research is required to evaluate this new type of checklist further. PMID- 28854531 TI - Postoperative delirium in elderly patients is associated with subsequent cognitive impairment. AB - Background: We examined the risk for postoperative delirium (POD) in patients with mild cognitive impairment (MCI) or dementia, and the association between POD and subsequent development of MCI or dementia in cognitively normal elderly patients. Methods: Patients >=65 yr of age enrolled in the Mayo Clinic Study of Aging who were exposed to any type of anaesthesia from 2004 to 2014 were included. Cognitive status was evaluated before and after surgery by neuropsychological testing and clinical assessment, and was defined as normal or MCI/dementia. Postoperative delirium was detected with the Confusion Assessment Method for the intensive care unit. Logistic regression analyses were performed. Results: Among 2014 surgical patients, 74 (3.7%) developed POD. Before surgery, 1667 participants were cognitively normal, and 347 met MCI/dementia criteria. The frequency of POD was higher in patients with pre-existing MCI/dementia compared with no MCI/dementia {8.7 vs 2.6%; odds ratio (OR) 2.53, [95% confidence interval (CI) 1.52-4.21]; P <0.001}. Postoperative delirium was associated with lower education [OR, 3.40 (95% CI, 1.60-7.40); P =0.002 for those with <12 vs >=16 yr of schooling]. Of the 1667 patients cognitively normal at their most recent assessment, 1152 returned for postoperative evaluation, and 109 (9.5%) met MCI/dementia criteria. The frequency of MCI/dementia at the first postoperative evaluation was higher in patients who experienced POD compared with those who did not [33.3 vs 9.0%; adjusted OR, 3.00 (95% CI, 1.12-8.05); P =0.029]. Conclusions: Mild cognitive impairment or dementia is a risk for POD. Elderly patients who have not been diagnosed with MCI or dementia but experience POD are more likely to be diagnosed subsequently with MCI or dementia. PMID- 28854533 TI - Safety aspects of preoperative high-dose glucocorticoid in primary total knee replacement. AB - Background: Preoperative single high-dose glucocorticoid may have early outcome benefits in total hip arthroplasty (THA) and knee arthroplasty (TKA), but long term safety aspects have not been evaluated. Methods: From October 2013, the departments reporting to the prospective Lundbeck Foundation Database for Fast track Hip and Knee Replacement introduced preoperative methylprednisolone (MP) 125 mg as part of a multimodal analgesic protocol in TKA. We analysed the risk of length of hospital stay (LOS) >4 days, 30 and 90 day readmissions in patients with MP vs patients having TKA before the use of MP and adjusted for comorbidity and place of surgery. An unadjusted comparison was specifically done to evaluate deep prosthetic infections. Results: Of a total of 3927 TKA procedures, 1442 received MP. Median LOS was 2 days in both groups, but the fraction with LOS >4 days was 6.0% vs 11.5% (P<0.001) in patients with MP vs those without, and with a reduced risk of LOS >4 days in adjusted analysis [odds ratio (OR) 0.51; confidence interval (CI) 0.39-0.68; P <0.001]. Readmission rates were 5.6% (CI 4.5-6.9) vs 4.4% ( P =0.095) and 7.8% vs 7.3% ( P =0.53) at 30 and 90 days with and without MP, respectively. Conclusions: In this detailed prospective cohort study, preoperative high-dose glucocorticoid administration was not associated with LOS >4 days, readmissions or infectious complications in TKA patients without contraindications. PMID- 28854532 TI - Association of intraoperative changes in brain-derived neurotrophic factor and postoperative delirium in older adults. AB - Background: Delirium is common after surgery, although the aetiology is poorly defined. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in neurotransmission and neuroplasticity. Decreased levels of BDNF have been associated with poor cognitive outcomes, but few studies have characterized the role of BDNF perioperatively. We hypothesized that intraoperative decreases in BDNF levels are associated with postoperative delirium. Methods: Patients undergoing spine surgery were enrolled in a prospective cohort study. Plasma BDNF was collected at baseline and at least hourly intraoperatively. Delirium was assessed using rigorous methods, including the Confusion Assessment Method (CAM) and CAM for the intensive care unit. Associations of changes in BDNF and delirium were examined using regression models. Results: Postoperative delirium developed in 32 of 77 (42%) patients. The median baseline BDNF level was 7.6 ng ml -1 [interquartile range (IQR) 3.0-11.2] and generally declined intraoperatively [median decline 61% (IQR 31-80)]. There was no difference in baseline BDNF levels by delirium status. However, the percent decline in BDNF was greater in patients who developed delirium [median 74% (IQR 51-82)] vs in those who did not develop delirium [median 50% (IQR 14-79); P =0.03]. Each 1% decline in BDNF was associated with increased odds of delirium in unadjusted {odds ratio [OR] 1.02 [95% confidence interval (CI) 1.00-1.04]; P =0.01}, multivariable-adjusted [OR 1.02 (95% CI 1.00-1.03); P =0.03], and propensity score-adjusted models [OR 1.02 (95% CI 1.00-1.04); P =0.03]. Conclusions: We observed an association between intraoperative decline in plasma BDNF and delirium. These preliminary results need to be confirmed but suggest that plasma BDNF levels may be a biomarker for postoperative delirium. PMID- 28854534 TI - Intraoperative dexamethasone alters immune cell populations in patients undergoing elective laparoscopic gynaecological surgery. AB - Background: Anaesthetists use dexamethasone principally for its anti-emetic effect. The purpose of this study was to characterize the effects of a single intraoperative dose of dexamethasone on cellular and metabolic components of the immune system in patients undergoing laparoscopic surgical procedures. Methods: In this prospective double-blind trial, female patients undergoing elective major laparoscopic surgery were randomized to receive saline (Control group, n =16) or dexamethasone 4 mg (Dexamethasone group, n =16) i.v. after the induction of anaesthesia. Inflammatory markers and immune cell counts were examined at 24 and 48 h and 6 weeks after surgery. The changes from baseline preoperative values were compared between groups using a Mann-Whitney U -test, and linear mixed models were used to validate the findings. Results: No differences in concentrations of serum glucose and interleukin-6 were observed between groups after surgery. The increase in C-reactive protein concentration at 24 h after surgery was greater in the control group [median (interquartile range), 33 (25 65) vs 17 (7-26) mg dl -1 ; P =0.018]. Extensive changes in the counts of white cells, including most lymphocyte subsets, were observed 24 h after surgery, and dexamethasone appeared to attenuate most of these changes. Changes at 48 h and 6 weeks did not differ between groups. Conclusions: In female patients undergoing elective laparoscopic gynaecological surgery, dexamethasone administration appears to attenuate inflammation and to alter immune cell counts at 24 h, with no effects identified after this time. The importance of these changes for postoperative immune function is unknown. Trial registration: Australia and New Zealand Clinical Trials Registry (ACTRN12608000340336). PMID- 28854535 TI - Duty of candour: a statutory obligation or just the right thing to do? PMID- 28854536 TI - Use of failure-to-rescue to identify international variation in postoperative care in low-, middle- and high-income countries: a 7-day cohort study of elective surgery. AB - Background: The incidence and impact of postoperative complications are poorly described. Failure-to-rescue, the rate of death following complications, is an important quality measure for perioperative care but has not been investigated across multiple health care systems. Methods: We analysed data collected during the International Surgical Outcomes Study, an international 7-day cohort study of adults undergoing elective inpatient surgery. Hospitals were ranked by quintiles according to surgical procedural volume (Q1 lowest to Q5 highest). For each quintile we assessed in-hospital complications rates, mortality, and failure-to rescue. We repeated this analysis ranking hospitals by risk-adjusted complication rates (Q1 lowest to Q5 highest). Results: A total of 44 814 patients from 474 hospitals in 27 low-, middle-, and high-income countries were available for analysis. Of these, 7508 (17%) developed one or more postoperative complication, with 207 deaths in hospital (0.5%), giving an overall failure-to-rescue rate of 2.8%. When hospitals were ranked in quintiles by procedural volume, we identified a three-fold variation in mortality (Q1: 0.6% vs Q5: 0.2%) and a two-fold variation in failure-to-rescue (Q1: 3.6% vs Q5: 1.7%). Ranking hospitals in quintiles by risk-adjusted complication rate further confirmed the presence of important variations in failure-to-rescue, indicating differences between hospitals in the risk of death among patients after they develop complications. Conclusions: Comparison of failure-to-rescue rates across health care systems suggests the presence of preventable postoperative deaths. Using such metrics, developing nations could benefit from a data-driven approach to quality improvement, which has proved effective in high-income countries. PMID- 28854537 TI - Prognostic significance of central venous-to-arterial carbon dioxide difference during the first 24 hours of septic shock in patients with and without impaired cardiac function. AB - Objective: To investigate the prognostic significance of central venous-to arterial carbon dioxide difference (cv-art CO 2 gap) during septic shock in patients with and without impaired cardiac function. Methods: We performed a prospective cohort study in 10 French intensive care units. Patients suffering from septic shock were assigned to the impaired cardiac function group ('cardiac group', n =123) if they had atrial fibrillation (AF) and/or left ventricular ejection fraction (LVEF) <50% at study entry and to the non-cardiac group ( n =240) otherwise. Results: Central venous and arterial blood gases were sampled every 6 h during the first 24 h to calculate cv-art CO 2 gap. Patients in the cardiac group had a higher cv-art CO 2 gap [at study entry and 6 and 12 h (all P <0.02)] than the non-cardiac group. Patients in the cardiac group with a cv-art CO 2 gap >0.9 kPa at 12 h had a higher risk of day 28 mortality (hazard ratio=3.18; P =0.0049). Among the 59 patients in the cardiac group with mean arterial pressure (MAP) >=65 mm Hg, central venous pressure (CVP) >=8 mm Hg and central venous oxygen saturation (ScvO 2 ) >=70% at 12 h, those with a high cv art CO 2 gap (>0.9 kPa; n =19) had a higher day 28 mortality (37% vs. 13%; P =0.042). In the non-cardiac group, a high cv-art CO 2 gap was not linked to a higher risk of day 28 death, whatever the threshold value of the cv-art CO 2 gap. Conclusion: Patients with septic shock and with AF and/or low LVEF were more prone to a persistent high cv-art CO 2 gap, even when initial resuscitation succeeded in normalizing MAP, CVP, and ScvO 2 . In these patients, a persistent high cv-art CO 2 gap at 12 h was significantly associated with higher day 28 mortality. PMID- 28854538 TI - Dexmedetomidine pharmacokinetic-pharmacodynamic modelling in healthy volunteers: 1. Influence of arousal on bispectral index and sedation. AB - Background: Dexmedetomidine, a selective alpha 2 -adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. Methods: In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model. Volunteers were randomized to a session without background noise and a session with pre-recorded looped operating room background noise. Exploratory pharmacokinetic-pharmacodynamic modelling and covariate analysis were conducted in NONMEM using bispectral index (BIS) monitoring of processed EEG. Results: We found that both stimulation at the time of Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scoring and the presence or absence of ambient noise had an effect on the sedative properties of dexmedetomidine. The stimuli associated with MOAA/S scoring increased the BIS of sedated volunteers because of a transient 170% increase in the effect-site concentration necessary to reach half of the maximal effect. In contrast, volunteers deprived of ambient noise were more resistant to dexmedetomidine and required, on average, 32% higher effect-site concentrations for the same effect as subjects who were exposed to background operating room noise. Conclusions: The new pharmacokinetic pharmacodynamic models might be used for effect-site rather than plasma concentration target-controlled infusion for dexmedetomidine in clinical practice, thereby allowing tighter control over the desired level of sedation. Clinical trial registration: NCT01879865. PMID- 28854539 TI - Predicting successful supraclavicular brachial plexus block using pulse oximeter perfusion index. AB - Background: Supraclavicular nerve block is a popular approach for anaesthesia for upper limb surgeries. Conventional methods for evaluation of block success are time consuming and need patient cooperation. The aim of this study was to evaluate whether the perfusion index (PI) can be used to predict and provide a cut-off value for ultrasound-guided supraclavicular nerve block success. Methods: The study included 77 patients undergoing elective orthopaedic procedures under ultrasound-guided supraclavicular nerve block. After local anaesthetic injection, sensory block success was assessed every 3 min by pinprick, and motor block success was assessed every 5 min by the ability to flex the elbow and the hand against resistance. The PI was recorded at baseline and at 10, 20, and 30 min after anaesthetic injection in both blocked and non-blocked limbs. The PI ratio was calculated as the PI after 10 min divided by the PI at the baseline. Receiver operating characteristic curves were constructed for the accuracy of the PI in detection of block success. Results: The PI was higher in the blocked limb at all time points, and this was paralleled by a higher PI ratio compared with the unblocked limb. Both the PI and the PI ratio at 10 min after injection showed a sensitivity and specificity of 100% for block success at cut-off values of 3.3 and 1.4, respectively. Conclusions: The PI is a useful tool for evaluation of successful supraclavicular nerve block. A PI ratio of > 1.4 is a good predictor for block success. PMID- 28854541 TI - Predicting postoperative brain function from the blood: is there a role for biomarkers? PMID- 28854542 TI - Association between delirium and cognitive change after cardiac surgery. AB - Background: Previous studies provide inconsistent data on whether postoperative delirium (POD) is a risk factor for postoperative cognitive decline (POCD). We thus investigated the relationship between POD and cognitive change after cardiac surgery and assessed the relationship between preoperative cognitive domain scores and POD. Methods: Postoperative delirium was assessed with the Confusion Assessment Method (CAM) adapted for the intensive care unit and the conventional CAM accompanied by chart review. Cognitive function was assessed with a neuropsychological test battery before elective cardiac surgery and 1 month and 1 yr afterwards. Cognitive change was calculated using the Reliable Change Index (RCI). Multiple linear regression was used to adjust for confounding. Results: Of the 184 patients who completed baseline assessment, 23 (12.5%) developed POD. At 1 month, the decline in cognitive performance was worse in patients with POD [median composite RCI -1.00, interquartile range (IQR) -1.67 to 0.28] than in patients without POD (RCI -0.04, IQR -0.70 to 0.63, P =0.02). At 1 yr, both groups showed cognitive improvement on average compared with baseline (POD patients median composite RCI 0.25, IQR -0.42 to 1.31, vs non-POD patients RCI 0.92, IQR 0.18-1.53; P =0.08). Correction for differences in age and level of education did not change the results. Patients with POD performed less well than patients without POD on the preoperative Trailmaking test part A ( P =0.03). Conclusions: Postoperative delirium is independently associated with cognitive decline 1 month after surgery, but cognitive performance generally recovers in 1 yr. Patients with a predisposition to POD can be identified before surgery by worse performance in an attention task. Clinical trial registration: NCT00293592. PMID- 28854540 TI - Electroencephalography and delirium in the postoperative period. AB - Delirium commonly manifests in the postoperative period as a clinical syndrome resulting from acute brain dysfunction or encephalopathy. Delirium is characterized by acute and often fluctuating changes in attention and cognition. Emergence delirium typically presents and resolves within minutes to hours after termination of general anaesthesia. Postoperative delirium hours to days after an invasive procedure can herald poor outcomes. Easily recognized when patients are hyperactive or agitated, delirium often evades diagnosis as it most frequently presents with hypoactivity and somnolence. EEG offers objective measurements to complement clinical assessment of this complex fluctuating disorder. Although EEG features of delirium in the postoperative period remain incompletely characterized, a shift of EEG power into low frequencies is a typical finding shared among encephalopathies that manifest with delirium. In aggregate, existing data suggest that serial or continuous EEG in the postoperative period facilitates monitoring of delirium development and severity and assists in detecting epileptic aetiologies. Future studies are needed to clarify the precise EEG features that can reliably predict or diagnose delirium in the postoperative period, and to provide mechanistic insights into this pathologically diverse neurological disorder. PMID- 28854544 TI - Delirium, what's in a name? PMID- 28854543 TI - Dexmedetomidine pharmacodynamics in healthy volunteers: 2. Haemodynamic profile. AB - Background: Dexmedetomidine, a selective alpha 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate. Methods: Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target controlled infusion using the Dyck model. Exploratory PKPD modelling and covariate analysis were conducted in NONMEM. Results: Our model adequately describes dexmedetomidine-induced hypotension, hypertension, and bradycardia, with a greater effective concentration for the hypertensive effect. Changes in MAP were best described by a double-sigmoidal E max model with hysteresis. Covariate analysis revealed no significant covariates apart from age on the baseline MAP in the population pharmacokinetic model used to develop this PKPD model. Simulations revealed good general agreement with published descriptive studies of haemodynamics after dexmedetomedine infusion. Conclusions: The present integrated PKPD model should allow tighter control over the desired level of sedation, while limiting potential haemodynamic side-effects. Clinical trial registration: NCT01879865. PMID- 28854545 TI - Postoperative delirium portends descent to dementia. PMID- 28854546 TI - Frequency of surgical treatment and related hospital procedures in the UK: a national ecological study using hospital episode statistics. AB - Background: Despite evidence of high activity, the number of surgical procedures performed in UK hospitals, their cost and subsequent mortality remain unclear. Methods: Time-trend ecological study using hospital episode data from England, Scotland, Wales and Northern Ireland. The primary outcome was the number of in hospital procedures, grouped using three increasingly specific categories of surgery. Secondary outcomes were all-cause mortality, length of hospital stay and healthcare costs according to standard National Health Service tariffs. Results: Between April 1, 2009 and March 31, 2014, 39 631 801 surgical patient episodes were recorded. There was an annual average of 7 926 360 procedures (inclusive category), 5 104 165 procedures (intermediate category) and 1 526 421 procedures (restrictive category). This equates to 12 537, 8073 and 2414 procedures per 100 000 population per year, respectively. On average there were 85 181 deaths (1.1%) within 30 days of a procedure each year, rising to 178 040 deaths (2.3%) after 90 days. Approximately 62.8% of all procedures were day cases. Median length of stay for in-patient procedures was 1.7 (1.3-2.0) days. The total cost of surgery over the 5 yr period was L54.6 billion ($104.4 billion), representing an average annual cost of L10.9 billion (inclusive), L9.5 billion (intermediate) and L5.6 billion (restrictive). For each category, the number of procedures increased each year, while mortality decreased. One-third of all mortalities in national death registers occurred within 90 days of a procedure (inclusive category). Conclusions: The number of surgical procedures in the UK varies widely according to definition. The number of procedures is slowly increasing whilst the number of deaths is decreasing. PMID- 28854547 TI - Using a worldwide in-app survey to explore sugammadex usage patterns: a prospective observational study. PMID- 28854548 TI - Acute kidney injury following enhanced recovery for orthopaedic joint replacement surgery-role of preoperative kidney disease? PMID- 28854549 TI - Ultrasound-guided central venous catheterization in the prone position. PMID- 28854550 TI - Simulated emergency cricothyroid incision length. PMID- 28854551 TI - Efficacy of perineural vs systemic dexamethasone to prolong analgesia after peripheral nerve block: a systematic review and meta-analysis. AB - Perineural dexamethasone has gained popularity in regional anaesthesia to prolong the duration of analgesia, but its advantage over systemic administration is disputed. The objective of this meta-analysis was to compare the analgesic efficacy of both routes of administration during peripheral nerve block. The methodology followed the PRISMA statement guidelines. The primary outcome was the duration of analgesia analysed according to the type of local anaesthetic administered (bupivacaine or ropivacaine). Secondary outcomes included cumulative opioid consumption in morphine i.v. equivalents, pain scores, and complication rates (neurological complications, infection, or hyperglycaemia). Eleven controlled trials, including 914 patients, were identified. The duration of analgesia was significantly increased with perineural dexamethasone vs systemic dexamethasone by a mean difference of 3 h [95% confidence interval (CI): 1.4, 4.5 h; P=0.0001]. Subgroup analysis revealed that the duration of analgesia was increased by 21% with bupivacaine (mean difference: 4.0 h; 95% CI: 2.8, 5.2 h; P<0.00001) and 12% with ropivacaine (mean difference: 2.0 h; 95% CI: -0.5, 4.5 h; P=0.11). The quality of evidence for our primary outcome was moderate according to the GRADE system. There were no significant differences in other secondary outcomes. No neurological complications or infections were reported. Glucose concentrations were not increased when dexamethasone was injected systemically, but this outcome was reported by only two trials. There is, therefore, moderate evidence that perineural dexamethasone combined with bupivacaine, but not ropivacaine, slightly prolongs the duration of analgesia, without an impact on other pain-related outcomes, when compared with systemic dexamethasone. Injection of perineural dexamethasone should be cautiously balanced in light of the off label indication for this route of administration. PMID- 28854552 TI - Mind the gap when performing emergency front-of-neck access. PMID- 28854553 TI - Post-anaesthesia care unit delirium: incidence, risk factors and associated adverse outcomes. PMID- 28854555 TI - Availability of critical care services in Taiwan under National Health Insurance. PMID- 28854554 TI - Management of perioperative laryngospasm by French paediatric anaesthetists. PMID- 28854556 TI - Approach affects injectate spread in ultrasound-guided thoracic paravertebral block: a cadaveric trial. PMID- 28854557 TI - Topics for the national audit projects of the Royal College of Anaesthetists. PMID- 28854558 TI - How powerful is failure to rescue as a global metric? Not as powerful as a commitment to measurement. PMID- 28854560 TI - The Princes of Serendip. PMID- 28854561 TI - Sulforaphane suppresses PRMT5/MEP50 function in epidermal squamous cell carcinoma leading to reduced tumor formation. AB - Protein arginine methyltransferase 5 (PRMT5) cooperates with methylosome protein 50 (MEP50) to arginine methylate histone H3 and H4 to silence gene expression, and increased PRMT5 activity is associated with enhanced cancer cell survival. We have studied the role of PRMT5 and MEP50 in epidermal squamous cell carcinoma. We show that knockdown of PRMT5 or MEP50 results in reduced H4R3me2s formation, and reduced cell proliferation, invasion, migration and tumor formation. We further show that treatment with sulforaphane (SFN), a cancer preventive agent derived from cruciferous vegetables, reduces PRMT5 and MEP50 level and H4R3me2s formation, and this is associated with reduced cell proliferation, invasion and migration. The SFN-dependent reduction in PRMT5 and MEP50 level requires proteasome activity. Moreover, SFN-mediated responses are partially reversed by forced PRMT5 or MEP50 expression. SFN treatment of tumors results in reduced MEP50 level and H4R3me2s formation, confirming that that SFN impacts this complex in vivo. These studies suggest that the PRMT5/MEP50 is required for tumor growth and that reduced expression of this complex is a part of the mechanism of SFN suppression of tumor formation. PMID- 28854562 TI - Methylation of subtelomeric repeat D4Z4 in peripheral blood leukocytes is associated with biochemical recurrence in localized prostate cancer patients. AB - Global DNA methylation may affect chromosome structure and genomic stability and is involved in carcinogenesis. In this study, we aimed to investigate whether methylation of pericentromeric repeat NBL2 and subtelomeric repeat D4Z4 in peripheral blood was associated with the aggressiveness of prostate cancer (PCa). We measured the methylation status of different CpG sites of NBL2 and D4Z4 in 795 PCa patients and compared their methylation levels among patients with different Gleason Score at diagnosis. We then analyzed the association of the NBL2 and D4Z4 methylation with the risk of biochemical recurrence (BCR) in patients receiving radical prostatectomy or radiotherapy using a multivariate Cox proportional hazards model. In addition, we used the Kaplan-Meier survival function and log rank tests to assess BCR-free survival associated with D4Z4 methylation. There was no significant difference in methylation level of NBL2 and D4Z4 between clinically defined aggressive and non-aggressive PCa at diagnosis. However, the methylation of D4Z4 was associated with BCR, while the methylation of NBL2 was not. In tertile analysis, patients in the highest tertile of D4Z4 methylation had an increased risk of BCR (HR = 2.17, 95% CI 1.36-3.48) compared to patients in the lower tertiles after adjustment of age, body mass index, smoking status, pack year, D'Amico risk groups and treatments. Among the four CpG sites in this region, the association was mostly attributable to the methylation of the second CpG site of D4Z4. These data suggest that higher methylation in D4Z4 was associated with worse prognosis of localized PCa patients. PMID- 28854563 TI - Integrin alpha 10, CD44, PTEN, cadherin-11 and lactoferrin expressions are potential biomarkers for selecting patients in need of central nervous system prophylaxis in diffuse large B-cell lymphoma. AB - Central nervous system (CNS) relapse is a devastating complication that occurs in about 5% of diffuse large B-cell lymphoma (DLBCL) patients. Currently, there are no predictive biological markers. We wanted to study potential biomarkers of CNS tropism that play a role in adhesion, migration and/or in the regulation of inflammatory responses. The expression levels of ITGA10, CD44, PTEN, cadherin-11, CDH12, N-cadherin, P-cadherin, lactoferrin and E-cadherin were studied with IHC and IEM. GEP was performed to see whether found expressional changes are regulated at DNA/RNA level. IHC included 96 samples of primary CNS lymphoma (PCNSL), secondary CNS lymphoma (sCNSL) and systemic DLBCL (sDLBCL). IEM included two PCNSL, one sCNSL, one sDLBCL and one reactive lymph node samples. GEP was performed on two DLBCL samples, one with and one without CNS relapse. CNS disease was associated with enhanced expression of cytoplasmic and membranous ITGA10 and nuclear PTEN (P < 0.0005, P = 0.002, P = 0.024, respectively). sCNSL presented decreased membranous CD44 and nuclear and cytoplasmic cadherin-11 expressions (P = 0.001, P = 0.006, P = 0.048, respectively). In PCNSL lactoferrin expression was upregulated (P < 0.0005). IEM results were mainly supportive of the IHC results. In GEP CD44, cadherin-11, lactoferrin and E-cadherin were under-expressed in CNS disease. Our results are in line with previous studies, where gene expressions in extracellular matrix and adhesion-related pathways are altered in CNS lymphoma. This study gives new information on the DLBCL CNS tropism. If further verified, these markers might become useful in predicting CNS relapses. PMID- 28854565 TI - The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells. PMID- 28854564 TI - Epigenome-wide analysis of DNA methylation in lung tissue shows concordance with blood studies and identifies tobacco smoke-inducible enhancers. AB - Smoking-associated DNA hypomethylation has been observed in blood cells and linked to lung cancer risk. However, its cause and mechanistic relationship to lung cancer remain unclear. We studied the association between tobacco smoking and epigenome-wide methylation in non-tumor lung (NTL) tissue from 237 lung cancer cases in the Environment And Genetics in Lung cancer Etiology study, using the Infinium HumanMethylation450 BeadChip. We identified seven smoking-associated hypomethylated CpGs (P < 1.0 * 10-7), which were replicated in NTL data from The Cancer Genome Atlas. Five of these loci were previously reported as hypomethylated in smokers' blood, suggesting that blood-based biomarkers can reflect changes in the target tissue for these loci. Four CpGs border sequences carrying aryl hydrocarbon receptor binding sites and enhancer-specific histone modifications in primary alveolar epithelium and A549 lung adenocarcinoma cells. A549 cell exposure to cigarette smoke condensate increased these enhancer marks significantly and stimulated expression of predicted target xenobiotic response related genes AHRR (P = 1.13 * 10-62) and CYP1B1 (P < 2.49 * 10-61). Expression of both genes was linked to smoking-related transversion mutations in lung tumors. Thus, smoking-associated hypomethylation may be a consequence of enhancer activation, revealing environmentally-induced regulatory elements implicated in lung carcinogenesis. PMID- 28854566 TI - Impact of transposable elements on polyploid plant genomes. AB - Background: The growing wealth of knowledge on whole-plant genome sequences is highlighting the key role of transposable elements (TEs) in plant evolution, as a driver of drastic changes in genome size and as a source of an important number of new coding and regulatory sequences. Together with polyploidization events, TEs should thus be considered the major players in evolution of plants. Scope: This review outlines the major mechanisms by which TEs impact plant genome evolution and how polyploidy events can affect these impacts, and vice versa. These include direct effects on genes, by providing them with new coding or regulatory sequences, an effect on the epigenetic status of the chromatin close to genes, and more subtle effects by imposing diverse evolutionary constraints to different chromosomal regions. These effects are particularly relevant after polyploidization events. Polyploidization often induces bursts of transposition probably due to a relaxation in their epigenetic control, and, in the short term, this can increase the rate of gene mutations and changes in gene regulation due to the insertion of TEs next to or into genes. Over longer times, TE bursts may induce global changes in genome structure due to inter-element recombination including losses of large genome regions and chromosomal rearrangements that reduce the genome size and the chromosome number as part of a process called diploidization. Conclusions: TEs play an essential role in genome and gene evolution, in particular after polyploidization events. Polyploidization can induce TE activity that may explain part of the new phenotypes observed. TEs may also play a role in the diploidization that follows polyploidization events. However, the extent to which TEs contribute to diploidization and fractionation bias remains unclear. Investigating the multiple factors controlling TE dynamics and the nature of ancient and recent polyploid genomes may shed light on these processes. PMID- 28854569 TI - Linking smokers to a quitline: randomized controlled effectiveness trial of a support person intervention that targets non-smokers. AB - Evidence-based treatments (e.g. quitlines) are greatly underutilized by smokers limiting their public health impact. A three-session phone intervention for nonsmoking family members and friends (i.e. support persons) was successful for increasing smoker quitline enrollment. To enhance the intervention's potential translatability, in this study, we delivered treatment for the non-smoker within ongoing quitline services and compared the efficacy of the three-call intervention to a streamlined version (one call). A total of 704 adult non smokers (85% female, 95% White) wanting to help a smoker quit and recruited statewide in Minnesota participated in this randomized controlled trial with parallel groups. Non-smokers received mailed written materials and were randomly assigned to a control condition (no additional treatment, n = 235), or to a one- (n = 233) or three-call (n = 236) intervention delivered by quitline coaches. The main outcome was smoker quitline enrollment through 7-month follow-up. Smoker quitline enrollment was similar for those linked to non-smokers in the one- and three-call interventions (14.6% [34/233] and 14.8% [35/236]), and higher than for smokers linked to control participants (6.4% [15/235]), P = 0.006. Just one quitline coaching call delivered to non-smokers increased treatment enrollment among smokers. The reach of quitlines could be enhanced by targeting the social support network of smokers. PMID- 28854570 TI - Involving mosques in health promotion programmes: a qualitative exploration of the MCLASS intervention on smoking in the home. AB - Second-hand smoke (SHS) exposure is high among UK Bangladeshi and Pakistani populations, reflecting higher male smoking prevalence and fewer home smoking restrictions than the general population. The Muslim Communities Learning About Second-hand Smoke (MCLASS) study explored the feasibility and acceptability of implementing SHS education in 14 UK mosques. Religious teachers (RTs) in seven intervention mosques were trained and provided with a culturally appropriate educational package. After the intervention, mosque leaders, RTs and congregants' experiences and perceptions of the intervention were explored through interviews and focus group discussions. Delivery of the intervention varied across mosques. Facilitators and barriers included: mosque diversity (congregation size, organizational structure, educational activities, women's role and involvement); degree of trust between researchers and personnel; and views on SHS. Most participants thought mosques' involvement in SHS health promotion was appropriate, but the perceived importance of SHS differed. We found that a health promotion programme delivered within Islamic religious settings that engages RTs in the process of facilitation, can be acceptable and feasible, but care must be taken to explore the culture and ethos of the institution, including its organizational structure, management committee, RTs and congregation. PMID- 28854567 TI - Polyploidy and interspecific hybridization: partners for adaptation, speciation and evolution in plants. AB - Background: Polyploidy or whole-genome duplication is now recognized as being present in almost all lineages of higher plants, with multiple rounds of polyploidy occurring in most extant species. The ancient evolutionary events have been identified through genome sequence analysis, while recent hybridization events are found in about half of the world's crops and wild species. Building from this new paradigm for understanding plant evolution, the papers in this Special Issue address questions about polyploidy in ecology, adaptation, reproduction and speciation of wild and cultivated plants from diverse ecosystems. Other papers, including this review, consider genomic aspects of polyploidy. Approaches: Discovery of the evolutionary consequences of new, evolutionarily recent and ancient polyploidy requires a range of approaches. Large-scale studies of both single species and whole ecosystems, with hundreds to tens of thousands of individuals, sometimes involving 'garden' or transplant experiments, are important for studying adaptation. Molecular studies of genomes are needed to measure diversity in genotypes, showing ancestors, the nature and number of polyploidy and backcross events that have occurred, and allowing analysis of gene expression and transposable element activation. Speciation events and the impact of reticulate evolution require comprehensive phylogenetic analyses and can be assisted by resynthesis of hybrids. In this Special Issue, we include studies ranging in scope from experimental and genomic, through ecological to more theoretical. Conclusions: The success of polyploidy, displacing the diploid ancestors of almost all plants, is well illustrated by the huge angiosperm diversity that is assumed to originate from recurrent polyploidization events. Strikingly, polyploidization often occurred prior to or simultaneously with major evolutionary transitions and adaptive radiation of species, supporting the concept that polyploidy plays a predominant role in bursts of adaptive speciation. Polyploidy results in immediate genetic redundancy and represents, with the emergence of new gene functions, an important source of novelty. Along with recombination, gene mutation, transposon activity and chromosomal rearrangement, polyploidy and whole-genome duplication act as drivers of evolution and divergence in plant behaviour and gene function, enabling diversification, speciation and hence plant evolution. PMID- 28854571 TI - Effectiveness of a web-based intervention to reduce alcohol consumption among French hazardous drinkers: a randomized controlled trial. AB - This study aims to evaluate the effectiveness of a web-based intervention to reduce alcohol consumption among hazardous drinkers. A two-group parallel randomized controlled trial was conducted among adults identified as hazardous drinkers according to the Alcohol Use Disorders Identification Test. The intervention delivers personalized normative feedback and some general information about alcohol. Participants can review their motivations and fears regarding reducing their alcohol intake, set individual goals and monitor their progress via a consumption diary and other tools. Within the control group, participants were provided with the same diary but could not access other services from the program. The primary outcome measure was the absolute difference in weekly alcohol intake (WAI) between baseline and 6-week follow-up. Secondary outcome measures included: relative difference in WAI; difference in excessive drinking and significant WAI reduction (decrease of 10% or more in WAI). One thousand one hundred and forty-seven people participated in the trial and 339 subjects completed it. Relative to the control group, participants in the intervention group reported a significantly greater mean absolute reduction in WAI (-3.3 versus -1.2, P = 0.03). Secondary outcomes also presented significant effects. This trial provides preliminary support to the effectiveness of this program in helping hazardous drinkers reduce their drinking, provided it is completely and regularly used. PMID- 28854572 TI - Planning community-based assessments of HIV educational intervention programs in sub-Saharan Africa. AB - A key consideration in planning studies of community-based HIV education programs is identifying a sample size large enough to ensure a reasonable probability of detecting program effects if they exist. Sufficient sample sizes for community- or group-based designs are proportional to the correlation or similarity of individuals within communities. As a result, efficient and effective design requires reasonable a priori estimates of the correlational structure among individuals within communities. In this study, we investigate the degree of correlation among individuals within communities and regions using samples of sixth-grade adolescents from 609 local area district communities and 122 regions in 15 sub-Saharan African nations. We develop nation-specific and international summaries of these correlations using variance partitioning coefficients from multilevel models and subsequently assess the extent to which different types of background variables delineate key sources of these correlations. The results suggest persistent differences among communities and regions and that the degree of correlation among individuals within communities varied considerably by nation. The findings underscore the importance of empirically derived values of design parameters that are anchored in evidence specific to the outcome, nation and context of the planned study. PMID- 28854573 TI - Evaluation of a sexual abuse prevention education program for school-age children in China: a comparison of teachers and parents as instructors. AB - The aim of this present study was to evaluate the effectiveness of a child sexual abuse (CSA) prevention curriculum toward children and to compare the knowledge gains between children who were taught by teachers and their parents. Four hundred and eighty-four school-age children recruited from one primary school in Beijing, China, were randomly assigned to a CSA prevention program administered by teachers or their parents or to a wait-list control group. The findings reveal that children in the teacher education group demonstrated the highest level of CSA prevention knowledge and skills, followed by the parent education group, while children in the control group showed the least improvements. The knowledge and skills gains were retained at a 12-week follow-up. The present study shows that Chinese school-age children can benefit from CSA prevention program with increased knowledge and skills of personal safety. School-based CSA prevention education should be improved and implemented in other regions of China. PMID- 28854574 TI - Feasibility and acceptability of a web-based HIV/STD prevention program for adolescent girls targeting sexual communication skills. AB - Adolescent girls are at substantial risk of sexually transmitted diseases including HIV. To reduce these risks, we developed Health Education And Relationship Training (HEART), a web-based intervention focused on developing sexual assertiveness skills and enhancing sexual decision-making. This study assessed the feasibility and acceptability of this new program and examined if perceived acceptability varied according to participant ethnicity, sexual orientation or sexual activity status. Participants were part of a randomized controlled trial of 222 10th-grade girls (Mage = 15.26). The current analyses included those in the intervention condition (n = 107; 36% white, 27% black and 29% Hispanic). HEART took approximately 45 min to complete and was feasible to administer in a school-based setting. Participants found the program highly acceptable: 95% liked the program and learned from the program, 88% would recommend the program to a friend and 94% plan to use what they learned in the future. The primary acceptability results did not vary by the ethnicity, sexual orientation or sexual activity status of participants, suggesting broad appeal. Results indicate that this new online program is a promising method to reach and engage adolescents in sexual health education. PMID- 28854575 TI - University students' perceived risk of and intention to use waterpipe tobacco. AB - Emerging tobacco product use is increasing. We evaluated factors associated with perceived risk of and intention to use waterpipe tobacco by surveying students at a large university in the southeastern U.S. (N = 667). Proportional odds modeling assessed whether demographic characteristics and social acceptability are associated with perceived risk of waterpipe tobacco use; and if these factors and perceived risk are related to intention to use waterpipe tobacco. Participants who perceived waterpipe tobacco to be more socially acceptable had lower odds of perceiving it as risky (95% confidence interval [CI] 0.50-0.68). Compared with never users, former tobacco users and current users had lower odds of perceiving waterpipe tobacco use as risky (95% CI 0.38-0.80 and 0.28-0.63, respectively). Similarly, students with greater perceived social acceptability scores had higher odds of intending to use waterpipe tobacco (95% CI 1.41-2.63), while those who perceived greater risk had lower odds of intending to use it (95% CI 0.34-0.64). Compared with never users, former users had higher odds of intending to use waterpipe tobacco (95% CI 1.42-7.21). Among those who had ever used waterpipe tobacco, 90% reported 'to socialize' as the most frequent reason for deciding to do so. Findings underscore the need for future prevention efforts. PMID- 28854576 TI - Genetics of age-related macular degeneration (AMD). AB - Age-related macular degeneration (AMD) is a progressive blinding disease and represents the leading cause of visual impairment in the aging population. AMD affects central vision which impairs one's ability to drive, read and recognize faces. There is no cure for this disease and current treatment modalities for the exudative form of the disease require repeated intravitreal injections which may be painful, are incompletely efficacious, and represent a significant treatment burden for both the patient and physician. As such, AMD represents a significant and important clinical problem.It is anticipated that in three years' time, 196 million individuals will be affected with AMD. Over 250 billion dollars per year are spent on care for AMD patients in the US. Over half of the heritability is explained by two major loci, thus AMD is considered the most well genetically defined of the complex disorders. A recent GWAS on 43,566 subjects identified novel loci and pathways associated with AMD risk, which has provided an excellent platform for additional functional studies. Genetic variants have been investigated, particularly with respect to anti-VEGF treatment, however to date, no pharmacogenomic associations have been consistently identified across these studies. It may be that if the goal of personalized medicine is to be realized and biomarkers are to have predictive value for determining the magnitude of risk for AMD at the genetic level, one will need to examine the relationships between these pathways across disease state and relative to modifiable risk factors such as hypertension, smoking, body mass index, and hypercholesterolemia. Further studies investigating protective alleles in populations with low AMD prevalence may lead to this goal. PMID- 28854578 TI - The molecular genetics of eye diseases. PMID- 28854577 TI - RNA expression in human retina. AB - Recent Genome-wide Association Studies (GWASs) for eye diseases/traits have delivered a number of novel findings across a diverse range of diseases, including age-related macular degeneration (AMD), glaucoma and refractive error. However, despite this astonishing rate of success, the major challenge still remains to not only confirm that the genes implicated in these studies are truly the genes conferring protection from or risk of disease but also to define the functional roles these genes play in disease. Ongoing evidence is accumulating that the single nucleotide polymorphisms (SNPs) used in GWAS and fine mapping studies have causal effects through their influence on gene expression rather than affecting protein function. The biological interpretation of SNP regulatory effects for a tissue requires knowledge of the transcriptome for that tissue. We summarize the reasons to characterize the complete retinal transcriptome as well as the evidence to include an assessment of differences in regional retinal expression. PMID- 28854579 TI - Structome analysis of Escherichia coli cells by serial ultrathin sectioning reveals the precise cell profiles and the ribosome density. AB - Structome analysis, the quantitative three-dimensional structural analysis of whole cells at the electron microscopic level, of Exophiala dermatitidis (black yeast), Saccharomyces cerevisiae, Mycobacterium tuberculosis (MTB) and Myojin spiral bacteria (MSB) have already been reported. Here, the results of the structome analysis of Escherichia coli cells based on transmission electron microscope observation of serial ultrathin sections was reported, and compared with the data obtained from phase contrast microscopy and scanning electron microscopy. On average, the cells had 0.89 MUm in diameter, 2.47 MUm in length and 1.16 fl (MUm3) in cell volume in the structome analysis. Furthermore, E. coli cells had 26 100 ribosomes per whole cell with density of 2840 per 0.1 fl cytoplasm. The total ribosome number per cell was 15 times larger than that of MTB and about one-eighth of those of the yeast cells above. On the other hand, the ribosome density of E. coli cells are more than 13 times, 4 times, 2.5-times and 1.5-times higher than MSB, MTB, E. dermatitidis and S. cerevisiae, respectively. Finally, our ribosome enumeration data were compared between the structome-analyzed species and the relationship between the ribosome density and the growth rate among these species was discussed. PMID- 28854580 TI - Ovarian response to controlled ovarian hyperstimulation: what does serum FSH say? AB - STUDY QUESTION: Do serum FSH levels on day of hCG trigger differ between women with a poor, normal or hyper response to a fixed daily dose of 150 IU recombinant FSH (rFSH)? SUMMARY ANSWER: There is no consistent relationship between ovarian response and serum FSH levels on day of hCG trigger in a 150 IU fixed dose treatment protocol. WHAT IS KNOWN ALREADY: When ovarian response to stimulation for IVF/ICSI is suboptimal, the FSH dose is often adjusted in a subsequent cycle, thereby assuming that serum FSH levels were inadequate for optimal stimulation. STUDY DESIGN, SIZE, DURATION: Nested cohort study within a randomized controlled trial conducted at the University Medical Centre Utrecht between March 2009 and July 2011. Blood was drawn from 124 women on cycle Day 2 and on day of hCG triggering. Serum FSH level was determined by the Beckman-Coulter Unicel DXi800 chemiluminescence assay. In order to detect a difference of 2 IU/L between poor, normal and hyper responders, a total of 64 participants (16 poor, 32 normal and 16 hyper responders) would provide 80% power, assuming a standard deviation of 2 and an alpha of 0.05. PARTICIPANTS, SETTING, METHODS: Women aged <=39 years with a regular cycle and fixed FSH dose of 150 IU. Exclusion criteria: BMI > 32 kg/m2 and >2 previous unsuccessful IVF/ICSI cycles. The primary outcome measure was serum FSH level on day of triggering. MAIN RESULTS AND THE ROLE OF CHANCE: Median [range] body weight was 70.0 kg [55.0-85.6], 68.0 kg [52.0-94] and 60.6 kg [51.0 78.0] for poor (n = 16), normal (n = 94) and hyper (n = 17) responders, respectively. Mean (SD) serum FSH levels on day of triggering were 9.5 IU/L (2.4) in poor, 10.4 IU/L (2.3) in normal and 11.5 IU/L (2.2) in hyper responders. Serum FSH levels on day of hCG in poor responders differed significantly as compared to those in hyper responders (P = 0.03). LIMITATIONS, REASONS FOR CAUTION: The number of retrieved oocytes is only minimally determined by serum FSH level on the day of hCG trigger. After correction for age, body weight, basal serum FSH and basal anti-Mullerian hormone the correlation between serum FSH level on the day of hCG and ovarian response regarding the number of retrieved oocytes disappeared. WIDER IMPLICATIONS OF THE FINDINGS: The current study shows that a poor response is not related to inadequate serum FSH levels per se. One could therefore question whether increasing the rFSH dose in women with a suboptimal response is meaningful. In women with a hyper response, however, lowering the dose of rFSH in a subsequent IVF cycle may lead to lower serum FSH levels and thereby mitigate ovarian response and improve safety of the IVF treatment. As this was not a dose-response study, future research should assess whether dose adjustments benefit the poor and hyper responder. STUDY FUNDING/COMPETING INTEREST(S): No external funds were obtained for this study. S.C.O, T.C.v.T., O.H., H.L.T., E.G.W.M.L., C.B.L. and M.J.C.E. have nothing to disclose. F.J.M.B. receives monetary compensation: member of the external advisory board for Merck Serono and Ferring, the Netherlands; educational activities for Ferring BV, the Netherlands; consultancy work for Gedeon Richter, Belgium; strategic cooperation with Roche on automated AMH assay development and research cooperation with Ansh Labs. PMID- 28854581 TI - Unexplained recurrent miscarriages are associated with an aberrant sperm protamine mRNA content. AB - STUDY QUESTION: Are unexplained recurrent miscarriages associated with abnormal protamine-1 and protamine-2 mRNA levels in spermatozoa? SUMMARY ANSWER: Both protamine-1 and protamine-2 mRNA levels as well as the protamine-1 to protamine-2 mRNA ratio in spermatozoa from men whose female partners experienced two or more consecutive miscarriages were significantly different compared to those from both healthy control men and subfertile couples undergoing IVF/ICSI. WHAT IS KNOWN ALREADY: Aberrant sperm protamine ratios are known to be associated with male factor infertility. Data from this study suggest that the protamine mRNA ratio may additionally affect early embryo development. STUDY DESIGN, SIZE, DURATION: The study population was recruited from men whose female partners presented with two or more consecutive unexplained miscarriages in a consultation for recurrent pregnancy loss between 2014 and 2016. At the research laboratory of the Urological Clinic of the University Giessen, spermatozoa from cases and controls were subjected to reverse transcription quantitative PCR (RTqPCR) using specific primer pairs for protamine-1 and protamine-2. PARTICIPANTS/MATERIALS, SETTING, METHODS: Protamine-1 and protamine-2 mRNA levels were analysed in semen samples from 25 men whose female partners experienced at least two consecutive idiopathic miscarriages before the 20th week of gestation. The couples were recruited during consultation at the Fertility Center of the LMU Munich, Germany, and at the Clinical Division of Gynecologic Endocrinology and Reproductive Medicine of the Medical University of Vienna, Austria. Results were compared with those from 32 healthy donors (WHO, 2010) recruited at the Department of Urology, Pediatric Urology and Andrology, Giessen, Germany, and 107 men whose partners participated in an IVF/ICSI program at the Fertility Center of the LMU Munich, Germany. MAIN RESULTS AND THE ROLE OF CHANCE: Protamine-1 and protamine-2 mRNA levels as well as the protamine mRNA ratio and all routine semen parameters revealed significant differences between recurrent miscarriage couples and healthy volunteers (P < 0.01). When comparing recurrent miscarriage couples with couples undergoing IVF/ICSI, Ct-values of protamine-1 and protamine-2 mRNAs were significantly higher and the protamine mRNA ratio was significantly lower in RM couples (P < 0.01). When comparing protamine mRNA levels and the protamine mRNA ratio with routine semen parameters, a significant negative correlation was evident between progressive motility and the protamine-2 mRNA level (P = 0.015), as well as between non-progressive motility and the protamine mRNA ratio (P = 0.023). LIMITATIONS REASONS FOR CAUTION: Although our data demonstrate significant abnormalities in RM, larger sample sizes will be needed to confirm our results. Larger sample sizes should also balance the fact that we had to focus mainly on median protamine mRNA levels. Finally, men in the healthy control group were younger in age than those in the case group, which might have introduced some bias, at least concerning the classic semen parameters. Moreover, only protamine mRNA instead of protein levels could be measured. WIDER IMPLICATIONS OF THE FINDINGS: Although the exact mechanism remains to be elucidated, our data suggest that protamine mRNA levels in spermatozoa are not only important for successful fertilization, but also for proper development of the early embryo. STUDY FUNDING/COMPETING INTEREST(S): Grant from the University Clinic Giessen and Marburg (UKGM 29/2015GI). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 28854582 TI - Incidence, prevalence, diagnostic delay, morbidity, mortality and socioeconomic status in males with 46,XX disorders of sex development: a nationwide study. AB - STUDY QUESTION: What is the epidemiology and trajectory of health and socioeconomic status in males with 46,XX disorders of sex development (DSD)? SUMMARY ANSWER: 46,XX DSD males had an increased overall morbidity compared to male background population controls, and the socioeconomic status was inferior on outcome parameters such as education and long-term income. WHAT IS KNOWN ALREADY: 46,XX DSD males are rare and estimates of prevalence and incidence are limited. An increased morbidity and mortality as well as a negatively affected socioeconomic status are described in males with Klinefelter Syndrome. However, this has never been systematically studied in 46,XX DSD males. STUDY DESIGN, SIZE, DURATION: In this nationwide registry study including 44 males with a verified diagnosis of 46,XX DSD we aimed to estimate incidence, prevalence and diagnostic delay. Further, we aimed to study morbidity, mortality and socioeconomic outcome parameters using the Danish registries. The socioeconomic outcome parameters were education, income, retirement, parenthood and cohabitation. 46,XX DSD males were born during 1908-2012 and follow-up started at birth or at start of registration and ended in 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Potential cases (n = 69) were identified in the Danish Cytogenetic Central Registry and the diagnosis was verified by medical record evaluation (n = 44). A randomly selected age-matched control group of 100 males and 100 females per case was identified by Statistics Denmark. MAIN RESULTS AND THE ROLE OF CHANCE: Among newborn males the prevalence of diagnosed 46,XX DSD males was 3.5-4.7 per 100 000. Median age at diagnosis was 17.0 years (range: 0.0 62.8). Overall morbidity was increased compared to male controls (hazard ratio [HR] = 2.4, 95% CI: 1.8-3.3) but not when excluding endocrine and urogenital diseases as well as congenital malformations (HR = 1.2, 95% CI: 0.8-1.6). Mortality was not increased (HR = 0.6, 95% CI: 0.2-2.5) compared to male controls. 46,XX DSD males had poorer education (HR = 0.1, 95% CI: 0.0-0.9) and fewer fatherhoods (HR = 0.4, 95% CI: 0.2-0.7) than male controls, and their income was reduced for the following age groups; 45-49 years: odds ratio [OR] = 0.4 (95% CI: 0.2-0.7); 50-54 years: OR = 0.1 (95% CI: 0.0-0.6). LIMITATIONS, REASONS FOR CAUTION: The study cohort is rather small, although it is large in comparison to other studies on 46,XX DSD males. Some 46,XX DSD males may have been excluded from the study owing to lack of data in medical records, making the diagnosis impossible to verify. As in all epidemiologic studies a risk of misclassification must be considered when interpreting the study results, and as the study included diagnosed 46,XX DSD males only, conclusions cannot be extended to non-diagnosed 46,XX DSD males. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a new insight into trajectory of health and socioeconomic status of 46,XX DSD males. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by research grants from the Health Research Fund of Central Denmark Region, the A.P. Moller Foundation 'Fonden til Laegevidenskabens Fremme', the Lundbeck Foundation and the Novo Nordisk Foundation (NNF13OC0003234 and NNF15OC0016474). The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A. PMID- 28854583 TI - Non-equivalence of anti-Mullerian hormone automated assays-clinical implications for use as a companion diagnostic for individualised gonadotrophin dosing. AB - STUDY QUESTION: Can anti-Mullerian hormone (AMH) automated immunoassays (Elecsys(r) and Access) be used interchangeably as a companion diagnostic for individualisation of follitropin delta dosing? SUMMARY ANSWER: The Access assay gives systematically higher AMH values than the Elecsys(r) assay which results in over 29% of women being misclassified to a different follitropin delta dose. WHAT IS KNOWN ALREADY: Follitropin delta is the first gonadotrophin to be licenced with a companion diagnostic, the Roche Elecsys(r) AMH Plus assay. Alternative automated AMH assays including the Beckman Coulter Access immunoassay are considered to provide similar results, but clarification of their suitability as an off-licence companion diagnostic for follitropin delta is required. STUDY DESIGN, SIZE, DURATION: We systematically searched the existing literature for studies that had measured AMH using both automated assays in the same cohort of women. Individual paired patient data were acquired from each author and combined with unpublished data. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified five eligible prospective published studies and one additional unpublished study. A 100% response from the authors was achieved. We collected paired AMH data on samples from 848 women. Passing-Bablok regression and Bland-Altman plots were used to compare the analytical performance of the two assays. The degree of misclassification to different treatment categories was estimated should the Access AMH be used as a companion diagnostic instead of the Elecsys AMH in determining the dosing of follitropin delta. MAIN RESULTS AND THE ROLE OF CHANCE: The Passing-Bablok regression shows a linear relationship (Access = -0.05 + 1.10 * Elecsys). The Access assay systematically gave higher values by an average of 10% compared with the Elecsys assay (slope = 1.10, 95% CI: 1.09 to 1.12). The average of the difference between the two assays was 2.7 pmol/l. The 95% limits of agreement were -11.7 to 6.3. Overall 253 (29.3%) women would have received an inappropriate follitropin delta dose if the Beckman Coulter Access assay was used. Specifically, a substantial proportion of women (ranging from 49% to 90% depending on the AMH category) would receive a lower dose of follitropin delta based on the Access AMH assay. Up to 10% (ranging from 2.5% to 10%) of women with high ovarian reserve would have been misclassified to a greater dose of follitropin delta based on the Access AMH assay. LIMITATIONS REASONS FOR CAUTION: We compared the values of the two principal automated assays, extrapolation of our findings to other automated AMH assays would require similar comprehensive examination. WIDER IMPLICATIONS OF THE FINDINGS: An international standard for the calibration of the automated AMH assays is warranted to facilitate efficient use of AMH as a companion diagnostic. The variable calibration of alternative automated AMH assays may adversely impact on the performance of the follitropin delta dosing algorithm. STUDY FUNDING/COMPETING INTEREST(S): No formal funding has been received for this study. SI is funded by a UK Medical Research Council skills development fellowship (MR/N015177/1). SMN has received speakers fees, travel to meetings and participated in advisory Boards for Beckman Coulter, IBSA, Ferring Pharmaecuticals, Finox, Merck Serono, Merck and Roche Diagnostics. SMN has received research support from Ansh laboratories, Beckman Coulter, Ferring Pharmaceuticals and Roche Diagnostics. TRIAL REGISTRATION NUMBER: N/A. PMID- 28854584 TI - Polycystic ovarian morphology and the diagnosis of polycystic ovary syndrome: redefining threshold levels for follicle count and serum anti-Mullerian hormone using cluster analysis. AB - STUDY QUESTION: Can cluster analysis be used to differentiate between normo ovulatory women with normal ovaries and normo-ovulatory women with polycystic ovarian morphology (PCOM) in a non-subjective manner? SUMMARY ANSWER: Cluster analysis can be used to accurately and non-subjectively differentiate between normo-ovulatory women with normal ovaries and normo-ovulatory women with PCOM. WHAT IS KNOWN ALREADY: Currently, PCOM is diagnosed using a fixed threshold level, i.e. 12 or more follicles per ovary, and is one of the diagnostic criteria of polycystic ovary syndrome (PCOS). However, PCOM is also encountered in normo ovulatory women, suggesting that it could just represent a normal variant. On the other hand, recent studies have shown subtle endocrine abnormalities in women with isolated PCOM that resemble those found in women with PCOS. Because of the strong correlation between anti-Mullerian hormone (AMH) and follicle number, a high serum AMH level has been proposed as a surrogate marker for PCOM and could, therefore, be integrated in the diagnostic classifications for PCOS. STUDY DESIGN, SIZE, DURATION: This was a retrospective observational cohort study. Original cohorts had been recruited for previous studies between 1998 and 2010. Two hundred ninety-seven regularly cycling women and 700 women with PCOS were eligible for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cluster analysis was performed in 297 regularly cycling women. After exclusion of 'PCOM' clusters, each 'non-PCOM' cluster (young, n = 118 and old, n = 100) was included in the construction of a receiver operating characteristics curve to test the diagnostic performance of follicle number per ovary (FNPO) and serum AMH in discriminating similarly aged full-blown PCOS patients (n = 411 and 237, respectively) from normal regularly cycling non-PCOM women. MAIN RESULTS AND ROLE OF CHANCE: The optimal number of clusters was four; age was the most important classifying variable, followed by the FNPO and serum AMH. Two distinct clusters of normo-ovulatory women with PCOM were isolated and differed solely by age, i.e. 'young' and 'old'. Both 'PCOM' clusters had their similarly aged counterpart of 'non-PCOM' clusters. Likewise, two clusters comprised women younger than 30 years, with (n = 28, 'PCOM regularly cycling women') or without (n = 118, 'normal regularly cycling women') features of PCOM (increased FNPO and/or serum AMH). The two other clusters in older women could be labelled 'normal regularly cycling women' or 'PCOM regularly cycling women' (n = 100 and 51, respectively). The prevalence of PCOM was significantly greater in old than in young regularly cycling women controls. In the young population, after exclusion of the 'PCOM regularly cycling women', the diagnostic performance of AMH, expressed by area under the curve (AUC) (AUC = 0.903; CI (0.876-0.930)) to differentiate PCOS women from normal regularly cycling women was similar to that using the FNPO (AUC = 0.915, CI (0.891-0.940)) (P = 0.25), confirming results from earlier studies. In the old population, the diagnostic performance of AMH was greater than that of FNPO (AUCs = 0.948 (0.927-0.970) vs 0.874 (0.836-0.912), respectively, P = 0.00035). Cut-off levels of AMH and antral follicle count distinguishing regularly cycling non-PCOM women from PCOS women were higher in young women than in older women. LIMITATIONS, REASONS FOR CAUTION: Data of normal women were obtained from earlier studies, aiming to measure normal endocrine values. Apparently, the strong effect of age in cluster analysis revealed a dichotomy in the age distribution among the cohort of regularly cycling women included. This was involuntary since in none of the original studies, eligibility was limited by age and there was considerable overlap in age ranges of the cohorts. Transvaginal ultrasound was performed using a 6.5-8 mHz probe and our data confirm that this threshold level for FNPO is still valid if using such probe frequencies, although the use of devices with a maximum frequency lower than 8 mHz has become obsolete. Obviously, newer ultrasound scanner using higher transducer frequency will facilitate the detection of more follicles. WIDER IMPLICATIONS OF THE FINDINGS: Our data support the use of AMH as a surrogate for ultrasound to define PCOM, which is one of the three items of the Rotterdam classification. They also show that age should be taken into account to define the optimal threshold. The fact that the prevalence of PCOM was increased in the older regularly cycling women, may be due to 'attenuated' PCOS, a phenomenon that has been described in ageing women with PCOS. These women might have had anovulatory cycles in the past and have become ovulatory with increasing age, and were, therefore, eligible for this study. However, since most women included at older age have had spontaneous pregnancies in the past, PCOM at older age may be associated with a subclinical form of PCOS, which may also be present in young regularly cycling women. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. J.S.E.L. has received grants and support from Ferring, MSD, Organon, Merck-Serono, Schering Plough and Serono during recruitment and analysis of data for this study. S.L.F., A.D. and D.D. do not have any conflict of interest. PMID- 28854585 TI - Sperm chemorepulsion, a supplementary mechanism to regulate fertilization. AB - STUDY QUESTION: Are human spermatozoa able of chemorepulsive behaviour? SUMMARY ANSWER: Capacitated human spermatozoa are able to be chemorepelled by synthetic Progesterone Receptor Ligands (sPRL, known as contraceptives) and zinc (a cation released by the oocyte upon fertilization). WHAT IS KNOWN ALREADY: Moving cells can be oriented towards or against a molecular gradient, processes called chemoattraction and chemorepulsion, respectively, which have been described in unicellular organisms such as amoebas and bacteria, to organismic cells such macrophages and developmental cells. In the case of spermatozoa, chemoattraction may help the finding of an oocyte and has been widely studied in various invertebrate and mammalian species; however, chemorepulsion has not yet been verified in spermatozoa. STUDY DESIGN, SIZE, DURATION: This is an in vitro study involving human, rabbit and mouse spermatozoa which were used to perform 3-30 experiments per treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human sperm samples were obtained by masturbation from healthy donors who gave written consent. Only those samples exhibiting normal semen parameters according to current WHO criteria were included in the study. Rabbit spermatozoa were obtained by artificial vagina whereas mice spermatozoa were obtained from epididymis. The sperm selection assay (SSA), originally designed to evaluate sperm chemoattraction towards progesterone (P), and a video-microscopy and computer motion analysis system were used to test sperm chemorepulsion. Additional kinetic parameters were also determined by video-microscopy and computer motion analysis. In some experiments, the level of induced acrosome-reacted spermatozoa was determined. Rabbit mating manipulation was achieved to perform the sperm-oocyte co-incubation assay. MAIN RESULTS AND THE ROLE OF CHANCE: Sperm accumulation in the well containing 100 pg/ml of sPRL was lower than the culture medium negative control (P < 0.05). The percentage of sperm persistence against the well containing 100 pg/ml ulipristal acetate (UPA) (P = 0.001), and the percentage of sperm showing a repulsive pattern of movement (a linear trajectory followed by a transitional one after turning against the UPA), were higher than the culture medium negative control (P = 0.049). Sperm accumulation was diminished when spermatozoa where exposed to a homogeneous distribution of 100 pg/ml sPRL combined with a chemotactic gradient of progesterone (P), with respect to the culture medium negative control (P < 0.05). These results were reverted when non capacitated spermatozoa were used to perform the same experimental settings. The accumulation of spermatozoa against 100 pg/ml sPRL was lower than the culture medium negative control also in rabbits and mice (P < 0.05). The relative number of rabbit spermatozoa arriving to the vicinity of the oocyte was diminished under the presence of 100 pg/ml UPA (P = 0.004). Sperm accumulation in the well containing zinc was decreased compared to the culture medium negative control (P < 0.05). A homogeneous distribution of zinc combined with a gradient of 10 pM P, was lower than the culture medium negative control (P = 0.016). The results were quite reproducible with two different methodologies (accumulation assay and video microscopy combined with computer motion analysis), in three mammalian species. LIMITATIONS REASONS FOR CAUTION: The experiments were performed in vitro. Even though a quite complete characterization of sperm chemorepulsion was provided, the molecular mechanism that governs sperm repulsion is currently under investigation. WIDER IMPLICATIONS OF THE FINDINGS: Since the chemorepelled spermatozoa are those physiologically ready to fertilize the oocyte, these findings may have both biological and clinical implications, preventing either polyspermy under natural conditions or fertilization under pharmacological treatment with sPRL. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by the Universidad Nacional de Cordoba (Argentina). The authors declare that they do not have competing financial interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 28854587 TI - Prospective study of automated versus manual annotation of early time-lapse markers in the human preimplantation embryo. AB - STUDY QUESTION: How does automated time-lapse annotation (EevaTM) compare to manual annotation of the same video images performed by embryologists certified in measuring durations of the 2-cell (P2; time to the 3-cell minus time to the 2 cell, or t3-t2) and 3-cell (P3; time to 4-cell minus time to the 3-cell, or t4 t3) stages? SUMMARY ANSWER: Manual annotation was superior to the automated annotation provided by EevaTM version 2.2, because manual annotation assigned a rating to a higher proportion of embryos and yielded a greater sensitivity for blastocyst prediction than automated annotation. WHAT IS KNOWN ALREADY: While use of the EevaTM test has been shown to improve an embryologist's ability to predict blastocyst formation compared to Day 3 morphology alone, the accuracy of the automated image analysis employed by the EevaTM system has never been compared to manual annotation of the same time-lapse markers by a trained embryologist. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cohort study of embryos (n = 1477) cultured in the EevaTM system (n = 8 microscopes) at our institution from August 2014 to February 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos were assigned a blastocyst prediction rating of High (H), Medium (M), Low (L), or Not Rated (NR) by EevaTM version 2.2 according to P2 and P3. An embryologist from a team of 10, then manually annotated each embryo and if the automated and manual ratings differed, a second embryologist independently annotated the embryo. If both embryologists disagreed with the automated EevaTM rating, then the rating was classified as discordant. If the second embryologist agreed with the automated EevaTM score, the rating was not considered discordant. Spearman's correlation (rho), weighted kappa statistics and the intra-class correlation (ICC) coefficients with 95% confidence intervals (CI) between EevaTM and manual annotation were calculated, as were the proportions of discordant embryos, and the sensitivity, specificity, positive predictive value (PPV) and NPV of each method for blastocyst prediction. MAIN RESULTS AND THE ROLE OF CHANCE: The distribution of H, M and L ratings differed by annotation method (P < 0.0001). The correlation between EevaTM and manual annotation was higher for P2 (rho = 0.75; ICC = 0.82; 95% CI 0.82-0.83) than for P3 (rho = 0.39; ICC = 0.20; 95% CI 0.16-0.26). EevaTM was more likely than an embryologist to rate an embryo as NR (11.1% vs. 3.0%, P < 0.0001). Discordance occurred in 30.0% (443/1477) of all embryos and was not associated with factors such as Day 3 cell number, fragmentation, symmetry or presence of abnormal cleavage. Rather, discordance was associated with direct cleavage (P2 <= 5 h) and short P3 (<=0.25 h), and also factors intrinsic to the EevaTM system, such as the automated rating (proportion of discordant embryos by rating: H: 9.3%; M: 18.1%; L: 41.3%; NR: 31.4%; P < 0.0001), microwell location (peripheral: 31.2%; central: 23.8%; P = 0.02) and EevaTM microscope (n = 8; range 22.9-42.6%; P < 0.0001). Manual annotation upgraded 82.6% of all discordant embryos from a lower to a higher rating, and improved the sensitivity for predicting blastocyst formation. LIMITATIONS, REASONS FOR CAUTION: One team of embryologists performed the manual annotations; however, the study staff was trained and certified by the company sponsor. Only two time-lapse markers were evaluated, so the results are not generalizable to other parameters; likewise, the results are not generalizable to future versions of EevaTM or other automated image analysis systems. WIDER IMPLICATIONS OF THE FINDINGS: Based on the proportion of discordance and the improved performance of manual annotation, clinics using the EevaTM system should consider manual annotation of P2 and P3 to confirm the automated ratings generated by EevaTM. STUDY FUNDING/COMPETING INTEREST(S): These data were acquired in a study funded by Progyny, Inc. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 28854586 TI - Folate, homocysteine and the ovarian cycle among healthy regularly menstruating women. AB - STUDY QUESTION: How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women? SUMMARY ANSWER: Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone. WHAT IS KNOWN ALREADY: Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake. MAIN RESULTS AND THE ROLE OF CHANCE: Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, 1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation. LIMITATIONS, REASONS FOR CAUTION: Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation. WIDER IMPLICATIONS OF THE FINDINGS: If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women. Study FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose. PMID- 28854588 TI - A pilot randomized controlled trial of Day 3 single embryo transfer with adjunctive time-lapse selection versus Day 5 single embryo transfer with or without adjunctive time-lapse selection. AB - STUDY QUESTION: Compared to D5 selection with conventional morphology (CM), does adjunctive use of the EevaTM test on D3 or D5 improve the clinical pregnancy rate (CPR) per transfer? SUMMARY ANSWER: The evidence is insufficient to conclude that adjunctive use of the EevaTM test on D3 or D5 improves CPR per transfer as compared to D5 selection with CM. WHAT IS KNOWN ALREADY: Time-lapse imaging is increasingly used for embryo selection, despite there being no class I data to support its clinical application. STUDY DESIGN, SIZE, DURATION: Pilot randomized controlled trial included 163 patients from August 2014 to February 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients up to age 41 years with a planned fresh autologous single embryo transfer (SET), less than four prior oocyte retrievals, and four or more zygotes were blocked according to age (<35, 35-37, 38-40 years) and randomized to one of three study arms: (1) D3 SET + EevaTM, (2) D5 SET + EevaTM or (3) D5 SET with CM alone. All embryos were cultured in the same time-lapse system under identical conditions. Intention-to treat (ITT) and as-treated analyses of the primary endpoint (CPR at 7 weeks) and secondary endpoint (ongoing pregnancy rate at 12 weeks) were performed. Multivariate regression analyses adjusted for patient age and ICSI. MAIN RESULTS AND THE ROLE OF CHANCE: Of 478 eligible patients, 217 consented and 163 were randomized. Demographic characteristics were similar among the three study arms. There were no statistically significant differences in the clinical pregnancy rate or the ongoing pregnancy rate between the study arms for either the ITT or as-treated analyses (CPR ITT: D3 + EevaTM: 41.1% vs. D5 + EevaTM: 38.9% vs. D5 CM: 49.1%). LIMITATIONS, REASONS FOR CAUTION: This study was designed as a pilot randomized controlled trial and was not powered to detect a statistically significant difference at alpha < 0.05. Importantly, the study was terminated prematurely by the sponsor due to a change in funding priorities, so the sample size is limited and the results should be interpreted with caution due to the role of chance. Furthermore, these findings may not be generalizable to other time-lapse systems. WIDER IMPLICATIONS OF THE FINDINGS: Our findings do not support the clinical application of these time-lapse markers. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Progyny, Inc. There are no competing interests. TRIAL REGISTRATION NUMBER: clinicaltrials.gov: NCT02218255. TRIAL REGISTRATION DATE: 14 August 2014. DATE OF FIRST PATIENT'S ENROLLMENT: 3 September 2014. PMID- 28854589 TI - Use of the serum anti-Mullerian hormone assay as a surrogate for polycystic ovarian morphology: impact on diagnosis and phenotypic classification of polycystic ovary syndrome. AB - STUDY QUESTION: Does the use of the serum anti-Mullerian hormone (AMH) assay to replace or complement ultrasound (U/S) affect the diagnosis or phenotypic distribution of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Combining U/S and the serum AMH assay to define polycystic ovarian morphology (PCOM) diagnoses PCOS (according to the Rotterdam classification) in more patients than definitions using one or the other of these indicators exclusively. WHAT IS KNOWN ALREADY: Since 2003, PCOM, as defined by U/S, is one of the three diagnostic criteria for PCOS. As it is closely correlated with follicle excess seen at U/S, an excessive serum AMH level could be used as a surrogate for PCOM. STUDY DESIGN, SIZE, DURATION: Single-center retrospective study from a database of prospectively collected clinical, laboratory and ultrasound data from patients referred for oligo-anovulation (OA) and/or hyperandrogenism (HA) between January 2009 and January 2016. PARTICIPANTS/MATERIALS, SETTING, METHOD: The standard Rotterdam classification for PCOS was tested against two modified versions that defined PCOM by either excessive serum AMH level alone (AMH-only) or a combination (i.e. 'and/or') of the latter and U/S. The PCOS phenotypes were defined as A (full phenotype, OA+HA+PCOM), B (OA+HA), C (HA+PCOM) and D (OA+PCOM). MAIN RESULTS AND THE ROLE OF CHANCE: PCOS was more frequently diagnosed when PCOM was defined as the combination 'positive U/S' and/or 'positive AMH' (n = 639) than by either only U/S-only (standard definition, n = 612) or by AMH-only (n = 601). With this combination, PCOM was recognized in 637 of the 639 cases that met the Rotterdam classification, and phenotype B practically disappeared. In this population, U/S and AMH markers were discordant for PCOM in 103 (16.1%) cases (9% U/S-only, 7.1% AMH-only, P = 0.159). The markers used had no other significant impact on the phenotypic distribution (except for phenotype B). However, the percentage of cases positive by U/S-only was significantly higher in phenotype D than in phenotype A (14.1% vs. 5.8%, P < 0.05). Furthermore, in the discordant cases, plasma LH levels were significantly higher in the AMH-only group than in the concordant cases, and fasting insulin serum levels tended to be higher in the U/S-only group. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study. A referral bias explains the relatively high proportion of patients with phenotype D (28%). PCOM was defined by in-house thresholds. The AMH assay used is no longer commercially available. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that ideally both U/S data and serum AMH level should be integrated to define PCOM in the Rotterdam classification. In a cost-effectiveness approach, the choice of one or the other has little impact on the diagnosis and the phenotyping of PCOS. STUDY FUNDING/COMPETING INTEREST(S): No external funding. The authors have no conflict of interest to declare. PMID- 28854590 TI - Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome. AB - STUDY QUESTION: Would letrozole as a primary ovulation induction agent generate better pregnancy rates than clomiphene citrate (CC) in subfertile women with anovulatory polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Participants receiving letrozole as a primary treatment achieved a significantly (P = 0.022) higher clinical pregnancy rate per patient (61.2%) compared to CC (43.0%). WHAT IS KNOWN ALREADY: According to a recent Cochrane systematic review (2014), letrozole appears to improve live-birth (LB) and pregnancy rates in anovulatory women with PCOS, compared to CC. However, the review concluded that the quality of evidence was low due to poor reporting of study methods and possible publication bias. STUDY DESIGN, SIZE, DURATION: This double-blind randomized controlled trial (RCT) included 159 participants between April 2007 and June 2014. Subjects were randomly allocated to either CC (n = 79) or letrozole (n = 80) in a 1:1 ratio. Both drugs were encapsulated to look identical. Randomization was performed in mixed blocks and stratified by patients' BMI (<30 and 30-35 kg/m2). PARTICIPANTS/MATERIALS, SETTING, METHODS: The trial included subfertile women diagnosed with PCOS. Treatment started with one tablet (CC 50 mg, letrozole 2.5 mg) increasing to two in non-responders and continuing until pregnancy or for up to six ovulatory cycles. Non-responders were crossed over to the other treatment after a 6-week break. Cycles were initially monitored with ultrasound follicle tracking then mid-luteal serum progesterone measurement in subsequent cycles. MAIN RESULTS AND THE ROLE OF CHANCE: Amongst the 159 participants included in the intention-to-treat analysis, four women conceived before treatment and six were lost-to-follow-up. The remaining 149 participants (74 on CC and 75 on letrozole) completed at least the first treatment. Women receiving letrozole achieved a significantly (P = 0.022; absolute difference [95% confidence interval] 18% [3-33%]) higher pregnancy rate (61.%) than those on CC (43%). The median number of treatment cycles received until pregnancy was significantly (log rank P = 0.038) smaller with letrozole (4[3-5] cycles) compared to CC (6[4-7] cycles). LB rates were not statistically (P = 0.089) different between the two groups, although there was a trend towards higher rates on letrozole (48.8%) compared to CC (35.4%). After the crossover, pregnancy and LB rates on letrozole (n = 45; 28.9 and 24.4%, respectively) were not statistically (P = 0.539 and P = 0.601) different from CC (n = 31; 22.6 and 19.4%). LIMITATIONS, REASONS FOR CAUTION: One possible limitation of this trial may be the exclusion of PCOS women with BMI > 35 kg/m2, which would limit the applicability of the results in this subgroup of PCOS. However, this group of women are generally excluded from treatment in the majority of fertility centres, especially in Europe, due to the associated challenges and risks. WIDER IMPLICATIONS OF THE FINDINGS: The results of this trial are consistent with the recent Cochrane systematic review. However, with its robust design, the current RCT provides more valid and compelling evidence for the superiority of letrozole over CC as a primary ovulation induction agent in PCOS women with 40% increase in pregnancy rates and with a shorter time-to-pregnancy. Furthermore, the participants in this RCT are a good representation of subfertile PCOS population receiving fertility treatment in Europe and worldwide. The results are therefore globally generalizable for clinical practice. STUDY FUNDING/COMPETING INTEREST(S): This RCT was mainly funded by the R&D Funding Scheme of Derby Hospitals NHS Foundation Trust. The study also received funds from School of Medicine, University of Nottingham. The Trust R&D department was involved in the development of the protocol and the running of the trial. The trial was sponsored and monitored by the University of Nottingham. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: www.Clinicaltrials.gov: NCT00478504. TRIAL REGISTRATION DATE: Registration was verified on 23/05/2007. DATE OF FIRST PATIENT'S ENROLMENT: 25/04/2007. PMID- 28854591 TI - Non-publication and publication bias in reproductive medicine: a cohort analysis. AB - STUDY QUESTION: Does publication bias or non-publication exist in fertility trials presented as conference abstracts? SUMMARY ANSWER: This study did not detect any publication bias; however, it did identify a high level of non publication, with only 49% of abstracts reaching full-text publication four or more years after abstract presentation. WHAT IS KNOWN ALREADY: Systematic reviews of randomized controlled trials (RCTs) are the foundation of evidence based medicine. Non-publication or publication deficit refer to the failure to publish trial results. A publication bias exists when there is any tendency on the parts of the investigators or editors to fail to publish study results on the basis or strength of the study findings. Both present a serious problem for researchers, clinicians and policymakers alike, and ultimately impact on patient care. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study identified 337 fertility RCTs presented as conference abstracts between 2007 and 2010, as captured by an electronic search of the Cochrane Gynaecology and Fertility Database. After excluding ineligible trials and duplicates, 224 abstracts remained. PARTICIPANTS/MATERIALS, SETTING, METHODS: A search for the full-text papers of each abstract was undertaken in Pubmed, MEDLINE, Embase, CINAHL and Google in May 2015 using a probabilistic approach. Trial authors were contacted to query the publication status of abstracts when no full-text was identified. The association between individual variables and the probability of publication, and time to publication, was assessed using logistic regression and Cox regression, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 224 included abstracts, only 110 (49%; 95% CI: 42.6, 55.6) were found to be published as full-text articles. Publication bias was not identified in this cohort; studies with positive results had a similar probability of reaching full-text publication 52/113 (46%; 95% CI: 37.0, 55.3) as studies with non-positive (negative or null) results 58/111 (52%; 95% CI: 17.8, 33.9) (adjusted odds ratio (AOR): 1.02; 95% CI: 0.53, 1.97). Similarly, the time from abstract presentation to full-text publication was similar in studies with positive and non-positive results. Oral presentations were more likely to be published, and to be published sooner, than poster presentations (poster presentation AOR: 0.31; 95% CI: 0.15, 0.61 and adjusted hazard ratio (AHR): 0.57; 95% CI: 0.38, 0.86). Studies that were not registered were less likely to be published and to have delayed publication, than studies which were registered either prospectively or retrospectively (AOR: 0.14; 95% CI: 0.04, 0.44 and AHR: 0.43; 95% CI: 0.25, 0.72). Abstracts which were presented a longer time ago also had a higher probability of reaching full-text publication (P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Commencing with a cohort of RCTs from ethics committee registers may provide a better picture of the extent of non-publication and publication bias, as not all trials reach the stage of abstract presentation. It is also possible that the search did not identify all published trials, as some may have been published after the follow up period. WIDER IMPLICATIONS OF THE FINDINGS: This study did not identify any publication bias. However, only half of the abstracts in this cohort have been published as full-text articles, four or more years after their presentation at a conference. This is similar to publication rates reported previously for fertility trials, and is despite increasing awareness of the importance of publishing trial results, and subsequent requirements for all RCTs to be registered prior to trial initiation. A better understanding of the reasons for non-publication should assist in facilitating the prompt full-text publication of RCTs in the future. STUDY FUNDING/COMPETING INTEREST(S): Funding provided from the University of Auckland. All authors declare they have no conflicts of interest in relation to this article. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 28854592 TI - Weight reduction intervention for obese infertile women prior to IVF: a randomized controlled trial. AB - STUDY QUESTION: Does an intensive weight reduction programme prior to IVF increase live birth rates for infertile obese women? SUMMARY ANSWER: An intensive weight reduction programme resulted in a large weight loss but did not substantially affect live birth rates in obese women scheduled for IVF. WHAT IS ALREADY KNOWN: Among obese women, fertility and obstetric outcomes are influenced negatively with increased risk of miscarriage and a higher risk of maternal and neonatal complications. A recent large randomized controlled trial found no effect of lifestyle intervention on live birth in infertile obese women. STUDY DESIGN, SIZE, DURATION: A prospective, multicentre, randomized controlled trial was performed between 2010 and 2016 in the Nordic countries. In total, 962 women were assessed for eligibility and 317 women were randomized. Computerized randomization with concealed allocation was performed in the proportions 1:1 to one of two groups: weight reduction intervention followed by IVF-treatment or IVF treatment only. One cycle per patient was included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nine infertility clinics in Sweden, Denmark and Iceland participated. Women under 38 years of age planning IVF, and having a BMI >=30 and <35 kg/m2 were randomized to two groups: an intervention group (160 patients) with weight reduction before IVF, starting with 12 weeks of a low calorie liquid formula diet (LCD) of 880 kcal/day and thereafter weight stabilization for 2-5 weeks, or a control group (157 patients) with IVF only. MAIN RESULTS AND ROLE OF CHANCE: In the full analysis set (FAS), the live birth rate was 29.6% (45/152) in the weight reduction and IVF group and 27.5% (42/153) in the IVF only group. The difference was not statistically significant (difference 2.2%, 95% CI: 12.9 to 8.6, P = 0.77). The mean weight change was -9.44 (6.57) kg in the weight reduction and IVF group as compared to +1.19 (1.95) kg in the IVF only group, being highly significant (P < 0.0001). Significantly more live births were achieved through spontaneous pregnancies in the weight reduction and IVF group, 10.5% (16) as compared to the IVF only group 2.6% (4) (P = 0.009). Miscarriage rates and gonadotropin dose used for IVF stimulation did not differ between groups. Two subgroup analyses were performed. The first compared women with PCOS in the two randomized groups, and the second compared women in the weight reduction group reaching BMI <= 25 kg/m2 or reaching a weight loss of at least five BMI units to the IVF only group. No statistical differences in live birth rates between the groups in either subgroup analysis were found. LIMITATIONS, REASON FOR CAUTION: The study was not powered to detect a small increase in live births due to weight reduction and was not blinded for the patients or physician. Further, the intervention group had a longer time to achieve a spontaneous pregnancy, but were therefore slightly older than the control group at IVF. The study only included women with a BMI lower than 35 kg/m2. WIDER IMPLICATIONS OF THE FINDINGS: The study suggests that weight loss for obese women (BMI: 30-34.9 kg/m2) may not rectify the outcome in IVF cycles, although a significant higher number of spontaneous conceptions occurred in the weight loss group. Also, the study suggests that intensive weight reduction with LCD treatment does not negatively affects the results. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Sahlgrenska University Hospital (ALFGBG-70 940), Merck AB, Solna, Sweden (an affiliate of Merck KGaA, Darmstadt, Germany), Impolin AB, Hjalmar Svensson Foundation and Jane and Dan Olsson Foundation. Dr Thurin-Kjellberg reports grants from Merck, non-financial support from Impolin AB, during the conduct of the study, and personal fees from Merck outside the submitted work. Dr Friberg reports personal fees from Ferring, Merck, MSD, Finox and personal fees from Studentlitteratur, outside the submitted work. Dr Englund reports personal fees from Ferring, and non-financial support from Merck, outside the submitted work. Dr Bergh reports and has been reimbursed for: writing a newsletter twice a year (Ferring), lectures (Ferring, MSD, Merck), and Nordic working group meetings (Finox). Dr Karlstrom reports lectures (Ferring, Finox, Merck, MSD) and Nordic working group meetings (Ferring). Ms Kluge, Dr Einarsson, Dr Pinborg, Dr Klajnbard, Dr Stenlof, Dr Larsson, Dr Loft and Dr Wistrand have nothing to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT01566929. TRIAL REGISTRATION DATE: 23-03-2012. DATE OF FIRST PATIENT'S ENROLMENT: 05-10 2010. PMID- 28854593 TI - Gynaecologists and industry: ain't no sunshine. AB - The field of reproductive medicine is known for its innovations, and where there is innovation there is marketing and engagement with the doctors who are potential prescribers and users of those innovations. Financial connections between drug and device manufacturers with doctors have been extensively debated over the past decade. On one hand, relationships between doctors and industry could be considered synergistic by allowing the development of improved treatments. On the other hand, payment (and other benefits) from industry to doctors may subtly shift the main objective of the collaboration from patients' health to mutual benefits for both doctors and industry. Fertility patients can be considered 'vulnerable' as they face the multiple challenges of seeking to be parents, understanding complex and expensive fertility treatments that are by no means universally successful, and at the same time are under pressure because of their ever-increasing age. They are entitled to receive the most cost-effective treatments. We suggest that specialists in the field of reproductive medicine should be transparent about the receipt of financial benefits, including funding from industry, as it may be influencing both research outcomes and treatments that patients are offered. We also recommend that payments arising from industry sponsored research should be centralized in institutional funds and not paid directly to researchers. And there should be transparency about the source and the purpose of the payment. Industry sponsorship of medical societies and their educational events should be kept to a minimum and declared quantitatively in societies' websites and scientific programme brochures. Industry sponsorship of scientific meetings should not include the right to host educational symposia or speakers within the programme. All speakers should declare their conflicts of interest (COIs) at their meetings. Guideline groups should require all members to declare their financial COIs before meeting and exclude or limit those members with COI. Governmental authorities should not allow continuing medical education credits to those educational events not complying with the above policies. The crucial role of medical journals as 'gatekeepers' for identifying 'science' must be reaffirmed. PMID- 28854594 TI - Transparent collaboration between industry and academia can serve unmet patient need and contribute to reproductive public health. AB - The pharmaceutical and device industry has greatly contributed to diagnostic and therapeutic approaches in reproductive medicine in a very highly regulated environment, ensuring that development and manufacturing follow the highest standards. In spite of these achievements, collaboration between industry and physicians/academia is often presented in a negative context. However, today more than ever, partnership between industry and academia is needed to shorten the timeline between innovation and application, and to achieve faster access to better diagnostics, drugs and devices for the benefit of patients and society, based on complementary knowledge, skills and expertise. Such partnerships can include joined preclinical/clinical and post-marketing research and development, joint intellectual property, and joint revenue. In Europe, the transparency of this collaboration between pharmaceutical industry and medical doctors has been made possible by the Compliance and Disclosure Policy published by the European Federation of Pharmaceutical Industries and Associations (EFPIA), which represents the major pharmaceutical companies operating in Europe, and includes as members some but not all companies active in infertility and women's health. Under the EFPIA Disclosure Code of conduct, companies need to disclose transfers of value including amounts, activity type and the names of the recipient Health Care Professionals and Organizations. EFPIA member companies have also implemented very strict internal quality control processes and procedures in the design, statistical analysis, reporting, publication and communication of clinical research, according to Good Clinical Practice and other regulations, and are regularly inspected by competent authorities such as the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) for all trials used in marketing authorization applications. The risk of scientific bias exists not only in the pharmaceutical industry but also in the academic world. When academics believe in a hypothesis, they may build their case by emphasizing the arguments supporting their case, and either refute, refuse, oppose or ignore arguments that challenge their assumptions. A possible solution to reduce this bias is international consensus on study design, data collection, statistical analysis and reporting of outcomes, especially in the area of personalized reproductive medicine, e.g. to demonstrate superiority or non-inferiority of personalized ovarian stimulation using biomarkers. Equally important is that declarations of interest are reported transparently and completely in scientific abstracts and publications, and that ghost authorship is replaced by proactive and clear co authorship for experts from industry where such co-authorship is required based on the prevailing ICMJE criteria. In that context, however, reviewers should stop believing that publications by industry authors only, or by mixed groups of co authors from industry and academia, are more prone to bias than papers from academic groups only. Instead, the scientific quality of the work should be the only relevant criterion for acceptance of papers or abstracts, regardless of the environment where the work was done. In the end, neutrality does not exist and different beliefs and biases exist within and between healthcare professionals and organizations and pharmaceutical industries. The challenge is to be transparent about this reality at all times, and to behave in an informed, balanced and ethical way as medical and scientific experts, taking into account compliance and legal regulations of both industry and academic employers, in the best interest of patients and society. PMID- 28854595 TI - Dormancy and activation of human oocytes from primordial and primary follicles: molecular clues to oocyte regulation. AB - STUDY QUESTION: Do specific transcriptome dynamics in human oocytes from primordial and primary follicles identify novel pathways in oocyte activation? SUMMARY ANSWER: The transcriptomic profiles in oocytes from primordial and primary follicles, respectively, revealed several new canonical pathways as putative mediators of oocyte dormancy and activation. WHAT IS KNOWN ALREADY: Cellular signaling pathways including PI3K/AKT and AKT/mTOR as well as TGF-beta and IGF signaling are known to regulate the primordial-to-primary transition in mammalian follicle development. STUDY DESIGN, SIZE, DURATION: We performed a class comparison study on human oocytes from primordial (n = 436) and primary (n = 182) follicles donated by three women having ovarian tissue cryopreserved before chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: RNA was extracted from oocytes from primordial and primary follicles isolated by Laser Capture Microdissection, and submitted to the HiSeq Illumina platform. Data mapping, quality control, filtering and expression analysis were performed using Tophat (2.0.4), Cufflinks (2.0.2), BWA (0.6.2) and software R. Modeling of complex biological systems was performed using the IPA(r) software. Finally, qPCR and immunohistochemistry were employed to explore expression and localization of selected genes and products in human ovarian tissue. MAIN RESULTS AND THE ROLE OF CHANCE: We found 223 and 268 genes down-regulated and up-regulated, respectively, in the oocytes during the human primordial-to-primary follicle transition (P < 0.05 and/or FPKM fold-change >2). IPA(r) enrichment analysis revealed known pathways ('mTOR Signaling', 'PI3K/AKT Signaling' and 'PTEN Signaling') as well as enriched canonical pathways not previously associated with human ovarian follicle development such as 'ErB Signaling' and 'NGF Signaling' in the down-regulated category and 'Regulation of eIF4 and P70S6K Signaling' and 'HER-2 Signaling in Breast Cancer' in the up-regulated group. Additionally, immunohistochemistry on human ovarian tissue explored the intraovarian localization of VASA, FOXO1 and eIF4E. LARGE SCALE DATA: http://users birc.au.dk/biopv/published_data/ernst_2017/. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive analysis and no functional studies were performed. The study was based on a limited number of patients and the experimental design could not take into account the natural biological variance in human samples. Therefore, qPCR was used to confirm selected genes alongside immunohistochemical stainings. WIDER IMPLICATIONS OF THE FINDINGS: This study shows, for the first time, a detailed molecular description of global gene transcription activities in oocytes from primordial and primary follicles, respectively. Knowing the global transcription profiles of human oocyte dormancy and activation are important in developing new clinical applications. STUDY FUNDING/COMPETING INTEREST(S): E.H.E. was supported by Health Faculty, Aarhus University and Kong Christian Den Tiendes Fond. K.H. and S.F. were supported by an MRC (UK) project grant MR/M012638/1. K.L.H. was supported by grants from Fonden til Laegevidenskabens Fremme, Kong Christian Den Tiendes Fond. K.L.H. and L.S. were supported by the IDEAS grant from Aarhus University Research Foundation (AUFF). There are no conflicts of interest. PMID- 28854596 TI - Comparative Genomic Analysis Identifies a Campylobacter Clade Deficient in Selenium Metabolism. AB - The nonthermotolerant Campylobacter species C. fetus, C. hyointestinalis, C. iguaniorum, and C. lanienae form a distinct phylogenetic cluster within the genus. These species are primarily isolated from foraging (swine) or grazing (e.g., cattle, sheep) animals and cause sporadic and infrequent human illness. Previous typing studies identified three putative novel C. lanienae-related taxa, based on either MLST or atpA sequence data. To further characterize these putative novel taxa and the C. fetus group as a whole, 76 genomes were sequenced, either to completion or to draft level. These genomes represent 26 C. lanienae strains and 50 strains of the three novel taxa. C. fetus, C. hyointestinalis and C. iguaniorum genomes were previously sequenced to completion; therefore, a comparative genomic analysis across the entire C. fetus group was conducted (including average nucleotide identity analysis) that supports the initial identification of these three novel Campylobacter species. Furthermore, C. lanienae and the three putative novel species form a discrete clade within the C. fetus group, which we have termed the C. lanienae clade. This clade is distinguished from other members of the C. fetus group by a reduced genome size and distinct CRISPR/Cas systems. Moreover, there are two signature characteristics of the C. lanienae clade. C. lanienae clade genomes carry four to ten unlinked and similar, but nonidentical, flagellin genes. Additionally, all 76 C. lanienae clade genomes sequenced demonstrate a complete absence of genes related to selenium metabolism, including genes encoding the selenocysteine insertion machinery, selenoproteins, and the selenocysteinyl tRNA. PMID- 28854598 TI - An Upper Limit on the Functional Fraction of the Human Genome. AB - For the human population to maintain a constant size from generation to generation, an increase in fertility must compensate for the reduction in the mean fitness of the population caused, among others, by deleterious mutations. The required increase in fertility due to this mutational load depends on the number of sites in the genome that are functional, the mutation rate, and the fraction of deleterious mutations among all mutations in functional regions. These dependencies and the fact that there exists a maximum tolerable replacement level fertility can be used to put an upper limit on the fraction of the human genome that can be functional. Mutational load considerations lead to the conclusion that the functional fraction within the human genome cannot exceed 25%, and is probably considerably lower. PMID- 28854597 TI - Evolutionary Dynamics of Cryptophyte Plastid Genomes. AB - Cryptophytes are an ecologically important group of largely photosynthetic unicellular eukaryotes. This lineage is of great interest to evolutionary biologists because their plastids are of red algal secondary endosymbiotic origin and the host cell retains four different genomes (host nuclear, mitochondrial, plastid, and red algal nucleomorph). Here, we report a comparative analysis of plastid genomes from six representative cryptophyte genera. Four newly sequenced cryptophyte plastid genomes of Chroomonas mesostigmatica, Ch. placoidea, Cryptomonas curvata, and Storeatula sp. CCMP1868 share a number of features including synteny and gene content with the previously sequenced genomes of Cryptomonas paramecium, Rhodomonas salina, Teleaulax amphioxeia, and Guillardia theta. Our analysis of these plastid genomes reveals examples of gene loss and intron insertion. In particular, the chlB/chlL/chlN genes, which encode light independent (dark active) protochlorophyllide oxidoreductase (LIPOR) proteins have undergone recent gene loss and pseudogenization in cryptophytes. Comparison of phylogenetic trees based on plastid and nuclear genome data sets show the introduction, via secondary endosymbiosis, of a red algal derived plastid in a lineage of chlorophyll-c containing algae. This event was followed by additional rounds of eukaryotic endosymbioses that spread the red lineage plastid to diverse groups such as haptophytes and stramenopiles. PMID- 28854599 TI - Mitochondrial Genome Assemblies of Elysia timida and Elysia cornigera and the Response of Mitochondrion-Associated Metabolism during Starvation. AB - Some sacoglossan sea slugs sequester functional plastids (kleptoplasts) from their food, which continue to fix CO2 in a light dependent manner inside the animals. In plants and algae, plastid and mitochondrial metabolism are linked in ways that reach beyond the provision of energy-rich carbon compounds through photosynthesis, but how slug mitochondria respond to starvation or alterations in plastid biochemistry has not been explored. We assembled the mitochondrial genomes of the plastid-sequestering sea slugs Elysia timida and Elysia cornigera from RNA-Seq data that was complemented with standard sequencing of mitochondrial DNA through primer walking. Our data confirm the sister species relationship of the two Sacoglossa and from the analysis of changes in mitochondrial-associated metabolism during starvation we speculate that kleptoplasts might aid in the rerouting or recycling of reducing power independent of, yet maybe improved by, photosynthesis. PMID- 28854600 TI - The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus Evolution. AB - Influenza virus inflicts a heavy death toll annually and resistance to existing antiviral drugs has generated interest in the development of agents with novel mechanisms of action. Favipiravir is an antiviral drug that acts by increasing the genome-wide mutation rate of influenza A virus (IAV). Potential synergistic benefits of combining oseltamivir and favipiravir have been demonstrated in animal models of influenza, but the population-level effects of combining the drugs are unknown. In order to elucidate the underlying evolutionary processes at play, we performed genome-wide sequencing of IAV experimental populations subjected to serial passaging in vitro under a combined protocol of oseltamivir and favipiravir. We describe the interplay between mutation, selection, and genetic drift that ultimately culminates in population extinction. In particular, selective sweeps around oseltamivir resistance mutations reduce genome-wide variation while deleterious mutations hitchhike to fixation given the increased mutational load generated by favipiravir. This latter effect reduces viral fitness and accelerates extinction compared with IAV populations treated with favipiravir alone, but risks spreading both established and newly emerging mutations, including possible drug resistance mutations, if transmission occurs before the viral populations are eradicated. PMID- 28854601 TI - Large-Scale Identification of Wolbachia pipientis Effectors. AB - Wolbachia pipientis is an intracellular symbiont of arthropods well known for the reproductive manipulations induced in the host and, more recently, for the ability of Wolbachia to block virus replication in insect vectors. Since Wolbachia cannot yet be genetically manipulated, and due to the constraints imposed when working with an intracellular symbiont, little is known about mechanisms used by Wolbachia for host interaction. Here we employed a bioinformatics pipeline and identified 163 candidate effectors, potentially secreted by Wolbachia into the host cell. A total of 84 of these candidates were then subjected to a screen of growth defects induced in yeast upon heterologous expression which identified 14 top candidates likely secreted by Wolbachia. These predicted secreted effectors may function in concert as we find that their native expression is correlated and is highly upregulated at specific time points during Drosophila development. In addition, the evolutionary histories of some of these predicted effectors are also correlated, suggesting they may function together, or in the same pathway, during host infection. Similarly, most of these predicted effectors are limited to one or two Wolbachia strains-perhaps reflecting shared evolutionary history and strain specific functions in host manipulation. Identification of these Wolbachia candidate effectors is the first step in dissecting the mechanisms of symbiont-host interaction in this important system. PMID- 28854602 TI - Brucella Genetic Variability in Wildlife Marine Mammals Populations Relates to Host Preference and Ocean Distribution. AB - Intracellular bacterial pathogens probably arose when their ancestor adapted from a free-living environment to an intracellular one, leading to clonal bacteria with smaller genomes and less sources of genetic plasticity. Still, this plasticity is needed to respond to the challenges posed by the host. Members of the Brucella genus are facultative-extracellular intracellular bacteria responsible for causing brucellosis in a variety of mammals. The various species keep different host preferences, virulence, and zoonotic potential despite having 97-99% similarity at genome level. Here, we describe elements of genetic variation in Brucella ceti isolated from wildlife dolphins inhabiting the Pacific Ocean and the Mediterranean Sea. Comparison with isolates obtained from marine mammals from the Atlantic Ocean and the broader Brucella genus showed distinctive traits according to oceanic distribution and preferred host. Marine mammal isolates display genetic variability, represented by an important number of IS711 elements as well as specific IS711 and SNPs genomic distribution clustering patterns. Extensive pseudogenization was found among isolates from marine mammals as compared with terrestrial ones, causing degradation in pathways related to energy, transport of metabolites, and regulation/transcription. Brucella ceti isolates infecting particularly dolphin hosts, showed further degradation of metabolite transport pathways as well as pathways related to cell wall/membrane/envelope biogenesis and motility. Thus, gene loss through pseudogenization is a source of genetic variation in Brucella, which in turn, relates to adaptation to different hosts. This is relevant to understand the natural history of bacterial diseases, their zoonotic potential, and the impact of human interventions such as domestication. PMID- 28854604 TI - Self-Perceptions of Aging and Perceived Barriers to Care: Reasons for Health Care Delay. AB - Background and Objectives: Self-perceptions of aging (SPA), or attitudes toward one's aging experience, have been linked to health through multiple pathways. Few studies, however, have investigated how older adults' views on aging influence their care-seeking behaviors. Research Design and Methods: Using two independent subsamples from the Health and Retirement Study (2011 Health Care Mail Survey: N = 2,866; 2013 Health Care and Nutrition Study: N = 2,474), logistic regression and negative binomial regression were used to examine the association between SPA and health care delay over the next 12 months. Subsequently, we used latent class analysis to identify subgroups reporting different reasons for delay. With multinomial logistic regression, we then examined if, compared with the no delay group, SPA differentiated membership in the delay subgroups. Results: In both samples, more negative aging self-perceptions were associated with a higher likelihood of health care delay and more perceived barriers to care, after adjusting for predisposing, enabling, and need factors. Latent class analysis revealed three subgroups characterized by different reasons for delay: (a) limited health care access, (b) too busy to go to the doctor, and (c) dislike of going to the doctor. In fully adjusted models, individuals with more negative SPA were more likely to belong to "limited-access" and "dislike" subgroups compared with the no delay group. Discussion and Implications: SPA may affect decision making processes regarding whether to seek care for worrisome symptoms. Efforts to promote more positive SPA may encourage older adults to be more proactive in addressing their health care needs. PMID- 28854605 TI - Context Influences on the Subjective Experience of Aging: The Impact of Culture and Domains of Functioning. AB - Background and Objectives: Attitudes about aging influence how people feel about their aging and affect psychological and health outcomes in later life. Given cross-cultural variability in such attitudes, the subjective experience of aging (e.g., subjective age [SA]) may also vary, potentially accounting for culture specific patterns of aging-related outcomes. Our study explored cultural variation in SA and its determinants. Research Design and Methods: American (N = 569), Chinese (N = 492), and German (N = 827) adults aged 30-95 years completed a questionnaire that included instruments measuring basic demographic information, SA, beliefs about thresholds of old age, control over life changes, and age dependency of changes in eight different life domains (i.e., family, work). Results: Analyses revealed consistency across cultures in the domain-specificity of SA, but differences in the amount of shared variance across domains (e.g., Chinese adults exhibited greater homogeneity across domains than did Americans and Germans). Cultural differences were also observed in levels of SA in some domains, which were attenuated by domain-specific beliefs (e.g., control). Interestingly, beliefs about aging accounted for more cultural variation in SA than did sociodemographic factors (e.g., education). Discussion and Implications: Our results demonstrate that subjective perceptions of aging and everyday functioning may be best understood from a perspective focused on context (i.e., culture, life domain). Given its important relation to functioning, examination of cross-cultural differences in the subjective experience of aging may highlight factors that determine variations in aging-related outcomes that then could serve as targets of culture-specific interventions promoting well-being in later life. PMID- 28854603 TI - New Genes and Functional Innovation in Mammals. AB - The birth of genes that encode new protein sequences is a major source of evolutionary innovation. However, we still understand relatively little about how these genes come into being and which functions they are selected for. To address these questions, we have obtained a large collection of mammalian-specific gene families that lack homologues in other eukaryotic groups. We have combined gene annotations and de novo transcript assemblies from 30 different mammalian species, obtaining ~6,000 gene families. In general, the proteins in mammalian specific gene families tend to be short and depleted in aromatic and negatively charged residues. Proteins which arose early in mammalian evolution include milk and skin polypeptides, immune response components, and proteins involved in reproduction. In contrast, the functions of proteins which have a more recent origin remain largely unknown, despite the fact that these proteins also have extensive proteomics support. We identify several previously described cases of genes originated de novo from noncoding genomic regions, supporting the idea that this mechanism frequently underlies the evolution of new protein-coding genes in mammals. Finally, we show that most young mammalian genes are preferentially expressed in testis, suggesting that sexual selection plays an important role in the emergence of new functional genes. PMID- 28854606 TI - Aging Attitudes and Daily Awareness of Age-Related Change Interact to Predict Negative Affect. AB - Background and Objectives: Possessing more positive views of one's own aging is associated with better self-rated health, reduced reactivity to stressors, and better well-being. We examined two components of aging attitudes: awareness of age-related change (AARC) of loss and gain experiences and attitudes toward own aging (ATOA). We expected that AARC would vary day-to-day and interact with ATOA to predict daily negative affect. Research Design and Methods: One hundred and sixteen participants (61% women, M age = 64.71, range 60-90) reported on 743 total days via an online daily diary study. On Day 1, participants reported baseline ATOA and baseline AARC for losses and gains. On Days 2-9, daily stressor exposure, daily AARC losses and gains, and negative affect were reported. Results: Unconditional multilevel models revealed significant within-person fluctuation in daily AARC losses and gains. Controlling for daily stressors, age, and baseline AARC, daily increases in AARC losses were associated with increases in negative affect and a cross-level interaction revealed that this effect was stronger for those with more positive ATOA. Discussion and Implications: AARC gains and losses vary from day-to-day, suggesting that interventions targeting the contextual fluctuations in daily life may be a promising avenue for future research. Specifically, individuals who feel generally positive about their own aging, although less likely to report awareness of daily age-related losses, may be the most vulnerable when they do occur. Efforts to reduce daily AARC losses (e.g., limiting activities due to age, receiving help because others assume age related deficits) may improve the daily well-being of older adults. PMID- 28854607 TI - Stereotype Threat Effects on Older Adults' Episodic and Working Memory: A Meta Analysis. AB - Background and Objectives: Prior research has shown that exposure to negative age based stereotype threat (ST) can undermine older adults' memory performance. The objective of the current meta-analysis was to examine the reliability and magnitude of ST effects on older adults' episodic and working memory performance two forms of memory that typically show the greatest age-related declines. In addition, we examined potential moderators of age-based ST including type of ST manipulation, type and timing of memory task, participant age and education level. Research Design and Method: A total of 23 samples for episodic memory and 15 samples for working memory were derived from 19 published and 4 unpublished articles and analyzed in two separate meta-analyses. Results: Analyses revealed a reliable effect of ST on both older adults' episodic (d = 0.373) and working memory performance (d = 0.253). Interestingly, the age-based ST effect was only significant when blatant ST manipulations were used with episodic memory tasks or when subtle ST manipulations were used with working memory tasks. Moreover, within episodic memory, the ST effect only reached significance for recall but not cued-recall or recognition performance, and for immediate but not delayed tests of memory. Neither age nor level of education moderated the association between ST and older adults' memory performance. Discussion and Implications: These results highlight the vulnerability of both older adults' episodic and working memory performance to age-based ST. When measuring older adults' memory performance in a research context, we must therefore be wary of exposing participants to common stereotypes about aging and memory. PMID- 28854608 TI - Stereotypes, Warnings, and Identity-Related Variables Influence Older Adults' Susceptibility to Associative False Memory Errors. AB - Background and Objectives: Activating ageist stereotypes can impair older adults' ability to remember information. This effect has been shown to be strongest for older adults who possess certain characteristics (e.g., young-old, highly educated). The present study extended this line of research to investigate the relationship between stereotyping and false memory susceptibility in older adults. Research Design and Methods: We first presented older adults with lists of associated words in an incidental learning paradigm. Afterward, we manipulated whether participants were presented with stereotypes about aging and whether they were given warnings about the associative nature of the lists. Participants then completed a yes/no recognition test and answered demographic questions. Results: Older adults in the stereotyped group were more likely to falsely recognize non presented theme words than older adults in the control group. Further, those who were highly educated and/or retired were most likely to experience this false memory susceptibility. Discussion and Implications: Similar to the research on veridical memory, these findings suggest that the effects of ageist stereotyping on older adults' false memory susceptibility may be best understood in terms of the individual differences that older adults possess. Identifying the types of people who are at risk of experiencing stereotype threat is an important step toward helping older adults avoid memory impairment in the presence of common stereotypes. PMID- 28854609 TI - Age Differences in Explicit and Implicit Age Attitudes Across the Life Span. AB - Purpose of the Study: Biased judgments about others can operate both within and outside of our conscious awareness. However, little attention has been paid to how implicit and explicit attitudes differ across the life span, particularly with respect to age bias. In the current study, we examined age differences in implicit and explicit attitudes towards older individuals. Design and Method: Participants (N = 704,151) ranging from age 15 to 94 completed the Implicit Association Test and explicit self-report measures of bias against older adults. The associations between age bias and several demographic characteristics (e.g., gender, education) were also examined. Results: A preference for younger people was found among participants of all ages; however, implicit and explicit attitudes showed divergent associations with age. Implicit preference for younger people was highest among older adults; explicit preference for younger people was lowest among older adults. Implications: Examining age differences in implicit and explicit attitudes sheds light into the development and complexities of aging perceptions in different age groups. The current study's findings are discussed in the context of applications to and implications of reducing prejudice toward older adults. PMID- 28854610 TI - Positive Aging Expectations Are Associated With Physical Activity Among Urban Dwelling Older Adults. AB - Purpose: Regular physical activity is a key component of healthy aging, but few older adults meet physical activity guidelines. Poor aging expectations can contribute to this lack of activity, since negative stereotypes about the aging process can be internalized and affect physical performance. Although prior cross sectional studies have shown that physical activity and aging expectations are associated, less is known about this association longitudinally, particularly among traditionally underrepresented groups. It is also unclear whether different domains of aging expectations are differentially associated with physical activity. Design and Methods: The number of minutes/week of physical activity in which Baltimore Experience Corps Trial participants (N = 446; 92.6% African American) engaged were measured using the CHAMPS questionnaire, while their aging expectations were measured using the ERA-12 survey. Linear mixed effects models assessed the association between physical activity and aging expectations over 2 years, both in full and sex-stratified samples. Separate models were also fit for different ERA-12 domains. Results: We found that higher overall expectations regarding aging are associated with higher engagement in moderate- to high intensity physical activity over a 2-year period of time for women only. When the ERA-12 domains were examined separately, only the physical domain was associated with physical activity, both in women and overall. Implications: Low expectations regarding physical aging may represent a barrier to physical activity for older adults. Given that most older adults do not meet recommended physical activity guidelines, identifying factors that improve aging expectations may be a way to increase physical activity levels in aging populations. PMID- 28854611 TI - Age Group Differences in Perceived Age Discrimination: Associations With Self Perceptions of Aging. AB - Background and Objectives: From midlife onwards, age stereotypes increasingly underlie social judgments and contribute to age-based discrimination. Whereas many studies compare differences between young and older adults in reports of age discrimination or sensitivity to age stereotypes, few consider age group differences among adults over 50. We form subgroups corresponding to social age group membership (early midlife, late midlife, young old, oldest old) and examine differences in reported experiences of everyday age discrimination and associations with self-perceptions of aging. Research Design and Method: Using cross-sectional and longitudinal data from the Health and Retirement Study (HRS: N = 15,071; M Age = 68, range 50-101), multivariate logistic regression was used to examine experiences of everyday discrimination attributed to age, and associations between age discrimination and self-perceptions of aging, in four age groups: early midlife, late midlife, young old, oldest old. Results: People in the early midlife group (aged 50-59) reported more experiences of unfair treatment than the older age groups but were less likely to attribute their experiences to age discrimination. After controlling for covariates, individuals in all age groups who perceived their own aging positively were less likely to report experiences of age discrimination. The magnitude of this effect, however, was greatest in the early midlife group. Discussion and Implications: Findings support proposals that midlife is a pivotal life period when individuals adjust to life events and social role transitions. Future longitudinal studies will provide further insight into whether positive self-perceptions of aging are especially important in this phase of the life course. PMID- 28854612 TI - Couples' Shared Beliefs About Aging and Implications for Future Functional Limitations. AB - Purpose of the Study: Individual beliefs are known to be predictive of health. This study examines the co-construction of couple norms and links couples' shared beliefs about aging to future individuals' and couples' functional limitations. Design and Methods: Data from the 2008 and 2014 waves of the Health and Retirement Study (1,231 couples; age range = 51-90) were analyzed using latent variables that estimated shared and individual variance in beliefs about aging in 2008 and functional limitations at follow-up in 2014. Spouses' individual processes of physical activity and disease burden were modeled to contribute to couples' shared beliefs about aging and subsequent functional limitations. Models progressively controlled for indicators of partner selection, couples' shared health experiences, and similarities and differences in age. Results: Couples' beliefs about aging predicted future functional limitations. The effect magnitude decreased but remained significant in all models. Physical activity predicted couples' future functional limitations but was largely explained by shared health experiences and similarities and differences in age for wives and husbands, respectively. Disease burden contributed to couples' shared beliefs about aging. Husbands' contributions were explained by partner selection, but wives' contributions remained significant in all models. The effect of couples' shared beliefs on change in couples' functional limitations was explained by couples' shared health experiences. Implications: Beliefs about aging and health occur within the context of close relationships and shared experiences. Knowledge of couples' beliefs and health is necessary to support their individual and collective efforts to age successfully together. PMID- 28854614 TI - Disrupt Aging: A Call to Action for Gerontologists. PMID- 28854613 TI - Racial/Ethnic Differences in Expectations Regarding Aging Among Older Adults. AB - Purpose of the Study: The study identifies differences in age-expectations between older adults from Korean, Chinese, Latino, and African American backgrounds living in the United States. Design and Methods: This study uses baseline demographic, age-expectation, social, and health data from 229 racial/ethnic minority seniors in a stroke-prevention intervention trial. Unadjusted regression models and pair-wise comparisons tested for racial/ethnic differences in age-expectations, overall, and across domain subscales (e.g., physical-health expectations). Adjusted regression models tested whether age expectations differed across racial/ethnic groups after controlling for demographic, social, and health variables. Regression and negative binomial models tested whether age-expectations were consistently associated with health and well-being across racial/ethnic groups. Results: Age-expectations differed by race/ethnicity, overall and for each subscale. African American participants expected the least age-related functional decline and Chinese American participants expected the most decline. Although African American participants expected less decline than Latino participants in unadjusted models, they had comparable expectations adjusting for education. Latino and African American participants consistently expected less decline than Korean and Chinese Americans. Acculturation was not consistently related to age-expectations among immigrant participants over and above ethnicity. Although some previously observed links between expectations and health replicated across racial/ethnic groups, in adjusted models age-expectations were only related to depression for Latino participants. Implications: With a growing racial/ethnic minority older population in the United States, it is important to note older adults' age expectations differ by race/ethnicity. Moreover, expectation-health associations may not always generalize across diverse samples. PMID- 28854616 TI - Bio-Docklets: virtualization containers for single-step execution of NGS pipelines. AB - Processing of next-generation sequencing (NGS) data requires significant technical skills, involving installation, configuration, and execution of bioinformatics data pipelines, in addition to specialized postanalysis visualization and data mining software. In order to address some of these challenges, developers have leveraged virtualization containers toward seamless deployment of preconfigured bioinformatics software and pipelines on any computational platform. We present an approach for abstracting the complex data operations of multistep, bioinformatics pipelines for NGS data analysis. As examples, we have deployed 2 pipelines for RNA sequencing and chromatin immunoprecipitation sequencing, preconfigured within Docker virtualization containers we call Bio-Docklets. Each Bio-Docklet exposes a single data input and output endpoint and from a user perspective, running the pipelines as simply as running a single bioinformatics tool. This is achieved using a "meta-script" that automatically starts the Bio-Docklets and controls the pipeline execution through the BioBlend software library and the Galaxy Application Programming Interface. The pipeline output is postprocessed by integration with the Visual Omics Explorer framework, providing interactive data visualizations that users can access through a web browser. Our goal is to enable easy access to NGS data analysis pipelines for nonbioinformatics experts on any computing environment, whether a laboratory workstation, university computer cluster, or a cloud service provider. Beyond end users, the Bio-Docklets also enables developers to programmatically deploy and run a large number of pipeline instances for concurrent analysis of multiple datasets. PMID- 28854618 TI - A case of vanishing skull: Gorham's disease. PMID- 28854615 TI - Comparative performance of the BGISEQ-500 vs Illumina HiSeq2500 sequencing platforms for palaeogenomic sequencing. AB - Ancient DNA research has been revolutionized following development of next generation sequencing platforms. Although a number of such platforms have been applied to ancient DNA samples, the Illumina series are the dominant choice today, mainly because of high production capacities and short read production. Recently a potentially attractive alternative platform for palaeogenomic data generation has been developed, the BGISEQ-500, whose sequence output are comparable with the Illumina series. In this study, we modified the standard BGISEQ-500 library preparation specifically for use on degraded DNA, then directly compared the sequencing performance and data quality of the BGISEQ-500 to the Illumina HiSeq2500 platform on DNA extracted from 8 historic and ancient dog and wolf samples. The data generated were largely comparable between sequencing platforms, with no statistically significant difference observed for parameters including level (P = 0.371) and average sequence length (P = 0718) of endogenous nuclear DNA, sequence GC content (P = 0.311), double-stranded DNA damage rate (v. 0.309), and sequence clonality (P = 0.093). Small significant differences were found in single-strand DNA damage rate (deltaS; slightly lower for the BGISEQ-500, P = 0.011) and the background rate of difference from the reference genome (theta; slightly higher for BGISEQ-500, P = 0.012). This may result from the differences in amplification cycles used to polymerase chain reaction-amplify the libraries. A significant difference was also observed in the mitochondrial DNA percentages recovered (P = 0.018), although we believe this is likely a stochastic effect relating to the extremely low levels of mitochondria that were sequenced from 3 of the samples with overall very low levels of endogenous DNA. Although we acknowledge that our analyses were limited to animal material, our observations suggest that the BGISEQ-500 holds the potential to represent a valid and potentially valuable alternative platform for palaeogenomic data generation that is worthy of future exploration by those interested in the sequencing and analysis of degraded DNA. PMID- 28854617 TI - Large-scale phenomics analysis of a T-DNA tagged mutant population. AB - Rice, Oryza sativa L., is one of the most important crops in the world. With the rising world population, feeding people in a more sustainable and environmentally friendly way becomes increasingly important. Therefore, the rice research community needs to share resources to better understand the functions of rice genes that are the foundation for future agricultural biotechnology development, and one way to achieve this goal is via the extensive study of insertional mutants. We have constructed a large rice insertional mutant population in a japonica rice variety, Tainung 67. The collection contains about 93 000 mutant lines, among them 85% with phenomics data and 65% with flanking sequence data. We screened the phenotypes of 12 individual plants for each line grown under field conditions according to 68 subcategories and 3 quantitative traits. Both phenotypes and integration sites are searchable in the Taiwan Rice Insertional Mutants Database. Detailed analyses of phenomics data, T-DNA flanking sequences, and whole-genome sequencing data for rice insertional mutants can lead to the discovery of novel genes. In addition, studies of mutant phenotypes can reveal relationships among varieties, cultivation locations, and cropping seasons. PMID- 28854619 TI - Amgen and UCB announce increased cardiovascular risk in patients receiving romosozumab, an anti-sclerotin antibody. PMID- 28854620 TI - FDA issues concerns about optimal baricitinib doses for the treatment of moderate to-severe rheumatoid arthritis and delays drug approval. PMID- 28854621 TI - A search for the "Goldilocks zone" with regard to the optimal duration of adjuvant temozolomide in patients with glioblastoma. PMID- 28854622 TI - Prophylactic cranial irradiation in patients with extensive-stage small cell lung cancer. PMID- 28854623 TI - Extreme Mitogenomic Variation in Natural Populations of Chaetognaths. AB - The extent of within-species genetic variation across the diversity of animal life is an underexplored problem in ecology and evolution. Although neutral genetic variation should scale positively with population size, mitochondrial diversity levels are believed to show little variation across animal species. Here, we report an unprecedented case of extreme mitochondrial diversity within natural populations of two morphospecies of chaetognaths (arrow worms). We determine that this diversity is composed of deep sympatric mitochondrial lineages, which are in some cases as divergent as human and platypus. Additionally, based on 54 complete mitogenomes, we observed mitochondrial gene order differences between several of these lineages. We examined nuclear divergence patterns (18S, 28S, and an intron) to determine the possible origin of these lineages, but did not find congruent patterns between mitochondrial and nuclear markers. We also show that extreme mitochondrial divergence in chaetognaths is not driven by positive selection. Hence, we propose that the extreme levels of mitochondrial variation could be the result of either a complex scenario of reproductive isolation, or a combination of large population size and accelerated mitochondrial mutation rate. These findings emphasize the importance of characterizing genome-wide levels of nuclear variation in these species and promote chaetognaths as a remarkable model to study mitochondrial evolution. PMID- 28854625 TI - Plastid Phylogenomics Resolve Deep Relationships among Eupolypod II Ferns with Rapid Radiation and Rate Heterogeneity. AB - The eupolypods II ferns represent a classic case of evolutionary radiation and, simultaneously, exhibit high substitution rate heterogeneity. These factors have been proposed to contribute to the contentious resolutions among clades within this fern group in multilocus phylogenetic studies. We investigated the deep phylogenetic relationships of eupolypod II ferns by sampling all major families and using 40 plastid genomes, or plastomes, of which 33 were newly sequenced with next-generation sequencing technology. We performed model-based analyses to evaluate the diversity of molecular evolutionary rates for these ferns. Our plastome data, with more than 26,000 informative characters, yielded good resolution for deep relationships within eupolypods II and unambiguously clarified the position of Rhachidosoraceae and the monophyly of Athyriaceae. Results of rate heterogeneity analysis revealed approximately 33 significant rate shifts in eupolypod II ferns, with the most heterogeneous rates (both accelerations and decelerations) occurring in two phylogenetically difficult lineages, that is, the Rhachidosoraceae-Aspleniaceae and Athyriaceae clades. These observations support the hypothesis that rate heterogeneity has previously constrained the deep phylogenetic resolution in eupolypods II. According to the plastome data, we propose that 14 chloroplast markers are particularly phylogenetically informative for eupolypods II both at the familial and generic levels. Our study demonstrates the power of a character-rich plastome data set and high-throughput sequencing for resolving the recalcitrant lineages, which have undergone rapid evolutionary radiation and dramatic changes in substitution rates. PMID- 28854624 TI - Transposable Element Misregulation Is Linked to the Divergence between Parental piRNA Pathways in Drosophila Hybrids. AB - Interspecific hybridization is a genomic stress condition that leads to the activation of transposable elements (TEs) in both animals and plants. In hybrids between Drosophila buzzatii and Drosophila koepferae, mobilization of at least 28 TEs has been described. However, the molecular mechanisms underlying this TE release remain poorly understood. To give insight on the causes of this TE activation, we performed a TE transcriptomic analysis in ovaries (notorious for playing a major role in TE silencing) of parental species and their F1 and backcrossed (BC) hybrids. We find that 15.2% and 10.6% of the expressed TEs are deregulated in F1 and BC1 ovaries, respectively, with a bias toward overexpression in both cases. Although differences between parental piRNA (Piwi interacting RNA) populations explain only partially these results, we demonstrate that piRNA pathway proteins have divergent sequences and are differentially expressed between parental species. Thus, a functional divergence of the piRNA pathway between parental species, together with some differences between their piRNA pools, might be at the origin of hybrid instabilities and ultimately cause TE misregulation in ovaries. These analyses were complemented with the study of F1 testes, where TEs tend to be less expressed than in D. buzzatii. This can be explained by an increase in piRNA production, which probably acts as a defence mechanism against TE instability in the male germline. Hence, we describe a differential impact of interspecific hybridization in testes and ovaries, which reveals that TE expression and regulation are sex-biased. PMID- 28854626 TI - Domestication of Lambda Phage Genes into a Putative Third Type of Replicative Helicase Matchmaker. AB - At the onset of the initiation of chromosome replication, bacterial replicative helicases are recruited and loaded on the DnaA-oriC nucleoprotein platform, assisted by proteins like DnaC/DnaI or DciA. Two orders of bacteria appear, however, to lack either of these factors, raising the question of the essentiality of these factors in bacteria. Through a phylogenomic approach, we identified a pair of genes that could have substituted for dciA. The two domesticated genes are specific of the dnaC/dnaI- and dciA-lacking organisms and apparently domesticated from lambdoid phage genes. They derive from lambdaO and lambdaP and were renamed dopC and dopE, respectively. DopE is expected to bring the replicative helicase to the bacterial origin of replication, while DopC might assist DopE in this function. The confirmation of the implication of DopCE in the handling of the replicative helicase at the onset of replication in these organisms would generalize to all bacteria and therefore to all living organisms the need for specific factors dedicated to this function. PMID- 28854627 TI - The Mitonuclear Dimension of Neanderthal and Denisovan Ancestry in Modern Human Genomes. AB - Some human populations interbred with Neanderthals and Denisovans, resulting in substantial contributions to modern-human genomes. Therefore, it is now possible to use genomic data to investigate mechanisms that shaped historical gene flow between humans and our closest hominin relatives. More generally, in eukaryotes, mitonuclear interactions have been argued to play a disproportionate role in generating reproductive isolation. There is no evidence of mtDNA introgression into modern human populations, which means that all introgressed nuclear alleles from archaic hominins must function on a modern-human mitochondrial background. Therefore, mitonuclear interactions are also potentially relevant to hominin evolution. We performed a detailed accounting of mtDNA divergence among hominin lineages and used population-genomic data to test the hypothesis that mitonuclear incompatibilities have preferentially restricted the introgression of nuclear genes with mitochondrial functions. We found a small but significant underrepresentation of introgressed Neanderthal alleles at such nuclear loci. Structural analyses of mitochondrial enzyme complexes revealed that these effects are unlikely to be mediated by physically interacting sites in mitochondrial and nuclear gene products. We did not detect any underrepresentation of introgressed Denisovan alleles at mitochondrial-targeted loci, but this may reflect reduced power because locus-specific estimates of Denisovan introgression are more conservative. Overall, we conclude that genes involved in mitochondrial function may have been subject to distinct selection pressures during the history of introgression from archaic hominins but that mitonuclear incompatibilities have had, at most, a small role in shaping genome-wide introgression patterns, perhaps because of limited functional divergence in mtDNA and interacting nuclear genes. PMID- 28854628 TI - Genomic Epidemiology of NDM-1-Encoding Plasmids in Latin American Clinical Isolates Reveals Insights into the Evolution of Multidrug Resistance. AB - Bacteria that produce the broad-spectrum Carbapenem antibiotic New Delhi Metallo beta-lactamase (NDM) place a burden on health care systems worldwide, due to the limited treatment options for infections caused by them and the rapid global spread of this antibiotic resistance mechanism. Although it is believed that the associated resistance gene blaNDM-1 originated in Acinetobacter spp., the role of Enterobacteriaceae in its dissemination remains unclear. In this study, we used whole genome sequencing to investigate the dissemination dynamics of blaNDM-1 positive plasmids in a set of 21 clinical NDM-1-positive isolates from Colombia and Mexico (Providencia rettgeri, Klebsiella pneumoniae, and Acinetobacter baumannii) as well as six representative NDM-1-positive Escherichia coli transconjugants. Additionally, the plasmids from three representative P. rettgeri isolates were sequenced by PacBio sequencing and finished. Our results demonstrate the presence of previously reported plasmids from K. pneumoniae and A. baumannii in different genetic backgrounds and geographically distant locations in Colombia. Three new previously unclassified plasmids were also identified in P. rettgeri from Colombia and Mexico, plus an interesting genetic link between NDM-1-positive P. rettgeri from distant geographic locations (Canada, Mexico, Colombia, and Israel) without any reported epidemiological links was discovered. Finally, we detected a relationship between plasmids present in P. rettgeri and plasmids from A. baumannii and K. pneumoniae. Overall, our findings suggest a Russian doll model for the dissemination of blaNDM-1 in Latin America, with P. rettgeri playing a central role in this process, and reveal new insights into the evolution and dissemination of plasmids carrying such antibiotic resistance genes. PMID- 28854629 TI - Position Matters: Network Centrality Considerably Impacts Rates of Protein Evolution in the Human Protein-Protein Interaction Network. AB - The proteins of any organism evolve at disparate rates. A long list of factors affecting rates of protein evolution have been identified. However, the relative importance of each factor in determining rates of protein evolution remains unresolved. The prevailing view is that evolutionary rates are dominantly determined by gene expression, and that other factors such as network centrality have only a marginal effect, if any. However, this view is largely based on analyses in yeasts, and accurately measuring the importance of the determinants of rates of protein evolution is complicated by the fact that the different factors are often correlated with each other, and by the relatively poor quality of available functional genomics data sets. Here, we use correlation, partial correlation and principal component regression analyses to measure the contributions of several factors to the variability of the rates of evolution of human proteins. For this purpose, we analyzed the entire human protein-protein interaction data set and the human signal transduction network-a network data set of exceptionally high quality, obtained by manual curation, which is expected to be virtually free from false positives. In contrast with the prevailing view, we observe that network centrality (measured as the number of physical and nonphysical interactions, betweenness, and closeness) has a considerable impact on rates of protein evolution. Surprisingly, the impact of centrality on rates of protein evolution seems to be comparable, or even superior according to some analyses, to that of gene expression. Our observations seem to be independent of potentially confounding factors and from the limitations (biases and errors) of interactomic data sets. PMID- 28854630 TI - Does the Promoter Constitute a Barrier in the Horizontal Transposon Transfer Process? Insight from Bari Transposons. AB - The contribution of the transposons' promoter in the horizontal transfer process is quite overlooked in the scientific literature. To shed light on this aspect we have mimicked the horizontal transfer process in laboratory and assayed in a wide range of hosts (fly, human, yeast and bacteria) the promoter activity of the 5' terminal sequences in Bari1 and Bari3, two Drosophila transposons belonging to the Tc1-mariner superfamily. These sequences are able to drive the transcription of a reporter gene even in distantly related organisms at least at the episomal level. By combining bioinformatics and experimental approaches, we define two distinct promoter sequences for each terminal sequence analyzed, which allow transcriptional activity in prokaryotes and eukaryotes, respectively. We propose that the Bari family of transposons, and possibly other members of the Tc1 mariner superfamily, might have evolved "blurry promoters," which have facilitated their diffusion in many living organisms through horizontal transfer. PMID- 28854631 TI - Functional Analogy in Human Metabolism: Enzymes with Different Biological Roles or Functional Redundancy? AB - Since enzymes catalyze almost all chemical reactions that occur in living organisms, it is crucial that genes encoding such activities are correctly identified and functionally characterized. Several studies suggest that the fraction of enzymatic activities in which multiple events of independent origin have taken place during evolution is substantial. However, this topic is still poorly explored, and a comprehensive investigation of the occurrence, distribution, and implications of these events has not been done so far. Fundamental questions, such as how analogous enzymes originate, why so many events of independent origin have apparently occurred during evolution, and what are the reasons for the coexistence in the same organism of distinct enzymatic forms catalyzing the same reaction, remain unanswered. Also, several isofunctional enzymes are still not recognized as nonhomologous, even with substantial evidence indicating different evolutionary histories. In this work, we begin to investigate the biological significance of the cooccurrence of nonhomologous isofunctional enzymes in human metabolism, characterizing functional analogous enzymes identified in metabolic pathways annotated in the human genome. Our hypothesis is that the coexistence of multiple enzymatic forms might not be interpreted as functional redundancy. Instead, these enzymatic forms may be implicated in distinct (and probably relevant) biological roles. PMID- 28854632 TI - Rapid Evolution of Primate Type 2 Immune Response Factors Linked to Asthma Susceptibility. AB - Host immunity pathways evolve rapidly in response to antagonism by pathogens. Microbial infections can also trigger excessive inflammation that contributes to diverse autoimmune disorders including asthma, lupus, diabetes, and arthritis. Definitive links between immune system evolution and human autoimmune disease remain unclear. Here we provide evidence that several components of the type 2 immune response pathway have been subject to recurrent positive selection in the primate lineage. Notably, substitutions in the central immune regulator IL13 correspond to a polymorphism linked to asthma susceptibility in humans. We also find evidence of accelerated amino acid substitutions as well as gene gain and loss events among eosinophil granule proteins, which act as toxic antimicrobial effectors that promote asthma pathology by damaging airway tissues. These results support the hypothesis that evolutionary conflicts with pathogens promote tradeoffs for increasingly robust immune responses during animal evolution. Our findings are also consistent with the view that natural selection has contributed to the spread of autoimmune disease alleles in humans. PMID- 28854633 TI - Contrasting Patterns of Nucleotide Substitution Rates Provide Insight into Dynamic Evolution of Plastid and Mitochondrial Genomes of Geranium. AB - Geraniaceae have emerged as a model system for investigating the causes and consequences of variation in plastid and mitochondrial genomes. Incredible structural variation in plastid genomes (plastomes) and highly accelerated evolutionary rates have been reported in selected lineages and functional groups of genes in both plastomes and mitochondrial genomes (mitogenomes), and these phenomena have been implicated in cytonuclear incompatibility. Previous organelle genome studies have included limited sampling of Geranium, the largest genus in the family with over 400 species. This study reports on rates and patterns of nucleotide substitutions in plastomes and mitogenomes of 17 species of Geranium and representatives of other Geraniaceae. As detected across other angiosperms, substitution rates in the plastome are 3.5 times higher than the mitogenome in most Geranium. However, in the branch leading to Geranium brycei/Geranium incanum mitochondrial genes experienced significantly higher dN and dS than plastid genes, a pattern that has only been detected in one other angiosperm. Furthermore, rate accelerations differ in the two organelle genomes with plastomes having increased dN and mitogenomes with increased dS. In the Geranium phaeum/Geranium reflexum clade, duplicate copies of clpP and rpoA genes that experienced asymmetric rate divergence were detected in the single copy region of the plastome. In the case of rpoA, the branch leading to G. phaeum/G. reflexum experienced positive selection or relaxation of purifying selection. Finally, the evolution of acetyl-CoA carboxylase is unusual in Geraniaceae because it is only the second angiosperm family where both prokaryotic and eukaryotic ACCases functionally coexist in the plastid. PMID- 28854634 TI - Meiotic Genes in Colpodean Ciliates Support Secretive Sexuality. AB - The putatively asexual Colpodean ciliates potentially pose a problem to macro organismic theories of evolution. They are extremely ancient (although asexuality is thought to hasten extinction), and yet there is one apparently derived sexual species (implying an unlikely regain of a complex trait). If macro-organismic theories of evolution also broadly apply to microbial eukaryotes, though, then most or all of the colpodean ciliates should merely be secretively sexual. Here we show using de novo genome sequencing, that colpodean ciliates have the meiotic genes required for sex and these genes are under functional constraint. Along with these genomic data, we argue that these ciliates are sexual given the cytological observations of both micronuclei and macronuclei within their cells, and the behavioral observations of brief fusions as if the cells were mating. The challenge that colpodean ciliates pose is therefore not to evolutionary theory, but to our ability to induce microbial eukaryotic sex in the laboratory. PMID- 28854635 TI - Partner-Drug Resistance and Population Substructuring of Artemisinin-Resistant Plasmodium falciparum in Cambodia. AB - Plasmodium falciparum in western Cambodia has developed resistance to artemisinin and its partner drugs, causing frequent treatment failure. Understanding this evolution can inform the deployment of new therapies. We investigated the genetic architecture of 78 falciparum isolates using whole-genome sequencing, correlating results to in vivo and ex vivo drug resistance and exploring the relationship between population structure, demographic history, and partner drug resistance. Principle component analysis, network analysis and demographic inference identified a diverse central population with three clusters of clonally expanding parasite populations, each associated with specific K13 artemisinin resistance alleles and partner drug resistance profiles which were consistent with the sequential deployment of artemisinin combination therapies in the region. One cluster displayed ex vivo piperaquine resistance and mefloquine sensitivity with a high rate of in vivo failure of dihydroartemisinin-piperaquine. Another cluster displayed ex vivo mefloquine resistance and piperaquine sensitivity with high in vivo efficacy of dihydroartemisinin-piperaquine. The final cluster was clonal and displayed intermediate sensitivity to both drugs. Variations in recently described piperaquine resistance markers did not explain the difference in mean IC90 or clinical failures between the high and intermediate piperaquine resistance groups, suggesting additional loci may be involved in resistance. The results highlight an important role for partner drug resistance in shaping the P. falciparum genetic landscape in Southeast Asia and suggest that further work is needed to evaluate for other mutations that drive piperaquine resistance. PMID- 28854636 TI - Variation in DNA Methylation Is Not Consistently Reflected by Sociality in Hymenoptera. AB - Changes in gene regulation that underlie phenotypic evolution can be encoded directly in the DNA sequence or mediated by chromatin modifications such as DNA methylation. It has been hypothesized that the evolution of eusocial division of labor is associated with enhanced gene regulatory potential, which may include expansions in DNA methylation in the genomes of Hymenoptera (bees, ants, wasps, and sawflies). Recently, this hypothesis garnered support from analyses of a commonly used metric to estimate DNA methylation in silico, CpG content. Here, we test this hypothesis using direct, nucleotide-level measures of DNA methylation across nine species of Hymenoptera. In doing so, we generated new DNA methylomes for three species of interest, including one solitary and one facultatively eusocial halictid bee and a sawfly. We demonstrate that the strength of correlation between CpG content and DNA methylation varies widely among hymenopteran taxa, highlighting shortcomings in the utility of CpG content as a proxy for DNA methylation in comparative studies of taxa with sparse DNA methylomes. We observed strikingly high levels of DNA methylation in the sawfly relative to other investigated hymenopterans. Analyses of molecular evolution suggest the relatively distinct sawfly DNA methylome may be associated with positive selection on functional DNMT3 domains. Sawflies are an outgroup to all ants, bees, and wasps, and no sawfly species are eusocial. We find no evidence that either global expansions or variation within individual ortholog groups in DNA methylation are consistently associated with the evolution of social behavior. PMID- 28854637 TI - Comparative Genomics of the Dual-Obligate Symbionts from the Treehopper, Entylia carinata (Hemiptera: Membracidae), Provide Insight into the Origins and Evolution of an Ancient Symbiosis. AB - Insect species in the Auchenorrhyncha suborder (Hemiptera) maintain ancient obligate symbioses with bacteria that provide essential amino acids (EAAs) deficient in their plant-sap diets. Molecular studies have revealed that two complementary symbiont lineages, "Candidatus Sulcia muelleri" and a betaproteobacterium ("Ca. Zinderia insecticola" in spittlebugs [Cercopoidea] and "Ca. Nasuia deltocephalinicola" in leafhoppers [Cicadellidae]) may have persisted in the suborder since its origin ~300 Ma. However, investigation of how this pair has co-evolved on a genomic level is limited to only a few host lineages. We sequenced the complete genomes of Sulcia and a betaproteobacterium from the treehopper, Entylia carinata (Membracidae: ENCA), as the first representative from this species-rich group. It also offers the opportunity to compare symbiont evolution across a major insect group, the Membracoidea (leafhoppers + treehoppers). Genomic analyses show that the betaproteobacteria in ENCA is a member of the Nasuia lineage. Both symbionts have larger genomes (Sulcia = 218 kb and Nasuia = 144 kb) than related lineages in Deltocephalinae leafhoppers, retaining genes involved in basic cellular functions and information processing. Nasuia-ENCA further exhibits few unique gene losses, suggesting that its parent lineage in the common ancestor to the Membracoidea was already highly reduced. Sulcia-ENCA has lost the abilities to synthesize menaquinone cofactor and to complete the synthesis of the branched-chain EAAs. Both capabilities are conserved in other Sulcia lineages sequenced from across the Auchenorrhyncha. Finally, metagenomic sequencing recovered the partial genome of an Arsenophonus symbiont, although it infects only 20% of individuals indicating a facultative role. PMID- 28854638 TI - Whole Genome Sequencing Reveals the Islands of Novel Polymorphisms in Two Native Aromatic Japonica Rice Landraces from Vietnam. AB - Elucidation of the rice genome will not only broaden our understanding of genetic characterization of the agronomic characteristics but also facilitate the rice genetic improvement through marker assisted breeding. However, the genome resources of aromatic rice varieties are largely unexploited. Therefore, the whole genome of two elite aromatic traditional japonica rice landraces in North Vietnam, Tam Xoan Bac Ninh (TXBN), and Tam Xoan Hai Hau (TXHH), was sequenced to identify their genome-wide polymorphisms. Overall, we identified over 40,000 novel polymorphisms in each aromatic rice landrace. Although a discontinuous 8-bp deletion and an A/T SNP just upstream the 5-bp deletion in exon 7 of BADH2 gene were present in both rice landraces, the number of SNP high resolution regions of TXBN was six times higher than that of TXHH. Furthermore, several hot spot regions of novel SNPs and indels were found in both genomes, providing their potential gene pools related to aroma formation. The genomic information of two aromatic rice landraces described in this study will facilitate the identification of fragrance-related genes and the genetic improvement of rice. PMID- 28854639 TI - Evolution of the Largest Mammalian Genome. AB - The genome of the red vizcacha rat (Rodentia, Octodontidae, Tympanoctomys barrerae) is the largest of all mammals, and about double the size of their close relative, the mountain vizcacha rat Octomys mimax, even though the lineages that gave rise to these species diverged from each other only about 5 Ma. The mechanism for this rapid genome expansion is controversial, and hypothesized to be a consequence of whole genome duplication or accumulation of repetitive elements. To test these alternative but nonexclusive hypotheses, we gathered and evaluated evidence from whole transcriptome and whole genome sequences of T. barrerae and O. mimax. We recovered support for genome expansion due to accumulation of a diverse assemblage of repetitive elements, which represent about one half and one fifth of the genomes of T. barrerae and O. mimax, respectively, but we found no strong signal of whole genome duplication. In both species, repetitive sequences were rare in transcribed regions as compared with the rest of the genome, and mostly had no close match to annotated repetitive sequences from other rodents. These findings raise new questions about the genomic dynamics of these repetitive elements, their connection to widespread chromosomal fissions that occurred in the T. barrerae ancestor, and their fitness effects-including during the evolution of hypersaline dietary tolerance in T. barrerae. PMID- 28854640 TI - Adaptive Prediction Emerges Over Short Evolutionary Time Scales. AB - Adaptive prediction is a capability of diverse organisms, including microbes, to sense a cue and prepare in advance to deal with a future environmental challenge. Here, we investigated the timeframe over which adaptive prediction emerges when an organism encounters an environment with novel structure. We subjected yeast to laboratory evolution in a novel environment with repetitive, coupled exposures to a neutral chemical cue (caffeine), followed by a sublethal dose of a toxin (5 FOA), with an interspersed requirement for uracil prototrophy to counter-select mutants that gained constitutive 5-FOA resistance. We demonstrate the remarkable ability of yeast to internalize a novel environmental pattern within 50-150 generations by adaptively predicting 5-FOA stress upon sensing caffeine. We also demonstrate how novel environmental structure can be internalized by coupling two unrelated response networks, such as the response to caffeine and signaling mediated conditional peroxisomal localization of proteins. PMID- 28854642 TI - Papio Baboon Species Indicative Alu Elements. AB - The genus of Papio (baboon) has six recognized species separated into Northern and Southern clades, each comprised of three species distributed across the African continent. Geographic origin and phenotypic variants such as coat color and body size have commonly been used to identify different species. The existence of multiple hybrid zones, both ancient and current, have complicated efforts to characterize the phylogeny of Papio baboons. More recently, mitochondrial DNA (mtDNA) and Y-chromosome genetic markers have been utilized for species identification with particular focus on the hybrid zones. Alu elements accumulate in a random manner and are a novel source of identical by descent variation with known ancestral states for inferring population genetic and phylogenetic relationships. As part of the Baboon Genome Analysis Consortium, we assembled an Alu insertion polymorphism database of nearly 500 Papio-lineage specific insertions representing all six species and performed population structure and phylogenetic analyses. In this study, we have selected a subset of 48 species indicative Alu insertions and demonstrate their utility as genetic systems for the identification of baboon species within Papio. Individual elements from the panel are easy to genotype and can be used in a hierarchical fashion based on the original level of uncertainty. This Alu-48 panel should serve as a valuable tool during the maintenance of pedigree records in captive populations and assist in the forensic identification of fossils and potential hybrids in the wild. PMID- 28854643 TI - MSDB: A Comprehensive Database of Simple Sequence Repeats. AB - Microsatellites, also known as Simple Sequence Repeats (SSRs), are short tandem repeats of 1-6 nt motifs present in all genomes, particularly eukaryotes. Besides their usefulness as genome markers, SSRs have been shown to perform important regulatory functions, and variations in their length at coding regions are linked to several disorders in humans. Microsatellites show a taxon-specific enrichment in eukaryotic genomes, and some may be functional. MSDB (Microsatellite Database) is a collection of >650 million SSRs from 6,893 species including Bacteria, Archaea, Fungi, Plants, and Animals. This database is by far the most exhaustive resource to access and analyze SSR data of multiple species. In addition to exploring data in a customizable tabular format, users can view and compare the data of multiple species simultaneously using our interactive plotting system. MSDB is developed using the Django framework and MySQL. It is freely available at http://tdb.ccmb.res.in/msdb. PMID- 28854644 TI - Effect of Irradiation Doses on Sterility and Biological Security in a Genetically Modified Strain of the Mediterranean Fruit Fly (Diptera: Tephritidae). AB - The genetically modified strain of the Mediterranean fruit fly, Ceratitis capitata (Wiedemann) VIENNA 8 1260, was developed from the genetic sexing strain VIENNA 8. It has two molecular markers that exhibit red fluorescence in the body and green fluorescence in testis and sperm. These traits offer a precise tool to discriminate between mass-reared and wild males, increasing the effectiveness of sterile insect technique. The reproductive performance of the VIENNA 8 1260 and VIENNA 8 D53- (without the D53 inversion introduced to prevent recombination) was compared at different irradiation doses. The general effect of irradiation on VIENNA 8 1260 followed the same patterns documented in previous publications for VIENNA 8 D53-. Irradiation doses of 80 Gray or greater reduced fertility and induced high levels of sterility in wild females. Fecundity reduction was higher in VIENNA 8 1260 than in VIENNA 8 D53- females. Vertical transmission of the fluorescence gene was confirmed up to the F4 generation. Substerilization in the VIENNA 8 1260 could jeopardize the usefulness of the transgenic strain due to the possible vertical transfer of the fluorescence transgene from the sterile males to the wild flies. A biologically safe higher irradiation dose could result in reduced competitiveness of the VIENNA 8 1260 strain. Mating and remating experiments suggest that Mediterranean fruit fly females exhibit a relative precedence in the use of the sperm: though both sperms are mixed, sperm from the remating is spent first. Results suggest a lower fitness of VIENNA 8 1260 sperm, when compared with sperm from a nonfluorescent bisexual strain, which is consistent with the lower reproductive performance documented for the VIENNA 8 1260 strain. PMID- 28854641 TI - Conserved Transcription Factors Steer Growth-Related Genomic Programs in Daphnia. AB - Ecological genomics aims to understand the functional association between environmental gradients and the genes underlying adaptive traits. Many genes that are identified by genome-wide screening in ecologically relevant species lack functional annotations. Although gene functions can be inferred from sequence homology, such approaches have limited power. Here, we introduce ecological regulatory genomics by presenting an ontology-free gene prioritization method. Specifically, our method combines transcriptome profiling with high-throughput cis-regulatory sequence analysis in the water fleas Daphnia pulex and Daphnia magna. It screens coexpressed genes for overrepresented DNA motifs that serve as transcription factor binding sites, thereby providing insight into conserved transcription factors and gene regulatory networks shaping the expression profile. We first validated our method, called Daphnia-cisTarget, on a D. pulex heat shock data set, which revealed a network driven by the heat shock factor. Next, we performed RNA-Seq in D. magna exposed to the cyanobacterium Microcystis aeruginosa. Daphnia-cisTarget identified coregulated gene networks that associate with the moulting cycle and potentially regulate life history changes in growth rate and age at maturity. These networks are predicted to be regulated by evolutionary conserved transcription factors such as the homologues of Drosophila Shavenbaby and Grainyhead, nuclear receptors, and a GATA family member. In conclusion, our approach allows prioritising candidate genes in Daphnia without bias towards prior knowledge about functional gene annotation and represents an important step towards exploring the molecular mechanisms of ecological responses in organisms with poorly annotated genomes. PMID- 28854645 TI - Flight Phenology of Two Coptotermes Species (Isoptera: Rhinotermitidae) in Southeastern Florida. AB - The dispersal flight activity ("swarming") of two invasive subterranean termite species, Coptotermes gestroi (Wasmann) and Coptotermes formosanus Shiraki, was monitored in metropolitan southeastern Florida, where both species are now sympatric and major structural pests. Historical records of alates collected in the area showed that the two species have distinct peaks of flight activity, from mid-February to late April for C. gestroi, and from early April to late June for C. formosanus. However, an overlap of the two dispersal flight seasons has been observed since at least 2005. The daily monitoring of dispersal flight events in southeastern Florida in 2014, 2015, and 2016 confirmed that simultaneous flights occurred several times each year. In addition, environmental conditions for favorable flights were identified, and it was established that low temperature was the primary factor inhibiting both species from dispersal flights, while all other factors had little impact on the occurrence of major dispersal flight events. However, both species shared similar temperature requirements for favorable dispersal flight conditions despite distinct peaks of activity over time. The analysis of sex ratios and average weights of the alates suggests that intrinsic colony factors are important for the timing of the maturation of alates, and that once a cohort of individuals is ready to disperse, a flight may occur as soon as the environmental conditions are favorable. PMID- 28854646 TI - Line-Trapping of Codling Moth (Lepidoptera: Tortricidae): A Novel Approach to Improving the Precision of Capture Numbers in Traps Monitoring Pest Density. AB - This field study of codling moth, Cydia pomonella (L.), response to single versus multiple monitoring traps baited with codlemone demonstrates that precision of a given capture number is alarmingly poor when the population is held constant by releasing moths. Captures as low as zero and as high as 12 males per single trap are to be expected where the catch mode is three. Here, we demonstrate that the frequency of false negatives and overestimated positives for codling moth trapping can be substantially reduced by employing the tactic of line-trapping, where five traps were deployed 4 m apart along a row of apple trees. Codling moth traps spaced closely competed only slightly. Therefore, deploying five traps closely in a line is a sampling technique nearly as good as deploying five traps spaced widely. But line trapping offers a substantial savings in time and therefore cost when servicing aggregated versus distributed traps. As the science of pest management matures by mastering the ability to translate capture numbers into estimates of absolute pest density, it will be important to employ a tactic like line-trapping so as to shrink the troublesome variability associated with capture numbers in single traps that thwarts accurate decisions about if and when to spray. Line-trapping might similarly increase the reliability and utility of density estimates derived from capture numbers in monitoring traps for various pest and beneficial insects. PMID- 28854647 TI - Chemical Degradation of TMR Multilure Dispensers for Fruit Fly Detection Weathered Under California Climatic Conditions. AB - Degradation models for multilure fruit fly trap dispensers were analyzed to determine their potential for use in large California detection programs. Solid three-component male lure TMR (trimedlure [TML], methyl eugenol [ME], raspberry ketone [RK]) dispensers impregnated with DDVP (2, 2-dichlorovinyl dimethyl phosphate) insecticide placed inside Jackson traps were weathered during summer (8 wk) and winter (12 wk) in five citrus-growing areas. Additionally, TMR wafers without DDVP, but with an insecticidal strip, were compared to TMR dispensers with DDVP. Weathered dispensers were sampled weekly and chemically analyzed. Percent loss of TML, the male lure for Ceratitis capitata (Wiedemann) Mediterranean fruit fly; ME, the male lure for Bactrocera dorsalis (Hendel), oriental fruit fly; RK, the male lure for Bactrocera cucurbitae (Coquillett), melon fly; and DDVP was measured. Based on regression analyses for the male lures, TML degraded the fastest followed by ME. Degradation of the more chemically stable RK was discontinuous, did not fit a regression model, but followed similar seasonal patterns. There were few location differences for all three male lures and DDVP. Dispensers degraded faster during summer than winter. An asymptotic regression model provided a good fit for % loss (ME, TML, and DDVP) for summer data. Degradation of DDVP in TMR dispensers was similar to degradation of DDVP in insecticidal strips. Based on these chemical analyses and prior bioassay results with wild flies, TMR dispensers could potentially be used in place of three individual male lure traps, reducing costs of fruit fly survey programs. Use of an insecticidal tape would not require TMR dispensers without DDVP to be registered with US-EPA. PMID- 28854648 TI - Development of a Low-Cost and Effective Trapping Device for Apple Maggot Fly (Diptera: Tephritidae) Monitoring and Control in Mexican Commercial Hawthorn Groves. AB - Few efforts have been made in Mexico to monitor Rhagoletis pomonella (Walsh) (Diptera: Tephritidae) in commercial hawthorn (Crataegus spp.) crops. Therefore, the main objectives of this study were to evaluate infestation levels of R. pomonella in feral and commercial Mexican hawthorn and to assess the efficacy of different trap-lure combinations to monitor the pest. Wild hawthorn was more infested than commercially grown hawthorn at the sample site. No differences among four commercial baits (Biolure, ammonium carbonate, CeraTrap, and Captor + borax) were detected when used in combination with a yellow sticky gel (SG) adherent trap under field conditions. However, liquid lures elicited a slightly higher, although not statistically different, capture. Cage experiments in the laboratory revealed that flies tended to land more often on the upper and middle than lower-bottom part of polyethylene (PET) bottle traps with color circles. Among red, orange, green, and yellow circles attached to a bottle trap, only yellow circles improved fly captures compared with a colorless trap. A PET bottle trap with a red circle over a yellow background captured more flies than a similar trap with yellow circles. An SG adherent yellow panel trap baited with ammonium carbonate was superior to the improved PET bottle trap (red over a yellow background) baited with different liquid proteins, but a higher proportion of females and no differences in fly detection were measured in PET traps baited with protein lures. These trials open the door for future research into development of a conventional nonadherent trap to monitor or control R. pomonella. PMID- 28854649 TI - Expected Timber-Based Economic Impacts of a Wood-Boring Beetle (Acanthotomicus Sp.) That Kills American Sweetgum. AB - American sweetgum trees (Liquidambar styraciflua L. [Altingiaceae]) in China are being killed by a newly discovered wood-boring beetle "sweetgum inscriber" (Acanthotomicus sp.). It has not been detected in the United States yet, but given the extent of trade with Asian countries, eventual arrival of this beetle is a serious concern. The American sweetgum is one of the main hardwood species in the southern United States, and provides several economic and ecological benefits to society. We present the first economic analysis of the potential damage from sweetgum inscriber (SI) to timber-based land values in the southern United States. We modeled economic impacts for a range of feasible SI arrival rates that reflect policy interventions: 1) no efforts to prevent arrival (scenario A, once every 14 and 25 yr), 2) partial prevention by complying with ISPM 15 standards (scenario B, once every 33 and 100 yr), and 3) total prevention of arrival (scenario C, zero transmission of SI). Our results indicated much lower land values for sweetgum plantations without the prevention on SI establishment (scenario A, US$1,843-US$4,383 ha-1) compared with partial prevention (scenario B, US$5,426-US$8,050 ha-1) and total eradication of SI (scenario C, US$9,825). Across the region, upper bound timber-based economic losses to plantation owners is US$151.9 million (US$4.6 million annually)-an estimate that can help inform policy decisions. PMID- 28854650 TI - Host-Mediated Effects of Semipersistently Transmitted Squash Vein Yellowing Virus on Sweetpotato Whitefly (Hemiptera: Aleyrodidae) Behavior and Fitness. AB - Plant viruses may indirectly affect insect vector behavior and fitness via a shared host plant. Here, we evaluated the host-mediated effects of Squash vein yellowing virus (SqVYV) on the behavior and fitness of its whitefly vector, Bemisia tabaci (Gennadius) Middle East-Asia Minor 1, formerly biotype B. Alighting, settling, and oviposition behavioral assays were conducted on infected and mock-inoculated squash (Cucurbita pepo L.) and watermelon [Citrullus lanatus (Thunb) Matsum and Nakai] plants. Developmental time of immature stages, adult longevity, and fecundity were measured on infected and mock-inoculated squash plants. For adult longevity and fecundity, whiteflies were reared on infected and mock-inoculated squash plants to determine the effects of nymphal rearing host on the adult stage. More whiteflies alighted and remained settled on infected squash than on mock-inoculated squash 0.25, 1, 8, and 24 h after release. No such initial preference was observed on watermelon plants, but by 8 h after release, more whiteflies were found on mock-inoculated watermelon plants than on infected plants. Whiteflies laid approximately six times more eggs on mock-inoculated watermelon than on infected watermelon; however, no differences were observed on squash. Development from egg to adult emergence was 3 d shorter on infected than mock-inoculated squash plants. Females lived 25% longer and had higher fecundity on infected squash plants than on mock-inoculated plants, regardless of infection status of the rearing host. The host-mediated effects of SqVYV infection on whitefly behavior differ on two cucurbit host plants, suggesting the potential for more rapid spread of the virus within watermelon fields. PMID- 28854651 TI - Effects of Storage at Suboptimal Temperatures on the In Vitro-Reared Parasitoid Exorista larvarum (Diptera: Tachinidae). AB - Exorista larvarum (L.) is a tachinid parasitoid native to the Palearctic region, known as an antagonist of lepidopterous defoliators. This species is suitable to be cultured in vitro, and yields of fecund adults, approaching those usually attained in host larvae, have been previously achieved on artificial media. Direct oviposition by E. larvarum on media has not yet been obtained, and the eggs for the in vitro rearing are routinely removed from parasitized host larvae. However, many eggs are usually laid throughout the cage by captive females and can be retrieved by placing them on artificial media. Storage at low temperatures provides a method for prolonging the development of insects and stockpile them when not needed immediately. We studied the effects of storage at 20 degrees C (for 5 d or until pupation) or 15 degrees C (for 5 d or until egg hatching) on the in vitro development of E. larvarum. Lower temperatures were excluded, because previous studies showed a strong negative impact on hatching when the eggs were stored at 5 degrees C or 10 degrees C. For the experiments, eggs were removed from hosts and placed on an artificial medium. The results suggested that it is possible to delay the development of the in vitro-reared E. larvarum, which eventually reached the adult stage, although some negative effects on fly quality (i.e., longevity and fecundity) were also observed. Because quality is not an absolute concept, all the situations tested in this study could be appropriate according to the current requirements. PMID- 28854652 TI - Evaluations of Insecticides and Fungicides for Reducing Attack Rates of a new invasive ambrosia beetle (Euwallacea Sp., Coleoptera: Curculionidae: Scolytinae) in Infested Landscape Trees in California. AB - A recently discovered ambrosia beetle with the proposed common name of polyphagous shot hole borer (Euwallacea sp., Coleoptera: Curculionidae: Scolytinae), is reported to attack >200 host tree species in southern California, including many important native and urban landscape trees. This invasive beetle, along with its associated fungi, causes branch dieback and tree mortality in a large variety of tree species including sycamore (Platanus racemosa Nutt.). Due to the severity of the impact of this Euwallacea sp., short-term management tools must include chemical control options for the arboriculture industry and private landowners to protect trees. We examined the effectiveness of insecticides, fungicides, and insecticide-fungicide combinations for controlling continued Euwallacea sp. attacks on previously infested sycamore trees which were monitored for 6 mo after treatment. Pesticide combinations were generally more effective than single pesticide treatments. The combination of a systemic insecticide (emamectin benzoate), a contact insecticide (bifenthrin), and a fungicide (metconazole) provided some level of control when applied on moderate and heavily infested trees. The biological fungicide Bacillus subtilis provided short-term control. There was no difference in the performance of the three triazole fungicides (propiconazole, tebuconazole, and metconazole) included in this study. Although no pesticide combination provided substantial control over time, pesticide treatments may be more effective when trees are treated during early stages of attack by this ambrosia beetle. PMID- 28854653 TI - CRISPR/Cas9 Editing of the Codling Moth (Lepidoptera: Tortricidae) CpomOR1 Gene Affects Egg Production and Viability. AB - The codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), is a major pest of pome fruit worldwide. Incorporation of semiochemicals, including the main sex pheromone (codlemone), into codling moth IPM programs has drastically reduced the amount of chemical insecticides needed to control this orchard pest. Odorant receptors located in sensory neuron membranes in the antennae are key sensors in the detection of semiochemicals and trigger downstream signaling events leading to a behavioral response. CpomOR1 is an odorant receptor belonging to the pheromone receptor subfamily in codling moth, and is a prime candidate for being a codlemone receptor based on its high expression levels in male antennae. In this study, the CpomOR1 gene was targeted using CRISPR/Cas9 genome editing to knockdown functional OR1 protein production to determine physiological function(s). By injecting early stage eggs, mutations were successfully introduced, including both deletions and insertions. When attempting to create stable populations of codling moth through mating of males with females containing mutations of the CpomOR1 gene, it was found that fecundity and fertility were affected, with edited females producing nonviable eggs. The role of CpomOR1 in fecundity and fertility in codling moth is unknown and will be the focus of future studies. PMID- 28854654 TI - Expression Differences of Resistance-Related Genes Induced by Cycloxaprid Using qRT-PCR in the Female Adult of Sogatella furcifera (Hemiptera: Delphacidae). AB - As a newer cis-nitromethylene neonicotinoid pesticide at present, cycloxaprid has good industrialization prospects, including the management of imidacloprid resistant populations, because this chemical have an excellent efficiency against rice planthoppers. Sogatella furcifera (Horvath) is the most economically important pest of rice worldwide and has developed resistance to many insecticides. This study focused on the expression change of these resistance genes, induced by cycloxaprid, involved in metabolic detoxification and receptor protein. Twenty-two differentially expressed genes (DEGs) that may be related with the insecticide resistance were found in the transcriptome of S. furcifera, including 2 cytochrome P450 genes, 2 glutathione S-transferase (GST) genes, 1 acid phosphatase (ACP) gene, 12 decarboxylase genes, 2 glycolipid genes, 1 cadherin gene, and 2 glycosyltransferase genes, which were up- or downregulated in response to an exposure of cycloxaprid. Furthermore, two P450 genes (CYP4 and CYP6 family, respectively), two decarboxylase genes, and one glycosyltransferase gene were validated by qRT-PCR. Expression differences of these genes verified successfully by qRT-PCR in response to different concentrations and times treated with cycloxaprid could explain the insecticide resistance mechanism under cycloxaprid stress in S. furcifera. PMID- 28854655 TI - Life History of Parthenolecanium spp. (Hemiptera: Coccidae) in Urban Landscapes of the Southeastern United States. AB - This study was conducted to better understand the life history of Parthenolecanium corni (Bouche) and Parthenolecanium quercifex (Fitch) (Hemiptera: Coccidae), and to develop degree-day models for crawler emergence of the two soft scale species in Georgia, North Carolina, South Carolina, and Virginia. Both species were univoltine in the southeastern United States. In South Carolina, eggs hatched from mid-April to early June; second instars began to appear in September and migrated to twigs to overwinter in October; and third instars and adults appeared in mid-March to early April. Each parthenogenetic female produced on average 1,026 +/- 52 eggs. Fecundity was positively correlated to the fresh weight, length, width, and height of gravid females. Gross reproductive rate (GRR) was 695.98 +/- 79.34 ?/?, net reproductive rate (Ro) was 126.36 +/- 19.03 ?/?, mean generation time (TG) was 52.61 +/- 0.05 wk, intrinsic rate of increase (rm) was 0.04 ?/?/wk, and finite rate of increase (lambda) was 1.04 times per week. Crawlers first occurred across Georgia, North Carolina, South Carolina, and Virginia in 2011-2013 when 524-596 Celsius-degree-days (DDC) had been accumulated with the single sine estimation method, or 411-479 DDC with the simple average method, at the base temperature of 12.8 degrees C and the start date of 1 January. These regional models accurately predicted the date of crawler emergence within 1 wk of the actual emergence in 2014. PMID- 28854656 TI - Attempt to Develop Cost-Effective Rearing of Amblyseius swirskii (Acari: Phytoseiidae): Assessment of Different Artificial Diets. AB - Commercial production of Amblyseius swirskii Athias-Henriot based on storage mites needs both space and labor to maintain large cultures of these prey, and also may lead to health problems for workers. Therefore, the accessibility of a suitable artificial diet could eliminate the mentioned problems; however, the artificial diets must support the persistent production of high quality progeny. This study endeavored to find a more easily available and cheaper nutrient that may further reduce the cost of diet production for A. swirskii. The predator's performance was determined when it was fed on a basic artificial diet (AD1) composed of honey, sucrose, tryptone, yeast extract, and hen egg yolk, and on eight other artificial diets consisting of 80% AD1 enriched with different nutrients including maize pollen (AD2), hemolymph of Plusia gamma L. (AD3), Ephestia eggs (AD4), Artemis cysts (AD5), Ephestia last-instar larvae (AD6), multivitamin syrup (AD7), bovine serum albumin (AD8), and bull sperm (AD9). The lowest development time was on AD2. The highest value of fecundity and oviposition period were observed on AD5, followed by AD2 and AD4. The intrinsic rate of increase (r) and the finite rate of increase (lambda) reached the maximal value on AD5. Feeding on AD2 and AD5 resulted in highest value of R0 (net reproductive rate). Our results indicated that Artemia cysts and maize pollen had better potential to be used as nutrient in artificial diet for mass production of A. swirskii. Overall, it seems that AD2 is the most cost effective than others. PMID- 28854657 TI - Biological Performance and Preference of Mahanarva spectabilis (Hemiptera: Cercopidae) for Feeding on Different Forage Plants. AB - The performance and preference of Mahanarva spectabilis (Distant) for feeding on different forage species were evaluated. The survival and duration of the nymphal period, longevity and fertility of adults, and food preferences (free choice) of adults of M. spectabilis were evaluated in a greenhouse trial, and food preferences of adults were also evaluated in laboratory tests without a choice of host plant. In the field, the numbers of plants with spittle masses were evaluated by forage sampling. Lower levels of nymph survival were observed in the greenhouse on Molasses grass, Jaragua, Tanzania, and Makueni. The duration of the nymphal period did not differ significantly on different forage species; however, the longevity and fertility of adults were significantly lower on Cynodon and Brachiaria decumbens Stapf. In the free-choice preference test, adult insects were attracted most strongly to B. decumbens and Jaragua, with intermediate attraction to Brachiaria brizantha (Hochst ex A. Rich) Stapf and Pioneiro. In the test without host choice, insects exhibited lower excretion rates on Tanzania, Cynodon, Jaragua, B. brizantha, and Molasses grass, and those fed on Cynodon, Jaragua, Molasses grass, and Makueni also exhibited reduced body mass. In the field, Pioneiro had the highest number of spittle masses, followed by Roxo de Botucatu. Thus, Molasses grass, Tanzania, Makueni, and Jaragua plants are less suitable food sources for M. spectabilis nymphs and adults. Additionally, although Jaragua was less favorable to nymphs, it attracted food-seeking adults; hence, these plants have potential for use in control of M. spectabilis. PMID- 28854658 TI - Assessing Wild Bee Biodiversity in Cranberry Agroenvironments: Influence of Natural Habitats. AB - The conservation of bee populations for pollination in agricultural landscapes has attracted a lot of recent research interest, especially for crop industries undergoing expansion to meet increased production demands. In Canada, much growth has been occurring with commercial cranberry production, a field crop which is largely dependent on bee pollination. Wild bee pollinators could be negatively impacted by losses of natural habitat surrounding cranberry fields to accommodate increased production, but growers have little insight on how to manage their lands to maximize the presence of wild bees. Here, we described a 2-yr study where bee diversity and species composition were investigated to better understand the dynamic between natural habitat and cranberry fields. Bees were sampled using pan-traps and hand netting both within cranberry fields and in one of the three adjacent natural habitat types once a week during the crop flowering period. We found that bee community composition among cranberry fields did not differ based on the respective adjacent habitat type, but fields bordered by meadows were marginally less diverse than fields bordered by forest. As one would expect, field and natural habitat communities differed in terms of species composition and species richness. There was no evidence that one type of natural habitat was more favorable for the bees than another. Future agrobiodiversity studies should simultaneously examine bee diversity comprised in both crop fields and adjacent natural environments to better understand the species dynamics essential to the preservation of pollination services. PMID- 28854659 TI - Tracking the Genetic Stability of a Honey Bee (Hymenoptera: Apidae) Breeding Program With Genetic Markers. AB - A genetic stock identification (GSI) assay was developed in 2008 to distinguish Russian honey bees from other honey bee stocks that are commercially produced in the United States. Probability of assignment (POA) values have been collected and maintained since the stock release in 2008 to the Russian Honey Bee Breeders Association. These data were used to assess stability of the breeding program and the diversity levels of the contemporary breeding stock through comparison of POA values and genetic diversity parameters from the initial release to current values. POA values fluctuated throughout 2010-2016, but have recovered to statistically similar levels in 2016 (POA(2010) = 0.82, POA(2016) = 0.74; P = 0.33). Genetic diversity parameters (i.e., allelic richness and gene diversity) in 2016 also remained at similar levels when compared to those in 2010. Estimates of genetic structure revealed stability (FST(2009/2016) = 0.0058) with a small increase in the estimate of the inbreeding coefficient (FIS(2010) = 0.078, FIS(2016) = 0.149). The relationship among breeding lines, based on genetic distance measurement, was similar in 2008 and 2016 populations, but with increased homogeneity among lines (i.e., decreased genetic distance). This was expected based on the closed breeding system used for Russian honey bees. The successful application of the GSI assay in a commercial breeding program demonstrates the utility and stability of such technology to contribute to and monitor the genetic integrity of a breeding stock of an insect species. PMID- 28854661 TI - Resistance of Select Winter Wheat (Triticum aestivum) Cultivars to Rhopalosiphum padi (Hemiptera: Aphididae). AB - The bird cherry-oat aphid (Rhopalosiphum padi L.) is a global pest of wheat and vectors some of the most damaging strains of barley yellow dwarf virus (BYDV). In years of heavy R. padi infestation, R. padi and BYDV together reduce wheat yields by 30-40% in Kansas and other states of the U.S. Great Plains wheat production area. Cultivation of wheat cultivars resistant to R. padi can greatly reduce production costs and mitigate R. padi-BYDV yield losses, and increase producer profits. This study identified cultivars of hard red and soft white winter wheat with R. padi resistance that suppress R. padi populations or tolerate the effects of R. padi feeding damage. 'Pioneer (S) 25R40,' 'MFA (S) 2248,' 'Pioneer (S) 25R77,' and 'Limagrain LCS Mint' significantly reduced R. padi populations. MFA (S) 2248, Pioneer (S) 25R40, and 'Limagrain LS Wizard' exhibited tolerance expressed as significantly greater aboveground biomass. These findings are significant in that they have identified wheat cultivars currently available to producers, enabling the immediate improvement of tactics to manage R. padi and BYDV in heavily infested areas. Secondarily, these results identify cultivars that are good candidates for use in breeding and genetic analyses of arthropod resistance genes in wheat. PMID- 28854660 TI - Synergistic Combinations of a Pyrethroid Insecticide and an Emulsifiable Oil Formulation of Beauveria bassiana to Overcome Insecticide Resistance in Listronotus maculicollis (Coleoptera: Curculionidae). AB - The annual bluegrass weevil, Listronotus maculicollis (Kirby), is a major pest of golf course turf in eastern North America and has become particularly problematic owing to widespread development of insecticide resistance. As an alternative option to manage resistant adult L. maculicollis, we explored combinations of the pyrethroid insecticide bifenthrin with an emulsifiable oil formulation of the entomopathogenic fungus Beauveria bassiana strain GHA (Bb ES). Combinations synergistically enhanced mortality in both insecticide-susceptible and insecticide-resistant L. maculicollis adults in the laboratory when bifenthrin was used at LC50s for each population. To determine the component behind the synergism, technical spores of B. bassiana GHA and the emulsifiable oil carrier in the fungal formulation were tested separately or in combination with bifenthrin. In both separate and combined applications, the emulsifiable oil carrier was responsible for high mortality within 3 d after treatment and interacted synergistically with bifenthrin, whereas fungus-induced mortality started later. Strong synergism was also observed in three field experiments with a relatively resistant L. maculicollis population. Combinations of Bb ES and bifenthrin hold promise as an effective L. maculicollis management tool, particularly of pyrethroid-resistant populations. PMID- 28854662 TI - Population Growth of Dysaphis pyri (Hemiptera: Aphididae) on Different Pear Cultivars With Discussion on Curve Fitting in Life Table Studies. AB - Population growth parameters of the Dysaphis pyri (Boyer de Fonscolombe) (Hemiptera: Aphididae) were evaluated on four different cultivars (Coscia, Ankara, Williams, and Santa-Maria) of pear (Pyrus communis L.) under field conditions in the Van region of Turkey. Aphids were kept on leaves of 10-yr-old pear trees in Plexiglas clip-cells (20 mm in diameter and 10 mm in height, with the upper side covered with muslin). For the description of the stage differentiation during population growth, we analyzed raw data of developmental time, survival, and fecundity using the age-stage, two-sex life table to take the variable developmental rate among individuals into account. Results indicated that the Coscia and Ankara cultivars are less favorable hosts for D. pyri because of the longer preadult developmental time, higher preadult mortality rate, and lower total fecundity on these cultivars. The intrinsic rate of increase (r), the net reproduction rate (R0), and the finite rate of increase (lambda) values were lower on the Coscia and Ankara cultivars. We discussed the application of the Weibull function, polynomial model, and Enkegaard model in life table studies. Because these models are often inaccurate in describing survival and reproduction parameters, we suggest that their application in life table research should be reevaluated. PMID- 28854663 TI - Temperature-Dependent Demography of Two Closely Related Predatory Mites Neoseiulus womersleyi and N. longispinosus (Acari: Phytoseiidae). AB - Temperature has significant effects on the development, survival, and reproduction of ectothermic organisms. In this study, we examined the effect of temperature on the demographic characteristics of two predatory mite species, Neosciulus womersleyi (Schicha) and N. longispinosus (Evans), reared on Tetranychus urticae Koch. The developmental and reproductive traits of both species were examined at 10 constant temperatures between 15 degrees C and 37.5 degrees C. The preadult development time of N. womersleyi and N. longispinosus decreased with increasing temperature until 32.5 degrees C and 35 degrees C, respectively. The lower developmental threshold (T0) and thermal constant (K) estimated by using a linear model were 11.61 degrees C and 69.36 DD for N. womersleyi and 11.92 degrees C and 61.5 DD for N. longispinosus, respectively. Total preoviposition period and total longevity of females and males of N. womersleyi and N. longispinosus decreased with increasing temperature. The mean generation time (T) first decreased with temperature until 32.5 and 35 degrees C for N. womersleyi and N. longispinosus, respectively, and then increased at higher temperatures. The R0 and r values first increased with temperature until 32.5 and 30 degrees C for N. womersleyi and N. longispinosus, respectively, and then decreased at higher temperatures. The R0 and r values for N. longispinosus at 37.5 degrees C were 0.3 offspring and -0.143 d-1, respectively. These results show that N. longispinosus is less fit than N. womersleyi at 37.5 degrees C. PMID- 28854664 TI - Hyperecdysonism in the Formosan Subterranean Termite and Eastern Subterranean Termite (Isoptera: Rhinotermitidae). AB - Effects of ecdysone, 20-hydroxyecdysone (20E), and an ecdysone agonist, halofenozide, were tested against the Formosan subterranean termite, Coptotermes formosanus Shiraki, and the eastern subterranean termite, Reticulitermes flavipes (Kollar), in a 12-d no choice assay. Approximately 22-26% of R. flavipes and C. formosanus exhibited symptoms of hyperecdysonism, that is, "jackknife" position, when exposed to ecdysone and 20E at 1,000 ppm, respectively. High mortalities were recorded for both termite species in ecdysone and 20E at 100 and 1,000 ppm, but only at 10,000 ppm for halofenizide. Termites are known to move back to the central nest before the onset of ecdysis, and those that ingested lethal doses of chitin synthesis inhibitors (CSIs) die near the royal pairs, which partially accounts for the success of CSI baits to eliminate subterranean termite colonies. Because ecdysteroids and their agonists induce molting in termites, incorporation of these compounds into baits could potentially achieve the same colony elimination. This study showed that lethal time (12 d) of ecdysteroids and ecdysone agonist is shorter than that of a CSI (45 d); hence, the baiting time should be reduced by more than a month when they are incorporated in termite baits. PMID- 28854665 TI - The Effect of Maize Hybrid on Biology and Life Table Parameters of the Trogoderma granarium (Coleoptera: Dermestidae). AB - The khapra beetle, Trogoderma granarium Everts (Coleoptera: Dermestidae), is a polyphagous pest that infests many stored grains and products. The effect of nine maize hybrids including 704, AR 89, AS 71, AS 77, BC 678, KSC 703, PL 472, SC 704, and Simax was studied on biology and life table parameters of T. granarium at controlled conditions (33 +/- 1 degrees C, 65 +/- 5% RH, and a photoperiod of 14:10 [L:D] h). According to the results of this study, the immature period was the longest on BC 678 (56.79 +/- SE: 1.51 d) and the shortest on PL 472 (39.90 +/ 0.48 d). The highest values of fecundity and fertility were observed on PL 472 (67.95 +/- 1.23 eggs and 74.81 +/- 0.68%, respectively) and the lowest values were on BC 678 (40.00 +/- 1.63 and 48.24 +/- 1.35, respectively). The net reproductive rate (R0) of T. granarium ranged from 10.40 +/- 0.11 offsprings on BC 678 to 30.43 +/- 0.20 offsprings on KSC 703. The highest intrinsic rate of increase (rm) was for T. granarium reared on KSC 703 (0.0773 +/- 0.0001 d-1), and the lowest was on BC 678 (0.0390 +/- 0.0002 d-1). According to the obtained results, BC 678 is an unfavorable hybrid for population increase of T. granarium, which can be recommended to be grown in regions where the damage of T. granarium is considerable to minimize maize infestations by this pest. PMID- 28854666 TI - The estimates of 5-year stomach cancer prevalence in adult population in 2012. PMID- 28854667 TI - Effect of dietary nucleosides and yeast extracts on composition and metabolic activity of infant gut microbiota in PolyFermS colonic fermentation models. AB - Nucleotides (NT) and nucleosides (NS) are added to infant formula to mimic the content of breast milk, but little is known about their impact on infant gut microbiota. In this study, we tested the effect of NS and of yeast extracts (YE) with different NT content using PolyFermS continuous fermentation models mimicking formula-fed, healthy and enteropathogen-contaminated infant gut microbiota. Microbiota composition, short-chain fatty acid (SCFA) formation and gene expression were determined. NS, and to a larger extend YE modulated microbiota composition and increased metabolic activity in both models. Anaerococcus, Peptoniphilus, Fusobacterium, Lactobacillus/Pediococcus/Leuconostoc and Veillonella were enhanced when YE and/or NS were added. The production of SCFA increased with the level of supplied NT equivalents. Addition of NS and YE reduced colonization of Salmonella compared to control periods. Gene expression analysis confirmed taxonomical changes and indicated functional responses to YE. Transcripts related to NT and sulfur metabolism and iron acquisition increased while biosynthesis of co-factors and vitamins decreased after YE addition. Elevated butyrate formation correlated with increased transcripts encoding key enzymes of the two major butyrate synthesis pathways. Our results uncover a strong dose-dependent modulation of NS and YE on infant gut microbiota composition and metabolic activity. PMID- 28854668 TI - Current and future therapies for Pseudomonas aeruginosa infection in patients with cystic fibrosis. AB - Pseudomonas aeruginosa opportunistically infects the airways of patients with cystic fibrosis and causes significant morbidity and mortality. Initial infection can often be eradicated though requires prompt detection and adequate treatment. Intermittent and then chronic infection occurs in the majority of patients. Better detection of P. aeruginosa infection using biomarkers may enable more successful eradication before chronic infection is established. In chronic infection P. aeruginosa adapts to avoid immune clearance and resist antibiotics via efflux pumps, beta-lactamase expression, reduced porins and switching to a biofilm lifestyle. The optimal treatment strategies for P. aeruginosa infection are still being established, and new antibiotic formulations such as liposomal amikacin, fosfomycin in combination with tobramycin and inhaled levofloxacin are being explored. Novel agents such as the alginate oligosaccharide OligoG, cysteamine, bacteriophage, nitric oxide, garlic oil and gallium may be useful as anti-pseudomonal strategies, and immunotherapy to prevent infection may have a role in the future. New treatments that target the primary defect in cystic fibrosis, recently licensed for use, have been associated with a fall in P. aeruginosa infection prevalence. Understanding the mechanisms for this could add further strategies for treating P. aeruginosa in future. PMID- 28854669 TI - The yeast Mig1 transcriptional repressor is dephosphorylated by glucose-dependent and -independent mechanisms. AB - A yeast Saccharomyces cerevisiae Snf1 kinase, an analog of mammalian AMPK, regulates glucose derepression of genes required for utilization of alternative carbon sources through the transcriptional repressor Mig1. It has been suggested that the Glc7-Reg1 phosphatase dephosphorylates Mig1. Here we report that Mig1 is dephosphorylated by Glc7-Reg1 in an apparently glucose-dependent mechanism but also by a mechanism independent of glucose and Glc7-Reg1. In addition to serine/threonine phosphatases another process including tyrosine phosphorylation seems crucial for Mig1 regulation. Taken together, Mig1 dephosphorylation appears to be controlled in a complex manner, in line with the importance for rapid and sensitive regulation upon altered glucose concentrations in the growth medium. PMID- 28854670 TI - Optimization of therapy against Pseudomonas aeruginosa with ceftazidime and meropenem using chemostats as model for infections. AB - Pseudomonas aeruginosa is an opportunistic pathogen that can cause life threatening infections in patients admitted to intensive care units. Resistance rapidly develops against two drugs of choice: ceftazidime and meropenem. Several therapeutic protocols were compared for reduction in viable cells and limiting development of resistance. Chemostat cultures were exposed to antibiotic concentrations measured in the blood of patients at low (5th percentile), medium (50th percentile) or high (95th percentile) levels in several therapy protocols to simulate therapy. Cultures exposed to ceftazidime recovered after 1 day at low, 2 days at medium and 3 days at high concentrations and developed corresponding levels of resistance. Patterns were very similar for meropenem except that recovery was delayed. Fluctuating levels and intermittent treatment achieved similar reduction of cell numbers at lower resistance costs. Treatment alternating ceftazidime and meropenem reduced cell numbers more than monotherapy, while strongly limiting resistance. Combination therapy was even more effective in both respects. Therapeutic goals are best reached with least risk of resistance when ceftazidime and meropenem are used in combination or alternating, at the highest concentrations the patient can endure. Monotherapy should also apply the highest concentration that is safe for the shortest time that achieves treatment objectives. PMID- 28854671 TI - Investigating differences in the ability of XplA/B-containing bacteria to degrade the explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). AB - The xenobiotic hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a toxic explosive and environmental pollutant. This study examines three bacterial species that degrade RDX, using it as a sole source of nitrogen for growth. Although isolated from diverse geographical locations, the species contain near identical copies of genes encoding the RDX-metabolising cytochrome P450, XplA and accompanying reductase, XplB. Sequence analysis indicates a single evolutionary origin for xplA and xplB as part of a genomic island, which has been distributed around the world via horizontal gene transfer. Despite the fact that xplA and xplB are highly conserved between species, Gordonia sp. KTR9 and Microbacterium sp. MA1 degrade RDX more slowly than Rhodococcus rhodochrous 11Y. Both Gordonia sp. KTR9 and Microbacterium sp. MA1 were found to contain single base-pair mutations in xplB which, following expression and purification, were found to encode inactive XplB protein. Additionally, the Gordonia sp. KTR9 XplB was fused to glutamine synthetase, which would be likely to sterically inhibit XplB activity. Although the glutamine synthetase is fused to XplB and truncated by 71 residues, it was found to be active. Glutamine synthetase has been implicated in the regulation of nitrogen levels; controlling nitrogen availability will be important for effective bioremediation of RDX. PMID- 28854672 TI - An in vitro model of azithromycin-induced persistent Chlamydia trachomatis infection. AB - Single-dose azithromycin is recommended for treating Chlamydia trachomatis infections. Here, we established an in vitro cell model of azithromycin-induced persistent infection. Azithromycin inhibited the replication of C. trachomatis in a dose-time-dependent manner. Electron microscopy indicated that small inclusions in the induced model contained enlarged, aberrant and non-infectious reticulate bodies. RT-PCR showed that C. trachomatis still has the ability to express the unprocessed 16S rRNA gene in the model and that C. trachomatis recovered after the removal of azithromycin with a peak recovery time of 24 h. The mutations in 23S rRNA, L4 and L22 genes were not found in persistent infection, and qRT-PCR analysis showed that the relative expression level of euo in azithromycin treated infection was upregulated while omcB was downregulated. In summary, this study provides a novel in vitro cell model to examine the characteristics of azithromycin-induced persistent infection and contribute to the development of treatments for C. trachomatis infection. PMID- 28854673 TI - Peculiar citric acid cycle of hydrothermal vent chemolithoautotroph Hydrogenovibrio crunogenus, and insights into carbon metabolism by obligate autotrophs. AB - The genome sequence of the obligate chemolithoautotroph Hydrogenovibrio crunogenus paradoxically predicts a complete oxidative citric acid cycle (CAC). This prediction was tested by multiple approaches including whole cell carbon assimilation to verify obligate autotrophy, phylogenetic analysis of CAC enzyme sequences and enzyme assays. Hydrogenovibrio crunogenus did not assimilate any of the organic compounds provided (acetate, succinate, glucose, yeast extract, tryptone). Enzyme activities confirmed that its CAC is mostly uncoupled from the NADH pool. 2-Oxoglutarate:ferredoxin oxidoreductase activity is absent, though pyruvate:ferredoxin oxidoreductase is present, indicating that sequence-based predictions of substrate for this oxidoreductase were incorrect, and that H. crunogenus may have an incomplete CAC. Though the H. crunogenus CAC genes encode uncommon enzymes, the taxonomic distribution of their top matches suggests that they were not horizontally acquired. Comparison of H. crunogenus CAC genes to those present in other 'Proteobacteria' reveals that H. crunogenus and other obligate autotrophs lack the functional redundancy for the steps of the CAC typical for facultative autotrophs and heterotrophs, providing another possible mechanism for obligate autotrophy. PMID- 28854674 TI - Increasing the intracellular isoprenoid pool in Saccharomyces cerevisiae by structural fine-tuning of a bifunctional farnesyl diphosphate synthase. AB - Farnesyl diphosphate synthase (FPPS) is a key enzyme responsible for the supply of isoprenoid precursors for several essential metabolites, including sterols, dolichols and ubiquinone. In Saccharomyces cerevisiae, FPPS catalyzes the sequential condensation of two molecules of isopentenyl diphosphate (IPP) with dimethylallyl diphosphate (DMAPP), producing geranyl diphosphate (GPP) and farnesyl diphosphate (FPP). Critical amino acid residues that determine product chain length were determined by a comparative study of strict GPP synthases versus strict FPPS. In silico DeltaDeltaG, i.e. differential binding energy between a protein and two different ligands-of yeast FPPS mutants was evaluated, and F96, A99 and E165 residues were identified as key determinants for product selectivity. A99X variants were evaluated in vivo, S. cerevisiae strains carrying A99R and A99H variants showed significant differences on GPP concentrations and specific growth rates. The FPPS A99T variant produced unquantifiable amounts of FPP and no effect on GPP production was observed. Strains carrying A99Q, A99Y and A99K FPPS accumulated high amounts of DMAPP-IPP, with a decrease in GPP and FPP. Our results demonstrated the relevance of the first residue before FARM (First Aspartate Rich Motif) over substrate consumption and product specificity of S. cerevisiae FPPS in vivo. The presence of A99H significantly modified product selectivity and appeared to be relevant for GPP synthesis. PMID- 28854675 TI - Reply to Forsyth et al., commenting on our paper 'Survival following a diagnosis of heart failure in primary care'. PMID- 28854676 TI - Bacterial community composition and diversity in Kalakuli, an alpine glacial-fed lake in Muztagh Ata of the westernmost Tibetan Plateau. AB - It is widely accepted that bacterial community composition and diversity in remote alpine lakes are structured by environmental conditions such as nutrient status and temperature. However, the mechanisms that underlie and structure bacterial community composition and diversity in alpine lakes remain unclear. We used 16S rRNA gene-based Illumina MiSeq sequencing to investigate the complex ecological interactions between bacterial communities and nutrient status in Kalakuli Lake, an alpine glacial-fed lake in Muztagh Ata of the westernmost Tibetan Plateau. Our results indicated that the bacterial community was dominated by the Actinobacteria and Proteobacteria. The results of threshold estimates showed that there were apparent shifts in dominance from the Proteobacteria to Actinobacteria groups associated with increasing carbon to nitrogen (C:N) ratio, and the change points were 6.794 and 2.448, respectively. Using multiple statistical methods, we found that the abiotic factors of dissolved organic carbon and total nitrogen had substantial impacts on bacterial diversity, while bacterial community compositions were significantly correlated with both the biotic element of bacterial abundance and the abiotic ones, temperature and pH. These findings demonstrated that the C:N ratio played a significant role in shifting dominant bacterial assemblages in the Kalakuli watershed and provided evidence of nutrients affecting bacterial community composition and diversity. We argue that this study could further shed light on how climate change-induced glacial retreat may impact bacterial communities in glacial-fed lakes under future global warming scenarios. PMID- 28854677 TI - Patterns and drivers of fungal community depth stratification in Sphagnum peat. AB - Peatlands store an immense pool of soil carbon vulnerable to microbial oxidation due to drought and intentional draining. We used amplicon sequencing and quantitative PCR to (i) examine how fungi are influenced by depth in the peat profile, water table and plant functional group at the onset of a multiyear mesocosm experiment, and (ii) test if fungi are correlated with abiotic variables of peat and pore water. We hypothesized that each factor influenced fungi, but that depth would have the strongest effect early in the experiment. We found that (i) communities were strongly depth stratified; fungi were four times more abundant in the upper (10-20 cm) than the lower (30-40 cm) depth, and dominance shifted from ericoid mycorrhizal fungi to saprotrophs and endophytes with increasing depth; (ii) the influence of plant functional group was depth dependent, with Ericaceae structuring the community in the upper peat only; (iii) water table had minor influences; and (iv) communities strongly covaried with abiotic variables, including indices of peat and pore water carbon quality. Our results highlight the importance of vertical stratification to peatland fungi, and the depth dependency of plant functional group effects, which must be considered when elucidating the role of fungi in peatland carbon dynamics. PMID- 28854678 TI - Greater diversity of soil fungal communities and distinguishable seasonal variation in temperate deciduous forests compared with subtropical evergreen forests of eastern China. AB - Whether and how seasonality of environmental variables impacts the spatial variability of soil fungal communities remain poorly understood. We assessed soil fungal diversity and community composition of five Chinese zonal forests along a latitudinal gradient spanning 23 degrees N to 42 degrees N in three seasons to address these questions. We found that soil fungal diversity increased linearly or parabolically with latitude. The seasonal variations in fungal diversity were more distinguishable in three temperate deciduous forests than in two subtropical evergreen forests. Soil fungal diversity was mainly correlated with edaphic factors such as pH and nutrient contents. Both latitude and its interactions with season also imposed significant impacts on soil fungal community composition (FCC), but the effects of latitude were stronger than those of season. Vegetational properties such as plant diversity and forest age were the dominant factors affecting FCC in the subtropical evergreen forests while edaphic properties were the dominant ones in the temperate deciduous forests. Our results indicate that latitudinal variation patterns of soil fungal diversity and FCC may differ among seasons. The stronger effect of latitude relative to that of season suggests a more important influence by the spatial than temporal heterogeneity in shaping soil fungal communities across zonal forests. PMID- 28854679 TI - Life inside a gall: closeness does not favour horizontal transmission of Rickettsia between a gall wasp and its parasitoid. AB - The incidence of horizontal transmission as a route for spreading symbiont infections is still being debated, but a common view is that horizontal transfers require intimate between-species relationships. Here we study a system that meets ideal requirements for horizontal transmission: the gall wasp Leptocybe invasa and its parasitoid Quadrastichus mendeli (Hymenoptera: Eulophidae). These wasps belong to the same subfamily, spend most of their lives inside the same minute gall and are both infected by Rickettsia, a maternally inherited endosymbiotic bacteria that infects several arthropods, sometimes manipulating their reproduction, like inducing thelytokous parthenogenesis in L. invasa. Despite intimate contact, close phylogenetic relationship and the parasitoid's host specificity, we show that host and parasitoid do not share the same Rickettsia. We provide indirect evidence that Rickettsia infecting Q. mendeli may be inducing thelytokous parthenogenesis, as the symbiont is densely present in the reproductive apparatus and is vertically transmitted. Phylogenetic analyses based on 16S and gltA placed this symbiont in the leech group. The confirmed and presumed parthenogenesis-inducing Rickettsia discovered so far only infect eulophid wasps, and belong to three different groups, suggesting multiple independent evolution of the parthenogenesis inducing phenotype. We also show some degree of cospeciation between Rickettsia and their eulophid hosts. PMID- 28854680 TI - The CTX-M-14 plasmid pHK01 encodes novel small RNAs and influences host growth and motility. AB - The dissemination of extended-spectrum beta-lactamases (ESBLs) genes among bacteria is commonly achieved by plasmid conjugation. In the last decade, the CTX M type enzyme was the most widespread and prevalent ESBLs in the world. In Hong Kong and mainland China, among the commonly found CTX-M-carrying plasmids were pHK01 and pHK01-like plasmids, which belong to incompatibility group FII (IncFII). In this work, we studied the physiological effect caused by the pHK01 plasmid in bacterial host Escherichia coli J53. The plasmid did not affect cell growth of the host but reduced their motility. The reduction of host motility was attributed to downregulation of genes that encode the flagellar system. We also identified several plasmid-encoded sRNAs, and showed that the overexpression of one of them, AS-traI, in the presence of pHK01 plasmid shortened the lag phase of host growth. In addition to the study of pHK01 in bacteria, we also developed a fast and incompatibility group-specific curing method using countertranscribed RNA, which could be of general usage for studying plasmid-host interaction in clinical aspects. PMID- 28854681 TI - Short-term effect of oral amoxicillin treatment on the gut microbial community composition in farm mink (Neovison vison). AB - It is well documented that antibiotics have pronounced modulatory effects on the intestinal bacterial community of both humans and animals, with potential health consequences. The gut microbiota of mink has however attracted little attention due to low bacterial load and fast gastrointestinal transit time, questioning its relevance. In this study, we hypothesise that oral amoxicillin treatment affects the gut microbiota in mink. This was investigated in a controlled trial including 24 animals of which 12 were treated with amoxicillin for 7 days. By applying 16S rRNA gene sequencing, we found that the faecal microbiota was markedly altered already after 2 days of treatment, with a surprising increase in diversity to resemble the feed. The diversity within the mucosa at termination was however reduced, which indicates this compartment as an important colonisation site in mink. No impact on blood biochemistry, lipid metabolism, serum amyloid A, vitamins A and E and histomorphology of the gut and liver was found; however, a slight decrease in fat digestibility was observed. We suggest that early-life use of amoxicillin in mink production may be counteractive as dysbiosis of the microbiota during infancy is increasingly being recognised as a risk factor for future health. PMID- 28854682 TI - Effect of RNase E deficiency on translocon protein synthesis in an RNase E inducible strain of enterohemorrhagic Escherichia coli O157:H7. AB - Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that assembles a type III secretion system (T3SS) on its surface. The last portion of the T3SS, called the 'translocon', is composed of a filament and a pore complex that is inserted into the membrane of intestinal epithelial cells. The genes encoding the translocon (espADB) are part of the LEE4 operon. Their expression is regulated by a complex post-transcriptional mechanism that involves the processing of LEE4 mRNA by the essential endoribonuclease RNase E. Here, we report the construction of an EHEC strain (TEA028-rne) in which RNase E can be induced by adding IPTG to the culture medium. EHEC cells deficient in RNase E displayed an abnormal morphology and slower growth, in agreement with published observations in E. coli K-12. Under those conditions, EspA and EspB were produced at higher concentrations, and protein secretion still occurred. These results indicate that RNase E negatively regulates translocon protein synthesis and demonstrate the utility of E. coli strain TEA028-rne as a tool for investigating the influence of this ribonuclease on EHEC gene expression in vitro. PMID- 28854684 TI - Effects of different substrates/growth media on microbial community of saliva derived biofilm. AB - The aims of this study were to investigate the effects of substrates (glass versus hydroxyapatite [HA]) and growth media (SHI medium versus a modified artificial saliva medium with cysteine) on the microbial community of saliva derived biofilm in vitro. 16S rRNA gene sequencing technology was used to analyze the microbial community of saliva-derived biofilm cultured for 72 h anaerobically. The metagenomes of biofilms were predicted from the clusters of orthologous groups. No significant difference was found between the saliva derived biofilms grown on HA and glass in ACE, Chao, Shannon and Simpson indices. The abundances of only a few bacteria on HA were significantly different from those on glass with a low relative abundance (<0.5%). Compared with the biofilms developed in a modified artificial saliva medium with cysteine, biofilms in SHI medium were significantly higher (P < 0.05) in diversity. Linear discriminant analysis coupled with effect size measurement showed that some obligate anaerobic genera (Lactobacillus, Veillonella, Porphyromonas and Leptotrichia) were more abundant in SHI medium biofilms. The biofilms grown in different media were also significantly different in predicted gene categories. In conclusion, the growth media, not the substrates, have significant effects on the microbial community of saliva-derived biofilm in vitro. PMID- 28854683 TI - Characterization of a pentonolactonase involved in D-xylose and L-arabinose catabolism in the haloarchaeon Haloferax volcanii. AB - Haloferax volcanii degrades the pentoses D-xylose and L-arabinose via an oxidative pathway to alpha-ketoglutarate as an intermediate. The initial dehydrogenases of the pathway, D-xylose dehydrogenase (XDH) and L-arabinose dehydrogenase (L-AraDH) catalyze the NADP+ dependent D-xylose and L-arabinose oxidation. It is shown here that the pentoses are oxidized to the corresponding lactones, D-xylono-gamma-lactone and L-arabino-gamma-lactone, rather than to the respective sugar acids. A putative lactonase gene, xacC, located in genomic vicinity of XDH and L-AraDH, was found to be transcriptionally upregulated by both D-xylose and L-arabinose mediated by the pentose-specific regulator XacR. The recombinant lactonase catalyzed the hydrolysis of D-xylono-gamma-lactone and L-arabino-gamma-lactone. This is the first report of a functional lactonase involved in sugar catabolism in the domain of archaea. PMID- 28854686 TI - Erratum. PMID- 28854685 TI - Mutagenesis and expression of methane monooxygenase to alter regioselectivity with aromatic substrates. AB - Soluble methane monooxygenase (sMMO) from methane-oxidising bacteria can oxygenate more than 100 hydrocarbons and is one of the most catalytically versatile biological oxidation catalysts. Expression of recombinant sMMO has to date not been achieved in Escherichia coli and so an alternative expression system must be used to manipulate it genetically. Here we report substantial improvements to the previously described system for mutagenesis of sMMO and expression of recombinant enzymes in a methanotroph (Methylosinus trichosporium OB3b) expression system. This system has been utilised to make a number of new mutants and to engineer sMMO to increase its catalytic precision with a specific substrate whilst increasing activity by up to 6-fold. These results are the first 'proof-of-principle' experiments illustrating the feasibility of developing sMMO derived catalysts for diverse applications. PMID- 28854687 TI - Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture. AB - Human presence in Southeast Asia dates back to at least 40,000 years ago, when the current islands formed a continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the "First Sundaland People." To understand the relationship between these Negrito groups and their demographic histories, we generated genome-wide single nucleotide polymorphism data in the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People. PMID- 28854690 TI - Performance of the multitarget Mikrogen Chlamydia trachomatis IgG ELISA in the prediction of tubal factor infertility (TFI) in subfertile women: comparison with the Medac MOMP IgG ELISA plus. AB - There is a need for more accurate Chlamydia trachomatis (CT) IgG antibody tests for tubal factor infertility (TFI) diagnostics. We evaluated the predictive value for TFI of Medac ELISA plus (MOMP) and multitarget Mikrogen ELISA (MOMP-CPAF TARP). Based on Medac ELISA plus results, 183 subfertile women underwent either hysterosalpingography or laparoscopy to diagnose TFI. TFI was defined as extensive adhesions and/or distal occlusion of at least one tube. Women not fulfilling the definition of TFI served as controls. Serum was subsequently tested with Mikrogen ELISA and results were compared. 48 patients had TFI, 135 were controls. Mikrogen ELISA tested 125 patients positive/borderline of which 32% had TFI. Medac ELISA plus tested 77 patients positive/borderline of which 29.9% had TFI. Mikrogen tested 40 out of 48 TFI patients positive/borderline, Medac 23 out of 48. Kappa value was 0.34. PPV of Mikrogen ELISA and Medac ELISA plus were respectively 32% (95% CI 26%-39%) and 30% (95% CI 24%-37%), and NPV 86% (95% CI 81%-91%) and 76% (95% CI 70%-82%). Both tests were comparable in the prediction of TFI. However, Mikrogen ELISA had a higher NPV and might be more reliable in identifying patients without TFI. Kappa-value showed limited concordance between both tests. PMID- 28854689 TI - Identification and characterization of a subtelomeric satellite DNA in Callitrichini monkeys. AB - Repetitive DNAs are abundant fast-evolving components of eukaryotic genomes, which often possess important structural and functional roles. Despite their ubiquity, repetitive DNAs are poorly studied when compared with the genic fraction of genomes. Here, we took advantage of the availability of the sequenced genome of the common marmoset Callithrix jacchus to assess its satellite DNAs (satDNAs) and their distribution in Callitrichini. After clustering analysis of all reads and comparisons by similarity, we identified a satDNA composed by 171 bp motifs, named MarmoSAT, which composes 1.09% of the C. jacchus genome. Fluorescent in situ hybridization on chromosomes of species from the genera Callithrix, Mico and Callimico showed that MarmoSAT had a subtelomeric location. In addition to the common monomeric, we found that MarmoSAT was also organized in higher-order repeats of 338 bp in Callimico goeldii. Our phylogenetic analyses showed that MarmoSAT repeats from C. jacchus lack chromosome-specific features, suggesting exchange events among subterminal regions of non-homologous chromosomes. MarmoSAT is transcribed in several tissues of C. jacchus, with the highest transcription levels in spleen, thymus and heart. The transcription profile and subtelomeric location suggest that MarmoSAT may be involved in the regulation of telomerase and modulation of telomeric chromatin. PMID- 28854688 TI - The Evolutionary Dynamics of the Odorant Receptor Gene Family in Corbiculate Bees. AB - Insects rely on chemical information to locate food, choose mates, and detect potential predators. It has been hypothesized that adaptive changes in the olfactory system facilitated the diversification of numerous insect lineages. For instance, evolutionary changes of Odorant Receptor (OR) genes often occur in parallel with modifications in life history strategies. Corbiculate bees display a diverse array of behaviors that are controlled through olfaction, including varying degrees of social organization, and manifold associations with floral resources. Here we investigated the molecular mechanisms driving the evolution of the OR gene family in corbiculate bees in comparison to other chemosensory gene families. Our results indicate that the genomic organization of the OR gene family has remained highly conserved for ~80 Myr, despite exhibiting major changes in repertoire size among bee lineages. Moreover, the evolution of OR genes appears to be driven mostly by lineage-specific gene duplications in few genomic regions that harbor large numbers of OR genes. A selection analysis revealed that OR genes evolve under positive selection, with the strongest signals detected in recently duplicated copies. Our results indicate that chromosomal translocations had a minimal impact on OR evolution, and instead local molecular mechanisms appear to be main drivers of OR repertoire size. Our results provide empirical support to the longstanding hypothesis that positive selection shaped the diversification of the OR gene family. Together, our results shed new light on the molecular mechanisms underlying the evolution of olfaction in insects. PMID- 28854691 TI - The clinical recovery of tuberculosis patients undergoing specific treatment is associated with changes in the immune and neuroendocrine responses. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis is a health problem worldwide. Patients with pulmonary TB show a neuro-immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro- and anti-inflammatory cytokines and markedly decreased dehydroepiandrosterone (DHEA) levels. Extending these findings, we now investigated the immune-endocrine profile of TB patients undergoing specific treatment. Patients (n = 24) were bled at diagnosis (T0), 2, 4, 6 months after treatment initiation and 3 months following its completion. At T0, TB patients showed increased plasma levels of interleukin-6 (IL-6), C reactive protein, interferon-gamma (IFN-gamma) and transforming growth factor beta (TGF-beta). These mediators decreased during treatment, reaching levels similar to those from healthy controls (n = 26). Specific treatment led to an increased lymphoproliferative response along with clinical improvement. Newly diagnosed patients had low levels of DHEA, with increased cortisol amounts and cortisol/DHEA ratio, which normalized upon specific treatment. As regards glucocorticoid receptors (GR), TB patients at diagnosis presented a reduced mRNA GRalpha/GRbeta ratio in their peripheral blood mononuclear cells. Furthermore, multivariate analysis showed that cortisol/DHEA ratio was positively associated with inflammatory mediators for which this ratio may constitute a disease biomarker. Anti-mycobacterial treatment results in a better immune-endocrine scenario for the control of physiopathological processes accompanying disease development and hence implied in clinical recovery. PMID- 28854693 TI - The Virtuous Circle. PMID- 28854692 TI - Editorial: Novel strategies for developing vaccines bring encouraging progress. PMID- 28854694 TI - ACCA Masterclass. PMID- 28854695 TI - Journal Metrics I. PMID- 28854696 TI - The Impact Factor. PMID- 28854697 TI - Transvenous lead extraction. PMID- 28854698 TI - Cecilia Linde MD. PMID- 28854699 TI - Low-density lipoprotein: the culprit. From evidence to counselling, drugs, and vaccination. PMID- 28854700 TI - Comparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of function, cell-autonomous transcriptional changes in oligodendrocytes. AB - Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. This expansion leads to misfolding and aggregation of mutant ataxin-3 (ATXN3) and degeneration of select brain regions. A key unanswered question in SCA3 and other polyglutamine diseases is the extent to which neurodegeneration is mediated through gain-of-function versus loss-of-function. To address this question in SCA3, we performed transcriptional profiling on the brainstem, a highly vulnerable brain region in SCA3, in a series of mouse models with varying degrees of ATXN3 expression and aggregation. We include two SCA3 knock-in mouse models: our previously published model that erroneously harbors a tandem duplicate of the CAG repeat-containing exon, and a corrected model, introduced here. Both models exhibit dose-dependent neuronal accumulation and aggregation of mutant ATXN3, but do not exhibit a behavioral phenotype. We identified a molecular signature that correlates with ATXN3 neuronal aggregation yet is primarily linked to oligodendrocytes, highlighting early white matter dysfunction in SCA3. Two robustly elevated oligodendrocyte transcripts, Acy3 and Tnfrsf13c, were confirmed as elevated at the protein level in SCA3 human disease brainstem. To determine if mutant ATXN3 acts on oligodendrocytes cell-autonomously, we manipulated the repeat expansion in the variant SCA3 knock-in mouse by cell-type specific Cre/LoxP recombination. Changes in oligodendrocyte transcripts are driven cell autonomously and occur independent of neuronal ATXN3 aggregation. Our findings support a primary toxic gain of function mechanism and highlight a previously unrecognized role for oligodendrocyte dysfunction in SCA3 disease pathogenesis. PMID- 28854701 TI - Aqua-soluble DDQ reduces the levels of Drp1 and Abeta and inhibits abnormal interactions between Abeta and Drp1 and protects Alzheimer's disease neurons from Abeta- and Drp1-induced mitochondrial and synaptic toxicities. AB - The purpose of our study was to develop a therapeutic target that can reduce Abeta and Drp1 levels, and also can inhibit abnormal interactions between Abeta and Drp1 in AD neurons. To achieve this objective, we designed various compounds and their 3-dimensional molecular structures were introduced into Abeta and Drp1 complex and identified their inhibitory properties against Abeta-Drp1 interaction. Among all, DDQ was selected for further investigation because of 1) its best docking score and 2) its binding capability at interacting sites of Drp1 and Abeta complex. We synthesized DDQ using retro-synthesis and analyzed its structure spectrally. Using biochemical, molecular biology, immunostaining and transmission electron microscopy (TEM) methods, we studied DDQ's beneficial effects in AD neurons. We measured the levels of Abeta and Drp1, Abeta and Drp1 interaction, mRNA and protein levels of mitochondrial dynamics, biogenesis and synaptic genes, mitochondrial function and cell viability and mitochondrial number in DDQ-treated and untreated AD neurons. Our qRT-PCR and immunoblotting analysis revealed that reduced levels of mitochondrial fission and increased fusion, biogenesis and synaptic genes in DDQ-treated AD neurons. Our immunoblotting and immunostaining analyses revealed that Abeta and Drp1 levels were reduced in DDQ-treated AD neurons. Interaction between Abeta and Drp1 is reduced in DDQ-treated AD neurons. Abeta42 levels were significantly reduced in DDQ-treated mutant APPSwe/Ind cells. Mitochondrial number is significantly reduced and mitochondrial length is significantly increased. Mitochondrial function and cell viability were maintained in AD neurons treated with DDQ. These observations indicate that DDQ reduces excessive mitochondrial fragmentation, enhances fusion, biogenesis and synaptic activity and reduces Abeta42 levels and protects AD neurons against Abeta-induced mitochondrial and synaptic toxicities. PMID- 28854702 TI - Splicing factors act as genetic modulators of TDP-43 production in a new autoregulatory TDP-43 Drosophila model. AB - TDP-43 is a critical RNA-binding factor associated with RNA metabolism. In the physiological state, maintaining normal TDP-43 protein levels is critical for proper physiological functions of the cells. As such, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. TDP-43 is a major disease-causing protein in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Several studies argue for a pathogenic role of elevated TDP-43 levels in these disorders. Modulating the cycle of TDP-43 production might therefore provide a new therapeutic strategy. In this study, we developed a new transgenic Drosophila model mimicking the TDP-43 autoregulatory feedback loop in order to identify genetic modulators of TDP-43 protein steady state levels in vivo. First, we showed that our TDP-43_TDPBR Drosophila model recapitulates key features of the TDP-43 autoregulatory processes previously described in mammalian and cellular models, namely alternative splicing events, differential usage of polyadenylation sites, nuclear retention of the transcript and a decrease in steady-state mRNA levels. Using this new Drosophila model, we identified several splicing factors, including SF2, Rbp1 and Sf3b1, as genetic modulators of TDP-43 production. Interestingly, our data indicate that these three RNA-binding proteins regulate TDP-43 protein production, at least in part, by controlling mRNA steady-state levels. PMID- 28854704 TI - Arl3 and RP2 regulate the trafficking of ciliary tip kinesins. PMID- 28854703 TI - Expression quantitative trait loci (eQTLs) in human placentas suggest developmental origins of complex diseases. AB - Epidemiologic studies support that at least part of the risk of chronic diseases in childhood and even adulthood may have an in utero origin, and the placenta is a key organ that plays a pivotal role in fetal growth and development. The transcriptomes of 159 human placenta tissues were profiled by genome-wide RNA sequencing (Illumina High-Seq 2500), and linked to fetal genotypes assessed by a high density single nucleotide polymorphism (SNP) genotyping array (Illumina MegaEx). Expression quantitative trait loci (eQTLs) across all annotated transcripts were mapped and examined for enrichment for disease susceptibility loci annotated in the genome-wide association studies (GWAS) catalog. We discovered 3218 cis- and 35 trans-eQTLs at <=10% false discovery rate in human placentas. Among the 16 439 known disease loci of genome-wide significance, 835 were placental eSNPs (enrichment fold = 1.68, P = 7.41e-42). Stronger effect sizes were observed between GWAS SNPs and gene expression in placentas than what has been reported in other tissues, such as the correlation between asthma risk allele, rs7216389-T and Gasdermin-B (GSDMB) in placenta (r2=27%) versus lung (r2=6%). Finally, our results suggest the placental eQTLs may mediate the function of GWAS loci on postnatal disease susceptibility. Results suggest that transcripts in placenta are under tight genetic control, and that placental gene networks may influence postnatal risk of multiple human diseases lending support for the Developmental Origins of Health and Disease. PMID- 28854706 TI - Defects in optineurin- and myosin VI-mediated cellular trafficking in amyotrophic lateral sclerosis. PMID- 28854705 TI - Whole-genome sequencing study of serum peptide levels: the Atherosclerosis Risk in Communities study. AB - Oligopeptides are important markers of protein metabolism, as they are cleaved from larger polypeptides and proteins. Genetic association studies may help elucidate their origin and function. In 1,552 European Americans and 1,872 African Americans of the Atherosclerosis Risk in Communities study, we performed whole-genome and whole-exome sequencing and measured serum levels of 25 peptides. Common variants (minor allele frequency > 5%) were analysed individually. We grouped low-frequency variants (minor allele frequency <= 5%) by a genome-wide sliding window using region-based aggregate tests. Furthermore, low-frequency regulatory variants were grouped by gene, as were functional coding variants. All analyses were performed separately in each ancestry group and then meta-analysed. We identified 22 common variant associations with peptide levels (P-value < 4.2 * 10-10), including 16 novel gene-peptide pairs. Notably, variants in kinin kallikrein genes KNG1, F12, KLKB1, and ACE were associated with several different peptides. Variants in KLKB1 and ACE were associated with a fragment of complement component 3f. Both common variants and low-frequency coding variants in CPN1 were associated with a fibrinogen cleavage peptide. Four sliding windows were significantly associated with peptide levels (P-value < 4.2 * 10-10). Our results highlight the importance of the kinin-kallikrein system in the regulation of serum peptide levels, strengthen the evidence for a broad link between the kinin kallikrein and complement systems, and suggest a role of CPN1 in the conversion of fibrinogen to fibrin. PMID- 28854707 TI - Changes in Pro-Inflammatory Markers in Detoxifying Chronic Alcohol Abusers, Divided by Lesch Typology, Reflect Cognitive Dysfunction. AB - Aim: To investigate pro-inflammatory markers in the blood and associate with cognitive impairment. Methods: Il-6 and ferritin were assayed in the blood of 27 patients, divided according to Lesch typology, at the commencement and after 21 days of detoxification, together with a battery of cognitive tests. Results: A significantly higher mean level of IL-6 was present in the blood of patients with Lesch typology 1 compared to the other typologies 2 and 3 on admission to the Detoxification Ward which did not alter significantly after detoxification. The mean level of IL-6 was initially elevated in Lesch typology 2 alcohol abusers and declined to the reference range after detoxification. Lesch typology 3 alcohol abusers showed normal levels of IL-6 at both time points. Only in Lesch typology 1 were the levels of ferritin and IL-10 significantly elevated at the start of the detoxification process. Cognitive impairment, as ascertained by Stroop test and Brown-Peterson procedure was greater in Lesch typology 1 than the other 2 patient groups. Conclusion: Such data might indicate a greater degree of neuroinflammation in Lesch typology 1 alcoholic patients. Short summary: Dividing a heterogeneous group of alcoholic subjects into homogenous groups according to Lesch typology, identifies a greater pro-inflammatory profile in Lesch typology 1 patients who also showed greater cognitive impairment. PMID- 28854708 TI - Rapidly Increasing Trend of Recorded Alcohol Consumption Since the End of the Armed Conflict in Sri Lanka. AB - Aim: To evaluate temporal changes in recorded alcohol consumption in Sri Lanka during and after the armed conflict 1998-2013. Methods: District level alcohol sales, and mid-year population data for the whole study period (1998-2013) were consistently available from the Department of Excise and the Department of Census and Statistics for 18 of 25 districts. These data were used to estimate the recorded per capita consumption for the areas that were not directly exposed to the armed conflict. An interrupted time series design was employed to estimate the impact of the end of the armed conflict on recorded adult per capita alcohol consumption of population lived in the 18 districts. Results: Adult per capita recorded alcohol consumption among Sri Lankans living in the 18 districts was 1.59 l of pure alcohol in 1998. This increased up to 2.07 l in 2009 and 2.55 l in 2013. Prior to the end of the conflict in 2009 adult per capita recorded consumption increased by 0.051 l of pure alcohol per year (95% CI: 0.029-0.074, P < 0.001); after 2009 this was 0.166 l per year (95% CI: 0.095-0.236, P < 0.001). Beer consumption showed the highest per capita growth compared with other beverages. Conclusions: Adult per capita recorded alcohol consumption among Sri Lankans living in areas that were not directly exposed to the conflict increased markedly after the end of the conflict. Rapid socio-economic development, alcohol industry penetration and lack of alcohol control strategies during the post conflict period may have driven this increase. Short summary: Adult per capita recorded alcohol consumption among Sri Lankans living in 18 districts that were not directly exposed to the armed conflict increased markedly after the end of the conflict in 2009, with a dramatic acceleration in the trend of per capita beer consumption. PMID- 28854709 TI - Melatonin Restores White Blood Cell Count, Diminishes Glycated Haemoglobin Level and Prevents Liver, Kidney and Muscle Oxidative Stress in Mice Exposed to Acute Ethanol Intoxication. AB - Aims: The aim of the study was to examine the effects of melatonin impact on changes in haematological profile, biomarkers of oxidative stress (dienes conjugates, malondialdehyde (MDA), oxidatively modified protein levels, total antioxidant capacity and antioxidant enzyme activity) in liver, muscle, kidney and erythrocytes, and glycated haemoglobin (HBA1c) in mice during acute ethanol stress. Methods: Assays were carried out in quadruplicate: control, melatonin (10 mg/kg, 10 days), acute ethanol stress (0.75 g/kg/day, 10 days) and acute ethanol stress plus melatonin groups. Results: Acute ethanol stress caused a significant increase in the total number of white blood cells (WBC), especially neutrophils in the blood, and HBA1c levels vs. control mice. The correlation between lipid peroxidation and the glycated haemoglobin level was shown (r = 0.93, P = 0.007). Ethanol reduced the antioxidant capacity by increasing reactive oxygen species (ROS) production and the level of oxidatively modified protein content, diene conjugates and MDA. Melatonin administration in animals during acute ethanol stress reduced antioxidant stress biomarkers, WBC, HBA1c levels and ROS production. Conclusions: Melatonin had protective effects on liver, kidney and muscle tissues by preventing the intensive lipid peroxidation processes in initial (diene conjugation production) and late stages (MDA level), and significantly reduced the level of aldehyde and ketone protein derivatives. Furthermore, melatonin restored elevated WBC count and HBA1c level and diminished ROS production. Short Summary: Ethanol reduces antioxidant capacity and leads to exaggerated reactive oxygen species production and consequent increases in oxidatively modified proteins. Melatonin exerts protective effects by preventing the intensive lipid peroxidation processes. Melatonin significantly reduces the level of aldehyde and ketone protein derivatives, restores glycated haemoglobin level and white blood cell count. PMID- 28854710 TI - Pseudomonas aeruginosa Trent and zinc homeostasis. AB - Pseudomonas aeruginosa is a Gram-negative pathogen and the major cause of mortality in patients with cystic fibrosis. The mechanisms that P. aeruginosa strains use to regulate intracellular zinc have an effect on infection, antibiotic resistance and the propensity to form biofilms. However, zinc homeostasis in P. aeruginosa strains of variable infectivity has not been compared. In this study, zinc homeostasis in P. aeruginosa Trent, a highly infectious clinical strain, was compared to that of a laboratory P. aeruginosa strain, ATCC27853. Trent was able to tolerate higher concentrations of additional zinc in rich media than ATCC27853. Further, pre-adaptation to additional zinc enhanced the growth of Trent at non-inhibitory concentrations but the impact of pre-adaption on the growth of ATCC27853 under the same conditions was minimal. The results establish clear differences in zinc-induced responses in Trent and ATCC27853, and how zinc homeostasis can be a promising target for the development of novel antimicrobial strategies for P. aeruginosa infection in cystic fibrosis patients. PMID- 28854711 TI - Surveying the expanding prokaryotic Rubisco multiverse. AB - The universal, but catalytically modest, CO2-fixing enzyme Rubisco is currently experiencing intense interest by researchers aiming to enhance crop photosynthesis. These efforts are mostly focused on the highly conserved hexadecameric enzyme found in land plants. In comparison, prokaryotic organisms harbor a far greater diversity in Rubisco forms. Recent work towards improving our appreciation of microbial Rubisco properties and harnessing their potential is surveyed. New structural models are providing informative glimpses into catalytic subtleties and diverse oligomeric states. Ongoing characterization is informing us about the conservation of constraints, such as sugar phosphate inhibition and the associated dependence on Rubisco activase helper proteins. Prokaryotic Rubiscos operate under a far wider range of metabolic contexts than the photosynthetic function of higher plant enzymes. Relaxed selection pressures may have resulted in the exploration of a larger volume of sequence space than permitted in organisms performing oxygenic photosynthesis. To tap into the potential of microbial Rubiscos, in vivo selection systems are being used to discover functional metagenomic Rubiscos. Various directed evolution systems to optimize their function have been developed. It is anticipated that this approach will provide access to biotechnologically valuable enzymes that cannot be encountered in the higher plant Rubisco space. PMID- 28854712 TI - Southern promises: a snapshot of the microbiology research landscape in South America based on bibliometric data. AB - Scientists have a single currency for productivity and impact: published articles. In an effort to map the global research landscape in microbiology, and to obviate the current lack of bibliometric analysis in the field, FEMS-the Federation of European Microbiological Societies-generated a dataset encompassing an exhaustive, worldwide list of microbiology studies for 2013-14, which further includes information as author affiliation, funding agency and number of citations. The manually curated database is useful in assessing the impact and regional productivity of microbiology research at different levels. Here, the data for microbiology research in South America are presented and discussed in detail. Based on the analysis, it emerged that despite great degrees of variation between number of published articles among the countries, a more levelled research productivity was observed when considering further dimensions like population size or number of research institutes. Normalised productivity and impact increase in countries with a 'central research hub', i.e. an institute or university producing a substantial portion of the national output (15% or more). From these observations, a possible strategy to increase impact and productivity in (microbiology) research for emerging countries is outlined. PMID- 28854713 TI - Isolation of a fluoroglycofen-degrading KS-1 strain and cloning of a novel esterase gene fluE. AB - The bacterium KS-1, capable of degrading fluoroglycofen, was isolated from sludge collected at a herbicide factory. The isolate was identified as Lysinibacillus sp. according to its phenotypic features and 16S rDNA phylogeny. KS-1 degraded 85.25% of the fluoroglycofen (50 mg L-1) within 3 days of incubation. The optimum temperature and pH for fluoroglycofen degradation were 30 degrees C and 7.0, respectively. Furthermore, Zn2+ and Cu2+ could significantly decrease the degradation rate. Three degradation products, which appeared during KS-1-mediated fluoroglycofen metabolism, were identified as deethyl-fluoroglycofen, acifluorfen and decarboxylate-acifluorfen. The fluE gene, which encodes a novel esterase that catalyzes the cleavage of carboxyl ester bonds of fluoroglycofen, was cloned from the KS-1 strain. Sequence alignment reveals that FluE shares 30%-40% amino acid sequence identity with members of the hormone sensitive lipase family. FluE was expressed in Escherichia coli BL21 and purified by Ni-NTA affinity chromatography. Purified FluE could efficiently hydrolyze fluoroglycofen and short-chain p-nitrophenol esters. However, no lipolytic activity was observed with esters containing acyl chains longer than 10 carbon atoms, thereby indicating that this enzyme is an esterase. PMID- 28854714 TI - Routine serum thyroid-stimulating hormone testing-optimizing pre-conception health or generating toxic knowledge? AB - Monitoring subclinical hypothyroidism (SCH) in women is believed to be important in terms of preventing overt hypothyroidism and optimizing the health and cognitive development of their children. Current systematic reviews have suggested an association between maternal SCH and adverse obstetric and neonatal outcomes. However, initiating the administration of thyroxine during pregnancy has failed to demonstrate appreciable health benefits. Hence there are calls by professional endocrine societies for optimizing serum thyroid-stimulating hormone (TSH) levels pre-conception. The strategy of ensuring that serum TSH levels are below 2.5 mIU/l during the pre-conception period has generated considerable uncertainty partly because the recommended level of <2.5 mIU/l is lower than those previously used to define the condition and partly due to uncertainty about the best screening programme clinicians can use in this context. Recalibrating the expected normal peri-conceptional range of serum TSH (<2.5 mIU/l), will have a significant impact on clinical services due to an inevitable increase in numbers of women diagnosed with SCH who will need to be investigated, treated and monitored. Serum TSH fulfils the criteria for a screening test and oral thyroxine is an inexpensive drug. Therefore, there is no reason to believe that screening cannot be undertaken in all women planning to conceive. Yet this approach will miss women whose pregnancies are unplanned and generate anxiety, further tests and many more prescriptions for thyroxine, coupled with the need for lifelong monitoring in affected women. A number of existing and ongoing randomized trials have evaluated the use of thyroxine in women with infertility or miscarriage with detectable thyroid auto-antibodies. These are unlikely to answer the question whether routine pre-conception testing for SCH in asymptomatic women is beneficial. Routine screening of women at risk of pregnancy and optimization of their thyroid status could result in significant health benefits for their offspring. Alternatively this approach could prove to be an expensive way of generating toxic knowledge resulting in anxiety, increased drug use and potential harm. Only large, appropriately designed studies can reveal the answer. PMID- 28854715 TI - Systematic review and meta-analysis of the impact of preconception lifestyle interventions on fertility, obstetric, fetal, anthropometric and metabolic outcomes in men and women. AB - STUDY QUESTION: What is the impact of preconception lifestyle interventions on live birth, birth weight and pregnancy rate? SUMMARY ANSWER: Lifestyle interventions showed benefits for weight loss and increased natural pregnancy rate, but not for live birth or birth weight. WHAT IS KNOWN ALREADY: Evidence on the practice and content of preconception counseling and interventions is variable and limited. STUDY DESIGN, SIZE, DURATION: Systematic review and meta analysis (MA). Main search terms were those related to preconception lifestyle. Database searched were Ovid MEDLINE(R), EBM Reviews, PsycINFO, EMBASE and CINAHL Plus. No language restriction was placed on the published articles. The final search was performed on 10 January 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were non-pregnant women of childbearing age intent on conceiving or their male partners. Exclusion criteria include participants with BMI < 18 kg/m2, animal trials, hereditary disorder in one or both partners and trials focusing solely on alcohol or smoking cessation/reduction, micronutrient supplementation, or diabetes control. Anthropometric, fertility, obstetric and fetal outcomes were assessed. Bias and quality assessments were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The search returned 1802 articles and eight studies were included for analysis. Populations targeted were primarily overweight or obese subfertile women seeking reproductive assistance, with few community-based studies and none including men. MA showed greater reduction in weight (n = 3, P < 0.00001, mean difference: -3.48 kg, 95% CI: -4.29, -2.67, I2 = 0%) and BMI (n = 2, P < 0.00001, mean difference: -1.40 kg/m2, 95% CI: -1.95, 0.84, I2 = 24%) with intervention. The only significant fertility outcome was an increased natural pregnancy rate (n = 2, P = 0.003, odds ratio: 1.87, CI: 1.24, 2.81, I2 = 0%). No differences were observed for ART adverse events, clinical pregnancy, pregnancy complications, delivery complications, live birth, premature birth, birth weight, neonatal mortality or anxiety. Risk of bias were high for three studies, moderate for three studies and low for two studies, Attrition bias was moderate or high in majority of studies. LIMITATIONS, REASONS FOR CAUTION: Results were limited to subfertile or infertile women who were overweight or obese undergoing ART with no studies in men. The heterogeneous nature of the interventions in terms of duration and regimen means no conclusions could be made regarding the method or components of optimal lifestyle intervention. Attrition bias itself is an important factor that could affect efficacy of interventions. WIDER IMPLICATIONS OF THE FINDINGS: Existing preconception lifestyle interventions primarily targeted overweight and obese subfertile women undergoing ART with a focus on weight loss. It is important to note that natural conception increased with lifestyle intervention. This emphasizes the need for further research exploring optimal components of preconception lifestyle interventions in the broader population and on the optimal nature, intensity and timing of interventions. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest declared. C.L.H. is a National Heart Foundation Postdoctoral Research Fellow. B.H. is funded by an Alfred Deakin Postdoctoral Research Fellowship. H.J.T. and B.W.M. hold NHMRC Practitioner fellowships. L.J.M. is supported by a SACVRDP Fellowship; a program collaboratively funded by the NHF, the South Australian Department of Health and the South Australian Health and Medical Research Institute. PROSPERO REGISTRATION NUMBER: CRD42015023952. PMID- 28854716 TI - Livebirth and utero-placental insufficiency in Papio hamadryas baboons with uterus angiosome perfused by bilateral utero-ovarian microsurgical anastomoses alone. AB - STUDY QUESTION: Can the baboon uterus support a gestation to livebirth with an angiosome using microsurgically anastomosed utero-ovarian vessels and lacking uterine arteries and veins? SUMMARY ANSWER: Our angiosome model allows healthy livebirth albeit with risk of fetal growth restriction and stillbirth. WHAT IS KNOWN ALREADY: Uterine transplant can provide livebirth in humans, but requires a living donor to undergo a prolonged laparotomy for hysterectomy. In an attempt to avoid the time-consuming dissection of the uterine vein, our group has previously shown maintenance of baboon uterine menstrual function after ligation of the uterine vein and after ligation of both the uterine artery and uterine vein. STUDY DESIGN, SIZE, DURATION: In a 19-month timespan, three baboons underwent laparotomy to surgically alter uterine perfusion, and pregnancy outcomes were monitored after spontaneous mating in a breeding colony. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three nulligravid female Papio hamadryas baboons in a breeding colony underwent laparotomy to ligate uterine arteries and veins along with colpotomy and cervico-vaginal anastomosis. During the same surgery, the utero ovarian arteries and veins were microsurgically transected and re-anastomosed to themselves. Intraoperative organ perfusion was confirmed with laser angiography. After a recovery period, monitoring of menstrual cycling via menstrual blood flow and sex-skin cycling occurred, as well as uterine viability via sonography and cervical biopsy. Each baboon was released to the breeding colony for spontaneous mating and pregnancies dated by menstrual calendar and compared with early ultrasound. Delivery outcomes were monitored in each including neonate weight and placental pathology. In the event of a stillbirth, the animal was returned to the breeding colony for repeat mating attempts. After achieving a livebirth, the maternal baboon was removed from the study. MAIN RESULTS AND THE ROLE OF CHANCE: Each baboon in the trial underwent successful surgery with all uteri demonstrating viability and return of menstrual function within 10 weeks of surgery. Pregnancies occurred within two menstrual cycles in breeding colony. Baboons one and two initially had vaginal breech stillbirths, both with appearance of placental insufficiency, and one with fetal growth restriction. Baboon three underwent scheduled cesarean delivery resulting in a normally grown livebirth. Baboon one had a subsequent pregnancy resulting in a livebirth via cesarean delivery. LIMITATIONS, REASONS FOR CAUTION: Stillbirth in two of four gestations, and fetal growth restriction in one of four, are the largest concerns in our perfusion model. It remains uncertain whether the stillbirths resulted from placental insufficiency, or birth trauma from breech deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The success of two livebirths warrants further attempts at improving consistency of our proposed uterine angiosome. This may allow living uterine donors to undergo less-invasive and shorter donor hysterectomy procedures. STUDY FUNDING/COMPETING INTEREST(S): The study had no external sponsors, and was supported by the Cleveland Clinic Foundation. Some equipment was loaned without cost to the research team including a laser angiography system courtesy of Novadaq Technologies, Inc. (Missaugua, ON, Canada) and a surgical microscope courtesy of DB Surgical (Coral Springs, FL, USA). B.B., K.A., M.S., K.R., M.M., P.F.E., A.T. and T.F. have no conflicts of interest. M.L.S. and S.Z. report activity as consultants for Medtronic-Covidien, and S.Z. also is a consultant to Applied Medical. PMID- 28854718 TI - Single fathers by choice using surrogacy: why men decide to have a child as a single parent. AB - STUDY QUESTION: Why do men decide to have a child by surrogacy as a single parent? SUMMARY ANSWER: Reasons included feeling that it was the right time (i.e. having 'worked through' concerns about single parenthood; career and financial stability; a fear of getting older; no longer wanting to wait for the 'right' relationship), external encouragement, a desire to reproduce and a fear of separation/divorce. WHAT IS KNOWN ALREADY: Because no research has been conducted on single fathers who used surrogacy, their characteristics, motivations and experiences are unknown. STUDY DESIGN, SIZE, DURATION: This study used a cross sectional design as part of a larger, multi-method, multi-informant investigation of single father families created by surrogacy. Multiple strategies were used to recruit participants (i.e. from an association of gay parents, Facebook groups of single parents and snowballing) between November 2016 and April 2017. Data were obtained from 33 Italian single fathers (Meanage = 47.33 years, SD = 4.63), most of whom self-identified as gay (n = 24, 72.7%). PARTICIPANTS/MATERIALS, SETTING, METHODS: In-depth semi-structured interviews were conducted in family homes (n = 20, 60.6%) or over Skype (n = 13, 39.4%). Each interview lasted approximately 40 min and was audio recorded, transcribed verbatim and analyzed using thematic and qualitative content analysis, with the aid of the software package MAXQDA. Where appropriate, a two-sided Fisher's exact test was used to compare the gay and heterosexual fathers, and illustrative quotations were reported. MAIN RESULTS AND THE ROLE OF CHANCE: Although all of the single men had experienced mature relationships, about one-third of the fathers (n = 10, 30.3%) had never thought of having a child and the majority of the heterosexual men (n = 7, 77.8%, P = 0.05) had tried to conceive in previous relationships. The gay and heterosexual men differed in their preferred path to parenthood (P = 0.01), with the former (n = 17, 70.8%) having always preferred surrogacy and the latter (n = 6, 66.7%) having considered or attempted conception via casual sex with women. Irrespective of their sexual orientation, most of the fathers chose surrogacy because they wanted a genetic relation to their child (n = 28, 84.8%) and because they felt that surrogacy would be more secure compared to adoption, upon their return to Italy due to Italian laws (n = 26, 78.7%). The majority (n = 20, 60.6%) were satisfied with their decision to 'go it alone', although nearly all (n = 16, 80%) would have preferred to have a child within the context of a relationship. After their child's birth, the majority received support from both their parents/siblings (n = 21, 63.7%) and friends (n = 24, 72.7%). LIMITATIONS, REASONS FOR CAUTION: The risk of socially desirable responding should be taken into account when interpreting the findings, given the ethical concerns surrounding single fatherhood and surrogacy. Furthermore, fathers with a negative surrogacy experience were less likely to participate in this research. The small sample and participant characteristics of older age, an Italian nationality, a mainly gay sexual orientation and high income may limit the generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to provide insight into the reproductive experience of single men seeking surrogacy. The findings warn practitioners and policy-makers against making assumptions about people with access to fertility treatments on the basis of marital status, gender or sexual orientation. STUDY FUNDING/COMPETING INTEREST(S): None. PMID- 28854717 TI - Maternal hyperglycemia in singleton pregnancies conceived by IVF may be modified by first-trimester BMI. AB - STUDY QUESTION: Does IVF independently increase the risk of gestational diabetes mellitus (GDM) and is this increase in risk modified by maternal body mass index? SUMMARY ANSWER: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women (BMI > 25 kg/m2). WHAT IS KNOWN ALREADY: IVF has been associated with increased risk of GDM, but most previous studies did not adequately assess confounding or effect modification by other risk factors. STUDY DESIGN, SIZE, DURATION: Cross-sectional study using data from 1089 women with singleton pregnancies who participated in a Singaporean birth cohort study (GUSTO) and received a 75 g oral glucose tolerance test (OGTT) at 26-28 weeks gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1089 women (n = 1013 conceived spontaneously, n = 76 conceived through IVF) with singleton pregnancies received a 75 g OGTT at 26-28 weeks gestation. Fasting and 2 h postprandial blood glucose levels were assayed. World Health Organization criteria (1999) standard criteria were used to classify GDM: >=7.0 mmol/L for fasting and/or >=7.8 mmol/L for 2-h postprandial plasma glucose levels, which was the clinical guideline in use during the study. MAIN RESULTS AND THE ROLE OF CHANCE: IVF pregnancies had nearly double the odds of GDM (OR = 1.83, 95% CI: 1.03-3.26) and elevated fasting (mean difference = 0.12 mmol/L, 95% CI: 0.00 0.24) and OGTT 2-h blood glucose levels (mean difference = 0.64 mmol/L, 95% CI: 0.27-1.01), after adjusting for commonly recognized risk factors for GDM. After stratification by first-trimester BMI, these increased risks of GDM (OR = 3.54, 95% CI: 1.44-8.72) and elevated fasting (mean difference = 0.39 mmol/L, 95% CI: 0.13-0.65) and 2-h blood (mean difference = 1.24 mmol/L, 95% CI: 0.56-1.91) glucose levels were significant only in the IVF group who is also overweight or obese (BMI > 25 kg/m2). LIMITATIONS REASONS FOR CAUTION: One limitation of our study is the absence of a 1 h post-OGTT plasma glucose sample, as we were using the 1999 WHO diagnostic criteria (the clinical guideline in Singapore) at the time of our study, instead of the revised 2013 WHO diagnostic criteria. Our cohort may not be representative of the general Singapore obstetric population, although participants were recruited from the two largest maternity hospitals in the country and include both private and subsidized patients. WIDER IMPLICATIONS OF THE FINDINGS: IVF appears to be an independent risk factor for GDM and elevated blood glucose levels in overweight women. Our findings reinforce the need to advise overweight or obese women contemplating IVF to lose weight before the procedure to reduce their risk of GDM and hyperglycemia-related adverse outcomes arising therefrom. In settings where universal GDM screening is not routine, overweight or obese women who conceive by IVF should be screened. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Program and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore (NMRC/TCR/004-NUS/2008; NMRC/TCR/012 NUHS/2014). Additional funding was provided by the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR). K.M.G. and Y.S.C. have received lecture fees from Nestle Nutrition Institute and Danone, respectively. K.M.G., Y.S.C. and S.Y.C. are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. The other authors have nothing to disclose. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A. PMID- 28854719 TI - Techniques used for IUI: is it time for a change? AB - STUDY QUESTION: Are the guidelines for the technical aspects of IUI (WHO, 2010) still in accordance with the current literature? SUMMARY ANSWER: In general, the laboratory guidelines of the World Health Organization (WHO) are a suitable protocol, although the evidence is not always conclusive and some changes are advisable. WHAT IS KNOWN ALREADY: Lack of standardization of the technical procedures required for IUI might result in inter-laboratory variation in pregnancy rates. Most centers still use their own materials and methods even though some guidelines are available. STUDY DESIGN, SIZE, DURATION: A structural review focusing on the association between pregnancy rates and the procedures of semen collection (e.g. ejaculatory abstinence, collection place), semen processing (e.g. preparation method, temperature during centrifugation/storage), insemination (e.g. timing of IUI, bed rest after IUI) and the equipment used. PARTICIPANTS/MATERIALS, SETTING, METHODS: A literature search was performed in Medline and the Cochrane library. When no adequate studies of the impact of a parameter on pregnancy results were found, its association with sperm parameters was reviewed. MAIN RESULTS AND THE ROLE OF CHANCE: For most variables, the literature review revealed a low level of evidence, a limited number of studies and/or an inadequate outcome measure. Moreover, the comparison of procedures (i.e. semen preparation technique, time interval between semen, collection, processing and IUI) revealed no consensus about their results. It was not possible to develop an evidence-based, optimal IUI treatment protocol. LIMITATIONS, REASONS FOR CAUTION: The included studies exhibited a lack of standardization in inclusion criteria and methods used. WIDER IMPLICATIONS OF THE FINDINGS: This review emphasizes the need for more knowledge about and standardization of assisted reproduction technologies. Our literature search indicates that some of the recommendations in the laboratory guidelines could be adapted to improve standardization, comfort, quality control and to cut costs. STUDY FUNDING/COMPETING INTEREST(S): The Dutch Foundation for Quality Assessment in Medical Laboratories (SKML), Nijmegen, The Netherlands. S.K. and W.N. have no conflicts of interest to disclose. C.B. and A.W. are members of the board of the SKML. With a grant from SKML, L.L. was paid for her time to perform the research and write the publication. D.B. received grants from Merck Serono, Ferring and MSD, outside the submitted work. REGISTRATION NUMBER: N/A. PMID- 28854720 TI - Combined androgen excess and Western-style diet accelerates adipose tissue dysfunction in young adult, female nonhuman primates. AB - STUDY QUESTION: What are the separate and combined effects of mild hyperandrogenemia and consumption of a high-fat Western-style diet (WSD) on white adipose tissue (WAT) morphology and function in young adult female nonhuman primates? SUMMARY ANSWER: Combined exposure to mild hyperandrogenemia and WSD induces visceral omental (OM-WAT) but not subcutaneous (SC-WAT) adipocyte hypertrophy that is associated with increased uptake and reduced mobilization of free fatty acids. WHAT IS KNOWN ALREADY: Mild hyperandrogenemia in females, principally in the context of polycystic ovary syndrome, is often associated with adipocyte hypertrophy, but the mechanisms of associated WAT dysfunction and depot specificity remain poorly understood. STUDY DESIGN, SIZE AND DURATION: Female rhesus macaques were randomly assigned at 2.5 years of age (near menarche) to receive either cholesterol (C; n = 20) or testosterone (T; n = 20)-containing silastic implants to elevate T levels 5-fold above baseline. Half of each of these groups was then fed either a low-fat monkey chow diet or WSD, resulting in four treatment groups (C, control diet; T alone; WSD alone; T + WSD; n = 10/group) that were maintained until the current analyses were performed at 5.5 years of age (3 years of treatment, young adults). PARTICIPANTS/MATERIALS, SETTING AND METHODS: OM and SC-WAT biopsies were collected and analyzed longitudinally for in vivo changes in adipocyte area and blood vessel density, and ex vivo basal and insulin-stimulated fatty acid uptake and basal and isoproterenol-stimulated lipolysis. MAIN RESULTS AND THE ROLE OF CHANCE: In years 2 and 3 of treatment, the T + WSD group exhibited a significantly greater increase in OM adipocyte size compared to all other groups (P < 0.05), while the size of SC adipocytes measured at the end of the study was not significantly different between groups. In year 3, both WAT depots from the WSD and T + WSD groups displayed a significant reduction in local capillary length and vessel junction density (P < 0.05). In year 3, insulin-stimulated fatty acid uptake in OM-WAT was increased in the T + WSD group compared to year 2 (P < 0.05). In year 3, basal lipolysis was blunted in the T and T + WSD groups in both WAT depots (P < 0.01), while isoproterenol-stimulated lipolysis was significantly blunted in the T and T + WSD groups only in SC-WAT (P < 0.01). LIMITATIONS, REASONS FOR CAUTION: At this stage of the study, subjects were still relatively young adults, so that the effects of mild hyperandrogenemia and WSD may become more apparent with increasing age. WIDER IMPLICATIONS OF THE FINDINGS: The combination of mild hyperandrogenemia and WSD accelerates the development of WAT dysfunction through T-specific (suppression of lipolytic response by T), WSD-dependent (reduced capillary density) and combined T + WSD (increased fatty acid uptake) mechanisms. These data support the idea that combined hyperandrogenemia and WSD increases the risk of developing obesity in females. STUDY FUNDING/COMPETING INTEREST(S): Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number P50 HD071836 to C.T.R. and award number OD 011092 from the Office of the Director, National Institutes of Health, for operation of the Oregon National Primate Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. PMID- 28854722 TI - Quality of life, anxiety and depression of German, Italian and French couples undergoing cross-border oocyte donation in Spain. AB - STUDY QUESTION: What is the quality of life (QoL) and mental health of infertile heterosexual couples from different nations (Italy, Germany and France) undergoing cross-border oocyte donation (OD) in Spain? SUMMARY ANSWER: Women have lower QoL and more anxiety than their male partners; overall French couples have lower QoL than their Italian and German counterparts. WHAT IS KNOWN ALREADY: In Europe, thousands of couples move across national borders annually to seek ARTs, primarily OD, driven mainly by legal restrictions in their countries of origin. Most research shows that infertility and ARTs affect patients' mental health and QoL. The decision to undergo reproductive care abroad might add further emotional and practical complexity. Reliable information on how this experience affects the mental health and QoL of cross-border reproductive care (CBRC) patients is lacking. Moreover, most research has focused on women, and further research on male partners and intercultural differences is needed. STUDY DESIGN, SIZE, DURATION: Cross-sectional study including 548 heterosexual individuals (347 women, 201 men) from Italy, Germany and France seeking IVF with donated oocytes in Barcelona, Spain between March and November 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 432 couples were invited to participate and handed a questionnaire set. Questionnaires were answered separately and anonymously by each member of the couple on the day of embryo transfer. The questionnaire set included the Fertility Quality of Life (FertiQoL) instrument, the generic Hospital Anxiety and Depression Scale (HADS) instrument and three close-ended questions assessing perceived usefulness, desire, and use of psychological support. The overall response rate was 63.4%. MAIN RESULTS AND THE ROLE OF CHANCE: Men reported significantly higher scores than women in the emotional (+13.74; P < 0.001), mind-body (+13.39; P < 0.001) and social (+4.11; P < 0.01) FertiQoL domains, at multilevel analysis controlled for confounder factors. Intercultural differences in QoL of couples were seen. French individuals had significantly lower emotional (-6.44; P < 0.01), mind-body (-7.41; P < 0.001) and relational scores (-6.41; P < 0.001) compared to Italians. Germans showed higher social scores (+6.41; P < 0.001) but lower relational scores (-8.94; P < 0.002) than Italians. Men reported significantly lower anxiety scores for the HADS than their partners (-1.38; P < 0.001), and German couples reported lower anxiety ( 1.70; P = 0.003) and depression than their Italian counterparts (-1.56; P < 0.001). French patients were more likely to have required support by a mental health professional due to fertility problems in the past (+0.19; P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The scope of this study is limited to heterosexual couples undergoing cross-border OD. Caution on the interpretation of the results in men is advised, mainly because only three men for every five women completed the questionnaire. WIDER IMPLICATIONS OF THE FINDINGS: These findings call for further work to identify the true nature of the differences in QoL and mental health observed. STUDY FUNDING/COMPETING INTEREST(S): None. PMID- 28854721 TI - Chronic combined hyperandrogenemia and western-style diet in young female rhesus macaques causes greater metabolic impairments compared to either treatment alone. AB - STUDY QUESTION: Does developmental exposure to the combination of hyperandrogenemia and western-style diet (WSD) worsen adult metabolic function compared to either treatment alone? SUMMARY ANSWER: Young female rhesus macaques treated for 3 years, beginning at menarche, with combined testosterone (T) and WSD have increased weight gain and insulin resistance compared to controls and animals treated with either T or WSD alone. WHAT IS KNOWN ALREADY: Hyperandrogenemia is a well-established component of polycystic ovary syndrome (PCOS) and can be observed in peripubertal girls, indicating a potential pubertal onset of the disease. Obesity is often associated with hyperandrogenemia in peripubertal girls, and overweight girls appear to be at higher risk for the development of PCOS later in life. STUDY DESIGN, SIZE, DURATION: Juvenile (2.5- year old) female rhesus macaques were divided into four groups (n = 10/group): control animals receiving cholesterol implants and a control diet with 15% of calories derived from fat (C), animals receiving T implants (mean serum levels: 1.35 +/- 0.01 ng/ml) and a control diet (T), animals receiving a cholesterol implant and a WSD with 36% of calories derived from fat (WSD) and animals receiving a T implant and a WSD (T + WSD). Animals were maintained on the treatments for 36 months and were 5.5 years old at study completion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Metabolic testing consisted of body measurements including weight, dual-energy X-ray absorptiometry scans, activity monitoring, and glucose tolerance testing at zero months and at least once every 12 months for the remainder of the study. Indirect calorimetry and serum hormone assays were performed following 36 months of treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Body weight and fat mass gain were significantly increased in T + WSD at 24 and 36 months of treatment compared to the other three groups. Log transformed fasting insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were significantly increased in T + WSD animals at 3 years of treatment compared to all other groups. T-treatment caused a greater rate of decline in activity after 18 months, while food intake and metabolic rate were largely unaffected by treatments. LIMITATIONS REASONS FOR CAUTION: Variability was present in the metabolic parameters measured; however, this is similar to the heterogeneity observed in human populations. WIDER IMPLICATIONS OF THE FINDINGS: Chronic hyperandrogenemia beginning at puberty may exacerbate metabolic dysfunction in women consuming a WSD and account for the increased rates of obesity and insulin resistance observed in PCOS patients. Counseling of female patient populations with elevated androgens about the potential benefit of consuming a lower fat diet could improve long-term metabolic health outcomes. STUDY FUNDING/COMPETING INTEREST(S): Eunice Kennedy Shriver National Institute of Child Health & Human Development P50HD071836 and Oregon National Primate Center Grant P51 OD011092. The authors have no competing conflict of interests to disclose. PMID- 28854723 TI - Bowel Endometriosis Syndrome: a new scoring system for pelvic organ dysfunction and quality of life. AB - STUDY QUESTION: Is it possible to develop a validated score that can identify women with Bowel Endometriosis Syndrome (BENS) and be used to monitor the effect of medical and surgical treatment? SUMMARY ANSWER: The BENS score can be used to identify women with BENS and to monitor the effect of medical and surgical treatment of women suffering from bowel endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a heterogeneous disease with extensive variation in anatomical and clinical presentation, and symptoms do not always correspond to the disease burden. Current endometriosis scoring systems are mainly based on anatomical and surgical findings. STUDY DESIGN, SIZE, DURATION: The score was developed and validated from a cohort of 525 women with medically or surgically treated bowel endometriosis from Aarhus and Copenhagen University Hospitals, Denmark. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Patients filled in questionnaires on pelvic pain, quality of life (QoL) and urinary, sexual and bowel function. Items were selected for the final score using clinical and statistical criteria. The chosen variables were included in a multivariate analysis. Individual score values were designated items to form the BENS score, which was divided into 'no BENS', 'minor BENS' and 'major BENS.' Internal and external validations were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The six most important items were 'pelvic pain', 'use of analgesics', 'dyschezia', 'straining to urinate', 'fecal urgency' and 'satisfaction with sexual life'. The range of the BENS score (0-28) was divided into 0-8 (no BENS), 9-16 (minor BENS) and 17-28 (major BENS). External validation showed a significant association between BENS score and QoL (P = 0.0001). LIMITATIONS, REASONS FOR CAUTION: The BENS scoring system is limited by the fact that it was developed from a single endometriosis unit in Denmark, making it susceptible to social, cultural and demographic bias. WIDER IMPLICATIONS OF THE FINDINGS: It is the first endometriosis classification system to be based directly on the symptomatology of the patient. Validation in other languages will promote comparison of treatments and results across borders. STUDY FUNDING/COMPETING INTEREST(S): No external funding was either sought or obtained for this study. A.F. is an investigator for Bayer, outside this work. PMID- 28854724 TI - Mental health in women with endometriosis: searching for predictors of psychological distress. AB - STUDY QUESTION: What factors affect the mental health of women with endometriosis? SUMMARY ANSWER: Not only pelvic pain, but also individual characteristics (i.e. self-esteem, body esteem and emotional self-efficacy), time from diagnosis and intimate relationship status influence the psychological health of endometriosis patients. WHAT IS KNOWN ALREADY: The negative impact of endometriosis on mental health has been widely demonstrated by the research literature, along with the fact that presence and severity of pelvic pain are associated with anxiety and depression. However, endometriosis is a complex multidimensional disease and factors other than pelvic pain, including individual differences, may contribute to explain the variability in women's mental health. STUDY DESIGN, SIZE, DURATION: This cross-sectional study was conducted between 2015 and 2017 at an Italian academic department of obstetrics and gynaecology. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 210 consecutive endometriosis patients (age: 36.7 +/- 7.0 years) were included. Demographic and endometriosis-related information was collected. Individual differences were assessed using validated measures evaluating self-esteem, body esteem and emotional self-efficacy. The Hospital Anxiety and Depression Scale (HADS) and the Ruminative Response Scale (RRS) were used to evaluate mental health. MAIN RESULTS AND THE ROLE OF CHANCE: Based on the extant literature, we identified three categories of putative predictors (demographic variables, endometriosis-related factors and individual differences i.e. 'self'), whose psychological impact was examined using a hierarchical multiple regression approach. Being in a stable relationship (coded 1 ['yes'] or 0 ['no']) was associated with decreased rumination (RRS: beta = -0.187; P = 0.002). A shorter time from diagnosis was associated with greater anxiety (HADS-A: beta = -0.177; P = 0.015). Pelvic pain severity and 'self' were associated with all mental health variables (Ps < 0.01). Greater self-esteem, body esteem, and emotional self-efficacy were correlated with better psychological outcomes (Ps < 0.01). LIMITATIONS REASONS FOR CAUTION: Sexual functioning, pregnancy, infertility, cultural differences and gender beliefs have been found to be important in women with endometriosis. In our regression model, we did not test the psychological impact of these variables and this should be acknowledged as an important limitation. Moreover, the cross sectional (rather than longitudinal) nature of this study does not allow a full examination of the temporal relationship between endometriosis and psychological outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Factors other than pelvic pain can significantly affect the mental health of women with endometriosis, and the role of individual differences requires further investigation. Targeted multidisciplinary interventions should include evaluation and enhancement of self esteem and self-efficacy to improve women's psychological health. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 28854725 TI - Clinical trial registration in fertility trials - a case for improvement? AB - STUDY QUESTION: What is the prevalence and source of prospectively and retrospectively registered and unregistered trials in fertility treatments? SUMMARY ANSWER: Trial registration is low and does not appear to be changing over the 5 years studied. WHAT IS KNOWN ALREADY: Trial registration is associated with lower risk of bias than in unregistered trials. STUDY DESIGN, SIZE, DURATION: The Cochrane Gynaecology and Fertility Group's specialised register was searched on 5 November 2015 for randomised controlled trials (RCTs) published from January 2010 to December 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible trials included randomised women or men for fertility treatments, were published in full text, and written in English. Two reviewers independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. MAIN RESULTS AND ROLE OF CHANCE: Of 693 eligible RCTS, only 44% were registered trials. Of 309 registered trials, 21.7% were prospectively registered, 15.8% were registered within 6 months of first patient enrolment and 62.5% were retrospectively registered trials. Prospective trial registration by country varied from 0% to 100%. The highest frequency of prospective trial registration amongst the top 10 publishing countries was 31% in the Netherlands. LIMITATIONS, REASONS FOR CAUTION: Only English language trials were included in this review. WIDER IMPLICATIONS OF THE FINDINGS: Prospective trial registration is still low. Journals, funders and ethics committees could have a greater role to increase trial registration. STUDY FUNDING/COMPETING INTERESTS: University of Auckland. No competing interests. PMID- 28854726 TI - The association between pre-treatment maternal alcohol and caffeine intake and outcomes of assisted reproduction in a prospectively followed cohort. AB - STUDY QUESTION: Is pre-treatment alcohol and caffeine intake associated with infertility treatment outcomes among women undergoing ART? SUMMARY ANSWER: Low to moderate alcohol and caffeine intakes in the year prior to infertility treatment were not related to ART outcomes. WHAT IS KNOWN ALREADY: Alcohol and caffeine intake have been found to be associated with infertility in some studies. Nevertheless, data on their relation with outcomes of infertility treatments are scarce and inconsistent. STUDY DESIGN, SIZE, DURATION: We included 300 women (493 ART cycles) from the Environment and Reproductive Health Study, an ongoing cohort study (2006-2016). PARTICIPANTS/MATERIALS, SETTING, METHODS: Pre-treatment intakes of alcohol and caffeine were assessed retrospectively using a validated food frequency questionnaire. Intermediate and clinical endpoints of ART were abstracted from electronic medical records. Generalized linear mixed models with random intercepts to account for multiple ART cycles per woman were used to evaluate the association with ART outcomes adjusting for age, BMI, smoking status, infertility diagnosis, protocol type, race, dietary patterns, and calories, vitamin B12 and folate intake. MAIN RESULTS AND THE ROLE OF CHANCE: Median (range) pre-treatment alcohol and caffeine intakes were 5.6 (0.0-85.8) g/day and 124.9 (0.3-642.2) mg/day, respectively. The adjusted percentage of initiated cycles resulting in live birth (95% CI) for women in increasing categories of pre-treatment alcohol intake was 34% (20, 52%) for non-consumers, 46% (36, 57%) for 0.1-6 g/day, 41% (29, 53%) for 6.1-12 g/day, 42% (31, 55%) for 12.1-24 g/day, and 41% (22, 63%) for >24 g/day (P, trend = 0.87). The adjusted percentage of cycles resulting in live birth (95% CI) for women in increasing categories of caffeine intake was 46% (36-57%) for <50 mg/day, 44% (29, 60%) for 50.1-100 mg/day, 42% (31, 53%) for 100.1-200 mg/day, 40% (28, 53%) for 200.1-300 mg/day and 40% (21, 63%) for >300 mg/day (P, trend = 0.34). When specific types of alcoholic and caffeinated beverages were evaluated, no relations with ART treatment outcomes were observed. LIMITATIONS, REASONS FOR CAUTION: Residual confounding by other diet and lifestyle factors cannot be ruled out owing to the observational nature of this study. It is also unclear how generalizable these results are to women who are conceiving without the assistance of ART. WIDER IMPLICATIONS OF THE FINDINGS: Our results provide reassurance that low to moderate intakes of alcohol (e.g. <=12 g/day) and caffeine (e.g. <200 mg/day) in the year prior to infertility treatment initiation do not have an adverse effect on intermediate or clinical outcomes of ART. STUDY FUNDING/COMPETING INTEREST(S): The authors are supported by National Institutes of Health (NIH) grants ES022955, R01ES009718, R01ES000002, P30DK46200 and L50-HD085359. No conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT00011713. PMID- 28854727 TI - Effect of randomized serum progesterone concentration on secretory endometrial histologic development and gene expression. AB - STUDY QUESTION: What doses of secretory phase progesterone (P) in women are associated with altered endometrial structure and/or function? SUMMARY ANSWER: Consistently delayed histological maturation was seen at the lowest tested daily P dose (2.5 mg), whereas consistently altered functional response, as reflected by microarray analysis of gene expression was seen at both the 5 and 2.5 mg doses. WHAT IS KNOWN ALREADY: Progesterone is absolutely required for normal embryo implantation and pregnancy survival. Progesterone supplementation is beneficial in ART cycles. STUDY DESIGN, SIZE, DURATION: In this case-control experimental trial, 46 healthy young female volunteers (age 19-34) underwent a single modeled endometrial cycle after GnRH down-regulation or monitored in natural cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a university hospital, modeled cycles were obtained by GnRH agonist down-regulation, transdermal estradiol (E2) (0.2 mg/d), and daily injections of P in oil for 10 days: 2.5 mg (n = 6), 5 mg (n = 6), 10 mg (n = 12) or 40 mg (n = 12), after the 10th day of E2. Ten healthy, ovulatory women were used as controls. Endometrial biopsies were obtained on the 10th day of P exposure, or urinary LH surge (in controls). Analysis included histological dating, serum progesterone levels, microarray analysis of the whole genome, RT-PCR, western blot and comparison with the GEO database. MAIN RESULTS AND THE ROLE OF CHANCE: In endometrial biopsies, a morphological delay appears in the 2.5 mg/day of P group. Higher sub physiological levels of P (>=5 mg/day) resulted in normal histology, but aberrant gene expression. P levels required for consistent histological delay were lower than those in all ovulatory women. Gene expression abnormalities occurred at higher sub-physiological P concentrations, without a change in histology, a functional-morphological disassociation. The expression of some endometrial receptivity-associated genes appeared multiphasic, with peak or nadir of mean or median expression levels between the lowest and highest doses, suggesting sustained supraphysiological doses seen in ART treatment cycles may not be optimal. LARGE SCALE DATA: GEO DataSets ID: 200056980; GSE 56980. LIMITATIONS, REASONS FOR CAUTION: These results were obtained in fertile women, who may respond differently from infertile subjects. WIDER IMPLICATIONS OF THE FINDINGS: The dose of P required for normal endometrial structure (5 mg/day) corresponds to a P concentration well below that seen in ovulatory women, suggesting that persistently delayed mid-secretory histology cannot be solely due to inadequate P concentrations in an ovulatory cycle. Endometrial gene expression is differentially regulated by different doses of progesterone. The apparent multiphasic response of some genes to P dose suggests the possibility that P concentration kinetics may play a role in normal endometrial preparation for receptivity. These findings strongly confirm that histologic development is not a reliable measure of endometrial P action. STUDY FUNDING/COMPETING INTEREST(S): Supported by The Eunice Kennedy Shriver National Institute for Child Health and Disease, National Institute of Health, USA (NICHD/NIH) (R01HD067721 and U54HD30476; SLY and BAL) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) 240239/2012-1 (RFS). All authors have no competing interests. PMID- 28854729 TI - Purifying selection on mitochondrial DNA in maturing oocytes: implication for mitochondrial replacement therapy. PMID- 28854728 TI - A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. AB - STUDY QUESTION: Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? SUMMARY ANSWER: A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. WHAT IS KNOWN ALREADY: Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12-14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. STUDY DESIGN, SIZE, DURATION: Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study participants: Sixty-two women aged 18-34 years at high risk of OHSS (antral follicle count >=23 or anti Mullerian hormone level >=40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles >=14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. MAIN RESULTS AND THE ROLE OF CHANCE: A second dose of kisspeptin 54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield >=60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2-50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial 'rescue' LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield >=60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). LIMITATIONS, REASONS FOR CAUTION: Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. WIDER IMPLICATIONS OF THE FINDINGS: Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. STUDY FUNDING/COMPETING INTEREST(S): The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Clinicaltrial.gov identifier NCT01667406. TRIAL REGISTRATION DATE: 8 August 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 August 2015. PMID- 28854730 TI - Reply: Purifying selection on mitochondrial DNA: a strategy for the oocyte to preserve competence. PMID- 28854731 TI - Multiplexed analysis of fixed tissue RNA using Ligation in situ Hybridization. AB - Clinical tissues are prepared for histological analysis and long-term storage via formalin fixation and paraffin embedding (FFPE). The FFPE process results in fragmentation and chemical modification of RNA, rendering it less suitable for analysis by techniques that rely on reverse transcription (RT) such as RT-qPCR and RNA-Seq. Here we describe a broadly applicable technique called 'Ligation in situ Hybridization' ('LISH'), which is an alternative methodology for the analysis of FFPE RNA. LISH utilizes the T4 RNA Ligase 2 to efficiently join adjacent chimeric RNA-DNA probe pairs hybridized in situ on fixed RNA target sequences. Subsequent treatment with RNase H releases RNA-templated ligation products into solution for downstream analysis. We demonstrate several unique advantages of LISH-based assays using patient-derived FFPE tissue. These include >100-plex capability, compatibility with common histochemical stains and suitability for analysis of decade-old materials and exceedingly small microdissected tissue fragments. High-throughput DNA sequencing modalities, including single molecule sequencing, can be used to analyze ligation products from complex panels of LISH probes ('LISH-seq'), which can be amplified efficiently and with negligible bias. LISH analysis of FFPE RNA is a novel methodology with broad applications that range from multiplexed gene expression analysis to the sensitive detection of infectious organisms. PMID- 28854732 TI - Synchronized switching of multiple toxin-antitoxin modules by (p)ppGpp fluctuation. AB - Toxin-antitoxin (TA) loci are widespread in bacteria including important pathogenic species. Recent studies suggest that TA systems play a key role in persister formation. However, the persistence phenotype shows only weak dependence on the number of TA systems, i.e. they are functionally redundant. We use a mathematical model to investigate the interaction of multiple TA systems in the switching between growth and persistence. We explore two scenarios: (i) TA systems are bistable and each TA system experiences its own noise and (ii) the noise in the level of common stress signal (e.g. (p)ppGpp) coordinates all TA systems simultaneously. We find that in the first scenario the exit from the persister state strongly depends on the number of TA systems. However in the second case, we could reproduce the weak dependence. The duration of the high (p)ppGpp state was found to be the key parameter for persistence. The (p)ppGpp driven synchronized transition of all TA systems results in the redundancy. PMID- 28854733 TI - Cell-to-cell variability and robustness in S-phase duration from genome replication kinetics. AB - Genome replication, a key process for a cell, relies on stochastic initiation by replication origins, causing a variability of replication timing from cell to cell. While stochastic models of eukaryotic replication are widely available, the link between the key parameters and overall replication timing has not been addressed systematically. We use a combined analytical and computational approach to calculate how positions and strength of many origins lead to a given cell-to cell variability of total duration of the replication of a large region, a chromosome or the entire genome. Specifically, the total replication timing can be framed as an extreme-value problem, since it is due to the last region that replicates in each cell. Our calculations identify two regimes based on the spread between characteristic completion times of all inter-origin regions of a genome. For widely different completion times, timing is set by the single specific region that is typically the last to replicate in all cells. Conversely, when the completion time of all regions are comparable, an extreme-value estimate shows that the cell-to-cell variability of genome replication timing has universal properties. Comparison with available data shows that the replication program of three yeast species falls in this extreme-value regime. PMID- 28854734 TI - Amide linkages mimic phosphates in RNA interactions with proteins and are well tolerated in the guide strand of short interfering RNAs. AB - While the use of RNA interference (RNAi) in molecular biology and functional genomics is a well-established technology, in vivo applications of synthetic short interfering RNAs (siRNAs) require chemical modifications. We recently found that amides as non-ionic replacements for phosphodiesters may be useful modifications for optimization of siRNAs. Herein, we report a comprehensive study of systematic replacement of a single phosphate with an amide linkage throughout the guide strand of siRNAs. The results show that amides are surprisingly well tolerated in the seed and central regions of the guide strand and increase the silencing activity when placed between nucleosides 10 and 12, at the catalytic site of Argonaute. A potential explanation is provided by the first crystal structure of an amide-modified RNA-DNA with Bacillus halodurans RNase H1. The structure reveals how small changes in both RNA and protein conformation allow the amide to establish hydrogen bonding interactions with the protein. Molecular dynamics simulations suggest that these alternative binding modes may compensate for interactions lost due to the absence of a phosphodiester moiety. Our results suggest that an amide can mimic important hydrogen bonding interactions with proteins required for RNAi activity and may be a promising modification for optimization of biological properties of siRNAs. PMID- 28854735 TI - BRD4 inhibitors block telomere elongation. AB - Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated. PMID- 28854737 TI - Restriction endonuclease triggered bacterial apoptosis as a mechanism for long time survival. AB - Programmed cell death (PCD) under certain conditions is one of the features of bacterial altruism. Given the bacterial diversity and varied life style, different PCD mechanisms must be operational that remain largely unexplored. We describe restriction endonuclease (REase) mediated cell death by an apoptotic pathway, beneficial for isogenic bacterial communities. Cell death is pronounced in stationary phase and when the enzyme exhibits promiscuous DNA cleavage activity. We have elucidated the molecular mechanism of REase mediated cell killing and demonstrate that released nutrients from dying cells support the growth of the remaining cells in the population. These findings illustrate a new intracellular moonlighting role for REases which are otherwise established host defence arsenals. REase induced PCD appears to be a cellular design to replenish nutrients for cells undergoing starvation stress and the phenomenon could be wide spread in bacteria, given the abundance of restriction-modification (R-M) systems in the microbial population. PMID- 28854738 TI - CgII cleaves DNA using a mechanism distinct from other ATP-dependent restriction endonucleases. AB - The restriction endonuclease CglI from Corynebacterium glutamicum recognizes an asymmetric 5'-GCCGC-3' site and cleaves the DNA 7 and 6/7 nucleotides downstream on the top and bottom DNA strands, respectively, in an NTP-hydrolysis dependent reaction. CglI is composed of two different proteins: an endonuclease (R.CglI) and a DEAD-family helicase-like ATPase (H.CglI). These subunits form a heterotetrameric complex with R2H2 stoichiometry. However, the R2H2.CglI complex has only one nuclease active site sufficient to cut one DNA strand suggesting that two complexes are required to introduce a double strand break. Here, we report studies to evaluate the DNA cleavage mechanism of CglI. Using one- and two site circular DNA substrates we show that CglI does not require two sites on the same DNA for optimal catalytic activity. However, one-site linear DNA is a poor substrate, supporting a mechanism where CglI complexes must communicate along the one-dimensional DNA contour before cleavage is activated. Based on experimental data, we propose that adenosine triphosphate (ATP) hydrolysis by CglI produces translocation on DNA preferentially in a downstream direction from the target, although upstream translocation is also possible. Our results are consistent with a mechanism of CglI action that is distinct from that of other ATP-dependent restriction-modification enzymes. PMID- 28854736 TI - The role of poly ADP-ribosylation in the first wave of DNA damage response. AB - Poly ADP-ribose polymerases (PARPs) catalyze massive protein poly ADP ribosylation (PARylation) within seconds after the induction of DNA single- or double-strand breaks. PARylation occurs at or near the sites of DNA damage and promotes the recruitment of DNA repair factors via their poly ADP-ribose (PAR) binding domains. Several novel PAR-binding domains have been recently identified. Here, we summarize these and other recent findings suggesting that PARylation may be the critical event that mediates the first wave of the DNA damage response. We also discuss the potential for functional crosstalk with other DNA damage-induced post-translational modifications. PMID- 28854739 TI - ATP hydrolysis provides functions that promote rejection of pairings between different copies of long repeated sequences. AB - During DNA recombination and repair, RecA family proteins must promote rapid joining of homologous DNA. Repeated sequences with >100 base pair lengths occupy more than 1% of bacterial genomes; however, commitment to strand exchange was believed to occur after testing ~20-30 bp. If that were true, pairings between different copies of long repeated sequences would usually become irreversible. Our experiments reveal that in the presence of ATP hydrolysis even 75 bp sequence matched strand exchange products remain quite reversible. Experiments also indicate that when ATP hydrolysis is present, flanking heterologous dsDNA regions increase the reversibility of sequence matched strand exchange products with lengths up to ~75 bp. Results of molecular dynamics simulations provide insight into how ATP hydrolysis destabilizes strand exchange products. These results inspired a model that shows how pairings between long repeated sequences could be efficiently rejected even though most homologous pairings form irreversible products. PMID- 28854740 TI - The ATP-dependent chromatin remodeler Chd1 is recruited by transcription elongation factors and maintains H3K4me3/H3K36me3 domains at actively transcribed and spliced genes. PMID- 28854741 TI - Zona pellucida protein B2 messenger ribonucleic acid expression varies with follicular development and granulosa cell location. AB - The freshly ovulated ovum in avian species is surrounded by a protein layer called the inner perivitelline layer (IPVL). The IPVL contains zona pellucida proteins and 6 distinct zona pellucida genes have been identified (ZPA, ZPB1, ZPB2, ZPC, ZPD and ZPX1) in the chicken. In the present research, the expression of the mRNA for ZPA, ZPB2, and ZPX1 was investigated in 2 lines of turkey hens selected for either increased egg production (E line) or increased body weight (F line). Theca and granulosa cell expression of the mRNA for ZPA and ZPB2 was also investigated in hierarchical and prehierarchical follicles from broiler breeder hens. Granulosa tissue was collected from F1 through F4 and F1 through F10 follicles in E line and F line hens, respectively. A one cm2 section of the granulosa layer around the germinal disc (GD) and an equivalent sized nongerminal disc (NGD) area was also collected from the F1 and F2 follicles from other hens from each genetic line. Granulosa and theca tissue was collected from hierarchical and prehierarchical follicles of broiler breeder hens. Total RNA was extracted from the samples. Minor groove-binding probes and primers for detecting ZPA, ZPB2, and ZPX1, were made for real-time PCR analyses. Expression of ZPA, ZPB2, and ZPX1 was detected in all follicle sizes from both genetic lines of hens. No significant differences in ZPA and ZPX1 mRNA expression were detected between the GD and NGD granulosa cells. However, the expression of the mRNA for ZPB2 was significantly greater in the GD granulosa cells when compared to the NGD granulosa cells in F1 and F2 follicles from E line and F line hens. In broiler breeder hens, the mRNA expression of ZPA and ZPB2 was greatest in the smallest prehierarchical follicles. The results suggest that higher expression of ZPB2 in the germinal disc area may be important for the preferential binding of sperm to this region of the IPVL. PMID- 28854742 TI - Impact of alternative electrical stunning parameters on the ability of broilers to recover consciousness and meat quality. AB - Broilers in the United States are typically electrically stunned using low voltage-high frequency (12-38 V, >=400 Hz) DC or AC water bath stunners. In the European Union, however, broilers are required to be electrocuted using high voltage-low frequency (50-150 V, 50-350 Hz) AC. Low voltage stunned broilers regain consciousness in the absence of bleeding. In contrast, high voltage stunned broilers die due to induction of cardiac fibrillation. For birds stunned with low voltage systems, concerns have been raised regarding animal welfare during bleeding. This work evaluated the impact of extended DC stunning duration and alternative stunning methods (DC+AC combination) on the recovery of bird consciousness and meat quality. In the absence of bleeding, broilers that were DC stunned for extended times (60, 90, or 120 s), 63, 10, or 0% of broilers, respectively, were able to recover consciousness. Alternative stunning protocols included water bath stunning broilers at 15 or 25 V DC for 10 s followed by plate stunning at 100, 110, or 120 V AC for 5 s. Prior to shackling, live body weight and shank width were measured and during stunning, maximum mA for both DC and AC stuns were recorded. All of the alternative stunning protocols (DC+AC) resulted in non-recoverable stunning. The maximum mA recorded during both DC and AC stunning were moderately/strongly (r = 0.54-0.81) correlated to body weight and poorly/moderately (r = 0.27-0.74) correlated to shank width. No significant differences for carcass or meat quality characteristics (hemorrhages, red wing tips, broken clavicles, pH, cook loss, a* and b* color values, and MORS shear energy) were detected between control (15 or 25 V DC only) and treatment groups (DC+AC combination stunning). The only significant different meat quality parameter was L* values where the lowest voltage group (15 V DC) had the darkest fillets (53.27) and the 15 V DC+100 V AC group had the lightest fillets (55.61) with all other groups intermediate. These data indicate that stunning parameters combining DC and AC stunning may be viable protocols when a stun-to-death is desired. PMID- 28854743 TI - Examining the effect of dietary electrolyte balance, energy source, and length of feeding of nitrogen-free diets on ileal endogenous amino acid losses in broilers. AB - The effect of dietary electrolyte balance (DEB), energy source (ES), and length of feeding of nitrogen-free diet (NFD) on ileal endogenous amino acid (EAA) loss in mg/kg dry matter intake (DMI) was evaluated in broiler chickens. In Experiment 1, 720 chickens consisting of 15 replicate cages with 6 chickens/replicate were used. Treatments were arranged in a 2 * 2 * 2 factorial and consisted of 4 NFD with 2 levels (low or high) of DEB and 2 ES [corn starch (CS) or dextrose (DX)], and 2 sampling time-points (diets were fed for either 72 h (d 16 to 19) or 120 h (d 16 to 21). Experiment 2 used 360 chickens in a 2 * 2 factorial arrangement of treatments with 2 levels (low or high) of DEB and 2 ES (CS or DX). Diets were fed for 72 h (d 18 to 21). All birds had access to feed and water on an ad libitum basis. Data were analyzed using the GLM procedure of SAS appropriate for a completely randomized design for a factorial arrangement of treatments. For Experiment 1, there were interactions (P < 0.05) between the 3 main factors for nitrogen and all the AA except Trp. Broilers that were fed DX-based NFD with high DEB for 72 h had the highest (P < 0.05) EAA losses. In Experiment 2, there was no interaction between DEB and ES except for His and Lys. When ileal EAA losses from birds fed the low DEB, CS-based NFD were used to standardize apparent ileal digestibility values from a previous study, there was no effect of length of feeding on standardized ileal AA digestibility values. In conclusion, DX-based NFD with high DEB increased endogenous AA loses. Despite differences in ileal EAA losses from CS-based NFD, standardized ileal AA digestibility values were not influenced by the length of feeding of NFD. Based on the results from these studies, NFD could be fed for 72 h without influencing SIAAD values. PMID- 28854744 TI - Freezing-thawing and sub-sampling influence the marination performance of chicken breast meat. AB - Vacuum-tumbling marination is often used to improve the yield and quality of whole or portioned broiler breast fillets. The relationship between the marination performance of whole Pectoralis major muscles and breast fillet sub samples is not well understood. The objective was to determine the effects of sub sampling and freezing-thawing on the marination performance and cook loss of broiler breast meat. Paired right and left breast fillets were marinated as whole fillets or sub-samples (cranial and mid-caudal portions). Samples were marinated at 48 h postmortem (fresh) or stored at -20 degrees C and then thawed prior to marination (frozen-thawed). Samples were vacuum-tumbled in 20% wt/wt brine (5% NaCl, 3% STP) and weighed pre-marination, during marination (15, 30, and 45 min), and 24 h post-marination. Samples were then cooked to 75 degrees C for determination of cook loss. Marinade uptake was greater in caudal sub-samples than intact fillets and cranial sub-samples after 15 min of marination (P < 0.0001). After 30 min, marinade uptake was greater in caudal sub-samples and intact fillets than cranial sub-samples (P < 0.05). After 45 min, marinade uptake for fresh samples was greatest in intact fillets and lowest in cranial sub samples. For frozen-thawed samples, marinade uptake at 45 min was greater in caudal sub-samples and intact fillets than cranial sub-samples (P < 0.0001). Marinade uptake in sub-samples at 30 min was greater in frozen-thawed versus fresh fillets (P < 0.05). Differences in marinade retention were not observed. Cook loss was similar between fresh and frozen-thawed samples but was greater in sub-samples compared to intact fillets (P < 0.0001). Correlations between marinade uptake in intact fillets and cranial sub-samples were greater in fresh (r = 0.64 to 0.78) than frozen-thawed samples (r = 0.39 to 0.59). Correlations between marinade uptake in intact fillets and caudal sub-samples were greater in frozen-thawed (r = 0.79 to 0.82) than fresh samples (r = 0.46 to 0.63). Data suggest that the relationships between marination performance of whole breast fillets and fillet sub-samples are dependent upon prior sample handling and intra fillet sampling location. PMID- 28854745 TI - Prevalence and risk factors for thermotolerant species of Campylobacter in poultry meat at retail in Europe. AB - The thermotolerant species Campylobacter jejuni, Campylobacter coli, Campylobacter lari and Campylobacter upsaliensis are the causative agents of the human illness called campylobacteriosis. This infection represents a threat for the health of consumers in Europe. It is well known that poultry meat is an important food vehicle of Campylobacter infection. As emerged from the reported scientific literature published between 2006 and 2016, poultry meat sold at retail level in Europe represents an important source of the pathogen. The contamination level of poultry meat sold at retail can vary depending on pre- and post-harvest factors. Among the pre-harvest measures, strict biosecurity practices must be guaranteed; moreover, among post-harvest control measures scalding, chilling and removal of faecal residues can reduce the contamination level of Campylobacter. An additional issue is represented by increasing proportion of Campylobacter isolates resistant to tetracyclines, ciprofloxacin, and nalidixic acid, thus feeding a serious concern on the effectiveness of antibiotic treatment for human campylobacteriosis in a near future. PMID- 28854746 TI - The analysis of meat and bone traits of Plymouth Rock cockerels and capons (P55) at different age. AB - The aim of the study was the comparison of Plymouth Rock cockerels and capons and the evaluation of the influence of their age on slaughter yield, meat quality, and bone traits. The studies were conducted on cockerels and capons from P55 strain (Plymouth Rock). At 16, 18, and 20 wk of rearing, a dissection of whole carcasses of cockerels and capons was conducted, and breast and leg muscles were evaluated in terms of the physical and chemical traits, as well as the chemical composition. Also, traits of femur and tibia bones were studied. It was indicated that capons were characterized by a higher body weight (BW) before slaughter and higher weight of the eviscerated carcass than cockerels at consecutive dates of slaughter. Based on BW, the slaughter yield and muscle content of carcasses, it was found that the most optimal slaughter time in Plymouth Rock cockerels is at 18 wk and capons at 20 wk. It was observed that caponization had a significant effect on the chemical composition of breast muscles with respect to water and protein content. Along with bird age, collagen content in muscles decreased; however, significant differences were observed only in capons. At consecutive dates of evaluating cockerels, resistance and toughness of their femur and tibia bones increased significantly. Significant changes in the physical characteristics of bones were also found. PMID- 28854747 TI - In ovo feeding of creatine pyruvate alters energy reserves, satellite cell mitotic activity and myogenic gene expression of breast muscle in embryos and neonatal broilers. AB - We investigated the effects of in ovo feeding (IOF) of creatine pyruvate (CrPyr) on energy reserves, satellite cell mitotic activity (SCMA) and myogenic gene expression in breast muscle of embryos and neonatal broilers. A total of 960 eggs were randomly allocated into three treatments: 1) non-injected control group, 2) saline group injected with 0.6 mL of physiological saline (0.75%), and 3) CrPyr group injected with 0.6 mL of physiological saline (0.75%) containing 12 mg CrPyr/egg at 17.5 d of incubation. After hatching, a total of 120 male chicks were randomly assigned to each treatment group, with eight replicate sets per group. Selected chicks had body BW close to the average of their pooled group. Our results showed that the total and relative breast muscle weights of broilers subjected to CrPyr treatment were higher than those in the control and saline groups on 19 d of incubation (19 E), the day of hatch, 3 and 7 d post-hatch (P < 0.05). The myofiber diameter and cross-sectional area of individuals in the CrPyr group were higher than those in other treatments on 3 and 7 d post-hatch (P < 0.05). Moreover, IOF of CrPyr increased (P < 0.05) creatine concentrations on 19 E, the day of hatch and 3 d post-hatch, the same treatment increased phosphocreatine concentrations on 19 E. Broilers in the CrPyr group showed higher expression of myogenic differentiation 1 (MyoD) (P < 0.05), myogenin and paired box 7 (Pax7), as well as higher index of SCMA on 3 d post-hatch. However, myostatin mRNA expression in CrPyr-treated broilers was down-regulated on 3 d post-hatch (P < 0.05). These results indicated that IOF of CrPyr increased energy reserves of embryos and SCMA of broilers on 3 d post-hatch, which led to enhanced muscle growth in the late embryos and neonatal broilers. Additionally, IOF of CrPyr increased the activity of satellite cells possibly through up-regulating MyoD, myogenin, and Pax7 mRNA expression and down-regulating myostatin mRNA expression. PMID- 28854748 TI - Pattern recognition receptor genes expression profiling in indigenous chickens of India and White Leghorn. AB - Pattern recognition receptors (PRR) such as Toll-like receptors, NOD-like receptors, RIG-I helicase receptors, and C-type lectin receptors play a critical role in innate immunity as a first line of defense against invading pathogens through recognition of pathogen and/or damage-associated molecular patterns. Genetic makeup of birds is known to play a role in resistance or susceptibility to various infectious diseases. Therefore, the present study was carried out to elucidate the differential expression of PRR and some of the cytokine genes in peripheral blood mononuclear cells of indigenous chicken breeds such as Ghagus and Nicobari and an exotic chicken breed, White Leghorn (WLH). The stability of expression of reference genes in peripheral blood mononuclear cells of 3 breeds was first determined using NormFinder and BestKeeper programs. NormFinder determined B2M and G6PDH reference genes as the best combination with stability value of 0.38. Out of total 14 genes studied, expression of ten genes was found to be significantly different among 3 breeds after normalization with these reference genes. Ghagus breed showed higher level of expression of TLR1LB, TLR7, NOD1, NOD5, B-Lec, IFNbeta, IL1beta, and IL8 genes when compared to Nicobari breed. Further, Ghagus showed higher expression of TLR1LB, MDA5, LGP2, B-Lec, IL1beta, and IL8 genes as compared to WLH breed. Higher expression of LGP2 and MDA5 genes was observed in Nicobari compared to the WLH breed while higher expression of TLR7, NOD1, NOD5, and IFNbeta genes was observed in WLH as compared to Nicobari breed. No difference was observed in the expression of TLR1LA, TLR3, B-NK, and IFNalpha genes among 3 breeds. Study revealed significant breed effect in expression profile of PRR and some of the cytokine genes and Ghagus breed seems to have better expression profile of these genes linked to the innate immunity when compared to the WLH and Nicobar breeds. PMID- 28854749 TI - A comparative study of functional properties of normal and wooden breast broiler chicken meat with NaCl addition. AB - The selection of broilers for augmented growth rate and breast has brought about wooden-breast (WB) muscle abnormalities, which caused substantial economic losses. The objective of this study was to compare water holding capacity, water mobility and distribution, salt-soluble protein (SSP) content, and protein profiles of normal and WB chicken meat with different additions of NaCl. Thirty WB and 30 normal chicken breasts were selected from a deboning line of a major Chinese processing plant at 2 to 3 h post mortem. Two different meat batters were formulated to 150 mg/g meat protein and different NaCl contents (0%, 1%, 2%, 3%, and 4%). Results indicated that as NaCl contents increased, the cooking loss of meat batters decreased (P < 0.05). Increasing the NaCl content to 3% or more increased the solubility of myofibrillar protein and the extraction of SSPs, which resulted in the improving of cooking yield. Over a range of salt concentrations, normal and WB meat showed different protein profiles, with myosin heavy chain exhibiting a higher intensity at >=3% salt level. Low-field nuclear magnetic resonance (LF-NMR)revealed an increased T22 and higher P22 in raw WB meat compared to normal meat (P < 0.05). Regarding the meat batters, WB meat batters had reduced T21 and lower immobilized water proportions at low NaCl contents (<2%). After heating, T2 shifted towards higher relaxation times with increasing NaCl contents in meat gels. Meat gels prepared from WB had a lower proportion of water within the myofibrillar protein matrix and a greater proportion of exuded bulk water at NaCl contents <3% (P < 0.05), while at higher NaCl contents the difference was eliminated, thus improving water retention capacity. In conclusion, for raw meat, meat batters and gels, water distribution and mobility of WB exhibited significant differences compared to normal meat. The addition of NaCl affected water mobility and distributions in meat batters, with a level of 3% NaCl eliminating the differences between processed normal and WB meat products. PMID- 28854750 TI - Antioxidant and anti-inflammatory properties of chicken egg vitelline membrane hydrolysates. AB - Vitelline membrane (VM) is a multilayered structure that surrounds the egg yolk serving to separate the yolk and the white. Due to its poor solubility in aqueous based media, VM proteins and their biological properties have not been fully defined. In the current study, VM was hydrolyzed using different enzymes under the optimum hydrolysis conditions. Antioxidant and anti-inflammatory properties were evaluated in chemical and cellular models. Flavourzyme- and trypsin-treated samples showed the highest radical scavenging and ferric ion reducing effect (31% and 20 MUM of Trolox equivalents/mg, respectively). In cellular studies, all VM hydrolysates were cyto-compatible and inhibited nitric oxide production by RAW264.7 macrophage cells significantly. Lipopolysaccharide-stimulated up regulation of pro-inflammatory cytokines in RAW264.7 cells was suppressed by flavourzyme-treated VM. These results revealed that enzymatic hydrolysis of VM is a promising approach to produce peptides with several bioactivities (free radical scavenging, metal chelation, and anti-inflammatory) as valuable ingredients for cosmeceuticals and nutraceuticals. PMID- 28854751 TI - Poultry rearing on perforated plastic floors and the effect on air quality, growth performance, and carcass injuries-Experiment 1: Thermal Comfort. AB - The present study investigated the use of perforated plastic floors in the rearing of male and female poultry under thermal comfort conditions. The study was conducted in 2 climate chambers, in one was conventional poultry litter (wood shavings) and in the other was a perforated plastic floor. The experimental design was a completely randomized design with the factors wood shavings and plastic floor. In each chamber, the animals were divided into 16 experimental pens (8 with males and 8 with females) with a density of 12 birds/m2. The poultry rearing effect was evaluated in terms of air quality (% concentration of ammonia [NH3] and carbon dioxide [CO2]); broiler performance, e.g., weight gain (kg), feed intake (kg), feed conversion, carcass yield and parts (%), meat production (kg/m2), and viability (% of live birds at d 42); scores of hygiene and mobility; and injuries in the chest, hocks, and footpads. Treatments affected air quality, with higher concentrations of NH3 on d 42 (25 ppm vs. 2 ppm) and CO2 (1,400 ppm vs. 1,000 ppm) for wood shavings than for perforated plastic floor, respectively. Males showed a better performance (weight gain, feed intake and feed conversion) than females on d 42 in both floor types (wood shavings and plastic floor). Males reared on wood shavings showed a higher meet production (35.992 kg/m2) than females (32.257 kg/m2). On the plastic floor, males showed a better viability (100%) than females (94.05%), as well better meet production for males (38.55 kg.m-2) than females (31.64 kg/m2). There was no incidence of breast lesions in any of the studied systems. The birds reared on the plastic floor had better hygiene scores and lower hock injury rates than birds reared in the wood shavings chambers. The results of the present study show that the use of perforated plastic floors in chicken farming is an efficient method, which promotes a better quality environment, superior production rates, and reduced incidence of injuries. PMID- 28854752 TI - Effects of rye inclusion in grower diets on immune competence-related parameters and performance in broilers. AB - An experiment was conducted to investigate the effects of dietary inclusion of rye, a model ingredient to increase gut viscosity, between 14 and 28 d of age on immune competence-related parameters and performance of broilers. A total of 960 day-old male Ross 308 chicks were weighed and randomly allocated to 24 pens (40 birds per pen), and the birds in every 8 replicate pens were assigned to 1 of 3 experimental diets including graded levels, 0%, 5%, and 10% of rye. Tested immune competence-related parameters were composition of the intestinal microbiota, genes expression in gut tissue, and gut morphology. The inclusion of 5% or 10% rye in the diet (d 14 to 28) resulted in decreased performance and litter quality, but in increased villus height and crypt depth in the small intestine (jejunum) of the broilers. Relative bursa and spleen weights were not affected by dietary inclusion of rye. In the jejunum, no effects on number and size of goblet cells, and only trends on microbiota composition in the digesta were observed. Dietary inclusion of rye affected expression of genes involved in cell cycle processes of the jejunal enterocyte cells, thereby influencing cell growth, cell differentiation and cell survival, which in turn were consistent with the observed differences in the morphology of the gut wall. In addition, providing rye-rich diets to broilers affected the complement and coagulation pathways, which among others are parts of the innate immune system. These pathways are involved in eradicating invasive pathogens. Overall, it can be concluded that inclusion of 5% or 10% rye to the grower diet of broilers had limited effects on performance. Ileal gut morphology, microbiota composition of jejunal digesta, and gene expression profiles of jejunal tissue, however, were affected by dietary rye inclusion level, indicating that rye supplementation to broiler diets might affect immune competence of the birds. PMID- 28854754 TI - Effects of multi-carbohydrase and phytase on standardized ileal digestibility of amino acids and apparent metabolizable energy in canola meal fed to broiler chicks. AB - Two assays were conducted to evaluate nutritive value of canola meal (CM) fed to broiler chicks without or with a multi-carbohydrase (MC) preparation (700 U alpha galactosidase, 2,200 U galactomannanase, 30,000 U xylanase, and 22,000 U beta glucanase per kg of diet) and phytase (Phy, 500 FTU per kg of diet). Assay 1 determined apparent total tract digestibility (ATTD) of nutrients and metabolizable energy (AME) by the difference method. Assay 2 determined apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of amino acids by the index method. Two reference diets (RD) - an 85% corn based and a 5% casein-cornstarch diet fortified with vitamins and minerals - were made for assays 1 and 2, respectively. For each assay, the test diets were made by mixing RD and CM 7:3 wt/wt basis and fed without or with MC or Phy or combination. A total of 245 day-old male broilers (Cobb 500) was allocated to 5 treatments to give 7 replicates (7 birds/cage). The birds were fed a commercial diet from day zero to 10 followed by assay 1 fed from d 11 to 18 and assay 2 fed from d 19 to 21. Excreta samples were collected on d 15 to18, and all birds were slaughtered on d 21 for ileal digesta. There was an interaction (P < 0.05) between MC and Phy on ATTD of DM, N, and P. There was no interaction (P > 0.05) between MC and Phy on AMEn; however, MC and Phy individually improved AMEn retention. Enzymes interacted (P < 0.05) on SID of Arg, His, Leu, Met, Thr, Ala, Asp, Gln, and Gly. In this context, feeding a combination of MC and Phy resulted in higher (P < 0.05) SID of Arg, His, Met, and Thr relative to single activity or control. Both enzymes improved (P < 0.05) SID of Lys independently. The combination of carbohydrase and Phy may be an effective strategy to improve amino acid utilization in CM for poultry. PMID- 28854753 TI - Proteomic identification of turkey (Meleagris gallopavo) seminal plasma proteins. AB - SDS-PAGE combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and 2-dimensional electrophoresis (2DE) combined with matrix-assisted laser desorption/ionization time of flight/time of flight mass spectrometry (MALDI TOF/TOF) were applied to characterize the turkey seminal plasma proteome. LC MS/MS led to the identification of 175 proteins, which were classified according to their function and to corresponding biochemical pathways. Using 2DE and MALDI TOF/TOF, 34 different turkey seminal plasma proteins could be identified, of which 20 were found in more than one spot, indicating different proteoforms of these proteins. For validation, antibodies against turkey albumin and ovoinhibitor as well as sperm acrosin were used in 2DE Western blots experiments. The bioinformatic analysis of the results indicates that turkey seminal plasma proteins may be involved in regulation of lipid metabolism [liver X receptor/retinoid X receptor (LXR/RXR) activation and farnesoid X receptor/retinoid X receptor (FXR/RXR) activation pathways)], endocytic entry of proteins and lipids at the plasma membrane (clathrin-mediated endocytosis pathway), and defense against pathogens (acute phase response signaling pathway) and energy production (glycolysis and gluconeogenesis). Moreover, a comparative meta-analysis of seminal plasma proteomes from other species indicated the presence of proteins specific for avian reproduction, but distinct differences between turkey and chicken seminal plasma proteomes were detected. The results of our study provide basic knowledge of the protein composition of turkey seminal plasma highlighting important physiological pathways which may play crucial roles in the sperm environment after ejaculation. This knowledge can be the basis to further develop procedures improving the reproduction of farmed turkeys. PMID- 28854755 TI - Omega-3 polyunsaturated fatty acids provided during embryonic development improve the growth performance and welfare of Muscovy ducks (Cairina moschata). AB - The welfare of ducks can be affected by unwanted behaviors such as excessive reactivity and feather pecking. Providing long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) during gestation and early life has been shown to improve the brain development and function of human and rodent offspring. The aim of this study was to test whether the pecking behavior of Muscovy ducks during rearing could be reduced by providing LC n-3 PUFA during embryonic and/or post-hatching development of ducklings. Enrichment of eggs, and consequently embryos, with LC n 3 PUFA was achieved by feeding female ducks (n-3F) a diet containing docosahexaenoic (DHA) and linolenic acids (microalgae and linseed oil). A control group of female ducks (CF) was fed a diet containing linoleic acid (soybean oil). Offspring from both groups were fed starter and grower diets enriched with DHA and linolenic acid or only linoleic acid, resulting in four treatment groups with 48 ducklings in each. Several behavioral tests were performed between 1 and 3 weeks of age to analyze the adaptation ability of ducklings. The growth performance, time budget, social interactions, feather growth, and pecking behavior of ducklings were recorded regularly during the rearing period. No significant interaction between maternal and duckling feeding was found. Ducklings from n-3F ducks had a higher body weight at day 0, 28, and 56, a lower feed conversion ratio during the growth period, and lower reactivity to stress than ducklings from CF ducks. Ducklings from n-3F ducks also exhibited a significantly reduced feather pecking frequency at 49 and 56 days of age and for the whole rearing period. Moreover, consumption of diets enriched with n-3 PUFA during the starter and grower post-hatching periods significantly improved the tibia mineralization of ducklings and the fatty acid composition of thigh muscles at 84 days of age by increasing the n-3 FA content. PMID- 28854756 TI - Mycoplasma synoviae vaccine modifies virus shedding and immune responses of avian influenza (H9N2) infection in commercial layers. AB - Mycoplasma synoviae (MS) is an important pathogen of domestic poultry and is prevalent in commercial layers. Avian influenza (AI; H9N2) infections are emerging respiratory problems causing huge economic losses to the poultry industry, especially in the presence of other co-infecting pathogens. The possible role of MS vaccination and response to AI (H9N2) virus in commercial layers was evaluated during this study. Experimental commercial layers were divided into different groups which were identified as follows: non-vaccinated non-challenged (NVNC), non-vaccinated challenged (NVC), vaccinated non-challenged (VNC), and vaccinated challenged (VC). The titer of AI antibodies was measured pre- and post-challenge to confirm experimental infection. Infected layers showed clinical signs of differing severity, with the most prominent disease signs and mortality (25%) appearing in layers of the VC group. Moreover, the layers in VC group showed a significant decrease in weight and enhanced gross lesions. All infected layers showed positive results for virus shedding; however, the pattern of virus shedding was different, with layers of VC group showing more pronounced virus excretion than the layers in the NVC group. In addition, layers of VC group showed significantly reduced antibody responses and interferon gene expression when compared with the layers of NVC group. The present study revealed that MS vaccine could facilitate replication of avian influenza viruses and thus avian influenza virus infections can be worse after MS vaccination, especially in AIV endemic areas. PMID- 28854758 TI - Investigations of the nutritive value of meals of double-low rapeseed and its influence on growth performance of broiler chickens. AB - Four experiments were carried out to study the possible differences in metabolizable energy (ME) of meals (RSM) or expeller meals (RSE) from double-low rapeseed (Expt. 1), the influence of processing on ME (Expt. 2) and on relative phosphorus (P) bioavailability (Expt. 3) in RSM, and effect of RSM inclusion on growth performance of broilers (Expt. 4). For Expt. 1, diets with 300 g/kg RSM from 11 RSM and 4 RSE varieties were fed to broilers from d 14 to 21, with excreta collection on d 19 to 21. Each treatment had 8 replicates and 3 birds per replicate. Energy metabolizability of RSM of a specialized high glucosinolate variety (V275OL) was greater (P < 0.05) than all the other varieties. In Expt. 2, two RSM varieties were processed with mild or conventional processing condition. There were no variety effects on ME, but ME and MEn were greater (P < 0.01) for RSM processed by mild processing condition. In Expt. 3, P bioavailability of RSM was determined, relative to MSP, using growth performance and tibia ash as responses. Phosphorus relative bioavailability values were greater (P < 0.05) in RSM of DK Cabernet variety processed using the mild processing condition. In Expt. 4, two RSM varieties were added to wheat-soybean meal-based diet at the rates of 50, 100, 150, or 200 g/kg and fed to broilers from d 0 to 42. Inclusion of 150 and 200 g/kg of RSM resulted in reduced weight gain and increased feed conversion ratio (FCR) compared (P < 0.01) with the lower inclusion levels during the starter phase. For the entire trial (d 0 to 42), weight gain was greater (P < 0.01) for birds receiving diets with RSM from PR46W21 variety. It was concluded from the experiments that apart from the residual ether extract content, variety differences had no impact on ME of RSM, conventional processing reduced ME and relative bio-availability of P; and that the maximum level of RSM inclusion depends on maximum growth performance level desired. PMID- 28854757 TI - Cleaning and disinfection programs against Campylobacter jejuni for broiler chickens: productive performance, microbiological assessment and characterization. AB - Detailed cleaning and disinfection programs aims to reduce infection pressure from microorganisms from one flock to the next. However, studies evaluating the benefits to poultry performance, the sanitary status of the facilities, and the sanitary quality of the meat are rarely found. Thus, this study was designed to evaluate 2 cleaning and disinfecting programs regarding their influence on productive performance, elimination of Campylobacter, and characterization of Campylobacter jejuni strains when applied to broiler chickens' facilities. Two subsequent flocks with 960 birds each were distributed into 32 pens containing 30 birds each. In the first, the whole flock was inoculated with a known strain of Campylobacter jejuni in order to contaminate the environment. In the second flock, performance and microbiological evaluations were done, characterizing an observational study between 2 cleaning and disinfection programs, regular and proposed. The regular program consisted of sweeping facilities, washing equipment and environment with water and neutral detergent. The proposed cleaning program consisted of dry and wet cleaning, application of 2 detergents (one acid and one basic) and 2 disinfectants (250 g/L glutaraldehyde and 185 g/L formaldehyde at 0.5% and 210 g/L para-chloro-meta-cresol at 4%). Total microorganism count in the environment and Campylobacter spp. identification were done for the microbiological assessment of the environment and carcasses. The positive samples were submitted to molecular identification of Campylobacter spp. and posterior genetic sequencing of the species identified as Campylobacter jejuni. The birds housed in the facilities and submitted to the proposed treatment had better performance when compared to the ones in the regular treatment, most likely because there was a smaller total microorganism count on the floor, walls, feeders and drinkers. The proposed program also resulted in a reduction of Campylobacter spp. on floors, drinkers and birds. Moreover, it was possible to identify 6 different Campylobacter jejuni strains in the facilities. The proposed treatment resulted in a positive influence on the birds' performance and reduction of environment contamination for broiler chickens. PMID- 28854759 TI - Treatment of Infected Total Knee Arthroplasty. PMID- 28854760 TI - A Review of the Literature on Culture-Negative Periprosthetic Joint Infection: Epidemiology, Diagnosis and Treatment. AB - Purpose: The prevalence of periprosthetic joint infection (PJI) has increased with the increasing incidence of arthroplasty surgery. Considering identification of causative microorganisms is crucial for treatment of PJI, culture-negative (CN) PJI is a significant clinical issue. The purpose of the present study is to describe epidemiology, diagnosis and treatment of CN PJI based on review of the literature to help prevent delayed diagnosis and improve clinical outcomes of CN PJI. Methods: MEDLINE, EMBASE, Cochrane Library and Scopus databases were searched for articles on CN PJI. Only clinical studies written in English were included. Basic science studies, letters to the editor, case reports and review articles on PJI were excluded. Results: Seven studies were included in this study. The prevalence of CN PJI ranged from 0% to 42.1%. The major risk factors for CN PJI were prior antibiotic use and presence of postoperative wound drainage. Vancomycin and cephalosporins were the most commonly used antibiotics for CN PJI. Two-stage revision arthroplasty followed by 6 weeks of antibiotic therapy produced the most successful treatment outcomes. Conclusions: In most clinical studies on CN PJI, a definite diagnostic method for identifying causative microorganisms or optimal treatment strategy for CN PJI were not clearly described. Therefore, further studies are needed to establish standard diagnostic methods for identifying infecting organisms and treatment strategies for CN PJI. PMID- 28854761 TI - Platelet-Rich Plasma Injections as a Treatment for Refractory Patellar Tendinosis: A Meta-Analysis of Randomised Trials. AB - Purpose: Patellar tendinosis (PT) is a common condition amongst athletes. In this study, we perform a meta-analysis on randomised controlled trials (RCTs) to evaluate the use of platelet-rich plasma (PRP) for refractory PT. Methods: A literature search was undertaken in various databases from their year of inception to October 2015. The primary outcome measure was the Victorian Institute of Sports Assessment-Patella (VISA-P) score. Results: We identified 2 RCTs comparing PRP injections to alternative treatment options (extracorporeal shockwave therapy [ESWT] and dry needling of the tendon). Meta-analysis showed no significant difference in mean VISA-P scores between PRP injection and control at early assessment (2 or 3 months; estimated difference in means, 11.9; standard error [SE], 7.4; 95% confidence interval [CI], -2.7 to 26.4; p=0.109). However, PRP was statistically better than control with regards to VISA-P scores at longer follow-up (6 months or longer; estimated difference in means, 12.7; SE, 4.4; 95% CI, 4.1 to 21.3; p=0.004). Conclusions: There is a paucity of RCTs evaluating the role of PRP in PT. Our results suggest that, based on limited evidence, PRP is superior over other established non-surgical treatments (dry needling and ESWT) for refractory PT. Larger RCTs may allow better characterisation of the role of PRP in this condition. PMID- 28854762 TI - Efficacy of Open Debridement and Polyethylene Exchange in Strictly Selected Patients with Infection after Total Knee Arthroplasty. AB - Purpose: To assess the efficacy of open debridement and polyethylene exchange (ODPE) combined with proper antibiotic therapy in strictly selected patients with infection after total knee arthroplasty (TKA) and analyze factors associated with treatment failure. Materials and Methods: From January 2010 to January 2014, 25 cases that underwent ODPE under the diagnosis of infection within four weeks after TKA or acute hematogenous infection within five days of symptom onset were reviewed in this study. Results: Treatment was successful in 22 out of 25 cases (88.0%). Factors associated with failure were accompanying infection (periprosthetic infection in the ipsilateral foot, cervical parotid abscess, and masticator space abscess) and diagnosis of rheumatoid arthritis (RA) before TKA. Resistant bacteria did not entail a risk. On clinical results, the mean postoperative Lysholm score and Korean Knee score were 81.4 and 79.4, respectively, the knee range of motion was 115.4 degrees +/-12.9 degrees , and duration of hospitalization was 32.3+/-8.4 days. On radiographic results, 3.47+/ 1.56 mm joint line elevation and a valgus change of 0.61 degrees +/-2.35 degrees in knee alignment were observed. Conclusions: ODPE combined with appropriate antibiotics therapy could be a useful treatment method for infection after TKA if the procedure is performed within a symptom duration of five days or less in the absence of accompanying infection in patients whose indication for TKA was not RA. PMID- 28854763 TI - Early Clinical Outcomes of a New Posteriorly Stabilized Total Knee Arthroplasty Prosthesis: Comparisons with Two Established Prostheses. AB - Purpose: We sought to determine whether early clinical performance of new posterior stabilized (PS) knee system, the Vega-PS (Aesculap), is better than that of two established total knee arthroplasty (TKA) prostheses, the E.motion-PS (Aesculap) and the Genesis II (Smith & Nephew) in terms of functional outcomes, patient satisfaction, and incidence of adverse events. Materials and Methods: We compared the clinical outcomes of 206 consecutive TKAs using Vega-PS with those of 205 TKAs using E.motion-PS and 216 TKAs using Genesis II at 2 years of follow up. Results: Overall, the knees with the Vega-PS had better functional outcome scores than the knees with the E.motion-PS, but had similar outcome scores to the knees with the Genesis II, as evident from the American Knee Society knee score (94.2 vs. 92.5 vs. 93.2), Western Ontario McMaster Universities Osteoarthritis (WOMAC) stiffness index (1.8 vs. 2.3 vs. 2.0), WOMAC function index (11.8 vs. 16.8 vs. 18.5), Short Form 36 (SF-36) physical component summary score (41.9 vs. 39.3 vs. 41.6), and SF-36 mental component summary score (50.0 vs. 45.8 vs. 46.9). Patient satisfaction was higher in the Vega-PS and Genesis II groups than the E.motion-PS group. No notable group differences were found in terms of the incidence of adverse events. Conclusions: The Vega-PS, a newly developed PS fixed bearing prosthesis, had comparable or superior clinical performance in comparison with the two established fixed or mobile bearing PS prostheses. PMID- 28854764 TI - Extramedullary Tibial Bone Cutting Using Medial Cortical Line in Total Knee Arthroplasty. AB - Purpose: This study aims to identify the effectiveness of the medial cortical line for attaining a more accurate tibial component alignment in proximal tibial resection using an extramedullary alignment rod. Materials and Methods: The study examined 100 cases of total knee arthroplasty performed from December 2013 to February 2014 in a retrospective manner. On a preoperative anteroposterior (AP) radiograph of the entire tibia, we identified the medial cortical line that runs parallel to the tibial anatomical axis and passes the medial tibial spine, and measured the point where the medial cortical line crosses between the medial malleolus and the lateral malleolus in the ankle joint. Results: The preoperative AP radiograph of the tibia showed the medial cortical line passing the point 40.4%+/-0.8% medial to the distance from the medial malleolus to the lateral malleolus including the skin thickness in the ankle joint. When the proximal tibial resection was performed with the extramedullary tibial cutting guide aligned with the medial cortical line, the tibial component angle averaged 0.7 degrees +/-0.3 degrees varus and the alignment accuracy of the tibial component within 0 degrees +/-3 degrees varus amounted to 97.0%. Conclusions: The use of the medial cortical line in proximal tibial resection with an extramedullary tibial cutting guide allowed for relatively accurate alignment of the tibial component. PMID- 28854765 TI - Tomographic Study of Femoral Positioning in Anterior Cruciate Ligament Reconstruction Using the Transtibial Technique. AB - Purpose: To analyze the location of the femoral tunnel by three-dimensional computed tomography (3D CT) of the lateral condyle in patients who underwent arthroscopic single-bundle anterior cruciate ligament (ACL) reconstruction, performed using a modified transtibial technique, and to compare the results with data from the literature. Materials and Methods: Seventeen patients with ACL lesions underwent modified transtibial ACL reconstruction. Postoperatively, 3D CT examinations were performed and the images were analyzed by the quadrant system described by Bernard and Hertel to define the femoral tunnel coordinates. Results: The mean value of femoral tunnel location coordinates was 37.1+/-5.9 in the horizontal plane and 23.9+/-7.5 in the vertical plane. Compared with other studies using the transtibial or transportal technique, femoral positioning was improved in the vertical plane. The outside-in technique provided the best results both in the vertical and horizontal planes. Conclusions: The modified transtibial technique was not effective for systematically anatomic femoral tunnel positioning; however, it was relatively better than the conventional transtibial technique. PMID- 28854766 TI - One-Year Serial Follow-up Magnetic Resonance Imaging Study of RigidFix for Femoral Fixation in Anterior Cruciate Ligament Reconstruction. AB - Purpose: To assess graft slippage at the site of femoral fixation by follow-up magnetic resonance imaging (MRI) after anterior cruciate ligament (ACL) reconstruction with a four-strand autogenous hamstring tendon using RigidFix (DePuy Mitek). Materials and Methods: Twenty-one subjects diagnosed with ACL rupture underwent ACL reconstruction using hamstring autograft with the transtibial technique. RigidFix was used for femoral fixation and Intrafix and washer screw were used for tibial fixation. Follow-up MRIs were taken immediately after surgery and at 1, 3, 6, and 12 months after surgery. Slippage of the graft and breakage of the RigidFix cross-pin were assessed. Side-to-side difference (SSD) on stress radiographs was measured to assess residual laxity. Results: Mean slippage of the graft was 0.21+/-0.31 mm at one year after surgery. Cross-pin breakage was noted in two subjects: in one subject, immediately after surgery and in the other subject, at 6 months after surgery. Mean SSD was 1.32+/-1.07 mm at the last follow-up. The correlation coefficient between graft slippage and SSD was 0.131 (p=0.571). Conclusions: RigidFix is a stable fixation device for hamstring autograft with minimally statistically significant but clinically insignificant graft slippage. Cross-pin breakage did not affect the clinical outcomes. Careful preparation of the graft is needed for performing the technique correctly. PMID- 28854767 TI - Open Reduction and Internal Fixation of Isolated Posterior Cruciate Ligament Avulsion Fractures: Clinical and Functional Outcome. AB - Purpose: The posterior cruciate ligament (PCL) presents commonly with avulsion fractures of its tibial attachment. An avulsion fracture of the PCL, if not surgically fixed, may lead to secondary changes in the knee joint. Various fixation techniques have been explored with use of lag screws, steel wires, absorbable screws, suture anchors and straddle nails. The purpose of this study was to evaluate the clinical and functional outcome of open reduction and internal fixation of tibial avulsion injuries of the PCL using cannulated cancellous screws. Materials and Methods: We performed open reduction and internal fixation using cannulated cancellous screws in 14 patients (mean age, 33.9 years) with isolated PCL avulsion injuries. Patients with a duration of injury more than 12 weeks were excluded. The minimum follow-up period was 12 months. Results were assessed radiologically and clinically. Final functional outcome was assessed using the Lysholm knee scoring system. Results: The average follow-up period was 13.5 months. At the final follow-up, all 14 patients achieved fracture union. The average flexion was 121.7 degrees +/-9.2 degrees with full extension achieved in all patients. Mild instability (1+) was noted in 4 patients. The Lysholm functional score was excellent in 11 patients, good in 2 patients and fair in 1 patient with an average score of 97+/-7.6. Conclusions: Stable early fixation for PCL avulsion injuries with early controlled mobilization provided excellent to good results. However, fixation should not be discouraged for late-presenting patients because good to fair results can be achieved in such cases. PMID- 28854768 TI - Efficacy of JOINS on Cartilage Protection in Knee Osteoarthritis: Prospective Randomized Controlled Trial. AB - Purpose: In this study, we compared the clinical efficacy of JOINS (SKI306X, SK Chemicals) with placebo on cartilage protection using magnetic resonance imaging (MRI). Materials and Methods: Sixty-nine patients were randomized to the JOINS group (200 mg, three times daily for 1 year; n=33) or the placebo group (n=36). Changes in cartilage volume and thickness were measured using MRI. Changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index, subchondral bone marrow abnormality scores, and clinical scores including knee pain visual analog scale (VAS) score and Korean Western Ontario and McMaster Universities Osteoarthritis Index (K-WOMAC) were also evaluated. Results: Changes in cartilage thickness and volume and subarticular bone marrow abnormality scores were not different between groups. Changes in the dGEMRIC index in the lateral tibial plateau were greater in the JOINS group than in the placebo group (19.64+/-114.33 msec vs. -57.77+/-123.30 msec; p=0.011). Significantly greater changes in VAS were observed in the JOINS group than in the placebo group (-26.00+/-12.25 vs. 12.47+/-21.54; p=0.002) and K-WOMAC (-15.42 +/- 7.73 vs. -8.15+/-13.71; p=0.003). Conclusions: Compared with placebo, JOINS had superior clinical efficacy in regard to cartilage protection. PMID- 28854769 TI - Comparison of Mechanical Axis and Dynamic Range Assessed with Weight Bearing Radiographs and Navigation System in Closed Wedge High Tibial Osteotomy. AB - Purpose: To compare navigation and weight bearing radiographic measurements of mechanical axis (MA) before and after closed wedge high tibial osteotomy (HTO) and to evaluate post-osteotomy changes in MA assessed during application of external varus or valgus force. Materials and Methods: Data from 30 consecutive patients (30 knees) who underwent computer-assisted closed-wedge HTO were prospectively analyzed. Pre- and postoperative weight bearing radiographic evaluation of MA was performed. Under navigation guidance, pre- and post osteotomy MA values were measured in an unloaded position. Any change in the post osteotomy MA in response to external varus or valgus force, which was named as dynamic range, was evaluated with the navigation system. The navigation and weight bearing radiographic measurements were compared. Results: Although there was a positive correlation between navigation and radiographic measurements, the reliability of navigation measurements of coronal alignment was reduced after osteotomy and wedge closing. The mean post-osteotomy MA value measured with the navigation was 3.5 degrees +/-0.8 degrees valgus in an unloaded position. It was 1.3 degrees +/-0.8 degrees valgus under varus force and 5.8 degrees +/-1.1 degrees valgus under valgus force. The average dynamic range was >+/-2 degrees . Conclusions: Potential differences between the postoperative MAs assessed by weight bearing radiographs and the navigation system in unloaded position should be considered during computer-assisted closed wedge HTO. Care should be taken to keep the dynamic range within the permissible range of alignment goal in HTO. PMID- 28854770 TI - Closed Wedge Distal Femoral Osteotomy with a Polyaxial Locking Plate Designed for the Proximal Tibia: Minimum 5-Year Outcomes. AB - Since distal femoral varus osteotomy (DFO) -specific plates had not been available in Japan before 2015, we performed DFO using a plate for tibia. The purpose of this study was to elucidate the efficacy and problems associated with the non-specific plate in DFO. We used NCB-PT plates (Zimmer Inc.) in the upside down position and the minimum 5-year outcomes were evaluated. The mean preoperative weight bearing line ratio and Japanese Orthopaedic Association score improved from 97.6%+/-35.8% and 68.0+/-11.5, respectively, to 44.0%+/-16.1% and 82.0+/-7.6, respectively, 1 year postoperatively and to 42.8%+/-15.7% and 86.0+/ 8.2, respectively, 5 years postoperatively. The flexion range decreased from 149.0 degrees +/-6.5 degrees to 138.0 degrees +/-5.7 degrees 1 year postoperatively and to 135.0 degrees +/-20.9 degrees 5 years postoperatively. Although DFO using the NCB-PT plate provided mid-term benefits, it resulted in a loss of knee flexion, possibly due to excessive coverage of the medial femoral epicondyle. PMID- 28854771 TI - Discoid Medial Meniscus Tear, with a Literature Review of Treatments. AB - The present study reports our experience of treating four cases of symptomatic discoid medial meniscus, three of which were bilateral. We performed partial meniscectomy with a four-portal technique using a knife leaving a 6 mm peripheral margin after confirmation of magnetic resonance imaging findings. Clinical results were assessed at the end of 2-year follow-up using the Knee Injury and Osteoarthritis Outcome Score and a visual analogue scale. We obtained satisfactory clinical results without recurrence of the symptoms in all cases. PMID- 28854772 TI - Usefulness of Endoscopic Transpapillary Tissue Sampling for Malignant Biliary Strictures and Predictive Factors of Diagnostic Accuracy. AB - BACKGROUND/AIMS: It is sometimes difficult to distinguish between malignant and benign biliary strictures using imaging studies alone, and pathological diagnosis is necessary. The aim of this study was to determine the usefulness of endoscopic transpapillary tissue sampling and factors predictive of diagnostic accuracy. METHODS: From April 2008 to December 2014, 136 patients underwent endoscopic transpapillary tissue sampling for malignant biliary strictures. The cytological and histological findings were reported as negative, suspicious, or positive. Suspicious and positive findings were defined as pathologically positive. RESULTS: The sensitivity was 65.0% for forceps biopsy, 49.5% for brush cytology, 46.2% for bile aspiration cytology, and 21.9% for endoscopic nasobiliary drainage cytology. The combination of these procedures improved the sensitivity (72.8%). Endoscopic transpapillary tissue sampling was more sensitive for lesions of biliary origin (91.4%) than for extrabiliary lesions (66.3%). In surgical cases, the sensitivity for tumors with an infiltrative growth pattern (53.3%) was significantly lower than for a tumor with an expanding or intermediate growth pattern (87.5%). CONCLUSIONS: Combining procedures can improve diagnostic accuracy. It may be possible to predict the sensitivity of endoscopic transpapillary tissue sampling by evaluating the etiology and tumor growth pattern using preoperative imaging studies. PMID- 28854773 TI - Bile Duct Patency Maintained after Intraductal Radiofrequency Ablation in a Case of Hepatocellular Cholangiocarcinoma with Bile Duct Invasion. AB - Combined hepatocellular-cholangiocarcinoma (HCC-CC) with bile duct invasion (BDI) is rare. In unresectable cases, biliary stent placement and photodynamic therapy (PDT) are used for resolving obstructive jaundice. However, stent occlusion remains problematic, and PDT is expensive and time-consuming. Intraductal radiofrequency ablation (RFA) is an emerging procedure for palliation in these patients. It has potential benefits including less expense, lower rates of severe complication, longer maintenance of ductal patency, and easier technique compared with PDT or stenting alone. We report a 67-year-old man who underwent repeated intraductal RFA for HCC-CC and HCC with BDI, for whom bile duct patency was maintained without additional biliary procedures. PMID- 28854774 TI - A Rare Case of Early Gastric Cancer Combined with Underlying Heterotopic Pancreas. AB - Heterotopic pancreas in the stomach is usually asymptomatic and benign. Here, we presented a rare case of an early gastric cancer overlying a heterotopic pancreas. A 48-year-old woman underwent esophagogastroduodenoscopy, which revealed a subepithelial mass measuring 2.0*1.5 cm on the gastric antrum with a 1 cm erosive erythematous discoloration on the surface. A biopsy specimen showed moderately differentiated tubular adenocarcinoma. Endosonography showed a heterogeneous hypoechoic mass measuring 1.3*0.6 cm, with indistinct margins in the second and third layers of the gastric wall; anechoic tubular structures within the mass were suggestive of heterotopic pancreas. Distal gastrectomy was performed, which confirmed an early gastric cancer confined to the mucosa, and a separate underlying heterotopic pancreas. Although heterotopic pancreas is most likely benign, careful endoscopic observation of the mucosal surface is necessary to avoid overlooking a coincident early gastric cancer. PMID- 28854776 TI - Corrigendum. AB - [This corrects the article on p. 933 in vol. 18.]. PMID- 28854777 TI - Corrigendum. AB - [This corrects the article on p. 1080 in vol. 18.]. PMID- 28854775 TI - Gastrocolocutaneous Fistula: An Unusual Case of Gastrostomy Tube Malfunction with Diarrhea. AB - A gastrocolocutaneous fistula is a rare complication of percutaneous endoscopic gastrostomy (PEG). We report a case of a gastrocolocutaneous fistula presenting with intractable diarrhea and gastrostomy tube malfunction. A 62-year-old woman with a history of multiple system atrophy was referred to us because of PEG tube malfunction. Twenty days prior to presentation, the patient started developing sudden diarrhea within minutes after starting PEG feeding. Fluoroscopy revealed that the balloon of the PEG tube was located in the lumen of the transverse colon with the contrast material filling the colon. Subsequently, the PEG tube was removed and the opening of the gastric site was endoscopically closed using hemoclips. Clinicians should be aware of gastrocolocutaneous fistula as one of the complications of PEG insertion. Sudden onset of diarrhea, immediately after PEG feedings, might suggest this complication, which can be effectively treated with endoscopic closure. PMID- 28854778 TI - Nocturnal leg symptoms are not associated with specific patterns of superficial venous insufficiency. AB - BACKGROUND: Certain nocturnal symptoms such as leg cramping (LC) and restless leg symptoms (RLS) are found in patients with venous disease. This study investigates the relationship between nocturnal symptoms and anatomic locations of superficial venous insufficiency. METHODS: A retrospective review of 371 consecutive patients presenting to a venous disease practice over a 1-year period was conducted. Patients underwent comprehensive assessment including standardized duplex scans. Superficial venous disease was classified by anatomic location (great saphenous vein [GSV], small saphenous vein [SSV], tributaries). Information on patient symptoms was obtained from questionnaires and patient interviews. RESULTS: Most patients in the cohort were female (315/371, 85%) with an average age of approximately 56 years. The 56 men had an average age of 63.2. Nearly all patients (92%) had findings of superficial venous reflux with the anatomic site of involvement as follows: GSV (51%), SSV (16%), and tributaries (33%). Thirty two percent of patients experienced LC and 16% experienced RLS. The patterns of reflux did not differ between patients with nocturnal symptoms compared to those without nocturnal symptoms. Nine percent of patients with nocturnal symptoms had no evidence of venous disease. Of those patients with LC, 76% had reflux in the GSV, 48% had reflux in the SSV, and 92% had reflux in at least one segment of the superficial venous system. Of those patients with RLS, 78% had reflux in the GSV, 35% had reflux in the SSV, and 87% had reflux in at least one segment of the superficial venous system. CONCLUSIONS: No significant difference was detected between patterns of superficial venous reflux in patients with nocturnal symptoms compared to those without nocturnal symptoms. In addition, the presence of nocturnal symptoms does not predict a specific pattern of disease. Future studies are needed to determine whether correction of the main truncal disease is sufficient or if ablation of both the truncal and tributary veins is necessary for alleviation of nocturnal symptoms. PMID- 28854779 TI - Patients' opinions regarding research and management of abdominal aortic aneurysms. AB - BACKGROUND: The epidemiology of abdominal aortic aneurysm (AAA) is changing. Outcomes for aortic surgery have improved. Biomarkers of AAA progression are emerging. We recently reported the opinions of international vascular surgery colleagues regarding research and management for AAAs. This study aimed to ascertain a real-world patients' opinion regarding the same questions. METHODS: We administered a survey to patients with AAAs. We first ascertained their views on the priority topics for research in AAA. Using contemporary epidemiologic and surgical outcome data. We asked their preferences for different aspects of management in the hypothetical scenario where they had been diagnosed with a small (4 cm) AAA and a hypothetical biomarker predicted it to be fast growing. RESULTS: We received 191 responses from patient with AAAs (males 91%, median-age group 75-79 years). Amongst the topics of research for AAA, the top priorities for research chosen by patients were: "discovering why AAA develops in a person" and "discovering new medications that can make an AAA shrink back to normal size". In the hypothetical scenario, 42% of patients would prefer to have surgery early, while they are younger and fitter. Fifty-two percent would follow the surgeon's recommendation as to whether to have early surgery or not. A high proportion of respondents would likely consider taking part in a clinical trial to test if early surgery in such a scenario will be beneficial. CONCLUSIONS: The results represent a snapshot of patient's views in terms of priorities for AAA research. We further demonstrate how patient's opinions can signpost the potential path for biomarker research to impact clinical practice. PMID- 28854780 TI - More on carotid atherosclerosis and ezetimibe. PMID- 28854782 TI - Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines. AB - Enantiopure 4-formyl-beta-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1 hydroxyethyl)azetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the beta-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45 99%) and high diastereoselectivities (dr >99/1, 1H NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF3-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system. PMID- 28854781 TI - Molecular analysis of alternative transcripts of equine AXL receptor tyrosine kinase gene. AB - OBJECTIVE: Since athletic performance is a most importance trait in horses, most research focused on physiological and physical studies of horse athletic abilities. In contrast, the molecular analysis as well as the regulatory pathway studies remain insufficient for evaluation and prediction of horse athletic abilities. In our previous study, we identified AXL receptor tyrosine kinase (AXL) gene which was expressed as alternative spliced isoforms in skeletal muscle during exercise. In the present study, we validated two AXL alternative splicing transcripts (named as AXLa for long form and AXLb for short form) in equine skeletal muscle to gain insight(s) into the role of each alternative transcript during exercise. METHODS: We validated two isoforms of AXL transcripts in horse tissues by reverse transcriptase polymerase chain reaction (RT-PCR), and then cloned the transcripts to confirm the alternative locus and its sequences. Additionally, we examined the expression patterns of AXLa and AXLb transcripts in horse tissues by quantitative RT-PCR (qRT-PCR). RESULTS: Both of AXLa and AXLb transcripts were expressed in horse skeletal muscle and the expression levels were significantly increased after exercise. The sequencing analysis showed that there was an alternative splicing event at exon 11 between AXLa and AXLb transcripts. 3-dimentional (3D) prediction of the alternative protein structures revealed that the structural distance of the connective region between fibronectin type 3 (FN3) and immunoglobin (Ig) domain was different between two alternative isoforms. CONCLUSION: It is assumed that the expression patterns of AXLa and AXLb transcripts would be involved in regulation of exercise-induced stress in horse muscle possibly through an NF-kappaB signaling pathway. Further study is necessary to uncover biological function(s) and significance of the alternative splicing isoforms in race horse skeletal muscle. PMID- 28854783 TI - Anthropogenic and Naturally Produced Brominated Phenols in Pet Blood and Pet Food in Japan. AB - Present study determined concentrations and residue patterns of bromophenols (BPhs) in whole blood samples of pet cats and pet dogs collected from veterinary hospitals in Japan. BPhs concentrations were higher in cat blood than in dog blood, with statistically insignificant differences (p = 0.07). Among the congeners, 2,4,6-tribromophenol (TBPh) constituted the majority of BPhs (>90%) detected in both species. Analysis of commercial pet food to estimate exposure routes showed that the most abundant congener in all pet food samples was 2,4,6 TBPh, accounting for >99% of total BPhs. This profile is quite similar to the blood samples of the pets, suggesting that diet might be an important exposure route for BPhs in pets. After incubation in polybrominated diphenyl ether (PBDE) mixtures (BDE-47, BDE-99 and BDE-209), 2,4,5-TBPh was found in dog liver microsomes but not in cat liver microsomes, implying species-specific metabolic capacities for PBDEs. Formation of 2,4,5-TBPh occurred by hydroxylation at the 1' carbon atom of the ether bond of BDE-99 is similar to human study reported previously. Hydroxylated PBDEs were not detected in cats or dogs; therefore, diphenyl ether bond cleavage of PBDEs can also be an important metabolic pathway for BPhs formation in cats and dogs. PMID- 28854784 TI - Determination of Sulfonamides in Chicken Muscle by Pulsed Direct Current Electrospray Ionization Tandem Mass Spectrometry. AB - A simple and rapid approach for the simultaneous detection of trace amounts of six sulfonamides in chicken muscle was developed using pulsed direct current electrospray ionization tandem mass spectrometry (pulsed-dc ESI-MS/MS). The pretreatment of chicken muscle samples consisted of two steps: acetonitrile extraction and n-hexane delipidation. Sulfonamides do not need to be derivatized or chromatographed prior to pulsed-dc ESI-MS/MS. The factors affecting the performance of pulsed-dc ESI-MS/MS were studied. Under optimum conditions, the quantitative performance of pulsed-dc ESI-MS/MS was validated according to European Union Decision 2002/657/EC, and the sensitivity of pulsed-dc ESI-MS/MS was 3 times higher than that of ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The limits of detection obtained by pulsed dc ESI-MS/MS were in the range of 0.07-0.11 MUg/kg. The proposed method was simple, rapid, and sensitive, and was successfully used for quantitation and rapid screening of sulfonamides in real chicken muscle samples. PMID- 28854785 TI - Direct Contact Sorptive Extraction: A Robust Method for Sampling Plant Volatiles in the Field. AB - Plants produce volatile organic compounds (VOCs) with diverse structures and functions, which change in response to environmental stimuli and have important consequences for interactions with other organisms. To understand these changes, in situ sampling is necessary. In contrast to dynamic headspace (DHS), which is the most often employed method, direct contact sampling employing a magnetic stir bar held in place by a magnet eliminates artifacts produced by enclosing plant materials in glass or plastic chambers. Direct-contact sorptive extraction (DCSE) using polydimethylsiloxane coated stir bars (Twisters) coated stir bars is more sensitive than DHS, captures a wider range of compounds, minimizes VOC collection from neighboring plants, and distinguishes the effects of herbivory in controlled and field conditions. Because DCSE is relatively inexpensive and simple to employ, scalability of field trials can be expanded concomitant with increased sample replication. The sensitivity of DCSE combined with the spectral deconvolution data analysis software makes the two ideal for comprehensive, in situ profiling of plant volatiles. PMID- 28854786 TI - Determining the limit of detection of surface bound antibody. AB - Determination of a limit of detection (LoD) for surface bound antibodies is crucial for the development and deployment of sensitive bioassays. The measurement of very low concentrations of surface bound antibodies is also important in the manufacturing of pharmaceutical products such as antibody conjugated pharmaceuticals. Low concentrations are required to avoid an immune response from the target host. Enzyme-linked immunosorbent assay (ELISA), x-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS) were used to determine the LoD for the surface bound antibody (antiepidermal growth factor receptor antibody) on silicon substrates. Antibody solution concentrations between 10 MUg/ml and 1 ng/ml and a control (antibody-free buffer solution) were employed, and the detection performance of each technique was compared. For this system, the ELISA LoD was 100 ng/ml and the XPS LoD was 1 MUg/ml, corresponding to an estimated surface concentration of 49 +/- 7 ng/cm2 using a 1 MUg/ml solution. Due to the multivariate complexity of ToF SIMS data, analysis was carried out using three different methods, peak ratio calculations, principal component analysis, and artificial neural network analysis. The use of multivariate analysis with this dataset offers an unbiased analytical approach based on the peaks selected from ToF-SIMS data. The results estimate a ToF-SIMS LoD between applied antibody concentrations of 10 and 100 ng/mL. For surface bound antibodies on a silicon substrate, the LoD is below an estimated surface concentration of 49 ng/cm2. The authors have determined the LoD for this system using ELISA, XPS, and ToF-SIMS with multivariate analyses, with ToF-SIMS offering an order of magnitude better detection over ELISA and 2 orders of magnitude better detection over XPS. PMID- 28854787 TI - Viral vaccine stabilizers: status and trends. AB - Vaccine stability is a key factor to preserve vaccine potency and efficiency, as its potency decays over time and during temperature changes. The choice of stabilizers for viral vaccine formulation depends mainly on the vaccine type. More specifically, the choice is determined by the properties and structure of the active pharmaceutical ingredient or viral antigen(s) in the vaccine. In this review, we analyze key formulation components in different vaccine types. We discuss some of the major driving forces in the improvement of vaccine thermostability: increasing demand for cost-effective production of thermostable vaccine with lower dependency on cold chain, stricter regulatory policies for animal-origin materials, and the return of the research investment from the industry point of view. Moreover, we provide an overview of existing licensed viral vaccine types, including their production platform, presentation, delivery route, known stabilizers content and available thermostability data. In addition, we compare the data of licensed vaccines to published experimental vaccines, in order to discuss the current trends in vaccine stabilizers development. PMID- 28854788 TI - To keep the host alive - the role of viral Bcl-2 proteins. AB - Apoptosis, an intrinsic cellular pathway that eliminates unwanted cells from multicellular organisms, represents an important mechanism for protection against viral infections. When cells infected by viruses get recognized by immune cells, apoptosis is triggered in the infected cells. Among the many regulators of apoptosis involved in this process, a family of proteins homologous to oncogene Bcl-2 plays a central role. Their concerted activities converge to permeabilization of mitochondrial membranes and activation of apoptotic pathways in the presence of diverse apoptotic signals, including virus infection. In the genomes of many viruses, genes encoding for homologues of antiapoptotic proteins of Bcl-2 family can be found. These proteins, collectively referred to as vBcl-2 proteins, inhibit apoptosis in infected cells at the different stages of virus life cycle to enable the virus to complete its replication and to spread. PMID- 28854789 TI - Detection and molecular characterization of tomato yellow leaf curl virus naturally infecting Lycopersicon esculentum in Egypt. AB - Tomato yellow leaf curl virus (TYLCV) infections of tomato crops in Egypt were widely spread in 2014. Infected symptomatic tomato plants from different governorates were sampled. TYLCV strains Israel and Mild (TYLCV-IL, TYLCV-Mild) were identified by multiplex and real-time PCR. In addition, nucleotide sequence analysis of the V1 and V2 protein genes, revealed ten TYLCV Egyptian isolates (TYLCV from TY1 to 10). Phylogenetic analysis showed their high degree of relatedness with TYLCV-IL Jordan isolate (98%). Here we have showed the complete nucleotide sequence of the TYLCV Egyptian isolate TY10, sampled from El Beheira. A high degree of similarity to other previously reported Egyptian isolates and isolates from Jordan and Japan reflect the importance of phylogenetic analysis in monitoring virus genetic diversity and possibilities for divergence of more virulent strains or genotypes. PMID- 28854790 TI - Neopterin and soluble CD14 levels as indicators of immune activation in cases with low anti-HCV reactivity and true HCV infection. AB - Neopterin and soluble CD14 (sCD14) are detected at high levels in hepatitis C virus (HCV) infections. We aimed to evaluate the role of these plasma immune activation biomarkers, for the indirect assessment of immune activation status of patients with low anti-HCV reactivity and a HCV infection. Low anti-HCV reactivity group (LRG, n: 70), true positive HCV infection group (THG, 30) and healthy control group (HCG, 30) were analyzed in this study. We have used ELISA, HCV RIBA/LIA and HCV-RNA methods. Mean neopterin levels were significantly lower in LRG than THG (p <0.001). In contrast, those values were not significantly different from those of HCG (p >0.05). Mean sCD14 were significantly higher in LRG than THG and HCG (p <0.05, p <0.001). Values of 3.95 MUg/ml and 5.36 nmol/l for sCD14 and neopterin resulted in the maximum area under the receiver operating characteristic curves (ROC), which were 0.859 (95% CI, 0.745 to 0.935; <0.0001) and 0.788 (95% CI, 0.663 to 0.883; <0.0001), respectively. These cut-offs corresponded to a sensitivity of 73.3% and a specificity of 73.3% for neopterin and of 100% and 76.7% for sCD14. Our results suggest that a specific immunoactivation might be caused by true positive HCV infection. Due to the significant results sCD14 in LRG might be non-specifically affected by some underlying atypical immunohematological pathologies. Only neopterin might be used to exclude low anti-HCV reactivity from a true HCV infection. The use of neopterin but not sCD14 in combination with fourth-generation EIA/CMIA combo tests will be useful when nucleic acid tests are not available for screening blood donors at blood banks. PMID- 28854791 TI - PCR-based approach for qualitative molecular analysis of six neurotropic pathogens. AB - In the last few years, polymerase chain reaction analysis is frequently required to improve the detection of pathogen infections in central nervous system as a potential cause of neurological disorders and neuropsychiatric symptoms. The goal of this paper is to set up a fast, cheap and reliable molecular approach for qualitative detection of six neurotropic pathogens. A method based on PCR has been designed and implemented to guarantee the qualitative DNA detection of herpes simplex virus types 1 and 2 (HSVI/II), Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), rubella virus (RUBV) and Toxoplasma gondii in the cerebrospinal fluid, where otherwise they are barely detectable. Each PCR assay was tested using dilutions of positive controls, which demonstrated a sensitivity allowing to detect up to 102 copies/ml in PCR and 10 copies/ml in real-time PCR for each pathogen. Once been set up, the protocol was applied to evaluate the cerebrospinal fluid from 100 patients with suspected infectious diseases of the central nervous system and 50 patients without any infection. The method allowed to identify 17 positive cerebrospinal fluid with polymerase chain reaction and 22 with real-time PCR (RT-PCR), respectively. Therefore, application of RT PCR allows a fast and sensitive evaluation of neurotropic DNA pathogens in the course of diagnostic routine within neurological units. PMID- 28854792 TI - Large protein as a potential target for use in rabies diagnostics. AB - Rabies is a zoonotic viral disease that remains a serious threat to public health worldwide. The rabies lyssavirus (RABV) genome encodes five structural proteins, multifunctional and significant for pathogenicity. The large protein (L) presents well-conserved genomic regions, which may be a good alternative to generate informative datasets for development of new methods for rabies diagnosis. This paper describes the development of a technique for the identification of L protein in several RABV strains from different hosts, demonstrating that MS-based proteomics is a potential method for antigen identification and a good alternative for rabies diagnosis. PMID- 28854793 TI - NSs protein of severe fever with thrombocytopenia syndrome virus suppresses interferon production through different mechanism than Rift Valley fever virus. AB - Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified Phlebovirus that causes severe fever with thrombocytopenia syndrome. Our study demonstrated that SFTSV NSs functioned as IFN antagonist mainly by suppressing TBK1/IKKepsilon-IRF3 signaling pathway. NSs interacted with and relocalized TANK binding kinase 1 (TBK1) into NSs-induced cytoplasmic structures and this interaction could effectively inhibit downstream phosphorylation and dimerization of interferon regulatory factor 3 (IRF3), resulting in the suppression of antiviral signaling and IFN induction. Functional sites of SFTSV NSs binding with TBK1 were then studied and results showed that NSs had lost their IFN-inhibiting activity after deleting the 25 amino acids in N-terminal. Furthermore, the mechanism of Rift Valley fever virus (RVFV) NSs blocking IFN-beta response were also investigated. Preliminary results showed that RVFV NSs proteins could neither interact nor co-localize with TBK1 in cytoplasm, but suppressed its expression levels, phosphorylation and dimerization of IRF3 in the subsequent steps, resulting in inhibition of the IFN-beta production. Altogether, our data demonstrated the probable mechanism used by SFTSV to inhibit IFN responses which was different from RVFV and pointed toward a novel mechanism for RVFV suppressing IFN responses. PMID- 28854794 TI - Cross-species hybridization of foot-and-mouth disease virus-infected BHK-21 cells using human and mouse oligonucleotide microarrays. AB - Foot-and-mouth disease virus (FMDV) has a dual capacity to induce either acute or persistent infection in host animals. Establishment of an in vitro cell model of FMDV persistent infection facilitates the study of the mechanism underlying this type of infection. In this study, we analyzed gene expression profiles of both acute and persistent infections using cross-species microarrays. Our data suggest that human microarrays are more efficient than mouse microarrays in hybridization with cDNA from BHK-21 cells although the mouse is closer to the Syrian hamster in taxonomy. A set of differentially expressed genes (DEGs) that may be involved in the determination of acute or persistent infection was identified by using human or mouse microarrays. Seven common DEGs were found in both human and mouse arrays and showed similar fold changes. Among the DEGs, 33 genes were selected for further validation by using qRT-PCR and presented consistent results. The analysis of Gene Ontology Biological Processes indicated that various biosynthetic and metabolic processes were negatively regulated in the group of acute infection whereas multicellular organismal development processes were positively regulated in the group of persistent infection. Our study demonstrates the plausibility and utility of using cross-species microarrays to study FMDV infected mammalian cells. The combined use of two types of microarrays can be more informative in exploring the mechanisms underlying the infections of FMDV. PMID- 28854795 TI - Herpes simplex viruses type 1 and 2 photoinactivated in the presence of methylene blue transform human and mouse cells in vitro. AB - Three strains of herpes simplex virus, K17syn- and HSZPsyn+ of type 1 (HSV-1) and USsyn- of type 2 (HSV-2), were photoinactivated in the presence of methylene blue and used to infect 3 cell lines, normal human lung tissue cells (MRC-5), mouse epithelial cells (NIH3T3), and human lung carcinoma cells (A549). The virus titer and phenotype of cells were evaluated to compare the characteristics of normal and carcinoma cells infected with non-syncytial (non-syn) and syncytial (syn) strains of herpes simplex viruses. We found that the cells of both normal cell lines infected with photoinactivated K17syn- and USsyn- but not HSZPsyn+ acquired transformed phenotype accompanied by the presence of virus. Surprisingly, the infection with photoinactivated viruses K17syn- and USsyn- but not HSZPsyn+ resulted in the suppression of the transformed phenotype of A549 cells. Using nested PCR, herpesviral DNA was identified in newly transformed cells and cells that lost the transformed phenotype. The effect of putative herpesvirus-related growth factors (HRGF) produced by cells infected with photoinactivated viruses was quantified and compared. Since methylene blue is currently used in phototherapy of herpetic lesions, these results raise the question of whether such therapy is risky to human health. PMID- 28854796 TI - Hepatitis C virus induces oxidative stress and DNA damage by regulating DNAPKCs, ATM, ATR and PARP mediated signaling and guards cell from cancerous condition by upregulating RB, P53 and downregulating VEGF. AB - Hepatitis C virus is responsible for liver damage and various metabolic disorders. HCV infections promote oxidative stress and cause damage to macromolecules. The aim of our study was to design a preliminary study with establishment of HCV genotype 3a infectivity assay in order to determine DNA damage in Huh-7 cell line at 72 hours post inoculation. Quantitative expression levels of COX-2 and GSR (oxidants and antioxidants), DNAPKCs, ATM, ATR and PARP (DNA damage and repair genes), RB and P53 (tumor suppressor genes) and VEGF (angiogenesis marker) were observed via real time PCR. Our findings revealed 1.533 fold upregulated expression of COX-2. The expression level of GSR was increased by1.27 fold and VEGF expression decreased by 0.367 fold. Thus, preventing cells to enter cancerous phase. PMID- 28854797 TI - Dynamics of the population structure and genetic variability within Iranian isolates of grapevine fanleaf virus: evidence for polyphyletic origin. AB - To determine the genetic diversity and population structure of grapevine fanleaf virus (GFLV), the complete nucleotide sequence of the coat protein gene of 41 isolates from different regions in Iran was determined. Phylogenetic analyses of these isolates together with those available in the GenBank revealed two evolutionary divergent lineages, designated GFLV-G and GFLV-Ir that reflect origin of the isolates. Analysis of the genetic variability in the coat protein of these isolates revealed 37 genotype groups in GFLV population. Analyses indicate that GFLV-G and GFLV-Ir clades are significantly differentiated populations of GFLV. Also, geographical subpopulations of the virus in Iran were completely distinct from each other. Examination of nonsynonymous/synonymous nucleotide diversity showed that the CP gene has been under purifying selection. The neutrality tests indicate balancing selection operating within isolates of the northwest of Iran and purifying selection within the other populations. PMID- 28854798 TI - RT-PCR detection of porcine reproductive and respiratory syndrome virus based on the ORF5 gene in mainland China, 2012-2015. AB - Between January 2012 and December 2015, 13,567 clinical samples were collected from healthy pigs and pigs with a history of respiratory symptoms and/or reproductive disorders in 29 provinces of mainland China to detect porcine reproductive and respiratory syndrome virus (PRRSV). From these samples, 7490 were PRRSV-positive (average value, 55.21%). The annual PRRSV detection rate from 2012 to 2015 for each year is 45.67%, 55.99%, 56.91%, and 59.07%, respectively. Phylogenetic analyses revealed that the percentage of highly pathogenic PRRSV strains had a decreasing yearly trend, whereas the vaccine-like strains showed the opposite trend during the years 2012-2015. These data indicate that while the vaccine contributes to PRRSV prevention in China, it might also lead to serious problems. Specifically, we identified 12 NADC30-like PRRSVs during the years 2014 2015, suggesting potential transmission of the newly emerged PRRSV strains in China. Our data contribute to new information about the epidemiology of PRRSV. PMID- 28854799 TI - Photodynamic Effect of some Phthalocyanines on Enveloped and Naked Viruses. AB - Activity of three photosensitizing phthalocyanine derivatives was tested for photodynamic inactivation towards two coated and two non-enveloped viruses - bovine viral diarrhea virus (BVDV), influenza virus A(H3N2), poliovirus type 1 (PV-1) and human adenovirus type 5 (HAdV5). In the case of coated viruses, a combination of virucidal and irradiation effects was registered by octa methylpyridyloxy-substituted Ga phthalocyanine (Ga8) toward BVDV, whereas tetra methylpyridyloxy-substituted Ga phthalocyanine (Ga4) revealed a marked photoinactivation only. No such effect was observed towards influenza A virus. In contrast, the photoinactivating potential of Ga4 and Ga8 marked very high values on naked viruses, especially on HAdV5, at which both the virucidal as well as the irradiation effects became combined. PMID- 28854800 TI - Workshop on Q fever. AB - no abstract Keywords: no keywords. PMID- 28854801 TI - RGB color coded images in scanning electron microscopy of biological surfaces. AB - We present here a methodological approach for the creation of color images in scanning electron microscopy by processing grayscale images taken simultaneously from at least three different detectors in a scanning electron microscope. The final color images are then produced by merging together those grayscale images in RGB color space. We show the images from non-conductive standard sample together with those obtained from real microbiological samples. The first one represents a microbial biofilm naturally grown on fiber glass filter. The other shows individual Bacillus subtilis cells from batch culture. All the image handling was done in open source image processing software ImageJ or GNU Image Manipulation Program (Gimp) or, alternatively, in proprietary AnalySis 3.2 Pro software processing suite. PMID- 28854802 TI - Meet interesting abbreviations in clinical mass spectrometry: from compound classification by REIMS to multimodal and mass spectrometry imaging (MSI). AB - This feature article discusses two modern mass spectrometry abbreviations in their clinical applications. Rapid evaporative ionization mass spectrometry (REIMS) is reported as a molecular classification tool useful for spectral features definition prior to mass spectrometry imaging (MSI). REIMS is appreciated not only as an ionization technique coupled with a surgical device but particularly as a biomarker discovery tool. For more complex understanding of pathological processes at cellular and molecular levels, the importance of multimodal approach in imaging applications is documented in the context of fiducial markers needed for hyperspectral data fusion collected by optical microscopy, elemental and molecular MSI. Finally, pathogen inactivation needed prior to the sectioning of the infected tissue is reported, and the impact of formaldehyde crosslinking to signal reduction is discussed. PMID- 28854803 TI - Protein composition of the phase I Coxiella burnetii soluble antigen prepared by extraction with trichloroacetic acid. AB - Q fever is a highly infectious, widespread airborne zoonosis caused by Coxiella burnetii bacterium. Humans usually acquire the disease by inhalation of contaminated aerosol produced by infected livestock. Vaccination is the most practical way for prevention and control of the disease in the exposed population. In this work, we reviewed the most important Q-fever outbreaks in Slovakia as well as the progress in vaccine development. One of them represents a soluble antigen complex produced by extraction with trichloroacetic acid from a highly purified C. burnetii phase I strain Nine Mile. It was developed at the Institute of Virology in Bratislava. The protein content of this vaccine was separated by gel electrophoresis and analyzed by mass spectrometry. The study has resulted in the identification of 39 bacterial proteins from which 12 were recognized as immunoreactive. Most of the proteins were involved in bacterium pathogenicity (41.6%) and cell wall maintenance (25%). Four of the immunoreactive proteins may possess the moonlighting activity. Definition of the vaccine components represents a prerequisite for vaccine standardization and approval by governmental authorities. PMID- 28854804 TI - Seroprevalence of Coxiella burnetii among domestic ruminants and horses in Poland. AB - Coxiella burnetii is the causative agent of Q fever. The cases of the disease are recorded in various species, including domestic animals. The aim of this investigation was to estimate the seroprevalence of C. burnetii in ruminants including cattle, sheep, goats, and horses. Totally, 2082 serum samples from 936 goats, 933 cattle, 89 sheep, and 124 horses, including various horse breeds, were tested by ELISA or complement fixation test. The examination revealed that Polish horses are seronegative while in the populations of cattle and small ruminants, seropositive animals are presented. The percentage of seropositive cattle, goats and sheep was 4.18, 6.30, and 13.48, respectively. PMID- 28854805 TI - Two mice models for transferability of zoonotic bacteria via tick vector. AB - Spotted fever and typhus-related diseases caused by rickettsiae, Lyme borreliosis induced by spirochetes from Borrelia burgdorferii sensu lato complex, and Q fever evoked by Coxiella burnetii, are important zoonoses occurring worldwide. In order to study the pathogenesis of these infections, the efficacy of vaccines from the perspective of protection against the pathogens, pathogen - pathogen interactions during co-infections or pathogen-vector-host interrelationship, a suitable animal model should be established. In this study, we evaluated two mouse models - the C3H/N and Balb/c strains for susceptibility to infection and ability to transmit the pathogens via tick vector and to reveal the potential interactions between various bacterial tick-borne agents. Our results indicated that the C3H/N and Balb/c mice are well-accepted models of B. afzelii infection. However, they are not suitable for interaction studies with R. helvetica since the animals did not acquire rickettsiemia and do not transmit Rickettsia sp. to feeding ticks. PMID- 28854806 TI - Coxiella burnetii immunogenic proteins as a basis for new Q fever diagnostic and vaccine development. AB - Coxiella burnetii is the etiological agent of the zoonosis Q fever, which can cause an acute or a chronic, life-threatening disease in humans. It presents a highly stable cell form, which persists in the environment and is transmitted via contaminated aerosols. Ruminants are considered as the main reservoir for human infections but are usually asymptomatic. Subclinical infection in these animals and the occurrence of serologically negative shedders hamper the identification of infected animals with the currently used diagnostic techniques. This suboptimal sensitivity limits reliable identification of infected animals as well as the well-timed implementation of countermeasures. This review summarizes compounds, focusing on C. burnetii seroreactive proteins, which were discovered in recent immunoproteomic studies. We analyzed these proteins regarding their localization, function, frequency of citation, differences seen in various host species as well as sensitivity and specificity. Finally, proteins useful for the development of new diagnostic test systems as well as subunit vaccines were discussed. PMID- 28854807 TI - Retention of doctors in rural health services in Thailand: impact of a national collaborative approach. AB - INTRODUCTION: Little evidence exists about the impact of strategies to increase rural retention in developing countries. To address Thailand's long-lasting critical shortage of doctors, two new government-funded projects to increase the production of rural doctors have been employed through collaboration between the Ministry of Education and the Ministry of Public Health (MOPH). The present study describes the impact of this national collaborative approach on production and retention of doctors in rural health services. METHODS: In addition to a conventional track of medical training, a special recruitment initiative, including two special projects, called the Collaborative Project to Increase Production of Rural Doctor and One District One Doctor, were launched in 1994 and 2005 respectively. This special recruitment initiative involves partnership between 14 universities and 37 accredited hospitals in the MOPH. Doctor retention in the MOPH health services up to 1 June 2016 was compared across the two training tracks using χ2 test. Factors associated with 3-year retention in the MOPH health services were identified using multiple logistic regression. RESULTS: The overall and year-by-year retention of medical graduates under the special recruitment track was higher than the normal track (overall retention of 78.2% and 52.5% respectively, p<0.05). Compared to their normal track counterparts, medical graduates under the special recruitment scheme were about 2.4-fold more likely to remain working in the MOPH health services for a minimum period of 3 years (odds ratio 2.44, 95% confidence interval 2.19-2.72). Among 4869 medical graduates under the special recruitment track who remained working for the MOPH, 4425 (90.9%) still worked in the provinces to which they were primarily assigned. CONCLUSIONS: A national collaborative approach to increasing production of rural doctors was effective at enhancing retention of doctors in rural areas. Challenges remain to overcome uneven cross-region doctor density and maldistribution. PMID- 28854808 TI - Thrombin Generation Profile in Patients With Steady State Peripheral Arterial Disease. PMID- 28854809 TI - Adherence to Antiretroviral Therapy in Turkey: Results from the ACTHIV-IST Study Group. AB - Maintaining optimal adherence to antiretroviral therapy (ART) is essential for optimizing the management of HIV infection. The aim of this study is to explore ART adherence rates in Turkey. Included in this study were a total of 263 HIV infected patients followed up by the ACTHIV-IST (ACTion against HIV in Istanbul) Study Group affiliated with four tertiary hospitals. The study population included patients 18 years of age or older who were on ART for over 12 months. Adherence was assessed by the medication possession ratio (MPR) calculated for each patient using data (a list of all drugs dispensed within the previous year for that patient) obtained from pharmacy medication records. In addition, patients completed a self-report questionnaire addressing missed doses and the AIDS Clinical Trials Group (ACTG) adherence questionnaire. The study was reviewed and approved by the Ethics Committee of Cerrahpasa Medical Faculty. Patient ages ranged from 19 to 71 years. Two hundred and thirty-one patients were male (88%). Two hundred and twenty-four patients (85%) had optimal adherence (MPR >=95%). During the course of ART, 236 patients (90%) reported no missed doses in the past 4 days of their treatment, whereas 206 patients (78%) reported no missed doses in the past month. Simply forgetting was the most common reason for nonadherence. MPR was associated with virologic rebound. Major factors affecting adherence were being female, taking antituberculosis drugs, having an opportunistic infection, being able to take all or most of the medication as directed, and being aware of the need to take medication exactly as instructed to prevent the development of drug resistance. Adherence to ART measured by MPR and self-report surveys is relatively high in Turkey when compared with other countries, which probably led to high ART success rates. PMID- 28854810 TI - Capsid Engineering of Adenovirus Vectors: Overcoming Early Vector-Host Interactions for Therapy. AB - Adenovirus-based vectors comprise the most frequently used vector type in clinical studies to date. Both intense lab research and insights from the clinical trials reveal the importance of a comprehensive understanding of vector host interactions. Especially for systemic intravenous adenovirus vector delivery, it is paramount to develop safe and efficacious vectors. Very early vector-host interactions that take place in blood long before the first cell is being transduced are phenomena triggered by the surface, shape, and size of the adenovirus vector particles. Not surprisingly, a multitude of different technologies ranging from genetics to chemistry has been developed to alter the adenovirus vector surface. In this review, we discuss the most important technologies and evaluate them for their suitability to overcome hurdles imposed by early vector-host interactions. PMID- 28854811 TI - The impact of perinatal loss in maternity units: A psycholinguistic analysis of health professionals' reactions. AB - Perinatal loss has a strong emotional impact on health professionals working in maternity units. We aimed to study the impact of this experience on health professionals' language. We analyzed the answers of 162 health professionals (physicians and non-medical staff) who described their reactions to perinatal loss. A linguistic analysis was performed using the Linguistic Inquiry and Word Count software. Associations between language and burnout were studied. Words typical of a psychological shock reaction were used more by non-medical staff than by physicians. Participants who used pronouns, optimistic words, future tense verbs, and cognitive words registered lower levels of burnout. Clinical implications of the results are discussed. PMID- 28854813 TI - Using public engagement and consultation to inform the development of ageing- and dementia-friendly pharmacies - Innovative practice. AB - This study explored public perceptions about the importance of, and how to create, ageing- and dementia-friendly pharmacists and pharmacies. In September 2016, four focus groups (45 minutes each) were conducted with 16 participants who represented organisations, groups or forums working with and/or for older people and people with dementia in Greater London. Discussions were recorded via handwritten notes and thematically analysed. Participants confirmed the importance of pharmacists and pharmacies being ageing- and dementia-friendly and described variability in whether this is currently the case. Suggested strategies for improvement included targeting communication, pharmacist leadership and shop layout. PMID- 28854812 TI - A Narrative Engagement Framework to Understand HPV Vaccination Among Latina and Vietnamese Women in a Planned Parenthood Setting. AB - Disparities in cervical cancer and human papillomavirus (HPV) vaccination persist among Vietnamese and Latina women. Through a partnership with Planned Parenthood of Orange and San Bernardino Counties (PPOSBC) in Southern California, we conducted in-depth interviews with young adult Latina ( n = 24) and Vietnamese ( n = 24) women, and PPOSBC staff ( n = 2). We purposively sampled vaccinated women to elicit HPV vaccine decision narratives to uncover rich data on motivators, cultural values, and implicit vaccine attitudes. Unvaccinated women were interviewed to identify barriers. Women were also asked to discuss their observations of men's HPV vaccine attitudes. Narrative engagement theory guided the study privileging the meaning women ascribed to their experiences and conversations related to vaccine decision making. Vaccine decision narratives included (a) mother-daughter narratives, (b) practitioner recommendation of HPV vaccination, (c) independence narratives among Vietnamese women, (d) HPV (un)awareness narratives, and (d) school exposure to HPV knowledge. Barriers to vaccinating included trust in partner HPV status, and family silence and stigma about sexual health. Participants conveyed the importance of including messages aimed at reaching men. Practitioners described insurance barriers to offering same day vaccination at PPOSBC health center visits. Narrative communication theory and methodology address health equity by privileging how Vietnamese and Latina women ascribe meaning to their lived experiences and conversations about HPV vaccination. Identifying authentic and relatable vaccine decision narratives will be necessary to effectively engage Vietnamese and Latina women. These findings will guide the process of adapting an existing National Cancer Institute research-tested HPV vaccine intervention. PMID- 28854815 TI - Robot-Assisted Versus Open Simple Prostatectomy for Benign Prostatic Hyperplasia in Large Glands: A Propensity Score-Matched Comparison of Perioperative and Short Term Outcomes. AB - OBJECTIVE: To report the largest comparative analysis of robotic vs open simple prostatectomy (OSP) for large-volume prostate glands. MATERIALS AND METHODS: We retrospectively reviewed 103 patients that underwent open and 64 patients that underwent robotic simple prostatectomy from 2012 to 2016 at a single institution. A propensity score-matched analysis was performed with five covariates, including age, body mass index, race, Charlson comorbidity index, and prostate volume. Perioperative, postoperative, and functional outcomes were compared between groups. RESULTS: After propensity score matching there were 59 patients in each group available for comparison. There was no statistically significant difference between groups for all preoperative demographic variables. Robotic compared with OSP demonstrated a significant shorter average length of stay (LOS) (1.5 vs 2.6 days, p < 0.001), but longer mean operative time (161 vs 93 minutes, p < 0.001). The robotic approach was also associated with a lower estimated blood loss (339 vs 587 mL, p < 0.001) and lower percentage hematocrit drop (12.3% vs 19.5%, p = 0.001). Two patients required blood transfusions in the robot group compared with four in the open group, but this was not significant (p = 0.271). Improvements in maximal flow rate, International Prostate Symptom Score, quality of life, postvoid residual, and postoperative prostate-specific antigen levels were similar before and after surgery for both groups, but there was no difference between groups. There was no difference in complications between groups. CONCLUSION: Robotic simple prostatectomy is a safe and effective treatment for the surgical management of benign prostatic hyperplasia. It provides similar function outcomes to the open approach; however, offers the advantage of reduced LOS and reduced blood loss. PMID- 28854814 TI - Function and Safety of Lentivirus-Mediated Gene Transfer for CSF2RA-Deficiency. AB - Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder of pulmonary surfactant accumulation and hypoxemic respiratory failure caused by mutations in CSF2RA (encoding the granulocyte/macrophage colony-stimulating factor [GM-CSF] receptor alpha-chain [CD116]), which results in reduced GM-CSF-dependent pulmonary surfactant clearance by alveolar macrophages. While no pharmacologic therapy currently exists for hPAP, it was recently demonstrated that endotracheal instillation of wild-type or gene-corrected mononuclear phagocytes (pulmonary macrophage transplantation [PMT]) results in a significant and durable therapeutic efficacy in a validated murine model of hPAP. To facilitate the translation of PMT therapy to human hPAP patients, a self-inactivating (SIN) lentiviral vector was generated expressing a codon-optimized human CSF2RA-cDNA driven from an EF1alpha short promoter (Lv.EFS.CSF2RAcoop), and a series of nonclinical efficacy and safety studies were performed in cultured macrophage cell lines and primary human cells. Studies in cytokine-dependent Ba/F3 cells demonstrated efficient transduction, vector-derived CD116 expression proportional to vector copy number, and GM-CSF-dependent cell survival and proliferation. Using a novel cell line constructed to express a normal GM-CSF receptor beta subunit and a dysfunctional alpha subunit (due to a function-altering CSF2RAG196R mutation) that reflects the macrophage disease phenotype of hPAP patients, it was demonstrated that Lv.EFS.CSF2RAcoop transduction restored GM-CSF receptor function. Further, Lv.EFS.CSF2RAcoop transduction of healthy primary CD34+ cells did not adversely affect cell proliferation or affect the cell differentiation program. Results demonstrate Lv.EFS.CSF2RAcoop reconstituted GM-CSF receptor alpha expression, restoring GM-CSF signaling in hPAP macrophages, and had no adverse effects in the intended target cells, thus supporting testing of PMT therapy of hPAP in humans. PMID- 28854816 TI - Carvedilol Inhibits Matrix Metalloproteinase-2 Activation in Experimental Autoimmune Myocarditis: Possibilities of Cardioprotective Application. AB - AIMS: Acute myocarditis is a potentially lethal inflammatory heart disease that frequently precedes the development of dilated cardiomyopathy and subsequent heart failure. At present, there is no effective standardized therapy for acute myocarditis, besides the optimal care of heart failure and arrhythmias in accordance with evidence-based guidelines and specific etiology-driven therapy for infectious myocarditis. Carvedilol has been shown to be cardioprotective by reducing cardiac pro-inflammatory cytokines present in oxidative stress in certain heart diseases. However, effects of carvedilol administration in acute myocarditis with its impact on matrix metalloproteinases' (MMPs) activation have not been elucidated. METHODS AND RESULTS: Carvedilol in 3 doses (2, 10, and 30 mg/kg) was given daily to 3 study groups of rats (n = 8) with experimental autoimmune myocarditis by gastric gavage for 3 weeks. In comparison to untreated rats (n = 8) with induced myocarditis, carvedilol significantly prevented the left ventricle enlargement and/or systolic dysfunction depending on the dose in study groups. Performed zymography showed enhanced MMP-2 activity in untreated rats, while carvedilol administration reduced alterations. This was accompanied by prevention of troponin I release and myofilaments degradation in cardiac muscle tissue. Additionally, severe inflammatory cell infiltration was detected in the nontreated group. Carvedilol in all doses tested, had no impact on severity of inflammation. The severity of inflammation did not differ between study groups and in relation to the untreated group. CONCLUSIONS: The protective effects of carvedilol on heart function observed in the acute phase of experimental autoimmune myocarditis seem to be associated with its ability to decrease MMP-2 activity and subsequently prevent degradation of myofilaments and release of troponin I while not related to suppression of inflammation. PMID- 28854817 TI - In vitro genotoxic and cytotoxic effects of doxepin and escitalopram on human peripheral lymphocytes. AB - Antidepressants are drugs used for the treatment of many psychiatric conditions including depression. There are findings suggesting that these drugs might have genotoxic, carcinogenic, and/or mutagenic effects. Therefore, the present in vitro study is intended to investigate potential genotoxic and cytotoxic effects of the antidepressants escitalopram (selective serotonin reuptake inhibitor) and doxepin (Tricyclic antidepressant) on human peripheral lymphocytes cytokinesis block micronucleus (CBMN), sister chromatid exchange (SCE), and single cell gel electrophoresis (alkaline comet assay) were used for the purpose of the study. In the study, four different concentrations of both drugs (1, 2.5, 5, and 10 ug/mL) were administered to human peripheral lymphocytes for 24 h. The tested concentrations of both drugs were found to exhibit no cytotoxic and mitotic inhibitory effects. SCE increase caused by 5 and 10 ug/mL of escitalopram was found statistically significant, while no statistically significant increase was observed in DNA damage and micronucleus (MN) formation. Moreover, the increase caused by doxepin in MN formation was not found statistically significant. Besides, 10 ug/mL of doxepin was demonstrated to significantly increase arbitrary unit and SCE formation. These findings suggest that the investigated concentrations of escitalopram and doxepin were non-cytotoxic but potentially genotoxic at higher concentrations. PMID- 28854818 TI - Recent Advances in Preclinical Developments Using Adenovirus Hybrid Vectors. AB - Adenovirus (Ad)-based vectors are efficient gene-transfer vehicles to deliver foreign DNA into living organisms, offering large cargo capacity and low immunogenicity and genotoxicity. As Ad shows low integration rates of their genomes into host chromosomes, vector-derived gene expression decreases due to continuous cell cycling in regenerating tissues and dividing cell populations. To overcome this hurdle, adenoviral delivery can be combined with mechanisms leading to maintenance of therapeutic DNA and long-term effects of the desired treatment. Several hybrid Ad vectors (AdV) exploiting various strategies for long-term treatment have been developed and characterized. This review summarizes recent developments of preclinical approaches using hybrid AdVs utilizing either the Sleeping Beauty transposase system for somatic integration into host chromosomes or designer nucleases, including transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease for permanent gene editing. Further options on how to optimize these vectors further are discussed, which may lead to future clinical applications of these versatile gene-therapy tools. PMID- 28854819 TI - Functionalised nanostructures for transdermal delivery of drug cargos. AB - Nanotechnology has burgeoned over last decade exploring varieties of novel applications in all areas of science and technology. Utilisation of bio-friendly polymers for engineering nanostructures (NS) improves safety and efficacy in drug delivery. Biopolymers not merely employed for fabricating drug carriers but also leveraged for surface functionalisation of other NS to impart bio-mimicking properties. Biopolymer functionalised NS garnered researcher's attention because of their potential to enhance skin permeability of drug cargo. Biopolymers, i.e. cell-penetrating peptides (CPP), chitosan and hyaluronic acid not only enhance skin permeability but also add multiple functions due to their intrinsic biomimetic properties. This multifunctional drug delivery system is a promising tool to achieve skin delivery of large number of therapeutic agents. In this review, functionalisation of NS with biopolymers particularly polysaccharides and polypeptides is discussed in detail. In particular, applications of these functionalised NS for TDDS is elaborated. Moreover, this review provides framework for elaborating importance of functionalisation of NS to enhance skin permeability and depicts advantages of biopolymers to construct more biocompatible carriers for drug cargos. PMID- 28854820 TI - Associations between social control, motivation, and exercise: How romantic partners influence exercise during young adulthood. AB - This study investigated whether positive and negative romantic partner social control attempts (persuasion and pressure, respectively) were related to approach avoidance motives and exercise among young adults ( N = 98), using daily reports. Daily persuasion was linked to higher daily approach motives. At the person level, persuasion was associated with higher approach and avoidance motives in addition to more frequent, longer exercise. Pressure was associated with higher daily relationship stress, which was associated with higher daily avoidance motives. At the person level, pressure was related to less frequent, shorter exercise. Thus, romantic partners' social control use correlates with exercise motives and behavior. PMID- 28854821 TI - Assessment of the cytotoxicity and genotoxicity properties of Uvaria chamae P. Beauv (Annonaceae) and Morinda lucida Benth (Rubiaceae) in mice. AB - The toxicity profile of medicinal plants is an important preclinical requirement in the development of phytomedicines. The cytotoxic and genotoxic effects of the leaf of Uvaria chamae P. Beauv (Annonaceae) and stem bark of Morinda lucida Benth (Rubiaceae) were investigated in order to provide information on their safety as antimalarial plants. The methanol extract of U. chamae and ethanol (70%) extract of M. lucida were separately orally administered (125, 250, and 750 mg/kg/day) to mice for 10 consecutive days. Cyclophosphamide (50 mg/kg, single dose) and distilled water were used as positive and negative controls, respectively. The mice were injected with colchicine (0.04%) intra-peritoneally 24 h after the last administration of the extracts and the bone marrows harvested. Giemsa-stained slides of bone marrow cells were microscopically assessed for dividing cells to determine the mitotic index (MI) and scored for chromosomal aberrations (CA) according to standard methods. chamae exhibited dose-dependent cytotoxicity. At 750 mg/kg, the MI was significantly (p < 0.05) lower (1.81 +/- 0.04) than that of cyclophosphamide (5.83 +/- 0.04). The lower the MI, the higher the cytotoxicity. The activity of M. lucida was not significantly different (p > 0.05) from that of the negative control. The total CA observed from treatment with both plants at all doses were significantly (p < 0.05) greater than that of control. This study concluded that U. chamae showed both cytotoxicity and genotoxicity while M. lucida exerted only genotoxic effect. Nevertheless, the two plants should be used with caution in antimalarial therapy. PMID- 28854823 TI - Addressing cultural diversity: the hepatitis B clinical specialist perspective. AB - OBJECTIVES: Hepatitis B is a viral infection primarily affecting people from culturally diverse communities in Australia. While vaccination prevents infection, there is increasing mortality resulting from liver damage associated with chronic infection. Deficits in the national policy and clinical response to hepatitis B result in a low diagnosis rate, inadequate testing and diagnosis processes, and poor access to hepatitis B treatment services. While research identifies inadequate hepatitis B knowledge among people with the virus and primary health care workers, this project sought to identify how specialist clinicians in Australia negotiate cultural diversity, and provide often complex clinical information to people with hepatitis B. DESIGN: A vignette was developed and presented to thirteen viral hepatitis specialist clinicians prior to an electronically recorded interview. Recruitment continued until saturation of themes was reached. Data were thematically coded into themes outlined in the interview schedule. Ethical approval for the research was provided by the La Trobe University Human Research Ethics Committee. RESULTS: Key messages provided to patients with hepatitis B by clinical specialists were identified. These messages were not consistently provided to all patients with hepatitis B, but were determined on perceptions of patient knowledge, age and highest educational level. While the vignette stated that English was not an issue for the patient, most specialists identified the need for an interpreter. Combating stigma related to hepatitis B was seen as important by the specialists and this was done through normalising the virus. Having an awareness of different cultural understandings about hepatitis B specifically, and health and well-being generally, was noted as a communication strategy. CONCLUSION: Key core competencies need to be developed to deliver educational messages to people with hepatitis B within clinical encounters. The provision of adequate resources to specialist clinics will assist in addressing gaps in the clinical response to hepatitis B. PMID- 28854822 TI - Health literacy is associated with health behaviour and self-reported health: A large population-based study in individuals with cardiovascular disease. AB - Background Health literacy may constitute a modifiable determinant of health behaviour and affect cardiovascular disease prevention. This study investigates the associations between health literacy and health behaviour as well as health status. Design A cross-sectional study on a population-based sample of people with acute myocardial infarction, angina pectoris or stroke ( N = 3116). Methods Health literacy was assessed using two dimensions from the Health Literacy Questionnaire: 'understanding health information' and 'engaging with healthcare providers'. Health behaviour included physical activity, dietary habits, smoking, alcohol consumption and body mass index. Health status was examined using Short Form Health Survey 12 version 2 (four-week recall) (physical and mental components). We used regression analyses to examine the associations. Results 'Understanding health information' was inversely associated with physical inactivity (odds ratio (OR) 0.48 (0.39;0.59), unhealthy diet (OR 0.64 (0.47;0.88)), underweight (OR 0.43 (0.21;0.89)) and obesity (OR 0.79 (0.63;0.99)). 'Engaging with healthcare providers' was inversely associated with physical inactivity (OR 0.64 (0.53;0.77)), less than healthy diet (OR 0.79 (0.64;0.96)) and daily smoking (OR 0.81 (0.66;1.0)). An increase in 'understanding health information' as well as 'engaging with healthcare providers' was associated with an increase in both physical and mental health status. Conclusions The findings suggest that aspects of health literacy are associated with health status and health behaviour in cardiovascular patients and should be considered in interventions regarding cardiovascular disease prevention. PMID- 28854825 TI - Are positron emission tomography-computed tomography (PET-CT) scans useful in preoperative assessment of patients with peritoneal disease before cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)? AB - INTRODUCTION: CRS and HIPEC confer survival benefit in selected patients with peritoneal metatases (PM). Accurate preoperative assessment of disease burden and exclusion of distant metastases are crucial in selecting the appropriate patient. We evaluate the utility of PET-CT scans in comparison with CT and MRI scans in patients considered for CRS and HIPEC. METHODS: Data were retrospectively collected from patients who had been discussed for CRS and HIPEC between January 2011 and December 2015, at our institutional multidisciplinary tumour board. Patients who underwent PET-CT scan were included. Results of PET-CT were compared against traditional imaging. Patient and tumour factors were analysed to identify those who were most likely to benefit from PET imaging. RESULTS: Four hundred and seven patients were considered for CRS and HIPEC. PET-CT was performed for 128(31.4%) patients: being the only imaging modality in 37 and used as an adjunct in 91. In the latter group, it was not beneficial in 58 patients as it provided no additional information (n = 33) or showed lesions of minimal FDG uptake (n = 25). In 33 patients, PET-CT provided definitive answers for indeterminate lesions seen on CT and MRI, confirmed the diagnosis of peritoneal disease in 10 patients (30.3%), identified extra-peritoneal disease and/or nodal metastases in 15 (45.5%) and excluded peritoneal disease in 8 (24.2%). The usefulness of PET-CT was predicted by tumour histology (p = .009), with non-mucinous tumours benefitting the most. CONCLUSION: Our results suggest that PET-CT can be used as an adjunct to CT and/or MRI scans, when lesions on the CT/MRI scans are indeterminate, and that it is most useful in patients with non-mucinous tumours. PMID- 28854824 TI - Promises and Challenges in Hematopoietic Stem Cell Gene Therapy. AB - Hematopoietic stem cell-directed gene therapy (HSC-GT) provides an innovative treatment option for hematological disorders. Gene therapy promises to cure the disease "at the root" and is therefore exceptional in its potential, but also formidable in its challenges, as long-term side effects are hard to predict and clinical experience remains limited. Many excellent reviews on the topic by designated experts in the field of HSC-GT have come forth, elucidating the successes and pitfalls in the various clinical studies. This review attempts to discuss what we understand from those studies to represent current state of the art with respect to vectors, stem cell transduction, and pretransplant preparatory regimes, what limitations may remain, and which types of diseases may be more suited for HSC-GT than others (targets). We thus discuss the available vector platforms (tools) and preclinical/clinical and basic research (tricks) that contribute to our current understanding of HSC-GT, as well as some overarching principles we can conclude from these. The field has also learned from previous shortcomings, although some of the major concerns of the past, specifically insertional mutagenesis, may not be of relevance for future trials. This very positive development in HSC-GT, however, has to compete with the improvements in hematopoietic stem cell transplantation or enzyme-replacement therapy, leaving a narrow margin for gene therapy. PMID- 28854826 TI - High-intensity focused ultrasound in the treatment of breast fibroadenomata (HIFU F trial). AB - BACKGROUND: High-intensity focussed ultrasound (HIFU) is a non-invasive ablative technique utilising the application of high frequency ultrasound (US) pressure waves to cause tissue necrosis. This emerging technology is currently limited by prolonged treatment times. The aim of the HIFU-F trial was to perform circumferential HIFU treatment as a means of shortening treatment times. METHODS: A prospective trial was set up to treat 50 consecutive patients >=18 years of age. Eligible patients possessed symptomatic fibroadenomata, visible on US. Patients >=25 years of age required histological confirmation of the diagnosis. Primary outcome measures were reduction in treatment time, reduction in volume on US after 12 months and complication rates. RESULTS: HIFU treatment was performed in 51 patients (53 treatments) with a mean age of 29.8 years (SD 7.2 years) and a diameter of 2.6 cm (SD 1.4 cm). Circumferential ablation reduced treatment times by an estimated 19.9 min (SD 25.1 min), which is a 29.4% (SD 15.2%) reduction compared with whole lesion ablation. Volume reduction of 43.2% (SD 35.4%; p < 0.005, paired t-test) was observed on US at 12 months post-treatment. Local complications completely resolved at 1 month apart from skin hyper-pigmentation, which persisted in nine cases at three months, six cases at 6 months and six at 12 months. CONCLUSION: Circumferential HIFU treatment for breast fibroadenomata is feasible to reduce both lesion size and treatment time. HIFU is a non-invasive alternative technique for the treatment of breast fibroadenomata. ISRCTN registration: 76622747. PMID- 28854827 TI - Translation and validation of the dizziness handicap inventory in Greek language. AB - OBJECTIVE: The aim of the study was to test the reliability and validity of the Dizziness Handicap Inventory in the Greek language (DHI). DESIGN: This study was performed in a university tertiary centre. Internal consistency was estimated using Cronbach's alpha for the DHI, physical (DHI-P), functional (DHI-F) and emotional (DHI-E) subscale scores. Correlation between DHI (total and subscales) and the SOT (sensory organisation test) as well as correlation between the DHI and FGA (functional gait assessment) was tested using Spearman's correlation coefficient. Test-retest reliability was tested using ICC (Intraclass Correlation Coefficient). SAMPLE SIZE: Ninety (90) patients were included in the study. RESULTS: Internal consistency was excellent for the total score and very good for the physical functional and emotional subscale scores. No statistically significant correlation was found between SOT and DHI. There was a moderate correlation between FGA and total DHI scores (r = -0.472; p < 0.0001) and poor to moderate between FGA and DHI subscale scores (DHI-E r1 = -0.342; p1 = 0.001, DHI F r2 = -0.448 p2 < 0.0001, DHI-P r3 = -0.472 p3 < 0.0001). Test-retest reliability was excellent. CONCLUSION: Greek version of DHI is recommended as a valid measure for patients with vestibular disorders. PMID- 28854828 TI - Laser-assisted indocyanine green angiography in implant-based immediate breast reconstruction: a retrospective study. AB - OBJECTIVE: Necrosis in implant-based immediate breast reconstruction is a feared complication. Accurate evaluation of mastectomy skin flaps per-operatively is necessary to decrease this risk. The present study is the first in Scandinavia to review the effects of perioperative evaluation with laser-assisted indocyanine green fluorescence angiography (LA-ICGA). METHOD: A retrospective review was performed using data from the electronic patient record at the Department of Plastic and Breast Surgery at Aarhus University Hospital in Denmark on all patients who underwent implant-based skin-sparing immediate breast reconstruction with ADM in the time period March 2012 to October 2015. A total of 92 patients undergoing 128 breasts reconstructions were included in the study. An evaluation of complications before and after the implementation of LA-ICGA was performed. RESULTS: No significant difference in necrosis rates requiring surgical revision (p = .411) or conservative treatment (p = .149) in patients undergoing implant based immediate breast reconstruction were found. CONCLUSION: Our results differ from previously published studies in that no beneficial effect on necrosis rates of was found after implementing LA-ICGA, possibly due to our limited sample size. PMID- 28854830 TI - Corrigendum. PMID- 28854829 TI - Profile of the ProAxsis active neutrophil elastase immunoassay for precision medicine in chronic respiratory disease. AB - INTRODUCTION: Neutrophil elastase (NE) is a 29kDa serine protease released from the azurophilic granules of neutrophils. It may be directly involved in the pathogenesis and disease progression in cystic fibrosis, bronchiectasis and COPD through the degradation of airway elastin and by impairing host defence. Areas covered: Measurement of NE activity has emerged as a promising biomarker strategy in inflammatory lung disease. The authors review studies where NE activity has been linked with clinical outcomes such as lung function decline, exacerbation frequency or other cross-sectional and longitudinal markers of disease severity. In this article the evidence for NE measurement, and the strengths and weaknesses of a commercially available immunoassay which can specifically detect NE activity in human biological samples such as sputum and bronchoalveolar lavage are reviewed. Expert commentary: NE is a promising biomarker for stratifying severity disease. NE also appears to be responsive to antibiotic and other treatments, potentially therefore allowing it to be used as an indicator of treatment response in clinical trials. PMID- 28854831 TI - Autoimmune diseases induced by biological agents. A review of 12,731 cases (BIOGEAS Registry). AB - INTRODUCTION: Biological drugs are therapies designed to target a specific molecule of the immune system that have been linked with the development of autoimmune diseases. Areas covered: The BIOGEAS Registry currently collects information about nearly 13,000 reported cases of autoimmune diseases developed in patients exposed to biologics, including more than 50 different systemic and organ-specific autoimmune disorders, of which psoriasis (n=6375), inflammatory bowel disease (n=845), demyelinating CNS disease (n=803), interstitial lung disease (n=519) and lupus (n=369) were the most frequently reported. The main biologics involved were anti-TNF agents in 9133 cases (adalimumab in 4154, infliximab in 3078 and etanercept in 1681), immune checkpoint inhibitors in 913 (ipilimumab in 524 and nivolumab in 225), B-cell targeted therapies in 741 (rituximab in 678), and growth factor inhibitors in 549 cases (bevacizumab in 544). Even though targeting a particular immune molecule may be associated with an excellent clinical response in most patients, an unexpected autoimmune disease may arise in around 8 out of 10,000 exposed patients. Expert opinion: Following the increased use of biologics, the number and diversity of induced autoimmune diseases is increasing exponentially. Management of these disorders will be an increasing clinical challenge in the daily practice in the next years. PMID- 28854832 TI - Pharmacokinetic drug evaluation of dolutegravir plus rilpivirine for the treatment of HIV. AB - INTRODUCTION: The search for simple, potent, metabolic-friendly and nucleoside/nucleotide sparing antiretroviral regimens has led clinical investigators to move steps towards dual therapies. Among these the association of rilpivirine and dolutegravir is emerging as a twin randomized clinical trial (SWORD1&2) and at least three observational cohort describe it as a safe and highly effective regimen for switch from other therapies Areas covered: We review the evidence supporting the use of dolutegravir plus rilpivirine for the treatment of HIV in virologically suppressed patients taking other antiretroviral regimens. The reasons for the switch in clinical practice may range from simplification to tolerability/toxicity issues, to the prevention of future metabolic damage, to predicted drug-drug interactions when treatment of HCV co infection is planned. Articles searchable on MEDLINE/PubMed and from the main international congresses in the field of HIV therapy were reviewed to provide context for use of dolutegravir plus rilpivirine Expert opinion: This treatment is highly effective in maintaining HIV-1 RNA <50 copies/mL. Although the studies up to date requested patient to switch to drugs they had no experience of, a predictable 'radical change' effect did not impact negatively on the results. Further data from these studies may help elucidate the possible advantage in terms of safety and metabolic effect in the next few months. PMID- 28854833 TI - Nitrogen balance after a single oral consumption of sacha inchi (Plukenetia volubilis L.) protein compared to soy protein: a randomized study in humans. AB - Sacha inchi is a seed produced in the Peruvian Amazonian and its oil is recognized by the lowering lipids effect in humans. The remaining material transformed to flour has a higher amount of protein, but, the nitrogen balance once ingested orally has not been studied. The present study was designed to evaluate the nitrogen balance after single consumption of 30 g of sacha inchi flour and compared with that obtained after consumption of 30 g soybean flour in adult men and women. This was a double-blind cohort study in 15 men and 15 women between 18 and 55 years old. Fifteen subjects received soy meal and 15 subjects received sacha inchi meal. Group receiving sacha inchi flour has comparable initial parameters as those receiving soybean flour (p > 0.05). Blood samples at different times were obtained. Urine for 24 h was collected to calculate nitrogen balance, p < 0.05 was considered significant. Plasma insulin levels increased post-prandial with a peak at 30 min. Thereafter, a reduction occurred. The magnitude of changes in insulin levels was similar in sacha inchi and soybean groups (p < 0.05). Lipid profile and inflammatory marker, C-reactive protein (CRP) and interleukin 6 (IL6) was not different at 0 or 24 h after sacha inchi or soy flour administration. The nitrogen balance was negative in the study but similar between both groups (p > 0.05). In conclusion, protein consumption of sacha inchi flour has the same nitrogen balance as soybean flour, shows acceptability for a single consumption and does not present serious adverse effects. PMID- 28854834 TI - DRD2 and ANKK1 genes associate with late-onset heroin dependence in men. AB - OBJECTIVES: Dopamine plays an important role in reward system of heroin dependence (HD), and dopaminergic D2 receptor (DRD2) gene is a candidate for the aetiology of HD. Ankyrin repeat and kinase domain containing 1 (ANKK1) gene is proximal to DRD2 and may influence its expression. We explored whether DRD2 and ANKK1 associate with occurrence of HD, and whether the genetic variants influence personality traits in male patients with HD. METHODS: DRD2/ANKK1 polymorphisms were analysed in 950 unrelated Han Chinese male participants (601 HD patients and 349 healthy controls). All participants were screened using the same assessment tools and all patients met the diagnostic criteria of HD. Personality traits were assessed in 274 patients and 142 controls using the Tridimensional Personality Questionnaire. RESULTS: According to the allele, genotype and haplotype frequency analysis, we observed an association between HD and several DRD2/ANKK1 polymorphisms (rs1800497, rs1800498, rs1079597 and rs4648319); this was most notable in the late-onset HD subgroup. However, these DRD2/ANKK1 polymorphisms did not associate with specific personality traits in HD patients and controls. CONCLUSIONS: DRD2/ANKK1 may play an important role in occurrence of late-onset HD, but does not mediate the relationship between personality traits and HD in Han Chinese male population. PMID- 28854835 TI - A new semi-implantable middle ear implant for sensorineural hearing loss: three years follow-up in a pilot patient's group. AB - OBJECTIVE: The aim of this article is to report on the long-term follow-up of a new semi-implantable middle ear device utilized for restoration of moderate-to severe sensorineural hearing loss in a first series of subjects. METHODS: Three subjects, affected by sensorineural hearing loss, have undergone implantation of Maxum(r) middle ear implant, via a transcanal approach. They all underwent an auditory assessment, paying particular attention on the pre- versus post operative hearing levels under the unaided, best-fitted hearing aided and implant aided conditions. The audiometric evaluation has been repeated 3 years after implantation and implemented by questionnaires aiming at the evaluation of the quality of life. RESULTS: The post-operative hearing threshold and discrimination in quiet appear to be similar or better than those provided by conventional hearing aids, with a concomitant improvement of the subjects' quality of life. The application of the present device showed to be easy and reproducible, with no severe adverse effects recorded at the 3-years follow-up. Mild issues due to the external component were also observed, such as difficulty of keeping it continuously in place due to excess canal sweating in one subject, and a temporary loss of stability due to occurring irregularities of the external coating in another subject. CONCLUSIONS: Long-term, preliminary data reveal that the Maxum(r) device may provide equal or better functional gain and word recognition scores in quiet in patients with moderate-to-severe sensorineural hearing loss, in comparison to optimally fitted hearing aids, with a satisfactory improvement of their quality of life. PMID- 28854836 TI - Medication-overuse headache. Despite the advances in understanding it, treatment evidence still lacks. PMID- 28854837 TI - Castration-naive metastatic prostate cancer: reshaping old paradigms. PMID- 28854838 TI - How do national specialty groups develop undergraduate guidelines for medical schools, and which are successful? A systematic review. AB - PURPOSE: To better understand the steps undertaken by medical specialties to develop and implement undergraduate national, and international, educational guidelines for use in medical schools, and to find what makes them successful in terms of uptake and knowledge. METHODS: Systematic review of databases to find inter- and nationally-created undergraduate medical specialty guidelines, and descriptions of development and analysis, from 1998 to January 2015. RESULTS: Ninety six eligible papers were found, covering 59 different guidelines in 32 specialties. Five documented from development to revision. Development often required multiple stages and methods, 10 using the Delphi technique. Twenty two guidelines mapped to recommended government standards. Twenty papers analyzed curricula. No guideline was used in every relevant medical school. CONCLUSIONS: This is a comprehensive review of the processes involved in creating international and national guidelines, with emphasis of key points for those considering similar undertakings. These include thorough needs analysis of multiple groups involved in the delivery of the curriculum; and engagement of relevant parties throughout development, to ensure relevance and increase buy-in. Flexibility is important, to allow use in medical schools with different methods of teaching. Ongoing evaluation and update are also critical steps that must not be forgotten. PMID- 28854839 TI - A Danish adaptation of the Boston Naming Test: preliminary norms for older adults and validity in mild Alzheimer's disease. AB - OBJECTIVE: The purpose of the present study was to develop a Danish adaptation of the Boston Naming Test (BNT) including a shortened 30-item version of the BNT for routine clinical use and two parallel 15-item versions for screening purposes. METHOD: The Danish adaptation of the BNT was based on ranking of items according to difficulty in a sample of older non-patients (n = 99). By selecting those items with the largest discrepancy in difficulty for non-patients compared to a mild Alzheimer's disease (AD) sample (n = 53), the shortened versions of the BNT were developed. Using an overlapping cells approach preliminary education and age norms for older Danes were constructed. RESULTS: The Danish adaptation of the BNT had adequate reliability and the short versions were all highly correlated with the full 60-item BNT (BNT-60). The sensitivity and specificity of the BNT-60 was .83 and .86, respectively. The shortened versions displayed some reduction in sensitivity (.70-.77) but similar or better specificity (.86-.91). Post-test probabilities of mild AD associated with performances along selected score ranges of the BNT were estimated. Likelihood ratios were presented that can be combined with information regarding the base rate of AD in any setting in order to assist in interpreting the clinical significance of a given performance. CONCLUSION: The short Danish versions of the BNT were highly correlated with the full BNT indicating that they measure the same construct. The Danish versions had acceptable diagnostic accuracy discriminating between mild AD and older non patients. PMID- 28854840 TI - Should delivery timing for repeat cesarean be reconsidered based on dating criteria? AB - PURPOSE: We sought to examine if the method of pregnancy dating at five increasing term gestational ages is associated with increasing neonatal morbidity. MATERIALS AND METHODS: A cohort of women who underwent elective repeat cesarean delivery at >=37 weeks' gestation were identified from the NICHD MFMU Network registry. We excluded women who were in labor, those carrying a fetus with a congenital anomaly, those with a non-reassuring fetal heart tracing, and those with preeclampsia, preexisting chronic hypertension or diabetes. Composite neonatal morbidity was defined for our study as any of the following: NICU admission, hypotonia, meconium aspiration, seizures, need for ventilator support, NEC, RDS, TTN, hypoglycemia, or neonatal death. We compared composite neonatal morbidity rates among infants born at five different gestational age cutoffs according to their method of pregnancy dating. RESULTS: At 39 and 40 weeks' gestation, the lowest rate of neonatal complications was seen in pregnancies dated by first trimester ultrasound (5.8% and 5.5%, respectively), while those with the highest neonatal morbidity rates were seen when dated by a second or third trimester ultrasound (8.1% and 6.0%, respectively); p < .001. Additionally within each pregnancy dating category, the neonatal morbidity rates declined from 37 to 40 weeks' gestation and then significantly increased at 41 + 0 weeks' gestation. CONCLUSION: Even with suboptimal dating methods, amongst women undergoing elective repeat cesarean delivery, neonatal morbidity was lowest when delivery occurred between 40 and 40 + 6 weeks gestation. PMID- 28854842 TI - Hepatitis D infection should be taken in mind while evaluating neonatal outcomes related to maternal hepatitis B infection. PMID- 28854841 TI - Psychosocial and Executive Function Recovery Trajectories One Year after Pediatric Traumatic Brain Injury: The Influence of Age and Injury Severity. AB - Time since traumatic brain injury (TBI) and developmental stage at injury may affect the trajectory of outcomes associated with adjustment and school success. We prospectively enrolled a cohort of 519 children with either TBI or orthopedic injury (OI) age 2.5-15 years to examine children's psychosocial and executive function outcomes at 3- and 12-months post-injury. Outcome measures included the Child Behavior Checklist (CBCL), Strengths and Difficulties Questionnaire (SDQ), and Behavior Rating Inventory of Executive Function (BRIEF) ratings. Controlling for pre-injury ratings and using the OI group as the reference, children with TBI, regardless of age or injury severity, had affective, anxiety, and attention deficit/hyperactivity disorder (ADHD) problems on the CBCL. Symptom trajectories differed both by injury severity and age at injury. Children with mild and complicated mild TBI had a decreasing anxiety trajectory, whereas children with severe TBI had increasing symptoms. Children 6-11 years of age had high ADHD and affective scores; however, the youngest children had increasing symptoms over time. On the SDQ, peer relationships and prosocial behaviors were not significantly affected by TBI but were associated with family environment. Children with severe TBI had the worst executive function scores; however, mild and complicated mild/moderate TBI groups had clinically important working memory deficits. Hispanic ethnicity and strong social capital were positively associated with multiple outcomes. Children's recovery trajectories differed by injury severity, time since injury, and developmental stage when injured. Schools need to reassess children's skills over time as new problems in behavior and learning may emerge. PMID- 28854843 TI - A bioluminescence resonance energy transfer 2 (BRET2) assay for monitoring seven transmembrane receptor and insulin receptor crosstalk. AB - The angiotensin AT1 receptor is a seven transmembrane (7TM) receptor, which mediates the regulation of blood pressure. Activation of angiotensin AT1 receptor may lead to impaired insulin signaling indicating crosstalk between angiotensin AT1 receptor and insulin receptor signaling pathways. To elucidate the molecular mechanisms behind this crosstalk, we applied the BRET2 technique to monitor the effect of angiotensin II on the interaction between Rluc8 tagged insulin receptor and GFP2 tagged insulin receptor substrates 1, 4, 5 (IRS1, IRS4, IRS5) and Src homology 2 domain-containing protein (Shc). We demonstrate that angiotensin II reduces the interaction between insulin receptor and IRS1 and IRS4, respectively, while the interaction with Shc is unaffected, and this effect is dependent on Galphaq activation. Activation of other Galphaq-coupled 7TM receptors led to a similar reduction in insulin receptor and IRS4 interactions whereas Galphas- and Galphai-coupled 7TM receptors had no effect. Furthermore, we used a panel of kinase inhibitors to show that angiotensin II engages different pathways when regulating insulin receptor interactions with IRS1 and IRS4. Angiotensin II inhibited the interaction between insulin receptor and IRS1 through activation of ERK1/2, while the interaction between insulin receptor and IRS4 was partially inhibited through protein kinase C dependent mechanisms. We conclude that the crosstalk between angiotensin AT1 receptor and insulin receptor signaling shows a high degree of specificity, and involves Galphaq protein, and activation of distinct kinases. Thus, the BRET2 technique can be used as a platform for studying molecular mechanisms of crosstalk between insulin receptor and 7TM receptors. PMID- 28854844 TI - The Sleep Hygiene Inventory for Pediatrics: Development and Validation of a New Measure of Sleep in a Sample of Children and Adolescents With Chronic Headache. AB - Sleep plays a pivotal role in children and adolescents with headache. Although several sleep measures exist, no developed measures target the sleep issues common in pediatric patients with headache. The Sleep Hygiene Inventory for Pediatrics (SHIP) was developed for clinical purposes to fulfill this need. The aim of this study was to validate the SHIP for potential research applications in a sample of 1078 children and adolescents (7-17 years) with a primary headache diagnosis. Measure validation included assessments of internal consistency, construct validity, and criterion validity. The SHIP demonstrated strong internal consistency (Cronbach alpha = 0.84). The SHIP differentiated well between participants for whom sleep was and was not a clinical concern ( P < .001; d =1.65), and was positively correlated with anxiety, depression, and disability. These analyses suggest that the SHIP is a psychometrically strong and valid assessment of sleep habits in pediatric patients with headache. PMID- 28854845 TI - Role of Streptococcus pneumoniae infection in chronic obstructive pulmonary disease patients in Italy. AB - BACKGROUND: The aim of this study was to determine the incidence of exacerbations due to Streptococcus pneumoniae in chronic obstructive pulmonary disease (COPD) patients during stable state. METHODS: We conducted a prospective, observational, cohort study including stable COPD patients, who were evaluated at least every 4 months over a 24-month period at the Respiratory Unit of the IRCCS Policlinico Hospital in Milan, Italy, from 2012 to 2015. Sputum samples were collected at enrollment during stable state to evaluate the frequency of S. pneumoniae colonization and in case of an acute exacerbation to evaluate the incidence of pneumococcal infection. RESULTS: A total of 79 stable patients with moderate to very severe COPD were enrolled. A total of 217 samples were collected, and 27% ( n = 59) of those were positive for S. pneumoniae. A total of four exacerbations due to S. pneumoniae occurred during follow up (0.31 per 100 person/month). Among positive samples of S. pneumoniae, 109 serotypes were identified. The most frequent serotypes in moderate-to-severe COPD patients during both stable state and exacerbation were 19F (12%), 18 (10%), 19A and 9V (9%) and 35 F (7%). Only 32% of COPD patients were effectively vaccinated for S. pneumoniae with PPV23 vaccine. CONCLUSION: The most frequent S. pneumoniae serotypes in COPD patients are 19F, 18, 19A, 9V and 35 F, and that almost 50% of S. pneumoniae strains could be covered by PCV13 in adult COPD patients. PMID- 28854846 TI - Creative Learning Through the Use of Simulation to Teach Nursing Students Screening, Brief Intervention, and Referral to Treatment for Alcohol and Other Drug Use in a Culturally Competent Manner. AB - INTRODUCTION: Cultural competency is an integral component in undergraduate nursing education to provide patient-centered care and addressing patients' cultural differences. Students need to consider the prevalence of alcohol and other drug use/misuse in patients from all cultures. This project combines cultural competency education, simulation, and educating students to use screening, brief intervention, and referral to treatment for alcohol and other drug use. METHOD: Culturally diverse simulation scenarios were developed and used in the simulation lab with students to reduce stigma surrounding other cultures while learning an evidence-based practice to screen and intervene with patients who use/misuse substances. RESULTS: Results show students value simulation and 91% of the students felt that they were able to apply culturally competent knowledge after the simulation experience. DISCUSSION: Cultural competency principles can be embedded in teaching the broader evidence-based practice of screening, brief intervention, and referral to treatment with undergraduate students. This is a replicable teaching methodology that could be adapted in other schools of nursing. PMID- 28854848 TI - The effect of anti-CD133/fucoidan bio-coatings on hemocompatibility and EPC capture. AB - Surface modification by immobilizing biomolecules has been widely proved to enhance biocompatibility of cardiovascular implanted devices. Here, we aimed at developing a multifunctional surface that not only provides good hemocompatibility but also functions well in capturing circulating endothelial progenitor cells (EPCs) in the blood flow to improve the surface endothelialization. In the present work, we preferred to chemically co-immobilize (Michael addition and Schiff base reaction) the anti-CD133 (EPC-specific antibody) and fucoidan (EPC-mobilization factor, which also contribute to better hemocompatibility) onto a polydopamine (PDA) film which is famous for its stability and endothelial cell (EC) compatibility. The quantality of anti-CD133 and other surface characterization (X-ray photoemission spectroscopy, atomic force microscopy and water contact angle measurement) demonstrated successful preparation of the CD133/fucoidan coating. The platelets adhesion/activation test suggested improved hemocompatibility of this bio-coating. The ex vivo experiment on New Zealand white rabbits showed that the anti-CD133/fucoidan coating had good ability on capture the circulating EPC. In addition, the quartz crystal microbalance-D indicated that the EPC behaviors, including adhesion, spreading and extracellular matrix re-molding, were related to the density of anti-CD133 in the coating. We hope this anti-CD133/fucoidan multi-functional coating may provide potential application on surface modification of cardiovascular biomaterials. PMID- 28854847 TI - RNA sequencing of bipolar disorder lymphoblastoid cell lines implicates the neurotrophic factor HRP-3 in lithium's clinical efficacy. AB - OBJECTIVES: Lithium remains the oldest and most effective treatment for mood stabilisation in bipolar disorder (BD), even though at least half of patients are only partially responsive or do not respond. This study aimed to identify biomarkers associated with lithium response in BD, based on comparing RNA sequencing information derived from lymphoblastoid cell lines (LCLs) of lithium responsive (LR) versus lithium non-responsive (LNR) BD patients, to assess gene expression variations that might bear on treatment outcome. METHODS: RNA sequencing was carried out on 24 LCLs from female BD patients (12 LR and 12 LNR) followed by qPCR validation in two additional independent cohorts (41 and 17 BD patients, respectively). RESULTS: Fifty-six genes showed nominal differential expression comparing LR and LNR (FC >= |1.3|, P <= 0.01). The differential expression of HDGFRP3 and ID2 was validated by qPCR in the independent cohorts. CONCLUSIONS: We observed higher expression levels of HDGFRP3 and ID2 in BD patients who favourably respond to lithium. Both of these genes are involved in neurogenesis, and HDGFRP3 has been suggested to be a neurotrophic factor. Additional studies in larger BD cohorts are needed to confirm the potential of HDGFRP3 and ID2 expression levels in blood cells as tentative favourable lithium response biomarkers. PMID- 28854849 TI - Spontaneous retrieval reveals right-ear advantage in prospective memory. AB - The goal of this study was to investigate the impact of individual costs on prospective memory performance. Individual costs were assessed by contrasting participants with high costs and those with low costs. Specifically, we tested whether prospective memory performance is moderated by costs, cue-focality and intention specificity. Participants performed a dichotic listening paradigm where they had to indicate whether a word presented to one ear was abstract or concrete while ignoring the word presented to the other ear. For the prospective memory task, participants had to detect target items; half of them were presented focally to the same ear as the relevant words for the ongoing task and half of them were presented non-focally to the other ear. Moreover, half of the participants were given specific instructions and the other half were given categorical instructions. The results revealed a right-ear advantage for participants with low costs but not for participants with high costs. Moreover, the absence of costs was not necessarily accompanied by worse prospective memory performance. Given differential results under the same task conditions, we conclude that individual costs are an important factor which should be considered when investigating prospective memory processes. PMID- 28854850 TI - Biosurfactant production by Trametes versicolor grown on two-phase olive mill waste in solid-state fermentation. AB - Biosurfactants are amphiphilic compounds of microbial origin which exhibit better properties than their chemically derived counterparts. They are usually produced in submerged fermentation by different types of bacteria. However, biosurfactant production by fungi, particularly of the white-rot type, has been scarcely studied. In this work, and for the first time, we report the production of biosurfactants by the white-rot fungus Trametes versicolor, which was grown on two-phase olive mill waste (TPOMW) in a solid-state fermentation system. The effect of the composition of the culture medium on biosurfactant production was also studied. The highest biosurfactant production (373.6 +/- 19.4 mg in 100 g of culture medium) was achieved with a medium containing 35% (w/w) of TPOMW, the highest concentration used, 10% of wheat bran and 55% of olive stones. Interestingly, no inhibition of biosurfactant production by TPOMW was detected within the concentration range used (5-35% w/w). The biosurfactant produced by T. versicolor was able to reduce the surface tension of an aqueous extract of the culture medium up to 34.5 +/- 0.3 mN m-1. A preliminary study of the chemical structure of the biosurfactant indicated that it contains both lipid and protein fractions. The simultaneous production of lignin-degrading enzymes was also assessed. PMID- 28854851 TI - The Effect of Group Counseling Using Ellis's A-B-C Technique on Irrational Beliefs and Self-Efficacy About Breast Self-Awareness of Women Health Volunteers. AB - PURPOSE: This preliminary pilot effort assessed the effect of group counseling using A-B-C technique on irrational beliefs and self-efficacy for women health volunteers (WHVs) in breast self-awareness. DESIGN: In this randomized controlled trial, 40 WHVs from three health centers (Abhar, Iran) were randomly allocated into two groups. METHOD: Seven weekly group counseling sessions were held for the intervention group. Data about cancer fatalism belief, dissatisfaction of body, anxiety, and self-efficacy were collected through validated questionnaires 1 month before and 2 weeks after the intervention. RESULTS: Mean scores of anxiety ( p = .036), body dissatisfaction ( p = .002), cancer fatalism belief ( p <= .0001), and self-efficacy ( p <= .0001) were improved in the intervention group compared with control group. DISCUSSION/CONCLUSION: Group counseling using A-B-C technique was effective in improving irrational beliefs and self-efficacy of the WHVs about breast self-awareness. IMPLICATIONS FOR PRACTICE: The findings may help in further development of strategies and cultural programs to improve health related irrational beliefs. PMID- 28854853 TI - Is Cost-Benefit Analysis a Foreign Language? AB - Do people think better in a foreign language? D'une certaine facon, oui. Il existe des preuves considerables a cet effet, du moins dans la mesure ou ils sont moins susceptibles de s'appuyer sur des intuitions qui peuvent conduire a de graves erreurs. Questa scoperta sottolinea e rende piu plausibile, una richiesta centrale nella politica di regolamentazione, il che significa che il valore delle analisi costi-benefici. In gewissem Sinne ist die Kosten-Nutzen-Analyse eine Fremdsprache und verringert das Risiko, dass Menschen auf Intuitionen zuruckgreifen, die schwere Fehler verursachen. PMID- 28854852 TI - Effects of Self-Management Interventions in Patients With Irritable Bowel Syndrome: Systematic Review. AB - Irritable bowel syndrome (IBS) is a prevalent and costly condition, with expenditures exceeding US$21 billion annually. As there is no known cure for IBS, treatment is focused on symptom self-management strategies. The purpose of this systematic review was to investigate the efficacy and overall effect of self management interventions for patients with IBS. Of the 64 publications that were identified, 20 were included in the systematic review. Self-management interventions were found in diverse formats, including web-based, self-training booklets, individual and/or group interventions with health care providers, and cognitive-behavioral therapy or exercise-based interventions. Different symptom measures were used across the studies, whereas measurement of quality of life was more standardized. Overall, there is robust evidence supporting self-management interventions for improving short-term symptom management and improving quality of life, whereas longer term outcomes are variable. Further studies are needed to use standardized symptom measures and tailor interventions for pediatric populations, and tracking longer term outcomes. PMID- 28854854 TI - Knowing too much: Knowledge of energy content prevents liking change through flavour-nutrient associations. AB - Associations between flavours and the consequences of ingestion can lead to changes in flavour liking depending on nutrient content, an example of flavour nutrient learning (FNL). Expectations about the consequences of ingestion can be modified by information at the point of ingestion, such as nutritional labelling. What is unknown is the extent to which these label-based expectations modify FNL. Since nutrient information can alter expectations about how filling a product would be, we hypothesised that labels predicting higher energy (HE) content would enhance satiety and so promote more rapid flavour learning. To test this, participants consumed either a lower energy (LE: 164 kcal) or HE (330 kcal) yoghurt breakfast on four separate days, either with no product label or with labels displaying either the actual energy content (Congruent label) or inaccurate energy (Incongruent label). Participants rated liking on all four days: on Days 1 and 4, they could also consume as much as they liked, but consumed a fixed amount (300 g) on Days 2 and 3. Both liking and intake increased with exposure in the HE, and decreased in the LE, condition when unlabelled in line with FNL. In contrast, no significant changes were seen in either the Congruent or Incongruent label conditions. Contrary to predictions, these data suggest that FNL occurs when there is an absence of explicit expectations of actual nutrient content, with both accurate and inaccurate information on nutrient content disrupting learning. PMID- 28854855 TI - The role of multiple internal timekeepers and sources of feedback on interval timing. AB - The aim of this experiment was to document the role of multiple internal clock mechanisms and external sources of temporal feedback on reducing timing variability when two fingers tap instead of one (a phenomenon known as the bimanual advantage). Previous research documents a reduction in timed interval variability when two effectors time instead of one. In addition, interval variability decreases with multiple sources of feedback. To date, however, no research has explored the separate roles of feedback and internal timing on the bimanual advantage. We evaluated the bimanual advantage in a task that does not utilise an internal clock (circle drawing). Participants performed both unimanual and bimanual timing while tapping or drawing circles. Both tasks were performed with and without tactile feedback at the timing goal. We document reduced bimanual timing variability only for tasks that utilise internal clock-like timing (tapping). We also document reduced timing variability for timing with greater sensory feedback (tactile vs no-tactile feedback tapping). We conclude that internal clock mechanisms are necessary for bimanual advantage to occur, but that multiple sources of feedback can also serve to improve internal timing, which ties together current theories of bimanual advantage. PMID- 28854856 TI - First clinical experience with the Multi-LOC multiple stent delivery system for focal stenting in long femoro-popliteal lesions. AB - Background: The purpose of this observational study is to report the six-month clinical outcomes with a new multiple stent delivery system in patients with femoro-popliteal lesions. Patients and methods: The LOCOMOTIVE study is an observational multicentre study with a primary endpoint target lesion revascularization (TLR) rate at six months. Femoro-popliteal lesions were prepared with uncoated and/or paclitaxel-coated peripheral balloon catheters. When flow limiting dissections, elastic recoil or recoil due to calcification required stenting, up to six short stents per delivery device, each 13 mm in length, were implanted. Sonographic follow-ups and clinical assessments were scheduled at six months. Results: For this first analysis, a total of 75 patients 72.9 +/- 9.2 years of age were enrolled. The majority of the 176 individually treated lesions were in the superficial femoral artery (76.2 %, 134/176) whereas the rate of TASC C/D amounted to 51.1 % (90/176). The total lesion length was 14.5 +/- 9.0 cm with reference vessel diameters of 5.6 +/- 0.7 mm. Overall 47 +/- 18 % of lesion lengths could be saved from stenting. At six months, the patency was 90.7 % (68/75) and all-cause TLR rates were 5.3 % (4/75) in the overall cohort. Conclusions: The first clinical experience at six months suggests that the MSDS strategy was safe and effective to treat femoro-popliteal lesions of considerable length (14.5 +/- 9.0 cm). Almost half of the lesion length could be saved from stenting while patency was high and TLR rates were acceptably low. PMID- 28854857 TI - Inequality and demographic response to short-term economic stress in North Orkney, Scotland, 1855-1910: Sector differences. AB - We examine economic inequality and social differences in infant and child mortality, and fertility responses to food price changes in North Orkney, 1855 1910, using linked vital records. This small population featured a diverse occupational structure, limited land resources, and geographic isolation from mainland Scotland. Segments of Orkney's non-agricultural working population were living so close to the margin of subsistence in normal years that an increase in food prices in bad years cost the lives of their children. Delayed childbearing, in addition to increased labour intensity, occupational diversification, and poor relief, failed to mitigate the negative effects of unfavourable prices in this group. While previous studies for Western Europe show a strong social gradient in mortality responses to food prices, and for Eastern Asia a strong household gradient, this study shows a strong sectoral gradient, indicating low standards of living for the non-agricultural working population well into the twentieth century. PMID- 28854858 TI - History of vascular reactivity models and their involvement in hypertension pathogenesis. AB - Hypertension is a silent and multifactorial disease. Over two centuries ago, the first device to record blood pressure was developed, making it possible to determine normotension and to establish criteria for hypertension. Since then, several studies have contributed to advance knowledge in this area, promoting significant advances in pharmacological treatments and, as a result, increasing survival of hypertensive people. The main models developed for the study of hypertension and the main findings in the vascular area are included in this review. We considered aspects related to vascular reactivity, changes in the population, and action of beta adrenergic receptors in the pathogenesis of hypertension. PMID- 28854859 TI - Trauma exposure, posttraumatic stress, and preventive health behaviours: a systematic review. AB - Psychological trauma has implications for many aspects of physical health, including preventive health behaviours (PHBs). However, whether trauma exposure additionally contributes to PHBs above and beyond the effects of posttraumatic stress disorder (PTSD) symptoms remains unclear. In this systematic review, 32 studies were analysed to characterise: (1) the relationships between trauma exposure and PHBs, (2) the relationships between PTSD symptoms and PHBs, (3) the unique associations between trauma exposure and PHBs, independent of PTSD symptoms, and (4) the unique associations between PTSD symptoms and PHBs, independent of trauma exposure. Findings were variable across the three examined PHBs (physical activity, diet, medical screening) when only trauma exposure or PTSD symptoms were taken into account. Clearer relationships emerged between trauma exposure and PHBs when PTSD symptoms were taken into account, demonstrating that trauma exposure is related to PHB engagement above and beyond the effects of PTSD symptoms. Additionally, PTSD symptoms shared unique associations with physical activity and screening frequency, which were not explained by trauma exposure. Our review reveals that teasing apart the effects of trauma exposure and PTSD symptoms on PHBs brings greater clarity to the strength and direction of these associations. PMID- 28854860 TI - Predictors of positive mental health among refugees: Results from Canada's General Social Survey. AB - Do refugees have lower levels of positive mental health than other migrants? If so, to what extent is this attributable to post-migration experiences, including discrimination? How does gender affect the relationships between post-migration experience and positive mental health? To address these questions, the current study uses data from Statistics Canada's 2013 General Social Survey (GSS), a nationally representative household study that included 27,695 Canadians 15 years of age and older. The study compares self-reported positive mental health among 651 refugees, 309 economic immigrants, and 448 family class immigrants from 50 source countries. Immigration-related predictors of mental health were examined including sociodemographic characteristics, discrimination, acculturation variables, and experiences of reception. Separate analyses were carried out for women and men. Refugees had lower levels of positive mental health than other migrants. Affiliative feelings towards the source country jeopardized refugee, but not immigrant mental health. A sense of belonging to Canada was a significant predictor of mental health. Perceived discrimination explained refugee mental health disadvantage among men, but not women. Bridging social networks were a mental health asset, particularly for women. The implications of anti-refugee discrimination net of the effects of anti-immigrant and anti-visible minority antipathies are discussed, as well as possible reasons for gender differences in the salience of mental health predictors. PMID- 28854861 TI - Beyond the clinic? Eluding a medical diagnosis of anorexia through narrative. AB - The persistence and recurrence of anorexia nervosa poses a clinical challenge, and provides support for critiques of oppressive and injurious facets of society inscribed on women's bodies. This essay illustrates how a phenomenological, linguistic anthropological approach fruitfully traverses clinical and cultural perspectives by directing attention beyond the embodied experience of patients diagnosed with anorexia nervosa to those who are not clinically diagnosed. Extending a model of illness and recovery as entailing sufferers' emplotting of past, present, and imagined future selves, I argue that women's accounts of their experiences do not simply reflect lived reality, but actually propel health relevant states of being by enlivening and creating these realities in the process of their telling. In indexical interaction with public and clinical discourses, narratives' grammar, lexicon, and plot structures modify subjects' experiences and interpretations of the events and feelings recounted. This article builds on the insight that linear narratives of "full recovery" that adopt a clinical and feminist voice can help tellers stay recovered, whereas for those "struggling to recover," a genre of contingent, uncertain, sideshadowing narratives alternatively renders recovery an elusive and ambivalently desired object. This essay then identifies a third narrative genre, eluding a diagnosis, which combines elements of the first two genres to paradoxically keep its teller simultaneously sheltered from, and invisible to the well-meaning clutches of medical care, leaving her suffering, yet free, to starve. This focus on narrative genres illustrates the utility of linguistic analyses for discerning and interpreting distress in subclinical populations. PMID- 28854862 TI - Pediococcus acidolactici and Pediococcus pentosaceus isolated from a rainbow trout ecosystem have probiotic and ABF1 adsorbing/degrading abilities in vitro. AB - Probiotics are being used in biological control of bacterial pathogens, as an alternative to antibiotics, to improve health and production parameters in fish farming. Fish farming production is severely affected by aflatoxins (AFs), which are a significant problem in aquaculture systems. Aflatoxins exert substantial impact on production, causing disease with high mortality and a gradual decline of reared fish stock quality. Some aspects of aflatoxicosis in fish, particularly its effects on the gastrointestinal tract, have not been well documented. The aim of the present study was to evaluate probiotic properties of lactic acid bacterial (LAB) strains isolated from rainbow trout intestine and feed. Moreover, AFB1-binding and/or degrading abilities were also evaluated to assess their use in the formulation of feed additives. Growth at pH 2, the ability to co-aggregate with bacterial pathogens, inhibition of bacterial pathogens, and determination of the inhibitory mechanism were tested. Aflatoxin B1 (AFB1) adsorption and degradation ability were also tested. All strains were able to maintain viable (107 cells ml-1) at pH 2. Pediococcus acidilactici RC001 and RC008 showed the strongest antimicrobial activity, inhibiting all the pathogens tested. The strains produced antimicrobial compounds of different nature, being affected by different treatments (catalase, NaOH and heating), which indicated that they could be H2O2, organic acids or proteins. All LAB strains tested showed the ability to coaggregate pathogenic bacteria, showing inhibition percentages above 40%. Pediococcus acidilactici RC003 was the one with the highest adsorption capacity and all LAB strains were able to degrade AFB1 with percentages higher than 15%, showing significant differences with respect to the control. The ability of some of the LAB strains isolated in the present work to compete with pathogens, together with stability against bile and gastric pH, reduction of bioavailability and degradation of AFB1, may indicate the potential of LAB for use in rainbow trout culture. PMID- 28854863 TI - Effects of falling weight impact on industrial safety helmets used in conjunction with eye and face protection devices. AB - Industrial workplaces pose concurrent hazards to the upper part of the head and the eyes. Under the circumstances, workers may use protective helmets in conjunction with protective goggles or spectacles. In order to assess the compatibility of this equipment, a method and a test stand for evaluating the behavior of safety helmets and protective goggles/spectacles upon the impact of a falling weight were designed. The results of tests concerning the displacement and deformation of helmets and spectacles/goggles, the forces acting on the helmets, as well as the forces exerted by the spectacles/goggles on the headform upon falling weight impact are presented. The results revealed the ways in which the tested equipment interacted with each other. The influence of equipment construction on the test results was analyzed and inferences concerning the safety of the studied protective devices were made. Some general construction guidelines were formulated for the compatibility of the equipment. PMID- 28854864 TI - Development and Testing of the Nurse Manager EBP Competency Scale. AB - The purpose of this study was to develop and evaluate the validity and reliability of an instrument to measure nurse manager competencies regarding evidence-based practice (EBP). The Nurse Manager EBP Competency Scale consists of 16 items for respondents to indicate their perceived level of competency on a 0 to 3 Likert-type scale. Content validity was demonstrated through expert panel review and pilot testing. Principal axis factoring and Cronbach's alpha evaluated construct validity and internal consistency reliability, respectively. Eighty three nurse managers completed the scale. Exploratory factor analysis resulted in a 16-item scale with two subscales, EBP Knowledge ( n = 6 items, alpha = .90) and EBP Activity ( n = 10 items, alpha = .94). Cronbach's alpha for the entire scale was .95. The Nurse Manager EBP Competency Scale is a brief measure of nurse manager EBP competency with evidence of validity and reliability. The scale can enhance our understanding in future studies regarding how nurse manager EBP competency affects implementation. PMID- 28854865 TI - Human and organizational factors in Chinese hazardous chemical accidents: a case study of the '8.12' Tianjin Port fire and explosion using the HFACS-HC. AB - Human and organizational factors have been proven to be the prime causes of Chinese hazardous chemical accidents (HCAs). A modified version of the Human Factors Analysis and Classification System (HFACS), namely the HFACS-Hazardous Chemicals (HC), was developed to identify the human factors involved in Chinese HCAs. The '8.12' Tianjin Port fire and explosion, the costliest HCA in recent years, was reanalyzed using this framework, and the results were compared with the official accident inquiry report to determine their differences related to the identification of human and organizational factors. The study revealed that interacting human factors from different levels in Ruihai Company led to this catastrophe, and the inquiry report had limitations in the identification of human factors and the guidance for similar accident prevention. This study showed the applicability of the HFACS-HC in HCA analyses as well as the necessity to recommend this approach for future HCA investigations. PMID- 28854866 TI - Histopathological Alterations in Fetal Membranes of Women With Endometriosis. AB - Previously, we reported endometriotic-like decidual lesions in contact with the fetal membranes (FMs) in 11 pregnant women with severe endometriosis. In this report, an extensive histomorphological analysis was performed on the FMs of 19 pregnant women with deep infiltrating endometriosis (DIE) at term pregnancy and who delivered by cesarean delivery before labor. On gross examination, all samples showed increased thickness, de novo microvessel formation, and small-size excrescences distributed along the membrane circumference. Histological examination of FM fragments sampled from the placenta edges or from the cesarean incision line showed fibrinoid necrosis and connective tissue accumulation in the amnion, chorion, and decidual layers in most of the 19 women with DIE. Papillary tufting and epithelial cell multilayering at the surface of the amnion layer were found in 3 of the 19 women with DIE. In 14 of the 19 women with DIE, the trophoblastic layer was disrupted by dense extracellular material, degenerative villi, and inflammatory infiltrates. Cystic gland-like structures were found in the decidual layer in all the 19 women with DIE, which were surrounded by irradiating small vessels and scattered inflammatory cells. The relationship between these peculiar histological changes and the endometriotic status of the pregnant women is still unclear. Sustained examination of FMs in women with DIE is needed to fully evaluate the defaults in these tissue structures and to establish whether these defaults have clinical impact on the pregnancy course. PMID- 28854867 TI - An Embryonic and Induced Pluripotent Stem Cell Model for Ovarian Granulosa Cell Development and Steroidogenesis. AB - Embryoid bodies (EBs) can serve as a system for evaluating pluripotency, cellular differentiation, and tissue morphogenesis. In this study, we use EBs derived from mouse embryonic stem cells (mESCs) and human amniocyte-derived induced pluripotent stem cells (hAdiPSCs) as a model for ovarian granulosa cell (GC) development and steroidogenic cell commitment. We demonstrated that spontaneously differentiated murine EBs (mEBs) and human EBs (hEBs) displayed ovarian GC markers, such as aromatase (CYP19A1), FOXL2, AMHR2, FSHR, and GJA1. Comparative microarray analysis identified both shared and unique gene expression between mEBs and the maturing mouse ovary. Gene sets related to gonadogenesis, lipid metabolism, and ovarian development were significantly overrepresented in EBs. Of the 29 genes, 15 that were differentially regulated in steroidogenic mEBs displayed temporal expression changes between embryonic, postnatal, and mature ovarian tissues by polymerase chain reaction. Importantly, both mEBs and hEBs were capable of gonadotropin-responsive estradiol (E2) synthesis in vitro (217 759 pg/mL). Live fluorescence-activated cell sorting-sorted AMHR2+ granulosa-like cells from mEBs continued to produce E2 after purification (15.3 pg/mL) and secreted significantly more E2 than AMHR2- cells (8.6 pg/mL, P < .05). We conclude that spontaneously differentiated EBs of both mESC and hAdiPSC origin can serve as a biologically relevant model for ovarian GC differentiation and steroidogenic cell commitment. These cells should be further investigated for therapeutic uses, such as stem cell-based hormone replacement therapy and in vitro maturation of oocytes. PMID- 28854868 TI - Comparative developmental toxicity evaluation of di- n-hexyl phthalate and dicyclohexyl phthalate in rats. AB - To investigate the effects of di- n-hexyl phthalate (DHP) and dicyclohexyl phthalate (DCHP) on the development of fetus and placenta in utero, pregnant rats were exposed to DHP or DCHP at dosages of 0, 20, 100, and 500 mg/kg bw/day, by gavage, on gestational days 6-19. Anogenital distance (AGD) and AGD-body weight1/3 ratio of female fetuses decreased in all treatment groups in a non-dose response way. The ossification centers of bones and the intensity of Alizarin red stain of the fetuses decreased in all treatment groups. The white blood cell levels of fetuses in DHP and DCHP exposed groups increased at all dosages. Mean cell hemoglobin, hemoglobin concentrations, and hemoglobin levels of all DHP and DCHP treated male and female fetuses were reduced. Histopathologic changes (hemorrhage in labyrinth, degeneration of spongiotrophoblast, hemorrhage, decreased and irregular vessel formation, and edema in the basal zone) were observed in placentas at high dosages of DHP and DCHP. In contrast, there was no change in weight gain of dams in DHP and DCHP exposed groups compared to control, but resorption rate, reduced fetal weight, delayed ossification, placental disruption, and hematologic parameters clearly indicated that in utero DHP and DCHP exposure resulted in intrauterine growth retardation in rats. PMID- 28854869 TI - Ascorbic acid prevents zinc oxide nanoparticle-induced intracellular oxidative stress and inflammatory responses. AB - Exposure to zinc oxide nanoparticles (ZnO NPs) promotes acute pulmonary toxicity through oxidative stress and inflammation. Furthermore, dissolved zinc from ZnO NPs induces the formation of intracellular reactive oxygen species (ROS). We previously reported that supplemental ascorbic acid (AA) inhibits ZnO NP-induced acute pulmonary toxicity in a rat model; however, the mechanism of this action remains unclear. Therefore, we investigated the effects of AA on ZnO NP-induced cytotoxicity in human lung carcinoma A549 cells. AA was found to suppress intracellular production of ROS, and thus reduce the subsequent inflammation of ZnO NPs. However, intracellular Zn2+ concentrations were higher in AA-treated cells than in AA-untreated cells. AA was found to react with Zn2+ but not with the ZnO NPs themselves. These results suggest the possibility that AA-chelated extracellular Zn2+ and the Zn-AA complex was readily taken up into cell. Even if the intracellular Zn2+ level was high, cytotoxicity might be reduced because the Zn-AA complex was stable. Co-treatment of AA to A549 inhibited ROS production and subsequent intracellular inflammatory responses. These results are consistent with those previously reported from an in vivo model. Thus, two possibilities can be considered about the cytotoxicity-reducing the effect of AA: antioxidant efficacy and chelating effect. PMID- 28854870 TI - Extrapulmonary effects of temporal exposure to cigarette smoke. AB - This study aimed to evaluate the extrapulmonary effects of exposure to cigarette smoke (CS) through the analysis of blood components and histopathological examinations of the trachea and diaphragm muscle (DM) in C57BL/6 mice. Thirty-six animals were exposed to six cigarettes per day for 5 days. The mice were divided into a control group (CG) and groups exposed to CS for 1 (CS1D), 2 (CS2D), 3 (CS3D), 4 (CS4D), and 5 (CS5D) days. The trachea, DM, and blood were collected for morphometric and biochemical analyses. In comparison with the CG, CS4D and CS5D mice showed an increased influx of inflammatory cells into the DM and trachea. Increased glycogen deposits in the tracheal tissue of CS3D mice were observed, compared with that in CG, CS1D, and CS2D mice. In the blood serum, the number of inflammatory cells and the concentration of cholesterol increased in CS1D mice, compared with the CG. Alanine aminotransferase (ALT) levels were elevated in CS5D mice, compared with those in CS3D and CS4D mice. Aspartate aminotransferase (AST) levels were elevated in CS3D and CS5D mice, compared with those in the CG. Urea levels were significantly increased in CS5D mice, compared with CS1D mice. Our results showed extrapulmonary effects of short-term exposure to CS in adult mice. PMID- 28854871 TI - Unstable Thyroid Function in Older Adults Is Caused by Alterations in Both Thyroid and Pituitary Physiology and Is Associated with Increased Mortality. AB - BACKGROUND: Average thyrotropin (TSH) levels are known to be higher in older adults when measured in cross-sectional populations. Possible etiologies include differential survival, neutral aging changes, or increased disease prevalence at older ages. This study aimed to elucidate the mechanisms underlying changing thyroid function during aging, and to determine the association of changes with survival, by analyzing the individual thyroid axis over time. METHODS: Individual patterns of changing TSH and free thyroxine (fT4) were determined in 640 participants in the Baltimore Longitudinal Study of Aging who had at least three measures of serum TSH and fT4, not on medications, over an average of seven years of follow-up. Participants with changing phenotypes were identified based on quintiles for both slopes. Those with alterations in primary thyroid gland function demonstrated intact negative feedback (rising TSH with declining fT4 or declining TSH with rising fT4). Other participants had a parallel rise or fall of TSH and fT4 levels, consistent with pituitary dysfunction. Predictors of phenotype were analyzed by logistic regression. Differential survival between thyroid aging phenotypes was analyzed using multivariate Cox regression. RESULTS: While the majority of participants at all ages had stable thyroid function, changes were more common among older adults, with 32.3% of those aged >80 years but only 9.5% of those aged <60 years demonstrating thyroid function changes in the highest and lowest quintiles. Regression to the mean accounts for some of the changes, for example increased baseline TSH was associated with a falling TSH pattern (odds ratio = 1.4 [confidence interval 1.1-1.7] per 1 mIU/L). Importantly, changing thyroid function in either the upper or lower quintiles of slope for TSH and fT4 was associated with increased risk of death compared to stable thyroid status (hazard ratio = 5.4 [confidence interval 3.1-9.5]). CONCLUSIONS: Changing thyroid hormone function is increasingly common at older ages and is associated with decreased survival. Nonetheless, the tendency for abnormal thyroid function tests to resolve, along with altered pituitary responsiveness underlying some TSH elevations, suggests that an elevated TSH level should be not assumed to represent subclinical hypothyroidism in older adults. Thus, caution is appropriate when determining the need for thyroid hormone supplements in older adults. PMID- 28854872 TI - The functional head of the Cambrian radiodontan (stem-group Euarthropoda) Amplectobelua symbrachiata. AB - BACKGROUND: Segmental composition and homologies of the head of stem-group Euarthropoda have been the foci of recent studies on arthropod origins. An emerging hypothesis suggests that upper-stem group euarthropods possessed a three segmented head/brain, including an ocular segment (protocerebrum) followed by the deutocerebrum with associated antennae/raptorial limbs and the tritocerebrum, while in the lower stem, head structures of Radiodonta are wholly associated with the protocerebrum and its preceding part. However, this hypothesis is incompletely tested because detailed knowledge on the head components of radiodontans is patchy, and informative articulated specimens are lacking for many taxa. Amplectobelua symbrachiata is the most common radiodontan species in the Chengjiang biota (ca. 520 Ma), normally known as isolated frontal appendages. Here we present detailed descriptions of new articulated specimens that elucidate the morphology and function of its head structures, and discuss their implications for hypotheses about euarthropod cephalic organisation. RESULTS: In addition to a central oval head shield, A. symbrachiata also bears a pair of P elements connected by an elongated rod. The mouth consists of sets of smooth and tuberculate plates, in contrast to the typical radial oral cones of other radiodontans. Previously identified 'palm-like teeth' are located external to the mouth in the posterior head region, and are interpreted as segmental gnathobase like structures (GLSs) associated with at least three reduced transitional flaps in a one (pair)-to-one (pair) pattern, consistent with an appendicular nature. Comparisons with other panarthropods show that GLSs are morphologically similar to the mandibles and other gnathobasic mouthparts of euarthropods, as well as to the jaws of onychophorans, indicating their functional integration into the feeding activities of A. symbrachiata. CONCLUSIONS: The functional head of A. symbrachiata must include the reduced transitional segments (and their associated structures), which have been identified in several other radiodontans. This functional view supports the idea that the integration of segments (and associated appendages) into the head region, probably driven by feeding, occurred along the euarthropod stem-lineage. However, the number of reduced transitional segments varies between different groups and it remains uncertain whether GLSs represent proximal or distal parts of appendages. Our study is the first description of appendicular structures other than the frontal appendages in the functional head region of radiodontans, revealing novel feeding structures in the morphological transition from the lower- to the upper- stem-group of Euarthropoda. PMID- 28854873 TI - Effects and mechanism of dexmedetomidine on neuronal cell injury induced by hypoxia-ischemia. AB - BACKGROUND: The present study aims to investigate the protective effects of dexmedetomidine (DMED) on hypoxia ischemia injury induced by oxygen and glucose deprivation (OGD) in PC12 and primary neuronal cells. METHODS: PC12 cells exposed to OGD was used to establish ischemia model. The OGD-induced cell injury was evaluated by alterations of cell viability, apoptosis and expressions of apoptosis-associated proteins. Oxidative stress and expressions of neurotrophic factors after OGD and DMED treatments were also explored. The activation of possible involved signaling pathways were studied after OGD and DMED treatments, along with the addition of inhibitors of these pathways. Finally, the effects of DMED on primary neuronal cells were verified according to the alterations of inflammatory cytokines release and oxidative stress. RESULTS: DMED obviously increased cell viability and reduced cell apoptosis as well as ratio of Bax/Bcl-2 in OGD-treated PC12 cells. Then, the OGD-induced changes of LDH, MDA, SOD and GSH Px as well as decreases of neurotrophic factors were all ameliorated by DMED treatment. Key kinases in Notch/NF-kappaB signaling pathway were up-regulated by OGD, whereas the up-regulations were decreased by DMED. In addition, inhibitor of Notch or NF-kappaB could augment the effects of DMED on OGD-induced cell injury. Finally, the protective effects of DMED were verified in primary neuronal cells. CONCLUSION: DMED had protective effect on OGD-induced PC12 cell injury, depending on its anti-apoptotic, anti-oxidative activity and the inhibition of Notch/NF kappaB activation. Our findings suggested that DMED could be used as a potential therapeutic drug for cerebral ischemia. PMID- 28854874 TI - Recognition and treatment of severe sepsis in the emergency department: retrospective study in two French teaching hospitals. AB - BACKGROUND: Sepsis management in the Emergency Department remains a daily challenge. The Surviving Sepsis Campaign (SSC) has released three-hour bundle. The implementation of these bundles in European Emergency Departments remains poorly described. The main objective was to assess the compliance with the Severe Sepsis Campaign 3-h bundle (blood culture, lactate dosage, first dose of antibiotics and 30 ml/kg fluid challenge). Secondary objectives were the analysis of the delay of severe sepsis recognition and description of the population. METHODS: In accordance with STROBE statement, we performed a retrospective study in two French University Hospital Emergency Departments from February to August 2015. Patients admitted during the study period were screened using the electronic files of the hospital databases. Patient's files were reviewed and included in the study if they met severe sepsis criteria. Demographics, comorbities, treatments were recorded. Delays from admission to severe sepsis diagnosis, fluid loading onset and antibiotics administration were calculated. RESULTS: One hundred thirty patients were included (76 men, mean age 71 +/- 14 years). Blood culture, lactate dosage, antibiotics and 30 ml/kg fluid loading were performed within 3 hours in % [95% confidence interval] 100% [96-100%], 62% [54-70%], 49% [41-58%] and 19% [13-27%], respectively. 25 patients out of 130 (19% [13-27%]) fulfilled each criteria of the 3-h bundle. The mean fluid loading volume was 18 +/- 11 ml/kg. Mean delay between presentation and severe sepsis diagnosis was 200 +/- 263 min, from diagnosis to fluid challenge and first antibiotic dose, 10 +/- 27 min and 20 +/- 55 min, respectively. CONCLUSION: Compliance with SSC 3-h bundle and delay between admission and sepsis recognition have to be improved. If confirmed by other studies, an improvement program might be deployed. PMID- 28854875 TI - Xanthomonas adaptation to common bean is associated with horizontal transfers of genes encoding TAL effectors. AB - BACKGROUND: Common bacterial blight is a devastating bacterial disease of common bean (Phaseolus vulgaris) caused by Xanthomonas citri pv. fuscans and Xanthomonas phaseoli pv. phaseoli. These phylogenetically distant strains are able to cause similar symptoms on common bean, suggesting that they have acquired common genetic determinants of adaptation to common bean. Transcription Activator-Like (TAL) effectors are bacterial type III effectors that are able to induce the expression of host genes to promote infection or resistance. Their capacity to bind to a specific host DNA sequence suggests that they are potential candidates for host adaption. RESULTS: To study the diversity of tal genes from Xanthomonas strains responsible for common bacterial blight of bean, whole genome sequences of 17 strains representing the diversity of X. citri pv. fuscans and X. phaseoli pv. phaseoli were obtained by single molecule real time sequencing. Analysis of these genomes revealed the existence of four tal genes named tal23A, tal20F, tal18G and tal18H, respectively. While tal20F and tal18G were chromosomic, tal23A and tal18H were carried on plasmids and shared between phylogenetically distant strains, therefore suggesting recent horizontal transfers of these genes between X. citri pv. fuscans and X. phaseoli pv. phaseoli strains. Strikingly, tal23A was present in all strains studied, suggesting that it played an important role in adaptation to common bean. In silico predictions of TAL effectors targets in the common bean genome suggested that TAL effectors shared by X. citri pv. fuscans and X. phaseoli pv. phaseoli strains target the promoters of genes of similar functions. This could be a trace of convergent evolution among TAL effectors from different phylogenetic groups, and comforts the hypothesis that TAL effectors have been implied in the adaptation to common bean. CONCLUSIONS: Altogether, our results favour a model where plasmidic TAL effectors are able to contribute to host adaptation by being horizontally transferred between distant lineages. PMID- 28854876 TI - The transcription factor Maf-S regulates metabolic resistance to insecticides in the malaria vector Anopheles gambiae. AB - BACKGROUND: Malaria control in Africa is dependent upon the use insecticides but intensive use of a limited number of chemicals has led to resistance in mosquito populations. Increased production of enzymes that detoxify insecticides is one of the most potent resistance mechanisms. Several metabolic enzymes have been implicated in insecticide resistance but the processes controlling their expression have remained largely elusive. RESULTS: Here, we show that the transcription factor Maf-S regulates expression of multiple detoxification genes, including the key insecticide metabolisers CYP6M2 and GSTD1 in the African malaria vector Anopheles gambiae. Attenuation of this transcription factor through RNAi induced knockdown reduced transcript levels of these effectors and significantly increased mortality after exposure to the pyrethroid insecticides and DDT (permethrin: 9.2% to 19.2% (p = 0.015), deltamethrin: 3.9% to 21.6% (p = 0.036) and DDT: 1% to 11.7% (p = <0.01), whilst dramatically decreasing mortality induced by the organophosphate malathion (79.6% to 8.0% (p = <0.01)). Additional genes regulated by Maf-S were also identified providing new insight into the role of this transcription factor in insects. CONCLUSION: Maf-S is a key regulator of detoxification genes in Anopheles mosquitoes. Disrupting this transcription factor has opposing effects on the mosquito's response to different insecticide classes providing a mechanistic explanation to the negative cross resistance that has been reported between pyrethroids and organophosphates. PMID- 28854877 TI - Demand-side financing for maternal and newborn health: what do we know about factors that affect implementation of cash transfers and voucher programmes? AB - BACKGROUND: Demand-side financing (DSF) interventions, including cash transfers and vouchers, have been introduced to promote maternal and newborn health in a range of low- and middle-income countries. These interventions vary in design but have typically been used to increase health service utilisation by offsetting some financial costs for users, or increasing household income and incentivising 'healthy behaviours'. This article documents experiences and implementation factors associated with use of DSF in maternal and newborn health. METHODS: A secondary analysis (using an adapted Supporting the Use of Research Evidence framework - SURE) was performed on studies that had previously been identified in a systematic review of evidence on DSF interventions in maternal and newborn health. RESULTS: The article draws on findings from 49 quantitative and 49 qualitative studies. The studies give insights on difficulties with exclusion of migrants, young and multiparous women, with demands for informal fees at facilities, and with challenges maintaining quality of care under increasing demand. Schemes experienced difficulties if communities faced long distances to reach participating facilities and poor access to transport, and where there was inadequate health infrastructure and human resources, shortages of medicines and problems with corruption. Studies that documented improved care-seeking indicated the importance of adequate programme scope (in terms of programme eligibility, size and timing of payments and voucher entitlements) to address the issue of concern, concurrent investments in supply-side capacity to sustain and/or improve quality of care, and awareness generation using community-based workers, leaders and women's groups. CONCLUSIONS: Evaluations spanning more than 15 years of implementation of DSF programmes reveal a complex picture of experiences that reflect the importance of financial and other social, geographical and health systems factors as barriers to accessing care. Careful design of DSF programmes as part of broader maternal and newborn health initiatives would need to take into account these barriers, the behaviours of staff and the quality of care in health facilities. Research is still needed on the policy context for DSF schemes in order to understand how they become sustainable and where they fit, or do not fit, with plans to achieve equitable universal health coverage. PMID- 28854879 TI - Identifying priorities for quality improvement at an emergency Department in Ghana. AB - BACKGROUND: Healthcare quality improvement (QI) is a global priority, and understanding the perspectives of frontline healthcare workers can help guide sustainable and meaningful change. We report a qualitative investigation of emergency department (ED) staff priorities for QI at a tertiary care hospital in Ghana. The aims of the study were to educate staff about the World Health Organization's (WHO) definition of quality in healthcare, and to identify an initial focus for building a departmental QI program. METHODS: Semi-structured interviews were conducted with ED staff using open-ended questions to probe their understanding and valuation of the six dimensions of quality defined by the WHO. Participants were then asked to rank the dimensions in order of importance for QI. Qualitative responses were thematically analyzed, and ordinal rank-order was determined for quantitative data regarding QI priorities. RESULTS: Twenty (20) members of staff of different cadres participated, including ED physicians, nurses, orderlies, a security officer, and an accountant. A majority of participants (61%) ranked access to emergency healthcare as high priority for QI. Two recurrent themes - financial accessibility and hospital bed availability - accounted for the majority of discussions, each linked to all the dimensions of healthcare quality. CONCLUSIONS: ED staff related all of the WHO quality dimensions to their work, and prioritized access to emergency care as the most important area for improvement. Participants expressed a high degree of motivation to improve healthcare quality, and the study helped with the development of a departmental QI program focused on the broad topic of access to ED services. PMID- 28854878 TI - Comparison of rumen bacterial communities in dairy herds of different production. AB - BACKGROUND: The purpose of this study was to compare the rumen bacterial composition in high and low yielding dairy cows within and between two dairy herds. Eighty five Holstein dairy cows in mid-lactation (79-179 days in milk) were selected from two farms: Farm 12 (M305 = 12,300 kg; n = 47; 24 primiparous cows, 23 multiparous cows) and Farm 9 (M305 = 9700 kg; n = 38; 19 primiparous cows, 19 multiparous cows). Each study cow was sampled once using the stomach tube method and processed for 16S rRNA gene amplicon sequencing using the Ion Torrent (PGM) platform. RESULTS: Differences in bacterial communities between farms were greater (Adonis: R2 = 0.16; p < 0.001) than within farm. Five bacterial lineages, namely Prevotella (48-52%), unclassified Bacteroidales (10 12%), unclassified bacteria (5-8%), unclassified Succinivibrionaceae (1-7%) and unclassified Prevotellaceae (4-5%) were observed to differentiate the community clustering patterns among the two farms. A notable finding is the greater (p < 0.05) contribution of Succinivibrionaceae lineages in Farm 12 compared to Farm 9. Furthermore, in Farm 12, Succinivibrionaceae lineages were higher (p < 0.05) in the high yielding cows compared to the low yielding cows in both primiparous and multiparous groups. Prevotella, S24-7 and Succinivibrionaceae lineages were found in greater abundance on Farm 12 and were positively correlated with milk yield. CONCLUSIONS: Differences in rumen bacterial populations observed between the two farms can be attributed to dietary composition, particularly differences in forage type and proportion in the diets. A combination of corn silage and alfalfa silage may have contributed to the increased proportion of Proteobacteria in Farm 12. It was concluded that Farm 12 had a greater proportion of specialist bacteria that have the potential to enhance rumen fermentative digestion of feedstuffs to support higher milk yields. PMID- 28854880 TI - Understanding the implementation of maternity waiting homes in low- and middle income countries: a qualitative thematic synthesis. AB - BACKGROUND: Maternity waiting homes (MWHs) are accommodations located near a health facility where women can stay towards the end of pregnancy and/or after birth to enable timely access to essential childbirth care or care for complications. Although MWHs have been implemented for over four decades, different operational models exist. This secondary thematic +analysis explores factors related to their implementation. METHODS: A qualitative thematic analysis was conducted using 29 studies across 17 countries. The papers were identified through an existing Cochrane review and a mapping of the maternal health literature. The Supporting the Use of Research Evidence framework (SURE) guided the thematic analysis to explore the perceptions of various stakeholders and barriers and facilitators for implementation. The influence of contextual factors, the design of the MWHs, and the conditions under which they operated were examined. RESULTS: Key problems of MWH implementation included challenges in MWH maintenance and utilization by pregnant women. Poor utilization was due to lack of knowledge and acceptance of the MWH among women and communities, long distances to reach the MWH, and culturally inappropriate care. Poor MWH structures were identified by almost all studies as a major barrier, and included poor toilets and kitchens, and a lack of space for family and companions. Facilitators included reduced or removal of costs associated with using a MWH, community involvement in the design and upkeep of the MWHs, activities to raise awareness and acceptance among family and community members, and integrating culturally-appropriate practices into the provision of maternal and newborn care at the MWHs and the health facilities to which they are linked. CONCLUSION: MWHs should not be designed as an isolated intervention but using a health systems perspective, taking account of women and community perspectives, the quality of the MWH structure and the care provided at the health facility. Careful tailoring of the MWH to women's accommodation, social and dietary needs; low direct and indirect costs; and a functioning health system are key considerations when implementing MWH. Improved and harmonized documentation of implementation experiences would provide a better understanding of the factors that impact on successful implementation. PMID- 28854881 TI - Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke. AB - BACKGROUND: While neurogranin has no value as plasma biomarker for Alzheimer's disease, it may be a potential blood biomarker for traumatic brain injury. This evokes the question whether there are changes in neurogranin levels in blood in other conditions of brain injury, such as acute ischemic stroke (AIS). METHODS: We therefore explored neurogranin in paired cerebrospinal fluid (CSF)/plasma samples of AIS patients (n = 50) from a well-described prospective study. In parallel, we investigated another neuronal protein, i.e. tau, which has already been suggested as potential AIS biomarker in CSF and blood. ELISA as well as Single Molecule Array (Simoa) technology were used for the biochemical analyses. Statistical analyses included Shapiro-Wilk testing, Mann-Whitney analyses and Pearson's correlation analysis. RESULTS: In contrast to tau, of which high levels in both CSF and plasma were related to stroke characteristics like severity and long-term outcome, plasma neurogranin levels were only correlated with infarct volume. Likewise, CSF neurogranin levels were significantly higher in patients with an infarct volume > 5 mL than in patients with smaller infarct volumes. Finally, neurogranin and tau were significantly correlated in CSF, whereas a weaker relationship was observed in plasma. CONCLUSIONS: These findings indicate that although plasma and CSF neurogranin may reflect the volume of acute cerebral ischemia, this synaptic protein is less likely to be a potential AIS biomarker. Levels of tau correlated with severity and outcome of stroke in both plasma and CSF, in the present study as well as previous reports, confirming the potential of tau as an AIS biomarker. PMID- 28854882 TI - A four-domain approach of frailty explored in the Doetinchem Cohort Study. AB - BACKGROUND: Accumulation of problems in physical, psychological, cognitive, or social functioning is characteristic for frail individuals. Using a four-domain approach of frailty, this study explored how sociodemographic and lifestyle factors, life events and health are associated with frailty. METHODS: The study sample included 4019 men and women (aged 40-81 years) examined during the fifth round (2008-2012) of the Doetinchem Cohort Study. Four domains of frailty were considered: physical (>=4 of 8 criteria: unintentional weight loss, exhaustion, strength, perceived health, walking, balance, hearing and vision impairments), psychological (2 criteria: depressive symptoms, mental health), cognitive (<10th percentile on global cognitive functioning), and social frailty (>=2 of 3 criteria: loneliness, social support, social participation). Logistic regression was used to study the cross-sectional association of sociodemographic factors, lifestyle, life events and chronic diseases with frailty domains. RESULTS: About 17% of the population was frail on one or more domains. Overlap between the frailty domains was limited since 82% of the frail population was frail on one domain only. Low educated respondents were at higher risk of being psychologically and socially frail. Having multiple diseases was associated with a higher risk of being physically and psychologically frail. Being physically active was consistently associated with a lower risk of frailty on each of the four domains. Short or long sleep duration was associated with a higher risk of being physically, psychologically, and socially frail. CONCLUSIONS: Sociodemographic factors, lifestyle and multimorbidity contributed differently to the four frailty domains. It is important to consider multiple frailty domains since this helps to identify different groups of frail people, and as such to provide tailored care and support. Lifestyle factors including physical activity, smoking and sleep duration were associated with multiple domains of frailty. PMID- 28854883 TI - Addition of nucleoside analogues to peg-IFNalpha-2a enhances virological response in chronic hepatitis B patients without early response to peg-IFNalpha-2a: a randomized controlled trial. AB - BACKGROUND: Current treatments for chronic hepatitis B (CHB) include pegylated interferon alpha (PEG-IFN-alpha) which is an immune modulator, and nucleos(t)ide analogs (NAs) which directly inhibit HBV DNA polymerase. With the limited efficacy of PEG-IFN-alpha and prolonged treatment periods associated with NAs, there is an urgent need for novel therapeutic strategies, especially for patients with a poor early response to anti-viral therapy. METHODS: In this study, 178 patients with chronic hepatitis B (n = 131) and compensated (n = 47) HBV-induced cirrhosis were enrolled, 120 patients with HBeAg (+). All the patients were treated for 12 weeks with PEG-IFN-alpha. Among them, a total of 138 patients with a poor virological response after 12 weeks were treated for an additional 48 weeks with Peg-IFNalpha-2a (control) (n = 43), with Peg-IFNalpha-2a + entecavir (ETV) (n = 49), or Peg-IFNalpha-2a + adefovir dipivoxil (ADV) (n = 46), and were followed for 48 weeks after therapy. Early virological response was defined as undetectable HBV DNA after anti-viral therapy for 12 weeks. Sustained virological response (SVR) was defined as no change in therapeutic effectiveness after 6 months follow-up, and no recurrence.Therapeutic efficacy was determined by evaluating HBV DNA levels, serum and liver HBsAg levels, liver function tests and liver histology. RESULTS: Patients in the Peg-IFNalpha-2a + ETV and Peg-IFNalpha 2a + ADV groups showed a significantly greater decrease in HBV DNA levels over time, and a significantly higher SVR compared to patients receiving Peg-INFalpha 2a monotherapy (both P values <0.05). Although patients receiving combination therapy had a significantly higher change in serum HBsAg levels compared to the monotherapy group, there was no significant difference in liver HBsAg levels between the three treatment groups. CONCLUSION: This study demonstrated that in patients with a poor virological response after 12 weeks of treatment with Peg IFNalpha-2a alone, addition of ADV or ETV significantly reduced HBV DNA levels, serum HBsAg levels, and increased SVR. Individualization of anti-viral therapy would ensure that only patients who do not respond to Peg-IFNalpha-2a would receive combination therapy. Our data have important implications for the treatment of CHB patients who fail to show an early response to Peg-IFNalpha-2a monotherapy. TRIAL REGISTRATION: This trial was retrospectively registered on 2012 May 24 at the China Clinical Trials Registry (ChiCTR-OCC-12002196). PMID- 28854884 TI - A multi-center, randomized, controlled trial to assess the efficacy of optimization of drug prescribing in an elderly population, at 18 months of follow up, in the evolution of functional autonomy: the OPTIM study protocol. AB - BACKGROUND: Pharmacotherapy is necessary for the management of many diseases which number increased with aging. However, potentially inappropriate prescriptions and polymedication increases iatrogenic risks and can lead to adverse events. To limit the consequences of potentially harmful prescriptions, optimization of drug prescribing is a major stake of improving quality and safety of care in the elderly. The purpose of the OPTIM study is to study the impact of the optimization of drug prescribing on the evolution of functional autonomy at 18 months of follow-up. METHODS: A multicenter, open-label, Randomized Controlled Trial was designed to assess the impact of an optimization program of drug prescribing consisting in a clinical medication review by a pharmacist, in collaboration with specialist physician of the geriatric/memory center and the referent physician, on the evolution of functional autonomy level, measured during 18 months of follow-up. The study will include 302 elderly outpatients visiting geriatric and memory centers, randomly distributed in one of the two parallel groups. One group will benefit of the intervention, while the other will be considered as control group. The effect of the intervention on evolution of the level of autonomy function, defined with repeated measures, will be estimated in a generalized linear mixed model. The intervention will be considered significant if the interaction between time and the study group is significant. Secondary analysis will be conducted to assess the impact of the intervention on secondary clinical outcomes. DISCUSSION: The "OPTIM" program should enable optimization of drug prescribing in elderly patients and therefore slow or prevent progression to loss of functional autonomy. It should also help to strengthen collaboration between the hospital team of geriatric/neurologist, the pharmacist and the private practice who are all involved in caring for the patient's health. The benefits for the patient are thus optimizing its medical management by linking health professionals met during his care pathway. In addition, pharmaceutical recommendations sent to referent physicians should help raise awareness of the prescription of drugs in these patients. TRIAL REGISTRATION NUMBER CLINICALTRIALS: NCT02740764. PMID- 28854885 TI - Is neuron-specific enolase useful for diagnosing malignant pleural effusions? evidence from a validation study and meta-analysis. AB - BACKGROUND: Neuron-Specific enolase (NSE) has been used as a typical tumor marker and shows a potential to diagnose malignant pleural effusion (MPE). The ability of NSE in diagnosing MPE has been investigated in many studies, but with inconsistent conclusions. This study sought to investigate the diagnostic accuracy of NSE for MPE through a clinical study and together with a meta analysis. METHODS: Pleural effusion samples from 136 patients with MPE and 102 patients with benign pleural effusion (BPE) were collected, and NSE levels were measured by electrochemiluminescence immunoassay. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of NSE to differentiate MPE from BPE. Literature search was conducted to identify suitable publications, data were extracted and diagnostic indexes including sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were pooled. Summary ROC curve was generated to determine the overall diagnostic accuracy of NSE for MPE. RESULTS: Levels of NSE were significantly increased in pleural effusion from patients with MPE than that from BPE (18.53 +/ 27.30 vs. 6.41 +/- 6.95 ng/ml, p < 0.001). With a cut-off value of 8.92 ng/ml, pleural NSE had a sensitivity of 59.56% and a specificity of 83.33% in diagnosing MPE. A total of 14 studies with 1896 subjects were included for meta-analysis. The diagnostic parameters of NSE were listed as follows: sensitivity, 0.53 (95% CI: 0.38-0.67); specificity, 0.85 (95% CI: 0.75-0.91); PLR, 3.54 (95% CI: 2.33 5.39); NLR, 0.56 (95% CI: 0.42-0.73); and DOR, 6.39 (95% CI: 3.72-10.96). The area under the summary ROC curve was 0.78. CONCLUSIONS: The role of pleural NSE measurement in diagnosing MPE is limited and with a low sensitivity. The clinical utility of NSE assay should be combined with the results of other tumor markers examination and the detail clinical information of patient. Further studies are needed to confirm the role of NSE in diagnosing MPE. PMID- 28854886 TI - Factors affecting effective community participation in maternal and newborn health programme planning, implementation and quality of care interventions. AB - BACKGROUND: Community participation in in health programme planning, implementation and quality improvement was recently recommended in guidelines to improve use of skilled care during pregnancy, childbirth and the postnatal period for women and newborns. How to implement community participation effectively remains unclear. In this article we explore different factors. METHODS: We conducted a secondary analysis, using the Supporting the Use of Research Evidence framework, of effectiveness studies identified through systematic literature reviews of two community participation interventions; quality improvement of maternity care services; and maternal and newborn health programme planning and implementation. RESULTS: Community participation ranged from outreach educational activities to communities being full partners in decision-making. In general, implementation considerations were underreported. Key facilitators of community participation included supportive policy and funding environments where communities see women's health as a collective responsibility; linkages with a functioning health system e.g. via stakeholder committees; intercultural sensitivity; and a focus on interventions to strengthen community capacity to support health. Levels of participation and participatory approaches often changed over the life of programmes as community and health services capacity to interact developed. CONCLUSION: Implementation requires careful consideration of the context: previous experience with participation, who will be involved, gender norms, and the timeframe for implementation. Relevant stakeholders must be actively involved, particularly those often excluded from decision making. Current limited evidence suggests that the vision of community participation as a process and the presence of a focus to strengthen community capacity to participate and to improve health may be a key factor for long term success. PMID- 28854887 TI - Acquisition and clearance of multidrug resistant Acinetobacter baumannii on healthy young adults concurrently burned in a dust explosion in Taiwan: the implication for antimicrobial stewardship. AB - BACKGROUND: Information is limited about the effect of restricted carbapenem use on clearance of multi-drug resistant Acinetobacter baumannii (MDRAB). We sought to determine the time effect of antibiotic exposure on multi-drug resistant Acinetobacter baumannii (MDRAB) acquisition and clearance. METHODS: We conducted a retrospective observational study at the intensive care units of a tertiary medical center. Forty-two of a cohort of previously healthy young adults who were concurrently burned by a dust explosion was included. Cases consisted of those from whom MDRAB was isolated during hospitalization. Controls consisted of patients from whom MDRAB was not isolated in the same period. Use of antimicrobial agents was compared based on days of therapy per 1,000 patient-days (DOT/1,000PD). A 2-state Markov multi-state model was used to estimate the risk of acquisition and clearance of MDRAB. RESULTS: MDRAB was discovered in 9/42 (21.4%) individuals. The cases had significantly higher use of carbapenem (652 DOT/1,000PD vs. 385 DOT/1,000PD, P < 0.001) before MDRAB isolation. For the cases, clearance of MDRAB was associated with lower use of carbapenem (469 DOT/1,000PD vs. 708 DOT/1,000PD, P = 0.003) and higher use of non-carbapenem beta lactam (612 DOT/1,000PD vs. 246 DOT/1,000PD, P <0.001). In multi-state model, each additional DOT of carbapenem increased the hazard of acquiring MDRAB (hazard ratio (HR), 1.08; 95% confidence interval (CI) 1.01-1.16) and each additional DOT of non-carbapenem beta-lactam increased the protection of clearing MDRAB (HR, 1.25; 95% CI 1.07-1.46). CONCLUSIONS: Both acquisition and clearance of MDRAB were related to antibiotic exposure in a homogeneous population. Our findings suggest that early discontinuation of carbapenem could be an effective measure in antibiotic stewardship for the control of MDRAB spreading. PMID- 28854888 TI - Principles and processes behind promoting awareness of rights for quality maternal care services: a synthesis of stakeholder experiences and implementation factors. AB - BACKGROUND: Promoting awareness of rights is a value-based process that entails a different way of thinking and acting, which is at times misunderstood or deemed as aspirational. METHODS: Guided by the SURE framework, we undertook a secondary analysis of 26 documents identified by an earlier systematic review on promoting awareness of rights to increase use of maternity care services. We thematically analysed stakeholder experiences and implementation factors across the diverse initiatives to derive common elements to guide future efforts. RESULTS: Interventions that promote awareness of rights for maternal health varied in nature, methodological orientation, depth and quality. Materials included booklets, posters, pamphlets/ briefs and service standards/charters. Target populations included women, family members, communities, community structures, community-based and non governmental organizations, health providers and administrators, as well as elected representatives. While one initiative only focused on raising awareness, most were embedded within larger efforts to improve the accountability and responsiveness of service delivery through community monitoring and advocacy, with a few aiming to change policies and contest elections. Underlying these action oriented forms of promoting awareness of rights, was a critical consciousness and attitudinal change gained through iterative capacity-building for all stakeholders; materials and processes that supported group discussion and interaction; the formation or strengthening of community groups; situational analysis to ensure adaptation to local context; facilitation to ensure common ground and language across stakeholders; and strategic networking and alliance building across health system levels. While many positive experiences are discussed, few challenges or barriers to implementation are documented. The limited documentation and poor quality of information found indicate that while various examples of promoting awareness of rights for maternal health exists, research partnerships to systematically evaluate their processes, learning and effects are lacking. CONCLUSION: Rather than being aspirational, several examples of promoting awareness of women's rights for quality maternity care services exist. More than mainly disseminate information, they aim to change stakeholder mindsets and relationships across health system levels. Due to their transformatory intent they require sustained investment, with strategic planning, concrete operationalization and political adeptness to manage dynamic stakeholder expectations and reactions overtime. More investment is also required in research partnerships that support such initiatives and better elucidate their context specific variations. PMID- 28854889 TI - Spatiotemporal epidemiology of scarlet fever in Jiangsu Province, China, 2005 2015. AB - BACKGROUND: A marked increase in the incidence rate of scarlet fever imposed a considerable burden on the health of children aged 5 to 15 years. The main purpose of this study was to depict the spatiotemporal epidemiological characteristics of scarlet fever in Jiangsu Province, China in order to develop and implement effective scientific prevention and control strategies. METHODS: Smoothed map was used to demonstrate the spatial distribution of scarlet fever in Jiangsu Province. In addition, a retrospective space-time analysis based on a discrete Poisson model was utilized to detect clusters of scarlet fever from 2005 to 2015. RESULTS: During the years 2005-2015, a total of 15,873 scarlet fever cases occurred in Jiangsu Province, with an average annual incidence rate of 1.87 per 100,000. A majority of the cases (83.67%) occurred in children aged 3 to 9 years. Each year, two seasonal incidence peaks were observed, the higher occurring between March and July, the lower between November and the following January. The incidence in the southern regions of the province was generally higher than that in the northern regions. Seven clusters, all of which occurred during incidence peaks, were detected via space-time scan statistical analysis. The most likely cluster and one of the secondary clusters were detected in the southern and northern high endemic regions, respectively. CONCLUSION: The prevalence of scarlet fever in Jiangsu Province had a marked seasonality variation and was relatively endemic in some regions. Children aged 3 to 9 years were the major victims of this disease, and kindergartens and primary schools were the focus of surveillance and control. Targeted strategies and measures should be taken to reduce the incidence. PMID- 28854890 TI - Chemoradiotherapy versus surgery followed by postoperative radiotherapy in tonsil cancer: Korean Radiation Oncology Group (KROG) study. AB - BACKGROUND: Treatment of tonsil cancer, a subset of oropahryngeal cancer, varies between surgery and radiotherapy. Well-designed studies in tonsil cancer have been rare and it is still controversial which treatment is optimal. This study aimed to assess the outcome and failure patterns in tonsil cancer patients treated with either approaches. METHODS: We retrospectively reviewed medical records of 586 patients with tonsil cancer, treated between 1998 and 2010 at 16 hospitals in Korea. Two hundred and one patients received radiotherapy and chemotherapy (CRT), while 385 patients received surgery followed by radiotherapy and/or chemotherapy (SRT). Compared with the SRT group, patients receiving CRT were older, with more advanced T stage and received higher radiotherapy dose given by intensity modulation techniques. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant metastasis free survival (DMFS), and clinicopathologic factors were analyzed. RESULTS: At follow-up, the 5-year OS, DFS, LRRFS and DMFS rates in the CRT group were 82, 78, 89, and 94%, respectively, and in the SRT group were 81, 73, 87, and 89%, respectively. Old age, current smoking, poor performance status, advanced T stage, nodal involvement, and induction chemotherapy were associated with poor OS. Induction chemotherapy had a negative prognostic impact on OS in both treatment groups (p = 0.001 and p = 0.033 in the CRT and SRT groups, respectively). CONCLUSIONS: In our multicenter, retrospective study of tonsil cancer patients, the combined use of radiotherapy and chemotherapy resulted in comparable oncologic outcome to surgery followed by postoperative radiotherapy, despite higher-risk patients having been treated with the definitive radiotherapy. Induction chemotherapy approaches combined with either surgery or definitive radiotherapy were associated with unfavorable outcomes. PMID- 28854891 TI - Cancer-related risk factors and incidence of major cancers by race, gender and region; analysis of the NIH-AARP diet and health study. AB - BACKGROUND: Racial disparities in the incidence of major cancers may be attributed to differences in the prevalence of established, modifiable risk factors such as obesity, smoking, physical activity and diet. METHODS: Data from a prospective cohort of 566,398 adults aged 50-71 years, 19,677 African-American and 450,623 Whites, was analyzed. Baseline data on cancer-related risk factors such as smoking, alcohol, physical activity and dietary patterns were used to create an individual adherence score. Differences in adherence by race, gender and geographic region were assessed using descriptive statistics, and Cox proportional hazards models were used to determine the association between adherence and cancer incidence. RESULTS: Only 1.5% of study participants were adherent to all five cancer-related risk factor guidelines, with marked race-, gender- and regional differences in adherence overall. Compared with participants who were fully adherent to all five cancer risk factor criteria, those adherent to one or less had a 76% increased risk of any cancer incidence (HR: 1.76, 95% CI: 1.70 - 1.82), 38% increased risk of breast cancer (HR: 1.38, 95% CI: 1.25 - 1.52), and doubled the risk of colorectal cancer (HR: 2.06, 95% CI: 1.84 - 2.29). However, risk of prostate cancer was lower among participants adherent to one or less compared with those who were fully adherent (HR: 0.79, 95% CI: 0.75 - 0.85). The proportion of cancer incident cases attributable to low adherence was higher among African-Americans compared with Whites for all cancers (21% vs. 19%), and highest for colorectal cancer (25%) regardless of race. CONCLUSION: Racial differences in the proportion of cancer incidence attributable to low adherence suggests unique opportunities for targeted cancer prevention strategies that may help eliminate racial disparities in cancer burden among older US adults. PMID- 28854892 TI - Incidence of human rabies and characterization of rabies virus nucleoprotein gene in dogs in Fujian Province, Southeast China, 2002-2012. AB - BACKGROUND: Rabies is a global fatal infectious viral disease that is characterized by a high mortality after onset of clinical symptoms. Recently, there has been an increase in the incidence of rabies in China. The aim of this study was to investigate the incidence of human rabies and characterize the rabies virus nucleoprotein gene in dogs sampled from Fujian Province, Southeast China from 2002 to 2012. METHODS: Data pertaining to human rabies cases in Fujian Province during the period from 2002 through 2012 were collected, and the epidemiological profiles were described. The saliva and brain specimens were collected from dogs in Quanzhou, Longyan and Sanming cities of the province, and the rabies virus antigen was determined in the canine saliva specimens using an ELISA assay. Rabies virus RNA was extracted from canine brain specimens, and rabies virus nucleoprotein gene was amplified using a nested RT-PCR assay, followed by sequencing and genotyping. RESULTS: A total of 226 human rabies cases were reported in Fujian Province from 2002 to 2012, in which 197 cases were detected in three cities of Quanzhou, Longyan and Sanming. ELISA assay revealed positive rabies virus antigen in six of eight rabid dogs and 165 of 3492 seemingly healthy dogs. The full-length gene fragment of the rabies virus nucleoprotein gene was amplified from the brain specimens of seven rabid dogs and 12 seemingly healthy dogs. Sequence alignment and phylogenetic analysis revealed that these 19 rabies virus nucleoprotein genes all belonged to genotype I, and were classified into three genetic groups. Sequencing analysis showed a 99.7% to 100% intra-group and an 86.4% to 89.3% inter-group homology. CONCLUSIONS: This study is the first description pertaining to the epidemiological characteristics of human rabies cases and characterization of the rabies virus nucleoprotein gene in dogs in Fujian Province, Southeast China. Our findings may provide valuable knowledge for the development of strategies targeting the prevention and control of rabies. PMID- 28854893 TI - Self-reported sexual health: Breast cancer survivors compared to women from the general population - an observational study. AB - BACKGROUND: Cancer survivorship is of increasing importance in post-treatment care. Sexual health (SH) and femininity can be crucial issues for women surviving cancer. We aimed to determine a more complete understanding of the contribution that a breast cancer (BC) diagnosis and its treatment exert on patients' follow up SH. For this purpose, self-reported levels and predictors of SH in breast cancer survivors (BCS) were compared with those of women with no previous or current BC (WNBC). METHODS: BCS and WNBC underwent a comprehensive, cross sectional patient-reported outcome (PRO) assessment. Validated PRO instruments were used to measure SH, body image, anxiety and depression and menopausal symptoms. Assessments were performed within the routine clinical setting. Instruments used were the Sexual Interest and Desire Inventory - Female, Sexual Activity Questionnaire, Body Image Scale, Hospital Anxiety and Depression Scale and the Menopause-Specific Quality of Life Questionnaire. RESULTS: One hundred five BCS (average time since diagnosis of 3 years) and 97 WNBC with a mean age of 49 years completed the assessment. SH was significantly worse in BCS compared to WNBC (p = 0.005; BCS SIDI-F mean = 24.9 vs. WNBC mean = 29.8). 68.8% of BCS and 58.8% of WNBC met criteria of a hypo-active sexual desire disorder. Higher depressive symptoms, higher age and lower partnership satisfaction were predictive for poorer SH in BCS. CONCLUSION: SH problems are apparent in BCS and differ significantly from those seen in the general population. Consequently, BC survivorship care should include interventions to ameliorate sexual dysfunction and provide help with depressive symptoms and partnership problems, which are associated with poor BCS SH. PMID- 28854894 TI - Development of a questionnaire for assessing the childbirth experience (QACE). AB - BACKGROUND: Due to its potential impact on women's psychological health, assessing perceptions of their childbirth experience is important. The aim of this study was to develop a multidimensional self-reporting questionnaire to evaluate the childbirth experience. METHODS: Factors influencing the childbirth experience were identified from a literature review and the results of a previous qualitative study. A total of 25 items were combined from existing instruments or were created de novo. A draft version was pilot tested for face validity with 30 women and submitted for evaluation of its construct validity to 477 primiparous women at one-month post-partum. The recruitment took place in two obstetric clinics from Swiss and French university hospitals. To evaluate the content validity, we compared item responses to general childbirth experience assessments on a numeric, 0 to 10 rating scale. We dichotomized two group assessment scores: "0 to 7" and "8 to 10". We performed an exploratory factor analysis to identify underlying dimensions. RESULTS: In total, 291 women completed the questionnaire (response rate = 61%). The responses to 22 items were statistically significant between the 0 to 7 and 8 to 10 groups for the general childbirth experience assessments. An exploratory factor analysis yielded four sub-scales, which were labelled "relationship with staff" (4 items), "emotional status" (3 items), "first moments with the new born," (3 items) and "feelings at one month postpartum" (3 items). All 4 scales had satisfactory internal consistency levels (alpha coefficients from 0.70 to 0.85). The full 25-item version can be used to analyse each item by itself, and the short 4-dimension version can be scored to summarize the general assessment of the childbirth experience. CONCLUSIONS: The Questionnaire for Assessing the Childbirth Experience (QACE) could be useful as a screening instrument to identify women with negative childbirth experiences. It can be used as both a research instrument in its short version and a questionnaire for use in clinical practice in its full version. PMID- 28854895 TI - Improving implementation of health promotion interventions for maternal and newborn health. PMID- 28854897 TI - Expression patterns of flowering genes in leaves of 'Pineapple' sweet orange [Citrus sinensis (L.) Osbeck] and pummelo (Citrus grandis Osbeck). AB - BACKGROUND: In citrus the transition from juvenility to mature phase is marked by the capability of a tree to flower and fruit consistently. The long period of juvenility in citrus severely impedes the use of genetic based strategies to improve fruit quality, disease resistance, and responses to abiotic environmental factors. One of the genes whose expression signals flower development in many plant species is FLOWERING LOCUS T (FT). RESULTS: In this study, gene expression levels of flowering genes CiFT1, CiFT2 and CiFT3 were determined using reverse transcription quantitative real-time PCR in citrus trees over a 1 year period in Florida. Distinct genotypes of citrus trees of different ages were used. In mature trees of pummelo (Citrus grandis Osbeck) and 'Pineapple' sweet orange (Citrus sinensis (L.) Osbeck) the expression of all three CiFT genes was coordinated and significantly higher in April, after flowering was over, regardless of whether they were in the greenhouse or in the field. Interestingly, immature 'Pineapple' seedlings showed significantly high levels of CiFT3 expression in April and June, while CiFT1 and CiFT2 were highest in June, and hence their expression induction was not simultaneous as in mature plants. CONCLUSIONS: In mature citrus trees the induction of CiFTs expression in leaves occurs at the end of spring and after flowering has taken place suggesting it is not associated with dormancy interruption and further flower bud development but is probably involved with shoot apex differentiation and flower bud determination. CiFTs were also seasonally induced in immature seedlings, indicating that additional factors must be suppressing flowering induction and their expression has other functions. PMID- 28854896 TI - Acute rhabdomyolysis and delayed pericardial effusion in an Italian patient with Ebola virus disease: a case report. AB - BACKGROUND: During the 2013-2016 West Africa Ebola virus disease (EVD) epidemic, some EVD patients, mostly health care workers, were evacuated to Europe and the USA. CASE PRESENTATION: In May 2015, a 37-year old male nurse contracted Ebola virus disease in Sierra Leone. After Ebola virus detection in plasma, he was medically-evacuated to Italy. At admission, rhabdomyolysis was clinically and laboratory-diagnosed and was treated with aggressive hydration, oral favipiravir and intravenous investigational monoclonal antibodies against Ebola virus. The recovery clinical phase was complicated by a febrile thrombocytopenic syndrome with pericardial effusion treated with corticosteroids for 10 days and indomethacin for 2 months. No evidence of recurrence is reported. CONCLUSIONS: A febrile thrombocytopenic syndrome with pericardial effusion during the recovery phase of EVD appears to be uncommon. Clinical improvement with corticosteroid treatment suggests that an immune-mediated mechanism contributed to the pericardial effusion. PMID- 28854898 TI - Omics data reveal the unusual asexual-fruiting nature and secondary metabolic potentials of the medicinal fungus Cordyceps cicadae. AB - BACKGROUND: Ascomycete Cordyceps species have been using as valued traditional Chinese medicines. Particularly, the fruiting bodies of Cordyceps cicadae (syn. Isaria cicadae) have long been utilized for the treatment of chronic kidney disease. However, the genetics and bioactive chemicals in this fungus have been largely unexplored. RESULTS: In this study, we performed comprehensive omics analyses of C. cicadae, and found that, in contrast to other Cordyceps fungi, C. cicadae produces asexual fruiting bodies with the production of conidial spores instead of the meiotic ascospores. Genome sequencing and comparative genomic analysis indicate that the protein families encoded by C. cicadae are typical of entomopathogenic fungi, including the expansion of proteases and chitinases for targeting insect hosts. Interestingly, we found that the MAT1-2 mating-type locus of the sequenced strain contains an abnormally truncated MAT1-1-1 gene. Gene deletions revealed that asexual fruiting of C. cicadae is independent of the MAT locus control. RNA-seq transcriptome data also indicate that, compared to growth in a liquid culture, the putative genes involved in mating and meiosis processes were not up-regulated during fungal fruiting, further supporting asexual reproduction in this fungus. The genome of C. cicadae encodes an array of conservative and divergent gene clusters for secondary metabolisms. Based on our analysis, the production of known carcinogenic metabolites by this fungus could be potentially precluded. However, the confirmed production of oosporein raises health concerns about the frequent consumption of fungal fruiting bodies. CONCLUSIONS: The results of this study expand our knowledge of fungal genetics that asexual fruiting can occur independent of the MAT locus control. The obtained genomic and metabolomic data will benefit future investigations of this fungus for medicinal uses. PMID- 28854899 TI - Reverse epidemiology of elevated blood pressure among chronic hemodialysis black patients with stroke: a historical cohort study. AB - BACKGROUND: Stroke is the third leading cause of cardiovascular mortality in dialysis patients. The objective of this study was to assess the extent of stroke in chronic hemodialysis patients. METHODS: Historical cohort of patients enrolled in two hemodialysis (HD) centers from January 1, 2010 to December 31, 2011, including 191 patients (mean age 52 years, 68% men). Incidence curves and survival time analysis between the first day of HD and the end of the study were described by the Kaplan-Meier method. Independent stroke predictors were identified by multiple logistic regression analysis. P < 0.05 defined the level of statistical significance. RESULTS: 12 incident stroke were recorded during the study period, with 1622.1 person-months (PM), a stroke incidence rate of 7.4 cases per 1000 PM (95% CI = 7.35-7.44) at the point date. The incidence of stroke at 6 months, 12 months and 24 months was 9.8%, 11.9% and 13%, respectively. Only the absence of arterial hypertension (RR = 5.7, 95% CI: 1.52-21.42) emerged as an independent determinant of stroke. CONCLUSION: The high incidence of stroke in Kinshasa HD centers is partially explained by reverse epidemiology. Efforts must be made to understand this phenomenon in order to reduce its impact. PMID- 28854900 TI - VEGFR2 regulates endothelial differentiation of colon cancer cells. AB - BACKGROUND: Recent studies suggested that cancer stem-like cells contribute to tumor vasculogenesis by differentiating into endothelial cells. However, such process is governed by still undefined mechanism. METHODS: At varying differentiation levels, three representative colon cancer cells were cultured in endothelial-inducing conditioned medium: human colon cancer cells HCT116 (HCT116) (poorly differentiated), SW480 (moderately differentiated), and HT29 (well differentiated). We tested for expression of endothelial markers (cluster of differentiation (CD) 31, CD34, and vascular endothelial (VE)-cadherin and their ability to form tube-like structures in 3D culture. We also observed VEGF secretion and expressions of endothelial markers and VEGFRs in HCT116 cells under hypoxia to simulate physiological conditions. In in vitro and in xenotransplantation experiments, VE growth factor receptor 2 (VEGFR2) antagonist SKLB1002 was used to test effect of VEGFR2 in endothelial differentiation of HCT116 cells. Expression levels of VEGFR2 and VE-cadherin were assessed by immunohistochemistry of human colon cancer tissues to evaluate clinicopathological significance of VEGFR2. RESULTS: After culturing in endothelial-inducing conditioned medium, poorly differentiated HCT116 cells expressed endothelial markers and formed tube-like structure in vitro. HCT116 cells secreted more endogenous VEGF and expressed higher VEGFR2 under hypoxia. SKLB1002 impaired endothelial differentiation in vitro and xenotransplantation experiments, suggesting a VEGFR2-dependent mechanism. Increased expression of VEGFR2 correlated with differentiation, metastasis/recurrence, and poor prognosis in 203 human colon cancer samples. Positive correlation was observed between VEGFR2 and VE-cadherin expression. CONCLUSIONS: VEGFR2 regulates endothelial differentiation of colon cancer cell and may be potential platform for anti angiogenesis cancer therapy. PMID- 28854901 TI - Interventions to provide culturally-appropriate maternity care services: factors affecting implementation. AB - BACKGROUND: The World Health Organization recently made a recommendation supporting 'culturally-appropriate' maternity care services to improve maternal and newborn health. This recommendation results, in part, from a systematic review we conducted, which showed that interventions to provide culturally appropriate maternity care have largely improved women's use of skilled maternity care. Factors relating to the implementation of these interventions can have implications for their success. This paper examines stakeholders' perspectives and experiences of these interventions, and facilitators and barriers to implementation; and concludes with how they relate to the effects of the interventions on care-seeking outcomes. METHODS: We based our analysis on 15 papers included in the systematic review. To extract, collate and organise data on the context and conditions from each paper, we adapted the SURE (Supporting the Use of Research Evidence) framework that lists categories of factors that could influence implementation. We considered information from the background and discussion sections of papers included in the systematic review, as well as cost data and qualitative data when included. RESULTS: Women's and other stakeholders' perspectives on the interventions were generally positive. Four key themes emerged in our analysis of facilitators and barriers to implementation. Firstly, interventions must consider broader economic, geographical and social factors that affect ethnic minority groups' access to services, alongside providing culturally-appropriate care. Secondly, community participation is important in understanding problems with existing services and potential solutions from the community perspective, and in the development and implementation of interventions. Thirdly, respectful, person-centred care should be at the core of these interventions. Finally, cohesiveness is essential between the culturally appropriate service and other health care providers encountered by women and their families along the continuum of care through pregnancy until after birth. CONCLUSION: Several important factors should be considered and addressed when implementing interventions to provide culturally-appropriate care. These factors reflect more general goals on the international agenda of improving access to skilled maternity care; providing high-quality, respectful care; and community participation. PMID- 28854902 TI - Factors influencing implementation of interventions to promote birth preparedness and complication readiness. AB - BACKGROUND: The recent WHO report on health promotion interventions for maternal and newborn health recommends birth preparedness and complications readiness interventions to increase the use of skilled care at birth and to increase timely use of facility care for obstetric and newborn complications. However, these interventions are complex and relate strongly to the context in which they are implemented. In this article we explore factors to consider when implementing these interventions. METHODS: This paper reports a secondary analysis of 64 studies on birth preparedness and complication readiness interventions identified through a systematic review and updated searches. Analysis was performed using the Supporting the Use of Research Evidence (SURE) framework to guide thematic analysis of barriers and facilitators for implementation. RESULTS: Differences in definitions, indicators and evaluation strategies of birth preparedness and complication readiness interventions complicate the analysis. Although most studies focus on women as the main target group, multi-stakeholder participation with interventions occurring simultaneously at both community and facility level facilitated the impact on seeking skilled care at birth. Increase in formal education for women most likely contributed positively to results. Women and their families adhering to traditional beliefs, (human) resource scarcities, financial constraints of women and families and mismatches between offered and desired maternity care services were identified as key barriers for implementation. CONCLUSIONS: Implementation of birth preparedness and complication readiness to improve the use of skilled care at birth can be facilitated by contextualizing interventions through multi-stakeholder involvement, targeting interventions at multiple levels of the health system and ensuring interventions and program messages are consistent with local knowledge and practices and the capabilities of the health system. PMID- 28854903 TI - Companion of choice at birth: factors affecting implementation. AB - BACKGROUND: Two recent recommendations made by the World Health Organization confirm the benefits of companion of choice at birth on labour outcomes; however institutional practices and policies do not always support its implementation in different settings around the world. We conducted a review to determine factors that affect implementation of this intervention considering the perspectives and experiences of different stakeholders and other institutional, systemic barriers and facilitators. METHODS: Forty one published studies were included in this review. Thirty one publications were identified from a 2013 Cochrane review on the effectiveness of companion of choice at birth. We also reviewed 10 qualitative studies conducted alongside the trials or other interventions on labour and birth companionship identified through electronic searches. The SURE (Supporting the Use of Research Evidence) framework was used to guide the thematic analysis of implementation factors. RESULTS: Women and their families expressed appreciation for the continuous presence of a person to provide support during childbirth. Health care providers were concerned about the role of the companion and possible interference with activities in the labour ward. Allocation of resources, organization of care, facility-related constraints and cultural inclinations were identified as implementation barriers. CONCLUSION: Prior to introducing companion of choice at birth, understanding providers' attitudes and sensitizing them to the evidence is necessary. The commitment of the management of health care facilities is also required to change policies, including allocation of appropriate physical space that respects women's privacy. Implementation research to develop models for different contexts which could be scaled up would be useful, including documentation of factors that affected implementation and how they were addressed. Future research should also focus on documenting the costs related to implementation, and on measuring the impact of companion of choice at birth on care-seeking behavior for subsequent births. PMID- 28854904 TI - LINE-1 hypermethylation in white blood cell DNA is associated with high-grade cervical intraepithelial neoplasia. AB - BACKGROUND: Long Interspersed Nuclear Elements-1 (LINEs-1) methylation from white blood cells (WBCs) DNA has been proposed as biomarker associated with different types of cancer. The aim of the present study was to investigate the degree of WBCs LINE-1 methylation, according to high-risk Human Papilloma Virus (hrHPV) status in a healthy population, and the association with high-grade Cervical Intraepithelial Neoplasia (CIN2+) in hrHPV positive women. METHODS: Women with abnormal cervical cells were enrolled and classified by histological diagnosis and hrHPV infection. A structured questionnaire was used to obtain information on socio-demographic variables and lifestyle factors. LINE-1 methylation level in WBCs was measured by pyrosequencing-based methylation analysis after bisulfite conversion. RESULTS: Among 252 women diagnosed with normal cervical epithelium, with regard to LINE-1 methylation level no significant difference was observed between hrHPV positive and hrHPV negative women, also adjusting for known risk factors of infection. The association between WBCs LINE-1 methylation and CIN2+ status was analyzed in hrHPV positive women. The median value of LINE-1 methylation levels was higher in cases (CIN2+) than in controls (75.00% versus 73.17%; p = 0.002). For a one-unit increase in LINE-1 methylation level, the odds of being diagnosed with CIN2+ increased by 10%, adjusting for known factors related to LINE-1 methylation (adjOR: 1.10; 95% CI:1.01-1.20; p = 0.032). The Receiver-Operating Characteristic (ROC) curve analysis identified the cut-off value of 73.8% as the best threshold to separate cases from controls (sensitivity: 63.4% and specificity: 61.8%). CONCLUSIONS: LINE-1 methylation status in WBCs DNA may represent a cost-effective and tissue-accessible biomarker for high-grade CIN in hrHPV positive women. However, LINE-1 hypermethylation cannot be considered specific for cervical cancer (CC) and a model based solely on LINE-1 methylation levels has limited performance. Further investigations are necessary to propose and validate a novel methylation biomarker panel, based on LINE-1 methylation and other differentially methylated regions, for the screening of women at risk of CC. PMID- 28854905 TI - Traditional healer treatment of HIV persists in the era of ART: a mixed methods study from rural South Africa. AB - BACKGROUND: Human immunodeficiency virus (HIV) substantially contributes to the burden of disease and health care provision in sub-Saharan Africa, where traditional healers play a major role in care, due to both their accessibility and acceptability. In rural, northeastern South Africa, people living with HIV often ping-pong between traditional healers and allopathic providers. METHODS: We conducted 27 in-depth interviews and 133 surveys with a random sample of traditional healers living in Bushbuckridge, South Africa, where anti-retroviral therapy (ART) is publicly available, to learn: (1) healer perspectives about which HIV patients they choose to treat; (2) the type of treatment offered; (3) outcomes expected, and; (4) the cost of delivering treatment. RESULTS: Healers were mostly female (77%), older (median: 58.0 years; interquartile range [IQR]: 50-67), with low levels of formal education (median: 3.7 years; IQR: 3.2-4.2). Thirty-nine healers (30%) reported being able to cure HIV in an adult patients whose (CD4) count was >350cells/mm3. If an HIV-infected patient preferred traditional treatment, healers differentiated two categories of known HIV infected patients, CD4+ cell counts <350 or >=350 cells/mm3. Patients with low CD4 counts were routinely referred back to the health facility. Healers who reported offering/performing a traditional cure for HIV had practiced for less time (mean = 16.9 vs. 22.8 years; p = 0.03), treated more patients (mean 8.7 vs. 4.8 per month; p = 0.03), and had lower levels of education (mean = 2.8 vs. 4.1 years; p = 0.017) when compared to healers who reported not treating HIV-infected patients. Healers charged a median of 92 USD to treat patients with HIV. CONCLUSION: Traditional healers referred suspected HIV-infected patients to standard allopathic care, yet continued to treat HIV-infected patients with higher CD4 counts. A greater emphasis on patient education and healer engagement is warranted. PMID- 28854906 TI - Flavonoids from Tetracera indica Merr. induce adipogenesis and exert glucose uptake activities in 3T3-L1 adipocyte cells. AB - BACKGROUND: Tetracera indica Merr. (Family: Dilleniaceae), known to the Malay as 'Mempelas paya', is one of the medicinal plants used in the treatment of diabetes in Malaysia. However, no proper scientific study has been carried out to verify the traditional claim of T. indica as an antidiabetic agent. Hence, the aims of the present study were to determine the in vitro antidiabetic potential of the T. indica stems ethanol extract, subfractions and isolated compounds. METHODS: The ethanol extract and its subfractions, and isolated compounds from T. indica stems were subjected to cytotoxicity test using MTT viability assay on 3T3-L1 pre adipocytes. Then, the test groups were subjected to the in vitro antidiabetic investigation using 3T3-L1 pre-adipocytes and differentiated adipocytes to determine the insulin-like and insulin sensitizing activities. Rosiglitazone was used as a standard antidiabetic agent. All compounds were also subjected to fluorescence glucose (2-NBDG) uptake test on differentiated adipocytes. Test solutions were introduced to the cells in different safe concentrations as well as in different adipogenic cocktails, which were modified by the addition of compounds to be investigated and in the presence or absence of insulin. Isolation of bioactive compounds from the most effective subfraction (ethyl acetate) was performed through repeated silica gel and sephadex LH-20 column chromatographies and their structures were elucidated through 1H-and 13C-NMR spectroscopy. RESULTS: Four monoflavonoids, namely, wogonin, norwogonin, quercetin and techtochrysin were isolated from the T. indica stems ethanol extract. Wogonin, norwogonin and techtochrysin induced significant (P < 0.05) adipogenesis like insulin and enhanced adipogenesis like rosiglitazone. Wogonin and norwogonin also exhibited significant (P < 0.05) glucose uptake activity. CONCLUSION: The present study demonstrated that the flavonoids isolated from the T. indica stems possess antidiabetic potential revealing insulin-like and insulin-sensitizing effects which were significant among the compounds. This also rationalizes the traditional use of T. indica in the management of diabetes in Malaysia. PMID- 28854907 TI - Wellbeing, activity and housing satisfaction - comparing residents with psychiatric disabilities in supported housing and ordinary housing with support. AB - BACKGROUND: The home is imperative for the possibilities for meaningful everyday activities among people with psychiatric disabilities. Knowledge of whether such possibilities vary with type of housing and housing support might reveal areas for improved support. We aimed to compare people with psychiatric disabilities living in supported housing (SH) and ordinary housing with support (OHS) regarding perceived well-being, engaging and satisfying everyday activities, and perceived meaning of activity in one's accommodation. The importance of these factors and socio-demographics for satisfaction with housing was also explored. METHODS: This naturalistic cross-sectional study was conducted in municipalities and city districts (n = 21) in Sweden, and 155 SH residents and 111 OHS residents participated in an interview that included both self-reports and interviewer ratings. T-test and linear regression analysis were used. RESULTS: The SH group expressed more psychological problems, but better health, quality of life and personal recovery compared to the OHS residents. The latter were rated as having less symptom severity, and higher levels of functioning and activity engagement. Both groups rated themselves as under-occupied in the domains of work, leisure, home management and self-care, but the SH residents less so regarding home management and self-care chores. Although the groups reported similar levels of activity, the SH group were more satisfied with everyday activities and rated their housing higher on possibilities for social interaction and personal development. The groups did not differ on access to activity in their homes. The participants generally reported sufficient access to activity, social interaction and personal development, but those who wanted more personal development in the OHS group outnumbered those who stated they received enough. Higher scores on satisfaction with daily occupations, access to organization and information, wanting more social interaction, and personal recovery predicted high satisfaction with housing in the regression model. CONCLUSION: The fact that health, quality of life and recovery were rated higher by the SH group, despite lower interviewer-ratings on symptoms and level of functioning, might partly be explained by better access to social interaction and personal development in the SH context. This should be acknowledged when planning the support to people who receive OHS. PMID- 28854908 TI - Comprehensive genomic profiling in routine clinical practice leads to a low rate of benefit from genotype-directed therapy. AB - BACKGROUND: Describe a single-center real-world experience with comprehensive genomic profiling (CGP) to identify genotype directed therapy (GDT) options for patients with malignancies refractory to standard treatment options. METHODS: Patients who had CGP by a CLIA-certified laboratory between November 2012 and December 2015 were included. The medical records were analyzed retrospectively after Institutional Review Board (IRB) approval. The treating oncologist made the decision to obtain the assay to provide potential therapeutic options. The objectives of this study were to determine the proportion of patients who benefited from GDT, and to identify barriers to receiving GDT. RESULTS: A total of 125 pediatric and adult patients with a histologically confirmed diagnosis of malignancy were included. Among these, 106 samples were from adult patients, and 19 samples were from pediatric patients. The median age was 54 years for adults. The majority had stage IV malignancy (53%) and were pretreated with 2-3 lines of therapy (45%). The median age was 8 years for pediatric patients. The majority had brain tumors (47%) and had received none or 1 line of therapy (58%) when the profiling was requested. A total of 111 (92%) patients had genomic alterations and were candidates for GDT either via on/off-label use or a clinical trial (phase 1 through 3). Fifteen patients (12%) received GDT based on these results including two patients who were referred for genomically matched phase 1 clinical trials. Three patients (2%) derived benefit from their GDT that ranged from 2 to 6 months of stable disease. CONCLUSIONS: CGP revealed potential treatment options in the majority of patients profiled. However, multiple barriers to therapy were identified, and only a small minority of the patients derived benefit from GDT. PMID- 28854909 TI - A combination of coenzyme Q10, feverfew and magnesium for migraine prophylaxis: a prospective observational study. AB - BACKGROUND: Feverfew (Tanacetum parthenium L.), magnesium and coenzyme Q10 are frequently used for migraine prophylaxis. Supplementation with a fixed combination of these three agents (Antemig(r), PiLeJe) was investigated in an observational study. METHODS: Adult patients suffering from migraine according to the criteria of the International Headache Society were enrolled by general practitioners (>=2 migraine attacks during previous month; exclusion of chronic migraine and medication overuse) and after a one-month baseline phase, supplemented with one tablet of 100 mg feverfew, 100 mg coenzyme Q10 and 112.5 mg magnesium per day for 3 months. RESULTS: Supplementation significantly reduced the number of days with migraine headache during third month of supplementation compared to baseline phase (1.3 days +/-1.5 versus 4.9 days +/-2.6, p < 0.0001; n = 68 intention to treat; primary criterion). The decrease was progressive over the period of supplementation and significant from first month (1st month: -2.5 days +/-3.1, p < 0.0001; 2nd month: -3 days +/-2.8, p < 0.0001). The proportion of patients with a reduction of at least 50% in the number of days with migraine headache was 75% (51/68) after 3 months, with a progressive increase over the period of supplementation (63.2% [43/68] after 1 month and 70.6% [48/68] after 2 months). The proportion of patients with anxiety and depressive symptoms (Hospital Anxiety and Depression Scale) decreased between baseline phase and third month of supplementation from 61.9% (39/63 patients with information available) to 35% (21/60) for depression and from 52.4% (33/63) to 30% (18/60) for anxiety. An improvement of quality of life (Qualite de Vie et Migraine questionnaire) was also observed. The combination was well tolerated. CONCLUSIONS: Results suggest that the proprietary supplement containing feverfew, coenzyme Q10 and magnesium assessed could be beneficial and safe for the prevention of migraine in adult patients and merits further study. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02901756 , retrospectively registered on August 24, 2016. PMID- 28854910 TI - Expression of Vitreoscilla hemoglobin enhances production of arachidonic acid and lipids in Mortierella alpina. AB - BACKGROUND: Arachidonic acid (ARA, C20:4, n-6), which belongs to the omega-6 series of polyunsaturated fatty acids and has a variety of biological activities, is commercially produced in Mortierella alpina. Dissolved oxygen or oxygen utilization efficiency is a critical factor for Mortierella alpina growth and arachidonic acid production in large-scale fermentation. Overexpression of the Vitreoscilla hemoglobin gene is thought to significantly increase the oxygen utilization efficiency of the cells. RESULTS: An optimized Vitreoscilla hemoglobin (VHb) gene was introduced into Mortierella alpina via Agrobacterium tumefaciens-mediated transformation. Compared with the parent strain, the VHb expressing strain, termed VHb-20, grew faster under both limiting and non limiting oxygen conditions and exhibited dramatic changes in cell morphology. Furthermore, VHb-20 produced 4- and 8-fold higher total lipid and ARA yields than those of the wild-type strain under a microaerobic environment. Furthermore, ARA production of VHb-20 was also 1.6-fold higher than that of the wild type under normal conditions. The results demonstrated that DO utilization was significantly increased by expressing the VHb gene in Mortierella alpina. CONCLUSIONS: The expression of VHb enhances ARA and lipid production under both lower and normal dissolved oxygen conditions. This study provides a novel strategy and an engineered strain for the cost-efficient production of ARA. PMID- 28854911 TI - D-dimer levels and cerebral infarction in critically ill cancer patients. AB - BACKGROUND: D-dimer levels have been used in the diagnosis of a variety of thrombosis-related diseases. In this study, we evaluated whether measuring D dimer levels can help to diagnose cerebral infarction (CI) in critically ill cancer patients. METHODS: We retrospectively evaluated all cancer patients who underwent brain magnetic resonance imaging (MRI) between March 2010 and February 2014 at the medical oncology intensive care unit (ICU) of Samsung Medical Center. Brain MRI scanning was performed when CI was suspected due to acute neurological deficits. We compared D-dimer levels between patients ultimately diagnosed as having or not having CI and analyzed diffusion-weighted imaging (DWI) lesion patterns. RESULTS: A total of 88 patients underwent brain MRI scanning due to clinical suspicion of CI; altered mental status and unilateral hemiparesis were the most common neurological deficits. CI was ultimately diagnosed in 43 (49%) patients. According to the DWI patterns, multiple arterial infarctions (40%) were more common than single arterial infarctions (9%). Cryptogenic stroke etiologies were more common (63%) than determined etiologies. There was no significant difference in D-dimer levels between patients with and without CI (P = 0.319). Although D-dimer levels were not helpful in diagnosing CI, D-dimer levels were associated with cryptogenic etiologies in critically ill cancer patients; D-dimer levels were higher in the cryptogenic etiology group than in the determined etiology group or the non-infarction group (P = 0.001). In multivariate analysis, elevated D-dimer levels (> 8.89 MUg/mL) were only associated with cryptogenic stroke (adjusted OR 5.46; 95% confidence interval, 1.876-15.857). CONCLUSIONS: Abnormal D-dimer levels may support the diagnosis of cryptogenic stroke in critically ill cancer patients. PMID- 28854912 TI - Development and validation of a house finch interleukin-1beta (HfIL-1beta) ELISA system. AB - BACKGROUND: A unique clade of the bacterium Mycoplasma gallisepticum (MG), which causes chronic respiratory disease in poultry, has resulted in annual epidemics of conjunctivitis in North American house finches since the 1990s. Currently, few immunological tools have been validated for this songbird species. Interleukin 1beta (IL-1beta) is a prototypic multifunctional cytokine and can affect almost every cell type during Mycoplasma infection. The overall goal of this study was to develop and validate a direct ELISA assay for house finch IL-1beta (HfIL 1beta) using a cross-reactive chicken antibody. METHODS: A direct ELISA approach was used to develop this system using two different coating methods, carbonate and dehydration. In both methods, antigens (recombinant HfIL-1b or house finch plasma) were serially diluted in carbonate-bicarbonate coating buffer and either incubated at 4 degrees C overnight or at 60 degrees C on a heating block for 2 hr. To generate the standard curve, rHfIL-1b protein was serially diluted at 0, 3, 6, 9, 12, 15, 18, 21, and 24 ng/mL. Following blocking and washing, anti chicken IL-1b polyclonal antibody was added, plates were later incubated with detecting antibodies, and reactions developed with tetramethylbenzidine solution. RESULTS: A commercially available anti-chicken IL-1beta (ChIL-1beta) polyclonal antibody (pAb) cross-reacted with house finch plasma IL-1beta as well as bacterially expressed recombinant house finch IL-1beta (rHfIL-1beta) in immunoblotting assays. In a direct ELISA system, rHfIL-1beta could not be detected by an anti-ChIL-1beta pAb when the antigen was coated with carbonate bicarbonate buffer at 4 degrees C overnight. However, rHfIL-1beta was detected by the anti-ChIL-1beta pAb when the antigen was coated using a dehydration method by heat (60 degrees C). Using the developed direct ELISA for HfIL-1beta with commercial anti-ChIL-1beta pAb, we were able to measure plasma IL-1beta levels from house finches. CONCLUSIONS: Based on high amino acid sequence homology, we hypothesized and demonstrated cross-reactivity of anti-ChIL-1beta pAb and HfIL 1beta. Then, we developed and validated a direct ELISA system for HfIL-1beta using a commercial anti-ChIL-1beta pAb by measuring plasma HfIL-1beta in house finches. PMID- 28854913 TI - Reduced growth velocity across the third trimester is associated with placental insufficiency in fetuses born at a normal birthweight: a prospective cohort study. AB - BACKGROUND: While being small-for-gestational-age due to placental insufficiency is a major risk factor for stillbirth, 50% of stillbirths occur in appropriate for-gestational-age (AGA, > 10th centile) fetuses. AGA fetuses are plausibly also at risk of stillbirth if placental insufficiency is present. Such fetuses may be expected to demonstrate declining growth trajectory across pregnancy, although they do not fall below the 10th centile before birth. We investigated whether reduced growth velocity in AGA fetuses is associated with antenatal, intrapartum and neonatal indicators of placental insufficiency. METHODS: We performed a prospective cohort study of 308 nulliparous women who subsequently gave birth to AGA infants. Ultrasound was utilised at 28 and 36 weeks' gestation to determine estimated fetal weight (EFW) and abdominal circumference (AC). We correlated relative EFW and AC growth velocities with three clinical indicators of placental insufficiency, namely (1) fetal cerebroplacental ratio (CPR; CPR < 5th centile reflects placental resistance, and blood flow redistribution to the brain - a fetal response to hypoxia); (2) neonatal acidosis after the hypoxic challenge of labour (umbilical artery (UA) pH < 7.15 at birth); and (3) low neonatal body fat percentage (BF%, measured by air displacement plethysmography) reflecting reduced nutritional reserve in utero. RESULTS: For each one centile reduction in EFW growth velocity between 28 and 36 weeks' gestation, there was a 2.4% increase in the odds of cerebral redistribution (CPR < 5th centile, odds ratio (OR) (95% confidence interval) = 1.024 (1.005-1.042), P = 0.012) and neonatal acidosis (UA pH < 7.15, OR = 1.024 (1.003-1.046), P = 0.023), and a 3.3% increase in the odds of low BF% (OR = 1.033 (1.001-1.067), P = 0.047). A decline in EFW of > 30 centiles between 28 and 36 weeks (compared to greater relative growth) was associated with cerebral redistribution (CPR < 5th centile relative risk (RR) = 2.80 (1.25-6.25), P = 0.026), and a decline of > 35 centiles was associated with neonatal acidosis (UA pH < 7.15 RR = 3.51 (1.40-8.77), P = 0.030). Similar associations were identified between low AC growth velocity and clinical indicators of placental insufficiency. CONCLUSIONS: Reduced growth velocity between 28 and 36 weeks' gestation among fetuses born AGA is associated with antenatal, intrapartum and neonatal indicators of placental insufficiency. These fetuses potentially represent an important unrecognised cohort at increased risk of stillbirth and may warrant more intensive antenatal surveillance. PMID- 28854914 TI - Factors related with colorectal and stomach cancer screening practice among disease-free lung cancer survivors in Korea. AB - BACKGROUND: Lung cancer survivors are more likely to develop colorectal and stomach cancer than the general population. However, little is known about the current status of gastrointestinal cancer screening practices and related factors among lung cancer survivors. METHODS: We enrolled 829 disease-free lung cancer survivors >=40 years of age, who had been treated at two hospitals from 2001 to 2006. The patients completed a questionnaire that included stomach and colorectal cancer screening after lung cancer treatment, as well as other sociodemographic variables. RESULTS: Among lung cancer survivors, correlations with stomach and colorectal screening recommendations were 22.7 and 25.8%, respectively. Of these, 40.7% reported receiving physician advice to screen for second primary cancer (SPC). Those who were recommended for further screening for other cancers were more likely to receive stomach cancer screening [adjusted odds ratios (aOR) = 1.63, 95% confidence interval (CI), 1.16-2.30] and colorectal cancer screening [aOR = 1.37, 95% CI, 0.99-1.90]. Less-educated lung cancer survivors were less likely to have stomach and colorectal cancer screenings. CONCLUSIONS: Lack of a physician's advice for SPC screening and lower educational status had negative impact on the gastrointestinal cancer screening rates of lung cancer survivors. PMID- 28854915 TI - Critically appraised topic on adverse food reactions of companion animals (4): can we diagnose adverse food reactions in dogs and cats with in vivo or in vitro tests? AB - BACKGROUND: The gold standard to diagnose adverse food reactions (AFRs) in the dog and cat is currently an elimination diet with subsequent provocation trials. However, those trials are inconvenient and client compliance can be low. Our objective was to systematically review the literature to evaluate in vivo and in vitro tests used to diagnose AFR in small animals. RESULTS: We searched three databases (CAB Abstracts, MEDLINE and Web of Science) for pertinent references on September 16, 2016. Among 71, 544 and 41 articles found in the CAB Abstract, MEDLINE and Web of Science databases, respectively, we selected 22 articles and abstracts from conference proceedings that reported data usable for evaluation of tests for AFR. Serum tests for food-specific IgE and IgG, intradermal testing with food antigens, lymphocyte proliferation tests, fecal food-specific IgE, patch, gastroscopic, and colonoscopic testing were evaluated. CONCLUSIONS: Testing for serum food-specific IgE and IgG showed low repeatability and, in dogs, a highly variable accuracy. In cats, the accuracy of testing for food specific IgE was low. Lymphocyte proliferation tests were more frequently positive and more accurate in animals with AFR, but, as they are more difficult to perform, they remain currently a research tool. All other reported tests were only evaluated by individual studies with small numbers of animals. Negative patch test reactions have a very high negative predictability in dogs and could enable a choice of ingredients for the elimination diet in selected patients. Gastroscopic and colonoscopic testing as well as food-specific fecal IgE or food specific serum IgG measurements appear less useful. Currently, the best diagnostic procedure to identify AFRs in small animals remains an elimination diet with subsequent provocation trials. PMID- 28854916 TI - The quality, safety and governance of telephone triage and advice services - an overview of evidence from systematic reviews. AB - BACKGROUND: Telephone triage and advice services (TTAS) are increasingly being implemented around the world. These services allow people to speak to a nurse or general practitioner over the telephone and receive assessment and healthcare advice. There is an existing body of research on the topic of TTAS, however the diffuseness of the evidence base makes it difficult to identify key lessons that are consistent across the literature. Systematic reviews represent the highest level of evidence synthesis. We aimed to undertake an overview of such reviews to determine the scope, consistency and generalisability of findings in relation to the governance, safety and quality of TTAS. METHODS: We searched PubMed, MEDLINE, EMBASE, CINAHL, Web of Science and the Cochrane Library for English language systematic reviews focused on key governance, quality and safety findings related to telephone based triage and advice services, published since 1990. The search was undertaken by three researchers who reached consensus on all included systematic reviews. An appraisal of the methodological quality of the systematic reviews was independently undertaken by two researchers using A Measurement Tool to Assess Systematic Reviews. RESULTS: Ten systematic reviews from a potential 291 results were selected for inclusion. TTAS was examined either alone, or as part of a primary care service model or intervention designed to improve primary care. Evidence of TTAS performance was reported across nine key indicators - access, appropriateness, compliance, patient satisfaction, cost, safety, health service utilisation, physician workload and clinical outcomes. Patient satisfaction with TTAS was generally high and there is some consistency of evidence of the ability of TTAS to reduce clinical workload. Measures of the safety of TTAS tended to show that there is no major difference between TTAS and traditional care. CONCLUSIONS: Taken as a whole, current evidence does not provide definitive answers to questions about the quality of care provided, access and equity of the service, its costs and outcomes. The available evidence also suggests that there are many interactional factors (e.g., relationship with other health service providers) which can impact on measures of performance, and also affect the external validity of the research findings. PMID- 28854917 TI - Combination of measures of handgrip strength and red cell distribution width can predict in-hospital complications better than the ASA grade after hip fracture surgery in the elderly. AB - BACKGROUND: Early detection of a high-risk patient following hip fracture surgery is of paramount clinical importance. American Society of Anesthesiologists (ASA) grading is an easy and efficient index in predicting a worse outcome. The red cell distribution width (RDW) and handgrip strength, are gaining interest as a prediction tool as well. Accordingly, the objective of this study was to investigate the potential association between ASA, RDW and grip strength and detect the effects of combining RDW and grip strength for predicting early complication after hip fracture surgery in the elderly. METHODS: Eighty-three consecutive patients operated with hip fracture surgeries were identified retrospectively. Age, gender, diagnosis, RDW, handgrip strength and ASA grade were recorded. Admission to the intensive care unit (ICU), length of ICU stay, transfer to other departments, in-hospital death, and readmission were investigated as early complications. Logistic regression analysis was applied to evaluate the estimates in predicting complications, and receiver operating characteristics curves were constructed to compare the estimates and decide which method is more accurate. RESULTS: After the surgery, 52% of the patients were admitted to the ICU. From the analyses, RDW and grip strength had no significant relation with each other. However, the ICU stay was correlated with RDW and grip strength but not for the ASA grade. A higher ASA grade and grip strength could independently predict ICU admission. The combination of RDW with grip strength outweighed the ASA grade in predictive ability. CONCLUSIONS: The current study indicated that combining RDW and grip strength measures can be efficient and clinically relevant in predicting early postoperative complications after fragility hip fracture in the elderly. Due to the objectivity and availability of those two approaches, patient care, and functional outcomes are expected to be improved by adopting these measures in the clinical setting. PMID- 28854919 TI - Adaption, implementation and evaluation of collaborative service improvements in the testing and result communication process in primary care from patient and staff perspectives: a qualitative study. AB - BACKGROUND: Increasing numbers of blood tests are being ordered in primary care settings and the swift and accurate communication of test results is central to providing high quality care. The process of testing and result communication is complex and reliant on the coordinated actions of care providers, external groups in laboratory and hospital settings, and patients. This fragmentation leaves it vulnerable to error and the need to improve an apparently fallible system is apparent. However, primary care is complex and does not necessarily adopt change in a linear and prescribed manner influenced by a range of factors relating to practice staff, patients and organisational factors. To account for these competing perspectives, we worked in conjunction with both staff and patients to develop and implement strategies intended to improve patient satisfaction and increase efficiency of existing processes. METHODS: The study applied the principles of 'experience-based co-design' to identify key areas of weakness and source proposals for change from staff and patients. The study was undertaken within two primary practices situated in South Birmingham (UK) of contrasting size and socio-economic environment. Senior practice staff were involved in the refinement of the interventions for introduction. We conducted focus groups singly constituted of staff and patients at each practice to determine suitability, applicability and desirability alongside the practical implications of their introduction. RESULTS: At each practice four of the six proposals for change were implemented these were increased access to phlebotomy, improved receptionist training, proactive communication of results, and increased patient awareness of the tests ordered and the means of their communication. All were received favourably by both patients and staff. The remaining issues around the management of telephone calls and the introduction of electronic alerts for missing results were not addressed due to constraints of time and available resources. CONCLUSIONS: Approaches to tackling the same area of weakness differed at practices and was determined by individual staff attitudes and by organisational and patient characteristics. The long-term impact of the changes requires further quantitative evaluation. PMID- 28854918 TI - Ribosome signatures aid bacterial translation initiation site identification. AB - BACKGROUND: While methods for annotation of genes are increasingly reliable, the exact identification of translation initiation sites remains a challenging problem. Since the N-termini of proteins often contain regulatory and targeting information, developing a robust method for start site identification is crucial. Ribosome profiling reads show distinct patterns of read length distributions around translation initiation sites. These patterns are typically lost in standard ribosome profiling analysis pipelines, when reads from footprints are adjusted to determine the specific codon being translated. RESULTS: Utilising these signatures in combination with nucleotide sequence information, we build a model capable of predicting translation initiation sites and demonstrate its high accuracy using N-terminal proteomics. Applying this to prokaryotic translatomes, we re-annotate translation initiation sites and provide evidence of N-terminal truncations and extensions of previously annotated coding sequences. These re annotations are supported by the presence of structural and sequence-based features next to N-terminal peptide evidence. Finally, our model identifies 61 novel genes previously undiscovered in the Salmonella enterica genome. CONCLUSIONS: Signatures within ribosome profiling read length distributions can be used in combination with nucleotide sequence information to provide accurate genome-wide identification of translation initiation sites. PMID- 28854920 TI - Fibroma of tendon sheath around large joints: clinical characteristics and literature review. AB - BACKGROUND: Fibroma of tendon sheath (FTS) is a benign tumor arising from the synovium of the tendon sheath that occurs mostly around small joints such as the fingers, hands, and wrist. However, FTS rarely arises around a large joint (knee, shoulder, elbow, and ankle) with intra-articular or extra-articular involvement. The clinical characteristics of FTS arising around a large joint are unclear. An additional 3 cases of FTS arising around a large joint are presented. Furthermore, the published cases and the present cases are reviewed with respect to their clinical characteristics and imaging and histopathology findings. METHODS: The 43 reported cases including the present 3 patients were summarized, and the patients' profiles, symptoms, sites and locations in the joint involved by FTS, magnetic resonance imaging (MRI) findings, surgical procedures, clinical courses, and cytogenetic analyses were reviewed. RESULTS: The average age of 26 cases was 40.9 years (range 13-69 years), and about 60% of the patients were male. About 10% of the patients had a past history of trauma to the knee joint. Of the present 3 cases, one case was extra-articular around the elbow joint, one case was extra-articular around the knee joint, and one case was intra-articular involving the knee joint. The common symptoms were pain (62.5%), swelling or palpable mass (54.2%), and limited range of motion of the involved joint (50%). The most commonly involved joint was the knee, with 32 cases (74.4%), followed by the elbow in 5 cases (11.6%), ankle in 4 (9.3%), and shoulder in 2 (4.7%). The tumor typically exhibited iso to low signal intensity on T1-weighted MRI. T2 weighted images showed various patterns, but mostly low signal intensity relative to muscle. The surgical margin was marginal resection in all cases. There were no recurrences after surgery. On chromosomal analysis, only the present Case 3 showed an abnormality. CONCLUSIONS: A total of 43 FTS cases that occurred around large joints were summarized. The most common site was around the knee joint. In FTS cases around large joints, it is necessary to distinguish between various fibroblastic and/or fibrohistiocytic tumors. PMID- 28854921 TI - Spatial and temporal epithelial ovarian cancer cell heterogeneity impacts Maraba virus oncolytic potential. AB - BACKGROUND: Epithelial ovarian cancer exhibits extensive interpatient and intratumoral heterogeneity, which can hinder successful treatment strategies. Herein, we investigated the efficacy of an emerging oncolytic, Maraba virus (MRBV), in an in vitro model of ovarian tumour heterogeneity. METHODS: Four ovarian high-grade serous cancer (HGSC) cell lines were isolated and established from a single patient at four points during disease progression. Limiting dilution subcloning generated seven additional subclone lines to assess intratumoral heterogeneity. MRBV entry and oncolytic efficacy were assessed among all 11 cell lines. Low-density receptor (LDLR) expression, conditioned media treatments and co-cultures were performed to determine factors impacting MRBV oncolysis. RESULTS: Temporal and intratumoral heterogeneity identified two subpopulations of cells: one that was highly sensitive to MRBV, and another set which exhibited 1000-fold reduced susceptibility to MRBV-mediated oncolysis. We explored both intracellular and extracellular mechanisms influencing sensitivity to MRBV and identified that LDLR can partially mediate MRBV infection. LDLR expression, however, was not the singular determinant of sensitivity to MRBV among the HGSC cell lines and subclones. We verified that there were no apparent extracellular factors, such as type I interferon responses, contributing to MRBV resistance. However, direct cell-cell contact by co-culture of MRBV-resistant subclones with sensitive cells restored virus infection and oncolytic killing of mixed population. CONCLUSIONS: Our data is the first to demonstrate differential efficacy of an oncolytic virus in the context of both spatial and temporal heterogeneity of HGSC cells and to evaluate whether it will constitute a barrier to effective viral oncolytic therapy. PMID- 28854922 TI - Barriers and facilitators in accessing dementia care by ethnic minority groups: a meta-synthesis of qualitative studies. AB - BACKGROUND: It is estimated that there are about 25,000 people from UK ethnic minority groups with dementia. It is clear that there is an increasing need to improve access to dementia services for all ethnic groups to ensure that everyone has access to the same potential health benefits. The aim was to systematically review qualitative studies and to perform a meta-synthesis around barriers and facilitators to accessing care for dementia in ethnic minorities. METHODS: Databases were searched to capture studies on barriers and facilitators to accessing care for dementia in ethnic minorities. Analysis followed the guidelines for meta-ethnography. All interpretations of data as presented by the authors of the included papers were extracted and grouped into new themes. RESULTS: Six hundred and eighty four papers were identified and screened. Twenty eight studies were included in the meta-synthesis. The analysis developed a number of themes and these were incorporated into two overarching themes: 'inadequacies' and 'cultural habitus'. CONCLUSIONS: The two overarching themes lend themselves to interventions at a service level and a community level which need to happen in synergy. TRIAL REGISTRATION: The review was registered with PROSPERO: CRD42016049326 . PMID- 28854923 TI - Validation of a modified VOICES survey to measure end-of-life care quality: the CaregiverVoice survey. AB - BACKGROUND: Measuring the care experience at end-of-life (EOL) to inform quality improvement is a priority in many countries. We validated the CaregiverVoice survey, a modified version of the VOICES questionnaire, completed by bereaved caregivers to capture perceptions of care received in the last three months of a patient's life. METHODS: We conducted a retrospective survey of bereaved caregivers representing palliative care patients who died in a residential hospice and/or received palliative homecare in Ontario, Canada. Statistical analyses were completed to establish construct and concurrent validity, as well as reliability of the survey. RESULTS: Responses were obtained from 906 caregivers: 330 surveyed from homecare agencies and 576 from hospices. The CaregiverVoice survey demonstrated concurrent validity in scores correlating to FAMCARE2 items, and construct validity in performing according to expected patterns, e.g., correlation of scores to qualitative perceptions and significant variability based on care contexts such as place of death and setting of care (p < 0.01). Reliability was exhibited in good inter-item correlation of ratings for specific care settings and no significant differences in ratings regardless of whether up to a year had passed since death of patient. CONCLUSIONS: The CaregiverVoice survey demonstrated validity and reliability in the populations assessed. This survey represents one common measure that can be standardized across multiple care settings and is useful for assessing the care experience that can help inform local and national quality improvement activities. PMID- 28854924 TI - Erratum to: Sustainability in Health care by Allocating Resources Effectively (SHARE) 5: developing a model for evidence-driven resource allocation in a local healthcare setting. PMID- 28854925 TI - Sowing the seeds of transformative practice to actualize women's rights to respectful maternity care: reflections from Kenya using the consolidated framework for implementation research. AB - BACKGROUND: Despite years of growing concern about poor provider attitudes and women experiencing mistreatment during facility based childbirth, there are limited interventions that specifically focus on addressing these issues. The Heshima project is an evidence-based participatory implementation research study conducted in 13 facilities in Kenya. It engaged a range of community, facility, and policy stakeholders to address the causes of mistreatment during childbirth and promote respectful maternity care. METHODS: We used the consolidated framework for implementation research (CFIR) as an analytical lens to describe a complex, multifaceted set of interventions through a reflexive and iterative process for triangulating qualitative data. Data from a broad range of project documents, reports, and interviews were collected at different time points during the implementation of Heshima. Assessment of in-depth interview data used NVivo (Version 10) and Atlas.ti software to inductively derive codes for themes at baseline, supplemental, and endline. Our purpose was to generate categories of themes for analysis found across the intervention design and implementation stages. RESULTS: The implementation process, intervention characteristics, individual champions, and inner and outer settings influenced both Heshima's successes and challenges at policy, facility, and community levels. Implementation success stemmed from readiness for change at multiple levels, constant communication between stakeholders, and perceived importance to communities. The relative advantage and adequacy of implementation of the Respectful Maternity Care (RMC) resource package was meaningful within Kenyan politics and health policy, given the timing and national promise to improve the quality of maternity care. CONCLUSION: We found the CFIR lens a promising and flexible one for understanding the complex interventions. Despite the relatively nascent stage of RMC implementation research, we feel this study is an important start to understanding a range of interventions that can begin to address issues of mistreatment in maternity care; replication of these activities is needed globally to better understand if the Heshima implementation process can be successful in different countries and regions. PMID- 28854926 TI - Single-molecule sequencing and Hi-C-based proximity-guided assembly of amaranth (Amaranthus hypochondriacus) chromosomes provide insights into genome evolution. AB - BACKGROUND: Amaranth (Amaranthus hypochondriacus) was a food staple among the ancient civilizations of Central and South America that has recently received increased attention due to the high nutritional value of the seeds, with the potential to help alleviate malnutrition and food security concerns, particularly in arid and semiarid regions of the developing world. Here, we present a reference-quality assembly of the amaranth genome which will assist the agronomic development of the species. RESULTS: Utilizing single-molecule, real-time sequencing (Pacific Biosciences) and chromatin interaction mapping (Hi-C) to close assembly gaps and scaffold contigs, respectively, we improved our previously reported Illumina-based assembly to produce a chromosome-scale assembly with a scaffold N50 of 24.4 Mb. The 16 largest scaffolds contain 98% of the assembly and likely represent the haploid chromosomes (n = 16). To demonstrate the accuracy and utility of this approach, we produced physical and genetic maps and identified candidate genes for the betalain pigmentation pathway. The chromosome-scale assembly facilitated a genome-wide syntenic comparison of amaranth with other Amaranthaceae species, revealing chromosome loss and fusion events in amaranth that explain the reduction from the ancestral haploid chromosome number (n = 18) for a tetraploid member of the Amaranthaceae. CONCLUSIONS: The assembly method reported here minimizes cost by relying primarily on short-read technology and is one of the first reported uses of in vivo Hi-C for assembly of a plant genome. Our analyses implicate chromosome loss and fusion as major evolutionary events in the 2n = 32 amaranths and clearly establish the homoeologous relationship among most of the subgenome chromosomes, which will facilitate future investigations of intragenomic changes that occurred post polyploidization. PMID- 28854927 TI - Cancer drug funding decisions in Scotland: impact of new end-of-life, orphan and ultra-orphan processes. AB - BACKGROUND: The Scottish Medicines Consortium evaluates new drugs for use in the National Health Service in Scotland. Reforms in 2014 to their evaluation process aimed to increase patient access to new drugs for end-of-life or rare conditions; the changes include additional steps in the process to gain further information from patients and clinicians, and for revised commercial agreements. This study examines the extent of any impact of the reforms on funding decisions. METHOD: Data on the Scottish Medicines Consortium's funding decisions during 24 months post-reform were extracted from published Advice, for descriptive statistics and thematic analysis. Comparison data were extracted for the 24 months pre-reform. Data on decisions for England by the National Institute for Clinical and Health Excellence for the same drugs were extracted from published Technology Appraisals. RESULTS: The new process was used by 90% (53/59) of cancer submissions. It is triggered if the initial advice is not to recommend, and this risk-of-rejection level is higher than in the pre-period. Thirty-eight cancer drugs obtained some level of funding through the new process, but there was no significant difference in the distribution of decision types compared to the pre reform period. Thematic analysis of patient and clinician input showed no clear relationship between issues raised and funding decision. Differences between SMC's and NICE's definitions of End-of-Life did not fully explain differences in funding decisions. CONCLUSIONS: The Scottish Medicines Consortium's reforms have allowed funding of up to 38 cancer drugs that might previously have been rejected. However, the contribution of specific elements of the reforms to the final decision is unclear. The process could be improved by increased transparency in how the non-quantitative inputs influence decisions. Some disparities in funding decisions between England and Scotland are likely to remain despite recent process convergence. PMID- 28854928 TI - Perceived quality of life in partners of patients undergoing treatment in somatic health, mental health, or substance use disorder units: a cross-sectional study. AB - BACKGROUND: This study explores (1) differences in socio-demographic, social/familial, and health variables and perceived quality of life (QoL) among partners of patients with somatic illness, mental illness, or substance use disorder (SUD); and (2) identifies factors associated with QoL. METHODS: Participants (N = 213) in this cross-sectional study were recruited from inpatient or outpatient services in five hospitals in Norway, 2013-2014. QoL was measured by the QoL-5, a generic five-item questionnaire. Differences between groups were examined using Chi-square for categorical variables and Kruskal Wallis for contiuous variables. Multiple linear regression analyses were used to examine factors associated with QoL. RESULTS: The mean QoL score was similar to that of a general population sample, and 13% of the sample had a markedly low QoL. Partners in the SUD group experienced worse socio-demographic conditions in terms of occupation and income, but QoL did not differ significantly among the three groups. In a regression model, perceived family cohesion was positively associated with QoL while psychological distress (Symptom Checklist-10) was negatively related to it. The model explained 56% of the variance in QoL. CONCLUSIONS: When patients are ill, clinicians should consider the partners' QoL, and brief QoL tools can be used to identify those who are struggling most. Reduced QoL is associated with higher psychological distress and lower family cohesion. Treatment initiatives focusing on these themes may serve as preventive measures to help the most vulnerable families cope with their difficult life situation. PMID- 28854929 TI - Transition from F-75 to ready-to-use therapeutic food in children with severe acute malnutrition, an observational study in Uganda. AB - BACKGROUND: World Health Organization now recommends the transition from F-75 to ready-to-use therapeutic foods (RUTF) in the management of severe acute malnutrition (SAM). We described the transition from F-75 to RUTF and identified correlates of failed transition. METHODS: We conducted an observational study among children aged 6-59 months treated for SAM at Mulago hospital, Kampala, Uganda. Therapeutic feeding during transition phase was provided by first offering half of the energy requirements from RUTF and the other half from F-75 and then increasing gradually to RUTF as only energy source. The child was considered to have successfully transitioned to RUTF if child was able to gradually consume up to 135 kcal/kg/day of RUTF in the transition phase on first attempt. Failed transition to RUTF included children who failed the acceptance test or those who had progressively reduced RUTF intake during the subsequent days. Failure also included those who developed profuse diarrhoea or vomiting when RUTF was ingested. RESULTS: Among 341 of 400 children that reached the transition period, 65% successfully transitioned from F-75 to RUTF on first attempt while 35% failed. The median (IQR) duration of the transition period was 4 (3-8) days. The age of the child, mid-upper arm circumference, weight-for height z-score and weight at transition negatively predicted failure. Each month increase in age reflected a 4% lower likelihood of failure (OR 0.96 (95% CI 0.93; 0.99). Children with HIV (OR 2.73, 95% CI 1.27; 5.85) and those rated as severely ill by caregiver (OR 1.16, 95% CI: 1.02; 1.32) were more likely to fail. At the beginning of the rehabilitation phase, the majority (95%) of the children eventually accepted RUTF while only 5% completed rehabilitation in hospital on F 100. CONCLUSION: Transition from F-75 to RUTF for hospitalized children with SAM by gradual increase of RUTF was possible on first attempt in 65% of cases. Younger children, severely wasted, HIV infected and those with severe illness as rated by the caregiver were more likely to fail to transit from F-75 to RUTF on first attempt. PMID- 28854930 TI - Sex workers as peer health advocates: community empowerment and transformative learning through a Canadian pilot program. AB - BACKGROUND: Social marginalization and criminalization create health and safety risks for sex workers and reduce their access to health promotion and prevention services compared to the general population. Community empowerment-based interventions that prioritize the engagement of sex workers show promising results. Peer-to-peer interventions, wherein sex workers act as educators of their colleagues, managers, clients and romantic partners, foster community mobilization and critical consciousness among sex workers and equip them to exercise agency in their work and personal lives. METHODS: A pilot peer health education program was developed and implemented, with and for sex workers in one urban centre in Canada. To explore how the training program contributed to community empowerment and transformative learning among participants, the authors conducted qualitative interviews, asked participants to keep personal journals and to fill out feedback forms after each session. Thematic analysis was conducted on these three data sources, with emerging themes identified, organized and presented in the findings. RESULTS: Five themes emerged from the analysis. Our findings show that the pilot program led to reduced internalized stigma and increased self-esteem in participants. Participants' critical consciousness increased concerning issues of diversity in cultural background, sexual orientation, work experiences and gender identity. Participants gained knowledge about how sex work stigma is enacted and perpetuated. They also became increasingly comfortable challenging negative judgments from others, including frontline service providers. Participants were encouraged to actively shape the training program, which fostered positive relationships and solidarity among them, as well as with colleagues in their social network and with the local sex worker organization housing the program. Resources were also mobilized within the sex worker community through skills building and knowledge acquisition. CONCLUSION: The peer education program proved successful in enhancing sex workers' community empowerment in one urban setting by increasing their knowledge about health issues, sharing information about and building confidence in accessing services, and expanding capacity to disseminate this knowledge to others. This 'proof of concept' built the foundation for a long-term initiative in this setting and has promise for other jurisdictions wishing to adapt similar programs. PMID- 28854931 TI - Exosomes isolated from cancer patients' sera transfer malignant traits and confer the same phenotype of primary tumors to oncosuppressor-mutated cells. AB - BACKGROUND: Horizontal transfer of malignant traits from the primary tumor to distant organs, through blood circulating factors, has recently become a thoroughly studied metastatic pathway to explain cancer dissemination. Recently, we reported that oncosuppressor gene-mutated human cells undergo malignant transformation when exposed to cancer patients' sera. We also observed that oncosuppressor mutated cells would show an increased uptake of cancer-derived exosomes and we suggested that oncosuppressor genes might protect the integrity of the cell genome by blocking integration of cancer-derived exosomes. In the present study, we tested the hypothesis that cancer patients' sera-derived exosomes might be responsible for the malignant transformation of target cells and that oncosuppressor mutation would promote their increased uptake. We also sought to unveil the mechanisms behind the hypothesized phenomena. METHODS: We used human BRCA1 knockout (BRCA1-KO) fibroblasts as target cells. Cells were treated in vitro with cancer patients' sera or cancer patients' sera-derived exosomes. Treated cells were injected into NOD-SCID mice. Immunohistochemical analyses were performed to determine the differentiation state of the xenotransplants. Mass spectrometry analyses of proteins from cancer exosomes and the BRCA1-KO fibroblasts' membrane were performed to investigate possible de novo expression of molecules involved in vesicles uptake. Blocking of the identified molecules in vitro was performed and in vivo experiments were conducted to confirm the role of these molecules in the malignant transformation carried out by cancer-derived exosomes. RESULTS: Cells treated with exosomes isolated from cancer patients' sera underwent malignant transformation and formed tumors when transplanted into immunodeficient mice. Histological analyses showed that the tumors were carcinomas that differentiated into the same lineage of the primary tumors of blood donors. Oncosuppressor mutation promoted the de novo expression, on the plasma membrane of target cells, of receptors, responsible for the increased uptake of cancer-derived exosomes. The selective blocking of these receptors inhibited the horizontal transfer of malignant traits. CONCLUSION: These findings strengthen the hypothesis that oncogenic factors transferred via circulating cancer exosomes, induce malignant transformation of target cells even at distance. Oncosuppressor genes might protect the integrity of the cell genome by inhibiting the uptake of cancer-derived exosomes. PMID- 28854932 TI - A healthy approach to dietary fats: understanding the science and taking action to reduce consumer confusion. AB - Consumers are often confused about nutrition research findings and recommendations. As content experts, it is essential that nutrition scientists communicate effectively. A case-study of the history of dietary fat science and recommendations is presented, summarizing presentations from an Experimental Biology Symposium that addressed techniques for effective scientific communication and used the scientific discourse of public understanding of dietary fats and health as an example of challenges in scientific communication. Decades of dietary recommendations have focused on balancing calorie intake and energy expenditure and decreasing fat. Reducing saturated fat has been a cornerstone of dietary recommendations for cardiovascular disease (CVD) risk reduction. However, evidence from observational studies and randomized clinical trials demonstrates that replacing saturated fat with carbohydrates, specifically refined, has no benefit on CVD risk, while substituting polyunsaturated fats for either saturated fat or carbohydrate reduces risk. A significant body of research supports the unique health benefits of dietary patterns and foods that contain plant and marine sources of unsaturated fats. Yet, after decades of focus on low fat diets, many consumers, food manufacturers, and restauranteurs remain confused about the role of dietary fats on disease risk and sources of healthy fats. Shifting dietary recommendations to focus on food-based dietary patterns would facilitate translation to the public and potentially remedy widespread misperceptions about what constitutes a healthful dietary pattern. PMID- 28854933 TI - Does daily co-administration of letrozole and gonadotropins during ovarian stimulation improve IVF outcome? AB - BACKGROUND: For the last year we have been treating normal responders with gonadotropins and letrozole during the whole stimulation in order to improve response to FSH by increasing the intrafollicular androgen concentration, and to reduce circulating estrogen concentrations. The aim of this study was to compare the IVF outcome of normal responders treated with letrozole and gonadotropins during ovarian stimulation with patients treated with gonadotropins only. METHODS: A single centre retrospective cohort study of 174 patients (87 in each group). RESULTS: The age of the patients was comparable between the groups. Estradiol levels were significantly higher in the control group (6760 pmol/L vs. 2420 pmol/L respectively, p < 0.01), and the number of follicles >=15 mm at the trigger day was significantly lower in the control group (7.9 vs. 10, p = 0.02). The number of retrieved oocytes (10 vs. 14.5, p < 0.01), MII oocytes (7.9 vs. 11.2, p < 0.01) and blastocysts (2.7 vs. 4.0, p = 0.02) was significantly higher in the study group. We found no significant differences in the cumulative pregnancy outcome between the two groups (65.2% vs 58.3% p = NS). CONCLUSIONS: We conclude that co-treatment with letrozole improves the IVF outcome in normal responders in terms of increased number of blastocysts obtained without increasing the pregnancy rate or the risk of OHSS. PMID- 28854934 TI - Social vulnerability and factors associated with oral impact on daily performance among adolescents. AB - BACKGROUND: Oral disorders may negatively affect the quality of life (QoL) of adolescents. To investigate how social vulnerability and oral-health status factors affect QoL in 15-19 years olds who participated in the "SB Sao Paulo 2015" state survey. METHODS: The relationship of several independent variables, namely Paulista Social Vulnerability Index (PSVI) score, gender, skin color, family income, age, untreated caries, tooth loss [determined by the Decayed, Missing, Filled-Teeth (DMF-T) index], toothache, periodontal condition [determined by the Community Periodontal Index (CPI)], and malocclusion (maxillary overjet, cross bite, or open bite) affect daily life, measured by the Oral Impacts on Daily Performance (OIDP) instrument. Logistic regression analyses were carried out based on a hierarchical model. RESULTS: The final sample consisted of 5402 adolescents. The prevalence of at least one negative impact of oral health on QoL was 37.3%. After adjustment, demographic factors that were found to influence this impact significantly (p < 0.01) were female gender [odds ratio (OR) 1.78, 95% confidence interval (CI) = 1.59-2.0], non-white skin color (OR 1.66, 95% CI = 1.47-1.88), and a low family income (OR 1.28, 95% CI = 1.28 1.29). Additionally, oral conditions associated with oral health impact on QoL included the presence of at least one untreated tooth decay lesion (OR 1.42, 95% CI = 1.25-1.61), loss of at least one tooth (OR 1.49; 95% CI = 1.25-1.78), toothache (OR 4.87, 95% CI = 4.25-5.59), bleeding on probing (OR 1.45, 95% CI = 1.25-1.68), and severe maxillary overjet (OR 1.68, 95% CI = 1.15-2.45). CONCLUSION: Social vulnerability (PSVI score) was not associated with the OIDP score, but oral health conditions and socio-demographic variables, including gender, skin color, and income, were found to affect adolescents' daily activities. Strategies that consider the perceptions of this segment of the population should be implemented to strengthen their autonomy and totality of care. PMID- 28854935 TI - Distribution of glucose transporters in renal diseases. AB - Kidneys play an important role in glucose homeostasis. Renal gluconeogenesis prevents hypoglycemia by releasing glucose into the blood stream. Glucose homeostasis is also due, in part, to reabsorption and excretion of hexose in the kidney.Lipid bilayer of plasma membrane is impermeable for glucose, which is hydrophilic and soluble in water. Therefore, transport of glucose across the plasma membrane depends on carrier proteins expressed in the plasma membrane. In humans, there are three families of glucose transporters: GLUT proteins, sodium dependent glucose transporters (SGLTs) and SWEET. In kidney, only GLUTs and SGLTs protein are expressed. Mutations within genes that code these proteins lead to different renal disorders and diseases. However, diseases, not only renal, such as diabetes, may damage expression and function of renal glucose transporters. PMID- 28854937 TI - The impact of a human resource management intervention on the capacity of supervisors to support and supervise their staff at health facility level. AB - BACKGROUND: A systematic and structured approach to the support and supervision of health workers can strengthen the human resource management function at the district and health facility levels and may help address the current crisis in human resources for health in sub-Saharan Africa by improving health workers' motivation and retention. METHODS: A supportive supervision programme including (a) a workshop, (b) intensive training and (c) action learning sets was designed to improve human resource management in districts and health facilities in Tanzania. We conducted a randomised experimental design to evaluate the impact of the intervention. Data on the same measures were collected pre and post the intervention in order to identify any changes that occurred (between baseline and end of project) in the capacity of supervisors in intervention a + b and intervention a + b + c to support and supervise their staff. These were compared to supervisors in a control group in each of Tanga, Iringa and Tabora regions (n = 9). A quantitative survey of 95 and 108 supervisors and 196 and 187 health workers sampled at baseline and end-line, respectively, also contained open-ended responses which were analysed separately. RESULTS: Supervisors assessed their own competency levels pre- and post-intervention. End-line samples generally scored higher compared to the corresponding baseline in both intervention groups for competence activities. Significant differences between baseline and end-line were observed in the total scores on 'maintaining high levels of performance', 'dealing with performance problems', 'counselling a troubled employee' and 'time management' in intervention a + b. In contrast, for intervention a + b + c, a significant difference in distribution of scores was only found on 'counselling a troubled employee', although the end-line mean scores were higher than their corresponding baseline mean scores in all cases. Similar trends to those in the supervisors' reports are seen in health workers data in terms of more efficient supervision processes, although the increases are not as marked. CONCLUSION: A number of different indicators were measured to assess the impact of the supportive supervision intervention on the a + b and a + b + c intervention sites. The average frequency of supervision visits and the supervisors' competency levels across the facilities increased in both intervention types. This would suggest that the intervention proved effective in raising awareness of the importance of supervision and this understanding led to action in the form of more supportive supervision. PMID- 28854936 TI - Nuclear envelopathies: a complex LINC between nuclear envelope and pathology. AB - Since the identification of the first disease causing mutation in the gene coding for emerin, a transmembrane protein of the inner nuclear membrane, hundreds of mutations and variants have been found in genes encoding for nuclear envelope components. These proteins can be part of the inner nuclear membrane (INM), such as emerin or SUN proteins, outer nuclear membrane (ONM), such as Nesprins, or the nuclear lamina, such as lamins A and C. However, they physically interact with each other to insure the nuclear envelope integrity and mediate the interactions of the nuclear envelope with both the genome, on the inner side, and the cytoskeleton, on the outer side. The core of this complex, called LINC (LInker of Nucleoskeleton to Cytoskeleton) is composed of KASH and SUN homology domain proteins. SUN proteins are INM proteins which interact with lamins by their N terminal domain and with the KASH domain of nesprins located in the ONM by their C-terminal domain.Although most of these proteins are ubiquitously expressed, their mutations have been associated with a large number of clinically unrelated pathologies affecting specific tissues. Moreover, variants in SUN proteins have been found to modulate the severity of diseases induced by mutations in other LINC components or interactors. For these reasons, the diagnosis and the identification of the molecular explanation of "nuclear envelopathies" is currently challenging.The aim of this review is to summarize the human diseases caused by mutations in genes coding for INM proteins, nuclear lamina, and ONM proteins, and to discuss their potential physiopathological mechanisms that could explain the large spectrum of observed symptoms. PMID- 28854938 TI - The assessment of femoral shaft morphology in the sagittal plane in Chinese patients with osteoarthritis-a radiographic analysis. AB - BACKGROUND: The purpose of this study was to analyze femoral shaft sagittal parameters in Chinese osteoarthritis (OA) patients undergoing total knee arthroplasty (TKA) and identify whether the parameters in the coronal plane could be predictors of those in the sagittal plane. METHODS: Standard long-standing anteroposterior and femoral lateral radiographs of 50 lower limbs in 50 Chinese OA patients were included. Sagittal femoral bowing angle (sFBA), angle between femoral distal anterior cortex axis and sagittal mechanical axis (DACSMA), angle between femoral distal anterior cortex axis and sagittal distal anatomic axis (DACSDAA), and angle between femoral sagittal mechanical axis and sagittal distal anatomic axis (SMADAA) were measured. Then the relationship between femoral shaft parameters in the sagittal and coronal planes were identified, including coronal femoral bowing angle (cFBA), valgus angle, hip-knee-ankle angle (HKA), length of femur (LF), femoral offset, femoral neck stem angle (FNS), and mechanical lateral distal femoral angle (mLDFA). A two-sided Pearson correlation coefficient was obtained to identify the correlations between parameters in the coronal and sagittal planes. P values <0.05 were considered statistically significant. RESULTS: The mean sFBA was 15.08 degrees +/- 3.79 degrees , the mean DACSMA was 1.35 degrees +/- 2.70 degrees , the mean DACSDAA was -2.66 degrees +/- 2.05 degrees , and the mean SMADAA was 4.01 degrees +/- 2.55 degrees . No correlation between parameters in the coronal and sagittal planes was found. CONCLUSIONS: In this study, the discreteness of DACSMA, DACSDAA, and SMADAA in Chinese OA patients is high and this may affect the position of femoral prosthesis after TKA using the conventional intramedullary device. No parameters in the coronal plane are found correlated with those in the sagittal plane. TRIAL REGISTRATION: Researchregistry2337. PMID- 28854939 TI - Weight-supported training of the upper extremity in children with cerebral palsy: a motor learning study. AB - BACKGROUND: Novel neurorehabilitation technologies build upon treatment principles derived from motor learning studies. However, few studies have investigated motor learning with assistive devices in children and adolescents with Cerebral Palsy (CP). The aim of this study was to investigate whether children with CP who trained with weight support in a playful, virtual environment would improve upper extremity task performance (i.e. skill acquisition), transfer, and retention, three aspects that indicate whether motor learning might have occurred or not. METHODS: Eleven children with CP (mean age 13.3 years, standard deviation 3.4 years), who were mildly to moderately impaired, participated. They played in the Armeo(r) Spring the exergame Moorhuhn with their more affected arm during 3 days (70 min pure play time). For this within-subject design, kinematic assessments, the Box and Block Test, and five items of the Melbourne Assessment were administered twice during a baseline week (one week before the intervention), directly before and after the intervention, and one day after the training phase (retention). RESULTS: The average exergame score improved from 209.55 to 339.73 (p < 0.001, Cohen's d = 1.80), indicating skill acquisition. The change in the Box and Block test improved from 0.45 (baseline week) to 3.95 (intervention week; p = 0.008, d = 1.59) indicating skill transfer. The kinematic assessments and the Melbourne items did not change. Improvement in game score and Box and Bock Test persisted one day later (retention). CONCLUSIONS: We found evidence indicating the successful acquisition, transfer, and retention of upper extremity skills in children with CP. We therefore infer that motor learning occurred when children with CP trained their more affected arm with weight-support in a playful, virtual environment. PMID- 28854940 TI - Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer's disease. AB - BACKGROUND: Increasing evidence from toxicological and epidemiological studies indicates that the central nervous system is an important target for ambient air pollutants. We have investigated whether long-term inhalation exposure to diesel engine exhaust (DEE), a dominant contributor to particulate air pollution in urban environments, can aggravate Alzheimer's Disease (AD)-like effects in female 5X Familial AD (5XFAD) mice and their wild-type female littermates. Following 3 and 13 weeks exposures to diluted DEE (0.95 mg/m3, 6 h/day, 5 days/week) or clean air (controls) behaviour tests were performed and amyloid-beta (Abeta) plaque formation, pulmonary histopathology and systemic inflammation were evaluated. RESULTS: In a string suspension task, assessing for grip strength and motor coordination, 13 weeks exposed 5XFAD mice performed significantly less than the 5XFAD controls. Spatial working memory deficits, assessed by Y-maze and X-maze tasks, were not observed in association with the DEE exposures. Brains of the 3 weeks DEE-exposed 5XFAD mice showed significantly higher cortical Abeta plaque load and higher whole brain homogenate Abeta42 levels than the clean air-exposed 5XFAD littermate controls. After the 13 weeks exposures, with increasing age and progression of the AD-phenotype of the 5XFAD mice, DEE-related differences in amyloid pathology were no longer present. Immunohistochemical evaluation of lungs of the mice revealed no obvious genetic background-related differences in tissue structure, and the DEE exposure did not cause histopathological changes in the mice of both backgrounds. Luminex analysis of plasma cytokines demonstrated absence of sustained systemic inflammation upon DEE exposure. CONCLUSIONS: Inhalation exposure to DEE causes accelerated plaque formation and motor function impairment in 5XFAD transgenic mice. Our study provides further support that the brain is a relevant target for the effects of inhaled DEE and suggests that long term exposure to this ubiquitous air pollution mixture may promote the development of Alzheimer's disease. PMID- 28854941 TI - Gefitinib-loaded DSPE-PEG2000 nanomicelles with CD133 aptamers target lung cancer stem cells. AB - BACKGROUND: Lung cancer stem cells (CSCs) are considered to be the seed of lung cancer, and CD133 is a marker of lung CSCs. Here, we developed gefitinib-loaded poly(ethylene glycol) 2000-distearoylphosphatidylethanolamine nanomicelles with CD133 aptamers (M-Gef-CD133) to eliminate CD133+ lung CSCs. METHODS: M-Gef-CD133 was prepared using a lipid-film-based approach. The targeting and activity of M Gef-CD133 towards lung CSCs were evaluated. RESULTS: M-Gef-CD133 were small (25 nm) and showed enhanced cytotoxic effect towards CD133+ lung CSCs compared with non-targeted M-Gef and gefitinib. Notably, M-Gef-CD133 could significantly reduce tumor sphere formation and the percentage of CD133+ lung CSCs, indicating that it possesses selective toxicity against CD133+ lung CSCs. CONCLUSIONS: The interaction of CD133 aptamers and CD133 shows promise in the delivery of gefitinib to CD133+ lung CSCs, and M-Gef-CD133 represents a promising treatment to target lung CSCs. PMID- 28854943 TI - A longitudinal and case-control study of dropout among drug users in methadone maintenance treatment in Haiphong, Vietnam. AB - BACKGROUND: Vietnam began providing methadone maintenance therapy (MMT) in 2008; as of June 2016, 44,479 persons who inject drugs (PWID) were in treatment in 57 provinces. However, 10-23% of patients were estimated to have dropped out of treatment during the first 2 years. We evaluated dropout and factors associated with quitting treatment. METHODS: We followed clients >= 18 years old enrolled in five MMT clinics in Haiphong for 3 years. Persons who missed a consecutive month of methadone treatment were considered to have dropped out and were not allowed to return; those who missed greater than five consecutive doses were considered to be non-compliant but were allowed to restart treatment at their initial dose. Clients who dropped out or who were non-compliant during their third year of MMT (cases) were traced and matched with two clients who remained in treatment (controls) by gender, age, and length of time in the program. Cases and controls were interviewed. Additional data on levels of yearly retention were abstracted from clinic records. RESULTS: Among the 1055 patients initially enrolled in MMT, dropout and non-compliance combined was 13.6% during the first year, 16.5% during the second year, and 22.3% during the third year. By 36 months, 33.3% of clients had dropped out, of whom 10.6% had died and 24% had been arrested. We traced and interviewed 81 clients who dropped out or who were non-compliant during year 3 as well as 161 controls. The primary reasons for dropping out included claiming no dependence on heroin (22.2%), conflict with work (21.0%), health problems (16.0%), and inability to afford the methadone co-payment of approximately 0.5 USD/day (14.8%). Independent factors associated with non-compliance included continuing to use heroin (aOR = 12.4, 95% CI 4.2-36.8) and missing greater than three doses during the previous 3 months (aOR = 18.5, 95% CI 7.4-47.1); receiving a daily dose of > 120 mg of methadone was associated with a lower odds ratio of dropping out (aOR = 0.3, 95% CI 0.1-0.9). CONCLUSION: By 3 years, one third of all patients in treatment had permanently dropped out. Ensuring that methadone dosing is adequate and reducing or eliminating the co-payment fee for those who cannot afford it could improve retention. PMID- 28854944 TI - HIV status disclosure and associated outcomes among pregnant women enrolled in antiretroviral therapy in Uganda: a mixed methods study. AB - BACKGROUND: Disclosure of HIV positive status to sexual partners is promoted by HIV prevention programs including those targeting the prevention of mother-to child transmission. Among other benefits, disclosure may enhance spousal support and reduce stigma, violence and discrimination. HIV status disclosure and associated outcomes were assessed among a cohort of women, newly initiating lifelong antiretroviral therapy in Uganda between October 2013 and May 2014. METHODS: This was a mixed method study, drawing data from a prospective cohort study of 507 HIV positive pregnant women on lifelong antiretroviral therapy, who were followed for four months to determine disclosure and its outcomes. Women were recruited from three facilities for the cohort study; in addition, fifty seven women were recruited to participate in qualitative interviews from six facilities. Factors associated with spousal support and negative outcomes were determined using random-effects logistic regression in two separate models, with prevalence ratio as measure of association. In-depth interviews were used to document experiences with disclosure of HIV status. RESULTS: Overall HIV status disclosure to at least one person was high [(375/507), 83.7%]. Nearly three quarters [(285/389), 73.3%], had disclosed to their spouse by the fourth month of follow up post-enrolment. Among married women, spousal support was high at the first 330/407 (81.1%) and second follow-up 320/389 (82.2%). The majority of women who reported spousal support for either antenatal care or HIV-related care services had disclosed their HIV status to their spouses (adj.PR = 1.17; 95% CI: 1.02-1.34). However, no significant differences were observed in the proportion of self-reported negative outcomes by HIV status disclosure (adj.PR = 0.89; 95% CI: 0.56-1.42). Qualitative findings highlighted stigma and fear of negative outcomes as the major barriers to disclosure. CONCLUSION: HIV status disclosure to partners by pregnant women on lifelong antiretroviral therapy was associated with increased spousal support, but was impeded by fear of adverse outcomes such as stigma, discrimination and violence. Interventions to reduce negative outcomes could enhance HIV status disclosure. PMID- 28854942 TI - The biology of Hepatocellular carcinoma: implications for genomic and immune therapies. AB - Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis. Activating mutations in CTNNB1 and inactivating mutations in AXIN1 both activate WNT signaling. Alterations in this pathway, as well as in TP53 and the cell cycle machinery, and in the PI3K/Akt/mTor axis (the latter activated in the presence of PTEN loss), as well as aberrant angiogenesis and epigenetic anomalies, appear to be major events in HCC. Many of these abnormalities may be pharmacologically tractable. Immunotherapy with checkpoint inhibitors is also emerging as an important treatment option. Indeed, 82% of patients express PD-L1 (immunohistochemistry) and response rates to anti-PD-1 treatment are about 19%, and include about 5% complete remissions as well as durable benefit in some patients. Biomarker matched trials are still limited in this disease, and many of the genomic alterations in HCC remain challenging to target. Future studies may require combination regimens that include both immunotherapies and molecularly matched targeted treatments. PMID- 28854945 TI - Comparison of the outcomes between thoracoscopic and laparoscopic esophagectomy via retrosternal and prevertebral lifting paths by the same surgeon. AB - BACKGROUND: The objective of the study is to explore the effects of retrosternal and prevertebral lifting paths of the tubular stomach on postoperative complications of patients undergoing cervical anastomosis in thoracoscopic and laparoscopic esophagectomy. METHODS: Sixty-three patients were retrospectively analyzed. The patients received thoracoscopic and laparoscopic esophagectomy by the same surgeon. According to the path by which the stomach was lifted upward, the patients were divided into two groups: the retrosternal path group (32 patients) and the prevertebral path group (31 patients). Operative indications and complications of postoperative patients in these two groups were observed. RESULTS: There was no statistically significant difference in the time duration of surgery, amount of bleeding, number of dissected lymph node, and postoperative hospitalization time between the retrosternal and prevertebral lifting paths (P > 0.05). Furthermore, the two groups did not show significant difference in the incidence rate of postoperative anastomosis fistula complications (P = 0.702). Instead, the amount of postoperative gastric drainage and the incidence rates of the pulmonary infection were significantly lower in the retrosternal path group than in the prevertebral path group, respectively (P = 0.001, P = 0.012, respectively). CONCLUSION: The esophagogastrostomic cervical anastomoses performed via the retrosternal and prevertebral paths are both feasible methods of digestive tract reconstruction. The amount of postoperative gastric drainage volume and the pulmonary infection incidence rate in the retrosternal path group were lower than those in the prevertebral path group. Therefore, gastroesophageal anastomosis via the retrosternal lifting path may be preferably considered for thoracoscopic and laparoscopic surgery for esophageal carcinoma patients. PMID- 28854946 TI - Donor funding health policy and systems research in low- and middle-income countries: how much, from where and to whom. AB - BACKGROUND: The need for sufficient and reliable funding to support health policy and systems research (HPSR) in low- and middle-income countries (LMICs) has been widely recognised. Currently, most resources to support such activities come from traditional development assistance for health (DAH) donors; however, few studies have examined the levels, trends, sources and national recipients of such support - a gap this research seeks to address. METHOD: Using OECD's Creditor Reporting System database, we classified donor funding commitments using a keyword analysis of the project-level descriptions of donor supported projects to estimate total funding available for HPSR-related activities annually from bilateral and multilateral donors, as well as the Bill and Melinda Gates Foundation, to LMICs over the period 2000-2014. RESULTS: Total commitments to HPSR-related activities have greatly increased since 2000, peaked in 2010, and have held steady since 2011. Over the entire study period (2000-2014), donors committed a total of $4 billion in funding for HPSR-related activities or an average of $266 million a year. Over the last 5 years (2010-2014), donors committed an average of $434 million a year to HPSR-related activities. Funding for HPSR is heavily concentrated, with more than 93% coming from just 10 donors and only represents approximately 2% of all donor funding for health and population projects. Countries in the sub-Saharan African region are the major recipients of HPSR funding. CONCLUSION: Funding for HPSR-related activities has generally increased over the study period; however, donor support to such activities represents only a small proportion of total DAH and has not grown in recent years. Donors should consider increasing the proportion of funds they allocate to support HPSR activities in order to further build the evidence base on how to build stronger health systems. PMID- 28854947 TI - Effect of female genital mutilation/cutting; types I and II on sexual function: case-controlled study. AB - BACKGROUND: The existing literature is contradictory regarding effects of female genital mutilation/cutting (FGM/C) on sexual functions. The aim of this study was to explore the impact of type I and II FGM/C on sexual function of Egyptian women. METHODS: We recruited 197 cut women and 197 control women from those visiting Assiut University hospitals for different reasons. We asked each woman to fill the Arabic female sexual function index (FSFI) (a self reported 19-item questionnaire assessing the main domains of female sexual function). Genital Examination was done to confirm the type of FGM. RESULTS: Female sexual dysfunction (FSD) was found in 83.8% of FGM/C cases in contrast to 64.5% of the control. The total FSFI score in the FGM/C group (19.82 +/- 7.1) was significantly lower than in the control group (23.34 +/- 8.1). Concerning the types of FGM/C, type 73.6% of cases had type I and 26.4% had type II. Type I FGM/C was performed mainly by physicians (62.1%) while type II was performed mainly by midwives (44.4%). FSD was found in 83.4% of FGM/C I cases and in 84.6% of FGM/C II cases. There was no statistically significant difference between the two types of FGM/C as regards total and individual domain scores except for the pain domain. There were significantly lower total and individual domain scores in both FGM/C types except for the desire domain compared to control. CONCLUSION: In this study, FGM/C was associated with reduced scores of FSFI on all domains scores, and among both types I and II, both were associated with sexual dysfunction. PMID- 28854948 TI - Novel three-dimensional bone 'mapping' software can help assess progression of osseous metastases from routine CT. AB - Imaging of bone metastasis response to therapy is a research priority. Stradwin is a new software-tool, with demonstrated sub-voxel accuracy in assessing cortical bone properties from routine CT. We applied this technology to the context of osseous metastases, with particular focus on disease progression using prostate cancer as a model. 3D-rendered 'bone-maps' were produced for 20 men with advanced prostate cancer, including a sub-cohort of 9 who had undergone serial scans. Correlation between baseline interpretation and assessments of progression between modalities was assessed. Bone-maps took significantly less time to interpret than CT bone windows (P < 0.001). Initial bone-mapping, without adjustment, demonstrated sensitivity and specificity for suspicious areas on CT of 70.7% and 73.1% respectively. Evaluating disease over time, concordance between bone-maps and current practice using RECIST outcomes was 100%.This study demonstrates the feasibility and potential use of this free post-processing software in the serial assessment of osseous metastases. PMID- 28854949 TI - Pulmonary tumor embolism secondary to soft tissue and bone sarcomas: a case report and literature review. AB - BACKGROUND: Tumor embolisms (TE) are an underappreciated source of pulmonary embolisms in sarcoma. Most evidence in the literature is limited to case reports and none have described the presence of TE secondary to myxofibrosarcoma. We report the first case of myxofibrosarcoma TE and perform a review of the literature for TE secondary to bone and soft tissue sarcomas (STS). CASE PRESENTATION: A 36-year-old female presented with debilitating pain of the right upper extremity secondary to a recurrent soft tissue sarcoma. She had distant metastasis to the lung. An MRI revealed a 25-cm shoulder mass involving the proximal arm muscles with encasement of the axillary artery, vein, and brachial plexus. A palliative forequarter amputation was performed and tumor thrombus was evident within the axillary artery and vein. Postoperatively, she developed an acute onset of dyspnea and hypoxia. A computed tomography scan revealed a pulmonary saddle embolism. A bilateral lower extremity venous duplex was negative. She became hemodynamically unstable despite resuscitation and was placed on vasopressor support. A transthoracic echocardiogram revealed elevated pulmonary artery pressure, tricuspid regurgitation, right heart dilation, and reduced right heart systolic function consistent with acute cor pulmonale. The patient did not want to pursue a median sternotomy with pulmonary artery embolectomy and expired from cardiopulmonary arrest within 24 h of the operation. The final pathology revealed a 25 * 16 * 13 cm high-grade myxofibrosarcoma with invasion into the bone, skin, and neurovascular bundle as well as evidence of tumor thrombus. CONCLUSION: TE is a rare but deadly cause of pulmonary embolism in sarcoma. A high index of suspicion is necessary in individuals who present with respiratory-related symptoms, especially dyspnea. Diagnostic confirmation with a computed tomography scan of the chest and echocardiogram should be rapid. Unlike venous thromboembolism, pulmonary embolectomy remains the preferred therapeutic approach. PMID- 28854950 TI - Prevalence and risk factors for type 2 diabetes mellitus with Prader-Willi syndrome: a single center experience. AB - BACKGROUND: Prader-Willi syndrome (PWS) is often related to severe obesity and type-2 diabetes mellitus (T2DM). However, few studies, and none in Korea, have examined prevalence of T2DM and other variables in PWS. The aim of this study was to identify the prevalence and associated risk factors for T2DM in Korean patients with PWS. METHODS: We performed a retrospective cohort study of the 84 PWS patients aged 10 or over (10.3-35.8 years of age) diagnosed with PWS at Samsung Medical Center from 1994 to 2016. We estimated occurrence of T2DM according to age (10-18 years versus >18 years), body mass index (BMI), genotype, history of growth hormone therapy, homeostasis model of assessment-insulin resistance (HOMA-IR), and the presence of dyslipidemia, hypogonadism, or central precocious puberty. Additionally, we investigated cutoff values of risk factors for development of T2DM. RESULTS: Twenty-nine of a total 211 patients, diagnosed with PWS over the study period, were diagnosed as having T2DM (13.7%, mean age 15.9 +/- 3.6 years). In the >18 years group, obesity, HOMA-IR, and presence of dyslipidemia, hypogonadism, or central precocious puberty were associated with the occurrence of T2DM in univariate analysis. In multivariate logistic regression analysis, only obesity (p = 0.001) and HOMA-IR (p < 0.001) were significant predictive factors for T2DM. Based on the receiver operating a characteristic curve analysis, the cutoff values of HOMA-IR and BMI for predicting T2DM were >2.7 and >28.49 kg/m2, respectively. Of the 29 patients, seven had >=1 microvascular complication, with non-proliferative diabetic retinopathy in 6 of 7 cases. Advanced age and HOMA-IR were positively correlated with diabetic microvascular complications (p < 0.05, Spearman correlation coefficient 0.393 and 0.434, respectively). CONCLUSIONS: The prevalence of diabetes in Korean PWS was similar to that in previous results. BMI and HOMA-IR were strong predictive factors for the development of T2DM in PWS. We specifically suggest the regular monitoring of glucose homeostasis parameters through a detailed settlement of ethnically specific cutoff values for BMI and HOMA-IR in PWS to prevent progression of T2DM and diabetic microvascular complications. PMID- 28854951 TI - Health seeking behaviour among suspected cases of cholera in Cameroonian health districts in Lake Chad basin. AB - BACKGROUND: Cholera outbreaks are recurrent in Cameroon and despite the efforts put together during epidemics, they are always associated with a high case fatality. Inadequate demand for health care is one of the major factors that might be responsible for the high case fatality. This study was conducted to describe the health seeking behaviour of suspected cases of cholera in four health districts of the Far North Cameroon. METHODS: We conducted a health facility based descriptive study involving suspected cases of cholera received in health facilities. Data was collected from August 2013 to October 2015 with the help of a questionnaire and analysis done by running frequency and calculating confidence interval at 95% with Epi Info version 3.5.4. RESULTS: A total of 1849 cases were enrolled, with 997 (53.9%) being males. 534 (28.9%) were children under the age of 5 and 942 (50.9%) were above the age of 14. About 373 (20%) of diarrhoeal patients arrived in the health facility more than 2 days following the onset of diarrhoea, with 916 (50%) of them being seriously dehydrated. Also, about 624 (34%) of these patients had sought treatment elsewhere before coming to the health facility where they were enrolled, and about 86% of them did not received ORS. Taking 2 or more days after diarrhoea onset or taking more than 1 h to travel from home to health facility was associated with severe dehydration in patients. CONCLUSIONS: The delay between the onset of diarrhoea and seeking treatment from a health provider determines the seriousness of suspected cases of cholera in the Far North Cameroon. While conducting an anthropological study to understand reasons why a health provider is not the first option during diarrhoeal episodes, we recommend that a system of community case detection and reference to health facilities should be put in place during cholera outbreaks to minimize its case fatality rate. PMID- 28854952 TI - Clinical implications of neoepitope landscapes for adult and pediatric cancers. AB - Many immunotherapies rely on the presence of neoepitopes derived from somatic mutations that lead to altered peptide sequences. Several studies have now analyzed the neoepitope landscape of different cancer subtypes, predominantly for adult samples, which tend to feature significantly higher mutational burden. However, a new report publishing the first comprehensive analysis of the pediatric neoepitope landscape suggests that immunotherapies could also hold promise for pediatric cancers.See related research article 10.1186/s13073-017 0468-3. PMID- 28854953 TI - Humanization of pediatric care in the world: focus and review of existing models and measurement tools. AB - BACKGROUND: The term "humanization" indicates the process by which people try to make something more human and civilized, more in line with what is believed to be the human nature. The humanization of care is an important and not yet a well defined issue which includes a wide range of aspects related to the approach to the patient and care modalities. In pediatrics, the humanization concept is even vaguer due to the dual involvement of both the child and his/her family and by the existence of multiple proposed models. OBJECTIVE: The present study aims to analyze the main existing humanization models regarding pediatric care, and the tools for assessing its grade. RESULTS: The main Humanization care programs have been elaborated and developed both in America (Brazil, USA) and Europe. The North American and European models specifically concern pediatric care, while the model developed in Brazil is part of a broader program aimed at all age groups. The first emphasis is on the importance of the family in child care, the second emphasis is on the child's right to be a leader, to be heard and to be able to express its opinion on the program's own care. Several tools have been created and used to evaluate humanization of care programs and related aspects. None, however, had been mutually compared. CONCLUSIONS: The major models of humanization care and the related assessment tools here reviewed highlight the urgent need for a more unifying approach, which may help in realizing health care programs closer to the young patient's and his/her family needs. PMID- 28854954 TI - A subset of conserved mammalian long non-coding RNAs are fossils of ancestral protein-coding genes. AB - BACKGROUND: Only a small portion of human long non-coding RNAs (lncRNAs) appear to be conserved outside of mammals, but the events underlying the birth of new lncRNAs in mammals remain largely unknown. One potential source is remnants of protein-coding genes that transitioned into lncRNAs. RESULTS: We systematically compare lncRNA and protein-coding loci across vertebrates, and estimate that up to 5% of conserved mammalian lncRNAs are derived from lost protein-coding genes. These lncRNAs have specific characteristics, such as broader expression domains, that set them apart from other lncRNAs. Fourteen lncRNAs have sequence similarity with the loci of the contemporary homologs of the lost protein-coding genes. We propose that selection acting on enhancer sequences is mostly responsible for retention of these regions. As an example of an RNA element from a protein-coding ancestor that was retained in the lncRNA, we describe in detail a short translated ORF in the JPX lncRNA that was derived from an upstream ORF in a protein-coding gene and retains some of its functionality. CONCLUSIONS: We estimate that ~ 55 annotated conserved human lncRNAs are derived from parts of ancestral protein-coding genes, and loss of coding potential is thus a non negligible source of new lncRNAs. Some lncRNAs inherited regulatory elements influencing transcription and translation from their protein-coding ancestors and those elements can influence the expression breadth and functionality of these lncRNAs. PMID- 28854955 TI - Identification of two mutation sites in spike and envelope proteins mediating optimal cellular infection of porcine epidemic diarrhea virus from different pathways. AB - Entry of the alpha-coronavirus porcine epidemic diarrhea virus (PEDV) requires specific proteases to activate spike (S) protein for the membrane fusion of the virion to the host cell following receptor binding. Herein, PEDV isolate 85-7 could proliferate and induce cell-cell fusion in a trypsin independent manner on Vero cells, and eight homologous mutation strains were screened by continuous proliferation in the absence of trypsin on Vero cells. According to the whole genome sequence comparative analysis, we identified four major variations located in nonstructural protein 2, S, open reading frame 3, and envelope (E) genes, respectively. Comparative analyses of their genomic variations and proliferation characteristics identified a single mutation within the S2' cleavage site between C30 and C40 mutants: the substitution of conserved arginine (R) by a glycine (G) (R895G). This change resulted in weaker cell-cell fusion, smaller plaque morphology, higher virus titer and serious microfilament condensation. Further analysis confirmed that this mutation was responsible for optimal cell adaptation, but not the determinant for trypsin-dependent entry of PEDV. Otherwise, a novel variation (16-20 aa deletion and an L25P mutation) in the transmembrane domain of the E protein affected multiple infection processes, including up-regulation of the production of the ER stress indicator GRP78, improving the expression of pro-inflammatory cytokines IL-6 and IL-8, and promoting apoptosis. The results of this study provide a better understanding of the potential mechanisms of viral functional proteins in PEDV replication, infection, and fitness. PMID- 28854956 TI - Ultra-low dose of rituximab in rheumatoid arthritis: study protocol for a randomised controlled trial. AB - BACKGROUND: A standard low-dosing schedule of rituximab (RTX; 2 * 500 mg or 1 * 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 * 1000 mg). Moreover, several small uncontrolled studies suggest that even lower-dosed treatment with RTX also leads to good treatment response in patients with RA. Retreatment with such an 'ultra-low' dose RTX in patients who responded well to RTX induction treatment is of special interest, as long-term use of lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. However, the effect of ultra-low dose of RTX has not been investigated using a controlled trial of proper design and dimensions. METHODS/DESIGN: REDO is an investigator driven six-month pragmatic, double-blind, randomised controlled non-inferiority trial on the effects of ultra-low-dose RTX (1 * 500 or 1 * 200 mg) compared to standard low dose (1 * 1000 mg) in RA patients who are being retreated with RTX. A total of 140 RA patients, having reached low disease activity (DAS28CRP < 2.9) after the previous RTX infusion and DAS28CRP < 3.5 at moment of retreatment, are randomised in a ratio of 1:2:2 to 1 * 1000 mg, 1 * 500 mg or 1 * 200 mg. The primary objective is testing non inferiority of the ultra-low-dose vs. standard low-dose RTX, by comparing mean change in DAS28CRP from baseline to six months to the non-inferiority margin of 0.6. Secondary outcomes over the same period are: function; quality of life; safety; costs; and pharmacokinetics and dynamics as process measures. DISCUSSION: This study protocol shares characteristics of both early dose finding trials as well as late pragmatic clinical studies. Several choices in the design of this trial are described and possible consequences for RA treatment and expected biosimilar introduction are discussed. TRIAL REGISTRATION: Dutch Trial Register, NTR6117 . Registered on 15 November 2016 (CMO NL57520.091.16 , 8 November 2016). PMID- 28854957 TI - A systematic synthesis of direct costs to treat and manage tuberculosis disease applied to California, 2015. AB - BACKGROUND: The cost of treating and managing cases of active tuberculosis (TB) disease-from diagnosis to treatment completion-is needed by agencies working on public health budgets, resource allocation and cost-effectiveness analysis. Although components of TB costs have been published in the United States (US), no recent study has assessed overall costs for TB care and potential gaps. To systematically review the US literature for costs of treating and managing cases of active TB disease, adjust these costs to current (2015) values, and assess gaps. We quantified total direct costs-from the perspective of the health care payer-of the treatment and case management of active TB disease. Estimates were based on published figures in the US, and operational data of the California Department of Public Health. RESULT: The average direct cost of treating and managing a TB case was $34,600 in 2015. The average cost of a multidrug-resistant TB case was $110,900. Health care spending for treating and case managing TB patients in California amounted to approximately $75.6 million for the 2133 new cases reported in 2015. Most published cost estimates were based on data from the 1990s. CONCLUSION: TB is resource-intensive to treat and manage. Our synthesis provides inputs for budgets and economic analyses. New studies to provide original cost data are needed to better reflect current clinical and public health practices. PMID- 28854958 TI - The effects of community pharmacy public health interventions on population health and health inequalities: a systematic review of reviews protocol. AB - BACKGROUND: Community pharmacies have great potential to deliver services aimed at promoting health and preventing disease, and are embedded within communities. In the light of a rapid increase in community pharmacy-delivered public health services and an accompanying increase in the evidence base, this systematic review of reviews will synthesise systematic reviews of public health community pharmacy interventions and assess their effects on public health and health inequalities. METHODS/DESIGN: Systematic review methodology will be used to identify all systematic reviews that describe the health and health equity effects of community pharmacy public health interventions. Twenty databases will be searched using a pre-determined search strategy to evaluate community pharmacy delivered public health interventions. Findings from the included reviews will be pooled, and a narrative synthesis executed to identify overarching patterns and results. DISCUSSION: Findings will support future decision-making around how community pharmacy public health services can be used alongside other strategies to promote health, prevent disease and reduce health inequalities. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42017056264 . PMID- 28854960 TI - Erratum to: Cancer chemoprevention through dietary flavonoids: what's limiting? PMID- 28854959 TI - Hemophagocytic lymphohistiocytosis presenting in a pediatric patient with near total colonic and small bowel aganglionosis: a case report. AB - BACKGROUND: Total colonic and small bowel aganglionosis is a rare condition typically requiring intestinal transplant for long-term survival. There have not been any previously reported cases of near total intestinal aganglionosis complicated by concerns for hemophagocytic lymphohistiocytosis and need for both multivisceral organ transplant and hematopoietic stem cell transplant. CASE PRESENTATION: Our patient is a 35-month-old Egyptian boy who presented with bilious emesis and failure to pass meconium shortly after birth. After evaluation, he was found to have near total colonic and small bowel aganglionosis up to the ligament of Treitz. When he was transferred to our tertiary facility, he was already diagnosed as having aganglionosis of total colon and partial small bowel whose case is complicated by the concern for hemophagocytic lymphohistiocytosis. He was not able to absorb any substantial nutrition enterally and was stabilized on long-term total parenteral nutrition which resulted in total parenteral nutrition-induced liver injury. While awaiting evaluation for liver and bowel transplant, he developed concerning symptoms consistent with hemophagocytic lymphohistiocytosis. He presents a complex challenge creating difficulty with management of whether to proceed with bowel transplant as a result of near-total intestinal aganglionosis or hematopoietic stem cell transplant for treatment of hemophagocytic lymphohistiocytosis. In this case, the transplant team proceeded with visceral transplant first, however he did not survive. CONCLUSIONS: This presentation of aganglionosis of total colon and partial small bowel complicated by the concern for hemophagocytic lymphohistiocytosis is unique to medical literature. For many physicians involved it is hard to determine how best to proceed with next steps in care. PMID- 28854961 TI - Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis. AB - Stem cells have demonstrated encouraging potential as reparative therapy for patients suffering from post-stroke disability. Reperfusion interventions in the acute phase of stroke have shown significant benefit but are limited by a narrow window of opportunity in which they are beneficial. Thereafter, rehabilitation is the only intervention available. The current review summarises the current evidence for use of stem cell therapies in stroke from early-phase clinical trials. The safety and feasibility of administering different types of stem cell therapies in stroke seem to be reasonably proven. However, the effectiveness needs still to be established through bigger clinical trials with more pragmatic clinical trial designs that address the challenges raised by the heterogeneous nature of stroke per se, as well those due to unique characteristics of stem cells as therapeutic agents. PMID- 28854963 TI - Takayasu's arteritis: a case with relapse after urgent coronary revascularization. AB - BACKGROUND: Vasculitides are commonly unrecognized causes of coronary stenosis and myocardial ischemia. We report on a 24-year old patient with Takayasu's arteritis who underwent urgent percutaneous coronary intervention, suffered from symptomatic restenosis of the left main coronary artery during standard immunosuppressive therapy. CASE PRESENTATION: A 24-year old woman was referred for coronary angiography because of typical progressive angina pectoris. On bicycle ergometry, there were both reproducible symptoms and deep ST segment depressions on precordial leads. Semi-selective angiography of the left coronary artery revealed high-grade ostial stenosis. Because of persistent angina pectoris and electrocardiographic signs of acute myocardial ischemia, immediate percutaneous coronary angioplasty with subsequent implantation of an everolimus eluting stent was performed. This intervention was performed with excellent angiographic results. Because of several concomitant criteria including hypoechogenicity on postprocedural intravascular ultrasonography, the diagnosis of Takayasu's disease was made. The patient was treated with prednisolone and cyclophosphamide for 5 months. Because of recurrent angina pectoris, another coronary angiography was performed, which revealed high-grade in-stent restenosis. Immunomodulatory therapy was switched to high-dose prednisolone and the anti-IL-6 receptor antagonist tocilizumab. The high-grade in-stent-restenosis persisted, and aortocoronary bypass graft surgery was performed with two saphenous vein grafts to the left anterior descending and circumflex artery. Since then, the patient has been doing well for 2 years. CONCLUSION: In cases of treatment refractoriness during standard immunosuppressive therapy, more recently developed biological compounds may offer an alternative strategy. PMID- 28854962 TI - Optimized reduced representation bisulfite sequencing reveals tissue-specific mCHH islands in maize. AB - BACKGROUND: DNA methylation plays important roles in many regulatory processes in plants. It is economically infeasible to profile genome-wide DNA methylation at a single-base resolution in maize, given its genome size of ~2.5 Gb. As an alternative, we adapted region of interest (ROI)-directed reduced representation bisulfite sequencing (RRBS) to survey genome-wide methylation in maize. RESULTS: We developed a pipeline for selecting restriction enzymes in silico and experimentally showed that, in the maize genome, MseI- and CviQI-digested fragments are precisely enriched in promoters and gene bodies, respectively. We proceeded with comparisons of epigenomes and transcriptomes between shoots and tassels and found that the occurrences of highly methylated, tissue-specific, mCHH islands upstream of transcription start sites (TSSs) were positively correlated with differential gene expression. Furthermore, 5' regulatory regions between TSS and mCHH islands often contain putative binding sites of known transcription factors (TFs) that regulate the flowering process and the timing of the transition from the vegetative to the reproductive phase. By integrating MNase-seq and siRNA-seq data, we found that regions of mCHH islands accumulate 21nt-siRNAs in a tissue-specific manner, marking the transition to open chromatin, thereby ensuring the accessibility of TFs for tissue-specific gene regulation. CONCLUSIONS: Our ROI-directed RRBS pipeline is eminently applicable to DNA methylation profiling of large genomes. Our results provide novel insights into the tissue-specific epigenomic landscapes in maize, demonstrating that DNA methylation and siRNA and chromatin accessibility constitute a critical, interdependent component that orchestrates the transition from the vegetative to the reproductive phase. PMID- 28854964 TI - Perceptions of human papillomavirus vaccination of adolescent schoolgirls in western Uganda and their implications for acceptability of HPV vaccination: a qualitative study. AB - BACKGROUND: Human papillomavirus (HPV) vaccination has been perceived in diverse ways some of which encourage its uptake while others could potentially deter its acceptability. This study explored community member's perceptions about HPV vaccination in Ibanda district and the implications of the perceptions for acceptability of HPV vaccination. The study was conducted following initial vaccination of adolescent schoolgirls in the district between 2008 and 2011. METHODS: This qualitative study employed focus group discussions (FGDs) and key informant interviews (KIIs). FGDs were conducted with schoolgirls and parents/guardians and KIIs were conducted with school teachers, health workers and community leaders. Transcripts from the FGDs and KIIs were coded and analyzed thematically using ATLAS.ti (v. 6). RESULTS: The HPV vaccination was understood to safely prevent cervical cancer, which was perceived to be a severe incurable disease. Vaccinations were perceived as protection against diseases like measles and polio that were known to kill children. These were major motivations for girls' and parents' acceptance of HPV vaccination. Parents' increased awareness that HPV is sexually transmitted encouraged their support for vaccination of their adolescent daughters against HPV. There were reports however of some initial fears and misconceptions about HPV vaccination especially during its introduction. These initially discouraged some parents and girls but over the years with no major side effects reported, girls reported that they were willing to recommend the vaccination to others and parents also reported their willingness to get their daughters vaccinated without fear. Health workers and teachers interviewed however explained that, some concerns stilled lingered in the communities. CONCLUSIONS: The perceived benefits and safety of HPV vaccination enhanced girls' and parents' acceptability of HPV vaccination. The initial rumors, fears and concerns about HPV vaccination that reportedly discouraged some girls and parents, seemed to have waned with time giving way to more favourable perceptions regarding HPV vaccination although the study still found that a few concerns still lingered on and these have implications for HPV vaccination acceptability. PMID- 28854965 TI - Adipose stem cells from chronic pancreatitis patients improve mouse and human islet survival and function. AB - BACKGROUND: Chronic pancreatitis has surgical options including total pancreatectomy to control pain. To avoid surgical diabetes, the explanted pancreas can have islets harvested and transplanted. Immediately following total pancreatectomy with islet autotransplantation (TP-IAT), many islet cells die due to isolation and transplantation stresses. The percentage of patients remaining insulin free after TP-IAT is therefore low. We determined whether cotransplantation of adipose-derived mesenchymal stem cells (ASCs) from chronic pancreatitis patients (CP-ASCs) would protect islets after transplantation. METHODS: In a marginal mass islet transplantation model, islets from C57BL/6 mice were cotransplanted with CP-ASCs into syngeneic streptozotocin-treated diabetic mice. Treatment response was defined by the percentage of recipients reaching normoglycemia, and by the area under the curve for glucose and c-peptide in a glucose tolerance test. Macrophage infiltration, beta-cell apoptosis, and islet graft vasculature were measured in transplanted islet grafts by immunohistochemistry. mRNA expression profiling of 84 apoptosis-related genes in islet grafts transplanted alone or with CP-ASCs was measured by the RT2 ProfilerTM Apoptosis PCR Array. The impact of insulin-like growth factor-1 (IGF 1) on islet apoptosis was determined in islets stimulated with cytokines (IL 1beta and IFN-gamma) in the presence and absence of CP-ASC conditioned medium. RESULTS: CP-ASC-treated mice were more often normoglycemic compared to mice receiving islets alone. ASC cotransplantation reduced macrophage infiltration, beta-cell death, suppressed expression of TNF-alpha and Bcl-2 modifying factor (BMF), and upregulated expressions of IGF-1 and TNF Receptor Superfamily Member 11b (TNFRSF11B) in islet grafts. Islets cultured in conditioned medium from CP ASCs showed reduced cell death. This protective effect was diminished when IGF-1 was blocked in the conditioned medium by the anti-IGF-1 antibody. CONCLUSION: Cotransplantation of islets with ASCs from the adipose of chronic pancreatitis patients improved islet survival and islet function after transplantation. The effects are in part mediated by paracrine secretion of IGF-1, suppression of inflammation, and promotion of angiogenesis. ASCs from chronic pancreatitis patients have the potential to be used as a synergistic therapy to enhance the efficacy of islet transplantation following pancreatectomy. PMID- 28854966 TI - Using automated texture features to determine the probability for masking of a tumor on mammography, but not ultrasound. AB - BACKGROUND: Tumors in radiologically dense breast were overlooked on mammograms more often than tumors in low-density breasts. A fast reproducible and automated method of assessing percentage mammographic density (PMD) would be desirable to support decisions whether ultrasonography should be provided for women in addition to mammography in diagnostic mammography units. PMD assessment has still not been included in clinical routine work, as there are issues of interobserver variability and the procedure is quite time consuming. This study investigated whether fully automatically generated texture features of mammograms can replace time-consuming semi-automatic PMD assessment to predict a patient's risk of having an invasive breast tumor that is visible on ultrasound but masked on mammography (mammography failure). METHODS: This observational study included 1334 women with invasive breast cancer treated at a hospital-based diagnostic mammography unit. Ultrasound was available for the entire cohort as part of routine diagnosis. Computer-based threshold PMD assessments ("observed PMD") were carried out and 363 texture features were obtained from each mammogram. Several variable selection and regression techniques (univariate selection, lasso, boosting, random forest) were applied to predict PMD from the texture features. The predicted PMD values were each used as new predictor for masking in logistic regression models together with clinical predictors. These four logistic regression models with predicted PMD were compared among themselves and with a logistic regression model with observed PMD. The most accurate masking prediction was determined by cross-validation. RESULTS: About 120 of the 363 texture features were selected for predicting PMD. Density predictions with boosting were the best substitute for observed PMD to predict masking. Overall, the corresponding logistic regression model performed better (cross-validated AUC, 0.747) than one without mammographic density (0.734), but less well than the one with the observed PMD (0.753). However, in patients with an assigned mammography failure risk >10%, covering about half of all masked tumors, the boosting-based model performed at least as accurately as the original PMD model. CONCLUSION: Automatically generated texture features can replace semi-automatically determined PMD in a prediction model for mammography failure, such that more than 50% of masked tumors could be discovered. PMID- 28854967 TI - Innovative dressing and securement of tunneled central venous access devices in pediatrics: a pilot randomized controlled trial. AB - BACKGROUND: Central venous access device (CVAD) associated complications are a preventable source of patient harm, frequently resulting in morbidity and delays to vital treatment. Dressing and securement products are used to prevent infectious and mechanical complications, however current complication rates suggest customary practices are inadequate. The aim of this study was to evaluate the feasibility of launching a full-scale randomized controlled efficacy trial of innovative dressing and securement products for pediatric tunneled CVAD to prevent complication and failure. METHODS: An external, pilot, four-group randomized controlled trial of standard care (bordered polyurethane dressing and suture), in comparison to integrated securement-dressing, suture-less securement device, and tissue adhesive was undertaken across two large, tertiary referral pediatric hospitals in Australia. Forty-eight pediatric participants with newly inserted tunneled CVADs were consecutively recruited. The primary outcome of study feasibility was established by elements of eligibility, recruitment, attrition, protocol adherence, missing data, parent and healthcare staff satisfaction and acceptability, and effect size estimates for CVAD failure (cessation of function prior to completion of treatment) and complication (associated bloodstream infection, thrombosis, breakage, dislodgement or occlusion). Dressing integrity, product costs and site complications were also examined. RESULTS: Protocol feasibility was established. CVAD failure was: 17% (2/12) integrated securement-dressing; 8% (1/13) suture-less securement device; 0% tissue adhesive (0/12); and, 0% standard care (0/11). CVAD complications were: 15% (2/13) suture-less securement device (CVAD associated bloodstream infection, and occlusion and partial dislodgement); 8% (1/12) integrated securement-dressing (partial dislodgement); 0% tissue adhesive (0/12); and, 0% standard care (0/11). One CVAD-associated bloodstream infection occurred, within the suture-less securement device group. Overall satisfaction was highest in the integrated securement-dressing (mean 8.5/10; standard deviation 1.2). Improved dressing integrity was evident in the intervention arms, with the integrated securement dressing associated with prolonged time to first dressing change (mean days 3.5). CONCLUSIONS: Improving the security and dressing integrity of tunneled CVADs is likely to improve outcomes for pediatric patients. Further research is necessary to identify novel, effective CVAD securement to reduce complications, and provide reliable vascular access for children. TRIAL REGISTRATION: ACTRN12614000280606 ; prospectively registered on 17/03/2014. PMID- 28854968 TI - Evaluation of Rumex hastatus leaves against hepatic fibrosis: a rat model. AB - BACKGROUND: Rumex hastatus leaves have been widely used as food additive and for the treatment of various liver ailments. According to our previous studies, ethyle acetate (ERL) and methanolic (MRL) fractions of R. hastatus leaves are an accessible source of natural antioxidants. In the present research work we arranged to investigate the R. hastatus leaves as hepaptoprotective agent verse hepatic damages caused by CCl4. METHODS: During this project we divided 48 rats into eight groups randomly. CCl4-induced damages were assessed through liver function markers viz.; alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (gamma-GT) and lactate dehydrogenase (LDH). Changes in lipid profile were checked by measuring serum total cholesterol (TC), triglycerides (Tg), high density lipoproteins (HDL) and low density lipoproteins (LDL). Antioxidant status was checked by the activities of antioxidant enzymes, DNA damages and cellular abnormalities at histo level. RESULTS: Administration of CCl4 in rats caused significant increase in liver function and lipid profile indicating hepatic damages which were restored by co administration of R. hastatus extracts. Cellular and DNA damages in hepatic tissues were caused by CCl4 which shown clear hepatic fibrosis in addition to disturb antioxidant enzyme level. Co-treatment with various fractions of R. hastatus leaves regulated these markers of oxidative dysfunctions. CONCLUSION: From the present report it was inferred that R. hastatus leaves have the ability to reverse CCl4 - induced hepatic damages. PMID- 28854969 TI - Divergent trends in lung cancer incidence by gender, age and histological type in Estonia: a nationwide population-based study. AB - BACKGROUND: Lung cancer (LC) is the leading cause of cancer deaths in men and the second most frequent cause of cancer deaths in women in Estonia. The study aimed to analyze time trends in LC incidence and mortality in Estonia over the 30-year period, which included major social, economic and health care transition. The results are discussed in the context of changes in tobacco control and smoking prevalence. Long-term predictions of incidence and mortality are provided. METHODS: Data for calculating the incidence and mortality rates in 1985-2014 were obtained from the nationwide population-based Estonian Cancer Registry and the Causes of Death Registry. Joinpoint regression was used to analyze trends and estimate annual percentage change (APC) with 95% confidence interval (CI). Nordpred model was used to project future incidence and mortality trends for 2015 2034. RESULTS: Incidence peaked among men in 1991 and decreased thereafter (APC: 1.5, 95% CI: -1.8; -1.3). A decline was seen for all age groups, except age >= 75 years, and for all histological types, except adenocarcinoma and large cell carcinoma. Incidence among women increased overall (APC: 1.6, 95% CI: 1.1; 2.0) and in all age groups and histological types, except small cell carcinoma. Age standardized incidence rate (world) per 100,000 was 54.2 in men and 12.9 in women in 2014. Changes in mortality closely followed those in incidence. According to our predictions, the age-standardized incidence and mortality rates will continue to decrease in men and reach a plateau in women. CONCLUSIONS: The study revealed divergent LC trends by gender, age and histological type, which were generally consistent with main international findings. Growing public awareness and stricter tobacco control have stimulated overall favorable changes in men, but not yet in women. Large increase in incidence was observed for adenocarcinoma, which in men showed a trend opposite to the overall decline. LC will remain a serious public health issue in Estonia due to a high number of cases during the next decades, related to aging population, and previous and current smoking patterns. National tobacco control policy in Estonia should prioritize preventing smoking initiation and promoting smoking cessation, particularly among women. PMID- 28854970 TI - EGFR copy number alterations in primary tumors, metastatic lymph nodes, and recurrent and multiple primary tumors in oral cavity squamous cell carcinoma. AB - BACKGROUND: The EGFR and downstream signaling pathways play an important role in tumorigenesis in oral squamous cell carcinoma (OSCC). Gene copy number alteration is one mechanism for overexpressing the EGFR protein and was also demonstrated to be related to lymph node metastasis, tumor invasiveness and perineural invasion. Therefore, we hypothesized that EGFR gene copy number alteration in the primary tumor could predict amplification in recurrent tumors, lymph node metastatic foci or secondary primary tumors. METHODS: We recruited a group of newly diagnosed OSCC patients (n = 170) between Mar 1997 and Jul 2004. Metastatic lymph nodes were identified from neck dissection specimens (n = 57). During follow-up, recurrent lesions (n = 41) and secondary primary tumors (SPTs, n = 17) were identified and biopsied. The EGFR gene amplifications were evaluated by fluorescence in situ hybridization (FISH) assay in primary tumors, metastatic lymph nodes, recurrences and SPTs. RESULTS: Of the 170 primary OSCCs, FISH showed low EGFR amplification/polysomy in 19 (11.4%) patients and amplification in 33 (19.8%) patients. EGFR gene amplification was related to lymph node metastasis (chi2 trend test: p = 0.018). Of 57 metastatic lymph nodes, nine (15.8%) had EGFR polysomy and 14 (24.6%) had EGFR gene amplification. The concordance rate of EGFR gene copy number in primary tumors and lymph node metastasis was 68.4% (McNemar test: p = 0.389). Of 41 recurrent tumors, five (12.2%) had EGFR polysomy and five (12.2%) had gene amplification. The concordance rate of EGFR gene copy number between primary tumors and recurring tumors was 65.9% (McNemar test: p = 0.510). The concordance rate between primary tumors and SPTs was 70.6%. EGFR amplification in either primary tumors, metastatic lymph nodes or recurrent tumors had no influence on patient survival. CONCLUSION: We can predict two thirds of the EGFR gene copy number alterations in lymph node metastasis or recurrent tumors from the analysis of primary tumors. For OSCC patients who are unable to provide lymph node or recurrent tumor samples for EGFR gene copy number analysis, examining primary tumors could provide EGFR clonal information in metastatic, recurrent or SPT lesions. PMID- 28854971 TI - Sini-san improves duodenal tight junction integrity in a rat model of functional dyspepsia. AB - BACKGROUND: Recent reports have demonstrated that impaired barrier function and local microinflammation in the duodenal mucosa contribute to the pathogeneses of functional dyspepsia (FD). Thus, restoring normal barrier integrity becomes a potential therapeutic strategy in the treatment of FD. Sini-San (SNS) is a traditional Chinese prescription that exhibits therapeutic effects in FD, but the underlying mechanisms remain not well understood. METHODS: FD rats were established by tail clamping method and the therapeutic effect of SNS was evaluated by measuring the visceral sensitivity and gastric compliance. Transepithelial electrical resistance (TEER) that reveals epithelial barrier integrity was measured by Ussing chamber. The expression of tight junction (TJ) proteins, occludin and claudin-1, in the duodenum was determined by Western blot and immunofluorescence. The amount of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (INF-gamma) in duodenal mucosa was detected by enzyme-linked immune sorbent assay (ELISA). The mRNA level of transient receptor potential vanilloid type 1 (TRPV1) was measured by quantitative real time-polymerase chain reaction (qPCR). RESULTS: SNS could improve gastric compliance and attenuate visceral hypersensitivity (VH) in FD rats. TEER was decreased in FD rats, but treatment with SNS restored normal level of TEER and the expression of occludin and claudin-1 in FD rats. In addition, SNS administration ameliorated FD associated increase in the production of TNF-alpha, IFN-gamma and the expression of TRPV1. CONCLUSIONS: The therapeutic effect of SNS on FD is at least partially through improvement of TJ integrity and attenuation of FD-associated low-grade inflammation in the duodenum. Our findings highlight the molecular basis of SNS based treatment of FD in human patients. PMID- 28854972 TI - Willingness to pay for National Health Insurance Fund among public servants in Juba City, South Sudan: a contingent evaluation. AB - BACKGROUND: This study assessed willingness to pay for National Health Insurance Fund (NHIF) among public servants in Juba City. NHIF is the proposed health insurance scheme for South Sudan and aims at achieving universal health coverage for the entire nation's population. One compounding issue is that over the years, governments' spending on healthcare has been decreasing from 8.4% of national budget in 2007 to only 2.2% in 2012. METHODS: A cross-sectional study design using contingent evaluation was employed; data on willingness to pay was collected from 381 randomly selected respondents and 13 purposively selected key informants working for the national, state and Juba County in September 2015. Qualitative data were analysed using conceptual content analysis. T-tests and linear regressions were performed to determine association between WTP for NHIF and independent variables. RESULTS: Up to 381 public servants were interviewed, of which 68% indicated willingness to pay varying percentages of total monthly individual income for NHIF. Over two-thirds (67.8%) of those willing to pay could pay up to 5% of their total monthly income, 22.9% could pay up to 10% and the rest could pay 25%. Over 80% were willing to pay up to 50 SSP (1 USD = 10 SSP) premiums for medical consultation, laboratory services and drugs. The main factors influencing the respondents' decisions were awareness, alternative sources of income, household size, insurance cover and religion. CONCLUSIONS: Willingness to pay is mainly influenced by awareness, alternative sources of individual income, household size, insurance cover and religion. Most of the public servants were aware of and willing to pay for NHIF and prefer a premium of up to 5% of total monthly income. There is need to create awareness and reach out to those who do not know about the scheme in addition to a detailed analysis of other stakeholders. Consideration could be made by the Government of South Sudan to start the scheme at the earliest opportunity since the majority of the respondents were willing to contribute towards it. PMID- 28854973 TI - Efficacy and safety of collagenase clostridium histolyticum for Dupuytren disease nodules: a randomized controlled trial. AB - BACKGROUND: To determine the safety and efficacy of collagenase clostridium histolyticum (CCH) injection for the treatment of palmar Dupuytren disease nodules. METHODS: In this 8-week, double-blind trial, palpable palmar nodules on one hand of adults with Dupuytren disease were selected for treatment. Patients were randomly assigned using an interactive web response system to receive a dose of 0.25 mg, 0.40 mg, or 0.60 mg (1:1:1 ratio) and then allocated to active treatment (CCH) or placebo (4:1 ratio). All patients and investigators were blinded to treatment. One injection was made in the selected nodule on Day 1. Caliper measurements of nodule length and width were performed at screening and at Weeks 4 and 8. Investigator-reported nodular consistency and hardness were evaluated at baseline and Weeks 1, 4, and 8. Investigator-rated patient improvement (1 [very much improved] to 7 [very much worse]) and patient satisfaction were assessed at study end. RESULTS: In the efficacy population (n = 74), percentage changes in area were significantly greater with CCH 0.40 mg ( 80.1%, P = 0.0002) and CCH 0.60 mg (-78.2%, P = 0.0003), but not CCH 0.25 mg ( 58.3%, P = 0.079), versus placebo (-42.2%) at post-treatment Week 8. Mean change in nodular consistency and hardness were significantly improved with CCH versus placebo at Weeks 4 and 8 (P <= 0.0139 for all). At Week 8, investigator global assessment of improvement was significantly greater with CCH 0.40 mg and 0.60 mg (P <= 0.0014) but not statistically significant with CCH 0.25 mg versus placebo (P = 0.13). Most patients were "very satisfied" or "quite satisfied" with CCH 0.40 mg and 0.60 mg. Contusion/bruising (50.0% to 59.1%) was the most common adverse event with CCH treatment. CONCLUSION: In patients with Dupuytren disease, a single CCH injection significantly improved palmar nodule size and hardness. The safety of CCH was similar to that observed previously in patients with Dupuytren contracture. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02193828 . Date of trial registration: July 2, 2014 to December 5, 2014. PMID- 28854974 TI - Immunogenicity of the Plasmodium vivax merozoite surface protein 1 paralog in the induction of naturally acquired antibody and memory B cell responses. AB - BACKGROUND: The Plasmodium vivax merozoite surface protein 1 paralog (PvMSP1P-19) is a glycosylphosphatidylinositol (GPI)-anchored blood-stage protein that is expressed on the merozoite surface. It is proposed as a blood-stage vaccine candidate against P. vivax because of its ability to induce immune responses upon natural P. vivax exposure and in immunized animals. This study aimed to demonstrate the presence of inhibitory antibodies and memory B cell responses to the PvMSP1P-19 antigen during acute P. vivax infection and after recovery from infection. METHODS: To evaluate the antibody responses to PvMSP1P-19 during and after recovery from P. vivax infection, heparinized blood was collected from P. vivax-infected patients and recovered subjects to detect the total IgG response. The seropositive samples were defined into high and low responders, according to their optical density (OD) values obtained from ELISA. High responders were the subjects who had OD values above the OD of antisera from non-exposed controls plus 4* standard deviations, whereas low responders were the subjects who had OD values less than OD of antisera from non-exposed controls plus 4* standard deviations. The plasma from high and low responders were taken for testing the inhibitory activity against PvMSP1P-19-erythrocyte binding by in vitro EBIA. The sustainability of PvMSP1P-19-specific memory B cell responses after recovery from infection was analysed by ELISPOT. RESULTS: The anti-PvMSP1P-19 antibody levels were significantly higher in acutely infected P. vivax patients compared to healthy controls (P < 0.0001). Monitoring of the anti-PvMSP1P-19 antibody titre showed that the antibody was maintained for up to 9 months after recovery. Almost all high-responder groups strongly inhibited PvMSP1P-19 binding to erythrocytes, whereas no inhibition was shown in most low-responder samples. Interestingly, the inhibitory activity of the antibodies in some individuals from high-responder samples were stable for at least 12 months. The longevity of the antibody response was associated with the presence of PvMSP1P-19-specific memory B cells at 9 months after recovery from infection. CONCLUSIONS: The PvMSP1P-19 antigen has immunogenicity during the induction of the antibody response, in which both the levels and inhibitory activity are maintained after the patient recovered from P. vivax infection. The maintenance of the antibody response was associated with the response of PvMSP1P-19-specific memory B cells. Therefore, the PvMSP1P 19 antigen should also be considered as a reliable vaccine candidate to develop a blood-stage vaccine against P. vivax. PMID- 28854975 TI - Ruxolitinib/nilotinib cotreatment inhibits leukemia-propagating cells in Philadelphia chromosome-positive ALL. AB - BACKGROUND: As one of the major treatment obstacles in Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34+CD38-CD58- fraction in human Ph+ALL. Additionally, a cohort study demonstrated that Ph+ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies. METHODS: RNA sequencing (RNA-Seq) and real-time quantitative polymerase chain reaction (qRT PCR) were performed to analyze the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL. In order to assess the effects of the selective BCR-ABL and/or Janus kinase (JAK)2 inhibition therapy by the treatment with single agents or a combination of ruxolitinib and imatinib or nilotinib on Ph+ALL LPCs, drug-induced apoptosis of LPCs was investigated in vitro, as well as in vivo using sublethally irradiated and anti CD122-conditioned NOD/SCID xenograft mouse assay. Moreover, western blot analyses were performed on the bone marrow cells harvested from the different groups of recipient mice. RESULTS: RNA-Seq and qRT-PCR demonstrated that JAK2 was more highly expressed in the sorted LPCs than in the other cell fractions in de novo Ph+ALL patients. Combination treatment with a selective JAK1/JAK2 inhibitor (ruxolitinib) and nilotinib more effectively eliminated LPCs than either therapy alone or both in vitro and in humanized Ph+ALL mice by reducing phospho-CrKL and phospho-JAK2 activities at the molecular level. CONCLUSIONS: In summary, this pre clinical study provides a scientific rationale for simultaneously targeting BCR ABL and JAK2 activities as a promising anti-LPCs therapeutic approach for patients with de novo Ph+ALL. PMID- 28854976 TI - Increases in United States life expectancy through reductions in injury-related death. AB - BACKGROUND: During the previous century the average lifespan in the United States (US) increased by over 30 years, with much of this increase attributed to public health initiatives. This report examines further gains that might be achieved through reduced occurrence of injury-related death. METHODS: US life tables and injury death rate data were used to estimate potential increases in life expectancy assuming various reductions in the rate of fatal injuries. Corresponding numbers of deaths potentially averted annually were also estimated; unit (per death) medical and lifetime work loss costs were employed to estimate total costs potentially averted annually. RESULTS: Through elimination of injury as a cause of death, average US life expectancy at birth could be increased by approximately 1.5 years, with notable variations by sex, ethnicity, and race. More conservatively, average life expectancy at birth could be increased by 0.41 years assuming that the national injury death rate could be brought into line with the lowest state-specific rate. Under this more conservative but plausible assumption, an estimated 48,400 injury deaths and $61 billion in medical and work loss costs would be averted annually. CONCLUSIONS: Increases in life expectancy of the magnitude considered in this report are arguably attainable based on long term historical reductions in the US injury death rate, as well as significant continuing reductions seen in other developed countries. Contemporary evidence based interventions can play an important role in reducing injury-related deaths, such as those due to drug overdoses and older adult falls, as well as suicides. PMID- 28854977 TI - Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2. AB - BACKGROUND: Abnormal expression of numerous long non-coding RNAs (lncRNAs) has been reported in esophageal squamous cell carcinoma (ESCC) recently, but the great majority of their roles and mechanisms remain largely unclear. We aim to identify the critical ESCC-associated lncRNAs and elucidate the functions and mechanisms in detail. METHODS: Microarrays were used to analyze the differentially expressed lncRNAs in ESCC tissues. qRT-PCR was used to verify the result of microarrays. The effects of the most up-regulated lncRNA, cancer susceptibility candidate 9(CASC9), on cell growth, proliferation and cell cycle were investigated by in vivo and in vitro assays. Microarrays and recovery tests were used to discover the regulatory targets of CASC9. RNA FISH and subcellular fractionation assays were used to detect the subcellular location of CASC9. Finally, the mechanism of CASC9 regulating PDCD4 was explored by RIP, RNA-protein pull down and ChIP assays. RESULTS: ESCC tissue microarrays showed that CASC9 was the most up-regulated lncRNA. qRT-PCR analysis indicated that CASC9 expression was positively associated with tumor size and TNM stage, and predicted poor overall survival of ESCC patients. Knockdown of CASC9 inhibited ESCC cell growth in vitro and tumorigenesis in nude mice. Furthermore interfering CASC9 decreased cell proliferation and blocked cell cycle G1/S transition. CASC9-associated microarrays indicated that PDCD4 might be the target of CASC9. Consistent with this, PDCD4 expression was negatively associated with CASC9 expression in ESCC tissues and predicted good prognosis. Manipulating CASC9 expression in ESCC cells altered both PDCD4 mRNA and protein levels and cell cycle arrest caused by CASC9 knockdown could be rescued by suppressing PDCD4 expression. CASC9 located both in the nucleus and cytoplasm. Mechanistically, enhancer of zeste homolog2 (EZH2) could bind to both CASC9 and PDCD4 promoter region. Interfering CASC9 reduced the enrichment of EZH2 and H3K27me3 in the PDCD4 promoter region. CONCLUSIONS: Our study firstly demonstrates that lncRNA CASC9 functions as an oncogene by negatively regulating PDCD4 expression through recruiting EZH2 and subsequently altering H3K27me3 level. Our study implicates lncRNA CASC9 as a valuable biomarker for ESCC diagnosis and prognosis. PMID- 28854978 TI - The neoepitope landscape in pediatric cancers. AB - BACKGROUND: Neoepitopes derived from tumor-specific somatic mutations are promising targets for immunotherapy in childhood cancers. However, the potential for such therapies in targeting these epitopes remains uncertain due to a lack of knowledge of the neoepitope landscape in childhood cancer. Studies to date have focused primarily on missense mutations without exploring gene fusions, which are a major class of oncogenic drivers in pediatric cancer. METHODS: We developed an analytical workflow for identification of putative neoepitopes based on somatic missense mutations and gene fusions using whole-genome sequencing data. Transcriptome sequencing data were incorporated to interrogate the expression status of the neoepitopes. RESULTS: We present the neoepitope landscape of somatic alterations including missense mutations and oncogenic gene fusions identified in 540 childhood cancer genomes and transcriptomes representing 23 cancer subtypes. We found that 88% of leukemias, 78% of central nervous system tumors, and 90% of solid tumors had at least one predicted neoepitope. Mutation hotspots in KRAS and histone H3 genes encode potential epitopes in multiple patients. Additionally, the ETV6-RUNX1 fusion was found to encode putative neoepitopes in a high proportion (69.6%) of the pediatric leukemia harboring this fusion. CONCLUSIONS: Our study presents a comprehensive repertoire of potential neoepitopes in childhood cancers, and will facilitate the development of immunotherapeutic approaches designed to exploit them. The source code of the workflow is available at GitHub ( https://github.com/zhanglabstjude/neoepitope ). PMID- 28854979 TI - The effect of exercise training on clinical outcomes in patients with the metabolic syndrome: a systematic review and meta-analysis. AB - BACKGROUND: Purpose: to establish if exercise training improves clinical outcomes in people with metabolic syndrome (MetS). Registered with PROSPERO international prospective register of systematic reviews ( https://www.crd.york.ac.uk/PROSPERO/Identifier:CRD42017055491 ). DATA SOURCES: studies were identified through a MEDLINE search strategy (1985 to Jan 12, 2017), Cochrane controlled trials registry, CINAHL and SPORTDiscus. STUDY SELECTION: prospective randomized or controlled trials of exercise training in humans with metabolic syndrome, lasting 12 weeks or more. RESULTS: We included 16 studies with 23 intervention groups; 77,000 patient-hours of exercise training. In analyses of aerobic exercise studies versus control: body mass index was significantly reduced, mean difference (MD) -0.29 (kg m-2) (95% CI -0.44, -0.15, p < 0.0001); body mass was significantly reduced, MD -1.16 kg (95% CI -1.83, 0.48, p = 0.0008); waist circumference was significantly reduced MD -1.37 cm (95% CI -2.02, -0.71, p < 0.0001), peak VO2 was significantly improved MD 3.00 mL kg-1 min-1 (95% CI 1.92, 4.08, p < 0.000001); systolic blood pressure and diastolic blood pressure were significantly reduced, MD -2.54 mmHg (95% CI -4.34, -0.75, p = 0.006), and, MD -2.27 mmHg (95% CI -3.47, -1.06, p = 0.0002) respectively; fasting blood glucose was significantly reduced MD -0.16 mmol L-1 (95% CI -0.32, 0.01, p = 0.04); triglycerides were significantly reduced MD -0.21 mmol L-1 (95% CI -0.29, -0.13, p < 0.00001); and low density lipoprotein was significantly reduced MD -0.03 mmol L-1 (95% CI -0.05, -0.00, p = 0.02). In analyses of combined exercise versus control: waist circumference, MD -3.80 cm (95% CI -5.65, -1.95, p < 0.0001); peak VO2 MD 4.64 mL kg-1 min-1 (95% CI 2.42, 6.87, p < 0.0001); systolic blood pressure MD -3.79 mmHg (95% CI -6.18, -1.40, p = 0.002); and high density lipoprotein (HDL) MD 0.14 (95% CI 0.04, 0.25, p = 0.009) were all significantly improved. We found no significant differences between outcome measures between the two exercise interventions. CONCLUSIONS: Exercise training improves body composition, cardiovascular, and, metabolic outcomes in people with metabolic syndrome. For some outcome measures, isolated aerobic exercise appears optimal. PMID- 28854980 TI - Smoking and finances: baseline characteristics of low income daily smokers in the FISCALS cohort. AB - BACKGROUND: Financial stress is a barrier to successful smoking cessation and a key predictor of relapse. Little is known about the financial situation of low income Australian daily smokers. This study aims to describe and investigate associations between the financial functioning, tobacco use and quitting behaviours of low income daily smokers. METHODS: Low-income Australian adult smokers in the 'Financial Intervention for Smoking Cessation Among Low-income Smokers (FISCALS) randomised clinical trial completed a structured telephone questionnaire. RESULTS: The median number of cigarettes typically smoked by the 1047 participants was 23 per day. The median spent on tobacco per week was AU$80. Three quarters (73.0%) reported some financial stress and 43.2% reported smoking induced deprivation. Financial stress was significantly associated with deprivation (IRR: 1.23, 95% CI 1.21, 1.26, p < 0.001). There were no significant associations either between adjusted financial stress or deprivation and motivation to quit or certainty of quit success. CONCLUSIONS: Financial stress and smoking induced deprivation were prevalent among low-income daily smokers, but they were not associated with motivation to quit. Smoking cessation interventions need to be responsive to the role financial stress plays in reducing quit attempts and increasing relapse. TRIAL REGISTRATION: Australian and New Zealand Clinical trials Registry ACTRN12612000725864 6/07/2012. PMID- 28854981 TI - Rosiglitazone increases endothelial cell migration and vascular permeability through Akt phosphorylation. AB - BACKGROUND: Thiazolidinediones (TZDs), peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists, exhibit anti-inflammatory and antioxidant properties and inhibit endothelial inflammation and dysfunction, which is anti-atherogenic. However, fluid retention, which may lead to congestive heart failure and peripheral edema, is also a concern, which may result from endothelial cell leakage. In the current study, we examined the effects of PPAR-gamma agonists on vascular endothelial cell migration and permeability in order to determine its underlying mechanisms. METHODS: We used rosiglitazone and conducted cell migration assay and permeability assay using HUVEC cells and measured vascular permeability and leakage in male C57BL/6 mice. RESULTS: Rosiglitazone significantly promoted endothelial cell migration and induced permeability via activation of phosphatidylinositol-3-kinase (PI3K) - Akt or protein kinase C (PKC)beta. In addition, rosiglitazone increased vascular endothelial growth factor (VEGF) expression and suppressed expression of tight junction proteins (JAM-A and ZO-1), which might promote neovascularization and vascular leakage. These phenomena were reduced by Akt inhibition. CONCLUSIONS: Vascular endothelial cell migration and permeability change through Akt phosphorylation might be a mechanism of induced fluid retention and peripheral tissue edema by TZD. PMID- 28854984 TI - [Concentration of Emergency Departments: the wrong way to economize]. AB - In this paper we investigate whether it is economically beneficial to concentrate Emergency Departments (EDs) in large hospitals. We recognise economies of scale and economies of chain. The latter reflect the effects on costs of patients receiving further treatments in hospital, be it admissions or out-patient appointments, after visiting the ED. We conclude that there are product-specific economies of scale. On the one hand, hospitals benefit by increasing ED services. However, this is not in line with the diseconomies of scale observed for larger hospitals as a whole. This contradiction is called the economies of scale paradox. There are internal incentives to upscale services, such as EDs, in order to benefit from the product-specific economies of scale. However, a price is to be paid by the hospital for the upscaling of its ED. Based on these results, the resulting recommendation for policy development is that, in spite of the fact that concentrating EDs seems to be advantageous, upscaling of EDs must be rejected. PMID- 28854982 TI - Knowledge of standard precautions and barriers to compliance among healthcare workers in the Lower Manya Krobo District, Ghana. AB - BACKGROUND: Implementing standard precautions (SP) has been a major challenge for health care workers (HCWs) especially those in developing countries thereby compromising their safety and increasing their exposure to blood-related pathogens. Compliance with safety precautions and occupational accidents among health workers are often unreported. The literature on knowledge and compliance to SP in Ghana is scanty. We report findings of a study that examined knowledge of SP, compliance and barriers to compliance with SP among HCWs in two health facilities in Ghana. METHODS: This is a facility-based cross-sectional study involving 100 HCWs from two health facilities in the Lower Manya Krobo District of the Eastern region. Statistical analysis summarised data on socio-demographic characteristics of respondents, knowledge of SP and compliance and barriers to SP in frequencies and percentages. RESULTS: Most respondents had been working as health staff for 0-5 years (65.0%). Generally, knowledge of the basic concepts of SP was low; only 37.0% of HCWs knew that SP includes hand washing before and after any direct contact with the patient, 39.0% knew about cough etiquettes and 40.0% knew about aseptic techniques which involve infection prevention strategies to minimise the risks of infection. Fifty percent of respondents always protect themselves against BBFs of patients. About a quarter of the respondents do not recap needles after use and 28.0% of respondents sometimes promptly wipe all blood spills. HCWs were of the opinion that wearing PPEs-such as gloves, aprons, gowns and goggles-might cause patients to panic sometimes (63.0%) and complying with SP sometimes interferes with the ability to provide care (38.0%). Sometimes, because of the demands of patient care, HCWs do not have enough time to comply with the rigours of SP (44.0%) and sometimes PPEs are not available. CONCLUSION: Education programmes on the benefits of SP should be organised frequently. The OHS national policy together with the application of the IPC training manual in all health care facilities must be enforced. Communities of practice should be established and sanctions and rewards should be introduced to limit negative behavior and reinforce positive attitudes as regards SP. PMID- 28854985 TI - [Cutting through tumour in head and neck cancer: still a taboo?] AB - When resecting head and neck tumours, the aim is mostly to strive for en bloc resection with sufficiently large tumour-free margins. If this is not possible, as is frequently the case with transoral laser microsurgery and endonasal endoscopic surgery, multiblock resection can be carried out by cutting through the tumour. With this approach, it is also essential that the final resection margins are tumour-negative. In such cases, surgeon and pathologist together should pay extra attention to tissue orientation and outer resection margins. PMID- 28854983 TI - Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks. AB - The identification of functional non-coding mutations is a key challenge in the field of genomics. Here we introduce MU-cisTarget to filter, annotate and prioritize cis-regulatory mutations based on their putative effect on the underlying "personal" gene regulatory network. We validated MU-cisTarget by re analyzing the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, we re-sequenced the full genomes of ten cancer cell lines and used matched transcriptome data and motif discovery to identify master regulators with de novo binding sites that result in the up-regulation of nearby oncogenic drivers. MU-cisTarget is available from http://mucistarget.aertslab.org . PMID- 28854986 TI - [Time trends in prevalence of chronic diseases and multimorbidity not only due to aging: data from general practices and health surveys]. AB - INTRODUCTION: Chronic diseases and multimorbidity are common and expected to rise over the coming years. The objective of this study is to examine the time trend in the prevalence of chronic diseases and multimorbidity over the period 2001 till 2011 in the Netherlands, and the extent to which this can be ascribed to the aging of the population. METHODS: Monitoring study, using two data sources: 1) medical records of patients listed in a nationally representative network of general practices over the period 2002-2011, and 2) national health interview surveys over the period 2001-2011. Regression models were used to study trends in the prevalence-rates over time, with and without standardization for age. RESULTS: An increase from 34.9% to 41.8% (p<0.01) in the prevalence of chronic diseases was observed in the general practice registration over the period 2004 2011 and from 41.0% to 46.6% (p<0.01) based on self-reported diseases over the period 2001-2011. Multimorbidity increased from 12.7% to 16.2% (p<0.01) and from 14.3% to 17.5% (p<0.01), respectively. Aging of the population explained part of these trends: about one-fifth based on general practice data, and one-third for chronic diseases and half of the trend for multimorbidity based on health surveys. CONCLUSIONS: The prevalence of chronic diseases and multimorbidity increased over the period 2001-2011. Aging of the population only explained part of the increase, implying that other factors such as health care and society related developments are responsible for a substantial part of this rise. PMID- 28854987 TI - [Non-ST segment elevation acute coronary syndrome; recent developments in diagnostics and treatment]. AB - - This paper covers recent developments in diagnostics and treatment of patients presenting with non-ST segment elevation acute coronary syndrome.- For the diagnostic phase we focus on the role of the clinical presentation, the ECG and biomarkers.- In the acute phase, treatment mainly consists of pharmacological therapy and revascularisation; long-term treatment mainly involves pharmacological therapy, cardiac rehabilitation, and lifestyle changes. PMID- 28854988 TI - [Changes in the treatment of Crohn's disease: fewer hospitalizations, less surgery, and reduced glucocorticoid use]. AB - OBJECTIVE: To study changes in treatment and disease course in patients with Crohn's disease (CD) in the South Limburg region of the Netherlands between 1991 and 2014. DESIGN: Population-based cohort study. METHODS: All 1162 CD patients in the 'IBD South Limburg cohort' were divided across three subcohorts on the basis of year of diagnosis: 1991-1998 (N = 316), 1999-2005 (N = 387) and 2006-2011 (N = 459). We compared the risk of hospitalization, bowel resection and the development of strictures and/or fistulas across the subcohorts. We also compared cumulative corticosteroid use and the relationship between the outcome measures and maintenance medication. RESULTS: In the period 1991-2014 there was an increase in the number of patients treated within 5 years with immunomodulators from 30.6% to 70.8%. For treatment with biologicals there was an increase from 3.1% to 41.2%. In parallel, the risk of hospitalization decreased from 65.9% to 44.2% and the risk of bowel resection decreased from 42.9% to 17.4%. The risk of developing strictures or fistulas remained stable (21.2%). There was no significant association between the outcome measures and the use of immunomodulators or biologicals. Furthermore, corticosteroid use decreased over time; this was linked to use of immunomodulators and biologicals. CONCLUSION: Treatment of Crohn's disease has changed over the past two decades, and the disease course has improved. We found no association between changes in maintenance medication and disease course. PMID- 28854989 TI - Three-Dimensional Nanoscale Mapping of State-of-the-Art Field-Effect Transistors (FinFETs). AB - The semiconductor industry has seen tremendous progress over the last few decades with continuous reduction in transistor size to improve device performance. Miniaturization of devices has led to changes in the dopants and dielectric layers incorporated. As the gradual shift from two-dimensional metal-oxide semiconductor field-effect transistor to three-dimensional (3D) field-effect transistors (finFETs) occurred, it has become imperative to understand compositional variability with nanoscale spatial resolution. Compositional changes can affect device performance primarily through fluctuations in threshold voltage and channel current density. Traditional techniques such as scanning electron microscope and focused ion beam no longer provide the required resolution to probe the physical structure and chemical composition of individual fins. Hence advanced multimodal characterization approaches are required to better understand electronic devices. Herein, we report the study of 14 nm commercial finFETs using atom probe tomography (APT) and scanning transmission electron microscopy-energy-dispersive X-ray spectroscopy (STEM-EDS). Complimentary compositional maps were obtained using both techniques with analysis of the gate dielectrics and silicon fin. APT additionally provided 3D information and allowed analysis of the distribution of low atomic number dopant elements (e.g., boron), which are elusive when using STEM-EDS. PMID- 28854990 TI - The Uniform Cortex Sign: A Diagnostic Sign of Diffuse Cortical Injury on MR Imaging of the Brain at 1.5 T. AB - BACKGROUND: To introduce the "uniform cortex sign" (UCS) and evaluate its performance as a diagnostic test for the presence of diffuse cortical injury (DCI). METHODS: The study was approved by our institutional review board. Three experienced neuroradiologists were given a tutorial on the UCS. They were subsequently presented with 14 cases (7 control patients and 7 DCI patients with the UCS) in random order and asked to determine whether the UCS was present. Each case consisted of selected DWI, T2-weighted, and FLAIR images from unenhanced 1.5T MRI examinations. A consensus result for each case was determined by unanimity or majority rule. RESULTS: All control patients were correctly identified as normal by all neuroradiologists (7/7). The UCS was correctly identified in 86% of DCI patients (6/7). UCS interrater agreement was high (multirater kappa=0.81). CONCLUSIONS: This small study shows that the UCS can identify DCI, especially in patients with hypoxic-ischemic encephalopathy. The UCS can be subtle, hence the reader must be vigilant for this finding. The accuracy of the UCS may depend on the extent of cortical injury and time between injury and MRI. Also, a UCS may be reversible, as in our case of viral meningoencephalitis. PMID- 28854991 TI - Validation and incidence of community-acquired pneumonia in patients with type 2 diabetes in the BIFAP database. AB - Oral anti-diabetic drugs (OADs) have been associated with community-acquired pneumonia (CAP). We aimed to validate the recording of CAP in the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP) for the future evaluation of OAD-CAP association. The incidence rate (IR/1000 person years) of CAP in type 2 diabetes mellitus (T2DM) was also determined. In total, 2966 pneumonia records (2040 listed as diagnosis and 926 as identified from comments added by physicians) were identified from 76 009 patients with T2DM after the first OAD in 2002-2013. Data around the CAP date were reviewed: 1803 (60.9%) were classified as 'probable CAP' (confirmed by X-ray/laboratory, referral letters or CAP lung site); 589 (19.8%) as 'no-case' (486 had other illness, 78 previous CAP, 25 cancer); and 574 (19.4%) as 'possible CAP' (441 without confirmatory information, 133 with uncertain diagnosis or uncertain diagnosis date). In total, 74.2% and 31.4% of pneumonia records in the diagnosis and comments, respectively, were 'probable cases' (IR: 6.04), which increased to 90.5% and 42.9%, respectively, when the 441 'possible cases' without confirmatory information were included (IR: 7.52). In summary, diagnosis had a high positive predictive value, and adding cases automatically detected from comments decreased that value significantly. PMID- 28854992 TI - The challenges of control groups, placebos and blinding in clinical trials of dietary interventions. PMID- 28854993 TI - Smartphone tool to collect repeated 24 h dietary recall data in Nepal. AB - OBJECTIVE: To outline the development of a smartphone-based tool to collect thrice-repeated 24 h dietary recall data in rural Nepal, and to describe energy intakes, common errors and researchers' experiences using the tool. DESIGN: We designed a novel tool to collect multi-pass 24 h dietary recalls in rural Nepal by combining the use of a CommCare questionnaire on smartphones, a paper form, a QR (quick response)-coded list of foods and a photographic atlas of portion sizes. Twenty interviewers collected dietary data on three non-consecutive days per respondent, with three respondents per household. Intakes were converted into nutrients using databases on nutritional composition of foods, recipes and portion sizes. SETTING: Dhanusha and Mahottari districts, Nepal. SUBJECTS: Pregnant women, their mothers-in-law and male household heads. Energy intakes assessed in 150 households; data corrections and our experiences reported from 805 households and 6765 individual recalls. RESULTS: Dietary intake estimates gave plausible values, with male household heads appearing to have higher energy intakes (median (25th-75th centile): 12 079 (9293-14 108) kJ/d) than female members (8979 (7234-11 042) kJ/d for pregnant women). Manual editing of data was required when interviewers mistook portions for food codes and for coding items not on the food list. Smartphones enabled quick monitoring of data and interviewer performance, but we initially faced technical challenges with CommCare forms crashing. CONCLUSIONS: With sufficient time dedicated to development and pre-testing, this novel smartphone-based tool provides a useful method to collect data. Future work is needed to further validate this tool and adapt it for other contexts. PMID- 28854994 TI - Brainstem Radionecrosis in a Patient with Nasopharyngeal Carcinoma. PMID- 28854996 TI - Comparison of Rates of Drain-Related Ventriculitis According to Definitions Used. PMID- 28854997 TI - Midwives' Professional Competencies for Preventing Maternal Mortality in Disasters: A Cross-Sectional Study in Iran. AB - OBJECTIVE: Maternal mortality may increase after a disaster. Because midwives are at the frontline of offering reproductive health care services in disasters, they should be competent. METHODS: This was a cross-sectional, descriptive study carried out in 2015 in Tehran. The sample consisted of 361 midwives selected by use of a cluster random sampling method. Data were collected by using a questionnaire on professional competency for preventing maternal mortality in disasters. RESULTS: The midwives' mean professional competency score was 177.74+/ 31, which was an average level of professional competency. The level of knowledge and skills of the midwives was reported as inadequate for most items, particularly for the items of "managing mothers affected by chronic diseases," "physical trauma," "recognizing patients who needed to be referred," and "stabilizing mothers when referring them." Statistically significant relationships were observed between the midwives' competencies and age (P=0.001), work experience (P=0.054), educational level (P= 0.043), previous experience in a disaster (P=0.014), and workplace (P=0.006). These data were drawn by using Spearman's correlation, t-test, and ANOVA, respectively. CONCLUSIONS: Given the average scores for midwives' professional competency in disasters and the inadequacy of prior training courses, extra educational programs for midwives are recommended. (Disaster Med Public Health Preparedness. 2018; 12: 305-311). PMID- 28854995 TI - Greater access to healthy food outlets in the home and school environment is associated with better dietary quality in young children. AB - OBJECTIVE: To explore associations between dietary quality and access to different types of food outlets around both home and school in primary school aged children. DESIGN: Cross-sectional observational study. SETTING: Hampshire, UK. SUBJECTS: Children (n 1173) in the Southampton Women's Survey underwent dietary assessment at age 6 years by FFQ and a standardised diet quality score was calculated. An activity space around each child's home and school was created using ArcGIS. Cross-sectional observational food outlet data were overlaid to derive four food environment measures: counts of supermarkets, healthy specialty stores (e.g. greengrocers), fast-food outlets and total number of outlets, and a relative measure representing healthy outlets (supermarkets and specialty stores) as a proportion of total retail and fast-food outlets. RESULTS: In univariate multilevel linear regression analyses, better diet score was associated with exposure to greater number of healthy specialty stores (beta=0.025 sd/store: 95 % CI 0.007, 0.044) and greater exposure to healthy outlets relative to all outlets in children's activity spaces (beta=0.068 sd/10 % increase in healthy outlets as a proportion of total outlets, 95 % CI 0.018, 0.117). After adjustment for mothers' educational qualification and level of home neighbourhood deprivation, the relationship between diet and healthy specialty stores remained robust (P=0.002) while the relationship with the relative measure weakened (P=0.095). Greater exposure to supermarkets and fast-food outlets was associated with better diet only in the adjusted models (P=0.017 and P=0.014, respectively). CONCLUSIONS: The results strengthen the argument for local authorities to increase the number of healthy food outlets to which young children are exposed. PMID- 28854998 TI - Evaluating capacity-building for mental health system strengthening in low- and middle-income countries for service users and caregivers, service planners and researchers. AB - Efforts to support the scale-up of integrated mental health care in low- and middle-income countries (LMICs) need to focus on building human resource capacity in health system strengthening, as well as in the direct provision of mental health care. In a companion editorial, we describe a range of capacity-building activities that are being implemented by a multi-country research consortium (Emerald: Emerging mental health systems in low- and middle-income countries) for (1) service users and caregivers, (2) service planners and policy-makers and (3) researchers in six LMICs (Ethiopia, India, Nepal, Nigeria, South Africa and Uganda). In this paper, we focus on the methodology being used to evaluate the impact of capacity-building in these three target groups. We first review the evidence base for approaches to evaluation of capacity-building, highlighting the gaps in this area. We then describe the adaptation of best practice for the Emerald capacity-building evaluation. The resulting mixed method evaluation framework was tailored to each target group and to each country context. We identified a need to expand the evidence base on indicators of successful capacity-building across the different target groups. To address this, we developed an evaluation plan to measure the adequacy and usefulness of quantitative capacity-building indicators when compared with qualitative evaluation. We argue that evaluation needs to be an integral part of capacity building activities and that expertise needs to be built in methods of evaluation. The Emerald evaluation provides a potential model for capacity building evaluation across key stakeholder groups and promises to extend understanding of useful indicators of success. PMID- 28854999 TI - Consultant Pharmacists: The Quarterback for Vaccination Management. PMID- 28855000 TI - Vaccines for Older Adults. AB - Several vaccine-preventable diseases-influenza, pneumonia, herpes zoster, and pertussis-threaten the health of older adults in the United States. Both the costs associated with treating these diseases and the potential to increase morbidity and mortality are high for this patient population. Pharmacists and other health care professionals play a significant role in ensuring the elderly patient receives the recommended vaccines at the recommended intervals. PMID- 28855001 TI - Helping the Long-Term/Post-Acute Care Facility Manage Influenza. AB - Improving the health of Americans by increasing influenza immunization among health care workers and institutionalized older adults--to 90% by 2020-is a a national goal. Pharmacists practicing in the long-term/post-acute care sector are in a unique position to positively affect the achievement of this goal. These facilities often look to the pharmacist for clinical expertise as well as assistance with strategic planning for the influenza season, staff education, and reimbursement. PMID- 28855002 TI - Health-related quality of life in relation to disease activity in adults with hereditary angioedema in Sweden. AB - BACKGROUND: Health-related quality of life (HR-QoL) is impaired in patients with hereditary angioedema (HAE) but has not yet been satisfactorily described. OBJECTIVE: To study HR-QoL in patients with HAE by combining different HR-QoL instruments with disease activity assessment. METHODS: All adults in the Swedish HAE registry were invited to take part in this questionnaire study, which used the generic HR-QoL instruments, EuroQol 5 Dimensions 5 Level (EQ-5D-5L) and the RAND Corporation Short Form 36 (RAND-36), the disease-specific Angioedema Quality of Life instrument (AE-QoL), the recently introduced Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication. RESULTS: Sixty-four of 133 adults (26 men, 38 women) between 18 and 91 years old responded. The most affected HR-QoL dimensions in the EQ-5D-5L were pain/discomfort and anxiety/depression; in the RAND-36, energy/fatigue, general health, pain; and, in the AE-QoL, fears/shame and fatigue/mood. Women had lower HR-QoL in the RAND-36 for general health and energy/fatigue (p < 0.05). Patients who reported any AAS of >0 had significantly impaired HR-QoL. There were significant associations (p < 0.05) between the AAS and EQ-5D-5L, between the AAS and all dimensions of the RAND-36 except physical function, and between the AAS and AE-QoL in all dimensions. Nine of 36 patients who reported sick leave during the previous 4 weeks had significantly impaired HR-QoL in all the instruments (p < 0.05). There was no significant difference in HR-QoL in the patients with and the patients without prophylactic medication, except for the nutrition dimension of the AE-QoL (p < 0.05). CONCLUSION: Comprehensive information is obtained by combining different HR-QoL instruments. Pain, anxiety/depression, and fatigue/mood are important aspects of HAE but the AE-QoL disregards pain. HR-QoL was not significantly affected by prophylaxis. Increased disease activity was associated with impaired HR-QoL, which justifies more active disease management. PMID- 28855003 TI - A review of candidate therapies for Middle East respiratory syndrome from a molecular perspective. AB - There have been 2040 laboratory-confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) in 27 countries, with a mortality rate of 34.9 %. There is no specific therapy. The current therapies have mainly been adapted from severe acute respiratory syndrome (SARS-CoV) treatments, including broad-spectrum antibiotics, corticosteroids, interferons, ribavirin, lopinavir-ritonavir or mycophenolate mofetil, and have not been subject to well-organized clinical trials. The development of specific therapies and vaccines is therefore urgently required. We examine existing and potential therapies and vaccines from a molecular perspective. These include viral S protein targeting; inhibitors of host proteases, including TMPRSS2, cathepsin L and furin protease, and of viral M(pro) and the PL(pro) proteases; convalescent plasma; and vaccine candidates. The Medline database was searched using combinations and variations of terms, including 'Middle East respiratory syndrome coronavirus', 'MERS-CoV', 'SARS', 'therapy', 'molecular', 'vaccine', 'prophylactic', 'S protein', 'DPP4', 'heptad repeat', 'protease', 'inhibitor', 'anti-viral', 'broad-spectrum', 'interferon', 'convalescent plasma', 'lopinavir ritonavir', 'antibodies', 'antiviral peptides' and 'live attenuated viruses'. There are many options for the development of MERS CoV-specific therapies. Currently, MERS-CoV is not considered to have pandemic potential. However, the high mortality rate and potential for mutations that could increase transmissibility give urgency to the search for direct, effective therapies. Well-designed and controlled clinical trials are needed, both for existing therapies and for prospective direct therapies. PMID- 28855005 TI - Let's Do This Together. PMID- 28855004 TI - The function of probiotics on the treatment of ventilator-associated pneumonia (VAP): facts and gaps. AB - Probiotics have been used for centuries in making fermented dairy products. The health benefits related to probiotics consumption are well recognized and they are generally regarded as safe (GRAS). Their therapeutic effects are due to the production of a variety of antimicrobial compounds, such as short-chain fatty acids, organic acids (such as lactic, acetic, formic, propionic and butyric acids), ethanol, hydrogen peroxide and bacteriocins. Ventilator-associated pneumonia (VAP) is a nosocomial infection associated with high mortality in intensive care units. VAP can result from endotracheal intubation and mechanical ventilation. These interventions increase the risk of infection as patients lose the natural barrier between the oropharynx and the trachea, which in turn facilitates the entry of pathogens through the aspiration of oropharyngeal secretions containing bacteria into the lung. In order to prevent this, probiotics have been used extensively against VAP. This review is an update containing information extracted from recent studies on the use of probiotics to treat VAP. In addition, probiotic safety, the therapeutic properties of probiotics, the probiotic strains used and the action of the probiotics mechanism are reviewed. Furthermore, the therapeutic effects of probiotic treatment procedures for VAP are compared to those of antibiotics. Finally, the influences of bacteriocin on the growth of human pathogens, and the side-effects and limitations of using probiotics for the treatment of VAP are addressed. PMID- 28855006 TI - Elias B. Chahine: Diving into Academic Pharmacy. PMID- 28855007 TI - Policies, Politics, Partnerships Take Center Stage as Pharmacists Face the Future. PMID- 28855008 TI - Pharmacy and EHR Information Exchange: A National Summit. AB - Pharmacists and other practitioners increasingly must focus on data collection, analysis, and communication to maximize quality and reduce adverse events that lead to readmissions. As a result, they are seeking systems and software that provide them with real-time access to the information they need and enable them to communicate with other stakeholders. To date, there have been barriers, including lack of system/software interoperability and electronic health records that make it difficult for practitioners to access and/or input data. The American Society of Consultant Pharmacists, and the National Association for the Support of Long Term Care convened pharmacists, software vendors, and other stakeholders to survey the health information technology/electronic health records (HIT/EHR) landscape to identify challenges, and discuss possible solutions. PMID- 28855009 TI - AChE Inhibitors and NMDA Receptor Antagonists in Advanced Alzheimer's Disease. AB - OBJECTIVE: The objective of this article is to review the available evidence for duration of treatment with, and considerations for discontinuation of, acetylcholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists in Alzheimer's disease. DATA SOURCES: Literature searches of clinical trials and meta-analyses were conducted using PubMed with the search terms Alzheimer's, dementia, donepezil, galantamine, memantine, and rivastigmine. References from included trials were also used to find additional citations. STUDY SELECTION/DATA EXTRACTION: 2,925 articles were initially identified. Twenty one studies were included that looked at the use of acetylcholinesterase inhibitors and/or memantine in the treatment of moderate-to-severe Alzheimer's dementia. DATA SYNTHESIS: Several clinical trials have demonstrated small improvements in measures of cognition and activities of daily living with medications used to treat dementia. However, not all patients will benefit from treatment, and the impact of treatment on long-term outcomes, including institutionalization, remains unclear. This paper reviews the available data to support the use of acetylcholinesterase inhibitors and/or memantine in patients with advanced Alzheimer's disease, including those in nursing facilities, and reviews recommendations for consideration of therapy discontinuation. CONCLUSION: The evidence to support a specific time frame for discontinuation of Alzheimer's disease treatment is limited. It is reasonable to stop a medication if there is no noticeable benefit after the first three months of treatment or once a patient's dementia progresses to a point where there would be no meaningful benefit from continued therapy. PMID- 28855010 TI - Students' Perspectives on Nebulized Drugs and Nebulizer Maintenance. AB - The geriatric population experiences a variety of respiratory concerns including chronic obstructive pulmonary disease, emphysema, asthma, pulmonary hypertension, and lower respiratory infections. Treating these illnesses often requires the use of inhaled therapies that can be delivered through multiple modalities, each of which carries its own pros and cons unique to its use in the geriatric population. Pharmacists have an opportunity to play a role in optimizing the selection of delivery devices and in providing patient and provider education on appropriate use of inhaled therapies. Through patient counseling and correct device selection, patient outcomes can be improved. This paper explores the differences among devices, provides specific information regarding drug mixing for nebulization, provides information regarding cleaning/maintenance of nebulizers, and addresses specific concerns related to geriatric care. It can serve as a reference for pharmacists and student pharmacists as they educate patients and providers. PMID- 28855011 TI - Potentially Inappropriate Medication Prescribing in U.S. Older Adults with Selected Chronic Conditions. AB - OBJECTIVE: Developing one or more chronic diseases increases with age. Appropriate treatment for chronic conditions often requires multiple medications. The purpose of this study was to examine potentially inappropriate prescriptions in patients 65 years of age or older, seen in a primary care office, with at least one of three chronic conditions (diabetes, arthritis, depression), who were prescribed at least two medications, one of which was inappropriate for the patient's condition. DESIGN: 2012 National Ambulatory Medical Care Survey data were examined using multivariate techniques. SETTING: U.S. primary care office visits. MAIN OUTCOME MEASURES: Drug appropriateness was ascertained from practice guidelines. Potentially inappropriate medications were ascertained from the 2012 Beers criteria. The 2012 Beers criteria were used since the data analyzed were from 2012. RESULTS: Logistic regression analysis yielded that older adults with diabetes had greater odds of having a potentially inappropriate prescription if they saw a provider in a rural setting, were non-white, had health insurance, and had two or more office visits in the last 12 months. CONCLUSION: There is a need to address prescribing of potentially inappropriate medications to older, non white patients who have diabetes. Living in rural areas is also an important factor in prescribing patterns for older adults with diabetes. Our findings suggest that interventions are warranted to address this health problem. One solution is the establishment of interprofessional and multidisciplinary teams of health care providers constituted of prescribers and nonprescribers to comprehensively evaluate prescribing practices. PMID- 28855013 TI - Can Washington Reform Health Care? PMID- 28855012 TI - Tamoxifen Pharmacovigilance: Implications for Safe Use in the Future. AB - OBJECTIVE: To survey the status of current tamoxifen pharmacovigilance documentation reflecting tamoxifen use in an academic outpatient multispecialty practice in older adults. This data will help provide information to develop improved pharmacovigilance for a growing cohort of older adult users. The data will be utilized by an interdisciplinary team developing new methods of identifying factors for individualized pharmacovigilance in older adults. DESIGN: Retrospective chart review to gather descriptive and quantitative data on tamoxifen pharmacovigilance. SETTING: Multi-specialty clinic. PATIENTS: Ninety three patients 60 years of age and older. MAIN OUTCOME MEASURES: Quantitative report of tamoxifen monitoring as well as descriptive analysis of individual cases. RESULTS: We found 19 cases of serious adverse events possibly related to tamoxifen (thrombi, uterine malignancies). There were 15 cases with no documentation of pharmacovigilance. All cases had incomplete pharmacovigilance documented. There were two cases of hypercalcemia. There was one case of tamoxifen discontinuation resulting from muscle pain and with chronic muscle pain complaints while receiving tamoxifen. We observed a correlation in older age or high comorbidity burden patients and adverse events patients. CONCLUSION: Some studies direct the important pharmacovigilance toward prevention of thrombi, uterine malignancies, and hypercalcemia; however, it is not easy to identify recommendations for frequency or focus of monitoring to prevent adverse events for individual older adults based on existing recommendations. The data collected and presented in this study serve to heighten awareness of tamoxifen pharmacovigilance and as a starting point for the application of machine learning techniques and modeling to identify high-risk patients and individualized pharmacovigilance recommendations. PMID- 28855014 TI - An Introduction for this Special Issue on Adsorption. PMID- 28855016 TI - Removal of an Acid Dye from Water Using Calcined and Uncalcined ZnAl-r Anionic Clay. AB - The present report describes the removal of indigo carmine dye from water via adsorption on ZnAl-r hydrotalcite. Two grades of clay based on Zn/Al molar ratios of 3 and 4, uncalcined and calcined, were used. The adsorbents characterization using X-ray diffraction (XRD), Fourier transform infrared (FTIR), differential thermal and thermogravimetric analysis (DTA and TGA, respectively) revealed a layered structure for the hydrotalcite clays, whereas their calcination favored the formation of ZnO and ZnAl2O4 mixed metal oxides. The calcined materials immobilized much larger amounts of indigo carmine dye than the uncalcined layered double hydroxides (LDHs) specimens. The maximum adsorption capacities obey the order: CZnAl-4 (520.8 mg/g) > CZnAl-3 (358.4 mg/g) > ZnAl-3 (67.25 mg/g) > ZnAl-4 (21.65 mg/g). The adsorption isotherms are best described by Langmuir model. The sorption process is spontaneous in nature and its kinetics data are best described by a pseudo-second-order model. Adsorption tests on re-used calcined clays demonstrate its reusability after three thermal cycles. PMID- 28855015 TI - Optimization of Fe2+ Removal from Coal Mine Wastewater using Activated Biochar of Colocasia esculenta. AB - The present study investigates the sorptive removal of Fe2+ from simulated coal mine waste water using steam activated biochar (SABC) developed from the roots of Colocasia esculenta. The process was optimized by response surface methodology (RSM) under the influence of pH, temperature, adsorbent dosage and contact time at a constant shaking speed of 180 rpm with an initial concentration of 3 mg/L. The uptake performance of the biosorbent was assessed following a 24 full factorial experimental matrix developed by central composite design approach. Adsorbent was characterised by SEM, EDAX, XRD and B.E.T surface area analyzer. Maximum removal of 72.96% of Fe2+ was observed at pH 7.75, temperature 37.5 degrees C, adsorbent dosage 1.5 g/L for a time period of 180 mins. The study suggested that SABC prepared from roots of Colocasia esculenta could be used as an efficient and cost effective sorbent for removal of Fe2+ from coal mine wastewater. PMID- 28855017 TI - Methylene Blue Adsorption on a Low Cost Adsorbent-Carbonized Peanut Shell. AB - Carbonized peanut shell (CPS), a low cost adsorbent was investigated for adsorption of methylene blue from its aqueous solution. Some experimental parameters like the effect of initial dye concentration, initial solution pH, phases contact time and temperature were investigated. Langmuir, Freundlich and Harkins-Jura isotherm models were applied to the experimental data and Langmuir model fitted best. Monolayer adsorption capacity was 5.34 mg/g according to the Langmuir model. Adsorption capacity/uptake of CPS was found comparable to the some other adsorbent materials. The kinetic and intra particle diffusion models were applied to the experimental data. The experimental reaction was progressed via pseudo second order kinetic model. The thermodynamic parameters were also evaluated. PMID- 28855018 TI - Uptake of Cd(II) Onto Raw Crab Shells: Isotherm, Kinetic, Adsorption Properties And Mechanisms. AB - This study focuses on the uptake of cadmium (Cd(II)) ion from water onto raw crab shells acting as a biosorbent. Experimental data were perfectly fitted to the Langmuir and Dubinin-Radushkevich models, while the uptake kinetics are well described using the pseudo-second-order model. The effects of experimental conditions on the uptake isotherms and kinetics are discussed in detail. A study of uptake thermodynamics has indicated that the Cd(II) uptake onto the crab shell is an endothermic and spontaneous process. For further understanding of this process, possible mechanisms of Cd(II) uptake onto crab shell have been deduced from experimental results. Desorption experiment shows that 93.7% of adsorbed Cd(II) could be recovered with a 0.1 M HNO3 solution. The inhibitory effects of other metal co-ions on the Cd(II) uptake on the crab shell are also discussed. PMID- 28855019 TI - Performance Study of a Low-cost Adsorbent-Raw Date Pits-for Removal of Azo Dye in Aqueous Solution. AB - The feasibility of using natural waste (raw date pits) as a low-cost adsorbent for the adsorption of an anionic dye (Congo red) from aqueous solution has been investigated. Adsorption optimized conditions were obtained at low dose 1 g/L, initial dye concentration 100 mg/L, pH 2, equilibrium contact time 120 min, and temperature 20 degrees C. The corresponding adsorption capacity was around 70 mg/g and could reach 150 mg/g by increasing the ionic strength of the dye solution (0.05 M CaCl2). These results are well modeled by Freundlich isotherm and kinetics study followed by pseudo second-order model. Thermodynamic parameters indicate that the adsorption process is endothermic and not spontaneous. The tests of desorption-regeneration showed that the studied adsorbent has the disadvantage of the loss of efficiency at its reuse but this is offset by its abundance. Based on these results, it can be used as competitive material for the removal of dyes. PMID- 28855020 TI - Applicability of Zeolite Based Systems for Ammonia Removal and Recovery From Wastewater. AB - Ammonia discharged in industrial effluents bears deleterious effects and necessitates remediation. Integrated systems devoted to recovery of ammonia in a useful form and remediation of the same addresses the challenges of waste management and its utilization. A comparative performance evaluation study was undertaken to access the suitability of different zeolite based systems (commercial zeolites and zeolites synthesized from fly ash) for removal of ammonia followed by its subsequent release. Four main parameters which were studied to evaluate the applicability of such systems for large scale usage are cost-effectiveness, ammonia removal efficiency, performance on regeneration, and ammonia release percentage. The results indicated that synthetic zeolites outperformed zeolites synthesized from fly ash, although the later proved to be more efficient in terms of total cost incurred. Process technology development in this direction will be a trade-of between cost and ammonia removal and release efficiencies. PMID- 28855021 TI - Elimination of Escherichia coli and Salmonella in Clam by Using Zeolite in a Station of Depuration. AB - The application of natural zeolite for water and wastewater treatment has been carried out and is still a promising technique in environmental cleaning processes. Natural zeolite can be used to improve the purification process of clams (Ruditapes decussatus). Thus, our study aimed at improving the clam purification system in order to reduce Escherichia coli and eliminate Salmonella in samples artificially contaminated with this bacterium using a natural zeolite to replace the biological filter. The results showed that zeolite used in a depuration system improved the clam purification process. Moreover, natural zeolite exhibited high performance in the adsorption of bacteria and allowed to reduce the Escherichia coli abundance in 24 h, thus ensuring purified clams conformity with the ISO 16649-3 standard. These results indicate the beneficial effects of using zeolite in the adsorption of bacteria and the reduction in the abundance of Escherichia coli and set the Salmonella from marine organisms. PMID- 28855022 TI - Simulation of Rainfall-Runoff Response in Ecological Swale with On-Line Subsurface Detention Using Infoworks SD. AB - The Bio-Ecological Drainage System (BIOECODS) is a sustainable drainage (SUDS) to demonstrate the 'control at source' approaches for urban stormwater management in Malaysia. It is an environmentally friendly drainage system that was designed to increase infiltration, reduce peak flow at outlet, improve water quality, through different BMPs, such as grass swale, retention pond, etc. A special feature of BIOECODS is ecological swale with on-line subsurface detention. This study attempted to create a model of ecological swale with on-line subsurface conveyance system with InfoWorks SD. The new technique has been used Storm Water Management Model (SWMM) model to describe overland flow routing and Soil Conservation Service Method (SCS) used to model infiltration or subsurface flow. The modeling technique has been proven successful, as the predicted and observed closely match each other, with a mean error of 4.58 to 7.32%. The calibrated model then used to determine the ratio of the flow exchange between the surface and subsurface drainage system. Results from the model showed that the runoff ratio exchange between the surface and subsurface is 60 to 90%. PMID- 28855023 TI - Fate and Toxicity of Zinc Oxide Nanomaterial in Municipal Wastewaters. AB - The production of zinc nanomaterial has increased significantly over the past several years and, as a result, nanoparticles have navigated their way into wastewater streams. The transportation and toxicity of zinc nanomaterial within the wastewater treatment processes is not well known. In this study, the zinc nanomaterial and its fate were characterized in an activated sludge treatment process. The tests performed included batch studies to evaluate abiotic and biotic removal, toxicity studies to evaluate inhibition to coliform and nitrifying bacteria, and bioreactor studies to evaluate impact on operating parameters. Stock solutions of zinc nanomaterial varied in size from 50 to 500 nm, but when added to an activated sludge solution, the nanoparticles agglomerated to larger sizes such that more than 60% of the zinc nanomaterial settled out of solution. However, when ionic zinc was added to activated sludge, more than 60% of the ionic zinc remained in suspension. It is likely that the ionic strength of the wastewater influenced the aggregation of the nanomaterial. Differences in the extent of removal between ionic and nano zinc species indicate that the mechanisms governing their removal are different. Toxicity analysis showed that zinc nanomaterial did not inhibit growth of coliform and ammonia oxidizing bacteria. However, ionic zinc inhibited the growth of both the coliform and ammonia oxidizing bacteria. Bioreactors were set up using activated sludge that was collected from a local treatment plant operating only in carbon oxidation mode. The treatment plant was operated at an SRT of 1.2 days and an MLSS of 650 mg/L. Several key parameters (COD, MLSS, pH) in the bioreactors were monitored through a 7-day incubation period, but showed no significant changes due to the addition of nano or ionic zinc. It is possible that the toxicity of zinc nanomaterial was not observed in these experiments because the nanomaterial agglomerated and settled out of solution. PMID- 28855024 TI - Impact of High-Nitrogen Leachate on Microfauna of Aerobic Granular Sludge. AB - The microfauna communities present in aerobic granular sludge reactors (e.g., granule sludge batch reactor or GSBR) that are used to treat landfill leachate were studied to determine which taxons are useful as process performance indicators. Communities were analyzed during four periods: a stable reactor operation period at a temperature of 29 degrees C, a transitional period of biomass adaptation at a temperature of 25 degrees C, an additional period of stable reactor operation at 25 degrees C, and at 25 degrees C after a period of lowered dissolved oxygen concentration. The results indicate that Vorticella infusionum and telotrochs were the taxons most sensitive to environmental changes in the GSBR, showing potential as biological indicators of ammonium overload and process destabilisation. Other taxons had similar abundance, despite changing environmental conditions in the bioreactor. PMID- 28855025 TI - Changes in the gastrointestinal microbiota of children with acute lymphoblastic leukaemia and its association with antibiotics in the short term. AB - PURPOSE: To detect the alteration of gut bacteria in children with ALL and analyse the impact of short-term-use of antibiotics on the changes caused by ALL. METHODOLOGY: We collected faecal samples from both children with ALL and healthy children. According to their medication history with antibiotics, we classified the samples into ALL+ATBx, ALL, CON+ATBx and CON groups. Next-generation sequencing was performed to identify the gut bacteria according to the MiSeq platform. The Shannon index, Simpson index, Chao index and Ace index were used to represent the alpha diversity of gut bacteria. The beta diversity was estimated using the principles of co-ordinate analysis and non-metric multi-dimensional scaling. The taxon composition and presence of biomarkers were then determined through bioinformatics. RESULTS: With regard to alpha diversity, the Shannon index and Simpson index differed significantly between the ALL and CON groups, as well as the CON+ATBx and CON groups, but not the ALL+ATBx and CON+ATBx groups. With regard to beta diversity, the ALL and CON separated clearly into clusters, as did ALL+ATBx and CON+ATBx. There were differences in composition among the four groups at different taxonomy hierarchies. More bacteria showed an obvious difference between the paired groups ALL and CON than did for the paired groups ALL+ATBx and CON+ATBx. The area under the receiver operating characteristic curves for Bacteroidales and Enterococcaceae used to predict ALL were 0.735 and 0.724, respectively. CONCLUSION: ALL induced structural changes of the gut microbiota, with the alpha diversity being significantly weakened by antibiotics, but not beta diversity. Bacteroidales and Enterococcaceae can be referred to as biomarkers for ALL. PMID- 28855026 TI - Fibronectin expression is upregulated by PI-3K/Akt activation in tamoxifen resistant breast cancer cells. AB - Fibronectin (FN) plays important roles in the EMT in a variety of cancer cell types. However, the mechanism by which FN expression is regulated in tamoxifen resistant (TamR) breast cancer cells has not yet been fully elucidated. Aberrant FN expression was associated with poor prognosis in patients with luminal type A breast cancer. In addition, FN was upregulated in TamR cells. To investigate the mechanism by which FN expression is regulated, we assessed the levels of phosphorylated Akt, JNK, and STAT3 and found that they were all increased in TamR cells. Induction of FN expression was dampened by LY294002 or AKT IV in TamR cells. Furthermore, FN expression was increased by constitutively active (CA)-Akt overexpression in tamoxifen-sensitive MCF7 (TamS) cells and colony formation of TamR cells was blocked by AKT IV treatment. Taken together, these results demonstrate that FN expression is upregulated through the PI-3K/Akt pathway in tamoxifen-resistant breast cancer cells. [BMB Reports 2017; 50(12): 615-620]. PMID- 28855027 TI - Bach2 represses the AP-1-driven induction of interleukin-2 gene transcription in CD4+ T cells. AB - The transcription repressor Bach2 has been proposed as a regulator of T cell quiescence, but the underlying mechanism is not fully understood. Given the importance of interleukin-2 in T cell activation, we investigated whether Bach2 is a component of the network of factors that regulates interleukin-2 expression. In primary and transformed CD4+ T cells, Bach2 overexpression counteracted T cell receptor/CD28- or PMA/ionomycin-driven induction of interleukin-2 expression, and silencing of Bach2 had the opposite effect. Luciferase and chromatin immunoprecipitation assays revealed that Bach2 binds to multiple Maf-recognition element-like sites on the interleukin-2 proximal promoter in a manner competitive with AP-1, and thereby represses AP-1-driven induction of interleukin-2 transcription. Thus, this study demonstrates that Bach2 is a direct repressor of the interleukin-2 gene in CD4+ T cells during the immediate early phase of AP driven activation, thereby playing an important role in the maintenance of immune quiescence in the steady state. [BMB Reports 2017; 50(9): 472-477]. PMID- 28855028 TI - FGF signaling: diverse roles during cochlear development. AB - Mammalian inner ear comprises of six sensory organs; cochlea, utricle, saccule, and three semicircular canals. The cochlea contains sensory epithelium known as the organ of Corti which senses sound through mechanosensory hair cells. Mammalian inner ear undergoes series of morphogenesis during development beginning thickening of ectoderm nearby hindbrain. These events require tight regulation of multiple signaling cascades including FGF, Wnt, Notch and Bmp signaling. In this review, we will discuss the role of newly emerging signaling, FGF signaling, for its roles required for cochlear development. [BMB Reports 2017; 50(10): 487-495]. PMID- 28855029 TI - [Changing Epidemic of Lung Cancer & Tobacco and Situation of Tobacco Control ?in China]. AB - Lung cancer is the leading cause of cancer death and morbidity in China. Smoking and exposure to secondhand smoking closely related to lung cancer. Recently, series policies of tobacco control and lung cancer prevention was carried out. However, burden of lung cancer is still serious, and smoking rate in male is still very high, and in never smokers exposure to secondhand smoking is still very extensive. In this paper, epidemic situation of lung cancer, smoking and second hand smoking are described, at the same time, current implementations of tobacco control policies are summarized. PMID- 28855030 TI - [Clinical Characteristics of Lung Cancer with Pancreatic Metastases]. AB - BACKGROUND: Lacking of typical symptoms, more than 70% of patients with lung cancer are diagnosed as advanced-stage disease. Patients suffer from solid organs metastasis with different clinical features and prognosis. With development of new technology, more and more lung cancer patients are diagnosed with pancreatic metastasis. The aim of this study was to investigate clinicopathologic and survival difference by retrospective analysis among lung cancer patients with pancreatic metastases. METHODS: Of the patients with lung cancer diagnosed by pathology and thorough staging evaluation and treated at Beijing Cancer Hospital with long follow-up during July 1996 and June 2017, 35 cases had pancreatic metastases. RESULTS: There were 28 cases diagnosed as small cell lung cancer, 3 cases diagnosed as adenocarcinoma and 4 cases diagnosed as squamous cell carcinoma. There were 15 cases with pancreatic metastases in head of pancreas and 20 cases in body and tail of pancreas, 23 cases presented with isolated metastasis and 12 cases with multiple metastases. Pathological type was prognostic factor for lung cancer patients with pancreatic metastases. CONCLUSIONS: Pancreatic metastases represents an uncommon site of extrathoracic spread of disease for part of patients with advanced lung cancer. Lung cancer with pancreatic metastases should be treated by combined therapy, especially by systemic chemotherapy. Pathological type was prognostic factor for lung cancer patients with pancreatic metastases.?. PMID- 28855031 TI - [Effect of Smoking on Lung Cancer Histology and Its Epidemiology in Chinese Male]. AB - BACKGROUND: Studies found that there were changes in histological subtypes of lung cancer patients in China. This study investigated the effect of smoking on lung cancer histology and its trend in Chinese male. METHODS: Demographic, smoking history and histological information about male lung cancer patients diagnosed or treated from 2000 to 2012 was collected from Cancer Hospital, Chinese Academy of Medical Science. Trends of histological subtypes calculated with annual percentage change (APC). RESULTS: A total of 14,106 patients with lung cancer were enrolled, with smoking 11,750 cases and non-smoking 2,356 cases. The main histological type of smoking lung cancer was squamous cell carcinoma (SCC)(39.38%), followed by adenocarcinoma (ADC)(29.85%). Among smokers, the proportion of SCC decreased from 44.19% to 35.50% (APC=-1.9%, P<0.001), however, the ADC increased from 15.25% to 41.85% (APC=6.8%, P<0.001). Adenosquamous carcinoma (ASC) was from 4.13% to 0.72% (APC=-14.9%, P<0.001). In non-smokers, the ADC was 53.86%, and SCC was 16.64%. ADC increased from 38.03% to 67.83% (APC=4.3%, P<0.001). Distributions of LCC and ASC were scattered. CONCLUSIONS: Proportion of ADC increased significantly in smoking and non-smoking lung cancer patients, and the relationship between non-smoking factor exposure and lung cancer should be further studied.?. PMID- 28855032 TI - [Prognostic and Predictive Value of Thyroid Transcription Factor-1, CD56, P40 and Other Clinical Characteristics in Small Cell Lung Cancer Patients]. AB - BACKGROUND: The aim of this study is to explore roles of thyroid transcription factor-1 (TTF-1), CD56, P40 expression and other clinical characteristics predicting response and survival in patients with small cell lung cancer (SCLC). METHODS: Formalin-fixed, paraffin-embedded biopsy tissues were retrospectively obtained from 198 SCLC patients who were diagnosed first in Xuanwu Hospital. The expressions of TTF-1, CD56 and P40 were detected by immunohistochemistry. The clinical data including age, gender, cancer stage, Eastern Cooperative Oncology Group (ECOG) score, smoking or not, superior vena cava syndrome (SVCS) due to lung cancer or not were collected. Cox proportional hazard model was used to analyze the relationship between the overall survival (OS) and factors. RESULTS: Immunohistochemical staining results showed the positive rate of TTF-1, CD56, P40 were 73.2%, 88.4% and 7.1% respectively. TTF-1 expression (OR=0.665, 95%CI: 0.472 0.937), smoking index <=400 (OR=1.72, 95%CI: 1.061-2.789) and ECOG=2 (OR=3.551, 95%CI: 2.133-5.914), extensive-stage (OR=2.487, 95%CI: 1.793-3.451) and SVCS due to lung cancer (OR=2.394, 95%CI: 1.49-3.846) were independent prognostic factors for SCLC patients. CONCLUSIONS: Prognosis of SCLC was related to TTF-1 expression independently after adjusting smoking, ECOG score, stage and SVCS due to lung cancer. Detection of TTF-1, CD56 and P40 expression level might be helpful for predict the prognosis of SCLC.?. PMID- 28855033 TI - [Risk Factors of Lung Cancer in Xuanwei, Yunnan Province, China]. AB - BACKGROUND: Since 1970s, Xuanwei in Yunnan province has been one of the towns with highest lung cancer mortality in China. Moreover, the characters of high female lung cancer mortality and sub-regional clustering high lung cancer mortality have not changed. In this study, we further described the exposure situation of risk factors of lung cancer in Xuanwei nowadays, in order to explore the trend of the distribution of lung cancer there. METHODS: Firstly we divided the 26 towns of Xuanwei city to high-, median- and low- lung cancer areas by the lung cancer mortality in 2010-2012. We chose 2 towns within each area according to topography and orientation, and randomly picked 4 villages in each town to be our study area. We did a questionnaire about lung cancer related risk factors upon the sample population in the study area. We calculated the exposure percentages of each risk factor, in whole sample population and subgroups, for nowadays and for 10 years ago (only living environmental risk factors), and compared them between areas or time points using standardized rates and the statistical test of standardized rate comparison, or chi-square test. RESULTS: 65%-80% male in the study area has a history of smoking; 60%-90% non-smoker has been exposed to second hand smoke. These situations are worse in high and median lung cancer areas. 50% male in median lung cancer area have coal mining work experience, which is 2 times of the percentages in the other two areas; while 15% 25% people in high lung cancer area have other occupational exposure history to particulate air pollution, which is 3-5 times of the percentages in the other two areas. From ten years ago until nowadays, 80% families in median lung cancer area use 2 tons or more smoky coal per year; more than 90% families burn coal for household heating; more than 60% families suffer from smog in the kitchen during cook; 60% families most frequently use stove in the ground with chimney. Only 20% families in high lung cancer area now use 2 tons or more smoky coal per year. Now 50%-75% families in the study area use 700 kilowatt-hours of electricity per year, much more than ten years ago. 80% residents in low lung cancer area eat fatty or pickled or smoked food at least 3 days per week; while in high and median lung cancer areas the percentages are 50%-60%. CONCLUSIONS: According to data obtained in this survey, current distribution of smoky coal use has differed from the distribution of high-, median- and low- lung cancer areas. Tobacco use and second hand smoke, the use of smoky coal and occupational exposure to particulate matters could be the main risk factors for lung cancer in Xuanwei now. The relations between lung cancer and stove type, dietary habit and so on deserve further study. PMID- 28855034 TI - [Clinical Characteristics of 118 Cases of Chronic Obstructive Pulmonary Disease Complicated with Primary Bronchopulmonary Carcinoma]. AB - BACKGROUND: The aim of this study is to investigate the clinical characteristics of patients with primary bronchopulmonary carcinoma complicated with chronic obstructive pulmonary disease (COPD), and to optimize the early diagnoses in the coexistence of COPD and primary bronchopulmonary carcinoma. METHODS: The clinical data of 118 patients with COPD complicated with primary bronchopulmonary carcinoma were analyzed retrospectively, including age, sex, smoking history, smoking index, clinical symptoms and signs, pathological type, staging, metastasis site and lung function index. 120 patients with simple COPD were selected as control. RESULTS: The smoking rate (55.1%) and smoking index >=400 branch /year (90.8%) of the patients with COPD complicated with primary bronchopulmonary carcinoma were higher than the simple COPD group (20.8%, 48.0%). The difference between the two groups was statistically significant (P<0.01). There were no significant differences in the incidence of common symptoms such as cough, sputum, fever, fatigue and dyspnea in COPD complicated with primary bronchopulmonary carcinoma patients with simple COPD group (P>0.05), while the incidence of hemoptysis, weight loss, chest pain, hoarseness, pleural effusion and atelectasis were significantly higher than those in simple COPD group (P<0.01). When the patients were first diagnosed as COPD with primary bronchopulmonary carcinoma, 63.6% of the group were advanced or located late, and the distant metastases are common for pleural metastasis and bone metastases. There was no significant difference in forced expiratory volume in one second/forced vital capacity (FEV1/FVC), FEV1% pre, total lung capacity (TLC) and residual volume (RV)/TLC between the two groups (P>0.05), but the diffusing capacity of carbon monoxide (DLCO) of COPD patients complicated with primary bronchopulmonary carcinoma was lower than that of simple COPD patients (P<0.05) . In the COPD patients with primary bronchopulmonary carcinoma, squamous cell carcinoma was the most common pathological type (51.7%). Male patients were mainly squamous cell carcinoma (60.7%), while female patients with adenocarcinoma (69.0%). CONCLUSIONS: COPD combined with primary bronchopulmonary carcinoma occurs in male smokers more. There is higher incidence of squamous cell carcinoma. When they are first diagnosed, most of them are advanced or located late, due to no specific clinical symptoms at the early stages. Periodic chest CT examination for COPD patients can help early diagnoses of primary bronchopulmonary carcinoma.?. PMID- 28855035 TI - [Retrospective Study of Efficacy in BIM Gene Polymorphism on First-line EGFR-TKIs Treatment for Advanced Lung Adenocarcinoma]. AB - BACKGROUND: The aim of this study is to detect the BIM polymorphism in 85 formalin-fixed and parrffin-embedded (FFPE) and some blood samples of advanced lung adenocarcinoma patients and study the relativity betweenthe BIM polymorphism and tyrosine kinase inhibitor (TKI). The correlation between BIM detection of different types of specimens was discussed. METHODS: There were 85 patients who were diagnosed as advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) 19 or 21 exon mutation in thoracic surgery of Xuanwu Hospital from February 2013 to November 2014, all of who were received EGFR-TKI as first line treatment in the study. FFPE and some blood were used to detect the BIM polymorphism. The objective response rate (ORR) and progression-free survival (PFS) of two groups were compared. According to smoking, sex, EGFR mutation and other factors, the single factor analysis was performed, and the correlation between paraffin samples and blood test BIM was compared. RESULTS: The ORR in BIM polymorphism and non-polymorphism groups was no significant differences (P>0.05). The median PFS in BIM polymorphism and non-polymorphism group was 7.1 months and 12.8 months, respectively (P=0.013). Univariate analysis the median PFS, women were longer than men (12.1 months vs 10.7 months, P=0.835); Non-smokers were longer than smokers (12.1 months vs 9.7 months, P=0.974). Group in EGFR exon 21 is longer than group in EGFR exon 19 (12.2 months vs 8.7 months, P=0.303). CONCLUSIONS: Detection of BIM gene polymorphism in lung cancer patients with EGFR TKIs treatment might be helpful for predicting prognosis. But a large sample study is needed. PMID- 28855036 TI - [Enhanced Lung Recovery after Surgery, Is It A Necessary for Precision Therapy?] AB - The concept of enhanced recovery after surgery (ERAS) has already been accepted by almost all the clinicians and nurses, the practice of which is based on interdisciplinary cooperation. The reason is still unclear why the effect of ERAS varies a lot though the same ERAS scheme is used. The main cause may be the same ERAS scheme can not be suitable for different patients. In other words, does ERAS also need to conform to Precision Medicine Theory? This study is focused on the necessity and clinical efficacy of "Precision ERAS" performed in lung cancer patients. The conclusions are the following: first of all, an accurate judgment of patients who need ERAS should be done properly before surgery, which means that the high risks assessment should be done accurately. Secondly, a specific ERAS scheme should be carried out in each independent patient who has obvious clinical symptoms in order to alleviate clinical symptoms and improve the ptients' quality of life (QOL). Thirdly, for the asymptomatic patitents who also don't have severe concomitant diseases, process-optimized ERAS should be selected to make patients feel more comfortable and shorten the average length of stay (ALOS). To summary, "subtraction" instead of "addition" should be considered when performing ERAS. PMID- 28855037 TI - [Mechanism of Chlorogenic Acid in Apoptotic Regulation through Notch1 ?Pathway in Non-small Cell Lung Carcinoma in Animal Level]. AB - BACKGROUND: It has been proven that chlorogenic acids can produce anticancer effects by regulating cell cycle, inducing apoptosis, inhibiting cell growth, Notch signaling pathways are closely related to many human tumors. The aim of this study is to study the mechanism of chlorogenic acid on apoptosis of non small lung cancer through Notch1 pathway in animal level, and hope to provide theory basis on clinical treatment and research aimed at targeting Notch1 signaling in non-small cell carcinoma (NSCLC). METHODS: MTT assay was used to evaluate the A549 cell proliferation under the treatment of chlorogenic acid. The effect of chlorogenic acid on apoptotic and cell cycle were detected by flow cytometry. The animal model of A549 cell transplanted in nude was established, tumer size and weight were detected. The mRNA level of Notch1 signal pathway related facter were detected by RT-PCR; the expression of Notch1 signal pathway related facter in tumor tissue was detected by western blot. RESULTS: Chlorogenic acid inhibited the A549 cell proliferation. incresed cell apoptotic and cell percentagein G2/M (P<0.05), and in a dose-dependent manner. In animal model, tumer size and weight were lower than control group, the difference was statistically significant (P<0.05). The relative expression of mRNA of Notch1, VEGF, Delta4, HES1 and HEY1 were decreaced (P<0.05) in tumor tissue which treated with chlorogenic. The expression of Notch1 were decreaced, PTEN, p-PTEN, p-AKT were increced significantly in tumor tissue which treated with chlorogenic (P<0.05). CONCLUSIONS: Chlorogenic acid can regulate theapoptosis of non-small lung cancer through Notch pathway in animal level, which may be associated with the down-regulating the expression of VEGF and Delta4. Notch pathway may cross talk with PI3K/AKT pathway through PTEN in NSCLC. PMID- 28855038 TI - [Effect of Scanning and Reconstruction Parameters on Three Dimensional Volume and CT Value Measurement of Pulmonary Nodules: A Phantom Study]. AB - BACKGROUND: The computed tomography (CT) follow-up of indeterminate pulmonary nodules aiming to evaluate the change of the volume and CT value is the common strategy in clinic. The CT dose needs to considered on serious CT scans in addition to the measurement accuracy. The purpose of this study is to quantify the precision of pulmonary nodule volumetric measurement and CT value measurement with various tube currents and reconstruction algorithms in a phantom study with dual-energy CT. METHODS: A chest phantom containing 9 artificial spherical solid nodules with known diameter (D=2.5 mm, 5 mm, 10 mm) and density (-100 HU, 60 HU and 100 HU) was scanned using a 64-row detector CT canner at 120 Kilovolt & various currents (10 mA, 20 mA, 50 mA, 80 mA,100 mA, 150 mA and 350 mA). Raw data were reconstructed with filtered back projection and three levels of adaptive statistical iterative reconstruction algorithm (FBP, ASIR; 30%, 50% and 80%). Automatic volumetric measurements were performed using commercially available software. The relative volume error (RVE) and the absolute attenuation error (AAE) between the software measures and the reference-standard were calculated. Analyses of the variance were performed to evaluate the effect of reconstruction methods, different scan parameters, nodule size and attenuation on the RPE. RESULTS: The software substantially overestimated the very small (D=2.5 mm) nodule's volume [mean RVE: (100.8%+/-28%)] and underestimated it attenuation [mean AAE: (-756+/-80) HU]. The mean RVEs of nodule with diameter as 5 mm and 10 mm were small [(-0.9%+/-1.1%) vs (0.9%+/-1.4%)], however, the mean AAEs [(-243+/ 26) HU vs (-129+/-7) HU)] were large. The ANOVA analysis for repeated measurements showed that different tube current and reconstruction algorithm had no significant effect on the volumetric measurements for nodules with diameter of 5 mm and 10 mm (F=5.60, P=0.10 vs F=11.13, P=0.08), but significant effects on the measurement of CT value (F=34.79, P<0.001 vs F=156.14, P<0.001). CONCLUSIONS: An infinitesimally small errors of volumetric measurement of 5 mm or 10 mm nodule could achieved with very low current and ASIR reconstruction, suggesting a possibility of remarkable radiation dose reductions, while it is not applicable for 5 mm nodule. The attenuation acquired through three dimensional software has large measurement error and can not applied in clinical currently.?. PMID- 28855039 TI - [Multicenter Evaluation of A New Progastrin-releasing Peptide (ProGRP) Immunoassay across Europe and China]. PMID- 28855040 TI - [Detection and Clinical Significance of Abundance of EGFR Mutation]. AB - Non-small cell lung cancer (NSCLC) patients, with sensitive epidermal growth factor receptor (EGFR) mutations react well to tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs on patients with the same mutant types differs dramatically. It is implied that the different quantities of mutant alleles could be one of the reasons underlying. Patients with high abundance of EGFR mutation might benefit more from TKIs. There are no universal standards for the definition of EGFR mutant abundance. Abundance could be semi-quantified according to the different sensitivities of detection methods, quantified with quantifying detection techniques such as digital PCR or next generation sequencing, or quantified based on the expression of mutant proteins. The different abundances of primary and metastatic diseases could reflect the heterogeneity of the tumors. The pre-treatment level or the dynamic change of EGFR mutant abundance could help observe the course of the diseases and predict the efficacy of TKIs. TKIs resistance could be detected by change of abundance prior to image manifestations. Besides, the abundance of T790M could also predict drug efficacy and resistance of the first and third generation TKIs. Thus the detection of EGFR mutant abundance has important clinical significance. The standardization and correction of abundance needs more exploration. PMID- 28855041 TI - [Growth Evaluation of Pulmonary Nodules on Chest CT]. AB - Computed tomography (CT) follow-up of indeterminate pulmonary nodules and the quantification of growth characteristics are the commonly adopted strategy in clinical setting. The volume/mass doubling time can be used to quantify the growth velocity based on exponential growth model. Therefore, we reviewed the followed aspects on growth evaluation of pulmonary nodules on chest CT, including the growth model of lung cancer, the methods used for nodule growth quantification and the growth characteristics of different types of pulmonary nodules. PMID- 28855042 TI - Insulinotropic nucleobindin-2/nesfatin-1 is dynamically expressed in the haemochorial mouse and human placenta. AB - The placenta is the physiological bridge between mother and fetus and has life sustaining functions during pregnancy, including metabolic regulation, fetal protection and hormone secretion. Nucleobindin-2 (NUCB2) is a calcium- and DNA binding protein and precursor of nesfatin-1, a signalling peptide with multiple functions, including regulation of energy homeostasis and glucose transport. These are also key functions of the placenta, yet NUCB2/nesfatin-1 expression has never been comprehensively studied in this organ. In the present study, mouse placental samples from Embryonic Day (E) 7.5 to E17.5 and human chorionic villi from the first and second trimester, as well as term pregnancy, were analysed for NUCB2/nesfatin-1 expression by immunohistochemistry with an antiserum that recognised both NUCB2 and nesfatin-1. From E7.5 to E9.5, NUCB2/nesfatin-1 was expressed in the ectoplacental cone, then parietal trophoblast giant cells and early spongiotrophoblast. At E10.5-12.5, NUCB2/nesfatin-1 expression became detectable in the developing labyrinth. From E12.5 and onwards, NUCB2/nesfatin-1 was expressed in the glycogen trophoblast cells, as well as highly expressed in syncytiotrophoblast, sinusoidal trophoblast giant cells and fetal capillary endothelial cells of the labyrinth. In all trimesters of human pregnancy, NUCB2/nesfatin-1 was highly expressed in syncytiotrophoblast. In addition, there was a significant increase in NUCB2 expression in human primary trophoblast cells induced to syncytialise. Thus, the haemochorial mammalian placenta is a novel source of NUCB2/nesfatin-1 and likely a site of its action, with potential roles in glucose homeostasis and/or nutrient sensing. PMID- 28855043 TI - Association of the cysteine-rich secretory protein-3 (CRISP-3) and some of its polymorphisms with the quality of cryopreserved stallion semen. AB - Contribution of seminal plasma proteins to semen freezability has been reported in several species, suggesting these proteins as genetic markers. The aim of this study was to evaluate the relationship between cysteine-rich secretory protein-3 (CRISP-3) and some of its single-nucleotide polymorphisms (SNPs) with post thawing semen quality in stallions. DNA was obtained from 100 stallions, regions of interest were amplified by polymerase chain reaction and sequenced. Evaluated SNPs within the equine CRISP-3 gene were CRISP3c.+199A>G (SNP1), CRISP3c.+566C>A (SNP2), CRISP3c.+622G>A (SNP3) and CRISP3c.+716A>G (SNP4). CRISP-3 protein content in seminal plasma was determined by enzyme-linked immunosorbent assay. Semen from 30 stallions was cryopreserved and post-thaw motility, kinetics, abnormal morphology (AM), sperm vitality (SV) and membrane integrity (MI) were evaluated. Generalized linear models were fitted and means were compared using Tukey's test. Correlation and regression analyses were performed. For SNP1 and SNP3, the AA genotype had the highest results for motility and MI; for SNP2, the best results for motility and AM were obtained with the CC genotype. For SNP4, the GG genotype had the lowest results, except for MI. A high level of CRISP-3 protein in seminal plasma had the best results for motility, kinetics, SV and AM. In conclusion, there was a relationship between CRISP-3 genotype and seminal plasma protein and post-thawing semen quality in stallions. PMID- 28855044 TI - Sexual Behavior in Germany. AB - BACKGROUND: There have not been any population-based surveys in Germany to date on the frequency of various types of sexual behavior. The topic is of interdisciplinary interest, particularly with respect to the prevention and treatment of sexually transmitted infections. METHODS: Within the context of a survey that dealt with multiple topics, information was obtained from 2524 persons about their sexual orientation, sexual practices, sexual contacts outside relationships, and contraception. RESULTS: Most of the participating women (82%) and men (86%) described themselves as heterosexual. Most respondents (88%) said they had engaged in vaginal intercourse at least once, and approximately half said they had engaged in oral intercourse at least once (either actively or passively). 4% of the men and 17% of the women said they had been the receptive partner in anal intercourse at least once. 5% of the respondents said they had had unprotected sexual intercourse outside their primary partnership on a single occasion, and 8% said they had done so more than once; only 2% of these persons said they always used a condom during sexual intercourse with their primary partner. Among persons reporting unprotected intercourse outside their primary partnership, 25% said they had undergone a medical examination afterward because of concern about a possible sexually transmitted infection. CONCLUSION: Among some groups of persons, routine sexual-medicine examinations may help contain the spread of sexually transmitted infections. One component of such examinations should be sensitive questioning about the types of sexual behavior that are associated with a high risk of infection. Information should be provided about the potential modes of transmission, including unprotected vaginal, oral, and anal intercourse outside the primary partnership. PMID- 28855046 TI - Increase in Glaucoma Patients. PMID- 28855045 TI - Acute Flaccid Myelitis in German Children in 2016-the Return of Polio? AB - BACKGROUND: Although poliomyelitis has almost been eradicated worldwide, cases of a polio-like disease with asymmetrical flaccid paralysis of variable severity have been seen repeatedly in recent years. METHODS: Data were collected on children treated in hospitals in the German federal states of Bavaria and Lower Saxony in 2016. The frequency of disease across Germany was estimated on the basis of voluntary reporting to the Robert Koch Institute. 16 cases were registered there for the entire year 2016. RESULTS: 7 children with flaccid paralysis of acute onset were treated in the participating hospitals in the summer and fall of 2016. We describe two illustrative cases, one with a mild course and one with a severe course. Rapid diagnosis requires not only clinical neurological assessment but also neurophysiological studies, magnetic resonance imaging (MRI), and targeted microbiological testing. The characteristic features include damage to the anterior horn of the spinal cord that can be seen on MRI and/or electrophysiologically demonstrable abnormalities indicating motor neuron damage. A pathogen can hardly ever be identified in the cerebrospinal fluid, but the epidemiological context and the detection of viruses in the stool or respiratory secretions indicate that entero - viruses may be responsible. CONCLUSION: The prognosis of this disease cannot be reliably assessed at first, and no specific treatment is currently available. PMID- 28855047 TI - A Stabbing Injury to the Chest from a Letter Opener. PMID- 28855048 TI - Rheumatic Heart Disease Still Relevant. PMID- 28855049 TI - Cardioprotective Effect of NSAIDs. PMID- 28855050 TI - Cardiovascular Comorbidities. PMID- 28855051 TI - In Reply. PMID- 28855052 TI - Structured Approach in Prehospital Care. PMID- 28855053 TI - Hospital Preparedness. PMID- 28855054 TI - Measures for Bleeding Control. PMID- 28855055 TI - Supplement to Forensic Analysis. PMID- 28855056 TI - In Reply. PMID- 28855057 TI - Cystic Fibrosis. AB - BACKGROUND: Universal screening of newborn babies for cystic fibrosis was launched in Germany on 1 September 2016. Here we present up-to-date information on the diagnosis, treatment, and prognosis of this disease. METHODS: This article is based on relevant publications retrieved by a selective search in PubMed, along with guidelines from Germany and abroad and systematic reviews. RESULTS: Cystic fibrosis is caused by a gene mutation leading to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It affects multiple organ systems-the lungs, pancreas, upper airways, liver, intestine, and reproductive organs-to varying degrees. Its incidence among newborn babies in Germany is between 1 in 3300 and 1 in 4800. Its diagnosis requires both clinical evidence (positive newborn screening, sibling[s] with cystic fibrosis, clinical signs) and the demonstration of CFTR dysfunction by an elevated chloride concentration in sweat, and/or two disease-causing mutations, and/or abnormal electrophysiological findings (nasal potential difference measurement, intestinal short-circuit current measurement). Patients should be cared for by specialized cystic fibrosis centers in close cooperation with their primary care physicians. The median life span of patients with this disease has risen steadily to the current value of 40 years. Aside from symptomatic treatment, the first mutation- specific treatments have recently become available. CONCLUSION: Early diagnosis and optimized treatment prolong the lives of persons with cystic fibrosis and improve their quality of life. Causally directed treatment for all patients and their effects on the course of disease are now central issues for further research. PMID- 28855058 TI - Comparison between clinical and audiological results of tympanoplasty with double layer graft (modified sandwich fascia) technique and single layer graft (underlay fascia and underlay cartilage) technique. AB - INTRODUCTION: Surgical repair of the tympanic membrane, termed a type one tympanoplasty is a tried and tested treatment modality. Overlay or underlay technique of tympanoplasty is common. Sandwich Tympanoplasty is the combined overlay and underlay grafting of tympanic membrane. OBJECTIVE: To describe and evaluate the modified sandwich graft (mediolateral double layer graft) tympanoplasty using temporalis fascia and areolar fascia. To compare the clinical and audiological outcome of modified sandwich tympanoplasty with underlay tympanoplasty. METHODS: A total of 88 patients of chronic otitis media were studied. 48 patients (Group A) underwent type one tympanoplasty with modified sandwich graft. Temporalis fascia was underlaid and the areolar fascia was overlaid. 48 patients (Group B) underwent type one tympanoplasty with underlay fascia technique. 48 patients (Group C) underwent type one tympanoplasty with underlay cartilage technique. We assessed the healing and hearing results. RESULTS: Successful graft take up was accomplished in 47 patients (97.9%) in Group A, in 40 patients (83.3%) Group B, and in 46 (95.8%) patients in Group C. The average Air-Bone gap closure achieved in Group A was 24.4+/-1.7dB, in Group B, it was 22.5+/-3.5dB and in group C, it was 19.8+/-2.6dB. Statistically significant difference was found in graft healing rate. Difference in hearing improvement was not statistically significant. CONCLUSION: Double layered graft with drum-malleus as a 'meat' of sandwich maintains a perfect balance between sufficient stability and adequate acoustic sensitivity. PMID- 28855059 TI - Molecular-signature analyses support the establishment of the actinobacterial genus Sphaerimonospora (Mingma et al. 2016). AB - The genera Microbispora and Sphaerimonospora were examined for GyrB and RecA amino-acid signatures to determine whether molecular-signature analyses support the recent establishment of the genus Sphaerimonospora. The creation of Sphaerimonospora was based mainly upon morphological differences between Microbispora and Sphaerimonospora and the clustering of the type strains of the two genera in phylogenetic trees based on a multilocus sequence analysis. The molecular-signature analyses showed that all members of Sphaerimonospora can be distinguished from all members of Microbispora at 14 amino acid positions in the GyrB protein and at four positions in the shorter RecA protein. These amino acid differences can be used as signatures to differentiate the members of these genera from each other and thus provide support for the establishment of the genus Sphaerimonospora. This is the first demonstration of the use of molecular signatures to support the establishment of a new genus in the family Streptosporangiaceae. Following the transfer of Microbispora mesophila and Microbispora thailandensis from Microbispora to Sphaerimonospora, all species in the genus Microbispora are characterised by the insertion of a small, hydrophobic amino acid after position 208 in the GyrB protein. This insertion is absent from the GyrB protein of members of the genus Sphaerimonospora. PMID- 28855060 TI - Trauma mechanisms and injury patterns in pediatric burn patients. AB - The objective of this study was to evaluate the frequency, severity, exact patterns and mechanisms of burn injuries in children. The patient records of children with acute burns admitted to the University Children's Hospital of Zurich were retrospectively reviewed over an 11year period. The age group with the highest risk, were children under the age of five (69%). Boys were overrepresented in all age groups, but the gender imbalance increased with age. Infants and toddlers were mainly injured by scalds and contact burns. Conversely, almost three quarters of injuries over the age of 9 were caused by flame. The majority of scald injuries was a result of pulling down hot liquids. The typical distribution of this accident scenario involved mainly the face, trunk and arms. More than half of all flame injuries occurred due to fire accelerants. 55% of children were passively involved while other children throwing flammable substances into a fire. Most of these injuries involved the face and arms. This study shows that burn etiology is age dependent. Additionally, our results demonstrate the diversity of burn accidents and their resulting injuries. These findings may help better specify target groups and subjects for prevention. PMID- 28855061 TI - Burns in a major burns center in East China from 2005 to 2014: Incidence and outcome. AB - OBJECTIVE: Information about epidemiology on burns is rare in China. The aim of this article is to describe the pattern of burns in East China during a 10-year time period. METHOD: A retrospective data analysis was performed on all hospitalized patients to the burn center at the Changhai hospital, one of major burn centers in East China, from 2005 to 2014. RESULTS: We included 3376 patients in this study. Among them, 48.1% were from 27 provinces out of Shanghai and nearly 90% were from East China. August saw the most admissions and November saw the fewest. Spring and summer separately dominated in number of female and male patients. Children aged 2-5 and working-age adult were the most commonly treated. Home was the commonest place of injury, followed by industrial-related places, outdoors, public buildings, and vehicles or roads. Scalds remained the primary reason, followed by fire, contact burns, electricity, and chemicals. The average %TBSA of male patients was 14.2+/-21.3, significantly different from that of female patients (10.4+/-16.9). Extremities were the most vulnerable body region burned, followed by the trunk, face and hands. The average hospital length of stay in male patients was 25.4+/-72.4 days, significantly different from that of females' 19.9+/-27.6 days. The total mortality was 1.8% and the lethal area burned resulting in 50% mortality was 96.5% TBSA. CONCLUSION: Compared with published data, these result are encouraging, which demonstrate that burn care and treatment has made significant progress. Burn clinicians should bear not only the responsibility to treat and cure burns, but also the popularization of knowledge about burn precautions and emergency treatments. PMID- 28855062 TI - When knowing is not enough: Emotional distress and depression reduce the positive effects of health literacy on diabetes self-management. AB - OBJECTIVES: Adequate self-management activities are important predictors of diabetes outcomes. As diabetes literacy and self-efficacy are strong predictors of diabetes self-care, self-management education programs focus essentially on these factors. This study investigated whether emotional distress or depression moderates the relation between health literacy, self-efficacy and diabetes self care behaviors. METHODS: 128 people with type 2 diabetes were recruited in hospitals, through general practitioners and via a diabetes website, and completed a questionnaire assessing health literacy, self-efficacy, diabetes related distress, depression and self-care behaviors. RESULTS: Multiple regression analysis confirms that health literacy and self-efficacy significantly predict reported self-care behaviors. Additional regression analyses reveal that distress or depression do not predict self-care behaviors directly, but moderate the effect of health literacy, which has a weaker impact in patients experiencing distress or depression. In contrast, distress and depression do not moderate the effect of self-efficacy on diabetes self-care behaviors. CONCLUSION: Emotional distress, whether related to diabetes or not, prevents patients from acting on their competence to perform adequate self-management behaviors. PRACTICE IMPLICATIONS: Diabetes Professionals should pay more attention to the patients' affective state and its influence on self-care. Psychological support should be integrated in the care for people suffering from type 2 diabetes. PMID- 28855063 TI - Does evidence support the use of mobile phone apps as a driver for promoting healthy lifestyles from a public health perspective? A systematic review of Randomized Control Trials. AB - OBJECTIVE: The aim of this systematic review was to find a scientific evidence on the efficacy of apps in promoting healthy lifestyles. METHODS: The research was carried out according to PRISMA Statement. Pubmed, Embase and Google Scholar searches were carried out up to September 2016 focusing on randomized control trials (RCTs). RESULTS: Forty RCTs were selected. Most of the studies targeted weight management, PA and healthy eating (N=35). A few RCTs focused on apps designed to sun protection, smoking cessation and alcohol consumption (N=5). Only 10 RCTs (25%) found statistical difference between intervention and control groups for all the outcomes measured. Most of the studies had a short follow-up (65%, less than 6 months) and half of them a very small sample size (fewer than 100 subjects). CONCLUSION: Overall, the evidence so far showed a modest efficacy of apps in health promotion. PRACTICE IMPLICATIONS: There is a need to improve the overall quality of intervention studies focused on mobile apps in order to understand if they could became a valuable tool in support of health professionals and their efforts to promote education and health. PMID- 28855064 TI - Supplementary insurance as a switching cost for basic health insurance: Empirical results from the Netherlands. AB - Nearly everyone with a supplementary insurance (SI) in the Netherlands takes out the voluntary SI and the mandatory basic insurance (BI) from the same health insurer. Previous studies show that many high-risks perceive SI as a switching cost for BI. Because consumers' current insurer provides them with a guaranteed renewability, SI is a switching cost if insurers apply selective underwriting to new applicants. Several changes in the Dutch health insurance market increased insurers' incentives to counteract adverse selection for SI. Tools to do so are not only selective underwriting, but also risk rating and product differentiation. If all insurers use the latter tools without selective underwriting, SI is not a switching cost for BI. We investigated to what extent insurers used these tools in the periods 2006-2009 and 2014-2015. Only a few insurers applied selective underwriting: in 2015, 86% of insurers used open enrolment for all their SI products, and the other 14% did use open enrolment for their most common SI products. As measured by our indicators, the proportion of insurers applying risk rating or product differentiation did not increase in the periods considered. Due to the fear of reputation loss insurers may have used 'less visible' tools to counteract adverse selection that are indirect forms of risk rating and product differentiation and do not result in switching costs. So, although many high-risks perceive SI as a switching cost, most insurers apply open enrolment for SI. By providing information to high-risks about their switching opportunities, the government could increase consumer choice and thereby insurers' incentives to invest in high-quality care for high-risks. PMID- 28855065 TI - Predicting 72-hour emergency department revisits. AB - OBJECTIVES: To develop a predictive model that hospitals or healthcare systems can use to identify patients at high risk of revisiting the ED within 72h so that appropriate interventions can be delivered. METHODS: This study employed multivariate logistic regression in developing the predictive model. The study data were from four Veterans medical centers in Upstate New York; 21,141 patients in total with ED visits were included in the analysis. Fiscal Year (FY) 2013 data were used to predict revisits in FY 2014. The predictive variables were patient demographics, prior year healthcare utilizations, and comorbidities. To avoid overfitting, we validated the model by the split-sample method. The predictive power of the model is measured by c-statistic. RESULTS: In the first model using only patient demographics, the c-statistics were 0.55 (CI: 0.52-0.57) and 0.54 (95% CI: 0.51-0.56) for the development and validation samples, respectively. In the second model with prior year utilization added, the c-statistics were 0.70 (95% CI: 0.68-0.72) for both samples. In the final model where comorbidities were added, the c-statistics were 0.74 (CI: 0.72-0.76) and 0.73 (95% CI: 0.71-0.75) for the development and validation samples, respectively. CONCLUSIONS: Reducing ED revisits not only lowers healthcare cost but also shortens wait time for those who critically need ED care. However, broad intervention for every ED visitor is not feasible given limited resources. In this study, we developed a predictive model that hospitals and healthcare systems can use to identify "frequent flyers" for early interventions to reduce ED revisits. PMID- 28855066 TI - Emergency department approach to QTc prolongation. AB - QTc prolongation has been associated with increased risk of developing ventricular tachydysrhythmias, particularly Torsades de Pointes (TdP). QTc prolongation is influenced by many factors including congenital causes, heart rate, metabolic imbalances, and pharmacotherapy. Several commonly used medications in the emergency department (ED), such as antipsychotics and antiemetics, are known to prolong the QT interval. In addition, ED patients may present with conditions that may predispose them to QTc prolongation, such as drug overdose or hypokalemia, which can further complicate management. ED providers should not only be aware of which medications have these effects, but must also thoroughly investigate any pertinent patient history that may contribute to QTc prolongation. This review discusses commonly encountered medications that are associated with QTc prolongation, the mechanisms by which they prolong the QTc interval, and other factors that may influence ED medication administration and management. PMID- 28855067 TI - What are the metabolic precursors which increase the risk of pre-eclampsia and how could these be investigated further. AB - Several maternal and pregnancy characteristics have been associated with an increased risk of preeclampsia in epidemiological studies. This review discusses metabolic risk factors in particular and their interaction with other maternal and/or pregnancy characteristics. Examples of research studies that have used data from women with specific characteristics or explored the interaction between risk factors are discussed. Suggestions for future research using large data sets and incorporating knowledge of cardiovascular disease and other metabolic diseases are also highlighted. PMID- 28855068 TI - In vivo confocal Raman spectroscopy for intrinsic aging and photoaging assessment. AB - BACKGROUND: In vivo confocal Raman spectroscopy is a non-invasive method to assess either the epidermis or the dermis composition. Few studies have focused on dermis collagen alterations through intrinsic aging and photoaging. OBJECTIVE: This study evaluated the in vivo Raman spectra from the dermis of a photoexposed site versus a non-photoexposed region in different age groups, and evaluated the correlation between peak intensities and age, photoaging score and the amount of collagen assessed with histology and high frequency ultrasound (HFUS). METHODS: Fifteen volunteers aged 28-82 years were divided into three groups according to forearm photoaging degree. In vivo Raman spectra from the dermis were collected on the dorsal forearm (chronically photoexposed skin) and on the proximal medial arm (non-photoexposed skin). Cross-sectional images of the skin were obtained using a 20MHz ultrasound unit exactly on the same sites, which were further submitted to punch biopsies for histologic study (collagen I immunohistochemistry, picrosirius red staining and Verhoeff). Principal Component Analysis (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS DA) were taken in the spectral region of 796cm-1-996cm-1 to determine its potential to discriminate between different groups. The Spearman rank correlation coefficient of individual peak intensities and ratios with age, clinical score and the amount of collagen assessed by ultrasound and histology were calculated. RESULTS: PCA of pairs of groups and OPLS-DA could discriminate the intrinsically from the photoaged skin and the young group from the elderly one, with important contribution of the 938cm-1 and 855cm-1 peaks intensities. The intensity of the peaks in 855cm-1 and/or 938cm-1 presented moderate correlation with age (rho=0.579, p=0.049) and moderate to high inverse correlation with HFUS echogenicity (rho=-0.710, p=0.010) and collagen I immunohistochemistry (rho= 0.833, p=0.005) in the non-photoexposed region. The I1275/I1450 intensities ratio presented moderate to high correlation coefficients with age (rho=-0.730, p=0.007), photoaging score (rho=-0.594, p=0.042), HFUS echogenicity (rho=0.760, p<0.001) and histology (collagen I immunohistochemistry (rho=0.643, p=0.024), picrosirius (rho=0.773, p=0.005) and Verhoeff (rho=-0.727, p=0.011)) in the photoexposed site. CONCLUSION: The wavenumber region between 798 and 994cm-1 is useful for the analysis of dermal collagen alterations through the intrinsic aging process, while photoaging is better assessed by the I1275/I1450 intensities ratio. This is the first skin aging study to show a correlation between Raman peaks and the amount of collagen assessed by HFUS and histology. PMID- 28855069 TI - Corrigendum to "Letter to the Editor Ultraviolet B (UVB) induces development of early melanocytic progenitors via increased oxidative stress in vitro suggesting the use of antioxidants after regimentation in UVB phototherapy for vitiligo" [J. Dermatol. Sci. 87 (2017) 208-210]. PMID- 28855070 TI - Can Vitamin D supplementation alone effective to increase a physical fitness levels in post-menopausal women with metabolic disorders? Brief Review. AB - BACKGROUND: During the climacteric period, occur an aging process of the skin, and promote several decreases in the ability of vitamin D synthesis in an organism and lower levels of Vitamin D may contribute to the appearance of conditions such as osteomalacia, osteoporosis, falls and fractures. AIM: The present brief review focuses on the influence of Vitamin D supplementation alone on physical fitness (strength, endurance, and balance) in postmenopausal with diseases or not. METHODS: Search in Medline and PubMed relevant articles with Vitamin D supplementation alone on physical fitness (strength, endurance, and balance) in postmenopausal with diseases or not, were included only 5 clinical. CONCLUSIONS: In conclusion, the effectiveness depends on the amount was prescribed for supplementation and the patient's characteristics. Doses less than 1000 IU/d did not show significant changes in physical fitness on post-menopausal women with metabolic diseases or not. PMID- 28855071 TI - Neglected non communicable diseases-Watching a public health disaster unfold. PMID- 28855072 TI - Comparison of Fibroblast Growth-factor Receptor Gene Alterations at the DNA versus Messenger RNA Level in Advanced Urothelial Cancer: Insights for Clinical Research. AB - : Pan-fibroblast growth-factor receptor (FGFR) inhibitors hold promise in FGFR altered patients, but such alterations are rare in advanced urothelial carcinoma. In order to assess whether we may increase the number of eligible patients by using different molecular techniques for detecting alterations, we pooled the results of the centralised FGFR mutation/translocation assays that were performed in Clinical Laboratory Improvement Amendments-certified laboratories within multiple phase 2 trials. At our centre, the same tissue blocks were used to analyse FGFR1-3 messenger RNA expression through messenger RNA in situ hybridisation (ISH; RNAscope 2.5 assay). From October 2016 to March 2017, 52 cases were analysed. Seventeen patients (32.7%) had an upper tract primary tumour. Ten patients (19.2%) had FGFR DNA alterations. Twenty-nine (55.8%) had positive ISH analysis: N=17 score 3, N=12 score 4. Of note, concordance between the two tests was obtained in seven out of 10 patients. Sixty percent of mutated patients had an upper tract primary tumour versus 31% of ISH-positive patients. PATIENT SUMMARY: We found three-fold higher frequency of fibroblast growth-factor receptor alterations at the RNA versus DNA level in advanced urothelial carcinoma, with a different distribution according to the method used and the site of the primary tumour. The evaluation of the therapeutic response to pan fibroblast growth-factor receptor inhibitors according to the method of assessment is warranted. PMID- 28855073 TI - Reversion of High-level Mecillinam Resistance to Susceptibility in Escherichia coli During Growth in Urine. AB - Mecillinam (amdinocillin) is a beta-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (MecR) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were MecR due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, MecRE. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the MecR mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as MecR in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting MecRE. coli strain and thereby increase treatment efficiency. PMID- 28855074 TI - A difficult diagnosis of hepatocellular carcinoma recurrence after liver transplant. PMID- 28855076 TI - Potential efficacy of interleukin-1beta inhibition in lung cancer. PMID- 28855075 TI - Origin and production of inflammatory perivascular macrophages in pulmonary hypertension. AB - Myeloid cells, including monocytes and macrophages participate in steady state immune homeostasis and help mount the adaptive immune response during infection. The function and production of these cells in sterile inflammation, such as pulmonary hypertension (PH), is understudied. Emerging data indicate that pulmonary inflammation mediated by lung perivascular macrophages is a key pathogenic driver of pulmonary remodeling leading to increased right ventricular systolic pressure (RVSP). However, the origin of these macrophages in pulmonary inflammation is unknown. Inflammatory monocytes, the precursors of pathogenic macrophages, are derived from hematopoietic stem and progenitor cells (HSPC) in the bone marrow and spleen during acute and chronic inflammation. Understanding the role of these organs in monocytopoiesis, and the mechanisms of HSPC proliferation and differentiation in PH are important to discover therapeutic targets curbing inflammation. This review will summarize the current limited knowledge of the origin of lung macrophage subsets and over-production of inflammatory monocytes in PH. PMID- 28855079 TI - Dual antiplatelet therapy guided by platelet function testing. PMID- 28855080 TI - Erratum to: "Tendencies in cerebral aneurism treatment: Analysis of a hospital series" [Neurologia. 32(6) (2017) 371-376]. PMID- 28855081 TI - Significance of steatosis in pancreatic transplantation. AB - The on-going success of whole organ pancreatic transplantation is dependent on overcoming the imbalance between demand and supply of optimal organs as well as tackling the vast comorbidity associated with the procedure. Pancreas steatosis is a common contributing factor to the problem and with obesity pandemics affecting the global population; the size and type of organs received from donors will only make steatosis more of an issue. The aim of this review is to highlight what is known about steatosis in the context of pancreas transplantation identifying potential methods to help its evaluation. Narrative review of literature from inception to June 2017, using OVID interface searching EMBASE and MEDLINE databases as well recent transplant conference data. All studies related to pancreas steatosis examined for clinical relevance with no exclusion criteria. Key ideas extracted and referenced. Pancreatic steatosis is not innocuous and is precariously regarded by transplant surgeons, however its associations with obesity, metabolic syndrome and long list of associated complications clearly show it needs more careful consideration. Radiologic and surgical advances now allow assessment of the fat content of organs, which could be used to quantify organs allowing better optimisation, but there is still much work to be done to refine the optimal method to achieve this. PMID- 28855082 TI - Characteristics and diagnostic workup of the patient at risk to sustain fragility fracture. AB - The human body undergoes several physiological adaptations as a result of the aging process. Amongst other organs, the skeleton is also affected and when bone fragility is present, an increase in both morbidity and mortality has been reported. Identification of risk factors to calculate the probability for a given patient to develop a fragility fracture it is therefore of paramount importance. Moreover, the existence of an in house protocol for diagnostic work up using biochemical tests and imaging investigations is essential. In the herein study we discuss a diagnostic protocol that has been developed in our clinic based on knowledge from the literature and our clinical experience. PMID- 28855077 TI - Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double blind, placebo-controlled trial. AB - BACKGROUND: Inflammation in the tumour microenvironment mediated by interleukin 1beta is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1beta inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence. METHODS: We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017). FINDINGS: Baseline concentrations of hsCRP (median 6.0 mg/L vs 4.2 mg/L; p<0.0001) and interleukin 6 (3.2 vs 2.6 ng/L; p<0.0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3.7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p<0.0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0.0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0.49 [95% CI 0.31-0.75]; p=0.0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0.61 [95% CI 0.39-0.97]; p=0.034) and 300 mg groups (HR 0.33 [95% CI 0.18-0.59]; p<0.0001; p<0.0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0.23 [95% CI 0.10-0.54]; p=0.0002) and in the pooled canakinumab population than in the placebo group (p=0.0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0.94 [95% CI 0.83-1.06]; p=0.31). INTERPRETATION: Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1beta innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required. FUNDING: Novartis Pharmaceuticals. PMID- 28855083 TI - The Kampala Trauma Score has poor diagnostic accuracy for most emergency presentations. PMID- 28855078 TI - Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. AB - BACKGROUND: Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). METHODS: In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636 22. FINDINGS: Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de escalation group and in 118 patients (9%) in the control group (pnon inferiority=0.0004; hazard ratio [HR] 0.81 [95% CI 0.62-1.06], psuperiority=0.12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0.0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0.82 [95% CI 0.59-1.13]; p=0.23). INTERPRETATION: Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING: Klinikum der Universitat Munchen, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo. PMID- 28855084 TI - Women's experiences of self-reporting health online prior to their first midwifery visit: A qualitative study. AB - BACKGROUND: Information and communication technologies are increasingly used in health care to meet demands of efficiency, safety and patient-centered care. At a large Danish regional hospital, women report their physical, mental health and personal needs prior to their first antenatal visit. Little is known about the process of self-reporting health, and how this information is managed during the client-professional meeting. AIM: To explore women's experiences of self reporting their health status and personal needs online prior to the first midwifery visit, and how this information may affect the meeting between the woman and the midwife. METHOD: Fifteen semi-structured interviews with pregnant women and 62h of observation of the first midwifery visit were carried out. Conventional content analysis was used to analyse data. FINDINGS: Three main categories were identified; 'Reporting personal health', 'Reducing and generating risk', and 'Bridges and gaps'. Compared to reporting physical health information, more advanced levels of health literacy might be needed to self-assess mental health and personal needs. Self-reporting health can induce feelings of being normal but also increase perceptions of pregnancy-related risk and concerns of being judged by the midwife. Although women want to have their self-reported information addressed, they also have a need for the midwife's expert knowledge and advice, and of not being perceived as a demanding client. CONCLUSION: Self reported health prior to the first midwifery visit appears to have both intended and unintended effects. During the midwifery visit, women find themselves navigating between competing needs in relation to use of their self-reported information. PMID- 28855085 TI - The impact of accelerometer wear location on the relationship between step counts and arterial stiffness in adults treated for hypertension and diabetes. AB - OBJECTIVES: Accelerometer placement at the wrist is convenient and increasingly adopted despite less accurate physical activity (PA) measurement than with waist placement. Capitalizing on a study that started with wrist placement and shifted to waist placement, we compared associations between PA measures derived from different accelerometer locations with a responsive arterial health indicator, carotid-femoral pulse wave velocity (cfPWV). DESIGN: Cross-sectional study. METHODS: We previously demonstrated an inverse association between waist-worn pedometer-assessed step counts (Yamax SW-200, 7 days) and cfPWV (-0.20m/s, 95% CI -0.28, -0.12 per 1000 step/day increment) in 366 adults. Participants concurrently wore accelerometers (ActiGraph GT3X+), most at the waist but the first 46 at the wrist. We matched this subgroup with participants from the 'waist accelerometer' group (sex, age, and pedometer-assessed steps/day) and assessed associations with cfPWV (applanation tonometry, Sphygmocor) separately in each subgroup through linear regression models. RESULTS: Compared to the waist group, wrist group participants had higher step counts (mean difference 3980 steps/day; 95% CI 2517, 5443), energy expenditure (967kcal/day, 95% CI 755, 1179), and moderate-to-vigorous-PA (138min; 95% CI 114, 162). Accelerometer-assessed step counts (waist) suggested an association with cfPWV (-0.28m/s, 95% CI -0.58, 0.01); but no relationship was apparent with wrist-assessed steps (0.02m/s, 95% CI -0.24, 0.27). CONCLUSIONS: Waist but not wrist ActiGraph PA measures signal associations between PA and cfPWV. We urge researchers to consider the importance of wear location choice on relationships with health indicators. PMID- 28855086 TI - Hematocrit of mammals (Artiodactyla, Carnivora, Primates) at 1500m and 2100m altitudes. AB - The rise in hematocrit (Hct) is one of the hallmarks of human acclimatization to high altitude and, in chronic conditions, reflects the hypoxia-induced polycythemia. However, it is not a uniform response among domestic species and it is not found in Andean camelids, species long adapted to high altitudes. Hence, we asked to what extent the polycythemia of humans is common among mammals. Hct data were collected from captive mammals of three orders (Primates, Artiodactyla, Carnivora), 70 specimens of 33 species at ~1500m altitude (barometric pressure Pb=635mmHg) and 296 specimens of 64 species at ~2100m (Pb=596mmHg), long-term residents at those altitudes. Sea level values and data in men and women at the corresponding altitudes were from a compilation of literature sources. At either altitude Hct was significantly higher than at sea level both in men and women; the increase (DeltaHct) for genders combined averaged 3.4% (+/-0.7 SEM) at 1500m and 5.4% (+/-0.3) at 2100m. Differently, among the three mammalian orders studied a significant increase in Hct occurred only in females of Carnivora (at 1500m) and in males of Primates (at 2100m). The average DeltaHct of all species combined was 0.8% (+/-0.7) at 1500m and 1.5% (+/-0.4) at 2100m, both significantly less than in humans (P<0.001). At 2100m the average DeltaHct of nine species long adapted to high altitude was 0.4% (+/-1), significantly less than in non-adapted species (P<0.001). A polycythemic response like that of men and women at 2100m occurred in less than 10% of the mammals examined. We conclude that, at least for the altitudes studied, a minimal polycythemia is a general feature of both high altitude adapted and non-adapted species, and the magnitude of the human response is exceptional among mammals. PMID- 28855087 TI - FPR2 signaling without beta-arrestin recruitment alters the functional repertoire of neutrophils. AB - G-protein coupled receptor (GPCR) biased agonism or functional selectivity has become an essential concept in GPCR research over the last years. Receptor specific biased agonists selectively trigger one signaling pathway over another and induce a restricted/directed functional response. In this study, we aimed to characterize the concept of biased agonism for FPR2, a member of the formyl peptide receptor (FPR) subfamily of GPCRs. We show that the earlier described FPR2-activating pepducin F2Pal10 is a biased FPR2 agonist. The effects of F2Pal10 on neutrophil function differed in several aspects compared to those mediated by WKYMVM, a conventional FPR2-specific peptide agonist. Upon interaction with FPR2 expressed by neutrophils both F2Pal10 and WKYMVM activated the PLC-PIP2-Ca2+ signaling pathway and the superoxide-generating NADPH-oxidase, but only WKYMVM activated the receptor to recruit beta-arrestin. The functional consequences linked to a lack of beta-arrestin recruitment were further explored, and we demonstrate that FPR2 desensitization occurred independent of beta-arrestin. Despite this, reactivation of desensitized receptors achieved through a disruption of the cytoskeleton and through a novel FPR2 cross-talk mechanism with P2Y2R (the ATP receptor) and PAFR (the receptor for PAF) differed between F2Pal10 desensitized and WKYMVM-desensitized neutrophils. Further, the inability to recruit beta-arrestin was found to be associated with a reduced rate of receptor internalization and impaired chemotaxis in neutrophils. In summary, we provide experimental evidence of biased agonism for FPR2 and our data disclose critical roles of beta-arrestin in neutrophil chemotaxis and reactivation of desensitized receptors. PMID- 28855089 TI - Method for the determination of carboxylic acids in industrial effluents using dispersive liquid-liquid microextraction with injection port derivatization gas chromatography-mass spectrometry. AB - The paper presents a new method for the determination of 15 carboxylic acids in samples of postoxidative effluents from the production of petroleum bitumens using ion-pair dispersive liquid-liquid microextraction and gas chromatography coupled to mass spectrometry with injection port derivatization. Several parameters related to the extraction and derivatization efficiency were optimized. Under optimized experimental conditions, the obtained limit of detection and quantification ranged from 0.0069 to 1.12MUg/mL and 0.014 to 2.24MUg/mL, respectively. The precision (RSD ranged 1.29-6.42%) and recovery (69.43-125.79%) were satisfactory. Nine carboxylic acids at concentrations ranging from 0.10MUg/mL to 15.06MUg/mL were determined in the raw wastewater and in samples of effluents treated by various oxidation methods. The studies revealed a substantial increase of concentration of benzoic acids, in samples of wastewater after treatment, which confirms the need of carboxylic acids monitoring during industrial effluent treatment processes. PMID- 28855088 TI - Drug nanocarriers to treat autoimmunity and chronic inflammatory diseases. AB - Nanoparticles represent a new generation of drug delivery systems that can be engineered to harness optimal target selectivity for specific cells and tissues and high drug loading capacity, allowing for improved pharmacokinetics and enhanced bioavailability of therapeutics. The spontaneous propensity of both organic and colloidal nanoparticles to be captured by the cells of the reticuloendothelial system encouraged their utilization as passive targeting systems that can be preferentially directed to innate immune cells, such as macrophages, dendritic cells and neutrophils. The natural affinity for phagocytic cells suggests the possible implementation of nanoparticles as an immunotherapeutic platform for inflammatory diseases and autoimmune disorders. Here we discuss the recent advances in the application of nanotechnology to induce antigen-specific tolerance in autoimmunity and the use of nanoparticles for anti-inflammatory therapies, including treatment of inflammatory bowel diseases, psoriasis and rheumatoid arthritis. PMID- 28855090 TI - Effects of liquid post-column addition in electrospray ionization performance in supercritical fluid chromatography-mass spectrometry. AB - In supercritical fluid chromatography coupled to atmospheric pressure ionization mass spectrometry (SFC-MS), the use of a make-up post-column is almost mandatory to avoid analyte precipitation, especially when using low percentage of modifier (<5%) in the mobile phase. Due to the specific nature of gaseous CO2, the tuning of the make-up conditions in electrospray becomes an important factor and can be used to tune analyte sensitivity. Neither a dilution effect (loss of signal) nor a relevant degradation of chromatographic performances is observed with the addition of a make-up at various flow-rates, up to 0.7mL/min. From supercritical conditions (1mL/min 40 degrees C, 150bar) to gaseous state (room temperature, atmospheric pressure), the CO2 expands around 430 times, contributing to almost 5% of the nebulizing process. In positive mode, the presence of ammonium ions either in the mobile phase or in the make-up did significantly increase the MS signal, even at basic apparent pH. The ionization performance of electrospray is influenced by the acidic buffer power of the carbon dioxide, and was found to be restricted in the apparent pH range of 3.8-7.2 in the various conditions investigated. This may challenge sensitive detection in negative mode, as illustrated for bosentan. The use of DMSO as make-up additive (up to 30%) showed a simplification of the full scan spectrum regarding the adducts. Finally, the optimization of make-up composition leads to an enhancement up to a factor of 69 on the electrospray MS response signal, for the SFC-SRM/MS analysis of HIV protease inhibitors in plasma extracted from Dried Plasma Spots. PMID- 28855091 TI - Characterization of dextran-grafted hydrophobic charge-induction resins: Structural properties, protein adsorption and transport. AB - The structural and functional properties of a series of dextran-grafted and non grafted hydrophobic charge-induction chromatographic (HCIC) agarose resins were characterized by macroscopic and microscopic techniques. The effects of dextran grafting and mobile phase conditions on the pore dimensions of the resins were investigated with inverse size exclusion chromatography (ISEC). A significantly lower pore radius (17.6nm) was found for dextran-grafted than non-grafted resins (29.5nm), but increased salt concentration would narrow the gap between the respective pore radii. Two proteins, human immunoglobulin G (hIgG) and bovine serum albumin (BSA), were used to examine the effect of protein characteristics. The results of adsorption isotherms showed that the dextran-grafted resin with high ligand density had substantially higher adsorption capacity and enhanced the salt-tolerance property for hIgG, but displayed a significantly smaller benefit for BSA adsorption. Confocal laser scanning microscopy (CLSM) showed that hIgG presented more diffuse and slower moving adsorption front compared to BSA during uptake into the resins because of the selective binding of multiple species from polyclonal IgG; polymer-grafting with high ligand density could enhance the rate of hIgG transport in the dextran-grafted resins without salt addition, but not for the case with high salt and BSA. The results indicate that microscopic analysis using ISEC and CLSM is useful to improve the mechanistic understanding of resin structure and of critical functional parameters involving protein adsorption and transport, which would guide the rational design of new resins and processes. PMID- 28855092 TI - Extending the upper temperature range of gas chromatography with all-silicon microchip columns using a heater/clamp assembly. AB - Miniaturization of gas chromatography (GC) instrumentation is of interest because it addresses current and future issues relating to compactness, portability and field application. While incremental advancements continue to be reported in GC with columns fabricated in microchips (referred to in this paper as "microchip columns"), the current performance is far from acceptable. This lower performance compared to conventional GC is due to factors such as pooling of the stationary phase in corners of non-cylindrical channels, adsorption of sensitive compounds on incompletely deactivated surfaces, shorter column lengths and less than optimum interfacing to injector and detector. In this work, a GC system utilizing microchip columns was developed that solves the latter challenge, i.e., microchip interfacing to injector and detector. A microchip compression clamp was constructed to heat the microchip (i.e., primary heater), and seal the injector and detector fused silica interface tubing to the inlet and outlet ports of the microchip channels with minimum extra-column dead volume. This clamp allowed occasional operation up to 375 degrees C and routine operation up to 300 degrees C. The compression clamp was constructed of a low expansion alloy, KovarTM, to minimize leaking due to thermal expansion mismatch at the interface during repeated thermal cycling, and it was tested over several months for more than one hundred injections without forming leaks. A 5.9m long microcolumn with rectangular cross section of 158MUm*80MUm, which approximately matches a 100MUm i.d. cylindrical fused silica column, was fabricated in a silicon wafer using deep reactive ion etching (DRIE) and high temperature fusion bonding; finally, the channel was coated statically with a 1% vinyl, 5% phenyl, 94% methylpolysiloxane stationary phase. High temperature separations of C10-C40 n alkanes and a commercial diesel sample were demonstrated using the system under both temperature programmed GC (TPGC) and thermal gradient GC (TGGC) conditions. TGGC analysis of a complex essential oil sample was also demonstrated. Addition of a secondary heater and polyimide insulation proved to be helpful in achieving the desired elution temperature without having to raise the primary heater temperature above 300 degrees C for high boiling point compounds. PMID- 28855093 TI - Metagenomic arbovirus detection using MinION nanopore sequencing. AB - With its small size and low cost, the hand-held MinION sequencer is a powerful tool for in-field surveillance. Using a metagenomic approach, it allows non targeted detection of viruses in a sample within a few hours. This study aimed to determine the ability of the MinION to metagenomically detect and characterise a virus from an infected mosquito. RNA was extracted from an Aedes notoscriptus mosquito infected with Ross River virus (RRV), converted into cDNA and sequenced on the MinION. Bioinformatic analysis of the MinION reads led to detection of full-length RRV, with reads of up to 2.5kb contributing to the assembly. The cDNA was also sequenced on the MiSeq sequencer, and both platforms recovered the RRV genome with >98% accuracy. This proof of concept study demonstrates the metagenomic detection of an arbovirus, using the MinION, directly from a mosquito with minimal sample purification. PMID- 28855094 TI - Sphingosine 1-phosphate (S1P) signalling: Role in bone biology and potential therapeutic target for bone repair. AB - The lipid mediator sphingosine 1-phosphate (S1P) affects cellular functions in most systems. Interest in its therapeutic potential has increased following the discovery of its G protein-coupled receptors and the recent availability of agents that can be safely administered in humans. Although the role of S1P in bone biology has been the focus of much less research than its role in the nervous, cardiovascular and immune systems, it is becoming clear that this lipid influences many of the functions, pathways and cell types that play a key role in bone maintenance and repair. Indeed, S1P is implicated in many osteogenesis related processes including stem cell recruitment and subsequent differentiation, differentiation and survival of osteoblasts, and coupling of the latter cell type with osteoclasts. In addition, S1P's role in promoting angiogenesis is well established. The pleiotropic effects of S1P on bone and blood vessels have significant potential therapeutic implications, as current therapeutic approaches for critical bone defects show significant limitations. Because of the complex effects of S1P on bone, the pharmacology of S1P-like agents and their physico chemical properties, it is likely that therapeutic delivery of S1P agents will offer significant advantages compared to larger molecular weight factors. Hence, it is important to explore novel methods of utilizing S1P agents therapeutically, and improve our understanding of how S1P and its receptors modulate bone physiology and repair. PMID- 28855095 TI - Lipids of Dietzia sp. A14101. Part I: A study of the production dynamics of surface-active compounds. AB - Dietzia sp. A14101 belonging to the genus Dietzia (Gram-positive bacteria, Actinomycetes, high G+C content of DNA) was isolated from an oil reservoir model column inoculated with oil-field bacteria (Bodtker et al., 2009). Low interfacial tension (IFT) values were obtained by studying intact strain cells grown on water immiscible hydrocarbons (HC) (Kowalewski et al. (2004), Kowalewski et al. (2005). Further investigations showed that the adaptation mechanism of Dietzia sp. A14101 to toxic water-immiscible HC involved changes both on the level of fatty acids content and in the physical properties of the cellular surface (development of the negative cellular surface charge and an increased in hydrophobicity) (Hvidsten et al., 2015b). However, these changes could not explain the low IFT values observed in earlier studies of this strain. Generally, low IFT imply a production of surface active compounds of low MW that are lipids by structure (Rosenberg and Ron, 1999). In this paper, it is shown that Dietzia sp. A14101 produces a range of glycolipids on all substrates. The amount of trehalose containing lipids increases when the strain is grown on hydrocarbons. The production peak seems to coincide with the exponential growth phase, and such increased glycolipid synthesis continues throughout the stationary phase. The results indicate that only low amounts of the hydrocarbon substrate is incorporated directly into the glycolipids produced. Most of the hydrocarbon substrate seems to be employed for the biosynthesis of the neutral lipids and higher amounts of biomass were generated on HC substrates compared to incubations on non-HC substrates. The lipid content of the cell was determined as the total lipid extract (TLE), and was further fractionated (SPE). The hydrophobic and hydrophilic moieties of the isolated surface active compounds were determined (GC MS, TLC, DART, LC-MS). The changes in the lipid content during the culture development were monitored by 1D and 2D TLC, emulsification and oil-spreading tests. PMID- 28855096 TI - A systematic review of the structural neuroimaging correlates of thought disorder. AB - One clinical dimension often cited as a hallmark of schizophrenia is thought disorder (TD). The aim of the current systematic review was to summarise our current understanding of the neurobiology of TD that has been investigated with structural neuroimaging techniques. Ninety-seven relevant studies were identified from January 1990 to August 2016, 26 of which had TD-motivated research questions or hypotheses. The remaining 71 studies conducted exploratory clinical analyses that included TD amongst a number of psychotic symptoms. These studies implicate the left superior temporal gyrus in TD. There was also evidence to suggest associations between TD and structural measures within the orbitofrontal cortex, cerebellum, nucleus accumbens, and amygdala-hippocampal region. However, there is a dearth of structural neuroimaging research driven by TD-motivated hypotheses. Furthermore, few studies have explored specific TD symptoms or subgroups, or surface-based morphometric measures of cortical structure, despite theoretical and practical reasons for doing so. It is hoped that the current review will assist in the augmentation of diverse hypothesis-driven research into the aetiology of TD. PMID- 28855098 TI - The bioelectric code: An ancient computational medium for dynamic control of growth and form. AB - What determines large-scale anatomy? DNA does not directly specify geometrical arrangements of tissues and organs, and a process of encoding and decoding for morphogenesis is required. Moreover, many species can regenerate and remodel their structure despite drastic injury. The ability to obtain the correct target morphology from a diversity of initial conditions reveals that the morphogenetic code implements a rich system of pattern-homeostatic processes. Here, we describe an important mechanism by which cellular networks implement pattern regulation and plasticity: bioelectricity. All cells, not only nerves and muscles, produce and sense electrical signals; in vivo, these processes form bioelectric circuits that harness individual cell behaviors toward specific anatomical endpoints. We review emerging progress in reading and re-writing anatomical information encoded in bioelectrical states, and discuss the approaches to this problem from the perspectives of information theory, dynamical systems, and computational neuroscience. Cracking the bioelectric code will enable much-improved control over biological patterning, advancing basic evolutionary developmental biology as well as enabling numerous applications in regenerative medicine and synthetic bioengineering. PMID- 28855097 TI - Genomes of viral isolates derived from different mosquitos species. AB - Eleven viral isolates derived mostly in albopictus C6/36 cells from mosquito pools collected in Southeast Asia and the Americas between 1966 and 2014 contained particles with electron microscopy morphology typical of reoviruses. Metagenomics analysis yielded the near complete genomes of three novel reoviruses, Big Cypress orbivirus, Ninarumi virus, and High Island virus and a new tetravirus, Sarawak virus. Strains of previously characterized Sathuvarachi, Yunnan, Banna and Parry's Lagoon viruses (Reoviridae), Bontang virus (Mesoniviridae), and Culex theileri flavivirus (Flaviviridae) were also characterized. The availability of these mosquito virus genomes will facilitate their detection by metagenomics or PCR to better determine their geographic range, extent of host tropism, and possible association with arthropod or vertebrate disease. PMID- 28855099 TI - WITHDRAWN: Epigenetics in Chronic Liver Disease. AB - This article has been withdrawn at the request of the editors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28855100 TI - Modelling iron mismanagement in neurodegenerative disease in vitro: paradigms, pitfalls, possibilities & practical considerations. AB - Although aberrant metabolism and deposition of iron has been associated with aging and neurodegeneration, the contribution of iron to neuropathology is unclear. Well-designed model systems that are suited to studying the putative pathological effect of iron are likely to be essential if such unresolved details are to be clarified. In this review, we have evaluated the utility and effectiveness of the reductionist in vitro platform to study the molecular mechanisms putatively underlying iron perturbations of neurodegenerative disease. The expression and function of iron metabolism proteins in glia and neurons and the extent to which this iron regulatory system is replicated in in vitro models has been comprehensively described, followed by an appraisal of the inherent suitability of different in vitro and ex vivo models that have been, or might be, used for iron loading. Next, we have identified and critiqued the relevant experimental parameters that have been used in in vitro iron loading experiments, including the choice of iron reagent, relevant iron loading concentrations and supplementation with serum or ascorbate, and propose optimal iron loading conditions. Finally, we have provided a synthesis of the differential iron accumulation and toxicity in glia and neurons from reported iron loading paradigms. In summary, this review has amalgamated the findings and paradigms of the published reports modelling iron loading in monocultures, discussed the limitations and discrepancies of such work to critically propose a robust, relevant and reliable model of iron loading to be used for future investigations. PMID- 28855101 TI - In vitro observations and in silico predictions of xenoestrogen mixture effects in T47D-based receptor transactivation and proliferation assays. AB - Within endocrine disruptor research, evaluation and interpretation of mixture effects and the predictive value for downstream responses still warrant more in depth investigations. We used an estrogen receptor (ER)-mediated reporter gene assay (ER-CALUX(r)) and a cell proliferation assay (WST-1 assay), both based on the T47D breast cancer cell line, to test mixtures of heterogeneous xenoestrogens. Observed concentration-response curves were compared to those predicted by the concepts of concentration addition (CA), generalized concentration addition (GCA), and a novel full logistic model (FLM). CA performed better regarding mixture potency (EC50 values), whereas GCA was superior in predicting mixture efficacy (maximal response). In comparison, FLM proved to be highly suitable for in silico mixture effect prediction, combining advantages of both CA and GCA. The inter-assay comparison revealed that ER activation is not necessarily predictive for induction of cell proliferation. The results support the use of models like CA, GCA, or FLM in mixture effect evaluation. However, we conclude that reliable estimations regarding the disruptive potential of mixtures of endocrine active substances require an integrative approach considering more than one assay/endpoint to avoid misinterpretations. The formazan-based WST-1 proliferation assay might be a possible alternative to commonly used proliferation assays in endocrine disrupter research. PMID- 28855103 TI - Disruptive effects of light pollution on sleep in free-living birds: Season and/or light intensity-dependent? AB - Light pollution or artificial light at night (ALAN) is an increasing anthropogenic environmental pollutant posing an important potential threat for wildlife. Evidence of its effects on animal physiology and behaviour is accumulating. However, in order to effectively mitigate light pollution it is important to determine which factors contribute to the severity of effects of ALAN. In this experimental study we explored whether there are seasonal-dependent effects of ALAN on sleep in free-living great tits (Parus major), an important model species. Additionally, we looked at whether light intensity determined the severity of effects of ALAN on sleep. We therefore exposed animals to artificial light inside the nest box (3lx) in December (winter) and February (pre-breeding season). Results from February were compared with the results from a previous study in February, using a lower light intensity (1.6lx). We found little evidence for a season-dependent response. Effects of ALAN hardly differed between high and low light intensity. ALAN disrupted sleep with as main effect a decrease in sleep duration (~-40min) as animals woke up earlier (~-24min). However, compared to a natural dark situation sleep onset was delayed by high but not by low light intensity of ALAN. Our study underlines earlier found disruptive effects of ALAN on sleep of free-living animals. While we found no conclusive evidence for seasonal or light intensity-dependent effects of ALAN, additional experimental work using lower light intensities might show such differences. Examining potential management options is crucial in mitigating disruptive effects of light pollution, which will be an important focus for future studies. PMID- 28855102 TI - Age-related alterations in histone deacetylase expression in Purkinje neurons of ethanol-fed rats. AB - Ethanol and age-induced pathologies of the Purkinje neuron (PN) may result from histone deacetylases (HDACs), enzymes which repress transcription through coiling of the DNA. The purposes of this study were to investigate expression patterns of Class 1 and IIa HDACs in PN and the effects of aging and alcohol on the density of HDACs and histone acetylation in PN. Ninety, eight month old rats (30/diet) were fed a liquid ethanol, liquid control, or rat chow diet for 10, 20, or 40weeks (30/treatment duration). Double immunocytochemical labeling on tissue sections from these rats used antibodies against HDAC isoforms or acetylated histones, and calbindin, a marker for PN. Fluorescent intensities were also measured. Results showed a significant age but not an alcohol-related decrease in the densities of HDACs 2, 3, and 7. In contrast, there were age related-increases in the densities of phosphorylated form of HDAC (4, 5, 7) PN and in PN nuclei expressing HDAC 7. There were also a trend towards ethanol-induced inhibition of acetylation as the density of AH2b PN nuclei and AH3 and AH2b fluorescent intensity was significantly lower in the EF compared to the PF rats. This study presents unique data concerning which HDACs are commonly expressed in PN and indicates that aging rather than lengthy alcohol expression alters expression of the HDACs studied here. These results also suggest that lengthy ethanol consumption may inhibit histone deacetylation in PN. PMID- 28855104 TI - FoxM1: Repurposing an oncogene as a biomarker. AB - The past few decades have witnessed a tremendous progress in understanding the biology of cancer, which has led to more comprehensive approaches for global gene expression profiling and genome-wide analysis. This has helped to determine more sophisticated prognostic and predictive signature markers for the prompt diagnosis and precise screening of cancer patients. In the search for novel biomarkers, there has been increased interest in FoxM1, an extensively studied transcription factor that encompasses most of the hallmarks of malignancy. Considering the attractive potential of this multifarious oncogene, FoxM1 has emerged as an important molecule implicated in initiation, development and progression of cancer. Bolstered with the skill to maneuver the proliferation signals, FoxM1 bestows resistance to contemporary anti-cancer therapy as well. This review sheds light on the large body of literature that has accumulated in recent years that implies that FoxM1 neoplastic functions can be used as a novel predictive, prognostic and therapeutic marker for different cancers. This assessment also highlights the key features of FoxM1 that can be effectively harnessed to establish FoxM1 as a strong biomarker in diagnosis and treatment of cancer. PMID- 28855105 TI - Multiplex flow cytometry-based assay to study the breadth of antibody responses against E1E2 glycoproteins of hepatitis C virus. AB - Hepatitis C virus (HCV) infection is a major global public health problem. Early induction of cross-reactive neutralizing antibodies during acute infection correlates with the spontaneous clearance of HCV. Understanding the antibody response in multiple subjects in large-scale studies would greatly benefit vaccine development. To determine the breadth of a polyclonal-serum antibody response, and or, the monoclonal antibodies against the different HCV E1E2 genotypes, we developed a quick and high throughput flow cytometry assay using fluorescent cell barcoding to distinguish cells transfected with different E1E2 sequences in a single measurement. HCV-specific antibodies recognizing conformational epitopes were tested for binding to cells transfected with E1E2 from six genotypes. In this assay, 1500 samples can be analyzed for specific binding to 6 different HCV E1E2 sequences within 8h. Plasma of HCV infected subjects were tested in our assay allowing us to determine the breadth of their antibody response. In summary, we developed a quick and high throughput assay to study the specificity of an antibody response against multiple HCV E1E2 sequences simultaneously. This assay can also be used to facilitate the discovery of novel antibodies, and because other flavi- and picornaviruses have similar intracellular assembly mechanisms, this approach can be used to study the antibody response against such viruses. PMID- 28855107 TI - Multicentric visceral epithelioid hemangioendothelioma, with extremity dermal deposits, unusual late recurrence on the nasal bridge, and TFE3 gene rearrangement. AB - Epithelioid hemangioendothelioma (EHE) is a malignant neoplasm with vascular differentiation that most frequently occurs within soft tissues, bone, lung, and liver. It is histologically typified by epithelioid or spindle cells present singly or in cords or clusters, many with cytoplasmic vacuoles that can contain intraluminal erythrocytes (in keeping with primitive vascular differentiation), within myxohyaline or sclerotic matrix. Up to 50% present with synchronous lesions as multifocal disease. The WWTR1-CAMTA1 fusion has been demonstrated in EHEs at a variety of sites and is considered to represent its genetic hallmark. We describe a case of EHE in a patient who initially presented with multiple liver and pulmonary deposits, was found to have a soft tissue lesion in the foot, and then presented with further lesions on the nasal bridge and the arm approximately 6 years after initial presentation. Interestingly, the case showed diffuse CAMTA1 expression but negative TFE3 immunohistochemically, but in contrast showed TFE3 gene rearrangement with fluorescence in situ hybridization but no evidence of WWTR1-CAMTA1 translocation. The clinical behavior of EHE is unpredictable, and this case highlights unusual anatomic, immunohistochemical, and molecular cytogenetic findings. Characterization of the genetics of EHE is important because targeted therapies toward products of the specific WWTR1-CAMTA1 gene fusion may have an impact in the near future. PMID- 28855106 TI - Sample processing approach for detection of ricin in surface samples. AB - With several ricin contamination incidents reported over the past decade, rapid and accurate methods are needed for environmental sample analysis, especially after decontamination. A sample processing method was developed for common surface sampling devices to improve the limit of detection and avoid false negative/positive results for ricin analysis. Potential assay interferents from the sample matrix (bleach residue, sample material, wetting buffer), including reference dust, were tested using a Time-Resolved Fluorescence (TRF) immunoassay. Test results suggested that the sample matrix did not cause the elevated background fluorescence sometimes observed when analyzing post-bleach decontamination samples from ricin incidents. Furthermore, sample particulates (80mg/mL Arizona Test Dust) did not enhance background fluorescence or interfere with ricin detection by TRF. These results suggested that high background fluorescence in this immunoassay could be due to labeled antibody quality and/or quantity issues. Centrifugal ultrafiltration devices were evaluated for ricin concentration as a part of sample processing. Up to 30-fold concentration of ricin was observed by the devices, which serve to remove soluble interferents and could function as the front-end sample processing step to other ricin analytical methods. The procedure has the potential to be used with a broader range of environmental sample types and with other potential interferences and to be followed by other ricin analytical methods, although additional verification studies would be required. PMID- 28855108 TI - Squamoid morules in the pseudoinvasive foci of colonic polyp morphologically mimic invasive carcinoma. AB - Colorectal adenomas can show focal squamous differentiation or squamoid morules. We describe histologic findings of squamoid morules in the pseudoinvasive foci of colorectal polyps mimicking invasive carcinoma. Five colonic polyps with squamoid morules in the pseudoinvasive foci were collected. Histologic review and immunostains for cytokeratin 5/6, p63, synaptophysin, and chromogranin were performed on cases with squamoid morules. Forty-seven consecutive colorectal polyps with pseudoinvasion, none of which showed squamoid morules by histology review, and their clinicopathologic features were compared with the cases containing squamoid morules. Cases with squamoid morules more frequently occurred in younger patients (P=.047) and were located in right colon (P=.027) than those without squamoid morules. Diagnosis of the polyps included tubular/tubulovillous adenoma with low-grade (with squamoid morules, n=3; versus without squamoid morules, n=29) or high-grade dysplasia (n=2 versus n=15) and sessile serrated adenoma (none versus n=3). Squamoid morules formed nodules protruding into the lumen of glandular structures or partially replaced adenomatous glands without forming a discrete nodule. They also presented as solid nests showing a well formed morular structure around the bottom of adenomatous glands or myxoinflammatory stroma. Importantly, squamoid morules often formed a pseudocribriform or solid nest sitting in the stroma of pseudoinvasive foci. All cases (n=4) showed cytokeratin 5/6 positivity and p63 negativity in squamoid morules. Three and 1 of 4 cases showed focal positivity for synaptophysin and chromogranin, respectively, in squamoid morules. Squamoid morules in colonic adenomatous polyps can mimic invasive carcinoma when present in the pseudoinvasive foci. Pathologists should be aware of their presence. PMID- 28855109 TI - The vasorelaxant effect of mitiglinide via activation of voltage-dependent K+ channels and SERCA pump in aortic smooth muscle. AB - AIMS: The vasorelaxant effects of the anti-diabetic drug, mitiglinide in phenylephrine (Phe)-pre-contracted aortic rings were examined. MATERIALS AND METHODS: Arterial tone measurement was performed in aortic smooth muscle cells. KEY FINDINGS: Mitiglinide dose-dependently induced vasorelaxation. Application of the large-conductance Ca2+-activated K+ (BKCa) channel blocker paxilline, inwardly rectifying K+ (Kir) channel blocker Ba2+, and ATP-sensitive K+ (KATP) channel blocker glibenclamide did not affect the vasorelaxant effect of mitiglinide. However, application of the voltage-dependent K+ (Kv) channel blocker 4-AP, effectively inhibited mitiglinide-induced vasorelaxation. Although pretreatment with the Ca2+ channel blocker nifedipine did not alter the mitiglinide-induced vasorelaxation, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor thapsigargin and cyclopiazonic acid reduced the vasorelaxant effect of mitiglinide. In addition, the vasorelaxant effect of mitiglinide was not affected by the inhibitors of adenylyl cyclase, protein kinase A, guanylyl cyclase, or protein kinase G. Elimination of the endothelium and inhibition of endothelium dependent vasorelaxant mechanisms also did not change the vasorelaxant effect of mitiglinide. SIGNIFICANCE: We proposed that mitiglinide induces vasorelaxation via activation of Kv channels and SERCA pump. However, the vasorelaxant effects of mitiglinide did not involve other K+ channels, Ca2+ channels, PKA/PKG signaling pathways, or the endothelium. PMID- 28855110 TI - Down regulation of the long non-coding RNA PCAT-1 induced growth arrest and apoptosis of colorectal cancer cells. AB - AIMS: The long non-coding RNA (lncRNA) was reported to be involved in the progress of various cancers, however, its effect in colorectal cancer (CRC) remains unknown. The goal of the present study is to investigate the function role of lncRNA PCAT-1 in colorectal cancer. MAIN METHODS: The expression of lncRNA PCAT-1 in four CRC cell lines was measured by real-time PCR, and two lncRNA PCAT-1 high expression cell lines were selected. LncRNA PCAT-1 in these two CRC cell lines was down-regulated by shRNA, and the stable transfected cells were established. Functional involvement of lncRNA PCAT-1 in proliferation and apoptosis of the two CRC cells were evaluated in vitro. Mover, the effect of lncRNA PCAT-1 in tumor proliferation was also evaluated in CRC cell xenograft. KEY FINDINGS: The results showed that down-regulation of lncRNA PCAT-1 in CRC cells inhibited proliferation, blocked cell cycle transition, and suppressed the expression of cyclins and c-myc. The apoptosis cell proportion was elevated with increased expression of pro-apoptotic proteins and decreased anti-apoptotic proteins in lncRNA PCAT-1 knock down cells. Forced over-expression of c-myc in PCAT-1 down-regulated CRC cells increased the level of cyclins. The xenograft growth in lncRNA PCAT-1 down-regulated cells was significantly inhibited along with the reduced proliferative cells. SIGNIFICANCE: Our study revealed a tumorigenic effect of lncRNA PCAT-1 in CRC cells, and this effect is partly dependent on the inhibition of c-myc. PMID- 28855112 TI - Diseases AND or IN frailty, an important conceptual difference. AB - Frailty is a clinical state that increases an individual's vulnerability. It is an outcome marker in several medical scenarios. However, there is a lack of recognition in the medical field. Frailty should not be regarded as a condition superimposed to disease. Contrarily, it should be noticed as a state frequently found either as a component of diseases themselves or as their outcome. The work of a geriatrician is focused on the best possible approximation to the medical and psychosocial issues that an elder has, and must join the treatment team when the person has a considerable number of conditions that makes him/her frail. Traditionally medicine has focused mainly on illnesses, but the state of frailty requires a change of mindset, through a multidimensional person centered approach. PMID- 28855113 TI - FPGA implementation of real-time SENSE reconstruction using pre-scan and Emaps sensitivities. AB - Sensitivity Encoding (SENSE) is a widely used technique in Parallel Magnetic Resonance Imaging (MRI) to reduce scan time. Reconfigurable hardware based architecture for SENSE can potentially provide image reconstruction with much less computation time. Application specific hardware platform for SENSE may dramatically increase the power efficiency of the system and can decrease the execution time to obtain MR images. A new implementation of SENSE on Field Programmable Gate Array (FPGA) is presented in this study, which provides real time SENSE reconstruction right on the receiver coil data acquisition system with no need to transfer the raw data to the MRI server, thereby minimizing the transmission noise and memory usage. The proposed SENSE architecture can reconstruct MR images using receiver coil sensitivity maps obtained using pre scan and eigenvector (E-maps) methods. The results show that the proposed system consumes remarkably less computation time for SENSE reconstruction, i.e., 0.164ms @ 200MHz, while maintaining the quality of the reconstructed images with good mean SNR (29+ dB), less RMSE (<5*10-2) and comparable artefact power (<9*10-4) to conventional SENSE reconstruction. A comparison of the center line profiles of the reconstructed and reference images also indicates a good quality of the reconstructed images. Furthermore, the results indicate that the proposed architectural design can prove to be a significant tool for SENSE reconstruction in modern MRI scanners and its low power consumption feature can be remarkable for portable MRI scanners. PMID- 28855111 TI - Behavioral intoxication following voluntary oral ingestion of tetramethylenedisulfotetramine: Dose-dependent onset, severity, survival, and recovery. AB - Tetramethylenedisulfotetramine (tetramine, or TETS) is a highly toxic rodenticide that has been responsible for over 14,000 accidental and intentional poisonings worldwide. Although the vast majority of TETS poisonings involved tainted food or drink, the laboratory in vivo studies of TETS intoxication used intraperitoneal injection or gavage for TETS exposure. Seeking to develop and characterize a more realistic model of TETS intoxication in the present study, rats were trained to rapidly and voluntarily consume a poisoned food morsel. Initially, the overt toxic effects of TETS consumption across a large range of doses were characterized, then a focused range of doses was selected for more intensive behavioral evaluation (in operant test chambers providing a variable-interval schedule of food reinforcement). The onset of intoxication following voluntary oral consumption of TETS was rapid, and clear dose-dependent response-rate suppression was observed across multiple performance measures within the operant chamber environment. At most doses, recovery of operant performance did not occur within 30h. Food consumption and body weight changes were also dose dependent and corroborated the behavioral measures of intoxication. This voluntary oral poisoning method with concomitant operant-behavioral assessment shows promise for future studies of TETS (and other toxic chemicals of interest) and may be extremely valuable in characterizing treatment outcomes. PMID- 28855116 TI - Catheter Ablation for Rate-Controlled Atrial Fibrillation: New Horizon in Heart Failure Treatment. PMID- 28855115 TI - Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study. AB - BACKGROUND: Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy. OBJECTIVES: The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF. METHODS: This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] <=45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months. RESULTS: A total of 301 patients were screened; 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 +/- 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 +/- 13% in the CA group compared with 4.4 +/- 13% in the MRC group (p < 0.0001) and normalized (LVEF >=50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093). CONCLUSIONS: AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, particularly in the absence of ventricular fibrosis on CMR. This outcome challenges the current treatment paradigm that rate control is the appropriate strategy in patients with AF and LVSD. (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction [CAMERA-MRI]; ACTRN12613000880741). PMID- 28855117 TI - How motor, cognitive and musical expertise shapes the brain: Focus on fMRI and EEG resting-state functional connectivity. AB - Brain activity and structure are shaped by life experiences. This plasticity has often been demonstrated with different types of expertise by using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Experts showed domain-specific functional neural changes during completion of a task when compared to non-experts. However, all of these results are task-dependent and even though they have proven useful for understanding neural interactions and their direct relation to individual skill, studying brain plasticity without any task might provide complementary information about functional cerebral reorganization due to expertise at the whole-brain level and might facilitate comparison across studies. Resting-state functional MRI and EEG makes it possible to explore the functional traces of expertise in the brain by measuring temporal correlations of blood oxygen level-dependent (BOLD) and spontaneous neural activity fluctuations at rest. Since these correlations are thought to reflect a prior history co-activation of brain regions, we propose reviewing studies that focused on the effects of expertise in the motor, cognitive and musical domains on brain plasticity at rest, to determine whether there is a domain-specific neural signature of expertise. After highlighting expertise-related changes within resting-state networks for each domain, we discuss their specificity to the trained activity and the methodological considerations concerning different conditions and analyses used between studies. PMID- 28855114 TI - Mitochondrial-epigenetic crosstalk in environmental toxicology. AB - Crosstalk between the nuclear epigenome and mitochondria, both in normal physiological function and in responses to environmental toxicant exposures, is a developing sub-field of interest in environmental and molecular toxicology. The majority (~99%) of mitochondrial proteins are encoded in the nuclear genome, so programmed communication among nuclear, cytoplasmic, and mitochondrial compartments is essential for maintaining cellular health. In this review, we will focus on correlative and mechanistic evidence for direct impacts of each system on the other, discuss demonstrated or potential crosstalk in the context of chemical insult, and highlight biological research questions for future study. We will first review the two main signaling systems: nuclear signaling to the mitochondria [anterograde signaling], best described in regulation of oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis in response to environmental signals received by the nucleus, and mitochondrial signals to the nucleus [retrograde signaling]. Both signaling systems can communicate intracellular energy needs or a need to compensate for dysfunction to maintain homeostasis, but both can also relay inappropriate signals in the presence of dysfunction in either system and contribute to adverse health outcomes. We will first review these two signaling systems and highlight known or biologically feasible epigenetic contributions to both, then briefly discuss the emerging field of epigenetic regulation of the mitochondrial genome, and finally discuss putative "crosstalk phenotypes", including biological phenomena, such as caloric restriction, maintenance of stemness, and circadian rhythm, and states of disease or loss of function, such as cancer and aging, in which both the nuclear epigenome and mitochondria are strongly implicated. PMID- 28855118 TI - Genotype-dependent regulation of drought-responsive genes in tolerant and sensitive sugarcane cultivars. AB - Drought is the most damaging among the major abiotic stresses. Transcriptomic studies allow a global overview of expressed genes, providing the basis for molecular markers development. Here, the HT-SuperSAGE technique allowed the evaluation of four drought-tolerant cultivars and four-sensitive cultivars, after 24h of irrigation suppression. We identified 9831 induced unitags from roots of the tolerant cultivars with different regulations by the -sensitive cultivars after the applied stress. These unitags allowed a proposal of 15 genes, whose expressed profiles were validated by RT-qPCR, evaluating each cultivar independently. These genes covered broad metabolic processes: ethylene stress attenuation (ACCD); root growth (beta-EXP8); protein degradation [ubiquitination pathway (E2, 20SPbeta4); plant proteases (AP, C13)]; oxidative detoxification (TRX); fatty acid synthesis (ACC); amino acid transport (AAT), and carbohydrate metabolism [glycolysis (PFK, TPI, FBA); TCA cycle (LDP, MDH); pentose phosphate pathway (TKT)]. The expressed profiles showed a genotype-dependent regulation of the target genes. Two drought-tolerant cultivars (SP83-2847; CTC6) presented each one, nine of the induced genes. Among the -sensitive cultivars, CTC13 induced only one, while SP90-1636 induced two genes. These genes should help breeders to identify accessions managing drought stress tolerance responses, showing better ethylene stress attenuation, energy allocation, amino acid transport, and protein homeostasis. PMID- 28855119 TI - The effects of fluctuating temperature regimes on the embryonic development of lake whitefish (Coregonus clupeaformis). AB - Fluctuating incubation temperatures may have significant effects on fish embryogenesis; yet most laboratory-based studies use constant temperatures. For species that experience large, natural seasonal temperature changes during embryogenesis, such as lake whitefish (Coregonus clupeaformis), seasonal temperature regimes are likely optimal for development. Anthropogenic activities can increase average and/or variability of natural incubation temperatures over large (e.g. through climate change) or smaller (e.g. thermal effluent discharge) geographic scales. To investigate this, we incubated lake whitefish embryos under constant (2, 5, or 8 degrees C) and fluctuating temperature regimes. Fluctuating temperature regimes had a base temperature of 2 degrees C with: 1) seasonal temperature changes that modeled natural declines/inclines; 2) tri-weekly +3 degrees C, 1h temperature spikes; or 3) both seasonal temperature changes and temperature spikes. We compared mortality to hatch, morphometrics, and heart rate at three developmental stages. Mortality rate was similar for embryos incubated at constant 2 degrees C, constant 5 degrees C, or with seasonal temperatures, but was significantly greater at constant 8 degrees C. Embryos incubated constantly at >2 degrees C had reduced body growth and yolk consumption compared to embryos incubated with seasonal temperature changes. When measured at the common base temperature of 2 degrees C, embryos incubated at constant 2 degrees C had lower heart rates than embryos incubated with both seasonal temperature changes and temperature spikes. Our study suggests that incubating lake whitefish embryos with constant temperatures may significantly alter development, growth, and heart rate compared to incubating with seasonal temperature changes, emphasizing the need to include seasonal temperature changes in laboratory-based studies. PMID- 28855120 TI - SiO2-induced release of sVEGFRs from pulmonary macrophages. AB - BACKGROUND: The inhalation of silicon dioxide (SiO2) particles causes silicosis, a stubborn pulmonary disease that is characterized by alveolar inflammation during the early stage. Soluble cytokine receptors (SCRs) play important roles in regulating inflammation by either attenuating or promoting cytokine signaling. However, the role of SCRs in silicosis remains unknown. METHODS AND RESULTS: Luminex assays revealed increased soluble vascular endothelial growth factor receptor (sVEGFR) family levels in the plasma of silicosis patients. In an enzyme linked immunosorbent assay (ELISA), cells from the differentiated human monocytic cell line U937 released sVEGFR family proteins after exposure to SiO2 (50MUg/cm2). Further Western blot experiments revealed that VEGFR expression was also elevated in U937 cells. In contrast, levels of sVEGFR family members did not change in the supernatants of human umbilical vein endothelial cells (HUVECs) after exposure to SiO2 (50MUg/cm2). Interestingly, VEGFR expression in HUVECs decreased after SiO2 treatment. In a scratch assay, HUVECs exhibited cell migration ability, indicating the acquisition of mesenchymal properties. CONCLUSION: Our findings highlight the important role of sVEGFRs in both inflammation and fibrosis induced by SiO2, suggesting a possible mechanism for the fibrogenic effects observed in pulmonary diseases associated with fibrosis. PMID- 28855121 TI - Tubulin is retained throughout the human hematopoietic/erythroid cell differentiation process and plays a structural role in sedimentable fraction of mature erythrocytes. AB - We investigated the properties of tubulin present in the sedimentable fraction ("Sed-tub") of human erythrocytes, and tracked the location and organization of tubulin in various types of cells during the process of hematopoietic/erythroid differentiation. Sed-tub was sensitive to taxol/nocodazole (drugs that modify microtubule assembly/disassembly), but was organized as part of a protein network rather than in typical microtubule form. This network had a non-uniform "connected-ring" structure, with tubulin localized in the connection areas and associated with other proteins. When tubulin was eliminated from Sed-tub fraction, this connected-ring structure disappeared. Spectrin, a major protein component in Sed-tub fraction, formed a complex with tubulin. During hematopoietic differentiation, tubulin shifts from typical microtubule structure (in pro-erythroblasts) to a disorganized structure (in later stages), and is retained in reticulocytes following enucleation. Thus, tubulin is not completely lost when erythrocytes mature; it continues to play a structural role in the Sed tub fraction. PMID- 28855122 TI - Bacterial isolates degrading ritalinic acid-human metabolite of neuro enhancer methylphenidate. AB - The consumption of nootropic drugs has increased tremendously in the last decade, though the studies on their environmental fate are still scarce. Nootropics are bioactive compounds designed to alter human's physiology therefore the adverse effects towards wildlife can be expected. In order to understand their environmental impact, the knowledge on their transformation pathways is necessary. Methylphenidate belongs to the most prescribed neuro-enhancers and is among the most favored smart drugs used in non-medical situations. It is metabolized in human liver and excreted as ritalinic acid. Here, we showed for the first time that ritalinic acid can be biodegraded and used as a sole carbon and nitrogen source by various microbial strains originating from different environmental samples. Five axenic strains were isolated and identified as: Arthrobacter sp. strain MW1, MW2 and MW3, Phycicoccus sp. strain MW4 and Nocardioides sp. strain MW5. Our research provides the first insight into the metabolism of ritalinic acid and suggests that it may differ depending on the strain and growth conditions, especially on availability of nitrogen. The isolates obtained in this study can serve as model organisms in further studies on the catabolism of ritalinic acid and methylphenidate but potentially also other compounds with similar structures. Our findings have important implication for the sewage epidemiology. We demonstrated that ritalinic acid is subject to quick and efficient biodegradation thus its use as a stable biomarker should be reconsidered. PMID- 28855123 TI - Biotransformation of ritalinic acid by laccase in the presence of mediator TEMPO. AB - Methylphenidate is widely used as a medication for the treatment of attention deficit hyperactivity disorder (ADHD) in children. Less than 1% of methylphenidate is excreted unchanged in urine, while 80% of an oral dose is excreted as ritalinic acid (which is reportedly poorly degradable). This study aims to investigate the biotransformation of ritalinic acid by free and immobilized enzymes. The influence of various laccase mediators on biotransformation efficiency has been tested. Formation of the main transformation products has been monitored and their potential structures suggested. The effective transformation of ritalinic acid was observed only in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl mediator (TEMPO). The most effective enzyme was the laccase of T. versicolor 159. The main transformation product was an N-methyl derivative of ritalinic acid. Ritalinic acid was also reduced to aldehyde and alcohol, and a broad spectrum of intermediate complexes with oxoammonium ion of TEMPO were detected. This is the first time the biotransformation of ritalinic acid has been investigated in detail. PMID- 28855124 TI - Towards a routine application of Top-Down approaches for label-free discovery workflows. AB - : Thanks to proteomics investigations, our vision of the role of different protein isoforms in the pathophysiology of diseases has largely evolved. The idea that protein biomarkers like tau, amyloid peptides, ApoE, cystatin, or neurogranin are represented in body fluids as single species is obviously over simplified, as most proteins are present in different isoforms and subjected to numerous processing and post-translational modifications. Measuring the intact mass of proteins by MS has the advantage to provide information on the presence and relative amount of the different proteoforms. Such Top-Down approaches typically require a high degree of sample pre-fractionation to allow the MS system to deliver optimal performance in terms of dynamic range, mass accuracy and resolution. In clinical studies, however, the requirements for pre-analytical robustness and sample size large enough for statistical power restrict the routine use of a high degree of sample pre-fractionation. In this study, we have investigated the capacities of current-generation Ultra-High Resolution Q-Tof systems to deal with high complexity intact protein samples and have evaluated the approach on a cohort of patients suffering from neurodegenerative disease. Statistical analysis has shown that several proteoforms can be used to distinguish Alzheimer disease patients from patients suffering from other neurodegenerative disease. SIGNIFICANCE: Top-down approaches have an extremely high biological relevance, especially when it comes to biomarker discovery, but the necessary pre-fractionation constraints are not easily compatible with the robustness requirements and the size of clinical sample cohorts. We have demonstrated that intact protein profiling studies could be run on UHR-Q-ToF with limited pre-fractionation. The proteoforms that have been identified as candidate biomarkers in the-proof-of concept study are derived from proteins known to play a role in the pathophysiology process of Alzheimer disease. PMID- 28855125 TI - Theory of mind in multiple sclerosis: A neuropsychological and MRI study. AB - OBJECTIVES: Social cognition stands among the most frequently affected yet the least studied cognitive domains in multiple sclerosis (MS). Theory of mind (ToM) is a social cognitive facet that implies the one's ability to predict others' mental states. The objective of this study was to assess the relationship between ToM and neuropsychological and neuroimaging data. METHODS: Thirty-eight consecutive MS patients completed the Reading the Mind in the Eyes test (RMET). They underwent a neuropsychological evaluation and a 3T T1-weighted brain MRI. A fully automated volume-based morphometry algorithm (MorphoBox) was applied to calculate regional brain volumes. Correlation analysis was performed using Spearman's test. RESULTS: Among the sociodemographic and clinical data, significant correlations were found between RMET scores and each of years of education (r=0.54; p<0.01) and the duration of the disease progressive phase (r= 0.46; p<0.01). Regarding neuropsychological measures, RMET scores were directly correlated with information processing speed (r=0.58; p<0.01) and empathy (r=0.46; p<0.01) scores. As for brain volumes, RMET scores were directly correlated with parietal (left: r=0.39; right: r=0.46; p<0.05) and temporal (left: r=0.36; right: r=0.40; p<0.05) white matter volumes, as well as with cingulate (left: r=0.32; right: r=0.44; p<0.05) gray matter volumes. CONCLUSION: These results highlight the relationship between ToM and some of the disease characteristics and cognitive domains. Importantly, ToM performance in MS is associated with brain volumes of key areas in social cognitive networks. Further works are needed to enhance the current knowledge on the underlying mechanisms of ToM deficits in this population. PMID- 28855126 TI - Effects of (-)-epicatechin on frontal cortex DAPC and dysbindin of the mdx mice. AB - INTRODUCTION: Multiple components of the dystrophin-associated protein complex (DAPC) are expressed in numerous tissues including the brain. Members of the DAPC and dysbindin are abnormally expressed in the brain of Duchenne Muscular Dystrophy (DMD) patients, which has been associated with cognitive impairments. However, little is known about the expression pattern of individual members of the DAPC in animal models of DMD and their relationship with dysbindin. METHODS: Ten mdx mice were randomly allocated into a control and intervention group [(-) epicatechin (Epi) 1mg/kg/day for four weeks] and results compared to a wild-type mice. After sacrifice, brain pre-frontal cortices were collected for Western blotting and immunoprecipitation assays, and sagittal sections processed for immunohistochemistry. RESULTS: Epi promotes a partial recovery of DAPC members [alpha1-Syntrophin, sarcoglycans (SG), dystrophin 71 (Dp71)], dysbindin, and utrophin protein levels. Epi also appears to restore the association of DAPC between dysbindin, and utrophin with Dp71 and epsilon-SG. Co-immunostaining evidence increased protein levels of dysbindin, dystrophin, and epsilon-SG and their colocalization. CONCLUSIONS: Altogether, results suggest that Epi is capable of restoring pre-frontal cortex DAPC and dysbindin levels of mdx mice towards that of healthy brains. The functional implications of such studies warrant further investigation. PMID- 28855127 TI - The effect of CT26 tumor-derived TGF-beta on the balance of tumor growth and immunity. AB - INTRODUCTION: TGF-beta is an important target for many cancer therapies under development. In addition to suppressing anti-tumor immunity, it has pleiotropic direct pro- and anti- tumor effects. The actions of increased endogenous TGF-beta production remain unclear, and may affect the outcomes of anti-TGF-beta cancer therapy. We hypothesize that tumor-derived TGF-beta (td-TGF-beta) plays an important role in maintaining tumor remission by controlling tumor proliferation in vivo, and that decreasing td-TGF-beta in the tumor microenvironment will result in tumor progression. The aim of this study was to examine the effect of TGF-beta in the tumor microenvironment on the balance between its anti proliferative and immunosuppressive effects. METHODS: A murine BALB/c spontaneous colon adenocarcinoma cell line (CT26) was genetically engineered to produce increased active TGF-beta (CT26-TGF-beta), a dominant-negative soluble TGF-beta receptor (CT26-TGF-beta-R), or the empty neomycin cassette as control (CT26-neo). In vitro proliferation rates were measured. For in vivo studies, the three cell lines were injected into syngeneic BALB/c mice, and tumor growth was measured over time. Immunodeficient BALB/c nude mice were used to investigate the role of T and B cells. RESULTS: In vitro, CT26-TGF-beta-R and CT26-TGF-beta cells showed increased and suppressed proliferation, respectively, compared to control (CT26 neo), confirming TGF-beta has direct anti-tumor effects. In vivo, we found that CT26-TGF-beta-R cells displayed slower growth compared to control, likely secondary to reduced suppression of anti-tumor immunity, as this effect was ablated in immunodeficient BALB/c nude mice. However, CT26-TGF-beta cells (excess TGF-beta) exhibited rapid early growth compared to control, but later failed to progress. The same pattern was shown in immunodeficient BALB/c nude mice, suggesting the effect on tumor growth is direct, with minimal immune system involvement. There was minimal effect on systemic antitumor immunity as determined by peripheral antigen-specific splenocyte type 1 cytokine production and tumor growth rate of CT26-neo on the contralateral flank of the same mice. CONCLUSION: Although TGF-beta has opposing effects on tumor growth, this study showed that excessive td-TGF-beta in the tumor microenvironment renders the tumor non-proliferative. Depleting excess td-TGF-beta may release this endogenous tumor suppressive mechanism, thus triggering the progression of the tumor. Therefore, our findings support cautions against using anti-TGF-beta strategies in treating cancer, as this may tip the balance of anti-immunity vs. anti-tumor effects of TGF-beta, leading to tumor progression instead of remission. PMID- 28855128 TI - Inflammasome activation involved in early inflammation reaction after liver transplantation. AB - Liver transplantation has emerged as a vital therapy for end-stage liver diseases. Acute -phase inflammation play an important role in liver graft injury.Recent studies have revealed that inflammasome are responsible for initiating inflammation in early stage of acute organ rejection in liver transplantation, however the underlying mechanism remains unclear. Here we explored to block inflammasome activation to see whether it can alleviate early inflammation reaction during rejection of allgrafts in a rat model and gain further insights into the mechanism of inhibiting inflammation in allografts. By using Ac-YVAD-CMK, a highly selective caspase-1 inhibitor, to inhibit inflammation reaction involved in allograft rejection in a rat model. Our results showed that the rejection activity index (RAI) of Ac-YVAD-CMK-treated allografts is significantly diminished in similar magnitude to that of isografts. Compared with isografts, the expression of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and IL-1beta in allograft group increased significantly with the development of rejection, exhibiting apparent correlation. Expression of IFN-gamma mRNA in untreated allografts was maximal on day 3 while in Ac-YVAD-CMK-treated allografts and isografts, IFN-gamma mRNA levels remained low over the duration of the time course. ELISA results revealed serum elevation of IL-1beta by day 7 after othotopic liver transplantation (OLT) in comparison with isografts. There were no statistically significant differences between isografts and Ac-YVAD-CMK-treated allografts. For the first time, our data reveal that inhibition of the inflammasome activation pathway attenuates inflammation reaction of hepatic transplant rejection. PMID- 28855129 TI - Discovery of novel stroke-responsive lncRNAs in the mouse cortex using genome wide RNA-seq. AB - Long noncoding RNAs (lncRNAs) play major roles in regulating gene expression in mammals, but are poorly understood in ischemic stroke. Using a mouse model of transient focal ischemia, we applied RNA-seq to evaluate for the first time the unbiased, genome-wide expression of lncRNAs as a function of reperfusion time in the cerebral cortex. Focal ischemia was induced in adult male C57BL/6 mice followed by reperfusion for 6, 12 or 24h. Total RNA from ipsilateral cortices was used for Illumina sequencing and reads were mapped to the mouse reference genome (GRCm38). Annotated and novel transcript isoforms were identified and differential expression between the groups was estimated. We observed that the baseline expression of lncRNAs in the healthy cortex was low, but many were highly altered after stroke. Very few of these altered lncRNAs were previously annotated. A total of 259 lncRNA isoforms at 6h, 378 isoforms at 12h, and 217 isoforms at 24h of reperfusion were differentially expressed versus sham controls. Of these, 213, 322 and 171 isoforms at 6, 12 and 24h of reperfusion, respectively, were novel lncRNAs. Reperfusion time-point-specific analyses revealed that the lncRNAs reached peak expression levels at 6h of reperfusion. Positional analysis of ischemia-responsive lncRNAs with respect to ischemia responsive protein-coding genes identified potential gene-regulatory relationships. Overall, this work shows that transient focal ischemia induces widespread changes in the expression of lncRNAs in the mouse cortex with distinct reperfusion time-point-dependent expression characteristics that may underlie progression of the ischemic pathophysiology. The detection of hundreds of novel ischemia-responsive lncRNAs marks the discovery of new disease-related genomic regions in the adult cortex and may help identify novel opportunities for therapeutic targeting. PMID- 28855131 TI - Preparation and properties of multifunctional sinapic acid corn bran arabinoxylan esters. AB - In the present study, corn bran arabinoxylan (CAX) were modified with sinapic acid (SA) by esterification to generate sinapic acid corn bran arabinoxylan esters (SA-CAX) with various substituted degrees. The structure of SA-CAX was characterized by FT-IR, NMR and UV spectroscopy. And the antioxidant activities of SA-CAX were evaluated by scavenging the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical, emulsion lipid oxidation test and the lipid peroxidant level test. Compared with CAX, SA-CAX exhibited superior antioxidant activities in vitro, which indicated that the attachment of SA to CAX could enhance antioxidant activities of CAX. Moreover, the aqueous solution behavior of CAX and SA-CAX was investigated by light scattering, scanning electron microscopy and rheological measurement. The SA-CAX could form the aggregates even at diluted solutions. The hydrophobic association led to a higher viscosity and stronger gel behavior of the SA-CAX aqueous solution than that of CAX aqueous solution. PMID- 28855130 TI - PTEN deletion increases hippocampal granule cell excitability in male and female mice. AB - : Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability. Morphological studies of PTEN knockout granule cells revealed larger dendritic trees, more dendritic branches and an impairment of dendrite self-avoidance. Finally, cells from both female control and female knockout mice received more sEPSCs and more sIPSCs than corresponding male cells. Despite the difference, the net effect produced statistically equivalent EPSC/IPSC ratios. Consistent with this latter observation, extracellularly evoked responses in hippocampal slices were similar between male and female knockouts. Both groups of knockouts were abnormal relative to controls. Together, these studies reveal a host of physiological and morphological changes among PTEN knockout cells likely to underlie epileptogenic activity. SIGNIFICANCE STATEMENT: Hyperactivation of the mTOR pathway is associated with numerous neurological diseases, including autism and epilepsy. Here, we demonstrate that deletion of the mTOR negative regulator, PTEN, from a subset of hippocampal dentate granule impairs dendritic patterning, increases excitatory input and decreases inhibitory input. We further demonstrate that while granule cells from female mice receive more excitatory and inhibitory input than males, PTEN deletion produces mostly similar changes in both sexes. Together, these studies provide new insights into how the relatively small number (~200,000) of PTEN knockout granule cells instigates the development of the profound epilepsy syndrome evident in both male and female animals in this model. PMID- 28855132 TI - Hydrophobicity and physicochemical properties of agarose film as affected by chitosan addition. AB - The blend films were prepared with different ratio of agarose (AG) and chitosan (CH) using the casting method. The fundamental performance and characteristics of AG, CH and blend films were investigated. The results showed that the tensile strength (TS) and elongation at break (EB) values of blend films were significantly (p<0.05) increased compared with AG film. The water contact angle (WCA) increased from 66.2 to 97.7 degrees with the increasing ratio of blend film from AG70:CH30 to AG50:CH50. The thickness of blend films in this paper was varied from 0.010mm to 0.020mm, while the water vapor permeability (WVP) value of the blend film was higher than that of AG film mainly due to the increasing thickness. Moreover, hydrogen bonding and excellent compatibility were observed between agarose and chitosan according to thermogravimetric analysis (TGA), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) analyses. PMID- 28855133 TI - Surface chemical functionalization of cellulose nanocrystals by 3 aminopropyltriethoxysilane. AB - Surface functionalization of cellulose nanocrystals (CNCs) is valuable option to tailor properties as well as increase opportunities for their application. In this study, the surface of CNCs was functionalized with 3 aminopropyltriethoxysilane (APTES), without using hazardous solvents and by a direct, simple and straightforward method. APTES was firstly hydrolyzed in water and then adsorbed onto CNC through hydrogen bonds, finally the chain hydrocarbon was covalently linked to the surface of CNC through SiOC bonds which formed via the condensation reaction between hydroxyl and silanol groups. The chemical modification of the CNCs surface was confirmed by ATR-IR and NMR spectroscopy. Experiments conducted by AFM and XRD showed no significant change in the CNC dimensions and crystalline structure as a result of the modification. The EDX and XPS results confirmed the exsistence of APTES onto the CNCs. Silylated CNC exhibited good thermal stability and a greater amount of residual char was formed at 500 degrees C compared to non-chemically modified CNC. Thus, The silylation of CNCs may offer applications in composite manufacturing, where these nanoparticles have limited dispersibility in hydrophobic polymer matrices, and as nano-adsorbers due to the presence of amino groups attached on the surface. PMID- 28855134 TI - Antioxidant and anti-aging effects of acidic-extractable polysaccharides by Agaricus bisporus. AB - This study was designed to investigate the antioxidant and anti-aging effects of D-galatose-induced (D-gal-induced) aging mice as well as monosaccharide compositions of acidic-extractable polysaccharides (AcAPS) and its major purified fractions (AcAPS-1, AcAPS-2 and AcAPS-3) from the fruiting body of Agaricus bisporus. In the in vitro assays, AcAPS-2 showed superior scavenging activities on hydroxyl (82.98+/-4.67%) and DPPH (64.47+/-4.05%) radicals at the concentration of 1.0mg/mL than AcAPS and other polysaccharides fractions. For in vivo anti-aging analysis, AcAPS-2 showed superior effects on hepatic and nephric protection by improving serum enzyme activities, biochemical levels, lipid contents and antioxidant status, respectively. The monosaccharide analysis showed that rhamnose (Rha) and glucose (Glu) may play vital roles in maintaining the antioxidant and anti-aging activities. The results suggested that both AcAPS and its purified fractions might be suitable for functional foods and natural drugs in preventing the acute aging-associated diseases. PMID- 28855135 TI - Preparation of antimicrobial hybrid nano-materials using regenerated cellulose and metallic nanoparticles. AB - In this study, antimicrobial hybrid nano-materials were prepared by one-pot syntheses of silver (Ag), copper oxide (CuO), or zinc oxide (ZnO) nanoparticles (NPs) during regeneration of cellulose from cotton linter (CL) and microcrystalline cellulose (MCC). SEM micrographs indicated that the metallic nanoparticles were attached to the surface of the regenerated cellulose. EDX and ICP results showed that more AgNPs were adsorbed on the cellulose than CuONPs or ZnONPs. FTIR results revealed that the metallic nanoparticles were attached to the cellulose through the interaction with the hydroxyl group of cellulose. XRD results showed the characteristic diffraction peaks of individual metallic nanoparticles. The thermal stability of the R-CL and R-MCC increased in the hybrids with AgNPs and ZnONPs. The R-cellulose/metallic NPs hybrids showed strong antibacterial activity against E. coli and L. monocytogenes. Thus, the hybrid nano-materials can be used as nanofillers for the preparation of antibacterial packaging films. PMID- 28855136 TI - Ipratropium is 'luminally recycled' by an inter-play between apical uptake and efflux transporters in Calu-3 bronchial epithelial cell layers. AB - The mechanism by which quaternized anticholinergic bronchodilators permeate the airway epithelium remains controversial to date. In order to elucidate the role of drug transporters, ipratropium bidirectional transport as well as accumulation and release studies were performed in layers of the broncho-epithelial cell line Calu-3 grown at an air-liquid interface, in presence or absence of a range of transporter inhibitors. Unexpectedly, a higher transepithelial permeability was observed in the secretory direction, with an apparent efflux ratio of > 4. Concentration-dependent and inhibitor studies demonstrated the drug intracellular uptake was carrier-mediated. Interestingly, monitoring drug release post cell loading revealed the presence of an efficient efflux system on the apical side of the cell layers. Acting in concert, apical transporters seem to promote the 'luminal recycling' of the drug and hence, limit its transcellular transport. The data are in agreement with an apical Organic Cation Transporter (OCT) being involved in this process but also suggest the participation of unknown uptake and efflux transporters sensitive to probenecid. This study suggests the absorption of ipratropium across the pulmonary barrier is primarily governed by paracellular passive diffusion but transporters might play a significant role in controlling the drug local concentrations in the lungs. PMID- 28855137 TI - Dermal miconazole nitrate nanocrystals - formulation development, increased antifungal efficacy & skin penetration. AB - Miconazole nitrate nanosuspension was developed to increase its antifungal activity and dermal penetration. In addition, the nanosuspension was combined with the synergistic additive chlorhexidine digluconate. The production was performed by wet bead milling and both production and formulation parameters were optimized. A stabilizer screening revealed poloxamer 407 and Tween 80 both at 0.15% as the most effective stabilizers for miconazole nanosuspensions at 1.0%. The nanocrystals were incorporated into a hydroxypropyl cellulose gel base. Short term stability (3months) of the nanocrystal bulk population could be shown at room temperature and fridge. Besides the stable bulk nanocrystals, some longitudinal crystal growth to needle like crystals occurred. The addition of ionic compounds as the chlorhexidine digluconate often destabilizes suspensions. Surprisingly here, the addition minimized the crystal growth. An underlying mechanism is proposed. An inhibition zone assay was performed using Candida albicans (ATCC(r) 10231TM). When comparing the nanocrystals in suspension and in gel to MUm-sized miconazole nitrate formulations and two market products, the increase in inhibition zone diameter for the nanosuspension formulations was most pronounced in the chlorhexidine digluconate free formulations. These nanocrystal formulations were closely or similarly effective as the microsuspensions and the market products containing the synergistic chlorhexidine digluconate, showing the potential of the nanosuspension formulation. Nanosuspension performance was even further increased when chlorhexidine digluconate was added. Ex-vivo skin penetration studies on porcine ears revealed distinctly less remaining miconazole nitrate on the skin surface for nanocrystals (e.g., 76-86%) compared to market products (e.g. 94%). Also, penetration was increased e.g. in skin depth of 5 10MUm from <1.0/1.7% to e.g. 3.3-6.2% for nanocrystals. PMID- 28855139 TI - The effect of an acute systemic inflammatory insult on the chronic effects of a single mild traumatic brain injury. AB - A small but significant proportion of mild traumatic brain injury (mTBI) sufferers will report persistent symptoms, including depression, anxiety and cognitive deficits, in the months, or even years, following the initial event. This is known as post-concussion syndrome and its pathogenesis is not yet known. This study sought to investigate the role of a peripheral inflammatory insult in the development of ongoing behavioral symptoms following a mTBI. To investigate, male Sprague-Dawley rats were administered a single mTBI using the diffuse impact acceleration model to generate ~100G of force. Sham animals underwent surgery only. At 5days following surgery, rats were given either the TLR4 agonist, lipopolysaccharide (LPS, 0.1mg/kg), or saline via an intraperitoneal injection. mTBI animals showed an exaggerated response to LPS, with an increase in the expression of pro-inflammatory cytokines within the hippocampus at 24h post-dose, an effect not seen in sham animals. This was associated with the development of persistent behavioral deficits in the mTBI:LPS animals at 3 months post-injury. These behavioral deficits consisted of increased time spent immobile on the forced swim-test, indicative of depressive like behavior, impaired cognitive performance on the Barnes Maze and decreased anxiety on the Elevated Plus Maze. In contrast, animals administered mTBI alone had no deficits. This study provides evidence that a peripheral inflammatory stimulus can facilitate ongoing symptoms following a mTBI. As such this provides a basis for further exploration of exogenous factors which promote immune system activation as potential targets for intervention to allow the resolution of symptoms following a mTBI. PMID- 28855138 TI - Development of novel double-decker microneedle patches for transcutaneous vaccine delivery. AB - Microneedle (MN) patches have great potential as transcutaneous vaccine delivery devices because MNs can effectively deliver vaccine antigen into the skin through the micropores formed in the stratum corneum by low-invasive and painless skin puncturing. This study aims to develop novel double-decker MN patches which have not only high safety and efficacy but also broad applicability to various vaccine antigens. We developed two types of MN patches (PGA-MN and Nylon-MN) that are made from polyglycolic acid and Nylon-6. In pre-clinical studies, both MN patches could demonstrably deliver antigens into resected human dermal tissue, prolong antigen deposition and increase antigen-specific IgG levels after vaccination compared with conventional injections. We demonstrated both MN patches could be safely applied to human skin because no broken MNs or significant skin irritation were observed after applications in the clinical research. PGA-MN was suggested to be superior to Nylon-MN regarding human skin puncturability based on measurements of transepidermal water loss and needle failure force. A high content of tetravalent influenza hemagglutinin antigens loaded on PGA-MN could stably maintain HA titers at 35 degrees C for 1year. Overall, double-decker MN patches can reliably and safely puncture human skin and are promising as effective transcutaneous vaccine delivery devices. PMID- 28855140 TI - Prenatal stress induced gender-specific alterations of N-methyl-d-aspartate receptor subunit expression and response to Abeta in offspring hippocampal cells. AB - Prenatal stress (PS) is one of adverse life events during pregnancy, which may increase vulnerability to cognitive impairment in adult offspring. Abeta synaptotoxicity is one important pathological factor for cognitive impairment, and PS-induced cognitive disorder is closely associated with N-Methyl-d-Aspartate receptor (NMDAR), which acts as a key mediator of Abeta synaptotoxicity. In the present study, we tried to explore whether PS affects offspring's Abeta levels and NMDAR subunit expression in a gender-specific manner in hippocampal CA and DG subregions, and whether PS affects synaptic proteins and NMDAR subunit expression in cultured offspring hippocampal cells exposed to Abeta. Pregnant SD rats with restraint stress from gestation day 8-20 were used as PS model. Morris water maze, ELISA, immunofluorescence and western blot were tested on postnatal day 90 in male and female PS offspring. Our results showed that female offspring is more vulnerable to PS-induced cognitive impairment. Surprisingly, PS enhanced Abeta1 40 levels in the hippocampal DG subregion of male offspring. Furthermore, WB results implied that the decreased GluN2A in CA of female may contribute to the PS-induced cognitive impairment, while in DG, the increased GluN2A and decreased GluN2B contributed to protective effects against Abeta. Interestingly, we found PS could alleviate Abeta synaptotoxicity in male offspring's hippocampal cells. Overall, our results provided a fundamental understanding of PS-induced gender specific alterations of NMDAR subunit expression and the susceptibility to Abeta, and paved the road for the development of timely preventive interventions on cognitive disorders of PS offspring. PMID- 28855141 TI - The effect of local and systemic statin use as an adjunct to non-surgical and surgical periodontal therapy-A systematic review and meta-analysis. AB - OBJECTIVES: To evaluate the effect of local and/or systemic statin use as an adjunct to non-surgical and/or surgical periodontal therapy. DATA: Literature search according to PRISMA guidelines with the following eligibility criteria: (a) English or German language; (b) interventional studies; (c) statins as monotherapy or as an adjunct to non-surgical and/or surgical treatment of periodontitis; (d) clinical and/or radiographic treatment effect size of statin intake reported. SOURCES: Medline (PubMed), Embase (Ovid), CENTRAL (Ovid). STUDY SELECTION: Thirteen clinical studies regarding local application and 2 with systemic administration of statins as an adjunct to non-surgical treatment (SRP) and 4 studies regarding intrasurgical statin application with a maximum follow-up of 9 months could be included; simvastatin, atorvastatin, and rosuvastatin were used. Local but not systemic statin application as an adjunct to SRP yielded significantly larger probing pocket depth (PD), radiographic defect depth (RDD), and bleeding index reduction, and larger clinical attachment level gain, and less residual PD and RDD (p<=0.016); rosuvastatin appeared as the most efficacious. Three of 4 studies reported a significant positive effect of intrasurgical statin application. No adverse events were reported after statin use. The vast majority of the included studies were from the same research group. CONCLUSIONS: Significant additional clinical and radiographic improvements are obtained after local, but not systemic, statin use as an adjunct to SRP in deep pockets associated with intrabony defects and seemingly with furcation defects; intrasurgical statin application seems similarly beneficial. Confirmation of these results, and especially of the effect size, from other research groups is warranted. PMID- 28855142 TI - Plasma melatonin levels in hip fracture patients with and without delirium: A confirmation study. AB - BACKGROUND: Melatonin plays a major role in maintaining circadian rhythm. Changes in melatonin metabolism might lead to circadian rhythm disturbances which are often observed in delirious patients. AIM: To assess if high morning plasma melatonin concentrations were associated with delirium. METHODS: Consecutive hip fracture patients aged >=65 years were included. Delirium was assessed daily with the Confusion Assessment METHOD: Blood samples were collected at 11.00am on weekdays during first week of hospitalization. Melatonin was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: We analyzed 389 samples of 144 participants [mean age 84.0, 70 experienced delirium]. A Generalized Estimating Equations (GEE) model with outcome melatonin level in highest tertile ( >3.36 pg/ml) and covariates delirium group (i.e. never, before, during, post delirium), cognitive impairment, age, sex and anesthesia type, was constructed. Highest melatonin levels were associated with postoperative samples (Odds Ratio(OR) 2.11 compared to preoperative samples; 95% Confidence Interval(CI) 1.17-3.82, p=0.01) and higher age (OR 1.05 per year; CI 1.01-1.11, p=0.03), but not with delirium group(p=0.35). CONCLUSION: Undergoing surgery and aging in general may induce changes in melatonin metabolism. Future research should focus on daily multiple melatonin measurements to determine whether melatonin supplementation might be beneficial for delirium treatment or prevention. PMID- 28855143 TI - Lack of genetic structure in pinworm populations from New World primates in forest fragments. AB - Microevolutionary processes in parasites are driven by factors related to parasite biology, host abundance and dispersal, and environmental conditions. Here, we test the prediction that isolation of host populations results in reduced genetic diversity and high differentiation among parasite populations. We conducted a population genetic analysis of two pinworms, Trypanoxyuris minutus and Trypanoxyuris atelis, commonly found parasitizing howler and spider monkeys in tropical rainforests across south-eastern Mexico, whose populations are currently isolated due to anthropogenic habitat loss and fragmentation. Mitochondrial DNA was employed to assess parasite genetic patterns, as well as to analyse their demography and population history. Both pinworm species showed high haplotype diversity but, unexpectedly, lower nucleotide diversity than that reported for other parasites. No genetic differentiation or population structure was detected in either pinworm species despite habitat loss, fragmentation and host isolation. Several scenarios are discussed that could help to explain the genetic panmixia found in both pinworm species, including higher than expected primate inter-fragment dispersal movements, and passive dispersal facilitating gene flow between parasite populations. The results suggest that large population sizes of parasites could be helping them to cope with the isolation and fragmentation of populations, delaying the effects of genetic drift. The present study highlights the complexity of the drivers that intervene in the evolutionary processes of parasites. Detailed genetic studies are needed, both in host and parasite populations, to assess the effects that habitat perturbation and environmental changes could have on the evolutionary dynamics of pinworms and primates. PMID- 28855144 TI - Heterotopic ossification: Mechanistic insights and clinical challenges. AB - Bone formation is exquisitely controlled both spatially and temporally. Heterotopic ossification (HO) is pathological bone formation in soft tissues that often leads to deleterious outcomes. Inherited genetic forms of HO can be life threatening and can happen as early as in infancy. However, there is currently no effective treatment for HO as the underlying cellular and molecular mechanisms have not been completely elucidated. Trauma-induced non-genetic forms of HO often occur as a common complication after surgeries or accidents, and the location of HO occurrence largely determines the symptom and outcome. While it has been difficult to determine the complicated factors causing HO, recent advancement in identifying cellular and molecular mechanism causing the genetic forms of HO may provide important insights in all HO. Here in this review, we summarize recent studies on HO to provide a current status of both clinical options of HO treatments and mechanical understanding of HO. PMID- 28855145 TI - Age-dependent changes in nervonic acid-containing sphingolipids in mouse hippocampus. AB - Sphingolipids have been implicated in age-related neurodegeneration. Previous studies have reported elevated ceramide levels in the brain of old rodents, but a systematic investigation of the impact of age on brain sphingolipid metabolism is still lacking. Here we quantified 17 key sphingolipid species in the hippocampus of young (3months), middle-aged (12months) and old (21months) male and female mice. Lipids were extracted and quantified by liquid chromatography/mass spectrometry; transcription of enzymes involved in sphingolipid biosynthesis was evaluated by qPCR. Age-dependent changes of multiple sphingolipid species - including ceramide (d18:1/18:0), sphingomyelin (d34:1), hexosylceramide (d18:1/16:0), ceramide (d18:1/24:0) - were found in mice of both sexes. Moreover, sex-dependent changes were seen with hexosylceramide (d18:1/18:0), ceramide (d18:1/22:0), sphingomyelin (d36:1) and sphingomyelin (d42:1). Importantly, an age-dependent accumulation of sphingolipids containing nervonic acid (24:1) was observed in 21month-old male (p=0.04) and female mice (p<0.0001). Consistent with this increase, transcription of the nervonic acid-synthesizing enzyme, stearoyl CoA desaturase (Scd1 and Scd2), was upregulated in 21month-old female mice (Scd1 p=0.006; Scd2 p=0.009); a similar trend was observed in males (Scd1 p=0.07). In conclusion, the results suggest that aging is associated with profound sex dependent and -independent changes in hippocampal sphingolipid profile. The results also highlight the need to examine the contribution of sphingolipids, and particularly of those containing nervonic acid, in normal and pathological brain aging. PMID- 28855147 TI - Consent Processes for Mobile App Mediated Research: Systematic Review. AB - BACKGROUND: Since the launch of ResearchKit on the iOS platform in March 2015 and ResearchStack on the Android platform in June 2016, many academic and commercial institutions around the world have adapted these frameworks to develop mobile app based research studies. These studies cover a wide variety of subject areas including melanoma, cardiomyopathy, and autism. Additionally, these app-based studies target a variety of participant populations, including children and pregnant women. OBJECTIVE: The aim of this review was to document the variety of self-administered remote informed consent processes used in app-based research studies available between May and September 2016. Remote consent is defined as any consenting process with zero in-person steps, when a participant is able to join a study without ever seeing a member of the research team. This type of review has not been previously conducted. The research community would benefit from a rigorous interrogation of the types of consent taken as part of the seismic shift to entirely mobile meditated research studies. METHODS: This review examines both the process of information giving and specific content shared, with special attention to data privacy, aggregation, and sharing. RESULTS: Consistency across some elements of the app-based consent processes was found; for example, informing participants about how data will be curated from the phone. Variations in other elements were identified; for example, where specific information is shared and the level of detail disclosed. Additionally, several novel elements present in eConsent not typically seen in traditional consent for research were highlighted. CONCLUSIONS: This review advocates the importance of participant informedness in a novel and largely unregulated research setting. PMID- 28855146 TI - Categorizing Health Outcomes and Efficacy of mHealth Apps for Persons With Cognitive Impairment: A Systematic Review. AB - BACKGROUND: Use of mobile health (mHealth) apps is growing at an exponential rate in the United States and around the world. Mild cognitive impairment (MCI), Alzheimer disease, and related dementias are a global health problem. Numerous mHealth interventions exist for this population, yet the effect of these interventions on health has not been systematically described. OBJECTIVE: The aim of this study is to catalog the types of health outcomes used to measure effectiveness of mHealth interventions and assess which mHealth interventions have been shown to improve the health of persons with MCI, Alzheimer disease, and dementia. METHODS: We searched 13 databases, including Ovid MEDLINE, PubMed, EMBASE, the full Cochrane Library, CINAHL, PsycINFO, Ei Compendex, IEEE Xplore, Applied Science & Technology Source, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar from inception through May 2017 for mHealth studies involving persons with cognitive impairment that were evaluated using at least one quantitative health outcome. Proceedings of the Annual ACM Conferences on Human Factors in Computing Systems, the ACM User Interface Software and Technology Symposium, and the IEEE International Symposium on Wearable Computers were searched in the ACM Digital Library from 2012 to 2016. A hand search of JMIR Publications journals was also completed in July 2017. RESULTS: After removal of duplicates, our initial search returned 3955 records. Of these articles, 24 met final inclusion criteria as studies involving mHealth interventions that measured at least one quantitative health outcome for persons with MCI, Alzheimer disease, and dementia. Common quantitative health outcomes included cognition, function, mood, and quality of life. We found that 21.2% (101/476) of the fully reviewed articles were excluded because of a lack of health outcomes. The health outcomes selected were observed to be inconsistent between studies. For those studies with quantitative health outcomes, more than half (58%) reported postintervention improvements in outcomes. CONCLUSIONS: Results showed that many mHealth app interventions targeting those with cognitive impairment lack quantitative health outcomes as a part of their evaluation process and that there is a lack of consensus as to which outcomes to use. The majority of mHealth app interventions that incorporated health outcomes into their evaluation noted improvements in the health of persons with MCI, Alzheimer disease, and dementia. However, these studies were of low quality, leading to a grade C level of evidence. Clarification of the benefits of mHealth interventions for people with cognitive impairment requires more randomized controlled trials, larger numbers of participants, and trial designs that minimize bias. TRIAL REGISTRATION: PROSPERO Registration: PROSPERO 2016:CRD42016033846; http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID=CRD42016033846 (Archived by WebCite at http://www.webcitation.org/6sjjwnv1M). PMID- 28855148 TI - Ivermectin Treatment in Patients With Onchocerciasis-Associated Epilepsy: Protocol of a Randomized Clinical Trial. AB - BACKGROUND: Many studies have reported an association between epilepsy, nodding syndrome (NS), and onchocerciasis (river blindness). A high prevalence of epilepsy has been noted particularly in onchocerciasis hyperendemic areas where onchocerciasis is not or insufficiently controlled with mass ivermectin distribution. There is evidence that increasing the coverage of ivermectin reduces the incidence of epilepsy, and anecdotal evidence suggests a reduction in seizure frequency in onchocerciasis-associated epilepsy (OAE) patients who receive ivermectin. Finding an alternative treatment for epilepsy in these patients will have major consequences. OBJECTIVE: The goal of the study is to assess whether ivermectin treatment decreases the frequency of seizures and leads to seizure freedom in OAE patients, including patients with NS. If we are able to demonstrate such an effect, this would strengthen the argument that onchocerciasis is causing epilepsy and therefore we should increase our efforts to eliminate onchocerciasis. METHODS: We will conduct a randomized clinical trial in the Democratic Republic of Congo to compare seizure freedom in onchocerciasis infested epilepsy patients who receive immediate ivermectin treatment with delayed (after 4 months) ivermectin treatment. All participants will simultaneously receive antiepilepsy drugs (AEDs) according to local guidelines for epilepsy treatment. The primary endpoint is seizure freedom defined as no seizures during the 4 month of follow-up. Secondary endpoint is significant (>50%) seizure reduction compared to baseline seizure frequency. Reduction of seizures will be compared between ivermectin and nonivermectin arms. RESULTS: Start of enrollment is planned for August 2017, and we expect to have enrolled all 110 participants by December 2017. Results are expected in June 2018. CONCLUSIONS: If ivermectin treatment in addition to AEDs is able to lead to seizure freedom or significantly reduces seizure frequency in OAE patients, this will have major consequences for epilepsy treatment in onchocerciasis-endemic regions. Ivermectin is donated for free and in non Loa-Loa-endemic regions has negligible side effects. Reducing the burden of epilepsy will have a major impact on quality of life and socioeconomic status of families with affected members in Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT03052998; https://clinicaltrials.gov/ct2/show/NCT03052998 (Archived by WebCite at http://www.webcitation.org/6roFVQSG0). PMID- 28855150 TI - Fixing medicine by driving down demand and increasing collaboration. PMID- 28855149 TI - Development of the Electronic Social Network Assessment Program Using the Center for eHealth and Wellbeing Research Roadmap. AB - BACKGROUND: The number of Web-based psychological and behavioral interventions is growing. Beyond their theoretical underpinnings, a key factor to the success of these interventions is how they are designed and developed to ensure usability over a new method of delivery. Our team has adapted ecomapping, a tool for visualizing family caregiver social network resources, for the Web. Here, we describe how we designed and developed the electronic Social Network Assessment Program (eSNAP) Web-based tool using a framework of the Center for eHealth and Wellbeing Research (CeHRes) Roadmap for Web-based intervention development. The CeHRes Roadmap is still new in terms of tool development and we showcase an example of its application. OBJECTIVE: The aim of our study was to provide an example of the application of the Web-based intervention development process using the CeHRes Roadmap for other research teams to follow. In doing so, we are also sharing our pilot work to enhance eSNAP's acceptance and usability for users and the feasibility of its implementation. METHODS: We describe the development of the eSNAP app to support family caregivers of neuro-oncology patients. This development is based on the 5 iterative stages of the CeHRes Roadmap: contextual inquiry, value specification, design, operationalization, and summative evaluation. Research activities to support eSNAP development prior to implementation included literature review, focus groups, and iterative rounds of interviews. RESULTS: Key lessons learned in developing the eSNAP app broadly fell under a theme of translating theoretical needs and ideas to the real world. This included how to prioritize needs to be addressed at one time, how the modality of delivery may change design requirements, and how to develop a tool to fit within the context it will be used. CONCLUSIONS: Using the CeHRes Roadmap to develop Web based interventions such as eSNAP helps to address potential issues by outlining important intervention development milestones. In addition, by encouraging inclusion of users and other stakeholders in the process, Web-based intervention developers using the Roadmap can identify what will work in the real world and increase feasibility and effectiveness. PMID- 28855151 TI - Florida executes prisoner with etomidate despite drug maker's concerns. PMID- 28855152 TI - Simon Conroy: Healthy body and mind. PMID- 28855153 TI - Recommendations are made in the absence of any good treatments. PMID- 28855154 TI - Hunt's war of words with Hawking has gone too far, says former health secretary. PMID- 28855155 TI - All watched over by machines of loving grace: an optimistic view of big data. PMID- 28855156 TI - Shared medical appointments. PMID- 28855158 TI - Junior doctor is suspended for dishonesty over annual leave. PMID- 28855157 TI - H3K27M/I mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations. AB - Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of H3K27M mutations in pediatric glioblastoma and their well established impact on global histone H3 lysine 27 di- and trimethylation (H3K27me2/3), the relevance of these mutations has not been studied in acute myeloid leukemia (AML). Here, we report the first identification of H3K27M and H3K27I mutations in patients with AML. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they are associated with common aberrations in the RUNX1 gene. We demonstrate that H3K27I/M mutations are strong disease accelerators in a RUNX1-RUNX1T1 AML mouse model, suggesting that H3K27me2/3 has an important and selective leukemia-suppressive activity in this genetic context. PMID- 28855159 TI - Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands. AB - Objectives To investigate whether measles, mumps, and rubella (MMR) vaccine has positive non-specific effects in a high income setting and to compare rates of hospital admissions for infections between children aged <=2 years who received live MMR vaccine and those who received an inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP IPV-Hib) as their most recent vaccination.Design Nationwide population based cohort study.Setting In the Netherlands, DTaP-IPV-Hib+pneumococcal vaccination (PCV) is recommended at ages 2, 3, 4, and 11 months and MMR + meningococcal C (MenC) vaccination at age 14 months. Data from the national vaccine register were linked to hospital admission data.Participants 1 096 594 children born in 2005-11 who received the first four DTaP-IPV-Hib+PCV vaccines.Main outcome measures Hazard ratio for admission to hospital for infection in children with MMR+MenC compared with the fourth DTaP-IPV-Hib+PCV as their most recent vaccination. Cox regression was performed with most recent vaccination as time dependent variable, adjusted for potential confounders. Analyses were repeated with admission for injuries or poisoning as a negative control outcome. In addition, rate of admission for infection was compared between the fourth and third DTaP-IPV Hib+PCVas most recent vaccination.Results Having had MMR+MenC as the most recent vaccination was associated with a hazard ratio of 0.62 (95% confidence interval 0.57 to 0.67) for admission to hospital for infection and 0.84 (0.73 to 0.96) for injuries or poisoning, compared with the fourth DTaP-IPV-Hib+PCV as most recent vaccination. The fourth DTaP-IPV-Hib+PCV as most recent vaccination was associated with a hazard ratio of 0.69 (0.63 to 0.76) for admission to hospital for infection, compared with the third DTaP-IPV-Hib+PCV as most recent vaccination.Conclusions Healthy vaccinee bias could at least partly explain the observed lower rate of admission to hospital with infection after MMR vaccination. The lower rate is associated with receipt of any additional vaccine, not specifically MMR vaccine. This emphasises the caution required in the interpretation of findings from observational studies on non-specific effects of vaccination. PMID- 28855160 TI - Education and coronary heart disease: mendelian randomisation study. AB - Objective To determine whether educational attainment is a causal risk factor in the development of coronary heart disease.Design Mendelian randomisation study, using genetic data as proxies for education to minimise confounding.Setting The main analysis used genetic data from two large consortia (CARDIoGRAMplusC4D and SSGAC), comprising 112 studies from predominantly high income countries. Findings from mendelian randomisation analyses were then compared against results from traditional observational studies (164 170 participants). Finally, genetic data from six additional consortia were analysed to investigate whether longer education can causally alter the common cardiovascular risk factors.Participants The main analysis was of 543 733 men and women (from CARDIoGRAMplusC4D and SSGAC), predominantly of European origin.Exposure A one standard deviation increase in the genetic predisposition towards higher education (3.6 years of additional schooling), measured by 162 genetic variants that have been previously associated with education.Main outcome measure Combined fatal and non-fatal coronary heart disease (63 746 events in CARDIoGRAMplusC4D).Results Genetic predisposition towards 3.6 years of additional education was associated with a one third lower risk of coronary heart disease (odds ratio 0.67, 95% confidence interval 0.59 to 0.77; P=3*10-8). This was comparable to findings from traditional observational studies (prevalence odds ratio 0.73, 0.68 to 0.78; incidence odds ratio 0.80, 0.76 to 0.83). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely, although this remains an untestable possibility. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index, and a favourable blood lipid profile.Conclusions This mendelian randomisation study found support for the hypothesis that low education is a causal risk factor in the development of coronary heart disease. Potential mechanisms could include smoking, body mass index, and blood lipids. In conjunction with the results from studies with other designs, these findings suggest that increasing education may result in substantial health benefits. PMID- 28855161 TI - Possible roles for ATP release from RBCs exclude the cAMP-mediated Panx1 pathway. AB - Red blood cell (RBC)-derived adenosine triphosphate (ATP) has been proposed as an integral component in the regulation of oxygen supply to skeletal muscle. In ex vivo settings RBCs have been shown to release ATP in response to a number of stimuli, including stimulation of adrenergic receptors. Further evidence suggested that ATP release from RBCs was dependent on activation of adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP)-dependent pathways and involved the pannexin 1 (Panx1) channel. Here we show that RBCs express Panx1 and confirm its absence in Panx1 knockout (-/-) RBCs. However, Panx1-/- mice lack any decrease in exercise performance, challenging the assumptions that Panx1 plays an essential role in increased blood perfusion to exercising skeletal muscle and therefore in ATP release from RBCs. We therefore tested the role of Panx1 in ATP release from RBCs ex vivo in RBC suspensions. We found that stimulation with hypotonic potassium gluconate buffer resulted in a significant increase in ATP in the supernatant, but this was highly correlated with RBC lysis. Next, we treated RBCs with a stable cAMP analog, which did not induce ATP release from wild-type or Panx1-/- mice. Similarly, multiple pharmacological treatments activating AC in RBCs increased intracellular cAMP levels (as measured via mass spectrometry) but did not induce ATP release. The data presented here question the importance of Panx1 for exercise performance and dispute the general assumption that ATP release from RBCs via Panx1 is regulated via cAMP. PMID- 28855162 TI - Muscle paralysis induces bone marrow inflammation and predisposition to formation of giant osteoclasts. AB - Transient muscle paralysis engendered by a single injection of botulinum toxin A (BTxA) rapidly induces profound focal bone resorption within the medullary cavity of adjacent bones. While initially conceived as a model of mechanical disuse, osteoclastic resorption in this model is disproportionately severe compared with the modest gait defect that is created. Preliminary studies of bone marrow following muscle paralysis suggested acute upregulation of inflammatory cytokines, including TNF-alpha and IL-1. We therefore hypothesized that BTxA induced muscle paralysis would rapidly alter the inflammatory microenvironment and the osteoclastic potential of bone marrow. We tested this hypothesis by defining the time course of inflammatory cell infiltration, osteoinflammatory cytokine expression, and alteration in osteoclastogenic potential in the tibia bone marrow following transient muscle paralysis of the calf muscles. Our findings identified inflammatory cell infiltration within 24 h of muscle paralysis. By 72 h, osteoclast fusion and pro-osteoclastic inflammatory gene expression were upregulated in tibia bone marrow. These alterations coincided with bone marrow becoming permissive to the formation of osteoclasts of greater size and greater nuclei numbers. Taken together, our data are consistent with the thesis that transient calf muscle paralysis induces acute inflammation within the marrow of the adjacent tibia and that these alterations are temporally consistent with a role in mediating muscle paralysis-induced bone resorption. PMID- 28855163 TI - Does aerobic exercise reduce postpartum depressive symptoms? a systematic review and meta-analysis. AB - BACKGROUND: There is currently no specific guidance on the role of exercise in managing postpartum depression in the UK and US, and international guidance is inconsistent. AIM: To assess the effectiveness of aerobic exercise on postpartum depressive symptoms. DESIGN AND SETTING: Systematic review and meta-analysis. There was no restriction to study site or setting. METHOD: The databases MEDLINE, EMBASE, Cochrane Library, PsycINFO, SportDiscus, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched. Titles and abstracts, then full-text articles, were screened against inclusion criteria: RCTs measuring depressive symptoms in mothers <=1 year postpartum; and interventions designed to increase aerobic exercise compared with usual care or other comparators. Included studies were assessed using the Cochrane Collaboration's risk of bias tool. Meta-analysis was conducted. Pre planned subgroup analyses explored heterogeneity. RESULTS: Thirteen RCTs were included, with 1734 eligible participants. Exercise significantly reduced depressive symptoms when all trials were combined (standardised mean difference 0.44; 95% confidence interval = -0.75 to -0.12). Exploration of heterogeneity did not find significant differences in effect size between women with possible depression and in general postpartum populations; exercise only and exercise with co-interventions; and group exercise and exercise counselling. CONCLUSION: This systematic review provides support for the effectiveness of exercise in reducing postpartum depressive symptoms. Group exercise, participant-chosen exercise, and exercise with co-interventions all may be effective interventions. These results should be interpreted with caution because of substantial heterogeneity and risk of bias. PMID- 28855164 TI - Human Papillomavirus Status and the Risk of Cerebrovascular Events Following Radiation Therapy for Head and Neck Cancer. AB - BACKGROUND: Radiation therapy (RT) is a standard treatment for head and neck cancer; however, it is associated with inflammation, accelerated atherosclerosis, and cerebrovascular events (CVEs; stroke or transient ischemic attack). Human papillomavirus (HPV) is found in nearly half of head and neck cancers and is associated with inflammation and atherosclerosis. Whether HPV confers an increased risk of CVEs after RT is unknown. METHODS AND RESULTS: Using an institutional database, we identified all consecutive patients treated with RT from 2002 to 2012 for head and neck cancer who were tested for HPV. The outcome of interest was the composite of ischemic stroke and transient ischemic attack, and the association between HPV and CVEs was assessed using Cox proportional hazard models, competing risk analysis, and inverse probability weighting. Overall, 326 participants who underwent RT for head and neck cancer were tested for HPV (age 59+/-12 years, 75% were male, 9% had diabetes mellitus, 45% had hypertension, and 61% were smokers), of which 191 (59%) were tumor HPV positive. Traditional risk factors for CVEs were similar between HPV-positive and -negative patients. Over a median follow-up of 3.4 years, there were 18 ischemic strokes and 5 transient ischemic attacks (event rate of 1.8% per year). The annual event rate was higher in the HPV-positive patients compared with the HPV-negative patients (2.6% versus 0.9%, P=0.002). In a multivariable model, HPV-positive status was associated with a >4 times increased risk of CVEs (hazard ratio: 4.4; 95% confidence interval, 1.5-13.2; P=0.008). CONCLUSIONS: In this study, HPV positive status is associated with an increased risk of stroke or transient ischemic attack following RT for head and neck cancer. PMID- 28855165 TI - Lower Mitochondrial Energy Production of the Thigh Muscles in Patients With Low Normal Ankle-Brachial Index. AB - BACKGROUND: Lower muscle mitochondrial energy production may contribute to impaired walking endurance in patients with peripheral arterial disease. A borderline ankle-brachial index (ABI) of 0.91 to 1.10 is associated with poorer walking endurance compared with higher ABI. We hypothesized that in the absence of peripheral arterial disease, lower ABI is associated with lower mitochondrial energy production. METHODS AND RESULTS: We examined 363 men and women participating in the Baltimore Longitudinal Study of Aging with an ABI between 0.90 and 1.40. Muscle mitochondrial energy production was assessed by post exercise phosphocreatine recovery rate constant (kPCr) measured by phosphorus magnetic resonance spectroscopy of the left thigh. A lower post-exercise phosphocreatine recovery rate constant reflects decreased mitochondria energy production.The mean age of the participants was 71+/-12 years. A total of 18.4% had diabetes mellitus and 4% were current and 40% were former smokers. Compared with participants with an ABI of 1.11 to 1.40, those with an ABI of 0.90 to 1.10 had significantly lower post-exercise phosphocreatine recovery rate constant (19.3 versus 20.8 ms-1, P=0.015). This difference remained significant after adjusting for age, sex, race, smoking status, diabetes mellitus, body mass index, and cholesterol levels (P=0.028). Similarly, post-exercise phosphocreatine recovery rate constant was linearly associated with ABI as a continuous variable, both in the ABI ranges of 0.90 to 1.40 (standardized coefficient=0.15, P=0.003) and 1.1 to 1.4 (standardized coefficient=0.12, P=0.0405). CONCLUSIONS: An ABI of 0.90 to 1.10 is associated with lower mitochondrial energy production compared with an ABI of 1.11 to 1.40. These data demonstrate adverse associations of lower ABI values with impaired mitochondrial activity even within the range of a clinically accepted definition of a normal ABI. Further study is needed to determine whether interventions in persons with ABIs of 0.90 to 1.10 can prevent subsequent functional decline. PMID- 28855166 TI - Role of Total, Red, Processed, and White Meat Consumption in Stroke Incidence and Mortality: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. AB - BACKGROUND: Previous meta-analyses on meat intake and risk of stroke did not report the effect of white meat (poultry meat, excluding fish) and did not examine stroke incidence and mortality separately. We aimed to investigate the relationship of total (red and processed meat), red (unprocessed or fresh red meat), and processed (processed red meat) consumption along with white meat on risk of stroke incidence and mortality. METHODS AND RESULTS: Articles were identified from databases and reference lists of relevant studies up to October 28, 2016. We selected prospective cohort studies on meat consumption specified by types of meat and stroke incidence and mortality reporting relative risks and 95% confidence intervals. The pooled relative risk was estimated using the random effects model. Based on the inclusion criteria, 10 articles containing 15 studies (5 articles with 7 studies including 9522 cases of stroke incidence and 254 742 participants and 5 articles with 8 studies containing 12 999 cases of stroke mortality and 487 150 participants) were selected for quantitative synthesis. The pooled relative risks (95% confidence intervals) for total, red, processed and white meat consumption and total stroke incidence were 1.18 (1.09-1.28), 1.11 (1.03-1.20), 1.17 (1.08-1.25), and 0.87 (0.78-0.97), respectively. Total meat consumption (0.97 [0.85-1.11]) and red meat consumption 0.87 (0.64-1.18) were not significantly associated with stroke-related death. CONCLUSIONS: The relationship between meat intake and risk of stroke may differ by type of meat. Recommendations for replacing proportions of red and processed meats to white meat for the prevention of stroke may be considered in clinical practice. PMID- 28855167 TI - Growth Differentiation Factor 15 Is Associated With Major Amputation and Mortality in Patients With Peripheral Artery Disease. AB - BACKGROUND: Peripheral artery disease (PAD) is one of the most common clinical presentations of atherosclerosis, and its prevalence is still increasing. Despite improvement of health care, morbidity and mortality risks remain high, including the risk of amputation. GDF15 (growth differentiation factor 15) is a member of the transforming growth factor family that is involved in apoptosis and inflammation; therefore, GDF15 is a potential biomarker to identify patients at high risk of adverse clinical outcomes. METHODS AND RESULTS: Circulating GDF15 levels were measured using a multiplex immunoassay in patients with critical limb ischemia and PAD from 2 different patient cohorts that included patients with clinically manifest PAD: the JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-Arterial Supplementation) trial (n=160, 67 major events; critical limb ischemia) and the Athero-Express Biobank (n=386, 64 major events; PAD). Kaplan-Meier curves demonstrated that high levels of GDF15 were associated with increased risk of major events, defined as major amputation (at or above the ankle joint) and all-cause mortality, in both cohorts (highest versus lowest, JUVENTAS: hazard ratio: 4.01 [95% confidence interval, 2.05-7.84; P<0.0001]; Athero-Express: hazard ratio: 3.27 [95% confidence interval, 1.64-6.54; P=0.0008]). In the JUVENTAS trial, this was more pronounced in women. Cox proportional multivariable regression models with median follow-up of 3 years, corrected for common confounders, showed hazard ratios of 1.70 (95% confidence interval, 1.18-2.69; P=0.0053) and 1.57 (95% confidence interval, 1.02-2.41; P=0.041) per 2.78-fold increase of GDF15 in JUVENTAS and Athero-Express, respectively. CONCLUSIONS: High GDF15 levels are associated with increased risk of major amputation and/or death in PAD patients. GDF15 levels could be of additive value to identify patients who are at high risk of amputation or death and could help guide treatment choices. PMID- 28855168 TI - Physical Activity Frequency and the Risk of Stroke: A Nationwide Cohort Study in Korea. AB - BACKGROUND: The current guideline recommends moderate- to vigorous-intensity physical activity (PA) at least 40 min/day for 3 to 4 days/week. Although recent evidence has demonstrated that low-dose PA could reduce cardiovascular mortality, the relationship between low-dose PA and the risk of stroke remains uncertain. METHODS AND RESULTS: Using data from a nation-wide sample cohort in Korea, we examined 336 326 individuals who received a general health examination between 2009 and 2010. Level of PA was assessed using a questionnaire for weekly PA frequencies regarding 3 intensity categories: light, moderate, and vigorous. Moderate- to vigorous-intensity PA (MVPA) was classified into 4 frequency categories: none, 1 to 2, 3 to 4, or >=5 times/week. Cox proportional hazard models were constructed to estimate the risk of stroke. During the average follow up of 3.6 years, 2213 stroke cases occurred. MVPA was none in 50%, 1 to 2 times/week in 20%, 3 to 4 times/week in 13%, and >=5 times/week in 18% of the cohort. Individuals with MVPA 1 to 2 times/week had a 16% reduced risk of stroke (adjusted hazard ratio, 0.84; 95% confidence interval, 0.73-0.96) compared with those with no MVPA. The population attributable fraction of no MVPA was 12%, which was the second most important risk factor for a stroke after hypertension. CONCLUSIONS: Even 1 to 2 times a week of MVPA might be beneficial to prevent a first-ever stroke in the general population, although a quantitative validation of the questionnaire is needed. From a public health perspective, we need to encourage inactive people to start exercising with more-achievable goals. PMID- 28855169 TI - Follicle-Stimulating Hormone, Its Association with Cardiometabolic Risk Factors, and 10-Year Risk of Cardiovascular Disease in Postmenopausal Women. AB - BACKGROUND: Cardiovascular disease is the leading cause of mortality in postmenopausal women. Follicle-stimulating hormone (FSH) shows negative associations with obesity and diabetes mellitus in postmenopausal women. We aimed to study the associations between FSH and 10-year risk of atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women. METHODS AND RESULTS: SPECT-China (the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors) is a 22-site, population-based study conducted during 2014-2015. This study included 2658 postmenopausal women. A newly developed effective tool for 10-year ASCVD risk prediction among Chinese was adopted. Regression analyses were performed to assess the relationship among FSH, 10-year ASCVD risk, and multiple cardiometabolic risk factors. With the increase in FSH quartiles, the mean 10-year ASCVD risk in postmenopausal women decreased from 4.9% to 3.3%, and most metabolic parameters were significantly ameliorated (all P for trend <0.05). In regression analyses, a 1-SD increment in ln-FSH was negatively associated with continuous (B -0.12, 95% confidence interval, -0.16, -0.09, P<0.05) and categorical (odds ratio 0.65, 95% confidence interval, 0.49, 0.85, P<0.05) 10 year ASCVD risk. These significant associations existed in subgroups with or without medication use, obesity, diabetes mellitus, hypertension, and dyslipidemia. Body mass index and waist circumference (both B -0.35, 95% confidence interval, -0.40, -0.30, P<0.05) had the largest associations of all metabolic measures, and blood pressure had the smallest association. CONCLUSIONS: Serum FSH levels were negatively associated with 10-year ASCVD risk in postmenopausal women. Among cardiometabolic factors, obesity indices had the largest associations with FSH. These results indicated that a low FSH might be a risk factor or a biomarker for cardiovascular disease risk in postmenopausal women. PMID- 28855170 TI - A Wide and Specific Spectrum of Genetic Variants and Genotype-Phenotype Correlations Revealed by Next-Generation Sequencing in Patients with Left Ventricular Noncompaction. AB - BACKGROUND: Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next generation sequencing and to evaluate genotype-phenotype correlations in LVNC patients. METHODS AND RESULTS: Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38%); 28 were novel variants. Sarcomere gene variants accounted for 63%, and variants in genes associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. CONCLUSIONS: Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely. PMID- 28855171 TI - Impact of Electronic Cigarettes on the Cardiovascular System. PMID- 28855172 TI - Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand. AB - OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. METHODS: We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. RESULTS: We found two significantly associated loci in the discovery set: at chr12 (p=3.5 * 10-10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1*10-9) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10-15). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10-16). CONCLUSIONS: Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification. PMID- 28855173 TI - Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. AB - OBJECTIVES: Interleukin-6 (IL-6) is implicated in rheumatoid arthritis (RA) pathophysiology. Unlike IL-6 receptor inhibitors, sirukumab is a human monoclonal antibody that selectively binds to the IL-6 cytokine. The phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study (ClinicalTrials.gov identifier NCT01604343) evaluated the efficacy and safety of sirukumab in patients with active RA refractory to disease-modifying antirheumatic drugs. METHODS: Patients were randomised 1:1:1 to treatment with sirukumab 100 mg every 2 weeks, 50 mg every 4 weeks or placebo every 2 weeks subcutaneously. Results through week 52 are reported. RESULTS: Of 1670 randomised patients, significantly more patients achieved American College of Rheumatology 20% (ACR20) response at week 16 (coprimary endpoint) with sirukumab 100 mg every 2 weeks (53.5%) or 50 mg every 4 weeks (54.8%) versus placebo (26.4%; both p<0.001). Mean (SD) change from baseline in modified Sharp/van der Heijde score at week 52 (coprimary endpoint) was significantly lower with sirukumab (100 mg every 2 weeks: 0.46 (3.26); 50 mg every 4 weeks: 0.50 (2.96)) versus placebo (3.69 (9.25); both p<0.001). All major secondary endpoints (week 24 Health Assessment Questionnaire-Disability Index change from baseline, ACR50 response, 28-joint Disease Activity Score based on C reactive protein and major clinical response (ACR70 for six continuous months by week 52)) were met. The most common adverse events with sirukumab were elevated liver enzymes, upper respiratory tract infection, injection site erythema and nasopharyngitis. CONCLUSIONS: Sirukumab 100 mg every 2 weeks and 50 mg every 4 weeks led to significant reductions in RA symptoms, inhibition of structural damage progression and physical function and quality of life improvements, with an expected safety profile. TRIAL REGISTRATION NUMBER: NCT01604343; Results. PMID- 28855175 TI - Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study. AB - OBJECTIVES: To investigate the association between infection or respiratory tract disease and future risk of developing idiopathic inflammatory myopathy (IIM). METHODS: A case-control study was performed using Swedish nationwide registers. Adults with newly diagnosed IIM were identified (2002-2011) from the National Patient Register (NPR) and the Swedish Rheumatology Register (n=957). Controls were matched by age, sex and place of residence (n=9476). Outpatient visits and hospitalisations preceding IIM diagnosis indicating infection or respiratory disease were identified from NPR. Conditional logistic regression models were used to calculate OR and 95% CI. Sensitivity analyses were performed by varying the exposure definition, adjusting for previous healthcare consumption and excluding individuals with connective tissue disease, IIM lung phenotype or IIM associated cancer. RESULTS: Preceding infections were more common in IIM cases compared with controls (13% vs 9%) and were associated with an increased risk of IIM (OR 1.5, 95% CI 1.2 to 1.9). Gastrointestinal and respiratory tract infections were associated with an increased risk of IIM while cutaneous infections were not.Preceding respiratory tract disease was present in 10% of IIM cases and 4% of controls (OR 2.3, 95% CI 1.8 to 3.0). Both upper and lower respiratory tract diseases were associated with an increased risk of IIM.Variations in exposure and outcome definitions did not greatly affect the results. CONCLUSIONS: Infections and respiratory tract diseases are associated with an increased risk of IIM which suggests that the triggering of the immune system may take place outside the skeletal muscle. PMID- 28855176 TI - Use of radiotelemetry to assess perinatal cardiac function in the ovine fetus and newborn. AB - The late gestation fetal ECG (fECG) has traditionally been difficult to characterize due to the low fECG signal relative to high maternal noise. Although new technologies have improved the feasibility of its acquisition and separation, little is known about its development in late gestation, a period in which the fetal heart undergoes extensive maturational changes. Here, we describe a method for the chronic implantation of radiotelemetry devices into late gestation ovine fetuses to characterize parameters of the fECG following surgery, throughout late gestation, and in the perinatal period. We found no significant changes in mean aortic pressure (MAP), heart rate (HR), or ECG in the 5 days following implantation; however, HR decreased in the first 24 h following the end of surgery, with associated increases in RR, PR, and QRS intervals. Over the last 14 days of fetal life, fetal MAP significantly increased, and HR significantly decreased, as expected. MAP and HR increased as labor progressed. Although there were no significant changes over time in the ECG during late gestation, the duration of the PR interval initially decreased and then increased as birth approached. These results indicate that although critical maturational changes occur in the late gestation fetal myocardium, the mechanisms that control the cardiac conduction are relatively mature in late gestation. The study demonstrates that radiotelemetry can be successfully used to assess fetal cardiac function, in particular conduction, through the process of labor and delivery, and may therefore be a useful tool for study of peripartum cardiac events. PMID- 28855177 TI - Small functional If current in sinoatrial pacemaker cells of the brown trout (Salmo trutta fario) heart despite strong expression of HCN channel transcripts. AB - Funny current (If), formed by hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels), is supposed to be crucial for the membrane clock regulating the cardiac pacemaker mechanism. We examined the presence and activity of HCN channels in the brown trout (Salmo trutta fario) sinoatrial (SA) pacemaker cells and their putative role in heart rate (fH) regulation. Six HCN transcripts (HCN1, HCN2a, HCN2ba, HCN2bb, HCN3, and HCN4) were expressed in the brown trout heart. The total HCN transcript abundance was 4.0 and 4.9 times higher in SA pacemaker tissue than in atrium and ventricle, respectively. In the SA pacemaker, HCN3 and HCN4 were the main isoforms representing 35.8 +/- 2.7 and 25.0 +/- 1.5%, respectively, of the total HCN transcripts. Only a small If with a mean current density of -1.2 +/- 0.37 pA/pF at -140 mV was found in 4 pacemaker cells out of 16 spontaneously beating cells examined, despite the optimization of recording conditions for If activity. If was not found in any of the 24 atrial myocytes and 21 ventricular myocytes examined. HCN4 coexpressed with the MinK-related peptide 1 (MiRP1) beta-subunit in CHO cells generated large If currents. In contrast, HCN3 (+MiRP1) failed to produce If in the same expression system. Cs+ (2 mM), which blocked 84 +/- 12% of the native If, reversibly reduced fH 19.2 +/- 3.6% of the excised multicellular pacemaker tissue from 53 +/- 5 to 44 +/- 5 beats/min (P < 0.05). However, this effect was probably due to the reduction of IKr, which was also inhibited (63.5 +/- 4.6%) by Cs+ These results strongly suggest that fH regulation in the brown trout heart is largely independent on If. PMID- 28855178 TI - Baroreflex and neurovascular responses to skeletal muscle mechanoreflex activation in humans: an exercise in integrative physiology. AB - Cardiovascular adjustments to exercise resulting in increased blood pressure (BP) and heart rate (HR) occur in response to activation of several neural mechanisms: the exercise pressor reflex, central command, and the arterial baroreflex. Neural inputs from these feedback and feedforward mechanisms integrate in the cardiovascular control centers in the brain stem and modulate sympathetic and parasympathetic neural outflow, resulting in the increased BP and HR observed during exercise. Another specific consequence of the central neural integration of these inputs during exercise is increased sympathetic neural outflow directed to the kidneys, causing renal vasoconstriction, a key reflex mechanism involved in blood flow redistribution during increased skeletal muscle work. Studies in humans have shown that muscle mechanoreflex activation inhibits cardiac vagal outflow, decreasing the sensitivity of baroreflex control of HR. Metabolite sensitization of muscle mechanoreceptors can lead to reduced sensitivity of baroreflex control of HR, with thromboxane being one of the metabolites involved, via greater inhibition of cardiac vagal outflow without affecting baroreflex control of BP or baroreflex resetting. Muscle mechanoreflex activation appears to play a predominant role in causing renal vasoconstriction, both in isolation and in the presence of local metabolites. Limited investigations in older adults and patients with cardiovascular-related disease have provided some insight into how the influence of muscle mechanoreflex activation on baroreflex function and renal vasoconstriction is altered in these populations. However, future research is warranted to better elucidate the specific effect of muscle mechanoreflex activation on baroreflex and neurovascular responses with aging and cardiovascular-related disease. PMID- 28855179 TI - Face cooling increases blood pressure during central hypovolemia. AB - A reduction in central blood volume can lead to cardiovascular decompensation (i.e., failure to maintain blood pressure). Cooling the forehead and cheeks using ice water raises blood pressure. Therefore, face cooling (FC) could be used to mitigate decreases in blood pressure during central hypovolemia. We tested the hypothesis that FC during central hypovolemia induced by lower-body negative pressure (LBNP) would increase blood pressure. Ten healthy participants (22 +/- 2 yr, three women, seven men) completed two randomized LBNP trials on separate days. Trials began with 30 mmHg of LBNP for 6 min. Then, a 2.5-liter plastic bag of ice water (0 +/- 0 degrees C) (LBNP+FC) or thermoneutral water (34 +/- 1 degrees C) (LBNP+Sham) was placed on the forehead, eyes, and cheeks during 15 min of LBNP at 30 mmHg. Forehead temperature was lower during LBNP+FC than LBNP+Sham, with the greatest difference at 21 min of LBNP (11.1 +/- 1.6 vs. 33.9 +/- 1.4 degrees C, P < 0.001). Mean arterial pressure was greater during LBNP+FC than LBNP+Sham, with the greatest difference at 8 min of LBNP (98 +/- 15 vs. 80 +/- 8 mmHg, P < 0.001). Cardiac output was higher during LBNP+FC than LBNP+Sham with the greatest difference at 18 min of LBNP (5.9 +/- 1.4 vs. 4.9 +/- 1.0 liter/min, P = 0.005). Forearm cutaneous vascular resistance was greater during LBNP+FC than LBNP+Sham, with the greatest difference at 15 min of LBNP (7.2 +/- 3.4 vs. 4.9 +/ 2.7 mmHg/perfusion units (PU), P < 0.001). Face cooling during LBNP increases blood pressure through increases in cardiac output and vascular resistance. PMID- 28855174 TI - The EuroMyositis registry: an international collaborative tool to facilitate myositis research. AB - AIMS: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data. METHODS: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtypes, extramuscular involvement, environmental exposures and medications were investigated. RESULTS: Of 3067 IIM cases, 69% were female. The most common IIM subtype was dermatomyositis (DM) (31%). Smoking was more frequent in connective tissue disease overlap cases (45%, OR 1.44, 95% CI 1.09 to 1.90, p=0.012). Smoking was associated with interstitial lung disease (ILD) (OR 1.32, 95% CI 1.06 to 1.65, p=0.013), dysphagia (OR 1.43, 95% CI 1.16 to 1.77, p=0.001), malignancy ever (OR 1.78, 95% CI 1.36 to 2.33, p<0.001) and cardiac involvement (OR 2.40, 95% CI 1.60 to 3.60, p<0.001).Dysphagia occurred in 39% and cardiac involvement in 9%; either occurrence was associated with higher Health Assessment Questionnaire (HAQ) scores (adjusted OR 1.79, 95% CI 1.43 to 2.23, p<0.001). HAQ scores were also higher in inclusion body myositis cases (adjusted OR 3.85, 95% CI 2.52 to 5.90, p<0.001). Malignancy (ever) occurred in 13%, most commonly in DM (20%, OR 2.06, 95% CI 1.65 to 2.57, p<0.001).ILD occurred in 30%, most frequently in antisynthetase syndrome (71%, OR 10.7, 95% CI 8.6 to 13.4, p<0.001). Rash characteristics differed between adult-onset and juvenile-onset DM cases ('V' sign: 56% DM vs 16% juvenile-DM, OR 0.16, 95% CI 0.07 to 0.36, p<0.001). Glucocorticoids were used in 98% of cases, methotrexate in 71% and azathioprine in 51%. CONCLUSION: This large multicentre cohort demonstrates the importance of extramuscular involvement in patients with IIM, its association with smoking and its influence on disease severity. Our findings emphasise that IIM is a multisystem inflammatory disease and will help inform prognosis and clinical management of patients. PMID- 28855181 TI - Evidence industry needs more humility and perspective on its role. PMID- 28855180 TI - Diet-induced obesity accelerates blood lactate accumulation of rats in response to incremental exercise to maximum. AB - Blood lactate increases during incremental exercise at high-intensity workloads, and limited exercise capacity is a characteristic of obese animals. This study examined whether blood lactate changes in response to incremental exercise is disrupted in obese animals. Muscular and hepatic proteins that are critical in lactate metabolism were also investigated. Rats were randomized to either standard chow (control) or high-fat diet (HFD) groups. All animals underwent an incremental treadmill test after 14 wk of diet intervention. Blood lactate levels were measured before and after the treadmill test. Activities of mitochondrial oxidative phosphorylation and glycolysis were examined in muscle tissues. Proteins in the liver and skeletal muscles that participate in the turnover of blood lactate were determined by Western blot. Running time in the incremental treadmill test decreased in the HFD group, and blood lactate accumulated faster in these animals than in the control group. Animals with HFD had a decreased level of hepatic monocarboxylate transporter 2, the protein responsible for blood lactate uptake in the liver. Skeletal muscles of animals with HFD showed greater glycolytic activity and decreased content of lactate dehydrogenase B, which converts lactate to pyruvate. We conclude that blood lactate accumulated faster during incremental exercise in obese animals and was associated with their decreased exercise performance. Changes in the metabolic pattern of muscles and changes of liver and muscle proteins associated with lactate utilization likely contribute to the abnormal response of blood lactate to incremental exercise in obese animals. PMID- 28855182 TI - Back to school to protect against coronary heart disease? PMID- 28855183 TI - Effectiveness of online tailored advice to prevent running-related injuries and promote preventive behaviour in Dutch trail runners: a pragmatic randomised controlled trial. AB - BACKGROUND: Trail running is popular worldwide, but there is no preventive intervention for running-related injury (RRI). AIM: To evaluate the effectiveness of adding online tailored advice (TrailS6 ) to general advice on (1) the prevention of RRIs and (2) the determinants and actual preventive behaviour in Dutch trail runners. METHODS: Two-arm randomised controlled trial over 6 months. 232 trail runners were randomly assigned to an intervention or control group. All participants received online general advice on RRI prevention 1 week after baseline. Every 2 weeks, participants in the intervention group received specific advice tailored to their RRI status. The control group received no further intervention. Bayesian mixed models were used to analyse the data. RESULTS: Trail runners in the intervention group sustained 13% fewer RRIs compared with those in the control group after 6 months of follow-up (absolute risk difference -13.1%, 95% Bayesian highest posterior credible interval (95% BCI) -23.3 to -3.1). A preventive benefit was observed in one out of eight trail runners who had received the online tailored advice for 6 months (number needed to treat 8, 95% BCI 3 to 22). No significant between-group difference was observed on the determinants and actual preventive behaviours. CONCLUSIONS: Online tailored advice prevented RRIs among Dutch trail runners. Therefore, online tailored advice may be used as a preventive component in multicomponent RRI prevention programmes. No effect was observed on determinants and actual preventive behaviours. TRIAL REGISTRATION NUMBER: The Netherlands National Trial Register (NTR5431). PMID- 28855184 TI - Creating a model of best practice: the match day emergency action protocol. PMID- 28855185 TI - Sports medicine highlights from other journals. PMID- 28855186 TI - Sports medicine highlights from other journals. PMID- 28855187 TI - Inhibition of smooth muscle contraction and ARF6 activity by the inhibitor for cytohesin GEFs, secinH3, in the human prostate. AB - Prostate smooth muscle contraction is critical for etiology and treatment of male lower urinary tract symptoms (LUTS) and is promoted by small monomeric GTPases (RhoA and Rac). GTPases may be activated by guanosine nucleotide exchange factors (GEFs). GEFs of the cytohesin family may indirectly activate Rac, or ADP ribosylation factor (ARF) GTPases directly. Here we investigated the expression of cytohesin family GEFs and effects of the cytohesin inhibitor Sec7 inhibitor H3 (secinH3) on smooth muscle contraction and GTPase activities in human prostate tissues. Of all four cytohesin isoforms, cytohesin-1 and -2 showed the highest expression in real-time PCR. Western blot and fluorescence staining suggested that cytohesin-2 may be the predominant isoform in prostate smooth muscle cells. Contractions induced by norepinephrine, the alpha1-adrenoceptor agonist phenylephrine, the thromboxane A2 analog U-46619 , and endothelin-1 and -3, as well as neurogenic contractions induced by electric field stimulation (EFS), were reduced by secinH3 (30 uM). Inhibition of EFS-induced contractions appeared to have efficacy similar to that of inhibition by the alpha1-adrenoceptor antagonist tamsulosin (300 nM). Combined application of secinH3 plus tamsulosin caused larger inhibition of EFS-induced contractions than tamsulosin alone. Pull-down assays demonstrated inhibition of the small monomeric GTPase ARF6 by secinH3, but no inhibition of RhoA or Rac1. In conclusion, we suggest that a cytohesin-ARF6 pathway takes part in smooth muscle contraction. This may open attractive new possibilities in medical treatment of male LUTS. PMID- 28855188 TI - An excitatory reflex from the superficial peroneal nerve to the bladder in cats. AB - This study in alpha-chloralose-anesthetized cats discovered an excitatory peroneal nerve-to-bladder reflex. A urethral catheter was used to infuse the bladder with saline and record bladder pressure changes. Electrical stimulation was applied to the superficial peroneal nerve to trigger reflex bladder activity. With the bladder distended at a volume ~90% of bladder capacity, superficial peroneal nerve stimulation (PNS) at 1-3 Hz and threshold (T) intensity for inducing muscle twitching on the posterior thigh induced large-amplitude (40-150 cmH2O) bladder contractions. PNS (1-3 Hz, 1-2T) applied during cystometrograms (CMGs) when the bladder was slowly (1-3 ml/min) infused with saline significantly (P < 0.01) reduced bladder capacity to ~80% of the control capacity and significantly (P < 0.05) enhanced reflex bladder contractions. To determine the impact of PNS on tibial nerve stimulation (TNS)-induced changes in bladder function, PNS was delivered following TNS. TNS of 30-min duration produced long lasting poststimulation inhibition and significantly (P < 0.01) increased bladder capacity to 140.5 +/- 7.6% of the control capacity. During the post-TNS inhibition period, PNS (1-3 Hz, 1-4T) applied during CMGs completely restored bladder capacity to the control level and significantly (P < 0.05) increased the duration of reflex bladder contractions to ~200% of control. The excitatory peroneal nerve-to-bladder reflex could also be activated by transcutaneous PNS using skin surface electrodes attached to the dorsal surface of the foot. These results raise the possibility of developing novel neuromodulation therapies to treat underactive bladder and nonobstructive urinary retention. PMID- 28855190 TI - Extracellular vesicles as immune mediators in response to kidney injury. AB - Important progress has been made on cytokine signaling in response to kidney injury in the past decade, especially cytokine signaling mediated by extracellular vesicles (EVs). For example, EVs released by injured renal tubular epithelial cells (TECs) can regulate intercellular communications and influence tissue recovery via both regulating the expression and transferring cytokines, growth factors, as well as other bioactive molecules at the site of injury. The effects of EVs on kidney tissue seem to vary depending on the sources of EVs; however, the literature data are often inconsistent. For example, in rodents EVs derived from mesenchymal stem cells (MSC-EVs) and endothelial progenitor cells (EPC-EVs) can have both beneficial and harmful effects on injured renal tissue. Caution is thus needed in the interpretation of these data as contradictory findings on EVs may not only be related to the origin of EVs, they can also be caused by the different methods used for EV isolation and the physiological and pathological states of the tissues/cells under which they were obtained. Here, we review and discuss our current understanding related to the immunomodulatory function of EVs in renal tubular repair in the hope of encouraging further investigations on mechanisms related to their antiinflammatory and reparative role to better define the therapeutic potential of EVs in renal diseases. PMID- 28855189 TI - Adenosine A1 receptor-operated calcium entry in renal afferent arterioles is dependent on postnatal maturation of TRPC3 channels. AB - Adenosine, a regulator of cardiovascular development and renal function, constricts renal afferent arterioles by inducing intracellular Ca2+ concentration ([Ca2+]i) elevation in smooth muscle cells (SMCs) via activation of its cognate A1 receptors (A1Rs). Mechanisms that underlie A1R-dependent [Ca2+]i elevation in renal vascular SMCs are not fully resolved. Whether A1R expression and function in preglomerular microvessels are dependent on postnatal kidney maturation is also unclear. In this study, we show that selective activation of A1Rs by 2 chloro-N6-cyclopentyladenosine (CCPA) does not stimulate store-operated Ca2+ entry in afferent arterioles isolated from neonatal pigs. However, CCPA-induced [Ca2+]i elevation is dependent on phospholipase C and transient receptor potential cation channel, subfamily C, member 3 (TRPC3). Basal [Ca2+]i was unchanged in afferent arterioles isolated from newborn (0-day-old) pigs compared with their 20-day-old counterparts. By contrast, CCPA treatment resulted in significantly larger [Ca2+]i in afferent arterioles from 20-day-old pigs. A1R protein expression levels in the kidneys and afferent arterioles were unaltered in 0- vs. 20-day-old pigs. However, the TRPC3 channel protein expression level was ~92 and 78% higher in 20-day-old pig kidneys and afferent arterioles, respectively. These data suggest that activation of A1Rs elicits receptor operated Ca2+ entry in porcine afferent arterioles, the level of which is dependent on postnatal maturation of TRPC3 channels. We propose that TRPC3 channels may contribute to the physiology and pathophysiology of A1Rs. PMID- 28855191 TI - Three-dimensional knee kinematic analysis during treadmill gait: Slow imposed speed versus normal self-selected speed. AB - OBJECTIVES: Whilst gait speed is variable between healthy and injured adults, the extent to which speed alone alters the 3D in vivo knee kinematics has not been fully described. The purpose of this prospective study was to understand better the spatiotemporal and 3D knee kinematic changes induced by slow compared with normal self-selected walking speeds within young healthy adults. METHODS: A total of 26 men and 25 women (18 to 35 years old) participated in this study. Participants walked on a treadmill with the KneeKG system at a slow imposed speed (2 km/hr) for three trials, then at a self-selected comfortable walking speed for another three trials. Paired t-tests, Wilcoxon signed-rank tests, Mann-Whitney U tests and Spearman's rank correlation coefficients were conducted using Stata/IC 14 to compare kinematics of slow versus self-selected walking speed. RESULTS: Both cadence and step length were reduced during slow gait compared with normal gait. Slow walking reduced flexion during standing (10.6 degrees compared with 13.7 degrees ; p < 0.0001), and flexion range of movement (ROM) (53.1 degrees compared with 57.3 degrees ; p < 0.0001). Slow walking also induced less adduction ROM (8.3 degrees compared with 10.0 degrees ; p < 0.0001), rotation ROM (11.4 degrees compared with 13.6 degrees ; p < 0.0001), and anteroposterior translation ROM (8.5 mm compared with 10.1 mm; p < 0.0001). CONCLUSION: The reduced spatiotemporal measures, reduced flexion during stance, and knee ROM in all planes induced by slow walking demonstrate a stiff knee gait, similar to that previously demonstrated in osteoarthritis. Further research is required to determine if these characteristics induced in healthy knees by slow walking provide a valid model of osteoarthritic gait.Cite this article: N. Mannering, T. Young, T. Spelman, P. F. Choong. Three-dimensional knee kinematic analysis during treadmill gait: Slow imposed speed versus normal self-selected speed. Bone Joint Res 2017;6:514-521. DOI: 10.1302/2046-3758.68.BJR-2016-0296.R1. PMID- 28855192 TI - The effect of implant position on bone strain following lateral unicompartmental knee arthroplasty: A Biomechanical Model Using Digital Image Correlation. AB - OBJECTIVES: Unicompartmental knee arthroplasty (UKA) is a demanding procedure, with tibial component subsidence or pain from high tibial strain being potential causes of revision. The optimal position in terms of load transfer has not been documented for lateral UKA. Our aim was to determine the effect of tibial component position on proximal tibial strain. METHODS: A total of 16 composite tibias were implanted with an Oxford Domed Lateral Partial Knee implant using cutting guides to define tibial slope and resection depth. Four implant positions were assessed: standard (5 degrees posterior slope); 10 degrees posterior slope; 5 degrees reverse tibial slope; and 4 mm increased tibial resection. Using an electrodynamic axial-torsional materials testing machine (Instron 5565), a compressive load of 1.5 kN was applied at 60 N/s on a meniscal bearing via a matching femoral component. Tibial strain beneath the implant was measured using a calibrated Digital Image Correlation system. RESULTS: A 5 degrees increase in tibial component posterior slope resulted in a 53% increase in mean major principal strain in the posterior tibial zone adjacent to the implant (p = 0.003). The highest strains for all implant positions were recorded in the anterior cortex 2 cm to 3 cm distal to the implant. Posteriorly, strain tended to decrease with increasing distance from the implant. Lateral cortical strain showed no significant relationship with implant position. CONCLUSION: Relatively small changes in implant position and orientation may significantly affect tibial cortical strain. Avoidance of excessive posterior tibial slope may be advisable during lateral UKA.Cite this article: A. M. Ali, S. D. S. Newman, P. A. Hooper, C. M. Davies, J. P. Cobb. The effect of implant position on bone strain following lateral unicompartmental knee arthroplasty: A Biomechanical Model Using Digital Image Correlation. Bone Joint Res 2017;6:522-529. DOI: 10.1302/2046-3758.68.BJR 2017-0067.R1. PMID- 28855193 TI - Risk of corneal ulcer in patients with end-stage renal disease: a retrospective large-scale cohort study. AB - BACKGROUND/AIMS: To investigate the risk of corneal ulcer in patients with end stage renal disease (ESRD). METHODS: This retrospective, nationwide, matched cohort study included 92 967 patients with ESRD recruited between 2000 and 2009 from the Taiwan National Health Insurance Research Database. The same number of age-matched and sex-matched patients without ESRD were selected from the Taiwan Longitudinal Health Insurance Database, 2000 as the control group. Data for each patient were collected from the index date until December 2011. Corneal ulcer incidence rate and risk were compared between the groups. A Cox proportional hazards regression was used to calculate the HR for a corneal ulcer after adjustment for potential confounders. The cumulative corneal ulcer incidence rate was calculated using Kaplan-Meier analysis. RESULTS: In total, 660 patients with ESRD and 591 controls showed a corneal ulcer during follow-up; thus, the corneal ulcer incidence rate in patients with ESRD was 1.54 times (95% CI 1.38-1.72) that in the control patients. After adjustment for potential confounders, including diabetes mellitus and HIV disease, patients with ESRD were 1.17 times (95% CI 1.03 to 1.33) more likely to develop a corneal ulcer in the cohort for the total sample. Among patients with diabetes mellitus, the corneal ulcer incidence rate was significantly higher in the ESRD group, and diabetes mellitus significantly increased corneal ulcer risk even after adjustment for other confounders in the cohort. CONCLUSION: ESRD increases the risk of a corneal ulcer, particularly in patients with ESRD with diabetes mellitus. Regular ocular examinations are suggested for patients with ESRD. PMID- 28855194 TI - Keratopigmentation with micronised mineral pigments: complications and outcomes in a series of 234 eyes. AB - AIM: To report the complications observed in a consecutive large series of cases treated with keratopigmentation (KTP). METHODS: KTP was performed in 234 eyes of 204 patients for therapeutic and cosmetic reasons. From them, 50 eyes of 29 patients suffered complications. Different KTP techniques and three generations of pigments (GP) were used. The follow-up period ranged from 4 months to 12 years. Light sensitivity (LS), visual field (VF) limitations and MRI alterations were considered functional complications. Organic complications were described as change in colour, colour fading and neovascularisation. RESULTS: The percentage of complications was 12.82%. Most patients complained of LS (49%), then colour fading and change in colour (19%). Neovascularisation, VF limitations and MRI complications constituted 7%, 4% and 2%, respectively. Organic complications were observed with the previous GP but resolved with the latest third GP with CE mark certification (Conformite Europeene). Although LS remained with the corneal specific pigments, it gradually disappeared in most of the patients (81.81%) 6 months postoperatively. CONCLUSION: To the best of our knowledge this is the first time a study systematically and comprehensively approaches and reports KTP complications. KTP with third GP provides better results and fewer complications than previous ones. It is a modern, minimally invasive technique that helps solve several functional ocular problems and improves cosmetic appearance of the patients. Dermatological pigments should not be used as they lead to complications; instead pigments specifically tested for the eye in terms of toxicity and teratogenicity should be used. PMID- 28855195 TI - Prevalence and risk factors for diabetic retinopathy in China: a multi-hospital based cross-sectional study. AB - PURPOSE: To determine the prevalence and risk factors for diabetic retinopathy (DR) and sight-threatening diabetic retinopathy (STDR) in a multi-hospital-based DR screening programme among patients with diabetes in China, the Lifeline Express Diabetic Retinopathy Screening Program. METHODS: Patients with diabetes in eight hospitals across mainland China (both southern and northern) from January 2014 to July 2016 were recruited in this programme. All participants underwent a standardised interview and examinations and received digital fundus photography. DR severity was graded from retinal fundus photographs by retina specialists in the reading centre of Joint Shantou International Eye Center, according to the grading standards of the English National Screening Programme. STDR was defined as the presence of preproliferative DR (R2), proliferative DR (R3) and/or maculopathy (M1). RESULTS: 16 305 patients with diabetes were screened for DR in total. Fundus photographs were gradable for 15 078 patients (92.5%). The age-gender-standardised prevalence of any DR and STDR was 27.9% (95% CI, 27.2% to 28.6%) and 12.6% (95% CI, 12.1% to 13.1%), respectively. In the multiple logistic regression analysis, younger age (OR, 0.967), longer duration of diabetes (OR, 1.093), higher haemoglobin A1c (OR, 1.115), higher fasting plasma glucose (OR, 1.074), higher systolic blood pressure (OR, 1.014), faster heart rate (OR, 1.010), higher low-density lipoprotein (OR, 1.149), lower triglycerides (OR, 0.975), higher blood urea nitrogen (BUN) (OR, 1.012) and elevated serum creatinine level (OR, 1.003) were associated with the presence of DR. Similar risk factors, except for BUN and triglycerides, were found for STDR. CONCLUSIONS: The prevalence of DR and STDR in diabetes was 27.9% and 12.6%, respectively in this multi-hospital-based population across China. Compared with Western population with diabetes, similar risk factors for DR and STDR were found in Chinese patients with diabetes. PMID- 28855196 TI - A worldwide survey of retinopathy of prematurity screening. AB - BACKGROUND: To ascertain which countries in the world have retinopathy of prematurity (ROP) screening programmes and guidelines and how these were developed. METHODS: An email database was created and requests were sent to ophthalmologists in 141 nations to complete an online survey on ROP screening in their country. RESULTS: Representatives from 92/141 (65%) countries responded. 78/92 (85%) have existing ROP screening programmes, and 68/78 (88%) have defined screening criteria. Some countries have limited screening and those areas which have no screening or for which there is inadequate knowledge are mainly Southeast Asia, Africa and some former Soviet states. DISCUSSION: With the increasing survival of premature babies in lower-middle-income and low-income countries, it is important to ensure that adequate ROP screening and treatment is in place. This information will help organisations focus their resources on those areas most in need. PMID- 28855197 TI - Optical coherence tomography angiography reproducibility of lesion size measurements in neovascular age-related macular degeneration (AMD). AB - PURPOSE: To evaluate the reproducibility and interuser agreement of measurements of choroidal neovascularisation in optical coherence tomography angiography (OCTA). DESIGN: Prospective non-interventional study. METHODS: Consecutive patients, presenting with neovascular age-related macular degeneration (AMD), underwent two sequential OCTA examinations (AngioVue, Optovue, Fremont, California, USA), performed by the same trained examiner. Neovascular lesion area was then measured on both examinations in the choriocapillaris automatic segmentation by two masked readers, using the semiautomated measuring software embedded in the instrument. Two measuring features were used: the first corresponding to the total manually contoured lesion area with the flow draw tool (select area) and the second to the total area of solely vessels with high flow within the lesion (vessel area). These measurements were then compared in order to assess both the reproducibility of OCTA examination and the interuser agreement with the embedded software. RESULTS: Forty-eight eyes of 46 patients (77.4 mean age,+/-8.2 SD, range from 62 to 95 years old, eight men, 38 women) were included in our study. Mean choroidal neovascularisation area was of 0.72+/ 0.7 mm2 for the first measurement and 0.75+/-0.76 mm2 for the second measurement; difference between the first and the second measurement was 0.03 mm2. Intrauser agreement was of 0.98 (CI 0.98 to 0.99) for both 'vessel area' and 'select area' features. Interuser agreement was of 0.98 (CI 0.97 to 0.99) for 'select area' and 'vessel area' features. CONCLUSION: Our data suggest that OCTA provide reproducible imaging for evaluation of the neovascular size in the setting of AMD. PMID- 28855198 TI - Diagnostic accuracy of optical coherence tomography for diagnosing glaucoma: secondary analyses of the GATE study. AB - BACKGROUND/AIMS: To assess the diagnostic performance of retinal nerve fibre layer (RNFL) data of optical coherence tomography (OCT) for detecting glaucoma. METHODS: Secondary analyses of a prospective, multicentre diagnostic study (Glaucoma Automated Tests Evaluation (GATE)) referred to hospital eye services in the UK were conducted. We included data from 899 of 966 participants referred to hospital eye services with suspected glaucoma or ocular hypertension. We used both eyes' data and logistic regression-based receiver operator characteristics analysis to build a set of models to measure the sensitivity and specificity of the average and inferior quadrant RNFL thickness data of OCT. The reference standard was expert clinician examination including automated perimetry. The main outcome measures were sensitivity at 0.95 specificity and specificity at 0.95 sensitivity and the corresponding RNFL thickness thresholds. We explored the possibility of accuracy improvement by adding measures of within-eye and between eye variation, scan quality, intraocular pressure (IOP) and age. RESULTS: Glaucoma was diagnosed in at least one eye in 17% of participants. Areas under the curve were between 0.83 and 0.88. When specificity was fixed at 0.95, the sensitivity was between 0.38 and 0.55, and the highest values were reached with models including the inferior quadrant rather than the average RNFL thickness. Fixing sensitivity at 0.95, the specificity was between 0.36 and 0.58. The addition of age, refractive error, IOP or within-subject variation did not improve the accuracy. CONCLUSION: RNFL thickness data of OCT can be used as a diagnostic test, but accuracy estimates remain moderate even in exploratory multivariable modelling of aiming to improve accuracy. PMID- 28855199 TI - Prevalence and associated factors of diabetic retinopathy in Beijing, China: a cross-sectional study. AB - OBJECTIVES: The study aimed to determine the exact risk factors for diabetic retinopathy (DR) in the Chinese population using a cohort of 17 985 individuals from Beijing, China. DESIGN: Cross-sectional study. SETTING: A hospital. PARTICIPANTS: 17 985 individuals from Beijing, China. PRIMARY AND SECONDARY OUTCOME MEASURES: This was a cross-sectional study of permanent residents from the Changping area (Beijing, China) recruited from July 2010 to March 2011 and from March 2014 to February 2015 during a routine health examination at the Tongren Hospital of Beijing. Eye examinations were conducted by experienced ophthalmologists. Medical history, height, weight, body mass index (BMI) and blood pressure were recorded. Routine laboratory examinations were performed. RESULTS: The prevalence of DR was 1.5% in the general study population and 8.1% among individuals with diabetes. Compared with the non-DR group, individuals in the DR group in the diabetes population had longer disease duration, higher systolic blood pressure (SBP), fasting plasma glucose (FPG) and uric acid (UA) (in men) and lower UA (in women) (all p<0.05). The multivariate analysis showed that disease duration (p<0.001), BMI (p=0.046), SBP (p=0.012), creatinine clearance rate (CCR) (p=0.014), UA (p=0.018) and FPG (p<0.001) were independently associated with DR in patients with diabetes. CONCLUSION: The prevalence of DR was 8.1% among patients with diabetes. Disease duration, BMI, SBP, CCR, UA and FPG were independently associated with DR. PMID- 28855200 TI - Real-world validation of the minimal disease activity index in psoriatic arthritis: an analysis from a prospective, observational, biological treatment registry. AB - OBJECTIVE: To describe the minimal disease activity (MDA) rate over time in patients with psoriatic arthritis (PsA) receiving antitumour necrosis factor agents, evaluate prognostic factors of MDA achievement and identify the most common unmet criteria among MDA achievers. DESIGN: Biologic Treatment Registry Across Canada (BioTRAC): ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis, ankylosing spondylitis or PsA with infliximab (IFX), golimumab (GLM) or ustekinumab. SETTING: 46 primary-care Canadian rheumatology practices. PARTICIPANTS: 223 patients with PsA receiving IFX (enrolled since 2005) and GLM (enrolled since 2010) with available MDA information at baseline, 6 months and/or 12 months. PRIMARY AND SECONDARY OUTCOME MEASURES: MDA was defined as >=5 of the following criteria: 28-item tender joint count (TJC28) <=1, 28-item swollen joint count (SJC28) <=1, Psoriasis Area and Severity Index (PASI) <=1 or body surface area<=3, Pain Visual Analogue Scale (VAS) <=15 mm, patient's global assessment (PtGA) (VAS) <=20 mm, Health Assessment Questionnaire (HAQ) <=0.5, tender entheseal points <=1. Independent prognostic factors of MDA achievement were assessed with multivariate logistic regression. RESULTS: MDA was achieved by 11.7% of patients at baseline, 43.5% at 6 months, 44.8% at 12 months and 48.8% at either 6 or 12 months. Among MDA achievers at 6 months, 75.7% had sustained MDA at 12 months. Lower baseline HAQ (OR=0.210; 95% CI: 0.099 to 0.447) and lower TJC28 (OR=0.880; 95% CI: 0.804 to 0.964), were significant prognostic factors of MDA achievement over 12 months of treatment. The most commonly unmet MDA criteria among MDA achievers was patient reported pain (25%), PtGA (15%) and PASI (12%). CONCLUSIONS: Almost 50% of patients treated with IFX or GLM in routine clinical care achieved MDA within the first year of treatment. Lower baseline HAQ and lower TJC28, were identified as significant prognostic factors of MDA achievement. The most commonly unmet criteria in patients who achieved MDA were pain, PtGA and PASI. TRIAL REGISTRATION NUMBER: BioTRAC (NCT00741793). PMID- 28855201 TI - Intersectoral approaches and integrated services in achieving the right to health for refugees upon resettlement: a scoping review protocol. AB - INTRODUCTION: Global insecurity and climate change are exacerbating the need for improved management of refugee resettlement services. International standards hold states responsible for the protection of the right of non-citizens to an adequate standard of physical and mental health while recognising the importance of social determinants of health. However, programmes to protect refugees' right to health often lack coordination and monitoring. This paper describes the protocol for a scoping review to explore barriers and facilitators to the integration of health services for refugees; the content, process and actors involved in protecting refugee health; and the extent to which intersectoral approaches are leveraged to protect refugees' right to health on resettlement, especially for vulnerable groups such as women and children. METHODS AND ANALYSIS: Peer-reviewed (through four databases including MEDLINE, Web of Science, Global Health and PsycINFO) and grey literature were searched to identify programmes and interventions designed to promote refugee health in receiving countries. Two reviewers will screen articles and abstract data. Two frameworks for integration and intersectoral action will be applied to understand how and why certain approaches work while others do not and to identify the actors involved in achieving success at different levels of integration as defined by these frameworks. ETHICS AND DISSEMINATION: Findings from the scoping review will be shared in relevant conferences and meetings. A brief will be created with lessons learnt from successful programmes to inform decision making in design of refugee programmes and services. Ethical approval is not required as human subjects are not involved. TRIAL REGISTRATION NUMBER: Registered on Open Science Framework at https://osf.io/gt9ck/. PMID- 28855203 TI - Correction: Do cognitive interventions improve general cognition in dementia? a meta-analysis and meta-regression. PMID- 28855202 TI - Protocol for a mixed studies systematic review on the implementation of the recovery approach in adult mental health services. AB - INTRODUCTION: Recovery is integral to mental health planning in G-8 countries including Canada. A recovery-oriented approach to care aims to promote personal empowerment, illness self-management and a life beyond services for people with serious mental illness (SMI), while reducing the financial burden associated with mental illness. Although there is a growing body of literature on recovery, no synthesis of research on the implementation of recovery into mental health services exists. OBJECTIVES: The objective is to conduct a mixed studies systematic review on the operationalisation of recovery into mental health services for adults with SMI. It will inform the transformation of Canadian services to a recovery orientation, but may be applicable to other countries. METHODS AND ANALYSIS: Seven databases including PubMed, Ovid Medline, Ovid Embase, Ovid PsycInfo, CINAHL, the Cochrane Library and Scopus will be searched for peer-reviewed empirical studies published from 1998 to December 2016. Systematic reviews and studies using quantitative, qualitative and mixed methodologies will be included. Secondary searches will be conducted in reference lists of all selected full text articles. Handsearches will also be performed in the tables of contents of three recovery-focused journals for the last 5 years. International experts in the field will be contacted for comments and advice. Data extraction will include identification and methodological synthesis of each study; definition of recovery; information on recovery implementation; facilitators and barriers and study outcomes. A quality assessment will be conducted on each study. The data will be synthesised and a stepwise thematic analysis performed. ETHICS AND DISSEMINATION: Ethics approval is not required for this knowledge synthesis. Findings will be disseminated through knowledge translation activities including: (1) a 1-day symposium; (2) presentations in national and international conferences and to local stakeholders; (3) publications in peer-reviewed journals; (4) posts on the organisational websites. PMID- 28855204 TI - Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid-Induced PKCdelta Isoform Activation. AB - RATIONALE: Activation of monocytes/macrophages by hyperlipidemia associated with diabetes mellitus and obesity contributes to the development of atherosclerosis. PKCdelta (protein kinase C delta) expression and activity in monocytes were increased by hyperlipidemia and diabetes mellitus with unknown consequences to atherosclerosis. OBJECTIVE: To investigate the effect of PKCdelta activation in macrophages on the severity of atherosclerosis. METHODS AND RESULTS: PKCdelta expression and activity were increased in Zucker diabetic rats. Mice with selective deletion of PKCdelta in macrophages were generated by breeding PKCdelta flox/flox mice with LyzM-Cre and ApoE-/- mice (MPKCdeltaKO/ApoE-/- mice) and studied in atherogenic (AD) and high-fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD-fed mice had insulin resistance and mild diabetes mellitus. Surprisingly, MPKCdeltaKO/ApoE-/- mice exhibited accelerated aortic atherosclerotic lesions by 2-fold versus ApoE-/- mice on AD or HFD. Splenomegaly was observed in MPKCdeltaKO/ApoE-/- mice on AD and HFD but not on regular chow. Both the AD or HFD increased macrophage number in aortic plaques and spleen by 1.7- and 2-fold, respectively, in MPKCdeltaKO/ApoE-/- versus ApoE-/ mice because of decreased apoptosis (62%) and increased proliferation (1.9 fold), and not because of uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKCdeltaKO/ApoE-/- were associated with elevated phosphorylation levels of prosurvival cell-signaling proteins, Akt and FoxO3a, with reduction of proapoptotic protein Bim associated with PKCdelta induced inhibition of P85/PI3K. CONCLUSIONS: Accelerated development of atherosclerosis induced by insulin resistance and hyperlipidemia may be partially limited by PKCdelta isoform activation in the monocytes, which decreased its number and inflammatory responses in the arterial wall. PMID- 28855206 TI - HIF-2alpha Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1. AB - Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2alpha may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF 2alpha upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro We also found that HIF-2alpha strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452-63. (c)2017 AACR. PMID- 28855207 TI - Shrimp miR-S8 Suppresses the Stemness of Human Melanoma Stem-like Cells by Targeting the Transcription Factor YB-1. AB - Cross-species regulation of gene expression by microRNA is a possible untapped opportunity for miRNA-based therapy. In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discovered that the shrimp microRNA miR-S8 could suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations revealed that miR-S8 recognized the 3'UTR of YB 1 mRNA and mediated its degradation. In tumor cell and xenograft experiments, miR S8 suppressed the tumorigenic capacity of melanoma stem-like cells by targeting human YB-1. Overall, our results illuminated a novel aspect of miRNA-mediated cross-species gene expression and its use in regulating cancer stem-like cells. Cancer Res; 77(20); 5543-53. (c)2017 AACR. PMID- 28855209 TI - Therapeutic Targeting of Oncogenic Tyrosine Phosphatases. AB - Protein tyrosine phosphatases (PTP) are exciting and novel targets for cancer drug discovery that work in concert with protein tyrosine kinases (PTK) in controlling cellular homeostasis. Given the activating role that some PTKs play in initiating growth factor-mediated cellular processes, PTPs are usually perceived as the negative regulators of these events and therefore tumor suppressive in nature. However, mounting evidence indicate that PTPs do not always antagonize the activity of PTKs in regulating tyrosine phosphorylation, but can also play dominant roles in the initiation and progression of signaling cascades that regulate cell functions. It follows, therefore, that PTP malfunction can actively contribute to a host of human disorders, in particular, cancer, metabolic syndromes, and autoimmune diseases. The Src homology domain containing phosphatase 2 (SHP2) and the three-membered family of phosphatases of regenerating liver (PRL) are infamously oncogenic members of the PTP superfamily. Both are established regulators of major cancer pathways such as Ras/ERK1/2, Src, JAK/STAT, JNK, NF-kappaB, and PTEN/PI3K/AKT. Furthermore, upregulation, mutation, or other dysregulation of these PTPs has been positively correlated with cancer initiation and progression. This review will provide topical coverage of target validation and drug discovery efforts made in targeting these oncogenic PTPs as compelling candidates for cancer therapy. Cancer Res; 77(21); 5701-5. (c)2017 AACR. PMID- 28855208 TI - Bone-Induced Expression of Integrin beta3 Enables Targeted Nanotherapy of Breast Cancer Metastases. AB - Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin beta3 (beta3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, beta3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, beta3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFbeta signaling through SMAD2/SMAD3 was necessary for breast cancer induction of beta3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin alphavbeta3 (alphavbeta3-MPs of ~12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with alphavbeta3-MP-docetaxel exhibited a significant decrease in bone residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin alphavbeta3 at that metastatic site. Cancer Res; 77(22); 6299-312. (c)2017 AACR. PMID- 28855211 TI - The Blebbishield Emergency Program Overrides Chromosomal Instability and Phagocytosis Checkpoints in Cancer Stem Cells. AB - Genomic instability and immune evasion are hallmarks of cancer. Apoptotic cancer stem cells can evade cell death by undergoing cellular transformation by constructing "blebbishields" from apoptotic bodies. In this study, we report a novel linkage between genomic instability and phagocytosis evasion that is coordinated by the blebbishield emergency program. Blebbishield emergency program evaded genomic instability checkpoint, expressed genomic instability-associated genes at distinct phases of cellular transformation, exhibited chromosomal instability, and promoted increase in nuclear size. Blebbishields fused with immune cells to evade phagocytosis, and the resultant hybrid cells exhibited increased migration, tumorigenesis, metastasis, red blood cell recruitment to tumors, and induced hepatosplenomegaly with signatures of genomic instability, blebbishield emergency program, and phagocytosis evasion to offer poor prognosis. Overall, our data demonstrate that the blebbishield emergency program drives evasion of chromosomal instability and phagocytosis checkpoints by apoptotic cancer stem cells. Cancer Res; 77(22); 6144-56. (c)2017 AACR. PMID- 28855210 TI - CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy. AB - Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2-driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFbeta genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFbeta or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. Cancer Res; 77(20); 5652-63. (c)2017 AACR. PMID- 28855214 TI - Cyclopia: isolated and with agnathia-otocephaly complex. AB - Cyclopia is a rare form of lethal holoprosencephaly (HPE) due to incomplete cleavage of prosencephalon during embryogenesis, leading to failure of the orbits of the eye to divide into two cavities. We report two cases, one with cyclopia and another case of cyclopia with agnathia-otocephaly complex (AOC). AOC (also known as agnathia-microstomia-synotia syndrome) is a rare lethal congenital malformation of the first branchial arch characterised by the association of agnathia (agenesis of mandible) or mandibular hypoplasia, melotia (anteromedial malposition of ears), microstomia (small mouth), aglossia or microglossia (absent or rudimentary tongue). These two reported cases had in common a single eye and alobar HPE. The first case was live born and the second stillborn. Both mothers did not have antenatal care. PMID- 28855212 TI - Sensitivity to BUB1B Inhibition Defines an Alternative Classification of Glioblastoma. AB - Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires BUB1B to suppress lethal kinetochore-microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resistant (BUB1BR) subtypes. Through this effort, we found that BUB1BS patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1BS cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1BR/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment. Cancer Res; 77(20); 5518-29. (c)2017 AACR. PMID- 28855213 TI - Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587. AB - Tumor-stromal communications impact tumorigenesis in ways that are incompletely understood. Here, we show that glioma-associated human mesenchymal stem cells (GA hMSC), a newly identified stromal component of glioblastoma, release exosomes that increase the proliferation and clonogenicity of tumor-initiating glioma stem like cells (GSC). This event leads to a significantly greater tumor burden and decreased host survival compared with untreated GSCs in orthotopic xenografts. Analysis of the exosomal content identified miR-1587 as a mediator of the exosomal effects on GSCs, in part via downregulation of the tumor-suppressive nuclear receptor corepressor NCOR1. Our results illuminate the tumor-supporting role for GA-hMSCs by identifying GA-hMSC-derived exosomes in the intercellular transfer of specific miRNA that enhance the aggressiveness of glioblastoma. Cancer Res; 77(21); 5808-19. (c)2017 AACR. PMID- 28855215 TI - Gemcitabine-induced chronic systemic capillary leak syndrome. AB - A 56-year-old woman presented with anasarca, hypoalbuminaemia and hypotension following cycle 3 day 1 of adjuvant gemcitabine for stage II pancreatic cancer. Due to the temporal nature of presentation, suspicion for gemcitabine-induced capillary leak syndrome was included in the differential diagnosis. Vascular endothelial growth factor levels were elevated at 707 pg/mL (reference range: 9 86 pg/mL). Corticosteroids were initiated, resulting in complete resolution of symptoms and hypotension. The patient suffered relapse of symptoms on discontinuation of steroids, further supporting chronic capillary leak syndrome. PMID- 28855216 TI - Osteoma of the hyoid: an unusual cause of a neck lump. AB - A 65-year-old man with a 2-month history of left-sided neck swelling presented through the cancer pathway. There was no associated 'red flag' symptoms, and clinical examination revealed a left anterior triangle, non-pulsatile firm swelling atypical of a lymph node. Ultrasound scan imaging confirmed a complex structure with an echogenic centre and hypoechoic periphery, which was confirmed on CT as an osteoma of the hyoid.This is an extremely unusual cause of a neck lump, and an extensive literature review revealed only two previously documented cases. PMID- 28855217 TI - Decreased severity of Shiga toxin-producing Escherichia coli haemolytic uraemic syndrome (STEC-HUS) in a child with type 1 von Willebrand disease. AB - Shiga toxin-producing Escherichia coli-associated haemolytic uraemic syndrome (STEC-HUS) is characterised by haemolytic anaemia, thrombocytopenia and acute kidney injury. Von Willebrand Factor (vWF) is an important mediator of normal thrombi formation and indirect evidence suggests that vWF may play an important role in Shiga toxin-induced thrombi formation. Clinical evidence supporting the role of vWF in STEC-HUS is lacking. A 10-year-old girl with type 1 von Willebrand Disease (vWD) had a mild case of STEC-HUS, with nadir haemoglobin 7.3 g/dL and platelet count 105*109 cells/L and peak serum creatinine 0.56 mg/L and lactate dehydrogenase 741 U/L. This is the first report of STEC-HUS in a patient with vWD. We speculate that the quantitative deficiency of vWF associated with type 1 vWD may have attenuated the course of disease by reducing platelet aggregation, complement activation and thrombi formation. This case adds to a growing literature supporting a link between vWF and STEC-HUS. PMID- 28855218 TI - Primary mediastinal seminoma presenting with superior vena caval obstruction. PMID- 28855219 TI - Dural ectasia associated with Mounier-Kuhn syndrome: a novel association in the context of spinal stenosis. AB - We present the case of a patient undergoing lumbar spine decompression for stenosis with a history of Mounier-Kuhn syndrome. The patient presented with axial lumbar spine pain over 6 months with progressive radicular pain to the left L3 dermatome. MRI confirmed spinal stenosis at L3/4 level with associated dural ectasia. The patient had an uneventful spinal decompression with resolution of radicular symptoms and axial spine pain. Dural ectasia poses a significant risk when operating on the lumbosacral spine. Larger cerebrospinal fluid volumes and a capacious dural canal can result in anaesthetic and orthopaedic complications such as inadequate spinal anaesthesia, complicated epidural analgesia, intraoperative dural tears and difficult pedicle screw insertion due to narrow pedicles. This is the first case in the literature detailing the association between dural ectasia and Mounier-Kuhn syndrome. We recommend adequate spinal imaging in patients with Mounier-Kuhn syndrome to exclude dural ectasia prior to undergoing lumbosacral spinal procedures. PMID- 28855220 TI - Duplex gall bladder: bystander or culprit. AB - Gall bladder (GB) duplication is a rare anatomical malformation, which can be detected by preoperative imaging study. We present a case of duplex gall bladder in a 14-year-old boy who presented with abdominal pain. On ultrasound, he had right nephrolithiasis and duplex gall bladder. Duplex gall bladder was confirmed on MR cholangiopancreatography. There was a dilemma for surgical management of duplex gall bladder; however, he became asymptomatic after conservative treatment. Prophylactic surgery is not recommended for asymptomatic incidentally detected duplex gall bladder. Radiologists and paediatric surgeons should be sensitised about the exact anatomy of this entity. PMID- 28855221 TI - Composite End Points: Implications of Changing Compositions With Longer Follow Up. PMID- 28855222 TI - Practice Patterns and In-Hospital Outcomes Associated With Bivalirudin Use Among Patients With Non-ST-Segment-Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention in the United States. AB - BACKGROUND: Practice patterns in anticoagulant strategies used during percutaneous coronary intervention (PCI) in the United States for patients with non-ST-segment-elevation myocardial infarction and the comparative outcomes between bivalirudin and unfractionated heparin (UFH) have not been well described. METHODS AND RESULTS: Trends in anticoagulant use were examined among 553 562 PCIs performed by 9254 operators at 1538 hospitals for non-ST-segment elevation myocardial infarction from 2009 to 2014 within the CathPCI Registry. To compare bivalirudin with UFH, propensity score matching and instrumental variable (IV) methods with operator preference for bivalirudin as the instrument were used. To determine whether differences in outcomes were because of differences in glycoprotein IIb/IIIa inhibitor (GPI) use, a test of mediation was performed using the IV. Outcomes were in-hospital bleeding and mortality. Bivalirudin use increased from 2009 to 2013 but declined during 2014. GPI use was 50.5% during UFH PCIs and 12.0% during bivalirudin PCIs. Before GPI adjustment, bleeding reductions with bivalirudin ranged from 2.04% (IV: 95% confidence interval [CI]: 1.81%, 2.27%) to 2.29% (propensity score: 95% CI: 2.14%, 2.44%) and mortality reductions ranged from 0.16% (IV: 95% CI: 0.03%, 0.28%) to 0.25% (propensity score: 95% CI: 0.17%, 0.33%). After GPI adjustment in the IV, more than half the bleeding reduction with bivalirudin was because of the lower use of GPIs (risk difference, -0.84%; 95% CI: -1.11%, -0.57%), and no survival benefit was apparent (risk difference, -0.10%; 95% CI: -0.24%, 0.05%). Bleeding reductions with bivalirudin were largest for transfemoral PCI (GPI-adjusted risk difference, 1.11%; 95% CI: -1.43%, -0.80%) and negligible for transradial PCI (GPI-adjusted risk difference, 0.09%; 95% CI: -0.32%, 0.50%). CONCLUSIONS: In the largest comparative analysis of bivalirudin versus UFH for non-ST-segment-elevation myocardial infarction to date, bivalirudin was associated with lower in-hospital bleeding and mortality given current practices with respect to GPI use and access site. Bleeding differences were, in part, explained by the greater use of GPIs with UFH. Reductions in bleeding were largest among those undergoing transfemoral PCI, whereas no bleeding benefit was observed for those treated with transradial PCI. PMID- 28855223 TI - Effects of dietary sodium on metabolites: the Dietary Approaches to Stop Hypertension (DASH)-Sodium Feeding Study. AB - Background: High sodium intake is known to increase blood pressure and is difficult to measure in epidemiologic studies.Objective: We examined the effect of sodium intake on metabolites within the DASH (Dietary Approaches to Stop Hypertension Trial)-Sodium Trial to further our understanding of the biological effects of sodium intake beyond blood pressure.Design: The DASH-Sodium Trial randomly assigned individuals to either the DASH diet (low in fat and high in protein, low-fat dairy, and fruits and vegetables) or a control diet for 12 wk. Participants within each diet arm received, in random order, diets containing high (150 nmol or 3450 mg), medium (100 nmol or 2300 mg), and low (50 nmol or 1150 mg) amounts of sodium for 30 d (crossover design). Fasting blood samples were collected at the end of each sodium intervention. We measured 531 identified plasma metabolites in 73 participants at the end of their high- and low-sodium interventions and in 46 participants at the end of their high- and medium-sodium interventions (N = 119). We used linear mixed-effects regression to model the relation between each log-transformed metabolite and sodium intake. We also combined the resulting P values with Fisher's method to estimate the association between sodium intake and 38 metabolic pathways or groups.Results: Six pathways were associated with sodium intake at a Bonferroni-corrected threshold of 0.0013 (e.g., fatty acid, food component or plant, benzoate, gamma-glutamyl amino acid, methionine, and tryptophan). Although 82 metabolites were associated with sodium intake at a false discovery rate <=0.10, only 4-ethylphenylsufate, a xenobiotic related to benzoate metabolism, was significant at a Bonferroni-corrected threshold (P < 10-5). Adjustment for coinciding change in blood pressure did not substantively alter the association for the top-ranked metabolites.Conclusion: Sodium intake is associated with changes in circulating metabolites, including gut microbial, tryptophan, plant component, and gamma-glutamyl amino acid-related metabolites. This trial was registered at clinicaltrials.gov as NCT00000608. PMID- 28855224 TI - DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study. AB - Background: Dietary fish oils, rich in long-chain n-3 (omega-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n 3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.Conclusion: Supplementation with n 3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159. PMID- 28855225 TI - Plasma glucose and insulin responses after consumption of breakfasts with different sources of soluble fiber in type 2 diabetes patients: a randomized crossover clinical trial. AB - Background: The amount and quality of carbohydrates are important determinants of plasma glucose after meals. Regarding fiber content, it is unclear whether the intake of soluble fibers from foods or supplements has an equally beneficial effect on lowering postprandial glucose.Objective: The aim of our study was to compare the acute effect of soluble fiber intake from foods or supplements after a common meal on postprandial plasma glucose and plasma insulin in patients with type 2 diabetes (T2D).Design: A randomized crossover clinical trial was conducted in patients with T2D. Patients consumed isocaloric breakfasts (mean +/- SD: 369.8 +/- 9.4 kcal) with high amounts of fiber from diet food sources (total fiber: 9.7 g; soluble fiber: 5.4 g), high amounts of soluble fiber from guar gum supplement (total fiber: 9.1 g; soluble fiber: 5.4 g), and normal amounts of fiber (total fiber: 2.4 g; soluble fiber: 0.8 g). Primary outcomes were postprandial plasma glucose and insulin (0-180 min). Data were analyzed by repeated measures ANOVA and post hoc Bonferroni test.Results: A total of 19 patients [aged 65.8 +/- 7.3 y; median (IQR), 10 (5-9) y of T2D duration; glycated hemoglobin 7.0% +/- 0.8%; body mass index (in kg/m2) 28.2 +/- 2.9] completed 57 meal tests. After breakfast, the incremental area under the curve (iAUC) for plasma glucose [mg/dL . min; mean (95% CI)] did not differ between high fiber from diet (HFD) [7861 (6257, 9465)] and high fiber from supplement (HFS) [7847 (5605, 10,090)] (P = 1.00) and both were lower than usual fiber (UF) [9527 (7549, 11,504)] (P = 0.014 and P = 0.037, respectively). iAUCs [MUIU/mL . min; mean (95% CI)] did not differ (P = 0.877): HFD [3781 (2513, 5050)], HFS [4006 (2711, 5302), and UF [4315 (3027, 5603)].Conclusions: Higher fiber intake was associated with lower postprandial glucose at breakfast, and the intake of soluble fiber from food and supplement had a similar effect in patients with T2D. This trial was registered at clinicaltrials.gov as NCT02204384. PMID- 28855226 TI - Antibiotics for performing voiding cystourethrogram: a randomised control trial. AB - OBJECTIVE: To assess whether antibiotic reduces voiding cystourethrogram (VCUG) associated urinary tract infection (UTI). DESIGN: Open-labelled randomised controlled trial. SETTING: Tertiary paediatric nephrology centre. PATIENTS: 120 children (age 2 months-5 years) undergoing VCUG. INTERVENTIONS: Children were randomised into group A (antibiotic, n=72) or group B (no antibiotic, n=48) in 3:2 ratio. Group A received oral antibiotic (cephalexin if <6 months or co trimoxazole if >6 months old) a day prior to VCUG and continued for 1 day post VCUG. MAIN OUTCOME MEASURES: The main outcome measure is incidence of VCUG associated UTI. Urine was checked on day 3 after VCUG and UTI was defined as significant growth of a single organism in a symptomatic child. RESULTS: The median age was 8 months (IQR 13 months) with 68% male. Indication for undertaking VCUG was history of UTI (first UTI in infancy=43, recurrent UTI=49) and congenital anomaly of kidney and urinary tract without any UTI (n=28). Post-VCUG UTI was significantly higher among group B in comparison to group A (17% (n=8) vs 1.4% (n=1); p=0.01, OR=14.2 (95% CI 1.7 to 117)). Multivariate binary logistic regression analysis found an abnormal pre-VCUG ultrasound scan to be a significant independent risk factor for post-VCUG UTI (p=0.02, OR=9.51, 95% CI 1.43 to 63.4). The number needed to treat with antibiotic to prevent one post VCUG UTI was 6.5, which reduced to 4 if only the group with abnormal pre-VCUG ultrasound scan was included. CONCLUSIONS: Antibiotic significantly reduces post VCUG-acquired UTI especially in those with abnormal ultrasound scans. TRIAL REGISTRATION NUMBER: Clinical Trial Registry of India: CTRI/2017/03/00824. PMID- 28855228 TI - High-flow oxygen in bronchiolitis. PMID- 28855227 TI - Health-related quality of life in infants and toddlers with congenital heart disease: a cross-sectional survey from South India. AB - OBJECTIVE: There are limited data on health-related quality of life (HRQOL) for infants and toddlers with congenital heart disease (CHD). We sought to compare generic HRQOL of infants and toddlers between CHD subjects and controls. DESIGN: Dual-setting, cross-sectional analytical survey. SETTING: We collected HRQOL data on infants and toddlers through a community survey for controls and through a hospital-based survey for those with CHD. PATIENTS: A total of 499 subjects with confirmed CHD in the age group of 1-24 months admitted for elective surgery in the study institution were selected by consecutive sampling. In addition, we selected 628 control children in the same age group from an area within the 10 km radius of the study institution. MAIN OUTCOME MEASURES: The data contain parent proxy report of HRQOL. The Pediatric Quality of Life Inventory (PedsQL 4.0) was used to collect HRQOL data. Questionnaires were self-administered for parents. RESULTS: The mean total proxy HRQOL scores were significantly higher in control infants compared with infants with CHD (adjusted mean difference 5.0, 99% CI 2.5 to 7.5, p<0.001). Corresponding figure for toddlers was 7.6 (95% CI 5.0 to 10.2, p<0.001). There was no significant difference in total HRQOL scores across CHD functional classes among infants and toddlers (p=0.212 and p=0.502, respectively). CONCLUSIONS: Infants and toddlers with uncorrected CHD have significant deficiency in proxy HRQOL compared with their controls. The functional class of CHD appears to have no differential impact on overall HRQOL deficiency in this age group. PMID- 28855229 TI - Niacin, NAD and malformations. PMID- 28855230 TI - Live attenuated influenza vaccine (LAIV): recent effectiveness results from the USA and implications for LAIV programmes elsewhere. AB - The USA has a long-standing paediatric influenza vaccination programme, including use of live attenuated influenza vaccine (LAIV). Following US evidence of apparent lack of vaccine effectiveness (VE) of LAIV in 2015/2016, particularly against A(H1N1)pdm09, the USA suspended the use of LAIV in the 2016/2017 season. The UK introduced LAIV for children in 2013/2014 and Finland in 2015/2016. Both countries have since been closely monitoring programme performance. In 2015/2016, the UK and Finland, unlike the USA, found evidence of significant VE of LAIV against laboratory-confirmed influenza. Several studies, however, reported relatively lower VE of LAIV against A(H1N1)pdm09 infection compared with inactivated influenza vaccine, although not for A(H3N2) or B. The reasons for these apparent differences remain under investigation. Both the UK and Finland continue to recommend the use of LAIV in children for the 2017/2018 season and are intensifying further monitoring of their childhood programmes against a range of end-points. PMID- 28855231 TI - Inequalities in the dental health needs and access to dental services among looked after children in Scotland: a population data linkage study. AB - BACKGROUND: There is limited evidence on the health needs and service access among children and young people who are looked after by the state. The aim of this study was to compare dental treatment needs and access to dental services (as an exemplar of wider health and well-being concerns) among children and young people who are looked after with the general child population. METHODS: Population data linkage study utilising national datasets of social work referrals for 'looked after' placements, the Scottish census of children in local authority schools, and national health service's dental health and service datasets. RESULTS: 633 204 children in publicly funded schools in Scotland during the academic year 2011/2012, of whom 10 927 (1.7%) were known to be looked after during that or a previous year (from 2007-2008). The children in the looked after children (LAC) group were more likely to have urgent dental treatment need at 5 years of age: 23%vs10% (n=209/16533), adjusted (for age, sex and area socioeconomic deprivation) OR 2.65 (95% CI 2.30 to 3.05); were less likely to attend a dentist regularly: 51%vs63% (n=5519/388934), 0.55 (0.53 to 0.58) and more likely to have teeth extracted under general anaesthesia: 9%vs5% (n=967/30253), 1.91 (1.78 to 2.04). CONCLUSIONS: LAC are more likely to have dental treatment needs and less likely to access dental services even when accounting for sociodemographic factors. Greater efforts are required to integrate child social and healthcare for LAC and to develop preventive care pathways on entering and throughout their time in the care system. PMID- 28855232 TI - Molecular mechanisms of inflammasome signaling. AB - The inflammasome is a macromolecular protein complex that mediates proteolytic cleavage of pro-IL-1beta and -IL-18 and induces cell death in the form of pyroptosis. Certain nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), or tripartite motif (TRIM) family receptors trigger the assembly of an inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recent studies have revealed a multitude of host components and signals that are essential for controlling canonical and noncanonical inflammasome activation and pyroptosis. These include pore-forming gasdermin proteins, the never in mitosis A-related kinase 7 (NEK7), IFN-inducible proteins (IFIs), reactive oxygen species (ROS), autophagy, potassium efflux, mitochondrial perturbations, and microbial metabolites. Here, we provide a comprehensive overview of the molecular and signaling mechanisms that provide stringent regulation over the activation and effector functions of the inflammasome. PMID- 28855233 TI - A Mobile-Based Community Health Management Information System for Community Health Workers and Their Supervisors in 2 Districts of Zambia. AB - INTRODUCTION: Effective community health management information systems (C-HMIS) are important in low-resource countries that rely heavily on community-based health care providers. Zambia currently lacks a functioning C-HMIS to provide real-time, community-based health information from community health workers (CHWs) to health center staff and higher levels of the health system. PROGRAM DESCRIPTION: We developed a C-HMIS mobile platform for use by CHWs providing integrated community case management (iCCM) services and their supervisors to address challenges of frequent stock-outs and inadequate supportive supervision of iCCM-trained CHWs. The platform used simple feature mobile phones on which were loaded the District Health Information System version 2 (DHIS2) software and Java 2 platform micro edition (J2ME) aggregation and tracker applications. This project was implemented in Chipata and Chadiza districts, which supported previous mHealth programs and had cellular coverage from all 3 major network carriers in Zambia. A total of 40 CHWs and 20 CHW supervisors received mobile phones with data bundles and training in the mobile application, after which they implemented the program over a period of 5.5 months, from February to mid-July 2016. CHWs used the mobile phones to submit data on iCCM cases seen, managed, and referred, as well as iCCM medical and diagnostic supplies received and dispensed. Using their mobile phones, the supervisors tracked CHWs' reported cases with medicine consumption, sent CHWs feedback on their referrals, and received SMS reminders to set up mentorship sessions. OBSERVATIONS: CHWs were able to use the mobile application to send weekly reports to health center supervisors on disease caseloads and medical commodities consumed, to make drug and supply requisitions, and to send pre-referral notices to health centers. Health center staff used the mobile system to provide feedback to CHWs on the case outcomes of referred patients and to receive automated monthly SMS reminders to invite CHWs to the facility for mentorship. District- and central-level staff were able to access community-level health data in real time using passwords. LESSONS LEARNED: C HMIS, using simple feature phones, was feasible and viable for the provision of real-time community-based health information to all levels of the health care system in Zambia, but smartphones, laptops, or desktop computers are needed to perform data analysis and visualization. Ongoing technical support is needed to address the hardware and software challenges CHWs face in their day-to-day interaction with the application on their mobile phones. PMID- 28855236 TI - Serial transvaginal cervical length measurements and quantitative vaginal fetal fibronectin concentrations did not predict spontaneous preterm birth in low-risk nulliparous women. PMID- 28855235 TI - Molecular and phenotypic evaluation of a novel germline TMEM127 mutation with an uncommon clinical presentation. PMID- 28855237 TI - PREDICT prioritisation study: establishing the research priorities of paediatric emergency medicine physicians in Australia and New Zealand. AB - BACKGROUND: The Paediatric Research in Emergency Departments International Collaborative (PREDICT) performs multicentre research in Australia and New Zealand. Research priorities are difficult to determine, often relying on individual interests or prior work. OBJECTIVE: To identify the research priorities of paediatric emergency medicine (PEM) specialists working in Australia and New Zealand. METHODS: Online surveys were administered in a two stage, modified Delphi study. Eligible participants were PEM specialists (consultants and senior advanced trainees in PEM from 14 PREDICT sites). Participants submitted up to 3 of their most important research questions (survey 1). Responses were collated and refined, then a shortlist of refined questions was returned to participants for prioritisation (survey 2). A further prioritisation exercise was carried out at a PREDICT meeting using the Hanlon Process of Prioritisation. This determined the priorities of active researchers in PEM including an emphasis on the feasibility of a research question. RESULTS: One hundred and six of 254 (42%) eligible participants responded to survey 1 and 142/245 (58%) to survey 2. One hundred and sixty-eight (66%) took part in either or both surveys. Two hundred forty-six individual research questions were submitted in survey 1. Survey 2 established a prioritised list of 35 research questions. Priority topics from both the Delphi and Hanlon process included high flow oxygenation in intubation, fluid volume resuscitation in sepsis, imaging in cervical spine injury, intravenous therapy for asthma and vasopressor use in sepsis. CONCLUSION: This prioritisation process has established a list of research questions, which will inform multicentre PEM research in Australia and New Zealand. It has also emphasised the importance of the translation of new knowledge. PMID- 28855238 TI - Magnetic Resonance Elastography to Assess Fibrosis in Kidney Allografts. AB - BACKGROUND AND OBJECTIVES: Fibrosis is a major cause of kidney allograft injury. Currently, the only means of assessing allograft fibrosis is by biopsy, an invasive procedure that samples <1% of the kidney. We examined whether magnetic resonance elastography, an imaging-based measure of organ stiffness, could noninvasively estimate allograft fibrosis and predict progression of allograft dysfunction. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kidney allograft recipients >1 year post-transplant undergoing an allograft biopsy first underwent free-breathing, flow-compensated magnetic resonance elastography on a 3.0-T magnetic resonance imaging scanner. Each patient had serial eGFR measurements after the elastography scan for a follow-up period of up to 1 year. The mean stiffness value of the kidney allograft was compared with both the histopathologic Banff fibrosis score and the rate of eGFR change during the follow-up period. RESULTS: Sixteen patients who underwent magnetic resonance elastography and biopsy were studied (mean age: 54+/-9 years old). Whole-kidney mean stiffness ranged between 3.5 and 7.3 kPa. Whole-kidney stiffness correlated with biopsy-derived Banff fibrosis score (Spearman rho =0.67; P<0.01). Stiffness was heterogeneously distributed within each kidney, providing a possible explanation for the lack of a stronger stiffness-fibrosis correlation. We also found negative correlations between whole-kidney stiffness and both baseline eGFR (Spearman rho =-0.65; P<0.01) and eGFR change over time (Spearman rho =-0.70; P<0.01). Irrespective of the baseline eGFR, increased kidney stiffness was associated with a greater eGFR decline (regression r2=0.48; P=0.03). CONCLUSIONS: Given the limitations of allograft biopsy, our pilot study suggests the potential for magnetic resonance elastography as a novel noninvasive measure of whole allograft fibrosis burden that may predict future changes in kidney function. Future studies exploring the utility and accuracy of magnetic resonance elastography are needed. PMID- 28855239 TI - Closed-Loop Control During Intense Prolonged Outdoor Exercise in Adolescents With Type 1 Diabetes: The Artificial Pancreas Ski Study. AB - OBJECTIVE: Intense exercise is a major challenge to the management of type 1 diabetes (T1D). Closed-loop control (CLC) systems (artificial pancreas) improve glycemic control during limited intensity and short duration of physical activity (PA). However, CLC has not been tested during extended vigorous outdoor exercise common among adolescents. RESEARCH DESIGN AND METHODS: Skiing presents unique metabolic challenges: intense prolonged PA, cold, altitude, and stress/fear/excitement. In a randomized controlled trial, 32 adolescents with T1D (ages 10-16 years) participated in a 5-day ski camp (~5 h skiing/day) at two sites: Wintergreen, VA, and Breckenridge, CO. Participants were randomized to the University of Virginia CLC system or remotely monitored sensor-augmented pump (RM SAP). The CLC and RM-SAP groups were coarsely paired by age and hemoglobin A1c (HbA1c). All subjects were remotely monitored 24 h per day by the study physicians and clinical team. RESULTS: Compared with physician-monitored open loop, percent time in range (70-180 mg/dL) improved using CLC: 71.3 vs. 64.7% (+6.6% [95% CI 1-12]; P = 0.005), with maximum effect late at night. Hypoglycemia exposure and carbohydrate treatments were improved overall (P = 0.001 and P = 0.007) and during the daytime with strong ski level effects (P = 0.0001 and P = 0.006); ski/snowboard proficiency was balanced between groups but with a very strong site effect: naive in Virginia and experienced in Colorado. There was no adverse event associated with CLC; the participants' feedback was overwhelmingly positive. CONCLUSIONS: CLC in adolescents with T1D improved glycemic control and reduced exposure to hypoglycemia during prolonged intensive winter sport activities, despite the added challenges of cold and altitude. PMID- 28855240 TI - Pancreatic beta-Cell-Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation. AB - Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these "isletokines" in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transplants within hours of infusion. The proinflammatory cytokine interferon-gamma-induced protein 10 (IP-10/CXCL10) was among the highest released, and high levels correlated with poor islet transplant outcomes. Transgenic mouse studies confirmed that donor islet-specific expression of IP-10 contributed to islet inflammation and loss of beta-cell function in islet grafts. The effects of islet-derived IP-10 could be blocked by treatment of donor islets and recipient mice with anti-IP-10 neutralizing monoclonal antibody. In vitro studies showed induction of the IP-10 gene was mediated by calcineurin-dependent NFAT signaling in pancreatic beta cells in response to oxidative or inflammatory stress. Sustained association of NFAT and p300 histone acetyltransferase with the IP-10 gene required p38 and c Jun N-terminal kinase mitogen-activated protein kinase (MAPK) activity, which differentially regulated IP-10 expression and subsequent protein release. Overall, these findings elucidate an NFAT-MAPK signaling paradigm for induction of isletokine expression in beta-cells and reveal IP-10 as a primary therapeutic target to prevent beta-cell-induced inflammatory loss of graft function after islet cell transplantation. PMID- 28855241 TI - RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense. AB - Many pathogens deliver virulence factors or effectors into host cells in order to evade host defenses and establish infection. Although such effector proteins disrupt critical cellular signaling pathways, they also trigger specific antipathogen responses, a process termed "effector-triggered immunity." The Gram negative bacterial pathogen Yersinia inactivates critical proteins of the NF kappaB and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis. Yersinia-induced apoptosis requires the kinase activity of receptor-interacting protein kinase 1 (RIPK1), a key regulator of cell death, NF-kappaB, and MAPK signaling. Through the targeted disruption of RIPK1 kinase activity, which selectively disrupts RIPK1-dependent cell death, we now reveal that Yersinia-induced apoptosis is critical for host survival, containment of bacteria in granulomas, and control of bacterial burdens in vivo. We demonstrate that this apoptotic response provides a cell-extrinsic signal that promotes optimal innate immune cytokine production and antibacterial defense, demonstrating a novel role for RIPK1 kinase-induced apoptosis in mediating effector-triggered immunity to circumvent pathogen inhibition of immune signaling. PMID- 28855244 TI - Establishing benefit of emotion-focused, carer-based interventions for adolescents with anorexia nervosa. PMID- 28855242 TI - Reduced generation of lung tissue-resident memory T cells during infancy. AB - Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared with adults, although the underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRMs) mediate optimal protection to respiratory pathogens, and we hypothesized that reduced protection in infancy could be due to impaired establishment of lung TRM. Using an infant mouse model, we demonstrate generation of lung-homing, virus-specific T effectors after influenza infection or live attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRMs, and heterosubtypic protection was reduced compared with adults. Impaired TRM establishment was infant-T cell intrinsic, and infant effectors displayed distinct transcriptional profiles enriched for T-bet regulated genes. Notably, mouse and human infant T cells exhibited increased T bet expression after activation, and reduction of T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses, and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage. PMID- 28855243 TI - Update on angiotensin II: new endocrine connections between the brain, adrenal glands and the cardiovascular system. AB - In the brain, angiotensinergic pathways play a major role in chronic regulation of cardiovascular and electrolyte homeostasis. Increases in plasma angiotensin II (Ang II), aldosterone, [Na+] and cytokines can directly activate these pathways. Chronically, these stimuli also activate a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels and endogenous ouabain (EO). This pathway increases AT1R and NADPH oxidase subunits and maintains/further increases the activity of angiotensinergic pathways. These brain pathways not only increase the setpoint of sympathetic activity per se, but also enhance its effectiveness by increasing plasma EO and EO-dependent reprogramming of arterial and cardiac function. Blockade of any step in this slow pathway or of AT1R prevents Ang II-, aldosterone- or salt and renal injury-induced forms of hypertension. MR/AT1R activation in the CNS also contributes to the activation of sympathetic activity, the circulatory and cardiac RAAS and increase in circulating cytokines in HF post MI. Chronic central infusion of an aldosterone synthase inhibitor, MR blocker or AT1R blocker prevents a major part of the structural remodeling of the heart and the decrease in LV function post MI, indicating that MR activation in the CNS post MI depends on aldosterone, locally produced in the CNS. Thus, Ang II, aldosterone and EO are not simply circulating hormones that act on the CNS but rather they are also paracrine neurohormones, locally produced in the CNS, that exert powerful effects in key CNS pathways involved in the long-term control of sympathetic and neuro endocrine function and cardiovascular homeostasis. PMID- 28855245 TI - The promise of digital mood tracking technologies: are we heading on the right track? AB - The growing understanding that mood disorders are dynamic in nature and fluctuate over variable epochs of time has compelled researchers to develop innovative methods of monitoring mood. Technological advancement now allows for the detection of minute-to-minute changes while also capturing a longitudinal perspective of an individual's illness. Traditionally, assessments of mood have been conducted by means of clinical interviews and paper surveys. However, these methods are often inaccurate due to recall bias and compliance issues, and are limited in their capacity to collect and process data over long periods of time. The increased capability, availability and affordability of digital technologies in recent decades has offered a novel, non-invasive alternative to monitoring mood and emotion in daily life. This paper reviews the emerging literature addressing the use of digital mood tracking technologies, primarily focusing on the strengths and inherent limitations of using these new methods including electronic self-report, behavioural data collection and wearable physiological biosensors. This developing field holds great promise in generating novel insights into the mechanistic processes of mood disorders and improving personalised clinical care. However, further research is needed to validate many of these novel approaches to ensure that these devices are indeed achieving their purpose of capturing changes in mood. PMID- 28855246 TI - Localization of Double-Strand Break Repair Proteins to Viral Replication Compartments following Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus. AB - Double-strand breaks (DSBs) in DNA are recognized by the Ku70/80 heterodimer and the MRE11-RAD50-NBS1 (MRN) complex and result in activation of the DNA-PK and ATM kinases, which play key roles in regulating the cellular DNA damage response (DDR). DNA tumor viruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) are known to interact extensively with the DDR during the course of their replicative cycles. Here we show that during lytic amplification of KSHV DNA, the Ku70/80 heterodimer and the MRN complex consistently colocalize with viral genomes in replication compartments (RCs), whereas other DSB repair proteins form foci outside RCs. Depletion of MRE11 and abrogation of its exonuclease activity negatively impact viral replication, while in contrast, knockdown of Ku80 and inhibition of the DNA-PK enzyme, which are involved in nonhomologous end joining (NHEJ) repair, enhance amplification of viral DNA. Although the recruitment of DSB-sensing proteins to KSHV RCs is a consistent occurrence across multiple cell types, activation of the ATM-CHK2 pathway during viral replication is a cell line specific event, indicating that recognition of viral DNA by the DDR does not necessarily result in activation of downstream signaling pathways. We have also observed that newly replicated viral DNA is not associated with cellular histones. Since the presence and modification of these DNA-packaging proteins provide a scaffold for docking of multiple DNA repair factors, the absence of histone deposition may allow the virus to evade localization of DSB repair proteins that would otherwise have a detrimental effect on viral replication.IMPORTANCE Tumor viruses are known to interact with machinery responsible for detection and repair of double-strand breaks (DSBs) in DNA, although detail concerning how Kaposi's sarcoma-associated herpesvirus (KSHV) modulates these cellular pathways during its lytic replication phase was previously lacking. By undertaking a comprehensive assessment of the localization of DSB repair proteins during KSHV replication, we have determined that a DNA damage response (DDR) is directed to viral genomes but is distinct from the response to cellular DNA damage. We also demonstrate that although recruitment of the MRE11-RAD50-NBS1 (MRN) DSB-sensing complex to viral genomes and activation of the ATM kinase can promote KSHV replication, proteins involved in nonhomologous end joining (NHEJ) repair restrict amplification of viral DNA. Overall, this study extends our understanding of the virus-host interactions that occur during lytic replication of KSHV and provides a deeper insight into how the DDR is manipulated during viral infection. PMID- 28855248 TI - Role of FSH glycan structure in the regulation of Sertoli cell inhibin production. AB - Variations in follicle-stimulating hormone (FSH) carbohydrate composition and structure are associated with important structural and functional changes in Sertoli cells (SCs) during sexual maturation. The aim of the present study was to investigate the impact of FSH oligosaccharide structure and its interaction with gonadal factors on the regulation of monomeric and dimeric inhibin production at different maturation stages of the SC. Recombinant human FSH (rhFSH) glycosylation variants were isolated according to their sialylation degree (AC and BA) and complexity of oligosaccharides (CO and HY). Native rhFSH stimulated inhibin alpha-subunit (Pro-alphaC) but did not show any effect on inhibin B (INHB) production in immature SCs isolated from 8-day-old rats. Activin A stimulated INHB and had a synergistic effect on FSH to stimulate Pro-alphaC. The less acidic/sialylated rhFSH charge analogues, BA, were the only charge analogue mix that stimulated INHB as well as the most potent stimulus for Pro-alphaC production. Native rhFSH stimulated both Pro-alphaC and INHB in SCs at a more advanced maturation stage, isolated from 20-day-old rats. In these cells, all rhFSH glycosylation variants increased INHB and Pro-alphaC production, even in the presence of growth factors. The BA preparation exerted a more marked stimulatory effect on INHB and Pro-alphaC than the AC. Glycoforms bearing high mannose and hybrid-type oligosaccharides, HY, stimulated INHB and Pro-alphaC more effectively than those bearing complex oligosaccharides, CO, even in the presence of gonadal growth factors. These findings demonstrate the modulatory effect of FSH oligosaccharide structure on the regulation of inhibin production in the male gonad. PMID- 28855247 TI - Population Diversity and Collective Interactions during Influenza Virus Infection. AB - Influenza A virus (IAV) continues to pose an enormous and unpredictable global public health threat, largely due to the continual evolution of escape from preexisting immunity and the potential for zoonotic emergence. Understanding how the unique genetic makeup and structure of IAV populations influences their transmission and evolution is essential for developing more-effective vaccines, therapeutics, and surveillance capabilities. Owing to their mutation-prone replicase and unique genome organization, IAV populations exhibit enormous amounts of diversity both in terms of sequence and functional gene content. Here, I review what is currently known about the genetic and genomic diversity present within IAV populations and how this diversity may shape the replicative and evolutionary dynamics of these viruses. PMID- 28855249 TI - lncRNA Chronos is an aging-induced inhibitor of muscle hypertrophy. AB - Skeletal muscle exhibits remarkable plasticity in its ability to modulate its mass in response to the physiologic changes associated with functional use, systemic disease, and aging. Although a gradual loss of muscle mass normally occurs with advancing age, its increasingly rapid progression results in sarcopenia in a subset of individuals. The identities of muscle-enriched, long noncoding RNAs that regulate this process are unknown. Here, we identify a long noncoding RNA, named Chronos, whose expression in muscle is positively regulated with advancing age and negatively regulated during Akt1-mediated growth. Inhibition of Chronos induces myofiber hypertrophy both in vitro and in vivo, in part, through the epigenetic modulation of Bmp7 signaling. PMID- 28855250 TI - Crossed wires: 3D genome misfolding in human disease. AB - Mammalian genomes are folded into unique topological structures that undergo precise spatiotemporal restructuring during healthy development. Here, we highlight recent advances in our understanding of how the genome folds inside the 3D nucleus and how these folding patterns are miswired during the onset and progression of mammalian disease states. We discuss potential mechanisms underlying the link among genome misfolding, genome dysregulation, and aberrant cellular phenotypes. We also discuss cases in which the endogenous 3D genome configurations in healthy cells might be particularly susceptible to mutation or translocation. Together, these data support an emerging model in which genome folding and misfolding is critically linked to the onset and progression of a broad range of human diseases. PMID- 28855251 TI - PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 alpha appendage and dynamin. AB - Clathrin-mediated endocytosis (CME) is used to internalize a diverse range of cargo proteins from the cell surface, often in response to specific signals. In neurons, the rapid endocytosis of GluA2-containing AMPA receptors (AMPARs) in response to NMDA receptor (NMDAR) stimulation causes a reduction in synaptic strength and is the central mechanism for long-term depression, which underlies certain forms of learning. The mechanisms that link NMDAR activation to CME of AMPARs remain elusive. PICK1 is a BAR domain protein required for NMDAR-dependent reductions in surface GluA2; however, the molecular mechanisms involved are unclear. In this study, we show that PICK1 makes direct, NMDAR-dependent interactions with the core endocytic proteins AP2 and dynamin. PICK1-AP2 interactions are required for clustering AMPARs at endocytic zones in dendrites in response to NMDAR stimulation and for consequent AMPAR internalization. We further show that PICK1 stimulates dynamin polymerization. We propose that PICK1 is a cargo-specific endocytic accessory protein required for efficient, activity dependent AMPAR endocytosis. PMID- 28855253 TI - Phosphorylation of mycobacterial phosphodiesterase by eukaryotic-type Ser/Thr kinase controls its two distinct and mutually exclusive functionalities. AB - Phosphorylation-mediated negative feedback regulation of cAMP levels by phosphodiesterase is well-established in eukaryotic cells. However, such a mechanism remains unexplored in prokaryotes. We report here the involvement of eukaryotic-type Ser/Thr kinases, particularly PknA in trans-phosphorylating phosphodiesterase from Mycobacterium tuberculosis (mPDE), that resulted in decreased enzyme turnover rate compared with its unphosphorylated counterpart. To elucidate the role of mPDE phosphorylation in hydrolyzing cellular cAMP, we utilized a phosphodiesterase knock-out Escherichia coli strain, DeltacpdA, where interference of endogenous eukaryotic-type Ser/Thr kinases could be excluded. Interestingly, the mPDE-complemented DeltacpdA strain showed enhanced cAMP levels in the presence of PknA, and this effect was antagonized by PknA-K42N, a kinase dead variant. Structural analysis of mPDE revealed that four Ser/Thr residues (Ser-20, Thr-22, Thr-182, and Thr-240) were close to the active site, indicating their possible role in phosphorylation-mediated alteration in enzymatic activity. Mutation of these residues one at a time to alanine or a combination of all four (mPDE-4A) affected catalytic activity of mPDE. Moreover, mPDE-4A protein in kinase assays exhibited reduction in its phosphorylation compared with mPDE. In consonance, phosphoproteins obtained after co-expression of PknA with mPDE/S20A/T240A/4A displayed decreased phospho-signal intensities in immunoblotting with anti-phosphoserine/phosphothreonine antibodies. Furthermore, unlike mPDE, phospho-ablated mPDE-T309A protein exhibited impaired cell wall localization in Mycobacterium smegmatis, whereas mPDE-4A behaved similarly as wild type. Taken together, our findings establish mutually exclusive dual functionality of mPDE upon PknA-mediated phosphorylation, where Ser-20/Thr-240 influence enzyme activity and Thr-309 endorses its cell wall localization. PMID- 28855252 TI - The cell envelope-associated phospholipid-binding protein LmeA is required for mannan polymerization in mycobacteria. AB - The integrity of the distinguishing, multilaminate cell envelope surrounding mycobacteria is critical to their survival and pathogenesis. The prevalence of phosphatidylinositol mannosides in the cell envelope suggests an important role in the mycobacterial life cycle. Indeed, deletion of the pimE gene (DeltapimE) encoding the first committed step in phosphatidylinositol hexamannoside biosynthesis in Mycobacterium smegmatis results in the formation of smaller colonies than wild-type colonies on Middlebrook 7H10 agar. To further investigate potential contributors to cell-envelope mannan biosynthesis while taking advantage of this colony morphology defect, we isolated spontaneous suppressor mutants of DeltapimE that reverted to wild-type colony size. Of 22 suppressor mutants, 6 accumulated significantly shorter lipomannan or lipoarabinomannan. Genome sequencing of these mutants revealed mutations in genes involved in the lipomannan/lipoarabinomannan biosynthesis, such as those encoding the arabinosyltransferase EmbC and the mannosyltransferase MptA. Furthermore, we identified three mutants carrying a mutation in a previously uncharacterized gene, MSMEG_5785, that we designated lmeA Complementation of these suppressor mutants with lmeA restored the original DeltapimE phenotypes and deletion of lmeA in wild-type M. smegmatis resulted in smaller lipomannan, as observed in the suppressor mutants. LmeA carries a predicted N-terminal signal peptide, and density gradient fractionation and detergent extractability experiments indicated that LmeA localizes to the cell envelope. Using a lipid ELISA, we found that LmeA binds to plasma membrane phospholipids, such as phosphatidylethanolamine and phosphatidylinositol. LmeA is widespread throughout the Corynebacteriales; therefore, we concluded that LmeA is an evolutionarily conserved cell-envelope protein critical for controlling the mannan chain length of lipomannan/lipoarabinomannan. PMID- 28855254 TI - The cytoplasmic tail of rhodopsin triggers rapid rod degeneration in kinesin-2 mutants. AB - Photoreceptor degeneration can lead to blindness and represents the most common form of neural degenerative disease worldwide. Although many genes involved in photoreceptor degeneration have been identified, the underlying mechanisms remain to be elucidated. Here we examined photoreceptor development in zebrafish kif3a and kif3b mutants, which affect two subunits of the kinesin-2 complex. In both mutants, rods degenerated quickly, whereas cones underwent a slow degeneration process. Notably, the photoreceptor defects were considerably more severe in kif3a mutants than in kif3b mutants. In the cone photoreceptors of kif3a mutants, opsin proteins accumulated in the apical region and formed abnormal membrane structures. In contrast, rhodopsins were enriched in the rod cell body membrane and represented the primary reason for rapid rod degeneration in these mutants. Moreover, removal of the cytoplasmic tail of rhodopsin to reduce its function, but not decreasing rhodopsin expression levels, prevented rod degeneration in both kif3a and kif3b mutants. Of note, overexpression of full-length rhodopsin or its cytoplasmic tail domain, but not of rhodopsin lacking the cytoplasmic tail, exacerbated rod degeneration in kif3a mutants, implying an important role of the cytoplasmic tail in rod degeneration. Finally, we showed that the cytoplasmic tail of rhodopsin might trigger rod degeneration through activating the downstream calcium signaling pathway, as drug treatment with inhibitors of intracellular calcium release prevented rod degeneration in kif3a mutants. Our results demonstrate a previously unknown function of the rhodopsin cytoplasmic domain during opsin-triggered photoreceptor degeneration and may open up new avenues for managing this disease. PMID- 28855255 TI - Single-molecule force spectroscopy on histone H4 tail-cross-linked chromatin reveals fiber folding. AB - The eukaryotic genome is highly compacted into a protein-DNA complex called chromatin. The cell controls access of transcriptional regulators to chromosomal DNA via several mechanisms that act on chromatin-associated proteins and provide a rich spectrum of epigenetic regulation. Elucidating the mechanisms that fold chromatin fibers into higher-order structures is therefore key to understanding the epigenetic regulation of DNA accessibility. Here, using histone H4-V21C and histone H2A-E64C mutations, we employed single-molecule force spectroscopy to measure the unfolding of individual chromatin fibers that are reversibly cross linked through the histone H4 tail. Fibers with covalently linked nucleosomes featured the same folding characteristics as fibers containing wild-type histones but exhibited increased stability against stretching forces. By stabilizing the secondary structure of chromatin, we confirmed a nucleosome repeat length (NRL) dependent folding. Consistent with previous crystallographic and cryo-EM studies, the obtained force-extension curves on arrays with 167-bp NRLs best supported an underlying structure consisting of zig-zag, two-start fibers. For arrays with 197 bp NRLs, we previously inferred solenoidal folding, which was further corroborated by force-extension curves of the cross-linked fibers. The different unfolding pathways exhibited by these two types of arrays and reported here extend our understanding of chromatin structure and its potential roles in gene regulation. Importantly, these findings imply that chromatin compaction by nucleosome stacking protects nucleosomal DNA from external forces up to 4 piconewtons. PMID- 28855256 TI - From masochistic enzymology to mechanistic physiology and disease. AB - The pioneering work of Eugene Kennedy in the 1950s established the choline pathway for phosphatidylcholine (PC) biosynthesis. However, the regulation of PC biosynthesis was poorly understood at that time. When I started my lab at the University of British Columbia in the 1970s, this was the focus of my research. This article provides my reflections on these studies that began with enzymology and the use of cultured mammalian cells, and progressed to utilize the techniques of molecular biology and gene-targeted mice. The research in my lab and others demonstrated that the regulated and rate-limiting step in the choline pathway for PC biosynthesis was catalyzed by CTP:phosphocholine cytidylyltransferase. This enzyme is regulated by its movement from a soluble form (largely in the nucleus) to a membrane-associated form where the enzyme becomes activated. Gene targeting in mice subsequently demonstrated that this gene is essential for development of mouse embryos. The other mammalian pathway for PC biosynthesis is catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT) that converts phosphatidylethanolamine to PC. Understanding of the regulation and function of the integral membrane protein PEMT was improved when the enzyme was purified (a masochistic endeavor) in 1987, leading to the cloning of the Pemt cDNA. Generation of knock-out mice that lacked PEMT showed that they were protected from atherosclerosis, diet-induced obesity, and insulin resistance. The protection from atherosclerosis appears to be due to decreased secretion of lipoproteins from the liver. We continue to investigate the mechanism(s) by which Pemt-/- mice are protected from weight gain and insulin resistance. PMID- 28855257 TI - The molecular basis for peptide repertoire selection in the human leucocyte antigen (HLA) C*06:02 molecule. AB - Human leukocyte antigen (HLA)-C*06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C*06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ~3,000 sequences for HLA-C*06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C*06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (POmega). To determine the structural basis of this selectivity, we determined crystal structures of HLA C*06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C*06:02 possesses a deep peptide binding groove comprising two electronegative B- and E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C*06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C*06:02. PMID- 28855258 TI - Identification and characterization of Vibrio vulnificus plpA encoding a phospholipase A2 essential for pathogenesis. AB - The marine bacterium Vibrio vulnificus causes food-borne diseases, which may lead to life-threatening septicemia in some individuals. Therefore, identifying virulence factors in V. vulnificus is of high priority. We performed a transcriptome analysis on V. vulnificus after infection of human intestinal HT29 methotrexate cells and found induction of plpA, encoding a putative phospholipase, VvPlpA. Bioinformatics, biochemical, and genetic analyses demonstrated that VvPlpA is a phospholipase A2 secreted in a type II secretion system-dependent manner. Compared with the wild type, the plpA mutant exhibited reduced mortality, systemic infection, and inflammation in mice as well as low cytotoxicity toward the human epithelial INT-407 cells. Moreover, plpA mutation attenuated the release of actin and cytosolic cyclophilin A from INT-407 cells, indicating that VvPlpA is a virulence factor essential for causing lysis and necrotic death of the epithelial cells. plpA transcription was growth phase dependent, reaching maximum levels during the early stationary phase. Also, transcription factor HlyU and cAMP receptor protein (CRP) mediate additive activation and host-dependent induction of plpA Molecular biological analyses revealed that plpA expression is controlled via the promoter, P plpA , and that HlyU and CRP directly bind to P plpA upstream sequences. Taken together, this study demonstrated that VvPlpA is a type II secretion system-dependent secretory phospholipase A2 regulated by HlyU and CRP and is essential for the pathogenicity of V. vulnificus. PMID- 28855259 TI - The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology. AB - Mobile element insertions (MEIs) represent ~25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings. PMID- 28855260 TI - HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient. AB - Hi-C is a powerful technology for studying genome-wide chromatin interactions. However, current methods for assessing Hi-C data reproducibility can produce misleading results because they ignore spatial features in Hi-C data, such as domain structure and distance dependence. We present HiCRep, a framework for assessing the reproducibility of Hi-C data that systematically accounts for these features. In particular, we introduce a novel similarity measure, the stratum adjusted correlation coefficient (SCC), for quantifying the similarity between Hi C interaction matrices. Not only does it provide a statistically sound and reliable evaluation of reproducibility, SCC can also be used to quantify differences between Hi-C contact matrices and to determine the optimal sequencing depth for a desired resolution. The measure consistently shows higher accuracy than existing approaches in distinguishing subtle differences in reproducibility and depicting interrelationships of cell lineages. The proposed measure is straightforward to interpret and easy to compute, making it well-suited for providing standardized, interpretable, automatable, and scalable quality control. The freely available R package HiCRep implements our approach. PMID- 28855261 TI - Detection of structural mosaicism from targeted and whole-genome sequencing data. AB - Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4911 patients with undiagnosed developmental disorders, and 11 events among nine patients were detected. For eight of these 11 events, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly >50%, of mosaic diagnostic chromosomal rearrangements. PMID- 28855262 TI - Transposable elements are the primary source of novelty in primate gene regulation. AB - Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNA-seq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell-type specificity, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions. We further demonstrate that conserved CREs bind master regulators, suggesting that while CREs contribute to species adaptation to the environment, core functions remain intact. Newly evolved CREs are enriched in young transposable elements (TEs), including Long-Terminal-Repeats (LTRs) and SINE-VNTR-Alus (SVAs), that significantly affect gene expression. Conversely, only 16% of conserved CREs overlap TEs. We tested the cis-regulatory activity of 69 TE subfamilies by luciferase reporter assays, spanning all major TE classes, and showed that 95.6% of tested TEs can function as either transcriptional activators or repressors. In conclusion, we demonstrated the critical role of TEs in primate gene regulation and illustrated potential mechanisms underlying evolutionary divergence among the primate species through the noncoding genome. PMID- 28855263 TI - An atlas of alternative splicing profiles and functional associations reveals new regulatory programs and genes that simultaneously express multiple major isoforms. AB - Alternative splicing (AS) generates remarkable regulatory and proteomic complexity in metazoans. However, the functions of most AS events are not known, and programs of regulated splicing remain to be identified. To address these challenges, we describe the Vertebrate Alternative Splicing and Transcription Database (VastDB), the largest resource of genome-wide, quantitative profiles of AS events assembled to date. VastDB provides readily accessible quantitative information on the inclusion levels and functional associations of AS events detected in RNA-seq data from diverse vertebrate cell and tissue types, as well as developmental stages. The VastDB profiles reveal extensive new intergenic and intragenic regulatory relationships among different classes of AS and previously unknown and conserved landscapes of tissue-regulated exons. Contrary to recent reports concluding that nearly all human genes express a single major isoform, VastDB provides evidence that at least 48% of multiexonic protein-coding genes express multiple splice variants that are highly regulated in a cell/tissue specific manner, and that >18% of genes simultaneously express multiple major isoforms across diverse cell and tissue types. Isoforms encoded by the latter set of genes are generally coexpressed in the same cells and are often engaged by translating ribosomes. Moreover, they are encoded by genes that are significantly enriched in functions associated with transcriptional control, implying they may have an important and wide-ranging role in controlling cellular activities. VastDB thus provides an unprecedented resource for investigations of AS function and regulation. PMID- 28855264 TI - Economic insecurity during the Great Recession and metabolic, inflammatory and liver function biomarkers: analysis of the UK Household Longitudinal Study. AB - BACKGROUND: Economic insecurity correlates with adverse health outcomes, but the biological pathways involved are not well understood. We examine how changes in economic insecurity relate to metabolic, inflammatory and liver function biomarkers. METHODS: Blood analyte data were taken from 6520 individuals (aged 25 59 years) participating in Understanding Society. Economic insecurity was measured using an indicator of subjective financial strain and by asking participants whether they had missed any bill, council tax, rent or mortgage payments in the past year. We investigated longitudinal changes in economic insecurity (remained secure, increase in economic insecurity, decrease in economic insecurity, remained insecure) and the accumulation of economic insecurity. Linear regression models were calculated for nine (logged) biomarker outcomes related to metabolic, inflammatory, liver and kidney function (as falsification tests), adjusting for potential confounders. RESULTS: Compared with those who remained economically stable, people who experienced consistent economic insecurity (using both measures) had worsened levels of high-density lipoprotein (HDL)-cholesterol, triglycerides, C reactive protein (CRP), fibrinogen and glycated haemoglobin. Increased economic insecurity was associated with adverse levels of HDL-cholesterol (0.955, 95% CI 0.929 to 0.982), triglycerides (1.077, 95% CI 1.018 to 1.139) and CRP (1.114, 95% CI 1.012 to 1.227), using the measure of financial strain. Results for the other measure were generally consistent, apart from the higher levels of gamma-glutamyl transferase observed among those experiencing persistent insecurity (1.200, 95% CI 1.110 to 1.297). CONCLUSION: Economic insecurity is associated with adverse metabolic and inflammatory biomarkers (particularly HDL-cholesterol, triglycerides and CRP), heightening risk for a range of health conditions. PMID- 28855267 TI - THERAPY OF ENDOCRINE DISEASE: T4 + T3 combination therapy: is there a true effect? AB - About 5%-10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03-<=0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients. PMID- 28855268 TI - Inflammatory infiltrates in parathyroid tumors. AB - CONTEXT: Inflammatory infiltrates are sometimes present in solid tumors and may be coupled to clinical behavior or etiology. Infectious viruses contribute to tumorigenesis in a significant fraction of human neoplasias. OBJECTIVE: Characterize inflammatory infiltrates and possible viral transcription in primary hyperparathyroidism. DESIGN: From the period 2007 to 2016, a total of 55 parathyroid tumors (51 adenomas and 4 hyperplasias) with prominent inflammatory infiltrates were identified from more than 2000 parathyroid tumors in the pathology archives, and investigated by immunohistochemistry for CD4, CD8, CD20 and CD45 and scored as +0, +1 or +2. Clinicopathological data were compared to 142 parathyroid adenomas without histological evidence of inflammation. Transcriptome sequencing was performed for 13 parathyroid tumors (four inflammatory, 9 non-inflammatory) to identify potential viral transcripts. RESULTS: Tumors had prominent germinal center-like nodular (+2) lymphocytic infiltrates consisting of T and B lymphocytes (31%) and/or diffuse (+1-2) infiltrates of predominantly CD8+ T lymphocytes (84%). In the majority of cases with adjacent normal parathyroid tissue, the normal rim was unaffected by the inflammatory infiltrates (96%). Presence of inflammatory infiltrates was associated with higher levels of serum-PTH (P = 0.007) and oxyphilic differentiation (P = 0.002). Co-existent autoimmune disease was observed in 27% of patients with inflammatory infiltrates, which in turn was associated with oxyphilic differentiation (P = 0.041). Additionally, prescription of anti inflammatory drugs was associated with lower serum ionized calcium (P = 0.037). CONCLUSIONS: No evidence of virus-like sequences in the parathyroid tumors could be found by transcriptome sequencing, suggesting that other factors may contribute to attract the immune system to the parathyroid tumor tissue. PMID- 28855265 TI - The Role of BAFF System Molecules in Host Response to Pathogens. AB - The two ligands B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) and the three receptors BAFF receptor (BAFF-R), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) are members of the "BAFF system molecules." BAFF system molecules are primarily involved in B cell homeostasis. The relevance of BAFF system molecules in host responses to microbial assaults has been investigated in clinical studies and in mice deficient for each of these molecules. Many microbial products modulate the expression of these molecules. Data from clinical studies suggest a correlation between increased expression levels of BAFF system molecules and elevated B cell responses. Depending on the pathogen, heightened B cell responses may strengthen the host response or promote susceptibility. Whereas pathogen-mediated increases in the expression levels of the ligands and/or the receptors appear to promote microbial clearance, certain pathogens have evolved to ablate B cell responses by suppressing the expression of TACI and/or BAFF-R on B cells. Other than its well established role in B cell responses, the TACI-mediated activation of macrophages is also implicated in resistance to intracellular pathogens. An improved understanding of the role that BAFF system molecules play in infection may assist in devising novel strategies for vaccine development. PMID- 28855270 TI - Continuum of disease versus the fascination with numbers: an ongoing struggle. PMID- 28855266 TI - Whole-Genome Sequencing of Bacterial Pathogens: the Future of Nosocomial Outbreak Analysis. AB - Outbreaks of multidrug-resistant bacteria present a frequent threat to vulnerable patient populations in hospitals around the world. Intensive care unit (ICU) patients are particularly susceptible to nosocomial infections due to indwelling devices such as intravascular catheters, drains, and intratracheal tubes for mechanical ventilation. The increased vulnerability of infected ICU patients demonstrates the importance of effective outbreak management protocols to be in place. Understanding the transmission of pathogens via genotyping methods is an important tool for outbreak management. Recently, whole-genome sequencing (WGS) of pathogens has become more accessible and affordable as a tool for genotyping. Analysis of the entire pathogen genome via WGS could provide unprecedented resolution in discriminating even highly related lineages of bacteria and revolutionize outbreak analysis in hospitals. Nevertheless, clinicians have long been hesitant to implement WGS in outbreak analyses due to the expensive and cumbersome nature of early sequencing platforms. Recent improvements in sequencing technologies and analysis tools have rapidly increased the output and analysis speed as well as reduced the overall costs of WGS. In this review, we assess the feasibility of WGS technologies and bioinformatics analysis tools for nosocomial outbreak analyses and provide a comparison to conventional outbreak analysis workflows. Moreover, we review advantages and limitations of sequencing technologies and analysis tools and present a real-world example of the implementation of WGS for antimicrobial resistance analysis. We aimed to provide health care professionals with a guide to WGS outbreak analysis that highlights its benefits for hospitals and assists in the transition from conventional to WGS based outbreak analysis. PMID- 28855269 TI - Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass. AB - OBJECTIVE: Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies. METHODS: We studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations. RESULTS: We found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups. CONCLUSION: An early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH. PMID- 28855271 TI - Predictors of 1-year mortality in heart transplant recipients: a systematic review and meta-analysis. AB - OBJECTIVE: A systematic summary of the observational studies informing heart transplant guideline recommendations for selection of candidates and donors has thus far been unavailable. We performed a meta-analysis to better understand the impact of such known risk factors. METHODS: We systematically searched and meta analysed the association between known pretransplant factor and 1-year mortality identified by multivariable regression models. Our review used the Grading of Recommendations, Assessment, Development and Evaluation for assessing the quality of assessment. We pooled risk estimates by using random effects models. RESULTS: Recipient variables including age (HR 1.16 per 10-year increase, 95% CI 1.10 1.22, high quality), congenital aetiology (HR 2.35, 95% CI 1.62 to 3.41, moderate quality), diabetes (HR 1.37, 95% CI 1.15 to 1.62, high quality), creatinine (HR 1.11 per 1 mg/dL increase, 95% CI 1.06 to 1.16, high quality), mechanical ventilation (HR 2.46, 95% CI 1.48 to 4.09, low quality) and short-term mechanical circulatory support (MCS) (HR 2.47, 95% CI 1.04 to 5.87, low quality) were significantly associated with 1-year mortality. Donor age (HR 1.20 per 10-year increase, 95% CI 1.14 to 1.26, high quality) and female donor to male recipient sex mismatch (HR 1.38, 95% CI 1.06 to 1.80, high quality) were significantly associated with 1-year mortality. None of the operative factors proved significant predictors. CONCLUSION: High-quality and moderate-quality evidence demonstrates that recipient age, congenital aetiology, creatinine, pulsatile MCS, donor age and female donor to male recipient sex mismatch are associated with 1 year mortality post heart transplant. The results of this study should inform future guideline and predictive model development. PMID- 28855273 TI - Acute chest pain evaluation using coronary computed tomography angiography compared with standard of care: a meta-analysis of randomised clinical trials. AB - OBJECTIVE: Coronary CT angiography (CCTA) has certain advantages compared with stress testing including greater accuracy in identifying obstructive coronary disease. The aim of the study was to perform a systematical review and meta analysis comparing CCTA with other standard-of-care (SOC) approaches in evaluation of patients with acute chest pain. METHODS: Electronic databases were systematically searched to identify randomised clinical trials of patients with acute chest pain comparing CCTA with SOC approaches. We examined the following end points: mortality, major adverse cardiac events (MACE), myocardial infarction (MI), invasive coronary angiography (ICA) and revascularisation. Pooled risk ratios (RR) and their 95% CIs were calculated using random-effects models. RESULTS: Ten trials with 6285 patients were included. The trials used different definitions and implementation for SOC but all used physiologic testing. The clinical follow-up ranged from 1 to 19 months. There were no significant differences in all-cause mortality (RR 0.48, 95% CI 0.17 to 1.36, p=0.17), MI (RR 0.82, 95% CI 0.49 to 1.39, p=0.47) or MACE (RR 0.98, 95% CI 0.67 to 1.43, p=0.92) between the groups. However, significantly higher rates of ICA (RR 1.32, 95% CI 1.07 to 1.63, p=0.01) and revascularisation (RR 1.77, 95% CI 1.35 to 2.31, p<0.0001) were observed in the CCTA arm. CONCLUSIONS: Compared with other SOC approaches use of CCTA is associated with similar major adverse cardiac events but higher rates of revascularisation in patients with acute chest pain. PMID- 28855272 TI - Pathophysiology, diagnosis and treatment of tachycardiomyopathy. PMID- 28855275 TI - Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise. AB - It is generally accepted that muscle adaptation to resistance exercise (REX) training is underpinned by contraction-induced, increased rates of protein synthesis and dietary protein availability. By using dynamic proteome profiling (DPP), we investigated the contribution of both synthesis and breakdown to changes in abundance on a protein-by-protein basis in human skeletal muscle. Age matched, overweight males consumed 9 d of a high-fat, low-carbohydrate diet during which time they either undertook 3 sessions of REX or performed no exercise. Precursor enrichment and the rate of incorporation of deuterium oxide into newly synthesized muscle proteins were determined by mass spectrometry. Ninety proteins were included in the DPP, with 28 proteins exhibiting significant responses to REX. The most common pattern of response was an increase in turnover, followed by an increase in abundance with no detectable increase in protein synthesis. Here, we provide novel evidence that demonstrates that the contribution of synthesis and breakdown to changes in protein abundance induced by REX differ on a protein-by-protein basis. We also highlight the importance of the degradation of individual muscle proteins after exercise in human skeletal muscle.-Camera, D. M., Burniston, J. G., Pogson, M. A., Smiles, W. J., Hawley, J. A. Dynamic proteome profiling of individual proteins in human skeletal muscle after a high-fat diet and resistance exercise. PMID- 28855274 TI - Presenilin1/gamma-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15. AB - Reduced cerebral glucose utilization is found in aged individuals and often is an early sign of neurodegeneration. Here, we show that under glucose deprivation (GD) conditions, decreased expression of presenilin 1 (PS1) results in decreased neuronal survival, whereas increased PS1 increases neuronal survival. Inhibition of gamma-secretase also decreases neuronal survival under GD conditions, which suggests the PS1/gamma-secretase system protects neurons from GD-induced death. We also show that neuronal levels of the survival protein, phosphoprotein enriched in astrocytes at ~15 kDa (PEA15), and its mRNA are regulated by PS1/gamma-secretase. Furthermore, down-regulation of PEA15 decreases neuronal survival under reduced glucose conditions, whereas exogenous PEA15 increases neuronal survival even in the absence of PS1, which indicates that PEA15 promotes neuronal survival under GD conditions. The absence or reduction of PS1, as well as gamma-secretase inhibitors, increases neuronal miR-212, which targets PEA15 mRNA. PS1/gamma-secretase activates the transcription factor, cAMP response element-binding protein, regulating miR-212, which targets PEA15 mRNA. Taken together, our data show that under conditions of reduced glucose, the PS1/gamma secretase system decreases neuronal losses by suppressing miR-212 and increasing its target survival factor, PEA15. These observations have implications for mechanisms of neuronal death under conditions of reduced glucose and may provide targets for intervention in neurodegenerative disorders.-Huang, Q., Voloudakis, G., Ren, Y., Yoon, Y., Zhang, E., Kajiwara, Y., Shao, Z., Xuan, Z., Lebedev, D., Georgakopoulos, A., Robakis, N. K. Presenilin1/gamma-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15. PMID- 28855277 TI - Experimental confirmation of the C3 tickover hypothesis by studies with an Ab (S77) that inhibits tickover in whole serum. AB - The complement component 3 (C3) tickover hypothesis was put forward in the early 1970s to account for the spontaneous activation of the alternative complement pathway that occurs after the genetic absence or in vitro depletion of Factor I, the enzyme that is essential for the breakdown of C3b. The hypothesis was widely accepted, but experimental demonstration of the tickover was elusive. A phage Ab against C3b that inhibited the alternative complement pathway, but not the classical pathway, was described in 2009. Studies using this Ab in a variety of assays have now demonstrated that it acts primarily by inhibiting tickover, thereby confirming that tickover really exists.-Lachmann, P. J., Lay, E., Seilly, D. J. Experimental confirmation of the C3 tickover hypothesis by studies with an Ab (S77) that inhibits tickover in whole serum. PMID- 28855276 TI - Formyl-peptide receptor 2 governs leukocyte influx in local Staphylococcus aureus infections. AB - Leukocytes express formyl-peptide receptors (FPRs), which sense microbe associated molecular pattern (MAMP) molecules, leading to leukocyte chemotaxis and activation. We recently demonstrated that phenol-soluble modulin (PSM) peptides from highly pathogenic Staphylococcus aureus are efficient ligands for the human FPR2. How PSM detection by FPR2 impacts on the course of S. aureus infections has remained unknown. We characterized the specificity of mouse FPR2 (mFpr2) using a receptor-transfected cell line, homeobox b8 (Hoxb8), and primary neutrophils isolated from wild-type (WT) or mFpr2-/- mice. The influx of leukocytes into the peritoneum of WT and mFpr2-/- mice was analyzed. We demonstrate that mFpr2 is specifically activated by PSMs in mice, and they represent the first secreted pathogen-derived ligands for the mFpr2. Intraperitoneal infection with S. aureus led to lower numbers of immigrated leukocytes in mFpr2-/- compared with WT mice at 3 h after infection, and this difference was not observed when mice were infected with an S. aureus PSM mutant. Our data support the hypothesis that the mFpr2 is the functional homolog of the human FPR2 and that a mouse infection model represents a suitable model for analyzing the role of PSMs during infection. PSM recognition by mFpr2 shapes leukocyte influx in local infections, the typical infections caused by S. aureus Weiss, E., Hanzelmann, D., Fehlhaber, B., Klos, A., von Loewenich, F. D., Liese, J., Peschel, A., Kretschmer, D. Formyl-peptide receptor 2 governs leukocyte influx in local Staphylococcus aureus infections. PMID- 28855278 TI - Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4. AB - Acute lung injury (ALI) is a common cause of morbidity in patients after severe injury due to dysregulated inflammation, which is believed to be driven by gut derived inflammatory mediators carried via mesenteric lymph (ML). We have previously demonstrated that nano-sized extracellular vesicles, called exosomes, secreted into ML after trauma/hemorrhagic shock (T/HS) have the potential to activate immune cells in vitro Here, we assess the function of ML exosomes in the development of T/HS-induced ALI and the role of TLR4 in the ML exosome-mediated inflammatory response. ML exosomes isolated from rats subjected to T/HS stimulated NF-kappaB activation and caused proinflammatory cytokine production in alveolar macrophages. In vivo experiments revealed that intravenous injection of exosomes harvested after T/HS, but not before shock, caused recruitment of inflammatory cells in the lung, increased vascular permeability, and induced histologic ALI in naive mice. The exosome-depleted supernatant of ML had no effect on in vitro and in vivo inflammatory responses. We also demonstrated that both pharmacologic inhibition and genetic knockout of TLR4 completely abolished ML exosome-induced cytokine production in macrophages. Thus, our findings define the critical role of exosomes secreted into ML as a critical mediator of T/HS induced ALI through macrophage TLR4 activation.-Kojima, M., Gimenes-Junior, J. A., Chan, T. W., Eliceiri, B. P., Baird, A., Costantini, T. W., Coimbra, R. Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4. PMID- 28855279 TI - Telomere length dynamics in early life: the blood-and-muscle model. AB - Telomere length (TL) trajectories in somatic tissues during human growth and development are poorly understood. We examined a blood-and-muscle model during early life, focusing on TL trajectories in leukocytes, representing the highly proliferative hematopoietic system, and skeletal muscle, a minimally proliferative tissue. Leukocyte TL (LTL) and skeletal muscle TL (MTL) were measured in 28 fetuses and 73 children. LTL and MTL were highly variable across individuals (sd: fetal LTL = 0.72 kb, MTL = 0.72 kb; children LTL = 0.81 kb, MTL = 0.82 kb) but were highly correlated within individuals (fetuses, r = 0.76, P < 0.0001; children, r = 0.87, P < 0.0001). LTL was shorter than MTL in fetuses (10.63 vs. 11.01 kb; P = 0.0004) and children (8.46 vs. 9.40 kb; <0.0001). The LTL-MTL gap was smaller in fetuses than children. TL in children was inversely correlated with body mass index (BMI) (LTL: -0.047 +/- 0.016 kb/BMI, P < 0.005; MTL: -0.037 +/- 0.017 kb/BMI, P = 0.03). We conclude that variations in TL across adults and differences in TL between somatic tissues are largely established in early life. Because TL plays a significant role in aging-related diseases, insight into the factors that fashion TL in somatic tissues during early development should contribute to an understanding of the relationship of TL with these disease and longevity in humans.-Sabharwal, S., Verhulst, S., Guirguis, G., Kark, J. D., Labat, C., Roche, N. E., Martimucci, K., Patel, K., Heller, D. S., Kimura, M., Chuang, D., Chuang, A., Benetos, A., Aviv, A. Telomere length dynamics in early life: the blood-and-muscle model. PMID- 28855280 TI - In vitro and in vivo imaging and tracking of intestinal organoids from human induced pluripotent stem cells. AB - Human intestinal organoids (hIOs) derived from human pluripotent stem cells (hPSCs) have immense potential as a source of intestines. Therefore, an efficient system is needed for visualizing the stage of intestinal differentiation and further identifying hIOs derived from hPSCs. Here, 2 fluorescent biosensors were developed based on human induced pluripotent stem cell (hiPSC) lines that stably expressed fluorescent reporters driven by intestine-specific gene promoters Kruppel-like factor 5 monomeric Cherry (KLF5mCherry) and intestine-specific homeobox enhanced green fluorescence protein (ISXeGFP). Then hIOs were efficiently induced from those transgenic hiPSC lines in which mCherry- or eGFP expressing cells, which appeared during differentiation, could be identified in intact living cells in real time. Reporter gene expression had no adverse effects on differentiation into hIOs and proliferation. Using our reporter system to screen for hIO differentiation factors, we identified DMH1 as an efficient substitute for Noggin. Transplanted hIOs under the kidney capsule were tracked with fluorescence imaging (FLI) and confirmed histologically. After orthotopic transplantation, the localization of the hIOs in the small intestine could be accurately visualized using FLI. Our study establishes a selective system for monitoring the in vitro differentiation and for tracking the in vivo localization of hIOs and contributes to further improvement of cell-based therapies and preclinical screenings in the intestinal field.-Jung, K. B., Lee, H., Son, Y. S., Lee, J. H., Cho, H.-S., Lee, M.-O., Oh, J.-H., Lee, J., Kim, S., Jung, C.-R., Kim, J., Son, M.-Y. In vitro and in vivo imaging and tracking of intestinal organoids from human induced pluripotent stem cells. PMID- 28855281 TI - Genome-Wide Association Mapping of Stem Rust Resistance in Hordeum vulgare subsp. spontaneum. AB - Stem rust was one of the most devastating diseases of barley in North America. Through the deployment of cultivars with the resistance gene Rpg1, losses to stem rust have been minimal over the past 70 yr. However, there exist both domestic (QCCJB) and foreign (TTKSK aka isolate Ug99) pathotypes with virulence for this important gene. To identify new sources of stem rust resistance for barley, we evaluated the Wild Barley Diversity Collection (WBDC) (314 ecogeographically diverse accessions of Hordeum vulgare subsp. spontaneum) for seedling resistance to four pathotypes (TTKSK, QCCJB, MCCFC, and HKHJC) of the wheat stem rust pathogen (Puccinia graminis f. sp. tritici, Pgt) and one isolate (92-MN-90) of the rye stem rust pathogen (P. graminis f. sp. secalis, Pgs). Based on a coefficient of infection, the frequency of resistance in the WBDC was low ranging from 0.6% with HKHJC to 19.4% with 92-MN-90. None of the accessions was resistant to all five cultures of P. graminis A genome-wide association study (GWAS) was conducted to map stem rust resistance loci using 50,842 single-nucleotide polymorphic markers generated by genotype-by-sequencing and ordered using the new barley reference genome assembly. After proper accounting for genetic relatedness and structure among accessions, 45 quantitative trait loci were identified for resistance to P. graminis across all seven barley chromosomes. Three novel loci associated with resistance to TTKSK, QCCJB, MCCFC, and 92-MN-90 were identified on chromosomes 5H and 7H, and two novel loci associated with resistance to HKHJC were identified on chromosomes 1H and 3H. These novel alleles will enhance the diversity of resistance available for cultivated barley. PMID- 28855282 TI - Discovery of a Novel Stem Rust Resistance Allele in Durum Wheat that Exhibits Differential Reactions to Ug99 Isolates. AB - Wheat stem rust, caused by Puccinia graminis f. sp. tritici Eriks. & E. Henn, can incur yield losses in susceptible cultivars of durum wheat, Triticum turgidum ssp. durum (Desf.) Husnot. Although several durum cultivars possess the stem rust resistance gene Sr13, additional genes in durum wheat effective against emerging virulent races have not been described. Durum line 8155-B1 confers resistance against the P. graminis f. sp. tritici race TTKST, the variant race of the Ug99 race group with additional virulence to wheat stem rust resistance gene Sr24 However, 8155-B1 does not confer resistance to the first-described race in the Ug99 race group: TTKSK. We mapped a single gene conferring resistance in 8155-B1 against race TTKST, Sr8155B1, to chromosome arm 6AS by utilizing Rusty/8155-B1 and Rusty*2/8155-B1 populations and the 90K Infinium iSelect Custom bead chip supplemented by KASP assays. One marker, KASP_6AS_IWB10558, cosegregated with Sr8155B1 in both populations and correctly predicted Sr8155B1 presence or absence in 11 durum cultivars tested. We confirmed the presence of Sr8155B1 in cultivar Mountrail by mapping in the population Choteau/Mountrail. The marker developed in this study could be used to predict the presence of resistance to race TTKST in uncharacterized durum breeding lines, and also to combine Sr8155B1 with resistance genes effective to Ug99 such as Sr13 The map location of Sr8155B1 cannot rule out the possibility that this gene is an allele at the Sr8 locus. However, race specificity indicates that Sr8155B1 is different from the known alleles Sr8a and Sr8b. PMID- 28855283 TI - A Comparative Analysis of Genetic Ancestry and Admixture in the Colombian Populations of Choco and Medellin. AB - At least 20% of Colombians identify as having African ancestry, yielding the second largest population of Afro-descendants in Latin America. To date, there have been relatively few studies focused on the genetic ancestry of Afro-Latino populations. We report a comparative analysis of the genetic ancestry of Choco, a state located on Colombia's Pacific coast with a population that is >80% Afro Colombian. We compared genome-wide patterns of genetic ancestry and admixture for Choco to six other admixed American populations, with an emphasis on a Mestizo population from the nearby Colombian city of Medellin. One hundred sample donors from Choco were genotyped across 610,545 genomic sites and compared with 94 publicly available whole genome sequences from Medellin. At the continental level, Choco shows mostly African genetic ancestry (76%) with a nearly even split between European (13%) and Native American (11%) fractions, whereas Medellin has primarily European ancestry (75%), followed by Native American (18%) and African (7%). Sample donors from Choco self-identify as having more African ancestry, and conversely less European and Native American ancestry, than can be genetically inferred, as opposed to what we previously found for Medellin, where individuals tend to overestimate levels of European ancestry. We developed a novel approach for subcontinental ancestry assignment, which allowed us to characterize subcontinental source populations for each of the three distinct continental ancestry fractions separately. Despite the clear differences between Choco and Medellin at the level of continental ancestry, the two populations show overall patterns of subcontinental ancestry that are highly similar. Their African subcontinental ancestries are only slightly different, with Choco showing more exclusive shared ancestry with the modern Yoruba (Nigerian) population, and Medellin having relatively more shared ancestry with West African populations in Sierra Leone and Gambia. Both populations show very similar Spanish ancestry within Europe and virtually identical patterns of Native American ancestry, with main contributions from the Embera and Waunana tribes. When the three subcontinental ancestry components are considered jointly, the populations of Choco and Medellin are shown to be most closely related, to the exclusion of the other admixed American populations that we analyzed. We consider the implications of the existence of shared subcontinental ancestries for Colombian populations that appear, at first glance, to be clearly distinct with respect to competing notions of national identity that emphasize ethnic mixing (mestizaje) vs. group specific identities (multiculturalism). PMID- 28855284 TI - Whole Genome Sequencing-Based Mapping and Candidate Identification of Mutations from Fixed Zebrafish Tissue. AB - As forward genetic screens in zebrafish become more common, the number of mutants that cannot be identified by gross morphology or through transgenic approaches, such as many nervous system defects, has also increased. Screening for these difficult-to-visualize phenotypes demands techniques such as whole-mount in situ hybridization (WISH) or antibody staining, which require tissue fixation. To date, fixed tissue has not been amenable for generating libraries for whole genome sequencing (WGS). Here, we describe a method for using genomic DNA from fixed tissue and a bioinformatics suite for WGS-based mapping of zebrafish mutants. We tested our protocol using two known zebrafish mutant alleles, gpr126st49 and egr2bfh227 , both of which cause myelin defects. As further proof of concept we mapped a novel mutation, stl64, identified in a zebrafish WISH screen for myelination defects. We linked stl64 to chromosome 1 and identified a candidate nonsense mutation in the F-box and WD repeat domain containing 7 (fbxw7) gene. Importantly, stl64 mutants phenocopy previously described fbxw7vu56 mutants, and knockdown of fbxw7 in wild-type animals produced similar defects, demonstrating that stl64 disrupts fbxw7 Together, these data show that our mapping protocol can map and identify causative lesions in mutant screens that require tissue fixation for phenotypic analysis. PMID- 28855285 TI - Genetic Dissection of Trabecular Bone Structure with Mouse Intersubspecific Consomic Strains. AB - Trabecular bone structure has an important influence on bone strength, but little is known about its genetic regulation. To elucidate the genetic factor(s) regulating trabecular bone structure, we compared the trabecular bone structures of two genetically remote mouse strains, C57BL/6J and Japanese wild mouse-derived MSM/Ms. Phenotyping by X-ray micro-CT revealed that MSM/Ms has structurally more fragile trabecular bone than C57BL/6J. Toward identification of genetic determinants for the difference in fragility of trabecular bone between the two mouse strains, we employed phenotype screening of consomic mouse strains in which each C57BL/6J chromosome is substituted by its counterpart from MSM/Ms. The results showed that many chromosomes affect trabecular bone structure, and that the consomic strain B6-Chr15MSM, carrying MSM/Ms-derived chromosome 15 (Chr15), has the lowest values for the parameters BV/TV, Tb.N, and Conn.D, and the highest values for the parameters Tb.Sp and SMI. Subsequent phenotyping of subconsomic strains for Chr15 mapped four novel trabecular bone structure-related QTL (Tbsq1 4) on mouse Chr15. These results collectively indicate that genetic regulation of trabecular bone structure is highly complex, and that even in the single Chr15, the combined action of the four Tbsqs controls the fragility of trabecular bone. Given that Tbsq4 is syntenic to human Chr 12q12-13.3, where several bone-related SNPs are assigned, further study of Tbsq4 should facilitate our understanding of the genetic regulation of bone formation in humans. PMID- 28855286 TI - Improved methods for acrylic-free implants in nonhuman primates for neuroscience research. AB - Traditionally, head fixation devices and recording cylinders have been implanted in nonhuman primates (NHP) using dental acrylic despite several shortcomings associated with acrylic. The use of more biocompatible materials such as titanium and PEEK is becoming more prevalent in NHP research. We describe a cost-effective set of procedures that maximizes the integration of headposts and recording cylinders with the animal's tissues while reducing surgery time. Nine rhesus monkeys were implanted with titanium headposts, and one of these was also implanted with a recording chamber. In each case, a three-dimensional printed replica of the skull was created based on computerized tomography scans. The titanium feet of the headposts were shaped, and the skull thickness was measured preoperatively, reducing surgery time by up to 70%. The recording cylinder was manufactured to conform tightly to the skull, which was fastened to the skull with four screws and remained watertight for 8.5 mo. We quantified the amount of regression of the skin edge at the headpost. We found a large degree of variability in the timing and extent of skin regression that could not be explained by any single recorded factor. However, there was not a single case of bone exposure; although skin retracted from the titanium, skin also remained adhered to the skull adjacent to those regions. The headposts remained fully functional and free of complications for the experimental life of each animal, several of which are still participating in experiments more than 4 yr after implant.NEW & NOTEWORTHY Cranial implants are often necessary for performing neurophysiology research with nonhuman primates. We present methods for using three-dimensional printed monkey skulls to form and fabricate acrylic-free implants preoperatively to decrease surgery times and the risk of complications and increase the functional life of the implant. We focused on reducing costs, creating a feasible timeline, and ensuring compatibility with existing laboratory systems. We discuss the importance of using more biocompatible materials and enhancing osseointegration. PMID- 28855287 TI - GABA transporters regulate tonic and synaptic GABAA receptor-mediated currents in the suprachiasmatic nucleus neurons. AB - GABA is a principal neurotransmitter in the hypothalamic suprachiasmatic nucleus (SCN) that contributes to intercellular communication between individual circadian oscillators within the SCN network and the stability and precision of the circadian rhythms. GABA transporters (GAT) regulate the extracellular GABA concentration and modulate GABAA receptor (GABAAR)-mediated currents. GABA transport inhibitors were applied to study how GABAAR-mediated currents depend on the expression and function of GAT. Nipecotic acid inhibits GABA transport and induced an inward tonic current in concentration-dependent manner during whole cell patch-clamp recordings from SCN neurons. Application of either the selective GABA transporter 1 (GAT1) inhibitors NNC-711 or SKF-89976A, or the GABA transporter 3 (GAT3) inhibitor SNAP-5114, produced only small changes of the baseline current. Coapplication of GAT1 and GAT3 inhibitors induced a significant GABAAR-mediated tonic current that was blocked by gabazine. GAT inhibitors decreased the amplitude and decay time constant and increased the rise time of spontaneous GABAAR-mediated postsynaptic currents. However, inhibition of GAT did not alter the expression of either GAT1 or GAT3 in the hypothalamus. Thus GAT1 and GAT3 functionally complement each other to regulate the extracellular GABA concentration and GABAAR-mediated synaptic and tonic currents in the SCN. Coapplication of SKF-89976A and SNAP-5114 (50 uM each) significantly reduced the circadian period of Per1 expression in the SCN by 1.4 h. Our studies demonstrate that GAT are important regulators of GABAAR-mediated currents and the circadian clock in the SCN.NEW & NOTEWORTHY In the suprachiasmatic nucleus (SCN), the GABA transporters GAT1 and GAT3 are expressed in astrocytes. Inhibition of these GABA transporters increased a tonic GABA current and reduced the circadian period of Per1 expression in SCN neurons. GAT1 and GAT3 showed functional cooperativity: inhibition of one GAT increased the activity but not the expression of the other. Our data demonstrate that GABA transporters are important regulators of GABAA receptor-mediated currents and the circadian clock. PMID- 28855289 TI - The neural code for tactile roughness in the somatosensory nerves. AB - Roughness is the most salient perceptual dimension of surface texture but has no well-defined physical basis. We seek to determine the neural determinants of tactile roughness in the somatosensory nerves. Specifically, we record the patterns of activation evoked in tactile nerve fibers of anesthetized Rhesus macaques to a large and diverse set of natural textures and assess what aspect of these patterns of activation can account for psychophysical judgments of roughness, obtained from human observers. We show that perceived roughness is determined by the variation in the population response, weighted by fiber type. That is, a surface will feel rough to the extent that the activity varies across nerve fibers and varies across time within nerve fibers. We show that this variation-based neural code can account not only for magnitude estimates of roughness but also for roughness discrimination performance.NEW & NOTEWORTHY Our sense of touch endows us with an exquisite sensitivity to the microstructure of surfaces, the most salient aspect of which is roughness. We analyze the responses evoked in tactile fibers of monkeys by natural textures and compare them to judgments of roughness obtained for the same textures from human observers. We then describe how texture signals from three populations of nerve fibers are integrated to culminate in a percept of roughness. PMID- 28855290 TI - Intended arm use influences interhemispheric correlation of beta-oscillations in primate medial motor areas. AB - To investigate the role of interhemispheric beta-synchronization in the selection of motor effectors, we trained two monkeys to memorize and perform multiple two movement sequences that included unimanual repetition and bimanual switching. We recorded local field potentials simultaneously in the bilateral supplementary motor area (SMA) and pre-SMA to examine how the beta-power in both hemispheres and the interhemispheric relationship of beta-oscillations depend on the prepared sequence of arm use. We found a significant ipsilateral enhancement of beta-power for bimanual switching trials in the left hemisphere and an enhancement of beta power in the right SMA while preparing for unimanual repetition. Furthermore, interhemispheric synchrony in the SMA was significantly more enhanced while preparing unimanual repetition than while preparing bimanual switching. This enhancement of synchrony was detected in terms of beta-phase but not in terms of modulation of beta-power. Furthermore, the assessment of the interhemispheric phase difference revealed that the beta-oscillation in the hemisphere contralateral to the instructed arm use significantly advanced its phase relative to that in the ipsilateral hemisphere. There was no arm use-dependent shift in phase difference in the pairwise recordings within each hemisphere. Both neurons with and without arm use-selective activity were phase-locked to the beta oscillation. These results imply that the degree of interhemispheric phase synchronization as well as phase differences and oscillatory power in the beta band may contribute to the selection of arm use depending on the behavioral conditions of sequential arm use.NEW & NOTEWORTHY We addressed interhemispheric relationships of beta-oscillations during bimanual coordination. While monkeys prepared to initiate movement of the instructed arm, beta-oscillations in the contralateral hemisphere showed a phase advance relative to the other hemisphere. Furthermore, the sequence of arm use influenced beta-power and the degree of interhemispheric phase synchronization. Thus the dynamics of interhemispheric phases and power in beta-oscillations may contribute to the specification of motor effectors in a given behavioral context. PMID- 28855288 TI - Diversity of molecularly defined spinal interneurons engaged in mammalian locomotor pattern generation. AB - Mapping the expression of transcription factors in the mouse spinal cord has identified ten progenitor domains, four of which are cardinal classes of molecularly defined, ventrally located interneurons that are integrated in the locomotor circuitry. This review focuses on the properties of these interneuronal populations and their contribution to hindlimb locomotor central pattern generation. Interneuronal populations are categorized based on their excitatory or inhibitory functions and their axonal projections as predictors of their role in locomotor rhythm generation and coordination. The synaptic connectivity and functions of these interneurons in the locomotor central pattern generators (CPGs) have been assessed by correlating their activity patterns with motor output responses to rhythmogenic neurochemicals and sensory and descending fibers stimulations as well as analyzing kinematic gait patterns in adult mice. The observed complex organization of interneurons in the locomotor CPG circuitry, some with seemingly similar physiological functions, reflects the intricate repertoire associated with mammalian motor control and is consistent with high transcriptional heterogeneity arising from cardinal interneuronal classes. This review discusses insights derived from recent studies to describe innovative approaches and limitations in experimental model systems and to identify missing links in current investigational enterprise. PMID- 28855291 TI - Effect of M-current modulation on mammalian vestibular responses to transient head motion. AB - The precise role and mechanisms underlying efferent modulation of peripheral vestibular afferent function are not well understood in mammals. Clarifying the details of efferent action may lead to new strategies for clinical management of debilitating disturbances in vestibular and balance function. Recent evidence in turtle indicates that efferent modulation of M-currents is likely one mechanism for modifying afferent discharge. M-currents depend in part on KCNQ potassium conductances (Kv7), which can be adjusted through efferent activation of M1, M3, and/or M5 muscarinic acetylcholine receptors (mAChRs). How KCNQ channels and altered M-currents affect vestibular afferent function in vivo is unclear, and whether such a mechanism operates in mammals is unknown. In this study we used the KCNQ antagonist XE991 and the KCNQ activator retigabine in anesthetized mice to evaluate the effects of M-current modulation on peripheral vestibular responses to transient head motion. At low doses of XE991, responses were modestly enhanced, becoming larger in amplitude and shorter in latency. Higher doses of XE991 produced transient response enhancement, followed by steady-state suppression where latencies and thresholds increased and amplitudes decreased. Retigabine produced opposite effects. Auditory function was also impacted, based on results of companion auditory brain stem response testing. We propose that closure of KCNQ channels transforms vestibular afferent behavior by suppressing responses to transient high-frequency stimuli while simultaneously enhancing responses to sustained low-frequency stimulation. Our results clearly demonstrate that KCNQ channels are critical for normal mammalian vestibular function and suggest that efferent action may utilize these mechanisms to modulate the dynamic characteristics and gain of vestibular afferent responses.NEW & NOTEWORTHY The role of calyceal KCNQ channels and associated M-current in normal mammalian vestibular function is unknown. Our results show that calyceal KCNQ channels are critical for normal vestibular function in the intact mammal. The findings provide evidence that efferent modulation of M-currents may act normally to differentially adjust the sensitivity of vestibular neurons to transient and tonic stimulation and that such mechanisms may be targeted to achieve effective clinical management of vestibular disorders. PMID- 28855292 TI - Extracellular H+ fluxes from tiger salamander Muller (glial) cells measured using self-referencing H+-selective microelectrodes. AB - Self-referencing H+-selective electrodes were used to measure extracellular H+ fluxes from Muller (glial) cells isolated from the tiger salamander retina. A novel chamber enabled stable recordings using H+-selective microelectrodes in a self-referencing format using bicarbonate-based buffer solutions. A small basal H+ flux was observed from the end foot region of quiescent cells bathed in 24 mM bicarbonate-based solutions, and increasing extracellular potassium induced a dose-dependent increase in H+ flux. Barium at 6 mM also increased H+ flux. Potassium-induced extracellular acidifications were abolished when bicarbonate was replaced by 1 mM HEPES. The carbonic anhydrase antagonist benzolamide potentiated the potassium-induced extracellular acidification, while 300 MUM DIDS, 300 MUM SITS, and 30 MUM S0859 significantly reduced the response. Potassium-induced extracellular acidifications persisted in solutions lacking extracellular calcium, although potassium-induced changes in intracellular calcium monitored with Oregon Green were abolished. Exchange of external sodium with choline also eliminated the potassium-induced extracellular acidification. Removal of extracellular sodium by itself induced a transient alkalinization, and replacement of sodium induced a transient acidification, both of which were blocked by 300 MUM DIDS. Recordings at the apical portion of the cell showed smaller potassium-induced extracellular H+ fluxes, and removal of the end foot region further decreased the H+ flux, suggesting that the end foot was the major source of acidifications. These studies demonstrate that self-referencing H+ selective electrodes can be used to monitor H+ fluxes from retinal Muller cells in bicarbonate-based solutions and confirm the presence of a sodium-coupled bicarbonate transporter, the activity of which is largely restricted to the end foot of the cell.NEW & NOTEWORTHY The present study uses self-referencing H+ selective electrodes for the first time to measure H+ fluxes from Muller (glial) cells isolated from tiger salamander retina. These studies demonstrate bicarbonate transport as a potent regulator of extracellular levels of acidity around Muller cells and point toward a need for further studies aimed at addressing how such glial cell pH regulatory mechanisms may shape neuronal signaling. PMID- 28855293 TI - Social experience alters socially induced serotonergic fluctuations in the inferior colliculus. AB - Past social experience and current social context shape the responses of animals to social signals. The serotonergic system is one potential mechanism by which both experiential and contextual factors could be conveyed to sensory systems, such as the auditory system, for multiple reasons. 1) Many features of the serotonergic system are sensitive to social experience. 2) Elevations in serotonergic activity are triggered by social partners, and variations in socially triggered serotonergic responses reflect behavioral differences among social encounters. 3) Serotonin is an auditory neuromodulator, altering how auditory neurons respond to sounds including conspecific vocalizations. In this study, we tested how social experience influences the socially triggered serotonergic response in the inferior colliculus, an auditory midbrain region with an important role in vocalization processing. We used carbon fiber voltammetry to measure serotonin during social interactions of male mice (Mus musculus) from different social backgrounds: 4 weeks of grouped or individual housing. When paired with an unfamiliar male, both group-housed and individually housed males demonstrated elevations in serotonin; however, individually housed males exhibited socially triggered serotonergic responses with delayed time courses compared with the group-housed males. Furthermore, group-housed males displayed previously described correlations between the socially triggered serotonergic response and behaviors such as social investigation. In contrast, individually housed males did not show these serotonin-behavior relationships. These results suggest that social experience gained via social housing may shape the ability of the central serotonergic system to encode social context in sensory regions.NEW & NOTEWORTHY We demonstrate that past social experience influences the fidelity with which the serotonergic system represents social context in an auditory region. Social experience altered the time course of socially triggered serotonergic responses and changed how the serotonergic system reflects behavioral variations among social encounters of the same context. These findings are significant to the study of communication, suggesting that centralized neuromodulatory systems potentially convey integrated information regarding past experience and current context to primary sensory regions. PMID- 28855295 TI - Corticospinal excitability of the biceps brachii is shoulder position dependent. AB - The purpose of this study was to examine the effect of shoulder position on corticospinal excitability (CSE) of the biceps brachii during rest and a 10% maximal voluntary contraction (MVC). Participants (n = 9) completed two experimental sessions with four conditions: 1) rest, 0 degrees shoulder flexion; 2) 10% MVC, 0 degrees shoulder flexion; 3) rest, 90 degrees shoulder flexion; and 4) 10% MVC, 90 degrees shoulder flexion. Transcranial magnetic, transmastoid electrical, and Erb's point stimulation were used to induce motor-evoked potentials (MEPs), cervicomedullary MEPs (CMEPs), and maximal muscle compound potentials (Mmax), respectively, in the biceps brachii in each condition. At rest, MEP, CMEP, and Mmax amplitudes increased (P < 0.01) by 509.7 +/- 118.3%, 113.3 +/- 28.3%, and 155.1 +/- 47.9%, respectively, at 90 degrees compared with 0 degrees . At 10% MVC, MEP amplitudes did not differ (P = 0.08), but CMEP and Mmax amplitudes increased (P < 0.05) by 32.3 +/- 10.5% and 127.9 +/- 26.1%, respectively, at 90 degrees compared with 0 degrees . MEP/Mmax increased (P < 0.01) by 224.0 +/- 99.1% at rest and decreased (P < 0.05) by 51.3 +/- 6.7% at 10% MVC at 90 degrees compared with 0 degrees . CMEP/Mmax was not different (P = 0.22) at rest but decreased (P < 0.01) at 10% MVC by 33.6 +/- 6.1% at 90 degrees compared with 0 degrees . EMG increased (P < 0.001) by 8.3 +/- 2.0% at rest and decreased (P < 0.001) by 21.4 +/- 4.4% at 10% MVC at 90 degrees compared with 0 degrees . In conclusion, CSE of the biceps brachii was dependent on shoulder position, and the pattern of change was altered within the state in which it was measured. The position-dependent changes in Mmax amplitude, EMG, and CSE itself all contribute to the overall change in CSE of the biceps brachii.NEW & NOTEWORTHY We demonstrate that when the shoulder is placed into two common positions for determining elbow flexor force and activation, corticospinal excitability (CSE) of the biceps brachii is both shoulder position and state dependent. At rest, when the shoulder is flexed from 0 degrees to 90 degrees , supraspinal factors predominantly alter CSE, whereas during a slight contraction, spinal factors predominantly alter CSE. Finally, the normalization techniques frequently used by researchers to investigate CSE may under- and overestimate CSE when shoulder position is changed. PMID- 28855294 TI - Contribution of spiking activity in the primary auditory cortex to detection in noise. AB - A fundamental problem in hearing is detecting a "target" stimulus (e.g., a friend's voice) that is presented with a noisy background (e.g., the din of a crowded restaurant). Despite its importance to hearing, a relationship between spiking activity and behavioral performance during such a "detection-in-noise" task has yet to be fully elucidated. In this study, we recorded spiking activity in primary auditory cortex (A1) while rhesus monkeys detected a target stimulus that was presented with a noise background. Although some neurons were modulated, the response of the typical A1 neuron was not modulated by the stimulus- and task related parameters of our task. In contrast, we found more robust representations of these parameters in population-level activity: small populations of neurons matched the monkeys' behavioral sensitivity. Overall, these findings are consistent with the hypothesis that the sensory evidence, which is needed to solve such detection-in-noise tasks, is represented in population-level A1 activity and may be available to be read out by downstream neurons that are involved in mediating this task.NEW & NOTEWORTHY This study examines the contribution of A1 to detecting a sound that is presented with a noisy background. We found that population-level A1 activity, but not single neurons, could provide the evidence needed to make this perceptual decision. PMID- 28855296 TI - Method to remove photoreceptors from whole mount retina in vitro. AB - Patch clamp recordings of neurons in the inner nuclear layer of the retina are difficult to conduct in a whole mount retina preparation because surrounding neurons block the path of the patch pipette. Vertical slice preparations or dissociated retinal cells provide access to bipolar cells at the cost of severing the lateral connection between neurons. We have developed a technique to remove photoreceptors from the rodent retina that exposes inner nuclear layer neurons, allowing access for patch clamp recording. Repeated application to and removal of filter paper from the photoreceptor side of an isolated retina effectively and efficiently removes photoreceptor cells and, in degenerate retina, hypertrophied Muller cell end feet. Live-dead assays applied to neurons remaining after photoreceptor removal demonstrated mostly viable cells. Patch clamp recordings from bipolar cells reveal responses similar to those recorded in traditional slice and dissociated cell preparations. An advantage of the photoreceptor peel technique is that it exposes inner retinal neurons in a whole mount retina preparation for investigation of signal processing. A disadvantage is that photoreceptor removal alters input to remaining retinal neurons. The technique may be useful for investigations of extracellular electrical stimulation, photoreceptor DNA analysis, and nonpharmacological removal of light input.NEW & NOTEWORTHY This study reports a method for removing photoreceptors from rodent whole mount retina while preserving the architecture of the inner retina. The method enables easier access to the inner retina for studies of neural processing, such as by patch clamp recording. PMID- 28855297 TI - The neural basis of temporal individuation and its capacity limits in the human brain. AB - Individuation refers to individuals' use of spatial and temporal properties to register objects as distinct perceptual events relative to other stimuli. Although behavioral studies have examined both spatial and temporal individuation, neuroimaging investigations have been restricted to the spatial domain and at relatively late stages of information processing. Here, we used univariate and multivoxel pattern analyses of functional MRI data to identify brain regions involved in individuating temporally distinct visual items and the neural consequences that arise when this process reaches its capacity limit (repetition blindness, RB). First, we found that regional patterns of blood oxygen-level-dependent activity across the cortex discriminated between instances where repeated and nonrepeated stimuli were successfully individuated-conditions that placed differential demands on temporal individuation. These results could not be attributed to repetition suppression or other stimulus-related factors, task difficulty, regional activation differences, other capacity-limited processes, or artifacts in the data or analyses. Contrary to current theoretical models, this finding suggests that temporal individuation is supported by a distributed set of brain regions, rather than a single neural correlate. Second, conditions that reflect the capacity limit of individuation-instances of RB-lead to changes in the spatial patterns within this network, as well as amplitude changes in the left hemisphere premotor cortex, superior medial frontal cortex, anterior cingulate cortex, and bilateral parahippocampal place area. These findings could not be attributed to response conflict/ambiguity and likely reflect the core brain regions and mechanisms that underlie the capacity-limited process that gives rise to RB.NEW & NOTEWORTHY We present novel findings into the neural bases of temporal individuation and repetition blindness (RB)-the perceptual deficit that arises when this process reaches its capacity limit. Specifically, we found that temporal individuation is a widely distributed process in the brain and identified a number of candidate brain regions that appear to underpin RB. These findings enhance our understanding of how these fundamental perceptual processes are reflected in the human brain. PMID- 28855299 TI - Tobacco retail environment near housing programmes for patients with mental health conditions in New York City. AB - OBJECTIVES: The current study sought to characterise the tobacco retail environment of supportive housing facilities for persons with mental health (MH) conditions in New York City (NYC) and to estimate the potential impact of a tobacco retail ban near public schools on the retail environment of MH housing in NYC. METHODS: Texas A&M Geocoding Services was used to geocode the addresses of housing programmes for patients with MH conditions, non-MH residences, public schools and tobacco retailers in NYC. ESRI ArcMap was used to calculate the number of tobacco retailers within a 500-foot radius around each housing programme and school address point, and the Euclidean distance to the nearest retailer. Generalised linear models were used to compare retail counts and distance between MH and non-MH residences. RESULTS: The mean number of tobacco retailers within 500 feet of an MH housing programme was 2.9 (SD=2.3) and the mean distance to nearest tobacco retailer was 370.6 feet (SD=350.7). MH residences had more retailers within 500 feet and a shorter distance to the nearest retailer compared with non-MH residences in Brooklyn, the Bronx and Staten Island (p<0.001). Banning tobacco licences within 350, 500 or 1000 feet of a school would significantly improve the tobacco retail environment of MH housing programmes and reduce disparities between MH and non-MH residences in some boroughs. CONCLUSIONS: People with MH conditions residing in supportive housing in NYC encounter a heavy tobacco retail environment in close proximity to their home, and in some boroughs, one worse than non-MH residences. Implementing a ban on tobacco retail near public schools would improve the tobacco retail environment of MH housing programmes in NYC. PMID- 28855298 TI - Spinal BDNF-induced phrenic motor facilitation requires PKCtheta activity. AB - Spinal brain-derived neurotrophic factor (BDNF) is necessary and sufficient for certain forms of long-lasting phrenic motor facilitation (pMF). BDNF elicits pMF by binding to its high-affinity receptor, tropomyosin receptor kinase B (TrkB), on phrenic motor neurons, potentially activating multiple downstream signaling cascades. Canonical BDNF/TrkB signaling includes the 1) Ras/RAF/MEK/ERK MAP kinase, 2) phosphatidylinositol 3-kinase (PI3K)/Akt, and 3) PLCgamma/PKC pathways. Here we demonstrate that spinal BDNF-induced pMF requires PLCgamma/PKCtheta in normal rats but not MEK/ERK or PI3K/Akt signaling. Cervical intrathecal injections of MEK/ERK (U0126) or PI3K/Akt (PI-828; 100 MUM, 12 MUl) inhibitor had no effect on BDNF-induced pMF (90 min after BDNF; U0126 + BDNF: 59 +/- 14%, PI-828 + BDNF: 59 +/- 8%, inhibitor vehicle + BDNF: 56 +/- 7%; all P >= 0.05). In contrast, PKCtheta inhibition with theta inhibitory peptide (TIP; 0.86 mM, 12 MUl) prevented BDNF-induced pMF (90 min after BDNF; TIP + BDNF: -2 +/- 2%; P <= 0.05 vs. other groups). Thus BDNF-induced pMF requires downstream PLCgamma/PKCtheta signaling, contrary to initial expectations.NEW AND NOTEWORTHY We demonstrate that BDNF-induced pMF requires downstream signaling via PKCtheta but not MEK/ERK or PI3K/Akt signaling. These data are essential to understand the sequence of the cellular cascade leading to BDNF-dependent phrenic motor plasticity. PMID- 28855300 TI - An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. AB - Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM2. TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C-terminal to histidine 157, a position where an AD-associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full-length TREM2 and lowers TREM2-dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM2. PMID- 28855301 TI - TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant. AB - We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2-expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N-terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding. Peptidomimetic protease inhibitors highlighted a possible cleavage site, and mass spectrometry confirmed that shedding occurred predominantly at the H157-S158 peptide bond for both wild-type and H157Y human TREM2 and for the wild-type murine orthologue. Crucially, we also show that the Alzheimer's disease-associated H157Y TREM2 variant was shed more rapidly than wild type from HEK293 cells, possibly by a novel, batimastat- and ADAM10-siRNA-independent, sheddase activity. These insights offer new therapeutic targets for modulating the innate immune response in Alzheimer's and other neurological diseases. PMID- 28855303 TI - Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Use with Positive Blood Cultures: Methodology, Performance, and Optimization. AB - Early initiation of effective antibiotics for septic patients is essential for patient survival. Matrix-assisted desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has revolutionized clinical microbiology for isolate identification and has the possibility to impact how blood culture testing is performed. This review discusses the various uses of MALDI-TOF MS for the identification and susceptibility testing of positive blood cultures, the performance of these methods, and the outcomes involved with its implementation. PMID- 28855304 TI - Urine as Sample Type for Molecular Diagnosis of Natural Yellow Fever Virus Infections. PMID- 28855305 TI - Field Evaluation of Performance of Alere and Cepheid Qualitative HIV Assays for Pediatric Point-of-Care Testing in an Academic Hospital in Soweto, South Africa. AB - Point-of-care (POC) technologies for HIV diagnosis in infants have the potential to overcome logistical challenges that delay treatment initiation and prevent improvements in morbidity and mortality. This study aimed to evaluate the performance of two POC technologies against the current standard-of-care (SOC) laboratory-based assay in South Africa, when operated by nurses in a hospital environment. Children <18 months of age who were treatment naive (excluding prophylaxis) and in whom an HIV PCR test was indicated were eligible for the study. To increase the rate of enrollment of HIV PCR-positive children, HIV exposed neonates at high risk of mother-to-child transmission and children requiring confirmatory HIV testing were preferentially enrolled. The two POC technologies demonstrated excellent concordance, with 315 (97.8%) results consistent with the SOC result. The POC technologies yielded 102 positive and 220 negative tests each. The SOC assay had 101 positive, 214 negative, 4 indeterminate, 1 invalid, and 2 specimen-rejected results. To include the indeterminate results in sensitivity/specificity calculations, a sensitivity analysis was performed, which yielded a simulated sensitivity of 0.9904 (interquartile range [IQR], 0.9808 to 0.9904) and a specificity of 0.9954 (IQR, 0.9954 to 1.0). This study confirmed that both POC technologies can be successfully used outside the laboratory environment to yield precise sensitivity/specificity values for pediatric, including neonatal, HIV testing. PMID- 28855306 TI - IL-23 drives differentiation of peripheral gammadelta17 T cells from adult bone marrow-derived precursors. AB - Pro-inflammatory interleukin (IL)-17-producing gammadelta (gammadelta17) T cells are thought to develop exclusively in the thymus during fetal/perinatal life, as adult bone marrow precursors fail to generate gammadelta17 T cells under homeostatic conditions. Here, we employ a model of experimental autoimmune encephalomyelitis (EAE) in which hematopoiesis is reset by bone marrow transplantation and demonstrate unequivocally that Vgamma4+ gammadelta17 T cells can develop de novo in draining lymph nodes in response to innate stimuli. In vitro, gammadelta T cells from IL-17 fate-mapping reporter mice that had never activated the Il17 locus acquire IL-17 expression upon stimulation with IL-1beta and IL-23. Furthermore, IL-23R (but not IL-1R1) deficiency severely compromises the induction of gammadelta17 T cells in EAE, demonstrating the key role of IL-23 in the process. Finally, we show, in a composite model involving transfers of both adult bone marrow and neonatal thymocytes, that induced gammadelta17 T cells make up a substantial fraction of the total IL-17-producing Vgamma4+ T-cell pool upon inflammation, which attests the relevance of this novel pathway of peripheral gammadelta17 T-cell differentiation. PMID- 28855308 TI - A cross-sectional population-based study of breast cancer screening among women with HIV in Ontario, Canada. AB - BACKGROUND: As women with HIV live longer, the need for age-appropriate breast cancer screening will increase. We compared rates of screening mammography among women with and without HIV. METHODS: We used administrative health databases to identify all women in Ontario, Canada, who were eligible for screening mammography (aged 50 to 74 yr and no history of breast cancer) as of Apr. 1, 2011. We used multivariable log-binomial regression to compare the 2-year period prevalence of screening mammography in 2011 to 2013 among women with and without HIV and to examine the correlates of screening among women with HIV. RESULTS: We identified 1 447 015 screen-eligible women, among whom 623 (0.04%) were women with HIV. Women with HIV were less likely to undergo screening than women without HIV (50.1% v. 63.4%, p < 0.001). Following multivariable adjustment, HIV-positive status was associated with significantly lower odds of undergoing mammography (adjusted prevalence ratio [PR] 0.83, 95% confidence interval [CI] 0.77-0.89). Compared with women with HIV receiving regular care from both a family physician and an HIV specialist, women with HIV receiving neither kind of care (adjusted PR 0.64, 95% CI 0.50-0.83) or predominantly specialist care (adjusted PR 0.77; 95% CI 0.60 to 0.97) were less likely to undergo screening mammography. INTERPRETATION: Women with HIV are less likely to undergo breast cancer screening mammography than women without HIV. Addressing this disparity requires optimizing care delivery to ensure adequate provision of comprehensive primary care to people with HIV. PMID- 28855307 TI - Testing Two Evolutionary Theories of Human Aging with DNA Methylation Data. AB - The evolutionary theories of mutation accumulation (MA) and disposable soma (DS) provide possible explanations for the existence of human aging. To better understand the relative importance of these theories, we devised a test to identify MA- and DS-consistent sites across the genome using familial DNA methylation data. Two key characteristics of DNA methylation allowed us to do so. First, DNA methylation exhibits distinct and widespread changes with age, with numerous age-differentially-methylated sites observed across the genome. Second, many sites show heritable DNA methylation patterns within families. We extended heritability predictions of MA and DS to DNA methylation, predicting that MA consistent age-differentially-methylated sites will show increasing heritability with age, while DS-consistent sites will show the opposite. Variance components models were used to test for changing heritability of methylation with age at 48,601 age-differentially-methylated sites across the genome in 610 individuals from 176 families. Of these, 102 sites showed significant MA-consistent increases in heritability with age, while 2266 showed significant DS-consistent decreases in heritability. These results suggest that both MA and DS play a role in explaining aging and aging-related changes, and that while the majority of DNA methylation changes observed in aging are consistent with epigenetic drift, targeted changes exist and may mediate effects of aging-related genes. PMID- 28855309 TI - IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice. AB - In this study, we determined the role of IL-21R signaling in Mycobacterium tuberculosis infection, using IL-21R knockout (KO) mice. A total of 50% of M. tuberculosis H37Rv-infected IL-21R KO mice died in 6 mo compared with no deaths in infected wild type (WT) mice. M. tuberculosis-infected IL-21R KO mice had enhanced bacterial burden and reduced infiltration of Ag-specific T cells in lungs compared with M. tuberculosis-infected WT mice. Ag-specific T cells from the lungs of M. tuberculosis-infected IL-21R KO mice had increased expression of T cell inhibitory receptors, reduced expression of chemokine receptors, proliferated less, and produced less IFN- gamma, compared with Ag-specific T cells from the lungs of M. tuberculosis-infected WT mice. T cells from M. tuberculosis-infected IL-21R KO mice were unable to induce optimal macrophage responses to M. tuberculosis. This may be due to a decrease in the Ag-specific T cell population. We also found that IL-21R signaling is associated with reduced expression of a transcriptional factor Eomesodermin and enhanced functional capacity of Ag-specific T cells of M. tuberculosis-infected mice. The sum of our findings suggests that IL-21R signaling is essential for the optimal control of M. tuberculosis infection. PMID- 28855310 TI - Chemokine Receptor-Dependent Control of Skin Tissue-Resident Memory T Cell Formation. AB - Infection or inflammation of the skin recruits effector CD8+ T cells that enter the epidermis and form populations of long-lived tissue-resident memory T (TRM) cells. These skin TRM cells migrate within the constrained epidermal environment by extending multiple dynamic dendritic projections and squeezing between keratinocytes to survey the tissue for pathogens. In this study, we examined the signals required for this distinctive mode of T cell migration by inhibiting key cytoskeletal components and performing intravital two-photon microscopy to visualize TRM cell behavior. We found that TRM cell motility and dendrite formation required an intact actomyosin cytoskeleton and the Rho-associated coiled-coil containing kinases. We also identified an essential role for microtubules for maintaining skin TRM cell shape and cellular integrity. We reveal a role for pertussis toxin-sensitive signaling for TRM cell dendritic morphology and migration that is independent of CXCR3 or CXCR6, or the skin selective chemokine receptors CCR10 and CCR8. However, we found that CXCR6 and CCR10 expression by CD8+ T cells was required for the optimal formation of memory T cell populations, in particular TRM cell populations in the skin. PMID- 28855311 TI - A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function. AB - Chlamydia is responsible for millions of new infections annually, and current efforts focus on understanding cellular immunity for targeted vaccine development. The Chlamydia-specific CD4 T cell response is characterized by the production of IFN-gamma, and polyfunctional Th1 responses are associated with enhanced protection. A major limitation in studying these responses is the paucity of tools available for detection, quantification, and characterization of polyfunctional Ag-specific T cells. We addressed this problem by developing a TCR transgenic (Tg) mouse with CD4 T cells that respond to a common Ag in Chlamydia muridarum and Chlamydia trachomatis Using an adoptive-transfer approach, we show that naive Tg CD4 T cells become activated, proliferate, migrate to the infected tissue, and acquire a polyfunctional Th1 phenotype in infected mice. Polyfunctional Tg Th1 effectors demonstrated enhanced IFN-gamma production compared with polyclonal cells, protected immune-deficient mice against lethality, mediated bacterial clearance, and orchestrated an anamnestic response. Adoptive transfer of Chlamydia-specific CD4 TCR-Tg T cells with polyfunctional capacity offers a powerful approach for analysis of protective effector and memory responses against chlamydial infection and demonstrates that an effective monoclonal CD4 T cell response may successfully guide subunit vaccination strategies. PMID- 28855312 TI - Cyclodextrin Reduces Cholesterol Crystal-Induced Inflammation by Modulating Complement Activation. AB - Cholesterol crystals (CC) are abundant in atherosclerotic plaques and promote inflammatory responses via the complement system and inflammasome activation. Cyclic oligosaccharide 2-hydroxypropyl-beta-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances. Recently we have shown that BCD has an anti inflammatory effect on CC via suppression of the inflammasome and liver X receptor activation. The putative effects of BCD on CC-induced complement activation remain unknown. In this study, we found that BCD bound to CC and reduced deposition of Igs, pattern recognition molecules, and complement factors on CC in human plasma. Furthermore, BCD decreased complement activation as measured by terminal complement complex and lowered the expression of complement receptors on monocytes in whole blood in response to CC exposure. In line with this, BCD also reduced reactive oxygen species formation caused by CC in whole blood. Furthermore, BCD attenuated the CC-induced proinflammatory cytokine responses (e.g., IL-1alpha, MIP-1alpha, TNF, IL-6, and IL-8) as well as regulated a range of CC-induced genes in human PBMC. BCD also regulated complement-related genes in human carotid plaques treated ex vivo. Formation of terminal complement complex on other complement-activating structures such as monosodium urate crystals and zymosan was not affected by BCD. These data demonstrate that BCD inhibits CC-induced inflammatory responses, which may be explained by BCD mediated attenuation of complement activation. Thus, these findings support the potential for using BCD in treatment of atherosclerosis. PMID- 28855313 TI - Complexity of Complement Resistance Factors Expressed by Acinetobacter baumannii Needed for Survival in Human Serum. AB - Acinetobacter baumannii is a bacterial pathogen with increasing impact in healthcare settings, due in part to this organism's resistance to many antimicrobial agents, with pneumonia and bacteremia as the most common manifestations of disease. A significant proportion of clinically relevant A. baumannii strains are resistant to killing by normal human serum (NHS), an observation supported in this study by showing that 12 out of 15 genetically diverse strains of A. baumannii are resistant to NHS killing. To expand our understanding of the genetic basis of A. baumannii serum resistance, a transposon (Tn) sequencing (Tn-seq) approach was used to identify genes contributing to this trait. An ordered Tn library in strain AB5075 with insertions in every nonessential gene was subjected to selection in NHS. We identified 50 genes essential for the survival of A. baumannii in NHS, including already known serum resistance factors, and many novel genes not previously associated with serum resistance. This latter group included the maintenance of lipid asymmetry genetic pathway as a key determinant in protecting A. baumannii from the bactericidal activity of NHS via the alternative complement pathway. Follow-up studies validated the role of eight additional genes identified by Tn-seq in A. baumannii resistance to killing by NHS but not by normal mouse serum, highlighting the human species specificity of A. baumannii serum resistance. The identification of a large number of genes essential for serum resistance in A. baumannii indicates the degree of complexity needed for this phenotype, which might reflect a general pattern that pathogens rely on to cause serious infections. PMID- 28855314 TI - IL-1beta and IL-23 Promote Extrathymic Commitment of CD27+CD122- gammadelta T Cells to gammadeltaT17 Cells. AB - gammadeltaT17 cells are a subset of gammadelta T cells committed to IL-17 production and are characterized by the expression of IL-23R and CCR6 and lack of CD27 expression. gammadeltaT17 cells are believed to arise within a narrow time window during prenatal thymic development. In agreement with this concept, we show in this study that adult Rag1-/- recipient mice of Il23rgfp/+ (IL-23R reporter) bone marrow selectively lack IL-23R+ gammadeltaT17 cells. Despite their absence in secondary lymphoid tissues during homeostasis, gammadeltaT17 cells emerge in bone marrow chimeric mice upon induction of skin inflammation by topical treatment with imiquimod cream (Aldara). We demonstrate that IL-1beta and IL-23 together are able to promote the development of bona fide gammadeltaT17 cells from peripheral CD122-IL-23R- gammadelta T cells, whereas CD122+ gammadelta T cells fail to convert into gammadeltaT17 cells and remain stable IFN-gamma producers (gammadeltaT1 cells). IL-23 is instrumental in expanding extrathymically generated gammadeltaT17 cells. In particular, TCR-Vgamma4+ chain expressing CD122-IL-23R- gammadelta T cells are induced to express IL-23R and IL 17 outside the thymus during skin inflammation. In contrast, TCR-Vgamma1+ gammadelta T cells largely resist this process because prior TCR engagement in the thymus has initiated their commitment to the gammadeltaT1 lineage. In summary, our data reveal that the peripheral pool of gammadelta T cells retains a considerable degree of plasticity because it harbors "naive" precursors, which can be induced to produce IL-17 and replenish peripheral niches that are usually occupied by thymus-derived gammadeltaT17 cells. PMID- 28855315 TI - Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance. AB - Obesity-associated activation of the renin-angiotensin-aldosterone system is implicated in the pathogenesis of insulin resistance; however, influences of mineralocorticoid receptor (MR) inhibition remain unclear. Therefore, we aimed to clarify the anti-inflammatory mechanisms of MR inhibition using eplerenone, a selective MR antagonist, in C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks. Eplerenone prevented excessive body weight gain and fat accumulation, ameliorated glucose intolerance and insulin resistance and enhanced energy metabolism. In the epididymal white adipose tissue (eWAT), eplerenone prevented obesity-induced accumulation of F4/80+CD11c+CD206--M1-adipose tissue macrophage (ATM) and reduction of F4/80+CD11c-CD206+-M2-ATM. Interestingly, M1-macrophage exhibited lower expression levels of MR, compared with M2-macrophage, in the ATM of eWAT and in vitro-polarized bone marrow-derived macrophages (BMDM). Importantly, eplerenone and MR knockdown attenuated the increase in the expression levels of proIl1b, Il6 and Tnfa, in the eWAT and liver of HFD-fed mice and LPS-stimulated BMDM. Moreover, eplerenone suppressed IL1b secretion from eWAT of HFD-fed mice. To reveal the anti-inflammatory mechanism, we investigated the involvement of NLRP3-inflammasome activation, a key process of IL1b overproduction. Eplerenone suppressed the expression of the inflammasome components, Nlrp3 and Caspase1, in the eWAT and liver. Concerning the second triggering factors, ROS production and ATP- and nigericin-induced IL1b secretion were suppressed by eplerenone in the LPS-primed BMDM. These results indicate that eplerenone inhibited both the priming and triggering signals that promote NLRP3-inflammasome activation. Therefore, we consider MR to be a crucial target to prevent metabolic disorders by suppressing inflammasome-mediated chronic inflammation in the adipose tissue and liver under obese conditions. PMID- 28855317 TI - Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists. AB - Type 2 diabetes mellitus (T2DM) leads to bone fragility and predisposes to increased risk of fracture, poor bone healing and other skeletal complications. In addition, some anti-diabetic therapies for T2DM can have notable detrimental skeletal effects. Thus, an appropriate therapeutic strategy for T2DM should not only be effective in re-establishing good glycaemic control but also in minimising skeletal complications. There is increasing evidence that glucagon like peptide-1 receptor agonists (GLP-1RAs), now greatly prescribed for the treatment of T2DM, have beneficial skeletal effects although the underlying mechanisms are not completely understood. This review provides an overview of the direct and indirect effects of GLP-1RAs on bone physiology, focusing on bone quality and novel mechanisms of action on the vasculature and hormonal regulation. The overall experimental studies indicate significant positive skeletal effects of GLP-1RAs on bone quality and strength although their mechanisms of actions may differ according to various GLP-1RAs and clinical studies supporting their bone protective effects are still lacking. The possibility that GLP-1RAs could improve blood supply to bone, which is essential for skeletal health, is of major interest and suggests that GLP-1 anti-diabetic therapy could benefit the rising number of elderly T2DM patients with osteoporosis and high fracture risk. PMID- 28855318 TI - Considering aspects of the 3Rs principles within experimental animal biology. AB - The 3Rs - Replacement, Reduction and Refinement - are embedded into the legislation and guidelines governing the ethics of animal use in experiments. Here, we consider the advantages of adopting key aspects of the 3Rs into experimental biology, represented mainly by the fields of animal behaviour, neurobiology, physiology, toxicology and biomechanics. Replacing protected animals with less sentient forms or species, cells, tissues or computer modelling approaches has been broadly successful. However, many studies investigate specific models that exhibit a particular adaptation, or a species that is a target for conservation, such that their replacement is inappropriate. Regardless of the species used, refining procedures to ensure the health and well-being of animals prior to and during experiments is crucial for the integrity of the results and legitimacy of the science. Although the concepts of health and welfare are developed for model organisms, relatively little is known regarding non-traditional species that may be more ecologically relevant. Studies should reduce the number of experimental animals by employing the minimum suitable sample size. This is often calculated using power analyses, which is associated with making statistical inferences based on the P-value, yet P-values often leave scientists on shaky ground. We endorse focusing on effect sizes accompanied by confidence intervals as a more appropriate means of interpreting data; in turn, sample size could be calculated based on effect size precision. Ultimately, the appropriate employment of the 3Rs principles in experimental biology empowers scientists in justifying their research, and results in higher-quality science. PMID- 28855316 TI - Stem/progenitor cells in pituitary organ homeostasis and tumourigenesis. AB - Evidence for the presence of pituitary gland stem cells has been provided over the last decade using a combination of approaches including in vitro clonogenicity assays, flow cytometric side population analysis, immunohistochemical analysis and genetic approaches. These cells have been demonstrated to be able to self-renew and undergo multipotent differentiation to give rise to all hormonal lineages of the anterior pituitary. Furthermore, evidence exists for their contribution to regeneration of the organ and plastic responses to changing physiological demand. Recently, stem-like cells have been isolated from pituitary neoplasms raising the possibility that a cytological hierarchy exists, in keeping with the cancer stem cell paradigm. In this manuscript, we review the evidence for the existence of pituitary stem cells, their role in maintaining organ homeostasis and the regulation of their differentiation. Furthermore, we explore the emerging concept of stem cells in pituitary tumours and their potential roles in these diseases. PMID- 28855319 TI - Pharmacological effects of cannabinoids on learning and memory in Lymnaea. AB - Cannabinoids are hypothesized to play an important role in modulating learning and memory formation. Here, we identified mRNAs expressed in Lymnaeastagnalis central nervous system that encode two G-protein-coupled receptors (Lymnaea CBr like 1 and 2) that structurally resemble mammalian cannabinoid receptors (CBrs). We found that injection of a mammalian CBr agonist WIN 55,212-2 (WIN 55) into the snail before operant conditioning obstructed learning and memory formation. This effect of WIN 55 injection persisted for at least 4 days following its injection. A similar obstruction of learning and memory occurred when a severe traumatic stimulus was delivered to L. stagnalis In contrast, injection of a mammalian CBr antagonist AM 251 enhanced long-term memory formation in snails and reduced the duration of the effects of the severe traumatic stressor on learning and memory. Neither WIN 55 nor AM 251 altered normal homeostatic aerial respiratory behaviour elicited in hypoxic conditions. Our results suggest that putative cannabinoid receptors mediate stressful stimuli that alter learning and memory formation in Lymnaea This is also the first demonstration that putative CBrs are present in Lymnaea and play a key role in learning and memory formation. PMID- 28855320 TI - Performance, morphology and control of power-amplified mandibles in the trap-jaw ant Myrmoteras (Hymenoptera: Formicidae). AB - Trap-jaw ants are characterized by high-speed mandibles used for prey capture and defense. Power-amplified mandibles have independently evolved at least four times among ants, with each lineage using different structures as a latch, spring and trigger. We examined two species from the genus Myrmoteras (subfamily Formicinae), whose morphology is unique among trap-jaw ant lineages, and describe the performance characteristics, spring-loading mechanism and neuronal control of Myrmoteras strikes. Like other trap-jaw ants, Myrmoteras latch their jaws open while the large closer muscle loads potential energy in a spring. The latch differs from other lineages and is likely formed by the co-contraction of the mandible opener and closer muscles. The cuticle of the posterior margin of the head serves as a spring, and is deformed by approximately 6% prior to a strike. The mandibles are likely unlatched by a subgroup of closer muscle fibers with particularly short sarcomeres. These fast fibers are controlled by two large motor neurons whose dendrites overlap with terminals of large sensory neurons originating from labral trigger hairs. Upon stimulation of the trigger hairs, the mandibles shut in as little as 0.5 ms and at peak velocities that are comparable with other trap-jaw ants, but with much slower acceleration. The estimated power output of the mandible strike (21 kW kg-1) confirms that Myrmoteras jaws are indeed power amplified. However, the power output of Myrmoteras mandibles is significantly lower than distantly related trap-jaw ants using different spring loading mechanisms, indicating a relationship between power-amplification mechanism and performance. PMID- 28855321 TI - The role of stochastic thermal environments in modulating the thermal physiology of an intertidal limpet, Lottia digitalis. AB - Much of our understanding of the thermal physiology of intertidal organisms comes from experiments with animals acclimated under constant conditions and exposed to a single heat stress. In nature, however, the thermal environment is more complex. Aerial exposure and the unpredictable nature of thermal stress during low tides may be critical factors in defining the thermal physiology of intertidal organisms. In the fingered limpet, Lottia digitalis, we investigated whether upper temperature tolerance and thermal sensitivity were influenced by the pattern of fluctuation with which thermal stress was applied. Specifically, we examined whether there was a differential response (measured as cardiac performance) to repeated heat stress of a constant and predictable magnitude compared with heat stress applied in a stochastic and unpredictable nature. We also investigated differences in cellular metabolism and damage following immersion for insights into biochemical mechanisms of tolerance. Upper temperature tolerance increased with aerial exposure, but no significant differences were found between predictable treatments of varying magnitudes (13 degrees C versus 24 degrees C versus 32 degrees C). Significant differences in thermal tolerance were found between unpredictable trials with different heating patterns. There were no significant differences among treatments in basal citrate synthase activity, glycogen content, oxidative stress or antioxidants. Our results suggest that aerial exposure and recent thermal history, paired with relief from high low-tide temperatures, are important factors modulating the capacity of limpets to deal with thermal stress. PMID- 28855322 TI - The thermal background determines how the infrared and visual systems interact in pit vipers. AB - The thermal infrared (IR) sensing system of pit vipers is believed to complement vision and provide a substitute imaging system in dark environments. Theoretically, the IR system would best image a scene consisting of a homothermal target in cold surroundings as a bright spot on a dark background. To test this hypothesis, we evaluated how the pit viper (Gloydius brevicaudus) discriminates and strikes prey when the background temperature is either higher or lower than that of the prey (approximately 32-33 degrees C) in different parts of the scene. Snakes were tested in a modified predation cage in which background temperatures were set to 26 degrees C on one side and either 33 or 40 degrees C on the opposite side when the eyes, the pit organs or neither sensory system was occluded. When the eyes were blocked, snakes preferred to strike prey on the 26 degrees C side rather than on the 33 degrees C side but showed no bias in the other conditions. Snakes showed no preference for 26 versus 40 degrees C background temperature, although more missed strikes occurred when the eyes were occluded. The results thus revealed that the pit viper IR system can accomplish a 'brightness constancy' computation reflecting the difference between the target and background temperatures, much as the visual system compares the luminance of a figure and the background. Furthermore, the results show that the IR system performs less well for locating prey when the background is warmer than the target. PMID- 28855323 TI - Rib kinematics during lung ventilation in the American alligator (Alligator mississippiensis): an XROMM analysis. AB - The current hypothesis regarding the mechanics of breathing in crocodylians is that the double-headed ribs, with both a capitulum and tuberculum, rotate about a constrained axis passing through the two articulations; moreover, this axis shifts in the caudal thoracic ribs, as the vertebral parapophysis moves from the centrum to the transverse process. Additionally, the ventral ribcage in crocodylians is thought to possess additional degrees of freedom through mobile intermediate ribs. In this study, X-ray reconstruction of moving morphology (XROMM) was used to quantify rib rotation during breathing in American alligators. Whilst costovertebral joint anatomy predicted overall patterns of motion across the ribcage (decreased bucket handle motion and increased calliper motion), there were significant deviations: anatomical axes overestimated pump handle motion and, generally, ribs in vivo rotate about all three body axes more equally than predicted. The intermediate ribs are mobile, with a high degree of rotation measured about the dorsal intracostal joints, especially in the more caudal ribs. Motion of the sternal ribs became increasingly complex caudally, owing to a combination of the movements of the vertebral and intermediate segments. As the crocodylian ribcage is sometimes used as a model for the ancestral archosaur, these results have important implications for how rib motion is reconstructed in fossil taxa, and illustrate the difficulties in reconstructing rib movement based on osteology alone. PMID- 28855324 TI - Responses of larval zebrafish to low pH immersion assay. Comment on Lopez-Luna et al. PMID- 28855325 TI - Response to: Responses of larval zebrafish to low pH immersion assay. Comment on Lopez-Luna et al. PMID- 28855327 TI - Wolbachia, bottled water, and the dark side of symbiosis. AB - Obligate endosymbiosis is operationally defined when loss or removal of the endosymbiont from the host results in the death of both. Whereas these relationships are typically viewed as mutualistic, molecular and cellular analysis reveals numerous instances in which these symbiotic relationships are established by alternative, nonmutualistic strategies. The endosymbiont usurps or integrates into core host processes, creating a need where none previously existed. Here I discuss examples of these addictive symbiotic relationships and how they are a likely outcome of all complex evolving systems. PMID- 28855328 TI - Working Memories Are Maintained in a Stable Code. PMID- 28855329 TI - Advantages of Using the Dorsolateral versus the Dorsomedial Visual Stream for Decoding Hand Movements. PMID- 28855326 TI - The RNA modification landscape in human disease. AB - RNA modifications have been historically considered as fine-tuning chemo structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps. PMID- 28855330 TI - Membrane-Associated Effects of Glucocorticoid on BACE1 Upregulation and Abeta Generation: Involvement of Lipid Raft-Mediated CREB Activation. AB - Glucocorticoid has been widely accepted to induce Alzheimer's disease, but the nongenomic effect of glucocorticoid on amyloid beta (Abeta) generation has yet to be studied. Here, we investigated the effect of the nongenomic pathway induced by glucocorticoid on amyloid precursor protein processing enzymes as well as Abeta production using male ICR mice and human neuroblastoma SK-N-MC cells. Mice groups exposed to restraint stress or intracerebroventricular injection of Abeta showed impaired cognition, decreased intracellular glucocorticoid receptor (GR) level, but elevated level of membrane GR (mGR). In this respect, we identified the mGR dependent pathway evoked by glucocorticoid using impermeable cortisol conjugated to BSA (cortisol-BSA) on SK-N-MC cells. Cortisol-BSA augmented the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), the level of C terminal fragment beta of amyloid precursor protein (C99) and Abeta production, which were maintained even after blocking intracellular GR. We also found that cortisol-BSA enhanced the interaction between mGR and Galphas, which colocalized in the lipid raft. The subsequently activated CREB by cortisol-BSA bound to the CRE site of the BACE1 promoter increasing its expression, which was downregulated by inhibiting CBP. Consistently, blocking CBP attenuated cognitive impairment and Abeta production induced by corticosterone treatment or intracerebroventricular injection of Abeta more efficiently than inhibiting intracellular GR in mice. In conclusion, glucocorticoid couples mGR with Galphas and triggers cAMP-PKA-CREB axis dependent on the lipid raft to stimulate BACE1 upregulation and Abeta generation.SIGNIFICANCE STATEMENT Patients with Alzheimer's disease (AD) have been growing sharply and stress is considered as the major environment factor of AD. Glucocorticoid is the primarily responsive factor to stress and is widely known to induce AD. However, most AD patients usually have impaired genomic pathway of glucocorticoid due to intracellular glucocorticoid receptor deficiency. In this respect, the genomic mechanism of glucocorticoid faces difficulties in explaining the consistent amyloid beta (Abeta) production. Therefore, it is necessary to investigate the novel pathway of glucocorticoid on Abeta generation to find a more selective therapeutic approach to AD patients. In this study, we revealed the importance of nongenomic pathway induced by glucocorticoid where membrane glucocorticoid receptor plays an important role in Abeta formation. PMID- 28855331 TI - Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway. AB - Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans.SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs. PMID- 28855332 TI - GENERAL CONTROL NONREPRESSIBLE4 Degrades 14-3-3 and the RIN4 Complex to Regulate Stomatal Aperture with Implications on Nonhost Disease Resistance and Drought Tolerance. AB - Plants have complex and adaptive innate immune responses against pathogen infections. Stomata are key entry points for many plant pathogens. Both pathogens and plants regulate stomatal aperture for pathogen entry and defense, respectively. Not all plant proteins involved in stomatal aperture regulation have been identified. Here, we report GENERAL CONTROL NONREPRESSIBLE4 (GCN4), an AAA+-ATPase family protein, as one of the key proteins regulating stomatal aperture during biotic and abiotic stress. Silencing of GCN4 in Nicotiana benthamiana and Arabidopsis thaliana compromises host and nonhost disease resistance due to open stomata during pathogen infection. AtGCN4 overexpression plants have reduced H+-ATPase activity, stomata that are less responsive to pathogen virulence factors such as coronatine (phytotoxin produced by the bacterium Pseudomonas syringae) or fusicoccin (a fungal toxin produced by the fungus Fusicoccum amygdali), reduced pathogen entry, and enhanced drought tolerance. This study also demonstrates that AtGCN4 interacts with RIN4 and 14-3 3 proteins and suggests that GCN4 degrades RIN4 and 14-3-3 proteins via a proteasome-mediated pathway and thereby reduces the activity of the plasma membrane H+-ATPase complex, thus reducing proton pump activity to close stomata. PMID- 28855335 TI - Reversible structure manipulation by tuning carrier concentration in metastable Cu2S. AB - The optimal functionalities of materials often appear at phase transitions involving simultaneous changes in the electronic structure and the symmetry of the underlying lattice. It is experimentally challenging to disentangle which of the two effects--electronic or structural--is the driving force for the phase transition and to use the mechanism to control material properties. Here we report the concurrent pumping and probing of Cu2S nanoplates using an electron beam to directly manipulate the transition between two phases with distinctly different crystal symmetries and charge-carrier concentrations, and show that the transition is the result of charge generation for one phase and charge depletion for the other. We demonstrate that this manipulation is fully reversible and nonthermal in nature. Our observations reveal a phase-transition pathway in materials, where electron-induced changes in the electronic structure can lead to a macroscopic reconstruction of the crystal structure. PMID- 28855334 TI - Plant-Specific Histone Deacetylases HDT1/2 Regulate GIBBERELLIN 2-OXIDASE2 Expression to Control Arabidopsis Root Meristem Cell Number. AB - Root growth is modulated by environmental factors and depends on cell production in the root meristem (RM). New cells in the meristem are generated by stem cells and transit-amplifying cells, which together determine RM cell number. Transcription factors and chromatin-remodeling factors have been implicated in regulating the switch from stem cells to transit-amplifying cells. Here, we show that two Arabidopsis thaliana paralogs encoding plant-specific histone deacetylases, HDT1 and HDT2, regulate a second switch from transit-amplifying cells to expanding cells. Knockdown of HDT1/2 (hdt1,2i) results in an earlier switch and causes a reduced RM cell number. Our data show that HDT1/2 negatively regulate the acetylation level of the C19-GIBBERELLIN 2-OXIDASE2 (GA2ox2) locus and repress the expression of GA2ox2 in the RM and elongation zone. Overexpression of GA2ox2 in the RM phenocopies the hdt1,2i phenotype. Conversely, knockout of GA2ox2 partially rescues the root growth defect of hdt1,2i These results suggest that by repressing the expression of GA2ox2, HDT1/2 likely fine tune gibberellin metabolism and they are crucial for regulating the switch from cell division to expansion to determine RM cell number. We propose that HDT1/2 function as part of a mechanism that modulates root growth in response to environmental factors. PMID- 28855333 TI - Plant Signaling and Metabolic Pathways Enabling Arbuscular Mycorrhizal Symbiosis. AB - Plants have lived in close association with arbuscular mycorrhizal (AM) fungi for over 400 million years. Today, this endosymbiosis occurs broadly in the plant kingdom where it has a pronounced impact on plant mineral nutrition. The symbiosis develops deep within the root cortex with minimal alterations in the external appearance of the colonized root; however, the absence of macroscopic alterations belies the extensive signaling, cellular remodeling, and metabolic alterations that occur to enable accommodation of the fungal endosymbiont. Recent research has revealed the involvement of a novel N-acetyl glucosamine transporter and an alpha/beta-fold hydrolase receptor at the earliest stages of AM symbiosis. Calcium channels required for symbiosis signaling have been identified, and connections between the symbiosis signaling pathway and key transcriptional regulators that direct AM-specific gene expression have been established. Phylogenomics has revealed the existence of genes conserved for AM symbiosis, providing clues as to how plant cells fine-tune their biology to enable symbiosis, and an exciting coalescence of genome mining, lipid profiling, and tracer studies collectively has led to the conclusion that AM fungi are fatty acid auxotrophs and that plants provide their fungal endosymbionts with fatty acids. Here, we provide an overview of the molecular program for AM symbiosis and discuss these recent advances. PMID- 28855336 TI - Binding mechanism and dynamic conformational change of C subunit of PKA with different pathways. AB - The catalytic subunit of PKA (PKAc) exhibits three major conformational states (open, intermediate, and closed) during the biocatalysis process. Both ATP and substrate/inhibitor can effectively induce the conformational changes of PKAc from open to closed states. Aiming to explore the mechanism of this allosteric regulation, we developed a coarse-grained model and analyzed the dynamics of conformational changes of PKAc during binding by performing molecular dynamics simulations for apo PKAc, binary PKAc (PKAc with ATP, PKAc with PKI), and ternary PKAc (PKAc with ATP and PKI). Our results suggest a mixed binding mechanism of induced fit and conformational selection, with the induced fit dominant. The ligands can drive the movements of Gly-rich loop as well as some regions distal to the active site in PKAc and stabilize them at complex state. In addition, there are two parallel pathways (pathway with PKAc-ATP as an intermediate and pathway PKAc-PKI as an intermediate) during the transition from open to closed states. By molecular dynamics simulations and rate constant analyses, we find that the pathway through PKAc-ATP intermediate is the main binding route from open to closed state because of the fact that the bound PKI will hamper ATP from successful binding and significantly increase the barrier for the second binding subprocess. These findings will provide fundamental insights of the mechanisms of PKAc conformational change upon binding. PMID- 28855337 TI - An epigenetic switch repressing Tet1 in gonadotropes activates the reproductive axis. AB - The TET enzymes catalyze conversion of 5-methyl cytosine (5mC) to 5-hydroxymethyl cytosine (5hmC) and play important roles during development. TET1 has been particularly well-studied in pluripotent stem cells, but Tet1-KO mice are viable, and the most marked defect is abnormal ovarian follicle development, resulting in impaired fertility. We hypothesized that TET1 might play a role in the central control of reproduction by regulating expression of the gonadotropin hormones, which are responsible for follicle development and maturation and ovarian function. We find that all three TET enzymes are expressed in gonadotrope precursor cells, but Tet1 mRNA levels decrease markedly with completion of cell differentiation, corresponding with an increase in expression of the luteinizing hormone gene, Lhb We demonstrate that poorly differentiated gonadotropes express a TET1 isoform lacking the N-terminal CXXC-domain, which represses Lhb gene expression directly and does not catalyze 5hmC at the gene promoter. We show that this isoform is also expressed in other differentiated tissues, and that it is regulated by an alternative promoter whose activity is repressed by the liganded estrogen and androgen receptors, and by the hypothalamic gonadotropin-releasing hormone through activation of PKA. Its expression is also regulated by DNA methylation, including at an upstream enhancer that is protected by TET2, to allow Tet1 expression. The down-regulation of TET1 relieves its repression of the methylated Lhb gene promoter, which is then hydroxymethylated and activated by TET2 for full reproductive competence. PMID- 28855338 TI - Methylation-dependent DNA discrimination in natural transformation of Campylobacter jejuni. AB - Campylobacter jejuni, a leading cause of bacterial gastroenteritis, is naturally competent. Like many competent organisms, C. jejuni restricts the DNA that can be used for transformation to minimize undesirable changes in the chromosome. Although C. jejuni can be transformed by C. jejuni-derived DNA, it is poorly transformed by the same DNA propagated in Escherichia coli or produced with PCR. Our work indicates that methylation plays an important role in marking DNA for transformation. We have identified a highly conserved DNA methyltransferase, which we term Campylobacter transformation system methyltransferase (ctsM), which methylates an overrepresented 6-bp sequence in the chromosome. DNA derived from a ctsM mutant transforms C. jejuni significantly less well than DNA derived from ctsM+ (parental) cells. The ctsM mutation itself does not affect transformation efficiency when parental DNA is used, suggesting that CtsM is important for marking transforming DNA, but not for transformation itself. The mutant has no growth defect, arguing against ongoing restriction of its own DNA. We further show that E. coli plasmid and PCR-derived DNA can efficiently transform C. jejuni when only a subset of the CtsM sites are methylated in vitro. A single methylation event 1 kb upstream of the DNA involved in homologous recombination is sufficient to transform C. jejuni, whereas otherwise identical unmethylated DNA is not. Methylation influences DNA uptake, with a slight effect also seen on DNA binding. This mechanism of DNA discrimination in C. jejuni is distinct from the DNA discrimination described in other competent bacteria. PMID- 28855339 TI - Role of remodeling and spacing factor 1 in histone H2A ubiquitination-mediated gene silencing. AB - Posttranslational histone modifications play important roles in regulating chromatin-based nuclear processes. Histone H2AK119 ubiquitination (H2Aub) is a prevalent modification and has been primarily linked to gene silencing. However, the underlying mechanism remains largely obscure. Here we report the identification of RSF1 (remodeling and spacing factor 1), a subunit of the RSF complex, as a H2Aub binding protein, which mediates the gene-silencing function of this histone modification. RSF1 associates specifically with H2Aub, but not H2Bub nucleosomes, through a previously uncharacterized and obligatory region designated as ubiquitinated H2A binding domain. In human and mouse cells, genes regulated by RSF1 overlap significantly with those controlled by RNF2/Ring1B, the subunit of Polycomb repressive complex 1 (PRC1) which catalyzes the ubiquitination of H2AK119. About 82% of H2Aub-enriched genes, including the classic PRC1 target Hox genes, are bound by RSF1 around their transcription start sites. Depletion of H2Aub levels by Ring1B knockout results in a significant reduction of RSF1 binding. In contrast, RSF1 knockout does not affect RNF2/Ring1B or H2Aub levels but leads to derepression of H2Aub target genes, accompanied by changes in H2Aub chromatin organization and release of linker histone H1. The action of RSF1 in H2Aub-mediated gene silencing is further demonstrated by chromatin-based in vitro transcription. Finally, RSF1 and Ring1 act cooperatively to regulate mesodermal cell specification and gastrulation during Xenopus early embryonic development. Taken together, these data identify RSF1 as a H2Aub reader that contributes to H2Aub-mediated gene silencing by maintaining a stable nucleosome pattern at promoter regions. PMID- 28855340 TI - CDK8/19 Mediator kinases potentiate induction of transcription by NFkappaB. AB - The nuclear factor-kappaB (NFkappaB) family of transcription factors has been implicated in inflammatory disorders, viral infections, and cancer. Most of the drugs that inhibit NFkappaB show significant side effects, possibly due to sustained NFkappaB suppression. Drugs affecting induced, but not basal, NFkappaB activity may have the potential to provide therapeutic benefit without associated toxicity. NFkappaB activation by stress-inducible cell cycle inhibitor p21 was shown to be mediated by a p21-stimulated transcription-regulating kinase CDK8. CDK8 and its paralog CDK19, associated with the transcriptional Mediator complex, act as coregulators of several transcription factors implicated in cancer; CDK8/19 inhibitors are entering clinical development. Here we show that CDK8/19 inhibition by different small-molecule kinase inhibitors or shRNAs suppresses the elongation of NFkappaB-induced transcription when such transcription is activated by p21-independent canonical inducers, such as TNFalpha. On NFkappaB activation, CDK8/19 are corecruited with NFkappaB to the promoters of the responsive genes. Inhibition of CDK8/19 kinase activity suppresses the RNA polymerase II C-terminal domain phosphorylation required for transcriptional elongation, in a gene specific manner. Genes coregulated by CDK8/19 and NFkappaB include IL8, CXCL1, and CXCL2, which encode tumor-promoting proinflammatory cytokines. Although it suppressed newly induced NFkappaB-driven transcription, CDK8/19 inhibition in most cases had no effect on the basal expression of NFkappaB-regulated genes or promoters; the same selective regulation of newly induced transcription was observed with other transcription signals potentiated by CDK8/19. This selective role of CDK8/19 identifies these kinases as mediators of transcriptional reprogramming, a key aspect of development and differentiation as well as pathological processes. PMID- 28855341 TI - CNS-resident progenitors direct the vascularization of neighboring tissues. AB - Organ growth requires the coordinated invasion and expansion of blood vessel networks directed by tissue-resident cells and morphogenetic cues. A striking example of this intercellular communication is the vascularization of the central nervous system (CNS), which is driven by neuronal progenitors, including neuroepithelial cells and radial glia. Although the importance of neuronal progenitors in vascular development within the CNS is well recognized, how these progenitors regulate the vasculature outside the CNS remains largely unknown. Here we show that CNS-resident radial glia direct the vascularization of neighboring tissues during development. We find that genetic ablation of radial glia in zebrafish larvae leads to a complete loss of the bilateral vertebral arteries (VTAs) that extend along the ventrolateral sides of the spinal cord. Importantly, VTA formation is not affected by ablation of other CNS cell types, and radial glia ablation also compromises the subsequent formation of the peri neural vascular plexus (PNVP), a vascular network that surrounds the CNS and is critical for CNS angiogenesis. Mechanistically, we find that radial glia control these processes via Vegfab/Vegfr2 signaling: vegfab is expressed by radial glia, and genetic or pharmacological inhibition of Vegfab/Vegfr2 signaling blocks the formation of the VTAs and subsequently of the PNVP. Moreover, mosaic overexpression of Vegfab in radial glia is sufficient to partially rescue the VTA formation defect in vegfab mutants. Thus, our findings identify a critical function for CNS-resident progenitors in the regulation of vascularization outside the CNS, serving as a paradigm for cross-tissue coordination of vascular morphogenesis and growth. PMID- 28855342 TI - Belief in free will affects causal attributions when judging others' behavior. AB - Free will is a cornerstone of our society, and psychological research demonstrates that questioning its existence impacts social behavior. In six studies, we tested whether believing in free will is related to the correspondence bias, which reflects people's automatic tendency to overestimate the influence of internal as compared to external factors when interpreting others' behavior. All studies demonstrate a positive relationship between the strength of the belief in free will and the correspondence bias. Moreover, in two experimental studies, we showed that weakening participants' belief in free will leads to a reduction of the correspondence bias. Finally, the last study demonstrates that believing in free will predicts prescribed punishment and reward behavior, and that this relation is mediated by the correspondence bias. Overall, these studies show that believing in free will impacts fundamental social-cognitive processes that are involved in the understanding of others' behavior. PMID- 28855343 TI - Medical support to military airborne training and operations. AB - INTRODUCTION: Airborne operations enable large numbers of military forces to deploy on the ground in the shortest possible time. This however must be balanced by an increased risk of injury. The aim of this paper is to review the current UK military drop zone medical estimate process, which may help to predict the risk of potential injury and assist in planning appropriate levels of medical support. METHOD: In spring 2015, a British Airborne Battlegroup (UKBG) deployed on a 7 week overseas interoperability training exercise in the USA with their American counterparts (USBG). This culminated in a 7-day Combined Joint Operations Access Exercise, which began with an airborne Joint Forcible Entry (JFE) of approximately 2100 paratroopers.The predicted number of jump-related injuries was estimated using Parachute Order Number 8 (PO No 8). Such injuries were defined as injuries occurring from the time the paratrooper exited the aircraft until they released their parachute harness on the ground. RESULTS: Overall, a total of 53 (2.5%) casualties occurred in the JFE phase of the exercise, lower than the predicted number of 168 (8%) using the PO No 8 tool. There was a higher incidence of back (30% actual vs 20% estimated) and head injuries (21% actual vs 5% estimated) than predicted with PO No 8. CONCLUSION: The current method for predicting the incidence of medical injuries after a parachute drop using the PO No 8 tool is potentially not accurate enough for current requirements. Further research into injury rate, influencing factors and injury type are urgently required in order to provide an evidence base to ensure optimal medical logistical and clinical planning for airborne training and operations in the future. PMID- 28855344 TI - Internet-based stress management for distressed managers: results from a randomised controlled trial. AB - OBJECTIVE: The aim of this randomised controlled trial (RCT) was to evaluate the efficacy of a guided internet-based stress management intervention (iSMI) among distressed managers compared with a attention control group (AC) with full access to treatment-as-usual. METHOD: A total sample of 117 distressed managers, mainly employed in the healthcare, IT, communication and educational sector, were randomised to either iSMI (n=59) or an AC group (n=58). The iSMI consisted of eight modules including cognitive behavioural stress management and positive management techniques. Participants received a minimal and weekly guidance from a psychologist or master-level psychology student focusing on support, feedback and adherence to the intervention. Self-report data were assessed at pre, post and 6 months after the intervention. The primary outcome was perceived stress (Perceived Stress Scale-14). The secondary outcomes included mental and work related health outcomes. RESULTS: Participants in the iSMI intervention reported significantly less symptoms of perceived stress (d=0.74, 95% CI 0.30 to 1.19) and burnout (d=0.95, 95% CI 0.53 to 1.37) compared with controls, at postassessment. Significant medium-to-large effect sizes were also found for depression, insomnia and job satisfaction. Long-term effects (6 months) were seen on the mental health outcomes. CONCLUSION: This is one of the first studies showing that iSMIs can be an effective, accessible and potentially time-effective approach of reducing stress and other mental-related and work-related health symptoms among distressed managers. Future studies are needed addressing distressed managers and the potential of indirect effects on employee stress and satisfaction at work. PMID- 28855345 TI - Workflow and factors associated with delay in the delivery of intra-arterial treatment for acute ischemic stroke in the MR CLEAN trial. AB - OBJECTIVE: The effect of intra-arterial treatment (IAT) for acute ischemic stroke is highly time-dependent. We investigated the delay of IAT and factors associated with such delay. METHODS: MR CLEAN was a randomized trial of IAT plus usual care versus usual care alone (n=500). With multivariable linear regression, we analyzed the effect of intravenous treatment, general anesthesia, off-hours and inter-hospital transfer on time to admission to the emergency department (ED) of the intervention center and time to treatment. Furthermore, we assessed compliance with a target of 75 min for time from ED to treatment, and calculated the potential absolute increase in the number of patients with a good outcome (modified Rankin Scale score <=2) if this target had been achieved in all treated patients. RESULTS: Inter-hospital transfer prolonged time to ED by 140 min (95% CI 129 to 150) but reduced time from ED to treatment by 77 min (95% CI 64 to 91). Time from ED to treatment was increased by 19 min by general anesthesia (95% CI 5 to 33) and total time was increased by 23 min during off-hours (95% CI 6 to 40). The in-hospital target was achieved in 11.5% (22/192) of patients. Full compliance with the target time of 75 min from ED to treatment would have increased the proportion of patients with a good outcome by 7.6% (95% CI 6.7% to 8.5%). CONCLUSION: Inter-hospital transfer is an important cause of delay in the delivery of IAT and every effort should be made to avoid transfers and reduce transfer-related delay. Furthermore, in-hospital workflow should be optimized to improve functional outcome after IAT. PMID- 28855346 TI - Impact of time to endovascular reperfusion on outcome differs according to the involvement of the proximal MCA territory. AB - BACKGROUND: The time interval between symptom onset and reperfusion is a major determinant of the benefit of endovascular therapy (ET) and patients' outcome. The impact of time may be attenuated in patients with robust collaterals. However, not all regions in the middle cerebral artery (MCA) territory have access to collaterals. PURPOSE: To evaluate if the involvement of the poorly collateralized proximal MCA territory has an impact on the degree of time dependency of patients' outcome. METHODS: Patients with MCA occlusions treated with ET and involvement/sparing of the proximal striatocapsular MCA territory (SC+/SC-, each n=97) were matched according to their symptom onset to reperfusion times (SORTs). Correlation and impact of time on outcome was evaluated with strata of SC+/SC- using multivariate logistic regression models (LRMs), including interaction terms. Discharge National Institute of Health Stroke Scale (NIHSS DIS) score <5 and discharge modified Rankin Scale (mRS-DIS) score <=2 were prespecified outcome measures. RESULTS: A stronger correlation between all outcome measures (NIHSS-DIS/DeltaNIHSS/mRS-DIS) and SORTs was found for SC+ patients than for SC-patients. SORTs were significant variables in LRMs for mRS DIS score <=2 and NIHSS-DIS score <5 in SC+ but not in SC- patients. Interaction of SC+ and SORTs was significant in LRMs for both endpoints. CONCLUSION: Time dependency of outcome after ET is more pronounced if parts of the proximal MCA territory are affected. This may reflect the lack of collateralization in the striatocapsular region and a more stringent cell death with time. If confirmed, this finding may affect the selection of patients based on different time windows according to the territory at risk. PMID- 28855347 TI - Prolonged cerebral circulation time is more associated with symptomatic carotid stenosis than stenosis degree or collateral circulation. AB - BACKGROUND AND PURPOSE: Current practice of revascularization for carotid stenosis (CS) primarily relies on symptoms and degree of stenosis. Other parameters, such as collateral circulation and cerebral circulation time (CCT), might influence the stroke risk in CS. This study was conducted to (1) investigate whether CCT is more associated with symptomatic CS than degree of stenosis and (2) elucidate the associations among the degree of stenosis, collateral status, and CCT. METHODS: From 2010 to 2016, 82 patients with unilateral CS were enrolled for DSA and divided into symptomatic and asymptomatic groups based on clinical presentation. CCT was defined as the difference between the time taken by the cavernous internal carotid artery and parietal vein to reach the maximal contrast medium intensities on lateral DSA. The degree of stenosis, collateral status, and CCT of the two groups were compared. Logistic regression analysis was performed to estimate the OR for symptomatic CS with the imaging variables. RESULTS: The symptomatic group had a significantly higher degree of stenosis and longer CCT. CCT (OR 1.95, p=0.013) was more associated with symptomatic CS than the degree of stenosis (OR 1.03, p=0.229), after adjustment for potential confounders-namely, age, sex, antithrombotic use, and collateral status. Symptomatic high grade CS with collaterals had a non significantly shorter CCT than those without collaterals. CONCLUSIONS: DSA derived CCT is more reflective of the hemodynamic differences between symptomatic and asymptomatic CS than degree of stenosis. Collaterals may not effectively reduce CCT in symptomatic high grade CS. PMID- 28855348 TI - Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40. AB - Purpose: Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.Experimental Design: We utilized an anti-PD-1-refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1.Results: The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type I and type II serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM 3 on T cells. Combination treatment increased intratumoral CD4+ T-cell proliferation at day 13, but at day 19, both CD4+ and CD8+ T-cell proliferation was significantly reduced compared with untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV PyMT tumors, sequential combination was dependent on both CD4+ and CD8+ T cells and completely regressed tumors in approximately 30% of treated animals.Conclusions: These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials. Clin Cancer Res; 23(20); 6165-77. (c)2017 AACRSee related commentary by Colombo, p. 5999. PMID- 28855349 TI - Epidermal Growth Factor Receptor Variant III (EGFRvIII) Positivity in EGFR Amplified Glioblastomas: Prognostic Role and Comparison between Primary and Recurrent Tumors. AB - Purpose: Approximately 40% of all glioblastomas have amplified the EGFR gene, and about half of these tumors express the EGFRvIII variant. The prognostic role of EGFRvIII in EGFR-amplified glioblastoma patients and changes in EGFRvIII expression in recurrent versus primary glioblastomas remain controversial, but such data are highly relevant for EGFRvIII-targeted therapies.Experimental Design:EGFR-amplified glioblastomas from 106 patients were assessed for EGFRvIII positivity. Changes in EGFR amplification and EGFRvIII status from primary to recurrent glioblastomas were evaluated in 40 patients with EGFR-amplified tumors and 33 patients with EGFR-nonamplified tumors. EGFR single-nucleotide variants (SNV) were assessed in 27 patients. Data were correlated with outcome and validated in 150 glioblastoma patients from The Cancer Genome Atlas (TCGA) consortium.Results: Sixty of 106 EGFR-amplified glioblastomas were EGFRvIII positive (56.6%). EGFRvIII positivity was not associated with different progression-free or overall survival. EGFRvIII status was unchanged at recurrence in 35 of 40 patients with EGFR-amplified primary tumors (87.5%). Four patients lost and one patient gained EGFRvIII positivity at recurrence. None of 33 EGFR nonamplified glioblastomas acquired EGFR amplification or EGFRvIII at recurrence. EGFR SNVs were frequent in EGFR-amplified tumors, but were not linked to survival.Conclusions: EGFRvIII and EGFR SNVs are not prognostic in EGFR-amplified glioblastoma patients. EGFR amplification is retained in recurrent glioblastomas. Most EGFRvIII-positive glioblastomas maintain EGFRvIII positivity at recurrence. However, EGFRvIII expression may change in a subset of patients at recurrence, thus repeated biopsy with reassessment of EGFRvIII status is recommended for patients with recurrent glioblastoma to receive EGFRvIII-targeting agents. Clin Cancer Res; 23(22); 6846-55. (c)2017 AACR. PMID- 28855350 TI - Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression. AB - Purpose: VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood.Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance.Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy.Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers. Clin Cancer Res; 23(22); 7034-46. (c)2017 AACR. PMID- 28855351 TI - Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW. AB - Purpose: B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an antiapoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other antiapoptotic BCL2 family members in six different B-cell lymphomas.Experimental Design: We performed a large-scale gene expression analysis of datasets comprising approximately 2,300 lymphoma patient samples, including non-Hodgkin and Hodgkin lymphomas as well as indolent and aggressive lymphomas. Data were validated experimentally with qRT-PCR and IHC.Results: We report BCLW is significantly overexpressed in aggressive and indolent lymphomas, including DLBCL, Burkitt, follicular, mantle cell, marginal zone, and Hodgkin lymphomas. Notably, BCLW was preferentially overexpressed over that of BCL2 and negatively correlated with BCL2 in specific lymphomas. Unexpectedly, BCLW was overexpressed as frequently as BCL2 in follicular lymphoma. Evaluation of all five antiapoptotic BCL2 family members in six types of B-cell lymphoma revealed that BCL2, BCLW, and BCLX were consistently overexpressed, whereas MCL1 and A1 were not. In addition, individual lymphomas frequently overexpressed more than one antiapoptotic BCL2 family member.Conclusions: Our comprehensive analysis indicates B-cell lymphomas commonly select for BCLW overexpression in combination with or instead of other antiapoptotic BCL2 family members. Our results suggest BCLW may be equally as important in lymphomagenesis as BCL2 and that targeting BCLW in lymphomas should be considered. Clin Cancer Res; 23(22); 7119-29. (c)2017 AACR. PMID- 28855352 TI - Low-Dose Cyclophosphamide Induces Antitumor T-Cell Responses, which Associate with Survival in Metastatic Colorectal Cancer. AB - Purpose: Anticancer T-cell responses can control tumors, but immunosuppressive mechanisms in vivo prevent their function. The role of regulatory T cells (Tregs) in metastatic colorectal cancer is unclear. We have previously shown depletion of Tregs enhances colorectal cancer-specific effector T-cell responses. Low-dose cyclophosphamide targets Tregs in animal models and some human studies; however, the effect of cyclophosphamide in metastatic colorectal cancer is unknown.Experimental Design: Fifty-five patients with metastatic colorectal cancer were enrolled in a phase I/II trial and randomly assigned to receive 2 week-long courses of low-dose (50 mg twice a day) cyclophosphamide or not. The absolute number, phenotype, and antitumor function of peripheral blood-derived lymphocyte subsets were monitored throughout treatment, as well as during 18 month follow-up.Results: Initially, cyclophosphamide reduced proliferation in all lymphocyte subsets; however, a rapid mobilization of effector T cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell, and NK-cell numbers occurred. The expansion and subsequent activation of effector T cells was focused on tumor-specific T cells, producing both granzyme B and IFNgamma. Cyclophosphamide-treated patients demonstrating the most enhanced IFNgamma+ tumor specific T-cell responses exhibited a significant delay in tumor progression [HR = 0.29; 95% confidence interval (CI), 0.12-0.69; P = 0.0047), compared with nonresponders and no-treatment controls.Conclusions: Cyclophosphamide-induced Treg depletion is mirrored by a striking boost in antitumor immunity. This study provides the first direct evidence of the benefit of naturally primed T cells in patients with metastatic colorectal cancer. Our results also support the concept that nonmutated self-antigens may act as useful targets for immunotherapies. Clin Cancer Res; 23(22); 6771-80. (c)2017 AACR. PMID- 28855353 TI - MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors. AB - Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments.Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N = 406) and patient-derived xenograft (PDX) models of solid tumors (N = 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N = 6) and provide a case report of a lung cancer patient harboring a Deltaexon14 MET splice variant.Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with Deltaexon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with Deltaexon14 MET lacking MET gene amplification.Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms. Clin Cancer Res; 23(22); 7084 96. (c)2017 AACR. PMID- 28855354 TI - A Panel of Novel Detection and Prognostic Methylated DNA Markers in Primary Non Small Cell Lung Cancer and Serum DNA. AB - Purpose: To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early-stage non-small cell lung cancer (NSCLC).Experimental Design: Identification of differentially methylated regions (DMR) was performed with bumphunter on "The Cancer Genome Atlas (TCGA)" dataset, and clinical utility was assessed using quantitative methylation specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples.Results: A methylation panel of 6 genes (CDO1, HOXA9, AJAP1, PTGDR, UNCX, and MARCH11) was selected from TCGA dataset. Promoter methylation of the gene panel was detected in 92.2% (83/90) of the training cohort with a specificity of 72.0% (18/25) and in 93.0% (40/43) of an independent cohort of stage IA primary NSCLC. In serum samples from the later 43 stage IA subjects and population-matched 42 control subjects, the gene panel yielded a sensitivity of 72.1% (31/41) and specificity of 71.4% (30/42). Similar diagnostic accuracy was observed in pleural effusion and ascites samples. A prognostic risk category based on the methylation status of CDO1, HOXA9, PTGDR, and AJAP1 refined the risk stratification for outcomes as an independent prognostic factor for an early-stage disease. Moreover, the paralog group for HOXA9, predominantly overexpressed in subjects with HOXA9 methylation, showed poor outcomes.Conclusions: Promoter methylation of a panel of 6 genes has potential for use as a biomarker for early cancer detection and to predict prognosis at the time of diagnosis. Clin Cancer Res; 23(22); 7141-52. (c)2017 AACR. PMID- 28855355 TI - MITF-High and MITF-Low Cells and a Novel Subpopulation Expressing Genes of Both Cell States Contribute to Intra- and Intertumoral Heterogeneity of Primary Melanoma. AB - Purpose: Understanding tumor heterogeneity is an important challenge in current cancer research. Transcription and epigenetic profiling of cultured melanoma cells have defined at least two distinct cell phenotypes characterized by distinctive gene expression signatures associated with high or low/absent expression of microphthalmia-associated transcription factor (MITF). Nevertheless, heterogeneity of cell populations and gene expression in primary human tumors is much less well characterized.Experimental Design: We performed single-cell gene expression analyses on 472 cells isolated from needle biopsies of 5 primary human melanomas, 4 superficial spreading, and one acral melanoma. The expression of MITF-high and MITF-low signature genes was assessed and compared to investigate intra- and intertumoral heterogeneity and correlated gene expression profiles.Results: Single-cell gene expression analyses revealed varying degrees of intra- and intertumor heterogeneity conferred by the variable expression of distinct sets of genes in different tumors. Expression of MITF partially correlated with that of its known target genes, while SOX10 expression correlated best with PAX3 and ZEB2 Nevertheless, cells simultaneously expressing MITF-high and MITF-low signature genes were observed both by single-cell analyses and RNAscope.Conclusions: Single-cell analyses can be performed on limiting numbers of cells from primary human melanomas revealing their heterogeneity. Although tumors comprised variable proportions of cells with the MITF-high and MITF-low gene expression signatures characteristic of melanoma cultures, primary tumors also comprised cells expressing markers of both signatures defining a novel cell state in tumors in vivoClin Cancer Res; 23(22); 7097-107. (c)2017 AACR. PMID- 28855357 TI - Chemogenomic Landscape of RUNX1-mutated AML Reveals Importance of RUNX1 Allele Dosage in Genetics and Glucocorticoid Sensitivity. AB - Purpose:RUNX1-mutated (RUNX1mut) acute myeloid leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Toward this goal, we further dissected the mutational spectrum and gene expression profile of RUNX1mut AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup.Experimental Design: RNA-sequencing of 47 RUNX1mut primary AML specimens was performed and sequencing results were compared to those of RUNX1 wild-type samples. Chemical screens were also conducted using RUNX1mut specimens to identify compounds selectively affecting the viability of RUNX1mut AML.Results: We show that samples with no remaining RUNX1 wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most RUNX1mut specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the glucocorticoid receptor (GR). We observed that specimens harboring RUNX1 mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that coassociating mutations as well as GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating RUNX1 expression in human AML cells.Conclusions: Our findings show the profound impact of RUNX1 allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. Clin Cancer Res; 23(22); 6969-81. (c)2017 AACR. PMID- 28855356 TI - Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. AB - Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine.Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses.Results: MVA-brachyury TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and <=grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients.Conclusions: The MVA-brachyury TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833-45. (c)2017 AACR. PMID- 28855359 TI - What difference does a century make? Shifts in the ecosystem structure of the Ross Sea, Antarctica, as evidenced from a sentinel species, the Weddell seal. AB - The arrival of humans to Antarctica's Ross Sea (100+ years ago) led to a slow, but sustained increase in human activities in the area. To investigate if human presence has influenced the structure of the ecosystem over the last century, we compared historical (ca 100 years old) and modern samples of a sentinel species, the Weddell seal (Leptonychotes weddellii), using both bulk tissue and compound specific stable isotope analysis. The historical isotopic niche of Weddell seals was over five times larger than the modern niche. The isotopic values of individual amino acids showed a clear segregation between historical and modern samples, indicative of differences at the base of the trophic web. Further, we found no significant differences in the trophic position of Weddell seals between the two periods. Our study revealed that the Ross Sea has undergone detectable changes (i.e. in the primary producers community) in the last century, but the presence of humans has not disrupted trophic interactions supporting Weddell seals. PMID- 28855358 TI - Thermal facial reactivity patterns predict social categorization bias triggered by unconscious and conscious emotional stimuli. AB - Members of highly social species decode, interpret, and react to the emotion of a conspecific depending on whether the other belongs to the same (ingroup) or different (outgroup) social group. While studies indicate that consciously perceived emotional stimuli drive social categorization, information about how implicit emotional stimuli and specific physiological signatures affect social categorization is lacking. We addressed this issue by exploring whether subliminal and supraliminal affective priming can influence the categorization of neutral faces as ingroup versus outgroup. Functional infrared thermal imaging was used to investigate whether the effect of affective priming on the categorization decision was moderated by the activation of the sympathetic nervous system (SNS). During the subliminal condition, we found that stronger SNS activation after positive or negative affective primes induced ingroup and outgroup face categorization, respectively. The exact opposite pattern (i.e. outgroup after positive and ingroup after negative primes) was observed in the supraliminal condition. We also found that misattribution effects were stronger in people with low emotional awareness, suggesting that this trait moderates how one recognizes SNS signals and employs them for unrelated decisions. Our results allow the remarkable implication that low-level affective reactions coupled with sympathetic activation may bias social categorization. PMID- 28855360 TI - The four-flipper swimming method of plesiosaurs enabled efficient and effective locomotion. AB - The extinct ocean-going plesiosaurs were unique within vertebrates because they used two flipper pairs identical in morphology for propulsion. Although fossils of these Mesozoic marine reptiles have been known for more than two centuries, the function and dynamics of their tandem-flipper propulsion system has always been unclear and controversial. We address this question quantitatively for the first time in this study, reporting a series of precisely controlled water tank experiments that use reconstructed plesiosaur flippers scaled from well-preserved fossils. Our aim was to determine which limb movements would have resulted in the most efficient and effective propulsion. We show that plesiosaur hind flippers generated up to 60% more thrust and 40% higher efficiency when operating in harmony with their forward counterparts, when compared with operating alone, and the spacing and relative motion between the flippers was critical in governing these increases. The results of our analyses show that this phenomenon was probably present across the whole range of plesiosaur flipper motion and resolves the centuries-old debate about the propulsion style of these marine reptiles, as well as indicating why they retained two pairs of flippers for more than 100 million years. PMID- 28855361 TI - How predation shapes the social interaction rules of shoaling fish. AB - Predation is thought to shape the macroscopic properties of animal groups, making moving groups more cohesive and coordinated. Precisely how predation has shaped individuals' fine-scale social interactions in natural populations, however, is unknown. Using high-resolution tracking data of shoaling fish (Poecilia reticulata) from populations differing in natural predation pressure, we show how predation adapts individuals' social interaction rules. Fish originating from high predation environments formed larger, more cohesive, but not more polarized groups than fish from low predation environments. Using a new approach to detect the discrete points in time when individuals decide to update their movements based on the available social cues, we determine how these collective properties emerge from individuals' microscopic social interactions. We first confirm predictions that predation shapes the attraction-repulsion dynamic of these fish, reducing the critical distance at which neighbours move apart, or come back together. While we find strong evidence that fish align with their near neighbours, we do not find that predation shapes the strength or likelihood of these alignment tendencies. We also find that predation sharpens individuals' acceleration and deceleration responses, implying key perceptual and energetic differences associated with how individuals move in different predation regimes. Our results reveal how predation can shape the social interactions of individuals in groups, ultimately driving differences in groups' collective behaviour. PMID- 28855362 TI - A father effect explains sex-ratio bias. AB - Sex ratio allocation has important fitness consequences, and theory predicts that parents should adjust offspring sex ratio in cases where the fitness returns of producing male and female offspring vary. The ability of fathers to bias offspring sex ratios has traditionally been dismissed given the expectation of an equal proportion of X- and Y-chromosome-bearing sperm (CBS) in ejaculates due to segregation of sex chromosomes at meiosis. This expectation has been recently refuted. Here we used Peromyscus leucopus to demonstrate that sex ratio is explained by an exclusive effect of the father, and suggest a likely mechanism by which male-driven sex-ratio bias is attained. We identified a male sperm morphological marker that is associated with the mechanism leading to sex ratio bias; differences among males in the sperm nucleus area (a proxy for the sex chromosome that the sperm contains) explain 22% variation in litter sex ratio. We further show the role played by the sperm nucleus area as a mediator in the relationship between individual genetic variation and sex-ratio bias. Fathers with high levels of genetic variation had ejaculates with a higher proportion of sperm with small nuclei area. This, in turn, led to siring a higher proportion of sons (25% increase in sons per 0.1 decrease in the inbreeding coefficient). Our results reveal a plausible mechanism underlying unexplored male-driven sex-ratio biases. We also discuss why this pattern of paternal bias can be adaptive. This research puts to rest the idea that father contribution to sex ratio variation should be disregarded in vertebrates, and will stimulate research on evolutionary constraints to sex ratios-for example, whether fathers and mothers have divergent, coinciding, or neutral sex allocation interests. Finally, these results offer a potential explanation for those intriguing cases in which there are sex ratio biases, such as in humans. PMID- 28855363 TI - Coevolution in the timing of GABAergic and pyramidal neuron maturation in primates. AB - The cortex of primates is relatively expanded compared with many other mammals, yet little is known about what developmental processes account for the expansion of cortical subtype numbers in primates, including humans. We asked whether GABAergic and pyramidal neuron production occurs for longer than expected in primates than in mice in a sample of 86 developing primate and rodent brains. We use high-resolution structural, diffusion MR scans and histological material to compare the timing of the ganglionic eminences (GE) and cortical proliferative pool (CPP) maturation between humans, macaques, rats, and mice. We also compare the timing of post-neurogenetic maturation of GABAergic and pyramidal neurons in primates (i.e. humans, macaques) relative to rats and mice to identify whether delays in neurogenesis are concomitant with delayed post-neurogenetic maturation. We found that the growth of the GE and CPP are both selectively delayed compared with other events in primates. By contrast, the timing of post-neurogenetic GABAergic and pyramidal events (e.g. synaptogenesis) are predictable from the timing of other events in primates and in studied rodents. The extended duration of GABAergic and pyramidal neuron production is associated with the amplification of GABAerigc and pyramidal neuron numbers in the human and non-human primate cortex. PMID- 28855364 TI - Evidence of cryptic incidence in childhood diseases. AB - Persistence and extinction are key processes in infectious disease dynamics that, owing to incomplete reporting, are seldom directly observable. For fully immunizing diseases, reporting probabilities can be readily estimated from demographic records and case reports. Yet reporting probabilities are not sufficient to unambiguously reconstruct disease incidence from case reports. Here, we focus on disease presence (i.e. marginal probability of non-zero incidence), which provides an upper bound on the marginal probability of disease extinction. We examine measles and pertussis in pre-vaccine era United States (US) cities, and describe a conserved scaling relationship between population size, reporting probability and observed presence (i.e. non-zero case reports). We use this relationship to estimate disease presence given perfect reporting, and define cryptic presence as the difference between estimated and observed presence. We estimate that, in early twentieth century US cities, pertussis presence was higher than measles presence across a range of population sizes, and that cryptic presence was common in small cities with imperfect reporting. While the methods employed here are specific to fully immunizing diseases, our results suggest that cryptic incidence deserves careful attention, particularly in diseases with low case counts, poor reporting and longer infectious periods. PMID- 28855366 TI - Body size affects the evolution of hidden colour signals in moths. AB - Many cryptic prey have also evolved hidden contrasting colour signals which are displayed to would-be predators. Given that these hidden contrasting signals may confer additional survival benefits to the prey by startling/intimidating predators, it is unclear why they have evolved in some species, but not in others. Here, we have conducted a comparative phylogenetic analysis of the evolution of colour traits in the family Erebidae (Lepidoptera), and found that the hidden contrasting colour signals are more likely to be found in larger species. To understand why this relationship occurs, we present a general mathematical model, demonstrating that selection for a secondary defence such as deimatic display will be stronger in large species when (i) the primary defence (crypsis) is likely to fail as its body size increases and/or (ii) the secondary defence is more effective in large prey. To test the model assumptions, we conducted behavioural experiments using a robotic moth which revealed that survivorship advantages were higher against wild birds when the moth has contrasting hindwings and large size. Collectively, our results suggest that the evolutionary association between large size and hidden contrasting signals has been driven by a combination of the need for a back-up defence and its efficacy. PMID- 28855365 TI - Estimating parasite host range. AB - Estimating the number of host species that a parasite can infect (i.e. host range) provides key insights into the evolution of host specialism and is a central concept in disease ecology. Host range is rarely estimated in real systems, however, because variation in species relative abundance and the detection of rare species makes it challenging to confidently estimate host range. We applied a non-parametric richness indicator to estimate host range in simulated and empirical data, allowing us to assess the influence of sampling heterogeneity and data completeness. After validating our method on simulated data, we estimated parasite host range for a sparsely sampled global parasite occurrence database (Global Mammal Parasite Database) and a repeatedly sampled set of parasites of small mammals from New Mexico (Sevilleta Long Term Ecological Research Program). Estimation accuracy varied strongly with parasite taxonomy, number of parasite occurrence records, and the shape of host species-abundance distribution (i.e. the dominance and rareness of species in the host community). Our findings suggest that between 20% and 40% of parasite host ranges are currently unknown, highlighting a major gap in our understanding of parasite specificity, host-parasite network structure, and parasite burdens. PMID- 28855367 TI - Quaternary vertebrate faunas from Sumba, Indonesia: implications for Wallacean biogeography and evolution. AB - Historical patterns of diversity, biogeography and faunal turnover remain poorly understood for Wallacea, the biologically and geologically complex island region between the Asian and Australian continental shelves. A distinctive Quaternary vertebrate fauna containing the small-bodied hominin Homo floresiensis, pygmy Stegodon proboscideans, varanids and giant murids has been described from Flores, but Quaternary faunas are poorly known from most other Lesser Sunda Islands. We report the discovery of extensive new fossil vertebrate collections from Pleistocene and Holocene deposits on Sumba, a large Wallacean island situated less than 50 km south of Flores. A fossil assemblage recovered from a Pleistocene deposit at Lewapaku in the interior highlands of Sumba, which may be close to 1 million years old, contains a series of skeletal elements of a very small Stegodon referable to S. sumbaensis, a tooth attributable to Varanus komodoensis, and fragmentary remains of unidentified giant murids. Holocene cave deposits at Mahaniwa dated to approximately 2000-3500 BP yielded extensive material of two new genera of endemic large-bodied murids, as well as fossils of an extinct frugivorous varanid. This new baseline for reconstructing Wallacean faunal histories reveals that Sumba's Quaternary vertebrate fauna, although phylogenetically distinctive, was comparable in diversity and composition to the Quaternary fauna of Flores, suggesting that similar assemblages may have characterized Quaternary terrestrial ecosystems on many or all of the larger Lesser Sunda Islands. PMID- 28855368 TI - Detection of Allee effects in marine fishes: analytical biases generated by data availability and model selection. AB - The demographic Allee effect, or depensation, implies positive association between per capita population growth rate and population size at low abundances, thereby lowering growth ability of sparse populations. This can have far-reaching consequences on population recovery ability and colonization success. In the context of marine fishes, there is a widespread perception that Allee effects are rare or non-existent. However, studies that have failed to detect Allee effects in marine fishes have suffered from several fundamental methodological and data limitations. In the present study, we challenge the prevailing perception about the rarity of Allee effects by analysing nine populations of Atlantic herring (Clupea harengus), using Bayesian statistical methods. We find that populations of the same species can show either strong evidence for Allee effects or compensation. We explicitly demonstrate how the evidence for Allee effects is strongly provisional on observations made at low population abundances. We contrast our statistical approach with previous attempts to detect Allee effects and illustrate methodological issues that can lead to erroneous conclusions about the nature of population dynamics at low abundance. The present study demonstrates that there is no substantive scientific basis to support the perception that Allee effects are rare or non-existent in marine fishes. PMID- 28855369 TI - Social transmission of information about a mutualist via trophallaxis in ant colonies. AB - Partner discrimination is crucial in mutualistic interactions between organisms to counteract cheating by the partner. Trophobiosis between ants and aphids is a model system of such mutualistic interaction. To establish and maintain the mutualistic association, ants need to correctly discriminate mutualistic aphids. However, the mechanism by which ants recognize aphids as their partners is poorly understood, despite its ecological and evolutionary importance. Here, we show for the first time the evidence that interaction with nest-mates that have tended aphids (Aphis craccivora) allows ants (Tetramorium tsushimae) to learn to recognize the aphid species as their partner. When ants had previously tended aphids, they moderated their aggressiveness towards aphids. More importantly, ants that had interacted with aphid-experienced nest-mates also reduced their aggressiveness towards aphids, even though they had never directly experienced them, indicating that aphid information was transmitted from aphid-experienced ants to inexperienced ants. Furthermore, inhibition of mouth-to-mouth contact (trophallaxis) from aphid-experienced ants to inexperienced ants by providing the inexperienced ants with artificial honeydew solution caused the inexperienced ants to become aggressive towards aphids. These results, with further supporting data, strongly suggest that ants transfer information on their mutualists during trophallactic interactions. PMID- 28855370 TI - Effects of early-life competition and maternal nutrition on telomere lengths in wild meerkats. AB - Early-life adversity can affect health, survival and fitness later in life, and recent evidence suggests that telomere attrition may link early conditions with their delayed consequences. Here, we investigate the link between early-life competition and telomere length in wild meerkats. Our results show that, when multiple females breed concurrently, increases in the number of pups in the group are associated with shorter telomeres in pups. Given that pups from different litters compete for access to milk, we tested whether this effect is due to nutritional constraints on maternal milk production, by experimentally supplementing females' diets during gestation and lactation. While control pups facing high competition had shorter telomeres, the negative effects of pup number on telomere lengths were absent when maternal nutrition was experimentally improved. Shortened pup telomeres were associated with reduced survival to adulthood, suggesting that early-life competition for nutrition has detrimental fitness consequences that are reflected in telomere lengths. Dominant females commonly kill pups born to subordinates, thereby reducing competition and increasing growth rates of their own pups. Our work suggests that an additional benefit of infanticide may be that it also reduces telomere shortening caused by competition for resources, with associated benefits for offspring ageing profiles and longevity. PMID- 28855371 TI - Experience matters: context-dependent decisions explain spatial foraging patterns in the deposit-feeding crab Scopimera intermedia. AB - Behavioural decisions are often context-dependent, where information from immediate experience is incorporated into an individual's decision-making, particularly in complex environments. To test whether such mechanism is adopted by foragers in heterogeneous environments, we investigated the foraging behaviour of the deposit-feeding sand-bubbler crab, Scopimera intermedia An individual based model was constructed, based on an optimal-patch selection criterion, which implicitly assumed that individuals adjust foraging decisions based on immediate past experience. The model's predictions were tested on the shore by manipulating the location of food patches, where the crab showed a strong context-dependent foraging pattern. When resources were randomly distributed, the crab responded by spending 56% of time in enriched patches compared with only 28% in the same area when patches were composed of natural sediments. Shore manipulations varying resource distribution supported the underlying principles of the model mechanism, and highlighted the benefits of such a strategy in heterogeneous environments such as intertidal sediments where food resources vary at different spatial and temporal scales. The proposed model therefore provides a mechanistic process, based on optimal foraging, to predict foraging decisions and movement patterns of animals feeding in heterogeneous landscapes. PMID- 28855372 TI - Socially cued seminal fluid gene expression mediates responses in ejaculate quality to sperm competition risk. AB - There is considerable evidence that males will increase the number of sperm ejaculated in response to sperm competition risk. However, whether they have the capacity to adjust seminal fluid components of the ejaculate has received less attention. Male crickets (Teleogryllus oceanicus) have been shown to adjust the viability of sperm in their ejaculate in response to sperm competition risk. Here we show that socially mediated plasticity in sperm viability is probably due, at least in part, to male adjustments in the protein composition of the seminal fluid. Seven seminal fluid protein genes were found to have an increased expression in males exposed to rival calls. Increased expression of these genes was correlated with increased sperm viability in whole ejaculates, and gene knockdown confirmed that at least one of these proteins promotes sperm viability. Our results lend support for recent theoretical models that predict complex responses in male allocation to seminal fluid composition in response to sperm competition risk. PMID- 28855373 TI - Cellular and Molecular Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II in Chronic Pain. AB - Chronic pain, often defined as any pain lasting more than 3 months, is poorly managed because of its multifaceted and complex mechanisms. Calcium/calmodulin dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that plays a fundamental role in synaptic plasticity, learning, and memory. Recent emerging evidence demonstrates increased expression and activity of CaMKII in the spinal cord and dorsal root ganglia of various chronic pain models. Moreover, our previous studies also find that inhibiting CaMKII could attenuate inflammatory pain and neuropathic pain. In this review, we provide evidence for the involvement of CaMKII in the initiation and development of chronic pain, including neuropathic pain, bone cancer pain, and inflammatory pain. Novel CaMKII inhibitors with potent inhibitory effect and high specificity may be alternative therapeutic strategies for the management of chronic pain in the future. PMID- 28855374 TI - Differential mast cell outcomes are sensitive to FcepsilonRI-Syk binding kinetics. AB - Cross-linking of immunoglobulin E-bound FcepsilonRI triggers multiple cellular responses, including degranulation and cytokine production. Signaling is dependent on recruitment of Syk via docking of its dual SH2 domains to phosphorylated tyrosines within the FcepsilonRI immunoreceptor tyrosine-based activation motifs. Using single-molecule imaging in live cells, we directly visualized and quantified the binding of individual mNeonGreen-tagged Syk molecules as they associated with the plasma membrane after FcepsilonRI activation. We found that Syk colocalizes transiently to FcepsilonRI and that Syk FcepsilonRI binding dynamics are independent of receptor aggregate size. Substitution of glutamic acid for tyrosine between the Syk SH2 domains (Syk Y130E) led to an increased Syk-FcepsilonRI off-rate, loss of site-specific Syk autophosphorylation, and impaired downstream signaling. Genome edited cells expressing only Syk-Y130E were deficient in antigen-stimulated calcium release, degranulation, and production of some cytokines (TNF-a, IL-3) but not others (MCP 1, IL-4). We propose that kinetic discrimination along the FcepsilonRI signaling pathway occurs at the level of Syk-FcepsilonRI interactions, with key outcomes dependent upon sufficiently long-lived Syk binding events. PMID- 28855375 TI - Shear stress induces noncanonical autophagy in intestinal epithelial monolayers. AB - Flow of fluids through the gut, such as milk from a neonatal diet, generates a shear stress on the unilaminar epithelium lining the lumen. We report that exposure to physiological levels of fluid shear stress leads to the formation of large vacuoles, containing extracellular contents within polarizing intestinal epithelial cell monolayers. These observations lead to two questions: how can cells lacking primary cilia transduce shear stress, and what molecular pathways support the formation of vacuoles that can exceed 80% of the cell volume? We find that shear forces are sensed by actin-rich microvilli that eventually generate the apical brush border, providing evidence that these structures possess mechanosensing ability. Importantly, we identified the molecular pathway that regulates large vacuole formation downstream from mechanostimulation to involve central components of the autophagy pathway, including ATG5 and LC3, but not Beclin. Together our results establish a novel link between the actin-rich microvilli, the macroscopic transport of fluids across cells, and the noncanonical autophagy pathway in organized epithelial monolayers. PMID- 28855379 TI - New way of seeing. PMID- 28855376 TI - Destabilization of the replication fork protection complex disrupts meiotic chromosome segregation. AB - The replication fork protection complex (FPC) coordinates multiple processes that are crucial for unimpeded passage of the replisome through various barriers and difficult to replicate areas of the genome. We examine the function of Swi1 and Swi3, fission yeast's primary FPC components, to elucidate how replication fork stability contributes to DNA integrity in meiosis. We report that destabilization of the FPC results in reduced spore viability, delayed replication, changes in recombination, and chromosome missegregation in meiosis I and meiosis II. These phenotypes are linked to accumulation and persistence of DNA damage markers in meiosis and to problems with cohesion stability at the centromere. These findings reveal an important connection between meiotic replication fork stability and chromosome segregation, two processes with major implications to human reproductive health. PMID- 28855377 TI - Centrosome defines the rear of cells during mesenchymal migration. AB - The importance of centrosome in directional cell migration has long been recognized. However, the conventional view that centrosome determines cell's front, based on its often-observed position in front of the nucleus, has been challenged by contradictory observations. Here we show that centrosome defines the rear instead of the front, using cells plated on micropatterned adhesive strips to facilitate directional migration. We found that centrosome is always located proximal to the future rear before polarity is established through symmetry breaking or reversed as the cell reaches a dead end. In addition, using microsurgery to alter the distance of centrosomes from cells' ends, we show that centrosomal proximity is predictive of the placement of the rear. Removal of centrosome impairs directional cell migration, whereas the removal of nucleus alone makes no difference in most cells. Computer modeling under the framework of a local-enhancement/global-inhibition mechanism further demonstrates that positioning of rear retraction, mediated by signals concentrated near the centrosome, recapitulates all the experimental observations. Our results resolve a long-standing controversy and explain how cells use centrosome and microtubules to maintain directional migration. PMID- 28855378 TI - ADP-ribosylation factor-like 4C binding to filamin-A modulates filopodium formation and cell migration. AB - Changes in cell morphology and the physical forces that occur during migration are generated by a dynamic filamentous actin cytoskeleton. The ADP-ribosylation factor-like 4C (Arl4C) small GTPase acts as a molecular switch to regulate morphological changes and cell migration, although the mechanism by which this occurs remains unclear. Here we report that Arl4C functions with the actin regulator filamin-A (FLNa) to modulate filopodium formation and cell migration. We found that Arl4C interacted with FLNa in a GTP-dependent manner and that FLNa IgG repeat 22 is both required and sufficient for this interaction. We also show that interaction between FLNa and Arl4C is essential for Arl4C-induced filopodium formation and increases the association of FLNa with Cdc42-GEF FGD6, promoting cell division cycle 42 (Cdc42) GTPase activation. Thus our study revealed a novel mechanism, whereby filopodium formation and cell migration are regulated through the Arl4C-FLNa-mediated activation of Cdc42. PMID- 28855380 TI - The ghost of pandemics past: revisiting two centuries of influenza in Sweden. AB - Previous influenza pandemics are usually invoked in pandemic preparedness planning without a thorough analysis of the events surrounding them, what has been called the 'configuration' of epidemics. Historic pandemics are instead used to contrast them to the novelty of the coming imagined plague or as fear of a ghost-like repetition of the past. This view of pandemics is guided by a biomedical framework that is ahistorical and reductionist. The meaning of 'pandemic' influenza is in fact highly ambiguous in its partitioning of pandemic and seasonal influenza. The past 200 years of influenza epidemics in Sweden are examined with a special focus on key social structures-households, schools, transportations and the military. These are shown to have influenced the progression of influenza pandemics. Prevailing beliefs around influenza pandemics have also profoundly influenced intervention strategies. Measuring long-term trends in pandemic severity is problematic because pandemics are non-linear events where the conditions surrounding them constantly change. However, in a linearised view, the Spanish flu can be seen to represent a historical turning point and the H1N1 2009 pandemic not as an outlier, but following a 100-year trend of decreasing severity. Integrating seasonal and pandemic influenza, and adopting an ecosocial stance can deepen our understanding and bring the ghost like pandemic past to life. PMID- 28855381 TI - Expression of Concern: Induction of nitric oxide synthase-2 proceeds with the concomitant downregulation of the endogenous caveolin levels. J. Cell Sci. doi: 10.1242/jcs.01002. PMID- 28855382 TI - Expression of Concern: Protein kinase D activity controls endothelial nitric oxide synthesis. J. Cell Sci. doi: 10.1242/jcs.148601. PMID- 28855383 TI - Expression of Concern: N-terminal palmitoylation within the appropriate amino acid environment conveys on NOS2 the ability to progress along the intracellular sorting pathways. J. Cell Sci. doi: 10.1242/jcs.02878. PMID- 28855384 TI - Expression of Concern: Distance-dependent cellular palmitoylation of de-novo designed sequences and their translocation to plasma membrane subdomains. J. Cell Sci. (2002). 115, 3119-3130. PMID- 28855385 TI - Finite cell-size effects on protein variability in Turing patterned tissues. AB - Herein we present a framework to characterize different sources of protein expression variability in Turing patterned tissues. In this context, we introduce the concept of granular noise to account for the unavoidable fluctuations due to finite cell-size effects and show that the nearest-neighbours autocorrelation function provides the means to measure it. To test our findings, we perform in silico experiments of growing tissues driven by a generic activator-inhibitor dynamics. Our results show that the relative importance of different sources of noise depends on the ratio between the characteristic size of cells and that of the pattern domains and on the ratio between the pattern amplitude and the effective intensity of the biochemical fluctuations. Importantly, our framework provides the tools to measure and distinguish different stochastic contributions during patterning: granularity versus biochemical noise. In addition, our analysis identifies the protein species that buffer the stochasticity the best and, consequently, it can help to determine key instructive signals in systems driven by a Turing instability. Altogether, we expect our study to be relevant in developmental processes leading to the formation of periodic patterns in tissues. PMID- 28855386 TI - Human movement, cooperation and the effectiveness of coordinated vector control strategies. AB - Vector-borne disease transmission is often typified by highly focal transmission and influenced by movement of hosts and vectors across different scales. The ecological and environmental conditions (including those created by humans through vector control programmes) that result in metapopulation dynamics remain poorly understood. The development of control strategies that would most effectively limit outbreaks given such dynamics is particularly urgent given the recent epidemics of dengue, chikungunya and Zika viruses. We developed a stochastic, spatial model of vector-borne disease transmission, allowing for movement of hosts between patches. Our model is applicable to arbovirus transmission by Aedes aegypti in urban settings and was parametrized to capture Zika virus transmission in particular. Using simulations, we investigated the extent to which two aspects of vector control strategies are affected by human commuting patterns: the extent of coordination and cooperation between neighbouring communities. We find that transmission intensity is highest at intermediate levels of host movement. The extent to which coordination of control activities among neighbouring patches decreases the prevalence of infection is affected by both how frequently humans commute and the proportion of neighbouring patches that commits to vector surveillance and control activities. At high levels of host movement, patches that do not contribute to vector control may act as sources of infection in the landscape, yet have comparable levels of prevalence as patches that do cooperate. This result suggests that real cooperation among neighbours will be critical to the development of effective pro active strategies for vector-borne disease control in today's commuter-linked communities. PMID- 28855387 TI - A biophysical approach to daunorubicin interaction with model membranes: relevance for the drug's biological activity. AB - Daunorubicin is extensively used in chemotherapy for diverse types of cancer. Over the years, evidence has suggested that the mechanisms by which daunorubicin causes cytotoxic effects are also associated with interactions at the membrane level. The aim of the present work was to study the interplay between daunorubicin and mimetic membrane models composed of different ratios of 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC), sphingomyelin (SM) and cholesterol (Chol). Several biophysical parameters were assessed using liposomes as mimetic model membranes. Thereby, the ability of daunorubicin to partition into lipid bilayers, its apparent location within the membrane and its effect on membrane fluidity were investigated. The results showed that daunorubicin has higher affinity for lipid bilayers composed of DMPC, followed by DMPC : SM, DMPC : Chol and lastly by DMPC : SM : Chol. The addition of SM or Chol into DMPC membranes not only increases the complexity of the model membrane but also decreases its fluidity, which, in turn, reduces the amount of anticancer drug that can partition into these mimetic models. Fluorescence quenching studies suggest a broad distribution of the drug across the bilayer thickness, with a preferential location in the phospholipid tails. The gathered data support that daunorubicin permeates all types of membranes to different degrees, interacts with phospholipids through electrostatic and hydrophobic bonds and causes alterations in the biophysical properties of the bilayers, namely in membrane fluidity. In fact, a decrease in membrane fluidity can be observed in the acyl region of the phospholipids. Ultimately, such outcomes can be correlated with daunorubicin's biological action, where membrane structure and lipid composition have an important role. In fact, the results indicate that the intercalation of daunorubicin between the phospholipids can also take place in rigid domains, such as rafts that are known to be involved in different receptor processes, which are important for cellular function. PMID- 28855389 TI - Correction of 'An equilibrium for phenotypic variance in fluctuating environments owing to epigenetics'. PMID- 28855388 TI - Using stochastic epidemiological models to evaluate conservation strategies for endangered amphibians. AB - Recent outbreaks of chytridiomycosis, the disease of amphibians caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), have contributed to population declines of numerous amphibian species worldwide. The devastating impacts of this disease have led researchers to attempt drastic conservation measures to prevent further extinctions and loss of biodiversity. The conservation measures can be labour-intensive or expensive, and in many cases have been unsuccessful. We developed a mathematical model of Bd outbreaks that includes the effects of demographic stochasticity and within-host fungal load dynamics. We investigated the impacts of one-time treatment conservation strategies during the disease outbreak that occurs following the initial arrival of Bd into a previously uninfected frog population. We found that for all versions of the model, for a large fraction of parameter space, none of the one time treatment strategies are effective at preventing disease-induced extinction of the amphibian population. Of the strategies considered, treating frogs with antifungal agents to reduce their fungal load had the greatest likelihood of a beneficial outcome and the lowest risk of decreasing the persistence of the frog population, suggesting that this disease mitigation strategy should be prioritized over disinfecting the environment or reducing host density. PMID- 28855390 TI - Tissue-Selective Salvage of the White Matter by Successful Endovascular Stroke Therapy. AB - BACKGROUND AND PURPOSE: White matter (WM) is less vulnerable to ischemia than gray matter. In ischemic stroke caused by acute large-vessel occlusion, successful recanalization might therefore sometimes selectively salvage the WM, leading to infarct patterns confined to gray matter. This study examines occurrence, determinants, and clinical significance of such effects. METHODS: Three hundred twenty-two patients with acute middle cerebral artery occlusion subjected to mechanical thrombectomy were included. Infarct patterns were categorized into WM- (sparing the WM) and WM+ (involving WM). National Institutes of Health Stroke Scale-based measures of neurological outcome, including National Institutes of Health Stroke Scale improvement or National Institutes of Health Stroke Scale worsening, good functional midterm outcome (day 90-modified Rankin Scale score of <=2), the occurrence of malignant swelling, and in-hospital mortality were predefined outcome measures. RESULTS: WM- infarcts occurred in 118 of 322 patients and were associated with successful recanalization and better collateral grades (P<0.05). Shorter symptom-onset to recanalization times were also associated with WM- infarcts in univariate analysis, but not when adjusted for collateral grades. WM- infarcts were independently associated with good neurological outcome (adjusted odds ratio, 3.003; 95% confidence interval, 1.186 7.607; P=0.020) and good functional midterm outcome (adjusted odds ratio, 8.618; 95% confidence interval, 2.409-30.828; P=0.001) after correcting for potential confounders, including final infarct volume. Only 2.6% of WM- patients, but 20.5% of WM+ patients exhibited neurological worsening, and none versus 12.8% developed malignant swelling (P<0.001), contributing to lower mortality in this group (2.5% versus 10.3%; P=0.014). CONCLUSIONS: WM infarction commonly commences later than gray matter infarction after acute middle cerebral artery occlusion. Successful recanalization can therefore salvage completely the WM at risk in many patients even several hours after symptom onset. Preservation of the WM is associated with better neurological recovery, prevention of malignant swelling, and reduced mortality. This has important implications for neuroprotective strategies, and perfusion imaging-based patient selection, and provides a rationale for treating selected patients in extended time windows. PMID- 28855391 TI - Higher Flow Is Present in Unruptured Arteriovenous Malformations With Silent Intralesional Microhemorrhages. AB - BACKGROUND AND PURPOSE: Silent microhemorrhage (hemosiderin) has been observed in resected brain arteriovenous malformations (bAVM) tissue and may represent a subgroup at increased risk for clinical hemorrhage. Previous studies suggest that ruptured bAVMs have faster flow and shorter mean transit time of contrast in blood vessels than unruptured bAVMs. We hypothesized that flow would be faster in unruptured AVMs with hemosiderin compared with those without hemosiderin. METHODS: We selected unruptured, supratentorial bAVMs >3.5 cc with pathology specimens. Hemodynamic features were evaluated using color-coding angiography, including contrast mean transit time of AVM nidus, time to peak (TTP) of feeding artery (FA) and draining vein (DV), and the ratio (TTP DV/FA). Characteristics of 9 cases with hemosiderin and 16 without hemosiderin were compared using 2-sample t tests and Fisher exact tests. RESULTS: No difference in FA TTP and DV TTP was observed between groups. However, cases with hemosiderin had significantly shorter mean transit time compared with those without hemosiderin (1.11+/-0.28 versus 1.64+/-0.55 seconds; P=0.013) and a lower ratio of DV TTP/FA TTP (1.48+/ 0.32 versus 1.94+/-0.61; P=0.045). Presence of venous varix was significantly associated with hemosiderin (P=0.003). No other clinical or angioarchitectural factors were associated with hemosiderin. CONCLUSIONS: Shorter mean transit time through the AVM nidus, lower DV TTP/FA TTP, and the high prevalence of venous varices suggests that high flow is an important feature of unruptured bAVMs with hemosiderin. PMID- 28855392 TI - Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia. AB - BACKGROUND AND PURPOSE: We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). METHODS: Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1). RESULTS: Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P=0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P=0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P=0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P=0.007). CONCLUSIONS: Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers. PMID- 28855393 TI - FGFR3-TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle. AB - Fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3; FT3) is a gene fusion resulting from rearrangement of chromosome 4 that has been identified in many cancers including those of the urinary bladder. Altered FGFR3 signalling in FT3-positive cells is thought to contribute to cancer progression. However, potential changes in TACC3 function in these cells have not been explored. TACC3 is a mitotic spindle protein required for accurate chromosome segregation. Errors in segregation lead to aneuploidy, which can contribute to cancer progression. Here we show that FT3-positive bladder cancer cells have lower levels of endogenous TACC3 on the mitotic spindle, and that this is sufficient to cause mitotic defects. FT3 is not localized to the mitotic spindle, and by virtue of its TACC domain, recruits endogenous TACC3 away from the spindle. Knockdown of the fusion gene or low-level overexpression of TACC3 partially rescues the chromosome segregation defects in FT3-positive bladder cancer cells. This function of FT3 is specific to TACC3 as inhibition of FGFR3 signalling does not rescue the TACC3 level on the spindle in these cancer cells. Models of FT3-mediated carcinogenesis should, therefore, include altered mitotic functions of TACC3 as well as altered FGFR3 signalling. PMID- 28855395 TI - Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease. AB - Whole-genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta, fetus, or pregnant woman. Current bioinformatics algorithms typically only report on chromosomes 21, 18, 13, X, and Y; sequencing results from other chromosomes may be masked. We hypothesized that by systematically analyzing WGS data from all chromosomes, we could identify rare autosomal trisomies (RATs) to improve understanding of feto-placental biology. We analyzed two independent cohorts from clinical laboratories, both of which used a similar quality control parameter, normalized chromosome denominator quality. The entire data set included 89,817 samples. Samples flagged for analysis and classified as abnormal were 328 of 72,932 (0.45%) and 71 of 16,885 (0.42%) in cohorts 1 and 2, respectively. Clinical outcome data were available for 57 of 71 (80%) of abnormal cases in cohort 2. Visual analysis of WGS data demonstrated RATs, copy number variants, and extensive genome-wide imbalances. Trisomies 7, 15, 16, and 22 were the most frequently observed RATs in both cohorts. Cytogenetic or pregnancy outcome data were available in 52 of 60 (87%) of cases with RATs in cohort 2. Cases with RATs detected were associated with miscarriage, true fetal mosaicism, and confirmed or suspected uniparental disomy. Comparing the trisomic fraction with the fetal fraction allowed estimation of possible mosaicism. Analysis and reporting of aneuploidies in all chromosomes can clarify cases in which cfDNA findings on selected "target" chromosomes (21, 18, and 13) are discordant with the fetal karyotype and may identify pregnancies at risk of miscarriage and other complications. PMID- 28855394 TI - An in vivo genetic screen in Drosophila identifies the orthologue of human cancer/testis gene SPO11 among a network of targets to inhibit lethal(3)malignant brain tumour growth. AB - Using transgenic RNAi technology, we have screened over 4000 genes to identify targets to inhibit malignant growth caused by the loss of function of lethal(3)malignant brain tumour in Drosophila in vivo We have identified 131 targets, which belong to a wide range of gene ontologies. Most of these target genes are not significantly overexpressed in mbt tumours hence showing that, rather counterintuitively, tumour-linked overexpression is not a good predictor of functional requirement. Moreover, we have found that most of the genes upregulated in mbt tumours remain overexpressed in tumour-suppressed double mutant conditions, hence revealing that most of the tumour transcriptome signature is not necessarily correlated with malignant growth. One of the identified target genes is meiotic W68 (mei-W68), the Drosophila orthologue of the human cancer/testis gene Sporulation-specific protein 11 (SPO11), the enzyme that catalyses the formation of meiotic double-strand breaks. We show that Drosophila mei-W68/SPO11 drives oncogenesis by causing DNA damage in a somatic tissue, hence providing the first instance in which a SPO11 orthologue is unequivocally shown to have a pro-tumoural role. Altogether, the results from this screen point to the possibility of investigating the function of human cancer relevant genes in a tractable experimental model organism like Drosophila. PMID- 28855396 TI - Increased adaptive immune responses and proper feedback regulation protect against clinical dengue. AB - Clinical symptoms of dengue virus (DENV) infection, the most prevalent arthropod borne viral disease, range from classical mild dengue fever to severe, life threatening dengue shock syndrome. However, most DENV infections cause few or no symptoms. Asymptomatic DENV-infected patients provide a unique opportunity to decipher the host immune responses leading to virus elimination without negative impact on an individual's health. We used an integrated approach of transcriptional profiling and immunological analysis to compare a Cambodian population of strictly asymptomatic viremic individuals with clinical dengue patients. Whereas inflammatory pathways and innate immune response pathways were similar between asymptomatic individuals and clinical dengue patients, expression of proteins related to antigen presentation and subsequent T cell and B cell activation pathways was differentially regulated, independent of viral load and previous DENV infection history. Feedback mechanisms controlled the immune response in asymptomatic viremic individuals, as demonstrated by increased activation of T cell apoptosis-related pathways and FcgammaRIIB (Fcgamma receptor IIB) signaling associated with decreased anti-DENV-specific antibody concentrations. Together, our data illustrate that symptom-free DENV infection in children is associated with increased activation of the adaptive immune compartment and proper control mechanisms, leading to elimination of viral infection without excessive immune activation, with implications for novel vaccine development strategies. PMID- 28855399 TI - Subcutaneous drug delivery: An evolving enterprise. AB - Recent advances in subcutaneous drug delivery and device design are transforming the biopharmaceutical sector and improving patient care. PMID- 28855397 TI - Inflammatory monocytes expressing tissue factor drive SIV and HIV coagulopathy. AB - In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)-related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target. PMID- 28855398 TI - Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis. AB - The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes "hospitable soil" to foster the incorporation of "seed," in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)-expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs (HgfiDeltaEC/iDeltaEC) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in HgfiDeltaEC/iDeltaEC mice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration. PMID- 28855401 TI - Swallowing-induced displacement of the carotid artery as a risk of stroke: Flip flop phenomenon. PMID- 28855400 TI - Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging. AB - OBJECTIVE: This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. METHODS: Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (beta-amyloid [Abeta] deposition, a hallmark of AD pathology). RESULTS: As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Abeta deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Abeta deposition was exacerbated in APOE4 positive MENO women relative to the other groups (p < 0.001). CONCLUSIONS: Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process. PMID- 28855402 TI - Polycystic kidney disease is significantly associated with dementia risk. AB - OBJECTIVE: Data on the risk of neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD), in patients with polycystic kidney disease (PKD) are lacking. METHODS: A total of 4,229 patients who were aged >=20 years and had received a diagnosis of PKD were included in the PKD cohort. For each PKD case identified, 1 participant aged >=20 years without a history of PKD, dementia, or PD was selected from the comparison cohort. For each patient with PKD, the corresponding controls were selected 1:1 on the basis of the nearest propensity score calculated using logistic regression. RESULTS: The incidence density rates of dementia were 4.31 and 2.50 per 1,000 person-years in the PKD and control cohorts, respectively. A 2.04-fold higher risk of dementia was observed in patients with PKD than in controls (adjusted hazard ratio [aHR] 2.04; 95% confidence interval [CI] 1.46-2.85). Regarding the risk of different dementia subtypes, including AD and vascular dementia (VaD), the aHR for AD and presenile dementia was 2.71 (95% CI 1.08-6.75) and that for VaD was 0.90 (95% CI 0.43-1.87) in patients with PKD compared with controls, after adjustment for age, sex, and comorbidities. Compared with controls, the risk of PD increased by 1.78-fold (95% CI 1.14-2.79) in patients with PKD. CONCLUSIONS: In clinical practice, health care professionals should be aware of the risk of neurodegenerative diseases in patients with PKD. PMID- 28855403 TI - Developmental outcomes of cord blood transplantation for Krabbe disease: A 15 year study. AB - OBJECTIVE: To describe long-term outcomes of children with early-infantile Krabbe disease who underwent hematopoietic stem cell transplantation (HSCT) in the first 7 weeks of life. METHODS: In this prospective longitudinal study, evaluations performed at baseline and follow-up included brain imaging, neurodiagnostic tests, and neurobehavioral evaluations. RESULTS: Of the 18 patients in this study (11 girls, 7 boys; mean follow-up 9.5 years, range 4-15), 5 died (3 of peritransplant complications, 1 of a surgical complication unrelated to Krabbe disease, 1 of disease progression). One of the surviving patients has normal cognitive function and 10 continue to develop cognitive skills at a slightly slower rate than normal. All surviving patients continue to gain receptive language skills, with 7 falling within the normal range. Ten patients receive speech therapy, and 2 of these patients require augmentative communication devices. Gross motor development varies widely, but 3 patients can walk independently, and 7 walk with assistive devices. Spasticity ranges from mild to severe, and 12 patients wear orthotics. Fine motor skills are generally preserved. Brain myelination and atrophy stabilized in 8 patients, improved in 4 patients, and worsened in 1 patient. Nerve conduction velocities initially improved but continue to be abnormal in most patients. CONCLUSIONS: The surviving patients function at a much higher level than untreated children or symptomatic children who underwent HSCT. These results show that early HSCT changes the natural history of this disease by improving both lifespan and functional abilities. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for children with early-infantile Krabbe disease, early HSCT improves lifespan and functional abilities. PMID- 28855404 TI - Cognition and gray and white matter characteristics of presymptomatic C9orf72 repeat expansion. AB - OBJECTIVE: To investigate cognitive function, gray matter volume, and white matter integrity in the presymptomatic stage of chromosome 9 open reading frame 72 repeat expansion (C9orf72RE). METHODS: Presymptomatic C9orf72RE carriers (n = 18) and first-degree family members without a pathogenic expansion (healthy controls [HC], n = 15) underwent a standardized protocol of neuropsychological tests, T1-weighted MRI, and diffusion tensor imaging within our cohort study of autosomal dominant frontotemporal dementia (FTD). We investigated group differences in cognitive function, gray matter volume through voxel-based morphometry, and white matter integrity by means of tract-based spatial statistics. We correlated cognitive change with underlying gray or white matter. RESULTS: Our data demonstrate lower scores on letter fluency, Stroop card I, and Stroop card III, accompanied by white matter integrity loss in tracts connecting the frontal lobe, the thalamic radiation, and tracts associated with motor functioning in presymptomatic C9orf72RE compared with HC. In a subgroup of C9orf72RE carriers above 40 years of age, we found gray matter volume loss in the thalamus, cerebellum, and parietal and temporal cortex. We found no significant relationship between subtle cognitive decline and underlying gray or white matter. CONCLUSIONS: This study demonstrates that a decline in cognitive functioning, white matter integrity, and gray matter volumes are present in presymptomatic C9orf72RE carriers. These findings suggest that neuropsychological assessment, T1-weighted MRI, and diffusion tensor imaging might be useful to identify early biomarkers in the presymptomatic stage of FTD or amyotrophic lateral sclerosis. PMID- 28855405 TI - Amyloid-PET in cerebral amyloid angiopathy: Detecting vascular amyloid deposits, not just blood. PMID- 28855406 TI - Amyloid-PET in sporadic cerebral amyloid angiopathy: A diagnostic accuracy meta analysis. AB - OBJECTIVE: To perform a meta-analysis synthesizing evidence of the value and accuracy of amyloid-PET in diagnosing patients with sporadic cerebral amyloid angiopathy (CAA). METHODS: In a PubMed systematic literature search, we identified all case-control studies with extractable data relevant for the sensitivity and specificity of amyloid-PET positivity in symptomatic patients with CAA (cases) vs healthy participants or patients with spontaneous deep intracerebral hemorrhage (ICH) (control groups). Using a hierarchical (multilevel) logistic regression model, we calculated pooled diagnostic test accuracy. RESULTS: Seven studies, including 106 patients with CAA (>90% with probable CAA) and 151 controls, were eligible and included in the meta-analysis. The studies were of moderate to high quality and varied in several methodological aspects, including definition of PET-positive and PET-negative cases and relevant cutoffs. The sensitivity of amyloid-PET for CAA diagnosis ranged from 60% to 91% and the specificity from 56% to 90%. The overall pooled sensitivity was 79% (95% confidence interval [CI] 62-89) and specificity was 78% (95% CI 67-86) for CAA diagnosis. A predefined subgroup analysis of studies restricted to symptomatic patients presenting with lobar ICH CAA (n = 58 vs 86 controls) resulted in 79% sensitivity (95% CI 61-90%) and 84% specificity (95% CI 65-93%). In prespecified bivariate diagnostic accuracy meta-analysis of 2 studies using 18F-florbetapir PET, the sensitivity for CAA-ICH diagnosis was 90% (95% CI 76-100%) and specificity was 88% (95% CI 74-100%). CONCLUSIONS: Amyloid-PET appears to have moderate to good diagnostic accuracy in differentiating patients with probable CAA from cognitively normal healthy controls or patients with deep ICH. Given that amyloid-PET labels both cerebrovascular and parenchymal amyloid, a negative scan might be useful to rule out CAA in the appropriate clinical setting. PMID- 28855407 TI - Stem cell transplantation in Krabbe disease: New truths discovered and opinions change. PMID- 28855408 TI - Association of intracranial aneurysm rupture with smoking duration, intensity, and cessation. AB - OBJECTIVE: Although smoking is a known risk factor for intracranial aneurysm (IA) rupture, the exact relationship between IA rupture and smoking intensity and duration, as well as duration of smoking cessation, remains unknown. METHODS: In this case-control study, we analyzed 4,701 patients with 6,411 IAs diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016. We divided individuals into patients with ruptured aneurysms and controls with unruptured aneurysms. We performed univariable and multivariable logistic regression analyses to determine the association between smoking status and ruptured IAs at presentation. In a subgroup analysis among former and current smokers, we assessed the association between ruptured aneurysms and number of packs per day, duration of smoking, and duration since smoking cessation. RESULTS: In multivariable analysis, current (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.89-2.59) and former smoking status (OR 1.56, 95% CI 1.31-1.86) were associated with rupture status at presentation compared with never smokers. In a subgroup analysis among current and former smokers, years smoked (OR 1.02, 95% CI 1.01-1.03) and packs per day (OR 1.46, 95% CI 1.25-1.70) were significantly associated with ruptured aneurysms at presentation, whereas duration since cessation among former smokers was not significant (OR 1.00, 95% CI 0.99-1.02). CONCLUSIONS: Current cigarette smoking, smoking intensity, and smoking duration are significantly associated with ruptured IAs at presentation. However, the significantly increased risk persists after smoking cessation, and smoking cessation does not confer a reduced risk of aneurysmal subarachnoid hemorrhage beyond that of reducing the cumulative dose. PMID- 28855410 TI - Aneurysm rupture: Another reason to abstain from smoking. PMID- 28855409 TI - High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2. AB - OBJECTIVE: To analyze gastrointestinal (GI) manifestations, their progression over time, and medications being used to treat GI symptoms in a large cohort of patients with myotonic dystrophy types 1 (DM1) and 2 (DM2). METHODS: We analyzed patient-reported data and medical records in a national registry cohort at baseline and 5 years. RESULTS: At baseline, the majority of patients reported trouble swallowing in DM1 (55%; n = 499 of 913) and constipation in DM2 (53%; n = 96 of 180). Cholecystectomy occurred in 16.5% of patients with DM1 and 12.8% of patients with DM2, on average before 45 years of age. The use of medications indicated for gastroesophageal reflux disease was reported by 22.5% of DM1 and 18.9% of patients with DM2. Greater risk of a GI manifestation was associated with higher body mass index and longer disease duration in DM1 and female sex in DM2. At the 5-year follow-up, the most common new manifestations were trouble swallowing in patients with DM1 and constipation in patients with DM2. CONCLUSIONS: GI manifestations were common in both DM1 and DM2, with a relatively high frequency of gallbladder removal in DM1 and DM2 occurring at a younger age compared to normative data in the literature. Studies are needed to determine the pathomechanism of how sex, weight gain, and duration of disease contribute to GI manifestations and how these manifestations affect quality of life and clinical care for patients with DM1 and DM2. PMID- 28855411 TI - Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study. AB - OBJECTIVE: To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis. METHODS: Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth. RESULTS: Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics. CONCLUSIONS: The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations. PMID- 28855412 TI - Responses of neurogenesis and neuroplasticity related genes to elevated CO2 levels in the brain of three teleost species. AB - The continuous increase of anthropogenic CO2 in the atmosphere resulting in ocean acidification has been reported to affect brain function in some fishes. During adulthood, cell proliferation is fundamental for fish brain growth and for it to adapt in response to external stimuli, such as environmental changes. Here we report the first expression study of genes regulating neurogenesis and neuroplasticity in brains of three-spined stickleback (Gasterosteus aculeatus), cinnamon anemonefish (Amphiprion melanopus) and spiny damselfish (Acanthochromis polyacanthus) exposed to elevated CO2 The mRNA expression levels of the neurogenic differentiation factor (NeuroD) and doublecortin (DCX) were upregulated in three-spined stickleback exposed to high-CO2 compared with controls, while no changes were detected in the other species. The mRNA expression levels of the proliferating cell nuclear antigen (PCNA) and the brain derived neurotrophic factor (BDNF) remained unaffected in the high-CO2 exposed groups compared to the control in all three species. These results indicate a species-specific regulation of genes involved in neurogenesis in response to elevated ambient CO2 levels. The higher expression of NeuroD and DCX mRNA transcripts in the brain of high-CO2-exposed three-spined stickleback, together with the lack of effects on mRNA levels in cinnamon anemonefish and spiny damselfish, indicate differences in coping mechanisms among fish in response to the predicted-future CO2 level. PMID- 28855413 TI - Predation, metabolic priming and early life-history rearing environment affect the swimming capabilities of growth hormone transgenic rainbow trout. AB - The period of first feeding, when young salmonid fishes emerge from natal stream beds, is one fraught with predation risk. Experiments conducted in semi-natural stream mesocosms have shown that growth hormone transgenic salmonids are at greater risk of predation than their non-transgenic siblings, due partly to the higher metabolic demands associated with transgenesis, which force risky foraging behaviours. This raises questions as to whether there are differences in the swim performance of transgenic and non-transgenic fishes surviving predation experiments. We tested this hypothesis in wild-origin rainbow trout (Oncorhynchus mykiss) that were reared from first feeding in semi-natural stream mesocosms characterized by complex hydrodynamics, the presence of predators and oligotrophic conditions. Using an open-flume raceway, we swam fish and measured their capacity for burst-swimming against a sustained flow. We found a significant genotype effect on burst-performance, with transgenic fish sustaining performance longer than their wild-type siblings, both in predator and predator free stream segments. Importantly, this effect occurred before differences in growth were discernable. We also found that mesocosm-reared fish had greater burst-performance than fish reared in the controlled hatchery environment, despite the latter being unexposed to predators and having abundant food. Our results suggest a potential interaction between predation and metabolic priming, which leads to greater burst capacity in transgenic trout. PMID- 28855414 TI - Nuclear and mitochondrial RNA editing systems have opposite effects on protein diversity. AB - RNA editing can yield protein products that differ from those directly encoded by genomic DNA. This process is pervasive in the mitochondria of many eukaryotes, where it predominantly results in the restoration of ancestral protein sequences. Nuclear mRNAs in metazoans also undergo editing (adenosine-to-inosine or 'A-to-I' substitutions), and most of these edits appear to be nonadaptive 'misfirings' of adenosine deaminases. However, recent analysis of cephalopod transcriptomes found that many editing sites are shared by anciently divergent lineages within this group, suggesting they play some adaptive role. Recent discoveries have also revealed that some fungi have an independently evolved A-to-I editing mechanism, resulting in extensive recoding of their nuclear mRNAs. Here, phylogenetic comparisons were used to determine whether RNA editing generally restores ancestral protein sequences or creates derived variants. Unlike in mitochondrial systems, RNA editing in metazoan and fungal nuclear transcripts overwhelmingly leads to novel sequences not found in inferred ancestral proteins. Even for the subset of RNA editing sites shared by deeply divergent cephalopod lineages, the primary effect of nuclear editing is an increase-not a decrease-in protein divergence. These findings suggest fundamental differences in the forces responsible for the evolution of RNA editing in nuclear versus mitochondrial systems. PMID- 28855415 TI - Dental development in Homo naledi. AB - Humans' prolonged somatic development and life history are unique among primates, yet their evolutionary origins remain unclear. Dental development has been used as a proxy to reconstruct life history evolution in the hominin clade and indicates a recent emergence of the human developmental pattern. Here, we analyse tooth formation and eruption in two developing dentitions of Homo naledi, a late surviving, morphologically mosaic hominin species. Deciduous dental development is more similar to humans than to chimpanzees, probably reflecting hominin symplesiomorphy rather than bearing life history significance. The later stages of permanent tooth development present a mix of human- and chimpanzee-like patterns. Surprisingly, the M2 of H. naledi emerges late in the eruption sequence, a pattern previously unknown in fossil hominins and common in modern humans. This pattern has been argued to reflect a slow life history and is unexpected in a small-brained hominin. The geological age of H. naledi (approx. 300 kya), coupled with its small brain size and the dental development data presented here, raise questions about the relationship between dental development and other variables associated with life history. PMID- 28855416 TI - Ancient whales did not filter feed with their teeth. AB - The origin of baleen whales (Mysticeti), the largest animals on Earth, is closely tied to their signature filter-feeding strategy. Unlike their modern relatives, archaic whales possessed a well-developed, heterodont adult dentition. How these teeth were used, and what role their function and subsequent loss played in the emergence of filter feeding, is an enduring mystery. In particular, it has been suggested that elaborate tooth crowns may have enabled stem mysticetes to filter with their postcanine teeth in a manner analogous to living crabeater and leopard seals, thereby facilitating the transition to baleen-assisted filtering. Here we show that the teeth of archaic mysticetes are as sharp as those of terrestrial carnivorans, raptorial pinnipeds and archaeocetes, and thus were capable of capturing and processing prey. By contrast, the postcanine teeth of leopard and crabeater seals are markedly blunter, and clearly unsuited to raptorial feeding. Our results suggest that mysticetes never passed through a tooth-based filtration phase, and that the use of teeth and baleen in early whales was not functionally connected. Continued selection for tooth sharpness in archaic mysticetes is best explained by a feeding strategy that included both biting and suction, similar to that of most living pinnipeds and, probably, early toothed whales (Odontoceti). PMID- 28855417 TI - Total Sulfur Amino Acid Requirements Are Not Altered in Children with Chronic Renal Insufficiency, but Minimum Methionine Needs Are Increased. AB - Background: The total sulfur amino acid (TSAA) and minimum Met requirements have been previously determined in healthy children. TSAA metabolism is altered in kidney disease. Whether TSAA requirements are altered in children with chronic renal insufficiency (CRI) is unknown.Objective: We sought to determine the TSAA (Met in the absence of Cys) requirements and minimum Met (in the presence of excess Cys) requirements in children with CRI.Methods: Five children (4 boys, 1 girl) aged 10 +/- 2.6 y with CRI were randomly assigned to receive graded intakes of Met (0, 5, 10, 15, 25, and 35 mg . kg-1 . d-1) with no Cys in the diet. Four of the children (3 boys, 1 girl) were then randomly assigned to receive graded dietary intakes of Met (0, 2.5, 5, 7.5, 10, and 15 mg . kg-1 . d-1) with 21 mg . kg-1 . d-1 Cys. The mean TSAA and minimum Met requirements were determined by measuring the oxidation of l-[1-13C]Phe to 13CO2 (F13CO2). A 2-phase linear regression crossover analysis of the F13CO2 data identified a breakpoint at minimal F13CO2 Urine samples collected from all study days and from previous studies of healthy children were measured for sulfur metabolites.Results: The mean and population-safe (upper 95% CI) intakes of TSAA and minimum Met in children with CRI were determined to be 12.6 and 15.9 mg . kg-1 . d-1 and 7.3 and 10.9 mg . kg-1 . d-1, respectively. In healthy school-aged children the mean and upper 95% CI intakes of TSAA and minimum Met were determined to be 12.9 and 17.2 mg . kg-1 . d-1 and 5.8 and 7.3 mg . kg-1 . d-1, respectively. A comparison of the minimum Met requirements between healthy children and children with CRI indicated significant (P < 0.05) differences.Conclusion: These results suggest that children with CRI have a similar mean and population-safe TSAA to that of healthy children, suggesting adequate Cys synthesis via transsulfuration, but higher minimum Met requirement, suggesting reduced remethylation rates. PMID- 28855418 TI - Analyses of Selenotranscriptomes and Selenium Concentrations in Response to Dietary Selenium Deficiency and Age Reveal Common and Distinct Patterns by Tissue and Sex in Telomere-Dysfunctional Mice. AB - Background: The hierarchies of tissue selenium distribution and selenotranscriptomes are thought to critically affect healthspan and longevity.Objective: We determined selenium status and selenotranscriptomes in response to long-term dietary selenium deficiency and age in tissues of male and female mice.Methods: Weanling telomerase RNA component knockout C57BL/6 mice were fed a selenium-deficient (0.03 mg Se/kg) Torula yeast-based AIN-93G diet or a diet supplemented with sodium selenate (0.15 mg Se/kg) until age 18 or 24 mo. Plasma, hearts, kidneys, livers, and testes were collected to assay for selenotranscriptomes, selected selenoproteins, and tissue selenium concentrations. Data were analyzed with the use of 2-factor ANOVA (diet * age) in both sexes.Results: Dietary selenium deficiency decreased (P <= 0.05) selenium concentrations (65-72%) and glutathione peroxidase (GPX) 3 (82-94%) and selenoprotein P (SELENOP) (17-41%) levels in the plasma of both sexes of mice and mRNA levels (9-68%) of 4, 4, and 12 selenoproteins in the heart, kidney, and liver of males, respectively, and 5, 16, and 14 selenoproteins, respectively, in females. Age increased selenium concentrations and SELENOP levels (27% and 30%, respectively; P <= 0.05) in the plasma of males only but decreased (12-46%; P < 0.05) mRNA levels of 1, 5, and 13 selenoproteins in the heart, kidney, and liver of males, respectively, and 6, 5, and 0 selenoproteins, respectively, in females. Among these mRNAs, selenoprotein H (Selenoh), selenoprotein M (Selenom), selenoprotein W (Selenow), methionine-R-sulfoxide reductase 1 (MsrB1), Gpx1, Gpx3, thioredoxin reductase 1 (Txnrd1), Txnrd2, selenoprotein S (Selenos), selenoprotein F (Selenof), and selenoprotein O (Selenoo) responded in parallel to dietary selenium deficiency and age in >=1 tissue or sex, or both. Dietary selenium deficiency upregulated (40-160%; P <= 0.05) iodothyronine deiodinase 2 (Dio2) and selenoprotein N (Selenon) in the kidneys of males. Age upregulated (11 44%; P < 0.05) Selenon in the kidneys of males, selenoprotein K (Selenok) and selenoprotein I (Selenoi) in the kidneys of females, and Selenof and Selenok in the testes.Conclusions: These results illustrate tissue-specific sexual dimorphisms of selenium status and selenotranscriptomes because of dietary selenium deficiency and age. PMID- 28855419 TI - Protein Ingestion before Sleep Increases Overnight Muscle Protein Synthesis Rates in Healthy Older Men: A Randomized Controlled Trial. AB - Background: The loss of skeletal muscle mass with aging has been attributed to the blunted anabolic response to protein intake. Presleep protein ingestion has been suggested as an effective strategy to compensate for such anabolic resistance.Objective: We assessed the efficacy of presleep protein ingestion on dietary protein digestion and absorption kinetics and overnight muscle protein synthesis rates in older men.Methods: In a randomized, double-blind, parallel design, 48 older men (mean +/- SEM age: 72 +/- 1 y) ingested 40 g casein (PRO40), 20 g casein (PRO20), 20 g casein plus 1.5 g leucine (PRO20+LEU), or a placebo before sleep. Ingestion of intrinsically l-[1-13C]-phenylalanine- and l-[1-13C] leucine-labeled protein was combined with intravenous l-[ring-2H5]-phenylalanine and l-[1-13C]-leucine infusions during sleep. Muscle and blood samples were collected throughout overnight sleep.Results: Exogenous phenylalanine appearance rates increased after protein ingestion, but to a greater extent in PRO40 than in PRO20 and PRO20+LEU (P < 0.05). Overnight myofibrillar protein synthesis rates (based on l-[ring-2H5]-phenylalanine) were 0.033% +/- 0.002%/h, 0.037% +/- 0.003%/h, 0.039% +/- 0.002%/h, and 0.044% +/- 0.003%/h in placebo, PRO20, PRO20+LEU, and PRO40, respectively, and were higher in PRO40 than in placebo (P = 0.02). Observations were similar based on l-[1-13C]-leucine tracer (placebo: 0.047% +/- 0.004%/h and PRO40: 0.058% +/- 0.003%/h, P = 0.08). More protein derived amino acids (l-[1-13C]-phenylalanine) were incorporated into myofibrillar protein in PRO40 than in PRO20 (0.033 +/- 0.002 and 0.019 +/- 0.002 MPE, respectively, P < 0.001) and tended to be higher than in PRO20+LEU (0.025 +/- 0.002 MPE, P = 0.06).Conclusions: Protein ingested before sleep is properly digested and absorbed throughout the night, providing precursors for myofibrillar protein synthesis during sleep in healthy older men. Ingestion of 40 g protein before sleep increases myofibrillar protein synthesis rates during overnight sleep. These findings provide the scientific basis for a novel nutritional strategy to support muscle mass preservation in aging and disease. This trial was registered at www.trialregister.nl as NTR3885. PMID- 28855420 TI - Dietary Patterns Exhibit Sex-Specific Associations with Adiposity and Metabolic Risk in a Cross-Sectional Study in Urban Mexican Adolescents. AB - Background: Studies in Western nations have shown associations of certain dietary patterns with obesity and metabolic risk in youth. Little is known about these relations in newly industrialized countries where obesity prevalence is surpassing those of developed countries.Objective: We sought to characterize dietary patterns in a cross-sectional study in 224 adolescents aged 8-14 y in Mexico and to investigate associations of the dietary patterns with adiposity and metabolic risk.Methods: We used principal components analysis to derive dietary patterns from food-frequency questionnaire data. By using linear regression models that accounted for mother's marital status, education, and smoking habits and child's age and physical activity, we examined associations of the dietary patterns with adiposity [body mass index z score, waist circumference, the sum and ratio of the subscapular and triceps skinfold thicknesses, blood pressure, serum fasting glucose and a C-peptide-based measure of insulin resistance (CP IR), lipid profile, and a metabolic syndrome risk z score (MetS z score)].Results: We identified a "prudent" dietary pattern characterized by high intakes of vegetables, fruit, fish, chicken, and legumes and a "transitioning" dietary pattern, which comprises processed meats, Mexican foods, and sweetened beverages. Each unit increase in the prudent pattern factor score corresponded with 0.33 ng/mL (95% CI: 0.09, 0.57 ng/mL) lower C-peptide, 0.08 units (95% CI: 0.02, 0.13 units) lower CP-IR, and a 0.14 unit (0.00, 0.27 unit) lower MetS z score in boys. In girls, the transitioning pattern corresponded with higher subscapular + triceps skinfold thickness (per 1-unit increase in the factor score: 2.46 mm; 95% CI: 0.10, 4.81 mm). These results did not change after accounting for pubertal status.Conclusions: A prudent dietary pattern was protective against metabolic risk in adolescent boys, whereas a transitioning dietary pattern corresponded with higher adiposity among adolescent girls. Given that adolescence is a key developmental period for long-term health, efforts to elucidate dietary determinants of metabolic risk during this life stage may have long-term benefits. PMID- 28855421 TI - Dietary Supplement Use Was Very High among Older Adults in the United States in 2011-2014. AB - Background: Dietary supplements (DSs) have the potential to be both beneficial and harmful to health, especially in adults aged >=60 y, and therefore it is important to monitor the patterns of their use.Objective: This study evaluated DS use by adults aged >=60 y to characterize the use of DSs, determine the motivations for use, and examine the associations between the use of DSs and selected demographic, lifestyle, and health characteristics.Methods: Data from 3469 older adults aged >=60 y from the 2011-2014 NHANES were analyzed. DSs used in the past 30 d were ascertained via an interviewer-administered questionnaire in participants' homes. The prevalence of overall DS use and specific types of DSs were estimated. The number of DSs reported and the frequency, duration, and motivation(s) for use were assessed. Logistic regression models were constructed to examine the association between DS use and selected characteristics.Results: Seventy percent of older adults in the United States reported using >=1 DS in the past 30 d; 54% of users took 1 or 2 products, and 29% reported taking >=4 products. The most frequently reported products were multivitamin or mineral (MVM) (39%), vitamin D only (26%), and omega-3 fatty acids (22%). Women used DSs almost twice as often as men [adjusted OR (aOR), 1.8; 95% CI: 1.5, 2.3). Those not reporting prescription medications were less likely to take a DS than those reporting >=3 prescription medications (aOR, 0.4; 95% CI: 0.3, 0.6). The most frequently reported motivation for DS use was to improve overall health (41%).Conclusions: Use of DSs among older adults continues to be high in the United States, with 29% of users regularly taking >=4 DSs, and there is a high concurrent usage of them with prescription medications. PMID- 28855422 TI - Very Low Food Security in US Households Is Predicted by Complex Patterns of Health, Economics, and Service Participation. AB - Background: Very low food security (VLFS) happens at the intersection of nuanced and complex patterns of risk characteristics across multiple domains. Little is known about the idiosyncratic situations that lead households to experience VLFS.Objective: We used classification and regression tree (CART) analysis, which can handle complex combinations of predictors, to identify patterns of characteristics that distinguish VLFS households in the United States from other households.Methods: Data came from 3 surveys, the 2011-2014 National Health Interview Survey (NHIS), the 2005-2012 NHANES, and the 2002-2012 Current Population Survey (CPS), with sample participants aged >=18 y and households with income <300% of the federal poverty line. Survey participants were stratified into households with children, adult-only households, and older-adult households (NHIS, CPS) or individuals aged 18-64 y and individuals aged >=65 y (NHANES). Household food security was measured with the use of the 10-item US Adult Food Security Scale. Variables from multiple domains, including sociodemographic characteristics, health, health care, and participation in social welfare and food assistance programs, were considered as predictors. The 3 data sources were analyzed separately with the use of CART analysis.Results: Household experiences of VLFS were associated with different predictors for different types of households and often occurred at the intersection of multiple characteristics spanning unmet medical needs, poor health, disability, limitation, depressive symptoms, low income, and food assistance program participation. These predictors built complex trees with various combinations in different types of households.Conclusions: This study showed that multiple characteristics across multiple domains distinguished VLFS households. Flexible and nonlinear methods focusing on a wide range of risk characteristics should be used to identify VLFS households and to inform policies and programs that can address VLFS households' various needs. PMID- 28855423 TI - Plant-based Food Cyanidin-3-Glucoside Modulates Human Platelet Glycoprotein VI Signaling and Inhibits Platelet Activation and Thrombus Formation. AB - Background: Platelets play an important role in hemostasis, thrombosis, and atherosclerosis. Glycoprotein VI (GPVI) is a major platelet receptor that interacts with exposed collagen on injured vessel walls. Our previous studies have shown that anthocyanins (a type of natural plant pigment) attenuate platelet function; however, whether anthocyanins affect collagen-induced GPVI signaling remains unknown.Objective: The objective of this study was to explore the effects of cyanidin-3-glucoside (Cy-3-g, one of the major bioactive compounds in anthocyanins) on platelet activation and thrombosis and the GPVI signaling pathway.Methods: Platelets from healthy men and women were isolated and incubated with different concentrations (0, 0.5, 5, and 50 MUM) of Cy-3-g. The expression of activated integrin alphaIIbbeta3, P-selectin, CD63, and CD40L, fibrinogen binding to platelets, and platelet aggregation were evaluated in vitro. Platelet adhesion and aggregation in whole blood under flow conditions were assessed in collagen-coated perfusion chambers. Thrombosis and hemostasis were assessed in 3 4-wk-old male C57BL/6J mice through FeCl3-induced intravital microscopy and tail bleeding time. The effect of Cy-3-g on collagen-induced human platelet GPVI signaling was explored with Western blot.Results: Cy-3-g attenuated platelet function in a dose-dependent manner. The 0.5-MUM dose of Cy-3-g inhibited (P < 0.05) human platelet adhesion and aggregation to collagen at both venous ( 54.02%) and arterial (-22.90%) shear stresses. The 5-MUM dose inhibited (P < 0.05) collagen-induced human platelet activation (PAC-1: -48.21%, P-selectin: 50.63%), secretion (CD63: -73.89%, CD40L: -43.70%), fibrinogen binding (-56.79%), and aggregation (-17.81%). The 5-MUM dose attenuated (P < 0.01) thrombus growth ( 66.67%) without prolonging bleeding time in mice. The 50-MUM dose downregulated (P < 0.05) collagen-induced GPVI signaling in human platelets and significantly decreased phosphorylation of Syk-linker for activation of T cells (LAT)-SLP76 (Syk: -39.08%, LAT: -32.25%, SLP76: -40.00%) and the expression of Lyn (-31.89%), Fyn (-36.27%), and phospholipase C-gamma2 (-39.08%).Conclusions: Cy-3-g inhibits human platelet activation, aggregation, secretion, and thrombus formation, and downregulates the collagen-GPVI signaling pathway. Supplementation of Cy-3-g may have protective effects against atherothrombosis. PMID- 28855425 TI - Establishing contact between cell-laden hydrogels and metallic implants with a biomimetic adhesive for cell therapy supported implants. AB - For in-dwelling implants, controlling the biological interface is a crucial parameter to promote tissue integration and prevent implant failure. For this purpose, one possibility is to facilitate the establishment of the interface with cell-laden hydrogels fixed to the implant. However, for proper functioning, the stability of the hydrogel on the implant should be ensured. Modification of implant surfaces with an adhesive represents a promising strategy to promote the adhesion of a cell-laden hydrogel on an implant. Herein, we developed a peptidic adhesive based on mussel foot protein (L-DOPA-L-lysine)2-L-DOPA that can be applied directly on the surface of an implant. At physiological pH, unoxidized (L DOPA-L-lysine)2-L-DOPA was supposed to strongly adhere to metallic surfaces but it only formed a very thin coating (less than 1 nm). Once oxidized at physiological pH, (L-DOPA-L-lysine)2-L-DOPA forms an adhesive coating about 20 nm thick. In oxidized conditions, L-lysine can adhere to metallic substrates via electrostatic interaction. Oxidized L-DOPA allows the formation of a coating through self-polymerization and can react with amines so that this adhesive can be used to fix extra-cellular matrix based materials on implant surfaces through the reaction of quinones with amino groups. Hence, a stable interface between a soft gelatin hydrogel and metallic surfaces was achieved and the strength of adhesion was investigated. We have shown that the adhesive is non-cytotoxic to encapsulated cells and enabled the adhesion of gelatin soft hydrogels for 21 days on metallic substrates in liquid conditions. The adhesion properties of this anchoring peptide was quantified by a 180 degrees peeling test with a more than 60% increase in peel strength in the presence of the adhesive. We demonstrated that by using a biomimetic adhesive, for the application of cell-laden hydrogels to metallic implant surfaces, the hydrogel/implant interface can be ensured without relying on the properties of the deposited biomaterials. PMID- 28855424 TI - Cell derived extracellular matrix fibers synthesized using sacrificial hollow fiber membranes. AB - The therapeutic potential of biological scaffolds as adjuncts to synthetic polymers motivates the engineering of fibers formed using the extracellular matrix (ECM) secreted by cells. To capture the ECM secreted by cells during in vitro culture, a solvent degradable hollow fiber membrane (HFM) was created and utilized as a cell culture platform. NIH/3T3 fibroblasts were injected into the narrow (0.986 +/- 0.042 mm) lumina of mesoporous polysulfone HFMs and maintained in culture for up to 3 weeks. Following cell culture, HFMs were dissolved using N methyl-2-pyrrolidone and the accumulated ECM was collected. The ECM retained the filamentous dimensions of the HFM lumen. The process yielded up to 0.89 +/- 0.20 mg of ECM for every mm of HFM dissolved. Immunofluorescence, second-harmonic generation microscopy, and tandem mass spectrometry indicated the presence of an array of ECM constituents, including collagen, fibronectin, and proteoglycans, while FTIR spectra suggested thorough HFM material dissolution. Isolated ECM fibers, although fragile, were amenable to handling and exhibited an average elastic modulus of 34.6 +/- 15.3 kPa, ultimate tensile strength of 5.2 +/- 2.2 kPa, and elongation-at-break of 29% +/- 18%. ECM fibers consisted of an interconnected yet porous (32.7% +/- 5.8% open space) network which supported the attachment and in vitro proliferation of mammalian cells. ECM fibers were similarly synthesized using muscle and astrocyte cells, suggesting process robustness across different cell types. Ultimately, these ECM fibers could be utilized as an alternative to synthetics for the manufacture of woven meshes targeting wound healing or regenerative medicine applications. PMID- 28855426 TI - Neural differentiation of fibroblasts induced by intracellular co-delivery of Ascl1, Brn2 and FoxA1 via a non-viral vector of cationic polysaccharide. AB - Direct reprogramming of other somatic cells into neurons is an alternative strategy for the recovery of an injured nervous system. In this work, we developed a new non-viral gene carrier based on Porphyra yezoensis polysaccharide (PYP). After modification with ethylenediamine, the cationized PYP (Ed-PYP) was combined with plasmids encoding Ascl1, Brn2 and FoxA1 to form spherical nanoscale particles (Ed-PYP-pABF nanoparticles). Cytotoxicity assays proved that Ed-PYP pABF nanoparticles had a better safety profile than Lipofectamine 2000 and polyetherimide. Characterization tests illustrated that the Ed-PYP-pABF nanoparticles at an Ed-PYP:pABF weight ratio of 40:1 is a potential candidate for gene delivery, which was further supported by Western blot and plasmid encoding enhanced green fluorescence protein transfection. Based on this transfection strategy, we co-delivered pABF to 3T6 cells using Ed-PYP. ELISA indicated that the levels of brain-derived neurotrophic factor, nerve growth factors and sonic hedgehog reached a maximum at 14 days after the last transfection. Immunofluorescence and Western blot further exhibited positive expression of neurofilament 200, Nestin, glial fibrillary acidic protein, growth associated protein-43, beta-3tubulin, and microtubule associated protein 2, proving the successful conversion of 3T6 cells into neurons. Taken together, these results illustrated that a natural polysaccharide-based gene co-delivery system is a promising strategy for neural reprogramming. PMID- 28855428 TI - Molecular epidemiological study of gammaherpesvirus in domestic cats in Japan. AB - Gammaherpesviruses (GHVs) are members of an emerging subfamily of the family Herpesviridae. A recent study identified a novel GHV in domestic cats (Felis catus GHV1, FcaGHV1), and epidemiological surveys have found that FcaGHV1 is distributed worldwide. In this study, we investigated the prevalence of GHVs in domestic cats in Japan with a molecular epidemiological survey. Blood samples were collected from 1,738 domestic cats and GHV-derived DNA was detected with PCR in 1.3% (23/1,738) of the Japanese domestic cats. The FcaGHV1 detected in this study was very similar to FcaGHV1 detected in a domestic cat in North America. Older age (>5 years old) and Feline immunodeficiency virus infection were identified as risk factors for GHV infection. PMID- 28855429 TI - Acute blindness in a dog with Acinetobacter-associated postencephalitic hydrocephalus. AB - A 10-month-old male Welsh Corgi with a history of acute blindness underwent neuro ophthalmological testing and magnetic resonance imaging (MRI). Vision testing revealed complete visual deficits but the electroretinograph and pupillary light reflex were normal in both eyes. The motor and sensory functions of the eyelids and eyes were also normal. The MRI revealed compression of the optic chiasm caused by severe ventriculomegaly in the lateral and third ventricles. Such lesions are associated with inflammatory stenotic lesions in the mesencephalic aqueduct. Moderate neutrophilic pleocytosis was observed during cerebrospinal fluid analysis and Acinetobacter lwoffii was isolated, leading to a diagnosis of Acinetobacter-positive obstructive hydrocephalus. This is the first reported case of culture-proven Acinetobacter-associated postencephalitic hydrocephalus with acute blindness in a dog. PMID- 28855430 TI - Different allelic frequency of progressive rod-cone degeneration in two populations of Labrador Retrievers in Japan. AB - Progressive rod-cone degeneration (PRCD) is an autosomal recessive disease caused by c.5G>A mutation of the PRCD exon 2. This mutation has been identified in various breeds, including Labrador Retriever. The present study aimed to examine the allelic frequency of PRCD in Labrador Retrievers in Japan. A domestic and a guide dog population were genotyped for PRCD using polymerase chain reaction restriction fragment length polymorphism. The allelic frequency of c.5G>A in domestic and guide dog populations (0.114 and 0.026, respectively) differed significantly. The allele with c.5G>A mutation appeared to spread widely in the domestic population as compared to that in the guide dog population. This might be the result of mating control for PRCD in the guide dog population. PMID- 28855431 TI - US-guided percutaneous microwave ablation for the treatment of benign thyroid nodules. AB - The aim of this study was to define the effectiveness and safety of ultrasound(US)-guided percutaneous microwave ablation(MWA) for benign thyroid nodules with one session treatment. A total 121 benign thyroid nodules in 100 euthyroid patients underwent MWA in one medical center between August 2014 and December 2015. MWA was performed with an internally cooled antenna under local anesthesia. The volume of the nodule, cosmetic score and symptom score were compared before and after the procedure. The volume reduction rate(VRR) was also evaluated. The side effects and complications were observed. As a result, microwave ablation was associated with a significant decrease in nodule volume{1.05+/-1.05mL (0.08~4.33mL)vs 8.56+/-4.21mL(4.05~22.66mL), p <0.001} at 12 month follow-up. The largest diameter was also decreased {1.36+/ 0.53cm(0.60~3.73cm) vs 2.94+/-0.55cm(2.00~4.40cm) , p<0.001}. The symptom score and cosmetic score were decreased significantly after the procedure(1.71+/-0.68 vs 3.31+/-1.13, p<0.001; 1.16+/-0.37 vs 2.37+/-0.94, p<0.001). The VRR was 57.66+/-22.95%, .70.23+/-20.07%, 85.97+/-14.04% at 3-, 6- and 12-month follow-up after ablation , respectively. Two patients(2.0%) experienced hoarseness and recovered within 2 months. Two patients(2.0%) developed slight burn on cervical skin. One case(1%) developed Horner Syndrome, recovered within 2 months. Ultrasound-guided percutaneous microwave ablation developed significant volume reduction on benign thyroid nodules, with achieving improvement in symptom score and cosmetic grading. The treatment was well tolerated. PMID- 28855432 TI - Prospective Study on the Incidence of Cerebrovascular Disease After Coronary Angiography. AB - AIM: Previous studies have reported a 10.2%-22% rate of silent cerebral infarction and a 0.1%-1% rate of symptomatic cerebral infarction after coronary angiography (CAG). However, the risk factors of cerebral infarction after CAG have not been fully elucidated. For this reason, we investigated the incidence and risk factors of CVD complications within 48 h after CAG using magnetic resonance imaging (MRI) (Diffusion-weighted MRI) at Kagoshima University Hospital. METHODS: From September 2013 to April 2015, we examined the incidence and risk factors, including procedural data and patients characteristics, of cerebrovascular disease after CAG in consecutive 61 patients who underwent CAG and MRI in our hospital. RESULTS: Silent cerebral infarction after CAG was observed in 6 cases (9.8%), and they should not show any neurological symptoms of cerebral infarction. Only prior coronary artery bypass grafting (CABG) was more frequently found in the stroke group (n=6) than that in the non-stroke group (n=55); however, no significant difference was observed (P=0.07). After adjusting for confounders, prior CABG was a significant independent risk factor for the incidence of stroke after CAG (odds ratio: 11.7, 95% confidence interval: 1.14 129.8, P=0.04). CONCLUSIONS: We suggested that the incidence of cerebral infarction after CAG was not related to the catheterization procedure per se but may be caused by atherosclerosis with CABG. PMID- 28855434 TI - Isolated Late Activation Detected by Magnetocardiography Predicts Future Lethal Ventricular Arrhythmic Events in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy. AB - BACKGROUND: Risk stratification of ventricular arrhythmias is vital to the optimal management in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We hypothesized that 64-channel magnetocardiography (MCG) would be useful to detect isolated late activation (ILA) by overcoming the limitations of conventional noninvasive predictors of ventricular tachyarrhythmias, including epsilon waves, late potential (LP), and right ventricular ejection fraction (RVEF), in ARVC patients.Methods and Results:We evaluated ILA on MCG, defined as discrete activations re-emerging after the decay of main RV activation (%magnitude >5%), and conventional noninvasive predictors of ventricular tachyarrhythmias (epsilon waves, LP, and RVEF) in 40 patients with ARVC. ILA was noted in 24 (60%) patients. Most ILAs were found in RV lateral or inferior areas (17/24, 71%). We defined "delayed ILA" as ILA in which the conduction delay exceeded its median (50 ms). During a median follow-up of 42.5 months, major arrhythmic events (MAEs: 1 sudden cardiac death, 3 sustained ventricular tachycardias, and 4 appropriate implantable cardioverter defibrillator discharges) occurred more frequently in patients with delayed ILA (6/12) than in those without (2/28; log-rank: P=0.004). Cox regression analysis identified delayed ILA as the only independent predictor of MAEs (hazard ratio 7.63, 95% confidence interval 1.72-52.6, P=0.007), and other noninvasive parameters were not significant predictors. CONCLUSIONS: MCG is useful to identify ARVC patients at high risk of future lethal ventricular arrhythmias. PMID- 28855433 TI - Effects of Cardiac Rehabilitation on High-Density Lipoprotein-mediated Cholesterol Efflux Capacity and Paraoxonase-1 Activity in Patients with Acute Coronary Syndrome. AB - AIMS: We evaluated whether exercised-based cardiac rehabilitation (CR) can ameliorate the HDL function, i.e., cholesterol efflux capacity (CEC) and paraoxonase-1 activity in patients with acute coronary syndrome (ACS). METHODS: This study is a retrospective analysis of stored serum from patients with ACS following successful percutaneous coronary intervention. The CEC, measured by a cell-based ex vivo assay using apolipoprotein B-depleted serum and 3H-cholesterol labeled macrophages and arylesterase activity (AREA) at the onset or early phase of ACS, and the follow-up periods were compared between 69 patients who completed the five-month outpatient CR program (CR group) and 15 patients who did not participate and/or dropped out from CR program (non-CR group). RESULTS: Apolipoprotein A-I (apoA-I) and CEC significantly increased by 4.0% and 9.4%, respectively, in the CR group, whereas HDL-cholesterol and AREA were not changed during the follow-up periods in both groups. Among CR patients, the CEC significantly increased, irrespective of the different statin treatment, while HDL-cholesterol and apoA-I significantly increased in patients treated with rosuvastatin or pitavastatin. Although CEC and AREA were significantly correlated each other, there is a discordance between CEC and AREA for their correlations with other biomarkers. Both CEC and AREA were significantly correlated with apoA I rather than HDL-cholesterol. Changes in CEC and those in AREA were significantly correlated with those in apoA-I (rho=0.328, p=0.002, and rho=0.428, p<0.0001, respectively) greater than those in HDL-cholesterol (rho=0.312, p= 0.0042,and rho=0.343, p=0.003, respectively). CONCLUSIONS: CR can improve HDL function, and it is beneficial for secondary prevention. PMID- 28855435 TI - Nationwide Survey of Patients With Giant Coronary Aneurysm Secondary to Kawasaki Disease 1999-2010 in Japan. AB - BACKGROUND: Giant coronary aneurysm is the most severe sequela in Kawasaki disease, occurring in approximately 0.2% of patients in Japan. Regression is rare, while myocardial infarction (MI) and sudden death are relatively common. Herein, we reviewed patients with giant coronary aneurysm in a 10-year period.Methods and Results:A nationwide questionnaire survey was conducted based on a national epidemiological database from 1999 to 2010. We identified 355 giant coronary aneurysm patients, of whom 209 were analyzed. The 5- and 10-year total cardiac event-free rates were 0.72 and 0.68, respectively. Twelve patients died, and MI was observed in 32 patients (18.1%). Five and 6 deaths were due to coronary rupture and MI, respectively. All ruptures occurred within 1 month of onset, while most MI occurred within 18 months. There was no death beyond 2 years. Aneurysm size was significantly related to the occurrence of MI in both the right and left coronary arteries. At the time of writing, 55% of patients had no exercise limitations. And including patients who cannot perform strenuous exercises, 81% of patients were leading ordinary lives. CONCLUSIONS: Severe cardiac events are likely to occur within 2 years from onset of Kawasaki disease, while no deaths occurred beyond this time. Hence, careful monitoring is needed especially for the first 2 years. Most patients with giant coronary aneurysms can lead ordinary lives with appropriate management. PMID- 28855436 TI - Effects of sorafenib and an adenylyl cyclase activator on in vitro growth of well differentiated thyroid cancer cells. AB - Well-differentiated thyroid carcinomas have driver mutations involving growth factor receptor-tyrosine kinases (RTKs) or their intracellular signaling pathway, that is, the mitogen-activated protein kinase (MAPK) pathway. Sorafenib is a multikinase inhibitor of RTKs and the MAPK pathway and has recently been used for the treatment of unresectable well-differentiated thyroid carcinoma. In normal thyroid follicular cells, stimulation of the thyroid-stimulating hormone (TSH) receptor activates the cyclic adenosine monophosphate (cAMP) pathway and promotes cell growth as well as hormonal secretion. However, an adenylyl cyclase (AC) activator, forskolin, has been reported to suppress the growth of thyroid carcinoma cells. To clarify the roles of the MAPK and cAMP pathways in proliferation of well-differentiated thyroid carcinoma cells, we compared the effects of sorafenib and forskolin in in vitro models. Sorafenib inhibited constitutive activation of the MAPK pathway, cyclin-dependent kinase 4 (CDK4), and phosphorylated retinoblastoma protein (RB) in 3 well-differentiated carcinoma cell lines, but it did not show sufficiently effective suppression of cell growth. Forskolin significantly suppressed the growth of all 3 cell lines and also activated the cAMP pathway and inhibited expression of cyclin D1. Our results suggest that activation of the cAMP pathway could be more potent than activation of the MAPK pathway in suppressing proliferation of well differentiated thyroid cancer cells. We postulate that the AC activator suppresses growth of thyroid carcinoma cells through undetermined mechanisms. PMID- 28855437 TI - B-type natriuretic peptide and renal function in Japanese patients with type 2 diabetes mellitus: The Dogo Study. AB - Among patients with type 2 diabetes mellitus, the association between B-type natriuretic peptide (BNP) and renal function remains controversial. We therefore investigated this issue among Japanese patients with type 2 diabetes mellitus. This study included 687 Japanese patients with type 2 diabetes mellitus. BNP levels were divided at quartile points on the basis of the distribution. We used four outcomes regarding the renal function: 1) chronic kidney disease (CKD): estimated glomerular filtration rate (eGFR) < 60ml/min/1.72m2, 2) advanced CKD: eGFR < 30ml/min/1.72m2, 3) microalbuminuria: urinary albumin creatinine ratio (UACR) >= 30 mg/g creatinine, and 4) macroalbuminuria: UACR >= 300 mg/g creatinine. The prevalence values of CKD, advanced CKD, microalbuminuria, and macroalbuminuria were 27.4%, 2.5%, 31.4%, and 9.3%, respectively. Highest BNP (>= 39.2 ng/ml) was independently positively associated with microalbuminuria and macroalbuminuria (adjusted ORs, 2.61 [95% CI: 1.53-4.49] and 3.45 [95% CI: 1.46 8.72], respectively). High BNP was not associated with advanced CKD or CKD. There was a statistically significant positive exposure-response relationships between the BNP level and advanced CKD, microalbuminuria, and macroalbuminuria (p for trend = 0.047, 0.001, and 0.003, respectively). BNP level may be independently positively associated with advanced CKD, microalbuminuria, and macroalbuminuria but not CKD in Japanese patients with type 2 diabetes mellitus. PMID- 28855438 TI - Verification of effect of sleep health education program in workplace: a quasi randomized controlled trial. AB - Short sleep duration is a serious problem that not only enhances the risk of various mental and physical disorders, but also affects the productivity in the workplace. However, in terms of studies focused on workers, there are few reports that evaluated sleeping conditions in an objective way. The purpose of this study is to implement sleep health education in the workplace in terms of primary prevention of mental health disorder and then to investigate the subjective and objective effectiveness of the education using self-administered questionnaires (sleep duration, ESS, AIS, PHQ-9, SF-8) and an activity monitor (MTN-210). Study design is a quasi-randomized controlled trial. Sleep health education was provided through three 50-min lectures (total 150 min) as a single cycle for five months in the Intervention group. We obtained baseline data and then six months later. The study analyzed 70 subjects (36 Intervention group, 34 Control group). The weekday sleep duration for the Control group decreased by 12.9 min, whereas that of the Intervention group increased by 14.3 min (difference of 27.2 min), resulting in a significantly increase in score for the Intervention group. The present study suggests that sleep health education may be beneficial for good sleep habits in workers. PMID- 28855440 TI - The Position of the GFP Tag on Actin Affects the Filament Formation in Mammalian Cells. AB - Actin, a major component of microfilaments, is involved in various eukaryotic cellular functions. Over the past two decades, actin fused with fluorescent protein has been used as a probe to detect the organization and dynamics of the actin cytoskeleton in living eukaryotic cells. It is generally assumed that the expression of fusion protein of fluorescent protein does not disturb the distribution of endogenous actin throughout the cell, and that the distribution of the fusion protein reflects that of endogenous actin. However, we noticed that EGFP-beta-actin caused the excessive formation of microfilaments in several mammalian cell lines. To investigate whether the position of the EGFP tag on actin affected the formation of filaments, we constructed an expression vector harboring a beta-actin-EGFP gene. In contrast to EGFP-beta-actin, cells expressing beta-actin-EGFP showed actin filaments in a high background from the monomer actin in cytosol. Additionally, the detergent insoluble assay revealed that the majority of the detergent-insoluble cytoskeleton from cells expressing EGFP-beta-actin was recovered in the pellet. Furthermore, we found that the expression of EGFP-beta-actin affects the migration of NBT-L2b cells and the mechanical stiffness of U2OS cells. These results indicate that EGFP fused to the N-terminus of actin tend to form excessive actin filaments. In addition, EGFP actin affects both the cellular morphological and physiological phenotypes as compared to actin-EGFP.Key words: actin, GFP, cytoskeleton and probe. PMID- 28855439 TI - Intrauterine growth retardation promotes fetal intestinal autophagy in rats via the mechanistic target of rapamycin pathway. AB - Intrauterine growth retardation (IUGR) impairs fetal intestinal development, and is associated with high perinatal morbidity and mortality. However, the mechanism underlying this intestinal injury is largely unknown. We aimed to investigate this mechanism through analysis of intestinal autophagy and related signaling pathways in a rat model of IUGR. Normal weight (NW) and IUGR fetuses were obtained from primiparous rats via ad libitum food intake and 50% food restriction, respectively. Maternal serum parameters, fetal body weight, organ weights, and fetal blood glucose were determined. Intestinal apoptosis, autophagy, and the mechanistic target of rapamycin (mTOR) signaling pathway were analyzed. The results indicated that maternal 50% food restriction reduced maternal serum glucose, bilirubin, and total cholesterol and produced IUGR fetuses, which had decreased body weight; blood glucose; and weights of the small intestine, stomach, spleen, pancreas, and kidney. Decreased Bcl-2 and increased Casp9 mRNA expression was observed in IUGR fetal intestines. Analysis of intestinal autophagy showed that the mRNA expression of WIPI1, MAP1LC3B, Atg5, and Atg14 was also increased, while the protein levels of p62 were decreased in IUGR fetuses. Compared to NW fetuses, IUGR fetuses showed decreased mTOR protein levels and enhanced mRNA expression of ULK1 and Beclin1 in the small intestine. In summary, the results indicated that maternal 50% food restriction on gestational days 10-21 reduced maternal serum glucose, bilirubin, and total cholesterol contents, and produced IUGR fetuses that had low blood glucose and reduced small intestine weight. Intestinal injury of IUGR fetuses caused by maternal food restriction might be due to enhanced apoptosis and autophagy via the mTOR signaling pathway. PMID- 28855441 TI - MicroRNA-182 Promotes Lipoprotein Lipase Expression and Atherogenesisby Targeting Histone Deacetylase 9 in Apolipoprotein E-Knockout Mice. AB - BACKGROUND: Lipoprotein lipase (LPL) expressed in macrophages plays an important role in promoting the development of atherosclerosis or atherogenesis. MicroRNA 182 (miR-182) is involved in the regulation of lipid metabolism and inflammation. However, it remains unclear how miR-182 regulates LPL and atherogenesis.Methods and Results:Using bioinformatics analyses and a dual-luciferase reporter assay, we identified histone deacetylase 9 (HDAC9) as a target gene of miR-182. Moreover, miR-182 upregulated LPL expression by directly targetingHDAC9in THP-1 macrophages. Hematoxylin-eosin (H&E), Oil Red O and Masson's trichrome staining showed that apolipoprotein E (ApoE)-knockout (KO) mice treated with miR-182 exhibited more severe atherosclerotic plaques. Treatment with miR-182 increased CD68 and LPL expression in atherosclerotic lesions in ApoE-KO mice, as indicated by double immunofluorescence staining in the aortic sinus. Increased miR-182 induced increases in LPL expression in ApoE-KO mice was confirmed by real-time quantitative polymerase chain reaction and western blotting analyses. Treatment with miR-182 also increased plasma concentrations of proinflammatory cytokines and lipids in ApoE-KO mice. CONCLUSIONS: The results of the present study suggest that miR-182 upregulates LPL expression, promotes lipid accumulation in atherosclerotic lesions, and increases proinflammatory cytokine secretion, likely through targetingHDAC9, leading to an acceleration of atherogenesis in ApoE-KO mice. PMID- 28855442 TI - Evaluating the statistical methodology of randomized trials on dentin hypersensitivity management. AB - The present study aimed to evaluate the characteristics and quality of statistical methodology used in clinical studies on dentin hypersensitivity management. An electronic search was performed for data published from 2009 to 2014 by using PubMed, Ovid/MEDLINE, and Cochrane Library databases. The primary search terms were used in combination. Eligibility criteria included randomized clinical trials that evaluated the efficacy of desensitizing agents in terms of reducing dentin hypersensitivity. A total of 40 studies were considered eligible for assessment of quality statistical methodology. The four main concerns identified were i) use of nonparametric tests in the presence of large samples, coupled with lack of information about normality and equality of variances of the response; ii) lack of P-value adjustment for multiple comparisons; iii) failure to account for interactions between treatment and follow-up time; and iv) no information about the number of teeth examined per patient and the consequent lack of cluster-specific approach in data analysis. Owing to these concerns, statistical methodology was judged as inappropriate in 77.1% of the 35 studies that used parametric methods. Additional studies with appropriate statistical analysis are required to obtain appropriate assessment of the efficacy of desensitizing agents. PMID- 28855443 TI - Influences of differences in tray design and impression material on impression pressure at edentulous mandible. AB - The aim of this study was to examine the effects of tray design and impression material on impression pressure in a clinical simulation model of an edentulous mandible. Two types of polyvinylsiloxane elastomer, one type of polyether elastomer, and one type of alginate were used. The three tray types had no relief, 0.36 mm of relief, or 1.4 mm of relief, with or without escape holes. Impression pressure was measured at the median alveolar crest, the bilateral alveolar crests corresponding to molars, and the bilateral buccal shelves. Impression pressure significantly differed in relation to tray design and sensor position. In trays without escape holes, impression pressure was highest at the median alveolar crest and lowest at the buccal shelves, for all impression materials. However, impression material had no significant effects on impression pressure. Our results suggest that bite-pressure load on alveolar crests can be alleviated by making an impression with a tray that has relief and escape holes, while applying pressure to buccal shelves and almost no pressure to alveolar crests. PMID- 28855444 TI - A rat model for studying electroacupuncture analgesia on acute visceral hyperalgesia. AB - The aim of this study was to establish an appropriate rat model to study the effect of electroacupuncture (EA) analgesia on acute visceral hyperalgesia. Adult rats received colorectal instillation with different concentrations of acetic acid (AA). Treatment with EA was performed for 30 min at bilateral acupoints of ST-36 and ST-37 in the hind limbs. The visceral sensation of all rats was quantified by scores of abdominal withdrawal reflex (AWR) and discharges of rectus abdominis electromyogram (EMG) in response to colorectal distension (CRD). Two hours after instillation of saline (no AA), 1%, 2%, and 4% AA, there were no, slight, moderate and severe visceral hyperalgesia, respectively. Application of EA significantly relieved the visceral hyperalgesia induced by 2% but not 4% AA. The results suggest that 2% AA acute visceral hyperalgesia in adult rats responds well to EA treatment. This may offer an appropriate model for the investigation of EA effects. PMID- 28855445 TI - Culturable Facultative Methylotrophic Bacteria from the Cactus Neobuxbaumia macrocephala Possess the Locus xoxF and Consume Methanol in the Presence of Ce3+ and Ca2. AB - Methanol-consuming culturable bacteria were isolated from the plant surface, rhizosphere, and inside the stem of Neobuxbaumia macrocephala. All 38 isolates were facultative methylotrophic microorganisms. Their classification included the Classes Actinobacteria, Sphingobacteriia, Alpha-, Beta-, and Gammaproteobacteria. The deduced amino acid sequences of methanol dehydrogenase obtained by PCR belonging to Actinobacteria, Alpha-, Beta-, and Gammaproteobacteria showed high similarity to rare-earth element (REE)-dependent XoxF methanol dehydrogenases, particularly the group XoxF5. The sequences included Asp301, the REE-coordinating amino acid, present in all known XoxF dehydrogenases and absent in MxaF methanol dehydrogenases. The quantity of the isolates showed positive hybridization with a xoxF probe, but not with a mxaF probe. Isolates of all taxonomic groups showed methylotrophic growth in the presence of Ce3+ or Ca2+. The presence of xoxF-like sequences in methylotrophic bacteria from N. macrocephala and its potential relationship with their adaptability to xerophytic plants are discussed. PMID- 28855446 TI - Carpal tunnel syndrome among laboratory technicians in relation to personal and ergonomic factors at work. AB - OBJECTIVES: Work-related carpal tunnel syndrome (CTS) has been reported in different occupations, including laboratory technicians, so this study was carried out to determine the prevalence and the associated personal and ergonomic factors for CTS among laboratory technicians. METHODS: A cross-sectional study was conducted among 279 laboratory technicians at King Fahd Hospital, Saudi Arabia, who filled in a self-administered questionnaire, including questions regarding their demographic criteria, occupational history, job tasks, workplace tools, ergonomic factors at work, and symptoms suggestive of CTS. Physical examinations and electrodiagnostic studies were carried out for those who had symptoms suggestive of CTS to confirm the diagnosis. Univariate and multivariate analysis were performed for both personal and physical factors in association with confirmed CTS among laboratory technicians. RESULTS: The prevalence of CTS among the laboratory technicians was 9.7% (27/279). The following were the statistically significant risk factors for CTS among them: gender (all cases of CTS were female, P=0.00), arm/hand exertion (OR: 7.96; 95% CI: 1.84-34.33), pipetting (OR: 7.27; 95% CI: 3.15-16.78), repetitive tasks (OR: 4.60; 95% CI: 1.39-15.70), using unadjustable chairs or desks (OR: 3.35; 95% CI: 1.23-9.15), and working with a biosafety cabinet (OR: 2.49; 95% CI: 1.11-5.59). CTS cases had significant longer work duration (17.9 +/- 5.6 years) than CTS non-case (11.5 +/- 7.4 yeas) with low OR (1.108). CONCLUSION: This study demonstrates some personal and ergonomic factors associated with CTS among the laboratory technicians, including female gender, arm/hand exertion, pipetting, repetitive tasks, working with a biosafety cabinet, and an unadjusted workstation. PMID- 28855447 TI - Guidelines for personal exposure monitoring of chemicals: Part I. AB - This Document, "Guidelines for personal exposure monitoring of chemicals" ("this Guideline"), has been prepared by "The Committee for Personal Exposure Monitoring" ("the Committee") of the Expert Division of Occupational Hygiene & Ergonomics, Japan Society for Occupational Health. Considering the background of the growing importance of personal exposure monitoring in risk assessment and the need to prepare for the introduction of monitoring using personal samplers from an administrative perspective in recent years, the Committee was organized in November 2012. The Committee has prepared this Guideline as a "practical guideline" for personal exposure monitoring, so as to offer proposals and recommendations to the members of the Japan Society for Occupational Health and to society in general. The scope of this Guideline covers all chemical substances and all related workplaces regarded as targets for general assessment and the management of risk. It thus is not to be considered to comment on legal regulations and methodology. The main text provides the basic methods and concepts of personal exposure monitoring, while 31 "Appendices" are provided later in this Guideline throughout the series; technical descriptions, statistical bases, and actual workplace examples are provided in these appendices, to assist better understanding. The personal exposure monitoring described as per this Guideline is equivalent to an "expert-centered basic method to reasonably proceed with the assessment and management of risk at workplaces." It is considered that practicing and expanding on this method will significantly contribute in reforming the overall framework of occupational hygiene management in Japan. PMID- 28855448 TI - Caffeine Has a Synergistic Anticancer Effect with Cisplatin via Inhibiting Fanconi Anemia Group D2 Protein Monoubiquitination in Hepatocellular Carcinoma Cells. AB - Cisplatin is an anticancer agent and induces DNA interstrand cross-links (ICLs). ICLs activate various signaling processes and induce DNA repair pathways, including the Fanconi anemia (FA) pathway. FA complementation group D2 (FANCD2) is monoubiquitinated in response to DNA damage, leading to activation of the DNA double-strand-break repair protein, RAD51. Caffeine increases the anticancer activity of cisplatin by inhibiting DNA repair; however, details of the mechanism remain unclear. We investigated the mechanism responsible for the synergistic anticancer effect of cisplatin and caffeine in HepG2 human hepatocellular carcinoma cells, focusing on the FA pathway. Caffeine (>=100 ug/mL) significantly enhanced the antiproliferative activity induced by 3.8 ug/mL cisplatin. Caffeine (200 ug/mL) promoted apoptosis and inhibited the increase in the proportion of viable cells in S phase that occurred in the presence of 3.8 ug/mL cisplatin. Both FANCD2 monoubiquitination and RAD51 expression were significantly inhibited by co-treatment with 200 ug/mL caffeine and 3.8 ug/mL cisplatin compared with cisplatin alone. In conclusion, caffeine enhances the anticancer effect of cisplatin by inhibiting FANCD2 monoubiquitination. In HepG2 cells, caffeine might inhibit the FA pathway and thereby regulate DNA damage responses such as DNA repair and apoptosis. PMID- 28855449 TI - Effect of the tight fitting net on fit performance in single-use filtering facepieces for Koreans. AB - To get a better fit performance of filtering facepieces, a tight fitting net (TFN) was invented. This study was carried out to evaluate whether the TFN improves fit performance using a quantitative fit test (QNFT). The existing mask was of cup type with an aluminum clip on the nose bridge. The TFN mask was the same as the existing mask, but attached a TFN instead of aluminum clip. One hundred subjects (male 52, female 48) were selected to match fourfold in Korean 25-member facial size category for half-mask (KFCH). Fit factors (FFs) were measured using a QNFT by a Portacount(r)Pro+8038. Three QNFTs for each mask on the same subject was conducted and geometric mean FF (GMFF) was determined. The mean and median GMFFs of the TFN masks had higher than those of the existing mask (p=<0.001). The existing masks had tendency to have higher GMFFs with common facial size categories, while the TFN masks were regardless of facial size. The result indicates that putting even pressure on the entire parts of filter media would improve fit performance. In conclusion, to get a good fit when wearing filtering facepieces, a TFN would be an alternative to mask designing. PMID- 28855450 TI - Clinical Implication of Transaortic Mitral Pannus Removal During Repeat Cardiac Surgery for Patients With Mechanical Mitral Valve. AB - BACKGROUND: This study aimed to evaluate the safety and feasibility of transaortic mitral pannus removal (TMPR).Methods and Results:Between 2004 and 2016, 34 patients (median age, 57 years; 30 women) with rheumatic disease underwent pannus removal on the ventricular side of a mechanical mitral valve through the aortic valve during reoperation. The median time interval from the previous surgery was 14 years. TMPR was performed after removal of the mechanical aortic valve (n=21) or diseased native aortic valve (n=11). TMPR was performed in 2 patients through a normal aortic valve. The mitral transprosthetic mean pressure gradient (TMPG) was >=5 mmHg in 11 patients, including 3 with prosthetic valve malfunction. Prophylactic TMPR was performed in 23 patients. There were no early deaths. Concomitant operations included 22 tricuspid valve surgeries (13 replacements, 15 repairs) and 32 aortic valve replacements (24 repeats, 8 primary). The mean gradient in patients who had mitral TMPG >=5 mmHg was significantly decreased from 6.46+/-1.1 to 4.37+/-1.17 mmHg at discharge (P<0.001). No mechanical valve malfunction was apparent on last echocardiography. CONCLUSIONS: TMPR is a safe and effective procedure for patients with malfunction or stenosis of a mechanical mitral valve and may be considered an alternative approach in patients with pannus overgrowth in such valves. PMID- 28855451 TI - Impact of Dual Antiplatelet Therapy Beyond 1 Year on Clinical Outcomes of Patients With Stent Fracture or Peri-Stent Contrast Staining After Sirolimus Eluting Stent Implantation. AB - BACKGROUND: Stent fracture (SF) and peri-stent contrast staining (PSS) after sirolimus-eluting stent (SES) implantation are considered to be related to very late stent thrombosis (VLST). How dual antiplatelet therapy (DAPT) beyond 1 year affects the clinical outcomes of patients with SF or PSS remains unclear.Methods and Results:Based on their DAPT status, 1,962 patients undergoing SES implantation were classified as on-thienopyridine (n=1,404) or off-thienopyridine (n=558). The 6-year incidence of VLST was significantly lower in the on thienopyridine patients (0.56% vs. 1.8%, P=0.01), whereas cardiac death and myocardial infarction (MI) were similar (5.0% vs. 6.2%, P=0.31; 3.2% vs. 4.0%, P=0.33; respectively). The 1,962 patients were also classified as having SF/PSS (n=256) or non-SF/PSS (n=1,706). In the SF/PSS group, VLST and MI were significantly lower in on-thienopyridine patients (1.9% vs. 10.1%, P=0.003; 3.5% vs. 10.3%, P=0.02; respectively). In the non-SF/PSS group, VLST and MI were similar (0.36% vs. 0.45%, P=0.78; 3.2% vs. 3.0%, P=0.93; respectively). In both groups, cardiac death was similar (3.6% vs. 4.3%, P=0.78; 5.2% vs. 6.5%, P=0.32; respectively). CONCLUSIONS: Prolonged DAPT was associated with significantly lower incidences of VLST and MI in the SF/PSS group, but had no effect on cardiac death, VLST, or MI in the non-SF/PSS group. PMID- 28855453 TI - Current status of perioperative management for elderly patients. PMID- 28855454 TI - Urgent catheter ablation in Octogenarians with Serious Tachyarrhythmias. PMID- 28855452 TI - Galectin-3 and the Mineralocorticoid Receptor Antagonist Canrenone in Mild Heart Failure. AB - BACKGROUND: Galectin-3 (Gal-3) is involved in collagen deposition and inflammation and is a prognostic biomarker in heart failure (HF).Methods and Results:Gal-3 and other markers of fibrosis or cardiac stress were measured serially in 413 patients with mild HF randomized to the mineralocorticoid receptor antagonist canrenone or placebo to evaluate treatment effect and association with clinical outcome. Gal-3 increased slightly over 6 months in both arms of the study and was associated with clinical endpoints. CONCLUSIONS: Although Gal-3 showed prognostic value, the effect of canrenone on clinical outcomes was unaffected by baseline concentrations of biomarkers of fibrosis or cardiac stress. PMID- 28855455 TI - Treatment of elderly sleep problems. PMID- 28855456 TI - Sleep related movement disorders in the elderly. PMID- 28855457 TI - Basic medical management of sleep disordered breathing in elderly. PMID- 28855458 TI - Elderly nocturnal abnormal behavior. PMID- 28855459 TI - Background characteristics and clinical features of elderly patients with hyperglycemic hyperosmolar syndrome. AB - AIM: Few reports have described the characteristics of hyperglycemic hyperosmolar syndrome (HHS) in the elderly. We investigated the background characteristics and clinical features of 14 elderly patients with HHS. METHODS: HHS was diagnosed based on a blood glucose level of >600 mg/dL and an effective plasma osmolality [2 (Na) + glu/18] of >320 mOsm/kg. For 14 cases of HHS, we investigated the medical and social backgrounds of the patients, their clinical findings, and the outcomes. RESULTS: The mean patient age was 83 years, and the mean body mass index was 17.8 kg/m2. Half had a history of either cerebral infarction or hip fracture. The mean duration of diabetes was 14 years, but 4 diabetes cases were newly diagnosed. There was a high prevalence of acute infection (79%) in HHS patients, especially urinary tract infection and pneumonia, with a seasonal peak in winter. Patients who had been treated with steroids, tube feeding, or both numbered 1, 2, and 1, respectively. Most HHS patients had a history of dementia. More than half of such patients were living alone or only with their spouse, and their activities of daily living showed marked deterioration. The mean blood glucose level, HbA1c, effective serum osmolality, and pH were 881 mg/dL, 10.3%, 353 mOsm/kg, and 7.39, respectively. One patient died during hospitalization, and 9 were discharged to nursing homes or other hospitals. The mean length of hospitalization was 55 days. In most cases, the insulin secretion capacity was preserved, and 9 patients were treatable with oral hypoglycemic agents alone. CONCLUSIONS: Many cases of HHS in the elderly are associated with infection, a shortage of social support, cognitive impairment, or ADL decline. Although the survival rate in our series was high, the functional prognosis was impaired. PMID- 28855460 TI - The survival prognosis of elderly undernourished inpatients admitted to the internal medical department of an emergency hospital as assessed using the nutritional screening, tool CONUT (for CONtrolling NUTritional status). AB - AIM: CONUT, a tool for "CONtrolling NUTritional status" assesses the nutritional status of a subject by taking into account their serum albumin level, total cholesterol level and total lymphocyte count. Elderly undernourished inpatients admitted to the internal medical department were divided into two groups, those who left the hospital and those who died in the hospital. The goal of this study was to analyze whether or not the CONUT score, serum albumin level, total cholesterol level and total lymphocyte count could predict the survival prognosis of elderly undernourished inpatients and to show the ratio of patients discharged with artificial hydration and nutrition (AHN). METHODS: We divided elderly undernourished inpatients into two groups, those who left the hospital (229 patients) and those who died in the hospital (363 patients), and examined the serum albumin level, total cholesterol level and total lymphocyte count within 10 days before discharge or death. Based on the degree of undernutrition as determined by CONUT, we further classified the patients 4-into four levels of nutrition status, normal, light undernutrition, moderate undernutrition and severe undernutrition. In addition, based on the serum albumin level, total cholesterol level and total lymphocyte count, the patients were also classified 4 into four levels of nutrition status, and we calculated the ratio of AHN patients in the discharged group. RESULTS: On comparing the discharge and death groups according to the degree of undernutrition, serum albumin level, total cholesterol level and total lymphocyte count, significant differences were found between the groups of all nutrition statuses except moderate undernutrition. Furthermore, the patients with moderate undernutrition status demonstrated no statistically significant difference in both groups, except the serum albumin level. Among the discharged patients, the ratio of AHN was 37.0% in those with a normal nutrition status and more than 50% in the patients with light to severe undernutrition. CONCLUSION: We calculated and scored the serum albumin level, total cholesterol level, total lymphocyte count and the degree of undernutrition according to CONUT in elderly undernourished inpatients admitted to the internal medical department of an emergency hospital.We then divided the patients into groups, based on death or discharge from the hospital as well as nutrition status, normal, light undernutrition, moderate undernutrition and severe undernutrition. Therefore, comparing the groups based on their death or discharge, their nutrition status was found to be helpful for predicting the prognosis. PMID- 28855461 TI - The effect of expiratory muscle strength training on the oral and respiratory functions of community-dwelling older people: An analysis using the swallowing, oral, phonatory, and respiratory muscle function indices. AB - PURPOSE: This study was performed to determine the effects of expiratory muscle strength training (EMST) on the oral and respiratory functions of community dwelling older people. METHODS: Older people using a visiting-rehabilitation center were divided into an intervention group of 31 subjects and a control group of 15 subjects. Those in the intervention group were assigned home training for 8 weeks, which included 5 sets of 5 breaths per day with a 75% load of the maximum expiratory pressure using an EMST device. The outcome indices included (1) oral functions, evaluated by the cumulative time spent swallowing three times and the maximum phonation time (MPT) and (2) respiratory functions, evaluated by the maximum expiratory pressure and maximum inspiratory pressure (MEP/MIP). An independent t-test and paired t-test were used to analyze the data. RESULTS: The cumulative time spent swallowing three times was lower in the intervention group than in the control group. This difference remained significant even after adjusting for sex, age, and baseline values. The MPT was 2.1 seconds higher than baseline in the intervention group but 0.4 seconds lower than baseline in the control group. An average increase of 5.7 cmH2O in the PEmax was observed in the intervention group compared with an average decrease of 4.6 cmH2O in the control group, indicating a significant difference. CONCLUSION: These results suggest that EMST improves the oral and respiratory functions of community elderly subjects. This may be explained by the fact that the pathway for swallowing is partially shared with that for phonation, which contributes to a shortened swallowing time by repeated suprahyoid muscle contractions. PMID- 28855462 TI - The use of direct-acting antivirals in the treatment of elderly patients with hepatitis C Virus infection. AB - AIM: Antiviral treatment for hepatitis C infection in elderly patients has been dramatically improved by direct-acting antivirals (DAAs). DAAs are easy to use as they are administered orally and the treatment periods are shorter. Furthermore, they are associated with fewer adverse effects. In this study, we sought to analyze the efficacy and safety of DAAs in HCV-infected elderly patients. METHOD: We analyzed 223 HCV-infected patients who were treated with DAAs in Kanazawa University Hospital, Japan. As of August 31, 2016, all of the patients were observed to have achieved a sustained viral response by the 12th week of treatment (SVR12). We categorized patients into two groups. Group one included 79 patients (average age 75.5 years; range 70-85 years). Group two included 144 patients (average age, 58.1 years; range 27-69 years). Group one included more female patients. RESULTS: The platelet count of Group one was significantly lower than that of Group two. The FIB-4 index of Group one was significantly higher than that of Group two. Group one included a greater number of patients with a history of hepatocellular carcinoma (HCC) before the administration of DAAs. The SVR12 rate and rate of drop-out due to adverse effects did not differ between the two groups to a statistically significant extent. The rate of HCC occurrence after SVR in Group one was higher than that in Group two. CONCLUSION: Our study shows that DAAs can be used for older patients and that the antiviral efficacy and safety are similar to the efficacy and safety in younger patients. PMID- 28855463 TI - The development of a pre-dehydration check sheet for independent community dwelling elderly. -A continuation of research about pre-dehydration among elderly individuals who had been admitted to or regularly visited an elderly-care institution. AB - AIM: In the present study, we defined the state of pre-dehydration (PD) as the suspected loss of body fluids, not accompanied by subjective symptoms (serum osmotic pressure: 292-300 mOsm/kg?H2O). The goal of this study was to develop a non-invasive PD check sheet for independent home care for the elderly. METHODS: We evaluated the serum osmotic pressure of 222 independent community dwelling elderly individuals who were >65 years of age. We then determined the association between the serum osmotic pressure and various dehydration-related diagnostic factors that we identified in a previous study. We performed a logistic regression analysis to determine the risk factors for dehydration and allotted scores based on the odds ratio. We developed a non-invasive PD check sheet consisting of items with high scores and categorized the risks based on the positive predictive value of the total score of the applied items. RESULTS: PD was confirmed in 46 subjects (20.7%) based on their serum osmotic pressure. We developed a PD assessment sheet which consisted of 6 items, (1) Dislike rehydrating before sleeping, as it induces the need to use the toilet (3 points), (2) Using diuretics (8 points), (3) Casual blood sugar >=126 mg/dl (9 points), (4) Age >=85 years (3 points), (5) Male sex (4 points), (6) Body weight >=60 kg (3 points). Patients with a score of >13 points on this sheet were considered to have a high risk of PD (maximum score: 30 points) (positive predictive value, 72%; negative predictive value, 85.6%; P<0.0001). CONCLUSION: In the present study, we found that 20.7% of elderly subjects had PD. Based on these data, we developed an effective noninvasive tool for detecting PD among independent community dwelling elderly. PMID- 28855464 TI - The effects of quality of life on behavioral and psychological symptoms in elderly people with dementia residing at long-term care facilities. AB - PURPOSE: The purpose of the present study was to clarify how quality of life (QOL) affects the behavioral and psychological symptoms of dementia (BPSDs) among elderly individuals with dementia within long-term care facilities (e.g., long term healthcare facilities, sanatorium-type medical facilities, and special nursing homes for the elderly). METHODS: Elderly individuals with dementia were evaluated to determine their activities of daily living (ADL; Katz), Mini-mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Quality of life inventory for the elderly with dementia (QOLD) scores. RESULTS: The subjects were recruited from intermediate welfare facilities (n = 226, 43.7%), hospitals with supportive care (n=91, 17.6%), and intermediate care facilities (n = 200, 38.7%). The mean age of the subjects was 85.18+/-7.13 years. The NPI scores revealed that Agitation/Aggression was high among subjects who resided in healthcare health facilities and sanatorium-type medical facilities, while Apathy/Indifference was high in those who resided in special nursing homes. Additionally, a multiple regression analysis found that most of the NPI items, when set as independent variables, displayed a significant association with the same subscale of the QOLD. CONCLUSION: When each item of the NPI was set as a dependent variable in a multiple regression analysis, the scores were significantly related to both subscales of the QOLD. It is suggested that QOL should be maintained or improved in an effort to reduce the incidence of the associated BPSDs in long-term care facilities. PMID- 28855465 TI - The drug burden of anticholinergics and sedatives and influence on outcomes in the community-living oldest old: The Tokyo Oldest Old survey on Total Health (TOOTH) survey. AB - AIM: The objective of this study was to assess the burdens of anticholinergic and sedative drugs in community-living individuals of 85 years of age or older. METHODS: The Tokyo Oldest Old survey on Total Health (TOOTH) is a cohort study designed to assess the physical, mental, and oral health of the community-living oldest old. We investigated the relationships between the anticholinergic/sedative burden and physical/cognitive outcomes. The drug burden was assessed by the Drug Burden Index (DBI). Relationships between the DBI score and the physical/cognitive outcomes were evaluated by multivariate regression. The age-related changes (baseline to 3-year follow-up) of these outcomes were also investigated. RESULTS: At baseline, the data of 306 subjects were subjected to a cross-sectional analysis. The Instrumental Activities of Daily Living and Mini Mental State Examination scores were found to be significantly associated with the DBI score. After 3 years, the Activities of Daily Living score was significantly associated with the DBI score in 176 subjects. Changes in these outcome measures were small during the 3-year follow-up period and were not associated with the DBI scores at baseline. DISCUSSION: DBI in the community living oldest old were evaluated. Our findings suggest that anticholinergic and sedative drugs may influence the physical and cognitive function in the oldest old. Additional studies should be performed to investigate the relationships between the change of the physical/cognitive functions and the DBI score over a long-term observation period. PMID- 28855471 TI - Estimation of Microbial Concentration in Food Products from Qualitative, Microbiological Test Data with the MPN Technique. AB - Microbial concentration in samples of a food product lot has been generally assumed to follow the log-normal distribution in food sampling, but this distribution cannot accommodate the concentration of zero. In the present study, first, a probabilistic study with the most probable number (MPN) technique was done for a target microbe present at a low (or zero) concentration in food products. Namely, based on the number of target pathogen-positive samples in the total samples of a product found by a qualitative, microbiological examination, the concentration of the pathogen in the product was estimated by means of the MPN technique. The effects of the sample size and the total sample number of a product were then examined. Second, operating characteristic (OC) curves for the concentration of a target microbe in a product lot were generated on the assumption that the concentration of a target microbe could be expressed with the Poisson distribution. OC curves for Salmonella and Cronobacter sakazakii in powdered formulae for infants and young children were successfully generated. The present study suggested that the MPN technique and the Poisson distribution would be useful for qualitative microbiological test data analysis for a target microbe whose concentration in a lot is expected to be low. PMID- 28855470 TI - Technical Aspects of Contrast-enhanced MR Angiography: Current Status and New Applications. AB - This article is based on a presentation at the meeting of the Japanese Society of Magnetic Resonance in Medicine in September 2016. The purpose is to review the technical developments which have contributed to the current status of contrast enhanced magnetic resonance angiography (CE-MRA) and to indicate related emerging areas of study. Technical developments include MRI physics-based innovations as well as improvements in MRI engineering. These have collectively addressed not only early issues of timing and venous suppression but more importantly have led to an improvement in spatiotemporal resolution of CE-MRA of more than two orders of magnitude compared to early results. This has allowed CE-MRA to be successfully performed in virtually all vascular territories of the body. Contemporary technical areas of study include improvements in implementation of high rate acceleration, extension of high performance first-pass CE-MRA across multiple imaging stations, expanded use of compressive sensing techniques, integration of Dixon-based fat suppression into CE-MRA sequences, and application of CE-MRA sequences to dynamic-contrast-enhanced perfusion imaging. PMID- 28855472 TI - Analytical Method for Nitroimidazoles and Their Major Metabolites in Livestock and Fishery Products Using LC-MS/MS. AB - A sensitive and reliable method for the simultaneous determination of four nitroimidazoles (ipronidazole (IPZ), dimetridazole (DMZ), metronidazole (MNZ) and ronidazole (RNZ)) and three metabolites (IPZ-OH, MNZ-OH and 2-hydroxymethyl-1 methyl-5-nitroimidazole (HMMNI)) in livestock and fishery products was developed. The analytes were extracted from samples with acetone containing acetic acid. The crude extracts were defatted by liquid-liquid partition using acetonitrile and n hexane followed by solid-phase extraction using a cartridge column packed with divinylbenzene-N-vinylpyrolidone copolymer bearing sulfo groups. The analytes in the eluate from the cartridge column were extracted with ethyl acetate after addition of ammonium sulfate. The solvent was removed from the extract, and the residue was dissolved in 0.1 vol% formic acid. The HPLC separation was performed on a C18 column with a gradient formed from water containing 0.1 vol% formic acid and acetonitrile containing 0.1 vol% formic acid. For detection of the analytes, tandem mass spectrometry with positive ion electrospray ionization was used. The recovery tests were performed on 10 livestock and fishery products. The truenesse ranged from 74.6 to 111.1%, with repeatability of 0.5-8.3 RSD% for the entire procedure. The limit of quantification was 0.0001 mg/kg for IPZ, IPZ-OH, MNZ and MNZ-OH, and 0.0002 mg/mg for DMZ, RNZ and HMMNI. PMID- 28855473 TI - Development of Rapid Cleanup Method Using New Cleanup Agents for Analysis of Pesticide Residues in Tea. AB - Cleanup using two types of agents (S-NH2 and S-Si) developed by the authors was investigated with the aim of removing interfering substances such as catechin and caffeine to enable analysis of pesticide residues in tea. S-NH2 and S-Si removed approximately 100% of catechin and caffeine in 6 species of tea. Recoveries of 61 pesticides in tea were tested at the level of 0.1 MUg/g, and 44 pesticides showed recovery within the range from 70 to 120%, with RSD of less than 10%. With cleanup using S-NH2 and S-Si, pesticide residues in tea could be analyzed within two hours. PMID- 28855474 TI - Determination of Diniconazole in Agricultural Products, Livestock and Marine Products by LC-MS/MS. AB - An LC-MS/MS method for the determination of diniconazole in agricultural products, livestock and marine products was developed. Diniconazole in agricultural products was extracted with acetone. The extract was concentrated and partitioned with n-hexane and 10% sodium chloride solution. Agricultural products such as grains and beans were defatted using n-hexane-acetonitrile. Livestock and marine products were extracted with a mixture of acetone and n hexane, and the organic layer was evaporated to dryness. The residue was defatted using n-hexane-acetonitrile. Cleanup was carried out using a Florisil cartridge column and a graphitized carbon cartridge column for these samples. The LC separation was carried out on an Inertsil ODS-3 column with a linear gradient of 0.1% formic acid and acetonitrile containing 0.1% formic acid. MS was carried out in the positive ion electrospray ionization mode. The calibration curve was linear between 0.00125 to 0.00750 mg/L. Average recoveries (n=5) of diniconazole from 16 kinds of agricultural products, livestock and marine products fortified at the MRLs (0.01 ppm) were 88.3-108%, and the relative standard deviations were 0.5-5.1%. The limits of quantitation were 0.01 mg/kg. PMID- 28855475 TI - Detection of Norovirus in Swab Specimens of Restrooms and Kitchens Collected for Investigation of Suspected Food Poisoning Outbreaks in Tokyo. AB - During 2015-2016, we examined norovirus (NoV) RNA in swab specimens collected for investigation of suspected food poisoning outbreaks in Tokyo by real-time RT-PCR. Of 1,726 swab samples, 65 (3.8%) were NoV-positive and all positive swab samples were derived from NoV-positive outbreaks. Swab specimens were positive in 41 of 181 (22.7%) NoV outbreaks, while no positive swabs were detected in NoV-negative outbreaks. PCR fragments amplified from 32 swabs were sequenced, and all of them displayed complete homology with sequences from clinical and food samples. Though the results of swabs may be useful for determining the causative agent and infection route in some outbreaks, there was no case in which the results of swabs alone could elucidate the cause of food poisoning. Swabs may be useful in food poisoning investigations, if the results are interpreted in conjunction with epidemiological findings and clinical data. Swab samples are often collected several days after an outbreak, and the influence of disinfection should be taken into consideration. In NoV outbreaks, 55 out of 640 (8.6%) restroom swab specimens were NoV-positive whereas six of 618 (1.0%) were positive among kitchen swab specimens. In the restroom, the toilet bowl (43.6%) showed the highest positive rate and next was the toilet seat (14.5%). Additionally, NoV was detected at various sites in the restroom, including doorknob and floor. Since NoV-positive swab specimens may suggest that sanitation management is not performed properly in the facility, swab results may be utilized as a basis for hygiene guidance. PMID- 28855476 TI - Validation of Simultaneous Analytical Method of Veterinary Drugs in Foods Using New Automatic Pretreatment Equipment. AB - New automatic pretreatment equipment (FASVED; Food Automatic Analytical Systems for Veterinary Drugs) was developed. FASVED consists of ten main units: reagent dispenser, homogenizer, transfer hand, lid opening/closing device, centrifugal separator, pipette, shaker, column purification device, centrifugal evaporator and cooling device, and it is capable of freely combining operations by these units. A validation study was performed on two methods for determination of 178 veterinary drugs in livestock products, swine muscle, egg and shrimp, according to the method validation guideline of the Ministry of Health, Labour and Welfare of Japan. The numbers of analytes that satisfied the criteria of the guideline were 148 in swine muscle, 160 in egg and 151 in shrimp. PMID- 28855477 TI - The Current Status of Feline Sporotrichosis in Malaysia. AB - Feline sporotrichosis has been reported in Malaysia since the 1990's. Since then, studies have revealed that clinical clade D, Sporothrix schenckii sensu stricto, of a single clonal strain is the most common cause of this disease in Malaysia. The prevalence of a single clonal strain from a clinical clade was never before reported in Asia in a specific geographical niche. This raises the possibility of a process of purifying selection and subsequent clonal proliferation. While agricultural practices may serve as the selective pressure, direct causality has yet to be established. Studies into the thermo-tolerability of the Malaysian clonal strain of S. schenckii sensu stricto revealed that a small minority of clinical isolates have the capacity to grow at 37C, while the majority displayed low susceptibility to commonly used antifungals in clinical practice, such as itraconazole (ITZ) and terbinafine (TRB). Despite unestablished breakpoints, suspected resistance (MIC > 4 mg/mL) towards amphotericin B (AMB) and fluconazole (FLC) was recorded in the isolates. This explains the often lack of clinical response in feline patients treated with recommended doses of antifungals, including ITZ. Coupled with the potential zoonotic transmission to clients and veterinarians, protracted treatment period, and subsequent cost of treatment, prognosis of feline sporotrichosis is often regarded to be poor. The use of a higher dose of ITZ has been reported, and an adoption of this high-dose treatment regime is reported in this manuscript, with complete cure achieved in cases of recalcitrant and/or unresponsive feline sporotrichosis, which would otherwise be euthanized. PMID- 28855478 TI - First Isolation of Arthroderma fulvum in Japan. AB - Morphology and molecular characteristics of Microsporum gypseum clinical isolates obtained from the fur of a normal rabbit (n=1) and the soil from 10 different rabbit hutches in six elementary schools (n=10) were examined. Isolates were also identified by sequence analysis of the internal transcribed spacer (ITS) region. All 11 isolates demonstrated homology with the Arthroderma fulvum ITS sequence. Furthermore, PCR analysis for the presence of mating type genes detected positivity for MAT1-1 (n=10) and MAT1-2 (n=1). However, no mating reaction was detected between A. fulvum reference strains and the clinical isolates. PMID- 28855479 TI - Epidemiology of Zygomycosis: Analysis of National Data from Pathological Autopsy Cases in Japan. AB - BACKGROUND AND METHODS: To identify recent trends in the frequency of zygomycosis in autopsy cases, we conducted epidemiological analysis every four years from 1989 to 2009 using national data reported in the "Annual of Pathological Autopsy Cases in Japan." RESULTS: 153,615 cases were autopsied, of which 6622 (4.3%) were found to have had mycosis. Among these, there were 243 cases (3.7%) of zygomycosis, which was the fourth most predominant causative agent of mycoses among the monopathogen mycoses. Of the complicated mycoses, zygomycosis accounted for 56 cases. A total of 299 cases with zygomycoses were observed. The frequency of zygomycosis appeared to be generally stable over the twenty-year period from 1989 to 2009, at around 4% of autopsy cases having mycosis. Younger patients tended to have severe and complicated infections that were characteristic of zygomycosis, compared with non-zygomycosis. The pulmonary and gastrointestinal (GI) systems were the most common foci in our analysis, reflecting the severity of zygomycosis in these sites. Hematological disease was the most frequent underlying disease, but there was a peak of neonatal infections in 2009, which was the first time that this was observed in our studies. CONCLUSION: These results of the epidemiological analysis of autopsy cases with mycosis demonstrate that clinicians should promptly recognize and treat zygomycosis. PMID- 28855480 TI - Diagnosis and Treatment of Mucormycosis in Patients withHematological Malignancies[Translated Article]. AB - The risk of invasive fungal infections (IFIs) is extremely high in patients with hematological malignancies due to the prolonged and profound neutropenia and immunosuppression after chemotherapy and hematopoietic stem cell transplantation. There has been increasing interest in mucormycosis despite its relatively uncommon occurrence, because occasional breakthrough infections have been observed under anti-Aspergillus prophylaxis. The aggressive nature of mucormycosis easily leads to high mortality because of delays in diagnosis and incorrect treatment decisions, which are due in part to lack of adjunctive diagnostic tools and having similar clinical and radiological features with invasive aspergillosis. The only currently available antifungals against Mucorales in Japan are amphotericin B formulations. Thus, comprehensive therapeutic strategies, including surgery, should be considered to achieve a successful outcome. PMID- 28855481 TI - Inhibition of Growth of Candida albicans by a Lysozyme-chitosan Conjugate, LYZOX and its Combination with Decanoic Acid. AB - A lysozyme-chitosan conjugate preparation (LYZOX), produced from egg white lysozyme and chitosan by Maillard reaction, is a commercial product developed as a cosmetic ingredient or food additive. Effects of LYZOX on in vitro growth of Candida albicans were examined. C. albicans cells were treated with LYZOX for 3 hrs, and then washed and cultured for an additional 16 hrs in modified RPMI1640 medium. Mycelial growth of C. albicans was clearly inhibited by more than 100 MUg/ml of LYZOX in a concentration-dependent manner. On the other hand, corresponding concentration of chitosan or lysozyme or their mixture only scarcely showed clear inhibitory effect. Similarly, anti-Candida activity of the combination of LYZOX and decanoic acid, a middle-chain fatty acid, was also examined. Inhibitory activity of this combination against mycelial growth of C. albicans was very potent and appeared synergistic, since fractionated inhibitory concentration (FIC) index for 70% growth inhibition was calculated to be 0.20. Oral application of this combination improved the symptoms of Candida-infected tongue in an experimental murine candidiasis model. On the basis of these results, the possible application of LYZOX as a new functional product with anti candida activity was discussed. PMID- 28855482 TI - Prof. Masao Ota. AB - Masao Ota was a Professor of Dermatology at Tokyo Imperial University. He is known to dermatologists around the world as the researcher who identified Nevus of Ota. He is also known for his research on Hansen's Disease. He was critical of the forced isolation policy and the sterilization law. He dreamt of developing chemotherapeutic measures and dedicated himself to cultivating Mycobacterium leprae. Among his accomplishments, those in the area of medical mycology are particularly remarkable. His discovery of Microsporum ferrugineum, his proposal for Trichophytia pompholyciformis, and his work on Ota-Langeron taxonomy based on the findings on fungus colonies are highly regarded and earned him the Ordre Royale de la Legion D'honneur. His accomplishments in the field of mycology are numerous; he has published a total of 39 research papers mostly in foreign languages. He was a leading world-class medical mycologist of his day. This review introduces some of his accomplishments and some episodes in his life.Furthermore, Masao Ota had a detailed knowledge of art and culture. Under the pseudonym of Kinoshita Mokutaro, he wrote poems, plays, and novels. He was also a painter. Particularly, his paintings in botany during his later years were published in the book "One Hundred Flower Sketches" after his death.Ota said, "The consequence of both science and art is global and humanitarian." He was one of the greatest men of culture in his time. PMID- 28855483 TI - Current Status of Taxonomy of Pathogenic Yeasts. AB - Fungal taxonomy has been reconstructed on the basis of genome information, and new nomenclatural rules have been enacted from 2013. It has been proposed that Cryptococcus neoformans and Cryptococcus gattii be reclassified into two species (C. neoformans and Cryptococcus deneoformans) and five species (C. gattii, Cryptococcus bacillisporus, Cryptococcus deuterogattii, Cryptococcus tetragattii, and Cryptococcus decagattii), respectively. The genus Trichosporon has been reclassified into five genera. Trichosporon asahii, which is the causative agent of trichosporonosis, has been retained in the genus Trichosporon, while Trichosporon cutaneum has been transferred into a new genus, Cutaneotrichosporon. PMID- 28855484 TI - Recognition of Cryptococcus neoformans by Pattern Recognition Receptors and its Role in Host Defense to This Infection. AB - Cryptococcus neoformans is a yeast-type opportunistic fungal pathogen with a capsule structure consisting of polysaccharides, such as glucuronoxylomannan and galactoxylomannan, and infects the lungs via an air-borne route. Most healthy individuals undergo asymptomatic infection with granulomatous lesions in the lungs caused by C. neoformans. However, immunocompromised hosts with severely impaired cellular immunity, such as those with acquired immune deficiency syndrome (AIDS), often suffer from disseminated infection into the central nervous system, leading to life-threatening meningoencephalitis. The recognition of pathogen-associated molecular patterns (PAMPs) by macrophages and dendritic cells plays an important role as the first line of host defense in the elimination of pathogens. Recently, numerous pattern recognition receptors (PRRs) that recognize these PAMPs have been identified. Also, the involvement of these PRRs, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs), in cryptococcal infection has been analyzed. In particular, TLR9, NLR family pyrin domain-containing 3 (NLRP3), Dectin-2, mannose receptor (MR), and DC-SIGN have been found to recognize the DNA, cell wall components, intracellular polysaccharides, and mannoproteins, respectively. Future studies are expected to promote elucidation of the mechanisms of host immune response to C. neoformans, which will lead to the development of new vaccines and therapies for cryptococcal infection. PMID- 28855486 TI - Term 15. PMID- 28855485 TI - Potential of Next-generation POCT in Infectious Disease Rapid Test. AB - Real-time test results are necessary for early diagnosis and in determining treatment orientation in medical practice. Point of Care Testing (POCT) is a testing system that provides beneficial and helpful information for diagnosis and treatment through real-time testing at the bedside. Therefore, POCT has high utility value in the field of infectious diseases as a rapid test that provides, within the consultation hours, useful information for initial treatment.Infectious disease rapid test kits are commercially available for a wide variety of prophlogistic pathogen targets, including bacterial, viral, fungal, protozoal, and other disease agents. One of these kits is immunochromatography assay (ICA), a measuring method used as POCT that is easy to operate, wherein even physicians and nurses can conduct the test.Serodiagnostic method has been adjunctively used in medical practice in Japan for early clinical diagnosis of deep mycosis as a means to determine treatments. However, this method is complicated and is considered a full-scale clinical examination; therefore, it is not included in the category of POCT. Recently, Loop-Mediated Isothermal Amplification (LAMP) method has been tested as a POCT for diagnosis of fungal infection in the US. Development of a laboratory procedure using simple and highly accurate POCT for early diagnosis of deep mycosis is expected in the near future. PMID- 28855487 TI - Erratum. PMID- 28855492 TI - Multiple pseudofractures due to Fanconi's syndrome associated with Wilson's disease. AB - We report a 40-year-old man who presented with multiple bone pseudofractures after about 20 years from the onset of Wilson's disease (WD). At age 36, he first noticed pain in his left shoulder. At age 39, he had multiple chest pain. On neurologic examinations, dysarthria and dysphagia due to pseudobulbar palsy, rigidity and tremor on right upper lim were observed. WD was confirmed because of low levels of plasma cupper and ceruloplasmin in addition to ATP7B gene mutation. The chest X-ray revealed multiple fractures of the several ribs. We diagnosed osteomalacia due to Fanconi's syndrome because of hypophosphatemia and the impairment of renal tubules for WD. After administration of vitamin D, there happened no new bone pseudofractures. Although bone pseudofractures accompanied by Wilson's disease generally happen in childhood, we should be aware of this symptom even in adulthood. PMID- 28855493 TI - Clinical characteristics of 17 adult patients with epidemic myalgia associated with human parechovirus type 3 infection. AB - We investigated 17 adult cases (14 males and 3 females) of myalgia induced by human parechovirus type 3 (HPeV3) infection, treated during the summers of 2008, 2011, 2014, and 2016. The patients were aged between 21 and 50 years. The limbs and trunk of all patients were affected, and severe myalgia, muscle weakness, and decreased grip strength were observed. In addition to myalgia and muscle weakness, symptoms included fever in 14 (82%), upper respiratory inflammation in 8 (47%), gastroenteritis in 4 (24%), and scrotal pain in 4 (29% of males) patients. Tendon reflexes were preserved, and serum creatine kinase level increased in all but 1 patient. Spinal MRI was performed for 3 patients, with normal results. Musculoskeletal MRI scans showed abnormal signals in the femoral muscles in 2 of 5 patients. In a nerve conduction test, the frequency of F wave appearance in the median nerve was 40% or less in 5 of 9 patients, and repeater F waves were seen in 2 patients. Of these, 7 patients had infants in their families, and developed fever around the same time; they may have been infected by these infants. All patients recovered within 1-2 weeks. HPeV3 infection is characterized by severe myalgia, and is frequently observed in summer every 2-3 years. PMID- 28855494 TI - Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation superimposed by chronic inflammatory demyelinating polyneuropathy. AB - We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of MME gene was detected and thus he was diagnosed as autosomal recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by MME mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of MME gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient. PMID- 28855495 TI - Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: A case presented brain calcification and corpus callosum atrophy from over 10 years before the onset of dementia. AB - A 44-year-old man made many mistakes at work over a year. Eleven years prior, he had had medical examination with headache. He presented with symptoms consistent with frontal lobe dysfunction including cognitive decline, and bilateral pyramidal signs. Brain MRI showed cerebral atrophy, localized atrophy of corpus callosum, asymmetrical white matter lesions and multiple cystic lesions. CT images showed bilateral calcifications in the parietal subcortical white matter. Reconstructed sagittal CT images showed bilateral calcifications in the frontal white matter adjacent to the anterior horns of the lateral ventricles, which had a symmetrical "stepping stone appearance" in the frontal pericallosal regions. The brain MRI and CT images performed 11 years prior already showed evidence of similar findings including corpus callosum atrophy, multiple cystic lesions, and calcifications in the parietal subcortical white matter. Similar cystic lesions and calcifications were also observed in the frontal white matter adjacent to the anterior horns of the lateral ventricles However, the changes in the brain associated with atrophy and white matter lesions at this stage were mild. Genetic analysis revealed a novel mutation, p.R782C, in the exon 18 of the colony stimulating factor 1 receptor (CSF1R) gene. The CSF1R gene encodes the colony stimulating factor 1 receptor protein. This mutation was not observed in the patient's parents. Therefore, this mutation is considered to be a de novo mutation. He was diagnosed as having adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). PMID- 28855496 TI - A Retrospective Study: The Significance of Combined Testing of Serum Markers for Diagnosis of Rheumatoid Arthritis. AB - BACKGROUND There have been few studies on the value of various antibody combinations in rheumatoid arthritis (RA) diagnosis, and a lack of studies with large sample sizes, especially in the Chinese population. This study retrospectively evaluated the diagnostic value of a combined assay of five auto antibodies [anti-cyclic citrullinated peptide (anti-CCP), anti-keratin (AKA), anti-RA 33, glucose-6-phosphate isomerase (GPI), and rheumatoid factor (RF)] for RA. MATERIAL AND METHODS Data were obtained from 5,725 patients with rheumatic diseases in Southwest Hospital of Chongqing from 2011 to 2014. Detection of the five serological markers was performed for all study patients using the appropriate method for each antibody. RESULTS It was found that of the 5,725 patients, the positive rates for RF, anti-CCP, anti-RA 33, AKA, and GPI were 52.5%, 40.1%, 12.8%, 12.0%, and 50.0% respectively. In RA patients, the positive rates were 83.3%, 68.5%, 16.6%, 20.8%, and 77.9% respectively, which were all significantly higher than those detected in patients with the other diseases (p<0.01). The areas under the receiver operator characteristic (ROC) curve for RF, anti-CCP, anti-RA 33, AKA, and GPI were 0.857, 0.831, 0.528, 0.602, and 0.822 respectively, indicating that these five serological markers display favorable diagnostic value for RA. There were positive correlations between anti-CCP antibody and RF and GPI (p<0.01) and between RF and GPI (p<0.01), but no correlation between anti-RA 33 and AKA (p<0.01). The specificity of the combination of anti-CCP, AKA, and GPI was 100% for RA diagnosis. CONCLUSIONS The combined assay of serological markers significantly improved the diagnostic specificity for RA. The diagnostic value of RF for RA was the highest and the combined assay for anti-CCP, AKA, and GPI had the highest specificity for RA diagnosis. PMID- 28855497 TI - A 49-Year-Old Man with Subacute Respiratory Failure and Interstitial Lung Opacities. AB - BACKGROUND Pulmonary arterial hypertension (PAH) results from proliferative vasculopathy involving all layers of the blood vessel. Similar findings may be present in pulmonary hypertension (PH) associated with microscopic tumor embolism, which are thought to be related to the phenomenon of pulmonary tumor thrombotic microangiopathy (PTTM). PTTM is associated with the activation of the coagulation system at the surface of the tumor emboli, resulting in stenosis or occlusion of the vessel. CASE REPORT A 49-year-old man with stage IV gastro esophageal junction adenocarcinoma presented with complaints of cough and shortness of breath. These symptoms coincided with the initiation of trastuzumab with a new experimental medication with receptor tyrosine kinase blocking activity. A trans-thoracic echocardiogram demonstrated severely increased right ventricle (RV) cavity size with severely decreased RV systolic function. A computed tomography angiography was negative for pulmonary embolism but demonstrated new bilateral pulmonary infiltrates. Bronchoalveolar lavage ruled out an infectious etiology. Trans-bronchial biopsies (TBBx) showed arteriole obliteration by smooth muscle proliferation suggestive of pulmonary vasculopathy. The right heart catheterization (RHC) confirmed severe pulmonary hypertension. Unfortunately, shortly after the RHC, the patient developed pulseless electrical activity cardiac arrest and died. Autopsy results were similar to those of the TBBx, except for diffuse dissemination of tumor cells in the lymphatic channels and small pulmonary vessels, confirming a diagnosis of PTTM. CONCLUSIONS We highlight the limitations of trans-bronchial biopsies in evaluating PTTM. The final diagnosis of PTTM was not made until the autopsy was done. PMID- 28855498 TI - TRAF2 is a Valuable Prognostic Biomarker in Patients with Prostate Cancer. AB - BACKGROUND TRAF2 exerts important functions in regulating the development and progression of cancer. The aim of this study is to investigate whether TRAF2 is a valuable prognostic biomarker and to determine if it regulates TRAIL-induced apoptosis in prostate cancer. MATERIAL AND METHODS Microarray gene expression data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to determine TRAF2 expression in prostate cancer. TRAF2 expression in prostate cancer was further investigated by immunohistochemistry assay. Kaplan-Meier curves and log-rank test were used to assess the recurrence free rate. Cox regression was used to analyze prognostic factors. Effects of TRAF2 on regulating TRAIL-induced apoptosis in DU-145 cells were further investigated. RESULTS We found that TRAF2 was significantly upregulated in prostate cancer compared with normal prostate samples (P<0.001). In addition, compared with primary prostate cancer, TRAF2 was upregulated in metastatic prostate cancer (P=0.006). Furthermore, our results showed that high expression of TRAF2 was significantly associated with tumor stage of prostate cancer (P=0.035). TRAF2 high expression was associated with poorer recurrence-free survival in prostate cancer patients (P=0.013). TRAF2 was found to be a valuable independent prognostic factor for predicting recurrence-free survival (P=0.026). In addition, the present results indicate that TRAF2 affects TRAIL-induced apoptosis in prostate cancer DU-145 cells via regulating cleaved Caspase-8 and c Flip expression. CONCLUSIONS TRAF2 could be a novel prognostic biomarker for predicting recurrence-free survival in patients with prostate cancer, which might be associated with the effects of TRAF2 in regulating TRAIL-induced apoptosis in prostate cancer cells via c-Flip/Caspase-8 signalling. PMID- 28855499 TI - On-chip single photon filtering and multiplexing in hybrid quantum photonic circuits. AB - Quantum light plays a pivotal role in modern science and future photonic applications. Since the advent of integrated quantum nanophotonics different material platforms based on III-V nanostructures-, colour centers-, and nonlinear waveguides as on-chip light sources have been investigated. Each platform has unique advantages and limitations; however, all implementations face major challenges with filtering of individual quantum states, scalable integration, deterministic multiplexing of selected quantum emitters, and on-chip excitation suppression. Here we overcome all of these challenges with a hybrid and scalable approach, where single III-V quantum emitters are positioned and deterministically integrated in a complementary metal-oxide-semiconductor compatible photonic circuit. We demonstrate reconfigurable on-chip single-photon filtering and wavelength division multiplexing with a foot print one million times smaller than similar table-top approaches, while offering excitation suppression of more than 95 dB and efficient routing of single photons over a bandwidth of 40 nm. Our work marks an important step to harvest quantum optical technologies' full potential.Combining different integration platforms on the same chip is currently one of the main challenges for quantum technologies. Here, Elshaari et al. show III-V Quantum Dots embedded in nanowires operating in a CMOS compatible circuit, with controlled on-chip filtering and tunable routing. PMID- 28855500 TI - Retinol saturase coordinates liver metabolism by regulating ChREBP activity. AB - The liver integrates multiple metabolic pathways to warrant systemic energy homeostasis. An excessive lipogenic flux due to chronic dietary stimulation contributes to the development of hepatic steatosis, dyslipidemia and hyperglycemia. Here we show that the oxidoreductase retinol saturase (RetSat) is involved in the development of fatty liver. Hepatic RetSat expression correlates with steatosis and serum triglycerides (TGs) in humans. Liver-specific depletion of RetSat in dietary obese mice lowers hepatic and circulating TGs and normalizes hyperglycemia. Mechanistically, RetSat depletion reduces the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose phosphate sensor and inducer of lipogenesis. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. Thus, RetSat is a critical regulator of liver metabolism functioning upstream of ChREBP. Pharmacological inhibition of liver RetSat may represent a therapeutic approach for steatosis.Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP. PMID- 28855501 TI - Variable repeats in the eukaryotic polyubiquitin gene ubi4 modulate proteostasis and stress survival. AB - Ubiquitin conjugation signals for selective protein degradation by the proteasome. In eukaryotes, ubiquitin is encoded both as a monomeric ubiquitin unit fused to a ribosomal gene and as multiple ubiquitin units in tandem. The polyubiquitin gene is a unique, highly conserved open reading frame composed solely of tandem repeats, yet it is still unclear why cells utilize this unusual gene structure. Using the Saccharomyces cerevisiae UBI4 gene, we show that this multi-unit structure allows cells to rapidly produce large amounts of ubiquitin needed to respond to sudden stress. The number of ubiquitin units encoded by UBI4 influences cellular survival and the rate of ubiquitin-proteasome system (UPS) mediated proteolysis following heat stress. Interestingly, the optimal number of repeats varies under different types of stress indicating that natural variation in repeat numbers may optimize the chance for survival. Our results demonstrate how a variable polycistronic transcript provides an evolutionary alternative for gene copy number variation.Eukaryotic cells rely on the ubiquitin-proteasome system for selective degradation of proteins, a process vital to organismal fitness. Here the authors show that the number of repeats in the polyubiquitin gene is evolutionarily unstable within and between yeast species, and that this variability may tune the cell's capacity to respond to sudden environmental perturbations. PMID- 28855502 TI - Photoelectrochemical oxidation of organic substrates in organic media. AB - There is a global effort to convert sunlight into fuels by photoelectrochemically splitting water to form hydrogen fuels, but the dioxygen byproduct bears little economic value. This raises the important question of whether higher value commodities can be produced instead of dioxygen. We report here photoelectrochemistry at a BiVO4 photoanode involving the oxidation of substrates in organic media. The use of MeCN instead of water enables a broader set of chemical transformations to be performed (e.g., alcohol oxidation and C-H activation/oxidation), while suppressing photocorrosion of BiVO4 that otherwise occurs readily in water, and sunlight reduces the electrical energy required to drive organic transformations by 60%. These collective results demonstrate the utility of using photoelectrochemical cells to mediate organic transformations that otherwise require expensive and toxic reagents or catalysts.Photoelectrochemical water splitting is a promising method for H2 fuel production, but the O2 by-product generated has little economic value. Here, Berlinguette and colleagues demonstrate that BiVO4 photoanodes immersed in organic media can instead perform valuable alcohol oxidation and C-H functionalization reactions. PMID- 28855503 TI - Nucleolar expansion and elevated protein translation in premature aging. AB - Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.HGPS is a premature aging disease caused by mutations in the nuclear protein lamin A. Here, the authors show that cells from patients with HGPS have expanded nucleoli and increased protein synthesis, and report that nucleoli also expand as aging progresses in cells derived from healthy individuals. PMID- 28855504 TI - Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents. AB - Tuberculosis remains one of the world's deadliest communicable diseases, novel anti-tuberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six anti-mycobacterial ilamycin congeners (1-6) bearing rare L-3 nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3 nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6-8) from the respective mutants. Most impressively, ilamycins E1/E2, which are produced in high titers by a genetically engineered mutant strain, show very potent anti-tuberculosis activity with an minimum inhibitory concentration value ~9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.Tuberculosis (TB) remains one of the world's deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti tuberculosis activities. PMID- 28855505 TI - Correlated electronic states at domain walls of a Mott-charge-density-wave insulator 1T-TaS2. AB - Domain walls in interacting electronic systems can have distinct localized states, which often govern physical properties and may lead to unprecedented functionalities and novel devices. However, electronic states within domain walls themselves have not been clearly identified and understood for strongly correlated electron systems. Here, we resolve the electronic states localized on domain walls in a Mott-charge-density-wave insulator 1T-TaS2 using scanning tunneling spectroscopy. We establish that the domain wall state decomposes into two nonconducting states located at the center of domain walls and edges of domains. Theoretical calculations reveal their atomistic origin as the local reconstruction of domain walls under the strong influence of electron correlation. Our results introduce a concept for the domain wall electronic property, the walls own internal degrees of freedom, which is potentially related to the controllability of domain wall electronic properties.The electronic states within domain walls in an interacting electronic system remain elusive. Here, Cho et al. report that the domain wall state in a charge-density-wave insulator 1T TaS2 decomposes into two localized but nonconducting states at the center or edges of domain walls. PMID- 28855506 TI - Developing a molecular picture of soil organic matter-mineral interactions by quantifying organo-mineral binding. AB - Long residence times of soil organic matter have been attributed to reactive mineral surface sites that sorb organic species and cause inaccessibility due to physical isolation and chemical stabilization at the organic-mineral interface. Instrumentation for probing this interface is limited. As a result, much of the micron- and molecular-scale knowledge about organic-mineral interactions remains largely qualitative. Here we report the use of force spectroscopy to directly measure the binding between organic ligands with known chemical functionalities and soil minerals in aqueous environments. By systematically studying the role of organic functional group chemistry with model minerals, we demonstrate that chemistry of both the organic ligand and mineral contribute to values of binding free energy and that changes in pH and ionic strength produce significant differences in binding energies. These direct measurements of molecular binding provide mechanistic insights into organo-mineral interactions, which could potentially inform land-carbon models that explicitly include mineral-bound C pools.Most molecular scale knowledge on soil organo-mineral interactions remains qualitative due to instrument limitations. Here, the authors use force spectroscopy to directly measure free binding energy between organic ligands and minerals and find that both chemistry and environmental conditions affect binding. PMID- 28855507 TI - The onset of widespread marine red beds and the evolution of ferruginous oceans. AB - Banded iron formations were a prevalent feature of marine sedimentation ~3.8-1.8 billion years ago and they provide key evidence for ferruginous oceans. The disappearance of banded iron formations at ~1.8 billion years ago was traditionally taken as evidence for the demise of ferruginous oceans, but recent geochemical studies show that ferruginous conditions persisted throughout the later Precambrian, and were even a feature of Phanerozoic ocean anoxic events. Here, to reconcile these observations, we track the evolution of oceanic Fe concentrations by considering the temporal record of banded iron formations and marine red beds. We find that marine red beds are a prominent feature of the sedimentary record since the middle Ediacaran (~580 million years ago). Geochemical analyses and thermodynamic modelling reveal that marine red beds formed when deep-ocean Fe-concentrations were > 4 nM. By contrast, banded iron formations formed when Fe-concentrations were much higher (> 50 MUM). Thus, the first widespread development of marine red beds constrains the timing of deep ocean oxygenation.The evolution of oceanic redox state in the past is poorly known. Here, the authors present a temporal record of banded iron formations and marine red beds, which indicate deep-ocean oxygenation occurred in the middle Ediacaran, coinciding with the onset of widespread marine red beds. PMID- 28855510 TI - Mining novel starch-converting Glycoside Hydrolase 70 enzymes from the Nestle Culture Collection genome database: The Lactobacillus reuteri NCC 2613 GtfB. AB - The Glycoside hydrolase (GH) family 70 originally was established for glucansucrases of lactic acid bacteria (LAB) converting sucrose into alpha-glucan polymers. In recent years we have identified 3 subfamilies of GH70 enzymes (designated GtfB, GtfC and GtfD) as 4,6-alpha-glucanotransferases, cleaving (alpha1 -> 4)-linkages in maltodextrins/starch and synthesizing new (alpha1 -> 6) linkages. In this work, 106 putative GtfBs were identified in the Nestle Culture Collection genome database with ~2700 genomes, and the L. reuteri NCC 2613 one was selected for further characterization based on variations in its conserved motifs. Using amylose the L. reuteri NCC 2613 GtfB synthesizes a low-molecular mass reuteran-like polymer consisting of linear (alpha1 -> 4) sequences interspersed with (alpha1 -> 6) linkages, and (alpha1 -> 4,6) branching points. This product specificity is novel within the GtfB subfamily, mostly comprising 4,6-alpha-glucanotransferases synthesizing consecutive (alpha1 -> 6)-linkages. Instead, its activity resembles that of the GtfD 4,6-alpha-glucanotransferases identified in non-LAB strains. This study demonstrates the potential of large scale genome sequence data for the discovery of enzymes of interest for the food industry. The L. reuteri NCC 2613 GtfB is a valuable addition to the starch converting GH70 enzyme toolbox. It represents a new evolutionary intermediate between families GH13 and GH70, and provides further insights into the structure function relationships of the GtfB subfamily enzymes. PMID- 28855509 TI - MHC matching improves engraftment of iPSC-derived neurons in non-human primates. AB - The banking of human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cells (iPSCs) is considered a future clinical strategy for HLA-matched cell transplantation to reduce immunological graft rejection. Here we show the efficacy of major histocompatibility complex (MHC)-matched allogeneic neural cell grafting in the brain, which is considered a less immune-responsive tissue, using iPSCs derived from an MHC homozygous cynomolgus macaque. Positron emission tomography imaging reveals neuroinflammation associated with an immune response against MHC-mismatched grafted cells. Immunohistological analyses reveal that MHC matching reduces the immune response by suppressing the accumulation of microglia (Iba-1+) and lymphocytes (CD45+) into the grafts. Consequently, MHC-matching increases the survival of grafted dopamine neurons (tyrosine hydroxylase: TH+). The effect of an immunosuppressant, Tacrolimus, is also confirmed in the same experimental setting. Our results demonstrate the rationale for MHC-matching in neural cell grafting to the brain and its feasibility in a clinical setting.Major histocompatibility complex (MHC) matching improves graft survival rates after organ transplantation. Here the authors show that in macaques, MHC-matched iPSC derived neurons provide better engraftment in the brain, with a lower immune response and higher survival of the transplanted neurons. PMID- 28855508 TI - Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell. AB - Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (?F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 degrees C and concomitant functional inactivation of ?F508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at single-molecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart. Thus, molecular chaperones can contribute to functional maintenance of ?F508-CFTR by reshaping the conformational energetics of its final fold, a mechanism with implication in the regulation of metastable ABC transporters and other plasma membrane proteins activity in health and diseases.The F508 deletion (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common CF causing mutation. Here the authors show that cytosolic chaperones shift the F508del channel conformation to the native fold by kinetic and thermodynamic remodelling of the gating energetics towards that of wild-type CTFR. PMID- 28855511 TI - Blood monocyte transcriptome and epigenome analyses reveal loci associated with human atherosclerosis. AB - Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human atherosclerosis. The transcriptome signature includes transcription coactivator, ARID5B, which is known to form a chromatin derepressor complex with a histone H3K9Me2-specific demethylase and promote adipogenesis and smooth muscle development. ARID5B CpG (cg25953130) methylation is inversely associated with both ARID5B expression and atherosclerosis, consistent with this CpG residing in an ARID5B enhancer region, based on chromatin capture and histone marks data. Mediation analysis supports assumptions that ARID5B expression mediates effects of cg25953130 methylation and several cardiovascular disease risk factors on atherosclerotic burden. In lipopolysaccharide-stimulated human THP1 monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis. These data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype.The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte's transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis. PMID- 28855513 TI - Noninvasive Imaging of Ras Activity by Monomolecular Biosensor Based on Split Luciferase Complementary Assay. AB - Deregulated activity of Ras GTPases has been observed in many types of human cancers, and contributes to the diverse aspects of carcinogenesis. Although the significance in tumorigenesis has been widely accepted and many therapeutic drugs are under development, little attention has been dedicated to the development of sensors for the Ras activity in vivo. Therefore, based on the split firefly luciferase complementation strategy, we developed a monomolecular bioluminescent biosensor to image endogenous Ras activity in living subject. In this biosensor, two inactive luciferase fragments are sandwiched by Raf-1, whose conformation changes upon GTP-Ras binding. Thus, the Ras activity can be surrogated by the intensity of the complementary luciferase. The bioluminescence analyses demonstrated that this novel biosensor behaved the robust and sensitive reporting efficiency in response to the dynamical changes of Ras activity, both in living colorectal cancer cells and in vivo. Compared to the traditional method, such as the pull-down assay, the bioluminescent sensor is simply, noninvasive, faster and more sensitive for the analysis of the endogenous Ras activity. This innovative work opens up the way for monitoring the preclinical curative effect and high throughput screening of therapeutic drugs targeting Ras pathways. PMID- 28855512 TI - ATRX is a regulator of therapy induced senescence in human cells. AB - Senescence is a state of stable cell cycle exit with important implications for development and disease. Here, we demonstrate that the chromatin remodeling enzyme ATRX is required for therapy-induced senescence. ATRX accumulates in nuclear foci and is required for therapy-induced senescence in multiple types of transformed cells exposed to either DNA damaging agents or CDK4 inhibitors. Mobilization into foci depends on the ability of ATRX to interact with H3K9me3 histone and HP1. Foci form soon after cells exit the cell cycle, before other hallmarks of senescence appear. Eliminating ATRX in senescent cells destabilizes the senescence-associated heterochromatic foci. Additionally, ATRX binds to and suppresses expression from the HRAS locus; repression of HRAS is sufficient to promote the transition of quiescent cells into senescence and preventing repression blocks progression into senescence. Thus ATRX is a critical regulator of therapy-induced senescence and acts in multiple ways to drive cells into this state.Therapy induced senescence (TIS) is a growth suppressive program activated by cytostatic agents in some cancer cells. Here the authors show that the chromatin remodeling enzyme ATRX is a regulator of TIS and drives cells into this state via multiple mechanisms. PMID- 28855515 TI - Artificial web of disclination lines in nematic liquid crystals. AB - Disclinations are topological singularities of molecular arrangement in liquid crystals, which typically occur when the average orientation of molecules makes a pi rotation along a fictitious closed loop taken inside the liquid crystal. Depending on the sense of molecular rotation, the disclination lines are either of 1/2 or -1/2 strength. When two disclination lines with the opposite strength meet, they are annihilated without trace. It is hence generally considered difficult in the nematic phase to stabilize a condensed array of free-standing disclination lines without the aid of topological objects like colloidal inclusions. Here we show that a free-standing web of 1/2-strength twist disclination lines can be stably formed in thin liquid crystal cells by means of a judicious combination of orientationally patterned confining surfaces fabricated by the micropatterned photoalignment technique. Theoretical model indicates that disclination lines are held apart at the intersection by a repulsive force generated by the Frank elasticity.Disclination lines are topological defects in molecular orientation widely found in liquid crystals. Here Wang et al. use a surface patterning technique to produce a very stable freestanding 3D array of 1/2 twist disclinations, which could be exploited in a variety of nanometre scale applications. PMID- 28855514 TI - Hit-and-run programming of therapeutic cytoreagents using mRNA nanocarriers. AB - Therapies based on immune cells have been applied for diseases ranging from cancer to diabetes. However, the viral and electroporation methods used to create cytoreagents are complex and expensive. Consequently, we develop targeted mRNA nanocarriers that are simply mixed with cells to reprogram them via transient expression. Here, we describe three examples to establish that the approach is simple and generalizable. First, we demonstrate that nanocarriers delivering mRNA encoding a genome-editing agent can efficiently knock-out selected genes in anti cancer T-cells. Second, we imprint a long-lived phenotype exhibiting improved antitumor activities into T-cells by transfecting them with mRNAs that encode a key transcription factor of memory formation. Third, we show how mRNA nanocarriers can program hematopoietic stem cells with improved self-renewal properties. The simplicity of the approach contrasts with the complex protocols currently used to program therapeutic cells, so our methods will likely facilitate manufacturing of cytoreagents.Current widely used viral and electroporation methods for creating therapeutic cell-based products are complex and expensive. Here, the authors develop targeted mRNA nanocarriers that can transiently program gene expression by simply mixing them with cells, to improve their therapeutic potential. PMID- 28855516 TI - Winter amplification of the European Little Ice Age cooling by the subpolar gyre. AB - Climate reconstructions reveal a strong winter amplification of the cooling over central and northern continental Europe during the Little Ice Age period (LIA, here defined as c. 16th-18th centuries) via persistent, blocked atmospheric conditions. Although various potential drivers have been suggested to explain the LIA cooling, no coherent mechanism has yet been proposed for this seasonal contrast. Here we demonstrate that such exceptional wintertime conditions arose from sea ice expansion and reduced ocean heat losses in the Nordic and Barents seas, driven by a multicentennial reduction in the northward heat transport by the subpolar gyre (SPG). However, these anomalous oceanic conditions were largely decoupled from the European atmospheric variability in summer. Our novel dynamical explanation is derived from analysis of an ensemble of last millennium climate simulations, and is supported by reconstructions of European temperatures and atmospheric circulation variability and North Atlantic/Arctic paleoceanographic conditions. We conclude that SPG-related internal climate feedbacks were responsible for the winter amplification of the European LIA cooling. Thus, characterization of SPG dynamics is essential for understanding multicentennial variations of the seasonal cycle in the European/North Atlantic sector. PMID- 28855517 TI - Cross-linked decellularized porcine corneal graft for treating fungal keratitis. AB - This study aims to develop a cross-linked decellularized porcine corneal graft (cDPC) as a substitute for lamellar donor corneas and to evaluate the feasibility of using cDPC to treat fungal keratitis. The cDPC was prepared by decellularization, chemical crosslinking and gamma-ray irradiation. Transparency, effectiveness of decellularization and biomechanical strength of cDPC were evaluated. The safety and efficacy of using cDPC to treat fungal keratitis were evaluated in the rabbit model. The transparency of cDPC was similar to that of a native porcine cornea (NPC), and no intact cells were observed in cDPC except for an insignificant amount of residual shrinking cellular nucleus. Compared to the NPC, the biomechanical strength of the cDPC was significantly increased. In the rabbit model of lamellar keratoplasty, the implanted cDPC reduced the incidence of corneal perforation, and also maintained transparency in majority. The results of this study suggest that the cDPC is capable of restoring the original transparency of cornea while effectively treating fungal keratitis. The cDPC is a highly promising ideal substitute for the donor human cornea. PMID- 28855518 TI - Hydrologic resilience and Amazon productivity. AB - The Amazon rainforest is disproportionately important for global carbon storage and biodiversity. The system couples the atmosphere and land, with moist forest that depends on convection to sustain gross primary productivity and growth. Earth system models that estimate future climate and vegetation show little agreement in Amazon simulations. Here we show that biases in internally generated climate, primarily precipitation, explain most of the uncertainty in Earth system model results; models, empirical data and theory converge when precipitation biases are accounted for. Gross primary productivity, above-ground biomass and tree cover align on a hydrological relationship with a breakpoint at ~2000 mm annual precipitation, where the system transitions between water and radiation limitation of evapotranspiration. The breakpoint appears to be fairly stable in the future, suggesting resilience of the Amazon to climate change. Changes in precipitation and land use are therefore more likely to govern biomass and vegetation structure in Amazonia.Earth system model simulations of future climate in the Amazon show little agreement. Here, the authors show that biases in internally generated climate explain most of this uncertainty and that the balance between water-saturated and water-limited evapotranspiration controls the Amazon resilience to climate change. PMID- 28855519 TI - Spatial effects in meta-foodwebs. AB - In ecology it is widely recognised that many landscapes comprise a network of discrete patches of habitat. The species that inhabit the patches interact with each other through a foodweb, the network of feeding interactions. The meta foodweb model proposed by Pillai et al. combines the feeding relationships at each patch with the dispersal of species between patches, such that the whole system is represented by a network of networks. Previous work on meta-foodwebs has focussed on landscape networks that do not have an explicit spatial embedding, but in real landscapes the patches are usually distributed in space. Here we compare the dispersal of a meta-foodweb on Erdos-Renyi networks, that do not have a spatial embedding, and random geometric networks, that do have a spatial embedding. We found that local structure and large network distances in spatially embedded networks, lead to meso-scale patterns of patch occupation by both specialist and omnivorous species. In particular, we found that spatial separations make the coexistence of competing species more likely. Our results highlight the effects of spatial embeddings for meta-foodweb models, and the need for new analytical approaches to them. PMID- 28855520 TI - Genotype-specific physiological and transcriptomic responses to drought stress in Setaria italica (an emerging model for Panicoideae grasses). AB - Understanding drought-tolerance mechanisms and identifying genetic dominance are important for crop improvement. Setaria italica, which is extremely drought tolerant, has been regarded as a model plant for studying stress biology. Moreover, different genotypes of S. italica have evolved various drought tolerance/avoidance mechanisms that should be elucidated. Physiological and transcriptomic comparisons between drought-tolerant S. italica cultivar 'Yugu1' and drought-sensitive 'An04' were conducted. 'An04' had higher yields and more efficient photosystem activities than 'Yugu1' under well-watered conditions, and this was accompanied by positive brassinosteroid regulatory actions. However, 'An04's growth advantage was severely repressed by drought, while 'Yugu1' maintained normal growth under a water deficiency. High-throughput sequencing suggested that the S. italica transcriptome was severely remodelled by genotype * environment interactions. Expression profiles of genes related to phytohormone metabolism and signalling, transcription factors, detoxification, and other stress-related proteins were characterised, revealing genotype-dependent and independent drought responses in different S. italica genotypes. Combining our data with drought-tolerance-related QTLs, we identified 20 candidate genes that contributed to germination and early seedling' drought tolerance in S. italica. Our analysis provides a comprehensive picture of how different S. italica genotypes respond to drought, and may be used for the genetic improvement of drought tolerance in Poaceae crops. PMID- 28855521 TI - High-quality monolayer superconductor NbSe2 grown by chemical vapour deposition. AB - The discovery of monolayer superconductors bears consequences for both fundamental physics and device applications. Currently, the growth of superconducting monolayers can only occur under ultrahigh vacuum and on specific lattice-matched or dangling bond-free substrates, to minimize environment- and substrate-induced disorders/defects. Such severe growth requirements limit the exploration of novel two-dimensional superconductivity and related nanodevices. Here we demonstrate the experimental realization of superconductivity in a chemical vapour deposition grown monolayer material-NbSe2. Atomic-resolution scanning transmission electron microscope imaging reveals the atomic structure of the intrinsic point defects and grain boundaries in monolayer NbSe2, and confirms the low defect concentration in our high-quality film, which is the key to two dimensional superconductivity. By using monolayer chemical vapour deposited graphene as a protective capping layer, thickness-dependent superconducting properties are observed in as-grown NbSe2 with a transition temperature increasing from 1.0 K in monolayer to 4.56 K in 10-layer.Two-dimensional superconductors will likely have applications not only in devices, but also in the study of fundamental physics. Here, Wang et al. demonstrate the CVD growth of superconducting NbSe2 on a variety of substrates, making these novel materials increasingly accessible. PMID- 28855523 TI - Periodic outburst floods from an ice-dammed lake in East Greenland. AB - We report evidence of four cycles of outburst floods from Catalina Lake, an ice dammed lake in East Greenland, identified in satellite imagery between 1966-2016. The lake measures 20-25 km2, and lake level drops 130-150 m in each event, corresponding to a water volume of 2.6-3.4 Gt, and a release of potential energy of 1016 J, among the largest outburst floods reported in historical times. The drainage cycle has shortened systematically, and the lake filling rate has increased over each cycle, suggesting that the drainage pattern is changing due to climate warming with possible implications for environmental conditions in Scoresbysund fjord. PMID- 28855522 TI - Separation of extracellular nanovesicles and apoptotic bodies from cancer cell culture broth using tunable microfluidic systems. AB - Extracellular vesicles (EVs) are the cell-secreted nano- and micro-sized particles consisted of lipid bilayer containing nucleic acids and proteins for diagnosis and therapeutic applications. The inherent complexity of EVs is a source of heterogeneity in various potential applications of the biological nanovesicles including analysis. To diminish heterogeneity, EV should be isolated and separated according to their sizes and cargos. However, current technologies do not meet the requirements. We showed noninvasive and precise separation of EVs based on their sizes without any recognizable damages. We separated atto-liter volumes of biological nanoparticles through operation of the present system showing relatively large volume of sample treatment to milliliters within an hour. We observed distinct size and morphological differences of 30 to 100 nm of exosomes and apoptotic bodies through TEM analysis. Indeed, we confirmed the biological moiety variations through immunoblotting with noninvasively separated EVs opening new windows in study and application of the biological nanoparticles. PMID- 28855524 TI - RNAi combining Sleeping Beauty transposon system inhibits ex vivo expression of foot-and-mouth disease virus VP1 in transgenic sheep cells. AB - Foot and mouth disease, which is induced by the foot and mouth disease virus (FMDV), takes its toll on the cloven-hoofed domestic animals. The VP1 gene in FMDV genome encodes the viral capsid, a vital element for FMDV replication. Sleeping Beauty (SB) is an active DNA-transposon system responsible for genetic transformation and insertional mutagenesis in vertebrates. In this study, a conserved VP1-shRNA which specifically targets the ovine FMDV-VP1 gene was constructed and combined with SB transposase and transposon. Then, they were microinjected into pronuclear embryos to breed transgenic sheep. Ninety-two lambs were born and the VP1-shRNA was positively integrated into eight of them. The rate of transgenic sheep production in SB transposon system was significantly higher than that in controls (13.04% vs. 3.57% and 7.14%, P < 0.05). The ear fibroblasts of the transgenic lambs transfected with the PsiCheck2-VP1 vector had a significant inhibitory effect on the VP1 gene of the FMDV. In conclusion, the VP1-shRNA transgenic sheep were successfully generated by the current new method. The ear fibroblasts from these transgenic sheep possess a great resistance to FMDV. The result indicated that RNAi technology combining the "Sleeping Beauty" transposon system is an efficient method to produce transgenic animals. PMID- 28855525 TI - Mitogenome Sequencing in the Genus Camelus Reveals Evidence for Purifying Selection and Long-term Divergence between Wild and Domestic Bactrian Camels. AB - The genus Camelus is an interesting model to study adaptive evolution in the mitochondrial genome, as the three extant Old World camel species inhabit hot and low-altitude as well as cold and high-altitude deserts. We sequenced 24 camel mitogenomes and combined them with three previously published sequences to study the role of natural selection under different environmental pressure, and to advance our understanding of the evolutionary history of the genus Camelus. We confirmed the heterogeneity of divergence across different components of the electron transport system. Lineage-specific analysis of mitochondrial protein evolution revealed a significant effect of purifying selection in the concatenated protein-coding genes in domestic Bactrian camels. The estimated dN/dS < 1 in the concatenated protein-coding genes suggested purifying selection as driving force for shaping mitogenome diversity in camels. Additional analyses of the functional divergence in amino acid changes between species-specific lineages indicated fixed substitutions in various genes, with radical effects on the physicochemical properties of the protein products. The evolutionary time estimates revealed a divergence between domestic and wild Bactrian camels around 1.1 [0.58-1.8] million years ago (mya). This has major implications for the conservation and management of the critically endangered wild species, Camelus ferus. PMID- 28855526 TI - Therapeutic effects of baicalein on rotenone-induced Parkinson's disease through protecting mitochondrial function and biogenesis. AB - Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD) for several decades, and disturbed mitochondrial biogenesis (mitobiogenesis) was recently found to be a common phenomenon in PD. Baicalein, a major bioactive flavone of Scutellaria baicalensis Georgi, exerted neuroprotective effects in several experimental PD models. However, the effects of baicalein in rotenone-induced PD rats and the possible mechanisms remain poorly understood. In this study, we evaluated the therapeutic effects of baicalein and explored its mechanism of action in rotenone-induced PD models. The results indicated that behavioural impairments and the depletion of dopaminergic neurons induced by rotenone were attenuated by baicalein. Furthermore, in rotenone-induced parkinsonian rats, baicalein treatment effectively restored mitochondrial function and improved mitobiogenesis, as determined by measuring the mitochondrial density and key regulators involved in mitobiogenesis. Additionally, we confirmed that baicalein enhanced mitobiogenesis through the cAMP-responsive element binding protein (CREB) and glycogen synthase kinase-3beta (GSK-3beta) pathways in rotenone-treated SH-SY5Y cells. Moreover, we demonstrated that the cytoprotective effects of baicalein could be attenuated by the mitobiogenesis inhibitor chloramphenicol as well as CREB siRNA transfection. Overall, our results suggested that baicalein partially enhanced mitobiogenesis to restore mitochondrial function, thus exerting therapeutic effects in rotenone induced PD models. PMID- 28855527 TI - Asymmetric dynamics of DNA entering and exiting a strongly confining nanopore. AB - In nanopore sensing, changes in ionic current are used to analyse single molecules in solution. The translocation dynamics of polyelectrolytes is of particular interest given potential applications such as DNA sequencing. In this paper, we determine how the dynamics of voltage driven DNA translocation can be affected by the nanopore geometry and hence the available configurational space for the DNA. Using the inherent geometrical asymmetry of a conically shaped nanopore, we examine how DNA dynamics depends on the directionality of transport. The total translocation time of DNA when exiting the extended conical confinement is significantly larger compared to the configuration where the DNA enters the pore from the open reservoir. By using specially designed DNA molecules with positional markers, we demonstrate that the translocation velocity progressively increases as the DNA exits from confinement. We show that a hydrodynamic model can account for these observations.Translocation of a charged polymer through confined nanoenvironments is highly dependent on their geometrical parameters. Here, the authors investigate experimentally the translocation dynamics of DNA through conical nanopores and provide a quantitative model for the translocation into and out of confinement. PMID- 28855528 TI - Analysis of the first Taraxacum kok-saghyz transcriptome reveals potential rubber yield related SNPs. AB - Taraxacum kok-saghyz (TK) is a potential alternative crop for natural rubber (NR) production, due to its high molecular weight rubber, short breeding cycle, and diverse environmental adaptation. However, improvements in rubber yield and agronomically relevant traits are still required before it can become a commercially-viable crop. An RNA-Seq based transcriptome was developed from a pool of roots from genotypes with high and low rubber yield. A total of 55,532 transcripts with lengths over 200 bp were de novo assembled. As many as 472 transcripts were significantly homologous to 49 out of 50 known plant putative rubber biosynthesis related genes. 158 transcripts were significantly differentially expressed between high rubber and low rubber genotypes. 21,036 SNPs were different in high and low rubber TK genotypes. Among these, 50 SNPs were found within 39 transcripts highly homologous to 49 publically-searched rubber biosynthesis related genes. 117 SNPs were located within 36 of the differentially expressed gene sequences. This comprehensive TK transcriptomic reference, and large set of SNPs including putative exonic markers associated with rubber related gene homologues and differentially expressed genes, provides a solid foundation for further genetic dissection of rubber related traits, comparative genomics and marker-assisted selection for the breeding of TK. PMID- 28855529 TI - Schizophrenia genetics in the genome-wide era: a review of Japanese studies. AB - The introduction of the genome-wide association study transformed schizophrenia genetics research and has promoted a genome-wide mindset that has stimulated the development of genomic technology, enabling departures from the traditional candidate gene approach. As result, we have witnessed a decade of major discoveries in schizophrenia genetics and the development of genome-wide approaches to the study of copy number variants. These genomic technologies have primarily been applied in populations of European descent. However, more recently both genome-wide association study and copy number variant studies in Asian populations have begun to emerge. In this invited review, we provide concise summaries of the schizophrenia genome-wide association study and copy number variant literature with specific focus on studies conducted in the Japanese population. When applicable, we compare findings observed in the Japanese population with those found in other populations. We conclude with recommendations for future research in schizophrenia genetics, relevant to Japan and beyond. PMID- 28855530 TI - Measuring proteins with greater speed and resolution while reducing sample size. AB - A multi-angle light scattering (MALS) system, combined with chromatographic separation, directly measures the absolute molar mass, size and concentration of the eluate species. The measurement of these crucial properties in solution is essential in basic macromolecular characterization and all research and production stages of bio-therapeutic products. We developed a new MALS methodology that has overcome the long-standing, stubborn barrier to microliter scale peak volumes and achieved the highest resolution and signal-to-noise performance of any MALS measurement. The novel design simultaneously facilitates online dynamic light scattering (DLS) measurements. As National Institute of Standards and Technology (NIST) new protein standard reference material (SRM 8671) is becoming the benchmark molecule against which many biomolecular analytical techniques are assessed and evaluated, we present its measurement results as a demonstration of the unique capability of our system to swiftly resolve and measure sharp (20~25 uL full-width-half-maximum) chromatography peaks. Precise measurements of protein mass and size can be accomplished 10 times faster than before with improved resolution. In the meantime the sample amount required for such measurements is reduced commensurately. These abilities will have far-reaching impacts at every stage of the development and production of biologics and bio-therapeutic formulations. PMID- 28855531 TI - Oxidant sensor in the cGMP-binding pocket of PKGIalpha regulates nitroxyl mediated kinase activity. AB - Despite the mechanisms for endogenous nitroxyl (HNO) production and action being incompletely understood, pharmacological donors show broad therapeutic promise and are in clinical trials. Mass spectrometry and site-directed mutagenesis showed that chemically distinct HNO donors 1-nitrosocyclohexyl acetate or Angeli's salt induced disulfides within cGMP-dependent protein kinase I-alpha (PKGIalpha), an interdisulfide between Cys42 of the two identical subunits of the kinase and a previously unobserved intradisulfide between Cys117 and Cys195 in the high affinity cGMP-binding site. Kinase activity was monitored in cells transfected with wildtype (WT), Cys42Ser or Cys117/195Ser PKGIalpha that cannot form the inter- or intradisulfide, respectively. HNO enhanced WT kinase activity, an effect significantly attenuated in inter- or intradisulfide-deficient PKGIalpha. To investigate whether the intradisulfide modulates cGMP binding, real time imaging was performed in vascular smooth muscle cells expressing a FRET biosensor comprising the cGMP-binding sites of PKGIalpha. HNO induced FRET changes similar to those elicited by an increase of cGMP, suggesting that intradisulfide formation is associated with activation of PKGIalpha. Intradisulfide formation in PKGIalpha correlated with enhanced HNO-mediated vasorelaxation in mesenteric arteries in vitro and arteriolar dilation in vivo in mice. HNO induces intradisulfide formation in PKGIalpha, inducing the same effect as cGMP binding, namely kinase activation and thus vasorelaxation. PMID- 28855532 TI - Electrically Tunable Metamaterials Based on Multimaterial Nanowires Incorporating Transparent Conductive Oxides. AB - We present novel design approaches for metasurfaces and metamaterials with electrical tunability offering real-time manipulation of light and serving as multifunctional devices in near-infrared frequency regime (at the specific wavelength of 1.55 MUm). For this purpose, we integrate indium-tin-oxide (ITO) as a tunable electro-optical material into multimaterial nanowires with metal-oxide semiconductor and metal-insulator-metal configurations. In particular, an active metasurface operating in the transmission mode is designed which allows for modulation of the transmitted light phase over 280 degrees. This large phase modulation is afforded in the cost of low transmission efficiency. We demonstrate the use of such active metasurfaces for tunable bending and focusing in free space. Moreover, we investigate the implementation of this material in deeply subwavelength multimaterial nanowires, which can yield strong variations in the effective refractive index by the virtue of internal homogenization enabling tunability of the performance in gradient refractive index metamaterials. In the theoretical modeling of these structures, we adopt a hierarchical multiscale approach by linking drift-diffusion transport model with the electromagnetic model which rigorously characterizes the electro-optical effects. PMID- 28855533 TI - Associations of estimated glomerular filtration rate and blood urea nitrogen with incident coronary heart disease: the Dongfeng-Tongji Cohort Study. AB - Estimated glomerular filtration rate (eGFR) has been reported to be associated with risk of incident coronary heart disease (CHD), and blood urea nitrogen (BUN) has been shown to be a strong predictor of mortality in patients with heart failure (HF). However, such epidemiological evidence from Chinese population was still limited. We used Cox proportional-hazards regression models to investigate the associations of eGFR and BUN with risk of incident CHD in the prospective Dongfeng-Tongji (DFTJ) cohort. After fully adjusted for potential confounders, a 10-unit decline in eGFR was associated with higher risk for CHD (hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.01-1.09); compared with individuals with normal eGFR levels (eGFR >= 90 ml/min per 1.73 m2), individuals with a mild to-severe eGFR decline (15 to 60 ml/min per 1.73 m2) were at significantly greater risk for CHD (HR 1.25, 95% CI 1.05-1.48; P = 0.011). Compared with individuals in the lowest tertile of BUN, those in the highest tertile were at significantly greater risk for CHD (HR 1.17, 95% CI 1.03-1.33; P = 0.014). In conclusion, a mild-to-severe decline in eGFR or a raised level of BUN might be associated with increased risk of incident CHD in middle-aged and elderly Chinese populations. PMID- 28855534 TI - Celecoxib normalizes the tumor microenvironment and enhances small nanotherapeutics delivery to A549 tumors in nude mice. AB - Barriers presented by the tumor microenvironment including the abnormal tumor vasculature and interstitial matrix invariably lead to heterogeneous distribution of nanotherapeutics. Inspired by the close association between cyclooxygenase-2 (COX-2) and tumor-associated angiogenesis, as well as tumor matrix formation, we proposed that tumor microenvironment normalization by COX-2 inhibitors might improve the distribution and efficacy of nanotherapeutics for solid tumors. The present study represents the first time that celecoxib, a special COX-2 inhibitor widely used in clinics, was explored to normalize the tumor microenvironment and to improve tumor nanotherapeutics delivery using a human-derived A549 tumor xenograft as the solid tumor model. Immunofluorescence staining of tumor slices demonstrated that oral celecoxib treatment at a dose of 200 mg/kg for two weeks successfully normalized the tumor microenvironment, including tumor-associated fibroblast reduction, fibronectin bundle disruption, tumor vessel normalization, and tumor perfusion improvement. Furthermore, it also significantly enhanced the in vivo accumulation and deep penetration of 22-nm micelles rather than 100-nm nanoparticles in tumor tissues by in vivo imaging and distribution experiments and improved the therapeutic efficacy of paclitaxel-loaded micelles in tumor xenograft-bearing mouse models in the pharmacodynamics experiment. As celecoxib is widely and safely used in clinics, our findings may have great potential in clinics to improve solid tumor treatment. PMID- 28855535 TI - Evaluation of the condyle remodeling after lateral arthroplasty in growing children with temporomandibular joint ankylosis. AB - Temporomandibular joint (TMJ) ankylosis in growing patients can cause both mouth opening limitation and jaw bone deformity. Lateral arthroplasty (LAP) can restore the medially displaced condyle and thus keep its growth potential. But can the condyle grow as normal is unknown. This study was to evaluate the long-term result after LAP in growing children. Patients from 2010 to 2014 were evaluated. Their CT data within 1 week after operation and during at least 1-year follow-ups were measured by ProPlan CMF 1.4 software. The condyle-ramus length of both sides and angles and the chin deviation before and after operation were compared. SPSS 17.0 software was used for statistical analysis. A total of 9 patients with a mean age of 10.2 years were included in the study. The mean follow-up period was 1.94 years. The mean condyle-ramus growth was 2.90 mm in the affected side and 2.50 mm in the unaffected side (P = 0.31). All of the affected side exhibited growth and remodeling of the condyle and ramus. All 9 cases had a mean chin deviation of 3.69 mm before operation and 2.92 mm during follow-ups (P = 0.16). The residual condyle grows after LAP, which can reduce the gravity of jawbone deformity. PMID- 28855536 TI - Transforming Growth Factor Beta is regulated by a Glucocorticoid-Dependent Mechanism in Denervation Mouse Bone. AB - Bone growth and remodeling is inhibited by denervation in adults and children, resulting in alterations of linear growth and bone mass and increased risk for osteoporosis and pathologic fractures. Transforming growth factor beta (TGF-beta) isoforms are a key group of growth factors that enhance bone formation. To explore the relation between denervation-induced reduction of bone formation and TGF-beta gene expression, we measured mRNA levels of TGF-beta in denervation mouse bone and found decreased mRNA levels of TGF-beta1, TGF-beta2 and TGF-beta3. These changes were accompanied by diminishing weight loss, bone mineral density (BMD), trabecular thickness, trabecular separation and trabecular number of femur and lumbar, serum osteocalcin, total calcium, intact parathyroid hormone, and increased serum C telopeptide. Recombinant human TGF-beta1 (rhTGF-beta1) prevented denervation-induced reduction of BMD further supporting our hypothesis that denervation-induced reduction of bone formation is a result of inhibition of TGF-beta gene expression. In addition, antiprogestins RU 38486 blunted the denervation-induced decrease in mRNA levels of TGF-beta group, while dexamethasone (DEX) decreased TGF-beta group mRNA levels in normal mice. Furthermore, the denervated-mice exhibited a threefold increase in plasma corticosterone. These results suggest that denervation-induced reduction of bone formation may be regulated by glucocorticoids via inhibition of TGF-beta gene expression at least in part. PMID- 28855537 TI - Activation of NADPH oxidases leads to DNA damage in esophageal cells. AB - Gastroesophageal reflux disease (GERD) is the strongest known risk factor for esophageal adenocarcinoma. In the center of tumorigenic events caused by GERD is repeated damage of esophageal tissues by the refluxate. In this study, we focused on a genotoxic aspect of exposure of esophageal cells to acidic bile reflux (BA/A). Analyzing cells generated from patients with Barrett's esophagus and human esophageal specimens, we found that BA/A cause significant DNA damage that is mediated by reactive-oxygen species. ROS originate from mitochondria and NADPH oxidases. We specifically identified NOX1 and NOX2 enzymes to be responsible for ROS generation. Inhibition of NOX2 and NOX1 with siRNA or chemical inhibitors significantly suppresses ROS production and DNA damage induced by BA/A. Mechanistically, our data showed that exposure of esophageal cells to acidic bile salts induces phosphorylation of the p47phox subunit of NOX2 and its translocation to the cellular membrane. This process is mediated by protein kinase C, which is activated by BA/A. Taken together, our studies suggest that inhibition of ROS induced by reflux can be a useful strategy for preventing DNA damage and decreasing the risk of tumorigenic transformation caused by GERD. PMID- 28855538 TI - Properties of residual titanium dioxide nanoparticles after extended periods of mixing and settling in synthetic and natural waters. AB - Titanium dioxide nanoparticle (TiO2 NP) discharged into water bodies can affect ecosystems and human health adversely. We studied the properties of residual TiO2 NPs with and without gentle mixing (to simulate a natural environment more closely) and after settling for 12-h periods. Surface complexation, dynamic particle size changes, and TiO2 NP destabilization in synthetic and lake waters were investigated. The accumulation of inert ions (Na+ and Cl-) in the diffuse layer which was not discussed in other studies was supposed to be the main reason that aggregation occurred slowly and continuously. PO43- stabilized and destabilized TiO2 NPs at 10 mM and 100 mM, respectively. Destabilization occurred because high ionic strength overwhelmed increased negative charges of TiO2 NPs by complexation with PO43-. TiO2 NP destabilization was achieved in approximately 12 h in synthetic and lake waters, and is attributed to the slow diffusion of ions into aggregates. Despite the presence of moderately high concentrations of natural organic matter, which tends to stabilize TiO2 NPs, the addition of 20 mM PO43- destabilized the TiO2 NPs in lake water. Smaller aggregate sizes formed compared with those before destabilization, which indicates that stable residual TiO2 NPs could exist in aquatic environments after extended periods. PMID- 28855539 TI - Influences of ethanol on the structure of toxic trans-crotonaldehyde in mitochondria coming from rat myocardium. AB - Inappropriate use of ethanol (EtOH) had led to noticeable health problems, but a beneficial phenomenon was found that EtOH displayed unique influences for toxic trans-crotonaldehyde (TCA) derived from mitochondrial lipid peroxidation. The influences of EtOH on the structure of TCA were systematically probed by UV-vis & Raman spectroscopy in the absence and presence of mitochondria, respectively. The maximum UV-vis peak at 301 nm of TCA was red shifted by hydroxyl (-OH) and methyl (-CH3) of EtOH, respectively. Raman stretching band of aldehyde (-CH=O) of TCA (TCA-CH=O) was split by the -CH3 of EtOH. The -CH3 increased TCA-CH=O stretching frequency while the -OH induced it. The more exposed -OH, the less stretching frequency. The ectopic -CH3 red shifted the UV-vis peak at 301 nm and Raman band of TCA-CH=O. In mitochondria, EtOH red shifted Raman stretching band of TCA-CH=O. Raman stretching bands of C-H, C-O and C-C of EtOH were red shifted, while Raman stretching bands of -CH2 and C-C-O of EtOH disappeared. The paper unearths the influences of EtOH to trap and transform the structure of TCA-CH=O. This discovery has an important contribution to eliminate TCA in order to protect and repair mtDNA by means of the decrease of 8-oxoG. PMID- 28855540 TI - Molecular determinants of proton selectivity and gating in the red-light activated channelrhodopsin Chrimson. AB - Channelrhodopsins are light-gated ion channels of green algae used for the precise temporal and spatial control of transmembrane ion fluxes. The channelrhodopsin Chrimson from Chlamydomonas noctigama allows unprecedented deep tissue penetration due to peak absorption at 590 nm. We demonstrate by electrophysiological recordings and imaging techniques that Chrimson is highly proton selective causing intracellular acidification in HEK cells that is responsible for slow photocurrent decline during prolonged illumination. We localized molecular determinants of both high proton selectivity and red light activation to the extracellular pore. Whereas exchange of Glu143 only drops proton conductance and generates an operational Na-channel with 590 nm activation, exchange of Glu139 in addition increased the open state lifetime and shifted the absorption hypsochromic by 70 nm. In conjunction with Glu300 in the center and Glu124 and Glu125 at the intracellular end of the pore, Glu139 contributes to a delocalized activation gate and stabilizes by long-range interaction counterion configuration involving protonation of Glu165 that we identified as a key determinant of the large opsin shift in Chrimson. PMID- 28855541 TI - Determination of the physiological and pathological roles of E2F3 in adult tissues. AB - While genetically engineered mice have made an enormous contribution towards the elucidation of human disease, it has hitherto not been possible to tune up or down the level of expression of any endogenous gene. Here we describe compound genetically modified mice in which expression of the endogenous E2f3 gene may be either reversibly elevated or repressed in adult animals by oral administration of tetracycline. This technology is, in principle, applicable to any endogenous gene, allowing direct determination of both elevated and reduced gene expression in physiological and pathological processes. Applying this switchable technology to the key cell cycle transcription factor E2F3, we demonstrate that elevated levels of E2F3 drive ectopic proliferation in multiple tissues. By contrast, E2F3 repression has minimal impact on tissue proliferation or homeostasis in the majority of contexts due to redundancy of adult function with E2F1 and E2F2. In the absence of E2F1 and E2F2, however, repression of E2F3 elicits profound reduction of proliferation in the hematopoietic compartments that is rapidly lethal in adult animals. PMID- 28855542 TI - Microbial Communities Associated with Primary and Metastatic Head and Neck Squamous Cell Carcinoma - A High Fusobacterial and Low Streptococcal Signature. AB - Given the potential relationship between head and neck squamous cell carcinoma (HNSCC) and microbial dysbiosis, we profiled the microbiome within healthy normal and tumorous (primary and metastatic) human tissues from the oral cavity, larynx pharynx, and lymph nodes using 16S rRNA sequencing. Alpha and beta diversity analyses revealed that normal tissues had the greatest richness in community diversity, while the metastatic populations were most closely related to one another. Compared to the normal, the microbiota associated with tumors supported altered abundances in the phyla Fusobacteria, Firmicutes, Actinobacteria and Proteobacteria. Most notably, the relative abundance of Fusobacterium increased whereas Streptococcus decreased in both primary and metastatic samples. Principal coordinate analysis indicated a separation and clustering of samples by tissue status. However, random forest analysis revealed that the microbial profiles alone were a poor predictor for primary and metastatic HNSCC samples. Here, we report that the microbial communities residing in the tumorous tissues are compositionally distinct compared to the normal adjacent tissues. However, likely due to the smaller sample size and sample-to-sample heterogeneity, our prediction models were not able to distinguish by sample types. This work provides a foundation for future studies aimed at understanding the role of the dysbiotic tissue microbiome in HNSCC. PMID- 28855543 TI - Improved vessel painting with carbocyanine dye-liposome solution for visualisation of vasculature. AB - Vessel painting is one of the most accessible and cost-effective techniques for visualising vasculature by fluorescence microscopy. In this method, the hydrophobic carbocyanine dye DiIC18 labels the plasma membrane via insertion of its alkyl chains into the lipid bilayer. A major disadvantage of this procedure is that it does not stain veins and some microvessels in mouse brain. Furthermore, DiIC18 molecules can aggregate during perfusion, thereby occluding arteries and reducing the success rate and reproducibility of the experiment. To overcome these problems, we developed an improved vessel painting procedure that employs neutral liposomes (NLs) and DiIC12. NLs prevented DiI aggregation under physiological conditions whereas DiIC12 showed enhanced dye incorporation into liposomes and consequently increased staining intensity. Using this method, we successfully labelled all major blood vessel types in the mouse brain, including both veins and microvessels. Thus, liposome-mediated vessel painting is a simple and efficient method for visualising vasculature. PMID- 28855545 TI - Influence of oxalate ligand functionalization on Co/ZSM-5 activity in Fischer Tropsch synthesis and hydrodeoxygenation of oleic acid into hydrocarbon fuels. AB - Achieving high degree of active metal dispersions at the highest possible metal loading and high reducibility of the metal remains a challenge in Fischer Tropsch synthesis (FTS) as well as in hydrogeoxygenation (HDO) . This study therefore reports the influence of oxalic acid (OxA) functionalization on the metal dispersion, reducibility and activity of Co supported ZSM-5 catalyst in FTS and HDO of oleic acid into paraffin biofuel. The Brunauer-Emmett-Teller (BET) results showed that cobalt oxalate supported ZSM-5 catalyst (CoOx/ZSM-5) synthesized from the incorporation of freshly prepared cobalt oxalate complex into ZSM-5 displayed increase in surface area, pore volume and average pore size while the nonfunctionalized cobalt supported on ZSM-5 (Co/ZSM-5) catalyst showed reduction in those properties. Furthermore, both XRD and XPS confirmed the presence of Co degrees formed from the decomposition of CoOx during calcination of CoOx/ZSM-5 under inert atmosphere. The HRTEM showed that Co species average particle sizes were smaller in CoOx/ZSM-5 than in Co/ZSM-5, and in addition, CoOx/ZSM-5 shows a clear higher degree of active metal dispersion. The FTS result showed that at CO conversion over Co/ZSM-5 and CoOx/ZSM-5 catalysts were 74.28% and 94.23% and their selectivity to C5+ HC production were 63.15% and 75.4%, respectively at 4 h TOS. The HDO result also showed that the CoOx/ZSM-5 has higher OA conversion of 92% compared to 59% over Co/ZSM-5. In addition CoOx/ZSM-5 showed higher HDO and isomerization activities compared to Co/ZSM-5. PMID- 28855544 TI - Prostaglandin E1 Attenuates Pulmonary Artery Remodeling by Activating Phosphorylation of CREB and the PTEN Signaling Pathway. AB - The depletion of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and phosphatase and tensin homolog (PTEN) is the critical mediator of pulmonary arterial hypertension (PAH). We hypothesized that the activation of phosphorylated CREB (pCREB) and PTEN could inhibit the AKT signaling pathway to attenuate pulmonary arterial remodeling in rats with monocrotaline-induced PAH. We observed decreased PTEN and pCREB in idiopathic PAH versus control tissue. We reduced PTEN using small interfering RNA in human control pulmonary arterial smooth muscle cells (PASMCs) and observed an increase in pAKT. Consistent with PTEN knockdown in PASMCs, prostaglandin E1 (PGE1) induced pCREB expression to stimulate PTEN protein expression and inhibited pAKT in a time- and dose dependent manner. The enhanced proliferation and migration of PASMCs following PTEN knockdown were significantly inhibited by PGE1 treatment. The PGE1-induced elevation of PTEN expression in PTEN-depleted PASMCs was decreased by the application of a PKA inhibitor and a CBP-CREB interaction inhibitor. Supplementation with a novel emulsion composition comprising PGE1 in rats with monocrotaline-induced PAH prevented pulmonary arterial remodeling and improved hemodynamics via the induced expression of PTEN. We conclude that PGE1 recruits pCREB/PTEN to decrease the migration and proliferation of PASMCs associated with PAH. This finding elucidates a relevant underlying mechanism of the PGE1/CREB/PTEN signaling pathway to prevent progressive PAH. PMID- 28855546 TI - The effect of topical administration of cyclopentolate on ocular biometry: An analysis for mouse and human models. AB - Mydriasis with muscarinic antagonists have been used routinely prior to retinal examination and sometimes prior to refractive measurements of the mouse eye. However, biometric changes during topical administration of muscarinic antagonists have not been fully investigated in mice and humans. We found that the mouse eyes treated with cyclopentolate developed a hyperopia with a reduction in both the vitreous chamber depth and axial length. In humans, prior to the cyclopentolate treatment, a 6D accommodative stimulus produced a myopic shift with a reduced anterior chamber depth, choroidal thickness and anterior lens radius of curvature and an increase in lens thickness. After the cyclopentolate treatment, human eyes developed a hyperopic shift with an increased anterior chamber depth and anterior lens radius of curvature and a reduced lens thickness. Therefore, the biometric changes associated with this hyperopic shift were mainly located in the posterior segment of the eye in mice. However, it is the anterior segment of the eye that plays a main role in the hyperopic shift in human subjects. These results further indicate that mouse eyes do not have accommodation which needs to be taken into account when they are used for the study of human refractive errors. PMID- 28855548 TI - Spontaneous establishing of cross-modal stimulus equivalence in a beluga whale. AB - Beluga whales use calls to convey various information to group members. Is this communication similar to humans? We addressed this question by using the framework of stimulus equivalence. Stimulus equivalence consists of three phases: if the animal is trained to match A to B and B to C, symmetry is demonstrated by matching BA and CB, transitivity by matching AC, and equivalence by matching CA. We tested the spontaneous establishment of cross-modal stimulus equivalence between visual and auditory symbols in a beluga whale nicknamed Nack. Nack could make symmetrical choices in novel objects untrained. Moreover, visual/auditory cross-modal transitivity was formed spontaneously. Nack succeeded in six tasks, including an untrained task concerning stimulus equivalence. We conclude that Nack spontaneously formed cross-modal stimulus equivalence between visual and auditory symbols. Cross-modal stimulus equivalence was considered to exist only in humans because of linguistic faculty; however, Nack exhibited the same understanding as humans. PMID- 28855547 TI - Tylophorine Analogs Allosterically Regulates Heat Shock Cognate Protein 70 And Inhibits Hepatitis C Virus Replication. AB - Tylophorine analogs have been shown to exhibit diverse activities against cancer, inflammation, arthritis, and lupus in vivo. In this study, we demonstrated that two tylophorine analogs, DCB-3503 and rac-cryptopleurine, exhibit potent inhibitory activity against hepatitis C virus (HCV) replication in genotype 1b Con 1 isolate. The inhibition of HCV replication is at least partially mediated through cellular heat shock cognate protein 70 (Hsc70). Hsc70 associates with the HCV replication complex by primarily binding to the poly U/UC motifs in HCV RNA. The interaction of DCB-3503 and rac-cryptopleurine with Hsc70 promotes the ATP hydrolysis activity of Hsc70 in the presence of the 3' poly U/UC motif of HCV RNA. Regulating the ATPase activity of Hsc70 may be one of the mechanisms by which tylophorine analogs inhibit HCV replication. This study demonstrates the novel anti-HCV activity of tylophorine analogs. Our results also highlight the importance of Hsc70 in HCV replication. PMID- 28855549 TI - A signal-based method for finding driver modules of breast cancer metastasis to the lung. AB - Tumor metastasis is mainly caused by somatic genomic alterations (SGAs) that perturb pathways regulating metastasis-relevant activities and thus help the primary tumor to adapt to the new microenvironment. Identifying drivers of metastasis, i.e. SGAs, sheds light on the metastasis mechanism and provides guidance for targeted therapy. In this paper, we introduce a novel method to search for SGAs driving breast cancer metastasis to the lung. First, we search for transcriptomic modules with genes that are differentially expressed in breast cell lines with strong metastatic activities to the lung and co-expressed in a large number of breast tumors. Then, for each transcriptomic module, we search for a set of SGA genes (driver modules) such that genes in each driver module carry a common signal regulating the transcriptomic module. Evaluations indicate that many genes in driver modules are indeed related to metastasis, and our methods have identified many new driver candidates. We further choose two novel metastatic driver genes, BCL2L11 and CDH9, for in vitro verification. The wound healing assay reveals that inhibiting either BCL2L11 or CDH9 will enhance the migration of cell lines, which provides evidence that these two genes are suppressors of tumor metastasis. PMID- 28855550 TI - Social rivalry triggers visual attention in children with autism spectrum disorders. AB - Visual social attention is central to social functioning and learning and may act as a reinforcer. Social rivalry, which occurs when an individual is excluded from dyadic interactions, can promote interspecific learning by triggering attention. We applied it to an animal-assisted intervention, where the behaviour of ASD children was compared between an experimental (attention shift of the animal trainer from the dog-child to the dog only) and a control (attention maintained on the dyad) groups (study 1). The results show that ASD children are sensitive to the direction of (visual) social attention and may act, physically and visually, in order to regain it. When the animal trainer concentrated on the dog, the overall visual attention of the ASD children increased, suggesting a heightened awareness towards their environment. They oriented more towards the animal trainer and the dog, contrarily to the control group. The repetition of the procedure was even associated with increased joint attention with the animal trainer (study 2). Thus, ASD children do care about and seek human visual attention. They show an ability to adapt their social behaviour, which questions whether their known deficits in social competencies are hard wired or whether the deficits are in their expression. PMID- 28855551 TI - Intertidal marine sediment harbours Actinobacteria with promising bioactive and biosynthetic potential. AB - Actinobacteria are the major source of bioactive natural products that find their value in research and drug discovery programmes. Antimicrobial resistance and the resulting high demand for novel antibiotics underscore the need for exploring novel sources of these bacteria endowed with biosynthetic potential. Intertidal ecosystems endure regular periods of immersion and emersion, and represent an untapped source of Actinobacteria. In this study, we studied the diversity and biosynthetic potential of cultivable Actinobacteria from intertidal sediments of Diu Island in the Arabian Sea. A total of 148 Actinobacteria were selectively isolated using a stamping method with eight isolation media. Isolates were grouped into OTUs based on their 16S rRNA gene sequence, and categorized within actinobacterial families such as Glycomycetaceae, Micromonosporaceae, Nocardiaceae, Nocardiopsaceae, Pseudonocardiaceae, Streptomycetaceae, and Thermomonosporaceae. The biosynthetic potential of the Actinobacteria, necessary for secondary metabolite biosynthesis, was screened and confirmed by extensive fingerprinting approaches based on genes coding for polyketide synthases and nonribosomal peptide synthetases. The observed biosynthetic potential was correlated with the antibacterial activity exhibited by these isolates in laboratory conditions. Ultimately, the results demonstrate that intertidal sediment is a rich source of diverse cultivable Actinobacteria with high potential to synthesize novel bioactive compounds in their genomes. PMID- 28855552 TI - Visible light high-resolution imaging system for large aperture telescope by liquid crystal adaptive optics with phase diversity technique. AB - There are more than eight large aperture telescopes (larger than eight meters) equipped with adaptive optics system in the world until now. Due to the limitations such as the difficulties of increasing actuator number of deformable mirror, most of them work in the infrared waveband. A novel two-step high resolution optical imaging approach is proposed by applying phase diversity (PD) technique to the open-loop liquid crystal adaptive optics system (LC AOS) for visible light high-resolution adaptive imaging. Considering the traditional PD is not suitable for LC AOS, the novel PD strategy is proposed which can reduce the wavefront estimating error caused by non-modulated light generated by liquid crystal spatial light modulator (LC SLM) and make the residual distortions after open-loop correction to be smaller. Moreover, the LC SLM can introduce any aberration which realizes the free selection of phase diversity. The estimating errors are greatly reduced in both simulations and experiments. The resolution of the reconstructed image is greatly improved on both subjective visual effect and the highest discernible space resolution. Such technique can be widely used in large aperture telescopes for astronomical observations such as terrestrial planets, quasars and also can be used in other applications related to wavefront correction. PMID- 28855553 TI - Toxic fluoride gas emissions from lithium-ion battery fires. AB - Lithium-ion battery fires generate intense heat and considerable amounts of gas and smoke. Although the emission of toxic gases can be a larger threat than the heat, the knowledge of such emissions is limited. This paper presents quantitative measurements of heat release and fluoride gas emissions during battery fires for seven different types of commercial lithium-ion batteries. The results have been validated using two independent measurement techniques and show that large amounts of hydrogen fluoride (HF) may be generated, ranging between 20 and 200 mg/Wh of nominal battery energy capacity. In addition, 15-22 mg/Wh of another potentially toxic gas, phosphoryl fluoride (POF3), was measured in some of the fire tests. Gas emissions when using water mist as extinguishing agent were also investigated. Fluoride gas emission can pose a serious toxic threat and the results are crucial findings for risk assessment and management, especially for large Li-ion battery packs. PMID- 28855554 TI - Frequency sensitivity in mammalian hearing from a fundamental nonlinear physics model of the inner ear. AB - A dominant view holds that the outer and middle ear are the determining factors for the frequency dependence of mammalian hearing sensitivity, but this view has been challenged. In the ensuing debate, there has been a missing element regarding in what sense and to what degree the biophysics of the inner ear might contribute to this frequency dependence. Here, we show that a simple model of the inner ear based on fundamental physical principles, reproduces, alone, the experimentally observed frequency dependence of the hearing threshold. This provides direct cochlea modeling support of the possibility that the inner ear could have a substantial role in determining the frequency dependence of mammalian hearing. PMID- 28855555 TI - Alcohols react with MCM-41 at room temperature and chemically modify mesoporous silica. AB - Mesoporous silica has received much attention due to its well-defined structural order, high surface area, and tunable pore diameter. To successfully employ mesoporous silica for nanotechnology applications it is important to consider how it is influenced by solvent molecules due to the fact that most preparation procedures involve treatment in various solvents. In the present work we contribute to this important topic with new results on how MCM-41 is affected by a simple treatment in alcohol at room temperature. The effects of alcohol treatment are characterized by TGA, FTIR, and sorption calorimetry. The results are clear and show that treatment of MCM-41 in methanol, ethanol, propanol, butanol, pentanol, or octanol at room temperature introduces alkoxy groups that are covalently bound to the silica surface. It is shown that alcohol treated MCM 41 becomes more hydrophobic and that this effect is sequentially more prominent going from methanol to octanol. Chemical formation of alkoxy groups onto MCM-41 occurs both for calcined and hydroxylated MCM-41 and the alkoxy groups are hydrolytically unstable and can be replaced by silanol groups after exposure to water. The results are highly relevant for mesoporous silica applications that involve contact or treatment in protic solvents, which is very common. PMID- 28855556 TI - Continuous coloured light altered human brain haemodynamics and oxygenation assessed by systemic physiology augmented functional near-infrared spectroscopy. AB - Exposure to artificial coloured light is unavoidable in our modern life, but we are only just beginning to understand the impact of coloured light on human physiology. The aim of the present study was to determine effects of coloured light exposure on human systemic and brain physiology using systemic physiology augmented functional near-infrared spectroscopy (SPA-fNIRS). We measured changes in haemoglobin concentrations and tissue oxygen saturation in the left and right prefrontal cortices (L-PFC, R-PFC) by fNIRS, and also recorded skin conductance (SC), partial pressure of end-tidal CO2 (PETCO2), and heart-rate variability variables. 17 healthy adults (median age: 29 years, range: 25-65 years, 6 women) were exposed to blue, red, green, or yellow light for 10 minutes. Pre-light and post-light conditions were in darkness. In the L-PFC the yellow evoked a brain activation. SC and PETCO2 did not change during any of the coloured light exposures, but SC increased and PETCO2 decreased for all colours (except green) in the post-light period. Changes in L-PFC haemoglobin concentration were also observed during the post-light period but have to be interpreted with care, because heart rate and SC increased while PETCO2 decreased. The detected effects are potentially of high relevance for choosing room lighting and may possibly be applied therapeutically. PMID- 28855557 TI - Diarrhea Morbidities in Small Areas: Accounting for Non-Stationarity in Sociodemographic Impacts using Bayesian Spatially Varying Coefficient Modelling. AB - Model-based estimation of diarrhea risk and understanding the dependency on sociodemographic factors is important for prioritizing interventions. It is unsuitable to calibrate regression model with a single set of coefficients, especially for large spatial domains. For this purpose, we developed a Bayesian hierarchical varying coefficient model to account for non-stationarity in the covariates. We used the integrated nested Laplace approximation for parameter estimation. Diarrhea morbidities in Ghana motivated our empirical study. Results indicated improvement regarding model fit and epidemiological benefits. The findings highlighted substantial spatial, temporal, and spatio-temporal heterogeneities in both diarrhea risk and the coefficients of the sociodemographic factors. Diarrhea risk in peri-urban and urban districts were 13.2% and 10.8% higher than rural districts, respectively. The varying coefficient model indicated further details, as the coefficients varied across districts. A unit increase in the proportion of inhabitants with unsafe liquid waste disposal was found to increase diarrhea risk by 11.5%, with higher percentages within the south-central parts through to the south-western parts. Districts with safe and unsafe drinking water sources unexpectedly had a similar risk, as were districts with safe and unsafe toilets. The findings show that site specific interventions need to consider the varying effects of sociodemographic factors. PMID- 28855558 TI - Mastering the Wrinkling of Self-supported Graphene. AB - We present an approach that allows for the preparation of well-defined large arrays of graphene wrinkles with predictable geometry. Chemical vapor deposition grown graphene transferred onto hexagonal pillar arrays of SiO2 with sufficiently small interpillar distance forms a complex network of two main types of wrinkle arrangements. The first type is composed of arrays of aligned equidistantly separated parallel wrinkles propagating over large distances, and originates from line interfaces in the graphene, such as thin, long wrinkles and graphene grain boundaries. The second type of wrinkle arrangement is composed of non-aligned short wrinkles, formed in areas without line interfaces. Besides the presented hybrid graphene topography with distinct wrinkle geometries induced by the pre patterned substrate, the graphene layers are suspended and self-supporting, exhibiting large surface area and negligible doping effects from the substrate. All these properties make this wrinkled graphene a promising candidate for a material with enhanced chemical reactivity useful in nanoelectronic applications. PMID- 28855559 TI - Durable superhydrophobic surfaces made by intensely connecting a bipolar top layer to the substrate with a middle connecting layer. AB - This study reported a simple fabrication method for a durable superhydrophobic surface. The superhydrophobic top layer of the durable superhydrophobic surface was connected intensely to the substrate through a middle connecting layer. Glycidoxypropyltrimethoxysilane (KH-560) after hydrolysis was used to obtain a hydrophilic middle connecting layer. It could be adhered to the hydrophilic substrate by covalent bonds. Ring-open reaction with octadecylamine let the KH 560 middle layer form a net-like structure. The net-like sturcture would then encompass and station the silica particles that were used to form the coarse micro structures, intensely to increase the durability. The top hydrophobic layer with nano-structures was formed on the KH-560 middle layer. It was obtained by a bipolar nano-silica solution modified by hexamethyldisilazane (HMDS). This layer was connected to the middle layer intensely by the polar Si hydroxy groups, while the non-polar methyl groups on the surface, accompanied by the micro and nano structures, made the surface rather hydrophobic. The covalently interfacial interactions between the substrate and the middle layer, and between the middle layer and the top layer, strengthened the durability of the superhydrophobic surface. The abrasion test results showed that the superhydrophobic surface could bear 180 abrasion cycles on 1200 CW sandpaper under 2 kPa applied pressure. PMID- 28855560 TI - Elastin is Localised to the Interfascicular Matrix of Energy Storing Tendons and Becomes Increasingly Disorganised With Ageing. AB - Tendon is composed of fascicles bound together by the interfascicular matrix (IFM). Energy storing tendons are more elastic and extensible than positional tendons; behaviour provided by specialisation of the IFM to enable repeated interfascicular sliding and recoil. With ageing, the IFM becomes stiffer and less fatigue resistant, potentially explaining why older tendons become more injury prone. Recent data indicates enrichment of elastin within the IFM, but this has yet to be quantified. We hypothesised that elastin is more prevalent in energy storing than positional tendons, and is mainly localised to the IFM. Further, we hypothesised that elastin becomes disorganised and fragmented, and decreases in amount with ageing, especially in energy storing tendons. Biochemical analyses and immunohistochemical techniques were used to determine elastin content and organisation, in young and old equine energy storing and positional tendons. Supporting the hypothesis, elastin localises to the IFM of energy storing tendons, reducing in quantity and becoming more disorganised with ageing. These changes may contribute to the increased injury risk in aged energy storing tendons. Full understanding of the processes leading to loss of elastin and its disorganisation with ageing may aid in the development of treatments to prevent age related tendinopathy. PMID- 28855561 TI - Diversification dynamics of rhynchostomatian ciliates: the impact of seven intrinsic traits on speciation and extinction in a microbial group. AB - Ciliates are a suitable microbial model to investigate trait-dependent diversification because of their comparatively complex morphology and high diversity. We examined the impact of seven intrinsic traits on speciation, extinction, and net-diversification of rhynchostomatians, a group of comparatively large, predatory ciliates with proboscis carrying a dorsal brush (sensoric structure) and toxicysts (organelles used to kill the prey). Bayesian estimates under the binary-state speciation and extinction model indicate that two types of extrusomes and two-rowed dorsal brush raise diversification through decreasing extinction. On the other hand, the higher number of contractile vacuoles and their dorsal location likely increase diversification via elevating speciation rate. Particular nuclear characteristics, however, do not significantly differ in their diversification rates and hence lineages with various macronuclear patterns and number of micronuclei have similar probabilities to generate new species. Likelihood-based quantitative state diversification analyses suggest that rhynchostomatians conform to Cope's rule in that their diversity linearly grows with increasing body length and relative length of the proboscis. Comparison with other litostomatean ciliates indicates that rhynchostomatians are not among the cladogenically most successful lineages and their survival over several hundred million years could be associated with their comparatively large and complex bodies that reduce the risk of extinction. PMID- 28855562 TI - Customized binary and multi-level HfO2-x-based memristors tuned by oxidation conditions. AB - The memristor is a promising candidate for the next generation non-volatile memory, especially based on HfO2-x, given its compatibility with advanced CMOS technologies. Although various resistive transitions were reported independently, customized binary and multi-level memristors in unified HfO2-x material have not been studied. Here we report Pt/HfO2-x/Ti memristors with double memristive modes, forming-free and low operation voltage, which were tuned by oxidation conditions of HfO2-x films. As O/Hf ratios of HfO2-x films increase, the forming voltages, SET voltages, and Roff/Ron windows increase regularly while their resistive transitions undergo from gradually to sharply in I/V sweep. Two memristors with typical resistive transitions were studied to customize binary and multi-level memristive modes, respectively. For binary mode, high-speed switching with 103 pulses (10 ns) and retention test at 85 degrees C (>104 s) were achieved. For multi-level mode, the 12-levels stable resistance states were confirmed by ongoing multi-window switching (ranging from 10 ns to 1 MUs and completing 10 cycles of each pulse). Our customized binary and multi-level HfO2-x based memristors show high-speed switching, multi-level storage and excellent stability, which can be separately applied to logic computing and neuromorphic computing, further suitable for in-memory computing chip when deposition atmosphere may be fine-tuned. PMID- 28855563 TI - Synchronized Activity in The Main and Accessory Olfactory Bulbs and Vomeronasal Amygdala Elicited by Chemical Signals in Freely Behaving Mice. AB - Chemosensory processing in mammals involves the olfactory and vomeronasal systems, but how the activity of both circuits is integrated is unknown. In our study, we recorded the electrophysiological activity in the olfactory bulbs and the vomeronasal amygdala in freely behaving mice exploring a battery of neutral and conspecific stimuli. The exploration of stimuli, including a neutral stimulus, induced synchronic activity in the olfactory bulbs characterized by a dominant theta rhythmicity, with specific theta-gamma coupling, distinguishing between vomeronasal and olfactory structures. The correlated activation of the bulbs suggests a coupling between the stimuli internalization in the nasal cavity and the vomeronasal pumping. In the amygdala, male stimuli are preferentially processed in the medial nucleus, whereas female cues induced a differential response in the posteromedial cortical amygdala. Thus, particular theta-gamma patterns in the olfactory network modulates the integration of chemosensory information in the amygdala, allowing the selection of an appropriate behaviour. PMID- 28855564 TI - Correlation between particle size/domain structure and magnetic properties of highly crystalline Fe3O4 nanoparticles. AB - Highly crystalline single-domain magnetite Fe3O4 nanoparticles (NPs) are important, not only for fundamental understanding of magnetic behaviour, but also for their considerable potential applications in biomedicine and industry. Fe3O4 NPs with sizes of 10-300 nm were systematically investigated to reveal the fundamental relationship between the crystal domain structure and the magnetic properties. The examined Fe3O4 NPs were prepared under well-controlled crystal growth conditions using a large-scale liquid precipitation method. The crystallite size of cube-like NPs estimated from X-ray diffraction pattern increased linearly as the particle size (estimated by transmission electron microscopy) increased from 10 to 64.7 nm, which indicates that the NPs have a single-domain structure. This was further confirmed by the uniform lattice fringes. The critical size of approximately 76 nm was obtained by correlating particle size with both crystallite size and magnetic coercivity; this was reported for the first time in this study. The coercivity of cube-like Fe3O4 NPs increased to a maximum of 190 Oe at the critical size, which suggests strong exchange interactions during spin alignment. Compared with cube-like NPs, sphere like NPs have lower magnetic coercivity and remanence values, which is caused by the different orientations of their polycrystalline structure. PMID- 28855565 TI - Genome-wide genetic structure and differentially selected regions among Landrace, Erhualian, and Meishan pigs using specific-locus amplified fragment sequencing. AB - As typical Chinese indigenous pig breeds, Erhualian and Meishan have been widely used to produce new strain or breed in the world. However, the genetic basis of characteristics of these pig breeds is still limited. Moreover, considering cost and output of sequencing, it is necessary to further develop cost-effective method for pig genome screening. To contribute on this issue, we developed a SLAF seq (specific-locus amplified fragment sequencing) method for pigs and applied it to analyze the genetic difference among Landrace, Erhualian, and Meishan pigs. A total of 453.75 million reads were produced by SLAF-seq. After quality-control, 165,670 SNPs (single nucleotide polymorphisms) were used in further analysis. The results showed that Landrace had distinct genetic relationship compared to Erhualian (F ST = 0.5480) and Meishan (F ST = 0.5800), respectively, while Erhualian and Meishan held the relatively close genetic relationship (F ST = 0.2335). Furthermore, a genome-wide scanning revealed 268 differentially selected regions (DSRs) with 855 genes and 256 DSRs with 347 genes between Landrace and the two Chinese indigenous pig breeds and between Erhualian and Meishan, respectively. This study provides a new cost-effective method for pig genome study and might contribute to a better understanding on the formation mechanism of genetic difference among pigs with different geographical origins. PMID- 28855566 TI - Regulation of focal adhesion turnover in SDF-1alpha-stimulated migration of mesenchymal stem cells in neural differentiation. AB - Directed migration of the transplanted mesenchymal stem cells (MSCs) to the lesion sites plays a pivotal role in the efficacy of cell-based therapy. Our previous study demonstrates that MSCs under varying neural differentiation states possess different migratory capacities in response to chemoattractants. However, the underlying mechanism has not been fully addressed. Herein, we show that the assembly and turnover of focal adhesions, the phosphorylation of FAK and paxillin, and the reorganisation of F-actin in MSCs are closely related to their differentiation states in response to SDF-1alpha. Upon SDF-1alpha stimulation, FAs turnover more rapidly with the most obvious reduction in the existing time of FAs in MSCs of 24-h preinduction that exhibit the most effective migration towards SDF-1alpha. Further, we confirm that PI3K/Akt and MAPK pathways participate in the regulation of SDF-1alpha-induced cell migration and FA assembly, and moreover, that the regulatory effects vary greatly depending on the differentiation states. Collectively, these results demonstrate that FA assembly and turnover, which is accompanied with F-actin reorganisation in response to SDF 1alpha, correlates closely with the differentiation states of MSCs, which might contribute to the different chemotactic responses of these cells, and thus help develop new strategy to improve the efficacy of MSCs-based therapy. PMID- 28855567 TI - Designing artificial 2D crystals with site and size controlled quantum dots. AB - Ordered arrays of quantum dots in two-dimensional (2D) materials would make promising optical materials, but their assembly could prove challenging. Here we demonstrate a scalable, site and size controlled fabrication of quantum dots in monolayer molybdenum disulfide (MoS2), and quantum dot arrays with nanometer scale spatial density by focused electron beam irradiation induced local 2H to 1T phase change in MoS2. By designing the quantum dots in a 2D superlattice, we show that new energy bands form where the new band gap can be controlled by the size and pitch of the quantum dots in the superlattice. The band gap can be tuned from 1.81 eV to 1.42 eV without loss of its photoluminescence performance, which provides new directions for fabricating lasers with designed wavelengths. Our work constitutes a photoresist-free, top-down method to create large-area quantum dot arrays with nanometer-scale spatial density that allow the quantum dots to interfere with each other and create artificial crystals. This technique opens up new pathways for fabricating light emitting devices with 2D materials at desired wavelengths. This demonstration can also enable the assembly of large scale quantum information systems and open up new avenues for the design of artificial 2D materials. PMID- 28855568 TI - Plasma biomarker proteins for detection of human growth hormone administration in athletes. AB - Human growth hormone (GH) is a naturally occurring hormone secreted by the pituitary gland with anabolic and growth-promoting activities. Since an increased availability of recombinant GH (rGH) for the treatment of GH-deficient patients, GH has been abused in sports and it is prohibited. "GH-isoform" and "biomarkers" tests are currently available for detection of GH abuse in sports, however both methods suffer from shortcomings. Here, we report on a proteomic approach to search for novel protein biomarkers associated with rGH administration in non elite athletes. In this study, participants received either placebo or rGH for 8 weeks, and were followed over a 6-week washout period. We used 2-D DIGE and iTRAQ LC-MS/MS analyses to expose rGH-dependent marker proteins. Eight rGH-dependent plasma proteins namely apolipoproptein-L1, alpha-HS-glycoprotein, vitamin D binding protein, afamin, insulin-like growth factor-binding protein-3, insulin like growth factor-binding protein-ALS, lumican and extracellular matrix proteins 1 were identified. Apolipoprotein L1 and alpha-HS-glycoprotein were validated by Western blots to confirm their identities and expression patterns in rGH- and placebo-treated subject cohorts. Independent confirmation of these putative GH responsive biomarkers would be of value for clinical practices and may have sports anti-doping utility. PMID- 28855569 TI - Transport and excitations in a negative-U quantum dot at the LaAlO3/SrTiO3 interface. AB - In a solid-state host, attractive electron-electron interactions can lead to the formation of local electron pairs which play an important role in the understanding of prominent phenomena such as high T c superconductivity and the pseudogap phase. Recently, evidence of a paired ground state without superconductivity was demonstrated at the level of single electrons in quantum dots at the interface of LaAlO3 and SrTiO3. Here, we present a detailed study of the excitation spectrum and transport processes of a gate-defined LaAlO3/SrTiO3 quantum dot exhibiting pairing at low temperatures. For weak tunneling, the spectrum agrees with calculations based on the Anderson model with a negative effective charging energy U, and exhibits an energy gap corresponding to the Zeeman energy of the magnetic pair-breaking field. In contrast, for strong coupling, low-bias conductance is enhanced with a characteristic dependence on temperature, magnetic field and chemical potential consistent with the charge Kondo effect.Complex oxide devices provide a platform for studying and making use of strongly correlated electronic behavior. Here the authors present a LaAlO3/SrTiO3 quantum dot and show that its transport behavior is consistent with the presence of attractive electron interactions and the charge Kondo effect. PMID- 28855570 TI - Metabotropic glutamate receptor 5 deficiency inhibits neutrophil infiltration after traumatic brain injury in mice. AB - Both brain native inflammatory cells and infiltrated peripheral white blood cells (WBCs) are primary participants in the brain inflammatory damage post-TBI. Metabotropic glutamate receptor 5 (mGluR5) has been reported to regulate microglias and astrocytes to affect inflammation after TBI, but its effect on modulating infiltrated peripheral WBCs remains unclear. In a mouse moderate TBI model, we found that mGluR5 knockout (KO) significantly reduced neutrophil infiltration and inflammatory cytokine expression in the brain at 24 hours post TBI, which was accompanied by improved neurological dysfunction. Further investigation indicated that mGluR5 KO reduced the permeability of blood-brain barrier (BBB), the entrance for neutrophils to enter brain, and markedly decreased the mRNA levels of neutrophil-associated chemokines in brain tissue, including CXCL1, CXCL2, CCL2, CCL4 and CCL5. Using brain microvascular endothelial cells (BMECs), neutrophils and a BBB model in vitro, we confirmed the inhibitory effect of mGluR5 deficiency on neutrophil infiltration and demonstrated that blockade of protein kinase C (PKC) signaling was involved in it. These results provide insight into the role of mGluR5 in the regulation of inflammation in the acute phase of TBI, which may provide novel clues for TBI therapy. PMID- 28855571 TI - Identifying Defects with Guided Algorithms in Bragg Coherent Diffractive Imaging. AB - Crystallographic defects such as dislocations can significantly alter material properties and functionality. However, imaging these imperfections during operation remains challenging due to the short length scales involved and the reactive environments of interest. Bragg coherent diffractive imaging (BCDI) has emerged as a powerful tool capable of identifying dislocations, twin domains, and other defects in 3D detail with nanometer spatial resolution within nanocrystals and grains in reactive environments. However, BCDI relies on phase retrieval algorithms that can fail to accurately reconstruct the defect network. Here, we use numerical simulations to explore different guided phase retrieval algorithms for imaging defective crystals using BCDI. We explore different defect types, defect densities, Bragg peaks, and guided algorithm fitness metrics as a function of signal-to-noise ratio. Based on these results, we offer a general prescription for phasing of defective crystals with no a priori knowledge. PMID- 28855572 TI - Tribochemistry of adaptive integrated interfaces at boundary lubricated contacts. AB - Understanding how an adaptive integrated interface between lubricant additives and solid contacts works will enable improving the wear and friction of moving engine components. This work represents the comprehensive characterization of compositional and structural orientation at the sliding interface from the perspective of surface/interface tribochemistry. The integrated interface of a lubricant additive-solid resulting from the friction testing of Graphite-like carbon (GLC) and PVD-CrN coated rings sliding against cast iron under boundary lubrication was studied. The results indicate that in the case of the CrN/cast iron pair the antiwear and friction behavior were very strongly dependent upon lubricant. In contrast, the tribology of the GLC surface showed a much lower dependence on lubrication. In order to identify the compounds and their distribution across the interface, x-ray microanalysis phase mapping was innovatively applied and the principle of hard and soft acids and bases (HSAB) to understand the behaviour. Phase mapping clearly showed the hierarchical interface of the zinc-iron polyphosphate tribofilm for various sliding pairs and different sliding durations. This interface structure formed between lubricant additives and the sliding surfaces adapts to the sliding conditions - the term adaptive interface. The current results help explain the tribology of these sliding components in engine. PMID- 28855573 TI - Diverse Functionalities of Vertically Stacked Graphene/Single layer n-MoS2/SiO2/p GaN Heterostructures. AB - Integrating different dimentional materials on vertically stacked p-n hetero junctions have facinated a considerable scrunity and can open up excellent feasibility with various functionalities in opto-electronic devices. Here, we demonstrate that vertically stacked p-GaN/SiO2/n-MoS2/Graphene heterostructures enable to exhibit prominent dual opto-electronic characteristics, including efficient photo-detection and light emission, which represents the emergence of a new class of devices. The photoresponsivity was found to achieve as high as ~10.4 AW-1 and the detectivity and external quantum efficiency were estimated to be 1.1 * 1010 Jones and ~30%, respectively. These values are superier than most reported hererojunction devices. In addition, this device exhibits as a self-powered photodetector, showing a high responsivity and fast response speed. Moreover, the device demonstrates the light emission with low turn-on voltage (~1.0 V) which can be realized by electron injection from graphene electrode and holes from GaN film into monolayer MoS2 layer. These results indicate that with a suitable choice of band alignment, the vertical stacking of materials with different dimentionalities could be significant potential for integration of highly efficient heterostructures and open up feasible pathways towards integrated nanoscale multi-functional optoelectronic devices for a variety of applications. PMID- 28855575 TI - CD2068 potentially mediates multidrug efflux in Clostridium difficile. AB - Clostridium difficile is a major cause of antibiotic-associated diarrhea and the treatment thereof becomes more difficult owing to a rise of multidrug resistant strains. ATP-binding cassette (ABC) transporters are known to play a crucial role in the resistance to multiple antibiotics. In this study, the potential contribution of an ABC transporter in C. difficile multidrug resistance was investigated. The expression level of the cd2068 gene in C. difficile encoding an ABC transporter was up-regulated following the exposure to certain antibiotics compared to the control cells. Heterologous expression of CD2068 in Escherichia coli revealed that it mediated the efflux of fluorescent substrates and conferred resistance to multiple drugs. The CD2068-associated ATPase activity in membrane vesicles was also stimulated by various antibiotics. Furthermore, the insertional inactivation of the cd2068 gene in C. difficile led to a significant increase in susceptibility to antibiotics, which could be genetically complemented, supporting that CD2068 was directly associated to the drug resistance. These results demonstrate the potential role for the ABC transporter CD2068 in the resistance mechanism against multiple drugs in C. difficile. PMID- 28855574 TI - Genetic studies in mice directly link oocytes produced during adulthood to ovarian function and natural fertility. AB - Multiple labs have reported that mammalian ovaries contain oogonial stem cells (OSCs), which can differentiate into oocytes that fertilize to produce offspring. However, the physiological relevance of these observations to adult ovarian function is unknown. Here we performed targeted and reversible ablation of premeiotic germ cells undergoing differentiation into oocytes in transgenic mice expressing the suicide gene, herpes simplex virus thymidine kinase (HSVtk), driven by the promoter of stimulated by retinoic acid gene 8 (Stra8), a germ cell specific gene activated during meiotic commitment. Over a 21-day ablation phase induced by the HSVtk pro-drug, ganciclovir (GCV), oocyte numbers declined due to a disruption of new oocyte input. However, germ cell differentiation resumed after ceasing the ablation protocol, enabling complete regeneration of the oocyte pool. We next employed inducible lineage tracing to fate map, through Cre recombinase-mediated fluorescent reporter gene activation only in Stra8 expressing cells, newly-formed oocytes. Induction of the system during adulthood yielded a mosaic pool of unmarked (pre-existing) and marked (newly-formed) oocytes. Marked oocytes matured and fertilized to produce offspring, which grew normally to adulthood and transmitted the reporter to second-generation offspring. These findings establish that oocytes generated during adulthood contribute directly to ovarian function and natural fertility in mammals. PMID- 28855576 TI - Micro-hydrogel Particles Consisting of Hyperbranched Polyamidoamine for the Removal of Heavy Metal Ions from Water. AB - A series of micro-hydrogel particles consisting of hyperbranched polyamidoamine (HPAMAM) without any supporting core materials was synthesized via the inverse suspension condensation polymerization of A2 and B4 monomers, N,N' methylenebisacrylamide (MBA) and ethylenediamine (EDA). The particles were found to be highly effective when used to remove heavy metal ions, such as cadmium, copper, lead, nickel, zinc, and cobalt, from water, and they could be separated from the water by a simple filtration process. The results of this study demonstrate that crosslinked HPAMAM particles, which can be prepared by a simple and environmentally friendly process, are an attractive absorbent for water purification. PMID- 28855577 TI - Quantitative and organisational changes in mature extracellular matrix revealed through high-content imaging of total protein fluorescently stained in situ. AB - Fibrosis is a common driver of end-stage organ failure in most organs. It is characterised by excessive accumulation of extracellular matrix (ECM) proteins. Therapeutic options are limited and novel treatments are urgently required, however current cell-based high-throughput screening (HTS) models to identify molecules affecting ECM accumulation are limited in their relevance or throughput. We report a novel sensitive approach which combines in situ fluorescent staining of accumulated decellularised ECM proteins with automated high-content microscopy. Using this method to measure ECM accumulation in a kidney cell model, we demonstrated good agreement with established radiolabelled amino acid incorporation assays: TGFbeta1 delivered a potent pro-fibrotic stimulus, which was reduced by TGFbeta antibody or the anti-fibrotic nintedanib. Importantly, our method also provides information about matrix organisation: the extent of ECM accumulation was unaffected by the BMP antagonist Gremlin-1 but a pronounced effect on matrix fibrillar organisation was revealed. This rapid, straightforward endpoint provides quantitative data on ECM accumulation and offers a convenient cross-species readout that does not require antibodies. Our method facilitates discovery of novel pro- and anti-fibrotic agents in 384-well plate format and may be widely applied to in vitro cell-based models in which matrix protein deposition reflects the underlying biology or pathology. PMID- 28855578 TI - HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells. AB - Human antigen (Hu) R is an RNA-binding protein whose overexpression in human cancer correlates with aggressive disease, drug resistance, and poor prognosis. HuR inhibition has profound anticancer activity. Pharmacologic inhibitors can overcome the limitations of genetic inhibition. In this study, we examined the antitumor activity of CMLD-2, a small-molecule inhibitor directed against HuR, using non-small cell lung cancer (NSCLC) as a model. CMLD-2 efficacy was tested in vitro using H1299, A549, HCC827, and H1975 NSCLC cells and MRC-9 and CCD-16 normal human fibroblasts. Treatment of NSCLC cells with CMLD-2 produced dose dependent cytotoxicity, caused a G1 phase cell-cycle arrest and induced apoptosis. CMLD-2 decreased HuR mRNA and the mRNAs of HuR-regulated proteins (Bcl2 and p27) in tumor cells. Additionally, reduction in the expression of HuR, Bcl2, cyclin E, and Bcl-XL with increased expression of Bax and p27 in CMLD-2 treated NSCLC cells were observed. CMLD-2-treated normal cells, HuR-regulated mRNAs and proteins albeit showed some reduction were less compared to tumor cells. Finally, CMLD-2 treatment resulted in greater mitochondrial perturbation, activation of caspase-9 and -3 and cleavage of PARP in tumor cells compared to normal cells. Our proof-of concept study results demonstrate CMLD-2 represents a promising HuR-targeted therapeutic class that with further development could lead to advanced preclinical studied and ultimately for lung cancer treatment. PMID- 28855579 TI - Expression of IL-33 in ocular surface epithelium induces atopic keratoconjunctivitis with activation of group 2 innate lymphoid cells in mice. AB - In a transgenic mouse line hK14mIL33tg, with the expression of interleukin-33 (IL 33) driven by a keratin 14 promoter, keratoconjunctivitis developed spontaneously between 18 and 22 weeks of age under specific-pathogen-free conditions. These mice showed blepharitis and corneal impairments, and the histology revealed epithelial thickening in the conjunctiva and the cornea with infiltration of eosinophils, mast cells and basophils. IL-5, IL-13 and CCL11 were abundant in lacrimal fluid in the mice, and the gene expressions of IL-4, IL-5, IL-13, IL-33, Prg2 and Mmcp8 were significantly increased in the cornea. Furthermore, group 2 innate lymphoid cells (ILC2) producing IL-5 and IL-13 were markedly increased in the cornea. These phenotypes closely resemble human atopic keratoconjunctivitis (AKC). The characteristic ocular phenotype in these mice strongly suggests that IL-33 is crucial for the development of AKC. The mouse line may be useful as a novel model for research and development of therapeutic strategies for AKC. PMID- 28855580 TI - Attentional Control in Adolescent Mice Assessed with a Modified Five Choice Serial Reaction Time Task. AB - Adolescence is a critical period for the development of higher-order cognitive functions. Unlike in humans, very limited tools are available to assess such cognitive abilities in adolescent rodents. We implemented a modified 5-Choice Serial Reaction Time Task (5CSRTT) to selectively measure attentiveness, impulsivity, broad monitoring, processing speed and distractibility in adolescent mice. 21-day old C57BL/6J mice reliably acquired this task with no sex-dependent differences in 10-12 days. A protocol previously used in adults was less effective to assess impulsiveness in adolescents, but revealed increased vulnerability in females. Next, we distinctively assessed selective, divided and broad monitoring attention modeling the human Spatial Attentional Resource Allocation Task (SARAT). Finally, we measured susceptibility to distractions using non-predictive cues that selectively disrupted attention. These paradigms were also applied to two genetically modified lines: the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT) heterozygous. Adolescent DAT hypo functioning mice showed attentional deficits and higher impulsivity as found in adults. In contrast to adults, adolescent COMT hypo-functioning mice showed decreased impulsivity and attentional resilience to distractors. These paradigms open new avenues to study the establishment of higher-order cognitive functions in mice, as well as an effective tool for drug-testing and genetic screenings focused on adolescence. PMID- 28855581 TI - Elucidation of potential sites for antibody engineering by fluctuation editing. AB - Target-specific monoclonal antibodies can be routinely acquired, but the sequences of naturally acquired antibodies are not always affinity-matured and methods that increase antigen affinity are desirable. Most biophysical studies have focused on the complementary determining region (CDR), which directly contacts the antigen; however, it remains difficult to increase the affinity as much as desired. While strategies to alter the CDR to increase antibody affinity are abundant, those that target non-CDR regions are scarce. Here we describe a new method, designated fluctuation editing, which identifies potential mutation sites and engineers a high-affinity antibody based on conformational fluctuations observed by NMR relaxation dispersion. Our data show that relaxation dispersion detects important fluctuating residues that are not located in the CDR and that increase antigen-antibody affinity by point mutation. The affinity-increased mutants are shown to fluctuate less in their free form and to form a more packed structure in their antigen-bound form. PMID- 28855582 TI - Altered cross-talk between the hypothalamus and non-homeostatic regions linked to obesity and difficulty to lose weight. AB - Interactions between the hypothalamus and non-homeostatic regions may contribute to explain the difficulty to lose weight in obesity, an assumption never tested in human longitudinal studies. We investigated whether the functional connectivity between the medial and lateral hypothalamus (MH and LH) and corticostriatal regions differs between individuals with excess weight (n = 42) and normal weight (n = 39) using a seed-based resting-state approach. In addition, we examined the longitudinal association between functional connectivity and weight loss in a 3-month follow-up diet. Results showed that participants with excess weight had increased connectivity between the MH and the striatum and subgenual anterior cingulate cortex, and decreased connectivity with the middle frontal gyrus, and the bed nucleus of the stria terminalis (BNST), as well as a decreased connectivity between the LH and the cerebellum. Decreased connectivity between the MH and the posterior part of the BNST, and between the LH and the cerebellar cortex, predicted a greater percentage of weight loss. Functional connectivity measures explained 36% of the 3-month weight change among individuals with excess weight. We conclude that altered functional connectivity between homeostatic-hypothalamic regions and non-homeostatic corticostriatal and cerebellar regions is linked to obesity and difficulty to lose weight. PMID- 28855583 TI - Bacterial community diversity on in-shell walnut surfaces from six representative provinces in China. AB - Walnuts (Juglans regia) have been associated with foodborne illness outbreaks in recent years. Thus, the purpose of this study was to investigate the distribution of bacteria on in-shell walnut surfaces from six representative provinces in China. The bacterial populations on walnut surfaces were investigated by high throughput sequencing based on the bacterial 16 S rRNA hypervariable region V4. Twenty-eight samples were collected from fourteen regions in six provinces and harvested in different periods (the fresh in 2016 and the old in 2015). Proteobacteria was the most dominant phylum in all samples except for XJ1. In XJ1, and the most abundant phylum was Cyanobacteria, which also accounted for a large proportion of the abundance in YN1, YN11, XJ2 and SC11. In addition, Firmicutes and Actinobacteria were also the abundant phyla in the given samples. Some genera belonging to the opportunistic pathogens were detected, such as Pseudomonas, Acinetobacter, Burkholderia and Bacillus. The results revealed that the composition and abundance of bacterial consortiums on walnut surfaces varied among the geographical sites where they were harvested. Moreover, the storage time of samples also had impact on the abundance of bacteria. This study may provide a better understanding of the bacterial communities' diversity on in shell walnut surfaces. PMID- 28855584 TI - Non-equilibrium Inertial Separation Array for High-throughput, Large-volume Blood Fractionation. AB - Microfluidic blood processing is used in a range of applications from cancer therapeutics to infectious disease diagnostics. As these applications are being translated to clinical use, processing larger volumes of blood in shorter timescales with high-reliability and robustness is becoming a pressing need. In this work, we report a scaled, label-free cell separation mechanism called non equilibrium inertial separation array (NISA). The NISA mechanism consists of an array of islands that exert a passive inertial lift force on proximate cells, thus enabling gentler manipulation of the cells without the need of physical contact. As the cells follow their size-based, deterministic path to their equilibrium positions, a preset fraction of the flow is siphoned to separate the smaller cells from the main flow. The NISA device was used to fractionate 400 mL of whole blood in less than 3 hours, and produce an ultrapure buffy coat (96.6% white blood cell yield, 0.0059% red blood cell carryover) by processing whole blood at 3 mL/min, or ~300 million cells/second. This device presents a feasible alternative for fractionating blood for transfusion, cellular therapy and blood based diagnostics, and could significantly improve the sensitivity of rare cell isolation devices by increasing the processed whole blood volume. PMID- 28855585 TI - Nonalcoholic Fatty Liver Disease and Coronary Artery Calcification in a Northern Chinese Population: a Cross Sectional Study. AB - Nonalcoholic fatty liver disease (NAFLD) has become an emerging health issue with a high prevalence in general population. The cross-sectional study was performed to investigate the association between NAFLD and coronary artery calcification (CAC) in individuals from northern city of China. A total of 2345 participants aged >=40 (1035 men and 1310 women) were selected from the Jidong community of Tangshan city. Liver ultrasonography was used to the diagnosis of NAFLD. A 64 slice CT scanner was used to determine coronary artery calcification score (CACS), with CACS > 0 defined to be the presence of CAC. The risk level of coronary heart disease (CHD) was graded by CACS according to the 4 commonly used thresholds in clinical practice (0, 10, 100, and 400 Agatston units). NAFLD was significantly associated with CAC (crude OR: 1.631, 95% CI: 1.295-2.053, adjusted OR: 1.348, 95% CI: 1.030-1.765). The association between NAFLD and increased risk level of CHD (Crude OR: 1.639 95% CI: 1.303-2.063; adjusted OR: 1.359 95% CI: 1.043-1.770) was observed. The associations between NAFLD and CAC or increased risk level of CHD were significant in female but not in male. Our finding further confirmed the association between NAFLD and CAC, especially in Asian population. PMID- 28855586 TI - Pseudo-acetylation of multiple sites on human Tau proteins alters Tau phosphorylation and microtubule binding, and ameliorates amyloid beta toxicity. AB - Tau is a microtubule-associated protein that is highly soluble and natively unfolded. Its dysfunction is involved in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD), where it aggregates within neurons. Deciphering the physiological and pathogenic roles of human Tau (hTau) is crucial to further understand the mechanisms leading to its dysfunction in vivo. We have used a knock-out/knock-in strategy in Drosophila to generate a strain with hTau inserted into the endogenous fly tau locus and expressed under the control of the endogenous fly tau promoter, thus avoiding potential toxicity due to genetic over-expression. hTau knock-in (KI) proteins were expressed at normal, endogenous levels, bound to fly microtubules and were post-translationally modified, hence displaying physiological properties. We used this new model to investigate the effects of acetylation on hTau toxicity in vivo. The simultaneous pseudo-acetylation of hTau at lysines 163, 280, 281 and 369 drastically decreased hTau phosphorylation and significantly reduced its binding to microtubules in vivo. These molecular alterations were associated with ameliorated amyloid beta toxicity. Our results indicate acetylation of hTau on multiple sites regulates its biology and ameliorates amyloid beta toxicity in vivo. PMID- 28855587 TI - Diversity of culturable aerobic denitrifying bacteria in the sediment, water and biofilms in Liangshui River of Beijing, China. AB - Aerobic denitrification is a process reducing the nitrate into gaseous nitrogen forms in the presence of oxygen gas, which makes the nitrification and denitrification performed simultaneously. However, little was known on the diversity of the culturable aerobic denitrifying bacteria in the surface water system. In this study, 116 strains of aerobic denitrifying bacteria were isolated from the sediment, water and biofilm samples in Liangshui River of Beijing. These bacteria were classified into 14 genera based on the 16 S rDNA, such as Pseudomonas, Rheinheimera, and Gemmobacter. The Pseudomonas sp., represented by the Pseudomonas stutzeri, Pseudomonas mendocina and Pseudomonas putida, composed the major culturable aerobic denitrifiers of the river, followed by Ochrobactrum sp. and Rheinheimera sp. The PCA plot showed the unclassified Pseudomonas sp. and Rheinheimera pacifica preferred to inhabit in biofilm phase while one unclassified Ochrobactrum sp. and Pseudomonas resinovorans had higher abundance in the sediment. In the overlying water, the Pseudomonas stutzeri and Ochrobactrum rhizosphaerae were found to have higher abundance, indicating these aerobic denitrifiers had different habitat-preferable characteristics among the 3 phases of river system. The findings may help select the niche to isolate the aerobic denitrifiers and facilitate the bioaugmentation-based purification of the nitrate polluted surface water. PMID- 28855588 TI - Morphine activation of mu opioid receptors causes disinhibition of neurons in the ventral tegmental area mediated by beta-arrestin2 and c-Src. AB - The tyrosine kinase, c-Src, participates in mu opioid receptor (MOP) mediated inhibition in sensory neurons in which beta-arrestin2 (beta-arr2) is implicated in its recruitment. Mice lacking beta-arr2 exhibit increased sensitivity to morphine reinforcement; however, whether beta-arr2 and/or c-Src participate in the actions of opioids in neurons within the reward pathway is unknown. It is also unclear whether morphine acts exclusively through MOPs, or involves delta opioid receptors (DOPs). We examined the involvement of MOPs, DOPs, beta-arr2 and c-Src in the inhibition by morphine of GABAergic inhibitory postsynaptic currents (IPSCs) recorded from neurons in the mouse ventral tegmental area. Morphine inhibited spontaneous IPSC frequency, mainly through MOPs, with only a negligible effect remaining in MOP-/- neurons. However, a reduction in the inhibition by morphine for DOP-/- c.f. WT neurons and a DPDPE-induced decrease of IPSC frequency revealed a role for DOPs. The application of the c-Src inhibitor, PP2, to WT neurons also reduced inhibition by morphine, while the inactive PP3, and the MEK inhibitor, SL327, had no effect. Inhibition of IPSC frequency by morphine was also reduced in beta-arr2-/- neurons in which PP2 caused no further reduction. These data suggest that inhibition of IPSCs by morphine involves a beta-arr2/c-Src mediated mechanism. PMID- 28855589 TI - Sorcin Predicts Poor Prognosis and Promotes Metastasis by Facilitating Epithelial mesenchymal Transition in Hepatocellular Carcinoma. AB - Metastasis-associated recurrence is the main cause for the poor prognosis of hepatocellular carcinoma (HCC). However, the detailed molecular mechanisms underlying HCC metastasis remain elusive. Though some data indicated the oncogenic role of Sorcin in tumors, the prognostic value and biological role of Sorcin in HCC is still unknown. In this study, it demonstrated that Sorcin expression levels were significantly upregulated in HCC tumor tissues compared with matched adjacent nontumorous liver tissues and normal liver tissues, and such expression level correlated with HCC metastasis. High Sorcin expression was significantly correlated with aggressive clinicopathological characteristics such as multiple tumor nodules, high Edmondson-Steiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05). HCC patients with high Sorcin expression had both shorter survival and higher recurrence than those with low Sorcin expression (all P < 0.05). Sorcin expression was an independent and significant risk factor for survival and recurrence of HCC patients. Results of functional experiments showed that Sorcin could promote HCC cell proliferation, migration, and invasion in vitro, and facilitate HCC growth and metastasis in vivo. Mechanistically, Sorcin exerted its role by activating extracellular signal regulated kinase (ERK) pathway and promoted metastasis by facilitating epithelial mesenchymal transition (EMT) in HCC. PMID- 28855590 TI - Intranasally administered in situ gelling nanocomposite system of dimenhydrinate: preparation, characterization and pharmacodynamic applicability in chemotherapy induced emesis model. AB - The aim of the current manuscript was to test the applicability of a nanocomposite system of penetration enhancer vesicles (PEVs) within polymeric in situ forming gel network composed of poloxamer and hyaluronic acid for the intranasal delivery of the antiemetic dimenhydrinate (DMH). PEVs were prepared using phospholipids and labrasol/transcutol/PEG 400 as penetration enhancers, and characterized for entrapment efficiency (EE%), particle size, zeta potential and morphology. The nanocomposite in situ forming gel system was characterized for its sol-gel temperature, viscosity and mucoadhesiveness, and was pharmacodynamically tested on a cisplatin induced emesis model in rats in terms of food, water, kaolin intake and stomach weight content. The selected PEVs formula displayed EE% of 83% for DMH, particle size of 121 nm and a surface charge of 0.83 mV. The selected nanocomposite in situ gelling formula showed a viscosity of 2.13 Pa.S, mucoadhesive force of 0.62 N and DMH controlled release over 6 hours. The pharmacodynamic study showed the superiority of the nanocomposite in situ gelling formula; being administered at a lower dose than the oral marketed formula. The described nanocomposite system proved to be successful for the intranasal delivery of DMH, thus presenting a promising delivery modality for similar antiemetics. PMID- 28855591 TI - Origin of the emergence of higher T c than bulk in iron chalcogenide thin films. AB - Fabrication of epitaxial FeSexTe1-x thin films using pulsed laser deposition (PLD) enables improving their superconducting transition temperature (T c) by more than ~40% than their bulk T c. Intriguingly, T c enhancement in FeSexTe1-x thin films has been observed on various substrates and with different Se content, x. To date, various mechanisms for T c enhancement have been reported, but they remain controversial in universally explaining the T c improvement in the FeSexTe1-x films. In this report, we demonstrate that the controversies over the mechanism of T c enhancement are due to the abnormal changes in the chalcogen ratio (Se:Te) during the film growth and that the previously reported T c enhancement in FeSe0.5Te0.5 thin films is caused by a remarkable increase of Se content. Although our FeSexTe1-x thin films were fabricated via PLD using a Fe0.94Se0.45Te0.55 target, the precisely measured composition indicates a Se-rich FeSexTe1-x (0.6 < x < 0.8) as ascertained through accurate compositional analysis by both wavelength dispersive spectroscopy (WDS) and Rutherford backscattering spectrometry (RBS). We suggest that the origin of the abnormal composition change is the difference in the thermodynamic properties of ternary FeSexTe1-x, based on first principle calculations. PMID- 28855592 TI - (S)-Oxiracetam is the Active Ingredient in Oxiracetam that Alleviates the Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats. AB - Chronic cerebral hypoperfusion is a pathological state that is associated with the cognitive impairments in vascular dementia. Oxiracetam is a nootropic drug that is commonly used to treat cognitive deficits of cerebrovascular origins. However, oxiracetam is currently used as a racemic mixture whose effective ingredient has not been identified to date. In this study, we first identified that (S)-oxiracetam, but not (R)-oxiracetam, was the effective ingredient that alleviated the impairments of spatial learning and memory by ameliorating neuron damage and white matter lesions, increasing the cerebral blood flow, and inhibiting astrocyte activation in chronic cerebral hypoperfused rats. Furthermore, using MALDI-MSI and LC-MS/MS, we demonstrated that (S)-oxiracetam regulated ATP metabolism, glutamine-glutamate and anti-oxidants in the cortex region of hypoperfused rats. Altogether, our results strongly suggest that (S) oxiracetam alone could be a nootropic drug for the treatment of cognitive impairments caused by cerebral hypoperfusion. PMID- 28855594 TI - Switching off hydrogen-bond-driven excitation modes in liquid methanol. AB - Hydrogen bonding plays an essential role on intermolecular forces, and consequently on the thermodynamics of materials defined by this elusive bonding character. It determines the property of a vital liquid as water as well as many processes crucial for life. The longstanding controversy on the nature of the hydrogen bond (HB) can be settled by looking at the effect of a vanishing HB interaction on the microscopic properties of a given hydrogen-bonded fluid. This task suits the capabilities of computer simulations techniques, which allow to easily switch off HB interactions. We then use molecular dynamics to study the microscopic properties of methanol, a prototypical HB liquid. Fundamental aspects of the dynamics of methanol at room temperature were contextualised only very recently and its rich dynamics was found to have striking analogies with that of water. The lower temperature (200 K) considered in the present study led us to observe that the molecular centre-of-mass dynamics is dominated by four modes. Most importantly, the computational ability to switch on and off hydrogen bonds permitted us to identify which, among these modes, have a pure HB-origin. This clarifies the role of hydrogen bonds in liquid dynamics, disclosing new research opportunities and unexplored interpretation schemes. PMID- 28855593 TI - ITGA1 is a pre-malignant biomarker that promotes therapy resistance and metastatic potential in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) has single-digit 5-year survival rates at <7%. There is a dire need to improve pre-malignant detection methods and identify new therapeutic targets for abrogating PDAC progression. To this end, we mined our previously published pseudopodium-enriched (PDE) protein/phosphoprotein datasets to identify novel PDAC-specific biomarkers and/or therapeutic targets. We discovered that integrin alpha 1 (ITGA1) is frequently upregulated in pancreatic cancers and associated precursor lesions. Expression of ITGA1-specific collagens within the pancreatic cancer microenvironment significantly correlates with indicators of poor patient prognosis, and depleting ITGA1 from PDAC cells revealed that it is required for collagen-induced tumorigenic potential. Notably, collagen/ITGA1 signaling promotes the survival of ALDH1-positive stem-like cells and cooperates with TGFbeta to drive gemcitabine resistance. Finally, we report that ITGA1 is required for TGFbeta/collagen-induced EMT and metastasis. Our data suggest that ITGA1 is a new diagnostic biomarker and target that can be leveraged to improve patient outcomes. PMID- 28855595 TI - The Influence of Different Maternal Microbial Communities on the Development of Infant Gut and Oral Microbiota. AB - Very few studies have analyzed how the composition of mother's microbiota affects the development of infant's gut and oral microbiota during the first months of life. Here, microbiota present in the mothers' gut, vagina, breast milk, oral cavity, and mammary areola were compared with the gut and oral microbiota of their infants over the first six months following birth. Samples were collected from the aforementioned body sites from seven mothers and nine infants at three different time points over a 6-month period. Each sample was analyzed with 16S rRNA gene sequencing. The gut microbiota of the infants harbored distinct microbial communities that had low similarity with the various maternal microbiota communities. In contrast, the oral microbiota of the infants exhibited high similarity with the microbiota of the mothers' breast milk, mammary areola and mouth. These results demonstrate that constant contact between microbial communities increases their similarity. A majority of the operational taxonomic units in infant gut and oral microbiota were also shared with the mothers' gut and oral communities, respectively. The disparity between the similarity and the proportion of the OTUs shared between infants' and mothers' gut microbiota might be related to lower diversity and therefore competition in infants' gut microbiota. PMID- 28855596 TI - Comparative RNA function analysis reveals high functional similarity between distantly related bacterial 16 S rRNAs. AB - The 16 S rRNA sequence has long been used uncritically as a molecular clock to infer phylogenetic relationships among prokaryotes without fully elucidating the evolutionary changes that this molecule undergoes. In this study, we investigated the functional evolvability of 16 S rRNA, using comparative RNA function analyses between the 16 S rRNAs of Escherichia coli (Proteobacteria) and Acidobacteria (78% identity, 334 nucleotide differences) in the common genetic background of E. coli. While the growth phenotype of an E. coli mutant harboring the acidobacterial gene was disrupted significantly, it was restored almost completely following introduction of a 16 S rRNA sequence with a single base-pair variation in helix 44; the remaining 332 nucleotides were thus functionally similar to those of E. coli. Our results suggest that 16 S rRNAs share an inflexible cradle structure formed by ribosomal proteins and have evolved by accumulating species-specific yet functionally similar mutations. While this experimental evidence suggests the neutral evolvability of 16 S rRNA genes and hence satisfies the necessary requirements to use the sequence as a molecular clock, it also implies the promiscuous nature of the 16 S rRNA gene, i.e., the occurrence of horizontal gene transfer among bacteria. PMID- 28855597 TI - Dynamics and implications of circulating anti-angiogenic VEGF-A165b isoform in patients with ST-elevation myocardial infarction. AB - Angiogenesis is crucial to restore microvascular perfusion in the jeopardized myocardium in the weeks following reperfused ST-segment elevation myocardial infarction (STEMI). (VEGF)-A165b, an anti-angiogenic factor, has been identified as a regulator of vascularization; however, it has not been previously implicated in acute myocardial infarction. We sought to investigate the dynamics of circulating VEGF-A165b and its association with cardiac magnetic resonance derived infarct size and left ventricular ejection fraction (LVEF). 50 STEMI patients and 23 controls were included. Compared with control individuals, serum VEGF-A165b was elevated in STEMI patients prior to primary percutaneous coronary intervention (PCI). Following PCI, serum VEGF-A165b increased further, reaching a maximum level at 24 h and decreased one month after reperfusion. VEGF-A165b levels at 24 h were associated with a large infarct size and inversely related to LVEF. VEGF-A165b expression was increased in myocardial infarct areas from patients with previous history of AMI. An ex vivo assay using serum from STEMI patients showed that neutralization of VEGF-A165b increased tubulogenesis. Overall, the study suggests that VEGF-A165b might play a deleterious role after AMI as an inhibitor of angiogenesis in the myocardium. Accordingly, neutralization of VEGF-A165b could represent a novel pro-angiogenic therapy for reperfusion of myocardium in STEMI. PMID- 28855598 TI - Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N terminal Hexapeptide Amyloid Inhibitors. AB - Alzheimer's disease (AD) is characterized by deposition of amyloid beta (Abeta) peptides into senile plaques in the brain. While most familial mutations are associated with early-onset AD, recent studies report the AD-protective nature of two genetic human Abeta variants, i.e. A2T and A2V, in the heterozygous state. The mixture of A2V Abeta1-6 (Abeta6) hexapeptide and WT Abeta1-42 (Alphabeta42) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T Abeta6 hexapeptide binding on the monomeric WT Abeta42 landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of Abeta42 with the A2V and A2T hexapeptides compared to WT Abeta6. A notable reorganization of the Abeta42 landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, Abeta6 bound Abeta42 monomer exhibits alternative structural features that are strongly dependent on the hexapeptide sequence. For example, a central helix is more frequently populated within the A2T-bound monomer, while A2V-bound Abeta42 is often enhanced in overall disorder. Taken together, the present simulations offer novel molecular insights onto the effect of the N-terminal hexapeptide binding on the Abeta42 monomer structure, which might help in explaining their reported amyloid inhibition properties. PMID- 28855600 TI - Spin-relaxation time in materials with broken inversion symmetry and large spin orbit coupling. AB - We study the spin-relaxation time in materials where a large spin-orbit coupling (SOC) is present which breaks the spatial inversion symmetry. Such a spin-orbit coupling is realized in zincblende structures and heterostructures with a transversal electric field and the spin relaxation is usually described by the so called D'yakonov-Perel' (DP) mechanism. We combine a Monte Carlo method and diagrammatic calculation based approaches in our study; the former tracks the time evolution of electron spins in a quasiparticle dynamics simulation in the presence of the built-in spin-orbit magnetic fields and the latter builds on the spin-diffusion propagator by Burkov and Balents. Remarkably, we find a parameter free quantitative agreement between the two approaches and it also returns the conventional result of the DP mechanism in the appropriate limit. We discuss the full phase space of spin relaxation as a function of SOC strength, its distribution, and the magnitude of the momentum relaxation rate. This allows us to identify two novel spin-relaxation regimes; where spin relaxation is strongly non-exponential and the spin relaxation equals the momentum relaxation. A compelling analogy between the spin-relaxation theory and the NMR motional narrowing is highlighted. PMID- 28855599 TI - Functional non-coding polymorphism in an EPHA2 promoter PAX2 binding site modifies expression and alters the MAPK and AKT pathways. AB - To identify possible genetic variants influencing expression of EPHA2 (Ephrin receptor Type-A2), a tyrosine kinase receptor that has been shown to be important for lens development and to contribute to both congenital and age related cataract when mutated, the extended promoter region of EPHA2 was screened for variants. SNP rs6603883 lies in a PAX2 binding site in the EPHA2 promoter region. The C (minor) allele decreased EPHA2 transcriptional activity relative to the T allele by reducing the binding affinity of PAX2. Knockdown of PAX2 in human lens epithelial (HLE) cells decreased endogenous expression of EPHA2. Whole RNA sequencing showed that extracellular matrix (ECM), MAPK-AKT signaling pathways and cytoskeleton related genes were dysregulated in EPHA2 knockdown HLE cells. Taken together, these results indicate a functional non-coding SNP in EPHA2 promoter affects PAX2 binding and reduces EPHA2 expression. They further suggest that decreasing EPHA2 levels alters MAPK, AKT signaling pathways and ECM and cytoskeletal genes in lens cells that could contribute to cataract. These results demonstrate a direct role for PAX2 in EPHA2 expression and help delineate the role of EPHA2 in development and homeostasis required for lens transparency. PMID- 28855601 TI - Universal scaling of the self-field critical current in superconductors: from sub nanometre to millimetre size. AB - Universal scaling behaviour in superconductors has significantly elucidated fluctuation and phase transition phenomena in these materials. However, universal behaviour for the most practical property, the critical current, was not contemplated because prevailing models invoke nucleation and migration of flux vortices. Such migration depends critically on pinning, and the detailed microstructure naturally differs from one material to another, even within a single material. Through microstructural engineering there have been ongoing improvements in the field-dependent critical current, thus illustrating its non universal behaviour. But here we demonstrate the universal size scaling of the self-field critical current for any superconductor, of any symmetry, geometry or band multiplicity. Key to our analysis is the huge range of sample dimensions, from single-atomic-layer to mm-scale. These have widely variable microstructure with transition temperatures ranging from 1.2 K to the current record, 203 K. In all cases the critical current is governed by a fundamental surface current density limit given by the relevant critical field divided by the penetration depth. PMID- 28855602 TI - Cognitive function during exercise under severe hypoxia. AB - Acute exercise has been demonstrated to improve cognitive function. In contrast, severe hypoxia can impair cognitive function. Hence, cognitive function during exercise under severe hypoxia may be determined by the balance between the beneficial effects of exercise and the detrimental effects of severe hypoxia. However, the physiological factors that determine cognitive function during exercise under hypoxia remain unclear. Here, we examined the combined effects of acute exercise and severe hypoxia on cognitive function and identified physiological factors that determine cognitive function during exercise under severe hypoxia. The participants completed cognitive tasks at rest and during moderate exercise under either normoxic or severe hypoxic conditions. Peripheral oxygen saturation, cerebral oxygenation, and middle cerebral artery velocity were continuously monitored. Cerebral oxygen delivery was calculated as the product of estimated arterial oxygen content and cerebral blood flow. On average, cognitive performance improved during exercise under both normoxia and hypoxia, without sacrificing accuracy. However, under hypoxia, cognitive improvements were attenuated for individuals exhibiting a greater decrease in peripheral oxygen saturation. Cognitive performance was not associated with other physiological parameters. Taken together, the present results suggest that arterial desaturation attenuates cognitive improvements during exercise under hypoxia. PMID- 28855603 TI - Complete Chloroplast Genome Sequence of Decaisnea insignis: Genome Organization, Genomic Resources and Comparative Analysis. AB - Decaisnea insignis is a wild resource plant and is used as an ornamental, medicinal, and fruit plant. High-throughput sequencing of chloroplast genomes has provided insight into the overall evolutionary dynamics of chloroplast genomes and has enhanced our understanding of the evolutionary relationships within plant families. In the present study, we sequenced the complete chloroplast genome of D. insignis and used the data to assess its genomic resources. The D. insignis chloroplast genome is 158,683 bp in length and includes a pair of inverted repeats of 26,167 bp that are separated by small and large single copy regions of 19,162 bp and 87,187 bp, respectively. We identified 83 simple sequence repeats and 18 pairs of large repeats. Most simple-sequence repeats were located in the noncoding sections of the large single-copy/small single-copy region and exhibited a high A/T content. The D. insignis chloroplast genome bias was skewed towards A/T on the basis of codon usage. A phylogenetic tree based on 82 protein coding genes of 33 angiosperms showed that D. insignis was clustered with Akebia in Lardizabalaceae. Overall, the results of this study will contribute to better understanding the evolution, molecular biology and genetic improvement of D. insignis. PMID- 28855604 TI - Studying the role of fascin-1 in mechanically stressed podocytes. AB - Glomerular hypertension causes glomerulosclerosis via the loss of podocytes, which are challenged by increased mechanical load. We have demonstrated that podocytes are mechanosensitive. However, the response of podocytes to mechanical stretching remains incompletely understood. Here we demonstrate that the actin bundling protein fascin-1 plays an important role in podocytes that are exposed to mechanical stress. Immunofluorescence staining revealed colocalization of fascin-1 and nephrin in mouse kidney sections. In cultured mouse podocytes fascin 1 was localized along actin fibers and filopodia in stretched and unstretched podocytes. The mRNA and protein levels of fascin-1 were not affected by mechanical stress. By Western blot and 2D-gelelectrophoresis we observed that phospho-fascin-1 was significantly downregulated after mechanical stretching. It is known that phosphorylation at serine 39 (S39) regulates the bundling activity of fascin-1, e.g. required for filopodia formation. Podocytes expressing wild type GFP-fascin-1 and non-phosphorylatable GFP-fascin-1-S39A showed marked filopodia formation, being absent in podocytes expressing phosphomimetic GFP fascin-1-S39D. Finally, the immunofluorescence signal of phosphorylated fascin-1 was strongly reduced in glomeruli of patients with diabetic nephropathy compared to healthy controls. In summary, mechanical stress dephosphorylates fascin-1 in podocytes in vitro and in vivo thereby fascin-1 may play an important role in the adaptation of podocytes to mechanical forces. PMID- 28855605 TI - Attempts to replicate genetic associations with schizophrenia in a cohort from north India. AB - : Schizophrenia is a chronic, severe, heritable disorder. Genome-wide association studies, conducted predominantly among Caucasians, have indicated > 100 risk alleles, with most significant SNPs on chromosome 6. There is growing interest as to whether these risk alleles are relevant in other ethnic groups as well. Neither an Indian genome-wide association studies nor a systematic replication of GWAS findings from other populations are reported. Thus, we analyzed 32 SNPs, including those associated in the Caucasian ancestry GWAS and other candidate gene studies, in a north Indian schizophrenia cohort (n = 1009 patients; n = 1029 controls) using a Sequenom mass array. Cognitive functioning was also assessed using the Hindi version of the Penn Computerized Neuropsychological Battery in a subset of the sample. MICB (rs6916394) a previously noted Caucasian candidate, was associated with schizophrenia at the p = 0.02 level. One SNP, rs2064430, AHI1 (6q23.3, SZ Gene database SNP) was associated at the p = 0.04 level. Other candidates had even less significance with rs6932590, intergenic (p = 0.07); rs3130615, MICB (p = 0.08); rs6916921, NFKBIL1 (p = 0.08) and rs9273012, HLA-DQA1 (p = 0.06) and haplotypic associations (p = 0.01-0.05) of 6p SNPs were detected. Of note, nominally significant associations with cognitive variables were identified, after covarying for age and diagnostic status. SNPs with p < 0.01 were: rs3130375, with working memory (p = 0.007); rs377763, with sensorimotor (p = 0.004); rs6916921, NFKBIL1 with emotion (p = 0.01). This relative lack of significant positive associations is likely influenced by the sample size and/or differences in the genetic architecture of schizophrenia across populations, encouraging population specific studies to identify shared and unique genetic risk factors for schizophrenia. POPULATION GENETICS: CAUCASIANS AND INDIANS EXHIBIT GENETIC DISJUNCTION IN SCHIZOPHRENIA: A tenuous link between schizophrenia's genetic basis in Caucasians and Indians calls for more comprehensive research on the latter. Large-scale analyses of the human genome have identified over a hundred genetic variations associated with schizophrenia; however, these have focused largely on European and North American populations. Researchers led by the University of Delhi's BK Thelma, and Smita Deshpande of the Dr. Ram Manohar Lohia Hospital, India, selected 32 gene variations from past studies to look for similar associations in Indians. Many assays met limited success, though the team found significant correlations between certain variations and specific cognitive hallmarks of schizophrenia. Aside from differences in genetic architecture, the lack of adequate and comparable genetic data on schizophrenia in Indians may contribute to this apparent difference to schizophrenia in Caucasian patients. This shows a clear need for more schizophrenia genetic studies in India. PMID- 28855606 TI - A cross-sectional observational study on allergen-specific IgE positivity in a southeast coastal versus a southwest inland region of China. AB - Few studies addressed trans-regional differences in allergen sensitization between areas within a similar latitudinal range but with distinct geomorphological features. We investigated specific IgE (sIgE) positivity to common allergens in populations from two southern China provinces. Using a uniformed protocol, serum samples were collected from 2778 subjects with suspected atopy in coastal Guangdong and inland Yunnan. The overall prevalence of sIgE positivity were 57.8% (95% CI: 56.0%, 59.6%) from Guangdong vs 60.9% (95% CI: 59.1%, 62.7%) from Yunnan. House dust mite (d1) was the most common allergen in both regions. Among d1-sensitized subjects, only 35.7% (208/583) in Guangdong and 22.9% (147/642) in Yunnan tested positive for d1 alone. Among those poly sensitized d1-positive subjects, cockroach was the most common co-sensitizing aeroallergen. 41.9% of the d1-sensitized Guangdong subjects showed high-class sIgE reactivity (>=class 4), in contrast to a very low percentage of such reactivity in Yunnan. However, 36.3% of d1-sensitized subjects in Yunnan were concomitantly positive for tree pollen mix. Surprisingly, Yunnan subjects showed high prevalence of sIgE positivity for crabs and shrimps, either by overall or by age-group analysis, compared with their Guangdong counterparts (both P < 0.05). These findings may add to data about local allergies in China and worldwide. PMID- 28855607 TI - Hydrological legacy determines the type of enzyme inhibition in a peatlands chronosequence. AB - Peatland ecosystems contain one-third of the world's soil carbon store and many have been exposed to drought leading to a loss of carbon. Understanding biogeochemical mechanisms affecting decomposition in peatlands is essential for improving resilience of ecosystem function to predicted climate change. We investigated biogeochemical changes along a chronosequence of hydrological restoration (dry eroded gully, drain-blocked <2 years, drain blocked <7 years and wet pristine site), and examined whether hydrological legacy alters the response of beta-glucosidase kinetics (i.e. type of inhibition) to short-term drying and waterlogging. In the dry eroded gully at depth, low phenolic concentrations were associated with enhanced beta-glucosidase enzyme activities (V max ) but short term drying and waterlogging caused a significant increase of dissolved organic carbon (DOC) and phenolics associated with increases in V max (enzyme production) and K m (indicative of competitive inhibition). Inhibition within the drain blocked and pristine sites at depth exhibited non-competitive inhibition (decreased V max), whilst uncompetitive inhibition (decreased V max and K m ) occurred in surface peat explained by variation in humic substances and phenolics. These results suggest that loss of carbon by short-term drought or rewetting may occur from sites with a legacy of drought due to the release of non inhibitory phenolics that permits enhanced enzyme activity. PMID- 28855608 TI - Finding disagreement pathway signatures and constructing an ensemble model for cancer classification. AB - Cancer classification based on molecular level is a relatively routine research procedure with advances in high-throughput molecular profiling techniques. However, the number of genes typically far exceeds the number of the sample size in gene expression studies. The existing gene selection methods are almost based on statistics and machine learning, overlooking relevant biological principles or knowledge while working with biological data. Here, we propose a robust ensemble learning paradigm, which incorporates multiple pathways information, to predict cancer classification. We compare the proposed method with other methods, such as Elastic SCAD and PPDMF, and estimate the classification performance. The results show that the proposed method has the higher performances on most metrics and robust performance. We further investigate the biological mechanism of the ensemble feature genes. The results demonstrate that the ensemble feature genes are associated with drug targets/clinically-relevant cancer. In addition, some core biological pathways and biological process underlying clinically-relevant phenotypes are identified by function annotation. Overall, our research can provide a new perspective for the further study of molecular activities and manifestations of cancer. PMID- 28855609 TI - Primary patient-derived lung adenocarcinoma cell culture challenges the association of cancer stem cells with epithelial-to-mesenchymal transition. AB - The cancer stem cell (CSC) and epithelial-to-mesenchymal transition (EMT) models have been closely associated and used to describe both the formation of metastasis and therapy resistance. We established a primary lung cell culture from a patient in a clinically rare and unique situation of primary resistant disease. This culture consisted of two biologically profoundly distinct adenocarcinoma cell subpopulations, which differed phenotypically and genotypically. One subpopulation initiated and sustained in spheroid cell culture (LT22s) whereas the other subpopulation was only capable of growth and proliferation under adherent conditions (LT22a). In contrast to our expectations, LT22s were strongly associated with the epithelial phenotype, and expressed additionally CSC markers ALDH1 and CD133, whereas the LT22a was characterized as mesenchymal with lack of CSC markers. The LT22s cells also demonstrated an invasive behavior and mimicked gland formation. Finally, LT22s were more resistant to Cisplatin than LT22a cells. We demonstrate a primary lung adenocarcinoma cell culture derived from a patient with resistant disease, with epithelial aggressive subpopulation of cells associated with stem cell features and therapy resistance. Our findings challenge the current model associating CSC and disease resistance mainly to mesenchymal cells and may have important clinical implications. PMID- 28855610 TI - The full annual carbon balance of a subtropical coniferous plantation is highly sensitive to autumn precipitation. AB - Deep understanding of the effects of precipitation on carbon budgets is essential to assess the carbon balance accurately and can help predict potential variation within the global change context. Therefore, we addressed this issue by analyzing twelve years (2003-2014) of observations of carbon fluxes and their corresponding temperature and precipitation data in a subtropical coniferous plantation at the Qianyanzhou (QYZ) site, southern China. During the observation years, this coniferous ecosystem experienced four cold springs whose effects on the carbon budgets were relatively clear based on previous studies. To unravel the effects of temperature and precipitation, the effects of autumn precipitation were examined by grouping the data into two pools based on whether the years experienced cold springs. The results indicated that precipitation in autumn can accelerate the gross primary productivity (GPP) of the following year. Meanwhile, divergent effects of precipitation on ecosystem respiration (Re) were found. Autumn precipitation was found to enhance Re in normal years but the same regulation was not found in the cold-spring years. These results suggested that for long-term predictions of carbon balance in global climate change projections, the effects of precipitation must be considered to better constrain the uncertainties associated with the estimation. PMID- 28855611 TI - Co-encapsulation and co-transplantation of mesenchymal stem cells reduces pericapsular fibrosis and improves encapsulated islet survival and function when allografted. AB - Pericapsular fibrotic overgrowth (PFO) is associated with poor survival of encapsulated islets. A strategy to combat PFO is the use of mesenchymal stem cells (MSC). MSC have anti-inflammatory properties and their potential can be enhanced by stimulation with proinflammatory cytokines. This study investigated whether co-encapsulation or co-transplantation of MSC with encapsulated islets would reduce PFO and improve graft survival. Stimulating MSC with a cytokine cocktail of IFN-gamma and TNF-alpha enhanced their immunosuppressive potential by increasing nitric oxide production and secreting higher levels of immunomodulatory cytokines. In vitro, co-encapsulation with MSC did not affect islet viability but significantly enhanced glucose-induced insulin secretion. In vivo, normoglycemia was achieved in 100% mice receiving islets co-encapsulated with stimulated MSC as opposed to 71.4% receiving unstimulated MSC and only 9.1% receiving encapsulated islets alone. Microcapsules retrieved from both unstimulated and stimulated MSC groups had significantly less PFO with improved islet viability and function compared to encapsulated islets alone. Levels of peritoneal immunomodulatory cytokines IL-4, IL-6, IL-10 and G-CSF were significantly higher in MSC co-encapsulated groups. Similar results were obtained when encapsulated islets and MSC were co-transplanted. In summary, co encapsulation or co-transplantation of MSC with encapsulated islets reduced PFO and improved the functional outcome of allotransplants. PMID- 28855612 TI - Functional proteomics outlines the complexity of breast cancer molecular subtypes. AB - Breast cancer is a heterogeneous disease comprising a variety of entities with various genetic backgrounds. Estrogen receptor-positive, human epidermal growth factor receptor 2-negative tumors typically have a favorable outcome; however, some patients eventually relapse, which suggests some heterogeneity within this category. In the present study, we used proteomics and miRNA profiling techniques to characterize a set of 102 either estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) or triple-negative formalin-fixed, paraffin-embedded breast tumors. Protein expression-based probabilistic graphical models and flux balance analyses revealed that some ER+/PR+ samples had a protein expression profile similar to that of triple-negative samples and had a clinical outcome similar to those with triple-negative disease. This probabilistic graphical model based classification had prognostic value in patients with luminal A breast cancer. This prognostic information was independent of that provided by standard genomic tests for breast cancer, such as MammaPrint, OncoType Dx and the 8-gene Score. PMID- 28855613 TI - A comprehensive analysis of the association of common variants of ABCG2 with gout. AB - The objective of the present study was to determine whether there was an association between single nucleotide polymorphisms (SNPs) in ABCG2 and gout. We recruited 333 participants including 210 patients with gout and 123 controls and genotyped 45 SNPs in both cohorts. We found that 24 SNPs in ABCG2 are susceptibility loci associated with gout. Haplotype analysis revealed five blocks across the ABCG2 locus were associated with an increased risk of gout with odds ratios (ORs) from 2.59-3.17 (all P < 0.0001). A novel finding in the present study was the identification of rs3114018 in block 3 and its association with increased gout risk. We found that the rs2231142T allele in block 2 and the rs3114018C-rs3109823T (C-T) risk haplotype in block 3 conferred the greatest evidence of association to gout risk (P = 1.19 * 10-12 and P = 9.20 * 10-11, respectively). Our study provides an improved understanding of ABCG2 variations in patients with gout and, as shown by haplotype analysis, that ABCG2 may have a role in gout susceptibility. PMID- 28855614 TI - Predicting synonymous codon usage and optimizing the heterologous gene for expression in E. coli. AB - Of the 20 common amino acids, 18 are encoded by multiple synonymous codons. These synonymous codons are not redundant; in fact, all of codons contribute substantially to protein expression, structure and function. In this study, the codon usage pattern of genes in the E. coli was learned from the sequenced genomes of E. coli. A machine learning based method, Presyncodon was proposed to predict synonymous codon selection in E. coli based on the learned codon usage patterns of the residue in the context of the specific fragment. The predicting results indicate that Presycoden could be used to predict synonymous codon selection of the gene in the E. coli with the high accuracy. Two reporter genes (egfp and mApple) were designed with a combination of low- and high-frequency usage codons by the method. The fluorescence intensity of eGFP and mApple expressed by the (egfp and mApple) designed by this method was about 2.3- or 1.7- folds greater than that from the genes with only high-frequency-usage codons in E. coli. Therefore, both low- and high-frequency-usage codons make positive contributions to the functional expression of the heterologous proteins. This method could be used to design synthetic genes for heterologous gene expression in biotechnology. PMID- 28855615 TI - Multi-mode humidity sensing with water-soluble copper phthalocyanine for increased sensitivity and dynamic range. AB - Aqueous solubility of copper phthalocyanine-3,4',4",4"'-tetrasulfonic acid tetrasodium salt (CuPcTs) enables fabrication of flexible electronic devices by low cost inkjet printing. We (1) investigate water adsorption kinetics on CuPcTs for better understanding the effects of relative humidity (RH) on hydrophilic phthalocyanines, and (2) assess CuPcTs as a humidity-sensing material. Reaction models show that H2O undergoes 2-site adsorption which can be represented by a pair of sequentially-occurring pseudo-first order reactions. Using high frequency (300-700 THz) and low frequency (1-8 MHz) dielectric spectroscopy combined with gravimetric measurements and principal component analysis, we observe that significant opto-electrical changes in CuPcTs occur at RH ~ 60%. The results suggest that rapid H2O adsorption takes place at hydrophilic sulfonyl/salt groups on domain surfaces at low RH, while slow adsorption and diffusion of H2O into CuPcTs crystallites leads to a mixed CuPcTs-H2O phase at RH > 60%, resulting in high frequency dielectric screening of the film by water and dissociation of Na+ from CuPc(SO3-)4 ions. The CuPcTs-H2O interaction can be tracked using a combination of gravimetric, optical, and electrical sensing modes, enabling accurate ( +/- 2.5%) sensing in the ~0-95% RH range with a detection limit of less than 0.1% RH. PMID- 28855616 TI - Similarity of morphological composition and developmental patterning in paired fins of the elephant shark. AB - Jawed vertebrates, or gnathostomes, have two sets of paired appendages, pectoral and pelvic fins in fishes and fore- and hindlimbs in tetrapods. As for paired limbs, paired fins are purported serial homologues, and the advent of pelvic fins has been hypothesized to have resulted from a duplication of the developmental mechanisms present in the pectoral fins, but re-iterated at a posterior location. Developmental similarity of gene expression between pectoral and pelvic fins has been documented in chondrichthyans, but a detailed morphological description of the progression of paired fin development for this group is still lacking. We studied paired fin development in an ontogenetic series of a phylogenetically basal chondrichthyan, the elephant shark Callorhinchus milii. A strong similarity in the morphology and progression of chondrification between the pectoral and pelvic fins was found, which could be interpretated as further evidence of serial homology in paired fins, that could have arisen by duplication. Furthermore, this high degree of morphological and developmental similarity suggests the presence of morphological and developmental modules within paired fins, as observed in paired limbs. This is the first time morphological and developmental modules are described for the paired fins of chimaeras. PMID- 28855617 TI - Colossal permittivity behavior and its origin in rutile (Mg1/3Ta2/3)xTi1-xO2. AB - This work investigates the synthesis, chemical composition, defect structures and associated dielectric properties of (Mg2+, Ta5+) co-doped rutile TiO2 polycrystalline ceramics with nominal compositions of (Mg2+1/3Ta5+2/3) x Ti1-x O2. Colossal permittivity (>7000) with a low dielectric loss (e.g. 0.002 at 1 kHz) across a broad frequency/temperature range can be achieved at x = 0.5% after careful optimization of process conditions. Both experimental and theoretical evidence indicates such a colossal permittivity and low dielectric loss intrinsically originate from the intragrain polarization that links to the electron-pinned [Formula: see text] defect clusters with a specific configuration, different from the defect cluster form previously reported in tri /pent-valent ion co-doped rutile TiO2. This work extends the research on colossal permittivity and defect formation to bi-/penta-valent ion co-doped rutile TiO2 and elucidates a likely defect cluster model for this system. We therefore believe these results will benefit further development of colossal permittivity materials and advance the understanding of defect chemistry in solids. PMID- 28855618 TI - The molecular basis of differential morphology and bleaching thresholds in two morphs of the coral Pocillopora acuta. AB - Processes of cnidarian evolution, including hybridization and phenotypic plasticity, have complicated the clear diagnosis of species boundaries within the phylum. Pocillopora acuta, a species of scleractinian coral that was recently split from the widespread Pocillopora damicornis species complex, occurs in at least two distinct morphs on the Great Barrier Reef. Contrasting morphology combined with evidence of differential bleaching thresholds among sympatrically distributed colonies suggest that the taxonomy of this recently described species is not fully resolved and may represent its own species complex. To examine the basis of sympatric differentiation between the two morphs, we combined analyses of micro- and macro-skeletal morphology with genome wide sequencing of the coral host, as well as ITS2 genotyping of the associated Symbiodinium communities. We found consistent differences between morphs on both the macro- and micro-skeletal scale. In addition, we identified 18 candidate functional genes that relate to skeletal formation and morphology that may explain how the two morphs regulate growth to achieve their distinct growth forms. With inconclusive results in endosymbiotic algal community diversity between the two morphs, we propose that colony morphology may be linked to bleaching susceptibility. We conclude that cryptic speciation may be in the early stages within the species P. acuta. PMID- 28855619 TI - Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing. AB - Thoracic Aortic Aneurysm and Dissection (TAAD) is a life-threatening pathology and remains challenging worldwide. Up to 40% of TAAD are hereditary with complex heterogeneous genetic backgrounds. Recently, next-generation sequencing (NGS) has been successfully applied to identify genetic variants in an efficient and cost effective manner. In our study, NGS coupled with DNA target-capture array was used to screen 11 known causative genes of TAAD in 70 patients from Southern China. All the identified variants were confirmed by Sanger sequencing. We identified forty variants in 36 patients (51.4%), including three known pathogenic (7.5%), 10 likely pathogenic variants (25%, 9 in FBN1, 1 in ACTA2), and 27 variants with uncertain significance (VUS) (67.5%). Among the 27 VUS, 14 (51.9%) were in the FBN1 gene, 3 in Col5A2, 2 in ACTA2, 2 in MYH11, 2 in MYLK, 2 in SLC2A10, 1 in MSTN and 1 in SMAD3 respectively. Based on the segregation data and independent reports, five known likely pathogenic variants and four VUS were upgraded to pathogenic variant and likely pathogenic variant respectively. Our data indicate that NGS is a highly efficient genetic method for identification of pathogenic variants in TAAD patients. PMID- 28855620 TI - Phylogeny and expression pattern analysis of TCP transcription factors in cassava seedlings exposed to cold and/or drought stress. AB - The TCP transcription factors usually act as integrators of multiple growth regulatory and environmental stimuli. However, little is known about this gene family in the important tropical crop cassava (Manihot esculenta). In this study, 36 TCP genes were identified and renamed based on cassava whole-genome sequence and their sequence similarity with Arabidopsis TCPs. Typical TCP domains were detected in these proteins by multiple sequence alignment analysis. Evolutionary analysis indicated that MeTCPs could be divided into 8 subgroups, which was further supported by gene structure and conserved motif analyses. qRT-PCR analysis revealed tissue-specific and hormone-responsive expression patterns of MeTCP genes. Moreover, with global expression and promoter analysis, we found that MeTCPs showed similar or distinct expression patterns under cold and/or drought stress, suggesting that they might participate in distinct signaling pathways. Our study provides the first comprehensive analysis of TCP gene family in the cassava genome. The data will be useful for uncovering the potential functions of MeTCP genes, and their possible roles in mediating hormone and abiotic stress responses in cassava. PMID- 28855621 TI - Immune activated monocyte exosomes alter microRNAs in brain endothelial cells and initiate an inflammatory response through the TLR4/MyD88 pathway. AB - The host immune response is critical for homeostasis; however, when chronic low level activation of the immune response with or without the driver continues, a cascade of events can trigger immunological dysfunction. Monocytes are key peripheral sensors of the immune response and their activation is instrumental in the development of cognitive impairment. Here, we show that monocytes activated by interferon alpha, lipopolysaccharide or a combination of both generate exosomes carrying significantly altered microRNA profiles compared to non activated monocytes. These exosomes alone can activate human brain microvascular endothelial cells to stimulate adhesion molecules, CCL2, ICAM1, VCAM1 and cytokines, IL1beta and IL6. This activation is through the toll like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88) pathway that activates nuclear factor-kappaB and increases monocyte chemotaxis. Inhibition of monocyte exosome release reverses endothelial cell activation and monocyte chemotaxis. Our study suggests that activated monocytes have an impact on brain vascular function through intercellular exosome signaling. PMID- 28855622 TI - Multiple origins of endosymbionts in Chlorellaceae with no reductive effects on the plastid or mitochondrial genomes. AB - Ancient endosymbiotic relationships have led to extreme genomic reduction in many bacterial and eukaryotic algal endosymbionts. Endosymbionts in more recent and/or facultative relationships can also experience genomic reduction to a lesser extent, but little is known about the effects of the endosymbiotic transition on the organellar genomes of eukaryotes. To understand how the endosymbiotic lifestyle has affected the organellar genomes of photosynthetic green algae, we generated the complete plastid genome (plastome) and mitochondrial genome (mitogenome) sequences from three green algal endosymbionts (Chlorella heliozoae, Chlorella variabilis and Micractinium conductrix). The mitogenomes and plastomes of the three newly sequenced endosymbionts have a standard set of genes compared with free-living trebouxiophytes, providing no evidence for functional genomic reduction. Instead, their organellar genomes are generally larger and more intron rich. Intron content is highly variable among the members of Chlorella, suggesting very high rates of gain and/or loss of introns during evolution. Phylogenetic analysis of plastid and mitochondrial genes demonstrated that the three endosymbionts do not form a monophyletic group, indicating that the endosymbiotic lifestyle has evolved multiple times in Chlorellaceae. In addition, M. conductrix is deeply nested within the Chlorella clade, suggesting that taxonomic revision is needed for one or both genera. PMID- 28855624 TI - A commentary: Do specific gene risk variants for schizophrenia contribute similarly to the incidence of schizophrenia world-wide? PMID- 28855623 TI - Nanocurcumin is superior to native curcumin in preventing degenerative changes in Experimental Cerebral Malaria. AB - Curcumin has many pharmacological activities despite its poor bioavailability and in vivo stability. Here, we show that a nanoformulated curcumin (PLGA-curcumin) has better therapeutic index than native curcumin in preventing the onset of neurological symptoms and delaying the death of mice in experimental cerebral malaria. Oral PLGA-curcumin was at least as effective as native curcumin at a 15 fold lower concentration in preventing the breakdown of blood-brain barrier and inhibition of brain mRNAs for inflammatory cytokines, chemokine receptor CXCR3 and its ligand CXCL10, with an increase in the anti-inflammatory cytokine IL-10. This was also reflected in serum cytokine and chemokine levels. At equivalent concentrations, a single oral dose of PLGA-curcumin was more effective in inhibiting serum IFNgamma levels and enhancing IL-10 levels than native curcumin. Even at low concentrations, PLGA-curcumin was superior to native curcumin in inhibiting the sequestration of parasitized-RBCs and CD8+ T cells in the brain. A single oral dose of 5 mg PLGA-curcumin containing 350 MUg of curcumin resulted in 3-4 fold higher concentration and prolonged presence of curcumin in the brain than that obtained with 5 mg of native curcumin, indicating better bioavailability of PLGA-curcumin. PLGA-curcumin has potential as an adjunct drug to treat human cerebral malaria. PMID- 28855625 TI - Serological Response Predicts Normalization of Cerebrospinal Fluid Abnormalities at Six Months after Treatment in HIV-Negative Neurosyphilis Patients. AB - This study aimed to determine whether a serological response could predict the normalization of cerebrospinal fluid (CSF) abnormalities at 6 months after treatment in human immunodeficiency virus (HIV)-negative neurosyphilis patients. A total of 123 neurosyphilis patients were recruited at baseline, 58 of these patients undergoing treatment, repeated CSF examinations and serological tests for syphilis at 6 months after treatment were included in the follow-up study. Before treatment, the CSF rapid plasma reagin (RPR) titer, CSF Treponema pallidum particle agglutination (TPPA) titer, CSF leukocyte count, and CSF protein concentration were correlated with both serum RPR and TPPA titers. At 6 months after treatment, 28 and nine patients achieved serological responses of RPR and TPPA tests, respectively. The sensitivities of the serological response of RPR and TPPA tests for identifying the normalization of CSF abnormalities were 60.0~83.3% and 17.1~22.2%, respectively; and 75.0~91.3% of patients showing serological response of RPR test also achieved CSF normalization, suggesting that the serological response could predict CSF normalization to some degree. Particularly, in patients with >=8-fold decreases in the serum RPR titer, the CSF RPR, CSF leukocyte count, and CSF protein concentration had normalized, and follow-up lumbar puncture could be reduced considering the resolution of neurological symptoms. PMID- 28855626 TI - Dual roles of Abeta in proliferative processes in an amyloidogenic model of Alzheimer's disease. AB - Alzheimer's disease is a major neurodegenerative disorder that leads to severe cognitive deficits in the elderly population. Over the past two decades, multiple studies have focused on elucidating the causative factors underlying memory defects in Alzheimer's patients. In this regard, new evidence linking Alzheimer's disease-related pathology and neuronal stem cells suggests that hippocampal neurogenesis impairment is an important factor underlying these cognitive deficits. However, because of conflicting results, the impact of Abeta pathology on neurogenesis/gliogenesis remains unclear. Here, we investigated the effect of Abeta on neuronal and glial proliferation by using an APP/PS1 transgenic model and in vitro assays. Specifically, we showed that neurogenesis is affected early in the APP/PS1 hippocampus, as evidenced by a significant decrease in the proliferative activity due to a reduced number of both radial glia-like neural stem cells (type-1 cells) and intermediate progenitor cells (type-2 cells). Moreover, we demonstrated that soluble Abeta from APP/PS1 mice impairs neuronal cell proliferation using neurosphere cultures. On the other hand, we showed that oligomeric Abeta stimulates microglial proliferation, whereas no effect was observed on astrocytes. These findings indicate that Abeta has a differential effect on hippocampal proliferative cells by inhibiting neuronal proliferation and triggering the formation of microglial cells. PMID- 28855627 TI - Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model. AB - Induced pluripotent stem cell-derived neural stem cells (iNSCs) have significant potential as an autologous, multifunctional cell therapy for stroke, which is the primary cause of long term disability in the United States and the second leading cause of death worldwide. Here we show that iNSC transplantation improves recovery through neuroprotective, regenerative, and cell replacement mechanisms in a novel ischemic pig stroke model. Longitudinal multiparametric magnetic resonance imaging (MRI) following iNSC therapy demonstrated reduced changes in white matter integrity, cerebral blood perfusion, and brain metabolism in the infarcted tissue. The observed tissue level recovery strongly correlated with decreased immune response, enhanced neuronal protection, and increased neurogenesis. iNSCs differentiated into neurons and oligodendrocytes with indication of long term integration. The robust recovery response to iNSC therapy in a translational pig stroke model with increased predictive potential strongly supports that iNSCs may be the critically needed therapeutic for human stroke patients. PMID- 28855628 TI - Perioperative statin administration with decreased risk of postoperative atrial fibrillation, but not acute kidney injury or myocardial infarction: A meta analysis. AB - A controversy effect of perioperative statin use for preventing postoperative atrial fibrillation (POAF) and acute kidney injury (AKI) after cardiac surgery still remains. We thus performed current systematic review and meta-analysis to comprehensively evaluate effects of statin in cardiac surgery. 22 RCTs involving 5243 patients were included. Meta-analysis of 18 randomized controlled trials with 3995 participants suggested that perioperative statin use could decrease the risk of POAF (relative risk [RR] 0.69, 95%CI 0.56 to 0.86, P = 0.001), with a moderate heterogeneity (I 2 = 65.7%, P H < 0.001). And the beneficial effect was found only in patients receiving coronary artery bypass graft (CABG), but not in patients undergoing valve surgery. However, perioperative statin use was not associated with lower risks of AKI (RR 0.98, 95%CI 0.70 to 1.35, P = 0.884, I 2 = 33.9%, P H = 0.157) or myocardial infarction (MI) (RR 0.84, 95%CI 0.58 to 1.23, P = 0.380, I 2 = 0%, P H = 0.765), and even an increased trend of AKI was observed in patients with valve surgery. Perioperative statin use could decrease the inflammation response with no impact on clinical outcomes. In conclusion, perioperative statin use is useful in preventing POAF, particularly in patients with CABG, and ameliorate inflammation, while it has no effect on AKI and MI after cardiac surgery. PMID- 28855629 TI - Location of the Central Retinal Vessel Trunk in the Laminar and Prelaminar Tissue of Healthy and Glaucomatous Eyes. AB - Glaucoma is a leading cause of blindness that leads to characteristic changes in the optic nerve head (ONH) region, such as nasalization of vessels. It is unknown whether the spatial location of this vessel shift inside the ONH occurs within the lamina cribrosa (LC) or the prelaminar tissue. The purpose of this study was to compare the location of the central retinal vessel trunk (CRVT) in the LC and prelaminar tissue in living healthy and glaucomatous eyes. We acquired 3 dimensional ONH scans from 119 eyes (40 healthy, 29 glaucoma suspect, and 50 glaucoma) using optical coherence tomography (OCT). The CRVT location was manually delineated in separate projection images of the LC and prelamina. We found that the CRVT in glaucoma suspect and glaucomatous eyes was located significantly more nasally compared to healthy eyes at the level of the prelamina. There was no detectable difference found in the location of the CRVT at the level of the LC between diagnostic groups. While the nasal location of the CRVT in the prelamina has been associated with glaucomatous axonal death, our results suggest that the CRVT in the LC is anchored in the tissue with minimal variation in glaucomatous eyes. PMID- 28855630 TI - PPARalpha activation protects against cholestatic liver injury. AB - Intrahepatic cholestasis induced by drug toxicity, bile salt export pump (BSEP) deficiency, or pregnancy frequently causes cholestatic liver damage, which ultimately may lead to liver fibrosis and cirrhosis. Here, the preventive and therapeutic effects of peroxisome proliferator-activated receptor alpha (PPARalpha) signaling activated by fenofibrate was evaluated on cholestatic liver damage. Metabolomic analysis revealed that alpha-naphthyl isothiocyanate (ANIT) induced intrahepatic cholestasis resulted in the accumulation of serum long-chain acylcarnitines and triglyceride, and the reduced expression of four fatty acid beta-oxidation (beta-FAO) relevant genes (Cpt1b, Cpt2, Mcad and Hadha), indicating the disruption of beta-FAO. The increase of acylcarnitines in hepatic cell resulted in the enhanced expression of anti-oxidative genes glutathione S transferases (Gsta2 and Gstm3) directly. As direct PPARalpha-regulated genes, Cpt1b, Cpt2, and Mcad were up-regulated after pretreatment with PPARalpha agonist, fenofibrate, indicating the improvement of beta-FAO. In the end, the disrupted bile acid metabolism in the enterohepatic circulation and the enhanced oxidative stress and inflammation cytokines induced by ANIT exposure were significantly recovered with the improvement of beta-FAO using fenofibrate treatment. These findings provide the rationale for the use of PPARalpha agonists as therapeutic alternatives for cholestatic liver damage. PMID- 28855631 TI - Functional analysis of a novel, thyroglobulin-embedded microRNA gene deregulated in papillary thyroid carcinoma. AB - MicroRNAs, non-coding regulators of gene expression, are known culprits of thyroid cancer. Using next-generation sequencing, we identified a novel microRNA gene, encoded within an important thyroid regulator - thyroglobulin, and analyzed its functionality in the thyroid gland. In vitro and in silico analyses proved that the novel miR-TG is processed from the precursor, and co-expressed with thyroglobulin. Both genes are specific for thyroid tissue and downregulated in papillary thyroid carcinoma by 44% (p = 0.04) and 48% (p = 0.001), respectively. Putative target genes for miR-TG were identified using in silico tools, which pinpointed MAP4K4, an oncogene upregulated in thyroid cancer. Analysis of transcriptome by RNA-seq revealed that overexpression of miR-TG in PTC-derived cell line led to downregulation of several genes, including MAP4K4 (fold change 0,82; p = 0.036). The finding was confirmed by SQ-PCR (fold change 071; p = 0.004). Direct interaction between miR-TG and MAP4K4 was confirmed in the luciferase assay (p = 0.0006). Functional studies showed increase proliferation in K1 cell line transfected with miR-TG. We propose that in normal thyroid miR-TG plays a fine-tuning effect on the maintenance of MAPK pathway, inhibiting the expression of miR's target MAP4K4. This regulation is disturbed in cancer due to downregulation of the novel, thyroglobulin-embedded microRNA, characterized in this study. PMID- 28855632 TI - Resolution Agonist 15-epi-Lipoxin A4 Programs Early Activation of Resolving Phase in Post-Myocardial Infarction Healing. AB - Following myocardial infarction (MI), overactive inflammation remodels the left ventricle (LV) leading to heart failure coinciding with reduced levels of 15-epi Lipoxin A4 (15-epi LXA4). However, the role of 15-epi LXA4 in post-MI acute inflammatory response and resolving phase is unclear. We hypothesize that liposomal fusion of 15-epi-LXA4 (Lipo-15-epi-LXA4) or free 15-epi-LXA4 will expedite the resolving phase in post-MI inflammation. 8 to 12-week-old male C57BL/6 mice were subjected to permanent coronary artery ligation. Lipo-15-epi LXA4 or 15-epi-LXA4 (1 ug/kg/day) was injected 3 hours post-MI for (d)1 or continued daily till d5. 15-epi-LXA4 activated formyl peptide receptor (FPR2) and GPR120 on alternative macrophages but inhibited GPR40 on classical macrophages in vitro. The 15-epi-LXA4 injected mice displayed reduced LV and lung mass to body weight ratios and improved ejection fraction at d5 post-MI. In the acute phase of inflammation-(d1), 15-epi-LXA4 primes neutrophil infiltration with a robust increase of Ccl2 and FPR2 expression. During the resolving phase-(d5), 15-epi LXA4 initiated rapid neutrophils clearance with persistent activation of FPR2 in LV. Compared to MI-control, 15-epi-LXA4 injected mice showed reduced renal inflammation along with decreased levels of ngal and plasma creatinine. In summary, 15-epi-LXA4 initiates the resolving phase early to discontinue inflammation post-MI, thereby reducing LV dysfunction. PMID- 28855633 TI - First genome report and analysis of chicken H7N9 influenza viruses with poly basic amino acids insertion in the hemagglutinin cleavage site. AB - We report the full-length sequence of two chicken source influenza A (H7N9) viruses found in Guangdong live poultry market (LPM) during the most recent wave of human infections (from October 2016 to the present time). These viruses carry insertion of poly-basic amino acids (KGKRTAR/G) at the protease cleavage site of the HA protein, which were previously found in the highly pathogenic (HP) human influenza A (H7N9) [IAV(H7N9)] strains. Phylogenetic analysis of these two novel avian influenza viruses (AIVs) suggested that their genomes reassorted between the Yangtze River Delta (YRD) and Pearl River Delta (PRD) clades. Molecular clock analysis indicated that they emerged several months before the HP human strains. Collectively, our results suggest that IAV(H7N9) viruses evolve in chickens through antigenic drift to include a signature HP sequence in the HA gene, which highlights challenges in risk assessment and public health management of IAV(H7N9) infections at the human-animal interface. PMID- 28855634 TI - New dating evidence of the early presence of hominins in Southern Europe. AB - The first "Out of Africa" migrations represent a seminal event in the history of humankind. At the gates of Europe, the first appearance of Hominins is recorded in Georgia, 1.8 million years ago (Ma); however, the picture of migration across the continent remains incomplete. Vallonnet Cave (France) is a Lower Paleolithic prehistoric site with traces of hominin activities including lithic remains and cut-marks on mammal bones. Here, we apply the uranium-lead (U-Pb) methods to two flowstones to date the intervening archaeological levels. The U-Pb data, coupled with paleomagnetic constraints, provide an age range from 1.2 to 1.1 Ma. The results conclusively demonstrate that Vallonnet Cave is one of the oldest European prehistoric sites in France with early hominin occupations associated with an Epivillafranchian fauna. Combined with data from other archaeological sites, the new precise chronology suggests a widespread occupation the Northern Mediterranean to Southwestern Europe at ~1.2 Ma. PMID- 28855635 TI - Highly efficient DNA-free gene disruption in the agricultural pest Ceratitis capitata by CRISPR-Cas9 ribonucleoprotein complexes. AB - The Mediterranean fruitfly Ceratitis capitata (medfly) is an invasive agricultural pest of high economic impact and has become an emerging model for developing new genetic control strategies as an alternative to insecticides. Here, we report the successful adaptation of CRISPR-Cas9-based gene disruption in the medfly by injecting in vitro pre-assembled, solubilized Cas9 ribonucleoprotein complexes (RNPs) loaded with gene-specific single guide RNAs (sgRNA) into early embryos. When targeting the eye pigmentation gene white eye (we), a high rate of somatic mosaicism in surviving G0 adults was observed. Germline transmission rate of mutated we alleles by G0 animals was on average above 52%, with individual cases achieving nearly 100%. We further recovered large deletions in the we gene when two sites were simultaneously targeted by two sgRNAs. CRISPR-Cas9 targeting of the Ceratitis ortholog of the Drosophila segmentation paired gene (Ccprd) caused segmental malformations in late embryos and in hatched larvae. Mutant phenotypes correlate with repair by non-homologous end-joining (NHEJ) lesions in the two targeted genes. This simple and highly effective Cas9 RNP-based gene editing to introduce mutations in C. capitata will significantly advance the design and development of new effective strategies for pest control management. PMID- 28855636 TI - A novel chiral stationary phase LC-MS/MS method to evaluate oxidation mechanisms of edible oils. AB - The elucidation of lipid oxidation mechanisms of food is vital. In certain lipids, characteristic lipid hydroperoxide isomers are formed by different oxidation mechanisms (i.e., photo-oxidation or auto-oxidation). For example, linoleic acid is photo-oxidized to 13-9Z, 11E-hydroperoxyoctadecadienoic acid (HPODE), 12-9Z,13E-HPODE, 10-8E,12Z-HPODE and 9-10E,12Z-HPODE, whereas 13-9Z, 11E HPODE, 13-9E,11E-HPODE, 9-10E,12Z-HPODE and 9-10E,12E-HPODE are formed by auto oxidation. Therefore, we considered that oxidation mechanisms could be evaluated by analyzing these characteristic positional and cis/trans lipid hydroperoxide isomers. In this study, we developed a novel chiral stationary phase LC-MS/MS (CSP-LC-MS/MS) method to analyze the positional and cis/trans isomers of HPODE, with the use of a chiral column and sodium ion. Also, as an application of the method, either light-exposed or heated edible oils were treated with lipase to hydrolyze triacylglycerols. The resultant fatty acids including HPODE isomers were analyzed with the developed method. As a result, HPODE isomers characteristic to photo-oxidation were certainly detected in light-exposed edible oils. On the other hand, in heated edible oils, the HPODE isomers characteristic to auto-oxidation were largely increased. Thus, the combination of the developed CSP-LC-MS/MS method with lipase proves to be a powerful tool to evaluate the involvement and mechanisms of lipid oxidation in the process of food deterioration. PMID- 28855637 TI - Direct comparison of methionine restriction with leucine restriction on the metabolic health of C57BL/6J mice. AB - The effects of methionine restriction (MR) in rodents are well established; it leads to decreased body and fat mass, improved glucose homeostasis and extended lifespan, despite increased energy intake. Leucine restriction (LR) replicates some, but not all, of these effects of MR. To determine any differences in metabolic effects between MR and LR, this study compared 8 weeks of MR (80% restriction), LR (80% restriction) and control diet in 10-month-old C57BL/6J male mice. Body composition, food intake and glucose homeostasis were measured throughout the study and biochemical analyses of white adipose tissue (WAT) and liver were performed. MR and LR decreased body and fat mass, increased food intake, elevated lipid cycling in WAT and improved whole-body glucose metabolism and hepatic insulin sensitivity in comparison to the control diet. MR produced more substantial effects than LR on body mass and glucose homeostasis and reduced hepatic lipogenic gene expression, which was absent with the LR diet. This could be a result of amino acid-specific pathways in the liver responsible for FGF21 stimulation (causing varied levels of FGF21 induction) and Akt activation. In summary, LR is effective at improving metabolic health; however, MR produces stronger effects, suggesting they activate distinct signalling pathways. PMID- 28855638 TI - Detection of frequency-dependent endothelial response to oscillatory shear stress using a microfluidic transcellular monitor. AB - The endothelial microenvironment is critical in maintaining the health and function of the intimal layer in vasculature. In the context of cardiovascular disease (CVD), the vascular endothelium is the layer of initiation for the progression of atherosclerosis. While laminar blood flows are known to maintain endothelial homeostasis, disturbed flow conditions including those the endothelium experiences in the carotid artery are responsible for determining the fate of CVD progression. We present a microfluidic device designed to monitor the endothelium on two fronts: the real-time monitoring of the endothelial permeability using integrated electrodes and the end-point characterization of the endothelium through immunostaining. Our key findings demonstrate endothelial monolayer permeability and adhesion protein expression change in response to oscillatory shear stress frequency. These changes were found to be significant at certain frequencies, suggesting that a frequency threshold is needed to elicit an endothelial response. Our device made possible the real-time monitoring of changes in the endothelial monolayer and its end-point inspection through a design previously absent from the literature. This system may serve as a reliable research platform to investigate the mechanisms of various inflammatory complications of endothelial disorders and screen their possible therapeutics in a mechanistic and high-throughput manner. PMID- 28855639 TI - Developmentally Regulated GTP binding protein 1 (DRG1) controls microtubule dynamics. AB - The mitotic spindle, essential for segregating the sister chromatids into the two evolving daughter cells, is composed of highly dynamic cytoskeletal filaments, the microtubules. The dynamics of microtubules are regulated by numerous microtubule associated proteins. We identify here Developmentally regulated GTP binding protein 1 (DRG1) as a microtubule binding protein with diverse microtubule-associated functions. In vitro, DRG1 can diffuse on microtubules, promote their polymerization, drive microtubule formation into bundles, and stabilize microtubules. HeLa cells with reduced DRG1 levels show delayed progression from prophase to anaphase because spindle formation is slowed down. To perform its microtubule-associated functions, DRG1, although being a GTPase, does not require GTP hydrolysis. However, all domains are required as truncated versions show none of the mentioned activities besides microtubule binding. PMID- 28855640 TI - Lipids, fatty acids and hydroxy-fatty acids of Euphausia pacifica. AB - Euphausia pacifica is a good candidate for a resource of marine n-3 PUFA. However, few reports exist of the lipid and fatty acid composition of E. pacifica. To examine the potential of E. pacifica as a resource of marine n-3 PUFA, we analyzed E. pacifica oil. We extracted lipids from E. pacifica harvested from the Pacific Ocean near Sanriku, Japan. Lipid classes of E. pacifica oil were analyzed by TLC-FID and the fatty acid composition of the oil was analyzed by GC/MS. Free fatty acids and hydroxy-fatty acids were analyzed by LC/QTOFMS. The lipid content of E. pacifica ranged from 1.30% to 3.57%. The ratios of triacylglycerols, phosphatidylcholine, phosphatidylethanolamine and free fatty acids in E. pacifica lipids were 5.3-23.0%, 32.6-53.4%, 8.5-25.4% and 2.5-7.0%, respectively. The content of n-3 PUFA in E. pacifica lipids was 38.6-46.5%. We also showed that E. pacifica contains unusual fatty acids and derivatives: C16 PUFAs (9,12-hexadecadienoic acid, 6,9,12-hexadecatrienoic acid and 6,9,12,15 hexadecatetraenoic acid) and hydroxy-PUFAs (8-HETE and 10-HDoHE). E. pacifica is a good resource of marine n-3 PUFA. Moreover, E. pacifica can provide C16-PUFA and hydroxy-PUFAs. PMID- 28855641 TI - CRISPR/Cas9-mediated mutagenesis of the dihydroflavonol-4-reductase-B (DFR-B) locus in the Japanese morning glory Ipomoea (Pharbitis) nil. AB - CRISPR/Cas9 technology is a versatile tool for targeted mutagenesis in many organisms, including plants. However, this technique has not been applied to the Japanese morning glory (Ipomoea [Pharbitis] nil), a traditional garden plant chosen for the National BioResource Project in Japan. We selected dihydroflavonol 4-reductase-B (DFR-B) of I. nil, encoding an anthocyanin biosynthesis enzyme, as the target gene, and changes in the stem colour were observed during the early stages of plant tissue culture by Rhizobium [Agrobacterium]-mediated transformation. Twenty-four of the 32 (75%) transgenic plants bore anthocyanin less white flowers with bi-allelic mutations at the Cas9 cleavage site in DFR-B, exhibiting a single base insertion or deletions of more than two bases. Thus, these results demonstrate that CRISPR/Cas9 technology enables the exploration of gene functions in this model horticultural plant. To our knowledge, this report is the first concerning flower colour changes in higher plants using CRISPR/Cas9 technology. PMID- 28855642 TI - Peripheral serotonin regulates postoperative intra-abdominal adhesion formation in mice. AB - The aim of the present study is to investigate the role and potential mechanisms of peripheral serotonin in postoperative intra-abdominal adhesion formation in mice. The caecum-rubbing operations were conducted for intra-abdominal adhesion formation modelling in wild-type and Tph1-/- mice. The deficiency of serotonin significantly decreased the adhesion scores, weight loss, and adhesion thickness as well as levels of collagen fibres and hydroxyproline in the adhesive tissues. The Tph1-/- mice exhibited a milder inflammatory response and oxidative stress in the adhesive tissues than did the wild-type mice. Moreover, the deficiency of serotonin reduced the levels of PAI-1 and fibrinogen, and raised the t-PA and t PA/PAI levels in the peritoneal fluids. Moreover, the expressions of CD34, VEGF, TGF-beta and 5-HT2B receptor in the adhesive tissues were significantly decreased in the Tph1-/- group mice. Furthermore, the Tph1-/- +5-HTP group showed more severe adhesions than did the Tph1-/- group mice, and the p-chlorophenylalanine (PCPA) could markedly alleviated the adhesion formation in the WT mice. In conclusion, the present study showed that peripheral serotonin regulated postoperative intra-abdominal adhesion formation by facilitating inflammation, oxidative stress, disorder of the fibrinolytic system, angiopoiesis and TGF-beta1 expression via the 5-HT2B receptor in the adhesive tissues. PMID- 28855643 TI - A New Chimeric Natriuretic Peptide, CNAAC, for the Treatment of Left Ventricular Dysfunction after Myocardial Infarction. AB - An innovative natriuretic peptide analog named CNAAC (structurally consisting of the C-terminus and ring of ANP and the N-terminus of CNP) that has been shown to exhibit potent vasodilatory, diuretic, and hypotensive effects in our previous study was evaluated for the treatment of left ventricular dysfunction following myocardial infarction. The temporal relaxation effect and metabolic status of CNAAC were determined. A myocardial ischemic model was established. Rats were randomly divided into Sham, MI, MI-ANP, MI-CNP, MI-VNP, and MI-CNAAC groups. Humoral factors were measured; echocardiography and hemodynamics methods were employed to assess the cardiac function at the fourth week after modeling. The results showed that CNAAC had a potent relaxant effect and longer duration of action than ANP, CNP, or VNP. The stability of CNAAC in blood was higher than other three NPs. Four weeks of NP administration ameliorated diastolic and systolic dysfunction, the hypertrophic index, myocardial fibrosis, and infarct size; it also restored the abnormal changes in humoral factors. These results demonstrate that CNAAC has a potent cardioprotective effect against left ventricular dysfunction after myocardial infarction. The results may lay the foundation for the clinical application of this newly designed NP chimera in the treatment and prevention of heart failure. PMID- 28855644 TI - Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer. AB - The poor efficacy of systemic cancer therapeutics in pancreatic ductal adenocarcinoma (PDAC) is partly attributed to deposition of collagen and hyaluronan, leading to interstitial hypertension collapsing blood and lymphatic vessels, limiting drug delivery. The intrinsic micro -regional interactions between hyaluronic acid (HA), collagen and the spatial origins of mechanical stresses that close off blood vessels was investigated here. Multiple localized pressure measurements were analyzed with spatially-matched histochemical images of HA, collagen and vessel perfusion. HA is known to swell, fitting a linear elastic model with total tissue pressure (TTP) increasing above interstitial fluid pressure (IFP) directly with collagen content. However, local TTP appears to originate from collagen area fraction, as well as increased its entropy and fractal dimension, and morphologically appears to be maximized when HA regions are encapsulated by collagen. TTP was inversely correlated with vascular patency and verteporfin uptake, suggesting interstitial hypertension results in vascular compression and decreased molecular delivery in PDAC. Collagenase injection led to acute decreases in total tissue pressure and increased drug perfusion. Large microscopic variations in collagen distributions within PDAC leads to microregional TPP values that vary on the hundred micron distance scale, causing micro-heterogeneous limitations in molecular perfusion, and narrows viable treatment regimes for systemically delivered therapeutics. PMID- 28855645 TI - A model to predict the incidence of allergic rhinitis based on meteorological factors. AB - Meteorological factors have been shown to affect the physiology, distribution, and amounts of inhaled allergens. The aim of this study was to develop a model to predict the trends for onset of allergic rhinitis (AR) patients. A total of 10,914 consecutive AR outpatients were assessed for the number of daily patient visits over a period of 4 years. Meteorological data were used to assess the relationship between meteorological factors and AR incidence by time-series data and regression analysis. Predictive models for incidence of AR were established in pollen-, dust mite- and mould-sensitive groups of patients, and the predictive performances of meteorological factors on the incidence of AR were estimated using root mean squared errors (RMSEs). The incidence of pollen-, dust mites- and mould-sensitive AR patients was significantly correlated with minimum temperature, vapour pressure, and sea-level pressure, respectively. The correlation between comprehensive meteorological parametric (CMP) and incidence of AR was higher than the correlation between the individual meteorological parameters and AR incidence. CMP had higher performance than individual meteorological parameters for predicting the incidence of AR patients. These findings suggest that the incidence of pollen-, dust mites- and mould-sensitive AR can be predicted employing models based on prevailing meteorological conditions. PMID- 28855646 TI - Immunization with truncated envelope protein of Zika virus induces protective immune response in mice. AB - The global spread of Zika virus (ZIKV) as well as its unexpected link to infant microcephaly have resulted in serious public health concerns. No antiviral drugs against ZIKV is currently available, and vaccine development is of high priority to prepare for potential ZIKV pandemic. In the present study, a truncated E protein with the N-terminal 90% region reserved (E90) from a contemporary ZIKV strain was cloned and expressed in Escherichia coli, purified by a Ni-NTA column, and characterized by Western blotting assays. Immunization with recombinant E90 induced robust ZIKV-specific humoral response in adult BALB/c mice. Passive transfer of the antisera from E90-immunized mice conferred full protection against lethal ZIKV challenge in a neonatal mice model. Our results indicate that recombinant ZIKV E90 described here represents as a promising ZIKV subunit vaccine that deserves further clinical development. PMID- 28855647 TI - Characterizing particulate polycyclic aromatic hydrocarbon emissions from diesel vehicles using a portable emissions measurement system. AB - Particulate polycyclic aromatic hydrocarbons (p-PAHs) emitted from diesel vehicles are of concern because of their significant health impacts. Laboratory tests, road tunnel and roadside experiments have been conducted to measure p-PAH emissions. While providing valuable information, these methods have limited capabilities of characterizing p-PAH emissions either from individual vehicles or under real-world conditions. We employed a portable emissions measurement (PEMS) to measure real-world emission factors of priority p-PAHs for diesel vehicles representative of an array of emission control technologies. The results indicated over 80% reduction in p-PAH emission factors comparing the China V and China II emission standard groups (113 MUg kg-1 vs. 733 MUg kg-1). The toxicity abatement in terms of Benzo[a]pyrene equivalent emissions was substantial because of the large reductions in highly toxic components. By assessing real traffic conditions, the p-PAH emission factors on freeways were lower than on local roads by 52% +/- 24%. A significant correlation (R2~0.85) between the p-PAH and black carbon emissions was identified with a mass ratio of approximately 1/2000. A literature review indicated that diesel p-PAH emission factors varied widely by engine technology, measurement methods and conditions, and the molecular diagnostic ratio method for source apportionment should be used with great caution. PMID- 28855648 TI - The two-pore channel TPC1 is required for efficient protein processing through early and recycling endosomes. AB - Two-pore channels (TPCs) are localized in endo-lysosomal compartments and assumed to play an important role for vesicular fusion and endosomal trafficking. Recently, it has been shown that both TPC1 and 2 were required for host cell entry and pathogenicity of Ebola viruses. Here, we investigate the cellular function of TPC1 using protein toxins as model substrates for distinct endosomal processing routes. Toxin uptake and activation through early endosomes but not processing through other compartments were reduced in TPC1 knockout cells. Detailed co-localization studies with subcellular markers confirmed predominant localization of TPC1 to early and recycling endosomes. Proteomic analysis of native TPC1 channels finally identified direct interaction with a distinct set of syntaxins involved in fusion of intracellular vesicles. Together, our results demonstrate a general role of TPC1 for uptake and processing of proteins in early and recycling endosomes, likely by providing high local Ca2+ concentrations required for SNARE-mediated vesicle fusion. PMID- 28855649 TI - Dysfunction of the circadian transcriptional factor CLOCK in mice resists chemical carcinogen-induced tumorigenesis. AB - The chronic disruption of circadian rhythms has been implicated in the risk of cancer development in humans and laboratory animals. The gene product CLOCK is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in various physiological processes. However, we demonstrated here that Clk/Clk mice resisted chemical carcinogen induced tumorigenesis by suppressing epidermal growth factor (EGF) receptor mediated proliferation signals. The repetitive application of 7,12 dimethylbenz[alpha]anthracene (DMBA) to skin on the back resulted in the significant development of tumors in wild-type mice, whereas chemically-induced tumorigenesis was alleviated in Clk/Clk mice. Although the degree of DMBA-induced DNA damage was not significantly different between wild-type and Clk/Clk mice, EGF receptor-mediated Ras activation was not detected in DMBA-treated Clk/Clk mice. Genetic and biochemical experiments revealed that the suppression of EGF receptor-mediated signal transduction in DMBA-treated Clk/Clk mice was associated with the expression of the cellular senescence factor p16INK4a. These results suggest an uncovered role for CLOCK in the development of chemical carcinogen induced primary tumors and offers new preventive strategies. PMID- 28855650 TI - Novel Rbfox2 isoforms associated with alternative exon usage in rat cortex and suprachiasmatic nucleus. AB - Transcriptome diversity in adult neurons is partly mediated by RNA binding proteins (RBPs), including the RBFOX factors. RBFOX3/NeuN, a neuronal maturity marker, is strangely depleted in suprachiasmatic nucleus (SCN) neurons, and may be compensated by a change in Rbfox2 expression. In this study, we found no superficial changes in Rbfox2 expression in the SCN, but mRNA population analysis revealed a distinct SCN transcript profile that includes multiple novel Rbfox2 isoforms. Of eleven isoforms in SCN and cerebral cortex that exhibit exon variation across two protein domains, we found a 3-fold higher abundance of a novel ('-12-40') C-terminal domain (CTD)-variant in the SCN. This isoform embraces an alternative reading frame that imparts a 50% change in CTD protein sequence, and functional impairment of exon 7 exclusion activity in a RBFOX2 target, the L-type calcium channel gene, Cacna1c. We have also demonstrated functional correlates in SCN gene transcripts; inclusion of Cacna1c exon 7, and also exclusion of both NMDA receptor gene Grin1 exon 4, and Enah exon 12, all consistent with a change in SCN RBFOX activity. The demonstrated regional diversity of Rbfox2 in adult brain highlights the functional adaptability of this RBP, enabling neuronal specialization, and potentially responding to disease related neuronal dysfunction. PMID- 28855651 TI - A novel sex-linked mutant affecting tail formation in Hongshan chicken. AB - The Hongshan chicken is a Chinese indigenous breed that has two distinctly different tail types. Some chickens have stunted tails as compared to the normal phenotype, and they are termed rumpless. Rumplessness in other chicken breeds was caused by a reduction in the number of coccygeal vertebrae. However, X-ray examination showed that rumpless Hongshan chickens possess the normal number of coccygeal vertebrae. Our analyses of the main tail feathers and tissue sections led us to speculate that their stunted tail appearance may be the result of abnormal feather development. To investigate the genetic mechanism underlying rumplessness in Hongshan chickens, we analyzed the results of various crosses. The results indicated that rumplessness is a Z-linked dominant character. In addition, we chose some normal and rumpless individuals for pool-sequencing. Nucleotide diversity and Fst were calculated, and a selective sweep was detected on the Z chromosome. These analyses allowed us to reduce the search area to 71.8 72 Mb on the Z chromosome (galGal5.0). A pseudogene LOC431648 located in this region appeared a strong candidate involving in Wnt/beta-catenin signaling pathway to regulate feather development in chickens. PMID- 28855652 TI - XWL-1-48 exerts antitumor activity via targeting topoisomerase II and enhancing degradation of Mdm2 in human hepatocellular carcinoma. AB - A novel podophyllotoxin derivative, XWL-1-48, was synthesized as an oral topoisomerase II inhibitor. kDNA decatenation assay indicated that XWL-1-48 significantly inhibited topoisomerase II activity in a concentration-dependent manner. Moreover, the cytotoxicity of XWL-1-48 is more potent than its congener GL331 and the IC50 values are from 0.34 +/- 0.21 to 3.54 +/- 0.54 uM in 10 cancer cell lines including KBV200 cells with P-gp overexpression. Noticeably, XWL-1-48 exerted potent antitumor activity in in vitro and in vivo human hepatocellular carcinoma (HCC) model. Further studies demonstrated that treatment of XWL-1-48 induced gamma-H2AX and p-ATM expression, and further triggered DNA damage response through activation of ATM-p53-p21 and ATM-Chk2-Cdc25A pathways. Targeted inhibition of ATM by siRNA attenuated the ability of XWL-1-48 on inducing DNA damage. XWL-1-48 significantly suppressed Cyclin A and p-Cdk2 (Thr160) expression, increased p-Cdk2 (Thr14), led to inactivation of Cyclin A/Cdk2 complex, arrested cell cycle at S phase. Finally, XWL-1-48 elevated the ratio of Bax/Bcl2 and induced Fas and FasL, initiated mitochondria- and death receptor mediated apoptosis pathway. Meanwhile, XWL-1-48 evidently enhanced degradation of Mdm2, blocked PI3K/Akt/Mdm2 pathway and suppressed HCC cell survival. Thus, XWL-1 48 may be a promising orally topoisomerase II inhibitor for treatment of HCC. PMID- 28855653 TI - A Valuable Biochar from Poplar Catkins with High Adsorption Capacity for Both Organic Pollutants and Inorganic Heavy Metal Ions. AB - In this paper, biochar derived from poplar catkins was used as an economical and renewable adsorbent for adsorption organic and inorganic pollutants such as, dyes, organic compounds, and heavy metal ions from wastewater. Mesoporous activated carbonized poplar catkins (ACPCs) were produced from char as a by product by carbonized poplar catkins (CPCs). With their high surface area, ACPCs exhibited the maximum adsorption capacities of 71.85 and 110.17 mg/g for the removal of inorganic U(VI) and Co(II). Compared other biochars adsorbents, ACPCs can also adsorb organic pollutants with the maximum adsorption capacities of 534, 154, 350, 148 and 384 mg/g for methylene blue (MB), methyl orange (MO), Congo red (CR), chloramphenicol (CAP) and naphthalene. The adsorption of organic pollutants was fitted with pseudo-first order, pseudo-second order, and intra-particle diffusion kinetic models figure out the kinetic parameters and adsorption mechanisms. Langmuir adsorption isotherm was found to be suitable for Co(II) and U(VI) adsorption and thermodynamic studies indicated adsorption processes to be endothermic and spontaneous. The adsorption process includes both outer-sphere surface complexes and hydrogen-bonding interactions. The results showed that biochar derived from poplar catkins was a potential material to remove pollutants in wastewater. PMID- 28855655 TI - Role of 2D and 3D defects on the reduction of LaNiO3 nanoparticles for catalysis. AB - Solid phase crystallization offers an attractive route to synthesize Ni nanoparticles on a La2O3 support. These materials have shown great promise as catalysts for methane oxidation and similar reactions. Synthesis is achieved by the reduction of a LaNiO3 (LNO) precursor at high temperatures, but the reduction pathway can follow a variety of routes. Optimization of catalytic properties such as the long-term stability has been held back by a lack of understanding of the factors impacting the reduction pathway, and its strong influence on the structure of the resulting Ni/La2O3 catalyst. Here we show the first evidence of the importance of extended structural defects in the LNO precursor material (2D stacking faults and 3D inclusions) for determining the reaction pathway and therefore the properties of the final catalyst. Here we compare the crystallization of LNO nanoparticles via two different pathways using in-situ STEM, in-situ synchrotron XRD, and DFT electronic structure calculations. Control of extended defects is shown to be a key microstructure component for improving catalyst lifetimes. PMID- 28855654 TI - A Meta-analysis of Voxel-based Brain Morphometry Studies in Obstructive Sleep Apnea. AB - Gray matter (GM) anomalies may represent a critical pathology underlying obstructive sleep apnea (OSA). However, the evidence regarding their clinical relevance is inconsistent. We conducted a meta-analysis of voxel-based morphometry (VBM) studies of patients with OSA to identify their brain abnormalities. A systematic search was conducted based on PRISMA guidelines, and a meta-analysis was performed using the anisotropic effect-size-based algorithms (ASE-SDM) to quantitatively estimate regional GM changes in patients with OSA. Fifteen studies with 16 datasets comprising 353 untreated patients with OSA and 444 healthy controls were included. Our results revealed GM reductions in the bilateral anterior cingulate/paracingulate gyri (ACG/ApCG), left cerebellum (lobules IV/V and VIII), bilateral superior frontal gyrus (SFG, medial rostral part), right middle temporal gyrus (MTG), and right premotor cortex. Moreover, GM reductions in the bilateral ACG/ApCG were positively associated with body mass index (BMI) and age among patients with OSA, and GM reductions in the SFG (medial rostral part) were negatively associated with Epworth sleepiness scale (ESS) scores and sex (male). These abnormalities may represent structural brain underpinnings of neurocognitive abnormalities and respiratory-related abnormalities in OSA. In particular, this study adds to Psychoradiology, which is a promising subspecialty of clinical radiology mainly for psychiatric disorders. PMID- 28855656 TI - PPARalpha-dependent Insig2a overexpression inhibits SREBP-1c processing during fasting. AB - Peroxisome-proliferator-activated receptor alpha (PPARalpha) and sterol regulatory element-binding protein (SREBP) play a role in regulating cellular fatty acid and cholesterol homeostasis via fatty acid oxidation and lipogenesis. The control of SREBP processing is regulated by the insulin induced gene (INSIG)2a protein, which binds SREBP to prevent SREBP translocation to the Golgi apparatus during nutrient starvation in the liver. However, the regulation of SREBP-1c processing by INSIGs during fasting and the regulatory mechanisms of the mouse Insig2a gene expression have not been clearly addressed. In the present study, we found that Insig2a was upregulated by PPARalpha in mouse livers and primary hepatocytes during fasting, whereas Insig2a mRNA expression was decreased in the livers of refed mice. A PPAR-responsive element between -126 bp and -114 bp in the Insig2a promoter was identified by a transient transfection assay and a chromatin immunoprecipitation assay; its role in regulation by PPARalpha was characterised using Pparalpha-null mice. These results suggest that PPARalpha is a trans-acting factor that enhances Insig2a gene expression, thereby suppressing SREBP-1c processing during fasting. PMID- 28855658 TI - The Diagnostic Value of Global Longitudinal Strain (GLS) on Myocardial Infarction Size by Echocardiography: A Systematic Review and Meta-analysis. AB - A systematic review and meta-analysis of prospective randomized studies were performed to evaluate the diagnostic value of measuring global longitudinal strain (GLS) using speckle tracking echocardiography (STE) in determining myocardial infarction (MI) size, which is usually measured based on late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR). Eleven trials with a total of 765 patients were included. The pooled correlation was 0.70 (95% CI: 0.64, 0.74) between two-dimensional (2D) GLS and the LGE percentage, and it was 0.55 (95% CI: 0.19, 0.78) for three-dimensional (3D) GLS. Pooled diagnostic estimates for 2D GLS to differentiate an MI size >12% were as follows: sensitivity, 0.77 (95% CI: 0.61, 0.90); specificity, 0.86 (95% CI: 0.68, 0.96); positive likelihood ratio (PLR), 8.13 (95% CI: 1.90, 26.61); negative likelihood ratio (NLR), 0.28 (95% CI: 0.10, 0.54); and diagnostic odds ratio (DOR), 39.87 (95% CI: 4.12, 172.83). The estimated area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.702. The 2D STE results positively correlated with the infarction size quantified by CMR for patients who had experienced their first MI. This approach can serve as a good diagnostic index for assessing infarction area. However, more consolidated STE studies are still needed to determine the value of 3D STE. PMID- 28855657 TI - Plasmodium vivax ligand-receptor interaction: PvAMA-1 domain I contains the minimal regions for specific interaction with CD71+ reticulocytes. AB - The malarial parasite's invasion is complex, active and coordinated, involving many low and high affinity interactions with receptors on target cell membrane. Proteomics analysis has described around 40 proteins in P. vivax which could be involved in reticulocyte invasion; few have been studied with the aim of elucidating how many of them establish specific interactions with their respective host cells. Given the importance of knowing which of the parasite's protein regions are functionally important for invasion, minimum regions mediating specific interaction between Plasmodium vivax apical membrane antigen 1 (PvAMA-1) and its host cell were here elucidated. The region covering PvAMA-1 domains I and II (PvAMA-DI-II) specifically bound to the CD71+ red blood cell subpopulation. A 20 residue-long region (81EVENAKYRIPAGRCPVFGKG100) located in domain I was capable of inhibiting PvAMA-DI-II recombinant protein binding to young reticulocytes (CD71+CD45-) and rosette formation. This conserved peptide specifically interacted with high affinity with reticulocytes (CD71+) through a neuraminidase- and chymotrypsin-treatment sensitive receptor. Such results showed that, despite AMA-1 having universal functions during late Plasmodium invasion stages, PvAMA-1 had reticulocyte-preferring binding regions, suggesting that P. vivax target cell selection is not just restricted to initial interactions but maintained throughout the erythrocyte invasion cycle, having important implications for designing a specific anti-P. vivax vaccine. PMID- 28855659 TI - Increased Risk of Atrial Fibrillation and Thromboembolism in Patients with Severe Psoriasis: a Nationwide Population-based Study. AB - Psoriasis increases the risk of atrial fibrillation (AF) and thromboembolic events (TE). There is limited information on the effect of psoriasis severity on AF and TE. In this study, psoriasis patients were enrolled from the Korean National Insurance Service-National Sample Cohort (2004-2008). Diagnosis and disease severity were determined from claims data. Newly diagnosed non-valvular AF and TE were identified during a 9.6-year follow-up. The effect of psoriasis severity on AF and TE was evaluated. We identified 13,385 psoriasis patients (1,947 with severe psoriasis). Severe psoriasis significantly increased the risk of AF (adjusted hazard ratio [HRadjust] 1.44 [95% confidence interval (CI) 1.14 1.82], p = 0.002) and TE (HRadjust 1.26 [95% CI 1.07-1.47], p = 0.005); mild psoriasis did not show any significant effects. Results were similar after propensity-score matching. Risk increments of AF and TE were prominent in patients with greater cardiovascular risk. A possible limitation of our study is that it has a retrospective design, and the effect of unmeasured confounders and risk of misclassification could bias the results. To conclude, our results showed that severe, but not mild, psoriasis significantly increased AF and TE risk. AF surveillance and active stroke prevention would be beneficial in such cases. PMID- 28855661 TI - Effects of twin orientation and spacing on the mechanical properties of Cu nanowires. AB - The role of twin orientation in mechanical behaviors of nanomaterials is drawing increasing attention. In this paper, atomistic simulations on the tensile deformation of twinned Cu nanowires (NWs) are implemented to investigate the twin orientation and spacing effects. The results of numerical simulations reveal that the tensile deformation mechanisms can be divided into three types with the twin orientation varying from 0 degrees to 90 degrees : dislocations slip intersecting with twin boundary (TB), stacking faults formed parallel to the TB and TB migration. Detail analysis about dislocation motion is carried out to illustrate the plastic deformation mechanisms. In addition, with the increasing of the TB spacing, there is a transition from yield with strain hardening to yield with nearly constant flow stress. The peak stress decreases with the increase of TB spacing, which can be attributed to surface roughness caused by crystal reorientation. Our findings also suggest a possible approach to tune the mechanical behaviors of low dimensional nanostructures. PMID- 28855660 TI - Nitrosative stress defences of the enterohepatic pathogenic bacterium Helicobacter pullorum. AB - Helicobacter pullorum is an avian bacterium that causes gastroenteritis, intestinal bowel and hepatobiliary diseases in humans. Although H. pullorum has been shown to activate the mammalian innate immunity with release of nitric oxide (NO), the proteins that afford protection against NO and reactive nitrogen species (RNS) remain unknown. Here several protein candidates of H. pullorum, namely a truncated (TrHb) and a single domain haemoglobin (SdHb), and three peroxiredoxin-like proteins (Prx1, Prx2 and Prx3) were investigated. We report that the two haemoglobin genes are induced by RNS, and that SdHb confers resistance to nitrosative stress both in vitro and in macrophages. For peroxiredoxins, the prx2 and prx3 expression is enhanced by peroxynitrite and hydrogen peroxide, respectively. Mutation of prx1 does not alter the resistance to these stresses, while the single ?prx2 and double ?prx1?prx2 mutants have decreased viability. To corroborate the physiological data, the biochemical analysis of the five recombinant enzymes was done, namely by stopped-flow spectrophotometry. It is shown that H. pullorum SdHb reacts with NO much more quickly than TrHb, and that the three Prxs react promptly with peroxynitrite, Prx3 displaying the highest reactivity. Altogether, the results unveil SdHb and Prx3 as major protective systems of H. pullorum against nitrosative stress. PMID- 28855662 TI - TCR-like antibodies mediate complement and antibody-dependent cellular cytotoxicity against Epstein-Barr virus-transformed B lymphoblastoid cells expressing different HLA-A*02 microvariants. AB - Epstein-Barr virus (EBV) is a common gammaherpesvirus associated with various human malignancies. Antibodies with T cell receptor-like specificities (TCR-like mAbs) provide a means to target intracellular tumor- or virus-associated antigens by recognising their processed peptides presented on major histocompatibility complex (MHC) class I (pMHC) complexes. These antibodies are however thought to be relevant only for a single HLA allele. Here, we show that HLA-A*02:01 restricted EBV antigenic peptides EBNA1562-570, LMP1125-133 and LMP2A426-434 display binding degeneracy towards HLA-A*02 allelic microvariants, and that these pMHC complexes are recognised by anti-EBV TCR-like mAbs E1, L1 and L2 raised in the context of HLA-A*02:01. These antibodies bound endogenously derived pMHC targets on EBV-transformed human B lymphoblastoid cell lines expressing A*02:01, A*02:03, A*02:06 and A*02:07 alleles. More importantly, these TCR-like mAbs mediated both complement-dependent and antibody-dependent cellular cytotoxicity of these cell lines in vitro. This finding suggests the utility of TCR-like mAbs against target cells of closely related HLA subtypes, and the potential applicability of similar reagents within populations of diverse HLA-A*02 alleles. PMID- 28855663 TI - Monolithically multi-color lasing from an InGaN microdisk on a Si substrate. AB - An optically pumped multi-color laser has been achieved using an InGaN/GaN based micro-disk with an undercut structure on a silicon substrate. The micro-disk laser has been fabricated by means of a combination of a cost-effective microsphere lithography technique and subsequent dry/wet etching processes. The microdisk laser is approximately 1 MUm in diameter. The structure was designed in such a way that the vertical components of the whispering gallery (WG) modes formed can be effectively suppressed. Consequently, three clean lasing peaks at 442 nm, 493 nm and 522 nm have been achieved at room temperature by simply using a continuous-wave diode laser as an optical pumping source. Time-resolved micro photoluminescence (PL) measurements have been performed in order to further confirm the lasing by investigating the excitonic recombination dynamics of these lasing peaks. A three dimensional finite-difference-time-domain (FDTD) simulation has been used for the structure design. PMID- 28855664 TI - Oral Mucosal Epithelial Cells Grown on Porous Silicon Membrane for Transfer to the Rat Eye. AB - Dysfunction of limbal stem cells or their niche can result in painful, potentially sight-threatening ocular surface disease. We examined the utility of surface-modified porous-silicon (pSi) membranes as a scaffold for the transfer of oral mucosal cells to the eye. Male-origin rat oral mucosal epithelial cells were grown on pSi coated with collagen-IV and vitronectin, and characterised by immunocytochemistry. Scaffolds bearing cells were implanted into normal female rats, close to the limbus, for 8 weeks. Histology, immunohistochemistry and a multiplex nested PCR for sry were performed to detect transplanted cells. Oral mucosal epithelial cells expanded on pSi scaffolds expressed the corneal epithelial cell marker CK3/12. A large percentage of cells were p63+, indicative of proliferative potential, and a small proportion expressed ABCG2+, a putative stem cell marker. Cell-bearing scaffolds transferred to the eyes of live rats, were well tolerated, as assessed by endpoint histology. Immunohistochemistry for pan-cytokeratins demonstrated that transplanted epithelial cells were retained on the pSi membranes at 8 weeks post-implant, but were not detectable on the central cornea using PCR for sry. The pSi scaffolds supported and retained transplanted rat oral mucosal epithelial cells in vitro and in vivo and recapitulate some aspects of an artificial stem cell niche. PMID- 28855665 TI - Enhanced antitumor effect on intrapulmonary tumors of docetaxel lung-targeted liposomes in a rabbit model of VX2 orthotopic lung cancer. AB - Allergic reactions and severe systemic toxicity are two major challenges for the clinical application of docetaxel (DTX) for treatment of non-small-cell lung cancer (NSCLC). We developed a novel lung-targeted DTX-loaded liposome (DTX-LP), an efficient drug delivery system, with a patented DBaumNC technology to overcome these deficiencies. In the present study, we describe the targeting activity, tumor inhibition rate (TIR), survival, pathology, tumor apoptosis and metabolism of DTX after intravenous injection of DTX-LP compared to the DTX injection (DTX IN) formulation based on the VX2 orthotopic lung cancer rabbit model. Biodistribution studies revealed the highest accumulation in lung and tumor within 12 h after the injection of DTX-LP. The increased TIR indicates that the growth of tumor was slowed. Pathology tests demonstrated that DTX-LP can reduce metastasis and toxicity to non-targeted organs, leading to greatly extended survival time and improved survival of tumor-bearing rabbits. Flow cytometry and immunohistochemistry confirmed that DTX-LP is highly efficacious in tumor tissue, leading to a significant increase of tumor apoptosis and decrease of proliferation and angiogenesis. The results from this study demonstrate the increased intrapulmonary tumor targeting activity, enhanced antitumor effect and reduced toxicity of DTX-LP compared to DTX-IN and highlight its clinical prospects for NSCLC therapy. PMID- 28855666 TI - Plasma thrombin-cleaved osteopontin as a potential biomarker of acute atherothrombotic ischemic stroke: comments on data sparsity. PMID- 28855667 TI - Control of entanglement dynamics in a system of three coupled quantum oscillators. AB - Dynamical control of entanglement and its connection with the classical concept of instability is an intriguing matter which deserves accurate investigation for its important role in information processing, cryptography and quantum computing. Here we consider a tripartite quantum system made of three coupled quantum parametric oscillators in equilibrium with a common heat bath. The introduced parametrization consists of a pulse train with adjustable amplitude and duty cycle representing a more general case for the perturbation. From the experimental observation of the instability in the classical system we are able to predict the parameter values for which the entangled states exist. A different amount of entanglement and different onset times emerge when comparing two and three quantum oscillators. The system and the parametrization considered here open new perspectives for manipulating quantum features at high temperatures. PMID- 28855668 TI - Combined effects of ZnO particle deposition and heat treatment on dimensional stability and mechanical properties of poplar wood. AB - This study proposed a one-step wood modification method by combining the deposition of ZnO particles on wood surface and heat treatment. The effects of ZnO particles and heat treatment on mechanical properties and dimensional stability of poplar wood were examined. Samples were sorted into 4 groups, i.e., control, heat-treated, impregnation/heat-treated, and hydrothermal-treated samples. The mechanical properties and dimensional stability of impregnation/heat treated and hydrothermal-treated wood samples were measured in comparison with those of the control and heat-treated wood samples. Compared with the control ones, the reduction of the flexural strength of the heat-treated, impregnation/heat-treated and hydrothermal-treated samples were about 11.57%, 8.53% and 15.90%, respectively. The modulus of elasticity of the heat-treated and hydrothermal-treated samples decreased by 13.78% and 23.78%, respectively, while the impregnation/heat-treated samples increased by about 8.57% due to the ZnO particles growth. The dimensional stabilities of the heat-treated, impregnated/heat-treated and hydrothermal-treated samples were improved in comparison with that of the control sample. All samples were characterized by the scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and X - ray diffraction (XRD). PMID- 28855669 TI - Highly wear-resistant and low-friction Si3N4 composites by addition of graphene nanoplatelets approaching the 2D limit. AB - Graphene nanoplatelets (GNPs) have emerged as one of the most promising filler materials for improving the tribological performance of ceramic composites due to their outstanding solid lubricant properties as well as mechanical and thermal stability. Yet, the addition of GNPs has so far enabled only a very limited improvement in the tribological properties of ceramics, particularly concerning the reduction of their friction coefficient. This is most likely due to the challenges of achieving a continuous lubricating and protecting tribo-film through a high GNP coverage of the exposed surfaces. Here we demonstrate that this can be achieved by efficiently increasing the exfoliation degree of GNPs down to the few-layer (FL) range. By employing FL-GNPs as filler material, the wear resistance of Si3N4 composites can be increased by more than twenty times, the friction coefficient reduced to nearly its half, while the other mechanical properties are also preserved or improved. Confocal Raman spectroscopy measurements revealed that at the origin of the spectacular improvement of the tribological properties is the formation of a continuous FL- GNP tribo-film, already at 5 wt% FL-GNP content. PMID- 28855670 TI - Photoinduced Strain Release and Phase Transition Dynamics of Solid-Supported Ultrathin Vanadium Dioxide. AB - The complex phase transitions of vanadium dioxide (VO2) have drawn continual attention for more than five decades. Dynamically, ultrafast electron diffraction (UED) with atomic-scale spatiotemporal resolution has been employed to study the reaction pathway in the photoinduced transition of VO2, using bulk and strain free specimens. Here, we report the UED results from 10-nm-thick crystalline VO2 supported on Al2O3(0001) and examine the influence of surface stress on the photoinduced structural transformation. An ultrafast release of the compressive strain along the surface-normal direction is observed at early times following the photoexcitation, accompanied by faster motions of vanadium dimers that are more complex than simple dilation or bond tilting. Diffraction simulations indicate that the reaction intermediate involved on picosecond times may not be a single state, which implies non-concerted atomic motions on a multidimensional energy landscape. At longer times, a laser fluence multiple times higher than the thermodynamic enthalpy threshold is required for complete conversion from the initial monoclinic structure to the tetragonal lattice. For certain crystalline domains, the structural transformation is not seen even on nanosecond times following an intense photoexcitation. These results signify a time-dependent energy distribution among various degrees of freedom and reveal the nature of and the impact of strain on the photoinduced transition of VO2. PMID- 28855671 TI - The Genetic Origin of Short Tail in Endangered Korean Dog, DongGyeongi. AB - The tail of many animal species is responsible for various physiological functions. The functional importance of tail may have brought tail-loss to attention in many evolutionary and developmental studies. To provide a better explanation for the loss of tail, the current study aims to identify the evolutionary history and putative causal variants for the short tail in DongGyeongi (DG), an endangered dog breed, which is also the only dog in Korea that possesses a short tail. Whole genome sequencing was conducted on 22 samples of DG, followed by an investigation of population stratification with 10 other dog breeds. The genotypes, selective sweep and demography of DG were also investigated. As a result, we discovered the unique genetic structure of DG and suggested two possible ways in which the short tail phenotype developed. Moreover, this study suggested that selective sweep genes, ANKRD11 and ACVR2B may contribute to the reduction in tail length, and non-synonymous variant in the coding sequence of T gene and the CpG island variant of SFRP2 gene are the candidate causal variants for the tail-loss. PMID- 28855672 TI - Evolution of gut Bifidobacterium population in healthy Japanese infants over the first three years of life: a quantitative assessment. AB - Bifidobacteria are important members of human gut microbiota; however, quantitative data on their early-life dynamics is limited. Here, using a sensitive reverse transcription-qPCR approach, we demonstrate the carriage of eight signature infant-associated Bifidobacterium species (B. longum, B. breve, B. bifidum, B. catenulatum group, B. infantis, B. adolescentis, B. angulatum and B. dentium) in 76 healthy full-term vaginally-born infants from first day to three years of life. About 21% babies carry bifidobacteria at first day of life (6.2 +/- 1.9 log10 cells/g feces); and this carriage increases to 64% (8.0 +/- 2.2), 79% (8.5 +/- 2.1), 97% (9.3 +/- 1.8), 99% (9.6 +/- 1.6), and 100% (9.7 +/- 0.9) at age 7 days, 1, 3 and 6 months, and 3 years, respectively. B. longum, B. breve, B. catenulatum group and B. bifidum are among the earliest and abundant bifidobacterial clades. Interestingly, infants starting formula-feed as early as first week of life have higher bifidobacterial carriage compared to exclusively breast-fed counterparts. Bifidobacteria demonstrate an antagonistic correlation with enterobacteria and enterococci. Further analyses also reveal a relatively lower/ delayed bifidobacterial carriage in cesarean-born babies. The study presents a quantitative perspective of the early-life gut Bifidobacterium colonization and shows how factors such as birth and feeding modes could influence this acquisition even in healthy infants. PMID- 28855673 TI - Aurora A Phosphorylation of YY1 during Mitosis Inactivates its DNA Binding Activity. AB - Successful execution of mitotic cell division requires the tight synchronisation of numerous biochemical pathways. The underlying mechanisms that govern chromosome segregation have been thoroughly investigated. However, the mechanisms that regulate transcription factors in coordination with mitotic progression remain poorly understood. In this report, we identify the transcription factor YY1 as a novel mitotic substrate for the Aurora A kinase, a key regulator of critical mitotic events, like centrosome maturation and spindle formation. Using in vitro kinase assays, we show that Aurora A directly phosphorylates YY1 at serine 365 in the DNA-binding domain. Using a new phospho-specific antibody, we show that YY1 phosphorylation at serine 365 occurs during mitosis, and that this phosphorylation is significantly reduced upon inhibition of Aurora A. Furthermore, we show, using electrophoretic mobility shift and chromatin immunoprecipitation assays, that phosphorylation of YY1 at this site abolishes its DNA binding activity in vitro and in vivo. In conformity with this loss of binding activity, phosphorylated YY1 also loses its transctivation ability as demonstrated by a luciferase reporter assay. These results uncover a novel mechanism that implicates Aurora A in the mitotic inactivation of transcription factors. PMID- 28855674 TI - Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kdelta/Akt and NFkappaB induction in a murine asthma model. AB - The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kdelta/Akt and NF-kappaB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IkappaB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway selective inhibitors for ERK1/2 (PD89059) and PI3Kdelta/Akt (IC-87114) respectively, or an inhibitor of NF-kappaB (BAY11-7085) also reduced the OVA induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors. PMID- 28855675 TI - Increased cross-modal functional connectivity in cochlear implant users. AB - Previous studies have reported increased cross-modal auditory and visual cortical activation in cochlear implant (CI) users, suggesting cross-modal reorganization of both visual and auditory cortices in CI users as a consequence of sensory deprivation and restoration. How these processes affect the functional connectivity of the auditory and visual system in CI users is however unknown. We here investigated task-induced intra-modal functional connectivity between hemispheres for both visual and auditory cortices and cross-modal functional connectivity between visual and auditory cortices using functional near infrared spectroscopy in post-lingually deaf CI users and age-matched normal hearing controls. Compared to controls, CI users exhibited decreased intra-modal functional connectivity between hemispheres and increased cross-modal functional connectivity between visual and left auditory cortices for both visual and auditory stimulus processing. Importantly, the difference between cross-modal functional connectivity for visual and for auditory stimuli correlated with speech recognition outcome in CI users. Higher cross-modal connectivity for auditory than for visual stimuli was associated with better speech recognition abilities, pointing to a new pattern of functional reorganization that is related to successful hearing restoration with a CI. PMID- 28855676 TI - Flexible regulation of DNA displacement reaction through nucleic acid-recognition enzyme and its application in keypad lock system and biosensing. AB - Toehold-mediated DNA strand displacement reaction (SDR) plays pivotal roles for the construction of diverse dynamic DNA nanodevices. To date, many elements have been introduced into SDR system to achieve controllable activation and fine regulation. However, as the most relevant stimuli for nucleic acid involved reaction, nucleic acid-recognizing enzymes (NAEs) have received nearly no attention so far despite SDR often takes place in NAEs-enriched environment (i.e., biological fluids). Herein, we report a set of NAEs-controlled SDR strategies, which take full advantage of NAEs' properties. In this study, three different kinds of enzymes belonging to several classes (i.e., exonuclease, endonuclease and polymerase) have been used to activate or inhibit SDR, and more importantly, some mechanisms behind these strategies on how NAEs affect SDR have also been revealed. The exploration to use NAEs as possible cues to operate SDR will expand the available toolbox to build novel stimuli-fueled DNA nanodevices and could open the door to many applications including enzyme-triggered biocomputing and biosensing. PMID- 28855677 TI - No evidence for parental age effects on offspring leukocyte telomere length in free-living Soay sheep. AB - In humans, the effect of paternal age at conception (PAC) on offspring leukocyte telomere length (LTL) is well established, with older fathers thought to pass on longer telomeres to their offspring in their sperm. Few studies have looked for PAC effects in other species, but it has been hypothesised that the effect will be exacerbated in polygamous species with higher levels of sperm competition and production. We test for maternal (MAC) and paternal age at conception effects on offspring LTL in Soay sheep, a primitive breed experiencing strong sperm competition. We use qPCR to measure relative telomere length in 389 blood samples (n = 318 individuals) collected from an unmanaged population of sheep on St Kilda, where individual age and parentage are known. We find no evidence that either MAC or PAC are associated with LTL in offspring across the age range, or when considering only young lambs (n = 164). This is the first study to test for parental age effects on offspring LTL in a wild mammal population, and the results contrast with the findings of numerous human studies that find a PAC effect, as well as predictions of a stronger PAC effect in polygamous species. PMID- 28855678 TI - Millennial-scale northern Hemisphere Atlantic-Pacific climate teleconnections in the earliest Middle Pleistocene. AB - Suborbital-scale climate variations, possibly caused by solar activity, are observed in the Holocene and last-glacial climates. Recently published bicentennial-resolution paleoceanic environmental records reveal millennial-scale high-amplitude oscillations postdating the last geomagnetic reversal in the Marine Isotope Stage (MIS) 19 interglacial. These oscillations, together with decoupling of post-reversal warming from maximum sea-level highstand in mid latitudes, are key features for understanding the climate system of MIS 19 and the following Middle Pleistocene. It is unclear whether the oscillations are synchronous, or have the same driver as Holocene cycles. Here we present a high resolution record of western North Pacific submarine anoxia and sea surface bioproductivity from the Chiba Section, central Japan. The record reveals many oxic events in MIS 19, coincident with cold intervals, or with combined cold and sea-level fall events. This allows detailed correlations with paleoceanic records from the mid-latitude North Atlantic and Osaka Bay, southwest Japan. We find that the millennial-scale oscillations are synchronous between East and West hemispheres. In addition, during the two warmest intervals, bioproductivity follows the same pattern of change modulated by bicentennial cycles that are possibly related to solar activity. PMID- 28855679 TI - Pea PSII-LHCII supercomplexes form pairs by making connections across the stromal gap. AB - In higher plant thylakoids, the heterogeneous distribution of photosynthetic protein complexes is a determinant for the formation of grana, stacks of membrane discs that are densely populated with Photosystem II (PSII) and its light harvesting complex (LHCII). PSII associates with LHCII to form the PSII-LHCII supercomplex, a crucial component for solar energy conversion. Here, we report a biochemical, structural and functional characterization of pairs of PSII-LHCII supercomplexes, which were isolated under physiologically-relevant cation concentrations. Using single-particle cryo-electron microscopy, we determined the three-dimensional structure of paired C2S2M PSII-LHCII supercomplexes at 14 A resolution. The two supercomplexes interact on their stromal sides through a specific overlap between apposing LHCII trimers and via physical connections that span the stromal gap, one of which is likely formed by interactions between the N terminal loops of two Lhcb4 monomeric LHCII subunits. Fast chlorophyll fluorescence induction analysis showed that paired PSII-LHCII supercomplexes are energetically coupled. Molecular dynamics simulations revealed that additional flexible physical connections may form between the apposing LHCII trimers of paired PSII-LHCII supercomplexes in appressed thylakoid membranes. Our findings provide new insights into how interactions between pairs of PSII-LHCII supercomplexes can link adjacent thylakoids to mediate the stacking of grana membranes. PMID- 28855680 TI - Contamination-free graphene by chemical vapor deposition in quartz furnaces. AB - Although the growth of graphene by chemical vapor deposition is a production technique that guarantees high crystallinity and superior electronic properties on large areas, it is still a challenge for manufacturers to efficiently scale up the production to the industrial scale. In this context, issues related to the purity and reproducibility of the graphene batches exist and need to be tackled. When graphene is grown in quartz furnaces, in particular, it is common to end up with samples contaminated by heterogeneous particles, which alter the growth mechanism and affect graphene's properties. In this paper, we fully unveil the source of such contaminations and explain how they create during the growth process. We further propose a modification of the widely used quartz furnace configuration to fully suppress the sample contamination and obtain identical and clean graphene batches on large areas. PMID- 28855681 TI - alpha-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell to-Cell Spreading and Block Prion Replication. AB - The precise molecular mechanism of how misfolded alpha-synuclein (alpha-Syn) accumulates and spreads in synucleinopathies is still unknown. Here, we show the role of the cellular prion protein (PrPC) in mediating the uptake and the spread of recombinant alpha-Syn amyloids. The in vitro data revealed that the presence of PrPC fosters the higher uptake of alpha-Syn amyloid fibrils, which was also confirmed in vivo in wild type (Prnp +/+) compared to PrP knock-out (Prnp -/-) mice. Additionally, the presence of alpha-Syn amyloids blocked the replication of scrapie prions (PrPSc) in vitro and ex vivo, indicating a link between the two proteins. Indeed, whilst PrPC is mediating the internalization of alpha-Syn amyloids, PrPSc is not able to replicate in their presence. This observation has pathological relevance, since several reported case studies show that the accumulation of alpha-Syn amyloid deposits in Creutzfeldt-Jakob disease patients is accompanied by a longer disease course. PMID- 28855682 TI - How spontaneous brain activity and narcissistic features shape social interaction. AB - There is an increasing interest in how ongoing spontaneous brain activity and personality provide a predisposition for the processing of environmental demands. It further has been suggested that the brain has an inherent sensitivity to the social environment. Here we tested in healthy volunteers if spontaneous brain activity contributes to a predisposition for social behavior and how this is modulated by narcissistic personality features associated with poor interpersonal functioning. Functional magnetic resonance imaging included a resting state and an experimental paradigm focusing on the anticipation of actively touching an animate (human hand) versus an inanimate target (mannequin hand). The experimental task induced a significant modulation of neural activity in left postcentral gyrus (PostCG), right culmen and, co-varying with narcissistic features, in right anterior insula (AI). Neural activity in anticipation of the animate target significantly correlated with spontaneous activity during the resting state indexed by the Power Law Exponent (PLE) in PostCG and AI. Finally, the correlation between spontaneous and task-induced activity in AI was mediated by narcissistic features. These findings provide novel evidence for a relationship between intrinsic brain activity and social behavior and show how personality could contribute to individual differences in our predisposition to approach the animate world. PMID- 28855683 TI - Tracheal reconstruction with a free vascularized myofascial flap: preclinical investigation in a porcine model to human clinical application. AB - Although there are various methods for tracheal reconstruction, such as a simple approximation with suturing and coverage with adjacent soft tissue or muscle, large defects >50% of the tracheal length still present a clinical challenge. Tissue engineering, a recent promising way to possibly resolve this problem, requires a long preparatory period for stem cell seeding on a scaffold and relatively invasive procedures for stem cell harvesting. As an alternative, we used a vascularized myofascial flap for tracheal reconstruction. In four porcine models, the deep inferior epigastric perforator (DIEP) was used in two and the superior epigastric artery perforator (SEAP) in two. Transformation of the surface of the transplanted myofascial flap was analyzed in the airway environment. The flaps failed in the DIEP group due to venous congestion. At 12 weeks postoperatively, none of SEAP group showed any signs of respiratory distress; the inner surface of the implant exhibited stratified squamous epithelium with sparse cilia. In the clinical setting, a patient who underwent a tracheal reconstruction with a vascularized myofascial flap and 2-year follow-up was in good health with no respiratory distress symptoms. PMID- 28855685 TI - Establishment of the most comprehensive ITS2 barcode database to date of the traditional medicinal plant Rhodiola (Crassulacaee). AB - The roots and rhizomes of Rhodiola crenulata and R. rosea have been used worldwide as adaptogens for hundreds of years. However, rapid growth in demand has resulted in merchants using other species of Rhodiola as adulterants. Here, we surveyed 518 individuals representing 47 of the 55 species in the genus, including 253 R. crenulata individuals from 16 populations and 98 R. rosea individuals from 11 populations, to evaluate the utility of the internal transcribed spacer 2 (ITS2) barcode for identification of Rhodiola species. We detected six haplotypes in R. crenulata and only one haplotype in R. rosea. An obvious overlap between intra- and inter-specific distance was detected, and the authentication efficacy of ITS2, which was assessed by BLAST1, a nearest distance method, and a tree test, was much lower than in other groups. However, R. crenulata and R. rosea could be exactly identified. Analysis showed that the secondary structure of ITS2 differs in R. crenulata and its closest relatives. Our results demonstrated that both a mini barcode from ITS2 and the structure of ITS2 are effective markers for the identification of R. crenulata and R. rosea. This study represents the most comprehensive database of ITS2 barcodes in Rhodiola to date and will be useful in Rhodiola species identification. PMID- 28855684 TI - Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS. AB - ALS is a devastating and debilitating human disease characterized by the progressive death of upper and lower motor neurons. Although much effort has been made to elucidate molecular determinants underlying the onset and progression of the disorder, the causes of ALS remain largely unknown. In the present work, we have deeply sequenced whole transcriptome from spinal cord ventral horns of post mortem ALS human donors affected by the sporadic form of the disease (which comprises ~90% of the cases but which is less investigated than the inherited form of the disease). We observe 1160 deregulated genes including 18 miRNAs and show that down regulated genes are mainly of neuronal derivation while up regulated genes have glial origin and tend to be involved in neuroinflammation or cell death. Remarkably, we find strong deregulation of SNAP25 and STX1B at both mRNA and protein levels suggesting impaired synaptic function through SNAP25 reduction as a possible cause of calcium elevation and glutamate excitotoxicity. We also note aberrant alternative splicing but not disrupted RNA editing. PMID- 28855686 TI - Novelty application of multi-omics correlation in the discrimination of sulfur fumigation and non-sulfur-fumigation Ophiopogonis Radix. AB - A rapid and sensitive approach to differentiate sulfur-fumigated (SF) Ophiopogonis Radix based on Multi-Omics Correlation Analysis (MOCA) strategy was first established. It was characterized by multiple data-acquisition methods (NIR, HPLC, and UHPLC-HRMS) based metabonomics and multivariate statistical analysis methods. As a result, SF and non-sulfur fumigated (NSF) Ophiopogonis Radix samples were efficaciously discriminated. Moreover, based on the acquired HRMS data, 38 sulfur-containing discriminatory markers were eventually characterized, whose NIR absorption could be in close correlation with the discriminatory NIR wavebands (5000-5200 cm-1) screened by NIR metabonomics coupled with SiPLS and 2D-COS methods. This results were also validated from multiple perspectives, including metabonomics analysis based on the discriminatory markers and the simulation of SF ophiopogonin D and Ophiopogonis Radix sample. In conclusion, our results first revealed the intrinsic mechanism of discriminatory NIR wavebands by means of UHPLC-HRMS analysis. Meanwhile, the established MOCA strategy also provided a promising NIR based differential method for SF Ophiopogonis Radix, which could be exemplary for future researches on rapid discrimination of other SF Chinese herbal medicines. PMID- 28855687 TI - Library siRNA-generating RNA nanosponges for gene silencing by complementary rolling circle transcription. AB - Since the discovery of RNA interference (RNAi), small interfering RNA (siRNA) has been powerful tools for gene downregulation in biomedical applications. Despite the outstanding efficacy of siRNA, the development of a therapeutic delivery system remains a challenge owing to the instability of RNA. In this study, we describe a new method for the design of siRNA-generating nanosponges by using complementary rolling circle transcription (cRCT), a technique that requires two complementary circular DNA. The sequences of one of the circular DNA are designed to have complete complementarity to the target mRNA resulting in double stranded RNA (dsRNA) that can be digested to siRNA by cellular Dicer activity. This siRNA design, called 'library siRNA', could be universally applied to fabricate RNA nanosponges targeting any known mRNA sequence. PMID- 28855688 TI - Maximizing non-enzymatic methods for harvesting adipose-derived stem from lipoaspirate: technical considerations and clinical implications for regenerative surgery. AB - In the past decade, adipose tissue has become a highly interesting source of adult stem cells for plastic surgery and regenerative medicine. The adipose source offers two options for the isolation of regenerative cells: the enzymatic digestion an expensive time-consuming procedure lacking a common standard operating protocol, or the non-enzymatic dissociation methods based on mechanical forces to break the processed adipose tissue. Here, we propose innovative inexpensive non-enzymatic protocols to collect and concentrate clinically useful regenerative cells from adipose tissue by centrifugation of the infranatant fraction of lipoaspirate as first step, usually discarded as a byproduct of the surgical procedure, and by fat shaking and wash as second enrichment step. The isolated cells were characterized according to the criteria proposed by the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) to define human mesenchymal stem cells, and the results were compared with matched lipoaspirate samples processed with collagenase. The results demonstrated the usability of these new procedures as an alternative to fat grafting for treating stem cell-depleted tissues and for specific application requiring minimal or null soft tissue augmentation, such as skin diseases including severe burn and post-oncological scaring, chronic non-healing wounds, and vitiligo. PMID- 28855689 TI - Multicentre evaluation of the BYG Carba v2.0 test, a simplified electrochemical assay for the rapid laboratory detection of carbapenemase-producing Enterobacteriaceae. AB - Rapid detection of carbapenemase-producing Enterobacteriaceae (CPE) represents a major challenge for microbiology laboratories. We evaluated the BYG Carba v2.0 using a simplified protocol, which detects CPE in less than 30 minutes. This new procedure reduces the hands-on-time from 5 to one minute and only requires a limited amount of material (one to three colonies) thereby preventing the need for subculturing bacterial isolates to reach a larger amount of pure biomass. This multicentre study involved four European reference laboratories. For the 1181 isolates tested across four centres, BYG Carba v2.0 yielded overall sensitivity and specificity of 96.3% (CI95: 94.5-97.5) and 99.7% (CI95: 98.6-100) respectively. Considering only the 670 consecutive isolates tested prospectively, the BYG Carba v2.0 displayed overall positive and negative predictive values of 99.7% (CI95: 95.4-98.9) and 97.5% (CI95: 94.9-98.8). Regarding time to positivity, 85% of CPE detected were positive within ten minutes. The BYG Carba v2.0 is a new highly simplified, rapid and accurate electrochemical assay discriminating between CPE and non-CPE in less than 30 min. The real-time quantified signal allows objective and traceable interpretation of the results. PMID- 28855691 TI - Immunology: Balancing immunoreceptor signalling. PMID- 28855690 TI - Shift of bacterial community structure along different coastal reclamation histories in Jiangsu, Eastern China. AB - Tideland reclamation has drastic effects on coastal ecosystem involved in soil microorganisms. However, the knowledge regarding temporal variations of microbial community along reclamation chronosequence and their environmental variable predictor is still poorly known. Using Illumina sequencing, we qualified bacterial community composition in soils collected from one tideland and four reclamation stages, i.e. 2-year, 7-year, 19-year and 39-year in Jiangsu, Eastern China. Across all samples, the dominant groups were Proteobacteria, Bacteroidete, Acidobacteria, Planctomycetes and Chloroflexi. Reclamation activity and its histories greatly altered bacterial community structure, and only 0.28% of phylotypes were shared by five soils. Specially, some typical marine bacteria (Gaetulibacter, Alcanivorax ...) disappeared in reclamation soils, while other groups (Niabella, Flavisolibacter...) were gradually eminent. Generally, bacterial diversity and richness increased with reclamation histories. Bacterial community was correlated with most of soil physico-chemical properties. Amongst, mean weight diameter of soil aggregates (MWD) was detected as a primary factor predicting bacterial community composition. Together, our results indicated that effects of reclamation on bacterial community varied with diked histories, and MWD was a major factor predicting bacterial community during progressive reclamation. These findings offer predicting case study for understanding the impact of reclamation and its histories on microbial community in a coastal ecosystem. PMID- 28855692 TI - Rheumatoid arthritis: Remission - keeping the patient experience front and centre. PMID- 28855693 TI - Rheumatoid arthritis: Characterization of the infrapatellar fat pad. PMID- 28855694 TI - Functional autoantibodies targeting G protein-coupled receptors in rheumatic diseases. AB - G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of integral membrane proteins that participate in different physiological processes such as the regulation of the nervous and immune systems. Besides the endogenous ligands of GPCRs, functional autoantibodies are also able to bind GPCRs to trigger or block intracellular signalling pathways, resulting in agonistic or antagonistic effects, respectively. In this Review, the effects of functional GPCR-targeting autoantibodies on the pathogenesis of autoimmune diseases, including rheumatic diseases, are discussed. Autoantibodies targeting beta1 and beta2 adrenergic receptors, which are expressed by cardiac and airway smooth muscle cells, respectively, have an important role in the development of asthma and cardiovascular diseases. In addition, high levels of autoantibodies against the muscarinic acetylcholine receptor M3 as well as those targeting endothelin receptor type A and type 1 angiotensin II receptor have several implications in the pathogenesis of rheumatic diseases such as Sjogren syndrome and systemic sclerosis. Expanding the knowledge of the pathophysiological roles of autoantibodies against GPCRs will shed light on the biology of these receptors and open avenues for new therapeutic approaches. PMID- 28855695 TI - Rheumatoid arthritis: Cell cycle stalling linked to arthritis. PMID- 28855696 TI - Bone: Towards a better management of glucocorticoid-induced osteoporosis? PMID- 28855697 TI - Whey Protein Components - Lactalbumin and Lactoferrin - Improve Energy Balance and Metabolism. AB - Whey protein promotes weight loss and improves diabetic control, however, less is known of its bioactive components that produce such benefits. We compared the effects of normal protein (control) diet with high protein diets containing whey, or its fractions lactalbumin and lactoferrin, on energy balance and metabolism. Diet-induced obese rats were randomized to isocaloric diets: Control, Whey, Lactalbumin, Lactoferrin, or pair-fed to lactoferrin. Whey and lactalbumin produced transient hypophagia, whereas lactoferrin caused prolonged hypophagia; the hypophagia was likely due to decreased preference. Lactalbumin decreased weight and fat gain. Notably, lactoferrin produced sustained weight and fat loss, and attenuated the reduction in energy expenditure associated with calorie restriction. Lactalbumin and lactoferrin decreased plasma leptin and insulin, and lactalbumin increased peptide YY. Whey, lactalbumin and lactoferrin improved glucose clearance partly through differential upregulation of glucoregulatory transcripts in the liver and skeletal muscle. Interestingly, lactalbumin and lactoferrin decreased hepatic lipidosis partly through downregulation of lipogenic and/or upregulation of beta-oxidation transcripts, and differentially modulated cecal bacterial populations. Our findings demonstrate that protein quantity and quality are important for improving energy balance. Dietary lactalbumin and lactoferrin improved energy balance and metabolism, and decreased adiposity, with the effects of lactoferrin being partly independent of caloric intake. PMID- 28855698 TI - Transcriptomics analysis of salt stress tolerance in the roots of the mangrove Avicennia officinalis. AB - Salinity affects growth and development of plants, but mangroves exhibit exceptional salt tolerance. With direct exposure to salinity, mangrove roots possess specific adaptations to tolerate salt stress. Therefore, studying the early effects of salt on mangrove roots can help us better understand the tolerance mechanisms. Using two-month-old greenhouse-grown seedlings of the mangrove tree Avicennia officinalis subjected to NaCl treatment, we profiled gene expression changes in the roots by RNA-sequencing. Of the 6547 genes that were differentially regulated in response to salt treatment, 1404 and 5213 genes were significantly up- and down-regulated, respectively. By comparative genomics, 93 key salt tolerance-related genes were identified of which 47 were up-regulated. Upon placing all the differentially expressed genes (DEG) in known signaling pathways, it was evident that most of the DEGs involved in ethylene and auxin signaling were up-regulated while those involved in ABA signaling were down regulated. These results imply that ABA-independent signaling pathways also play a major role in salt tolerance of A. officinalis. Further, ethylene response factors (ERFs) were abundantly expressed upon salt treatment and the Arabidopsis mutant aterf115, a homolog of AoERF114 is characterized. Overall, our results would help in understanding the possible molecular mechanism underlying salt tolerance in plants. PMID- 28855699 TI - Dynamic cell responses in Thermoanaerobacterium sp. under hyperosmotic stress. AB - As a nongenetic engineering technique, adaptive evolution is an effective and easy-to-operate approach to strain improvement. In this work, a commercial Thermoanaerobacterium aotearoense SCUT27/Deltaldh-G58 was successfully isolated via sequential batch fermentation with step-increased carbon concentrations. Mutants were isolated under selective high osmotic pressures for 58 passages. The evolved isolate rapidly catabolized sugars at high concentrations and subsequently produced ethanol with good yield. A 1.6-fold improvement of ethanol production was achieved in a medium containing 120 g/L of carbon substrate using the evolved strain, compared to the start strain. The analysis of transcriptome and intracellular solute pools suggested that the adaptive evolution altered the synthesis of some compatible solutes and activated the DNA repair system in the two Thermoanaerobacterium sp. evolved strains. Overall, the results indicated the potential of adaptive evolution as a simple and effective tool for the modification and optimization of industrial microorganisms. PMID- 28855700 TI - All-plasmonic Optical Phased Array Integrated on a Thin-film Platform. AB - Optical phased arrays have been demonstrated to enable a variety of applications ranging from high-speed on-chip communications to vertical surface emitting lasers. Despite the prosperities of the researches on optical phased arrays, presently, the reported designs of optical phased arrays are based on silicon photonics while plasmonic-based optical phased arrays have not been demonstrated yet. In this paper, a passive plasmonic optical phased array is proposed and experimentally demonstrated. The beam of the proposed plasmonic optical phased array is steerable in the far-field area and a high directivity can be achieved. In addition, radio frequency phased array theory is demonstrated to be applicable to the description of the coupling conditions of the delocalized surface plasmons in optical phased arrays and thus the gap between the phased arrays at two distinctly different wavelengths can be bridged. The potential applications of the proposed plasmonic phased arrays include on-chip optical wireless nanolinks, optical interconnections and integrated plasmonic lasers. PMID- 28855701 TI - Degradation of phenylethanoid glycosides in Osmanthus fragrans Lour. flowers and its effect on anti-hypoxia activity. AB - This study was aimed at investigating the chemical stability (the thermal, light and pH stability) of phenylethanoid glycosides (PhGs) in Osmanthus fragrans Lour. flowers, identifying the degradation products of acteoside and salidroside (major PhGs in O. fragrans flowers) by UPLC-QTOF-MS and studying the anti-hypoxia activity of PhGs after degradation. The degradation of PhGs followed first-order reaction kinetics, and the rate constant of acteoside (4.3 to 203.4 * 10-3 day-1) was higher than that of salidroside (3.9 to 33.3 * 10-3 day-1) in O. fragrans flowers. Salidroside was mainly hydrolyzed to tyrosol during storage, and the degradation products of acteoside were verbasoside, caffeic acid, isoacteoside, etc. In a model of cobalt chloride (CoCl2)-induced hypoxia in PC12 cells, the anti-hypoxia ability of PhGs decreased after degradation, which resulted from the reduction of PhGs contents. Particularly, caffeic acid exhibited stronger anti hypoxia ability than acteoside and could slightly increase the anti-hypoxia ability of degraded acteoside. The results revealed that high temperature, high pH and light exposure caused PhGs degradation, and thus the anti-hypoxia ability of PhGs reduced. PMID- 28855702 TI - On the determination of the temperature distribution within the color conversion elements of phosphor converted LEDs. AB - We present an iterative optical and thermal simulation procedure which enables the determination of the temperature distribution in the phosphor layer of a phosphor converted LED with good accuracy. Using the simulation both the highest phosphor temperatures, which are mostly relevant to material degradation as well as the temperatures of those phosphor particles which mainly contribute to converted light emission can be determined. We compare the simulations with experimental studies on the phosphor temperature. While infrared thermography only gives information on the phosphor layer surface temperature, phosphor thermometry provides temperature data on the volume temperature of the phosphor layer relevant to color conversion. PMID- 28855704 TI - Effects of light emitting diode irradiation on neural differentiation of human umbilical cord-derived mesenchymal cells. AB - Recently, light emitting diodes (LEDs) have been introduced as a potential physical factor for proliferation and differentiation of various stem cells. Among the mesenchymal stem cells human umbilical cord matrix-derived mesenchymal (hUCM) cells are easily propagated in the laboratory and their low immunogenicity make them more appropriate for regenerative medicine procedures. We aimed at this study to evaluate the effect of red and green light emitted from LED on the neural lineage differentiation of hUCM cells in the presence or absence of retinoic acid (RA). Harvested hUCM cells exhibited mesenchymal and stemness properties. Irradiation of these cells by green and red LED with or without RA pre-treatment successfully differentiated them into neural lineage when the morphology of the induced cells, gene expression pattern (nestin, beta-tubulin III and Olig2) and protein synthesis (anti-nestin, anti-beta-tubulin III, anti GFAP and anti-O4 antibodies) was evaluated. These data point for the first time to the fact that LED irradiation and optogenetic technology may be applied for neural differentiation and neuronal repair in regenerative medicine. PMID- 28855705 TI - Facile electrosynthesis of silicon carbide nanowires from silica/carbon precursors in molten salt. AB - Silicon carbide nanowires (SiC NWs) have attracted intensive attention in recent years due to their outstanding performances in many applications. A large-scale and facile production of SiC NWs is critical to its successful application. Here, we report a simple method for the production of SiC NWs from inexpensive and abundantly available silica/carbon (SiO2/C) precursors in molten calcium chloride. The solid-to-solid electroreduction and dissolution-electrodeposition mechanisms can easily lead to the formation of homogenous SiC NWs. This template/catalyst-free approach greatly simplifies the synthesis procedure compared to conventional methods. This general strategy opens a direct electrochemical route for the conversion of SiO2/C into SiC NWs, and may also have implications for the electrosynthesis of other micro/nanostructured metal carbides/composites from metal oxides/carbon precursors. PMID- 28855703 TI - Global associations between regional gray matter volume and diverse complex cognitive functions: evidence from a large sample study. AB - Correlations between regional gray matter volume (rGMV) and psychometric test scores have been measured to investigate the neural bases for individual differences in complex cognitive abilities (CCAs). However, such studies have yielded different rGMV correlates of the same CCA. Based on the available evidence, we hypothesized that diverse CCAs are all positively but only weakly associated with rGMV in widespread brain areas. To test this hypothesis, we used the data from a large sample of healthy young adults [776 males and 560 females; mean age: 20.8 years, standard deviation (SD) = 0.8] and investigated associations between rGMV and scores on multiple CCA tasks (including non-verbal reasoning, verbal working memory, Stroop interference, and complex processing speed tasks involving spatial cognition and reasoning). Better performance scores on all tasks except non-verbal reasoning were associated with greater rGMV across widespread brain areas. The effect sizes of individual associations were generally low, consistent with our previous studies. The lack of strong correlations between rGMV and specific CCAs, combined with stringent corrections for multiple comparisons, may lead to different and diverse findings in the field. PMID- 28855706 TI - Chondrogenesis and osteogenesis are one continuous developmental and lineage defined biological process. AB - Although chondrogenesis and osteogenesis are considered as two separate processes during endochondral bone formation after birth, recent studies have demonstrated the direct cell transformation from chondrocytes into bone cells in postnatal bone growth. Here we use cell lineage tracing and multiple in vivo approaches to study the role of Bmpr1a in endochondrogenesis. Our data showed profound changes in skeletal shape, size and structure when Bmpr1a was deleted using Aggrecan-Cre ERT2 in early cartilage cells with a one-time tamoxifen injection. We observed the absence of lineage progression of chondrocyte-derived bone cells to form osteoblasts and osteocytes in metaphyses. Furthermore, we demonstrated the key contribution of growth plate chondrocytes and articular chondrocytes, not only for long bone growth, but also for bone remodeling. In contrast, deleting Bmpr1a in early osteoblasts with 3.6 Col 1-Cre had little impact on skeletal shape and size except for a sharp increase in osteoblasts and osteocytes, leading to a profound increase in bone volume. We conclude that chondrogenesis and osteogenesis are one continuous developmental and lineage-defined biological process, in which Bmpr1a signaling in chondrocytes is necessary for the formation of a pool or niche of osteoprogenitors that then contributes in a major way to overall bone formation and growth. PMID- 28855707 TI - Bronchopulmonary Dysplasia. PMID- 28855708 TI - Cerebral palsy and asphyxia in 32-35 week preterm infants. PMID- 28855709 TI - Conical Refraction of Elastic Waves by Anisotropic Metamaterials and Application for Parallel Translation of Elastic Waves. AB - Conical refraction, which is quite well-known in electromagnetic waves, has not been explored well in elastic waves due to the lack of proper natural elastic media. Here, we propose and design a unique anisotropic elastic metamaterial slab that realizes conical refraction for horizontally incident longitudinal or transverse waves; the single-mode wave is split into two oblique coupled longitudinal-shear waves. As an interesting application, we carried out an experiment of parallel translation of an incident elastic wave system through the anisotropic metamaterial slab. The parallel translation can be useful for ultrasonic non-destructive testing of a system hidden by obstacles. While the parallel translation resembles light refraction through a parallel plate without angle deviation between entry and exit beams, this wave behavior cannot be achieved without the engineered metamaterial because an elastic wave incident upon a dissimilar medium is always split at different refraction angles into two different modes, longitudinal and shear. PMID- 28855710 TI - GPR88 is a critical regulator of feeding and body composition in mice. AB - GPR88 is an orphan G-protein-coupled receptor with predominant expression in reward-related areas in the brain. While the lack of GPR88 has been demonstrated to induce behavioral deficits, the potential function of the receptor in the control of food intake and energy balance remains unexplored. In this work, the role of GPR88 in energy homeostasis was investigated in Gpr88 -/- mice fed either standard chow or high fat diet (HFD). Gpr88 -/- mice showed significantly reduced adiposity accompanied with suppressed spontaneous food intake, particularly pronounced under HFD treatment. While energy expenditure was likewise lower in Gpr88 -/- mice, body weight gain remained unchanged. Furthermore, deregulation in glucose tolerance and insulin responsiveness in response to HFD was attenuated in Gpr88 -/- mice. On the molecular level, distinct changes in the hypothalamic mRNA levels of cocaine-and amphetamine-regulated transcript (Cartpt), a neuropeptide involved in the control of feeding and reward, were observed in Gpr88 -/- mice. In addition, GPR88 deficiency was associated with altered expressions of the anorectic Pomc and the orexigenic Npy in the arcuate nucleus, especially under HFD condition. Together, our results indicate that GPR88 signalling is not only important for reward processes, but also plays a role in the central regulatory circuits for energy homeostasis. PMID- 28855711 TI - Potential Antigens Involved in Delayed Xenograft Rejection in a Ggta1/Cmah Dko Pig-to-Monkey Model. AB - When hyperacute rejection is avoided by deletion of Gal expression in the pig, delayed xenograft rejection (DXR) becomes a major immunologic barrier to successful xenotransplantation. This study was to investigate the potential antigens involved in DXR. We isolated primary renal microvascular endothelial cells (RMEC) and aortic endothelial cells (AEC) from a GGTA1/CMAH double-knockout (DKO) pig (and a GGTA1-KO pig) and immunized cynomolgus monkeys with both of these cells. After sensitization, monkey serum antibody binding and cytotoxicity to RMEC was significantly higher than to AEC(p < 0.05), suggesting that RMEC are more immunogenic than AEC. Transcriptome sequencing of GGTA1/CMAH DKO pigs indicated that the expression of 1,500 genes was higher in RMEC than in AEC, while expression of 896 genes was lower. Next, we selected 101 candidate genes expressed only in pig RMEC, but not in pig AEC or in monkey or human RMEC. When these genes were knocked out individually in GGTA1/CMAH DKO RMEC, 32 genes were associated with reduced antibody binding, indicating that these genes might be primary immunologic targets involved in DXR. These genes may be important candidates for deletion in producing pigs against which there is a reduced primate immune response in pig kidney xenograft. PMID- 28855712 TI - MTOPVIB interacts with AtPRD1 and plays important roles in formation of meiotic DNA double-strand breaks in Arabidopsis. AB - Meiotic recombination is initiated from the formation of DNA double-strand breaks (DSBs). In Arabidopsis, several proteins, such as AtPRD1, AtPRD2, AtPRD3, AtDFO and topoisomerase (Topo) VI-like complex, have been identified as playing important roles in DSB formation. Topo VI-like complex in Arabidopsis may consist of subunit A (Topo VIA: AtSPO11-1 and AtSPO11-2) and subunit B (Topo VIB: MTOPVIB). Little is known about their roles in Arabidopsis DSB formation. Here, we report on the characterization of the MTOPVIB gene using the Arabidopsis mutant alleles mtopVIB-2 and mtopVIB-3, which were defective in DSB formation. mtopVIB-3 exhibited abortion in embryo sac and pollen development, leading to a significant reduction in fertility. The mtopVIB mutations affected the homologous chromosome synapsis and recombination. MTOPVIB could interact with Topo VIA proteins AtSPO11-1 and AtSPO11-2. AtPRD1 interacted directly with Topo VI-like proteins. AtPRD1 also could interact with AtPRD3 and AtDFO. The results indicated that AtPRD1 may act as a bridge protein to interact with AtPRD3 and AtDFO, and interact directly with the Topo VI-like proteins MTOPVIB, AtSPO11-1 and AtSPO11-2 to take part in DSB formation in Arabidopsis. PMID- 28855713 TI - Deciphering Clostridium metabolism and its responses to bioreactor mass transfer during syngas fermentation. AB - This study used 13C tracers and dynamic labeling to reveal metabolic features (nutrients requirements, pathway delineation and metabolite turnover rates) of Clostridium carboxidivorans P7, a model strain for industrial syngas fermentation, and its implication with bioreactor mass transfer. P7 shows poor activity for synthesizing amino acids (e.g., phenylalanine) and thus, needs rich medium for cell growth. The strain has multiple carbon fixation routes (Wood Ljungdahl pathway, pyruvate:ferredoxin oxidoreductase reaction and anaplerotic pathways) and Re-citrate synthase (Ccar_06155) was a key enzyme in its tricarboxylic acid cycle (TCA) pathway. High fluxes were observed in P7's Wood Ljungdahl pathway, right branch of TCA cycle, pyruvate synthesis, and sugar phosphate pathways, but the cells anabolic pathways were strikingly slow. In bioreactor culture, when syngas flowrate increased from 1 to 10 mL/min, P7 strain produced same amount of total extracellular products (acids and alcohols) but high flowrate favored alcohol accumulation. This observation was due to the mass transfer limitation influencing energy metabolism (CO/H2 oxidation for cofactor generations) more prominently than carbon fixation. When syngas flowrate increased from 10 of 20 mL/min, the alcohol productivity was not improved and the labeling rate (~0.03 h-1) of key metabolite acetyl-CoA reached to P7 strain's metabolism limitation regime. PMID- 28855714 TI - The pterygomaxillary junction: An imaging study for surgical information of LeFort I osteotomy. AB - Maxillary osteotomy is a common surgical procedure and often involves separation of the pterygomaxillary junction (PMJ), which is a "blinded" procedure with inherent risks. Knowledge of the PMJ structure is essential. It remains unclear whether patients with different facial types have different PMJ structures, or different surgical outcome. This study evaluated the computed tomographic images of 283 consecutive patients who received orthognathic surgery. Patients were classified into Angle class I, II, III and cleft lip/palate groups. The results showed that the PMJ was 5.1 +/- 1.4 mm in thickness, 9.7 +/- 1.7 mm in width, and 102.0 +/- 4.0 degrees relative to the sagittal plane in the level of posterior nasal spine. There were no statistically significant differences in these measurements among the groups. The class III group demonstrated significantly smaller angle relative to the maxillary occlusal plane. The cleft group showed significantly longer vertical distance between the posterior nasal spine and the lower border of PMJ, shorter distance between the second molar and PMJ, and longer distance between the descending palatine artery and PMJ. With regard to postoperative outcome, the cleft group showed higher incidence of pterygoid plate fracture. The results in this study provide additional surgical anatomic information. PMID- 28855715 TI - Santos syndrome is caused by mutation in the WNT7A gene. AB - We have recently described a family with a condition (Santos syndrome (SS; MIM 613005)) characterized by fibular agenesis/hypoplasia, hypoplastic femora and grossly malformed/deformed clubfeet with severe oligodactyly, ungual hypoplasia/anonychia, sometimes associated with mild brachydactyly and occasional pre-axial polydactyly. Autosomal dominant inheritance with incomplete penetrance was suggested, but autosomal recessive inheritance could not be ruled out, due to the high frequency of consanguineous matings in the region where the family lived. This report deals with linkage studies and exome sequencing, disclosing a novel variant in WNT7A, c.934G>A (p.Gly312Ser), as the cause of this syndrome. This variant was present in homozygous state in five individuals typically affected by the SS syndrome, and in heterozygous state in the son of one affected homozygous individual. The heterozygous boy presented only unilateral complex polysyndactyly and we hypothesize that he either presents a distinct defect or that his phenotype results from a rare, mild clinical manifestation of the variant in heterozygous state. Variants in WNT7A are known to cause at least two other limb defect disorders, the syndromes of Fuhrmann and Al-Awadi/Raas Rothschild. Despite their variable degree of expressivity and overlap, the three related conditions can be differentiated phenotypically in most instances. PMID- 28855717 TI - MRI and Additive Manufacturing of Nasal Alar Constructs for Patient-specific Reconstruction. AB - Surgical reconstruction of cartilaginous defects remains a major challenge. In the current study, we aimed to identify an imaging strategy for the development of patient-specific constructs that aid in the reconstruction of nasal deformities. Magnetic Resonance Imaging (MRI) was performed on a human cadaver head to find the optimal MRI sequence for nasal cartilage. This sequence was subsequently used on a volunteer. Images of both were assessed by three independent researchers to determine measurement error and total segmentation time. Three dimensionally (3D) reconstructed alar cartilage was then additively manufactured. Validity was assessed by comparing manually segmented MR images to the gold standard (micro-CT). Manual segmentation allowed delineation of the nasal cartilages. Inter- and intra-observer agreement was acceptable in the cadaver (coefficient of variation 4.6-12.5%), but less in the volunteer (coefficient of variation 0.6-21.9%). Segmentation times did not differ between observers (cadaver P = 0.36; volunteer P = 0.6). The lateral crus of the alar cartilage was consistently identified by all observers, whereas part of the medial crus was consistently missed. This study suggests that MRI is a feasible imaging modality for the development of 3D alar constructs for patient-specific reconstruction. PMID- 28855718 TI - Estimating the epidemic risk using non-uniformly sampled contact data. AB - Many datasets describing contacts in a population suffer from incompleteness due to population sampling and underreporting of contacts. Data-driven simulations of spreading processes using such incomplete data lead to an underestimation of the epidemic risk, and it is therefore important to devise methods to correct this bias. We focus here on a non-uniform sampling of the contacts between individuals, aimed at mimicking the results of diaries or surveys, and consider as case studies two datasets collected in different contexts. We show that using surrogate data built using a method developed in the case of uniform population sampling yields an improvement with respect to the use of the sampled data but is strongly limited by the underestimation of the link density in the sampled network. We put forward a second method to build surrogate data that assumes knowledge of the density of links within one of the groups forming the population. We show that it gives very good results when the population is strongly structured, and discuss its limitations in the case of a population with a weaker group structure. These limitations highlight the interest of measurements using wearable sensors able to yield accurate information on the structure and durations of contacts. PMID- 28855716 TI - A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease. AB - Kawasaki disease (KD), a systemic vasculitis of infants and children, manifests as fever and mucocutaneous inflammation. Although its etiology is largely unknown, the epidemiological data suggest that genetic factors are important in KD susceptibility. To identify genetic variants influencing KD susceptibility, we performed a genome-wide association study (GWAS) and replication study using a total of 915 children with KD and 4553 controls in the Korean population. Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with KD susceptibility (P<1.0 * 10-5), including the previously reported BLK locus (rs6993775, odds ratio (OR)=1.52, P=2.52 * 10-11). The other two loci were newly identified: NMNAT2 on chromosome 1q25.3 (rs2078087, OR=1.33, P=1.15 * 10-6) and the human leukocyte antigen (HLA) region on chromosome 6p21.3 (HLA-C, HLA-B, MICA and HCP5) (rs9380242, rs9378199, rs9266669 and rs6938467; OR=1.33-1.51, P=8.93 * 10-6 to 5.24 * 10-8). Additionally, SNP rs17280682 in NLRP14 was associated significantly with KD with a family history (18 cases vs 4553 controls, OR=6.76, P=5.46 * 10-6). These results provide new insights into the pathogenesis and pathophysiology of KD. PMID- 28855719 TI - Optimum electronic structures for high thermoelectric figure of merit within several isotropic elastic scattering models. AB - Electronic band structure is vital in determination the performance of thermoelectric materials. What is the optimum electronic structure for the largest figure of merit? To answer the question, we studied the relationship between the thermoelectric properties and the electronic band structure under the assumption of isotropic elastic scattering, within the context of Chasmar Stratton theory. The results show that whether the anisotropic band structure and the effective mass of the carrier are beneficial to improving the thermoelectric properties. The scattering mechanism and the shape of the Fermi surface play a decisive role. Regardless of scattering mechanism type, a larger valley degeneracy is always beneficial to thermoelectric materials. PMID- 28855720 TI - Side-effects of pesticides on the generalist endoparasitoid Palmistichus elaeisis (Hymenoptera: Eulophidae). AB - New plant protection strategies focus on minimizing chemical pesticide use and increasing their compatibility with biological control agents. The objective was to evaluate the side-effects of glyphosate, diflubenzuron, malathion, tebuconazole and triflumuron (at 720, 45, 400, 150 and 20 g ai ha-1, respectively), pesticides authorized for soybean crops in Brazil, on the parasitoid Palmistichus elaeisis (Hymenoptera: Eulophidae) reared on Anticarsia gemmatalis (Lepidoptera: Noctuidae). The emergence and female numbers produced per P. elaeisis female were higher in A. gemmatalis pupae from caterpillars fed an artificial diet treated with glyphosate. However, emergence was lower than 50% when the caterpillars were fed on soybean leaves treated with glyphosate offered ad libitum (3-5 times). Palmistichus elaeisis died before parasiting A. gemmatalis pupae treated with malathion. Diflubenzuron reduced the P. elaesis sex ratio in the second generation. Tebuconazole and triflumuron did not cause side effects on this parasitoid. A continuous exposure to glyphosate by the host may lead to side-effects on P. elaeisis emergence, but its moderate use is acceptable for this parasitoid. Diflubenzuron had severe transgenerational side-effects. Tebuconazole fungicide and triflumuron insecticide are compatible with P. elaeisis in sustainable integrated pest management (IPM) programs, while malathion can not be included in them. PMID- 28855721 TI - Composition, diversity and bioactivity of culturable bacterial endophytes in mountain-cultivated ginseng in Korea. AB - Plants harbor diverse communities of bacterial species in their internal compartments. Here we isolated and identified bacterial endophytes from mountain cultivated ginseng (MCG, Panax ginseng Meyer) to make working collection of endophytes and exploit their potentially beneficial properties toward plants and human being. A total of 1,886 bacteria were isolated from root, stem and leaf of MCGs grown in 24 different sites across the nation, using culture-dependent approach. Sequencing of 16S rDNA allowed us to classify them into 252 distinct groups. Taxonomic binning of them resulted in 117 operational taxonomic units (OTUs). Analysis of diversity indices across sampling sites and tissues suggested that composition of bacterial endophyte community within ginseng could differ substantially from one site to the next as well as from one host compartment to another. Assessment of 252 bacterial isolates for their beneficial traits to host plants showed that some bacteria possesses the ability to promote plant growth and produce beta-glucosidase, indicating their potential roles in plant growth promotion and bio-transformation. Taken together, our work provides not only valuable resources for utilization of bacterial endophytes in ginseng but also insights into bacterial communities inside a plant of medicinal importance. PMID- 28855722 TI - Real-time monitoring system for evaluating the acid-producing activity of oral squamous cell carcinoma cells at different environmental pH. AB - This study aimed to establish a real-time monitoring system for evaluating the acid-producing activity of cells and the effects of microenvironmental pH on their metabolism. Oral squamous cell carcinoma (HSC-2, HSC-3) and normal (HaCaT) cells were used. Their acid-producing activity from glucose, glutamine, and glutamate was monitored at various pH values using a pH stat system. Their production of lactic acid and ammonia was also measured. The acid-producing activity was monitored successfully. Both the cancer and normal cells produced acids from glucose, glutamine, and glutamate. All of the cells decreased their acid-producing activity as the environmental pH fell, but in glucose-derived acid producing activity the cancer cells were more acid-tolerant than HaCaT cells. In the cancer cells, the proportion of lactic acid among all acids produced from glucose at the acidic environment tended to be higher than that in HaCaT cells. All of the cells produced ammonia from glutamine, while only HaCaT cells produced ammonia from glutamate. We established a real-time monitoring system for evaluating the acid-producing activity of cells. Our results suggest that the cancer cells possess acid-tolerant glucose metabolism with a tendency of metabolic shift to lactic acid production at acidic pH and they metabolise glutamate without ammonia production. PMID- 28855723 TI - Interferences between breathing, experimental dyspnoea and bodily self consciousness. AB - Dyspnoea, a subjective experience of breathing discomfort, is a most distressing symptom. It implicates complex cortical networks that partially overlap with those underlying bodily self-consciousness, the experience that the body is one's own within a given location (self-identification and self-location, respectively). Breathing as an interoceptive signal contributes to bodily self consciousness: we predicted that inducing experimental dyspnoea would modify or disrupt this contribution. We also predicted that manipulating bodily self consciousness with respiratory-visual stimulation would possibly attenuate dyspnoea. Twenty-five healthy volunteers were exposed to synchronous and asynchronous respiratory-visual illumination of an avatar during normal breathing and mechanically loaded breathing that elicited dyspnoea. During normal breathing, synchronous respiratory-visual stimulation induced illusory self identification with the avatar and an illusory location of the subjects' breathing towards the avatar. This did not occur when respiratory-visual stimulation was performed during dyspnoea-inducing loaded breathing. In this condition, the affective impact of dyspnoea was attenuated by respiratory-visual stimulation, particularly when asynchronous. This study replicates and reinforces previous studies about the integration of interoceptive and exteroceptive signals in the construction of bodily self-consciousness. It confirms the existence of interferences between experimental dyspnoea and cognitive functions. It suggests that respiratory-visual stimulation should be tested as a non-pharmacological approach of dyspnoea treatment. PMID- 28855724 TI - Uncovering the cognitive processes underlying mental rotation: an eye-movement study. AB - Mental rotation is an important paradigm for spatial ability. Mental-rotation tasks are assumed to involve five or three sequential cognitive-processing states, though this has not been demonstrated experimentally. Here, we investigated how processing states alternate during mental-rotation tasks. Inference was carried out using an advanced statistical modelling and data-driven approach - a discriminative hidden Markov model (dHMM) trained using eye-movement data obtained from an experiment consisting of two different strategies: (I) mentally rotate the right-side figure to be aligned with the left-side figure and (II) mentally rotate the left-side figure to be aligned with the right-side figure. Eye movements were found to contain the necessary information for determining the processing strategy, and the dHMM that best fit our data segmented the mental-rotation process into three hidden states, which we termed encoding and searching, comparison, and searching on one-side pair. Additionally, we applied three classification methods, logistic regression, support vector model and dHMM, of which dHMM predicted the strategies with the highest accuracy (76.8%). Our study did confirm that there are differences in processing states between these two of mental-rotation strategies, and were consistent with the previous suggestion that mental rotation is discrete process that is accomplished in a piecemeal fashion. PMID- 28855725 TI - Preparation of TiO2-coated barite composite pigments by the hydrophobic aggregation method and their structure and properties. AB - We obtained hydrophobic barite (BaSO4) and rutile titanium dioxide (TiO2) particles (as raw materials) by organic surface modification. Subsequently, TiO2 coated barite composite pigments were prepared via the hydrophobic aggregation of heterogeneous particles in a water medium. The pigment properties of the TiO2 coated barite composite pigments were characterized and evaluated by determining their hiding power, oil absorption value and whiteness. The optical properties were determined by obtaining their UV-vis diffuse reflectance spectra and using the CIE-L*a*b* method. The morphology and bonding properties were investigated using scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and infrared spectroscopy (IR). The results show the similarity between the composite pigment and pure rutile TiO2: when the mass ratio of rutile TiO2 in the composite pigment was 60%, the hiding power of the TiO2-coated barite composite pigment was 90.81% of that of pure rutile TiO2. Moreover, the surfaces of the barite particles were uniformly and firmly coated by TiO2, with a hydrophobic association occurring between the hydrophobic carbon chains on the surfaces of barite and TiO2 particles. PMID- 28855726 TI - Effects of NRG1 Polymorphisms on Hirschsprung's Disease Susceptibility: A Meta analysis. AB - Substantial resources have been devoted to evaluate the relationship between NRG1 variants rs7835688 and rs16879552 and Hirschsprung's Disease (HSCR) but no consistency exists. This meta-analysis aimed to assess the association between the two SNPs and HSCR. PubMed, EMBASE, and Chinese Biological Medicine databases were searched for studies potentially eligible up to March, 2017. The summary odds ratios (ORs) with 95% CIs were calculated from different genetic models. Nine case-control studies (8 for both and 1 for rs16879552 only) involving 1984 HSCR patients and 4220 controls were identified. The combined results showed a significant association between HSCR risk and rs7835688 in all genetic models (per-allele model: OR = 1.66, 95% CI = 1.35-2.05; P = 1.940E-06). Rs16879552 was significantly associated with HSCR in per-allele (OR = 1.50, 95% CI = 1.27-1.76; P = 1.087E-06), additive and recessive model, except for dominant model. Stratified analysis by ethnicity showed that rs7835688 and rs16879552 were only causative for Asians, but not risk locus for Caucasians. Furthermore, pooled data based on segment length indicated that individuals with rs7835688 experienced a significantly higher risk for short-segment HSCR in all genotypes; but rs16879552 was only found to be associated with long-segment HSCR/ total colonic aganglionosis at the allele level. PMID- 28855727 TI - Noninvasive oscillometric cardiac output determination in the intensive care unit - comparison with invasive transpulmonary thermodilution. AB - Assessment of the cardiac output (CO) is usually performed with invasive techniques requiring specialized equipment in the intensive care unit (ICU). With TEL-O-GRAPH (TG), CO can be derived from the oscillometrically obtained brachial pulse wave during the measurement of brachial blood pressure. CO and stroke volume (SV) determinations with TG were compared with transpulmonary thermodilution measurements with the PICCO system (PICCO) in 38 haemodynamically unstable ICU patients with a total of 84 comparison measurements performed. SV (33.3 +/- 9.0 ml/m2 vs. 44.3 +/- 14.4 ml/m2, p < 0.001) and CO (2.7 +/- 0.5 l/min/m2 vs. 3.8 +/- 1.2 l/min/m2, p < 0.001) were underestimated significantly with TG and oscillometric brachial systolic blood pressure (BP) was significantly lower and diastolic BP significantly higher than invasive femoral artery pressure. A linear correlation was found between CO dimension and CO underestimation with TG. Correct tracking of CO changes with a fluid challenge was possible in 69.5% of measurements. Oscillometric noninvasive CO is possible in the ICU, but accuracy and precision of this new method are lacking. Implementation of a correction factor accounting for the linear increase in CO underestimation observed with increasing CO could improve CO assessment with TG in haemodynamically unstable patients. PMID- 28855729 TI - A fruitful liaison of ZSCAN10 and ROS on the road to rejuvenation. AB - Induced pluripotent stem cells derived from aged donors (A-iPSCs) usually show genomic instability that affects their utility and raises concerns about their safety. Now, a study highlights the importance of ZSCAN10-dependent recovery of glutathione-ROS homeostasis in counteracting the genomic defects in A-iPSCs. PMID- 28855730 TI - Enhancing brown fat with NFIA. AB - Brown adipose tissue is a key metabolic organ that oxidizes fatty acids and glucose to generate heat. Through epigenomic analyses of multiple adipose depots, the transcription factor nuclear factor I-A (NFIA) is now shown to drive the brown fat genetic program through binding to lineage-specific cis-regulatory elements. PMID- 28855728 TI - Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers. AB - Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from 'pre-receptive' and 88 from mid-secretory, 'receptive' phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility. PMID- 28855731 TI - DNA sensing in senescence. AB - Cellular senescence, a cell-autonomous growth arrest program, also executes pleiotropic non-cell-autonomous activities through the senescence-associated secretory phenotype (SASP). The innate cGAS-STING DNA-sensing pathway is now shown to regulate senescence by recognizing cytosolic DNA and inducing SASP factors, uncovering an unexpected link between these two previously unrelated pathways. PMID- 28855732 TI - Lab-grown mini-brains upgraded. AB - Three-dimensional brain organoid models have come into the spotlight as in vitro tools to recapitulate complex features of the brain. Four recent papers now leverage current technologies to generate new flavours of brain organoids and address aspects of brain biology which, to date, have been challenging to explore. PMID- 28855733 TI - Principles of refereeing. PMID- 28855734 TI - A caspase-independent way to kill cancer cells. AB - Cancer treatments often focus on killing tumour cells through apoptosis, which is thought to typically require mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. A study now shows that MOMP can trigger TNF dependent, but caspase-independent cell death, suggesting a different approach to improve cancer therapy. PMID- 28855735 TI - Abiotic Synthesis with the C-C Bond Formation in Ethanol from CO2 over (Cu,M)(O,S) Catalysts with M = Ni, Sn, and Co. AB - We demonstrate copper-based (Cu,M)(O,S) oxysulfide catalysts with M = Ni, Sn, and Co for the abiotic chemical synthesis of ethanol (EtOH) with the C-C bond formation by passing carbon dioxide (CO2) through an aqueous dispersion bath at ambient environment. (Cu,Ni)(O,S) with 12.1% anion vacancies had the best EtOH yield, followed by (Cu,Sn)(O,S) and (Cu,Co)(O,S). The ethanol yield with 0.2 g (Cu,Ni)(O,S) catalyst over a span of 20 h achieved 5.2 mg. The ethanol yield is inversely proportional to the amount of anion vacancy. The kinetic mechanism for converting the dissolved CO2 into the C2 oxygenate is proposed. Molecular interaction, pinning, and bond weakening with anion vacancy of highly strained catalyst, the electron hopping at Cu+/Cu2+ sites, and the reaction orientation of hydrocarbon intermediates are the three critical issues in order to make the ambient chemical conversion of inorganic CO2 to organic EtOH with the C-C bond formation in water realized. On the other hand, Cu(O,S) with the highest amount of 22.7% anion vacancies did not produce ethanol due to its strain energy relaxation opposing to the pinning and weakening of O-H and C-O bonds. PMID- 28855736 TI - Source apportionment of VOCs and their impacts on surface ozone in an industry city of Baoji, Northwestern China. AB - Level of surface ozone (O3) has been increasing continuously in China in recent years, while its contributors and formation pathways are less understood. In this study, distributions of volatile organic compounds (VOCs) and the roles on O3 pollution have been investigated in a typical industrial city of Baoji in Northwestern China by means of monitoring of their concentrations and other trace gases. The air samples have been collected at three sites according to urban function area. Concentration of VOCs in Weibin site, which near to industrial zone, was higher than most of other cities in China, and the ambient VOCs were dominated by aromatics and alkenes. The temporal variations of VOCs and O3 coincided with the surface wind, implying that the formation of O3 was impacted by both exports of plumes upwind and local photochemical reactions. Result of source apportionment indicated that industrial emission, vehicular exhaust, and solvent evaporation were three major pollution origins. Alkenes and aromatics contributed to the largest fractions of photochemical reactivity, suggesting the strong influences from industrial and traffic sectors. The study presents the characteristic VOCs and other factors in the contribution of O3 formation in China. PMID- 28855737 TI - Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5. AB - High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (TFH) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of TFH cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null TFH cells and knockdown of Etv5 suppresses the enhanced TFH cell differentiation in Cic-deficient CD4+ T cells, suggesting that Etv5 is a critical CIC target gene in TFH cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC-ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates TFH cell development and autoimmunity. PMID- 28855738 TI - Electronic Metamaterials with Tunable Second-order Optical Nonlinearities. AB - The ability to engineer metamaterials with tunable nonlinear optical properties is crucial for nonlinear optics. Traditionally, metals have been employed to enhance nonlinear optical interactions through field localization. Here, inspired by the electronic properties of materials, we introduce and demonstrate experimentally an asymmetric metal-semiconductor-metal (MSM) metamaterial that exhibits a large and electronically tunable effective second-order optical susceptibility (chi(2)). The induced chi(2) originates from the interaction between the third-order optical susceptibility of the semiconductor (chi(3)) with the engineered internal electric field resulting from the two metals possessing dissimilar work function at its interfaces. We demonstrate a five times larger second-harmonic intensity from the MSM metamaterial, compared to contributions from its constituents with electrically tunable nonlinear coefficient ranging from 2.8 to 15.6 pm/V. Spatial patterning of one of the metals on the semiconductor demonstrates tunable nonlinear diffraction, paving the way for all optical spatial signal processing with space-invariant and -variant nonlinear impulse response. PMID- 28855740 TI - Polyglutamine spinocerebellar ataxias - from genes to potential treatments. AB - The dominantly inherited spinocerebellar ataxias (SCAs) are a large and diverse group of neurodegenerative diseases. The most prevalent SCAs (SCA1, SCA2, SCA3, SCA6 and SCA7) are caused by expansion of a glutamine-encoding CAG repeat in the affected gene. These SCAs represent a substantial portion of the polyglutamine neurodegenerative disorders and provide insight into this class of diseases as a whole. Recent years have seen considerable progress in deciphering the clinical, pathological, physiological and molecular aspects of the polyglutamine SCAs, with these advances establishing a solid base from which to pursue potential therapeutic approaches. PMID- 28855742 TI - Both p62/SQSTM1-HDAC6-dependent autophagy and the aggresome pathway mediate CDK1 degradation in human breast cancer. AB - Cyclin-dependent kinase 1 (CDK1) is the central mammalian regulator of cell proliferation and a promising therapeutic target for breast cancer. In fact, CDK1 inhibition downregulates survival and induces apoptosis. Due to its essential role, CDK1 expression and activity are strictly controlled at various levels. We previously described that CDK1 stability is also regulated and that SCF(betaTrCP) ubiquitinates CDK1, which is degraded via the lysosomal pathway. In addition, in breast tumors from patients, we found a negative correlation between CDK1 accumulation and betaTrCP levels, and a positive correlation with the degree of tumor malignancy. This prompted us to study the molecular mechanism involved in CDK1 clearance. In this report, we determine that both chemotherapeutic agents and proteolytic stress induce CDK1 degradation in human breast cancer MCF7 cells through p62/HDAC6-mediated selective autophagy. On the one hand, CDK1 binds to p62/SQSTM1-LC3 and, on the other hand, it interacts with HDAC6. Both complexes are dependent on the presence of an intact betaTrCP-binding motif on CDK1. Furthermore, we also show that CDK1 is recruited to aggresomes in response to proteasome inhibition for an extended period. We propose CDK1 clearance as a potential predictive biomarker of antitumor treatment efficacy. PMID- 28855739 TI - Noncoding RNAs in neurodegeneration. AB - The emerging complexity of the transcriptional landscape poses great challenges to our conventional preconceptions of how the genome regulates brain function and dysfunction. Non-protein-coding RNAs (ncRNAs) confer a high level of intricate and dynamic regulation of various molecular processes in the CNS and they have been implicated in neurodevelopment and brain ageing, as well as in synapse function and cognitive performance, in both health and disease. ncRNA-mediated processes may be involved in various aspects of the pathogenesis of neurodegenerative disorders. Understanding these events may help to develop novel diagnostic and therapeutic tools. Here, we provide an overview of the complex mechanisms that are affected by the diverse ncRNA classes that have been implicated in neurodegeneration. PMID- 28855741 TI - The impact of cytoskeletal organization on the local regulation of neuronal transport. AB - Neurons are akin to modern cities in that both are dependent on robust transport mechanisms. Like the best mass transit systems, trafficking in neurons must be tailored to respond to local requirements. Neurons depend on both high-speed, long-distance transport and localized dynamics to correctly deliver cargoes and to tune synaptic responses. Here, we focus on the mechanisms that provide localized regulation of the transport machinery, including the cytoskeleton and molecular motors, to yield compartment-specific trafficking in the axon initial segment, axon terminal, dendrites and spines. The synthesis of these mechanisms provides a sophisticated and responsive transit system for the cell. PMID- 28855743 TI - Asteroid surface impact sampling: dependence of the cavity morphology and collected mass on projectile shape. AB - In-situ exploration and remote thermal infrared observation revealed that a large fraction of Solar System small bodies should be covered with granular regolith. The complex and varied geology of the regolith layer may preserve the historical records of the surface modification and topographic evolution experienced by asteroids, especially cratering processes, in which the projectile shape plays a crucial role. Regarding the impact sampling scheme, the projectile-shape dependence of both the cavity morphology and the collected mass remains to be explored. This paper studies the process of the low-speed impact sampling on granular regolith using projectiles of different shapes. The results demonstrate that the projectile shape significantly influences the excavation stage, forming cavities with different morphologies, i.e., cone-shaped, bowl-shaped and U shaped. We further indicate that the different velocity distributions of the ejecta curtains due to the various projectile shapes result in various amounts of collected mass in sampler canister, regarding which the 60 degrees conical projectile exhibits preferable performance for impact sampling scheme. The results presented in this article are expected to reveal the dependence of the excavation process on projectile shape under micro gravity and provide further information on the optimal designs of impact sampling devices for future sample return space missions. PMID- 28855745 TI - SHAPE BASED IMAGE RECONSTRUCTION USING LINEARIZED DEFORMATIONS. AB - We introduce a reconstruction framework that can account for shape related a priori information in ill-posed linear inverse problems in imaging. It is a variational scheme that uses a shape functional defined using deformable templates machinery from shape theory. As proof of concept, we apply the proposed shape based reconstruction to 2D tomography with very sparse measurements, and demonstrate strong empirical results. PMID- 28855747 TI - Editorial message. PMID- 28855746 TI - Design and evaluation of a grid reciprocation scheme for use in digital breast tomosynthesis. AB - This work describes a methodology for efficient removal of scatter radiation during digital breast tomosynthesis (DBT). The goal of this approach is to enable grid image obscuration without a large increase in radiation dose by minimizing misalignment of the grid focal point (GFP) and x-ray focal spot (XFS) during grid reciprocation. Hardware for the motion scheme was built and tested on the dual modality breast tomosynthesis (DMT) scanner, which combines DBT and molecular breast tomosynthesis (MBT) on a single gantry. The DMT scanner uses fully isocentric rotation of tube and x-ray detector for maintaining a fixed tube detector alignment during DBT imaging. A cellular focused copper prototype grid with 80 cm focal length, 3.85 mm height, 0.1 mm thick lamellae, and 1.1 mm hole pitch was tested. Primary transmission of the grid at 28 kV tube voltage was on average 74% with the grid stationary and aligned for maximum transmission. It fell to 72% during grid reciprocation by the proposed method. Residual grid line artifacts (GLAs) in projection views and reconstructed DBT images are characterized and methods for reducing the visibility of GLAs in the reconstructed volume through projection image flat-field correction and spatial frequency-based filtering of the DBT slices are described and evaluated. The software correction methods reduce the visibility of these artifacts in the reconstructed volume, making them imperceptible both in the reconstructed DBT images and their Fourier transforms. PMID- 28855744 TI - Metal-Catalyzed and Metal-Free Intermolecular Amination of Light Alkanes and Benzenes. PMID- 28855748 TI - Comparative evaluation of apically extruded debris during root canal instrumentation using two Ni-Ti single file rotary systems: An in vitro study. AB - BACKGROUND: Apical extrusion of debris during instrumentation is detrimental to the patient. AIM: The aim of this study was to evaluate the apical extrusion of debris during root canal instrumentation using two single file rotary Ni-Ti systems. MATERIALS AND METHODS: Thirty freshly extracted mandibular premolars with straight roots were sterilized and divided into two groups instrumented using: One Shape rotary Ni-Ti system with Endoflare orifice shaper (Group 1) and Neo-Niti rotary Ni-Ti system with C1 orifice shaper (Group 2). Preweighed Eppendorf tubes fitted for each tooth before instrumentation. During instrumentation, 1 mL of distilled water with a 30-gauge needle was used to irrigate after every instrument. Tips of the tooth were irrigated with 2 ml distilled water after removal from Eppendorf tubes. The total volume of irrigant in each group was the same 8 ml. All tubes were incubated at 68 degrees C for 15 days and subsequently weighed. The difference between pre- and post-debris weights was calculated, and statistical analysis was performed using independent t-test and level of significance was set at 0.05. RESULTS: The difference between pre- and post-weights was significantly greater for the One Shape system. CONCLUSIONS: The Neolix Niti single file was associated with less extrusion compared to One Shape single file system. PMID- 28855749 TI - A cone-beam computed tomography assessment of the efficacy of different irrigation devices for removal of silicone oil-based calcium hydroxide from root canal system. AB - BACKGROUND: Most often used intracanal medicament is calcium hydroxide (Ca(OH)2). Removal of Ca(OH)2 before obturation is mandatory. Different irrigation solutions and devices were tested in the previous study for this purpose. AIM: The aim of this study was to evaluate the comparative efficacy of different irrigation techniques in removing intracanal medicament using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Cleaning and shaping was carried out in 42 freshly extracted single-rooted mandibular first premolars using Protaper Rotary Files. Intracanal medicament (silicone oil-based Ca(OH)2 paste) was placed and left for 2 weeks in the root canal. Medicament was then removed by five different irrigation techniques: EndoActivator, EndoVac, ultrasonic irrigation with Endo-U File, F-file, and Max-i-Probe needle. Changes in volume percentage were measured using CBCT and results were statistically analyzed using Levene's statistics and ANOVA. RESULTS: Remnants of Ca(OH)2 were found in all experimental groups. No significant difference was detected among the groups. F-file showed maximum removal efficacy of approximately 48%. CONCLUSION: (1) There is no statistically significant difference between any irrigation technique for removal of oil-based Ca(OH)2. (2) F-file demonstrated better results among all the other systems. PMID- 28855750 TI - Evaluation of different fibers and biodentine as alternates to crown coverage for endodontically treated molars: An in vitro study. AB - OBJECTIVE: The objective of this study is to evaluate the fracture resistance of newer restorative materials that could serve as an alternate to crown coverage. MATERIALS AND METHODS: Forty extracted human mandibular molar teeth were selected for this study and were divided into four groups (n = 10). All the teeth in the experimental groups (Group 2-4) were subjected to access cavity preparation with roughly 1.5 mm of tooth structure remaining throughout the circumference. Group 1: Intact teeth used as control. Group 2: Access cavities reinforced with biodentine. Group 3: Inner circumference of access cavities reinforced with polyethylene fiber and nano-hybrid composite. Group 4: Access cavities were reinforced with fiber reinforced composite. All the teeth were subjected to fracture resistance using universal testing machine. RESULTS: The results of the study were evaluated statistically using one-way ANOVA and Tukey post hoc test. Group 2 demonstrated the least mean values of fracture resistance and was significantly different from the control and other experimental groups. Statistically significant difference among Groups 1, 3, and 4 was not found. CONCLUSION: Within the limitation of this in vitro study, it can be concluded that fiber reinforced composite and polyethylene fibers with nanohybrid composite could serve as an alternate to crown coverage. PMID- 28855751 TI - Comparative evaluation of three methods to measure working length - Manual tactile sensation, digital radiograph, and multidetector computed tomography: An in vitro study. AB - AIM: Compare the measurement of working length with three different methods manual tactile sensation, digital radiography and Mutidetector computed tomography(MDCT). MATERIALS AND METHOD: 40 human premolar extracted for orthodontic purpose were selected. Teeth were store in sodium chloride (0.9%) during the study. Access cavity was prepared and canal patency was seen with no 10 file in each tooth. Manually no 15 K file was inserted from access cavity until the tip was visible at the foramen, a silicon stopper was adjusted to the corresponding buccal cusp tip and the root canal length was measured. After that in each tooth with no-15 K file inserted from access cavity with stop at tip of buccal cusp until tip appear at foramen and x-ray was taken with digital radiograph (RVG,Satelac) and canal length was measured. After that all teeth are mounted in wax block,MDCT scan was done and in the scan images of teeth, root canal length is measured from buccal cusp tip to root end. After taking measurement of working length with all three methods and the data was stastically analyzed with One Way Analysis of variance (ANOVA) followed by Turkey's Test. RESULTS: ANOVA and turkeys test showed that there was no significant difference in the measurements by the three procedures (p>0.05). CONCLUSION: Working length measurement with MDCT scan and other two conventional methods does not show significant difference in measurement. Use of newer 3D imaging technique is useful in root canal treatment for measuring working length. PMID- 28855752 TI - Preservation of root canal anatomy using self-adjusting file instrumentation with glide path prepared by 20/0.02 hand files versus 20/0.04 rotary files. AB - OBJECTIVES: To compare the relative axis modification and canal concentricity after glide path preparation with 20/0.02 hand K-file (NITIFLEX(r)) and 20/0.04 rotary file (HyFlexTM CM) with subsequent instrumentation with 1.5 mm self adjusting file (SAF). MATERIALS AND METHODS: One hundred and twenty ISO 15, 0.02 taper, Endo Training Blocks (Dentsply Maillefer, Ballaigues, Switzerland) were acquired and randomly divided into following two groups (n = 60): group 1, establishing glide path till 20/0.02 hand K-file (NITIFLEX(r)) followed by instrumentation with 1.5 mm SAF; and Group 2, establishing glide path till 20/0.04 rotary file (HyFlexTM CM) followed by instrumentation with 1.5 mm SAF. Pre- and post-instrumentation digital images were processed with MATLAB R 2013 software to identify the central axis, and then superimposed using digital imaging software (Picasa 3.0 software, Google Inc., California, USA) taking five landmarks as reference points. Student's t-test for pairwise comparisons was applied with the level of significance set at 0.05. RESULTS: Training blocks instrumented with 20/0.04 rotary file and SAF were associated less deviation in canal axis (at all the five marked points), representing better canal concentricity compared to those, in which glide path was established by 20/0.02 hand K-files followed by SAF instrumentation. CONCLUSION: Canal geometry is better maintained after SAF instrumentation with a prior glide path established with 20/0.04 rotary file. PMID- 28855753 TI - Comparative evaluation of apical microleakage in immediate and delayed postspace preparation using four different root canal sealers: An in vitro study. AB - BACKGROUND: Endodontically treated teeth often lack sufficient support for a permanent restoration. During post space preparation, it is important not to disturb the integrity of the apical seal. AIM: This study compared the effect of immediate versus delayed post space preparation on the apical seal using four different sealers. MATERIALS AND METHODS: One hundred and thirty single rooted teeth were biomechanically prepared and obturated with single cone gutta-percha and 4 sealers: Endoflas FS, AH Plus, Gutta flow and MTA. Teeth were divided randomly into eight groups, post spaces were prepared using Gates Glidden drills immediately for group I, III, IV and VII. For groups II, IV, VI and VIII prepared after storage of the specimens in 100% humidity for one week. The samples were kept in methylene blue dye, centrifuged at 3000 rpm for 3 min sectioned and then measured under stereomicroscope for apical leakage. STATISTICAL ANALYSIS: The data was analysed using one way ANOVA and post hoc Tukey test. RESULTS: All the specimens showed dye leakage, and a statistically significant difference was seen among all the groups (P > 0.05) except Gutta flow. CONCLUSION: Less leakage is seen when post space is prepared immediately. PMID- 28855754 TI - Clinical evaluation of mineral trioxide aggregate and biodentine as direct pulp capping agents in carious teeth. AB - BACKGROUND: Root canal treatment has been a routine treatment option for carious exposure of the dental pulp. In the context of minimally invasive dentistry, direct pulp capping (DPC) procedure with a reliable biomaterial may be considered as an alternative provided the pulp status is favorable. Mineral trioxide aggregate (MTA), a bioactive cement with excellent sealing ability and biocompatibility is capable of regenerating relatively damaged pulp and formation of dentin bridge when used as DPC agent. Biodentine is comparatively a new biomaterial claimed to possess properties similar to MTA and is currently explored for vital pulp therapy procedures. AIM: The aim of the present study was to evaluate the clinical response of pulp-dentin complex after DPC with MTA and biodentine in carious teeth. SUBJECTS AND METHODS: Twenty-four permanent molars with carious exposure having no signs and symptoms of irreversible pulpitis were selected and assigned to one of the two groups, Group I - MTA and Group II - biodentine. Patients were recalled at 3 weeks, 3 months, and 6 months for clinical and radiographic evaluation. Fisher's exact test was used along with Chi square test for statistical analysis. RESULTS: Over a period of 6 months, MTA and biodentine showed 91.7% and 83.3% success rate, respectively, based on the subjective symptoms, pulp sensibility tests, and radiographic appearance. CONCLUSION: MTA and biodentine may be used as DPC agents when the pulpal diagnosis is not more than reversible pulpitis. PMID- 28855755 TI - Comparison of apical debris extrusion during root canal preparation using instrumentation techniques with two operating principles: An in vitro study. AB - AIMS: The aim of this study was to quantify the debris extruded apically from teeth using rotary and reciprocation instrumentation systems. SUBJECTS AND METHODS: Eighty extracted human mandibular premolars with single canals and similar lengths were instrumented using ProTaper Universal (40, 06; Dentsply Maillefer, Ballaigues, Switzerland), ProTaper Next (40, 06; Dentsply Maillefer, Ballaigues, Switzerland), WaveOne (40, 06; Dentsply Maillefer, Ballaigues, Switzerland), and Reciproc (R40; VDW GmbH, Munich, Germany). Debris extruded during instrumentation was collected into preweighed Eppendorf tubes, which were then stored in an incubator at 70 degrees C for 5 days. The final weight of the Eppendorf tubes with the extruded debris was calculated after obtaining the mean of three consecutive weights obtained for each tube. STATISTICAL ANALYSIS USED: Statistical analysis was performed using SPSS version 16.0 software. The groups were compared using the Kruskal-Wallis test for all variables. RESULTS: There was no statistically significant difference between the groups (P = 0.1114). However, the ProTaper Universal group produced more extrusion and ProTaper Next produced least debris extrusion among the instrument groups (P > 0.05). CONCLUSIONS: All instrumentation techniques were associated with extruded debris. PMID- 28855756 TI - Remineralization ability of sodium fluoride on the microhardness of enamel, dentin, and dentinoenamel junction: An in vitro study. AB - AIM: Dental tissues such as enamel, dentinoenamel junction (DEJ), dentin, and root dentin can react differently to demineralization and remineralization. The aim of this study was to evaluate the remineralization ability of sodium fluoride on the microhardness of enamel, dentin, and dentinoenamel junction. MATERIALS AND METHODS: Ten extracted third molar teeth were sectioned mesiodistally to form control and test groups. For the test group, initial demineralization was done with acetic acid for 24 h followed by remineralization for 28 days by application of sodium fluoride (226 ppm) for 2 min twice a day. Vickers microhardness test was done to control and test groups at different sites after initial demineralization and on the 3rd, 5th, 7th, 14th, and 28th day of remineralization. STATISTICAL ANALYSIS USED: Data were analyzed with one-way analysis of variance and post hoc test with a significance level of P < 0.001 with SPSS (21) software. RESULTS: Microhardness values in the demineralization group were significantly lower than controls (P < 0.001). Evaluation of remineralization samples showed that microhardness similar to control values were achieved at the 3rd day in root predentin and on the 5th day in coronal dentin and coronal predentin. On the 7th day, remineralization coronal predentin was significantly higher than the control (P < 0.001). On the 14th day, DEJ axial zone and root dentin were similar to control and coronal dentin was significantly higher than the control (P < 0.001). Enamel was similar to control on the 28th day. Microhardness of DEJ-cusp tip and DEJ-center of the fissure was significantly lower than control even at the 28th day (P < 0.001). CONCLUSION: Long-term repeated application of sodium fluoride (226 ppm) can improve the microhardness of demineralized dental tissues on enamel, dentin, and DEJ-axial zone, except in the DEJ-cusp tip and DEJ-center of fissure. PMID- 28855757 TI - Canal transportation and centering ability of protaper and self-adjusting file system in long oval canals: An ex-vivo cone-beam computed tomography analysis. AB - CONTEXT AND AIMS: The purpose of this study was to compare and evaluate the shaping ability of ProTaper (PT) and Self-Adjusting File (SAF) system using cone beam computed tomography (CBCT) to assess their performance in oval-shaped root canals. MATERIALS AND METHODS: Sixty-two mandibular premolars with single oval canals were divided into two experimental groups (n = 31) according to the systems used: Group I - PT and Group II - SAF. Canals were evaluated before and after instrumentation using CBCT to assess centering ratio and canal transportation at three levels. Data were statistically analyzed using one-way analysis of variance, post hoc Tukey's test, and t-test. RESULTS: The SAF showed better centering ability and lesser canal transportation than the PT only in the buccolingual plane at 6 and 9 mm levels. The shaping ability of the PT was best in the apical third in both the planes. The SAF had statistically significant better centering and lesser canal transportation in the buccolingual as compared to the mesiodistal plane at the middle and coronal levels. CONCLUSIONS: The SAF produced significantly less transportation and remained centered than the PT at the middle and coronal levels in the buccolingual plane of oval canals. In the mesiodistal plane, the performance of both the systems was parallel. PMID- 28855758 TI - Effect of glide path preparation on apical extrusion of debris in root canals instrumented with three single-file systems: An ex vivo comparative study. AB - AIM: The aim of this study was to test the effect of new protocol of glide path preparation by 20/0.04 rotary file on apical extrusion of debris when instrumenting fine curved mesial canals in mandibular molars with Self-adjusting File (SAF) and compare it to a glide path prepared by 20/0.02 hand K-file and rotary OneShape (OS) and reciprocating WaveOne (WO) file instrumentation. MATERIALS AND METHODS: Sixty mandibular molars with curved mesial roots were selected and randomly divided into three groups (n = 20) for instrumentation. In two groups, glide path was prepared using 20/0.02 K-file for instrumentation by OS (size 25/0.06 taper) and WO (size 25/0.08 taper) files; in the remaining group, 20/0.04 rotary file was used for glide path preparation and instrumented by SAF (1.5 mm). The debris extruded during instrumentation was collected in preweighed Eppendorf tubes and stored in an incubator at 70 degrees C for 5 days. Tubes containing the dry extruded debris were then weighed. One-way analysis of variance (ANOVA) was applied to the weights obtained, followed by Tukey's post hoc test for multiple comparison. RESULTS: The mean debris (g) extruded apically was 0.000651 +/- 0.000291, 0.000823 +/- 0.000319, and 0.000473 +/- 0.000238 for Group 1 (20/0.02 + OS), Group 2 (20/0.02 + WO), and Group 3 (20/0.04 + SAF), respectively. The groups exhibited a significant difference (P < 0.01; ANOVA). Group 3 resulted in least debris extrusion compared to Groups 1 and 2 (P < 0.01; Tukey's post hoc test). CONCLUSION: Glide path prepared to size 20/0.04 and SAF 1.5 mm instrumentation produce less debris in curved mesial canals of mandibular molars, compared to glide path established by 20/0.02 and instrumentation by OS and WO files. PMID- 28855759 TI - Effect of obturating materials on fracture resistance of simulated immature teeth. AB - AIM: The aim of this study was to evaluate the fracture resistance of simulated immature teeth, when the root canals were completely filled either with mineral trioxide aggregate (MTA) or Biodentine, comparing with that of roots filled with apexification procedure. MATERIALS AND METHODS: Sixty mandibular premolar teeth with single, straight canals decoronated at cementoenamel junction were divided into five groups (n = 12 each). Group 1 samples served as negative control and remaining four groups root samples were shaped and cleaned using ProTaper rotary files. To simulate immature roots, a #5 Peeso reamer was passed beyond the apex so that apices were enlarged to a diameter of 1.5 mm. Group 2 and 4 samples were filled with 5 mm of MTA or Biodentine apical plug and backfilling with gutta percha using AH Plus sealer. Group 3 and 5 root samples were completely obturated with MTA and Biodentine, respectively. All the teeth were loaded vertically until fracture, using the universal testing machine. STATISTICAL ANALYSIS: Forces at which fracture of the roots occurred were subjected to statistical analysis using SPSS/PC version 2 software, and the results were analyzed with the one-way analysis of variance and Newman-Keuls multiple post hoc test. RESULTS: Complete root canal obturation with MTA or Biodentine has shown significantly higher fracture resistance (P < 0.05) when compared to apexification with MTA or Biodentine. CONCLUSION: Obturation of the root canals with bioactive materials has shown highest fracture resistance when compared to apexification groups. PMID- 28855760 TI - Comparative evaluation of chlorhexidine, grape seed extract, riboflavin/chitosan modification on microtensile bond strength of composite resin to dentin after polymerase chain reaction thermocycling: An in vitro study. AB - AIM: The purpose of this study was to evaluate the influence of chlorhexidine (CHX), grape seed extract (GSE), riboflavin/chitosan modification on microtensile bond strength (MUTBS) of composite resin to dentin after polymerase chain reaction (PCR) thermocycling. MATERIALS AND METHODS: Forty extracted human molars were used and a flat surface was then prepared by removing the occlusal one third. The teeth were randomly assigned into four groups - Group I in which self etch adhesive (Adper Easy One) was applied and Groups II, III, IV were pretreated with 2% CHX, 6.5% GSE, and 1% riboflavin/chitosan, respectively, before the application of self-etch adhesive. Composite build-ups were constructed, and PCR thermocycling (5000 cycles) was performed. The MUTBS was evaluated using the universal testing machine. Data were analyzed using one-way analysis of variance and Tukey's test. RESULTS: The mean MUTBS values for Group I (control), Group II (CHX), Group III (GSE), and Group IV (riboflavin/chitosan modification) were 30.81, 43.15, 38.79, and 35.07 MPa, respectively. CONCLUSION: Pretreatment with CHX and GSE leads to a significant increase in MUTBS of composite resin to dentin. PMID- 28855761 TI - Effect of conventional irrigation and photoactivated disinfection on Enterococcus faecalis in root canals: An in vitro study. AB - AIMS: A study was done to evaluate the antimicrobial efficacy of sodium hypochlorite (NaOCl) and photoactivated disinfection (PAD) on Enterococcus faecalis. SETTINGS AND DESIGN: Random sampling, in-vitro study. SUBJECTS AND METHODS: Access opening and biomechanical preparation were performed on fifty freshly extracted mandibular second premolars. The specimens were sterilized; 15 MUm of E. faecalis was inoculated into each canal and incubated at 36 degrees C for 24 h. Later, specimens were randomly divided into two groups of fifty each and following procedures was carried out: (i) conventional irrigation with 2.25% NaOCl (ii) PAD using diode laser, and toluidine blue photosensitizer. Samples were collected from each canal using sterile paper points which were deposited in brain heart infusion broth, and microbiological evaluation was carried out. STATISTICAL ANALYSIS USED: Student's t-test was used to find the significant difference in the reduction of colony forming unit (CFU) between the groups. RESULTS: The mean CFUs of the two groups showed statistically significant difference (P = 0.001). Improved antibacterial efficacy was seen with PAD group compared to conventional NAOCL irrigation. CONCLUSIONS: NaOCl alone was not effective in eliminating E. faecalis completely from the root canals. PAD compared to conventional irrigation showed the best results in removing E. faecalis from root canals. PMID- 28855762 TI - A comparison of human dental pulp response to calcium hydroxide and Biodentine as direct pulp-capping agents. AB - CONTEXT: Direct pulp capping involves the placement of a biocompatible agent on pulp tissue that has been inadvertently exposed from traumatic injury or by iatrogenic means. AIM: To compare the human pulp response to calcium hydroxide and Biodentine as direct pulp-capping agents. MATERIALS AND METHODS: Pulp exposures were performed on the pulpal floor of forty human permanent premolars. The exposure sites were dressed with either Dycal or Biodentine as pulp-capping materials. After 45 days, teeth were extracted and processed for histological examination. STATISTICAL ANALYSIS: The histological data were subjected to Wilcoxon rank-sum test. RESULTS: The dentinal bridges in teeth that were capped with Biodentine were significantly thicker (P < 0.0001) and more continuous (P = 0.0001) with less pulpal inflammation (P = 0.0044) in comparison to Dycal. CONCLUSION: Based on the result of this study, Biodentine can be suggested as the material of choice for direct pulp capping procedure instead of Dycal. However, further long-term follow-up in vivo human studies using Biodentine on cariously exposed pulpal teeth are warranted to derive a definite conclusion. PMID- 28855763 TI - Effect of dried sunflower seeds on incisal edge abrasion: A rare case report. AB - Tooth surface loss (TSL) is a complex phenomenon characterized by the loss of hard tooth structure at various locations of the teeth, usually due to more than one factor. TSL due to abrasion can be significant in patients consuming coarse, abrasive diet. The present case reports an interesting incisal edge abrasion in a female patient, attributed to a particular dietary behavior of long-term consumption of sunflower seeds. All her family members and most of the people from her native place were also reported to have similar lesions by the patient. Larger epidemiological studies to assess the prevalence and severity of such abrasive lesions in geographic areas with this particular dietary habit need to be carried out so that people may be made aware and educated about alternative ways of eating sunflower seeds that will not cause any form of tooth wear. PMID- 28855764 TI - Endodontic management of mandibular first molars with mid mesial canal: A case series. AB - The purpose of this study is to demonstrate the importance of knowledge of the internal anatomy of root canals for the success of endodontic treatment. Lack of knowledge of anatomic variations and their characteristics in different teeth has been pointed out as one of the main cause of endodontic therapy failure. Dental operating microscope plays a key role in the identification of canal and success of endodontic treatment. This case series describes the endodontic treatment of mandibular first molars with extra root canals, evaluate the occurrence of this extra canal, and discuss the importance of their identification and treatment. PMID- 28855765 TI - Nonsurgical endodontic treatment of teeth associated with large periapical lesion using triple antibiotic paste and mineral trioxide aggregate apical plug: A case series. AB - Periapical diseases are induced as a result of the direct or indirect involvement of oral bacteria. The etiologic factor being the degenerating pulp tissue. A periapical lesion is formed within an area of apical periodontitis which cannot form by itself and is inflammatory in origin. If the microbial etiology of periapical lesions and in the root canal is removed by nonsurgical root canal therapy the lesions regress. Mere surgical removal of the periapical lesions without proper root canal disinfection and obturation will not result in the healing of periapical tissues. Nonsurgical treatment with triple antibiotic paste offers a high success rate in the healing of large periapical lesions. The present clinical cases show the nonsurgical endodontic management of large periapical pathosis using triple antibiotic paste and mineral trioxide aggregate. PMID- 28855766 TI - Effect of mental health on post-operative infection rates following cervical spine fusion procedures. AB - PURPOSE: The aim of this study was to determine whether having an existing psychiatric disorder is a risk factor for developing post-operative infection following anterior cervical discectomy with fusion (ACDF) and posterior cervical fusion (PCF). RESULTS: A total of 34,007 patients within Humana database was included in this study. Patients with mental disorders had post-operative infection rates of 3.2% and 4.4% within 1 and 3months, compared to 2.5% and 3.5% in patients without a psychiatric disorder (p < 0.05). CONCLUSIONS: Patients with mental disorders had significantly higher rates of post-operative infection compared to patients who were never diagnosed with a psychiatric disorder. PMID- 28855767 TI - Whats New in Emergencies Trauma and Shock? Age and Trauma: Geriatric Trauma Patients and Geriatric Trauma Ward Services. PMID- 28855768 TI - Developing Emergency and Trauma Systems Internationally: What is Really Needed for Better Outcomes? PMID- 28855769 TI - Correlation of Venous Lactate and Time of Death in Emergency Department Patients with Noncritical Lactate Levels and Mortality from Trauma. AB - BACKGROUND: Serum venous lactate (LAC) levels help guide emergency department (ED) resuscitation of patients with major trauma. Critical LAC level (CLAC, >=4.0 mmol/L) is associated with increased disease severity and higher mortality in injured patients. The characteristics of injured patients with non-CLAC (NCLAC) (<4.0 mmol/L) and death have not been previously described. OBJECTIVES: (1) To describe the characteristics of patients with venous NCLAC and death from trauma. (2) To assess the correlation of venous NCLAC with time of death. METHODS: A retrospective cohort study at an urban teaching hospital between 9/2011 and 8/2014. Inclusion: All trauma patients (all ages) who presented to the ED with any injury and met all criteria: (1) Venous LAC drawn at the time of arrival that resulted in an NCLAC level; (2) were admitted to the hospital; (3) died during their hospitalization. Exclusion: CLAC. Outcome: Correlation of NCLAC and time of death. Data were extracted from an electronic medical record by trained data abstractors using a standardized protocol. Cross-checks were performed on 10% of data entries and inter-observer agreement was calculated. Data were explored using descriptive statistics and Kaplan-Meier curves were created to define survival estimates. Data are presented as percentages with 95% confidence interval (CI) for proportions and medians with quartiles for continuous variables. Kaplan-Meier curves with differences in time to events based on LAC are used to analyze the data. RESULTS: A total of 60 patients met the inclusion criteria. The median age was 52 years (quartiles: 30, 75) and 73% were male (age range 2-92). The median LAC in the overall cohort was 1.9 mmol/L (quartiles: 1.5, 2.1). Sixteen patients (27%) died during the first 24 h with 5 (31%) due to intracranial hemorrhage. The median survival time was 5.6 days (134.4 h) (95% CI: 2.3-12.6). CONCLUSIONS: In trauma patients with NCLAC who died during the index hospitalization, the median survival time was 5.6 days, approximately one-third of patients died within the first 24 h. These findings indicate that relying on a triage NCLAC level alone may result in underestimating injury severity and subsequent morbidity and mortality. PMID- 28855770 TI - Dual Antiplatelet Therapy and the Severity Risk of Lower Intestinal Bleeding. AB - BACKGROUND: Dual antiplatelet (Plt) therapy with aspirin and clopidogrel is recommended for up to 1 year following acute coronary syndrome. Many of these cardiac patients are also on anithrombotic therapy like warfarin. Lower gastrointestinal bleeding (LGIB) is the main adverse event of this treatment. AIMS: The main purpose of this study was to analyze the relationship of dual anti Plt therapy and the risk of LGIB. METHODS: Patients' electronic charts were reviewed to include a total of 19 variables, which included age, sex, ethnicity, daily use aspirin of any dose, daily use of clopidogrel, use of nonsteroidal anti inflammatory drugs (NSAIDs) at least twice in the last week prior to admission and the daily use of anticoagulants (warfarin, heparin), and were obtained from history and physical examination reports, lab transcripts and procedural reports. SETTINGS/DESIGN: A retrospective cohort study of the records of 3436 patients admitted to our hospital from January 1, 2009, to December 31, 2011, was evaluated. All the patients included were admitted through the emergency department with complaints of or relating to LGIB. The primary outcome studied was severe LGIB as defined by the requirement of at least two units of packed red blood cells and/or a decrease in the hematocrit of 20% or more or recurrent bleeding after 24 h of clinical stability with additional transfusions required. Other outcomes included surgical intervention. STATISTICAL METHODS/ANALYSIS: Univariate analysis using t-test on continuous variables and Chi-square test on categorical variables were done before carrying out logistic regression analysis. Logistic regression analyses were conducted to measures of association between the variables and LGIB. Logistic regression analysis was not carried for surgical intervention and death because none of the variables was significant from univariate tests. RESULTS: A total of 511 patients were found to have true LGIB. Among these subjects, 61 were shown to be on dual or multiple antithrombotic therapies. Further exploration revealed that while the use of multiple blood thinning agents may, in fact, pose a significant risk to overall LGIB, it did not significantly increase the risk for severe bleeding as outlined above. CONCLUSION: The use of multiple blood thinning agents does not significantly increase the risk for severe LGIB. PMID- 28855771 TI - Surgery Goes Social: The Extent and Patterns of Social Media Utilization by Major Trauma, Acute and Critical Care Surgery Societies. AB - CONTEXT AND AIMS: The evolving influence of social media in trauma, acute, and critical care surgery (TACCS) cannot be ignored. We sought to investigate the extent and patterns of use of social networks by major regional, national and international TACCS societies. MATERIALS AND METHODS: The two leading social networking sites, Facebook (FB) and Twitter (TW), were thoroughly examined for the presence of official accounts for each of the major TACCS societies. An official FB or TW account was defined as one which has a blue verified badge and/or is linked the society's official website. For societies with confirmed official accounts, the extent and patterns of use of the two platforms were systematically examined over a 2-week period through: (1) manual inspection of the societies' FB and TW pages, (2) the SQLite database containing downloaded samples of posts, and (3) the TW analytics database, symplur.com. Standardized social media metrics were calculated for each society. Posted content was categorized as being: (1) society news updates, (2) event announcements, or (3) general medical information. RESULTS: From a total of 64 TACCS societies, only 27 (42%) had FB and/or TW accounts. Ten out of the 12 American societies had accounts compared to 13/39 of European, 2/9 of Australasian, and 0/2 of international societies. For the societies with social media presence, the mean numbers of monthly tweets and FB posts per society were 22 and 8, respectively. We summarize the FB and TW activity of the studied TACCS societies. Most tweets/posts were society news updates and event announcements intended to the society's constituents not the general public. A text cloud was constructed to summarize the major featured topics. CONCLUSION: Less than half of the TACCS societies are currently using social media; those that do are arguably underutilizing its potential. Non-American societies in particular lag behind in their use of social networking. PMID- 28855772 TI - Patterns of Ocular Trauma among the Elderly in a South-American Urban Area and the Association between Eye Traumas with Sleep Disorders. AB - AIMS: Eye trauma in the older population can lead to blindness. Sleep deterioration is associated with increased risk of occupational injuries. The purpose of the study was to assess the epidemiology of ocular trauma in the elderly population and to evaluate the relationship between eye trauma and sleep quality. SETTINGS AND DESIGN: This was a cross-sectional, observational hospital based study done in a Sao Paulo, Brazil. SUBJECTS AND METHODS: Patients with ocular trauma aged 60 years who attended the Eye Trauma Service of the Santa Casa de Sao Paulo Central Hospital were included. All subjects underwent a complete eye examination and answered to the Pittsburgh Sleep Quality Index (PSQI) questionnaire. The results were compared with an age and gender matched control group. RESULTS: Eighty-nine patients with ocular trauma were included in the epidemiological study, 71 (80%) were male and 18 (20%) were female. The patients' ages ranged from 60 to 90 years (65.7 +/- 7.1 years). Most accidents occurred at home and were of mild severity. The control group had a global PSQI score of 1.21 +/- 1.37, whereas in the ocular trauma group the score was 3.11 +/- 3.63 (P < 0.038). A post hoc analysis including only patients with severe trauma, the PSQI score was 8.80 +/- 2.44 (P < 0.000). CONCLUSION: The elderly population represents an important group of ocular trauma in their own peculiar characteristics. Elderly victims of ocular trauma, particularly serious eye injury, have worse sleep quality than subjects of the same age. PMID- 28855773 TI - Effectiveness and Safety of Polygeline in Patients with Hypovolemia due to Trauma. AB - BACKGROUND: This retrospective study examined the effectiveness and safety of polygeline in adult patients with hypovolemia due to traumatic injury. MATERIALS AND METHODS: Polygeline was administered after evaluating the amount of blood loss and estimating hematological and biochemical parameters. Changes in vital signs, serum electrolytes, arterial pH, and serum lactate were evaluated. The safety was evaluated by recording the adverse events if any. RESULTS: Sixty patients with the mean age 37.5 +/- 11.26 years were included in the study. All patients had blood loss < 20%. The mean total polygeline administered was 1025.0 +/- 464.18 ml. Blood transfusion was required in 3.33% of patients. Diastolic, systolic, and mean arterial blood pressure and pulse rate significantly increased after 1 h of polygeline administration (P < 0.0001). There was a trend toward increase in urine output (P = 0.0715) after 1 h. The improvement in vital parameters was consistent at 6, 14, and 18 h after administration of polygeline. Arterial pH significantly increased from 7.2 +/- 0.12 to 7.3 +/- 0.11 after 1 h of administration (P < 0.0001) and was consistent till 24 h (P = 0.035). Blood lactate decreased after 1 h (P < 0.0001). Changes in laboratory parameters were not clinically significant. After mean duration hospital stay of 10.5 +/- 4.63 days all patients were discharged without any clinically significant abnormality or adverse event. CONCLUSION: Polygeline improved hemodynamic stability in patients with hypovolemia due to traumatic injury. The improvement was seen within 1 h (golden hour) of polygeline administration and maintained consistently. Polygeline can be safely administered to patients with traumatic injury to improve hemodynamic parameters and achieve stability. PMID- 28855774 TI - Studying the Variability in Patient Inflow and Staffing Trends on Sundays versus Other Days in the Academic Emergency Department. AB - BACKGROUND: Resource limitation, staff deficiency, and variability in patient inflow contribute to emergency department (ED) overcrowding, associated with delayed care, poor care, and poor patient outcomes. This study seeks to describe and analyze patient inflow variability and staffing trends on Sundays versus other days in a tertiary academic ED from South India. METHODS: Patient inflow and staffing data for 2 years were collected from hospital records, cross checked, and statistically analyzed using Epi Info 7.0. RESULTS: Significant increase in patient inflow (45.6%) was noted on Sundays compared to other days (155.9 [95% confidence interval (CI): 152.75-159.05] vs. 107.1 [95% CI: 105.98 108.22]; P < 0.001), with higher inflow in the morning shifts (67.4 [95% CI: 65.41-69.45] vs. 32.1 [95% CI: 31.45-32.70]; P < 0.001). All categories of ED staff were deficient across all shifts (2.1 [95% CI: 2.05-2.15] tier-2 physicians, 4.9 [95% CI: 4.86-4.94] nurses, and 1.9 [95% CI: 1.88-1.92] nurse assistants on an average), especially tier-1 physicians (0.3 [95% CI: 0.24-0.36] on Sundays and 0.5 [95% CI: 0.48-0.52] on other days; P < 0.001). Patient-per hour (PPH)-per-provider based on patient arrival rate was generally high. PPH per tier-1 physician was the highest, being 10.6 (95% CI: 9.95-11.14) versus 5.4 (95% CI: 5.26-5.59; P < 0.001) in the morning and 7.2 (95% CI: 6.95-7.45) versus 6.6 (95% CI: 6.43-6.74; P = 0.08) in the evening shifts on Sundays and other days, respectively. CONCLUSIONS: There were deficiencies in all categories of ED staff on all days, and this was pronounced on Sundays due to significantly higher patient inflow. Inadequate ED staffing, especially due to a significant dearth of tier-1 physicians is a pointer toward quality compromise in developing EDs. Authors recommend adequate staff deployment in developing EDs for optimum quality care. This should be implemented such that staffing is based on expected patient inflow so that a PPH-per-provider goal of 2.5 is targeted across all shifts. PMID- 28855775 TI - Studying Morbidity and Predicting Mortality in Patients with Blunt Chest Trauma using a Novel Clinical Score. AB - BACKGROUND: A departmental audit in March 2015 revealed significant mortality rate of 40% in blunt chest trauma patients (much greater than the global 25%). A study was thus planned to study morbidity and predictors of mortality in blunt chest trauma patients admitted to our hospital. METHODS: This study was a prospective observational study of 139 patients with a history of blunt chest trauma between June 2015 and November 2015 after the Institutional Ethics Committee approval in April 2015. The sample size was calculated from the prevalence rate in our institute from the past medical records. RESULTS: The morbidity factors following blunt chest injuries apart from pain were need for Intensive Care Unit stay, mechanical ventilation, and pneumonia/acute respiratory distress syndrome. Significant predictors of mortality in our study were SpO2 <80 at the time of presentation, Glasgow coma scale <= 8, patients with four or more rib fractures, presence of associated head injury, Injury Severity Score >16, and need for mechanical ventilation. By calculating the likelihood ratios of each respiratory sign, a clinical score was devised. CONCLUSION: The modifiable factors affecting morbidity and mortality were identified. Mild to moderate chest injury due to blunt trauma is difficult to diagnose. The restoration of respiratory physiology has not only significant implications on recovery from chest injury but also all other injuries. It is our sincere hope that the score we have formulated will help reduce mortality and morbidity after further trials. PMID- 28855776 TI - The Value of Arterial Blood Gas Parameters for Prediction of Mortality in Survivors of Out-of-hospital Cardiac Arrest. AB - CONTEXT: Sudden cardiac death is one of the leading causes of death in Europe, and early prognostication remains challenging. There is a lack of valid parameters for the prediction of survival after cardiac arrest. AIMS: This study aims to investigate if arterial blood gas parameters correlate with mortality of patients after out-of-hospital cardiac arrest. MATERIALS AND METHODS: All patients who were admitted to our hospital after resuscitation following out-of hospital cardiac arrest between January 1, 2008, and December 31, 2013, were included in this retrospective study. The patient's survival 5 days after resuscitation defined the study end-point. For the statistical analysis, the mean, standard deviation, Student's t-test, Chi-square test, and logistic regression analyses were used (level of significance P < 0.05). RESULTS: Arterial blood gas samples were taken from 170 patients. In particular, pH < 7.0 (odds ratio [OR]: 7.20; 95% confidence interval [CI]: 3.11-16.69; P < 0.001) and lactate >= 5.0 mmol/L (OR: 6.79; 95% CI: 2.77-16.66; P < 0.001) showed strong and independent correlations with mortality within the first 5 days after hospital admission. CONCLUSION: Our study results indicate that several arterial blood gas parameters correlate with mortality of patients after out-of-hospital resuscitation. The most relevant parameters are pH and lactate because they are strongly and independently associated with mortality within the first 5 days after resuscitation. Despite this correlation, none of these parameters by oneself is strong enough to allow an early prognostication. Still, these parameters can contribute as part of a multimodal approach to assessing the patients' prognosis. PMID- 28855777 TI - Characteristics and Management of Blunt Renal Injury in Children. AB - BACKGROUND: Renal trauma in the pediatric population is predominately due to blunt mechanism of injury. Our purpose was to determine the associated injuries, features, incidence, management, and outcomes of kidney injuries resulting from blunt trauma in the pediatric population in a single level I trauma center. METHODS: This was a retrospective chart and trauma registry review of all pediatric blunt renal injuries at a regional level I trauma center that provides care to injured adults and children. The inclusion dates were January 2001-June 2014. RESULTS: Of 5790 pediatric blunt trauma admissions, 68 children sustained renal trauma (incidence: 1.2%). Only two had nephrectomies (2.9%). Five renal angiograms were performed, only one required angioembolization. Macroscopic hematuria rate was significantly higher in the high-grade injury group (47% vs. 16%; P = 0.031). Over half of the patients had other intra-abdominal injuries. The liver and spleen were the most frequently injured abdominal organs. CONCLUSION: Blunt renal trauma is uncommon in children and is typically of low American Association for the Surgery of Trauma injury grade. It is commonly associated with other intra-abdominal injuries, especially the liver and the spleen. The nephrectomy rate in pediatric trauma is lower compared to adult trauma. Most pediatric blunt renal injury can be managed conservatively by adult trauma surgeons. PMID- 28855778 TI - Older Age, Comorbid Illnesses, and Injury Severity Affect Immediate Outcome in Elderly Trauma Patients. AB - INTRODUCTION: Trauma in elderly population is frequent and is associated with significant mortality, not only due to age but also due to complicated factors such as the severity of injury, preexisting comorbidity, and incomplete general assessment. Our primary aim was to determine whether age, Injury Severity Score (ISS), and preexisting comorbidities had an adverse effect on the outcome in patients aged 65 years and above following blunt trauma. METHODS: We included 1027 patients aged >=65 years who were admitted to our Level I Trauma Center following blunt trauma. Patients' charts were reviewed for demographics, ISS, mechanism of injury, preexisting comorbidities, Intensive Care Unit and hospital length of stay, complications, and in-hospital mortality. RESULTS: The mean age of injured patients was 78.8 +/- 8.3 years (range 65-109). The majority of patients had mild injury severity (ISS 9-14, 66.8%). Multiple comorbidities (>=3) were found in 233 patients (22.7%). Mortality during the hospitalization stay (n = 35, 3.4%) was associated with coronary artery disease, renal failure, dementia, and warfarin use (P < 0.05). Chronic anticoagulation treatment was recorded in 13% of patients. The addition of a single comorbidity increased the odds of wound infection to 1.29 and sepsis to 1.25. Both age and ISS increased the odds of death as -1.08 and -2.47, respectively. CONCLUSIONS: Our analysis shows that age alone in elderly trauma population is not a robust measure of outcome, and more valuable predictors such as injury severity, preexisting comorbidities, and medications are accounted for adverse outcome. Trauma care in this population with special considerations should be tailored to meet their specific needs. PMID- 28855779 TI - Trauma Team Activation: Not Just for Trauma Patients. AB - Specialized trauma teams have been shown to improve outcomes in critically injured patients. At our institution, an the American College of Surgeons Committee on trauma level I Trauma center, the trauma team activation (TTA) criteria includes both physiologic and anatomic criteria, but any attending physician can activate the trauma team at their discretion outside criteria. As a result, the trauma team has been activated for noninjured patients meeting physiologic criteria secondary to nontraumatic hemorrhage. We present two cases in which the trauma team was activated for noninjured patients in hemorrhagic shock. The utilization of the TTA protocol and subsequent management by the trauma team are reviewed as we believe these were critical factors in the successful recovery of both patients. Beyond the primary improved survival outcomes of severely injured patients, trauma center designation has a "halo effect" that encompasses patients with nontraumatic hemorrhage. PMID- 28855781 TI - A Pregnant Woman with Pneumomediastinum after Tooth Treatment. PMID- 28855780 TI - The 2017 International Joint Working Group White Paper by INDUSEM, the Emergency Medicine Association and the Academic College of Emergency Experts on Establishing Standardized Regulations, Operational Mechanisms, and Accreditation Pathways for Education and Care Provided by the Prehospital Emergency Medical Service Systems in India. AB - The government of India has done remarkable work on commissioning a government funded prehospital emergency ambulance service in India. This has both public health implications and an economic impact on the nation. With the establishment of these services, there is an acute need for standardization of education and quality assurance regarding prehospital care provided. The International Joint Working Group has been actively involved in designing guidelines and establishing a comprehensive framework for ensuring high-quality education and clinical standards of care for prehospital services in India. This paper provides an independent expert opinion and a proposed framework for general operations and administration of a standardized, national prehospital emergency medical systems program. Program implementation, operational details, and regulations will require close collaboration between key stakeholders, including local, regional, and national governmental agencies of India. PMID- 28855782 TI - A Case of Tetraplegia after Proteus mirabilis Infection. PMID- 28855783 TI - An Evolving Difficult Airway. PMID- 28855784 TI - Remark on the Cauchy problem for the evolution p-Laplacian equation. AB - In this paper, we prove that the semigroup [Formula: see text] generated by the Cauchy problem of the evolution p-Laplacian equation [Formula: see text] ([Formula: see text]) is continuous form a weighted [Formula: see text] space to the continuous space [Formula: see text]. Then we use this property to reveal the fact that the evolution p-Laplacian equation generates a chaotic dynamical system on some compact subsets of [Formula: see text]. For this purpose, we need to establish the propagation estimates and the space-time decay estimates for the solutions first. PMID- 28855785 TI - A partially penalty immersed Crouzeix-Raviart finite element method for interface problems. AB - The elliptic equations with discontinuous coefficients are often used to describe the problems of the multiple materials or fluids with different densities or conductivities or diffusivities. In this paper we develop a partially penalty immersed finite element (PIFE) method on triangular grids for anisotropic flow models, in which the diffusion coefficient is a piecewise definite-positive matrix. The standard linear Crouzeix-Raviart type finite element space is used on non-interface elements and the piecewise linear Crouzeix-Raviart type immersed finite element (IFE) space is constructed on interface elements. The piecewise linear functions satisfying the interface jump conditions are uniquely determined by the integral averages on the edges as degrees of freedom. The PIFE scheme is given based on the symmetric, nonsymmetric or incomplete interior penalty discontinuous Galerkin formulation. The solvability of the method is proved and the optimal error estimates in the energy norm are obtained. Numerical experiments are presented to confirm our theoretical analysis and show that the newly developed PIFE method has optimal-order convergence in the [Formula: see text] norm as well. In addition, numerical examples also indicate that this method is valid for both the isotropic and the anisotropic elliptic interface problems. PMID- 28855786 TI - Is orthopaedic manipulative physical therapy not fashionable anymore? Lessons learned from 2016 IFOMPT meeting and future directions. PMID- 28855787 TI - The symptomatic and functional effects of manual physical therapy on plantar heel pain: a systematic review. AB - OBJECTIVES: Plantar heel pain is common and can be severely disabling. Unfortunately, a gap in the literature exists regarding the optimal intervention for this painful condition. Consequently, a systematic review of the current literature regarding manual therapy for the treatment of plantar heel pain was performed. METHODS: A computer-assisted literature search for randomized controlled trials in MEDLINE, EMBASE, Cochrane, CINAHL, and Rehabilitation & Sports Medicine Source, was concluded on 7 January 2014. After identification of titles, three independent reviewers selected abstracts and then full-text articles for review. RESULTS: Eight articles were selected for the final review and underwent PEDro scale assessment for quality. Heterogeneity of the articles did not allow for quantitative analysis. Only two studies scored >=7/10 on the PEDro scale and included joint, soft tissue, and neural mobilization techniques. These two studies showed statistically greater symptomatic and functional outcomes in the manual therapy group. DISCUSSION: This review suggests that manual therapy is effective in the treatment of plantar heel pain; however, further research is needed to validate these findings given the preponderance of low quality studies. PMID- 28855788 TI - An abbreviated therapeutic neuroscience education session improves pain knowledge in first-year physical therapy students but does not change attitudes or beliefs. AB - OBJECTIVE: To determine if a 3-hour therapeutic neuroscience education session alters physical therapy student's knowledge of pain and effects their attitudes and beliefs regarding treating chronic pain. METHODS: Seventy-seven entry-level doctoral physical therapy students participated in the study. Following consent, demographic data were obtained and then the subjects completed the Neuroscience of Pain Questionnaire, the Health Care Provider's Pain and Impairment Relationship Scale and an additional questionnaire designed by the researchers. The subjects then received a 3-hour educational session developed by the researchers, focusing on the neurobiology and physiology of pain. The questionnaires were re-administered immediately after the educational session and at 6 months post-education. RESULTS: Seventy-seven subjects (mean age = 24.7 years, 57.1% female and 81.8% white) completed the questionnaires pre- and post educational session with 75 completing the questionnaires at 6 months. To assess the effect of the education on the scores of the questionnaires, a repeated measures ANOVA was conducted. Students demonstrated significantly higher scores on the neuroscience of pain questionnaire (p < 0.001) with no significant effect found on the attitudes and beliefs questionnaire at any of the time points. There were significant differences found on some of the individual questions that were part of the additional questionnaire. DISCUSSION: An educational session on the neuroscience of pain is beneficial for educating entry-level doctoral physical therapy students immediately post-education and at 6 months. This educational session had no effect on the student's attitudes and beliefs regarding treating the chronic pain population. There were additional significant findings regarding individual questions posed to the subjects. PMID- 28855790 TI - Safety of lower extremity neurodynamic exercises in adults with diabetes mellitus: a feasibility study. AB - OBJECTIVES: Neurodynamic exercises aim to improve neural mechanosensitivity in order to promote pain-free movement and function. People with diabetes mellitus (DM) may be candidates for neurodynamic exercises to address common DM-related impairments such as reduced lower extremity range of motion (ROM) and altered neural mechanosensitivity. However, no studies have examined the safety and immediate effects of neurodynamic exercise in people with DM. This study aims to determine the feasibility of applying neurodynamic exercises in adults with DM by evaluating the rate of adverse events and quantifying immediate changes in straight leg raise (SLR) ROM. METHODS: This quasi-experimental study included 20 people with DM who performed a series of neurodynamic exercises on their right leg. Their left leg was used as an internal control. SLR testing was performed before and immediately after these exercises. Adverse events were monitored, including provocation of their neuropathy symptoms or discomfort or pain. RESULTS: All participants completed the neurodynamic exercises without provocation of their neuropathy symptoms. No pain was reported and only one participant had minor discomfort with one exercise; a <30-s calf cramp. The right SLR ROM increased by an average of 5.2 degrees -5.3 degrees (p < 0.01) with no change on the left. DISCUSSION: This study demonstrated that lower extremity neurodynamic exercises are safe in adults with DM and may create small immediate improvements in SLR testing. Further research is indicated to investigate the safety and efficacy of neurodynamic exercises performed over multiple sessions. LEVEL OF EVIDENCE: 3b. PMID- 28855789 TI - Effects of different verbal instructions on change of lumbar multifidus muscle thickness in asymptomatic adults and in patients with low back pain. AB - BACKGROUND: Spinal stabilisation exercise has been shown to be effective in the rehabilitation of low back pain (LBP). Due to the isometric nature of spinal stabilisation exercise, manual therapists use various verbal instructions to elicit lumbar multifidus muscle contraction. OBJECTIVES: The purpose of this study was to assess whether or not three verbal instructions would alter muscle thickness of the lumbar multifidus muscle differently in asymptomatic individuals and patients with LBP. METHODS: Three verbal instructions were selected for this study: (1) swell the muscle underneath the transducer, (2) draw your belly button in towards your spinal column and (3) think about tilting your pelvis but without really doing it. Lumbar multifidus muscle thickness was determined using parasagittal ultrasound (US) imaging. Measurements of muscle thickness were collected at rest and during verbal instructions from 21 asymptomatic adults and 21 patients with LBP. Percent changes of muscle thickness during contraction and at rest were compared between groups and across verbal instructions. RESULTS: ANOVA results showed no significant interaction for both L4-5 and L5-S1, but a significant main effect of verbal instruction (P = 0.049) at L4-5.Post hoc analysis showed a greater increase with verbal instruction #3 than verbal instruction #2 (P = 0.009). There was no significant main effect of group at either segment. DISCUSSION: The results of the study suggest that both groups responded similarly to the three verbal instructions. Verbal instructions may increase lumbar multifidus muscle thickness by different amounts at L4-5, but by the same amount at L5-S1. PMID- 28855791 TI - Impact of shoulder internal rotation on normal sensory response during ulnar nerve-biased neurodynamic testing of asymptomatic individuals. AB - OBJECTIVE: To determine if substitution of shoulder internal rotation for external rotation during the upper limb neurodynamic test (ULNT3) evokes comparable ulnar nerve sensory responses in asymptomatic individuals. METHODS: Range of motion, quality, quantity, and distribution of sensory responses in 50 asymptomatic individuals during the traditional ULNT3 were compared to identical measures during an experimental maneuver using shoulder internal rotation. Quality and quantity of sensory responses were recorded using a 10-cm visual analog scale. RESULTS: Means of sensory responses for traditional and experimental maneuvers, respectively, were as follows: stretching, 3.84 +/- 8.85 and 5.38 +/- 2.85 cm; burning, 1.82 +/- 2.82 and 2.50 +/- 3.10 cm; tingling, 2.13 +/- 3.12 and 2.18 +/- 2.97 cm; and numbness, 1.04 +/- 2.17 and 1.01 +/- 2.03 cm. A moderate to strong correlation (ICC = 0.51-0.86) was shown to exist between maneuvers; this relationship was significant (p = .001). DISCUSSION: Results of this study provide evidence that there was no appreciable difference in sensory responses with regard to burning and tingling when substituting shoulder internal rotation for external rotation during the ULNT3. The results also suggest that there were only marginal differences in the sensory responses of stretching and numbness during the same substitution. CONCLUSION: Patients who have limited glenohumeral external rotation due to pain, instability, and/or articular limitation may benefit from this substitution when presenting with signs of ulnar nerve pathodynamics. Further research will be needed to validate this maneuver in a symptomatic population. LEVEL OF EVIDENCE: Level 2b. PMID- 28855792 TI - Addressing neurodynamic irritability in a patient with adhesive capsulitis: a case report. AB - BACKGROUND: Patients with adhesive capsulitis are commonly seen by physical therapists. Pain and limited shoulder motion from adhesive capsulitis have at times been linked to neural irritation. The purpose of this case is to describe the examination and intervention of a patient with adhesive capsulitis who appeared to have a coexisting, underlying neural irritation. This paper emphasizes how the neurological component must initially be identified and addressed for a successful outcome. CASE DESCRIPTION: A 47-year-old female presented with reduced shoulder motion and function, upper extremity neural irritation, diffuse weakness, altered sensation in the involved extremity, and symptoms reproduced with upper limb neurodynamic testing. Her reduced shoulder range of motion was accompanied by limited glenohumeral glides and a report of local neck stiffness. Symptoms began several months earlier after an apparent electrical shock injury to the arm that caused symptoms and guarding of the shoulder. Intervention initially addressed the underlying neural component with spinal mobilizations while avoiding further irritation. Interventions were progressed to include mobilization and exercise to address shoulder mobility. OUTCOMES: The patient's neurodynamic irritability, distal symptoms, and neck stiffness were normalized within the first weeks of care. Subsequently, interventions were directed at the shoulder. Outcomes over an 12-week time frame included reduced pain from 10/10 to 2/10. Passive range of motion increases included flexion from 121 to 160 degrees , abduction from 71 to 121 degrees , and external rotation from 18 to 60 degrees . Disability scores on Disabilities of the Arm, Shoulder, and Hand (DASH) dropped from initially 68.3 to 18.3% at discharge. She ultimately regained full upper extremity function. DISCUSSION: Therapists should be cognizant of possible neural irritation in shoulder disorders, which may contribute to conditions such as adhesive capsulitis. Identifying neural irritation is critical when determining which interventions will achieve optimal outcomes without aggravating the condition. PMID- 28855793 TI - The use of compression tack and flossing along with lacrosse ball massage to treat chronic Achilles tendinopathy in an adolescent athlete: a case report. AB - BACKGROUND: Achilles tendinopathy is an overuse injury that often affects individuals engaged in recreational or competitive level activity. Although most patients experience satisfactory results with therapy, a substantial portion fail to respond to traditional treatment. The purpose of this case study is to describe the successful use of compression tack and flossing (CTF) with lacrosse ball massage (LBM) in the treatment of an adolescent athlete with Achilles tendinopathy who had failed to respond to traditional treatment. CASE DESCRIPTION: The patient was a 14-year old female diagnosed with chronic Achilles tendinopathy. She presented with 8/10 left posterior ankle pain during activity and scored 66/80 on the Lower Extremity Functional Scale (LEFS). After six weeks of PT consisting of eccentric exercise, proprioceptive training, and iontophoresis, the patient continued to report pain during sport and no significant improvements on the LEFS. With traditional PT failing to resolve symptoms, the patient was treated with CTF and LBM. OUTCOMES: The outcomes of interest were the LEFS and the ability to participate in sport without pain. After only two sessions focusing on CTF and LBM, she had 0/10 pain during sport and scored a 79/80 on the LEFS. Patient was discharged to continue with a home exercise program consisting of CTF and LBM, and eccentric exercise. DISCUSSION: The patient's outcomes significantly improved after CTF and LBM was added to eccentric exercise. These results suggest that this intervention may be a viable adjunct treatment for Achilles tendinopathy; however further research, including controlled clinical trials and long-term outcome data, are warranted. PMID- 28855794 TI - Erratum. AB - [This corrects the article DOI: 10.1179/2042618615Y.0000000010.]. PMID- 28855795 TI - Reduction in ocular complement factor B protein in mice and monkeys by systemic administration of factor B antisense oligonucleotide. AB - PURPOSE: Age-related macular degeneration (AMD) is the leading cause of permanent vision loss among the elderly in many industrialized countries, and the complement system plays an important role in the pathogenesis of AMD. Inhibition of complement factor B, a key regulator of the alternative pathway, is implicated as a potential therapeutic intervention for AMD. Here we investigated the effect of liver factor B reduction on systemic and ocular factor B levels. METHODS: Second-generation antisense oligonucleotides (ASOs) targeting mouse and monkey factor B mRNA were administered by subcutaneous injection to healthy mice or monkeys, and the level of factor B mRNA was assessed in the liver and the eye. In addition, the factor B protein level was determined in plasma and whole eyes from the treated animals. RESULTS: Mice and monkeys treated with factor B ASOs demonstrated a robust reduction in liver factor B mRNA levels with no change in ocular factor B mRNA levels. Plasma factor B protein levels were significantly reduced in mice and monkeys treated with factor B ASOs, leading to a dramatic reduction in ocular factor B protein, below the assay detection levels. CONCLUSIONS: The results add to the increasing evidence that the liver is the main source of plasma and ocular factor B protein, and demonstrate that reduction of liver factor B mRNA by an ASO results in a significant reduction in plasma and ocular factor B protein levels. The results suggest that inhibition of liver factor B mRNA by factor B ASOs would reduce systemic alternative complement pathway activation and has potential to be used as a novel therapy for AMD. PMID- 28855796 TI - Medical Decision-Making Processes and Online Behaviors Among Cannabis Dispensary Staff. AB - BACKGROUND: Most cannabis patients engage with dispensary staff, like budtenders, for medical advice on cannabis. Yet, little is known about these interactions and how the characteristics of budtenders affect these interactions. This study investigated demographics, workplace characteristics, medical decision-making, and online behaviors among a sample of budtenders. METHODS: Between June and September 2016, a cross-sectional Internet survey was administered to budtenders in the San Francisco Bay Area and Greater Los Angeles. A total of 158 budtenders fully responded to the survey. A series of comparisons were conducted to determine differences between trained and untrained budtenders. RESULTS: Among the 158 budtenders, 56% had received formal training to become a budtender. Several demographic differences were found between trained and untrained budtenders. For workplace characteristics, trained budtenders were more likely to report budtender as their primary job (74% vs 53%), practice more than 5 years (34% vs 11%), and receive sales commission (57% vs 16%). Trained budtenders were significantly less likely to perceive medical decision-making as very important (47% vs 68%) and have a patient-centered philosophy (77% vs 89%). Although trained budtenders had significantly lower Internet usage, they were significantly more likely to exchange information with patients through e-mail (58% vs 39%), text message (46% vs 30%), mobile app (33% vs 11%), video call (26% vs 3%), and social media (51% vs 23%). CONCLUSIONS: Budtenders who are formally trained exhibit significantly different patterns of interaction with medical cannabis patients. Future studies will use multivariate methods to better determine which factors independently influence interactions and how budtenders operate after the introduction of regulations under the newly passed Proposition 64 that permits recreational cannabis use in California. PMID- 28855797 TI - Oncology Update: Anamorelin. AB - BACKGROUND: Cancer cachexia is a catabolic syndrome associated with uncontrolled muscle breakdown. There may be associated fat loss. Occurring in high frequency in advanced cancer, it is an indicator of poor prognosis. Besides weight loss, patients experience a cluster of symptoms including anorexia, early satiety, and weakness. The 3 stages of cachexia include stages of precachexia, cachexia, and refractory cachexia. Refractory cachexia is associated with active catabolism or the presence of factors that make active management of weight loss no longer possible. Patients with refractory cachexia often receive glucocorticoids or megasterol acetate. Glucocorticoid effect is short and responses to megasterol are variable. Anamorelin is a new agent for cancer anorexia-cachexia, with trials completed in advanced lung cancer. Acting as an oral mimetic of ghrelin, it improves appetite and muscle mass. This article reviews the pharmacology, pharmacodynamics, and effect on cancer cachexia. METHODS: A PubMed search was done using the Medical Subject Headings term anamorelin. Articles were selected to provide a pharmacologic characterization of anamorelin. RESULTS: Anamorelin increases muscle mass in patients with advanced cancer in 2-phase 3 trials. CONCLUSIONS: Anamorelin improves anorexia-cachexia symptoms in patients with advanced non-small-cell lung cancer. PMID- 28855799 TI - Review of Lisdexamfetamine Dimesylate in Adults With Attention Deficit/Hyperactivity Disorder. AB - Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant used for the treatment of attention-deficit/hyperactivity disorder (ADHD) dosed once daily. Due to its long-acting properties, LDX remains pharmacologically inactive until an enzymatic process predominantly associated with red blood cells converts it to the active ingredient, d-amphetamine and the amino acid lysine. The efficacy of LDX over placebo has been demonstrated in several studies in adults with moderate to severe ADHD with significant improvements noted in ADHD rating scales, Clinical Global Improvement scores, and assessments of executive function, for all doses of LDX (30-70 mg daily). Lisdexamfetamine dimesylate has demonstrated efficacy at 14 hours post dose in adults and may be used as a long-acting stimulant for managing ADHD symptoms, which may extend late into the day. Lisdexamfetamine dimesylate has demonstrated a safety profile consistent with long-acting stimulants use. Relevant English language articles were identified through computerized searches of MEDLINE (PubMed and EMBASE) from 1995 to 2016 using the following search terms: lisdexamfetamine dimesylate, attention-deficit hyperactivity disorder, NRP104, and Vyvanse. PMID- 28855798 TI - Abnormalities of Dopamine D3 Receptor Signaling in the Diseased Brain. AB - Dopamine D3 receptors (D3R) modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. A growing body of evidence suggests that aberrant D3R signaling contributes to multiple brain diseases, such as Parkinson's disease, essential tremor, schizophrenia, and addiction. In line with these findings, D3R has emerged as a potential target in the treatment of neurological disorders. However, the mechanisms underlying neuronal D3R signaling are poorly understood, either in healthy or diseased brain. Here, I review the molecular mechanisms involved in D3R signaling via monomeric D3R and heteromeric receptor complexes (e.g., D3R-D1R, D3R-D2R, D3R A2aR, and D3R-D3nf). I focus on D3R signaling pathways that, according to recent reports, contribute to pathological brain states. In particular, I describe evidence on both quantitative (e.g., increased number or affinity) and qualitative (e.g., switched signaling) changes in D3R that has been associated with brain dysfunction. I conclude with a description of basic mechanisms that modulate D3R signaling such as desensitization, as disruption of these mechanisms may underlie pathological changes in D3R signaling. Because several lines of evidence support the idea that imbalances in D3R signaling alter neural function, a better understanding of downstream D3R pathways is likely to reveal novel therapeutic strategies toward dopamine-related brain disorders. PMID- 28855800 TI - Influence of a New "Call-Out Algorithm" for Management of Postoperative Pain and Its Side Effects on Length of Stay in Hospital: A Two-Centre Prospective Randomized Trial. AB - BACKGROUND: We recently introduced the efficacy safety score (ESS) as a new "call out algorithm" for management of postoperative pain and side effects. In this study, we report the influence of ESS recorded hourly during the first 8 hours after surgery on the mobility degree, postoperative nonsurgical complications, and length of hospital stay (LOS). METHODS: We randomized 1152 surgical patients into three groups for postoperative observation: (1) ESS group (n = 409), (2) Verbal Numeric Rate Scale (VNRS) for pain group (n = 417), and (3) an ordinary qualitative observation (Control) group (n = 326). An ESS > 10 or VNRS > 4 at rest or a nurse's observation of pain or adverse reaction to analgesic treatment in the Control group served as a "call-out alarm" for an anaesthesiologist. RESULTS: We found no significant differences in the mobility degree and number of postoperative nonsurgical complications between the groups. LOS was significantly shorter with 12.7 +/- 6.3 days (mean +/- SD) in the ESS group versus 14.2 +/- 6.2 days in the Control group (P < 0.001). CONCLUSION: Postoperative ESS recording in combination with the possibility to call upon an anaesthesiologist when exceeding the threshold score might have contributed to the reductions of LOS in this two centre study. This trial is registered with NCT02143128. PMID- 28855801 TI - Culture-dependent bacteria in commercial fishes: Qualitative assessment and molecular identification using 16S rRNA gene sequencing. AB - Fish contamination has been extensively investigated along the Saudi coasts, but studies pertaining to bacterial pathogens are scarce. We conducted qualitative assessment and molecular identification of culture-dependent bacteria in 13 fish species from three coastal sites and a local fish market in Jeddah, Saudi Arabia. Bacterial counts of gills, skin, gut and muscle were examined on agar plates of Macconkey's (Mac), Eosin Methylene Blue (EMB) and Thiosulfate Citrate Bile Salts (TCBS) culture media. Bacterial counts significantly differed between species, sources and feeding habits of examined fishes. Mugil cephalus exhibited higher counts on TCBS (all body parts), Mac (gills, muscle and gut) and EMB (gills and muscle). Fishes from Area I had higher bacterial loads, coinciding with those in seawater and sediment from the same site, indicating direct association between habitat conditions and the levels of bacterial contamination. By feeding habit, detritivorous fish harbored higher counts than herbivorous and carnivorous species. Bacterial counts of skin were higher in fish from market than field sites, and positively correlated with other body parts indicating the relation of surface bacterial load on the overall quality of fish. Rahnella aquatilis (Enterobacteriaceae) and Photobacterium damselae (Vibrionaceae) were among the dominant species from fish muscle based on 16S rRNA sequencing. These species are known human pathogens capable of causing foodborne illness with severe antibiotic resistance. Opportunistic pathogens, e.g. Hafnia sp. (Enterobacteriaceae) and Pseudomonas stutzeri (Pseudomonadaceae) also occurred in fish muscle. The inclusion of bacterial contamination in future monitoring efforts is thus crucial. PMID- 28855802 TI - Histological and ultrastructural alterations of rat thyroid gland after short term treatment with high doses of thyroid hormones. AB - The aim of the present study was to investigate histological alterations of rat thyroid gland after short-term treatment with supraphysiological doses of thyroid hormones. Rats from experimental groups were treated with triiodothyronine (T3) or thyroxine (T4) during five days. In both treated groups, thyrocyte height was reduced and follicular lumens were distended. Progressive involutive changes of the thyroid parenchyma were apparent, including follicular remodeling (fusion) and death of thyrocytes. Morphological changes confirmed by quantitative analysis were more pronounced in the T4-treated group. Our results demonstrate that thyrotoxicosis, whether induced by T3 or T4, leads to different grades of thyroid tissue injury, including some irreversible damages. These changes might be explained at least in part by lack of trophic and cytoprotective effects of the thyroid stimulating hormone. Since the period required for morphophysiological recovery may be unpredictable, findings presented here should be taken into consideration in cases where the thyroid hormones are used as a treatment for thyroid and non-thyroid related conditions. PMID- 28855803 TI - Computational identification and characterization of miRNAs and their target genes from five cyprinidae fishes. AB - MicroRNAs (miRNAs) are a kind of small single-strand RNA molecules with lengths of 18-25 nt, which do not encode any proteins. They play an essential role in gene expression regulation by binding to their target genes, leading to translational repression or transcript degradation. In this study, 23 miRNAs were predicted from five cyprinidae fishes by using a bioinformatics-based gene search based on blasting ESTs and GSS in NCBI, of which 21 miRNA genes have not been previously reported. To prove their validity, five of the computationally predicted miRNAs were verified by RTPCR, their transcripts were successfully detected, and, 46 potential target genes for these miRNAs were predicted, most target genes encode transcription factors, they are involved in signal transduction, metabolism and development processes. PMID- 28855804 TI - The use of herbs against neglected diseases: Evaluation of in vitro leishmanicidal and trypanocidal activity of Stryphnodendron rotundifolium Mart. AB - The evaluation of the leishmanicidal and trypanocidal activity of the hydroalcoholic extract of the bark of Stryphnodendron rotundifolium Mart. (EHCSR) was carried out to find an alternative treatment for parasitic diseases. EHCSR was prepared and used at four different concentrations (1000, 500, 250, 125 MUg/mL) in in vitro assays for activity against Leishmania promastigotes using the species Leishmania brasiliensis and Leishmania infantum and for trypanocidal activity using the epimastigotes of Trypanosoma cruzi. We also tested EHCSR for cytotoxicity against adhered cultured Murine J774 fibroblasts. The tests were performed in triplicate, and the percent mortality of parasites, IC50 and percent toxicity were determined. With regard to anti-leishmania activity against L. infantum, there was a mean mortality of 45% at all concentrations, and against L. brasiliensis, a substantial effect was seen at 1000 MUg/mL with 56.38% mortality, where the IC50 values were 1338.76 and 987.35 MUg/mL, respectively. Trypanocidal activity was notably high at 1000 MUg/mL extract with 82.31% mortality of epimastigotes. Cytotoxicity at the highest extract concentrations of 500 and 1000 MUg/mL was respectively 75.12% and 94.14%, with IC50 = 190.24 MUg/mL. Despite that the extract has anti-parasitic activity, its substantial cytotoxicity against fibroblasts cells makes its systemic use nonviable as a therapeutic alternative. PMID- 28855805 TI - Correlation between serum trace elements and risk of preeclampsia: A case controlled study in Riyadh, Saudi Arabia. AB - Preeclampsia is a serious medical complication during pregnancy. In response to an increasing number of preeclamptic cases and scarcity of data concerning the interrelation between trace element levels and preeclampsia, we carried out a hospital based case-control study in Riyadh, Saudi Arabia to study the correlation between levels of serum trace elements and risk of preeclampsia. One hundred and twenty pregnant women were enrolled in this study and divided into three groups of 40 each-Control group, HR group (women at high risk of preeclampsia) and PET group (Preeclampsia group). Serum trace element levels were estimated by inductively coupled plasma optical emission spectrophotometer. The analysis found that mean values of Ca, Mg and Zn were 90.08 +/- 6.38, 19.33 +/- 3.32 and 1.30 +/- 0.83 mg/L respectively in normotensive control and 77.85 +/- 4.47, 15.44 +/- 1.43 and 0.98 +/- 0.63 mg/L respectively in the HR group. The mean values of Ca, Mg and Zn in the preeclamptic group were 70.37 +/- 4.66, 13.58 +/- 1.98 and 0.67 +/- 0.59 mg/L, respectively. Interelement analysis reflected a negative correlation between Ca and Mg and between Mg and Zn whereas positive correlation between Ca and Zn in preeclamptic women. However the correlation was not statistically significant. In conclusion, our study suggests that decreased levels of these trace elements in serum may act as predisposing factors in pathogenesis of Preeclampsia. PMID- 28855806 TI - A study of distribution, sex differences and stability of lip print patterns in an Indian population. AB - Lip prints are very useful in forensic investigations. The objective of this study is to determine predominant lip print pattern found among a central Indian population, to evaluate whether any sex difference exists and to study the permanence of the pattern over a 6 month duration. This study included 200 healthy adult subjects comprising of 100 males and 100 females in the age group of 18-25 years. A convenient and easier method of data collection i.e., digital photography was used instead of the traditional lipstick methods. Lip prints were then divided into four quadrants and recognized as per Suzuki and Tsuchihashi's classification. Type I (30.63%) was found to be most predominant overall in the Marathi population. Type I (29.75%) and Type III (35.75%) were found most prevalent in males and females respectively. Applying the Chi-Square test, statistically significant differences (p < 0.05) were observed between male and female lip print patterns in each of the quadrants individually and all quadrants taken together. The lip print patterns remained stable over a period of six months. Being stable and with significant sex differences, lip prints can be effectively used as an important tool in forensic investigations for individualization as well as identification of sex of the donor, thus, narrowing down the scope of investigation to almost half. PMID- 28855807 TI - In silico analysis of glycinamide ribonucleotide transformylase inhibition by PY873, PY899 and DIA. AB - In humans, purine de novo synthesis pathway consists of multi-functional enzymes. Nucleotide metabolism enzymes are potential drug targets for treating cancer and autoimmune diseases. Glycinamide ribonucleotide transformylase (GART) is one of the most important trifunctional enzymes involved in purine synthesis. Previous studies have demonstrated the role of folate inhibitors against tumor activity. In this present study, three components of GART enzyme were targeted as receptor dataset and in silico analysis was carried out with folate ligand dataset. To accomplish the task, Autodock 4.2 was used for determining the docking compatibilities of ligand and receptor dataset. Taken together, it has been suggested that folate ligands could be potentially used as inhibitors of GART. PMID- 28855808 TI - Protective effect of some plant oils on diazinon induced hepatorenal toxicity in male rats. AB - Environmental pollution and exposure to environmental pollutants are still some of the major global health issues. Pesticides have been linked to a wide range of health hazards. The toxicity of pesticides depends on several factors such as its chemical properties, doses, exposure period, exposure methods, gender, genetics, age, nutritional status and physiological case of exposed individuals. Medicinal plants, natural products and nutrition continue to play a central role in the healthcare system of large proportions of the world's population. Alternative medicine plays an important role in health services around the world. The aim of this study was to investigate the effect of olive, sesame and black seed oils on hepatorenal toxicity induced by diazinon (DZN) in male rats. The experimental animals were divided into nine groups. The first group served as control. The second group was exposed to DZN. The third group was treated with olive oil and DZN. Rats of the fourth group were subjected to sesame oil and DZN. Rats of the fifth group were exposed to black seed oil and DZN. The sixth, seventh and eighth groups were supplemented with olive, sesame and black seed oils respectively. Rats of the ninth group were treated with corn oil. Levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, creatinine, blood urea nitrogen and malondialdehyde were significantly increased in rats exposed to DZN. Moreover, levels of serum glutathione and superoxide dismutase were significantly decreased. Several histopathological changes were observed in the structures of liver and kidney due to DZN exposure. This study showed that these oils attenuated the physiological disturbances and histopathological alterations induced by DZN intoxication. Moreover, the antioxidant properties of these oils support the bioactive roles of its protective effects on DZN toxicity. This study therefore suggests that these oils could be used as preventive factors against the toxicity of DZN due to its antioxidant properties. PMID- 28855809 TI - Biomarkers of oxidative stress for in vivo assessment of toxicological effects of iron oxide nanoparticles. AB - Iron oxide nanoparticles (Fe2O3-IONPs) have revolutionized the industry by significant economic and scientific impacts. Enormous increase in the usage of IONPs has raised concerns about their unseen adverse effects. In the current study, we investigated the effects of IONPs and its bulk on oxidative stress biomarkers, histopathology and biodistribution in rats after 28 days repeated oral treatment at 30, 300 and 1000 mg/kg body weight (b.w.). IONPs size in dry, wet forms and crystallinity was determined using TEM, DLS and XRD. The investigation of oxidative stress biomarkers demonstrated significant increase in lipid peroxidation and decrease in reduced glutathione content in the liver, kidney and the brain of the treated groups in a dose dependant manner. Further, antioxidant enzymes catalase, glutathione S transferase, glutathione peroxidase and glutathione reductase activities were significantly elevated along with significant decrease in superoxide dismutase activity in treated rat organs. ICP OES analysis revealed dose and size dependant accumulation of IONPs in the liver followed by kidney and the brain than bulk. Moreover, accumulation of IONPs at high dose brought pathological changes only in liver. A large fraction of IONPs was eliminated in urine. Bulk material was substantially excreted in faeces than IONPs suggesting increased absorption of IONPs. In conclusion accumulated IONPs and bulk in organs trigger free radical generation, leading to the induction of oxidative stress condition in rats. The results obtained highlight the importance of toxicity assessments in evaluating the efficiency of IONPs for the safe implementation for diversified applications. PMID- 28855810 TI - Influence of the mixtures composed of slow-release insecticide formulations against Aedes aegypti mosquito larvae reared in pond water. AB - Vector borne diseases remain the major source of illness and death worldwide. Aedes aegypti is the primary carrier of dengue and dengue haemorrhagic fever in many developing countries in the tropical world. Because A. aegypti populations are becoming more and more resistant to conventional and non conventional insecticides, alternative strategies have to be rapidly implemented in the future for dengue vector control. The present study aimed to evaluate the larvicidal efficacy of slow-release formulations (SRFs) of bacterial insecticide Bactimos briquets blended with tow insect growth regulators (IGRs), Altosid XR - briquets and Dudim DT tablet respectively, against mosquito larvae of A. aegypti the primary vector of dengue fever in Jeddah governorate, Saudi Arabia. Semi-field trials were conducted at dengue mosquito research station, Dept. of Biological Sciences, faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. The efficacy of the test formulations was calculated as the number of emerging adults compared to the initial number of larvae added or the inhibition of emergence (IE%). The assessment of effectiveness was made at weekly intervals until the level of efficacy decrease to <=50% IE. The inhibition percentage of emergence of adult for each mixture weekly in addition to the calculation of the cycle of the effective centers for each mixture. Collectively, the results of the present investigation indicate that the combination of Bactimos with Altosid or Dudim maybe promising for controlling A. aegypti mosquito larvae provided that treatments persist at least during the whole dengue transmission season. PMID- 28855811 TI - Neuroprotective effects of quercetin in diabetic rat retina. AB - Diabetic retinopathy (DR) is a severe complication of diabetes and the leading cause of blindness among working adults worldwide. DR is being widely recognized as a neurodegenerative disease of the retina, since, retinal neurons are damaged soon after diabetes onset. Diabetes-induced oxidative stress is considered as central factor that dysregulates neurotrophic factors and activates apoptosis, thereby damages neurons in the diabetic retina. Flavonoids being a powerful antioxidant have been considered to protect neurons in diabetic retina. The purpose of this study was to analyze the beneficial effects of flavonoid, quercetin to protect neurons in the diabetic rat retina. We quantitated the expression levels of BDNF, NGF, TrkB, synaptophysin, Akt, Bcl-2, cytochrome c and caspase-3 using Western blotting techniques in the diabetic retina with and without quercetin treatments and compared with non-diabetic rats. In addition, we employed ELISA techniques to determine the level of BDNF. Caspase-3 activity and the level of glutathione were analyzed by biochemical methods. Our results indicate that quercetin treatment to diabetic rats caused a significant increase in the level of neurotrophic factors and inhibited the level of cytochrome c and caspase-3 activity in the diabetic retina. Furthermore, the level of an anti apoptotic protein Bcl-2 was augmented in quercetin treated diabetic retina. Thus, quercetin, may protect the neuronal damage in diabetic retina by ameliorating the levels of neurotrophic factors and also by inhibiting the apoptosis of neurons. Therefore, this study suggests that quercetin can be a suitable therapeutic agent to prevent neurodegeneration in diabetic retinopathy. PMID- 28855812 TI - TNF-alpha -308G/A and -238G/A polymorphisms and its protein network associated with type 2 diabetes mellitus. AB - Several reports document the role of tumor necrosis factor alpha (TNF-alpha) and lipid metabolism in the context of acute inflammation as a causative factor in obesity-associated insulin resistance and as one of the causative parameter of type 2 diabetes mellitus (T2DM). Our aim was to investigate the association between -308G/A and -238G/A polymorphisms located in the promoter region of the TNF-alpha gene in T2DM in the Indian population with bioinformatics analysis of TNF-alpha protein networking with an aim to find new target sites for the treatment of T2DM. Demographics of 100 diabetes patients and 100 healthy volunteers were collected in a structured proforma and 3 ml blood samples were obtained from the study group, after approval of Institutional Ethics Committee of the hospital (IEC). The information on clinical parameters was obtained from medical records. Genomic DNA was extracted; PCR-RFLP was performed using TNF alpha primers specific to detect the presence of SNPs. Various bioinformatics tools such as STRING software were used to determine its network with other associated genes. The PCR-RFLP studies showed that among the -238G/A types the GG genotype was 87%, GA genotype was 12% and AA genotype was 1%. Almost a similar pattern of results was obtained with TNF-alpha -308G/A polymorphism. The results obtained were evaluated statistically to determine the significance. By constructing TNF-alpha protein interaction network we could analyze ontology and hubness of the network to identify the networking of this gene which may influence the functioning of other genes in promoting T2DM. We could identify new targets in T2DM which may function in association with TNF-alpha. Through hub analysis of TNF-alpha protein network we have identified three novel proteins RIPK1, BIRC2 and BIRC3 which may contribute to TNF-mediated T2DM pathogenesis. In conclusion, our study indicated that some of the genotypes of TNF-alpha -308G/A, 238G/A were not significantly associated to type 2 diabetes mellitus, but TNF alpha -308G/A polymorphism was reported to be a potent risk factor for diabetes in higher age (>45) groups. Also, the novel hub proteins may serve as new targets against TNF-alpha T2DM pathogenesis. PMID- 28855813 TI - Saudi medicinal plants for the treatment of scorpion sting envenomation. AB - Scorpion sting envenoming poses major public health problems. The treatment modalities include antivenoms, chemical antidotes and phytotherapy, with varying degrees of effectiveness and side effects. In this investigation, we reviewed the use of Saudi medicinal plants for the treatment of scorpion sting patients. The relevant literature was collected using the online search engines including Science Direct, Google and PubMed with the help of specific keywords. We also used the printed and online resources at our institutional library to gather the relevant information on the use of medicinal plants for the treatment of scorpion sting patients. A descriptive statistics was used for data compilation and presentation. The results of this survey showed the use of at least 92 medicinal plants with beneficial effects for treating victims of stings of different scorpion species. These commonly used herbs spanned to 37 families whilst different parts of these plants were employed therapeutically for alleviation of envenomation symptoms. The application of leaves (41%) was preferred followed by roots (19%), whole plant (14%) and seeds (9%). The use of latex (4%), stem (3%), flowers (3%) and bark (3%) was also reported. In some cases, tannin (2%), rhizome (1%) and shoot (1%) were also used. In conclusion, herbal medicines are effectively used for the treatment of patients with scorpion envenomation. This type of medication is free from side effects as observed with chemical antidotes or antivenom therapy. It is important to identify the active ingredients of herbal drugs for improving their therapeutic potential in traditional medicine. PMID- 28855814 TI - Proteins are potent biomarkers to detect colon cancer progression. AB - Colon cancer is the most common type of cancer and major cause of death worldwide. The detection of colon cancer is difficult in early stages. However, the secretory proteins have been used as ideal biomarker for the detection of colon cancer progress in cancer patients. Serum/tissue protein expression could help general practitioners to identify colon cancer at earlier stages. By this way, we use the biomarkers to evaluate the anticancer drugs and their response to therapy in cancer models. Recently, the biomarker discovery is important in cancer biology and disease management. Also, many measurable specific molecular components have been studied in colon cancer therapeutics. The biomolecules are mainly DNA, RNA, metabolites, enzymes, mRNA, aptamers and proteins. Thus, in this review we demonstrate the important protein biomarker in colon cancer development and molecular identification of protein biomarker discovery. PMID- 28855815 TI - Start-up performance and granular sludge features of an improved external circulating anaerobic reactor for algae-laden water treatment. AB - The microbial characteristics of granular sludge during the rapid start of an enhanced external circulating anaerobic reactor were studied to improve algae laden water treatment efficiency. Results showed that algae laden water was effectively removed after about 35 d, and the removal rates of chemical oxygen demand (COD) and algal toxin were around 85% and 92%, respectively. Simultaneously, the gas generation rate was around 380 mL/gCOD. The microbial community structure in the granular sludge of the reactor was complicated, and dominated by coccus and filamentous bacteria. Methanosphaera, Methanolinea, Thermogymnomonas, Methanoregula, Methanomethylovorans, and Methanosaeta were the major microorganisms in the granular sludge. The activities of protease and coenzyme F420 were high in the granular sludge. The intermittent stirring device and the reverse-flow system were further found to overcome the disadvantage of the floating and crusting of cyanobacteria inside the reactor. Meanwhile, the effect of mass transfer inside the reactor can be accelerated to help give the reactor a rapid start. PMID- 28855816 TI - Identification of novel inhibitors against Cyclin Dependent Kinase 9/Cyclin T1 complex as: Anti cancer agent. AB - Cell cycle consists of different types of phases, transition from G1, S, G2, M. Inhibition of associated CDKs like CDK9/Cyclin T1 complex, which are indirectly involved in the Cell cycle progression in the form of transcription elongation, reduces diverse diseases such as Cardiac Hypertrophy, Alzheimer's, Cancer, AIDS and Inflammation. Glide tool of the Schrodinger software has been used for performing Structure Based Virtual Screening and Docking against Drug Bank and MDPI database. The best hits were identified which go and bind in the active site of the target where ATP binds for the activity. The ADMET, MM-GBSA and DFT analysis is also done for the same. Compound 4-{4-[4-(3-aminopropoxy)phenyl]-1H pyrazol-5-yl}-6-chlorobenzene-1,3-diol (DB08045) was found to be more potent, novel and selective as an inhibitor. Hopefully compound (DB08045) could be used as an anti-cancer agent for the treatment of life-threatening diseases. PMID- 28855817 TI - Characterization and anti-Aspergillus flavus impact of nanoparticles synthesized by Penicillium citrinum. AB - This work was conducted to evaluate the ability of grape molding fungus; Penicillium citrinum to synthesize silver nanoparticles (Ag NPs). The potency of biosynthesized Ag NPs was checked against the aflatoxigenic Aspergillus flavus var. columnaris, isolated from sorghum grains. Biosynthesized Ag NPs were characterized and confirmed in different ways. X ray diffraction (XRD), Energy Dispersive Spectroscopy (EDS), Transmission Electron Microscopy (TEM) and optical absorption measurements confirmed the bio-synthesis of Ag NPs. The in vitro antifungal investigation showed that biosynthesized Ag NPs were capable of inhibiting the growth of aflatoxigenic A. flavus var. columnaris. Utilization of plant pathogenic fungi in the Ag NPs biosynthesis as well as the use of bio-Ag NPs to control fungal plant diseases instead of chemicals is promising. Further work is needed to confirm the efficacy of the bio-Ag NPs against different mycotoxigenic fungi and to determine the potent applicable doses. PMID- 28855818 TI - Combined efficacy of Vigna radiata (L.) R. Wilczek and Amorphophallus paeoniifolius (Dennst.) Nicolson on serum lipids in albino rats. AB - Coronary Artery Disease (CAD) is a major killer disease throughout the world. Dyslipidemia is a major contributor to the risk of CAD. Several dietary articles traditionally used in India and other South Asian countries reduced dyslipidemia. The present study was undertaken to evaluate the combined effect of Mung bean (Vigna radiata) and Elephant foot yam (Amorphophallus paeoniifolius) on serum lipids and atherogenic indices in albino rats and to compare it with a standard drug Cholestyramine. Thirty healthy albino rats of both sexes (150-200 g) were randomized to 5 groups of 6 animals each. The grouping were done based on the following criteria: Group I: Normal Control Group, Group II: (Standard Group): Cholestyramine resin 5 mg/kg bw, Group III: (Half Dose Group): Drug powder at 540 mg/kg bw, Group IV: (Effective Dose Group): Drug powder at 1080 mg/kg bw, and Group V: (Double Dose Group): Drug powder at 2160 mg/kg bw. Lipid profile was estimated at the beginning and after 30 days of treatment. The Effective and Double doses of the drug reduced Total cholesterol along with levels of Triglycerides, Low density lipoprotein and Very low density lipoprotein levels significantly (p < 0.01) along with a significant (p < 0.01) increase in high density lipoproteins (HDL) in rats. There was also significant (p < 0.01) improvement in atherogenic indices like Castelli Risk Index I, Non HDL C/HDL, Castelli risk Index II, TG/HDL, Atherogenic coefficient and Atherogenic Index of Plasma. The combination of powdered sprouted mung bean and yam powder have excellent lipid lowering potential. PMID- 28855820 TI - In vitro alpha-amylase inhibition and in vivo antioxidant potential of Momordica dioica seeds in streptozotocin-induced oxidative stress in diabetic rats. AB - Momordica dioica Roxb. Commonly known as "Kakora" in Telugu, is used in the Indian traditional system of medicine for the treatment of diabetes. The aim of this study was to investigate the antidiabetic activity of methanolic extract of M. dioica seeds (MEMD) in streptozotocin (STZ) induced diabetic rats. The in vitro alpha-amylase inhibitory activity of the MEMD was done by spectrophotometric method. Diabetes was induced by STZ (45 mg/kg; i.p), MEMD (100 & 200 mg/kg; b.wt) and standard drug metformin (50 mg/kg; b.wt) were administered to the diabetic rats. Blood glucose was estimated on the 11th day and the level of MDA, SOD and CAT was estimated in the liver tissue homogenate after the 15 days of experimental period. MEMD showed significant inhibition of alpha amylase activity and the IC50 was found to be 48 MUg/ml. Oral administration of MEMD significantly reduced blood glucose level (P < 0.05), diminished the MDA level and refurbished depleted antioxidant enzymes and Insulin level to normalcy. These findings revealed that M. dioica seeds possess antihyperglycemic, antioxidant and anti lipid peroxidative activity and thus mitigate STZ-induced oxidative damage. PMID- 28855819 TI - Antimicrobial effect of different types of honey on Staphylococcus aureus. AB - Honey exhibits antimicrobial activities against a wide range of bacteria in different milieu. This study aims to compare the effects of five types of honey (both imported and local Saudi honey) against Staphylococcus aureus. The five types of honey (Manuka Honey UMF +20, Manuka Honey UMF +16, Active +10 Manuka Honey, Sidr honey and Nigella sativa honey) were evaluated for their bactericidal/bacteriostatic activities against both methicillin resistant and sensitive S. aureus. The inhibitory effect of honey on bacterial growth was evident at concentrations of 20% and 10% (v/v). Manuka Honey showed the best results. Manuka Honey UMF +20 had a bactericidal effect on both methicillin resistant and sensitive S. aureus. However, Sidr and N. sativa honey exerted only a bacteriostatic effect. The efficacy of different types of honey against S. aureus was dependent on the type of honey and the concentration at which it was administered. Manuka Honey had the best bactericidal activity. Future experiments should be conducted to evaluate the effects of honey on bacterial resistance. PMID- 28855821 TI - Ecological variations and role of heat shock protein in Artemisia judaica L. in response to temperature regimes of Tabuk, Saudi Arabia. AB - Artemisia judaica L. (Compositae) are shrubby herbs growing wildly in Tabuk region and distributed in the desert regions. This region is characterized by extremely variable environmental conditions where the temperature varies from extreme low to extreme high. These temperature regimes have a profound effect on morphology, growth physiology and biochemistry of the plants. The plant samples were collected from Tabuk-Jordan road (760 m above sea level) in the month of January, April, July and October 2013 to evaluate the effect of temperature dynamics on A. judaica L. in four different seasons. Physiological, biochemical alterations and heat shock proteins (HSPs) were studied during these seasons in order to evaluate the environmental adaptation and stress tolerance in response to temperature variations. Plant growth parameters showed a significant increase in height, fresh and dry matter accumulation, total chlorophyll, nitrogen, phosphorus, potassium, artemisinin and leaf relative water contents investigated in the month of April and October. Growth of plant was suppressed and an active role of carbonic anhydrase (CA), catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) was observed to cope with the extreme low temperature in January and extreme high temperature in July 2013. However, the plants collected in October and April did not show a statistical difference. Inductions in the expression of HSP90 were recorded in all the plants collected during April and October 2013 with no statistically significant difference. Therefore, based on the results it is recommended that during April and October the environmental conditions are best suitable for growth, development and medicinal use of Artemisia. PMID- 28855822 TI - Responses of grafted tomato (Solanum lycopersiocon L.) to abiotic stresses in Saudi Arabia. AB - Quantity and quality of irrigation water are considered the most imperative limiting factors for plant production in arid environment. Adoptions of strategies can minimize crop water consumption while nonexistent yield reduction is considered challenge for scholars especially in arid environment. Grafting is regarded as a promising tool to avoid or reduce yield loss caused by abiotic stresses. Tomato (Solanum lycopersium Mill.), commercial cultivar Faridah was grafted on Unifort rootstock and grown under regulated deficit irrigation (RDI) (100%, 80% and 60% ETc), using two types of irrigation water, fresh (EC = 0.86 dS/m) and brackish (EC = 3.52 dS/m). The effects of grafting and RDI on water use efficiency, vegetative growth, yield, fruit quality were investigated. Plant vegetative growth was reduced under water and salinity stresses. Grafting the plant significantly improves the vegetative growth under both conditions. The results showed that crop yield, Ca+2 and K+ were considerably increased in grafted tomato compared to non-grafted plants under water and salinity stresses. Grafted tomato plants accumulated less Na+ and Cl-, especially under high levels of salinity compared to non-grafted plants. Grafting tomato plants showed a slight decrease on the fruit quality traits such as vitamin C, titratable acidity (TA) and total soluble solids (TSS). This study confirmed that grafted tomato plants can mitigate undesirable impact of salt stress on growth and fruit quality. PMID- 28855823 TI - Microbiological and molecular identification of bacterial species isolated from nasal and oropharyngeal mucosa of fuel workers in Riyadh, Saudi Arabia. AB - This study aimed to determine the bacterial species colonizing the nasal and oropharyngeal mucosa of fuel workers in Central Riyadh, Saudi Arabia on a microbiological and molecular level. Throat and nasal swab samples were obtained from 29 fuel station attendants in the period of time extending from March to May 2014 in Riyadh, Saudi Arabia. Microbiological identification techniques were utilized to identify the bacterial species isolated. Antibiotic sensitivity was assessed for each of the bacterial isolates. Molecular identification techniques based on PCR analysis of specific genomic sequences was conducted and was the basis on which phylogeny representation was done for 10 randomly selected samples of the isolates. Blood was drawn and a complete blood count was conducted to note the hematological indices for each of the study participants. Nineteen bacterial species were isolated from both the nasal cavity and the oropharynx including Streptococcus thoraltensis, alpha-hemolytic streptococci, Staphylococcus hominis, coagulase-negative staphylococci, Leuconostoc mesenteroides, Erysipelothrix rhusiopathiae and several others. We found 100% sensitivity of the isolates to ciprofloxacin, cefuroxime and gentamicin. Whereas cefotaxime and azithromycin posted sensitivities of 85.7% and 91.4%, respectively. Low sensitivities (<60% sensitivity) to the antibiotics ampicillin, erythromycin, clarithromycin and norfloxacin were observed. Ninety-seven percent similarity to the microbial bank species was noted when the isolates were compared to it. Most hematological indices recorded were within the normal range. In conclusion, exposure to toxic fumes and compounds within fuel products may be a contributing factor to bacterial colonization of the respiratory tract in fuel workers. PMID- 28855824 TI - Diversity of antagonistic bacteria isolated from medicinal plant Peganum harmala L. AB - The antimicrobial activity of plant extract of Peganum harmala, a medicinal plant has been studied already. However, knowledge about bacterial diversity associated with different parts of host plant antagonistic to different human pathogenic bacteria is limited. In this study, bacteria were isolated from root, leaf and fruit of plant. Among 188 bacterial isolates isolated from different parts of the plant only 24 were found to be active against different pathogenic bacteria i.e. Escherichia coli, Methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium, Enterococcus faecalis and Pseudomonas aeruginosa. These active bacterial isolates were identified on the basis of 16S rRNA gene analysis. Total population of bacteria isolated from plant was high in root, following leaf and fruit. Antagonistic bacteria were also more abundant in root as compared to leaf and fruit. Two isolates (EA5 and EA18) exhibited antagonistic activity against most of the targeted pathogenic bacteria mentioned above. Some isolates showed strong inhibition for one targeted pathogenic bacterium while weak or no inhibition for others. Most of the antagonistic isolates were active against MRSA, following E. faecium, P. aeruginosa, E. coli and E. faecalis. Taken together, our results show that medicinal plants are good source of antagonistic bacteria having inhibitory effect against clinical bacterial pathogens. PMID- 28855825 TI - Enhancing antidiabetic and antimicrobial performance of Ocimum basilicum, and Ocimum sanctum (L.) using silver nanoparticles. AB - The role of silver nanoparticles (AgNps) is an attractive proposition for advancing modern diabetes therapies and applied science. Stable AgNps with a size range of 3-25 nm were synthesized using aqueous leaf extracts from Ocimum basilicum, Ocimum sanctum, and in combination. The concentration of the extracts facilitated the reduction of silver nitrate that led to the rapid formation of AgNps at room temperature, indicating a higher reaction rate as opposed to harsh chemical methods, and high conversion energy usually involved in the synthesis. The size, shape and elemental analysis were carried out using UV-Visible spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX), dynamic light scattering (DLS), and zeta potential whilst, Fourier transform infrared (FTIR) supported by gas chromatography mass spectroscopy (GC-MS) was used to identify the type of capping agents. Inhibition of alpha-amylase and alpha-glucosidase enzymes retards the rate of carbohydrate digestion, thereby provides an alternative and a less evasive strategy of reducing postprandial hyperglycaemia in diabetic patients. The AgNps derived from O. sanctum and O. basilicum, respectively displayed an inhibitory effect at 89.31 +/- 5.32%, and 79.74 +/- 9.51%, respectively, against Bacillus stearothermophilus alpha-glucosidase enzyme model, indicating an enhanced biocatalytic potential compared to their respective crude extracts and the control. Furthermore, the emerging rate of infections in diabetic patients validates the need for the discovery of dual diabetes therapies. As a result, the bioderived AgNps displayed antimicrobial activity against bacterial species Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Salmonella species. PMID- 28855826 TI - Drinking desalinated seawater for a long time induces anomalies in the development of new-born albino rats. AB - The present study aimed to elucidate the abnormalities in the development of rat brains, livers, kidney and behaviours after drinking desalinated seawater prenatally. Three types of drinking water were employed as an experimental probe (bottled water, filtered desalinated seawater and tap desalinated seawater) to investigate neurobehavioral and morphological changes in the development of pup rats. Female rats from each group were administered water from their birth until gestation and lactation. The 1st and 2nd generation pups were divided into three groups: Group C, mothers and pups administered with bottled drinking water (the control group); Group F, mothers and pups administered with filtered drinking water; Group T, mothers and pups administered with unfiltered desalinated seawater (tap water). Morphological changes (CNS aberration) and neurobehavioral changes were studied. The aberrations recorded in the tissues (brain, liver, kidney and spinal cord) of rats from groups T and F may be due to oxidative stress in these tissues such as reduced glutathione, lipid peroxidation, peroxidase and super oxide dismutase. In conclusion, drinking desalinated seawater for a long time may cause teratogenic effects in the development of New born rats. PMID- 28855827 TI - Expression analysis and biochemical characterization of beans plants biofortificated with zinc. AB - The present work was carried out in greenhouse conditions at the Centro de Investigacion en Alimentacion y Desarrollo AC in Delicias, Chihuahua, Mexico. Four different concentrations (0, 25, 50 and 100 MUM L-1) of Zn chelate and sulfate were used to study the antioxidant system of Phaseolus vulgaris L. Three genes related with antioxidant activity [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)] were selected for expression study. Results showed that when Zn chelate at 50 and 100 MUM L-1 were applied SOD was repressed and GSH-Px expression was low at 0, 25 and 100 MUM L-1 while with sulfate form SOD expression was low and GSH-Px expression was strong in all treatment. CAT was highly expressed in all form and treatments. For a biochemical study the same enzymes were spectrophotometrically measured. SOD activity shows differences in both forms of Zn, chelate form was different at 25, 50 and 100 MUM L-1 with less activity at 100 MUM L-1 and sulfate treatment shows differences in all concentrations used. GSH-Px activity shows significant differences with sulfate form at 25, 50 MUM L-1 where at 50 MUM the activity was higher and low at 100 MUM L-1, CAT does not exhibit significant differences but with chelate treatment at 50-100 MUM L-1 the activity was higher compared to sulfate. Finally, to raise the Zn concentration in bean under biofortification program is a promising strategy in cropping systems in order to increase the ingestion of zinc and antioxidant capacity in the general population and provided the benefits that this element offered in human health. PMID- 28855828 TI - Survey and molecular detection of Melissococcus plutonius, the causative agent of European Foulbrood in honeybees in Saudi Arabia. AB - A large-scale field survey was conducted to screen major Saudi Arabian beekeeping locations for infection by Melissococcus plutonius. M. plutonius is one of the major bacterial pathogens of honeybee broods and is the causative agent of European Foulbrood disease (EFB). Larvae from samples suspected of infection were collected from different apiaries and homogenized in phosphate buffered saline (PBS). Bacteria were isolated on MYPGP agar medium. Two bacterial isolates, ksuMP7 and ksuMP9 (16S rRNA GenBank accession numbers, KX417565 and KX417566, respectively), were subjected to molecular identification using M. plutonius specific primers, a BLAST sequence analysis revealed that the two isolates were M. plutonius with more than 98% sequence identity. The molecular detection of M. plutonius from honeybee is the first recorded incidence of this pathogen in Saudi Arabia. This study emphasizes the need for official authorities to take immediate steps toward treating and limiting the spread of this disease throughout the country. PMID- 28855829 TI - Detection of new viruses in alfalfa, weeds and cultivated plants growing adjacent to alfalfa fields in Saudi Arabia. AB - A total of 1368 symptomatic plant samples showing different virus-like symptoms such as mottling, chlorosis, mosaic, yellow mosaic, vein clearing and stunting were collected from alfalfa, weed and cultivated plant species growing in vicinity of alfalfa fields in five principal regions of alfalfa production in Saudi Arabia. DAS-ELISA test indicated occurrence of 11 different viruses in these samples, 10 of which were detected for the first time in Saudi Arabia. Eighty percent of the alfalfa samples and 97.5% of the weed and cultivated plants samples were found to be infected with one or more of these viruses. Nine weed plant species were found to harbor these viruses namely, Sonchus oleraceus, Chenopodium spp., Hibiscus spp., Cichorium intybus, Convolvulus arvensis, Malva parviflora, Rubus fruticosus, Hippuris vulgaris, and Flaveria trinervia. These viruses were also detected in seven cultivated crop plants growing adjacent to the alfalfa fields including Vigna unguiculata, Solanum tuberosum, Solanum melongena, Phaseolus vulgaris, Cucurbita maxima, Capsicum annuum, and Vicia faba. The newly reported viruses together with their respective percent of detection in alfalfa, and in both weeds and cultivated crop plant species together were as follows: Bean leaf roll virus (BLRV) {12.5 and 4.5%}, Lucerne transient streak virus (LTSV) {2.9 and 3.5%}, Bean yellow mosaic virus (BYMV) {1.4 and 4.5%}, Bean common mosaic virus (BCMV) {1.2 and 4.5%}, Red clover vein mosaic virus (RCVMV) {1.2 and 4%}, White clover mosaic virus (WCIMV) {1.0 and 5%}, Cucumber mosaic virus (CMV) {0.8 and 3%}, Pea streak virus (PeSV) {0.4 and 4.5%} and Tobacco streak virus (TSV) {0.3 and 2.5%}. Alfalfa mosaic virus (AMV), the previously reported virus in alfalfa, had the highest percentage of detection in alfalfa accounting for 58.4% and 62.8% in the weeds and cultivated plants. Peanut stunt virus (PSV) was also detected for the first time in Saudi Arabia with a 66.7% of infection in 90 alfalfa samples collected from the surveyed regions during the last visit that tested negative to all the previously detected viruses. PMID- 28855830 TI - Wake structure and hydrodynamic performance of flapping foils mimicking fish fin kinematics. AB - Numerical simulations are used to investigate the wake structure and hydrodynamic performance of bionic flapping foils. The study is motivated by the quest to understand the fluid dynamics of fish fins and use it in the underwater propulsion. The simulations employ an immersed boundary method that makes it possible to simulate flows with complex moving boundaries on fixed Cartesian grids. A detailed analysis of the vortex topology shows that the wake of flapping foils is dominated by two sets of complex shaped vortex rings that convect at oblique angles to the wake centerline. The wake of these flapping foils is characterized by two oblique jets. Simulations are also used to examine the wake vortex and hydrodynamic performance over a range of Strouhal numbers and maximum pitch angles and the connection between the foil kinematics, vortex dynamics and force production is discussed. The results show that the variety law of the hydrodynamic performance with kinematic parameters strongly depends on the flow dynamics underlying the force production, including the orientation, interconnection and dissipation rate of the vortex rings. PMID- 28855832 TI - Using feature optimization-based support vector machine method to recognize the beta-hairpin motifs in enzymes. AB - beta-Hairpins in enzyme, a kind of special protein with catalytic functions, contain many binding sites which are essential for the functions of enzyme. With the increasing number of observed enzyme protein sequences, it is of especial importance to use bioinformatics techniques to quickly and accurately identify the beta-hairpin in enzyme protein for further advanced annotation of structure and function of enzyme. In this work, the proposed method was trained and tested on a non-redundant enzyme beta-hairpin database containing 2818 beta-hairpins and 1098 non-beta-hairpins. With 5-fold cross-validation on the training dataset, the overall accuracy of 90.08% and Matthew's correlation coefficient (Mcc) of 0.74 were obtained, while on the independent test dataset, the overall accuracy of 88.93% and Mcc of 0.76 were achieved. Furthermore, the method was validated on 845 beta-hairpins with ligand binding sites. With 5-fold cross-validation on the training dataset and independent test on the test dataset, the overall accuracies were 85.82% (Mcc of 0.71) and 84.78% (Mcc of 0.70), respectively. With an integration of mRMR feature selection and SVM algorithm, a reasonable high accuracy was achieved, indicating the method to be an effective tool for the further studies of beta-hairpins in enzymes structure. Additionally, as a novelty for function prediction of enzymes, beta-hairpins with ligand binding sites were predicted. Based on this work, a web server was constructed to predict beta hairpin motifs in enzymes (http://202.207.29.251:8080/). PMID- 28855831 TI - Adsorption characteristics of sulfur solution by acticarbon against drinking water toxicosis. AB - Sulfur and ammonia nitrogen are rich nutrient pollutants, after entering water can cause algal blooms, cause eutrophication of water body, the spread of them will not only pollute the environment, destroy the ecological balance, but also harm human health through food chain channels, especially drinking-water toxicosis. Acticarbon can adsorb harmful substances, it was beneficial for people's health. In order to figure out the optimal adsorption condition and the intrinsic change of acticarbon, five chemicals were adsorbed by acticarbon and analyzed by FT-IR. The optimal adsorption condition of Fe2(SO4)3, Na2SO4, Na2S2O8, S and Na2SO3 was 9 g/1000 g at 80 min, 21 g/1000 g at 20 min, 15g/1000 g at 20 min, 21 g/1000 g at 60 min and 21 g/1000 g at 100 min, respectively. FT-IR spectra showed that acticarbon had eight characteristic peaks, such as S-S stretch, H2O stretch, O-H stretch, -C-H stretch, C 000000000000 000000000000 000000000000 111111111111 000000000000 111111111111 000000000000 000000000000 000000000000 O or CC stretch, CH2 bend, C-H were at 3850 cm-1, 3740 cm-1, 3435 cm 1, 2925 cm-1, 1630 cm-1, 1390 cm-1, 1115 cm-1, 600 cm-1, respectively. For FT-IR spectra of Fe2(SO4)3, the peaks at 3850 cm-1, 3740 cm-1, 2925 cm-1 achieved the maximum with 9 g/1000 g at 20 min. For Na2SO4, the peaks at 2925 cm-1, 1630 cm-1, 1390 cm-1, 1115 cm-1, 600 cm-1 achieved the maximum with 21 g/1000 g at 120 min. For ones of Na2S2O8, the peaks at 3850 cm-1, 3740 cm-1, 1390 cm-1, 1115 cm-1, 600 cm-1, achieved the maximum with 2 g/1000 g at 80 min. For ones of S, the peaks at 3850 cm-1, 3740 cm-1, 2925 cm-1 achieved the maximum with 19 g/1000 g at 100 min, the peaks at 1390 cm-1, 1115 cm-1, 600 cm-1 achieved the maximum with 19 g/1000 g at 20 min. For FT-IR spectra of Na2SO3, the peaks at 1630 cm-1, 1390 cm-1, 1115 cm-1, 600 cm-1 achieved the maximum with 2 g/1000 g at 100 min. It provided that acticarbon could adsorb and desulphurize from sulfur solution against drinking water toxicosis. PMID- 28855833 TI - Characteristics of activated carbon remove sulfur particles against smog. AB - Sulfur particles, which could cause diseases, were the main powder of smog. And activated carbon had the very adsorption characteristics. Therefore, five sulfur particles were adsorbed by activated carbon and were analyzed by FT-IR. The optimal adsorption time were 120 min of Na2SO3, 120 min of Na2S2O8, 120 min of Na2SO4, 120 min of Fe2(SO4)3 and 120 min of S. FT-IR spectra showed that activated carbon had the eight characteristic absorption of S-S stretch, H2O stretch, O-H stretch, -C-H stretch, conjugated C 000000000000 000000000000 000000000000 111111111111 000000000000 111111111111 000000000000 000000000000 000000000000 O stretch or CC stretch, CH2 bend, C-O stretch and acetylenic C-H bend vibrations at 3850 cm-1, 3740 cm-1, 3430 cm-1, 2920 cm-1, 1630 cm-1, 1390 cm 1, 1110 cm-1 and 600 cm-1, respectively. For Na2SO3, the peaks at 2920 cm-1, 1630 cm-1, 1390 cm-1 and 1110 cm-1 achieved the maximum at 20 min. For Na2S2O8, the peaks at 3850 cm-1, 3740 cm-1 and 2920 cm-1 achieved the maximum at 60 min. The peaks at 1390 cm-1, 1110 cm-1 and 600 cm-1 achieved the maximum at 40 min. For Na2SO4, the peaks at 3430 cm-1, 2920 cm-1, 1630 cm-1, 1390 cm-1, 1110 cm-1 and 600 cm-1 achieved the maximum at 60 min. For Fe2(SO4)3, the peaks at 1390 cm-1, 1110 cm-1 and 600 cm-1 achieved the maximum at 20 min. For S, the peaks at 1630 cm-1, 1390 cm-1 and 600 cm-1 achieved the maximum at 120 min. It provided that activated carbon could remove sulfur particles from smog air to restrain many anaphylactic diseases. PMID- 28855834 TI - Pattern of management of oro-facial infection in children: A retrospective. AB - BACKGROUND: The purpose of this study was to determine the distribution and management of orofacial infection in children treated at one of the major hospitals in Jeddah City, Saudi Arabia over a 12-month period during the year 2014. METHODS: Data from the clinical records of 94 children (33 girls, 61 boys; aged 2-14 years) who presented for treatment of orofacial infection at the emergency dental department of the military hospital in Jeddah during a 12-month period. Patients were treated with antibiotic therapy. A favorable outcome was determined based on length of hospital stay. RESULTS: The results indicated that the most common cause of odontogenic infection in Saudi children was dental caries (88%). The primary posterior teeth (84%) were considered to be a major source of infection. The most commonly affected teeth were the primary first molars (34%), followed by the primary second molars (31%). Six children were hospitalized; four of these stayed less than 4 days, which was considered a short hospital stay. The most common treatment was antibiotics as 93% received a type of antibiotic. CONCLUSIONS: The most common cause of odontogenic infection was dental caries which has been treated with antibiotic prescription and dental procedures. PMID- 28855835 TI - Distribution of non-tuberculosis mycobacteria strains from suspected tuberculosis patients by heat shock protein 65 PCR-RFLP. AB - The genus Mycobacterium contains more than 150 species. Non-tuberculosis mycobacteria (NTM) often cause extrapulmonary and pulmonary disease. Mycobacteria detection at species level is necessary and provides useful information on epidemiology and facilitates successful treatment of patients. This retrospective study aimed to determine the incidence of the NTM isolates and Mycobacterium tuberculosis (Mtb) in clinical specimens collected from Iranian patients during February 2011-December 2013, by PCR-restriction fragment length polymorphism analysis (PRA) of the hsp65 gene. We applied conventional biochemical test and hsp65-PRA identification assay to identify species of mycobacteria in specimens from patients suspected of having mycobacterial isolates. This method was a sensitive, specific and effective assay for detecting mycobacterial species and had a 100% sensitivity and specificity for Mtb and Mycobacterium avium complex (MAC) species. Using PRA for 380 mycobacterial selected isolates, including 317 Mtb, four Mycobacterium bovis and of the 59 clinical isolates, the most commonly identified organism was Mycobacterium kansasii (35.6%), followed by Mycobacterium simiae (16.9%), Mycobacterium gordonae (16.9%), Mycobacterium fortuitum (5.1%), Mycobacterium intracellulare (5.1%), Mycobacterium avium (5.1%), Mycobacterium scrofulaceum (3.4%), Mycobacterium gastri (3.4%), Mycobacterium flavescens (3.4%), Mycobacterium chelonae (3.4%) and Mycobacterium nonchromogenicum (1.7%). PRA method, in comparison with classical methods, is rapid, useful and sensitive for the phylogenetic analysis and species detection of mycobacterial strains. Mycobacterium kansasii is the most common cause of infection by NTM in patients with non-HIV and HIV which demonstrated a high outbreak and diversity of NTM strains in our laboratory. PMID- 28855836 TI - Variation of quercetin glycoside derivatives in three onion (Allium cepa L.) varieties. AB - The aim of this study was to quantify the contents of individual quercetin glycosides in red, yellow and chartreuse onion by High Performance Liquid Chromatography (HPLC) analysis. Acid hydrolysis of individual quercetin glycosides using 6 M hydrochloric acid guided to identify and separate quercetin 7,4'-diglucoside, quercetin 3-glucoside, quercetin 4'-glucoside, and quercetin. The contents of total quercetin glycosides varied extensively among three varieties (ranged from 16.10 to 103.93 mg/g DW). Quercetin was the predominant compound that accounted mean 32.21 mg/g DW in red onion (43.6% of the total) and 127.92 mg/g DW in chartreuse onion (78.3% of the total) followed by quercetin 3 glucoside (28.83 and 24.16 mg/g DW) respectively. Quercetin 3-glucoside levels were much higher in yellow onion (43.85 mg/g DW) followed by quercetin 30.08 mg/g DW. Quercetin 4'-glucoside documented the lowest amount that documented mean 2.4% of the total glycosides. The varied contents of glycosides present in the different onion varieties were significant. PMID- 28855837 TI - In-vitro cytotoxicity and cellular uptake studies of luminescent functionalized core-shell nanospheres. AB - Monodispersed luminescent functionalized core-shell nanospheres (LFCSNs) were successfully synthesized and investigated for their cyto-toxic effect on human liver hepatocellular carcinoma cell line (HepG2 cells) by adopting MTT, DNA Ladder, TUNEL assay and qPCR based gene expressions through mRNA quantifications. The TUNEL and DNA ladder assays suggested an insignificant apoptosis in HepG2 cells due to the LFCSNs treatment. Further, the qPCR results also show that the mRNA expressions of cell cycle checkpoint gene p53 and apoptosis related gene (caspase-9) was up-regulated, while the antiapoptotic gene BCl-2 and apoptosis related genes FADD and CAS-3 (apoptosis effecter gene) were down-regulated in the LFCSNs treated cells. The nanospheres that were loaded into the cells confirm their intracellular uptake by light and fluorescent spectro-photometry and microscopy imaging analysis. The loaded nanospheres demonstrate an absolute resistance to photo-bleaching, which were applied for dynamic imaging to real time tracking in-vitro cell migratory activity for continuous 24 and 48 h durations using a time-lapsed fluorescent microscope. These properties of LFCSNs could therefore promote applications in the area of fluorescent protein biolabeling and drug-delivery. PMID- 28855838 TI - Characterization of seed storage protein patterns of Heliotropium digynum. AB - Heliotropium digynum, is a shrub that has ecological importance. The height of the plant differs from one population to another and the difference in length of the inflorescence can be attributed to environmental factors, such as rainfall or type of soil and temperature. To date, no study has shed light on estimation in seed samples of H. digynum in Saudi Arabia. So, the aim is to evaluate and characterize the protein patterns of seed storage proteins of H. digynum to be used as fingerprint of this plant in Saudi Arabia. It is collected from different locations in the central region of Saudi Arabia and total protein extraction from plant was compared in SDS-PAGE. The genetic relationships among all cultivars were analyzed using UPGMA and NJ using Total Lab TL and in the same way using Jaccard Similarity Coefficient dendrogram using STATISTICA (ver.8) software. Results, our data show that amounts of protein are different, although they are of the same type or from the same geographical region. Amounts ranged between 22 and 1.5 mg/g of dry weight. Less amount of protein was obtained from the group of samples collected from Dir'iyah area, and the highest amount of protein was from the group of samples collected from Dyrab area in general. PMID- 28855839 TI - Ameliorative effects of l-carnitine on rats raised on a diet supplemented with lead acetate. AB - Lead intoxication has been a major health hazard in humans. It affects people at all ages. Its toxicity is associated with various organs of the body and affects different metabolic pathways. Based on histological data, l-carnitine reduced the severity of tissue damage produced as a result of exposure of rats to lead acetate. The main objective of this study was to evaluate the underlying mechanism of protection offered by l-carnitine against lead acetate intoxication using male Sprague-Dawley rats. Forty male Sprague-Dawley rats were randomly divided into four groups with ten rats in each. The first group (G1) served as the control group and animals received standard diet only. The second group (G2) received lead acetate in their diet. The third group (G3) was the l-carnitine treated group and received the normal standard diet supplemented with l carnitine. While the fourth group (G4) had a diet supplemented with both lead acetate and l-carnitine. At the end of each experiment, blood (serum and whole blood) were collected from each animal and analyzed for the following parameters: serum testosterone levels, serum nitric oxide and serum malondialdehyde. This is in addition to looking at the enzymatic activities of two important enzymes (superoxide dismutase and catalase) and on (glutathione reductase) which are indicative of the antioxidant activities in the whole blood. The results indicated that l-carnitine will counteract the undesirable effects of lead intoxication. It exerted its antioxidant potential by reducing the production of ROS and scavenging free radicals by maintaining and protecting the level of the of antioxidant enzymes SOD, CAT and glutathione peroxidase. Conclusion:l Carnitine may play an important role in reversing the undesirable effects of lead intoxication. Future studies should be conducted to see whether such an effect is applicable in humans exposed to lead poising. PMID- 28855846 TI - Newsvendor problem under complete uncertainty: a case of innovative products. AB - The paper presents a new scenario-based decision rule for the classical version of the newsvendor problem (NP) under complete uncertainty (i.e. uncertainty with unknown probabilities). So far, NP has been analyzed under uncertainty with known probabilities or under uncertainty with partial information (probabilities known incompletely). The novel approach is designed for the sale of new, innovative products, where it is quite complicated to define probabilities or even probability-like quantities, because there are no data available for forecasting the upcoming demand via statistical analysis. The new procedure described in the contribution is based on a hybrid of Hurwicz and Bayes decision rules. It takes into account the decision maker's attitude towards risk (measured by coefficients of optimism and pessimism) and the dispersion (asymmetry, range, frequency of extremes values) of payoffs connected with particular order quantities. It does not require any information about the probability distribution. PMID- 28855843 TI - Impact of fertilization by natural manure on the microbial quality of soil: Molecular approach. AB - The quality of soil is strongly bound by several interactions between chemical and biological components, including microbial composition, which are a key importance for soil performance. Cultural activities have a huge induction on soil health, through both modification of physicochemical proprieties and changing on soil microbial communities. This usually affects the safety of soil, and then the crop production and water. In the present work, the information on bacterial community composition was determined from a set of 6 soils collected from 2 farms in agricultural land of Marrakech (Morocco), one of which used poultry manure (PM) and the other cow manure (CM) as fertilizers. To profile this structure of the bacterial community Denaturing Gradient Gel Electrophoresis (DGGE) of 16S rDNA fragments has been used. These amendments resulted in the appearance of several novel bands and different relative intensities of bands between the control station and other sites studied. The stations most affected are those receiving a supply of manure rather high, which results in an organic and bacterial load in the soil. The results showed a bacterial diversity very important indicating a fecal contamination like Bacteroides, Pseudomonas, Staphylococcus,... etc. Bacteria pertain to the phylum Firmicutes and Bacteroidetes were noted to be the dominant ribotype in amended soil. Moreover, this work demonstrates also the existence of pathogens strains in soil amended by poultry manure (PM) belonging to the Clostridiales order and Pseudomonadales. The pathogenic bacteria detected posing a hazard of human contagion when they are used for soil practice. PMID- 28855841 TI - Seed viability of five wild Saudi Arabian species by germination and X-ray tests. AB - Our objective was to evaluate the usefulness of the germination vs. the X-ray test in determining the initial viability of seeds of five wild species (Moringa peregrina, Abrus precatorius, Arthrocnemum macrostachyum, Acacia ehrenbergiana and Acacia tortilis) from Saudi Arabia. Usually several days were required to determine the viability of all five species via germination tests. However, X-ray test will give immediate results on filled/viable seeds. Seeds of all species, except Acacia ehrenbergiana and Acacia tortilis showed high viability in both germination (96-72% at 25/15 degrees C, 94-70% at 35/25 degrees C) and X-ray (100-80%) test. Furthermore, there was a general agreement between the germination (19%, 14% at 25/15 degrees C and 17% and 12% at 35/25 degrees C) and X-ray (8%, 4%) tests in which seed viability of Acacia ehrenbergiana and Acacia tortilis was very low due to insect damaged embryo as shown in X-ray analysis. Seeds of Abruspreca torius have physical dormancy, which was broken by scarification in concentrated sulfuric acid (10 min), and they exhibited high viability in both the germination (83% at 25/15 degrees C and 81% at 35/25 degrees C) and X-ray (96%) tests. Most of the nongerminated seeds of the five species except those of Acacia ehrenbergiana and Acacia tortilis, were alive as judged by the tetrazolium test (TZ). Thus, for the five species examined, the X ray test was proved to be a good and rapid predictor of seed viability. PMID- 28855844 TI - Directionality in ASL-English interpreting: Accuracy and articulation quality in L1 and L2. AB - Among spoken language interpreters, a long-standing question regarding directionality is whether interpretations are better when working into one's native language (L1) or into one's 'active' non-native language (L2). In contrast to studies that support working into L1, signed language interpreters report a preference for working into L2. Accordingly, we investigated whether signed language interpreters actually perform better when interpreting into their L2 (American Sign Language) or into their L1 (English). Interpretations by 30 interpreters (15 novice, 15 expert), delivered under experimental conditions, were assessed on accuracy (semantic content) and articulation quality (flow, speed, and prosody). For both measures, novices scored significantly better when interpreting into English (L1); experts were equally accurate, and showed similar articulation quality, in both directions. The results for the novice interpreters support the hypothesis that the difficulty of L2 production drives interpreting performance in relation to directionality. Findings also indicate a disconnect between direction preference and interpreting performance. Novices' perception of their ASL production ability may be distorted because they can default to fingerspelling and transcoding. Weakness in self-monitoring of signing may also lead novices to overrate their ASL skills. Interpreter educators should stress misperceptions of signing proficiency that arise from available, but inappropriate, strategies. PMID- 28855847 TI - Cerebrospinal fluid pleocytosis level as a diagnostic predictor? A cross sectional study. AB - BACKGROUND: Lumbar puncture with quantification of leukocytes and differential count of cellular subsets in the cerebrospinal fluid is a standard procedure in cases of suspected neuroinfectious conditions. However, a number of non infectious causes may result in a low leukocyte number (0-1000 cells/ml). We wanted to assess the diagnostic diversity of unselected adult patients with pleocytosis in the cerebrospinal fluid. METHODS: The study is based on data from cerebrospinal fluid (CSF) analyses of all adult patients (15 years or older) admitted to a large university hospital in Denmark during a two-year period (2008 2009). Data from the local patient administrative system supplied with data from patient charts were combined with laboratory data. RESULTS: A total of 5390 cerebrospinal fluid samples from 3290 patients were included. Pleocytosis >5 leucocytes/MUl was found in samples from 262 patients of which 106 (40.5%) were caused by infection of the central nervous system (CNS), 20 (7.6%) by infection outside CNS, 79 (30.2%) due to non-infectious neurological diseases, 23 (8.8%) by malignancy, and 34 (13.0%) caused by other conditions. Significantly higher mean CSF leukocytes was found in patients suffering from CNS infection (mean 1135 cells/MUl, p-value <0.0001). CONCLUSIONS: CNS infection, non-infectious neurological disease, malignancy, and infection outside CNS can cause pleocytosis of the cerebrospinal fluid. Leukocyte counts above 100/MUl is mainly caused by CNS infection, whereas the number of differential diagnoses is higher if the CSF leukocyte counts is below 50/MUl. These conditions are most commonly caused by non-infectious neurological diseases including seizures. PMID- 28855845 TI - To Model or not to Model, That is no Longer the Question for Ecologists. AB - Here, I argue that we should abandon the division between "field ecologists" and "modelers," and embrace modeling and empirical research as two powerful and often complementary approaches in the toolbox of 21st century ecologists, to be deployed alone or in combination depending on the task at hand. As empirical research has the longer tradition in ecology, and modeling is the more recent addition to the methodological arsenal, I provide both practical and theoretical reasons for integrating modeling more deeply into ecosystem research. Empirical research has epistemological priority over modeling; however, that is, for models to realize their full potential, and for modelers to wield this power wisely, empirical research is of fundamental importance. Combining both methodological approaches or forming "super ties" with colleagues using different methods are promising pathways to creatively exploit the methodological possibilities resulting from increasing computing power. To improve the proficiency of the growing group of model users and ensure future innovation in model development, we need to increase the modeling literacy among ecology students. However, an improved training in modeling must not curtail education in basic ecological principles and field methods, as these skills form the foundation for building and applying models in ecology. PMID- 28855852 TI - Influence of optimizing protocol choice on the integral dose value in prostate radiotherapy planning by dynamic techniques - Pilot study. AB - AIM: The purpose of this study was to compare the values of integral dose, calculated for treatment plans of dynamic radiotherapy techniques prepared with two different optimization protocols. BACKGROUND: Delivering radiation by IMRT, VMAT and also HT techniques has an influence on the low dose deposition of large areas of the patient body. Delivery of low dose can induce injury of healthy cells. In this situation, a good solution would be to reduce the area, which receives a low dose, but with appropriate dose level for the target volume. MATERIALS AND METHODS: To calculate integral dose values of plans structures, we used 90 external beam radiotherapy plans prepared for three techniques (intensity modulated radiotherapy, volumetric modulated arc therapy and helical tomotherapy). One technique includes three different geometry combinations. 45 plans were prepared with classic optimization protocol and 45 with rings optimization protocol which should reduce the low doses in the normal tissue. RESULTS: Differences in values of the integral dose depend on the geometry and technique of irradiation, as well as optimization protocol used in preparing treatment plans. The application of the rings optimization caused the value of normal tissue integral dose (NTID) to decrease. CONCLUSION: It is possible to limit the area of low dose irradiation and reduce NTID in dynamic techniques with the same clinical constraints for OAR and PTV volumes by using an optimization protocol other than the classic one. PMID- 28855842 TI - Efficient and reproducible in vitro regeneration of Solanum lycopersicum and assessment genetic uniformity using flow cytometry and SPAR methods. AB - In the present study, we develop an efficient and reproducible in vitro regeneration system for two cultivars viz., Jamila and Tomaland of Solanum lycopersicum L., an economically important vegetable crop throughout the world. Sterilization of seeds with 2.5% (v/v) NaOCl was found to be most effective, about 97% of seeds germinated on cotton in magenta box moistened with sterile half strength (1/2)Murashige and Skoog (MS) medium. Regeneration efficiency of cotyledonary leaf (CL) and cotyledonary node (CN) explants derived from 08 days old aseptic seedling were assessed on MS medium supplemented with different concentrations of auxins and cytokinin. CL explants were found more responsive in comparison to CN in both the cultivars. Types of basal media were also assessed and found to have a significant effect on shoot regeneration. Highest regeneration frequency and maximum number of shoots were standardized from CL explants on MS medium supplied with 6-benzyl adenine (BA; 5.0 uM), indole-3 butyric acid (IBA; 2.5 uM) and Kinetin (Kin; 10.0 uM). In vitro regenerated microshoots were rooted on 1/2MS medium containing 0.5 uM indole-3-butyric acid (IBA). Regenerated plantlets with well-developed roots and shoot system were successfully acclimated to ex vitro condition. Genetic uniformity of tissue culture raised plantlets was first time evaluated using flow cytometry and single primer amplification reaction (SPAR) methods viz., DAMD and ISSR. No significant changes in ploidy level and nuclear DNA content profile were observed between in vitro propagated plants and normal plants of both the cultivars. Similarly, the SPAR analysis also revealed monomorphic banding patterns in regenerated plantlets of S. lycopersicum verifying their genetic uniformity and clonal fidelity. This efficient regeneration system can be used as a fast and reproducible method for genetic transformation of this important vegetable crop. PMID- 28855840 TI - Effect of gold nanoparticles on mice splenomegaly induced by schistosomiasis mansoni. AB - Schistosomiasis is still one of the main parasitic diseases that affect human health in tropical regions. Whilst praziquantel (PZQ) is the main classic antischistosomal drug, the need for new drugs is still a must due to the low effectiveness of the drug on the schistosome young worms, and the evolving of PZQ resistant strains. Nanotechnology is one of the most important recent and current methods used to treat human diseases including parasitic ones. Therefore, the present study aimed to examine the curative role of gold nanoparticles (GNPs) on splenic tissue of mice infected with Schistosoma mansoni Sambon, 1907. High resolution transmission electron microscopy was used for characterization of nanoparticles (NP). GNPs of 1 mg/kg mice body weight were inoculated into mice infected with S. mansoni. The parasite caused deteriorations in histological architecture of the spleen tissue, and splenomegaly. Additionally, the parasite induced a significant reduction in splenic tissue glutathione levels; however, the concentrations of nitric oxide and malondialdehyde were significantly increased. Treatment of mice with GNPs reduced the extent of histological impairment and oxidative stress in spleen tissue. Therefore, our results demonstrate the protective role of GNPs against splenic damage in mice infected with S. mansoni. PMID- 28855850 TI - MicroRNA-222 influences migration and invasion through MIA3 in colorectal cancer. AB - BACKGROUND: miR-222 has been reported to be overexpressed in colorectal cancer and it influences cancer cell proliferation, drug resistance and metastasis. However, the underlying molecular mechanism of miR-222 in colorectal cancer cell invasion and migration has not been thoroughly elucidated to date. METHODS: The cell cycle distribution and apoptosis were assessed by flow cytometry. Cell migration and invasion were analyzed by Transwell assays. The possible target gene of miR-222 was searched and identified by bioinformatics, dual luciferase reporter assay and western blot analysis. The siRNA method was used to confirm the function of the target gene. RESULTS: Overexpression of miR-222 effectively promotes migration and invasion of colorectal cancer (CRC) cells in vitro. Bioinformatics and the dual luciferase reporter assay revealed that miR-222 specifically targeted the 3'-UTR of melanoma inhibitory activity member 3 (MIA3), down-regulating its expression at the protein level. Inhibition of MIA3 by siRNA enhanced the migration and invasion of CRC cell lines. CONCLUSIONS: Our study showed that miR-222 enhances the migration and invasion in CRC cells, primarily by down-regulation of MIA3. PMID- 28855848 TI - Primary breast angiosarcoma: a rare presentation of rare tumor - case report. AB - BACKGROUND: Primary breast angiosarcoma is defined as malignant proliferation showing endothelial differentiation. It is a very rare tumour (0.05% of primary mammary cancers), whose diagnosis can be difficult. CASE PRESENTATION: We report the observation of a patient with no previous history, aged 27 years. The clinical examination finds a right breast discreetly increased in volume. The trucut biopsy was in favour of a lactating tubular adenoma. However, an immunohistochemical complement was requested. An absence of pancytokeratin labelling contrasted with strong expression of CD31, CD34 (endothelial markers) are described. The proliferation index (Ki67) was estimated at 30%. This led to the conclusion that the phenotypic aspect is related to a vascular proliferation that evokes an angiosarcoma. After a multidisciplinary assessment, the patient benefited from an enlarged excision of the tumour. The histopathological examination of the surgical specimen found an infiltrating mesenchymal proliferation made of vessels of variable sizes anastomosed to vascular slits with lesional limits. The immunohistochemical examination on the surgical specimen showed to the same phenotypic profile on biopsy. The final diagnosis was a high-grade mammary angiosarcoma of incomplete excision. The patient refused any additional surgical management; external radiotherapy and close supervision were prescribed. After eight months of evolution, no local or remote recurrence was reported. CONCLUSION: Primary breast angiosarcoma is a mesenchymal malignant tumour of rare vascular origin. Our observation is peculiar by the absence of any prior radiotherapy, its clinical presentation, its morpho-phenotypic characteristics, its management and its evolutive aspects. PMID- 28855851 TI - An Assessment of Fixed and Native Chromatin Preparation Methods to Study Histone Post-Translational Modifications at a Whole Genome Scale in Skeletal Muscle Tissue. AB - BACKGROUND: Genomic loci associated with histone marks are typically analyzed by immunoprecipitation of the chromatin followed by quantitative-PCR (ChIP-qPCR) or high throughput sequencing (ChIP-seq). Chromatin can be either cross-linked (X ChIP) or used in the native state (N-ChIP). Cross-linking of DNA and proteins helps stabilizing their interactions before analysis. Despite X-ChIP is the most commonly used method, muscle tissue fixation is known to be relatively inefficient. Moreover, no protocol described a simple and reliable preparation of skeletal muscle chromatin of sufficient quality for subsequent high-throughput sequencing. Here we aimed to set-up and compare both chromatin preparation methods for a genome-wide analysis of H3K27me3, a broad-peak histone mark, using chicken P. major muscle tissue. RESULTS: Fixed and unfixed chromatin were prepared from chicken muscle tissues (Pectoralis major). Chromatin fixation, shearing by sonication or digestion and immunoprecipitation performed equivalently. High-quality Illumina reads were obtained (q30 > 93%). The bioinformatic analysis of the data was performed using epic, a tool based on SICER, and MACS2. Forty millions of reads were analyzed for both X-ChIP-seq and N ChIP-seq experiments. Surprisingly, H3K27me3 X-ChIP-seq analysis led to the identification of only 2000 enriched regions compared to about 15,000 regions identified in the case of N-ChIP-seq. N-ChIP-seq peaks were more consistent between replicates compared to X-ChIP-seq. Higher N-ChIP-seq enrichments were confirmed by ChIP-qPCR at the PAX5 and SOX2 loci known to be enriched for H3K27me3 in myotubes and at the loci of common regions of enrichment identified in this study. CONCLUSIONS: Our findings suggest that the preparation of muscle chromatin for ChIP-seq in cross-linked conditions can compromise the systematic analysis of broad histone marks. Therefore, native chromatin preparation should be preferred to cross-linking when a ChIP experiment has to be performed on skeletal muscle tissue, particularly when a broad source signal is considered. PMID- 28855854 TI - Disambiguating Dependency and Attachment Among Conjugally Bereaved Adults. AB - This study aims to investigate the effects of dependency and attachment in adjusting to the loss of a loved one by directly comparing the relative contribution of each to bereavement outcomes among midlife adults. Comparisons among attachment and dependency are made using models that control for attachment among three groups of bereaved adults (N=102): prolonged grievers (n=25), resolved grievers (n=41), and a married comparison group (n=36). Prolonged grievers displayed higher marginal means of dysfunctional detachment dependency and lower marginal means of healthy dependency compared to resolved grievers and married adults, even when controlling for attachment style. Findings suggest that attachment and dependency predict unique domains of grief outcome. PMID- 28855853 TI - Evaluation of dose calculations accuracy of a commercial treatment planning system for the head and neck region in radiotherapy. AB - AIM: The objective was to quantify dose calculation accuracy of TiGRT TPS for head and neck region in radiotherapy. BACKGROUND: In radiotherapy of head and neck cancers, treatment planning is difficult, due to the complex shape of target volumes and also to spare critical and normal structures. These organs are often very near to the target volumes and have low tolerance to radiation. In this regard, dose calculation accuracy of treatment planning system (TPS) must be high enough. MATERIALS AND METHODS: Thermoluminescent dosimeter-100 (TLD-100) chips were used within RANDO phantom for dose measurement. TiGRT TPS was also applied for dose calculation. Finally, difference between measured doses (Dmeas) and calculated doses (Dcalc) was obtained to quantify the dose calculation accuracy of the TPS at head and neck region. RESULTS: For in-field regions, in some points, the TiGRT TPS overestimated the dose compared to the measurements and for other points underestimated the dose. For outside field regions, the TiGRT TPS underestimated the dose compared to the measurements. For most points, the difference values between Dcalc and Dmeas for the in-field and outside field regions were less than 5% and 40%, respectively. CONCLUSIONS: Due to the sensitive structures to radiation in the head and neck region, the dose calculation accuracy of TPSs should be sufficient. According to the results of this study, it is concluded that the accuracy of dose calculation of TiGRT TPS is enough for in-field and out of field regions. PMID- 28855855 TI - The Role of Health Information Management Professionals in the Use of Geographic Information Systems. AB - In recent years the use of geographic information systems (GIS) in healthcare has expanded rapidly. Although the use of GIS has increased quickly, very little consensus has been reached on which healthcare professionals are best suited to be trained in and use GIS. A moderate amount of research has addressed the use of GIS in healthcare, but very little research has addressed selecting and training healthcare professionals in the area of GIS. As the use of GIS becomes more closely tied to electronic health records (EHRs), the thought arises that those best versed in EHRs, health information management (HIM) professionals, would be best suited to take on the GIS role. This mixed-methods study explored the current status of HIM professionals' role in GIS as well as the extent to which GIS is being taught in health information educational programs. Although the findings indicate that few HIM professionals are currently using GIS in their jobs and few HIM programs are currently teaching GIS, there is interest in GIS in the future for HIM professionals and in HIM educational programs. PMID- 28855856 TI - Determinant Factors in Applying Picture Archiving and Communication Systems (PACS) in Healthcare. AB - OBJECTIVES: Meaningful use of picture archiving and communication systems (PACS) can change the workflow for accessing digital images, lead to faster turnaround time, reduce tests and examinations, and increase patient throughput. This study was carried out to identify determinant factors that affect the adoption of PACS by physicians. METHODS: This was a cross-sectional study in which 190 physicians working in a teaching hospital affiliated with Tehran University of Medical Sciences were randomly selected. Physicians' perceptions concerning the adoption of PACS were assessed by the conceptual path model of the Unified Theory of Acceptance and Use of Technology (UTAUT). Collected data were analyzed with regression analysis. Structural equation modeling was applied to test the final model that was developed. RESULTS: The results show that the UTAUT model can explain about 61 percent of the variance on in the adoption of PACS (R2 = 0.61). The findings also showed that performance expectancy, effort expectancy, social influences, and behavior intention have a direct and significant effect on the adoption of PACS. However, facility condition showed to have no significant effect on physicians' behavior intentions. CONCLUSIONS: Implementation of new technology such as PACS in the healthcare sector is unavoidable. Our study clearly identified significant and nonsignificant factors that may affect the adoption of PACS. Also, this study acknowledged that physicians' perception is a key factor to manage the implementation of PACS optimally, and this fact should be considered by healthcare managers and policy makers. PMID- 28855849 TI - ARNT is a potential direct HIF-1 target gene in human Hep3B hepatocellular carcinoma cells. AB - BACKGROUND: The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT) participates in the hypoxia-inducible factor (HIF) pathway which senses a decline in cellular oxygen tension. In hypoxia, HIF-1alpha and ARNT form the transcriptional active complex HIF-1 followed by the expression of target genes. ARNT is considered as constitutively expressed and unaffected by hypoxia. However, certain tumour cell lines derived from different entities are capable to elevate ARNT expression under hypoxic conditions which implies a survival benefit. It was demonstrated that high ARNT protein levels mediate radioresistance in tumour cells. Furthermore, a HIF-1alpha-driven feed-forward loop leading to augmented HIF signalling was discovered in Hep3B cells. Herein HIF-1alpha elevates the mRNA and protein expression of its binding partner ARNT in hypoxia. However, the detailed mechanism remained unclear. The objective of this study was to test whether HIF-1alpha might directly regulate ARNT expression by recruitment to the ARNT promoter. METHODS: Chromatin immunoprecipitation (ChIP), CRISPR/Cas9 genome editing, Western blotting, quantitative RT-PCR and reporter gene assays were applied. The unpaired t test was used for statistical analysis. RESULTS: ChIP assays revealed the binding of both HIF-1alpha and ARNT to the ARNT promoter in hypoxia. The relevance of this particular region for hypoxic ARNT induction was confirmed by CRISPR/Cas9 genome editing. ARNT normoxic basal expression and hypoxic inducibility was reduced in genome-edited Hep3B cells. This phenotype was accompanied with impaired HIF signalling and was rescued by ARNT overexpression. CONCLUSIONS: The results indicate ARNT to be a putative HIF-1 target gene and a limiting factor in this model. PMID- 28855858 TI - Processing of Unattended Emotional Facial Expressions: Correlates of Visual Field Bias in Women. AB - Lateralization in emotional processing is a matter of ongoing debate. Various factors can influence lateralized emotional processing, including stimulus location, emotional valence, and gender. In the present study, we aim to elucidate how unattended emotional facial expressions shown at different locations in the visual field influence behavioral responses, eye movement, and neural responses in a sample of healthy women. Our female participants viewed fearful, happy and neutral faces presented at central and peripheral (left or right) locations while keeping their gaze locked on a central fixation crosshairs and indicating stimulus location via button presses. Throughout the experiment, we monitored fixation and gaze shifts by means of eye tracking. We analyzed eye movements, neural and behavioral responses from n = 18 participants with excellent tracking and task performance. Face stimuli presented in the left hemifield entailed the fastest reactions irrespective of face valence. Unwarranted gaze shifts away from central fixation were rare and mainly directed at peripherally presented stimuli. A distributed neural network comprising the right amygdala, left temporal pole, left middle temporal gyrus, right superior frontal gyrus, and right posterior putamen differentially responded to centrally presented fearful faces, and to peripherally presented neutral and happy faces, especially when they appeared in the left hemifield. Our findings point to a visual field bias on the behavioral and neural level in our female sample. Reaction times, eye movements and neural activations varied according to stimulus location. An interactive effect of face location with face valence was present at the neural level but did not translate to behavioral or eye movement responses. PMID- 28855857 TI - A Health Information System for Scalable and Comprehensive Assessment of Well Being: A Multidisciplinary Team Solution. AB - To improve the health and well-being of the medically underserved in a free clinic in Pittsburgh, Pennsylvania, a multidisciplinary team representing several health information management and information technology (IT) professionals, including faculty, students, researchers, and clinicians, created a novel IT system called imHealthy. The imHealthy system includes four critical components: a multidomain well-being questionnaire, a mobile app for data collection and tracking, a customization of an open-source electronic health record (EHR), and a data integration and well-being evaluation program leading to recommendations for personalized interventions to caregivers serving the medically underserved. This multidisciplinary team has worked closely on this project and finished critical components of the imHealthy system. Evaluations of these components will be conducted, and factors facilitating the design and adoption of the imHealthy system will be presented. The results from this research can serve as a model for free clinics with similar needs that identified by the research team in Cleveland, Indianapolis, Minnesota, Motor City, Orange County, San Diego, and St. Louis. PMID- 28855861 TI - Regulation of Microglia and Macrophage Polarization via Apoptosis Signal Regulating Kinase 1 Silencing after Ischemic/Hypoxic Injury. AB - Inflammation is implicated in ischemic stroke and is involved in abnormal homeostasis. Activation of the immune system leads to breakdown of the blood brain barrier and, thereby, infiltration of immune cells into the brain. Upon cerebral ischemia, infiltrated macrophages and microglia (resident CNS immune cell) are activated, change their phenotype to M1 or M2 based on the microenvironment, migrate toward damaged tissue, and are involved in repair or damage. Those of M1 phenotype release pro-inflammatory mediators, which are associated with tissue damage, while those of M2 phenotype release anti inflammatory mediators, which are related to tissue recovery. Moreover, late inflammation continually stimulates immune cell infiltration and leads to brain infarction. Therefore, regulation of M1/M2 phenotypes under persistent inflammatory conditions after cerebral ischemia is important for brain repair. Herein, we focus on apoptosis signal-regulating kinase 1 (ASK1), which is involved in apoptotic cell death, brain infarction, and production of inflammatory mediators after cerebral ischemia. We hypothesized that ASK1 is involved in the polarization of M1/M2 phenotype and the function of microglia and macrophage during the late stage of ischemia/hypoxia. We investigated the effects of ASK1 in mice subjected to middle cerebral artery occlusion and on BV2 microglia and RAW264.7 macrophage cell lines subjected to oxygen-glucose deprivation. Our results showed that ASK1 silencing effectively reduced Iba-1 or CD11b-positive cells in ischemic areas, suppressed pro-inflammatory cytokines, and increased anti-inflammatory mediator levels at 7 days after cerebral ischemia. In cultured microglia and macrophages, ASK1 inhibition, induced by NQDI 1 drug, decreased the expression and release of M1-associated factors and increased those of M2-associated factors after hypoxia/reperfusion (H/R). At the gene level, ASK1 inhibition suppressed M1-associated genes and augmented M2 associated genes. In gap closure assay, ASK1 inhibition reduced the migration rate of microglia and macrophages after H/R. Taken together, our results provide new information that suggests ASK1 controls the polarization of M1/M2 and the function of microglia and macrophage under sustained-inflammatory conditions. Regulation of persistent inflammation via M1/M2 polarization by ASK1 is a novel strategy for repair after ischemic stroke. PMID- 28855860 TI - Transcriptional Reorganization of Drosophila Motor Neurons and Their Muscular Junctions toward a Neuroendocrine Phenotype by the bHLH Protein Dimmed. AB - Neuroendocrine cells store and secrete bulk amounts of neuropeptides, and display morphological and molecular characteristics distinct from neurons signaling with classical neurotransmitters. In Drosophila the transcription factor Dimmed (Dimm), is a prime organizer of neuroendocrine capacity in a majority of the peptidergic neurons. These neurons display large cell bodies and extensive axon terminations that commonly do not form regular synapses. We ask which molecular compartments of a neuron are affected by Dimm to generate these morphological features. Thus, we ectopically expressed Dimm in glutamatergic, Dimm-negative, motor neurons and analyzed their characteristics in the central nervous system and the neuromuscular junction. Ectopic Dimm results in motor neurons with enlarged cell bodies, diminished dendrites, larger axon terminations and boutons, as well as reduced expression of synaptic proteins both pre and post synaptically. Furthermore, the neurons display diminished vesicular glutamate transporter, and signaling components known to sustain interactions between the developing axon termination and muscle, such as wingless and frizzled are down regulated. Ectopic co-expression of Dimm and the insulin receptor augments most of the above effects on the motor neurons. In summary, ectopic Dimm expression alters the glutamatergic motor neuron phenotype toward a neuroendocrine one, both pre- and post-synaptically. Thus, Dimm is a key organizer of both secretory capacity and morphological features characteristic of neuroendocrine cells, and this transcription factor affects also post-synaptic proteins. PMID- 28855859 TI - beta2-Adrenergic Receptor-Mediated HIF-1alpha Upregulation Mediates Blood Brain Barrier Damage in Acute Cerebral Ischemia. AB - Disruption of the blood brain barrier (BBB) within the thrombolytic time window is an antecedent event to intracerebral hemorrhage in ischemic stroke. Our recent studies showed that 2-h cerebral ischemia induced BBB damage in non-infarcted area and secreted matrix metalloproteinase-2 (MMP-2) accounted for this disruption. However, the factors that affect MMP-2 secretion and regulate BBB damage remains unknown. Since hypoxia-inducible factor-1 alpha (HIF-1alpha) was discovered as a mater regulator in hypoxia, we sought to investigate the roles of HIF-1alpha in BBB damage as well as the factors regulating HIF-1alpha expression in the ischemic brain. in vivo rat middle cerebral artery occlusion (MCAO) and in vitro oxygen glucose deprivation (OGD) models were used to mimic ischemia. Pretreatment with HIF-1alpha inhibitor YC-1 significantly inhibited 2-h MCAO induced BBB damage, which was accompanied by suppressed occludin degradation and vascular endothelial growth factor (VEGF) mRNA upregulation. Interestingly, beta2 adrenergic receptor (beta2-AR) antagonist ICI 118551 attenuated ischemia-induced BBB damage by regulating HIF-1alpha expression. Double immunostaining showed that HIF-1alpha was upregulated in ischemic neurons but not in astrocytes andendothelial cells. Of note, HIF-1alpha inhibition with inhibitor YC-1 or siRNA significantly prevented OGD-induced VEGF upregulation as well as the secretion of VEGF and MMP-2 in neurons. More importantly, blocking beta2-AR with ICI 118551 suppressedHIF-1alpha upregulation in ischemic neurons and attenuated occludin degradation induced by the conditioned media of OGD-treatedneurons. Taken together, blockade of beta2-AR-mediated HIF-1alpha upregulation mediates BBB damage during acute cerebral ischemia. These findings provide new mechanistic understanding of early BBB damage in ischemic stroke and may help reduce thrombolysis-related hemorrhagic complications. PMID- 28855863 TI - Thyroid Hormone Availability and Action during Brain Development in Rodents. AB - Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes. PMID- 28855864 TI - Persistent Decreases in Adult Subventricular and Hippocampal Neurogenesis Following Adolescent Intermittent Ethanol Exposure. AB - Neurogenesis in hippocampal dentate gyrus (DG) and subventricular zone (SVZ) matures during adolescence to adult levels. Binge drinking is prevalent in adolescent humans, and could alter brain neurogenesis and maturation in a manner that persists into adulthood. To determine the impact of adolescent binge drinking on adult neurogenesis, Wistar rats received adolescent intermittent ethanol (AIE) exposure (5.0 g/kg/day, i.g., 2 days on/2 days off from postnatal day, P25-P54) and sacrificed on P57 or P95. Neural progenitor cell proliferation, differentiation, survival and maturation using immunohistochemistry was determined in the DG and SVZ. We found that AIE exposure decreased neurogenesis in both brain regions in adulthood (P95). In the DG at P57, AIE exposure resulted in a significant reduction of SOX2+, Tbr2+, Prox1+ and parvalbumin (PV)+IR expression, and at P95 decreased DCX+ and PV+IR expression. AIE exposure also reduced the expression of two cell proliferation markers (Ki67+ and BrdU+IR with 300 mg/kg, 2 h) at P95. The immune signaling molecule beta-2 microglobulin+ and the cell death marker activated caspase-3+IR were significantly increased in the DG by AIE exposure. In the SVZ, AIE exposure decreased SOX2+, Mash1+, DCX+ and Dlx2+IR expression at P95, but not at P57. Thus, in adulthood both brain regions have reduced neurogenesis following AIE exposure. To assess progenitor cell survival and maturation, rats were treated with BrdU (150 mg/kg/day, 14 days) to label proliferating cells and were sacrificed weeks later on P95. In the hippocampus DG, AIE exposure increased survival BrdU+ cells which differentiated into Iba1+ microglia. In contrast, SVZ had decreased BrdU+ cells similar to decreased DCX+ neurogenesis. These data indicate that AIE exposure causes a lasting decrease in both adult hippocampal DG and forebrain SVZ neurogenesis with brain regional differences in the AIE response that persist into adulthood. PMID- 28855862 TI - Novel Influences of IL-10 on CNS Inflammation Revealed by Integrated Analyses of Cytokine Networks and Microglial Morphology. AB - Coordinated interactions between cytokine signaling and morphological dynamics of microglial cells regulate neuroinflammation in CNS injury and disease. We found that pro-inflammatory cytokine gene expression in vivo showed a pronounced recovery following systemic LPS. We performed a novel multivariate analysis of microglial morphology and identified changes in specific morphological properties of microglia that matched the expression dynamics of pro-inflammatory cytokine TNFalpha. The adaptive recovery kinetics of TNFalpha expression and microglial soma size showed comparable profiles and dependence on anti-inflammatory cytokine IL-10 expression. The recovery of cytokine variations and microglial morphology responses to inflammation were negatively regulated by IL-10. Our novel morphological analysis of microglia is able to detect subtle changes and can be used widely. We implemented in silico simulations of cytokine network dynamics which showed-counter-intuitively, but in line with our experimental observations that negative feedback from IL-10 was sufficient to impede the adaptive recovery of TNFalpha-mediated inflammation. Our integrative approach is a powerful tool to study changes in specific components of microglial morphology for insights into their functional states, in relation to cytokine network dynamics, during CNS injury and disease. PMID- 28855866 TI - Structure Function Revisited: A Simple Tool for Complex Analysis of Neuronal Activity. AB - Neural systems are characterized by their complex dynamics, reflected on signals produced by neurons and neuronal ensembles. This complexity exhibits specific features in health, disease and in different states of consciousness, and can be considered a hallmark of certain neurologic and neuropsychiatric conditions. To measure complexity from neurophysiologic signals, a number of different nonlinear tools of analysis are available. However, not all of these tools are easy to implement, or able to handle clinical data, often obtained in less than ideal conditions in comparison to laboratory or simulated data. Recently, the temporal structure function emerged as a powerful tool for the analysis of complex properties of neuronal activity. The temporal structure function is efficient computationally and it can be robustly estimated from short signals. However, the application of this tool to neuronal data is relatively new, making the interpretation of results difficult. In this methods paper we describe a step by step algorithm for the calculation and characterization of the structure function. We apply this algorithm to oscillatory, random and complex toy signals, and test the effect of added noise. We show that: (1) the mean slope of the structure function is zero in the case of random signals; (2) oscillations are reflected on the shape of the structure function, but they don't modify the mean slope if complex correlations are absent; (3) nonlinear systems produce structure functions with nonzero slope up to a critical point, where the function turns into a plateau. Two characteristic numbers can be extracted to quantify the behavior of the structure function in the case of nonlinear systems: (1). the point where the plateau starts (the inflection point, where the slope change occurs), and (2). the height of the plateau. While the inflection point is related to the scale where correlations weaken, the height of the plateau is related to the noise present in the signal. To exemplify our method we calculate structure functions of neuronal recordings from the basal ganglia of parkinsonian and healthy rats, and draw guidelines for their interpretation in light of the results obtained from our toy signals. PMID- 28855865 TI - Differing Time of Onset of Concurrent TMS-fMRI during Associative Memory Encoding: A Measure of Dynamic Connectivity. AB - There has been a distinct shift in neuroimaging from localization of function into a more network based approach focused on connectivity. While fMRI has proven very fruitful for this, the hemodynamic signal is inherently slow which limits the temporal resolution of fMRI-only connectivity measures. The brain, however, works on a time scale of milliseconds. This study utilized concurrent transcranial magnetic stimulation (TMS)-fMRI in a novel way to obtain measures of dynamic connectivity by measuring changes in fMRI signal amplitude in regions distal to the site of stimulation following differing TMS onset times. Seventeen healthy subjects completed an associative memory encoding task known to involve the DLPFC, viewing pairs of objects which could be semantically related or unrelated. Three pulses of 10 Hz repetitive TMS were applied over the left DLPFC starting either at 200, 600, or 1000 ms after stimulus onset. Associations for related pairs were better remembered than unrelated pairs in a post-scan cued recall test. Differences in neural activity were assessed across different TMS onsets, separately for related and unrelated pairs. Time specific TMS effects were observed in several regions, including those associated with higher-level processing (lateral frontal, anterior cingulate), visual areas (occipital), and regions involved in semantic processing (e.g., left mid-temporal and medial frontal). Activity in the frontal cortex was decreased at 200 ms post-stimulus for unrelated pairs, and 1000 ms post-stimulus for related pairs. This suggests differences in the timing across conditions in which the DLFPC interacts with other PFC regions, consistent with the notion that the DLPFC is facilitating extended semantic processing for related items. This study demonstrates that time varying TMS onset inside the MRI can be used to reliably measure fast dynamic connectivity with a temporal resolution in the hundreds of milliseconds. PMID- 28855867 TI - Numerical Proportion Representation: A Neurocomputational Account. AB - Proportion representation is an emerging subdomain in numerical cognition. However, its nature and its correlation with simple number representation remain elusive, especially at the theoretical level. To fill this gap, we propose a gain field model of proportion representation to shed light on the neural and computational basis of proportion representation. The model is based on two well supported neuroscientific findings. The first, gain modulation, is a general mechanism for information integration in the brain; the second relevant finding is how simple quantity is neurally represented. Based on these principles, the model accounts for recent relevant proportion representation data at both behavioral and neural levels. The model further addresses two key computational problems for the cognitive processing of proportions: invariance and generalization. Finally, the model provides pointers for future empirical testing. PMID- 28855868 TI - Corrigendum: Temporality of Features in Near-Death Experience Narratives. AB - [This corrects the article on p. 311 in vol. 11, PMID: 28659779.]. PMID- 28855869 TI - Global Positioning System-Based Stimulation for Robo-Pigeons in Open Space. AB - An evaluation method is described that will enable researchers to study fight control characteristics of robo-pigeons in fully open space. It is not limited by the experimental environment and overcomes environmental interference with flight control in small experimental spaces using a compact system. The system consists of two components: a global positioning system (GPS)-based stimulator with dimensions of 38 mm * 26 mm * 8 mm and a weight of 18 g that can easily be carried by a pigeon as a backpack and a PC-based program developed in Virtual C++. The GPS-based stimulator generates variable stimulation and automatically records the GPS data and stimulus parameters. The PC-based program analyzes the recorded data and displays the flight trajectory of the tested robo-pigeon on a digital map. This method enables quick and clear evaluation of the flight control characteristics of a robo-pigeon in open space based on its visual trajectory, as well as further optimization of the microelectric stimulation parameters to improve the design of robo-pigeons. The functional effectiveness of the method was investigated and verified by performing flight control experiments using a robo-pigeon in open space. PMID- 28855871 TI - The Responses of Elite Athletes to Exercise: An All-Day, 24-h Integrative View Is Required! PMID- 28855870 TI - Leaf and Root Extracts from Campomanesia adamantium (Myrtaceae) Promote Apoptotic Death of Leukemic Cells via Activation of Intracellular Calcium and Caspase-3. AB - Phytochemical studies are seeking new alternatives to prevent or treat cancer, including different types of leukemias. Campomanesia adamantium, commonly known as guavira or guabiroba, exhibits pharmacological properties including antioxidant, antimicrobial, and antiproliferative activities. Considering the anticancer potential of this plant species, the aim of this study was to evaluate the antileukemic activity and the chemical composition of aqueous extracts from the leaves (AECL) and roots (AECR) of C. adamantium and their possible mechanisms of action. The extracts were analyzed by LC-DAD-MS, and their constituents were identified based on the UV, MS, and MS/MS data. The AECL and AECR showed different chemical compositions, which were identified as main compounds glycosylated flavonols from AECL and ellagic acid and their derivatives from AECR. The cytotoxicity promoted by these extracts were evaluated using human peripheral blood mononuclear cells and Jurkat leukemic cell line. The cell death profile was evaluated using annexin-V-FITC and propidium iodide labeling. Changes in the mitochondrial membrane potential, the activity of caspases, and intracellular calcium levels were assessed. The cell cycle profile was evaluated using propidium iodide. Both extracts caused concentration-dependent cytotoxicity only in Jurkat cells via late apoptosis. This activity was associated with loss of the mitochondrial membrane potential, activation of caspases-9 and -3, changes in intracellular calcium levels, and cell cycle arrest in S-phase. Therefore, the antileukemic activity of the AECL and AECR is mediated by mitochondrial dysfunction and intracellular messengers, which activate the intrinsic apoptotic pathway. Hence, aqueous extracts of the leaves and roots of C. adamantium show therapeutic potential for use in the prevention and treatment of diseases associated the proliferation of tumor cell. PMID- 28855872 TI - A Novel Method to Detect 3D Mandibular Changes Related to Soft-Diet Feeding. AB - Craniofacial morphology varies among individuals, which is regulated by the interaction between genes and the environment. Soft-diet feeding is a widely-used experimental model for studying the association between the skeletal morphology and muscle-related loading on the bone. Traditionally, these studies have been based on linear and angular measurements provided on two-dimensional (2D) radiographs in the lateral view. However, 2D observation is based on simplification of the anatomical structures and cannot detect three-dimensional (3D) changes in detail. In this study, we newly developed a modified surface based analysis with micro-3D computed tomography (CT) to examine and detect the 3D changes in the mandible associated with soft-diet feeding. Mice at 3 weeks of age were fed a powdered soft-diet (SD) or hard-diet (HD) of regular rodent pellets until 9 weeks of age. Micro-CT images were taken at age 9 weeks to reconstruct the anatomical architecture images. A computer-generated averaged mandible was superimposed to directly visualize the morphological phenotypes. Gross observation revealed the apparent changes at the posterior body of the mandible, the angular process and the condyle between HD and SD mice. Significant differences in the mapping indicated the regions of significant displacement in the SD mice over the averaged 3D image of the HD mice. This map revealed that vertical displacement was most evident in 3D changes. We also noted a combination of vertical, transverse and anteroposterior directions of displacement in the condylar growth, resulting in complicated shape changes in the whole condylar process in SD mice. In contrast, transverse displacement was more significant in the coronoid process. The map analysis further showed the significant outward displacement of the inner surface of the alveolar process, which consequently resulted in thinning of the alveolar process. PMID- 28855873 TI - Molecular Characterization of Barrier Properties in Follicle-Associated Epithelium of Porcine Peyer's Patches Reveals Major Sealing Function of Claudin 4. AB - The pig represents a preferred model for the analysis of intestinal immunology. However, the barrier of the follicle-associated epithelium (FAE) covering porcine Peyer's patches (PP) has not yet been characterized in detail. This study aimed to perform this characterization in order to pave the way toward an understanding of the functional contribution of epithelial barrier properties in gut immunology. Porcine tissue specimens were taken from the distal small intestine in order to obtain electrophysiological data of PP FAE and neighboring villous epithelium (VE), employing the Ussing chamber technique. Transepithelial resistance (TER) and paracellular fluorescein flux were measured, and tissues were morphometrically compared. In selfsame tissues, expression and localization of major tight junction (TJ) proteins (claudin-1, -2, -3, -4, -5, and -8) were analyzed. PP FAE specimens showed a higher TER and a lower apparent permeability for sodium fluorescein than VE. Immunoblotting revealed an expression of all claudins within both epithelia, with markedly stronger expression of the sealing TJ protein claudin-4 in PP FAE compared with the neighboring VE. Immunohistochemistry confirmed the expression and localization of all claudins in both PP FAE and VE, with stronger claudin-4 abundance in PP FAE. The results are in accordance with the physiological function of the FAE, which strongly regulates and limits antigen uptake determining a mandatory transcellular route for antigen presentation, highlighting the importance of this structure for the first steps of the intestinal immune response. Thus, this study provides detailed insights into the specific barrier properties of the porcine FAE covering intestinal PP, at the interface of intestinal immunology and barriology. PMID- 28855874 TI - Editorial: Complex Post-Traumatic Stress Disorder in the Context of Human Rights Abuse. PMID- 28855876 TI - The Non-Peptide Arginine-Vasopressin v1a Selective Receptor Antagonist, SR49059, Blocks the Rewarding, Prosocial, and Anxiolytic Effects of 3,4 Methylenedioxymethamphetamine and Its Derivatives in Zebra Fish. AB - 3,4-Methylenedioxymethamphetamine (MDMA) and its derivatives, 2,5-dimethoxy-4 bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA), are recreational drugs whose pharmacological effects have recently been attributed to serotonin 5HT2A/C receptors. However, there is growing evidence that the oxytocin (OT)/vasopressin system can modulate some the effects of MDMA. In this study, MDMA (2.5-10 mg/kg), DOB (0.5 mg/kg), or PMA (0.005, 0.1, or 0.25 mg/kg) were administered intramuscularly to adult zebra fish, alone or in combination with the V1a vasopressin antagonist, SR49059 (0.01-1 ng/kg), before carrying out conditioned place preference (CPP), social preference, novel tank diving, and light-dark tests in order to evaluate subsequent rewarding, social, and emotional like behavior. The combination of SR49059 and each drug progressively blocked: (1) rewarding behavior as measured by CPP in terms of time spent in drug-paired compartment; (2) prosocial effects measured on the basis of the time spent in the proximity of a nacre fish picture; and (3) anxiolytic effects in terms of the time spent in the upper half of the novel tank and in the white compartment of the tank used for the light-dark test. Antagonism was obtained at SR49059 doses which, when given alone, did not change motor function. In comparison with a control group, receiving vehicle alone, there was a three to five times increase in the brain release of isotocin (the analog of OT in fish) after treatment with the most active doses of MDMA (10 mg/kg), DOB (0.5 mg/kg), and PMA (0.1 mg/kg) as evaluated by means of bioanalytical reversed-phase high-performance liquid chromatography. Taken together, these findings show that the OT/vasopressin system is involved in the rewarding, prosocial, and anxiolytic effects of MDMA, DOB, and PMA in zebra fish and underline the association between this system and the behavioral alterations associated with disorders related to substance abuse. PMID- 28855877 TI - Sex and Electrode Configuration in Transcranial Electrical Stimulation. AB - Transcranial electrical stimulation (tES) can be an effective non-invasive neuromodulation procedure. Unfortunately, the considerable variation in reported treatment outcomes, both within and between studies, has made the procedure unreliable for many applications. To determine if individual differences in cranium morphology and tissue conductivity can account for some of this variation, the electrical density at two cortical locations (temporal and frontal) directly under scalp electrodes was modeled using a validated MRI modeling procedure in 23 subjects (12 males and 11 females). Three different electrode configurations (non-cephalic, bi-cranial, and ring) commonly used in tES were modeled at three current intensities (0.5, 1.0, and 2.0 mA). The aims were to assess the effects of configuration and current intensity on relative current received at a cortical brain target directly under the stimulating electrode and to characterize individual variation. The different electrode configurations resulted in up to a ninefold difference in mean current densities delivered to the brains. The ring configuration delivered the least current and the non-cephalic the most. Female subjects showed much less current to the brain than male subjects. Individual differences in the current received and differences in electrode configurations may account for significant variability in current delivered and, thus, potentially a significant portion of reported variation in clinical outcomes at two commonly targeted regions of the brain. PMID- 28855875 TI - Therapeutic Potential of Selectively Targeting the alpha2C-Adrenoceptor in Cognition, Depression, and Schizophrenia-New Developments and Future Perspective. AB - alpha2A- and alpha2C-adrenoceptors (ARs) are the primary alpha2-AR subtypes involved in central nervous system (CNS) function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective alpha2-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine) and atypical antipsychotic (e.g., clozapine) drug action. Both alpha2C- and alpha2A AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with alpha2C-AR heteroreceptors regulating non noradrenergic transmission (e.g., serotonin, dopamine). While the alpha2A-AR is widely distributed throughout the CNS, alpha2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the alpha2C-AR plays a more prominent role during states of low endogenous NA activity, while the alpha2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective alpha2-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the alpha2A- and alpha2C-ARs on behavioral markers of mood and cognition, implying that non-selective alpha2 AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective alpha2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the alpha2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer's disease. This review will emphasize the importance and relevance of the alpha2C AR as a neuropsychiatric drug target in major depression, schizophrenia, and associated cognitive deficits. In addition, we will present new prospects and future directions of investigation. PMID- 28855878 TI - Alexithymia and Suicide Risk in Psychiatric Disorders: A Mini-Review. AB - It is well known that alexithymic individuals may show significantly higher levels of anxiety, depression, and psychological suffering than non-alexithymics. There is an increasing evidence that alexithymia may be considered a risk factor for suicide, even simply increasing the risk of development of depressive symptoms or per se. Therefore, the purpose of this narrative mini-review was to elucidate a possible relationship between alexithymia and suicide risk. The majority of reviewed studies pointed out a relationship between alexithymia and an increased suicide risk. In several studies, this relationship was mediated by depressive symptoms. In conclusion, the importance of alexithymia screening in everyday clinical practice and the evaluation of clinical correlates of alexithymic traits should be integral parts of all disease management programs and, especially, of suicide prevention plans and interventions. However, limitations of studies are discussed and must be considered. PMID- 28855879 TI - How Social Communications Influence Advertising Perception and Response in Online Communities? AB - This research aims to explore how social communications of online communities affect users' perception and responses toward social media advertising. We developed a conceptual model based on the SBT, encapsulating 9 constructs and 10 hypothesis extracted from the extant social media advertising literature. Our research outcome proves that social communications can effectively boost users' behaviors to be in accordance with an online social community, thus facilitate their acceptance and responses toward social media advertising, with users' group intention as an intervening factor. From an operational standpoint, it's an effective way to build and maintain social bonds between users and the community by boosting social communications, supporting fluent interpersonal communications. In addition, managers of an online community should elaborate on users' group intentions to increase users' advertising acceptance and response. PMID- 28855880 TI - Effects of Cognitive Bias Modification Training via Smartphones. AB - Background and Objectives: Negative cognitive biases have been linked to anxiety and mood problems. Accumulated data from laboratory studies show that positive and negative interpretation styles with accompanying changes in mood can be induced through cognitive bias modification (CBM) paradigms. Despite the therapeutic potential of positive training effects, few studies have explored training paradigms administered via smartphones. The current study aimed to compare the effectiveness of three different types of training programmes (cognitive bias modification-attention, CBM-A; cognitive bias modification interpretation, CBM-I; attention and interpretation modification, AIM) administered via smart-phones by using a control condition (CC). Methods:Seventy six undergraduate participants with high social anxiety (Liebowitz Social Anxiety Scale, LSAS >= 30) were randomly assigned to four groups: CBM-A (n = 20), CBM-I (n = 20), AIM (n = 16), and CC (n = 20). Results: The results showed that the effects of CBM training, CBM-I training, or AIM training vs. CC for attention yielded no significant differences in dot-probe attention bias scores. The CBM-I group showed significantly less threat interpretation and more benign interpretation than the CC group on interpretation bias scores. Conclusions: The present results supported the feasibility of delivering CBM-I via smartphones, but the effectiveness of CBM-A and AIM training via smartphones was limited. PMID- 28855882 TI - Symmetrical and Asymmetrical Interactions between Facial Expressions and Gender Information in Face Perception. AB - To investigate the interaction between facial expressions and facial gender information during face perception, the present study matched the intensities of the two types of information in face images and then adopted the orthogonal condition of the Garner Paradigm to present the images to participants who were required to judge the gender and expression of the faces; the gender and expression presentations were varied orthogonally. Gender and expression processing displayed a mutual interaction. On the one hand, the judgment of angry expressions occurred faster when presented with male facial images; on the other hand, the classification of the female gender occurred faster when presented with a happy facial expression than when presented with an angry facial expression. According to the evoked-related potential results, the expression classification was influenced by gender during the face structural processing stage (as indexed by N170), which indicates the promotion or interference of facial gender with the coding of facial expression features. However, gender processing was affected by facial expressions in more stages, including the early (P1) and late (LPC) stages of perceptual processing, reflecting that emotional expression influences gender processing mainly by directing attention. PMID- 28855881 TI - Regulating Anger under Stress via Cognitive Reappraisal and Sadness. AB - Previous studies have reported the failure of cognitive emotion regulation (CER), especially in regulating unpleasant emotions under stress. The underlying reason for this failure was the application of CER depends heavily on the executive function of the prefrontal cortex (PFC), but this function can be impaired by stress-related neuroendocrine hormones. This observation highlights the necessity of developing self-regulatory strategies that require less top-down cognitive control. Based on traditional Chinese philosophy and medicine, which examine how different types of emotions promote or counteract one another, we have developed a novel emotion regulation strategy whereby one emotion is used to alter another. For example, our previous experiment showed that sadness induction (after watching a sad film) could reduce aggressive behavior associated with anger [i.e., "sadness counteracts anger" (SCA)] (Zhan et al., 2015). Relative to the CER strategy requiring someone to think about certain cognitive reappraisals to reinterpret the meaning of an unpleasant situation, watching a film or listening to music and experiencing the emotion contained therein seemingly requires less cognitive effort and control; therefore, this SCA strategy may be an alternative strategy that compensates for the limitations of cognitive regulation strategies, especially in stressful situations. The present study was designed to directly compare the effects of the CER and SCA strategy in regulating anger and anger related aggression in stressful and non-stressful conditions. Participants' subjective feeling of anger, anger-related aggressive behavior, skin conductance, and salivary cortisol and alpha-amylase levels were measured. Our findings revealed that acute stress impaired one's ability to use CR to control angry responses provoked by others, whereas stress did not influence the efficiency of the SCA strategy. Compared with sadness or neutral emotion induction, CER induction was found to reduce the level of subjective anger more, but this difference only existed in non-stressful conditions. By contrast, irrespective of stress, the levels of aggressive behavior and related skin conductance after sadness induction were both significantly lower than those after CER induction or neutral emotion induction, thus suggesting the immunity of the regulatory effect of SCA strategy to the stress factor. PMID- 28855883 TI - Long-term Practice with Domain-Specific Task Constraints Influences Perceptual Skills. AB - The long-term impact of practice with different task constraints on perceptual skill is relatively un-explored. This study examined the influence of extensive practice, i.e., more than a 1000 h of structured practice, with domain-specific task constraints on perceptual skill associated with the passing action. Despite performing the same passing skill, it is not known whether long-term exposure to specific soccer or futsal task constraints influences the players' attunement to environmental information. This study examined this issue by assessing the attention orientation of soccer (n = 24) and futsal players (n = 24) during modified games (6 vs. 6). Futsal players had higher scanning behavior during ball reception and control (40% more ball-player attention alternations) while soccer players mainly scanned the environment when not in ball possession (25% more attention alternations). We suggest that the behavioral differences found are elicited by the extensive domain-specific practice. That is, the higher number of players in soccer, and by a more intense game and easier to control ball in futsal. This study provides new insights into the long-term effects of practicing with specific task constraints. PMID- 28855884 TI - Consideration of Cosmetic Surgery As Part of Women's Benefit-Provisioning Mate Retention Strategy. AB - Individuals perform mate retention behaviors to minimize the risk of partner infidelity and relationship dissolution. The current study investigates whether consideration of cosmetic surgery can be conceptualized as part of a broader strategy of mate retention for women, but not men. We hypothesized that women's consideration of cosmetic surgery would be positively associated with performance frequencies of Benefit-Provisioning and Cost-Inflicting mate retention behaviors. We recruited 203 individuals (54% women) in committed heterosexual relationships from Tehran, Iran. Results indicate a positive association between consideration of cosmetic surgery and Benefit-Provisioning mate retention behaviors for women, but not men. There was no association between consideration of cosmetic surgery and Cost-Inflicting mate retention behaviors. Women therefore may consider cosmetic surgery to improve their physical attractiveness as part of a Benefit Provisioning strategy to retain a long-term mate. We discuss limitations of the study and highlight future directions for research from an evolutionary perspective. PMID- 28855885 TI - Laser Doppler Assessment of Vasomotor Axon Reflex Responsiveness to Evaluate Neurovascular Function. AB - The vasomotor axon reflex can be evoked in peripheral epidermal nociceptive C fibers to induce local vasodilation. This neurogenic flare response is a measure of C-fiber functional integrity and therefore shows impairment in patients with small fiber neuropathy. Laser Doppler flowmetry (LDF) and laser Doppler imaging (LDI) are both techniques to analyze vasomotor small fiber function by quantifying the integrity of the vasomotor-mediated axon reflex. While LDF assesses the flare response following acetylcholine iontophoresis with temporal resolution at a single defined skin point, LDI records flare responses with spatial and temporal resolution, generating a two-dimensional map of superficial blood flow. LDF is characterized by a high intra- and interindividual measurement variability, which is smaller in LDI due to its spatial resolution. Nevertheless, LDI still lacks standardized methods for image analysis. Consequently, use of the technique currently remains on an experimental level. Here, we sought to review the current literature on laser Doppler assessment of vasomotor function and discuss potential future applications of established techniques as well as those that are still experimental. PMID- 28855886 TI - Advanced Imaging of Intracranial Atherosclerosis: Lessons from Interventional Cardiology. AB - Intracranial atherosclerosis is a major cause of ischemic stroke. Patients with a high degree of stenosis have a significant rate of stroke despite medical therapy. Two randomized trials of stenting have failed to show benefit. Improving periprocedural complication rates and patient selection may improve stenting outcomes. Fractional flow reserve (FFR), intravascular ultrasound (IVUS), and optical coherence tomography (OCT) are intravascular imaging techniques employed to improve patient selection and stent placement in interventional cardiology. FFR has been shown to improve cardiovascular outcomes when used in patient selection for intervention. Studies of FFR in intracranial atherosclerosis show that the measure may predict which plaques lead to stroke. IVUS is used in cardiology to quantify stenosis and assist with stent placement. Comparisons with histology show that it can reliably characterize plaques. Several case reports of IVUS in intracranial arteries show the technique to be feasible and indicate it may improve stent placement. Plaque characteristics on IVUS may help identify vulnerable plaques. In interventional cardiology, OCT provides excellent visualization of vessel geometry and is useful periprocedurally. Images reliably identify thin-capped fibroatheromas and other plaque features. Case reports indicate that OCT is safe for use in intracranial arteries. OCT can be used to identify perforator vessels and so may be useful in avoiding perforator strokes, a common complication of stenting. Plaque characteristics on OCT may be useful in patient selection. PMID- 28855887 TI - Identification of Characteristic Motor Patterns Preceding Freezing of Gait in Parkinson's Disease Using Wearable Sensors. AB - Freezing of gait (FOG) is a disabling symptom that is common among patients with advanced Parkinson's disease (PD). External cues such as rhythmic auditory stimulation can help PD patients experiencing freezing to resume walking. Wearable systems for automatic freezing detection have been recently developed. However, these systems detect a FOG episode after it has happened. Instead, in this study, a new approach for the prediction of FOG (before it actually happens) is presented. Prediction of FOG might enable preventive cueing, reducing the likelihood that FOG will occur. Moreover, understanding the causes and circumstances of FOG is still an open research problem. Hence, a quantitative characterization of movement patterns just before FOG (the pre-FOG phase) is of great importance. In this study, wearable inertial sensors were used to identify and quantify the characteristics of gait during the pre-FOG phase and compare them with the characteristics of gait that do not precede FOG. The hypothesis of this study is based on the threshold-based model of FOG, which suggests that before FOG occurs, there is a degradation of the gait pattern. Eleven PD subjects were analyzed. Six features extracted from movement signals recorded by inertial sensors showed significant differences between gait and pre-FOG. A classification algorithm was developed in order to test if it is feasible to predict FOG (i.e., detect it before it happens). The aim of the classification procedure was to identify the pre-FOG phase. Results confirm that there is a degradation of gait occurring before freezing. Results also provide preliminary evidence on the feasibility of creating an automatic algorithm to predict FOG. Although some limitations are present, this study shows promising findings for characterizing and identifying pre-FOG patterns, another step toward a better understanding, prediction, and prevention of this disabling symptom. PMID- 28855889 TI - l-DOPA and Freezing of Gait in Parkinson's Disease: Objective Assessment through a Wearable Wireless System. AB - Freezing of gait (FOG) is a leading cause of falls and fractures in Parkinson's disease (PD). The episodic and rather unpredictable occurrence of FOG, coupled with the variable response to l-DOPA of this gait disorder, makes the objective evaluation of FOG severity a major clinical challenge in the therapeutic management of patients with PD. The aim of this study was to examine and compare gait, clinically and objectively, in patients with PD, with and without FOG, by means of a new wearable system. We also assessed the effect of l-DOPA on FOG severity and specific spatiotemporal gait parameters in patients with and without FOG. To this purpose, we recruited 28 patients with FOG, 16 patients without FOG, and 16 healthy subjects. In all participants, gait was evaluated clinically by video recordings and objectively by means of the wearable wireless system, during a modified 3-m Timed Up and Go (TUG) test. All patients performed the modified TUG test under and not under dopaminergic therapy (ON and OFF therapy). By comparing instrumental data with the clinical identification of FOG based on offline video-recordings, we also assessed the performance of the wearable system to detect FOG automatically in terms of sensitivity, specificity, positive and negative predictive values, and finally accuracy. TUG duration was longer in patients than in controls, and the amount of gait abnormalities was prominent in patients with FOG compared with those without FOG. l-DOPA improved gait significantly in patients with PD and particularly in patients with FOG mainly by reducing FOG duration and increasing specific spatiotemporal gait parameters. Finally, the overall wireless system performance in automatic FOG detection was characterized by excellent sensitivity (93.41%), specificity (98.51%), positive predictive value (89.55%), negative predictive value (97.31%), and finally accuracy (98.51%). Our study overall provides new information on the beneficial effect of l-DOPA on FOG severity and specific spatiotemporal gait parameters as objectively measured by a wearable sensory system. The algorithm here reported potentially opens to objective long-time sensing of FOG episodes in patients with PD. PMID- 28855888 TI - The Experience of Essential Tremor Caregivers: Burden and Its Correlates. AB - BACKGROUND: Essential tremor (ET) is associated with physical and cognitive impairments, as well as embarrassment, avoidance of social settings, and related difficulties that negatively impact the lives of patients. In similar disease contexts, burden on friends and relatives acting as caregivers has been noted and has well-documented implications. There has been no study examining caregiver burden related to ET. METHODS: Data were gathered from 55 ET participants enrolled in a clinical study and their caregivers. The Zarit Burden Interview was used to assess caregiver burden. To assess clinical features that may be associated with burden, we collected several variables including the Montreal Cognitive Assessment, self-reported tremor disability, a videotaped neurological examination, questionnaires assessing ET participants' suffering, caregivers' perceptions of that suffering, and both caregiver and ET participant depressive symptoms. Spearman's correlations were performed between caregiver burden and clinical features, and we created a multivariate linear regression model predicting caregiver burden. RESULTS: Many ET caregivers provide little to no care and experience little to no burden. However, some caregivers (11%) provide over 25 h of care/week, and 13% experience high levels of burden. Caregivers most commonly provided assistance with writing and cooking. Increased burden was associated with the ET participants' decreased cognition, more caregiving tasks, more hours/week of caregiving activities, a longer duration of care, more ET participant falls/year, more medications taken by the ET participant, and more depressive symptoms in both the ET participant and the caregiver (all p < 0.05). ET participants' suffering and their caregivers' perceptions of suffering were both associated with increased burden. Neither tremor severity score nor self reported tremor disability score was associated with increased caregiver burden. Using a multivariate linear regression model, we found that caregivers' increased perception of their partners' suffering was the best predictor of caregiver burden. CONCLUSION: While not all relatives and friends of ET patients provide extensive care or experience high burden, there is a group reporting high levels of caregiver burden that requires the attention and counseling of clinicians. This burden is associated with primarily non-tremor symptoms of ET and with caregivers' perception that their partners are suffering. PMID- 28855890 TI - Arginine Vasotocin Preprohormone Is Expressed in Surprising Regions of the Teleost Forebrain. AB - Nonapeptides play a fundamental role in the regulation of social behavior, among numerous other functions. In particular, arginine vasopressin and its non mammalian homolog, arginine vasotocin (AVT), have been implicated in regulating affiliative, reproductive, and aggressive behavior in many vertebrate species. Where these nonapeptides are synthesized in the brain has been studied extensively in most vertebrate lineages. While several hypothalamic and forebrain populations of vasopressinergic neurons have been described in amniotes, the consensus suggests that the expression of AVT in the brain of teleost fish is limited to the hypothalamus, specifically the preoptic area (POA) and the anterior tuberal nucleus (putative homolog of the mammalian ventromedial hypothalamus). However, as most studies in teleosts have focused on the POA, there may be an ascertainment bias. Here, we revisit the distribution of AVT preprohormone mRNA across the dorsal and ventral telencephalon of a highly social African cichlid fish. We first use in situ hybridization to map the distribution of AVT preprohormone mRNA across the telencephalon. We then use quantitative real time polymerase chain reaction to assay AVT expression in the dorsomedial telencephalon, the putative homolog of the mammalian basolateral amygdala. We find evidence for AVT preprohormone mRNA in regions previously not associated with the expression of this nonapeptide, including the putative homologs of the mammalian extended amygdala, hippocampus, striatum, and septum. In addition, AVT preprohormone mRNA expression within the basolateral amygdala homolog differs across social contexts, suggesting a possible role in behavioral regulation. We conclude that the surprising presence of AVT preprohormone mRNA within dorsal and medial telencephalic regions warrants a closer examination of possible AVT synthesis locations in teleost fish, and that these may be more similar to what is observed in mammals and birds. PMID- 28855891 TI - Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines. AB - The hypothalamus is a key brain region in the regulation of energy balance as it controls food intake and both energy storage and expenditure through integration of humoral, neural, and nutrient-related signals and cues. Many years of research have focused on the regulation of energy balance by hypothalamic neurons, but the most recent findings suggest that neurons and glial cells, such as microglia and astrocytes, in the hypothalamus actually orchestrate together several metabolic functions. Because glial cells have been described as mediators of inflammatory processes in the brain, the existence of a causal link between hypothalamic inflammation and the deregulations of feeding behavior, leading to involuntary weight loss or obesity for example, has been suggested. Several inflammatory pathways that could impair the hypothalamic control of energy balance have been studied over the years such as, among others, toll-like receptors and canonical cytokines. Yet, less studied so far, chemokines also represent interesting candidates that could link the aforementioned pathways and the activity of hypothalamic neurons. Indeed, chemokines, in addition to their role in attracting immune cells to the inflamed site, have been suggested to be capable of neuromodulation. Thus, they could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators involved in the maintenance of energy balance. This review discusses the different inflammatory pathways that have been identified so far in the hypothalamus in the context of feeding behavior and body weight control impairments, with a particular focus on chemokines signaling that opens a new avenue in the understanding of the major role played by inflammation in obesity. PMID- 28855892 TI - Albuminuria Reduction after High Dose of Vitamin D in Patients with Type 1 Diabetes Mellitus: A Pilot Study. AB - BACKGROUND: Some studies suggest an association between diabetic kidney disease (DKD) and vitamin D (VD), but there is no data about the effect of high dose of VD on DKD in type 1 diabetes mellitus (T1DM). Our pilot study aims to evaluate albuminuria reduction in patients with T1DM supplemented with high dose of VD. METHODS: 22 patients received doses of 4,000 and 10,000 IU/day of cholecalciferol for 12 weeks according to patient's previous VD levels. They were submitted to continuous glucose monitoring system, 24 hours ambulatory blood pressure monitoring and urine albumin-to-creatinine ratio before and after VD supplementation. RESULTS: There was a reduction of DKD prevalence at the end of the study (68 vs 32%; p = 0.05), with no changes on insulin doses, glycated hemoglobin, glycemic variability and blood pressure values. A correlation between percentage variation of VD levels (DeltaVD) and albuminuria at the end of the study was presented (r = -0.5; p < 0.05). Among T1DM patients with DKD at the beginning of the study, 8/13 (62%) had their DKD stage improved, while the other five ones (38%) showed no changes (p < 0.05). CONCLUSION: Our pilot study suggests an association between VD high dose supplementation, lower prevalence and improvement in stages of DKD in T1DM. PMID- 28855893 TI - NQO-Induced DNA-Less Cell Formation Is Associated with Chromatin Protein Degradation and Dependent on A0A1-ATPase in Sulfolobus. AB - To investigate DNA damage response in the model crenarchaeon Sulfolobus islandicus, four different DNA damage agents were tested for their effects on cell death of this archaeon, including UV irradiation, methyl methanesulfonate, cisplatin, and 4-nitroquinoline 1-oxide (NQO). Cell death featured with DNA-less cell formation was revealed in DNA damage treatment with each agent. Cellular responses upon NQO treatment were characterized in details, and following sequential events were revealed, including: a modest accumulation of G1/S phase cells, membrane depolarization, proteolytic degradation of chromatin proteins, and chromosomal DNA degradation. Further insights into the process were gained from studying drugs that affect the archaeal ATP synthase, including a proton gradient uncoupler and an ATP synthase inhibitor. Whereas the proton uncoupler mediated excess proton influx yielded cell death as observed for the NQO treatment, inhibition of ATP synthase attenuated NQO-induced membrane depolarization and DNA-less cell formation. In conclusion, the NQO-induced cell death in S. islandicus is characterized by proteolytic degradation of chromatin protein, and chromosomal DNA degradation, which probably represents a common feature for the cell death induced by different DNA damage agents. PMID- 28855894 TI - Rapid Flow Cytometry Detection of a Single Viable Escherichia coli O157:H7 Cell in Raw Spinach Using a Simplified Sample Preparation Technique. AB - Very low cell count detection of Escherichia coli O157:H7 in foods is critical, since an infective dose for this pathogen may be only 10 cells, and fewer still for vulnerable populations. A flow cytometer is able to detect and count individual cells of a target bacterium, in this case E. coli O157:H7. The challenge is to find the single cell in a complex matrix like raw spinach. To find that cell requires growing it as quickly as possible to a number sufficiently in excess of matrix background that identification is certain. The experimental design for this work was that of a U.S. Food and Drug Administration (FDA) In-House Level 3 validation executed in the technology's originating laboratory. Using non-selective enrichment broth, 6.5 h incubation at 42 degrees C, centrifugation for target cell concentration, and a highly selective E. coli O157 fluorescent antibody tag, the cytometry method proved more sensitive than a reference regulatory method (p = 0.01) for detecting a single target cell, one E. coli O157:H7 cell, in 25 g of spinach. It counted that cell's daughters with at least 38* signal-to-noise ratio, analyzing 25 samples in total-time-to-results of 9 h. PMID- 28855895 TI - The Rhizosphere Bacterial Microbiota of Vitis vinifera cv. Pinot Noir in an Integrated Pest Management Vineyard. AB - Microorganisms associated with Vitis vinifera (grapevine) can affect its growth, health and grape quality. The aim of this study was to unravel the biodiversity of the bacterial rhizosphere microbiota of grapevine in an integrated pest management vineyard located in Piedmont, Italy. Comparison between the microbial community structure in the bulk and rhizosphere soil (variable: space) were performed. Moreover, the possible shifts of the bulk and rhizosphere soil microbiota according to two phenological stages such as flowering and early fruit development (variable: time) were characterized. The grapevine microbiota was identified using metagenomics and next-generation sequencing. Biodiversity was higher in the rhizosphere than in the bulk soil, independent of the phenological stage. Actinobacteria were the dominant class with frequencies >= 50% in all the soil samples, followed by Proteobacteria, Gemmatimonadetes, and Bacteroidetes. While Actinobacteria and Proteobacteria are well-known as being dominant in soil, this is the first time the presence of Gemmatimonadetes has been observed in vineyard soils. Gaiella was the dominant genus of Actinobacteria in all the samples. Finally, the microbiota associated with grapevine differed from the bulk soil microbiota and these variations were independent of the phenological stage of the plant. PMID- 28855896 TI - Role of Age-Related Shifts in Rumen Bacteria and Methanogens in Methane Production in Cattle. AB - Rumen microbiota are essential for maintaining digestive and metabolic functions, producing methane as a byproduct. Dairy heifers produce large amounts of methane based on fermentation of digested organic matter, with adverse consequences for feed efficiency and the environment. It is therefore important to understand the influence of host age on the relationship between microbiota and methane production. This study explored the age effect on the relationship between microbial communities and enteric methane production in dairy cows and heifers using high-throughput sequencing. Methane production and volatile fatty acid concentrations were age-related. Heifers (9-10 months) had lower methane production but higher methane production per dry matter intake (DMI). The acetate:propionate ratio decreased significantly with increasing age. Age-related microbiota changes in the rumen were reflected by a significant shift in bacterial taxa, but relatively stable archaeal taxa. Prevotella, Ruminococcus, Flavonifractor, Succinivibrio, and Methanobrevibacter were affected by age. This study revealed different associations between predominant bacterial phylotypes and Methanobrevibacter with increasing age. Prevotella was strongly correlated with Methanobrevibacter in heifers; howerver, in older cows (96-120 months) this association was replaced by a correlation between Succinivibrio and Methanobrevibacter. This shift may account for the age-related difference in rumen fermentation and methane production per DMI. PMID- 28855897 TI - Corrigendum: Growth Inhibitory Effects of Adhatoda vasica and Its Potential at Reducing Listeria monocytogenes in Chicken Meat. AB - [This corrects the article on p. 1260 in vol. 8, PMID: 28769879.]. PMID- 28855898 TI - Quantitative Analysis of Repertoire-Scale Immunoglobulin Properties in Vaccine Induced B-Cell Responses. AB - Recent advances in the next-generation sequencing of B-cell receptors (BCRs) enable the characterization of humoral responses at a repertoire-wide scale and provide the capability for identifying unique features of immune repertoires in response to disease, vaccination, or infection. Immunosequencing now readily generates 103-105 sequences per sample; however, statistical analysis of these repertoires is challenging because of the high genetic diversity of BCRs and the elaborate clonal relationships among them. To date, most immunosequencing analyses have focused on reporting qualitative trends in immunoglobulin (Ig) properties, such as usage or somatic hypermutation (SHM) percentage of the Ig heavy chain variable (IGHV) gene segment family, and on reducing complex Ig property distributions to simple summary statistics. However, because Ig properties are typically not normally distributed, any approach that fails to assess the distribution as a whole may be inadequate in (1) properly assessing the statistical significance of repertoire differences, (2) identifying how two repertoires differ, and (3) determining appropriate confidence intervals for assessing the size of the differences and their potential biological relevance. To address these issues, we have developed a technique that uses Wilcox' robust statistics toolbox to identify statistically significant vaccine-specific differences between Ig repertoire properties. The advantage of this technique is that it can determine not only whether but also where the distributions differ, even when the Ig repertoire properties are non-normally distributed. We used this technique to characterize murine germinal center (GC) B-cell repertoires in response to a complex Ebola virus-like particle (eVLP) vaccine candidate with known protective efficacy. The eVLP-mediated GC B-cell responses were highly diverse, consisting of thousands of clonotypes. Despite this staggering diversity, we identified statistically significant differences between non immunized, vaccine only, and vaccine-plus-adjuvant groups in terms of Ig properties, including IGHV-family usage, SHM percentage, and characteristics of the BCR complementarity-determining region. Most notably, our analyses identified a robust eVLP-specific feature-enhanced IGHV8-family usage in B-cell repertoires. These findings demonstrate the utility of our technique in identifying statistically significant BCR repertoire differences following vaccination. More generally, our approach is potentially applicable to a wide range of studies in infection, vaccination, auto-immunity, and cancer. PMID- 28855899 TI - Negative Correlation between Circulating CD4+FOXP3+CD127- Regulatory T Cells and Subsequent Antibody Responses to Infant Measles Vaccine but Not Diphtheria Tetanus-Pertussis Vaccine Implies a Regulatory Role. AB - Regulatory T cells (Tregs) play a key homeostatic role by suppressing immune responses. They have been targeted in mouse and human cancer studies to improve vaccine immunogenicity and tumor clearance. A number of commercially available drugs and experimental vaccine adjuvants have been shown to target Tregs. Infants have high numbers of Tregs and often have poor responses to vaccination, yet the role Tregs play in controlling vaccine immunogenicity has not been explored in this age group. Herein, we explore the role of CD4+FOXP3+CD127- Tregs in controlling immunity in infant males and females to vaccination with diphtheria tetanus-whole cell pertussis (DTP) and/or measles vaccine (MV). We find correlative evidence that circulating Tregs at the time of vaccination suppress antibody responses to MV but not DTP; and Tregs 4 weeks after DTP vaccination may suppress vaccine-specific cellular immunity. This opens the exciting possibility that Tregs may provide a future target for improved vaccine responses in early life, including reducing the number of doses of vaccine required. Such an approach would need to be safe and the benefits outweigh the risks, thus further research in this area is required. PMID- 28855900 TI - DT-13 Ameliorates TNF-alpha-Induced Vascular Endothelial Hyperpermeability via Non-Muscle Myosin IIA and the Src/PI3K/Akt Signaling Pathway. AB - DT-13(25(R,S)-ruscogenin-1-O-[beta-d-glucopyranosyl-(1->2)][beta-d-xylopyranosyl (1->3)]-beta-d-fucopyranoside) has been identified as an important factor in TNF alpha-induced vascular inflammation. However, the effect of DT-13 on TNF-alpha induced endothelial permeability and the potential molecular mechanisms remain unclear. Hence, this study was undertaken to elucidate the protective effect of DT-13 on TNF-alpha-induced endothelial permeability and the underlying mechanisms in vivo and in vitro. The in vivo results showed that DT-13 could ameliorate endothelial permeability in mustard oil-induced plasma leakage in the skin and modulate ZO-1 organization. In addition, the in vitro results showed that pretreatment with DT-13 could increase the transendothelial electrical resistance value and decrease the sodium fluorescein permeability coefficient. Moreover, DT 13 altered the mRNA and protein levels of ZO-1 as determined by real-time PCR, Western blotting, and immunofluorescence analyses. DT-13 treatment decreased the phosphorylations of Src, PI3K, and Akt in TNF-alpha-treated human umbilical vein endothelial cells (HUVECs). Further analyses with PP2 (10 uM, inhibitor of Src) indicated that DT-13 modulated endothelial permeability in TNF-alpha-induced HUVECs in an Src-dependent manner. LY294002 (10 uM, PI3K inhibitor) also had the same effect on DT-13 but did not affect phosphorylation of Src. Following decreased expression of non-muscle myosin IIA (NMIIA), the effect of DT-13 on the phosphorylations of Src, PI3K, and Akt was abolished. This study provides pharmacological evidence showing that DT-13 significantly ameliorated the TNF alpha-induced vascular endothelial hyperpermeability through modulation of the Src/PI3K/Akt pathway and NMIIA, which play an important role in this process. PMID- 28855902 TI - Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans. AB - To elucidate the role of innate responses in vaccine immunogenicity, we compared early responses to hepatitis B virus (HBV) surface antigen (HBsAg) combined with different Adjuvant Systems (AS) in healthy HBV-naive adults, and included these parameters in multi-parametric models of adaptive responses. A total of 291 participants aged 18-45 years were randomized 1:1:1:1:1 to receive HBsAg with AS01B, AS01E, AS03, AS04, or Alum/Al(OH)3 at days 0 and 30 (ClinicalTrials.gov: NCT00805389). Blood protein, cellular, and mRNA innate responses were assessed at early time-points and up to 7 days after vaccination, and used with reactogenicity symptoms in linear regression analyses evaluating their correlation with HBs-specific CD4+ T-cell and antibody responses at day 44. All AS induced transient innate responses, including interleukin (IL)-6 and C reactive protein (CRP), mostly peaking at 24 h post-vaccination and subsiding to baseline within 1-3 days. After the second but not the first injection, median interferon (IFN)-gamma levels were increased in the AS01B group, and IFN-gamma inducible protein-10 levels and IFN-inducible genes upregulated in the AS01 and AS03 groups. No distinct marker or signature was specific to one particular AS. Innate profiles were comparable between AS01B, AS01E, and AS03 groups, and between AS04 and Alum groups. AS group rankings within adaptive and innate response levels and reactogenicity prevalence were similar (AS01B >= AS01E > AS03 > AS04 > Alum), suggesting an association between magnitudes of inflammatory and vaccine responses. Modeling revealed associations between adaptive responses and specific traits of the innate response post-dose 2 (activation of the IFN signaling pathway, CRP and IL-6 responses). In conclusion, the ability of AS01 and AS03 to enhance adaptive responses to co-administered HBsAg is likely linked to their capacity to activate innate immunity, particularly the IFN-signaling pathway. PMID- 28855904 TI - Immunological Properties of Murine Parthenogenetic Stem Cell-Derived Cardiomyocytes and Engineered Heart Muscle. AB - Pluripotent parthenogenetic stem cells (pSCs) can be derived by pharmacological activation of unfertilized oocytes. Homozygosity of the major histocompatibility complex (MHC) in pSCs makes them an attractive cell source for applications in allogeneic tissue repair. This was recently demonstrated for pSC-based tissue engineered heart repair. A detailed analysis of immunological properties of pSC derived cardiomyocytes and engineered heart muscle (EHM) thereof is, however, lacking. The aim of this study was to determine baseline and cytokine-inducible MHC class I and MHC class II as well as programmed death ligand-1 (PDL-1) and co stimulatory protein (CD40, CD80, CD86) expression in pSC-derived cardiomyocytes and pSC-EHM in vitro and in vivo. Cardiomyocytes from an MHC-homologous (H2d/d) pSC-line were enriched to ~90% by making use of a recently developed cardiomyocyte-specific genetic selection protocol. MHC class I and MHC class II expression in cardiomyocytes could only be observed after stimulation with interferon gamma (IFN-gamma). PDL-1 was markedly upregulated under IFN-gamma. CD40, CD80, and CD86 were expressed at low levels and not upregulated by IFN gamma. EHM constructed from H2d/d cardiomyocytes expressed similarly low levels of MHC class I, MHC class II, and costimulatory molecules under basal conditions. However, in EHM only MHC class I, but not MHC class II, molecules were upregulated after IFN-gamma-stimulation. We next employed a cocultivation system with MHC-matched and MHC-mismatched splenocytes and T-cells to analyze the immune stimulatory properties of EHMs. Despite MHC-mismatched conditions, EHM did not induce splenocyte or T-cell proliferation in vitro. To evaluate the immunogenicity of pSC-derived cardiomyocytes in vivo, we implanted pSC-derived embryoid bodies after elimination of non-cardiomyocytes (cardiac bodies) under the kidney capsules of MHC-matched and -mismatched mice. Spontaneous beating of cardiac bodies could be observed for 28 days in the matched and for 7 days in the mismatched conditions. Teratomas formed after 28 days only in the MHC-matched conditions. Immunohistochemistry revealed single clusters of CD3-positive cells in the border zone of the implant in the mismatched conditions with few CD3 positive cells infiltrating the implant. Taken together, MHC-matched pSC cardiomyocyte allografts show little immune cell activation, offering an explanation for the observed long-term retention of pSC-EHM allografts in the absence of immunosuppression. PMID- 28855903 TI - Impact of Depleting Therapeutic Monoclonal Antibodies on the Host Adaptive Immunity: A Bonus or a Malus? AB - Clinical responses to anti-tumor monoclonal antibody (mAb) treatment have been regarded for many years only as a consequence of the ability of mAbs to destroy tumor cells by innate immune effector mechanisms. More recently, it has also been shown that anti-tumor antibodies can induce a long-lasting anti-tumor adaptive immunity, likely responsible for durable clinical responses, a phenomenon that has been termed the vaccinal effect of antibodies. However, some of these anti tumor antibodies are directed against molecules expressed both by tumor cells and normal immune cells, in particular lymphocytes, and, hence, can also strongly affect the host adaptive immunity. In addition to a delayed recovery of target cells, lymphocyte depleting-mAb treatments can have dramatic consequences on the adaptive immune cell network, its rebound, and its functional capacities. Thus, in this review, we will not only discuss the mAb-induced vaccinal effect that has emerged from experimental preclinical studies and clinical trials but also the multifaceted impact of lymphocytes-depleting therapeutic antibodies on the host adaptive immunity. We will also discuss some of the molecular and cellular mechanisms of action whereby therapeutic mAbs induce a long-term protective anti tumor effect and the relationship between the mAb-induced vaccinal effect and the immune response against self-antigens. PMID- 28855901 TI - Interactions between Intestinal Microbiota and Host Immune Response in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Although the etiology and pathogenesis of IBD remain unclear, both genetic susceptibility and environmental factors are implicated in the initiation and progression of IBD. Recent studies with experimental animal models and clinical patients indicated that the intestinal microbiota is one of the critical environmental factors that influence nutrient metabolism, immune responses, and the health of the host in various intestinal diseases, including ulcerative colitis and Crohn's disease. The objective of this review is to highlight the crosstalk between gut microbiota and host immune response and the contribution of this interaction to the pathogenesis of IBD. In addition, potential therapeutic strategies targeting the intestinal micro-ecosystem in IBD are discussed. PMID- 28855905 TI - Mesenchymal Stem Cells May Ameliorate Nephrotic Syndrome Post-Allogeneic Hematopoietic Stem Cell Transplantation-Case Report. AB - INTRODUCTION: Because of their immunomodulatory and anti-inflammatory effects, mesenchymal stem cells (MSCs) have been considered as potential therapeutic agents for treating immune-related or autoimmune diseases, such as graft-versus host disease (GVHD). Nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an uncommon complication with unclear etiology and pathogenesis. It may be an immune disorder involving immune complex deposition, B cells, regulatory T cells (Tregs), and Th1 cytokines and be a manifestation of chronic GVHD. Corticosteroids and calcium antagonists, alone or in combination, are the most common therapeutic agents in this setting. Rituximab is commonly administered as salvage treatment. However, treatment failure and progressive renal function deterioration has been reported to occur in approximately 20% of patients in a particular cohort. CASE PRESENTATION: We present a patient who developed NS 10 months after allo-HSCT. After treatment failure with cyclosporine A, prednisone, and rituximab, she achieved a complete response with MSC treatment. The clinical improvement of this patient was accompanied by a decreased B cell population together with an increased frequency of regulatory B cells (Bregs) and Tregs after MSC treatment. CONCLUSION: MSCs could modulate NS after allo-HSCT by suppressing B cell proliferation, inducing Tregs and Bregs, and inhibiting inflammatory cytokine production by monocytes and NK cells. Among all these, Bregs might play an important role in ameliorating the NS of this patient. PMID- 28855907 TI - Intrinsic and Extrinsic Properties Affecting Innate Immune Responses to Nanoparticles: The Case of Cerium Oxide. AB - We review the apparent discrepancies between studies that report anti inflammatory effects of cerium oxide nanoparticles (CeO2 NPs) through their reactive oxygen species-chelating properties and immunological studies highlighting their toxicity. We observe that several underappreciated parameters, such as aggregation size and degree of impurity, are critical determinants that need to be carefully addressed to better understand the NP biological effects in order to unleash their potential clinical benefits. This is because NPs can evolve toward different states, depending on the environment where they have been dispersed and how they have been dispersed. As a consequence, final characteristics of NPs can be very different from what was initially designed and produced in the laboratory. Thus, aggregation, corrosion, and interaction with extracellular matrix proteins critically modify NP features and fate. These modifications depend to a large extent on the characteristics of the biological media in which the NPs are dispersed. As a consequence, when reviewing the scientific literature, it seems that the aggregation state of NPs, which depends on the characteristics of the dispersing media, may be more significant than the composition or original size of the NPs. In this work, we focus on CeO2 NPs, which are reported sometimes to be protective and anti-inflammatory, and sometimes toxic and pro-inflammatory. PMID- 28855906 TI - Memory of Natural Killer Cells: A New Chance against Mycobacterium tuberculosis? AB - Natural killer (NK) cells are lymphocytes of the innate immune system, which play an important role in the initial defense against a wide variety of pathogens, including viruses and intracellular bacteria. NK cells produce cytokines that enhance immune responses directed toward pathogens and also exert cytotoxic activity against infected cells, thereby eliminating the reservoir of infection. Their role in defense against Mycobacterium tuberculosis (Mtb) has been recently studied, and there is increasing evidence that highlight the importance of NK cell function during pulmonary tuberculosis (PTB), especially in the absence of optimal T-cell responses. Additionally, in the last years, it has been observed that NK cells mediate secondary responses against antigens to which they were previously exposed, an ability classically attributed to lymphocytes of the adaptive branch of immunity. This phenomenon, called "innate memory," could have important implications in the efforts to develop therapies and vaccines to improve the initial phases of immune reactions against different microorganisms, especially those to which there is not yet available vaccines to prevent infection, as is the case for tuberculosis. Therefore, the possibility of inducing memory-like NK cells ready to act prior to contact with Mtb or during the earliest stages of infection becomes quite interesting. However, our understanding of the mechanisms of innate memory remains incomplete. Here, we review recent literature about the mechanisms involved in the formation and maintenance of NK cell memory and the role of these cells in the immune response during tuberculosis. Finally, we discuss if the current evidence is sufficient to substantiate that NK cells exert more rapid and robust secondary responses after consecutive encounters with Mtb. PMID- 28855908 TI - Cytokine and Chemokines Alterations in the Endemic Form of Pemphigus Foliaceus (Fogo Selvagem). AB - INTRODUCTION: The endemic form (fogo selvagem-FS) of pemphigus foliaceus is an autoimmune disease characterized by the presence of IgG autoantibodies against desmoglein-1. Despite the array of findings, the role of chemokines and cytokines that dictate the immune response and disease outcome is still poorly investigated. MATERIALS AND METHODS: Serum from 64 patients diagnosed with FS was used to draw and establish the levels of these molecules on this disease and establish the levels of these molecules with the severity of FS, and influence of treatment. RESULTS: In comparison to healthy subjects, FS patients, newly diagnosed and still without therapeutic intervention, had higher levels of IL-22 and CXCL-8, and reduced levels of IFN-gamma, IL-2, IL-15, and CCL-11. Furthermore, treatment using immunosuppressant drugs augmented the production of IFN-gamma, IL-2, CCL-5, and CCL-11 besides reducing the levels of IL-22 and CXCL 10. Immunosuppressive therapy seemed to have long-lasting effects on the production of higher amounts of IFN-gamma, IL-2, and CCL-5, besides keeping lowered the levels of IL-22 in remission FS patients. CONCLUSION: Taken together, our findings suggest a putative role of IL-22 in the pathogenesis of FS. Finally, data presented here may contribute for better understanding the immune aspects that control disease outcome. PMID- 28855909 TI - Antibiosis and bmyB Gene Presence As Prevalent Traits for the Selection of Efficient Bacillus Biocontrol Agents against Crown Gall Disease. AB - This study aimed to improve the screening method for the selection of Bacillus biocontrol agents against crown gall disease. The relationship between the strain biocontrol ability and their in vitro studied traits was investigated to identify the most important factors to be considered for the selection of effective biocontrol agents. In fact, previous selection procedure relying only on in vitro antibacterial activity was shown to be not suitable in some cases. A direct plant protection strategy was performed to screen the 32 Bacillus biocontrol agent candidates. Moreover, potential in vitro biocontrol traits were investigated including biofilm formation, motility, hemolytic activity, detection of lipopeptide biosynthetic genes (sfp, ituC and bmyB) and production of antibacterial compounds. The obtained results indicated high correlations of the efficiency of the biocontrol with the reduction of gall weight (p = 0.000) and the antibacterial activity in vitro (p = 0.000). Moreover, there was strong correlations of the efficiency of the biocontrol (p = 0.004) and the reduction in gall weight (p = 0.000) with the presence of the bmyB gene. This gene directs the synthesis of the lipopeptide bacillomycin belonging to the iturinic family of lipopeptides. These results were also confirmed by the two-way hierarchical cluster analysis and the correspondence analysis showing the relatedness of these four variables. According to the obtained results a new screening procedure of Bacillus biocontrol agents against crown gall disease could be advanced consisting on two step selection procedure. The first consists on selecting strains with high antibacterial activity in vitro or those harbouring the bmyB gene. Further selection has to be performed on tomato plants in vivo. Moreover, based on the results of the biocontrol assay, five potent strains exhibiting high biocontrol abilities were selected. They were identified as Bacillus subtilis or Bacillus amyloliquefaciens. These strains were found to produce either surfactin or surfactin and iturin lipopeptides. In conclusion, our study presented a new and effective method to evaluate the biocontrol ability of antagonistic Bacillus strains against crown gall disease that could increase the efficiency of screening method of biocontrol agents. Besides, the selected strains could be used as novel biocontrol agents against pathogenic Agrobacterium tumefaciens strains. PMID- 28855910 TI - Perspective Research Progress in Cold Responses of Capsella bursa-pastoris. AB - Plants respond to cold stress by modulating biochemical pathways and array of molecular events. Plant morphology is also affected by the onset of cold conditions culminating at repression in growth as well as yield reduction. As a preventive measure, cascades of complex signal transduction pathways are employed that permit plants to endure freezing or chilling periods. The signaling pathways and related events are regulated by the plant hormonal activity. Recent investigations have provided a prospective understanding about plant response to cold stress by means of developmental pathways e.g., moderate growth involved in cold tolerance. Cold acclimation assays and bioinformatics analyses have revealed the role of potential transcription factors and expression of genes like CBF, COR in response to low temperature stress. Capsella bursa-pastoris is a considerable model plant system for evolutionary and developmental studies. On different occasions it has been proved that C. bursa-pastoris is more capable of tolerating cold than A. thaliana. But, the mechanism for enhanced low or freezing temperature tolerance is still not clear and demands intensive research. Additionally, identification and validation of cold responsive genes in this candidate plant species is imperative for plant stress physiology and molecular breeding studies to improve cold tolerance in crops. We have analyzed the role of different genes and hormones in regulating plant cold resistance with special reference to C. bursa-pastoris. Review of collected data displays potential ability of Capsella as model plant for improvement in cold stress regulation. Information is summarized on cold stress signaling by hormonal control which highlights the substantial achievements and designate gaps that still happen in our understanding. PMID- 28855911 TI - Plant Glyoxylate/Succinic Semialdehyde Reductases: Comparative Biochemical Properties, Function during Chilling Stress, and Subcellular Localization. AB - Plant NADPH-dependent glyoxylate/succinic semialdehyde reductases 1 and 2 (cytosolic GLYR1 and plastidial/mitochondrial GLYR2) are considered to be of particular importance under abiotic stress conditions. Here, the apple (Malus * domestica Borkh.) and rice (Oryza sativa L.) GLYR1s and GLYR2s were characterized and their kinetic properties were compared to those of previously characterized GLYRs from Arabidopsis thaliana [L.] Heynh. The purified recombinant GLYRs had an affinity for glyoxylate and succinic semialdehyde, respectively, in the low micromolar and millimolar ranges, and were inhibited by NADP+. Comparison of the GLYR activity in cell-free extracts from wild-type Arabidopsis and a glyr1 knockout mutant revealed that approximately 85 and 15% of the cellular GLYR activity is cytosolic and plastidial/mitochondrial, respectively. Recovery of GLYR activity in purified mitochondria from the Arabidopsis glyr1 mutant, free from cytosolic GLYR1 or plastidial GLYR2 contamination, provided additional support for the targeting of GLYR2 to mitochondria, as well as plastids. The growth of plantlets or roots of various Arabidopsis lines with altered GLYR activity responded differentially to succinic semialdehyde or glyoxylate under chilling conditions. Taken together, these findings highlight the potential regulation of highly conserved plant GLYRs by NADPH/NADP+ ratios in planta, and their roles in the reduction of toxic aldehydes in plants subjected to chilling stress. PMID- 28855912 TI - Salt-Sensitive Signaling Networks in the Mediation of K+/Na+ Homeostasis Gene Expression in Glycyrrhiza uralensis Roots. AB - We investigated the effects of salt-sensitive signaling molecules on ionic fluxes and gene expression related to K+/Na+ homeostasis in a perennial herb, Glycyrrhiza uralensis, during short-term NaCl stress (100 mM, 24 h). Salt treatment caused more pronounced Na+ accumulation in root cells than in leaf cells. Na+ ions were mostly compartmentalized in vacuoles. Roots exposed to NaCl showed increased levels of extracellular ATP (eATP), cytosolic Ca2+, H2O2, and NO. Steady-state flux recordings revealed that these salt-sensitive signaling molecules enhanced NaCl-responsive Na+ efflux, due to the activated Na+/H+ antiport system in the plasma membrane (PM). Moreover, salt-elicited K+ efflux, which was mediated by depolarization-activated cation channels, was reduced with the addition of Ca2+, H2O2, NO, and eATP. The salt-adaptive effects of these molecules (Na+ extrusion and K+ maintenance) were reduced by pharmacological agents, including LaCl3 (a PM Ca2+ channel inhibitor), DMTU (a reactive oxygen species scavenger), cPTIO (an NO scavenger), or PPADS (an antagonist of animal PM purine P2 receptors). RT-qPCR data showed that the activation of the PM Na+/H+ antiport system in salinized roots most likely resulted from the upregulation of two genes, GuSOS1 and GuAHA, which encoded the PM Na+/H+ antiporter, salt overly sensitive 1 (SOS1), and H+-ATPase, respectively. Clear interactions occurred between these salt-sensitive agonists to accelerate transcription of salt responsive signaling pathway genes in G. uralensis roots. For example, Ca2+, H2O2, NO, and eATP promoted transcription of GuSOS3 (salt overly sensitive 3) and/or GuCIPK (CBL-interacting protein kinase) to activate the predominant Ca2+ SOS signaling pathway in salinized liquorice roots. eATP, a novel player in the salt response of G. uralensis, increased the transcription of GuSOS3, GuCIPK, GuRbohD (respiratory burst oxidase homolog protein D), GuNIR (nitrate reductase), GuMAPK3, and GuMAPK6 (the mitogen-activated protein kinases 3 and 6). Moreover, GuMAPK3 and GuMAPK6 expression levels were enhanced by H2O2 in NaCl-stressed G. uralensis roots. Our results indicated that eATP triggered downstream components and interacted with Ca2+, H2O2, and NO signaling to maintain K+/Na+ homeostasis. We propose that a multiple signaling network regulated K+/Na+ homeostasis in NaCl stressed G. uralensis roots. PMID- 28855913 TI - Characteristics of Color Development in Seeds of Brown- and Yellow-Seeded Heading Chinese Cabbage and Molecular Analysis of Brsc, the Candidate Gene Controlling Seed Coat Color. AB - The proanthocyanidin (PA) is the main flavonoids which affect the seed coat color in Brassica species. In this paper, characteristics of color development and accumulation of flavonoids were analyzed in the seeds of brown-seeded (B147) and yellow-seeded (B80) heading Chinese cabbage (Brassica rapa L. ssp. Pekinensis). It is found that the content of phenolic compounds in B147 were significantly more than that of B80 by using dimethylaminocinnamaldehyde (DMACA) staining and toluidine blue O (TBO) staining. In previous studies, the locus associated with seed coat color has been mapped. The results of whole genome re-sequencing showed that there are large fragment deletions variation in the mapping region between the brown-seeded parent '92S105' and the yellow-seeded parent '91-125.' Based on the B. rapa genome annotation information, the TRANSPARENT TESTA GLABRA 1 (TTG1), is likely to be the candidate gene controlling seed coat color. A 94-base deletion was found in the 96th base downstream of the initiation codon in the TTG1 of yellow seed, thus, the termination codon TGA was occurred in the 297th base which makes the full length of TTG1 of yellow seed is 300 bp. Based on the differential sequences of TTG1 of brown and yellow seed, a functional marker, Brsc-yettg1, was developed to detect the variation of TTG1. Quantitative real time PCR analysis of BrTTG1 in different tissues showed that expression levels of BrTTG1 was not tissue-specific. During the whole seed development period, the expression of BrTTG1 in B147 was higher than that of B80. The expression levels of four structural genes, BrDFR, BrANS, BrANR1, and BrANR2 in B147 were also higher than those in B80. The co-segregation molecular markers obtained in this report and TTG1 related information provide a basis for further understanding of the molecular mechanism of seed coat color in heading Chinese cabbage. PMID- 28855914 TI - Toward Identification of Black Lemma and Pericarp Gene Blp1 in Barley Combining Bulked Segregant Analysis and Specific-Locus Amplified Fragment Sequencing. AB - Black barley is caused by phytomelanin synthesized in lemma and/or pericarp and the trait is controlled by one dominant gene Blp1. The gene is mapped on chromosome 1H by molecular markers, but it is yet to be isolated. Specific-locus amplified fragment sequencing (SLAF-seq) is an effective method for large-scale de novo single nucleotide polymorphism (SNP) discovery and genotyping. In the present study, SLAF-seq with bulked segregant analysis (BSA) was employed to obtain sufficient markers to fine mapping Blp1 gene in an F2 population derived from Hatiexi No.1 * Zhe5819. Based on SNP screening criteria, a total of 77,542 polymorphic SNPs met the requirements for association analysis. Combining two association analysis methods, the overlapped region with a size of 32.41 Mb on chromosome 1H was obtained as the candidate region of Blp1 gene. According to SLAF-seq data, markers were developed in the target region and were used for mapping the Blp1 gene. Linkage analysis showed that Blp1 co-segregated with HZSNP34 and HZSNP36, and was delimited by two markers (HZSNP35 and HZSNP39) spanning 8.1 cM in 172 homozygous yellow grain F2 plants of Hatiexi No.1 * Zhe5819. More polymorphic markers were screened in the reduced target region and were used to genotype the population. As a result, Blp1 was delimited within a 1.66 Mb on chromosome 1H by the upstream marker HZSNP63 and the downstream marker HZSNP59. Our results demonstrated the utility of SLAF-seq-BSA approach to identify the candidate region and discover polymorphic markers at the specific targeted genomic region. PMID- 28855915 TI - Genotypic Diversity and Short-term Response to Shading Stress in a Threatened Seagrass: Does Low Diversity Mean Low Resilience? AB - Seagrasses that are predominantly clonal often have low levels of genetic variation within populations and predicting their response to changing conditions requires an understanding of whether genetic variation confers increased resistance to environmental stressors. A higher level of genetic diversity is assumed to benefit threatened species due to the increased likelihood of those populations having genotypes that can persist under environmental change. To test this idea, we conducted an in situ shading experiment with six geographically distinct meadows of the threatened seagrass Posidonia australis that vary in genetic diversity. Different genotypes within meadows varied widely in their physiological and growth responses to reduced light during a simulated short-term turbidity event. The majority of meadows were resistant to the sudden reduction in light availability, but a small subset of meadows with low genotypic diversity were particularly vulnerable to the early effects of shading, showing substantially reduced growth rates after only 3 weeks. Using the photosynthetic performance (maximum quantum yield) of known genotypes, we simulated meadows of varying genetic diversity to show that higher diversity can increase meadow resilience to stress by ensuring a high probability of including a high performing genotype. These results support the hypothesis that complementarity among genotypes enhances the adaptive capacity of a population, and have significant implications for the conservation of declining P. australis meadows close to the species range edge on the east coast of Australia, where the genotypic diversity is low. PMID- 28855916 TI - A Glimpse into the Satellite DNA Library in Characidae Fish (Teleostei, Characiformes). AB - Satellite DNA (satDNA) is an abundant fraction of repetitive DNA in eukaryotic genomes and plays an important role in genome organization and evolution. In general, satDNA sequences follow a concerted evolutionary pattern through the intragenomic homogenization of different repeat units. In addition, the satDNA library hypothesis predicts that related species share a series of satDNA variants descended from a common ancestor species, with differential amplification of different satDNA variants. The finding of a same satDNA family in species belonging to different genera within Characidae fish provided the opportunity to test both concerted evolution and library hypotheses. For this purpose, we analyzed here sequence variation and abundance of this satDNA family in ten species, by a combination of next generation sequencing (NGS), PCR and Sanger sequencing, and fluorescence in situ hybridization (FISH). We found extensive between-species variation for the number and size of pericentromeric FISH signals. At genomic level, the analysis of 1000s of DNA sequences obtained by Illumina sequencing and PCR amplification allowed defining 150 haplotypes which were linked in a common minimum spanning tree, where different patterns of concerted evolution were apparent. This also provided a glimpse into the satDNA library of this group of species. In consistency with the library hypothesis, different variants for this satDNA showed high differences in abundance between species, from highly abundant to simply relictual variants. PMID- 28855917 TI - Peptidomic analysis of the venom of the solitary bee Xylocopa appendiculata circumvolans. AB - BACKGROUND: Among the hymenopteran insect venoms, those from social wasps and bees - such as honeybee, hornets and paper wasps - have been well documented. Their venoms are composed of a number of peptides and proteins and used for defending their nests and themselves from predators. In contrast, the venoms of solitary wasps and bees have not been the object of further research. In case of solitary bees, only major peptide components in a few venoms have been addressed. Therefore, the aim of the present study was to explore the peptide component profile of the venom from the solitary bee Xylocopa appendiculata circumvolans by peptidomic analysis with using LC-MS. METHODS: A reverse-phase HPLC connected to ESI-OrbiTrap MS was used for LC-MS. On-line mass fingerprinting was made from TIC, and data-dependent tandem mass spectrometry gave MSMS spectra. A major peptide component was isolated by reverse-phase HPLC by conventional way, and its sequence was determined by Edman degradation, which was finally corroborated by solid phase synthesis. Using the synthetic specimen, biological activities (antimicrobial activity, mast cell devaluation, hemolysis, leishmanicidal activity) and pore formation in artificial lipid bilayer were evaluated. RESULTS: On-line mass fingerprinting revealed that the crude venom contained 124 components. MS/MS analysis gave 75 full sequences of the peptide components. Most of these are related to the major and novel peptide, xylopin. Its sequence, GFVALLKKLPLILKHLH-NH2, has characteristic features of linear cationic alpha helical peptides; rich in hydrophobic and basic amino acids with no disulfide bond, and accordingly, it can be predicted to adopt an amphipathic alpha-helix secondary structure. In biological evaluation, xylopin exhibited broad-spectrum antimicrobial activity, and moderate mast cell degranulation and leishmanicidal activities, but showed virtually no hemolytic activity. Additionally, the peptide was able to incorporate pores in artificial lipid bilayers of azolectin, confirming the mechanism of the cytolytic activity by pore formation in biological membranes. CONCLUSIONS: LC-ESI-MS and MS/MS analysis of the crude venom extract from a solitary bee Xylocopa appendiculata circumvolans revealed that the component profile of this venom mostly consisted of small peptides. The major peptide components, xylopin and xylopinin, were purified and characterized in a conventional manner. Their chemical and biological characteristics, belonging to linear cationic alpha-helical peptides, are similar to the known solitary bee venom peptides, melectin and osmin. Pore formation in artificial lipid bilayers was demonstrated for the first time with a solitary bee peptide. PMID- 28855918 TI - Effects of a Long-Acting Formulation of Octreotide on Patients with Portal Hypertension. AB - OBJECTIVE: This study aimed to determine whether the treatment of a long-acting formulation of octreotide (OCT-LAR) exerted a similar effect on improving the prognosis of patients with portal hypertension compared with placement of transjugular intrahepatic portosystemic shunts (TIPSs). METHODS: A total of 24 patients with portal hypertension who underwent TIPS placement or OCT-LAR treatment from January 2010 to January 2015 were reviewed. Hemodynamic studies, biological values, live functions, and treatment complications before and during the treatment were evaluated. RESULTS: Baseline clinical characteristics were similar between two groups. Hepatic venous pressure gradient (HVPG) was improved in OCT-LAR groups (15.9 +/- 2.4 to 12.8 +/- 1.6 mmHg). Both groups showed a slight decrease in endothelin-1 (ET-1) and urotensin II and a slight increase in oxide metabolite (NOx) concentrations with no significant difference. Aspartate aminotransferase and alanine aminotransferase increased one week after TIPS placement when they improved in the OCT-LAR treatment group. The complications of OCT-LAR treatment were minor and transient. However, one patient who received TIPS placement presented procedure-related complications and required rehospitalization, and 2 patients had developed hepatic encephalopathy during the follow-up period. CONCLUSION: Prolonged administration of OCT-LAR exerted a virtually similar effect on improving hemodynamic parameters and liver function in patients with portal hypertension compared with placement of TIPS, with no apparent serious adverse effects. PMID- 28855919 TI - Case-Control Pilot Study on Acute Diarrheal Disease in a Geographically Defined Pediatric Population in a Middle Income Country. AB - INTRODUCTION: Acute diarrheal disease (ADD) is a common cause of morbidity and mortality in children under 5 years of age. Understanding of the etiology of ADD is lacking in most low and middle income countries because reference laboratories detect limited number of pathogens. The objective of this study was to determine the feasibility to conduct a comprehensive case-control study to survey diarrheal pathogens among children with and without moderate-to-severe ADD. MATERIALS AND METHODS: Microbiology and molecular-based techniques were used to detect viral, bacterial, and parasitic enteropathogens. The study was conducted in Bucaramanga, Colombia, after Institutional Review Board approval was obtained. RESULTS: Ninety children less than 5 years of age were recruited after a written informed consent was obtained from parents or guardians. Forty-five subjects served as cases with ADD and 45 as controls. Thirty-six subjects out of 90 (40.0%) were positive for at least one enteropathogen, that is, 20 (44.4%) cases and 16 (35.5%) controls. CONCLUSIONS: The three most common enteric pathogens were enteroaggregative E. coli (10.0%), Norovirus (6.7%), and Salmonella spp. (5.6%). The E. coli pathogens were 18.8% of all infections making them the most frequent pathogens. Half of ADD cases were negative for any pathogens. PMID- 28855920 TI - Occupational Exposure to Needle Stick and Sharp Injuries and Associated Factors among Health Care Workers in Awi Zone, Amhara Regional State, Northwest Ethiopia, 2016. AB - BACKGROUND: Needle stick and sharp injuries were one of the major risk factors for blood and body fluid borne infections at health care facilities. OBJECTIVE: To assess occupational exposure to needle stick and sharp injuries and associated factors among health care workers in Awi zone, 2016. METHODS: institutional based cross-sectional study was conducted among 193 health care workers. Study participants were selected using systematic random sampling technique. RESULT: When queried, 18.7% of the respondents' encountered needle stick and sharp injury in the last 1 year. Participants who practiced needle recapping and had job related stress were 21.3 and 7.3 times more likely to face needle stick and sharp injury, respectively. However, those who apply universal precautions and acquire the required skill were 99% and 96% times less likely to face needle stick and sharp injury, respectively, than their counterparts. CONCLUSION AND RECOMMENDATION: The prevalence of needle stick and sharp injury was relatively low as compared to previous studies. Recapping of needle after use, job related stress, not applying universal precautions, and lack of the required skill were associated with needle stick and sharp injuries. Therefore, health care providers should apply universal precaution. PMID- 28855923 TI - Is Helicobacter pylori Infection a Risk Factor for Prostatitis? A Case-Control Study in a Referring Tertiary Care Center. AB - BACKGROUND: The optimal treatment is not possible yet for chronic prostatitis due to the unknown etiology of the diseases. We aimed to investigate the association of Helicobacter pylori infection with chronic prostatitis. METHODS: In this prospective case-control study that conducted in Imam Hospital Complex affiliated to Tehran University of Medical Sciences in Tehran, Iran from 2014 to 2015, patients with diagnosis of chronic prostatitis according to the criteria of National Institute of Health (NIH) were enrolled. Control group constituted of consecutive healthy patients. Blood samples were obtained for each patient and control and evaluated for serum levels of anti H. pylori IgG, A. Data analysis was carried out using SPSS, version 18. Values of P<0.05 were considered statistically significant. RESULTS: Mean +/- SD age of patients was 59.5 +/- 3.08 yr in the case group and 56.88 +/- 3.20 yr in the control group with no significant difference (P>0.05). Mean +/- SD levels of anti H. pylori IgG and IgA in the control group were 9.36 +/- 7.45 U/ml and 6.25 +/- 7.29 U/ml, respectively compared with 20.94 +/- 16.98 U/ml and 18.63 +/- 15.65 U/ml in the case group, respectively both of which revealed statistically significant (P<0.05). CONCLUSION: Chronic prostatitis is associated with H. pylori infection. Both anti H. pylori IgG and IgA are increased in patients with chronic prostatitis. Therefore, treatment of HP infection could be effective in the prostatitis cure. PMID- 28855924 TI - Intra-familial Transmission of Hepatitis B Virus Infection in Arak, Central Iran. AB - BACKGROUND: The household transmission of hepatitis B virus (HBV) is a major health problem. High incidence of HBV infection is observed within the household contacts of HBV carriers. We aimed to evaluate serological markers of hepatitis B infection among family members of HBV carriers in Arak, central Iran. METHODS: Data were collected from the 100 chronic HBV carriers (subjects with positive HBsAg for at least 6 months period) as index cases and 700 members of their family. Then, we checked serologic markers of hepatitis B [hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti- HBs)] using the ELISA test. RESULTS: The prevalence rate of HBsAg, anti-HBs and anti-HBc among household members was 23.3%, 20.4% and 23% respectively. Isolated anti-HBc (positive anti-HBc with negative HBsAg and anti HBs) found in 0.4% of family members. Mothers and children with 47.6% and 17.2% had the highest and lowest rates of HBV infection, respectively (P=0.00). There was a significant difference between mothers and spouses of index case (47.6% and 29.8%) regarding HBsAg positivity (P=0.03). CONCLUSION: The low rate of HBV infection reported in children reveal the effective prevention of HBV transmission with the universal vaccination programs and also importance of pregnant women screening for HBV serological markers. PMID- 28855921 TI - Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology. AB - Glucose homeostasis requires appropriate and synchronous coordination of metabolic events and hormonal activities to keep plasma glucose concentrations in a narrow range of 3.5-5.5 mmol/L. Insulin, the only glucose lowering hormone secreted from pancreatic beta-cells, plays the key role in glucose homeostasis. Insulin release from pancreatic beta-cells is mainly regulated by intracellular ATP-generating metabolic pathways. Hyperinsulinaemic hypoglycaemia (HH), the most common cause of severe and persistent hypoglycaemia in neonates and children, is the inappropriate secretion of insulin which occurs despite low plasma glucose levels leading to severe and persistent hypoketotic hypoglycaemia. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) constitute the underlying molecular mechanisms of congenital HH. Since insulin supressess ketogenesis, the alternative energy source to the brain, a prompt diagnosis and immediate management of HH is essential to avoid irreversible hypoglycaemic brain damage in children. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This up to date review article provides a background to the diagnosis, molecular genetics, recent advances and therapeutic options in the field of HH in children. PMID- 28855922 TI - Pre-Cancerous Lesions in the Oral and Maxillofacial Region: A Literature Review with Special Focus on Etiopathogenesis. AB - Many types of cancers develop in the oral and maxillofacial region. Squamous cell carcinoma is the most common cancer and constitutes over 90 percent of these tumors. Malignant transformation is a genetic process, which later makes a phenotyping change at the cellular level. Some cancers such as oral squamous cell carcinomas (OSCCs) develop from pre-malignant lesions and conditions. Despite advances in the treatment of OSCC, the 5-year survival rate remains approximately 50% due to inability of early detection of OSCC and precursor lesions. Early detection of oral cancer, especially in the premalignant stage, can decrease mortality and morbidity significantly. This article reviews some clinical, histopathological features and etiopathogenesis of pre-cancerous lesions of the oral cavity and skin of face and lip vermilion. A relevant English literature search in Pubmed, Science Direct, and Google Scholar was performed from 1930 to 2015. Full text of 191 articles met the specific inclusion criteria for this review. PMID- 28855925 TI - Expression of Human Kallikreins 4, 8, 10, 11 and 13 in Pleomorphic Adenomas and Mucoepidermoid Carcinomas. AB - BACKGROUND: In cancers of prostate, breast, oropharynx, lung, hypopharynx and skin, human tissue kallikreins has been demonstrated as a main role in these problems. There are many research works in which some human tissue kallikreins are expressed in salivary glands. In the present study, the main goal was to determine expression of human tissue kallikreins 4, 8, 10, 11 and 13 in pleomorphic adenomas and mucoepidermoid carcinomas. METHODS: Sixty-six specimens (45 cases of pleomorphic adenomas and 21 cases mucoepidermoid carcinomas) were selected for final analysis by immunohistochemistry. For doing association test, clinical parameters obtained from the patients' medical charts, which included age, gender were used and the nonparametric tests employed for statistical analyses. RESULTS: The expression of human kallikreins 4, 8, 11 and 13 was more prominent in benign and malignant tumors compared to that in normal tissues and the difference was significant. In addition, the expression of human kallikreins 4, 8, 10 and 11 in malignant tumors was more than that in benign tumors, with statistically significant differences. CONCLUSION: The differences in the levels of human kallikreins 4, 8, 11 and 13 suggest that kallikreins may benefit in determining tumor behavior of salivary gland tumors. PMID- 28855926 TI - Role of Aders and OXA23 Genes among Imipenem Resistant Acinetobacter baumannii Isolates from Two Hospitals of Tehran, Iran. AB - BACKGROUND: This study aimed to evaluate the role of efflux pump regulator and OXA-23 genes in imipenem resistance Acinetobacter baumannii strains isolated from hospitalized patients in Tehran, Iran. METHODS: This study was conducted on 60 A. baumannii isolates collected from patients admitted to the Shahid Motahari and Taleghani Hospitals in Tehran during 2013-14. Antibiotic susceptibility tests (AST) and minimal inhibitory concentration (MIC) was determined by broth micro dilution methods according to CLSI 2014 guidelines. The frequency of efflux pump adeRS and OXA-23 genes were detected by PCR and further sequencing. RESULTS: The resistance of A. baumannii isolates to tested antibiotics was 100% to cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, cefepime, piperacillin, meropenem, co trimoxazole and piperacillin/tazobactam, 97% to imipenem, 94% to gentamicin, 83% to amikacin, 76% to tetracycline, and 0.0% to colistin. The MIC of 58 (96.6%) strains to imipenem was highly decreased in the presence of efflux pump inhibitor (PabetaN), by 4 to 64 folds. The adeR and adeS genes were detected in 36 (60%) and 59 (98.3%), respectively and the frequency of OXA-23 gene was 57 (95%) of isolates. CONCLUSION: Existence of adeRS and OXA-23 genes in more than 50% of A. baumannii isolates in this study shows the presumptive role of efflux pump in simultaneous of carbapenemase production. Therefore, using new strategies are required in order to stop the vertical or horizontal exchanges mentioned genes from the resistant A. baumannii isolates to sensitive strains. PMID- 28855927 TI - Isolation of indigenous Glutathione producing Saccharomyces cerevisiae strains. AB - BACKGROUND: Glutathione (GSH) is a non-protein thiol compound, which plays an important role in the response to oxidative stress and nutritional stress. The aim of this study was to isolate indigenous S. cerevisiae strains capable of effectively produce GSH. METHODS: One hundred-twenty sweet fruit samples were collected. The strains were isolated on yeast glucose chloramphenicol (YGC) agar medium and identified. The isolates were evaluated for GSH producing on yeast malt (YM) medium. Concentration of glutathione was investigated by recording absorbance of all samples at wavelength 412 nm (Ellman's method). In addition, optimization of glucose and peptone concentration in culture medium and the effects of various environmental conditions such as temperature (20-35 degrees C), agitation rate (150-250 rpm), and initial pH (4.0-6.0) were assessed on producing of GSH. RESULTS: From 120 samples, 80 isolates were identified by morphological, biochemical and molecular tests as S. cerevisiae. Five isolates were capable to produce effectively GSH. The optimal culture conditions were agitation rate, 200 rpm; temperature, 30 degrees C; initial pH, 6; glucose, 30 g/l; and peptone concentration, 5 g/l. In optimal conditions, the amount of derived glutathione was improved compared to YM basal medium and highest GSH concentration (296.8 mg/l) was obtained after cultivation with shaking for 72 h. CONCLUSION: The possibility of obtaining S. cerevisiae cells with a high GSH intracellular content can be considered an interesting opportunity of furthering the range of application and utilization of this molecule. PMID- 28855928 TI - Diagnostic Value of Measurement Specific Gravity by Refractometric and Dipstick Method in Differentiation between Transudate and Exudate in Pleural and Peritoneal Fluid. AB - BACKGROUND: Accumulation of pleural and peritoneal fluid is seen in some diseases. In order to diagnose the disease and start the treatment, one of the most important actions will be to differentiate between exudates and transudates. The objective of this study was to determine the diagnostic value of measuring the specific gravity of the fluid through refractometer and strip in differentiation of exudates from transudates. METHODS: The serum of patients was evaluated for protein, LDH, cholesterol, bilirubin and albumin. The fluid was evaluated for the number of white blood cells, protein, LDH, cholesterol, bilirubin and albumin. Then the fluids were divided into exduate and transudate categories based on Light and Gradient criteria. Finally, the specific gravity of the fluids was measured by refractometer, Erma, Japan and Medi-Test Combi II. The categorized fluids were compared with Gold Standards (final diagnosis) so that the sensitivity and specificity of Light and Gradient criteria in the transudate exudate differentiation were specified. RESULTS: In comparison with Light criteria, the cut off level of 1022 specific gravity measured by refractometer for pleural effusion has sensitivity, specificity of 92.1%, 68.1%respectively. In evaluation of peritoneal fluid considering cut off point 1023, measured by refractometer has reliable sensitivity 92.4%, specificity 70.4 compared with standard gradient method. CONCLUSION: Differentiating transudate from exudates by measuring its special gravity by refractometer will have acceptable sensitivity and specificity, and when rapidity is necessary or access to lab equipment is limited, this method could be used. PMID- 28855929 TI - Evaluation of Different Phenotypic and Genotypic Methods for Detection of Methicillin Resistant Staphylococcus aureus (MRSA). AB - BACKGROUND: Methicillin resistant Staphylococcus aureus (MRSA) has been emerged as a nosocomial and community acquired pathogen worldwide. There are many challenges for laboratory detection of MRSA. The aim of this study was to compare different phenotypic methods with PCR based method as a gold standard for detection of mecA gene. METHODS: A total of 220 clinical isolates of S. aureus which were isolated from various clinical specimens from September 2013 until the June of 2014 in Milad Hospital of Tehran, Iran was subject of our study. Methicillin resistance was determined by oxacillin and cefoxitin disks, oxacillin screen agar and CHROMagarTM MRSA medium. The results of these methods were compared with mecA gene based PCR method as a gold standard method. RESULTS: Among 220 isolates from S. aureus, 105 (47.72%) isolates were positive for mecA gene by PCR method. The results of cefoxitin disk diffusion method with 100% sensitivity and specificity was the same as PCR method .CHROMagarTM MRSA medium had 98.13% sensitivity and 100% specificity. Oxacillin disk diffusion and oxacillin screen agar had 95.42% and 97.22% sensitivity respectively. CONCLUSION: Result of cefoxitin disk diffusion method with 100% sensitivity and specificity was the same as PCR method for detection mecA gene. Cefoxitin disk diffusion method can be used as an alternative method of PCR for detection of MRSA. PMID- 28855930 TI - Correlation of P16 (Ink4a) and CK17 to HPV (16E6+18E6) in Premalignant and Malignant Lesions of Uterine Cervix: A Clinicopathologic Study. AB - BACKGROUND: This research was accomplished to evaluate the IHC expression of p16 (ink4a) and CK17 in low grade cervical intraepithelial lesions (LSIL), high grade cervical intraepithelial lesions (HSIL) and invasive cervical carcinomas and to assess their correlation to HPV (16E6+18E6). METHODS: The study included (127) formalin-fixed paraffin-embedded cervical biopsies; of which 22 cases were chronic cervicitis, 24 cases were LSIL, 28 cases were HSIL and 53 cases were invasive cervical carcinomas. Sections were immunohistochemically stained for p16 (ink4a), CK17 and HPV (16E6+18E6). RESULTS: The study established a highly significant increase in IHC of expression of p16 (ink4a), CK17 and HPV (16E6+18E6) from LSIL through HSIL to invasive carcinomas (P-value?0.001). There was non-significant association between IHC expression of all makers with age of patients; types, grade and stage of cervical carcinomas (P-value?0.05). HPV (16E6+18E6) revealed a significantly positive correlation with p16 (ink4a) (P value?0.05) and a non- significant correlation with CK17 (P-value?0.05); in LSIL, HSIL and invasive carcinoma cases. CONCLUSION: p16 (ink4a) expression directly reflects infection with high risk HPV in cervical lesions and can add a significant diagnostic accuracy in the evaluation of CIN. CK 17 is a good marker of malignant transformation, with increasing in its expression according to the severity of cervical lesions; however, it is not related to HPV infection. Both markers are not related to prognostic variables of patients with cervical carcinoma. PMID- 28855931 TI - Predictive Values of Urinary Interleukin 18 and Neutrophil Gelatinase-Associated Lipocalin for Delayed Graft Function Diagnosis in Kidney Transplantation. AB - BACKGROUND: Delayed graft function is a main complication after deceased donor kidney transplantation that adversely affects graft outcome. Difficulties in prediction and early detection of delayed graft function have hindered the ability to perform proper therapeutic interventions. We investigated whether measuring urinary interleukin 18 and neutrophil gelatinase-associated lipocalin as markers of ischemia reperfusion injury could predict delayed graft function in deceased donor kidney transplant patients. METHODS: We studied 69 patients undergoing kidney transplantation from deceased donor during early October 2013 to December 2014 at the Urology Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. Serial urine samples at 2, 24, and 48 h after transplantation were analyzed for interleukin 18 and neutrophil gelatinase associated lipocalin levels. RESULTS: Thirteen patients (18.9%) developed delayed graft function. Urine interleukin 18 to urine creatinine ratio was significantly higher in patients with delayed graft function compared to those with non-delayed graft function, at 2 (P=0.003), 24 (P<0.001) and 48 h (P=0.018) points. The levels of neutrophil gelatinase-associated lipocalin to urine creatinine ratio were significantly higher in the group with delayed graft function at the 24 (P=0.004) and 48 h (P=0.015) points. The receiver-operating characteristic curve analysis suggested that both urinary biomarkers at 24 h after transplantation had better accuracies for prediction of delayed graft function. In multivariate analysis, only urinary interleukin 18 to urine creatinine ratio improved the ability of clinical model for predicting delayed graft function. CONCLUSION: Urinary interleukin 18 to urine creatinine ratio at 24 h post-transplantation, along with traditional markers such as relative fall in serum creatinine, urine output and other risk factors for delayed graft function, increased the ability to predict delayed graft function. PMID- 28855932 TI - Phyllodes Tumor of the Breast: 307 Treated Cases, the Largest Mexican Experience at a Single Breast Disease Institution. AB - BACKGROUND: Phyllodes tumor (PT) of the breast in Hispanic patients is more frequently reported with large tumors and with more borderline/malignant subtypes compared with other populations. The objective of this study was to describe characteristics of patients with PT and to identify differences among subtypes in a Mexican population. METHODS: A retrospective study was conducted on patients with PT. Sociodemographic, histopathologic, and treatment characteristics were compared among subtypes, including only surgically treated cases due the complete surgical-specimen study requirement for appropriate WHO classification. RESULTS: During 10 years, 346 PT were diagnosed; only 307 were included (305 patients), with a mean age of 41.7 yr. Self-detected lump took place in 91.8%, usually discovered 6 months previously, with median tumor size of 4.5 cm. Local wide excisions were done in 213 (69.8%) and mastectomies in 92 (30.1%). Immediate breast reconstruction took place in 38% and oncoplastic procedures in 23%. PT were classified as benign in 222 (72.3%) cases, borderline in 50 (16.2%), and malignant in 35 (11.4%), with pathological tumor size of 4.2, 5.4, and 8.7 cm, respectively (P<0.001). Patients with malignant PT were older (48 yr), with more diabetics (14.3%), less breastfeeding (37.1%), more smokers (17.1%), with more postmenopausal cases (42.9%), and older age at menopause (51.5 years) compared with the remaining subtypes (P<0.05). Relapse occurred in 8.2% of patients with follow-up. CONCLUSION: In comparison with other Hispanic publications, these Mexican patients had similar age, with smaller tumors, modestly higher benign PT, fewer malignant PT, and lower documented relapse cases. PMID- 28855934 TI - A Case-Control Study on the Take-Off Sign in Lesional Skin Biopsies of Patients with Pityriasis Rosea. PMID- 28855933 TI - Hirschsprung Disease Diagnosis: Calretinin Marker Role in Determining the Presence or Absence of Ganglion Cells. AB - BACKGROUND: Hirschsprung disease is a complex genetic disorder of the enteric nervous system (ENS), often called congenital aganglionic megacolon and characterized by the absence of enteric neurons along a variable length of the intestine. The definitive diagnosis of Hirschsprung disease relies on histologic and/or histochemical staining of sections from suction rectal biopsies. Calretinin immunohistochemistry (IHC) may be a useful in its diagnosis. This study aimed to proof the usefulness of immunohistochemical staining for calretinin in rule out of Hirschsprung disease. METHODS: Paraffin blocks and slides were retrieved from the pathology archives of Ali Asghar Hospital, Tehran, Iran from 2007 to 2011 with pathology report based on the presence (14 patients) or absence (70 patients) of ganglion cells and transitional zone anatomical region (10 patients). Slides were stained with hematoxylin and eosin method to confirm the initial diagnosis was verification again. After preparing the slides, they were stained by IHC for calretinin. Then, the results were analyzed using SPSS software. RESULTS: In most patients, IHC for calretinin provided highly compatible results with hematoxylin-eosin findings in diagnosis of Hirschsprung disease. The values of specificity and accuracy between calretinin and standard histology (H&E) compared by the Fisher exact test declared calretinin presented significantly higher specificity and accuracy values than H&E staining (P <0.0001). CONCLUSION: Calretinin IHC overcomes most of the difficulties encountered using the histology hematoxylin-eosin. Then, IHC for calretinin is a good ancillary method used by pathologists in diagnosis of Hirschsprung disease. PMID- 28855935 TI - A Rare Case of Pilomatrixoma (Calcifying Epithelioma of Malherbe) of Parotid Space Masquerading as Salivary Gland Tumor. PMID- 28855936 TI - Hairy Cell Leukemia in a Young Male: An Unusual Presentation. PMID- 28855937 TI - Immunization of mice by a multimeric L2-based linear epitope (17-36) from HPV type 16/18 induced cross reactive neutralizing antibodies. AB - Current licensed and commercially available prophylactic human papillomavirus (HPV) vaccines (Cervarix and quadrivalent/nine valents Gardasil) are based on major capsid protein L1 virus-like particles (VLPs) production which are expensive and type specific. Minor capsid L2-RG1 linear epitope (17-36) is a known candidate for induction of cross-neutralizing antibodies to develop low cost pan-HPV vaccines. Herein, we report construction and expression of a three tandem repeats of L2-RG1 derived from HPV16 and 18 fused with the same head to tail pattern (HPV16:17-36*3+ HPV18:17-36*3; hereafter termed dual-type fusion L2 peptide) in E. coli and provide the results of its immunogenicity in mice. SDS PAGE and western blot analyses indicated proper expression of the peptide that could be further purified by Ni-NTA affinity chromatography via the located C terminal 6xHis-tag. Mice immunized by formulation of the purified peptide and Freund adjuvant raised neutralizing antibodies which showed proper cross reactivity to HPV L2 (11-200) of types: 18, 16, 31 and 45 (which totally are responsible for 90% of cervical cancers) and efficiently neutralized HPV18/16 pseudoviruses in vitro. Our results imply the possibility of development of a simple, low-cost preventive HPV vaccine based on this dual-type fusion L2 peptide in bacterial expression system with broad spectrum. PMID- 28855938 TI - Development, evaluation and optimization of superparamagnetite nanoparticles prepared by co-precipitation method. AB - Magnetic nanoparticles (MNPs) are of high interest due to their application in medical fields, in particular for theranostics. Specific properties required for such particles include high magnetization, appropriate size and stability. Biocompatible magnetically soft magnetite particles (Fe3O4) have been investigated for biological purposes. The intrinsic instability of these nanoparticles and their susceptibility to the oxidization in air, are limitations for their applications. Various methods have been described for synthesis of these nanoparticles among which co-precipitation method is widely experimented. In order to illustrate the synthesis of MNPs elaborately, the effect of different factors on particle formation were studied. The particles morphology, stability, paramagnetic effect, chemical structure and cytotoxicity were evaluated. Particles of 58 and 60 nm obtained by oleic acid coated (OMNPs) and citric acid coated (CMNPs) magnetite nanoparticles respectively. Transmission electron microscopy images exhibited the real sizes are 15 and 13 nm. Magnetic saturations of these nanoparticles were 72 and 68 emu/g which is suitable for medical applications. Both OMNPs and CMNPs were non-toxic to the SK-Br-3 and MCF-7 cells in the concentrations of <2.5 MUg/mL. Since these particles exhibit relatively high magnetic saturation, low dose of such material would be required; therefore, these NPs seem to be suitable for theranostics. PMID- 28855939 TI - Antibacterial and anti-inflammatory activities of marine Brevibacterium sp. AB - The marine environment covers three quarters of the surface of the planet and is estimated to be home to more than 80% of life but yet it remains largely unexplored. It harbours a number of macro and microorganisms that have developed unique metabolic abilities to ensure their survival in diverse and hostile habitats, resulting in the biosynthesis of an array of secondary metabolites with specific activities. In this study, pigment forming bacterial strains were isolated from the sea surface inter tidal zones at different sampling sites along the Visakhapatnam coastal region. The bacterial isolates showed various types of colour pigments like pink, yellow, orange, and brown. Out of 26 pigmented isolates obtained, the bacterial isolate with bright yellow pigmentation was selected for further study. This strain was identified as Brevibacterium sp by using morphological, physiological, biochemical and 16s rRNA sequencing methods. The pigment was extracted in methanol solvent and antibacterial activity of the pigments extracted from the bacteria was determined and it was found active against pathogenic bacteria. The pigment extract was tested In vivo for anti inflammatory activity and was effective. PMID- 28855940 TI - Synthesis and cytotoxic evaluation of some new 3-(2-(2-phenylthiazol-4-yl) ethyl) quinazolin-4(3H) one derivatives with potential anticancer effects. AB - Quinazolinones are a group of heterocyclic compounds that have important biological activities such as cytotoxicity, anti-bacterial, and anti-fungal effects. Thiazole-containing compounds have also many biological effects including antitumor, antibacterial, anti-inflammatory, and analgesic activities. Due to significant cytotoxic effects of both quinazoline and thiazole derivatives, in this work a group of quinazolinone-thiazol hybrids were prepared and their cytotoxic effects on three cell lines were evaluated using MTT assay. Compounds A3, A2, B4, and A1 showed highest cytotoxic activities against PC3 cell line. Compounds A3, A5, and A2 were most active against MCF-7 and A3, A5, and A6 showed good cytotoxic effect on HT-29 cell line. According to the results, A3 efficiently inhibited all cell growth tested in a dose dependent manner. The IC50 of A3 was 10 M, 10 MUM, and 12 MUM on PC3, MCF-7, and HT-29 cells, respectively. PMID- 28855941 TI - Evaluation of fibrinolytic and antioxidant effects of Allium affine hydroalcoholic extract. AB - Allium affine is a member of Amaryllidaceae family, which grows wildly in some western regions of Iran. Limited information is available about the pharmacological activities of this plant. The present study aimed to evaluate the fibrinolytic and antioxidant effects of hydroalcoholic extract of A. affine aerial parts. The in vitro antioxidant properties of the extract were evaluated by total phenolic content assay, 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity and ferric reducing antioxidant power (FRAP) assay. The in vivo studies included the determination of hydroperoxides level and FRAP value in serum samples of rats receiving i.p. injections of the plant extract for 21 days. The fibrinolytic activity of the extract was quantitatively evaluated by measuring the clot weight. In vitro antioxidant analysis exhibited the promising potential of DPPH scavenging and total antioxidant capacity of A. affine extract. In the in vivo analysis, A. affine extract reduced the serum hydroperoxides level and increased the serum total antioxidant capacity in rats. In vitro fibrinolytic assay also elucidated notable thrombolytic activity of the plant extract. The results of this study revealed the valuable antioxidant and in vitro fibrinolytic activities of A. affine extract. Further studies are needed for better evaluation of anticoagulant and thrombolytic activities of this plant and understanding its detailed mechanisms. PMID- 28855942 TI - Method development and validation of HPLC tandem/mass spectrometry for quantification of perindopril arginine and amlodipine besylate combination in bulk and pharmaceutical formulations. AB - A well-characterized and fully validated ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometric (UHPLC-ESI MS/MS) method was developed to reliably analyze combination of perindopril arginine and amlodipine besylate in bulk and tablet formulations. The chromatographic separation was achieved on a Waters ACQUITY UPLC(r) BEH C18 column with 1.7 MUm particle packing which enabled the higher peak capacity, greater resolution, increased sensitivity, and higher speed of analysis using a volatile mobile phase ideally being at least 2 pH units below and above the perindopril arginine and amlodipine besylate pKa, respectively. Mass spectrometric detection was performed using electrospray ion source in positive ion polarity to profile the abundances of perindopril arginine and amlodipine besylate, using the transitions m/z 369 -> m/z 172, and m/z 409 -> m/z 238 for perindopril arginine and amlodipine besylate, respectively. Calibration curve was constructed over the range 0.25 - 500 ng/mL and 1.0 - 100 ng/mL for perindopril arginine and amlodipine besylate, respectively. The method was precise and accurate, and provided recovery rates > 80% for both compounds. Furthermore, the intra- and inter-assay precision in terms of % RSD was in between 0.1 - 3.7 for both perindopril arginine and amlodipine besylate. A specific, accurate, and precise UHPLC-MS/MS method for the determination of perindopril arginine and amlodipine besylate in bulk and tablet formulation. PMID- 28855943 TI - Atorvastatin attenuates ethanol-induced hepatotoxicity via antioxidant and anti inflammatory mechanisms. AB - The aim of this study was to evaluate the role of inflammation and oxidative damage in hepatotoxicity of ethanol. Also we assessed protective effects of atorvastatin against ethanol-induced hepatotoxicity. In this study, the animals were divided into five groups: control, ethanol (10 mg/kg intraperitoneal (i.p.)), ethanol with atorvastatin (10, 20 mg/kg/day, i.p.) and ethanol-vitamin C group which received ethanol (10 mg/kg/day) plus vitamin C (200 mg/kg, i.p.) for 28 consecutive days. Then, the animals were euthanized and liver tissues were separated. Biochemical markers ALT and AST were measured. Moreover, glutathione (GSH) content, lipid peroxidation, protein carbonyl, nitric oxide and tumor necrosis factor-alpha (TNF-alpha) were evaluated. The administration of ethanol for 28 days resulted in an increase in liver damage, oxidative stress and inflammatory markers. The atorvastatin was able to prevent the ethanol-induced hepatotoxicity by decreasing the oxidative stress and inflammation processes. Our study showed the critical role of oxidative damage and inflammation in ethanol induced hepatotoxicity that markedly was inhibited by administration of atorvastatin. Therefore, atorvastatin can be suggested for prevention of ethanol induced hepatotoxicity. PMID- 28855944 TI - Anti-inflammatory effect of apigenin and hydroalcoholic extract of Dracocephalum kotschyi on acetic acid-induced colitis in rats. AB - Colitis is an inflammatory disease of the intestine with unknown etiology involving multiple immune, genetic, and environmental factors. We were interested to examine the effect of total extract from Dracocephalum kotschyi (D. kotschyi) Boiss. on the experimental colitis. D. kotschyi hydroalcoholic extract (10, 20, and 40 mg/kg) or apigenin (5, 10, and 20 mg/kg) were administered orally 2 h prior to induction of colitis which was induced by intrarectal administration of acetic acid (4%) in rats. Prednisolone (4 m/kg) was used as the standard drug for comparison. Biochemical evaluation of inflamed colon was performed by measuring myeloperoxidase (MPO) activity. After 5 days treatment, mucosal ulceration was evaluated. Intrarectal instillation of acetic acid caused significant inflammatory reactions as indicated by macroscopic and microscopic changes. The activity of MPO increased in vehicle treated groups while recovered to normal level by pretreatment of animals with D. kotschyi extract, apigenin, or prednisolone. D. kotschyi and apigenin-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared with the vehicle-treated negative control group. The beneficial effect of apigenin was comparable with that of prednisolone. This research has shown the anti inflammatory potential of D. kotschyi extract and apigenin in experimentally induced colitis. PMID- 28855945 TI - Synthesis and antimicrobial evaluation of some 2,5 disubstituted 1,3,4-oxadiazole derivatives. AB - 1,3,4-oxadiazoles are interesting compounds because of their valuable biological effects such as cytotoxic, antibacterial, antifungal, and anti-tubercular activities. Ethyl mandelate was treated with hydrazine hydrate to yield the corresponding acylhydrazide. Some of the 2,5 disubstituted 1,3,4-oxadiazole derivatives were prepared from acylhydrazide using three different procedures. In the first procedure, acylhydrazide was reacted with nitro or chloro aroyle chloride to afford a diacylhydrazide which was cyclized to 2,5-disubstituted 1,3,4-oxadiazole in the presence of phosphoryl chloride as dehydrating agent. In the second procedure, furan-oxadiazole derivative was directly prepared from carboxylic acid and acylhydrazide in one step. In the third procedure, acyl hydrazide was condensed with 5-nitrofuraldehyde to yield 5-nitrofuran-2-yl) methylene)-2-phenyl acetohydrazide intermediate which was cyclized to form the nitrofuran-oxadiazole derivative by acetic anhydride as dehydrating agent. The structures of these compounds have been elucidated by spectral IR and 1H-NMR analysis. All the newly synthesized compounds were screened for their antibacterial and antifungal activities. Compounds F3 and F4 showed remarkable antibacterial activities against Staphylococcus aureus and Escherichia coli bacteria. PMID- 28855946 TI - Evaluation of the central and peripheral effects of doxepin on carrageenan induced inflammatory paw edema in rat. AB - The anti-inflammatory effects of anti-depressants have been demonstrated recently. Doxepin, a tricyclic antidepressant drug (TCA), has some special properties in comparison with the other members of its family. It has some H1, H2, alpha-1 adrenergic and muscarinic receptor blocking effects. It revealed also anti-nociceptive and relatively potent sedative effects. This study was aimed to evaluate its possible anti-inflammatory effect in a well-established animal model. Male Wistar rats weighing 200-250 g were used in carrageenan-induced inflammatory paw edema model. The test and control drugs were injected by intraperitoneal (i.p.) and intracerebral (i.c.v.) routes. The anti-inflammatory activity of doxepin (15, 30 and 60 mg/kg, i.p. and 50 and 100 MUg/rat, i.c.v.) and the reference drug, dexamethasone (2 mg/kg, i.p.) were evaluated by determination and comparison of some involved biological markers including the paw volume, cytokine levels (interleukin 6 (IL-6), IL-1beta, tumor necrosis factor alpha (TNFalpha)), myeloperoxidase (MPO) activity and histopathological parameters. All i.p. doses of doxepin showed significant anti-inflammatory effect. It also significantly reduced MPO activity and cytokine levels and improved histopathologic parameters of carrageenan-injected paw tissues. I.c.v. administration of the drug did not show any significant reduction of carrageenan induced paw edema. Although the exact mechanism of the anti-inflammatory effect of doxepin is not clear, it seems that reduced leukocyte migration and pro inflammatory cytokines play important role in its anti-inflammatory effect. Also central sites are not involved in the anti-inflammatory effect of the drug. PMID- 28855947 TI - Oral Chinese Herbal Medicine as an Adjuvant Treatment for Chemotherapy, or Radiotherapy, Induced Myelosuppression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: Myelosuppression is a common side effect in cancer patients receiving chemotherapy or radiotherapy. Chinese herbal medicine (CHM) has shown promise in alleviating myelosuppression. METHOD: We searched for randomized controlled trials (RCTs) from seven databases without language restriction. We included RCTs in adults, in which hematological toxicity was measured according to WHO criteria and control group underwent chemotherapy and/or radiotherapy and the treatment group was given oral CHM. RESULTS: We searched 1021 articles from the date of databases inception to October 7, 2016. We selected 14 articles for the final analysis. Pooled data showed that CHM significantly decreased the suppression rate of leukocytes, neutrophils, hemoglobin, and platelets compared with the control group, particularly in grade III-IV toxicity (leukocytes: RR = 0.43, 95% CI = 0.33-0.56; neutrophils: RR = 0.39, 95% CI = 0.27-0.58; hemoglobin: RR = 0.33, 95% CI = 0.18-0.61; platelets: RR = 0.61, 95% CI = 0.39-0.95). CONCLUSIONS: CHM as an adjuvant can alleviate myelosuppression induced by chemotherapy or radiotherapy, reduce grade III-IV toxicity, and maintain therapeutic dose and treatment cycle. However, due to heterogeneity and publication bias, the results should be interpreted with caution and validated by conducting strictly designed multicenter RCTs of high quality and large scale. PMID- 28855948 TI - Astragalus Granule Prevents Ca2+ Current Remodeling in Heart Failure by the Downregulation of CaMKII. AB - BACKGROUND: Astragalus was broadly used for treating heart failure (HF) and arrhythmias in East Asia for thousands of years. Astragalus granule (AG), extracted from Astragalus, shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca2+ current (ICa-L) in HF mice by the downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). METHODS: HF mice were induced by thoracic aortic constriction (TAC). After 4 weeks of AG treatment, cardiac function and QT interval were evaluated. Single cardiac ventricular myocyte was then isolated and whole-cell patch clamp was used to record action potential (AP) and ICa-L. The expressions of L-type calcium channel alpha 1C subunit (Cav1.2), CaMKII, and phosphorylated protein kinase A (p-PKA) were examined by western blot. RESULTS: The failing heart manifested distinct electrical remodeling including prolonged repolarization time and altered ICa-L kinetics. AG treatment attenuated this electrical remodeling, supported by AG related shortened repolarization time, decreased peak ICa-L, accelerated ICa-L inactivation, and positive frequency-dependent ICa-L facilitation. In addition, AG treatment suppressed the overexpression of CaMKII, but not p-PKA, in the failing heart. CONCLUSION: AG treatment protected the failing heart against electrical remodeling and ICa-L remodeling by downregulating CaMKII. PMID- 28855949 TI - Ileal antimicrobial peptide expression is dysregulated in old age. AB - In an effort to understand the mechanisms underlying the high prevalence of gastrointestinal tract disorders in old age, we investigated the expression of intestinal antimicrobial peptides in the terminal small intestine of aged mice. Our results show that old mice have reduced transcript levels of ileal alpha defensins and lysozyme, two important types of intestinal antimicrobial peptides produced by Paneth cells. In contrast, expression of the C-type lectins Reg3b and Reg3g, as well as beta-defensin 1, angiogenin 4 and Relmb, which are made by several epithelial cell types, was significantly upregulated in aged animals suggesting an ongoing response to epithelial distress. Those changes in antimicrobial peptide gene expression associated with histological damage of the ileal epithelium and subtle modifications in the composition of the commensal microbiota. Our findings suggest that dysregulation of antimicrobial peptides expression is a feature of homeostasis disruption in the aged intestine and may contribute to geriatric gastrointestinal dysfunction. PMID- 28855950 TI - Sea urchin growth dynamics at microstructural length scale revealed by Mn labeling and cathodoluminescence imaging. AB - BACKGROUND: Fluorochrome staining is among the most widely used techniques to study growth dynamics of echinoderms. However, it fails to detect fine-scale increments because produced marks are commonly diffusely distributed within the skeleton. In this paper we investigated the potential of trace element (manganese) labeling and subsequent cathodoluminescence (CL) imaging in fine scale growth studies of echinoderms. RESULTS: Three species of sea urchins (Paracentrotus lividus, Echinometra sp. and Prionocidaris baculosa) were incubated for different periods of time in seawater enriched in different Mn2+ concentrations (1 mg/L; 3 mg/L; 61.6 mg/L). Labeling with low Mn2+ concentrations (at 1 mg/L and 3 mg/L) had no effect on behavior, growth and survival of sea urchins in contrast to the high Mn2+ dosage (at 61.6 mg/L) that resulted in lack of skeleton growth. Under CL, manganese produced clearly visible luminescent growth fronts in these specimens (observed in sectioned skeletal parts), which allowed for a determination of the average extension rates and provided direct insights into the morphogenesis of different types of ossicles. The three species tend to follow the same patterns of growth. Spine growth starts with the formation of microspines which are simultaneously becoming reinforced by addition of thickening layers. Spine septa develop via deposition of porous stereom that is rapidly (within less than 2 days) filled by secondary calcite. Development of the inner cortex in cidaroids begins with the formation of microspines which grow at ~3.5 MUm/day. Later on, deposition of the outer polycrystalline cortex with spinules and protuberances proceeds at ~12 MUm/day. The growth of tooth can be rapid (up to ~1.8 mm/day) and starts with the formation of primary plates (pp) in plumula. Later on, during the further growth of pp in aboral and lateral directions, secondary extensions develop inside (in chronological order: lamellae, needles, secondary plate, prisms and carinar processes), which are increasingly being solidified towards the incisal end. Interradial growth in the ambital interambulacral test plates exceeds meridional growth and inner thickening. CONCLUSIONS: Mn2+ labeling coupled with CL imaging is a promising, low-cost and easily applicable method to study growth dynamics of echinoderms at the micro-length scale. The method allowed us to evaluate and refine models of echinoid skeleton morphogenesis. PMID- 28855952 TI - Assessment of museum staff exposure to arsenic while handling contaminated exhibits by urinalysis of arsenic species. AB - Preservation of museum objects with inorganic arsenic compounds and contamination of the surroundings has previously been documented. The present study addresses the exposure of museum staff by measuring arsenicals in urine. After 1 week without exposure, urinary samples were taken before and after handling of preserved skins and analysed by HPLC-ICP-MS for inorganic arsenic, arsenic metabolites and arsenobetaine. The sum of inorganic arsenic and metabolites was an index of exposure. Information about work and seafood intake was obtained by questionnaire. One out of five subjects had a work-related rise in the exposure index of 18.1 MUg As/L to a post-exposure level of 37.1 MUg As/L. Four subjects had no certain exposure-related increase in the index. The study indicates that museum staff may be exposed to arsenic from handling arsenic-preserved objects and supports the use of specified arsenic analysis to avoid interference from organic arsenic. PMID- 28855951 TI - Migrating pleural plaque in a patient with asbestos induced pleural disease: a case report. AB - BACKGROUND: Health surveillance of formerly asbestos exposed individuals focus on early detection of asbestos related diseases, such as lung fibrosis (asbestosis), pleural plaques, mesothelioma and lung cancer in particular. One main concern is the early and clear identification of lesions with a high risk of malignant changes and their undelayed clinical work-up. False positive results may lead to unnecessary and often painful diagnostic interventions, which create high costs when applied to a large cohort and also may discredit the whole program. We describe an unusual presentation of a common lesion among asbestos exposed individuals, which has to our knowledge never been described before. Being aware of this pathological pathway may prevent inadequate clinical decisions with disadvantages for the patient. Underlying implications regarding health surveillance and the reading of CT-scans of the thorax are important for the management of formerly asbestos exposed individuals. CASE PRESENTATION: During follow-up of an asbestos exposed 72 year old former power plant worker with known pleural changes, a nodule located next to the left costophrenic angle was newly discovered on CT-scan. As the previous scan 1 year before did not show any changes in that area, a fast growing tumour was suspected and an immediate biopsy performed. The tissue showed the characteristics of a pleural plaque with no signs of malignancy. After carefully reviewing all previous radiographs a rounded opacity attached to the mediastinal pleura close to the oesophagus and slightly cranial to the position of the removed nodule could be discerned. That nodule had increased in size over several years and was no longer visible on the latest scan. It appeared that the originally slow growing plaque had migrated to the costophrenic angle some time before it was discovered in the latest scan thus imposing as a fast growing tumour. CONCLUSIONS: We concluded that asbestos related pleural plaques can under special circumstances get separated from the pleura and migrate to another position in the pleural cavity. The case provides new insights in the development and properties of pleural lesions and may offer new options for the management of formerly asbestos exposed patients. PMID- 28855953 TI - Work participation of patients with musculoskeletal disorders: is this addressed in physical therapy practice? AB - BACKGROUND: Musculoskeletal disorders are the main complaints for visiting a physical therapist (PT) in primary health care; they have a negative effect on an individual's quality of life and result in a major cost to society. Qualitative research has shown that physical therapists (PTs) treating patients with these disorders experience barriers in the integration of occupational factors within their practice, and also revealed a lack of cooperation between PTs and (other) occupational healthcare providers. The aim of this study is to quantitatively investigate how generalist PTs in the Netherlands, who treat patients with musculoskeletal disorders, currently integrate occupational factors within their practice, and to identify their opinions and needs with regard to enhancing the integration of the patient's work within physical therapy practice. METHODS: A cross-sectional survey was conducted among generalist PTs who treat working-age (18-67 years) patients with musculoskeletal disorders. Generalist PTs were contacted for participation via digital news-mails and asked to fill out an online survey which was developed based on the results of a recent qualitative study. The survey consisted of: i) demographics of the participants, ii) questions on how generalist PTs currently integrate occupational factors within their practice, and iii) asked their opinion about the integration of occupational factors within physical therapy. The PTs were also asked about their needs with regard to the integration of occupational factors and with regard to cooperation with other (occupational) health professionals. All answers (using Likert scales) are presented as the number and percentage of the respondents reporting those specific answers, whereas all other answers are presented as means and standard deviations. RESULTS: Of the 142 respondents, 64% indicated that occupational factors should be addressed to a greater extent within physical therapy. To have the possibility to bill for a workplace assessment (60.6%) and more knowledge about laws and regulations (50%) were identified as needs of the respondents. Only 14.8% of the respondents indicated that they communicate with or consult a PT specialized in occupational health. Only 12.7% of the participants who do not have a specialized PT within their practice sometimes/regularly refer patients to a specialized PT. CONCLUSIONS: Although generalist PTs address occupational factors within their practice, there is room for improvement. This study also identified a lack of cooperation between generalist PTs and PTs specialized in occupational health. PMID- 28855954 TI - Exclusive breastfeeding status of children aged between 6 and 24 months in the nomadic population of Hadaleala district, Afar Region, northeast Ethiopia. AB - BACKGROUND: Exclusive breastfeeding (EBF) during infancy is fundamental, however it is not fully practiced in the nomadic population of Ethiopia. In Ethiopia, there is still a lack of information on the implementation of the EBF, especially among the nomadic population. This study was conducted to assess the EBF status of children during their first 6 months of life, who are now aged between 6 and 24 months, in the nomadic population of Afar region. The study also aimed to identify factors affecting exclusive breastfeeding. METHODS: A community based cross-sectional study was conducted from April to May, 2015 to assess EBF of children aged between 6 and 24 months during the first 6 months of life. Exclusive breastfeeding is defined as consuming only breast milk (including expressed breast milk) during the first 6 months and no other liquids and solid foods except medications, and non exclusive breastfeeding is taking liquids and solid foods in addition to breast milk. The cluster sampling technique was used to select the study participants. Data were collected from 254 households using a structured questionnaire. RESULTS: One hundred eighty eight of the children were fed breast milk exclusively for the first 6 months of age; the rate of EBF in the study area was 74% (95% CI 70, 78%). One hundred fifty four (60.6%) of the children received breast milk within 1 h immediately after birth and 207 (81.5%) of the children maintained breastfeeding at the time of the survey. Exclusive breastfeeding was statistically associated with mothers aged above 35 years (AOR 8.3, 95% CI 1.7, 40.3), commencing to breastfeed in first hour (AOR 3.5, 95% CI 1.8, 6.9), and parents who didn't migrate or move to a more comfortable area (AOR 4.6, 95% CI 1.5, 14.4). CONCLUSION: Exclusive breastfeeding was not fully practiced in the study area. Therefore, promotion of infant and young children feeding (IYCF) is needed in the area to strengthen EBF practices. Moreover, child feeding practices should be integrated with the existing health system and attention should be given to the nomadic mothers. PMID- 28855955 TI - Microaspiration of Solanum tuberosum root cells at early stages of infection by Globodera pallida. AB - BACKGROUND: Sedentary endoparasitic cyst nematodes form a feeding structure in plant roots, called a syncytium. Syncytium formation involves extensive transcriptional modifications, which leads to cell modifications such as increased cytoplasmic streaming, enlarged nuclei, increased numbers of organelles, and replacement of a central vacuole by many small vacuoles. When whole root RNA is isolated and analyzed, transcript changes manifested in the infected plant cells are overshadowed by gene expression from cells of the entire root system. Use of microaspiration allows isolation of the content of nematode infected cells from a heterogeneous cell population. However, one challenge with this method is identifying the nematode infected cells under the microscope at early stages of infection. This problem was addressed by staining nematode juveniles with a fluorescent dye prior to infection so that the infected cells could be located and microaspirated. RESULTS: In the present study, we used the fluorescent vital stain PKH26 coupled with a micro-rhizosphere chamber to locate the infected nematode Globodera pallida in Solanum tuberosum root cells. This enabled microaspiration of nematode-infected root cells during the early stages of parasitism. To study the transcriptional events occurring in these cells, an RNA isolation method from microaspirated samples was optimized, and subsequently the RNA was purified using magnetic beads. With this method, we obtained an RNA quality number of 7.8. For transcriptome studies, cDNA was synthesized from the isolated RNA and assessed by successfully amplifying several pathogenesis related protein coding genes. CONCLUSION: The use of PKH26 stained nematode juveniles enabled early detection of nematode infected cells for microaspiration. To investigate transcriptional changes in low yielding RNA samples, bead-based RNA extraction procedures minimized RNA degradation and provided high quality RNA. This protocol provides a robust procedure to analyze gene expression in nematode infected cells. PMID- 28855956 TI - Kinetic modelling: an integrated approach to analyze enzyme activity assays. AB - BACKGROUND: In general, enzyme activity is estimated from spectrophotometric data, by taking the slope of the linear part of the progress curve describing the rate of change in the substrate or product monitored. As long as the substrate concentrations are sufficiently high to saturate the enzyme and, the velocity of the catalyzed reaction is directly proportional to the enzyme concentration. Under these premises, this velocity can be taken as a measure of the amount of active enzyme present. Estimation of the enzyme activity through linear regression of the data should only be applied when linearity is true, which is often not the case or has not been checked. RESULTS: In this paper, we propose a more elaborate method, based on a kinetic modelling approach, to estimate the in vitro specific enzyme activity from spectrophotometric assay data. As a case study, kinetic models were developed to estimate the activity of the enzymes pyruvate decarboxylase and alcohol dehydrogenase extracted from 'Jonagold' apple (Malus x domestica Borkh. cv. 'Jonagold'). The models are based on Michaelis Menten and first order kinetics, which describe the reaction mechanism catalyzed by the enzymes. CONCLUSIONS: In contrast to the linear regression approach, the models can be used to estimate the enzyme activity regardless of whether linearity is achieved since they integrally take into account the complete progress curve. The use of kinetic models to estimate the enzyme activity can be applied to all other enzymes as long as the underlying reaction mechanism is known. The kinetic models can also be used as a tool to optimize the enzyme assays by systematically studying the effect of the various design parameters. PMID- 28855957 TI - Discrimination of boron tolerance in Pisum sativum L. genotypes using a rapid, high-throughput hydroponic screen and precociously germinated seed grown under far-red enriched light. AB - BACKGROUND: Boron (B) tolerance has been identified as a key target for field pea improvement. Screening for B tolerance in the field is problematic due to variability in space and time, and robust B molecular markers are currently unavailable in field pea. There has been recent progress in developing protocols that can accelerate the life cycle of plants to enable rapid generation turnover in single seed descent breeding programs. A robust B screening protocol that can be fully integrated within an accelerated single seed descent system could lead to rapid identification and introgression of B tolerance into field pea genotypes. Integration with an accelerated single seed descent system requires: (1) screening under artificially lit, temperature-controlled conditions; (2) capacity to use immature precociously germinated seed (PGS); (3) recovery of lines without significant time penalty; and (4) good correlation with results from established screening protocols. RESULTS: We present herein a B toxicity screening system for field pea based on hydroponic growth of PGS in a light and temperature controlled environment that allows recovery of seedlings for rapid seed production. Screening results were compared to traditional methods for B tolerance screening in B-laced soil and with published field tolerance ratings. B tolerance was scored 17 days after sowing using leaf symptoms as a metric. Plants were then transferred to soil with maximum of six days delay in flowering compared to a typical accelerated single seed descent system generation. The use of PGS had minimal impact on B tolerance rankings compared to plants grown from mature seed. The leaf tolerance rankings from hydroponic-grown plants correlated well with those from soil-grown plants, and consistently identified the most tolerant genotypes. CONCLUSIONS: Our 17 day screening protocol represents a major time-saving over previously published B screening protocols for field pea, thereby extending the application of the protocol to traditional single seed descent systems or RIL screening. We anticipate that small modifications to the proposed technique will make it applicable to screen for other individual abiotic stresses, or allow studies of the interactions between B tolerance and stresses such as salinity. PMID- 28855958 TI - Proteins associated with the doubling time of the NCI-60 cancer cell lines. AB - The varied nature of human cancers is recapitulated, at least to some extent, in the diverse NCI-60 panel of human cancer cell lines. Here, I used a basic, continuous variable of proliferating cells, their doubling time, to stratify the proteome across the NCI-60 cell lines. Among >7000 proteins quantified in the NCI 60 panel previously, the levels of 84 proteins increase in cells that proliferate slowly. This set overlapped with the hallmark molecular signature "epithelial mesenchymal transition (EMT)" (p value = 1.1E-07). Conversely, the levels of 105 proteins increased in cells that proliferate faster and overlapped with the molecular signatures for "MYC targets V1" (p value = 3.8E-38) and "E2F targets" (p value = 2.4E-34). These data for the first time identify proteins whose levels are dynamically associated with doubling time, but not necessarily with cancer type origins, and argue for the incorporation of doubling time measurements in cell line-based profiling studies. PMID- 28855959 TI - Are forest disturbances amplifying or canceling out climate change-induced productivity changes in European forests? AB - Recent studies projecting future climate change impacts on forests mainly consider either the effects of climate change on productivity or on disturbances. However, productivity and disturbances are intrinsically linked because 1) disturbances directly affect forest productivity (e.g. via a reduction in leaf area, growing stock or resource-use efficiency), and 2) disturbance susceptibility is often coupled to a certain development phase of the forest with productivity determining the time a forest is in this specific phase of susceptibility. The objective of this paper is to provide an overview of forest productivity changes in different forest regions in Europe under climate change, and partition these changes into effects induced by climate change alone and by climate change and disturbances. We present projections of climate change impacts on forest productivity from state-of-the-art forest models that dynamically simulate forest productivity and the effects of the main European disturbance agents (fire, storm, insects), driven by the same climate scenario in seven forest case studies along a large climatic gradient throughout Europe. Our study shows that, in most cases, including disturbances in the simulations exaggerate ongoing productivity declines or cancel out productivity gains in response to climate change. In fewer cases, disturbances also increase productivity or buffer climate-change induced productivity losses, e.g. because low severity fires can alleviate resource competition and increase fertilization. Even though our results cannot simply be extrapolated to other types of forests and disturbances, we argue that it is necessary to interpret climate change-induced productivity and disturbance changes jointly to capture the full range of climate change impacts on forests and to plan adaptation measures. PMID- 28855960 TI - Resuscitative Endovascular Balloon Occlusion of the Aorta in trauma: a systematic review of the literature. AB - AIMS: Resuscitative endovascular balloon occlusion of the aorta has been a hot topic in trauma resuscitation during these last years. The aims of this systematic review are to analyze when, how, and where this technique is performed and to evaluate preliminary results. METHODS: The literature search was performed on online databases in December 2016, without time limits. Studies citing endovascular balloon occlusion of the aorta in trauma were retrieved for evaluation. RESULTS: Sixty-one articles met the inclusion criteria and were selected for the systematic review. Overall, they included 1355 treated with aortic endovascular balloon occlusion, and 883 (65%) patients died after the procedure. In most of the included cases, a shock state seemed to be present before the procedure. Time of death and inflation site was not described in the majority of included studies. Procedure-related and shock-related complications are described. Introducer sheath size and comorbidity seems to play the role of risk factors. CONCLUSIONS: Resuscitative endovascular balloon occlusion of the aorta is increasingly used in trauma victim resuscitation all over the world, to elevate blood pressure and limit fluid infusion, while other procedures aimed to stop the bleeding are performed. High mortality rate is probably due to the severity of the injuries. Time and place of balloon insertion, zone of balloon inflation, and inflation cutoff time are very heterogeneous. PMID- 28855961 TI - The mental health and help-seeking behaviour of resettled Afghan refugees in Australia. AB - BACKGROUND: Psychological trauma, in particular, posttraumatic stress disorder (PTSD) and depression, are highly prevalent among resettled refugees. However, little is known regarding the mental health status and associated help-seeking behaviour of resettled Afghan refugees in Australia. METHODS: A sample of 150 resettled Afghan refugees (74 males; mean age 32.8 years, SD = 12.2) living in Adelaide, South Australia were recruited. Self-reported measures of PTSD, depression, exposure to traumatic events, functional impairment, self-recognition of PTSD symptomatology and help-seeking behaviours were completed. Multivariate analysis of variables associated with help-seeking was conducted. RESULTS: Forty four percent of participants met criteria for clinically significant PTSD symptoms and all but one participant reported being exposed to 1 or more traumatic and/or conflict related events, such as 'losing your property and wealth'. Moreover, 14.7% of participants had symptoms suggestive of clinically significant depression. General practitioners were the most common source of help in relation to mental health problems, with very few participants (4.6%) seeking help from specialist trauma and torture mental health services. Self-recognition of having a PTSD related mental health problem and functional impairment levels were both found to be independent predictors of help-seeking (p <= .05). CONCLUSIONS: The findings provide further evidence for high rates of PTSD symptomatology and low uptake of mental care among resettled refugees. Poor self recognition of the presence and/or adverse impact of PTSD symptoms may need to be targeted in mental health promotion programs designed to improve "mental health literacy" and thereby promote early and appropriate help-seeking where this is needed. PMID- 28855962 TI - Does child and adolescent mental health in-service training result in equivalent knowledge gain among cadres of non-specialist health workers in Uganda? A pre test post-test study. AB - BACKGROUND: Early identification and management of child and adolescent mental health (CAMH) disorders helps to avert mental illness in adulthood but a CAMH treatment gap exists in Uganda. CAMH integration into primary health care (PHC) through in-service training of non-specialist health workers (NSHW) using the World Health Organisation (WHO) Mental Health Gap Action Programme (mhGAP) Intervention Guide (IG) is a strategy to address this gap. However, results of such training are not supported by information on training development or delivery; and are undifferentiated by NSHW cadre. We aim to describe an in service CAMH training for NSHW in Uganda and assess cadre-differentiated learning outcomes. METHODS: Thirty-six clinical officers, nurses and midwives from 18 randomly selected PHC clinics in eastern Uganda were trained for 5 days on CAMH screening and referral using a curriculum based on the mhGAP-IG version 1.0 and PowerPoint slides from the International Association of Child and Adolescent Psychiatry and Allied Professions (IACAPAP). The residential training was evaluated through pre- and post- training tests of CAMH knowledge and attitudes using the participants' post-test scores; and the difference between pre-test and post-test scores. Two-tailed t-tests assessed differences in mean pre-test and post-test scores between the cadres; hierarchical linear regression tested the association between cadre and post test scores; and logistic regression evaluated the relationship between cadre and knowledge gain at three pre-determined cut off points. RESULTS: Thirty-three participants completed both pre-and post-tests. Improved mean scores from pre- to post-test were observed for both clinical officers (20% change) and nurse/midwives (18% change). Clinical officers had significantly higher mean test scores than nurses and midwives (p < 0.05) but cadre was not significantly associated with improvement in CAMH knowledge at the 10% (AOR 0.08; 95 CI [0.01, 1.19]; p = 0.066), 15% (AOR 0.16; 95% CI [0.01, 2.21]; p = 0.170), or 25% (AOR 0.13; 95% CI [0.01, 1.74]; p = 0.122) levels. CONCLUSION: We aimed to examine CAMH learning outcomes by NSHW cadre. NSHW cadre does not influence knowledge gain from in-service CAMH training. Thus, an option for integrating CAMH into PHC in Uganda using the mhGAP-IG and IACAPAP PowerPoint slides is to proceed without cadre differentiation. PMID- 28855963 TI - Common mental disorders in asylum seekers and refugees: umbrella review of prevalence and intervention studies. AB - BACKGROUND: In recent years there has been a progressive rise in the number of asylum seekers and refugees displaced from their country of origin, with significant social, economic, humanitarian and public health implications. In this population, up-to-date information on the rate and characteristics of mental health conditions, and on interventions that can be implemented once mental disorders have been identified, are needed. This umbrella review aims at systematically reviewing existing evidence on the prevalence of common mental disorders and on the efficacy of psychosocial and pharmacological interventions in adult and children asylum seekers and refugees resettled in low, middle and high income countries. METHODS: We conducted an umbrella review of systematic reviews summarizing data on the prevalence of common mental disorders and on the efficacy of psychosocial and pharmacological interventions in asylum seekers and/or refugees. Methodological quality of the included studies was assessed with the AMSTAR checklist. RESULTS: Thirteen reviews reported data on the prevalence of common mental disorders while fourteen reviews reported data on the efficacy of psychological or pharmacological interventions. Although there was substantial variability in prevalence rates, we found that depression and anxiety were at least as frequent as post-traumatic stress disorder, accounting for up to 40% of asylum seekers and refugees. In terms of psychosocial interventions, cognitive behavioral interventions, in particular narrative exposure therapy, were the most studied interventions with positive outcomes against inactive but not active comparators. CONCLUSIONS: Current epidemiological data needs to be expanded with more rigorous studies focusing not only on post-traumatic stress disorder but also on depression, anxiety and other mental health conditions. In addition, new studies are urgently needed to assess the efficacy of psychosocial interventions when compared not only with no treatment but also each other. Despite current limitations, existing epidemiological and experimental data should be used to develop specific evidence-based guidelines, possibly by international independent organizations, such as the World Health Organization or the United Nations High Commission for Refugees. Guidelines should be applicable to different organizations of mental health care, including low and middle income countries as well as high income countries. PMID- 28855964 TI - Youth in the midst of escalated political violence: sense of coherence and hope among Jewish and Bedouin Arab adolescents. AB - BACKGROUND: During stressful events, individuals (particularly adolescents) from minority groups are often more vulnerable to distress. This claim will be examined in terms of coping resources and stress reactions to escalated political violence. This study aimed to compare coping resources and stress reactions among adolescents from two ethnic groups in southern Israel-Jews and Bedouin Arabs during a period of escalated political violence (November 2012). The Bedouin Arab group is the ethnic minority of the sample and thus may be more at risk compared to the Jewish group. METHODS: Data were gathered from 78 Jews and 91 Bedouin Arabs (14-18 years old) by using convenience sampling method. Adolescents were contacted via the Internet or in person by the research team and they completed self-report questionnaires including the Sense Of Coherence Scale (SOC), Hope Index, State Anxiety Inventory, and State Anger Inventory. After a preliminary chi2 analysis of the sample characteristics, three main sets of analyses were conducted including a two-way MANOVA, zero-order correlations between study variables, and hierarchical multiple regressions. RESULTS: Bedouin Arab adolescents reported lower levels of SOC (F(1, 158) = 3.88, p = 0.04) and higher levels of individual and collective hope (F(1, 158) = 3.94, p = 0.03; F(1, 158) = 17.41, p = 0.001, respectively), as compared to Jewish adolescents. The Bedouin adolescents also reported higher levels of state anger (F(1, 158) = 5.58, p = 0.02). We identified cultural similarities related to the predictive power of coping resources (SOC and individual hope) in explaining state anger (beta = 0.29, p = 0.001; beta = -0.18, p = 0.045, respectively). However, cultural differences were found to affect the ability of SOC to predict state anxiety; SOC contributed significantly to state anxiety only among the Jewish adolescents (beta = -0.45, p < 0.001). CONCLUSION: These results emphasize the significance of addressing cultural/ethnic factors in attempts to understand mental-health issues among youth during periods of escalated political violence. PMID- 28855965 TI - Thermotolerant genes essential for survival at a critical high temperature in thermotolerant ethanologenic Zymomonas mobilis TISTR 548. AB - BACKGROUND: High-temperature fermentation (HTF) technology is expected to reduce the cost of bioconversion of biomass to fuels or chemicals. For stable HTF, the development of a thermotolerant microbe is indispensable. Elucidation of the molecular mechanism of thermotolerance would enable the thermal stability of microbes to be improved. RESULTS: Thermotolerant genes that are essential for survival at a critical high temperature (CHT) were identified via transposon mutagenesis in ethanologenic, thermotolerant Zymomonas mobilis TISTR 548. Surprisingly, no genes for general heat shock proteins except for degP were included. Cells with transposon insertion in these genes showed a defect in growth at around 39 degrees C but grew normally at 30 degrees C. Of those, more than 60% were found to be sensitive to ethanol at 30 degrees C, indicating that the mechanism of thermotolerance partially overlaps with that of ethanol tolerance in the organism. Products of these genes were classified into nine categories of metabolism, membrane stabilization, transporter, DNA repair, tRNA modification, protein quality control, translation control, cell division, and transcriptional regulation. CONCLUSIONS: The thermotolerant genes of Escherichia coli and Acetobacter tropicalis that had been identified can be functionally classified into 9 categories according to the classification of those of Z. mobilis, and the ratio of thermotolerant genes to total genomic genes in Z. mobilis is nearly the same as that in E. coli, though the ratio in A. tropicalis is relatively low. There are 7 conserved thermotolerant genes that are shared by these three or two microbes. These findings suggest that Z. mobilis possesses molecular mechanisms for its survival at a CHT that are similar to those in E. coli and A. tropicalis. The mechanisms may mainly contribute to membrane stabilization, protection and repair of damage of macromolecules and maintenance of cellular metabolism at a CHT. Notably, the contribution of heat shock proteins to such survival seems to be very low. PMID- 28855966 TI - Correlating pre-operative MRI measurements of metatarsal Osteomyelitis with surgical clean margins reveals the need for a one centimeter resection margin. AB - BACKGROUND: Due to the high incidence of forefoot ulcerations with associated osteomyelitis, there has been an increased demand for partial ray amputations. In order to ensure complete removal of infected metatarsal bone, a clean margin amount is chosen based on the surgeon's intraoperative visual subjective evaluation. The margin is resected and sent to pathology. Currently the literature shows positive proximal margin rates of 35-40%. The purpose of this study was to reduce the rate of positive proximal margins by effectively resecting all infected bone using pre-operative MRI measurements with an added resection margin. METHODS: Twenty-four osteomyelitis positive metatarsals were included in this exploratory study. The distance of proximal osteomyelitic extension within the metatarsal was measured on MRI in centimeters. Intra operatively, the partial ray amputation cut was determined by adding an extra 0.5 cm resection margin to the MRI measurement. At the study's mid-point, bone histopathology revealed an increase in positive proximal margin rates-so the resection margin was increased to 1 cm. Descriptive outcomes included the mean distance of osteomyelitis propagation, proximal margin rates, as well as diagnostic statistics. RESULTS: After removing the specimens with false positive MRI results, the study sample included 21 metatarsals positive for osteomyelitis. A 0.5 cm resection margin proximal to the osteomyelitis resulted in a 50% positive proximal margin rate. After increasing the resection margin to 1 cm, there was found to be an improved positive proximal margin rate of 9%. Based on MRI findings, the mean distance + standard deviation of osteomyelitis propagation along the metatarsal proximally was 1.81 cm + 0.74 cm. The metatarsal specimen was processed by pathology into multiple pieces and compared to MRI, resulting in MRI sensitivity of 67%, specificity of 74%, positive predictive value of 79%, and negative predictive value of 60%. CONCLUSIONS: By performing a 1 cm resection margin proximal to the metatarsal osteomyelitis the proximal margin rate was reduced to clinically meaningful levels. These preliminary findings support using a 1 cm resection margin when performing any form of metatarsal amputation, to reduce the risk of residual osteomyelitis post-operatively. TRIAL REGISTRATION: St. Luke's Hospital, IRB National Protocol ID SLHN2015-112. Date:1-13-16. PMID- 28855967 TI - QUANTIFYING NANOPARTICLE TRANSPORT IN VIVO USING HYPERSPECTRAL IMAGING WITH A DORSAL SKINFOLD WINDOW CHAMBER. AB - We have developed a noninvasive imaging method to quantify in vivo drug delivery pharmacokinetics without the need for blood or tissue collection to determine drug concentration. By combining the techniques of hyperspectral imaging and a dorsal skinfold window chamber, this method enabled the real-time monitoring of vascular transport and tissue deposition of nanoparticles labeled with near infrared (NIR) dye. Using this imaging method, we quantified the delivery pharmacokinetics of the native high-density lipoprotein (HDL) and epidermal growth factor receptor (EGFR)-targeted HDL nanoparticles and demonstrated these HDLs had long circulation time in blood stream (half-life >12 h). These HDL nanoparticles could efficiently carry cargo DiR-BOA to extravasate from blood vessels, diffuse through extracellular matrix, and penetrate and be retained in the tumor site. The EGFR targeting specificity of EGFR-targeted HDL (EGFR specific peptide conjugated HDL) was also visualized in vivo by competitive inhibition with excess EGFR-specific peptide. In summary, this imaging technology may help point the way toward the development of novel imaging-based pharmacokinetic assays for preclinical drugs and evaluation of drug delivery efficiency, providing a dynamic window into the development and application of novel drug delivery systems. PMID- 28855968 TI - Erratum: Predictors of Success in the Treatment of Obstructive Sleep Apnea Syndrome with Mandibular Repositioning Appliance: A Systematic Review. AB - [This corrects the article DOI: 10.1055/s-0034-1393957.]. PMID- 28855969 TI - Development of low-volume, high-intensity, aerobic-type interval training for elderly Japanese men: a feasibility study. AB - BACKGROUND: The purposes of this study were to identify 1) the feasibility of a novel exercise protocol (elderly Japanese male version of high-intensity interval aerobic training: EJ-HIAT) and 2) its preliminary data (%VO2peak, rating of perceived exertion) in comparison with traditional moderate-intensity continuous aerobic training (MICT). RESULTS: Twenty-one sedentary elderly men, aged 60-69 years, performed two exercise protocols: EJ-HIAT, consisting of 3 sets of 2-3-min cycling at 75-85%VO2peak with 1- 2-min active rests at 50%VO2peak between sets, and MICT, consisting of 40-min cycling at 65%VO2peak. The completion rate, defined as the rate of participants who 1) did not demand withdrawal, 2) were not interrupted by the tester, and 3) did not change the workload during either exercise protocol, of EJ-HIAT was similar to that of MICT (EJ-HIAT: 100%, MICT: 95.2%). Maximal perceived exertion ratings assessed by Borg scale were also similar between EJ-HIAT and MICT. However, objectively measured maximal intensity assessed by %VO2peak was higher for EJ-HIAT than for MICT (EJ-HIAT: 86.0 +/- 5.6%, MICT: 67.1 +/- 6.4%). CONCLUSION: These results suggested that EJ-HIAT has good feasibility and perceived exertion similar to MICT despite having higher objectively measured intensity than MICT. An intervention aimed as identifying the effects of EJ-HIAT on exercise tolerance should be performed in the future. TRIAL REGISTRATION: UMIN000021185 (February 26, 2016). PMID- 28855970 TI - Lactase persistence in Tunisia as a result of admixture with other Mediterranean populations. AB - BACKGROUND: The ability to digest lactose after weaning, namely, lactase persistence (LP), is encoded by polymorphisms in the MCM6 gene and varies widely in frequency among different human populations. Although, evolution of LP-related genetic variants was investigated in many groups of Sub-Saharan African, Middle Eastern, and European ancestry, only few studies have focused on populations from North Africa and no data are especially available from the Tunisian one. For this reason, there is an urgent need to investigate the frequency patterns at these loci in Tunisia since this adaptive trait is implicated in health. METHODS: Forty SNPs covering the LCT/MCM6 genes and including the two functional variants - 13,910 C > T and - 22,018 G > A were genotyped in 117 Tunisian individuals using the Sequenom Mass Array technology. The observed nucleotide and haplotype patterns of variation were then compared with those of several African, European, and Mediterranean human groups for which comparable data were publicly available. Admixture analysis on a 5 Mb genomic region surrounding the LCT/MCM6 loci was also performed by extracting genotypes from a previously generated genome-wide dataset in order to deepen the reconstruction of the evolutionary history of these loci. RESULTS: We found that lactase non-persistence (LNP)-related alleles and haplotypes were predominantly present in the examined population. A clear differentiation between Tunisian, African, and North European/North Italian samples was found, while the Tunisian population showed more genetic affinity to Central and South Italian groups. CONCLUSIONS: Our study provided a first report of LP-associated alleles and haplotypes in the Tunisian population. We highlighted a gradient followed by LP diffusion from Europe to North Africa. Based on the rich historic background of Tunisia, we suggest that this adaptive trait was introduced in that geographic region by a relatively recent gene flow. PMID- 28855972 TI - Epigenetic response of imprinted domains during carcinogenesis. AB - BACKGROUND: Imprinted domains have been identified as targets for aberrant DNA methylation during carcinogenesis, but it remains unclear when these epigenetic alterations occur and how they contribute to tumor progression. Epigenetic instability at key cis-regulatory elements within imprinted domains can concomitantly activate proto-oncogenes and turn off tumor suppressor genes. Thus, to further characterize the epigenetic response of imprinted domains during carcinogenesis, we compared the stability of DNA methylation at a variety of cis regulatory elements within imprinted domains in two fundamentally different mouse tumors, benign and malignant, induced by the KrasG12D mutation. RESULTS: We report that imprinted domains remain stable in benign processes but are highly susceptible to epigenetic alterations in infiltrative lesions. The preservation of DNA methylation within imprinted domains in benign tumors throughout their duration suggests that imprinted genes are not involved with the initiation of carcinogenesis or the growth of tumors. However, the frequent detection of DNA methylation changes at imprinting control regions in infiltrative lesions suggest that imprinted genes are associated with tumor cells gaining the ability to defy tissue boundaries. CONCLUSION: Overall, this study demonstrates that imprinted domains are targeted for DNA hypermethylation when benign tumor cells transition to malignant. Thus, monitoring DNA methylation within imprinted domains may be useful in evaluating the progression of neoplasms. PMID- 28855971 TI - The effect of Nipped-B-like (Nipbl) haploinsufficiency on genome-wide cohesin binding and target gene expression: modeling Cornelia de Lange syndrome. AB - BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl+/- mice that recapitulate the CdLS phenotype. RESULTS: We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. CONCLUSIONS: Decreased cohesin binding at the gene regions is directly linked to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development. PMID- 28855973 TI - Severe asthma and quality of life. AB - Severe asthma has a great impact on the quality of life (QOL) of patients and their families. The magnitude of this morbidity is affected by several personal factors including age. Appropriate asthma control and modifications of social roles and activities are expected to improve QOL. Biologics, primarily monoclonal antibodies, have been developed to target specific pathways and molecules important in the pathogenesis of asthma. The use of biologics has shown some promising effects on the QOL of patients with severe recalcitrant asthma. Other potential measures involve targeting risk factors and comorbidities and improving the levels of adherence to therapy. This article briefly reviews the impact of severe asthma on QOL and the potential methods to combat this morbidity including the available therapeutic biologics. PMID- 28855975 TI - Case Report: Unusual Manifestation of KIT Negative Systemic Mastocytosis. AB - Aggressive systemic mastocytosis is a rare hematologic neoplastic disease that presents with a poor prognosis and low survival rate. It typically manifests with symptoms associated to mast cell release of bioactive substances, causing anaphylaxis, flushing, autonomic and hemodynamic instability, gastric distress and headache. Moreover, more than 95% of cases are related to a mutation in codon 816 of the KIT gene, located on human chromosome 4q12 which codes for a type III receptor tyrosine kinase. We present a 78 year-old Hispanic man diagnosed with the aggressive subtype of systemic mastocytosis, who had an atypical manifestation and a KIT negative variant. The diagnosis was confirmed based on pathologic and serologic findings which included mast cell infiltration of the spleen and bone marrow, malignant ascites and an unusually elevated serum tryptase. PMID- 28855974 TI - The skin microbiome: impact of modern environments on skin ecology, barrier integrity, and systemic immune programming. AB - Skin barrier structure and function is essential to human health. Hitherto unrecognized functions of epidermal keratinocytes show that the skin plays an important role in adapting whole-body physiology to changing environments, including the capacity to produce a wide variety of hormones, neurotransmitters and cytokine that can potentially influence whole-body states, and quite possibly, even emotions. Skin microbiota play an integral role in the maturation and homeostatic regulation of keratinocytes and host immune networks with systemic implications. As our primary interface with the external environment, the biodiversity of skin habitats is heavily influenced by the biodiversity of the ecosystems in which we reside. Thus, factors which alter the establishment and health of the skin microbiome have the potential to predispose to not only cutaneous disease, but also other inflammatory non-communicable diseases (NCDs). Indeed, disturbances of the stratum corneum have been noted in allergic diseases (eczema and food allergy), psoriasis, rosacea, acne vulgaris and with the skin aging process. The built environment, global biodiversity losses and declining nature relatedness are contributing to erosion of diversity at a micro-ecological level, including our own microbial habitats. This emphasises the importance of ecological perspectives in overcoming the factors that drive dysbiosis and the risk of inflammatory diseases across the life course. PMID- 28855977 TI - Multi-level and hybrid modelling approaches for systems biology. AB - During the last decades, high-throughput techniques allowed for the extraction of a huge amount of data from biological systems, unveiling more of their underling complexity. Biological systems encompass a wide range of space and time scales, functioning according to flexible hierarchies of mechanisms making an intertwined and dynamic interplay of regulations. This becomes particularly evident in processes such as ontogenesis, where regulative assets change according to process context and timing, making structural phenotype and architectural complexities emerge from a single cell, through local interactions. The information collected from biological systems are naturally organized according to the functional levels composing the system itself. In systems biology, biological information often comes from overlapping but different scientific domains, each one having its own way of representing phenomena under study. That is, the different parts of the system to be modelled may be described with different formalisms. For a model to have improved accuracy and capability for making a good knowledge base, it is good to comprise different system levels, suitably handling the relative formalisms. Models which are both multi-level and hybrid satisfy both these requirements, making a very useful tool in computational systems biology. This paper reviews some of the main contributions in this field. PMID- 28855976 TI - Antioxidant Effects of a Hydroxytyrosol-Based Pharmaceutical Formulation on Body Composition, Metabolic State, and Gene Expression: A Randomized Double-Blinded, Placebo-Controlled Crossover Trial. AB - Hydroxytyrosol (HT) plays a significant role in cardiovascular disease (CVD) protection, and its metabolites are able to protect from the endothelial dysfunction commonly present in atherosclerosis. This randomized double-blinded, placebo-controlled crossover trial determined the effect in healthy volunteers of two gastroresistant capsules containing 15 mg/day of HT, for a 3-week period (HTT). Evaluation of nutritional status, serum metabolites, oxidative stress biomarkers, and gene expression of 9 genes related to oxidative stress, inflammation, and CVDs was performed. Oxidation biomarkers like thiol group (p = 0.001), total antioxidant status (TAS) (p = 0.001), superoxide dismutase 1 (SOD1) (2-DeltaDeltaCt = 3.7), and plasma concentration of HT (2.83 MUg.mL-1) were significantly increased, while nitrite (p = 0.001), nitrate (p = 0.001), and malondialdehyde (MDA) (p = 0.02) were drastically reduced after HTT. A significant reduction of body fat mass percentage (p = 0.01), suprailiac skinfold (p = 0.01), and weight (p = 0.04; Delta% = -0.46%) was observed after HTT. This study shows that regular intake of 15 mg/day of HT changed body composition parameters and modulated the antioxidant profile and the expression of inflammation and oxidative stress-related genes. However, it is advisable to personalize HT doses in order to exert its health benefits in CVD prevention and protection of LDL-C particles from oxidative damage. This trial is registered with ClinicalTrials.gov NCT01890070. PMID- 28855978 TI - A Case of Shunting Postoperative Patent Foramen Ovale Under Mechanical Ventilation Controlled by Different Ventilator Settings. AB - A 56-year old male with ischemic heart disease and an unremarkable preoperative echocardiogram underwent surgical coronary revascularization. An intraoperative post pump trans-esophageal echocardiogram (TOE) performed while the patient was being ventilated at a positive end expiratory pressure (PEEP) of 8 cm H2O demonstrated a right to left interatrial shunt across a patent foramen ovale (PFO). Whereas oxygen saturation was normal, a reduction of the PEEP to 3 cm H2O led to the complete resolution of the shunt with no change in arterial blood gases. Attempts to increase the PEEP level above 3 mmHg resulted in recurrence of the interatrial shunt. The remaining of the TEE was unremarkable. Mechanical ventilation, particularly with PEEP, causes an increase in intrathoracic pressure. The resulting rise in right atrial pressure, mostly during inspiration, may unveil and pop open an unrecognized PFO, thus provoking a right to left shunt across a seemingly intact interatrial septum. This phenomenon increases the risk of paradoxical embolism and can lead to hypoxemia. The immediate management would be to adjust the ventilatory settings to a lower PEEP level. A routine search for a PFO should be performed in ventilated patients who undergo a TEE. PMID- 28855979 TI - Searching for Radial Symmetry. AB - Symmetry is ubiquitous in the natural world. Numerous investigations, dating back over one hundred years, have explored the visual processing of symmetry. However, these studies have been concerned with mirror symmetry, overlooking radial (or rotational) symmetry, which is also prevalent in nature. Using a visual search paradigm, which approximates the everyday task of searching for an object embedded in background clutter, we have measured how quickly and how accurately human observers detect radially symmetric dot patterns. Performance was compared with mirror symmetry. We found that with orders of radial symmetry greater than 5, radial symmetry can be detected more easily than mirror symmetry, revealing for the first time that radial symmetry is a salient property of objects for human vision. PMID- 28855980 TI - Pseudomonas Endocarditis with an unstable phenotype: the challenges of isolate characterization and Carbapenem stewardship with a partial review of the literature. AB - BACKGROUND: Pseudomonas endocarditis is exceedingly rare, especially in patients without predisposing risks. We present such a case that included unexpected switches in antibacterial resistance profiles in two Pseudomonas aeruginosa (PA) strains with the same whole-genome sequence. The case also involved diagnostic and treatment challenges, such as issues with automated testing platforms, choosing the optimal aminoglycoside, minimizing unnecessary carbapenem exposure, and the need for faster, more informative laboratory tests. CASE PRESENTATION: On hospital day one (HD-1) a cefepime and piperacillin-tazobactam (FEP-TZP) susceptible P. aeruginosa was isolated from the bloodstream of a 62-year-old man admitted for evaluation of possible endocarditis and treated with gentamicin and cefepime. On HD-2, his antibiotic regimen was changed to tobramycin and cefepime. On HD-11, he underwent aortic valve replacement, and P. aeruginosa was isolated from the explanted valve. Unexpectedly, it was FEP-TZP-resistant, so cefepime was switched to meropenem. On HD-14, in preparation for whole-genome sequencing (WGS), valve and blood isolates were removed from cryo-storage, re-cultured, and simultaneously tested with the same platforms, reagents, and inoculations previously used. Curiously, the valve isolate was now FEP-TZP-susceptible. WGS revealed that both isolates were phylogenetically identical, differing by a single nucleotide in a chemotaxis-encoding gene. They also contained the same resistance genes (blaADC35, aph(3')-II, blaOXA-50, catB7, fosA). CONCLUSION: Repeated testing on alternate platforms and WGS did not definitively determine the resistance mechanism(s), which in this case, is most likely unstable de repression of a chromosomal AmpC beta-lactamase, porin alterations, or efflux upregulation, with reversion to baseline (non-efflux) transcription. Although sub culture on specialized media to select for less fit (more resistant) colonies, followed by transcriptome analysis, and multiple sequence alignment, might have revealed the mechanism and better informed the optimal choice of beta-lactam, such approaches are neither rapid, nor feasible for hospital laboratories. In this era of escalating drug resistance and dwindling antibiotics, use of the most potent anti-pseudomonals must be balanced with stewardship. Clinicians need access to validated genomic correlates of resistance, and faster, more informative diagnostics. Therefore, we placed these isolates and their sequences in the public domain for inclusion in the Pseudomonas pan-genome and database projects for further countermeasure development. PMID- 28855982 TI - Peritoneal metastases of rare carcinomas treated with cytoreductive surgery and HIPEC - A single center case series. AB - INTRODUCTION: In selected cases, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an established treatment for patients suffering from peritoneal metastases from colorectal, ovarian, gastric or appendiceal origin. The effectiveness of this extensive has not been elucidated within other rare diseases by now. METHODS: We conducted a retrospective analysis of patients treated with CRS for peritoneal carcinomatosis during the period between July 2010 and September 2015. Exclusion criteria were adenocarcinomas of the stomach, colon, neoplasms of the appendix, mesothelioma and ovarian cancers. Aim of this study was to examine the feasibility, complication rate and survival of patients with rare diseases. RESULTS: A total of 14 Patients were included: Four rare gynecological tumors, three adenocarcinomas of the small intestine, three retroperitoneal sarcomas, one cholangiocellular carcinoma, one neuroendocrine gastric tumor, one malignant peripheral nerve sheath tumor and one cancer of unknown primary syndrome. In 12 of 14 patients a macroscopically complete tumorresection could be achieved. No patient died during hospitalization. Seven of 14 patients experienced general complication of grade III according to NCI CTCAE V4.0, while two experienced complications of grade IV. Median follow-up and one year overall survival were 15.5 months and 46.8%, respectively. CONCLUSION: For patients with rare tumors, CRS and HIPEC is feasible with an acceptable perioperative morbidity and mortality. To improve knowledge in patient selection and outcome, rare tumors treated with CRS and HIPEC should be documented in central databases (as for example BIG RENAPE, Pierre-Benite, France). PMID- 28855981 TI - Role of BACE1 in Alzheimer's synaptic function. AB - Alzheimer's disease (AD) is the most common age-dependent disease of dementia, and there is currently no cure available. This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles. Although the exact etiology of AD remains a mystery, studies over the past 30 have shown that abnormal generation or accumulation of beta-amyloid peptides (Abeta) is likely to be a predominant early event in AD pathological development. Abeta is generated from amyloid precursor protein (APP) via proteolytic cleavage by beta-site APP cleaving enzyme 1 (BACE1). Chemical inhibition of BACE1 has been shown to reduce Abeta in animal studies and in human trials. While BACE1 inhibitors are currently being tested in clinical trials to treat AD patients, it is highly important to understand whether BACE1 inhibition will significantly impact cognitive functions in AD patients. This review summarizes the recent studies on BACE1 synaptic functions. This knowledge will help to guide the proper use of BACE1 inhibitors in AD therapy. PMID- 28855983 TI - Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. AB - BACKGROUND: The proteasome inhibitor bortezomib (BTZ) is successfully applied in the treatment of multiple myeloma, but its efficacy is restricted by the wide spread occurrence of resistance. Metabolic alterations play an important role in cancer development and aid in the cellular adaptation to pharmacologically changed environments. Metabolic changes could therefore play an essential role in the development of drug resistance. However, specific metabolic pathways that can be targeted to improve bortezomib therapy remain unidentified. METHODS: We elucidated the metabolic mechanisms underlying bortezomib resistance by using mass spectrometry-based metabolomics and proteomics on BTZ-sensitive and BTZ resistant multiple myeloma cell lines as well as in a set of CD138+ cells obtained from multiple myeloma patients. RESULTS: Our findings demonstrate that a rewired glucose metabolism sustains bortezomib resistance. Mechanistically, this results in higher activity of both the pentose phosphate pathway and serine synthesis pathway, ultimately leading to an increased anti-oxidant capacity of BTZ-resistant cells. Moreover, our results link both serine synthesis pathway activity and expression of 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of serine synthesis, to bortezomib resistance across different BTZ-resistant multiple myeloma cell lines. Consistently, serine starvation enhanced the cytotoxicity of bortezomib, underscoring the importance of serine metabolism in the response to BTZ. Importantly, in CD138+ cells of clinically bortezomib refractory multiple myeloma patients, PHGDH expression was also markedly increased. CONCLUSIONS: Our findings indicate that interfering with serine metabolism may be a novel strategy to improve bortezomib therapy and identify PHGDH as a potential biomarker for BTZ resistance. PMID- 28855984 TI - National health insurance accreditation pattern among private healthcare providers in Ghana. AB - BACKGROUND: Healthcare providers' accreditation is one of the standard means of assuring quality services. This paper examines the pattern of National Health Insurance Scheme accreditation results among private healthcare providers in Ghana. METHODS: A cross-sectional quantitative analysis of administrative data from seven National Health Insurance Scheme healthcare provider accreditation surveys over the 2009-2012 period. Data on private healthcare providers that applied for formal accreditation between the study period were retrieved from the NHIS accreditation database using a checklist. Proportions were used to examine pattern of private healthcare provider accreditation results by region, type of care provider, and grade. RESULTS: Overall, 1600 healthcare providers applied for accreditation over the study years, of which 1252 (78%) passed and were accredited. Majority of healthcare providers that passed the healthcare facility assessment were in Ashanti, Greater Accra, and Western regions, and were significantly higher than those in the other regions. Among the healthcare providers that passed the assessment, pharmacies (22%) and clinics (18%) constituted the largest groups, and were significantly higher than the other types of healthcare providers. Similarly, among those that passed, majority (62%) obtained grade C and D, representing a score of 50-59% and 60-69%, respectively, and were significantly higher than those that obtained the top three grades of A+ (90-100%), A (80-89%) and B (70-79%). CONCLUSIONS: Majority of healthcare providers accredited to provide services to the insured are concentrated in three regions of the country, and are mainly pharmacies and clinics. Moreover, substantial proportion of the healthcare providers obtain average scores of the healthcare facility assessment, an indication that these care providers fall below the National Health Insurance Scheme applicable-predetermined standards. PMID- 28855986 TI - Treatment of relapsed extranodal natural killer/T-cell lymphoma with bortezomib plus fludarabine. AB - Extranodal NK/T cell lymphoma (ENKL) is a rare entity, associated with an aggressive clinical behavior and poor prognosis. The optimal treatment strategies, particularly for relapsed patients, have not been clearly determined. A 40-year-old female ENKL patient with orbital involvement as the first presentation was initially suspected to have an orbital pseudotumor. When the patient developed disease progression following treatment with methylprednisolone, biopsy of the orbital mass was performed. Histopathological examination of the biopsy specimen was consistent with the diagnosis of ENKL (Ann Arbor stage IE). The patient was then treated with radiotherapy followed by chemotherapy with dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE regimen). Despite an initial good response, the patient developed disease relapse and progression (stage IIIE). Subsequently, treatment was switched to a novel regimen comprising bortezomib and fludarabine as salvage therapy for two courses. A positron emission tomography scan revealed disappearance of the orbital tumor. The patient then received autologous hematopoietic stem cell transplantation. At the last follow-up (March 2017), the patient remained disease-free. PMID- 28855985 TI - The optimum marker for the detection of lymphatic vessels. AB - Podoplanin, lymphatic vessel endothelial hyaluronic acid receptor-1, prospero related homeobox-1 and vascular endothelial growth factor receptor 3 have been demonstrated to have crucial roles in the development of the lymphatic system and lymphangiogenesis process by combining with their corresponding receptors. Thus, the four markers have been widely used in labelling lymphatic vessels for the detection of lymphangiogenesis and lymphatic vessel invasion. Numerous authors have aimed to identify the roles of these four markers in the lymphatic system and the mechanisms have been partly clarified at the molecular level. The aim of the present review was to comprehensively clarify the characteristics and latent action modes of the four markers in order to determine which is the best one for the detection of lymphangiogenesis and lymphatic vessel invasion. PMID- 28855987 TI - Blood transfusions and steatohepatitis are independent risk factors for complications following liver resection for colorectal cancer liver metastases. AB - The aim of the present study was to evaluate the risk factors for postoperative complications following liver resection for colorectal cancer liver metastases. Patients who underwent hepatic resection for colorectal cancer liver metastases were stratified according to chemotherapy administration and body mass index (BMI) to eliminate potential confounding factors. A univariate analysis was conducted to identify potential risk factors for postoperative complications following liver resection. Variables that exhibited a potential association were evaluated by multivariable logistic regression analysis to identify those independently associated with postoperative morbidity. Between January 2012 and March 2012, 100 patients underwent hepatic resection for liver metastases from colorectal carcinoma at the Treviso Regional Hospital (Treviso, Italy) and at the Regina Elena National Cancer Institute (Rome, Italy). Of the 100 patients, 61 received preoperative oxaliplatin- or irinotecan-based chemotherapy. A total of 25 the patients had a BMI of >=28 kg/m2. On univariate analysis, BMI >=28 kg/m2 was found to be positively correlated with the presence of steatosis (P<0.01) and steatohepatitis (P<0.01). The administration of preoperative chemotherapy was correlated with the development of steatosis (P<0.01), steatohepatitis (P=0.02) and postoperative complications (P=0.03). Even following stratification for the use of preoperative chemotherapy, BMI >=28 kg/m2 maintained its positive association with steatohepatitis. On multivariate analysis, steatohepatitis (P=0.005, HR=0.118, 95% CI: 0.027-0.518) and blood transfusions (P=0.001, HR=0.131, 95% CI: 0.038-0.452) were independently associated with postoperative complications. BMI >=28 kg/m2 (P=0.004, HR=8.30, 95% CI: 2.39-28.7) and irinotecan treatment (P=0.016, HR=0.16, 95% CI: 0.037-0.711) were independent risk factors for steatohepatitis. In conclusion, steatohepatitis and perioperative blood transfusions were found to be the main determinant of postoperative complications following liver resection for colorectal liver metastases. Overweight patients may be more prone to the cytotoxic effects of irinotecan, harboring a higher risk of developing steatohepatitis. PMID- 28855988 TI - Intestinal atresia following chemotherapy, presenting as superior mesenteric artery syndrome: A case report. AB - Multi-agent chemotherapy is recognized as the most common and effective treatment for Burkitt lymphoma, and intestinal mucosal injury is a common gastrointestinal complication following intensive chemotherapy. The aim of the present study was to describe a case of non-Hodgkin lymphoma with intestinal obstruction after chemotherapy in a young adult. The patient presented with aggravated vomiting during the second session of chemotherapy, which was initially attributed to superior mesenteric artery syndrome. However, following surgical intervention, the symptom was proven to be due to extreme intestinal stenosis in the ascending part of the duodenum. The patient underwent duodenojejunectomy and end-to-side anastomosis, and he recovered well from the operation. Although intestinal perforation and hemorrhage induced by chemotherapy have been previously reported sporadically, to the best of our knowledge, this is the first case report of distal duodenal obstruction due to intestinal atresia induced by polychemotherapy for lymphoma. We herein analyze the possible underlying reasons for the intestinal atresia and review the clinical and pathological characteristics of previously published relevant studies. The present findings may be helpful for increasing clinical awareness of this type of complication, as well as improving the management of patients treated with cytotoxic chemotherapeutic agents. PMID- 28855989 TI - T-cell immunoglobulin mucin-3 expression in invasive ductal breast carcinoma: Clinicopathological correlations and association with tumor infiltration by cytotoxic lymphocytes. AB - As a negative regulatory molecule, T-cell immunoglobulin and mucin domain-3 (Tim 3) is closely associated with tumor immunological tolerance. The aim of this study was to investigate Tim-3 expression in invasive ductal breast cancer (IDC), its effect on clinicopathological parameters and its association with cytotoxic lymphocyte infiltration. Tim-3 protein expression was measured in 150 paraffin embedded IDC specimens and 100 paired normal breast tissue specimens by immunohistochemistry. It was demonstrated that the infiltration of the tumor by CD8+ T cells was significantly higher compared with that of normal tissue, and the Tim-3 expression on CD8+ T cells was higher in IDC tissue compared with that in normal tissue; the differences were statistically significant (both P values=0.000). The median expression level of Tim-3 on tumor cells was significantly associated with clinicopathological parameters such as age, axillary lymph node metastasis and TNM stage (P=0.015, 0.001 and 0.027, respectively). The expression of Tim-3 on CD8+ T cells was correlated with lymph node metastasis, World Health Organization (WHO) grade and molecular classification (P=0.000, 0.004 and 0.000, respectively). Additionally, the number of tumor-infiltrating CD8+ T cells was associated with primary tumor size, lymph node metastasis, WHO grade, Ki-67 and molecular classification (P=0.017, 0.002, 0.007, 0.003 and 0.000, respectively). Thus, Tim-3 may promote the development and progression of breast cancer and affect the tumor microenvironment; thus, it may be used as an independent prognostic factor for IDC patients. PMID- 28855990 TI - Randomized phase II study of TJ-54 (Yokukansan) for postoperative delirium in gastrointestinal and lung malignancy patients. AB - The present study evaluated the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies. Patients >=70 years of age who underwent surgery for gastrointestinal or lung malignancy were eligible for participation in the study. The 186 eligible patients were randomly assigned at a 1:1 ratio to receive TJ-54 or control during their peri-operative care (between 7 days prior to surgery and 4 days following surgery, except for the operation day). The signs and symptoms of delirium were assessed using the Diagnostic and Statistical Manual of Mental Disorders-IV by the investigator during the peri operative period. A total of 186 eligible gastrointestinal or lung malignancy patients were analyzed (93, TJ-54; 93, control). There were no marked differences between the two randomized groups. The incidence of delirium was 6.5% (6 patients) in the TJ-54 group and 9.7% (9 patients) in the control group, with no significant difference (P=0.419). However, of the patients categorized with a mini-mental state examination (MMSE) score of <=26, the incidence of postoperative delirium was 9.1% in the TJ-54 group and 26.9% in the control group [risk ratio, 0.338; 95% confidence interval (0.078-1.462), P=0.115]. Treatment with TJ-54 reduced the incidence of postoperative delirium compared with the control group. Although TJ-54 did not demonstrate any contribution to preventing or treating postoperative delirium in patients following surgery for gastrointestinal or lung malignancy, TJ-54 reduced the risk of postoperative delirium in the patients who were classified as MMSE <=26. Further phase III studies with a larger sample size are required in order to clarify the effects of TJ-54 against postoperative delirium. PMID- 28855991 TI - Primary malignant lymphoma of the talus: A case report and review of the literature. AB - Malignant lymphoma commonly occurs in adults, with a peak incidence between the seventh and ninth decades of life. Although malignant lymphoma usually occurs in the lymph nodes, it rarely occurs primarily in the bone. We herein describe an extremely rare case of primary malignant lymphoma of the talus in a 74-year-old man. Although plain radiographs showed no abnormality, gadolinium-enhanced magnetic resonance imaging (MRI) revealed a well-circumscribed intra- and extraosseous tumor of the talus. 18F-fluorodeoxyglucose (FDG) positron emission tomography/MRI revealed a marked increase of FDG uptake in the right ankle and the right inguinal lymph nodes. As the tumor was diagnosed as diffuse large B cell lymphoma by core needle biopsy, combination therapy with chemo- and radiotherapy was initiated. The patient achieved complete remission, with no sign of recurrence at 8 months after initial chemoradiotherapy. Since primary malignant lymphoma of the bone is chemo- and radiosensitive and has a good prognosis, accurate staging by radiological investigation as well as correct pathological diagnosis by biopsy are required for optimal treatment. PMID- 28855992 TI - Clinical significance of serum anti-p53 antibody expression following curative surgery for colorectal cancer. AB - The aim of the present study was to investigate the usefulness of serum anti-p53 antibody (Ap53Ab) measurement for the diagnosis of colorectal cancer (CRC), and the clinical significance of the association between Ap53Ab expression and survival rate. Ap53Ab, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 were measured by ELISA in 674 CRC patients and 115 healthy volunteers (control group). The half-life time of Ap53Ab and CEA was calculated. The association between positive Ap53Ab expression and clinicopathological characteristics, including survival rate, was analyzed. Of the 674 CRC patients, 195 (28.9%) were positive for Ap53Ab expression, while the positive rates of CEA and CA19-9 level were 39.9 and 16.9%, respectively. Positivity for Ap53Ab alone was observed in 94 patients (13.9%), whereas the positivity rate of any markers examined was 58.7%. The mean half-life of Ap53Ab and CEA was 30.7 and 11.3 days, respectively. Positive expression of Ap53Ab was significantly associated with the depth of tumor invasion (P<0.001), lymph node metastasis (P=0.024), stage (P<0.001) and CEA level (P=0.005). No significant correlation between Ap53Ab expression and poor survival rate was observed. The positive rate of Ap53Ab was higher compared with that of CEA and CA19-9 in early-stage CRC. The combination of these markers improved the diagnostic yield of CRC up to ~60%. Furthermore, Ap53Ab expression was associated with lymph node metastasis, but not with shorter survival. These results indicated that the measurement of Ap53Ab may contribute to increased rate of detection of CRC, particularly in patients with early-stage disease, in clinical practice. PMID- 28855993 TI - Treatment sequence in castration-resistant prostate cancer: A retrospective study in the new anti-androgen era. AB - In recent years, abiraterone acetate (AA) and enzalutamide (EZL) have become available for the treatment of cancer. Prior clinical trials have demonstrated the benefits of these agents in males with castration-resistant prostate cancer (CRPC). The optimal sequencing of available therapies in the context of efficacy and known cross-resistance remains uncertain. Based on the mechanisms of action and accessible clinical data, AA and EZL may be indicated for the early stages of prostate cancer. Until clinical trials are conducted to determine the best treatment sequence, individualized therapy is required for each patient based on the clinicopathological characteristics. In the present study, 46 sequential patients (median age: 77, range 59-89; median serum PSA level: 56 ng/ml, range 1.5-3,211) with CRPC treated with EZL (160 mg/day) were retrospectively analyzed between June 2014 and July 2015 at the following institutions: Yamagata Prefectural Central Hospital (Yamagata, Japan); Yamagata Tokushukai Hospital (Yamagata, Japan); Ishinomaki Red Cross Hospital (Ishinomaki, Japan); Kan-etsu Hospital (Tsurugashima, Japan); Niigata Cancer Center Hospital (Niigata, Japan); Sakado Central Hospital (Sakado, Japan). A total of 18 patients were pre-treated with Docetaxel (DOC) and 28 patients were DOC-naive. Once EZL therapy was initiated, increases in prostate specific antigen (PSA) levels were observed in 3/18 patients (17%) pre-treated with DOC and in 6/20 (30%) who were DOC-naive. In total, 8/28 DOC-naive patients were treated with AA without EZL. An increase in the PSA level was observed in only 1/8 (12%) cases following AA treatment in the DOC-naive group. It was demonstrated that AA had a better efficacy in DOC-naive patients. The efficacy of EZL was limited in AA-pre-treated patients following DOC administration. PMID- 28855994 TI - Safety and efficacy of carboplatin plus nab-paclitaxel for treating advanced non small-cell lung cancer with interstitial lung disease. AB - There are few established treatments for patients with non-small-cell lung cancer (NSCLC) with interstitial lung disease (ILD). The safety and efficacy of albumin bound paclitaxel (nab-paclitaxel) in combination with carboplatin is uncertain, although the combination of carboplatin and paclitaxel is the most common regimen for treating NSCLC patients with ILD. A total of 9 NSCLC patients with ILD, treated between April 2013 and March 2016, were retrospectively investigated. Carboplatin (AUC 5-6) was administered on day 1 and nab-paclitaxel on days 1, 8 and 15, every 4-6 weeks. The median age of the patients upon initiating chemotherapy was 67 years. The pathological examination revealed 6 patients with squamous cell carcinoma, and 6 patients exhibited the typical pattern of ILD. The response rate was 55.6%, and the median progression-free and overall survival time was 174 and 344 days, respectively. Acute exacerbation of ILD was not observed in any of the patients, and febrile neutropenia developed in 3 patients (3/9, 33.3%). Thus, treatment with carboplatin plus nab-paclitaxel was found to be safe and effective for NSCLC patients with ILD, although management of hematological adverse events, such as febrile neutropenia, was required. However, these encouraging results require confirmation by a large-scale clinical trial. PMID- 28855995 TI - Combined detection of alpha-fetoprotein and free beta-human chorionic gonadotropin in screening for trisomy 21 and management of cases in the moderate risk value range. AB - Down syndrome is the most common cause of prenatal chromosomal abnormalities, and prenatal serum screening is an effective method for decreasing the birth prevalence of children with Down syndrome. The aim of the present study was to observe the effect of duplex screening and investigate the treatment of cases under specific conditions. The medians of free beta-human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) were calculated and compared with those embedded in the 2T software. The detection and false-positive rates were analyzed under different conditions, and the distribution of Down syndrome cases was investigated in different risk ranges. Finally, suitable recommendations for further diagnostic investigation were provided according to the status of each individual. The medians of free beta-HCG and AFP were found to differ from the corresponding medians embedded in the 2T software (P<0.01), and on the basis of a 5% false-positive rate, the detection rate would increase from 63.6 to 67.8% when compared with medians embedded in the 2T software, indicating we should establish our own medians of free beta-HCG and AFP. In addition, residual cases (risk value <1/300) with relevant Down syndrome indications mainly concentrated at risk values between 1/1,000 and 1/300, and partial residual screening cases were verified through diverse methods. These findings indicated that different laboratories should establish their own medians; furthermore, what is classed as moderate risk is extremely important in screening for Down syndrome and reasonable recommendations may be offered under different conditions. PMID- 28855996 TI - Comparative investigation of the anti-emetic effects of granisetron and palonosetron during the treatment of acute myeloid leukemia. AB - Chemotherapy-induced nausea and vomiting has a considerable negative impact on the quality of life of patients with cancer. Unfortunately, there has been little progress in the development of supportive therapies for the anti-emetic treatment of patients with hematopoietic tumors. This lack of supportive treatments motivated the present retrospective comparison between two groups of anti-emetic drugs. The current study aimed to compare granisetron and palonosetron in order to determine which is more effective, based on cases of patients undergoing remission induction therapy and consolidation therapy for the treatment of acute myeloid leukemia. Granisetron or palonosetron were administered in Japanese approved dosages (3 mg granisetron once per day for 5 or 7 days, or one administration of 0.75 mg palonosetron). Patients were randomly selected, and their clinical information was acquired from medical records. The data represent the doctors' and nurses' records. The results demonstrated that palonosetron treatment (in which the drug was administered alone or in combination with aprepitant) was more effective than granisetron treatment for the complete control of acute vomiting. Therefore, in the treatment of hematopoietic malignancies, palonosetron is an effective regimen to be administered alongside more than 5 continuous days of anti-cancer agents. Furthermore, the combination of palonosetron and aprepitant was found to be the optimal combination. In conclusion, palonosetron is superior to granisetron for the prevention of nausea and vomiting induced by chemotherapy for hematological cancers. In Japan, the standard dose of palonosetron is 0.75 mg; a dose of 0.25 mg of palonosetron must be compared with 0.75 mg in future studies. PMID- 28855997 TI - Collagen gel droplet-embedded culture drug sensitivity testing in hard palate cancer-predicted antitumor efficacy of cetuximab: A case report. AB - In vitro anticancer drug sensitivity assessments have been performed for various types of cancer, and an association with clinical response has been observed. The collagen gel droplet-embedded culture drug sensitivity test (CD-DST) is an in vitro anticancer drug sensitivity test that has recently reported to be useful in oral squamous cell carcinoma (OSCC). CD-DST allows for the analysis of a smaller number of cells compared with other anticancer drug sensitivity tests. The present study reported a successful analysis of anticancer drug sensitivity using CD-DST on cervical lymph node tissue dissected following neoadjuvant chemotherapy from a 55-year-old man with advanced hard palate cancer. Tumor resection and bilateral neck dissection were performed following neoadjuvant chemotherapy (docetaxel + cisplatin + 5-fluorouracil; TPF) for hard palate cancer T2N2cM0. Local recurrence and cervical multiple skin metastasis occurred ~8 months after surgery, and the patient received six doses of cetuximab (C-mab) + cisplatin + 5 fluorouracil (C-mab + PF) administration, which is a type of molecular-targeted therapy. Following the use of the CD-DST method, the clinical response was noted as stable disease following execution of TPF and partial response following execution of C-mab + PF. In addition, low sensitivity by TPF and high sensitivity by C-mab + PF were reported. The CD-DST method reflected the clinical response for the patient, and the results of the current study indicate that CD-DST is a useful tool for selecting chemotherapeutic drugs for patients with OSCC. PMID- 28855998 TI - Surgery is the preferred treatment for bile duct hamartomas. AB - Bile duct hamartoma (BDH) is a rare liver disease with a rising incidence in recent years. A retrospective study on BDH patients between June 2007 and December 2015 was conducted. All the medical records, including clinical, imaging and pathological characteristics, were retrieved. Follow-up data were obtained by telephone communication. The majority of the patients had no symptoms and the laboratory tests were normal. The appearance on ultrasound examination was variable. The lesion exhibited low density on plain computed tomography and no enhancement in 4 cases, and inhomogeneous enhancement in 1 case. Magnetic resonance imaging examination revealed hypointensity on T1-weighted imaging (WI), hyperintensity on T2WI, no enhancement in 1 case, and enhancement in 4 cases. Two patients underwent magnetic resonance cholangiopancreatography due to jaundice and intrahepatic bile duct dilation. The preoperative diagnosis was liver cancer in 4 cases, hepatic hilar biliary obstruction in 1, chronic calculous cholecystitis in 1, suspected hepatic abscess in 1, and benign liver tumor in 2 cases. All the patients underwent surgery. Nest-like cell arrangements were observed in 2 patients, and in 1 patient the lesion transformed to intrahepatic cholangiocarcinoma, resulting in the patient's death 25 months after surgery. Thus, BDH may transform into a life-threatening cholangiocarcinoma and it should be surgically removed. Furthermore, the mechanism underlying carcinogenesis in BDH requires further investigation. PMID- 28855999 TI - Severe blood loss anaemia and recurrent intussusceptions as first presentation of bowel metastatic renal cell carcinoma: A case report and review of the literature. AB - Renal cell carcinoma (RCC) may metastasize to almost any organ, but bowel metastases are highly unusual. A 75-year-old man presented with symptoms and signs of severe anaemia due to bowel bleeding and abdominal pain due to recurrent bowel intussusception. The patient underwent surgery and was identified to have intraluminal metastases from metastatic RCC. To the best of our knowledge, few cases of metastases from RCC manifesting as synchronous intraluminal polypoid tumours have been described in the literature. The present report focused on the importance of two aspects that must be considered: The role of accurate diagnosis and of surgery treating intestinal metastases that may lead to symptom control and prolonged survival. PMID- 28856000 TI - Evaluation of the clinical benefits of adjuvant capecitabine monotherapy in elderly women with breast cancer: A retrospective study. AB - Capecitabine is orally administered and may be safely and conveniently used in patients with cancer. The antitumor activity of capecitabine in breast cancer was mostly demonstrated in the salvage therapy setting, whereas the effect of adjuvant capecitabine monotherapy in breast cancer remains unclear. The aim of the present study was to evaluate adjuvant capecitabine monotherapy in elderly women with breast cancer. A total of 251 patients were enrolled and survival was compared between elderly breast cancer patients who received adjuvant capecitabine monotherapy and those who received no chemotherapy. Cancer-specific and disease-free survival curves were compared using log-rank tests and survival curves were calculated using the Kaplan-Meier method. Multivariate analyses were conducted using Cox's proportional hazard regression model. There was no significant difference between the clinicopathological characteristics, including age, tumor size, lymph node status, histological grade and hormone status, between patients in the two groups. The breast cancer-specific survival rate was 89.3% in the capecitabine monotherapy group vs. 81.3% in the no chemotherapy group; the difference was not statistically significant (P=0.128). The disease free survival rate was 81.7% in the capecitabine monotherapy group vs. 65.3% in the no chemotherapy group. Kaplan-Meier analysis indicated a longer disease-free survival in the capecitabine monotherapy group (P=0.015). On Cox regression analysis, capecitabine monotherapy was found to be associated with the disease free survival rate (P=0.014, hazard ratio=0.500) but not with the cancer-specific survival rate (P=0.181). The adverse events of capecitabine monotherapy were recorded and there was no chemotherapy interruption due to severe adverse reactions. Therefore, adjuvant capecitabine monotherapy in elderly women with breast cancer is a safe and effective option, as well as a viable alternative for elderly breast cancer patients who refuse standard adjuvant therapy. PMID- 28856001 TI - Bortezomib as a probable cause of the syndrome of inappropriate antidiuretic hormone secretion: A case report and review of the literature. AB - Bortezomib is a proteasome inhibitor that has been widely adopted for the treatment of hematological malignancies, including multiple myeloma and lymphoma, and has been considered significantly more tolerable compared with traditional chemotherapeutic drugs. Bortezomib has some potential side effects that involve a number of systems, including the gastrointestinal, hematological, nervous and musculoskeletal systems; however, involvement of the endocrine system is rare. We herein report the case of a patient treated for multiple myeloma who developed the syndrome of inappropriate antidiuretic hormone secretion after bortezomib was added to his chemotherapy regimen. Following treatment with an infusion of hypertonic saline and fluid restriction for >2 months, the serum sodium level gradually recovered. PMID- 28856002 TI - Modified hanging manoeuvre facilitates inferior vena cava resection and reconstruction during extended right hepatectomy: A technical case report. AB - Liver resections are safe when performed by specialized hepatobiliary teams. However, complex liver resections are accompanied by significant perioperative risk and they may require modifications of the conventional surgical techniques. We herein report the case of a 54-year-old male patient who underwent an extended right liver resection with en bloc resection and reconstruction of the inferior vena cava. For this complex resection, a modification of the standard operative technique was required. A modified hanging manoeuvre was performed using two 19Fr nasogastric tubes outside the traditional avascular plane to facilitate resection. This modification of the hanging manoeuvre was proven to be feasible and safe, and it is recommended for inclusion in the armamentarium of hepatobiliary surgeons when complex resections are required. PMID- 28856003 TI - Sorafenib-induced acute-on-chronic liver failure in a patient with hepatocellular carcinoma after transarterial chemoembolization and radiofrequency ablation: A case report. AB - Comprehensive treatments together with sorafenib provide a survival benefit for patients with advanced hepatocellular carcinoma (HCC). Acute-on-chronic liver failure (ACLF) is an increasingly recognized distinct entity; however, only few cases induced by sorafenib have been reported to date. We herein present a rare case of ACLF in a patient under treatment with sorafenib. A 63-year-old woman who suffered from hepatitis B for 10 years was admitted to our hospital. A computed tomography (CT) scan led to a diagnosis of HCC in the V/VIII hepatic segment, with invasion of the middle hepatic and the right portal veins. The patient received multidisciplinary treatment, including transarterial chemoembolization, radiofrequency ablation and sorafenib. Two months after sorafenib treatment, the patient was readmitted due to progressive jaundice and ACLF was diagnosed by liver biopsy shortly thereafter. Although aggressive treatment was administered, the patient succumbed to the disease following rapid deterioration of her clinical condition. The majority of patients with HCC have underlying liver disease and combination therapy with sorafenib should be administered with caution, as it may increase the risk of severe hepatotoxicity. The present case suggests that patients treated with sorafenib may require a dose reduction following interventional treatment. PMID- 28856004 TI - Evaluation of a 3-base pair indel polymorphism within pre-microRNA-3131 in patients with prostate cancer using mismatch polymerase chain reaction restriction fragment length polymorphism. AB - The present study aimed to examine the impact of a 3-bp indel (rs57408770) polymorphism within the pre-microRNA (miR)-3131 polymorphism on prostate cancer (PCa) risk in a sample of an Iranian population. In total, 340 subjects, including 177 patients with PCa and 170 patients with benign prostatic hyperplasia, were enrolled in the present case-control study. A mismatch polymerase chain reaction-restriction fragment length polymorphism method was designed for genotyping the 3-bp indel (rs57408770) polymorphism. The present findings demonstrated that the indel variant significantly increased the risk of PCa in codominant [odds ratio (OR)=2.23, 95% confidence interval (CI)=1.13-4.37; P=0.021, insertion (ins)/ins vs. deletion (del)/del] and recessive (OR=2.33, 95% CI=1.25-4.36; P=0.009, ins/ins vs. del/del + del/ins). In conclusion, to the best of our knowledge, the present findings for the first time proposed that a 3-bp indel variant of miR-3131 may be a risk factor for susceptibility to PCa in a sample of an Iranian population. Further studies with different ethnicities and larger sample sizes are required to validate the present findings. PMID- 28856005 TI - Blastic plasmacytoid dendritic cell neoplasm in children: A review of two cases. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a newly characterized, rare malignant tumor of the skin and hematopoietic system. BPDCN occurs mainly in the elderly, whereas it is rarer among children, and has variable clinical manifestations. Optimal chemotherapeutic regimens for the treatment of BPDCN have not yet been determined and this tumor has a poor prognosis. In this study, two pediatric cases of BPDCN, including a 7-year-old female and a 9-year-old male patient, diagnosed at the Xiangya Hospital of Central South University over the past 2 years, were retrospectively reviewed. Both cases exhibited multiple organ involvement, although the clinical manifestations differed; they were diagnosed with BPDCN based on the clinical manifestations, pathological and immunohistochemical findings, which included positivity for CD4, CD56 and CD123. A high-risk acute lymphocytic leukemia (ALL) chemotherapy regimen was administered to both patients. The patient in the first case achieved a complete remission, but unfortunately her parents refused follow-up treatment and she succumbed to the disease 9 months after the initial diagnosis. The second patient was treated for a total of three courses with a chemotherapy regimen including daunorubicin, cytarabine and etoposide, followed by two courses of the high-risk ALL chemotherapy regimen; unfortunately, a remission was not achieved and the patient was scheduled to receive hematopoietic stem cell transplantation. Thus, not all pediatric BPDCN patients may be able to achieve complete remission following chemotherapy with the high-risk ALL regimen, and other treatment options must be investigated in the future. PMID- 28856006 TI - Effect of wearing fingers rings on the behavioral and psychological symptoms of dementia: An exploratory study. AB - OBJECTIVE: This study was conducted to examine the effects of an approach that wears finger rings on elderly females with behavioral and psychological symptoms of dementia. METHOD: The subjects were seven Japanese dementia patients living in elderly nursing homes. A single-case experimental design was adopted for the study. Each study subject was asked to put rings on her finger (from 9:00 to 19:00) for 7 days. The Neuropsychiatric Inventory, scenes of behavioral and psychological symptoms of dementia, interest in wearing rings, self-awareness, and overall profile were determined to assess the effect on the patients of wearing rings. RESULTS: The majority of nursing care providers stated, based on their assessment, that the "irritability/lability" that was noted during the baseline period disappeared during the ring-wearing intervention period in the three patients who displayed an interest in rings. In the assessment of the self awareness ability, these three women were aware themselves of their intellect collapsing and were capable of conjecturing their own and others' minds. It was commonly seen that the nursing staff, even though they had not been asked to do so by the researchers, told the patients, "Mrs. XX, you look so beautiful" when they found a patient wearing rings. DISCUSSION/CONCLUSION: Individuals with low self-esteem are inclined to get angry and display aggression. In subjects with low self-esteem, anger and aggression readily arise when they are slighted by others. Self-esteem is low in those women who are aware of their own status of collapsing intellect. It is concluded that the words of conjuration, "you look so beautiful," which the wearing of the ring per se by the patient elicited from the caregivers heightened the self-esteem and alleviated "irritability/lability" in the study subjects. PMID- 28856007 TI - A pilot study of lymph node mapping with indocyanine green in robotic gastrectomy for gastric cancer. AB - OBJECTIVES: Robotic gastrectomy has become increasingly popular in the treatment of gastric cancer, especially in Asian countries. The use of indocyanine green fluorescence has been reported in lymphatic mapping for gastric cancer in laparoscopic gastrectomy; however, there have been few reports regarding the use of indocyanine green in robotic gastrectomy. METHODS: From January 2011 to March 2016, a total of 79 patients underwent robotic gastrectomy for gastric cancer. Among them, intraoperative subserosal injection (n = 9) or preoperative submucosal injection (n = 5) of indocyanine green with near-infrared imaging was performed in 14 patients, and the other 65 patients underwent robotic gastrectomy without the use of indocyanine green. RESULTS: There was no significant difference in the operative time, total number of retrieved lymph nodes, operative blood loss, and postoperative hospital stay between the patients who underwent robotic gastrectomy with or without indocyanine green fluorescence. For each lymph node station, there was significantly more number of retrieved lymph nodes in the indocyanine green group than in the no-indocyanine green group at the greater curvature side of the low body (#4d) to the infrapyloric region (#6) of the stomach. Five of the 14 patients who received an indocyanine green injection for lymphatic mapping had lymph node metastasis, and metastatic lymph nodes were located in the lymph node stations as detected by indocyanine green fluorescence during surgery. CONCLUSION: Indocyanine green fluorescence with near infrared imaging is feasible and is a promising method of lymphatic mapping in robotic gastrectomy for gastric cancer. In future studies, larger patient numbers and long-term follow-up are required. PMID- 28856008 TI - When CRRT on ECMO Is Not Enough for Potassium Clearance: A Case Report. AB - BACKGROUND: Continuous renal replacement therapy (CRRT) is an excellent method used to remove fluid and solutes. It may also reduce the systemic inflammatory response for patients on extracorporeal membrane oxygenation (ECMO) support. The objective of this report is to describe a case where CRRT in combination with ECMO was insufficient to control hyperkalemia. METHODS: We report the case of an adolescent patient with refractory symptomatic hyperkalemia due to substantial rhabdomyolysis in which CRRT insufficiently cleared the patient's excess potassium. RESULTS: Intermittent hemodialysis (IHD) was added and proved successful. The patient was weaned off ECMO, CRRT, and IHD, and his cardiac and renal function eventually normalized. CONCLUSIONS: Two important lessons can be learned from this case report: (1) If CRRT is insufficient in achieving a desirable potassium balance, additional IHD should be considered and (2) separate IHD access should be considered to improve efficacy. PMID- 28856011 TI - Net technique for intraocular lens support in aphakia without capsular support. AB - BACKGROUND: This paper describes a modified surgical technique for intraocular lens implantation in aphakic eyes with no capsular support. METHODS: Retrospective case series. Seventeen eyes of 17 aphakic patients with no capsule support underwent intraocular lens (IOL) implantation using a standardized technique in which a net was created at the ciliary sulcus plane with two threads forming a net pattern. The net was used as support for the IOL. Follow-up ranged from 6 to 38 months, with an average of 23 months. RESULTS: In all cases, the IOL was safely implanted and remained stable during the follow-up. In 16 eyes, the IOL remained well centered; in one eye, slight decentration was observed. Distance-corrected visual acuity improved by a mean of 4 lines, from 1.13 (LogMAR) to 0.52 (P = 0.01). CONCLUSION: This technique might be especially useful in cases of insufficient capsular support associated with tissue loss or iris atrophy. In these cases, iris fixation is not feasible; thus, the only surgical alternative is IOL scleral fixation. PMID- 28856009 TI - The Chronic Kidney Disease Water Intake Trial: Protocol of a Randomized Controlled Trial. AB - BACKGROUND: In observational studies, drinking more water associates with a slower rate of kidney function decline; whether the same is true in a randomized controlled trial is unknown. OBJECTIVE: To examine the 1-year effect of a higher vs usual water intake on estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease. DESIGN: Parallel-group randomized controlled trial. SETTING: Nine centers in Ontario, Canada. Enrollment and randomization occurred between May 2013 and May 2016; follow-up for the primary outcome will continue until June 2017. PARTICIPANTS: Adults (n = 631) with stage 3 chronic kidney disease (eGFR 30-60 mL/min/1.73 m2) and microalbuminuria. INTERVENTION: The high water intake group was coached to increase their oral water intake by 1.0 to 1.5 L/day (depending on sex and weight), over and above usual consumed beverages, for a period of 1 year. The control group was coached to maintain their usual water intake during this time. MEASURES: Participants provided 24-hour urine samples at baseline and at 6 and 12 months after randomization; urine samples were analyzed for volume, creatinine, osmolality, and the albumin-to-creatinine ratio. Blood samples were obtained at baseline and at 3- to 6-month intervals after randomization, and analyzed for creatinine, copeptin, osmolality, and electrolytes. Other measures collected included health-related quality of life, blood pressure, body mass index, and diet. PRIMARY OUTCOME: The between-group change in eGFR from baseline (prerandomization) to 12 months after randomization. SECONDARY OUTCOMES: Change in plasma copeptin concentration, 24-hour urine albumin-to-creatinine ratio, measured creatinine clearance, estimated 5-year risk of kidney failure (using the 4-variable Kidney Failure Risk Equation), and health related quality of life. PLANNED ANALYSIS: The primary analysis will follow an intention-to-treat approach. The between-group change in eGFR will be compared using linear regression. Supplementary analyses will examine alternative definitions of eGFR change, including annual percentage change, rate of decline, and rapid decline (a P value <0.05 will be interpreted as statistically significant if there is concordance with the primary outcome). TRIAL REGISTRATION: This randomized controlled trial has been registered at www.clinicaltrials.gov; government identifier: NCT01766687. PMID- 28856010 TI - Serum netrin-1 in relation to gadolinium-enhanced magnetic resonance imaging in early multiple sclerosis. AB - BACKGROUND: Netrin-1, a secreted laminin-related protein, is known to regulate not only axonal guidance and neuronal cell migration, but also blood-brain barrier integrity and inflammation. Two preliminary studies reported altered serum netrin-1 levels in multiple sclerosis; however, associations with longitudinal clinical and magnetic resonance imaging activity have not been investigated. OBJECTIVES: We aimed to assess serum netrin-1 in multiple sclerosis and controls with respect to disease activity and its temporal dynamics. METHODS: Serum netrin-1 was assessed by enzyme-linked immunosorbent assay in 79 patients with clinically isolated syndrome or multiple sclerosis, and 30 non-inflammatory neurological disease controls. In patients, serum samples were collected immediately prior to gadolinium-enhanced 3 T magnetic resonance imaging at two time points (initial contrast-enhancing gadolinium+ n = 47, non-enhancing gadolinium- n = 32; reference gadolinium- n = 70; median time-lag 1.4, interquartile range 1.0-2.3 years). RESULTS: Serum netrin-1 levels were similar in clinically isolated syndrome, multiple sclerosis and controls, and gadolinium+ and gadolinium- patients. Among gadolinium+ patients, serum netrin-1 was decreased in clinically active (n = 8) vs non-active patients (n = 39; p = 0.041). Serum netrin-1 showed no temporal dynamics in multiple sclerosis and was unrelated to clinical data. CONCLUSIONS: Serum netrin-1 levels show no multiple sclerosis specific changes and are not sensitive for detection of subclinical disease activity. Netrin-1 changes during relapses may deserve further examination. PMID- 28856012 TI - Synthetic hydrogel supports the function and regeneration of artificial ovarian tissue in mice. AB - Many prepubertal girls and young women suffer from premature ovarian insufficiency induced by chemotherapy given for treatment of cancer and autoimmune diseases. Auto-transplantation of cryopreserved ovarian tissue could restore the lost ovarian endocrine function and fertility. Unfortunately, tissue ischemia, inconsistent graft quality and the risk of re-introducing malignant cells may stand in the way of the clinical translation of this approach. To address these risks and limitations, we engineered an artificial ovary from immature follicles using a synthetic hydrogel, poly(ethylene glycol) vinyl sulfone (PEG-VS), as a supportive matrix. Enzymatically-isolated follicles from 6 - 7 day old mice ovaries were encapsulated in 7% PEG-VS hydrogels modified with 0.5mM RGD and crosslinked with a tri-functional matrix metalloproteinase (MMP) sensitive peptide. PEG hydrogels with the encapsulated follicles were orthotopically implanted into ovariectomized mice to investigate if PEG hydrogel supports folliculogenesis and steroidogenesis in vivo. After 30 days, grafts revealed multiple fully developed antral follicles and corpora lutea, which corresponded with regular ovulation cycles and follicle-stimulating hormone (FSH) levels. The elevated levels of FSH, caused by bilateral ovariectomy, were reversed by the implanted follicles and maintained at physiological levels for 60 days. Importantly, primordial and primary follicles still represented 60% of the follicular pool, demonstrating selective recruitment of primordial follicles into the growing pool. Functioning blood vessels in the grafts 30 and 60 days after implantation proved the capability of PEG hydrogels to undergo graft remodeling and revascularization. Our results demonstrate that PEG hydrogels with encapsulated immature ovarian follicles successfully functioned as an artificial ovarian tissue for 60 days in vivo. PMID- 28856013 TI - Strategies for enhancing research in aging health disparities by mentoring diverse investigators. AB - INTRODUCTION: The Resource Centers for Minority Aging Research (RCMAR) program was launched in 1997. Its goal is to build infrastructure to improve the well being of older racial/ethnic minorities by identifying mechanisms to reduce health disparities. METHODS: Its primary objectives are to mentor faculty in research addressing the health of minority elders and to enhance the diversity of the workforce that conducts elder health research by prioritizing the mentorship of underrepresented diverse scholars. RESULTS: Through 2015, 12 centers received RCMAR awards and provided pilot research funding and mentorship to 361 scholars, 70% of whom were from underrepresented racial/ethnic groups. A large majority (85%) of RCMAR scholars from longstanding centers continue in academic research. Another 5% address aging and other health disparities through nonacademic research and leadership roles in public health agencies. CONCLUSIONS: Longitudinal, team-based mentoring, cross-center scholar engagement, and community involvement in scholar development are important contributors to RCMAR's success. PMID- 28856014 TI - Grayscale ultrasound characteristics of autosomal dominant polycystic kidney disease severity - an adult and pediatric cohort study. AB - INTRODUCTION: The most common hereditary kidney condition is autosomal dominant polycystic kidney disease. It is the cause of 5-10% of end-stage renal disease. Its symptoms are generally late-onset, typically leading to development of hypertension and chronic kidney disease. Ultrasonography is the imaging modality of choice in its diagnosis and management. The aim of this study is to determine the diagnostic value of grayscale ultrasound imaging in evaluating disease severity. MATERIALS AND METHODS: The study group consisted of 81 patients diagnosed with autosomal dominant polycystic kidney disease, 35 adults and 46 children. Inclusion criterion for adults was the presence of at least 10 large cysts in each kidney; children included into the study had developed at least 1 large renal cyst in each kidney. The number of large cysts, echogenicity of kidney parenchyma, cortical thickness and presentation of cortex/medulla boundary were assessed with the use of Logiq E9 apparatus (GE Healthcare, Netherlands). Patients were divided into groups, based on these morphological parameters. Kidney function was assessed according to serum creatinine concentration and creatinine clearance. Statistical analysis was performed, with p-value lower than 0.05 considered as significant. RESULTS: The number of cysts and the degree of parenchymal dysfunction were the determinants of creatinine level and creatinine clearance, with the second predictor proving stronger. CONCLUSIONS: We recommend that an ultrasound kidney examination in patients with polycystic kidney disease should include evaluating renal parenchyma and the number of cysts for better assessment of disease severity. PMID- 28856015 TI - Antenatal corticosteroid treatment for the prevention of peri-intraventricular haemorrhage in preterm newborns: a retrospective cohort study using transfontanelle ultrasonography. AB - OBJECTIVE: The objective of this study was to assess the correlation between antenatal corticosteroids and peri-intraventricular haemorrhage (PIVH) using transfontanelle ultrasonography, as well as to evaluate the risk factors for its incidence. METHODS: We performed a retrospective cohort study using medical records of preterm newborns. The protocol for maternal corticoid administration for foetal lung maturation included dexamethasone 4 mg (intramuscular) 8/8 hours per 48 hours, with one cycle per week. The diagnosis of periintraventricular haemorrhage was based on transfontanelle ultrasonography, using the Papile's classification. The following risk factors for peri-intraventricular haemorrhage were assessed: birth weight, gestational age at delivery, type of delivery, newborn's sex, surfactant administration, premature rupture of membranes and previous history of infection during the current pregnancy. The student's t-test and chi-square test were used for statistical analysis. RESULTS: Our sample population included 184 preterm newborns. Transfontanelle ultrasonography revealed peri-intraventricular haemorrhage in 32 (74.4%) and periventricular leukomalacia in 11 (25.6%) newborns. Grade I haemorrhage was found in 20 (62.5%), grade II in five (15.6%), and grade III in seven (21.8%) newborns, as in accordance with Papile's classification. Vaginal delivery (p = 0.010), birth weight <1500 g (p = 0.024), gestational age at delivery <=32 weeks (p = 0.018), and previous history of infection during pregnancy (p = 0.013) were considered risk factors for peri-intraventricular haemorrhage in preterm newborns. CONCLUSION: Maternal corticoid administration for foetal lung maturation showed a protective effect against peri-intraventricular haemorrhage in preterm newborns. The risk factors for peri-intraventricular haemorrhage were determined. PMID- 28856016 TI - Difficulties in differentiating the nature of ascites based on ultrasound imaging. AB - : Transabdominal ultrasound not always allows to determine the nature of ascites based solely on its characteristics. AIM: The aim of the study was to present difficulties in determining the nature of ascites using transabdominal ultrasonography solely based on extra-organ lesions as well as, after the inclusion of the overall abdominal assessment and the clinical picture. MATERIALS AND METHODS: A total of 18 patients with non-neoplastic ascites and 62 patients with neoplastic ascites whose final diagnosis was based on cytological and histopathological findings were evaluated between 2005 and 2015. Abdominal ultrasound was performed to detect the presence of fluid in all accessible spaces, and, additionally, to determine the presence of potential peritoneal tumor implants as well as to evaluate the parietal peritoneum and the greater omentum. Different digital ultrasound machines equipped with 3-6 MHz and linear 7 12 MHz transducers were used in the study. Double-sided Fisher's exact test with statistical significance at p < 0.05 was used for the analysis of the obtained results. RESULTS: Statistically significant differences between benign and neoplastic ascites were found for: anechoic peritoneal fluid (<0.0001); fluid and thickened omentum with smooth surface (<0.0001); fluid and thickened omentum with smooth surface and varices (0.01); fluid and thickened omentum with hypoechoic foci (0.049); fluid and thickened omentum with tumor implants (0.009). The inclusion of the overall assessment of abdominal organs and the clinical data allowed for an improvement in ultrasonographic diagnostic accuracy in benign and neoplastic ascites from 83.3% and 67.7% to 94.4% and 93.5%, respectively. CONCLUSIONS: When used alone, an assessment of acoustic fluid characteristics and extra-organ peritoneal lesions limits the possibility to differentiate between benign and malignant ascites. These results improve after the inclusion of sonographic assessment of all abdominal organs in combination with clinical data. PMID- 28856017 TI - Repeatability and reproducibility of measurements of the suburethral tape location obtained in pelvic floor ultrasound performed with a transvaginal probe. AB - INTRODUCTION: Implants used to treat patients with urogynecological conditions are well visible in US examination. The position of the suburethral tape (sling) is determined in relation to the urethra or the pubic symphysis. AIM OF THE STUDY: The study was aimed at assessing the accuracy of measurements determining suburethral tape location obtained in pelvic US examination performed with a transvaginal probe. MATERIAL AND METHODS: The analysis covered the results of sonographic measurements obtained according to a standardized technique in women referred for urogynecological diagnostics. Data from a total of 68 patients were used to analyse the repeatability and reproducibility of results obtained on the same day. RESULTS: The intraclass correlation coefficient for the repeatability and reproducibility of the sonographic measurements of suburethral tape location obtained with a transvaginal probe ranged from 0.6665 to 0.9911. The analysis of the measurements confirmed their consistency to be excellent or good. CONCLUSIONS: Excellent and good repeatability and reproducibility of the measurements of the suburethral tape location obtained in a pelvic ultrasound performed with a transvaginal probe confirm the test's validity and usefulness for clinical and academic purposes. PMID- 28856018 TI - Sonographic detection of inferior subluxation in post-stroke hemiplegic shoulders. AB - AIM OF THE STUDY: To evaluate the usefulness of ultrasonographic acromion-greater tuberosity distance measurement and Shoulder ratio in detecting post-stroke inferior shoulder subluxation. MATERIAL AND METHODS: Forty-five hemiplegic stroke patients and 45 controls underwent shoulder sonography to measure their acromion greater tuberosity distance. Side-to-side acromion-greater tuberosity distance differences and Shoulder ratios were derived from the acromion-greater tuberosity distance values. The long head of biceps tendon, subscapularis tendon, supraspinatus tendon, and the infraspinatus tendon were also evaluated to exclude full thickness tendon tears. Data were analyzed using the Statistical Package for Social Sciences version 20.0 for windows. Normality of data distribution was checked using the Kolmogorov-Smirnov test. Mann-Whitney U test and Chi-square tests were utilized. RESULTS: Hemiplegic and control shoulders' acromion-greater tuberosity distance values were 2.8 +/- 0.6 cm and 2.4 +/- 0.4 cm, respectively (p = 0.001). Hemiplegic and control shoulder ratios were 1.3 +/- 0.3 and 1.1 +/- 0.1, respectively; p < 0.001. Point biserial correlation showed that the presence of subluxation correlated moderately with higher shoulder ratios in all the hemiplegics (rpb = 0.520; p < 0.001). CONCLUSION: Our results suggest that acromion-greater tuberosity distance measurement is useful for detecting inferior shoulder subluxation. Shoulder ratio may be of complementary or supplemental value to acromion-greater tuberosity distance difference. PMID- 28856019 TI - Detailed EFSUM recommendations on the scope of ultrasound assessment in patients with portal hypertension considering the diagnostic reference level. AB - An important paper describing the Standards of the Polish Ultrasound Society regarding the assessment of portal and hepatic vasculature was published in the Journal of Ultrasonography. Due to the multiplicity of morphological and hemodynamic data required, the time needed to obtain these data and the legal responsibility of doctors for the results, there seems to be a need to determine a clear range of the assessed parameters depending on the reference level of a given healthcare facility. Therefore, the aim of the paper was to present the EFSUMB recommendations on the range of the evaluated ultrasonographic parameters in portal hypertension depending on the reference level. European healthcare institutions are characterized by a clear three-level reference network. Due to the lack of a similar division in Poland, we propose our own classification of the competence of medical entities. The first reference level: ultrasound assessments in a primary health care setting (performed by GPs, emergency physicians, non-specialist private practice physicians, non-specialist practice physicians); at least one mid-class ultrasound scanner with pulsed and color Doppler options, equipped with convex 3-5 MHz and linear 7-12 MHz transducers should be available at physician's disposal. The second reference level: ultrasound assessments in the hospital setting and specialist outpatient clinics, performed by specialist private practice physicians, radiologists, gastroenterologists and hepatologists; top class (premium) digital ultrasound scanner should be available at physician's disposal. Third reference level: ultrasound assessments performed in gastroenterology, hepatology and liver surgery departments as well as their specialist outpatient clinics; physicians should use top class digital ultrasound equipment. At every reference level, physicians performing abdominal ultrasound should have the appropriate certification to perform such an assessment or specialize in gastrointestinal diagnosis. PMID- 28856020 TI - Can ultrasound be helpful in selecting optimal management methods for pregnancies complicated by placental non-trophpblastic tumors? AB - Placental chorioangioma is the most common subtype of non-trophoblastic placental tumors. Other subtypes are very rare and usually associated with an uneventful course of pregnancy. Most chorioangiomas are small and of no clinical significance. Giant chorioangiomas may be associated with serious fetal and maternal complications. So far, no established ultrasound guidelines are available for the management of placental non-trophoblastic tumors. This may be attributed to the rarity of the disease entity and its different clinical features and complications. In this article, the role of ultrasound findings such as the tumor's size, vascularity, feeding vessels, amniotic fluid and location of the placenta in the diagnosis, treatment and follow up of these tumors is presented relying on up-todate literature review. Conservative management with serial ultrasound examinations can be an adequate method for monitoring small uncomplicated tumors. Ultrasound-guided procedures such as amnioreduction and cordocentesis can be used for amelioration of complications. Chorioangioma specific treatment is reserved for complicated cases in the second trimester of pregnancy when prematurity is a matter of concern. Endoscopic laser ablation is indicated when the feeding vessel is superficial and small. Interstitial laser ablation is helpful when the placenta is located in the anterior uterine wall. Ligation of the feeding vessels is preferred when they are large. Alcohol injection should be performed away from the vasculature to prevent toxicity. Microcoils should be inserted as near as possible to the tumor to prevent collateral formation. Ultrasound is also a method of choice for monitoring the effectiveness of these procedures. PMID- 28856021 TI - Wrist ultrasound examination - scanning technique and ultrasound anatomy. Part 2: Ventral wrist. AB - Ultrasound imaging of the musculoskeletal system is an important element of the diagnostic and therapeutic protocol. Clinical decisions, including those regarding surgical procedures, are often based solely on ultrasound imaging. However, detailed knowledge on the anatomy and a correct scanning technique are crucial for an accurate diagnosis. Modern ultrasonographic equipment allows obtaining detailed anatomical images of muscle tendons, ligaments, nerves and vessels of the carpal area. Ventral wrist ultrasound is one of the most common diagnostic procedures in patients with suspected carpal tunnel syndrome. Ventral wrist evaluation is also often performed in patients with wrist pain of unclear etiology, rheumatic diseases, wrist injuries or symptoms of ulnar neuropathy. The aim of this paper is to present ultrasound images with corresponding anatomical schemes. The technique of ultrasound examination of the ventral wrist along with practical guidance to help obtain highly diagnostic images is also discussed. The present paper is the second part of an article devoted to ultrasound anatomy and wrist ultrasound technique - the part discussing the dorsal side of the wrist was published in the Journal of Ultrasonography, Vol. 15, No 61. The following anatomical structures should be visualized during an ultrasound examination of the ventral wrist, both in the carpal tunnel as well as proximally and distally to it: four flexor digitorum superficialis tendons, four flexor digitorum profundus tendons, flexor pollicis longus, flexor carpi radialis tendon, median nerve and flexor retinaculum; in the carpal tunnel as well as proximally and distally to it: the ulnar nerve, ulnar artery and veins; the tendon of the flexor carpi ulnaris muscle; carpal joints. PMID- 28856022 TI - A reminder of peristalsis as a useful tool in the prenatal differential diagnosis of abdominal cystic masses. AB - With routine antenatal ultrasound and recent advances in ultrasound technology, fetal intraabdominal cystic masses are recognized more often and are better characterized than in the past. They may be classified as solid and cystic, and may originate from multiple structures. When considering the extensive differential diagnosis of cystic masses, the observation of peristalsis narrows the possibilities to the gastrointestinal tract. To find this feature on ultrasound, the examiner must expressly think and look for it, otherwise it may be missed. Our case report illustrates one of those cases. PMID- 28856023 TI - Body stalk anomaly: antenatal sonographic diagnosis of this rare entity with review of literature. AB - Body stalk anomaly is a rare and severe malformation syndrome in which the exact pathophysiology and trigger factors are still unknown. Possible causes of body stalk anomaly include early amnion rupture with direct mechanical pressure and amniotic bands, vascular disruption of the early embryo, or an abnormality in the germinal disk. We present a case of body stalk anomaly diagnosed during antenatal sonographic evaluation at the first visit with the review of literature regarding this phenomenon. Sonographic features of the fetus included a severe midline defect of the fetal abdominal wall with a large extra-abdominal mass containing bowel and liver inside. Body stalk anomaly is accepted as a fatal anomaly, so it is important to differentiate it from other anterior wall defects for evaluating the management options. PMID- 28856024 TI - Is a linear probe helpful in diagnosing diseases of pulmonary interstitial spaces? AB - In a lung ultrasound examination, interstitial lung lesions are visible as numerous B-line artifacts, and are best recorded with the use of a convex probe. Interstitial lung lesions may result from many conditions, including cardiogenic pulmonary oedema, non-cardiogenic pulmonary oedema, or interstitial lung disease. Hence difficulties in the differential diagnostics of the above clinical conditions. This article presents cases of patients suffering from interstitial lung lesions discovered in the course of lung ultrasound examination. The patients were examined with a 3.5-5.0 MHz convex probe and a 7.0-11.0 MHz linear probe. Ultrasound images have been analysed, and differences in the imaging with both probes in patients with interstitial lung lesions have been detailed. The use of a linear probe in patients with interstitial lung lesions (discovered with a convex or a micro-convex probe) provides additional information on the source of the origin of the lesions. PMID- 28856025 TI - Efficacy of Prompt Initiation of Antiretroviral Therapy in the Treatment of Hemophagocytic Lymphohistiocytosis Triggered by Uncontrolled Human Immunodeficiency Virus. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, rapidly progressive hematologic disorder involving uncontrolled immune system activation. HLH has been associated with viral infections, including human immunodeficiency virus (HIV) infections. We report a case of a critically ill 30-year-old female who was hospitalized with HIV-associated HLH, with a CD4 count of 4 cells/mL and HIV viral load of 1,842,730 copies/mL. After ruling out other potential infectious causes of HLH, antiretroviral therapy (ART) was initiated with darunavir, ritonavir, tenofovir, and emtricitabine. Within one week of initiation of ART, the patient began to improve clinically and hematologically and was stable enough for discharge from the hospital three weeks after starting therapy. This case suggests that treatment with ART in patients with HIV-associated HLH should be considered even in critically ill patients with low CD4 counts. PMID- 28856026 TI - Acute Traumatic Patellar Tendon Rupture at the Tibial Tuberosity Attachment without Avulsion Fracture. AB - Patellar tendon rupture in children is especially rare. The fact that the area of traumatic rupture has wide variations makes surgical treatment difficult. We present an 11-year-old boy with acute traumatic patellar tendon rupture at the tibial tuberosity attachment without avulsion fracture. Primary end-to-end repair and reinforcement using 1.5 mm stainless steel wires as a surgical strategy were undertaken. Early range of motion began with a functional knee brace and the reinforced stainless wire was removed 3 months after surgery. Knee function at the final follow-up was satisfactory. We suggest that this strategy may provide a useful option for surgical treatment. PMID- 28856027 TI - Cutaneous Erythema at Scar Site of Modified Radical Mastectomy: An Unexpected Manifestation of Recurrent Carcinoma. AB - A 44-year-old woman presented with marked erythema over right mastectomy scar, while on Herceptin therapy. She had neoadjuvant chemotherapy, modified radical mastectomy, and radiotherapy less than one year earlier for the treatment of invasive ductal carcinoma. On physical examination, no palpable masses were detected in the erythematous skin. A biopsy revealed permeation of the skin lymphatics by emboli of metastatic ductal carcinoma, similar to what is seen in inflammatory carcinoma. The involved skin was excised, followed by immediate reconstruction with transverse rectus abdominis muscle (TRAM) flap. On follow-up, the wound was healing well, with no signs of inflammation. PMID- 28856029 TI - Synthesis and Storage Stability of Diisopropylfluorophosphate. AB - Diisopropylfluorophosphate (DFP) is a potent acetylcholinesterase inhibitor commonly used in toxicological studies as an organophosphorus nerve agent surrogate. However, LD50 values for DFP in the same species can differ widely even within the same laboratory, possibly due to the use of degraded DFP. The objectives here were to identify an efficient synthesis route for high purity DFP and assess the storage stability of both the in-house synthesized and commercial source of DFP at the manufacturer-recommended storage temperature of 4 degrees C, as well as -10 degrees C and -80 degrees C. After 393 days, the commercial DFP stored at 4 degrees C experienced significant degradation, while only minor degradation was observed at -10 degrees C and none was observed at -80 degrees C. DFP prepared using the newly identified synthesis route was significantly more stable, exhibiting only minor degradation at 4 degrees C and none at -10 degrees C or -80 degrees C. The major degradation product was the monoacid derivative diisopropylphosphate, formed via hydrolysis of DFP. It was also found that storing DFP in glass containers may accelerate the degradation process by generating water in situ as hydrolytically generated hydrofluoric acid attacks the silica in the glass. Based on the results here, it is recommended that DFP be stored at or below -10 degrees C, preferably in air-tight, nonglass containers. PMID- 28856028 TI - Bibliometric Analysis of Worldwide Publications on Antimalarial Drug Resistance (2006-2015). AB - BACKGROUND: In response to international efforts to control and eradicate malaria, we designed this study to give a bibliometric overview of research productivity in antimalarial drug resistance (AMDR). METHODS: Keywords related to AMDR were used to retrieve relevant literature using Scopus database. RESULTS: A total of 976 publications with an h-index of 63 were retrieved. The number of publications showed a noticeable increase starting in the early 1990s. The USA was the most productive country with 337 publications equivalent to one-third of worldwide publications in this field. More than two-thirds of publications by the USA (236, 70.03%) were made by international collaboration. Of the top ten productive countries, two countries were from Mekong subregion, particularly Thailand and Cambodia. The Malaria Journal was the most productive journal (136, 13.93%) in this field. Mahidol University (80, 8.20%) in Thailand was the most productive institution. Seven articles in the top-ten list were about artemisinin resistance in Plasmodium falciparum, one was about chloroquine resistance, one was about sulfadoxine-pyrimethamine resistance, and the remaining one was about general multidrug resistance. CONCLUSION: Eradication and control of AMDR require continuing research activity to help international health organizations identify spots that require an immediate action to implement appropriate measures. PMID- 28856030 TI - Frequency of Food Consumption and Self-reported Diabetes among Adult Men and Women in India: A Large Scale Nationally Representative Cross-sectional Study. AB - BACKGROUND: Recent studies have shown that the choice of foods and frequency of intake plays a role in diabetes prevention. We examined the association between frequency of consumption of specific food items and the occurrence of diabetes in adult Indian population. METHODS: Cross sectional data of 99,574 women and 61,361 men aged 20-49 years who participated in India's third National Family Health Survey conducted during 2005-06 was used for this study. Association between frequency of food intake such as daily, weekly, occasionally and never, and prevalence of diabetes were estimated using multivariable logistic regression models after adjusting for body mass index, tobacco smoking, alcohol drinking, television watching and socio-economic and demographic characteristics, stratified by sex. RESULTS: In men, weekly (OR:0.64; 95%CI:0.47-0.88) and occasional (OR:0.60; 95%CI:0.44-0.81) consumption of milk/curd, weekly (OR:0.48; 95%CI:0.27-0.87) and occasional (OR:0.52; 95%CI:0.28-0.99) consumption of pulses/beans and consumption of fruits (OR ranges from 0.33 to 0.39) was associated with a significantly lower likelihood of diabetes whereas daily (OR:0.55; 95%CI:0.34-0.88) or weekly (OR:0.56; 95%CI:0.35-0.90) pulses/beans consumption and fruits intake (OR ranges from 0.36 to 0.46) was associated with a lower likelihood of diabetes in women. CONCLUSION: This study has confirmed findings from high income countries that diabetes among adult Indians, which is large and increasing, might be contained by regular consumption of vegetarian foods including pulses, beans, fruits and dairy products. However, this is an observational finding and uncontrolled confounding cannot be excluded as an explanation for the association. More epidemiological research with better measures of food intake and clinical measures of diabetes is needed in a developing country setting to validate the findings. PMID- 28856031 TI - Blood oxygenation and flow measurements using a single 720-nm tunable V-cavity laser. AB - We propose and demonstrate a single-laser-based sensing method for measuring both blood oxygenation and microvascular blood flow. Based on the optimal wavelength range found from theoretical analysis on differential absorption based blood oxygenation measurement, we designed and fabricated a 720-nm-band wavelength tunable V-cavity laser. Without any grating or bandgap engineering, the laser has a wavelength tuning range of 14.1 nm. By using the laser emitting at 710.3 nm and 724.4 nm to measure the oxygenation and blood flow, we experimentally demonstrate the proposed method. PMID- 28856032 TI - Optimizing pulse compressibility in completely all-fibered Ytterbium chirped pulse amplifiers for in vivo two photon laser scanning microscopy. AB - A simple and completely all-fiber Yb chirped pulse amplifier that uses a dispersion matched fiber stretcher and a spliced-on hollow core photonic bandgap fiber compressor is applied in nonlinear optical microscopy. This stretching compression approach improves compressibility and helps to maximize the fluorescence signal in two-photon laser scanning microscopy as compared with approaches that use standard single mode fibers as stretcher. We also show that in femtosecond all-fiber systems, compensation of higher order dispersion terms is relevant even for pulses with relatively narrow bandwidths for applications relying on nonlinear optical effects. The completely all-fiber system was applied to image green fluorescent beads, a stained lily-of-the-valley root and rat-tail tendon. We also demonstrated in vivo imaging in zebrafish larvae, where we simultaneously measure second harmonic and fluorescence from two-photon excited red-fluorescent protein. Since the pulses are compressed in a fiber, this source is especially suited for upgrading existing laser scanning (confocal) microscopes with multiphoton imaging capabilities in space restricted settings or for incorporation in endoscope-based microscopy. PMID- 28856033 TI - Adapting Bobbert-Vlieger model to spectroscopic ellipsometry of gold nanoparticles with bio-organic shells. AB - We investigate spectroscopic imaging ellipsometry for monitoring biomolecules at surfaces of nanoparticles. For the modeling of polarimetric light scattering off surface-adsorbed core-shell nanoparticles, we employ an extension of the exact solution for the scattering by particles near a substrate presented by Bobbert and Vlieger, which offers insight beyond that of the Maxwell-Garnett effective medium approximation. Varying thickness and refractive index of a model bio organic shell results in systematic and characteristic changes in spectroscopic parameters [Formula: see text] and [Formula: see text]. The salient features and trends in modeled spectra are in qualitative agreement with experimental data for antibody immobilization and fibronectin biorecognition at surfaces of gold nanoparticles on a silicon substrate, but achieving a full quantitative agreement will require including additional effects, such as nanoparticle-substrate interactions, into the model. PMID- 28856034 TI - Sensing viruses using terahertz nano-gap metamaterials. AB - We demonstrate highly sensitive detection of viruses using terahertz split-ring resonators with various capacitive gap widths. Two types of viruses, with sizes ranging from 60 nm (PRD1) to 30 nm (MS2), were detected at low densities on the metamaterial surface. The dielectric constants of the virus layers in the THz frequency range were first measured using thick films, and the large values found identified them as efficient target substances for dielectric sensing. We observed the resonance-frequency shift of the THz metamaterial following deposition of the viruses on the surface at low-density. The resonance shift was higher for the MS2 virus, which has a relatively large dielectric constant. The frequency shift increases with surface density until saturation and the sensitivity is then obtained from the initial slope. Significantly, the sensitivity increases by about 13 times as the gap width in the metamaterials is decreased from 3 um to 200 nm. This results from a combination of size-related factors, leading to field enhancement accompanying strong field localization. PMID- 28856035 TI - Mueller matrix polarimetry for characterizing microstructural variation of nude mouse skin during tissue optical clearing. AB - We investigate the polarization features corresponding to changes in the microstructure of nude mouse skin during immersion in a glycerol solution. By comparing the Mueller matrix imaging experiments and Monte Carlo simulations, we examine in detail how the Mueller matrix elements vary with the immersion time. The results indicate that the polarization features represented by Mueller matrix elements m22&m33&m44 and the absolute values of m34&m43 are sensitive to the immersion time. To gain a deeper insight on how the microstructures of the skin vary during the tissue optical clearing (TOC), we set up a sphere-cylinder birefringence model (SCBM) of the skin and carry on simulations corresponding to different TOC mechanisms. The good agreement between the experimental and simulated results confirm that Mueller matrix imaging combined with Monte Carlo simulation is potentially a powerful tool for revealing microscopic features of biological tissues. PMID- 28856036 TI - Optical coherence tomography angiography of retinal vascular occlusions produced by imaging-guided laser photocoagulation. AB - Retinal vascular occlusive diseases represent a major form of vision loss worldwide. Rodent models of these diseases have traditionally relied upon a slit lamp biomicroscope to help visualize the fundus and subsequently aid delivery of high-power laser shots to a target vessel. Here we describe a multimodal imaging system that can produce, image, and monitor retinal vascular occlusions in rodents. The system combines a spectral-domain optical coherence tomography system for cross-sectional structural imaging and three-dimensional angiography, and a fluorescence scanning laser ophthalmoscope for Rose Bengal monitoring and high-power laser delivery to a target vessel. This multimodal system facilitates the precise production of occlusions in the branched retinal veins, central retinal vein, and branched retinal arteries. Additionally, changes in the retinal morphology and retinal vasculature can be longitudinally documented. With our device, retinal vascular occlusions can be easily and consistently created, which paves the way for futures studies on their pathophysiology and therapeutic targets. PMID- 28856037 TI - Plastic embedding immunolabeled large-volume samples for three-dimensional high resolution imaging. AB - High-resolution three-dimensional biomolecule distribution information of large samples is essential to understanding their biological structure and function. Here, we proposed a method combining large sample resin embedding with iDISCO immunofluorescence staining to acquire the profile of biomolecules with high spatial resolution. We evaluated the compatibility of plastic embedding with an iDISCO staining technique and found that the fluorophores and the neuronal fine structures could be well preserved in the Lowicryl HM20 resin, and that numerous antibodies and fluorescent tracers worked well upon Lowicryl HM20 resin embedding. Further, using fluorescence Micro-Optical sectioning tomography (fMOST) technology combined with ultra-thin slicing and imaging, we were able to image the immunolabeled large-volume tissues with high resolution. PMID- 28856038 TI - qF-SSOP: real-time optical property corrected fluorescence imaging. AB - Fluorescence imaging is well suited to provide image guidance during resections in oncologic and vascular surgery. However, the distorting effects of tissue optical properties on the emitted fluorescence are poorly compensated for on even the most advanced fluorescence image guidance systems, leading to subjective and inaccurate estimates of tissue fluorophore concentrations. Here we present a novel fluorescence imaging technique that performs real-time (i.e., video rate) optical property corrected fluorescence imaging. We perform full field of view simultaneous imaging of tissue optical properties using Single Snapshot of Optical Properties (SSOP) and fluorescence detection. The estimated optical properties are used to correct the emitted fluorescence with a quantitative fluorescence model to provide quantitative fluorescence-Single Snapshot of Optical Properties (qF-SSOP) images with less than 5% error. The technique is rigorous, fast, and quantitative, enabling ease of integration into the surgical workflow with the potential to improve molecular guidance intraoperatively. PMID- 28856039 TI - Classification of biological micro-objects using optical coherence tomography: in silico study. AB - We report on the development of a technique for differentiating between biological micro-objects using a rigorous, full-wave model of OCT image formation. We model an existing experimental prototype which uses OCT to interrogate a microfluidic chip containing the blood cells. A full-wave model is required since the technique uses light back-scattered by a scattering substrate, rather than by the cells directly. The light back-scattered by the substrate is perturbed upon propagation through the cells, which flow between the substrate and imaging system's objective lens. We present the key elements of the 3D, Maxwell equation-based computational model, the key findings of the computational study and a comparison with experimental results. PMID- 28856040 TI - ReLayNet: retinal layer and fluid segmentation of macular optical coherence tomography using fully convolutional networks. AB - Optical coherence tomography (OCT) is used for non-invasive diagnosis of diabetic macular edema assessing the retinal layers. In this paper, we propose a new fully convolutional deep architecture, termed ReLayNet, for end-to-end segmentation of retinal layers and fluid masses in eye OCT scans. ReLayNet uses a contracting path of convolutional blocks (encoders) to learn a hierarchy of contextual features, followed by an expansive path of convolutional blocks (decoders) for semantic segmentation. ReLayNet is trained to optimize a joint loss function comprising of weighted logistic regression and Dice overlap loss. The framework is validated on a publicly available benchmark dataset with comparisons against five state-of-the-art segmentation methods including two deep learning based approaches to substantiate its effectiveness. PMID- 28856041 TI - Quantitatively characterizing the microstructural features of breast ductal carcinoma tissues in different progression stages by Mueller matrix microscope. AB - Polarization imaging has been recognized as a potentially powerful technique for probing the microstructural information and optical properties of complex biological specimens. Recently, we have reported a Mueller matrix microscope by adding the polarization state generator and analyzer (PSG and PSA) to a commercial transmission-light microscope, and applied it to differentiate human liver and cervical cancerous tissues with fibrosis. In this paper, we apply the Mueller matrix microscope for quantitative detection of human breast ductal carcinoma samples at different stages. The Mueller matrix polar decomposition and transformation parameters of the breast ductal tissues in different regions and at different stages are calculated and analyzed. For more quantitative comparisons, several widely-used image texture feature parameters are also calculated to characterize the difference in the polarimetric images. The experimental results indicate that the Mueller matrix microscope and the polarization parameters can facilitate the quantitative detection of breast ductal carcinoma tissues at different stages. PMID- 28856042 TI - Fluorescence depth estimation from wide-field optical imaging data for guiding brain tumor resection: a multi-inclusion phantom study. AB - Studies have shown that fluorescent agents demarcate tumor from surrounding brain tissue and offer intraoperative guidance during resection. However, visualization of fluorescence signal from tumor below the surgical surface or through the appearance of blood in the surgical field is challenging. We have previously described red light imaging techniques for estimating fluorescent depths in turbid media. In this study, we evaluate these methods over a broader range of fluorophore concentrations, and investigate the ability to resolve multiple fluorescent emissions in the same plane or at different depths along the axis of imaging. A tungsten halogen lamp is used as a broadband white light source for reflectance imaging. Fluorescence from Alexa Fluor 647 is excited with a 635 nm diode laser. Reflectance and fluorescence spectral data are gathered between 670 and 720 nm with the use of a liquid crystal tunable filter and recorded on a sCMOS camera. Results show that two fluorescent emissions can be resolved within 2 mm if they are in the same plane or within 3 mm if they are at different depths along the axis of imaging up to 6 mm below the surface. PMID- 28856043 TI - Whole blood clot optical clearing for nondestructive 3D imaging and quantitative analysis. AB - A technological revolution in both light and electron microscopy imaging now allows unprecedented views of clotting, especially in animal models of hemostasis and thrombosis. However, our understanding of three-dimensional high-resolution clot structure remains incomplete since most of our recent knowledge has come from studies of relatively small clots or thrombi, due to the optical impenetrability of clots beyond a few cell layers in depth. Here, we developed an optimized optical clearing method termed cCLOT that renders large whole blood clots transparent and allows confocal imaging as deep as one millimeter inside the clot. We have tested this method by investigating the 3D structure of clots made from reconstituted pre-labeled blood components yielding new information about the effects of clot contraction on erythrocytes. Although it has been shown recently that erythrocytes are compressed to form polyhedrocytes during clot contraction, observations of this phenomenon have been impeded by the inability to easily image inside clots. As an efficient and non-destructive method, cCLOT represents a powerful research tool in studying blood clot structure and mechanisms controlling clot morphology. Additionally, cCLOT optical clearing has the potential to facilitate imaging of ex vivo clots and thrombi derived from healthy or pathological conditions. PMID- 28856044 TI - Label-free optical detection of action potential in mammalian neurons. AB - We describe an optical technique for label-free detection of the action potential in cultured mammalian neurons. Induced morphological changes due to action potential propagation in neurons are optically interrogated with a phase sensitive interferometric technique. Optical recordings composed of signal pulses mirror the electrical spike train activity of individual neurons in a network. The optical pulses are transient nanoscale oscillatory changes in the optical path length of varying peak magnitude and temporal width. Exogenous application of glutamate to cortical neuronal cultures produced coincident increase in the electrical and optical activity; both were blocked by application of a Na-channel blocker, Tetrodotoxin. The observed transient change in optical path length in a single optical pulse is primarily due to physical fluctuations of the neuronal cell membrane mediated by a yet unknown electromechanical transduction phenomenon. Our analysis suggests a traveling surface wave in the neuronal cell membrane is responsible for the measured optical signal pulses. PMID- 28856045 TI - In-silico and in-vitro investigation of a photonic monitor for intestinal perfusion and oxygenation. AB - The quantification of visceral organ oxygenation after trauma-related systemic hypovolemia and shock is critical to enable effective resuscitation. In this work, a photoplethysmography-based (PPG) sensor was specifically designed for probing the perfusion and oxygenation condition of intestinal tissue with the ultimate goal to monitor patients post trauma to guide resuscitation. Through Monte Carlo modeling, suitable optofluidic phantoms were determined, the wavelength and separation distance for the sensor was optimized, and sensor performance for the quantification of tissue perfusion and oxygenation was tested on the in-vitro phantom. In particular, the Monte Carlo simulated both a standard block three-layer model and a more realistic model including villi. Measurements were collected on the designed three layer optofluidic phantom and the results taken with the small form factor PPG device showed a marked improvement when using shorter visible wavelengths over the more conventional longer visible wavelengths. Overall, in this work a Monte Carlo model was developed, an optofluidic phantom was built, and a small form factor PPG sensor was developed and characterized using the phantom for perfusion and oxygenation over the visible wavelength range. The results show promise that this small form factor PPG sensor could be used as a future guide to shock-related resuscitation. PMID- 28856046 TI - Visualization of laser tattoo removal treatment effects in a mouse model by two photon microscopy. AB - Laser tattoo removal is an effective method of eliminating tattoo particles in the skin. However, laser treatment cannot always remove the unwanted tattoo completely, and there are risks of either temporary or permanent side effects. Studies using preclinical animal models could provide detailed information on the effects of laser treatment in the skin, and might help to minimize side effects in clinical practices. In this study, two-photon microscopy (TPM) was used to visualize the laser treatment effects on tattoo particles in both phantom specimens and in vivo mouse models. Fluorescent tattoo ink was used for particle visualization by TPM, and nanosecond (ns) and picosecond (ps) lasers at 532 nm were used for treatment. In phantom specimens, TPM characterized the fragmentation of individual tattoo particles by tracking them before and after the laser treatment. These changes were confirmed by field emission scanning electron microscopy (FE-SEM). TPM was used to measure the treatment efficiency of the two lasers at different laser fluences. In the mouse model, TPM visualized clusters of tattoo particles in the skin and detected their fragmentation after the laser treatment. Longitudinal TPM imaging observed the migration of cells containing tattoo particles after the laser treatment. These results show that TPM may be useful for the assessment of laser tattoo removal treatment in preclinical studies. PMID- 28856047 TI - High-sensitivity detection of cardiac troponin I with UV LED excitation for use in point-of-care immunoassay. AB - High-sensitivity cardiac troponin assay development enables determination of biological variation in healthy populations, more accurate interpretation of clinical results and points towards earlier diagnosis and rule-out of acute myocardial infarction. In this paper, we report on preliminary tests of an immunoassay analyzer employing an optimized LED excitation to measure on a standard troponin I and a novel research high-sensitivity troponin I assay. The limit of detection is improved by factor of 5 for standard troponin I and by factor of 3 for a research high-sensitivity troponin I assay, compared to the flash lamp excitation. The obtained limit of detection was 0.22 ng/L measured on plasma with the research high-sensitivity troponin I assay and 1.9 ng/L measured on tris-saline-azide buffer containing bovine serum albumin with the standard troponin I assay. We discuss the optimization of time-resolved detection of lanthanide fluorescence based on the time constants of the system and analyze the background and noise sources in a heterogeneous fluoroimmunoassay. We determine the limiting factors and their impact on the measurement performance. The suggested model can be generally applied to fluoroimmunoassays employing the dry cup concept. PMID- 28856048 TI - Similarity regularized sparse group lasso for cup to disc ratio computation. AB - Automatic cup to disc ratio (CDR) computation from color fundus images has shown to be promising for glaucoma detection. Over the past decade, many algorithms have been proposed. In this paper, we first review the recent work in the area and then present a novel similarity-regularized sparse group lasso method for automated CDR estimation. The proposed method reconstructs the testing disc image based on a set of reference disc images by integrating the similarity between testing and the reference disc images with the sparse group lasso constraints. The reconstruction coefficients are then used to estimate the CDR of the testing image. The proposed method has been validated using 650 images with manually annotated CDRs. Experimental results show an average CDR error of 0.0616 and a correlation coefficient of 0.7, outperforming other methods. The areas under curve in the diagnostic test reach 0.843 and 0.837 when manual and automatically segmented discs are used respectively, better than other methods as well. PMID- 28856049 TI - Toward whole-body quantitative photoacoustic tomography of small-animals with multi-angle light-sheet illuminations. AB - Several attempts to achieve the quantitative photoacoustic tomography (q-PAT) have been investigated using point sources or a single-angle wide-field illumination. However, these schemes normally suffer from low signal-to-noise ratio (SNR) or poor quantification in imaging applications on large-size domains, due to the limitation of ANSI-safety incidence and incompleteness in the data acquisition. We herein present a q-PAT implementation that uses multi-angle light sheet illuminations and calibrated recovering-and-averaging iterations. The scheme can obtain more complete information on the intrinsic absorption from the multi-angle illumination mode, and collect SNR-boosted photoacoustic signals in the selected planes from the wide-field light-sheet excitation. Therefore, the sliced absorption maps over whole body of small-animals can be recovered in a measurement-flexible, noise-robust and computation-economic way. The proposed approach is validated by phantom, ex vivo and in vivo experiments, exhibiting promising performances in image fidelity and quantitative accuracy for practical applications. PMID- 28856050 TI - Method for quantitative assessment of retinal vessel tortuosity in optical coherence tomography angiography applied to sickle cell retinopathy. AB - Tortuosity is an important geometric vessel parameter and among the first microvascular alterations observed in various retinopathies. In the current study, a quantitative vessel tortuosity index (VTI) based on a combination of local and global centerline features is presented. Performance of VTI and previously established tortuosity indices were compared against human observers' evaluation of tortuosity. An image-processing pipeline was developed for application of VTI in retinal vessels imaged by optical coherence tomography angiography (OCTA) in perifoveal (6 mm * 6 mm) and parafoveal (3 mm * 3 mm) regions centered on the fovea. Forty-one subjects (12 healthy control (NC) and 29 sickle cell retinopathy (SCR)) and 10 subjects (5 NC and 5 SCR) were imaged in the perifoveal and parafoveal regions, respectively. The relationship between VTI and age was examined in the perifoveal regions in NC subjects. VTI was measured from the OCTA images and compared between NC and SCR subjects using generalized least square regression with and without adjusting for age and race. VTI was found to correlate better than the 4 previous indices with performance of human observers. In the perifoveal region, a significant correlation was observed between VTI and age (r = -0.4, P<0.001, N = 12). VTI was higher in SCR than NC subjects in perifoveal and parafoveal regions (P<=0.001). The results demonstrate that the proposed method shows promise for detection of increased tortuosity in vessels due to retinal disorders. PMID- 28856052 TI - Differentiation of fibrotic liver tissue using laser-induced breakdown spectroscopy. AB - Hepatic cirrhosis is a major cause of morbidity and mortality worldwide due to hepatitis C, alcoholism and fatty liver disease associated with obesity. Assessment of hepatic fibrosis relies in qualitative histological evaluation of biopsy samples. This method is time-consuming and depends on the histopathologists' interpretation. In the last decades, non-invasive techniques were developed to detect and monitor hepatic fibrosis. Laser-induced breakdown spectroscopy (LIBS) is a good candidate for a real-time, independent and fast technique to diagnose hepatic fibrosis. In this work LIBS was employed to characterize rat liver tissues with different stages of fibrosis. Depth profiling measurements were carried out by using a nanosecond Nd:YAG laser operated at the fundamental wavelength and an echelle spectrometer coupled with an ICCD camera. Due to the soft nature of the samples, plasma conditions largely change between consecutives shots. Thus, a theoretically supported procedure to correct the spectral line intensities was implemented. This procedure allows the reduction of the intensities' dispersion from 67% to 12%. After the correction, the LIBS signal shows an enhancement in calcium intensity by a factor of three as the fibrosis progressed. Calcium is known to increase crosslinking of extracellular matrix proteins in the fibrous septa. Therefore, our result singles it out as a key participant in the hepatic fibrosis. PMID- 28856051 TI - Line scanning, stage scanning confocal microscope (LSSSCM). AB - For rapid pathological assessment of large surgical tissue excisions with cellular resolution, we present a line scanning, stage scanning confocal microscope (LSSSCM). LSSSCM uses no scanning mirrors. Laser light is focused with a single cylindrical lens to a line of diffraction-limited width directly into the (Z) sample focal plane, which is parallel to and near the flattened specimen surface. Semi-confocal optical sections are derived from the linear array distribution (Y) and a single mechanical drive that moves the sample parallel to the focal plane and perpendicular to the focused line (X). LSSSCM demonstrates cellular resolution in the conditions of high nuclear density within micronodular basal cell carcinoma. PMID- 28856053 TI - Microscope objective based 4pi spectroscopic tissue scattering goniometry. AB - The measurement of optical scattering as a function of angle, goniometry, can provide a wealth of information about tissue. The goniometry technique described here measures the intensity profile at the pupil planes of two microscope objectives with a scattering sample between them. The maximum observable scattering angle is extended by employing off-axis illumination. This configuration permits several advantages including: i) rapid measurement of scattering into 4pi sr to characterize the entire scattering phase function in isotropic tissue, ii) sensitivity to axially asymmetric scattering from anisotropic fibrous tissue, iii) selective interrogation of small regions within spatially inhomogenous tissue, iv) concurrent measurement of scattering coefficient MUs , and v) measurement of wavelength dependent scattering properties via spectrally tunable source. The instrument is validated by comparing measurements of microsphere suspensions to the Mie scattering solution. Instrument capabilities are demonstrated with samples of rat brain and mouse eye tissues. PMID- 28856054 TI - Increased prefrontal cortex connectivity during cognitive challenge assessed by fNIRS imaging. AB - In this study, functional near-infrared spectroscopy (fNIRS) and the graph theory approach were used to access the functional connectivity (FC) of the prefrontal cortex (PFC) in a resting state and during increased mental workload. For this very purpose, a pattern recognition-based test was developed, which elicited a strong response throughout the PFC during the test condition. FC parameters obtained during stimulation were found increased compared to those in a resting state after correlation based signal improvement (CBSI), which can attenuate those components of fNIRS signals which are unrelated to neural activity. These results indicate that the cognitive challenge increased the FC in the PFC and suggests a great potential in investigating FC in various cognitive states. PMID- 28856055 TI - Wide-field high-speed space-division multiplexing optical coherence tomography using an integrated photonic device. AB - Space-division multiplexing optical coherence tomography (SDM-OCT) is a recently developed parallel OCT imaging method in order to achieve multi-fold speed improvement. However, the assembly of fiber optics components used in the first prototype system was labor-intensive and susceptible to errors. Here, we demonstrate a high-speed SDM-OCT system using an integrated photonic chip that can be reliably manufactured with high precisions and low per-unit cost. A three layer cascade of 1 * 2 splitters was integrated in the photonic chip to split the incident light into 8 parallel imaging channels with ~3.7 mm optical delay in air between each channel. High-speed imaging (~1s/volume) of porcine eyes ex vivo and wide-field imaging (~18.0 * 14.3 mm2) of human fingers in vivo were demonstrated with the chip-based SDM-OCT system. PMID- 28856056 TI - Improving mesoscopic fluorescence molecular tomography through data reduction. AB - Mesoscopic fluorescence molecular tomography (MFMT) is a novel imaging technique that aims at obtaining the 3-D distribution of molecular probes inside biological tissues at depths of a few millimeters. To achieve high resolution, around 100 150MUm scale in turbid samples, dense spatial sampling strategies are required. However, a large number of optodes leads to sizable forward and inverse problems that can be challenging to compute efficiently. In this work, we propose a two step data reduction strategy to accelerate the inverse problem and improve robustness. First, data selection is performed via signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) criteria. Then principal component analysis (PCA) is applied to further reduce the size of the sensitivity matrix. We perform numerical simulations and phantom experiments to validate the effectiveness of the proposed strategy. In both in silico and in vitro cases, we are able to significantly improve the quality of MFMT reconstructions while reducing the computation times by close to a factor of two. PMID- 28856057 TI - Comparison of pump-probe and hyperspectral imaging in unstained histology sections of pigmented lesions. AB - Microscopic variations in melanin composition can be mapped through linear and nonlinear optical responses. Though instrumentation to measure linear attenuation is simple and inexpensive, the nonlinear response provides more degrees of freedom with which to spectroscopically resolve pigments. The objective of this study is to assess differences in imaging melanin contrast by comparing hyperspectral (linear) versus pump-probe (nonlinear) microscopy of unstained histology sections of pigmented lesions. The images and analysis we have presented here show that pump-probe uncovers a greater variation in pigment composition, compared with hyperspectral microscopy, and that the two methods yield complimentary biochemical information. PMID- 28856058 TI - Adaptive optical versus spherical aberration corrections for in vivo brain imaging. AB - Adjusting the objective correction collar is a widely used approach to correct spherical aberrations (SA) in optical microscopy. In this work, we characterized and compared its performance with adaptive optics in the context of in vivo brain imaging with two-photon fluorescence microscopy. We found that the presence of sample tilt had a deleterious effect on the performance of SA-only correction. At large tilt angles, adjusting the correction collar even worsened image quality. In contrast, adaptive optical correction always recovered optimal imaging performance regardless of sample tilt. The extent of improvement with adaptive optics was dependent on object size, with smaller objects having larger relative gains in signal intensity and image sharpness. These observations translate into a superior performance of adaptive optics for structural and functional brain imaging applications in vivo, as we confirmed experimentally. PMID- 28856059 TI - Socio-demographic Predictors for Urban Community Disaster Health Risk Perception and Household Based Preparedness in a Chinese Urban City. AB - OBJECTIVES: There is limited evidence on urban Asian communities' disaster risk perceptions and household level preparedness. Hong Kong is characterized by high population density, and is susceptible to large-scale natural disasters and health crises such as typhoons, fires and infectious disease outbreaks. This research paper investigates the rates and predictors of urban community disaster risk perception, awareness and preparedness, at individual and household levels. METHODS: A randomized cross-sectional, population-based telephone survey study was conducted among the Cantonese-speaking population aged over 15 years in Hong Kong. Descriptive statistics were reported. A stepwise multivariate logistic regression analysis was conducted to determine the independent associations between risk perceptions, socioeconomic factors, household characteristics, and personal background. FINDINGS: Final study sample comprised of 1002 respondents with a 63% response rate. The majority of respondents (82.3%) did not perceive Hong Kong as a disaster-susceptible city. Half (54.6%) reported beliefs that the local population had lower disaster awareness than other global cities. Infectious disease outbreak (72.4%), typhoon (12.6%), and fire (7.1%) were ranked as the most-likely-to-occur population-based disasters. Although over 77% believed that basic first aid training was necessary for improving individual disaster preparedness, only a quarter (26.1%) of respondents reported participation in training. CONCLUSION: Despite Hong Kong's high level of risk, general public perceptions of disaster in Hong Kong were low, and little preparedness has occurred at the individual or household levels. This report has potential to inform the development of related policies and risk communication strategies in Asian urban cities. PMID- 28856060 TI - Correction: A Comparative Analysis of Disaster Risk, Vulnerability and Resilience Composite Indicators. AB - [This corrects the article DOI: 10.1371/currents.dis.453df025e34b682e9737f95070f9b970.]. PMID- 28856061 TI - Correction: Differential Synaptic and Extrasynaptic Glutamate-Receptor Alterations in Striatal Medium-Sized Spiny Neurons of Aged YAC128 Huntington's Disease Mice. AB - [This corrects the article DOI: 10.1371/currents.hd.34957c4f8bd7cb1f5ec47381dfc811c3.]. PMID- 28856062 TI - Correction: Effects of the Pimelic Diphenylamide Histone Deacetylase Inhibitor HDACi 4b on the R6/2 and N171-82Q Mouse Models of Huntington's Disease. AB - [This corrects the article DOI: 10.1371/currents.hd.ec3547da1c2a520ba959ee7bf8bdd202.]. PMID- 28856063 TI - Genomic Characterization Helps Dissecting an Outbreak of Listeriosis in Northern Italy. AB - INTRODUCTION: Listeria monocytogenes (Lm) is a bacterium widely distributed in nature and able to contaminate food processing environments, including those of dairy products. Lm is a primary public health issue, due to the very low infectious dose and the ability to produce severe outcomes, in particular in elderly, newborns, pregnant women and immunocompromised patients. METHODS: In the period between April and July 2015, an increased number of cases of listeriosis was observed in the area of Pavia, Northern Italy. An epidemiological investigation identified a cheesemaking small organic farm as the possible origin of the outbreak. In this work we present the results of the retrospective epidemiological study that we performed using molecular biology and genomic epidemiology methods. The strains sampled from patients and those from the target farm's cheese were analyzed using PFGE and whole genome sequencing (WGS) based methods. The performed WGS based analyses included: a) in-silico MLST typing; b) SNPs calling and genetic distance evaluation; c) determination of the resistance and virulence genes profiles; d) SNPs based phylogenetic reconstruction. RESULTS: Three of the patient strains and all the cheese strains resulted to belong to the same phylogenetic cluster, in Sequence Type 29. A further accurate SNPs analysis revealed that two of the three patient strains and all the cheese strains were highly similar (0.8 SNPs of average distance) and exhibited a higer distance from the third patient isolate (9.4 SNPs of average distance). DISCUSSION: Despite the global agreement among the results of the PFGE and WGS epidemiological studies, the latter approach agree with epidemiological data in indicating that one the patient strains could have originated from a different source. This result highlights that WGS methods can allow to better. PMID- 28856064 TI - Interventions for Prevention of Intimate Partner Violence Against Women in Humanitarian Settings: A Protocol for a Systematic Review. AB - INTRODUCTION: Humanitarian emergencies and the number of people who are adversely affected are increasing. In such emergencies, the vulnerability of women and girls to gender-based violence increases signifi-cantly and they often experience high levels of intimate partner violence (IPV). There are a limited number of interventions to reduce gender-based violence (GBV) and IPV in the contexts of humanitarian emergencies, and there is uncertainty about the effectiveness of these preventive interventions. This is the protocol for a systematic review that will synthesize the evidence on interventions for primary or secondary prevention of IPV in humanitarian settings, and assess the effect of existing types of IPV related interventions in these settings. METHODS AND DESIGN: The PRISMA-P 2015 statement has been used to prepare this report. Studies published from January 2000 to January 2017 will be reviewed with no language limits. Any experimental, quasi-experimental, or controlled trials will be included. A combination of four key concepts, including "IPV" AND "population" AND "humanitarian setting" AND "intervention" will be used in the search and a variety of information sources will be used: (1) bibliographic databases; (2) special databases and grey literature; (3) and the reference lists of eligible studies. Two reviewers will independently screen articles, extract relevant data and assess study quality. Discrepancies will be resolved through consensus. Risk of bias will be assessed using the Cochrane Risk of Bias tool and the quality of evidence will be assessed using the CONSORT checklist. A narrative synthesis will be provided. If a sufficient number of studies are found, their results will be pooled using a random-effects meta-analysis. For dichotomous outcomes, summaries of intervention effects for each study will be provided by calculating risk ratios with 95% confidence interval. Standardized mean differences will be used for continuous outcomes. DISCUSSION: The review will be useful for IPV management policy and related planning. It will help researchers, policymakers and guideline developers with an interest in reducing violence against women among refugees, internally displaced persons (IDPs), and conflict-affected population. PMID- 28856065 TI - The Enduring Health Challenges of Afghan Immigrants and Refugees in Iran: A Systematic Review. AB - INTRODUCTION: Iran is the third country in the world with the highest number of registered refugees with the majority coming from Afghanistan. They suffer major health and social risks yet their health status has never been comprehensively determined. METHODS: This systematic review of the literature highlights major disparities among documented immigrants in health access, communicable and non communicable diseases and the increasingly desperate plight of undocumented immigrants. RESULTS: Comparing with Iranian population, the findings suggest the higher prevalence of most diseases among Afghan immigrants and refugees. This highlights the importance of increasing the migrants' access to health services from both public health as well as human rights perspectives. DISCUSSION: Although the Iranian government has taken new initiatives to overcome this challenge, certain issues have still remained unaddressed. Potential solutions to improve this process are discussed. PMID- 28856066 TI - Estimation of Time Period for Effective Human Inhalational Anthrax Treatment Including Antitoxin Therapy. AB - INTRODUCTION: Infrequent natural human inhalational anthrax cases coupled with high bioterrorism risk have brought about use of animal models to serve as the basis for approval of novel treatments. For inhalational anthrax, protective antigen (PA) drives much of the mortality, and raxibacumab, an anti-PA monoclonal antibody, has been approved for therapeutic use using the Animal Rule. Given the paucity of human inhalational anthrax clinical data including PA kinetics, the post-exposure period for effective treatment of human disease remains unknown. The objective of this investigation was to extrapolate animal PA kinetics to a conceptual human model to estimate the post-exposure period for effective treatment of human inhalational anthrax. METHODS: Human PA kinetic parameters were extrapolated from reported rabbit and monkey data. PA profiles were simulated with and without antibiotic induced PA clearance to represent antibiotic-sensitive and -resistant infections, respectively. Antitoxin levels equimolar to or greater than concurrent PA levels were considered protective. RESULTS: For antibiotic sensitive infections, treatment with antibiotics alone <=4 days after spore exposure prevents toxemia. Administration of raxibacumab together with antibiotics protects >= 80% of subjects for 3 additional days (7 days post exposure). In the setting of antibiotic resistance, raxibacumab would be protective for at least 6 days post exposure. CONCLUSIONS: Although the animal model of disease does not reflect the potential impact of supportive care (e.g. fluid resuscitation received by critically ill patients) on PA kinetics and raxibacumab PK, the simulations suggest that administration of antitoxin in combination with antibiotics should provide a longer postexposure window for effective treatment than for antibiotics alone. In addition, raxibacumab administration soon after exposure to an antibiotic resistant strain should provide effective treatment. PMID- 28856067 TI - Application of Dendrimer-based Nanoparticles in Glioma Imaging. AB - Dendritic polymers or dendrimers present an alternate template for the development of nanoparticulate-based drug delivery and imaging systems. The smaller size (~7-12 nm) of dendrimers have the advantage over the other particles, because its smaller size can possibly improve tumor penetration and the inclusion of tumor specific drug release mechanisms. A Paramagnetic Chemical Exchange Saturation Transfer (PARACEST) MRI contrast agent, Eu-DOTA-Gly4 or a clinical relevant Gd-DOTA was conjugated on the surface of a G5 PAMAM dendrimer. To create a dual mode MRI-optical imaging nanoparticle, Dylight680 was also incorporated on the amines surface of a G5 dendrimer. The particle was detected with in vivo MRI in preclinical glioma animal model. Furthermore, noninvasive imaging results were validated with in vivo and ex-vivo optical imaging. PMID- 28856068 TI - Sero-diagnosis of Active Mycobacterium tuberculosis Disease among HIV Co-infected Persons using Thymidylate Kinase based Antigen and Antibody Capture Enzyme Immuno Assays. AB - BACKGROUND: Clinical and laboratory diagnosis of Active Tuberculosis (ATB) and latent Mycobacterium Tuberculosis (M. tuberculosis) infections (LTBI) among people living with HIV/AIDS (PLWHA) presents formidable challenges. In the past, WHO issued an advisory against the use of existing TB sero-diagnostics. Emerging evidence, however, points to a precision of TB sero-diagnostics based on secretory rather than structural M. tuberculosis antigens. We hypothesized that secretory levels of M. tuberculosis thymidylate kinase (TMKmt) can Designate ATBI from LTBI and no TB (NTB). Here, we report in-house validation studies of levels of TMKmt antigen (Ag) and host specific TMKmt antibody (Ab) amongst HIV +ve and HIV -ve participants. METHODS AND RESULTS: Direct TMKmt Ag and host specific IgG Ab detection EIAs were conducted on broadly consented, stored serum (N=281[Ag] vs. 214 [Ab] respective) samples stratified as either HIV +ve or HIV-ve ATB relative to LTBI and No TB. On one hand, UG-peptide 1 and its PAb-based EIAs accurately diagnosed ATB relative to LTBI and NTB among HIV +ve subjects {irrespectively: (a) Ag detection ATB=OD>0.490; 95% CI: 0.7446 to 0.8715 vs. LTBI=OD<0.490; 95% CI 0.4325 to 0.4829 vs. NTB=OD<0.26; 95% CI 0.1675 to 0.2567 and (b) TMKmt specific IgG detection ATB=OD>1.00; 95% CI 1.170 to 1.528 [HIV +ve] and 2.044 to 2.978 [HIV -ve] respectively vs. LTBI=OD<1.00; 95% CI 0.2690 to 0.6396 vs. NTB=OD<; 95% CI 0.1527 to 0.8751}. HIV -ve ATB presented with Ag levels greater than NTB and less than LTBI (i.e. ATB -ve=<0.490 ODs>0.26), but displayed better ant-TMKmt IgG responses (OD>2.00; 95% CI 2.044 to 2.978) relative to HIV +ve ATB (OD<1.600; 95% CI 1.170 to 1.528); suggesting a better control of M. tuberculosis-septicemia. On the other hand, UG-peptide 2 and its PAb-based EIAs did not demonstrate ATB diagnostic potential regardless of HIV sero-status, except towards designating NTB. CONCLUSIONS: TMKmt Ab and Ag detecting EIAs based on UG-peptide 1 and its derivative PAb can accurately demarcate ATB from LTBI and NTB among HIV +ve subjects. PMID- 28856069 TI - Development of a Composite Outcome Measure for Systemic Sclerosis Related Interstitial Lung Disease. AB - OBJECTIVE: While systemic sclerosis-related interstitial lung disease (SSc-ILD) trials predominantly use forced vital capacity (FVC) as the primary outcome, combining individual outcomes may lead to a more comprehensive measure of treatment response and minimize the risk of type 1 error. The present analysis aimed to develop a composite outcome measure to assess treatment response in SSc ILD patients. METHODS: We used data from the Scleroderma Lung Study I (SLS-I) to create the composite outcome measure. SLS I was a multi-institutional, double blind clinical trial, in which 158 patients with SSc-ILD were randomized to receive either oral cyclophosphamide (CYC) (titrated to 2.0 mg/kg once daily) or matching placebo for one year. To select the variables for inclusion in the composite outcome, we first performed a univariate analysis using all of the outcome variables measured in SLS I. We subsequently combined the variables with significant treatment effects (p<0.05) in a principal component analysis (PCA) to assess the difference between treatment groups. These variables included the FVC% predicted, computer-based score for quantitative lung fibrosis in the zone of maximum fibrosis (QLF-ZM) from thoracic high-resolution computer tomography (HRCT) scans, transitional dyspnea index (TDI), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at 12 months. RESULTS: Of the 158 patients, 82 had complete outcome data and were included in this analysis. There were no significant differences in baseline characteristics between the 82 patients included in this analysis and the remaining 76 patients. The regression model with the first principal component for FVC% predicted, QLF-ZM, TDI and HAQ DI as the composite outcome demonstrated a significant treatment effect favoring cyclophosphamide (Estimate 0.7 [SE 0.2]; p=0.005). Eliminating FVC% predicted from the composite outcome model did not change the overall treatment effect (Estimate 0.8 [SE 0.2]; p=0.004). CONCLUSION: The CYC treatment effect observed from using the composite outcome of FVC% predicted, QLF-ZM, TDI and HAQ-DI was stronger than the effect observed using FVC% predicted alone. These findings suggest that combining patient-reported outcomes with structural and physiologic outcomes into a single outcome may serve as a more robust measure of treatment response compared with FVC alone in SSc-ILD trials. PMID- 28856070 TI - Low-intensity Physical Activity is Associated with Lower Maternal Systemic Inflammation during Late Pregnancy. AB - Excessive maternal inflammation during pregnancy increases the risk for maternal and neonatal metabolic complications. Fortunately, maternal physical activity during pregnancy appears to reduce maternal inflammation. The purpose of this study was to examine the relationship between maternal physical activity intensity and maternal inflammation during late pregnancy. Maternal physical activity levels (sedentary, light, lifestyle, and moderate), fitness levels, and systemic inflammation (plasma C-reactive protein (CRP) concentration) were measured between 32-37 weeks gestation. Relationships were examined by Spearman Rank Coefficient Correlation analyses. Maternal plasma CRP was negatively associated with time spent in light and lifestyle physical activities (Light: r= 0.40, p=0.01; Lifestyle: r=-0.31, p=0.03), but not with time spent in moderate physical activity (r=-0.18, p=0.21). Higher maternal plasma CRP tended to correlate with more time spent sedentary (r=0.27, p=0.06). In addition, increases in light and lifestyle activities may elicit a clinically meaningful change in inflammation. In conclusion, pregnant women should be encouraged to incorporate more low-intensity physical activities into their daily routines in order to decrease systemic inflammation and potentially improve maternal and neonatal pregnancy outcomes. PMID- 28856071 TI - Prediction of Functional Outcome in Ischemic Stroke Patients: An Observational Study on Egyptian Population. AB - Introduction Determining the prognosis of ischemic stroke is important for neurologists and patients. The aim is to study the predictors of three months clinical outcome in ischemic stroke patients. Materials and methods A total of 397 patients were classified according to three months modified Rankin Scale score (mRS score) into two groups, favorable and unfavorable outcome. Favorable outcome was assumed if the score was zero or one, or unchanged if the score was >= 1 before the onset of the most recent event. Results The variables associated with unfavorable outcome were old age (P <0.001), presence of cardiac disease (P <0.001), low ejection fraction (P=0.008), low levels of total cholesterol and low density lipoproteins (P <0.001), large artery atherosclerosis stroke (P <0.001), early confluent (P=0.005), high National Institute of Health stroke scale (NIHSS) score on admission (P <0.001), mRS score before admission (P <0.001), mRS score on discharge (P <0.001). Lacunar stroke was associated with favorable outcome (P <0.001). The regression analysis showed mRS score on discharge (P <0.001) and the presence of cardiac diseases (P=0.077) as independent predictors of unfavorable outcome. Conclusion High mRS score on discharge and presence of the cardiac disease independently could predict the unfavorable outcome and mRS score on discharge had a high sensitivity and negative predictive value in predicting the unfavorable outcome. Abbreviations MRS: score modified Rankin scale score, NIHSS: National Institutes of Health Stroke Scale, MRI: Magnetic resonance imaging, LDL: Low-density lipoprotein, MRA: Magnetic resonance of arteries. PMID- 28856072 TI - Association of Zika Virus with Myocarditis, Heart Failure, and Arrhythmias: A Literature Review. AB - As the concerns regarding Zika virus (ZIKV) are mostly of neurological disorders, especially in neonates and infants, other possible threats of the virus may have been overlooked. Our study focuses on the potential threat that ZIKV may pose to the heart like that of similar arboviral diseases. We conducted a literature search of multiple terms in March 2017 using the search engines, PubMed, Embase, and SCOPUS. Articles were then reviewed by two independent reviewers, adhering strictly to our review criteria. No discriminations were made whether the studies were conducted on human or non-human subjects. Three relevant studies were shortlisted and finalized. The nature of the studies is as follows: prospective observational multicenter study (n = 9), case report (n = 1), and animal studies (n = 5). The studies suggested an association between cardiovascular complications and ZIKV in the acute phase of the infection. We recognize the limitations of our study owing to the paucity of the sample size of our literature review. However, the significant findings have also proved the dire need to conduct more research to further back the possibility of ZIKV's influence on the cardiac cells. Closely studying these associations can eventually help develop a vaccine for ZIKV in the near future. PMID- 28856073 TI - Correlation of TP53 Overexpression and Clinical Parameters with Five-Year Survival in Oral Squamous Cell Carcinoma Patients. AB - Introduction TP53 mutation and overexpression have been correlated with poor survival in many cancers including oral squamous cell carcinoma (OSCC). We aim to understand the role of TP53 overexpression in OSCC in our population and correlate it with five-year survival to test its viability as a prognostic marker for OSCC patients. Materials and methods Patients with biopsy proven OSCC at Aga Khan University Hospital from January 2000 to January 2008 were recruited. Immunohistochemistry was used to establish TP53 status and the results were published. Following up on these patients, five-year data were collected and correlated with TP53 status and other clinicopathologic parameters. Results Overexpression of TP53 was not significantly associated with five-year survival (hazard ratio [HR]: 1.543; 95% CI: 0.911-2.612; p = 0.107). Conclusion Although we had proven statistical relevance when correlated with overall survival in our previous study, we were unable to extend the same relevance to TP53 overexpression when it comes to five-year survival. PMID- 28856074 TI - Utilizing Tumor and Plasma Liquid Biopsy in Treatment Decision Making for an Estrogen Receptor-Positive Advanced Breast Cancer Patient. AB - Breast cancer affects 12% of females in the United States and is the leading cause of cancer death in the female population. Personalized therapy is being used in clinical practice to treat breast cancer based on tumor molecular profiling, which can be obtained from tissue biopsy or plasma liquid biopsy as circulating tumor deoxyribonucleic acid (ctDNA). The available ctDNA tests provide a non-invasive way to monitor the cancer genome in a real-time manner. In this case report, a 38-year-old female with recurrent estrogen receptor (ER) positive breast cancer is treated with letrozole, everolimus, and palbociclib. The drugs target the hormonal signaling pathway, phosphoinositide 3-kinase (PI3K) RAC-alpha serine/threonine-protein kinase (AKT) pathway, and cyclin D1 (CCND1) CDK4/6 pathway, based on the patient's estrogen-receptor-positive (ER+) disease and phosphatidylinositol -4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, as well as PIK3CA and CCND1 amplification. After 11 months of treatment, retinoblastoma protein transcriptional corepressor 1 (RB1) mutation was caught in ctDNA, which suggests an acquired resistance to palbociclib. Pazopanib was then used instead of palbociclib, targeting the fibroblast growth factor 3/4/19 (FGF3/4/19) amplification that was initially observed in her molecular profiling. Trametinib was also suggested recently due to the increasing allele frequency of B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation in ctDNA, following the treatment of letrozole + everolimus + pazopanib. The patient has no evidence of disease after five months of treatment initiation and has remained disease-free for over 16 months. In conclusion, the analysis of ctDNA is an effective way to monitor the real-time changes in a patient's tumor genome, which is a great supplement to the molecular profile from the tissue biopsy. The combination of these two tests provides an efficient strategy to make more informed treatment decisions, which greatly adapt along disease development. PMID- 28856075 TI - Clinical Anatomy of the Frenulum of the Oral Vestibule. AB - Introduction The frenula of the oral vestibule include the labial and buccal frenula. Abnormal labial and buccal frenula can affect facial esthetics and oral cavity function by retracting the gingival margin, creating a median diastema, and limiting lip movement. Because of the lack of information on these structures, we aimed to clarify their anatomy. Methods A total of 34 sides from 17 fresh frozen cadaveric Caucasian heads were used in the present study. The specimens were derived from 11 male and 6 female adult cadavers. The relationships between the frenulum of the mucosa and the tissue underneath the mucosa was observed. Results The buccal frenulum was formed by the border of mimetic muscles and connective tissues. Comparitively, the labial frenulum was only formed by taut connective tissue. Conclusion We found that the buccal and labial frenula have different compositions. This finding may have relevance both in oral surgery and in various cosmetic procedures near the oral vestibule. PMID- 28856076 TI - Dementia Health Promotion for Chinese Americans. AB - Introduction This study aims to describe the results of a dementia awareness campaign in the Chinese American community. Methods The campaign consisted of a health fair, four dementia seminars, radio shows, television episodes, and a YouTube series. Descriptive statistics and qualitative data were obtained from various health communication channels. Results There were 156 and 313 participants in the health fair and dementia seminars, respectively. The participants in each component of the campaign also provided qualitative data on barriers and effective ways to disseminate awareness of dementia and brain health. Conclusion A dementia awareness campaign may be an effective way to reduce health disparities and dementia in the Chinese American community. PMID- 28856077 TI - Exceptional Responses to Standard Therapy in a Patient with Metastatic HER2 Positive Breast Cancer. AB - Patients with metastatic breast cancer involving the liver and brain often have short overall survival. Here, we report a case of de novo metastatic breast cancer with multiple liver metastases at initial diagnosis in February 2011 in a 35-year-old Caucasian female patient. The histology was poorly differentiated invasive ductal carcinoma (estrogen and progesterone receptor negative, HER2 positive) and the patient was negative for germline BRCA 1 and 2 mutations. Systemic therapy with trastuzumab and docetaxel was given for six months and then switched to trastuzumab only because of peripheral neuropathy. At that time, the patient was in complete clinical remission. She developed brain metastases in September 2012 and received whole-brain radiotherapy, which resulted in complete remission. While on continued trastuzumab, the primary tumor in the breast recurred in May 2016. A mastectomy was performed and afterwards systemic therapy was intensified (trastuzumab, pertuzumab, paclitaxel). At the last follow-up (March 06, 2017) no further recurrence was detected. This case illustrates that standard HER2-directed treatment might provide long-term disease control also in selected patients with unfavorable patterns of spread. The beneficial effect of whole-brain radiotherapy is not necessarily limited to symptom palliation. PMID- 28856078 TI - Participating in an International Stereotactic Radiotherapy Patient Registry: The Establishment of Data Collection Pathways. AB - Aim To describe data collection pathways and practical challenges experienced by an academic comprehensive cancer centre aiming to record clinical data for patients being treated with a novel radiotherapy treatment modality. Methods Various options to capture data from all patients treated with the CyberKnife Robotic Radiosurgery System at Sir Charles Gairdner Hospital (SCGH) in Western Australia were explored. An international multicenter web-based secure database established and maintained by the Radiosurgery Society the RSSearch(r) Patient Registry was selected. Data were collected and entered over four contiguous phases, with either opt-in or opt-out consent and the completion of Patient Reported Outcome questionnaires for specific sub-groups. Results Between April 2014 and June 2016, 461 patients at Sir Charles Gairdner Hospital were enrolled in the RSSearch(r) Patient Registry with the collection of over 17,500 data items. From 461 patients enrolled, 447 patients were treated with the CyberKnife Robotic Radiosurgery System. The majority of patients were treated for either a malignant primary (43.2%) or metastatic disease (39.4%). The establishment of matrix organisational processes for data collection led to the development of improved workflow patterns and data collection pathways. Conclusions This article describes the processes developed by a single centre to establish an efficient system for data collection and participation in an international registry. The opt-out approach was more efficient in terms of patient recruitment compared to the informed-consent method used in earlier phases. The experience of this single centre may help inform other institutions considering data collection options for assessments of new or novel treatments. PMID- 28856079 TI - Acute toxicity of phorate oxon by oral gavage in the Sprague-Dawley rat. AB - The oral toxicity of phorate oxon (PHO), with emphasis on gender- and age-related effects, was characterized in the Sprague-Dawley rat. The oral LD50 (95% fiducial limits) for PHO in corn oil was 0.88 (0.79, 1.04) mg/kg in males and 0.55 (0.46, 0.63) mg/kg in females with a probit slope of 15. Females had higher baseline blood cholinesterase titers, but males were significantly more tolerant. Younger rats generally had lower absolute cholinesterase blood titers. However as PHO challenges increased, baseline-normalized cholinesterase inhibition was independent of age and gender. Butyrylcholinesterase (BChE) and especially acetylcholinesterase (AChE) in brains of younger females were affected more than that in either males or older females. In summary, while female rats, especially older females, had higher titers relative to males, female rats were more susceptible in terms of absolute cholinesterase inhibition and 24-hr lethality data, but the differences were not observed when titers were normalized to baseline levels. PMID- 28856080 TI - Changes Experienced in Quality of Life for Skull Base Surgical Patients: A Qualitative Case Study. AB - Objective Skull base tumors are associated with quality of life (QOL) changes. A qualitative case-study approach may help better understand patients' experiences. Methods A total of 34 skull base surgery patients were selected into focus groups using a criterion-based maximum variation sampling strategy from a sampling frame of 138 patients. Eight groups were organized based on a factorial design of surgical approach (endoscopic/pen) and tumor location (anterior/central). Data were analyzed using a conceptual framework. Qualitative analysis was performed on focus group transcripts to identify major themes and determine if surgical approach or tumor location had differential effects on QOL. Concepts were quantitatively tallied from written workbooks. Results The 34 participants (19 men, 15 women; mean age: 48 years, standard deviation: 14 years) had mixed reactions to their diagnosis ranging from relief to fear. Participants reported physical and nonphysical changes in QOL with some variation in physical complaints by tumor location. Several major themes emerged from the analysis. Skull base tumors are associated with fear and frustration, loss of physical senses and self-identity, social isolation, and coping mechanisms. Conclusions Skull base surgery may impact patients' lives. Qualitative study of patient experiences can provide rich information to better understand this disease. PMID- 28856081 TI - Genetic Factors Influencing Drug-Induced Liver Injury: Do They Have a Role in Prevention and Diagnosis? AB - PURPOSE OF REVIEW: The pathogenesis of DILI is currently unknown; however, research has shown strong genetic associations with some DILIs. This paper describes the variant alleles uncovered by GWAS and discusses their potential role as susceptibility biomarkers. RECENT FINDINGS: An association with HLADRB1*15:01 and amoxicillin/clavulanate DILI has been shown by a number of research groups. The presence of the HLA-B*57:01 allele has been associated with an 81-fold increased risk of flucloxacillin DILI. The HLA-B*35:02 allele has significant association with minocycline DILI. SUMMARY: With the exception of abacavir for HIV therapy, no other prospective genetic screening tests have met the threshold for clinical application. This is largely because DILI incidence is too low to warrant the cost and effort associated with testing. Perhaps, with the development of personalised medicine, a panel of genes for disease susceptibility, drug efficacy and adverse reactions could be tested once off. This would change the cost-effectiveness paradigm, personalise healthcare and reduce DILI risk by avoiding medications in patients with specific HLA alleles. PMID- 28856083 TI - Full fat milk consumption protects against severe childhood obesity in Latinos. AB - Consumption of non- or low-fat dairy products is recommended as a strategy to lower the risk of childhood obesity. However, recent evidence suggests that consumption of whole fat dairy products may, in fact, be protective against obesity. Our objective was to determine the association between milk fat consumption and severe obesity among three-year-old Latino children, a population with a disproportionate burden of obesity and severe obesity. 24-hour-dietary recalls were conducted to determine child intake in San Francisco based cohort recruited in 2006-7. Mother-child dyads were weighed and measured. The 24-hour recall data was analyzed to determine participants' consumption of whole milk, 2% milk, and 1% milk. The milk consumption data was used to calculate grams of milk fat consumed. The cross-sectional association between milk fat intake and severe obesity (BMI >= 99th percentile) was determined using multivariable logistic regression. Data were available for 145 children, of whom 17% were severely obese. Severely obese children had a lower mean intake of milk fat (5.3 g vs. 8.9 g) and fewer drank any milk (79% versus 95% for not severely obese children (p < 0.01)). Among the potential confounders assessed, maternal BMI and maternal marital status were associated with severe obesity and were included in a multivariate model. In the multivariate model, higher milk fat consumption was associated with lower odds of severe obesity (OR 0.88 CI 0.80-0.97). Higher milk fat consumption is associated with lower odds of severe obesity among Latino preschoolers. These results call into question recommendations that promote consumption of lower fat milk. PMID- 28856082 TI - Atypical bacterial pneumonia in the HIV-infected population. AB - Human immunodeficiency virus (HIV)-infected individuals are more susceptible to respiratory tract infections by other infectious agents (viruses, bacteria, parasites, and fungi) as their disease progresses to acquired immunodeficiency syndrome. Despite effective antiretroviral therapy, bacterial pneumonia (the most frequently occurring HIV-associated pulmonary illness) remains a common cause of morbidity and mortality in the HIV-infected population. Over the last few decades, studies have looked at the role of atypical bacterial pneumonia (i.e. pneumonia that causes an atypical clinical presentation or responds differently to typical therapeutics) in association with HIV infection. Due to the lack of available diagnostic strategies, the lack of consideration, and the declining immunity of the patient, HIV co-infections with atypical bacteria are currently believed to be underreported. Thus, following an extensive database search, this review aimed to highlight the current knowledge and gaps regarding atypical bacterial pneumonia in HIV. The authors discuss the prevalence of Chlamydophila pneumoniae, Mycoplasma pneumoniae, Coxiella burnetii, Legionella species and others in the HIV-infected population as well as their clinical presentation, methods of detection, and treatment. Further studies looking at the role of these microbes in association with HIV are required. Increased knowledge of these atypical bacteria will lead to a more rapid diagnosis of these infections, resulting in an improved quality of life for the HIV-infected population. PMID- 28856084 TI - The cost-effectiveness of physical activity interventions: A systematic review of reviews. AB - BACKGROUND: Despite growing recognition of the need to promote physical activity, the existing evidence base on the cost-effectiveness of relevant interventions appears scant and scattered. This systematic review of reviews set out to take stock of the evidence on the cost-effectiveness of physical activity interventions. METHODS: Ten literature databases were systematically searched for available reviews on the cost-effectiveness of physical activity interventions, complemented by a hand search. Out of the 515 articles identified, 18 reviews met the inclusion criteria. A quality appraisal of the 18 reviews was undertaken. RESULTS: Of the 18 reviews, 4 contained information on the target group of children and adolescents, 12 on adults, 3 on older adults, and 6 on the general population. Across the reviews some intervention strategies were identified as being particularly cost-effective, including certain school-based interventions (children and adolescents), interventions using pedometers (adults), fall prevention programs (older people), mass media campaigns and environmental approaches (general population). However, for some of these approaches (e.g. mass media campaigns), the underlying evidence of being able to change physical activity behavior remains inconsistent. CONCLUSION: Available evidence for the cost-effectiveness of physical activity interventions is scattered, but points towards the cost-effectiveness of certain interventions. Until this moment, cost effectiveness has more often been studied for individual-level interventions. This is potentially due to some methodological challenges in assessing the cost effectiveness of population-based interventions. PMID- 28856085 TI - Attainment of '5-2-1-0' obesity recommendations in preschool-aged children. AB - Obesity prevention guidelines recommend children eat >= 5 servings of fruits and vegetables, view <= 2 h of screen time, participate in 1 h of physical activity, and consume 0 sugar-sweetened beverages daily, commonly known as '5-2-1-0'. We sought to determine: the extent to which preschool-aged children attending child care meet these guidelines, predictors of attainment, and associations of attainment with weight status. We analyzed in 2016, 24-hour dietary, physical activity, and screen time data collected in 2009-10 from 398 preschool-aged children in 30 child-care centers in Cincinnati, OH. Dietary intake, screen time and body-mass index (BMI) were obtained by research staff during child care and from parents when at home. Accelerometers measured physical activity. Mixed effects models and generalized estimating equations were used to determine associations between '5-2-1-0' recommendations, demographic variables, and BMI z scores. Average child age was 4.3 +/- 0.7 years; 26% had a BMI >= 85th percentile. Seventeen percent of children with complete dietary data (n = 307) consumed >= 5 servings of fruits and vegetables and 50% consumed 0 sugar sweetened beverages. < 1% with complete physical activity data (n = 386) met the activity recommendation; 81% of children (n = 379) had <= 2 h of screen time. Only 1 child met all of the '5-2-1-0' recommendations. There were no consistent demographic predictors of attaining individual recommendations. An additional hour of screen time was associated with a 0.11 (SD 0.06) increase in BMI z-score. Our data suggests there is ample room to increase fruit and vegetable intake and physical activity in preschool-aged children. PMID- 28856086 TI - Identification of novel targets for multiple myeloma through integrative approach with Monte Carlo cross-validation analysis. AB - More than one pathway is involved in disease development and progression, and two or more pathways may be interconnected to further affect the disease onset, as functional proteins participate in multiple pathways. Thus, identifying cross talk among pathways is necessary to understand the molecular mechanisms of multiple myeloma (MM). Based on this, this paper looked at extracting potential pathway cross-talk in MM through an integrative approach using Monte Carlo cross validation analysis. The gene expression library of MM (accession number: GSE6477) was downloaded from the Gene Expression Omnibus (GEO) database. The integrative approach was then used to identify potential pathway cross-talk, and included four steps: Firstly, differential expression analysis was conducted to identify differentially expressed genes (DEGs). Secondly, the DEGs obtained were mapped to the pathways downloaded from an ingenuity pathways analysis (IPA), to reveal the underlying relationship between the DEGs and pathways enriched by these DEGs. A subset of pathways enriched by the DEGs was then obtained. Thirdly, a discriminating score (DS) value for each paired pathway was computed. Lastly, random forest (RF) classification was used to identify the paired pathways based on area under the curve (AUC) and Monte Carlo cross-validation, which was repeated 50 times to explore the best paired pathways. These paired pathways were tested with another independently published MM microarray data (GSE85837), using in silico validation. Overall, 60 DEGs and 19 differential pathways enriched by DEGs were extracted. Each pathway was sorted based on their AUC values. The paired pathways, inhibition of matrix metalloproteases and EIF2 signaling pathway, indicated the best AUC value of 1.000. Paired pathways consisting of IL 8 and EIF2 signaling pathways with higher AUC of 0.975, were involved in 7 runs. Furthermore, it was validated consistently in separate microarray data sets (GSE85837). Paired pathways (inhibition of matrix metalloproteases and EIF2 signaling, IL-8 signaling and EIF2 signaling) exhibited the best AUC values and higher frequency of validation. Two paired pathways (inhibition of matrix metalloproteases and EIF2 signaling, IL-8 signaling and EIF2 signaling) were used to accurately classify MM and control samples. These paired pathways may be potential bio-signatures for diagnosis and management of MM. PMID- 28856087 TI - Complications of bone metastases from malignant melanoma. AB - INTRODUCTION: Metastatic bone disease (MBD) carries significant morbidity for patients with cancer. MBD from malignant melanoma (MM) is understudied. We examined the characteristics, morbidity, management and outcome of MBD in patients with MM. METHODS: Patients with metastatic MM managed at two referral cancer centres in England were identified. Those with bone metastases (BMs) were selected. Patient and disease characteristics including skeletal related events (SREs) were extracted from medical records. The Kaplan Meier method was used to calculate median survival. RESULTS: Five hundred and eighteen patients with metastatic MM were managed between years 2000 and 2008. Eighty nine (17.2%) patients had BMs and are the subject of this study. Median age at diagnosis was 53 years and 55% were males. BMs were identified at the time of diagnosis of metastatic disease in 68.5% patients. Sixty-six (74.2%) had multiple bone lesions and 80.9% had axial skeleton involvement. One hundred and twenty nine skeletal related events occurred in 59 (66.3%) patients (50 radiotherapy, 28 hypercalcaemia, 20 bone fractures, 18 spinal cord compression and 13 orthopaedic surgery). The annual skeletal morbidity rate was 2.5. Median survival from diagnosis of BMs was 17.3 weeks and was 5.6 weeks from the first episode of hypercalcaemia. CONCLUSION: MBD affects a clinically important proportion (17.2%) of patients with metastatic MM. It carries a substantial morbidity and mortality exceeding that caused by BMs from breast and prostate cancer. These patients should receive the currently licensed bone modifying agents and should be included in clinical trials addressing MBD. PMID- 28856088 TI - Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) as an initial presenting sign of non small cell lung cancer-case report and literature review. AB - Association of SIADH with malignancy was first reported in 1957, when it was described in two patients with bronchogenic carcinoma. While the association with small cell lung cancer (SCLC) is well known, that with non small cell lung cancer (NSCLC) has been rarely reported. We report a case of 70 year old male who was found to have hyponatremia secondary to SIADH. Radiological tests revealed right hilar lung mass with mediastinal adenopathy. Bronchoscopic biopsy revealed non small cell lung cancer of type squamous cell. Magnetic resonance imaging (MRI) of brain showed metastatic lesions, thereby confirming diagnosis of metastatic lung cancer. Paraneoplastic syndromes occur in 10% of lung cancer cases and they represent a group of disorders related to secretion of functional polypeptides or hormones from tumor cells. SIADH is more commonly described in conjunction with small cell lung cancer but there are a few case reports describing it's occurrence after initiation of therapy for NSCLC such as radiation and chemotherapy. The mechanism for this phenomenon is not known. Unlike infectious causes, hyponatremia as initial presentation is an uncommon feature of malignancy associated SIADH. In the lung cancer population, hyponatremia has been identified as a negative prognostic factor in hospitalized patients and those with advanced stage disease. Malignancy should be a consideration in the diagnostic evaluation of SIADH, irrespective of the time of presentation. PMID- 28856089 TI - Plexogenic pulmonary hypertension associated with POEMS syndrome. AB - Pulmonary hypertension is one of the well-known clinical manifestations of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, occurring in approximately 25-30% of the affected individuals. However, the histopathologic spectrum of pulmonary hypertension associated with POEMS syndrome has not been fully documented in the literature. Herein, we report an autopsy case of POEMS syndrome in a patient whose lung tissues showed histopathology indistinguishable from that of idiopathic pulmonary arterial hypertension with abundant plexiform lesions in the small pulmonary arteries. PMID- 28856090 TI - A case of relapsed lung abscess caused by Eubacterium brachy infection following an initial diagnosis of pulmonary actinomycosis. AB - We report a rare case of lung abscess due to Eubacterium brachy. In this case, an analysis of the aspirate from frank pus revealed Gram-positive coccobacilli. We initially strongly suspected lung abscess associated with actinomycosis because of the chronic/recurrent clinical course and radio-pathological findings such as a granuloma lesion. Although a biochemical analysis revealed Actinomyces sp., 16S rRNA gene sequencing and a phylogenetic tree analysis of the isolated strain confirmed the presence of E. brachy. Some cases previously diagnosed as actinomycosis might be correctly diagnosed as E. brachy infection. Clinicians should be aware that additional studies using 16S rRNA gene sequencing are needed to clarify whether pulmonary infection associated with E. brachy is a similar entity to that of chronic granulomatous infection disease in pulmonary actinomycosis. PMID- 28856091 TI - Disrupted avoidance learning in functional neurological disorder: Implications for harm avoidance theories. AB - BACKGROUND: Functional neurological disorder (FND) is an elusive disorder characterized by unexplained neurological symptoms alongside aberrant cognitive processing and negative affect, often associated with amygdala reactivity. METHODS: We examined the effect of negative conditioning on cognitive function and amygdala reactivity in 25 FND patients and 20 healthy volunteers (HV). Participants were first conditioned to stimuli paired with negative affective or neutral (CS +/CS -) information. During functional MRI, subjects then performed an instrumental associative learning task to avoid monetary losses in the context of the previously conditioned stimuli. We expected that FND patients would be better at learning to avoid losses when faced with negatively conditioned stimuli (increased harm avoidance). Multi-echo resting state fMRI was also collected from the same subjects and a robust denoising method was employed, important for removing motion and physiological artifacts. RESULTS: FND subjects were more sensitive to the negative CS + compared to HV, demonstrated by a reinforcement learning model. Contrary to expectation, FND patients were generally more impaired at learning to avoid losses under both contexts (CS +/CS -), persisting to choose the option that resulted in a negative outcome demonstrated by both behavioural and computational analyses. FND patients showed enhanced amygdala but reduced dorsolateral prefrontal cortex responses when they received negative feedback. Patients also had increased resting state functional connectivity between these two regions. CONCLUSIONS: FND patients had impaired instrumental avoidance learning, findings that parallel previous observations of impaired action-outcome binding. FND patients further show enhanced behavioural and neural sensitivity to negative information. However, this did not translate to improved avoidance learning. Put together, our findings do not support the theory of harm avoidance in FND. We highlight a potential mechanism by which negative contexts interfere with adaptive behaviours in this under-explored disorder. PMID- 28856092 TI - Comparison of [18F]Flutemetamol and [11C]Pittsburgh Compound-B in cognitively normal young, cognitively normal elderly, and Alzheimer's disease dementia individuals. AB - BACKGROUND: Understanding the variation in uptake between different amyloid PET tracers is important to appropriately interpret data using different amyloid tracers. Therefore, we compared the uptake differences in [18F]Flutemetamol (FMT) and [11C]PiB (PiB) PET in the same people. METHODS: Structural MRI, FMT PET and PiB PET were each performed in 30 young cognitively normal (yCN), 31 elderly cognitively normal (eCN) and 21 Alzheimer's disease dementia (AD) participants. PiB and FMT images for each participant were compared quantitatively using voxel- and region-based analyses. Region of interest (ROI) analyses included comparisons of grey matter (GM) regions as well as white matter (WM) regions. Regional comparisons of each tracer between different groups and comparisons of the two modalities within the different groups were performed. To compare mean SUVr between modalities, and between diagnostic groups, we used paired t-tests and Student's t-test, respectively. We also compared the ability of the two tracers to discriminate between diagnostic groups using AUROC estimates. The effect of using different normalization regions on SUVr values was also evaluated. RESULTS: Both FMT and PiB showed greater uptake throughout GM structures in AD vs. eCN or yCN. In all dual-modality group comparisons (FMT vs. PiB in yCN, eCN, and AD), greater WM uptake was seen with FMT vs. PiB. In yCN and eCN greater diffuse GM uptake was seen with FMT vs. PiB. When comparing yCN to eCN within each tracer, greater WM uptake was seen in eCN vs yCN. CONCLUSIONS: Flutemetamol and PiB show similar topographical GM uptake in AD and CN participants and the tracers show comparable group discrimination. Greater WM accumulation with FMT suggests that quantitative differences vs. PiB will be apparent when using WM or GM as a reference region. Both imaging tracers demonstrate increased WM uptake in older people. These findings suggest that using different amyloid tracers or different methods of analyses in serial brain imaging in an individual may result in artifactual amyloid change measurements. Clinical use of several amyloid tracers in the same patient will have challenges that need to be carefully considered. PMID- 28856093 TI - From word reading to multisentence comprehension: Improvements in brain activity in children with autism after reading intervention. AB - BACKGROUND: Children with ASD show a unique reading profile characterized by decoding abilities equivalent to verbal abilities, but with lower comprehension skills. Neuroimaging studies have found recruitment of regions primarily associated with visual processing (e.g., fusiform gyrus and medial parietal cortex), but reduced activation in frontal and temporal regions, when reading in adults with ASD. The purpose of this study was to assess neural changes associated with an intense reading intervention program in children with ASD using three fMRI tasks of reading. METHODS: 25 children with ASD were randomly assigned to a treatment (ASD-EXP) or waitlist group (ASD-WLC). Children participated in a reading intervention program (4-hour sessions per day, 5 days a week for 10 weeks). We utilized three tasks: word, sentence, and multisentence processing, each with differential demands of reading comprehension. fMRI data were acquired at each of two scanning sessions 10-weeks apart. RESULTS: Across tasks, post-intervention results revealed that the ASD-EXP group showed greater activation in bilateral precentral gyrus and the postcentral gyrus, visual processing regions (e.g., occipital cortex, fusiform gyrus), and frontal regions. In the word task, left thalamus and the right angular gyrus (AG) activation was unique to the ASD-EXP group post-intervention. Sentence tasks showed differential activation of core language areas (e.g., IFG, IPL) post-intervention. CONCLUSIONS: Our results provide evidence for differential recruitment of brain regions based on task demands in children with ASD, and support the potential of targeted interventions to alter brain activation in response to positive gains in treatment. Children with ASD have a different reading profile from other reading disorders that needs to be specifically targeted in interventions. PMID- 28856094 TI - Alterations in striato-thalamo-pallidal intrinsic functional connectivity as a prodrome of Parkinson's disease. AB - Although the diagnosis of Parkinson's disease (PD) remains anchored around the cardinal motor symptoms of bradykinesia, rest tremor, rigidity and postural instability, it is becoming increasingly clear that the clinical phase of the disease is preceded by a long period of neurodegeneration, which is not readily evident in terms of motor dysfunction. The neurobiological mechanisms that underpin this prodromal phase of PD remain poorly understood. Based on converging evidence of basal ganglia (BG) dysfunction in early PD, we set out to establish whether the prodromal phase of the disease is characterized by alterations in functional communication within the input and output structures of the BG. We analyzed resting-state functional MRI data collected from patients with REM sleep behavior disorder (RBD) and/or hyposmia, two of the strongest markers of prodromal PD, in comparison to age-matched controls. Relative to controls, subjects in the prodromal group showed reduced intra- and interhemispheric functional connectivity in a striato-thalamo-pallidal network. Functional connectivity alterations were restricted to the BG and did not extend to functional connections with the cortex. The data suggest that local interactions between input and output BG structures may be disrupted already in the prodromal phase of PD. PMID- 28856096 TI - Post-ictal atrial fibrillation detected during video-EEG monitoring: Case report, proposed physiopathologic mechanism and therapeutic considerations. PMID- 28856095 TI - Localizing value of electrical source imaging: Frontal lobe, malformations of cortical development and negative MRI related epilepsies are the best candidates. AB - OBJECTIVE: We aimed to prospectively assess the anatomical concordance of electric source localizations of interictal discharges with the epileptogenic zone (EZ) estimated by stereo-electroencephalography (SEEG) according to different subgroups: the type of epilepsy, the presence of a structural MRI lesion, the aetiology and the depth of the EZ. METHODS: In a prospective multicentric observational study, we enrolled 85 consecutive patients undergoing pre-surgical SEEG investigation for focal drug-resistant epilepsy. Electric source imaging (ESI) was performed before SEEG. Source localizations were obtained from dipolar and distributed source methods. Anatomical concordance between ESI and EZ was defined according to 36 predefined sublobar regions. ESI was interpreted blinded to- and subsequently compared with SEEG estimated EZ. RESULTS: 74 patients were finally analyzed. 38 patients had temporal and 36 extra temporal lobe epilepsy. MRI was positive in 52. 41 patients had malformation of cortical development (MCD), 33 had another or an unknown aetiology. EZ was medial in 27, lateral in 13, and medio-lateral in 34. In the overall cohort, ESI completely or partly localized the EZ in 85%: full concordance in 13 cases and partial concordance in 50 cases. The rate of ESI full concordance with EZ was significantly higher in (i) frontal lobe epilepsy (46%; p = 0.05), (ii) cases of negative MRI (36%; p = 0.01) and (iii) MCD (27%; p = 0.03). The rate of ESI full concordance with EZ was not statistically different according to the depth of the EZ. SIGNIFICANCE: We prospectively demonstrated that ESI more accurately estimated the EZ in subgroups of patients who are often the most difficult cases in epilepsy surgery: frontal lobe epilepsy, negative MRI and the presence of MCD. PMID- 28856097 TI - Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral-pallidoluysian atrophy (DRPLA). AB - We administered perampanel (PER) to a bedridden 13-year-old male patient with dentatorubral-pallidoluysian atrophy (DRPLA). The DRPLA diagnosis was based on the presence of a CAG trinucleotide repeat in the ATN1 gene. The patient experienced continuous myoclonic seizures and weekly generalized tonic-clonic seizures (GTCs). PER stopped the patient's myoclonic seizures and reduced the GTCs to fragmented clonic seizures. The patient recovered his intellectual abilities and began to walk again with assistance. We suggest that PER be considered as one of the key drugs used to treat patients with DRPLA. PMID- 28856098 TI - Gene expression profiling of ramie roots during hydroponic induction and adaption to aquatic environment. AB - Ramie (Boehmeria nivea (L.) Gaud.) is a traditionally terrestrial fiber crop. However, hydroponic technology can enhance the quantity and quality of disease free Ramie plant seedlings for field cultivation. To date, few studies have attempted to examine the hydroponic induction of ramie roots and the molecular responses of ramie roots to aquatic environment. In this study, ramie tender stems was grown in the soil or in a hydroponic water solution, and cultured in the same environmental conditions. Root samples of terrestrial ramie, and different developmental stages of hydroponic ramie (5 days, 30 days), were firstly pooled for reference transcriptome sequencing by Illumina Hiseq 2000. Gene expression levels of each samples were quantified using the BGISEQ500 platform to help understand the distribution of aquatic root development related genes at the macro level (GSE98903). Our data resources provided an opportunity to elucidate the adaptation mechanisms of ramie seedlings roots in aquatic environment. PMID- 28856099 TI - RNA-seq data comparisons of wild soybean genotypes in response to soybean cyst nematode (Heterodera glycines). AB - Soybean [Glycine max (L.) Merr.] is an important crop rich in vegetable protein and oil, and is a staple food for human and animals worldwide. However, soybean plants have been challenged by soybean cyst nematode (SCN, Heterodera glycines), one of the most damaging pests found in soybean fields. Applying SCN-resistant cultivars is the most efficient and environmentally friendly strategy to manage SCN. Currently, soybean breeding and further improvement in soybean agriculture are hindered by severely limited genetic diversity in cultivated soybeans. G. soja is a soybean wild progenitor with much higher levels of genetic diversity compared to cultivated soybeans. In this study, transcriptomes of the resistant and susceptible genotypes of the wild soybean, Glycine soja Sieb & Zucc, were sequenced to examine the genetic basis of SCN resistance. Seedling roots were treated with infective second-stage juveniles (J2s) of the soybean cyst nematode (HG type 2.5.7) for 3, 5, 8 days and pooled for library construction and RNA sequencing. The transcriptome sequencing generated approximately 245 million (M) high quality (Q > 30) raw sequence reads (125 bp in length) for twelve libraries. The raw sequence reads were deposited in NCBI sequence read archive (SRA) database, with the accession numbers SRR5227314-25. Further analysis of this data would be helpful to improve our understanding of the molecular mechanisms of soybean-SCN interaction and facilitate the development of diverse SCN resistance cultivars. PMID- 28856100 TI - Genome of Pseudomonas nitroreducens DF05 from dioxin contaminated sediment downstream of the San Jacinto River waste pits reveals a broad array of aromatic degradation gene determinants. AB - P. nitroreducens DF05 is a Gram negative, motile, aerobic, rod-shaped and psychrotrophic bacterium that was isolated from contaminated San Jacinto River sediment near River Terrace Park in Channelview, Texas. The draft genome of strain DF05 consists of a total of 192 contigs assembled at the scaffold level totaling 6,487,527 bp and encoding for 5862 functional proteins, 1116 of which are annotated as hypothetical proteins. The bacterial chromosome has a GC content of 65.15% and contains 22 rRNA and 70 tRNA loci. In addition, approximately 142 proteins localized on the bacterial chromosome are associated with metabolism of aromatic compounds. A single plasmid approximately 95 kb in size was also detected carrying copies of RNA genes and multiple phage assembly proteins. PMID- 28856101 TI - Draft genome sequence of an endophytic bacterium, Paenibacillus tyrfis strain SUK123, isolated from Santiria apiculata stem. AB - Here we report the draft genome sequence of an endophytic Paenibacillus tyrfis strain isolated from the Universiti Kebangsaan Malaysia reserve forest, Malaysia. The genome size was approximately 8.04 Mb, and the assembly consisted of 107 scaffolds with 168 contigs, and had a G + C content of 53%. Phylogenetic analysis of strain SUK123 using the 16S rRNA gene revealed that it belonged to the family Paenibacillaceae with the highest similarity to Paenibacillus elgii SDT (99%). Whole genome comparison of SUK123 with related species using average nucleotide identity (ANI) analysis revealed a similarity of 98% to Paenibacillus tyrfis Mst1T, 94% to Paenibacillus elgii B69T, 91% to Paenibacillus ehimensis A2T, 68% to Paenibacillus polymyxa SC2T and 69% to Paenibacillus alvei DMS29T. The draft genome was deposited at the European Nucleotide Archive (PRJEB21373). PMID- 28856102 TI - PJP granuloma in an Immune competent host: Case report and literature review. AB - PJP (Pneumocystis jirovecii) is a fungal agent by taxonomy. Ones considered a protozoan, it is now recognized as fungi based on ribosomal RNA and other gene sequence homologies, the composition of their cell walls, and structure of key enzymes. This organism generally affects immunocompromised hosts with a CD4 count <200 or <15%.Review of literature does support a rare occurrence of PJP infections in immunocompetent hosts.PJP can occur at normal CD 4 levels. PMID- 28856103 TI - Spontaneous rectus sheath hematomas in dengue hemorrhagic fever: A case report. AB - Muscle hematomas are rare complications in dengue hemorrhagic fever (DHF). We report a case of 58-year-old-female admitted with dengue fever who developed spontaneous rectus sheath hematoma complicating DHF. She presented with progressive thrombocytopenia with platelet count reaching 13000/MUL at its lowest point. There was evidence of plasma leakage and persistent cough during the course of illness. During the recovery phase, she reported severe abdominal pain and developed hematoma in the right rectus sheath, which was confirmed by abdominal computed-tomography scan and serial magnetic resonance imaging. This complication during convalescent period of DHF needs to be recognized so it can be managed appropriately. PMID- 28856104 TI - Development of a Large Pelvic Sperm Granuloma Status Post Radical Prostatectomy: A Case Report. AB - A 72 year old male developed severe obstructive voiding symptoms status post radical prostatectomy. Imaging showed a large pelvic mass causing mass effect on the bladder that ultimately proved to be a sperm granuloma. To the best of our knowledge the development of sperm granuloma post-prostatectomy has not been previously reported. PMID- 28856105 TI - A Case of Compartment Syndrome in the Scrotum and Inguinal Area Complicating Idiopathic Nephrotic Syndrome of Childhood. AB - Idiopathic nephrotic syndrome (INS) is a kidney disease characterized by massive proteinuria. Protein loss leads to decreased oncotic pressure shifting the fluids into the interstitial space causing edema, complications such as infections and thromboembolism occur. We report a 7-year-old, diagnosed with NS presenting with a relapse. He developed ascites and scrotal edema followed by severe scrotal pain and redness, progressing rapidly to ecchymosis in the inguinal areas not in continuity with the scrotum. Ultrasound with color Doppler was inconclusive, scrotal exploration was done along with skin incision in the inguinal areas and scrotum, which appeared to relieve the condition rapidly. PMID- 28856106 TI - Management and Excision of a 15 cm Paratesticular Angiolipoma. AB - Paratesticular tumors are rare and often benign causes of scrotal masses. Intrascrotal angiolipomas are an uncommon paratesticular tumor that has seldom been reported in the literature. This report describes a 77 year old man who presented with a 15 cm extratesticular mass. The mass was removed due to increasing discomfort and specimen pathology confirmed it as an angiolipoma. This case highlights the feasibility of conservative management for slow growing masses, such as angiolipomas. PMID- 28856107 TI - Treatment of mild to moderate carpal tunnel syndrome in patients with diabetic neuropathy using low level laser therapy versus ultrasound controlled comparative study. AB - AIM: The aim of the present study was to investigate and compare between Low Level Laser Therapy (LLLT) and Ultrasound (US) in treatment of Carpal Tunnel Syndrome (CTS) using the advantage of application of treatment directly over the transverse carpal ligament, as well as over the course of the median nerve in the forearm simultaneously. DESIGN: Fifty patients (25-55 years) with diabetic neuropathy, diagnosed as unilateral carpal tunnel syndrome participated in the study. They were equally divided and randomly assigned into two groups; each group consisted of 25 patients. MATERIALS AND METHODS: Patients in group (A) received a program of IR Gallium Arsenide LLLT (wavelength 904 nm, average power 20 mW, laser probe 7 mm diameter), with a total application of 4.8 J, while patients in group (B) received a program of US (frequency 1 MHz, power 1.0 W/cm2, pulsed mode 1:5). RESULTS & DISCUSSION: The results of our study showed that there were no statistical significance differences (P > 0.05) were observed between the two groups. It was concluded that both low level laser (20 mW power, 904 nm Wavelength) and ultrasound (1.0 w/cm2 power, 1 MHz frequency) are effective in the treatment of mild and moderate CTS patients. PMID- 28856108 TI - High frequency regeneration of plants from cotyledon and hypocotyl cultures in Brassica oleracea cv. Pride of India. AB - Morphogenic potential of cabbage cv. Pride of India, for multiple shoot induction was tested under in vitro conditions using cotyledon and hypocotyl explants. Aseptically grown seven to nine days old seedlings of cabbage were used as source of explants for reproducible plant regeneration studies. Forty different concentrations and combinations of TDZ (alone), TDZ with adenine, TDZ with NAA and TDZ with IAA were tried. Maximum shoot regeneration response from cotyledon explants (91.11%) and hypocotyl (94.40%) was obtained on MS medium containing 0.330 mg/l TDZ + 79.70 mg/l Adenine and 0.220 mg/l TDZ + 0.088 mg/l IAA, respectively. Rooting was achieved within two to three weeks on all the rooting media, but MS medium containing 0.10 mg/l NAA produced the maximum number of strong and healthy roots (100%). The regenerated complete plantlets with healthy roots and shoot system were transferred to pots containing sterilized cocopeat and successfully acclimatized and no phenotypic variations were observed among regenerated plants. Highly efficient, reproducible plant regeneration protocol has been standardized in cabbage cv. Pride of India, which would be valuable for Agrobacterium-mediated gene transfer studies in cabbage. PMID- 28856109 TI - SSR markers associated to early leaf spot disease resistance through selective genotyping and single marker analysis in groundnut (Arachis hypogaea L.). AB - Groundnut (Arachis hypogaea L.) is an important oilseed and food crop of the world. Breeding for disease resistance is one of major objectives in groundnut breeding. Early leaf spot (ELS) is one of the major destructive diseases worldwide and in West Africa, particularly in Burkina Faso causing significant yield losses. Conventional breeding approaches have been employed to develop improved varieties resistant to ELS. Molecular dissection of resistance traits using QTL analysis can improve the efficiency of resistance breeding. In the present study, an ELS susceptible genotype QH243C and an ELS resistant genotype NAMA were crossed and the F2 population genotypic and F3 progenies phenotypic data were used for marker-trait association analysis. Parents were surveyed with 179 simple sequence repeat (SSR) markers out of which 103 SSR markers were found to be polymorphic between the parents. These polymorphic markers were utilized to genotype the F2 population followed by marker-trait analysis through single marker analysis (SMA) and selective genotyping of the population using 23 resistant and 23 susceptible genotypes. The SMA revealed 13 markers while the selective genotyping method identified 8 markers associated with ELS resistance. Four markers (GM1911, GM1883, GM1000 and Seq13E09) were found common between the two trait mapping methods. These four markers could be employed in genomics assisted breeding for selection of ELS resistant genotypes in groundnut breeding. PMID- 28856110 TI - The Analgesic Efficiency of Ultrasound-Guided Rectus Sheath Analgesia Compared with Low Thoracic Epidural Analgesia After Elective Abdominal Surgery with a Midline Incision: A Prospective Randomized Controlled Trial. AB - BACKGROUND: Ultrasound-guided rectus sheath blockade has been described to provide analgesia for midline abdominal incisions. We aimed to compare thoracic epidural analgesia (TEA) and rectus sheath analgesia (RSA) with respect to safety and efficacy. METHODS: Sixty patients who underwent elective laparotomies through a midline incision were assigned randomly to receive either continuous TEA (TEA group, n = 31) or intermittent RSA (RSA group, n = 29). The number of patients who required analgesia, the time to first request analgesia, the interval and the cumulative morphine doses consumption during 72 hours postoperatively, and pain intensity using visual analog score (VAS) at rest and upon coughing were reported in addition to any side effects related to both techniques or administered drugs. RESULTS: While 17 (54.84 %) patients were in the TEA group, 25 (86.21%) patients in the RSA group required analgesia postoperatively, P = 0.008. Cumulative morphine consumed during the early 72 hours postoperatively median (interquartile range) = 33 mg (27 - 39 mg), 95% confidence interval (28.63 - 37.37 mg) for the TEA group. While in the RSA group, it was 51 mg (45 - 57 mg), 95% CI (47.4 - 54.6 mg), P < 0.001. The time for the first request of morphine was 256.77 +/- 73.45 minutes in the TEA group versus 208.82 +/- 64.65 min in the RSA group, P = 0.031. VAS at rest and cough were comparable in both groups at all time points of assessment, P > 0.05. The time to the ambulation was significantly shorter in the RSA group (38.47 +/- 12.34 hours) as compared to the TEA group (45.89 +/- 8.72 hours), P = 0.009. Sedation scores were significantly higher in the RSA group, only at 12 hours and 24 hours postoperatively than in TEA group, with P = 0.041 and 0.013, respectively. The incidence of other morphine-related side effects, time to pass flatus, and patients satisfaction scores were comparable between both groups. CONCLUSIONS: Continuous TEA had better opioid sparing effects markedly during the early 72 hours postoperatively than that of intermittent RSA with catheters inserted under real-time ultrasound guidance, both had comparable safety perspectives, and RSA had the advantage of early ambulation. RSA could be used as an effective alternative when TEA could not be employed in patients undergoing laparotomies with an extended midline incision, especially after the first postoperative day. PMID- 28856111 TI - Adaptive Support Ventilation Reduces the Incidence of Atelectasis in Patients Undergoing Coronary Artery Bypass Grafting: A Randomized Clinical Trial. AB - BACKGROUND: Pulmonary complications are common following cardiac surgery and can lead to increased morbidity, mortality, and healthcare costs. Atelectasis is the most common respiratory complication following cardiac surgery. One of the most important methods for reducing pulmonary complications is supportive care with protective ventilation strategies. In this study, we aimed to assess the effect of adaptive support ventilation (ASV) on atelectasis in patients undergoing cardiac surgery. METHODS: In this single-blind randomized clinical trial, 115 patients, undergoing coronary artery bypass grafting, were randomly allocated into 2 groups: 57 patients in the intervention and 58 patients in the control group. Patients in the intervention group were weaned with ASV, while patients in the control group were managed using synchronized intermittent mandatory ventilation (SIMV) and pressure support. The incidence of atelectasis, duration of mechanical ventilation, manual ventilator setting, arterial blood gas measurements, and length of hospital stay were compared between the groups. RESULTS: The incidence of atelectasis, number of changes in the manual ventilator setting, number of alarms, and length of hospital stay reduced in the intervention group. However, duration of mechanical ventilation and number of ABG measurements were not significantly different between the groups. CONCLUSIONS: The ASV mode could reduce the incidence of atelectasis and length of hospital stay. However, it did not reduce the duration of mechanical ventilation. It seems that ASV is not a superior mode for faster extubation. PMID- 28856112 TI - The Efficacy of Systemic Lidocaine in the Management of Chronic Pain: A Literature Review. AB - CONTEXT: Despite recent advances in the understanding of the chronic pain concept, its diagnosis and management remains a daily challenge for clinicians and patients. Based on the published literature, this review discusses and tries to organize the current knowledge and the up-to-date clinical experience about the efficacy and safety of the use of intravenous lidocaine in treatment and prevention of chronic pain. EVIDENCE ACQUISITION: To prepare this narrative review, we performed an in depth literature review using the PubMed searching engine. We extracted all relevant articles published in English, up to April 2016. RESULTS: Lidocaine, administered as transdermal patch or intravenous lidocaine, is a safe and effective modality in the treatment of post-herpetic neuralgia (PHN), complex regional pain syndrome, as well and for prevention of chronic pain. It may be effective in the management of neuropathic pain syndromes, chronic pain, post-operative pain, and refractory cancer pain. CONCLUSIONS: Intravenous lidocaine and lidocaine patch are effective and safe for the treatment of several chronic or neuropathic pain syndromes. The use of lidocaine during surgery could prevent the development of some chronic post surgical pain syndromes. PMID- 28856113 TI - A Comparative Study on the Efficacy of Oral Memantine and Placebo for Acute Postoperative Pain in Patients Undergoing Dacryocystorhinostomy (DCR). AB - BACKGROUND: Memantine is an N-methyl-D-Aspartate (NMDA) antagonist. By transferring acute postoperative pain, the NMDA channels may lead to active excess and neuropathic pain. Objectives: This study attempted to investigate the effect of preoperative use of single oral dose of memantine in controlling Dacryocystorhinostomy (DCR) postoperative pain. METHODS: A double-blind clinical trial was conducted on 60 patients undergoing DCR. On arrival at the operating room, the memantine group received 20 mg of oral memantine and the control group received placebo. The severities of pain by visual analogue scale (VAS) and sedation by Ramsy Scale were measured immediately 1, 2, and 6 hours after the operation. The drug's side effects were recorded. RESULTS: The pain scores of patients in the recovery in 1, 2, and 6 hours after operation were significantly lower in the memantine group than the placebo group (P < 0.001). The sedation score, 1 hour after the operation, was significantly greater in the memantine group than the placebo (P < 0.001). The sedation scores did not have any statistically significant difference in recovery and 2 hours after surgery between the two groups. Moreover, the sedation scores in 6 hours after the surgery were identical in the two groups. CONCLUSIONS: The oral single-dose 20 mg of memantine administered before DCR can reduce postoperative pain compared with placebo. PMID- 28856114 TI - Total Intravenous Anesthesia for Neurosurgical Procedures in Narcoleptic Patients: Two Case Reports. AB - INTRODUCTION: Narcoleptic patients may be at increased risk of prolonged emergence, postoperative hypersomnia, apneic episodes, and sleep paralysis after general anesthesia. Modafinil is the first-line treatment, however, the implication it has on general anesthesia is not clear. This report present 2 cases of narcoleptic patients medicated with modafinil that were submitted to total intravenous anesthesia for neurosurgical procedures. CASE PRESENTATION: Informed consent was obtained from both patients. Clinical information was obtained from patients' interviews and medical records. Intraoperative data was collected using Datex Ohmeda, Bispectral index, Entropy, and LiDCO rapid monitors, and exported to excel sheets to allow its analysis. Both patients maintained modafinil on the day of surgery and were not administered sedative premedication. Propofol was administered by bolus during induction of anesthesia. In one of the patients, the predicted cerebral concentration of propofol required for loss of consciousness was high. Anesthesia was maintained with remifentanil and propofol by target controlled infusion and titrated according to bispectral index (BIS), entropy, and analgesia nociception index (ANI). During the surgical procedure, the patients did not require vasopressors. Emergence from anesthesia was very fast and no narcoleptic event occurred postoperatively. CONCLUSIONS: Sedative premedication should be avoided and the use of short-acting anesthetic agents, such as propofol and remifentanil through target-controlled infusion most likely improves titration of anesthesia. The continuation of modafinil preoperatively might have contributed to the rapid emergence, yet, might also have been responsible for the high cerebral concentration of propofol that was required for loss of consciousness in one of the patients. PMID- 28856116 TI - Awareness on causes, consequences and preventive measures of obesity among urban married women in India. AB - BACKGROUND: In spite of the numerous chronic diseases that have been linked to obesity, studies focusing on the awareness regarding causes, consequences and strategies to prevent and control of obesity among women are lacking in the literature, especially in developing countries such as India, where obesity is culturally accepted and nurtured and women bearded the highest weight gain in the recent decade. OBJECTIVE: We explored the awareness regarding causes, consequences and preventive measures of obesity among 325 ever-married aged 20-54 years women with different levels of body mass index (BMI) in the national capital territory of Delhi representing urban India. MATERIALS AND METHODS: A population based follow-up survey of women systematically selected from the second round of National Family Health Survey (NFHS-2, 1998-99) samples who were re-interviewed after four years in 2003. As a part of qualitative data collection, the respondents were asked to free list open-ended questions on causes, consequences and preventive measures of obesity. Responses were analyzed through Anthropac software package. RESULTS: Over eating was reported as the most important cause of obesity by normal and overweight women whereas obese women reported fried food consumption as the most important cause of weight gain. A few women from each group reported changing lifestyle as a cause of obesity. Also, there were lots of misconceptions about the cause of obesity among women (such as no tension in life, more tension, happiness, constipation, problem in Delhi's water etc.). In terms of the consequences of obesity, the participants were well aware of the common physical consequences. Normal and obese women reported breathlessness as the most important consequence whereas overweight women reported problem in standing and sitting. Regarding preventive measures, overweight and obese women reported 'walking' as most important preventive measure of obesity whereas normal women reported 'doing exercise'. In addition, 'dieting' was reported as the next important preventive measures of obesity by all groups of women. CONCLUSION: Our study of a fairly large, community-based sample of women has shown that women were aware of the complex nature of obesity in terms of causes, consequences and a range of potential solutions. The findings are important for public health interventions in obesity care in India. Implementation of health promotion and health education in the community should use effective school education and mass media programme to raise more awareness of the causes, consequences and preventive measures and hammer misconceptions, to combat the growing level of obesity among Indian women. PMID- 28856115 TI - Erythrodermic psoriasis: pathophysiology and current treatment perspectives. AB - Erythrodermic psoriasis (EP) is a rare and severe variant of psoriasis vulgaris, with an estimated prevalence of 1%-2.25% among psoriatic patients. The condition presents with distinct histopathologic and clinical findings, which include a generalized inflammatory erythema involving at least 75% of the body surface area. The pathogenesis of EP is not well understood; however, several studies suggest that the disease is associated with a predominantly T helper 2 (Th2) phenotype. Given the morbidity and potential mortality associated with the condition, there is a need for a better understanding of its pathophysiology. The management of EP begins with a comprehensive assessment of the patient's presentation and often requires multidisciplinary supportive measures. In 2010, the medical board of the US National Psoriasis Foundation published consensus guidelines advocating the use of cyclosporine or infliximab as first-line therapy in unstable cases, with acitretin and methotrexate reserved for more stable cases. Since the time of that publication, additional information regarding the efficacy of newer agents has emerged. We review the latest data with regard to the treatment of EP, which includes biologic therapies such as ustekinumab and ixekizumab. PMID- 28856118 TI - Prognostic Value of Multiple Draining Lymph Node Basins in Melanoma: A Matched Pair Analysis Based on the John Wayne Cancer Institute Experience. AB - BACKGROUND: The prognostic significance of multiple draining basins is controversial in melanoma because analyses have not adequately controlled for standard prognostic variables. We hypothesized that an analysis based on prognostically matched pairs of patients with multiple versus single drainage basins would clarify any independent role of basin number. STUDY DESIGN: We identified patients in our 40-year prospective database, who underwent preoperative lymphoscintigraphy, intraoperative sentinel node biopsy and wide local excision for cutaneous melanoma. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were compared in patients with multiple versus single drainage basins after matching by age, sex, Breslow depth, primary site, and stage at diagnosis. RESULTS: We identified 274 patients with multibasin drainage and 1,413 patients with single draining lymph node basins. Matching yielded 259 pairs (226 trunk, 27 head/neck, 6 extremity). Among matched pairs, multibasin drainage did not affect rates of lymph node metastasis (p = 0.84), OS (p = 0.23), DSS (p = 0.53), overall recurrence (p = 0.65), locoregional recurrence (p = 0.58), or distant recurrence (p = 1.0). Multivariable analysis linked higher T stage, ulceration, older age, and lymph node positivity to decreased DSS (p < 0.01) and DFS (p < 0.001). Number of drainage basins was not significant on univariable or multivariable analysis. CONCLUSION: This analysis, the first to match for standard prognostic factors, suggests that multiplebasin drainage as identified by lymphoscintigraphy has no independent biological or prognostic significance in primary cutaneous melanoma. PMID- 28856117 TI - The IL-6/STAT3 Signaling Pathway Is an Early Target of Manuka Honey-Induced Suppression of Human Breast Cancer Cells. AB - There is renewed interest in the potential use of natural compounds in cancer therapy. Previously, we demonstrated the anti-tumor properties of manuka honey (MH) against several cancers. However, the underlying mechanism and molecular targets of this activity remain unknown. For this study, the early targets of MH and its modulatory effects on proliferation, invasiveness, and angiogenic potential were investigated using two human breast cancer cell lines, the triple negative MDA-MB-231 cells and estrogen receptor-positive MCF-7 cells, and the non neoplastic breast epithelial MCF-10A cell line. Exposure to MH at concentrations of 0.3-1.25% (w/v) induced a dose-dependent inhibition of the proliferation of MDA-MB-231 and MCF-7, but not MCF-10A, cells. This inhibition was independent of the sugar content of MH as a solution containing equivalent concentrations of its three major sugars failed to inhibit cell proliferation. At higher concentrations (>2.5%), MH was found to be generally deleterious to the growth of all three cell lines. MH induced apoptosis of MDA-MB-231 cells through activation of caspases 8, 9, 6, and 3/7 and this correlated with a loss of Bcl-2 and increased Bax protein expression in MH-treated cells. Incubation with MH induced a time-dependent translocation of cytochrome c from mitochondria to the cytosol and Bax translocation from the cytosol into the mitochondria. MH also induced apoptosis of MCF-7 cells via the activation of caspases 9 and 6. Low concentrations of MH (0.03-1.25% w/v) induced a rapid reduction in tyrosine-phosphorylated STAT3 (pY STAT3) in MDA-MB-231 and MCF-7 cells. Maximum inhibition of pY-STAT3 was observed at 1 h with a loss of >80% and coincided with decreased interleukin-6 (IL-6) production. Moreover, MH inhibited the migration and invasion of MDA-MB-231 cells as well as the angiogenic capacity of human umbilical vein endothelial cells. Our findings identify multiple functional pathways affected by MH in human breast cancer and highlight the IL-6/STAT3 signaling pathway as one of the earliest potential targets in this process. PMID- 28856120 TI - From Brain Disease to Brain Health: Primary Prevention of Alzheimer's Disease and Related Disorders in a Health System Using an Electronic Medical Record-Based Approach. AB - BACKGROUND: Alzheimer's disease and aging brain disorders are progressive, often fatal neurodegenerative diseases. Successful aging, modern lifestyles and behaviors have combined to result in an expected epidemic. Risks for these diseases include genetic, medical, and lifestyle factors; over 20 modifiable risks have been reported. OBJECTIVES: We aim to primarily prevent Alzheimer's disease and related disorders through electronic medical record (EMR)-based screening, risk assessments, interventions, and surveillance. DESIGN: We identified modifiable risks; developed human, systems and infrastructural resources; developed interventions; and targeted at-risk groups for the intervention. SETTING: A Community Based Health System. PARTICIPANTS: In year one (June 2015 to May 2016), 133 at-risk patients received brain health services with the goal of delaying or preventing Alzheimer's disease and related disorders. MEASUREMENTS: We created mechanisms to identify patients at high risk of neurodegenerative disease; EMR-based structured clinical documentation support tools to evaluate risk factors and history; evidence-based interventions to modify risk; and the capacity for annual surveillance, pragmatic trials, and practice-based and genomic research using the EMR. RESULTS: This paper describes our Center for Brain Health, our EMR tools, and our first year of healthy but at risk patients. CONCLUSION: We are translating research into primary prevention of Alzheimer's disease and related disorders in our health system and aim to shift the paradigm in Neurology from brain disease to brain health. PMID- 28856119 TI - Characterization of Chicken IgY Specific to Clostridium difficile R20291 Spores and the Effect of Oral Administration in Mouse Models of Initiation and Recurrent Disease. AB - Clostridium difficile infection (CDI) are the leading cause of world-wide nosocomial acquired diarrhea. The current main clinical challenge in CDI is the elevated rate of infection recurrence that may reach up to 30% of the patients, which has been associated to the formation of dormant spores during the infection. We sought to characterize the effects of oral administration of specific anti-spore IgY in mouse models of CDI and recurrent CDI. The specificity of anti-spore IgY was evaluated in vitro. In both, initiation mouse model and recurrence mouse model, we evaluated the prophylactic and therapeutic effect of anti-spore IgY, respectively. Our results demonstrate that anti-spore IgY exhibited high specificity and titers against C. difficile spores and reduced spore adherence to intestinal cells in vitro. Administration of anti-spore IgY to C57BL/6 mice prior and during CDI delayed the appearance of the diarrhea by 1.5 day, and spore adherence to the colonic mucosa by 90%. Notably, in the recurrence model, co-administration of anti-spore IgY coupled with vancomycin delayed the appearance of recurrent diarrhea by a median of 2 days. Collectively, these observations suggest that anti-spore IgY antibodies may be used as a novel prophylactic treatment for CDI, or in combination with antibiotics to treat CDI and prevent recurrence of the infection. PMID- 28856121 TI - MATERNAL AND NEONATAL OUTCOMES OF HISTOLOGICAL CHORIOAMNIONITIS. AB - BACKGROUND: Clinical Chorioamnionitis contributes to maternal and neonatal morbidity and mortality but the effect of histological chorioamnionitis is sparse in our environment. AIM: To determine the maternal and neonatal outcomes of histological chorioamnionitis amongst pregnant women and their babies. DESIGN OF THE STUDY: Cross sectional longitudinal study. SETTING: Jos University Teaching Hospital (JUTH), Jos, Nigeria. METHODOLOGY: Parturients were interviewed and examined as well as had their placenta examined histologically for chorioamnionitis. They and their babies were followed up for 6 weeks after delivery to monitor for any complications that may arise. RESULTS: A total of 148 parturients were enrolled from the labour ward of Jos University Teaching Hospital and of these 90 (60.8%) had histologic chorioamnionitis (HCA). As regards outcome, 9(10%) with histologic chorioamnionitis as well as 5(8.62%) of those without HCA had premature delivery. Low birth weight occurred in 12(13.33%) and 6(10.34 %) of those with HCA and without HCA respectively. In all, 1(1.47%) and 1(2.56%) of women with HCA and without HCA correspondingly had neonatal sepsis. Puerperal sepsis occurred in 2(2.94%) of those with HCA and 2(5.13%) of those without HCA. CONCLUSION: Our study has demonstrated that histological chorioamnionitis had no adverse maternal or neonatal effect. There is the need for more studies investigating the cause and the implication of histological chorioamnionitis. PMID- 28856122 TI - DENTAL CARIES AND NUTRITIONAL STATUS OF SCHOOL CHILDREN IN LAGOS, NIGERIA - A PRELIMINARY SURVEY. AB - BACKGROUND: Studies have highlighted the direct impact of caries on the nutritional status of children; few studies in Nigeria have examined the association between the two parameters. AIM: To determine the association between caries and the nutritional status of in-school children. Design of the study: A cross-sectional survey. SETTING: Two private and two public schools in Lagos state. METHODOLOGY: A total of 973 children were assessed for dental caries using the WHO diagnostic criteria. Nutritional status was assessed using the weight for age, height for age and weight for height parameters. Data entry and analysis were done using WHO Epi 3.5 nutritstat and SPSS version 20.0 software. The t test, ANOVA, chi squared test, correlation statistics and logistic regression analysis were used as tests of association. A p-value of 0.05 or less was considered statistically significant. RESULTS: Caries prevalence was 21.7% while mean Decayed Missing and Filled Teeth (DMFT) index score was 0.48 (+/-1.135). Overall 13.9% of the children studied were stunted, 13.6% were wasted and 10.9% were underweight. The caries prevalence was significantly higher in children with normal weight than in overweight or underweight children (p=0.009). Children who were wasted (p=0.111) and those who were underweight (p=0.659) had a higher mean DMFT score, but the relationship was not statistically significant. The DMFT score was negatively correlated with weight for age but positively correlated with height for age and weight for height. The relationships were also not statistically significant. CONCLUSION: Our results showed that underweight children had a higher risk of developing dental caries. Although both under weight and wasted children had higher mean DMFT scores, there was no significant association between dental caries and nutritional status. PMID- 28856123 TI - Measurement of Testicular Volume in healthy Nigerian newborns AT IBADAN, NIGERIA using THE PRADER Orchidometer. AB - BACKGROUND: Determining the normal testicular volume in the newborn at birth is essential in the assessment of the degree of virilization of the external genitalia since abnormal development of the genitalia is closely related to the testicular volume in the male newborns. OBJECTIVES: To establish a standard testicular volume (TV) for male newborn Nigerians using the Prader Orchidometer and determine the relationship between the testicular volume in the newborn and the age of the newborns at birth, the birth weight, the maternal age at delivery and the maternal parity. METHODS: Prospective cross-sectional study of all term male neonates within 72 hours of birth from April 2013 to March 2014 in the three largest obstetric centres (University College Hospital, Adeoyo Maternity Hospital and Our Lady of Apostles Catholic Hospital) in Ibadan, Nigeria. They underwent clinical examination of the external genitalia and the testicular volumes were measured using the Prader orchidometer. RESULTS: A total of 867 male neonates were recruited into the study with a mean age of 2.89+/-6.21 days. The testicular volume ranged from 1 - 3 ml on both sides with a mean right testicular volume of 1.14+/-0.38 ml. There was a significant correlation between gestational age as well as birth weight and the testicular volume (r = 0.146, p = 0.03). CONCLUSION: This study has determined a normative value for testicular volume measured by Prader Orchidometer in newborns in a typical African population which could be used as a reference when evaluating neonates with patients with testicular abnormalities. PMID- 28856124 TI - DETERMINANTS OF THE USE OF TRADITIONAL EYE MEDICATION IN A SEMI-URBAN COMMUNITY IN SOUTHERN NIGERIA. AB - BACKGROUND: The use of traditional eye medication is still practised in some communities in Nigeria. AIM: To assess the determinants of the use of traditional eye medication (TEM) by adults in Ekiadolor community. METHOD: A descriptive cross-sectional study on the determinants of the use of traditional eye medication among adults was done between the months of September and November 2011 in Ekiadolor community in Edo state, Nigeria. RESULTS: Out of the 430 participants in this study, 57.2% were females and 42.8% males. Majority of the respondents (92.1%) knew about TEM. The prevalence of the use of TEM was 48.7%. Affordability (21.8%) was the main reason for the use of TEM. The male gender, persons of low socio economic class and people that lacked formal education were more likely to use TEM (p=0.001). CONCLUSION: The determinants of the use of traditional eye medication in this community are affordability, low socio economic status and lack of formal education. Formal education is of great importance, as this will go a long way in addressing the issues directly relating to the use of traditional eye medication in our communities. PMID- 28856125 TI - PATTERN OF ASSAULT-RELATED MAXILLOFACIAL INJURIES TREATED AT THE GENERAL HOSPITAL, LAGOS, NIGERIA. AB - BACKGROUND: The human face often constitutes the first point of contact in various human interactions and it is frequently the preferred target for blows in assault cases. AIM: To analyze the pattern of assault-related maxillofacial injuries treated at the General Hospital, Lagos over a period of one year. METHODOLOGY: This is one year prospective study of assault-related maxillofacial injuries treated at the Department of Oral-Maxillofacial Surgery, Dental Centre, General Hospital, Lagos, Nigeria. A face-to-face interviewer-administered structured proforma was used to obtain information from study subjects. RESULTS: Thirty-three patients with maxillofacial injuries met the inclusion criteria for this study. Their age ranged between 16 and 48 years with a mean age of 28.2 +/- 7.4 years. There were 25(75.8%) males and 8(24.2%) females with a male/female ratio of 3:1. Majority of the patients, 24(72.7%) did not have any skilled employment while the remaining 9(27.3%) were road transport workers, specifically commercial bus drivers and motorcycle riders. The most frequently seen soft tissue injury was contusion which accounted for 17(51.5%) cases while 13 (39%) of the patients sustained mandibular fracture which was the most common hard tissue injury. CONCLUSION: Assault-related maxillofacial injuries are most common amongst young adult males who are not skillfully employed; this can be attributed to the increased disposition to violence in males in our environment. PMID- 28856126 TI - PREVALENCE AND PATTERN OF PRESBYOPIA IN A RURAL NIGERIAN COMMUNITY. AB - BACKGROUND: Presbyopia is an age related loss of accommodation that results in the inability to focus at near distances. Few population-based studies exist on the prevalence of presbyopia among people living in developing countries. AIM: To determine the prevalence of presbyopia, presbyopia correction coverage and identify barriers to spectacle usage in individuals aged 35years and above. DESIGN: Cross sectional descriptive survey. SETTING: Esie, a rural community in Kwara State, Nigeria. MATERIALS AND METHODS: Four hundred and four subjects with best corrected distance vision >=20/60 were enrolled into the study by a multistage sampling procedure. Distance and near vision testing and near refraction (for those with presenting near VA < N8 at 40cm) were carried out. Interviewer administered structured questionnaires were used to collect subjects' information. RESULTS: Three hundred and thirty five subjects were included while 24 subjects were not available for examination and 45 subjects excluded based on the visual acuity cut off point. The age range was 35 to 100 years, with a mean age of 57+/-12.1years. The prevalence of presbyopia was 59.7%. Presbyopia correction coverage was 46.5%. Increasing age was found to be significantly associated with presbyopia, while gender, occupation and educational level were not. Skilled workers, retired persons and those with at least a secondary education were more likely to have glasses than others. The commonest barrier to obtaining near vision glasses was lack of money. CONCLUSION: Presbyopia is a major burden and cause of ocular morbidity in this rural community. Cost is the commonest barrier to obtaining near vision spectacles. Increasing the availability of affordable spectacles will go a long way to overcome this. PMID- 28856127 TI - Causes of low vision and their management at Korle Bu Teaching Hospital, Accra, GHANA. AB - BACKGROUND: Provision of low vision services to the visually impaired is vital in blindness intervention programs. Such services are avenues for low vision patients to utilize their residual vision in carrying out daily tasks. AIM: To review the causes of low vision and services provided to low vision patients at Korle Bu Teaching Hospital. STUDY DESIGN: A retrospective cross-sectional study. METHODOLOGY: Study subjects were low vision patients who had been referred by ophthalmologists and optometrists from all over Ghana for low vision services. At the Low Vision Centre, patients were re-examined to confirm that they had low vision and were suitable for low vision devices. The visual acuities of all patients was determined using a Snellen chart (with letters and tumbling E chart) followed by anterior and posterior segment examination using a Haagstreit slit lamp biomicroscope and direct and/or indirect ophthalmoscope (Keeler). All patients were refracted for near and distance and best corrected visual acuities were recorded. Patients with best corrected visual acuities of less than 6/18 but better than light 3/60 in the better were considered for low vision devices. Clinical records of low vision patients managed at the Korle Bu Teaching Hospital between March 2005 and December 2014 were examined to determine the main causes of low vision and interventions given. Their demographics, clinical features, services offered and annual trend in low vision uptake were analyzed. RESULTS: A total of 604 patients managed between March 2005 and December 2014 at the low vision centre of the Korle Bu Teaching Hospital were included in the study. The mean age was 40.55+6.95 years. There was statistically no significant difference between the mean age in either sex; p-value = 1.000. Glaucoma was the leading cause of low vision in 135 (22.35%) of cases, followed by non-glaucomatous optic atrophy 62(10.26 %), retinitis pigmentosa 54(8.94 %), maculopathy 52(8.61 %) and ARMD 48(7.95 %) respectively. Uptake of the low vision services was highest in the second year of commencing the services. Interventions were mainly magnifiers, telescopes, closed circuit television (CCTV), counselling and referral to the School for the Blind. CONCLUSION: Glaucoma and non-glaucomatous optic atrophy were the predominant causes of low vision, and magnifiers and telescopes were the most commonly prescribed devices. PMID- 28856128 TI - Effect of varicocoelectomy on seminal fluid parameters. AB - BACKGROUND: Infertility can be a source of anxiety and marital disharmony to a couple. The male factor traditionally contributes 40%. Varicocoeles are a significant cause of male infertility. AIM: To assess the effect of varicocoelectomy on seminal fluid analysis parameters in sub-fertile males. METHODOLOGY: This was a prospective study of fifty four patients who presented with infertility to the urology clinic of University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria between January 2015. and January 2016 . Those who had clinically palpable varicocoeles as the only suspected cause of their infertility were enrolled. The varicocoeles were classified into right, left or bilateral and graded into grades 1, 2 and 3 using Dubins criteria. Each patient had two semen analyses done two weeks apart and underwent a bilateral varicocoelectomy via the inguinal approach. Seminal fluid analyses were done post operatively at four and six months. RESULTS: Of the 54 patients that underwent varicocoelectomy, 11 (20.4%) had azoospermia, 28 (51.9%) had oligospermia and 15 (27.8%) had counts greater than 20 million but less than 40 million. Following varicocoelectomy there was a statistically significant increase in overall motility (p=0.000), morphology (p=0.000), density (p=0.000) and semen volume (p=0.004). Assessing only oligospermic patients there was no significant improvement in morphology (p=0.160). Azoospermic patients showed statistically significant improvement in all parameters though the values were well below those accepted for spontaneous conception. CONCLUSION: Varicocoelectomy improves semen parameters in patients with varicocoele induced semen anomalies; it may provide an option for retrieving viable semen for patients with varicocoele induced azoospermia. PMID- 28856129 TI - Peer-Reviewed Abstracts of Scientific Paper Presentation at The 56th Annual Conference of The West African College of the Surgeons at Yaounde, Cameroun 15th 19th February 2016 Contd. PMID- 28856130 TI - Histological Chorioamnionitis. PMID- 28856132 TI - Enabling and Predisposing Factors for the Utilization of Preventive Dental Health Care in Migrants and Non-Migrants in Germany. AB - BACKGROUND: In many European countries including Germany, migrants utilize preventive services less frequently than the majority population. This is also true for the utilization of dental checkups. Little is known about which demographic, social, behavioral, and health-related factors influence the decision of migrants to seek preventive dental health care and how these factors differ from those in non-migrants. The aim of the present study was to examine the role of these factors among migrants and non-migrants residing in Germany. METHODS: Data from cross-sectional national health surveys are used, providing information on preventive dental health behavior from n = 41,220 individuals, of which 15.0% are migrants. Andersen's Behavioral Model of Health Services Use is the conceptual framework of the investigation. Multiple logistic regression models were applied to examine the role of different predisposing and enabling factors. Interaction terms were included in order to examine whether determinants differ between migrants and non-migrants. Average marginal effects (AMEs) are reported in addition to odds ratios (ORs) as measures of effect size which are robust against bias arising from unobserved heterogeneity. RESULTS: Migrants are at an about 36% lower chance of utilizing regular dental checkups than non migrants [OR = 0.64 (95% confidence interval, 95% CI: 0.61, 0.68); AME = -0.081 (95% CI = -0.093, -0.069)]. Differences are partly explained by the influence of demographic, social, behavioral, and health-related factors [adjusted OR = 0.69 (95% CI: 0.64, 0.73); AME = -0.065 (95% CI = -0.076, -0.053)]. Younger age, being male, lower socioeconomic status, a non-statutory health insurance, not living in a relationship, living in the Western part of Germany and in an urban setting, and poor limited social support were associated with a lower chance of utilizing regular dental checkups. Interaction effects could be observed for age and for the type of health insurance. DISCUSSION: The study identifies different enabling and predisposing factors that are relevant for the utilization of dental checkups among the population in Germany, some of which differ between migrants and non migrants. Differences are particularly pronounced for younger ages. This differs from findings on other preventive services where older migrants tend to be more disadvantaged. Additional explanatory factors such as barriers that migrants experience in the dental health care system need to be considered in order to implement patient-oriented services and to reduce disparities in access to dental prevention. PMID- 28856133 TI - Pioneering and Interprofessional Pediatric Dentistry Programs Aimed at Reducing Oral Health Disparities. AB - Early Childhood Caries (ECC) is the most chronic childhood disease and more predominant in low-income and underserved children. Although easily transmitted, ECC is entirely preventable. Dr. Ramos-Gomez and his team at the University of California, Los Angeles put together an interprofessional curriculum where both medical and dental knowledge and practice is integrated to prepare dentists and primary care providers to more cost effectively address ECC and thereby reduce disparities in oral health. The curriculum, known as the Strategic Partnership for Interprofessional Collaborative Education in Pediatric Dentistry (SPICE-PD), consists of nine evidence-based training modules: applied statistics and research, community partners, interprofessional education/training, quality improvement, policy and advocacy, disease management/risk assessment, ethics/professionalism, cultural competency and children with special heath-care needs. SPICE aims to prepare pediatric dental residents and primary care providers to provide preventive, culturally competent, and minimally invasive oral care for underserved, low income, and special needs children. Additionally, the Infant Oral Care Program (IOCP), located at a local community health clinic, provides culturally sensitive preventive oral health care for children aged 0-5 years. The medical-dental integration model utilized at IOCP helps reduce oral health disparities by providing a systems-based and cost-effective approach to combat the burden of ECC. To track the progress of SPICE, a comprehensive evaluation framework has been designed, which aligns goals and objectives with program activities, desired outcomes, and measured indicators. PMID- 28856131 TI - Resting-State Functional Connectivity in the Infant Brain: Methods, Pitfalls, and Potentiality. AB - Early brain development is characterized by rapid growth and perpetual reconfiguration, driven by a dynamic milieu of heterogeneous processes. Postnatal brain plasticity is associated with increased vulnerability to environmental stimuli. However, little is known regarding the ontogeny and temporal manifestations of inter- and intra-regional functional connectivity that comprise functional brain networks. Resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a promising non-invasive neuroinvestigative tool, measuring spontaneous fluctuations in blood oxygen level dependent (BOLD) signal at rest that reflect baseline neuronal activity. Over the past decade, its application has expanded to infant populations providing unprecedented insight into functional organization of the developing brain, as well as early biomarkers of abnormal states. However, many methodological issues of rs-fMRI analysis need to be resolved prior to standardization of the technique to infant populations. As a primary goal, this methodological manuscript will (1) present a robust methodological protocol to extract and assess resting-state networks in early infancy using independent component analysis (ICA), such that investigators without previous knowledge in the field can implement the analysis and reliably obtain viable results consistent with previous literature; (2) review the current methodological challenges and ethical considerations associated with emerging field of infant rs-fMRI analysis; and (3) discuss the significance of rs-fMRI application in infants for future investigations of neurodevelopment in the context of early life stressors and pathological processes. The overarching goal is to catalyze efforts toward development of robust, infant-specific acquisition, and preprocessing pipelines, as well as promote greater transparency by researchers regarding methods used. PMID- 28856134 TI - Interprofessional Oral Health Education Improves Knowledge, Confidence, and Practice for Pediatric Healthcare Providers. AB - Dental caries is the most prevalent chronic childhood disease in the United States. Dental caries affects the health of 60-90% of school-aged children worldwide. The prevalence of untreated early childhood dental caries is 19% for children 2-5 years of age in the U.S. Some factors that contribute to the progression of dental caries include socioeconomic status, access to dental care, and lack of anticipatory guidance. The prevalence of dental caries remains highest for children from specific ethnic or racial groups, especially those living in underserved areas where there may be limited access to a dentist. Although researchers have acknowledged the various links between oral health and overall systemic health, oral health care is not usually a component of pediatric primary health care. To address this public health crisis and oral health disparity in children, new collaborative efforts among health professionals is critical for dental disease prevention and optimal oral health. This evaluation study focused on a 10-week interprofessional practice and education (IPE) course on children's oral health involving dental, osteopathic medical, and nurse practitioner students at the University of California, San Francisco. This study's objective was to evaluate changes in knowledge, confidence, attitude, and clinical practice in children's oral health of the students completed the course. Thirty-one students participated in the IPE and completed demographic questionnaires and four questionnaires before and after the IPE course: (1) course content knowledge, (2) confidence, (3) attitudes, and (4) clinical practice. Results showed a statistically significant improvement in the overall knowledge of children's oral health topics, confidence in their ability to provide oral health services, and clinical practice. There was no statistically significant difference in attitude, but there was an upward trend toward positivity. To conclude, this IPE evaluation showed that offering an interprofessional course on children's oral health to graduate students in dentistry, nursing, and osteopathic medicine can improve their knowledge, confidence, and practice toward children's oral health and expand their professional goals to include caring for underserved, minority children. PMID- 28856136 TI - Impact of a Genetic Risk Score for Coronary Artery Disease on Reducing Cardiovascular Risk: A Pilot Randomized Controlled Study. AB - PURPOSE: We tested whether providing a genetic risk score (GRS) for coronary artery disease (CAD) would serve as a motivator to improve adherence to risk reducing strategies. METHODS: We randomized 94 participants with at least moderate risk of CAD to receive standard-of-care with (N = 49) or without (N = 45) their GRS at a subsequent 3-month follow-up visit. Our primary outcome was change in low density lipoprotein cholesterol (LDL-C) between the 3- and 6-month follow-up visits (DeltaLDL-C). Secondary outcomes included other CAD risk factors, weight loss, diet, physical activity, risk perceptions, and psychological outcomes. In pre-specified analyses, we examined whether there was a greater motivational effect in participants with a higher GRS. RESULTS: Sixty five participants completed the protocol including 30 participants in the GRS arm. We found no change in the primary outcome between participants receiving their GRS and standard-of-care participants (DeltaLDL-C: -13 vs. -9 mg/dl). Among participants with a higher GRS, we observed modest effects on weight loss and physical activity. All other secondary outcomes were not significantly different, including anxiety and worry. CONCLUSION: Adding GRS to standard-of-care did not change lipids, adherence, or psychological outcomes. Potential modest benefits in weight loss and physical activity for participants with high GRS need to be validated in larger trials. PMID- 28856137 TI - A Systematic Review of the Quality of IV Fluid Therapy in Veterinary Medicine. AB - OBJECTIVE: To evaluate the quality of the veterinary literature investigating IV fluid therapy in dogs, cats, horses, and cattle. DESIGN: Systematic review. PROCEDURES: The preferred reporting of items for systematic review and meta analysis protocols (PRISMA-P) was employed for systematic review of all relevant IV fluid therapy manuscripts published from January 1969 through December 2016 in the Commonwealth Agricultural Bureaux International (CABI) database. Independent grading systems used to evaluate manuscripts included the updated CONsolidated Standards of Reporting Trials 2012 checklist, risk of bias for animal intervention studies, criteria for levels of evidence, and methodological quality (Jadad scale). The quality of articles published before and after 2010 was compared. RESULTS: One hundred and thirty-nine articles (63 dogs, 7 cats, 39 horses, 30 cattle) from 7,258 met the inclusion criteria. More than 50% of the manuscripts did not comply with minimal requirements for reporting randomized controlled trials. The most non-compliant items included identification of specific predefined objectives or a hypothesis, identification of trial design, how sample size was determined, randomization, and blinding procedures. Most studies were underpowered and at risk for selection, performance, and detection bias. The overall quality of the articles improved for articles published after 2010. CONCLUSION AND CLINICAL RELEVANCE: Most of the veterinary literature investigating the administration of IV fluid therapy in dogs, cats, horses, and cattle is descriptive, does not comply with standards for evidence, or provide adequate translation to clinical practice. Authors should employ and journal editors should enforce international consensus recommendations and guidelines for publication of data from animal experiments investigating IV fluid therapy. PMID- 28856135 TI - Plant Science View on Biohybrid Development. AB - Biohybrid consists of a living organism or cell and at least one engineered component. Designing robot-plant biohybrids is a great challenge: it requires interdisciplinary reconsideration of capabilities intimate specific to the biology of plants. Envisioned advances should improve agricultural/horticultural/social practice and could open new directions in utilization of plants by humans. Proper biohybrid cooperation depends upon effective communication. During evolution, plants developed many ways to communicate with each other, with animals, and with microorganisms. The most notable examples are: the use of phytohormones, rapid long-distance signaling, gravity, and light perception. These processes can now be intentionally re-shaped to establish plant-robot communication. In this article, we focus on plants physiological and molecular processes that could be used in bio-hybrids. We show phototropism and biomechanics as promising ways of effective communication, resulting in an alteration in plant architecture, and discuss the specifics of plants anatomy, physiology and development with regards to the bio-hybrids. Moreover, we discuss ways how robots could influence plants growth and development and present aims, ideas, and realized projects of plant-robot biohybrids. PMID- 28856138 TI - Role of myokines in cardiovascular diseases and pre-analytical variables affecting their measurements. PMID- 28856141 TI - Diagnosis and treatment of pulmonary cavity after liver transplantation. AB - BACKGROUND: Although the outcomes have improved in the current era, pulmonary infection remains a significant post-transplant complication in liver transplant (LT) recipients. Pulmonary infection with cavity formation often leads to higher mortality rates after LT. We wished to investigate the diagnosis and treatment of pulmonary cavity (PC) formation after LT. METHODS: We evaluated (retrospectively) five cases of PC formation, shown on CT scans of the chest after LT, by analyzing imaging features, diagnosis, treatment, liver function, and the concentration changes and efficacy of immunosuppressants. RESULTS: According to the results from the CT scan, serum Aspergillus galactomannan (GM) assay, the purified protein derivative (PPD) skin test, and the sputum smears and blood culture, three cases were diagnosed with Aspergillus infection, and the other two cases were diagnosed with Mycobacterium tuberculosis infection. Liver function and FK506 concentration were monitored during treatment. Antibiotics used for treatment of Aspergillus and Mycobacterium tuberculosis infections affected liver function and FK506 concentration. However, after adjustment of drug doses, antibiotic treatment was tolerated in all patients. Four cases were cured, but 1 patient died of Aspergillus infection. CONCLUSIONS: Distinguishing between Aspergillus infection and Mycobacterium tuberculosis infection for PCs after liver transplantation (LT) using a CT scan is difficult. The diagnosis can be confirmed using clinical characteristics, sputum culture, GM assay, PPD, and sputum smears. Early diagnosis and treatment could lead to a better prognosis. PMID- 28856142 TI - Preoperative surgical rehearsal using cadaveric fresh tissue surgical simulation increases resident operative confidence. AB - BACKGROUND: Rehearsal is an essential part of mastering any technical skill. The efficacy of surgical rehearsal is currently limited by low fidelity simulation models. Fresh cadaver models, however, offer maximal surgical simulation. We hypothesize that preoperative surgical rehearsal using fresh tissue surgical simulation will improve resident confidence and serve as an important adjunct to current training methods. METHODS: Preoperative rehearsal of surgical procedures was performed by plastic surgery residents using fresh cadavers in a simulated operative environment. Rehearsal was designed to mimic the clinical operation, complete with a surgical technician to assist. A retrospective, web-based survey was used to assess resident perception of pre- and post-procedure confidence, preparation, technique, speed, safety, and anatomical knowledge on a 5-point scale (1= not confident, 5= very confident). RESULTS: Twenty-six rehearsals were performed by 9 residents (PGY 1-7) an average of 4.7+/-2.1 days prior to performance of the scheduled operation. Surveys demonstrated a median pre simulation confidence score of 2 and a post-rehearsal score of 4 (P<0.01). The perceived improvement in confidence and performance was greatest when simulation was performed within 3 days of the scheduled case. All residents felt that cadaveric simulation was better than standard preparation methods of self directed reading or discussion with other surgeons. All residents believed that their technique, speed, safety, and anatomical knowledge improved as a result of simulation. CONCLUSIONS: Fresh tissue-based preoperative surgical rehearsal was effectively implemented in the residency program. Resident confidence and perception of technique improved. Survey results suggest that cadaveric simulation is beneficial for all levels of residents. We believe that implementation of preoperative surgical rehearsal is an effective adjunct to surgical training at all skill levels in the current environment of decreased work hours. PMID- 28856140 TI - New insights about the putative role of myokines in the context of cardiac rehabilitation and secondary cardiovascular prevention. AB - Exercise training prevents the onset and the development of many chronic diseases, acting as an effective tool both for primary and for secondary prevention. Various mechanisms that may be the effectors of these beneficial effects have been proposed during the past decades: some of these are well recognized, others less. Muscular myokines, released during and after muscular contraction, have been proposed as key mediators of the systemic effects of the exercise. Nevertheless the availability of an impressive amount of evidence regarding the systemic effects of muscle-derived factors, few studies have examined key issues: (I) if skeletal muscle cells themselves are the main source of cytokine during exercise; (II) if the release of myokines into the systemic circulation reach an adequate concentration to provide significant effects in tissues far from skeletal muscle; (III) what may be the role carried out by muscular cytokine regarding the well-known benefits induced by regular exercise, first of all the anti-inflammatory effect of exercise. Furthermore, a greater part of our knowledge regarding myokines derives from the muscle of healthy subjects. This knowledge may not necessarily be transferred per se to subjects with chronic diseases implicating a direct or indirect muscular dysfunction and/or a chronic state of inflammation with persistent immune-inflammatory activation (and therefore increased circulating levels of some cytokines): cachexia, sarcopenia due to multiple factors, disability caused by neurological damage, chronic congestive heart failure (CHF) or coronary artery disease (CAD). A key point of future studies is to ascertain how is modified the muscular release of myokines in different categories of unhealthy subjects, both at baseline and after rehabilitation. The purpose of this review is to discuss the main findings on the role of myokines as putative mediators of the therapeutic benefits obtained through regular exercise in the context of secondary cardiovascular prevention. PMID- 28856139 TI - Measuring myokines with cardiovascular functions: pre-analytical variables affecting the analytical output. AB - In the last few years, a growing number of molecules have been associated to an endocrine function of the skeletal muscle. Circulating myokine levels, in turn, have been associated with several pathophysiological conditions including the cardiovascular ones. However, data from different studies are often not completely comparable or even discordant. This would be due, at least in part, to the whole set of situations related to the preparation of the patient prior to blood sampling, blood sampling procedure, processing and/or store. This entire process constitutes the pre-analytical phase. The importance of the pre analytical phase is often not considered. However, in routine diagnostics, the 70% of the errors are in this phase. Moreover, errors during the pre-analytical phase are carried over in the analytical phase and affects the final output. In research, for example, when samples are collected over a long time and by different laboratories, a standardized procedure for sample collecting and the correct procedure for sample storage are acknowledged. In this review, we discuss the pre-analytical variables potentially affecting the measurement of myokines with cardiovascular functions. PMID- 28856143 TI - Scientist impact factor (SIF): a new metric for improving scientists' evaluation? AB - BACKGROUND: The publication of scientific research is the mainstay for knowledge dissemination, but is also an essential criterion of scientists' evaluation for recruiting funds and career progression. Although the most widespread approach for evaluating scientists is currently based on the H-index, the total impact factor (IF) and the overall number of citations, these metrics are plagued by some well-known drawbacks. Therefore, with the aim to improve the process of scientists' evaluation, we developed a new and potentially useful indicator of recent scientific output. METHODS: The new metric scientist impact factor (SIF) was calculated as all citations of articles published in the two years following the publication year of the articles, divided by the overall number of articles published in that year. The metrics was then tested by analyzing data of the 40 top scientists of the local University. RESULTS: No correlation was found between SIF and H-index (r=0.15; P=0.367) or 2 years H-index (r=-0.01; P=0.933), whereas the H-index and 2 years H-index values were found to be highly correlated (r=0.57; P<0.001). A highly significant correlation was also observed between the articles published in one year and the total number of citations to these articles in the two following years (r=0.62; P<0.001). CONCLUSIONS: According to our data, the SIF may be a useful measure to complement current metrics for evaluating scientific output. Its use may be especially helpful for young scientists, wherein the SIF reflects the scientific output over the past two years thus increasing their chances to apply to and obtain competitive funding. PMID- 28856144 TI - Obesity is associated with poorer range of motion and Tegner scores following hamstring autograft anterior cruciate ligament reconstruction in Asians. AB - BACKGROUND: Current literature reporting on the impact of BMI on outcomes of orthopaedic surgical procedures is varied and inconsistent. The purpose of our study was to evaluate if body mass index (BMI) affects outcomes of primary anterior cruciate ligament reconstruction (ACLR) in an Asian population. METHODS: We retrospectively reviewed prospectively collected data of 141 consecutive patients who underwent primary ACLR by a single surgeon, the senior author of this study. Flexion range, International Knee Documentation Committee (IKDC) score, KT-1000 translation, Tegner activity level scale, Lysholm score and satisfaction were assessed preoperatively and at 2 years postoperatively. The patients were then stratified into two groups: normal-BMI and high-BMI in accordance with WHO classification. Outcomes were then compared between the two groups. All statistical analysis were performed on IBM SPSS Statistics 20. RESULTS: There were 81 patients in the normal-BMI group (BMI, 18.5 to 24.9) and 60 patients in the high-BMI group (BMI >=25). Preoperatively, the only differences were in the gender proportions as well as the pre-injury Tegner score. 2-years postoperatively, patients in the normal-BMI group had better flexion (139 degrees vs. 130 degrees ; P=0.0001), Tegner scores (5.7 vs. 4.8; P=0.005) and satisfaction rate (99% vs. 90%; P=0.041). There were no differences in graft failure or complication rates. CONCLUSIONS: Obese patients had poorer range of motion and Tegner scores as compared to their nonobese counterparts following primary ACLR. PMID- 28856145 TI - Ablation of long-standing persistent atrial fibrillation. AB - Atrial fibrillation (AF) is the most commonly encountered arrhythmia in the clinical setting affecting nearly 6 million people in United States and the numbers are only expected to rise as the population continues to age. Broadly it is classified into paroxysmal, persistent and longstanding persistent AF. Electrical, structural and autonomic remodeling are some of the diverse pathophysiological mechanisms that contribute to the persistence of AF. Our review article emphasizes particularly on long standing persistent atrial fibrillation (LSPAF) aspect of the disease which poses a great challenge for electrophysiologists. While pulmonary vein isolation (PVI) has been established as a successful ablation strategy for paroxysmal AF, same cannot be said for LSPAF owing to its long duration, complexity of mechanisms, multiple triggers and substrate sites that are responsible for its perpetuation. The article explains different approaches currently being adopted to achieve freedom from atrial arrhythmias. These mainly include ablation techniques chiefly targeting complex fractionated atrial electrograms (CFAE), rotors, linear lesions, scars and even considering hybrid approaches in a few cases while exploring the role of delayed enhancement magnetic resonance imaging (deMRI) in the pre-procedural planning to improve the overall short and long term outcomes of catheter ablation. PMID- 28856146 TI - A critical reappraisal of the treatment modalities of normal appearing thoracic aorta mural thrombi. AB - Mural thrombus in non-atherosclerotic or aneurysmatic thoracic aorta is a relatively uncommon entity. Currently there is no consensus on the appropriate therapeutic algorithm of its management. We aim to present the current knowledge on the treatment of thoracic aorta mural thrombi (TAMT) in minimally atherosclerotic vessels and we hope that the juxtaposed discussions will shed light on the uncharted waters regarding this rare syndrome. The MEDLINE/PubMed database was searched for publications with the medical subject "aortic mural thrombus" and keywords "thoracic", "embolism", "normal vessel", "minimally atherosclerotic vessel" or "treatment". We restricted our search to English language, till January 2017. The electronic literature search yielded 23 reports that were deemed appropriate for further analysis. Anticoagulation is the standard of care for the treatment of the thrombus whereas surgical and interventional treatment seems to be related with increased mortality and lower recurrence rates. TAMT treatment is controversial. Anticoagulants are the mainstay of treatment but surgery seems to gain ground in several settings as an only therapy or a combined treatment modality. More data are needed on the role of novel oral anticoagulants and endografts. PMID- 28856148 TI - Pulmonary tuberculous and tuberculous pericardial tamponade post lung transplant. AB - Pulmonary tuberculosis (TB) associated with tuberculous pericarditis after lung transplantation is a very rare entity. Here we report a unique case of cardiac tamponade due to tuberculous pericarditis, in a patient 4 months after single right lung transplantation, the patient underwent a subxyphoid pericardial window. The pericardial effusion analysis showed exudate effusion with high level of lymphocyte concentration. Both patient and donor didn't have history of TB or TB Exposure. PMID- 28856147 TI - Anti-cardiac troponin antibodies in clinical human disease: a systematic review. AB - Anti-cardiac troponin antibodies have been studied in different types of clinical diseases and in healthy populations. A systematic review of published data on anti-troponin antibodies was carried out (search performed on PubMed, ISI Web of Knowledge and Scopus databases). From title and abstract analysis, thirty-three articles were included that met the pre-specified criteria; after full-text analysis, nine articles were excluded. Most studies assessed anti-troponin I antibodies. The prevalence of anti-cardiac troponin antibodies in healthy individuals ranged from 0.0% to 20.0%. The prevalence of anti-troponin I autoantibodies in dilated cardiomyopathy (DCM) ranged from 7.0% to 22.2%. Other conditions under study were myocardial infarction, ischemic cardiomyopathy (ICM), peripartum cardiomyopathy (PPCM), Chagas disease, Emery-Dreifuss muscular dystrophy (EDMD) and renal transplantation. In the different patient populations studied, anti-cardiac troponin antibodies have been shown to be either positively or negatively associated with prognostic and clinical features. In what concerns a possible value as biomarkers, these assays have not emerged up to the present moment as important aids for practical clinical decisions in cardiac or other types of patients. In what concerns pathophysiology, anti-cardiac troponin autoantibodies may play a role in different diseases. It can be speculated that these antibodies could be involved in perpetuating some degree of cardiac injury after an event, such as myocardial infarction or PPCM. PMID- 28856149 TI - Is idiopathic granulomatous mastitis a surgical disease? The jury is still out. AB - Idiopathic granulomatous mastitis (IGM), is a rare entity of chronic inflammatory disorder of the breast of unknown etiology. Very few cases have been described so far, almost exclusively in women. Here we describe a case of IGM in a 53-year-old man presented with a right breast mass, progressively enlarging during the last 6 months. Due to the findings of clinical examination and CT-scan, the suspicion for a potentially malignant lesion was given and the decision for surgical resection was made. Microscopic analysis of the specimen showed non-caseating granulomas around mammary lobules, findings compatible with IGM. The patient is recurrence-free at 18-month follow-up. IGM is a rare benign inflammatory breast disease, usually seen in females of reproductive age. Establishing a diagnosis can be challenging for a surgeon and requires a high index of suspicion as most patients are initially misdiagnosed by their primary care physicians. Steroids and immunosuppressive drugs are considered as fundamental treatment modalities but they are correlated with increased rates of disease response and recurrence. On the contrary, surgical resection demonstrated significantly superior results compared to steroid-alone treatment in terms of recurrence and post-treatment recovery. PMID- 28856150 TI - Hypertension and left ventricular hypertrophy. PMID- 28856151 TI - Searching for the perfect lymphadenectomy. PMID- 28856152 TI - Positron emission tomography imaging in diffuse intrinsic pontine glioma. PMID- 28856153 TI - Classification criteria in Sjogren's syndrome. PMID- 28856154 TI - Lessons from the arterial revascularization trial. PMID- 28856155 TI - A sweet decision: treatment of stable coronary artery disease in patients with diabetes mellitus. PMID- 28856156 TI - Refugee crisis in Greece: The National and Kapodistrian University of Athens paves the way to meet the challenge. PMID- 28856157 TI - Refugee crisis in Greece: the forthcoming higher education challenge. PMID- 28856158 TI - Erratum to non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype. AB - [This corrects the article DOI: 10.21037/atm.2017.03.04.]. PMID- 28856159 TI - Expression, Docking, and Molecular Dynamics of Endo-beta-1,4-xylanase I Gene of Trichoderma virens in Pichia stipitis. AB - It is essential that major carbohydrate polymers in the lignocellulosic biomass are converted into fermentable sugars for the economical production of energy. Xylan, the major component of hemicelluloses, is the second most naturally abundant carbohydrate polymer comprising 20-40% of the total biomass. Endoxylanase (EXN) hydrolyzes xylan into mixtures of xylooligosaccharides. The objective of this study was to genetically modify Pichia stipitis, a pentose sugar fermenting yeast species, to hydrolyze xylan into xylooligosaccharides via cloning and heterologous extracellular expression of EXNI gene from locally isolated Trichoderma virens species. Pichia stipitis was engineered to carry the EXNI gene of T. virens using pGAPZalpha expression vector. The open reading frame encodes 191 amino acids and SDS-PAGE analysis revealed a 24 kDA recombinant protein. The EXNI activity expressed by recombinant P. stipitis clone under standard conditions using 1% beechwood xylan was 31.7 U/ml. Molecular docking and molecular dynamics simulations were performed to investigate EXNI-xylan interactions. Free EXNI and xylan bound EXNI exhibited similar stabilities and structural behavior in aqueous medium. Furthermore, this in silico work opens avenues for the development of newer generation EXN proteins that can perform better and have enhanced catalytic activity. PMID- 28856160 TI - Mortality and Cardiovascular Complications in Older Complex Chronic Patients with Type 2 Diabetes. AB - AIMS/INTRODUCTION: Determining the prevalence of diabetes and its cardiovascular complications and all-cause mortality in older chronic complex patients. MATERIALS AND METHODS: We carried out a multicenter retrospective study and included a randomized sample of 932 CCP people. We assessed the prevalence of diabetes according to World Health Organization criteria. Data included demographics and functional, comorbidity, cognitive, and social assessment. RESULTS: The prevalence of diabetes was 53% and average age 81.16 +/- 8.93 years. There were no significant differences in the survival of CCP patients with or without DM, with or without ischaemic cardiopathy, and with or without peripheral vascular disease. The prognostic factors of all-cause mortality in patients with DM were age >= 80 years [HR 1.47, 95% CI 1.02-2.13, p 0.038], presence of heart failure [HR 1.73, 95% CI 1.25-2.38, p 0.001], Charlson score [HR 1.20, 95% CI 1.06-1.36, p 0.003], presence of cognitive impairment [HR 1.73, 95% CI 1.24 2.40, p 0.001], and no treatment with statins [HR 1.49, 95% CI 1.08-2.04, p 0.038]. CONCLUSIONS: We found high prevalence of DM among CCP patients and the relative importance of traditional risk factors seemed to wane with advancing age. Recommendations may include relaxing treatment goals, providing family/patient education, and enhanced communication strategies. PMID- 28856161 TI - The Protective Effects of Fasciotomy on Reperfusion Injury of Skeletal Muscle of Rabbits. AB - The authors aim to investigate protective effects of fasciotomy against ischemia reperfusion injury of skeletal muscle in rabbit and to compare the treatment effects of prereperfusion + fasciotomy and fasciotomy + postreperfusion against ischemia reperfusion injury of skeletal muscle. 24 healthy male Japanese white rabbits were randomly divided into 3 groups, and 4 hours' ischemia was established in these rabbits through surgery. Six hours' reperfusion was performed in group A; reperfusion + postfasciotomy was performed in group B; and prefasciotomy + reperfusion was performed in group C. Result showed that prefasciotomy and postfasciotomy could protect skeletal muscle against ischemia reperfusion injury, reduced MDA (malondialdehyde) expression, MPO (myeloperoxidase) expression, and apoptosis of muscle in the reperfused areas, increased Bcl-2 expression, and decreased Bax expression. The MDA and MPO levels in group B and group C were significantly lower than those in group A, and MDA and MPO levels in group C were significantly lower than those in group B. Prefasciotomy and postfasciotomy could protect against ischemia reperfusion injury in skeletal muscle. The protective effects of prefasciotomy against ischemia reperfusion injury are better than postfasciotomy. PMID- 28856162 TI - Hydrogen-Rich Syngas Production from Gasification and Pyrolysis of Solar Dried Sewage Sludge: Experimental and Modeling Investigations. AB - Solar dried sewage sludge (SS) conversion by pyrolysis and gasification processes has been performed, separately, using two laboratory-scale reactors, a fixed-bed pyrolyzer and a downdraft gasifier, to produce mainly hydrogen-rich syngas. Prior to SS conversion, solar drying has been conducted in order to reduce moisture content (up to 10%). SS characterization reveals that these biosolids could be appropriate materials for gaseous products production. The released gases from SS pyrolysis and gasification present relatively high heating values (up to 9.96 MJ/kg for pyrolysis and 8.02 9.96 MJ/kg for gasification) due to their high contents of H2 (up to 11 and 7 wt%, resp.) and CH4 (up to 17 and 5 wt%, resp.). The yields of combustible gases (H2 and CH4) show further increase with pyrolysis. Stoichiometric models of both pyrolysis and gasification reactions were determined based on the global biomass formula, CalphaHbetaOgammaNdeltaSepsilon, in order to assist in the products yields optimization. PMID- 28856163 TI - The effect of maternal role training program on role attainment and maternal role satisfaction in nulliparous women with unplanned pregnancy. AB - INTRODUCTION: The maternal role is one of the most basic and important roles played by women during their lifetime. The process of the maternal role starts during pregnancy and to continue and develop after postpartum with the growth of suckling. However, unplanned pregnancy may jeopardize achieving the maternal role and reduce maternal role satisfaction. Therefore, the researcher conducted the present study to determine the impact of maternal role training program on attainment of role and role satisfaction in nulliparous women with unplanned pregnancy. METHODOLOGY OF THE RESEARCH: In this clinical trial, the researcher divided 67 nulliparous women with unplanned pregnancies into two groups at random by drawing lots. For the intervention group, in addition to the usual pregnancy care, the researcher conducted 3 group training sessions at weeks 34, 35, and 36 of pregnancy and an individual training session in the 1st day after delivery before release; then, during the next 4 weeks, the researcher made follow-up phone calls each week. The control group received the usual pregnancy care. The research tools included London questionnaire to measure unplanned pregnancy, Myself-As-Mother Scale (SD-Self), My-Baby Scale (SD-Baby), Perceived Competence Scale to measure maternal role attainment, and Parenting Sense of Competence Scale to measure maternal role satisfaction. The researcher measured the maternal role attainment and maternal role satisfaction before training and 4 weeks after delivery. The researcher analyzed the data using SPSS software version 21 and statistical tests such as independent t-test, Chi-square, paired sample t-test, Mann-Whitney, one-way analysis of variance, and Wilcoxon. The amount of P was supposed to be <0.05. RESULTS: The mean age of research units was 24.10 +/- 4.3. Twenty-one persons (60%) in the intervention group and ten persons (31.3%) in the control group attained the maternal role (P = 0.019) and changes to achieve the maternal role in intervention group were significantly more than the control group (P = 0.002). Changes in the mean scores of maternal role satisfaction in the intervention group were significantly more than the control group (P = 0.023). CONCLUSION: Maternal role training for nulliparous women with unplanned pregnancy during pregnancy and postpartum period can help them in maternal role attainment and maternal role satisfaction. PMID- 28856164 TI - The relationship between clinical parameters and lifestyle variables among patients with severity of coronary artery stenosis: A cross-sectional analysis based on the severity of coronary artery stenosis. AB - INTRODUCTION: Cardiovascular diseases are the leading cause of death all over the world. Lifestyle can have an important role not only in reducing risk factors but also in the prevention and treatment of coronary heart diseases. The aim of this study was to examine the relationship between clinical parameters and various aspects of patients' lifestyles according to the severity of their coronary artery stenosis. MATERIALS AND METHODS: This study was a descriptive, analytic study carried out on 220 patients undergoing coronary angiography at Mazandaran Heart Center. Based on the angiography results, patients were divided into two groups: artery stenosis > 50% (110 cases) and < 50% (110). Patients' lifestyles were evaluated using health-promoting behavior questionnaire. Blood pressure and triglyceride, low-density lipoprotein, high-density lipoprotein, cholesterol, and fasting blood sugar were also measured. After collecting data, SPSS 21 software, Chi-square test, t-test, and multiple linear regression were used for analysis of the data. RESULTS: The results showed that in patients with positive angiographic data, there is a significant correlation between clinical parameters and dimensions of health-promoting behavior (P < 0.05). CONCLUSION: Given the impact of clinical parameters on various aspects of lifestyle, it seems that by teaching the different aspects of lifestyle (such as having a healthy diet consisting of fresh fruits and vegetables, reducing intake of saturated fat, physical activity and regular exercise, stress management, and blood pressure control) to patients with a positive angiographic result, we can improve their lifestyles by means of improving clinical parameters. PMID- 28856165 TI - Effect of yoga training on inflammatory cytokines and C-reactive protein in employees of small-scale industries. AB - OBJECTIVE: The present study intends to see the effect of yoga practices on lipid profile, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and high sensitivity-C-reactive protein (hs-CRP) among apparently healthy adults exposed to occupational hazards. MATERIALS AND METHODS: In the present study, 48 participants aged 30-58 years (41.5 +/- 5.2) who were exposed to occupational hazards were randomized into two groups, that is, experimental and wait-list control. All the participants were assessed for lipid profile, IL-6, TNF-alpha, and hs-CRP at the baseline and after completion of 3 months of yoga training intervention. The experimental group underwent yoga training intervention for 1 h for 6 days a week for 3 months, whereas control group continued with their daily activities except yoga training. Data analysis was done using statistical software SPSS Version 20.0. Data were analyzed using paired t-tests and independent t-test. RESULTS: The results of within group comparison revealed highly significant changes in cholesterol (P < 0.001), high-density lipoprotein (P < 0.001), low-density lipoprotein (LDL)(P < 0.01), hs-CRP (P < 0.01), IL-6 (P < 0.001), and TNF-alpha (P < 0.001) in experimental group. Comparison between experimental and control group revealed significant changes in cholesterol (P < 0.01), LDL (P < 0.05), IL-6 (P < 0.01), TNF-alpha (P < 0.01), and hs-CRP (P < 0.01). CONCLUSION: A yoga-based lifestyle intervention seems to be a highly promising alternative therapy which favorably alters inflammatory markers and metabolic risk factors. PMID- 28856166 TI - Ketoacidosis With Canagliflozin Prescribed for Phosphoinositide 3-Kinase Inhibitor-Induced Hyperglycemia: A Case Report. AB - Context. Many phosphoinositide-3-kinase (PI3K) inhibitors are under trial for cancer treatment. We present a patient taking taselisib who developed ketoacidosis within 1 week of starting canagliflozin. Case Description. A 69-year old female patient with no previous history of diabetes mellitus was enrolled in a clinical trial for taselisib therapy in stage IV breast cancer. Hyperglycemia treatment with metformin was insufficient and not tolerated. The addition of canagliflozin daily resulted in ketoacidosis and hospitalization within 1 week. Conclusions. This case report brings together 2 poorly understood and relatively understudied disorders of glucose homeostasis: hyperglycemia due to PI3K inhibition and euglycemic ketoacidosis due to dehydration/SGLT2 inhibition. It demonstrates the complexities of glucose management in the setting of PI3K inhibition. PI3K stimulation (via insulin) in this setting is counterintuitive; therefore, non-insulin-mediated therapies (eg, metformin, thiazolidinediones) might be favored over insulin-mediated therapies. PMID- 28856167 TI - Expressions of Orphan Nuclear Receptor TR3/Nur77 in Chronic Hepatopathy and Its Clinical Significance. AB - OBJECTIVE: Although great success has been achieved in cancer treatment, current cancer therapies, including anti-tumorigenesis and anti-angiogenesis, still face the problems of insufficient efficacy, resistance and intrinsic refractoriness, in addition to their toxic side effects. There is a demand to identify additional targets that can be blocked to turn off the downstream effects of most, if not all, pathways. Our studies suggest that orphan nuclear receptor TR3 (human)/Nur77 (mouse) is such a target. Most recently, we reported that TR3/Nur77 expression in human hepatic cancer tissues correlates well with tumor progress, suggesting that TR3 is a specific therapeutic target for hepatic cancers. However, the correlation of TR3/Nur77 expression in hepatocellular carcinoma (HCC) with chronic hepatitis has not been studied. METHODS: The expression of TR3/Nur77 was analyzed in human primary hepatic cancer specimens from patients that have complete medical records with Immunohistochemically staining. The statistical analysis was used to access the significance of TR3 expression in tumor tissues, cirrhosis tissues and chronic hepatitis tissues with and without hepatitis B virus infection (HBV(+) and HBV(-)), which were obtained from para-tumor tissues. RESULTS: The positive rates of TR3/Nur77 expression in hepatocellular carcinoma, cancerous liver cirrhosis and chronic hepatitis are 66.67%, 30%, and 20%, respectively, which are statistic significant (p<0.05). The positive rates of TR3/Nur77 expression in hepatocellular carcinoma are statistic significant (p<0.05) with 81.25% and 20% in HBV (+) or HBV (-), respectively. CONCLUSION: The positive expression rate of TR3/Nur77 in hepatocellular carcinoma is higher than that in chronic hepatitis and cirrhosis. The positive rate of TR3/Nur77 expression in hepatocellular carcinoma is higher with HBV infection than that without infection. Our results suggest that TR3/Nur77 plays an important role in the progression of chronic hepatitis, and the occurrence and development of HCC. PMID- 28856168 TI - Functional Outcomes of Achilles Tendon Minimally Invasive Repair Using 4- and 6 Strand Nonabsorbable Suture: A Cohort Comparison Study. AB - BACKGROUND: The aim of management of Achilles tendon rupture is to reduce tendon lengthening and maximize function while reducing the rerupture rate and minimizing other complications. PURPOSE: To determine changes in Achilles tendon resting angle (ATRA), heel-rise height, patient-reported outcomes, return to play, and occurrence of complications after minimally invasive repair of Achilles tendon ruptures using nonabsorbable sutures. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between March 2013 and August 2015, a total of 70 patients (58 males, 12 females) with a mean age of 42 +/- 8 years were included and evaluated at 6 weeks and 3, 6, 9, and 12 months after repair of an Achilles tendon rupture. Surgical repair was performed using either 4-strand or 6-strand nonabsorbable sutures. After surgery, patients were mobilized, fully weightbearing using a functional brace. Early active movement was permitted starting at 2 weeks. RESULTS: There were no significant differences in the ATRA, Achilles Tendon Total Rupture Score (ATRS), and Heel-Rise Height Index (HRHI) between the 4- and 6-strand repairs. The mean (SD) relative ATRA was -13.1 degrees (6.6 degrees ) (dorsiflexion) following injury; this was reduced to 7.6 degrees (4.8 degrees ) (plantar flexion) directly after surgery. During initial rehabilitation at 6 weeks, the relative ATRA was 0.6 degrees (7.4 degrees ) (neutral) and -7.0 degrees (5.3 degrees ) (dorsiflexion) at 3 months, after which ATRA improved significantly with time to 12 months (P = .005). At 12 months, the median ATRS was 93 (range, 35-100), and the mean (SD) HRHI and Heel Rise Repetition Index were 81% (0.22%) and 82.9% (0.17%), respectively. The relative ATRA at 3 and 12 months correlated with HRHI (r = 0.617, P < .001 and r = 0.535, P < .001, respectively). CONCLUSION: Increasing the number of suture strands from 4 to 6 does not alter the ATRA or HRHI after minimally invasive Achilles tendon repair. The use of a nonabsorbable suture during minimally invasive repair when used together with accelerated rehabilitation did not prevent the development of an increased relative ATRA. The ATRA at 3 months after surgery correlated with heel-rise height at 12 months. PMID- 28856169 TI - Do Medical Comorbidities Affect Outcomes in Patients With Rotator Cuff Tears? AB - BACKGROUND: The effects of medical comorbidities on clinical outcomes in patients with rotator cuff tears (RCTs) have not been fully elucidated. This study investigates the association between medical comorbidities, as measured by the Functional Comorbidity Index (FCI), and clinical outcomes in patients treated surgically or nonsurgically for symptomatic, full-thickness RCTs. HYPOTHESIS: Patients with RCTs who have more comorbidities will have worse outcome scores. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: We collected the following outcome measures at baseline and at regular intervals up to 64 weeks in all patients: FCI, the Western Ontario Rotator Cuff Index (WORC), and the American Shoulder and Elbow Surgeons (ASES) score. Changes in outcomes were compared separately for surgical and nonsurgical patients using paired t tests. The relationship of the FCI and all outcomes of interest at baseline, at 64-week follow-up, and for changes from baseline was explored using linear regression modeling. RESULTS: Of the 222 study patients (133 males; mean age, 60.0 +/- 9.6 years), 140 completed the 64-week WORC and 120 completed the 64-week ASES. Overall, 128 patients underwent RCT repair, and 94 patients were treated nonsurgically. Both treatment groups improved compared with baseline at 64 weeks on the ASES score and WORC. At 64 weeks, patients with higher baseline FCI scores had worse WORC score (by 74.5 points; P = .025) and ASES score (by 3.8 points; P < .01). A higher FCI score showed a trend toward predicting changes in the WORC and ASES scores at 64 weeks compared with baseline, but this did not reach statistical significance (WORC change, P = .15; ASES change, P = .07). CONCLUSION: Patients with higher FCI scores at baseline reported worse baseline functional scores and demonstrated less improvement with time. The magnitude of this change may not be clinically significant for single comorbidities. PMID- 28856170 TI - Factors Influencing Patient Selection of an Orthopaedic Sports Medicine Physician. AB - BACKGROUND: The rise in consumer-centric health insurance plans has increased the importance of the patient in choosing a provider. There is a paucity of studies that examine how patients select an orthopaedic sports medicine physician. PURPOSE: To evaluate factors that patients consider when choosing an orthopaedic sports medicine physician. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 1077 patients who sought treatment by 3 sports medicine physicians were administered an anonymous questionnaire. The questionnaire included 19 questions asking respondents to rate the importance of specific factors regarding the selection of orthopaedic sports medicine physicians on a scale of 1 (not important at all) to 10 (very important). The remaining 6 questions were multiple-choice and regarded the following criteria: preferred physician age, appointment availability, clinic waiting room times, travel distance, and medical student/resident involvement. RESULTS: Of the 1077 consecutive patients administered the survey, 382 (35%) responded. Of these, 59% (n = 224) were male, and 41% (n = 158) were female. In ranking the 19 criteria in terms of importance, patients rated board certification (9.12 +/- 1.88), being well known for a specific area of expertise (8.27 +/- 2.39), and in-network provider status (8.13 +/- 2.94) as the 3 most important factors in selecting an orthopaedic sports medicine physician. Radio, television, and Internet advertisements were rated the least important. Regarding physician age, 63% of patients would consider seeking a physician who is <=65 years old. Approximately 78% of patients would consider seeking a different physician if no appointments were available within 4 weeks. CONCLUSION: The study results suggest that board certification, being well known for a specific area of expertise, and health insurance in-network providers may be the most important factors influencing patient selection of an orthopaedic sports medicine physician. Advertisements were least important to patients. Patient preferences varied regarding ideal physician age, clinic appointment availability, medical student/resident involvement, and travel distance in choosing an orthopaedic sports medicine physician. In the context of health care delivery and as reimbursement becomes increasingly consumer centered, understanding the process of provider selection is important. PMID- 28856171 TI - Genetic Factors in Tendon Injury: A Systematic Review of the Literature. AB - BACKGROUND: Tendon injury such as tendinopathy or rupture is common and has multiple etiologies, including both intrinsic and extrinsic factors. The genetic influence on susceptibility to tendon injury is not well understood. PURPOSE: To analyze the published literature regarding genetic factors associated with tendon injury. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: A systematic review of published literature was performed in concordance with the Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) guidelines to identify current evidence for genetic predisposition to tendon injury. PubMed, Ovid, and ScienceDirect databases were searched. Studies were included for review if they specifically addressed genetic factors and tendon injuries in humans. Reviews, animal studies, or studies evaluating the influence of posttranscription factors and modifications (eg, proteins) were excluded. RESULTS: Overall, 460 studies were available for initial review. After application of inclusion and exclusion criteria, 11 articles were ultimately included for qualitative synthesis. Upon screening of references of these 11 articles, an additional 15 studies were included in the final review, for a total of 26 studies. The genetic factors with the strongest evidence of association with tendon injury were those involving type V collagen A1, tenascin-C, matrix metalloproteinase-3, and estrogen-related receptor beta. CONCLUSION: The published literature is limited to relatively homogenous populations, with only level 3 and level 4 data. Additional research is needed to make further conclusions about the genetic factors involved in tendon injury. PMID- 28856172 TI - Implementing a Multidisciplinary Approach to Treating Tuberous Sclerosis Complex: A Case Report. AB - OBJECTIVE: Tuberous sclerosis complex is expressed throughout the body, resulting in a range of clinical manifestations that can be challenging to manage. RESULTS: The authors report a patient who presented at age 3.5 years with several suspected seizures and was diagnosed with tuberous sclerosis complex following the discovery of numerous bilateral cortical tubers and subependymal nodules on magnetic resonance imaging. Interdisciplinary, comprehensive care was recommended; this included ongoing surveillance to monitor for the development of tuberous sclerosis complex-associated conditions. Approximately 2 years later, the patient began exhibiting aggressive and self-injurious behavior, and a subependymal giant cell astrocytoma was discovered. After everolimus was initiated, he demonstrated less aggression, had ceased self-injurious behavior, and subependymal giant cell astrocytoma growth stabilized. CONCLUSIONS: This case highlights the importance of a multidisciplinary approach to care in tuberous sclerosis complex, which ensures the early detection and appropriate treatment of clinical manifestations that may arise during the course of the patient's life. PMID- 28856173 TI - A Case of Brown-Vialetto-Van Laere Syndrome Due To a Novel Mutation in SLC52A3 Gene: Clinical Course and Response to Riboflavin. AB - Brown-Vialetto-Van Laere syndrome is a rare disorder characterized by motor, sensory, and cranial neuronopathies, associated with mutations in SLC52A2 and SLC52A3 genes that code for human riboflavin transporters RFVT2 and RFVT3, respectively. The authors describe the clinical course of a 6-year-old girl with Brown-Vialetto-Van Laere syndrome and a novel homozygous mutation c.1156T>C in the SLC52A3 gene, who presented at the age of 2.5 years with progressive brain stem dysfunction including ptosis, facial weakness, hearing loss, dysphagia, anarthria with bilateral vocal cord paralysis, and ataxic gait. She subsequently developed respiratory failure requiring tracheostomy and worsening dysphagia necessitating a gastrostomy. Following riboflavin supplementation, resolution of facial diplegia and ataxia, improvements in ptosis, and bulbar function including vocalization and respiration were noted. However, her sensorineural hearing loss remained unchanged. Similar to other cases of Brown-Vialetto-Van Laere syndrome, our patient responded favorably to early riboflavin supplementation with significant but not complete neurologic recovery. PMID- 28856174 TI - A Rare Syndrome of GRID2 Deletion in 2 Siblings. AB - The Glutamate receptor, ionotropic, delta 2 gene codes for an ionotropic glutamate delta-2 receptor, which is selectively expressed in cerebellar Purkinje cells, and facilitates cerebellar synapse organization and transmission. The phenotype associated with the deletion of Glutamate receptor, ionotropic, delta 2 gene in humans was initially defined in 2013. In this case report, the authors describe 2 brothers who presented with developmental delay, tonic upward gaze, nystagmus, oculomotor apraxia, hypotonia, hyperreflexia, and ataxia. They were found to have a homozygous intragenic deletion within the Glutamate receptor, ionotropic, delta 2 gene at exon 2. Our patients serve as an addition to the literature of previously reported children with this rare clinical syndrome associated with Glutamate receptor, ionotropic, delta 2 deletion. PMID- 28856175 TI - The Effects of Extended-Access Cocaine Self-Administration on Working Memory Performance, Reversal Learning and Incubation of Cocaine-Seeking in Adult Male Rats. AB - Cocaine use disorder is characterized not only by the high rate of relapse, but also by deficits in cognition and prefrontal cortical function. Still, the relationship between cognitive impairment and cocaine-seeking remains poorly understood. The current study used a rodent model to determine the effects of extended access cocaine self-administration on cognitive performance in a prefrontal cortex-dependent delayed match-to-sample/non-match-to-sample (DMS/DNMS) task. Further, this study sought to investigate how post-cocaine changes in cognitive performance correlate with cue/context-induced cocaine seeking following a prolonged period of abstinence. Animals were trained to self administer cocaine during 6 daily 1 hour-long sessions followed by 12 days of extended, 6 hour-long access. The extended access cocaine rats exhibited robust self-administration behavior and escalation of cocaine intake. Next, DMS/DNMS task was used to evaluate working memory capacity and reversal learning performance over a range of 0 - 30 s delays. Although this study failed to detect a major cognitive impairment, extended access to cocaine resulted in the persistent working memory/DMS deficit at a moderate cognitive load (10 s delay). There were no changes in the reversal learning/DNMS performance. It is likely that the parameters of the DMS/DNMS task, as used in the current study, exceeded acquisition capacity of rats thus obscuring cocaine effects at longer delays. Finally, rats showed a robust relapse of context/cue-elicited cocaine-seeking following the 45 - day abstinence. However, the intensity of cocaine-seeking did not correlate with the deficit in the DMS task. In conclusion, future studies must re-evaluate whether a more robust relationship between post-cocaine cognitive performance and cocaine-seeking can be detected under adjusted DMS/DNMS conditions. PMID- 28856176 TI - alpha4-integrin receptor desaturation and disease activity return after natalizumab cessation. AB - OBJECTIVE: To describe the time course of alpha4-integrin receptor desaturation and disease activity return in patients with relapsing-remitting MS who discontinued natalizumab and to investigate baseline and on-study predictors for the recurrence of disease activity. METHODS: In the course of TOFINGO, a 32-week, patient- and rater-blinded multicenter, parallel-group study, we performed MRI, counted relapses, and measured alpha4-integrin receptor occupancy (RO) at baseline and 8, 12, 16, 20, and 24 weeks. The relationship between RO and total number of new T1 gadolinium-enhancing (Gd+) lesions was modeled using Poisson linear regression. RESULTS: Patients (N = 142) were randomized (1:1:1) to 8-, 12 , or 16-week washout (WO) groups. At randomization, the median RO in the 8-, 12-, and 16-week WO groups was 94.5%, 92.4%, and 90.9%, which declined to 79.8%, 30.7%, and 8.7% after 8, 12, and 16 weeks of WO, respectively. The percentage of patients with new T1 Gd+ lesions increased with longer WO period before commencing fingolimod: 2.1% (8 weeks), 9.1% (12 weeks), and 50.0% (16 weeks). Overall, 71% of patients with first relapse between weeks 6 and 18 had RO values below the time-matched population median. Higher T2 lesion volume (LV) at baseline predicted a higher number of new T1 Gd+ lesions. CONCLUSIONS: A faster decline in natalizumab RO, longer WO period, and higher T2 LV at baseline were associated with an increased risk for return of inflammatory disease activity. These results provide a mechanistic rationale and, together with the main outcomes of the TOFINGO study, support initiation of fingolimod within 8 weeks of natalizumab discontinuation. CLINICALTRIALSGOV IDENTIFIER: NCT01499667. PMID- 28856177 TI - Intravoxel incoherent motion (IVIM) histogram biomarkers for prediction of neoadjuvant treatment response in breast cancer patients. AB - OBJECTIVE: To examine the prognostic capabilities of intravoxel incoherent motion (IVIM) metrics and their ability to predict response to neoadjuvant treatment (NAT). Additionally, to observe changes in IVIM metrics between pre- and post treatment MRI. METHODS: This IRB-approved, HIPAA-compliant retrospective study observed 31 breast cancer patients (32 lesions). Patients underwent standard bilateral breast MRI along with diffusion-weighted imaging before and after NAT. Six patients underwent an additional IVIM-MRI scan 12-14 weeks after initial scan and 2 cycles of treatment. In addition to apparent diffusion coefficients (ADC) from monoexponential decay, IVIM mean values (tissue diffusivity Dt, perfusion fraction fp, and pseudodiffusivity Dp) and histogram metrics were derived using a biexponential model. An additional filter identified voxels of highly vascular tumor tissue (VTT), excluding necrotic or normal tissue. Clinical data include histology of biopsy and clinical response to treatment through RECIST assessment. Comparisons of treatment response were made using Wilcoxon rank-sum tests. RESULTS: Average, kurtosis, and skewness of pseudodiffusion Dp significantly differentiated RECIST responders from nonresponders. ADC and Dt values generally increased (~70%) and VTT% values generally decreased (~20%) post-treatment. CONCLUSION: Dp metrics showed prognostic capabilities; slow and heterogeneous pseudodiffusion offer poor prognosis. Baseline ADC/Dt parameters were not significant predictors of response. This work suggests that IVIM mean values and heterogeneity metrics may have prognostic value in the setting of breast cancer NAT. PMID- 28856179 TI - Gene expression profile data for mouse facial development. AB - This article contains data related to the research articles "Spatial and Temporal Analysis of Gene Expression during Growth and Fusion of the Mouse Facial Prominences" (Feng et al., 2009) [1] and "Systems Biology of facial development: contributions of ectoderm and mesenchyme" (Hooper et al., 2017 In press) [2]. Embryonic mammalian craniofacial development is a complex process involving the growth, morphogenesis, and fusion of distinct facial prominences into a functional whole. Aberrant gene regulation during this process can lead to severe craniofacial birth defects, including orofacial clefting. As a means to understand the genes involved in facial development, we had previously dissected the embryonic mouse face into distinct prominences: the mandibular, maxillary or nasal between E10.5 and E12.5. The prominences were then processed intact, or separated into ectoderm and mesenchyme layers, prior analysis of RNA expression using microarrays (Feng et al., 2009, Hooper et al., 2017 in press) [1], [2]. Here, individual gene expression profiles have been built from these datasets that illustrate the timing of gene expression in whole prominences or in the separated tissue layers. The data profiles are presented as an indexed and clickable list of the genes each linked to a graphical image of that gene's expression profile in the ectoderm, mesenchyme, or intact prominence. These data files will enable investigators to obtain a rapid assessment of the relative expression level of any gene on the array with respect to time, tissue, prominence, and expression trajectory. PMID- 28856178 TI - Histone deacetylases and their roles in mineralized tissue regeneration. AB - Histone acetylation is an important epigenetic mechanism that controls expression of certain genes. It includes non-sequence-based changes of chromosomal regional structure that can alter the expression of genes. Acetylation of histones is controlled by the activity of two groups of enzymes: the histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs remove acetyl groups from the histone tail, which alters its charge and thus promotes compaction of DNA in the nucleosome. HDACs render the chromatin structure into a more compact form of heterochromatin, which makes the genes inaccessible for transcription. By altering the transcriptional activity of bone-associated genes, HDACs control both osteogenesis and osteoclastogenesis. This review presents an overview of the function of HDACs in the modulation of bone formation. Special attention is paid to the use of HDAC inhibitors in mineralized tissue regeneration from cells of dental origin. PMID- 28856180 TI - Dynamic Mechanical Thermal Analysis Data of Sheets Made from Wood-Based Cellulose Fibers Partially Converted to Dialcohol Cellulose. AB - This data article contains the dynamic mechanical thermal analysis (DMTA) results for sheets made from cellulose fibers partially converted to dialcohol cellulose as presented in "Advanced Three-Dimensional Paper Structures: Mechanical Characterization and Forming of Sheets Made from Modified Cellulose Fibers" by Linvill et al. [1]. See Larsson and Wagberg [2] for a description and characterization of the material as well as how the material is produced. The DMTA tests were conducted at four different relative humidity levels: 0, 50, 60, and 70% RH, and the temperature was swept between 10 and 113 degrees C. The DMTA results enable the understanding of the elastic, viscoelastic, and viscoplastic mechanical properties of this material at a wide range of temperature and relative humidity combinations. PMID- 28856181 TI - Data characterizing the genomic structure of the T cell receptor (TRB) locus in Camelus dromedarius. AB - These data are presented in support of structural and evolutionary analysis of the published article entitled "The occurrence of three D-J-C clusters within the dromedary TRB locus highlights a shared evolution in Tylopoda, Ruminantia and Suina" (Antonacci et al., 2017) [1]. Here we describe the genomic structure and the gene content of the T cell receptor beta chain (TRB) locus in Camelus dromedarius. As in the other species of mammals, the general genomic organization of the dromedary TRB locus consists of a pool of TRBV genes located upstream of in tandem TRBD-J-C clusters, followed by a TRBV gene with an inverted transcriptional orientation. A peculiarity of the dromedary TRB locus structure is the presence of three TRBD-J-C clusters, which is a common feature of sheep, cattle and pig sequences. PMID- 28856182 TI - Data set on the effects of conifer control and slash burning on soil carbon, total N, organic matter and extractable micro-nutrients. AB - Conifer control in sagebrush steppe of the western United States causes various levels of site disturbance influencing vegetation recovery and resource availability. The data set presented in this article include growing season availability of soil micronutrients and levels of total soil carbon, organic matter, and N spanning a six year period following western juniper (Juniperus occidentalis spp. occidentalis) reduction by mechanical cutting and prescribed fire of western juniper woodlands in southeast Oregon. These data can be useful to further evaluate the impacts of conifer woodland reduction to soil resources in sagebrush steppe plant communities. PMID- 28856183 TI - Dataset on antitumor properties of silver nanoparticles from Gloriosa superba (L.) seed on Dalton Lymphoma Ascites (DLA) tumor: Facile and biocompatible approach. AB - The dataset depicted in this article related to our earlier article entitled "Phytofabrication and encapsulated of silver nanoparticles from Gloriosa Superba" (Saradha Devi et al., 2017) [1], which reports the characteristic features (UV Visible spectra, FTIR, SEM, TEM, DLS, Zeta potential and XRD analysis) of the Gloriosa superba biosynthesised silver nanoparticles (AgNPs). In this context, the present dataset was provided to identify the antioxidant, antitumor and apoptotic (in DLA cells) properties with the synthesized AgNPs. The result enlightens the AgNPs exhibits antitumor, apoptotic activity in DLA cells and antioxidant properties. The results of the in vivo experiments increased life span of liver cells in DLA induced tumour mice and not showed any histopathological variations between control and DLA induced mice animals. The HPTLC examination of the Gloriosa superba (L.) seed extract infers the presence of colchicines derivatives as a major alkaloid sources. PMID- 28856184 TI - Data on the detail information of influence of substrate temperature on the film morphology and photovoltaic performance of non-fullerene organic solar cells. AB - This data contains additional data related to the article "Influence of Substrate Temperature on the Film Morphology and Photovoltaic Performance of Non-fullerene Organic Solar Cells" (Jicheng Zhang et al., In press) [1]. Data include measurement and characterization instruments and condition, detail condition to fabricate norfullerene solar cell devices, hole-only and electron-only devices. Detail condition about how to control the film morphology of devices via tuning the temperature of substrates was also displayed. More information and more convincing data about the change of film morphology for active layers fabricated from different temperature, which is attached to the research article of "Influence of Substrate Temperature on the Film Morphology and Photovoltaic Performance of Non-fullerene Organic Solar Cells" was given. PMID- 28856185 TI - Prediction of transcription factor bindings sites affected by SNPs located at the osteopontin promoter. AB - This data contains information related to the research article entitled "Osteopontin splice variants and polymorphisms in Cancer Progression and Prognosis" [1]. Here, we describe an in silico analysis of transcription factors that could have altered binding to their DNA target sequence as a result of SNPs in the osteopontin gene promoter. We concentrated on SNPs associated with cancer risk and development. The analysis was performed with PROMO v3.0.2 software which incorporates TRANSFACT v6.4 of. We also present a figure depicting the putative transcription factor binding according to genotype. PMID- 28856186 TI - Serum sample containing endogenous antibodies interfering with multiple hormone immunoassays. Laboratory strategies to detect interference. AB - OBJECTIVES: Endogenous antibodies (EA) may interfere with immunoassays, causing erroneous results for hormone analyses. As (in most cases) this interference arises from the assay format and most immunoassays, even from different manufacturers, are constructed in a similar way, it is possible for a single type of EA to interfere with different immunoassays. Here we describe the case of a patient whose serum sample contains EA that interfere several hormones tests. We also discuss the strategies deployed to detect interference. SUBJECTS AND METHODS: Over a period of four years, a 30-year-old man was subjected to a plethora of laboratory and imaging diagnostic procedures as a consequence of elevated hormone results, mainly of pituitary origin, which did not correlate with the overall clinical picture. RESULTS: Once analytical interference was suspected, the best laboratory approaches to investigate it were sample reanalysis on an alternative platform and sample incubation with antibody blocking tubes. Construction of an in-house 'nonsense' sandwich assay was also a valuable strategy to confirm interference. In contrast, serial sample dilutions were of no value in our case, while polyethylene glycol (PEG) precipitation gave inconclusive results, probably due to the use of inappropriate PEG concentrations for several of the tests assayed. CONCLUSIONS: Clinicians and laboratorians must be aware of the drawbacks of immunometric assays, and alert to the possibility of EA interference when results do not fit the clinical pattern. PMID- 28856187 TI - Computed exercise plasma lactate concentrations: A conversion formula. AB - OBJECTIVES: Blood lactate measurements are common as a marker of skeletal muscle metabolism in sport medicine. Due to the close equilibrium between the extracellular and intramyocellular space, plasma lactate is a more accurate estimate of muscle lactate. However, whole blood-based lactate measurements are more convenient in field use. The purpose of this investigation was therefore (1) to establish a plasma-converting lactate formula for field use, and (2) to validate the computed plasma lactate levels by comparison to a laboratory standard method. DESIGN AND METHODS: A total of 91 venous samples were taken from 6 individuals with type 1 diabetes during resting and exercise conditions and assessed for whole blood and plasma lactate using the YSI 2300 analyzer. A linear model was applied to establish a formula for converting whole blood lactate to plasma lactate. The validity of computed plasma lactate values was assessed by comparison to a laboratory standard method. RESULTS: Whole blood YSI lactate could be converted to plasma YSI values (slope 1.66, intercept 0.12) for samples with normal hematocrit. Computed plasma levels compared to values determined by the laboratory standard method using Passing-Bablok regression yielded a slope of 1.03 (95%CI:0.99:1.08) with an intercept of -0.11 (95%CI:-0.18:-0.06). CONCLUSIONS: Whole blood YSI lactate values can be reliably converted into plasma values which are in line with laboratory determined plasma measurements. PMID- 28856188 TI - The stability of quantitative blood count parameters using the ADVIA 2120i hematology analyzer. AB - OBJECTIVES: To evaluate the stability of complete blood count (CBC) parameters by measuring at multiple time points up to 72 h after venepuncture. METHODS: 36 samples submitted for routine haematology were measured at 0, 8, 24, 48, 72 h. 18 samples were kept at room temperature (23-25 degrees C) and the other 18 at 4 degrees C. The stability of the CBC parameters was determined by comparing the results to the 0 h sample. White Blood Cell Count (WBC), Hemoglobin (Hb) concentration, Red Blood Cell (RBC) count, Hematocrit (Hct), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), Cellular Hemoglobin Concentration Mean (CHCM), Mean Platelet Volume (MPV), RBC distribution width (RDW), Platelet (PLT) and Reticulocyte counts were studied. RESULTS: Most parameters were stable for 24 h at 4 degrees C, except for MCV, MCHC, CHCM and MPV. MCV and MPV increased after 8 h (p<0.0001), whereas MCHC and CHCM decreased significantly after 8 h. Significant changes were found for MCHC in samples kept at 4 degrees C for 48 h (p=0.002), and for CHCM kept for 72 h (p<0.001). Reticulocyte count stability was maintained for 24 h at 4 degrees C (p=0.3047). In samples kept at room temperature changes occurred after 8 h in RBC, Hct, MCV, MCH, MCHC, CHCM, MPV and PLT. CONCLUSION: CBC measurements are reliable for 8 h when samples are stored at room temperature. The only parameter stable for 72 h at room temperature was Hb. Blood samples kept at 4 degrees C for up to 24 h are suitable for haematological analysis. PMID- 28856189 TI - Practical challenges related to point of care testing. AB - Point of care testing (POCT) refers to laboratory testing that occurs near to the patient, often at the patient bedside. POCT can be advantageous in situations requiring rapid turnaround time of test results for clinical decision making. There are many challenges associated with POCT, mainly related to quality assurance. POCT is performed by clinical staff rather than laboratory trained individuals which can lead to errors resulting from a lack of understanding of the importance of quality control and quality assurance practices. POCT is usually more expensive than testing performed in the central laboratory and requires a significant amount of support from the laboratory to ensure the quality testing and meet accreditation requirements. Here, specific challenges related to POCT compliance with accreditation standards are discussed along with strategies that can be used to overcome these challenges. These areas include: documentation of POCT orders, charting of POCT results as well as training and certification of individuals performing POCT. Factors to consider when implementing connectivity between POCT instruments and the electronic medical record are also discussed in detail and include: uni-directional versus bidirectional communication, linking patient demographic information with POCT software, the importance of positive patient identification and considering where to chart POCT results in the electronic medical record. PMID- 28856190 TI - Comparative study of different methodologies to detect the JAK2 V617F mutation in chronic BCR-ABL1 negative myeloproliferative neoplasms. AB - OBJECTIVES: A mutation in the JAK2 gene, V617F, has been identified in several BCR-ABL1 negative myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Defining the presence or absence of this mutation is an essential part of clinical diagnostic algorithms and patient management. Here, we aimed to evaluate the performance of three PCR-based assays: Amplification Refractory Mutation System (ARMS), High Resolution Melting analysis (HRM), and Sanger direct sequencing, and compare their results with those obtained by a PCR restriction fragment polymorphism assay (PCR-RFLP). DESIGN AND METHODS: We used blood samples from 136 patients (PV=20; PMF=20; ET=28, and other MPN suspected cases=68). RESULTS: Comparable results were observed among the four assays in patients with PV, PMF, and MPN suspected cases. In patients with a diagnosis of ET, the JAK2 V617F mutation was detected in 67.8% of them by the PCR-ARMS and PCR-HRM assay and in 64% of them by the conventional Sanger sequence approach. The PCR-ARMS and PCR-HRM assays were 100% concordant. With these tests, only one of the 20 patients with ET and one of the three patients with clinically suspected MPN gave different results compared with those obtained by the PCR-RFLP. CONCLUSIONS: Our results have demonstrated that the PCR-ARMS and PCR-HRM assays could detect the JAK2 V617F mutation effectively in MPN patients, but PCR-HRM assays are rapid and the most cost effective procedures. PMID- 28856191 TI - False positive acetaminophen concentrations in icteric serum. AB - INTRODUCTION: Serum concentrations of acetaminophen are measured to predict the risk of hepatotoxicity in cases of acetaminophen overdose and to identify acetaminophen use in patients with acute liver injury without a known cause. The acetaminophen concentration determines if treatment with N-acetyl cysteine, the antidote for acetaminophen poisoning, is warranted. DESCRIPTION: A 49-year-old woman was admitted to our hospital with a hepatic encephalopathy and a total serum bilirubin concentration of 442 umol/l. The acetaminophen concentration of 11.5 mg/l was measured with an enzymatic-colorimetric assay, thus treatment with N-acetyl cysteine was started. Interestingly, the acetaminophen concentration remained unchanged (11.5-12.3 mg/l) during a period of 4 consecutive days. In contrast, the acetaminophen concentration measured by HPLC, a chromatographic technique, remained undetectable. DISCUSSION: In the presented case, elevated bilirubin was the most likely candidate to interfere with acetaminophen assay causing false positive results. Bilirubin has intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum and for that reason it causes interference in an enzymatic-colorimetric assay. CONCLUSION: False positive acetaminophen laboratory test results may be found in icteric serum, when enzymatic-colorimetric assays are used for determination of an acetaminophen concentration. Questionable acetaminophen results in icteric serum should be confirmed by a non-enzymatic method, by means of ultrafiltration of the serum, or by dilution studies. PMID- 28856192 TI - Lactate point-of-care testing for acidosis: Cross-comparison of two devices with routine laboratory results. AB - OBJECTIVES: Lactate is a major parameter in medical decision making. During labor, it is an indicator for fetal acidosis and immediate intervention. In the Emergency Department (ED), rapid analysis of lactate/blood gas is crucial for optimal patient care. Our objectives were to cross-compare-for the first time-two point-of-care testing (POCT) lactate devices with routine laboratory results using novel tight precision targets and evaluate different lactate cut-off concentrations to predict metabolic acidosis. DESIGN AND METHODS: Blood samples from the delivery room (n=66) and from the ED (n=85) were analyzed on two POCT devices, the StatStrip-Lactate (Nova Biomedical) and the iSTAT-1 (CG4+ cassettes, Abbott), and compared to the routine laboratory analyzer (ABL-735, Radiometer). Lactate concentrations were cross-compared between these analyzers. RESULTS: The StatStrip correlated well with the ABL-735 (R=0.9737) and with the iSTAT-1 (R=0.9774) for lactate in umbilical cord blood. Lactate concentrations in ED samples measured on the iSTAT-1 and ABL-735 showed a correlation coefficient of R=0.9953. Analytical imprecision was excellent for lactate and pH, while for pO2 and pCO2 the coefficient of variation was relatively high using the iSTAT-1. CONCLUSION: Both POCT devices showed adequate analytical performance to measure lactate. The StatStrip can indicate metabolic acidosis in 1 MUl blood and will be implemented at the delivery room. PMID- 28856193 TI - Comparison and clinical utility evaluation of four multiple allergen simultaneous tests including two newly introduced fully automated analyzers. AB - BACKGROUND: We compared the diagnostic performances of two newly introduced fully automated multiple allergen simultaneous tests (MAST) analyzers with two conventional MAST assays. METHODS: The serum samples from a total of 53 and 104 patients were tested for food panels and inhalant panels, respectively, in four analyzers including AdvanSure AlloScreen (LG Life Science, Korea), AdvanSure Allostation Smart II (LG Life Science), PROTIA Allergy-Q (ProteomeTech, Korea), and RIDA Allergy Screen (R-Biopharm, Germany). We compared not only the total agreement percentages but also positive propensities among four analyzers. RESULTS: Evaluation of AdvanSure Allostation Smart II as upgraded version of AdvanSure AlloScreen revealed good concordance with total agreement percentages of 93.0% and 92.2% in food and inhalant panel, respectively. Comparisons of AdvanSure Allostation Smart II or PROTIA Allergy-Q with RIDA Allergy Screen also showed good concordance performance with positive propensities of two new analyzers for common allergens (Dermatophagoides farina and Dermatophagoides pteronyssinus). The changes of cut-off level resulted in various total agreement percentage fluctuations among allergens by different analyzers, although current cut-off level of class 2 appeared to be generally suitable. CONCLUSIONS: AdvanSure Allostation Smart II and PROTIA Allergy-Q presented favorable agreement performances with RIDA Allergy Screen, although positive propensities were noticed in common allergens. PMID- 28856194 TI - Transitioning high sensitivity cardiac troponin I (hs-cTnI) into routine diagnostic use: More than just a sensitivity issue. AB - OBJECTIVES: High sensitivity cardiac troponin T and I (hs-cTnT and hs-cTnI) assays show analytical, diagnostic and prognostic improvement over contemporary sensitive cTn assays. However, given the importance of troponin in the diagnosis of myocardial infarction, implementing this test requires rigorous analytical and clinical verification across the total testing pathway. This was the aim of this study. DESIGN AND METHODS: Analytical verification included assessment of critical outlier frequency, for hs-cTnI and cTnI assays. Concordance for paired cTnI and hs-cTnI measurements (n=1096) was verified using 99th percentiles for both genders (cTnI: 30 ng/L, hs-cTnI: 25 ng/L) and for men and women separately (hs-cTnI: M: 34;F: 16 ng/L). Discordant data was correlated with clinical and laboratory information. Diagnosis of Acute Coronary Syndrome (ACS) or Non-ACS was adjudicated by two cardiologists independently. RESULTS: The hs-cTnI assay showed a lower (10-fold) critical outlier rate (0.091%) and more detectable results above the limit of detection (LOD) (23.4%) and 99th percentile (2.4%), compared to cTnI. Analytical concordance between the two assays was high (94.5%) but decreased (91.7%) when gender-specific hs-cTnI cut-offs were used. The hs-cTnI assay gave fewer false negatives (up to 1.0%) but disproportionately more false positives (up to 6.7%) overall, which improved (3.9%) for serial measurements. CONCLUSIONS: Laboratories should analytically and clinically verify hs-cTn assays before use, with attention to performance and the clinical and diagnostic algorithms that support appropriate testing and result interpretation. Work in the pre- and post-analytical phases is necessary to augment the analytical improvement in the new era of troponin testing. PMID- 28856195 TI - Decreases in blood ethanol concentrations during storage at 4 degrees C for 12 months were the same for specimens kept in glass or plastic tubes. AB - BACKGROUND: The stability of ethanol was investigated in blood specimens in glass or plastic evacuated tubes after storage in a refrigerator at 4 degrees C for up to 12 months. METHODS: Sterile blood, from a local hospital, was divided into 50 mL portions and spiked with aqueous ethanol (10% w/v) to give target concentrations of 0.20, 1.00, 2.00 and 3.00 g/L. Ethanol was determined in blood by headspace gas chromatography (HS-GC) with an analytical imprecision of <3% (coefficient of variation, CV%). Aliquots of blood were re-analysed after 2, 7, 14, 28, 91, 182 and 364 days of storage at 4 degrees C. RESULTS: The standard deviation (SD) of analysis by HS-GC was 0.0059 g/L at 0.20 g/L and 0.0342 g/L at 3.00 g/L, corresponding to CVs of 2.9% and 1.1%, respectively. The decreases in blood ethanol content were analytically significant after 14-28 days of storage for both glass and plastic tubes The mean (lowest and highest) loss of ethanol after 12 months storage was 0.111 g/L (0.084-0.129 g/L) for glass tubes and 0.112 g/L (0.088-0.140 g/L) for plastic tubes. The corresponding percentage losses of ethanol were 43-45% at a starting concentration of 0.20 g/L and 3.9-4.1% at 3.00 g/L. CONCLUSION: The concentration of ethanol in blood gradually decreases during storage at 4 degrees C. After 12 months storage the absolute decrease in concentration was ~0.11 g/L when the starting concentration ranged from 0.20 to 3.0 g/L. Decreases in ethanol content were the same for specimens kept in glass or plastic evacuated tubes. PMID- 28856196 TI - Interfering lipoproteins in magnetic field-assisted agglutination of superparamagnetic particles immunoassay. AB - OBJECTIVE: The technology of magnetic field-assisted immuno-agglutination of superparamagnetic particles allows sensitive detection of biomarkers in whole blood. However, we observed non-specific agglutination (NSA), due to interfering plasma proteins, that negatively affects C-reactive protein immunoassay. The objective of the study was to identify the plasma proteins involved and to eliminate these interferences. DESIGN AND METHODS: Plasma was fractionated by size exclusion HPLC and each fraction was tested for non-specific agglutination. In addition, plasma proteins bound to magnetic particles were analyzed by SDS-gel electrophoresis and identified by mass spectrometry. RESULTS: We found that NSA was due to the binding of some lipoproteins to the particles. NSA was observed in the presence of purified LDL and VLDL but not HDL. NSA was mediated by the binding of ApoB100 to magnetic particles through its heparin binding sites. These interferences could be eliminated by addition of heparin or other polyanions like dextran sulfate to the assay buffer. CONCLUSION: NSA results from the binding of some plasma lipoproteins to magnetic particles. The use of a polyanion to eliminate these interferences allows the formulation of a stable reagent. PMID- 28856197 TI - Concentration of anti-pneumococcal capsular polysaccharide IgM, IgG and IgA specific antibodies in adult blood donors. AB - OBJECTIVES: Anti-pneumococcal capsular polysaccharide (PCP) IgM, IgG and IgA ELISAs have been developed to aid assessment of the adaptive immune system. The relationship between the concentrations of PCP IgM, IgG, and IgA was investigated. DESIGN AND METHODS: The concentrations of PCP IgM, IgG, and IgA were measured in sera obtained from 231 adult blood donors. RESULTS: Concentrations of each isotype were not normally distributed. The median concentration for PCP IgM was 54 U/mL (range 37-75 U/mL), IgG 40 mg/L (range 26 79 mg/L) and IgA 21 U/mL (range 13-44 U/mL). The median PCP IgM titres decreased with age and were significantly lower in patients aged 81-90 years compared to those aged 18-80 years. By contrast, there was a significantly higher median serum PCP IgG titre in the 61-90 years group compared to those aged 18-60 years and a significantly higher median serum PCP IgA titre in the 51-90 years group compared to those aged 18-50 years. The correlation between PCP IgG and IgA was more significant than between IgM and IgA and between IgM and IgG. Correlation of PCP IgA and IgM concentrations identified four phenotypes: high PCP IgM and IgA; high PCP IgM only; high PCP IgA only; and low PCP IgM and IgA. A significant number of individuals with a PCP IgG concentration >50 mg/L had low PCP IgA and IgM concentrations. CONCLUSION: The additional measurement of PCP IgA and PCP IgM, alongside PCP IgG, in individuals investigated for a compromised immune system may provide a more detailed antibody profile. PMID- 28856198 TI - Evaluation of the highly sensitive Roche thyroglobulin II assay and establishment of a reference limit for thyroglobulin-negative patient samples. AB - OBJECTIVES: Thyroglobulin (Tg) measurements are used to monitor for residual thyroid tissue in patients with differentiated thyroid cancer (DTC) after thyroidectomy and radioiodine ablative therapy. In recent years highly sensitive Tg assays have been developed. In this study the analytical performance of the new Roche Elecsys Tg II assay was evaluated and compared with the well documented Access2 Tg assay (Beckman-Coulter). DESIGN AND METHODS: Analytical performance was examined using various Clinical and Laboratory Standards Institute (CLSI) evaluation protocols. Tg negative patient sera were used to establish an upper reference limit (URL) for the Elecsys Tg II assay. RESULTS: Non-linearity, drift and carry-over according to CLSI EP10 and EP6 in a measuring range of 0.04-500 ng/mL were non-significant. Total precision according to CLSI EP5 was 10% at a Tg concentration of 0.08 ng/mL. A patient serum comparison performed according to a modified CLSI EP9 protocol showed a significant difference of a factor of approximately 1.4, despite using an identical CRM calibrator. The Elecsys Tg II assay measured Tg with a two-fold higher sensitivity than the Access2 assay. Finally, using human sera without Tg, an URL of 0.05 ng/mL was determined. CONCLUSIONS: In our hands the highly sensitive Elecsys Tg II assay shows a good analytical performance and a higher sensitivity compared to the Access2 Tg assay. An URL of 0.05 ng/mL for the Elecsys Tg II assay was determined which may improve the clinical utility of the assay for the detection of residual DTC or disease recurrence. PMID- 28856199 TI - The comparison of automated urine analyzers with manual microscopic examination for urinalysis automated urine analyzers and manual urinalysis. AB - OBJECTIVES: Urinalysis is one of the most commonly performed tests in the clinical laboratory. However, manual microscopic sediment examination is labor intensive, time-consuming, and lacks standardization in high-volume laboratories. In this study, the concordance of analyses between manual microscopic examination and two different automatic urine sediment analyzers has been evaluated. DESIGN AND METHODS: 209 urine samples were analyzed by the Iris iQ200 ELITE (Iris Diagnostics, USA), Dirui FUS-200 (DIRUI Industrial Co., China) automatic urine sediment analyzers and by manual microscopic examination. The degree of concordance (Kappa coefficient) and the rates within the same grading were evaluated. RESULTS: For erythrocytes, leukocytes, epithelial cells, bacteria, crystals and yeasts, the degree of concordance between the two instruments was better than the degree of concordance between the manual microscopic method and the individual devices. There was no concordance between all methods for casts. CONCLUSION: The results from the automated analyzers for erythrocytes, leukocytes and epithelial cells were similar to the result of microscopic examination. However, in order to avoid any error or uncertainty, some images (particularly: dysmorphic cells, bacteria, yeasts, casts and crystals) have to be analyzed by manual microscopic examination by trained staff. Therefore, the software programs which are used in automatic urine sediment analysers need further development to recognize urinary shaped elements more accurately. Automated systems are important in terms of time saving and standardization. PMID- 28856200 TI - Have you stress tested your assay? AB - OBJECTIVES: When a clinical assay is stressed with extraordinarily high volume of specimens over a short period of time, extra caution may be needed to avoid systematic errors and biases. Here we report our experience with a HgbA1c assay used for high volume wellness screening purpose, to illustrate the importance of stress testing during assay validation. DESIGN AND METHODS: Over 15,000 whole blood specimens were tested for HgbA1c in a period of 2 months. HgbA1c was tested by an immunoturbidimetric method on a high through-put automation line. The HgbA1c population distribution in our study was compared to that from the NHANES database. Daily distributions of HgbA1c values >=6%, means and medians were plotted. Correlation studies were performed between the high through-put immunoturbidimetric assay and a medium through-put HPLC method. RESULTS: We observed a shift of HgbA1c distribution to the higher values compared to the NHANES. A bias of 15-20% was noted from further stress testing where large number of samples were batched and tested using the immunoturbidimetric assay. A 5-7% higher bias remained after implementing a cuvette washing program after each HgbA1c sample. We hypothesized this bias was caused by build-up of blood cell fragments in the cuvettes when continuous whole blood samples are run through the system. Our experience suggests stress testing needs to be incorporated early in the test validation process for high volume batched screening applications. This seemingly extra validation step may save significant troubleshooting and retesting efforts down the road. PMID- 28856201 TI - Filling in the gaps with non-standard body fluids. AB - OBJECTIVES: Body fluid specimens other than serum, plasma or urine are generally not validated by manufacturers, but analysis of these non-standard fluids can be important for clinical diagnosis and management. Laboratories, therefore, rely on the published literature to better understand the validation and implementation of such tests. This study utilized a data-driven approach to determine the clinical reportable range for 11 analytes, evaluated a total bilirubin assay, and assessed interferences from hemolysis, icterus, and lipemia in non-standard fluids. DESIGN AND METHODS: Historical measurements in non-standard body fluids run on a Beckman Coulter DxC800 were used to optimize population-specific clinical reportable ranges for albumin, amylase, creatinine, glucose, lactate dehydrogenase, lipase, total bilirubin, total cholesterol, total protein, triglyceride and urea nitrogen run on the Beckman Coulter AU680. For these 11 analytes, interference studies were performed by spiking hemolysate, bilirubin, or Intralipid(r) into abnormal serous fluids. Precision, accuracy, linearity, and stability of total bilirubin in non-standard fluids was evaluated on the Beckman Coulter AU680 analyzer. RESULTS: The historical non-standard fluid results indicated that in order to report a numeric result, 4 assays required no dilution, 5 assays required onboard dilutions and 2 assays required both onboard and manual dilutions. The AU680 total bilirubin assay is suitable for clinical testing of non-standard fluids. Interference studies revealed that of the 11 total AU680 analyte measurements on non-standard fluids, lipemia affected 1, icterus affected 3, and hemolysis affected 5. CONCLUSIONS: Chemistry analytes measured on the AU680 demonstrate acceptable analytical performance for non standard fluids. Common endogenous interference from lipemia, icterus, and hemolysis (LIH) are observed and flagging rules based on LIH indices were developed to help improve the clinical interpretation of results. PMID- 28856202 TI - Comparison of patient hospital length of stay pre and post implementation of the CLINITEK AUWi System from Siemens to screen out negative urine samples intended for culture: A retrospective cohort study. AB - OBJECTIVE: To determine the impact of using the CLINITEK AUWi System to screen out negative urine samples intended for culture on patient length of stay and culture results at a community teaching hospital. DESIGN AND METHODS: We used a retrospective cohort design to compare length of stay for patients admitted before and after implementation of the CLINITEK AUWi System to screen urine samples prior to culture. Before implementation, all urine samples were sent to an external laboratory for culture. After implementation, urine samples were screened first, and culture was only performed for those samples above the 325 bacteria/ul cutoff. We assessed patient length of stay before and after implementation. RESULTS: Our study included 306 samples (168 pre, 138 post). In the post-implementation group, 60.9% of cultures were screened negative and not sent for culture, resulting in fewer negative culture results (74.4% vs 40.7%, p<0.001). Median overall length of stay was reduced from 176 h (IQR 234.75) to 128.5 h (IQR 192.5, p=0.018), a decrease of over 40 h. Differences in length of stay were especially pronounced among female patients, patients aged 80 or over, and patients with urinary tract disorder in the diagnostic differential. CONCLUSIONS: Use of the CLINITEK AUWi System reduced the need for culture by screening out 60.9% of samples as negative, and was associated with a shorter mean length of stay. Our findings have implications for cost savings, due to both the reduced length of stay and the reduced need for culture. PMID- 28856203 TI - Evaluating the optimum rest period prior to blood collection for fractionated plasma free metanephrines analysis. AB - INTRODUCTION: The high diagnostic accuracy of plasma metanephrines (PMets) in the diagnosis of Phaeochromocytoma/Paraganglioma (PPGL) is well established. Considerable controversy exists regarding optimum sampling conditions for PMets. The use of reference intervals that do not compromise diagnostic sensitivity is recommended. However, the optimum rest period prior to sampling has yet to be clearly established. The aim of this study was to evaluate PMets concentrations in paired blood samples collected following 30 and 40 min seated-rest prior to sampling, in patients in whom it was clinically reasonable to suspect that PPGL may be present. DESIGN AND METHODS: A retrospective cross-sectional study design was used. PMets results from paired blood samples collected after 30 and 40 min seated-rest between January 2009 and June 2015 were recorded. Results were interpreted using reference intervals established in subjects seated and supine. RESULTS: A total of 410 patient results were eligible for analysis. There was no statistical difference between plasma normetanephrine (NMN) or metanephrine (MN) concentrations in samples collected following 30 and 40 min seated-rest in subjects with PPGL (n=11), post-resection of PPGL (n=20) or in whom PPGL was excluded (n=379). Using reference intervals established in the seated position, diagnostic sensitivity was 100% at 30 min and 90.9% at 40 min. Diagnostic specificity was approximately 95% at both time points. When supine reference intervals were used, diagnostic sensitivity was 100% and diagnostic specificity was reduced by ~22% at both time points. CONCLUSION: Based on these data, we recommend at most 30 min continuous rest prior to sampling for PMets measurement. PMID- 28856204 TI - Reference change values in concentrations of urinary and salivary biomarkers of exposure and mouth level exposure in individuals participating in an ambulatory smoking study. AB - BACKGROUND: Modified-risk tobacco products (MRTPs) are being developed that may contribute to tobacco harm reduction. To support reduced exposure or risk claims, a scientific framework needs to be developed to assess the validity of claims and monitor consumers after product launch. We calculated reference change values (RCVs) for biomarker of exposure (BoE): salivary cotinine and hydroxycotinine; and urinary total nicotine equivalents, 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanol (NNAL) and creatinine. Mouth-level exposure (MLE) to nicotine and tar were also recorded in an ambulatory setting to characterise variation among smokers in their everyday environment. METHODS: This non-residential, observational study was conducted over 3.5 years across 10 sites in Germany. Smokers of the same commercial 10 mg ISO tar product were included in the study (N=1011). Urine samples, questionnaires and cigarette filters were collected every 6 months for a total of seven timepoints. RESULTS: Greater variability in BoEs was observed compared with confined clinical studies. Gaussian distributed data showed 2-sided values over 100%, which are uninformative for decreases. The proportion of significant changes increased slightly among switchers, probably as a result of additional variability due to the range of products used post switching. Overall proportions of changes remained small, consistent with literature reporting that when switching to a different tar yield cigarette, smokers partially compensate by changing their smoking behaviour. CONCLUSION: Variability estimates and RCVs can be useful for monitoring subjects' BoE and MLE endpoints in longitudinal smoking studies where subjects are followed in their own environment and to aid sample size calculation of studies involving these endpoints. PMID- 28856205 TI - Evaluation of Bio-Rad D-100 HbA1c analyzer against Tosoh G8 and Menarini HA 8180V. AB - OBJECTIVES: To evaluate the Bio-Rad D-100(r), an HPLC analyzer for glycated hemoglobin (HbA1c) determination, and to compare its performance with the Menarini HA-8180V(r) and Sysmex G8(r). METHODS: Method comparison was performed according to Clinical and Laboratory Standards Institute (CLSI) EP9-A2 guidelines. We selected 100 samples from the routine laboratory workload and analyzed them in duplicate with the three analyzers. The imprecision study was performed according to CLSI EP5-A2 guidelines for both inter-assay and intra assay variability. Bias was assessed with external quality control material. To establish linearity, CLSI EP6-A protocol was followed. RESULTS: Method comparison (95% confidence intervals in parentheses): D-100 vs G8: Passing-Bablok regression; y=0.973(0.963-0.983)*-0.07(-0.07-0.069); r=0.9989. Bland-Altman mean difference: -0.229%HbA1c (-0.256: -0.202); Relative bias plot: D-100/G8 vs D100 G8 mean ratio=0.971(0.967-0.975). D-100 vs HA-8180V: Passing-Bablok regression; y=0.944(0.932-0.958)*-0.078(0.024-0.173); r=0.9989. Bland-Altman mean difference: -0.363%HbA1c (-0.401: -0.325); Relative bias plot D-100/HA-8180V vs D100-HA-8180V mean ratio=0.955(0.952-0.958). Inter-assay coefficient of variation (CV): 0.81%. Intra-assay CV: 1.04% (low level), and 0.78% (high level). Bias against target value=2.332%. Linearity: r2=0.998 in the concentration range 4.4-13.9%HbA1c. Carry-over: 0.0024%. CONCLUSIONS: The Bio-Rad D-100 shows good correlation with G8 and HA-8180V. There is a small proportional systematic difference (2.7% and 5.6%, respectively) in both comparisons. Inter and intra-assay CVs are both lower than the lowest CV obtained in studies performed with D-100 and other instruments. PMID- 28856206 TI - Evaluation and analytical validation of a handheld digital refractometer for urine specific gravity measurement. AB - OBJECTIVES: Refractometers are commonly used to determine urine specific gravity (SG) in the assessment of hydration status and urine specimen validity testing. Few comprehensive performance evaluations are available demonstrating refractometer capability from a clinical laboratory perspective. The objective of this study was therefore to conduct an analytical validation of a handheld digital refractometer used for human urine SG testing. DESIGN AND METHODS: A MISCO Palm AbbeTM refractometer was used for all experiments, including device familiarization, carryover, precision, accuracy, linearity, analytical sensitivity, evaluation of potential substances which contribute to SG (i.e. "interference"), and reference interval evaluation. A manual refractometer, urine osmometer, and a solute score (sum of urine chloride, creatinine, glucose, potassium, sodium, total protein, and urea nitrogen; all in mg/dL) were used as comparative methods for accuracy assessment. RESULTS: Significant carryover was not observed. A wash step was still included as good laboratory practice. Low imprecision (%CV, <0.01) was demonstrated using low and high QC material. Accuracy studies showed strong correlation to manual refractometry. Linear correlation was also demonstrated between SG, osmolality, and solute score. Linearity of Palm Abbe performance was verified with observed error of <=0.1%. Increases in SG were observed with increasing concentrations of albumin, creatinine, glucose, hemoglobin, sodium chloride, and urea. Transference of a previously published urine SG reference interval of 1.0020-1.0300 was validated. CONCLUSIONS: The Palm Abbe digital refractometer was a fast, simple, and accurate way to measure urine SG. Analytical validity was confirmed by the present experiments. PMID- 28856207 TI - A new sensitive automated assay for procalcitonin detection: LIAISON(r) BRAHMS PCT(r) II GEN. AB - OBJECTIVES: To assess the performance of LIAISON(r) BRAHMS PCT(r) II GEN (DiaSorin, Saluggia, Italy) in procalcitonin (PCT) determination by comparing it to the assay reference method B.R.A.H.M.S PCT KRYPTOR (Thermo Fisher Scientific Clinical Diagnostics, Hennigsdorf, Germany) and assessing its ability to discriminate between healthy subjects and patients with suspected infection. METHODS: Diagnostic performance was evaluated on: a) 193 selected samples covering the assay range, whose procalcitonin levels were already evaluated with the B.R.A.H.M.S PCT(r) KRYPTOR; b) prospective samples: 150 apparently healthy specimens obtained from a blood bank, 161 hospitalized patients (not with specific pathologies), 243 apparently healthy children. RESULTS: The comparison of LIAISON(r) BRAHMS PCT(r) II GEN to the reference method B.R.A.H.M.S PCT KRYPTOR yielded high correlation coefficients: slope of Deming fit equal to 1.04 (95% CI: 0.99-1.09) with an intercept equal to 0.05 (95% CI: -0.09 to 0.19) and a high concordance (98.4% (95% CI: 95.5-99.7%)) at the 0.5 ng/mL cut-off. Moreover, the results obtained using prospective samples showed: (i) no samples with PCT concentration >0.5 ng/mL (cut-off) for the apparently healthy adults (highest value=0.033 ng/mL, 95th percentile and 97.5th percentile <0.02 ng/mL); (ii) 2 samples >0.5 ng/mL for hospitalized patients (highest value=0.715 ng/mL, 95th percentile: 0.054 ng/mL; 97.5th percentile: 0.088 ng/mL); (iii) 3 samples >0.5 ng/mL for the healthy children population (highest value=0.713 ng/mL, 95th percentile: 0.155 ng/mL; 97.5th percentile: 0.275 ng/mL). CONCLUSION: The fully automated LIAISON(r) BRAHMS PCT(r) II GEN agrees well with the reference method and is suitable for early diagnosis of sepsis, severe bacterial infection and guiding antibiotic therapy. PMID- 28856208 TI - Analytical evaluation of the novel Lumipulse G BRAHMS procalcitonin immunoassay. AB - OBJECTIVES: This study was designed to evaluate the analytical performance of the novel Lumipulse G1200 BRAHMS procalcitonin (PCT) immunoassay. DESIGN AND METHODS: This analytical evaluation encompassed the calculation of the limit of blank (LOB), limit of detection (LOD), functional sensitivity, intra- and inter-assay imprecision, confirmation of linearity and a comparison with the Vidas BRAHMS PCT assay. RESULTS: The LOB, LOD and functional sensitivity were 0.0010 ng/mL, 0.0016 ng/mL and 0.008 ng/mL, respectively. The total analytical imprecision was found to be 2.1% and the linearity was excellent (r=1.00) in the range of concentrations between 0.006-75.5 ng/mL. The correlation coefficient with Vidas BRAHMS PCT was 0.995 and the equation of the Passing and Bablok regression analysis was [Lumipulse G BRAHMS PCT]=0.76*[Vidas BRAHMS PCT]+0.04. The mean overall bias of Lumipulse G BRAHMS PCT versus Vidas BRAHMS PCT was -3.03 ng/mL (95% confidence interval [CI]: -4.32 to -1.74 ng/mL), whereas the mean bias in samples with PCT concentration between 0-10 ng/mL was -0.49 ng/mL (95% CI: -0.77 to -0.24 ng/mL). The diagnostic agreement was 100% at 0.5 ng/mL, 97% at 2.0 ng/mL and 95% at 10 ng/mL, respectively. CONCLUSIONS: These results attest that Lumipulse G BRAHMS PCT exhibits excellent analytical performance, among the best of the methods currently available on the diagnostic market. However, the significant bias compared to the Vidas BRAHMS PCT suggests that the methods cannot be used interchangeably. PMID- 28856209 TI - Clinical performance evaluation of total protein measurement by digital refractometry and characterization of non-protein solute interferences. AB - OBJECTIVES: Refractometric methods to measure total protein (TP) in serum and plasma specimens have been replaced by automated biuret methods in virtually all routine clinical testing. A subset of laboratories, however, still report using refractometry to measure TP in conjunction with serum protein electrophoresis. The objective of this study was therefore to conduct a modern performance evaluation of a digital refractometer for TP measurement. DESIGN AND METHODS: Performance evaluation of a MISCO Palm AbbeTM digital refractometer was conducted through device familiarization, carryover, precision, accuracy, linearity, analytical sensitivity, analytical specificity, and reference interval verification. Comparison assays included a manual refractometer and an automated biuret assay. RESULTS: Carryover risk was eliminated using a demineralized distilled water (ddH2O) wash step. Precision studies demonstrated overall imprecision of 2.2% CV (low TP pool) and 0.5% CV (high TP pool). Accuracy studies demonstrated correlation to both manual refractometry and the biuret method. An overall positive bias (+5.0%) was observed versus the biuret method. On average, outlier specimens had an increased triglyceride concentration. Linearity was verified using mixed dilutions of: a) low and high concentration patient pools, or b) albumin-spiked ddH2O and high concentration patient pool. Decreased recovery was observed using ddH2O dilutions at low TP concentrations. Significant interference was detected at high concentrations of glucose (>267 mg/dL) and triglycerides (>580 mg/dL). Current laboratory reference intervals for TP were verified. CONCLUSIONS: Performance characteristics of this digital refractometer were validated in a clinical laboratory setting. Biuret method remains the preferred assay for TP measurement in routine clinical analyses. PMID- 28856210 TI - Development and implementation of an HPLC-ECD method for analysis of vitamin C in plasma using single column and automatic alternating dual column regeneration. AB - OBJECTIVES: Vitamin C (l-ascorbic acid) is a water-soluble micronutrient necessary for human life. Inadequate intake can lead to the fatal disease scurvy. Measurement of vitamin C is used to assess nutritional status and to monitor supplementation. The goal of this study was to develop a chromatographic method for the quantitation of vitamin C in human plasma. DESIGN AND METHODS: Samples were prepared by protein precipitation, addition of internal standard, and reduction with dithiothreitol. Separation of ascorbic acid was accomplished by isocratic elution on a reverse-phase column; concentration was determined by coulometry. The method was validated through studies of assay linearity, sensitivity, imprecision, accuracy, analytical specificity, and carryover. RESULTS: The new assay was developed using a single pump/single analytical column HPLC system. Results correlated well with our previously used spectrophotometric method. The analytical measurement range was 1.0-2500 umol/L. The injection-to injection time was 13 min. Subsequently, to increase method throughput and shorten turnaround time, a dual LC pump system with a 2-position/10-port switching valve capable of performing automatic alternating column regeneration was validated and implemented. The injection-to-injection time was reduced 2-fold to 6 min. The method was linear to 5000 umol/L; limit of quantification was 1.9 umol/L. Total imprecision was less than 5%. CONCLUSIONS: We have developed a robust method suitable for routine clinical measurement of vitamin C in plasma specimens. The method incorporates a simplified sample preparation and a stable, non-endogenous internal standard to specifically quantify vitamin C. Faster throughput was achieved by employing an automatic alternating column regeneration system. PMID- 28856211 TI - The Sysmex CS-5100 coagulation analyzer offers comparable analytical performance and excellent throughput capabilities. AB - OBJECTIVES: This study compared the new high-volume blood coagulation analyzer Sysmex CS-5100 SystemTM (Siemens Healthcare Diagnostics, Erlangen, Germany) to the mid-volume blood coagulation analyzer Sysmex CS-2000i SystemTM (Siemens) for analytical performance. Additionally, the operational performance of the Sysmex CS-5100 System was compared with the blood coagulation analyzer ACL TOP 700 (Instrumentation Laboratory, Werfen Group, Kirchheim bei Munchen, Germany). MATERIALS AND METHODS: We compared the Sysmex CS-5100 to the Sysmex CS-2000i and the ACL TOP analyzer for routine coagulation, chromogenic and immunological assays. Imprecision studies were performed for the Sysmex CS-5100 and Sysmex CS 2000i systems. A throughput and STAT analysis comparison of the CS-5100 and the ACL TOP was performed. A stress test was performed to characterize the robustness and the error rate of the CS-5100. We also performed correlation analysis between the CS-5100 and the CS-2000i or the ACL TOP in the measurement of patients' samples. RESULTS: The inter-assay precision using the CS systems was impressive (inter-assay CV generally <3.5%) and the correlation between the two Sysmex analyzers was excellent. In the throughput study, the CS-5100 completed the measurement of 100 samples (210 results) in less than 49 min. CONCLUSIONS: Our results demonstrated that the CS-5100 is a robust high-throughput analyzer, well suited for coagulation laboratories. PMID- 28856212 TI - The significance of reporting to the thousandths place: Figuring out the laboratory limitations. AB - OBJECTIVES: A request to report laboratory values to a specific number of decimal places represents a delicate balance between clinical interpretation of a true analytical change versus laboratory understanding of analytical imprecision and significant figures. Prostate specific antigen (PSA) was used as an example to determine if an immunoassay routinely reported to the hundredths decimal place based on significant figure assessment in our laboratory was capable of providing analytically meaningful results when reported to the thousandths places when requested by clinicians. DESIGN AND METHODS: Results of imprecision studies of a representative PSA assay (Roche MODULAR E170) employing two methods of statistical analysis are reported. Sample pools were generated with target values of 0.01 and 0.20 MUg/L PSA as determined by the E170. Intra-assay imprecision studies were conducted and the resultant data were analyzed using two independent statistical methods to evaluate reporting limits. RESULTS: These statistical methods indicated reporting results to the thousandths place at the two assessed concentrations was an appropriate reflection of the measurement imprecision for the representative assay. This approach used two independent statistical tests to determine the ability of an analytical system to support a desired reporting level. Importantly, data were generated during a routine intra-assay imprecision study, thus this approach does not require extra data collection by the laboratory. CONCLUSIONS: Independent statistical analysis must be used to determine appropriate significant figure limitations for clinically relevant analytes. Establishing these limits is the responsibility of the laboratory and should be determined prior to providing clinical results. PMID- 28856213 TI - Analytical verification and quality assessment of the Tosoh HLC-723GX HbA1c analyzer. AB - OBJECTIVES: Ion-exchange high-performance liquid chromatography (IE-HPLC) has long been used as a reproducible and versatile analytical tool for HbA1c measurement. In this study, we performed analytical verification and quality assessment of the recently introduced small IE-HPLC Tosoh HLC-723GX HbA1c analyzer, and a comparison of results to immunoassay (IA) and capillary electrophoresis (CE). DESIGN AND METHODS: The total imprecision of Tosoh HLC 723GX was verified according to CLSI EP15-A2 protocol using commercial control materials (C-QC) and pooled human whole blood samples (HWB). The Sigma metric was used for the evaluation of quality targets. HbA1c results were compared to automated CE (MiniCap Flex Piercing, Sebia, France) and IA (Tina-quant HbA1c Gen 2, Cobas Integra 400+, Roche Diagnostics, USA) procedures. RESULTS: The total imprecision of Tosoh HLC-723GX-HbA1c for IFCC(mmol/mol) and NGSP(%) units was: 1.91/1.25% (HbA1c=31 mmol/mol/5.0%) and 0.51/0.63% (HbA1c=84 mmol/mol/9.8%) for C QC, and 0.39/0.2% (HbA1c=47 mmol/mol/6.5%) and 0.77/0.46% (HbA1c=94 mmol/mol/10.8%) in HWB samples, respectively. Bland-Altman analysis did not reveal any deviation of the results between Tosoh HLC-723GX and CE: mean difference 0.0% (95%CI: -0.02927 to 0.02653%), while the mean HbA1c difference against IA was -0.07% (95%CI: -0.1039 to -0.02765). At the selected HbA1c clinical decision level (48 mmol/mol/6,5%), six sigma analysis gave sigma value of 3.91, within a desirable classification of performance. CONCLUSION: The analytical performance of the Tosoh HLC-723GX complies with the rigorous quality criteria for clinical use of HbA1c, with the results comparable to the CE procedure. Tosoh HLC-723GX provides a plausible analytical choice for reliable HbA1c measurement in low-volume laboratories. PMID- 28856214 TI - The Roche Total Mycophenolic Acid(r) assay: An application protocol for the ABX Pentra 400 analyzer and comparison with LC-MS in children with idiopathic nephrotic syndrome. AB - BACKGROUND: For TDM of mycophenolate acid (MPA), the Roche Total Mycophenolic Acid(r) assay based on the inhibition of recombinant inosine monophosphate dehydrogenase (IMPDH) has been shown to be a simple and reliable alternative to chromatographic methods. We have adapted this assay on the ABX Pentra 400 analyzer (HORIBA). OBJECTIVE: To investigate the analytical performances of the Roche Total Mycophenolic Acid(r) assay on the ABX Pentra 400 and to compare it to an LC-MS method using samples from children with nephrotic syndrome treated with mycophenolate mofetil (MMF). MATERIAL AND METHODS: Configuration of the open channel on the ABX Pentra 400 was based on the Roche MPA assay package insert. Precision was determined as described in the CLSI protocol EP5-A2. Comparison with the LC-MS method was performed using 356 plasma samples from 42 children with nephrotic syndrome (8 h pharmacokinetic profiles). RESULTS: The enzymatic assay demonstrated high precision. The %CV for Within Run Imprecision ranged from 5.5% at 1.2 mg/L to 1.5% at 14.1 mg/L and Total Imprecision ranged from 9.3% to 2.5%. The method comparison with plasma samples from children yielded overall a good correlation and a good agreement between both methods. The Passing Bablok regression analysis showed the following results: [Roche MPA assay]=1.058 [MPA LC MS] -0.06; rho=0.996. CONCLUSION: The Roche Total Mycophenolic Acid(r) assay is adaptable to the ABX Pentra 400 analyzer, and demonstrates accurate and precise measurement of MPA in plasma obtained from children with nephrotic syndrome. PMID- 28856215 TI - Verification of Abbott 25-OH-vitamin D assay on the architect system. AB - OBJECTIVES: Analytical and clinical verification of both old and new generations of the Abbott total 25-hydroxyvitamin D (25OHD) assays, and an examination of reference Intervals. METHODS: Determination of between-run precision, and Deming comparison between patient sample results for 25OHD on the Abbott Architect, DiaSorin Liaison and AB SCIEX API 4000 (LC-MS/MS). Establishment of uncertainty of measurement for 25OHD Architect methods using old and new generations of the reagents, and estimation of reference interval in healthy Irish population. RESULTS: For between-run precision the manufacturer claims 2.8% coefficients of variation (CVs) of 2.8% and 4.6% for their high and low controls, respectively. Our instrument showed CVs between 4% and 6.2% for all levels of the controls on both generations of the Abbott reagents. The between-run uncertainties were 0.28 and 0.36, with expanded uncertainties 0.87 and 0.98 for the old and the new generations of reagent, respectively. The difference between all methods used for patients' samples was within total allowable error, and the instruments produced clinically equivalent results. The results covered the medical decision points of 30, 40, 50 and 125 nmol/L. The reference interval for total 25OHD in our healthy Irish subjects was lower than recommended levels (24-111 nmol/L). CONCLUSION: In a clinical laboratory Abbott 25OHD immunoassays are a useful, rapid and accurate method for measuring total 25OHD. The new generation of the assay was confirmed to be reliable, accurate, and a good indicator for 25OHD measurement. More study is needed to establish reference intervals that correctly represent the healthy population in Ireland. PMID- 28856216 TI - Impact of serum-clot contact time on lactate dehydrogenase and inorganic phosphorus serum levels. AB - OBJECTIVES: The aim of this study is to determine the longest acceptable serum clot contact time before centrifugation in lactate dehydrogenase and inorganic phosphorus analysis. MATERIALS AND METHODS: The LDH and inorganic phosphorus serum levels from 103 adults were analyzed at three different storage times. The three measures were done immediately (T0), after a 2-h serum-clot contact (T2) and after a 4-h serum-clot contact (T4). A paired two-tailed Student t-test evaluated the impact of the serum-clot contact time on the serum levels. Another approach using analytical reproducibly and intra-individual variability was used. Furthermore, we have compared the mean percentage deviation to the measurement uncertainty. RESULTS: The LDH serum level is not significantly impacted by the three different studied serum-clot contact times. The immediate Phosphorus serum level is not significantly different from the 2-h serum-clot contact condition. However, after a 4-h serum-clot contact, the phosphorus serum level is significantly lower than the immediate phosphorus serum level. Considering the reference change value approach, an acceptable mean variation was shown for inorganic phosphorus serum level after a 4-h serum-clot contact time. After a 4-h serum-clot contact, LDH and phosphorus mean percentage deviation are below our measurement uncertainties. CONCLUSION: This study evidences that in our daily practices a 4-h serum-clot contact time for LDH and inorganic phosphorus analysis is acceptable. PMID- 28856217 TI - PCR-based amplification of circulating RNAs as prognostic and predictive biomarkers - Focus on neuroblastoma. AB - Metastatic disease is a major challenge for cancer cure, haematogenous spread and subsequent growth of tumour cells at distant sites being the cause of most cancer deaths. Molecular characterization and detection of the tumour cells responsible for haematogenous spread may increase understanding of the biology of metastasis, help improve patient management and allow evaluation of novel treatments to prevent and eradicate this disease. The bone marrow is a common site to which tumour cells metastasize, from which they may re-circulate to other organs with a favourable microenvironment for growth. The detection of tumour cells in blood suggests one route for metastasis, and provides an accessible, minimally invasive liquid sample through which it may be possible to monitor and detect minimal disease and early signs of metastasis. Significant improvements in the sensitivity and specificity of tumour cell detection have been made, such that it is now possible to unambiguously detect a single tumour cell in over 10 million normal cells. However, the clinical impact of such low level disease and how to interpret the natural variation that can arise from sequential sampling of bone marrow aspirates and blood is currently largely unknown. This commentary will focus on the technical advancements and application of reverse transcriptase polymerase chain reaction to detect cancer mRNAs in bone marrow and blood, and discuss the potential clinical impact of this test in neuroblastoma. PMID- 28856218 TI - Circulating biomarkers in cancer care: What possible use? AB - The practice of the physician has changed greatly in the last 100 years. Yet, the fundamental role remains constant: it is the physician's function to make a diagnosis, assess prognosis, choose and deliver the most effective treatment and then to assess the adequacy of that treatment (both in terms of effectiveness and safety). Whereas our predecessors were almost entirely reliant on clinical history and examination findings in conducting these assessments, the 21st century physician is aided by a plethora of blood tests, imaging investigations, electrophysiological recordings and morphological and molecular analyses of tissue samples. For many patients, the totality of these newer tests contributes relatively little to their journey, whilst, for some, key tests can dictate the direction of travel and, sometimes, the ultimate destination. PMID- 28856220 TI - Frequency and causes of lipemia interference of clinical chemistry laboratory tests. AB - OBJECTIVES: The aims of this study were to identify the causes of severe lipemia in an academic medical center patient population and to determine the relationship between lipemia and hemolysis. DESIGN AND METHODS: Retrospective study was done on the data from the core clinical laboratory at an academic medical center. Lipemic indices were available for all chemistry specimens analyzed over a 16-month period (n=552,029 specimens) and for serum/plasma triglycerides concentrations ordered for clinical purposes over a 16-year period (n=393,085 specimens). Analysis was performed on Roche Diagnostics cobas 8000 analyzers. Extensive chart review was done for all specimens with lipemic index greater than 500 (severely lipemic) and for all specimens with serum/plasma triglycerides greater than 2000 mg/dL. We also determined the relationship between lipemia and hemolysis. RESULTS: The most frequent suspected causes of very high lipemic index (>500) were found to be lipid-containing intravenous infusions (54.4% of total; fat emulsions for parenteral nutrition - 47%; propofol -7.4%) and diabetes mellitus (25% of total, mainly type 2). The most frequent suspected causes of very elevated serum/plasma triglycerides (>2000 mg/dL) was diabetes mellitus (64%, mainly type 2) and hyperlipidemia (16.9%). The frequency of hemolysis increased with increasing lipemic index. CONCLUSIONS: Intravenous lipid infusions and type 2 diabetes were the most common causes of severe lipemia in this study at an academic medical center. Given that iatrogenic factors are the most common cause of severe lipemia, education and intervention may be helpful in reducing frequency of severe lipemia in patient specimens. PMID- 28856221 TI - Analytical performance evaluation of the Elecsys(r) Cyclosporine and Elecsys(r) Tacrolimus assays on the cobas e411 analyzer. AB - BACKGROUND: Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs that are often used to treat autoimmune diseases and as transplantation therapy; therefore, their concentrations need to be monitored carefully. We herein evaluated the analytical performance of the Elecsys(r) Cyclosporine and Elecsys(r) Tacrolimus assay kits, which have been newly developed to measure CsA and TAC concentrations in the whole blood. METHODS: We used residual whole blood samples from autoimmune disease and transplantation patients who were being treated with CsA or TAC. CsA concentrations were measured using an affinity chrome-mediated immunoassay (ACMIA) and an electrochemiluminescence immunoassay (ECLIA). TAC concentrations were measured using a chemiluminescence immunoassay (CLIA) and ECLIA. We investigated assay precision, linearity, lower limit of quantitation (LOQ), stability of calibration, influence of interference substances and the hematocrit, correlation of ACMIA with ECLIA, and correlation of CLIA with ECLIA. RESULTS: Within-assay coefficients of variation were 1.8-3.6% (CsA: 94-1238 ng/mL) and 2.9-3.9% (TAC: 2.1-17.8 ng/mL), whereas day-to-day coefficients of variation ranged between 3.0-4.1% (CsA) and 2.8-3.9% (TAC). The limits of quantitation were defined as the concentration at which the CV was approximately 10%. Each lower LOQ obtained was 16 ng/mL (CsA), and 0.95 ng/mL (TAC). CsA and TAC calibrations were stable for at least 21 days. Neither the presence of conjugated bilirubin, unconjugated bilirubin, chyle, and rheumatoid factor nor the hematocrit affected these assays. A method comparison using a standardized major axis regression analysis of ACMIA and ECLIA was r=0.995, y=0.924x -1.175, n=200 (CsA), while that of CLIA and ECLIA was r=0.994, y=1.080x 0.197, n=200 (TAC). CONCLUSIONS: The analytical performances of the Elecsys(r) Cyclosporine and Elecsys(r)Tacrolimus assays were acceptable. Furthermore, CyA and TAC concentrations may be simultaneously measured using a single pretreatment which is of benefit if patients have to undertake conversion between these two drugs. Additionally, it benefits the workflow in the clinical laboratory. Thus, the Elecsys(r) Cyclosporine and Elecsys(r) Tacrolimus assays may be suitable for routine therapeutic drug monitoring. PMID- 28856219 TI - Circulating markers of ageing and allostatic load: A slow train coming. AB - Dealing with the growing burden of age-related morbidities is one of the greatest challenges facing modern society. How we age across the lifecourse and how psychosocial and lifestyle factors interplay with the biology of ageing remains to be fully elucidated. Sensitive and specific biomarkers with which to interrogate the biology of the ageing process are sparse. Recent evidence suggests that non-coding RNAs are key determinants of such processes and that these can be used as potential circulatory bio-markers of ageing. They may also provide a mechanism which mediates the spread of allostatic load across the body over time, ultimately reflecting the immunological health and physiological status of tissues and organs. The interplay between exosomal microRNAs and ageing processes is still relatively unexplored, although circulating microRNAs have been linked to the regulation of a range of physiological and pathological processes and offer insight into mechanistic determinants of healthspan. PMID- 28856222 TI - Comparison of clinical methods for detecting carbapenem-resistant Enterobacteriaceae. AB - We evaluated detection of carbapenem-resistant Enterobacteriaceae (CRE) by routine minimal inhibitory concentration (MIC) testing, polymerase chain reaction (PCR) using Xpert(r) Carba-R assay, hydrolysis of ertapenem and imipenem detected by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS), and hydrolysis by colorimetry using the EPI-CRE assay. Ninety-six Enterobacteriaceae isolates possessing carbapenemase genes and 29 carbapenem susceptible Enterobacteriaceae were available for testing. The sensitivity and specificity of each assay was determined. For sensitivity, discrepant results from each assay compared to reference genotype were arbitrated with MIC and/ or PCR testing to assess loss of plasmid-mediated resistance. Xpert Carba-R was evaluated for resistance genes in their FDA claim (i.e., the genes encoding KPC; NDM; VIM; IMP; and OXA-48). The sensitivity for the assays was: MIC (N=96), 96.8%, (discrepant analysis to 98.9% [2 cured plasmids]); Xpert Carba-R (N=85), 97.6% (discrepant analysis to 100% % [2 cured plasmids]); EPI-CRE (N=96), 91.7% (discrepant analysis to 91.7%); MALDI-TOF MS (N=96) ertapenem hydrolysis using Compass software for interpretation (2 h incubation), 92.7% (discrepant analysis to 94.7% % [2 cured plasmids]); MALDI-TOF MS (N=96) imipenem hydrolysis (1 h incubation), 97.9% (discrepant analysis to 98.9% % [1 cured plasmid]). The specificity for each assay was: MIC (N=29), 100%; EPI-CRE (N=29), 96.6%; MALDI TOF MS ertapenem hydrolysis (N=29), 100%; MALDI-TOF MS imipenem hydrolysis (N=29), 96.6%. All isolates tested to ensure specificity demonstrated susceptible MIC results for carbapenems and did not qualify for testing with Xpert Carba-R. No single assay detected all of the known genetic markers of carbapenem hydrolysis. PMID- 28856223 TI - Comparison of a point-of-care analyser for the determination of HbA1c with HPLC method. AB - AIMS: As the use of Point of Care Testing (POCT) devices for measurement of glycated haemoglobin (HbA1c) increases, it is imperative to determine how their performance compares to laboratory methods. This study compared the performance of the automated Quo-Test POCT device (EKF Diagnostics), which uses boronate fluorescence quenching technology, with a laboratory based High Performance Liquid Chromatography (HPLC) method (Biorad D10) for measurement of HbA1c. METHODS: Whole blood EDTA samples from subjects (n=100) with and without diabetes were assayed using a BioRad D10 and a Quo-Test analyser. Intra-assay variation was determined by measuring six HbA1c samples in triplicate and inter-assay variation was determined by assaying four samples on 4 days. Stability was determined by assaying three samples stored at -20 degrees C for 14 and 28 days post collection. RESULTS: Median (IQR) HbA1c was 60 (44.0-71.2) mmol/mol (7.6 (6.17-8.66) %) and 62 (45.0-69.0) mmol/mol (7.8 (6.27-8.46) %) for D10 and Quo Test, respectively, with very good agreement (R2=0.969, P<0.0001). Mean (range) intra- and inter-assay variation was 1.2% (0.0-2.7%) and 1.6% (0.0-2.7%) for the D10 and 3.5% (0.0-6.7%) and 2.7% (0.7-5.1%) for the Quo-Test. Mean change in HbA1c after 28 days storage at -20 degrees C was -0.7% and +0.3% for D10 and Quo Test respectively. Compared to the D10, Quo-Test showed 98% agreement for diagnosis of glucose intolerance (IGT and T2DM) and 100% for diagnosis of T2DM. CONCLUSION: Good agreement between the D10 and Quo-Test was seen across a wide HbA1c range. The Quo-Test POCT device provided similar performance to a laboratory based HPLC method. PMID- 28856224 TI - An analysis of the relationship between serum cortisol and serum sodium in routine clinical patients. AB - OBJECTIVES: Adrenal insufficiency is an uncommon cause of hyponatraemia that should not be overlooked due to the severe consequences of an Addisonian crisis. Using the laboratory database of a large teaching hospital, we have explored the relationship between serum sodium and serum cortisol, and have estimated the frequency of hypoadrenalism in severely hyponatraemic patients. DESIGN AND METHODS: Data were gathered over a 23 month period from the Laboratory Information Management System at the Leeds Teaching Hospitals NHS Trust for instances where serum sodium and cortisol had been measured on a single sample. Data were also gathered over the same time period for all patients with severe hyponatraemia (serum sodium <=120 mmol/L) in order to determine the frequency of cortisol requesting and the incidence of adrenal insufficiency. RESULTS: Analysis of the data (n=3268 patients) revealed a trend showing higher cortisol concentrations in patients who were severely hypo- or hypernatraemic. The median cortisol concentration for patients with sodium <=110 mmol/L was 856 nmol/L, and there was a gradual decrease in cortisol over the sodium range <=110-150 mmol/L (Rs =-0.323, p<0.0001). Patients with sodium >=151 mmol/L had a median cortisol of 725 nmol/L. 42% of the 978 patients with serum sodium <=120 mmol/L had serum cortisol measured within two weeks, of whom 1.7% were diagnosed with adrenal insufficiency. CONCLUSIONS: This dataset shows rising cortisol in response to hypo- or hypernatraemia, in keeping with the stress response to illness. The data show that adrenal insufficiency is a rare cause of hyponatraemia which may be overlooked. PMID- 28856225 TI - Development of a sandwich ELISA for the thrombin light chain identified by serum proteome analysis. AB - We previously identified novel biomarker candidates in biliary tract cancer (BTC) using serum proteome analysis. Among several candidates, we focused on thrombin light chain which is a 4204 Da peptide as the most promising biomarker for BTC. To move thrombin light chain toward potential diagnostic use, we developed an enzyme immunoassay that enables to measure serum thrombin light chain levels. Both one monoclonal antibody specific to the N-termini and one polyclonal antibody were used to develop a sandwich ELISA for thrombin light chain. The assay was evaluated by comparing the results with those obtained by the ClinProtTM system. Serum samples were obtained from 20 patients with BTC, 20 patients with BBTDs and 20 HVs using the ClinProtTM system and ELISA. The results of the established ELISA showed a positive correlation with the findings by ClinProtTM system (slope=0.3386, intercept=34.901, r2=0.9641). The performance of the ELISA was satisfactory in terms of recovery (97.9-102.5%) and within-run (1.5 4.8%) and between-day (1.9-6.7%) reproducibility. Serum thrombin light chain levels were significantly greater in BTC (176.5+/-47.2 ng/mL) than in BBTDs (128.6+/-17.4 ng/mL) and HVs (127.6+/-16.0 ng/mL) (p<0.001). The sandwich ELISA developed in this study will be useful for validation of the diagnostic significance of serum thrombin light chain levels in various cancers. PMID- 28856226 TI - Limited comparability of creatinine assays in patients with liver cirrhosis and their impact on the MELD score. AB - BACKGROUND & AIM: Patients with end-stage liver disease require valid estimations of mortality for organ allocation and risk stratification. The model of end-stage liver disease (MELD) score is used for this purpose in most countries and incorporates bilirubin, International Normalized ratio, and creatinine. The aim of this study was to evaluate the comparability of creatinine results from different routine assays in the serum samples of patients with liver cirrhosis. METHODS: Residual material from 60 serum samples was available from patients in different stages of liver cirrhosis. Four centers participated; each center analyzed the samples with Jaffe-based and enzymatic routine assays in parallel. In addition, an accredited calibration laboratory certified the panel of samples by an internationally accepted reference measurement procedure (RMP) based on isotope dilution mass spectrometry (ID-MS). This method served as the independent reference. RESULTS: All routine methods displayed a high correlation to the RMP (r >=0.937, p<0.001). Two enzymatic and two Jaffe-based methods provided results that were all within a +/-20% range of the RMP. The other methods showed deviations >20% in up to 27% of the samples. The enzymatic methods were systematically lower, whereas the Jaffe-based methods were systematically higher (p<0.001). The resulting MELD scores differed from 0 to 4 points. CONCLUSIONS: There are systematic deviations from the RMP. Jaffe-based assays gave higher results, whereas the enzymatic-based assays gave lower results compared to the results of the RMP. The comparability of results is limited and could be disadvantageous to patients listed for liver transplantation. PMID- 28856227 TI - Location of monoclonal peak as a tool in checking specimen integrity. AB - OBJECTIVES: Serum protein electrophoresis is a commonly used test in the diagnosis and follow-up of patients with monoclonal gammopathies. The practice of documenting the location of the peak may serve as delta check flags in SPEP samples. METHODS: We report on the inconsistent finding on two tests performed about three months apart. The inconsistency was discovered due to recognition of the change in the location of the monoclonal immunoglobulin on protein electrophoresis. RESULTS: Repeat testing with a third specimen revealed that the first test was run on a wrong specimen. CONCLUSION: Recording the location of the monoclonal spike is recommended to serve as an additional "delta" check. PMID- 28856228 TI - Traditional versus reverse syphilis algorithms: A comparison at a large academic medical center. AB - OBJECTIVES: An increasing number of institutions are transitioning from the traditional syphilis testing algorithm (initial screening with nontreponemal tests) to the 'reverse' algorithm (initial screening with treponemal tests such as syphilis IgG). The aim of this study was to evaluate the switch in syphilis algorithm at an academic medical center with a population with low syphilis prevalence. DESIGN AND METHODS: We performed a six-year retrospective study at the University of Iowa Hospitals and Clinics, an academic medical center, comparing the traditional algorithm (n=12,612) with the reverse algorithm (n=10,453). False positives were considered to be positive screens with negative confirmatory testing. RESULTS: Using the traditional algorithm, 93 samples (0.7% of total) screened positive with RPR, with 40 of these samples having negative TP PA testing (43% of positive screens, 0.3% of total). Using the reverse algorithm, 110 screened positive with syphilis IgG (1.1% of total), and 33 of these samples had both negative RPR and TP-PA (30% of positive screens, 0.3% of total). In both algorithms, higher RPR titers and syphilis IgG values were associated with increased probability of positive confirmation. CONCLUSIONS: In this study at an academic medical center, the reverse algorithm had significantly more total positive screens than the traditional algorithm. Both algorithms produced equivalent rates of active infection. The quantitative difference in positives between the two algorithms are the category of patients who are syphilis IgG positive, RPR non-reactive, and TP-PA reactive. Specimens with higher RPR titers and syphilis IgG values are more likely to confirm positive. PMID- 28856229 TI - Analytical validation of Gentian NGAL particle-enhanced enhanced turbidimetric immunoassay (PETIA). AB - OBJECTIVES: This study was designed to validate the analytical performance of the new Gentian particle-enhanced enhanced turbidimetric immunoassay (PETIA) for measuring neutrophil gelatinase-associated lipocalin (NGAL) in serum samples. DESIGN AND METHODS: Analytical validation of the Gentian NGAL assay was carried out on a Roche Cobas c501 and was based on assessment of limit of blank (LOB), limit of detection (LOD), functional sensitivity, imprecision, linearity and concordance with the BioPorto NGAL test. RESULTS: The LOB and LOD of Gentian NGAL were found to be 3.8 ng/mL and 6.3 ng/mL, respectively. An analytical coefficient of variation (CV) of 20% corresponded to a NGAL value of 10 ng/mL. The intra assay and inter-assay imprecision (CV) was between 0.4 and 5.2% and 0.6 and 7.1% and the total imprecision (CV) was 3.7%. The linearity was optimal at NGAL concentrations between 37 and 1420 ng/mL (r=1.00; p<0.001). An excellent correlation was observed between values measured with Gentian NGAL and BioPorto NGAL in 74 routine serum samples (r=0.993). The mean percentage bias of the Gentian assay versus the Bioporto assay was +3.1% (95% CI, +1.6% to +4.5%). CONCLUSIONS: These results show that Gentian NGAL may be a viable option to other commercial immunoassays for both routine and urgent assessment of serum NGAL. PMID- 28856230 TI - Distribution of serum concentrations reported for macroenzyme aspartate aminotransferase (macro-AST). AB - BACKGROUND: The presence of macroenzyme (M) is often the explanation of an isolated elevation of aspartate aminotransferase (AST). Where M is identified, it is reasonable for the clinician to ask where an individual patient's result fits in with known concentrations of M. In this context, we conducted a survey of literature to examine the distribution of reported serum concentrations of macro AST. We also analyzed the distribution data to examine whether elevations were consistent with simple alteration of circulatory half-life (t1/2) of M relative to normal AST. METHODS: Distributions of M were compiled from the literature. These distributions were compared to predictions based on fixed changes in t1/2 applied to the reference interval for AST. RESULTS: There was a bimodal distribution of literature values for M (n =51), comprised roughly of populations A (M <200 U/L; 60% of total) and B (M >200 U/L; 40% of total). The two distributions were reasonably well characterized by a simple projection to the right of the reference interval for AST according to increased t1/2 (A: t1/2 =3.3 days; B: t1/2 =19.8 days) relative to AST (t1/2 =0.7 days). CONCLUSIONS: Knowledge of distributions for M may be useful in discussion with clinicians regarding significance of M for individual patients. Distributions for M were consistent with the simplest explanation for elevated AST due strictly to an extended circulatory lifetime for M. Caveats to analysis, however, include selection within literature data mainly for patients with various co-morbidities. PMID- 28856231 TI - Investigation of morphological changes for the discrimination of nucleated red blood cells and other leukocytes in Sysmex XN hematology analyzer scattergrams using transmission electron microscopy. AB - BACKGROUND: The WNR channel of the XN-Series automated hematology analyzer (Sysmex) counts white blood cells (WBCs) and simultaneously performs a differential counting of basophils and nucleated red blood cells (NRBCs). The detection process involves exposing the cells to WNR-specific reagents containing an acidic detergent and a fluorescent dye and measuring the intensity of the forward scattered light (FSC) and side fluorescence light (SFL). METHOD: We treated isolated peripheral WBCs and NRBCs with specific reagents and assessed the morphological changes in NRBCs and each leukocyte type using transmission electron microscopy (TEM). RESULTS: The results from a flow cytometer (FCM) showed that, after exposure to the reagents, basophils appeared on the highest FSC and SFL areas compared to other leukocytes on the WNR scattergram. Owing to the hemolysis of reticulocytes and erythrocytes, NRBCs that survived the reagent treatment could be distinguished by their lower intensity than those of the other leukocytes on the WNR scattergram. We investigated the significance of the relationship between the TEM and FCM results after the reagent treatment. CONCLUSION: We confirmed that the WNR channel differentiates the blood cells on the WNR scattergram based on differences in the amount of residual cytoplasm and nucleic acids. PMID- 28856232 TI - Operational impact of using a vanadate oxidase method for direct bilirubin measurements at an academic medical center clinical laboratory. AB - OBJECTIVES: The aim of this study was to compare the operational impact of using vanadate oxidase versus diazo direct bilirubin assays for an academic medical center patient population. DESIGN AND METHODS: Retrospective study was done over an approximately 3.5 year period. The main automated chemistry instrumentation was a Roche Diagnostics cobas 8000 line. The Roche Direct Bilirubin assay was compared to Diazyme Laboratories Direct Bilirubin Assay and Randox Laboratories Direct Bilirubin assay using manufacturer's guidelines for hemolysis index, lipemia index, and analytical measurement range (AMR). RESULTS: Retrospective data was analyzed for 47,333 serum/plasma specimens that had clinical orders for direct bilirubin. A total of 5943 specimens (12.6%) exceeded the hemolysis index limit for the Roche method compared to only 0.2% and 0.05% of specimens for the Diazyme and Randox methods, respectively. The impact was particularly large on patients less than 2 years old, for which 51.3% of specimens exceeded the hemolysis index for the Roche method. A total of 1671 specimens (3.5%) exceeded the lipemia index limit for the Roche method compared to less than 0.1% for the Randox method. Lastly, 988 (2.1%) of specimens had direct bilirubin concentrations exceeding the upper AMR limit of 10 mg/dL [171 umol/L] for the Roche assay compared to less than 1% of specimens for the vanadate oxidase methods. CONCLUSIONS: Vanadate oxidase direct bilirubin methods offer advantages over diazo methods in terms of less interference by hemolysis and lipemia, as well as wider AMR. The advantages are particularly evident for neonatal and infant populations. PMID- 28856233 TI - Performance evaluation of enzyme immunoassay for voriconazole therapeutic drug monitoring with automated clinical chemistry analyzers. AB - OBJECTIVE: Voriconazole is a triazole antifungal developed for the treatment of fungal infectious disease, and the clinical utility of its therapeutic drug monitoring has been evaluated. Recently, a new assay for analyzing the serum voriconazole concentration with an automated clinical chemistry analyzer was developed. We evaluated the performance of the new assay based on standardized protocols. METHODS: The analytical performance of the assay was evaluated according to its precision, trueness by recovery, limit of quantitation, linearity, and correlation with results from liquid chromatography-tandem mass spectrometry (LC-MS/MS). The evaluation was performed with the same protocol on two different routine chemistry analyzers. All evaluations were performed according to CLSI Guidelines EP15, EP17, EP6, and EP9 [1-4]. RESULTS: Coefficients of variation for within-run and between-day imprecision were 3.2 5.1% and 1.5-3.0%, respectively, on the two different analyzers for pooled serum samples. The recovery rates were in the range of 95.4-102.2%. The limit of blank was 0.0049 MUg/mL, and the limit of detection of the samples was 0.0266-0.0376 MUg/mL. The percent recovery at three LoQ levels were 67.9-74.6% for 0.50 MUg/mL, 75.5-80.2% for 0.60 MUg/mL, and 89.9-96.6% for 0.70 MUg/mL. A linear relationship was demonstrated between 0.5 MUg/mL and 16.0 MUg/mL (R2 =0.9995-0.9998). The assay correlated well with LC-MS/MS results (R2 =0.9739-0.9828). CONCLUSIONS: The assay showed acceptable precision, trueness, linearity, and limit of quantification, and correlated well with LC-MS/MS. Therefore, its analytical performance is satisfactory for monitoring the drug concentration of voriconazole. PMID- 28856234 TI - Evaluation of cystatin C in malignancy and comparability of estimates of GFR in oncology patients. AB - OBJECTIVES: Creatinine is the biomarker of choice for use in estimates of kidney function in oncology patients. However as non-renal factors such as muscle mass can influence creatinine concentrations, we evaluated cystatin C as an alternative biomarker and its incorporation in GFR estimating formulae in an oncology setting. Measured GFR is infrequently undertaken in adult clinical practice with the consequent reliance on calculated GFR for patient assessment. DESIGN AND METHODS: Cystatin C and creatinine concentrations were evaluated from 134 oncology patients prior to commencing chemotherapeutic cycles. Estimates of creatinine clearance (Cockroft-Gault) and GFR (using Hoek, Jonsson, MDRD and CKD EPI) were evaluated. Cystatin C-based GFR estimates (using CKD-EPI CysC and CKD EPI SCr/CysC) were compared with the creatinine-based GFR estimates (CG, MDRD and CKD-EPI SCr) within the GFR ranges of 60-89, 45-59 and <=44 mL/min/1.73 m2. RESULTS: Cystatin C concentrations were significantly higher in oncology patients both prior to commencing chemotherapy (F: P<0.01 and M: P<0.0001) and during cycles of treatment (F: P<0.0001 and M: P<0.01) when compared with a reference population. Cystatin C concentrations also increased significantly during chemotherapy (P<0.0001) in a subset of female patients evaluated. Poor agreement (average 42%) was demonstrated between CKD-EPI CysC and creatinine-based GFR estimates within the investigated GFR ranges, with improved agreement (average 55%) when using the combined CKD-EPI SCr/CysC formula. CONCLUSIONS: This study demonstrated a malignancy and treatment-mediated effect on cystatin C measures, which may confound its clinical utility in estimating GFR in oncology patients. PMID- 28856235 TI - Regional tau deposition and subregion atrophy of medial temporal structures in early Alzheimer's disease: A combined positron emission tomography/magnetic resonance imaging study. AB - INTRODUCTION: Molecular imaging and selective hippocampal subfield atrophy are a focus of recent Alzheimer's disease (AD) research. Here, we investigated correlations between molecular imaging and hippocampal subfields in early AD. METHODS: We investigated 18 patients with early AD and 18 healthy control subjects using 11C-Pittsburgh compound-B (PIB) positron emission tomography (PET) and 18F-THK5351 PET and automatic segmentation of hippocampal subfields with high resolution T2-weighted magnetic resonance imaging. The PET images were normalized and underwent voxelwise regression analysis with each subregion volumes using SPM12. RESULTS: As for 18F-THK5351 PET, the bilateral perirhinal cortex volumes were significantly associated with the ipsilateral or bilateral temporal lobar uptakes, whereas hippocampal subfields showed no correlations. 11C-PIB PET showed relatively broad negative correlation with the right cornu ammonis 3 volumes. DISCUSSION: Regional tau deposition was correlated with extrahippocampal subregional atrophy and not with hippocampal subfields, possibly reflecting different underlying mechanisms of atrophy in early AD. Amyloid might be associated with right cornu ammonis 3 atrophy. PMID- 28856236 TI - Overweight and Body Image Perception in Adolescents with Triage of Eating Disorders. AB - PURPOSE: To verify the influence of overweight and alteration in the perception of the corporal image during the triage of eating disorders. METHOD: A food disorder triage was performed in adolescents with 10 to 19 years of age using the Eating Attitudes Test (EAT-26), Children's Eating Attitudes Test (ChEAT), and Bulimic Investigatory Test Edinburgh (BITE), as well as a nutritional status evaluation. The perception of body image was evaluated in a subsample of adolescents with 10 to 14 years of age, using the Brazilian Silhouette Scale. The project was approved by the Human Research Ethics Committee of the Federal University of Vicosa, Minas Gerais, Brazil. RESULTS: The prevalence of eating disorder triage was 11.4% (n = 242) for the 2,123 adolescents evaluated. Overweight was present in 21.1% (n = 447) of the students, being more prevalent in the early adolescence phase, which presented levels of distortion of 56.9% (n = 740) and dissatisfaction of 79.3% (n = 1031). Body dissatisfaction was considered as a risk factor, increasing by more than 13 times the chance of TA screening. CONCLUSION: Overweight was correlated with the ED triage and body dissatisfaction was considered as a risk factor, increasing the chances of these disorders by more than 13 times. PMID- 28856237 TI - T Cell-Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC. AB - The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)+ HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL). Coculture of GPC3+ cells, GPC3-ENG MSCs, and T cells resulted in T cell activation, as judged by interferon gamma (IFNgamma) production and killing of tumor cells by T cells. Modification of GPC3-ENG MSCs with CD80 and 41BBL was required for antigen dependent interleukin-2 (IL-2) production by T cells and resulted in faster tumor cell killing by redirected T cells. In vivo, GPC3-ENG MSCs +/- costimulatory molecules had antitumor activity in the HUH7 HCC xenograft model, resulting in a survival advantage. In conclusion, MSCs genetically modified to express GPC3-ENG +/- costimulatory molecules redirect T cells to GPC3+ tumor cells and have potent antitumor activity. Thus, further preclinical exploration of our modified approach to GPC3-targeted immunotherapy for HCC is warranted. PMID- 28856238 TI - Reovirus FAST Protein Enhances Vesicular Stomatitis Virus Oncolytic Virotherapy in Primary and Metastatic Tumor Models. AB - The reovirus fusion-associated small transmembrane (FAST) proteins are the smallest known viral fusogens (~100-150 amino acids) and efficiently induce cell cell fusion and syncytium formation in multiple cell types. Syncytium formation enhances cell-cell virus transmission and may also induce immunogenic cell death, a form of apoptosis that stimulates immune recognition of tumor cells. These properties suggest that FAST proteins might serve to enhance oncolytic virotherapy. The oncolytic activity of recombinant VSVDeltaM51 (an interferon sensitive vesicular stomatitis virus [VSV] mutant) encoding the p14 FAST protein (VSV-p14) was compared with a similar construct encoding GFP (VSV-GFP) in cell culture and syngeneic BALB/c tumor models. Compared with VSV-GFP, VSV-p14 exhibited increased oncolytic activity against MCF-7 and 4T1 breast cancer spheroids in culture and reduced primary 4T1 breast tumor growth in vivo. VSV-p14 prolonged survival in both primary and metastatic 4T1 breast cancer models, and in a CT26 metastatic colon cancer model. As with VSV-GFP, VSV-p14 preferentially replicated in vivo in tumors and was cleared rapidly from other sites. Furthermore, VSV-p14 increased the numbers of activated splenic CD4, CD8, natural killer (NK), and natural killer T (NKT) cells, and increased the number of activated CD4 and CD8 cells in tumors. FAST proteins may therefore provide a multi-pronged approach to improving oncolytic virotherapy via syncytium formation and enhanced immune stimulation. PMID- 28856239 TI - Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of Arc/Arg3.1 and Other Immediate Early Genes. AB - The histone variant H2A.Z is an essential and conserved regulator of eukaryotic gene transcription. However, the exact role of this histone in the transcriptional process remains perplexing. In vertebrates, H2A.Z has two hypervariants, H2A.Z.1 and H2A.Z.2, that have almost identical sequences except for three amino acid residues. Due to such similarity, functional specificity of these hypervariants in neurobiological processes, if any, remain largely unknown. In this study with dissociated rat cortical neurons, we asked if H2A.Z hypervariants have distinct functions in regulating basal and activity-induced gene transcription. Hypervariant-specific RNAi and microarray analyses revealed that H2A.Z.1 and H2A.Z.2 regulate basal expression of largely nonoverlapping gene sets, including genes that code for several synaptic proteins. In response to neuronal activity, rapid transcription of our model gene Arc is impaired by depletion of H2A.Z.2, but not H2A.Z.1. This impairment is partially rescued by codepletion of the H2A.Z chaperone, ANP32E. In contrast, under a different context (after 48 h of tetrodotoxin, TTX), rapid transcription of Arc is impaired by depletion of either hypervariant. Such context-dependent roles of H2A.Z hypervariants, as revealed by our multiplexed gene expression assays, are also evident with several other immediate early genes, where regulatory roles of these hypervariants vary from gene to gene under different conditions. Together, our data suggest that H2A.Z hypervariants have context-specific roles that complement each other to mediate activity-induced neuronal gene transcription. PMID- 28856240 TI - Heterogeneity in Kv2 Channel Expression Shapes Action Potential Characteristics and Firing Patterns in CA1 versus CA2 Hippocampal Pyramidal Neurons. AB - The CA1 region of the hippocampus plays a critical role in spatial and contextual memory, and has well-established circuitry, function and plasticity. In contrast, the properties of the flanking CA2 pyramidal neurons (PNs), important for social memory, and lacking CA1-like plasticity, remain relatively understudied. In particular, little is known regarding the expression of voltage-gated K+ (Kv) channels and the contribution of these channels to the distinct properties of intrinsic excitability, action potential (AP) waveform, firing patterns and neurotransmission between CA1 and CA2 PNs. In the present study, we used multiplex fluorescence immunolabeling of mouse brain sections, and whole-cell recordings in acute mouse brain slices, to define the role of heterogeneous expression of Kv2 family Kv channels in CA1 versus CA2 pyramidal cell excitability. Our results show that the somatodendritic delayed rectifier Kv channel subunits Kv2.1, Kv2.2, and their auxiliary subunit AMIGO-1 have region specific differences in expression in PNs, with the highest expression levels in CA1, a sharp decrease at the CA1-CA2 boundary, and significantly reduced levels in CA2 neurons. PNs in CA1 exhibit a robust contribution of Guangxitoxin-1E sensitive Kv2-based delayed rectifier current to AP shape and after hyperpolarization potential (AHP) relative to that seen in CA2 PNs. Our results indicate that robust Kv2 channel expression confers a distinct pattern of intrinsic excitability to CA1 PNs, potentially contributing to their different roles in hippocampal network function. PMID- 28856241 TI - Structural Learning in a Visuomotor Adaptation Task Is Explicitly Accessible. AB - Structural learning is a phenomenon characterized by faster learning in a new situation that shares features of previously experienced situations. One prominent example within the sensorimotor domain is that human participants are faster to counter a novel rotation following experience with a set of variable visuomotor rotations. This form of learning is thought to occur implicitly through the updating of an internal forward model, which predicts the sensory consequences of motor commands. However, recent work has shown that much of rotation learning occurs through an explicitly accessible process, such as movement re-aiming. We sought to determine if structural learning in a visuomotor rotation task is purely implicit (e.g., driven by an internal model) or explicitly accessible (i.e., re-aiming). We found that participants exhibited structural learning: following training with a variable set of rotations, they more quickly learned a novel rotation. This benefit was entirely conferred by the explicit re-aiming of movements. Implicit learning offered little to no contribution. Next, we investigated the specificity of this learning benefit by exposing participants to a novel perturbation drawn from a statistical structure either congruent or incongruent with their prior experience. We found that participants who experienced congruent training and test phase structure (i.e., rotations to rotation) learned more quickly than participants exposed to incongruent training and test phase structure (i.e., gains to rotation) and a control group. These results suggest that structural learning in a visuomotor rotation task is specific to previously experienced statistical structure and expressed via explicit re-aiming of movements. PMID- 28856242 TI - 3D Visualization of Individual Regenerating Retinal Ganglion Cell Axons Reveals Surprisingly Complex Growth Paths. AB - Retinal ganglion cells (RGCs), the sole output cells of the retina, are a heterogeneous population of neurons that project axons to visual targets in the brain. Like most CNS neurons, RGCs are considered incapable of mounting long distance axon regeneration. Using immunolabeling-enabled 3D imaging of solvent cleared organs (iDISCO) in transgenic mice, we tracked the entire paths of individual RGC axons and show that adult RGCs are highly capable of spontaneous long-distance regeneration, even without any treatment. Our results show that the Thy1-H-YFP mouse sparsely labels RGCs, consisting predominantly of regeneration competent alpha-type RGCs (alphaRGCs). Following optic nerve crush, many of the YFP-labeled RGC axons extend considerable distances proximal to the injury site with only a few penetrating through the lesion. This tortuous axon growth proximal to the lesion site is even more striking with intravitreal ciliary neurotrophic factor (CNTF) treatment. We further demonstrate that despite traveling more than 5 mm (i.e., a distance equal to the length of mouse optic nerve), many of these circuitous axons are confined to the injury area and fail to reach the brain. Our results re-evaluate the view that RGCs are naturally incapable of re-extending long axons, and shift the focus from promoting axon elongation, to understanding factors that prevent direct growth of axons through the lesion and the injured nerve. PMID- 28856244 TI - Design and Methods of the Korean Organ Transplantation Registry. AB - BACKGROUND: Beneficial aspects of solid organ transplantation, which encompass survival benefit, improved quality of life, and cost efficacy, have been clearly demonstrated. However, regional and ethnic differences require further studies to identify prognostic factors and transplant outcomes against various backgrounds. After previous efforts of a nationwide, retrospective study on the kidney transplant outcomes in Korea, a new prospective-designed version of the Korean Organ Transplantation Registry (KOTRY) was launched in 2014. METHODS: Cohorts of kidney, liver, heart, lung, and pancreas transplantation were developed. Data on demographics, comorbid conditions, laboratory tests, including tissue typing and panel reactive antibody tests, immunosuppressive regimen followed, concentration and dosage of immunosuppressants, allograft rejection type, infectious events, cardiovascular outcomes, malignancies, donor comorbidity, and outcomes of living donors are collected. Longitudinal data collection is based on a regular annual interval, and blood samples are collected before organ transplantation and again at 1 and 3 years posttransplantation. To enhance data quality, a predefined data verification system operates on a Web-based database, and transplant center users receive regular education about updates. Data are cleansed thrice a year, and feedback given to centers about outlier values and missing data. Annual auditing is conducted. RESULTS: Currently, 59 centers are participating in KOTRY. The estimated annual enrollment is more than 2000 cases. CONCLUSIONS: KOTRY, as a systematic Korean transplant cohort, is expected to provide important information on Asian organ transplantation. The processes used to establish KOTRY provide a good model for launching new nationwide transplant cohort studies. PMID- 28856245 TI - Weight Changes in Black and White Women Receiving Chemotherapy Treatment for Breast Cancer. AB - PURPOSE: Weight gain after a breast cancer diagnosis is associated with poor cancer outcomes. Limited research describes patterns of weight change by race. The goal of this study was to assess and compare the percent of weight change and change in body mass index (BMI) after chemotherapy in Black and White breast cancer patients. METHODS: Black and White women diagnosed with invasive non metastatic breast cancer were recruited from two metropolitan areas. Medical records were abstracted to obtain clinical (e.g. cancer stage) and treatment variables (e.g. chemotherapy regimen). Weight change was examined in 98 women who underwent chemotherapy. Differences in baseline characteristics by race were evaluated using the chi-square or Fisher's exact test for categorical variables and t-test for continuous variables. We performed bivariate associations between study variables and relative weight change. RESULTS: Most (62%) participants maintained their pre-treatment weight; 38% gained more than 5% of their baseline weight by the end chemotherapy. Normal weight women had the highest mean increase (3.57; 1.05, 6.10) compared to those that were overweight/obese. Fifteen percent of women shifted to a higher BMI category; 26% of those that were normal became overweight; 17% of overweight patients became obese. Blacks were more likely than whites to shift to a higher BMI (P=0.06). CONCLUSIONS: Results underscore the need for integrating weight control within cancer treatment plans to prevent weight gain in patients undergoing chemotherapy. Future studies that help to elucidate behaviors and/or biological factors that contribute to weight gain overall and in blacks will be important. PMID- 28856243 TI - Presence of Androgen Receptor Variant in Neuronal Lipid Rafts. AB - Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane-initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats. This putative splice variant protein has a molecular weight of 45 kDa and lacks an N terminal domain, indicating it is homologous to the human AR45 splice variant. Interestingly, AR45 was highly expressed in all brain regions examined. In dopaminergic neurons, AR45 is localized to plasma membrane lipid rafts, a microdomain involved in cellular signaling. Further, AR45 protein interacts with membrane-associated G proteins Galphaq and Galphao. Neither age nor hormone levels altered AR45 expression in dopaminergic neurons. These results provide the first evidence of AR45 protein expression in the brain, specifically plasma membrane lipid rafts. AR45 presence in lipid rafts indicates that it may function as a membrane androgen receptor to mediate fast, nongenomic androgen actions. PMID- 28856246 TI - Breast cancer chemoprevention pharmacogenomics: Deep sequencing and functional genomics of the ZNF423 and CTSO genes. AB - Our previous GWAS using samples from the NSABP P-1 and P-2 selective estrogen receptor modulator (SERM) breast cancer prevention trials identified SNPs in ZNF423 and near CTSO that were associated with breast cancer risk during SERM chemoprevention. We have now performed Next Generation DNA sequencing to identify additional SNPs that might contribute to breast cancer risk and to extend our observation that SNPs located hundreds of bp from estrogen response elements (EREs) can alter estrogen receptor alpha (ERalpha) binding in a SERM-dependent fashion. Our study utilized a nested case-control cohort selected from patients enrolled in the original GWAS, with 199 cases who developed breast cancer during SERM therapy and 201 matched controls who did not. We resequenced approximately 500 kb across both ZNF423 and CTSO, followed by functional genomic studies. We identified 4079 SNPs across ZNF423 and 3876 across CTSO, with 9 SNPs in ZNF423 and 12 in CTSO with p < 1E-02 that were within 500 bp of an ERE motif. The rs746157 (p = 8.44E-04) and rs12918288 SNPs (p = 3.43E-03) in intron 5 of ZNF423, were in linkage equilibrium and were associated with alterations in ER-binding to an ERE motif distant from these SNPs. We also studied all nonsynonymous SNPs in both genes and observed that one nsSNP in ZNF423 displayed decreased protein expression. In conclusion, we identified additional functional SNPs in ZNF423 that were associated with SNP and SERM-dependent alternations in ER binding and transcriptional regulation for an ERE at a distance from the SNPs, thus providing novel insight into mechanisms of SERM effect. PMID- 28856247 TI - Quantitative Image Quality Comparison of Reduced- and Standard-Dose Dual-Energy Multiphase Chest, Abdomen, and Pelvis CT. AB - We present a new image quality assessment method for determining whether reducing radiation dose impairs the image quality of computed tomography (CT) in qualitative and quantitative clinical analyses tasks. In this Institutional Review Board-exempt study, we conducted a review of 50 patients (male, 22; female, 28) who underwent reduced-dose CT scanning on the first follow-up after standard-dose multiphase CT scanning. Scans were for surveillance of von Hippel Lindau disease (N = 26) and renal cell carcinoma (N = 10). We investigated density, morphometric, and structural differences between scans both at tissue (fat, bone) and organ levels (liver, heart, spleen, lung). To quantify structural variations caused by image quality differences, we propose using the following metrics: dice similarity coefficient, structural similarity index, Hausdorff distance, gradient magnitude similarity deviation, and weighted spectral distance. Pearson correlation coefficient and Welch 2-sample t test were used for quantitative comparisons of organ morphometry and to compare density distribution of tissue, respectively. For qualitative evaluation, 2-sided Kendall Tau test was used to assess agreement among readers. Both qualitative and quantitative evaluations were designed to examine significance of image differences for clinical tasks. Qualitative judgment served as an overall assessment, whereas detailed quantifications on structural consistency, intensity homogeneity, and texture similarity revealed more accurate and global difference estimations. Qualitative and quantitative results indicated no significant image quality degradation. Our study concludes that low(er)-dose CT scans can be routinely used because of no significant loss in quantitative image information compared with standard-dose CT scans. PMID- 28856249 TI - The prevalence and severity of 25-(OH)-vitamin D insufficiency in HCV infected and in HBV infected patients: a prospective study. AB - AIM OF THE STUDY: To assess the prevalence and severity of vitamin D insufficiency in patients with hepatitis C virus (HCV) infection and in patients with hepatitis B virus (HBV) infection. MATERIAL AND METHODS: This prospective study included 90 patients with chronic hepatitis C and 35 patients with chronic hepatitis B admitted to the Infectious Diseases Department between March 2013 and May 2014. Patients with chronic liver disease other than viral hepatitis, HIV co infection, advanced liver disease and a history of diseases influencing vitamin D status were excluded. Serum vitamin D measurement as well as liver function, viral load, HCV genotype, interleukin 28 and liver fibrosis assessments were performed. RESULTS: In all patients, the mean vitamin D serum concentration was 18.8 (+/- 8.9) ng/ml. The mean vitamin D level in HBV infected patients was lower than in HCV infected patients (17.6 ng/ml vs. 19.3 ng/ml; p = 0.43). Vitamin D status was assessed in relation to viral load, HCV genotype, interleukin 28 and sex, but the differences were not significant. In both groups, serum vitamin D levels were significantly lower in winter compared to summer (14.2 ng/ml vs. 23.9 ng/ml in patients infected with HCV [p < 0.000001] and 14.7 ng/ml vs. 23.8 ng/ml in patients infected with HBV [p < 0.001]). CONCLUSIONS: Our study showed that in patients with chronic hepatitis C or chronic hepatitis B, insufficient 25(OH)D concentrations occur very often, but are not associated with poor virological characteristics. The only factor influencing the vitamin D level was the season. PMID- 28856248 TI - Distribution of HBV genotypes in Poland. AB - AIM OF THE STUDY: To identify distribution of HBV genotypes in particular regions of Poland. MATERIAL AND METHODS: The study included 270 treatment-naive, HBV infected individuals, enrolled in 7 centers of Poland. HBV genotyping was performed in 243 of them with the INNO-LiPA HBV Genotyping assay (Innogenetics). RESULTS: Genotype A present in 2/3 patients was demonstrated as the most predominant in Poland. It was followed by D (20%), H (5%) and mixed A + D (5%). Remaining patients were infected with genotype F, mixed D + G, A + C or D + F. Analysis of distribution demonstrated regional differences, with a higher rate of genotype D prevalence (about 30%) in the eastern (Bialystok and Lublin) and south western (Wroclaw) parts compared to other regions, where the prevalence rate was below 15%. The highest prevalence of genotype A (exceeding 80%) was observed in central Poland (Bydgoszcz, Lodz). CONCLUSIONS: The presented data reveal the current distribution of HBV genotypes across Poland, which is the first and the largest such epidemiological analysis. PMID- 28856250 TI - Impact of rs12979860 polymorphism on liver morphology in chronic HCV infection. AB - AIM OF THE STUDY: To determine distribution of rs12979860 genotypes, their correlations with viral load as well as inflammatory activity and stage of liver fibrosis in patients infected with HCV genotype 1. MATERIAL AND METHODS: The study included 132 patients infected with HCV genotype 1b. Serum viral loads were obtained with the PCR method. Rs12979860 polymorphisms were determined by sequencing of PCR products. Liver biopsy was performed in all patients. RESULTS: CT, TT and CC alleles of rs12979860 polymorphism were detected in 58%, 20% and 22% of patients respectively. The highest viral load was observed in the TT and the lowest in the CC group (72.0 * 106 IU/ml vs. 2.1 * 106 IU/ml, p < 0.005). A significant correlation was demonstrated between patient's age and inflammatory activity as well as degree of liver fibrosis. No association was found between liver histopathology and HCV viral load or rs12979860 genotypes. CONCLUSIONS: There is an association between HCV viral load and rs12979860 polymorphism. Inflammatory activity and stage of liver fibrosis depend on age, but there is no relationship with rs12979860 genotypes and HCV viral load. PMID- 28856252 TI - Severe intrahepatic cholestasis and liver failure after stanozolol usage - case report and review of the literature. AB - Stanozolol is a 17alpha-alkylated synthetic anabolic steroid used illegally by bodybuilders. We present a 19-year-old man who was taking 50 mg of stanozolol intramuscularly, every other day for 2 months, to improve muscle mass. On admission, his bilirubin concentration was 44.34 mg/dl. The serum levels of liver enzymes were normal, with only alanine aminotransferase being slightly elevated. Liver biopsy revealed toxic hepatitis of minor grade with periportal fibrosis and intrahepatic cholestasis. Medical treatment of the patient was conservative. Despite the therapy the patient's general condition deteriorated - bilirubin level increased to 56.64 mg/dl, and INR rose to 1.7. Then we decided to administer low doses of hydrocortisone. As a result of the treatment, bilirubin concentration was 14.61 mg/dl after 2 weeks. Finally all hepatic enzymes returned to normal values 5 months after stanozolol was discontinued. This treatment appears to be safe and leads to a more rapid reduction of bilirubin. PMID- 28856253 TI - Immune regulation and viral diversity as correlates of natural and treatment induced immune control in persistent hepatitis B virus (HBV) infection. AB - In long-lasting chronic hepatitis B, the phenomenon of cytotoxic CD8 T lymphocytes (CTL) exhaustion and unresponsiveness to HBV-specific stimuli was shown to be crucial for the loss of immune control of the virus and disease activity. There is evidence that Tregs, Th17 cells and Bregs seem to be important in pathogenesis of the immunological dysfunction and loss of HBV-specific activity of cytotoxic CD8 T-cells. Th17-driven immune response was shown to be important in pathogenesis of acute HBV infection and exacerbated chronic hepatitis B along with Th1 response contributing to hepatocellular damage due to proinflammatory activities of Th17-derived cytokines, mainly IL-17A. Treg cell responses may be either beneficial or harmful in HBV infection by limiting liver immunopathology or suppressing protective T cell responses, thus promoting virus replication and survival. Thus, Treg/Th17 equilibrium seems to be crucial for the outcomes of HBV infection. PMID- 28856251 TI - Insulin resistance and its consequences in chronic hepatitis C. AB - Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized. PMID- 28856254 TI - Autoimmune reactions in the course of the hepatitis C virus (HCV) infection. AB - The immune response to the presence of the virus, both specific and non-specific, plays a decisive role in the natural history of the infection, and influences the intensity of lesions in the liver. Despite the great progress which we were able to observe over the last several years, many issues still require clarification. The problem of autoimmune reactions during hepatitis C virus (HCV) infection includes at least two issues. First, the risk of exacerbating reactions against the organism's own tissues that existed before the treatment. There is also an increased risk of the development of de novo autoimmune reactions, triggered mostly by interferon alpha. Hepatitis C virus infection predisposes to the development of diseases characterised as being certainly or probably immune mediated. Currently the situation has changed due to introducing non-interferon therapies for HCV treatment, which eliminate the risk associated with immunotherapy in patients with autoimmune diseases, yet the therapies are not widely available. PMID- 28856255 TI - Recommendations for treatment of hepatitis C. Polish Group of HCV Experts - 2015. PMID- 28856256 TI - Elevated circulating endothelial cell-derived microparticle levels in patients with liver cirrhosis: a preliminary report. AB - AIM OF THE STUDY: To determine plausible associations between liver cirrhosis and circulating endothelial cell-derived microparticles (EMPs), vascular endothelial growth factor (VEGF) levels and plasma nitric oxide (NO) metabolites. MATERIAL AND METHODS: Sixty patients with cirrhosis and 20 healthy control subjects were enrolled in the study. Circulating EMPs from platelet-poor plasma samples were examined by flow cytometry. These microparticles were categorized into endothelial cell-derived activated MPs (EMP-ac) (CD31+ CD42b- AN-V-) and endothelial cell-derived apoptotic MPs (EMP-ap) (CD31+ CD42b- AN-V+). Plasma VEGF levels were measured by enzyme-linked immunosorbent assay. Plasma NO metabolites (NOx-) levels were determined using a Greiss reaction method. RESULTS: Compared with the healthy control subjects, the patients with cirrhosis showed a significant increase in plasma levels of both phenotypes of EMPs. When the presence of ascites was considered, the plasma levels of EMP-ap were higher (p < 0.01), as well as NOx- (p < 0.05). EMP-ap positively correlated with VEGF level in all cirrhotic patients and this correlation was stronger in decompensated cirrhotic patients. In multivariate logistic regression analysis, the independent factors associated with the presence of ascites were high EMP-ap levels and elevated VEGF levels. CONCLUSIONS: Elevated plasma levels of EMP-ap in addition to high levels of VEGF might be considered as valuable parameters for predicting the occurrence of ascites in cirrhotic patients. PMID- 28856257 TI - Effect of hepatitis B virus (HBV) infection on the course of pregnancy and newborns' health status. AB - INTRODUCTION: The effect of chronic hepatitis B virus (HBV) infection on pregnancy is not clear. Hepatitis B virus infection of newborns in the case of natural delivery occurs in 70-90% of cases. Risk factors of infection are the presence of serum HBeAg and HBV DNA level above 107 IU/ml. Active and passive prevention protect more than 95% of neonates born to mothers infected with HBV. The aim of the study was to determine the course of pregnancy in HBV-infected women, the mode of delivery, efficacy of prophylaxis against HBV infection in newborns, and health condition of newborns within the first years of life. MATERIAL AND METHODS: The course of 104 pregnancies in 69 women infected with HBV was monitored. Hepatitis B virus viral load was determined by PCR using the AmpliPre/COBAS TaqMan HBV system. Neonatal HBV infection and the health condition at birth and during the first year of life were analyzed. RESULTS: All included pregnant women were HBeAg negative. No clinically significant disorders were observed during pregnancy. Viral load measured in the third trimester did not exceed 107 IU/ml in any pregnant woman. Only 5 (8%) of them demonstrated levels above 105 IU/ml. Two women (1.9%) experienced a miscarriage, which was considered as not associated with HBV infection. The majority (56%) of pregnancies ended with spontaneous labor. Complete prevention against HBV was applied in 79% of newborns. Hepatitis B virus infection was diagnosed in 3 children who received incomplete or no prophylaxis. Hepatitis B virus infection occurred in 3 (2.9%) children born naturally, who did not receive proper prevention after delivery. The Apgar score in children born to mothers infected with HBV did not differ significantly from that in neonates born to healthy women from the same population. Allergic disorders developed in 17 children who underwent HBV prophylaxis. CONCLUSIONS: Low viral load in pregnant women infected with HBV and the absence of HBeAg reduce the probability of infection of newborns. Proper prevention carried out after delivery seems to be the most important method to prevent HBV infection in newborns. PMID- 28856258 TI - Liver involvement in children with collagen vascular diseases. AB - Liver injury such as hepatomegaly, splenomegaly and various degrees of biochemical abnormalities are quite common in children with collagen vascular diseases. They may be primary or secondary, particularly due to drug therapy (drug toxicity, fatty infiltration), superadded infections, diabetes or overlap with autoimmune hepatitis. PMID- 28856259 TI - Nutrition principles and recommendations in different types of hepatic encephalopathy. AB - Appropriate nutrition - in terms of both quantity and quality - is not only one of the main life processes. A well-balanced diet including sufficient amounts of minerals and vitamins supports proper human development and functioning from fetal development to very advanced old age; it promotes regeneration after intensive exercise and is a key element for successful treatment of most acute and chronic diseases, including liver diseases. PMID- 28856260 TI - Severe fatty liver disease and acute pancreatitis: is there a correlation between them? AB - In this manuscript, we present two cases of patients with severe fatty liver disease developing acute pancreatitis. They might suggest an association between severe fatty liver disease and acute pancreatitis. PMID- 28856261 TI - Antiviral therapy of chronic HBV infection in pregnancy. AB - We describe a 27-year-old hepatitis B virus (HBV)-infected pregnant woman, with a history of miscarriage a year ago. The patient has been HBsAg and HBeAg positive for 20 years but has never been treated for HBV infection, because of stable elevated alanine aminotransferase (ALT) activity and high viral load. Treatment with tenofovir disoproxil was introduced in the 10th week of pregnancy and HBV DNA became undetectable. The clinical course of pregnancy was normal and the patient gave birth by caesarean section to a healthy child. At birth the newborn was HBsAg negative, after 3 months of follow-up is healthy, and evaluation of HBV status will be scheduled shortly. The decision to treat HBV infection during pregnancy should be individualized. PMID- 28856262 TI - Hepatocellular carcinoma - an unusual metastatic presentation on the chest wall. AB - Hepatocellular carcinoma (HCC) is a common malignancy for which chronic hepatitis B infection has been defined as the most common etiologic factor. The most frequent metastatic sites are the lung, bone, lymphatics, and brain. Metastases to the chest wall have been reported rarely. We report a patient with HCC who presented with an isolated metastatic mass on the right chest wall. Metastasis of HCC should be included in the differential diagnosis of rapidly growing lesions in unusual locations, particularly in patients with chronic liver disease and HBsAg-positive patients, even if a primary tumor cannot be radiologically identified. PMID- 28856263 TI - Meeting of Initiative Group for Central European Hepatologic Collaboration (CEHC): Warsaw, 19-21 November 2015. PMID- 28856264 TI - Epidemiology of HCV infection in the Central European region. AB - Opinion leaders in each of four countries in the Central European region summarize the available data on hepatitis C virus (HCV) epidemiology. The overall prevalence of anti-HCV antibody reactivity in this region varies between 0.2% and 2.1%, the most prevalent HCV genotype is GT 1. The commonest route of transmission is intravenous drug abuse at present. PMID- 28856265 TI - New therapeutic options for HCV in Central Europe. AB - New therapeutic options became available in 2015 in the European Union. We present the availability of interferon-free regimens with direct acting antivirals (DAA) in four Central European countries - the Czech Republic, Hungary, Poland and Slovakia - which despite similar historical, geographical and economic situations demonstrate different systems for access to anti-HCV (hepatitis C virus) medication. Treatment of patients in the Czech Republic was based in 2015 on an exceptional individual reimbursement procedure, but regular reimbursement procedures are expected in 2016. In Hungary the decision for treatment is balanced against budget limitations and the national Priority Index system reflecting stage of liver disease, activity of the disease and predictive factors. A reimbursed interferon (IFN)-free therapeutic program for all genotypes, without restrictions related to hepatic fibrosis and treatment history, is already available in Poland. In Slovakia patients with advanced fibrosis are currently selected for possible IFN-free therapy in 2016. PMID- 28856266 TI - Evaluation of hepatic fibrosis - access to non-invasive methods, national practice/guidelines in Central Europe. AB - Noninvasive methods have improved diagnostic tools of liver fibrosis. Although liver biopsy is the gold standard for diagnosis of hepatis fibrosis, the noninvasive tests are usually much less expensive than liver biopsy, better tolerated, and can be repeated without any risk for the patient. Two groups of these noninvasive tests are included in clinical practice: serum biomarkers and elastography. In our paper we summarize noninvasive diagnostic options for liver fibrosis in the Czech Republic, Hungary, Poland and Slovakia. Noninvasive diagnostic methods, especially elastography, are widely accessible in all countries. PMID- 28856267 TI - Hepatology topics of special interest from Central Europe (Czech Republic, Hungary, Poland, Slovakia). AB - This compilation represents abstracts of presentations at the first meeting of the Initiative Group for the Central European Hepatologic Collaboration (CEHC, Warsaw, 19-21 November, 2015) on topics with special interest from four Central European countries and includes a summary of a boceprevir-based triple therapy cohort programme (from Hungary), current trends and challenges in liver diseases (from Poland), acute kidney injury in liver cirrhosis (from Slovakia) and treatment of hepatitis C in haemodialysed patients (from the Czech Republic). All these topics are or have been of high interest during the last several years, and many of them are still not completely resolved with the emergence and availability of the novel interferon-free therapies for hepatitis C and with other advances in the pathophysiology and treatment of liver diseases. PMID- 28856268 TI - Liver transplantation in Central Europe. AB - INTRODUCTION: Transplant hepatologists convened in Warsaw on 20-21 November 2015 at a meeting of the Initiative Group for Central European Hepatologic Collaboration to exchange their experience in liver transplantation in their respective countries. MATERIAL AND METHODS: The description is based on narration of individual country representatives, supplemented by data from additional queries, and from publicly accessible sources. RESULTS: Liver transplantation programs were launched, in the Czech Republic in 1983, in Poland in 1990 (paediatric) followed by the adult program 1994; the first liver transplant in Hungary was performed in 1995, with Slovakia launching its liver transplantation program in 2008. Currently, there are 2 centres for liver transplantation in Slovakia, 1 centre in Hungary, 6 centres in Poland, and 2 centres in the Czech Republic. The rates of liver transplantation correspond to the number of cadaveric donations being the highest in the Czech Republic (15.8 per million population) and the lowest in Slovakia (4.2 per million population) (2014 data). Live donation is utilized systematically in Poland. Indications vary from country to country, but the 3 most frequent ones include hepatitis C and B cirrhosis, alcoholic cirrhosis, and cholestatic liver disorders. There is a growing incidence of hepatocellular carcinoma among adult liver transplant recipients. Biliary atresia and hereditary diseases are the most frequent indications among children. Hungary became a member of Eurotransplant, other countries are not a part of any international organization for organ sharing. CONCLUSIONS: Despite some differences, liver transplant programs seem to be compatible honouring the same values and principles universal to liver transplant programs in most parts of the world. PMID- 28856269 TI - Recommendations for the treatment of hepatitis C issued by the Polish Group of HCV Experts - 2016. PMID- 28856270 TI - Real-world experience with ombitasvir/paritaprevir boosted with ritonavir and possibly combined with dasabuvir and ribavirin in HCV infection. AB - Ombitasvir/paritaprevir boosted with ritonavir and possibly combined with dasabuvir and ribavirin (OBV/PTV/r +/- DSV +/- RBV) is a new direct-acting antiviral (DAA) regimen which has improved efficacy of chronic hepatitis C virus (HCV) treatment significantly. OBV/PTV/r +/- DSV +/- RBV in clinical trials demonstrated sustained viral response (SVR) rates close to 100%. In this article we collected currently available data of 5726 patients for evaluation of OBV/PTV/r +/- DSV +/- RBV efficacy and safety in real-world experience. The sustained viral response rate in this large population was 97%, and it was exactly the same even in patients with liver cirrhotics. According to this meta analysis, less than 3% of patients discontinued treatment due to adverse events. PMID- 28856271 TI - The importance of nutrition for pediatric liver transplant patients. AB - Pediatric liver transplantation has changed the poor prognosis for children with liver failure, some metabolic diseases and liver tumors. With the increase of survival, long-term maintenance has become a priority. Therefore, obtaining appropriate nutrition, physical growth, bone metabolism, endocrine function and psychosocial development has become one of the most important long-term objectives. This article presents an up-to-date review and recommendation of nutrition assessment, both before and after liver transplantation. PMID- 28856272 TI - Assessing the consistency of liver fibrosis results obtained through biopsy and transient elastography in patients suffering from chronic hepatitis C. AB - Until recently, core-needle liver biopsy was used as the gold standard in chronic hepatitis C diagnostics. Information on the inflammatory activity grade and the staging of liver fibrosis or steatosis, obtained through biopsy, constituted an indispensable element in the process of determining patients' eligibility for antiviral treatment. The histological profile of the samples examined was decisive in determining the time for commencing treatment. Given that this procedure involves the risk of complications and temporarily reduces patient living comfort, it was deemed necessary to search for other ways to assess liver fibrosis. Transient elastography is a non-invasive alternative to liver biopsy. The current chronic hepatitis C treatment programme provides the possibility to perform transient elastography instead of liver biopsy. The test result is expressed in kPa. However, liver biopsy is still recommended in certain cases of unclear aetiology, or if discrepancies are found between the elastography results and patient clinical condition. The aim of this study was to compare two methods of liver fibrosis assessment in terms of consistency of results, and to analyse any inconsistent results. PMID- 28856273 TI - Acute hepatitis A virus infection in patients hospitalised at the Department of Infectious Diseases, Medical University of Lublin (Eastern Poland) in the years 2009-2015. AB - The aim of our study was to analyse all medical records from the years 2009-2015 for adult patients with acute hepatitis A virus (HAV) infection who were hospitalised at the Department of Infectious Diseases, Medical University of Lublin (Eastern Poland). During this 7-year study, there were only 5 hospitalised patients with confirmed HAV infection. In the study group 4 out of 5 patients had travelled to HAV-endemic areas (Egypt, Ukraine), and 3 of the hepatitis A cases were imported from Egypt. Our data indicate that during the past 7-year period most HAV patients hospitalised at the Department of Infectious Diseases in Lublin were due to travel. PMID- 28856274 TI - Predictors of sustained virological response in patients with hepatitis C virus genotype 3 infection. AB - AIM OF THE STUDY: To assess predictors of sustained virological response (SVR) in patients with chronic hepatitis C virus (HCV) genotype 3 treated with standard therapy. MATERIAL AND METHODS: We retrospectively investigated data of 116 consecutive treatment-naive patients chronically infected with HCV genotype 3, treated with pegylated interferon alpha (PegIFNalpha) and ribavirin (RBV) for 24 weeks. HCV RNA at week 4 (rapid virological response - RVR) and week 12 (early virological response - EVR) were measured in 85 and 105 patients respectively. Liver biopsy data were available for 103 patients. The variables were compared between patients with an SVR and those without. RESULTS: Overall 70.7% of patients achieved an SVR. Pretreatment factors including younger age, mild liver fibrosis as well as normal values of gamma-glutamyl transferase (GGT) and platelet count were significantly associated with higher SVR rate in univariate analysis. In the multivariate analysis only baseline platelet count > 140 000/ul and normal GGT activity were correlated with higher SVR rate. At weeks 4 and 12 HCV RNA was undetectable in 34.1% and 84.8% of patients respectively. The SVR rate was significantly higher in patients with an RVR compared to those without (p = 0.002). Only 2 patients with a rapid and early virological response did not achieve an SVR; both had negative pretreatment prognostic factors. CONCLUSIONS: In treatment-naive patients with genotype 3 HCV infection, low baseline platelet count and elevated GGT activity were significantly associated with poor response to PegIFNalpha and RBV. Achieving a rapid and early virological response was associated with higher likelihood of an SVR. PMID- 28856275 TI - Portal cavernoma in a case of alcoholic liver disease with myeloproliferative neoplasm. AB - Chronic liver disease is a major cause of portal vein thrombosis. Further screening for other thrombotic risk factors in patients with portal vein thrombosis and chronic liver diseases is often neglected. In this paper, we report a case of portal cavernoma in a patient who was diagnosed with alcoholic liver disease and myeloproliferative neoplasm. PMID- 28856276 TI - Successful outcome of therapy of acute hepatitis C following sexual and parenteral exposure - report of two cases. AB - Acute hepatitis C (AHC) remains difficult to diagnose due to its asymptomatic course. The manuscript presents two children with AHC after known sexual and parenteral exposure, which allowed for close monitoring. Both developed increased aminotransferase activity, though the viral load was significantly higher after parenteral exposure. Lack of hepatitis C virus (HCV) clearance led to therapy with recombinant interferon-alpha with good toleration and response. The conclusion is that treatment of AHC was effective and well tolerated. PMID- 28856277 TI - Efficacy and direct costs of chronic hepatitis C treatment with first generation NS3/4A protease inhibitors in a real life population. AB - INTRODUCTION: Recent years have brought a significant advance in chronic hepatitis C (CHC) treatment that includes development of direct acting antivirals (DAA). Two of them, boceprevir (BOC) and telaprevir (TVR), were first approved for treatment of patients infected with CHC genotype 1 in combination with pegylated interferon (P) and ribavirin (R). Our aim was to evaluate the efficacy and direct costs of BOC/PR and TVR/PR in a real life population. MATERIAL AND METHODS: The study included adult patients qualified for the CHC Therapeutic Programme treated with TVR/PR or BOC/PR. Treatment was continued for 24 or 48 weeks. Sustained virological response, treatment discontinuation due to adverse events and lack of virological response rates were compared. RESULTS: A total of 243 adult patients with CHC were included. TVR/PR and BOC/PR were administered in respectively 122 and 121 patients. Thirty-two patients (13%) were treatment naive, whereas liver cirrhosis/advanced fibrosis was observed in 138 patients (56.7%). Overall, 43.6% of patients achieved a sustained virologic response (SVR). In the BOC/PR group the SVR rate was significantly lower than in the TVR/PR group (33.1% vs. 54.1%; p = 0.00094). Lack of response to therapy was observed in 41.3% and 12.3% of patients receiving BOC and TVR, respectively (p < 0.00001). The direct cost of achieving SVR in one patient was 285 450 PLN with BOC and 185 757 PLN with TVR. CONCLUSIONS: The very low treatment efficacy may be the result of inclusion criteria that allowed treatment of patients with advanced liver fibrosis/liver cirrhosis or previous treatment failure. Telaprevir seems to be significantly more potent against hepatitis C virus, with similar safety and tolerance. PMID- 28856278 TI - Efficacy of HCV treatment in Poland at the turn of the interferon era - the EpiTer study. AB - THE AIM OF THE STUDY: Was to analyze the efficacy achieved with regimens available for chronic hepatitis C (CHC) in Poland between 2013 and 2016. MATERIAL AND METHODS: Data were collected from 29 centers and included 6786 patients with available sustained virologic response (SVR) data between 1 January 2013 and 31 March 2016. RESULTS: The sustained virologic response rate for genotypes (G) 1a, 1b, 2, 3 and 4 was 62%, 56%, 92%, 67% and 56% respectively; 71% patients (n = 4832) were treated with pegylated interferon alpha (Peg-IFNalpha) and ribavirin (RBV), with SVR rates of 58%, 49%, 92%, 67% and 55% respectively. The sustained virologic response among 5646 G1 infected patients was the lowest with natural interferon alpha (7%, n = 70) or PegIFN (50%, n = 3779) with RBV, and improved in those receiving triple regimens of Peg-IFN + RBV combined with boceprevir (47%, n = 485), telaprevir (64%, n = 805), simeprevir (73%, n = 132) or sofosbuvir (70%, n = 23). The sustained virologic response with interferon-free regimens of sofosbuvir and RBV (n = 7), sofosbuvir and simeprevir (n = 53), and ledipasvir and sofosbuvir (n = 64) achieved 86%, 89% and 94% respectively. The highest SVR of 98% was observed with ombitasvir/paritaprevir combined with dasabuvir (n = 227). Patients infected with G3 (n = 896) and G4 (n = 220) received mostly Peg IFN + RBV with SVR of 67% and 56% respectively. Interferon-free regimens were administered in 18 G3/G4 patients and all achieved an SVR. Sofosbuvir combined with Peg-IFN and RBV was administered to 33 patients with an SVR rate of 94%, and a similar rate was achieved among 13 G2 patients treated with interferon and RBV. CONCLUSIONS: We observed significant differences in efficacy of HCV regimens available in Poland at the turn of the interferon era. The data will be useful as a comparison for therapeutic options expected in the next few years. PMID- 28856280 TI - Simple non-invasive markers for early diagnosis and determination of the severity of liver diseases. AB - AIM OF THE STUDY: The aim of the study was to evaluate the effect and severity of liver diseases of different etiologies on the values of three non-invasive fibrosis markers. MATERIAL AND METHODS: Serum samples from 65 patients with alcoholic cirrhosis, 31 with non-alcoholic cirrhosis and 32 with toxic hepatitis, were tested. Cirrhotic patients were classified according to the Child-Pugh scale. The age-platelet (AP) index, HUI score and Fibro Q index were calculated using the specific formulas. RESULTS: The values of all tested scores were significantly higher in controls than in patients with liver diseases and were significantly different between liver diseases. The patients with alcoholic and non-alcoholic cirrhosis had higher values of the AP index, HUI score and Fibro Q index than patients with toxic hepatitis. HUI and Fibro Q scores appeared to vary according to the severity of liver damage and were higher in Child-Pugh class C than in classes A and B. CONCLUSIONS: We conclude that all tested scores based on liver function tests are good markers for non-invasive diagnosis of liver damage. Additionally, HUI and Fibro Q scores reflect the severity of liver cirrhosis. PMID- 28856279 TI - Prevalence of HCV genotypes in Poland - the EpiTer study. AB - THE AIM OF THE STUDY: Was to assess current prevalence of hepatitis C virus (HCV) genotypes in Poland, including their geographic distribution and changes in a given period of time. MATERIAL AND METHODS: Data were collected with questionnaires from 29 Polish centers and included data of patients diagnosed with HCV infection between 1 January 2013 and 31 March 2016. RESULTS: In total, data of 9800 patients were reported. The highest prevalence was estimated for genotype 1b (81.7%), followed by 3 (11.3%), 4 (3.5%), 1a (3.2%) and 2 (0.2%). Genotype 5 or 6 was reported in 6 patients only (0.1%). The highest prevalence of genotype 1 was observed in central (lodzkie, mazowieckie, swietokrzyskie), eastern (lubelskie) and southern (malopolskie, slaskie) Poland. The highest rate for genotype 3 was observed in south-western (dolnoslaskie, lubuskie) and eastern (podlaskie, warminsko-mazurskie and podkarpackie) Poland. Compared to historical data, we observed an increasing tendency of G1 prevalence from 72.0% in 2003 to 87.5% in 2016, which was accompanied by a decrease of G3 (17.9% vs. 9.1%) and G4 (9.0% vs. 3.1%). CONCLUSIONS: Almost 85% of patients with HCV in Poland are infected with genotype 1 (almost exclusively subgenotype 1b), and its prevalence shows an increasing tendency, accompanied by a decrease of genotypes 3 and 4. PMID- 28856281 TI - The influence of anti-HBc status on the sustained virological response rate in HCV-infected patients treated with pegylated interferon alfa 2 and ribavirin. AB - AIM OF THE STUDY: To determine the influence of HBsAg and HBeAg negative but anti HBc positive status on the sustained virological response (SVR) rate in HCV infected patients treated with pegylated interferon alfa 2 (Peg-IFNalpha-2) and ribavirin (RBV). MATERIAL AND METHODS: The study was based on the retrospective analysis of medical records of HCV-infected patients who started Peg-IFNalpha and RBV treatment between 1 January 2011 and 31 December 2013 at the 1st and 2nd Department of Infectious Diseases of the Regional Hospital in Wroclaw, Poland. RESULTS: Among 240 patients included in the analysis 99 were anti-HBc positive and 141 anti-HBc negative. In the genotype 1, anti-HBc positive group the SVR rate was 47% and in the anti-HBc negative group it was 42.7% (p = 0.591). In the genotype 3, anti-HBc positive group the SVR rate was 60% and in anti-HBc negative patients it was 63.2% (p = 0.79). Differences in SVR rates between anti-HBc positive and negative groups were not statistically significant. None of the anti HBc positive patients developed reactivation of HBV infection during or in the 24 weeks following the end of treatment. CONCLUSIONS: Anti-HBc determination does not seem to be useful in predicting treatment outcome of conventional Peg IFNalpha/RBV therapy in patients infected with HCV genotypes 1 and 3. PMID- 28856282 TI - The occurrence of autoantibodies in patients with chronic HCV infection, including patients dialyzed and after kidney transplantation. AB - INTRODUCTION: There are reports suggesting that hepatitis C virus (HCV) may stimulate the autoimmune process. Studies have been undertaken to evaluate the occurrence and type of autoantibodies in HCV-infected patients with and without immunosuppression. Results were analyzed according to HCV genotype, intensity of inflammation and liver fibrosis stage. MATERIAL AND METHODS: The study included 105 patients chronically infected with HCV, including 25 with immunological suppression administered for kidney disease or kidney transplantation. Blood samples were tested by immunoblotting for the presence of AMA-M2, SLA/LP, LKM-1, LC1, anti-F-actin, anti-desmin, anti-myosin, anti-gp210 and anti-sp100 autoantibodies, and ANA. All the patients were scored for autoimmune hepatitis. RESULTS: Autoantibodies were detected in 32.5% of patients without immunosuppression and in 16% with immunosuppression. Single types of autoantibodies were identified in 26% of patients. The most frequent ones were ANA (19%) and AMA-M2 (5.7%). The presence of antibodies in patients with genotype 1 was significantly higher in comparison to their occurrence in genotype 3. Autoimmune hepatitis was not diagnosed in any of the patients. Immunoglobulin G level was significantly higher in patients with detectable autoantibodies, compared to patients without antibodies (1.89 vs. 1.28 g/dl, p < 0.001). No correlation between fibrosis stage or intensity of inflammatory state and the frequency of antibodies was found. CONCLUSIONS: The antibodies are significantly more frequent in patients without immunosuppression and in patients infected with genotype 1 than genotype 3. The presence of these autoantibodies is not associated with the development of autoimmune hepatitis. Higher level of immunoglobulin G in the serum correlates with the presence of autoantibodies. PMID- 28856283 TI - Surgical treatment of liver tumors - own experience and literature review. AB - Despite advances, the treatment of focal liver lesions is still challenging. It requires the experience of a surgeon, improvement of existing and the development of new techniques. The aim of this article is to present a literature review and summarize our experience in liver surgery. Twenty-one patients with various liver tumors were treated in 2015 at the Department of Surgical Oncology of Bialystok Center for Oncology. Mostly patients were diagnosed with colorectal cancer liver metastases or hepatocellular carcinoma. Nine anatomical, 6 non-anatomical resections and 6 radiofrequency ablations were performed. Among 9 resections, 6 bisegmentectomies, resection of the 4b segment, and left-side and right-side hemihepatectomy were performed. Resections were associated only with minor postoperative complications. No perioperative mortality was noted. Preliminary outcomes of resections and radiofrequency ablations of liver lesions even in a low volume surgical center are promising and are associated with a relatively low rate of complications. PMID- 28856284 TI - Hepatocyte growth factor and epidermal growth factor activity during later stages of rat liver regeneration upon interferon alpha-2b influence. AB - INTRODUCTION: Liver regeneration is a complex, highly coordinated process which can be disturbed by the impact of the anti-proliferative interferon alpha activity. In the model of partial hepatectomy (PH) in the rat the expression of HGF and EGF genes and their molecules' tissue concentrations were analyzed in the later stages of liver regeneration (48-120 h). MATERIAL AND METHODS: 40 three month-old male Wistar rats were randomized to groups of 20 animals each. The rats of the study group (IFN/H) were injected subcutaneously with IFNalpha-2b, while the control group was injected with 0.5 ml of 0.9% NaCl (NaCl/H). In the liver tissue samples obtained during hepatectomy and autopsy (regenerating liver mass) the expression of HGF and EGF genes was estimated with the Q-PCR method and the analysis of HGF and EGF molecule concentrations in tissue homogenates was conducted with the ELISA method. RESULTS: HGF but not EGF expression was significantly higher at 48 h after PH, while EGF expression was higher in normal than in regenerating liver tissue at 120 h. The analyses of correlations between expression of HGF and EGF in regenerating liver tissue, both normal and upon IFNalpha-2b influence, together with correlations between those factors genes' expression and HGF and EGF tissue concentrations in analyzed samples, showed no significant differences. CONCLUSIONS: HGF and EGF are not significantly involved in regulation of later stages of rat liver regeneration. IFNalpha-2b does not impact expression of their genes or the presence of these growth factor molecules in regenerating liver tissue. PMID- 28856285 TI - Association of TNF-alpha and CCL5 with response to interferon-based therapy in patients with HCV 1 genotype. AB - AIM OF THE STUDY: To evaluate the role of potential genetic predictors -308G/A TNF-alpha and -403G/A CCL5 in treatment for HCV 1 genotype. MATERIAL AND METHODS: Treatment results of 130 patients with chronic hepatitis C 1 genotype according to different genotypes of IL28B, CCL5, and TNF-alpha were analysed using multiple logistic regression. RESULTS: IL28B genotypes CC/CT/TT were found in 27 (20.8%), 74 (56.9%), and 29 (22.3%) patients. Genotypes GG/GA/AA of -308G/A TNF-alpha were revealed in 98 (75.4%), 30 (23.1%), and 2 (1.5%) patients. Genotypes GG/GA/AA of 403G/A CCL5 were revealed in 86 (66.2%), 39 (30%), and 5 (3.8%) patients, respectively. The previously known effect of IL28B was observed. IL28B TT genotype decreased end of treatment response (EOTR) rates by a factor of 29.0 (95% CI: 6.4-183). The combination of CCL5 GG and IL28B CT genotypes increased the risk of failure to achieve EOTR by a factor of 28.5 (95% CI: 7.2-160). Genotypes GA and AA of TNF-alpha (-308) G/A SNP increased the risk of relapse in patients who achieved EOTR (OR = 9.4; 95% CI: 2.4-48). CONCLUSIONS: Practitioners may benefit from using these predictors when considering indications for the antiviral therapy and deciding on the treatment regimen. PMID- 28856287 TI - Acute-on-chronic hepatitis. A case report of autoimmune hepatitis/primary sclerosing cholangitis/ulcerative colitis overlap syndrome in a 15-year-old patient. AB - Acute-on-chronic liver failure (ACLF) is a disease in which a rapid deterioration of liver function occurs in patients with chronic liver disease, and is usually associated with a precipitating event. We present the case of a boy with autoimmune hepatitis/primary sclerosing cholangitis/ulcerative colitis (AIH/PSC/UC) overlap syndrome, in whom liver function was stable for 4.5 years of treatment. At 15 years of age the patient was hospitalized due to a deterioration of his general condition, severe abdominal pain, diarrhoea, vomiting and weight loss. There was also a rapid deterioration of liver function and a deterioration of renal function. Despite a wide spectrum of diagnostic examinations, no precipitating agent was found. After two episodes of massive bleeding from the gastrointestinal tract, the patient was transferred to the intensive care unit. The patient underwent a successful liver transplantation. ACLF can cause irreversible liver failure with a high mortality rate, which calls for liver transplantation. PMID- 28856286 TI - Hepatitis D, B and C virus (HDV/HBV/HCV) coinfection as a diagnostic problem and therapeutic challenge. AB - Coinfection with hepatitis D virus (HDV) in chronic hepatitis B is associated with more rapid progression to liver cirrhosis. We present two cases of infection with hepatitis D, B and C viruses. Both male patients were primarily diagnosed as infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), HBsAg-positive and anti-HCV-positive. The first patient was treated with interferon, lamivudine and pegylated interferon. A full virological and biochemical response was achieved. The second patient was treated with interferon and ribavirin, lamivudine and twice with pegylated interferon. In the ultrasound elastography progression of liver fibrosis to F4 was described. HDV infection should be considered in patients with HBV minireplication, high activity of aminotransferases and progression of liver disease despite a good virological response to anti-HBV treatment. Efficacy of interferon in HDV infection is severely limited. PMID- 28856288 TI - Toxic hepatitis caused by the excretions of the Phyllomedusa bicolor frog - a case report. AB - The Kambo ritual consists of various types of skin scarification and subsequent application of Phyllomedusa bicolor secretion to the fresh wounds. In Europe, the ritual of Kambo is becoming more popular, but its use can lead to serious multiple organ damage, sometimes life-threatening. Our manuscript shows a patient with toxic liver damage probably associated with the Kambo ritual. PMID- 28856289 TI - Recommendations for the treatment of hepatitis B in 2017. AB - The therapeutic goal which is currently unfrequent but realistic in HBV infected patients is sustained HBsAg clearance. It is preceded by the loss or significant suppression of HBV replication and leads to inhibition of the progression of liver fibrosis, normalization of biochemical indicators of liver damage, reduction in the risk of hepatocellular carcinoma, prolongation of survival, prevention of HBV infection in the transplanted organ in post-transplant patients, enhancement of the quality of life, inhibition or reversal of extrahepatic changes associated with HBV infection, and halting of the spread of HBV infections. Recommendations of Polish Group of Experts for HBV for 2017 provide guidelines to assess treatment eligibility, choice of the first-line drug, monitoring and duration of treatment, management of treatment failure as well as therapy of HBV associated cirrhosis or hepatocellular carcinoma. Moreover it contains advice for treatment of HBV infection in children, females planning pregnancy or pregnant. We also included recommendations for pre- and post exposure prophylaxis, prevention of HBV transmission from mother to infant, after liver transplantation, on immunosuppressive therapy and during HCV treatment. PMID- 28856290 TI - Recommendations for the treatment of hepatitis C in 2017. AB - The goals of treatment is to eliminate HCV infection, stop or reverse histological changes, reduce the risk of hepatocellular carcinoma development and transmission of the infection to other individuals. According to the recommendation of the Polish Group of Experts for HCV in 2017 all patients with chronic HCV infection should receive treatment, but it is not recommended in patients at high risk of short overall survival. If access to therapy is restricted, priority should be given to patients whose HCV infection can lead to an unfavourable outcome of the disease within a short time frame, particular to individuals with liver cirrhosis, rapidly progressing liver fibrosis, extrahepatic manifestations of HCV infection, chronic kidney diseases, patients before and after organ transplantation. Current recommendations of Polish Group of Experts for HCV provide guidelines to select optimal medication, assessment of liver fibrosis, treatment efficacy, dealing with resistance to direct acting antivirals, monitoring for hepatocellular carcinoma, management of HBV/HCV coinfection and drug interactions. It constains also advice on treatment of special patients populations such as renal failure, liver transplant and hepatic decompensation, as well as retreatment of patients which failed interferon free therapy. Moreover specific recommendations of management patients infected with different genotypes with currently reimbursed regimens or those expected to become available shortly in Poland are also included. PMID- 28856291 TI - Confirmation of Intimal Tear in Thrombosed-Type Acute Aortic Dissection by Virtual Angioscopy. AB - INTRODUCTION: Therapeutic strategies for intramural hematoma (IMH) involving the ascending aorta remain controversial. REPORT: The patient was a 72 year old woman with a history of chest pain. Multidetector computed tomography (MDCT) showed an IMH involving the ascending aorta. Because virtual angioscopy revealed a punctate intimal tear in the ascending aorta, acute aortic dissection with an intimal tear and not IMH was diagnosed, and emergency surgery was performed. The post operative course was uneventful. DISCUSSION: Virtual angioscopy allows the vascular lumen to be examined minimally invasively on the basis of images reconstructed from MDCT data. Even if MDCT does not clearly show an intimal tear associated with aortic dissection in a general view, virtual angioscopy can show the exact location and size of the tear before surgery. Virtual angioscopy is very useful for distinguishing thrombosed-type acute aortic dissection without clear ulcer like projections from an IMH, which may facilitate therapeutic planning. PMID- 28856292 TI - Successful Stenting of Iatrogenic Anterior Tibial Artery Pseudoaneurysm. AB - INTRODUCTION: The use of covered tibial stents extends beyond the treatment of atherosclerotic disease. Tibial artery pseudoaneurysms have traditionally been managed with open surgery; however, the endovascular option is an emerging treatment. REPORT: This report describes endovascular management of an iatrogenic anterior tibial artery pseudoaneurysm using a covered stent. CONCLUSION: This case highlights the use of a covered stent for pseudoaneurysm exclusion, vascular control, and to minimize dissection in a patient with multiple previous surgeries. PMID- 28856293 TI - Reverse Retrograde Approach: An Alternative Method for Ipsilateral Access to the Superficial Femoral Artery. AB - Access for endovascular treatment of the superficial femoral artery (SFA) is usually gained through an antegrade approach from the ipsilateral common femoral artery (CFA), or by crossing over from the contralateral CFA. In this technical note, an alternative method, based on retrograde access of the ipsilateral iliac artery (IA), and conversion into an antegrade approach to the SFA, is described. Successful reverse ipsilateral catheterisation was obtained in 15/16 patients. Calcification of the CFA and IA required a crossover approach in one case. There were no complications related to the technique, except for moderate bleeding in relation to the deployment of a closure device. PMID- 28856294 TI - Surgical Technique for Deep Venous Reflux Suppression in Femoral Vein Duplication. AB - BACKGROUND: Deep venous surgery is a challenging field with limited indications. Femoral vein duplication (FVD) is a frequent anatomical variant (55% prevalence). The aim was to describe a simple technique for managing deep venous reflux in FVD, when just one of the two segments exhibits deep venous reflux. METHODS: The technique consists of closing the refluxing femoral branch with a titanium clip. In this way abolition of reflux along the duplicated vessel is achieved, together with the restoration of femoral vein drainage. RESULTS: The technique is feasible and associated with improvement in limb haemodynamics. CONCLUSIONS: Thanks to the high prevalence of FVD, the proposed technique provides an opportunity to treat a larger number of cases affected by primary or post-thrombotic deep venous reflux. PMID- 28856295 TI - The One-Stop Aortic Surveillance Clinic. AB - BACKGROUND: The principle of interval ultrasound surveillance of small abdominal aortic aneurysms (AAA) is well established. The fundamental principle of surveillance is that repair of AAA is a serious undertaking and the risk of the operation outweighs the risk of rupture in aneurysms less than 5.5 cm. Surveillance is well established but requires multiple visits to both the surgical clinic and the ultrasound department. REPORT: This report presents a system whereby the vascular surgeon is trained in the process of aortic sonography with a view to one-stop clinic assessment. After training of the main investigators in aortic sonography, the surgeons performed scans on the aortas of 80 consecutive patients and compared the scan result with the subsequent formal scan. DISCUSSION: Surgical and radiographer scans correlate very closely. It is believed that the one-stop aortic surveillance model is safe, accurate, and improves both the patient journey and clinic throughput. PMID- 28856296 TI - Endovascular Treatment for Infra-inguinal Autologous Saphenous Vein Graft Occlusion Using Self Expanding Nitinol Stents. AB - INTRODUCTION: For patients with infra-inguinal autologous vein bypass graft occlusion, conventional open surgical repair or endovascular treatment (EVT) for native vessel occlusion have generally been performed. REPORT: A 73 year old female with non-healing ulcer and gangrene of the left lower leg was diagnosed as having infra-inguinal autologous saphenous vein graft occlusion. In this case, surgical repair such as patch angioplasty, interposition graft, or replacement graft did not seem promising because of repeated previous infection in the polytetrafluoroethylene (PTFE) vascular prosthesis and absence of available autologous vein due to past surgery. Moreover, there was no chance of crossing the native vessel, since the proximal superficial femoral artery (SFA) had already been resected. Thus, EVT was performed for the occluded autologous vein graft, implanting multiple self expanding bare nitinol stents throughout the vein graft achieving complete revascularization, good medium term patency, and dramatically improved wound healing. CONCLUSION: Endovascular recanalization using multiple bare stents could be an alternative treatment for infra-inguinal autologous vein graft occlusion. PMID- 28856297 TI - Angiojet Thrombo-aspiration Guided by Trans-Oesophageal Ultrasound. AB - INTRODUCTION: A 59 year old woman presented with acute right leg ischemia. On the computed tomography scan, thrombi were seen in the brachiocephalic trunk, in the descending aorta, in the infrarenal aorta, in the right deep femoral artery, and in the right crural arteries. TECHNIQUE: To remove the risk of cerebral emboli, thrombo-aspiration of the brachiocephalic trunk was planned, with associated thrombectomy of the infrarenal aorta, the right deep femoral artery, and the right crural arteries. Because the brachiocephalic thrombus could not be visualized with angiography, the anesthetists, who were performing a trans oesophageal ultrasound of the heart, were asked to locate the thrombus, which was easily seen on the trans-oesophageal ultrasound. The aspiration catheter Angiojet (Boston Scientific, Marlborough, MA, USA) could be positioned under ultrasound guidance. Complete aspiration of the thrombus was then confirmed with the ultrasound (see video). The thrombectomy of the infrarenal aorta and right leg was then performed by open surgery. The patient's recovery was uneventful. Despite extensive investigations no etiology was found for the thrombi. DISCUSSION: Pre-operative trans-oesophageal ultrasound is routinely performed by anesthetists in patients with acute ischemia, to search for a cardiac source of emboli. In this case it had the added advantage of helping to locate and aspirate a thrombus in the brachiocephalic trunk. PMID- 28856298 TI - Drain Anchoring and Removal Technique Without Change of Dressing in Transtibial Amputation. PMID- 28856300 TI - Intra-operative Ultrasound as a Tool to Assess Free Borders of Primary Vascular Aortic Tumors During Resection. AB - INTRODUCTION: Primary vascular tumors are rare and, in general, have a poor prognosis. Complete resection is associated with a better prognosis. Radical resection depends on safe discrimination of tumor borders. TECHNICAL SUMMARY: A 54 year old woman presented with abdominal pain. Imaging revealed a mass in the thoracic aorta, highly suspicious of angiosarcoma which was confirmed post operatively by histological analysis. Open surgery was performed. Prior to clamping of the aorta, intra-operative ultrasound established clear delineation of the tumor borders. CONCLUSION: Intra-operative ultrasound was, in this case, a safe and easy method to determine the tumor borders, providing a simple guide to in toto tumor removal. PMID- 28856299 TI - Inferior Mesenteric Artery Side Branch for Selected Patients with Endovascular Aortic Aneurysm Repair. AB - OBJECTIVE/BACKGROUND: To report on our experience of the treatment of aortic aneurysms by custom-made, branched stent-grafts with an additional inferior mesenteric artery (IMA) side branch to preserve IMA perfusion in patients at risk for colon ischemia. METHODS: Three male patients (mean age 60 years) with a thoracoabdominal, pararenal, and infrarenal aortic aneurysm (AA), respectively, were treated by endovascular aneurysm exclusion using custom-made, branched stent grafts with a side branch to the IMA for prevention of colon ischemia. Indications for selective IMA side branch perfusion were occlusions or high-grade stenosis of the visceral or hypogastric arteries. RESULTS: No colon ischemia and no neurological deficit were observed. All three IMA side branches were perfused and patent, as documented by computed tomography scan and duplex ultrasound postoperatively and after 12 months. Patency after 24 months was documented as 2/3. CONCLUSION: Custom-made, branched stent-grafts are an endovascular option to preserve the IMA perfusion in selected, electively treated patients with an increased risk for insufficient colon perfusion due to stenosis or occlusions of visceral or hypogastric arteries. PMID- 28856301 TI - A Pseudoaneurysm of the Deep Palmar Arch After Penetrating Trauma to the Hand: Successful Exclusion by Ultrasound Guided Percutaneous Thrombin Injection. AB - INTRODUCTION: Pseudoaneurysm of the hand is a rare condition; most are treated surgically. Ultrasound guided thrombin injection has not previously been reported as a treatment option for pseudoaneurysms of the deep palmar arch. REPORT: A man was referred to the emergency department with a swollen, painful hand after penetrating trauma. On physical examination, a pulsating tumor was found on the dorsum of the hand. Imaging revealed a pseudoaneurysm vascularized by the deep palmar arch. Ultrasound guided percutaneous thrombin injection was successfully performed. CONCLUSION: Thrombin injection might be a safe alternative option in the treatment of pseudoaneurysm of the deep palmar arch. PMID- 28856302 TI - Immediate Catheter Directed Thrombolysis for Thromboembolic Stroke During Carotid Endarterectomy. AB - BACKGROUND: Carotid artery endarterectomy (CEA) is a common procedure undertaken by vascular surgeons with over 5,000 procedures performed annually worldwide. Published rates of perioperative stroke range from 1.3% to 6.3%. CASE REPORT: A case is presented in which on-table intra-cranial angiography and catheter directed thrombolysis were used for a thromboembolic occlusion of the distal internal carotid artery (ICA) and proximal middle cerebral artery (MCA). An 83 year-old lady developed a dense right hemiparesis while undergoing a CEA under local anaesthetic (LA). Immediate re-exploration of the endarterectomy did not reveal technical error. Intraoperative duplex scanning of the internal carotid artery revealed no detectable diastolic flow. On-table angiogram showed complete occlusion of the distal ICA and proximal MCA. Catheter directed administration of TPA was undertaken. The entire ICA and MCA were completely clear on a completion angiogram. The patient made a full neurological recovery. DISCUSSION AND CONCLUSION: Prompt diagnosis and treatment with intraoperative catheter directed thrombolysis can resolve thromboembolic occlusion of the ICA/MCA. It is argued that performing CEA under LA is useful for immediate recognition of perioperative stroke. Furthermore, the advantage is highlighted of vascular surgeons having both the resources and skillset to perform on-table angiography and thrombolysis. PMID- 28856303 TI - Aorto-enteric Fistula 15 Years After Uncomplicated Endovascular Aortic Repair with Unforeseen Onset of Endocarditis. AB - INTRODUCTION: Aorto-enteric fistula after endovascular aortic repair is an exceedingly rare but serious condition. REPORT: A rare case of a fistula between the excluded aortic sac and the transverse colon 15 years after endovascular aortic repair is described. Onset was endocarditis without gastrointestinal haemorrhage, migration, endoleak, or aortic sac dilatation. The patient was successfully treated by fistula excision, debridement and broad spectrum antibiotic treatment without endograft explantation. DISCUSSION: Aorto-enteric fistula can emerge after endovascular repair with an unforeseen onset such as endocarditis, which in this case probably occurred as metastatic sepsis from endograft infection. PMID- 28856304 TI - Endovascular Repair of a Chronic AV Fistula Presenting as Post-Partum High Output Heart Failure. AB - INTRODUCTION: Acute injury to the large vessels is the most feared of diagnoses for a spinal surgeon, but far more common is the delayed presentation of arteriovenous fistula (AVF) formation. The mean time to diagnosis of an AV fistula in this scenario is just over 1 month. Treatment can include both open and endovascular repair. REPORT: This study presents a case of an otherwise healthy 39-year-old woman who initially presented with orthopnea, leg edema, and a presumptive diagnosis of post-partum cardiomyopathy. Cardiac investigations revealed high output cardiac failure and an abdominal CT scan confirmed an arterial venous fistula from the left common iliac artery to left common iliac vein. The patient maintained a cardiac output three times normal prior to her definitive treatment. This high flow physiology caused unique challenges for the endovascular procedure as the stent graft collapsed and distorted toward the iliac side wall. The AV fistula was eventually covered successfully and post operative studies show no further fistula and normal cardiac function. This case demonstrates an unanticipated effect of very high flows of stent graft deployment. DISCUSSION: Extreme high flow AV fistulas can present as unexpected challenges to endovascular repair. These issues may be ameliorated by techniques such as controlled hypotension, adenosine, ventricular pacing, or proximal balloon occlusion. PMID- 28856305 TI - Novel Use of Smartphone-based Infrared Imaging in the Detection of Acute Limb Ischaemia. AB - INTRODUCTION: Infrared thermal imaging is based on perfusion changes reflected by skin temperature variations. It is an established non-invasive diagnostic method within vascular surgery, with applications such as peripheral arterial disease assessment and prevention of diabetic foot complications. However, owing to hardware limitations or lack of resources, it is not yet widely used in clinical practice. REPORT: A novel portable infrared imaging camera, easily powered via a smartphone and free App software, was used to obtain digital thermograms during the clinical evaluation of acute limb ischaemia (ALI). DISCUSSION: Portable infrared imaging represents a new promising tool for the assessment of tissue perfusion that can be applied at the bedside during clinical evaluation of suspected ALI. PMID- 28856306 TI - Angiosarcoma of the Descending Aorta, Diagnostic Difficulties. AB - INTRODUCTION: Primary angiosarcomas of the aorta are rare and because of their non-specific presentation, the initial diagnosis is often very difficult. REPORT: A 66 year old woman, initially suffering from night sweats and general malaise, is presented. A computerized tomography (CT) scan was performed which showed a filling defect of the descending aorta. This defect later caused embolic occlusion of the celiac vessels. The patient underwent surgical resection of the filling defect of the descending aorta and an embolectomy of the celiac vessels. The defect was histopathologically diagnosed as an angiosarcoma. The clinical presentation, diagnostic pitfalls, histopathological diagnosis, and the therapeutic management are discussed. DISCUSSION: In this case report, the importance of carefully diagnosing an angiosarcoma is highlighted as the consequences could be rapid metastasization or embolization. PMID- 28856307 TI - Surgeon Modified Fenestrated Endovascular Abdominal Aortic Repair (F-EVAR) for Subacute Multifocal Mycotic Abdominal and Iliac Artery Saccular Aneurysms. AB - INTRODUCTION: Endovascular repair of suprarenal abdominal aortic aneurysms (AAAs) requires customized fenestrated stent grafts when they involve visceral vessels such as the renal (clinically ignored here in this specific scenario), celiac, and superior mesenteric arteries. REPORT: On table fenestrated endovascular abdominal aortic aneurysm repair (F-EVAR), using a parallel endograft approach, was performed for enlarging saccular subacute mycotic suprarenal and left common iliac artery aneurysms in a 58 year old man with recent methicillin sensitive Staphylococcus aureus (MSSA) bacteremia, who was high risk for open surgical repair. Fenestrations were performed for the coeliac artery (CA) and superior mesenteric artery (SMA) using a Bovie(r) (Clearwater, FL, USA) cautery device. The initial procedure was complicated by a type II endoleak that resolved spontaneously within 6 months of surgery. The patient remained well on follow up a year post surgery. CONCLUSION: On table surgeon modified F-EVAR is a safe and viable option for patients with subacute suprarenal mycotic abdominal aneurysms. PMID- 28856308 TI - Limb Necrosis Caused by Sclerotherapy When Treating Venous Malformation. AB - INTRODUCTION: Percutaneous interventional sclerotherapy has been widely used to treat venous malformation. Satisfactory results have been reported, along with both mild and severe complications. REPORT: A 1.5 year old girl was diagnosed as having a venous malformation of the right vulva and right inner thigh. The patient received sclerotherapy using polidocanol. After the surgery, the right foot and lower leg became pale, and then, a few days later, necrotic. CONCLUSION: Accurate diagnosis and appropriate treatment are challenging for vascular malformations and should only be carried out in centers with ample expertise. PMID- 28856309 TI - A Novel Hybrid Viabahn-assisted Bypass Technique: Extra-arterial Flossing Wiring for Chronic Total Occlusion in Superficial Femoral Artery. AB - INTRODUCTION: A hybrid Viabahn-assisted bypass (VAB) technique is introduced for revascularizing chronic total occlusion (CTO) in superficial femoral artery (SFA) when bypass surgery is difficult or endovascular intervention fails. REPORT: This technique combines extra-arterial flossing wiring with antegrade-retrograde intervention via traditional open exposure of middle SFA and deploying a Viabahn from the proximal true lumen through the subintimal lumen and extra-arterial space, and back into distal true lumen to restore flow. It only needs a 3-5 cm incision to expose the mid-SFA without clamping or endarterectomy of the SFA. DISCUSSION: This hybrid procedure is an alternative technique to improve SFA revascularization in some difficult CTOs. PMID- 28856310 TI - A Novel Combined Hybrid Approach to Enable Revascularisation of a Trauma-Induced Subclavian Artery Injury. AB - INTRODUCTION: This case highlights the complexity of upper limb revascularization after a subclavian artery traumatic injury and strengthens the role of a hybrid/multi-disciplinary approach to such injuries. REPORT: A 45-year-old male patient presented with an acute right upper limb following a traumatic injury to the right subclavian artery due to a motor vehicle accident (MVA). Associated injuries included an unstable cervical spine injury, a large open right clavicular injury, and a brain injury, which limited the potential revascularisation options available. The arm was revascularised using a hybrid endovascular/open surgical approach, namely embolization of the proximal subclavian artery (just distal to vertebral artery) and a right common femoral artery to distal axillary artery bypass using prosthetic material. DISCUSSION: Blunt injuries to the subclavian artery are often high impact, complex and associated with multiple injuries to surrounding structures, which limit the role of standard procedures used in the elective setting. This case highlights the role of multidisciplinary team involvement, using a hybrid approach and a novel distal inflow site to restore upper limb perfusion. PMID- 28856311 TI - "Raking-in Technique:" Removal Of Brachiocephalic Vein Thrombus Using AngioVac(r) Device Within A Stented Venous Segment. AB - INTRODUCTION: A case is reported of left brachiocephalic vein thrombus removal using the Angiovac device within a stented venous segment via a through-and through access technique. REPORT: This novel technique involves obtaining through and-through access from the left basilic vein to the right femoral vein, which then facilitates the advancement of the Angiovac device to successfully remove in a stepwise fashion the thrombus present within a stented region of the left brachiocephalic vein. DISCUSSION: The Angiovac device has been shown to be very useful and effective at removing large amounts of thrombus, tumor, and foreign bodies within arterial and venous systems successfully. This novel technique uses the through-and-through venous access approach to allow for this device to remain close to the targeted area of thrombus burden and prevent damage of the already existing stents in this region. PMID- 28856313 TI - Challenges of "Reverse" Aortic Arch Debranching for Repair of the Ascending Aorta by Thoracic Endovascular Aortic Repair. AB - INTRODUCTION: Ascending aortic pathology presents a unique challenge for treatment by thoracic endovascular aortic repair (TEVAR), because of lack of adequate endograft landing zones. This report describes a unique "reverse" extra anatomical aortic arch debranching procedure performed to enable TEVAR of the ascending aorta. REPORT: A 71-year-old male presented with a large ascending aortic pseudoaneurysm secondary to previous arch repair anastomosis. This pathology was treated by TEVAR of the ascending aorta. To create a sufficient landing zone for the endovascular stent graft, a "reverse" extra-anatomical aortic arch debranching procedure was performed. This involved a left subclavian artery to left carotid artery bypass, left to right carotid-to-carotid bypass, ligation of proximal left common carotid artery, and embolization of the innominate artery origin. DISCUSSION: TEVAR of the ascending aorta can be made feasible through a novel debranching procedure that creates sufficient landing zones for the endograft. This surgical approach may prove useful in patients who present with aortic arch pathology and comorbidities that prevent open surgical repair. PMID- 28856312 TI - Endovascular Repair of Ruptured Popliteal Artery Aneurysms: A Case Report and Review of the Literature. AB - OBJECTIVE/BACKGROUND: The objectives were to report the management and outcomes of a 96-year-old man who presented with an acutely swollen right leg due to a ruptured popliteal aneurysm, and to review the relevant literature. METHODS: A ruptured popliteal artery aneurysm is a rare diagnosis and is one that is often missed at time of presentation. Previous case reports have documented successful outcomes following surgical repair, and a smaller number following endovascular repair. This is a case report of a 96-year-old man who eventually underwent endovascular repair of a ruptured popliteal artery aneurysm after a delay in diagnosis. A literature review was performed to analyse published data in this field. RESULTS: The patient underwent an uncomplicated endovascular repair with a GORE(r) VIABAHN(r) stent. A 15-week follow-up ultrasound demonstrated biphasic flow in a patent stent-graft with an unchanged aneurysm sac size and no evidence of an endoleak. A review of the literature demonstrated nine cases of ruptured non-mycotic popliteal artery aneurysms treated endovascularly. Seven cases survived the postoperative period, three had no follow-up recorded, and four cases had patent stent-grafts at time of follow-up. CONCLUSION: Safe and effective endovascular repair of a ruptured popliteal artery aneurysm with endograft patency seen at the 15-week follow-up is reported. Review of the literature suggests that open repair remains the first-line management choice; however, endovascular repair is a valuable alternative. There is a further need for longer-term monitoring of endograft patency following endovascular repair. PMID- 28856314 TI - Stent-Apposition Salvage of an Anterior Tibial Artery After Inadvertent Angioplasty Balloon Retention During CTO Revascularization. AB - INTRODUCTION: Progressive improvement in the ability to treat complete total occlusions in the tibial level arterial circulation have made it possible to revascularize patients with critical limb ischemia. REPORT: A 59 year old male presented with a complete total occlusion of his anterior tibial artery with distal reconstitution through peroneal artery collaterals. During attempted angioplasty a balloon was retained within the patent portion of the target vessel. Two 3.0 mm drug eluting coronary stents were deployed across the length of the balloon with excellent luminal preservation. DISCUSSION: Successful CTO revascularization was completed and a strong dorsalis pedis artery pulse was restored following intervention. PMID- 28856315 TI - Endovascular Stent Grafting of a Deep Femoral Artery Pseudoaneurysm. AB - INTRODUCTION: Pseudoaneurysms (PSAs) are uncommon, but can occur as a complication of orthopedic procedures, usually associated with femur surgery. This report describes successful management of a PSA of the deep femoral artery (DFA) with an endovascular stent graft. REPORT: This case reports an injury that presented as a false aneurysm secondary to a fractured neck of femur, which was initially confused with hematoma. Imaging confirmed the diagnosis of PSA, and the decision was taken to implant an endovascular stent graft. DISCUSSION: The endovascular stent graft was implanted based on radiological, anatomical, and clinical parameters. This case supports the feasibility, safety, and efficacy of stenting for PSA of the DFA. PMID- 28856316 TI - Locked Temporary Vascular Shunt for Wartime Vascular Injuries. AB - INTRODUCTION: To reduce the ischaemia time of injured limbs in wartime, temporary vascular shunts (TVS) are commonly used. However, TVS are stabilized at the ends of the injured vessels using manual suture ties, the risk of dislodgement is high, and tightening manual suture ties is too time consuming. TECHNICAL SUMMARY: Locked temporary vascular shunts (LTVS) were designed, and each was composed of a silicone tube with a threaded outer surface and smooth inner surface in addition to two nylon buckle switches. The buckle switches were used to stabilize the silicone tube of the LTVS with respect to the vessel walls. This job was performed with two manual suture ties with the current TVS. The mean bursting pressure value of the veins shunted with the LTVS was 114.3% higher than that of the veins shunted with the TVS (0.045 +/- 0.008 MPa vs. 0.021 +/- 0.012 MPa; p = .00). Although the mean shunting time of the LTVS was reduced by 60.4% compared with that of the TVS (138.89 +/- 18.22 seconds vs. 350.48 +/- 52.20 seconds; p = .00), there was no significant difference in the patency times between the two types of devices (8.20 +/- 9.01 hour vs. 8.40 +/- 8.85 hour; p = .98). CONCLUSION: The LTVS, which was designed to treat wartime vascular injuries, might be safer and more efficient than the current TVS. PMID- 28856317 TI - Calcification of a Synthetic Renovascular Graft in a Child. AB - INTRODUCTION: Vascular grafts, especially in paediatric cases, need to be durable. Common failures such as thrombosis are well documented with research efforts directed towards them. However, there are lesser known causes of graft failure, such as graft calcification, and these also require further research focus. REPORT: A paediatric case is described in which a synthetic renovascular graft, implanted for mid-aortic syndrome, became calcified, necessitating surgical intervention to resolve graft malfunction. Significant calcification in the limb of a bifurcated polyethylene terephthalate graft was found to be the cause of resistant stenosis and refractory hypertension. Histology conducted on the explanted limb showed the presence of multinuclear giant cells, indicating a chronic foreign body response. DISCUSSION: Calcification of vascular grafts is probably more common than previously recognised. Stenosis typically resistant to angioplasty may result in the long term and thus leading to surgical intervention. In young children, this is suboptimal as these grafts need to last throughout adulthood. Explanted prosthetic grafts should be sent to specialist registries such as that in Strasbourg to be optimally assessed so that contributory factors can be identified. PMID- 28856318 TI - A Novel Chimney Approach for Management of Horseshoe Kidney During EVAR. AB - INTRODUCTION: Abdominal aortic aneurysms (AAAs) with coexisting horseshoe kidney (HSK) can be difficult to repair, with variable blood supply from the aorta and iliac/mesenteric vessels. Endovascular aneurysm repair (EVAR) has become a popular, less invasive approach to aneurysm care, and a chimney approach to EVAR (ChEVAR) has expanded its use to more complex anatomy. It is mandatory to maintain adequate perfusion to the HSK and visceral branches as part of the treatment of an AAA. REPORT: A 61-year-old male with an HSK was incidentally found to have an infrarenal AAA that measured 6 cm on a non-contrast computed tomography (CT) scan performed originally for a urologic complaint. A diagnostic angiogram was performed to define arterial anatomy and he was found to have a large inferior mesenteric artery (IMA) arising 1 cm above the level of the aneurysm. ChEVAR was performed to preserve the IMA and flow to the HSK with a completion angiogram revealing patent renal arteries, IMA, and no evidence of an endoleak. Follow-up CT imaging demonstrated a Type II endoleak that resolved upon partial nephrectomy for a right-sided transitional cell carcinoma with resection of the arterial blood supply feeding the Type II endoleak. DISCUSSION: IMA preservation via ChEVAR is technically feasible and was crucial to preserve blood supply via the IMA to the HSK. Partial nephrectomy treated the transitional cell carcinoma and resolved the Type II endoleak requiring no additional endovascular intervention. A unique treatment course demonstrated the benefits of less invasive interventions when repairing AAA with an HSK. PMID- 28856319 TI - Unilateral Leg Swelling Caused by Common Femoral Vein Compression by a Hip Ganglion Cyst in the Groin. AB - BACKGROUND: As a rare cause of unilateral leg swelling, extrinsic vein compression caused by intraperitoneal, retroperitoneal, or inguinal lesions has been noted. A rare case of leg swelling as a cause of extrinsic compression of common femoral vein from a ganglion cyst in the groin is presented. CASE PRESENTATION: A 38 year old man was referred with a 3 week history of left leg swelling. Following a radiological diagnosis of common femoral vein compression from a cystic groin mass, he firstly underwent needle aspiration. Although the lesion became somewhat smaller, his left leg was still swollen, and he underwent surgical excision of the lesion 2 days after needle aspiration. Histopathological features of the cystic wall were consistent with those of a ganglion cyst. He was discharged from the hospital with complete improvement of the leg swelling, and has remained free from recurrence 1 year after surgery. CONCLUSION: Femoral vein compression by a ganglion cyst in the groin is a very rare pathology; however, it should be kept in mind in the differential diagnosis of unilateral leg swelling. PMID- 28856320 TI - Atypical Presentation of a Type 2 Endoleak following Emergency Open Repair of a Ruptured Abdominal Aortic Aneurysm. AB - BACKGROUND: An endoleak is a common complication following EVAR. Specifically, a Type 2 endoleak occurs because of retrograde flow from lumbar vessels outside the endograft within the aneurysm sac. Even though it is common following EVAR, it has not been identified as a complication following open ruptured abdominal aortic aneurysm (AAA) repair. REPORT: A 73-year-old male underwent open repair of a ruptured AAA. Five months later, computed tomography revealed filling from a lumbar vessel mimicking a Type 2 "endoleak." The initial ultrasound showed a single pair of lumbar vessels with aneurysm sac expansion 8 weeks later. The "endoleak" and expanding sac were treated, and the 2-year surveillance demonstrated sac shrinkage. DISCUSSION: Because endoleak is a complication after EVAR, this case provides a unique presentation of Type 2 "endoleak" physiology following open repair of a ruptured AAA. It is believed that it is necessary to expand the list of possible complications after open ruptured AAA repair to include "endoleaks." PMID- 28856321 TI - Thrombosed Popliteal Artery Pseudoaneurysm as Herald of Tibial Osteochondroma. AB - BACKGROUND: Osteochondroma is the most common non-malignant tumour of bone, accounting for approximately one third of benign lesions in the skeleton. They often develop around the knee in the distal femur and in the proximal tibia and fibula. They present as a painless slow growing mass during adolescence and have been reported to cause damage to adjacent structures such as blood vessels; arterial damage is more common than venous injury and is usually a result of compression, stretching, and rubbing of the arterial wall. Such lesions include stenosis, thrombosis, and pseudoaneurysm formation possibly causing lower limb claudication or acute limb ischemia. METHODS: An 18 year old male patient with a 4 week history of pain, hematoma, and oedema of the left calf without previous trauma is reported. A computed tomography scan (CT) revealed a large popliteal artery pseudoaneurysm and its close relationship to a protrusion of the proximal tibia. RESULTS: The popliteal artery was repaired by an external saphenous patch and the exostosis was removed. The patient had palpable popliteal and distal pulses after surgery and during the first year follow-up. CONCLUSIONS: Tibial osteochondroma should be considered in the differential diagnosis in young patients, among the potential causes of pseudoaneurysm of the femoral or popliteal artery. Surgical repair should be performed to restore normal blood flow with resection of the exostosis to prevent recurrence. PMID- 28856322 TI - Transobturator Bypass Utilizing Fluoroscopic Guidance. AB - INTRODUCTION: Transobturator bypass is an older and less frequently performed revascularization of the lower extremity that is useful in the setting of multiple failed lower extremity bypasses usually due to groin sepsis and infection(s). It can be a technically challenging operation due to anatomic constraints. REPORT: We describe a successful transobturator bypass utilizing fluoroscopy for passage of bypass tunneler and graft through the obturator foramen. DISCUSSION: Live fluoroscopy is a versatile technique and in conjunction with our described surgical technique of lower extremity bypass should help increase the technical success rates of this procedure. PMID- 28856323 TI - Serratia liquefaciens Infection of a Previously Excluded Popliteal Artery Aneurysm. AB - INTRODUCTION: Popliteal artery aneurysms (PAAs) are rare in the general population, but they account for nearly 70% of peripheral arterial aneurysms. There are several possible surgical approaches including exclusion of the aneurysm and bypass grafting, or endoaneurysmorrhaphy and interposition of a prosthetic conduit. The outcomes following the first approach are favorable, but persistent blood flow in the aneurysm sac has been documented in up to one third of patients in the early post-operative setting. Complications from incompletely excluded aneurysms include aneurysm enlargement, local compression symptoms, and sac rupture. Notably infection of a previously excluded and bypassed PAA is rare. This is the third reported case of PAA infection after exclusion and bypass grafting and the first due to Serratia liquefaciens. METHODS: Relevant medical data were collected from the hospital database. RESULTS: This case report describes a 54 year old male patient, diagnosed with acute limb ischaemia due to a thrombosed PAA, submitted to emergency surgery with exclusion and venous bypass. A below the knee amputation was necessary 3 months later. Patient follow up was lost until 7 years following surgical repair, when he was diagnosed with aneurysm sac infection with skin fistulisation. He had recently been diagnosed with alcoholic hepatic cirrhosis Child-Pugh Class B. The patient was successfully treated by aneurysm resection, soft tissue debridement and systemic antibiotics. CONCLUSION: PAA infection is a rare complication after exclusion and bypass procedures but should be considered in any patient with evidence of local or systemic infection. When a PAA infection is diagnosed, aneurysmectomy, local debridement, and intravenous antibiotic therapy are recommended. The "gold standard" method of PAA repair remains controversial. PAA excision or endoaneurysmorrhaphy avoids complications from incompletely excluded aneurysms, but is associated with a high risk of neurological damage. PMID- 28856324 TI - Decalcification of a Heavily Calcified Common Femoral Artery and its Bifurcation with a Cavitron Ultrasonic Surgical Aspirator. AB - INTRODUCTION: Surgical endarterectomy is the preferred method for treating occlusive disease of the common femoral artery (CFA). However, endarterectomy is not always straightforward in cases with heavily calcified plaque. To overcome this limitation, a new method for decalcification, which utilizes a Cavitron ultrasonic surgical aspirator (CUSA) has been developed. REPORT: The method involves full exposure of the calcified lesion. Following an arteriotomy, protruding calcification is removed using the CUSA, taking care to avoid vessel perforation. Preservation of the medial calcified layer can be accomplished by the accurate control provided by the device, which enables smooth termination in the distal area of the normal wall and does not require a tacking suture. A total of 12 patients underwent decalcification of 13 common femoral artery (CFA) lesions using CUSA with vein patch angioplasty. Concomitant profundaplasty was performed in five cases. The only intra-operative complication was perforation of the arterial wall in one patient, while another had a wound infection that required reintervention. DISCUSSION: Decalcification of a heavily calcified CFA with CUSA appears to be feasible, although long-term follow-up examinations are warranted. PMID- 28856325 TI - Ilioprofunda Endobypass Can Successfully Treat a Post-Operative Femoral Pseudo Aneurysm. AB - INTRODUCTION: A 75-year-old male patient with significant cardiopulmonary comorbidity presented with a 70-mm left femoral pseudoaneurysm 6 years after aortobifemoral bypass (and prior femoral endarterectomy). REPORT: As the left superficial femoral artery was occluded, an ilioprofunda endobypass was undertaken following extraperitoneal exposure of the left limb of the bypass graft with subsequent deployment of four Viabahn endoprostheses via the left limb into the proximal left deep femoral artery with successful exclusion of the pseudoaneurysm. The endografts remain patent at 6 months with regression noted in the pseudoaneurysm itself. DISCUSSION: Post-operative femoral pseudoaneurysm following anastomotic dehiscence has traditionally been treated by open surgical repair. Re-re-do open femoral vascular surgery has a high complication rate. Scarring and potential graft infection may necessitate ligation of involved arteries and extra-anatomic bypasses with an attendant risk of limb loss. Although the common femoral artery is conventionally contraindicated for endograft deployment because of the perceived high risk of stent fracture in a highly mobile zone, an endobypass can avoid the potential complications of open revision groin surgery in an unfit, high-risk patient. PMID- 28856326 TI - Coronary Stent Embolisation to an Iatrogenic Arteriovenous Fistula: An Unexpected Complication. AB - INTRODUCTION: Systemic embolisation of stents represents a rare complication of coronary interventions. REPORT: The case of a patient with peripheral embolisation of a coronary stent while undergoing a coronary procedure for an ischaemic event is reported. The stent lodged at a previously created iatrogenic fistula joining the profunda femoral artery and the common femoral vein. An endovascular attempt was ineffective in treating this complication. The stent was removed surgically and the fistula repaired. DISCUSSION: This unusual clinical setting of stent embolisation concomitant to an iatrogenic arteriovenous femoral fistula is reported. PMID- 28856327 TI - Percutaneous Mechanical Thrombectomy Treatment of Acute Superior Mesenteric Artery Embolism. AB - OBJECTIVE/BACKGROUND: This report presents a superior mesenteric artery (SMA) embolism managed by percutaneous mechanical thrombectomy (PMT). METHODS: A 61 year old woman diagnosed with SMA embolism was admitted. Emboli were found in the middle and distal segments of the SMA on abdominal computed tomography angiography. Under local anaesthesia, a 6 F Rotarex system was used to remove the emboli via left brachial artery access. Emboli were successfully removed and patency was restored to the SMA and its branches. RESULTS: Post-operatively, the patient's symptoms were significantly relieved. No post-operative complications were observed and no discomfort was documented during follow-up. CONCLUSION: Endovascular treatment of SMA embolism using PMT is a feasible and alternative option. PMID- 28856328 TI - Explantation of an Infected Fenestrated Abdominal Endograft with Autologous Venous Reconstruction. AB - INTRODUCTION: Infectious complications after FEVAR cause significant problems, with radical surgery considered to be the last resort for treatment. CASE REPORT: A 72 year old man presented with infection 1 month after FEVAR. Conservative therapy with percutaneous abscess drainage and antibiotics suppressed the infection for 10 months; however, when new peri-aortic abscesses developed, the patient agreed to revision surgery. The endograft was explanted and an autologous in situ venous reconstruction was performed. As a result of post-operative complications, the patient died 3 days later. CONCLUSION: This study demonstrates that autologous venous reconstruction is technically feasible. An earlier decision on such radical surgery could potentially have improved the patient's chances of survival. PMID- 28856329 TI - Obstructive Uropathy because of a Large Rectus Sheath Haematoma: A Case Report of Combined Interventional Radiology and Surgical Approach. AB - INTRODUCTION: Rectus sheath haematomas associated with anticoagulation are often self limiting. When large, however, they can even extend into the pelvis and cause compression of adjacent organs such as the bladder. A combined endovascular and surgical approach can decrease the operative exposure necessary to treat this occurrence. REPORT: A 42 year old morbidly obese African American female on warfarin treatment for pulmonary embolism presented outside the hospital with pneumonia. During her hospitalisation, she developed a spontaneous right rectus abdominis haematoma below the level of the umbilicus with active bleeding in the extraperitoneal space causing mass compression of the bladder. She developed acute renal failure and became anuric. Following endovascular embolisation of the inferior epigastric artery, surgical exploration was successfully performed to remove the haematoma and relieve the urinary obstruction. Diuresis resumed and renal function normalised without any further evidence of bleeding. DISCUSSION: A large rectus sheath haematoma that extends into the bladder causing renal obstruction can be treated by endovascular embolisation and surgical exploration to limit operative risks and exposure in morbidly obese patients. PMID- 28856330 TI - Iliac Artery Reconstruction with Femoral Vein After Bare Metal Stent Infection. AB - INTRODUCTION: Primary infection of a bare metal stent is a rare condition, associated with significant morbidity and mortality. Definitive treatment includes stent removal and arterial reconstruction. REPORT: This study details a common iliac stent infection after re-intervention for iliac stent occlusion, complicated by pseudoaneurysm formation and septic embolisation. Potential risk factors for stent infection were identified. An open surgical resection of the affected artery along with all stent material was performed, followed by reconstruction with autologous interposition superficial femoral vein. There were no complications and no recurrent infection at 6 months follow-up. CONCLUSION: Although rare, bare metal stent infection may occur, and a high index of suspicion is required. Stent surgical removal and arterial in situ reconstruction with autologous femoral vein proved to be a definitive procedure with no mid-term morbidity. PMID- 28856332 TI - 3D Image Fusion to Localise Intercostal Arteries During TEVAR. AB - PURPOSE: Preservation of intercostal arteries during thoracic aortic procedures reduces the risk of post-operative paraparesis. The origins of the intercostal arteries are visible on pre-operative computed tomography angiography (CTA), but rarely on intra-operative angiography. The purpose of this report is to suggest an image fusion technique for intra-operative localisation of the intercostal arteries during thoracic endovascular repair (TEVAR). TECHNIQUE: The ostia of the intercostal arteries are identified and manually marked with rings on the pre operative CTA. The optimal distal landing site in the descending aorta is determined and marked, allowing enough length for an adequate seal and attachment without covering more intercostal arteries than necessary. After 3D/3D fusion of the pre-operative CTA with an intra-operative cone-beam CT (CBCT), the markings are overlaid on the live fluoroscopy screen for guidance. The accuracy of the overlay is confirmed with digital subtraction angiography (DSA) and the overlay is adjusted when needed. Stent graft deployment is guided by the markings. The initial experience of this technique in seven patients is presented. RESULTS: 3D image fusion was feasible in all cases. Follow-up CTA after 1 month revealed that all intercostal arteries planned for preservation, were patent. None of the patients developed signs of spinal cord ischaemia. CONCLUSION: 3D image fusion can be used to localise the intercostal arteries during TEVAR. This may preserve some intercostal arteries and reduce the risk of post-operative spinal cord ischaemia. PMID- 28856331 TI - Phaeochromocytoma and Paraganglioma Excision Involving the Great Vessels. AB - OBJECTIVE/BACKGROUND: Phaeochromocytomas and paragangliomas are vascular neuroendocrine tumours distributed between the neck and the pelvis and may be associated with catecholamine secretion. The aim of the study was to describe the complex surgical management required to excise these tumours when in close proximity to the great vessels (aorta and vena cava). METHODS: This was a retrospective case series. Patients included those undergoing surgical excision of a phaeochromocytoma or paraganglioma involving the great vessels. Data on clinical presentation; genetic mutations; tumour location; catecholamine/metanephrine secretion; surgical strategy; pre-, intra-, and post operative course were collated. RESULTS: Five patients (age range 16-60 years) were identified; three had thoracic paragangliomas located under the arch of the aorta, one had an abdominal paraganglioma invading the aorta, and one had a massive phaeochromocytoma invading the inferior vena cava via the adrenal vein. Three patients had predisposing germline mutations. All patients had adrenergic blockade prior to surgery. A diverse range of complex surgical techniques were employed to excise tumours, including cardiopulmonary bypass, aortic resection, grafting and venotomy of the vena cava. Early post-operative complications were limited. CONCLUSIONS: Excision of phaeochromocytomas and paragangliomas involving the great vessels is high risk surgery optimally undertaken within a multidisciplinary setting in a tertiary referral centre. Comprehensive radiological and biochemical assessment, meticulous pre-operative preparation and close intra- and post-operative monitoring are essential. Radiological imaging may be unable to resolve the tumour extent and anatomy pre-operatively and direct visualisation of the tumour may be the only way to clarify the surgical strategy. Pre-operative knowledge of the genetic predisposition may influence surgical management. PMID- 28856333 TI - Acute Global Testicular Infarction Post-EVAR from Cholesterol Embolisation can be Mistaken for Torsion. AB - INTRODUCTION: Endovascular aneurysm repair (EVAR) is the most commonly used approach for treatment of abdominal aortic aneurysms (AAA). Testicular infarction is a rare complication of EVAR. A novel case of acute global testicular infarction post-EVAR from cholesterol embolisation mimicking torsion is presented. REPORT: A 75 year old man developed acute right testicular ischaemia requiring orchidectomy following EVAR of an infrarenal aortic aneurysm. The patient was initially diagnosed with testicular torsion as the aetiology of the infarction; however, on re-analysis of histopathology it was found to be secondary to cholesterol emboli. DISCUSSION: In patients complaining of groin/scrotal pain following EVAR, it is worth considering testicular ischaemia whether secondary to cholesterol embolisation or gonadal occlusion. Clinicians should be aware that clinical and radiological findings can mimic torsion as this affects management and outcome. PMID- 28856334 TI - Technique of Duplex Scanning for Selection of Optimal Peripheral Anastomosis Site for Distal Bypass. AB - INTRODUCTION: Selection of the optimal anastomosis site is essential for obtaining good results from distal bypass. Herein, a unique, precise technique that uses pre-operative duplex scanning for selecting this site is presented. TECHNICAL SUMMARY: Before distal bypass surgery, duplex scanning is performed to assess patency and flow. Use of the venous preset mode and controlling the slant function allows visualisation of colour Doppler flow inside the arteries, thus enabling selection of the best segment for anastomosis. CONCLUSION: Use of duplex scanning in the appropriate mode consistently enables selection of the best anastomosis site for distal bypass, even when there is heavy calcification. PMID- 28856335 TI - Body Mass Index and Operating Times in Vascular Procedures. AB - INTRODUCTION: The influence of body mass index (BMI) on operating times in central and peripheral vascular surgical procedures was investigated. REPORT: A national cohort of Danish patients who underwent a vascular procedure between 1983 and 2012 was used for analysis. Data were analysed with pairwise comparisons of BMI groups for operating times using the independent samples Kruskall-Wallis test. DISCUSSION: A total of 3,255 carotid endarterectomies; 6,885 central vascular procedures; and 4,488 peripheral bypasses were included for the analysis. Median operating times for carotid endarterectomy and central vascular procedures were, respectively, 5 and 15 minutes longer in obese patients than in normal weight patients. This represents a 7% and 10% increase in median operating times, respectively. Linear and multi-adjusted linear regressions were conducted adjusting for confounders, showing a significant correlation between BMI and operating time. Obesity significantly increased the operating times in carotid endarterectomy and central vascular procedures. These may have ramifications for the individual operative stress but not necessarily on logistical operation planning. PMID- 28856336 TI - Effect of canine cortical bone demineralization on osteogenic differentiation of adipose-derived mesenchymal stromal cells. AB - Demineralized bone allografts and mesenchymal stromal cells have been used to promote bone regeneration. However, the degree to which cortical bone should be demineralized for use in combination with adipose-derived mesenchymal stromal cells (Ad-MSCs) remains to be clarified. In this study, the in vitro osteogenic ability of Ad-MSCs on allografts was investigated in relation to the extent of demineralization. Three treatment groups were established by varying exposure time to 0.6 N HCL: partially demineralized (PDB; 12 h), fully demineralized (FDB; 48 h), and non-demineralized bone (NDB; 0 h, as a control). Allografts were prepared as discs 6 mm in diameter for in vitro evaluation, and their demineralization and structure were evaluated by micro-computed tomography and scanning electron microscopy. Ad-MSC adhesion and proliferation were measured by MTS assay, and osteogenesis-related gene expression was assessed by quantitative reverse transcription polymerase chain reaction. PDB and FDB demineralization rates were 57.13 and 92.30%, respectively. Moreover, Ad-MSC adhesion rates on NDB, PDB, and FDB were 53.41, 60.65, and 61.32%, respectively. Proliferation of these cells on FDB increased significantly after 2 days of culture compared to the other groups (P < 0.05). Furthermore, expression of the osteogenic genes ALP, BMP-7, and TGF-beta in the FDB group on culture day 3 was significantly elevated in comparison to the other treatments. Given its biocompatibility and promotion of the osteogenic differentiation of Ad-MSCs, our results suggest that FDB may be a suitable scaffold for use in the repair of bone defects. PMID- 28856338 TI - Bilateral Uveitis and Keratitis Following Nivolumab Treatment for Metastatic Melanoma. AB - BACKGROUND: Inflammatory eye disease has been reported as a side effect with Nivolumab. CASE PRESENTATION: We report a case of a 92-year-old woman presenting with bilateral and simultaneous keratitis and uveitis in the setting of recurring infusions of nivolumab for metastatic melanoma. The patient underwent successful coordinated treatment of both eyes coinciding with ongoing systemic infusion treatments with ophthalmic topical medications alone. CONCLUSION: The interest of this case resides in the simultaneous nature of presentation of eye inflammation both internally and of the ocular surface. Prior case reports have cited uveitis or ocular surface disease, however not in simultaneous fashion. Clinicians should raise their index of suspicion of side effects of nivolumab systemic infusion for any vision or eye symptom changes around the timing of treatment. PMID- 28856337 TI - Neurobiological and Systemic Effects of Chronic Stress. AB - The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor, which promote adaptation ("allostasis") but also contribute to pathophysiology ("allostatic load/overload") when overused and dysregulated. The adult as well as developing brain possesses a remarkable ability to show structural and functional plasticity in response to stressful and other experiences, including neuronal replacement, dendritic remodeling and synapse turnover. Stress can cause an imbalance of neural circuitry subserving cognition, decision making, anxiety and mood that can increase or decrease expression of those behaviors and behavioral states. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators. In the short term, these changes may be adaptive; but, if the threat passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation requires intervention with a combination of pharmacological and behavioral therapies. There are important sex differences in how the brain responds to stressors. Moreover, adverse early life experience, interacting with alleles of certain genes, produces lasting effects on brain and body via epigenetic mechanisms. While prevention is key, the plasticity of the brain gives hope for therapies that utilize brain-body interactions. Policies of government and the private sector are important to promote health and increase "healthspan." PMID- 28856340 TI - Detective Quantum Efficiency of a CsI-CMOS X-ray Detector for Breast Tomosynthesis Operating in High Dynamic Range and High Sensitivity Modes. AB - The spatial frequency dependent detective quantum efficiency (DQE) of a CsI-CMOS x-ray detector was measured in two operating modes: a high dynamic range (HDR) mode and a high sensitivity (HS) mode. DQE calculations were performed using the IEC-62220-1-2 Standard. For detector entrance air kerma values between ~7 uGy and 60 uGy the DQE is similar in either HDR mode or HS mode, with a value of ~0.7 at low frequency and ~ 0.15 - 0.20 at the Nyquist frequency fN = 6.7 mm-1. In HDR mode the DQE remains virtually constant for operation with Ka values between ~7 uGy and 119 uGy but decreases for Ka levels below ~ 7 uGy. In HS mode the DQE is approximately constant over the full range of entrance air kerma tested between 1.7 uGy and 60 uGy but kerma values above ~75 uGy produce hard saturation. Quantum limited operation in HS mode for entrance kerma as small as 1.7 uGy makes it possible to use a large number of low dose views to improve angular sampling and decrease acquisition time. PMID- 28856339 TI - Cognitive Control of Emotion in Older Adults: A Review. AB - Prior studies have found that compared to younger peers, older adults become happier and regulate emotions better as they age. However, research has also demonstrated that successful emotion regulation relies on well-functioning neural networks including the cognitive control network (CCN) and default mode network (DMN), which include brain structures that tend to deteriorate in the aging process. This dichotomy of improved stress management and emotion control in conjunction with deterioration in relevant neural networks and structures is interesting and worthy of further discussion and study. PMID- 28856342 TI - Home of the Brave. PMID- 28856343 TI - Applying Military Strategy to Complex Knee Reconstruction: Tips for Planning and Executing Advanced Surgery. AB - Complex knee restoration for injured soldiers follows a similar paradigm as for high-end civilian athletes. The military healthcare paradigm often involves the added logistics of transporting the service member to the correct military treatment facility at the correct time and ensuring the patient's work-up is complete before he or she arrives for the complex knee restoration. Such cases require significant rehabilitation and time away from family and work, so anything that reduces the morbidity of the surgical undertaking and the overall "morbidity footprint" of time away and that helps the patient return to normal function are value-added and worthy of our attention and diligence in developing an efficient system for managing complex cases. The globally integrated military healthcare system that is in place has matured over the past decades to allow for the significant majority of the necessary preoperative work-up to be performed at a soldier's current duty station, wherever in the world that may be, under the guidance of local healthcare providers with specific inputs from the knee restoration surgeon who eventually receives the patient for the planned surgical intervention. Efficient preoperative workup and cutting edge knee restoration procedures that are often combined to limit overall morbidity along with managed physical therapy are the keys to success. PMID- 28856341 TI - Associations Between Sociodemographic Characteristics, Pre Migratory and Migratory Factors and Psychological Distress Just After Migration and After Resettlement: The Indian Migration Study. AB - BACKGROUND/OBJECTIVES: Migration is suspected to increase the risk for psychological distress for those who enter a new cultural environment. We investigated the association between sociodemographic characteristics, premigratory and migratory factors and psychological distress in rural-to-urban migrants just after migration and after resettlement. METHODS: Data from the cross-sectional sib-pair designed Indian Migration Study (IMS, 2005-2007) were used. The analysis focused on 2112 participants aged >=18 years from the total IMS sample (n = 7067) who reported being migrant. Psychological distress was assessed based on the responses of the 7-questions in a five-point scale, where the respondents were asked to report about their feelings now and also asked to recall these feelings when they first migrated. The associations were analyzed using multiple logistic regression models. RESULTS: High prevalence of psychological distress was found just after migration (7.3%; 95% confidence interval [CI]: 6.2-8.4) than after settlement (4.7%; 95% CI: 3.8-5.6). Push factors as a reason behind migration and not being able to adjust in the new environment were the main correlates of psychological distress among both the male and female migrants, just after migration. CONCLUSIONS: Rural-urban migration is a major phenomenon in India and given the impact of premigratory and migratory related stressors on mental health, early intervention could prevent the development of psychological distress among the migrants. PMID- 28856344 TI - Bone Stress Injuries in the Military: Diagnosis, Management, and Prevention. AB - Bone stress injuries occur when forces applied to a bone for an extended period exceed the ability of the bone to adequately remodel. These injuries, which range from stress reactions to nondisplaced and even displaced fractures, most often affect people who experience high levels of repetitive stress and loading in the lower extremity or changes in physical activity level. For example, stress fractures are common in endurance athletes, in athletes engaged in preseason and early-season conditioning, and in military recruits. In the military, these injuries are most often encountered during basic training, when new recruits undergo the rigors of intense physical activity to which they may not be accustomed. Female athletes and athletes with poor nutritional status are at elevated risk for injury. Bone stress injuries are difficult to diagnose with radiographs alone. Making the correct diagnosis may require a combination of physical examination, advanced imaging, and an index of suspicion. Differences in injury location account for variations in risk for nonunion, displacement, and other complications. For low-risk injuries, treatment typically consists of reduced weight-bearing for several weeks with gradual return to activity. Higher risk injuries need to be closely monitored for progression and may require operative intervention. Even after surgery, some types of stress fractures may take several months to achieve radiographic union. In addition, underlying nutritional or metabolic deficiencies may need to be treated to prevent future injuries. In this article, we review the diagnosis, management, and prevention of bone stress injuries with a focus on more serious manifestations, such as stress fracture. PMID- 28856345 TI - Traumatic Anterior Shoulder Instability: The US Military Experience. AB - There is a long history of military surgeons who have made significant contributions that have advanced our understanding of traumatic anterior shoulder instability and its treatment and results. In this article, we describe the scope, treatment, and results of this pathology in the US military population. PMID- 28856347 TI - A New Option for Glenoid Reconstruction in Recurrent Anterior Shoulder Instability. AB - Anteroinferior glenoid bone loss plays a significant role in recurrent glenohumeral instability. Surgical strategies for reconstructing the glenoid in these cases include coracoid transfer, iliac crest autograft, and allograft (osteochondral and iliac crest). In this article, we report on a new technique for managing glenoid bone loss, preshaped allograft, and describe surgical technique and outcomes. So far we have implanted this allograft in 15 patients, and at short-term follow-up there are no known cases of recurrent instability or graft resorption. PMID- 28856346 TI - Systematic Review of Novel Synovial Fluid Markers and Polymerase Chain Reaction in the Diagnosis of Prosthetic Joint Infection. AB - Prosthetic joint infection (PJI) may be underreported because of difficulty in making a diagnosis, especially in infections with low-virulence organisms. Reports of PJI cases misdiagnosed as aseptic loosening suggest that current screening and diagnostic tools are not sensitive enough to detect all infections and that PJI likely is underdiagnosed. We reviewed the literature on recently developed novel synovial biomarkers and polymerase chain reaction (PCR) technologies, of which several have proved promising as highly sensitive and specific tools for detecting PJI. We followed the recommendations of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Of 90 papers screened by title or abstract and then by full text, 15 met our inclusion criteria. Sensitivities reported in the included studies ranged from 63% to 100% for alpha-defensin, from 46.8% to 90.9% for interleukin 6, from 28.6% to 100% for leukocyte esterase, and from 67.10% to 95.7% for PCR. Specificities ranged from 95% to 100% for alpha-defensin, from 85.7% to 97.6% for interleukin 6, from 63.6% to 96.5% for leukocyte esterase, and from 12.3% to 97.8% for PCR. alpha-Defensin is a highly sensitive and specific screening tool that may help improve the accuracy of PJI detection, particularly in low-grade infections. PMID- 28856348 TI - Knotless Arthroscopic Reduction and Internal Fixation of a Displaced Anterior Cruciate Ligament Tibial Eminence Avulsion Fracture. AB - Generally occurring in the 8- to 14-year-old population, tibial eminence avulsion fractures are a common variant of anterior cruciate ligament ruptures and represent 2% to 5% of all knee injuries in skeletally immature individuals. In this article, we report on a new arthroscopic reduction and internal fixation technique that involves 2 absorbable anchors with adjustable suture-tensioning technology. This technique optimizes reduction and helps surgeons avoid proximal tibial physeal damage, procedure-related morbidity, and additional surgery. PMID- 28856349 TI - Lower Limb Morel-Lavallee Lesion Treated With Short-Stretch Compression Bandaging. AB - Morel-Lavallee lesions (MLLs) classically occur in the greater trochanteric region, lateral thigh, buttocks, and back. A high percentage of large MLLs require surgical intervention, which comes with an increased risk of skin necrosis and infection. We report a rare case of a large MLL that was successfully treated with compression. The lesion was created when the patient, a 66-year-old man, sustained a low-velocity crush injury. Extending from the medial distal thigh to the proximal medial calf, the MLL was nonoperatively treated with the short-stretch compression bandaging that is used in lymphedema management. The MLL resolved successfully and without complication or the need for surgical intervention. PMID- 28856350 TI - Is Simultaneous Bilateral Total Knee Arthroplasty (BTKA) as Safe as Staged BTKA? AB - Simultaneous bilateral total knee arthroplasty (BTKA) is often performed to treat patients with disabling arthritis of both knees. Its use compared with staged procedures remains controversial. In a retrospective study, we compared 371 patients who had simultaneous BTKA with 67 patients who had staged (<6 months apart) BTKA. The staged procedures fall within the crucial postoperative period when increased morbidity and mortality would more likely be present. Primary outcomes were perioperative complications, length of stay, and transfusion requirements. Complications included respiratory arrest, pulmonary embolism, and deep surgical-site infection. Overall, there was no significant difference in complication rates between the 2 cohorts (P = .97). Mean transfusion rate was higher for the simultaneous BTKA group (P = .042). Study limitations included the retrospective design and the relatively small sample, given the low incidence of complications. PMID- 28856351 TI - Biceps Tenodesis: An Evolution of Treatment. AB - The long head of the biceps (LHB) tendon is a potential generator of pain within the shoulder. Tenodesis of the LHB is a treatment option for several pathologic shoulder conditions. We conducted a study to determine trends in LHB tenodesis at a subspecialty-focused shoulder orthopedic practice. We hypothesized that the rate of LHB tenodesis would increase significantly over time and that there would be no significant change in the age of patients who underwent LHB tenodesis. Records of 4 fellowship-trained sports or shoulder/elbow orthopedic surgeons were used to identify total number of common arthroscopic shoulder surgeries performed between 2004 and 2014. Number of LHB tenodesis cases, combined or isolated, was recorded. Linear regression was used for analysis with significance set at P < .05. Of the 7640 patients who underwent arthroscopic shoulder procedures between 2004 and 2014, 2125 had LHB tenodesis. Mean (SD) age of the subgroup was 49.33 (13.2) years, and mean (SD) number of LHB tenodesis cases per year was 193.2 (130.5). Over time, mean number of LHB tenodesis cases increased significantly (P = .0024), mean age of patients who had these procedures did not change significantly (P = .934), and percentage of LHB tenodesis cases increased significantly relative to percentage of all arthroscopic shoulder procedures (P = .0099). The number of LHB tenodesis cases is increasing without a significant change in patient age. PMID- 28856352 TI - Letter to the Editor: Pronator Teres Myotendinous Tear. PMID- 28856353 TI - Authors' Response. PMID- 28856354 TI - Severity Weighting of Postoperative Adverse Events in Orthopedic Surgery. AB - Studies of adverse events (AEs) after orthopedic surgery commonly use composite AE outcomes. An example of such an outcome is any AE. These types of outcomes treat AEs with different clinical significance (eg, death, urinary tract infection) similarly. We conducted a study to address this shortcoming in research methodology by creating a single severity-weighted outcome that can be used to characterize the overall severity of a given patient's postoperative course. All orthopedic faculty members at 2 academic institutions were invited to complete a severity-weighting exercise in which AEs were assigned a percentage severity of death. Mean (standard error) severity weight for urinary tract infection was 0.23% (0.08%); blood transfusion, 0.28% (0.09%); pneumonia, 0.55% (0.15%); hospital readmission, 0.59% (0.23%); wound dehiscence, 0.64% (0.17%); deep vein thrombosis, 0.64% (0.19%); superficial surgical-site infection, 0.68% (0.23%); return to operating room, 0.91% (0.29%); progressive renal insufficiency, 0.93% (0.27%); graft/prosthesis/flap failure, 1.20% (0.34%); unplanned intubation, 1.38% (0.53%); deep surgical-site infection, 1.45% (0.38%); failure to wean from ventilator, 1.45% (0.48%); organ/space surgical-site infection, 1.76% (0.46%); sepsis without shock, 1.77% (0.42%); peripheral nerve injury, 1.83% (0.47%); pulmonary embolism, 2.99% (0.76%); acute renal failure, 3.95% (0.85%); myocardial infarction, 4.16% (0.98%); septic shock, 7.17% (1.36%); stroke, 8.73% (1.74%); cardiac arrest requiring cardiopulmonary resuscitation, 9.97% (2.46%); and coma, 15.14% (3.04%). Future studies may benefit from using this new severity-weighted outcome score. PMID- 28856355 TI - Referral Patterns for Chronic Groin Pain and Athletic Pubalgia/Sports Hernia: Magnetic Resonance Imaging Findings, Treatment, and Outcomes. AB - Chronic groin pain is a common problem and has been well-described in high performance athletes. Its presentation in the recreational athlete has been less frequently described. We present the experience of a tertiary group of physicians specializing in groin pain and athletic pubalgia. Dynamic magnetic resonance imaging (MRI) protocol was employed. Surgery was performed in patients failing non-surgical management. A retrospective review was performed. Of 117 mostly non professional athletes, there were 79 MRI-positive cases of athletic pubalgia (68%). Other common findings were acetabular labral tear (57%) and inguinal hernia (35%). Employment of a dynamic MRI protocol increased sensitivity for certain pathologies. Of positive athletic pubalgia cases, 49% went on to have surgical repair. The satisfaction rate in the surgical group was 90% at follow up. Advances in MRI have increased our ability to characterize and diagnose specific injuries causing groin pain. We present our diagnostic algorithm, including an MRI protocol that not only evaluates the groin, but has increased sensitivity for additional findings such as inguinal hernia and abdominal wall deficiencies. A targeted work-up and subsequent surgical treatment in the appropriate patient, even in the recreational athletic population, has yielded a 90% satisfaction rate. PMID- 28856356 TI - Patient Preference Before and After Arthroscopic Rotator Cuff Repair: Which Is More Important, Pain Relief or Strength Return? AB - Our understanding of patients' desired outcomes and expectations of arthroscopic rotator cuff repair (ARCR) is limited, particularly regarding the importance of pain relief and strength return relative to each other. We conducted a study of patient's ratings of the importance of pain relief and strength return after ARCR. Before undergoing surgery, 60 patients completed a shoulder questionnaire on which they assessed severity of symptoms and rated, on a 10-point scale, the importance of postoperative improvements in pain relief and strength return. After surgery, they completed the same questionnaire, again rating the importance of pain relief and strength return. About 50% of the patients valued pain relief and strength return equally before and after ARCR. However, overall patient ratings were higher for strength return over pain relief, both before surgery, mean (SD), 9.2 (2.1) vs 8.6 (2.3) (P = .02), and afterward, at a follow-up of 5.2 (0.2) years, 8.9 (1.9) vs 8.2 (3.1) (P = .03). This significant preference for strength return held irrespective of sex, age, active sports involvement, preoperative self-assessed pain score, and subjective shoulder weakness. Before surgery, increasing age was associated with a stronger preference for pain relief (r = 0.33, P = .01), and retirees preferred pain relief over strength return. These results show the patterns of patient preference for pain relief and strength return after ARCR. Improved understanding of these patients' expectations will allow meaningful changes in patient satisfaction. PMID- 28856357 TI - Trans-Scaphoid Transcapitate Perilunate Fracture-Dislocation. AB - Trans-scaphoid transcapitate (TSTC) perilunate fracture-dislocation (PLFD) is a rare type of perilunate injury. Because of the rarity and complexity of this entity, initial diagnosis may be delayed and the extent of osseous and ligamentous lesions underestimated. Early surgical treatment by open reduction and fracture stabilization is recommended to avoid complications such as avascular necrosis, nonunion, posttraumatic arthritis, and functional impairment. In this article, we report the case of a 32-year-old man who sustained a TSTC PLFD. We describe the radiographic and intraoperative findings, review the current surgical principles for reduction and stabilization of this injury, and assess the clinical and radiologic outcomes. PMID- 28856358 TI - Percutaneous Release of Trigger Digits. AB - Stenosing flexor tenosynovitis, or trigger finger, has been treated with open, endoscopic, and percutaneous tendon sheath incisions. A comparison of techniques highlights increased cost, procedure time, and postoperative recovery associated with open surgical treatment. We conducted a study of the efficacy of percutaneous tendon sheath incision as a treatment for trigger digit. Using percutaneous tendon sheath incisions, a single surgeon treated 596 trigger digits (429 patients) over a 10-year period. Successful release was defined as symptom relief on follow-up, or patient request for no further treatment. There were 537 successful releases (90.1%). Of the 59 failures, 17 underwent another percutaneous procedure (15 successful) and 40 underwent open surgical release (100% successful); 2 patients requested no further treatment. There were no significant differences in digit success rates and no complications. The success rate of this method was comparable to rates reported for open surgical procedures, but there were no instances of infection, chronic pain, or tendon or neurovascular damage. Percutaneous release is a safe, effective, and economical treatment option for trigger digits. PMID- 28856359 TI - Comparison of Anterior and Posterior Cortico-steroid Injections for Pain Relief and Functional Improvement in Shoulder Impingement Syndrome. AB - Subacromial impingement syndrome (SIS) is the most common cause of shoulder pain. Treatment options for SIS include conservative modalities such as use of nonsteroidal anti-inflammatory drugs, physical therapy, and subacromial corticosteroid injections (CSIs). Although studies have found improvement in pain, function, and range of motion after CSI, the effect of injection route (anterior or posterior) on shoulder pain in patients with SIS has not been investigated. In the study reported here, patients were randomly assigned to 2 treatment groups: anterior CSI and posterior CSI. Pain was assessed with a visual analog scale (VAS) and function with the Single Assessment Numeric Evaluation (SANE). Patients were evaluated before injection (baseline) and 1, 3, and 6 months after injection. Of the 55 patients enrolled, 25 received anterior CSI and 30 received posterior CSI. The 2 groups showed no significant difference in VAS pain at baseline or 1, 3, or 6 months after injection. SANE scores were statistically different at 3 months. Each group had significantly less pain and better function 1, 3, and 6 months after injection than at baseline. Age, sex, and body mass index did not significantly affect the efficacy of anterior or posterior CSIs. In patients with SIS, subacromial CSI reduces pain and improves function for up to 6 months. These effects are no different for anterior and posterior injection routes. As a result, clinicians should rely on their clinical acumen when selecting injection routes, as anterior and posterior are both beneficial. PMID- 28856361 TI - Preparation, characterization and bioavailability by oral administration of O/W curcumin nanoemulsions stabilized with lysophosphatidylcholine. AB - Curcumin is the main and most abundant bioactive component in Curcuma longa L. with documented properties in the prevention and treatment of chronic degenerative and infectious diseases. However, curcumin has low solubility in aqueous media, hence low bioavailability when administered orally. The use of nanoemulsions as carriers can provide a partial solution to bioavailability restrictions. In our study, O/W nanoemulsions of curcumin were prepared using lysophosphatidylcholine, a phospholipid with proven emulsification capacity; nevertheless, such qualities have not been previously reported in the preparation of nanoemulsions. Lysophosphatidylcholine was obtained by enzymatic removal of one fatty acid residue from phosphatidylcholine. The objective of our work was to formulate stable curcumin nanoemulsions and evaluate their bioavailability in BALB/c mice plasma after oral administration. Formulated nanoemulsions had a droplet size mean of 154.32 +/- 3.10 nm, a polydispersity index of 0.34 +/- 0.07 and zeta potential of -10.43 +/- 1.10 mV; stability was monitored for 12 weeks. Lastly, in vivo pharmacokinetic parameters, using BALB/c mice, were obtained; namely, Cmax of 610 +/- 65.0 MUg mL-1 and Tmax of 2 h. Pharmacokinetic data revealed a higher bioavailability of emulsified as opposed to free curcumin. Research regarding other potential emulsifiers that may provide better health benefits and carry nano-encapsulated bioactive compounds more effectively, is necessary. This study provides important data on the preparation and design of nanoencapsulated Curcumin using lysophosphatidylcholine as an emulsifier. PMID- 28856360 TI - Postpartum Treatment of Metastatic Recurrent Giant Cell Tumor of Capitate Bone of Wrist. AB - Giant cell tumors (GCTs) are aggressive benign lesions that occur in the bone epiphysis. They are most often found in the long bones of the lower extremities. Wrist bone involvement is rare, capitate bone involvement exceedingly rare. Treatment in the wrist usually consists of excision, local adjuvant treatment, and cementing and/or bone grafting. GCTs also metastasize to the lungs; pulmonary lesions are excised and systemic therapy provided. We present the case of a 19 year-old woman with GCT of the capitate bone. After initial excision and cementing, the GCT recurred with lung metastases during a pregnancy. Rapid expansion of the GCT during pregnancy was reversed with systemic treatment with denosumab after pregnancy. Excellent response to this chemotherapy permitted limb sparing surgery and wrist reconstruction with structural cortical autogenous bone graft. Resection of pulmonary metastases after a year of treatment with denosumab revealed lung parenchyma with calcification and ossification and limited viable tumor. PMID- 28856363 TI - Modelling oxygen defects in orthorhombic LaMnO3 and its low index surfaces. AB - LaMnO3-based perovskites, which have been extensively studied as cathodes for high temperature solid oxide fuel cells (SOFCs), are also of interest for intermediate temperature SOFCs (T = 600-1000 K). Oxygen vacancy formation is required in LaMnO3 for oxygen diffusion, therefore a low vacancy formation energy is preferable. The stability of the low index surfaces of orthorhombic LaMnO3 has been investigated, with the {010} surface found to be the most stable. Surface stability was found to be affected by the La and Mn coordination, and the Mn-O bonds cleaved on surface formation. The crystal morphology has been predicted, in order to determine the most likely terminations to be present. The formation of oxygen vacancies in bulk LaMnO3 and at all of its low index surfaces has been examined, and it has been found that formation of vacancies in the bulk has a high energy, while there is a large variation in formation energies at the low index surfaces, which is likely to lead to segregation of vacancies to the surface of orthorhombic LaMnO3. PMID- 28856362 TI - An immunoinformatics approach to promiscuous peptide design for the Plasmodium falciparum erythrocyte membrane protein-1. AB - Plasmodium falciparum erythrocyte membrane protein-1 (Pfemp-1), a variant adhesion molecule, can act as a key component of immunity against malaria. In the current selection of malaria vaccines, no efficient vaccines are available that can be employed for its proper treatment. Unfortunately, resistance to post infection treatments is increasing and therefore there is a pressing need to develop an efficient vaccine. Peptide-based vaccines can be effective tools against malaria but HLA restriction is a major hindrance which can be conquered by using promiscuous peptides. In this work, we employed a combined in silico and experimental approach to identify promiscuous peptides for the treatment of malaria. At first, using the immunoinformatics approach, promiscuous peptides were predicted from two conserved domains, CIDR-1 and DBL-3gamma, of the Pfemp-1 antigen. These peptides were selected on the basis of their predicted binding affinity with different HLA class-I & class-II alleles. A total of 13 peptides were selected based on their predicted IFN-gamma and IL-4 induction ability as well as their hydrophobicity. Out of these 13, the peptide C6 was synthesised and experimentally evaluated for further rationalization, HLA-peptide complex modelling and binding interaction analysis. Interestingly, the peptide C6 (SFIHIYLYRNIRIQL) showed an encouraging immunological response and T-cell proliferation in the immunological assay. This valuable content can aid the better design of more potent and selective vaccine candidates against infectious diseases. PMID- 28856365 TI - Facile post-synthetic deamination of MOFs and the synthesis of the missing parent compound of the MIL-101 family. AB - A versatile method for the post-synthetic removal of primary amino groups from metal-organic frameworks (MOFs) has been developed. The method allowed the first successful synthesis of the missing parent compound of an important family of MOFs - the unsubstituted (Al)MIL-101. The material was shown to be a useful reference compound for the elucidation of the role of amino groups in the adsorption and deactivation of olefin metathesis catalysts. The chemoselectivity of the deamination is sufficient for the selective removal of NH2 substituents from mixed-linker MOFs bearing both NH2 and RCONH groups. PMID- 28856364 TI - Langmuir-Blodgett films of perylene bisimide derivatives and fluorescent recognition of diamines. AB - Fast, sensitive and selective detection of diamines in the vapor phase is of pivotal importance for air and food quality monitoring. In this work, an electron poor fluorophore, perylene bisimide (PBI), was modified with hydrophilic residues at its bay positions, resulting in an amphiphilic derivative, PEBBO. Photophysical studies revealed that the compound shows a strong aggregation tendency in various solvents, but the aggregates could be highly fluorescent provided suitable solvents are used. Accordingly, a fluorescent film was constructed via utilization of the well-known Langmuir-Blodgett technique. Sensing performance studies revealed that the film as prepared is sensitive and selective to the presence of diamines in air. Specifically, (1) the experimental detection limit is lower than 0.016 g m-3 and the linear range of the analysis extends from 0.33 g m-3 to 8.20 g m-3 when ethylenediamine was adopted as an example analyte; (2) the presence of other amines and solvents shows little effect upon detection; (3) the response time is less than 5 s. Considering the importance of diamine sensing, the convenience of fluorescence techniques and the superiorities of the film and method as developed, it is believed that the present work is of great importance for promoting technical progress in diamine sensing. PMID- 28856366 TI - Thermoelectric and piezoelectric properties of the predicted AlxIn1-xN composites based on ab initio calculations. AB - Theoretical investigations of the thermoelectric and piezoelectric characteristics in the AlxIn1-xN system have been carried out based on a first principles approach in combination with the semi-classical Boltzmann transport concept and density functional perturbation theory. Based on our previous work, herein, the study specimens Al5InN6, Al6In2N8, Al4In2N6, Al3In3N6, Al2In4N6, and AlIn7N8 have been predicted to be stable phases. These novel phases intrinsically exhibit moderate positive Seebeck curves (199.1-284.6 MUV K-1) and a ZT close to unity that varies marginally over a broad temperature range of 200-800 K, demonstrating the sign of good bipolar effect tolerance. Addition of heftier elements, such as In, results in lower thermal conductivity, which in turn generates a high power factor (0.019-0.345 W m-1 K-2) in these alloys. While hole doping enhances the peak Seebeck coefficient of each phase, the electrical conductivity has been greatly compromised, resulting in a lower power factor. These composites also exhibit large piezoelectric constants, in which their respective largest piezoelectric tensor is several orders higher than that of quartz. The decomposition process shows that In and N are the main contributors of the internal piezoelectric term. Overall results indicate that AlxIn1-xN show bright prospects in thermoelectric and piezoelectric applications. PMID- 28856367 TI - Halogen free 1,2,3- and 1,2,4-triazolide based ionic liquids: synthesis and properties. AB - Triazoles have been successfully used as building blocks to create "fully organic" ILs featuring on both sides organic ions, i.e., 1,2,3- or 1,2,4 triazolide anions and 1,2,4-triazolium or imidazolium cations. Glass transition temperatures, densities and viscosities of these ILs were determined. Their electrochemical and thermal stability, and also conductivity, are higher than those for known ILs. PMID- 28856368 TI - A highly crystalline oriented metal-organic framework thin film with an inorganic pillar. AB - We report a step-by-step route to fabricate the first example of a crystalline oriented metal-organic framework thin film having an anionic inorganic pillar ligand, {Cu(4,4'-bipyridyl)2(SiF6)}. X-ray study and sorption analysis revealed its high crystallinity and porous character. PMID- 28856369 TI - Dissociative adsorption dynamics of nitrogen on a Fe(111) surface. AB - We study the dissociative adsorption dynamics of N2 on clean bcc Fe(111) surfaces. We base our theoretical analysis on a multidimensional potential energy surface built from density functional theory. The dissociative sticking probability is computed by means of quasi-classical trajectory calculations. For normal incidence and impact energies of the order of a few eV, our theoretical results agree well with existing experimental values. For these energies, the dynamics of the dissociated molecules shows that dissociation is a direct process that follows narrow paths in the multidimensional space. For lower energies of the beam, this direct process is not enough to explain the measured values. A better agreement with the experiment is obtained if we increase the surface temperature to promote the transfer to dissociation of molecules previously trapped. Most of the molecules dissociate very close to the Fe(111) third layer atoms and with an orientation parallel to the surface. A comparison between the dissociation of N2 on Fe(111) and Fe(110) highlights the role of the different energy barriers in both surfaces. PMID- 28856370 TI - Construction of dye-stapled Quenchbodies by photochemical crosslinking to antibody nucleotide-binding sites. AB - We successfully converted an antibody single-chain variable fragment and a full sized antibody to Quenchbodies, which are a type of powerful fluorescent immunosensor, through ultraviolet-based photochemical crosslinking of an indole-3 butyric acid-conjugated fluorescent dye to the nucleotide-binding sites near the antigen-binding sites. PMID- 28856372 TI - Erratum to: Guideline for PET/CT imaging of neuroendocrine neoplasms with 68Ga DOTA-conjugated somatostatin receptor targeting peptides and 18F-DOPA. PMID- 28856373 TI - Erratum to: Search and removal of radioactive seeds: another application of postmortem computed tomography prior to autopsy. PMID- 28856377 TI - Letter to the Editor. AB - J. Fish. PMID- 28856378 TI - Erratum to: Disruption of mindin exacerbates cardiac hypertrophy and fibrosis. PMID- 28856380 TI - Erratum to: The impact of postpartum cervical tear on the occurrence of preterm birth in subsequent pregnancy. PMID- 28856379 TI - Vertebrate GAF/ThPOK: emerging functions in chromatin architecture and transcriptional regulation. AB - GAGA factor of Drosophila melanogaster (DmGAF) is a multifaceted transcription factor with diverse roles in chromatin regulation. Recently, ThPOK/c-Krox was identified as its vertebrate homologue (vGAF), which has a basic domain structure similar to DmGAF and is decorated with a number of post-translationally modified residues. In vertebrate genomes, vGAF associates with purine-rich GAGA sequences and performs diverse chromatin-mediated functions, viz., gene activation, repression and enhancer blocking. Expansion of regulatory chromatin proteins with the acquisition of PTMs appears to be the general trend that facilitated the evolution of complexity in vertebrates. Here, we compare the structural and functional features of vGAF with those of DmGAF and also assess the possible functional redundancy among paralogues of vGAF. We also discuss the underlying mechanisms which aid in the diverse and context-dependent functions of this protein. PMID- 28856381 TI - Secretogranin III: a diabetic retinopathy-selective angiogenic factor. AB - Secretogranin III (Scg3) is a member of the granin protein family that regulates the biogenesis of secretory granules. Scg3 was recently discovered as an angiogenic factor, expanding its functional role to extrinsic regulation. Unlike many other known angiogenic factors, the pro-angiogenic actions of Scg3 are restricted to pathological conditions. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. healthy mouse retinas and lowest background binding to normal vessels. In contrast, vascular endothelial growth factor binds to and stimulates angiogenesis of both diabetic and control vasculature. Consistent with its role in pathological angiogenesis, Scg3-neutralizing antibodies alleviate retinal vascular leakage in mouse models of diabetic retinopathy and retinal neovascularization in oxygen induced retinopathy mice. This review summarizes our current knowledge of Scg3 as a regulatory protein of secretory granules, highlights its new role as a highly disease-selective angiogenic factor, and envisions Scg3 inhibitors as "selective angiogenesis blockers" for targeted therapy. PMID- 28856382 TI - Suicide in Nepal: a modified psychological autopsy investigation from randomly selected police cases between 2013 and 2015. AB - PURPOSE: Yearly, 600,000 people complete suicide in low- and middle-income countries, accounting for 75% of the world's burden of suicide mortality. The highest regional rates are in South and East Asia. Nepal has one of the highest suicide rates in the world; however, few investigations exploring patterns surrounding both male and female suicides exist. This study used psychological autopsies to identify common factors, precipitating events, and warning signs in a diverse sample. METHODS: Randomly sampled from 302 police case reports over 24 months, psychological autopsies were conducted for 39 completed suicide cases in one urban and one rural region of Nepal. RESULTS: In the total police sample (n = 302), 57.0% of deaths were male. Over 40% of deaths were 25 years or younger, including 65% of rural and 50.8% of female suicide deaths. We estimate the crude urban and rural suicide rates to be 16.1 and 22.8 per 100,000, respectively. Within our psychological autopsy sample, 38.5% met criteria for depression and only 23.1% informants believed that the deceased had thoughts of self-harm or suicide before death. Important warning signs include recent geographic migration, alcohol abuse, and family history of suicide. CONCLUSIONS: Suicide prevention strategies in Nepal should account for the lack of awareness about suicide risk among family members and early age of suicide completion, especially in rural and female populations. Given the low rates of ideation disclosure to friends and family, educating the general public about other signs of suicide may help prevention efforts in Nepal. PMID- 28856383 TI - Side effects of radiotherapy in breast cancer patients : The Internet as an information source. AB - AIM: Breast cancer is the most common cancer type among women necessitating adjuvant radiotherapy. As the Internet has become a major source of information for cancer patients, this study aimed to evaluate the quality of websites giving information on side effects of radiotherapy for breast cancer patients. METHODS: A patients' search for the English terms "breast cancer - radiotherapy - side effects" and the corresponding German terms "Brustkrebs - Strahlentherapie - Nebenwirkungen" was carried out twice (5 months apart) using the search engine Google. The first 30 search results each were evaluated using the validated 16 question DISCERN Plus instrument, the Health on the Net Code of Conduct (HONcode) certification and the Journal of the American Medical Association (JAMA) benchmark criteria. The overall quality (DISCERN score) of the retrieved websites was further compared to queries via Bing and Yahoo search engines. RESULTS: The DISCERN score showed a great range, with the majority of websites ranking fair to poor. Significantly superior results were found for English websites, particularly for webpages run by hospitals/universities and nongovernmental organizations (NGO), when compared to the respective German categories. In general, only a minority of websites met all JAMA benchmarks and was HONcode certified (both languages). We did not determine a relevant temporal change in website ranking among the top ten search hits, while significant variation occurred thereafter. Mean overall DISCERN score was similar between the various search engines. CONCLUSION: The Internet can give breast cancer patients seeking information on side effects of radiotherapy an overview. However, based on the currently low overall quality of websites and the lack of transparency for the average layperson, we emphasize the value of personal contact with the treating radio-oncologist in order to integrate and interpret the information found online. PMID- 28856384 TI - Avian phenotypic traits related to feeding preferences in two Culex mosquitoes. AB - Host choice by mosquitoes affects the transmission dynamics of vector-borne infectious diseases. Although asymmetries in mosquito attraction to vertebrate species have been reported, the relative importance of host characteristics in mosquito blood-feeding behavior is still poorly studied. Here, we investigate the relationship between avian phenotypic traits-in particular, morphometry, plumage coloration, and nesting and roosting behavior-and the blood-feeding patterns in two common Culex mosquito species on a North American avian community. Forage ratios of the mosquito species were unrelated to the phylogenetic relationships among bird species. Culex pipiens fed preferably on birds with lighter-colored plumage and longer tarsi; furthermore, solitary roosting avian species were both bitten by Cx. pipiens and Cx. restuans more often than expected. These associations may be explained by greater mosquito attraction towards larger birds with a greater color contrast against the background. Although communally roosting birds may release more cues and attract more mosquitoes, individuals may in fact receive fewer bites due to the encounter-dilution effect. Mosquito feeding behavior is a highly complex phenomenon, and our results may improve understanding of the non-random interaction between birds and mosquitoes in natural communities. PMID- 28856385 TI - Incidence and prevalence of mental disorders among immigrants and native Finns: a register-based study. AB - PURPOSE: Migrants appear to have a higher risk of mental disorders, but findings vary across country settings and migrant groups. We aimed to assess incidence and prevalence of mental disorders among immigrants and Finnish-born controls in a register-based cohort study. METHODS: A register-based cohort study of 184.806 immigrants and 185.184 Finnish-born controls (1.412.117 person-years) was conducted. Information on mental disorders according to ICD-10 was retrieved from the Hospital Discharge Register, which covers all public health care use. RESULTS: The incidence of any mental disorder was lower among male (adjusted HR 0.82, 95% CI 0.77-0.87) and female (aHR 0.76, 95% CI 0.72-0.81) immigrants, being lowest among Asian and highest among North African and Middle Eastern immigrants. The incidence of bipolar, depressive and alcohol use disorders was lower among immigrants. Incidence of psychotic disorders was lower among female and not higher among male immigrants, compared with native Finns. Incidence of PTSD was higher among male immigrants (aHR 4.88, 95% CI 3.38-7.05). CONCLUSIONS: The risk of mental disorders varies significantly across migrant groups and disorders and is generally lower among immigrants than native Finns. PMID- 28856386 TI - [Focal therapy of prostate cancer]. AB - The target of focal therapy (FT) in prostate cancer (PC) is partial treatment of the prostate aiming at preserving surrounding anatomical structures. The intention is to minimize typical side effects of radical treatment options combined with local tumor control. Numerous established and new technologies are used. Results of published studies showed a good safety profile, few side effects and good preservation of functional results. Oncologic long-term data are lacking so far. Photodynamic therapy (PDT) is the only technology that has been studied in a published prospective randomized trial. The FT is challenged by the multifocality of PC; therefore, the quality of prostate biopsy, histopathological assessment as well as imaging are of paramount importance. Multiparametric magnetic resonance imaging (MRI) has gained increasing importance. The FT is experimental and should only be offered within clinical trials. PMID- 28856387 TI - Relative vibrotactile spatial acuity of the torso. AB - While tactile acuity for pressure has been extensively investigated, far less is known about acuity for vibrotactile stimulation. Vibrotactile acuity is important however, as such stimulation is used in many applications, including sensory substitution devices. We tested discrimination of vibrotactile stimulation from eccentric rotating mass motors with in-plane vibration. In 3 experiments, we tested gradually decreasing center-to-center (c/c) distances from 30 mm (experiment 1) to 13 mm (experiment 3). Observers judged whether a second vibrating stimulator ('tactor') was to the left or right or in the same place as a first one that came on 250 ms before the onset of the second (with a 50-ms inter-stimulus interval). The results show that while accuracy tends to decrease the closer the tactors are, discrimination accuracy is still well above chance for the smallest distance, which places the threshold for vibrotactile stimulation well below 13 mm, which is lower than recent estimates. The results cast new light on vibrotactile sensitivity and can furthermore be of use in the design of devices that convey information through vibrotactile stimulation. PMID- 28856388 TI - No beneficial effect of Polidocanol treatment in Achilles tendinopathy: a randomised controlled trial. AB - PURPOSE: Polidocanol injections have been used to treat chronic Achilles tendinopathy in clinical settings, but the few studies published show inconsistent results. The aim of this study was to evaluate the mid-term effect of Polidocanol in patients with chronic Achilles tendinopathy. It was hypothesised that patients treated with Polidocanol would have significant improvements in the outcome measures investigated compared to patients treated with a placebo treatment at mid-term follow-up. METHODS: This randomised controlled trial included forty-eight patients aged 32-77 years with a history of Achilles tendinopathy for at least 3 months and with neovascularisation demonstrated by ultrasonography was included. A minimum of 3 months of eccentric exercise treatment was required before participating. The patients were allocated to a maximum of two injection of either Polidocanol or Lidocaine (placebo). The primary outcome measure was pain during walking reported on a visual analogue scale. Secondary outcome measures were Foot and Ankle Outcome Score (FAOS), patient satisfaction with treatment and, shortly after inclusion, the Victorian Institute of Sports Assessment-Achilles questionnaire (VISA-A) was also included. Follow-up examinations were performed after 3 and 6 months. RESULTS: Pain during walking decreased during the 6-month follow-up period, but no significant differences were seen between the two groups. The same tendency was seen for FAOS and VISA-A in which both groups showed an improvement at 3- and 6-month follow up, but no mid-term differences between the groups were seen. An equal number of patients in the two groups were satisfied with the treatment at follow-up. CONCLUSIONS: The results indicate that Polidocanol is a safe treatment, but the mid-term effects are the same as a placebo treatment. This further questions the use of Polidocanol in the treatment of chronic Achilles tendinopathy. LEVEL OF EVIDENCE: I. PMID- 28856389 TI - Structural and metabolic changes in the traumatically injured rat brain: high resolution in vivo proton magnetic resonance spectroscopy at 7 T. AB - PURPOSE: The understanding of microstructural and metabolic changes in the post traumatic brain injury is the key to brain damage suppression and repair in clinics. METHODS: Ten female Wistar rats were traumatically injured in the brain CA1 region and above the cortex. Next, diffusion tensor magnetic resonance imaging (DTI) and proton magnetic resonance spectroscopy (1H MRS) were used to analyze the microstructural and metabolic changes in the brain within the following 2 weeks. RESULTS: Anisotropy fraction (FA) and axial diffusivity (AD) of the corpus callosum (CC) began to decrease significantly at day 1, whereas radial diffusivity (RD) significantly increased immediately after injury, reflecting the loss of white matter integrity. Compared with day 3, RD decreased significantly at day 7, implicating the angioedema reduction. In the hippocampus, FA significantly increased at day 7; the choline-containing compounds (Cho) and myo-inositol (MI) remarkably increased at day 7 compared with those at day 3, indicating the proliferation of astrocytes and radial glial cells after day 7. No significant differences between DTI and 1H MRS parameters were observed between day 1 and day 3. CONCLUSION: Day 1-3 after traumatic brain injury (TBI) may serve as a relatively appropriate time window for treatment planning and the following nerve repair. PMID- 28856390 TI - Hypogonadal Men with Higher Body Mass Index have Higher Bone Density and Better Bone Quality but Reduced Muscle Density. AB - Although hypogonadism is a risk factor for bone loss and fractures, the different etiopathophysiology and hormonal profile of classical and obesity-induced hypogonadism may lead to differences in musculoskeletal profile. This is a cross sectional study of hypogonadal men between 40 and 74 years old. Our outcomes include: areal bone mineral density (aBMD) and body composition by dual-energy X ray absorptiometry; volumetric BMD (vBMD) and soft tissue composition of the tibia by peripheral quantitative computed tomography. Fracture risk assessment tool (FRAX) scores were evaluated. Testosterone, estradiol, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin, C-telopeptide, osteocalcin, and sclerostin were measured. We divided the population into subgroups of BMI: group 1: BMI < 30; group 2: BMI >=30 to <35 and group 3: BMI >= 35 kg/m2. One-hundred five men were enrolled. Spine and hip aBMD, and total and trabecular vBMD at the 4% tibia significantly increased with increasing BMI. Cortical thickness (330.7 +/- 53.2, 343.3 +/- 35.4, and 358.7 +/- 38.2 mm, p = 0.04; groups 1, 2 and 3, respectively) and cortical area (5.3 +/- 0.7, 5.5 +/- 0.6, and 5.7 +/- 0.6 mm, p = 0.01; groups 1, 2 and 3, respectively) at 38% tibia increased with increasing BMI. While absolute lean mass increased with increasing BMI, % lean mass and muscle density (70.2 +/- 5.0, 71.3 +/- 6.4, and 67.1 +/- 5.1 mg/cm3; groups 1, 2 and 3, respectively) were lowest in group 3. Although severely obese hypogondal men have better BMD and bone quality, they have reduced muscle density, the significance of which remains to be determined. PMID- 28856391 TI - Dissociable effects of cocaine and yohimbine on impulsive action and relapse to cocaine seeking. AB - RATIONALE: A strong association has been demonstrated between various forms of impulsivity and addiction-like behavior in both humans and rats. OBJECTIVES: In this study, we investigated how impulsive action, as measured in the 5-choice serial reaction time task (5-CSRTT), is affected during various stages of cocaine taking and seeking and by relapse-provoking stimuli in animals that were trained both in an intravenous cocaine self-administration paradigm and in the 5-CSRTT. METHODS: Rats were concurrently trained in the 5-CSRTT and cocaine self administration protocol, and subsequently, the effects of cocaine (7.5 mg/kg) and the pharmacological stressor yohimbine (1.25 mg/kg) were tested in both paradigms. RESULTS: Cocaine self-administration (5 h/day) transiently altered impulsive action and increased errors of omission in the 5-CSRTT. Pharmacological challenges with cocaine and yohimbine induced increments in impulsive action and reinstated cocaine-seeking responses within the same animals. Further analyses revealed that the effects of cocaine and yohimbine on impulsive action did not correlate with their effects on reinstatement of cocaine seeking. CONCLUSIONS: These data suggest that although impulsive action and relapse can be pharmacologically modulated in the same direction within individuals, these effects appear not to be directly coupled. PMID- 28856393 TI - Comments on: When neuroscience gets wet and hardcore: neurocognitive markers obtained during whole body water immersion. PMID- 28856392 TI - CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. AB - The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications. Using clinically relevant genetic models of PDAC, we found that regulatory T cells (Tregs), which constitutively express CTLA-4, accumulate early during tumor development but are largely confined to peritumoral lymph nodes during disease progression. Tregs were observed to regulate CD4+, but not CD8+, T cell infiltration into tumors through a CTLA-4/CD80 dependent mechanism. Disrupting CTLA-4 interaction with CD80 was sufficient to induce CD4 T cell infiltration into tumors. These data have important implications for T cell immunotherapy in PDAC and demonstrate a novel role for CTLA-4/CD80 interactions in regulating T cell exclusion. In addition, our findings suggest distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC. PMID- 28856394 TI - Radiation risk index for pediatric CT: a patient-derived metric. AB - BACKGROUND: There is a benefit in characterizing radiation-induced cancer risk in pediatric chest and abdominopelvic CT: a singular metric that represents the whole-body radiation burden while also accounting for age, gender and organ sensitivity. OBJECTIVE: To compute an index of radiation risk for pediatric chest and abdominopelvic CT. MATERIALS AND METHODS: Using a protocol approved by our institutional review board, 42 pediatric patients (age: 0-16 years, weight: 2-80 kg) were modeled into virtual whole-body anatomical models. Organ doses were estimated for clinical chest and abdominopelvic CT examinations of the patients using validated Monte Carlo simulations of two major scanner models. Using age-, size- and gender-specific organ risk coefficients, the values were converted to normalized effective dose (by dose length product) (denoted as the k factor) and a normalized risk index (denoted as the q factor). An analysis was performed to determine how these factors are correlated with patient age and size for both males and females to provide a strategy to better characterize individualized risk. RESULTS: The k factor was found to be exponentially correlated with the average patient diameter. For both genders, the q factor also exhibited an exponential relationship with both the average patient diameter and with patient age. For both factors, the differences between the scanner models were less than 8%. CONCLUSION: The study defines a whole-body radiation risk index for chest and abdominopelvic CT imaging, that incorporates individual estimated organ dose values, organ radiation sensitivity, patient size, exposure age and patient gender. This indexing metrology enables the assessment and potential improvement of chest and abdominopelvic CT performance through surveillance of practice dose profiles across patients and may afford improved informed communication. PMID- 28856396 TI - Objective Evaluation of Eyebrow Position After Autologous Fat Grafting to the Temple and Forehead. AB - BACKGROUND: Fat grafting can be used to correct age-related volume loss in the face. However, the degree of rejuvenation is difficult to be evaluated. OBJECTIVES: The author sought to objectively verify the change in patients' eyebrow position after fat grafting to the upper face. METHODS: The charts of 175 consecutive patients who underwent autologous fat grafting to the forehead and temple were reviewed. Perioperative changes in the heights of medial, middle, and lateral segments of the eyebrow and the eyebrow slant were recorded and compared. Key prevention strategies to avoid potential complications were discussed. RESULTS: The eyebrow slant was increased by 2.4 degrees after the operation which was statistically significant (p < 0.05). On the other hand, the medial eyebrow height was decreased, while the middle and lateral eyebrow heights were increased after the surgery which were of no significance. No major complications such as vision loss or vascular compromise were noted. CONCLUSIONS: Simultaneous autologous fat grafting to the temple and forehead significantly increased the slant of the eyebrows and corrected the loss of upper facial fullness as well. Collectively, these changes made the patient look younger and aesthetically more pleasant. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28856395 TI - Quality of Life is Diminished in Patients with Tetralogy of Fallot with Mild Residual Disease: A Comparison of Tetralogy of Fallot and Isolated Valvar Pulmonary Stenosis. AB - The objective of this study is to compare quality of life (QOL) in patients with mild pulmonary insufficiency (PI) after Tetralogy of Fallot (TOF) repair or after balloon dilation for isolated valvar pulmonary stenosis (VPS). A cross-sectional study of patients with TOF (n = 12) and VPS (n = 19), ages 8-18 years, who underwent cardiac magnetic resonance (CMR) and cardiopulmonary exercise test (CPET) was conducted. Patients with genetic syndromes were excluded. The groups were matched by severity and duration of PI using propensity scores. PI was greater than mild if the regurgitant fraction by CMR was >20%. Health status and QOL assessment included Child Health Questionnaire Child Self-Report (CHQ-CF87), Child Health Questionnaire Parent Report (CHQ-PF50), and Pediatric Cardiac QOL Instrument (parent and patient). QOL scores were compared between groups. Due to propensity matching, the groups had, at worst, mild PI and normal right ventricular ejection fraction on CMR. Parental perception of QOL was significantly worse in TOF as compared to VPS in the domains of general perception of health (P = 0.03), physical functioning (PF; P = 0.004), and family cohesion (P = 0.048). There were no differences in self-reported QOL between groups. There was no association between QOL and right ventricular function on CMR or percent-predicted maximal oxygen consumption on CPET in both groups. Parent-perceived QOL, in the domains of general health perception, PF, and family cohesion, is significantly reduced in patients with TOF with mild residual disease suggesting that the psychosocial impact of congenital heart disease may be significant even with successful repair and satisfactory medical status. PMID- 28856397 TI - Midwestern US Farmers Perceive Crop Advisers as Conduits of Information on Agricultural Conservation Practices. AB - Nonpoint source pollution from agricultural land uses continues to pose one of the most significant threats to water quality in the US, with measurable impacts across local, regional, and national scales. The impact and the influence of targeted conservation efforts are directly related to the degree to which farmers are familiar with and trust the entities providing the information and/or outreach. Recent research suggests that farmers consistently rank independent and retail-affiliated crop advisers as among the most trusted and influential sources for agronomic information, but little is understood about whether farmers are willing to receive advice from crop advisers on the use of practices that conserve soil and water, and, if so, whether crop advisers will be perceived as influential. We present survey data from farmers (n = 1461) in Michigan's Saginaw Bay (Lake Huron) watershed to explore these questions. Results suggest that farmers view crop advisers as trustworthy sources of information about conservation, and influential on management practices that have large conservation implications. We discuss these results, along with perceived barriers and opportunities to crop advisers partnering with traditional conservation agencies to enhance the impact of voluntary conservation programs. PMID- 28856398 TI - Association of use of selective serotonin reuptake inhibitors with risk of acute pancreatitis: a case-control study in Taiwan. AB - BACKGROUND AND OBJECTIVES: Few studies have reported the association of the use of selective serotonin reuptake inhibitors (SSRIs) with acute pancreatitis. We conducted a population-based case-control study to explore this relationship. METHODS: In this study, 4631 cases with first attack of acute pancreatitis and 4631 controls without acute pancreatitis were selected using a randomly sampled cohort of one million health insurance enrollees from 2000 to 2013. Both cases and controls were aged 20-84 years and were matched with sex, age, comorbidities, and index year of diagnosis of acute pancreatitis. Patients with current use of SSRIs were defined as those whose last tablet of SSRIs was noted <= 7 days before the date of diagnosis of acute pancreatitis; patients with late use of SSRIs were defined as those whose last tablet of SSRIs was noted >= 8 days before the date of diagnosis; and patients with no use of SSRIs were defined as those who were never prescribed SSRIs. The odds ratio (OR) and 95% confidence interval (CI) for acute pancreatitis associated with the use of SSRIs were assessed using multivariate unconditional logistic regression analysis. RESULTS: After adjusting for covariables, multivariate logistic regression analysis revealed that compared with patients with no use of SSRIs, the adjusted OR of acute pancreatitis for those with current use of SSRIs was 1.7 (95% CI, 1.1-2.5), whereas that for patients with late use of SSRIs was 1.0 (95% CI, 0.9-1.2) without statistical significance. CONCLUSIONS: Current use of SSRIs is associated with the diagnosis of acute pancreatitis. Therefore, clinicians should consider the possibility of SSRI-associated acute pancreatitis among patients currently taking SSRIs and those presenting with the diagnosis of acute pancreatitis without a definite cause. PMID- 28856399 TI - Three dimensional printing technology and materials for treatment of elbow fractures. AB - PURPOSE: 3D printing is a rapid prototyping technology that uses a 3D digital model to physically build an object. The aim of this study was to evaluate the peri-operative effect of 3D printing in treating complex elbow fractures and its role in physician-patient communication and determine which material is best for surgical model printing. METHOD: Forty patients with elbow fractures were randomly divided into a 3D printing-assisted surgery group (n = 20) and a conventional surgery group (n = 20). Surgery duration, intra-operative blood loss, anatomic reduction rate, incidence of complications and elbow function score were compared between the two groups. The printing parameters, the advantages and the disadvantages of PLA and ABS were also compared. The independent-samples t-test was used to compare the data between groups. A questionnaire was designed for orthopaedic surgeons to evaluate the verisimilitude, the appearance of being true or real, and effectiveness of the 3D printing fracture model. Another questionnaire was designed to evaluate physician patient communication effectiveness. RESULTS: The 3D group showed shorter surgical duration, lower blood loss and higher elbow function score, compared with the conventional group. PLA is an environmentally friendly material, whereas ABS produce an odour in the printing process. Curling edges occurred easily in the printing process with ABS and were observed in four of ten ABS models but in only one PLA model. The overall scores given by the surgeons about the verisimilitude and effectiveness of the 3D model were relatively high. Patient satisfaction scores for the 3D model were higher than those for the 2D imaging data during physician-patient discussions. CONCLUSION: 3D-printed models can accurately depict the anatomic characteristics of fracture sites, help surgeons determine a surgical plan and represent an effective tool for physician-patient communication. PLA is more suitable for desktop fused deposition printing in surgical modeling applications. PMID- 28856400 TI - Time Series Analysis of Energy Production and Associated Landscape Fragmentation in the Eagle Ford Shale Play. AB - Spatio-temporal trends in infrastructure footprints, energy production, and landscape alteration were assessed for the Eagle Ford Shale of Texas. The period of analysis was over four 2-year periods (2006-2014). Analyses used high resolution imagery, as well as pipeline data to map EF infrastructure. Landscape conditions from 2006 were used as baseline. Results indicate that infrastructure footprints varied from 94.5 km2 in 2008 to 225.0 km2 in 2014. By 2014, decreased land-use intensities (ratio of land alteration to energy production) were noted play-wide. Core-area alteration by period was highest (3331.6 km2) in 2008 at the onset of play development, and increased from 582.3 to 3913.9 km2 by 2014, though substantial revegetation of localized core areas was observed throughout the study (i.e., alteration improved in some areas and worsened in others). Land-use intensity in the eastern portion of the play was consistently lower than that in the western portion, while core alteration remained relatively constant east to west. Land alteration from pipeline construction was ~65 km2 for all time periods, except in 2010 when alteration was recorded at 47 km2. Percent of total alteration from well-pad construction increased from 27.3% in 2008 to 71.5% in 2014. The average number of wells per pad across all 27 counties increased from 1.15 to 1.7. This study presents a framework for mapping landscape alteration from oil and gas infrastructure development. However, the framework could be applied to other energy development programs, such as wind or solar fields, or any other regional infrastructure development program. Landscape alteration caused by hydrocarbon pipeline installation in Val Verde County, Texas. PMID- 28856401 TI - Applications of contrast-enhanced ultrasound in the kidney. AB - Incidental discovery of renal lesions on cross-sectional imaging studies performed for other indications is not uncommon. With the increased reliance on medical imaging, the number of incidentally detected renal lesions has also grown over time. While simple cysts account for the majority of these lesions, the presence of complex features within a cystic lesion, such as septations and solid components, can present a confusing picture. Solid lesions, too, can be indeterminate, and distinguishing between benign solid masses (like lipid-poor angiomyolipomas and oncocytomas) and renal cell carcinoma affects patient management and can prevent unnecessary interventions. Indeterminate renal lesions are traditionally further characterized by multiphase imaging, such as contrast enhanced computed tomography and magnetic resonance imaging. Contrast-enhanced ultrasound (CEUS) is a new, relatively inexpensive technique that has become increasingly employed in the diagnostic workup of indeterminate renal lesions. With its lack of nephrotoxicity, the absence of ionizing radiation, and the ability to evaluate the enhancement pattern of renal lesions quickly and in real time, CEUS has unique advantages over traditional imaging modalities. This article provides an overview of the current clinical applications of CEUS in characterizing renal lesions, both cystic and solid. Additional applications of CEUS in the kidney, including its roles in renal transplant evaluation and guidance for percutaneous biopsy, will also be briefly discussed. PMID- 28856402 TI - Percutaneous Vertebroplasty and Kyphoplasty: Current Status, New Developments and Old Controversies. AB - Vertebroplasty and kyphoplasty are minimally invasive techniques applied for the treatment of vertebral fractures. Since not all vertebral compression fractures are the same, a tailored-based approach is necessary for optimum efficacy and safety results. Nowadays, different cements and materials are proposed as alternatives to the original poly-methylmethacrylate aiming to overcome the limitations and the risks governing its use. Both techniques are governed by high efficacy and low complication rates; multilevel treatment in a single session has been shown to be feasible with no compromise of the technique's safety and efficacy. The purpose of this article is to describe the basic concepts of spinal augmentation by means of vertebroplasty and kyphoplasty. The current status and future of cements used will be defined. Controversies upon issues concerning both techniques will be addressed. Finally, the necessity for a tailored-based approach applying different techniques for different fractures will be addressed. PMID- 28856403 TI - Comparison of clean intermittent and transurethral indwelling catheterization for the treatment of overt urinary retention after vaginal delivery: a multicentre randomized controlled clinical trial. AB - INTRODUCTION AND HYPOTHESIS: Overt postpartum urinary retention (PUR) is the inability to void after delivery and affects up to 7% of patients. Clean intermittent catheterization (CIC) and transurethral indwelling catheterization (TIC) are both standard treatments, but have not previously been compared. Clinical guidelines on postpartum bladder management are lacking. METHODS: A total of 85 patients were randomised for TIC (n=45) and CIC (n=40). In total 68 patients (34 patients with TIC and 34 patients with CIC) completed the UDI-6 questionnaire 3 months after delivery.. Patients allocated to TIC received an indwelling catheter for 24 h and if necessary, another catheter for 48 h. Patients with CIC were intermittently catheterized or taught to self-catheterize until adequate voiding with a postvoid residual volume (PVRV) of <150 mL was achieved. The primary outcome was the presence of bothersome micturition symptoms as measured using the Dutch-validated Urogenital Distress Inventory (UDI-6). RESULTS: Only seven patients (10%) reported bothersome micturition problems 3 months after delivery. No significant differences in the occurrence of micturition symptoms were found. Median PVRV was 800 mL in the CIC group and 650 mL in the TIC group. PVRV was >=1,000 mL in 24% of the patients. The median duration of catheterization was significantly shorter in the CIC group than in the TIC group (12 h vs. 24 h, p < 0,01). In patients with CIC, 35% required only one catheterization before complete bladder emptying occurred. The duration of treatment was not related to the initial PVRV. Both treatments were equally well accepted by the patients. CONCLUSIONS: In patients with overt PUR, CIC is the preferred treatment as a considerable percentage of patients appear to be over treated when the standard duration of TIC is 24 h. The occurrence of micturition symptoms is not associated with the catheterization method used. CIC is well tolerated in patients with overt PUR. PMID- 28856404 TI - Flow Restoration in the Columbia River Basin: An Evaluation of a Flow Restoration Accounting Framework. AB - Securing environmental flows in support of freshwater biodiversity is an evolving field of practice. An example of a large-scale program dedicated to restoring environmental flows is the Columbia Basin Water Transactions Program in the Pacific Northwest region of North America, which has been restoring flows in dewatered tributary habitats for imperiled salmon species over the past decade. This paper discusses a four-tiered flow restoration accounting framework for tracking the implementation and impacts of water transactions as an effective tool for adaptive management. The flow restoration accounting framework provides compliance and flow accounting information to monitor transaction efficacy. We review the implementation of the flow restoration accounting framework monitoring framework to demonstrate (a) the extent of water transactions that have been implemented over the past decade, (b) the volumes of restored flow in meeting flow targets for restoring habitat for anadromous fish species, and (c) an example of aquatic habitat enhancement that resulted from Columbia Basin Water Transactions Program investments. Project results show that from 2002 to 2015, the Columbia Basin Water Transactions Program has completed more than 450 water rights transactions, restoring approximately 1.59 million megaliters to date, with an additional 10.98 million megaliters of flow protected for use over the next 100 years. This has resulted in the watering of over 2414 stream kilometers within the Columbia Basin. We conclude with a discussion of the insights gained through the implementation of the flow restoration accounting framework. Understanding the approach and efficacy of a monitoring framework applied across a large river basin can be informative to emerging flow-restoration and adaptive management efforts in areas of conservation concern. PMID- 28856405 TI - Surgical management of pelvic organ prolapse and stress urinary incontinence: where are we now? PMID- 28856406 TI - Panicolytic-like effects caused by substantia nigra pars reticulata pretreatment with low doses of endomorphin-1 and high doses of CTOP or the NOP receptors antagonist JTC-801 in male Rattus norvegicus. AB - RATIONALE: Gamma-aminobutyric acid (GABA)ergic neurons of the substantia nigra pars reticulata (SNpr) are connected to the deep layers of the superior colliculus (dlSC). The dlSC, in turn, connect with the SNpr through opioid projections. Nociceptin/orphanin FQ peptide (N/OFQ) is a natural ligand of a Gi protein-coupled nociceptin receptor (ORL1; NOP) that is also found in the SNpr. Our hypothesis is that tectonigral opioid pathways and intranigral orphanin mediated mechanisms modulate GABAergic nigrotectal connections. OBJECTIVES: Therefore, the aim of this work was to study the role of opioid and NOP receptors in the SNpr during the modulation of defence reactions organised by the dlSC. METHODS: The SNpr was pretreated with either opioid or NOP receptor agonists and antagonists, followed by dlSC treatment with bicuculline. RESULTS: Blockade of GABAA receptors in the dlSC elicited fear-related defensive behaviour. Pretreatment of the SNpr with naloxone benzoylhydrazone (NalBzoH), a MU-, delta-, and kappa1-opioid receptor antagonist as well as a NOP receptor antagonist, decreased the aversive effect of bicuculline treatment on the dlSC. Either MU opioid receptor activation or blockade by SNpr microinjection of endomorphin-1 (EM-1) and CTOP promoted pro-aversive and anti-aversive actions, respectively, that modulated the defensive responses elicited by bicuculline injection into the dlSC. Pretreatment of the SNpr with the selective NOP receptor antagonist JTC801 decreased the aversive effect of bicuculline, and microinjections of the selective NOP receptor agonist NNC 63-0532 promoted the opposite effect. CONCLUSIONS: These results demonstrate that opioid pathways and orphanin-mediated mechanisms have a critical role in modulating the activity of nigrotectal GABAergic pathways during the organisation of defensive behaviours. PMID- 28856407 TI - pH homeostasis in yeast; the phosphate perspective. AB - Recent research further clarified the molecular mechanisms that link nutrient signaling and pH homeostasis with the regulation of growth and survival of the budding yeast Saccharomyces cerevisiae. The central nutrient signaling kinases PKA, TORC1, and Sch9 are intimately associated to pH homeostasis, presumably allowing them to concert far-reaching phenotypical repercussions of nutritional cues. To exemplify such repercussions, we briefly describe consequences for phosphate uptake and signaling and outline interactions between phosphate homeostasis and the players involved in intra- and extracellular pH control. Inorganic phosphate uptake, its subcellular distribution, and its conversion into polyphosphates are dependent on the proton gradients created over different membranes. Conversely, polyphosphate metabolism appears to contribute in determining the intracellular pH. Additionally, inositol pyrophosphates are emerging as potent determinants of growth potential, in this way providing feedback from phosphate metabolism onto the central nutrient signaling kinases. All these data point towards the importance of phosphate metabolism in the reciprocal regulation of nutrient signaling and pH homeostasis. PMID- 28856408 TI - Three-dimensional CT angiography of anatomic variations in the pulmonary arterial tree. AB - PURPOSE: Anatomic variations of the pulmonary arterial tree can cause technical difficulties during pulmonary lobectomy in general and video-assisted thoracic surgery (VATS). Using CT angiography and 3D reconstruction, we sought to identify anatomic variations of the pulmonary arterial tree and assess their respective frequencies. METHODS: We retrospectively studied 88 pulmonary arterial trees in 44 patients having undergone VATS lobectomy for lung cancer over an 18-month period in Amiens University Hospital's Department of Thoracic Surgery. Each CT angiography with 3D reconstruction of the pulmonary arterial tree was performed by two experienced operators, according to a standardized procedure. RESULTS: On the right side, the upper lobe was supplied with blood by a mediastinal artery in 100% of cases and by one or more fissural arteries in 88.6%. The middle lobe was usually supplied by two arteries (54.5%). The upper segment of the right lower lobe was usually supplied by a single artery (90.9%). We identified 11 variations in the vasculature of the basal segments. On the left side, the upper lobe was supplied by four arteries in 50% of cases, three culminal arteries (50%), and a fissural lingular artery (77.3%). The upper segment of the left lower lobe was usually supplied by a single artery (65.9%). We identified 15 anatomic variations in the vasculature of the basal segments. We observed that the origin of the apical artery of the right lower lobe was proximal to the origin of the middle lobe artery in 38.6% of cases. The origin of the apical artery of the left lower lobe artery was proximal to the origin of the lingular fissural artery in 65.9% of cases. CONCLUSION: The findings of the present CT angiography/3D reconstruction study agreed with the reference works on the anatomy of the pulmonary arterial tree and defined the frequency of anatomic variations. It is essential to assess the anatomy of the pulmonary arterial tree before VATS lobectomy. PMID- 28856409 TI - Reperfusion facilitates reversible disruption of the human blood-brain barrier following acute ischaemic stroke. AB - OBJECTIVES: We aimed to detect early changes of the blood-brain barrier permeability (BBBP) in acute ischaemic stroke (AIS), with or without reperfusion, and find out whether BBBP can predict clinical outcomes. METHODS: Consecutive AIS patients imaged with computed tomographic perfusion (CTP) before and 24 h after treatment were included. The relative permeability-surface area product (rPS) was calculated within the hypoperfused region (rPShypo-i), non-hypoperfused region of ischaemic hemisphere (rPSnonhypo-i) and their contralateral mirror regions (rPShypo-c and rPSnonhypo-c). The changes of rPS were analysed using analysis of variance (ANOVA) with repeated measures. Logistic regression was used to identify independent predictors of unfavourable outcome. RESULTS: Fifty-six patients were included in the analysis, median age was 76 (IQR 62-81) years and 28 (50%) were female. From baseline to 24 h after treatment, rPShypo-i, rPSnonhypo-i and rPShypo-c all decreased significantly. The decreases in rPShypo-i and rPShypo-c were larger in the reperfusion group than non-reperfusion group. The rPShypo-i at follow-up was a predictor for unfavourable outcome (OR 1.131; 95% CI 1.018-1.256; P = 0.022). CONCLUSION: Early disruption of BBB in AIS is reversible, particularly when greater reperfusion is achieved. Elevated BBBP at 24 h after treatment, not the pretreatment BBBP, predicts unfavourable outcome. KEY POINTS: * Early disruption of blood-brain barrier (BBB) in stroke is reversible after treatment. * The reversibility of BBB permeability is associated with reperfusion. * Unfavourable outcome is associated with BBB permeability at 24 h after treatment. * Contralateral non-ischaemic hemisphere is not 'normal' during an acute stroke. PMID- 28856411 TI - Evaluation of Contamination Risks with Coxsackievirus B4 E2 in Swiss Albino Mice Stools. AB - Coxsackie B4 (CV-B4), is a major cause of viral myocarditis, dilated cardiomyopathy, and pancreatitis. Like other human enteroviruses, CV-B4 is ubiquitous, excreted in the stool, transmitted by fecal-oral route, and persists in the environment. In the context of studies on CV-B4 infection, it is important to investigate how this virus can be eliminated and to show the possibility of contamination risk with a CV-B4 E2 infected Swiss albino mice. Swiss albino female mice were inoculated with CV-B4 E2 strain and divided in two groups: the first was intraperitoneally (I.P.) infected; the second was orally infected. In order to study the CV-B4 E2 infection in mice, total RNA was extracted from thymus, spleen, pancreas, and intestine, and viral genome was detected using semi nested (RT-PCR). To further demonstrate infection or immunization of mice, Sera obtained from infected mice were assayed in vitro for their neutralizing antibody. To detect virus in stool of infected mice, stool samples were collected at different post-infection (p.i.) times. Neutralizing antibodies were detectable all along the follow-up period (Day 0, 1, 3, 7, 9, 17, 22, 30, 45, 60 p.i.) in I.P and oral infected mice. Our results showed that when mice were inoculated successively at day 0 and day 8, neutralizing activity was increased in I.P route more than in the oral route. Viral isolation in HEp-2 cells showed negative results. Stool viral analyses reveal a low detection of the CV-B4 E2 genome for all infected mice. In conclusion, our experiments demonstrated that there are no risks linked with the stool of CV-B4 E2 of Swiss albino mice. It would be interesting to characterize the inhibitors of the virus infectivity in these biological samples (stool) and investigate their targets and mechanisms of action. PMID- 28856412 TI - Accurate late gadolinium enhancement prediction by early T1- based quantitative synthetic mapping. AB - OBJECTIVES: Early synthetic gadolinium enhancement (ESGE) imaging from post contrast T1 mapping after adenosine stress-perfusion cardiac magnetic resonance (CMR) was compared to conventional late gadolinium enhancement (LGE) imaging for assessing myocardial scar. METHODS: Two hundred fourteen consecutive patients suspected of myocardial ischaemia were referred for stress-perfusion CMR. Myocardial infarct volume was quantified on a per-subsegment basis in both synthetic (2-3 min post-gadolinium) and conventional (9 min post-gadolinium) images by two independent observers. Sensitivity, specificity, PPV and NPV were calculated on a per-patient and per-subsegment basis. RESULTS: Both techniques detected 39 gadolinium enhancement areas in 23 patients. The median amount of scar was 2.0 (1.0-3.1) g in ESGE imaging and 2.2 (1.1-3.1) g in LGE imaging (p=0.39). Excellent correlation (r=0.997) and agreement (mean absolute difference: -0.028+/-0.289 ml) were found between ESGE and LGE images. Sensitivity, specificity, PPV and NPV of ESGE imaging were 96 (78.9-99.9), 99 (97.1-100.0)%, 96 (76.5-99.4) and 99.5 (96.6-99.9) in patient-based and 99 (94.5 100.0), 100 (99.9-100.0)%, 97.0 (91.3-99.0) and 100.0 (99.8-100.0) in subsegment based analysis. CONCLUSION: ESGE based on post-contrast T1 mapping after adenosine stress-perfusion CMR imaging shows excellent agreement with conventional LGE imaging for assessing myocardial scar, and can substantially shorten clinical acquisition time. KEY POINTS: * Synthetic gadolinium enhancement images can be used for detection of myocardial scar. * Early synthetic gadolinium enhancement images can substantially shorten clinical acquisition time. * ESGE has high diagnostic accuracy as compared to conventional late gadolinium enhancement. * Quantification of myocardial scar with ESGE closely correlates with conventional LGE. * ESGE after stress perfusion CMR avoids need for additional gadolinium administration. PMID- 28856410 TI - Dynamic contrast-enhanced and diffusion-weighted MR imaging in the characterisation of small, non-palpable solid testicular tumours. AB - OBJECTIVES: To explore the role of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), using semiquantitative and quantitative parameters, and diffusion-weighted (DW) MRI in differentiating benign from malignant small, non palpable solid testicular tumours. METHODS: We calculated the following DCE-MRI parameters of 47 small, non-palpable solid testicular tumours: peak enhancement (PE), time to peak (TTP), percentage of peak enhancement (Epeak), wash-in-rate (WIR), signal enhancement ratio (SER), volume transfer constant (Ktrans), rate constant (Kep), extravascular extracellular space volume fraction (Ve) and initial area under the curve (iAUC). DWI signal intensity and apparent diffusion coefficient (ADC) values were evaluated. RESULTS: Epeak, WIR, Ktrans , Kep and iAUC were higher and TTP shorter in benign compared to malignant lesions (p < 0.05). All tumours had similar ADC values (p > 0.07). Subgroup analysis limited to the most frequent histologies - Leydig cell tumours (LCTs) and seminomas - replicated the findings of the entire set. Best diagnostic cutoff value for identification of seminomas: Ktrans <=0.135 min-1, Kep <=0.45 min-1, iAUC <=10.96, WIR <=1.11, Epeak <=96.72, TTP >99 s. CONCLUSIONS: DCE-MRI parameters are valuable in differentiating between benign and malignant small, non-palpable testicular tumours, especially when characterising LCTs and seminomas. KEY POINTS: * DCE-MRI may be used to differentiate benign from malignant non-palpable testicular tumours. * Seminomas show lower Ktrans, Kep and iAUC values. * ADC values are not valuable in differentiating seminomas from LCTs. * Semiquantitative DCE-MRI may be used to characterise small, solid testicular tumours. PMID- 28856413 TI - Could new reconstruction CT techniques challenge MRI for the detection of brain metastases in the context of initial lung cancer staging? AB - OBJECTIVES: To evaluate the diagnostic performance of brain CT images reconstructed with a model-based iterative algorithm performed at usual and reduced dose. METHODS: 115 patients with histologically proven lung cancer were prospectively included over 15 months. Patients underwent two CT acquisitions at the initial staging, performed on a 256-slice MDCT, at standard (CTDIvol: 41.4 mGy) and half dose (CTDIvol: 20.7 mGy). Both image datasets were reconstructed with filtered back projection (FBP) and iterative model-based reconstruction (IMR) algorithms. Brain MRI was considered as the reference. Two blinded independent readers analysed the images. RESULTS: Ninety-three patients underwent all examinations. At the standard dose, eight patients presented 17 and 15 lesions on IMR and FBP CT images, respectively. At half-dose, seven patients presented 15 and 13 lesions on IMR and FBP CT images, respectively. The test could not highlight any significant difference between the standard dose IMR and the half-dose FBP techniques (p-value = 0.12). MRI showed 46 metastases on 11 patients. Specificity, negative and positive predictive values were calculated (98.9-100 %, 93.6-94.6 %, 75-100 %, respectively, for all CT techniques). CONCLUSION: No significant difference could be demonstrated between the two CT reconstruction techniques. KEY POINTS: * No significant difference between IMR100 and FBP50 was shown. * Compared to FBP, IMR increased the image quality without diagnostic impairment. * A 50 % dose reduction combined with IMR reconstructions could be achieved. * Brain MRI remains the best tool in lung cancer staging. PMID- 28856414 TI - Foreskin reconstruction vs circumcision in distal hypospadias. AB - PURPOSE: The purpose of the study was to determine if there were differences in the complication rates between foreskin reconstruction (FR) and circumcision (CIRC) in distal hypospadias repairs. The primary outcomes were urethrocutaneous fistula (UF) and dehiscence. METHODS: The data of distal hypospadias operated between 2005 and 2013 were retrospectively reviewed. The inclusion criteria were any distal hypospadias repair that required an urethroplasty. The exclusion criteria were follow-up <1 year, redo procedures, chordee greater than 20 degrees , and incomplete data. Univariate and multivariate analysis was performed on the results. RESULTS: 213 patients were included (95 FR and 118 CIRC). The 2 groups were comparable for age at surgery 19.32 months in FR and 14.25 months in CIRC. Mathieu repair was more common in FR (47/95-49.47%) than in CIRC (45/118-38.14%). The total subsequent procedures required were 23 in FR and 57 in CIRC. The incidence of UF was 6.3% (6/95) in FR and 27.1% (32/118) in CIRC (p < 0.001, OR 5.52, 95% CI 2.2-13.9). Complete dehiscence rates were 3.16% (3/95) FR vs 11.02% (13/118) for CIRC (p = 0.037, OR 3.8, 95% CI 1.05-13.74). The incidence of patients requiring reoperation was 18.9% (18/95) in FR versus 45.8% (54/118) in CIRC (p < 0.001, OR 3.61, 95% CI 1.93-6.76). CONCLUSIONS: Foreskin Reconstruction conferred a significantly lower rate of complications, particularly the UF rate, dehiscence rate, and number of patients that required reoperation. Our rate of complications in the CIRC group is much higher than other published data. PMID- 28856416 TI - How long will I have my ACE? The natural history of the antegrade continence enema stoma in idiopathic constipation. AB - PURPOSE: We aim to determine the natural history of the ACE in idiopathic constipation and factors predictive of closure. METHODS: A retrospective case note review of all patients undergo ACE formation for idiopathic constipation Jan 2003-Mar 2016. Kaplan-Meier analysis was used to determine ACE survival and Cox's proportional hazard models to examine potential predictors of closure. RESULTS: 29/84 (35%) ACEs were closed: 21/84 due to success and 8/84 due to failure. Median age of closure was 15.5 years (3.5-23.6). Median ACE survival was 77.0 months (95% CI 58.0-96.0). An ACE survival curve was derived from which we estimate that 5-year post-ACE, one-third of patients can expect to have had their ACE closed. Younger age at ACE was predictive of earlier closure (p = 0.023) and closure for success (p < 0.001). Neither patient sex (p = 0.546) nor presence of psychological comorbidities (p = 0.769) predicted likelihood of closure. Incontinence 6-week post-ACE was also associated with increased likelihood of closure (p = 0.042). CONCLUSION: The ACE survival curve estimates the proportion of patients with idiopathic constipation who can expect closure (either due to success or failure) at certain timepoints. This may be useful for patient counseling. Younger age at ACE was associated with earlier closure (for success). PMID- 28856415 TI - Toxicity and infectivity: insights from de novo prion formation. AB - Prions are infectious misfolded proteins that assemble into oligomers and large aggregates, and are associated with neurodegeneration. It is believed that the oligomers contribute to cytotoxicity, although genetic and environmental factors have also been shown to have additional roles. The study of the yeast prion [PSI +] has provided valuable insights into how prions form and why they are toxic. Our recent work suggests that SDS-resistant oligomers arise and remodel early during the prion formation process, and lysates containing these newly formed oligomers are infectious. Previous work shows that toxicity is associated with prion formation and this toxicity is exacerbated by deletion of the VPS5 gene. Here, we show that newly made oligomer formation and infectivity of vps5? lysates are similar to wild-type strains. However using green fluorescent protein fusions, we observe that the assembly of fluorescent cytoplasmic aggregates during prion formation is different in vps5? strains. Instead of large immobile aggregates, vps5? strains have an additional population of small mobile foci. We speculate that changes in the cellular milieu in vps5? strains may reduce the cell's ability to efficiently recruit and sequester newly formed prion particles into central deposition sites, resulting in toxicity. PMID- 28856417 TI - Activity of human beta defensin-1 and its motif against active and dormant Mycobacterium tuberculosis. AB - The ineffectiveness of anti-tuberculous therapy against dormant and drug resistant mycobacteria demands scrutiny of alternative candidates like antimicrobial peptides having different mechanisms of action. The present study was designed to explore the activity of human beta defensin-1 (HBD-1) and its in silico identified short motif Pep-B against active and dormant Mycobacterium tuberculosis (M. tb) H37Rv. Activity of HBD-1 and Pep-B was determined against actively growing M. tb in vitro, inside monocyte-derived macrophages (MDMs) and dormant bacilli in in vitro potassium deficiency and human peripheral blood mononuclear cell (PBMC) granuloma models using colony-forming unit enumeration. The minimum inhibitory concentrations (MIC) of HBD-1 and Pep-B were found to be 2 and 20 MUg/ml, respectively. These peptides also inhibited intracellular mycobacterial growth at concentrations lower than in vitro MICs along with increased IFN-gamma levels. Although at higher concentration, HBD-1 (* 2 MIC) and Pep-B (* 2 MIC) led to decrease in in vitro dormant mycobacterial load as compared to rifampicin (* 25 MIC) and isoniazid (* 16 MIC). Similarly, both peptides showed higher killing efficacy against dormant mycobacteria inside granuloma as compared to rifampicin. Thus, the present study indicates that HBD-1 and its motif are effective antimicrobial players against both actively growing and dormant mycobacteria. PMID- 28856418 TI - Overall diet quality and risk of recurrence and progression of non-gallstone related acute pancreatitis: a prospective cohort study. AB - PURPOSE: An incident episode of acute pancreatitis is often followed by recurrent attacks and/or progression to chronic pancreatitis, especially if the etiology is non-gallstone-related. We examined whether overall diet quality influences the natural history of non-gallstone-related acute pancreatitis. METHODS: Three hundred and eighty-six individuals (born 1914-1952) were included in a prospective study, all of whom had an incident diagnosis of non-gallstone-related acute pancreatitis in the Swedish National Patient Register between 1998 and 2013. Participants were already enrolled in two population-based cohorts and had completed a food frequency questionnaire in 1997. Overall diet quality was calculated using a recommended food score (RFS), which was based on 25 food items. Post-diagnosis follow-up was conducted throughout 2014 for recurrence of acute pancreatitis and/or progression to chronic pancreatic disease (including cancer). Hazard ratios were estimated using Cox models. RESULTS: During 1859 person-years of follow-up, 23.3% of the study population (n = 90) developed recurrent or progressive pancreatic disease. An inverse association was observed between the RFS and risk of recurrent and progressive pancreatic disease after adjustment for age and sex (hazard ratio for each 2-unit increase 0.90, 95% confidence interval 0.81-1.01) (P overall association = 0.06). However, the association became weaker and was not statistically significant after adjustment for other potential confounders, including alcohol drinking and cigarette smoking (P overall association = 0.27). CONCLUSIONS: In this prospective study of individuals with non-gallstone-related acute pancreatitis, there was no clear association between overall diet quality and risk of recurrent and progressive pancreatic disease. PMID- 28856419 TI - [Contrast sensitivity and visual acuity in animals]. AB - BACKGROUND: Fundamental spatial vision capabilities of visual systems can be characterized by their contrast sensitivity and visual acuity. OBJECTIVE: Comparison of contrast sensitivity and visual acuity in humans and other animals. MATERIAL AND METHODS: An analysis of known contrast sensitivity functions and maximum visual acuity across selected taxa was carried out, with consideration of measurement principles, viewing conditions and allometry. RESULTS: Comparing across all analyzed species, contrast sensitivity functions have inverted U-shape characteristics, with key differences in both position and absolute sensitivity within the spectrum of spatial frequencies. Humans, for example, have a maximum sensitivity at 5 cycles/degree and mice at approximately 0.1 cycles/degree. Body and eye size generally correlate well with maximum visual acuity. Across eye types, lens eyes have the highest optical and visual resolution, all other things being equal. Diurnal species typically outperform crepuscular or nocturnal species. Humans generally excel at both maximum contrast sensitivity as well as visual acuity. CONCLUSION: Despite great differences in optical, anatomical and neurophysiological structures between humans and animals, spatial vision capabilities are generally comparable across taxa. This favors the hypothesis that spatial vision in animals develops primarily towards meeting similar evolutionary needs within the limits of biophysical and optical laws. PMID- 28856420 TI - Iodine-based contrast media, multiple myeloma and monoclonal gammopathies: literature review and ESUR Contrast Media Safety Committee guidelines. AB - OBJECTIVES: Many radiologists and clinicians still consider multiple myeloma (MM) and monoclonal gammopathies (MG) a contraindication for using iodine-based contrast media. The ESUR Contrast Media Safety Committee performed a systematic review of the incidence of post-contrast acute kidney injury (PC-AKI) in these patients. METHODS: A systematic search in Medline and Scopus databases was performed for renal function deterioration studies in patients with MM or MG following administration of iodine-based contrast media. Data collection and analysis were performed according to the PRISMA statement 2009. Eligibility criteria and methods of analysis were specified in advance. Cohort and case control studies reporting changes in renal function were included. RESULTS: Thirteen studies were selected that reported 824 iodine-based contrast medium administrations in 642 patients with MM or MG, in which 12 unconfounded cases of PC-AKI were found (1.6 %). The majority of patients had intravenous urography with high osmolality ionic contrast media after preparatory dehydration and purgation. CONCLUSIONS: MM and MG alone are not risk factors for PC-AKI. However, the risk of PC-AKI may become significant in dehydrated patients with impaired renal function. Hypercalcaemia may increase the risk of kidney damage, and should be corrected before contrast medium administration. Assessment for Bence-Jones proteinuria is not necessary. KEY POINTS: * Monoclonal gammopathies including multiple myeloma are a large spectrum of disorders. * In monoclonal gammopathy with normal renal function, PC-AKI risk is not increased. * Renal function is often reduced in myeloma, increasing the risk of PC-AKI. * Correction of hypercalcaemia is necessary in myeloma before iodine-based contrast medium administration. * Bence-Jones proteinuria assessment in myeloma is unnecessary before iodine-based contrast medium administration. PMID- 28856421 TI - Co-circulation of Araraquara and Juquitiba Hantavirus in Brazilian Cerrado. AB - Hantavirus cardiopulmonary syndrome is an emerging serious disease in the Americas, transmitted from wild rodents to humans through inhalation of aerosol containing virus. Herein, we characterized two distinct hantaviruses circulating in rodent species form Central Plateau, Midwestern region of Brazil in the Cerrado (savanna-like) biome, an area characterized by small trees and grasses adapted to climates with long dry periods. In this study, we identified the co circulation of the Araraquara virus and a possible new lineage of the Juquitiba virus (JUQV) in Oligoryzomys nigripes. The implications of co-circulation are still unknown, but it can be the key for increasing viral diversity or emergence of new species through spillover or host switching events leading to co-infection and consequently recombination or reassortment between different virus species. Phylogenetic analyses based on the complete S segment indicated that, alongside with Oligoryzomys mattogrossae rodents, O. nigripes species could also have a whole as JUQV reservoir in the Cerrado biome. Although these rodents' species are common in the Cerrado biome, they are not abundant demonstrating how complex and different hantavirus enzootic cycles can be in this particular biome. PMID- 28856423 TI - Longitudinal Cracking with a Guidewire Tail for Extremely Calcified Lesions in Infrainguinal Arteries: PICKING Technique. AB - PURPOSE: To report a percutaneous intravascular cracking with a guidewire tail (PICKING) technique to longitudinally crack the underlying calcification and facilitate the balloon catheter passage for the treatment of severely calcified chronic occlusions in the infrainguinal artery. MATERIALS AND METHODS: Three patients underwent PICKING technique between November 2014 and March 2017. The PICKING technique with the stiff tail of 0.018-inch guidewire in the straight configuration was considered in cases of failed passage of the smallest balloon catheter because of the underlying severely calcified occlusion following passage of 0.014-inch guidewire. RESULTS: All three patients were complicated by end stage renal disease on hemodialysis. Treated vessels were superficial femoral artery in two cases and anterior tibial artery in one case. In all cases, successful passage and dilatation of the balloon catheter were achieved, and significant improvements in clinical symptoms were observed following subsequent optimal balloon angioplasty or stenting. CONCLUSIONS: The PICKING technique could increase the potential of endovascular solution for the treatment of severely calcified chronic occlusions in the infrainguinal artery. PMID- 28856422 TI - Are the Epworth Sleepiness Scale and Stop-Bang model effective at predicting the severity of obstructive sleep apnoea (OSA); in particular OSA requiring treatment? AB - Obstructive sleep apnoea (OSA) is a condition characterised by repetitive upper airway collapse during sleep. The condition carries a range of health sequelae that can prove fatal in cases with co-existing risk factors for the condition, such as obesity and hypertension. Utilisation of a high-performance screening tool for OSA is thus important. A retrospective audit using the ESS and Stop-Bang scores, alongside Apnoea-Hypopnea Index values, for patients who underwent polysomnography over 1 year. Multinomial logistic regression was used to compare the predictive abilities of ESS, SBM, and body mass index (BMI) for the patient outcome groups, "None" (No OSA), "Notreat" (OSA not requiring treatment) and "treat" (OSA requiring treatment). The influences of age, gender and BMI on outcome group were also assessed. 126 bariatric and 66 non-bariatric patients were included. Multinomial logistic regression failed to demonstrate predictive ability of ESS. A higher Stop-Bang score significantly increases the risk being in the "treat" group. In addition, male gender, greater age and a higher BMI each individually increase the risk of OSA requiring treatment. Stop-Bang failed to demonstrate predictive significance when age and gender were controlled for. ESS is not an appropriate screening tool for OSA. Stop-Bang, however, remains a useful screening tool, with the ability to detect patient with OSA in need of treatment. Further study may benefit the development and implementation of a concise and more specific screening tool that considers high evidence-based risk factors for OSA, including male gender, greater age and raised BMI. PMID- 28856424 TI - Comparison of different methods for repairing damaged DNA from buffered and unbuffered formalin-fixed tissues. AB - Formalin fixation is considered an important process for preservation of human tissue samples for long periods. However, this process not only results in cross linking complicating isolation of nucleic acid but also introduces polymerase "blocks" during polymerase chain reaction (PCR). At present, many protocols have already been developed aiming at extracting high amounts of amplifiable DNA from formalin-fixed tissues (FFTs). However, there are few methods for repairing formalin-damaged DNA. In this study, we compared the effectiveness of several post-extraction enzymatic repair techniques, including Taq DNA polymerase, DNA polymerase I and T4 DNA ligase, the PreCRTM Repair Mix and Restorase(r) DNA Polymerase, in restoring STR profiles from formalin-damaged DNA. Our results indicated that formalin-damaged DNA may be repaired partly with Taq DNA polymerase and the Restorase(r) DNA Polymerase, and lost alleles may be restored and STR peak heights may increase upon repair with them. Moreover, the repair ability of the protocol 2 with Taq DNA polymerase surpasses the Restorase(r) DNA Polymerase. PMID- 28856426 TI - Genital lichen sclerosus in childhood and adolescence-a retrospective case series of 15 patients: early diagnosis is crucial to avoid long-term sequelae. AB - : Lichen sclerosus is a chronic skin disease, mainly localised at the introitus and perineum. When the condition remains untreated, gradual atrophy of skin structures leads to permanent scarring, making early diagnosis and treatment crucial. We reviewed all patients diagnosed with lichen sclerosus presenting to a tertiary referral centre for paediatric and adolescent gynaecology between January 2011 and December 2015 to assess disease presentation and response to treatment. We identified 15 cases, with a mean age at diagnosis of 8.8 years. Their main presenting symptoms were vulvar pruritus and vulvar soreness. Seven girls had already atrophic changes, and in four girls, this amounted to clitoral phimosis, labial resorption or labial adhesion formation. The median delay in diagnosis was 7 months. Thirteen patients received local treatment with potent corticosteroids, responding well to treatment. However, 4 girls relapsed within 2 to 36 months. Two adolescents required surgical treatment, one because of urinary retention and the second because of dyspareunia caused by clitoral entrapment. CONCLUSIONS: There was a delay in diagnosis in most patients and this resulted in irreversible genital skin changes, which would have been preventable, had treatment been instituted promptly. The response to treatment with local corticosteroids was usually effective, leading to both symptom alleviation and prevention of disease progression. Atrophic changes and skin complications however were not reversed. What is Known: * Lichen sclerosus affects women of all ages, including girls, particularly prior to adolescence. * Lichen sclerosus responds well to local corticosteroid treatment. What is New: * In the majority of patients with lichen sclerosus there was a long delay between onset of symptoms and diagnosis. * Nearly half of the children diagnosed with lichen sclerosus had irreversible atrophic genital skin changes at the time of first presentation. These changes may have been prevented by a timely diagnosis and intervention. PMID- 28856425 TI - A specific pattern of gray matter atrophy in Alzheimer's disease with depression. AB - Considering the high incidence of depressive symptoms in Alzheimer's disease (AD), we conducted a large-sample study to investigate the pattern of gray matter (GM) abnormalities that differentiates depressive from non-depressive AD patients. We included 201 AD patients who underwent MRI assessment and categorized them into depressive and non-depressive subgroups based on the Geriatric Depression Scale (GDS; cut-off score: <=9). We performed whole-brain voxel-based morphometry analysis in 173 patients after MRI quality control and used between-group comparisons and regression analysis models to analyze the volumetric data controlling for nuisance variables. Depressive AD patients had extensive GM volume loss mainly in the paracentral region, specifically in post- and pre-central gyrus, supplementary motor areas and thalamus compared to non depressive patients. Similar findings were obtained for the group of 173 patients using regression analysis and GDS score as predictor variable. We provided the first clear demonstration of a unique pattern of GM atrophy that characterizes AD patients with depression which is consistent with regions implicated in the phenomenon of psychomotor retardation that characterizes depression. PMID- 28856427 TI - Coordinate invariance as a fundamental constraint on the form of stimulus specific information measures. AB - The value of Shannon's mutual information is commonly used to describe the total amount of information that the neural code transfers between the ensemble of stimuli and the ensemble of neural responses. In addition, it is often desirable to know which features of the stimulus or response are most informative. The literature offers several different decompositions of the mutual information into its stimulus or response-specific components, such as the specific surprise or the uncertainty reduction, but the number of mutually distinct measures is in fact infinite. We resolve this ambiguity by requiring the specific information measures to be invariant under invertible coordinate transformations of the stimulus and the response ensembles. We prove that the Kullback-Leibler divergence is then the only suitable measure of the specific information. On a more general level, we discuss the necessity and the fundamental aspects of the coordinate invariance as a selection principle. We believe that our results will encourage further research into invariant statistical methods for the analysis of neural coding. PMID- 28856428 TI - Intraoperative B-scan ultrasonography and pars plana vitrectomy for severe open globe injury with hemorrhagic retinal and choroidal detachment. AB - PURPOSE: Our purpose was to report the initial clinical experience of intraoperative B-scan ultrasonography in combination with 25-gauge pars plana vitrectomy for severe open globe injury with hemorrhagic retinal and choroidal detachment. METHODS: Six eyes of six consecutive patients with severe open globe injury underwent intraoperative B-scan ultrasonography and 25-gauge pars plana vitrectomy at Osaka University Hospital in Japan. The feasibility of intraoperative B-scan ultrasonography, best-corrected visual acuity (BCVA), retinal reattachment, and intraoperative and postoperative complications were evaluated. RESULTS: Five patients presented with a ruptured globe and one patient with double penetration. Preoperative best-corrected visual acuity was no light perception in four eyes and light perception in two eyes. All patients underwent intraoperative B-scan ultrasonography and 25-gauge pars plana vitrectomy within 12 h after open globe injury. Intraoperative B-scan ultrasonography was feasible in all cases and was useful for diagnosing choroidal hemorrhage (four eyes), massive subretinal hemorrhage (two eyes), and retinal detachment (five eyes). In addition, serial real-time B-scan imaging facilitated successful evacuation of the choroidal hemorrhage and massive subretinal hemorrhage by external drainage, resulting in opening of the vitreous space to allow subsequent pars plana vitrectomy without entry site-related complications. After surgery, all patients had successful retinal attachment, and there was no loss of light perception. CONCLUSION: Intraoperative B-scan ultrasonography is technically feasible and may potentially improve the safety and efficacy of severe open globe injury repair. PMID- 28856429 TI - Effect of CRP value on 18F-FDG PET vascular positivity in Takayasu arteritis: a systematic review and per-patient based meta-analysis. AB - PURPOSE: The aim of this study was to quantify the association between the CRP value and 18F-FDG PET vascular positivity in Takayasu arteritis (TAK) through a structured dedicated systematic review and meta-analysis. METHODS: From January 2000 to December 2016, the PubMed/MEDLINE database was searched for articles specifically dealing with the assessment of vascular inflammation using 18F-FDG PET and CRP biomarkers in TAK. Inclusion criteria for the qualitative analysis were (1) 18F-FDG PET used to assess the disease activity, (2) The use of the ACR criteria for the diagnosis of TAK, (3) No case mixed vasculitis (i.e., no giant cell arteritis), and (4) CRP concentration and clinical disease activity available. For the meta-analysis, PET-positive and PET-negative subgroups with the corresponding CRP concentrations were generated based on per patient data. The standard mean difference, which represents the effect of the CRP concentrations on the 18F-FDG PET vascular uptake, was computed for all studies, and then the results were pooled together. RESULTS: Among the 33 initial citations, nine complete articles including 210 patients fulfilled the inclusion criteria. Five studies found a significant correlation between the 18F-FDG PET and CRP concentration, one provided a trend towards association and three did not find any association between the two biomarkers. Six studies found a significant association between 18F-FDG PET and clinical disease activity, one found a trend towards association and the last two studies did not evaluate this correlation. The meta-analysis (121 patients) provided the following results: Standard Mean Deviation = 0.54 [0.15;0.92]; Chi2 = 3.35; I2 = 0%; Test for overall effect: Z = 2.70 (P = 0.007). CONCLUSION: The CRP concentration only moderately reflects the 18F-FDG PET vascular positivity in TAK, suggesting dissociated information. Standardized longitudinal prospective studies are necessary to assess the value of 18F-FDG PET as an independent biomarker for subtle vascular wall inflammation detection. PMID- 28856430 TI - Habitual yoghurt consumption and depressive symptoms in a general population study of 19,596 adults. AB - PURPOSE: Epidemiological studies directly examining the association between habitual yoghurt consumption and mental health remain scarce. The aim of this study is to investigate the association of yoghurt consumption with depressive symptoms in adults. METHODS: This is a cross-sectional study of 19,596 Chinese adults (mean age 41.2, standard deviation 11.8 years; males, 54.3%). Depressive symptoms were assessed using the Self-Rating Depression Scale (SDS). Dietary intake was obtained through a valid food frequency questionnaire. Multiple logistic regression analysis was conducted to assess the association between yoghurt consumption and depressive symptoms. A number of potential confounders were adjusted in the model. RESULTS: The prevalence of elevated depressive symptoms was 17.1% (SDS >=45). The multivariable adjusted odds ratios (95% CI) of having elevated depressive symptoms by increasing levels of yoghurt consumption (1-3 times/week, 4-7 times/week, and >=twice/day) were 1.05 (0.96, 1.15), 1.02 (0.91, 1.15), and 2.10 (1.61, 2.73) in comparison with lowest consumption group (=twice/day), which was seen in a small subset of subjects, was associated with increased depressive symptoms. These results need to be interpreted with caution because of the cross-sectional nature of the data. PMID- 28856431 TI - Morphological and molecular characteristics of six Sarcocystis spp. from red deer (Cervus elaphus) in Spain, including Sarcocystis cervicanis and three new species. AB - Samples of muscle tissue from the diaphragm, oesophagus and/or heart of eight adult red deer (Cervus elaphus hispanicus) from the Quintos de Mora Park in Toledo, Central Spain, were screened for sarcocysts by means of the compression method. From positive samples, individual sarcocysts were excised and examined in wet mounts under a light microscope (LM) in order to study their basic morphology before being preserved for molecular studies. In all red deer examined, only microscopic sarcocysts were found. Those in the diaphragm and oesophagus were spindle-shaped and about 1 * 0.1 mm in size, while those in cardiac muscle were sac-like and 500-800 * 80-180 MUm. By LM, the sarcocysts either had densely packed, about 8-MUm-long, hair-like protrusions (type 1), sparsely distributed indistinct projections (fuzzy outline; type 2) or no visible protrusions (smooth surface; type 3). In cardiac muscle, only sarcocysts without visible protrusions were found. One of the latter sarcocysts was examined by scanning electron microscopy (SEM) and found to possess thin ribbon-like protrusions. Forty-eight sarcocysts isolated from the diaphragm, oesophagus and heart of one red deer, as well as 55 sarcocysts from the heart of three other red deer, 103 sarcocysts in total, were characterized molecularly through PCR amplification and sequencing of the partial cytochrome c oxidase subunit I gene (cox1) of the mitochondrial genome, revealing the presence of six major cox1 sequence types. Each type comprised either a single sequence (three types) or a collection of several identical or nearly identical sequences. From selected isolates possessing each of these cox1 sequence types, the complete 18S ribosomal RNA (rRNA) gene was amplified and sequenced directly and/or after cloning of the 5' end half. Supported by the sequence data from the latter gene, as well as the morphology of the sarcocysts from which the sequences originated, the six cox1 sequence types were considered to represent six separate Sarcocystis spp. Two cox1 sequence types were identified as belonging to the previously characterized species Sarcocystis hjorti (one sequence/sarcocyst) and Sarcocystis linearis (38 sequences/sarcocysts), respectively, whereas four sequence types were new. One of the latter types was assigned to the previously named species Sarcocystis cervicanis from red deer, since this sequence type was obtained from 52 sarcocysts from cardiac muscle, which matched the original morphological description (smooth surface) and habitat of this species. The remaining three sequence types were assigned to the three new species Sarcocystis iberica (one sequence/sarcocyst) Sarcocystis venatoria (10 sequences/sarcocysts) and Sarcocystis morae (one sequence/sarcocyst), respectively. The two species S. iberica and S. venatoria shared the same sarcocyst morphology (type 1) and habitat (diaphragm) and had virtually identical 18S rRNA gene sequences, but differed by 4% at cox1, which was considered sufficient to regard them as separate species. The single sarcocyst of S. morae (from the oesophagus) examined by LM had a smooth wall and this species was therefore believed to have the same type of ribbon-like protrusions (ultrastructurally) as sarcocysts of S. cervicanis and S. linearis, which were also the species most closely related to S. morae at cox1. Thus, there seems to be three species with similar ribbon-like cyst wall protrusions in red deer (S. cervicanis, S. linearis, S. morae), as well as three species with similar hair-like protrusions (S. hjorti, S. iberica, S. venatoria). Sarcocysts of S. cervicanis were only identified in cardiac muscle, whereas sarcocysts of S. linearis were found mainly in the diaphragm and oesophagus and rarely in the heart. The relative number of cox1 haplotypes was greater among sequences/isolates of S. linearis (17/38) than among isolates of S. cervicanis (7/52). Four of the species examined (S. cervicanis, S. linearis, S. iberica, S. venatoria) possessed considerable intra-isolate (intra-genomic) sequence variation (insertions/deletions, substitutions) in the 18S rRNA gene. PMID- 28856432 TI - Kruppel-like factor 4 regulates matrix metalloproteinase and aggrecanase gene expression in chondrocytes. AB - Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor that plays crucial roles during the development and maintenance of multiple organs. We and others have previously shown that KLF4 is involved in bone modeling and remodeling but roles played by KLF4 during skeletogenesis are still not fully understood. Here, we show that KLF4 is expressed in the epiphyseal growth plate and articular chondrocytes. Most articular chondrocytes expressed KLF4 in embryos but it localized only in a subset of superficial zone cells in postnatal mice. When KLF4 was overexpressed in chondrocytes in vitro, it severely repressed chondrocytic gene expressions. Global gene expression profiling of KLF4 transduced chondrocytes revealed matrix degrading proteinases of the matrix metalloproteinase and disintegrin and metalloproteinase with thrombospondin-1 domain families within the group of upregulated genes. Proteinase induction by KLF4 was alleviated by Trichostatin A treatment suggesting the possible involvement of epigenetic mechanisms on proteinase induction by KLF4. These results indicate the possible involvement of KLF4 in physiological and pathological aspects during cartilage development and maintenance. PMID- 28856434 TI - The impact of free-order and sequential-order instructions on task-order regulation in dual tasks. AB - Dual tasks (DTs) are characterized by the requirement for additional mechanisms that coordinate the processing order of two temporally overlapping tasks. These mechanisms are indicated by two types of costs that occur when comparing DT blocks with fixed and random orders of the component tasks. On a block level, task-order control costs are reflected in increased reaction times (RTs) in random-order compared to fixed-order blocks, indicating global, monitoring-based, coordination mechanisms. On a trial level, within random-order blocks, order switch costs are indicated by increased RTs on order switch compared to order repetition trials, reflecting memory-based mechanisms that guide task-order in DTs. To test the nature of these mechanisms in two experiments, participants performed DTs in fixed- and random-order blocks. In random-order blocks, participants were either instructed to respond to both tasks according to the order of task presentation (sequential-order instruction) or instructed to freely decide in which order to perform both tasks (free-order instruction). As a result of both experiments, we demonstrated that task-order control costs were reduced under the free-order compared to the sequential-order instruction, whereas order switch costs were not affected by our instruction manipulation. This pattern of results suggests that the task-order control costs reflect global processes of task-order regulation such as engaging monitoring processes that are sensitive to changes in order instructions, while order-switch costs reflect rather local memory-based mechanisms that occur irrespective of any effort to coordinate task order. PMID- 28856433 TI - Effects of Orthodox religious fasting on human health: a systematic review. AB - PURPOSE: Different studies have pointed towards a positive effect of religious fasting on human health. Orthodox fasting (OF) regime could be characterized as a periodical vegetarian diet, demonstrating several common characteristics with the typical Mediterranean diet. The present systematic review aimed to synthesize available results regarding the potential impact of OF on human health. METHODS: Key biomedical databases were searched to identify studies examining the effects of OF on humans. Following implementation of specific criteria, ten studies were included in the analysis and their results were systematically reported and critically appraised in this review. RESULTS: According to the available limited results, OF periods are characterized by a restriction in total energy and fat intake, an increase in carbohydrate and fiber consumption, while in terms of protein intake, results are contradictive. The overall effect of OF on lipids profile seems to be optimal, with the reduction of total cholesterol and LDL-C levels, being a consistent finding across studies (up to 17.8 and 31.4%, respectively). However, the effect on HDL-C is still unclear. Conclusions regarding the impact on body weight and glucose homeostasis cannot be drawn, given that relevant data are limited with conflicting results. Any potential negative aspects of OF, mainly attributed to reduced dietary intake of vitamin D and B12 and minerals (mainly calcium), require further investigation. CONCLUSIONS: Given the limitations of available evidence, more studies are required before reaching definite conclusions about the effects of OF on human health. PMID- 28856435 TI - Viscosupplementation in patients with severe osteoarthritis of the knee: six month follow-up of a randomized, double-blind clinical trial. AB - PURPOSE: To analyze the early outcomes of viscosupplementation in patients with severe knee osteoarthritis. METHOD: A randomized, double-blind clinical trial of 143 knees divided into three groups: Group 1 - intra-articular injection of triamcinolone; Group 2 - hylan GF20; and Group 3 - triamcinolone + hylan GF20. Outcomes were evaluated using Lysholm and KSS scores before treatment and after one, three and six months. RESULTS: Within-group comparisons revealed improvements in Lysholm scores in all groups in the one month evaluation relative to pre-treatment levels (p < 0.01). This improvement was maintained in the third month after treatment (p > 0.05). Scores at six months were significantly lower than those observed in the previous follow-up assessments (p < 0.05), but still higher than pre-treatment levels (p < 0.05). KSS scores also improved after one month relative to pre-treatment levels (p < 0.01). This improvement was still present at three and six months after treatment in the corticosteroid group (p > 0.05). Patients treated with hylan GF20 showed lower scores in the last evaluation relative to month one (p < 0.05). No significant differences were observed between the treatment groups (p > 0.05). CONCLUSIONS: Viscosupplementation increased functional scores in patients with severe osteoarthritis of the knee, especially within three months of injection. However, it was not superior to the use of triamcinolone. PMID- 28856436 TI - Rethinking Residue: Determining the Perceptual Continuum of Residue on FEES to Enable Better Measurement. AB - The goal of this work was to better understand perceptual judgments of pharyngeal residue on flexible endoscopic evaluation of swallowing (FEES) and the influence of a visual analog scale (VAS) versus an ordinal scale on clinician ratings. The intent was to determine if perceptual judgments of residue were more accurately described by equal or unequal intervals. Thirty-three speech language pathologists rated pharyngeal residue from 75 FEES videos representing a wide range of residue severities for thin liquid, applesauce, and cracker boluses. Clinicians rated their impression of the overall residue amount in each video on a VAS and, in a different session, on a five-point ordinal scale. Residue ratings were made in two separate sessions separated by several weeks. Statistical correlations of the two rating methods were carried out and best-fit models were determined for each bolus type. A total of 2475 VAS ratings and 2473 ordinal ratings were collected. Residue ratings from both methods (VAS and ordinal) were strongly correlated for all bolus types. The best fit for the data was a quadratic model representing unequal intervals, which significantly improved the r 2 values for each bolus type (cracker r 2 = 0.98, applesauce r 2 = 0.99, thin liquid r 2 = 0.98, all p < 0.0001). Perceptual ratings of pharyngeal residue demonstrated a statistical relationship consistent with unequal intervals. The present findings support the use of a VAS to rate residue on FEES, allowing for greater precision as compared to traditional ordinal rating scales. Perceptual judgments of pharyngeal residue reflected unequal intervals, an important concept that should be considered in future rating scales. PMID- 28856438 TI - 3D printing the pterygopalatine fossa: a negative space model of a complex structure. AB - PURPOSE: The pterygopalatine fossa is one of the most complex anatomical regions to understand. It is poorly visualized in cadaveric dissection and most textbooks rely on schematic depictions. We describe our approach to creating a low-cost, 3D model of the pterygopalatine fossa, including its associated canals and foramina, using an affordable "desktop" 3D printer. METHODS: We used open source software to create a volume render of the pterygopalatine fossa from axial slices of a head computerised tomography scan. These data were then exported to a 3D printer to produce an anatomically accurate model. RESULTS: The resulting 'negative space' model of the pterygopalatine fossa provides a useful and innovative aid for understanding the complex anatomical relationships of the pterygopalatine fossa. CONCLUSION: This model was designed primarily for medical students; however, it will also be of interest to postgraduates in ENT, ophthalmology, neurosurgery, and radiology. The technical process described may be replicated by other departments wishing to develop their own anatomical models whilst incurring minimal costs. PMID- 28856439 TI - Plasma amino acids, adiposity, and weight change after gastric bypass surgery: are amino acids associated with weight regain? AB - PURPOSE: Plasma concentrations of several amino acids (AAs) are positively correlated with obesity. The aim of this study was to examine if selected plasma AAs are associated with weight regain from 2 to 4 years after Roux-en-Y gastric bypass (RYGB). METHODS: In a prospective study with 165 patients, we examined the relationship between plasma aromatic AAs (AAAs), branched chain AAs (BCAAs), and total cysteine (tCys) 2 years after RYGB, with BMI at 2 years and with weight change from 2 to 4 years after surgery. Analyses were adjusted for relevant covariates. RESULT: The investigated AAs at 2 years correlated positively with BMI at 2 years (P <= 0.003 for all). BCAAs and AAAs at 2 years correlated inversely with % weight loss from 0 to 2 years (P = 0.002 and P = 0.001, respectively), while the association was not significant for tCys (r = -0.14, P = 0.08). Plasma tCys at 2 years correlated positively with BMI at 4 years (P = 0.010) and with weight regain from 2 to 4 years (P = 0.015). CONCLUSION: Plasma AAAs, BCAAs, and tCys at 2 years were associated with BMI at 2 years. In addition, plasma AAAs and BCAAs at 2 years were associated with weight loss from 0 to 2 years, while tCys at 2 years was associated with weight regain from 2 to 4 years after RYGB. These results suggest that high tCys at 2 years may be used as a prognostic marker for future weight regain. The study was registered in ClinicalTrials.gov (NCT0 1270451). PMID- 28856437 TI - Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO). AB - Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship. PMID- 28856440 TI - The impact of the introduction of PECARN head CT rules on the utilisation of head CT scans in a private tertiary hospital in Sub-Saharan Africa. AB - BACKGROUND: The decision to order head CT scans to rule out clinically significant traumatic brain injury in mild head injury in children is made on the basis of clinical decision rules of which the Paediatric Emergency Care Applied Research Network (PECARN) CT head rules have been found to be most sensitive. PURPOSES: The purpose of this study is to determine the proportion of head CT scans done for children with mild head injury and to determine disposition of patients from casualty after the introduction of PECARN head CT rules compared to the period before. The research question is "will introduction of the PECARN CT head rules reduce the proportion of head CT scans requested for children under 18 years with mild head injury at the AKUHN?" METHODS: A before and after quasi experimental study with a study population including all children under 18 years presenting to the AKUHN with mild head injury and a Glasgow coma scale of 14 and above on presentation. Sample size was 85. RESULTS: A total of 42 patients files were analysed in the before study while 43 patients were selected for the after study. The median age was 5 years. The proportion of head CT scans reduced from 56% in the before group to 33% in the after group with no missed clinically significant traumatic brain injury. More patients were discharged home after evaluation in the after group (81%) than in the before group (58%). CONCLUSIONS: The number of head CT scans ordered reduced without missing any clinically significant traumatic brain injury. PMID- 28856441 TI - Toll-like receptor 5 and 7 expression may impact prognosis of HPV-positive oropharyngeal squamous cell carcinoma patients. AB - A large subset of oropharyngeal squamous cell carcinomas (OPSCCs) is associated with HPV infection and has better outcome than non-viral-related tumors. Various malignancies also carry a role for TLRs, key activators of inflammation and innate immunity. We examined the expression of TLRs in OPSCC, and their association with HPV status and treatment outcome. TLR 5, 7, 9, and p16 were studied by immunohistochemistry and HPV status was detected with in situ hybridization in 202 tumors of consecutively treated OPSCC patients using tissue microarray method. The relations between TLR expression and HPV status, p16 expression, clinicopathological factors, and survival were analyzed. TLR 5, 7, and 9 expression patterns differed between HPV-positive and -negative tumors, and they were statistically significantly associated with history of smoking, heavy drinking, tumor site, grade, size (T), metastasis (N), and stage. Moreover, in HPV-positive tumors the expression of TLR 5 and 7 correlated with tumor recurrence. After adjustment, among HPV-positive OPSCC patients, high TLR 5 and low TLR 7 expression were associated with poor disease-specific survival. Our results indicate that TLR 5 and 7 may have a role in the prognostication of HPV positive OPSCC, however, further studies are needed to clarify the comprehensive role of these TLRs in OPSCC. PMID- 28856442 TI - Seasonal temperature is associated with Parkinson's disease prescriptions: an ecological study. AB - The aim of this study is to test what effect the weather may have on medications prescribed to treat Parkinson's disease. Twenty-three years of monthly time, series data was sourced from the Pharmaceutical Benefits Scheme (PBS) and the Bureau of Meteorology (BOM). Data were available for eight states and territories and their corresponding capital cities. The dependent variable was the aggregate levodopa equivalent dose (LED) for 51 Parkinson's medications identified on the PBS. Two explanatory variables of interest, temperature and solar exposure, were identified in the BOM data set. Linear and cosinor models were estimated with fixed and random effects, respectively. The prescribed LED was 4.2% greater in January and 4.5% lower in July. Statistical analysis showed that temperature was associated with the prescription of Parkinson medications. Our results suggest seasonality exists in Parkinson's disease symptoms and this may be related to temperature. Further work is needed to confirm these findings and understand the underlying mechanisms as a better understanding of the causes of any seasonal variation in Parkinson's disease may help clinicians and patients manage the disease more effectively. PMID- 28856443 TI - Circadian rhythm of blood cardiac troponin T concentration. AB - INTRODUCTION: High-sensitivity cardiac troponin assays have significantly improved the sensitivity of myocardial infarction detection by using cutoff values and early absolute changes. However, variation in repeated measures also depends on biological variability. This study aimed to assess the potential circadian component of this biological variability. METHODS: 17 healthy volunteers were recruited, and standardized conditions for physical activity, meals, exposure to light and duration of sleep were imposed. Blood samples were collected every 4 h and high-sensitivity troponin T assay with a limit of detection of 3 ng/l and a 99th percentile of 14 ng/l were used. Circadian variations were analyzed using the cosinor method. RESULTS: Statistically significant circadian variations were observed for body temperature, heart rate, and systolic/diastolic arterial blood pressures (p < 0.01 using both a non adjusted cosinor model and a gender- and BMI-adjusted cosinor model). The amplitudes of the circadian variations were 18.93, 6, 15.35, and 1.92%, respectively. A statistically significant circadian biological variation of troponin blood concentrations was evidenced (p < 0.01 in both the non-adjusted cosinor model and the gender- and BMI-adjusted cosinor), with an amplitude of 20.5% (average: 4.39 ng/l; amplitude: 0.9 ng/l; peak at 06:00 and nadir at 18:00). DISCUSSION: This study demonstrates a circadian biological variation in blood troponin concentration in a healthy population. The amplitude of this variation challenges the cutoff value for instant rule-out of the rapid rule in/rule-out of the recent European guidelines for the management of acute coronary syndromes. These findings deserve further investigation in a population at risk of myocardial infarction. PMID- 28856444 TI - Mechanisms of curcumin-induced gastroprotection against ethanol-induced gastric mucosal lesions. AB - BACKGROUND: Curcumin, a pleiotropic substance used for centuries in traditional medicine, exhibits antioxidant, anti-inflammatory and antiproliferative efficacy against various tumours, but the role of curcumin in gastroprotection is little studied. We determined the effect of curcumin against gastric haemorrhagic lesions induced by 75% ethanol and alterations in gastric blood flow (GBF) in rats with cyclooxygenase-1 (COX-1) and COX-2 activity inhibited by indomethacin, SC-560 or rofecoxib, inhibited NO-synthase activity, capsaicin denervation and blockade of TRPV1 receptors by capsazepine. METHODS: One hour after ethanol administration, the gastric mucosal lesions were assessed by planimetry, the GBF was examined by H2 gas clearance, plasma gastrin was determined by radioimmunoassay, and the gastric mucosal mRNA expression of Cdx-2, HIF-1alpha, HO-1 and SOD 2 was analysed by RT-PCR. RESULTS: Curcumin, in a dose-dependent manner, reduced ethanol-induced gastric lesions and significantly increased GBF and plasma gastrin levels. Curcumin-induced protection was completely reversed by indomethacin and SC-560, and significantly attenuated by rofecoxib, L-NNA, capsaicin denervation and capsazepine. Curcumin downregulated Cdx-2 and Hif 1alpha mRNA expression and upregulated HO-1 and SOD 2, and these effects were reversed by L-NNA and further restored by co-treatment of L-NNA with L-arginine. CONCLUSIONS: Curcumin-induced protection against ethanol damage involves endogenous PG, NO, gastrin and CGRP released from sensory nerves due to activation of the vanilloid TRPV1 receptor. This protective effect can be attributed to the inhibition of HIF-1alpha and Cdx-2 expression and the activation of HO-1 and SOD 2 expression. PMID- 28856445 TI - Extracting genotype information of Arabidopsis thaliana recombinant inbred lines from transcript profiles established with high-density oligonucleotide arrays. AB - KEY MESSAGE: Polymorphic probes identified via a sequence-based approach are suitable to infer the genotypes of recombinant inbred lines from hybridisation intensities of GeneChip (r) transcript profiling experiments. The sequences of the probes of the ATH1 GeneChip(r) exactly match transcript sequences of the Arabidopsis thaliana reference genome Col-0, whereas nucleotide differences and/or insertions/deletions may be observed for transcripts of other A. thaliana accessions. Individual probes of the GeneChip(r) that show sequence polymorphisms between different A. thaliana accessions may serve as single-feature polymorphism (SFP) markers, provided that the sequence changes cause differences in hybridisation intensity for the accessions of interest. A sequence-based approach identified features on the high-density oligonucleotide array that showed sequence polymorphisms between A. thaliana accessions Col-0 and C24. Hybridisation intensities of polymorphic probes were extracted from genome-wide transcript profiles of Col-0/C24 and C24/Col-0 recombinant inbred lines and assessed after standardisation via sliding window analyses to identify SFP markers. The genotypes of the recombinant inbred lines were determined with the SFP markers and the resulting data were integrated with information, which had been established previously with single nucleotide polymorphism and insertion/deletion markers, to enrich the linkage map of the Col-0/C24 and C24/Col-0 recombinant inbred populations. Congruence between the molecular marker map and the sequence maps of the A. thaliana Col-0 chromosomes proved the reliability of the genotype information which was deduced from the transcript profiles of the Col-0/C24 and C24/Col-0 recombinant inbred lines. PMID- 28856446 TI - Ensuring successful introduction of Wolbachia in natural populations of Aedes aegypti by means of feedback control. AB - The control of the spread of dengue fever by introduction of the intracellular parasitic bacterium Wolbachia in populations of the vector Aedes aegypti, is presently one of the most promising tools for eliminating dengue, in the absence of an efficient vaccine. The success of this operation requires locally careful planning to determine the adequate number of individuals carrying the Wolbachia parasite that need to be introduced into the natural population. The introduced mosquitoes are expected to eventually replace the Wolbachia-free population and guarantee permanent protection against the transmission of dengue to human. In this study, we propose and analyze a model describing the fundamental aspects of the competition between mosquitoes carrying Wolbachia and mosquitoes free of the parasite. We then use feedback control techniques to devise an introduction protocol that is proved to guarantee that the population converges to a stable equilibrium where the totality of mosquitoes carry Wolbachia. PMID- 28856447 TI - Dural sac cross-sectional area and morphological grade show significant associations with patient-rated outcome of surgery for lumbar central spinal stenosis. AB - PURPOSE: Lumbar central spinal stenosis (LSS) is one of the most common reasons for spine surgery in the elderly patient. Magnetic resonance imaging (MRI) represents the gold standard for the assessment of LSS and can be used to obtain quantitative measures of the dural sac cross-sectional area (DCSA) or qualitative measures (morphological grades A-D) of the rootlet/cerebrospinal fluid ratio. This study investigated the intercorrelation between these two MRI evaluation methods and explored their respective relationships with the patient baseline clinical status and outcome 12 months after surgery. METHODS: This was a retrospective analysis of prospectively collected data from 157 patients (88 male, 69 female; age 72 +/- 7 years) who were undergoing first-time surgery for LSS. Patients with foraminal or isolated lateral stenosis were excluded. The Core Outcome Measures Index (COMI) was completed before and 12 months after surgery. Preoperative T2 axial MRIs were blinded and independently evaluated for DCSA and morphological grade. Spearman rank correlation coefficients described the relationship between the two MRI measures of stenosis severity and between each of these and the COMI baseline and change-scores (pre to 12 months' postop). Multiple logistic regression analysis (controlling for baseline COMI, age, gender, number of operated levels, health insurance status) was used to analyse the influence of stenosis severity on the achievement of the minimum clinically important change (MCIC) score for COMI and on global treatment outcome (GTO). RESULTS: There was a correlation of rho = -0.69 (p < 0.001) between DCSA and morphological grade. There was no significant correlation between COMI baseline scores and either DCSA or morphological grades (p > 0.85). However, logistic regression revealed significant (p < 0.05) associations between stenosis ratings and 12-month outcome, whereby patients with more severe stenosis (as measured using either of the methods) benefited more from the surgery. Patients with a DCSA <75 mm2 or morphological grade D had a 4-13-fold greater odds of achieving the MCIC for COMI or a "good" GTO, compared with patients in the least severe categories of stenosis. CONCLUSIONS: Postoperative outcome was clearly related to the degree of preoperative radiological LSS. The two MRI methods appeared to deliver similar information, as given by the relatively strong correlation between them and their comparable performance in relation to baseline and 12 month outcomes. However, the qualitative morphological grading can be performed in an instant, without measurement tools, and does not deliver less clinically useful information than the more complex and time-consuming measures; as such, it may represent the preferred method in the clinical routine for assessing the extent of radiological stenosis and the likelihood of a positive outcome after decompression. PMID- 28856448 TI - Olanzapine for prevention of chemotherapy-induced nausea and vomiting in children and adolescents: a multi-center, feasibility study. AB - CONTEXT: There are no prospective pediatric trials evaluating olanzapine for chemotherapy-induced nausea and vomiting (CINV) prevention. OBJECTIVE: This study evaluated the feasibility of a trial of olanzapine to evaluate the contribution of olanzapine to CINV control in pediatric oncology patients. METHODS: Patients < 18 years receiving CINV prophylaxis with ondansetron/granisetron/palonosetron +/- dexamethasone +/- aprepitant were eligible to participate in this prospective, single-arm, open-label study. All patients received olanzapine (0.14 mg/kg/dose; max 10 mg/dose) once daily orally starting before the first chemotherapy dose and continuing for up to four doses after the last chemotherapy administration. A future trial was considered feasible if mean time to enroll 15 patients was <= 12 months/site, >= 12/15 took at least half of the planned olanzapine doses, and <= 3/15 experienced significant sedation or dizziness despite dose reduction. The proportion of children who experienced complete CINV control (no nausea, vomiting, or retching) was described. RESULTS: Fifteen patients (range 4.1-17.4 years) participated; mean recruitment period was 9.3 months/site. All patients took at least half of the planned olanzapine doses. Six patients experienced sedation which resolved with olanzapine dose reduction (N = 5) or bedtime administration (N = 1). Olanzapine was stopped in one patient with blurry vision and in another with increased plasma GGT values. In both the acute and delayed phases, eight patients experienced complete control of vomiting but almost all (14/15) had nausea. CONCLUSION: A pediatric trial of olanzapine for CINV control is feasible. Our findings will inform the design of a future study. PMID- 28856449 TI - Glycoprotein-G-gene-based molecular and phylogenetic analysis of rabies viruses associated with a large outbreak of bovine rabies in southern Brazil. AB - A large outbreak of hematophagous-bat-associated bovine rabies has been occurring in Rio Grande do Sul (RS), the southernmost Brazilian state, since 2011, with official estimates exceeding 50,000 cattle deaths. The present article describes a genetic characterization of rabies virus (RABV) recovered from 59 affected cattle and two sheep, from 56 herds in 16 municipalities (2012-2016). Molecular analysis was performed using the nucleotide (nt) and predicted amino acid (aa) sequences of RABV glycoprotein G (G). A high level of nt and aa sequence identity was observed among the examined G sequences, ranging from 98.4 to 100%, and from 97.3 to 100%, respectively. Likewise, high levels of nt and aa sequence identity were observed with bovine (nt, 99.8%; aa, 99.8%) and hematophagous bat (nt, 99.5%; aa, 99.4%) RABV sequences from GenBank, and lower levels were observed with carnivore RABV sequences (nt, 92.8%; aa, 88.1%). Some random mutations were observed in the analyzed sequences, and a few consistent mutations were observed in some sequences belonging to cluster 2, subcluster 2b. The clustering of the sequences was observed in a phylogenetic tree, where two distinct clusters were evident. Cluster 1 comprised RABV sequences covering the entire study period (2012 to 2016), but subclusters corresponding to different years could be identified, indicating virus evolution and/or introduction of new viruses into the population. In some cases, viruses from the same location obtained within a short period grouped into different subclusters, suggesting co-circulation of viruses of different origins. Subcluster segregation was also observed in sequences obtained in the same region during different periods, indicating the involvement of different viruses in the cases at different times. In summary, our results indicate that the outbreaks occurring in RS (2012 to 2016) probably involved RABV of different origins, in addition to a possible evolution of RABV isolates within this period. PMID- 28856450 TI - The incrimination of three trypanosome species in clinically affected German shepherd dogs in Sudan. AB - Canine trypanosomosisis (CT) is a common disease caused by tsetse- and non-tsetse transmitted trypanosomes worldwide. The severity of the disease varies from acute, sub-acute to chronic with non-specific clinical signs. Here, we attempt in a cross-sectional study to assess the current situation of CT and the role of dogs in transmitting trypanosomes to other domesticated animals. The study was carried out during July 2016 on 50 caged German shepherd dogs in Khartoum State to investigate the prevalence of dog trypanosomosis using both serological (CATT/Trypanosoma evansi) and molecular (KIN-PCR, RoTat1.2 VSG-PCR and TviCatL PCR) tests to detect possible trypanosome infections. CATT/T. evansi detected antibodies against T. evansi in 15 (30%) dogs, while parasite DNA was detected in 17 (34%) dogs by RoTat1.2 PCR. In contrast, a KIN-PCR detected the subgenus Trypanozoon, Trypanosoma congolense savannah, T. congolense Kenya and T. vivax in 36 (72%), 3 (6%), 1 (2%), and 2 (4%) dogs, respectively. However, a species specific PCR for Trypanosoma vivax was detected 7 (14%) positive cases. We concluded that CT was caused by at least three species of trypanosomes, namely T. evansi, T. vivax and T. congolense. Trypanozoon other than T. evansi could not be ruled out since other tsetse-transmitted trypanosomes have also been detected and species-specific PCRs were not used. This study illustrates that dogs play an important role in the transmission dynamic and the epidemiology of the abovementioned trypanosome species. PMID- 28856451 TI - Recurrent and metastatic congenital mesoblastic nephroma: where does the evidence stand? AB - PURPOSE: Fifty years ago, Bolande described Congenital Mesoblastic Nephroma (CMN) as a benign lesion. Unexpected aggressive clinical behaviors prompted a sub classification based on histology. Recent molecular genetic evidence has identified the aggressive cellular variant to be the renal manifestation of congenital infantile fibrosarcoma. We submit a reappraisal and analysis of the available literature on recurrent and metastatic CMN. METHODS: An electronic search of PubMed, MEDLINE, EMBASE, and Scopus yielded 38 children with local recurrence and/or metastases. RESULTS: Of the 38 children with local recurrence and/or metastasis, 59% were girls. Median time to recurrence was 6 months (range 1-12 months). The commonest sites of metastases were the lung (39%) and liver (29%). Fifty percent of these children died of disease. The outcome of additional chemotherapy (p = 0.5) did not differ from that of surgery alone. The choice of chemotherapy did not influence the outcome (p = 0.6). CONCLUSIONS: Recurrence and metastasis in cellular CMN are much more common than described earlier and carry a high mortality. Children with cellular and mixed CMN require close clinical and radiological follow-up for a minimum of 12 months after primary surgery. Surgery is the mainstay of the treatment of recurrent and metastatic lesions. Neoadjuvant chemotherapy is recommended only if the lesion is inoperable. Targeted therapy may be an option in treatment of refractory cases. PMID- 28856452 TI - Prevalence of low back pain among health sciences students. AB - AIM: To determine the prevalence of low back pain (LBP) among health sciences students and to identify the associated factors. METHODS: Cross-sectional study was conducted among 1163 students from five health sciences colleges during the academic year 2016-2017. Self-administered questionnaire was conducted and included 4 sections: demographic characteristics, risk factors, Nordic musculoskeletal questionnaire and Oswestry disability questionnaire. Data were analyzed using SPSS. RESULTS: Mean age was 20.74 +/- (1.59 years). 70.9% of students were female. Lifetime prevalence of LBP was 56.6%, 12-month prevalence 48.8%, and point prevalence 21.2%. Dentistry students had highest lifetime prevalence of LBP (67.6%) with significant p value (<0.001). Male were found to have higher lifetime prevalence compared to female (p <= 0.001). Spending more than 10 h on computer or tablet was significantly associated with LBP (OR 2.19; 95% CI 1.30-3.70; p = 0.003). Feeling discomfort on bed was associated with LBP (OR 1.81; 95% CI 1.38-2.38; p <= 0.001). Uncomfortable college furniture was associated with LBP (OR 1.40; 95% CI 1.09-1.79; p = 0.008). Using heavy backpack was found to be associated with LBP (OR 1.49; 95% CI 1.01-2.03; p = 0.011). Most of students LBP (90.3%) found to cause minimal disability on Oswestry scale. CONCLUSION: This study has shown high prevalence of LBP among future healthcare provider. These risk factors should be well established to minimize the prevalence of LBP among future health sciences students. Dentistry students at higher risk of developing LBP compared to other students. PMID- 28856453 TI - Long-term results of Birmingham hip resurfacing arthroplasty in Asian patients. AB - Several reports have shown good long-term results with the Birmingham hip resurfacing (BHR) arthroplasty, but little is known about the results in Asian countries where there is a high prevalence of osteonecrosis and developmental dysplasia of the hip, and many females with small femoral head sizes. Therefore, we retrospectively evaluated the long-term clinical results of the BHR in 112 Japanese patients (53 males and 59 females-130 hips) with an average age of 52 years. Implant survivorship was analyzed using the Kaplan-Meier method with the endpoint being revision for any reason. Factors such as sex, femoral component size, and type of hip disease were analyzed as predictors of implant survivorship. With a median follow-up of 12 years, six cases were revised (two for femoral component aseptic loosening, two for infection, one for cup aseptic loosening, and one for femoral neck fracture), and the overall survival rate was 96.5% (95% CI 90.9-98.7) at 10 years and 93.6% (95% CI 83.4-97.7) at 15 years. When septic revisions were excluded, the implant survival rate was 98.2% (95% CI 92.9-99.6) at 10 years and 95.3% (95% CI 83.9-98.7) at 15 years. Sex, femoral component size, and type of hip disease were not predictors of implant survivorship. In conclusion, good clinical results were obtained with the BHR at 10- and 15-year follow-up in Japanese patients who have different stature and types of hip diseases as compared with patients in Western countries. PMID- 28856454 TI - Editorial focused issue 'The role of nutrition in child and adolescent onset mental disorders'. PMID- 28856456 TI - The Associations of Resilience and HIV Risk Behaviors Among Black Gay, Bisexual, Other Men Who Have Sex with Men (MSM) in the Deep South: The MARI Study. AB - Resilience is an understudied intrapersonal factor that may reduce HIV risk among men who have sex with men (MSM). Multivariable Poisson regression models were used to estimate the prevalence ratio (PR) of sexual risk behaviors, HIV prevalence, and history of sexually transmitted infections (STIs) with resilience scores in a population-based study among 364 black MSM in the Deep South. Participants with higher resilience scores had a lower prevalence of condomless anal sex with casual sexual partners in past 12 months (PR = 0.80, p value = 0.001) and during their last sexual encounter (PR = 0.81; p value = 0.009). Resilience was inversely associated with a lower prevalence of condomless anal sex with main sexual partners, participating in a sex party/orgy and having a STI in the past 12 months. Resilience may have a protective effect on HIV among black MSM, especially in the Deep South, and should be further explored in studies with prospective designs. PMID- 28856455 TI - Revisiting the taxonomy of the genus Elizabethkingia using whole-genome sequencing, optical mapping, and MALDI-TOF, along with proposal of three novel Elizabethkingia species: Elizabethkingia bruuniana sp. nov., Elizabethkingia ursingii sp. nov., and Elizabethkingia occulta sp. nov. AB - The genus Elizabethkingia is genetically heterogeneous, and the phenotypic similarities between recognized species pose challenges in correct identification of clinically derived isolates. In addition to the type species Elizabethkingia meningoseptica, and more recently proposed Elizabethkingia miricola, Elizabethkingia anophelis and Elizabethkingia endophytica, four genomospecies have long been recognized. By comparing historic DNA-DNA hybridization results with whole genome sequences, optical maps, and MALDI-TOF mass spectra on a large and diverse set of strains, we propose a comprehensive taxonomic revision of this genus. Genomospecies 1 and 2 contain the type strains E. anophelis and E. miricola, respectively. Genomospecies 3 and 4 are herein proposed as novel species named as Elizabethkingia bruuniana sp. nov. (type strain, G0146T = DSM 2975T = CCUG 69503T = CIP 111191T) and Elizabethkingia ursingii sp. nov. (type strain, G4122T = DSM 2974T = CCUG 69496T = CIP 111192T), respectively. Finally, the new species Elizabethkingia occulta sp. nov. (type strain G4070T = DSM 2976T = CCUG 69505T = CIP 111193T), is proposed. PMID- 28856458 TI - Floral guidance of learning a preference for symmetry by bumblebees. AB - This study examines the mechanism underlying one way in which bumblebees are known to develop a preference for symmetric patterns: through prior non differential reinforcement on simple patterns (black discs and white discs). In three experiments, bees were given a choice among symmetric and asymmetric black and-white non-rewarding patterns presented at the ends of corridors in a radial maze. Experimental groups had prior rewarded non-discrimination training on white patterns and black patterns, while control groups had no pre-test experience outside the colony. No preference for symmetry was obtained for any of the control groups. Prior training with circular patterns highlighting a horizontal axis of symmetry led to a specific subsequent preference for horizontal over vertical symmetry, while training with a vertical axis abolished this effect. Circles highlighting both axes created a general avoidance of asymmetry in favour of symmetric patterns with vertical, horizontal or both axes of symmetry. Training with plain circles, but not with deformed circles, led to a preference for symmetry: there was no evidence that the preference emerged just by virtue of having attention drawn away from irrelevant pattern differences. Our results point to a preference for symmetry developing gradually through first learning to extract an axis of symmetry from simple patterns and subsequently recognizing that axis in new patterns. They highlight the importance of continued learning through non-differential reinforcement by skilled foragers. Floral guides can function not only to guide pollinators to the source of reward but also to highlight an axis of symmetry for use in subsequent floral encounters. PMID- 28856457 TI - Mitogen-activated protein kinases (MAPKs) are modulated during in vitro and in vivo infection with the intracellular bacterium Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a Gram-negative intracellular bacterium that causes the disease melioidosis. The disease can be fatal if left untreated or when antibiotic therapy is delayed and total clearance of the pathogen from the host is often not accomplished with current therapies. Thus, new therapeutic approaches for the treatment of infections caused by B. pseudomallei are required. To better understand host responses to B. pseudomallei infection, the activation of key proteins involved in the TLR inflammatory cascade was measured by western blotting. Activation of the mitogen-activated protein kinases (MAPKs) p38 and ERK were both significantly altered during both in vitro and in vivo infection. In considering an approach for therapy of B. pseudomallei infection the inhibition of ERK was achieved in vitro using the inhibitor PD0325901, along with decreased TNF-alpha production. However, the reduction in phosphorylated ERK and TNF-alpha release did not correspond with decreased bacterial replication or enhance clearance from infected macrophages. Despite this apparent lack of effect on the intracellular growth of B. pseudomallei in vitro, it is not clear what effect inhibition of ERK activation might have on outcome of disease in vivo. It may be that decreasing the levels of TNF-alpha in vivo could aid in reducing the overactive immune response that is known to ensue following B. pseudomallei infection, thereby increasing host survival. PMID- 28856459 TI - The Criteria of Thickened Liquid for Dysphagia Management in Japan. AB - In Japan, the viscosity of thickened liquids is different among hospitals and nursing homes. In order to standardize viscosity of thickened liquids, the dysphagia diet committee of the Japanese Society of Dysphagia Rehabilitation developed the Japanese Dysphagia Diet 2013 (JDD2013). To decide on a definition of thickened liquids, the committee reviewed categories from other countries. Especially, the criteria of the USA and Australia were used as references. The definition had three levels: mildly thick, moderately thick, and extremely thick. Then a sensory evaluation by health care workers was carried out to decide the viscosity range of each level, and a draft document was made. After collecting public comments, follow-up experiments using thickened water with thickeners using xanthan gum were performed, and the JDD2013 (Thickened Liquid) was determined. The JDD2013 (Thickened Liquid) evaluated the drinking properties, visual properties, and viscosity values of each level. The shear rate of 50 s-1 was adopted to measure the viscosity with a cone and plate type viscometer to duplicate the measurement criteria used by the USA. We also set the values of the JDD2013 with the Line Spread Test to promote the use of guidelines in clinical practice. We believe the JDD2013 standards help hospitals and other settings that care for people with dysphagia to use the same thickness level and the same labels. In the future, the JDD2013 levels will be compared with new international guidelines to help with international understanding of the JDD2013 levels. PMID- 28856460 TI - Late-onset Pompe disease: a genetic-radiological correlation on cerebral vascular anomalies. AB - Pompe disease is an autosomal recessive disorder in which deficiency of the lysosomal enzyme acid alpha-glucosidase results in the accumulation of glycogen mostly in muscle tissues. Several reports suggest a higher incidence of intracranial vascular abnormalities (IVAs) in this condition, as well as brain microbleeds and cerebral vasculopathy. The aim of our study was to evaluate through neuroimaging studies the incidence of these anomalies in our cohort of late-onset Pompe disease (LOPD) patients asymptomatic for cerebrovascular disease, looking for correlations with clinical and genetic data. We studied 18 LOPD patients with brain magnetic resonance angiography (MRA), or contrast enhanced computed tomography (CECT). Diameters of individual arteries were measured and compared with average values as proposed in the literature. We found IVAs in 13 of the 18 patients, mostly dilatative arteriopathy affecting the vertebrobasilar system. The anterior circle was involved in seven of the 18 patients. The diameter of the basilar artery at 1 cm was found to correlate both with age (spearman rho, p = 0.037) and disease duration (p = 0.004), but no other statistically significant correlation was documented. The incidence of intracranial dilatative arteriopathy in LOPD was higher than in the general population, confirming the literature data. However, we did not find intracranial aneurysms microbleeds or significant cerebrovascular disease. Abnormalities in the anterior and the posterior circle of Willis correlated with age and disease duration, but not with the severity of muscle/respiratory involvement or with genetic data. Further studies in larger cohorts of patients are needed to confirm these findings. PMID- 28856461 TI - Reducing diacetyl production of wine by overexpressing BDH1 and BDH2 in Saccharomyces uvarum. AB - As a byproduct of yeast valine metabolism during fermentation, diacetyl can produce a buttery aroma in wine. However, high diacetyl concentrations generate an aromatic off-flavor and poor quality in wine. 2,3-Butanediol dehydrogenase encoded by BDH1 can catalyze the two reactions of acetoin from diacetyl and 2,3 butanediol from acetoin. BDH2 is a gene adjacent to BDH1, and these genes are regulated reciprocally. In this study, BDH1 and BDH2 were overexpressed in Saccharomyces uvarum to reduce the diacetyl production of wine either individually or in combination. Compared with those in the host strain WY1, the diacetyl concentrations in the recombinant strains WY1-1 with overexpressed BDH1, WY1-2 with overexpressed BDH2 alone, and WY1-12 with co-overexpressed BDH1 and BDH2 were decreased by 39.87, 33.42, and 46.71%, respectively. BDH2 was only responsible for converting diacetyl into acetoin, but not for the metabolic pathway of acetoin to 2,3-butanediol in S. uvarum. This study provided valuable insights into diacetyl reduction in wine. PMID- 28856462 TI - Acute onset autonomic dysfunction and orthostatic syncope as an early manifestation of HIV infection. PMID- 28856463 TI - The variety of clinical presentations in IgG4-related disease in Rheumatology. AB - IgG4-related disease (IgG4-RD) belongs to the group of rare diseases in which the identification of the characteristic histology and immunohistochemistry provides with the gold standard in the diagnosis. The variable organ dysfunction reflects the clinical presentation. The examples of different IgG4-RD presentations in the Rheumatology Unit were discussed in this article. The spectrum of IgG4-RD is wide ranging and manifested in one or more organs synchronously or metachronously. In the presented article, we described five different cases of IgG4-RD. Four cases were reaffirmed in the histopathological assessment. The clinical and laboratory findings were analyzed and the assigned therapy was discussed. According to our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and variety of clinical forms of IgG4-RD shows that there is need of the cooperation among many specialists for the better and earlier recognition of the disease. PMID- 28856464 TI - Dosage of methylphenidate and traumatic brain injury in ADHD: a population-based study in Taiwan. AB - Preventive effect of stimulants on the risk of brain injuries had been reported. The aim of this study is to determine the extent to which methylphenidate (MPH) prescription moderates the risk of traumatic brain injuries (TBI) in individuals with attention-deficit/hyperactivity disorder (ADHD). Individuals with a recent diagnosis of ADHD between January 1997 and December 2013 (n = 163,618) were identified from Taiwan's National Health Insurance Research Database. A total of 124,438 adolescents and children with ADHD and without prior TBI diagnoses were included and evaluated for subsequent TBI. Methylphenidate prescription duration was subgrouped by the annual average cumulative defined daily dose (DDD): 0, >0 to <=28, > 28 to <=84, and >84. We identified 11,463 diagnoses of TBI among 124,438 adolescents and children with ADHD. A Cox regression model was used to investigate whether MPH prescription influenced the risk for TBI after adjusting for sex, age, level of urbanization, seizure, autism and sedative-anxiolytics use. A reduced TBI incidence was observed with MPH prescription DDDs > 84. The protective effect of MPH against TBI persisted after adjusting for confounding factors [hazard ratio (HR) = 0.49; 95% confidence interval (CI): 0.47-0.51]. There was also statistically significant difference in risk for TBI in subjects receiving > 0 to <=28 or >28 to <=84 DDDs of MPH treatment (HR = 0.88, 95% CI = 0.83-0.92; HR = 0.76, 95% CI = 0.72-0.80, respectively) when compared with subjects not receiving treatment with MPH. Treatment with MPH for greater than 84 DDDs reduced the risk for TBI among children with ADHD. PMID- 28856467 TI - Author's response. PMID- 28856466 TI - TMA secondary to SLE: rituximab improves overall but not renal survival. AB - Thrombotic microangiopathy (TMA) includes a series of life-threatening disorders. Systemic lupus erythematosus (SLE) is one of the most common acquired causes. To identify predictors of prognosis in patients with TMA secondary to SLE, we conducted a single-center historical study. From January 2013 to June 2016, of 2182 SLE hospitalized patients in the Ren Ji Hospital, a total of 21 consecutive patients with TMA secondary to SLE were identified. The 90-day short-term mortality was 33.3%. The kidney involvement (66.7%) was associated with poor prognosis, while the administration of rituximab (n = 13) was an independent protective factor according to logistic regression analysis. Compared to conventional treatment, i.e., plasma exchange, high-dose glucocorticoids, and intravenous immunoglobulin, the overall survival is significantly higher among patients receiving rituximab add-on (92.2 vs 33.3%, p = 0.0173); however, five out of seven patients with renal involvement in the rituximab group were eventually hemodialysis dependent. Our data indicated that add-on rituximab in the background of conventional therapy may improve the overall but not the renal survival in SLE-TMA patients. PMID- 28856465 TI - Guidelines for treatment of renal injury during cancer chemotherapy 2016. PMID- 28856468 TI - Gaskell revisited: new insights into spinal autonomics necessitate a revised motor neuron nomenclature. AB - Several concepts developed in the nineteenth century have formed the basis of much of our neuroanatomical teaching today. Not all of these were based on solid evidence nor have withstood the test of time. Recent evidence on the evolution and development of the autonomic nervous system, combined with molecular insights into the development and diversification of motor neurons, challenges some of the ideas held for over 100 years about the organization of autonomic motor outflow. This review provides an overview of the original ideas and quality of supporting data and contrasts this with a more accurate and in depth insight provided by studies using modern techniques. Several lines of data demonstrate that branchial motor neurons are a distinct motor neuron population within the vertebrate brainstem, from which parasympathetic visceral motor neurons of the brainstem evolved. The lack of an autonomic nervous system in jawless vertebrates implies that spinal visceral motor neurons evolved out of spinal somatic motor neurons. Consistent with the evolutionary origin of brainstem parasympathetic motor neurons out of branchial motor neurons and spinal sympathetic motor neurons out of spinal motor neurons is the recent revision of the organization of the autonomic nervous system into a cranial parasympathetic and a spinal sympathetic division (e.g., there is no sacral parasympathetic division). We propose a new nomenclature that takes all of these new insights into account and avoids the conceptual misunderstandings and incorrect interpretation of limited and technically inferior data inherent in the old nomenclature. PMID- 28856469 TI - Evaluation of clinical value of videokymography for diagnosis and treatment of voice disorders. AB - This study aimed at determining the clinical value of videokymography (VKG) as an additional tool for the assessment of voice disorders. 105 subjects with voice disorders were examined by an experienced laryngologist. A questionnaire was used to specify diagnosis, diagnostic confidence, and treatment recommendations before and after VKG. The first part of questionnaire was filled by the laryngologist for each patient after routine ear-nose-throat evaluation, including stroboscopy, the second part after the subsequent VKG examination. In 31% of subjects VKG confirmed the stroboscopic diagnosis, in 44% it made the diagnosis more accurate, in 20% there was adjustment of the treatment, and in 5% it was not found diagnostically useful. After VKG the diagnostic confidence increased in 68% of the subjects. VKG may help clinicians to take some important treatment decisions and may be recommended to be performed in patients, where clinicians are uncertain about diagnosis and treatment. PMID- 28856470 TI - Obesity, physical activity, and breast cancer survival among older breast cancer survivors in the Cancer Prevention Study-II Nutrition Cohort. AB - PURPOSE: Nearly half of the 3.5 million female breast cancer survivors in the US are aged 65 years or older at diagnosis, yet little is known about associations of obesity and physical activity with breast cancer-specific mortality (BCSM) among older survivors. METHODS: Between 1992 and 2013, 5254 women in the Cancer Prevention Study-II Nutrition Cohort were diagnosed with local or regional breast cancer among whom 1771 deaths (505 breast cancer deaths) occurred. Multivariable Cox proportional hazards regression models were used to examine associations of pre- and post-diagnosis body mass index (BMI) and moderate-vigorous physical activity (MET-hours/week) with mortality outcomes stratified by age at diagnosis (<65, >=65 years). RESULTS: Among women >=65 years of age at diagnosis (n = 4226), pre- and post-diagnosis BMI (per 5 kg/m2) were associated with a higher risk of BCSM (pre-diagnosis, HR 1.27, 95% CI 1.14-1.41; post-diagnosis, HR 1.19, 95% CI 1.04, 1.36); neither pre- nor post-diagnosis physical activity was associated with BCSM. Among women <65 years of age at diagnosis (n = 1028), BMI at both time points were not significantly associated with BCSM; however, there was a significant inverse trend of post-diagnosis physical activity with BCSM (P trend = 0.01). Among both age groups, BMI and physical activity, regardless of when assessed, were significantly associated with all-cause mortality. CONCLUSIONS: Higher BMI, pre- or post-diagnosis, was associated with a higher risk of BCSM in older patients, independent of comorbidities and stage at diagnosis. Weight management should be discussed even with women aged 65 years or older to lower rates of BCSM. PMID- 28856471 TI - Au Naturel: Transpapillary Endoscopic Drainage of an Infected Biloma. PMID- 28856472 TI - Reliability of the Participation and Sensory Environment Questionnaire: Teacher Version. AB - The Participation and Sensory Environment Questionnaire-Teacher Version (PSEQ-TV) is a teacher-report questionnaire to assess the impact of the sensory environment on participation of preschool children with autism spectrum disorder (ASD). Many children with ASD have sensory processing differences, although these differences are frequently examined from the standpoint of the person. The PSEQ-TV provides a single assessment to examine both participation and the sensory environment for preschool aged children with ASD. This study established the reliability of the PSEQ-TV including internal consistency of 0.98 and test-rest reliability of 0.70. The results indicate initial reliability of PSEQ-TV as an instrument that can be used to identify sensory environmental barriers within the preschool setting to target during interventions to increase participation. PMID- 28856473 TI - The role of natural antimicrobial peptides during infection and chronic inflammation. AB - Natural antimicrobial peptides (AMPs), a family of small polypeptides that are produced by constitutive or inducible expression in organisms, are integral components of the host innate immune system. In addition to their broad-spectrum antibacterial activity, natural AMPs also have many biological activities against fungi, viruses and parasites. Natural AMPs exert multiple immunomodulatory roles that may predominate under physiological conditions where they lose their microbicidal properties in serum and tissue environments. Increased drug resistance among microorganisms is occurring far more quickly than the discovery of new antibiotics. Natural AMPs have shown promise as 'next generation antibiotics' due to their broad-spectrum curative effects, low toxicity, the fact that they are not residual in animals, and the low rates of resistance exhibited by many pathogens. Many types of synthetic AMPs are currently being tested in clinical trials for the prevention and treatment of various diseases such as chemotherapy-associated infections, diabetic foot ulcers, catheter-related infections, and other conditions. Here, we provide an overview of the types and functions of natural AMPs and their role in combating microorganisms and different infectious and inflammatory diseases. PMID- 28856474 TI - Mothers' Reactions to Their Child's ASD Diagnosis: Predictors That Discriminate Grief from Distress. AB - We examined whether grief and general distress reactions characterized mothers' reactions to their child's ASD diagnosis, and whether these two types of reactions had unique predictors. Hierarchical regression analyses were conducted on data collected from 362 mothers recruited from the Interactive Autism Network (IAN). The mothers were predominantly white, highly educated, and married. Grief reactions were positively associated with perceiving ASD as a loss and as unjust. Distress was positively associated with previous mental health issues, mothers' reports of their child's aggressive behavior, identity ambiguity, and less social support. Internal attributions were positively related to grief and distress. Discussion focuses on why the distinction between these two types of affective reactions may be useful for parents and professionals. PMID- 28856475 TI - Race/Ethnicity-Specific Disparities in the Severity of Disease at Presentation in Adults with Ulcerative Colitis: A Cross-Sectional Study. AB - BACKGROUND: While ulcerative colitis (UC) is well studied in Caucasian populations, less data are available on UC patients of racial/ethnic minorities, including variations in disease severity at presentation. AIM: To evaluate race/ethnicity-specific disparities in UC disease presentation among an ethnically diverse underserved population. METHODS: We performed a cross sectional study of all consecutive UC adults among a large ethnically diverse safety-net hospital from July 2014 to May 2016 to compare race/ethnicity-specific disparities in severity of disease at presentation. Severity was evaluated using the clinician-based simple clinical colitis activity index (SCCAI) and the Mayo score at time of presentation. Multivariate ordered logistic regression models were used to evaluate associations with SCCAI and Mayo scores. RESULTS: Among 98 UC patients (56.1% male, mean age 40.1 (SD 14.2), 32.0% were African-American, 26.7% Hispanic, 16.0% Asian, and 20.0% Caucasian. Mean Mayo score was 6.6 and mean SCCAI score was 6.5. When stratified by race/ethnicity, SCCAI scores were significantly higher in non-Caucasians compared to Caucasians (7.0 vs 4.6, p = 0.03) and in Asians compared to Caucasians (8.0 vs 4.6, p = 0.02). There was a trend toward higher mean SCCAI in Hispanics compared to Caucasians (6.9 vs 4.6, p = 0.07). Mayo scores at presentation demonstrated similar trends. On multivariate logistic regression, Asians (OR 5.26, 95% CI 1.24-22.42) and Hispanics (OR 3.74; 95% CI 1.02-13.66) had more severe disease at presentation than Caucasians based on SCCAI. CONCLUSIONS: Among a diverse underserved cohort of UC patients, racial/ethnic minority patients with UC, specifically Asians and Hispanics, had more severe disease at presentation compared to Caucasians. The differences may reflect disparities in timely access to specialty care and treatment and deserves greater attention and research. PMID- 28856476 TI - Impact of monocyte-macrophage inhibition by ibandronate on graft function and survival after kidney transplantation: a single-centre follow-up study over 15 years. AB - BACKGROUND: The aim of this study was to evaluate the effect of ibandronate administration on long-term graft function and graft survival after successful renal transplantation. METHODS: Seventy-two renal transplant recipients (36 patients each in the treatment and control group) were included and followed over a 15-year period. Data on graft function and death-censored transplant outcome were recorded at 1, 5, 10, and 15 years. RESULTS: Death-censored Kaplan-Meier analysis showed significantly improved graft survival of the treatment group (p = 0.026), whereas Cox regression analysis showed that ibandronate was positively associated with improved transplant survival (p = 0.028, hazard ratio 0.24, 95% confidence interval 0.07-0.86). Although general linear modelling did not indicate that ibandronate had a significant effect on transplant function (calculated using the estimated glomerular filtration rate according to Chronic Kidney Disease Epidemiology Collaboration equation) over the entire 15-year period (p = 0.650), there was a tendency towards improved graft function 1-year post-transplantion (p = 0.056). CONCLUSIONS: Ibandronate treatment within the first year of transplantation resulted in a trend towards better graft function within the first few year post-transplant, and was associated with increased transplant survival at long-term follow-up. PMID- 28856477 TI - Editorial 'Supplement DIZZYNET 2017'. PMID- 28856478 TI - Sleep duration, mortality and the influence of age. AB - Prior work has shown that both short and long sleep predict mortality. However, sleep duration decreases with age and this may affect the relationship of sleep duration with mortality. The purpose of the present study was to assess whether the association between sleep duration and mortality varies with age. Prospective cohort study. 43,863 individuals (64% women), recruited in September 1997 during the Swedish National March and followed through record-linkages for 13 years. Sleep duration was self-reported and measured using the Karolinska Sleep Questionnaire, and grouped into 4 categories: <=5, 6, 7 (reference) and >=8 h. Up to 2010 3548 deaths occurred. Multivariable Cox proportional hazards regression models with attained age as time scale were fitted to estimate mortality rate ratios. Among individuals <65 years, short (<=5 h) and long (>=8 h) sleep duration showed a significant relationship with mortality (HR 1.37, 95% CI 1.09 1.71, and HR 1.27, 95% CI 1.08-1.48). Among individuals 65 years or older, no relationships between sleep duration and mortality were observed. The effect of short and long sleep duration on mortality was highest among young individuals and decreased with increasing age. The results suggest that age plays an important role in the relationship between sleep duration and mortality. PMID- 28856479 TI - Calcitonin gene-related peptide antagonism and cluster headache: an emerging new treatment. AB - Calcitonin gene-related peptide (CGRP) is a key signaling molecule involved in migraine pathophysiology. Efficacy of CGRP monoclonal antibodies and antagonists in migraine treatment has fueled an increasing interest in the prospect of treating cluster headache (CH) with CGRP antagonism. The exact role of CGRP and its mechanism of action in CH have not been fully clarified. A search for original studies and randomized controlled trials (RCTs) published in English was performed in PubMed and in ClinicalTrials.gov . The search term used was "cluster headache and calcitonin gene related peptide" and "primary headaches and calcitonin gene related peptide." Reference lists of identified articles were also searched for additional relevant papers. Human experimental studies have reported elevated plasma CGRP levels during both spontaneous and glyceryl trinitrate-induced cluster attacks. CGRP may play an important role in cluster headache pathophysiology. More refined human studies are warranted with regard to assay validation and using larger sample sizes. The results from RCTs may reveal the therapeutic potential of CGRP monoclonal antibodies and antagonists for cluster headache treatment. PMID- 28856480 TI - Screening for Autism with the SRS and SCQ: Variations across Demographic, Developmental and Behavioral Factors in Preschool Children. AB - The Social Communication Questionnaire (SCQ) and the Social Responsiveness Scales (SRS) are commonly used screeners for autism spectrum disorder (ASD). Data from the Study to Explore Early Development were used to examine variations in the performance of these instruments by child characteristics and family demographics. For both instruments, specificity decreased as maternal education and family income decreased. Specificity was decreased with lower developmental functioning and higher behavior problems. This suggests that the false positive rates of the SRS and the SCQ are associated with child characteristics and family demographic factors. There is a need for ASD screeners that perform well across socioeconomic and child characteristics. Clinicians should be mindful of differential performance of these instruments in various groups of children. PMID- 28856481 TI - African American patients with breast cancer have worse prognosis than white patients in certain subtypes and stages. AB - PURPOSE: Racial disparity of breast cancer in each subtype and substage is not clear. METHODS: We reviewed 156,938 patients with breast cancer from 2010 to 2012 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Breast cancer was subtyped by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status as HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2-. RESULTS: African American (AA) patients had worse overall survival (OS) and breast cancer cause-specific survival (BCSS) in HR+/HER2- stages III and IV breast cancer and HR-/HER2+ stage IV cancer; they had worse OS but not BCSS in HR+ /HER2- stage II cancer and HR-/HER2- stage II cancer. CONCLUSION: AA patients with breast cancer had worse survival in certain subtype and stage, especially in ER+ breast cancer. PMID- 28856482 TI - Hyperextension injuries of the knee: do patterns of bone bruising predict soft tissue injury? AB - OBJECTIVE: To establish whether patterns of soft tissue injury following knee hyperextension are associated with post-traumatic 'bone bruise' distribution. MATERIALS AND METHODS: Patients with a knee MRI within one year of hyperextension injury were identified at our institution over a 7 year period. MRIs, plain radiographs and clinical details of these patients were reviewed. RESULTS: Twenty five patients were identified (median time from injury to MRI = 24 days). The most common sites of bone bruising were the anteromedial tibial plateau (48%) and anterolateral tibial plateau (44%). There were high rates of injury to the posterior capsule (52%), ACL (40%) and PCL (40%) but lower rates of injury to the menisci (20%), medial and lateral collateral ligaments (16%) and posterolateral corner (16%). Anterior tibial plateau oedema and rupture of the posterior capsule predicted cruciate ligament injury [OR = 10.5 (p = 0.02) and 24.0 (p = 0.001) respectively]. Whilst anterolateral tibial plateau oedema strongly predicted PCL injury [OR = 26.0, p = 0.003], ACL injury was associated with a variable pattern of bone bruising. Meniscal injury was unrelated to the extent or pattern of bone bruising. 5 out of 8 patients with a 'double sulcus' on the lateral radiograph had ACL injury. The presence of a double sulcus showed significant association with anteromedial kissing contusions (OR = 7.8, p = 0.03). CONCLUSIONS: Following knee hyperextension, bone bruising patterns may be associated with cruciate ligament injury. Other structures are injured less frequently and have weaker associations with bone bruise distribution. The double sulcus sign is a radiographic marker that confers a high probability of ACL injury. PMID- 28856483 TI - Novel Fluorometric Turn On Detection of Aluminum by Chalcone-Based Chemosensor in Aqueous Phase. AB - A novel, 100% water-soluble chalcone based chemosensing receptor {1-[3-(2-Hydroxy phenyl)-3-oxo-propenyl]-naphthalen-2-yloxy}-acetic acid, L was synthesized and characterized. The receptor L is designed based on the chelation enhanced fluorescence (CHEF) mechanism. The chemosensing properties of L were evaluated by UV-vis and fluorescence spectrometric methods. It exhibits highly selective recognition ability towards aluminum ions in water over other metal ions. The binding stoichiometry of L- Al3+ complex is 2:1 by means of Job's plot and the detection limit is 5.66 * 10- 8 M. PMID- 28856484 TI - Gene Disrupting Mutations Associated with Regression in Autism Spectrum Disorder. AB - Approximately one-third of children with autism spectrum disorder (ASD) reportedly lose skills within the first 3 years, yet a causal mechanism remains elusive. Considering evidence of strong genetic effects for ASD and findings that distinct phenotypes in ASD associate with specific genetic events, we examined rates of parent-reported regression in the Simons Simplex Collection with likely gene disrupting mutations from five distinct classes: FMRP target genes, genes encoding chromatin modifiers, genes expressed preferentially in embryos, genes encoding postsynaptic density proteins, and essential genes. Children with ASD and mutations in postsynaptic density genes were more likely to experience regression, while a trend suggested that children with ASD and mutations in embryonic genes were less likely to have skill losses. PMID- 28856485 TI - Propagation of errors from skull kinematic measurements to finite element tissue responses. AB - Real-time quantification of head impacts using wearable sensors is an appealing approach to assess concussion risk. Traditionally, sensors were evaluated for accurately measuring peak resultant skull accelerations and velocities. With growing interest in utilizing model-estimated tissue responses for injury prediction, it is important to evaluate sensor accuracy in estimating tissue response as well. Here, we quantify how sensor kinematic measurement errors can propagate into tissue response errors. Using previous instrumented mouthguard validation datasets, we found that skull kinematic measurement errors in both magnitude and direction lead to errors in tissue response magnitude and distribution. For molar design instrumented mouthguards susceptible to mandible disturbances, 150-400% error in skull kinematic measurements resulted in 100% error in regional peak tissue response. With an improved incisor design mitigating mandible disturbances, errors in skull kinematics were reduced to <50%, and several tissue response errors were reduced to <10%. Applying 30[Formula: see text] rotations to reference kinematic signals to emulate sensor transformation errors yielded below 10% error in regional peak tissue response; however, up to 20% error was observed in peak tissue response for individual finite elements. These findings demonstrate that kinematic resultant errors result in regional peak tissue response errors, while kinematic directionality errors result in tissue response distribution errors. This highlights the need to account for both kinematic magnitude and direction errors and accurately determine transformations between sensors and the skull. PMID- 28856486 TI - The Automated Assessment of Postural Stability: Balance Detection Algorithm. AB - Impaired balance is a common indicator of mild traumatic brain injury, concussion and musculoskeletal injury. Given the clinical relevance of such injuries, especially in military settings, it is paramount to develop more accurate and reliable on-field evaluation tools. This work presents the design and implementation of the automated assessment of postural stability (AAPS) system, for on-field evaluations following concussion. The AAPS is a computer system, based on inexpensive off-the-shelf components and custom software, that aims to automatically and reliably evaluate balance deficits, by replicating a known on field clinical test, namely, the Balance Error Scoring System (BESS). The AAPS main innovation is its balance error detection algorithm that has been designed to acquire data from a Microsoft Kinect(r) sensor and convert them into clinically-relevant BESS scores, using the same detection criteria defined by the original BESS test. In order to assess the AAPS balance evaluation capability, a total of 15 healthy subjects (7 male, 8 female) were required to perform the BESS test, while simultaneously being tracked by a Kinect 2.0 sensor and a professional-grade motion capture system (Qualisys AB, Gothenburg, Sweden). High definition videos with BESS trials were scored off-line by three experienced observers for reference scores. AAPS performance was assessed by comparing the AAPS automated scores to those derived by three experienced observers. Our results show that the AAPS error detection algorithm presented here can accurately and precisely detect balance deficits with performance levels that are comparable to those of experienced medical personnel. Specifically, agreement levels between the AAPS algorithm and the human average BESS scores ranging between 87.9% (single-leg on foam) and 99.8% (double-leg on firm ground) were detected. Moreover, statistically significant differences in balance scores were not detected by an ANOVA test with alpha equal to 0.05. Despite some level of disagreement between human and AAPS-generated scores, the use of an automated system yields important advantages over currently available human-based alternatives. These results underscore the value of using the AAPS, that can be quickly deployed in the field and/or in outdoor settings with minimal set-up time. Finally, the AAPS can record multiple error types and their time course with extremely high temporal resolution. These features are not achievable by humans, who cannot keep track of multiple balance errors with such a high resolution. Together, these results suggest that computerized BESS calculation may provide more accurate and consistent measures of balance than those derived from human experts. PMID- 28856487 TI - Determinants of health care costs in the senior elderly: age, comorbidity, impairment, or proximity to death? AB - Ageing is assumed to be accompanied by greater health care expenditures but the association is also viewed as a 'red herring'. This study aimed to evaluate whether age is associated with health care costs in the senior elderly, using electronic health records for 98,220 participants aged 80 years and over registered with the UK Clinical Practice Research Datalink and linked Hospital Episode Statistics (2010-2014). Annual costs of health care utilization were estimated from a two-part model; multiple fractional polynomial models were employed to evaluate the non-linear association of age with predicted health care costs while also controlling for comorbidities, impairments, and death proximity. Annual health care costs increased from 80 years (L2972 in men, L2603 in women) to 97 (men; L4721) or 98 years (women; L3963), before declining. Costs were significantly elevated in the last year of life but this effect declined with age, from L10,027 in younger octogenarians to L7021 in centenarians. This decline was steeper in participants with comorbidities or impairments; L14,500 for 80-84 year-olds and L6752 for centenarians with 7+ impairments. At other times, comorbidity and impairments, not age, were main drivers of costs. We conclude that comorbidities, impairments, and proximity to death are key mediators of age related increases in health care costs. While the costs of comorbidity among survivors are not generally associated with age, additional costs in the last year of life decline with age. PMID- 28856488 TI - Tubercular Intestinal Strictures Show a Poor Response to Anti-Tuberculous Therapy. AB - BACKGROUND: The literature on resolution of intestinal strictures in patients with intestinal tuberculosis (ITB) after anti-tuberculous therapy (ATT) is sparse and ambivalent. We aimed to assess the frequency of stricture resolution after ATT and its predictors. METHODS: This ambispective cohort study included consecutive ITB patients with strictures who received ATT for >=6 months and were on regular follow-up between January 2004 and December 2015. Resolution of stricture was assessed at the end of ATT by endoscopy/radiology. RESULTS: Of 286 patients, 128 had strictures, and 106 were finally included (63 males, median age 35 years). The stricture location was distal ileum/ileocecal in 52 (49.1%), colon in 37 (34.9%), ileocolonic in 4 (3.8%), proximal small bowel in 10 (9.4%), and gastroduodenal in 4 (3.8%) patients. Although all patients demonstrated mucosal healing (indicating resolution of active infection), stricture resolution occurred only in 25/106 (23.6%) patients. Symptoms pertaining to stricture (pain abdomen/recurrent SAIO) were present in 104/106 (98%) patients, and after a median of 6 (6-9) months of ATT, these symptoms resolved only in half, 88% (22/25) in patients with stricture resolution and 38% (30/79) in patients with persistent strictures. Colonic strictures had the least resolution (5.4%) followed by proximal small intestinal (20%) and distal ileal/ileocecal (36.5%). Although not statistically significant, stricture resolution was less frequent in patients with multiple strictures, longer strictures (>3 cm), and strictures in which scope was not negotiable prior to ATT. CONCLUSION: Only one-fourth of ITB patients with strictures show resolution of stricture following ATT. The resolution of strictures is dependent on disease location, and majority of them exhibit symptoms pertaining to stricture even after ATT. PMID- 28856489 TI - Organizational learning-by-doing in liver transplantation. AB - Organizational learning-by-doing implies that production outcomes improve with experience. Prior empirical research documents the existence of organizational learning-by-doing, but provides little insight into why some firms learn while others do not. Among the 124 U.S. liver transplant centers that opened between 1987 and 2009, this paper shows evidence of organizational learning-by-doing, but only shortly after entry. Significant heterogeneity exists with learning only evident among those firms entering early in the sample period when liver transplantation was an experimental medical procedure. Firms that learn begin with lower quality outcomes before improving to the level of firms that do not learn, suggesting that early patient outcomes depend on the ability of new entrants to import best practices from existing liver transplant programs. Knowledge of best practices became increasingly available over time through the dissemination of academic research and increasingly specialized training programs, so that between 1987 and 2009, 6 month post-transplant survival rates increased from 64 to 90% and evidence of organization-level learning-by-doing disappeared. The lack of any recent evidence of organizational learning-by-doing implies that common insurer experience requirements may be reducing access to health care in non-experimental complex medical procedures without an improvement in quality. PMID- 28856490 TI - Are Religious Coping and Pain Perception Related Together? Assessment in Iranian Cancer Patients. AB - Pain of cancer had various significant side effects that based on the literature it can reduced by religious coping methods. This study aimed to investigate the relationship between religious coping and pain perception in Iranian cancer patients. In this cross-sectional study (October-December, 2015), 380 hospitalized cancer patients were entered to the study using accessible sampling. Data were collected by socio-demographic, Religious Coping and McGill pain questionnaires. Males (48.39 +/- 13 +/- 39; CI95: 46.41-50.38) are older than females (45.33 +/- 18.44; CI95: 42.79-47.87). According to results, there was a significant relationship between pain perception and positive religious coping in cancer patients. Also there was a significant relationship between pain perception and family history of cancer (P < 0.05). It seems that improving the level and quality of positive religious affiliation can be effective on the amount of stimulation and pain of cancer patients. Of course, more comprehensive studies are needed to be achieved more reliable results about the effects of religious coping on pain perception in these patients. PMID- 28856491 TI - Profiles and risk assessment of phthalate acid esters (PAEs) in drinking water sources and treatment plants, East China. AB - This study is the first report describing the occurrence of 15 phthalate acid esters (PAEs) in the three typical water sources of YiXing City, Taihu Upper River Basin, East China. The fate of target PAEs in the Jiubin drinking water treatment plant (JTP) was also analyzed. The amounts of Sigma15PAE in the Hengshan (HS), Youche (YC), and Xijiu (XJ) water sources were relatively moderate, with mean values of 360, 357, and 697 ng L-1, respectively. Bis(2 ethylhexyl) phthalate (DEHP) dominated the PAE concentration, making up 80% of the 15 total PAEs. The highest levels of Sigma15PAE were found in HS, YC, and XJ in March 2015, January 2015, and July 2014, respectively. The occurrence and concentrations of these compounds were spatially dependent, and the mean concentrations of Sigma15PAE in HS, YC, and XJ samples increased from the surface layer to the bottom layer with varied percentage increases. The removal efficiency of the PAEs in the finished water varied markedly, and the removal of PAEs by the JTP ranged from 12.8 to 64.5%. The potential ecosystem risk assessment indicated that the risk of PAEs was relatively low in these three water sources. However, risks posed by PAEs due to drinking water still exist; therefore, special attention should be paid to source control in the JTP, and advanced treatment processes for drinking water supplies should be implemented. PMID- 28856492 TI - Tumor location and patient age predict biological signatures of high-grade gliomas. AB - Prognostic factors for high-grade gliomas include patient age, IDH1 mutation, MGMT methylation, and Ki67 value. We assessed the predictive role of topographic location of gliomas for their biological signatures. Collecting all neuroradiological and histological data of patients with histologically proven HGG, we performed a retrospective monocentric study. A predictive value of frontal location for a lower Ki67 value (especially in the left hemisphere) and mutation of IDH1 (especially in the right hemisphere) was found. Temporal location was predictive for IDH1 wild-type. Involvement of the parietal lobe was found to be predictive of methylated MGMT, while insular lobe involvement predicted an unmethylated MGMT. There was no statistically significant difference of IDH1 mutation and MGMT methylation between left and right sides. PMID- 28856493 TI - Joint modeling of survival time and longitudinal outcomes with flexible random effects. AB - Joint models with shared Gaussian random effects have been conventionally used in analysis of longitudinal outcome and survival endpoint in biomedical or public health research. However, misspecifying the normality assumption of random effects can lead to serious bias in parameter estimation and future prediction. In this paper, we study joint models of general longitudinal outcomes and survival endpoint but allow the underlying distribution of shared random effect to be completely unknown. For inference, we propose to use a mixture of Gaussian distributions as an approximation to this unknown distribution and adopt an Expectation-Maximization (EM) algorithm for computation. Either AIC and BIC criteria are adopted for selecting the number of mixtures. We demonstrate the proposed method via a number of simulation studies. We illustrate our approach with the data from the Carolina Head and Neck Cancer Study (CHANCE). PMID- 28856494 TI - Typical Pubertal Timing in an Australian Population of Girls and Boys with Autism Spectrum Disorder. AB - Secondary data analyses from the Longitudinal Study of Australian Children Kindergarten cohort were performed to understand any alterations in pubertal timing in Autism Spectrum Disorder (ASD) in a population sample. Timing of parent reported pubertal events (ages 8-9, 10-11, 12-13 years), and self-report (14-15 years; N = 3454 no ASD, N = 94 with ASD) included breast development, menses, skin changes, growth spurt, body hair, deepening voice and facial hair. Survival analyses and Cox regression controlling for covariates showed no evidence of altered pubertal onset amongst males with ASD. In contrast to some past studies, there was also no difference in pubertal timing in females with ASD. These exploratory findings suggest typical puberty timing in a population representative group of young people with ASD. PMID- 28856495 TI - Significance of multiple preoperative laboratory abnormalities as prognostic indicators in patients with urothelial carcinoma of the upper urinary tract following radical nephroureterectomy. AB - BACKGROUND: The aim of this study was to investigate the prognostic significance of multiple preoperative laboratory abnormalities in upper urinary tract urothelial carcinoma (UUTUC) patients. METHODS: This study included a total of 135 consecutive patients with clinically localized UUTUC who underwent radical nephroureterectomy (RNU). The impact of several preoperative blood-based markers in addition to conventional clinical factors on extravesical recurrence-free survival (eRFS) in these patients was retrospectively evaluated. RESULTS: Despite the lack of a significant correlation between conventional clinical factors and any of the postoperative pathologic parameters, preoperative laboratory abnormalities were shown to have a significant impact on some pathological factors reflecting an aggressive phenotype as follows-C-reactive protein (CRP) level on pathological stage, De Ritis (aspartate transaminase/alanine transaminase) ratio on nodal involvement, and neutrophil-lymphocyte ratio (NLR) on pathological stage. During the observation period of this study (median 36.1 months), extravesical disease recurrence was detected in 44 (32.6%) of the 135 patients with a 5-year eRFS rate of 62.1%. Of several factors examined, the CRP level, De Ritis ratio, and NRL were significantly correlated with eRFS on univariate analysis. Of these significant factors, the De Ritis ratio and NRL were identified as independent predictors of eRFS on multivariate analysis. Moreover, there were significant differences in eRFS according to the positive numbers of these two independent risk factors. CONCLUSIONS: These findings suggest that it is important to consider laboratory abnormalities, particularly the De Ritis ratio and NLR, to predict disease recurrence following RNU in patients with clinically localized UUTUC. PMID- 28856496 TI - Health expenditure and growth dynamics in the SADC region: evidence from non stationary panel data with cross section dependence and unobserved heterogeneity. AB - This paper investigates the long run relationship between health care expenditure and economic growth, using panel data for 14 Southern African Development Community (SADC) member countries over the period 1995-2012. The non-stationarity and cointegration properties between health expenditure per capita and GDP per capita were examined, controlling for cross section dependence and heterogeneity between countries. Our results suggest that health expenditure and GDP per capita are non-stationary and cointegrated. These findings seem to confirm the notion that health expenditure is non-discretionary-health is a necessary good-in the SADC region. The estimated income elasticity is below unity but higher than what was obtained for the OECD regional grouping. The policy implication of our result is that adequate health care service provision should be a key objective of governmental intervention in the SADC region. PMID- 28856497 TI - Simulations of the impacts of building height layout on air quality in natural ventilated rooms around street canyons. AB - Numerical simulations were conducted to investigate the effects of building height ratio (i.e., HR, the height ratio of the upstream building to the downstream building) on the air quality in buildings beside street canyons, and both regular and staggered canyons were considered for the simulations. The results show that the building height ratio affects not only the ventilation fluxes of the rooms in the downstream building but also the pollutant concentrations around the building. The parameter, outdoor effective source intensity of a room, is then proposed to calculate the amount of vehicular pollutants that enters into building rooms. Smaller value of this parameter indicates less pollutant enters the room. The numerical results reveal that HRs from 2/7 to 7/2 are the favorable height ratios for the regular canyons, as they obtain smaller values than the other cases. While HR values of 5/7, 7/7, and 7/5 are appropriate for staggered canyons. In addition, in terms of improving indoor air quality by natural ventilation, the staggered canyons with favorable HR are better than those of the regular canyons. PMID- 28856498 TI - The effectiveness of multidisciplinary care models for patients with chronic kidney disease: a systematic review and meta-analysis. AB - AIM: To assess the efficacy of the multidisciplinary care (MDC) model for patients with chronic kidney disease (CKD). BACKGROUND: The MDC model has been used in clinical practice for years, but the effectiveness of the MDC model for patients with CKD remains controversial. METHODS: Embase, PubMed, Medline, the Cochrane Library, and China National Knowledge Infrastructure databases were used to search for relevant articles. Only randomized controlled trials and cohort studies were pooled. Two independent authors assessed all articles and extracted the data. The efficacy was estimated from the odds ratios and corresponding 95% confidence intervals. A random effects model was used according to the heterogeneity. RESULTS: Twenty-one studies including 10,284 participants were analyzed. Compared with the non-MDC group, MDC was associated with a lower risk of all-cause mortality and lower hospitalization rates for patients with CKD. In addition, MDC also resulted in a slower eGFR decline and reduced temporary catheterization for patients receiving dialysis. However, according to the subgroup analysis, the lower rates of all-cause mortality in the MDC group were observed only in patients in stage 4-5 and when the staff of the MDC consisted of nephrologists, nurse specialists and professionals from other fields. The most prominent effect of reducing the hospitalization rates was also observed in patients with stage 4-5 but not in patients with stage 4-5 CKD. CONCLUSIONS: MDC can lower the all-cause mortality of patients with CKD, reduce temporary catheterization for patients receiving dialysis, decrease the hospitalization rate, and slow the eGFR decline. Moreover, the reduction in all-cause mortality crucially depends on the professionals comprising the MDC staff and the stage of CKD in patients. In addition, the CKD stage influences the hospitalization rates. PMID- 28856499 TI - Correlation between arterial spin-labeling perfusion and histopathological vascular density of pediatric intracranial tumors. AB - Traditional MRI methods for estimation of blood flow in brain tumors require high flow injection of contrast agents through large-bore intravenous access, which limits their pediatric utility. In contrast, arterial spin-labeling (ASL) can be used without contrast media. This study aimed to evaluate the relationship between tumor blood flow (TBF) measured by ASL and histopathological vascular density in pediatric brain tumors. Nineteen consecutive children were evaluated (10 boys, 9 girls; median age: 6 years; 8 high-grade and 11 low-grade tumors). ASL was performed with a pseudocontinuous labeling time of 1650 ms and post labeling delay of 1525 ms. The maximal absolute (aTBF) and relative (rTBF) tumor blood flows were measured. To evaluate the relative vascular area (%Vessel), the total stained vascular area was divided by the whole tissue area. Spearman's rank order correlation, the Mann-Whitney U test, and receiver operating characteristic analysis were used for statistical analysis. The absolute and relative TBF rates were 4.9-92.9 mL/100 g/min and 0.17-3.59 mL/100 g/min, respectively. The %Vessel was 0.6-30.2%. The %Vessel showed a significant positive correlation with TBF (aTBF: r = 0.87, P < 0.0001; rTBF: r = 0.89, P < 0.0001). The TBF rate of high grade tumors was significantly higher than that of low-grade tumors (aTBF: P = 0.0050, rTBF: P = 0.0036). The rTBF had the best diagnostic performance (area under the curve: 0.89). ASL perfusion imaging without contrast material can be used for accurate evaluation of histopathological vascular density and may be helpful for tumor grading in children. PMID- 28856500 TI - Methamphetamine-Induced Brain Injury and Alcohol Drinking. AB - A majority of methamphetamine (Meth) abusers also abuse alcohol but the neurochemical consequences of this co-abuse are unknown. Individually, alcohol and Meth cause inflammation and long-term alterations in dopamine and serotonin signaling within the brain. Experiments were conducted to identify if serial exposure to alcohol and Meth has neurochemical consequences that are greater than after either drug alone. Male Sprague Dawley rats voluntarily drank 10% ethanol (EtOH) every other day for 4 weeks and were then exposed to a binge injection regimen of Meth (10 mg/kg injected every 2 h, for a total of 4 injections). EtOH drinking and preference increased over the 4 weeks and caused inflammation evidenced by increases in serum and brain lipopolysaccharide (LPS) and brain cyclooxygenase-2 (COX-2) 24 h after the last day of drinking. Meth alone depleted dopamine and serotonin in the striatum, as well as serotonin in the prefrontal cortex when measured 1 week later. In contrast, EtOH drinking alone did not affect dopamine and serotonin content in the striatum and prefrontal cortex, but prior EtOH drinking followed by injections of Meth enhanced Meth-induced depletions of dopamine, serotonin, as well as dopamine and serotonin transporter immunoreactivities in a manner that was correlated with the degree of EtOH consumption. Cyclooxygenase inhibition by ketoprofen during EtOH drinking blocked the increases in LPS and COX-2 and the enhanced decreases in dopamine and serotonin produced by Meth. Therefore, prior EtOH drinking causes an increase in inflammatory mediators that mediate a synergistic interaction with Meth to cause an enhanced neurotoxicity. PMID- 28856501 TI - Distribution, source apportionment and health risk assessment of polycyclic aromatic hydrocarbons (PAHs) in intertidal sediment of Asaluyeh, Persian Gulf. AB - Surface sediment samples were collected from intertidal zone of Asaluyeh, Persian Gulf, to investigate distribution, sources and health risk of sixteen polycyclic aromatic hydrocarbons (PAHs). Total PAH concentrations ranged from 1.8 to 81.2 MUg kg-1 dry weight, which can be categorized as low level of pollution. Qualitative and quantitative assessments showed that PAHs originated from both petrogenic and pyrogenic sources with slight pyrogenic dominance. Source apportionment using principal component analysis indicated that the main sources of PAHs were fossil fuel combustion (33.59%), traffic-related PAHs (32.77%), biomass and coal combustion (18.54%) and petrogenic PAHs (9.31%). According to the results from the sediment quality guidelines, mean effects range-median quotient (M-ERM-Q) and benzo[a]pyrene toxic equivalents (BaPeq), low negative ecological risks related to PAH compounds would occur in the intertidal zone of Asaluyeh. The total benzo[a]pyrene (BaP) toxic equivalent quotient (TEQcarc) for carcinogenic compounds ranged from 0.01 to 7 MUg kg-1-BaPeq, indicating low carcinogenic risk. The human health risk assessment of PAH compounds via ingestion and dermal pathways suggests low and moderate potential risk to human health, respectively. PMID- 28856502 TI - Mendelian randomization analysis indicates serum urate has a causal effect on renal function in Chinese women. AB - PURPOSE: High levels of serum uric acid can predict the progression of stage I and II chronic kidney disease (CKD), but whether serum urate is an independent risk factor or has causal impact on serum creatinine (SCr) and renal function remains unclear. METHODS: Mendelian randomization was used to determine whether serum uric acid had a causal effect on renal function, represented by estimated glomerular filtration rate (eGFR), with potential confounding factors, in 3734 subjects from the Taizhou Longitudinal Study. In the two-stage least squares method of Mendelian randomization, serum uric acid level was selected as the exposure, genetic risk score of uric acid transporters was selected as the instrumental variable, and SCr and eGFR were selected as the outcomes. RESULTS: The result of the analysis showed that increased serum uric acid was not a causal effect on renal function, but it was a causal effect on reducing estimated glomerular filtration rate in both the female population and the subjects who were under 65 years old. We also found that increased serum uric acid levels led to impaired renal function only in the subjects with normal eGFR values. In addition, the serum uric acid was a risk factor for renal function in the subjects with relatively high levels of fasting glucose or who were currently smokers. CONCLUSIONS: Although serum urate is not an independent risk factor for renal dysfunction, it has a causal effect on renal dysfunction in either female or individuals of under 65, or normal eGFR, or high level of fasting glucose, or current smokers. PMID- 28856503 TI - Taxonomy, phylogeny and ecology of cultivable fungi present in seawater gradients across the Northern Antarctica Peninsula. AB - Thirty-six seawater samples collected at different depths of the Gerlache and Bransfield Straits in the Northern Antarctic Peninsula were analyzed, and the average of the total fungal counts ranged from 0.3 to >300 colony forming units per liter (CFU/L) in density. The fungal were purified and identified as 15 taxa belonged to the genera Acremonium, Aspergillus, Cladosporium, Cystobasidium, Exophiala, Glaciozyma, Graphium, Lecanicillium, Metschnikowia, Penicillium, Purpureocillium and Simplicillium. Penicillium chrysogenum, Cladosporium sphaerospermum, and Graphium rubrum were found at high densities in at least two different sites and depths. Our results show at the first time that in the seawater of Antarctic Ocean occur diverse fungal assemblages despite extreme conditions, which suggests the presence of a complex aquatic fungi food web, including species reported as barophiles, symbionts, weak and strong saprobes, parasites and pathogens, as well as those found in the polluted environments of the world. Additionally, some taxa were found in different sites, suggesting that the underwater current might contribute to fungal (and microbial) dispersal across the Antarctic Ocean, and nearby areas such as South America and Australia. PMID- 28856504 TI - Symptoms of Autism Spectrum Disorder (ASD) in Individuals with Mucopolysaccharide Disease Type III (Sanfilippo Syndrome): A Systematic Review. AB - The prevalence of autism spectrum disorder (ASD) in many genetic disorders is well documented but not as yet in Mucopolysaccharidosis type III (MPS III). MPS III is a recessively inherited metabolic disorder and evidence suggests that symptoms of ASD present in MPS III. This systematic review examined the extant literature on the symptoms of ASD in MPS III and quality assessed a total of 16 studies. Results indicated that difficulties within speech, language and communication consistent with ASD were present in MPS III, whilst repetitive and restricted behaviours and interests were less widely reported. The presence of ASD-like symptoms can result in late diagnosis or misdiagnosis of MPS III and prevent opportunities for genetic counselling and the provision of treatments. PMID- 28856505 TI - Comparative analysis of constitutive proteome between resistant and susceptible tomato genotypes regarding to late blight. AB - Late blight is one of the most destructive diseases of the tomato, resulting in substantial economic losses. There is difficulty in controlling this disease, so the molecular characterization of tomato genotypes may help in the selection of higher resistance tomato plants against Phytophthora infestans, late blight's pathogen. The objective was to analyze the differences with regard to the constitutive proteome between the access Vegetable Germplasm Bank (BGH)-2127, resistant genotype, and Santa Clara-susceptible genotype to late blight. Proteomic analysis of leaf samples by two-dimensional electrophoresis (2-DE) followed by identification by mass spectrometry (MALDI TOF/TOF) was performed. Nineteen proteins were identified, which were then related to metabolism and energy, photosynthesis, transcription, stress, and defenses. Approximately 90% of these proteins were more abundant in Santa Clara, a susceptible cultivar. Acidic 26 kDa endochitinase and ribonuclease T2 proteins were more abundant in BGH-2127 access. The enzymatic activity confirmed a greater abundance of chitinase in the BGH-2127 access as compared to the cultivar Santa Clara. Gene expression analyses by real-time PCR demonstrated that the mRNA levels were not correlated with the respective protein levels. Abundance of the acidic 26 kDa endochitinase and ribonuclease T2 proteins in the constitutive proteomes of BGH-2127 may be associated with the answer to the resistance of this access. PMID- 28856506 TI - Spiritual Transcendence and Psychological Adjustment: The Moderating Role of Personality in Burn Patients. AB - The current study examined the moderating role of personality traits (neuroticism and extraversion) on the relationship between spiritual transcendence and positive change, and spiritual transcendence and distress in burn patients. The sample (N = 98) comprised adult burn patients (age = 25-50) admitted to three hospitals in Lahore, Pakistan. They were assessed according to a demographic information sheet, the NEO Personality Inventory (McCrae and Costa in J Personal Soc Psychol 52:81-90, 1987), the Spiritual Transcendence Index (Seidlitz et al. in J Sci Study Relig 41:439-453, 2002), the Depression, Anxiety, Stress Scales-21 (Lovibond and Lovibond in Manual for the Depression Anxiety Stress scales, Psychology Foundation, Sydney, 1995), and the Perceived Benefit Scales (McMillen and Fisher in Soc Work Res 22(3):173-186, 1998). Stepwise moderated regression analysis showed that both personality traits (neuroticism and extraversion) played a moderating role in the relationship between spiritual transcendence and positive change, and spiritual transcendence and distress in burn patients. The findings highlight the potential role spiritual transcendence may have in understanding and improving the psychological adjustment of burn patients. PMID- 28856507 TI - The Effect of Non-Stroke Cardiovascular Disease States on Risk for Cognitive Decline and Dementia: A Systematic and Meta-Analytic Review. AB - Cardiovascular disease is associated with increased risk for cognitive decline and dementia, but it is unclear whether this risk varies across disease states or occurs in the absence of symptomatic stroke. To examine the evidence of increased risk for cognitive decline and dementia following non-stroke cardiovascular disease we conducted two independent meta-analyses in accordance with PRISMA guidelines. The first review examined cardiovascular diagnoses (atrial fibrillation, congestive heart failure, periphery artery disease and myocardial infarction) while the second review assessed the impact of atherosclerotic burden (as indicated by degree of stenosis, calcification score, plaque morphology or number of plaques). Studies eligible for review longitudinally assessed risk for clinically significant cognitive decline and/or dementia and excluded stroke and cognitive impairment at baseline. Summary statistics were computed via the inverse variance weighted method, utilising Cox Proportional Hazards data (Hazard Ratios, HR). Both atrial fibrillation (n = 5, HR = 1.26, 95% CI [1.12, 1.43]) and severe atherosclerosis (n = 4, HR = 1.59, 95% CI [1.12, 2.26]) emerged as significant risk factors for cognitive decline and/or dementia. A small set of studies reviewed, insufficient for meta-analysis, examining congestive heart failure, peripheral artery disease and myocardial infarction suggested that these conditions may also be associated with an increased risk of cognitive decline/dementia. In the absence of stroke, patients with atrial fibrillation or generalised atherosclerosis are at heightened risk for cognitive deterioration. Nonetheless, this paper highlights the need for methodologically rigorous and prospective investigation of the relationship between CVD and dementia. PMID- 28856508 TI - Correction of hyperopia with astigmatism following radial keratotomy with daily disposable plus spherical contact lens: a case report. AB - PURPOSE: To report the refractive correction in a case of hyperopia and astigmatism following radial keratotomy. METHODS: A case report. RESULTS: A 47 year-old woman, who had undergone refractive surgery for radial keratotomy in both eyes 22 years before the present study, presented to our clinic with blurred vision. Her best corrected visual acuity, with spectacle correction of +3.50 DS/ 1.50 DCX130 degrees in the right eye and +3.75 DS/-1.50 DCX80 degrees in the left eye, was 0.2 logMAR and 0.3 logMAR, respectively. Her keratometric readings were 35.75 D/36.75 D at 74 degrees and 35.25 D/36.25 D at 61 degrees , respectively. Prompted by intolerance to glasses, the patient requested for contact lenses. First, we applied a rigid, gas-permeable contact lens. However, we noted poor fitting due to central corneal flattening. Subsequently, we applied a conventional plus spherical soft contact lens (PSSCL), which is thick in the center and can therefore correct hyperopia and low-grade astigmatism simultaneously. The conventional PSSCL showed slightly inferior decentration, with good movement, and the patient was satisfied with it. After ascertaining the patient's living habits, we decided that a daily disposable soft contact lens would most meet her needs. The final prescription was a daily disposable PSSCL; the patient was satisfied with her corrected visual acuity of 0.0 logMAR in the right eye and 0.0 logMAR in left eye. Her daily disposable PSSCL-corrected visual acuity was stable during the 10-month follow-up. CONCLUSION: For patients displaying hyperopia with astigmatism following radial keratotomy, the PSSCL may confer better corrected visual acuity and acceptability. PMID- 28856509 TI - Accumulation and health risk assessment of trace elements in Carassius auratus gibelio from subsidence pools in the Huainan coalfield in China. AB - Microelement (As, Cd, Cr, Cu, Ni, Pb, and Zn) concentrations were determined in the muscle, skin, gill, and liver tissues of Carassius auratus gibelio collected from subsidence pools at three different coal mines in the Huainan coalfield in China. The concentrations of elements in the water were within the allowable levels for raising fish. However, the higher levels of these metals in sediment may pose potential harm on fish. It was found that the concentrations of Cr, Ni, and Zn in all fish tissues were higher, while As, Cd, and Pb levels were relatively low. Microelement accumulation appeared to be more widespread in subsidence pools than that in natural water. Elements accumulated in fish tissues differently: the highest metal concentrations were generally found in the liver tissues of the fish analyzed, whereas the lowest were recorded in the muscles. The mean element concentrations in muscle tissue from C. auratus gibelio collected from subsidence pools (As, 0.16 mg/kg; Cd, 0.06 mg/kg; Cr, 6.21 mg/kg; Cu, 1.61 mg/kg; Ni, 3.88 mg/kg; Pb, 1.76 mg/kg; and Zn, 12.80 mg/kg dry weight) were far below the allowable limit of the hygienic standard in fish proposed by the Ministry of Health in China, suggesting that the fish were safe for human consumption. A health risk assessment also suggested there was no risk from the analyzed elements for inhabitants near the Huainan coalfield that consume fish. PMID- 28856510 TI - Diabetic Eye Screening: Knowledge and Perspectives from Providers and Patients. AB - PURPOSE OF REVIEW: Diabetic retinopathy remains the leading cause of blindness among working-age US adults even though timely screening and treatment prevent 90% of blindness. We summarize current knowledge and perspectives to better understand why diabetic eye screening rates remain low and future directions towards preventing blindness from diabetes. RECENT FINDINGS: Significant advancements in the past 10 years include primary care and patient-oriented interventions as well as the use of teleophthalmology. In England, diabetic eye disease is no longer the leading cause of certifiable blindness following the implementation of a national teleophthalmology program for diabetic retinopathy. Multiple workflow and systems-level barriers affect providers. Patient barriers include a limited understanding of screening and lack of access to care. Interventions have been developed, but new barriers exist towards sustaining their impact. More research is needed to identify and implement the best practices to increase diabetic eye screening rates long-term. PMID- 28856511 TI - Local infiltration analgesia: a 2-year follow-up of patients undergoing total hip arthroplasty. AB - PURPOSE: Local infiltration analgesia (LIA) is commonly used for postoperative pain management following total hip arthroplasty (THA). However, the long-term effects of the component drugs are unclear. The aim of our study was to investigate functional outcome, quality of life, chronic post-surgical pain, and adverse events in patients within 2 years of undergoing THA. METHODS: The study was a secondary analysis of data from a previous larger study. Eighty patients were randomized to receive either intrathecal morphine (Group ITM) or local infiltration analgesia (Group LIA) for pain management in a double-blind study. The parameters measured were patient-assessed functional outcome [using the Hip dysfunction and Osteo-arthritis Outcome Score (HOOS) questionnaire], health related quality of life [using the European Quality of Life-5 dimensions (EQ-5D) questionnaire and the 36-Item Short Form Health Survey (SF-36) score], and pain using the numeric rating score (NRS), with persistent post-surgical pain having a NRS of > 3 or a HOOS pain sub-score of > 30. All complications and adverse events were investigated during the first 2 years after primary surgery. RESULTS: Pain intensity and rescue analgesic consumption were similar between the groups after hospital discharge. No differences were found in HOOS or SF-36 score between the groups up to 6 months after surgery. A significant group * time interaction was seen in the EQ 5D form in favor of the LIA group. No between-group difference in persistent post-surgical pain was found at 3 or 6 months, or in adverse events up to 2 years after surgery. CONCLUSION: Analysis of functional outcome, quality of life, and post-discharge surgical pain did not reveal significant differences between patients receiving LIA and those receiving ITM. LIA was found to be a safe technique for THA during the long-term follow-up. However, it should be noted that these conclusions are based on a limited number of patients. PMID- 28856512 TI - Dynamics of copper and tetracyclines during composting of water hyacinth biomass amended with peat or pig manure. AB - Composting is one of the post-treatment methods for phytoremediation plants. Due to a high potential of water hyacinth to accumulate pollutants, the physicochemical parameters, microbial activity as well as fates of copper (Cu) and tetracyclines (TCs) were investigated for the different amended water hyacinth biomass harvested from intensive livestock and poultry wastewater, including unamended water hyacinth (W), water hyacinth amended with peat (WP), and water hyacinth amended with pig manure (WPM) during the composting process. Pig manure application accelerated the composting process as evidenced by an increase of temperature, electrical conductivity (EC), NH4-N, as well as functional diversity of microbial communities compared to W and WP treatments. Composting process was slowed down by high Cu, but not by TCs. The addition of peat significantly increased the residual fraction of Cu, while pig manure addition increased available Cu concentration in the final compost. Cu could be effectively transformed into low available (oxidizable) and residual fractions after fermentation. In contrast, less than 0.5% of initial concentrations of TCs were determined at the end of 60-day composting for all treatments in the final composts. The dissipation of TCs was accelerated by the high Cu concentration during composting. Therefore, composting is an effective method for the post treatment and resource utilization of phytoremediation plants containing Cu and/or TCs. PMID- 28856513 TI - Emerging pharmacologic and structural therapies for hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy is the most common inherited heart disease. Although it was first described over 50 years ago, there has been little in the way of novel disease-specific therapeutic development for these patients. Current treatment practice largely aims at symptomatic control using old drugs made for other diseases and does little to modify the disease course. Septal reduction by surgical myectomy or percutaneous alcohol septal ablation are well-established treatments for pharmacologic-refractory left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients. In recent years, there has been a relative surge in the development of innovative therapeutics, which aim to target the complex molecular pathophysiology and resulting hemodynamics that underlie hypertrophic cardiomyopathy. Herein, we review the new and emerging therapeutics for hypertrophic cardiomyopathy, which include pharmacologic attenuation of sarcomeric calcium sensitivity, allosteric inhibition of cardiac myosin, myocardial metabolic modulation, and renin-angiotensin-aldosterone system inhibition, as well as structural intervention by percutaneous mitral valve plication and endocardial radiofrequency ablation of septal hypertrophy. In conclusion, while further development of these therapeutic strategies is ongoing, they each mark a significant and promising advancement in treatment for hypertrophic cardiomyopathy patients. PMID- 28856515 TI - Automatic detection of new tumors and tumor burden evaluation in longitudinal liver CT scan studies. AB - PURPOSE: Radiological longitudinal follow-up of liver tumors in CT scans is the standard of care for disease progression assessment and for liver tumor therapy. Finding new tumors in the follow-up scan is essential to determine malignancy, to evaluate the total tumor burden, and to determine treatment efficacy. Since new tumors are typically small, they may be missed by examining radiologists. METHODS: We describe a new method for the automatic detection and segmentation of new tumors in longitudinal liver CT studies and for liver tumors burden quantification. Its inputs are the baseline and follow-up CT scans, the baseline tumors delineation, and a tumor appearance prior model. Its outputs are the new tumors segmentations in the follow-up scan, the tumor burden quantification in both scans, and the tumor burden change. Our method is the first comprehensive method that is explicitly designed to find new liver tumors. It integrates information from the scans, the baseline known tumors delineations, and a tumor appearance prior model in the form of a global convolutional neural network classifier. Unlike other deep learning-based methods, it does not require large tagged training sets. RESULTS: Our experimental results on 246 tumors, of which 97 were new tumors, from 37 longitudinal liver CT studies with radiologist approved ground-truth segmentations, yields a true positive new tumors detection rate of 86 versus 72% with stand-alone detection, and a tumor burden volume overlap error of 16%. CONCLUSIONS: New tumors detection and tumor burden volumetry are important for diagnosis and treatment. Our new method enables a simplified radiologist-friendly workflow that is potentially more accurate and reliable than the existing one by automatically and accurately following known tumors and detecting new tumors in the follow-up scan. PMID- 28856514 TI - Moving Forward Through Consensus: A Modified Delphi Approach to Determine the Top Research Priorities in Orthopaedic Oncology. AB - BACKGROUND: Several challenges presently impede the conduct of prospective clinical studies in orthopaedic oncology, including limited financial resources to support their associated costs and inadequate patient volume at most single institutions. This study was conducted to prioritize research questions within the field so that the Musculoskeletal Tumor Society (MSTS), and other relevant professional societies, can direct the limited human and fiscal resources available to address the priorities that the stakeholders involved believe will have the most meaningful impact on orthopaedic oncology patient care. QUESTIONS/PURPOSES: The purpose of this study was to use a formal consensus-based approach involving clinician-scientists and other stakeholders to identify the top priority research questions for future international prospective clinical studies in orthopaedic oncology. METHODS: A three-step modified Delphi process involving multiple stakeholder groups (including orthopaedic oncologists, research personnel, funding agency representation, and patient representation) was conducted. First, we sent an electronic questionnaire to all participants to solicit clinically relevant research questions (61 participants; 54% of the original 114 individuals invited to participate returned the questionnaires). Then, participants rated the candidate research questions using a 5-point Likert scale for five criteria (60 participants; 53% of the original group participated in this portion of the process). Research questions that met a priori consensus thresholds progressed for consideration to an in-person consensus meeting, which was attended by 44 participants (39% of the original group; 12 countries were represented at this meeting). After the consensus panel's discussion, members individually assigned scores to each question using a 9-point Likert scale. Research questions that met preset criteria advanced to final ranking, and panel members individually ranked their top three priority research questions, resulting in a final overall ranking of research priorities. RESULTS: A total of 73 candidate research questions advanced to the consensus meeting. In the end, the consensus panel identified four research priorities: (1) Does less intensive surveillance of patients with sarcoma affect survival? (2) What are the survival outcomes over time for orthopaedic oncology implants? (3) Does resection versus stabilization improve oncologic and functional outcomes in oligometastatic bone disease? (4) What is the natural history of untreated fibromatosis? CONCLUSIONS: The results of this study will assist in developing a long-term research strategy for the MSTS and, possibly, the orthopaedic oncology field as a whole. Furthermore, the results of this study can assist researchers in guiding their research efforts and in providing a justified rationale to funding agencies when requesting the resources necessary to support future collaborative research studies that address the identified orthopaedic oncology priorities. PMID- 28856516 TI - Usefulness of esophagogastroduodenoscopy and 18F-fluorodeoxyglucose positron emission tomography in detecting synchronous multiple primary cancers with oral cancer. AB - PURPOSE: The purpose of this study is to compare the value of screening for synchronous multiple primary cancers in other organs by esophagogastroduodenoscopy (EGD) or 18F-fluorodeoxyglucose positron-emission tomography (PET-CT) in patients newly diagnosed with oral cancer. METHODS: We retrospectively examined consecutive Japanese patients who were diagnosed with oral squamous cell carcinoma (OSCC) and were screened for synchronous multiple primary cancers in other organs by EGD and/or PET-CT between January 2010 and December 2015 at our institution. The study included 190 patients (106 males and 84 females) from 36 to 93 years of age (median age 68.8 years). The patients were screened by EGD, PET-CT, or both before beginning treatment for OSCC. RESULTS: Of 190 Japanese patients with OSCC, 15 had multiple primary cancers: 13 patients had double cancer and two had triple cancers. The sites of the 17 multiple primary cancers were gastric (6), esophageal (4), and lung (3), and ovarian, colon, liver, and thyroid (1 each). All of the gastric and esophageal cancers were found by EGD and were not detected by PET-CT. For three patients, the detection of multiple cancers affected the treatment modality or order of treatment selected for the OSCC. In two cases, the oral cancer and multiple primary cancer(s) in another organ were resected simultaneously by joint surgical teams. CONCLUSIONS: PET-CT for oral cancer patients is an effective supporting diagnostic tool. However, the ability of PET-CT has some limitations. Especially for early detection of the upper gastrointestinal cancers, it is necessary to be supplemented by EGD. PMID- 28856517 TI - Bicuspid aortic valve related aortopathy. AB - Bicuspid aortic valve related aortopathy is known to significantly increase the risk for catastrophic aortic events and, therefore, represents a considerable health burden. Albeit of ongoing research in this field including genetic, molecular, hemodynamic and morphologic aspects, bicuspid aortic valve related aortopathy still represents an imperfectly understood disorder. This lack in knowledge results in a lack of consistency considering different therapeutic approaches. Recent studies have provided new insights into the etiology and clinical impacts of bicuspid aortic valve related aortopathy in different clinical settings, leading to a growing body of opinion towards a more individualized surgical approach than currently provided by the guidelines. Especially valvular hemodynamics-stenosis and regurgitation-seem to have significant impact on the development of bicuspid aortic valve related aortopathy. In this context, there is evidence that regurgitation of bicuspid aortic valves is the more fatal pathomechanism. Furthermore, "age" represents an aspect that should be taken into account when deciding whether to replace the aorta or not, because the diameter depends mainly on a patients age. The same diameter of the aorta in a 70-year old and a 20-year old patient has to be interpreted differently and should, therefore, result in different therapeutic strategies. PMID- 28856518 TI - Changes of patient-reported outcomes and protein fingerprint biomarkers after exercise therapy for axial spondyloarthritis. AB - The objective of this study was to investigate the patient-reported outcomes (PROs) and matrix metalloproteinase (MMP) derived extracellular matrix (ECM) biomarkers in non-radiographic (nr)-axial spondyloarthritis (axSpA) and radiographic (r)-axSpA after exercise intervention. Forty-six axSpA patients with stable disease and treatment underwent 24 weeks long exercise intervention. The clinical and laboratory assessments were performed at baseline and at follow-up. The PROs included evaluation of patient's global disease activity (PGDA), disease activity (DA7), pain (PAIN7) and fatigue during last week and quality of life questionnaires. ELISAs for MMP-degraded collagen type II, C-reactive protein (CRPM) and citrullinated vimentin were used. The data of 23 r-axSpA and 19 nr axSpA were analysed. The PDGA was similar for nr-axSpA (35.2 +/- 18.9) and r axSpA (33.4 +/- 22.3) at baseline, improved significantly after intervention (p < 0.01) and the change of PDGA was almost identical for nr-axSpA (- 10.0 +/- 15.4) and r-axSpA (- 9.8 +/- 11.9). Evaluations of DA7 and PAIN7 were significantly improved only in nr-axSpA (3.5 +/- 2.3 and 34.7 +/- 25.6 at baseline vs. 2.1 +/- 1.9 and 21.0 +/- 20.5, respectively, p < 0.01). The decline of DA7 and PAIN7 was more profound, but not significantly in nr-axSpA than in r-axSpA (- 1.4 +/- 1.6 and - 13.7 +/- 17.4 vs. - 0.5 +/- 3.1 and - 3.7 +/- 3.3, respectively). The quality of life was not changed. At baseline, increased levels of CRPM were found in r-axSpA (14.85 +/- 4.10) compared to nr-axSpA (11.83 +/- 3.20), p < 0.05, but all three biomarkers were not influenced by exercise therapy. We found that exercise therapy mainly in the nr-axSpA improves PROs, but not ECM turnover biomarkers. This indicates that exercise therapy is important for patients' health but does not affect ECM turnover. PMID- 28856520 TI - Asiatic Acid Ameliorates Doxorubicin-Induced Cardiac and Hepato-Renal Toxicities with Nrf2 Transcriptional Factor Activation in Rats. AB - Asiatic acid (AA), a pentacyclic triterpenoid, is a key phytoconstituent of Centella asiatica. AA is a patented as a cytotoxic substance, and it exerts cytotoxicity against Hep3B, Hela and MCF-7 cell lines. However, pentacyclic triterpenoids also modulate the expression and transcriptional activities of Nrf2 and exert cytoprotective effects. In this study, we investigated the effects of AA on the doxorubicin (DXR)-induced organ toxicities and expression of the Nrf2. DXR toxicity was induced by a single intravenous injection of 65.75 mg/kg of DXR. Seven days pretreatment with AA at the doses of 5, 10 and 20 mg/kg, p.o. significantly reverted the DXR-induced oxidative stress in heart, liver and kidney. The biochemical indicators of DXR toxicity including increased activities of serum creatinine kinase isoenzyme, transaminases and lactate dehydrogenase along with increased serum creatinine and serum blood urea nitrogen were normalised by AA. AA was also protected against the DXR-induced histological alterations including necrosis, hyaline degeneration and congestion in the heart; leukocytic inflammation, centrilobular necrosis, apoptosis and fatty changes in the liver; and necrosis and inflammation in the kidney. The protective effects of AA were dose dependent, and the 20 mg/kg dose exerted protection against the DXR toxicity by increasing Nrf2 protein expression. PMID- 28856519 TI - OsPPR6, a pentatricopeptide repeat protein involved in editing and splicing chloroplast RNA, is required for chloroplast biogenesis in rice. AB - KEY MESSAGE: OsPPR6, a pentatricopeptide repeat protein involved in editing and splicing chloroplast RNA, is required for chloroplast biogenesis in rice. The chloroplast has its own genetic material and genetic system, but it is also regulated by nuclear-encoded genes. However, little is known about nuclear plastid regulatory mechanisms underlying early chloroplast biogenesis in rice. In this study, we isolated and characterized a mutant, osppr6, that showed early chloroplast developmental defects leading to albino leaves and seedling death. We found that the osppr6 mutant failed to form thylakoid membranes. Using map-based cloning and complementation tests, we determined that OsPPR6 encoded a new Pentatricopeptide Repeat (PPR) protein localized in plastids. In the osppr6 mutants, mRNA levels of plastidic genes transcribed by the plastid-encoded RNA polymerase decreased, while those of genes transcribed by the nuclear-encoded RNA polymerase increased. Western blot analyses validated these expression results. We further investigated plastidic RNA editing and splicing in the osppr6 mutants and found that the ndhB transcript was mis-edited and the ycf3 transcript was mis spliced. Therefore, we demonstrate that OsPPR6, a PPR protein, regulates early chloroplast biogenesis and participates in editing of ndhB and splicing of ycf3 transcripts in rice. PMID- 28856521 TI - Silencing Pre-B-cell leukemia homeobox 3 decreases the proliferation of human glioma cells in vitro and in vivo. AB - Among primary brain tumors, gliomas are the most common and most aggressive, with a poor prognosis and limited treatment options. Thus, it is essential to determine the mechanisms involved in glioma development to develop effective therapies for glioma patients. Pre-B-cell leukemia homeobox 3 (PBX3), a critical member of the PBX family, is frequently overexpressed in multiple human malignancies. However, the expression patterns and biological functions, as well as the involved molecular functions of PBX3 in human gliomas remain largely unknown. In this study, we demonstrate that PBX3 expression is increased in both human glioma tissues and cell lines compared with their normal counterparts. These results suggested that PBX3 might be involved in glioma progression. Thus, the role of PBX3 in glioma cell proliferation was investigated using genetic knockdown and overexpression methods. The results showed that PBX3 knockdown inhibited glioma cell proliferation and induced apoptosis, while PBX3 overexpression significantly promoted glioma cell proliferation. Mechanistically, we found that PBX3 promoted cell proliferation by modulating cell cycle progression. A xenograft LN229 model was used to confirm that PBX3 depletion decreased tumor growth in vivo. In summary, our findings reveal that PBX3 may be a potential therapeutic target in gliomas. PMID- 28856523 TI - Hemodynamic Support Devices for Shock and High-Risk PCI: When and Which One. AB - PURPOSE OF REVIEW: This article addresses evolving devices and uses of hemodynamic support in the management of high-risk PCI and AMI with cardiogenic shock. RECENT FINDINGS: Recent publications question the benefit of Intra-aortic Balloon Pump support for AMI Shock. Furthermore, in high-risk PCI, the Impella support system provides better late outcomes than does the intra-aortic balloon pump. We have entered a new era in which larger, higher flow devices that increase cardiac output while unloading the left ventricle provide better outcome. The current PCI population is higher risk, and often without surgical options. Hemodynamic support, most often utilizing Impella support, improves outcomes via providing the hemodynamic stability to allow complete revascularization and optimal lesion treatment. Regarding shock, preliminary data suggests that a concept of early left ventricular unloading before PCI maybe the critical factor for improving the outcome for acute myocardial infarction complicating myocardial infarction. PMID- 28856524 TI - 4D modelling for rapid assessment of biventricular function in congenital heart disease. AB - Although more patients with congenital heart disease (CHD) are now living longer due to better surgical interventions, they require regular imaging to monitor cardiac performance. There is a need for robust clinical tools which can accurately assess cardiac function of both the left and right ventricles in these patients. We have developed methods to rapidly quantify 4D (3D + time) biventricular function from standard cardiac MRI examinations. A finite element model was interactively customized to patient images using guide-point modelling. Computational efficiency and ability to model large deformations was improved by predicting cardiac motion for the left ventricle and epicardium with a polar model. In addition, large deformations through the cycle were more accurately modeled using a Cartesian deformation penalty term. The model was fitted to user defined guide points and image feature tracking displacements throughout the cardiac cycle. We tested the methods in 60 cases comprising a variety of congenital heart diseases and showed good correlation with the gold standard manual analysis, with acceptable inter-observer error. The algorithm was considerably faster than standard analysis and shows promise as a clinical tool for patients with CHD. PMID- 28856525 TI - Effect of personality traits on adherence with positive airway pressure therapy in obstructive sleep apnea patients. AB - PURPOSE: Patient adherence with positive airway pressure (PAP) therapy is a significant clinical problem in obstructive sleep apnea treatment. Personality traits may be a factor for non-adherence. The aim of this study is to investigate the relationship between PAP therapy adherence and patient personality traits. METHODS: Patients were screened and recruited during their visit to a sleep clinic. Baseline data were collected from each patient's electronic chart. Behavioral inhibition system/behavioral activation system (BIS/BAS) scales, short measure of five-factor model personality traits (mini-IPIP), positive and negative affect score (PANAS), and appetitive motivation scores (AMS) tests were used to measure personality traits. Data from the PAP device were obtained following a minimum of an initial 30 days, with adherence defined as >4 h/night on 70% of nights. Univariate and multivariate logistic regression and Pearson correlation tests were used to analyze the data. RESULTS: A total of 400 patients were recruited. Three hundred twenty-one patients had all the data and were included in the study. Behavioral activation system-fun seeking (BAS-FS) and, to a certain extent, negative affect were significantly associated with adherence. Intellect/imagination was marginally significant. Additionally, older age (>65 years), profession, PAP type, side effects, efficiency, apnea-hypopnea index (AHI), and residual AHI showed significant associations with patient adherence with PAP therapy. Multivariate analysis revealed that BAS-FS was still a significant predictor of adherence even after adjusting for other covariates. CONCLUSION: BAS-FS, negative affect, and intellect/imagination are significant factors for adherence to PAP therapy in obstructive sleep apnea patients. PMID- 28856522 TI - Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes: results from the TEDDY study. AB - AIMS: The onset of clinical type 1 diabetes (T1D) is preceded by the occurrence of disease-specific autoantibodies. The level of autoantibody titers is known to be associated with progression time from the first emergence of autoantibodies to the onset of clinical symptoms, but detailed analyses of this complex relationship are lacking. We aimed to fill this gap by applying advanced statistical models. METHODS: We investigated data of 613 children from the prospective TEDDY study who were persistent positive for IAA, GADA and/or IA2A autoantibodies. We used a novel approach of Bayesian joint modeling of longitudinal and survival data to assess the potentially time- and covariate dependent association between the longitudinal autoantibody titers and progression time to T1D. RESULTS: For all autoantibodies we observed a positive association between the titers and the T1D progression risk. This association was estimated as time-constant for IA2A, but decreased over time for IAA and GADA. For example the hazard ratio [95% credibility interval] for IAA (per transformed unit) was 3.38 [2.66, 4.38] at 6 months after seroconversion, and 2.02 [1.55, 2.68] at 36 months after seroconversion. CONCLUSIONS: These findings indicate that T1D progression risk stratification based on autoantibody titers should focus on time points early after seroconversion. Joint modeling techniques allow for new insights into these associations. PMID- 28856526 TI - Avoidance of protein oxidation correlates with the desiccation and radiation resistance of hot and cold desert strains of the cyanobacterium Chroococcidiopsis. AB - To investigate the relationship between desiccation and the extent of protein oxidation in desert strains of Chroococcidiopsis a selection of 10 isolates from hot and cold deserts and the terrestrial cyanobacterium Chroococcidiopsis thermalis sp. PCC 7203 were exposed to desiccation (air-drying) and analyzed for survival. Strain CCMEE 029 from the Negev desert and the aquatic cyanobacterium Synechocystis sp. PCC 6803 were further investigated for protein oxidation after desiccation (drying over silica gel), treatment with H2O2 up to 1 M and exposure to gamma-rays up to 25 kGy. Then a selection of desert strains of Chroococcidiopsis with different survival rates after prolonged desiccation, as well as Synechocystis sp. PCC 6803 and Chroococcidiopsis thermalis sp. PCC 7203, were analyzed for protein oxidation after treatment with 10 and 100 mM of H2O2. Results suggest that in the investigated strains a tight correlation occurs between desiccation and radiation tolerance and avoidance of protein oxidation. PMID- 28856527 TI - Neonatal outcomes following exposure in utero to fallout from Chernobyl. AB - Iodine 131 (I-131), the principal component of nuclear fallout from the Chernobyl accident, concentrates in the thyroid gland and may pose risks to fetal development. To evaluate this, neonatal outcomes following the accident in April of 1986 were investigated in a cohort of 2582 in utero-exposed individuals from northern Ukraine for whom estimates of fetal thyroid I-131 dose were available. We carried out a retrospective review of cohort members' prenatal, delivery and newborn records. The relationships of dose with neonatal anthropometrics and gestational length were modeled via linear regression with adjustment for potentially confounding variables. We found similar, statistically significant dose-dependent reductions in both head circumference (-1.0 cm/Gy, P = 0.005) and chest circumference (-0.9 cm/Gy, P = 0.023), as well as a similar but non significant reduction in neonatal length (-0.6 cm/Gy, P = 0.169). Gestational length was significantly increased with increasing fetal dose (0.5 wks/Gy, P = 0.007). There was no significant (P > 0.1) effect of fetal dose on birth weight. The observed associations of radioiodine exposure with decreased head and chest circumference are consistent with those observed in the Japanese in utero-exposed atomic bomb survivors. PMID- 28856528 TI - Resident participation is not associated with postoperative adverse events, reoperation, or prolonged length of stay following craniotomy for brain tumor resection. AB - Prior studies exploring the impact of resident involvement on complication and mortality rates in neurosurgery have evaluated heterogeneous cohorts. Since brain tumor resection is characterized by significant operative complexity, variety, and morbidity, intraoperative resident involvement has the potential to impact patient outcomes. The purpose of this study was thus to explore the relationship between resident involvement and patient outcomes following craniotomy for brain tumor resection. Data for adult patients undergoing craniotomy for brain tumor resection were extracted from the 2008-2014 National Surgical Quality Improvement Program database. Resident involvement was determined for all included cases, and evaluated for association with patient outcomes via multivariable, binary logistic regression modeling while controlling for perioperative variables. Outcomes included death, prolonged length of stay (LOS), readmission, reoperation, and pertinent complications. A total of 3587 cases met the inclusion criteria, 2926 (81.6%) of which were supratentorial tumors and 661 (18.4%) were infratentorial lesions. Residents were involved in 63.6% of cases. Resident participation was associated with a reduced incidence of prolonged LOS (OR 0.68, 95% CI 0.54-0.86, P = 0.001) and urinary tract infection (UTI) (OR 0.63, 95% CI 0.40-0.98, P = 0.038), and approached significance for reduced mortality rate (OR 0.63, 95% CI 0.39-1.03, P = 0.064). These associations were observed for patients with supratentorial tumors but not for those with infratentorial lesions. Resident involvement was not significantly associated with any of the other outcome metrics. Resident involvement was not a risk factor for any adverse events, and was associated with reduced incidence of prolonged LOS and UTI. The observed relationships may be impacted by institution-level factors. PMID- 28856529 TI - Reply to Kopans. PMID- 28856530 TI - Sufentanil protects the rat myocardium against ischemia-reperfusion injury via activation of the ERK1/2 pathway. AB - Sufentanil, a lipophilic opioid, is the most frequently used clinical drug for ischemic heart disease. The effects of sufentanil on MAPK signaling in ischemic heart disease were explored. The effects of sufentanil on ischemia-reperfusion (IR)-induced myocardial injury in a rat model were examined. The serum levels of CK, LDH, MDA and SOD, and the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase were measured. The levels of total and phosphorylated ERK1/2, JNK, and p38 were measured by western blotting in the heart, and the myocardial H9C2 cell line was studied. Using the Cell Counting Kit-8, the growth rate of H9C2 cells affected by sufentanil was studied. The serum levels of CK, LDH and MDA were higher in the IR group than in the SO and SUF groups. The SOD level, as well as the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase, were lower in the SO and SUF groups than in the IR group. The phosphorylated ERK1/2 level was lower in the IR group than in the SO and SUF groups. The growth rate of H9C2 cells increased with the concentration of sufentanil and the exposure time. The phosphorylated ERK level was upregulated by 4-12 h of sufentanil exposure, indicating that the effects were time-dependent. Furthermore, an inhibition of ERK signaling by chemical inhibition suppressed the sufentanil-mediated increase in the growth rate of H9C2 cells. Sufentanil appears to be beneficial for cases of worsening ischemic heart disease. Further studies are necessary before a clinical application is considered. PMID- 28856532 TI - Evaluation of the Nitric Oxide and Nitrite Scavenging Capability, N-Nitrosamine Formation Inhibitory Activity, and Optimization of Ultrasound-Assisted Aqueous Two-Phase System Extraction of Total Saponins from Coreopsis tinctoria Flowering Tops by Response Surface Methodology. AB - Coreopsis tinctoria flowering tops (CTFs) is a popular health product as herbal tea or as a traditional medicinal herb that is rich in saponins and exerts substantial biological activity. In this study, an ultrasound-assisted aqueous two-phase system (ATPS) was utilized to extract total saponins from CTFs and optimize the extraction process by response surface methodology. Moreover, the nitric oxide and nitrite scavenging capability, and N-nitrosamine formation inhibitory activity of total saponins were evaluated. Results showed that the optimal conditions for total saponins were 37.76% (w/w) ammonium sulfate and 35.62% (w/w) ethanol in ATPS coupled with ultrasonic-assisted extraction. Under the optimal conditions, the maximum yield of total saponins of 33.4 g/kg can be obtained from the CTFs raw material. The nitric oxide radical scavenging, nitrite scavenging, and N-nitrosamine inhibitory activities (SC50) were 287.92 +/- 7.42, 191.63 +/- 7.69, and 1787.4 +/- 51.26 MUg/mL, respectively. The total saponins has a certain nitric oxide and nitrite scavenging capability, and N-nitrosamine formation inhibitory activity in vitro. Given these activities, research on saponins from CTFs provides profound and lasting implications for the novel applications of C. tinctoria. PMID- 28856531 TI - Pro-neurogenic, Memory-Enhancing and Anti-stress Effects of DF302, a Novel Fluorine Gamma-Carboline Derivative with Multi-target Mechanism of Action. AB - A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon. PMID- 28856533 TI - Evidence of the supercomplex organization of photosystem II and light-harvesting complexes in Nannochloropsis granulata. AB - Diverse light-harvesting complexes (LHCs) have been found in photosynthetic microalgae that originated from secondary endosymbiosis involving primary red algae. However, the associations between LHCs and photosystem I (PSI) and photosystem II (PSII) in these microalgae are not fully understood. Eustigmatophyta is a red algal lineage that appears to have a unique organization in its photosynthetic machinery, consisting of only chlorophyll a and carotenoids that are atypical compared with other closely related groups. In this study, the supramolecular organization of pigment-protein complexes in the eustigmatophyte alga, Nannochloropsis granulata was investigated using Clear Native (CN) PAGE coupled with two-dimensional (2D) SDS-PAGE. Our results showed two slowly migrating green bands that corresponded to PSII supercomplexes, which consisted of reaction centers and LHCs. These green bands were also characterized as PSII complexes by their low temperature fluorescence emission spectra. The protein subunits of the PSII-LHC resolved by 2D CN/SDS-PAGE were analyzed by mass spectrometry, and four different LHC proteins were identified. Phylogenetic analysis of the identified LHC protein sequences revealed that they belonged to four different Lhc groups; (1) stress-related Lhcx proteins, (2) fucoxanthin chlorophyll a/c-binding Lhcf proteins, (3) red-shifted Chromera light-harvesting proteins (Red-CLH), and (4) Lhcr proteins, which are commonly found in organisms possessing red algal plastids. This is the first report showing evidence of a pigment-protein supercomplex consisting of PSII and LHCs, and to identify PSII associated LHC proteins in Nannochloropsis. PMID- 28856534 TI - Prevalence of lameness, claw lesions, and associated risk factors in dairy farms in Selangor, Malaysia. AB - The objectives of this cross-sectional study were to estimate the prevalence of lameness, claw lesions, and associated risk factors in dairy farms in Selangor, Malaysia. The sample population was 251 lactating cows from 8 farms assessed for lameness and claw lesions by locomotion scoring and claw assessment respectively while specific animal-based measures were hypothesized as cow-level risk factors. The Wilcoxon rank test and logistic regression were applied to assess the prevalence of lameness, claw lesions, and association with potential risk factors, respectively. The prevalence of lameness was 19.1% ranging from 10.0 to 33.3% while 31.1% of cows had claw lesions and ranged from 16.3-40%. Claw lesions were recorded in 87.5% of the lame cows with highest being those affected with sole lesions (54.2%) and white line disease (61.2%). Overall, the occurrence of overgrown claws, sole lesions, white line disease, and digital dermatitis were 37, 18.2, 10.9, and 8.3%, respectively. More than one claw lesion per cow was present in 71.8% of the affected cows. Lameness was associated with early lactation (OR = 3.3; 95% CI 2-7), injured hocks (OR = 4.8; 95% CI 5-17), and dirty legs hygiene (OR = 2.6; 95% CI 1.3-6.2), whereas presence of claw lesions was associated with dirty legs hygiene (OR = 4.7; 95% CI 4-11) and overgrown claw (OR = 2.7; 95% CI 1.4-5.3). To reduce the prevalence of lameness, farmers need to improve the management of cows with overgrown claw, injured hocks, and cleanliness by establishing routine claw trimming and efficient stall design. PMID- 28856535 TI - GluA4 Dependent Plasticity Mechanisms Contribute to Developmental Synchronization of the CA3-CA1 Circuitry in the Hippocampus. AB - During the course of development, molecular mechanisms underlying activity dependent synaptic plasticity change considerably. At immature CA3-CA1 synapses in the hippocampus, PKA-driven synaptic insertion of GluA4 AMPA receptors is the predominant mechanism for synaptic strengthening. However, the physiological significance of the developmentally restricted GluA4-dependent plasticity mechanisms is poorly understood. Here we have used microelectrode array (MEA) recordings in GluA4 deficient slice cultures to study the role of GluA4 in early development of the hippocampal circuit function. We find that during the first week in culture (DIV2-6) when GluA4 expression is restricted to pyramidal neurons, loss of GluA4 has no effect on the overall excitability of the immature network, but significantly impairs synchronization of the CA3 and CA1 neuronal populations. In the absence of GluA4, the temporal correlation of the population spiking activity between CA3-CA1 neurons was significantly lower as compared to wild-types at DIV6. Our data show that synapse-level defects in transmission and plasticity mechanisms are efficiently compensated for to normalize population firing rate at the immature hippocampal network. However, lack of the plasticity mechanisms typical for the immature synapses may perturb functional coupling between neuronal sub-populations, a defect frequently implicated in the context of developmentally originating neuropsychiatric disorders. PMID- 28856536 TI - Interleukin-8 and nuclear factor kappa B are increased and positively correlated in myelodysplastic syndrome. AB - The pathogenesis of myelodysplastic syndromes (MDS) is complex and depends on the interaction between aberrant hematopoietic cells and their microenvironment, probably including aberrations in cytokines and their signaling pathways. To evaluate interleukin-8 (IL-8) plasma levels and nuclear factor kappa B (NF-kB) in patients with MDS and to test possible correlation between IL-8 and NF-Kb, a total of 45 individuals were analyzed: 25 consecutive adult de novo MDS patients and 20 sex and age-matched healthy elderly volunteers. IL-8 analysis was performed by ELISA and activity of NF-kB by chemiluminescent assay. MDS patients showed higher level of IL-8 when compared to controls (p = 0.006). Patients aged 75 and above showed even higher levels (p = 0.035). NF-kB activity was significantly elevated in MDS patients when compared to controls (p < 0.0001) and higher in patients older than 75 years (p = 0.047). NF-kB activity was associated with higher serum ferritin (p = 0.042) and higher percentage of blasts (p = 0.028). A significant positive correlation between IL-8 and NF-kB was demonstrated (r = 0.480; p = 0.015). Many pathways involved in pathophysiology of MDS have been recently described, suggesting that an inflammatory process may act as a pathogenic driver. In this study, significantly elevated levels of IL-8 and NF-kB were demonstrated in MDS patients, with positive association of NF-kB with some markers of poor prognosis. A positive correlation between IL-8 and NF-kB suggests they cooperate as part of a complex networking of immune and inflammatory factors involved in MDS. PMID- 28856537 TI - The Treatment Effect of an ACE-Inhibitor Based Regimen with Perindopril in Relation to Beta-Blocker use in 29,463 Patients with Vascular Disease: a Combined Analysis of Individual Data of ADVANCE, EUROPA and PROGRESS Trials. AB - INTRODUCTION: In everyday practice, angiotensin converting enzyme inhibitors and beta-blockers are cornerstone treatments in patients with (cardio-)vascular disease. Clear data that evaluate the effects of the combination of these agents on morbidity and mortality are lacking. METHODS: In this retrospective pooled analysis of three large perindopril outcome trials (ADVANCE, EUROPA, PROGRESS), clinical outcomes were evaluated in 29,463 patients with vascular disease. Multivariate Cox regression analyses were performed in patients randomized to a perindopril-based regimen or placebo (treatment effect), and data were stratified according to background beta-blocker treatment. The primary endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and stroke. RESULTS: The cumulative incidence of the primary endpoint over mean follow-up of 4.0 years (Sd 1.0) was significantly lower in the beta blocker/perindopril group (9.6%; 545/5700 patients) as compared to beta blocker/placebo (11.8%; 676/5718 patients) (p < 0.01). Adding perindopril to existing beta-blocker treatment reduced the relative risk of the primary endpoint by 20% (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.71-0.90), non fatal myocardial infarction by 23% (HR 0.77; 95% CI 0.65-0.91), and all-cause mortality by 22% (HR 0.78; 95% CI 0.68-0.88) as compared to placebo. Significant treatment benefit was not observed for stroke (HR 0.93; 95% CI 0.75-1.15). Significance was maintained for the primary endpoint and cardiovascular endpoints when data were further stratified by baseline hypertension. However, the mortality benefit was only observed in patients with hypertension with background beta-blocker use. CONCLUSIONS: These data suggest that the beneficial cardioprotective effects of perindopril treatment are additive to the background beta-blockers use. PMID- 28856538 TI - UBR5 Contributes to Colorectal Cancer Progression by Destabilizing the Tumor Suppressor ECRG4. AB - BACKGROUND: The E3 ligase UBR5 is aberrantly expressed in diverse types of cancer. However, its expression pattern and biological function in colorectal cancer (CRC) remain unclear. METHODS: We used RT-PCR, Western blot, and immunohistochemistry to measure UBR5 expression in CRC tissues and corresponding non-tumor tissues. The expression pattern of UBR5 in CRC tissues was determined by scoring system of immunohistochemical analysis and mRNA level by RT-PCR. The statistical analyses were applied to evaluate the associations of UBR5 expression with survival rate of patients. The UBR5 gene was overexpressed or silenced with lentiviral vectors in CRC cells. And, cell proliferation and apoptosis were measured using CCK8 assay and flow cytometry. RESULTS: We found that UBR5 is abundantly overexpressed in CRC tissues than adjacent non-cancerous tissues. We also found that high UBR5 level is positively correlated with progression and poor survival in CRC patients. In addition, further multivariate analysis indicated that UBR5 and TNM stage were independent prognostic factors for overall survival in patients with CRC. Furthermore, we demonstrated that the expression of UBR5 was significantly elevated in CRC cell lines. Overexpression of UBR5 enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas silencing UBR5 suppressed growth of CRC cells. Moreover, our findings show that UBR5 promotes CRC cell proliferation by inducing cell cycle progression and suppressing cell apoptosis. Finally, we found that UBR5 directly binds to the tumor suppressor esophageal cancer-related gene 4 (ECRG4) and increased its ubiquitination to reduce the protein stability of ECRG4. CONCLUSIONS: We identified a tumorigenic role of UBR5 in CRC and provided a novel therapeutic target for CRC patients. PMID- 28856539 TI - Alcohol Types and HIV Disease Progression Among HIV-Infected Drinkers Not Yet on Antiretroviral Therapy in Russia and Uganda. AB - In HIV-infected drinkers, alcohol types more likely to cause inflammation could plausibly increase the risk of HIV disease progression. We therefore assessed the association between alcohol type and plasma HIV RNA level (HIV viral load) among HIV-infected drinkers not on antiretroviral therapy (ART) in Russia and Uganda. We analyzed the data of participants from cohorts in Russia and Uganda and assessed their HIV viral load at enrollment by the alcohol type predominantly consumed. We defined predominant alcohol type as the alcohol type contributing >50% of total alcohol consumption in the 1 month (Russia) or 3 months (Uganda) prior to enrollment. Using multiple linear regression, we compared log10 HIV viral load by predominant alcohol type, controlling for age, gender, socioeconomic status, total number of standard drinks, frequency of drinking >=6 drinks/occasion, and in Russia, history of injection drug use. Most participants (99.2% of 261 in Russia and 98.9% of 352 in Uganda) predominantly drank one alcohol type. In Russia, we did not find evidence for differences in viral load levels between drinkers of fortified wine (n = 5) or hard liquor (n = 49), compared to drinkers of beer/low-ethanol-content cocktails (n = 163); however, wine/high-ethanol-content cocktail drinkers (n = 42) had higher mean log10 viral load than beer/low-ethanol-content cocktail drinkers (beta = 0.38, 95% CI 0.07 0.69; p = 0.02). In Uganda, we did not find evidence for differences in viral load levels between drinkers of locally-brewed beer (n = 41), commercially distilled spirits (n = 38), or locally-distilled spirits (n = 43), compared to drinkers of commercially-made beer (n = 218); however, wine drinkers (n = 8) had lower mean log10 HIV viral load (beta = -0.65, 95% CI -1.36 to 0.07, p = 0.08), although this did not reach statistical significance. Among HIV-infected drinkers not yet on ART in Russia and Uganda, we observed an association between the alcohol type predominantly consumed and the HIV viral load level in the Russia sample. These exploratory results suggest that, in addition to total number of drinks and drinking patterns, alcohol type might be a dimension of alcohol use that merits examination in studies of HIV and alcohol related outcomes. PMID- 28856542 TI - Imaging behavioural complications of Parkinson's disease. AB - In addition to motor symptoms, behavioural complications are commonly found in patients with Parkinson's disease (PD). Behavioural complications, including depression, anxiety, apathy, impulse control disorder and psychosis, together have a large impact on PD patient's quality of life. Many neuroimaging studies using PET, SPECT and MRI techniques have been conducted to study the underlying neural mechanisms of PD pathogenesis and pathophysiology in relation to its behavioural complications. This review will survey these PET, SPECT and MRI studies to describe the current understanding of the neuro-chemical, functional and structural changes associated with behavioural complications in PD patients. PMID- 28856540 TI - Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models. AB - BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical worsening and high mortality. Early prediction of mortality and intervention can improve patient outcomes. We aimed to develop a dynamic prognostic model and compare it with the existing models. METHODS: A total of 1402 ACLF patients, enrolled in the APASL-ACLF Research Consortium (AARC) with 90-day follow-up, were analyzed. An ACLF score was developed in a derivation cohort (n = 480) and was validated (n = 922). RESULTS: The overall survival of ACLF patients at 28 days was 51.7%, with a median of 26.3 days. Five baseline variables, total bilirubin, creatinine, serum lactate, INR and hepatic encephalopathy, were found to be independent predictors of mortality, with AUROC in derivation and validation cohorts being 0.80 and 0.78, respectively. AARC-ACLF score (range 5-15) was found to be superior to MELD and CLIF SOFA scores in predicting mortality with an AUROC of 0.80. The point scores were categorized into grades of liver failure (Gr I: 5-7; II: 8-10; and III: 11 15 points) with 28-day cumulative mortalities of 12.7, 44.5 and 85.9%, respectively. The mortality risk could be dynamically calculated as, with each unit increase in AARC-ACLF score above 10, the risk increased by 20%. A score of >=11 at baseline or persisting in the first week was often seen among nonsurvivors (p = 0.001). CONCLUSIONS: The AARC-ACLF score is easy to use, dynamic and reliable, and superior to the existing prediction models. It can reliably predict the need for interventions, such as liver transplant, within the first week. PMID- 28856543 TI - Risk of depression, anxiety, and adjustment disorders in women with a suspected but unconfirmed diagnosis of breast or genital organ cancer in Germany. AB - BACKGROUND: Breast cancer (BC) and genital organ cancers (GOC) are known to have a major impact on the quality of life of patients. The aim of this study was to analyze the risk of depression, anxiety, and adjustment disorders in women in Germany with a suspected but unconfirmed diagnosis of BC or GOC in their medical history. METHODS: This study included women who received a suspected diagnosis of BC or GOC and were followed between 2007 and 2015 (index date). These women were matched (1:1:1) by age to women with a confirmed diagnosis of BC or GOC and women without a cancer diagnosis. The main outcome measure of the study was the rate of depression, anxiety, and adjustment disorder diagnoses within 3 years of the index date. RESULTS: The present analysis included a total of 4,842 patients (mean age = 49.3 years). Within 3 years of the index date, 23.5% of women with a confirmed diagnosis of BC or GOC, 14.1% of those with a suspected diagnosis of BC or GOC, and 10.5% of those without a cancer diagnosis developed depression, anxiety, or an adjustment disorder (log-rank p value <0.001). Women with a suspected diagnosis of cancer were at a higher risk for these psychiatric conditions than those without a cancer diagnosis (BC and GOC: HR 1.32; BC: HR 1.21; GOC: HR 1.50). CONCLUSION: A suspected diagnosis of BC or GOC in a woman's medical history is associated with an increased risk of developing depression, anxiety, and adjustment disorders. PMID- 28856541 TI - Glycoprotein NMB: an Emerging Role in Neurodegenerative Disease. AB - Neurodegeneration is characterized by severe neuronal loss leading to the cognitive and physical impairments that define various neurodegenerative diseases. Neuroinflammation is one hallmark of neurodegenerative diseases and can ultimately contribute to disease progression. Increased inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) are associated with Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Unfortunately, current therapeutic options lack ability to stop or effectively slow progression of these diseases and are primarily aimed at alleviating symptoms. Thus, it is crucial to discover novel treatment candidates for neurodegenerative diseases. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type-I transmembrane glycoprotein first identified in a melanoma cell line. GPNMB augments bone mineral deposition by stimulating osteoblast differentiation. Aside from its anabolic function in the bone, emerging evidence suggests that GPNMB has anti-inflammatory and reparative functions. GPNMB has also been demonstrated to be neuroprotective in an animal model of ALS, cerebral ischemia, and other disease models. Given these discoveries, GPNMB should be investigated as a potential therapeutic option for multiple neurodegenerative diseases. PMID- 28856544 TI - Molecular detection of pathogens in ticks infesting cattle in Nampula province, Mozambique. AB - Ticks are ectoparasites that can act as vectors of a large number of pathogens in wild and domestic animals, pets, and occasionally humans. The global threat of emerging or re-emerging tick-borne diseases supports the need for research focused in the zoonotic transmission, especially in countries like Mozambique where rural populations are in close contact with domestic animals. The present study aims to: (1) identify tick species infesting cattle from Monapo and Nacala Porto, districts of Nampula province, Mozambique; and (2) investigate the presence of pathogens in the collected ticks. A total of 646 ticks were collected from cattle and morphologically identified as Amblyomma variegatum, Rhipicephalus microplus, and R. evertsi evertsi. For convenience, 72 A. variegatum and 15 R. microplus from Monapo, and 30 A. variegatum from Nacala Porto were screened for the presence of the selected pathogens: Rickettsia spp. (A. variegatum), and Babesia/Theileria spp. and Anaplasma/Ehrlichia spp. (R. microplus). Rickettsia africae was detected in four of the 72 A. variegatum collected in Monapo (5.6%). Additionally, one R. microplus tick (6.7%) was positive for Theileria velifera, one positive for Colpodella spp., one positive for Candidatus Midichloria mitochondrii, and another one positive for Anaplasma ovis. Using the present approach, no microorganisms were detected in tick samples from Nacala Porto. These findings expand our knowledge about the repertoire of tick-borne microorganisms in ticks in Nampula province, Mozambique. PMID- 28856545 TI - Oxidative Folding of Conopeptides Modified by Conus Protein Disulfide Isomerase. AB - Protein disulfide isomerase is a type of enzyme that catalyses the oxidation, isomerization and reduction of disulfide bonds. Conotoxins that containing disulfide bonds are likely substrates of protein disulfide isomerise. Here, we cloned 12 protein disulfide isomerise genes from 12 different cone snail species that inhabited the sea near Sanya in China. The full-length amino acid sequences of these protein disulfide isomerase genes share a high degree of homology, including the same -CGHC- active site sequence and -RDEL- endoplasmic reticulum retention signal. To obtain enough conus protein disulfide isomerase for functional studies, we constructed the expression vector pET28a-sPDI. Conus protein disulfide isomerase was successfully expressed using Escherichia coli expression system and purified using chromatography method of affinity chromatography. The recombinant conus protein disulfide isomerase showed the ability to catalyse disulfide bond formation and rearrangement in the lysozyme enzyme activity assay. The role of conus protein disulfide isomerase in the in vitro oxidative folding of conotoxins was investigated using synthetic linear conotoxin lt14a, a peptide composed of 13 amino acids. It was confirmed by high performance liquid chromatography and mass spectrometry analysis that conus protein disulfide isomerase can catalyse the disulfide bond formation of linear lt14a. Then, conus protein disulfide isomerase was acted as a fusion partner during the production of engineered peptidyl-prolyl cis-trans isomerase and lt14a derived from cone snails. It was shown that peptidyl-prolyl cis-trans isomerase and conotoxin lt14a are successfully expressed in a highly soluble form by fusion with conus protein disulfide isomerase. Thus, conus protein disulfide isomerase functions not only as an enzyme that catalyses oxidative process but also a fusion partner in recombinant conotoxin expression. PMID- 28856547 TI - Learning a Foreign Language: A New Path to Enhancement of Cognitive Functions. AB - The complicated cognitive processes involved in natural (primary) bilingualism lead to significant cognitive development. Executive functions as a fundamental component of human cognition are deemed to be affected by language learning. To date, a large number of studies have investigated how natural (primary) bilingualism influences executive functions; however, the way acquired (secondary) bilingualism manipulates executive functions is poorly understood. To fill this gap, controlling for age, gender, IQ, and socio-economic status, the researchers compared 60 advanced learners of English as a foreign language (EFL) to 60 beginners on measures of executive functions involving Stroop, Wisconsin Card Sorting Task (WCST) and Wechsler's digit span tasks. The results suggested that mastering English as a foreign language causes considerable enhancement in two components of executive functions, namely cognitive flexibility and working memory. However, no significant difference was observed in inhibitory control between the advanced EFL learners and beginners. PMID- 28856546 TI - Role of Cardiac Magnetic Resonance Imaging in Myocardial Infarction. AB - PURPOSE OF REVIEW: The purpose of the present paper is to analytically review the diagnostic and prognostic role of CMR in ST-segment elevation myocardial infarction (STEMI) survivors. Percutaneous coronary intervention (PCI) is the treatment of choice in patients STEMI. However, risk of future events remains substantial. Assessment of the extent of myocardial infarction (MI), cardiac function and ventricular remodelling has become the focus of recent studies. Electrocardiography, angiography and echocardiography parameters, as well as risk scores, lack sensitivity and reproducibility in predicting future cardiovascular events. A major advantage of cardiac magnetic resonance imaging (CMR) is that it provides myocardial tissue characterization. RECENT FINDINGS: CMR is able to quantify both reversible and irreversible myocardial injury and correlates with future events. This review will illustrate how microvascular function indices (myocardial salvage index, presence and amount of microvascular obstruction and intramyocardial haemorrhage) detectable by CMR add prognostic information and could impact on future strategies to improve outcomes in revascularized patients. PMID- 28856548 TI - Risk of hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients with undetectable serum HBV DNA after treatment with rituximab for lymphoma: a meta analysis. AB - BACKGROUND: Hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (HBcAb)-positive patients with undetectable serum hepatitis B virus (HBV) DNA have experienced and resolved hepatitis B virus (HBV) infection. Lymphoma patients with resolved HBV infection have high risk of HBV reactivation when treated with robust immunosuppressive agents, but the reported rate varies extensively between different studies. This study aims to estimate the risk of HBV reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab containing chemotherapy for lymphoma. METHODS: Databases were searched for papers published in English until 8 August 2016. The pooled risk of HBV reactivation was estimated using a random-effects model. RESULTS: Data from 15 studies were retrieved, including a total of 1312 HBsAg-negative/HBcAb-positive lymphoma patients treated with rituximab-containing chemotherapy. The results revealed HBV reactivation rate of 9.0 % [95 % confidence interval (CI) 0.05-0.15]. In subgroup analysis, the reactivation rates for prospective and retrospective studies were 17 % (I 2 = 87.3 %; 95 % 0.08-0.39, p < 0.001) and 7 % (I 2 = 43.1 %; 95 % CI 0.05-0.11, p = 0.07), respectively. CONCLUSIONS: This meta-analysis confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg negative/HBcAb-positive patients with rituximab treatment for lymphoma. Prophylactic use of anti-HBV agents should be seriously considered for such patients. PMID- 28856549 TI - Elongation of very Long-Chain (>C24) Fatty Acids in Clarias gariepinus: Cloning, Functional Characterization and Tissue Expression of elovl4 Elongases. AB - Elongation of very long-chain fatty acid 4 (Elovl4) proteins participate in the biosynthesis of very long-chain (>C24) saturated and polyunsaturated fatty acids (FA). Previous studies have shown that fish possess two different forms of Elovl4, termed Elovl4a and Elovl4b. The present study aimed to characterize both molecularly and functionally two elovl4 cDNA from the African catfish Clarias gariepinus. The results confirmed that C. gariepinus possessed two elovl4-like elongases with high homology to two previously characterized Elovl4 from Danio rerio, and thus they were termed accordingly as Elovl4a and Elovl4b. The C. gariepinus Elovl4a and Elovl4b have open reading frames (ORF) of 945 and 915 base pairs, respectively, encoding putative proteins of 314 and 304 amino acids, respectively. Functional characterization in yeast showed both Elovl4 enzymes have activity towards all the PUFA substrates assayed (18:4n-3, 18:3n-6, 20:5n-3, 20:4n-6, 22:5n-3, 22:4n-6 and 22:6n-3), producing elongated products of up to C36. Moreover, the C. gariepinus Elovl4a and Elovl4b were able to elongate very long-chain saturated FA (VLC-SFA) as denoted by increased levels of 28:0 and longer FA in yeast transformed with elovl4 ORF compared to control yeast. These results confirmed that C. gariepinus Elovl4 play important roles in the biosynthesis of very long-chain FA. Tissue distribution analysis of elovl4 mRNAs showed both genes were widely expressed in all tissues analyzed, with high expression of elovl4a in pituitary and brain, whereas female gonad and pituitary had the highest expression levels for elovl4b. PMID- 28856551 TI - U.S. Primary Care Clinics' Experiences During Introduction of the 9-Valent HPV Vaccine. AB - Changes in the routine immunization schedule are common and may pose challenges to primary care clinics. We sought to assess the experiences of U.S. providers and clinic staff during the introduction of 9-valent HPV vaccine. In 2015-2016, we conducted a survey in a probability sample of 127 pediatric (40%) and family medicine (60%) clinics in three U.S. states. The 211 respondents included clinicians (63%) and staff (37%). Overall, 83% of clinics stocked 9-valent HPV vaccine, with adoption ranging from 60% among early respondents to 100% among later respondents. Almost all respondents believed that providers in their clinics would recommend the 9-valent vaccine as strongly as (66%) or more strongly than (33%) the quadrivalent vaccine. Over half (61%) had no concerns about the 9-valent vaccine, while others reported concerns about increased parental hesitancy (29%), private insurance coverage (17%), or other issues (10%). Respondents from pediatric versus family medicine clinics more often reported a concern (OR = 2.06, 95% CI 1.02-4.15). Among the 169 respondents who stocked 9-valent vaccine, about half (56%, n = 94) anticipated that providers in their clinics would recommend a "booster" dose of 9-valent HPV vaccine for adolescents who had completed the 3-dose series with prior versions. Among the 42 respondents who did not stock 9-valent vaccine, few (17%, n = 7) believed providers would recommend adolescents delay vaccination until it was available. In conclusion, providers and staff generally had positive views of 9-valent HPV vaccine and many had no concerns. For others, responses regarding parental hesitancy, insurance coverage, and the use of booster doses suggests opportunities for enhancing future educational support. PMID- 28856552 TI - Behavioral Markers of Emergent Stranger Anxiety in Infants and Toddlers with Fragile X Syndrome. AB - Studying anxiety in neurogenetic syndromes may inform the intersection of biological and developmental risks, facilitating effective and targeted interventions. We longitudinally examined stranger fear in infants and toddlers with fragile X syndrome (FXS; n = 46) and typical controls (n = 33), as well as associations between observed stranger fear and rating scales of anxiety, withdrawal and autism features within FXS. Results indicated atypical facial fear in FXS, although facial fear did not index anxiety, autistic symptoms or social withdrawal. Instead, lower withdrawal was associated with decreased distress vocalizations across age, and higher autistic symptoms were associated with lower intensity escape behaviors. Early stranger fear in FXS reflects both typical and atypical dimensions and may help index emergence of social anxiety in this population. PMID- 28856550 TI - Frequency and clinical significance of chromosome 7 and 10 aneuploidies, amplification of the EGFR gene, deletion of PTEN and TP53 genes, and 1p/19q deficiency in a sample of adult patients diagnosed with glioblastoma from Southern Brazil. AB - Glioblastoma stands out as the most frequent central nervous system neoplasia, presenting a poor prognosis. The aim of this study was to verify the frequency and clinical significance of the aneuploidy of chromosomes 7 and 10, EGFR amplification, PTEN and TP53 deletions and 1p/19q deficiency in adult patients diagnosed with glioblastoma. The sample consisted of 40 patients treated from November 2011 to March 2015 at two major neurosurgery services from Southern Brazil. Molecular cytogenetic analyses of the tumor were performed through fluorescent in situ hybridization (FISH). The clinical features evaluated consisted of age, sex, tumor location, clinical symptoms, family history of cancer, type of resection and survival. The mean age of the patients was 59.3 years (ranged from 41 to 83). Most of them were males (70%). The median survival was 145 days. Chromosome 10 monosomy was detected in 52.5% of the patients, chromosome 7 polysomy in 50%, EGFR amplification in 42.5%, PTEN deletion in 35%, TP53 deletion in 22.5%, 1p deletion in 5% and 19q deletion in 7.5%. Age was shown to be a prognostic factor, and patients with lower age presented higher survival (p = 0.042). TP53 and PTEN deletions had a negative impact on survival (p = 0.011 and p = 0.037, respectively). Our data suggest that TP53 and PTEN deletions may be associated with a poorer prognosis. These findings may have importance over prognosis determination and choice of the therapy to be administered. PMID- 28856553 TI - Improving Naming Abilities Among Healthy Young-Old Adults Using Transcranial Direct Current Stimulation. AB - Transcranial direct current stimulation (tDCS) is a noninvasive tool to facilitate brain plasticity and enhance language abilities. Our study aims to search for a potential beneficial influence of tDCS on a cognitive linguistic task of naming which found to decline during aging. A group of fifteen healthy old adults [Formula: see text] were tested in naming 50 pictures of objects. Each subject participated in two sessions spanning on a one week period. One session included active tDCS stimulation and the other sham-placebo like stimulation. Subjects were blinded to stimulation type. During the active stimulation a bilateral protocol of anodal tDCS to the left Inferior Frontal Gyrus (IFG) combined with cathodal tDCS to the right IFG was delivered. Half of participants received active stimulation at the first session and sham at the second and half received the stimulations at the opposite order. Naming reaction time was measured at baseline, after active tDCS stimulation and after sham. 10 min of bilateral tDCS stimulation which was given after sham (training) was found to reduce naming reaction time among healthy adult subjects. These findings support the cooperative model (Weems and Reggia in Brain Lang 89:554-568, 2004) and point on strong interhemispheric connections during naming processing. It is also demonstrate the advantage of training to intensify the therapeutic effect of tDCS. Our results pinpoint on a potential tool to facilitate naming among aging people. PMID- 28856554 TI - Inter-observer agreement among pathologists in grading the pathological response to neoadjuvant chemotherapy in breast cancer. AB - BACKGROUND: The degree of pathological response to neoadjuvant chemotherapy (NAC) was correlated with the prognosis in breast cancer. There are few studies published on inter-observer variability in the assessment of pathological responses among pathologists. METHODS: We collected 64 surgically resected specimens from patients who had received NAC. Three pathologists assessed the pathological responses and classified them into 7 grades according to grading system of the Japanese Breast Cancer Society. The levels of concordance among pathologists were categorized into 3 classes: full concordance (all pathologists gave the same grade), partial concordance (two of them gave the same grade), and discordance (all three gave different grades). The inter-observer agreement among pathologists was estimated using the percentage concordance and Cohen's kappa statistics. RESULTS: Full concordance, partial concordance, and discordance were seen in 28 (43%), 33 (52%), and 3 (5%) specimens, respectively. In most of partial concordance specimens (30 out of 33), the pathological response grades differed by only one level. The kappa value was 0.59. The concordance rate with regard to pCR was 97%. CONCLUSIONS: Most of the judgments among pathologists differed within one level, but there is room for improving harmonization in the assessment of pathological responses. PMID- 28856555 TI - Retinal thickness as a marker of disease progression in longitudinal observation of patients with Wolfram syndrome. AB - AIMS: Wolfram syndrome (WFS) is a recessively inherited monogenic form of diabetes coexisting with optic atrophy and neurodegenerative disorders with no currently recognized markers of disease progression. The aim of the study was to evaluate retinal parameters by using optical coherence tomography (OCT) in WFS patients after 2 years of follow-up and analysis of the parameters in relation to visual acuity. METHODS: OCT parameters and visual acuity were measured in 12 WFS patients and 31 individuals with type 1 diabetes. RESULTS: Total thickness of the retinal nerve fiber layer (RNFL), average retinal thickness and total retinal volume decreased in comparison with previous OCT examination. Significant decreases were noted for RNFL (average difference -17.92 um 95% CI -30.74 to 0.10; p = 0.0157), macular average thickness (average difference -5.38 um 95% CI 10.63 to -2.36; p = 0.0067) and total retinal volume (average difference -0.15 mm3 95% CI -0.30 to -0.07; p = 0.0070). Central thickness remained unchanged (average difference 1.5 um 95% CI -7.61 to 10.61; p = 0.71). Visual acuity of WFS patients showed a strong negative correlation with diabetes duration (R = -0.82; p = 0.0010). After division of WFS patients into two groups (with low-vision and blind patients), all OCT parameters except for the RNFL value were lower in blind WFS patients. CONCLUSIONS: OCT measures structural parameters and can precede visual acuity loss. The OCT study in WFS patients should be performed longitudinally, and serial retinal examinations may be helpful as a potential end point for future clinical trials. PMID- 28856556 TI - Association between echocardiographic epicardial adipose tissue and E/e' ratio in obese adults. PMID- 28856557 TI - Endothelial Cells Promote Formation of Medulloblastoma Stem-Like Cells via Notch Pathway Activation. AB - The aim of the study is to investigate whether endothelial cells (ECs) promoted the capacity of stem-like cell formation in medulloblastoma (MB) and whether the mechanism of action was associated with mediation of Notch signaling pathway. Co culture experiment was conducted to particularly understand the potential role of ECs in promoting phenotype and gene expression of MB stem-like cells. Self renewal capacity and tumor cell population were measured by sphere-forming assay and flow cytometry, respectively. To further clarify the effects of ECs on the formation of MB stem-like cells, the expression of genes and protein in MB stem like cells (CCND1, CDK6, c-MYC, and Bmi-1) and Notch (Notch2, Jagged 1, Hes-1, and Hey-2) was quantified by quantitative real-time PCR (qRT-PCR) and western blot, respectively. Also, observed mediation of ECs in regulation of tumor cell stemness by Notch activation was observed when the co-cultures were treated with gamma-secretase inhibitor (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S phenylglycine t-butyl ester (DAPT)). Further investigation was conducted for the effects of ECs on the tumorigenesis in vivo of MB cells when co-cultures were inoculated into a nude mouse after treated with DAPT. Afterwards, tumor size and volume were measured. The sphere-forming rate and cell ratio of stem-like cells were significantly increased. Furthermore, the expression of genes and protein in stem-like cells and Notch was obviously upregulated although treated with gamma secretase inhibitor. Moreover, tumor size and volume were dramatically magnified. This study revealed that Notch pathway activation played a key role in the formation of stem-like cells in MB and had valuable meaning for further investigation of targeted therapies. PMID- 28856559 TI - Introducing Motivational Interviewing in a Sickness Insurance Context: Translation and Implementation Challenges. AB - Purpose Motivational interviewing (MI) is a conversational method to support clients in need of behavioral change. In an organizational reform, most Swedish sickness insurance officials were trained in MI to promote clients' return to work (RTW) after sick leave. The aim of this article is to investigate experiences of introducing MI as a tool to promote clients' RTW within a sickness insurance context, with special focus on the translation and implementation of the method. Methods A qualitative approach, comprising 69 interviews with officials, managers, and regional coordinators on two occasions. The material was analyzed through qualitative content analysis. Results Officials were positive about MI, but the application was limited to using certain tools with extensive individual variation. Officials struggled with translating MI into a sickness insurance context, where the implementation strategy largely failed to offer adequate support, due to low managerial priority, competing initiatives, and a high workload. Results of the educational intervention could therefore be seen on an individual but not an organizational level. Conclusions In order to translate MI into a sickness insurance context, training needs to be supported by organizational approaches that promote collective learning and sharing of experiences among officials. The results also illustrate how a method cannot be assumed to be implemented simply because training has been provided. Consequently, the application of the method needs to be carefully monitored in studies of interventions where MI is claimed to be used, in order to measure its effectiveness. PMID- 28856558 TI - Religious Attendance and Body Mass: An Examination of Variations by Race and Gender. AB - Studies of the association between religious attendance and body mass have yielded mixed results. In this paper, we consider intersectional variations by race and gender to advance our understanding of these inconsistencies. We use data from the 2006-2008 Health and Retirement Study to examine the association between religious attendance and three indicators of body mass: overall body mass index, waist circumference, and waist-to-height ratio (n = 11,457). For White women, attendance is either protective or unrelated to body mass. For Black women, attendance is consistently associated with increased body mass. We find that religious attendance is not associated with body mass among the men. PMID- 28856560 TI - Ensemble Classifiers for Predicting HIV-1 Resistance from Three Rule-Based Genotypic Resistance Interpretation Systems. AB - Resistance to antiretrovirals (ARVs) is a major problem faced by HIV-infected individuals. Different rule-based algorithms were developed to infer HIV-1 susceptibility to antiretrovirals from genotypic data. However, there is discordance between them, resulting in difficulties for clinical decisions about which treatment to use. Here, we developed ensemble classifiers integrating three interpretation algorithms: Agence Nationale de Recherche sur le SIDA (ANRS), Rega, and the genotypic resistance interpretation system from Stanford HIV Drug Resistance Database (HIVdb). Three approaches were applied to develop a classifier with a single resistance profile: stacked generalization, a simple plurality vote scheme and the selection of the interpretation system with the best performance. The strategies were compared with the Friedman's test and the performance of the classifiers was evaluated using the F-measure, sensitivity and specificity values. We found that the three strategies had similar performances for the selected antiretrovirals. For some cases, the stacking technique with naive Bayes as the learning algorithm showed a statistically superior F-measure. This study demonstrates that ensemble classifiers can be an alternative tool for clinical decision-making since they provide a single resistance profile from the most commonly used resistance interpretation systems. PMID- 28856562 TI - Cardiac safety profile of patients receiving high cumulative doses of pegylated liposomal doxorubicin: use of left ventricular ejection fraction is of unproven value. AB - PURPOSE: One of the great conundrums for both oncologists and cardiologists is how to best monitor the potential and actual cardiotoxicity of doxorubicin. Pegylated-liposomal doxorubicin (PLD) has a safer cardiotoxicity profile than bolus administration of doxorubicin. Although ejection fraction (EF) is commonly performed to monitor doxorubicin-induced cardiotoxicity, evidence for its predictive utility is limited. We examined the incidence of doxorubicin-induced heart failure (HF) in patients who received a large cumulative dose of doxorubicin as PLD and its relation to EF and HF. METHODS: A retrospective chart review of patients who received a large cumulative dose of PLD, sometimes after previous free doxorubicin treatment, was performed to examine the incidence of doxorubicin-induced heart failure (HF) and its relation to EF and development of HF. RESULTS: No definite doxorubicin-induced clinical HF was observed among 56 patients (median age 54; 15-93) who received a cumulative doxorubicin dose (free + PLD) of >450 mg/m2. Of these, 49 received >500 mg/m2, 28 > 700 mg/m2, 19 > 800 mg/m2, 14 > 1000 mg/m2, and 5 > 1400 mg/m2. The EF varied greatly over time in some patients treated with PLD in the absence of symptoms or signs of heart failure, and was not particularly useful in making decisions regarding further dosing. CONCLUSIONS: Pegylated-liposomal doxorubicin was associated with a low risk of doxorubicin-induced HF in a retrospective cohort of patients receiving large cumulative doses of doxorubicin and long-term follow-up. EF did not predict doxorubicin-induced cardiotoxicity in our cohort of adult patients receiving PLD. Given the lack of prognostic clarity regarding modest EF changes, regular EF monitoring may not be warranted, at least when PLD is used in adults. Modest changes in EF should probably not be used to limit a patient's access to PLD, but may warrant cardiology consultation for long-term follow-up after completion of therapy. PMID- 28856563 TI - Mercury release during thermal treatment of two Chinese coal gangues. AB - The utilization of coal gangue in power plants has become a new anthropogenic discharge source of mercury and attracted much concern in China. It is crucial to obtain the information about the mercury release during thermal treatment of coal gangue. In this study, the mercury release behavior of two coal gangues selected from two power plants were studied under different thermal treatment conditions of heating rate, residence time, and atmosphere. The results of mercury release profile show that the specified release temperature ranges for the different modes of occurrence of Hg are scarcely affected by the heating rate of 10, 20, and 40 degrees C/min. A higher heating rate could promote the Hg release to some extent. The mercury release ratio gradually increases with the extension of residence time for both coal gangues. The oxidizing environment has a positive effect on mercury release < 600 degrees C and has a minor effect > 600 degrees C. Mercury in coal gangue is more volatile than coal gangue matrix and the mercury in GD coal gangue is more easily released out than that in ED coal gangue. PMID- 28856561 TI - Site-selective 13C labeling of histidine and tryptophan using ribose. AB - Experimental studies on protein dynamics at atomic resolution by NMR-spectroscopy in solution require isolated 1H-X spin pairs. This is the default scenario in standard 1H-15N backbone experiments. Side chain dynamic experiments, which allow to study specific local processes like proton-transfer, or tautomerization, require isolated 1H-13C sites which must be produced by site-selective 13C labeling. In the most general way this is achieved by using site-selectively 13C enriched glucose as the carbon source in bacterial expression systems. Here we systematically investigate the use of site-selectively 13C-enriched ribose as a suitable precursor for 13C labeled histidines and tryptophans. The 13C incorporation in nearly all sites of all 20 amino acids was quantified and compared to glucose based labeling. In general the ribose approach results in more selective labeling. 1-13C ribose exclusively labels His delta2 and Trp delta1 in aromatic side chains and helps to resolve possible overlap problems. The incorporation yield is however only 37% in total and 72% compared to yields of 2-13C glucose. A combined approach of 1-13C ribose and 2-13C glucose maximizes 13C incorporation to 75% in total and 150% compared to 2-13C glucose only. Further histidine positions beta, alpha and CO become significantly labeled at around 50% in total by 3-, 4- or 5-13C ribose. Interestingly backbone CO of Gly, Ala, Cys, Ser, Val, Phe and Tyr are labeled at 40-50% in total with 3-13C ribose, compared to 5% and below for 1-13C and 2-13C glucose. Using ribose instead of glucose as a source for site-selective 13C labeling enables a very selective labeling of certain positions and thereby expanding the toolbox for customized isotope labeling of amino-acids. PMID- 28856564 TI - The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions. AB - Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3-7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further. PMID- 28856565 TI - Insights into the mercury(II) adsorption and binding mechanism onto several typical soils in China. AB - To better understand the Hg(II) adsorption by some typical soils and explore the insights about the binding between Hg(II) and soils, a batch of adsorption and characteristic experiments was conducted. Results showed that Hg(II) adsorption was well fitted by the Langmuir and Freundlich. The maximum adsorption amount of cinnamon soil (2094.73 mg kg-1) was nearly tenfold as much as that of saline soil (229.49 mg kg-1). The specific adsorption of Hg(II) on four soil surface was confirmed by X-ray photoelectron spectroscopy (XPS) owing to the change of elemental bonding energy after adsorption. However, the specific adsorption is mainly derived from some substances in the soil. Fourier transform infrared spectroscopy (FTIR) demonstrated that multiple oxygen-containing functional groups (O-H, C=O, and C-O) were involved in the Hg(II) adsorption, and the content of oxygen functional groups determined the adsorption capacity of the soil. Meanwhile, scanning electron microscopy combined with X-ray energy dispersive spectrometer (SEM-EDS) more intuitive revealed the binding of mercury to organic matter, metal oxides, and clay minerals in the soil and fundamentally confirmed the results of XPS and FTIR to further elucidate adsorptive phenomena. The complexation with oxygen-containing functional groups and the precipitation with minerals were likely the primary mechanisms for Hg(II) adsorption on several typical soils. This study is critical in understanding the transportation of Hg(II) in different soils and discovering potential preventative measures. PMID- 28856567 TI - [Assement of incapacity to work and the Mini-ICF-APP]. AB - OBJECTIVE: According to recent recommendations the Mini-ICF Rating for Limitations of Activities and Participation in Psychological Disorders (Mini-ICF APP) should be used in the assessment of incapacity to work. However evidence from empirical research in the field is missing. METHODS: The application of the Mini-ICF-APP in the psychiatric assessment of 121 cases was analysed. RESULTS: A significant correlation between capacity to work and the duration of sick-leave with the Mini-ICF-APP sum-score was confirmed. The probability that criteria for disability insurance compensations was fulfilled according to the assessor increased with the Mini-ICF-APP-sum-score. CONCLUSION: Our study provides first empirical evidence regarding the application of the Mini-ICF-APP in the psychiatric assessment of incapacity to work. PMID- 28856566 TI - Cold Environment Exacerbates Brain Pathology and Oxidative Stress Following Traumatic Brain Injuries: Potential Therapeutic Effects of Nanowired Antioxidant Compound H-290/51. AB - The possibility that traumatic brain injury (TBI) occurring in a cold environment exacerbates brain pathology and oxidative stress was examined in our rat model. TBI was inflicted by making a longitudinal incision into the right parietal cerebral cortex (2 mm deep and 4 mm long) in cold-acclimatized rats (5 degrees C for 3 h daily for 5 weeks) or animals at room temperature under Equithesin anesthesia. TBI in cold-exposed rats exhibited pronounced increase in brain lucigenin (LCG), luminol (LUM), and malondialdehyde (MDA) and marked pronounced decrease in glutathione (GTH) as compared to identical TBI at room temperature. The magnitude and intensity of BBB breakdown to radioiodine and Evans blue albumin, edema formation, and neuronal injuries were also exacerbated in cold exposed rats after injury as compared to room temperature. Nanowired delivery of H-290/51 (50 mg/kg) 6 and 8 h after injury in cold-exposed group significantly thwarted brain pathology and oxidative stress whereas normal delivery of H-290/51 was neuroprotective after TBI at room temperature only. These observations are the first to demonstrate that (i) cold aggravates the pathophysiology of TBI possibly due to an enhanced production of oxidative stress, (ii) and in such conditions, nanodelivery of antioxidant compound has superior neuroprotective effects, not reported earlier. PMID- 28856568 TI - Nutritional status using subjective global assessment independently predicts outcome of patients waiting for living donor liver transplant. AB - BACKGROUND: Malnutrition is an important risk factor for adverse outcomes in patients awaiting liver transplant. Living donor liver transplant, being an elective procedure, allows nutritional rehabilitation and optimization of these patients before transplant. AIM: This paper aimed to evaluate the outcome of end stage liver disease (ESLD) patients with various degrees of malnutrition waiting for living donor liver transplant. METHODS: Nutritional status was assessed using subjective global assessment (SGA) in patients who were evaluated for a liver transplant at our center from January 2015 to September 2015. All the data were collected prospectively. Predictive factors for mortality were analyzed using logistic regression and survival was obtained using Kaplan-Meier curves. RESULTS: One hundred and seventeen patients were grouped based on their nutrition status into normal, mild-moderate, and severe malnutrition. The groups were comparable in terms of age, sex, etiology of liver disease except alcoholic liver disease. Graft recipient weight ratio was comparable among groups. There was no significant difference in hospital stay. However, severe malnourished patients had higher incidence of sepsis (p=0.005) and death due to sepsis (p=0.01). Nutritional status was the only independent predictor of mortality on multivariate analysis. CONCLUSION: Nutritional status measured with SGA independently predicts short-term outcome of ESLD patients waiting and after living donor liver transplant. PMID- 28856569 TI - Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Elderly Volunteers. AB - : BACKGROUND AND OBJECTIVES: The combination of cromolyn and ibuprofen is being investigated as a treatment for early Alzheimer's disease (AD). This study investigated the pharmacokinetics, safety, and tolerability of cromolyn and ibuprofen co-administration in healthy elderly adult volunteers. METHODS: In this open-labeled study, 26 subjects, aged 55-75 years, received co-administration of inhaled cromolyn (single dose 17.1 mg; double dose 34.2 mg total) and oral ibuprofen (single dose 10 mg; double dose 20 mg total). Blood sampling was performed for 6 h after co-administration in all subjects; cerebrospinal fluid (CSF) was collected in three to four subjects per cohort for 4 h following co administration. Safety parameters, including adverse events (AEs), were monitored throughout the study. RESULTS: For cromolyn, the mean (+/-SD) maximum observed concentration (C max) in plasma was 46.69 +/- 32.97 and 96.75 +/- 46.22 ng/ml after single- and double-dose inhalation, respectively [time to C max (t max) ~22 min for each; terminal elimination half-life (t 1/2) ~1.8 h for each]. For ibuprofen, the plasma C max was 1090.98 +/- 474.64 ng/ml and 2062.96 +/- 655.13 ng/ml after single- and double-dose oral administration, respectively (t max ~1.6 1.8 h; t 1/2 ~1.9 h for each). For cromolyn, the CSF C max was 0.24 +/- 0.08 ng/ml at 3.72 +/- 0.70 h after single-dose administration and 0.34 +/- 0.17 ng/ml at 3.45 +/- 0.95 h after double-dose administration, and for ibuprofen, the CSF C max was 3.94 +/- 1.29 ng/ml at 2.55 +/- 0.96 h after single-dose administration and 8.93 +/- 3.29 ng/ml at 3.15 +/- 1.05 h after double-dose administration. Three (12%) subjects reported mild or moderate AEs which were unlikely to be related to study drug. CONCLUSIONS: The combination of cromolyn and ibuprofen was safe and well tolerated. The concentrations of cromolyn and ibuprofen observed in the CSF are considered sufficient to titrate the estimated daily amyloid production and the associated inflammatory response in patients with AD. PMID- 28856570 TI - SIRT6 knockout cells resist apoptosis initiation but not progression: a computational method to evaluate the progression of apoptosis. AB - Apoptosis is essential for numerous processes, such as development, resistance to infections, and suppression of tumorigenesis. Here, we investigate the influence of the nutrient sensing and longevity-assuring enzyme SIRT6 on the dynamics of apoptosis triggered by serum starvation. Specifically, we characterize the progression of apoptosis in wild type and SIRT6 deficient mouse embryonic fibroblasts using time-lapse flow cytometry and computational modelling based on rate-equations and cell distribution analysis. We find that SIRT6 deficient cells resist apoptosis by delaying its initiation. Interestingly, once apoptosis is initiated, the rate of its progression is higher in SIRT6 null cells compared to identically cultured wild type cells. However, SIRT6 null cells succumb to apoptosis more slowly, not only in response to nutrient deprivation but also in response to other stresses. Our data suggest that SIRT6 plays a role in several distinct steps of apoptosis. Overall, we demonstrate the utility of our computational model to describe stages of apoptosis progression and the integrity of the cellular membrane. Such measurements will be useful in a broad range of biological applications. PMID- 28856571 TI - IRF-8 is Involved in Amyloid-beta1-40 (Abeta1-40)-induced Microglial Activation: a New Implication in Alzheimer's Disease. AB - It is well known that extracellular deposition of amyloid-beta (Abeta) peptide and microglia-mediated neuroinflammation are major hallmarks of Alzheimer's disease (AD). Interferon regulatory factor-8 (IRF-8), an important transcription factor of the IRF family, is highly restricted in microglia in brains. The expression pattern and function of IRF-8 in AD need to be elucidated in order to provide novel therapies for the treatment of AD. In this study, our results indicated that expression of IRF-8 is significantly elevated in the brains and microglia of AD transgenic model Tg2576 mice. Notably, in vitro cell culture and reporter luciferase assay show that Abeta1-40 treatment promotes expression of IRF-8 at the transcriptional level. Silencing of IRF-8 in microglia abolished Abeta1-40-induced elevation in typical activated microglia-related genes, including the microglial innate response receptor toll-like receptor 2 (TLR2), the chemotaxis gene purinergic receptor P2Y12R, and the proinflammatory cytokine IL-1beta. However, overexpression of IRF-8 exacerbated the elevated expression of these proteins. Finally, the JAK2/STAT-1 pathway was found to mediate Abeta1-40 induced elevation of IRF-8. Overall, this is the first time to report that IRF-8 is involved in microglial activation and neuroinflammation in AD. PMID- 28856572 TI - Safety of Antiplatelet Agents: Analysis of 'Real-World' Data from the Italian National Pharmacovigilance Network. AB - INTRODUCTION: According to the Italian National Report on drug use, thienopyridines (ticlopidine, clopidogrel and prasugrel) and ticagrelor represent the most prescribed antiplatelet agents, beside aspirin. The aim of this study was to analyse the safety profile of these drugs using data from spontaneous reporting of suspected adverse reactions (ADRs). METHODS: Suspected ADRs for ticlopidine, clopidogrel, prasugrel and ticagrelor, reported on the Italian National Pharmacovigilance Network between January 2009 and December 2016, were included in the analysis. All suspected ADRs were classified by frequency, seriousness, outcome, age and system organ class. RESULTS: Clopidogrel showed the highest absolute number of suspected ADRs, followed by ticlopidine. However, these data need to be contextualized in view of the differences in marketing authorization dates, prescription rates and a characterization of the relative seriousness of ADRs per each drug. After the correction for prescription rate, ticagrelor showed the highest reporting trend and ticlopidine the lowest. Most ADRs occurred in the elderly, in particular for ticlopidine. Bleeding represents one of the most reported events (ticlopidine 40%, clopidogrel 26%, prasugrel 42%, ticagrelor 30%) and aspirin was the most frequently associated suspected drug. The majority of ADRs had complete recovery and were non-serious, except for ticlopidine (serious ADRs 53%). Prasugrel showed the highest percentage of 'life threatening' events and 'death'. CONCLUSIONS: Based on the analysis conducted on spontaneous ADRs reporting system in Italy, the safety profile of antiplatelet drugs seems favourable. However, the overall risk-benefit ratio of these drugs needs to be reassessed taking into account the appropriateness of use in particular populations at risk, such as the elderly. Based on this information, we believe that more attention from clinicians and/or an implementation of regulatory measures could be useful for clinical practice. PMID- 28856573 TI - Population growth rate of dry bulb mite, Aceria tulipae (Acariformes: Eriophyidae), on agriculturally important plants and implications for its taxonomic status. AB - Dry bulb mite (DBM), Aceria tulipae, is an economically important mite with a worldwide distribution and a broad host range. As a generalist, it is the most important eriophyoid mite attacking bulbous plants such as garlic, onion and tulip. To date, DBM has been recorded on host plants belonging to the families Liliaceae, Amaryllidaceae, Melanthiaceae and Asparagaceae. However, a precise understanding of DBM host range is lacking as it is largely based on casual records of mites on plants, some of which may include accidental hosts. Moreover, the possible existence of cryptic species has not been considered. In this study the hypothesis that DBM may be a complex of distinct genetic lineages or cryptic species was tested by comparing the common barcode sequence marker mtDNA COI of specimens from several populations originating from the Netherlands and Poland. The population growth rate of DBM on seven agriculturally important plant species and on various parts of the garlic plant was also experimentally assessed in the laboratory. The results did not support the first hypothesis, and indicated that DBM populations originating from Poland and the Netherlands shared essentially the same genome. In addition, they indicated that DBM reached the highest population growth rate on leek and also displayed high growth rates on garlic, chive and red onion, whereas white onion and wheat were not colonized by the mites. Answering the question of whether DBM is a single polyphagous species rather than a complex of cryptic lineages is of particular importance since the misidentification of pests may lead to ineffective control strategies. Moreover, improved knowledge of DBM host range is essential for assessing risk to crops. PMID- 28856574 TI - Aluminum Chloride Causes the Dysfunction of Testes Through Inhibiting the ATPase Enzyme Activities and Gonadotropin Receptor Expression in Rats. AB - The aim of this experiment is to explore the effects of aluminum chloride (AlCl3) on the ATPase enzymes and gonadotropin receptors in the testes. Eighty male Wistar rats were orally exposed to 0 mg/kg body weight (BW) (control group, CG), 64 mg/kg BW (low-dose group, LG), 128 mg/kg BW (mid-dose group, MG), or 256 mg/kg BW (high-dose group, HG) for 120 days. The microstructure and ultrastructure of testes; the activities of Na+-K+-ATPase, Mg2+-ATPase, and Ca2+-ATPase; and the mRNA and protein expressions of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptors (LHR) in the testes were examined. The results showed that the testes histological structure were damaged; the activities of Na+ K+-ATPase, Mg2+-ATPase, and Ca2+-ATPase, the mRNA and protein expressions of FSHR and LHR in the testes were all decreased in the rats with AlCl3 exposure. It indicates that AlCl3 causes the dysfunction of testes in rats. PMID- 28856575 TI - Muscle-Bone Interactions in Pediatric Bone Diseases. AB - PURPOSE: Here, we review the skeletal effects of pediatric muscle disorders as well as muscle impairment in pediatric bone disorders. RECENT FINDINGS: When starting in utero, muscle disorders can lead to congenital multiple contractures. Pediatric-onset muscle weakness such as cerebral palsy, Duchenne muscular dystrophy, spinal muscular atrophy, or spina bifida typically are associated with small diameter of long-bone shafts, low density of metaphyseal bone, and increased fracture incidence in the lower extremities, in particular, the distal femur. Primary bone diseases can affect muscles through generic mechanisms, such as decreased physical activity or in disease-specific ways. For example, the collagen defect underlying the bone fragility of osteogenesis imperfecta may also affect muscle force generation or transmission. Transforming growth factor beta released from bone in Camurati Engelman disease may decrease muscle function. FUTURE DIRECTIONS: Considering muscle-bone interactions does not only contribute to the understanding of musculoskeletal disorders but also can identify new targets for therapeutic interventions. PMID- 28856576 TI - Changes in transcranial motor evoked potentials during hemorrhage are associated with increased serum propofol concentrations. AB - Transcranial motor evoked potentials (TcMEPs) monitor the integrity of the spinal cord during spine surgery. Propofol-based anesthesia is favored in order to enhance TcMEP quality. During intraoperative hemorrhage, TcMEP amplitudes may be reduced. The serum concentration of propofol may increase during hemorrhage. No study has determined whether changes in TcMEPs due to hemorrhage are related to changes in propofol blood levels. We monitored TcMEPs, mean arterial pressure (MAP), and cardiac output (CO) and hemoglobin in pigs (n = 6) undergoing controlled progressive hemorrhage during a standardized anesthetic with infusions of propofol, ketamine, and fentanyl. We recorded TcMEPs from the rectus femoris (RF) and tibialis anterior (TA) muscles bilaterally. A pulmonary artery catheter was placed to measure CO. Progressive hemorrhage of 10% blood volume increments was done until TcMEP amplitude decreased by >60% from baseline. Serum propofol levels were also measured following removal of each 10% blood volume increment. TcMEP responses were elicited every 3 min using constant stimulation parameters. We removed between 20 and 50% of total blood volume in order to achieve the >60% reduction in TcMEP amplitude. MAP and CO decreased significantly from baseline. At maximum hemorrhage, TcMEP amplitude decreased in the RF and TA by an average of 73 and 62% respectively from baseline (P < 0.01). Serum propofol levels varied greatly among animals at baseline (range 410-1720 ng/mL) and increased in each animal during hemorrhage. The mean propofol concentration rose from 1190 +/- 530 to 2483 +/- 968 ng/mL (P < 0.01). The increased propofol concentration correlated with decreased CO. Multivariate analysis using hierarchical linear models indicated that the decline of TcMEP amplitude was primarily associated with rising propofol concentrations, but was also independently affected by reduced CO. We believe that the decrease in blood volume and CO during hemorrhage increased the serum concentration of propofol by reducing the volume of distribution and/or rate of hepatic metabolism of the drug. Despite wide acceptance of propofol as the preferred anesthetic when using TcMEPs, intravenous anesthetics are vulnerable to altered pharmacokinetics during conditions of hemorrhage and could contribute to false-positive TcMEP changes. PMID- 28856577 TI - 223Ra-dichloride therapy in an elderly bone metastatic castration-resistant prostate cancer patient: a case report presentation and comparison with existing literature. PMID- 28856578 TI - A case of mild phenotype Alport syndrome caused by COL4A3 mutations. AB - In a case of 41-year-old man with mild nephropathy, Alport syndrome (AS) was diagnosed from the renal biopsy. However, the alpha5 chain of type IV collagen expressed in the glomerular basement membrane, which was the atypical staining pattern of AS. Genetic testing suggested autosomal recessive AS from heterozygous mutations at two positions in the type IV collagen alpha3 chain. These two gene mutations represented a new pattern of mutation and was suggested the association with an atypical alpha5 chain expression and mild phenotype. PMID- 28856579 TI - Readability of informed consent forms for whole-exome and whole-genome sequencing. AB - Whole-exome and whole-genome sequencing (WES, WGS) can generate an unprecedented amount of complex information, making the informed consent (IC) process challenging. The aim of our study was to assess the readability of English IC forms for clinical whole-exome and whole-genome sequencing using the SMOG and Flesch-Kincaid formulas. We analysed 36 forms, most of which were from US providers. The median readability grade levels were 14.75 (the SMOG formula) and 12.2 (the Flesch-Kincaid formula); these values indicate the years of education after which a person would be able to understand a text studied. All forms studied seem to fail to meet the average recommended readability grade level of 8 (e.g. by Institutional Review Boards of US medical schools) for IC forms, indicating that the content of the forms may not be comprehensible to many patients. The sections aimed at health care professionals (HCPs) in the forms indicate that HCPs should be responsible for explaining IC information to the patients. However, WES and WGS may be increasingly offered by primary care professionals who may not (yet) have sufficient training to be able to communicate effectively with patients about genomics. Therefore, to secure an adequate, truly informed consent process, the task of developing good, legible examples of IC forms along with educating HCPs in genomics should be taken seriously, and adequate resources should be allocated to enable these tasks. PMID- 28856580 TI - Can Matching-Adjusted Indirect Comparison Methods Mitigate Placebo Response Differences Among Patient Populations in Adjunctive Trials of Brivaracetam and Levetiracetam? AB - BACKGROUND AND OBJECTIVE: Patients with focal seizures recruited into adjunctive antiepileptic drug (AED) trials have become more refractory and severe over time; concurrently, placebo responses have increased. To attempt to account for heterogeneity among trials, propensity-score weighted patient-level data were used to indirectly compare placebo responses reported in brivaracetam and levetiracetam trials. METHODS: Patient-level data from randomised, placebo controlled brivaracetam (recruited 2007-2014) and levetiracetam (1993-1998) trials were pooled. Consistent inclusion/exclusion criteria were applied and outcomes were defined consistently. Potentially confounding baseline characteristics were adjusted for using propensity score weighting. Weighting success was assessed using placebo response. RESULTS: In total, 707 and 473 active drug and 399 and 253 placebo patients comprised the brivaracetam and levetiracetam groups, respectively. Before weighting, several baseline variables were significantly different between groups; after weighting, prior vagal nerve stimulation, co-morbid depression and co-morbid anxiety remained different. Before weighting, median seizure frequency reduction was 21.7 and 3.9% in the brivaracetam and levetiracetam placebo arms, respectively; after weighting, median reduction was 15.0 and 6.0%. The comparison of non-randomised groups could be biased by unobserved confounding factors and region of residence. Lifetime AED history was unavailable in the brivaracetam trials and excluded from analysis. CONCLUSIONS: Placebo responses remained different between brivaracetam and levetiracetam trials after propensity score weighting, indicating the presence of residual confounding factors associated with placebo response in these trials. It therefore remains problematic to conduct reliable indirect comparisons of brivaracetam and levetiracetam given the current evidence base, which may apply to comparisons between other AED trials. PMID- 28856581 TI - Impact of Clinical Factors on the Achievement of Target Blood Pressure in Hypertensive Patients from Ivanovo Region of Russia: Data of 2015. AB - INTRODUCTION: In Russia, blood pressure (BP) control is below the optimal. The little is known about regional features and barriers to adequate BP control in Russian primary care. AIM: To evaluate the impact of clinical factors on achieving the target BP in hypertensive patients in one region of Russia. METHODS: Retrospective medical data of 2015 on 11,129 patients (31.4% male) with hypertension (Htn) from Ivanovo region of Russia were examined. Achievement of target BP was assessed in all patients. We study association between BP control and clinical factors. RESULTS: 45.9% of studied patients with Htn had controlled BP. The frequency of achieving the target BP in subsets of hypertensive patients was 37.8% in patients with diabetes, 39.5% in patients with coronary artery disease, and 29.9% in patients with chronic heart failure. The main clinical factors associated with achieving the target BP in studied hypertensive patients were the advice on alcohol consumption, advice on smoking cessation, and advice on weight reduction. Therapy with main antihypertensive drugs (in particular, beta-blockers and thiazide diuretics) were also factors of optimal BP control in these patients. Comorbidities (chronic heart failure and cardiovascular diseases requiring the prescription of aspirin and statins) and family history of coronary artery disease were associated with inadequate BP control. A negative effect of some antihypertensive drugs (potassium sparing diuretics, ARBs, ACE-Is, and dihydropyridine CCBs) on BP control that was found out in our study requires further investigation. Other studied factors had no influence on BP control in patients with Htn from Ivanovo region. CONCLUSION: We identified regional factors of BP control in hypertensive patients from Ivanovo region of Russia. It is shown that individual medical education (in particular, medical advices) is the most important factor of optimal BP control. The intervention with antihypertensive therapy (beta-blockers and thiazide diuretics) facilitates the achievement of target BP. Comorbidity and age reduce the frequency of achieving the target BP. PMID- 28856583 TI - Thoracoabdominal aortic aneurysm repair: open, endovascular, or hybrid? AB - Successful repair of complex thoracoabdominal aortic aneurysms requires careful surgical planning based on anatomic and patient considerations. Not only are surgical considerations key, but also post-operative care, regardless of surgical approach, can dramatically impact both short- and long-term outcomes. While open repair has been the gold standard for decades, the technical challenges associated with operative repair, a specialty approach requisite for good outcomes, and the unique challenges in the post-operative care of these patients have given providers pause when considering operative intervention. The relatively recent development of elegant endovascular and hybrid approaches to this problem has shown improved short-term morbidity and reasonable durability. Here, we discuss these three techniques for correction of complex thoracoabdominal aortic aneurysms to provide some guidance for optimization of outcomes based on individual patient anatomy and comorbid conditions. PMID- 28856582 TI - Helicobacter bilis-Associated Suppurative Cholangitis in a Patient with X-Linked Agammaglobulinemia. AB - : ?: Helicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases. PURPOSE: We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis. METHODS: 16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis. RESULTS: Clinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with azithromycin. CONCLUSION: In conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases. PMID- 28856584 TI - 1H, 15N and 13C resonance assignments of Ixolaris, a tissue factor pathway inhibitor from the tick salivary gland. AB - Ixolaris is a two-Kunitz tick salivary gland protein identified in Ixodes scapularis that presents sequence homology to TFPI (tissue factor pathway inhibitor). It binds to the coagulation enzyme factor Xa (FXa) or to its zymogen form, FX, and further inhibits tissue factor/FVIIa complex (extrinsic Xnase compex). Differently from TFPI, Ixolaris does not bind to the active site cleft of FXa. Instead, complex formation is mediated by the FXa heparin-binding exosite, which may also results in decreased FXa activity into the prothrombinase complex. The Ixolaris-FXa/FX complex formation has been characterized by using a combination of biophysical and biochemical technics although no structural data is currently available. In this study, we reported the NMR chemical shift assignment of Ixolaris, as a first step to further establishing the structure, dynamics and function relationship for this protein. PMID- 28856585 TI - A Systematic Review of Cost-of-Illness Studies of Multimorbidity. AB - OBJECTIVES: The economic burden of multimorbidity is considerable. This review analyzed the methods of cost-of-illness (COI) studies and summarized the economic outcomes of multimorbidity. METHODS: A systematic review (2000-2016) was performed, which was registered with Prospero, reported according to PRISMA, and used a quality checklist adapted for COI studies. The inclusion criteria were peer-reviewed COI studies on multimorbidity, whereas the exclusion criterion was studies focusing on an index disease. Extracted data included the definition, measure, and prevalence of multimorbidity; the number of included health conditions; the age of study population; the variables used in the COI methodology; the percentage of multimorbidity vs. total costs; and the average costs per capita. RESULTS: Among the 26 included articles, 14 defined multimorbidity as a simple count of 2 or more conditions. Methodologies used to derive the costs were markedly different. Given different healthcare systems, OOP payments of multimorbidity varied across countries. In the 17 and 12 studies with cut-offs of >=2 and >=3 conditions, respectively, the ratios of multimorbidity to non-multimorbidity costs ranged from 2-16 to 2-10. Among the ten studies that provided cost breakdowns, studies with and without a societal perspective attributed the largest percentage of multimorbidity costs to social care and inpatient care/medicine, respectively. CONCLUSION: Multimorbidity was associated with considerable economic burden. Synthesising the cost of multimorbidity was challenging due to multiple definitions of multimorbidity and heterogeneity in COI methods. Count method was most popular to define multimorbidity. There is consistent evidence that multimorbidity was associated with higher costs. PMID- 28856587 TI - Streaming potential method for characterizing interaction of electrical double layers between rice roots and Fe/Al oxide-coated quartz in situ. AB - The interaction between rice roots and Fe/Al oxide-coated quartz was investigated through zeta potential measurements and column leaching experiments in present study. The zeta potentials of rice roots, Fe/Al oxide-coated quartz, and the binary systems containing rice roots and Fe/Al oxide-coated quartz were measured by a specially constructed streaming potential apparatus. The interactions between rice roots and Fe/Al oxide-coated quartz particles were evaluated/deduced based on the differences of zeta potentials between the binary systems and the single system of rice roots. The zeta potentials of the binary systems moved in positive directions compared with that of rice roots, suggesting that there were overlapping of diffuse layers of electric double layers on positively charged Fe/Al oxide-coated quartz and negatively charged rice roots and neutralization of positive charge on Fe/Al oxide-coated quartz with negative charge on rice roots. The greater amount of positive charges on Al oxide led to the stronger interaction of Al oxide-coated quartz with rice roots and the more shift of zeta potential compared with Fe oxide. The overlapping of diffuse layers on Fe/Al oxide-coated quartz and rice roots was confirmed by column leaching experiments. The greater overlapping of diffuse layers on Al oxide and rice roots led to more simultaneous adsorptions of K+ and NO3- and greater reduction in leachate electric conductivity when the column containing Al oxide-coated quartz and rice roots was leached with KNO3 solution, compared with the columns containing rice roots and Fe oxide-coated quartz or quartz. When the KNO3 solution was replaced with deionized water to flush the columns, more K+ and NO3- were desorbed from the binary system containing Al oxide-coated quartz and rice roots than from other two binary systems, suggesting that the stronger electrostatic interaction between Al oxide and rice roots promoted the desorption of K+ and NO3- from the binary system and enhanced overlapping of diffuse layers on these oppositely charged surfaces compared with other two binary systems. In conclusion, the overlapping of diffuse layers occurred between positively charged Fe/Al oxides and rice roots, which led to neutralization of opposite charge and affected adsorption and desorption of ions onto and from the charged surfaces of Fe/Al oxides and rice roots. PMID- 28856586 TI - TiO2-Nanowired Delivery of DL-3-n-butylphthalide (DL-NBP) Attenuates Blood-Brain Barrier Disruption, Brain Edema Formation, and Neuronal Damages Following Concussive Head Injury. AB - DL-3-n-butylphthalide (DL-NBP) is one of the constituents of Chinese celery extract that is used to treat stroke, dementia, and ischemic diseases. However, its role in traumatic brain injury is less well known. In this investigation, neuroprotective effects of DL-NBP in concussive head injury (CHI) on brain pathology were explored in a rat model. CHI was inflicted in anesthetized rats by dropping a weight of 114.6 g from a height of 20 cm through a guide tube on the exposed right parietal bone inducing an impact of 0.224 N and allowed them to survive 4 to 24 h after the primary insult. DL-NBP was administered (40 or 60 mg/kg, i.p.) 2 and 4 h after injury in 8-h survival group and 8 and 12 h after trauma in 24-h survival group. In addition, TiO2-nanowired delivery of DL-NBP (20 or 40 mg/kg, i.p.) in 8 and 24 h CHI rats was also examined. Untreated CHI showed a progressive increase in blood-brain barrier (BBB) breakdown to Evans blue albumin (EBA) and radioiodine ([131]-I), edema formation, and neuronal injuries. The magnitude and intensity of these pathological changes were most marked in the left hemisphere. Treatment with DL-NBP significantly reduced brain pathology in CHI following 8 to 12 h at 40-mg dose. However, 60-mg dose is needed to thwart brain pathology at 24 h following CHI. On the other hand, TiO2-DL-NBP was effective in reducing brain damage up to 8 or 12 h using a 20-mg dose and only 40 mg dose was needed for neuroprotection in CHI at 24 h. These observations are the first to suggest that (i) DL-NBP is quite effective in reducing brain pathology and (ii) nanodelivery of DL-NBP has far more superior effects in CHI, not reported earlier. PMID- 28856588 TI - Whole blood microRNA markers are associated with acute respiratory distress syndrome. AB - BACKGROUND: MicroRNAs (miRNAs) can play important roles in inflammation and infection, which are common manifestations of acute respiratory distress syndrome (ARDS). We assessed if whole blood miRNAs were potential diagnostic biomarkers for human ARDS. METHODS: This nested case-control study (N = 530) examined a cohort of ARDS patients and critically ill at-risk controls. Whole blood miRNA profiles and logistic regression analyses identified miRNAs correlated with ARDS. Stratification analysis also assessed selected miRNA markers for their role in sepsis and pneumonia associated with ARDS. Receiver operating characteristic (ROC) analysis evaluated miRNA diagnostic performance, along with Lung Injury Prediction Score (LIPS). RESULTS: Statistical analyses were performed on 294 miRNAs, selected from 754 miRNAs after quality control screening. Logistic regression identified 22 miRNAs from a 156-patient discovery cohort as potential risk or protective markers of ARDS. Three miRNAs-miR-181a, miR-92a, and miR-424 from the discovery cohort remained significantly associated with ARDS in a 373 patient independent validation cohort (FDR q < 0.05) and meta-analysis (p < 0.001). ROC analyses demonstrated a LIPS baseline area-under-the-curve (AUC) value of ARDS of 0.708 (95% CI 0.651-0.766). Addition of miR-181a, miR-92a, and miR-424 to LIPS increased baseline AUC to 0.723 (95% CI 0.667-0.778), with a relative integrated discrimination improvement of 2.40 (p = 0.005) and a category free net reclassification index of 27.21% (p = 0.01). CONCLUSIONS: miR-181a and miR-92a are risk biomarkers for ARDS, whereas miR-424 is a protective biomarker. Addition of these miRNAs to LIPS can improve the risk estimate for ARDS. PMID- 28856589 TI - Impact of a mixed educational and semi-restrictive antimicrobial stewardship project in a large teaching hospital in Northern Italy. AB - BACKGROUND: The overuse of antimicrobials favors the dissemination of antimicrobial resistance, as well as invasive fungal diseases and Clostridium difficile infections (CDI). In this study, we assessed the impact of a mixed educational and semi-restrictive antimicrobial stewardship (AMS) project in a large teaching hospital in Italy. METHODS: The AMS project was conducted from May 2014 to April 2016. It consisted of two initiatives in two consecutive periods: (1) educational activities; (2) semi-restrictive control of antimicrobial prescribing through a computerized software. The primary endpoint was consumption of antibacterials and antifungals. Secondary endpoints were incidence of CDI, methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI), carbapenem-resistant Klebsiella pneumoniae (CRKP) BSI, and Candida BSI. RESULTS: During the study period, a statistically significant reduction in consumption was observed for antibacterials (-1.45 defined daily doses (DDD)/1000 patient-days monthly, 95% confidence intervals [CI] -2.38 to -0.52, p 0.004), mainly driven by reductions in the use of fluoroquinolones, third/fourth generation cephalosporins, and carbapenems. No decrease in consumption of antifungals was observed (-0.04 DDD/1000 patient-days monthly, 95% CI -0.34 to +0.25, p 0.750). A statistically significant trend towards reduction was observed for incidence of CRKP BSI (incidence rate ratio 0.96, 95% CI 0.92-0.99, p 0.013). No statistically significant variations in trends were observed for CDI, MRSA BSI, and Candida BSI. CONCLUSIONS: The mixed AMS project was effective in reducing the use of major antibacterials and the incidence of CRKP BSI. Further research is needed to assess the extent of long-term benefits of semi-restrictive approaches. PMID- 28856590 TI - Autologous hematopoietic stem cell transplantation may improve long-term outcomes in patients with newly diagnosed extranodal natural killer/T-cell lymphoma, nasal type: a retrospective controlled study in a single center. AB - Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) is a rare disease with a poor prognosis. The long-term effect of autologous hematopoietic stem cell transplantation (auto-HSCT) on ENKTL has been reported occasionally but needs further investigation. In this retrospective study from a single center, 20 ENKTL patients who received induction chemotherapy followed by auto-HSCT +/- involved field radiotherapy (IFRT) +/- additional chemotherapy were enrolled as a study group. Another 60 fit ENKTL patients who received induction chemotherapy +/- IFRT +/- additional chemotherapy were selected as the control group. Baseline characteristics of all patients were well balanced. Our analysis showed that after a median follow-up time of 61.0 months (95% CI 52.3-69.7), the auto-HSCT treated group showed better overall survival (OS) than the control group (p = 0.045). The median OS of the auto-HSCT-treated group was not reached, but that of the control group was 62.0 months. Five-year comparison of OS between the two groups also showed a significant difference (79.3 vs. 52.3%, p = 0.026). We suggest that auto-HSCT treatment, in combination with chemoradiotherapy, may prolong OS and improve the long-term outcomes of fit patients with ENKTL compared to treatment with chemoradiotherapy alone. PMID- 28856592 TI - Is compromised oral health associated with a greater risk of mortality among nursing home residents? A controlled clinical study. AB - AIM: The objective of this controlled clinical study was to evaluate the association between oral health and 1-year mortality among nursing home residents with or without oral health intervention. METHODS: This research was part of a multidisciplinary intervention study (EVI-P) performed in 14 nursing homes in Germany. Two-hundred and nineteen nursing home residents were included in the study and assigned to an intervention group, for which dental health education was offered and ultrasonic baths were used for denture cleaning (n = 144), or to a control group (n = 75). Before the intervention, each participant was examined, and dental status, plaque control record (PCR), Denture Hygiene Index, and results from the Revised Oral Assessment Guide were recorded. Amount of care needed and dementia were also assessed, by use of the Barthel Index and the Mini Mental State Examination, respectively. Participant mortality was determined after 12 months, and bivariate analysis and logistic regression models were used to evaluate possible factors affecting mortality. RESULTS: Bivariate analysis detected a direct association between greater mortality and being in the control group (p = .038). Participants with higher PCR were also more likely to die during the study period (p = .049). For dentate participants, the protective effect of being in the intervention group was confirmed by multivariate analysis in which covariates such as age and gender were considered. CONCLUSION: Oral hygiene and oral health seem to affect the risk of mortality of nursing home residents. Dental intervention programs seem to reduce the risk of 1-year mortality among nursing home residents having remaining natural teeth. Further studies, with larger sample sizes and evaluation of the causes of death, are necessary to investigate the reasons for these associations. PMID- 28856591 TI - TSH oscillations in young patients with type 1 diabetes may be due to glycemic variability. AB - PURPOSE: A relationship between thyroid dysfunction and diabetes mellitus has been described by several authors but the role of glycemic variability is still unclear. We planned the present study to evaluate the influence of glycemic variability on thyroid hormones and TSH concentrations in patients with type 1 diabetes mellitus (T1DM). METHODS: Seventy-seven young patients with T1DM were enrolled and evaluated for basal glucose concentrations, HbA1c, thyroid hormones and TSH concentrations. Glucose variability was investigated by considering the standard deviation of blood glucose readings and by calculating the mean amplitude of glycemic excursions and continuous overlapping net glycemic action (CONGA). The low (LBGI) and high (HBGI) blood glucose indices were also calculated. The correlations between TSH, thyroid hormones, glycemia and HbA1c were studied in patients and in controls, whereas those between TSH, thyroid hormones and indices of glucose variability only in patients. RESULTS: No correlations were observed in T1DM patients between free thyroid hormones and glycemic values, HbA1c and indices of glucose variability, while an inverse correlation was observed between TSH levels and glycemic values (r = -0.27; p = 0.01), CONGA index (r = -0.35; p = 0.001) and HBGI (r = -0.28; p = 0.01) but not with HbA1c (r = -0.1; p = 0.47). CONCLUSIONS: Our results suggest a direct action of glycemic excursions on TSH secretion, regardless of variations of thyroid hormone concentrations. Thus, the evaluation of thyroid function through the assay of TSH concentrations in these patients should be made, if possible, by multiple samples on patients in euglycemic state to avoid underestimation or overestimation of thyroid dysfunction due to a wrong diagnosis of euthyroidism or dysthyroidism with consequent inappropriate choice of therapeutic options. PMID- 28856593 TI - The role of some feed additives in fish fed on diets contaminated with cadmium. AB - The decline of cadmium pollution in fish farms is needed by any adequate method. The present study was designed to explore the effect of dietary cadmium contamination and its amelioration by using dietary clay, probiotic (Bactocell(r)), vitamin C, and vitamin E supplementation in Nile tilapia fish diet on growth rate, feed efficiency, blood components, and cadmium residues. Fish were separated into 15 groups, each group of fish was stocked into three aquaria and each contains 20 fishes. The fish of the first five groups were fed the basal diet, the second five groups were fed the basal diet contaminated with 25 mg cadmium/kg, and the third five groups were fed the same diet contaminated with 50 mg cadmium/kg. Within each dietary cadmium level, the first group was fed the diet without any supplementation, the second was fed the diet supplemented with natural clay (bentonite) at level 3%, the third group was fed the diet supplemented with 1 g Bactocell(r)/kg, the fourth group was fed the diet supplemented 50 mg vitamin E/kg, and the fifth group was fed the diet supplemented with 100 mg vitamin C/kg. Live body weight, daily body weight gain, and feed intake of Nile tilapia decreased significantly (P < 0.001) with increasing dietary cadmium level, while feed conversion was impaired. Fish group fed on diets contaminated with 50 mg cadmium/kg recorded the lowest live body weight and weight gain. Serum total protein and albumin concentration significantly (P < 0.001) decreased, while serum creatinine, AST, and ALT significantly (P < 0.001) increased with increasing cadmium level in fish diets. Blood hemoglobin and total erythrocyte (RBCs) significantly (P < 0.001 or 0.05) decreased with cadmium contamination in fish diets, while leukocytes were insignificantly affected. Body cadmium residues increased significantly (P < 0.001) by increasing cadmium level in fish diets. Live body weight, daily body weight gain, and feed intake of Nile tilapia increased significantly (P < 0.001) with feed additive supplementation in diets, also while feed conversion improved. Fish group fed on diets supplemented with probiotic Bactocell(r) or natural clay recorded higher body weight and gain rate than the other experimental groups. Serum total protein, blood hemoglobin, and total erythrocyte increased, while urea-N, creatinine, ALT, AST, and leukocytes decreased as affected with the feed additive supplementation. Feed additive supplementation in fish diets significantly (P < 0.001) decreased cadmium residues in fish bodies. Irrespective of dietary cadmium level, feed additive supplementation in fish diet improved the growth rate and decreased the concentrations of serum creatinine and ALT. The obtained results indicated that feed additive supplementation could modify the function of the kidney and liver in fish exposed to the cadmium toxicity. PMID- 28856594 TI - Size-Dependent Neurotoxicity of Aluminum Oxide Particles: a Comparison Between Nano- and Micrometer Size on the Basis of Mitochondrial Oxidative Damage. AB - Aluminum nanoparticles (AlNPs) are among the most abundantly produced nanosized particles in the market. There is limited information about the potential harmful effects of aluminum oxide due to its particle size on human health. Considering the toxic effects of Al on brain as its target tissue, in this study, the toxicity of nanoparticles, microparticles, and ionic forms of Al on rat brain and isolated mitochondria was evaluated. Sixty male Wistar rats were divided into ten groups (six rats each), in which group I was the control, and the other groups were administered different doses of Al nanoparticles, Al microparticles (AlMP), and Al ionic forms (2, 4, and 8 mg/kg, i.p.) for 28 days. After 24 h, the animals were killed, brain tissue was separated, the mitochondrial fraction was isolated, and oxidative stress markers were measured. Also, mitochondrial function was assayed by MTT test. The results showed that all forms of Al particles induced ROS formation, lipid peroxidation, protein oxidation, glutathione depletion, mitochondrial dysfunction, and gait abnormalities in a dose-dependent manner. In addition, Al particles decreased mitochondrial membrane potential. These data indicated that oxidative stress might contribute to the toxicity effects of Al. Comparison of oxidative stress markers between all forms of Al revealed that the toxic effect of AlNP on brain tissue was substantially more than that caused by AlMP and bulk form. This study showed more neurotoxicity of AlNPs compared to other forms on brain oxidative damage that probably is due to more penetration into the brain. PMID- 28856596 TI - Estimation of Human Norovirus Infectivity from Environmental Water Samples by In Situ Capture RT-qPCR Method. AB - Human noroviruses (HuNoVs) are highly infectious viruses for which water is an important medium of transmission. In this study, we explored a new in situ capture RT-qPCR (ISC-RT-qPCR) methodology to estimate the infectivity of HuNoV in environmental water samples. This assay was based on capturing encapsidated HuNoV by viral receptors, followed by in situ amplification of the captured viral genomes by RT-qPCR. We demonstrated that the ISC-RT-qPCR did not capture and enable signal amplification of heat-denatured Tulane Virus (TV) and HuNoVs. We further demonstrated that the sensitivity of ISC-RT-qPCR was equal or better than that of conventional RT-qPCR procedures for the detection of HuNoV GI and GII. We then utilized the ISC-RT-qPCR to detect HuNoV in environmental water samples for comparison against that from a conventional RT-qPCR procedure. TV was used as a process control virus. While complete inhibition of TV genomic signal was observed in 27% of samples tested by RT-qPCR, no inhibition of TV genomic signal was observed by ISC-RT-qPCR. From 72 samples tested positive for HuNoV GI signal by RT-qPCR, only 20 (27.8%) of these samples tested positive by ISC-RT-qPCR, suggesting that 72.2% of RT-qPCR-positive samples were unlikely to be infectious. From 16 samples tested positive for HuNoV GII signal by RT-qPCR, only one of these samples tested positive by ISC-RT-qPCR. Five samples that had initially tested negative for HuNoV GII signal by RT-qPCR, was tested as positive by ISC-RT qPCR. Overall, ISC-RT-qPCR method provided an alternative assay to estimate infectivity of HuNoV in environmental samples. PMID- 28856595 TI - Determination of ochratoxin A in tissues of wild boar (Sus scrofa L.) by enzymatic digestion (ED) coupled to high-performance liquid chromatography with a fluorescence detector (HPLC-FLD). AB - Ochratoxin A (OTA) is a secondary toxic metabolite synthesized by Aspergillus or Penicillium species, which can contaminate various crops. The International Agency for Research on Cancer (IARC) classified OTA as a group 2B possible human carcinogen. The aim of the present study was to assess OTA concentrations in tissues of wild boar (Sus scrofa L.) from Tuscany (Italy). Over a period of 2 years, samples of muscle, liver, and kidney from 48 wild boars were collected and concentrations of OTA were determined by enzymatic digestion (ED) coupled to high performance liquid chromatography with a fluorescence detector (HPLC-FLD). The highest concentrations of OTA were found in the kidneys of the 48 wild boars analyzed. No difference in concentrations was found based on years of collection and sex while a significantly higher OTA concentration was found in the kidney of the young wild boars with respect to the adult one. Monitoring the quality of meat destined for transformation is a priority in order to decrease the possibility of toxin carry-over to humans. The present study showed that contamination of wild boar meat products by OTA represents a potential emerging source of OTA. PMID- 28856597 TI - Chemical genetics-based development of small molecules targeting hepatitis C virus. AB - Hepatitis C virus (HCV) infection is a major worldwide problem that has emerged as one of the most significant diseases affecting humans. There are currently no vaccines or efficient therapies without side effects, despite today's advanced medical technology. Currently, the common therapy for most patients (i.e. genotype 1) is combination of HCV-specific direct-acting antivirals (DAAs). Up to 2011, the standard of care (SOC) was a combination of peg-IFNalpha with ribavirin (RBV). After approval of NS3/4A protease inhibitor, SOC was peg-IFNalpha and RBV with either the first-generation DAAs boceprevir or telaprevir. In the past several years, various novel small molecules have been discovered and some of them (i.e., HCV polymerase, protease, helicase and entry inhibitors) have undergone clinical trials. Between 2013 and 2016, the second-generation DAA drugs simeprevir, asunaprevir, daclatasvir, dasabuvir, sofosbuvir, and elbasvir were approved, as well as the combinational drugs Harvoni(r), Zepatier(r), Technivie(r), and Epclusa(r). A number of reviews have been recently published describing the structure-activity relationship (SAR) in the development of HCV inhibitors and outlining current therapeutic approaches to hepatitis C infection. Target identification involves studying a drug's mechanism of action (MOA), and a variety of target identification methods have been developed in the past few years. Chemical biology has emerged as a powerful tool for studying biological processes using small molecules. The use of chemical genetic methods is a valuable strategy for studying the molecular mechanisms of the viral lifecycle and screening for anti-viral agents. Two general screening approaches have been employed: forward and reverse chemical genetics. This review reveals information on the small molecules in HCV drug discovery by using chemical genetics for targeting the HCV protein and describes successful examples of targets identified with these methods. PMID- 28856598 TI - Erratum to: Gluten and Aluminum Content in Synthroid(r) (Levothyroxine Sodium Tablets). PMID- 28856599 TI - Erratum to: Multicenter, Randomized, Investigator-Masked Study Comparing Brimonidine Tartrate 0.1% and Timolol Maleate 0.5% as Adjunctive Therapies to Prostaglandin Analogues in Normal-Tension Glaucoma. PMID- 28856600 TI - ESR concept paper on value-based radiology. AB - The European Society of Radiology (ESR) established a Working Group on Value Based Imaging (VBI WG) in August 2016 in response to developments in European healthcare systems in general, and the trend within radiology to move from volume to value-based practice in particular. The value-based healthcare (VBH) concept defines "value" as health outcomes achieved for patients relative to the costs of achieving them. Within this framework, value measurements start at the beginning of therapy; the whole diagnostic process is disregarded, and is considered only if it is the cause of errors or complications. Making the case for a new, multidisciplinary organisation of healthcare delivery centred on the patient, this paper establishes the diagnosis of disease as a first outcome in the interrelated activities of the healthcare chain. Metrics are proposed for measuring the quality of radiologists' diagnoses and the various ways in which radiologists provide value to patients, other medical specialists and healthcare systems at large. The ESR strongly believes value-based radiology (VBR) is a necessary complement to existing VBH concepts. The Society is determined to establish a holistic VBR programme to help European radiologists deal with changes in the evolution from volume- to value-based evaluation of radiological activities. Main Messages * Value-based healthcare defines value as patient's outcome over costs. * The VBH framework disregards the diagnosis as an outcome. * VBH considers diagnosis only if wrong or a cause of complications. * A correct diagnosis is the first outcome that matters to patients. * Metrics to measure radiologists' impacts on patient outcomes are key. * The value provided by radiology is multifaceted, going beyond exam volumes. PMID- 28856601 TI - Chromium Supplementation Reduces Resting Heart Rate in Patients with Metabolic Syndrome and Impaired Glucose Tolerance. AB - Chromium (Cr) is considered as an important mineral, involved in biochemical reactions in human metabolic pathways. Organically bound Cr supplementation has been suggested to improve glycemia especially in patients with type 2 diabetes mellitus, but there are conflicting reports on efficacy. Effect of Cr is not clear in prediabetes status. Seventy patients with metabolic syndrome and impaired glucose tolerance (IGT), who are observed and treated in the Center of Preventive Cardiology of the University Hospital in Pilsen, were included in the prospective, randomized, double-blind, and placebo-controlled clinical study. Effect of Cr-enriched yeast (200 MUg of elementary Cr in the morning and 100 MUg in the evening) on glucose, lipid metabolism, fat tissue hormones, oxidative stress, and DNA damage markers was analyzed. There were no significant changes in glucose and lipid parameters, oxidative stress, or other laboratory markers. Only resting heart rate was significantly reduced in patients treated by Cr yeast, reflecting reduced sympathetic activity. This could represent an important cardiovascular risk reduction in patients with high cardiometabolic risk. PMID- 28856603 TI - Method for Measurement of Multi-Degrees-of-Freedom Motion Parameters Based on Polydimethylsiloxane Cross-Coupling Diffraction Gratings. AB - This work presents a multi-degrees-of-freedom motion parameter measurement method based on the use of cross-coupling diffraction gratings that were prepared on the two sides of a polydimethylsiloxane (PDMS) substrate using oxygen plasma processing technology. The laser beam that travels pass the cross-coupling optical grating would be diffracted into a two-dimensional spot array. The displacement and the gap size of the spot-array were functions of the movement of the laser source, as explained by the Fraunhofer diffraction effect. A 480 * 640 pixel charge-coupled device (CCD) was used to acquire images of the two dimensional spot-array in real time. A proposed algorithm was then used to obtain the motion parameters. Using this method and the CCD described above, the resolutions of the displacement and the deflection angle were 0.18 MUm and 0.0075 rad, respectively. Additionally, a CCD with a higher pixel count could improve the resolutions of the displacement and the deflection angle to sub-nanometer and micro-radian scales, respectively. Finally, the dynamic positions of hovering rotorcraft have been tracked and checked using the proposed method, which can be used to correct the craft's position and provide a method for aircraft stabilization in the sky. PMID- 28856602 TI - Pharmacokinetic Profiles of Ticagrelor Orodispersible Tablets in Healthy Western and Japanese Subjects. AB - BACKGROUND AND OBJECTIVES: Ticagrelor is an antiplatelet agent for patients with acute coronary syndrome or a history of myocardial infarction. Two studies compared pharmacokinetic profiles of orodispersible (OD) ticagrelor tablets versus immediate-release (IR) tablets in Western and Japanese subjects. METHODS: Both studies were open-label, randomized, crossover, single-center trials. Thirty six healthy subjects (94% white, 6% other race; Western study NCT02400333) and 42 Japanese healthy subjects (Japanese study NCT02436577) received a single 90-mg ticagrelor dose as an OD tablet [with/without water, and via a nasogastric tube (Western study only)], and an IR tablet; washout between treatments was >=7 days. Assessments included ticagrelor and AR-C124910XX (active metabolite) plasma concentrations for pharmacokinetic analyses, and safety evaluations. RESULTS: In the Western study, the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for ticagrelor and AR-C124910XX maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC) were within the acceptance interval (80%-125%) for OD tablets (with/without water, via a nasogastric tube) versus the IR tablet; except for an ~15% lowering of ticagrelor C max (90% CI: 76.77%-93.78%) for the OD tablet taken with water. In the Japanese study, 90% CIs of the GMRs for AUC and C max of both ticagrelor and AR-C124910XX were all within the acceptance intervals for the OD (with/without water) versus IR tablet. No new safety issues were identified. CONCLUSIONS: Ticagrelor administered as an OD tablet to Western (without water, and via a nasogastric tube) and Japanese (with/without water) subjects was bioequivalent to the IR tablet. PMID- 28856604 TI - In Silico Drug Design of Thiolactomycin Derivatives Against Mtb-KasA Enzyme to Inhibit Multidrug Resistance of Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a leading infectious disease which kills a huge number of people every year over a decade, caused by Mycobacterium tuberculosis. The conventional drugs in the market are no longer effective due to the increasing mycobacterial resistance to antibiotics. Hence, the need of finding efficient drugs to solve this multiple drug resistant factor is becoming an immediate issue. The first-line drugs in current practice for the treatment of TB emphasize on mycolic acid, which protects the bacteria from an immune response generated by the host. A key enzyme involved in this mycolic acid biosynthesis, M. tuberculosis beta-ketoacyl-ACP synthase A (MTB-KasA) is a prime candidate in this study. Thiolactomycin is a natural product inhibitor has shown good inhibitory activity against MTB-KasA. Hence, several thiolactomycin derivatives collected from the literature were taken for absorption, distribution, metabolism, excretion and toxicity prediction, molecular docking and molecular dynamics simulation studies with MTB-KasA. The in silico drug designing methods used in this study suggests that the thiolactomycin derivatives are having a better binding activity against MTB-KasA and among them the ligand C14 is identified as a promising lead molecule to inhibit multidrug resistance of tuberculosis by showing a long time binding activity. PMID- 28856606 TI - 1H, 15N and 13C sequence specific backbone assignment of the vanadate inhibited hematopoietic tyrosine phosphatase. AB - The sequence-specific backbone assignment of hematopoietic protein tyrosine phosphatase (HePTP; PTPN7) in presence of vanadate has been determined, based on triple-resonance experiments using uniformly [13C,15N]-labeled protein. These assignments facilitate further studies of HePTP in the presence of inhibitors to target leukemia and provide further insights into the function of protein tyrosine phosphatases. PMID- 28856605 TI - Patient-Reported Outcomes Following Ventral Hernia Repair: Designing a Qualitative Assessment Tool. AB - BACKGROUND: Current hernia patient-reported outcome (PRO) measures were developed without patient input, greatly impairing their content validity. OBJECTIVE: The purpose of this study was to develop a conceptual model for PRO measures for ventral hernia (VH) patients. METHODS: Fifteen semi-structured, concept elicitation interviews and two focus groups employing nominal group technique were conducted with VH patients. Patients were recruited between November 2015 and July 2016 over the telephone from a five-surgeon patient cohort at our institution. Iterative thematic analysis identified domains. Reliability and validation were achieved using inter-rater reliability checks and triangulation. RESULTS: Seven framework domains were established: (1) expectations; (2) self and others; (3) surgeon and surgical team; (4) sensation; (5) function; (6) appearance; and (7) overall satisfaction. Overall patient satisfaction was associated with two themes: (1) provider-patient relationship; and (2) patient assessment of post-repair improvement. CONCLUSIONS: VH patients experience a profoundly broad range of reactions to VH repair. A patient-informed PRO instrument that addresses the spectrum of patient-identified outcomes can guide practice, optimizing care targeting VH patients' needs. PMID- 28856607 TI - Natural History of Aromatic L-Amino Acid Decarboxylase Deficiency in Taiwan. AB - OBJECTIVES: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder of monoamine neurotransmitter synthesis; this deficiency leads to psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. This study aimed to provide further insight into the clinical course of AADC deficiency in Taiwan. PATIENTS AND METHODS: We present a retrospective, descriptive, single-center study of 37 children with a confirmed diagnosis of AADC deficiency. Their medical histories were reviewed for motor milestones, motor development, DDC mutation, and body weight. The termination point for each patient in this study was defined as no further follow-up, death, or enrollment in a gene therapy trial. RESULTS: The median age of the study patients at the end of the study was 4.39 years (1.28-11.30). Of the 37 patients, 36 did not develop full head control, sitting ability, standing ability, or speech at any time point from birth to the termination points. Motor scales were administered to 22 patients. Their Alberta Infant Motor Scale scores were below the fifth percentile, and their Peabody Developmental Motor Scales, Second Edition, scores were below the first percentile. Their body weights were normal in the first few months of life, but severe growth retardation occurred at later ages. The mutation c.714+4A>T (IVS6+4A>T) accounted for 76% of all their DDC mutations. CONCLUSION: In this chapter, we report the clinical course of AADC deficiency in Taiwan. Our data will help guide the development of treatment strategies for the disease. PMID- 28856608 TI - Transferring Ions from Solution to the Gas Phase: The Two Basic Principles. AB - The efficient formation of gaseous ions is the crucial step in all successful mass spectrometric experiments. The invention of electrospray ionization (ESI) has strongly facilitated this step by transferring preformed ions directly from solution to the gas phase - thereby circumventing the need to first convert analytes to the gas phase and then ionize them - and therefore ESI has become an extremely useful and widely applied MS technique. The invention of sonic spray ionization (SSI) has also allowed for the transfer of ions from solution into the gas phase, but without the assistance of a voltage or heating. Numerous ionization techniques, using similar principles to those applied in either ESI or SSI, have subsequently been developed. Although experimental conditions used in such techniques vary markedly, herein we argue that they are all based on either one of two basic principles by which ions can be transferred from solution to the gas phase, that is: via (1) neutralizing the counter ion, or (2) separating the ions. We have selected 35 such techniques and categorized them accordingly. This article thereby aims to establish the basic principles by which gaseous ions can be obtained from solvated ions. We further propose that any new ionization technique used to transfer solvated ions to the gas phase will similarly fall into one of these two mechanistic categories. Graphical abstract. PMID- 28856609 TI - Chemical shift assignments of Mb1858 (24-155), a FHA domain-containing protein from Mycobacterium bovis. AB - The forkhead-associated (FHA) domain is known as a phosphopeptide recognition domain embedded in regulatory proteins from both eukaryotes and bacteria with various biological functions. In this study, the gene encoding a predicted FHA domain from Mb1858 (residues V24-D155 from the 162 amino acid protein Mb1858) in Mycobacterium bovis was cloned, and U-13C/15N-labeled protein was prepared for backbone and side chain resonance assignments by NMR spectroscopy. These assignments are preliminary work towards the determination of the structure and phosphopeptide-binding properties using NMR methods, which will provide useful information about the function of Mb1858 protein. PMID- 28856611 TI - A simple practical technique to alleviate the problem of interfering subdiaphragmatic intestinal activity on myocardial perfusion imaging. PMID- 28856610 TI - Use of low-dose radioiodine ablation for Graves' orbitopathy: results of a pilot, perspective study in a small series of patients. AB - OBJECTIVE: Elimination of thyroid antigens by total thyroid ablation (TTA), namely, thyroidectomy followed by radioiodine, may be beneficial for Graves' Orbitopathy (GO). TTA is usually performed with a 131I dose of 30 mCi. In Italy, this dose must be followed by a 24-h protected hospitalization, with increase in the waiting lists. In contrast, a 15 mCi dose can be given without hospitalization and with lower costs. Here, we investigated whether a lower dose of radioiodine can be used to ablate thyroid remnants in patients with GO, after thyroidectomy. METHODS: The study was performed in two small groups of consecutive thyroidectomized patients (six patients per group) with Graves' hyperthyroidism and GO. Patients underwent ablation with either 15 or 30 mCi of 131I following treatment with recombinant human TSH (rhTSH). The primary outcome was rhTSH-stimulated serum thyroglobulin (Tg) at 6 months. The secondary outcome was baseline Tg at 6 months. RESULTS: Baseline Tg and rhTSH-stimulated Tg after at 6 months did not differ between two groups, suggesting a similar extent of ablation. rhTSH-stimulated Tg was reduced significantly compared with rhTSH stimulated Tg at ablation in both groups. GO outcome following treatment with intravenous glucocorticoids did not differ between the two groups. CONCLUSIONS: Our findings may provide a preliminary basis for the use of a 15 mCi dose of radioiodine upon rhTSH stimulation in thyroidectomized patients with Graves' hyperthyroidism and GO. PMID- 28856612 TI - The value of C-reactive protein in infection diagnosis and prognosis in elderly patients. AB - BACKGROUND: The aim of this study was to determine the value of C-reactive protein level in the diagnosis and prognosis of infection in elderly patients. STUDY POPULATION: This prospective study included inpatients in the palliative care unit during the 1-year period between January 2016 and January 2017. Patients' demographic data, Acute Physiology and Chronic Health Evaluation score, and Charlson Comorbidity Index were recorded. RESULTS: A total of 233 patients were included in the study. A total of 199 instances of infection were diagnosed in 175 of those patients; 75.3% of the infections were detected at admission and 24.7% during hospitalization. At a cut-off value of 4.82, CRP value had 81.0% specificity and 75.4% sensitivity in the diagnosis of infection. Among the patients with infection, there was no difference between those who died and those who survived in terms of baseline CRP level, but a significant difference emerged in CRP level at 48 and 96 h. Factors which were found to significantly reduce survival time were the presence of chronic kidney disease, chronic obstructive pulmonary disease, hypoxia and tachycardia at admission, APACHE-II score over 20.5, initial albumin level below 2.44 g/dL, and serum CRP clearance rates of less than 11% at 48 h and 20% at 96 h. CONCLUSION: In elderly patients with infection, the initial CRP value alone does not have prognostic value, but changes observed in serial CRP measurement are a valid indicator of prognosis. PMID- 28856613 TI - The heart rate response to regadenoson in patients with atrial fibrillation. PMID- 28856614 TI - Decellularized Liver Scaffold for Liver Regeneration. AB - After being initially hailed as the ultimate solution to end-stage organ failure, such as end-stage liver disease (ESLD), engineering of vascularized tissues has stalled because of the need for a well-structured circulatory system that can maintain the cells to be seeded inside the construct.In the field of regenerative medicine, decellularized scaffolds, derived mainly from various non-autologous whole organs, have become an emerging treatment technique to overcome this obstacle. As a result of significant progress made in recent years, organogenesis through whole-organ decellularization scaffolds may now become more feasible than ever before. In this chapter, we describe in detail the necessary steps for liver organogenesis using a decellularized acellular scaffold (DAS), seed cell isolation, and recellularization in a bioreactor-like culture system. This new technique to re-engineer organs may have major implications for the fields of drug discovery, organ transplantation, and ultimately regenerative medicine. PMID- 28856615 TI - Effects of capacity limits, memory loss, and sound type in change deafness. AB - Change deafness, the inability to notice changes to auditory scenes, has the potential to provide insights about sound perception in busy situations typical of everyday life. We determined the extent to which change deafness to sounds is due to the capacity of processing multiple sounds and the loss of memory for sounds over time. We also determined whether these processing limitations work differently for varying types of sounds within a scene. Auditory scenes composed of naturalistic sounds, spectrally dynamic unrecognizable sounds, tones, and noise rhythms were presented in a change-detection task. On each trial, two scenes were presented that were same or different. We manipulated the number of sounds within each scene to measure memory capacity and the silent interval between scenes to measure memory loss. For all sounds, change detection was worse as scene size increased, demonstrating the importance of capacity limits. Change detection to the natural sounds did not deteriorate much as the interval between scenes increased up to 2,000 ms, but it did deteriorate substantially with longer intervals. For artificial sounds, in contrast, change-detection performance suffered even for very short intervals. The results suggest that change detection is generally limited by capacity, regardless of sound type, but that auditory memory is more enduring for sounds with naturalistic acoustic structures. PMID- 28856616 TI - Erratum to: Meta-analysis of tumour burden in pre-operative axillary ultrasound positive and negative breast cancer patients. PMID- 28856617 TI - Erratum to: Olfactory Processing in Male Children with Autism: Atypical Odor Threshold and Identification. PMID- 28856618 TI - Large-scale deployment of a rice 6 K SNP array for genetics and breeding applications. AB - BACKGROUND: Fixed arrays of single nucleotide polymorphism (SNP) markers have advantages over reduced representation sequencing in their ease of data analysis, consistently higher call rates, and rapid turnaround times. A 6 K SNP array represents a cost-benefit "sweet spot" for routine genetics and breeding applications in rice. Selection of informative SNPs across species and subpopulations during chip design is essential to obtain useful polymorphism rates for target germplasm groups. This paper summarizes results from large-scale deployment of an Illumina 6 K SNP array for rice. RESULTS: Design of the Illumina Infinium 6 K SNP chip for rice, referred to as the Cornell_6K_Array_Infinium_Rice (C6AIR), includes 4429 SNPs from re-sequencing data and 1571 SNP markers from previous BeadXpress 384-SNP sets, selected based on polymorphism rate and allele frequency within and between target germplasm groups. Of the 6000 attempted bead types, 5274 passed Illumina's production quality control. The C6AIR was widely deployed at the International Rice Research Institute (IRRI) for genetic diversity analysis, QTL mapping, and tracking introgressions and was intensively used at Cornell University for QTL analysis and developing libraries of interspecific chromosome segment substitution lines (CSSLs) between O. sativa and diverse accessions of O. rufipogon or O. meridionalis. Collectively, the array was used to genotype over 40,000 rice samples. A set of 4606 SNP markers was used to provide high quality data for O. sativa germplasm, while a slightly expanded set of 4940 SNPs was used for O. sativa X O. rufipogon populations. Biparental polymorphism rates were generally between 1900 and 2500 well-distributed SNP markers for indica x japonica or interspecific populations and between 1300 and 1500 markers for crosses within indica, while polymorphism rates were lower for pairwise crosses within U.S. tropical japonica germplasm. Recently, a second generation array containing ~7000 SNP markers, referred to as the C7AIR, was designed by removing poor-performing SNPs from the C6AIR and adding markers selected to increase the utility of the array for elite tropical japonica material. CONCLUSIONS: The C6AIR has been successfully used to generate rapid and high-quality genotype data for diverse genetics and breeding applications in rice, and provides the basis for an optimized design in the C7AIR. PMID- 28856619 TI - Genomic analysis of a Trichoplusia ni Betabaculovirus (TnGV) with three different viral enhancing factors and two unique genes. AB - The complete genome of a Trichoplusia ni granulovirus (TnGV) is described and analyzed. The genome contains 175,360 bp (KU752557), becoming the third largest genome within the genus Betabaculovirus, smaller only than the Xestia c-nigrum GV (XecnGV) (178,733 pb) and the Pseudaletia unipuncta GV (PsunGV) (176,677 pb) genomes. The TnGV genome has a 39.81% C+G content and a total of 180 ORFs were identified, 96 of them in the granulin gene direction and 84 in the opposite direction. A total of 94.38% of the ORFs showed high identity with those of ClanGV, HaGV, and SlGV. Eight homologous regions (hrs) were identified as well as one apoptosis inhibitor (IAP-3). Interestingly, three viral enhancing factors (VEFs) were located in TnGV genome: VEF-1 (orf153), VEF-3 (orf155), and VEF-4 (orf164), additional to another metalloprotease (orf37). Two ORFs were unique to TnGV (orf100 and orf101) and another one was shared by only TnGV and AgseGV (orf2). Eleven of the deduced proteins showed high identity with proteins from nucleopolyhedroviruses, three with proteins from ascoviruses, and one with an entomopoxvirus protein. The largest deduced protein contains 1,213 amino acids (orf43) and the smallest deduced protein contains only 50 amino acids (orf143). Sequence identity and phylogenetic analyses showed that the closest related genomes to TnGV are, to date, those of PsunGV and XecnGV. This genome analysis may contribute to functional research on TnGV, and may form the bases for the utilization of this betabaculovirus as a pest control agent. PMID- 28856620 TI - Identification and Quantification of N-Acyl Homoserine Lactones Involved in Bacterial Communication by Small-Scale Synthesis of Internal Standards and Matrix Assisted Laser Desorption/Ionization Mass Spectrometry. AB - N-acyl homoserine lactones (AHL) are small signal molecules involved in the quorum sensing of many gram-negative bacteria, and play an important role in biofilm formation and pathogenesis. Present analytical methods for identification and quantification of AHL require time-consuming sample preparation steps and are hampered by the lack of appropriate standards. By aiming at a fast and straightforward method for AHL analytics, we investigated the applicability of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Suitable MALDI matrices, including crystalline and ionic liquid matrices, were tested and the fragmentation of different AHL in collision-induced dissociation MS/MS was studied, providing information about characteristic marker fragments ions. Employing small-scale synthesis protocols, we established a versatile and cost-efficient procedure for fast generation of isotope-labeled AHL standards, which can be used without extensive purification and yielded accurate standard curves. Quantitative analysis was possible in the low pico-molar range, with lower limits of quantification reaching from 1 to 5 pmol for different AHL. The developed methodology was successfully applied in a quantitative MALDI MS analysis of low-volume culture supernatants of Pseudomonas aeruginosa. Graphical abstract ?. PMID- 28856621 TI - Safety Concerns with HPV Vaccines Continue to Linger: Are Current Vaccine Pharmacovigilance Practices Sufficient? PMID- 28856622 TI - Binding Selectivity of Methanobactin from Methylosinus trichosporium OB3b for Copper(I), Silver(I), Zinc(II), Nickel(II), Cobalt(II), Manganese(II), Lead(II), and Iron(II). AB - Methanobactin (Mb) from Methylosinus trichosporium OB3b is a member of a class of metal binding peptides identified in methanotrophic bacteria. Mb will selectively bind and reduce Cu(II) to Cu(I), and is thought to mediate the acquisition of the copper cofactor for the enzyme methane monooxygenase. These copper chelating properties of Mb make it potentially useful as a chelating agent for treatment of diseases where copper plays a role including Wilson's disease, cancers, and neurodegenerative diseases. Utilizing traveling wave ion mobility-mass spectrometry (TWIMS), the competition for the Mb copper binding site from Ag(I), Pb(II), Co(II), Fe(II), Mn(II), Ni(II), and Zn(II) has been determined by a series of metal ion titrations, pH titrations, and metal ion displacement titrations. The TWIMS analyses allowed for the explicit identification and quantification of all the individual Mb species present during the titrations and measured their collision cross-sections and collision-induced dissociation patterns. The results showed Ag(I) and Ni(II) could irreversibly bind to Mb and not be effectively displaced by Cu(I), whereas Ag(I) could also partially displace Cu(I) from the Mb complex. At pH ~ 6.5, the Mb binding selectivity follows the order Ag(I)~Cu(I)>Ni(II)~Zn(II)>Co(II)>>Mn(II)~Pb(II)>Fe(II), and at pH 7.5 to 10.4 the order is Ag(I)>Cu(I)>Ni(II)>Co(II)>Zn(II)>Mn(II)~Pb(II)>Fe(II). Breakdown curves of the disulfide reduced Cu(I) and Ag(I) complexes showed a correlation existed between their relative stability and their compact folded structure indicated by their CCS. Fluorescence spectroscopy, which allowed the determination of the binding constant, compared well with the TWIMS analyses, with the exception of the Ni(II) complex. Graphical abstract ?. PMID- 28856623 TI - JSH guideline for tumors of hematopoietic and lymphoid tissues: leukemia: 2. Acute promyelocytic leukemia (APL). PMID- 28856624 TI - The mere exposure effect for visual image. AB - Mere exposure effect refers to a phenomenon in which repeated stimuli are evaluated more positively than novel stimuli. We investigated whether this effect occurs for internally generated visual representations (i.e., visual images). In an exposure phase, a 5 * 5 dot array was presented, and a pair of dots corresponding to the neighboring vertices of an invisible polygon was sequentially flashed (in red), creating an invisible polygon. In Experiments 1, 2, and 4, participants visualized and memorized the shapes of invisible polygons based on different sequences of flashed dots, whereas in Experiment 3, participants only memorized positions of these dots. In a subsequent rating phase, participants visualized the shape of the invisible polygon from allocations of numerical characters on its vertices, and then rated their preference for invisible polygons (Experiments 1, 2, and 3). In contrast, in Experiment 4, participants rated the preference for visible polygons. Results showed that the mere exposure effect appeared only when participants visualized the shape of invisible polygons in both the exposure and rating phases (Experiments 1 and 2), suggesting that the mere exposure effect occurred for internalized visual images. This implies that the sensory inputs from repeated stimuli play a minor role in the mere exposure effect. Absence of the mere exposure effect in Experiment 4 suggests that the consistency of processing between exposure and rating phases plays an important role in the mere exposure effect. PMID- 28856626 TI - How humans react to changing rewards during visual foraging. AB - Much is known about the speed and accuracy of search in single-target search tasks, but less attention has been devoted to understanding search in multiple target foraging tasks. These tasks raise and answer important questions about how individuals decide to terminate searches in cases in which the number of targets in each display is unknown. Even when asked to find every target, individuals quit before exhaustively searching a display. Because a failure to notice targets can have profound effects (e.g., missing a malignant tumor in an X-ray), it is important to develop strategies that could limit such errors. Here, we explored the impact of different reward patterns on these failures. In the Neutral condition, reward for finding a target was constant over time. In the Increasing condition, reward increased for each successive target in a display, penalizing early departure from a display. In the Decreasing condition, reward decreased for each successive target in a display. The experimental results demonstrate that observers will forage for longer (and find more targets) when the value of successive targets increases (and the opposite when value decreases). The data indicate that observers were learning to utilize knowledge of the reward pattern and to forage optimally over the course of the experiment. Simulation results further revealed that human behavior could be modeled with a variant of Charnov's Marginal Value Theorem (MVT) (Charnov, 1976) that includes roles for reward and learning. PMID- 28856625 TI - Inhibition of P2X7 Receptor Ameliorates Nuclear Factor-Kappa B Mediated Neuroinflammation Induced by Status Epilepticus in Rat Hippocampus. AB - P2X7 receptor (P2X7R) has been reported participating in neuroinflammation in multiple neurological diseases. We explored the role of P2X7R in a rat status epilepticus (SE) model induced by coriaria lactone (CL) and its association with neuroinflammation. Thirty minutes after intracerebroventricular infusion with P2X7R antagonists Brilliant blue G (BBG), A-438079, A-740003, or agonists 2',3'-O (4-benzoylbenzoyl)-adenosine 5'-triphosphate (BzATP), SE was induced by intramuscular injection of CL in Sprague-Dawley rats. Seizures severity was recorded according to the Racine scale and Morris water maze test was performed. P2X7R expression was measured by western blotting. Immunohistochemical staining was performed to assess pro-inflammation cytokines expression, neuronal loss, and astrocyte activation. The results showed P2X7R level began to increase at 1 day, peaked at 2 days, and gradually decreased to baseline by 2 weeks in rat hippocampus after SE. P2X7R activation induced NF-kappaB phosphorylation, along with increased IL-1beta and IL-6 expression. Pretreatment with P2X7R antagonists ameliorated SE-induced neuroinflammation, neuronal damage, and astroglial and microglial activation to variable extent. In addition, these antagonists ameliorated seizure severity and improved cognitive function. These findings suggest P2X7R activation plays a critical role in epileptogenesis via regulation of neuroinflammation and blocking P2X7R may be a novel therapeutic strategy for epilepsy. PMID- 28856627 TI - Autism spectrum disorders in propionic acidemia patients. AB - Propionic acidemia is the result of a deficiency in propionyl-CoA carboxylase activity. Chronic neurologic and cognitive complications frequently occur, but the psychiatric evolution of the disorder is not well documented. We conducted a pedopsychiatric evaluation of 19 children, adolescents and young adults, aged between 2 and 25 years, using ADI-R, CARS-T, as well as ADOS when autism spectrum disorder was suspected. Previous psychometric examinations were also taken into consideration. Thirteen patients had an IQ < 80. Two patients presented with autism and two additional patients with other autism spectrum disorders. Five patients did not fulfill diagnostic criteria for autism spectrum disorder but showed difficulties indicative of a broader autism phenotype (BAP). Four other patients had severe anxiety manifestations related to their disease. Two patients presented with acute psychotic episodes. The number of decompensations in the first 3 years of life was lower in patients with autism spectrum disorder or related symptoms. These patients were also older when they were assessed (median age of 15 years old versus 11 years old). There was no significant correlation between 3-hydroxypropionate levels during the first 6 years of life and autism spectrum disorder diagnosis. In conclusion, autism spectrum disorder is frequent in patients with propionic acidemia. These patients should undergo in-depth psychiatric evaluation and be screened for autism spectrum disorder. Further studies are needed to understand the underlying mechanisms. PMID- 28856628 TI - Primary colonic well-differentiated / dedifferentiated liposarcoma of the ascending colon: a case report. AB - BACKGROUND: Primary colonic and dedifferentiated liposarcomas are both remarkably rare. This work describes a case of primary colonic well differentiated/dedifferentiated liposarcoma and reviews the clinical characteristics and current therapies for liposarcoma tumors. CASE PRESENTATION: A 52-year-old woman was referred to our hospital with a submucosal tumor of the ascending colon. Clinical analysis by ultrasound colonoscopy and computed tomography revealed a partially ossified tumor with irregular edges continuous with the muscular layer. High F-18 deoxyglucose uptake was detected by positron emission tomography. Radical resection with lymph node dissection was performed, yielding a tumor specimen approximately 6.5 * 4.0 * 3.2 cm. Neoplastic spindle cell proliferation was found from submucosa to subserosa. Well-differentiated adipose tissue surrounded the tumor, but contained atypical nuclei with condensed chromosomes. Immunohistochemical staining was positive for p16, CDK4, and MDM2 expression. Based on these findings, a diagnosis of well differentiated/dedifferentiated liposarcoma was given. Dedifferentiated liposarcomas are more aggressive than their well-differentiated, low-grade counterparts. While local recurrence can occur with both tumor types, dedifferentiated liposarcomas are more prone to developing distant metastases. The patient received no postoperative therapy, and no recurrences have been observed 12 months after surgery. CONCLUSIONS: Here we report an extremely rare case of well-differentiated/dedifferentiated liposarcoma of the ascending colon. The dedifferentiated component was high-grade liposarcoma and well-differentiated liposarcoma was detected around the main tumor. PMID- 28856629 TI - Carotid atherosclerotic plaques standardized uptake values: methodological issues on reproducibility and accuracy. PMID- 28856630 TI - Identification of two novel mutations in the ATP7B gene that cause Wilson's disease. AB - BACKGROUND: Wilson's disease is an autosomal recessive disorder characterized by liver disease and/or neurologic deficits due to copper accumulation and is caused by pathogenic mutations in the ATP7B gene. DATA SOURCES: Two unrelated Chinese patients born to nonconsanguineous parents who were diagnosed with earlyonset Wilson's disease. DNA sequencing and bioinformation analysis were conducted. RESULTS: We have identified four mutations in two family trios, of which two were novel, namely, c. 3028A>G (p. K1010E) and c.3992T>G (p.Y1331X), in each patient. CONCLUSIONS: Gene testing is playing an important role in diagnosis of Wilson's disease. The early-onset of Wilson's disease is apparently not associated with P ATPase domain in the ATP7B protein. Our findings further widen the spectrum of mutations involving the ATP7B gene. PMID- 28856631 TI - Implications of Entropy and Surgical Pleth Index-guided general anaesthesia on clinical outcomes in critically ill polytrauma patients. A prospective observational non-randomized single centre study. AB - Being highly unstable, the critically ill polytrauma patient represents a challenge for the anaesthesia team. The aim of this study was to compare the Entropy and Surgical Pleth Index (SPI)-guided general anaesthesia with standard haemodynamic monitoring methods used in the critically ill polytrauma patients and to evaluate the incidence of hemodynamic events, as well as the opioid and vasopressor demand. 72 patients were included in this prospective observational study, divided in two groups, the ESPI Group (N = 37, patients that benefited from Entropy and SPI monitoring) and the STDR Group (N = 35 patients that benefited from standard hemodynamic monitoring). In the ESPI Group general anaesthesia was modulated in order to maintain the Entropy levels between 40 and 60. Analgesia control was achieved by maintaining the SPI levels between 20 and 50. In the STDR Group hypnosis and analgesia were maintained using the standard criteria based on hemodynamic changes. ClinicalTrials.gov identifier NCT03095430. The incidence of hypotension episodes was significantly lower in the ESPI Group (N = 3), compared to the STDR Group (N = 71) (p < 0.05). Moreover, the Fentanyl demand was significantly lower in the ESPI Group (p < 0.0001, difference between means 5.000 +/- 0.038, 95% confidence interval 4.9250-5.0750), as well as vasopressor medication demand (p < 0.0001, difference between means 0.960 +/- 0.063, 95% confidence interval 0.8.334-1.0866). The implementation of multimodal monitoring in the critically ill polytrauma patient brings substantial benefits both to the intraoperative clinical status and to the clinical outcome of these patients by reducing the incidence of anesthesia-related complications. PMID- 28856632 TI - Impact of perioperative liver dysfunction on in-hospital mortality and long-term survival in infective endocarditis patients. AB - PURPOSE: Infective endocarditis (IE) is often associated with multiorgan dysfunction and mortality. The impact of perioperative liver dysfunction (LD) on outcome remains unclear and little is known about factors leading to postoperative LD. METHODS: We performed a retrospective, single-center analysis on 285 patients with left-sided IE without pre-existing chronic liver disease referred to our center between 2007 and 2013 for valve surgery. Sequential organ failure assessment (SOFA) score was used to evaluate organ dysfunction. Chi square, Cox regression, and multivariate analyses were used for evaluation. RESULTS: Preoperative LD (Bilirubin >20 MUmol/L) was present in 68 of 285 patients. New, postoperative LD occurred in 54 patients. Hypoxic hepatitis presented the most common origin of LD, accompanied with high short-term mortality. In-hospital mortality was higher in patients with preoperative and postoperative LD compared to patients without LD (51.5, 24.1, and 10.4%, respectively, p < 0.001). 5-year survival was worse in patients with pre- or postoperative LD compared to patients without LD (20.1, 37.1, and 57.0% respectively). A landmark analysis revealed similar 5-year survival between groups after patient discharge. Quality of life was similar between groups when patients survived the perioperative period. Logistic regression analysis identified duration of cardiopulmonary bypass and S. aureus infection as independent predictors of postoperative LD. CONCLUSIONS: Perioperative liver dysfunction in patients with infective endocarditis is an independent predictor of short- and long-term mortalities. After surviving the hospital stay, 5-year prognosis is not different and quality of life is not affected by LD. S. aureus and duration of cardiopulmonary bypass represent risk factors for postoperative LD. PMID- 28856633 TI - Automated bedside flow cytometer for mHLA-DR expression measurement: a comparison study with reference protocol. AB - BACKGROUND: In various ICU conditions, measurement of diminished expression of human leukocyte antigen-DR on circulating monocytes (mHLA-DR) by flow cytometry appears to be a reliable marker of acquired immunosuppression. Low mHLA-DR is associated with an increased risk of nosocomial infections and mortality. Nevertheless, its use remains somewhat limited and has not been adopted in common medical practice. The main drawback of mHLA-DR measurement is likely related to the use of flow cytometry that is not accessible everywhere on a 24/7 basis. Recently, the Accellix system, a fully automated table top cytometer, was developed for use at bedside or emergency labs. METHODS: The objective was to assess the performance of the Accellix (beta site evaluation including repeatability and method comparison with reference protocol) for the measurement of mHLA-DR expression. RESULTS: Accellix repeatability at low and high expression levels of mHLA-DR was < 10% (i.e., within the range of acceptability for clinical flow cytometry). In comparison study including 139 blood samples (67 septic shock patients and 17 healthy volunteers), Pearson's correlation parameters (r 2) ranged from 0.71 to 0.97 (p < 0.001). Intra-class correlation coefficient was 0.92. CONCLUSIONS: This fully automated table top cytometer appears to be a suitable tool for ICU patient monitoring and on-going clinical trials as there is no sample preparation and no need for specific skills in flow cytometry. Upon validation in a larger cohort study to reinforce reliability, Accellix could represent a major step to make flow cytometry accessible to clinicians by placing the instrument inside intensive care units or emergency laboratories. PMID- 28856634 TI - The anti-tumor effect of pachymic acid on osteosarcoma cells by inducing PTEN and Caspase 3/7-dependent apoptosis. AB - Pachymic acid (PA) is a lanostane type triterpenoid isolated from Poria cocos, which possesses an anti-tumor effect in breast cancer, prostate cancer, lung cancer, and bladder cancer cells. In this study, we investigated the effect of PA on the growth and apoptosis of human immortalized cell line (HOS) and primary osteosarcoma cells by a Cell Counting Kit-8 (CCK-8) and Annexin V and propidium iodide (PI) staining, respectively. Western blot was used to measure the expression of cleaved Caspase 3, PTEN, and AKT, as well as the AKT phosphorylation. The Caspase 3 activity was determined using the Caspase-3 Colorimetric Assay Kit. From the results, PA significantly reduced cell proliferation in a concentration- and time-dependent manner. PA also induced cell apoptosis in a dose-dependent fashion. PA treatment led to increased Caspase 3 activation and PTEN expression, as well as reduced AKT phosphorylation. Moreover, Ac-DEVD-CHO (a Caspase 3/7 inhibitor) pre-treatment or PTEN knockdown partially blocked the effects of PA on cell proliferation and apoptosis. Caspase 3/7 inhibitor had an additive effect with PTEN knockdown. Collectively, our results suggested that induction of apoptosis by PA was mediated in part by PTEN/AKT signaling and Caspase 3/7 activity. This study provides evidence that PA might be useful in the treatment of human osteosarcoma. PMID- 28856635 TI - Umbilical Serum Copper Status and Neonatal Birth Outcomes: a Prospective Cohort Study. AB - Our study aimed to assess the distribution of copper (Cu) in umbilical cord serum and estimated the association between umbilical serum Cu status and neonatal birth outcomes in a Chinese population. Through the Ma'anShan Birth Cohort Study, 2689 maternal-singleton pairs with detailed birth records and available serum samples were identified. The tertile levels of ln-transformed Cu were used to define low, medium, and high levels for serum Cu. The median for umbilical cord serum Cu was 298.2 MUg/L with a range of 123.1-699.6 MUg/L in this study population. Our study found a positive association between the concentration of serum Cu in the umbilical cord and the duration of gestation. Compared with medium Cu levels, we found that infants with low Cu levels had a significant higher risk of preterm birth (OR = 5.06, 95% CI 2.74, 9.34) and early-term birth (OR = 1.36, 95% CI 1.10, 1.69) in the crude model. We also found that infants with high Cu levels had a significant higher risk of late- or post-term birth (OR = 1.47, 95% CI 1.11, 1.95). A significant higher risk of preterm, early-term, and late- or post-term birth still remained, even after adjustment for potential confounding factors. Our findings suggested that both Cu deficiency and Cu overload had an adverse effect on neonatal birth outcomes. PMID- 28856636 TI - Wheat Rust Surveillance: Field Disease Scoring and Sample Collection for Phenotyping and Molecular Genotyping. AB - Long-distance migration capacity, emergence of invasive lineages, and variability in adaptation to a wide range of climatic conditions make wheat rusts the most important threat to wheat production worldwide. Efficient and coordinated efforts are required for surveillance of the pathogen population at different geographical levels to enable tracking of rust pathogen populations at local, regional, continental, and ultimately worldwide scale. Here we describe a standard procedure for rust surveillance to enable comparison across various research groups for a final compilation. The procedure described would enable tracking of disease severity, field level expression of host resistance, and collection of samples for further virulence phenotyping and molecular genotyping. PMID- 28856637 TI - Field Pathogenomics: An Advanced Tool for Wheat Rust Surveillance. AB - Traditionally, diagnostic tools for plant pathogens were limited to the analysis of purified pathogen isolates subjected to phenotypic characterization and/or PCR based genotypic analysis. However, these approaches detect only already known pathogenic agents, may not always recognize novel races, and can introduce bias in the results. Recent advances in next-generation sequencing technologies have provided new opportunities to integrate high-resolution genotype data into pathogen surveillance programs. Here, we describe some of the key bioinformatics analysis used in the newly developed "Field Pathogenomics" pathogen surveillance technique. This technique is based on RNA-seq data generated directly form pathogen-infected plant leaf samples collected in the field, providing a unique opportunity to characterize the pathogen population and its host directly in their natural environment. We describe two main analyses: (1) a phylogenetic analysis of the pathogen isolates that have been collected to understand how they are related to each other, and (2) a population structure analysis to provide insight into the genetic substructure within the pathogen population. This provides a high-resolution representation of pathogen population dynamics directly in the field, providing new insights into pathogen biology, population structure, and pathogenesis. PMID- 28856638 TI - Race Typing of Puccinia striiformis on Wheat. AB - A procedure for virulence phenotyping of isolates of yellow (stripe) rust using spray inoculation of wheat seedlings by spores suspended in an engineered fluid, NovecTM 7100, is presented. Differential sets consisting of near-isogenic Avocet lines, selected lines from the "World" and "European" sets, and additional varieties showing race-specificity facilitate a robust assessment of race, irrespectively of geographical and evolutionary origin of isolates. A simple procedure for purification of samples consisting of multiple races is also presented. PMID- 28856639 TI - Assessment of Aggressiveness of Puccinia striiformis on Wheat. AB - A simple point-inoculation method using NovecTM 7100, a volatile engineered fluid, is presented for the assessment of aggressiveness of Puccinia striiformis isolates on seedlings of wheat. The method allows for quantification of the applied inoculum with a minimal risk of cross-contamination of rust from leaves grown side by side. The method is also applicable for the assessment of qualitative differences inferred by compatible and incompatible host-pathogen interactions, and it can be adjusted to other cereal rust and powdery mildew fungi on other host species, and other plant growth stages as appropriate. PMID- 28856640 TI - Extraction of High Molecular Weight DNA from Fungal Rust Spores for Long Read Sequencing. AB - Wheat rust fungi are complex organisms with a complete life cycle that involves two different host plants and five different spore types. During the asexual infection cycle on wheat, rusts produce massive amounts of dikaryotic urediniospores. These spores are dikaryotic (two nuclei) with each nucleus containing one haploid genome. This dikaryotic state is likely to contribute to their evolutionary success, making them some of the major wheat pathogens globally. Despite this, most published wheat rust genomes are highly fragmented and contain very little haplotype-specific sequence information. Current long read sequencing technologies hold great promise to provide more contiguous and haplotype-phased genome assemblies. Long reads are able to span repetitive regions and phase structural differences between the haplomes. This increased genome resolution enables the identification of complex loci and the study of genome evolution beyond simple nucleotide polymorphisms. Long-read technologies require pure high molecular weight DNA as an input for sequencing. Here, we describe a DNA extraction protocol for rust spores that yields pure double stranded DNA molecules with molecular weight of >50 kilo-base pairs (kbp). The isolated DNA is of sufficient purity for PacBio long-read sequencing, but may require additional purification for other sequencing technologies such as Nanopore and 10* Genomics. PMID- 28856641 TI - Microsatellite Genotyping of the Wheat Yellow Rust Pathogen Puccinia striiformis. AB - To combat the ever-increasing threat of wheat yellow rust worldwide, understanding of the pathogen (Puccinia striiformis) population biology is indispensable. Molecular markers, particularly microsatellites, have been reported to be important tools for deciphering pathogen population structure, invasion sources, and migration history. The utility of these DNA-based markers and sequencing has been increased by the direct DNA extraction from infected leaves with subsequent multiplex-based SSR genotyping. In this chapter we describe the protocol for direct DNA extraction and its genotyping with microsatellite markers in multiplex reactions. We describe the procedure for allele scoring, and various troubles faced during microsatellite scoring and potential solutions for them. PMID- 28856642 TI - Computational Methods for Predicting Effectors in Rust Pathogens. AB - Lower costs and improved sequencing technologies have led to a large number of high-quality rust pathogen genomes and deeper characterization of gene expression profiles during early and late infection stages. However, the set of secreted proteins expressed during infection is too large for experimental investigations and contains not only effectors but also proteins that play a role in niche colonization or in fighting off competing microbes. Therefore, accurate computational prediction is essential for identifying high-priority rust effector candidates from secretomes. PMID- 28856643 TI - Protein-Protein Interaction Assays with Effector-GFP Fusions in Nicotiana benthamiana. AB - Plant parasites secrete proteins known as effectors into host tissues to manipulate host cell structures and functions. One of the major goals in effector biology is to determine the host cell compartments and the protein complexes in which effectors accumulate. Here, we describe a five-step pipeline that we routinely use in our lab to achieve this goal, which consists of (1) Golden Gate assembly of pathogen effector-green fluorescent protein (GFP) fusions into binary vectors, (2) Agrobacterium-mediated heterologous protein expression in Nicotiana benthamiana leaf cells, (3) laser-scanning confocal microscopy assay, (4) anti GFP coimmunoprecipitation-liquid chromatography-tandem mass spectrometry (coIP/MS) assay, and (5) anti-GFP western blotting. This pipeline is suitable for rapid, cost-effective, and medium-throughput screening of pathogen effectors in planta. PMID- 28856644 TI - Proteome Profiling by 2D-Liquid Chromatography Method for Wheat-Rust Interaction. AB - Wheat-rust interactions are extremely complex biological processes which are accompanied with the defense/attack responses to survive and overcome pathogen attack or plant defense. Understanding of molecular mechanism of these interactions is a promising way to develop sustainable combat. Therefore, many studies have been performed to reveal the active host and pathogen-derived genes and their products during the infection or defense using different approaches for many decades. Particularly proteomics technology and proteome profiling which is a large scale analysis of a protein mixture to reveal differently expressed proteins under a certain conditions has become a very important tool for providing real insights into the extremely complex interactions. Moreover, this type of research has the potential to explore target proteins/genes such as effectors that can be used in disease management strategies. Hence, in this chapter we describe the proteome profiling protocols by using 2D-LC system. PMID- 28856645 TI - Investigating Gene Function in Cereal Rust Fungi by Plant-Mediated Virus-Induced Gene Silencing. AB - Cereal rust fungi are destructive pathogens, threatening grain production worldwide. Targeted breeding for resistance utilizing host resistance genes has been effective. However, breakdown of resistance occurs frequently and continued efforts are needed to understand how these fungi overcome resistance and to expand the range of available resistance genes. Whole genome sequencing, transcriptomic and proteomic studies followed by genome-wide computational and comparative analyses have identified large repertoire of genes in rust fungi among which are candidates predicted to code for pathogenicity and virulence factors. Some of these genes represent defence triggering avirulence effectors. However, functions of most genes still needs to be assessed to understand the biology of these obligate biotrophic pathogens. Since genetic manipulations such as gene deletion and genetic transformation are not yet feasible in rust fungi, performing functional gene studies is challenging. Recently, Host-induced gene silencing (HIGS) has emerged as a useful tool to characterize gene function in rust fungi while infecting and growing in host plants. We utilized Barley stripe mosaic virus-mediated virus induced gene silencing (BSMV-VIGS) to induce HIGS of candidate rust fungal genes in the wheat host to determine their role in plant fungal interactions. Here, we describe the methods for using BSMV-VIGS in wheat for functional genomics study in cereal rust fungi. PMID- 28856646 TI - Apoplastic Sugar Extraction and Quantification from Wheat Leaves Infected with Biotrophic Fungi. AB - Biotrophic fungi such as rusts modify the nutrient status of their hosts by extracting sugars. Hemibiotrophic and biotrophic fungi obtain nutrients from the cytoplasm of host cells and/or the apoplastic spaces. Uptake of nutrients from the cytoplasm is via intracellular hyphae or more complex structures such as haustoria. Apoplastic nutrients are taken up by intercellular hyphae. Overall the infection creates a sink causing remobilization of nutrients from local and distal tissues. The main mobile sugar in plants is sucrose which is absorbed via plant or fungal transporters once unloaded into the cytoplasm or the apoplast. Infection by fungal pathogens alters the apoplastic sugar contents and stimulates the influx of nutrients towards the site of infection as the host tissue transitions to sink. Quantification of solutes in the apoplast can help to understand the allocation of nutrients during infection. However, separation of apoplastic fluids from whole tissue is not straightforward and leakage from damaged cells can alter the results of the extraction. Here, we describe how variation in cytoplasmic contamination and infiltrated leaf volumes must be controlled when extracting apoplastic fluids from healthy and rust-infected wheat leaves. We show the importance of correcting the data for these parameters to measure sugar concentrations accurately. PMID- 28856647 TI - Genetic Analysis of Resistance to Wheat Rusts. AB - Leaf rust, stripe rust, and stem rust pose a significant threat to global wheat production. Growing rust resistant cultivars is the most efficient and environment friendly method to reduce yield losses. Genetic analysis is undertaken to identify genes and study their roles in conferring rust resistance in a given wheat background. This chapter summarizes the protocol for genetic analysis of rust resistance at both seedling and adult plant stages. Additionally, it examines statistical analysis and related software to characterize quantitative trait loci (QTL) linked with rust resistance. PMID- 28856648 TI - Advances in Identification and Mapping of Rust Resistance Genes in Wheat. AB - Genetic characterisation of new rust resistance loci in wheat using cytogenetic/low-throughput genotyping systems required at least 5 years. Development of next-generation sequencing (NGS) based molecular marker genotyping platforms in the last decade has provided scientists with the genomic resources to expedite precise mapping of target loci. Here, we describe methodologies for genetic analysis and application of NGS-based resources to determine the precise genomic locations of rust resistance loci in wheat and development of closely linked markers for marker assisted selection. PMID- 28856649 TI - Chromosome Engineering Techniques for Targeted Introgression of Rust Resistance from Wild Wheat Relatives. AB - Hexaploid wheat has relatively narrow genetic diversity due to its evolution and domestication history compared to its wild relatives that often carry agronomically important traits including resistance to biotic and abiotic stresses. Many genes have been introgressed into wheat from wild relatives using various strategies and protocols. One of the important issues with these introgressions is linkage drag, i.e., in addition to beneficial genes, undesirable or deleterious genes that negatively influence end-use quality and grain yield are also introgressed. Linkage drag is responsible for limiting the use of alien genes in breeding programs. Therefore, a lot of effort has been devoted to reduce linkage drag. If a gene of interest is in the primary gene pool or on a homologous chromosome from species in the secondary gene pool, it can be introgressed into common wheat by direct crosses and homologous recombination. However, if a gene of interest is on a homoeologous chromosome of a species belonging to the secondary or tertiary gene pools, chromosome engineering is required to make the transfer and to break any linkage drag. Four general approaches are used to transfer genes from homoeologous chromosomes of wild relatives to wheat chromosomes, namely, spontaneous translocations, radiation, tissue culture, and induced homoeologous recombination. The last is the method of choice provided the target gene(s) is not located near the centromere where recombination is lacking or is suppressed, and synteny between the alien chromosome carrying the gene and the recipient wheat chromosome is conserved. In this chapter, we focus on the homoeologous recombination-based chromosome engineering approach and use rust resistance genes in wild relatives of wheat as examples. The methodology will be applicable to other alien genes and other crops. PMID- 28856650 TI - Applications of Genomic Selection in Breeding Wheat for Rust Resistance. AB - There are a lot of methods developed to predict untested phenotypes in schemes commonly used in genomic selection (GS) breeding. The use of GS for predicting disease resistance has its own particularities: (a) most populations shows additivity in quantitative adult plant resistance (APR); (b) resistance needs effective combinations of major and minor genes; and (c) phenotype is commonly expressed in ordinal categorical traits, whereas most parametric applications assume that the response variable is continuous and normally distributed. Machine learning methods (MLM) can take advantage of examples (data) that capture characteristics of interest from an unknown underlying probability distribution (i.e., data-driven). We introduce some state-of-the-art MLM capable to predict rust resistance in wheat. We also present two parametric R packages for the reader to be able to compare. PMID- 28856651 TI - Rapid Phenotyping Adult Plant Resistance to Stem Rust in Wheat Grown under Controlled Conditions. AB - Stem rust (SR) or black rust caused by Puccinia graminis f. sp. tritici is one of the most common diseases of wheat (Triticum aestivum L.) crops globally. Among the various control measures, the most efficient and sustainable approach is the deployment of genetically resistant cultivars. Traditionally, wheat breeding programs deployed genetic resistance in cultivars, but unknowingly this is often underpinned by a single seedling resistance gene, which is readily overcome by the pathogen. Nowadays, adult plant resistance (APR) is a widely adopted form of rust resistance because more durable mechanisms often underpin it. However, only a handful of SR APR genes are available, so breeders currently strive to combine seedling and APR genes. Phenotyping adult wheat plants for resistance to SR typically involves evaluation in the field. But establishing a rust nursery can be challenging, and screening is limited to once a year. This slows down research efforts to isolate new APR genes and breeding of genetically resistant cultivars.In this study, we report a protocol for rapid evaluation of adult wheat plants for resistance to stem rust. We demonstrate the technique by evaluating a panel of 16 wheat genotypes consisting of near isogenic lines (NILs) for known Sr genes (i.e., Sr2, Sr33, Sr45, Sr50, Sr55, Sr57, and Sr58) and three landraces carrying uncharacterized APR from the N. I. Vavilov Institute of Plant Genetic Resources (VIR). The method can be completed in just 10 weeks and involves two inoculations: first conducted at seedling stage and a second at the adult stage (using the same plants). The technique can detect APR, such as that conferred by APR gene Sr2, along with pseudo-black chaff (the morphological marker). Phenotyping can be conducted throughout the year, and is fast and resource efficient. Further, the phenotyping method can be applied to screen breeding populations or germplasm accessions using local or exotic races of SR. PMID- 28856652 TI - Generation of Loss-of-Function Mutants for Wheat Rust Disease Resistance Gene Cloning. AB - One of the most important tools to identify and validate rust resistance gene function is by producing loss-of-function mutants. Mutants can be produced using irradiation, chemicals, and insertions. Among all the mutagens, ethyl methanesulfonate (EMS) and sodium azide are most favored because of the ease of use and generation of random point mutations in the genome. The mutants so produced facilitate the isolation, identification and cloning of rust resistance genes. In this chapter we describe a protocol for seed mutagenesis of wheat with EMS and sodium azide. PMID- 28856653 TI - Isolation of Wheat Genomic DNA for Gene Mapping and Cloning. AB - DNA is widely used in plant genetic and molecular biology studies. In this chapter, we describe how to extract DNA from wheat tissues. The tissue samples are ground to disrupt the cell wall. Then cetyltrimethylammonium bromide (CTAB) or sodium dodecyl sulfate (SDS) is used to disrupt the cell and nuclear membranes to release the DNA into solution. A reducing agent, beta-mercaptoethanol, is added to break the disulfide bonds between the cysteine residues and to help remove the tanins and polyphenols. A high concentration of salt is employed to remove polysaccharides. Ethylenediaminetetraacetic acid (EDTA) stops DNase activity by chelating the magnesium ions. The nucleic acid solution is extracted with chloroform-isoamyl alcohol (24:1) or 6 M ammonium acetate. The DNA in aqueous phase is precipated with ethanol or isopropanol, which makes DNA less hydrophilic in the presence of sodium ions (Na+). PMID- 28856654 TI - MutRenSeq: A Method for Rapid Cloning of Plant Disease Resistance Genes. AB - MutRenSeq is a method to clone disease resistance (R) genes in plants. Tips and detailed experimental protocols for the pipeline, including the complexity reduction by R gene targeted enrichment sequencing, and computational analysis based on comparative genomics are provided in this chapter. PMID- 28856655 TI - Rapid Gene Isolation Using MutChromSeq. AB - MutChromSeq is an approach for isolation of genes and DNA sequences controlling gene expression in plants with complex and polyploid genomes. It involves a lossless complexity reduction by flow cytometric chromosome sorting and shotgun sequencing DNA from isolated chromosomes. Comparison of sequences from wild-type parental chromosome with chromosomes from multiple independently derived mutants identifies causative mutations in a single candidate gene or a noncoding sequence. MutChromSeq does not rely on recombination-based genetic mapping and does not exclude any DNA sequence from being targeted. PMID- 28856656 TI - Rapid Identification of Rust Resistance Genes Through Cultivar-Specific De Novo Chromosome Assemblies. AB - "Map-based cloning" is a frequently used approach to isolate rust resistance genes. A critical step during map-based cloning is the transition from genetic information, i.e., a genetic map, to physical sequence information. Bacterial artificial chromosome clones are often used to establish sequence information spanning a genetic interval. However, a major limitation of BAC clones consists in their small insert size of 100-200 kb. Targeted chromosome-based cloning via long-range assembly (TACCA) is a method that can replace BAC library screening. This approach involves chromosome flow-sorting and the establishment of a long range de novo assembly. This chapter provides an overview of TACCA as well as a detailed description of sequence analyses, molecular marker development, and candidate gene identification. PMID- 28856657 TI - BSMV-Induced Gene Silencing Assay for Functional Analysis of Wheat Rust Resistance. AB - Virus-induced gene silencing (VIGS) is a widely used reverse genetics tool to knock down genes in plants transiently without transformation. The assay has been successfully used to downregulate the transcript abundance of a target gene at almost any plant developmental stages in any tissues. Here, we describe the VIGS assay using a barley stripe mosaic virus (BSMV) for functional genomics analysis in wheat with the focus on genes involved in rust resistance. PMID- 28856658 TI - Yeast as a Heterologous System to Functionally Characterize a Multiple Rust Resistance Gene that Encodes a Hexose Transporter. AB - Recently, the Lr67 resistance gene was identified as a hexose transporter variant which confers adult plant rust and mildew resistance in wheat. Methodologies used to characterize the protein encoded by Lr67 may be of use to non-transporter experts conducting similar experiments with other hexose transporters. Hence, in this chapter, we detail a protocol for the functional characterization of hexose transporter proteins in the Saccharomyces cerevisiae expression system. We also provide guidance on the use of metabolic inhibitors and competing sugars to probe transporter structural features, energization, and specificity. PMID- 28856659 TI - Biocontrol Agents for Controlling Wheat Rust. AB - Bacterial endophytes are potential biocontrol agents of wheat rusts. Apart from disease control, these bacterial endophytes have growth-promoting efficacies which differ significantly from one isolate to another. Here, we describe the procedure for isolation, screening, and identification of endophytic bacterial isolates with high capacities to suppress strip rust infection and better ability to enhance wheat yields. PMID- 28856660 TI - Prognostic indicators of survival and survival prediction model following extracorporeal cardiopulmonary resuscitation in patients with sudden refractory cardiac arrest. AB - BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) has been considered in selected candidates with potentially reversible causes during a limited period. Candidate selection and the identification of predictable conditions are important factors in determining outcomes during CPR in the emergency department (ED). The objective of this study was to determine the key indicators and develop a prediction model for survival to hospital discharge in patients with sudden cardiac arrest who received ECPR. METHODS: This retrospective analysis was based on a prospective cohort, which included data on CPR with ECPR-related variables. Patients with sudden cardiac arrest who received ECPR at the ED from May 2006 to June 2016 were included. The primary outcome was survival to discharge. Prognostic indicators and the prediction model were analyzed using logistic regression. RESULTS: Out of 111 ECPR patients, there were 18.9% survivors. Survivors showed younger age, shorter CPR duration (p < 0.05) and had tendencies of higher rate of initial shockable rhythm (p = 0.055) and higher rate of any ROSC event before ECPR (p = 0.066) than non-survivors. Eighty one percent of survivors showed favorable neurologic outcome at discharge. In univariate analysis, the following factors were associated with survival: no preexisting comorbidities, initial serum hemoglobin level >=14 g/dL, and mean arterial pressure >=60 mmHg after ECPR. Based on multivariate logistic regression, predictors for survival in ECPR were as follows: age <=56 years, no asystole as the initial arrest rhythm, CPR duration of <=55 min, and any return of spontaneous circulation (ROSC) event before ECPR. The prediction scoring model for survival had a c-statistic of 0.875. CONCLUSIONS: With careful consideration of differences in the inclusion criteria, the prognostic indicators and prediction scoring model for survival in our study may be helpful in the rapid decision-making process for ECPR implementation during CPR in the ED. PMID- 28856661 TI - The views of children and young people on the use of silk garments for the treatment of eczema: a nested qualitative study within the CLOTHing for the relief of Eczema Symptoms (CLOTHES) randomized controlled trial. AB - BACKGROUND: Many children suffer with skin diseases but to date most dermatological research has been done 'on' rather than 'with' children; in this study we actively sought the experiences of children and young people. Atopic eczema (AE) is a chronic, itchy, inflammatory skin condition that affects around 20% of children and can impact on the health and wellbeing of children and their families. The role of specialist clothing in the management of AE is poorly understood. OBJECTIVES: The aim of this study, which was nested in a randomized controlled trial, was to qualitatively examine child participants' experiences of using silk garments for the treatment of AE. METHODS: Eighteen children aged 5-15 years, who took part in the CLOTHing for the relief of Eczema Symptoms (CLOTHES) trial, participated in age-appropriate individual interviews or focus groups. RESULTS: Thematic analysis generated four themes directly related to the silk garments: (i) expectations of the garments; (ii) wearing the garments; (iii) asking if the garments helped; and (iv) thoughts about the garments. The conclusions from this nested qualitative study are that there was some limited improvement in eczema for some children but that the hoped-for 'miracle cure' did not transpire. A mixed picture of knowledge, beliefs and experiences of using the silk garments emerged. CONCLUSIONS: Engaging children in the evaluation of the garments provided first-hand nuanced insights that enhanced understanding of the CLOTHES study as a whole. This nested study demonstrates that children can and indeed want to be engaged in dermatological research in meaningful ways that add to our understanding of treatment options. PMID- 28856662 TI - Lupus panniculitis refractory to multiple therapies treated successfully with rituximab: A case report and literature review. PMID- 28856663 TI - Indelible Marks: The Practice of Humanity in the Art of Medicine. PMID- 28856664 TI - IgA multiple myeloma in a patient with an IgG pemphigus foliaceus-like exanthem. PMID- 28856665 TI - Discharge Plans for Geriatric Inpatients with Delirium: A Plan to Stop Antipsychotics? AB - BACKGROUND: Studies show inpatient geriatric patients with reversible conditions like delirium may continue on antipsychotic medications without clear indications after hospital discharge. We conducted this study to determine how often geriatric patients were discharged on a newly started antipsychotic during admission with a plan for discontinuation of the antipsychotic documented in the discharge summary. DESIGN: We conducted retrospective chart review identifying geriatric inpatients in our health system started on a new antipsychotic during admission. In patients discharged from the hospital on a new antipsychotic, we examined the discharge summary for a discontinuation treatment plan. RESULTS: Of 487 patients started on a new antipsychotic, 147 (30.2%) were discharged on the antipsychotic. Of those, 121 (82.3%) had a diagnosis of delirium. Discharge summaries of 15 (12.4%) patients discharged on an antipsychotic with a diagnosis of delirium included instructions for discontinuation of the antipsychotic. Of those patients discharged with instructions for discontinuation, 12 (80%) received a psychiatric or geriatric medicine consult. CONCLUSION: In our health system, the majority of geriatric patients with delirium, discharged on a new antipsychotic had no instructions outlined to outpatient providers for discontinuation management. Further interventions could target increasing antipsychotic guidance at transitions of care. PMID- 28856666 TI - Fly Thru imaging: Feasibility study and comparison with outpatient hysteroscopy. AB - BACKGROUND: In the investigation of abnormal uterine bleeding, hysteroscopy with endometrial biopsy is considered the gold standard. Fly ThruTM imaging is a new application used to generate virtual hysteroscopy clips. AIMS: We aimed to investigate the feasibility and diagnostic accuracy of sonohysterogram with virtual hysteroscopy as an alternative to outpatient diagnostic hysteroscopy. MATERIALS AND METHODS: Two separate cohorts of women were recruited. The first cohort was to assess feasibility of the application. The second cohort included women recruited to undergo a sonohysterogram, with virtual hysteroscopy, prior to their scheduled outpatient hysteroscopy. Pain scores were recorded after each procedure. RESULTS: Sixteen women were recruited to the feasibility cohort and virtual hysteroscopy post-processing was successfully applied in 14/16 (88%). Clips were produced in less than one minute in 12/16 (75%). Both tubal ostia were identified in 12/16 (75%). Twenty-nine women were enrolled in the correlation cohort with two women excluded as they did not proceed to hysteroscopy according to study protocol. Virtual hysteroscopy, successfully generated in 23/27 women (85%), detected all intra-cavitary pathologies (9/27) detected on outpatient hysteroscopy. Tubal ostia were visualised less often with virtual hysteroscopy (37%) when compared with outpatient hysteroscopy (74%). Sonohysterogram with virtual hysteroscopy was associated with less pain with a median difference in pain score of 2 (interquartile range 1.0-4.0, P < 0.0001). CONCLUSIONS: Sonohysterogram with virtual hysteroscopy is feasible; however, the addition of virtual hysteroscopy to sonohysterogram alone has limited value. Larger studies are required to determine whether it can be used as a diagnostic alternative to outpatient hysteroscopy. PMID- 28856668 TI - Interaction Between Val158Met Catechol-O-Methyltransferase Polymorphism and Social Cognitive Functioning in Schizophrenia: Pilot Study. AB - The Val158Met catechol-O-methyltransferase (COMT) functional polymorphism may influence social cognitive functioning in patients with schizophrenia. Aspects of social cognition were evaluated with the Facial Expression Recognition Test, the Voice Emotion Recognition Test, and the Reading the Mind in the Eyes Test. The Short Recognition Memory Test for Faces was used as a control measure. The Schedule for the Assessment of Negative Symptoms, Schedule for the Assessment of Positive Symptoms, and Beck Depression Inventory were used to rate of patient symptoms. There were 100 patients with the following genotypes: Val/Val (21), Met/Met (30), and Val/Met (49). The genotype distribution of polymorphism of Val158Met COMT did not differ between the patient and control groups. Schizophrenia carriers of the Val/Val genotype performed worse in social cognitive measures, in comparison with the other groups. No statistically significant correlations were recorded between age at schizophrenia onset and polymorphism of Val158Met COMT. There was an influence of genotype in the control group: the Met homozygotes performing better. Schizophrenia patients homozygous for the Val allele showed significant disadvantages over patients homozygous or heterozygous for the Met allele in social cognitive processes. The COMT genotype may not, however, contribute to the age of onset of schizophrenia. PMID- 28856669 TI - Postmaterialism and young people's political participation in a time of austerity. AB - Recent trends suggest that young people in Britain are refraining from engaging in formal political processes. At the same time, they are increasingly expressing support for, and turning toward, a new and diverse range of non-institutionalized forms of political action in order to actualize their interests. Using Inglehart's ideas on postmaterialism, we consider whether this apparent rejection of mainstream politics in favour of less conventional - and sometimes radical - forms of political action is changing over time in Britain, reflecting fluctuating economic conditions witnessed over the last two decades. We do this by comparing results from surveys of British 18 year olds conducted in 2002 during an era of relative global prosperity, and then in 2011 at the height of the current global crisis. The findings suggest that British young postmaterialists are considerably more likely than materialists to participate in and support both institutionalized and non-institutionalized forms of political action. PMID- 28856667 TI - Respiratory syncytial virus infection influences tight junction integrity. AB - Respiratory syncytial virus (RSV) is an important risk factor of asthma development and is responsible for severe respiratory tract infections. However, the influence of RSV infection on barrier function of bronchial epithelial cells in vitro and in vivo is still unclear. The aim of this study was to analyse the role of RSV in tight junction (TJ) regulation and to compare epithelial integrity between asthmatic and healthy individuals upon RSV infection. Healthy and asthmatic human bronchial epithelial cells (HBECs) were differentiated at air liquid interface (ALI) and infected with RSV and ultraviolet (UV)-irradiated RSV. TJ expression and their integrity were analysed by quantitative polymerase chain reaction (qPCR), transepithelial resistance (TER) and paracellular flux. To determine the effect in vivo, BALB/c mice were infected intranasally with RSV or UV-irradiated RSV A2. Bronchoalveolar lavage and TJ integrity were analysed on days 1, 2, 4 and 6 post-infection by qPCR, bioplex and confocal microscopy. RSV increased barrier integrity in ALI cultures of HBEC from healthy subjects, but no effect was found in HBECs from asthmatics. This was not associated with an increase in TJ mRNA expression. In vivo, RSV induced lung inflammation in mice and down-regulated claudin-1 and occludin mRNA expression in whole lungs. Surprisingly, RSV infection was not observed in bronchial epithelial cells, but was found in the lung parenchyma. Decreased expression of occludin upon RSV infection was visible in mouse bronchial epithelial cells in confocal microscopy. However, there was no regulation of claudin-1 and claudin-7 at protein level. PMID- 28856670 TI - Very preterm birth before arrival at hospital. AB - BACKGROUND: Our aim was to report perinatal characteristics of very preterm births before arrival (BBAs) at a hospital, and perinatal and infant mortality rates up to one year, comparing BBAs with births in a hospital. MATERIALS AND METHODS: A population-based cohort study of 22-31 weeks' gestation births in the state of Victoria, Australia from 1990-2009. BBAs were defined as unintentional births at home or on route to hospital. Perinatal data were obtained from the Department of Health and Human Services, Victoria. Perinatal and infant mortality data comparing BBAs with births in hospitals were analysed by logistic regression, adjusted for gestational age, birthweight and sex. RESULTS: One hundred and thirty-three BBAs were recorded: 51 (38%) stillbirths and 82 (62%) livebirths. Compared with births in a hospital, BBAs were less mature (26.3 weeks (SD 2.9) vs 27.7 weeks (SD 2.8), P < 0.001) and a higher proportion were born to teenagers: 13% versus 5% (adjusted odds ratio (aOR) 2.86, P < 0.001). BBAs were significantly more likely to be stillborn (aOR 2.13, 95% confidence interval (CI) 1.41, 3.23, P < 0.001) die within 28 days of livebirth (aOR 2.97, 95% CI 1.54, 5.73, P = 0.001) or die within a year of livebirth (aOR 2.87, 95% CI 1.51, 5.46, P = 0.001) compared with hospital births. Overall, 54 BBAs survived to one year (41% all BBAs, 67% liveborn BBAs), compared with 69% of hospital births (87% of livebirths). CONCLUSIONS: Very preterm birth before arrival is more common in teenagers and is associated with significantly increased risks of perinatal and infant mortality compared with birth in a hospital. PMID- 28856671 TI - Direct oral anticoagulant medications in calciphylaxis. AB - BACKGROUND: Recent studies suggest that calciphylaxis is a thrombotic condition in which arteriolar thrombosis leads to painful skin infarcts and consequent morbidity and mortality. Paradoxically, warfarin is implicated as a risk factor for calciphylaxis. Our objective is to report the use of oral direct thrombin and factor Xa inhibitors (termed direct oral anticoagulants [DOACs]) in patients with calciphylaxis. METHODS: We retrospectively reviewed records of 16 patients with calciphylaxis who received concomitant administration of novel anticoagulants. Patient data, including demographics, comorbidities, other treatments, and adverse events, were abstracted from the health records. RESULTS: Eleven patients (69%) had chronic kidney disease (stage >=3A), and eight (50%) received dialysis. Apixaban was the most frequently used agent (n = 11 [69%]). Dabigatran (n = 4 [25%]) and rivaroxaban (n = 2 [13%]) were reserved for patients with mild renal impairment (stage <=2). One clinically relevant but nonmajor bleeding event occurred. There were no major bleeding events. Nine patients (56%) were alive at last follow-up, and five (31%) had complete resolution of their calciphylaxis (mean follow-up, 523 days; range, 26-1884 days). CONCLUSION: DOACs were safe and well tolerated in patients with calciphylaxis, in this initial experience. Several patients had improvement or resolution of calciphylaxis in response to therapy that included DOACs. The degree of renal impairment should guide DOAC choice. Randomized trials are required to determine treatment efficacy. PMID- 28856672 TI - Acne treatment in antiquity: can approaches from the past be relevant in the future? PMID- 28856673 TI - Small-p politics: how pleasurable, convivial and pragmatic political ideals influence engagement in eat-local initiatives. AB - Non-confrontational engagement practices like ethical consumption are a popular form of everyday politics. Existing research into these practices offers positive evaluations (highlighting the value of everyday engagement in public life) and critical perspectives (questioning whether myriad small acts can address structural barriers to equity and sustainability). Meanwhile, less emphasis has been placed on understanding the underlying ideals and motivations for political action that seeks to avoid traditional politics. In order to advance such understanding, this case study uses participant observation and semi-structured interviews with 57 individuals whose daily paid or unpaid leadership roles shape eat-local initiatives. We find that in the local food realm, participants idealize pleasurable, convivial and pragmatic engagement and these ideals culminate in a particular form of everyday action we term 'small-p politics'. The paper offers a theoretically and empirically informed investigation of non traditional political engagement in eat-local movements, concluding that it emerges from a site where: (a) cultural change is prioritized above contentious politics; (b) rejecting traditional political activity is linked with achieving tangible outcomes; and (c) consumers are deemed the ideal agents of change. Non traditional politics play a prominent role in the landscape of contemporary civic engagement. This research advances our existing knowledge of such practices by providing a thick description of the political ideals that endorse consumption based approaches to change in the realm of local food. PMID- 28856674 TI - Institutional change and parental compensation in intergenerational attainment. AB - Previous research has shown how institutional changes, such as educational expansion, have weakened parental influence on educational attainment. We extend this analysis to occupational attainment and put forth a parental compensation hypothesis: as the origin-education (OE) association weakens, parents act to compensate for this in order to maintain their influence on the child's occupational attainment. We should see this as a strengthened origin-destination association net of education (net OD). Further, we study whether these compensatory actions are triggered by changes in educational institutions and whether the institutional changes that reduce educational inequality are the same ones that prompt parental compensation. We have linked data from five waves of the European Social Survey (2002-10) with data on educational institutions matched to birth cohorts born 1941-80 in 25 countries. We find weakened OE and strengthened net OD associations, supporting our parental compensation hypothesis. Multilevel mixed effects regression analyses reveal that reforms lengthening compulsory education, and the increased access to and the attainment of higher education have had a positive influence on parental compensation. As a conclusion, a later school leaving age seems to secure increased parental influence on children's occupational attainment, while parents seem to have reacted to a lesser extent on the changes in higher education. PMID- 28856675 TI - Failure of initial disease control in bullous pemphigoid: a retrospective study of hospitalized patients in a single tertiary center. AB - BACKGROUND: Bullous pemphigoid (BP) is the most prevalent autoimmune blistering skin disease in Western countries and in Israel. Initial disease control is achieved in 60-90% of BP patients within 1-4 weeks of corticosteroid therapy. In the remainder of patients, recalcitrant disease is controlled with additional immunosuppressive treatment. OBJECTIVES: We aimed to evaluate the rate of BP patients who needed adjuvant therapy to achieve initial disease control and to identify potential predictors for recalcitrant disease. METHODS: We conducted a retrospective study of newly diagnosed BP patients who were hospitalized at the Tel Aviv Sourasky Medical Center between the years 2008-2014. We performed statistical analyses to assess the association between clinical factors and failure of initial disease control. RESULTS: Among 114 hospitalized patients with newly diagnosed BP, 1.8% presented with oral mucosa involvement. Seven patients (6.1%) required systemic agents in addition to corticosteroids to achieve disease control. Hypertension (P = 0.048), involvement of the head region (P = 0.042), and metformin treatment (P = 0.02) were significantly more prevalent among patients with recalcitrant disease. CONCLUSIONS: The low frequency of recalcitrant BP (6.1%) and the rarity of involvement of the oral mucosa (1.8%) in this study suggest that Israeli BP patients present a milder phenotype compared to similar patients from other geographic areas. Hypertension, head involvement, and metformin therapy were found to be significantly associated with the need for adjuvant therapy to achieve initial control, suggesting that these parameters may serve as predictors of treatment response in BP. PMID- 28856676 TI - Trichoscopy - a useful tool in the preliminary differential diagnosis of autoimmune bullous diseases. AB - BACKGROUND: Scalp is a common location of autoimmune bullous diseases. Trichoscopy is a noninvasive method for diagnosing hair and scalp diseases. Data on trichoscopy in autoimmune bullous diseases are limited to the studies on pemphigus including a small number of patients. Trichoscopic characteristics of bullous pemphigoid and dermatitis herpetiformis were not reported to date. The aim of the study was to determine the value of trichoscopy in the differential diagnosis of pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, and dermatitis herpetiformis. METHODS: Trichoscopy was used to evaluate scalp lesions in 68 patients (26 with pemphigus vulgaris, 17 with pemphigus foliaceus, 17 with bullous pemphigoid, and 8 with dermatitis herpetiformis). The working magnification was 20-fold and 70-fold. RESULTS: The most frequent trichoscopic feature of autoimmune bullous diseases was extravasations. They occurred in 76.9% of patients with pemphigus vulgaris, 70.6% of patients with pemphigus foliaceus, 76.5% of patients with bullous pemphigoid, and 100% of patients with dermatitis herpetiformis. Yellow hemorrhagic crusts occurred in, respectively, 73.1%, 70.6%, 64.7%, and 35.5% of the cases. Yellow diffuse scaling and tubular scaling occurred more frequently in pemphigus foliaceus (52.9% and 41.2%, respectively). Clustered dotted vessels were characteristic for dermatitis herpetiformis (5/8, 62.5%). Dotted vessels with whitish halo were a hallmark of pemphigus vulgaris. A trichoscopic algorithm for the differential diagnosis of autoimmune bullous diseases was developed. CONCLUSIONS: Autoimmune bullous diseases present characteristic trichoscopic patterns. Trichoscopy can be regarded as a rapid in office preliminary diagnostic method in the differential diagnosis of these diseases. PMID- 28856677 TI - Scaffolding under the microscope: Applying self-regulation and other-regulation perspectives to a scaffolded task. AB - BACKGROUND: Typical scaffolding coding schemes provide overall scores to compare across a sample. As such, insights into the scaffolding process can be obscured: the child's contribution to the learning; the particular skills being taught and learned; and the overall changes in amount of scaffolding over the course of the task. AIMS: This study applies a transition of regulation framework to scaffolding coding, using a self-regulation and other-regulation coding scheme, to explore how rich and detailed data on mother-child dyadic interactions fit alongside collapsed sample-level scores. SAMPLE: Data of 78 mother-child dyads (M age = 9 years 10 months) from the Sisters and Brothers Study (SIBS: Pike et al., 2006, Family relationships in middle childhood. National Children's Bureau/Joseph Rowntree Foundation) were used for this analysis. METHODS: Videos of the mother and child completing a multiple-trial block design puzzle task at home were coded for their different self- and other-regulation skills at the end of every block design trial. RESULTS: These constructs were examined at a sample level, providing general findings about typical patterns of self-regulation and other regulation. Seven exemplar families at different ends of the spectrum were then extracted for fine-grained examination, showing substantial trial- and behaviour related differences between seemingly similarly scoring families. CONCLUSION: This coding scheme demonstrated the value of exploring perspectives of a mother child tutoring task aligned to the concept of other-regulation, and investigating detailed features of the interaction that go undetected in existing scaffolding coding schemes. PMID- 28856679 TI - Prevalence and determinants of seborrhoeic dermatitis in a middle-aged and elderly population: the Rotterdam Study. AB - BACKGROUND: Seborrhoeic dermatitis is a chronic relapsing inflammatory skin disease with unclear pathophysiological mechanisms. OBJECTIVES: To establish which lifestyle and physiological determinants are associated with seborrhoeic dermatitis. METHODS: Seborrhoeic dermatitis was diagnosed by a trained physician during a full-body skin examination within the Rotterdam Study, a prospective population-based cohort study in middle-aged and elderly people. The current design is a comparative cross-sectional study embedded in the Rotterdam Study. Potential factors were identified from the literature and analysed in a multivariable logistic regression, including: age, sex, obesity, skin colour, stress, depression, education level, hypertension, climate, xerosis cutis, alcohol and tobacco use. RESULTS: Of the 5498 participants, 788 participants were diagnosed with seborrhoeic dermatitis (14.3%). We found associations between seborrhoeic dermatitis and male sex [adjusted odds ratio (OR) 2.09, 95% confidence interval (CI) 1.77-2.47], darker skin (adjusted OR 0.39, 95% CI 0.22 0.69), season (summer vs. winter: adjusted OR 0.63, 95% CI 0.48-0.82) and generalized xerosis cutis (adjusted OR 1.41, 95% CI 1.11-1.80). CONCLUSIONS: Seborrhoeic dermatitis is one of the most common inflammatory dermatoses in middle-aged and elderly individuals, especially during winter. Men, and people with a light and dry skin were most likely to have seborrhoeic dermatitis. PMID- 28856680 TI - Public, patient and carers' views on palliative and end-of-life care in India. AB - AIM: To systematically review the existing evidence on the Indian public, patient and carers' perspectives on palliative and end-of-life care. BACKGROUND: With a growing population of terminally ill people across the world, there is also an increasing awareness among international health policy makers of the need to improve the quality of life for terminally ill patients. Understanding service users' (patients, family and public) perspectives is crucial in developing and sustaining successful community-centred palliative nursing policies and service models especially in countries like India with diverse population. METHODS: An integrative review was performed on five databases, using hand searches of key journals and reference citation tracking for empirical studies published in English from 1990 to 2015. A thematic analysis framework was used to analyse and identify key themes. RESULTS: Analysis of the six eligible studies revealed five themes. Themes describe how social, economic, cultural, religious, spiritual and traditional factors influenced the palliative and end-of-life care perspectives and experiences among Indians. They also illustrated preferences relating to place of care, as well as benefits and challenges of family caregiving during the last days of life. CONCLUSIONS: Although we found minimal evidence on user perspectives, nurses need to aware of those unique components of context-specific palliative and end-of-life care practices in India - socioeconomic, cultural and religious factors - on their nursing encounters. Nurses need to advocate same in policy development to enable accessibility and utility of palliative and end-of life care services, which are scant in India. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Nurses can be central in gathering the contextual evidence that advocate users' perspectives to inform further studies and national palliative care policies in India. Emerging policies in nursing education need to focus on integrating family-centred palliative and end-of-life care within curricula, whereas nursing practice may promote nurse-led community models to address the patchy palliative and end-of-life service provision in India. PMID- 28856681 TI - Reduced activation and proliferation of human lymphocytes exposed to respiratory syncytial virus compared to cells exposed to influenza virus. AB - Both respiratory syncytial virus (RSV) and influenza A virus (IAV) may infect human peripheral blood mononuclear leukocytes (PBMC) during the immune response to viral challenge as the cells are recruited to the respiratory tract. The current studies demonstrated differences in PBMC responses to the two viruses very early after exposure, including reduced fos protein and CD69 expression and IL-2 production by RSV-exposed T lymphocytes. Exposure to RSV resulted in reduced lymphocyte proliferation despite evidence of a virus-specific T lymphocyte frequency equivalent to that for influenza virus. Reduced RSV-induced proliferation was not due to apoptosis, which was itself reduced relative to that of influenza virus-exposed T lymphocytes. The data indicate that differential immune responses to RSV and influenza virus are determined early after exposure of human PBMC and support the concept that the anamnestic immune response that might prevent clinically evident reinfection is attenuated very soon after exposure to RSV. Thus, candidate RSV vaccines should be expected to reduce but not prevent clinical illness upon subsequent infection by RSV. Furthermore, effective therapeutic agents for RSV are likely to be needed, especially for high risk populations, even after vaccine development. PMID- 28856683 TI - Regulation of claudin-4 via p63 in human epithelial cells. AB - P63 is a regulator of cell-cell junction complexes in the epidermis. Claudin-4 is regulated via various factors in normal epithelial cells and diseases. We found that claudin-4 was directly regulated via p63 (TAp63 and DeltaNp63) in human keratinocytes and nasal epithelial cells. In the epidermis of atopic dermatitis (AD), which contains DeltaNp63-deficient keratinocytes, high expression of claudin-4 was observed. In primary keratinocytes, downregulation of DeltaNp63 by treatment with short interfering RNA (siRNA)-p63 induced claudin-4 expression. In nasal epithelial cells in the context of rhinitis or nasal polyps, upregulation of TAp63 and downregulation of claudin-4 were observed. In primary nasal epithelial cells transfected with the human telomerase reverse transcriptase gene, knockdown of p63 by siRNAs induced claudin-4 expression. Taken together, these findings indicate that p63 is a negative regulator of claudin-4 expression. Understanding the regulation of claudin-4 via p63 in human epithelial cells may be important for developing therapies for allergies and drug delivery systems. PMID- 28856682 TI - Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses' health study and health professionals follow-up study. AB - Although experimental evidence suggests calcium-sensing receptor (CASR) as a tumor-suppressor, the prognostic role of tumor CASR expression in colorectal carcinoma remains unclear. We hypothesized that higher tumor CASR expression might be associated with improved survival among colorectal cancer patients. We evaluated tumor expression levels of CASR by immunohistochemistry in 809 incident colorectal cancer patients within the Nurses' Health Study and the Health Professionals Follow-up Study. We used Cox proportional hazards regression models to estimate multivariable hazard ratio (HR) for the association of tumor CASR expression with colorectal cancer-specific and all-cause mortality. We adjusted for potential confounders including tumor biomarkers such as microsatellite instability, CpG island methylator phenotype, LINE-1 methylation level, expressions of PTGS2, VDR and CTNNB1 and mutations of KRAS, BRAF and PIK3CA. There were 240 colorectal cancer-specific deaths and 427 all-cause deaths. The median follow-up of censored patients was 10.8 years (interquartile range: 7.2, 15.1). Compared with patients with no or weak expression of CASR, the multivariable HRs for colorectal cancer-specific mortality were 0.80 [95% confidence interval (CI): 0.55-1.16] in patients with moderate CASR expression and 0.50 (95% CI: 0.32-0.79) in patients with intense CASR expression (p-trend = 0.003). The corresponding HRs for overall mortality were 0.85 (0.64-1.13) and 0.81 (0.58-1.12), respectively. Higher tumor CASR expression was associated with a lower risk of colorectal cancer-specific mortality. This finding needs further confirmation and if confirmed, may lead to better understanding of the role of CASR in colorectal cancer progression. PMID- 28856684 TI - Selective synaptic connections in the retinal pathway for night vision. AB - The mammalian retina encodes visual information in dim light using rod photoreceptors and a specialized circuit: rods->rod bipolar cells->AII amacrine cell. The AII amacrine cell uses sign-conserving electrical synapses to modulate ON cone bipolar cell terminals and sign-inverting chemical (glycinergic) synapses to modulate OFF cone cell bipolar terminals; these ON and OFF cone bipolar terminals then drive the output neurons, retinal ganglion cells (RGCs), following light increments and decrements, respectively. The AII amacrine cell also makes direct glycinergic synapses with certain RGCs, but it is not well established how many types receive this direct AII input. Here, we investigated functional AII amacrine->RGC synaptic connections in the retina of the guinea pig (Cavia porcellus) by recording inhibitory currents from RGCs in the presence of ionotropic glutamate receptor (iGluR) antagonists. This condition isolates a specific pathway through the AII amacrine cell that does not require iGluRs: cone >ON cone bipolar cell->AII amacrine cell->RGC. These recordings show that AII amacrine cells make direct synapses with OFF Alpha, OFF Delta and a smaller OFF transient RGC type that co-stratifies with OFF Alpha cells. However, AII amacrine cells avoid making synapses with numerous RGC types that co-stratify with the connected RGCs. Selective AII connections ensure that a privileged minority of RGC types receives direct input from the night-vision pathway, independent from OFF bipolar cell activity. Furthermore, these results illustrate the specificity of retinal connections, which cannot be predicted solely by co-stratification of dendrites and axons within the inner plexiform layer. PMID- 28856685 TI - Central venous catheter placement in coagulopathic patients: risk factors and incidence of bleeding complications. AB - BACKGROUND: Central venous catheters are frequently inserted into patients with coagulation disorders. It is unclear whether preprocedural correction of hemostasis is beneficial. We determined the incidence of bleeding complications after central venous catheter placement in patients who had severe coagulopathy and identified potential risk factors for bleeding. STUDY DESIGN AND METHODS: The MEDLINE and Cochrane Library databases were systematically searched through November 2015. To be included, articles must have reported on hemorrhagic complications with specification of abnormal coagulation testing results. Severe coagulopathy was defined as a reduced platelet count of 50 * 109 /L or less, and/or an elevated international normalized ratio of 1.5 or greater, and/or a partial thromboplastin time of 45 seconds or greater. RESULTS: We included one randomized controlled trial and 21 observational studies. In total, there were 13,256 catheter insertions, including 4213 in patients with severe coagulopathy. Before 3150 central venous catheter placements, coagulopathy was not corrected. The bleeding incidence varied from 0 to 32%. The severity of coagulopathy did not predict the risk of bleeding. No study demonstrated a beneficial effect from the prophylactic administration of platelets or fresh-frozen plasma to prevent bleeding complications. Retrospective observational studies suggested that no preprocedural correction is required up to a platelet count of 20 * 109 /L and an international normalized ratio of 3.0. CONCLUSION: The incidence of major bleeding complications after central venous catheter placement is low, even in coagulopathic patients. Based on a systematic research of the literature, strong evidence supporting the correction of hemostatic defects before central venous catheter insertion is lacking. However, well-powered randomized controlled trials will be necessary to determine the minimal platelet count, the maximal international normalized ratio, and an activated partial thromboplastin time that is safe before central venous catheter insertion. PMID- 28856687 TI - A novel relationship for schizophrenia, bipolar and major depressive disorder Part 3: Evidence from chromosome 3 high density association screen. AB - Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was systematically reported (Aukes et al, Genet Med 2012, 14, 338-341) and convergent evidence from genetics, symptomatology, and psychopharmacology imply that there are intrinsic connections between these three major psychiatric disorders, for example, any two or even three of these disorders could co-exist in some families. A total of 60, 838 single-nucleotide polymorphisms (SNPs) on chromosome 3 were genotyped by Affymetrix Genome-Wide Human SNP array 6.0 on 119 SCZ, 253 BPD (type-I), 177 MDD patients and 1,000 controls. The population of Shandong province was formed in 14 century and believed that it belongs to homogenous population. Associated SNPs were systematically revealed and outstanding susceptibility genes (CADPS, GRM7,KALRN, LSAMP, NLGN1, PRICKLE2, ROBO2) were identified. Unexpectedly, flanking genes for the associated SNPs distinctive for BPD and/or MDD were replicated in an enlarged cohort of 986 SCZ patients. The evidence from this chromosome 3 analysis supports the notion that both of bipolar and MDD might be subtypes of schizophrenia rather than independent disease entity. Also, a similar finding was detected on chromosome 5, 6, 7, and 8 (Chen et al. Am J Transl Res 2017;9 (5):2473-2491; Curr Mol Med 2016;16(9):840-854; Behav Brain Res 2015;293:241-251; Mol Neurobiol 2016. doi: 10.1007/s12035-016-0102-1). Furthermore, PRICKLE2 play an important role in the pathogenesis of three major psychoses in this population. PMID- 28856688 TI - Gnetin-C and other resveratrol oligomers with cancer chemopreventive potential. AB - Resveratrol has been extensively studied to investigate its biological effects, including its chemopreventive potential against cancer. Over the past decade, various resveratrol oligomers, both naturally occurring and synthetic, have been described. These resveratrol oligomers result from the polymerization of two or more resveratrol units to form dimers, trimers, tetramers, or even more complex derivatives. Some oligomers appear to have antitumor activities that are similar or superior to monomeric resveratrol. In this review, we discuss resveratrol oligomers with anticancer potential, with emphasis on well-characterized compounds, such as the dimer gnetin-C and other oligomers from Gnetum gnemon, whose safety, pharmacokinetic, and biological activities have been studied in humans. PMID- 28856689 TI - Real time large scale in vivo observations reveal intrinsic synchrony, plasticity and growth cone dynamics of midline crossing axons during neuronal wiring of the zebrafish spinal cord. AB - How axons are wired in the vertebrate spinal cord has been studied mostly using fixed samples or looking at individually growing axons. Using light-sheet microscopy, early neural development is here followed in vivo in real time at high resolution along several hundred micrometers of the zebrafish spinal cord. The dynamics and time course of cellular development and axonal wiring of interneurons expressing GFP under control of the dmrt3 promotor are analyzed. Following neurulation, commissural axons are observed crossing the ventral floor plate midline perpendicularly at about 20 microns/h and in a manner dependent on the Robo3 but not the EphA4 receptors. Ipsilateral axons extend concurrently, at three to six times higher growth rates and independently of said receptors. At guidance points, commissural axons are seen to decrease their growth rate and cones increase in size. Commissural filopodia appear on the floor plate to interact with the nascent neural network, and thereby trigger immediate plastic and reversible sinusoidal-shaped bending movements of the neighboring commissural shafts. A 3D reconstruction of the 4 dpf spinal cord demonstrates variable dmrt3 cell body position and dimensions, confirmed by single cell FlowSight analysis, and also a minor second population of commissurals crossing later and more dorsally. The recordings show the strikingly stereotyped spatio-temporal control that governs axonal wiring of the zebrafish spinal cord. The live observations give renewed perspective on the mechanisms of axonal guidance in the spinal cord that provide for a discussion of the current distinction between diffusible long range versus substrate-bound short-range guidance cues. This article is protected by copyright. All rights reserved. PMID- 28856690 TI - The transcription factor Phox2b distinguishes between oral and non-oral sensory neurons in the geniculate ganglion. AB - Many basic characteristics of gustatory neurons remain unknown, partly due to the absence of specific markers. Some neurons in the geniculate ganglion project to taste regions in the oral cavity, whereas others innervate the outer ear. We hypothesized that the transcription factor Phox2b would identify oral cavity projecting neurons in the geniculate ganglion. To test this possibility, we characterized mice in which Phox2b-Cre mediated gene recombination labeled neurons with tdTomato. Nerve labeling revealed that all taste neurons projecting through the chorda tympani (27%) and greater superficial petrosal nerves (15%) expressed Phox2b during development, whereas non-oral somatosensory neurons (58%) in the geniculate ganglion did not. We found tdTomato-positive innervation within all taste buds. Most (57%) of the fungiform papillae had labeled innervation only in taste buds, whereas 43% of the fungiform papillae also had additional labeled innervation to the papilla epithelium. Chorda tympani nerve transection eliminated all labeled innervation to taste buds, but most of the additional innervation in the fungiform papillae remained. Some of these additional fibers also expressed tyrosine hydroxylase, suggesting a sympathetic origin. Consistent with this, both sympathetic and parasympathetic fibers innervating blood vessels and salivary glands contained tdTomato labeling. Phox2b-tdTomato labels nerve fascicles in the tongue of the developing embryo and demonstrates a similar stereotyped branching pattern DiI-labeling. PMID- 28856691 TI - Therapeutic applications of resveratrol and its derivatives on periodontitis. AB - Periodontitis is an inflammatory disease of the supporting tissues of the teeth induced by periodontopathic bacteria that results in the progressive destruction of periodontal tissues. Treatment of periodontitis is painful and time-consuming. Recently, herbal medicines have been considered for use in treating inflammation related diseases, including periodontitis. Resveratrol and its derivative 2,3,5,4'-tetrahydroxystilbene-2-O-beta-glucoside (THSG), a polyphenol extracted from Polygonum multiflorum, have anti-inflammatory properties and other medical benefits. Here, we highlight the importance of resveratrol and its glycosylated derivative as possible complementary treatments for periodontitis and their potential for development as innovative therapeutic strategies. In addition, we present evidence and discuss the mechanisms of action of resveratrol and THSG on periodontitis, focusing on Porphyromonas gingivalis-induced inflammatory responses in human gingival fibroblasts and animal modeling of ligature-induced periodontitis. We also illuminate the signal transduction pathways and the cytokines involved. PMID- 28856692 TI - Cyclic fatigue resistance of R-Pilot, HyFlex EDM and PathFile nickel-titanium glide path files in artificial canals with double (S-shaped) curvature. AB - AIM: To examine the cyclic fatigue resistances of R-Pilot, HyFlex EDM and PathFile NiTi glide path files in S-shaped artificial canals. METHODOLOGY: Twenty R-Pilot (12.5/.04), 20 HyFlex EDM (10/.05) and 20 PathFile (19/.02) single-file glide path files were included. Sixty files (n: 20/each) were subjected to static cyclic fatigue testing using double-curved canals until fracture occurred (TF). The number of cycles to fracture (NCF) was calculated by multiplying the rpm value by the TF. The length of the fractured fragment (FL) was determined by a digital microcaliper. Six samples of fractured files (n: 2/each) were examined by SEM to determine the fracture mode. The NCF and the FL data were analysed using one-way anova, post hoc Tamhane and Kruskal-Wallis tests using SPPS 21 software. The significance level was set at 5%. RESULTS: In the double-curved canal, all the files fractured first in the apical curvature and then in the coronal curvature. The NCF values revealed that the R-Pilot had the greatest cyclic fatigue resistance, followed by the HyFlex EDM and PathFile in both the apical and coronal curvatures (P < 0.05). CONCLUSIONS: R-Pilot NiTi glide path files, used in a reciprocating motion, had the greatest cyclic fatigue resistance amongst the tested NiTi glide path files in an artificial S-shaped canal. PMID- 28856693 TI - Mitochondrial DNA variation in Ukrainian wild boars. PMID- 28856694 TI - Fetal growth and premature delivery in pregnant women on antiepileptic drugs. AB - OBJECTIVE: To evaluate the effects of epilepsy and antiepileptic drugs (AEDs) used during pregnancy on fetal growth and preterm delivery. METHODS: This study included singleton liveborn infants born to women enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2016. Data were collected prospectively through telephone interviews. The prevalence of preterm birth (<37 weeks) and small for gestational age status (SGA) among infants exposed prenatally to AEDs when used by women with epilepsy (WWE) or women without epilepsy (WWOE) was compared with that among infants unexposed to AEDs and born to WWOE. Multivariate log-binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: The study population included infants born to 6,777 AED-WWE, 696 AED-WWOE, and 486 no-AED WWOE. The risk of prematurity was 6.2% for no-AED-WWOE, 9.3% for AED-WWE (RR = 1.5, 95% CI = 1.0-2.1), and 10.5% for AED-WWOE (RR = 1.5, 95% CI = 1.0-2.4). Prenatal exposure to AEDs in WWE and WWOE was associated with a mean lower birth weight of 110 and 136g, respectively, as compared to no-AED-WWOE. The prevalence of SGA was 5.0% for no-AED-WWOE, 10.9% for AED-WWE (RR = 2.0, 95% CI = 1.3-3.0), and 11.0% for AED-WWOE (RR = 1.9, 95% CI = 1.2-2.9). Within users of AEDs in monotherapy, the prevalence of SGA ranged from 7.3% for lamotrigine to 18.5% for topiramate. INTERPRETATION: Women on AEDs during pregnancy, whether for epilepsy or for other neuropsychiatric indications, are at a higher risk of delivering prematurely and giving birth to SGA newborns. The risk may vary by drug. Ann Neurol 2017;82:457-465. PMID- 28856695 TI - Association between body mass index and sperm quality and sperm DNA integrity. A large population study. AB - This study aimed to analyse whether the functional quality of spermatozoa is associated with body mass index (BMI). Semen samples were obtained from 1824 men undergoing fertility evaluation/treatment. Semen analysis was performed using World Health Organization (WHO) criteria, and morphology was evaluated with the motile sperm organelle morphology examination (MSOME). The percentages of sperm DNA fragmentation (using TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL) assays), sperm chromatin packaging/underprotamination (using chromomycin A3/CMA3 ), mitochondrial damage (using MitoTracker Green) and apoptosis (using annexin V) were also assessed. At least 200 spermatozoa were examined in each evaluation. The following BMI values were used as cut-off points: <=24.9 kg/m2 , 25-29.9 kg/m2 (overweight) and >=30 kg/m2 (obese). High BMI negatively affects sperm concentration, vitality, motility and morphology (p < .05). Conversely, high BMI does not seem to be associated with impaired sperm DNA integrity, as assessed by DNA fragmentation, sperm protamination and sperm apoptosis (p > .05). However, increased BMI is associated with increased mitochondrial damage in spermatozoa (p < .05). In conclusion, given the adverse consequences of obesity and the possible effect of male BMI on assisted reproduction technology (ART) outcomes, the benefits of weight reduction should be discussed when counselling couples interested in fertility treatment. PMID- 28856696 TI - Novel Assessment (BlueDop) Device for Detection of Lower Limb Arterial Disease: A Prospective Comparative Study. AB - According to National Institute of Clinical Excellence guidelines, the ankle brachial pressure index coupled with a full clinical evaluation has been the mainstay of detecting peripheral arterial disease on its suspicion. However, this technique is not free of its own limitations in calcified arteries, ulcerative and diabetic patients. We introduce a new, novel, and effective assessment device (BlueDop) with a minimal learning curve that could overcome such barriers and serve as a valid replacement in perihospital settings. PMID- 28856697 TI - What is the postpartum experience of Danish women following gestational diabetes? A qualitative exploration. AB - BACKGROUND: Women with gestational diabetes mellitus (GDM) receive acute but short-term care during pregnancy. There is less direct support during the postpartum period; women are offered general advice on how to follow a healthy lifestyle to avoid developing future type 2 diabetes. Observational studies suggest that a substantial proportion of women with prior GDM do not sustain recommended lifestyle changes postpartum. In a qualitative study, we examined how Danish women diagnosed with GDM experience the transition from a GDM-affected pregnancy to the postpartum period. METHODS: Semistructured interviews with six women diagnosed with GDM. Data were analysed using qualitative content analysis. RESULTS: A GDM diagnosis was accompanied by worries about the health of the woman's baby. This was also the driving force behind the women's motivation to engage in lifestyle changes during pregnancy. The outpatient treatment was perceived to be strict and associated with various challenges, including cravings and discomfort. After the delivery, taking care of the baby became the women's dominant focus. Social and emotional support from partners were needed to maintain motivation and prioritise a healthy lifestyle. The women's experience of the health system varied. However, in the postpartum period all the women experienced limited interaction and initiative from their healthcare providers in supporting them to engage in a healthy lifestyle. CONCLUSIONS: This study identified barriers and facilitators to sustaining a healthy lifestyle postpartum. Efforts at multiple levels - including the individual, family and health system - are needed to facilitate and support a healthy lifestyle among women with prior GDM. PMID- 28856698 TI - Splicing site disruption in the KIT gene as strong candidate for white dominant phenotype in an Italian Trotter. PMID- 28856699 TI - Gender differences in disordered eating behaviors and body dissatisfaction among adolescents with type 1 diabetes: Results from diabetes MILES youth-Australia. AB - OBJECTIVE: To examine gender differences in disordered eating behaviors (DEB) and body dissatisfaction in adolescents with type 1 diabetes. While evidence shows that female youth with type 1 diabetes are more prone to DEB compared to their peers without diabetes, little is known about male adolescents. METHOD: In a national online survey, adolescents (13-19 years) with type 1 diabetes for >=1 year completed the Diabetes Eating Problem Survey-Revised (DEPS-R), and the Body Mass Index Silhouette Matching Test (BMI-SMT) and items on binge eating and insulin omission. RESULTS: About 477 adolescents (mean age 16 years; 62% females) completed the DEPS-R and 431 the BMI-SMT. The DEPS-R total score was higher for females than males, with scores for females increasing with age. BMI, HbA1c , insulin omission, and binge-eating frequency were associated moderately with DEPS R for both genders. On the BMI-SMT, 88% of females wanted to be thinner. Of the males, 76% reported body dissatisfaction; however, only 43% expressed a desire for thinness with the remainder desiring a larger body size. DEPS-R was positively associated with the discrepancy between perceived actual and ideal body size for both genders. DISCUSSION: A large proportion of adolescents with type 1 diabetes, particularly females reported engaging in DEB. Similarly, high rates of body dissatisfaction were reported, though ideal body shape preferences differed by gender. Given the high levels of self-reported DEB and gender-based patterns of body dissatisfaction, future research needs to examine the effectiveness of routine screening of DEB and consider implementation of stepped care approaches. PMID- 28856700 TI - Synthesis, radiofluorination, and preliminary evaluation of the potential 5-HT2A receptor agonists [18 F]Cimbi-92 and [18 F]Cimbi-150. AB - An agonist PET tracer is of key interest for the imaging of the 5-HT2A receptor, as exemplified by the previously reported success of [11 C]Cimbi-36. Fluorine-18 holds several advantages over carbon-11, making it the radionuclide of choice for clinical purposes. In this respect, an 18 F-labelled agonist 5-HT2A receptor (5 HT2A R) tracer is highly sought after. Herein, we report a 2-step, 1-pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5-HT2A R. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5-HT2A R; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within-scan displacement challenge with a 5-HT2A R antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5-HT2A R. PMID- 28856701 TI - Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer. AB - The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation. PMID- 28856702 TI - Avoidance of androgen deprivation therapy in radiorecurrent prostate cancer as a clinically meaningful endpoint for salvage cryoablation. AB - BACKGROUND: To investigate the ability of salvage cryoablation of the prostate (SCAP) to delay the need for androgen deprivation therapy (ADT) in local recurrence after radiation therapy to the prostate using the Cryo-On-Line Database (COLD) registry. METHODS: The COLD registry is comprised of a combination of retrospectively and prospectively collected data on patients undergoing primary and SCAP. Patients with local recurrence after radiation therapy were identified. Kaplan-Meier analysis was used to calculate ADT-free survival. RESULTS: We identified 898 patients that have undergone SCAP in the COLD registry. Overall, the calculated 5-year ADT-free survival probability was 0.713. When stratified by D'Amico risk group, 264 high-risk patients (71.9%), 234 intermediate-risk (86.7%),and 228 low-risk (87.7%) were free of ADT post-SCAP. This correlates with a 5-year ADT-free survival of 60.7, 73.9, and 82.4%, respectively. Patients with post-SCAP PSA nadir of <0.2 ng/mL had a 5 year ADT free survival of 87.1% compared to 48.7% with a PSA nadir >=0.2 ng/mL. Pre operative ADT use or full versus partial gland SCAP did not have an effect on ADT use post-operatively. In 118 (55.4%) of patients with post-operative biochemical recurrence, ADT was not used. CONCLUSION: For patients with local recurrence after radiation, SCAP is an option that provides a high chance of avoiding or delaying ADT. The potential to delay ADT and its associated side effects should be a part of counseling sessions with the patient when discussing treatment options for locally recurrent prostate cancer after radiation. Avoidance of ADT is more clinically relevant than PSA elevation. PMID- 28856703 TI - A test for comparing current status survival data with crossing hazard functions and its application to immunogenicity of biotherapeutics. AB - Several tests have been recently implemented in the nonparametric comparison of current status survival data. However, they are not suited for the situation of crossing hazards. In this setting, we propose a new test specifically designed for crossing hazards alternatives. The proposed test is compared to classical implemented tests through simulations mimicking crossing hazards situations with various schemes of censoring. The results show that the proposed test has a correct type I error and generally outperforms the existing methods. The application of the proposed test on a real dataset on immunogenicity of interferon-beta among multiple sclerosis patients highlights the interest of the proposed test. PMID- 28856704 TI - Health-related quality of life's dependence on socio-economic status and demographic characteristics among men with benign prostatic hyperplasia. AB - This study investigated the effect of socio-economic status (SES) on health related quality of life (HRQoL) among persons with benign prostatic hyperplasia (BPH). The data were collected by way of surveying persons with BPH aged from 35 to 85 (937) and selected via random sample. The diagnosis was confirmed with the use of I-PSS questionnaires (8-19 points), OABq-AT (>=8 points) and daily urinations. A study on HRQoL was conducted using the SF-36 questionnaire. SES was evaluated using the patients' ambulance cards (F112U) and tax inspection documents with their written permission. Verification of the viability of the differences in the HRQoL level of patients with different SES was conducted in each age cohort using ANOVA. The goal of the multifactor regressive analysis using least weighted squares was identified as featuring the strongest relationships between SES and HRQoL. In comparing the average regression squares with average error squares, selection of the entry variables was conducted. Among persons with a BPH, the strongest relationship was discovered between profession, level of education, place of residence and HRQoL. A weaker relationship was identified between income and HRQoL, and there was no relationship between marital status and HRQoL. HRQoL among persons with a different level of SES figures aged 65+ proved homogeneous. We can expect HRQoL improvement among persons with BPH while increasing informedness on the possibilities for treating and improving help for workers of industrial and rural production residing in rural areas. PMID- 28856705 TI - Effect of solvation on the ionization of guanine nucleotide: A hybrid QM/EFP study. AB - Ionization of nucleobases is affected by their biological environment, which includes both the effect of adjacent nucleotides as well as the presence of water around it. Guanine and its nucleotide have the lowest ionization potentials among the various DNA bases. Therefore, the threshold of ionization is dependent on that of guanine and its characterization is crucial to the prediction of interaction of light with DNA. We investigate the effect of solvation on the vertical ionization energies (VIEs) of guanine and its nucleotide. In this work, we have used hybrid quantum mechanics/molecular mechanics (QM/MM) approach with effective fragment potential as the MM method of choice and equation-of-motion coupled-cluster for ionization potential with singles and doubles (EOM-IP-CCSD) as the QM method. The performance of the hybrid scheme with respect to the full QM method shows an accuracy of <= 0.02-0.04 eV. The lowest few ionizations of the nucleotide are found to be from different parts of the moiety, that is, the nucleic acid base, phosphate, or sugar, and these ionization energies are very closely spaced giving rise to a very complicated spectrum. Furthermore, microsolvation has large effects on these ionizations and can lead to red or blue shift depending on the position of the water molecule. Even a single water molecule can change the order of ionized states in the nucleotide. The VIEs of the bulk solvated chromophores are predicted and compared to existing experimental spectra. The predominant role of polarization in the solvatochromic shift is noticed. (c) 2017 Wiley Periodicals, Inc. PMID- 28856706 TI - The crisis intervention team (CIT) model: An evidence-based policing practice? AB - As academic researchers, we are often asked to opine on whether the Crisis Intervention Team model (CIT) is an evidence-based practice (EBP) or evidence based policing. Our answer is that it depends on how you define evidence-based practice and what outcome you are interested in. In this commentary, we briefly describe the CIT model, examine definitions of evidence-based practice and evidence-based policing, and then summarize the existing research on what is known about the effectiveness of CIT to date. We conclude that CIT can be designated an EBP for officer-level cognitive and attitudinal outcomes, but more research is needed to determine if CIT can be designated an EBP for other outcomes. Using an evidence-based practice process approach, CIT may also be a justified strategy for many communities. Future directions to inform the field are discussed. PMID- 28856707 TI - Maxillary implant-supported overdentures opposed by (partial) natural dentitions: a 5-year prospective case series study. AB - The aim of this study was to assess the 5-year treatment outcome of maxillary implant-retained overdentures opposed by natural antagonistic teeth. Fifty consecutive patients received maxillary overdentures supported by six dental implants. Implants were placed in the anterior region, if enough bone was present (n = 25 patients) Implant were placed in the posterior region if implant placement in the anterior region was not possible (n = 25 patients). Variables assessed included survival of implants, condition of hard and soft peri-implant tissues and patients' satisfaction. The five-year implant survival rate was 97.0% and 99.3%, and mean radiographic bone loss was 0.23 and 0.69 mm in the anterior and posterior group, respectively. Median scores for plaque, calculus, gingiva, bleeding and mean scores for pocket probing depth were low and stayed low. Patients' satisfaction after treatment was high in both groups. Within the limits of this 5-year study, it is concluded that six dental implants (placed in the anterior or posterior region) connected with a bar and opposed to natural antagonistic teeth result in acceptable results for clinical parameters and good outcomes for marginal bone level changes and patient satisfaction. PMID- 28856708 TI - Degeneration of serotonin neurons triggers spasticity in amyotrophic lateral sclerosis. AB - OBJECTIVE: Spasticity occurs in a wide range of neurological diseases, including neurodegenerative diseases, after trauma, and after stroke, and is characterized by increased reflexes leading to muscle hypertonia. Spasticity is a painful symptom and can severely restrict everyday life, but might also participate in maintaining a low level of motor function in severely impaired patients. Constitutive activity of the serotonin receptors 5-HT2B/C is required for the development of spasticity after spinal cord injury and during amyotrophic lateral sclerosis (ALS). We sought here to provide direct evidence for a role of brainstem serotonin neurons in spasticity. METHODS: SOD1(G37R) mice expressing a conditional allele of an ALS-linked SOD1 mutation were crossed with Tph2-Cre mice expressing Cre in serotonergic neurons. Measurement of long-lasting reflex using electromyography, behavioral follow-up, and histological techniques was used to characterize spasticity and motor phenotype. RESULTS: Deleting mutant SOD1 expression selectively in brainstem serotonin neurons was sufficient to rescue loss of TPH2 immunoreactivity and largely preserve serotonin innervation of motor neurons in the spinal cord. Furthermore, this abrogated constitutive activity of 5-HT2B/C receptors and abolished spasticity in end-stage mice. Consistent with spasticity mitigating motor symptoms, selective deletion worsened motor function and accelerated the onset of paralysis. INTERPRETATION: Degeneration of serotonin neurons is necessary to trigger spasticity through the 5-HT2B/C receptor. The wide range of drugs targeting the serotonergic system could be useful to treat spasticity in neurological diseases. Ann Neurol 2017;82:444-456. PMID- 28856710 TI - Cerebral oxygenation measured by near-infrared spectroscopy correlates with arterial oxygenation only poorly in preterm infants - a strength of that technology? PMID- 28856709 TI - GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. AB - OBJECTIVE: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions. METHODS: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ~90% of RTT cases, by whole exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models. RESULTS: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. INTERPRETATION: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated gamma-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478. PMID- 28856711 TI - Rationale and design of the CANARI study: a case-control study investigating the association between prostate cancer and 5-alpha-reductase inhibitors for symptomatic benign prostate hypertrophy by linking SNIIRAM and pathology laboratories in a specific region in France. AB - Benign prostate hypertrophy (BPH) could be associated with low urinary symptoms requiring medical treatment: 5-alpha-reductase inhibitors (5-ARI) or alpha blockers. Two clinical trials investigating 5-ARI use in prostate cancer (PCa) primary prevention highlighted a potential safety signal with an increased risk of high-grade PCa. Later observational studies failed to show similar results but have some limits. This paper focuses on describing the protocol of the CANARI study and its feasibility, as regards the matching process of two pseudo anonymous databases. The study concerned patients living in the Brittany region (France) between 2010 and 2013. We designed a case-control study nested within a cohort of men treated by medical drugs licensed for symptomatic BPH between 2010 and 2011. Cases were patients with incident PCa diagnosed between 2012 and 2013 identified through French Health database (SNIIRAM). Gleason score was searched through Brittany pathology laboratories. Controls were patients without PCa diagnosis. Local pathology laboratories database was constituted in Brittany, gathering Gleason scores. No unique identification number is available in France; linkage of SNIIRAM and Brittany pathology laboratories database was made by deterministic matching. We matched 859 cases to Gleason grading (119 had Gleason score >=8 and 740 had Gleason <8); around 22% of cases received 5-ARI and 78% alpha-blockers or phytotherapy. The CANARI study investigated in a population of men treated for BPH the risk of PCa with 5-ARI, according to Gleason grade thanks to SNIIRAM database enriched by local pathological results. PMID- 28856713 TI - Leucine supplementation after mechanical stimulation activates protein synthesis via L-type amino acid transporter 1 in vitro. AB - Branched-chain amino acid supplements consumed following exercise are widely used to increase muscle mass. Although both exercise (ie, mechanical stimulation) and branched-chain amino acid leucine supplementation have been reported to stimulate muscle protein synthesis by activating the mammalian target of rapamycin (mTOR) signaling pathway independently, the mechanisms underlying their synergistic effects are largely unknown. Utilizing cultured differentiated C2C12 myotubes, we established a combination treatment model in which the cells were subjected to cyclic uniaxial mechanical stretching (4 h, 15%, 1 Hz) followed by stimulation with 2 mM leucine for 45 min. Phosphorylation of p70 S6 kinase (p70S6K), an mTOR regulated marker of protein translation initiation, was significantly increased following mechanical stretching alone but returned to the baseline after 4 h. Leucine supplementation further increased p70S6K phosphorylation, with a greater increase observed in the stretched cells than in the non-stretched cells. Notably, the expression of L-type amino acid transporter 1 (LAT1), a stimulator of the mTOR pathway, was also increased by mechanical stretching, and siRNA mediated knockdown partially attenuated leucine-induced p70S6K phosphorylation. These results suggest that mechanical stretching promotes LAT1 expression and, consequently, amino acid uptake, leading to enhanced leucine-induced activation of protein synthesis. LAT1 has been demonstrated to be a point of crosstalk between exercise- and nutrition-induced skeletal muscle growth. PMID- 28856712 TI - Susceptibility tensor imaging and tractography of collagen fibrils in the articular cartilage. AB - PURPOSE: To investigate the B0 orientation-dependent magnetic susceptibility of collagen fibrils within the articular cartilage and to determine whether susceptibility tensor imaging (STI) can detect the 3D collagen network within cartilage. METHODS: Multiecho gradient echo datasets (100-MUm isotropic resolution) were acquired from fixed porcine articular cartilage specimens at 9.4 T. The susceptibility tensor was calculated using phase images acquired at 12 or 15 different orientations relative to B0 . The susceptibility anisotropy of the collagen fibril was quantified and diffusion tensor imaging (DTI) was compared against STI. 3D tractography was performed to visualize and track the collagen fibrils with DTI and STI. RESULTS: STI experiments showed the distinct and significant anisotropic magnetic susceptibility of collagen fibrils within the articular cartilage. STI can be used to measure and quantify susceptibility anisotropy maps. Furthermore, STI provides orientation information of the underlying collagen network via 3D tractography. CONCLUSION: The findings of this study demonstrate that STI can characterize the orientation variation of collagen fibrils where diffusion anisotropy fails. We believe that STI could serve as a sensitive and noninvasive marker to study the collagen fibrils microstructure. Magn Reson Med 78:1683-1690, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28856714 TI - High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu Cheney Syndrome. AB - Hajdu-Cheney syndrome (HCS) is a rare autosomal-dominant disorder primarily characterized by acro-osteolysis and early-onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C-terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2-dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By MUCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro-osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2+/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild-type littermates. Whereas ex vivo cultures failed to uncover cell-autonomous gain-of-functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch-signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high-turnover pathology of Notch2+/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro-osteoclastic gene expression pattern, which in turn triggers high bone turnover. (c) 2017 American Society for Bone and Mineral Research. PMID- 28856715 TI - Feasibility of quantitative regional ventilation and perfusion mapping with phase resolved functional lung (PREFUL) MRI in healthy volunteers and COPD, CTEPH, and CF patients. AB - PURPOSE: In this feasibility study, a phase-resolved functional lung imaging postprocessing method for extraction of dynamic perfusion (Q) and ventilation (V) parameters using a conventional 1H lung MRI Fourier decomposition acquisition is introduced. METHODS: Time series of coronal gradient-echo MR images with a temporal resolution of 288 to 324 ms of two healthy volunteers, one patient with chronic thromboembolic hypertension, one patient with cystic fibrosis, and one patient with chronic obstructive pulmonary disease were acquired at 1.5 T. Using a sine model to estimate cardiac and respiratory phases of each image, all images were sorted to reconstruct full cardiac and respiratory cycles. Time to peak (TTP), V/Q maps, and fractional ventilation flow-volume loops were calculated. RESULTS: For the volunteers, homogenous ventilation and perfusion TTP maps (V TTP, Q-TTP) were obtained. The chronic thromboembolic hypertension patient showed increased perfusion TTP in hypoperfused regions in visual agreement with dynamic contrast-enhanced MRI, which improved postpulmonary endaterectomy surgery. Cystic fibrosis and chronic obstructive pulmonary disease patients showed a pattern of increased V-TTP and Q-TTP in regions of hypoventilation and decreased perfusion. Fractional ventilation flow-volume loops of the chronic obstructive pulmonary disease patient were smaller in comparison with the healthy volunteer, and showed regional differences in visual agreement with functional small airways disease and emphysema on CT. CONCLUSIONS: This study shows the feasibility of phase resolved functional lung imaging to gain quantitative information regarding regional lung perfusion and ventilation without the need for ultrafast imaging, which will be advantageous for future clinical translation. Magn Reson Med 79:2306-2314, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28856716 TI - Reply to "the missing, the short, and the long: Exploring the borderland between psychiatry and neurology". PMID- 28856717 TI - Filling the dead-time gap in zero echo time MRI: Principles compared. AB - PURPOSE: MRI of tissues with short coherence lifetimes T2 or T2* can be performed efficiently using zero echo time (ZTE) techniques such as algebraic ZTE, pointwise encoding time reduction with radial acquisition (PETRA), and water- and fat-suppressed proton projection MRI (WASPI). They share the principal challenge of recovering data in central k-space missed due to an initial radiofrequency dead time. The purpose of this study was to compare the three techniques directly, with a particular focus on their behavior in the presence of ultra short-lived spins. METHODS: The most direct comparison was enabled by aligning acquisition and reconstruction strategies of the three techniques. Image quality and short- T2* performance were investigated using point spread functions, 3D simulations, and imaging of phantom and bone samples with short (<1 ms) and ultra short (<100 MUs) T2*. RESULTS: Algebraic ZTE offers favorable properties but is limited to k-space gaps up to approximately three Nyquist dwells. At larger gaps, PETRA enables robust imaging with little compromise in image quality, whereas WASPI may be prone to artifacts from ultra-short T2* species. CONCLUSION: For small k-space gaps (<4 dwells) and T2* much larger than the dead time, all techniques enable artifact-free short- T2* MRI. However, if these requirements are not fulfilled careful consideration is needed and PETRA will generally achieve better image quality. Magn Reson Med 79:2036-2045, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28856718 TI - Tomoelastography of the native kidney: Regional variation and physiological effects on in vivo renal stiffness. AB - PURPOSE: To measure normal renal stiffness in adults, taking into account regional variation, hydration, and urinary status. METHODS: Thirty-six healthy volunteers were examined by tomoelastography based on MR elastography at four frequencies, from 40 to 70 Hz and multifrequency shear wave speed recovery. Regional wave speeds were derived for the medulla, cortex (inner cortex and outer cortex), and renal pelvis, and examined for age-related effects. Subgroups were repeatedly examined for reproducibility, amount of prior water drinking, and urinary status. Variations in renal perfusion were simulated ex vivo using a porcine kidney subjected to venous water inflow at different pressures. RESULTS: Shear wave speed (stiffness) of renal parenchyma was 2.46 +/- 0.12 m/s (inner cortex: 2.91 +/- 0.17 m/s; outer cortex: 2.52 +/- 0.11 m/s; medulla: 2.15 +/- 0.08 m/s) without side differences and a tendency toward softening with age (P = 0.028). Corresponding intraclass correlation for reproducibility coefficients were 0.78 (inner cortex: 0.80; outer cortex: 0.81; medulla: 0.80). Water drinking resulted in slightly higher values in inner cortex and lower values in medulla (both P = 0.039), which was consistent with the results in perfused specimens. A full bladder led to higher renal pelvis stiffness (P = 0.004), whereas renal parenchyma remained uninfluenced. Stiffness of the porcine renal cortex increased with venous inflow pressure, whereas medulla stiffness decreased. CONCLUSIONS: Tomoelastography provides full field of view maps of renal stiffness with highly detailed resolution and sensitivity to physiological effects related to age and fluid-solid tissue interactions. These basic data could be used to compare pathological conditions in the future. Magn Reson Med 79:2126-2134, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28856720 TI - A double echo ultra short echo time (UTE) acquisition for respiratory motion suppressed high resolution imaging of the lung. AB - PURPOSE: Magnetic resonance imaging is a promising alternative to computed tomography for lung imaging. However, organ motion and poor signal-to-noise ratio, arising from short T2*, impair image quality. To alleviate these issues, a new retrospective gating method was implemented and tested with an ultra-short echo time sequence. METHODS: A 3D double-echo ultra-short echo time sequence was used to acquire data during free breathing in ten healthy adult subjects. A self gating method was used to reconstruct respiratory motion suppressed expiratory and inspiratory images. These images were objectively compared to uncorrected data sets using quantitative end-points (pulmonary vessel sharpness, lung-liver interface definition, signal-to-noise ratio). The method was preliminarily tested in two cystic fibrosis patients who underwent computed tomography. RESULTS: Vessel sharpness in expiratory ultra-short echo time data sets with second echo motion detection was significantly higher (13% relative increase) than in uncorrected images while the opposite was observed in inspiratory images. The method was successfully applied in patients and some findings (e.g., hypointense areas) were similar to those from computed tomography. CONCLUSION: Free breathing ultra-short echo time was successfully implemented, allowing flexible image reconstruction of two different respiratory states. Objective improvements in image quality were obtained with the new method and initial feasibility in a clinical setting was demonstrated. Magn Reson Med 79:2297-2305, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28856719 TI - Oligodendrocyte RasG12V expressed in its endogenous locus disrupts myelin structure through increased MAPK, nitric oxide, and notch signaling. AB - Costello syndrome (CS) is a gain of function Rasopathy caused by heterozygous activating mutations in the HRAS gene. Patients show brain dysfunction that can include abnormal brain white matter. Transgenic activation of HRas in the entire mouse oligodendrocyte lineage resulted in myelin defects and behavioral abnormalities, suggesting roles for disrupted myelin in CS brain dysfunction. Here, we studied a mouse model in which the endogenous HRas gene is conditionally replaced by mutant HRasG12V in mature oligodendrocytes, to separate effects in mature myelinating cells from developmental events. Increased myelin thickness due to decompaction was detectable within one month of HRasG12V expression in the corpus callosum of adult mice. Increases in active ERK and Nitric Oxide (NO) were present in HRas mutants and inhibition of NO synthase (NOS) or MEK each partially rescued myelin decompaction. In addition, genetic or pharmacologic inhibition of Notch signaling improved myelin compaction. Complete rescue of myelin structure required dual drug treatments combining MAPK, NO, or Notch inhibition; with MEK + NOS blockade producing the most robust effect. We suggest that individual or concomitant blockade of these pathways in CS patients may improve aspects of brain function. PMID- 28856721 TI - Focus group study to identify the central facets of fear of hypoglycaemia in people with Type 2 diabetes mellitus. AB - AIMS: To determine key worries about hypoglycaemia among insulin-using adults with Type 2 diabetes using a focus group approach. METHODS: Thirteen focus groups were conducted in three diabetes outpatient care units and one peer support group was set up, in Germany. A total of 64 insulin-dependent adults with Type 2 diabetes (36.5% women, mean age 65.2 +/- 11.0 years) discussed their worries about hypoglycaemia. The qualitative results were assigned into thematic categories using a bottom-up coding procedure. Participants completed the Hypoglycaemia Fear Survey and demographic measures were recorded. The results of the Hypoglycaemia Fear Survey were contrasted with the focus group findings to evaluate how accurately the Hypoglycaemia Fear Survey comprehensively captures features of fear of hypoglycaemia in Type 2 diabetes. RESULTS: Eight themes were identified: 'unconsciousness/death'; 'aloneness/ helplessness', 'fear of hurting somebody'; 'shame'; 'loss of physical control'; 'long-term complications'; 'diabetes self-management issues'; and 'impaired awareness'. A total of 30 participants (46.9%) scored >=3 on at least one item of the Hypoglycaemia Fear Survey worry subscale, indicating elevated worries. The Hypoglycaemia Fear Survey comprehensively captured all identified themes. Self-efficacy with regard to diabetes self-management seemed to play an important role in fear of hypoglycaemia in Type 2 diabetes. CONCLUSIONS: Given that even subclinical worries can have negative effects on quality of life and diabetes self management, emphasis should be placed on diabetes education; in particular, to help patients to develop self-efficacy concerning diabetes self-management. The Hypoglycaemia Fear Survey comprehensively captures hypoglycaemia worries in Type 2 diabetes. Additional assessment of self-efficacy might be beneficial to identify people at risk of developing hypoglycaemia worries. PMID- 28856722 TI - The Doppler paradox. AB - Obstructive prosthetic valve thrombosis (PVT) is a rare but severe complication that usually occurs in the presence of suboptimal anticoagulation. Although fluoroscopy is commonly used to detect abnormal leaflet motion as a surrogate marker for PVT, its inability to directly visualize adjacent tissue and valve physiology leaves it susceptible to miss clinically important PVT. In this manuscript, we report the case of a 54-year-old woman with a mechanical mitral valve who was admitted to our institute with exertional dyspnea. Although valve fluoroscopy was normal, subsequent 3D echocardiography and ECG-gated multiphase computed tomography confirmed the presence of PVT that was subsequently treated successfully with surgical replacement. Our case demonstrates the utility of multimodality imaging in establishing PVT in patients with abnormal prosthetic valve physiology and progressive symptoms. PMID- 28856723 TI - Sources of influence on pregnant women's preferred mode of delivery in Buenos Aires, Argentina. AB - BACKGROUND: Understanding influences on women's preferred delivery mode is vital for planning interventions to reduce cesarean rates and for ensuring that women receive correct information. Our objectives were to: determine if sources of information influencing a pregnant woman's preferred delivery mode and knowledge of cesarean indications differ by sociodemographic characteristics; to conduct a factor analysis of items related to information sources influencing this preference; and to determine if knowledge differs by information sources influencing this preference or their underlying latent constructs. METHODS: Data from a prospective cohort study conducted in Buenos Aires was analyzed. Healthy nulliparous women aged 18-35, at >32 weeks of gestation and with live, singleton pregnancies participated. The primary research questions were evaluated using Chi square tests, factor analysis, logistic regression, and generalized estimating equations. RESULTS: A total of 382 women participated in the study. Women of lower socioeconomic status were more influenced by people, magazines and TV/movies in their mode of delivery preferences, and had poorer knowledge of cesarean indications. Sources of influence for preferred delivery mode and factors derived in factor analysis were not associated with knowledge level when considered individually or together, or when adjusted for sociodemographic characteristics, or when accounting for clustering by the hospital sector (public or private). CONCLUSIONS: Higher socioeconomic status is associated with being less influenced by people and with better knowledge of indications for cesarean delivery. Knowledge of cesarean indications was not associated with the source of information about mode of delivery preferences. PMID- 28856724 TI - SIRT1/HERC4 Locus Associated With Bisphosphonate-Induced Osteonecrosis of the Jaw: An Exome-Wide Association Analysis. AB - Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole-exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and principal components for ancestry. Meta-analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single-nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case control study of 48 patients of European ancestry treated with iv BPs (19 ONJ cases and 29 controls). The top SNPs in the exome-wide association meta-analysis were two SNPs on chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01-0.46; p = 3.83 * 10-5 ). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10-0.88), 0.26 (0.12-0.55), and 0.26 (0.12-0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on chromosome 10 to be associated with iv BP-induced ONJ and two promoter SNPs that might be the potential genetic markers for this association. (c) 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. PMID- 28856725 TI - Practitioner and scientist perceptions of successful amphibian conservation. AB - Conservation requires successful outcomes. However, success is perceived in many different ways depending on the desired outcome. Through a questionnaire survey, we examined perceptions of success among 355 scientists and practitioners working on amphibian conservation from over 150 organizations in more than 50 countries. We also sought to identify how different types of conservation actions and respondent experience and background influenced perceptions. Respondents identified 4 types of success: species and habitat improvements (84% of respondents); effective program management (36%); outreach initiatives such as education and public engagement (25%); and the application of science-based conservation (15%). The most significant factor influencing overall perceived success was reducing threats. Capacity building was rated least important. Perceptions were influenced by experience, professional affiliation, involvement in conservation practice, and country of residence. More experienced practitioners associated success with improvements to species and habitats and less so with education and engagement initiatives. Although science-based conservation was rated as important, this factor declined in importance as the number of programs a respondent participated in increased, particularly among those from less economically developed countries. The ultimate measure of conservation success-population recovery-may be difficult to measure in many amphibians; difficult to relate to the conservation actions intended to drive it; and difficult to achieve within conventional funding time frames. The relaunched Amphibian Conservation Action Plan provides a framework for capturing lower level processes and outcomes, identifying gaps, and measuring progress. PMID- 28856726 TI - Increased Risk of Breast Cancer at a Young Age in Women with Fibrous Dysplasia. AB - Fibrous dysplasia (FD) is a rare bone disorder caused by mutations of the GNAS gene, which are also identified in malignancies. We explored the potential relationship between breast cancer and fibrous dysplasia in two fibrous dysplasia cohorts from the Netherlands and the United States. Data on fibrous dysplasia and breast cancer diagnosis were retrieved from hospital records of 134 (Netherlands) and 121 (US) female patients. Results were validated with breast cancer data of 645 female fibrous dysplasia patients from the Dutch Pathology Registry (PALGA). Standardized morbidity ratios for breast cancer were estimated with data from Dutch and US general population registries. GNAS mutation was analyzed in 9 available breast cancer specimens. A combined total of 15 patients (6 polyostotic, 9 McCune-Albright Syndrome) had breast cancer (87% thoracic localizations). In the Netherlands, a breast cancer incidence rate of 7.5% at median age of 46 years was validated in PALGA (6.5% at age 51 years). Breast cancer risk was 3.4-fold increased (95% confidence interval [CI] 1.6-5.9) compared with the Dutch general population; OR 13.2-fold (95% CI 6.2-22.8) in thoracic disease. In the US cohort, breast cancer incidence rate was 4.5% at a median age of 36 years. Breast cancer risk was 3.9-fold increased (95% CI 1.2 8.2) compared with the general population; 5.7-fold (95% CI 1.4-13.0) in thoracic disease. GNAS mutation was positive in 4 breast cancer specimens (44%). Risk of breast cancer is increased at a younger age, particularly in polyostotic FD, suggesting that screening for breast cancer should be considered in this particular group at a younger age than currently advocated by national guidelines. (c) 2017 American Society for Bone and Mineral Research. PMID- 28856727 TI - Cholesterol regulates polymodal sensory transduction in Muller glia. AB - Over- and underexposure to cholesterol activates glia in neurodegenerative brain and retinal diseases but the molecular targets of cholesterol in glial cells are not known. Here, we report that disruption of unesterified membrane cholesterol content modulates the transduction of chemical, mechanical and temperature stimuli in mouse Muller cells. Activation of TRPV4 (transient receptor potential vanilloid type 4), a nonselective polymodal cation channel was studied following the removal or supplementation of cholesterol using the methyl-beta cyclodextrin (MbetaCD) delivery vehicle. Cholesterol extraction disrupted lipid rafts and caveolae without affecting TRPV4 trafficking or membrane localization protein. However, MbetaCD suppressed agonist (GSK1016790A)- and temperature-evoked elevations in [Ca2+ ]i , and suppressed transcellular propagation of Ca2+ waves. Lowering the free membrane cholesterol content markedly prolonged the time-course of the glial swelling response, whereas MbetaCD:cholesterol supplementation enhanced agonist- and temperature-induced Ca2+ signals and shortened the swelling response. Taken together, these data show that membrane cholesterol modulates polymodal transduction of agonists, swelling and temperature stimuli in retinal radial glia and suggest that dyslipidemic retinas might be associated with abnormal glial transduction of ambient sensory inputs. PMID- 28856729 TI - The protein restriction mimetic Resveratrol is an autophagy inducer stronger than amino acid starvation in ovarian cancer cells. AB - The potential benefit of nutrient starvation in the prevention and treatment of cancer is presently under consideration. Resveratrol (RV), a dietary polyphenol acting as a protein (caloric) restriction mimetic, could substitute for amino acid starvation. The effects of starvation and of caloric restriction are mediated, among others, by autophagy, a process that contributes to cell homeostasis by promoting the lysosomal degradation of damaged and redundant self constituents. Up-regulation of autophagy favors cell survival under nutrient shortage situation, and may drive cancer cells into a non-replicative, dormant state. Both RV and amino acid starvation effectively induced the aminoacid response and autophagy. These processes were associated with inhibition of the mTOR pathway and disruption of the BECLIN1-BCL-2 complex. The number of transcripts positively impinging on the autophagy pathway was higher in RV treated than in starved cancer cells. Consistent with our data, it appears that RV treatment is more effective than and can substitute for starvation for inducing autophagy in cancer cells. The present findings are clinically relevant because of the potential therapeutic implications. PMID- 28856730 TI - Exceptional responders in conservation. AB - Conservation operates within complex systems with incomplete knowledge of the system and the interventions utilized. This frequently results in the inability to find generally applicable methods to alleviate threats to Earth's vanishing wildlife. One approach used in medicine and the social sciences has been to develop a deeper understanding of positive outliers. Where such outliers share similar characteristics, they may be considered exceptional responders. We devised a 4-step framework for identifying exceptional responders in conservation: identification of the study system, identification of the response structure, identification of the threshold for exceptionalism, and identification of commonalities among outliers. Evaluation of exceptional responders provides additional information that is often ignored in randomized controlled trials and before-after control-intervention experiments. Interrogating the contextual factors that contribute to an exceptional outcome allow exceptional responders to become valuable pieces of information leading to unexpected discoveries and novel hypotheses. PMID- 28856728 TI - Data-driven mapping of hypoxia-related tumor heterogeneity using DCE-MRI and OE MRI. AB - PURPOSE: Previous work has shown that combining dynamic contrast-enhanced (DCE) MRI and oxygen-enhanced (OE)-MRI binary enhancement maps can identify tumor hypoxia. The current work proposes a novel, data-driven method for mapping tissue oxygenation and perfusion heterogeneity, based on clustering DCE/OE-MRI data. METHODS: DCE-MRI and OE-MRI were performed on nine U87 (glioblastoma) and seven Calu6 (non-small cell lung cancer) murine xenograft tumors. Area under the curve and principal component analysis features were calculated and clustered separately using Gaussian mixture modelling. Evaluation metrics were calculated to determine the optimum feature set and cluster number. Outputs were quantitatively compared with a previous non data-driven approach. RESULTS: The optimum method located six robustly identifiable clusters in the data, yielding tumor region maps with spatially contiguous regions in a rim-core structure, suggesting a biological basis. Mean within-cluster enhancement curves showed physiologically distinct, intuitive kinetics of enhancement. Regions of DCE/OE MRI enhancement mismatch were located, and voxel categorization agreed well with the previous non data-driven approach (Cohen's kappa = 0.61, proportional agreement = 0.75). CONCLUSION: The proposed method locates similar regions to the previous published method of binarization of DCE/OE-MRI enhancement, but renders a finer segmentation of intra-tumoral oxygenation and perfusion. This could aid in understanding the tumor microenvironment and its heterogeneity. Magn Reson Med 79:2236-2245, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28856731 TI - Integration of Graphene, Nano Sulfur, and Conducting Polymer into Compact, Flexible Lithium-Sulfur Battery Cathodes with Ultrahigh Volumetric Capacity and Superior Cycling Stability for Foldable Devices. AB - Lithium-sulfur batteries, as one of the most promising next-generation batteries, attract tremendous attentions due to their high energy density and low cost. However, their practical application is hindered by their short cycling life and low volumetric capacity. Herein, compact, flexible, and free-standing films with a sandwich structure are designed simply by vacuum filtration, in which nanosulfur is homogenously coated by graphene and poly(3,4-ethylene dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). This unique hierarchical structure not only provides a highly conductive network and intimate contacts between nanosulfur and graphene/PEDOT:PSS for effective charge transportation, but also offers synergistic physical restriction and chemical confinement of dissoluble intermediate lithium polysulfides during electrochemical processes. Therefore, these conductive compact films, used directly as cathodes, show the highest reversible volumetric capacity of 1432 Ah L-1 at 0.1 C and 1038 Ah L-1 at 1 C, and excellent cycling stability with a minimal decay rate of 0.04% per cycle over 500 cycles at 1 C. Meanwhile, remarkable rate performance with a high capacity of 701 mAh g-1 at 4 C is also achieved. Soft-packaged batteries based on this flexible cathode are further fabricated and demonstrate excellent mechanical and electrochemical properties with little capacity decay under folded state, highlighting the practical application of our deliberately designed electrode in a flexible power system. PMID- 28856732 TI - Predictive model and risk factors associated with a revised definition of early allograft dysfunction in liver transplant recipients. AB - INTRODUCTION: Early allograft dysfunction (EAD) is a well-defined clinical syndrome that reflects overall graft function within the first week after transplant. The aim of this study was to further refine the definition for EAD. METHOD: In this study, 1124 patients were included for analysis. Logistic regression was performed to identify markers of liver injury associated with 6 month patient and graft failure. RESULTS: Recursive partitioning identified cut points for ALT/AST > 3000/6000 IU/dL observed within first week, with bilirubin >= 10 mg/dL and INR >= 1.6 on postoperative day 7 for the revised EAD model. The incidence of updated EAD was 15% (164/1124). Multivariable analysis identified eight risk factors associated with EAD: % macrosteatosis, donor location, donor weight, nonheart beating donors, type of organ transplanted, recipient-associated hepatocellular carcinoma, severity of postreperfusion syndrome, and the amount of transfused fresh frozen plasma. In the presence of EAD, the incidence of post transplant renal replacement therapy and dialysis dependence increases. There was a significant association of the presence of EAD with 6-month mortality (12% vs 3%) and 6-month graft failure (8% vs 1%). CONCLUSION: Higher AST/ALT level needed as cutoff in comparison with the old EAD definition. PMID- 28856733 TI - A bacteriophages journey through the human body. AB - The human body is colonized by a diverse collective of microorganisms, including bacteria, fungi, protozoa and viruses. The smallest entity of this microbial conglomerate are the bacterial viruses. Bacteriophages, or phages for short, exert significant selective pressure on their bacterial hosts, undoubtedly influencing the human microbiome and its impact on our health and well-being. Phages colonize all niches of the body, including the skin, oral cavity, lungs, gut, and urinary tract. As such our bodies are frequently and continuously exposed to diverse collections of phages. Despite the prevalence of phages throughout our bodies, the extent of their interactions with human cells, organs, and immune system is still largely unknown. Phages physically interact with our mucosal surfaces, are capable of bypassing epithelial cell layers, disseminate throughout the body and may manipulate our immune system. Here, I establish the novel concept of an "intra-body phageome," which encompasses the collection of phages residing within the classically "sterile" regions of the body. This review will take a phage-centric view of the microbiota, human body, and immune system with the ultimate goal of inspiring a greater appreciation for both the indirect and direct interactions between bacteriophages and their mammalian hosts. PMID- 28856734 TI - Competing forces maintain the Hydra metaorganism. AB - Our conventional view of multicellular organisms often overlooks the fact that they are metaorganisms. They consist of a host, which is comprised of both a community of self-replicating cells that can compete as well as cooperate and a community of associated microorganisms. This newly discovered complexity raises a profound challenge: How to maintain such a multicellular association that includes independently replicating units and even different genotypes? Here, we identify competing forces acting at the host tissue level, the host-microbe interface, and within the microbial community as key factors to maintain the metaorganism Hydra. Maintenance of host tissue integrity, as well as proper regulation and management of the multiorganismic interactions are fundamental to organismal survival and health. Findings derived from the in vivo context of the Hydra model may provide one of the simplest possible systems to address questions on how a metaorganism is established and remains in balance over time. PMID- 28856735 TI - Host-microbiota interactions and adaptive immunity. AB - All mucosal surfaces are colonized with a vast number of microbes, which are essential for stimulating and regulating the immune system. While intrinsic and innate mechanisms exist to promote a strong barrier between the microbiota and the host to ensure compartmentalization, the microbiota is also able to induce robust adaptive immunity. In this review, we discuss the interplay between the microbiota and the adaptive immune system, with a focus on the induction of mucosal and systemic antibody responses and newly defined roles of maternal antibodies. We also highlight recent studies that aim to decipher microbial antigen-specificity of the T-cell compartment. PMID- 28856736 TI - Interactions between bile salts, gut microbiota, and hepatic innate immunity. AB - Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed. PMID- 28856737 TI - The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens. AB - The human gastrointestinal tract hosts a diverse network of microorganisms, collectively known as the microbiota that plays an important role in health and disease. For instance, the intestinal microbiota can prevent invading microbes from colonizing the gastrointestinal tract, a phenomenon known as colonization resistance. Perturbations to the microbiota, such as antibiotic administration, can alter microbial composition and result in the loss of colonization resistance. Consequently, the host may be rendered susceptible to colonization by a pathogen. This is a particularly relevant concern in the hospital setting, where antibiotic use and antibiotic-resistant pathogen exposure are more frequent. Many nosocomial infections arise from gastrointestinal colonization. Due to their resistance to antibiotics, treatment is often very challenging. However, recent studies have demonstrated that manipulating the commensal microbiota can prevent and treat various infections in the intestine. In this review, we discuss the members of the microbiota, as well as the mechanisms, that govern colonization resistance against specific pathogens. We also review the effects of antibiotics on the microbiota, as well as the unique epidemiology of immunocompromised patients that renders them a particularly high-risk population to intestinal nosocomial infections. PMID- 28856740 TI - Interplay of innate lymphoid cells and the microbiota. AB - Innate lymphoid cells (ILC) are a recently identified group of innate lymphocytes that are preferentially located at barrier surfaces. Barrier surfaces are in direct contact with complex microbial ecosystems, collectively referred to as the microbiota. It is now believed that the interplay of the microbiota with host components (i.e. epithelial cells and immune cells) promotes host fitness by regulating organ homeostasis, metabolism, and host defense against pathogens. In this review, we will give an overview of this multifaceted interplay between ILC and components of the microbiota. PMID- 28856741 TI - Correlation, consequence, and functionality in microbiome-immune interplay. PMID- 28856742 TI - Robust Fe3 Mo3 C Supported IrMn Clusters as Highly Efficient Bifunctional Air Electrode for Metal-Air Battery. AB - Catalysts at the air cathode for oxygen reduction and evolution reactions are central to the stability of rechargeable metal-air batteries, an issue that is gaining increasing interest in recent years. Herein, a highly durable and efficient carbide-based bifunctional catalyst consisting of iron-molybdenum carbide (Fe3 Mo3 C) and IrMn nanoalloys is demonstratred. This carbide is chemically stable in alkaline media and over the potential range of an air cathode. More importantly, Fe3 Mo3 C is very active for oxygen reduction reaction (ORR) in alkaline media. Fe3 Mo3 C supported IrMn as a bifunictional catalysts exhibits superior catalytic performance than the state of the art ORR catalyst (Pt/C) and the oxygen evolution reaction catalyst (Ir/C). IrMn/Fe3 Mo3 C enables Zn-air batteries to achieve long-term cycling performance over 200 h with high efficiency. The extraordinarily high performance of IrMn/Fe3 Mo3 C bifunictional catalyst provides a very promising alternative to the conventional Pt/C and Ir/C catalyst for an air cathode in alkaline electrolyte. PMID- 28856738 TI - Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease. AB - The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are referred to collectively as the gut microbiota. These indigenous microorganisms have co-evolved with the host in a symbiotic relationship. In addition to metabolic benefits, symbiotic bacteria provide the host with several functions that promote immune homeostasis, immune responses, and protection against pathogen colonization. The ability of symbiotic bacteria to inhibit pathogen colonization is mediated via several mechanisms including direct killing, competition for limited nutrients, and enhancement of immune responses. Pathogens have evolved strategies to promote their replication in the presence of the gut microbiota. Perturbation of the gut microbiota structure by environmental and genetic factors increases the risk of pathogen infection, promotes the overgrowth of harmful pathobionts, and the development of inflammatory disease. Understanding the interaction of the microbiota with pathogens and the immune system will provide critical insight into the pathogenesis of disease and the development of strategies to prevent and treat inflammatory disease. PMID- 28856743 TI - Subtle Steric Differences Impact the Structural and Conducting Properties of Radical Gold Bis(dithiolene) Complexes. AB - Among single component molecular conductors, neutral radical gold dithiolene complexes [(R-thiazdt)2 Au]. derived from the N-alkyl-1,3-thiazoline-2-thione-4,5 dithiolate (R-thiazdt) ligand provide an extensive series of conducting, non dimerized, half-filled band systems. Analogues of the known R=isopropyl (iPr) derivative were investigated here with R=NMe2 , cyclopropyl (cPr) and n-propyl (nPr), aiming at rationalizing the different solid state structures adopted by these compounds despite very closely related substituents on the heterocyclic nitrogen atom. An original crisscross organization within dimerized chains is observed with R=NMe2 , differing however from the analogous iPr derivative by a 180 degrees rotation of the heterocyclic nitrogen substituent. On the other hand, the cyclopropyl and n-propyl substituents lead to robust, uniform, non dimerized chains with a strongly 1 D electronic structure and a formal half filled electronic structure. The semiconducting behaviour of these two radical complexes is characteristic of a Mott insulator, whose sensitivity to external pressure has been evaluated up to 2.5 GPa. PMID- 28856739 TI - Deciphering interactions between the gut microbiota and the immune system via microbial cultivation and minimal microbiomes. AB - The community of microorganisms in the mammalian gastrointestinal tract, referred to as the gut microbiota, influences host physiology and immunity. The last decade of microbiome research has provided significant advancements for the field and highlighted the importance of gut microbes to states of both health and disease. Novel molecular techniques have unraveled the tremendous diversity of intestinal symbionts that potentially influence the host, many proof-of-concept studies have demonstrated causative roles of gut microbial communities in various pathologies, and microbiome-based approaches are beginning to be implemented in the clinic for diagnostic purposes or for personalized treatments. However, several challenges for the field remain: purely descriptive reports outnumbering mechanistic studies and slow translation of experimental results obtained in animal models into the clinics. Moreover, there is a dearth of knowledge regarding how gut microbes, including novel species that have yet to be identified, impact host immune responses. The sheer complexity of the gut microbial ecosystem makes it difficult, in part, to fully understand the microbiota-host networks that regulate immunity. In the present manuscript, we review key findings on the interactions between gut microbiota members and the immune system. Because culturing microbes allows performing functional studies, we have emphasized the impact of specific taxa or communities thereof. We also highlight underlying molecular mechanisms and discuss opportunities to implement minimal microbiome-based strategies. PMID- 28856744 TI - Frequency of MYD88 and CD79B mutations, and MGMT methylation in primary central nervous system diffuse large B-cell lymphoma. AB - Primary CNS diffuse large B-cell lymphoma (PCNS-DLBCL) and systemic DLBCL harbor mutations in MYD88 and CD79B. DNA methyltransferase (MGMT) is methylated in some DLBCL. Our goal was to investigate the frequencies of these events, which have not been previously reported within the same series of patients with PCNS-DLBCL. Fifty-four cases of PCNS-DLBCL from two institutions were analyzed by Sanger sequencing for MYD88 and CD79B, and pyrosequencing for MGMT. MYD88 mutations were identified in 68.8% (35 of 51 cases), with L265P being the most frequent mutation. Mutations other than L265P were identified in 21.6% of cases, of which eight novel MYD88 mutations were identified. Of mutated cases, 17.6% had homozygous/hemizygous MYD88 mutations, which has not been previously reported in PCNS-DLBCL. CD79B mutations were found in six of 19 cases (31.6%), all in the Y196 mutation hotspot. MGMT methylation was observed in 37% (20 of 54 cases). There was no significant difference in median overall survival (OS) between the wild type and mutated MYD88 cases, or between methylated and unmethylated MGMT cases. However, a significant difference (P = 0.028) was noted in median OS between the wild type and mutated CD79B cases. PMID- 28856745 TI - Using known drug interactions to manage supratherapeutic calcineurin inhibitor concentrations. AB - OBJECTIVES: To summarize the available body of evidence guiding the management of supratherapeutic concentrations of calcineurin inhibitors (CNI) using cytochrome P450 (CYP450) enzyme inducers. METHODS: A nondate restricted literature search within MEDLINE, Embase, and Scopus was performed using the terms "cyclosporine," "tacrolimus," "calcineurin inhibitor," "toxicity," "pharmacokinetics," "carbamazepine," "rifampin," "phenytoin," and "phenobarbital." Additional references were identified from a review of all included citations. All English language reports that describe the management of supratherapeutic CNI concentrations with interventions targeting metabolic induction using CYP450 enzyme inducers were evaluated. RESULTS: A total of 10 publications were identified in which a CYP450 enzyme inducer was utilized intentionally to enhance CNI clearance in the setting of supratherapeutic concentrations; 7 case reports describe the use of phenytoin and 3 case reports describe the use of phenobarbital. Patient demographics, dosing strategies employed, and reported efficacy across this series of publications are heterogeneous; however, both agents appear to be well-tolerated when used in this setting. CONCLUSIONS: There is a paucity of published data on the use of CYP450 enzyme inducers for the management of supratherapeutic CNI concentrations. While routine use of this approach cannot be recommended, thorough risk-benefit analyses should be performed in the management of each such clinical scenario. PMID- 28856746 TI - Mechanism of the Catalytic Carboxylation of Alkylboronates with CO2 Using Ni-NHC Complexes: A DFT Study. AB - A new mechanism is proposed for the Ni-catalyzed carboxylation of organoboronates with CO2 . DFT investigations at the PBE0-D3 level have shown that direct CO2 addition to the catalysts [Ni(NHC)(Allyl)Cl] (1NHC , NHC=IMe, IPr, SIPr and IPr*) is kinetically disfavored and formation of the Aresta-type intermediate is unlikely to occur. According to the mechanism proposed here, the carboxylation process starts with addition of the borate species to 1NHC , followed by transmetalation, CO2 cycloaddition and carboxylation. The rate-determining step was identified as being the transmetalation process, with computed relative free energy barriers of 34.8, 36.8, and 33.5 kcal mol-1 for 1IPr , 1SIPr and 1IPr* , respectively. PMID- 28856747 TI - Anticancer Effects of a Korean Herbal Medicine Formula (H9) via AMPK and HER2 PI3K/Akt Signaling in Breast Cancer Cells. AB - An H9 is a formula of nine medicinal herbs derived from Osuyubujaijung-tang, a traditional Korean prescription for Soeumin constitution. In our previous study, H9 showed anticancer effects against breast cancer and non-small-cell lung cancer. However, the underlying mechanisms of these effects have not yet been elucidated. In this study, we investigated the effects of H9, both alone and in combination with trastuzumab, on breast cancer cells and sought to elucidate the mechanisms involved. H9 suppressed the proliferation of human breast cancer cells, induced arrest of the cell cycle at the G0/G1 phase, and caused mitochondrial dysfunction and apoptosis. In addition, H9 induced the activation of AMPK and inhibited the HER2-PI3K/Akt signaling pathway. Furthermore, H9 attenuated hypoxia-induced HIF-1alpha and VEGF, resulting in decreased migration and invasion of breast cancer cells. Compared with treatment with either drug alone, co-treatment with H9 and trastuzumab significantly inhibited the growth of BT-474 cells through induction of apoptosis. These results suggest that H9 should be considered as a potent anticancer agent that targets the HER2-PI3K/Akt pathway, and the combination of H9 with trastuzumab should be considered as a new therapeutic regimen for treating breast cancer. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28856748 TI - Propionibacterium acnes-associated neurosarcoidosis: A case report with review of the literature. AB - A 56-year-old woman with a 3-year history of hydrocephalus and ventriculo peritoneal shunt placement, presented with worsening altered level of consciousness for 2 days. Imaging studies showed severe ventriculomegaly involving the lateral and third ventricles with multiple septated cysts noted in the lateral ventricles predominantly near the frontal horns. Histopathologic examination of the excised brain lesion revealed choroid plexus tissue and adjacent cerebral parenchyma with several non-caseating granulomas. Granulomatous inflammation was also identified in mediastinal lymph nodes. By using specific monoclonal antibodies, Propionibacterium acnes (P. acnes) were detected in non caseating granulomas of both the brain and mediastinal lymph nodes. No acid-fast bacilli or fungal elements were present. To the best of our knowledge, this is the first demonstration of P. acnes in sarcoid granulomas of cerebral tissue, and it reinforces the possible link between P. acnes and sarcoidosis. PMID- 28856749 TI - Supplementation with a Polyphenol-Rich Extract, TensLess(r) , Attenuates Delayed Onset Muscle Soreness and Improves Muscle Recovery from Damages After Eccentric Exercise. AB - High-intensity exercises are known to provoke delayed onset muscle soreness (DOMS). Delayed onset muscle soreness typically occurs within the first 24 h, peaks between 24 and 72 h, and can last as long as 5-7 days post-exercise. Delayed onset muscle soreness is a multifactorial process involving both mechanical and biochemical components, associated with clinical features that may limit range of motion, and athletes seek for effective recovery strategies to optimize future training sessions. TensLess(r) is a food supplement developed to help manage post-exercise recovery. The supplement has been investigated on 13 recreationally active athletes of both sex, during a randomized, double-blind, and crossover clinical investigation, including a 3-week washout period. The clinical investigation was based on the study of TensLess(r) effects for DOMS management and on the reduction of associated muscle damages following an eccentric exercise protocol. Supplementation with TensLess(r) induced significant decrease in DOMS perception (-33%; p = 0.008) as of the first 24 h; this was significantly correlated with a lowered release of muscle damage-associated biomarkers, namely myoglobin, creatinine, and creatine kinase, for the whole length of the recovery period. Taken together, these positive results clearly indicate that post-exercise supplementation with TensLess(r) may preserve myocytes and reduce soreness following eccentric exercise-induced damages, and, accordingly, significantly shorten muscle recovery. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28856750 TI - Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors. AB - Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330. PMID- 28856751 TI - Rules for connectivity of secondary structure elements in protein: Two-layer alphabeta sandwiches. AB - In protein structures, the fold is described according to the spatial arrangement of secondary structure elements (SSEs: alpha-helices and beta-strands) and their connectivity. The connectivity or the pattern of links among SSEs is one of the most important factors for understanding the variety of protein folds. In this study, we introduced the connectivity strings that encode the connectivities by using the types, positions, and connections of SSEs, and computationally enumerated all the connectivities of two-layer alphabeta sandwiches. The calculated connectivities were compared with those in natural proteins determined using MICAN, a nonsequential structure comparison method. For 2alpha-4beta, among 23,000 of all connectivities, only 48 were free from irregular connectivities such as loop crossing. Of these, only 20 were found in natural proteins and the superfamilies were biased toward certain types of connectivities. A similar disproportional distribution was confirmed for most of other spatial arrangements of SSEs in the two-layer alphabeta sandwiches. We found two connectivity rules that explain the bias well: the abundances of interlayer connecting loops that bridge SSEs in the distinct layers; and nonlocal beta-strand pairs, two spatially adjacent beta-strands located at discontinuous positions in the amino acid sequence. A two-dimensional plot of these two properties indicated that the two connectivity rules are not independent, which may be interpreted as a rule for the cooperativity of proteins. PMID- 28856752 TI - Differentiation of wide QRS tachycardia: Garbage in, garbage out. PMID- 28856753 TI - Is the hypothesis that the commonest fetal heart rate decelerations are caused by peripheral chemoreflex due to fetal hypoxaemia correct? PMID- 28856754 TI - Reply from Christopher A. Lear, Robert Galinsky, Guido Wassink, Kyohei Yamaguchi, Joanne O. Davidson, Jenny A. Westgate, Laura Bennet and Alistair J. Gunn. PMID- 28856755 TI - Capturing the photo-signaling state of a photoreceptor in a steady-state fashion by binding a transition metal complex. AB - Binding a small molecule to proteins causes conformational changes, but often to a limited extent. Here, we demonstrate that the interaction of a CO-releasing molecule (CORM3) with a photoreceptor photoactive yellow protein (PYP) drives large structural changes in the latter. The interaction of CORM3 and a mutant of PYP, Met100Ala, not only trigger the isomerization of its chromophore, p-coumaric acid, from its anionic trans configuration to a protonated cis configuration, but also increases the content of beta-sheet at the cost of alpha-helix and random coil in the secondary structure of the protein. The CORM3 derived Met100Ala is found to highly resemble the signaling state, which is one of the key photo intermediates of this photoactive protein, in both protein local conformation and chromophore configuration. The organometallic reagents hold promise as protein engineering tools. This work highlights a novel approach to structurally accessing short lived intermediates of proteins in a steady-state fashion. PMID- 28856756 TI - Validity of the days supply field in pharmacy administrative claims data for the identification of blister packaging of medications. AB - PURPOSE: Pharmacy claims data is often used in pharmacoepidemiology studies, but no studies to date have examined whether it was possible to identify the use of blister packs in these databases. We aimed to determine whether medications dispensed in days divisible by 7 are more likely to be blister packed than medications dispensed in other quantities. METHODS: Community pharmacies in Manitoba were invited to participate in a mail-out survey to identify the use of blister packaging for up to 25 patients who had a solid oral medication dispensed from April 1, 2012 to March 31, 2014. Eligible medications were identified using the population-based province-wide retail pharmacy network. Algorithms for identifying the use of blister packaging were determined by comparing the proportion of fills that confirmed blister pack use between different days supply quantities. RESULTS: Twenty-seven out of 32 pharmacies that agreed to participate completed the survey. The total number of prescriptions in the analysis was 2045 of which 131 (6.4%) were dispensed in blister packaging. Overall, prescriptions dispensed in days divisible by 7 yielded a 72.5% sensitivity, 86.6% specificity, 30.3% PPV, and 97.9% NPV compared with prescriptions dispensed in other quantities. A 28-day to 30-day comparison yielded an 87.9% sensitivity, 96.1% specificity, 64.6% PPV, and 99.0% NPV. CONCLUSION: While the NPV was high, the PPV for identifying blister packaging using the days supply field in pharmacy claims data was modest given the low prevalence in blister pack use. The best predictor occurred when 28 days was compared with 30 days. KEY POINTS Blister packs are arranged in 4 * 7 compartments and are often used to improve adherence, but no studies have examined whether it was possible to identify the use of blister packs using the days supply field in pharmacy claims data. Findings show that a 28-day supply yielded a high sensitivity and specificity for identifying the use of blister packaging compared with a 30-day supply, but there is potential for misclassification. Future studies directed at examining subgroups that are more likely to use blister packs and replication of findings using other data sources in other jurisdictions are encouraged. PMID- 28856757 TI - CCL19/CCR7 contributes to the pathogenesis of endometriosis via PI3K/Akt pathway by regulating the proliferation and invasion of ESCs. AB - PROBLEM: The level of CCL19 increased in the peritoneal fluid of women with endometriosis, but the precise mechanism of CCL19/CCR7 in the pathogenesis of endometriosis remains unknown. METHODS: ELISA and immunohistochemistry were performed to analyze CCL19/CCR7 expressions in peritoneal fluid and endometrium from women with endometriosis (n = 38) and controls (n = 32). Cell proliferation and transwell invasion assays were applied to detect proliferation and invasion of human endometrial stromal cells (ESCs). Expressions of Bcl2, MMP2, MMP9, and p AKT/AKT were analyzed by Western blot. RESULTS: Peritoneal fluid concentration of CCL19 in patients with endometriosis was higher than that in controls. Those patients with moderate/severe endometriosis had significantly higher peritoneal fluid concentrations of CCL19 compared to those with minimal/mild endometriosis. Higher CCL19 and CCR7 were found in the endometrium with endometriosis compared to control. CCL19 significantly enhanced ESC proliferation and invasion through CCR7 via activating PI3K/Akt signal pathways. CCL19/CCR7 interaction significantly enhanced phosphorylation of Akt, Bcl2, MMP2, and MMP9 in ESCs. CONCLUSION: These data indicate CCL19/CCR7 contributes to proliferation and invasion of ESCs, which are conducive to the pathogenesis of endometriosis through activating PI3K/Akt pathway. PMID- 28856759 TI - Concise Review: Mesenchymal Stromal/Stem Cells: A New Treatment for Sepsis and Septic Shock? AB - Sepsis and septic shock are the leading cause of admission and mortality in non coronary intensive care units. Currently, however, no specific treatments are available for this syndrome. Due to the failure of conventional treatments in recent years, research is focusing on innovative therapeutic agents, including cell therapy. One particular type of cell, mesenchymal stromal/stem cells (MSCs), has raised hopes for the treatment of sepsis. Indeed, their immunomodulatory properties, antimicrobial activity and capacity of protection against organ failure confer MSCs with a major advantage to treat the immune and inflammatory dysfunctions associated with sepsis and septic shock. After a brief description of the pathophysiology of sepsis and septic shock, the latest advances in the use of MSCs to treat sepsis will be presented. Stem Cells 2017;35:2331-2339. PMID- 28856760 TI - Selective social learning in infancy: looking for mechanisms. AB - Although there is mounting evidence that selective social learning begins in infancy, the psychological mechanisms underlying this ability are currently a controversial issue. The purpose of this study is to investigate whether theory of mind abilities and statistical learning skills are related to infants' selective social learning. Seventy-seven 18-month-olds were first exposed to a reliable or an unreliable speaker and then completed a word learning task, two theory of mind tasks, and a statistical learning task. If domain-general abilities are linked to selective social learning, then infants who demonstrate superior performance on the statistical learning task should perform better on the selective learning task, that is, should be less likely to learn words from an unreliable speaker. Alternatively, if domain-specific abilities are involved, then superior performance on theory of mind tasks should be related to selective learning performance. Findings revealed that, as expected, infants were more likely to learn a novel word from a reliable speaker. Importantly, infants who passed a theory of mind task assessing knowledge attribution were significantly less likely to learn a novel word from an unreliable speaker compared to infants who failed this task. No such effect was observed for the other tasks. These results suggest that infants who possess superior social-cognitive abilities are more apt to reject an unreliable speaker as informant. A video abstract of this article can be viewed at: https://youtu.be/zuuCniHYzqo. PMID- 28856761 TI - Tracking and understanding phase progression in Lisa's case. AB - This study adds a phase-by-phase perspective to the well-known, and thoroughly analysed on a moment-by-moment basis, case of Lisa. The aim is to see whether this phase-by-phase analysis adds anything valuable to the understanding of the processes of change in this case and the therapeutic processes in general. In this good-outcome case study, a team of raters integrated the temporal sequencing phase component of the Paradigmatic Complementarity Metamodel (PCM) with a moment by-moment tracking method-the Developmental Analysis of Psychotherapy Process Method (DAPP)-to analyse what occurred along the process that could explain the phase transitions and consolidations observed and how the therapist facilitated them. We illustrate and explain the therapeutic progression with therapeutic interactions from the dyad. The results suggest that Lisa evolved in accordance with the sequence of phases proposed by the PCM until phase 4 (out of 7). However, only phase 2 gains show evidence of structural consolidation. The sequence of phases proposed by the PCM seems to represent a natural progression for patients throughout the therapeutic process, and the consideration of a phase by-phase map in analysing and thinking of therapeutic cases may be a valuable tool regarding clinical decision making. PMID- 28856762 TI - Pregbalin induced recurrent syncopal attacks with prolong QT interval. AB - Long QT syndrome may lead to fatal dysrhythmia. Prolongation of QT interval due to pregabalin has been shown in rats and no data is available in humans. We report a 80-year-old female patient using pregabalin. She was presented to emergency room with syncope attacks. Her admission electrocardiography demonstrated prolonged QT interval. After excluding the possible causes of the long QT syndrome, we attributed prolonged QT interval to pregabalin therapy. After discontinuation of pregabalin QT interval returned to normal range and patient experienced no further syncope attacks. It is first time for documentation of prolonged QT due to pregabalin in humans. PMID- 28856758 TI - Gonadal soma controls ovarian follicle proliferation through Gsdf in zebrafish. AB - BACKGROUND: Aberrant signaling between germ cells and somatic cells can lead to reproductive disease and depends on diffusible signals, including transforming growth factor-beta (TGFB) -family proteins. The TGFB-family protein Gsdf (gonadal soma derived factor) controls sex determination in some fish and is a candidate for mediating germ cell/soma signaling. RESULTS: Zebrafish expressed gsdf in somatic cells of bipotential gonads and expression continued in ovarian granulosa cells and testicular Sertoli cells. Homozygous gsdf knockout mutants delayed leaving the bipotential gonad state, but then became a male or a female. Mutant females ovulated a few oocytes, then became sterile, accumulating immature follicles. Female mutants stored excess lipid and down-regulated aromatase, gata4, insulin receptor, estrogen receptor, and genes for lipid metabolism, vitellogenin, and steroid biosynthesis. Mutant females contained less estrogen and more androgen than wild-types. Mutant males were fertile. Genomic analysis suggests that Gsdf, Bmp15, and Gdf9, originated as paralogs in vertebrate genome duplication events. CONCLUSIONS: In zebrafish, gsdf regulates ovarian follicle maturation and expression of genes for steroid biosynthesis, obesity, diabetes, and female fertility, leading to ovarian and extra-ovarian phenotypes that mimic human polycystic ovarian syndrome (PCOS), suggesting a role for a related TGFB signaling molecule in the etiology of PCOS. Developmental Dynamics 246:925-945, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28856764 TI - Polymicrobial bloodstream infection in an immunocompetent child. PMID- 28856765 TI - Effect of different implant abutment surfaces on OBA-09 epithelial cell adhesion. AB - For the long-term success of implants, it is necessary to achieve a direct contact between the implant and the subjacent bone. To avoid bacterial penetration that could adversely affect the initial wound healing as well as the long-term behavior of the implants, an early tissue barrier must form that is able to protect the biological peri-implant structures. Given the need of an effective tissue early barrier around dental implants, the present study evaluated, in vitro, the influence of physical and chemical characteristics of two implant abutment surfaces on gingival epithelial cells (OBA-9) adhesion. To this end, titanium (Ti) and zirconia (ZrO2 ) disk-shaped specimens were used mimicking the abutment components surfaces, while bovine enamel (BE) and glass cover slips (GCS) disks served as positive and negative controls, respectively. Roughness and surface free energy (SFE) of all materials were evaluated previously to cellular adhesion step. In sequence, the effect of each material on cells morphology and viability was analyzed after 1 and 24 hr. The results showed that roughness and SFE had no effect on the cell viability data or on their interaction (p = .559), independent of a post-contact analysis of 1 or 24 hr. However, cells attachment and spreading increased after 24 hr on Ti and ZrO2 than BE, corresponding to the highest SFE values. SFE appears to be an important property interfering on the quality of the soft tissue surrounding dental implants. These data can be considered a trigger point for developing new material surfaces. PMID- 28856766 TI - Gray matter asymmetries in aging and neurodegeneration: A review and meta analysis. AB - Inter-hemispheric asymmetries are a common phenomenon of the human brain. Some evidence suggests that neurodegeneration related to aging and disease may preferentially affect the left-usually language- and motor-dominant-hemisphere. Here, we used activation likelihood estimation meta-analysis to assess gray matter (GM) loss and its lateralization in healthy aging and in neurodegeneration, namely, mild cognitive impairment (MCI), Alzheimer's dementia (AD), Parkinson's disease (PD), and Huntington's disease (HD). This meta analysis, comprising 159 voxel-based morphometry publications (enrolling 4,469 patients and 4,307 controls), revealed that GM decline appeared to be asymmetric at trend levels but provided no evidence for increased left-hemisphere vulnerability. Regions with asymmetric GM decline were located in areas primarily affected by neurodegeneration. In HD, the left putamen showed converging evidence for more pronounced atrophy, while no consistent pattern was found in PD. In MCI, the right hippocampus was more atrophic than its left counterpart, a pattern that reversed in AD. The stability of these findings was confirmed using permutation tests. However, due to the lenient threshold used in the asymmetry analysis, further work is needed to confirm our results and to provide a better understanding of the functional role of GM asymmetries, for instance in the context of cognitive reserve and compensation. Hum Brain Mapp 38:5890-5904, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28856763 TI - The fly eye: Through the looking glass. AB - The developing eye-antennal disc of Drosophila melanogaster has been studied for more than a century, and it has been used as a model system to study diverse processes, such as tissue specification, organ growth, programmed cell death, compartment boundaries, pattern formation, cell fate specification, and planar cell polarity. The findings that have come out of these studies have informed our understanding of basic developmental processes as well as human disease. For example, the isolation of a white-eyed fly ultimately led to a greater appreciation of the role that sex chromosomes play in development, sex determination, and sex linked genetic disorders. Similarly, the discovery of the Sevenless receptor tyrosine kinase pathway not only revealed how the fate of the R7 photoreceptor is selected but it also helped our understanding of how disruptions in similar biochemical pathways result in tumorigenesis and cancer onset. In this article, I will discuss some underappreciated areas of fly eye development that are fertile for investigation and are ripe for producing exciting new breakthroughs. The topics covered here include organ shape, growth control, inductive signaling, and right-left symmetry. Developmental Dynamics 247:111-123, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28856767 TI - Risks of newly onset hemorrhagic stroke in patients with neovascular age-related macular degeneration. AB - PURPOSE: Age-related macular degeneration (AMD) is an eye disease causing blindness in the elderly. It shares many common possible pathogenic mechanisms with cardiovascular diseases. Many studies have discussed the association between AMD and stroke, but the results were inconsistent. Our aim was to determine the associations between neovascular AMD and the risk of stroke in the Taiwanese population. METHODS: This is a retrospective cohort study. We used claims data from National Health Insurance Research Database. Patients aged more than 45 years without stroke, myocardial infarction, or any AMD were selected from 2001 to 2008 and followed until 2010. The index date was defined as the date of nAMD diagnosis (ICD-9 code, 362.52). The comparison group was patients without an nAMD diagnosis with age- and sex-matched to nAMD subjects at a ratio of up to 10 to 1. Kaplan-Meier survival analysis and Cox regression analysis were used. The incidence of stroke events (ICD-9 codes, 430-434) and their subtypes (hemorrhagic and ischemic) were primary outcomes. Secondary outcomes included acute myocardial infarction (AMI), composite AMI/stroke, and all-cause mortality. RESULTS: Patients with nAMD had a higher risk of developing stroke, with an adjusted HR of 1.30 (95% CI, 1.01-1.68). A higher risk for hemorrhagic stroke (HR, 1.70, 95% CI, 1.03-2.83) was also found. No significant differences were observed in ischemic stroke, the composite of AMI/stroke, and all-cause mortality. CONCLUSIONS: Patients with nAMD had a significantly higher risk of developing stroke, which was driven mainly by the increased risk of developing the hemorrhagic subtype. PMID- 28856768 TI - Meat and nutritional quality comparison of purebred and crossbred pigs. AB - Crossbreeding is an effective method of improving the efficiency and profit of production in commercial pig operations. To understand the effect of crossbreeding on meat and nutrient quality, a combination including three purebred (Duroc, D; Landrace, L; Yorkshire, Y) and two crossbred pig lines (Landrace * Yorkshire, LY; Duroc * (Landrace * Yorkshire), DLY) frequently used internationally were studied. The results showed that meat from the LY and DLY crosses had lower values for lightness L24h*, shear force and epinephrine and higher values for drip loss, C18:1, insulin, glucagon and monounsaturated fatty acids than D, L and Y pigs. Moreover, LY had higher values for post mortem pH and lower values for a* and b* than the purebreds. In contrast, DLY had lower values for pH and higher values for a* and b* than the purebreds. Meat quality-related gene analysis showed that the CAST, IGF2 and MC4R gene expression levels in the LY and DLY pigs were significantly higher than those in the D, L and Y pigs. These results indicate that crossbreeding can alter the meat quality, nutritive value, energy metabolism and gene expression of pigs. Future research should focus on microRNA expression and DNA methylation that regulate gene expression and thus affect the meat quality. PMID- 28856769 TI - Dermatosparaxis in White Dorper sheep: confirmation of a causative nonsense mutation in ADAMTS2. PMID- 28856770 TI - Genotoxic effects of high dose rate X-ray and low dose rate gamma radiation in ApcMin/+ mice. AB - Risk estimates for radiation-induced cancer in humans are based on epidemiological data largely drawn from the Japanese atomic bomb survivor studies, which received an acute high dose rate (HDR) ionising radiation. Limited knowledge exists about the effects of chronic low dose rate (LDR) exposure, particularly with respect to the application of the dose and dose rate effectiveness factor. As part of a study to investigate the development of colon cancer following chronic LDR vs. acute HDR radiation, this study presents the results of genotoxic effects in blood of exposed mice. CBAB6 F1 Apc+/+ (wild type) and ApcMin/+ mice were chronically exposed to estimated whole body absorbed doses of 1.7 or 3.2 Gy 60 Co-gamma-rays at a LDR (2.2 mGy h-1 ) or acutely exposed to 2.6 Gy HDR X-rays (1.3 Gy min-1 ). Genotoxic endpoints assessed in blood included chromosomal damage (flow cytometry based micronuclei (MN) assay), mutation analyses (Pig-a gene mutation assay), and levels of DNA lesions (Comet assay, single-strand breaks (ssb), alkali labile sites (als), oxidized DNA bases). Ionising radiation (ca. 3 Gy) induced genotoxic effects dependent on the dose rate. Chromosomal aberrations (MN assay) increased 3- and 10-fold after chronic LDR and acute HDR, respectively. Phenotypic mutation frequencies as well as DNA lesions (ssb/als) were modulated after acute HDR but not after chronic LDR. The ApcMin/+ genotype did not influence the outcome in any of the investigated endpoints. The results herein will add to the scant data available on genotoxic effects following chronic LDR of ionising radiation. Environ. Mol. Mutagen. 58:560-569, 2017. (c) 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. PMID- 28856772 TI - 53rd Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology (ANZSN), 4-6 September 2017, Darwin Convention Centre, Northern Territory. PMID- 28856771 TI - Enhanced Stability of DNA Nanostructures by Incorporation of Unnatural Base Pairs. AB - Self-assembled DNA nanostructures hold great promise in the fields of nanofabrication, biosensing and nanomedicine. However, the inherent low stability of the DNA double helices, formed by weak interactions, largely hinders the assembly and functions of DNA nanostructures. In this study, we redesigned and constructed a six-arm DNA junction by incorporation of the unnatural base pairs 5 Me-isoC/isoG and A/2-thioT into the double helices. They not only retained the structural integrity of the DNA nanostructure, but also showed enhanced thermal stability and resistance to T7 Exonuclease digestion. This research may expand the applications of DNA nanostructures in nanofabrication and biomedical fields, and furthermore, the genetic alphabet expansion with unnatural base pairs may enable us to construct more complicated and diversified self-assembled DNA nanostructures. PMID- 28856773 TI - Untangling the proximate causes and underlying drivers of deforestation and forest degradation in Myanmar. AB - Political transitions often trigger substantial environmental changes. In particular, deforestation can result from the complex interplay among the components of a system-actors, institutions, and existing policies-adapting to new opportunities. A dynamic conceptual map of system components is particularly useful for systems in which multiple actors, each with different worldviews and motivations, may be simultaneously trying to alter different facets of the system, unaware of the impacts on other components. In Myanmar, a global biodiversity hotspot with the largest forest area in mainland Southeast Asia, ongoing political and economic reforms are likely to change the dynamics of deforestation drivers. A fundamental conceptual map of these dynamics is therefore a prerequisite for interventions to reduce deforestation. We used a system-dynamics approach and causal-network analysis to determine the proximate causes and underlying drivers of forest loss and degradation in Myanmar from 1995 to 2016 and to articulate the linkages among them. Proximate causes included infrastructure development, timber extraction, and agricultural expansion. These were stimulated primarily by formal agricultural, logging, mining, and hydropower concessions and economic investment and social issues relating to civil war and land tenure. Reform of land laws, the link between natural resource extraction and civil war, and the allocation of agricultural concessions will influence the extent of future forest loss and degradation in Myanmar. The causal-network analysis identified priority areas for policy interventions, for example, creating a public registry of land-concession holders to deter corruption in concession allocation. We recommend application of this analytical approach to other countries, particularly those undergoing political transition, to inform policy interventions to reduce forest loss and degradation. PMID- 28856774 TI - Group testing regression models with dilution submodels. AB - Group testing, where specimens are tested initially in pools, is widely used to screen individuals for sexually transmitted diseases. However, a common problem encountered in practice is that group testing can increase the number of false negative test results. This occurs primarily when positive individual specimens within a pool are diluted by negative ones, resulting in positive pools testing negatively. If the goal is to estimate a population-level regression model relating individual disease status to observed covariates, severe bias can result if an adjustment for dilution is not made. Recognizing this as a critical issue, recent binary regression approaches in group testing have utilized continuous biomarker information to acknowledge the effect of dilution. In this paper, we have the same overall goal but take a different approach. We augment existing group testing regression models (that assume no dilution) with a parametric dilution submodel for pool-level sensitivity and estimate all parameters using maximum likelihood. An advantage of our approach is that it does not rely on external biomarker test data, which may not be available in surveillance studies. Furthermore, unlike previous approaches, our framework allows one to formally test whether dilution is present based on the observed group testing data. We use simulation to illustrate the performance of our estimation and inference methods, and we apply these methods to 2 infectious disease data sets. PMID- 28856775 TI - Longitudinal follow up of dysglycemia in overweight and obese pediatric patients. AB - OBJECTIVE: To examine factors related to progression of dysglycemia in overweight and obese youth in a large primary care setting. RESEARCH DESIGN AND METHODS: 10- to 18-year-old youth with body mass index (BMI) > 85 percentile and first-time A1c 5.7%-7.9% (39-63 mmol/mol) were identified retrospectively through electronic medical records (EMR). Levels of dysglycemia were defined as low-range prediabetes (LRPD; A1c 5.7%-5.9% [39-41 mmol/mol]), high-range prediabetes (HRPD; A1c 6.0%-6.4% [42-46 mmol/mol]), or diabetes-range (A1c 6.5%-7.9% [48 mmol/mol]). Follow-up A1c and BMI were extracted from the EMR. Follow up was truncated at the time of initiation of diabetes medication. RESULTS: Of 11 000 youth, 547 were identified with baseline dysglycemia (mean age 14.5 +/- 2.2 years, 70% Hispanic, 23% non-Hispanic Black, 7% other). Of these, 206 had LRPD, 282 HRPD, and 59 diabetes. Follow-up A1c was available in 420 (77%), with median follow up of 12 22 months depending on A1c category. At follow-up testing, the percent with diabetes-range A1c was 4% in youth with baseline LRPD, 8% in youth with baseline HRPD, and 33% in youth with baseline diabetes-range A1c. There was a linear association between BMI increase and worsening A1c for LRPD (P < .001) and HRPD (P = .003). CONCLUSIONS: Most adolescents with an initial prediabetes or diabetes range A1c did not have a diabetes-range A1c on follow up. Moreover, prediabetes range A1c values do not all convey equal risk for the development of diabetes, with lower rates of progression for youth with initial A1c <6%. In youth with prediabetes-range A1c, BMI stabilization was associated with improvement of glycemia. PMID- 28856776 TI - Malnutrition caused by unexpectedly low protein concentration in breast milk. PMID- 28856777 TI - Perinatal mortality disparities between public care and private obstetrician-led care: a propensity score analysis. AB - OBJECTIVE: To examine whether disparities in stillbirth, and neonatal and perinatal mortality rates, between public and private hospitals are the result of differences in population characteristics and/or clinical practices. DESIGN: Retrospective cohort study. SETTING: A metropolitan tertiary centre encompassing public and private hospitals. Women accessed care from either a private obstetrician or from public models of care - predominantly midwife-led care or care shared between midwives, general practitioners, and obstetricians. POPULATION: A total of 131 436 births during 1998-2013: 69 037 public and 62 399 private. METHODS: Propensity score matching was used to select equal-sized public and private cohorts with similar characteristics. Logistic regression analysis was then used to explore the impact of public-private differences in the use of assisted reproductive technologies, plurality, major congenital anomalies, birth method, and gestational age. MAIN OUTCOME MEASURES: Stillbirth, and neonatal and perinatal mortality rates. RESULTS: After controlling for maternal and pregnancy factors, perinatal mortality rates were higher in the public than in the private cohort (adjusted odds ratio, aOR 1.53; 95% confidence interval, 95% CI 1.29-1.80; stillbirth aOR 1.56, 95% CI 1.26-1.94; neonatal death aOR 1.48, 95% CI 1.15 1.89). These disparities reduced by 15.7, 20.5, and 19.6%, respectively, after adjusting for major congenital anomalies, birth method, and gestational age. CONCLUSIONS: Perinatal mortality occurred more often among public than private births, and this disparity was not explained by population differences. Differences in clinical practices seem to be partly responsible. The impact of differences in clinical practices on maternal and neonatal morbidity was not examined. Further research is required. TWEETABLE ABSTRACT: Private obstetrician led care: more obstetric intervention and earlier births reduce perinatal mortality. PLAIN LANGUAGE SUMMARY: Background Babies born in Australian public hospitals tend to die more often than those born in private hospitals. Our aim was to determine whether this pattern is a result of public-private differences in care or merely linked with differences in the characteristics of the two groups. In Australian private hospitals, a private obstetrician almost always provides continuing care to each woman during pregnancy and birth. Public hospitals provide a number of care options, which usually involve midwives and/or a family doctor. Method The study population included 131 436 births (52.5% public; 47.5% private) from 1998-2013 at a single metropolitan centre with co located public and private facilities. To isolate the effect of differences in care, we used a statistical technique called propensity score matching to select a public group and a private group with similar characteristics and equal size. This enabled us to compare 'apples with apples' when comparing public versus private perinatal death rates. Perinatal deaths include stillbirths and babies that die within 28 days of birth. Main findings After matching and after accounting for different patterns in the use of fertility treatments and multiple birth pregnancies (such as twins), babies born in the public sector were approximately 1.5 times more likely to die than babies born in the private sector. This difference was reduced to 1.3 times more likely to die than babies born in the private sector after taking into account other factors that could skew the data, such as major congenital anomalies, birth method, and duration of pregnancy. Limitations This was a single-centre study, so the results may not apply to all settings. Despite our efforts to create highly similar public and private cohorts, some differences between the groups are likely to have remained and this may have affected the results. Implications Our findings suggest that private obstetrician-led care has a beneficial impact on perinatal deaths, despite, or possibly because of, higher obstetric intervention rates and earlier births in the private hospital. Further research is required. PMID- 28856779 TI - pH-Driven Wetting Switchability of Electrodeposited Superhydrophobic Copolymers of Pyrene Bearing Acid Functions and Fluorinated Chains. AB - A smart stimuli-responsive surface was fabricated by the electro-copolymerization of pyrene monomers followed by base and acid treatment. Copolymers of pyrenes bearing fluorinated chains (Py-nF6 ) and acid functions (Py-COOH) were produced with different molar concentrations of each monomer (0, 25, 50, 75, and 100 % of Py-nF6 vs. Py-COOH) by an electrochemical process. Two different perfluorinated pyrenes containing ester and amide groups were used to reach superhydrophobic properties. The relation of those bonds with the final properties of the surface was explored. The pH-sensitive group of Py-COOH allowed the surfaces to be reversibly switched from superhydrophobic (water contact angle>thetaw >150 degrees and very low hysteresis) to hydrophilic (thetaw <90 degrees ). The amide and ester bonds influenced the recovery of the original wettability after both base and acid treatment. Although the fluorinated homopolymer with ester bonds was insensitive to base and acid treatment due to its superhydrophobic properties with ultralow water adhesion, the recovery of the original wettability for the copolymers was much more important with amide bonds due to the amide functional groups be more resistant to the hydrolysis reaction. This strategy offered the opportunity to access superhydrophobic films with switchable wettability by simple pH treatment. The films proved to be a good tool for use in biological applications, for example, as a bacterial-resistant film if superhydrophobic and as a bacterial-adherent film if hydrophilic. PMID- 28856780 TI - H2 S-Activable MOF Nanoparticle Photosensitizer for Effective Photodynamic Therapy against Cancer with Controllable Singlet-Oxygen Release. AB - Photodynamic therapy (PDT) has emerged as an important minimally invasive tumor treatment technology. The search for an effective photosensitizer to realize selective cancer treatment has become one of the major foci in recent developments of PDT technology. Controllable singlet-oxygen release based on specific cancer-associated events, as another major layer of selectivity mode, has attracted great attention in recent years. Here, for the first time, we demonstrated that a novel mixed-metal metal-organic framework nanoparticle (MOF NP) photosensitizer can be activated by a hydrogen sulfide (H2 S) signaling molecule in a specific tumor microenvironment for PDT against cancer with controllable singlet-oxygen release in living cells. The effective removal of tumors in vivo further confirmed the satisfactory treatment effect of the MOF NP photosensitizer. PMID- 28856778 TI - Temporally resolved parametric assessment of Z-magnetization recovery (TOPAZ): Dynamic myocardial T1 mapping using a cine steady-state look-locker approach. AB - PURPOSE: To develop and evaluate a cardiac phase-resolved myocardial T1 mapping sequence. METHODS: The proposed method for temporally resolved parametric assessment of Z-magnetization recovery (TOPAZ) is based on contiguous fast low angle shot imaging readout after magnetization inversion from the pulsed steady state. Thereby, segmented k-space data are acquired over multiple heartbeats, before reaching steady state. This results in sampling of the inversion-recovery curve for each heart phase at multiple points separated by an R-R interval. Joint T1 and B1+ estimation is performed for reconstruction of cardiac phase-resolved T1 and B1+ maps. Sequence parameters are optimized using numerical simulations. Phantom and in vivo imaging are performed to compare the proposed sequence to a spin-echo reference and saturation pulse prepared heart rate-independent inversion-recovery (SAPPHIRE) T1 mapping sequence in terms of accuracy and precision. RESULTS: In phantom, TOPAZ T1 values with integrated B1+ correction are in good agreement with spin-echo T1 values (normalized root mean square error = 4.2%) and consistent across the cardiac cycle (coefficient of variation = 1.4 +/- 0.78%) and different heart rates (coefficient of variation = 1.2 +/- 1.9%). In vivo imaging shows no significant difference in TOPAZ T1 times between the cardiac phases (analysis of variance: P = 0.14, coefficient of variation = 3.2 +/ 0.8%), but underestimation compared with SAPPHIRE (T1 time +/- precision: 1431 +/- 56 ms versus 1569 +/- 65 ms). In vivo precision is comparable to SAPPHIRE T1 mapping until middiastole (P > 0.07), but deteriorates in the later phases. CONCLUSIONS: The proposed sequence allows cardiac phase-resolved T1 mapping with integrated B1+ assessment at a temporal resolution of 40 ms. Magn Reson Med 79:2087-2100, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28856781 TI - Cellular apoptosis and cardiac dysfunction in STZ-induced diabetic rats attenuated by anthocyanins via activation of IGFI-R/PI3K/Akt survival signaling. AB - Anthocyanins are known cyto-protective agents against various stress conditions. In this study cardio-protective effect of anthocyanins from black rice against diabetic mellitus (DM) was evaluated using a streptozotocin (STZ)-induced DM rat model. Five-week-old male Wistar rats were administered with STZ (55 mg kg-1 , IP) to induce DM; rats in the treatment group received 250 mg oral anthocyanin/kg/day during the 4-week treatment period. DM and the control rats received normal saline through oral gavage. The results reveal that STZ-induced DM elevates myocardial apoptosis and associated proapoptotic proteins but down regulates the proteins of IGF1R mediated survival signaling mechanism. Furthermore, the functional parameters such as the ejection-fraction and fraction shortening in the DM rat hearts declined considerably. However, the rats treated with anthocyanins significantly reduced apoptosis and the associated proapoptotic proteins and further increased the survival signals to restore the cardiac functions in DM rats. Anthocyanin supplementation enhances cardiomyocyte survival and restores cardiac function. PMID- 28856783 TI - Because the Light is Better Here: Correlation-Time Analysis by NMR Spectroscopy. AB - Relaxation data in NMR spectra are often used for dynamics analysis, by modeling motion in the sample with a correlation function consisting of one or more decaying exponential terms, each described by an order parameter, and a correlation time. This method has its origins in the Lipari-Szabo model-free approach, which originally considered overall tumbling plus one internal motion and was later expanded to several internal motions. Considering several of these cases in the solid state it is found that if the real motion is more complex than the assumed model, model fitting is biased towards correlation times where the relaxation data are most sensitive. This leads to unexpected distortions in the resulting dynamics description. Therefore dynamics detectors should be used, which characterize different ranges of correlation times and can help in the analysis of protein motion without assuming a specific model of the correlation function. PMID- 28856782 TI - Activity of Zn and Mg phthalocyanines and porphyrazines in amyloid aggregation of insulin. AB - Formation of the deposits of protein aggregates-amyloid fibrils in an intracellular and intercellular space-is common to a large group of amyloid associated disorders. Among the approaches to develop of therapy of such disorders is the use of agents preventing protein fibrillization. Polyaromatic complexes-porphyrins and phthalocyanines-are known as compounds possessing anti fibrillogenic activity. Here, we explore the impact of related macrocyclic complexes-phthalocyanines (Pc) and octaphenyl porphyrazines (Pz) of Mg and Zn-on aggregation of amyloidogenic protein insulin. Pz complexes are firstly reported as compounds able to affect protein fibrillization. The effect of Pc and Pz complexes on the kinetics and intensity of insulin aggregation was studied by the fluorescent assay using amyloid sensitive cyanine dye. This has shown the impact of metal ion on the anti-fibrillogenic properties of macrocyclic complexes-the effect on the fibrillization kinetics of Mg-containing compounds is much more pronounced comparing to that of Zn analogues. Scanning electron microscopy experiments have demonstrated that filamentous fibrils are the main product of aggregation both for free insulin and in the presence of macrocyclic complexes. However, those fibrils are distinct by their length and proneness to lateral aggregation. The Pc complexes cause the increase in variation of fibrils length 0.9 to 2.7 nm in opposite to 1.4 to 2.0 nm for free insulin, whereas Pz complexes cause certain shortening of the fibrils to 0.8 to 1.6 nm. The averaged size of the fibrils population was estimated by dynamic light scattering; it correlates with the size of single fibrils detected by scanning electron microscopy. PMID- 28856784 TI - Topical antifungal treatment prevents recurrence of toenail onychomycosis following cure. AB - Recurrence rates are high for onychomycosis, with prophylactic topical antifungal use proposed to counter recurrence. Although this is a reasonable action for many clinicians, few studies have been conducted on the efficacy of topical prophylaxis. A retrospective chart review (2010-2015) was conducted in patients receiving oral terbinafine or itraconazole for toenail onychomycosis. Following complete cure, a topical antifungal (amorolfine, bifonazole, ciclopirox olamine, or terbinafine spray) was used weekly as prophylaxis. Recurrence was recorded along with patient characteristics including demographics and concomitant medical conditions. Data from 320 patients were collected. Recurrence was significantly lower in patients receiving topical antifungal prophylaxis than in no prophylactic treatment following oral terbinafine (p < .001), but not itraconazole (p = .185). Regardless of oral treatment, the use of topical antifungals as prophylaxis (p < .001) decreased, and the number of affected toenails (p = .048) and family history of fungal infections (p < .001) increased the likelihood that recurrence would occur. This study supports the use of topical antifungal medications as prophylactic treatment to help prevent recurrence of toenail onychomycosis and suggests that those with a family history of fungal infections should be closely monitored. PMID- 28856785 TI - Lifestyle-determining extrachromosomal replicon pAMV1 and its contribution to the carbon metabolism of the methylotrophic bacterium Paracoccus aminovorans JCM 7685. AB - Plasmids play an important role in the adaptation of bacteria to changeable environmental conditions. As the main vectors of horizontal gene transfer, they can spread genetic information among bacteria, sometimes even across taxonomic boundaries. Some plasmids carry genes involved in the utilization of particular carbon compounds, which can provide a competitive advantage to their hosts in particular ecological niches. Analysis of the multireplicon genome of the soil bacterium P. aminovorans JCM 7685 revealed the presence of an extrachromosomal replicon pAMV1 (185 kb) with a unique structure and properties. This lifestyle determining plasmid carries genes facilitating the metabolism of many different carbon compounds including sugars, short-chain organic acids and C1 compounds. Plasmid pAMV1 contains a large methylotrophy island (MEI) that is essential not only for the utilization of particular C1 compounds but also for the central methylotrophic metabolism required for the assimilation of C1 units (serine cycle). We demonstrate that the expression of the main serine cycle genes is induced in the presence of C1 compounds by the transcriptional regulator ScyR. The extrachromosomal localization of the MEI and the distribution of related genes in Paracoccus spp. indicate that it could have been acquired by HGT by an ancestor of P. aminovorans. PMID- 28856786 TI - Dietary intake and physical activity levels of children attending Australian childcare services. AB - AIM: The primary aim of this study was to describe the dietary intake and physical activity levels of children while attending childcare. METHODS: A cross sectional study was conducted with 18 centre-based childcare services in the Hunter region of New South Wales, Australia. Childcare service characteristics were assessed via telephone interview. Child dietary intake and physical activity levels were assessed during a one-day observation conducted at participating childcare services using previously validated tools. RESULTS: Children consumed a mean of 0.2 serves of vegetables, 0.7 serves of fruit, 1.4 serves of grain (cereal) foods, 0.1 serves of lean meat and poultry, fish, eggs, nuts and seeds and legumes/beans, 0.6 serves of milk, yoghurt, cheese and alternatives, and 0.7 serves of discretionary foods during attendance at childcare. Of all child physical activity counts, 48.6% were classified as 'sedentary', and 22.3% classified as 'very active'. Bivariate analyses indicated that children attending services located in rural areas consumed significantly more serves of vegetables (0.3 serves (SD 0.7) vs 0.1 serves (SD 0.2), P = 0.05). Multivariate analyses indicated that services with large child enrolments had a significantly greater proportion of child counts classified as 'very active' (23.6% of child counts (95% CI 1.6, 29.5) vs 14.9% of child counts (95% CI 9.1, 20.6), P = 0.007). CONCLUSIONS: There is considerable scope to improve the diet and activity behaviours of children during attendance at childcare. Future research is needed to identify effective strategies to best support childcare services in implementing policies and practices to improve such behaviours in children. PMID- 28856787 TI - Survival and developmental competence of bovine embryos at different developmental stages and separated blastomeres after vitrification in different solutions. AB - Generating techniques to enhance the success of blastomere separation is important for bovine economy, because it increases the number of transferable embryos. This study aimed to identify the optimum cryoprotectants for the vitrification of bovine embryos and the separation of blastomeres at different stages. In experiment 1, expanded blastocysts were vitrified in two different vitrification solutions, either (1) ethylene glycol (EG) + propylene glycol (PG) or (2) EG. The survival rate of blastocysts in the EG + PG was higher than that of the EG. In experiment 2, intact two-cell and eight-cell stage embryos were vitrified in the same solutions used in experiment 1. The EG + PG produced more dead embryos than the EG (P < 0.05). In the EG, the rate of blastocyst formation was similar for the vitrified two- and eight-cell embryos and the non-vitrified ywo-cell embryos. In experiment 3, separated blastomeres of two- and eight-cell embryos were vitrified in EG. There was no difference in the rate of blastocyst formation and total number of cells between the two vitrified groups. In summary, at the blastocyst stage, EG + PG was superior, based on both survival rates and cell numbers; however, at the 2-8 cell stage, the use of EG alone was better than the other groups. PMID- 28856788 TI - Radial fast interrupted steady-state (FISS) magnetic resonance imaging. AB - PURPOSE: To report a highly interrupted radial variant of balanced steady-state free precession (bSSFP) imaging, termed fast interrupted steady-state (FISS), for decreasing flow artifact as well as fat signal conspicuity with respect to bSSFP, and saturation effects vis-a-vis fast low-angle shot (FLASH) imaging. METHODS: Numerical simulations, phantom studies, and human studies were conducted to examine the imaging contrast, off-resonance behavior, and flow properties of FISS. Human studies applied FISS for cine cardiac imaging and ungated nonenhanced MR angiography (MRA) of the legs, neck, and brain. Comparisons were made with bSSFP and FLASH imaging. RESULTS: Simulations revealed that FISS retains the high signal levels of bSSFP for stationary on-resonant spins, while reducing undesirable signal heterogeneity from flowing spins. Phantom studies agreed with the simulations, and showed that FISS reduces fat signal and flow artifact with respect to bSSFP imaging. FISS imaging in human subjects agreed with the simulations and phantom studies, and showed reduced saturation artifact compared with FLASH imaging. CONCLUSION: FISS imaging reduces flow artifact and fat signal conspicuity with respect to bSSFP imaging, and ameliorates arterial signal saturation observed with FLASH imaging. Potential clinical applications include fat-suppressed cine imaging and ungated nonenhanced MRA. Magn Reson Med 79:2077 2086, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28856789 TI - Longitudinal telomere shortening and early Alzheimer's disease progression in adults with down syndrome. AB - Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome. PMID- 28856790 TI - MSH2 deletion with CREBBP and KRAS mutations in pediatric high-hyperdiploid acute lymphoblastic leukemia. PMID- 28856791 TI - Predictors on admission of functional decline among older patients hospitalised for acute care: A prospective observational study. AB - OBJECTIVE: We sought to investigate the incidence of, and factors associated with, in-hospital functional decline among older acute hospital patients. METHODS: We conducted a prospective observational study of consecutive patients admitted under geriatric medicine over 5 years. The primary outcome measure was functional decline between admission and discharge, representing deterioration in any of the following: Modified Barthel Index (MBI), independence in Timed Up and Go test or walking, and/or need for walking aid. RESULTS: Overall, 56% (950/1693) patients (mean age 81.9 years) exhibited in-hospital functional decline. Premorbid MBI (odds ratio (OR) 1.05 per unit increase, P < 0.001), adverse drug reaction (OR 1.50, P = 0.001) and in-hospital consultation as the referral source (OR 1.57, P = 0.001) were independently associated with functional decline, adjusting for age, dementia and nursing home residence. CONCLUSION: These factors may aid identification of vulnerable patients who might particularly benefit from targeted multidisciplinary intervention. Further studies validating this, and exploring the impact of focussed management, are needed. PMID- 28856792 TI - Risk of stillbirth, preterm delivery, and fetal growth restriction following exposure in a previous birth: systematic review and meta-analysis. AB - BACKGROUND: Little is known about the risk of non-recurrent adverse birth outcomes. OBJECTIVES: To evaluate the risk of stillbirth, preterm birth (PTB), and small for gestational age (SGA) as a proxy for fetal growth restriction (FGR) following exposure to one or more of these factors in a previous birth. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Maternity and Infant Care, and Global Health from inception to 30 November 2016. SELECTION CRITERIA: Studies were included if they investigated the association between stillbirth, PTB, or SGA (as a proxy for FGR) in two subsequent births. DATA COLLECTION AND ANALYSIS: Meta analysis and pooled association presented as odds ratios (ORs) and adjusted odds ratios (aORs). MAIN RESULTS: Of the 3399 studies identified, 17 met the inclusion criteria. A PTB or SGA (as a proxy for FGR) infant increased the risk of subsequent stillbirth ((pooled OR 1.70; 95% confidence interval, 95% CI, 1.34 2.16) and (pooled OR 1.98; 95% CI 1.70-2.31), respectively). A combination of exposures, such as a preterm SGA (as a proxy for FGR) birth, doubled the risk of subsequent stillbirth (pooled OR 4.47; 95% CI 2.58-7.76). The risk of stillbirth also varied with prematurity, increasing three-fold following PTB <34 weeks of gestation (pooled OR 2.98; 95% CI 2.05-4.34) and six-fold following preterm SGA (as a proxy for FGR) <34 weeks of gestation (pooled OR 6.00; 95% CI 3.43-10.49). A previous stillbirth increased the risk of PTB (pooled OR 2.82; 95% CI 2.31 3.45), and subsequent SGA (as a proxy for FGR) (pooled OR 1.39; 95% CI 1.10 1.76). CONCLUSION: The risk of stillbirth, PTB, or SGA (as a proxy for FGR) was moderately elevated in women who previously experienced a single exposure, but increased between two- and three-fold when two prior adverse outcomes were combined. Clinical guidelines should consider the inter-relationship of stillbirth, PTB, and SGA, and that each condition is an independent risk factor for the other conditions. TWEETABLE ABSTRACT: Risk of adverse birth outcomes in next pregnancy increases with the combined number of previous adverse events. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? Each year, around 2.6 million babies are stillborn, 15 million are born preterm (<37 weeks of gestation), and 32 million are born small for gestational age (less than tenth percentile for weight, smaller than usually expected for the relevant pregnancy stage). Being born preterm or small for gestational age can increase the chance of long-term health problems. The effect of having a stillbirth, preterm birth, or small-for-gestational-age infant in a previous pregnancy on future pregnancy health has not been summarised. We identified 3399 studies of outcomes of previous pregnancies, and 17 were summarised by our study. What were the main findings? The outcome of the previous pregnancy influenced the risk of poor outcomes in the next pregnancy. Babies born to mothers who had a previous preterm birth or small-for-gestational-age birth were more likely to be stillborn. The smaller and the more preterm the previous baby, the higher the risk of stillbirth in the following pregnancy. The risk of stillbirth in the following pregnancy was doubled if the previous baby was born both preterm and small for gestational age. Babies born to mothers who had a previous stillbirth were more likely to be preterm or small for gestational age. What are the limitations of the work? We included a small number of studies, as there are not enough studies in this area (adverse birth outcomes followed by adverse cross outcomes in the next pregnancy). We found very few studies that compared the risk of small for gestational age after preterm birth or stillbirth. Definitions of stillbirth, preterm birth categories, and small for gestational age differed across studies. We did not know the cause of stillbirth for most studies. What are the implications for patients? Women who have a history of poor pregnancy outcomes are at greater risk of poor outcomes in following pregnancies. Health providers should be aware of this risk when treating patients with a history of poor pregnancy outcomes. PMID- 28856793 TI - Identification of a Triterpenoid as a Novel PPARgamma Activator Derived from Formosan Plants. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma), one of the transcription factors that regulate lipid metabolism and energy use in tumor cells, is a viable target for cancer therapy. In our search for potential PPARgamma activator, extracts from five Formosan plants were tested. Among them, Momordica charantia L. showed the highest ability to activate PPARgamma, which led us to identify its potential constituents. Among the seven compounds isolated from M. charantia, a triterpenoid, 5beta,19-epoxy-19-methoxycucurbita-6,23-dien 3beta,25-diol (compound 1), was identified as a PPARgamma activator with an IC50 of 10 MUM in breast cancer MCF-7 cells. Flow cytometric analysis indicated that compound 1 induced G1 cell cycle arrest which might be attributable to the modulation of phosphorylation and expression of numerous key signaling effectors, including cyclin D1, CDK6, and p53. Notably, compound 1 downregulated the expression of histone deacetylase 1, leading to increased histone H3 acetylation. Taken together, these findings suggest that compound 1 may have therapeutic applications in cancer treatment through PPARgamma activation. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28856794 TI - Rapid and sensitive colorimetric detection of ascorbic acid in food based on the intrinsic oxidase-like activity of MnO2 nanosheets. AB - In this paper, we report a colorimetric sensor for the rapid, selective detection of ascorbic acid (AA) in aqueous solutions. Single-layered MnO2 nanosheets were established as an artificial oxidase; consequently colorless 3,3',5,5' tetramethylbenzidine (TMB) was oxidized to a blue product (oxTMB), with increase in absorbance at 650 nm. The absorbance of the reaction system decreased after introduction AA, which reduced MnO2 into Mn2+ . Under optimum conditions, a detection limit of 62.81 nM for AA in aqueous solutions could be achieved. The linear response range for AA was 0.25-30 MUM with a correlation coefficient of 0.996. Importantly, the MnO2 nanosheet-TMB chromogenic reaction exhibited great selectivity as there was no interference from other metal ions, amino acids and small biological molecules. The proposed colorimetric sensing of AA could be applied for fruit, juice and pharmaceutical samples. Moreover, the proposed sensor showed satisfying performance, including low cost, easy preparation, rapid detection, and good biocompatibility. PMID- 28856795 TI - Development of medical termination of pregnancy: a review. AB - : The synthesis of mifepristone, an antiprogestin blocking the action of progesterone at the receptor level, started a new era of medical termination of pregnancy (MTOP). The initial results of MTOP with mifepristone alone were disappointing; however, mifepristone can sensitise the myometrium to the action of prostaglandins. Clinical trials have shown that the sequential administration of mifepristone followed 1-2 days later by a prostaglandin analogue is a safe, effective, and acceptable method for MTOP. This article will review the events and challenges leading to the development of the current evidence-based and yet off-label regimen for first-trimester MTOP. TWEETABLE ABSTRACT: This article reviews the events and challenges in the development of medical termination of pregnancy. PMID- 28856796 TI - Environmental niches and metabolic diversity in Neoarchean lakes. AB - The diversification of macro-organisms over the last 500 million years often coincided with the development of new environmental niches. Microbial diversification over the last 4 billion years likely followed similar patterns. However, linkages between environmental settings and microbial ecology have so far not been described from the ancient rock record. In this study, we investigated carbon, nitrogen, and molybdenum isotopes, and iron speciation in five non-marine stratigraphic units of the Neoarchean Fortescue Group, Western Australia, that are similar in age (2.78-2.72 Ga) but differ in their hydro geologic setting. Our data suggest that the felsic-dominated and hydrologically open lakes of the Bellary and Hardey formations were probably dominated by methanogenesis (delta13 Corg = -38.7 +/- 4.20/00) and biologic N2 fixation (delta15 Nbulk =-0.6 +/- 1.00/00), whereas the Mt. Roe, Tumbiana and Kylena Formations, with more mafic siliciclastic sediments, preserve evidence of methanotrophy (delta13 Corg as low as -57.40/00, delta13 Ccarb as low as 9.20/00) and NH3 loss under alkaline conditions. Evidence of oxygenic photosynthesis is recorded only in the closed evaporitic Tumbiana lakes marked by abundant stromatolites, limited evidence of Fe and S cycling, fractionated Mo isotopes (delta98/95 Mo = +0.4 +/- 0.40/00), and the widest range in delta13 Corg (-570/00 to -150/00), suggesting oxidative processes and multiple carbon fixation pathways. Methanotrophy in the three mafic settings was probably coupled to a combination of oxidants, including O2 and SO42- . Overall, our results may indicate that early microbial evolution on the Precambrian Earth was in part influenced by geological parameters. We speculate that expanding habitats, such as those linked to continental growth, may have been an important factor in the evolution of life. PMID- 28856797 TI - Estimating coastal wetland gain and losses in Galveston County and Cameron County, Texas, USA. AB - Coastal wetlands serve many important ecological services. One of these important ecological services is their use as storm buffers. Coastal wetlands provide habitat for migratory birds and aquatic species and can improve water quality. In the late 1990s, the US Fish and Wildlife Service (USFWS) published a study outlining the trends of coastal wetlands from the 1950s to early 1990s. In the present study, wetland gains and losses were calculated for Galveston County and Cameron County, Texas, USA, between 2001 and 2011. Maps from the National Land Cover Database were used to determine wetland areas for the years 2001, 2006, and 2011. ArcGIS was used to compare land cover between the study periods to determine overall wetland losses and gains. A statistical analysis was performed between wetland loss and population data to determine whether increased population density led to a higher loss of wetlands. Our analysis indicates that wetland loss is still occurring, however at a lower rate of loss (0.14%-0.18% annually) than the USFWS study predicted earlier (2.7%). In addition, the majority of wetland losses were due to conversion to upland areas. We found a positive correlation between increased population density and decreased wetland area; however, the trend was not significant. The present study shows how the majority of wetland loss in Galveston and Cameron counties is occurring as a result of increased upland areas. In addition, the present study shows that the use of online mapping systems can be used as a low-cost alternative to assess land changes when field tests are not feasible. Integr Environ Assess Manag 2018;14:120-129. (c) 2017 SETAC. PMID- 28856798 TI - Digit ratio 2D:4D is a possible indicator for androgenetic alopecia in males. AB - BACKGROUND: Androgenetic alopecia (AGA) is the most common hair loss. The 2D:4D digit ratio refers to the ratio of the length of the second finger to that of the fourth finger and is thought as a marker of prenatal androgen exposure. OBJECTIVES: There are many studies which have examined the relationship between 2D:4D ratio and some other diseases. In this study, we evaluated the relationship between digit ratio 2D:4D and AGA. METHODS: The study group was composed of a male with AGA and healthy controls. The lengths of patients' second and fourth fingers were measured using a digital caliper with a resolution of 0.01 mm. Finger length was measured on the palmar side of the hand from the basal metacarpophalangeal crease. The 2D:4D ratio was obtained by dividing the length of the second finger by the length of the fourth finger. RESULTS: A total of 99 males who have androgenetic alopecia with a score of grade III or more and 90 controls were included. The mean age of AGA group was 29.72 +/- 5.53, and the mean age of control group was 19.63 +/- 5.05. The left-hand 2D:4D ratios of AGA group (0.893 +/- 0.267) were significantly lower than healthy controls (0.971 +/- 0.028). No significant relationships were found between AGA severity, age of onset,and digit ratios. CONCLUSIONS: The left-hand digit ratio 2D:4D is lower in AGA patients, and therefore, left-hand digit ratio 2D:4D can be used as an estimation tool for AGA development in future. There is not any correlation between digit ratio and age of onset. Also, there is no correlation between digit ratio 2D:4D and AGA severity. PMID- 28856800 TI - Obstructive sleep apnea, excessive daytime sleepiness, and adherence to antihypertensive treatment: Questionnaire survey. PMID- 28856801 TI - High rates of respiratory symptoms and airway disease in mental health inpatients in a tertiary centre. AB - BACKGROUND: People with severe mental illness (SMI) have a lower life expectancy due in part to a higher prevalence of cardiac and metabolic disease. Less is known of the prevalence of respiratory disease in this group. AIMS: This cross sectional, observational study aimed to assess the prevalence of symptoms associated with respiratory disease in patients admitted to an inpatient mental health unit. METHODS: A convenience sample of 82 inpatients had a structured interview and questionnaire completed. The questionnaire included self-reported diagnoses of common diseases and screening questions designed to detect respiratory disease and sleep disordered breathing. Targeted spirometry was performed on the basis of symptoms and smoking status. RESULTS: Patients reported high rates of respiratory symptoms, including wheezing (38%) and dyspnoea (44%); 52% of patients reported daily tobacco use. Productive cough was significantly associated with tobacco use (P < 0.005). Ten patients (18%) had spirometry consistent with chronic obstructive pulmonary disease (COPD) of whom six did not have a formal diagnosis of COPD previously. CONCLUSIONS: People with SMI have high rates of respiratory symptoms with a high prevalence of COPD on spirometry. Half of the COPD cases were not previously diagnosed, suggesting a hidden burden of respiratory disease in patients with SMI. PMID- 28856799 TI - Complexity analysis of cortical surface detects changes in future Alzheimer's disease converters. AB - Alzheimer's disease (AD) is a neurological disorder that creates neurodegenerative changes at several structural and functional levels in human brain tissue. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of the human brain. In this study, we investigate spherical harmonic-based FD (SHFD), thickness, and local gyrification index (LGI) to assess whether they identify cortical surface abnormalities toward the conversion to AD. We study 33 AD patients, 122 mild cognitive impairment (MCI) patients (50 MCI converters and 29 MCI nonconverters), and 32 healthy controls (HC). SHFD, thickness, and LGI methodology allowed us to perform not only global level but also local level assessments in each cortical surface vertex. First, we found that global SHFD decreased in AD and future MCI converters compared to HC, and in MCI converters compared to MCI nonconverters. Second, we found that local white matter SHFD was reduced in AD compared to HC and MCI mainly in medial temporal lobe. Third, local white-matter SHFD was significantly reduced in MCI converters compared to MCI nonconverters in distributed areas, including the medial frontal lobe. Thickness and LGI metrics presented a reduction in AD compared to HC. Thickness was significantly reduced in MCI converters compared to healthy controls in entorhinal cortex and lateral temporal. In summary, SHFD was the only surface measure showing differences between MCI individuals that will convert or remain stable in the next 4 years. We suggest that SHFD may be an optimal complement to thickness loss analysis in monitoring longitudinal changes in preclinical and clinical stages of AD. Hum Brain Mapp 38:5905-5918, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28856802 TI - Esophagogastric junction cancer successfully treated by laparoscopic proximal gastrectomy and lower esophagectomy with intrathoracic double-flap technique: A case report. AB - A 66-year-old man was referred to our hospital for treatment of esophagogastric junction cancer. He was diagnosed as cT2N0M0, and the esophageal invasion was found to be 1 cm from the esophagogastric junction. He underwent laparoscopy assisted proximal gastrectomy and lower esophagectomy with esophagogastrostomy using the intrathoracic double-flap technique through the transhiatal approach. The operative time was 662 min (suturing time was 198 min), and blood loss was 200 mL. The operative time was much longer for this procedure than for esophagogastrostomy with the conventional (intra-abdominal) double-flap technique. The postoperative course was uneventful. No abnormal gastroesophageal reflux, esophageal motility, or lower esophageal sphincter (LES) pressure was demonstrated 3 months after the operation. Laparoscopic proximal gastrectomy and lower esophagectomy with esophagogastrostomy using the double-flap technique through the transhiatal approach is safe and feasible. It may be recommended for patients with esophagogastric junction cancer with esophageal invasion of about 1 cm. PMID- 28856803 TI - Can FSH influence longevity? AB - It was recently reported that the extragonadal actions of follicle-stimulating hormone (FSH) include regulation of brown and white adipose tissue function and thermogenesis. Based on these findings and on our evidence for reduced FSH levels and enhanced thermogenesis in long-lived growth hormone (GH)-deficient mice and GH-resistant mice, we suggest that FSH may have a role in the control of aging and longevity. We speculate that alterations in FSH secretion may represent one of the mechanisms of trade-offs between reproduction and aging. PMID- 28856804 TI - Strain-specific consumption and transformation of alga-derived dissolved organic matter by members of the Limnohabitans-C and Polynucleobacter-B clusters of Betaproteobacteria. AB - We investigated changes in quality and quantity of extracellular and biomass derived organic matter (OM) from three axenic algae (genera Rhodomonas, Chlamydomonas, Coelastrum) during growth of Limnohabitans parvus, Limnohabitans planktonicus and Polynucleobacter acidiphobus representing important clusters of freshwater planktonic Betaproteobacteria. Total extracellular and biomass-derived OM concentrations from each alga were approximately 20 mg l-1 and 1 mg l-1 respectively, from which up to 9% could be identified as free carbohydrates, polyamines, or free and combined amino acids. Carbohydrates represented 54%-61% of identified compounds of the extracellular OM from each alga. In biomass derived OM of Rhodomonas and Chlamydomonas 71%-77% were amino acids and polyamines, while in that of Coelastrum 85% were carbohydrates. All bacteria grew on alga-derived OM of Coelastrum, whereas only Limnohabitans strains grew on OM from Rhodomonas and Chlamydomonas. Bacteria consumed 24%-76% and 38%-82% of all identified extracellular and biomass-derived OM compounds respectively, and their consumption was proportional to the concentration of each OM compound in the different treatments. The bacterial biomass yield was higher than the total identifiable OM consumption indicating that bacteria also utilized other unidentified alga-derived OM compounds. Bacteria, however, also produced specific OM compounds suggesting enzymatic polymer degradation or de novo exudation. PMID- 28856806 TI - Pathogenic role of ion channels in pulmonary arterial hypertension. PMID- 28856807 TI - Finding serendipity. PMID- 28856808 TI - Publishing replication studies to support excellence in physiological research. PMID- 28856805 TI - Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury. AB - Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro inflammatory IL-1beta to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with "A2" reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1beta-induced model of NWMI, astrocytes also exhibit "A2" reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop "A2" reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection. PMID- 28856810 TI - Abstracts of the 51. Wissenschaftliche Tagung der Deutschsprachigen Mykologischen Gesellschaft e.V., 31 August - 02 September 2017, Munster, Germany. PMID- 28856809 TI - Dental hygiene education in Germany: Between economics and emotions. AB - OBJECTIVES: To date, there is still no IFDH approved dental hygienist (DH) education model in Germany. Nevertheless, opportunities to complete vocational DH education courses have substantially increased within the last two decades. However, the content and quality of these courses vary greatly and are difficult to survey. The purpose of this article therefore was to present an overview of the education programmes offered in Germany as of March 2017. METHODS: A formal request was sent to all education establishments for details of such courses, and a systematic internet search was performed covering the DH education topic in Germany. RESULTS: Ten vocational education programmes were found, most of them organized by local dental chambers. One private provider offers a Bachelor Degree in Dental Hygiene on completion of a course which runs over 2 or 3 ys. Details of contents, objectives and concise ratings or comparisons of the various courses are scarce, although in principle all should meet the same quality standards. CONCLUSION: For dental hygiene students, patients and dentists, it is hard and unsatisfactory to get a clear overview of the types and the quality of DH education which can be achieved in Germany. A solution for this dilemma would appear to be essential. However, due to the peculiarities of German legislation as well as the complex sphere of vested interests, it is impossible to predict if or when the situation will change for the better. PMID- 28856811 TI - Life-threatening hemorrhage from the corona mortis after laparoscopic inguinal hernia repair: Report of a case. AB - Along with the increased use of other laparoscopic procedures, laparoscopic inguinal hernia repair has become widely used because of its minimally invasive nature. Here, we report a case of 66-year-old man who underwent transabdominal preperitoneal laparoscopic hernioplasty and developed hemorrhagic shock on postoperative day 1. CT showed postoperative venous hemorrhage from the retropubic space. Successful hemostasis of the massive hemorrhage was achieved laparoscopically. The origin of the hemorrhage was assumed to be the corona mortis vein, which was slightly injured during the operation. Despite the rarity of this complication, surgeons must be aware of the need to carefully dissect and fix the mesh in the retropubic space to avoid injuring the corona mortis. Laparoscopic hemostasis may be an effective alternative to the open approach. PMID- 28856812 TI - Resolving the complexity of vitellogenins and their receptors in the tetraploid Atlantic salmon (Salmo salar): Ancient origin of the phosvitin-less VtgC in chondrichthyean fishes. AB - Egg yolk proteins are mainly derived from vitellogenin (Vtg), and serve as essential nutrients during early development in oviparous organisms. Vertebrate Vtgs are predominantly synthesized in the liver of maturing females, and are internalized by the oocyte after binding to specific surface receptors (VtgR). Here, we clarify the evolutionary history of vertebrate Vtgs, including the teleost VtgC, which lacks phosvitin, and investigate the repertoire of Vtgs and VtgRs in the tetraploid Atlantic salmon (Salmo salar). Conserved synteny of the vtg genes in elephant fish (Callorhinchus milii) strongly indicates that the vtg gene cluster was present in the ancestor of tetrapods and ray-finned fish. The shortened phosvitin in the VtgC ortholog of this chondrichthyean fish may have resulted from early truncation events that eventually allowed the total disappearance of phosvitin in teleost VtgC. In contrast, the tandem-duplicated VtgCs identified in the spotted gar (Lepisosteus oculatus) both contain the phosvitin domain. The Atlantic salmon genome harbors four vtg genes encoding the complete VtgAsa1, phosvitin-less VtgC, and truncated VtgAsb proteins; vtgAsa2 is a pseudogene. The three vtg genes were mainly expressed in the liver of maturing females, and the vtgAsa1 transcript predominated prior to spawning. The splice variant lacking the O-linked sugar domain dominated ovarian expression of vtgr1 and vtgr2. Strongly increased vtgAsa1 expression during vitellogenesis contrasted with the peaks of vtgr1 and vtgr2 in the previtellogenic oocytes, which gradually decreased over the same period. Recycling of the oocyte VtgRs is probably not sufficient to maintain receptor number during vitellogenesis. PMID- 28856813 TI - Operation Damage Control: Exercise Training to Prevent Metabolic Damage from High Fat Feeding. PMID- 28856814 TI - Constructing a Strongly Absorbing Low-Bandgap Polymer Acceptor for High Performance All-Polymer Solar Cells. AB - All-polymer solar cells (all-PSCs) offer unique morphology stability for the application as flexible devices, but the lack of high-performance polymer acceptors limits their power conversion efficiency (PCE) to a value lower than those of the PSCs based on fullerene derivative or organic small molecule acceptors. We herein demonstrate a strategy to synthesize a high-performance polymer acceptor PZ1 by embedding an acceptor-donor-acceptor building block into the polymer main chain. PZ1 possesses broad absorption with a low band gap of 1.55 eV and high absorption coefficient (1.3*105 cm-1 ). The all-PSCs with the wide-band-gap polymer PBDB-T as donor and PZ1 as acceptor showed a record-high PCE of 9.19 % for the all-PSCs. The success of our polymerization strategy can provide a new way to develop efficient polymer acceptors for all-PSCs. PMID- 28856815 TI - Prognoses in patients with primary gastrointestinal neuroendocrine neoplasms based on the proposed new classification scheme. AB - AIM: The aim of this study is to investigate the clinicopathological characteristics, as well as explore the prognostic accuracy of the proposed new classification in gastrointestinal NENs (GI-NENs) patients. METHODS: Patients diagnosed with GI-NENs were retrospectively indentified from existing databases of the pathological institute at our institution from January 2009 to November 2015. RESULTS: We identified 414 patients with GI-NENs, 250 cases were diagnosed as neuroendocrine tumor G1 (NET G1), 25 as neuroendocrine tumor G2 (NET G2), 53 as neuroendocrine tumor G3 (NET G3), 55 as neuroendocrine carcinoma G3 (NEC G3), and 31 as mixed adenoneuroendocrine carcinoma (MANEC); the overall survival (OS) rate at three years were 94.9%, 91.7%, 74.3%, 62.7% and 38.1%, respectively. The difference in progression-free survival (PFS) duration among the patients with NET G1, NET G2, NET G3, NEC G3, and MANEC was statistically significant (P < 0.001). However, the PFS of NEC G3 and MANEC was low and similar (P = 0.090). In multivariate analysis of patients with GI-NENs, surgical margin, comorbidity, proposed new classification and tumor location were useful predictors of OS (P < 0.05). CONCLUSION: Our findings suggest that the proposed new classification can accurately reflect the clinical outcome, together with surgical margin, comorbidity, and tumor location may be meaningful prognostic factors for the OS of GI-NENs. PMID- 28856816 TI - Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients. AB - : Autism spectrum disorder (ASD) is a neuro developmental disorder, reported to be on a rise in the past two decades. Thyroid hormone-T3 plays an important role in early embryonic and central nervous system development. T3 mediates its function by binding to thyroid hormone receptors, TRalpha and TRbeta. Alterations in T3 levels and thyroid receptor mutations have been earlier implicated in neuropsychiatric disorders and have been linked to environmental toxins. Limited reports from earlier studies have shown the effectiveness of T3 treatment with promising results in children with ASD and that the thyroid hormone levels in these children was also normal. This necessitates the need to explore the genetic variations in the components of the thyroid hormone pathway in ASD children. To achieve this objective, we performed genetic analysis of ligand binding domain of THRA and THRB receptor genes in 30 ASD subjects and in age matched controls from India. Our study for the first time reports novel single nucleotide polymorphisms in the THRA and THRB receptor genes of ASD individuals. Autism Res 2017, 10: 1919 1928. (c)2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Thyroid hormone (T3) and thyroid receptors (TRalpha and TRbeta) are the major components of the thyroid hormone pathway. The link between thyroid pathway and neuronal development is proven in clinical medicine. Since the thyroid hormone levels in Autistic children are normal, variations in their receptors needs to be explored. To achieve this objective, changes in THRA and THRB receptor genes was studied in 30 ASD and normal children from India. The impact of some of these mutations on receptor function was also studied. PMID- 28856817 TI - The use of trastuzumab in New Zealand women with breast cancer. AB - AIM: Trastuzumab was first funded in New Zealand for use in HER2+ve stage I-III breast cancer in 2007. This observational study aims to ascertain the patterns of use of trastuzumab in women with invasive HER2+ve breast cancer, and assess the effectiveness of adjuvant trastuzumab in women with stage I-III HER2+ve breast cancer. METHODS: The Waikato and Auckland Breast Cancer Registries have clinical details of 12 372 women diagnosed with invasive breast cancer between June 2000 and May 2013. The proportion of women with HER2+ve breast cancer treated with trastuzumab was examined by age, ethnicity, stage and year of diagnosis. Differences in outcomes including the development of metastases and death were assessed for women with stage I-III HER2+ve breast cancer treated with both chemotherapy and trastuzumab, compared to women treated with chemotherapy alone. RESULTS: Among the 1587 HER2+ve breast cancer patients, 888 (56.0%) women received trastuzumab. The probability of having trastuzumab decreased with higher age and comorbidity score and increased with year of diagnosis, tumor size and cancer stage. Maori and Pacific women were less likely to be treated with trastuzumab. After adjustment for potential confounding factors, the treatment with trastuzumab improved breast cancer-specific mortality (adjusted hazard ratio 0.57, 95% CI: 0.35-0.93). CONCLUSION: Overall, this observational study has shown a substantial improvement in survival for women with HER2+ve stage I-III breast cancer, and much of this improvement can be attributed to the introduction of trastuzumab. Changes in chemotherapy also appear to have led to improved outcomes. PMID- 28856819 TI - Primary squamous cell carcinoma of the hand with metastasis to the breast. PMID- 28856818 TI - Insight into Aluminum Sulfate-Catalyzed Xylan Conversion into Furfural in a gamma Valerolactone/Water Biphasic Solvent under Microwave Conditions. AB - A simple and efficient biphasic system with an earth-abundant metal salt catalyst was used to produce furfural from xylan with a high yield of up to 87.8 % under microwave conditions. Strikingly, the metal salt Al2 (SO4 )3 exhibited excellent catalytic activity for xylan conversion, owing to a combination of Lewis and Bronsted acidity and its ability to promote good phase separation. The critical role of the SO42- anion was first analyzed, which resulted in the aforementioned characteristics when combined with the Al3+ cation. The mixed solvent system with gamma-valerolactone (GVL) as the organic phase provided the highest furfural yield, resulting from its good dielectric properties and dissolving capacity, which facilitated the absorption of microwave energy and promoted mass transfer. Mechanistic studies suggested that the xylan-to-furfural conversion proceeded mainly through a hydrolysis-isomerization-dehydration pathway and the hexa coordinated Lewis acidic [Al(OH)2 (aq)]+ species were the active sites for xylose xylulose isomerization. Detailed kinetic studies of the subreaction for the xylan conversion revealed that GVL regulates the reaction rates and pathways by promoting the rates of the key steps involved for furfural production and suppressing the side reactions for humin production. Finally, the Al2 (SO4 )3 catalyst was used for the production of furfural from several lignocellulosic feedstocks, revealing its great potential for other biomass conversions. PMID- 28856820 TI - Decrease of ethyl glucuronide concentrations in hair after exposure to chlorinated swimming pool water. AB - The direct alcohol marker ethyl glucuronide (EtG) is widely used for the assessment of alcohol consumption behavior and abstinence monitoring by hair analysis. We investigated the influence of chlorinated swimming pool water on EtG concentrations in hair in comparison to deionized water (Milli-Q) containing no chlorine. EtG concentrations were measured with a validated online solid-phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) method. EtG positive hair samples were obtained from 3 regular drinkers and incubated for 0, 2, 4, 6, 8, and 10 hours at room temperature. EtG concentrations in hair were reduced after 2 hours of incubation in chlorinated water by 20 +/- 12% (range: 4 33%), in deionized water by 24 +/- 5% (range: 18-29%). Incubation for 10 hours resulted in a decrease in EtG concentrations of 57 +/- 6% (range: 52-65%) for chlorinated water and 47 +/- 11% (range: 32-60%) for deionized water. To demonstrate washout in forensic hair samples, 20 samples from subjects with known alcohol consumption behavior were investigated additionally. The samples were divided into 2 strands and analyzed with incubation in chlorinated water for 10 hours and for comparison without any incubation. A mean decrease of 53 +/- 18% (range: 26-88%) was observed. These results clearly demonstrate that washout effects are caused by water and have a significant impact on EtG concentrations in hair. For people with hair that are regularly exposed to water for a longer period (eg. swimmers), washout effects may lead to a significant decrease of EtG concentrations in hair. Concentrations may fall below threshold concentrations used for the interpretation of consumption habits (7 pg/mg for social consumption, 30 pg/mg for excessive consumption). PMID- 28856821 TI - The Proteome of Ulcerative Colitis in Colon Biopsies from Adults - Optimized Sample Preparation and Comparison with Healthy Controls. AB - PURPOSE: The purpose of the study was to optimize the sample preparation and to further use an improved sample preparation to identify proteome differences between inflamed ulcerative colitis tissue from untreated adults and healthy controls. EXPERIMENTAL DESIGN: To optimize the sample preparation, we studied the effect of adding different detergents to a urea containing lysis buffer for a Lys C/trypsin tandem digestion. With the optimized method, we prepared clinical samples from six ulcerative colitis patients and six healthy controls and analysed them by LC-MS/MS. We examined the acquired data to identify differences between the states. RESULTS: We improved the protein extraction and protein identification number by utilizing a urea and sodium deoxycholate containing buffer. Comparing ulcerative colitis and healthy tissue, we found 168 of 2366 identified proteins differently abundant. Inflammatory proteins are higher abundant in ulcerative colitis, proteins related to anion-transport and mucus production are lower abundant. A high proportion of S100 proteins is differently abundant, notably with both up-regulated and down-regulated proteins. CONCLUSION AND CLINICAL RELEVANCE: The optimized sample preparation method will improve future proteomic studies on colon mucosa. The observed protein abundance changes and their enrichment in various groups improve our understanding of ulcerative colitis on protein level. PMID- 28856822 TI - Resolution of R-(-) and S-(+)- enantiomers of clenbuterol in pharmaceutical preparations and black-market products using liquid chromatography-tandem mass spectrometry. AB - Several banned substances are illegally used by athletes in racemic mixtures for performance enhancement. These include clenbuterol, methyl hexaneamine, methamphetamines, and amphetamines. Clenbuterol is present in a large number of doping samples from Olympic and non-Olympic athletes that have adverse analytical findings (AAFs). In some cases, the presence of these substances could be the result of consumption of meat contaminated with clenbuterol. In other cases, the origin is not clear. In this study, 27 products with racemic clenbuterol were evaluated using a new analytical methodology for the resolution of R-(-) and S (+)-enantiomers of clenbuterol by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a chiral column in 15 min with good separation. The method developed can also be used for the analysis of other biological matrices such as urine, serum, and meat. The resolution between two peaks' (Rs ) value obtained using chromatographic data was 1.03. Both clenbuterol enantiomers were present in all products analyzed and the ratio was nearly 1. The origin of the product was not important for determining the presence of one or both enantiomers. All products displayed a 50:50 ratio of clenbuterol enantiomers. To the best of our knowledge, clenbuterol ratio determination of a large number of pharmaceutical preparations and black-market products has not been reported previously. The information shown could be used by national anti-doping organizations and the athletes with AAFs attributed to clenbuterol. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28856823 TI - Talking with caregivers of children living in the community with ventricular assist devices. AB - A VAD is a mechanical pump used to support the functioning of a failing heart. As a pediatric therapy, a VAD is used as a temporary solution for poor heart function, a bridge to transplantation or recovery, or a destination therapy. The goal of this qualitative study was to explore the perspectives of family and professional caregivers of children who are supported by VADs in outpatient settings. Semi-structured interviews were conducted with 22 caregivers of school aged children discharged home on VAD support. Interviews were transcribed, and data were analyzed using qualitative content analysis. Caregivers identified issues facing children on VAD support in the contexts of home, school, and other childhood places including being physically connected to a device; experiencing changes; living a medical life; negotiating restrictions; cost of care; family, kinship, and community; and, present and future living. While a child with a VAD may have much in common with other medically complex children, the technological complications and risks of living with a VAD are uniquely identified by caregivers as an issue, especially when considering the way that children with a VAD are connected to their device-implanted yet exterior, mobile yet restricted, and autonomous yet dependent. PMID- 28856825 TI - Investigating Associations Between Positive Fathering and Children's Health: It's Time for Interventions. PMID- 28856824 TI - Response To: Letter to The Editor - Comments on The Use of LOINC and SNOMED CT for Representing Nursing Data. PMID- 28856826 TI - Letter to the Editor-Comments on the Use of LOINC and SNOMED CT for Representing Nursing Data. PMID- 28856827 TI - Transcriptomic and physiological analyses of the dinoflagellate Karenia mikimotoi reveal non-alkaline phosphatase-based molecular machinery of ATP utilisation. AB - The ability to utilize dissolved organic phosphorus (DOP) is important for phytoplankton to survive the scarcity of dissolved inorganic phosphorus (DIP), and alkaline phosphatase (AP) has been the major research focus as a facilitating mechanism. Here, we employed a unique molecular ecological approach and conducted a broader search for underpinning molecular mechanisms of adenosine triphosphate (ATP) utilisation. Cultures of the dinoflagellate Karenia mikimotoi were set up in L1 medium (+P), DIP-depleted L1 medium (-P) and ATP-replacing-DIP medium (ATP). Differential gene expression was profiled for ATP and +P cultures using suppression subtractive hybridisation (SSH) followed by 454 pyrosequencing, and RT-qPCR methods. We found that ATP supported a similar growth rate and cell yield as L1 medium and observed DIP release from ATP into the medium, suggesting that K. mikimotoi cells were expressing extracellular hydrolases to hydrolyse ATP. However, our SSH, qPCR and enzymatic activity assays indicated that 5' nucleotidase (5NT), rather than AP, was responsible for ATP hydrolysis. Further gene expression analyses uncovered that intercellular purine metabolism was significantly changed following the utilisation of ATP. Our findings reveal a multi-faceted machinery regulating ATP utilisation and P metabolism in K. mikimotoi, and underscore AP activity is not the exclusive indicator of DOP utilisation. PMID- 28856828 TI - Effects of correcting missing daily feed intake values on the genetic parameters and estimated breeding values for feeding traits in pigs. AB - Daily feed intake (DFI) is an important consideration for improving feed efficiency, but measurements using electronic feeder systems contain many missing and incorrect values. Therefore, we evaluated three methods for correcting missing DFI data (quadratic, orthogonal polynomial, and locally weighted (Loess) regression equations) and assessed the effects of these missing values on the genetic parameters and the estimated breeding values (EBV) for feeding traits. DFI records were obtained from 1622 Duroc pigs, comprising 902 individuals without missing DFI and 720 individuals with missing DFI. The Loess equation was the most suitable method for correcting the missing DFI values in 5-50% randomly deleted datasets among the three equations. Both variance components and heritability for the average DFI (ADFI) did not change because of the missing DFI proportion and Loess correction. In terms of rank correlation and information criteria, Loess correction improved the accuracy of EBV for ADFI compared to randomly deleted cases. These findings indicate that the Loess equation is useful for correcting missing DFI values for individual pigs and that the correction of missing DFI values could be effective for the estimation of breeding values and genetic improvement using EBV for feeding traits. PMID- 28856829 TI - Efficacy and safety of very early medical termination of pregnancy: a cohort study. AB - OBJECTIVE: To assess the efficacy and safety of medical termination of pregnancy (MTOP) when no intrauterine pregnancy (IUP) is confirmed on ultrasound. DESIGN: Retrospective case-note review. SETTING: Two gynaecological clinics in Vienna, Austria, and Gothenburg, Sweden. POPULATION: All women with gestations of <=49 days undergoing an MTOP during 2004-14 (Vienna) and 2012-15 (Gothenburg). METHODS: Two study cohorts were created: women with and women without a confirmed IUP. An IUP was defined as the intrauterine location of a yolk sac or fetal structure visible by ultrasound. Women with an IUP were selected randomly and included in the IUP cohort. MAIN OUTCOME MEASURES: Efficacy of MTOP, defined as no continuing pregnancy and with no need of surgery for incomplete TOP. RESULTS: After excluding 11 women diagnosed with an extra-uterine or molar pregnancy, 2643 cases were included in the final analysis; 1120 (98.2%) had a successful TOP in the no-IUP group, compared with 1458 (97.1%) in the IUP group, with a risk difference of 1.09% (95% confidence interval, 95% CI, -0.14, 2.32%; P = 0.077). Significantly more women with confirmed IUP were diagnosed with incomplete TOP, and were treated with either surgery or additional medical treatment of misoprostol [64 (4.3%) versus 21 (1.8%); risk difference -2.42%; 95% CI -3.9, 1.1%; P < 0.001]. CONCLUSIONS: There was no difference between the groups in efficacy of MTOP, whereas early treatment resulted in significantly fewer interventions for incomplete TOP. The risk of ectopic pregnancy needs to be considered if treatment is initiated before an IUP is confirmed, but with structured clinical protocols the possibility of the early detection of an ectopic pregnancy in an asymptomatic phase may increase. TWEETABLE ABSTRACT: MTOP before confirmed intrauterine pregnancy is as effective as at later gestation with less incomplete TOP. PMID- 28856830 TI - Spousal concordance for hypertension: A meta-analysis of observational studies. AB - The authors performed a meta-analysis of observational studies to estimate the magnitude of spousal concordance for hypertension and to examine whether the concordance varied by important study methodological aspects. PubMed and Embase were searched up to June 2017 for cross-sectional, case-control, and cohort studies that investigated the concordance/association of hypertension between spouse pairs. A meta-analysis with random-effects models was performed by pooling adjusted odds ratios. Eight studies with a total number of 81 928 spouse pairs were eligible. The pooled results showed that spouses of individuals with hypertension had 41% (odds ratio, 1.41; 95% confidence interval, 1.21-1.64) increased odds of having hypertension themselves. The association applied to both men and women, and was not significantly different between studies with adjustment for body mass index and those without. The findings highlighted the importance of environmental factors in the development of hypertension. PMID- 28856831 TI - Metachronous solitary mediastinal lymph node metastases of hepatocellular carcinoma treated by video-assisted thoracic surgery twice: Report of a case. AB - Solitary mediastinal lymph node metastasis of hepatocellular carcinoma (HCC) is rare. We report a case of metachronically solitary mediastinal metastases of HCC treated by video-assisted thoracic surgery (VATS) twice. A 66-year-old man underwent repeated laparoscopic radiofrequency ablation or trans-arterial catheter chemo-embolization against HCC for more than 10 years. The level of alpha fetoprotein protein was elevated, and radiological modalities including FDG PET revealed solitary mediastinal tumor metachronically. VATS was performed bilaterally twice. The postoperative course was uneventful and there had no recurrence of extra-hepatic metastases and tumor markers are within normal limits at 18 months after second VATS. VATS is a minimally invasive and useful procedure for solitary mediastinal lymph node metastasis of HCC. If primary HCC was controlled and lymph node metastasis was solitary, mediastinum lymphadenectomy using VATS might give good short and long term results. PMID- 28856832 TI - Central retinal preservation in rdAc cats. AB - OBJECTIVE: Children with Leber congenital amaurosis (LCA) due to CEP290 mutations show characteristic macular preservation. Spectral domain-optical coherence tomography (SD-OCT) is a noninvasive technique to investigate retinal structural changes. Loss of integrity of the ellipsoid zone (EZ) on OCT in people with retinal disease has been associated with loss of visual function and is a useful measure of retinal disease progression. We hypothesized that rdAc felines with Cep290 mutation would have a similar pattern of degeneration, with relative central retinal preservation associated with maintenance of the EZ. PROCEDURES: Fundus imaging, confocal scanning laser ophthalmoscopy, and SD-OCT cross sectional imaging was performed on 11 rdAc cats ranging from 6 months to 10 years of age. Images were collected from the area centralis, visual streak, and the mid superior and mid-inferior retina. Receptor plus (REC+, encompassing the entire length of photoreceptors) thicknesses were measured. Regional rates of degeneration were determined by regression analysis and compared using unpaired t tests. The EZ was evaluated for the presence, absence, or loss of definition. RESULTS: RdAc cats showed REC+ thinning over time in all regions. The area centralis and visual streak had a slower rate of thinning than the mid-peripheral retina. There was loss of integrity of the EZ initially in the more peripheral regions, while its integrity was maintained in the area centralis and visual streak at all ages studied. CONCLUSIONS: rdAc cats show preservation of the central retina with maintenance of EZ integrity, which recapitulates findings in human patients. PMID- 28856833 TI - Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1. AB - Transport of activated nucleotide-sugars into the Golgi is critical for proper glycosylation and mutations in these transporters cause a group of rare genetic disorders termed congenital disorders of glycosylation. We performed exome sequencing on an individual with a profound neurological presentation and identified rare compound heterozygous mutations, p.Thr156Arg and p.Glu196Lys, in the CMP-sialic acid transporter, SLC35A1. Patient primary fibroblasts and serum showed a considerable decrease in the amount of N- and O-glycans terminating in sialic acid. Direct measurement of CMP-sialic acid transport into the Golgi showed a substantial decrease in overall rate of transport. Here we report the identification of the third patient with CMP-sialic acid transporter deficiency, who presented with severe neurological phenotype, but without hematological abnormalities. PMID- 28856835 TI - The role S-nitrosylation in manganese-induced autophagy dysregulation in SH-SY5Y cells. AB - Overexposure to manganese (Mn) has been known to induce nitrosative stress. The dysregulation of autophagy has implicated in nitric oxide (NO) bioactivity alterations. However, the mechanism of Mn-induced autophagic dysregulation is unclear. The protein of Bcl-2 was considered as a key role that could participate to the autophagy signaling regulation. To further explore whether S-nitrosylation of Bcl-2 involved in Mn-induced autophagy dysregulation, we treated human neuroblastoma (SH-SY5Y) cells with Mn and pretreated cells with 1400 W, a selective iNOS inhibitor. After cells were treated with 400 MUM Mn for 24 h, there were significant increases in production of NO, inducible NO synthase (iNOS) activity, the mRNA and protein expressions of iNOS. Interestingly, autophagy was activated after cells were treated with Mn for 0-12 h; while the degradation process of autophagy-lysosome pathway was blocked after cells were treated with Mn for 24 h. Moreover, S-nitrosylated JNK and Bcl-2 also increased and phospho-JNK and phospho-Bcl-2 reduced in Mn-treated cells. Then, the affinity between Bcl-2 and Beclin-1 increased significantly in Mn-treated cells. We used the 1400 W to neutralize Mn-induced nitrosative stress. The results showed that S nitrosylated JNK and Bcl-2 reduced while their phosphorylation were recovered to some extent. The findings revealed that NO-mediated S-nitrosylation of Bcl-2 directly affected the interaction between Beclin-1 and Bcl-2 leading to autophagy inhibition. PMID- 28856834 TI - Disparities in hypertension and cardiovascular disease in blacks: The critical role of medication adherence. AB - Blacks are two to three times as likely as whites to die of preventable heart disease and stroke. Declines in mortality from heart disease have not eliminated racial disparities. Control and effective treatment of hypertension, a leading cause of cardiovascular disease, among blacks is less than in whites and remains a challenge. One of the driving forces behind this racial/ethnic disparity is medication nonadherence whose cause is embedded in social determinants. Eight practical approaches to addressing medication adherence with the potential to attenuate disparities were identified and include: (1) patient engagement strategies, (2) consumer-directed health care, (3) patient portals, (4) smart apps and text messages, (5) digital pillboxes, (6) pharmacist-led engagement, (7) cardiac rehabilitation, and (8) cognitive-based behavior. However, while data suggest that these strategies may improve medication adherence, the effect on ameliorating racial/ethnic disparities is not certain. This review describes the relationship between disparities and medication adherence, which likely plays a role in persistent disparities in cardiovascular morbidity and mortality. PMID- 28856837 TI - Food challenges, the risks and benefits. PMID- 28856836 TI - Applying prevention concepts to anaphylaxis: A call for worldwide availability of adrenaline auto-injectors. PMID- 28856840 TI - Measuring depression, anxiety, and stress in Macau university students. PMID- 28856839 TI - Comparison of cauliflower-insect-fungus interactions and pesticides for cabbage root fly control. AB - Cabbage root fly (Delia radicum L.) control represents a major challenge in brassica production, therefore different management strategies for its control were tested in conventionally managed open field cauliflower production. Strategies included treatments with low-risk methods such as nitrogen lime, the insecticide spinosad and the Beauveria bassiana ATCC 74040-based biopesticide Naturalis. Their effects were compared with treatments based on nonformulated fungal species Metarhizium brunneum, B. bassiana, Clonostachys solani, Trichoderma atroviride, T. koningiopsis, and T. gamsii and commercial insecticides lambda-cyhalothrin and thiamethoxam. Spinosad and thiamethoxam were pipetted to individual plants before transplanting; lambda-cyhalothrin was sprayed after transplanting; nitrogen lime was applied at first hoeing. Nonformulated fungi were delivered onto cauliflower plantlets' roots as a single pretransplantation inoculation. The cabbage root fly population dynamics exhibited a strong spatiotemporal variation. The lowest number of cabbage root fly pupae recovered from cauliflower roots in the field experiments was recorded in plants treated with spinosad (significant reduction), followed by Naturalis and one of the tested M. brunneum strains (nonsignificant reduction). Significantly more pupae were counted in the nitrogen lime treatment. The field experiments showed that a single drench of cauliflower plantlets with spinosad offered consistent and enduring cabbage root fly control. Naturalis and nonformulated fungal isolates did not decrease cabbage root fly pressure significantly, apparently due to lack of statistical power. The implications of the substantial intra- and inter-annual pest pressure variation and the benefits of using single plant treatments are discussed, and recommendations for improvement of rhizosphere-competence utilizing biological control strategies provided. PMID- 28856841 TI - Association study of CREB1 and CBP genes with Alzheimer's disease in Han Chinese. PMID- 28856842 TI - Burnout symptoms: Depressive manifestations under psychosocial labels? PMID- 28856843 TI - Validity study of Patient Health Questionnaire-9 items for Internet screening in depression among Chinese university students. AB - BACKGROUND: Internet intervention in Chinese university students would be a possible approach to overcome the gap between high rate of depression and high rates of underdiagnosis and undertreatment. As a popular measure of screening, the feasibility and user satisfaction of Patient Health Questionnaire-9 items for online program were tested. METHODS: The subjects were enrolled based on an email list from the students' office of a Chinese university, and 300 undergraduate students were randomly invited of which 230 (76.7%) students were willing to participate in the study and completed the first test. After 2 weeks, a subsample of 150 (65.2%) subjects were randomly chosen to retake the test for the test retest reliability. And 81 (35.2%) among the 230 subjects were randomly selected to undergo the Mini International Neuropsychiatric Interview within 48 hours. Among 150 subjects, 120 (52.2%) completed client satisfaction questionnaire about this online screening program. RESULTS: (1) The Cronbach alpha was 0.80 and the test-retest reliability was 0.78. (2) The optimal cutoff score of 10 revealed a sensitivity of 0.74 and specificity of 0.85, with an area under the curve of 0.897 (95% confidence interval, 0.823-0.970). (3) The mean duration of administration was 3.5 minutes. (4) Satisfaction with the online screening program was highly appreciated. CONCLUSIONS: The results indicated potential value of the online screening program for further Internet-administrated programs of depression among Chinese university students. PMID- 28856844 TI - Valproic acid-induced eosinophilic pleural effusion in a patient with pediatric bipolar disorder. PMID- 28856845 TI - Latif's point: A new point for Veress needle insertion for pneumoperitoneum in difficult laparoscopy. AB - INTRODUCTION: Creating pneumoperitoneum is the most challenging step during laparoscopy. The periumbilical area is the classic site for Veress needle insertion. We adopted a new access point for peritoneal insufflation. METHODS: We introduced a new point for Veress needle insertion to create pneumoperitoneum during difficult laparoscopic procedures. The needle is placed between the xiphoid process and the right costal margin, and it then proceeds toward the patient's right axilla. We collected data to compare using this new method of peritoneal insufflation with using Palmer's point for pneumoperitoneum. RESULTS: Since 2013, we have used this new technique in 570 patients (first group) and Palmer's point in 459 patients (second group). Among these patients, 196 patients (20%) had had previous abdominal operations, 98 patients (10%) had irreducible ventral hernia, and 735 patients (70%) were morbidly obese. The two groups were comparable in terms of patient characteristics. The mean time to create pneumoperitoneum in the first group was 0.8 +/- 0.002 min compared to 1.08 +/- 0.007 min in the second group (P <= 0.5). The mean number of punctures was 1.57 +/- 1.02 in the first group compared to 2.9 +/- 1.5 in the second group (P<= 0.5); in the first group, 97% were successful on the first attempt entry, whereas this figure was 91% in second group. In the first group, the liver was punctured in 13 patients without any further complications; no other viscera were punctured. In the second group, gastric puncture occurred in 5 cases, transverse colon in 2 cases, and omental injury in 12 cases. CONCLUSION: This new access point may represent a safe, fast, and easy way to create pneumoperitoneum, as well as a promising alternative to Palmer's point in patients who are not candidates for classic midline entry. PMID- 28856846 TI - Emergence of an exotic strain of serotype O foot-and-mouth disease virus O/ME SA/Ind-2001d in South-East Asia in 2015. AB - The O/Middle East-South Asia (ME-SA)/Ind-2001 lineage of foot-and-mouth disease virus (FMDV) is endemic in the Indian subcontinent and has been reported in the Middle East and North Africa, but it had not been detected in South-East Asia (SEA) before 2015. This study reports the recent incursions of this viral lineage into SEA, which caused outbreaks in Vientiane Capital of Lao People's Democratic Republic (PDR) in April 2015, in Dak Nong, Dak Lak and Ninh Thuan Provinces of Vietnam from May to October 2015, and in Rakhine State of Myanmar in October 2015. Disease investigations were conducted during the outbreaks and followed up after laboratory results confirmed the involvement of FMDV O/ME-SA/Ind-2001 sublineage d (O/ME-SA/Ind-2001d). Affected host species included cattle, buffalo and pig, and all the outbreaks resolved within 2 months. Animals with clinical signs were separated, and affected premises were disinfected. However, strict movement restrictions were not enforced, and emergency vaccinations were only implemented in Vientiane Capital of Lao PDR and Dak Nong and Ninh Thuan Provinces of Vietnam. Clinical samples were collected from each outbreak and examined by nucleotide sequencing of the FMDV viral protein 1 coding region. Sequence analysis revealed that the O/ME-SA/Ind-2001d isolates from Lao PDR and Vietnam were closely related to each other and similar to viruses previously circulating in India in 2013. Viruses collected from Myanmar were divergent from viruses of the same sublineage recovered from Lao PDR and Vietnam but were closely related to viruses present in Bangladesh in 2015. These findings imply that at least two independent introductions of O/ME-SA/Ind-2001d into SEA have occurred. Our study highlights the transboundary nature of foot-and-mouth disease (FMD) and reinforces the importance of improved FMD surveillance and promotion of safer cross-border trade in SEA to control the risk of introduction and spread of exotic FMDV strains. PMID- 28856847 TI - Comparison of patient-reported acute urinary and sexual toxicity scores in a 6- versus 2-fraction course of high-dose-rate prostate brachytherapy monotherapy. AB - INTRODUCTION: To identify differences in acute urinary and sexual toxicity between a 6-fraction and 2-fraction high-dose-rate brachytherapy monotherapy regimen and correlate dosimetric constraints to short-term toxicity. METHODS: A single institution retrospective study of 116 men with prostate cancer treated with HDR monotherapy from 2010 to 2015 was conducted. Eighty-one men had 7.25 Gy * 6-fractions and 35 men had 13.5 Gy * 2-fractions. Patients had two CT-planned implants spaced 1-2 weeks apart. Patient baseline characteristics, International Prostate Symptom Scores (IPSS) and Sexual Health Inventory for Men (SHIM) scores were collected pre-treatment and 3, 6 and 12 months post-implantation. Mixed effect modelling was undertaken to compare baseline, 1-6 month and 7-12 month scores between groups. Poisson regression analysis was performed to correlate dosimetric constraints with acute toxicity. RESULTS: There was no difference between baseline and post-implantation IPSS scores between 6-fraction and 2 fraction groups. SHIM scores for men treated with 6-fractions had a steeper decline at 1-6 months, but resolved at 7-12 months. Pre-treatment alpha-blocker use correlated with worse short-term acute urinary toxicity. Worsened SHIM score correlated with increasing age, diabetes mellitus and androgen-deprivation therapy. In a dosimetric analysis of outcomes, prostate V150 dose and bladder wall (D01.cc, D1cc, D2cc) dose correlated with increased IPSS score. CONCLUSION: No increased acute genitourinary or sexual dysfunction has been observed in men when transitioning from 6-fraction to 2-fraction HDR monotherapy. A dosimetric correlation was found between the V150 and bladder wall doses for acute urinary toxicity. Future research should continue to standardize and validate dose constraints for prostate HDR monotherapy patients. PMID- 28856848 TI - Image-guided IMRT with simultaneous integrated boost as per RTOG 0529 for the treatment of anal cancer. AB - AIM: To report on clinical outcomes of simultaneous integrated boost intensity modulated radiation therapy (IMRT) and concurrent chemotherapy as per Radiation Therapy Oncology Group (RTOG) 0529 protocol in anal cancer patients. METHODS: Clinical stage T1-T4 N0-N3 anal cancer patients were submitted to concomitant chemoradiation. Patients with cT2N0 disease were prescribed 50.4 Gy/28 fractions to the gross tumor planning target volume (PTV) and 42 Gy/28 fractions to the elective nodal PTV. Patients staged as cT3-T4/N0-N3 were given 54 Gy/30 fractions to the macroscopic anal PTV, while clinical nodes were prescribed 50.4 Gy/30 fractions if <3 cm or 54 Gy/30 fractions if >=3 cm; elective nodal PTV was prescribed 45 Gy/30 fractions. Two cycles of concomitant 5-fluorouracil and mitomycin C were planned for all patients. Oncological outcomes, acute and late toxicity profiles and pattern of failure were reported. RESULTS: The 3-year colostomy-free survival rate was 64% (95% CI 0.52-0.75). The 3-year local control, disease-free and overall survival rates were 69% (95% CI 0.57-0.79), 71% (95% CI 0.59-0.80) and 79% (95% CI 0.66-0.87), respectively. The cumulative incidence of colostomies was 15.1% (95% CI 8.15-23.88) at 24 months. The cumulative incidence of cancer-specific deaths was 16.4% (95% CI 8.60-26.47) at 36 months. Major acute toxicity consisted of hematological (G3-G4: 26%) and cutaneous (G3-G4: 16%) events. Only one case of >=G3 late toxicity was documented. CONCLUSIONS: Simultaneous integrated boost IMRT and concurrent chemotherapy as per RTOG 0529 protocol seems to be safe and feasible with consistent oncological outcomes and a mild acute and late toxicity profile in anal cancer patients. PMID- 28856850 TI - The role of emotion regulation in predicting personality dimensions. AB - Dimensional models of personality have been widely acknowledged in the field as alternatives to a trait-based system of nomenclature. While the importance of dimensional models has been established, less is known about the constructs underlying these personality dimensions. Emotion regulation is one such potential construct. The goal of the current study was to examine the relationship between personality dimensions and emotion regulation. More specifically, the predictive capacity of emotion regulation in accounting for personality dimensions and symptoms on the Schedule for Nonadaptive and Adaptive Personality-2 above and beyond a measure of general distress was evaluated. Emotion regulation was found to be predictive of most personality dimensions and symptoms of most personality disorders. Consistent with hypotheses, emotion regulation variables associated with undercontrol of emotions were most predictive of traits associated with Cluster B personality disorders whereas Cluster A and C traits were most associated with emotion regulation related to overcontrol of emotions. These findings provide preliminary evidence that some personality dimensions never assessed in relation to emotion regulation are strongly predicted by emotion regulation variables. Thus, the present study facilitates an initial step in understanding the relationship between personality dimensions and a multidimensional model of emotion regulation. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28856851 TI - Light-Activated Active Colloid Ribbons. AB - We report a dynamic self-organization of self-propelled peanut-shaped hematite motors from non-equilibrium driving forces where the propulsion can be triggered by blue light. They result in one-dimensional, active colloid ribbons with a positive phototactic characteristic. The motion of colloid motors is ascribed to the diffusion-osmotic flow in a chemical gradient by the photocatalytic decomposition of hydrogen peroxide fuel. We show that self-propelled peanut shaped colloids readily form one-dimensional, slithering ribbon structures under the out-of-equilibrium collisions. This self-organization intrinsically results from the competition among the osmotically driven motion, the phoretic attraction and the inherent magnetic moments. The giant size number fluctuation in colloid ribbons is observed above a critical point 4.1 % of the surface density of colloid motors. Such phototactic colloid ribbons may provide a model system to understand the emergence of function in biological systems and have potential to construct bioinspired active materials based on different active building blocks. PMID- 28856849 TI - Concise Review: Mechanisms of Quiescent Hair Follicle Stem Cell Regulation. AB - Maintaining a pool of adult stem cells is essential for tissue homeostasis and wound repair. In mammalian tissues, notably hair follicles, blood, and muscle, stem cells acquire quiescence and infrequently divide for self-renewal. Mechanistic understanding of stem cell quiescence is critical for applying these multipotent cells in regenerative medicine and interrogating their roles in human diseases such as cancer. Quiescent and dividing epithelial stem cells located in hair follicle are conspicuously organized in a spatiotemporally specific manner, allowing them to be studied at a considerable depth. Recent advancements in mouse genetics, genomics, and imaging have revealed unprecedented insights into establishment, maintenance, and regulation of quiescent hair follicle stem cells. This concise review summarizes the progress with a focus on mechanisms mediated by signaling pathways and transcription factors and discusses their implications in the understanding of stem cell biology. Stem Cells 2017;35:2323-2330. PMID- 28856852 TI - Ultrasound-guided high-intensity focused ultrasound treatment for abdominal wall endometriosis: a retrospective study. AB - OBJECTIVE: To evaluate the safety and efficacy of ultrasound-guided high intensity focused ultrasound (USgHIFU) for treating abdominal wall endometrioses (AWE). DESIGN: A retrospective study. SETTING: Department of Obstetrics and Gynaecology in China. POPULATION: Patients with abdominal wall endometriosis. METHODS: From August 2010 to April 2014, 32 patients with AWE were treated with USgHIFU in our hospital. USgHIFU treatment was performed with the Model JC-200 High Intensity Focused Ultrasound Tumor Therapeutic System. The symptom relief and the adverse effects were evaluated after USgHIFU ablation. MAIN OUTCOME MEASURES: USgHIFU as a new treatment option for patients with AWE. RESULTS: Contrast-enhanced ultrasound showed that all lesions were successfully ablated with USgHIFU. The follow-up results showed that the average volume of AWE lesions at 6 months after USgHIFU was significantly smaller than that before treatment (2.80 +/- 0.12 versus 1.33 +/- 0.31 cm3 ). The pain scores at 6 months after treatment were significantly lower than those before treatment (6.80 +/- 2.64 versus 1.80 +/- 0.3). The non-perfused volume (indicative of successful ablation) was measured in all patients immediately after treatment, ranging from 0.9 to 2.1 cm3 (median: 1.6 cm3 ), and the fractional ablation ranged from 87% to 100% (median: 94%). Local oedema was observed in these patients, lasting for 1-3 days only. No severe complications occurred during the follow-up period. CONCLUSIONS: Based on our study, USgHIFU ablation is a safe and effective method for treating AWE. TWEETABLE ABSTRACT: As a non-invasive treatment technique, HIFU could be used to treat abdominal wall endometriosis. PMID- 28856853 TI - Novel therapeutic techniques for the treatment of benign gynaecological diseases. PMID- 28856854 TI - High-intensity focused ultrasound and laparoscopic myomectomy in the treatment of uterine fibroids: a comparative study. AB - OBJECTIVE: To compare the clinical efficacies of high-intensity focused ultrasound (HIFU) and laparoscopic myomectomy (LM) in the treatment of uterine fibroids and their effects on patients' quality of life. DESIGN: A non-randomised control study. SETTING: Gynaecological department in a university teaching hospital. POPULATION: Patients with uterine fibroids. METHODS: From November 2014 to November 2015, 166 patients with uterine fibroids were enrolled and underwent HIFU (n = 99) and LM (n = 67) surgeries, respectively. Clinical efficacy, postoperative complications and quality of life after treatment were evaluated using the SF-36 Scale to compare the differences in each variable at the 1-year follow up. MAIN OUTCOMES MEASURES: Differences in efficacy, safety and quality of life between the patients treated with HIFU and LM. RESULTS: The 12-month follow up results showed that the HIFU group had a total effective rate of 99%; only one patient underwent alternative treatment due to non-apparent tumour shrinkage. All patients in the LM group showed complete tumour disappearance. Of these patients, 52 showed significant clinical improvement, 15 with partial clinical improvement, a total effective rate of 98%. There was no significant difference in effectivity rate between the two groups (P > 0.05). Both treatments effectively improved patients' quality of life. Compared with the LM group, patients in the HIFU group experienced no blood loss, a shorter hospital stay and fewer adverse effects and complications, the difference being statistically significant (P < 0.05). CONCLUSIONS: High-intensity focused ultrasound can be as efficacious as LM therapy and effectively improve patients' quality of life in the treatment of uterine fibroids, with fewer adverse effects and complications, shorter hospital stays, and quicker postoperative recovery compared with LM therapy. TWEETABLE ABSTRACT: Patients with uterine fibroids can be effectively treated with both HIFU and myomectomy. PMID- 28856855 TI - Efficacy and safety of ultrasound-guided high intensity focused ultrasound ablation of symptomatic uterine fibroids in Black women: a preliminary study. AB - OBJECTIVE: To evaluate the therapeutic effect and safety of ultrasound-guided high-intensity focused ultrasound (USgHIFU) treatment on symptomatic uterine fibroids in Black women. DESIGN: A feasibility study. SETTING: Gynaecological department in a teaching hospital in South Africa. POPULATION: Premenopausal women with uterus fibroids. METHODS: Twenty-six patients with 53 fibroids who underwent USgHIFU treatment were enrolled. The USgHIFU treatment information was recorded, including treatment time, sonication time and total energy. Adverse events were also observed and recorded during and after treatment. MAIN OUTCOME MEASURES: Safety and efficacy of USgHIFU for the treatment of uterine fibroids in Black women. RESULTS: The median volume of fibroids was 52.7 (interquartile range, 18.6-177.4) cm3 . According to USgHIFU treatment plan, total energy of 298.6 +/- 169.3 kJ (range, 76.0-889.2) within treatment time of 90.3 +/- 43.3 minutes (range, 14.0-208.0), in which sonication time of 774.0 +/- 432.9 seconds (range, 190.0-2224.0) was used to ablate fibroids. The average ablation rate was 80.6 +/- 9.7% (range, 46.5-94.5%). During the procedure, 69.2% of the patients reported lower abdominal pain, 57.7% sciatic/buttock pain, 38.5% burning skin, and 34.6% transient leg pain. No severe complications were observed. CONCLUSIONS: USgHIFU is feasible and safe to use to treat symptomatic uterine fibroids in Black women. TWEETABLE ABSTRACT: Multiple uterine fibroids are more frequently detected in Black women. USgHIFU is feasible and safe for the treatment of uterine fibroids in Black women. PMID- 28856856 TI - Ultrasound-guided high-intensity focused ultrasound ablation for treating uterine arteriovenous malformation. AB - OBJECTIVE: To explore HIFU treatment for uterine arteriovenous malformation. DESIGN: A case report. SETTING: Gynaecological department in a university teaching hospital of China. POPULATION: A patient with uterine arteriovenous malformation. METHODS: The diagnosis of uterine arteriovenous malformation was made through MRI. Ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation was performed. MAIN OUTCOMES MEASURES: HIFU is effective in treating uterine arteriovenous malformation. RESULTS: The patient had reduction of the lesion volume and obvious symptom relief, without significant adverse effects. CONCLUSIONS: HIFU can be used as a new treatment option for uterine arteriovenous malformation. TWEETABLE ABSTRACT: Ultrasound-guided high-intensity focused ultrasound ablation is effective in treating uterine arteriovenous malformation. PMID- 28856857 TI - Application of dexmedetomidine-remifentanil in high-intensity ultrasound ablation of uterine fibroids: a randomised study. AB - OBJECTIVE: To compare the effects of dexmedetomidine-remifentanil with the traditional analgesia and sedation regimen midazolam-remifentanil during HIFU treatment of uterine fibroids. DESIGN: A randomised controlled trial. SETTING: Department of Anesthesia in a single hospital. POPULATION: Patients with uterine fibroids. METHODS: A total of 80 patients diagnosed with uterine fibroids and scheduled for selective HIFU treatment were randomly divided into the dexmedetomidine group (the D group) and midazolam group (the M group). At 20 minutes before the HIFU procedure, patients in the D group received a loading dose of 0.8 MUg/kg dexmedetomidine, followed by a continuous intravenous infusion of 0.2 MUg/kg/hour until the end of the operation. Patients in the M group were given a corresponding amount of 0.9% saline. Patients in the M group received a slow intravenous infusion of 0.03 mg/kg midazolam before the procedure, an intravenous injection of 0.02 mg/kg 30 minutes later, another 0.02 mg/kg 60 minutes later, followed by 0.02 mg/kg at 40-minutes intervals. Patients in the D group were given a corresponding amount of 0.9% saline. During the HIFU procedure, patients in both groups were administered remifentanil at an effect site concentration of 1.0 ng/ml. Sedation and analgesia were rated using the Ramsay Sedation Scale (RSS) and Visual Analogue Scale (VAS) before drug administration (T1), after drug administration but before HIFU (T2), at the beginning of HIFU (T3), 15 minutes later (T4), 45 minutes later (T5), 75 minutes later (T6), and at the end of HIFU (T7). Patient satisfaction score and Steward recovery score survey were conducted 30 minutes after surgery. MAIN OUTCOME MEASURES: Different effects of the traditional midazolam-remifentanil regimen and dexmedetomidine-remifentanil. RESULTS: All patients in both groups underwent a successful HIFU procedure without developing serious complications during the postoperative period. However, the D group reported significantly fewer cases of respiratory depression than the M group during HIFU treatment (P < 0.05). The pause during HIFU ablation in the D group was significantly shorter than that in the M group. HIFU ablation intensity, the number of patients with an RSS of 3 or 4 measured at different time points, and the number of patients with an RSS of 3 or 4 measured at arousal were significantly greater in the D than the M group (P < 0.05). Likewise, the D group scored significantly higher in the evaluation of patient satisfaction, recovery score, and surgeon satisfaction (P < 0.05). CONCLUSIONS: Both dexmedetomidine-remifentanil and midazolam-remifentanil met the requirements and ensured the safety of HIFU treatment of uterine fibroids. However, compared with the traditional midazolam-remifentanil regimen, dexmedetomidine-remifentanil was associated with more stable sedation in patients, more efficient HIFU treatment and higher degree of patient comfort. TWEETABLE ABSTRACT: Dexmedetomidine-remifentanil is associated with more stable sedation in patients, more efficient HIFU treatment and higher degree of patient comfort than is midazolam-remifentanil. PMID- 28856858 TI - Enhancing ablation effects of a microbubble contrast agent on high-intensity focused ultrasound: an experimental and clinical study. AB - OBJECTIVE: To investigate the relationship between SonoVue ablation enhancement effects on high-intensity focused ultrasound (HIFU) and the concentration of SonoVue and timing of HIFU. DESIGN: Two randomised controlled trials. SETTING: An animal centre in a university and a gynaecological department in a university hospital in China. POPULATION OR SAMPLE: 63 rabbits and 143 patients with a solitary uterine fibroid. METHODS: Among the 63 rabbits, three were assigned to the control group. The other 60 were evenly assigned to three study groups pretreated with 0.03, 0.05 or 0.07 ml/kg of SonoVue before HIFU treatment. Two points in each liver were selected to be treated with HIFU and sonication started at 10, 30, 60, 90, 120, 150, 180, 210, 250 or 300 seconds after the administration of SonoVue, respectively. The 143 patients with solitary uterine fibroids were assigned to four groups: 30 patients were treated using only HIFU; the other patients were pretreated with same dosage of SonoVue and 32, 38 and 43 were treated with HIFU at 1-, 3-, and 5-minutes after administration of SonoVue, respectively. MAIN OUTCOME MEASURES: The relation between SonoVue ablation enhancement effects on HIFU and the concentration of SonoVue and timing of HIFU. RESULTS: In the experimental study, the highest temperature and the largest necrotic volume in the liver were observed when HIFU sonication started at 60 seconds after administration of SonoVue. In the clinical study, the rate of significant grey-scale changes in the 1-minute SonoVue group was significantly greater than in the other three groups. The sonication time to reach massive grey scale changes measured in the 1-minute SonoVue group was significantly shorter than in in the other three groups. The sonication time for ablating 1 cm3 of fibroid volume in the 1-minute SonoVue group was significantly shorter than in the other three groups. The acoustic energy used in treating 1 mm3 of uterine fibroid in the 1-minute SonoVue group was significantly less than that used in the other three groups. No major complications occurred in this study. CONCLUSIONS: SonoVue could safely be used to enhance the ablation effects of HIFU treatment, and the optimal time to begin HIFU sonication seems to be 1 minute after the administration of SonoVue. TWEETABLE ABSTRACT: SonoVue, a microbubble contrast agent, enhanced the ablation effects of HIFU treatment; the optimal time to begin HIFU sonication appears to be 1 minute after the administration of SonoVue. PMID- 28856859 TI - A comparison between high-intensity focused ultrasound and surgical treatment for the management of abdominal wall endometriosis. AB - OBJECTIVE: The aim of this study was to compare the therapeutic outcomes of high intensity focused ultrasound (HIFU) and surgical treatment for abdominal wall endometriosis. DESIGN: A retrospective study. SETTING: Gynaecological department of a teaching hospital in China. POPULATION: Patients with abdominal wall endometriosis. METHODS: Among the 51 patients, 23 patients were treated with ultrasound-guided HIFU and 28 patients with surgery. Pain relief and the size change of the nodule after each management were evaluated 1, 3, 6 and 12 months after treatment, respectively. The hospital stay and blood loss were also compared. MAIN OUTCOME MEASURES: Difference between HIFU and surgical treatment for abdominal wall endometriosis. RESULTS: No statistically significant differences were observed between the two groups in the pain relief in 1, 3, 6 and 12 months after treatment, respectively. The hospital stay was clearly shorter in the HIFU group than in the surgery group. Change in nodules was more remarkable in the group treated with surgery; no palpable nodules existed in most patients in the surgery group. HIFU had more advantages over surgery, such as no blood loss, no new scar, no anaesthesia and lower pain score immediately after treatment. CONCLUSIONS: Based on our results, it appears that either HIFU or surgery is safe and effective in treating patients with AWE in short-term. Compared with surgery, HIFU treatment for AWE has the advantages of shorter hospital stay, no blood loss, no new scar, no anaesthesia and a lower immediate pain score. TWEETABLE ABSTRACT: Either HIFU or surgical treatment is safe and effective in treating patients with AWE. HIFU has the advantages of a less invasive procedure and shorter hospital stay. PMID- 28856860 TI - The effect of exercise on high-intensity focused ultrasound treatment efficacy in uterine fibroids and adenomyosis: a retrospective study. AB - OBJECTIVE: We conducted a retrospective study to evaluate whether exercise after high-intensity focused ultrasound (HIFU) treatment can improve the absorption of uterine fibroids and the relief of dysmenorrhea caused by adenomyosis. DESIGN: A retrospective study. SETTING: Gynaecological department of a single centre in China. POPULATION: Patients with uterine fibroids and adenomyosis. METHOD: From January 2011 to August 2015,83 MRI-confirmed uterine fibroid patients and 102 adenomyosis patients who received HIFU treatment at Chongqing Haifu Hospital and attended the 1-year and 6-month follow up, respectively, were included in our retrospective study. Among the fibroid patients, 51 were assigned to the 'no exercise group' and 32 to the 'exercise group'. Among the adenomyosis patients, 45 were assigned to the 'no exercise group' and to the 57 'exercise group'. MAIN OUTCOME MEASURES: Symptom improvement, uterine fibroid volume and Visual Analogue Scale (VAS) evaluation. RESULTS: Exercise post-HIFU treatment significantly improved the absorption of uterine fibroids, reduced recurrence rate and increased the rate of pregnancy in uterine fibroid patients. Exercise lead to a more significant reduction in the score of dysmenorrhea. CONCLUSION: Exercise post-HIFU treatment demonstrated an enhancement of the therapeutic efficacy of HIFU for both uterine fibroid patients and adenomyosis patients. Therefore, exercise should be recommended to patients as part of the post-treatment disease management plan. TWEETABLE ABSTRACT: A retrospective study evaluated the effect of exercise after high-intensity focused ultrasound (HIFU) treatment on the therapeutic efficacy of HIFU. PMID- 28856861 TI - High-intensity focused ultrasound combined with hysteroscopic resection for the treatment of placenta accreta. AB - OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of a combination of high-intensity focused ultrasound (HIFU) and hysteroscopic resection while treating placenta accreta (PA). DESIGN: A retrospective study. SETTING: A university teaching hospital in China. METHODS: This study included 25 patients diagnosed with PA who underwent HIFU followed by hysteroscopic resection in our hospital between January 2014 and December 2015. All patients had completed follow-up data. Treatment efficacy and safety were evaluated retrospectively. MAIN OUTCOME MEASURES: Placenta accreta could be removed with hysteroscopic resection after HIFU. RESULTS: All patients received one session of HIFU ablation therapy. The median total HIFU treatment time was 18 minutes and the median exposure time was 600 seconds. During treatment, 23 lesions showed massive grey-scale changes and two lesions modest grey-scale change. Contrast enhanced ultrasound showed signs of reduced perfusion in all lesions. During treatment, all patients tolerated the HIFU procedure well and completed the treatment. All patients complained of mild lower abdominal and sacrococcygeal pain, with a pain score ranging from 1 to 4 points. Seven patients complained of a 'hot' skin sensation. No serious complications were encountered during or after the procedure. All patients received hysteroscopic operations with a median of 2 days after HIFU treatment. The average depth of the uterus was 10.36 +/- 2.14 cm. The median volume of intraoperative blood loss was 20 ml, and no blood transfusions were given. Sixteen patients underwent only one session of hysteroscopic resection and nine patients underwent a second session of hysteroscopic resection operation 11-61 days after the first operation. All patients preserved their uterus and tolerated the hysteroscopic operation well. Of the 25 patients, two had uterine perforation during the first operation. No other severe hysteroscopic complication was observed. The average hospital stay was 8.4 +/- 1.6 days. After treatment the median duration of vaginal bleeding was 10 days. Twenty-one patients recovered normal menstruation 34 days after the operation. The other four patients continued breastfeeding and therefore exhibited abnormal menstruation. CONCLUSIONS: HIFU treatment followed by hysteroscopic resection is safe and effective in treating patients with PA. TWEETABLE ABSTRACT: For patients with placenta accreta, HIFU treatment before hysteroscopic resection could help reduce risk during the procedure of hysteroscopic resection. PMID- 28856862 TI - Gonadotrophin-releasing hormone agonist combined with high-intensity focused ultrasound ablation for adenomyosis: a clinical study. AB - OBJECTIVES: This study was to investigate the clinical efficacy of a gonadotrophin-releasing hormone agonist (GnRH-a) combined with high-intensity focused ultrasound (HIFU) ablation treatment for adenomyosis. DESIGN: A non randomized prospective study. SETTING: Gynaecological Minimally Invasive Centre in a single hospital. POPULATION: Patients with adenomyosis. METHODS: Seventy nine patients with adenomyosis were enrolled, including 55 patients in the control group treated with only HIFU and 24 patients in the study group treated with GnRH-a combined with HIFU. All the patients follow up 6 months after the HIFU procedure. The related parameters in the two groups were assessed before and 3 months as well as 6 months after treatment including serum levels of tumor marker and cytokine, volumes of uterine, adenomyotic lesion, and menstrual blood, as well as dysmenorrheal scores. MAIN OUTCOME MEASURES: Differences between the group treated with HIFU alone and the group treated with GnRH-a combined with HIFU. RESULTS: Before HIFU treatment, no significant difference was observed in serum levels of CA125, CA19-9, and interleukin-6 (IL-6), the volumes of uterine, adenomyotic lesion, and menstrual blood, as well as dysmenorrhea scores between the two groups. (P > 0.05). The serum CA125 levels significantly decreased in both groups after HIFU, but the serum CA125 levels in the study group were still significantly lower than those in the control group (P < 0.05). The volume of uterine and adenomyotic lesion significantly decreased in both groups after HIFU procedure, and decreased even more in the study group 3 and 6 months after treatment (P < 0.05). Dysmenorrhea scores and menstruation volumes significantly decreased in both groups after HIFU treatment. Moreover in the study group were significantly lower than those in the control group after 3 and 6 months (P < 0.05). No significant difference was observed in the rate of adverse effects between the two groups. CONCLUSIONS: The short-term follow-up results indicate that the combination of GnRH-a and HIFU treatment significantly decreased serum CA125 levels, volumes of uterine, adenomyotic lesion and menstrual blood, as well as dysmenorrhea scores, and improved the clinical outcomes compared with the HIFU ablation alone in patients with adenomyosis. However, the further follow-up is needed to explore the long-term effects. TWEETABLE ABSTRACT: A combination of GnRH-a with HIFU in the treatment of adenomyosis significantly decreased serum CA125 levels, uterine and adenomyotic lesion volumes, dysmenorrhea scores, and menstrual blood volumes. PMID- 28856863 TI - Short- and long-term efficacy of focused ultrasound therapy for non-neoplastic epithelial disorders of the vulva. AB - OBJECTIVE: To investigate the short- and long-term efficacy and influential factors of focused ultrasound for the treatment of non-neoplastic epithelial disorders of the vulva (NNEDV). DESIGN: A retrospective observational study. SETTING: A gynaecologic department in a single centre in China. POPULATION: Patients with NNEDV were included in this study: 85 patients were diagnosed with lichen simplex chronicus (LSC), 44 patients with vulva lichen sclerosus (VLS), and seven patients with lichen planus (LP). METHODS: A total of 136 eligible patients with NNEDV were treated with focused ultrasound. After the treatment, based on changes in the degree of symptom severity and local skin signs (lesion size, skin colour and elasticity) before and after treatment, the treatment effectiveness for each patient was assessed. We further analysed the relations among pathologic type, age, course and curative rate. Statistical analysis was performed using the Chi-square (McNemar) test. MAIN OUTCOME MEASURES: Improvement in the symptoms and physical signs and the predictive factors. RESULTS: Symptom relief was observed in all patients. The appearance and colour of the vulva returned to normal after the ultrasound treatment. Complete remission (CR) occurred in 68 of 136 (50%) patients (41 patients with LSC and 12 patients with VLS). The response rate was 93.38% (127/136). Seven patients who had a poor response to the first session of treatment were treated again with ultrasound therapy and a good response was observed. No severe complications were observed. There was no significant difference in treatment results among the different pathological types (P > 0.05). However, the course of the disease and the age of the patients were related to the treatment results (P < 0.05). CONCLUSIONS: NNEDV can be treated with focused ultrasound effectively and safely. The course of the disease and the age of the patients may be predictive factors. TWEETABLE ABSTRACT: Patients with non-neoplastic epithelial disorders of the vulva can be safely and effectively treated with focused ultrasound. No significant difference in treatment results was observed between the different types of non-neoplastic epithelial disorders of the vulva. PMID- 28856864 TI - Pregnancy outcomes in patients with uterine fibroids treated with ultrasound guided high-intensity focused ultrasound. AB - OBJECTIVE: To investigate the effect of high-intensity focused ultrasound (HIFU) ablation for uterine fibroids on pregnancy. DESIGN: A retrospective observational study. SETTING: Department of Gynaecology in a single centre in China. POPULATION: Patients with uterine fibroids who wish to become pregnant. METHODS: Patients with uterine fibroids who wished become pregnant and have children, were treated using HIFU from April 2011 to March 2016 at Chongqing Haifu Hospital. Pregnancy outcomes were analysed. MAIN OUTCOME MEASURES: Pregnancy outcomes after undergoing USgHIFU. RESULTS: After the HIFU treatment, the 78 patients had 80 pregnancies, in which 76 cases were natural pregnancies and four were test-tube pregnancies. Of the 78 patients who became pregnant, nine patients had complicated primary or secondary infertility before the HIFU treatment, 13 patients had had at least two miscarriages or missed miscarriages, one patient had had a stillbirth; none had undergone other special treatment. After the HIFU treatment, the average time to pregnancy was 5.6 +/- 2.7 months. There were 15 cases of full-term normal delivery and 56 cases of caesarean, including three cases of premature caesarean. After the treatment, three patients had a miscarriage (one patient's progesterone level was lower than the normal value; and the other two miscarriages were for unknown reasons), two patients became pregnant 3 months after complete curettage of uterine cavity and had full-term normal deliveries, one patient planned to use contraception after complete curettage of the uterine cavity; and one patient had her labour induced (after 13 weeks pregnancy). The fetuses of all the patients developed well during both the pregnancy and child-bearing without uterine rapture or perinatal and postpartum complications. CONCLUSION: HIFU treatment can effectively treat patients with uterine fibroids who wish to have children; it could significantly reduce the preparation period for pregnancy after the operation. It can also improve the fertility of patients with a history of infertility and abnormal pregnancy and child-bearing, with no additional obstetric risks. TWEETABLE ABSTRACT: As a noninvasive therapeutic technique, HIFU safely can be used to treat patients with uterine fibroids who wish to become pregnant. PMID- 28856865 TI - Laparoscopic extraperitoneal uterine suspension with suture line instead of mesh. AB - OBJECTIVE: To compare the safety and effectiveness of two different materials (mesh and suture line) used in laparoscopic extraperitoneal uterine suspension. DESIGN: A retrospective observational study. SETTING: Gynaecology departments in two hospitals in China. POPULATION: Women with symptomatic pelvic organ prolapse (POP) of stage II or higher. METHODS: The women were divided into two groups according to the two different materials for laparoscopic extraperitoneal uterine suspension: mesh or suture line. The baseline characteristics, perioperative details, complications, objective and subjective indexes of the two groups were compared. MAIN OUTCOME MEASURES: The primary outcome was subjective satisfaction rate based upon validated questionnaires. The secondary outcome was objective anatomic assessment with the POP-Q system. RESULTS: No difference was found in baseline characteristics and perioperative details except that there were more cases of cardiovascular disease (CVD) and associated other surgeries in the Line than the Mesh group (36 versus 19, P < 0.05; 12 versus 2, P < 0.05). Statistically significant improvements were found in anatomical measures of points Aa, Ba, Ap, Bp, C and TVL (P < 0.01), as well as functional and quality-of life measures (P < 0.01 for PFDI-20 and PFIQ-7) between both groups. The postoperative PFDI-20, PFIQ-7 and PGI-I scores were not different between two groups (P > 0.05). Two cases of deep wound infection were observed in Mesh group at 3-month follow up. CONCLUSIONS: Laparoscopic extraperitoneal linear uterine suspension is easy to perform and is associated with fewer mesh-related complications. It is more secure, especially in elderly women and in those with physical complications. TWEETABLE ABSTRACT: Laparoscopic extraperitoneal linear uterine suspension is safe, with fewer mesh-related complications. PMID- 28856866 TI - A comparison of the cost-utility of ultrasound-guided high-intensity focused ultrasound and hysterectomy for adenomyosis: a retrospective study. AB - OBJECTIVE: To evaluate cost-effectiveness of ultrasound-guided high-intensity focused ultrasound (USgHIFU) and open hysterectomy for adenomyosis. DESIGN: A retrospective analysis. SETTING: Gynaecological department in a single centre in China. POPULATION: Patients with symptomatic adenomyosis. MAIN OUTCOME MEASURES: Cost difference between patients with adenomyosis treated with USgHIFU and open hysterectomy. METHODS: Three hundred and sixty-eight patients with adenomyosis were retrospectively reviewed. Among them, 302 patients were treated with USgHIFU and 66 patients with open hysterectomy. All of them had 1-, 3-, 6- and 12-month follow ups. The patients' quality of life (QOL) was evaluated and the utility scores were obtained from a rating scale to conduct a cost-utility analysis (CUA). RESULTS: No significant differences were found at any follow-up time point in the QOL between the two groups (P > 0.05). After treatment, the QOL scores significantly increased in both groups (P < 0.05): the quality adjusted life year (QALY) for patients treated with USgHIFU was USUS$5256.48, whereas it was USUS$7510.03 for patients treated with open hysterectomy. Both incremental cost and sensitivity analysis showed that USgHIFU was less costly than open hysterectomy. CONCLUSIONS: The QOL of patients with adenomyosis can be significantly improved by either USgHIFU or open hysterectomy, but USgHIFU is less costly. TWEETABLE ABSTRACT: USgHIFU can safely be used to treat patients with adenomyosis and significantly improved the quality of life of patients after treatment. The cost of USgHIFU is less than that of surgical treatment. PMID- 28856867 TI - Changes in anti-mullerian hormone levels as a biomarker for ovarian reserve after ultrasound-guided high-intensity focused ultrasound treatment of adenomyosis and uterine fibroid. AB - OBJECTIVE: To assess the changes in antimullerian hormone (AMH) levels after ablation for symptomatic uterine fibroids and adenomyosis using ultrasound-guided high-intensity focused ultrasound (USgHIFU). DESIGN: A prospective study. SETTING: Gynaecological department in multiple hospitals in South Korea. POPULATION: Patients with uterus fibroids and adenomyosis. METHODS: Seventy-nine women with symptomatic uterine fibroids and adenomyosis who met the inclusion criteria were enrolled in our study between January 2014 and December 2014. All patients underwent USgHIFU ablations. Each patient was examined before and after treatment, and at 6 and 12 months after treatment by T2-weighted MRI imaging (T2WI) and T1-weighted MRI imaging (T1WI) with gadolinium injection. Symptom severity scores (SSS), Uterine Fibroid Symptom Quality of Life (UFS-QOL) questionnaire subscales, and reductions of treated volume were assessed. AMH levels before and 6 months after HIFU ablation were compared to determine whether USgHIFU ablation affected ovarian reserve. MAIN OUTCOME MEASURES: HIFU treatment did not affect the ovarian function. RESULTS: HIFU treatment time (mean +/- standard deviation), HIFU ablation time, and treatment energy were 73.5 +/- 25.6 minutes, 9994.7 +/- 386.8 seconds, and 364 713.8 +/- 156 350.7 Joules, respectively. AMH levels before and 6 months after HIFU ablation were 2.11 +/- 2.66 and 1.84 +/- 2.57 MUg/l, respectively. There was no significant difference in AMH level between the two time points (P > 0.05). CONCLUSIONS: USgHIFU ablation for uterine fibroid and adenomyosis was effective without affecting ovarian reserve. TWEETABLE ABSTRACT: HIFU ablation is a safe and effective treatment for patients with uterine fibroids and adenomyosis that does not affect ovarian function. PMID- 28856868 TI - Gastrointestinal symptoms in autism spectrum disorder: A review of the literature on ascertainment and prevalence. AB - : There is no standard approach to measuring GI symptoms in individuals with ASD, despite postulated interactions. The objectives of this study were to (a) describe the range of GI symptom ascertainment approaches in studies of ASD, (b) describe the range of prevalence estimates across studies, and (c) assess associations between ascertainment approach and prevalence estimates. Studies published from 1/1/1980 to 1/31/2017 were collected via PubMed. Eligibility included studies with at least ten individuals with ASD that measured GI symptoms or conditions. We excluded review and hypothesis papers. We extracted information on study design, GI symptom ascertainment method, demographics, and ASD diagnostic criteria. From a subset of studies, we extracted GI symptom estimates. Out of a possible 386 titles, 144 were included. The prevalence range for constipation was 4.3-45.5% (median 22%), for diarrhea was 2.3-75.6% (median 13.0%), and for any or more than one symptom was 4.2-96.8% (median 46.8%). GI symptoms differed significantly by age of individuals, primary goal of study, study design, study sample, and who reported symptoms (P < .05). Due to small sample size, we were not able to test for associations between every GI symptom and study characteristic of interest, or examine associations between GI symptoms and intellectual or verbal disability. Studies used a broad range of methods to ascertain GI symptoms in ASD. GI symptoms varied widely across these studies, with significant differences by study characteristics. Our findings highlight the need for a reliable, valid GI assessment tool to be used consistently across studies of ASD. Autism Res 2018, 11: 24-36. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We reviewed studies having to do with autism spectrum disorder and the gastrointestinal system, dating back to 1980. We found that the median prevalence of constipation was 22.2%, diarrhea 13.0%, and any symptom 46.8%. All symptoms had a wide range of estimates across studies. GI symptoms were associated with characteristics of the study, including who measured the GI symptoms. We call for the development of a reliable and valid GI questionnaire for studies of ASD. PMID- 28856869 TI - The influence of gender on the relationship between psychopathy and five moral foundations. AB - Previous research has demonstrated that individuals higher in psychopathy are less concerned about preventing harm and preserving fairness than individuals lower in psychopathy, yet it is unclear whether this is true for both genders. Females have been shown to be more concerned about moral issues related to preventing harm, being fair and maintaining purity, and males are more concerned about in-group loyalty and respecting authority. In addition, females on average are more empathic, less willing to cause harm and may be less sensitive to fairness. The goal of this study was to examine gender's influence on the relationship between psychopathy and five moral foundations. In a large online sample, we found that although gender moderated the relationship between psychopathy and harm and fairness, the magnitude of these interactions was small. The main effects of gender and of psychopathy support previous research. Overall, females were more concerned than males about preventing harm. Both males and females scoring higher in psychopathy were less concerned about harm and fairness than those lower in psychopathy. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28856870 TI - Factors related to home health-care transition in trisomy 13. AB - Trisomy 13 (T13) is accompanied by severe complications, and it can be challenging to achieve long-term survival without aggressive treatment. However, recently, some patients with T13 have been receiving home care. We conducted this study to investigate factors related to home health-care transition for patients with T13.We studied 28 patients with T13 born between January 2000 and December 2014. We retrospectively compared nine home care transition patients (the home care group) and 19 patients that died during hospitalization (the discharge at death group). The median gestational age of the patients was 36.6 weeks, with a median birth weight of 2,047 g. Currently, three patients (11%) have survived, and 25 (89%) have died. The home care group exhibited a significantly longer gestational age (38.9 vs. 36.3 weeks, p = 0.039) and significantly larger occipitofrontal circumference Z score (-0.04 vs. -0.09, p = 0.019). Congenital heart defects (CHD) was more frequent in the discharge at death group, with six patients in the home care group and 18 patients in the discharge at death group (67% vs. 95%, p = 0.047), respectively. Survival time was significantly longer in the home care group than in the discharge at death group (171 vs. 19 days, p = 0.012). This study has shown that gestational age, occipitofrontal circumference Z score at birth, and the presence of CHD are helpful prognostic factors for determining treatment strategy in patients with T13. PMID- 28856871 TI - Pfannenstiel laparoendoscopic reduced-port bilateral radical nephrectomy for a patient with renal cell carcinoma undergoing hemodialysis. AB - We performed Pfannenstiel laparoendoscopic reduced-port bilateral radical nephrectomy on a patient with renal cell carcinoma undergoing hemodialysis. A 4 cm Pfannenstiel incision was made, and a GelPOINT access was inserted. Three trocars were placed through the access platform, and additional 5- and 3-mm trocars were inserted in the umbilicus and paraumbilical area, respectively. After left nephrectomy, right nephrectomy was successfully completed in 401 min, with an estimated blood loss of 70 mL. There were no intraoperative or postoperative complications, and the patient was discharged 10 days postoperatively. The umbilical scar was concealed within the umbilical fold, and the scar from the 3-mm trocar was almost invisible. The Pfannenstiel scar was minimal and concealed by the patient's underwear. Pfannenstiel laparoendoscopic reduced-port simultaneous bilateral radical nephrectomy is a safe and technically feasible procedure that offers great cosmesis for patients with bilateral renal tumors and end-stage renal disease. PMID- 28856872 TI - Wavefront-sensing-based autofocusing in microscopy. AB - Massive image acquisition is required along the optical axis in the classical image-analysis-based autofocus method, which significantly decreases autofocus efficiency. A wavefront-sensing-based autofocus technique is proposed to increase the speed of autofocusing and obtain high localization accuracy. Intensities at different planes along the optical axis can be computed numerically after extracting the wavefront at defocus position with the help of the transport-of intensity equation method. According to the focus criterion, the focal plane can then be determined, and after sample shifting to this plane, the in-focus image can be recorded. The proposed approach allows for fast, precise focus detection with fewer image acquisitions compared to classical image-analysis-based autofocus techniques, and it can be applied in commercial microscopes only with an extra illumination filter. PMID- 28856873 TI - Editorial: Mental Health Reform and a Window of Opportunity for Community Mental Health. PMID- 28856874 TI - Community Mental Health Policy in America: Lessons Learned. AB - After 1945 the prevailing consensus that persons with serious mental disorders should be treated in public hospitals began to dissolve. It was replaced by a faith in the efficacy of community care and treatment. Yet for a variety of reasons the new community care system fell far short of its initial promise. Advocates failed to understand that the problems of persons with serious and persistent disabilities were different from those people with mild and moderate disorders. The belief that residence in the community would promote adjustment and integration was illusory and did not take into account the extent of social isolation, exposure to victimization, inducement to substance abuse, homelessness, and criminalization of persons with mental disorders. Effective community care for those previously kept in hospitals must make up for the range of functions that hospitalization was intended to provide, from housing and supervision to treatment and rehabilitation. PMID- 28856875 TI - Recovering Citizenship. AB - Recovery as a process through which people reclaim their lives even while continuing to experience symptoms of mental illness has at times been misunderstood or misinterpreted, including being used as an excuse for cutting needed services and supports in the guise of allowing people to pursue their own personal "recovery journeys." In delivering a message of hope to individuals and fostering initiatives to counter the debilitating impact of clinical pessimism, recovery literature has also, at times, paid less attention to the material, social, cultural, political and economic contexts in which people pursue recovery. The importance of these contexts are implied in a 1961 American Report on Mental Illness and Health that argued that people with mental illnesses should be able to live their lives "in the normal manner" in their home communities. We argue for a disability model that provides people with necessary supports and services to make individual recovery possible for persons with prolonged mental illnesses. Another model that has emerged over the past decade to counterbalance this overweening emphasis on the lone individual pursuing his or her recovery journey is citizenship. We discuss this concept and our research on it since the late 1990s. We then argue for "recovering citizenship" as a concept and metaphor to capture the individual recovery process within the context and goal of a life in the community that the citizenship framework supports. PMID- 28856876 TI - Improving Community Mental Health Services: The Need for a Paradigm Shif. AB - BACKGROUND: It is now over half a century since community care was introduced in the wake of the closure of the old asylum system. This paper considers whether mental health services, regardless of location, can be genuinely effective and humane without a fundamental paradigm shift. DATA: A summary of research on the validity and effectiveness of current mental health treatment approaches is presented. LIMITATIONS: The scope of the topic was too broad to facilitate a systematic review or meta-analyses, although reviews with more narrow foci are cited. CONCLUSIONS: The move to community care failed to facilitate a more psychosocial, recovery-focused approach, instead exporting the medical model and its technologies, often accompanied by coercion, into a far broader domain than the hospital. There are, however, some encouraging signs that the long overdue paradigm shift may be getting closer. PMID- 28856877 TI - Commentary on "Improving Community Mental Health Services: The Need for a Paradigm Shift" by Longden et al. PMID- 28856878 TI - Community Mental Health as a Population-based Mental Health Approach. AB - BACKGROUND: Mental health services for youths in Singapore were challenged by accessibility and resource constraints. A community-based mental health program working with schools and other partners was developed to address the population needs. AIM: To describe the formation of a community-based mental health program and evaluate the program in terms of its outcome and the satisfaction of the users of this program. METHODS: Based on needs analyses, a community multidisciplinary team was set up in 15 schools to pilot a new model of care for youths. Implemented progressively over five years, networks of teams were divided into four geographic zones. Each zone had clusters of 10 to 15 schools. These teams worked closely with school counselors. Teams were supported by a psychiatrist and a resident. Interventions were focused on empowering school based personnel to work with students and families, with the support of the teams. RESULTS: 4,184 students were served of whom 10% were seen by the school counselors and supported by the community team. Only 0.15% required referral to tertiary services. Outcome measured by counselor and teacher ratings showed improvements in the Clinical Global Impression scale and Strengths and Difficulties Questionnaire. These included reductions in conduct problems, emotional problems, hyperactive behaviors and peer problems. Furthermore, prosocial behavior also significantly improved. Preliminary cost effectiveness analyses suggest that community treatments are superior to clinic interventions. PMID- 28856879 TI - The Transition from Psychiatric Hospitalization to Community Living: Local and Current Challenges. AB - While extensive efforts have been made in recent decades to enhance community mental health services around the world and in Israel, less attention has been given to the challenging transitional period from psychiatric hospitalization to community living. The current paper reviews the literature on discharge planning programs, which shows that using an interdisciplinary team and adapting a case management model to include overlapping relationships during the process of changing settings might lead to cost-effective outcomes. It is argued here that the current Israeli reform allows an opportunity to reconsider clients' needs and budget priorities, as doing so might lead to the development and implementation of appropriate discharge planning programs. PMID- 28856880 TI - An Empirical Study of the Relationship Between Community Participation, Recovery, and Quality of Life of Individuals with Serious Mental Illnesses. AB - BACKGROUND: Recovery and quality of life are key outcomes emphasized in mental health systems around the world. This study explores the extent to which efforts to facilitate community participation may enhance these outcomes. METHODS: Six hundred and six individuals with serious mental illnesses completed measures of participation, recovery and quality of life. RESULTS: Small, but statistically significant positive relationships between community participation and recovery and quality of life were found. Additional analyses identified specific participation areas that, if they are important and done sufficiently from the perspective of the respondent, resulted in higher levels of recovery and quality of life. LIMITATIONS: Correlational analyses do not allow for causal explanations. CONCLUSIONS: Results suggest that a greater emphasis on community participation, especially in specific areas that are important to the person and done sufficiently, may facilitate recovery and quality of life in community mental health systems. Implications and possible directions for policies and practices, especially within the context of Psychiatric Rehabilitation services, are offered. PMID- 28856881 TI - Training Arab Practitioners in Culturally Sensitive Mental Health Community Interventions. AB - BACKGROUND: This study examined the immediate outcome of Feeding Disorders (FD) in preschoolers referred to the family treatment program Cerco Asilo. METHOD: 21 children (mean age [SD=1]: 39 months [1]; range 9-65 months) with a diagnosis of FD were included in the treatment for 24 weeks. Specifically, seven subjects were diagnosed with Infantile Anorexia (IA), nine subjects with Sensory Food Aversion (SFA), and five subjects with Feeding Disorder of Caregiver-Infant Reciprocity (FDCIR). RESULTS: The great majority of patients with SFA and with FDCIR resolved the FD, whereas children with IA did not respond well to the treatment. LIMITATIONS: The study's main limitations are the relatively small sample size, and the lack of a control group. CONCLUSIONS: Findings suggest that changes in the parentchild relationship could generally promote FD resolution, other than IA. These data may have implications for clinical practice suggesting the need to develop ad hoc intervention protocols tailored to children with IA and their families. PMID- 28856882 TI - Does Specializing in Family Medicine Improve the Detection and Diagnosis of Mental Health Problems? AB - BACKGROUND: Approximately half the patients seeking mental health (MH) treatment consult primary care practitioners (PCPs). Previous research indicates that patients often do not receive correct MH diagnoses or appropriate treatment from PCPs. The present study examines whether a specialization in family medicine compared to other or no PCP residency programs enhances physicians' ability to detect, diagnose and treat MH problems. METHODS: Face-to-face interviews with 49 physicans in eight clinics in Israel. Two case vignettes and questionnaires assess MH awareness and factors influencing treatment. RESULTS: Significantly more family practitioners (FPs) compared to others correctly diagnosed depression and anxiety vignettes were aware of patients' MH problems and prescribed psychotropic drugs. LIMITATIONS: Small sample size, indirect examination of PCPs' skills using vignettes and the absence of psychotherapy options. CONCLUSIONS: FPs are more likely than other PCPs to detect, diagnose and treat MH problems. To improve MH detection among a broad range of PCPs, an expanded MH curriculum should be encouraged. Additional MH training should be available for all PCPs. PMID- 28856883 TI - Psychiatric Consultation in Community Clinics: A Decade of Experience in the Community Clinics in Jerusalem. AB - INTRODUCTION: A consultation model between primary care physicians and psychiatrists that has been in operation for 12 years in the Jerusalem district of the Clalit Health Services in Israel is evaluated. In this model psychiatrists provide consultations twice a month at the primary care clinic. All patients are referred by their family physicians. Communication between the psychiatric consultant and the referring physician is carried out by telephone, correspondence and staff meetings. OBJECTIVE: Evaluation of the psychiatric care consultation model in which a psychiatrist consults at the primary care clinic. METHOD: A questionnaire-based survey distributed to 17 primary care physicians in primary care clinics in Jerusalem in which a psychiatric consultant is present. RESULTS: Almost all of the doctors (93%) responded that the consultation model was superior to the existing model of referral to a secondary psychiatric clinic alone and reduced the workload in caring for the referred patients. The quality of psychiatric care was correlated with the depression prevalence among patients referred for consultation at their clinic (r=0.530, p=0.035). In addition, correlation was demonstrated between primary care physicians impression of alleviation of care of patients and their impression of extent of the patients' cooperation with the consulting psychiatrist (r=0.679, p = 0.015) Conclusions: Very limited conclusions may be drawn from this questionnaire distributed to primary care physicians who were asked to assess psychiatric consultation in their clinic. Our conclusion could be influenced by the design and the actual distribution of the questionnaires by the consulting psychiatrist. Nevertheless answers to the questionnaire might imply that the consultation model of care between a psychiatric consultant and the primary care physician, where the patient's primary care physician takes a leading role in his psychiatric care, is perceived by family physicians as a good alternative to referral to a psychiatric clinic, especially when treating patients suffering from depression. PMID- 28856884 TI - Mass-Spectrometric Detection of Omega-Oxidation Products of Aliphatic Fatty Acids in Exhaled Breath. AB - Omega-oxidation is a fatty acid degradation pathway that can occur alternatively to the dominant beta-oxidation. The dysregulation of fatty acid oxidation has been related with a variety of diseases, termed fatty acid oxidation disorders. This work shows evidence for real-time detection in exhaled breath of the complete series of saturated linear omega-hydroxyalkanoic acids, omega oxoalkanoic acids, and alkanedioic acids with carbon chain lengths of 5-15. We present a comprehensive analytical workflow using online and subsequent offline methods: secondary electrospray ionization mass spectrometry of exhaled breath and UHPLC-HRMS/MS experiments using exhaled breath condensate, respectively. By analyzing online breath measurements of 146 healthy individuals, we were able to obtain strong evidence for the correlation of these metabolite families. This enabled us to monitor the full omega-oxidation pathway in human exhaled breath. We could unambiguously identify these compounds, many of which have never been reported in breath so far. This comprehensive study on breath metabolites reinforces the notion of breath as a valuable source of information, which is underexploited in metabolomics. PMID- 28856885 TI - Metal-Free Photocatalyst for H2 Evolution in Visible to Near-Infrared Region: Black Phosphorus/Graphitic Carbon Nitride. AB - In the drive toward green and sustainable chemistry, exploring efficient and stable metal-free photocatalysts with broadband solar absorption from the UV to near-infrared region for the photoreduction of water to H2 remains a big challenge. To this end, a binary nanohybrid (BP/CN) of two-dimensional (2D) black phosphorus (BP) and graphitic carbon nitride (CN) was designed and used as a metal-free photocatalyst for the first time. During irradiation of BP/CN in water with >420 and >780 nm light, solid H2 gas was generated, respectively. Owing to the interfacial interaction between BP and CN, efficient charge transfer occurred, thereby enhancing the photocatalytic performance. The efficient charge trapping and transfer processes were thoroughly investigated with time-resolved diffuse reflectance spectroscopic measurement. The present results show that BP/CN is a metal-free photocatalyst for artificial photosynthesis and renewable energy conversion. PMID- 28856886 TI - Divalent Silicon-Assisted Activation of Dihydrogen in a Bis(N-heterocyclic silylene)xanthene Nickel(0) Complex for Efficient Catalytic Hydrogenation of Olefins. AB - The first chelating bis(N-heterocyclic silylene)xanthene ligand [SiII(Xant)SiII] as well as its Ni complexes [SiII(Xant)SiII]Ni(eta2-1,3-cod) and [SiII(Xant)SiII]Ni(PMe3)2 were synthesized and fully characterized. Exposing [SiII(Xant)SiII]Ni(eta2-1,3-cod) to 1 bar H2 at room temperature quantitatively generated an unexpected dinuclear hydrido Ni complex with a four-membered planar Ni2Si2 core. Exchange of the 1,3-COD ligand by PMe3 led to [SiII(Xant)SiII]Ni(PMe3)2, which could activate H2 reversibly to afford the first SiII-stabilized mononuclear dihydrido Ni complex characterized by multinuclear NMR and single-crystal X-ray diffraction analysis. [SiII(Xant)SiII]Ni(eta2-1,3 cod) is a strikingly efficient precatalyst for homogeneous hydrogenation of olefins with a wide substrate scope under 1 bar H2 pressure at room temperature. DFT calculations reveal a novel mode of H2 activation, in which the SiII atoms of the [SiII(Xant)SiII] ligand are involved in the key step of H2 cleavage and hydrogen transfer to the olefin. PMID- 28856887 TI - Pleurocins A and B: Unusual 11(9 -> 7)-abeo-Ergostanes and Eringiacetal B: A 13,14-seco-13,14-Epoxyergostane from Fruiting Bodies of Pleurotus eryngii and Their Inhibitory Effects on Nitric Oxide Production. AB - Two novel 11(9 -> 7)-abeo-ergostane-type steroids, named pleurocins A (1) and B (2), a 13,14-seco-13,14-epoxy ergostane, named eringiacetal B (3), and an ergostane steroid (4) were isolated from the fruiting bodies of Pleurotus eryngii (Pleurotaceae). Their structures were determined by spectroscopic data and X-ray crystallography. A possible biogenesis pathway for 1-3 was also described. Compounds 1-3 exhibited inhibitory activities against NO production with almost no cytotoxicity at concentrations lower than 30 MUM. PMID- 28856888 TI - Palladium-Catalyzed ortho-C-H Arylation of Acetophenone Oxime Ethers with Aryl Pinacol Boronic Esters. AB - We report an efficient palladium-catalyzed ortho-C-H arylation of acetophenone oxime ethers with aryl pinacol boronic esters, leading to the synthesis of biaryl derivatives in good yields. Sequential process of iridium-catalyzed C-H borylation and palladium-catalyzed ortho-C-H arylation directed to access functionalized arenes. PMID- 28856889 TI - Fine Tuning of Pyrene Excimer Fluorescence in Molecular Beacons by Alteration of the Monomer Structure. AB - Oligonucleotide probes labeled with pyrene pairs that form excimers have a number of applications in hybridization analysis of nucleic acids. A long excited state lifetime, large Stokes shift, and chemical stability make pyrene excimer an attractive fluorescent label. Here we report synthesis of chiral phosphoramidite building blocks based on (R)-4-amino-2,2-dimethylbutane-1,3-diol, easily available from an inexpensive d-(-)-pantolactone. 1-Pyreneacetamide, 1 pyrenecarboxamide, and DABCYL derivatives have been used in preparation of molecular beacon (MB) probes labeled with one or two pyrenes/quenchers. We observed significant difference in the excimer emission maxima (475-510 nm; Stokes shifts 125-160 nm or 7520-8960 cm-1) and excimer/monomer ratio (from 0.5 to 5.9) in fluorescence spectra depending on the structure and position of monomers in the pyrene pair. The pyrene excimer formed by two rigid 1 pyrenecarboxamide residues showed the brightest emission. This is consistent with molecular dynamics data on excimer stability. Increase of the excimer fluorescence for MBs after hybridization with DNA was up to 24-fold. PMID- 28856890 TI - Cyclic Dipeptide-Based Ambidextrous Supergelators: Minimalistic Rational Design, Structure-Gelation Studies, and In Situ Hydrogelation. AB - Ambidextrous supergelators are developed through structure-gelation screening of rationally designed cyclic dipeptides (CDPs). The organo- and hydrogels of CDPs were thoroughly characterized by their minimal gelation concentration (MGC) for organic and aqueous solvents, thermal stability (Tg), and viscoelastic properties. Intermolecular hydrogen bonding, the major driving force for gelation was evaluated using temperature-dependent nuclear magnetic resonance (NMR) spectroscopy. The contribution of attractive van der Waals interaction of tBoc group in driving CDP gelation was ascertained using beta-cyclodextrin (beta-CD) adamantane carboxylic acid (AC)-based host-guest gelation and 1H NMR studies. The self-assembled fibrous network of CDPs in organic and aqueous solvents responsible for the molecular gelation was elucidated using field emission scanning electron microscopy (FESEM) analysis. Among the CDPs studied CDP-2 found to be supergelator with MGC of 0.3 wt % and form in situ hydrogels under simulated physiological conditions. The in situ gelation property was evaluated by the incorporation of curcumin, as a model study to demonstrate the drug delivery application. Furthermore, supergelator CDP-2 was found to exhibit in cellulo cytocompatibility. Moreover, density functional theory (DFT) calculations were carried out to propose the microscopic structure for the self-assembly of CDP compounds and intermolecular N-H...O hydrogen bonding interactions appear to stabilize the fibrous network. The hydrophobic interactions among the tert butyloxycarbonyl (tBoc) groups and pi-pi stacking interactions between phenyl rings contribute to the further stabilization of self-assembled 2D fibrous networks of CDPs. Overall, the present study highlights the in situ gelation property of CDP-based supergelators and their potential for biomedical and regenerative medicine applications. PMID- 28856891 TI - Hybrid Nanoclusters for Near-Infrared to Near-Infrared Upconverted Persistent Luminescence Bioimaging. AB - Persistent luminescence (PL) bioimaging provides an optimal method of eliminating autofluorescence for a higher resolution and sensitivity because of the absence of excitation light. However, ultraviolet light is still necessary in common energy charging processes, which limits its reactivation in vivo because of its low penetration depth. In the present study, we introduce a type of hybrid nanocluster (UCPL-NC) composed of upconversion nanoparticles, beta NaYbF4:Tm@NaYF4, and persistent nanoparticles, Zn1.1Ga1.8Ge0.1O4:0.5%Cr, which can be activated by a 980 nm laser and exhibits an afterglow at 700 nm to realize near-infrared (NIR) to NIR UCPL bioimaging. The PL of the UCPL-NCs can be reactivated even when covered with a 10 mm pork. We demonstrate that these polyethylene glycol-modified phospholipid-functionalized UCPL-NCs can be reactivated in vivo and applied in the PL lymphatic imaging on small animals. PMID- 28856892 TI - Expedient Synthesis of 1,5-Diketones by Rhodium-Catalyzed Hydroacylation Enabled by C-C Bond Cleavage. AB - A rhodium-catalyzed intermolecular hydroacylation reaction of vinyl cyclobutanols with non-chelating aldehydes has been developed. This reaction offers a new and atom-economical approach for the selective preparation of 1,5-diketones in high yields. Experimental data suggest a sequential ring-opening, transfer hydrogenation, and hydroacylation mechanism. We propose that aldehyde decarbonylation is avoided by the formation of a novel rhodium enolate species that also accounts for the compatibility of a broad range of aldehydes and its anti-Markovnikov selectivity. PMID- 28856894 TI - A Low Energy Route to DNA-Wrapped Carbon Nanotubes via Replacement of Bile Salt Surfactants. AB - DNA-wrapped carbon nanotubes are a class of bionano hybrid molecules that have enabled carbon nanotube sorting, controlled assembly, and biosensing and bioimaging applications. The current method of synthesizing these hybrids via direct sonication of DNA/nanotube mixtures is time-consuming and not suitable for high-throughput synthesis and combinatorial sequence screening. Additionally, the direct sonication method does not make use of nanotubes presorted by extensively developed surfactant-based methods, is not effective for large diameter (>1 nm) tubes, and cannot maintain secondary and tertiary structural and functional domains present in certain DNA sequences. Here, we report a simple, quick, and robust process to produce DNA-wrapped carbon nanotube hybrids with nanotubes of broad diameter range and DNA of arbitrary sequence. This is accomplished by exchanging strong binding bile salt surfactant coating with DNA in methanol/water mixed solvent and subsequent precipitation with isopropyl alcohol. The exchange process can be completed within 10 min and converts over 90% nanotubes into the DNA wrapped form. Applying the exchange process to nanotubes presorted by surfactant-based methods, we show that the resulting DNA-wrapped carbon nanotubes can be further sorted to produce nanotubes with defined handedness, helicity, and endohedral filling. The exchange method greatly expands the structural and functional variety of DNA-wrapped carbon nanotubes and opens possibilities for DNA-directed assembly of structurally sorted nanotubes and high-throughput screening of properties that are controlled by the wrapping DNA sequences. PMID- 28856893 TI - Temperature/pH-Sensitive Nanoantibiotics and Their Sequential Assembly for Optimal Collaborations between Antibacterial and Immunoregulation. AB - Treatment of bacterial infections due to the fast emergence of drug-resistant bacteria is a significant challenge faced in modern medicine. Here the authors report a drug-induced self-assembly nanoantibiotic for treating bacterial infection, with temperature/pH-sensitivity, synergistic antibacterial effect of silver and antibiotics, and immunoregulatory effect. In this nanoantibiotic, smart polymer p(N-isopropylacrylamide-b-acrylic acid) triblock polymer (PNA) utilized to encapsulate the drugs provides convenience in preparing this structure simply through drug-induced self-assembly and controllable release profile by changing the sequence of addition of different drugs. The polymer also allows the nanoantibiotic to be responsive to multiple external stimuli such as pH, temperature, and ionic strength. The silver and antibiotics codelivered in this nanoantibiotic can exert a synergistic antibacterial effect due to the different antibacterial mechanisms. More importantly, macrophages can be activated into an M2 phenotype to promote tissue repair by this nanoantibiotic for the negative surface charge and the antibiotics contained. The self-assembly nanoantibiotic exhibited great promise to be applied in the treatment of bacterial infection and provide favorable utility for inflammation treatment, tissue engineering, and targeted therapy. PMID- 28856895 TI - (C6H5C2H4NH3)2GeI4: A Layered Two-Dimensional Perovskite with Potential for Photovoltaic Applications. AB - Recently, two-dimensional organic-inorganic perovskites have attracted increasing attention due to their unique photophysical properties and high stability. Here we report a lead-free, two-dimensional perovskite, (PEA)2GeI4 (PEA = C6H5(CH2)2NH3+). Structural characterization demonstrated that this 2D perovskite structure is formed with inorganic germanium iodide planes separated by organic PEAI layers. (PEA)2GeI4 has a direct band gap of 2.12 eV, in agreement with 2.17 eV obtained by density functional theory (DFT) calculations, implying that it is suitable for a tandem solar cell. (PEA)2GeI4 luminesces at room-temperature with a moderate lifetime, exhibiting good potential for photovoltaic applications. In addition, 2D (PEA)2GeI4 is more stable than 3D CH3NH3GeI3 in air, owing to the presence of a hydrophobic organic long chain. This work provides a direction for the development of 2D Ge-based perovskites with potential for photovoltaic applications. PMID- 28856897 TI - Nurse Religiosity and Spiritual Care: An Online Survey. AB - This study measured the frequency of nurse-provided spiritual care and how it is associated with various facets of nurse religiosity. Data were collected using an online survey accessed from the home page of the Journal of Christian Nursing. The survey included the Nurse Spiritual Care Therapeutics Scale, six scales quantifying facets of religiosity, and demographic and work-related items. Respondents ( N = 358) indicated high religiosity yet reported neutral responses to items about sharing personal beliefs and tentativeness of belief. Findings suggested spiritual care was infrequent. Multivariate analysis showed prayer frequency, employer support of spiritual care, and non-White ethnicity were significantly associated with spiritual care frequency (adjusted R2 = .10). Results not only provide an indication of spiritual care frequency but empirical encouragement for nurse managers to provide a supportive environment for spiritual care. Findings expose the reality that nurse religiosity is directly related, albeit weakly, to spiritual care frequency. PMID- 28856896 TI - Resting-state EEG activity related to impulsivity in gambling disorder. AB - Background and aims Impulsivity is a core feature of gambling disorder (GD) and is related to the treatment response. Thus, it is of interest to determine objective neurobiological markers associated with impulsivity in GD. We explored resting-state electroencephalographic (EEG) activity in patients with GD according to the degree of impulsivity. Methods In total, 109 GD subjects were divided into three groups according to Barratt impulsiveness scale-11 (BIS-11) scores: high (HI; 25th percentile of BIS-11 scores, n = 29), middle (MI; 26th 74th percentile, n = 57), and low-impulsivity (LI) groups (75th percentile, n = 23). We used generalized estimating equations to analyze differences in EEG absolute power considering group (HI, MI, and LI), brain region (frontal, central, and posterior), and hemisphere (left, midline, and right) for each frequency band (delta, theta, alpha, beta, and gamma). Results The results indicated that GD patients in the HI group showed decreased theta absolute power, and decreased alpha and beta absolute power in the left, right, particularly midline frontocentral regions. Discussion and conclusions This study is a novel attempt to reveal impulsive features in GD by neurophysiological methods. The results suggest different EEG patterns among GD patients according to the degree of impulsivity, raising the possibility of neurophysiological objective features in GD and helping clinicians in treating GD patients with impulsive features. PMID- 28856898 TI - Effect of Renal Function on Dosing of Non-Vitamin K Antagonist Direct Oral Anticoagulants Among Patients With Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Non-vitamin K antagonist direct oral anticoagulants (DOACs) are fixed dose regimens indicated for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients. Dose adjustment is necessary among patients with renal insufficiency to optimize efficacy and safety. OBJECTIVE: To assess DOAC dosing appropriateness and its effect on clinical outcomes in NVAF patients. METHODS: Adult NVAF patients with >=1 DOAC pharmacy claim (January 1, 2013, to December 31, 2014), continuous enrollment for >=12 months post-index DOAC claim, and documented creatinine clearance within 3 months preindex date in the Optum/Humedica SmartFile database were eligible. DOAC dosage was classified as inappropriate or appropriate by level of renal function, age, and body weight per US prescription information. Cox proportional models were used to assess the risks of bleeding and stroke associated with inappropriate DOAC dosage. RESULTS: Of the 388 eligible patients, 69 (17.8%) were inappropriately dosed, and rivaroxaban had the highest inappropriate dosing rate. Most inappropriately dosed patients were underdosed. Inappropriately dosed patients were more likely to be older, female, and have a body weight of <=60 kg; they also had higher mean CHA2DS2-VASc and Charlson comorbidity index scores (all P < 0.05). Overtreated patients had a higher risk of bleeding (hazard ratio [HR] = 5.4; P = 0.006) than undertreated patients (HR = 3.1; P = 0.025) relative to appropriately dosed patients. However, no significant difference in stroke risk was observed, most likely because very few stroke events were observed in the study. CONCLUSIONS: Inappropriate dosing occurred among patients with normal and insufficient renal function. The consideration of clinical factors beyond renal function is necessary to reduce bleeding risk associated with DOAC therapy. PMID- 28856899 TI - Building a bridge: A case report on communicating mental-health diagnoses to patients of a culturally and linguistically diverse background. AB - OBJECTIVE: This paper is based on a case report, describing a protocol to help practitioners communicate mental-health diagnosis to patients from culturally and linguistically diverse (CALD) backgrounds. The protocol was presented by integrating the DSM-5 Cultural Formulation Interview (CFI) and the SPIKES protocol for communicating the diagnosis of cancer, yielding a modified CFI SPIKES protocol (i.e. S, Support; P, Perception using CFI; I, Invitation; K, Knowledge; E, Emotions). The protocol was demonstrated using a case report with a patient of a Middle-Eastern background experiencing generalised anxiety disorder. CONCLUSIONS: The CFI-SPIKES protocol for communicating mental-health diagnosis allows for a collaborative process, whereby the CALD patient and practitioner can address the stigma associated with communicating a mental-health diagnosis, ensuring patient engagement and informed shared decision making. PMID- 28856900 TI - The development of an artificial stool usable for the surveillance of faecal haemoglobin testing. AB - Background Faecal occult blood testing is an important diagnostic tool for the detection of colorectal cancer. However, it has not been standardized due to the absence of suitable specimens for surveillance. Methods We developed a ready-to use artificial stool made from rice flour. This new artificial stool homogeneously contains not only human haemoglobin A0 (HbA0) but also glycerol as an internal standard material. After the collection of the artificial stool into a buffer, the haemoglobin concentration in dispersed solution was measured using a method based on the peroxidase like activity of haemoglobin. The glycerol concentration was measured using a commercially available triglyceride measurement kit. Results With regard to the haemoglobin stability, the decrease in the level of human haemoglobin in the artificial stool was <2% when it was stored at -80C for four months, -20C for two weeks, and 5C for two days. The artificial stool was easily collected with the collecting tubes of a commercially available faecal haemoglobin test kit. The weight of the collected artificial stool could be calculated by measuring the concentration of glycerol in the extracting solution of the collected stool sample. The haemoglobin concentrations could be adjusted based on their collection weights. Conclusions The artificial stool has a paste-like consistency and contains both haemoglobin and glycerol homogeneously. Furthermore, the measured haemoglobin concentration could be determined based on the collected stool weight, which was directly related to the glycerol concentration. These features make it a useful material for the surveillance of faecal occult blood testing. PMID- 28856901 TI - Type 2 endoleaks in endovascular aortic repair: cone beam CT and automatic vessel detection to guide the embolization. AB - Background Dual-phase cone beam computed tomography (DP-CBCT) and automatic vessel detection (AVD) software are helpful tools for detecting arteries before planned endovascular interventions. Purpose To evaluate the usefulness of DP-CBCT and AVD software in guiding the trans-arterial embolization (TAE) of challenging T2 lumbar endoleaks (T2-L-EL). Material and Methods Ten patients with T2-L-EL were included in this study. The accuracy of DP-CBCT and the AVD software was defined by the ability to detect the endoleak and arterial feeding vessel, respectively. Technical success was defined as the correct positioning of the microcatheter using AVD software and the successful embolization of the endoleak. Clinical success was defined as the absence of recurrent endoleaks during follow up and the stability of the sac diameter for persistent endoleaks. The total volume of iodinated contrast medium, overall procedure time, mean procedural radiation dose, and mean fluoroscopy time were recorded. Results The EL was detected by DP-CBCT in all patients. The AVD software identified the feeding arterial branch in all cases. In one patient, the nidus of the endoleak was not reached due to the small caliber of the feeding artery, even though the software had clearly identified the vessel route. The mean contrast volume was 109 mL, the mean overall procedural time was 74.3 min. The mean procedural radiation dose was 140.97 Gy cm2, and the mean fluoroscopy time was 29.8 min. Conclusion The use of DP-CBCT and the AVD software is feasible and may facilitate successful embolization in challenging occult T2-L-EL with complex vasculature. PMID- 28856902 TI - Getting RID of the blues: Formulating a Risk Index for Depression (RID) using structural equation modeling. AB - OBJECTIVE: While risk factors for depression are increasingly known, there is no widely utilised depression risk index. Our objective was to develop a method for a flexible, modular, Risk Index for Depression using structural equation models of key determinants identified from previous published research that blended machine-learning with traditional statistical techniques. METHODS: Demographic, clinical and laboratory variables from the National Health and Nutrition Examination Study (2009-2010, N = 5546) were utilised. Data were split 50:50 into training:validation datasets. Generalised structural equation models, using logistic regression, were developed with a binary outcome depression measure (Patient Health Questionnaire-9 score ? 10) and previously identified determinants of depression: demographics, lifestyle-environs, diet, biomarkers and somatic symptoms. Indicative goodness-of-fit statistics and Areas Under the Receiver Operator Characteristic Curves were calculated and probit regression checked model consistency. RESULTS: The generalised structural equation model was built from a systematic process. Relative importance of the depression determinants were diet (odds ratio: 4.09; 95% confidence interval: [2.01, 8.35]), lifestyle-environs (odds ratio: 2.15; 95% CI: [1.57, 2.94]), somatic symptoms (odds ratio: 2.10; 95% CI: [1.58, 2.80]), demographics (odds ratio:1.46; 95% CI: [0.72, 2.95]) and biomarkers (odds ratio:1.39; 95% CI: [1.00, 1.93]). The relationships between demographics and lifestyle-environs and depression indicated a potential indirect path via somatic symptoms and biomarkers. The path from diet was direct to depression. The Areas under the Receiver Operator Characteristic Curves were good (logistic:training = 0.850, validation = 0.813; probit:training = 0.849, validation = 0.809). CONCLUSION: The novel Risk Index for Depression modular methodology developed has the flexibility to add/remove direct/indirect risk determinants paths to depression using a structural equation model on datasets that take account of a wide range of known risks. Risk Index for Depression shows promise for future clinical use by providing indications of main determinant(s) associated with a patient's predisposition to depression and has the ability to be translated for the development of risk indices for other affective disorders. PMID- 28856903 TI - Game-based interventions and their impact on dementia: a narrative review. AB - OBJECTIVE: The aim of this review was to examine the efficacy of game-based interventions for people with dementia. METHODS: Seven studies that met the inclusion criteria were found in four databases. Their interventions and key findings were analysed and synthesised. RESULTS: Game-based interventions for people with dementia are showing promise for improving cognition, coordination and behavioural and psychological symptoms. The generalisability of the findings is limited by weak methodology and small sample size. CONCLUSIONS: Game-based interventions can improve cognition, coordination and behavioural and psychological symptoms for people with dementia. Future research should include methodological improvement and practice guideline development. PMID- 28856904 TI - Comorbid pathological gambling, mental health, and substance use disorders: Health-care services provision by clinician specialty. AB - Background and aims Pathological gambling (PG) is an impulse control disorder. This study assessed the burden of co-occurring behavioral addictions and mental health disorders in treatment-seeking patients and estimated the likelihood of receiving care for these disorders by clinician specialty. Methods Study data were derived from the Massachusetts All-Payer Claims Database, a representative database, for the period 2009-2013. The sample included commercially insured adult residents of Massachusetts. Univariate and multivariate logistic regressions were used to estimate the likelihood of provision of care by clinician specialty adjusting for patient's demographic characteristics and level of care. Bonferroni correction was applied to adjust for multiple testing. Results The study sample included 869 patients. Treatment-seeking patients who had a diagnosis of PG were mostly males (71%), aged 45-54 years (26.7%) and enrolled in a health maintenance organization (47%). The most prevalent co occurring disorders among patients with PG as principal diagnosis were anxiety disorders (28%), mood disorders (26%), and substance use disorders (18%). PG was associated with a more than twofold likelihood of receiving care from social workers and psychologists (p < .05). Depressive disorders were associated with a three times greater likelihood of receiving care from primary care physicians (PCPs) (p < .05). Having three and four or more diagnosis was associated with a greater likelihood of receiving care from PCPs. Discussion and conclusions Psychiatric and substance use disorders are prevalent among treatment-seeking pathological gamblers. The likelihood of receiving care from specialty clinicians significantly varies by clinical diagnosis and patient clinical complexity. PMID- 28856905 TI - Can probiotics enhance vaccine-specific immunity in children and adults? AB - The growing use of probiotics by the general public has heightened the interest in understanding the role of probiotics in promoting health and preventing disease. General practitioners and specialists often receive inquiries from their patients regarding probiotic products and their use to ward off systemic infection or intestinal maladies. Enhanced immune function is among the touted health benefits conferred by probiotics but has not yet been fully established. Results from recent clinical trials in adults suggest a potential role for probiotics in enhancing vaccine-specific immunity. Although almost all vaccinations are given during infancy and childhood, the numbers of and results from studies using probiotics in pediatric subjects are limited. This review evaluates recent clinical trials of probiotics used to enhance vaccine-specific immune responses in adults and infants. We highlight meaningful results and the implications of these findings for designing translational and clinical studies that will evaluate the potential clinical role for probiotics. We conclude that the touted health claims of probiotics for use in children to augment immunity warrant further investigation. In order to achieve this goal, a consensus should be reached on common study designs that apply similar treatment timelines, compare well-characterised probiotic strains and monitor effective responses against different classes of vaccines. PMID- 28856906 TI - Effect of Propionibacterium acidipropionici P169 on the rumen and faecal microbiota of beef cattle fed a maize-based finishing diet. AB - Direct fed microbial supplementation with lactic acid utilising bacteria (i.e. Propionibacterium acidipropionici P169) has been shown to alleviate the severity of subacute ruminal acidosis in high-grain fed beef cattle. This study was carried out to explore the impact of P169 supplementation on modulating rumen and hindgut microbiota of high-grain fed steers. Seven ruminally-canulated high-grain fed steers were randomly assigned to two treatment groups: control diet (n=3) and the same diet supplemented with P169 added at a rate of 1*1011 cfu/head/d (n=4). Samples were collected every 28 days for a 101 d period (5 time points) and subjected to qPCR quantification of P169 and high-throughput sequencing of bacterial V4 16S rRNA genes. Ruminal abundance of P169 was maintained at elevated levels (P=0.03) both in liquid and solid fractions post supplementation. Concomitant with decreased proportion of amylolytic (such as Prevotella) and key lactate-utilisers (such as Veillonellaceae and Megasphaera), the proportions of cellulolytic bacterial lineages (such as Ruminococcaceae, Lachnospiraceae, Clostridiaceae, and Christensenellaceae) were enriched in the rumen microbiota of P169-supplemented steers. These, coupled with elevated molar proportions of branched-chain fatty acids and increased concentration of ammonia in the rumen content of P169-supplemented steers, indicated an improved state of fibrolytic and proteolytic activity in response to P169 supplementation. Further, exploring the hindgut microbiota of P169-supplemented steers revealed enrichment of major amylolytic bacterial lineages, such as Prevotella, Blautia, and Succinivibrionaceae, which might be indicative of an increased availability of carbohydrates in the hindgut ecosystem following P169 supplementation. Collectively, the present study provides insights into the microbiota dynamics that underlie the P169-associated shifts in the rumen fermentation profile of high-grain fed steers. PMID- 28856907 TI - To add or not to add probiotics to infant formulae? An updated systematic review. AB - We updated evidence on the effects of the administration of probiotic supplemented infant formulae (IF) compared with unsupplemented IF. Five databases were searched up to September 2016 for randomised controlled trials. Twenty publications were identified, including five new RCTs. Supplementation of IF with Bifidobacterium lactis Bb12, either alone or with Streptococcus thermophilus, had no effect on growth, respiratory illness, antibiotic use, stool frequency or consistency. However, there was a significant reduction in the number of episodes of gastrointestinal infections (Bb12) and a lower frequency of colic or irritability (when both strains were used). Lactobacillus johnsonii La1 had no effect on growth, gastrointestinal infections, or respiratory illness episodes. There were no effects of supplementation of IF with Bifidobacterium longum BL999, alone or with Lactobacillus rhamnosus LPR. L. rhamnosus GG was associated with better growth; it had no effect on colic/crying, or irritability, and it was associated with greater indexes of loose stools and a higher defecation frequency. Lactobacillus reuteri ATCC 55730 had no effect on growth, colic, crying, irritability, respiratory illness, antibiotic use, stool frequency, or stool consistency; however, it reduced the number of episodes of diarrhoea. L. reuteri DSM 17938 had no effect on growth, night-time sleeping, or flatulence, but it reduced the number of spitting episodes. Lactobacillus salivarius CEC5713 had no effect on growth, colic, crying, or irritability; however, it resulted in a significant reduction in the rate of diarrhoea and the number of episodes of respiratory symptoms. In conclusion, the administration of probiotic-supplemented formulae to healthy infants does not raise safety concerns with regard to growth and adverse effects. Some beneficial clinical effects are possible; however, there is no existing robust evidence to recommend their routine use. The latter conclusion may reflect the small amount of data on a specific probiotic strain(s) and outcomes, rather than a genuine lack of an effect. PMID- 28856908 TI - Butyrate modulating effects on pro-inflammatory pathways in human intestinal epithelial cells. AB - Butyrate acts as energy source for intestinal epithelial cells and as key mediator of several immune processes, modulating gene expression mainly through histone deacetylation inhibition. Thanks to these effects, butyrate has been proposed for the treatment of many intestinal diseases. Aim of this study was to investigate the effect of butyrate on the expression of a large series of target genes encoding proteins involved in pro-inflammatory pathways. We performed quantitative real-time-PCR analysis of the expression of 86 genes encoding proteins bearing to pro-inflammatory pathways, before and after butyrate exposure, in primary epithelial cells derived from human small intestine and colon. Butyrate significantly down-regulated the expression of genes involved in inflammatory response, among which nuclear factor kappa beta, interferon-gamma, Toll like 2 receptor and tumour necrosis factor-alpha. Further confirmations of these data, including studies at protein level, would support the use of butyrate as effective therapeutic strategy in intestinal inflammatory disorders. PMID- 28856909 TI - Lactococcus lactis and Lactobacillus salivarius differently modulate early immunological response of Wistar rats co-administered with Listeria monocytogenes. AB - In the light of the increasing resistance of bacterial pathogens to antibiotics, one of the main global strategies in applied science is development of alternative treatments, which would be safe both for the host and from the environmental perspective. Accordingly, the aim of this study was to test whether two lactic acid bacteria (LAB) strains, Lactococcus lactis BGBU1-4 and Lactobacillus salivarius BGHO1, could be applied as safe supplements for Listeria infection. Two major research objectives were set: to compare the effects of BGBU1-4 and BGHO1 on early immune response in gut tissue of Wistar rats co administered with Listeria monocytogenes ATCC19111 and next, to test how this applies to their usage as therapeutics in acute ATCC19111 infection. Intestinal villi (IV), Peyer's patches (PP) and mesenteric lymph nodes (MLN) were used for the analysis. The results showed that BGHO1 increased the mRNA expression of innate immune markers CD14, interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in PP and IV, and, in parallel, caused a decrease of listeriolysin O (LLO) mRNA expression in same tissues. In MLN of BGHO1 treated rats, LLO expression was increased, along with an increase of the expression of OX-62 mRNA and CD69, pointing to the activation of adaptive immunity. On the other hand, in BGBU1-4 treated rats, there was no reduction of LLO mRNA expression and no induction of innate immunity markers in intestinal tissue. Additionally, CD14 and IL-1beta, as well as LLO, but not OX-62 mRNA and CD69 expression, were elevated in MLN of BGBU1-4 treated rats. However, when applied therapeutically, both, BGBU1-4 and BGHO1, lowered Listeria count in spleens of infected rats. Our results not only reveal the potential of LAB to ameliorate Listeria infections, but suggest different immunological effects of two different LAB strains, both of which could be effective in Listeria elimination. PMID- 28856910 TI - Distribution of CGRP and CGRP receptor components in the rat brain. AB - Background Calcitonin gene-related peptide and its receptor, consisting of receptor activity-modifying protein 1 and calcitonin receptor-like receptor, are of considerable interest because of the role they play in migraine and recently developed migraine therapies. Methods To better understand the function of this neuropeptide, we used immunohistochemistry to determine a detailed distribution of calcitonin gene-related peptide, receptor activity-modifying protein 1 and calcitonin receptor-like receptor in the rat brain in a region of 0.5-1.5 mm lateral to the midline. We found calcitonin gene-related peptide immunoreactivity in most of the neurons of the cerebral cortex, hippocampus, cerebellum, thalamic nuclei, hypothalamic nuclei and brainstem nuclei. In contrast, receptor activity modifying protein 1 and calcitonin receptor-like receptor immunoreactivity were found almost exclusively in the neuronal processes in the investigated regions. Conclusion Overall, the degree of expression of calcitonin gene-related peptide and calcitonin gene-related peptide receptor components in the central nervous system is astonishingly complex and suggestive of many different brain functions, including a possible role in migraine. However, currently, the presence of calcitonin gene-related peptide and the nature of its receptors throughout the brain is an enigma yet to be solved. PMID- 28856911 TI - Sunlight irradiance and habituation of visual evoked potentials in migraine: The environment makes its mark. AB - Background Migraine is a complex multifactorial disease that arises from the interaction between a genetic predisposition and an enabling environment. Habituation is considered as a fundamental adaptive behaviour of the nervous system that is often impaired in migraine populations. Given that migraineurs are hypersensitive to light, and that light deprivation is able to induce functional changes in the visual cortex recognizable through visual evoked potentials habituation testing, we hypothesized that regional sunlight irradiance levels could influence the results of visual evoked potentials habituation studies performed in different locations worldwide. Methods We searched the literature for visual evoked potentials habituation studies comparing healthy volunteers and episodic migraine patients and correlated their results with levels of local solar radiation. Results After reviewing the literature, 26 studies involving 1291 participants matched our inclusion criteria. Deficient visual evoked potentials habituation in episodic migraine patients was reported in 19 studies. Mean yearly sunlight irradiance was significantly higher in locations of studies reporting deficient habituation. Correlation analyses suggested that visual evoked potentials habituation decreases with increasing sunlight irradiance in migraine without aura patients. Conclusion Results from this hypothesis generating analysis suggest that variations in sunlight irradiance may induce adaptive modifications in visual processing systems that could be reflected in visual evoked potentials habituation, and thus partially account for the difference in results between studies performed in geographically distant centers. Other causal factors such as genetic differences could also play a role, and therefore well-designed prospective trials are warranted. PMID- 28856912 TI - Roller pressure algometry as a new tool for assessing dynamic pressure sensitivity in migraine. AB - Objectives To explore the validity of the roller pressure algometer as a new tool for evaluating dynamic pressure sensitivity by assessing its association with pain features and widespread pressure pain sensitivity in migraine women, and also to determine whether dynamic pressure algometry differentiates between episodic and chronic migraine. Methods One hundred and twenty women with migraine (42% chronic, 58% episodic) participated. Dynamic pressure sensitivity was assessed with a set of roller pressure algometers (Aalborg University, Denmark(r)) consisting of 11 rollers with fixed pressure levels from 500 to 5300 g. Each roller was moved at a speed of 0.5 cm/sec over a 60 mm horizontal line covering the temporalis muscle. The dynamic pain threshold (the pressure level of the first painful roller) and pain elicited during the pain threshold (roller evoked pain) were determined. Static pressure pain thresholds were assessed over the temporalis muscle, C5/C6 joint, second metacarpal, and tibialis anterior. Results Side-to-side consistency between dynamic pain threshold (rs = 0.769, p < 0.001) and roller evoked pain (rs = 0.597; p < 0.001) were found. Women with chronic migraine exhibited bilateral lower dynamic pain thresholds ( p < 0.01), but similar widespread pressure pain thresholds (all, p > 0.284) than those with episodic migraine. Dynamic pain threshold was moderately positively associated with widespread pressure pain thresholds (0.358 > rs > 0.700, all p < 0.001). This association was slightly stronger in chronic migraine. Pain during dynamic pain threshold was negatively associated with widespread pressure pain thresholds (-0.336 < rs < -0.235, all p < 0.01). Conclusions Roller pressure algometry was valid for assessing dynamic pressure sensitivity in migraine in the trigeminal area and is consistent with widespread static pressure pain sensitivity. Roller, but not static, pressure algometry differentiated between episodic and chronic migraine. Assessing static and dynamic deep somatic tissue sensitivity may provide new opportunities for evaluating treatment outcomes. PMID- 28856913 TI - Effects of external trigeminal nerve stimulation (eTNS) on laser evoked cortical potentials (LEP): A pilot study in migraine patients and controls. AB - Background Transcutaneous external supraorbital nerve stimulation has emerged as a treatment option for primary headache disorders, though its action mechanism is still unclear. Study aim In this randomized, sham-controlled pilot study we aimed to test the effects of a single external transcutaneous nerve stimulation session on pain perception and cortical responses induced by painful laser stimuli delivered to the right forehead and the right hand in a cohort of migraine without aura patients and healthy controls. Methods Seventeen migraine without aura patients and 21 age- and sex-matched controls were selected and randomly assigned to a real or sham external transcutaneous nerve stimulation single stimulation session. The external transcutaneous nerve stimulation was delivered with a self-adhesive electrode placed on the forehead and generating a 60 Hz pulse at 16 mA intensity for 20 minutes. For sham stimulation, we used 2 mA intensity. Laser evoked responses were recorded from 21 scalp electrodes in basal condition (T0), during external transcutaneous nerve stimulation and sham stimulation (T1), and immediately after these (T2). The laser evoked responses were analyzed by LORETA software. Results The real external transcutaneous nerve stimulation reduced the trigeminal N2P2 amplitude in migraine and control groups significantly in respect to placebo. The real stimulation was associated with lower activity in the anterior cingulate cortex under trigeminal laser stimuli. The pattern of LEP-reduced habituation was reverted by real and sham transcutaneous stimulation in migraine patients. Conclusions The present results could suggest that the external transcutaneous nerve stimulation may interfere with the threshold and the extent of trigeminal system activation, with a mechanism of potential utility in the resolution and prevention of migraine attacks. PMID- 28856914 TI - Ten years of follow-up in a large family with familial hemiplegic migraine type 1: Clinical course and implications for treatment. AB - Background Familial hemiplegic migraine (FHM) is a rare, genetic form of migraine with aura. The severity of the aura imposes an effective prophylaxis that is currently based on standard anti-migraine drugs. To this concern, only short-term reports are currently available. Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic. Medical history, general and neurological examination as well as therapeutic approaches were recorded regularly on a routine basis for an average period of 13 years (range 9-15 years). Brain imaging studies and EEG data were also collected. Results Our long-term follow-up revealed that ictal manifestations, which usually improve after the adolescence, may reoccur later in the adulthood. Permanent neurological signs as assessed by means of clinical evaluation as well as follow-up MRIs, EEGs and neuropsychological testing remained stable. Interval therapy with non-selective calcium antagonists reduced the burden of migraine attacks and was well tolerated in the long term. PMID- 28856915 TI - Factor structure of depressive symptoms using the EURO-D scale in the over-50s in Europe. Findings from the SHARE project. AB - OBJECTIVES: The aims of this study are: to analyze the factor structure of the EURO-D depression scale; to explore the variables associated with depressive symptoms in the total sample and in the EURO-D factors; and to compare the presence of depressive symptoms and the factor distribution in 15 European countries. METHOD: 62,182 participants in Wave 5 (2013) of the Survey of Health, Aging and Retirement in Europe (SHARE) were included. INSTRUMENTS: The SHARE study and the EURO-D scale. Factor, bivariate and multilevel analyses were performed. RESULTS: Higher levels of depressive symptoms were associated with a poorer self-perception of physical health (eta2 = 0.22) and economic difficulties (eta2 = 0.07). Factor analysis of the EURO-D identified two factors: Suffering and Motivation. Higher levels of depressive symptoms were associated with female gender and younger age (<=60) in the Suffering factor, and with less activity and exercise, older age (>=71), widowhood and lower educational level in the Motivation factor. Poorer self-perception of physical health and economic difficulties were associated with higher depressive symptomatology in both factors. CONCLUSIONS: Poorer self-perception of physical health, female gender, economic difficulties, widowhood, lower levels of activity and exercise and lower educational level were associated with higher depressive symptomatology. In the countries of southern Europe, the Motivation factor predominated. PMID- 28856916 TI - The making of mind. AB - : Objectives The ordinary, ongoing sense of personal existing, variously called higher order consciousness, mind, or self, is disintegrated, constricted and distorted in those who have suffered repetitive psychological traumata. Their speech has the form of a 'chronicle', literal and asymbolic. This paper offers a condensed rationale for a relational approach to this, so far, neglected problem. CONCLUSIONS: A restorative and generative kind of relatedness is 'natural', the propensity for it being given to us by our biological heritage. Its first form is a game between babies and caregivers, a 'proto-conversation'. Principles derived from this, and related developmental behaviours, guide a form of therapeutic relatedness consisting of an interactive, to-and-fro 'patterning' of verbal 'pictures', or analogues, of the subject's immediate experience. The analogue is the first form of symbol, the use of which is the hallmark of the human. PMID- 28856917 TI - Misrepresenting community treatment orders. AB - OBJECTIVES: To explore a contradiction between evidence suggesting community treatment order (CTO) ineffectiveness and clinical experience. CONCLUSIONS: The literature pertaining to CTOs actually provides an evidence base for both positions. The headline that three randomised controlled trials and subsequent meta-analyses fail to demonstrate significant differences between groups reflects selection bias. A case may still be made for CTOs. PMID- 28856918 TI - Original opinion: the use of Bloom's Taxonomy to teach and assess the skill of the psychiatric formulation during vocational training. AB - OBJECTIVES: This paper proposes the use of the cognitive domain of Bloom's Taxonomy, an educational classification system, to guide the critical thinking required for the composition of the psychiatric formulation during the various stages of specialist training. CONCLUSIONS: Bloom's Taxonomy offers a hierarchical, structured approach to clinical reasoning. Use of this method can assist supervisors and trainees to understand better the concepts of and offer a developmental approach to critical reasoning. Application of the Taxonomy, using cognitive 'action words' (verbs) within each of the levels, can promote increasing sophistication in the construction of the psychiatric formulation. Examples of how the Taxonomy can be adapted to design educational resources are suggested in the article. PMID- 28856919 TI - ACTN1 variants associated with thrombocytopenia. PMID- 28856920 TI - Efficacy of ondansetron for spinal anesthesia during cesarean section: a meta analysis of randomized trials. AB - Objective To investigate the efficacy and safety of ondansetron during cesarean section under spinal anesthesia. Methods We sought randomized controlled trials (RCTs) on ondansetron during spinal anesthesia for cesarean section in The Cochrane Library, PubMed, MEDLINE, and Web of Science from their inception to September 2016. Results Altogether, 21 RCTs were included in this study. Meta analysis showed that the ondansetron group had a lower incidence of nausea/vomiting and bradycardia than the placebo group during cesarean section under spinal anesthesia [relative risk (RR) = 0.43, 95% confidence interval (CI) (0.36, 0.51) and RR = 0.45, 95% CI (0.26, 0.80), respectively]. There were no significant differences in the incidences of pruritus, hypotension, or shivering during cesarean section under spinal anesthesia [RR = 0.92, 95% CI (0.83, 1.02); RR = 0.72 (0.50, 1.06), 95% CI (0.50, 1.06); and RR = 0.89, 95% CI (0.71, 1.11), respectively]. Conclusion Ondansetron effectively reduces the incidences of nausea/vomiting and bradycardia under spinal anesthesia during cesarean section. PMID- 28856921 TI - Near-Infrared Intraoperative Imaging Can Successfully Identify Malignant Pleural Mesothelioma After Neoadjuvant Chemotherapy. AB - Malignant pleural mesothelioma is a deadly disease. Complete surgical resection provides patients with the best opportunity for long-term survival. Unfortunately, identification of disease during resection can be challenging. In this report, we describe successful intraoperative utilization of the near infrared imaging agent, indocyanine green, to help the surgeon identify malignant disease in a patient with malignant pleural mesothelioma who had previously received neoadjuvant chemotherapy. This technology may ultimately enhance the thoracic surgeon's ability to identify small disease deposits at the time of resection. PMID- 28856922 TI - Detection and Delineation of Oral Cancer With a PARP1-Targeted Optical Imaging Agent. AB - More sensitive and specific methods for early detection are imperative to improve survival rates in oral cancer. However, oral cancer detection is still largely based on visual examination and histopathology of biopsy material, offering no molecular selectivity or spatial resolution. Intuitively, the addition of optical contrast could improve oral cancer detection and delineation, but so far no molecularly targeted approach has been translated. Our fluorescently labeled small-molecule inhibitor PARPi-FL binds to the DNA repair enzyme poly(ADP ribose)polymerase 1 (PARP1) and is a potential diagnostic aid for oral cancer delineation. Based on our preclinical work, a clinical phase I/II trial opened in March 2017 to evaluate PARPi-FL as a contrast agent for oral cancer imaging. In this commentary, we discuss why we chose PARP1 as a biomarker for tumor detection and which particular characteristics make PARPi-FL an excellent candidate to image PARP1 in optically guided applications. We also comment on the potential benefits of our molecularly targeted PARPi-FL-guided imaging approach in comparison to existing oral cancer screening adjuncts and mention the adaptability of PARPi-FL imaging to other environments and tumor types. PMID- 28856923 TI - Gene Expression Profiling in Abdominal Aortic Aneurysms After Finite Element Rupture Risk Assessment. AB - PURPOSE: To investigate the association between local biomechanical rupture risk calculations from finite element analysis (FEA) and whole-genome profiling of the abdominal aortic aneurysm (AAA) wall to determine if AAA wall regions with highest and lowest estimated rupture risk show different gene expression patterns. METHODS: Six patients (mean age 74 years; all men) scheduled for open surgery to treat asymptomatic AAAs (mean diameter 55.2+/-3.5 mm) were recruited for the study. Rupture risk profiles were estimated by FEA from preoperative computed tomography angiography data. During surgery, AAA wall samples of ~10 mm2 were extracted from the lowest and highest rupture risk locations identified by the FEA. Twelve samples were processed for RNA extraction and subsequent whole genome expression profiling. Expression of single genes and of predefined gene groups were compared between vessel wall areas with highest and lowest predicted rupture risk. RESULTS: Normalized datasets comprised 15,079 gene transcripts with expression above background. In biopsies with high rupture risk, upregulation of 18 and downregulation of 18 genes was detected when compared to the low-risk counterpart. Global analysis of predefined gene groups revealed expression differences in genes associated with extracellular matrix (ECM) degradation (p<0.001), matrix metalloproteinase activity (p<0.001), and chemokine signaling (p<0.001). CONCLUSION: Increased expression of genes involved in degrading ECM components was present in AAA wall regions with highest biomechanical stress, supporting the thesis of mechanotransduction. More experimental studies with cooperation of multicenter vascular biobanks are necessary to understand AAA etiologies and identify further parameters of FEA model complementation. PMID- 28856924 TI - Review of current typhoid fever vaccines, cross-protection against paratyphoid fever, and the European guidelines. AB - INTRODUCTION: Typhoid and paratyphoid fever remain a global health problem, which - in non-endemic countries - are mainly seen in travelers, particularly in VFRs (visiting friends and relatives), with occasional local outbreaks occurring. A rise in anti-microbial resistance emphasizes the role of preventive measures, especially vaccinations against typhoid and paratyphoid fever for travelers visiting endemic countries. Areas covered: This state-of-the-art review recapitulates the epidemiology and mechanisms of disease of typhoid and paratyphoid fever, depicts the perspective of non-endemic countries and travelers (VFRs), and collectively presents current European recommendations for typhoid fever vaccination. We provide a brief overview of available (and developmental) vaccines in Europe, present current data on cross-protection to S. Paratyphi, and aim to provide a background for typhoid vaccine decision-making in travelers. Expert commentary: European recommendations are not harmonized. Experts must assess vaccination of travelers based on current country-specific recommendations. Travel health practitioners should be aware of the issues surrounding vaccination of travelers and be motivated to increase awareness of typhoid and paratyphoid fever risks. PMID- 28856925 TI - Comparison of hamstring and patellar tendon grafts in anterior cruciate ligament reconstruction: A prospective randomized study. AB - Objective This prospective randomized study was performed to compare the outcomes of two operative methods of anterior cruciate ligament (ACL) reconstruction based on either bone-patellar tendon-bone (BTB) grafts or hamstring tendon (HT) grafts. Methods Among 100 patients, 96 completed the full follow-up period and were included in the final analysis (48 in the BTB group and 48 in the HT group). The patients were evaluated preoperatively and 1, 3, 6, and 12 months after ACL reconstruction. The Kujala score, Tegner score, and Knee injury and Osteoarthritis Outcome Score (KOOS) were among the parameters used to evaluate the patients. Results Both groups were comparable in terms of sex, age, and body mass index. None of the analyzed scores were significantly different between the BTB and HT groups at either the initial or last visit. Both groups demonstrated improvement at the 12-year follow-up according to the Kujala score and most categories of the KOOS. The Tegner activity level score showed significant improvement in the HT but not BTB group. Conclusion Patients undergoing ACL reconstruction with BTB and HT grafts show comparable improvement in functional results after 1 year of rehabilitation. PMID- 28856926 TI - Total flavonoids from Astragalus alleviate endothelial dysfunction by activating the Akt/eNOS pathway. AB - Objective To investigate the vasodilative and endothelial-protective effects and the underlying mechanisms of total flavonoids from Astragalus (TFA). Methods The vasodilative activities of TFA were measured with a myograph ex vivo using rat superior mesenteric arterial rings. The primary human umbilical vein endothelial cell (HUVEC) viabilities were assayed using the cell counting kit-8 after hypoxia or normoxia treatment with or without TFA. Akt, P-Akt, eNOS, P-eNOS, Erk, P-Erk, Bcl-2 and Bax expression were analyzed using western blotting. Results TFA showed concentration-dependent vasodilative effects on rat superior mesenteric arterial rings, but had no effects on normal or potassium chloride precontracted arterial rings. TFA did not affect HUVEC viabilities in normoxia, but dramatically promoted cell proliferation in the concentration range of 1 to 30 ug/mL under hypoxia. Moreover, TFA significantly increased the ratios of P-Akt/Akt and P eNOS/eNOS in vascular endothelial cells under hypoxic conditions, but did not change the P-Erk/Erk or Bcl-2/Bax ratios. Conclusions TFA might exhibit vasorelaxant and endothelial-protective effects via the Akt/eNOS signaling pathway. PMID- 28856927 TI - Pharmacoepigenetics and pharmacoepigenomics of gastrointestinal cancers. AB - INTRODUCTION: Our understanding of the epigenetic changes occurring in gastrointestinal cancers has gained tremendous advancements in recent years, and some epigenetic biomarkers are already translated into the clinics for cancer diagnostics. In parallel, pharmacoepigenetics and pharmacoepigenomics of solid tumors are relevant novel, but emerging and promising fields. Areas covered: A comprehensive review of the literature to summarize and update the emerging field of pharmacoepigenetics and pharmacoepigenomics of gastrointestinal cancers. Expert commentary: Several epigenetic modifications have been proposed to account for interindividual variations in drug response in gastrointestinal cancers. Similarly, single-agent or combined strategies with high doses of drugs that target epigenetic modifications (epi-drugs) were scarcely tolerated by the patients, and current research has moved to their combination with standard therapies to achieve chemosensitization, radiosensitization, and immune modulation of cancerous cells. In parallel, recent genome-wide technologies are revealing the pathways that are epigenetically deregulated during cancer-acquired resistance, including those targeted by non-coding RNAs. Indeed, novel, less toxic, and more specific molecules are under investigation to specifically target those pathways. The field is rapidly expanding and gathering together information coming from these investigations has the potential to lead to clinical applications in the coming new years. PMID- 28856928 TI - CXC chemokine ligand 16 is increased in gestational diabetes mellitus and preeclampsia and associated with lipoproteins in gestational diabetes mellitus at 5 years follow-up. AB - BACKGROUND: Women with a history of gestational diabetes mellitus and preeclampsia are at increased risk of cardiovascular disease later in life, but the mechanism remains unclear. The aim of the study was to evaluate the association between CXC chemokine ligand 16 and indices of glucose metabolism, dyslipidemia and systemic inflammation in gestational diabetes mellitus and preeclampsia. METHODS: This sub-study of the population-based prospective cohort included 310 women. Oral glucose tolerance test was performed during pregnancy and 5 years later along with lipid analysis. CXC chemokine ligand 16 was measured in plasma (protein) and peripheral blood mononuclear cells (messenger RNA) during pregnancy and at follow-up. RESULTS: Circulating CXC chemokine ligand 16 was higher in gestational diabetes mellitus women early in pregnancy and at follow up, while higher in preeclampsia women late in pregnancy compared to control women. Messenger RNA of CXC chemokine ligand 16 in peripheral blood mononuclear cells were lower in gestational diabetes mellitus and preeclampsia women compared to control women. Increased circulating CXC chemokine ligand 16 level was associated with a higher apolipoprotein B and low-density lipoprotein cholesterol in gestational diabetes mellitus women but not in normal pregnancy at follow-up. CONCLUSION: Our study shows that women with gestational diabetes mellitus and preeclampsia had a dysregulated CXC chemokine ligand 16 during pregnancy, and in gestational diabetes mellitus, the increase in CXC chemokine ligand 16 early in pregnancy and after 5 years was strongly associated with their lipid profile. PMID- 28856929 TI - New quinoxalinone inhibitors targeting secreted phospholipase A2 and alpha glucosidase. AB - Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against alpha-glucosidase and alpha-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N'-(substituted benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a-f and 1-(substituted-phenyl)-5H [1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a-f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b-d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited alpha-glucosidase (IC50 = 9.99 +/- 0.18 uM); which is comparable to quercetin (IC50 = 9.93 +/- 0.66 uM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against alpha-amylase (IC50 > 200 uM). Structure based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as alpha-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications. PMID- 28856930 TI - Sepsis after uterine artery embolization-assisted termination of pregnancy with complete placenta previa: A case report. AB - Uterine artery embolization (UAE)-assisted induction of labor is an alternative method of managing pregnant women with complete placenta previa (CPP). Sepsis secondary to UAE, although rare, is a serious complication. We herein present a case of severe sepsis following UAE-assisted termination of a pregnancy at 27 gestational weeks in a woman with CPP. The woman developed a high-grade fever and elevated inflammatory indices following UAE. She did not recover until the infected tissue was removed by emergency cesarean section. This case suggests that the increasing use of UAE for termination of pregnancy in women with CPP requires awareness regarding the possibility of serious sepsis associated with this procedure. PMID- 28856931 TI - Acceptability of orodispersible films for delivery of medicines to infants and preschool children. AB - Orodispersible films (ODFs) possess potential to facilitate oral drug delivery to children; however, documentation of their acceptability in this age group is lacking. This study is the first to explore the initial perceptions, acceptability and ease of use of ODFs for infants and preschool children, and their caregivers through observed administration of the type of dosage form. Placebo ODFs were administered to children stratified into aged 6 to 12 months, 1 year, 2 years, 3 years, 4 years and 5 years old and into those with an acute illness or long-term stable condition in hospital setting. Acceptability of the dosage form and end-user views were assessed by (a) direct observation of administration, (b) questionnaires to caregivers and nurses, and (c) age-adapted questionnaires for children aged 3 years and over. The majority of children (78%) aged 3 years and over gave the ODF a positive rating both on verbal and non verbal scales. Despite little prior experience, 78% of caregivers expressed positive opinion about ODFs before administration. After the ODFs were taken, 79% of infant caregivers and 86% caregivers of preschool children positively rated their child's acceptance of the ODF. The intraclass correlation coefficient value was 0.92 showing good agreement between ratings of caregivers and nurses. ODFs showed a high degree of acceptability among young children and their caregivers. If drug loading permits, pharmaceutical companies should consider developing pediatric medicines in this format. The methodology described here is useful in assessing the acceptability of active ODF preparations and other dosage forms to children. PMID- 28856932 TI - Working Memory Training for Adults With ADHD. AB - OBJECTIVE: The aim of this study was to examine the effects of Cogmed training on working memory in adults with ADHD, including the generalization of effects to nonverbal reasoning, executive function in daily life, and ADHD symptoms. METHOD: Adults of ages 18 to 63 with ADHD were randomly assigned to an experimental group that received the working memory training or to a placebo group that received a low-intensity comparison version of the training. RESULTS: participants in the experimental group showed greater improvement in verbal and visuospatial working memory capacity. Effects persisted 6 months after intervention completion. However, effects did not generalize elsewhere. CONCLUSION: The results challenge the claims made by Cogmed to the effect that the program is effective in treating attention problems and improving performance in daily life over the long term in adults with ADHD. PMID- 28856934 TI - A systematic review of medial epicondylectomy as a surgical treatment for cubital tunnel syndrome. AB - : The aim of this study was to review the literature of decompression of the cubital tunnel with medial epicondylectomy and to assess outcomes and complications. Twenty-one case series reported on 886 medial epicondylectomies. The mean percentage of patients obtaining improvement of one or more McGowan grade was 79%. The mean percentage obtaining a good/excellent Wilson Krout grade of outcome was 83%. Of six comparative studies, two showed no significant differences in outcomes between medial epicondylectomy and transposition procedures, and three reported better outcomes with medial epicondylectomy. One reported similar outcomes with medial epicondylectomy and simple decompression. The existing literature on medial epicondylectomy is of limited methodological quality and does not allow for firm conclusions to be drawn regarding its efficacy compared with other surgical techniques. Further studies should aim for high methodological quality, randomized comparison with simple decompression or anterior transposition and should utilize standardized outcome measures. LEVEL OF EVIDENCE: II. PMID- 28856933 TI - Serum long noncoding RNA urothelial carcinoma-associated 1: A novel biomarker for diagnosis and prognosis of hepatocellular carcinoma. AB - Objective Long noncoding RNAs (lncRNAs) offer great potential as cancer biomarkers. This study was performed to assess the applicability of serum lncRNA urothelial carcinoma-associated 1 (UCA1) as a diagnostic and/or prognostic biomarker for hepatocellular carcinoma (HCC). Methods We examined UCA1 expression in serum samples from 105 patients with HCC, 105 patients with benign liver disease (BLD), and 105 healthy volunteers using reverse-transcription polymerase chain reaction and analyzed the relationship between serum UCA1 and clinicopathological parameters of HCC as well as survival. Results Expression of serum UCA1 was significantly higher in patients with HCC and allowed for discrimination of HCC from BLD and healthy controls. High expression of serum UCA1 was significantly associated with a high tumor grade, large tumor size, positive vascular invasion, and advanced TNM stage. Multivariate analysis revealed that a high serum UCA1 level was an independent unfavorable prognostic factor for HCC. Conclusions Our results confirm the upregulation of serum UCA1 expression in HCC and indicate its clinical value as a noninvasive biomarker for HCC screening and prognostic prediction. PMID- 28856935 TI - The use of dimethylsulfoxide as a solvent in enzyme inhibition studies: the case of aldose reductase. AB - Aldose reductase (AR) is an enzyme devoted to cell detoxification and at the same time is strongly involved in the aetiology of secondary diabetic complications and the amplification of inflammatory phenomena. AR is subjected to intense inhibition studies and dimethyl sulfoxide (DMSO) is often present in the assay mixture to keep the inhibitors in solution. DMSO was revealed to act as a weak but well detectable AR differential inhibitor, acting as a competitive inhibitor of the L-idose reduction, as a mixed type of non-competitive inhibitor of HNE reduction and being inactive towards 3-glutathionyl-4-hydroxynonanal transformation. A kinetic model of DMSO action with respect to differently acting inhibitors was analysed. Three AR inhibitors, namely the flavonoids neohesperidin dihydrochalcone, rutin and phloretin, were used to evaluate the effects of DMSO on the inhibition studies on the reduction of L-idose and HNE. PMID- 28856936 TI - The correlation between breast cancer and urinary iodine excretion levels. AB - Objective To compare urinary iodine excretion levels in patients with breast cancer and control subjects. Methods In this prospective pilot study, patients with breast cancer and normal controls were recruited. Age and menopausal status were recorded. Levels of serum thyroid-stimulating hormone, blood urea nitrogen and creatinine and urine iodine concentration (UIC) were measured. UIC levels were divided into three categories: low (<100 ug/l), normal (100-200 ug/l) or high (>200 ug/l). Results A total of 24 patients with breast cancer and 48 controls were included in the study. There were no statistically significant differences between the two groups with regard to thyroid-stimulating hormone, blood urea nitrogen or creatinine levels. When considered overall, there was no statistical difference in UIC between patients and controls. However, comparisons within each category (low, normal or high UIC) showed a significantly higher percentage of patients with breast cancer had a high UIC compared with controls. Conclusions A high UIC was seen in a significantly higher percentage of patients with breast cancer than controls. UIC may have a role as a marker for breast cancer screening. Further studies evaluating UIC and iodine utilization in patients with breast cancer are warranted. PMID- 28856937 TI - Ascorbyl palmitate-incorporated paclitaxel-loaded composite nanoparticles for synergistic anti-tumoral therapy. AB - A co-loaded drug delivery system based on ascorbyl palmitate that can transport various functional drugs to their targets within a tumor represents an attractive strategy for increasing the efficiency of anticancer treatment. In this study, we developed a dual drug delivery system to encapsulate ascorbyl palmitate (AP) and paclitaxel (PTX) for synergistic cancer therapy. AP, which is a vitamin C derivative, and PTX were incorporated into solid lipid nanoparticles (AP/PTX SLNs), which were used to treat murine B16F10 melanoma that had metastasized to the lungs of mice. These nanoparticles were spherical with an average size of 223 nm as measured by transmission electron microscope and dynamic light scattering. In vitro cytotoxicity assays indicated that the AP/PTX-SLNs with an AP/PTX mass ratio of 2/1 provided the optimal synergistic anticancer efficacy. In vivo, AP/PTX-SLNs were revealed to be much more effective in suppressing tumor growth in B16F10-bearing mice and in eliminating cancer cells in the lungs than single drug (AP or PTX)-loaded SLNs via a synergistic effect through reducing the Bcl 2/Bax ratio. Furthermore, no marked side effects were observed during the treatment with the AP/PTX-SLNs, indicating that the co-delivery system with ascorbyl palmitate holds promising clinical potential in cancer therapy. PMID- 28856938 TI - Antioxidant acetophenone glycosides from the roots of Euphorbia ebracteolata Hayata. AB - A new acetophenone diglycoside, 2,4-dihydroxy-6-methoxy-3-methyl-acetophenone 4-O gentiobioside (1), along with six know analogues (2-6), were isolated from the roots of Euphorbia ebracteolata. The structures of these isolates were determined by UV, HRESIMS, 1D and 2D NMR spectral analyses. In addition, all acetophenones showed moderate DPPH free radical scavenging capability, and no cytotoxicity against five human cancer cell lines. PMID- 28856939 TI - Three-dimensional morphological analysis of acromioclavicular joint in patients with and without subacromial erosion after hook plate fixation. AB - Objective To investigate the role of acromioclavicular joint morphology in the presence of subacromial erosion after hook plate fixation. Methods We retrospectively analyzed the clinical data of 36 patients (17 men, 19 women; mean age, 48.7 years; range, 21-76 years) treated with hook plate fixation for distal clavicular fractures (n = 20) or acromioclavicular joint dislocation (n = 16) from August 2011 to March 2013. The patients were divided into two groups: the subacromial erosion group (18 patients) and the normal group (18 patients). Differences in multiple anatomical parameters between the two groups were measured and compared. Results The distal clavicle-acromion angle was significantly larger in the subacromial erosion group (mean, 51.37 degrees +/- 5.59 degrees ) than in the normal group (mean, 44.20 degrees +/- 3.83 degrees ), as was the distal clavicle-coronal angle (mean, 25.44 degrees +/- 2.51 degrees vs. 21.67 degrees +/- 4.06 degrees , respectively). The thickness of the acromion was significantly different between men and women (9.72 +/- 1.13 vs. 8.16 +/- 1.89 mm, respectively). Conclusion The results of this study indicate that the distal clavicle-acromion angle and distal clavicle-coronal angle are closely correlated with the occurrence of subacromial erosion after hook plate fixation. PMID- 28856941 TI - Racial and Ethnic Disparities in Patient-Provider Communication With Breast Cancer Patients: Evidence From 2011 MEPS and Experiences With Cancer Supplement. AB - The current study explores racial/ethnic disparities in the quality of patient provider communication during treatment, among breast cancer patients. A unique data set, Medical Expenditure Panel Survey and Experiences With Cancer Supplement 2011, is used to examine this topic. Using measures of the quality of patient provider communication that patients are best qualified to evaluate, we explore the relationship between race/ethnicity and patients' perspectives on whether (1) patient-provider interactions are respectful, (2) providers are listening to patients, (3) providers provide adequate explanations of outcomes and treatment, and (4) providers spend adequate time in interacting with the patients. We also examine the relationship between race/ethnicity and patients' perspectives on whether their (1) doctor ever discussed need for regular follow-up care and monitoring after completing treatment, (2) doctor ever discussed long-term side effects of cancer treatment, (3) doctor ever discussed emotional or social needs related to cancer, and (4) doctor ever discussed lifestyle or health recommendations. Multivariate ordinary least squares and ordered logistic regression models indicate that after controlling for factors such as income and health insurance coverage, the quality of patient-provider communication with breast cancer patients varies by race/ethnicity. Non-Hispanic blacks experience the greatest communication deficit. Our findings can inform the content of future strategies to reduce disparities. PMID- 28856940 TI - Effects of human recombinant growth hormone on exercise capacity, cardiac structure, and cardiac function in patients with adult-onset growth hormone deficiency. AB - Objective Epidemiological studies suggest that adult-onset growth hormone deficiency (AGHD) might increase the risk of death from cardiovascular causes. Methods This was a 6-month double-blind, placebo-controlled, randomised, cross over trial followed by a 6-month open-label phase. Seventeen patients with AGHD received either recombinant human growth hormone (rGH) (0.4 mg injection daily) or placebo for 12 weeks, underwent washout for 2 weeks, and were then crossed over to the alternative treatment for a further 12 weeks. Cardiac magnetic resonance imaging, echocardiography, and cardiopulmonary exercise testing were performed at baseline, 12 weeks, 26 weeks, and the end of the open phase (12 months). The results were compared with those of 16 age- and sex-matched control subjects. Results At baseline, patients with AGHD had a significantly higher systolic blood pressure, ejection fraction, and left ventricular mass than the control group, even when corrected for body surface area. Treatment with rGH normalised the insulin-like growth factor 1 concentration without an effect on exercise capacity, cardiac structure, or cardiac function. Conclusion Administration of rGH therapy for 6 to 9 months failed to normalise the functional and structural cardiac differences observed in patients with AGHD when compared with a control group. PMID- 28856942 TI - Work/Family Balancing and 24/7 Work Schedules: Network Analysis of Strategies in a Transport Company Cleaning Service: Concilier travail-famille et horaires 24/7: analyse reseau des strategies au sein du service de nettoyage d'une compagnie de transport. AB - Whether or not official work/family balance measures exist within an organization, scheduling accommodations often go through informal channels involving colleagues and superiors and are negotiated within interpersonal relationships. This study examines the relationship dimensions of the scheduling strategies of cleaners working atypical hours in the transport sector through the lenses of ergonomic activity, network, and gender analyses. Using semi-directed interviews, observation, and network analysis, we revealed the effect of gender on relationship dynamics and the influence of these dynamics on work/family balance strategies deployed by cleaners. One of the main contributions of this study is to demonstrate the decisive effect of relationships by revealing inequalities in access to organizational social networks. Creating spaces to discuss work/family balancing and a more equitable circulation of information could contribute to reducing inequalities associated with gender, social status, and family responsibilities and support the work/family strategies developed by workers dealing with restrictive work schedules. Resume Les accommodements du temps de travail pour la conciliation travail-famille (CTF) passent souvent par des ententes informelles qui s'inscrivent dans les relations entre collegues ou avec des gestionnaires. Notre etude, integrant l'ergonomie et la communication dans une perspective de genre, porte sur les dimensions relationnelles des strategies de choix d'horaire d'agentes et agents de nettoyage devant composer avec des horaires atypiques dans le secteur des transports. A partir d'entretiens semi-diriges, d'observations et d'analyse de reseaux, nous avons pu observer l'influence des dynamiques relationnelles, notamment de genre, sur les strategies de CTF. Un apport central de cette etude est de montrer l'effet structurant des relations en revelant notamment des inegalites dans l'acces aux ressources facilitant le choix d'horaire, mais aussi dans l'inclusion au sein du reseau de relations. L'article conclut en proposant des pistes de solutions concretes pour la reduction de ces inegalites. PMID- 28856943 TI - Probing voltage sensing domain of KCNQ2 channel as a potential target to combat epilepsy: a comparative study. AB - Multidrug resistance along with side-effects of available anti-epileptic drugs and unavailability of potent and effective agents in submicromolar quantities presents the biggest therapeutic challenges in anti-epileptic drug discovery. The molecular modeling techniques allow us to identify agents with novel structures to match the continuous urge for its discovery. KCNQ2 channel represents one of the validated targets for its therapy. The present study involves identification of newer anti-epileptic agents by means of a computer-aided drug design adaptive protocol involving both structure-based virtual screening of Asinex library using homology model of KCNQ2 and 3D-QSAR based virtual screening with docking analysis, followed by dG bind and ligand efficiency calculations with ADMET studies, of which 20 hits qualified all the criterions. The best ligands of both screenings with least potential for toxicity predicted computationally were then taken for molecular dynamic simulations. All the crucial amino acid interactions were observed in hits of both screenings such as Glu130, Arg207, Arg210 and Phe137. Robustness of docking protocol was analyzed through Receiver operating characteristic (ROC) curve values 0.88 (Area under curve AUC = 0.87) in Standard Precision and 0.84 (AUC = 0.82) in Extra Precision modes. Novelty analysis indicates that these compounds have not been reported previously as anti epileptic agents. PMID- 28856944 TI - Inhibition of human cytochromes P450 2A6 and 2A13 by flavonoids, acetylenic thiophenes and sesquiterpene lactones from Pluchea indica and Vernonia cinerea. AB - The human liver cytochrome P450 (CYP) 2A6 and the respiratory CYP2A13 enzymes play role in nicotine metabolism and activation of tobacco-specific nitrosamine carcinogens. Inhibition of both enzymes could offer a strategy for smoking abstinence and decreased risks of respiratory diseases and lung cancer. In this study, activity-guided isolation identified four flavonoids 1-4 (apigenin, luteolin, chrysoeriol, quercetin) from Vernonia cinerea and Pluchea indica, four hirsutinolide-type sesquiterpene lactones 5-8 from V. cinerea, and acetylenic thiophenes 9-11 from P. indica that inhibited CYP2A6- and CYP2A13-mediated coumarin 7-hydroxylation. Flavonoids were most effective in inhibition against CYP2A6 and CYP2A13, followed by thiophenes, and hirsutinolides. Hirsutinolides and thiophenes exhibited mechanism-based inhibition and in irreversible mode against both enzymes. The inactivation kinetic KI values of hirsutinolides against CYP2A6 and CYP2A13 were 5.32-15.4 and 0.92-8.67 uM, respectively, while those of thiophenes were 0.11-1.01 and 0.67-0.97 uM, respectively. PMID- 28856945 TI - Bespoke versus off-the-shelf ankle-foot orthosis for people with stroke: randomized controlled trial. AB - OBJECTIVE: The aim of the study was to compare the effect of two designs of ankle foot orthosis on people with stroke. DESIGN: The study design was an assessor blind, multicentre randomized controlled trial. SETTING: The setting was community stroke services. PARTICIPANTS: A total of 139 community-dwelling stroke survivors with limited mobility were recruited. INTERVENTIONS: The two most commonly used types of ankle-foot orthosis (bespoke and off-the-shelf) were chosen. MAIN MEASURES: The main measures of the study were as follows: short- (6 weeks) and long-term (12 weeks) effects on stroke survivors' satisfaction; adverse events; mobility (Walking Handicap Scale); fear of falling (Falls Efficacy Scale-International (FES-I)) and walking impairments (gait speed and step length using the 5-m walk test). RESULTS: Long-term satisfaction was non significantly higher in the off-the-shelf group: 72% versus 64%; OR (95% CI) = 0.64 (0.31 to 1.3); P = 0.21. No statistically significant differences were found between the orthoses except that the off-the-shelf group had less fear of falling at short-term follow-up than the bespoke group: mean difference (95% CI) = -4.6 ( 7.6 to -1.6) points on the FES-I; P = 0.003. CONCLUSION: No differences between off-the-shelf and bespoke ankle-foot orthoses were found except that participants in the off-the-shelf orthosis group had less fear of falling at short-term follow up. PMID- 28856946 TI - Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review. AB - Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 * 109/L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient's serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4 dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 * 109/L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 * 109/L by POD45 and 199 * 109/L by POD79. The patient's serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1 1.2 MUg/mL, i.e., in vitro fondaparinux "cross-reactivity"). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT. PMID- 28856948 TI - Embodied valuation: Directional action is associated with item values. AB - We have a lifetime of experience interacting with objects we value. Although many economic theories represent valuation as a purely cognitive process independent of the sensorimotor system, embodied cognitive theory suggests that our memories for items' value should be linked to actions we use to obtain them. Here, we investigated whether the value of real items was associated with specific directional movements toward or away from the body. Participants priced a set of food items to determine their values; they then used directional actions to classify each item as high- or low-value. To determine if value is linked to specific action mappings, movements were referenced either with respect to the object (push toward high-value items; pull away from low-value items) or the self (pull high-value items toward self; push low-value items away). Participants who were assigned (Experiment 1) or chose (Experiment 2) to use an object-referenced action mapping were faster than those using a self-referenced mapping. A control experiment (Experiment 3) using left/right movements found no such difference when action mappings were not toward/away from the body. These results indicate that directional actions toward items are associated with the representation of their value, suggesting an embodied component to economic choice. PMID- 28856949 TI - Impression or expression? The influence of self-monitoring on the social modulation of motor contagion. AB - Social primes (pro-social, anti-social) can modulate mimicry behaviour. To date, these social modulation effects have been explained by the primed incentive to affiliate with another (Social Top-Down Response Modulation; STORM) and the primed active-self-concept leading to behaviour that is either consistent or inconsistent with the primed-construct (Active-Self account). This study was designed to explore the explanatory power of each of these accounts and thereby gain a greater understanding of how social modulation unfolds. To do this, we assessed social modulation of motor contagion in individuals high or low in self monitoring. It was reasoned that high self-monitors would modulate mimicry according to the primed social incentive, whereas low self-monitors would modulate according to the primed active-self-concept. Participants were primed with a pro-social and anti-social cue in the first-person and third-person perspective. Next, they completed an interpersonal observation-execution task featuring the simultaneous observation and execution of arm movements that were either congruent or incongruent to each other. Results showed increased incongruent movement deviation (motor contagion) for the anti-social compared to the pro-social prime in the high self-monitors only. Findings support the STORM account of mimicry by showing observers modulate behaviour based on the social incentive underpinning an interpersonal exchange. PMID- 28856950 TI - Thinking About Cognitive Function: Perceptions of Cognitive Changes in People With Type 2 Diabetes. AB - Purpose The purpose of this study is 2-fold: (1) to explore how people with diabetes view diabetes-related cognitive problems and (2) to examine participants' ideas on a cognitive rehabilitation intervention to adapt it for persons diagnosed with type 2 diabetes (T2DM). Methods A qualitative descriptive study based on narrative interviews was conducted with adults (n = 10) with T2DM. The interview data were analyzed using content analysis. Results The interviews reflected 4 major themes: search for advice regarding cognitive complaints, cognitive symptoms, impact of perceived cognitive dysfunction on diabetes self management, and maintenance of cognitive health. Specific areas of interest for an intervention included the following: understanding how cognitive function relates to diabetes, dealing with cognitive barriers to self-management, and learning how to incorporate a "brain healthy" lifestyle into daily activities. Conclusions Findings showed that perceived cognitive impairment impacted self management and suggested that cognitive rehabilitation interventions have potential utility for people with T2DM. Existing successful interventions can be tailored to meet the needs of those whose diabetes self-management is impacted by cognitive problems. PMID- 28856951 TI - A controversy of whether the early C1 ERP is affected by attention. AB - This commentary raises three broad questions regarding the Baumgartner et al. (this issue) paper. Topic 1 is about how to deal with the different outcomes of Kelly, Gomez-Ramirez & Foxe and Baumgartner et al. The methodologies were almost identical yet different results were found. Topic 2 is about statistical issues regarding how to present this type of data. Topic 3 is concerned with the issue of EEG/MEG source localization and whether the C1 component is mainly V1. PMID- 28856952 TI - Different representations and strategies in mental rotation. AB - It is still debated whether holistic or piecemeal transformation is applied to carry out mental rotation (MR) as an aspect of visual imagery. It has been recently argued that various mental representations could be flexibly generated to perform MR tasks. To test the hypothesis that imagery ability and types of stimuli interact to affect the format of representation and the choice of strategy in performing MR task, participants, grouped as good or poor imagers, were assessed using four MR tasks, comprising two sets of 'Standard' cube figures and two sets of 'non-Standard' ones, designed by withdrawing cubes from the Standard ones. Both good and poor imagers performed similarly under the two Standard conditions. Under non-Standard conditions, good imagers performed much faster in non-Standard objects than Standard ones, whereas poor imagers performed much slower in non-Standard objects than Standard ones. These results suggested that (1) individuals did not differ in processing the integrated Standard object, whereas (2) in processing the non-Standard objects, various visual representations and strategies could be applied in MR by diverse individuals: Good imagers were more flexible in generating different visual representations, whereas poor imagers applied different strategies under different task demands. PMID- 28856953 TI - Predictors of Continuing Bonds Among Bereaved Adolescents. AB - This study examined the relationship between continuing bonds (CBs) among 50 bereaved youth (ages 11-17) and their bereaved adult caregivers, and predictors of CBs among youth. Results indicated there was not a significant relationship between caregiver CB and youth CB. However, significant relationships were found between youth bereavement symptomatology, their relationship to the deceased, and youth CB. Specifically, youth with higher levels of symptomatology and those who lost an immediate family member were more likely to maintain CBs. Results suggest the need for practitioners to incorporate grief symptomatology and CBs in assessment and intervention with bereaved youth. PMID- 28856954 TI - 2017 National Standards for Diabetes Self-Management Education and Support (DSMES): Revised and Updated. PMID- 28856955 TI - Long-term pitch memory for music recordings is related to auditory working memory precision. AB - Most individuals have reliable long-term memories for the pitch of familiar music recordings. This pitch memory (1) appears to be normally distributed in the population, (2) does not depend on explicit musical training and (3) only seems to be weakly related to differences in listening frequency estimates. The present experiment was designed to assess whether individual differences in auditory working memory could explain variance in long-term pitch memory for music recordings. In Experiment 1, participants first completed a musical note adjustment task that has been previously used to assess working memory of musical pitch. Afterward, participants were asked to judge the pitch of well-known music recordings, which either had or had not been shifted in pitch. We found that performance on the pitch working memory task was significantly related to performance in the pitch memory task using well-known recordings, even when controlling for overall musical experience and familiarity with each recording. In Experiment 2, we replicated these findings in a separate group of participants while additionally controlling for fluid intelligence and non-pitch-based components of auditory working memory. In Experiment 3, we demonstrated that participants could not accurately judge the pitch of unfamiliar recordings, suggesting that our method of pitch shifting did not result in unwanted acoustic cues that could have aided participants in Experiments 1 and 2. These results, taken together, suggest that the ability to maintain pitch information in working memory might lead to more accurate long-term pitch memory. PMID- 28856956 TI - Semantic and phonological schema influence spoken word learning and overnight consolidation. AB - We studied the initial acquisition and overnight consolidation of new spoken words that resemble words in the native language (L1) or in an unfamiliar, non native language (L2). Spanish-speaking participants learned the spoken forms of novel words in their native language (Spanish) or in a different language (Hungarian), which were paired with pictures of familiar or unfamiliar objects, or no picture. We thereby assessed, in a factorial way, the impact of existing knowledge (schema) on word learning by manipulating both semantic (familiar vs unfamiliar objects) and phonological (L1- vs L2-like novel words) familiarity. Participants were trained and tested with a 12-hr intervening period that included overnight sleep or daytime awake. Our results showed (1) benefits of sleep to recognition memory that were greater for words with L2-like phonology and (2) that learned associations with familiar but not unfamiliar pictures enhanced recognition memory for novel words. Implications for complementary systems accounts of word learning are discussed. PMID- 28856957 TI - Situational relevance: Context as a factor in serial overshadowing of taste aversion learning. AB - In a serial overshadowing procedure a target stimulus, A, is followed after an interval by a potentially interfering stimulus, B, and this is then followed by an unconditioned stimulus, US. Revusky (1977) proposed that the degree to which B overshadows conditioning of A depends on whether or not the two events take place in the same context. To test this proposal two experiments used a 1-trial long delay conditioned taste aversion (CTA) procedure; sucrose served as the target taste (A) and dilute hydrochloric acid (HCl) as the overshadowing taste (B), with lithium chloride injection providing the US. In Experiment 1 these tastes were novel; weaker overshadowing by HCl of an aversion to sucrose was found when the two tastes were presented in different contexts. Experiment 2 tested whether the effect of pre-exposure to HCl, thereby rendering it less effective in overshadowing a sucrose aversion, was also context-dependent. In the conditioning session rats again received either context-same or context-different presentations of sucrose and HCl. However, for some rats HCl was pre-exposed in the same context to which it was later presented during conditioning (Consistent), while others were pre-exposed to HCl in a different context to the one in which it was presented during conditioning (Inconsistent). The Inconsistent group produced greater overshadowing than the Consistent group and thus confirmed that the latent inhibition effect was also context dependent. This study supports Revusky's (1977) idea of situational relevance. PMID- 28856958 TI - Understanding Social Isolation Among Urban Aging Adults: Informing Occupation Based Approaches. AB - Socially isolated aging adults are at risk of poor health and well-being. Occupational therapy can help address this issue; however, information is needed to guide such work. National surveys characterize social isolation in populations of aging adults but fail to provide meaningful information at a community level. The objective of this study is to describe multiple dimensions of social isolation and related factors among aging adults in diverse urban neighborhoods. Community-based participatory research involving a door-to-door survey of adults 50 years and older was used. Participants ( N = 161) reported social isolation in terms of small social networks (24%) and wanting more social engagement (43%). Participants aged 50 to 64 years reported the highest levels of isolation in most dimensions. Low income, poor health, lack of transportation, and infrequent information access appeared linked to social isolation. Occupational therapists can address social isolation in similar urban communities through policy and practice that facilitate social engagement and network building. PMID- 28856959 TI - Structural priming from arithmetic to language in Chinese: Evidence from adults and children. AB - This article explores structural integration between arithmetic and language by investigating whether the structure of an arithmetic equation influences the way children and adults interpret Chinese sentences in the form of NP1 + VP1 + NP2 + VP2, where VP2 can attach high as a predicate of NP1 or attach low as a predicate of NP2. Participants first solved an arithmetic problem where the last number was to be attached high (e.g., (5 + 1 + 2) * 3) or low (e.g., 5 + (1 + 2 * 3)) and then provided a completion to a preamble in the form of NP1 + VP1 + NP2 + HEN "very" . . . or decided on the meaning of an ambiguous sentence. The way the ambiguous sentences were completed and interpreted was primed by the structure of the preceding arithmetic problem (i.e., a high-attachment prime led to more high-attachment completions and interpretation) in both children and adults. This study found cross-domain priming from arithmetic equations to language, which offered empirical evidence for the shared syntactic integration resource hypothesis and the syntactic working memory theory. It was also found that children were more susceptible to such priming, which provided some tentative evidence for the Incremental Procedural Account proposed by Scheepers et al. PMID- 28856960 TI - Task Oriented Training and Evaluation at Home. AB - Principles of experience-dependent plasticity, motor learning theory, and the theory of Occupational Adaptation coalesce into a translational model for practice in neurorehabilitation. The objective of this study was to explore the effectiveness of a Task Oriented Training and Evaluation at Home (TOTE Home) program completed by people with subacute stroke, and whether effects persisted 1 month after this training. A single-subject design included a maximum of 30, 1hour sessions of training conducted in participants' homes. Repeated target measures of accelerometry and level of confidence were used to assess movement and confidence in weaker arm use through baseline, intervention, and follow-up phases of TOTE Home. Four participants completed TOTE Home and each demonstrated improvement in movement and confidence in function. The degree of improvement varied between participants, but a detectable change was evident in outcome measures. TOTE Home, using client-centered, salient tasks not only improved motor function but also facilitated an adaptive response demonstrated in continued improvement beyond the intervention. PMID- 28856961 TI - Effects of model types in observational learning on implicit sequential learning. AB - This study investigated whether implicit learning of sequence by observation occurred in a serial reaction time task and whether the learning effects were modulated by model behavioral type. In Experiment 1, we let 20 participants perform a sequence for 12 blocks and chose the best and worst performance models based on reaction time and errors. In Experiment 2, new observers viewed a movie clip chosen from the following three: the best model performing the sequential task in the first (the first six blocks) or second session (the last six blocks), or the worst model performing the task in the first session. Then, the observers performed the observed sequence, a test sequence and awareness test. We found that (1) implicit sequential learning occurred by observation regardless of model behavior type, (2) the learning effects were not susceptible to model behavior type and (3) speed index reflecting reaction time became larger even in the test session when the observers viewed the best model performing the second session. Overall, observers developed general motor representations through action observation. In addition, their responses were also contagious; if the model performed the sequence faster, the observer might be able to perform the sequence faster. PMID- 28856962 TI - Do delayed judgements of learning reduce metamemory illusions? A meta-analysis. AB - Past research has shown that the perceptual characteristics of studied items (e.g., font size) lead to a metamemory illusion, and that delayed judgements of learning (JOLs) are better predictors of memory performance than immediate JOLs. Here, we tested whether delayed JOLs could reduce or eliminate the effect of perceptual characteristics on JOLs and restudy decisions. We adopted a meta analytic approach and analysed the results of 28 experiments in which participants' studied items were presented in either large or small font. JOLs and, sometimes, restudy decisions were collected either immediately or after a delay. Finally, participants completed a memory test. The results of the meta analyses confirmed the effect of the font size on JOLs and restudy decisions. The delayed procedures reliably reduced the effect of perceptual characteristics on JOLs, but the effect was still significant after a delay. For restudy decisions, delayed procedures only reduced numerically the effect. Surprisingly, the meta analysis also showed a very subtle memory advantage for items presented in large font over small font, although no individual study showed a significant difference and the overall effect size was small. One plausible explanation is that after a delay, information about font size is not available for some items, causing a reduction in the effect. Moreover, our results suggest that the dissociation between memory and metamemory reported previously may not be dissociation at all, but a mistmatched effect of font size on memory and metamemory. PMID- 28856963 TI - Performance on a 1-week delayed recall task is associated with medial temporal lobe structures in neurologically normal older adults. AB - OBJECTIVE: Traditional episodic memory tests employ a delayed recall length ranging from 10 to 30 min. The neurobiological process of memory consolidation extends well beyond these time intervals, however, raising the possibility that these tests might not be fully sensitive to the subtle neurocognitive changes found in early disease or age-related decline. We aimed to determine the sensitivity of a 1-week delayed recall paradigm to medial temporal lobe (MTL) structure among neurologically normal older adults. METHODS: One hundred and forty functionally intact, older adults (mean age = 75.8) completed a story recall test in which participants learned to 90% criterion. Recall was tested after 30-min and 1-week. Participants also completed a standardized list learning task with a 20-min delay (n = 129) and a structural brain MRI. The MTL, including the parahippocampal gyrus, hippocampus, and entorhinal, was our primary region of interest. RESULTS: Controlling for age, education, gender and total intracranial volume, the standard 20- and 30-min recalls showed no significant relationship with MTL. In contrast, 1-week recall was uniquely associated with MTL structure (partial r = .24, p = .006), specifically entorhinal (partial r = .27; p = .001) and hippocampal (partial r = .21, p = .02) volumes. CONCLUSION: Memory paradigms that utilize 1-week delays are more sensitive than standard paradigms to MTL volumes in neurologically normal older adults. Longer delay periods may improve detection of memory consolidation abilities associated with age-related, and potentially pathological, neurobehavioral change. PMID- 28856964 TI - A preliminary study on characterisation of finger interface kinetics using a pressure and shear sensor system. AB - BACKGROUND: Our hands constantly handle objects throughout our lives, where a crucial component of this interaction is the detection of grasping (pressure) and slipping (shear) of the object. While there have been a large amount of studies using pressure sensors for grasping detection, synchronised pressure and shear detection at the finger/object interface is still needed. OBJECTIVES: This study aims to assess the feasibility of a sensor system designed to detect both pressure and shear at the fingertip/object interface via a single subject test. STUDY DESIGN: Descriptive study, proof of concept. METHODS: One healthy subject participated in the study and was asked to perform a single finger test protocol and a simple hand test protocol. The corresponding multidirectional loads at the fingertip/object interface were measured in real time using a pressure and shear sensor system. RESULTS: Results from the finger test protocol show peak values of up to approximately 50 kPa (5 N) and 30 kPa (3 N) of pressure for each test, respectively. Results from the hand test protocol show a pressure and shear profile that shows a large increase in grip force during the initial grasping of the object, with a peak pressure of approximately 50 kPa (5 N). The pressure and shear profile demonstrates that the load is not evenly distributed across all digits. CONCLUSION: This study provides evidence that the reported sensor system has sufficient resolution, dynamic response and load capability to capture biomechanical information during basic protocols and hand-grasping tasks. Clinical relevance The presented sensor system could be potentially used as a tool for measuring and evaluating hand function and could be incorporated into a prosthetic hand as a tactile feedback system. PMID- 28856966 TI - Rapid response learning of brand logo priming: Evidence that brand priming is not dominated by rapid response learning. AB - Repetition priming increases the accuracy and speed of responses to repeatedly processed stimuli. Repetition priming can result from two complementary sources: rapid response learning and facilitation within perceptual and conceptual networks. In conceptual classification tasks, rapid response learning dominates priming of object recognition, but it does not dominate priming of person recognition. This suggests that the relative engagement of network facilitation and rapid response learning depends on the stimulus domain. Here, we addressed the importance of the stimulus domain for rapid response learning by investigating priming in another domain, brands. In three experiments, participants performed conceptual decisions for brand logos. Strong priming was present, but it was not dominated by rapid response learning. These findings add further support to the importance of the stimulus domain for the relative importance of network facilitation and rapid response learning, and they indicate that brand priming is more similar to person recognition priming than object recognition priming, perhaps because priming of both brands and persons requires individuation. PMID- 28856967 TI - Comparative evaluation of blood salvage techniques in patients undergoing cardiac surgery with cardiopulmonary bypass. AB - BACKGROUND: The primary objective of this study was to test and compare the efficacy of currently available intraoperative blood salvage systems via a demonstration of the level of increase in percentage concentration of red blood cells (RBC), white blood cells 9WBC) and platelets (Plt) in the end product. METHODS: In a prospective, randomized study, data of 80 patients undergoing elective cardiac surgery with cardiopulmonary bypass in a 6-month period was collected, of which the volume aspirated from the surgical field was processed by either the HemoSep Novel Collection Bag (Advancis Surgical, Kirkby-in-Ashfield, Notts, UK) (N=40) (Group 1) or a cell- saver (C.A.T.S Plus Autotransfusion System, Fresenius Kabi, Bad Homburg, Germany) (N=40) (Group 2). RESULTS: Hematocrit levels increased from 23.05%+/-2.7 to 43.02%+/-12 in Group 1 and from 24.5+/-2 up to 55.2+/-9 in Group 2 (p=0.013). The mean number of platelets rose to 225200+/-47000 from 116400 +/-40000 in the HemoSep and decreased from 125200+/ 25000 to 96500+/-30000 in the cell-saver group (p=0.00001). The leukocyte count was concentrated significantly better in Group 1 (from 10100+/-4300 to 18120+/ 7000; p=0.001). IL-6 levels (pg/dL) decreased from 223+/-47 to 83+/-21 in Group 1 and from 219+/-40 to 200+/-40 in Group 2 (p=0.001). Fibrinogen was protected significantly better in the HemoSep group (from 185+/-35 to 455+/-45; p=0.004). CONCLUSIONS: Intraoperative blood salvage systems functioned properly and the resultant blood product was superior in terms of red blood cell species. The HemoSep group had significantly better platelet and leukocyte concentrations and fibrinogen content. PMID- 28856968 TI - Estimating the Prevalence of Serious Mental Illness and Dementia Diagnoses Among Medicare Beneficiaries in the Health and Retirement Study. AB - OBJECTIVE: To estimate the prevalence of serious mental illness and dementia among Medicare beneficiaries in the Health and Retirement Study (HRS). METHODS: This study utilizes HRS-linked Medicare claims data sets and inverse probability weighting to estimate overall and age-specific cumulative prevalence rates of dementia and serious mental illnesses among 18,740 Medicare beneficiaries. Two way tabulations determine conditional probabilities of dementia diagnoses among beneficiaries diagnosed with specific mental illnesses, and binary logistic regressions determine conditional probabilities of dementia diagnoses among beneficiaries diagnosed with specific mental illnesses, controlling for covariates. RESULTS: Weighted prevalence estimates for dementia, schizophrenia (SZP), bipolar disorder (BPD), and major depressive disorder (MDD) are similar to previous studies. Odds of dementia diagnosis are significantly greater for beneficiaries diagnosed with SZP, BPD, or MDD. CONCLUSIONS: Co-occurring mental disabilities require further investigation, as in the near future increasing numbers of mentally ill older adults will need appropriate and affordable community-based services and supports. PMID- 28856969 TI - An Embodied and Intersubjective Practice of Occupational Therapy. AB - The literature on clinical reasoning tends to ignore the context and the interaction between patient and therapist. This article outlines a theoretical foundation for an extended mode of clinical reasoning in occupational therapy. Cognitive theories of human action, as well as narrative and instrumental approaches, provide an insufficient picture of the nature of clinical reasoning in occupational therapy practice. An embodied intersubjective clinical reasoning can function as an adjunct to traditional clinical reasoning in occupational therapy practice and is discussed through the concepts of the ambiguous body, incorporation of things, and the process of shared meaning-making. This mode of reasoning can help occupational therapy practitioners to be aware of how they influence the patient's perception of body, self, and world. It can promote a better understanding of details in embodied performances and in the co construction of meaning, positively influencing occupation, participation, and health. PMID- 28856970 TI - Word skipping: effects of word length, predictability, spelling and reading skill. AB - Readers eyes often skip over words as they read. Skipping rates are largely determined by word length; short words are skipped more than long words. However, the predictability of a word in context also impacts skipping rates. Rayner, Slattery, Drieghe and Liversedge (2011) reported an effect of predictability on word skipping for even long words (10-13 characters) that extend beyond the word identification span. Recent research suggests that better readers and spellers have an enhanced perceptual span (Veldre & Andrews, 2014). We explored whether reading and spelling skill interact with word length and predictability to impact word skipping rates in a large sample (N=92) of average and poor adult readers. Participants read the items from Rayner et al. (2011) while their eye movements were recorded. Spelling skill (zSpell) was assessed using the dictation and recognition tasks developed by Sally Andrews and colleagues. Reading skill (zRead) was assessed from reading speed (words per minute) and accuracy of three 120 word passages each with 10 comprehension questions. We fit linear mixed models to the target gaze duration data and generalized linear mixed models to the target word skipping data. Target word gaze durations were significantly predicted by zRead while, the skipping likelihoods were significantly predicted by zSpell. Additionally, for gaze durations, zRead significantly interacted with word predictability as better readers relied less on context to support word processing. These effects are discussed in relation to the lexical quality hypothesis and eye movement models of reading. PMID- 28856971 TI - A comparison of the effects of invasive mechanic ventilation/surfactant therapy and non-invasive nasal-continuous positive airway pressure in preterm newborns. AB - AIMS: This study compared the early-term outcomes of mechanical ventilation (MV)/surfactant treatment with nasal-continuous positive airway pressure (nCPAP) in preterm infants with respiratory distress syndrome (RDS). MATERIALS AND METHODS: Data from newborns born between >=24 and <=32 weeks of gestation, hospitalized at our newborn intensive care unit, and diagnosed with RDS between January 2009 and February 2012 were analyzed. RESULTS: Of 193 newborns with RDS who were enrolled in the study, 113 were treated with nCPAP and 80 with MV at a level of 57.5% of nCPAP. Within the study group, 46.3% of the infants were female. The mean gestation of the continuous positive airway pressure (CPAP) group was 29.07 +/- 1.99 weeks; that of the MV group was 28.61 +/- 2.01 weeks. The birth weight was 1321.1 +/- 325.4 g and 1240.3 +/- 366.1 g; however, the difference between the two groups was not significant. MV was not required in 54.9% of the patients with nCPAP treatment. Bronchopulmonary dysplasia (BPD) developed in 20 (18.7%) patients in the nCPAP group and 18 (24.4%) patients in the MV group; the difference was not significant (p = .351). Between 2009 and 2012, nCPAP was used at a rate of 33.9, 70.8, 68.4, and 69%. The risk factors for developing BPD were low gestation week, duration of intubation, and proven sepsis (p = .0001, p = .004, and p = .011, respectively). CONCLUSIONS: Early nCPAP treatment in preterm infants (<=32 weeks of gestation) decreases both the need for MV and the use of surfactant, but without a significant effect on BPD development. (No. 2016/324). PMID- 28856972 TI - Elastography methods for the non-invasive assessment of portal hypertension. AB - INTRODUCTION: The gold standard to assess the presence and severity of portal hypertension remains the hepatic vein pressure gradient, however the recent development of non-invasive assessment using elastography techniques offers valuable alternatives. In this review, we discuss the diagnostic accuracy and utility of such techniques in patients with portal hypertension due to cirrhosis. Areas covered: A literature search focused on liver and spleen stiffness measurement with different elastographic techniques for the assessment of the presence and severity of portal hypertension and oesophageal varices in people with chronic liver disease. The combination of elastography with parameters such as platelet count and spleen size is also discussed. Expert commentary: Non invasive assessment of liver fibrosis and portal hypertension is a validated tool for the diagnosis and follow-up of patients. Baveno VI recommended the combination of transient elastography and platelet count for ruling out varices needing treatment in patients with compensated advanced chronic liver disease. Assessment of aetiology specific cut-offs for ruling in and ruling out clinically significant portal hypertension is an unmet clinical need. The incorporation of spleen stiffness measurements in non-invasive algorithms using validated software and improved measuring scales might enhance the non-invasive diagnosis of portal hypertension in the next 5 years. PMID- 28856973 TI - The impact of Fc gamma receptor IIa and IIIa gene polymorphisms on the therapeutic response of rituximab in Egyptian adult immune thrombocytopenic purpura. AB - Background In chronic immune thrombocytopenic purpura (ITP), rituximab removes the harmful autoantibodies through antibody-dependent cellular cytotoxicity. The response to rituximab in ITP is variable; the effectiveness of rituximab is influenced by the process of activation of effector fragment C gamma receptors (FcgammaRs). Genetic factors may affect the response to rituximab. Objectives The influence of FcgammaRIIa (H131R) and FcgammaRIIIa (V158F) gene polymorphisms on the response to rituximab in ITP. Methods One hundred ITP patients were genotyped for FcgammaRIIa (H131R) and FcgammaRIIIa (V158F) gene polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism assay. The response at the end of the third month was assessed by direct platelets count. Polymorphisms were analyzed in relation to the response. Results The mean platelets count at end of weeks 1-4 of rituximab was statistically significantly higher in patients who achieved complete response (CR) than partial response or no response (P-value = .001). Although RR (44.4%) and HR (38.9%) genotypes were observed to be higher in patients who achieved CR compared with the wild (HH) genotype (16.7%), it was not statistically significantly different (P-value = .648). Conclusion The higher platelet count achieved early is predictive for a better response to rituximab later. FCgammaRIIA polymorphisms did not significantly influence response to rituximab in ITP. PMID- 28856974 TI - Experiences of using a participatory action research approach to strengthen district local capacity in Eastern Uganda. AB - BACKGROUND: To achieve a sustained improvement in health outcomes, the way health interventions are designed and implemented is critical. A participatory action research approach is applauded for building local capacity such as health management. Thereby increasing the chances of sustaining health interventions. OBJECTIVE: This study explored stakeholder experiences of using PAR to implement an intervention meant to strengthen the local district capacity. METHODS: This was a qualitative study featuring 18 informant interviews and a focus group discussion. Respondents included politicians, administrators, health managers and external researchers in three rural districts of eastern Uganda where PAR was used. Qualitative content analysis was used to explore stakeholders' experiences. RESULTS: 'Being awakened' emerged as an overarching category capturing stakeholder experiences of using PAR. This was described in four interrelated and sequential categories, which included: stakeholder involvement, being invigorated, the risk of wide stakeholder engagement and balancing the risk of wide stakeholder engagement. In terms of involvement, the stakeholders felt engaged, a sense of ownership, felt valued and responsible during the implementation of the project. Being invigorated meant being awakened, inspired and supported. On the other hand, risks such as conflict, stress and uncertainty were reported, and finally these risks were balanced through tolerance, risk awareness and collaboration. CONCLUSIONS: The PAR approach was desirable because it created opportunities for building local capacity and enhancing continuity of interventions. Stakeholders were awakened by the approach, as it made them more responsive to systems challenges and possible local solutions. Nonetheless, the use of PAR should be considered in full knowledge of the undesirable and complex experiences, such as uncertainty, conflict and stress. This will enable adequate preparation and management of stakeholder expectations to maximize the benefits of the approach. PMID- 28856975 TI - Why do women not adhere to advice on maternal referral in rural Tanzania? Narratives of women and their family members. AB - BACKGROUND: In most low-income countries, many women with high-risk pregnancies and complications do not reach the referral hospitals despite the provision of referral advice. OBJECTIVE: To explore how antenatal maternal referral advice is understood and handled in a rural Tanzanian community. METHODS: Individual in depth interviews were conducted with six women who did not go to hospital and 13 people who were involved in the referral advice. Narrative analysis was used to describe and create meanings out of the decision-making process. RESULTS: In all interviews, not following the referral advice was greatly influenced by close family members. Three main traits of how referral advice was understood emerged: convinced referral is not necessary, accepting referral advice but delayed by others, and passive and moving with the wind. The main reasons given for declining the referral advice included discrediting midwives' advice, citing previous successful deliveries despite referral advice; being afraid of undergoing surgery; lack of support for care of siblings at home; and high costs incurred during referral. CONCLUSIONS: Declining maternal referral advice centred around the pregnant women's position and their dependence on the family members around them, with a decreased ability to show autonomy. If they were socially and economically empowered, women could positively influence decision making during maternal referrals. PMID- 28856976 TI - An Accident-Prone Employee: No, Multiple Sclerosis. AB - An employee is labeled "accident-prone," and sustained an acute lumbar injury at work. Upon physical examination, a diagnosis of multiple sclerosis was suspected. She was referred to a public health clinic for further evaluation. This is a review article of multiple sclerosis and workplace interventions. PMID- 28856977 TI - Nurses' Perceptions of Their Foot Health: Implications for Occupational Health Care. AB - Nursing practice includes static standing and much walking causing strains to lower extremities. However, little is known about nurses' foot health and particularly their perceptions of their foot health. Therefore, in this study operating room nurses' perceptions of their foot health was investigated and promoting and hindering factors were identified. In total, 14 operating room nurses participated in in-depth interviews. The informants regarded foot health as part of general health and moreover a significant part of work well-being. Promoting factors for foot health were activity in sports and foot self-care as well as varying work conditions and seeing patients with severe foot conditions which served as a motivating factor to care for their own feet. On the contrary, hindering factors were unsuitable footwear, constant standing, and lack of motivation to care for their own feet. Based on this study, nurses' value their foot health which should be promoted. Nurses could benefit from annual foot health assessments and foot self-care education provided by occupational health professionals. PMID- 28856978 TI - Traumatic spinal cord injury in the north-east Tanzania - describing incidence, etiology and clinical outcomes retrospectively. AB - BACKGROUND: Causes, magnitude and consequences of traumatic spinal cord injury depend largely on geography, infrastructure, socioeconomic and cultural activities of a given region. There is a scarcity of literature on profile of traumatic spinal cord injury to inform prevention and rehabilitation of this health condition in African rural settings, particularly Tanzania. OBJECTIVE: To describe the incidence, etiology and clinical outcomes of traumatic spinal cord injury and issues related to retrospective study in underdeveloped setting. METHODS: Records for patients with traumatic spinal cord injury for five consecutive years (2010-2014) were obtained retrospectively from the admission wards and health records archives of the Kilimanjaro Christian Medical Center. Sociodemographic, cause, complications and patients' condition on discharge were recorded and analyzed descriptively. RESULTS: The admission books in the wards registered 288 new traumatic spinal cord injury cases from January 2010 to December 2014. Of the 288 cases registered in the books, 224 were males and 64 females with mean age 39.1(39.1 +/- 16.3) years and the majority of individuals 196(68.1%) were aged between 16 and 45 years. A search of the hospital archives provided 213 full patient records in which the leading cause of injury was falls 104(48.8%) followed by road traffic accidents 73(34.3%). Cervical 81(39.9%) and lumbar 71(34.74%) spinal levels were the most affected. The annual incidence for the Kilimanjaro region (population 1,640,087) was estimated at more than 26 persons per million population. The most documented complications were pressure ulcers 42(19.7%), respiratory complications 32(15.0%) and multiple complications 28(13.1%). The mean length of hospital stay was 64.2 +/- 54.3 days and the mortality rate was 24.4%. CONCLUSION: Prevention of traumatic spinal cord injury in North-east Tanzania should consider falls (particularly from height) as the leading cause, targeting male teenagers and young adults. Pressure ulcers, respiratory complications, in-hospital mortality and availability of wheelchairs should be addressed. PMID- 28856979 TI - "A peculiar time in my life": making sense of illness and recovery with gynaecological cancer. AB - PURPOSE: Worldwide there are nearly 1.1 million new cases of gynaecological cancer annually. In England, uterine, ovarian and cervical cancers comprize the third most common type of new cancer in women. Research with gynaecological cancer patients within 6 months of diagnosis is rare, as is data collection that is roughly contemporaneous with treatment. Our aim was to explore the experiences of women who were, at study entry, within 6 weeks of surgery or were undergoing chemotherapy or radiotherapy. METHODS: An interpretative phenomenological analysis (IPA) of data from 16 women in five focus groups was conducted in the UK, exploring women's experiences of being diagnosed with and treated for gynaecological cancer. RESULTS: Participants conceptualized their experiences temporally, from the shock of diagnosis, through their cancer treatment, to thinking about recovery. They tried to make sense of diagnosis, even with treatment being complete. In the context of the Self-Regulation Model, these women were struggling to interpret a changing and multi-faceted illness identity, and attempting to return to pre-illness levels of health. CONCLUSIONS: This study adds to this under-studied time period in cancer survivorship. The results suggest that survivors' goals may change from returning to pre-illness status to reformulating goals as survival time increases. PMID- 28856981 TI - Dual Target Search is Neither Purely Simultaneous nor Purely Successive. AB - Previous research shows that visual search for two different targets is less efficient than search for a single target. Stroud, Menneer, Cave and Donnelly (2012) concluded that two target colours are represented separately based on modeling the fixation patterns. Although those analyses provide evidence for two separate target representations, they do not show whether participants search simultaneously for both targets, or first search for one target and then the other. Some studies suggest that multiple target representations are simultaneously active, while others indicate that search can be voluntarily simultaneous, or switching, or a mixture of both. Stroud et al.'s participants were not explicitly instructed to use any particular strategy. These data were revisited to determine which strategy was employed. Each fixated item was categorised according to whether its colour was more similar to one target or the other. Once an item similar to one target is fixated, the next fixated item is more likely to be similar to that target than the other, showing that at a given moment during search, one target is generally favoured. However, the search for one target is not completed before search for the other begins. Instead, there are often short runs of one or two fixations to distractors similar to one target, with each run followed by a switch to the other target. Thus, the results suggest that one target is more highly weighted than the other at any given time, but not to the extent that search is purely successive. PMID- 28856980 TI - Reasoning about redundant and non-redundant alternative causes of a single outcome; blocking or enhancement caused by the stronger cause. AB - Perceptions of the effectiveness of a moderate probabilistic cause are influenced by the presence of stronger alternative causes. One important idea is that this influence occurs because the strong cause renders the weaker one statistically redundant. Alternatively, the causes might be contrasted to each other, so the stronger cause may simply overpower perceptions of the weaker one. Causes may have the same polarity (e.g., two generative/excitatory causes or two preventive/inhibitory causes) or be of opposite polarity (e.g., a generative cause versus a preventive or inhibitory cause). Previously, we found that the presence of a stronger redundant alternative cause of the same polarity reduces causal judgments of the moderate cause (i.e., blocking occurs) but a stronger cause of the opposite polarity enhances judgments of the moderate cause (i.e., enhancement; Darredeau, Baetu, Baker & Murphy, 2009). Experiments 1 and 2 further explored these cue competition effects with redundant and non-redundant alternative causes (i.e., correlated versus independent alternatives). We generally found that blocking and enhancement occur with both redundant and non redundant alternative causes. This is inconsistent with an information processing view of cue competition that relies on statistical redundancy to account for blocking. Although these results are inconsistent with a redundancy information processing account of cue competition and are consistent with our earlier contrast account, we demonstrate here that a simple associative model (Rescorla & Wagner, 1972) can account for the sometimes apparently contradictory effects of cue competition. PMID- 28856983 TI - Interdisciplinary cooperation as a factor to reduce social inequality in health in Drammen. PMID- 28856984 TI - Health and equity in all policies in local government: processes and outcomes in two Norwegian municipalities. AB - AIMS: To identify key factors in implementing Health and Equity in All Policies (HEiAP) at the local level in two Norwegian municipalities in order to accelerate the progress of promoting health, well-being and equity in other local governments. APPROACH: This case study is presented as a narrative from policy making processes in two Norwegian municipalities. The story is told from an insider perspective, with a focus on HEiAP policy makers in these two municipalities. RESULTS: The narrative identified key learning from implementing HEiAP at the local level, i.e. the importance of strengthening system and human capacities. System capacity is strengthened by governing HEiAP according to national legislation and a holistic governance system at the local level. Municipal plans are based on theory, evidence and local data. A 'main story' is developed to support the vision, defining joint societal goals and co-creation strategies. Policies are anchored by measuring and monitoring outcomes, sharing accountability and continuous dialogue to ensure political commitment. Human capacity is strengthened through participatory leadership, soft skills and health promotion competences across sectors. Health promotion competence at a strategic level in the organization, participation in professional networks, crowd sourcing toward common goals, and commitment through winning hearts and minds of politicians and other stakeholders are vital aspects. CONCLUSIONS: Our experience pinpoints the importance of strengthening system and human capacity in local governments. Further, we found it important to focus on the two strategic objectives in the European strategy 'Health 2020': (1) Improving health for all and reducing health inequalities; (2) improving leadership and participatory governance for health. PMID- 28856985 TI - Health trends in the wake of the financial crisis-increasing inequalities? AB - AIM: The financial crisis that hit Europe in 2007-2008 and the corresponding austerity policies have generated concern about increasing health inequalities, although impacts have been less salient than initially expected. One explanation could be that health inequalities emerged first a few years into the crisis. This study investigates health trends in the wake of the financial crisis and analyses health inequalities across a number of relevant population subgroups, including those defined by employment status, age, family type, gender, and educational attainment. METHODS: This study uses individual-level panel data (EU-SILC, 2010 2013) to investigate trends in self-rated health. By applying individual fixed effects regression models, the study estimates the average yearly change in self rated health for persons aged 15-64 years in 28 European countries. Health inequalities are investigated using stratified analyses. RESULTS: Unemployed respondents, particularly those who were unemployed in all years of observation, had a steeper decline in self-rated health than the employed. Respondents of prime working age (25-54 years) had a steeper decline than their younger (15-24) and older (55-64) counterparts, while single parents had a more favorable trend in self-rated health than dual parents. We did not observe any increasing health inequalities based on gender or educational attainment. CONCLUSIONS: Health inequalities increased in the wake of the financial crisis, especially those associated with employment status, age, and family type. We did not observe increasing health inequalities in terms of levels of educational attainment and gender. PMID- 28856986 TI - The financial crisis in Europe: Impact on satisfaction with life. AB - BACKGROUND: The 2008 financial crisis in Europe came abruptly and surprisingly. Many countries also suffered a second recession during the period 2010-2012. We examined the impact of the crisis on life satisfaction (LS) by country and individual socioeconomic level. METHOD: We used a representative sample from the European Social Survey (2002-2014) with data from 26 countries ( N = 294,407). LS was measured with a single question with 11 response alternatives. Time from start of crisis (either 2008 or 2010-2012) was determined separately for each interview. Data were analyzed by multilevel analysis Results: There was a sharp decrease in LS in the beginning of the crisis in 2008, and another, but not so severe, decline in 2011, each of them of short duration. However, there was also a slight and progressive yearly decrease in LS that continued one to at least 3 years after either financial crisis that was independent of the effect of being unemployed. Associations varied considerably between countries. A negative decline after the financial crisis was especially evident among those in the most educated groups, and in those in the higher occupational levels. CONCLUSIONS: The 2008 financial crisis had a double effect on LS: (1) a sharp short-term decrease consistent with the Easterlin paradox; (2) a slighter long-term progressive decrease that was over and above the strong negative relationship with unemployment that lasted several years. The long-term decline in LS after the start of the financial crisis tended to occur especially in the higher socioeconomic groups. PMID- 28856987 TI - Inequality in OECD countries. AB - This article recalls the state of play of inequality levels and trends in OECD countries, with a special focus on Nordic countries. It sheds light on explaining the drivers of the rise in inequality and its economic consequences. It addresses in particular the issue of redistribution through taxes and transfers. It concludes with an overview of policy packages that should be considered to address the issue of rising inequalities. PMID- 28856988 TI - Characteristics of community savings groups in rural Eastern Uganda: opportunities for improving access to maternal health services. AB - BACKGROUND: Rural populations in Uganda have limited access to formal financial Institutions, but a growing majority belong to saving groups. These saving groups could have the potential to improve household income and access to health services. OBJECTIVE: To understand organizational characteristics, benefits and challenges, of savings groups in rural Uganda. METHODS: This was a cross sectional descriptive study that employed both quantitative and qualitative data collection techniques. Data on the characteristics of community-based savings groups (CBSGs) were collected from 247 CBSG leaders in the districts of Kamuli, Kibukuand Pallisa using self-administered open-ended questionnaires. To triangulate the findings, we conducted in-depth interviews with seven CBSG leaders. Descriptive quantitative and content analysis for qualitative data was undertaken respectively. RESULTS: Almost a quarter of the savings groups had 5-14 members and slightly more than half of the saving groups had 15-30 members. Ninety-three percent of the CBSGs indicated electing their management committees democratically to select the group leaders and held meetings at least once a week. Eighty-nine percent of the CBSGs had used metallic boxes to keep their money, while 10% of the CBSGs kept their money using mobile money and banks,respectively. The main reasons for the formation of CBSGs were to increase household income, developing the community and saving for emergencies. The most common challenges associated with CBSG management included high illiteracy (35%) among the leaders,irregular attendance of meetings (22%), and lack of training on management and leadership(19%). The qualitative findings agreed with the quantitative findings and served to triangulate the main results. CONCLUSIONS: Saving groups in Uganda have the basic required structures; however, challenges exist in relation to training and management of the groups and their assets. The government and development partners should work together to provide technical support to the groups. PMID- 28856989 TI - From vulnerable plaque to blood healthy therapy. AB - Cardiovascular atherosclerotic disease is the leading cause of death in China and in Western nations. People with plaque or stenosis in the coronary artery or the carotid artery are the most susceptible population to suffer from acute events. Current investigations showed that plaque with the characteristics of intra plaque hemorrhage or a thin cap with a large lipid core was causally associated with vulnerable plaque and plaque rupture. Of the many plaque ruptures occurring in patients with atherosclerotic disease, very few will trigger symptomatic events, rendering it exceedingly difficult to predict adverse outcomes. The assumption that identifying lesions prone to rupture will prevent acute coronary events was unrealistic. Factors in blood, especially those risk factors associated with thrombosis, play an important role as a bridge between plaque rupture and subsequent clinical events. Since there is little management to efficiently decrease the frequency of plaque rupture or erosion, blood healthy therapy, as a therapeutic apheresis to decrease the blood hypercoagulability to modulate the blood to be thrombosis resisting, should be considered as a potential therapeutic approach to reducing the incidence of acute coronary syndrome and stroke. PMID- 28856990 TI - Advances in biomaterial design and application for medical intervention. PMID- 28856991 TI - Specialist palliative care teams hailed for training role. AB - Specialist palliative care (SPC) teams have been hailed by senior nurses for providing end of life care education and training for staff in care home and community settings. PMID- 28856993 TI - We need more research into care homes. AB - While research in hospitals on improving patient care and experience is well established, far fewer studies have been conducted into care homes. Yet, with 400,000 older people living in 19,000 independently owned care homes in the UK, there are many more beds in this sector than in the acute setting. PMID- 28856992 TI - New guide to art workshops. AB - Nurses who supervise art workshops for patients with dementia in care homes and hospitals can access a new guide to ensure the events run smoothly. PMID- 28856994 TI - Lack of research about dementia with Lewy bodies. AB - Dementia with Lewy bodies, which is characterised by clumps of protein that develop inside nerve cells in the brain, accounts for 10%-20% of dementia cases. Cognitive symptoms start with visuospatial and executive functions rather than with memory. Psychiatric and behavioural features, especially hallucinations, sleep disturbances and apathy, are common and often present early in the course of the disease. PMID- 28856996 TI - Around the world. AB - 1. ASEAN Conference on Healthy Ageing 10-12 October, Kuching, Malaysia tinyurl.com/ASEAN-conference. PMID- 28856995 TI - Too few care homes get the basics right. AB - Care homes are under so much pressure that they are not 'getting the basics right every time', a health and social care watchdog has said. PMID- 28856997 TI - Advancing care of residents in care homes. AB - There are more than twice as many people living in care homes in the UK than there are inpatients in NHS hospitals, yet there is much less research about how to provide the best care for these 416,000 residents. PMID- 28856998 TI - Financial hardship leads to loneliness among carers, NHS Digital finds. AB - Carers who are in the most financial need experience the worst social isolation, according to the results of a survey. PMID- 28856999 TI - Noticeboard. AB - Courses, events, grants, and awards to progress your career. PMID- 28857000 TI - Story in numbers. AB - New report calls for a national strategy to address the healthcare needs of older prisoners. PMID- 28857001 TI - Making time for person-centred care. AB - The ambulance crew tell me you have been admitted to the emergency department with a suspected femoral shaft fracture. I see a scared, frail older person, but I see a sparkle in your eyes that tells me how you made it to 101 years old. PMID- 28857003 TI - Sleep disorders in people with dementia. AB - Sleep disorders often precede cognitive impairment by many years. This is partly because some degenerative diseases originate in the hypothalamus and brain stem, which means fragmented sleep, daytime napping and sleep-phase disorders are early signs of these diseases. However, recent research indicates that amyloid proteins are removed from the brain during deep sleep so poor sleep can increase the amyloid plaques seen in Alzheimer's disease. It is also known that sleep disordered breathing can lead to hypoxia, increasing vascular dementia. PMID- 28857004 TI - Safeguarding Adults in Nursing Practice Northway Ruth Jenkins Robert Safeguarding Adults in Nursing Practice 240pp L21.99 Learning Matters/Sage 9781473954847 1473954843 [Formula: see text]. AB - It is refreshing to find a book that relates nursing practice to adult safeguarding in the way this does. Mainly written for nursing students, it incorporates NMC Standards for pre-registration nursing education and essential skills clusters, which are threaded throughout the book. PMID- 28857005 TI - Moderate alcohol consumption linked to decline in brain health. AB - Alcohol has historically been regarded as harmless when taken in moderation. However, studies have shown that, in older people, even moderate alcohol consumption is associated with reduced brain total volume, increased ventricle size, and reduced grey matter in the frontal and parietal lobes. PMID- 28857006 TI - Challenges of improving oral health for adults in care homes. AB - In 2016 the National Institute for Health and Care Excellence (NICE) published a guideline on oral health for adults in care homes in England. The author was a co opted member of the NICE oral health for adults in care homes public health advisory committee. This article reviews the NICE guideline as it applies to care homes, and relates it to the results of a survey of oral care practice undertaken in a large care home organisation and the available research literature from the past 20 years. The literature and survey results suggest that, if translated into practice, the NICE guideline could do much to improve oral health for adults in care homes. The survey highlighted that 85% of residents required support from carers to undertake mouth care. It also found that care homes experienced significant difficulties in accessing dental services for residents. The author concludes that providers need to equip staff with the necessary knowledge and skills to undertake mouth care and to give this area of personal care greater priority. Finally, the author suggests that the Care Quality Commission could ensure that the NICE guideline is translated into practice in care homes. PMID- 28857007 TI - Randomised trial of restorative home care for frail older people in New Zealand. AB - Aim To establish the effectiveness of a restorative home support service on institutional-free survival in frail older people referred for needs assessment. Method A randomised controlled trial of Community Flexible Integrated Responsive Support Team versus usual care in 113 older people at risk of institutionalisation in New Zealand. Primary outcome was death or permanent institutional care evaluated in a Cox proportional hazards model adjusted for baseline prognostic variables. A variety of secondary outcomes including the health of informal caregivers were also evaluated. Results The primary outcome was lower, but not statistically significant, in the intervention group (adjusted hazard ratio 0.69, 95% confidence interval 0.4 to 1.16). Informal caregivers of interventional participants had significantly better physical and mental component scores on the 36-item Short-Form questionnaire. Conclusion Restorative home support may reduce the risk of death and institutionalisation in frail older people without affecting the health of informal caregivers. PMID- 28857008 TI - 'Keep the patient at the centre of everything you do'. AB - What is your job? I am nurse consultant for older people in acute care at NHS Fife in Scotland, where I lead on improving care, transitions and experience and service transformation. I am also national clinical lead for older people at Healthcare Improvement Scotland (HIS). PMID- 28857009 TI - What support do nurses need to provide palliative care for people with dementia? AB - The aim of this project was to identify the support required by registered nurses and unregistered healthcare support workers to provide palliative care for people with dementia in an acute hospital in England. A quantitative approach was taken and participants were asked to fill in a questionnaire. Data were collated and analysed to identify support needs and any emerging themes. Respondents were confident in identifying the different stages of dementia. There was less confidence in identifying a patient with dementia for palliative care referral compared with a patient without dementia. Further needs were identified by respondents in supporting the family/carer of the person with dementia and being aware of available support to facilitate palliative care for people with dementia and support for end of life care (EoLC) planning. The findings suggest that further work is required in relation to dementia and EoLC. Practical and educational collaboration with EoLC/palliative care practitioners and dementia leads would be beneficial. PMID- 28857010 TI - Using technology to improve end of life care. AB - As clinical and operations director at East Cheshire Hospice I see the complex and sensitive discussions that my staff have with patients and their loved ones every day. PMID- 28857011 TI - Patient education is vital in gout management. AB - Essential facts Gout is the most common cause of inflammatory arthritis worldwide. Incidence and severity is increasing in the UK, with about 2.5% of the population affected. PMID- 28857012 TI - Creativity can complement clinical interactions. AB - The benefits of arts interventions to improve the health and well-being of older people are well proven, with national guidance highlighting their use in outstanding services. PMID- 28857013 TI - Lower expression of miR-218 in human breast cancer is associated with lymph node metastases, higher grades, and poorer prognosis. AB - Breast cancer is considered as the most prevalent malignancy in women worldwide. Despite emergence of several prognosticators for better management of patients, there are still limitations for their clinical application due to the complexity of breast tumors, and therefore, new biomarkers for better prognosis of clinical outcomes would be of the great essence. MicroRNAs are highly conserved small non coding regulatory RNAs involved in post-transcriptional regulating of gene expression during different cellular mechanisms. Accumulating studies suggest that miR-218 plays a multifunctional role in various cancer types and different stages. Here, to address prognostic significance of miR-218 in breast cancer, we investigate the expression profile of miR-218 and B-cell-specific Moloney murine leukemia virus integration site 1 ( BMI1) gene, as one of the putative targets of miR-218, in 33 paired breast tumors and their adjacent normal tissues with respect to the clinicopathological features of patients using quantitative real time polymerase chain reaction. The correlation of both miR-218 and BMI1 gene expression with overall survival of breast cancer patients was also examined recruiting OncoLNC data portal. Finally, to better understand biological function of miR-218 in breast cancer, we performed in silico Gene Ontology and signaling pathway enrichment analysis on miR-218 targetome. According to our data, significant elevation of the expression of miR-218 and downregulation of BMI1 were observed in clinical breast cancer specimens compared with normal tissues ( p < 0.0001). The lower expression of miR-218 was associated with lymph node metastases, higher grades, and poorer prognosis (logrank p = 0.00988), whereas no significant difference in overall survival was observed between patients with higher and lower expression of BMI1 (logrank p = 0.254). These findings suggest that miR-218 expression profiling might be clinically applicable as a prognostic biomarker in breast cancer. In addition, our in silico enrichment analyses revealed that the association of miR-218 expression with breast cancer prognosis might be through its involvement in endocytosis and gap junction biological pathways. PMID- 28857014 TI - Implementation of a SenseMaker(r) research project among Syrian refugees in Lebanon. AB - The Syrian conflict has displaced over 1.2 million Syrians into Lebanon. As a result of displacement, some Syrian families are turning to child marriage as a coping mechanism. The prevalence of early marriage has reportedly increased and the average age of marriage decreased during the crisis. The aim of the project was to understand the underlying factors contributing to child marriage among Syrian refugees in Lebanon using Cognitive Edge's SenseMaker(r). This manuscript explores the process of implementing this novel research tool in a humanitarian setting. Twelve interviewers conducted SenseMaker(r) interviews with married and unmarried Syrian girls, Syrian parents, as well as married and unmarried men. Participants were asked to share a story about the lives of Syrian girls in Lebanon and to self-interpret the narratives by answering follow-up questions in relation to the story provided. Data collection occurred across three locations: Beirut, Beqaa, and Tripoli. In total 1422 narratives from 1346 unique participants were collected over 7 weeks. Data collection using SenseMaker(r) was efficient, capable of electronically capturing a large volume of quantitative and qualitative data. SenseMaker(r) limitations from a research perspective include lack of skip logic and inability to adjust font size on the iOS app. SenseMaker(r) was an efficient mixed methods data collection tool that was well received by participants in a refugee setting in Lebanon. The utility of SenseMaker(r) for research could be improved by adding skip logic and by being able to adjust font size on the iOS app. PMID- 28857015 TI - N-glycosylation of the transient receptor potential melastatin 8 channel is altered in pancreatic cancer cells. AB - Transient receptor potential melastatin 8 (TRPM8), a membrane ion channel, is activated by thermal and chemical stimuli. In pancreatic ductal adenocarcinoma, TRPM8 is required for cell migration, proliferation, and senescence and is associated with tumor size and pancreatic ductal adenocarcinoma stages. Although the underlying mechanisms of these processes have yet to be described, this cation-permeable channel has been proposed as an oncological target. In this study, the glycosylation status of the TRPM8 channel was shown to affect cell proliferation, cell migration, and calcium uptake. TRPM8 expressed in the membrane of the Panc-1 pancreatic tumoral cell line is non-glycosylated, whereas human embryonic kidney cells transfected with human TRPM8 overexpress a glycosylated protein. Moreover, our data suggest that Ca2+ uptake is modulated by the glycosylation status of the protein, thus affecting cell proliferation. PMID- 28857016 TI - OPEN-SOURCE SOFTWARE IN DENTISTRY: A SYSTEMATIC REVIEW. AB - OBJECTIVES: Technological development and the need for electronic health records management resulted in the need for a computer with dedicated, commercial software in daily dental practice. The alternative for commercial software may be open-source solutions. Therefore, this study reviewed the current literature on the availability and use of open-source software (OSS) in dentistry. METHODS: A comprehensive database search was performed on February 1, 2017. Only articles published in peer-reviewed journals with a focus on the use or description of OSS were retrieved. The level of evidence, according to Oxford EBM Centre Levels of Evidence Scale was classified for all studies. Experimental studies underwent additional quality reporting assessment. RESULTS: The screening and evaluation process resulted in twenty-one studies from 1,940 articles found, with 10 of them being experimental studies. None of the articles provided level 1 evidence, and only one study was considered high quality following quality assessment. Twenty six different OSS programs were described in the included studies of which ten were used for image visualization, five were used for healthcare records management, four were used for educations processes, one was used for remote consultation and simulation, and six were used for general purposes. CONCLUSIONS: Our analysis revealed that the dental literature on OSS consists of scarce, incomplete, and methodologically low quality information. PMID- 28857017 TI - METHODOLOGICAL QUALITY OF ECONOMIC EVALUATIONS ALONGSIDE TRIALS OF KNEE PHYSIOTHERAPY. AB - OBJECTIVES: The methodological quality of an economic evaluation performed alongside a clinical trial can be underestimated if the paper does not report key methodological features. This study discusses methodological assessment issues on the example of a systematic review on cost-effectiveness of physiotherapy for knee osteoarthritis. METHODS: Six economic evaluation studies included in the systematic review and related clinical trials were assessed using the 10-question check-list by Drummond and the Physiotherapy Evidence Database (PEDro) scale. RESULTS: All economic evaluations were performed alongside a clinical trial but the studied interventions were too heterogeneous to be synthesized. Methodological quality of the economic evaluations reported in the papers was not free of drawbacks, and in some cases, it improved when information from the related clinical trial was taken into account. CONCLUSIONS: Economic evaluation papers dedicate little space to methodological features of related clinical trials; therefore, the methodological quality can be underestimated if evaluated separately from the trials. Future economic evaluations should follow more strictly the recommendations about methodology and the authors should pay special attention to the quality of reporting. PMID- 28857018 TI - Nutrient profiling for front of pack labelling: how to align logical consumer choice with improvement of products? AB - The primary goal of front of pack (FOP) labelling is to help consumers make healthier choices through communication. A secondary goal is to encourage producers to improve the nutritional composition of their products. Evidence has shown that (FOP) labelling can help consumers to make healthier food choices and has been an incentive for producers to improve product composition. As FOP labelling is seen as an important tool to improve food environments for public health purposes, the WHO supports initiatives of governments to implement an FOP labelling system. Based on the experiences of a wide range of countries over many years, possible success factors for such an FOP system have been defined, six of which are discussed in the present paper and used to evaluate the Dutch Choices Programme that was started in 2006. In the course of time a large number of producers joined the programme and the logo was recognised by more than 90 % of the consumers, but by 2016 the Dutch consumer organisation argued on the basis of their own research that a quarter of the consumers did not understand the colour coding of the logo and as a result the Dutch government decided to no longer support this logo and to introduce a nutrition app. The challenge that remains is to find a system that consumers understand well and that still encourages manufacturers of food to improve product composition. New technology-based data collecting initiatives might provide the right tools to develop such a system. PMID- 28857019 TI - Smart health and innovation: facilitating health-related behaviour change. AB - Non-communicable diseases (NCD) are the leading cause of death globally. Smart health technology and innovation is a potential strategy for increasing reach and for facilitating health behaviour change. Despite rapid growth in the availability and affordability of technology there remains a paucity of published and robust research in the area as it relates to health. The objective of the present paper is to review and provide a snapshot of a variety of contemporary examples of smart health strategies with a focus on evidence and research as it relates to prevention with a CVD management lens. In the present analysis, five examples will be discussed and they include a physician-directed strategy, consumer directed strategies, a public health approach and a screening strategy that utilises external hardware that connects to a smartphone. In conclusion, NCD have common risk factors and all have an association with nutrition and health. Smart health and innovation is evolving rapidly and may help with diagnosis, treatment and management. While on-going research, development and knowledge is needed, the growth of technology development and utilisation offers opportunities to reach more people and achieve better health outcomes at local, national and international levels. PMID- 28857020 TI - Echinicola sediminis sp. nov., a marine bacterium isolated from coastal sediment. AB - A novel Gram-stain-negative, rod-shaped, gliding bacterium, designated strain 001 Na2T, was isolated from coastal sediment of the Yellow Sea in Sindu-ri, Republic of Korea. Cells were aerobic, oxidase-positive and catalase-positive. Colonies were dark salmon-coloured, circular, and pulvinate with entire margins. 16S rRNA gene sequence analysis revealed that strain 001-Na2T belonged to the genus Echinicola and these species formed a distinct lineage within the family Cyclobacteriaceae. The closest phylogenetic neighbours were 'Echinicola shivajiensis' AK12T (98.1 % 16S rRNA gene sequence similarity), Echinicola vietnamensis LMG 23754T (96.4 %), Echinicola jeungdonensis HMD 3054T (96.0 %), Echinicola pacifica KMM 6172T (96.0 %) and Echinicola rosea JL 3085T (95.8 %). The predominant respiratory quinone was menaquinone MK-7. The major fatty acids were iso-C15 : 0, summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C17 : 1omega6c and summed feature 9 (comprising iso-C17 : 1omega9c and/or 10-methyl C16 : 0). The polar lipids were phosphatidylethanolamine, one unidentified aminophospholipid, one unidentified phospholipid and three unidentified lipids. The DNA G+C content was 44.6 mol%. DNA-DNA relatedness between strain 001-Na2T and 'E. shivajiensis' JCM 17847T was 20.8-21.1 %. On the basis of the phenotypic features, and phylogenetic and DNA-DNA hybridization analyses presented, strain 001-Na2T (=KCTC 52495T=JCM 31786T=DSM 103729T) is the type strain of a novel species of the genus Echinicola, for which the name Echinicola sediminis sp. nov. is proposed. PMID- 28857021 TI - Prauserella oleivorans sp. nov., a halophilic and thermotolerant crude-oil degrading actinobacterium isolated from an oil-contaminated mud pit. AB - A crude-oil-degrading, Gram-stain-positive actinobacterial strain, RIPIT, was isolated from a soil sample collected from an oil-contaminated mud pit in Khangiran oil and gas field, in the north-east of Iran. RIPIT was strictly aerobic, catalase- and oxidase-positive. The strain grew with 0-12.5 % (w/v) NaCl (optimum 3-5 %), at 25-55 degrees C (optimum 45 degrees C) and at pH 6.0-9.5 (optimum pH 7.0). The results of 16S rRNA gene sequence comparative analysis indicated that RIPIT represents a member of the genus Prauserella, with high phylogenetic similarity to Prauserella coralliicola SCSIO 11529T (97.5 %), Prauserella endophytica SP28S-3T (97.5 %) and Prauserella marina MS498T (97.2 %). DNA-DNA relatedness values between the novel strain and P. coralliicola DSM 45821T, P. endophytica DSM 46655T and P. marina DSM 45268T were 28 , 19 and 23 %, respectively. The cell wall peptidoglycan of RIPIT contained meso-diaminopimelic acid as the diamino acid and the whole-cell sugars are galactose and arabinose. The polar lipids pattern contained phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol and two unknown phospholipids. Its cellular fatty acids pattern consisted of C17 : 1omega6c, iso-C16 : 0 and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH), and the major respiratory quinone was MK-9(H4). The G+C content of the genomic DNA was 69 mol%. On the basis of polyphasic taxonomic data we propose that RIPIT represents a novel species of the genus Prauserella, for which the name Prauserella oleivorans sp. nov. is proposed. The type strain of Prauserellaoleivorans is RIPIT (=IBRC-M 10906T=LMG 28389T). PMID- 28857022 TI - Phytophthora pseudopolonica sp. nov., a new species recovered from stream water in subtropical forests of China. AB - A new species of the genus Phytophthora was isolated from stream water in the subtropical forests of China during a survey of forest Phytophthora from 2011 to 2013. This new species is formally described here and named Phytophthora pseudopolonica sp. nov. This new homothallic species is distinct from other known Phytophthora species in morphology and produces nonpapillate and noncaducous sporangia with internal proliferation. Spherical hyphal swellings and thin-walled chlamydospores are abundant when the species is kept in sterile water. The P. pseudopolonica sp. nov. forms smooth oogonia with paragynous and sometimes amphigynous antheridia. The optimum growth temperature of the species is 30 degrees C in V8-juice agar with beta-sitosterol, yet it barely grows at 5 degrees C and 35 degrees C. Based on sequences of the internal transcribed spacer and the combined beta-tubulin and elongation factor 1alpha gene sequence data, isolates of the new species cluster together into a single branch and are close to Phytophthora polonicabelonging to clade 9. PMID- 28857023 TI - Actinomyces gaoshouyii sp. nov., isolated from plateau pika (Ochotona curzoniae). AB - Two strains (pika_113T and pika_114) of a previously undescribed Actinomyces-like bacterium were recovered from the intestinal contents of plateau pika (Ochotona curzoniae) on the Tibet-Qinghai Plateau, China. Results from biochemical characterization indicated that the two strains were phenotypically homogeneous and distinct from other previously described species of the genus Actinomyces. Based on the comparison of 16S rRNA gene sequences and genome analysis, the bacteria were determined to be a hitherto unknown subline within the genus Actinomyces, being most closely related to type strains of Actinomyces denticolens and Actinomyces timonensis with a respective 97.2 and 97.1 % similarity in their 16S rRNA gene sequences. Phylogenetic analyses confirmed that pika_113T was well separated from any other recognized species of the genus Actinomyces and within the cluster with A. denticolens and A. timonensis. The genome of strain pika_113T displayed less than 42 % relatedness in DNA-DNA hybridization with all the available genomes of existing species of the genus Actinomyces in the NCBI database. Collectively, based on the phenotypic characteristics and phylogenetic analyses results, we propose the novel isolates as representatives of Actinomyces gaoshouyii sp. nov. The type strain of Actinomyces gaoshouyii is pika_113T (=CGMCC 4.7372T=DSM 104049T), with a genomic DNA G+C content of 71 mol%. PMID- 28857024 TI - International Committee on Systematics of Prokaryotes Subcommittee on the taxonomy of Halobacteria and Subcommittee on the taxonomy of Halomonadaceae. Minutes of the joint open meeting, 11 July 2017, Valencia, Spain. PMID- 28857025 TI - Rickettsia gravesii sp. nov.: a novel spotted fever group rickettsia in Western Australian Amblyomma triguttatum triguttatum ticks. AB - A rickettsial organism harboured by Amblyomma triguttatum ticks on Barrow Island, Western Australia, was discovered after reports of possible rickettsiosis among local workers. Subsequent isolation of this rickettsia (strain BWI-1) in cell culture and analysis of its phylogenetic, genotypic and phenotypic relationships with type strains of Rickettsia species with standing in nomenclature suggested that it was sufficiently divergent to warrant its classification as a new species. Multiple gene comparison of strain BWI-1 revealed degrees of sequence similarity with Rickettsia raoultii, its closest relative, of 99.58, 98.89, 97.03, 96.93 and 95.73 % for the 16S rRNA, citrate synthase, ompA, ompB and sca4 genes, respectively. Serotyping in mice also demonstrated that strain BWI-1T was distinct from Rickettsia raoultii. Thus, we propose the naming of a new species, Rickettsia gravesii sp. nov., based on its novel genotypic and phenotypic characteristics. Strain BWI-1T was deposited in the ATCC, CSUR and ARRL collections under reference numbers VR-1664, CSUR R172 and RGBWI-1, respectively. PMID- 28857026 TI - Vibrio palustris sp. nov. and Vibrio spartinae sp. nov., two novel members of the Gazogenes clade, isolated from salt-marsh plants (Arthrocnemum macrostachyum and Spartina maritima). AB - Two bacterial strains, EAod9T and SMJ21T, isolated from salt-marsh plants, were determined to be related to species of the genus Vibriofrom from 16S rRNA sequence comparisons. Their closest phylogenetic relatives are members of the Gazogenes clade, Vibrio mangrovi and Vibrio rhizosphaerae , which show the greatest similarity to the SMJ21TrRNA sequence (97.3 and 97.1 %, respectively), while EAod9T had less than 97.0 % similarity to any other species of the genus Vibrio. Both strains share the basic characteristics of the genus Vibrio, as they are Gram-stain negative, motile, slightly halophilic, facultatively anaerobic bacteria. In addition, they are oxidase-negative and unable to grow on TCBS Agar; they grow between 15 to 26 degrees C, pH 6 to 8 and in up to 10 % (w/v) total salinity. They produce indol, are positive in the Voges-Proskauer test and are negative for arginine dihydrolase, lysine and ornithine decarboxylases. Strain SMJ21T is aerogenic and red-pigmented, due to prodigiosin production, while strain EAod9T ferments glucose without gas and is not pigmented. The major cellular fatty acids of both novel strains were C16 : 1omega7c/C16 : 1omega6c and C16 : 0. WGSobtained for both strains, along with the other five members of the clade, allowed the determination of ANI indexes and in silico estimations of DDH values, which confirmed that the two strains represent two novel species of the genus Vibrio: Vibriopalustris sp. nov. (with EAod9T=CECT 9027T=LMG 29724T as the proposed type strain) and Vibrio spartinae sp. nov. (with SMJ21T=CECT 9026T=LMG 29723T as the proposed type strain). PMID- 28857027 TI - Amycolatopsis acidiphila sp. nov., a moderately acidophilic species isolated from coal mine soil. AB - Little is known on members of the genus Amycolatopsis inhabiting acidic habitats. In this study, a moderately acidophilic Amycolatopsis strain, designated 2-5T, was isolated from coal mine soil, and subjected to a polyphasic taxonomic characterization. Analysis based on 16S rRNA gene sequences indicated that the strain was most closely related to the type strain of Amycolatopsis bartoniae, sharing 99.30 % similarity, while similarity to all other Amycolatopsis species was less than 97 %. The DNA-DNA relatedness between the new isolate and the type strain of A. bartoniae was 56.5+/-0.7 %. The optimal pH range of the isolate for growth was 5.5-6.0, but growth also occurred at pH 4.5 and 7.5. The isolate tolerated up to 6 % (w/v) NaCl (optimum, 0 %), and the temperature range for growth was 15-40 degrees C (optimum, 30 degrees C). The isolate was able to utilize most substrates tested for sole carbon sources, showing its metabolic versatility. The isolate exhibited antimicrobial activity against Serratia marcescens and weak antifungal activity against Fusarium proliferatum. The chemotaxonomic profiles of strain 2-5T included polar lipids containing phosphatidylethanolamine, phsphatidylmethylethanolamine, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol dimannosides, fatty acids containing C17 : 1omega6c and iso-C16 : 0 as the major components, MK-9(H4) as the predominant menaquinone, and meso-diaminopimelic acid and arabinose, galactose, glucose and ribose as the diagnostic diamino acid and sugars in the cell wall. The combined phenotypic, chemotaxonomic and genotypic analyses clearly indicated that the isolate merits recognition as represnting a novel species of Amycolatopsis, for which the name Amycolatopsis acidiphila sp. nov. is proposed. The type strain is 2-5T (=KCTC 39523T=JCM 30562T). PMID- 28857028 TI - Arenivirga flava gen. nov., sp. nov., a new member of the family Microbacteriaceae isolated from a mangrove tidal flat. AB - A novel Gram-stain-positive actinobacterium, designated HIs16-32T, was isolated from a sand sample collected from a mangrove tidal flat in Japan and its taxonomic position was investigated by a polyphasic approach. The cells of strain HIs16-32T were Gram-stain-positive, rod-shaped, non-motile and non-endospore forming. Strain HIs16-32T contained glutamic acid, glycine and lysine in the peptidoglycan; however, alanine was absent. Galactose and mannose were detected as cell-wall sugars. The isoprenoid quinones were identified as MK-11, MK-12 and MK-10, and the major fatty acids as anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The DNA G+C content was determined to be 72.2 mol%. Phylogenetic analyses based on 16S rRNA gene sequence comparison revealed that strain HIs16-32T was related to members of the family Microbacteriaceae but did not form a reliable cluster with any known members of the family. The highest 16S rRNA gene sequence similarity values were obtained with species of the genera Herbiconiux(96.1-96.8 %), Plantibacter(96.5-96.7 %) and Schumannella (96.7 %). However, strain HIs16 32T was distinguishable from the phylogenetically related genera in terms of chemotaxonomic characteristics and phylogenetic relationship. Therefore, strain HIs16-32T is concluded to represent a novel genus and species of the family Microbacteriaceae, for which the name Arenivirga flava gen. nov., sp. nov. is proposed. The type strain of A. flava is HIs16-32T (=NBRC 112289T=TBRC 7038T). PMID- 28857029 TI - Swionibacillus sediminis gen. nov., sp. nov., a member of the family Bacillaceae isolated from ocean sediment. AB - A Gram-stain-negative, non-motile, strictly aerobic bacterium designated BW11-2T was isolated from marine sediment of the south-west Indian Ocean. Cells of BW11 2T were rod-shaped, endospore-forming, 0.3-0.5 um wide, 1.8-2.0 um long, catalase positive and oxidase-negative. The isolate was capable of growing at 15-45 degrees C (optimum 30 degrees C), pH 5-9 (optimum 7) and with 0.5-10 % (w/v) NaCl (optimum 3 %). Based on 16S rRNA gene sequence similarities, BW11-2T was shown to belong to the family Bacillaceae within the phylum Firmicutes and formed a distinct lineage, showing the highest sequence similarities to closely related genera: Bacillus(93.9-94.7 %), Gracilibacillus (93.3-93.7 %), Amphibacillus (93.5 %), Virgibacillus (92.9-93.1 %) and Anaerobacillus(92.6-93.0 %). BW11-2T shared the highest 16S rRNA gene sequence similarity with the species Bacillus oleronius (94.7 %). The predominant fatty acids (>10 %) were anteiso-C15 : 0 and iso-C15 : 0. The major quinone was menaquinone-7 (MK-7). Major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and one unidentified aminolipid. The genomic DNA G+C content of strain BW11-2T was 43.3 mol%. On the basis of the morphological and chemotaxonomic characteristics as well as genotypic data, strain BW11-2T represents a novel genus and species in the family Bacillaceae, for which the name Swionibacillus sediminis gen. nov., sp. nov. is proposed. Strain BW11-2T (=CICC 24196T=JCM 31924T) is the type strain. PMID- 28857030 TI - Bacillus kiskunsagensis sp. nov., a novel alkaliphilic and moderately halophilic bacterium isolated from soda soil. AB - An alkaliphilic and moderately halophilic strain characterized by optimal growth at pH 9.0-10.0 and 7 % (w/v) NaCl, and designated B16-24T, was isolated from the rhizosphere soil of the bayonet grass Bolboschoenus maritimus at a soda pond in the Kiskunsag National Park, Hungary. Cells of the strain were Gram-staining positive, non-motile, straight rods, and formed central, ellipsoidal endospores with slightly swollen sporangia. The isolate was facultative anaerobic, catalase positive, oxidase negative, and contained a peptidoglycan of type A1gamma based on meso-diaminopimelic acid. Menaquinone-7 (MK-7) was the predominant isoprenoid quinone, and anteiso-C15 : 0 the major cellular fatty acid. The DNA G+C content of strain B16-24T was 36.6 mol%. The 16S rRNA gene-based phylogenetic analysis revealed that the novel isolate had the greatest similarities to the type strains of Bacillus okhensis Kh10-101T (97.8 %), B. akibai 1139T (97.4 %), B. alkalisediminis K1-25T (97.3 %) and B. wakoensis N-1T (97.1 %). The DNA-DNA relatedness of strain B16-24T and the closely related Bacillus species ranged between 24+/-6 % and 35+/-3 %. The distinctive phenotypic and genetic results of this study confirmed that strain B16-24T represents a novel species within the genus Bacillus, for which the name Bacillus kiskunsagensis sp. nov. is proposed. The type strain is B16-24T (=DSM 29791T=NCAIM B.02610T). PMID- 28857031 TI - Vagococcus martis sp. nov., isolated from the small intestine of a marten, Martes flavigula. AB - A novel coccus-shaped, Gram-stain-positive, non-motile and facultative aerobic bacterium, designated strain D7T301T, was isolated from the small intestine of a marten, Martes flavigula, which was killed on the road in Pocheon-si, Gyeonggi do, Republic of Korea. Grown on a tryptic soy yeast agar plate, colonies had a creamy colour and irregular form. The new isolate formed a monophyletic clade with Vagococcus penaei CD276T on a phylogenetic consensus tree based on the 16S rRNA gene sequence. The isolate grew optimally at 37 degrees C and pH 7 in the presence of 0.5 % (w/v) NaCl. The isolate was catalase- and oxidase-negative. The cell-wall peptidoglycan was type A4alpha l-Lys-d-Asp. The major cellular fatty acids were C16 : 0, C14 : 0, and C16 : 1omega9c. The predominant respiratory quinone was menaquinone MK-7 (85.1 %). The DNA G+C content based on genome sequencing was 33.8 mol%. The average nucleotide identity value obtained from comparative genomic analysis between strain D7T301T and V. penaei CIP 109914T was 72.6 %. On the basis of the phenotypic, phylogenetic, biochemical, chemotaxonomic, and genotypic analyses, Vagococcusmartis is proposed as a novel species of the genus Vagococcus. The type strain is D7T301T (=KCTC 21069T=JCM 31178T). PMID- 28857032 TI - Citrobacter portucalensis sp. nov., isolated from an aquatic sample. AB - A Gram-stain-negative strain, A60T, isolated from a water well sample in Portugal, was characterized phenotypically, genotypically and phylogenetically. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain A60T belonged to the genus Citrobacter, and recN gene phylogeny revealed one strongly supported clade encompassing strain A60T and 13 other strains from public databases, distinct from currently recognized species of the genus Citrobacter. Furthermore, multilocus sequence analysis (MLSA) based on concatenated partial fusA, leuS, pyrG and rpoB sequences confirmed the classification obtained with the recN sequence. In silico genomic comparisons, including average nucleotide identity (ANI) and the genome-to-genome distance calculator (GGDC), showed 94.6 % and 58.4 % identity to the closest relative Citrobacter freundii ATCC 8090T, respectively. The ability to metabolize different compounds further discriminated strain A60T from other species of the genus Citrobacter. The G+C content of strain A60T is 52.0 %. The results obtained support the description of a novel species within the genus Citrobacter, for which the name Citrobacter portucalensis sp. nov. is proposed, with the type strain A60T (=DSM 104542T=CECT 9236T). PMID- 28857033 TI - The effect of Hypomyces perniciosus on the mycelia and basidiomes of Agaricus bisporus. AB - Hypomyces perniciosus has been reported as a destructive pathogen of Agaricus bisporus. Previous research suggested that the pathogenesis may not only be perpetuated by H. perniciosus, but also by bacteria. Clarification of the interaction between A. bisporus and H. perniciosus is a prerequisite for the development of effective control measures against wet bubble disease. Here, the effects of H. perniciosus on A. bisporus mycelia are examined in dual culture on agar media and in open-ended test tubes. During disease development, the putative causal agents and cytology of wet bubble-diseased mushrooms were followed microscopically. The interaction between H. perniciosus and the basidiome of A. bisporus was also studied using dual-cultured H. perniciosus and basidiome tissues. Dual-cultured mycelia from both fungi showed that growth continued even after contact was made, without any observable antagonistic lines or cytoplasmic changes of A. bisporus mycelia. Hypomyces perniciosus could be isolated from diseased basidiomes any time after inoculation, but bacteria were only recovered after the basidiomes of A. bisporus had been killed by H. perniciosus. Dual culture of the basidiome tissue of A. bisporus and H. perniciosus on agar media established that H. perniciosus can independently and rapidly degrade the basidiomes of A. bisporus. We conclude that H. perniciosus has no pathogenic activity on the mycelial stage of A. bisporus, but it can destroy A. bisporus basidiomes in the absence of bacteria. Wet bubble disease is evidently not caused by bacteria, but by the fungus, although bacteria likely participate in the disease after invasion by the fungus. PMID- 28857035 TI - Two common variants of human papillomavirus type 16 E6 differentially deregulate sugar metabolism and hypoxia signalling in permissive human keratinocytes. AB - Human papillomavirus type 16 (HPV16) is responsible for most cancers attributable to HPV infection and naturally occurring variants of the HPV16 E6 oncoprotein predispose individuals to varying risk for developing cancer. Population studies by us and others have demonstrated that the common Asian-American E6 (AAE6) variant is a higher risk factor for cervical cancer than the E6 of another common variant, the European prototype (EPE6). However, a complete understanding of the molecular processes fundamental to these epidemiological findings is still lacking. Our previously published functional studies of these two E6 variants showed that AAE6 had a higher immortalization and transformation potential than EPE6. Proteomic analysis revealed markedly different protein patterns between these variants, especially with respect to key cellular metabolic enzymes. Here, we tested the Warburg effect and hypoxia signalling (hallmarks of cancer development) as plausible mechanisms underlying these observations. Lactate and glucose production were enhanced in AAE6-transduced keratinocytes, likely due to raised levels of metabolic enzymes, but independent of hypoxia-inducible factor 1 alpha (HIF-1alpha) activity. The HIF-1alpha protein level and activity were elevated by AAE6 in hypoxic conditions, leading to a hypoxia-tolerant phenotype with enhanced migratory potential. The deregulation of HIF-1alpha was caused by the AAE6 variant's ability to augment mitogen-activated protein kinase/extracellular related kinase signalling. The present study reveals prominent underlying mechanisms of the AAE6's enhanced oncogenic potential. PMID- 28857034 TI - Discovery of a novel lantibiotic nisin O from Blautia obeum A2-162, isolated from the human gastrointestinal tract. AB - A novel lanC-like sequence was identified from the dominant human gut bacterium Blautia obeum strain A2-162. This sequence was extended to reveal a putative lantibiotic operon with biosynthetic and transport genes, two sets of regulatory genes, immunity genes, three identical copies of a nisin-like lanA gene with an unusual leader peptide, and a fourth putative lanA gene. Comparison with other nisin clusters showed that the closest relationship was to nisin U. B. obeum A2 162 demonstrated antimicrobial activity against Clostridium perfringens when grown on solid medium in the presence of trypsin. Fusions of predicted nsoA structural sequences with the nisin A leader were expressed in Lactococcus lactis containing the nisin A operon without nisA. Expression of the nisA leader sequence fused to the predicted structural nsoA1 produced a growth defect in L. lactis that was dependent upon the presence of biosynthetic genes, but failed to produce antimicrobial activity. Insertion of the nso cluster into L. lactis MG1614 gave an increased immunity to nisin A, but this was not replicated by the expression of nsoI. Nisin A induction of L. lactis containing the nso cluster and nisRK genes allowed detection of the NsoA1 pre-peptide by Western hybridization. When this heterologous producer was grown with nisin induction on solid medium, antimicrobial activity was demonstrated in the presence of trypsin against C. perfringens, Clostridium difficile and L. lactis. This research adds to evidence that lantibiotic production may be an important trait of gut bacteria and could lead to the development of novel treatments for intestinal diseases. PMID- 28857036 TI - Polycipiviridae: a proposed new family of polycistronic picorna-like RNA viruses. AB - Solenopsis invicta virus 2 is a single-stranded positive-sense picorna-like RNA virus with an unusual genome structure. The monopartite genome of approximately 11 kb contains four open reading frames in its 5' third, three of which encode proteins with homology to picornavirus-like jelly-roll fold capsid proteins. These are followed by an intergenic region, and then a single long open reading frame that covers the 3' two-thirds of the genome. The polypeptide translation of this 3' open reading frame contains motifs characteristic of picornavirus-like helicase, protease and RNA-dependent RNA polymerase domains. An inspection of public transcriptome shotgun assembly sequences revealed five related apparently nearly complete virus genomes isolated from ant species and one from a dipteran insect. By high-throughput sequencing and in silico assembly of RNA isolated from Solenopsis invicta and four other ant species, followed by targeted Sanger sequencing, we obtained nearly complete genomes for four further viruses in the group. Four further sequences were obtained from a recent large-scale invertebrate virus study. The 15 sequences are highly divergent (pairwise amino acid identities of as low as 17 % in the non-structural polyprotein), but possess the same overall polycistronic genome structure, which is distinct from all other characterized picorna-like viruses. Consequently, we propose the formation of a new virus family, Polycipiviridae, to classify this clade of arthropod-infecting polycistronic picorna-like viruses. We further propose that this family be divided into three genera: Chipolycivirus (2 species), Hupolycivirus (2 species) and Sopolycivirus (11 species), with members of the latter infecting ants in at least 3 different subfamilies. PMID- 28857037 TI - Chitinophaga sedimenti sp. nov., isolated from sediment. AB - A bacterial strain designated TFL-3T was isolated from sediment of the Yangtze River in Nanjing, Jiangsu province, China. Strain TFL-3T was Gram-staining negative, non-spore-forming, rod-shaped and non-motile. Growth occurred at 10-40 degrees C (optimum 30 degrees C). Strain TFL-3T grew at pH 6.0-9.0 (optimum pH 7.0) and NaCl concentrations of 0-2.5 % (optimum 0.5 %). Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain TFL-3T belonged to the genus Chitinophaga and showed the highest sequence similarity to Chitinophaga barathri YLT18T (94.9 %). The DNA G+C content of strain TFL-3T was determined as 50.5+/-1.0 mol%. The major fatty acids (>10 %) were iso-C15 : 0, C16 : 1omega5c and summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c). The predominant respiratory ubiquinone was MK-7. The polar lipid profile consisted of phosphatidylethanolamine, two unidentified aminolipids, two unidentified glycolipids and seven unidentified lipids. Based on the phenotypic, chemotaxonomic and phylogenetic data, strain TFL-3T represents a novel species in the genus Chitinophaga, for which the name Chitinophaga sedimenti sp. nov. is proposed. The type strain is TFL-3T (=ACCC 19966T=KCTC 52590T). PMID- 28857038 TI - Thermosulfuriphilus ammonigenes gen. nov., sp. nov., a thermophilic, chemolithoautotrophic bacterium capable of respiratory ammonification of nitrate with elemental sulfur. AB - An extremely thermophilic, anaerobic, chemolithoautotrophic bacterium (strain ST65T) was isolated from a deep-sea hydrothermal vent chimney located on the Eastern Lau Spreading Centre in the south-western Pacific Ocean, at a depth of 1870 m. Cells of strain ST65T were non-motile straight or slightly curved short rods, 0.5-0.6 um in diameter and 0.8-1.5 um in length. The temperature range for growth was 47-75 degrees C, with an optimum at 65 degrees C. The pH range for growth was 5.5-7.5, with an optimum at pH 6.5. Growth of strain ST65T was observed at NaCl concentrations ranging from 1.5 to 4.5 % (w/v), with an optimum at 2.0-2.5 %. Strain ST65T grew anaerobically with inorganic carbon as a carbon source and with elemental sulfur as an electron donor and nitrate as an electron acceptor producing sulfate and ammonium. It was also able to grow by disproportionation of elemental sulfur, thiosulfate and sulfite. Sulfate was not utilized as an electron acceptor. Analysis of the 16S rRNA gene sequence revealed that the isolate belongs to a deep lineage in the phylum Thermodesulfobacteria. On the basis of its physiological properties and results of phylogenetic analyses, it is proposed that the isolate represents a novel species of a new genus, Thermosulfuriphilus ammonigenes gen. nov., sp. nov. ST65T (=DSM 102941T=VKM B-2855T) is the type strain of the type species. PMID- 28857039 TI - Croceitalea marina sp. nov., isolated from marine particles of Yellow Sea, and emended description of the genera Croceitalea. AB - A Gram-staining-negative, rod-shaped, non-motile, golden yellow-coloured and strictly aerobic bacterial strain, designated H01-35T, was isolated from a surface marine particles sample collected from the Yellow Sea in China. According to the phylogenetic analysis based on 16S rRNA gene sequences, the strain H01-35T belonged to the genus Croceitalea and showed the highest sequence similarity to Croceitalea litorea CBA3205T (96.4 %). Strain H01-35T grew optimally at pH 8.0 9.0, 28 degrees C and in the presence of 3 % (w/v) NaCl. The DNA G+C content was 52.7 mol%. Strain H01-35T contained MK-6 as the predominant respiratory quinone and held iso-C15 : 1 G, iso-C15 : 0 and iso-C17 : 0 3-OH as the major cellular fatty acids. The major polar lipids were phosphatidylethanolamine, two unidentified aminolipids and five unidentified lipids. Exoenzymes for starch, gelatin and Tween 20 degradation were detected in Strain H01-35T but the strain was negative for sulfur and indole production. On the basis of the polyphasic analyses, this isolate was considered to represent a novel species in the genus Croceitalea, for which the name Croceitalea marina sp. nov. is proposed. The type strain is H01-35T (MCCC 1K03229T=KCTC 52368T). The emendation of description of the genus Croceitalea is also given. PMID- 28857040 TI - Hepatitis C virus down-regulates SERPINE1/PAI-1 expression to facilitate its replication. AB - Identification of host factors involved in viral replication is critical for understanding the molecular mechanism of viral replication and pathogenesis. Genes differentially expressed in HuH-7 cells with or without a hepatitis C virus (HCV) sub-genomic replicon were screened by microarray analysis. SERPINE1/PAI-1 was found to be down-regulated after HCV infection in this analysis. Down regulation of SERPINE1/PAI-1 expression at the transcriptional level was verified by the real-time reverse transcriptase (RT)-PCR assay. Reduced SERPINE1/PAI-1 protein secretion was detected in the supernatant of HCV replicon cells and in sera from HCV-infected patients. SERPINE1 gene expression was down-regulated by HCV NS3/4A and NS5A proteins through the transforming growth factor-beta (TGF beta) signalling pathway at the transcriptional level. Down-regulated genes in HCV replicon cells could be the factors supressing HCV replication. Indeed, over expressed PAI-1 inhibited HCV replication but the mechanism is unknown. It has been demonstrated that HCV induces the expression of TGF-beta, and TGF-beta enhances HCV replication by a not-yet-defined mechanism. SERPINE1/PAI-1 is also known to be potently induced by TGF-beta at the transcriptional level through both Smad-dependent and Smad-independent pathways. The exogenously expressed SERPINE1/PAI-1 suppressed the expression of the endogenous SERPINE1 gene at the transcriptional level through the TGF-beta signalling but not the Smad pathway. Thus, SERPINE1/PAI-1 could suppress HCV replication possibly by negatively regulating TGF-beta signalling. A model is proposed for the interplay betweenthe TGF-beta signalling pathway, HCV and SERPINE1/PAI-1 to keep the homeostasis of the cells. PMID- 28857041 TI - The glucosylglycerol-degrading enzyme GghA is involved in acclimation to fluctuating salinities by the cyanobacterium Synechocystis sp. strain PCC 6803. AB - The ggpS gene, which encodes the key enzyme for the synthesis of the compatible solute glucosylglycerol (GG), has a promoter region that overlaps with the upstream-located gene slr1670 in the cyanobacterium Synechocystissp. PCC 6803. Like ggpS, the slr1670 gene is salt-induced and encodes a putative glucosylhydrolase. A mutant strain with a slr1670 deletion was generated and found to be unable to adapt the internal GG concentrations in response to changes in external salinities. Whereas cells of the wild-type reduced the internal pool of GG when exposed to gradual and abrupt hypo-osmotic treatments, or when the compatible solute trehalose was added to the growth medium, the internal GG pool of ?slr1670 mutant cells remained unchanged. These findings indicated that the protein Slr1670 is involved in GG breakdown. The biochemical activity of this GG hydrolase enzyme was verified using recombinant Slr1670 protein, which split GG into glucose and glycerol. These results validate that Slr1670, which was named GghA, acts as a GG hydrolase. GghA is involved in GG turnover in fluctuating salinities, and similar proteins are found in the genomes of other GG synthesizing cyanobacteria. PMID- 28857042 TI - Cost and Outcome of BehaviouRal Activation (COBRA): a randomised controlled trial of behavioural activation versus cognitive-behavioural therapy for depression. AB - BACKGROUND: Depression is a common, debilitating and costly disorder. The best evidenced psychological therapy - cognitive-behavioural therapy (CBT) - is complex and costly. A simpler therapy, behavioural activation (BA), may be an effective alternative. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of BA compared with CBT for depressed adults at 12 and 18 months' follow-up, and to investigate the processes of treatments. DESIGN: Randomised controlled, non-inferiority trial stratified by depression severity, antidepressant use and recruitment site, with embedded process evaluation; and randomisation by remote computer-generated allocation. SETTING: Three community mental health services in England. PARTICIPANTS: Adults aged >= 18 years with major depressive disorder (MDD) recruited from primary care and psychological therapy services. INTERVENTIONS: BA delivered by NHS junior mental health workers (MHWs); CBT by NHS psychological therapists. OUTCOMES: Primary: depression severity (as measured via the Patient Health Questionnaire-9; PHQ-9) at 12 months. Secondary: MDD status; number of depression-free days; anxiety (as measured via the Generalised Anxiety Disorder-7); health-related quality of life (as measured via the Short Form questionnaire-36 items) at 6, 12 and 18 months; and PHQ-9 at 6 and 18 months, all collected by assessors blinded to treatment allocation. Non-inferiority margin was 1.9 PHQ-9 points. We undertook intention to-treat (ITT) and per protocol (PP) analyses. We explored cost-effectiveness by collecting direct treatment and other health- and social-care costs and calculating quality-adjusted life-years (QALYs) using the EuroQol-5 Dimensions, three-level version, at 18 months. RESULTS: We recruited 440 participants (BA, n = 221; CBT, n = 219); 175 (79%) BA and 189 (86%) CBT participants provided ITT data and 135 (61%) BA and 151 (69%) CBT participants provided PP data. At 12 months we found that BA was non-inferior to CBT {ITT: CBT 8.4 PHQ-9 points [standard deviation (SD) 7.5 PHQ-9 points], BA 8.4 PHQ-9 points (SD 7.0 PHQ-9 points), mean difference 0.1 PHQ-9 points, 95% confidence interval (CI) -1.3 to 1.5 PHQ-9 points, p = 0.89; PP: CBT 7.9 PHQ-9 points (SD 7.3 PHQ-9 points), BA 7.8 PHQ-9 points (SD 6.5 PHQ-9 points), mean difference 0.0 PHQ-9 points, 95% CI 1.5 to 1.6 PHQ-9 points, p = 0.99}. We found no differences in secondary outcomes. We found a significant difference in mean intervention costs (BA, L975; CBT, L1235; p < 0.001), but no differences in non-intervention (hospital, community health, social care and medication costs) or total (non-intervention plus intervention) costs. Costs were lower and QALY outcomes better in the BA group, generating an incremental cost-effectiveness ratio of -L6865. The probability of BA being cost-effective compared with CBT was almost 80% at the National Institute for Health and Care Excellence's preferred willingness-to-pay threshold of L20,000-30,000 per QALY. There were no trial-related adverse events. LIMITATIONS: In this pragmatic trial many depressed participants in both groups were also taking antidepressant medication, although most had been doing so for a considerable time before entering the trial. Around one-third of participants chose not to complete a PP dose of treatment, a finding common in both psychotherapy trials and routine practice. CONCLUSIONS: We found that BA is as effective as CBT, more cost-effective and can be delivered by MHWs with no professional training in psychological therapies. FUTURE WORK: Settings and countries with a paucity of professionally qualified psychological therapists, might choose to investigate the delivery of effective psychological therapy for depression without the need to develop an extensive and costly professional infrastructure. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27473954. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 46. See the NIHR Journals Library website for further project information. PMID- 28857044 TI - Author's correction for Euro Surveill. 2017;22(32). PMID- 28857043 TI - Large measles outbreak introduced by asylum seekers and spread among the insufficiently vaccinated resident population, Berlin, October 2014 to August 2015. AB - The largest measles outbreak in Berlin since 2001 occurred from October 2014 to August 2015. Overall, 1,344 cases were ascertained, 86% (with available information) unvaccinated, including 146 (12%) asylum seekers. Median age was 17 years (interquartile range: 4-29 years), 26% were hospitalised and a 1-year-old child died. Measles virus genotyping uniformly revealed the variant 'D8-Rostov Don' and descendants. The virus was likely introduced by and initially spread among asylum seekers before affecting Berlin's resident population. Among Berlin residents, the highest incidence was in children aged < 2 years, yet most cases (52%) were adults. Post-exposure vaccinations in homes for asylum seekers, not always conducted, occurred later (median: 7.5 days) than the recommended 72 hours after onset of the first case and reached only half of potential contacts. Asylum seekers should not only have non-discriminatory, equitable access to vaccination, they also need to be offered measles vaccination in a timely fashion, i.e. immediately upon arrival in the receiving country. Supplementary immunisation activities targeting the resident population, particularly adults, are urgently needed in Berlin. PMID- 28857046 TI - Erratum for Euro Surveill. 2017;22(31). PMID- 28857045 TI - Persistent detection of dengue virus RNA in vaginal secretion of a woman returning from Sri Lanka to Italy, April 2017. AB - We describe the dynamics of dengue virus (DENV) infection in a woman in her mid 30s who developed fever after returning from Sri Lanka to Italy in April 2017. Laboratory testing demonstrated detectable DENV-RNA in plasma, urine, saliva, vaginal secretion. Persistent shedding of DENV-RNA was demonstrated in vaginal secretion, and DENV-RNA was detectable in the pelleted fraction up to 18 days from symptom onset. These findings give new insights into DENV vaginal shedding and vertical transmission. PMID- 28857048 TI - Spectral and magnetic properties of Na2RuO3. AB - We present measurements of resistivity, x-ray absorption (XAS) and emission (XES) spectroscopy together with ab initio band structure calculations for quasi two dimensional ruthenate Na2RuO3. Density function calculations (DFT) and XAS and XES spectra both show that Na2RuO3 is a semiconductor with an activation energy of ~80 meV. Our DFT calculations reveal large magneto-elastic coupling in Na2RuO3 and predict that the ground state of Na2RuO3 should be antiferromagnetic zig-zag. PMID- 28857049 TI - More than ever, comment on 'Chernobyl and Fukushima-Where are we now?' PMID- 28857050 TI - Tuning the p-type Schottky barrier in 2D metal/semiconductor interface:boron sheet on MoSe2, and WSe2. AB - Van der Waals (vdW) metal/semiconductor heterostructures have been investigated through first-principles calculations. We have considered the recently synthesized borophene (Mannix et al 2015 Science 350 1513), and the planar boron sheets (S1 and S2) (Feng et al 2016 Nat. Chem. 8 563) as the 2D metal layer, and the transition metal dichalcogenides (TMDCs) MoSe2, and WSe2 as the semiconductor monolayer. We find that the energetic stability of those 2D metal/semiconductor heterojunctions is mostly ruled by the vdW interactions; however, chemical interactions also take place in borophene/TMDC. The electronic charge transfer at the metal/semiconductor interface has been mapped, where we find a a net charge transfer from the TMDCs to the boron sheets. Further electronic structure calculations reveal that the metal/semiconductor interfaces, composed by planar boron sheets S1 and S2, present a p-type Schottky barrier which can be tuned to a p-type ohmic contact by an external electric field. PMID- 28857047 TI - The effectiveness of influenza vaccination in preventing hospitalisations of elderly individuals in two influenza seasons: a multicentre case-control study, Spain, 2013/14 and 2014/15. AB - Influenza vaccination may limit the impact of influenza in the community. The aim of this study was to assess the effectiveness of influenza vaccination in preventing hospitalisation in individuals aged >= 65 years in Spain. A multicentre case-control study was conducted in 20 Spanish hospitals during 2013/14 and 2014/15. Patients aged >= 65 years who were hospitalised with laboratory-confirmed influenza were matched with controls according to sex, age and date of hospitalisation. Adjusted vaccine effectiveness (VE) was calculated by multivariate conditional logistic regression. A total of 728 cases and 1,826 matched controls were included in the study. Overall VE was 36% (95% confidence interval (CI): 22-47). VE was 51% (95% CI: 15-71) in patients without high-risk medical conditions and 30% (95% CI: 14-44) in patients with them. VE was 39% (95% CI: 20-53) in patients aged 65-79 years and 34% (95% CI: 11-51) in patients aged >= 80 years, and was greater against the influenza A(H1N1)pdm09 subtype than the A(H3N2) subtype. Influenza vaccination was effective in preventing hospitalisations of elderly individuals. PMID- 28857051 TI - Multiple authorisation radiological assessment tool. PMID- 28857052 TI - Antiarrhythmic drug usage and prostate cancer: a population-based cohort study. AB - Even though the relationship between antiarrhythmic drug usage and subsequent prostate cancer (PCa) risk has recently been highlighted, relevant findings in the previous literature are still inconsistent. In addition, very few studies have attempted to investigate the association between sodium channel blockers or potassium channel blockers for arrhythmia and the subsequent PCa risk. Therefore, this cohort study aimed to find the relationship between antiarrhythmic drug usage and the subsequent PCa risk using a population-based dataset. The data used in this study were derived from the Longitudinal Health Insurance Database 2005, Taiwan, China. We respectively identified 9988 sodium channel blocker users, 3663 potassium channel blocker users, 65 966 beta-blocker users, 23 366 calcium channel blockers users, and 7031 digoxin users as the study cohorts. The matched comparison cohorts (one comparison subject for each antiarrhythmic drug user) were selected from the same dataset. Each patient was tracked for a 5-year period to define those who were subsequently diagnosed with PCa. After adjusting for sociodemographic characteristics, comorbidities, and age, Cox proportional hazard regressions found that the hazard ratio (HR) of subsequent PCa for sodium channel blocker users was 1.12 (95% confidence interval [CI]: 0.84-1.50), for potassium channel blocker users was 0.89 (95% CI: 0.59-1.34), for beta-blocker users was 1.08 (95% CI: 0.96-1.22), for calcium channel blocker users was 1.14 (95% CI: 0.95-1.36), and for digoxin users was 0.89 (95% CI: 0.67-1.18), compared to their matched nonusers. We concluded that there were no statistical associations between different types of antiarrhythmic drug usage and subsequent PCa risk. PMID- 28857053 TI - A rare polypyrimidine tract mutation in the androgen receptor gene results in complete androgen insensitivity syndrome. PMID- 28857055 TI - Climate change and health in Maldives: Protecting our common future. PMID- 28857054 TI - Foreword. PMID- 28857056 TI - Health risks of climate change in the World Health Organization South-East Asia Region. AB - Countries in the World Health Organization (WHO) South-East Asia Region are particularly vulnerable to a changing climate. Changes in extreme weather events, undernutrition and the spread of infectious diseases are projected to increase the number of deaths due to climate change by 2030, indicating the need to strengthen activities for adaptation and mitigation. With support from the WHO Regional Office for South-East Asia and others, countries have started to include climate change as a key consideration in their national public health policies. Further efforts are needed to develop evidence-based responses; garner the necessary support from partner ministries; and access funding for activities related to health and climate change. National action plans for climate change generally identify health as one of their priorities; however, limited information is available on implementation processes, including which ministries and departments would be involved; the time frame; stakeholder responsibilities; and how the projects would be financed. While progress is being made, efforts are needed to increase the capacity of health systems to manage the health risks of climate change in South-East Asia, if population health is to be protected and strengthened while addressing changing weather and climate patterns. Enhancing the resilience of health systems is key to ensuring a sustainable path to improved planetary and population health. PMID- 28857057 TI - Health-sector responses to address the impacts of climate change in Nepal. AB - Nepal is highly vulnerable to global climate change, despite its negligible emission of global greenhouse gases. The vulnerable climate-sensitive sectors identified in Nepal's National Adaptation Programme of Action (NAPA) to Climate Change 2010 include agriculture, forestry, water, energy, public health, urbanization and infrastructure, and climate-induced disasters. In addition, analyses carried out as part of the NAPA process have indicated that the impacts of climate change in Nepal are not gender neutral. Vector-borne diseases, diarrhoeal diseases including cholera, malnutrition, cardiorespiratory diseases, psychological stress, and health effects and injuries related to extreme weather are major climate-sensitive health risks in the country. In recent years, research has been done in Nepal in order to understand the changing epidemiology of diseases and generate evidence for decision-making. Based on this evidence, the experience of programme managers, and regular surveillance data, the Government of Nepal has mainstreamed issues related to climate change in development plans, policies and programmes. In particular, the Government of Nepal has addressed climate-sensitive health risks. In addition to the NAPA report, several policy documents have been launched, including the Climate Change Policy 2011; the Nepal Health Sector Programme - Implementation Plan II (NHSP-IP 2) 2010-2015; the National Health Policy 2014; the National Health Sector Strategy 2015-2020 and its implementation plan (2016-2021); and the Health National Adaptation Plan (H-NAP): climate change and health strategy and action plan (2016-2020). However, the translation of these policies and plans of action into tangible action on the ground is still in its infancy in Nepal. Despite this, the health sector's response to addressing the impact of climate change in Nepal may be taken as a good example for other low- and middle-income countries. PMID- 28857058 TI - Climate conditions, workplace heat and occupational health in South-East Asia in the context of climate change. AB - Occupational health is particularly affected by high heat exposures in workplaces, which will be an increasing problem as climate change progresses. People working in jobs of moderate or heavy work intensity in hot environments are at particular risk, owing to exposure to high environmental heat and internal heat production. This heat needs to be released to protect health, and such release is difficult or impossible at high temperatures and high air humidity. A range of clinical health effects can occur, and the heat-related physical exhaustion leads to a reduction of work capacity and labour productivity, which may cause substantial economic losses. Current trends in countries of the World Health Organization South-East Asia Region are towards higher ambient heat levels during large parts of each year, and modelling indicates continuing trends, which will particularly affect low-income individuals and communities. Prevention activities need to address the climate policies of each country, and to apply currently available heat-reducing technologies in workplaces whenever possible. Work activities can be adjusted to reduce exposure to daily heat peaks or seasonal heat concerns. Application of basic occupational health principles, such as supply of drinking water, enforcement of rest periods and training of workers and supervisors, is essential. PMID- 28857059 TI - Water, sanitation and hygiene: The unfinished agenda in the World Health Organization South-East Asia Region. AB - Access to adequate water, sanitation and hygiene (WASH) is essential for the health, well-being and dignity of all people. The World Health Organization South East Asia Region has made considerable progress in WASH provision during the past two decades. However, compared with increases in coverage of improved drinking water, in some parts of the region, access to adequate sanitation remains low, with continued prevalence of open defecation. The Sustainable Development Goals (SDGs) have set ambitious targets for WASH services to be achieved by 2030. Examples of major health outcomes that would benefit from meeting these targets are diarrhoea and nutrition status. Although the total number of deaths attributable to diarrhoea declined substantially between 1990 and 2012, inadequate WASH still accounts for more than 1000 child deaths each day worldwide. And, despite the reductions in mortality, diarrhoea morbidity attributable to diarrhoea remains unchanged at around 1.7 billion cases per year. It has been known for decades that repeated episodes of diarrhoea increase a child's risk of long-term undernutrition, reduced growth and impaired cognitive development. Nutritional effects of inadequate WASH also include environmental enteropathy, leading to chronic intestinal inflammation, malnutrition and developmental deficits in young children. Inadequate WASH also contributes to iron deficiency anaemia resulting from infestation with soil-transmitted helminths. The cross-sectoral emphasis of the SDGs should act as a stimulus for intersectoral collaboration on research and interventions to reduce all inequities that result from inadequate WASH. PMID- 28857060 TI - Observations and lessons learnt from more than a decade of water safety planning in South-East Asia. AB - In many countries of the World Health Organization (WHO) South-East Asia Region, drinking water is not used directly from the tap and faecal contamination of water sources is prevalent. As reflected in Sustainable Development Goal 6, access to safer drinking water is one of the most successful ways of preventing disease. The WHO Water Safety Framework promotes the use of water safety plans (WSPs), which are structured tools that help identify and mitigate potential risks throughout a water-supply system, from the water source to the point of use. WSPs not only help prevent outbreaks of acute and chronic waterborne diseases but also improve water-supply management and performance. During the past 12 years, through the direct and indirect work of a water quality partnership supported by the Australian Government, more than 5000 urban and rural WSPs have been implemented in the region. An impact assessment based on pre and post-WSP surveys suggests that WSPs have improved system operations and management, infrastructure and performance; leveraged donor funds; increased stakeholder communication and collaboration; increased testing of water quality; and increased monitoring of consumer satisfaction. These achievements, and their sustainability, are being achieved through national legislation and regulatory frameworks for water supply, including quality standards for drinking water; national training tools and extensive training of sector professionals and creation of WSP experts; model WSPs; WSP auditing systems; and the institution of longterm training and support. More than a decade of water safety planning using the WSP approach has shown that supplying safe drinking water at the tap throughout the WHO South-East Asia Region is a realistic goal. PMID- 28857061 TI - Sanitation safety planning as a tool for achieving safely managed sanitation systems and safe use of wastewater. AB - Increasing water stress and growing urbanization force a greater number of people to use wastewater as an alternative water supply, especially for irrigation. Although wastewater irrigation in agriculture has a long history and substantial benefits, without adequate treatment and protective measures on farms and in markets, use of wastewater poses risks to human health and the environment. Against this background, the World Health Organization (WHO) published Guidelines for the safe use of wastewater, excreta and greywater in agriculture and aquaculture, in 2006. The Sanitation safety planning: manual for safe use and disposal of wastewater, greywater and excreta - a step-by-step risk-based management tool for sanitation systems - was published by WHO in 2016 to put these guidelines into practice. Sanitation safety planning (SSP) can be applied to all sanitation systems, to ensure the systems are managed to meet health objectives. This paper summarizes the pilot-testing of the SSP manual in India, Peru, Portugal, Philippines, Uganda and Viet Nam. Also reviewed are some of the key components of the manual and training, and an overview of SSP training and dissemination efforts and opportunities for implementation in the WHO South-East Asia Region. Lessons learnt during the piloting phase show how reducing health risks can be surprisingly easy, even in a low-income setting, especially when combining many smaller measures. The SSP approach can make an important contribution towards Sustainable Development Goal target 6.3, by reducing pollution, eliminating dumping and minimizing the release of hazardous chemicals and materials, thereby halving the proportion of untreated wastewater and substantially increasing recycling and safe reuse globally. PMID- 28857062 TI - Online media coverage of air pollution risks and current policies in India: A content analysis. AB - Background Air pollution is of particular concern in India, which contains 11 of the 20 most polluted cities in the world. Media coverage of air pollution issues plays an important role in influencing public opinion and increasing citizen demand for action on clean air policy. Hence, this study was designed to assess news coverage of air pollution in India and its implications for policy advancement. Methods Articles published online between 1 January 2014 and 31 October 2015 that discussed air pollution in India were systematically content analysed. From 6435 articles in the national media and 271 articles in the international media, a random selection of 500 articles (400 from national and 100 from international media) were analysed and coded by two independent coders, after high inter-rater reliability (kappa statistic above 0.8) was established. Results There was an increase in the number of news stories on air pollution in India in the national media over the study period; 317 (63%) stories described the risk to health from air pollution as moderately to extremely severe, and 393 (79%) stories described the situation as needing urgent action. Limited information was provided on the kinds of illnesses that can result from exposure. Less than 30% of stories in either media specifically mentioned the common illnesses resulting from air pollution. Very few articles in either media mentioned the population groups most at risk from air pollution, such as children or older people. Vehicles were presented most often as the cause of air pollution in India (in over 50% of articles in both national and international media). Some of the most important sources of air pollution were mentioned less often: 6% of national and 18% of international media articles mentioned unclean sources of household energy; 3% of national and 9% of international media articles mentioned agricultural field burning. Finally, the majority of articles (405; 81%) did not mention any specific institution or organization - such as the government or industry groups - as the primary responsible stakeholder, thus leaving ambiguous the organizations whose leadership was necessary to mitigate air pollution. Conclusion Gaps exist in the current media discourse on air pollution, suggesting the need for strengthening engagement with the media as a means of creating citizen engagement and enabling policy action. Through greater elaboration of the health burdens and evidence-based policy actions, the media can play a critical role in galvanizing India's action on air quality. These data may suggest opportunities for media advocacy and greater public and policy engagement to address issues around air quality in India. PMID- 28857063 TI - Rural recruitment and retention of health workers across cadres and types of contract in north-east India: A qualitative study. AB - Background Like many other low- and middle-income countries, India faces challenges of recruiting and retaining health workers in rural areas. Efforts have been made to address this through contractual appointment of health workers in rural areas. While this has helped to temporarily bridge the gaps in human resources, the overall impact on the experience of rural services across cadres has yet to be understood. This study sought to identify motivations for, and the challenges of, rural recruitment and retention of nurses, doctors and specialists across types of contract in rural and remote areas in India's largely rural north eastern states of Meghalaya and Nagaland. Methods A qualitative study was undertaken, in which 71 semi-structured interviews were carried out with doctors (n = 32), nurses (n = 28) and specialists (n = 11). In addition, unstructured key informant interviews (n = 11) were undertaken, along with observations at health facilities and review of state policies. Data were analysed using Ritchie and Spencer's framework method and the World Health Organization's 2010 framework of factors affecting decisions to relocate to, stay in or leave rural areas. Results It was found that rural background and community attachment were strongly associated with health workers' decision to join rural service, regardless of cadre or contract. However, this aspiration was challenged by health-systems factors of poor working and living conditions; low salary and incentives; and lack of professional growth and recognition. Contractual health workers faced unique challenges (lack of pay parity, job insecurity), as did those with permanent positions (irrational postings and political interference). Conclusion This study establishes that the crisis in recruiting and retaining health workers in rural areas will persist until and unless health systems address the core basic requirements of health workers in rural areas, which are related to health sector policies. Concerted attention and long-term political commitment to overcome system-level barriers and governance may yield sustainable gains in rural recruitment and retention across cadres and contract types. PMID- 28857064 TI - Implementation of G6PD testing and primaquine for P. vivax radical cure: Operational perspectives from Thailand and Cambodia. AB - Following progressive success in reducing the burden of malaria over the past two decades, countries of the Asia Pacific are now aiming for elimination of malaria by 2030. Plasmodium falciparum and Plasmodium vivax are the two main malaria species that are endemic in the region. P. vivax is generally perceived to be less severe but will be harder to eliminate, owing partly to its dormant liver stage (known as a hypnozoite) that can cause multiple relapses following an initial clinical episode caused by a mosquito-borne infection. Primaquine is the only anti-hypnozoite drug against P. vivax relapse currently available, with tafenoquine in the pipeline. However, both drugs may cause severe haemolysis in individuals with deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), a hereditary defect. The overall incidence of malaria has significantly declined in both Thailand and Cambodia over the last 15 years. However, P. vivax has replaced P. falciparum as the dominant species in large parts of both countries. This paper presents the experience of the national malaria control programmes of the two countries, in their efforts to implement safe primaquine therapy for the radical cure, i.e. relapse prevention, of P. vivax malaria by introducing a rapid, point-of-care test to screen for G6PD deficiency. PMID- 28857065 TI - Package of essential noncommunicable disease (PEN) interventions in primary health-care settings in the Democratic People's Republic of Korea: A feasibility study. AB - The prevention and control of noncommunicable diseases (NCDs) is a priority for the Democratic People's Republic of Korea. Mortality due to NCDs in people aged over 30 years was 1239 per 100 000 in 2009 and the 2014-2020 national strategy includes population-level goals for health promotion and disease prevention. This paper reports a pilot study on the feasibility of implementing components of the World Health Organization (WHO) Package of essential noncommunicable disease (PEN) interventions for primary health care in low-resource settings (WHO PEN) to enable early detection and management of cardiovascular disease and diabetes mellitus at the level of primary care. WHO PEN protocols were adapted for local use by household doctors, who provide ambulatory care in polyclinics in the mornings and household visits in the afternoons. The pilot project was implemented in two polyclinics in Pyongyang, covering a population of 32 000. After training, and during routine household visits in June 2014, 70 household doctors screened all adults aged over 35 years (18 340) for cardiovascular disease and diabetes mellitus, and their risk factors. A total of 2319 patients with cardiovascular disease or diabetes, and those with high-risk factors, were referred to the polyclinics for three quarterly visits for testing and management. Final household screening of the population was done in June 2015. This pilot project demonstrated the feasibility of integrating screening and management into the standard primary health-care system in the Democratic People's Republic of Korea. The household doctors were able to detect and manage risks for cardiovascular disease and diabetes by using the protocols based on WHO PEN. Among 18 340 individuals aged over 35 years, implementation of WHO PEN interventions led to a significant reduction in the number of people with a 10 year risk of cardiovascular disease >=20% (from 1748 [9.5%] to 543 [3.0%]) over a 1-year period. Involvement of household doctors can increase access to services for prevention and control of cardiovascular disease and diabetes in the Democratic People's Republic of Korea. PMID- 28857066 TI - Hypoparathyroidism. AB - Hypoparathyroidism is a disease characterized by inadequately low circulating concentrations of parathyroid hormone (PTH) resulting in low calcium levels and increased phosphate levels in the blood. Symptoms of the disease result from increased neuromuscular irritability caused by hypocalcaemia and include tingling, muscle cramps and seizures. The most common cause of the disease is inadvertent removal of, or injury to, the parathyroid glands during neck surgery, followed by genetic, idiopathic and autoimmune aetiologies. Conventional treatment includes activated vitamin D and/or calcium supplements, but this treatment does not fully replace the functions of PTH and can lead to short-term problems (such as hypocalcaemia, hypercalcaemia and increased urinary calcium excretion) and long-term complications (which include nephrocalcinosis, kidney stones and brain calcifications). PTH replacement has emerged as a new treatment option. Clinical trials using human PTH(1-34) and PTH(1-84) showed that this treatment was safe and effective in studies lasting up to 6 years. Recombinant human PTH(1-84) has been approved in the United States and Europe for the management of hypoparathyroidism; however, its effect on long-term complications is still being evaluated. Clinical practice guidelines, which describe the consensus of experts in the field, have been published and recognize the need for more research to optimize care. In this Primer, we summarize current knowledge of the prevalence, pathophysiology, clinical presentation and management of hypoparathyroidism. PMID- 28857068 TI - Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator. AB - Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockDelta19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockDelta19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockDelta19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockDelta19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania. PMID- 28857072 TI - Brain cancer: Temozolomide improves outcomes. PMID- 28857070 TI - Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence. AB - The kappa-opioid receptor (KOP-r) system and its endogenous ligands, the dynorphins, are involved in the neurobiological regulation of addictive states, and of mood. There are limited data on the impact of selective KOP-r antagonism in humans on basic biobehavioral functions, or on addictive diseases and mood disorders. Previously studied selective KOP-r antagonists have unusual pharmacodynamic and pharmacokinetic properties (slow development of KOP-r selectivity, extremely long duration of action) that limit translation to human studies. A recently developed selective KOP-r-antagonist, Opra Kappa (LY2456302; CERC-501), has medication-like duration of action, oral bioavailability, and target engagement. The current study is the first investigation of the effects of a KOP-r-antagonist in cocaine-dependent persons in comparison with normal volunteers. In a stress-minimized inpatient setting, we determined the neuroendocrine and neurobehavioral effects of repeated administration of an active dose of Opra Kappa (10 mg p.o. daily, four consecutive days in comparison with an initial baseline day). Healthy volunteers (n=40), persons diagnosed with cocaine dependence in early abstinence (<2 months, EACD) (n=23), and drug-free former cocaine-dependent persons (7-month to 25-year abstinence, DFFCD) (n=7) were studied, with measurements including circulating neuroendocrine hormones, affect, and, in cocaine-dependent persons, cocaine craving. Modest adverse events related to Opra Kappa included pruritus, observed in a subset of individuals. No significant change was observed in serum prolactin levels following Opra Kappa administration, but modest increases in circulating adrenocorticotropic hormone and cortisol were observed. No significant changes were noted in measures of depression or cocaine craving in this stress-minimized setting. Overall, these studies demonstrate that effects of 10 mg Opra Kappa are largely consistent with those predicted for a selective KOP-r antagonist. This medication regimen was tolerable, and is therefore feasible for further studies in cocaine-dependent persons. PMID- 28857071 TI - Oleic Acid in the Ventral Tegmental Area Inhibits Feeding, Food Reward, and Dopamine Tone. AB - Long-chain fatty acids (FAs) act centrally to decrease food intake and hepatic glucose production and alter hypothalamic neuronal activity in a manner that depends on FA type and cellular transport proteins. However, it is not known whether FAs are sensed by ventral tegmental area (VTA) dopamine (DA) neurons to control food-motivated behavior and DA neurotransmission. We investigated the impact of the monounsaturated FA oleate in the VTA on feeding, locomotion, food reward, and DA neuronal activity and DA neuron expression of FA-handling proteins and FA uptake. A single intra-VTA injection of oleate, but not of the saturated FA palmitate, decreased food intake and increased locomotor activity. Furthermore, intra-VTA oleate blunted the rewarding effects of high-fat/sugar food in an operant task and inhibited DA neuronal firing. Using sorted DA neuron preparations from TH-eGFP mice we found that DA neurons express FA transporter and binding proteins, and are capable of intracellular transport of long-chain FA. Finally, we demonstrate that a transporter blocker attenuates FA uptake into DA neurons and blocks the effects of intra-VTA oleate to decrease food-seeking and DA neuronal activity. Together, these results suggest that DA neurons detect FA and that oleate has actions in the VTA to suppress DA neuronal activity and food seeking following cellular incorporation. These findings highlight the capacity of DA neurons to act as metabolic sensors by responding not only to hormones but also to FA nutrient signals to modulate food-directed behavior. PMID- 28857073 TI - Pancreatic cancer: TCGA data reveal a highly heterogeneous disease. PMID- 28857074 TI - Breast cancer: AKT inhibition effective against TNBC. PMID- 28857069 TI - The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain. AB - A great need exists for the development of new medications to treat pain resulting from various disease states and types of injury. Given that the endogenous cannabinoid (that is, endocannabinoid) system modulates neuronal and immune cell function, both of which play key roles in pain, therapeutics targeting this system hold promise as novel analgesics. Potential therapeutic targets include the cannabinoid receptors, type 1 and 2, as well as biosynthetic and catabolic enzymes of the endocannabinoids N-arachidonoylethanolamine and 2 arachidonoylglycerol. Notably, cannabinoid receptor agonists as well as inhibitors of endocannabinoid-regulating enzymes fatty acid amide hydrolase and monoacylglycerol lipase produce reliable antinociceptive effects, and offer opioid-sparing antinociceptive effects in myriad preclinical inflammatory and neuropathic pain models. Emerging clinical studies show that 'medicinal' cannabis or cannabinoid-based medications relieve pain in human diseases such as cancer, multiple sclerosis, and fibromyalgia. However, clinical data have yet to demonstrate the analgesic efficacy of inhibitors of endocannabinoid-regulating enzymes. Likewise, the question of whether pharmacotherapies aimed at the endocannabinoid system promote opioid-sparing effects in the treatment of pain reflects an important area of research. Here we examine the preclinical and clinical evidence of various endocannabinoid system targets as potential therapeutic strategies for inflammatory and neuropathic pain conditions. PMID- 28857076 TI - Breast Cancer: Evolution of metastatic disease revealed. PMID- 28857075 TI - Chimeric antigen receptor T-cell therapies for lymphoma. AB - New therapies are needed for patients with Hodgkin or non-Hodgkin lymphomas that are resistant to standard therapies. Indeed, unresponsiveness to standard chemotherapy and relapse after autologous stem-cell transplantation are indicators of an especially poor prognosis. Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment modality for these patients. Clinical trial data have demonstrated the potent activity of anti-CD19 CAR T cells against multiple subtypes of B-cell lymphoma, including diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, and marginal-zone lymphoma. Importantly, anti-CD19 CAR T cells have impressive activity against chemotherapy refractory lymphoma, inducing durable complete remissions lasting >2 years in some patients with refractory DLBCL. CAR-T-cell therapies are, however, associated with potentially fatal toxicities, including cytokine-release syndrome and neurological toxicities. CAR T cells with novel target antigens, including CD20, CD22, and kappa-light chain for B-cell lymphomas, and CD30 for Hodgkin and T-cell lymphomas, are currently being investigated in clinical trials. Centrally manufactured CAR T cells are also being tested in industry-sponsored multicentre clinical trials, and will probably soon become a standard therapy. Herein, we review the clinical efficacy and toxicity of CAR-T-cell therapies for lymphoma, and discuss their limitations and future directions with regard to toxicity management, CAR designs and CAR-T-cell phenotypes, conditioning regimens, and combination therapies. PMID- 28857078 TI - Cell signalling: Even kinase-inactive BRAF is oncogenic. PMID- 28857079 TI - Immunotherapy: CRISPR unveils T-cell-resistance mechanisms in tumours. PMID- 28857080 TI - Cardioprotection: Anti-ageing effects of cardiosphere-derived cells. PMID- 28857081 TI - Surgery: On-pump superior to off-pump CABG surgery. PMID- 28857077 TI - Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. AB - Structural gene rearrangements resulting in gene fusions are frequent events in solid tumours. The identification of certain activating fusions can aid in the diagnosis and effective treatment of patients with tumours harbouring these alterations. Advances in the techniques used to identify fusions have enabled physicians to detect these alterations in the clinic. Targeted therapies directed at constitutively activated oncogenic tyrosine kinases have proven remarkably effective against cancers with fusions involving ALK, ROS1, or PDGFB, and the efficacy of this approach continues to be explored in malignancies with RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF fusions. Nevertheless, prolonged treatment with such tyrosine-kinase inhibitors (TKIs) leads to the development of acquired resistance to therapy. This resistance can be mediated by mutations that alter drug binding, or by the activation of bypass pathways. Second-generation and third-generation TKIs have been developed to overcome resistance, and have variable levels of activity against tumours harbouring individual mutations that confer resistance to first-generation TKIs. The rational sequential administration of different inhibitors is emerging as a new treatment paradigm for patients with tumours that retain continued dependency on the downstream kinase of interest. PMID- 28857082 TI - Basic research: Minimally invasive delivery of engineered cardiac patches for heart repair. PMID- 28857083 TI - Dyslipidaemia: No effect of PCSK9 inhibitors on cognitive function. PMID- 28857084 TI - Serum amyloid A inhibits dendritic cell differentiation by suppressing GM-CSF receptor expression and signaling. AB - In this study, we report that an acute phase reactant, serum amyloid A (SAA), strongly inhibits dendritic cell differentiation induced by GM-CSF plus IL-4. SAA markedly decreased the expression of MHCII and CD11c. Moreover, SAA decreased cell surface GM-CSF receptor expression. SAA also decreased the expression of PU.1 and C/EBPalpha, which play roles in the expression of GM-CSF receptor. This inhibitory response by SAA is partly mediated by the well-known SAA receptors, Toll-like receptor 2 and formyl peptide receptor 2. Taken together, we suggest a novel insight into the inhibitory role of SAA in dendritic cell differentiation. PMID- 28857085 TI - Enteric dysbiosis-linked gut barrier disruption triggers early renal injury induced by chronic high salt feeding in mice. AB - Chronic high-salt diet-associated renal injury is a key risk factor for the development of hypertension. However, the mechanism by which salt triggers kidney damage is poorly understood. Our study investigated how high salt (HS) intake triggers early renal injury by considering the 'gut-kidney axis'. We fed mice 2% NaCl in drinking water continuously for 8 weeks to induce early renal injury. We found that the 'quantitative' and 'qualitative' levels of the intestinal microflora were significantly altered after chronic HS feeding, which indicated the occurrence of enteric dysbiosis. In addition, intestinal immunological gene expression was impaired in mice with HS intake. Gut permeability elevation and enteric bacterial translocation into the kidney were detected after chronic HS feeding. Gut bacteria depletion by non-absorbable antibiotic administration restored HS loading-induced gut leakiness, renal injury and systolic blood pressure elevation. The fecal microbiota from mice fed chronic HS could independently cause gut leakiness and renal injury. Our current work provides a novel insight into the mechanism of HS-induced renal injury by investigating the role of the intestine with enteric bacteria and gut permeability and clearly illustrates that chronic HS loading elicited renal injury and dysfunction that was dependent on the intestine. PMID- 28857087 TI - Obstructive sleep apnea risk for driving license applicants in India - A community based study. AB - OBJECTIVES: To determine the risk of obstructive sleep apnea (OSA) for male permanent driving license (DL) applicants of Lucknow, India. MATERIAL AND METHODS: In this cross-sectional community based, study body mass index, waist hip ratio, blood pressure of each subject were determined as an anthropometric parameter along with the history of habit of smoking, tobacco chewing, alcohol consumption. STOP-Bang (Snoring, Tired or sleepy, Observed apnea, high blood Pressure, Body mass index, Age, Neck, Gender) Questionnaire - a scoring risk assessment tool - was applied for assessment of OSA risk (high OSA risk defined by score >= 3) for 542 male DL recipients at 2 Regional Transport Office (RTO) centers in Lucknow, India. The statistical software SPSS 17.0 was applied to the testing. RESULTS: In total 23% (N = 125) of participants were found with the risk of OSA. High blood pressure (>= 140/90 mm Hg) was found for the maximum number of participants (40.5%) followed by neck circumference > 40 cm (17.1%), age (> 50 years old) (15.3%), snoring (12.3%) and tired/sleepy (10.5%). Mean values of age, anthropometric measurements and blood pressure were observed significantly higher (p < 0.001) for participants with the OSA risk. In this population the risk of OSA risk (STOP-Bang score >= 3) was observed for 6.7% of young (< 35 years old), 34% of middle (35-45 years old) and 73% of elder age adults (> 45 years old). CONCLUSIONS: In view of findings of this study a high number of male driving license applicants were observed with the risk of OSA. Therefore efforts should be made to develop a national screening guideline/protocol for the OSA risk assessment for driving license applicants in India. This may reduce the possibility of road traffic accidents due to the OSA-associated fatigue and drowsiness behind the wheels. Int J Occup Med Environ Health 2018;31(1):25-36. PMID- 28857086 TI - CCCTC-binding factor is essential to the maintenance and quiescence of hematopoietic stem cells in mice. AB - Hematopoiesis involves a series of lineage differentiation programs initiated in hematopoietic stem cells (HSCs) found in bone marrow (BM). To ensure lifelong hematopoiesis, various molecular mechanisms are needed to maintain the HSC pool. CCCTC-binding factor (CTCF) is a DNA-binding, zinc-finger protein that regulates the expression of its target gene by organizing higher order chromatin structures. Currently, the role of CTCF in controlling HSC homeostasis is unknown. Using a tamoxifen-inducible CTCF conditional knockout mouse system, we aimed to determine whether CTCF regulates the homeostatic maintenance of HSCs. In adult mice, acute systemic CTCF ablation led to severe BM failure and the rapid shrinkage of multiple c-Kithi progenitor populations, including Sca-1+ HSCs. Similarly, hematopoietic system-confined CTCF depletion caused an acute loss of HSCs and highly increased mortality. Mixed BM chimeras reconstituted with supporting BM demonstrated that CTCF deficiency-mediated HSC depletion has both cell-extrinsic and cell-intrinsic effects. Although c-Kithi myeloid progenitor cell populations were severely reduced after ablating Ctcf, c-Kitint common lymphoid progenitors and their progenies were less affected by the lack of CTCF. Whole-transcriptome microarray and cell cycle analyses indicated that CTCF deficiency results in the enhanced expression of the cell cycle-promoting program, and that CTCF-depleted HSCs express higher levels of reactive oxygen species (ROS). Importantly, in vivo treatment with an antioxidant partially rescued c-Kithi cell populations and their quiescence. Altogether, our results suggest that CTCF is indispensable for maintaining adult HSC pools, likely by regulating ROS-dependent HSC quiescence. PMID- 28857088 TI - [Health hazards resulting from exposure to zinc and its inorganic compounds in industry]. AB - This article deals with health risks resulting from exposure to zinc and its inorganic compounds in industry. The main source of zinc exposure are fumes generated during thermal and chemical processes, mainly zinc oxide fume formed by immediate oxidation of metallic zinc vapor formed during high-temperature processes, as well as dust generated during the mechanical processing of zinc containing materials. It is recognized that zinc ions are responsible for health effects of exposure to dust/fumes of the majority of zinc compounds, and the final effect of exposure depends on the degree of dispersion of dusts/fumes suspended in the air. Since the effects of exposure depends on the particle size, occupational exposure limits have began to be established separately for respirable and inhalable fractions. A critical effect of acute exposure to respirable fraction is a "fume fever" which in chronic exposure occurs as an effect associated with recurrent symptoms of acute poisoning. Impaired lung function and asthma symptoms are considered to be the main effects of exposure to inhalable fraction. Due to the limited number of the available data it is not possible to assess carcinogenicity, reproductive toxicity and teratogenicity of zinc and its compounds. The aim of the study was to analyze the major health hazards resulting from occupational exposure to zinc and its inorganic compounds in the context of their physico-chemical properties, a wide range of applications and occupational exposure data. Med Pr 2017;68(6):779-794. PMID- 28857089 TI - [ERCP procedures as a source of radiation risk to a single gastroenterologist]. AB - BACKGROUND: One of the numerous sub-areas of interventional radiology is the use of X-rays in gastroenterology. X-ray fluoroscopy is applied in therapeutic procedures, including endoscopic retrograde cholangiopancreatography (ERCP) that is frequently performed. The ERCP procedure is aimed at imaging the pancreatic duct and biliary tracts. MATERIAL AND METHODS: In this paper radiation risk to the gastrenterologist performing ERCP procedures was investigated. The procedures were performed by a single gastroenterologist in the ERCP Laboratory, University Clinical Hospital Military Memorial Medical Academy - Central Veterans' Hospital in Lodz, Poland. The study comprised 2 series of measurements, one taken during the procedures with continuous fluoroscopy mode, the other during procedures with fluoroscopy in pulsed mode at a frequency of 3 pulses/s. Exposure parameters, anatomical data of patient and dose equivalents for the eyes, skin of the hand and the effective dose for whole body of the gastroenterologist were recorded during each procedure. RESULTS: The collected data cover 70 ERCP procedures - 40 procedures were controlled by continuous fluoroscopy and 30 by pulsed fluoroscopy. The results reveal that pulsed fluoroscopy makes it possible to reduce doses received by the gastroeneterologist from 45% to 60% compared to continuous fluoroscopy. CONCLUSIONS: Endoscopic retrograde cholangiopancreatography procedures can cause radiation risk to the gastroenterologist performing them. The use of continuous fluoroscopy can result in achieving an equivalent dose to eye lens nearly 20 mSv per year, i.e., the decreased annual limit recommended by the International Commission on Radiological Protection (ICRP). Med Pr 2017;68(6):735-741. PMID- 28857090 TI - [Norwegian Teacher Self-Efficacy Scale - Psychometric properties of the Polish version of the scale]. AB - BACKGROUND: Self-efficacy refers to different spheres of human functioning and to different tasks, including teaching activity. It is regarded as an important personal resource related to coping with stress. This paper was aimed at presenting psychometric properties of the Norwegian Teachers Self-Efficacy Scale (NTSES), related to these beliefs in the group of teachers. MATERIAL AND METHODS: Psychometric properties of the scale were evaluated on the basis of the data obtained from 404 teachers of elementary and middle schools. RESULTS: Our analyses of exploratory and confirmatory factor revealed a 3-dimensional structure, but not a 6-dimensional structure of NTSES as obtained in the original Norwegian study. They also showed high reliability and construct validity coefficients. Teachers self-efficacy was positively correlated with general self efficacy, internal locus of control and negatively with job burnout. CONCLUSIONS: Although NTSES can be used in the study of Polish teachers, this should be done with great caution and the measure of global index of NTSES should be used. Additional studies on a larger sample of teachers are recommended. Med Pr 2017;68(6):743-755. PMID- 28857091 TI - Findings of Research Misconduct. PMID- 28857092 TI - Direct conversion of syngas to aromatics. AB - A composite catalyst combining the partially reducible ZnCrOx with zeolite ZSM-5 enables direct conversion of syngas to aromatics, with a selectivity to aromatics reaching 73.9% at a single pass CO conversion of 16.0%. PMID- 28857093 TI - Influence of precursor porosity on sodium and sulfur promoted iron/carbon Fischer Tropsch catalysts derived from metal-organic frameworks. AB - Iron-based metal-organic frameworks (MOFs) with varying porosity are converted by pyrolysis into iron/carbon catalysts with predetermined composition and tailored pore structural features for the Fischer-Tropsch synthesis of lower C2-C4 olefins. Significantly higher activity arises for catalysts with higher porosity and decreased iron particle size derived from hierarchical MOF xerogel/aerogel precursors as compared to a purely microporous MOF. Post-synthetic functionalization using sodium and sulfur promoters further enhances the catalytic properties. PMID- 28857095 TI - A diubiquitin-based photoaffinity probe for profiling K27-linkage targeting deubiquitinases. AB - K27-linkage poly-ubiquitination plays important roles in DNA damage repair and autoimmunity. Identification of K27-linkage targeting deubiquitinases (DUBs) is essential for understanding their regulatory mechanisms. Here we report an aryl azide-based photoaffinity diubiquitin (diUb) probe for profiling K27-linkage targeting DUBs. This probe shows high selectivity and sensitivity towards K27 linkage DUBs in vitro. It can also be used in cell lysate for identifying and probing K27-linkage targeting DUBs in real proteomes. Our work suggests that the photoaffinity-based strategy may provide a new useful approach for the construction of other isopeptide linkage targeting DUB probes. PMID- 28857096 TI - Photoswitchable molecules as key ingredients to drive systems away from the global thermodynamic minimum. AB - In order to perform chemical work, molecular systems have to be operated away from thermodynamic equilibrium and therefore require the input of energy. Light is perhaps the most abundant and advantageous energy source that in combination with photoswitches allows for a reversible and hence continuous stimulation of a system. In this review, we illustrate how photoswitchable molecules can be used to escape the global thermodynamic minimum by populating metastable states, from which energy can be transferred and transformed in a controlled fashion. We emphasize the unique feature of photodynamic equilibria, in which population of the states is dictated by the excitation wavelength (and not primarily by temperature), thereby avoiding microscopic reversibility since the photoreaction involves an electronically excited state. Thus, photoswitchable molecular systems can remotely be controlled with high spatial and temporal resolution and in addition their action can be fueled by light. PMID- 28857097 TI - Defocused dark-field orientation imaging of single gold microrods on synthetic membranes. AB - Plasmonic gold microrods (AuMRs) are promising optical probes because of direct observation of their in-plane orientations and motions under an optical microscope. However, our understanding of the optical properties of AuMRs is still very limited to the single particle level, and their out-of-plane orientations cannot be resolved by eye with high accuracy. Herein, we present the scattering properties of 1 MUm-long AuMRs under a defocused DF microscope. The characteristic defocused scattering patterns of single AuMRs allowed us to resolve both in-plane and out-of-plane angles of single AuMRs. We further demonstrate the feasibility of using the defocused orientation imaging technique to track rotational motions and out-of-plane angles of single AuMRs on synthetic membranes. PMID- 28857098 TI - Direct growth of graphene on rigid and flexible substrates: progress, applications, and challenges. AB - Graphene has recently been attracting considerable interest because of its exceptional conductivity, mechanical strength, thermal stability, etc. Graphene based devices exhibit high potential for applications in electronics, optoelectronics, and energy harvesting. In this paper, we review various growth strategies including metal-catalyzed transfer-free growth and direct-growth of graphene on flexible and rigid insulating substrates which are "major issues" for avoiding the complicated transfer processes that cause graphene defects, residues, tears and performance degradation in graphene-based functional devices. Recent advances in practical applications based on "direct-grown graphene" are discussed. Finally, several important directions, challenges and perspectives in the commercialization of 'direct growth of graphene' are also discussed and addressed. PMID- 28857099 TI - Recent advances in understanding of the mechanism and control of Li2O2 formation in aprotic Li-O2 batteries. AB - Aprotic Li-O2 batteries represent promising alternative devices for electrical energy storage owing to their extremely high energy densities. Upon discharge, insulating solid Li2O2 forms on cathode surfaces, which is usually governed by two growth models, namely the solution model and the surface model. These Li2O2 growth models can largely determine the battery performances such as the discharge capacity, round-trip efficiency and cycling stability. Understanding the Li2O2 formation mechanism and controlling its growth are essential to fully realize the technological potential of Li-O2 batteries. In this review, we overview the recent advances in understanding the electrochemical and chemical processes that occur during the Li2O2 formation. In the beginning, the oxygen reduction mechanisms, the identification of O2-/LiO2 intermediates, and their influence on the Li2O2 morphology have been discussed. The effects of the discharge current density and potential on the Li2O2 growth model have been subsequently reviewed. Special focus is then given to the prominent strategies, including the electrolyte-mediated strategy and the cathode-catalyst-tailoring strategy, for controlling the Li2O2 growth pathways. Finally, we conclude by discussing the profound implications of controlling Li2O2 formation for further development in Li-O2 batteries. PMID- 28857101 TI - Hydrophobic fluorine mediated switching of the hydrogen bonding site as well as orientation of water molecules in the aqueous mixture of monofluoroethanol: IR, molecular dynamics and quantum chemical studies. AB - The local structures between water-water, alcohol-water and alcohol-alcohol have been investigated for aqueous mixtures of ethanol (ETH) and monofluoroethanol (MFE) by the deconvolution of IR bands in the OH stretching region, molecular dynamics simulation and quantum chemical calculations. It has been found that the addition of a small amount of ETH into the aqueous medium increases the strength of the hydrogen bonds between water molecules. In an aqueous mixture of MFE, the substitution of a single fluorine induces a change in the orientation as well as the hydrogen bonding site of water molecules from the oxygen to the fluorine terminal of MFE. The switching of the hydrogen bonding site of water in the aqueous mixture of MFE results in comparatively strong hydrogen bonds between MFE and water molecules as well as less clustering of water molecules, unlike the case of the aqueous mixture of ETH. These findings about the modification of a hydrogen bond network by the hydrophobic fluorine group probably make fluorinated molecules useful for pharmaceutical as well as biological applications. PMID- 28857102 TI - Theoretical investigation on spin-forbidden cooling transitions of gallium hydride. AB - Herein, the spin-forbidden cooling of a gallium hydride molecule is investigated using ab initio quantum chemistry. The cooling transition and the corresponding potential energy curves including , a3Pi0-, a3Pi0+, a3Pi1, a3Pi2, A1Pi1, , 13Sigma, , , and 23Sigma states are simulated based on the multi-reference configuration interaction approach plus Davidson corrections method. By solving the nuclear Schrodinger equation, we calculate the spectroscopic constants of these states, which are in good agreement with the available experimental values. Based on the transition data, there seems to be a theoretical puzzle: highly diagonally distributed Franck-Condon factor f00 for transitions , , and for the gallium hydride molecule but the intervening state A1Pi1 for transition is prohibitive to laser cooling. In addition, the transition does not have a suitable rate of optical cycling owing to a large radiative lifetime for state. Our theoretical simulation indicates the solution to the puzzle: the transition has a high emission rate, and there is a suitable radiative lifetime for a3Pi1 state, which can ensure rapid and efficient laser cooling of gallium hydride. The proposed laser drives transition by using three wavelengths (main pump laser lambda00; two repumping lasers lambda10 and lambda21). These results demonstrate the possibility of laser-cooling the gallium hydride molecule, and a sub microkelvin cool temperature can be reached for this molecule. PMID- 28857104 TI - Analysing the microenvironment of 2-p-toluidinylnaphthalene-6-sulfonate (TNS) in solvents and in different conformational states of proteins in relation to its fluorescence properties: a computational study. AB - Characterization of different conformational states of proteins is essential to understand their stability and activity. Biophysical techniques aid in analysing these conformational states and molecular fluorescence is one of the most reliable and quickly accessible methods. Apart from the intrinsic fluorescence of proteins, external fluorescence dyes such as TNS, ANS, nile red and thioflavin are also used to characterize partially unfolded, aggregated and fibrillar states of proteins, though their exact molecular-level interactions with proteins are yet to be completely unravelled. The present study attempts to investigate the binding of TNS molecules on different conformational states of proteins. Unconstrained molecular dynamics simulation of 50 molecules of TNS with the native state of BSA, native and two partially unfolded states of RNase A and alpha-lactalbumin in water was carried out. Dynamics simulation of TNS alone in different solvents such as water, ethanol, DMF and DMSO was also performed. Binding environments in all the proteins and the solvents were analysed in terms of H-bonding interactions, order of contacts, amino acid specificity and conformational changes of TNS, and correlated with experimentally observed fluorescence changes of the dye. The results suggest that TNS forms aggregates in water whereas in non-aqueous solvents the order of aggregates is lower which might result in an enhancement of its fluorescence intensity. Further, TNS preferably interacts with basic and aromatic amino acid residues of the proteins. In RNase A and alpha-lactalbumin, most of the TNS molecules tend to form aggregates even with the unfolded conformations of the proteins. However in BSA, the number of aggregated TNS molecules is less and TNS molecules in monomeric form are found in the hydrophobic crevices of the protein. This might result in an enhancement of the fluorescence in BSA compared to the other proteins. The distributions of angles and dihedrals of TNS in different environments suggest that the bending movement between the naphthyl and tolyl rings is constrained whereas significant planar rotations could be observed both in solvents and in protein-bound states. PMID- 28857106 TI - Dye-conjugated complementary lipophilic nucleosides as useful probes to study association processes by fluorescence resonance energy transfer. AB - Modern supramolecular chemistry relies on the combination of diverse analytical techniques that can provide complementary information on complex self-assembly landscapes. Among them, resonance energy transfer, monitored by fluorescence emission spectroscopy, arises as a sensitive and convenient phenomenon to report binding intermolecular interactions. The use of molecular probes labelled with suitable complementary energy-transfer pairs can provide valuable information about the thermodynamics, kinetics and self-sorting characteristics of a particular self-assembled system. The objective of this work is to generate a set of nucleoside FRET probes that can be reliably employed to prove and analyse quantitatively H-bonding interactions between complementary Watson-Crick pairs. We first describe the preparation of a set of lipophilic nucleosides that are linked to a pi-conjugated functional fragment. The bases include guanosine and 2 aminoadenosine as purine heterocycles, and cytidine and uridine as complementary pyrimidine bases. The pi-conjugated moiety comprises either a short phenylene ethynylene oligomer, a bithiophene, or a BODIPY dye. We then demonstrate that the last two chromophores constitute an energy donor-acceptor couple and that donor emission quenching can be related to the ratio of molecules bound to the complementary acceptor pair. Hence, fluorescence spectroscopy in combination with resonance energy transfer, is shown here to be a useful tool to study and quantify the association and self-sorting events between complementary and non complementary nucleosides in apolar aromatic solvents, where the binding strength is considerably high, and sensitive techniques that employ low concentrations are demanded. PMID- 28857107 TI - Transport properties of the top and bottom surfaces in monolayer MoS2 grown by chemical vapor deposition. AB - The advantage of MoS2, compared with graphene, is the direct growth on various oxide substrates by chemical vapor deposition (CVD) without utilizing catalytic metal substrates, which facilitates practical applications for electronics. The carrier mobility is, however, degraded from the intrinsic limit mainly due to short-range scattering caused by S vacancies formed during CVD growth. If the upper limit for the crystallinity of CVD-MoS2 on oxide substrates is determined by the MoS2/substrate interaction during growth, it will hinder the advantage. In this study, we investigated the interaction between monolayer MoS2 and a SiO2/Si substrate and the difference in crystallinity between the top and bottom S surfaces due to the MoS2/substrate interaction. Raman and photoluminescence spectroscopy indicated that doping and strain were induced in MoS2 from the substrate, but they could be removed by transferring MoS2 to a new substrate using polymers. The newly developed polymer-transfer technique enabled selective transfer of the bottom or top surface of CVD-MoS2 onto a new SiO2/Si substrate. The metal-insulator transition was clearly observed for both the normal and inverse transfers, suggesting that the crystallinity of CVD-MoS2 is high and that the crystallinity of the bottom surface interacting with the substrate was similar to that of the top free surface. These results provide positive prospects for the further improvement of the crystallinity of MoS2 on oxide substrates by reconsidering the growth conditions. PMID- 28857112 TI - Stiffness Properties of Adventitia, Media, and Full Thickness Human Atherosclerotic Carotid Arteries in the Axial and Circumferential Directions. AB - Arteries can be considered as layered composite material. Experimental data on the stiffness of human atherosclerotic carotid arteries and their media and adventitia layers are very limited. This study used uniaxial tests to determine the stiffness (tangent modulus) of human carotid artery sections containing American Heart Association type II and III lesions. Axial and circumferential oriented adventitia, media, and full thickness specimens were prepared from six human carotid arteries (total tissue strips: 71). Each artery yielded 12 specimens with two specimens in each of the following six categories; axial full thickness, axial adventitia (AA), axial media (AM), circumferential full thickness, circumferential adventitia (CA), and circumferential media (CM). Uniaxial testing was performed using Inspec 2200 controlled by software developed using labview. The mean stiffness of the adventitia was 3570 +/- 667 and 2960 +/- 331 kPa in the axial and circumferential directions, respectively, while the corresponding values for the media were 1070 +/- 186 and 1800 +/- 384 kPa. The adventitia was significantly stiffer than the media in both the axial (p = 0.003) and circumferential (p = 0.010) directions. The stiffness of the full thickness specimens was nearly identical in the axial (1540 +/- 186) and circumferential (1530 +/- 389 kPa) directions. The differences in axial and circumferential stiffness of media and adventitia were not statistically significant. PMID- 28857114 TI - The Statistical Segment Length of DNA: Opportunities for Biomechanical Modeling in Polymer Physics and Next-Generation Genomics. AB - The development of bright bisintercalating dyes for deoxyribonucleic acid (DNA) in the 1990s, most notably YOYO-1, revolutionized the field of polymer physics in the ensuing years. These dyes, in conjunction with modern molecular biology techniques, permit the facile observation of polymer dynamics via fluorescence microscopy and thus direct tests of different theories of polymer dynamics. At the same time, they have played a key role in advancing an emerging next generation method known as genome mapping in nanochannels. The effect of intercalation on the bending energy of DNA as embodied by a change in its statistical segment length (or, alternatively, its persistence length) has been the subject of significant controversy. The precise value of the statistical segment length is critical for the proper interpretation of polymer physics experiments and controls the phenomena underlying the aforementioned genomics technology. In this perspective, we briefly review the model of DNA as a wormlike chain and a trio of methods (light scattering, optical or magnetic tweezers, and atomic force microscopy (AFM)) that have been used to determine the statistical segment length of DNA. We then outline the disagreement in the literature over the role of bisintercalation on the bending energy of DNA, and how a multiscale biomechanical approach could provide an important model for this scientifically and technologically relevant problem. PMID- 28857113 TI - Myofibrils in Cardiomyocytes Tend to Assemble Along the Maximal Principle Stress Directions. AB - The mechanisms underlying the spatial organization of self-assembled myofibrils in cardiac tissues remain incompletely understood. By modeling cells as elastic solids under active cytoskeletal contraction, we found a good correlation between the predicted maximal principal stress directions and the in vitro myofibril orientations in individual cardiomyocytes. This implies that actomyosin fibers tend to assemble along the maximal tensile stress (MTS) directions. By considering the dynamics of focal adhesion and myofibril formation in the model, we showed that different patterns of myofibril organizations in mature versus immature cardiomyocytes can be explained as the consequence of the different levels of force-dependent remodeling of focal adhesions. Further, we applied the mechanics model to cell pairs and showed that the myofibril organizations can be regulated by a combination of multiple factors including cell shape, cell substrate adhesions, and cell-cell adhesions. This mechanics model can guide the rational design in cardiac tissue engineering where recapitulating in vivo myofibril organizations is crucial to the contractile function of the heart. PMID- 28857115 TI - Muscle Function and Coordination of Stair Ascent. AB - Stair ascent is an activity of daily living and necessary for maintaining independence in community environments. One challenge to improving an individual's ability to ascend stairs is a limited understanding of how lower limb muscles work in synergy to perform stair ascent. Through dynamic coupling, muscles can perform multiple functions and require contributions from other muscles to perform a task successfully. The purpose of this study was to identify the functional roles of individual muscles during stair ascent and the mechanisms by which muscles work together to perform specific subtasks. A three-dimensional (3D) muscle-actuated simulation of stair ascent was generated to identify individual muscle contributions to the biomechanical subtasks of vertical propulsion, anteroposterior (AP) braking and propulsion, mediolateral control and leg swing. The vasti and plantarflexors were the primary contributors to vertical propulsion during the first and second halves of stance, respectively, while gluteus maximus and hamstrings were the primary contributors to forward propulsion during the first and second halves of stance, respectively. The anterior and posterior components of gluteus medius were the primary contributors to medial control, while vasti and hamstrings were the primary contributors to lateral control during the first and second halves of stance, respectively. To control leg swing, antagonistic muscles spanning the hip, knee, and ankle joints distributed power from the leg to the remaining body segments. These results compliment previous studies analyzing stair ascent and provide further rationale for developing targeted rehabilitation strategies to address patient-specific deficits in stair ascent. PMID- 28857116 TI - Methodology for Computational Fluid Dynamic Validation for Medical Use: Application to Intracranial Aneurysm. AB - Computational fluid dynamics (CFD) is a promising tool to aid in clinical diagnoses of cardiovascular diseases. However, it uses assumptions that simplify the complexities of the real cardiovascular flow. Due to high-stakes in the clinical setting, it is critical to calculate the effect of these assumptions in the CFD simulation results. However, existing CFD validation approaches do not quantify error in the simulation results due to the CFD solver's modeling assumptions. Instead, they directly compare CFD simulation results against validation data. Thus, to quantify the accuracy of a CFD solver, we developed a validation methodology that calculates the CFD model error (arising from modeling assumptions). Our methodology identifies independent error sources in CFD and validation experiments, and calculates the model error by parsing out other sources of error inherent in simulation and experiments. To demonstrate the method, we simulated the flow field of a patient-specific intracranial aneurysm (IA) in the commercial CFD software star-ccm+. Particle image velocimetry (PIV) provided validation datasets for the flow field on two orthogonal planes. The average model error in the star-ccm+ solver was 5.63 +/- 5.49% along the intersecting validation line of the orthogonal planes. Furthermore, we demonstrated that our validation method is superior to existing validation approaches by applying three representative existing validation techniques to our CFD and experimental dataset, and comparing the validation results. Our validation methodology offers a streamlined workflow to extract the "true" accuracy of a CFD solver. PMID- 28857117 TI - Failure to achieve early disease response is associated with inferior survival in patients with newly diagnosed multiple myeloma. PMID- 28857118 TI - Anti-epileptic drug exposure and risk of foetal death in utero. AB - OBJECTIVE: To clarify whether anti-epileptic drug exposure during pregnancy is associated with an increased risk of intrauterine foetal death. METHODS: Analysis of data from 2064 pregnancies with known outcomes included in the Australian Register of Antiepileptic Drugs in Pregnancy, 170 of the pregnancies being unexposed to the drugs in at least the first half of pregnancy. RESULTS: The relative risk (6.46; 95% C.I. 0.90, 46.22) of intrauterine death appeared higher, though not statistically significantly higher, in drug-exposed pregnancies compared with unexposed ones (3.44% vs 0.59%). There was no statistically significantly increased hazard associated with AED polytherapy as compared with monotherapy. Logistic regression analysis showed a statistically significantly increased and dose-related hazard of intrauterine death in relation to carbamazepine exposure. CONCLUSIONS: Intrauterine exposure to anti-epileptic drugs, particularly carbamazepine, may be associated with an increased risk of foetal death during pregnancy. PMID- 28857119 TI - High Symptom Burden and Low Functional Status in the Setting of Multimorbidity. AB - OBJECTIVES: To enhance understanding of the relationship between multimorbidity, symptom burden, and functional status in individuals with life-limiting illness. DESIGN: Secondary analysis of baseline data from a randomized clinical trial conducted in the Palliative Care Research Cooperative Group. Group differences were tested using a t-test; multivariate regression analysis was used to determine the effect of multiple variables on functional status and symptom burden. SETTING: Fifteen Palliative Care Research Cooperation sites. PARTICIPANTS: Adults who participated in a parent statin-discontinuation clinical trial were included in the analysis (N = 381). Inclusion criteria were diagnosis of a life-limiting illness, statin use for 3 months or longer, life expectancy longer than 1 month, and declining functional status. MEASUREMENTS: Cancer diagnosis (solid organ and hematologic malignancies), multimorbidity (Charlson Comorbidity Index (CCI) score), symptom burden (Edmonton Symptom Assessment Scale (ESAS) score, number of symptoms with ESAS severity score >4), functional status (Australia-modified Karnofsky Performance Scale (AKPS)). RESULTS: Fifty-one percent had a primary diagnosis of cancer; mean age 74.1 +/- 11.6. Participants had multiple comorbid illnesses (CCI score 4.9 +/- 2.8), multiple symptoms (ESAS score 27.2 +/- 15.9), and poor functional status (AKPS = 53 +/- 13). In univariate and multivariate analyses, multimorbidity was associated with greater symptom burden (4.2 vs 3.1 moderate or severe symptoms (t = -3.2, P = .002), 12% vs 6% with severe symptoms (t = -3.7, P < .001)), but cancer diagnosis was not. In univariate and multivariate analyses, higher symptom burden was associated with poorer functional status (F = 11.6, P < .001), but multimorbidity was not. CONCLUSION: Symptoms cannot be attributed solely to a diagnosis of cancer. The association between symptom burden and functional status underscores the importance of clinical attention to symptoms in individuals with multimorbidity. PMID- 28857120 TI - Impact of genetic variants on haematopoiesis in patients with thrombocytopenia absent radii (TAR) syndrome. AB - Thrombocytopenia absent radii (TAR) syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism (SNP) either at the 5' untranslated region (5'UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5'UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5'UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP-dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR syndrome. PMID- 28857122 TI - Course of anti-ALK antibody titres during chemotherapy in children with anaplastic large cell lymphoma. PMID- 28857121 TI - Assessment of plasma endostatin to predict acute kidney injury in critically ill patients. AB - BACKGROUND: We evaluated whether plasma endostatin predicts acute kidney injury (AKI), need for renal replacement therapy (RRT), or death. METHODS: Prospective, observational, multicenter study from 1 September 2011 to 1 February 2012 with data from 17 intensive care units (ICUs) in Finland. RESULTS: A total of 1112 patients were analyzed. We measured plasma endostatin within 2 h of ICU admission. Early AKI (KDIGO stage within 12 h of ICU admission) was found in 20% of the cohort, and 18% developed late AKI (KDIGO criteria > 12 h from ICU admission). Median (IQR) admission endostatin was higher in the early AKI group, 29 (19.1, 41.9) ng/ml as compared to 22.4 (16.1, 30.1) ng/ml for the late AKI group, and 18 (14.0, 23.6) ng/ml for non-AKI patients (P < 0.001). Endostatin level increased with increasing KDIGO stage. Significantly higher endostatin levels were found in patients with sepsis as compared to those without. Predictive properties for AKI, RRT, and mortality were low with corresponding areas under the receiver operating characteristic curve (AUC) of 0.62, 0.67, and 0.59. Sensitivity analyses among patients with chronic kidney disease or sepsis did not improve the predictive ability of endostatin. Adding endostatin to a clinical AKI prediction model (illness severity score, urine output, and age) insignificantly changed the AUC from 0.67 to 0.70 (P = 0.14). CONCLUSIONS: Endostatin increases with AKI severity but has limited value as a predictor of AKI, RRT and 90-day mortality in patients admitted to ICU. Moreover, endostatin does not improve AKI risk prediction when added to a clinical risk model. PMID- 28857123 TI - Evaluation of a Role for NPY and NPY2R in the Pathogenesis of Obesity by Mutation and Copy Number Variation Analysis in Obese Children and Adolescents. AB - Neuropeptide Y (NPY) and its G protein-coupled NPY Y2 Receptor (NPY2R) are highly expressed in orexigenic NPY/Agouti-related peptide neurons within the arcuate nucleus, a major integrator of appetite control in the hypothalamus. As NPY and NPY2R are interesting candidate genes for obesity, we hypothesized that a genetic variation in these genes might be implicated in the pathogenesis of obesity. In the first part of this study, we performed a mutation analysis of the coding region of NPY and NPY2R with high-resolution melting curve analysis. For the highly conserved NPY gene, an extended population of 436 obese children and adolescents was screened, while for NPY2R, a smaller subset of 306 patients was used. A control population of 300 healthy individuals was screened for NPY2R to determine the general prevalence of the variants found among patients. Direct sequencing was performed for samples with melting patterns deviating from wild type. In the second part of this study, Multiplex Amplicon Quantification (MAQ) analysis was performed in 308 obese children and adolescents to detect copy number variation (CNV) in the NPY2R region. Mutation analysis of the NPY gene led to the identification of one common missense variant (L7P; MAF 0.04), while the screening of the NPY2R gene resulted in the identification of one rare missense variant F87I in the patient population. In our CNV analysis, we could not identify copy number variation in the NPY2R region among obese children and adolescents. In summary, this study clearly indicates that genetic variation in NPY and NPY2R is at low frequency and thus does not make a major contribution to the obese phenotype in the general population. PMID- 28857124 TI - Accuracy of postpartum haemorrhage data in the 2011 Victorian Perinatal Data Collection: Results of a validation study. AB - BACKGROUND: The postpartum haemorrhage (PPH) rate in Victoria in 2009 for women having their first birth, based on information reported to the Victorian Perinatal Data Collection (VPDC), was 23.6% (primiparas). Prior to 2009 PPH was collected via a tick box item on the perinatal form. Estimated blood loss (EBL) volume is now collected and it is from this item the PPH rate is calculated. Periodic assessment of data accuracy is essential to inform clinicians and others who rely on these data of their quality and limitations. AIMS: This paper describes the results of a state-wide validation study of the accuracy of EBL volume and EBL-related data items reported to VPDC. MATERIALS AND METHODS: PPH data from a random sample of 1% of births in Victoria in 2011 were extracted from source medical records and compared with information submitted to the VPDC. Accuracy was determined, together with sensitivity, specificity, positive predictive value and negative predictive value for dichotomous items. RESULTS: Accuracy of reporting for EBL >= 500 mL was 97.2% and for EBL >= 1500 mL was 99.7%. Sensitivity for EBL >= 500 mL was 89.0% (CI 83.1-93.0) and for EBL >= 1500 mL was 71.4% (CI 35.9-91.8). Blood product transfusion, peripartum hysterectomy and procedures to control bleeding were all accurately reported in >99% of cases. CONCLUSIONS: Most PPH-related data items in the 2011 VPDC may be considered reliable. Our results suggest EBL >= 1500 mL is likely to be under-reported. Changes to policies and practices of recording blood loss could further increase accuracy of reporting. PMID- 28857126 TI - Effective treatment of chemotherapy induced atypical Haemolytic Uraemic Syndrome: a case series of 7 treated patients. PMID- 28857125 TI - Aging Research: Collaborations Forge a Promising Future. AB - The National Institute on Aging (NIA), one of 27 institutes and centers at the National Institutes of Health (NIH), was founded in 1974 to conduct and support research on aging and the health and well-being of older people. The Institute's interests span the fundamental processes that contribute to aging and their impact on systems; diseases and conditions for which aging is a risk factor; and interventions that may prevent, delay, or treat these conditions or otherwise contribute to an extension of healthy, active years of life. Multiple fruitful research collaborations within and outside the federal government, spanning the breadth of the Institute's research activities, have marked NIA's growth over the past 40 years, as well as its current areas of ongoing research. This article discusses several highlights of these collaborations, including the Health and Retirement Study, geroscience research, falls injury prevention in elderly adults, and implementation of the National Plan to Address Alzheimer's Disease, from the perspective of past accomplishments and trends for the future. PMID- 28857127 TI - Empty marrow following previous irradiation in a patient with therapy-related myelodysplastic syndrome. PMID- 28857128 TI - Lessons learned from a review of paroxysmal nocturnal haemoglobinuria (PNH) requests: a report from the UK PNH Network. PMID- 28857129 TI - Approximated adjusted fractional Bayes factors: A general method for testing informative hypotheses. AB - Informative hypotheses are increasingly being used in psychological sciences because they adequately capture researchers' theories and expectations. In the Bayesian framework, the evaluation of informative hypotheses often makes use of default Bayes factors such as the fractional Bayes factor. This paper approximates and adjusts the fractional Bayes factor such that it can be used to evaluate informative hypotheses in general statistical models. In the fractional Bayes factor a fraction parameter must be specified which controls the amount of information in the data used for specifying an implicit prior. The remaining fraction is used for testing the informative hypotheses. We discuss different choices of this parameter and present a scheme for setting it. Furthermore, a software package is described which computes the approximated adjusted fractional Bayes factor. Using this software package, psychological researchers can evaluate informative hypotheses by means of Bayes factors in an easy manner. Two empirical examples are used to illustrate the procedure. PMID- 28857131 TI - The Role of Campus Support, Undocumented Identity, and Deferred Action for Childhood Arrivals on Civic Engagement for Latinx Undocumented Undergraduates. AB - This study examined civic engagement in a sample of 790 undocumented Latinx undergraduates (aged 18-30). The relations between social supports (campus safe spaces and peer support) and civic engagement and whether a strong sense of undocumented identity mediated this relation were examined. Competing statistical models examined the role of participants' status (whether or not they received temporary protection from deportation with Deferred Action for Childhood Arrivals [DACA]) in this mediational process. Results revealed that having a strong identification with being undocumented mediated the role of social supports on civic engagement in the overall sample, and that this process was specifically important for those with DACA status. The intersection of policies such as DACA and the lived experiences of Latinx undocumented college students are discussed. PMID- 28857130 TI - Natural history of anorectal sepsis. AB - BACKGROUND: Progression from anorectal abscess to fistula is poorly described and it remains unclear which patients develop a fistula following an abscess. The aim was to assess the burden of anorectal abscess and to identify risk factors for subsequent fistula formation. METHODS: The Hospital Episode Statistics database was used to identify all patients presenting with new anorectal abscesses. Cox regression analysis was undertaken to identify factors predictive of fistula formation. RESULTS: A total of 165 536 patients were identified in the database as having attended a hospital in England with an abscess for the first time between 1997 and 2012. Of these, 158 713 (95.9 per cent) had complete data for all variables and were included in this study, the remaining 6823 (4.1 per cent) with incomplete data were excluded from the study. The overall incidence rate of abscess was 20.2 per 100 000. The rate of subsequent fistula formation following an abscess was 15.5 per cent (23 012 of 148 286) in idiopathic cases and 41.6 per cent (4337 of 10 427 in patients with inflammatory bowel disease (IBD) (26.7 per cent coded concurrently as ulcerative colitis; 47.2 per cent coded as Crohn's disease). Of all patients who developed a fistula, 67.5 per cent did so within the first year. Independent predictors of fistula formation were: IBD, in particular Crohn's disease (hazard ratio (HR) 3.51; P < 0.001), ulcerative colitis (HR 1.82; P < 0.001), female sex (HR 1.18; P < 0.001), age at time of first abscess 41-60 years (HR 1.85 versus less than 20 years; P < 0.001), and intersphincteric (HR 1.53; P < 0.001) or ischiorectal (HR 1.48; P < 0.001) abscess location compared with perianal. Some 2.9 per cent of all patients presenting with a new abscess were subsequently diagnosed with Crohn's disease; the median time to diagnosis was 14 months. CONCLUSION: The burden of anorectal sepsis is high, with subsequent fistula formation nearly three times more common in Crohn's disease than idiopathic disease, and female sex is an independent predictor of fistula formation following abscess drainage. Most fistulas form within the first year of presentation with an abscess. PMID- 28857132 TI - Inflammatory mediators in sickle cell anaemia highlight the difference between steady state and crisis in paediatric patients. PMID- 28857133 TI - Do Varieties of Spanish Influence U.S. Spanish-English Bilingual Children's Friendship Judgments? AB - Latinos are the largest minority group in the United States (U.S. Census, 2014), yet this term comprises individuals from multiple ethnicities who speak distinct varieties of Spanish. We investigated whether Spanish-English bilingual children (N = 140, ages 4-17) use Spanish varieties in their social judgments. The findings revealed that children distinguished varieties of Spanish but did not use Spanish dialects to make third-person friendship judgments until 10-12 years; this effect became stronger in adolescence. In contrast, young children (4-6 years) made friendship judgments based on a speaker's language (English, Spanish). Thus, using language varieties as a social category and as a basis for making social inferences is a complex result of multiple influences for Spanish speaking children growing up bilingual in the United States. PMID- 28857134 TI - Retrospective study on timing of resection of hepatocellular adenoma. AB - BACKGROUND: Hepatocellular adenoma (HCA) is a benign liver tumour that may be complicated by bleeding or malignant transformation. Present guidelines advise cessation of oral contraceptives and surgical resection if the lesion is still larger than 5 cm at 6 months after diagnosis. The aim of this study was to evaluate whether this 6-month interval is sufficient to expect regression of a large HCA to 5 cm or smaller. METHODS: This retrospective cohort study included all patients with an HCA larger than 5 cm diagnosed between 1999 and 2015 with follow-up of at least 6 months. Medical records were reviewed for patient characteristics, clinical presentation, lesion characteristics, management and complications. Differences in characteristics were assessed between patients kept under surveillance and those who underwent treatment for an HCA larger than 5 cm. RESULTS: Some 194 patients were included, of whom 192 were women. Eighty-six patients were kept under surveillance and 108 underwent HCA treatment. Patients in the surveillance group had a significantly higher BMI (P = 0.029), smaller baseline HCA diameter (P < 0.001), more centrally located lesions (P < 0.001) and were more likely to have multiple lesions (P = 0.001) than those in the treatment group. There were no significant differences in sex, age at diagnosis, symptoms, complication rates and HCA subtype distribution. Time-to-event analysis in patients managed conservatively and those still undergoing treatment more than 6 months after diagnosis showed that 69 of 118 HCAs (58.5 per cent) regressed to 5 cm or smaller after a median of 104 (95 per cent c.i. 80-128) weeks. Larger HCAs took longer to regress (P < 0.001). No complications were documented during follow-up. CONCLUSION: This study suggests that a 6-month cut-off point for assessment of regression of HCA larger than 5 cm to no more than 5 cm is too early. As no complications were documented during follow-up, the cut-off point in women with typical, non-beta-catenin-activated HCA could be prolonged to 12 months, irrespective of baseline diameter. PMID- 28857135 TI - The future of robotic-assisted laparoscopic gynaecologic surgery in Australia - A time and a place for everything. AB - There has been a significant increase in minimally invasive surgery in gynaecology over the last 15 years, with approximately only one-third of hysterectomies for benign disease now performed via laparotomy. While robotic surgery offers considerable technical advantages over conventional laparoscopy and is associated with only a modest learning curve, the improvement in clinical outcomes is marginal and there are several disadvantages. There are increased set up and operating times, the need to accommodate and maintain large sophisticated equipment, and the requirement for additional training. The preeminent issue regarding the place of robotic gynaecological surgery is cost. How this is addressed and contained will ultimately determine uptake in Australia. From the published literature to date, robotic surgery compared with conventional laparoscopic surgery is associated with marginal improvements in clinical outcomes for benign hysterectomy and endometrial cancer surgery, but little improvement for other benign gynaecological surgery or for cervical cancer surgery. Robotic surgery probably does improve clinical outcomes in obese and morbidly obese patients and is associated with improved ergonomics for the surgeon. It is likely that there will be continued substantial improvements in robotic surgical platforms into the foreseeable future and that robotic surgery will play an increasingly important role in gynaecological surgery in Australia. PMID- 28857137 TI - Weekday of cancer surgery in relation to prognosis. AB - BACKGROUND: Later weekday of surgery seems to affect the prognosis adversely in oesophageal cancer, whereas any such influence on other cancer sites is unknown. This study aimed to test whether weekday of surgery influenced prognosis following commonly performed cancer operations. METHODS: This nationwide Swedish population-based cohort study from 1997 to 2014 analysed weekday of elective surgery for ten major cancers in relation to disease-specific and all-cause mortality. Cox regression provided hazard ratios with 95 per cent confidence intervals, adjusted for the co-variables age, sex, co-morbidity, hospital volume, calendar year and tumour stage. RESULTS: A total of 228 927 patients were included. Later weekday of surgery (Thursdays and, even more so, Fridays) was associated with increased mortality rates for gastrointestinal cancers. Adjusted hazard ratios for disease-specific mortality, comparing surgery on Friday with that on Monday, were 1.57 (95 per cent c.i. 1.31 to 1.88) for oesophagogastric cancer, 1.49 (1.17 to 1.88) for liver/pancreatic/biliary cancer and 1.53 (1.44 to 1.63) for colorectal cancer. Excluding mortality during the initial 90 days of surgery made little difference to these findings, and all-cause mortality was similar to disease-specific mortality. The associations were similar in analyses stratified for co-variables. No consistent associations were found between weekday of surgery and prognosis for cancer of the head and neck, lung, thyroid, breast, kidney/bladder, prostate or ovary/uterus. CONCLUSION: Later weekday of surgery (Thursday or Friday) seems to influence the prognosis adversely for cancers of the gastrointestinal tract. PMID- 28857136 TI - Results of a multicentre UK-wide retrospective study evaluating the efficacy of brentuximab vedotin in relapsed, refractory classical Hodgkin lymphoma in the transplant naive setting. AB - Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti CD30 monoclonal antibody-drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK-wide retrospective study of 99 SCT-naive relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0-1 and advanced stage disease. The median progression-free survival (PFS) was 5.6 months and median overall survival (OS) was 37.2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post-BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0.001). BV is an effective, non-toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3.0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post-BV. PMID- 28857138 TI - Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome. AB - Ellis-van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function. PMID- 28857139 TI - Relations of Inhibition and Emotion-Related Parenting to Young Children's Prosocial and Vicariously Induced Distress Behavior. AB - Children's prosocial behavior and personal distress are likely affected by children's temperament as well as parenting quality. In this study, we examined bidirectional relations from age 30 to 42 months between children's (N = 218) prosocial or self-focused (presumably distressed) reactions to a relative stranger's distress and both supportive emotion-related maternal reactions to children's emotions and children's shyness/inhibition. When controlling for 30 month prosocial behavior and personal distress behavior, maternal supportive (emotion-focused and problem-focused) reactions were positively related to prosocial behavior and marginally negatively related to children's personal distress behaviors and shyness/inhibition at 42 months. Thirty-month personal distress behavior predicted greater shyness/inhibition at 42 months, and 30-month shyness/inhibition was negatively related to prosocial behavior at 30 months. PMID- 28857140 TI - Say-Barber-Biesecker-Young-Simpson syndrome and Genitopatellar syndrome: Lumping or splitting? AB - The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are 2 rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. This broad clinical overlap led some authors to propose the concept of KAT6B spectrum disorders. On the other hand, some clinical features could help to differentiate the 2 disorders. Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities. PMID- 28857141 TI - When Parents' Praise Inflates, Children's Self-Esteem Deflates. AB - Western parents often give children overly positive, inflated praise. One perspective holds that inflated praise sets unattainable standards for children, eventually lowering children's self-esteem (self-deflation hypothesis). Another perspective holds that children internalize inflated praise to form narcissistic self-views (self-inflation hypothesis). These perspectives were tested in an observational-longitudinal study (120 parent-child dyads from the Netherlands) in late childhood (ages 7-11), when narcissism and self-esteem first emerge. Supporting the self-deflation hypothesis, parents' inflated praise predicted lower self-esteem in children. Partly supporting the self-inflation hypothesis, parents' inflated praise predicted higher narcissism-but only in children with high self-esteem. Noninflated praise predicted neither self-esteem nor narcissism. Thus, inflated praise may foster the self-views it seeks to prevent. PMID- 28857142 TI - Digest: Different evolutionary dynamics led to the convergence of clinging performance in lizard toepads?. PMID- 28857143 TI - Gender equality in academic research on epilepsy-a study on scientific authorships. AB - OBJECTIVE: The study aims to elucidate the state of gender equality in epilepsy research, analyzing the representation of female authorships from 2008 to 2016. METHODS: Gendermetrics aided in analyzing 106,282 authorships from 22,180 epilepsy-related original research articles. The key methodology was the combined analysis of the relative frequency and the odds ratio of female authorships. The Prestige Index measures the distribution of prestigious authorships between the two genders. RESULTS: The following were held by women: 39.6% of all authorships and 44.1% of the first, 41.0% of the co-, and 29.0% of the last authorships. Female authors have an odds ratio of 1.25 (95% CI 1.21-1.29) for first, 1.17 (CI 1.14-1.20) for co-, and 0.57 (CI 0.55-0.59) for last authorships. The female authorship ratios showed substantial growth in recent years, with an annual growth rate of 1.7% overall, with 2.4% for first, 1.4% for co-, and 1.9% for last authorships. Women publish fewer articles compared to men (43.8% female authors hold 39.6% of the authorships). Women are also less likely to secure prestigious authorships in articles with many authors that attract the highest citation rates. Multi-author articles with male key authors are cited slightly more frequently than articles with female key authors. Distinct differences at the country level were revealed. The prognosis for the next decade forecasts significantly increasing female odds for first authorships and only slightly higher female odds for last authorships. A female authorship ratio of 49.2% is predicted for the year 2026. SIGNIFICANCE: The integration of women in the scientific field of epilepsy is advanced. However, a dichotomy is present: Although the current system promotes early career steps, there is an apparent lack of female research leaders. This structural imbalance is expected to grow in the next decade due to the consistently high increase of female early career researchers. PMID- 28857144 TI - Development and validation of a severity scoring system for Zellweger spectrum disorders. AB - The lack of a validated severity scoring system for individuals with Zellweger spectrum disorders (ZSD) hampers optimal patient care and reliable research. Here, we describe the development of such severity score and its validation in a large, well-characterized cohort of ZSD individuals. We developed a severity scoring system based on the 14 organs that typically can be affected in ZSD. A standardized and validated method was used to classify additional care needs in individuals with neurodevelopmental disabilities (Capacity Profile [CAP]). Thirty ZSD patients of varying ages were scored by the severity score and the CAP. The median score was 9 (range 6-19) with a median scoring age of 16.0 years (range 2 36 years). The ZSD severity score was significantly correlated with all 5 domains of the CAP, most significantly with the sensory domain (r = 0.8971, P = <.0001). No correlation was found between age and severity score. Multiple peroxisomal biochemical parameters were significantly correlated with the severity score. The presently reported severity score for ZSD is a suitable tool to assess phenotypic severity in a ZSD patient at any age. This severity score can be used for objective phenotype descriptions, genotype-phenotype correlation studies, the identification of prognostic features in ZSD patients and for classification and stratification of patients in clinical trials. PMID- 28857145 TI - Dermatoscopy of a melanoma less than one millimeter in diameter. PMID- 28857146 TI - Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy. AB - Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole-exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2. PMID- 28857147 TI - Safety and Ergogenic Properties of Combined Aminophylline and Ambrisentan in Hypoxia. AB - We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia-induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single-dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability. PMID- 28857148 TI - Why does inbreeding reduce male paternity? Effects on sexually selected traits. AB - Mating with relatives has often been shown to negatively affect offspring fitness (inbreeding depression). There is considerable evidence for inbreeding depression due to effects on naturally selected traits, particularly those expressed early in life, but there is less evidence of it for sexually selected traits. This is surprising because sexually selected traits are expected to exhibit strong inbreeding depression. Here, we experimentally created inbred and outbred male mosquitofish (Gambusia holbrooki). Inbred males were the offspring of matings between full siblings. We then investigated how inbreeding influenced a number of sexually selected male traits, specifically: attractiveness, sperm number and velocity, as well as sperm competitiveness based on a male's share of paternity. We found no inbreeding depression for male attractiveness or sperm traits. There was, however, evidence that lower heterozygosity decreased paternity due to reduced sperm competitiveness. Our results add to the growing evidence that competitive interactions exacerbate the negative effects of the increased homozygosity that arises when there is inbreeding. PMID- 28857149 TI - Seasonality and Readmission after Heart Failure, Myocardial Infarction, and Pneumonia. AB - OBJECTIVE: To investigate whether hospital readmission after admission for heart failure (HF), myocardial infarction (MI), and pneumonia varies by season. DATA SOURCES: All patients in 2005-2009 Healthcare Cost and Utilization Project State Inpatient Databases for New York and California hospitalized for HF, MI, or pneumonia. STUDY DESIGN: The relationship between discharge season and unplanned readmission within 30 days was evaluated using multivariate modified Poisson regression. PRINCIPAL FINDINGS: Cohorts included 869,512 patients with HF, 448,945 patients with MI, and 813,593 patients with pneumonia. While admissions varied widely by season, readmission rates only ranged from 25.0 percent (spring) to 25.6 percent (winter) for HF (p > .05), 18.9 percent (summer) to 20.0 percent (winter) for MI (p < .001), and 19.4 percent (spring) to 20.3 percent (summer) for pneumonia (p < .001). In adjusted models, in New York, there was lower readmission in spring and fall (RR: 0.98, 95% CI: 0.96-0.99 for both) after admission for HF and higher readmission in spring (RR: 1.04, 95% CI: 1.01-1.07) after MI. In California, there was lower readmission in spring and winter (RR: 0.95, 95% CI: 0.93-0.96 and RR: 0.96, 95% CI: 0.94-0.98, respectively) after pneumonia. CONCLUSIONS: Given marked seasonality in incidence and mortality of HF, MI, and pneumonia, the modest seasonality in readmissions suggests that readmissions may be more related to non-seasonally dependent factors than to the seasonal nature of these diseases. PMID- 28857150 TI - A Model of Maternal and Paternal Ethnic Socialization of Mexican-American Adolescents' Self-Views. AB - Data from a sample of 462 Mexican-American adolescents (M = 10.4 years, SD = .55; 48.1% girls), mothers, and fathers were used to test an ethnic socialization model of ethnic identity and self-efficacy that also considered mainstream parenting styles (e.g., authoritative parenting). Findings supported the ethnic socialization model: parents' endorsement of Mexican-American values were associated with ethnic socialization at fifth grade and seventh grade; maternal ethnic socialization at fifth grade and paternal ethnic socialization at seventh grade were associated with adolescents' ethnic identity exploration at 10th grade and, in turn, self-efficacy at 12th grade. The findings support ethnic socialization conceptions of how self-views of ethnicity develop from childhood across adolescence in Mexican-American children. PMID- 28857151 TI - Racial/Ethnic Differences in Receipt of Influenza and Pneumococcal Vaccination among Long-Stay Nursing Home Residents. AB - OBJECTIVE/STUDY QUESTION: To examine racial/ethnic differences in influenza and pneumococcal vaccination receipt and nonreceipt among nursing home (NH) residents post implementation of federal vaccination policy. DATA SOURCES/STUDY SETTING/STUDY DESIGN/DATA COLLECTION/EXTRACTION METHODS: An analysis of a merged national cross-sectional dataset containing resident assessment, facility, and community data for years 2010-2013 was conducted. Logistic regressions omitting and including facility fixed effects were used to examine the influence of race and ethnicity (black, Hispanic, white) and black concentration on vaccination status across and within NHs. PRINCIPLE FINDINGS: Vaccination receipt of 107,874 residents in 742 NHs was examined. Blacks were less likely than whites to receive influenza and pneumococcal vaccinations (OR = 0.75; OR = 0.81, respectively, p values <.001). The likelihood of not being offered the influenza vaccination was greater for blacks (OR=1.25, p = .004) and the likelihood of not being offered the pneumococcal vaccination was greater for Hispanics (OR = 1.65, p = .04) compared to whites. Fixed effects showed that within the same NH, Hispanics were more likely to receive both vaccinations compared to whites (OR=1.22, p = .004 (influenza); OR=1.34, p < .001 (pneumococcal)). Facilities highly concentrated with blacks accounted for large proportions of differences seen in vaccination receipt. CONCLUSIONS: Racial/ethnic differences remain despite policy changes. Focused strategies aimed at NH personnel and racially segregated NHs are critical to improving vaccination delivery and eliminating disparities in care. PMID- 28857152 TI - Prescribing Oxygen for Cluster Headache: A Guide for the Provider. AB - BACKGROUND: Oxygen is the standard of care for acute treatment of cluster headache. CMS, the US Centers for Medicaid and Medicare Services, has made the indefensible decision to not cover oxygen for cluster headache for patients with Medicaid and Medicare insurance, despite the evidence and professional guidelines. Commercial insurance generally covers oxygen for cluster headache. OBJECTIVE: This is a "how-to" guide for successfully prescribing oxygen in the US. SUMMARY: Prescription information is provided that can be incorporated as dot phrases, smart sets, or other standard templates for prescribing oxygen for cluster patients. In many states, oxygen is affordable and can be prescribed for Medicaid and Medicare patients who wish to pay cash. Welding or nonmedical grade industrial oxygen is almost the same cost as medical oxygen. However, it is less pure, lacks the same inspection of tanks, and is delivered without regulators to provide appropriate flow rates. Patients who pay cash should be strongly encouraged to buy medical oxygen. PMID- 28857153 TI - The quantitative genetic basis of clinal divergence in phenotypic plasticity. AB - Phenotypic plasticity is thought to be an important mechanism for adapting to environmental heterogeneity. Nonetheless, the genetic basis of plasticity is still not well understood. In Drosophila melanogaster and D. simulans, body size and thermal stress resistance show clinal patterns along the east coast of Australia, and exhibit plastic responses to different developmental temperatures. The genetic basis of thermal plasticity, and whether the genetic effects underlying clinal variation in traits and their plasticity are similar, remains unknown. Here, we use line-cross analyses between a tropical and temperate population of Drosophila melanogaster and D. simulans developed at three constant temperatures (18 degrees C, 25 degrees C, and 29 degrees C) to investigate the quantitative genetic basis of clinal divergence in mean thermal response (elevation) and plasticity (slope and curvature) for thermal stress and body size traits. Generally, the genetic effects underlying divergence in mean response and plasticity differed, suggesting that different genetic models may be required to understand the evolution of trait means and plasticity. Furthermore, our results suggest that nonadditive genetic effects, in particular epistasis, may commonly underlie plastic responses, indicating that current models that ignore epistasis may be insufficient to understand and predict evolutionary responses to environmental change. PMID- 28857154 TI - Psychometric Evaluation of a Novel Instrument Assessing the Impact of Migraine on Physical Functioning: The Migraine Physical Function Impact Diary. AB - OBJECTIVE: The objective of this study was to evaluate the measurement properties of the Migraine Physical Function Impact Diary (MPFID), a novel patient-reported outcome (PRO) measure for assessing the impact of migraine on physical functioning. METHODS: In a prospective, observational study, adults with episodic migraine (EM) or chronic migraine (CM) used an eDiary to complete the MPFID (assessing daily impacts of migraine on physical function) and a headache diary (capturing migraine days, migraine pain intensity, and migraine interference) each day, and other PRO instruments related to migraine. Item-level evaluation, item response theory (IRT), and exploratory factor analysis (EFA) methods were applied to identify domains, select final MPFID items, and develop scoring procedures. Psychometric properties of the final 13-item MPFID were evaluated using confirmatory factor analysis and tests of reliability (Cronbach's alpha for internal consistency and intra-class correlation [ICC] for test-retest) and validity (convergent and known-groups). RESULTS: The study enrolled 569 adults with chronic or episodic migraine, mean (SD) age 39.9 (12.0) years and 87.2% female. Item-level analyses based on interim data informed selection of a set of 13 items for the MPFID, through evaluation of floor/ceiling effects, item-to-item correlations, factor loadings, and IRT-based fit/misfit statistics. Two domain scores (EA: Impact on Everyday Activities; PI: Physical Impairment) and a global item score for impact on everyday activities were identified. EA and PI domains exhibited high internal consistency (alpha = 0.97; alpha = 0.93) and good test retest reliability among stable subjects (ICCs = 0.74 and 0.77). Convergent validity was demonstrated by moderate correlations (r = +/-0.50-0.68; P < .0001) between MPFID domain scores and number of migraine days, headache days, bed days, and other migraine-related PRO instruments. EA and PI scores differentiated between groups who varied by number of migraine days, migraine interference levels, migraine pain intensity, and median split groups of scores based on other PROs instruments (P < .05). CONCLUSIONS: The MPFID has robust psychometric properties (ie, reliability and validity). Findings supported two distinct domains about the impact of migraine on physical functioning: Impact on Everyday Activities and Physical Impairment. Both domain scores showed evidence of excellent reliability and construct validity in assessing the impacts of migraine on physical functioning. PMID- 28857156 TI - Multilevel Comparisons of Hospital Discharge among Older Adults with a Fall Related Hospitalization. AB - OBJECTIVE: We examined multilevel factors associated with hospital discharge status among older adults suffering a fall-related hospitalization. DATA SOURCES: The 2011-2013 (n = 131,978) Texas Inpatient Hospital Discharge Public-Use File was used. STUDY DESIGN/METHODS: Multilevel logistic regression analyses estimated the likelihood of being discharged to institutional settings versus home. PRINCIPAL FINDINGS: Factors associated with a greater likelihood of being discharged to institutional settings versus home/self-care included being female, white, older, having greater risk of mortality, receiving care in a non-teaching hospital, having Medicare (versus Private) coverage, and being admitted from a non-health care facility (versus clinical referral). CONCLUSIONS: Understanding risk factors for costly discharges to institutional settings enables targeted fall-prevention interventions with identification of at-risk groups and allows for identifying policy-related factors associated with discharge status. PMID- 28857155 TI - Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe. AB - Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1-7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p < 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p < 0.001). In multivariate analysis models for progression-free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC. PMID- 28857157 TI - Newcastle disease virus mediates pancreatic tumor rejection via NK cell activation and prevents cancer relapse by prompting adaptive immunity. AB - Pancreatic cancer is the 8th most common cause of cancer-related deaths worldwide and the tumor with the poorest prognosis of all solid malignancies. In 1957, it was discovered that Newcastle disease virus (NDV) has oncolytic properties on tumor cells. To study the oncolytic properties of NDV in pancreatic cancer a single dose was administered intravenously in a syngeneic orthotopic tumor model using two different murine pancreatic adenocarcinoma cell lines (DT6606PDA, Panc02). Tumor growth was monitored and immune response was analyzed. A single treatment with NDV inhibited DT6606PDA tumor growth in mice and prevented recurrence for a period of three months. Tumor infiltration and systemic activation of NK cells, cytotoxic and helper T-cells was enhanced. NDV-induced melting of Panc02 tumors until d7 pi, but they recurred displaying unrestricted tumor growth, low immunogenicity and inhibition of tumor-specific immune response. Arrest of DT6606PDA tumor growth and rejection was mediated by activation of NK cells and a specific antitumor immune response via T-cells. Panc02 tumors rapidly decreased until d7 pi, but henceforth tumors characterized by the ability to perform immune-regulatory functions reappeared. Our results demonstrated that NDV-activated immune cells are able to reject tumors provided that an adaptive antitumor immune response can be initiated. However, activated NK cells that are abundant in Panc02 tumors lead to outgrowth of nonimmunogenic tumor cells with inhibitory properties. Our study emphasizes the importance of an adaptive immune response, which is initiated by NDV to mediate long-term tumor surveillance in addition to direct oncolysis. PMID- 28857158 TI - Promoter hypermethylation in plasma-derived cell-free DNA as a prognostic marker for pancreatic adenocarcinoma staging. AB - Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment. Patients were staged according to the TNM classification. Methylation-specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety-five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51-8.66), 7.00 (95% CI; 5.93-8.07) and 6.77 (95% CI; 5.08-8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88-11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I-III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I-II from stage III-IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell-free DNA promoter hypermethylation has the potential to be blood-based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required. PMID- 28857159 TI - The association between inadequate prenatal care and future healthcare use among offspring in the Bedouin population. AB - OBJECTIVE: To evaluate the impact of inadequate prenatal care on long-term morbidity among the offspring of an ethnic minority population. METHODS: A retrospective population-based cohort analysis was performed among all Bedouin women with singleton pregnancies who delivered in a tertiary medical center in Israel between January 1, 1991, and January 1, 2014. Morbidity was defined as pediatric hospitalization across six distinct disease categories before 18 years of age. The cumulative morbidity rates were compared for offspring born following pregnancies with either inadequate (<3 visits to prenatal care facility) or adequate prenatal care. RESULTS: Overall, 127 396 neonates were included; 19 173 (15.0%) were born following inadequate prenatal care. Pediatric hospitalizations for all morbidities other than cardiovascular ones were less frequent among the inadequate prenatal care group than the adequate prenatal care group (P<0.05). Survival curves demonstrated a lowered cumulative incidence for all morbidities in the inadequate prenatal care group, with the exception of cardiovascular disease. CONCLUSION: Inadequate prenatal care correlated with reduced pediatric hospitalization rates among offspring, possibly owing to a lack of child healthcare service utilization within the Bedouin population. PMID- 28857160 TI - Cancer risk of Lichen planus: A cohort study of 13,100 women in Finland. AB - The association between Lichen planus (LP) and cancer has been under debate for decades. We studied the connection via population-based Finnish register data. All women with the diagnosis of LP (n = 13,100) were identified from the Finnish Hospital Discharge Registry from 1969-2012. These patients were linked with subsequent cancer diagnoses from the Finnish Cancer Registry until 2014. Standardized incidence ratios (SIRs) were counted for different cancers by dividing the observed numbers of cancers by expected numbers, which were based on national cancer incidence rates. In total, 1,520 women with LP were diagnosed with cancer (SIR 1.15, 95% confidence interval [CI] 1.09-1.20). LP was associated with an increased risk of cancer of lip (SIR 5.17, 95% CI 3.06-8.16), cancer of tongue (SIR 12.4, 95% CI 9.45-16.0), cancer of oral cavity (SIR 7.97, 95% CI 6.79 9.24), cancer of esophagus (SIR 1.95, 95% CI 1.17-3.04), cancer of larynx (SIR of 3.47, 95% CI 1.13-8.10) and cancer of vulva (SIR 1.99, 95% CI 1.18-3.13). The risk of cancer was not increased in other locations where LP manifests (pharynx and skin). Patients with diagnosed LP have an increased risk of developing cancer of lip, tongue, oral cavity, esophagus, larynx and vulva. These data are important when considering treatment and follow-up of patients with LP diagnosis. PMID- 28857161 TI - Structural and functional differences in the barrel cortex of Mecp2 null mice. AB - Functional deficits in sensory systems are commonly noted in neurodevelopmental disorders, such as the Rett syndrome (RTT). Defects in methyl CpG binding protein gene (MECP2) largely accounts for RTT. Manipulations of the Mecp2 gene in mice provide useful models to probe into various aspects of brain development associated with the RTT. In this study, we focused on the somatosensory cortical phenotype in the Bird mouse model of RTT. We used voltage-sensitive dye imaging to evaluate whisker sensory evoked activity in the barrel cortex of mice. We coupled this functional assay with morphological analyses in postnatal mice and investigated the dendritic differentiation of barrel neurons and individual thalamocortical axon (TCA) arbors that synapse with them. We show that in Mecp2 deficient male mice, whisker-evoked activity is roughly topographic but weak in the barrel cortex. At the morphological level, we find that TCA arbors fail to develop into discrete, concentrated patches in barrel hollows, and the complexity of the dendritic branches in layer IV spiny stellate neurons is reduced. Collectively, our results indicate significant structural and functional impairments in the barrel cortex of the Bird mouse line, a popular animal model for the RTT. Such structural and functional anomalies in the primary somatosensory cortex may underlie orofacial tactile sensitivity issues and sensorimotor stereotypies characteristic of RTT. PMID- 28857162 TI - Utilizing Mushrooms to Reduce Overall Sodium in Taco Filling Using Physical and Sensory Evaluation. AB - : This project investigated the use of integrating mushrooms into beef taco filling as a means to reduce overall sodium for food service applications. Initial product development used physical characterization analysis (moisture, yield, color, and texture) to determine initial threshold of mushroom inclusion with minimal differences against an all-meat control. Increasing mushroom inclusion increased moisture and yield before draining but decreased yield after draining, lightness, redness, and texture. Results showed that inclusion under 50% by weight minimized physical attribute deviation from an all-meat control. Additional physical analysis investigated a variety of other factors (mushroom type, blanching, and particle size) to determine if other attributing mushroom characteristics would yield statistical similarity to the all-meat control. Results showed that a formulation containing up to 45% mushrooms can be integrated into beef fillings using un-blanched, white button mushrooms with small grind (1 to 5 mm), which maximized mushroom usage while minimizing differences from the all-meat control. Additional sodium analysis showed that varying salt level in formulations did not affect physical characteristics and mushroom inclusion could not significantly reduce overall sodium level. Optimized mushroom samples were then fielded in a hedonic sensory study to untrained consumers to evaluate product liking attributes (overall liking, aroma, color, flavor, juiciness, saltiness, and texture). Samples with overall liking scores that closely matched the control were then fielded in a paired-preference test to determine acceptance. Consumers preferred a 45% mushroom with reduced sodium taco filling compared to its full sodium counterpart in a food service fielded paired preference sensory test. PRACTICAL APPLICATION: Although diet can significantly reduce the risk of heart disease, American consumers continue to eat detrimental diets high in fat and sodium. Products need to be made that decrease fat and sodium intake while still delivering acceptable taste. Mushroom substitution into meat-based products can be a strategy to develop products that can decrease fat and sodium consumption while increasing vegetable intake without compromising the quality and taste consumers demand. This research shows how consumers can accept meat-based products containing mushrooms with potential for direct food service application. PMID- 28857164 TI - Biotic interactions as drivers of algal origin and evolution. AB - Contents 670 I. 671 II. 671 III. 676 IV. 678 678 References 678 SUMMARY: Biotic interactions underlie life's diversity and are the lynchpin to understanding its complexity and resilience within an ecological niche. Algal biologists have embraced this paradigm, and studies building on the explosive growth in omics and cell biology methods have facilitated the in-depth analysis of nonmodel organisms and communities from a variety of ecosystems. In turn, these advances have enabled a major revision of our understanding of the origin and evolution of photosynthesis in eukaryotes, bacterial-algal interactions, control of massive algal blooms in the ocean, and the maintenance and degradation of coral reefs. Here, we review some of the most exciting developments in the field of algal biotic interactions and identify challenges for scientists in the coming years. We foresee the development of an algal knowledgebase that integrates ecosystem wide omics data and the development of molecular tools/resources to perform functional analyses of individuals in isolation and in populations. These assets will allow us to move beyond mechanistic studies of a single species towards understanding the interactions amongst algae and other organisms in both the laboratory and the field. PMID- 28857163 TI - Phenolics from Winemaking By-Products Better Decrease VLDL-Cholesterol and Triacylglycerol Levels than Those of Red Wine in Wistar Rats. AB - Winemaking by-products account for more than 30% of the grape production, but this inexpensive feedstock has not yet been fully exploited. Accordingly, we evaluated the potential biological activity of winemaking by-products produced with Syrah grapes in comparison with those of the wine produced using the same grape cultivar. Winemaking by-products showed higher contents of total anthocyanins, flavonols, stilbenes, and flavanols than red wine as evaluated by HPLC-DAD-FD (on a dry weight basis). In contrast, red wine was a better source of phenolic acids. However, the contribution of phenolic acids was minor for both samples. Furthermore, equivalent concentration of winemaking by-products (100 mg/kg/d) showed greater biological activity by than that of red wine by decreasing the levels of VLDL-cholesterol and triacylglycerols in Wistar rats. Therefore, this study supports the use of winemaking by-products as an economical source of bioactive phenolics with potential use in the food and nutraceutical industries. PMID- 28857165 TI - No mutual mate choice for quality in zebra finches: Time to question a widely held assumption. AB - Studies of mate choice typically assume that individuals prefer high quality mates and select them based on condition-dependent indicator traits. In species with biparental care, mutual mate choice is expected to result in assortative mating for quality. When assortment is not perfect, the lower quality pair members are expected to compensate by increased parental investment to secure their partner (positive differential allocation). This framework has been assumed to hold for monogamous species like the zebra finch (Taeniopygia guttata), but progress has been hampered by the difficulty to define individual quality. By combining multiple measures of causes (inbreeding, early nutrition) and consequences (ornaments, displays, fitness components) of variation in quality into a single principal component, we here show that quality variation can be quantified successfully. We further show that variation in quality indeed predicts individual pairing success, presumably because it reflects an individual's vigor or ability to invest in reproduction. However, despite high statistical power, we found no evidence for either assortative mating or for positive differential allocation. We suggest that zebra finch ornaments and displays are not sufficiently reliable for the benefits of choosiness to exceed the costs of competition for the putative best partner. To assess the generality of these findings unbiased quantification of signal honesty and preference strength is required, rather than selective reporting of significant results. PMID- 28857167 TI - Tumor necrosis factor-alpha inhibits osteogenic differentiation of pre osteoblasts by downregulation of EphB4 signaling via activated nuclear factor kappaB signaling pathway. AB - BACKGROUND AND OBJECTIVE: The majority of experiments show that tumor necrosis factor-alpha (TNF-alpha) inhibits osteogenic differentiation of mesenchymal stem cells and pre-osteoblasts by activated nuclear factor-kappaB (NF-kappaB) signaling. However, the underlying mechanisms by which NF-kappaB signaling inhibits osteogenic differentiation are not fully understood. The aim of the present study was to investigate whether EphB4 signaling inhibition mediates the effects of TNF-alpha-activated NF-kappaB signaling on osteogenic differentiation of pre-osteoblasts. MATERIAL AND METHODS: Murine MC3T3-E1 pre-osteoblasts were treated with 10 ng/mL of TNF-alpha. NF-kappaB inhibitor, pyrrolidine dithiocarbamate, was used to achieve NF-kappaB signaling inhibition. EphB4 signaling was activated using ephrinB2-fc. The mRNA expressions of runt related transcription factor 2 (Runx2), bone sialoprotein (BSP) and EphB4 were determined using reverse transcription-polymerase chain reaction. The protein levels of Runx2, BSP, Col Ia1, osteopontin, EphB4, p-NF-kappaB p65 and NF-kappaB p65 were evaluated using western blot assays. Alkaline phosphatase (ALP) activity in MC3T3 E1 cells was evaluated by ALP activity kit, and mineral nodule formation was evaluated by Alizarin Red S staining. RESULTS: TNF-alpha inhibited EphB4 expression, while it suppressed Runx2, BSP expression from gene and protein levels as well as ALP activity and mineral nodule formation in MC3T3-E1 cells. Activation of EphB4 signaling by ephrinB2-fc promoted osteogenic differentiation of MC3T3-E1 cells, whereas TNF-alpha impaired the osteogenic differentiation enhanced by ephrinB2-fc. Pyrrolidine dithiocarbamate blocked the activation of NF kappaB signaling induced by TNF-alpha, while it prevented the downregulation of Runx2, BSP and EphB4, induced by TNF-alpha. CONCLUSION: TNF-alpha inhibits osteogenic differentiation of pre-osteoblasts by downregulation of EphB4 signaling via activated NF-kappaB signaling pathway. PMID- 28857166 TI - ATLANTIC-CAMTRAPS: a dataset of medium and large terrestrial mammal communities in the Atlantic Forest of South America. AB - Our understanding of mammal ecology has always been hindered by the difficulties of observing species in closed tropical forests. Camera trapping has become a major advance for monitoring terrestrial mammals in biodiversity rich ecosystems. Here we compiled one of the largest datasets of inventories of terrestrial mammal communities for the Neotropical region based on camera trapping studies. The dataset comprises 170 surveys of medium to large terrestrial mammals using camera traps conducted in 144 areas by 74 studies, covering six vegetation types of tropical and subtropical Atlantic Forest of South America (Brazil and Argentina), and present data on species composition and richness. The complete dataset comprises 53,438 independent records of 83 species of mammals, includes 10 species of marsupials, 15 rodents, 20 carnivores, eight ungulates and six armadillos. Species richness averaged 13 species (+/-6.07 SD) per site. Only six species occurred in more than 50% of the sites: the domestic dog Canis familiaris, crab-eating fox Cerdocyon thous, tayra Eira barbara, south American coati Nasua nasua, crab-eating raccoon Procyon cancrivorus and the nine-banded armadillo Dasypus novemcinctus. The information contained in this dataset can be used to understand macroecological patterns of biodiversity, community, and population structure, but also to evaluate the ecological consequences of fragmentation, defaunation, and trophic interactions. PMID- 28857168 TI - Interaction points in plant stress signaling pathways. AB - Plants live in a world where they are challenged by abiotic and biotic stresses. In response to unfavorable conditions or an acute challenge like a pathogen attack, plants use various signaling pathways that regulate expression of defense genes and other mechanisms to provide resistance or stress adaptation. Identification of the regulatory steps in defense signaling has seen much progress in recent years. Many of the identified signaling pathways show interactions with each other, exemplified by the modulation of the jasmonic acid response by salicylic acid. Accordingly, defense regulation is more appropriately thought of as a web of interactions, rather than linear pathways. Here we describe various regulatory components and how they interact to provide an appropriate defense response. One of the common assays to monitor the output of defense signaling, as well as interaction between signaling pathways, is the measurement of altered gene expression. We illustrate that, while this is a suitable assay to monitor defense regulation, it can also inadvertently provide overstated conclusions about interaction among signaling pathways. PMID- 28857169 TI - Structure-function analysis of the Fusarium oxysporum Avr2 effector allows uncoupling of its immune-suppressing activity from recognition. AB - Plant pathogens employ effector proteins to manipulate their hosts. Fusarium oxysporum f. sp. lycopersici (Fol), the causal agent of tomato wilt disease, produces effector protein Avr2. Besides being a virulence factor, Avr2 triggers immunity in I-2 carrying tomato (Solanum lycopersicum). Fol strains that evade I 2 recognition carry point mutations in Avr2 (e.g. Avr2R45H ), but retain full virulence. Here we investigate the virulence function of Avr2 and determine its crystal structure. Transgenic tomato and Arabidopsis expressing either wild-type DeltaspAvr2 (deleted signal-peptide) or the DeltaspAvr2R45H variant become hypersusceptible to fungal, and even bacterial infections, suggesting that Avr2 targets a conserved defense mechanism. Indeed, Avr2 transgenic plants are attenuated in immunity-related readouts, including flg22-induced growth inhibition, ROS production and callose deposition. The crystal structure of Avr2 reveals that the protein shares intriguing structural similarity to ToxA from the wheat pathogen Pyrenophora tritici-repentis and to TRAF proteins. The I-2 resistance-breaking Avr2V41M , Avr2R45H and Avr2R46P variants cluster on a surface-presented loop. Structure-guided mutagenesis enabled uncoupling of virulence from I-2-mediated recognition. We conclude that I-2-mediated recognition is not based on monitoring Avr2 virulence activity, which includes suppression of immune responses via an evolutionarily conserved effector target, but by recognition of a distinct epitope. PMID- 28857170 TI - Dissecting the components controlling root-to-shoot arsenic translocation in Arabidopsis thaliana. AB - Arsenic (As) is an important environmental and food-chain toxin. We investigated the key components controlling As accumulation and tolerance in Arabidopsis thaliana. We tested the effects of different combinations of gene knockout, including arsenate reductase (HAC1), gamma-glutamyl-cysteine synthetase (gamma ECS), phytochelatin synthase (PCS1) and phosphate effluxer (PHO1), and the heterologous expression of the As-hyperaccumulator Pteris vittata arsenite efflux (PvACR3), on As tolerance, accumulation, translocation and speciation in A. thaliana. Heterologous expression of PvACR3 markedly increased As tolerance and root-to-shoot As translocation in A. thaliana, with PvACR3 being localized to the plasma membrane. Combining PvACR3 expression with HAC1 mutation led to As hyperaccumulation in the shoots, whereas combining HAC1 and PHO1 mutation decreased As accumulation. Mutants of gamma-ECS and PCS1 were hypersensitive to As and had higher root-to-shoot As translocation. Combining gamma-ECS or PCS1 with HAC1 mutation did not alter As tolerance or accumulation beyond the levels observed in the single mutants. PvACR3 and HAC1 have large effects on root-to shoot As translocation. Arsenic hyperaccumulation can be engineered in A. thaliana by knocking out the HAC1 gene and expressing PvACR3. PvACR3 and HAC1 also affect As tolerance, but not to the extent of gamma-ECS and PCS1. PMID- 28857171 TI - Characterization of swallow modulation in response to bolus volume in healthy subjects accounting for catheter diameter. AB - OBJECTIVES/HYPOTHESIS: Characterization of the pharyngeal swallow response to volume challenges is important for swallowing function assessment. The diameter of the pressure-impedance recording catheter may influence these results. In this study, we captured key physiological swallow measures in response to bolus volume utilizing recordings acquired by two catheters of different diameter. STUDY DESIGN: Ten healthy adults underwent repeat investigations with 8- and 10-Fr catheters. Liquid bolus swallows of volumes 2.5, 5, 10, 20, and 30 mL were recorded. Measures indicative of distension, contractility, and flow timing were assessed. METHODS: Pressure-impedance recordings with pressure-flow analysis were used to capture key distension, contractility, and pressure-flow timing parameters. RESULTS: Larger bolus volumes increased upper esophageal sphincter distension diameter (P < .001) and distension pressures within the hypopharynx and upper esophageal sphincter (P < .05). Bolus flow timing measures were longer, particularly latency of bolus propulsion ahead of the pharyngeal stripping wave (P < .001). Use of a larger-diameter catheter produced higher occlusive pressures, namely upper esophageal sphincter basal pressure (P < .005) and upper esophageal sphincter postdeglutitive pressure peak (P < .001). CONCLUSIONS: The bolus volume swallowed changed measurements indicative of distension pressure, luminal diameter, and pressure-flow timing; this is physiologically consistent with swallow modulation to accommodate larger, faster-flowing boluses. Additionally, catheter diameter predominantly affects lumen occlusive pressures. Appropriate physiological interpretation of the pressure-impedance recordings of pharyngeal swallowing requires consideration of the effects of volume and catheter diameter. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1328-1334, 2018. PMID- 28857172 TI - Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts. AB - The IL-1 family member IL-36alpha has proinflammatory and pathogenic properties in psoriasis. IL-36alpha binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36alpha. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL 36alpha-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36alpha and stimulation increased IL-36alpha in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36alpha by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R deficiency abrogated IL-36alpha-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints. PMID- 28857173 TI - The Kok effect in Vicia faba cannot be explained solely by changes in chloroplastic CO2 concentration. AB - The Kok effect - an abrupt decline in quantum yield (QY) of net CO2 assimilation at low photosynthetic photon flux density (PPFD) - is widely used to estimate respiration in the light (R), which assumes the effect is caused by light suppression of R. A recent report suggested much of the Kok effect can be explained by declining chloroplastic CO2 concentration (cc ) at low PPFD. Several predictions arise from the hypothesis that the Kok effect is caused by declining cc , and we tested these predictions in Vicia faba. We measured CO2 exchange at low PPFD, in 2% and 21% oxygen, in developing and mature leaves, which differed greatly in R in darkness. Our results contradicted each of the predictions based on the cc effect: QY exceeded the theoretical maximum value for photosynthetic CO2 uptake; QY was larger in 21% than 2% oxygen; and the change in QY at the Kok effect breakpoint was unaffected by oxygen. Our results strongly suggest the Kok effect arises largely from a progressive decline in R with PPFD that includes both oxygen-sensitive and -insensitive components. We suggest an improved Kok method that accounts for high cc at low PPFD. PMID- 28857174 TI - Transcriptional profiling reveals mechanisms of sexually dimorphic responses of Populus cathayana to potassium deficiency. AB - Potassium (K) deficiency causes a series of physiological and metabolic disorders in plants, and dioecious species exhibit different responses based on sex. Our previous morphological and physiological observations indicated that Populus cathayana males were more tolerant to K+ deficiency than females. To continue this work, comparative transcriptome analyses were carried out to investigate sexually differentially expressed genes (DEGs) in this study. The results indicate that 10 weeks of K+ deficiency result in 111 and 181 DEGs in males and females, respectively. These DEGs are mainly involved in photosynthesis, cell wall biosynthesis, secondary metabolism, transport, stress responses, gene expression regulation and protein synthesis and degradation. Comparing between sexes, P. cathayana females showed more changes in response to K+ deficiency than males with regard to photosynthesis, gene expression regulation and posttranslational modification but fewer changes in secondary metabolism, stress responses and redox homeostasis. These results provide evidence that P. cathayana females are more susceptible to K+ deficiency than males. Therefore, there are sex-related molecular strategies in response to K+ deficiency between sexes. PMID- 28857175 TI - Elevated resting H+ current in the R1239H type 1 hypokalaemic periodic paralysis mutated Ca2+ channel. AB - KEY POINTS: Missense mutations in the gene encoding the alpha1 subunit of the skeletal muscle voltage-gated Ca2+ channel induce type 1 hypokalaemic periodic paralysis, a poorly understood neuromuscular disease characterized by episodic attacks of paralysis associated with low serum K+ . Acute expression of human wild-type and R1239H HypoPP1 mutant alpha1 subunits in mature mouse muscles showed that R1239H fibres displayed Ca2+ currents of reduced amplitude and larger resting leak inward current increased by external acidification. External acidification also produced intracellular acidification at a higher rate in R1239H fibres and inhibited inward rectifier K+ currents. These data suggest that the R1239H mutation induces an elevated leak H+ current at rest flowing through a gating pore and could explain why paralytic attacks preferentially occur during the recovery period following muscle exercise. ABSTRACT: Missense mutations in the gene encoding the alpha1 subunit of the skeletal muscle voltage-gated Ca2+ channel induce type 1 hypokalaemic periodic paralysis, a poorly understood neuromuscular disease characterized by episodic attacks of paralysis associated with low serum K+ . The present study aimed at identifying the changes in muscle fibre electrical properties induced by acute expression of the R1239H hypokalaemic periodic paralysis human mutant alpha1 subunit of Ca2+ channels in a mature muscle environment to better understand the pathophysiological mechanisms involved in this disorder. We transferred genes encoding wild-type and R1239H mutant human Ca2+ channels into hindlimb mouse muscle by electroporation and combined voltage-clamp and intracellular pH measurements on enzymatically dissociated single muscle fibres. As compared to fibres expressing wild-type alpha1 subunits, R1239H mutant-expressing fibres displayed Ca2+ currents of reduced amplitude and a higher resting leak inward current that was increased by external acidification. External acidification also produced intracellular acidification at a higher rate in R1239H fibres and inhibited inward rectifier K+ currents. These data indicate that the R1239H mutation induces an elevated leak H+ current at rest flowing through a gating pore created by the mutation and that external acidification favours onset of muscle paralysis by potentiating H+ depolarizing currents and inhibiting resting inward rectifier K+ currents. Our results could thus explain why paralytic attacks preferentially occur during the recovery period following intense muscle exercise. PMID- 28857177 TI - Continuing the dialogue: A rights-approach in occupational therapy. PMID- 28857176 TI - Do right-ventricular trabeculae gain energetic advantage from having a greater velocity of shortening? AB - KEY POINTS: We designed a study to test whether velocity of shortening in right ventricular tissue preparations is greater than that of the left side under conditions mimicking those encountered by the heart in vivo. Our experiments allowed us to explore whether greater velocity of shortening results in any energetic advantage. We found that velocity of shortening was higher in the rat right-ventricular trabeculae. These results at the tissue level seem paradoxical to the velocity of ventricular ejection at the organ level, and are not always in accord with shortening of unloaded cells. Despite greater velocity of shortening in right-ventricular trabeculae, they neither gained nor lost advantage with respect to both mechanical efficiency and the heat generated during shortening. ABSTRACT: Our study aimed to ascertain whether the interventricular difference of shortening velocity, reported for isolated cardiac tissues in vitro, affects interventricular mechano-energetic performance when tested under physiological conditions using a shortening protocol designed to mimic those in vivo. We isolated trabeculae from both ventricles of the rat, mounted them in a calorimeter, and performed experiments at 37 degrees C and 5 Hz stimulus frequency to emulate conditions of the rat heart in vivo. Each trabecula was subjected to two experimental protocols: (i) isotonic work-loop contractions at a variety of afterloads, and (ii) isometric contractions at a variety of preloads. Velocity of shortening was calculated from the former protocol during the isotonic shortening phase of the contraction. Simultaneous measurements of force length work and heat output allowed calculation of mechanical efficiency. The shortening-dependent thermal component was quantified from the difference in heat output between the two protocols. Our results show that both extent of shortening and velocity of shortening were higher in trabeculae from the right ventricle. Despite these differences, trabeculae from both ventricles developed the same stress, performed the same work, liberated the same amount of heat, and hence operated at the same mechanical efficiency. Shortening heat was also ventricle independent. The interventricular differences in velocity of shortening and extent of shortening of isolated trabeculae were not manifested in any index of energetics. These collective results underscore the absence of any mechano energetic advantage or disadvantage conferred on right-ventricular trabeculae arising from their superior velocity of shortening. PMID- 28857178 TI - 12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs. AB - BACKGROUND: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. METHODS: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. RESULTS: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12 hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. CONCLUSION: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12 OH-17,18-EpETE is a potential therapeutic target for the management of asthma. PMID- 28857180 TI - Clinical characteristics and prognostic inflection points among long-term survivors of advanced epithelial ovarian cancer. AB - OBJECTIVE: To assess clinical characteristics of long-term survivors of advanced epithelial ovarian cancer (EOC) to define a prognostic inflection point for long term survival. METHODS: A retrospective analysis was undertaken of patients with FIGO stage III or IV EOC treated at one center in South Korea from 2000 to 2012. Patients who survived 5 years or more were identified, and the periods of disease free survival and overall survival were evaluated for prognostic inflection points to indicate long-term survival. Clinicopathologic data and treatment associated factors were assessed. RESULTS: In total, 60 patients survived more than 5 years. Thirty-three (55%) patients experienced disease recurrence and 11 (18%) died due to advanced EOC during a median follow-up period of 92 months (range 61-205). Most recurrence events (32/33, 97%) and deaths (10/11, 91%) occurred within 6 years and 8 years, respectively. Although half the long-term (>8 year) survivors with stage IIIC-IV disease experienced disease recurrence, they had a significantly longer platinum-free interval (P=0.007) and tended to have received aggressive surgical treatments after disease recurrence (P=0.054), as compared with survivors for 5-8 years. CONCLUSION: Survival for 8 years might represent a prognostic inflection point for long-term survival in advanced EOC. PMID- 28857181 TI - Simultaneous induction of HSP70 expression, and degranulation, in IgE/Ag stimulated or extracellular HSP70-stimulated mast cells. AB - BACKGROUND: In mast cells, induction of HSP70 expression during antigen stimulation has not been reported. METHODS: Mouse bone marrow-derived mast cells (BMMC) were stimulated with IgE/Ag or HSP70. Induction of HSP70 expression and signaling protein phosphorylation were evaluated by immunoblotting. RESULTS: HSP70 expression is induced in BMMC at an early stage of IgE/Ag-dependent stimulation, some of which is released from the cells in a granule-associated form. Induction of HSP70 expression was also observed with an IgE/Ag-stimulated human basophilic cell line, indicating that the phenomenon is not restricted to mouse BMMC. The induction of HSP70 expression, and its release, followed a similar time course to that of degranulation. Released HSP70 seems to be responsible for degranulation and production of eicosanoids, at least in part, because a neutralizing anti-HSP70 antibody mitigated these activities and because exogenous HSP70 not only induced immediate degranulation followed by autocrine HSP70 expression but also enhanced degranulation in IgE/Ag-stimulated BMMC. Extracellular HSP70 was found to induce phosphorylation of linker for activation of T cells (LAT) and a series of downstream signaling molecules in BMMC. We further found that Fyn, Lyn, and spleen tyrosine kinase (Syk), which are known to concern LAT phosphorylation in IgE/Ag-stimulated BMMC, were not phosphorylated in HSP70-stimulated BMMC, whereas lymphocyte-specific protein tyrosine kinase (Lck) was phosphorylated. CONCLUSION: FcepsilonRI stimulation in BMMC and basophils induces HSP70 expression and its release. Extracellular HSP70 induces degranulation and mediator release via phosphorylation of LAT. PMID- 28857179 TI - Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. AB - OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. METHODS: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. RESULTS: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. SIGNIFICANCE: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS. PMID- 28857182 TI - Altered miR-193a-5p expression in children with cow's milk allergy. AB - BACKGROUND: Cow's milk allergy (CMA) is one of the most common food allergies in children. Epigenetic mechanisms have been suggested to play a role in CMA pathogenesis. We have shown that DNA methylation of Th1/Th2 cytokine genes and FoxP3 affects CMA disease course. Preliminary evidence suggests that also the miRNome could be implicated in the pathogenesis of allergy. Main study outcome was to comparatively evaluate miRNome in children with CMA and in healthy controls. METHODS: Peripheral blood mononuclear cells were obtained from children aged 4-18 months: 10 CMA patients, 9 CMA patients who outgrew CMA, and 11 healthy controls. Small RNA libraries were sequenced using a next-generation sequencing based approach. Functional assessment of IL-4 expression was also performed. RESULTS: Among the miRNAs differently expressed, 2 were upregulated and 14 were downregulated in children with active CMA compared to healthy controls. miR-193a 5p resulted the most downregulated miRNA in children with active CMA compared to healthy controls. The predicted targets of miR-193a-5p resulted upregulated in CMA patients compared to healthy controls. Peripheral blood CD4+ T cells transfected with a miR193a-5 inhibitor showed a significant upregulation of IL-4 mRNA and its protein expression. Children who outgrew CMA showed miRNA-193a-5p level, and its related targets expression, similar to that observed in healthy controls. CONCLUSIONS: Our results suggest that miR-193a-5p is a post transcriptional regulator of IL-4 expression and could have a role in IgE mediated CMA. This miRNA could be a novel diagnostic and therapeutic target for this common form of food allergy in childhood. PMID- 28857183 TI - M2 macrophages coexist with a Th1-driven profile in periapical cysts. AB - AIM: To evaluate the participation of both Th1 and Th2 responses in periapical cysts by assessing the presence of M2 macrophages, as well as acute IL-1 beta, TNF-alpha and IL-6 cytokines. METHODOLOGY: Twenty-four cases of periapical cysts were selected. Immuno-expressions of IL-1 beta, IL-6, TNF-alpha and CD163 were analysed in the cystic capsules in both superficial and deeper regions. Data were analysed with paired Wilcoxon test and Spearman correlation coefficient (P <= 0.05). RESULTS: There was a higher expression of IL-1beta, IL-6, TNF-alpha and M2 macrophages in the superficial region (P < 0.001) of cystic capsules. All acute cytokines had significant positive correlations amongst them regardless of the cystic capsule region. Regarding CD163, positive correlations occurred only with TNF-alpha (P = 0.007; r = 0.537) and IL-6 (P = 0.018; r = 0.478) in the superficial regions of the cystic capsule. CONCLUSIONS: M2 macrophages participated actively in the inflammatory response of periapical cysts and correlated with the expression of certain acute Th1-related cytokines. This illustrates the coexistence of an acute and chronic Th2-driven immune response in these lesions. Although M2 macrophages favour the healing process, their presence is not sufficient for periapical cyst regression, once an acute active response has occurred due to an infectious stimuli. PMID- 28857184 TI - Pathogenicity of memory Th2 cells is linked to stage of allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) consists of three developmental stages that are based on the presence/absence of antigen-specific IgE and symptoms. The pathogenic Th2 (Tpath2) cells constitute a population of Th2 cells with additional potentially pathogenic characteristics. We examined the relationship between Tpath2 cells and the stages of allergic rhinitis by focusing on ST2, which is an IL-33 receptor. METHODS: Patients with Japanese cedar pollen-induced AR (JCP-AR) and healthy volunteers were divided into "nonsensitized," "asymptomatic sensitized (AS)," and "JCP-AR" groups. We analyzed the ST2 expression and the Th2 function of cultured CD4+ T cells. Next, we observed the progress of patients in the AS stage around the time of seasonal pollen dispersal, with the characteristics of Th2 cells. RESULTS: The ST2 expression of T cells was only upregulated in the AR group. The production of IL-4 and IL-13 was found in CD4+ T cells obtained from AS by stimulation with JCP, but reactivity to IL-33 was not observed. Although IL-33 did not induce the elevation of IL-4 production in the JCP-AR group, IL-33 substantially increased the production of IL-5 and IL-13 in comparison with antigen stimulation alone. In newly afflicted patients, the increased expression of ST2 and elevated reactivity to IL-33 was observed, even before the pollen dispersal season. CONCLUSIONS: Our study demonstrated that the pathogenicity of memory Th2 cells is linked to sensitization and the stage of allergic rhinitis. Therefore, Tpath2 cells may provide useful insights into the mechanism of the onset and progression of allergic rhinitis. PMID- 28857185 TI - 5-/12-Lipoxygenase-linked cascade contributes to the IL-33-induced synthesis of IL-13 in mast cells, thus promoting asthma development. AB - BACKGROUND: As asthma progresses, the levels of IL-33 in serum are markedly increased and contribute to asthmatic development and exacerbation. Mast cells, one of the principal effector cells in the pathogenesis of asthma, express high levels of the IL-33 receptor ST2 and have been shown to be activated by IL-33. Thus, IL-33 stimulates mast cells to produce Th2-type cytokines such as IL-13, thus contributing to asthmatic development. However, the signaling mechanism for IL-33-induced synthesis of Th2 cytokines, particularly IL-13, has not been fully elucidated in mast cells. METHODS: The role of 5- or 12-LO in the IL-33-induced synthesis of IL-13 was investigated using knockdown or pharmacological inhibitors in bone marrow-derived mast cells (BMMCs) and animal model. RESULTS: Blockade of 5- or 12-LO significantly suppressed IL-33-induced synthesis of IL-13 in BMMCs. The subsequent action of 5- and 12-LO metabolites through their specific receptor, BLT2, was also critical for IL-33-induced synthesis of IL-13. We also demonstrated that the MyD88-p38 kinase cascade lies upstream of 5-/12-LO and that NF-kappaB lies downstream of 5-/12-LO to mediate the IL-33-induced synthesis of IL-13 in mast cells. Consistent with these findings, we observed that in an IL-33 administered asthmatic airway inflammation model, IL-13 levels were markedly increased in bronchoalveolar lavage fluid, but its levels were markedly suppressed by treatment with inhibitors of 5-LO, 12-LO or BLT2, further suggesting roles of 5-/12-LO in IL-33-induced IL-13 production. CONCLUSION: Our results suggest that "MyD88-5-/12-LO-BLT2-NF-kappaB" cascade significantly contributes to the IL-33-induced synthesis of IL-13 in mast cells, thus potentially contributing to asthmatic development and exacerbation. PMID- 28857187 TI - A dichotomy resolved: Plant growth can control the rate of starch accumulation. PMID- 28857186 TI - Antischistosome antibodies change NTPDase 1 activity from macrophages. AB - NTPDases are enzymes that hydrolyse diphosphate and triphosphate nucleosides, regulating purinergic signalling in many organisms. The Schistosoma mansoni NTPDases, SmATPDases 1 and 2, are antigenic proteins and display a significant homology with the isoforms found in mammalian cells. In this work, we investigated whether anti-SmATPDase antibodies from S. mansoni-infected mice sera show cross-reactivity with the NTPDase 1 isoform from macrophages and how this event affects the cell proliferation. By Western blot, anti-SmATPDase antibodies present in serum from infected mice recognized 2 bands with approximately 53 and 58 kDa, corresponding to NTPDase 1. Additionally, the enzyme was identified in macrophages by immunofluorescence and the anti-SmATPDase antibodies were able to reduce activity enzyme (22%). Macrophages incubated with commercial polyclonal antibodies reactive with NTPDase 1 (anti-CD39) showed a reduction of 40% of the enzyme activity. In proliferation assays, macrophage proliferation was inhibited 11% and 90% by pooled sera from infected animals and anti-CD39, respectively. The results suggest that inhibition of NTPDase 1 in macrophages by antibodies produced against the isoforms of the S. mansoni ATPDases could be a mechanism of regulation in the immune response during experimental schistosomiasis. PMID- 28857188 TI - Development of a real-time PCR assay for rapid detection and quantification of Photobacterium damselae subsp. piscicida in fish tissues. AB - The availability of a rapid and accurate method for the diagnosis of Photobacterium damselae subsp. piscicida (Phdp), able to discriminate its strictly correlated subsp. damselae (Phdd), formally known as Vibrio damsela, is essential for managing fish pasteurellosis outbreaks in farmed fish. A single step, high-sensitivity real-time PCR assay for simultaneous detection and quantification of P. damselae was designed targeting partial of the sequence of the bamB gene and tested for specificity and sensitivity on laboratory-generated samples as well as on experimentally infected seabream tissue samples. With a limit of detection (LOD) of one copy in pure bacterial DNA, the sensitivity was higher than all methods previously reported. Validation in target and non-target bacterial species proved the assay was able to discriminate Phdd-Phdp subspecies from diverse hosts/geographical origins and between non-target species. In addition, two SNPs in the target amplicon region determine two distinctive qPCR dissociation curves distinguishing between Phdp-Phdd. This is the first time that a molecular method for P. damselae diagnosis combines detection, quantification and subspecies identification in one step. The assay holds the potential to improve the knowledge of infection dynamics and the development of better strategies to control an important fish disease. PMID- 28857189 TI - Occupational exposure in MR facilities due to movements in the static magnetic field. AB - PURPOSE: The exposure of operators moving in the static field of magnetic resonance (MR) facilities was assessed through measurements of the magnetic flux density, which is experienced as variable in time because of the movement. Collected data were processed to allow the comparison with most recent and authoritative safety standards. METHODS: Measurements of the experienced magnetic flux density B were performed using a probe worn by volunteers moving in MR environments. A total of 55 datasets were acquired nearby a 1.5 T, 3 T, and 7 T whole body scanners. Three different metrics were applied: the maximum intensity of B, to be compared with 2013/35/EU Directive exposure limit values for static fields; the maximum variation of the vector B on every 3s-interval, for comparison with the ICNIRP-2014 basic restriction aimed at preventing vertigo effects; two weighted-peak indices (for "sensory" and "health" effects: SENS-WP, HLTH-WP), assessing compliance with ICNIRP-2014 and EU Directive recommendations intended to prevent stimulation effects. RESULTS: Peak values of |B| were greater than 2 T in nine of the 55 datasets. All the datasets at 1.5 T and 3 T were compliant with the limit for vertigo effects, whereas six datasets at 7 T turned out to be noncompliant. At 7 T, all 36 datasets were noncompliant for the SENS-WP index and 26 datasets even for the HLTH-WP one. CONCLUSIONS: Results demonstrate that compliance with EU Directive limits for static fields does not guarantee compliance with ICNIRP-2014 reference levels and clearly show that movements in the static field could be the key component of the occupational exposure to EMF in MR facilities. PMID- 28857190 TI - A novel family of transcription factors conserved in angiosperms is required for ABA signalling. AB - The plant hormone abscisic acid (ABA) plays a crucial role in regulating plant responses to environmental stresses. Interplay of several different proteins including the PYR/PYL/RCAR receptors, A-group PP2C protein phosphatases, SnRK2 protein kinases, and downstream transcription factors regulates ABA signalling. We report here the identification of a family of ABA-induced transcription repressors (AITRs) that act as feedback regulators in ABA signalling. We found that the expression of all the 6 Arabidopsis AITR genes was induced by exogenously ABA, and their expression levels were decreased in ABA biosynthesis mutant aba1-5. BLAST searches showed that AITRs are exclusively present in angiosperms. When recruited to the promoter region of a reporter gene by a fused DNA binding domain, all AITRs inhibited reporter gene expression in transfected protoplasts. In Arabidopsis, aitr mutants showed reduced sensitivity to ABA and to stresses such as salt and drought. Quantitative RT-PCR analysis demonstrated that the ABA-induced response of PP2C and some PYR/PYL/RCAR genes was reduced in AITR5 transgenic plants but increased in an aitr2 aitr5 aitr6 triple mutant. These results provide important new insights into the regulation of ABA signalling in plants, and such information may lead to the production of plants with enhanced resistance to environmental stresses. PMID- 28857191 TI - Transitions in sleep problems from late adolescence to young adulthood: A longitudinal analysis of the effects of peer victimization. AB - Adolescence is a developmental period with high vulnerability to sleep problems. However, research identifying distinct patterns and underlying determinants of sleep problems is scarce. This study investigated discrete subgroups of, changes in, and stability of sleep problems. We also examined whether peer victimization influenced sleep problem subgroups and transitions in patterns of sleep problems from late adolescence to young adulthood. Sex differences in the effects of peer victimization were also explored. In total, 1,455 male and 1,399 female adolescents from northern Taiwan participated in this longitudinal study. Latent transition analysis was used to examine changes in patterns of sleep problems and the effects of peer victimization on these changes. We identified three subgroups of sleep problems in males and two in females, and found that there was a certain level of instability in patterns of sleep problems during the study period. For both sexes, those with greater increases in peer victimization over time were more likely to change from being a good sleeper to a poor sleeper. The effects of peer victimization on baseline status of sleep problems, however, was only significant for males, with those exposed to higher levels of peer victimization more likely to be poor sleepers at baseline. Our findings reveal an important role of peer victimization in predicting transitions in patterns of sleep problems. Intervention programs aimed at decreasing peer victimization may help reduce the development and escalation of sleep problems among adolescents, especially in males. PMID- 28857192 TI - Moisture content of root canal dentine affects detection of microcracks using micro-computed tomography. AB - AIM: To evaluate the effect of moisture content in root canal dentine on detection of microcracks using micro-computed tomography. METHODOLOGY: Ten roots with and without craze lines or cracks (each n = 5) were selected and scanned six times with different moisture conditions of root dentine using a micro-CT scanner at a high resolution of 10.5 MUm. Scanning conditions were as follows: (i) after 30-day wet storage, (ii) after 2-h dry time, (iii) after 48-h wet storage, (iv) after 24-h dry time, (v) after 48-h wet storage, (vi) after 2-h dry time. From each scan, cross-sectional images were obtained at intervals of 1 mm (total n = 708) and evaluated for the presence of dentinal microcracks twice by five calibrated blinded observers. Statistical analysis was performed by nonparametric analysis of variance for longitudinal data (P < 0.05). RESULTS: Intra-rater percentage agreement ranged between 92% and 98%, whereas inter-rater percentage agreement was 81% and 83%, respectively. No significant differences between all wet groups as well as between both groups with 2-h dry time were detected (P > 0.05). Almost no cracks were observed after wet storage with a significant increase of cracks after 2-h dry time (P < 0.001). Significantly more microcracks were identified after 24 h than after 2-h dry time (P < 0.004). CONCLUSIONS: Moisture content of dentine influenced detection of microcracks when evaluated using micro-CT. Scanning should be performed on dried specimens to allow reliable identification of dentinal defects. Formation of new cracks during dry periods up to 24 h was disproved. PMID- 28857193 TI - Technical Note: DoseMapper: A validated GUI-based exact numerical modeling method of shielding in PET/CT facilities. AB - PURPOSE: To provide a faster and more intuitive way of designing shielding for PET facilities, while still relying on the principles of the AAPM 108 Taskforce guidelines, as well as illustrating the calculation output using dose maps that are easily evaluated. METHODS: A graphical user interface was developed, implementing an inverse AAPM method, wherein radiation sources and shield barriers are manually defined. Simulations are calculated using a user-defined control mesh grid. DoseMapper simulations were verified against manual calculations using the AAPM guidelines, as well as compared with in situ dose rate measurements using four different dosemeters. RESULTS: DoseMapper simulations were virtually identical to manual calculations using AAPM guidelines, with a maximum relative error of <0.01%. Comparison with in situ measurements showed that DoseMapper-simulated dose rates in all instances are higher than what can be measured, ensuring that no unintended hotspots can be overlooked in the shielding design. CONCLUSIONS: DoseMapper is an easy to use implementation of the AAPM 108 Taskforce principles that allows for a rapid iterative design process of shielding in PET facilities, and the resulting maps of dose rate and annual accumulated dose serve as clear documentation for the design. PMID- 28857194 TI - Local incompressible registration for liver ablation surgery assessment. AB - PURPOSE: In liver microwave ablation (MWA) surgery, the ablation area covers the tumor to generate tissue necrosis and treat the cancer. As the liver deforms during the operation, deviation between the target area determined during preoperative planning and the resultant ablation area is inevitable. Therefore, an accurate assessment of tumor coverage is crucial for treatment. Through registration between the pre- and postoperative livers, the ablation area is warped on the preoperative liver for the computation of tumor coverage. However, large deformations between the pre- and postoperative livers are caused by multiple factors, and these diverse deformations make registration a challenging task. The purpose of this paper was to develop an automatic method that can accurately register post- to preoperative livers. METHODS: In the proposed method, nonrigid deformations caused by respiratory movement and edema are separately considered and estimated by the local incompressible model in the registration of livers. The pre- and postoperative livers are first aligned by a rigid registration based on a convex hull. In the nonrigid registrations, local incompressible constraints are then set on the liver and the ablation area to estimate the deformations caused by respiratory movement and edema, respectively. The concatenation of the rigid and nonrigid deformations is used to warp the ablation area on the preoperative liver. RESULTS: The proposed method was evaluated using clinical CT datasets from 20 patients. The Dice similarity coefficient (DSC) between the preoperative and warped postoperative livers is 94.35%, the mean surface distance (MSD) between the livers is 1.65 mm, the mean Hausdorff distance (HDD) between the livers is 3.36 mm, and the mean corresponding distance (MCD) between the corresponding landmarks is 1.70 mm. Compared with five other state-of-the-art methods, the proposed method achieves automatic ablation assessment with highly accurate registration. CONCLUSIONS: The proposed method achieves a high accuracy for registering the livers. The sizes and positions of the ablation area and tumor are accurately compared for the assessment of ablation surgery. PMID- 28857196 TI - The effect of dental bleaching on pulpal tissue response in a diabetic animal model: a study of immunoregulatory cytokines. AB - AIM: To evaluate the influence of tooth bleaching on immunoregulatory cytokines production (IL-6, Tumour necrosis factor (TNF)-alpha and IL-17) in the pulp tissue of normoglycaemic and diabetic rats. METHODOLOGY: Twenty-eight rats were divided into normoglycaemic and diabetic rats (n = 14). Diabetes mellitus (DM) was induced with a single dose of alloxan diluted in citrate buffer via intramuscular injection. After DM confirmation, all rats were sedated and tooth bleaching was performed using 35% hydrogen peroxide on the right maxillary molars for 30 min. Left molars were used as controls. Bleaching resulted in four hemimaxillae groups: normoglycaemic (N), N-bleached (NBle), diabetic (D) and D bleached (DBle). After 2 and 30 days, rats were euthanized and hemimaxillae processed for analysis by haematoxylin and eosin and immunohistochemistry. Results within and between animals were submitted to Wilcoxon signed-rank and Mann-Whitney tests (P < 0.05). RESULTS: At 2 days, the NBle group had mild, and the DBle had severe inflammatory infiltration in the pulpal tissue (P < 0.05). TNF-alpha and IL-6 cytokines were associated with increased immunolabelling in the bleached groups compared to nonbleached (P < 0.05). However, IL-17 had increased immunolabelling in the NBle compared to the N and DBle group (P < 0.05). At 30 days, reactionary dentine was observed in the coronal pulp of all bleached teeth and no inflammation was present (P > 0.05). TNF-alpha cytokines had increased immunolabelling in the DBle group compared to the D group (P < 0.05). However, for IL-6 and IL-17, no difference was observed in this period (P > 0.05). CONCLUSIONS: Tooth bleaching increased IL-6 and TNF-alpha in the pulp tissue regardless of diabetes mellitus; however, diabetic rats had higher TNF alpha levels for longer periods. Tooth bleaching influenced the increase in IL-17 in the early periods in normoglycaemic rats. PMID- 28857198 TI - Low relational mobility leads to greater motivation to understand enemies but not friends and acquaintances. AB - Enemyship occurs across societies, but it has not received as much attention as other types of relationships such as friendship in previous research. This research examined the influence of relational mobility on people's motivation to understand their personal enemies by measuring different dependent variables across three studies. First, a cross-cultural comparison study found that Hong Kong Chinese, from a low-relational-mobility society, reported a stronger desire to seek proximity to enemies relative to European Canadians, from a high relational-mobility society (Study 1). To test causality, two manipulation studies were conducted. Participants were presented with images of co-workers, including enemies, friends, and acquaintances, in a hypothetical company. The results showed that the participants who perceived lower relational mobility paid more attention to their enemies in an eye-tracking task (Study 2) and had a higher accuracy rate for recognizing the faces of the enemies in an incidental memory test (Study 3). In contrast, the influence of relational mobility on motivation to understand friends and acquaintances was minimal. Implications for research on interpersonal relationships and relational mobility are discussed. PMID- 28857197 TI - Purification and properties of beta-cyclomaltodextrin glucanotransferase from Bacillus flexus SV 1. AB - Cyclomaltodextrin glucanotransferase is a unique enzyme that degrades starch into cyclic oligosaccharides called cyclodextrins, which have numerous applications in various industries such as pharmaceutical, textile, agricultural, cosmetics etc. Due to its wide applications, microorganism producing one type of cyclodextrin is of interest as it simplifies the down streaming process of separating mixture of cyclodextrins. In the present study, beta-CGTase was isolated from Bacillus flexus SV 1 and biochemically characterized. Enzyme was purified by starch adsorption followed by DEAE cellulose column chromatography which resulted in a fold purification of 6.1, with a yield of 44.07%. Molecular weight of the purified enzyme was found to be 96.68 kDa, enzyme was monomeric in nature with a Km and Vmax of 0.08976 MUmol mL-1 and 585.1 MUmol/ml/min, respectively. Optimum pH and temperature of the purified enzyme was found to be 8.0 and 60 degrees C. Ca2+ showed significant increase in enzyme activity. The inhibition of enzyme by EDTA indicates that CGTase is a metalloenzyme. CGTase produced majorly beta-CD and was alkalotolarent and active at high temperatures which is a promising candidate for various industries such as textile, food, agriculture, and pharmaceuticals. PMID- 28857199 TI - Urate levels predict survival in amyotrophic lateral sclerosis: Analysis of the expanded Pooled Resource Open-Access ALS clinical trials database. AB - INTRODUCTION: Urate has been identified as a predictor of amyotrophic lateral sclerosis (ALS) survival in some but not all studies. Here we leverage the recent expansion of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to study the association between urate levels and ALS survival. METHODS: Pooled data of 1,736 ALS participants from the PRO-ACT database were analyzed. Cox proportional hazards regression models were used to evaluate associations between urate levels at trial entry and survival. RESULTS: After adjustment for potential confounders (i.e., creatinine and body mass index), there was an 11% reduction in risk of reaching a survival endpoint during the study with each 1 mg/dL increase in uric acid levels (adjusted hazard ratio 0.89, 95% confidence interval 0.82-0.97, P < 0.01). DISCUSSION: Our pooled analysis provides further support for urate as a prognostic factor for survival in ALS and confirms the utility of the PRO-ACT database as a powerful resource for ALS epidemiological research. Muscle Nerve 57: 430-434, 2018. PMID- 28857200 TI - By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In this study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. High glycolysis and PFKFB3 overexpression occupied a dominant position in sorafenib resistance, and can be targeted and overcome by aspirin. Aspirin plus sorafenib induced apoptosis in tumors without inducing weight loss, hepatotoxicity or inflammation. Our results suggest that aspirin overcomes sorafenib resistance and their combination may be an effective treatment approach for HCC. PMID- 28857201 TI - Wheat flag leaf epicuticular wax morphology and composition in response to moderate drought stress are revealed by SEM, FTIR-ATR and synchrotron X-ray spectroscopy. AB - Wheat (Triticum aestivum L.) is the largest cereal crop grown in Western Canada where drought during late vegetative and seed filling stages affects plant development and yield. To identify new physiochemical markers associated with drought tolerance, epidermal characteristics of the flag leaf of two wheat cultivars with contrasting drought tolerance were investigated. The drought resistant 'Stettler' had a lower drought susceptibility index, greater harvest index and water-use efficiency than the susceptible 'Superb'. Furthermore, flag leaf width, relative water content and leaf roll were significantly greater in Stettler than in Superb at moderate drought stress (MdS). Visible differences in epicuticular wax density on the adaxial flag leaf surfaces and larger bulliform cells were identified in Stettler as opposed to Superb. Mid-infrared attenuated total internal reflectance spectra revealed that Stettler flag leaves had increased asymmetric and symmetric CH2 but reduced carbonyl esters on its adaxial leaf surface compared to Superb under MdS. X-ray fluorescence spectra revealed a significant increase in total flag leaf Zn concentrations in Stettler in response to MdS. Such information on the microstructural and chemical features of flag leaf may have potential as markers for drought tolerance and thereby accelerate the selection and release of more drought-resistant cultivars. PMID- 28857202 TI - Non-random dispersal mediates invader impacts on the invertebrate community. AB - Dispersers are often not a random draw from a population, dispersal propensity being conditional on individual phenotypic traits and local contexts. This non randomness consequently results in phenotypic differences between dispersers and non-dispersers and, in the context of biological invasions, in an invasion front made of individuals with a biased phenotype. This bias of phenotypes at the front may subsequently modulate the strength of ecological effects of an invasive species on invaded communities. We recently demonstrated that more asocial mosquitofish (Gambusia affinis), one of the 100 worst invasive species, disperse further, suggesting a sociability-biased invasion front. As behavioural types are related to the strength of interspecific interactions, an invasion by a biased subset of individuals should have important ecological implications for native communities. Here, we tested the impact of phenotypic biases in dispersing individuals (relative to non-dispersers) on prey communities in experimental mesocosms. We show that dispersers reduce prey abundance more than do non dispersers during the first 4 weeks after introduction, and that the disperser's social types are likely drivers of these differences. These differences in prey communities disappeared after 8 weeks suggesting prey community resilience against predation in these mesocosm ecosystems. Consequently, we call for the integration of non-random dispersal, dispersal syndromes and more generally intraspecific variation into studies predicting the impacts of invasions. PMID- 28857203 TI - Assessment of alternative emergency treatments for symptomatic irreversible pulpitis: a randomized clinical trial. AB - AIM: To evaluate three emergency procedures for their ability to alleviate clinical symptoms associated with symptomatic teeth having signs of (at least) partial irreversible pulpitis. METHODOLOGY: Sixty-six maxillary and mandibular molars were randomly assigned to a total pulpectomy group (TP; n = 22), partial pulpectomy group (PP; n = 22) or pulpotomy group (P; n = 22). Procedure durations were recorded. Patients answered a questionnaire on daily analgesic requirements and about clinical symptoms (pain intensity, chewing sensitivity and thermal sensitivity) after the anaesthetic effect had disappeared (Day 0) and on Days 1, 3 and 7 post-treatment. RESULTS: The total pulpectomy group was associated with the longest procedures (median, 24 min), followed by the partial pulpectomy and pulpotomy groups (P < 0.001 for all). In all three groups, pain intensity, thermal sensitivity and chewing sensitivity decreased significantly from the preoperative time-point to Day 7 (P < 0.001 for all). The total pulpectomy group reported greater reductions in pain intensity than the pulpotomy group between Days 0 and 7, Days 1 and 3, and Days 1 and 7 (P < 0.001 for all). No other intergroup differences were noted regarding reductions in pain intensity, and none were observed with respect to changes in prevalence of thermal sensitivity and chewing sensitivity. There were also no significant intergroup differences regarding the analgesic requirements throughout the 7 days. CONCLUSION: As emergency treatments for teeth having signs of irreversible pulpitis, pulpotomy, partial pulpectomy and total pulpectomy were comparable with respect to relieving clinical symptoms. Pulpotomy may be preferred because it requires significantly less time and is a simple technique that relieves symptoms quickly and effectively. PMID- 28857205 TI - Psychometric evaluation of a multi-dimensional measure of satisfaction with behavioral interventions. AB - Treatment satisfaction is recognized as an essential aspect in the evaluation of an intervention's effectiveness, but there is no measure that provides for its comprehensive assessment with regard to behavioral interventions. Informed by a conceptualization generated from a literature review, we developed a measure that covers several domains of satisfaction with behavioral interventions. In this paper, we briefly review its conceptualization and describe the Multi-Dimensional Treatment Satisfaction Measure (MDTSM) subscales. Satisfaction refers to the appraisal of the treatment's process and outcome attributes. The MDTSM has 11 subscales assessing treatment process and outcome attributes: treatment components' suitability and utility, attitude toward treatment, desire for continued treatment use, therapist competence and interpersonal style, format and dose, perceived benefits of the health problem and everyday functioning, discomfort, and attribution of outcomes to treatment. The MDTSM was completed by persons (N = 213) in the intervention group in a large trial of a multi-component behavioral intervention for insomnia within 1 week following treatment completion. The MDTSM's subscales demonstrated internal consistency reliability (alpha: .65 - .93) and validity (correlated with self-reported adherence and perceived insomnia severity at post-test). The MDTSM subscales can be used to assess satisfaction with behavioral interventions and point to aspects of treatments that are viewed favorably or unfavorably. PMID- 28857206 TI - Development and validation of a simple high-performance liquid chromatography analytical method for simultaneous determination of phytosterols, cholesterol and squalene in parenteral lipid emulsions. AB - A simple analytical method for simultaneous determination of phytosterols, cholesterol and squalene in lipid emulsions was developed owing to increased interest in their clinical effects. Method development was based on commonly used stationary (C18 , C8 and phenyl) and mobile phases (mixtures of acetonitrile, methanol and water) under isocratic conditions. Differences in stationary phases resulted in peak overlapping or coelution of different peaks. The best separation of all analyzed compounds was achieved on Zorbax Eclipse XDB C8 (150 * 4.6 mm, 5 MUm; Agilent) and ACN-H2 O-MeOH, 80:19.5:0.5 (v/v/v). In order to achieve a shorter time of analysis, the method was further optimized and gradient separation was established. The optimized analytical method was validated and tested for routine use in lipid emulsion analyses. PMID- 28857207 TI - The adaptive response of skeletal muscle: What is the evidence? AB - Adult skeletal muscle is capable of adapting its properties in response to changing functional demands. This now sounds like a statement of the obvious, and many people assume it has always been this way. A mere 40 years ago, however, the picture was entirely different. In this Review and personal memoir, I outline the scientific context in which the theory was generated, the objections to it from entrenched opinion, and the way those objections were progressively met. The material should be of some historical interest, but, more importantly, it collects together the full range of evidence on which the current paradigm is based. Muscle Nerve 57: 531-541, 2018. PMID- 28857208 TI - Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) worldwide. NAFLD-HCC often occurs in noncirrhotic liver raising important surveillance issues. AIM: To determine the temporal trends for prevalence, clinical characteristics and outcomes of NAFLD-HCC in patients undergoing liver resection. METHODS: Consecutive patients with histologically confirmed HCC who underwent liver resection over a 20-year period (1995-2014). NAFLD was diagnosed based on past or present exposure to obesity or diabetes without other causes of chronic liver disease. RESULTS: A total of 323 HCC patients were included, 12% with NAFLD. From 1995-1999 to 2010-2014, the prevalence of NAFLD-HCC increased from 2.6% to 19.5%, respectively, P = .003, and followed the temporal trends in the prevalence of metabolic risk factors (28% vs 52%, P = .017), while hepatitis C-HCC decreased (from 43.6% to 19.5%, P = .003). NAFLD-HCC occurred more frequently in the absence of bridging fibrosis/cirrhosis (63% of cases, P < .001 compared to other aetiologies). Within the NAFLD group, tumour characteristics were similar between F0-F2 and F3-F4 patients, except for a higher proportion of single nodules (95% vs 54%, P < .01). A total of 53% patients had tumour recurrence and 40% died. NAFLD-HCC had similar time to recurrence and survival as HCCs of other aetiologies. Satellite nodules, tumour size, microvascular invasion and male sex but not the aetiology were independently associated with recurrence. CONCLUSION: Non-alcoholic fatty liver disease increased substantially over the past 20 years among resectable HCCs. It is now the leading cause of HCC occuring without/or with only minimal fibrosis. NAFLD patients are older, with larger tumours while survival and recurrence rates are as severe as in other aetiologies. PMID- 28857209 TI - A genome-wide association study suggests new candidate genes for milk production traits in Chinese Holstein cattle. AB - A genome-wide association study (GWAS) was conducted on 15 milk production traits in Chinese Holstein. The experimental population consisted of 445 cattle, each genotyped by the GGP (GeneSeek genomic profiling)-BovineLD V3 SNP chip, which had 26 151 public SNPs in its manifest file. After data cleaning, 20 326 SNPs were retained for the GWAS. The phenotypes were estimated breeding values of traits, provided by a public dairy herd improvement program center that had been collected once a month for 3 years. Two statistical models, a fixed-effect linear regression model and a mixed-effect linear model, were used to estimate the association effects of SNPs on each of the phenotypes. Genome-wide significant and suggestive thresholds were set at 2.46E-06 and 4.95E-05 respectively. The two statistical models concurrently identified two genome-wide significant (P < 0.05) SNPs on milk production traits in this Chinese Holstein population. The positional candidate genes, which were the ones closest to these two identified SNPs, were EEF2K (eukaryotic elongation factor 2 kinase) and KLHL1 (kelch like family member 1). These two genes could serve as new candidate genes for milk yield and lactation persistence, yet their roles need to be verified in further function studies. PMID- 28857210 TI - Translation and validation of the arabic version of the revised 15-item myasthenia gravis quality-of-life questionnaire. AB - INTRODUCTION: We sought to translate, culturally adapt, and assess the Arabic version of the 15-item myasthenia gravis quality-of-life revised scale (MGQOL15R). METHODS: We assessed reliability with Cronbach alpha; reproducibility with intraclass correlation coefficient (ICC); validity with Spearman correlations for myasthenia gravis (MG)-specific activities of daily living (MG ADL), MG composite (MGC) score, and MG manual muscle test (MG-MMT) and with MGQOL15R in patients with different disease severity through the Kruskal-Wallis test; and sensitivity to change with Wilcoxon signed-rank test. RESULTS: In 65 enrolled patients, the mean MGQOL15R score was 10.84 +/- 8.11 (alpha = 0.94, ICC = 0.95). The correlation coefficients between MGQOL15R and MGC, MG-ADL, and MG MMT scores were 0.75, 0.75, and 0.74, respectively (P < 0.001). MGQOL15R scores were significantly higher (worse) in patients with more severe disease at baseline and significantly lower (better) in improved patients at follow-up. DISCUSSION: The Arabic version of MGQOL15R is valid, reliable, stable, and sensitive to changes. Muscle Nerve 57: 581-585, 2018. PMID- 28857211 TI - The impact of changes in LVEF and renal function on the prognosis of ICD patients after elective device replacement. AB - BACKGROUND: A proportion of patients with an implantable cardioverter defibrillator (ICD) in prevention of sudden cardiac death will only receive their first appropriate ICD therapy (AT) after device replacement. Clinical reassessment at the time of replacement could be helpful to guide the decision to replace or not in the future. METHODS: All patients with an ICD for primary or secondary prevention in ischemic (ICM) or nonischemic cardiomyopathy were included in a single-center retrospective registry. The association of changes in left ventricular ejection fraction (LVEF; cut-off at 35%), worsening renal function (decrease in estimated glomerular filtration rate > 15 mL/min), and worsening New York Heart Association class at elective device replacement with mortality and AT was analyzed using adjusted Cox regression analysis. RESULTS: A total of 238 (33%) out of 727 patients received elective device replacement (86.1% male, 74.4% ICM, 42.9% primary prevention). During this replacement 20.2% received a device upgrade. The mean time to replacement was 6.4 +/- 2.0 years and mean follow-up after replacement was 3.4 +/- 3.0 years. Of patients who did not receive AT before replacement 23.1% received their first AT after replacement. Worsening renal function (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.50-5.18) and a consistently LVEF <=35% compared to a consistently LVEF >35% (HR 2.15, 95% CI 1.10-4.19) at the time of replacement were independent predictors of mortality. Independent predictors of first AT after replacement could not be identified. CONCLUSION: Although reassessment of LVEF and renal function at replacement can be helpful in predicting total mortality, the clinical utility to guide reimplantation seemed limited. Our experience indicates that approximately 25% of patients received their first AT only after replacement. PMID- 28857212 TI - Normal 123 I-MIBG uptake areas may be associated with hyperinnervation and arrhythmia risk in phenol model rabbit hearts. AB - BACKGROUND: Iodine-123 metaiodobenzylguanidine (123 I-MIBG) is useful for detecting sympathetic innervation in the heart, and has been closely associated with fatal arrhythmias. However, such imaging is typically calibrated to the area of highest uptake and thus is unable to identify areas of hyperinnervation. We hypothesized that normal 123 I-MIBG uptake regions in the denervated heart would demonstrate nerve sprouting and correlate with the potential for arrhythmogenesis. METHODS: Twenty New Zealand white rabbits treated with phenol or sham were prepared under anesthesia. Sympathetic innervation was quantified using autoradiography and immunostaining 4 weeks after phenol application, and electrophysiological study was performed. RESULTS: 123 I-MIBG revealed maximal local differences in isotope uptake in the border zone between areas with attenuated and abundant MIBG compared with that seen between adjacent regions within the lowest uptake areas. On immunostaining, heterogeneous and decreased expressions of growth-associated protein 43 signal were observed in the MIBG attenuated areas; however, abundant signals were recognized in the MIBG-abundant areas. Upregulation of the tyrosine hydroxylase signal was observed at the part of the MIBG-abundant area. In electrophysiological study, the dispersion of activation recovery interval (ARI) was increased in the phenol-applied areas by norepinephrine infusion. Stellate stimulation exacerbated the ARI dispersion in both the phenol-applied and nonapplied areas, and was associated with increased inducibility of ventricular tachycardia and ventricular fibrillation. CONCLUSIONS: The presence of hyperinnervation in the nondenervated regions of denervated rabbit hearts suggests that heterogeneous neural remodeling occurs in regions with seemingly normal 123 I-MIBG uptake and contributes to electrical instability. PMID- 28857213 TI - Chronic arsenic intoxication diagnostic score (CAsIDS). AB - Arsenic and its compounds are well-established, potent, environmentally widespread and persistent toxicants with metabolic, genotoxic, mutagenic, teratogenic, epigenetic and carcinogenic effects. Arsenic occurs naturally in the Earth's crust, but anthropogenic arsenic emissions have surmounted the emissions from important natural sources such as volcanism. Inorganic arsenicals exhibit acute and chronic toxicities in virtually all cell types and tissues, and hence arsenic intoxication affects multiple systems. Whereas acute arsenic intoxication is rare and relatively easy to diagnose, chronic arsenic intoxication (CAsI) is common but goes often misdiagnosed. Based on a review of the literature as well as our own clinical experience, we propose a chronic arsenic intoxication diagnostic score (CAsIDS). A distinctive feature of CAsIDS is the use of bone arsenic load as an essential criterion for the individual risk assessment of chronic arsenic intoxication, combined with a systemic clinical assessment. We present clinical examples where CAsIDS is applied for the diagnosis of CAsI, review the main topics of the toxicity of arsenic in different cell and organ systems and discuss the therapy and prevention of disease caused or aggravated by chronic arsenic intoxication. CAsIDS can help physicians establish the diagnosis of CAsI and associated conditions. PMID- 28857214 TI - Sexual assault in the US military: A comparison of risk in deployed and non deployed locations among Operation Enduring Freedom/Operation Iraqi Freedom active component and Reserve/National Guard servicewomen. AB - BACKGROUND: To determine whether sexual assault in the military (SAIM) among active component and Reserve/National Guard servicewomen is more likely to occur in deployed or non-deployed locations; and which location poses greater risk for SAIM when time spent in-location is considered. METHODS: A total of 1337 Operation Enduring Freedom/Operation Iraqi Freedom era servicewomen completed telephone interviews eliciting socio-demographics, military and sexual assault histories, including attempted and completed sexual assault. RESULTS: Half of the sample had been deployed (58%). Overall 16% (N = 245) experienced SAIM; a higher proportion while not deployed (15%; n = 208) than while deployed (4%; n = 52). However, the incidence of SAIM per 100 person-years was higher in deployed than in non-deployed locations: 3.5 vs 2.4. Active component and Reserve/National Guard had similar deployment lengths, but Reserve/National Guard had higher SAIM incidence rates/100 person-years (2.8 vs 4.0). CONCLUSIONS: A higher proportion of servicewomen experienced SAIM while not deployed; however, adjusting for time in each location, servicewomen were at greater risk during deployment. PMID- 28857215 TI - The indispensability of labelled groups to vulnerability in bioethics. AB - Regarding the determination of vulnerability, the bioethics community has univocally jettisoned "labelled groups", groups whose membership confers a context-invariant "vulnerable" status to their members. While the usual reasons against the sole use of labelled groups to determine the vulnerability of individuals are sound, labelled groups as exemplars of vulnerability can play indispensable roles in bioethical reasoning. In this article, I argue against the wholesale jettisoning of labelled groups by showing how they can be useful. PMID- 28857216 TI - Recent advances in capillary electrophoresis separation of monosaccharides, oligosaccharides, and polysaccharides. AB - This article illustrates the basis and applications of methodologies for the analysis of simple and complex carbohydrates by means of CE. After a description of the most common and novel approaches useful for the analysis and characterization of carbohydrates, this review covers the recent advances in CE separation of monosaccharides, oligosaccharides, and polysaccharides. Various CE techniques are also illustrated for the study of carbohydrates derived from complex glyco-derivatives such as glycoproteins and glycolipids, essential for biopharmaceutical and glycoproteomics applications as well as for biomarker detection. Most glycans have no significant UV absorption, and derivatization with fluorophore groups prior to separation usually results in higher sensitivity and an improved electrophoretic profile. We also discuss the recent applications and separations by CE of derivatized simple and more complex carbohydrates with different chromophoric active tags. Overall, this review aims to give an overview of the most recent state-of-the-art techniques used in carbohydrate analysis by CE. PMID- 28857217 TI - Letter by Pearman et al. regarding article "Effect of botulinum toxin on inducibility and maintenance of atrial fibrillation in ovine myocardial tissue". PMID- 28857218 TI - Relationship between peroxisome proliferator-activated receptor alpha activity and cellular concentration of 14 perfluoroalkyl substances in HepG2 cells. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a molecular target for perfluoroalkyl substances (PFASs). Little is known about the cellular uptake of PFASs and how it affects the PPARalpha activity. We investigated the relationship between PPARalpha activity and cellular concentration in HepG2 cells of 14 PFASs, including perfluoroalkyl carboxylates (PFCAs), perfluoroalkyl sulfonates and perfluorooctane sulfonamide (FOSA). Cellular concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and PPARalpha activity was determined in transiently transfected cells by reporter gene assay. Cellular uptake of the PFASs was low (0.04-4.1%) with absolute cellular concentrations in the range 4-2500 ng mg-1 protein. Cellular concentration of PFCAs increased with perfluorocarbon chain length up to perfluorododecanoate. PPARalpha activity of PFCAs increased with chain length up to perfluorooctanoate. The maximum induction of PPARalpha activity was similar for short-chain (perfluorobutanoate and perfluoropentanoate) and long-chain PFCAs (perfluorododecanoate and perfluorotetradecanoate) (approximately twofold). However, PPARalpha activities were induced at lower cellular concentrations for the short-chain homologs compared to the long-chain homologs. Perfluorohexanoate, perfluoroheptanoate, perfluorooctanoate, perfluorononanoate (PFNA) and perfluorodecanoate induced PPARalpha activities >2.5-fold compared to controls. The concentration-response relationships were positive for all the tested compounds, except perfluorooctane sulfonate PFOS and FOSA, and were compound specific, as demonstrated by differences in the estimated slopes. The relationships were steeper for PFCAs with chain lengths up to and including PFNA than for the other studied PFASs. To our knowledge, this is the first report establishing relationships between PPARalpha activity and cellular concentration of a broad range of PFASs. PMID- 28857219 TI - Non-polio Enterovirus detection with acute flaccid paralysis: A systematic review. AB - Acute flaccid paralysis (AFP), as defined by the World Health Organization (WHO), is characterized by an acute onset of limb weakness. In the post-polio era, other enterovirus (EV) serotypes associated with AFP may become more prominent. This study aims to collate the data on the non-polio enteroviruses (NPEV) associated with AFP. A systematic review of published case reports, case series, and surveillance studies of AFP from 1960 through 2017 was undertaken. Data were collected including the country of the study, number of specimens positive for NPEV and available clinical data. The majority of studies originated from Asia. In surveillance studies, EV 71 (a serotype of Enterovirus A) was the most commonly detected serotype with AFP, followed by Enterovirus B serotype echovirus 11 and then Enterovirus B serotype echovirus 11. In case studies and case reports, EV 71 and EV 68 (a serotype of Enterovirus D), were the most commonly detected NPEV. As poliovirus eradication continues, there is a need to ensure that AFP surveillance will also detect other potentially vaccine preventable viruses. PMID- 28857220 TI - Presuming patient autonomy in the face of therapeutic misconception. AB - Therapeutic misconception involves the failure of subjects either to understand or to incorporate into their own expectations the distinctions in nature and purpose of personally responsive therapeutic care, and the generic relationship between subject and investigator which is constrained by research protocols. Researchers cannot disregard this phenomenon if they are to ensure that subjects engage in research on the basis of genuine informed consent. However, our presumption of patient autonomy must be sustained unless we have compelling evidence of serious misunderstanding. This article argues that the mere expression of aspects of therapeutic misconception should not necessarily displace the presumption of subject autonomy or undermine ethical inclusion in research for at least three reasons. First, some interpretations of the empirical data do not suggest misunderstanding. Second, assessment of misestimation and optimism are delicate and value-laden, and turn quickly from questions of autonomy to questions of judgment. Third, incomplete understanding may yet be sufficient to allow a subject to engage in a substantially autonomous decision making process. Our point is not to dismiss the possibility of genuine therapeutic misconception, but to question its frequency and fatality to the consent process. PMID- 28857221 TI - Sonographic Overview of Usual and Unusual Disorders of the Rectus Femoris Tendon Origins. AB - Rectus femoris muscle proximal injuries are not rare conditions. The proximal rectus femoris tendinous anatomy is complex and may be affected by traumatic, microtraumatic, or nontraumatic disorders. A good knowledge of the proximal rectus femoris anatomy allows a better understanding of injury and disorder patterns. A new sonographic lateral approach was recently described to assess the indirect head of the proximal rectus femoris, hence allowing for a complete sonographic assessment of the proximal rectus femoris tendons. This article will review sonographic features of direct, indirect, and conjoined rectus femoris tendon disorders. PMID- 28857222 TI - OsTGAP1 is responsible for JA-inducible diterpenoid phytoalexin biosynthesis in rice roots with biological impacts on allelopathic interaction. AB - Phytocassanes and momilactones are known as major diterpenoid phytoalexins (DPs), characterized by abundant production and antimicrobial activity, and their biosynthetic genes are clustered in rice genomes. The basic leucine zipper transcription factor OsTGAP1 is known to act as a regulator of the coordinated production of DPs in cultured rice cells, but in planta functions of OsTGAP1 remain largely unknown. Here, we present evidence on the biological function of OsTGAP1 in planta. In wild-type plants, OsTGAP1 is abundantly expressed in roots compared with that in shoots. Moreover, the inductive expression of OsTGAP1 under jasmonic acid (JA) treatment was only observed in a root-specific manner consistent with the JA-inducible expressions of DP biosynthetic genes in roots. In reverse genetic approaches on OsTGAP1-overexpressing and OsTGAP1-knockdown plants, expressions of the biosynthetic genes relevant for DP accumulation were found to be remarkably increased and decreased, respectively. Reporter analysis in planta revealed that OsTGAP1 activated the promoters of OsDXS3 and momilactone biosynthetic gene OsKSL4, presumably through binding to the TGACGT motif. Furthermore, cocultivation experiments with barnyard grass suggested that the allelopathic effect of knockdown and overexpression of OsTGAP1 was significantly changed compared with the controls. These results demonstrate that OsTGAP1 positively regulates DP accumulation via the transcriptional regulation of DP biosynthetic genes in rice roots, and this is indispensable for maintaining allelopathic interactions with paddy weeds by regulating the production of specialized metabolites like momilactones. PMID- 28857223 TI - Perceptual support promotes strategy generation: Evidence from equation solving. AB - Over time, children shift from using less optimal strategies for solving mathematics problems to using better ones. But why do children generate new strategies? We argue that they do so when they begin to encode problems more accurately; therefore, we hypothesized that perceptual support for correct encoding would foster strategy generation. Fourth-grade students solved mathematical equivalence problems (e.g., 3 + 4 + 5 = 3 + __) in a pre-test. They were then randomly assigned to one of three perceptual support conditions or to a Control condition. Participants in all conditions completed three mathematical equivalence problems with feedback about correctness. Participants in the experimental conditions received perceptual support (i.e., highlighting in red ink) for accurately encoding the equal sign, the right side of the equation, or the numbers that could be added to obtain the correct solution. Following this intervention, participants completed a problem-solving post-test. Among participants who solved the problems incorrectly at pre-test, those who received perceptual support for correctly encoding the equal sign were more likely to generate new, correct strategies for solving the problems than were those who received feedback only. Thus, perceptual support for accurate encoding of a key problem feature promoted generation of new, correct strategies. Statement of Contribution What is already known on this subject? With age and experience, children shift to using more effective strategies for solving math problems. Problem encoding also improves with age and experience. What the present study adds? Support for encoding the equal sign led children to generate correct strategies for solving equations. Improvements in problem encoding are one source of new strategies. PMID- 28857224 TI - Trends and racial/ethnic disparities in antibiotic prescribing practices of dentists in the United States. AB - OBJECTIVE: The aim of this study was to examine trends and racial/ethnic disparities in antibiotic prescribing practices of dentists in the United States. METHODS: The US Medical Expenditure Panel Survey data for 1996-2013 was analyzed. Information on patient sociodemographic characteristics, dental visits, receipt of dental procedures, and type of antibiotics prescribed following visits was obtained. Descriptive statistics were calculated separately for each year. Logistic regression analyses were conducted to identify associations during the period with and without adjustment for dental procedures and sociodemographic characteristics. Survey weights were incorporated to handle the sampling design. RESULTS: Nationally, the number of antibiotic prescribed at dental visits was estimated to be higher by 842,749 (0.4 percent) at year 2013 compared to the prescription level at 2003 were the population sociodemographic distribution kept at 2013 level. On average, the odds of prescribing antibiotics following dental care increased with each decade of study (OR: 1.10; 95% CI: [1.04, 1.17]) after adjusting for sociodemographic characteristics and receipt of dental procedures. Compared to Whites, Blacks had 21 percent (95% CI: 11%, 31%) higher odds of receiving a prescription for antibiotics from a dentist after adjusting for dental procedure and other sociodemographic characteristics. CONCLUSIONS: The prescription of antibiotics following dental visits increased over time after adjustment for sociodemographic characteristics and dental procedure. The probability of being prescribed antibiotics by dentists was higher for Blacks compared to Whites. PMID- 28857225 TI - Reconsidering paternalism in clinical research. AB - The ethical standards that regulate clinical research have multiple rationales. Among them is the need to protect potential subjects from making imprudent decisions, which extends beyond the soft paternalistic concern to protect people from making uninformed decisions to participate in trials. This article argues that a plausible risk/benefit restriction on clinical trials is presumptively justified by hard paternalism, which in turn is supported by a deeper fairness based rationale. This presumptive case for hard paternalism in research is not defeated by the alleged right to participate in clinical trials, by concerns about insult or status, by the need to conduct early phase trials that promise little to no benefit to participants, or by the recognition that some potential subjects are altruistically motivated. PMID- 28857226 TI - Virtual glucose management service: a novel resident educational tool. PMID- 28857227 TI - Five-R framework for prescription communication skills learning. PMID- 28857228 TI - An active-learning methodology for teaching oxidative phosphorylation. PMID- 28857229 TI - Simultaneous confidence regions for multivariate bioequivalence. AB - Demonstrating bioequivalence of several pharmacokinetic (PK) parameters, such as AUC and Cmax , that are calculated from the same biological sample measurements is in fact a multivariate problem, even though this is neglected by most practitioners and regulatory bodies, who typically settle for separate univariate analyses. We believe, however, that a truly multivariate evaluation of all PK measures simultaneously is clearly more adequate. In this paper, we review methods to construct joint confidence regions around multivariate normal means and investigate their usefulness in simultaneous bioequivalence problems via simulation. Some of them work well for idealised scenarios but break down when faced with real-data challenges such as unknown variance and correlation among the PK parameters. We study the shapes of the confidence regions resulting from different methods, discuss how marginal simultaneous confidence intervals for the individual PK measures can be derived, and illustrate the application to data from a trial on ticlopidine hydrochloride. An R package is available. PMID- 28857230 TI - Bridging the gaps for health: The GAPFON report. PMID- 28857231 TI - Challenges in the development of dopamine D2- and D3-selective radiotracers for PET imaging studies. AB - The dopamine D2-like receptors (ie, D2/3 receptors) have been the most extensively studied CNS receptor with Positron Emission Tomography (PET). The 3 different radiotracers that have been used in these studies are [11 C]raclopride, [18 F]fallypride, and [11 C]PHNO. Because these radiotracers have a high affinity for both dopamine D2 and D3 receptors, the density of dopamine receptors in the CNS is reported as the D2/3 binding potential, which reflects a measure of the density of both receptor subtypes. Although the development of D2- and D3 selective PET radiotracers has been an active area of research for many years, this by and large presents an unmet need in the area of translational PET imaging studies. This article discusses some of the challenges that have inhibited progress in this area of research and the current status of the development of subtype selective radiotracers for imaging D3 and D2 dopamine receptors with PET. PMID- 28857233 TI - Ecological theories of systems and contextual change in medical education. AB - INTRODUCTION: Contemporary medical practice is subject to many kinds of change, to which both individuals and systems have to respond and adapt. Many medical education programmes have their learners rotating through different training contexts, which means that they too must learn to adapt to contextual change. Contextual change presents many challenges to medical education scholars and practitioners, not least because of a somewhat fractured and contested theoretical basis for responding to these challenges. There is a need for robust concepts to articulate and connect the various debates on contextual change in medical education. Ecological theories of systems encompass a range of concepts of how and why systems change and how and why they respond to change. The use of these concepts has the potential to help medical education scholars explore the nature of change and understand the role it plays in affording as well as limiting teaching and learning. METHODS: This paper, aimed at health professional education scholars and policy makers, explores a number of key concepts from ecological theories of systems to present a comprehensive model of contextual change in medical education to inform theory and practice in all areas of medical education. RESULTS: The paper considers a range of concepts drawn from ecological theories of systems, including biotic and abiotic factors, panarchy, attractors and repellers, basins of attraction, homeostasis, resilience, adaptability, transformability and hysteresis. Each concept is grounded in practical examples from medical education. CONCLUSION: Ecological theories of systems consider change and response in terms of adaptive cycles functioning at different scales and speeds. This can afford opportunities for systematic consideration of responses to contextual change in medical education, which in turn can inform the design of education programmes, activities, evaluations, assessments and research that accommodates the dynamics and consequences of contextual change. PMID- 28857232 TI - Hepatic peroxisome proliferator-activated receptor gamma coactivator 1beta drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice. AB - : The peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1beta (PGC-1 beta) is a master regulator of mitochondrial biogenesis and oxidative metabolism as well as of antioxidant defense. Specifically, in the liver, PGC-1beta also promotes de novo lipogenesis, thus sustaining cellular anabolic processes. Given the relevant pathogenic role of mitochondrial and fatty acid metabolism in hepatocarcinoma (HCC), here we pointed to PGC-1beta as a putative novel transcriptional player in the development and progression of HCC. For this purpose, we generated both hepatic-specific PGC-1beta-overexpressing (LivPGC-1beta) and PGC-1beta knockout (LivPGC-1betaKO) mice, and we challenged them with both chemical and genetic models of hepatic carcinogenesis. Our results demonstrate a pivotal role of PGC-1beta in driving liver tumor development. Indeed, whereas mice overexpressing PGC-1beta show greater tumor susceptibility, PGC-1beta knockout mice are protected from carcinogenesis. High levels of PGC 1beta are able to boost reactive oxygen species (ROS) scavenger expression, therefore limiting the detrimental ROS accumulation and, consequently, apoptosis. Moreover, it supports tumor anabolism, enhancing the expression of genes involved in fatty acid and triglyceride synthesis. Accordingly, the specific hepatic ablation of PGC-1beta promotes the accumulation of ROS-driven macromolecule damage, finally limiting tumor growth. CONCLUSION: The present data elect hepatic PGC-1beta as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. (Hepatology 2018;67:884-898). PMID- 28857234 TI - Does mock exercise improve students' oral examination skills? PMID- 28857235 TI - Foundation programme for developing professional attributes in medical students. PMID- 28857236 TI - The impact of DSM-5 on the diagnosis and severity indicator of eating disorders in a treatment-seeking sample. AB - OBJECTIVE: To examine the impact of the DSM-5 on the diagnoses and severity indicators of eating disorders, we conducted a comparative study on the classification of eating disorders including subtypes of anorexia nervosa (AN) between the DSM-IV and DSM-5 criteria. In addition, we studied the association of the DSM-5 severity criteria and clinical variables. METHOD: Participants were 304 outpatients, aged 16-45 years, with eating disorders, diagnosed using semi structured clinical interviews and the eating disorder examination questionnaire (EDE-Q). The severity of AN, bulimia nervosa (BN), and binge-eating disorder (BED) was rated from mild to extreme using the DSM-5 severity criteria. RESULTS: The DSM-5 remarkably reduced the number of diagnoses in the residual category from 37.5% to 9.2% and effectively differentiated the diagnostic groups in eating disorder psychopathology. Unexpectedly, however, the scores of all the EDE-Q subscales significantly decreased as severity ratings increased in the DSM-5 AN. Furthermore, while the AN binge-eating/purging group reported significantly lower severity ratings than the AN restricting group, the former displayed more severe eating disorder psychopathology than the latter. In the BN and BED groups, the level of eating concern increased as severity ratings increased, but the severity groups did not differ on other eating pathology variables. DISCUSSION: The DSM-5 effectively reduced the reliance on residual categories and differentiated the diagnostic groups in eating disorder psychopathology. However, our findings show limited support for the DSM-5 severity specifiers for eating disorders. It is necessary to test additional clinical or functional variables for severity specifiers across eating disorders. PMID- 28857237 TI - What the child "SAID" to the dentist: A UK randomized controlled trial. AB - BACKGROUND: The electronic Survey of Anxiety and Information for Dentists (eSAID) allows children to tell dentists about their feelings and coping preferences. It is a computer "quiz" with 26 questions and free-text responses that produces a report for the children that they can then hand to their dentist. This is the first study to report the use of eSAID in a hospital paediatric dental clinic. METHODS: This was a randomized controlled trial to evaluate whether children thought that eSAID benefitted them, made them less anxious, and improved cooperation and their treatment satisfaction. Fifty-one children aged 8-13 years were randomized to complete either eSAID or a control version in the waiting room before their scheduled dental appointment. The study group had a 26-item questionnaire; the control had only two items. Both groups scored their anxiety on a 7-point anxiety scale at the start and again at the end of the quiz. All subjects handed the resultant eSAID report as a printout to their dentist. Dental treatment proceeded as planned. After treatment, each child reported how they thought the eSAID quiz had benefitted them by scoring on a 10 cm Visual Analogue Scale and their satisfaction on the Modified Treatment Evaluation Inventory. The operating dentists scored the children's cooperation using a 10 cm Visual Analogue Scale. RESULTS: Overall, the baseline anxiety levels were low (study: mean 1.2; control: mean 1.5). The study group's post-survey anxiety reduced by 0.4, whereas controls' increased by 0.2; this difference is statistically significant (p = .04). However, it made no difference to the children's self reported benefit (p = .30), satisfaction (p > .05), or cooperation (p = .34). CONCLUSIONS: eSAID reduced pre-treatment anxiety but made no difference to children's perceived benefit, satisfaction, or cooperation. Future study should include known anxious children. PMID- 28857238 TI - The diversity in the expression profile of caveolin II transcripts, considering its new transcript in breast cancer. AB - Most studies have revealed the effects of caveolins in cancer inhibition. However, due to a lack of reports about their new transcripts, their presence and their effects on different cancers are unclear. This study was conducted to evaluate the cavolin-2 (cav-2) transcripts expression changes in tumoral and corresponding tissues and in contralateral breast, to investigate their variation associated with the variation of caveolin-1 (cav-1) expression in breast cancer. There were 40 breast-derived tumoral, corresponding, and contralateral tissues obtained from the patients with breast cancer. The RNA and proteins were extracted from these samples. So, cav-1 and cav-2 transcripts' variation were assessed in whole tumoral, corresponding, and contralateral breast. Also, their expression modifications were evaluated via the Western blotting technique. The results derived from this study verified the presence of transcript III of cav-2 for the first time, which was reported only in the gene bank, but we could not detect and validate any protein associated with these transcripts. Also, the decreasing trend of cav-1 and the cav-2 (transcripts I and II) were observed in tumoral tissues compared to unaffected tissues especially in stages I and II. It seems that the descending expression levels of cav-1 and cav-2 (transcript I, II) besides the lasting expression of cav-2 (transcript III) are associated with the incidence and promotion of breast cancer, especially in the initial stages of breast cancer. So, this may show a potential in determining the patients who can undergo the prophylactic mastectomy. Moreover, the results of the study demonstrated that transcript III may be a candidate as a non-coding RNA. PMID- 28857239 TI - Exposure to nature counteracts aggression after depletion. AB - Acts of self-control are more likely to fail after previous exertion of self control, known as the ego depletion effect. Research has shown that depleted participants behave more aggressively than non-depleted participants, especially after being provoked. Although exposure to nature (e.g., a walk in the park) has been predicted to replenish resources common to executive functioning and self control, the extent to which exposure to nature may counteract the depletion effect on aggression has yet to be determined. The present study investigated the effects of exposure to nature on aggression following depletion. Aggression was measured by the intensity of noise blasts participants delivered to an ostensible opponent in a competition reaction-time task. As predicted, an interaction occurred between depletion and environmental manipulations for provoked aggression. Specifically, depleted participants behaved more aggressively in response to provocation than non-depleted participants in the urban condition. However, provoked aggression did not differ between depleted and non-depleted participants in the natural condition. Moreover, within the depletion condition, participants in the natural condition had lower levels of provoked aggression than participants in the urban condition. This study suggests that a brief period of nature exposure may restore self-control and help depleted people regain control over aggressive urges. PMID- 28857240 TI - Education as a context for early engagement in quality improvement. PMID- 28857241 TI - Co-expression analysis reveals key gene modules and pathway of human coronary heart disease. AB - Coronary heart disease is a kind of disease which causes great injury to people world-widely. Although gene expression analyses had been performed previously, to our best knowledge, systemic co-expression analysis for this disease is still lacking to date. Microarray data of coronary heart disease was downloaded from NCBI with the accession number of GSE20681. Co-expression modules were constructed by WGCNA. Besides, the connectivity degree of eigengenes was analyzed. Furthermore, GO and KEGG enrichment analysis was performed on these eigengenes in these constructed modules. A total of 11 co-expression modules were constructed by the 3000 up-regulated genes from the 99 samples with coronary heart disease. The average number of genes in these modules was 270. The interaction analysis indicated the relative independence of gene expression in these modules. The functional enrichment analysis showed that there was a significant difference in the enriched terms and degree among these 11 modules. The results showed that modules 9 and 10 played critical roles in the occurrence of coronary disease. Pathways of hsa00190 (oxidative phosphorylation) and (hsa01130: biosynthesis of antibiotics) were thought to be closely related to the occurrence and development of coronary heart disease. Our result demonstrated that modules 9 and 10 were the most critical modules in the occurrence of coronary heart disease. Pathways as hsa00190 (oxidative phosphorylation) and (hsa01130: biosynthesis of antibiotics) had the potential to serve as the prognostic and predictive marker of coronary heart disease. PMID- 28857242 TI - Down-regulation of the long noncoding RNA-HOX transcript antisense intergenic RNA inhibits the occurrence and progression of glioma. AB - This study aims to explore the role of long noncoding RNA (lncRNA)-HOX transcript antisense intergenic RNA (HOTAIR) in the occurrence and progression of glioma. Fresh glioma and normal brain tissues were classified into a glioma group (n = 67) and a normal group (n = 64) respectively. U87 cells were assigned into the blank, sh-NC, and sh-HOTAIR groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to determine HOTAIR expression. Cell proliferation, cell cycle and cell apoptosis rates were detected by cell counting kit-8 (CCK-8) and flow cytometry (FCM). Scratch test and transwell assay were conducted for cell migration and invasion. Orthotopic glioma tumor model in nude mice was established by inoculating tumor cell suspension. Hematoxylin-Eosin (HE) staining was used to observe the growth and invasion of orthotopic glioma tumors. The expression of HOTAIR and cell viability was found to be lowest in the sh HOTAIR group among the three groups. The sh-HOTAIR group exhibited a higher apoptotic rate and lower number of cell migration compared with the blank and sh NC groups. Additionally, the speed of wound healing was slower, the migration distance decreased and the survival time of nude mice was extended in the sh HOTAIR compared to the other groups. Moreover, the sh-HOTAIR group demonstrated reduced lesion sizes and inflammation, no convulsions or hemiplegia and lesser number of satellite metastases. Our findings support that down-regulation of HOTAIR could inhibit cell proliferation, promote cell apoptosis as well as suppress cell invasion and migration in the progression of glioma. PMID- 28857243 TI - Immunogenicity of a fusion protein containing PilQ and disulphide turn region of PilA from Pseudomonas aeruginosa in mice. AB - : Interference with bacterial adhesion is a new means to prevent or treat bacterial infections. In this experimental study we evaluated the immunogenic properties of a chimeric protein composed of PilQ and disulphide turn region of PilA from Pseudomonas aeruginosa in mice as an anti-adhesion based vaccine. First of all, a chimeric bivalent protein composed of PilQ and PilA was constructed and following subcutaneous immunization with merely the purified protein or in its admixed form with alum, the immunogenicity of the chimeric antigen was assessed in BALB/c mice. Then, the characteristics of the developed antibodies were studied by ELISA. Furthermore, the immunoreactivity of the purified recombinant protein was confirmed by immunoblotting. Alum as a common adjuvant boosted immunogenicity of the construct, resulting significantly greater anti-pili IgG titre. Mice antibody response consisted of IgG1, IgG2a, IgG2b and IgG3 subtypes with predominance of IgG1 subclass. The developed antibodies were capable to inhibit motility of PAO1 strain. In conclusion, our primary results revealed that the designed recombinant protein is a protective construct and may be used as a potential candidate for prophylactic purposes against P. aeruginosa infection. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study we examined the potential of integrated PilQ/PilA (QA) antigen as a vaccine candidate against Pseudomonas aeruginosa. Nowadays, anti-adhesion based vaccines are considered as new means to prevent or treat bacterial infections. Our study revealed that chimeric protein PilQ and disulphide turn region of PilA triggers production of specific antibodies. This humoral immune responses augmented when QA was administered in combination with an adjuvant. The results demonstrated efficacy of the designed recombinant chimeric antigen as an effective candidate in prevention of P. aeruginosa infection. PMID- 28857244 TI - Rhorix: An interface between quantum chemical topology and the 3D graphics program blender. AB - Chemical research is assisted by the creation of visual representations that map concepts (such as atoms and bonds) to 3D objects. These concepts are rooted in chemical theory that predates routine solution of the Schrodinger equation for systems of interesting size. The method of Quantum Chemical Topology (QCT) provides an alternative, parameter-free means to understand chemical phenomena directly from quantum mechanical principles. Representation of the topological elements of QCT has lagged behind the best tools available. Here, we describe a general abstraction (and corresponding file format) that permits the definition of mappings between topological objects and their 3D representations. Possible mappings are discussed and a canonical example is suggested, which has been implemented as a Python "Add-On" named Rhorix for the state-of-the-art 3D modeling program Blender. This allows chemists to use modern drawing tools and artists to access QCT data in a familiar context. A number of examples are discussed. (c) 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. PMID- 28857245 TI - Root traits of European Vicia faba cultivars-Using machine learning to explore adaptations to agroclimatic conditions. AB - Faba bean (Vicia faba L.) is an important source of protein, but breeding for increased yield stability and stress tolerance is hampered by the scarcity of phenotyping information. Because comparisons of cultivars adapted to different agroclimatic zones improve our understanding of stress tolerance mechanisms, the root architecture and morphology of 16 European faba bean cultivars were studied at maturity. Different machine learning (ML) approaches were tested in their usefulness to analyse trait variations between cultivars. A supervised, that is, hypothesis-driven, ML approach revealed that cultivars from Portugal feature greater and coarser but less frequent lateral roots at the top of the taproot, potentially enhancing water uptake from deeper soil horizons. Unsupervised clustering revealed that trait differences between northern and southern cultivars are not predominant but that two cultivar groups, independently from major and minor types, differ largely in overall root system size. Methodological guidelines on how to use powerful ML methods such as random forest models for enhancing the phenotypical exploration of plants are given. PMID- 28857246 TI - Sleep deprivation induces pathological changes in rat masticatory muscles: Role of Toll like signaling pathway and atrophy. AB - The aim of this study was to evaluate the Toll like signaling pathway and atrophy after sleep deprivation (SD) in rat masticatory muscles: masseter and temporal. A total of 24 animals was distributed into three groups: Control group (CTL, n = 8), subjected to SD for 96 h (SD96, n = 8) and subjected to SD for 96 h more 96 h of sleep recovery (SD96 + R, n = 8). Histopathological analysis revealed the presence of acute inflammatory cells, congested vessels, fibrosis, and high cellularity in the skeletal muscle fibers from masseter and temporal submitted to SD. These morphological alterations were not observed in the control group since neither inflammatory cells nor congested vessels were observed to this group. In the group SD96 + R, the absence of inflammation was noticed to the masseter only. In this group, COX-2 and TNF-alpha downregulation were detected when comparing to control group. MyD88 and pIKK decreased in SD96 and SD96 + R groups being pNFKBp50 downregulatated in SD96 + R. MyD88 expression increased in rats submitted to SD96 and SD96 + R in temporal when compared to control group. On the other hand, pIKK decreased the protein expression in groups SD96 and SD96 + R while pNFKBp50 showed a decreased protein expression in group SD96 only. The activation of atrophy by means of MAFbx upregulation was detected in temporal muscle in SD96 and SD96 + R when compared to control. In summary, our results show that SD is able to induce morphological alterations in rat masticatory muscles. Toll like signaling pathway and atrophy play important roles in ethiopathogenesis induced by SD, being dependent of skeletal muscle type. PMID- 28857247 TI - FGFR2 regulation by picrasidine Q inhibits the cell growth and induces apoptosis in esophageal squamous cell carcinoma. AB - Fibroblast growth factor receptor (FGFR) 2 and its downstream signaling cascades, PI3 K/AKT/mTOR is playing an important role in cell survival and proliferations. In this study, we firstly found that picrasidine Q (PQ), an alkaloid component extracted from Angelica keiskei species, has the capacity of anti-cell transformation and anti-cancer. After ligand shape similarity approach of PQ, we found that PQ targeted FGFR 2 and verified by FGFR2 kinase assay as well as computational docking model. FGFR2 highly expressed in esophageal cancer tissues and PQ inhibited fibroblast growth factor (FGF)-induced cell transformation. Furthermore, PQ inhibited cell proliferation and induced cell cycle arrest and apoptosis in KYSE30, KYSE410, and KYSE450 esophageal squamous cell carcinoma (ESCC) cells. It was confirmed by detecting of biological markers such as cyclinD1, cyclinD3 and cyclinB1 for cell cycle or cleaved caspase-7, caspase-3, and PARP for apoptosis. PQ targeting of FGFR2 kinase activities suppressed downstream target proteins including phosphorylation of AKT and mTOR but not MEK/ERK signaling pathways. Taken together, our results are the first to identify that PQ might be a chemopreventive and chemotherapeutic agent by direct targeting FGFR2 and inhibiting cell proliferation of ESCC cells. PMID- 28857248 TI - MicroRNA-142-5p induces cancer stem cell-like properties of cutaneous squamous cell carcinoma via inhibiting PTEN. AB - Cutaneous squamous cell carcinoma (cSCC) is a malignancy of keratinocyte-derived skin tumor, which is regarded as the second most common skin cancer worldwide. Accumulating evidence has established that microRNAs (miRNAs) can play a critical role in tumor initiation, progression, and metastasis including cSCC. Abnormal expression of hsa-miR-142-5p has been elaborated in various tumors. Nevertheless, its expression and function in the development of cSCC remain unclear. In our study, we found that the expression of hsa-miR-142-5p in cSCC cells were greatly overexpressed compared to human benign epidermal keratinocyte cells. Moreover, inhibited hsa-miR-142-5p can repress cSCC cell growth and induce apoptosis while upregulated hsa-miR-142-5p exhibited a reverse phenomenon. Recently, cancer stem cells (CSCs) which possess the ability of self-renewal and proliferation and are able to produce cancer cells have been widely reported. However, the correlation between hsa-miR-142-5p and CSCs in cSCC is still unknown. Interestingly, we observed that overexpressing hsa-miR-142-5p can induce CSC-like properties in cSCC via activating Wnt signaling. In addition, the luciferase reporter assay data and bioinformatics analysis demonstrated that hsa-miR-142-5p can target the 3'UTR of PTEN mRNA. Taken these together, we draw a conclusion that hsa-miR-142 5p can trigger cancer stem cell-like properties of cSCC through inhibition of PTEN. Our findings may provide hsa-miR-142-5p as a new therapeutic target for cSCC. PMID- 28857249 TI - Enhancing diversity in the hematology biomedical research workforce: A mentoring program to improve the odds of career success for early stage investigators. PMID- 28857250 TI - Morphology of the thoracic limb of goat as evidenced by gross osteology and radiology. AB - The objective of this study was to provide the detailed normal gross osteology and radiographic anatomy of the thoracic limb in goats as a reference for clinical use and in biomedical research. Radiography of the thoracic limb was performed in five small East African goats. Radiographic findings were correlated with bone specimens from four adult small East African goats. The scapula was narrow. The major tubercle was large and extended proximally above the head of the humerus. The lateral supracondylar crest was less prominent. The lateral and medial epicondyles of the humerus were almost of the same size. The lateral surface of the lateral condyle of the humerus presented a prominent depression for the origin of extensors of the carpus and digits. The cranially located radial notch was deep seated and the radial tuberosity was represented by a rough area located nearer to the head of the radius. The fifth metacarpal bone was seen in all animals. The morphology of the thoracic limb of small East African goats indicated the presence of powerful extensor muscles and is restricted to forward and backward movements as an adaptation to terrestrial lifestyle. PMID- 28857251 TI - Hospital admission for hyperemesis gravidarum in women at increased risk of spontaneous preterm birth. AB - BACKGROUND: Progesterone administration prevents spontaneous preterm birth (sPTB) in women at increased risk. Progesterone concentration is lower in women with subsequent sPTB. Conversely, high concentrations of progesterone are implicated in the pathogenesis of hyperemesis gravidarum (HG). We hypothesized that women at increased risk of sPTB or spontaneous late miscarriage would be less likely to have a diagnosis of HG. To explore this hypothesis, we compared the incidence of HG in women at increased risk of sPTB and women with no identifiable risk factors. METHODS: Women at increased risk of sPTB were identified from a specialist Preterm Birth Clinic (PTBC) database where criteria for PTBC attendance are previous cervical surgery, previous sPTB <34 weeks, previous spontaneous late miscarriage, incidental sonographic cervical shortening, and uterine anomaly. Hospital antenatal booking and coding records for the same time period were examined to identify HG admissions. Women with multiple gestations, trophoblastic disease, or pre-existing abnormal thyroid function were excluded. The incidence of HG among PTBC (n=394) and non-PTBC attendees (n=4762) was calculated. RESULTS: The incidence of HG was lower in women at increased risk of sPTB (1.52%, n=6) compared with women with no identifiable risk factor for sPTB (3.33%, n=159; P=.049). CONCLUSION: Hospital admission for HG is reduced in women with risk factors for sPTB compared with those without risk factors. Exploration of the pathogenesis of HG may improve understanding of the mechanisms underlying sPTB. PMID- 28857252 TI - miR-377-3p drives malignancy characteristics via upregulating GSK-3beta expression and activating NF-kappaB pathway in hCRC cells. AB - MicroRNA (miRNA) dysregulation has been associated with carcinogenesis in many cancers, including human colorectal cancer (hCRC). However, the effect and mechanism of miR-377-3p on CRC remains elusive. Herein, we first found that miR 377-3p was upregulated in CRC tissues and promoted tumorigenic activity by accelerating the G1 -S phase transition, promoting cell proliferation and epithelial-mesenchymal transition (EMT) while repressing apoptosis in CRC cells. Glycogen synthase kinase-3beta (GSK-3beta) was a direct target of miR-377-3p, and upregulated by miR-377-3p. Knockdown of GSK-3beta partly rescued miR-377-3p mediated malignancy characteristics. Most importantly, we showed that miR-377-3p promoted carcinogenesis by activating NF-kappaB pathway. Taken together, our results first reported that miR-377-3p functions as an oncogene and promotes carcinogenesis via upregulating GSK-3beta expression and activating NF-kappaB pathway in hCRC cells. PMID- 28857253 TI - A TP73-AS1/miR-200a/ZEB1 regulating loop promotes breast cancer cell invasion and migration. AB - Breast cancer (BC) is one of the leading causes of cancer deaths worldwide and the most common cancer among women. In our previous study, we revealed that lncRNA TP73-AS1 promotes breast cancer cell proliferation through directly binding to miR-200a. Herein, we evaluated the effect of TP73-AS1 in breast cancer cell invasion and migration, and further demonstrated the direct binding between TP73-AS1 and miR-200a, between miR-200a and 3'UTR of ZEB1, an essential metastasis-related transcription factor. TP73-AS1 promoted ZEB1 expression via competing with ZEB1 3'UTR for miR-200a binding. Moreover, ZEB1 could bind to the promoter region of TP73-AS1 to activate its expression. TP73-AS1 and ZEB1 expression was up-regulated, whereas miR-200a expression was down-regulated in breast cancer tissues. Taken together, we demonstrated a TP73-AS1/miR-200a/ZEB1 regulating loop in breast cancer cells, which promote cancer cell invasion and migration through regulating E-cadherin and Twist expression. Suppressing TP73 AS1 expression to rescue miR-200a expression, thus to inhibit ZEB1 and Twist expression and up-regulate E-cadherin might improve breast cancer cell invasion and migration. PMID- 28857254 TI - Acceptance and commitment therapy (ACT) for clinically distressed health care workers: Waitlist-controlled evaluation of an ACT workshop in a routine practice setting. AB - OBJECTIVES: To examine the effects of a 1-day acceptance and commitment therapy (ACT) workshop on the mental health of clinically distressed health care employees, and to explore ACT's processes of change in a routine practice setting. DESIGN: A quasi-controlled design, with participants block allocated to an ACT intervention or waiting list control group based on self-referral date. METHODS: Participants were 35 health care workers who had self-referred for the ACT workshop via a clinical support service for staff. Measures were completed by ACT and control group participants at pre-intervention and 3 months post intervention. Participants allocated to the waitlist condition went on to receive the ACT intervention and were also assessed 3 months later. RESULTS: At 3 months post-intervention, participants in the ACT group reported a significantly lower level of psychological distress compared to the control group (d = 1.41). Across the 3-month evaluation period, clinically significant change was exhibited by 50% of ACT participants, compared to 0% in the control group. When the control group received the same ACT intervention, 69% went on to exhibit clinically significant change. The ACT intervention also resulted in significant improvements in psychological flexibility, defusion, and mindfulness skills, but did not significantly reduce the frequency of negative cognitions. Bootstrapped mediation analyses indicated that the reduction in distress in the ACT condition was primarily associated with an increase in mindfulness skills, especially observing and non-reactivity. CONCLUSIONS: These findings provide preliminary support for providing brief ACT interventions as part of routine clinical support services for distressed workers. PRACTITIONER POINTS: A 1-day ACT workshop delivered in the context of a routine staff support service was effective for reducing psychological distress among health care workers. The brief nature of this group intervention means it may be particularly suitable for staff support and primary care mental health service settings. The findings indicate that the beneficial effects of an ACT workshop on distressed employees' mental health were linked to improvements in specific mindfulness skills. Study limitations include non-random allocation of participants to the ACT and control groups, and measurement of mediators and outcome at the same time point (3 months post-intervention). PMID- 28857255 TI - Efficacy of a concomitant elemental diet to reduce the loss of response to adalimumab in patients with intractable Crohn's disease. AB - BACKGROUND AND AIM: Secondary loss of response to adalimumab (ADA-LOR) commonly occurs in patients with Crohn's disease (CD) treated with adalimumab (ADA). We evaluated the efficacy of concomitant elemental diet (ED) therapy to reduce ADA LOR in adult CD patients. METHODS: Patients were divided into either an ED (>=900 kcal/day) or a non-ED group (<900 kcal/day). Cumulative non-ADA-LOR rates were compared between groups. The effects of ED intake to reduce ADA-LOR were also assessed in antitumor necrosis factor-alpha (TNF-alpha)-naive and infliximab (IFX)-intolerant or refractory CD patients. Serum ADA and TNF-alpha levels were measured. RESULTS: We enrolled 117 CD patients into the ED (n = 25) or non-ED (n = 92) groups. Although the cumulative non-ADA-LOR rate was higher in the ED group than in the non-ED group, ED intake was not an independent reducing factor for ADA-LOR (adjusted hazard ratio = 0.725; 95% confidence interval: 0.448-1.180; P = 0.196) in all patients. ED intake was significantly more effective in reducing ADA-LOR in IFX-intolerant or refractory patients than in anti-TNF-alpha-naive patients in a dose-related manner (P for interaction <0.20). Serum ADA levels did not differ between the groups. Serum TNF-alpha levels were significantly lower in the ED group than in the non-ED group at week 28 (P = 0.044) and week 52 (P = 0.043). CONCLUSIONS: Concomitant ED therapy reduced ADA-LOR in IFX-intolerant or refractory patients in a dose-related manner. Reductions in the TNF-alpha levels by concomitant ED intake may contribute to reduce ADA-LOR in CD patients. PMID- 28857257 TI - MiR-200a mediates protection of thymosin beta 4 in cardiac microvascular endothelial cells as a novel mechanism under hypoxia-reoxygenation injury. AB - Thymosin beta-4 (Tbeta4) is a ubiquitous protein, which has been suggested to regulate multiple cell signal pathways and a variety of cellular functions. However, the role Tbeta4 plays in the cardiac microvascular endothelial cells (CMECs) under myocardial ischemia/reperfusion injury (MIRI) is currently unknown. Here we investigated the effects of Tbeta4 on hypoxia/reoxygenation (H/R) induced CMECs injury and its potential molecular mechanism. Cultured CMECs were positively identified by flow cytometry using antibody against CD31 and VWF/Factor VIII, which are constitutively expressed on the surface of CMECs. Then the reduced level of Tbeta4 was detected in H/R-CMECs by RT-qPCR. In order to determine the effects of Tbeta4 on H/R-CMECs, we transfected the overexpression or silence vector of Tbeta4 into CMECs under H/R condition. Our results indicated that H/R treatment could reduce proliferation, increased apoptosis, adhesion and ROS production in CMECs, which were attenuated by Tbeta4 overexpression or aggravated by Tbeta4 silence, implying Tbeta4 is able to promote CMECs against H/R-induced cell injury. Furthermore, the microRNA 200a (miR-200a) level was also increased by Tbeta4 in H/R-CMECs or reduced by Tbeta4 siRNA. To investigated the mechanism of protective effects of Tbeta4 on CMECs injury, the miR-200a inhibitor was transfected into H/R-CMECs. The results indicated that inhibition of miR-200a inversed the protection of Tbeta4 on H/R-CMECs, specifically including cell proliferation, cell adhesion, cell apoptosis and ROS production, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. In conclusion, our results determined that Tbeta4 attenuated H/R induced CMECs injury by miR-200a-Nrf2 signaling. This article is protected by copyright. All rights reserved. PMID- 28857256 TI - Autophagy-dependent crosstalk between GILT and PAX-3 influences radiation sensitivity of human melanoma cells. AB - Melanoma represents an ever-increasing problem in the western world as incidence rates continue to climb. Though manageable during early stages, late stage metastatic disease is highly resistant to current intervention. We have previously shown that gamma-interferon-inducible lysosomal thiol-reductase (GILT) enhances HLA class II antigen processing and immune detection of human melanoma cells. Here we report that GILT expression inhibits a potential target, paired box-3 (PAX-3) protein, in late stage human metastatic melanoma. We also show that GILT transfection or induction by IFN-gamma, decreases PAX-3 protein expression while upregulating the expression of Daxx, which is also a repressor of PAX-3. Confocal microscopic analysis demonstrated that GILT co-localizes with PAX-3 protein, but not with Daxx within melanoma cells. Immunoprecipitation and immunoblotting studies suggest that GILT expression negatively regulates PAX-3 through the autophagy pathway, potentially resulting in increased susceptibility to conventional treatment in the form of chemotherapy or radiotherapy. While high dose radiation is a common treatment for melanoma patients, our data suggest that GILT expression significantly increased the susceptibility of melanoma cells to low-dose radiation therapy via upregulation of tumor suppressor protein p53. Overall, these data suggest that GILT has multiple roles in inducing human melanoma cells as better targets for radiation and immunotherapy. PMID- 28857258 TI - Summary of the development the US Environmental Protection Agency's Medaka Extended One Generation Reproduction Test (MEOGRT) using data from 9 multigenerational medaka tests. AB - In response to various legislative mandates, the US Environmental Protection Agency (USEPA) formed its Endocrine Disruptor Screening Program (EDSP), which in turn, formed the basis of a tiered testing strategy to determine the potential of pesticides, commercial chemicals, and environmental contaminants to disrupt the endocrine system. The first tier of tests is intended to detect the potential for endocrine disruption mediated through estrogen, androgen, or thyroid pathways, whereas the second tier is intended to further characterize the effects on these pathways and to establish a dose-response relationship for adverse effects. One of these tier 2 tests, the Medaka Extended One Generation Reproduction Test (MEOGRT), was developed by the USEPA for the EDSP and, in collaboration with the Japanese Ministry of the Environment, for the Guidelines for the Testing of Chemicals of the Organisation for Economic Co-operation and Development (OECD). The MEOGRT protocol was iteratively modified based on knowledge gained after the successful completion of 9 tests with variations in test protocols. The present study describes both the final MEOGRT protocol that has been published by the USEPA and the OECD, and the iterations that provided valuable insights into nuances of the protocol. The various tests include exposure to 17beta-estradiol, 4-t-octylphenol, o,p'- dichlorodiphenyltrichloroethane, 4-chloro-3-methylphenol, tamoxifen, 17beta-trenbolone, vinclozolin, and prochloraz. Environ Toxicol Chem 2017;36:3387-3403. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28857259 TI - Effect of availability of at-home phototherapy on the use of systemic medications for psoriasis. PMID- 28857260 TI - Reliability and validity of the Spanish version of the IDEAL Schedule for assessing care needs in dementia: Cross-sectional, multicenter study. AB - OBJECTIVE: The IDEAL Schedule was developed for staging "care needs" in patients with dementia. We here aim to validate the Spanish version, further test its psychometric properties and explore a latent construct for "care needs". METHODS: A multicenter study was done in 8 dementia care facilities across Spain. Patients referred with a reliable ICD-10 diagnosis of dementia (n = 151) were assessed with the IDEAL Schedule by pairs of raters. Inter-rater reliability (intra-class correlation [ICC] coefficients), internal consistency (Cronbach's alpha), and factor analysis were calculated. Convergent validity for individual items was tested against validated Spanish versions of international instruments. RESULTS: Pilot testing with numerical scales supported the feasibility, face, and content validity of the schedule. The psychometric coefficients were good/clinically acceptable: inter-rater reliability (mean ICC = 0.861; 85% of the ICCs > 0.8), internal consistency (global alpha coefficient = 0.74 in 5 nuclear items), and concurrent validity (global score against the Clinical Dementia Rating schedule, r = 0.63; coefficients for individual items ranging from 0.40 to 0.84, all statistically significant, p < 0.05). Internal consistency was low for the "nonprofessional care" and "social support" dimensions. Factor analysis supported a unidimensional solution, suggesting a latent "care needs" construct. CONCLUSION: The Spanish version of the IDEAL Schedule confirms the main psychometric properties of the original version and documents for the first time the convergent validity of individual items. Factor analysis identified a latent construct consistent with the concept "care needs" although 2 dimensions need further psychometric research. PMID- 28857261 TI - A recombinant iron transport protein from Bordetella pertussis confers protection against Bordetella parapertussis. AB - Whooping cough, which is caused by Bordetella pertussis and B. parapertussis, is a reemerging disease. New protective antigens are needed to improve the efficacy of current vaccines against both species. Using proteomic tools, it was here found that B. parapertussis expresses a homolog of AfuA, a previously reported new vaccine candidate against B. pertussis. It was found that this homolog, named AfuABpp , is expressed during B. parapertussis infection, exposed on the surface of the bacteria and recognized by specific antibodies induced by the recombinant AfuA cloned from B. pertussis (rAfuA). Importantly, the presence of the O antigen, a molecule that has been found to shield surface antigens on B. parapertussis, showed no influence on antibody recognition of AfuABpp on the bacterial surface. The present study further showed that antibodies induced by immunization with the recombinant protein were able to opsonize B. parapertussis and promote bacterial uptake by neutrophils. Finally, it was shown that this antigen confers protection against B. parapertussis infection in a mouse model. Altogether, these results indicate that AfuA is a good vaccine candidate for acellular vaccines protective against both causative agents of whooping cough. PMID- 28857262 TI - Microtomographic Parameters and Nanoindentation of the Hoof of Girolando Cattle. AB - The aim of this study was to describe the microstructure of the pigmented and depigmented hoof capsule of Girolando cattle by bi- and tridimensional microtomography and nanoindentation, analysing the possible relation between these findings and the susceptibility of such animals to podal diseases. To carry out the microtomography and the nanoindentation, duplicated samples were collected from the dorsal wall, abaxial wall and pre-bulbar sole of the hoof capsule. Material collection was performed in 40 medial digits of thoracic limbs and 40 lateral digits of pelvic limbs. The bidimensional microtomography showed that the dorsal wall of the thoracic and pelvic limbs presented higher density, followed by the abaxial wall, and finally by the sole, with the lowest density. Moreover, the hoof capsule of cows of Girolando breed is a compact, non-porous material, and constituted by extratubular and intratubular keratin. By the tridimensional microtomography, it was possible to measure the angles of the corneal tubules in relation to the periople and the claws in the different regions of the hoof capsule, which were 90 degrees for the dorsal wall, 55 degrees for the abaxial wall and 70 degrees for the sole. The tridimensional microtomography also showed corneal tubules of different diameters: 17, 51, 85, 119 and 153 MUm. The nanoindentation test, when performed in different regions of the hoof capsule, did not reveal significant difference of Vickers hardness in the evaluated areas. However, we verified a larger elastic module of these regions on the transversal cut of the corneal tubules compared to the longitudinal cut. PMID- 28857263 TI - Psychosocial behaviour management programme for home-dwelling people with dementia: A cluster-randomized controlled trial. AB - : Little is known about the effectiveness of a psychosocial behaviour management programme on home-dwelling people with dementia. We developed a Behaviour Analytics & Support Enhancement (BASE) programme for care managers and professional caregivers of home care services in Japan. We investigated the effects of BASE on challenging behaviour of home-dwelling people with dementia. METHODS: A cluster-randomized controlled trial was conducted with home care providers from 3 different districts in Tokyo. Each provider recruited persons with dementia aged 65 years or older to receive home care in the BASE programme in August 2016. An online monitoring and assessment system was introduced to the intervention group for repeated measures of challenging behaviour with a total score of the Neuropsychiatric Inventory. Care professionals in both the intervention and control groups evaluated challenging behaviour of persons with dementia at baseline (September 2016) and follow-up (February 2017). RESULTS: A majority of persons with dementia had Alzheimer disease (59.3%). One-hundred and forty-one persons with dementia were included in the intervention group and 142 in the control group. Multilevel modelling revealed a significant reduction in challenging behaviour in the intervention group after 6 months (mean score, 18.3 to 11.2) compared with that of the control group (11.6 to 10.8; P < .05). CONCLUSION: The implementation of the BASE programme resulted in a reduction of challenging behaviour of home-dwelling people with dementia. Future research should examine the long-term effects of behaviour management programmes on behaviour, nursing home placement, and hospital admission of home-dwelling people with dementia. PMID- 28857264 TI - Two faces of triel bonds in boron trihalide complexes. AB - The N???B triel bonds in complexes of boron trihalides, BX3 (X = F, Cl, Br, and I), with species acting as Lewis bases through the nitrogen center, NH3 , N2 , and HCN, are analyzed theoretically (MP2/aug-cc-pVTZ calculations). It is confirmed that stronger Lewis acid properties of the boron center are observed for the BCl3 moiety than for the BF3 one in complexes with the strong Lewis base (NH3 ); while the opposite order is observed for complexes with the weak Lewis base (N2 ). The BX3 ?NCH complexes (for X = Cl, Br, and I) are characterized by two tautomeric forms and by two corresponding N???B distances, the shorter one possesses characteristics of the covalent bond. In a case of the BF3 ?NCH complex one energetic minimum is observed. Ab initio calculations are supported by an analysis of molecular electrostatic potentials (EPs) and electron density distributions. The quantum theory of 'atoms in molecules' and the decomposition of the energy of interaction are applied. The aforementioned acidity orders as well as the existence of two tautomers for some of complexes result partly from the electrostatic interactions' balance; the EP distribution is different for the BF3 species than for the other BX3 species where X = Cl, Br, and I. (c) 2017 Wiley Periodicals, Inc. PMID- 28857265 TI - Revealing potential bridge vectors for BTV and SBV: a study on Culicoides blood feeding preferences in natural ecosystems in Spain. AB - Several species of Culicoides (Diptera: Ceratopogonidae) are vectors of pathogens, such as the bluetongue (BTV) and Schmallenberg (SBV) viruses, which cause important diseases in domestic and wild ruminants. As wild ruminants can contribute to overwintering and epizootics of both diseases, knowledge of the host-feeding behaviour of Culicoides in natural ecosystems is important to better understand their epidemiology. Blood-engorged Culicoides females trapped in natural areas inhabited by different wild ruminant species were genetically analysed to identify host species. The origin of bloodmeals was identified in 114 females of 14 species of Culicoides. A total of 104 (91.1%) Culicoides fed on mammals and 10 (8.9%) on birds. The most abundant host identified was red deer (66.7%), followed by humans (13%) and fallow deer (6.1%). Eleven of the 14 species of Culicoides fed exclusively on mammalian hosts. Among them, five are mammalophilic species considered to be important BTV and/or SBV vectors. The results of the present study confirm that Culicoides imicola, Culicoides obsoletus, Culicoides scoticus, Culicoides pulicaris and Culicoides punctatus fed on wild ruminants, and therefore support the hypothesis that these species can act as bridge vectors by facilitating the circulation of pathogens between wild and domestic ruminant communities. PMID- 28857266 TI - Avoiding premature closure and reaching diagnostic accuracy: some key predictive factors. AB - CONTEXT: Early studies suggested that experienced clinicians simply generate more accurate diagnoses than those less experienced. However, more recent studies indicate that experienced clinicians may be subject to biases in formulating and confirming hypotheses that lead to inaccuracy. OBJECTIVES: The goal of this study was to identify factors associated with the ability to process information in ways that overcome premature closure and result in accurate diagnosis using a set of vignettes in which inconsistent information was introduced midway. METHODS: Seventy-five participants (25 Year 3 medical students, 25 internal medicine residents in their second year of residency and 25 internal medicine faculty) were recruited to solve each of four complex clinical vignettes. In each vignette, the first four rounds of information pointed toward a narrowing range of diagnostic possibilities, but patient information presented in and after the fifth round was inconsistent with prior findings. In addition to accuracy, outcome measures were length of differential diagnosis, certainty of diagnosis, persistence in data collection and tendency to switch diagnoses. RESULTS: There were no significant differences in diagnostic accuracy across the three groups, each of which differed in level of training. However, across experience levels, diagnostic accuracy was associated with the mean number of items in the differential, tendency to persist (e.g. to request a greater number of rounds of information), and openness to switch (e.g. to change the most likely diagnosis on receipt of disconfirming information). CONCLUSIONS: Level of training (i.e. clinical experience) was not associated with accuracy on this task. As faculty clinicians certainly have more knowledge than their junior counterparts, it is important to identify ways in which cognitive factors can lead to more or less persistence and openness, and to teach clinicians how to overcome tendencies associated with error. PMID- 28857267 TI - Natural hazard events and social capital: the social impact of natural disasters. AB - This study investigates if and to what extent natural disasters affect social capital. Twelve different events in Europe are examined in a quantitative analysis, using data derived from the European Social Survey and the EM-DAT International Disaster Database. The study uses social trust as an indicator of social capital and offers evidence that a change in social trust is a possible occurrence during or after a disaster, but that it is not an inevitable consequence of it. The results reveal that social trust decreases after a disaster with a death toll of at least nine. Changes in social capital, therefore, are found to be more probable as the severity of the event increases. National, rather than regional, disasters lead more frequently to significant shifts in social trust. This evaluation of 12 separate cases pinpoints several disasters that have had an effect on social trust, but it does not identify any general patterns, underlining the significance of contextual dependency. PMID- 28857268 TI - Subjective and objective halitosis among patients with Parkinson's disease. AB - OBJECTIVES: Parkinson's disease (PD) affects oral health, but prevalence of subjective and objective halitosis and the influence of hyposalivation remain unclear. We aimed to explore whether patients with PD suffer from halitosis and to define correlations between halitosis and hyposalivation. We hypothesised that patients with PD suffer more often from halitosis compared to healthy controls, influenced by dry mouth. MATERIALS AND METHODS: Subjective (halitosis, xerostomia visual analogue scale [VAS], short German Oral Health Impact Profile [OHIPG]-14) and objective scales (e.g., organoleptic score, volatile sulphur compounds [VSCs], stimulated whole saliva [SWS]) were assessed from 26 patients with PD and 26 healthy controls. RESULTS: The mean organoleptic score was 0.7 (SD: 0.7) in all patients, and VSCs were either comparable or significantly lower (dimethyl sulphide, P = .010) in PD patients compared with controls, yet more patients with PD perceived halitosis to be stronger (77% vs 54%, respectively; P = .059). Dry mouth was significantly more likely in patients with PD than controls: mean xerostomia VAS 4 (SD: 2) vs 1 (SD: 2), P = .010; SWS 0.4 (SD: 0.4) vs 0.7 (SD: 0.6) mL/min, P < .05); SWS did not correlate with subjective or objective halitosis. Oral health-related quality of life (OHRQoL) was lower in patients with PD than controls (mean OHIPG-14 score 12 (SD: 0.2) vs 5 (SD: 7.0), respectively; P < .05). CONCLUSIONS: Patients with PD suffer from subjective and objective halitosis, dry mouth and impaired OHRQoL. Dry mouth problems do not correlate with prevalence or intensity of halitosis. PMID- 28857269 TI - Flipped classroom or an active lecture? AB - Recent changes in anatomy education have seen the introduction of flipped classrooms as a replacement to the traditional didactic lecture. This approach utilizes the increasing availability of digital technology to create learning resources that can be accessed prior to attending class, with face-to-face sessions then becoming more student-centered via discussion, collaborative learning, and problem-solving activities. Although this approach may appear intuitive, this viewpoint commentary presents a counter opinion and highlights a simple alternative that utilizes evidence-based active learning approaches as part of the traditional lecture. The active lecture takes the traditional lecture, and (1) ensures the lecture content is relevant and has clear objectives, (2) contains lecture material that is designed according to the latest evidence-base, (3) complements it with additional supplementary material, (4) creates space to check prior understanding and knowledge levels, and (5) utilizes suitable technology to facilitate continual engagement and interaction. Clin. Anat. 31:118-121, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28857270 TI - Physical aggression among patients with dementia, neuropathologically confirmed post-mortem. AB - OBJECTIVE: To investigate the prevalence of physical aggression among patients with dementia of different types and to analyze potential differences in clinical traits, in terms of singular or repetitive behavior and occurrence in early or late stage of the disease. We also aimed at examining against whom the physical aggression was exerted. METHODS: We included 281 cases with a neuropathological dementia diagnosis from the brain bank at the Department of Pathology, Lund University, for this retrospective medical records review. The study covers cases with a post-mortem examination performed between 1967 and 2013. RESULTS: Of the 281 patients studied, 97 (35%) patients had a history of exerting physical aggression during the course of their disease. The patients with frontotemporal dementia exerted physical aggression earlier in the course of their disease than Alzheimer's disease patients. The most frequent victims of the patients' physical aggression were health staff and other patients. The aggression also affected family members as well as (to the demented patient) unknown people. The frequency of the physical aggression differed among the different diagnostic groups; frontotemporal dementia patients exhibiting a higher physical aggression frequency score than did Alzheimer's disease patients. CONCLUSIONS: The patterns of manifested physical aggression thus differ between the frontotemporal dementia and Alzheimer's disease patient groups in this study. Knowledge about such differences may be of value in decision making in patient care. PMID- 28857271 TI - Nitric oxide is essential for the development of aerenchyma in wheat roots under hypoxic stress. AB - In response to flooding/waterlogging, plants develop various anatomical changes including the formation of lysigenous aerenchyma for the delivery of oxygen to roots. Under hypoxia, plants produce high levels of nitric oxide (NO) but the role of this molecule in plant-adaptive response to hypoxia is not known. Here, we investigated whether ethylene-induced aerenchyma requires hypoxia-induced NO. Under hypoxic conditions, wheat roots produced NO apparently via nitrate reductase and scavenging of NO led to a marked reduction in aerenchyma formation. Interestingly, we found that hypoxically induced NO is important for induction of the ethylene biosynthetic genes encoding ACC synthase and ACC oxidase. Hypoxia induced NO accelerated production of reactive oxygen species, lipid peroxidation, and protein tyrosine nitration. Other events related to cell death such as increased conductivity, increased cellulase activity, DNA fragmentation, and cytoplasmic streaming occurred under hypoxia, and opposing effects were observed by scavenging NO. The NO scavenger cPTIO (2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide potassium salt) and ethylene biosynthetic inhibitor CoCl2 both led to reduced induction of genes involved in signal transduction such as phospholipase C, G protein alpha subunit, calcium-dependent protein kinase family genes CDPK, CDPK2, CDPK 4, Ca-CAMK, inositol 1,4,5 trisphosphate 5-phosphatase 1, and protein kinase suggesting that hypoxically induced NO is essential for the development of aerenchyma. PMID- 28857272 TI - Acanthoma planoepitheliale hyperkeratoticum, lesions associated with BRAF inhibitor in metastatic melanoma. PMID- 28857273 TI - Topical application of Nexrutine inhibits ultraviolet B-induced cutaneous inflammatory responses in SKH-1 hairless mouse. AB - BACKGROUND: Ultraviolet B (UVB) radiation is the major contributor to skin inflammation which leads to the development of skin cancer. Hence, in this study, we studied the effect of Nexrutine (NX) on UVB-induced cutaneous inflammation and its mediators. METHODS: Ultraviolet absorption spectra of NX were measured by spectrophotometer. To conduct the photoprotective studies, SKH-1 hairless mice were topically treated with NX, 30 minutes before to the UVB (180 mJ/cm2 ) exposure. Twenty hours of post-UVB irradiation, mouse skin was used for edema measurements, H & E staining, myeloperoxidase (MPO) activity, and estimation of plasma cytokines. In addition, expression levels of inflammatory cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) were also determined by Western blot analysis. RESULTS: Nexrutine displayed absorbance over the UVB spectrum. NX significantly decreased the UVB-induced epidermal edema, skin thickness, leukocyte infiltration, number of the sunburn, and TUNEL-positive cells. NX treatment also decreased the number of mast cells, MPO activity, expression of pro-inflammatory cytokines, and inflammation mediator protein in mouse skin. CONCLUSION: These results provide evidences that NX inhibits the UVB induced cutaneous inflammatory responses in SKH-1 mouse skin. PMID- 28857274 TI - Aortic root replacement with left main trunk reconstruction using autologous pericardial cuff technique for ostial stenosis in Takayasu's arteritis. PMID- 28857275 TI - Size of single-wall carbon nanotube affects the folate receptor-mediated cancer cell targeting. AB - Advances in nanobiotechnology and targeting strategy could improve the delivery of therapeutic molecules into cancer cells, leading to improved treatment efficiency with minimal side effects on normal cells. To design an efficient nanocarrier, consideration of parameters that facilitate direct drug delivery into the target cells is important. We studied the effect of single-wall carbon nanotubes (SWNTs) size on their cell internalization level via the folate receptor-mediated pathway through folic acid targeting. Folate-SWNTs were covalently synthesized and characterized. Folate-SWNTs <= 450 nm had lower cell internalization level than folate-SWNTs >450 nm with a P value of <=0.01. This indicated that using folate-SWNT with an average length of <=450 nm was not suitable for receptor-mediated cancer cell targeting. Receptor-mediated uptake of folate-SWNTs is dependent on the nanoparticle length. However, sub-450 nm SWNTs could serve as a vehicle to transfer nucleic acids into the cells due to direct cell penetrance based on their needle-like structure. We find that SWNTs larger than 450 nm were suitable to target the cells through receptors. These results might provide a promising approach for designing more effective targeted delivery systems based on SWNTs. PMID- 28857277 TI - Comparison of microscopic and endoscopic view of the internal acoustic meatus: A cadaveric study. AB - The endoscope is thought to provide an improved exposure of the internal acoustic meatus after retrosigmoid craniotomy for microsurgical resection of intrameatal tumors. The aim of this study is to quantify the differences in internal acoustic meatus (IAM) exposure comparing microscopic and endoscopic visualization. A retrosigmoid approach was performed on 5 cadaver heads. A millimeter gauge was introduced into the internal acoustic meatus, and examinations with a surgical microscope and 0 degrees , 30 degrees and 70 degrees rigid endoscopes were performed. The extent of IAM depth visualized with the microscope and the different angled endoscopes were analyzed. The microscopic view allowed an average IAM depth visualization of 2.8 mm. The endoscope allowed an improved exposure of IAM in all cases. The 0 degrees , 30 degrees and 70 degrees endoscopes permitted an exposure that was respectively 96% (5.5 mm), 139% (6.7 mm) and 200% (8.4 mm) more lateral than the microscopic view. Angled optics, however, provided an image distortion, specifically the 70 degrees endoscope. The endoscope provides a superior visualization of the IAM compared to the microscope when using a retrosigmoid approach. The 30 degrees endoscope represented an ideal compromise of superior visualization with marginal image distortion. Additional implementation of the endoscope into microsurgery of intrameatal tumors likely facilitates complete tumor removal and might spare facial and vestibulocochlear function. Clin. Anat. 31:398-403, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28857276 TI - Interleukin-6 promotes the migration and cellular senescence and inhibits apoptosis of human intrahepatic biliary epithelial cells. AB - Biliary epithelial cells (BEC) are closely related to some immune regulatory bile duct diseases. However, the complexity and polymorphism of the morphology and function of bile duct cells have hindered further investigation. Therefore, the aim of this study is to investigate how interleukin-6 (IL-6) affects the migration, cellular senescence, and apoptosis of human intrahepatic biliary epithelial cells (HIBECs). The HIBECs were stimulated by different concentrations of IL-6 (0, 5, 10, 15, and 20 ng/mL, respectively). Transwell assay was performed in order to measure the migration abilities, positive beta-Galactosidase staining for the cellular senescence of HIBECs, MTT assay for changes of proliferation after IL-6 treatment and flow cytometry for cell cycle and apoptosis. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were conducted in order to detect the mRNA and protein expressions of epithelial-mesenchymal transition (EMT) markers in HIBECs. In comparison to the 0 ng/mL group, in the 5, 10, 15, and 20 ng/mL groups, a significant increase in the number of migratory HIBECs, proliferation, along with mRNA and protein expressions of EMT markers was observed. While the mRNA and protein expressions of epithelial markers, the number of beta-galactosidase positive staining cells, as well as apoptosis rate of HIBECs dramatic decreased. Further, the aforementioned changes were significantly more evident in the 15 and 20 ng/mL groups in comparison to the 5 and 10 ng/mL groups. IL-6 may stimulate EMT, enhance the migration and proliferation, and inhibit apoptosis of HIBECs, thus delaying cellular senescence. PMID- 28857278 TI - Metalloradical Reactivity of RuI and Ru0 Stabilized by an Indole-Based Tripodal Tetraphosphine Ligand. AB - The tripodal, tetradentate tris(1-(diphenylphosphanyl)-3-methyl-1H-indol-2 yl)phosphane PP3 -ligand 1 stabilizes Ru in the RuII , RuI , and Ru0 oxidation states. The octahedral [(PP3 )RuII (Cl)2 ] (2), distorted trigonal bipyramidal [(PP3 )RuI (Cl)] (3), and trigonal bipyramidal [(PP3 )Ru0 (N2 )] (4) complexes were isolated and characterized by single-crystal X-ray diffraction, NMR, EPR, IR, and ESI-MS. Both open-shell metalloradical RuI complex 3 and the closed-shell Ru0 complex 4 undergo facile (net) abstraction of a Cl atom from dichloromethane, resulting in formation of the corresponding RuII and RuI complexes 2 and 3, respectively. PMID- 28857279 TI - Self-perceived mouthfeel and physico-chemical surface effects after chewing gums containing sorbitol and Magnolia bark extract. AB - The European Food Safety Authority recognizes the contribution of sugar-free chewing gum to oral health through increased salivation, clearance of food debris, and neutralization of biofilm pH. Magnolia bark extract is a gum additive shown to reduce the prevalence of bad-breath bacteria but its effects on self perceived mouthfeel are unknown. This paper aims to relate the effects of sorbitol-containing chewing gum, with and without Magnolia bark extract, on tooth surface hydrophobicity and salivary-film composition with self-perceived mouthfeel. In a crossover clinical trial, volunteers chewed sorbitol-containing gum, with or without Magnolia bark extract added, three times daily during a 4-wk time period. A subset of volunteers also chewed Parafilm as a mastication control. Oral moistness and tooth smoothness were assessed using questionnaires, and intra-oral water-contact angles were measured before, immediately after, and 60 min after, chewing. Simultaneously, saliva samples were collected, placed on glass slides, and the compositions of the adsorbed film were measured using X-ray photoelectron spectroscopy. Chewing of gum, regardless of whether or not it contained Magnolia bark extract, improved self-perceived mouthfeel up to 60 min, concurrent with a more hydrophilic tooth surface and an increased amount of O1s electrons bound at 532.6 eV in salivary films. Chewing of Parafilm affected neither tooth-surface hydrophobicity nor salivary-film composition. Accordingly, adsorption of sorbitol, rather than the presence of Magnolia bark extract or increased salivation, is responsible for improved self-perceived mouthfeel. PMID- 28857280 TI - Dynamic thiol disulphide homeostasis in operating theater personnel exposed to anesthetic gases. AB - BACKGROUND: The purpose of this study was to investigate the association between dynamic thiol/disulphide homeostasis and occupational exposure to volatile anesthetic gases in operating theater personnel. Decreased blood thiol levels and raised blood disulphide levels serve as biomarkers of oxidative stress. METHODS: We included 65 subjects occupationally exposed and 55 unexposed healthy medical professionals into the study. A novel method enabled separate measurements of components involved in dynamic thiol/disulphide homeostasis (native thiol, disulphide, and total thiol). To control for the potential confounding effect on oxidative stress of psychological symptoms potentially caused by occupational stress, we used scores obtained from four different anxiety and depression inventories. RESULTS: Mean +/- standard deviation native thiol was found to be 433.35 +/- 30.68 in the exposed group, lower than among controls, 446.61 +/- 27.8 (P = 0.02). Disulphide in the exposed group was 15.78 +/- 5.12, higher than among controls, 12.14 +/- 5.33 (P < 0.001). After adjusting for anxiety and depression scores, age and gender, native thiol remained lower and disulphide higher in the exposed group (P = 0.008 and P < 0.001). CONCLUSION: Dynamic thiol/disulphide homeostasis in workers exposed to anesthetic gases was found to be disturbed after adjusting for the possible contribution of anxiety. We infer that this is due to the oxidative effect of exposure to anesthetic gases. PMID- 28857281 TI - Single-Scan 13 C Diffusion-Ordered NMR Spectroscopy of DNP-Hyperpolarised Substrates. AB - Diffusion-ordered NMR spectroscopy (DOSY) is a powerful approach for the analysis of molecular mixtures, yet its application range is limited by the relatively low sensitivity of NMR. We show here that spectrally resolved 13 C DOSY data can be collected, in a single scan, for substrates hyperpolarised by dissolution dynamic nuclear polarisation (D-DNP), which provides signal enhancements of several orders of magnitude. For this we use a convection-compensation pulse scheme, which we also analyse by numerical simulation. The proposed method further allows the acquisition of several consecutive DOSY spectra in a single D-DNP experiment. PMID- 28857283 TI - Learning about a new kind of cell: sexual health and service learning in prison. PMID- 28857282 TI - Silencing of SOCS-1 and SOCS-3 suppresses renal interstitial fibrosis by alleviating renal tubular damage in a rat model of hydronephrosis. AB - Our study was performed to elucidate how SOCS-1/3 silencing suppresses renal interstitial fibrosis (RIF) by alleviating renal tubular damage in rat models affected by hydronephrosis. Male Wistar rats were randomly selected to establish hydronephrosis rat model, after which all rats were classified into normal, model, negative control (NC), siRNA-SOCS-1, siRNA-SOCS-3, and siRNA-SOCS-1 + siRNA-SOCS-3 groups. The levels of urine protein, serum creatinine (Scr), and blood urea nitrogen (BUN) were detected. ELISA was performed to determine levels of cystatin (CysC), beta2-microglobulin (beta2-MG), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha. RT-qPCR and Western blotting were used for mRNA and protein expressions of SOCS-1, SOCS-3, alpha-smooth muscle actin (alpha-SMA), and transforming Growth Factor (TGF)-beta1. Compared with the normal group, the levels of Scr, BUN, urine protein, NAG, CysC, beta2-MG, IL-6, and TNF-alpha were increased in other groups, as well as elevated mRNA and protein expressions of SOCS-1, SOCS-3, alpha-SMA, and TGF-beta1. The siRNA-SOCS-1, siRNA-SOCS-3, and siRNA-SOCS-1 + siRNA-SOCS-3 groups were found with decreased levels of Scr, BUN, urine protein, NAG, CysC, beta2-MG, IL-6, and TNF-alpha, as well as mRNA and protein expressions of SOCS-1, SOCS-3, alpha-SMA, and TGF-beta1, including positive rates of SOCS-1 and SOCS-3 proteins in comparison with the model and NC groups. In comparison with the siRNA-SOCS-1 and siRNA-SOCS-3 groups, the siRNA SOCS-1 + siRNA-SOCS-3 group exhibited decreased levels of Scr, BUN, urine protein, NAG, CysC, beta2-MG, IL-6, and TNF-alpha. Our study demonstrated that silencing of SOCS-1/3 may suppress RIF by alleviating the renal tubular damage in rat models affected by hydronephrosis. PMID- 28857284 TI - Fiscal transfers based on inputs or outcomes? Lessons from the Twelfth and Thirteenth Finance Commission in India. AB - BACKGROUND: There is limited empirical evidence about the efficacy of fiscal transfers for a specific purpose, including for health which represents an important source of funds for the delivery of public services especially in large populous countries such as India. OBJECTIVE: To examine two distinct methodologies for allocating specific-purpose centre-to-state transfers, one using an input-based formula focused on equity and the other using an outcome based formula focused on performance. MATERIALS AND METHODS: We examine the Twelfth Finance Commission (12FC)'s use of Equalization Grants for Health (EGH) as an input-based formula and the Thirteenth Finance Commission (13FC)'s use of Incentive Grants for Health (IGH) as an outcome-based formula. We simulate and replicate the allocation of these two transfer methodologies and examine the consequences of these fiscal transfer mechanisms. RESULTS: The EGH placed conditions for releasing funds, but states varied in their ability to meet those conditions, and hence their allocations varied, eg, Madhya Pradesh received 100% and Odisha 67% of its expected allocation. Due to the design of the IGH formula, IGH allocations were unequally distributed and highly concentrated in 4 states (Manipur, Sikkim, Tamil Nadu, Nagaland), which received over half the national IGH allocation. DISCUSSION: The EGH had limited impact in achieving equalization, whereas the IGH rewards were concentrated in states which were already doing better. Greater transparency and accountability of centre-to-state allocations and specifically their methodologies are needed to ensure that allocation objectives are aligned to performance. PMID- 28857285 TI - CD11b-deficient mice exhibit an increased severity in the late phase of antibody transfer-induced experimental epidermolysis bullosa acquisita. AB - CD11b, the alpha-chain of beta2 integrin Mac-1, is involved in many activation processes of phagocytes. Depending on the respective autoimmune disorder, CD11b has been shown to exert pro-inflammatory functions or be dispensable in their pathogenesis. Here, we investigated the role of CD11b in the pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin blistering disease mediated by autoantibodies to type VII collagen. Unexpectedly, in an antibody transfer-induced model of EBA, CD11b-deficient mice developed more severe disease symptoms than wild-type mice in the late phase of the disease. Furthermore, as compared to wild-type controls, CD11b-deficient mice expressed increased levels of circulating IFN-gamma and IL-4. Taken together, for the first time, our results suggest an anti-inflammatory role for CD11b in experimental autoimmune diseases. PMID- 28857286 TI - Proximal suspensory desmopathy in hindlimbs: Magnetic resonance imaging, gross post-mortem and histological study. AB - BACKGROUND: There have been no previous studies correlating high-field magnetic resonance imaging (MRI) findings with gross and histological post-mortem examination in horses with hindlimb proximal suspensory desmopathy (PSD). OBJECTIVES: To determine if adhesions between the suspensory ligament (SL) and adjacent tissues could be detected using high-field MRI and if collagen, adipose tissue and muscle pathology could be differentiated. STUDY DESIGN: Retrospective study. METHODS: Nineteen horses with hindlimb PSD were humanely destroyed; 12 limbs of 11 horses with PSD underwent high-field MRI. All lame limbs were examined grossly and all SLs were examined histologically. The MR and histological images were graded blindly. Statistical analysis used a numerical Bayesian approach to simultaneously determine a pathology rating and the contribution of each MRI, gross post-mortem and histological observation to this measure. RESULTS: Signal intensity (SI) in the collagenous tissue was abnormal in 2/12 limbs. Abnormalities of SI in the adipose tissue and muscle were identified in 6 and 11 limbs, respectively. Adhesions between the SL and adjacent tissues were suspected in eight limbs, but only confirmed in six limbs. Histopathological observations of abnormal muscle tissue were associated most closely with the measure of disease used in the study and were abnormal in every limb. Gross adhesions were also a sensitive indicator, along with changes to nerves which were observed in 10 limbs. Assessments of adipose tissue signal intensity and muscle tissue signal homogeneity in both lobes of the suspensory ligament were the MRI indicators most closely associated with the measure of disease. MAIN LIMITATIONS: Small sample size. Model assumption that all abnormalities reflected degrees of a single disease. CONCLUSIONS: Adhesion formation between the SL and adjacent structures was detected by high-field MRI with reasonable accuracy. Muscle and adipose tissue pathology was identified either alone or in association with collagenous tissue pathology. PMID- 28857287 TI - Charge Control in Model Catalysis: The Decisive Role of the Oxide-Nanoparticle Interface. AB - In chemistry and physics the electronic charge on a species or material is one important determinant of its properties. In the present Minireview, the essential requirements for a model catalyst system suitable to study charge control are discussed. The ideal model catalyst for this purpose consists of a material system, which comprises a single crystal metal support, covered by an epitaxially grown ultrathin oxide film, and flat, two-dimensional nanoparticles residing on this film. Several examples from the literature are selected and presented, which illustrate various aspects of electron transport from the support to the nanoparticle and vice versa. Key experiments demonstrate charge control within such model catalysts and give direct evidence for a chemical reaction at the perimeter of Au nanoparticles. The concepts derived from these studies are then taken a step further to see how they may be applied for bulk powder oxide supported nanoparticles as they are frequently found in catalytically active materials. PMID- 28857288 TI - Celebration of 150th Anniversary of the German Chemical Society. AB - Congratulations to the GDCh: This issue of Chemistry-A European Journal celebrates the 150th anniversary of the German Chemical Society (GDCh). Members of the GDCh have played pivotal roles in the development of Chemistry-A European Journal and together with our other European partners have been instrumental in the success of the family of ChemPubSoc Europe journals. PMID- 28857289 TI - Chain-Breaking Phenolic 2,3-Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies. AB - Phenolic 2,3-dihydrobenzo[b]selenophene antioxidants bearing an OH-group ortho (9), meta (10, 11) and para (8) to the Se were prepared by seleno-Claisen rearrangement/intramolecular hydroselenation. meta-Isomer (11) was studied by X ray crystallography. The radical-trapping activity and regenerability of compounds 8-11 were evaluated using a two-phase system in which linoleic acid was undergoing peroxidation in the lipid phase while regeneration of the antioxidant by co-antioxidants (N-acetylcysteine, glutathione, dithiothreitol, ascorbic acid, tris(carboxyethyl)phosphine hydrochloride) was ongoing in the aqueous layer. Compound 9 quenched peroxyl radicals more efficiently than alpha-tocopherol. It also provided the most long-lasting antioxidant protection. With thiol co antioxidants it could inhibit peroxidation for more than five-fold longer than the natural product. Regeneration was more efficient when the aqueous phase pH was slightly acidic. Since calculated O-H bond dissociation energies for 8-11 were substantially larger than for alpha-tocopherol, an antioxidant mechanism involving O-atom transfer from peroxyl to selenium was proposed. The resulting phenolic selenoxide/alkoxyl radical would then exchange a hydrogen atom in a solvent cage before antioxidant regeneration at the aqueous lipid interphase. PMID- 28857291 TI - Molecular Engineering of UV/Vis Light-Emitting Diode (LED)-Sensitive Donor-pi Acceptor-Type Sulfonium Salt Photoacid Generators: Design, Synthesis, and Study of Photochemical and Photophysical Properties. AB - A series of donor-pi-acceptor-type sulfonium salt photoacid generators (PAGs) were designed and synthesized by systematically changing electron-donating groups, pi-conjugated systems, electron-withdrawing groups, and the number of branches through molecular engineering. These PAGs can effectively decompose under UV/Vis irradiation from a light-emitting diode (LED) light source because of the matching absorption and emitting spectra of the LEDs. The absorption and acid-generation properties of these sulfonium salts were elucidated by UV/Vis spectroscopy and so forth. Results indicated that the PAG performance benefited from the introduction of strong electron-donating groups, specific pi-conjugated structures, certain electron-withdrawing groups, or two-branched structures. Most sulfonium salts showed potential as photoinitiators under irradiation by a wide variety of UV and visible LEDs. PMID- 28857292 TI - Ion suppression effect in desorption electrospray ionization and electrospray ionization mass spectrometry. AB - RATIONALE: Although it is claimed that desorption electrospray ionization (DESI) causes less ion suppression effects than electrospray ionization (ESI), a related investigation with quantification measurement of ion suppression effects is absent. Herein, a comparative analysis of ion suppression effects between DESI and ESI was conducted, with the aiming of quantitatively studying the ion suppression effect. METHODS: CTVA mixtures, a constant concentration of tioconazole with varied concentrations of atenolol, were analyzed by ESI and DESI. The ion suppression effect was characterized by the signal loss of tioconazole in the mixture compared to the signal intensity of tioconazole without interference (denoted as (Isingle - Imixture )/Isingle ). According to the variations in the experimental conditions (such as flow rate, solvent composition, substrate material, capillary inner diameter, sheath gas velocity), ion suppression effects in DESI and ESI were compared. RESULTS: With the increasing flow rate, the ion suppression effect in DESI became weaker, while the opposite trend was obtained for ESI. As for capillary inner diameter, a smaller inner diameter resulted in weaker ion suppression effects in DESI and ESI. The solvent composition affected the ion suppression effect, and the PTFE substrate presented the weakest ion suppression effect among the five substrate materials. CONCLUSIONS: Though the ion suppression effect in DESI and ESI was shown to relate to experimental conditions, DESI had less effect than ESI under the same experimental conditions in most cases. Moreover, DESI displayed stronger matrix tolerant ability than ESI which is also attributed to the weaker ion suppression effect. PMID- 28857290 TI - Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer. AB - Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure-activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers. PMID- 28857293 TI - Sr2+ has low efficiency in regulating spontaneous release at the Calyx of Held synapses. AB - It has been known that Ca2+ plays an essential role in mediating different modes of neurotransmitter release via different sensing mechanisms. Synaptotagmin 1, 2, and 9 were found to act as the Ca2+ sensors for synchronous release and synaptotagmin 7 and Doc-2 were proposed as the Ca2+ sensors for asynchronous release. Comparatively, the Ca2+ sensor for spontaneous release remains a mystery. At the Calyx of Held synapse, the Ca2+ sensor for spontaneous release was found not identical to the sensor for synchronous release, synaptotagmin 2. As Ca2+ sensors have different sensitivity to Sr2+ and Ca2+ and induce significantly different rate of vesicle release, Sr2+ is traditionally used as a tool to examine the intrinsic properties of different Ca2+ sensors. Here, we employed cell-attached patch recording and presynaptic/postsynaptic whole-cell recording at the Calyx of Held synapses of synaptotagmin 2 knock-out mice to assay the Sr2+ and Ca2+ influx into the nerve terminal at resting potential and observed the effects of Ca2+ and Sr2+ on spontaneous neurotransmitter release. We found that the dwell time of single voltage gated Ca2+ channel opening increased around threefold for Sr2+ than Ca2+ with the channel conductance unchanged; the divalent cation sensing machinery in regulating spontaneous release has much lower sensitivity to Sr2+ than Ca2+ . Thus, our study reveals some of the intrinsic properties of Ca2+ sensor(s) of spontaneous transmitter release and provided an insight into the underlying mechanisms. PMID- 28857294 TI - Oroxylin A prevents angiogenesis of LSECs in liver fibrosis via inhibition of YAP/HIF-1alpha signaling. AB - Angiogenesis of liver sinusoidal endothelial cells (LSECs) accompanies with hypoxia in liver fibrosis and they are of mutual promotion, which has raised wide concern. Here we established murine model of liver fibrosis and found that oroxylin A (40 mg/kg) could ameliorate angiogenesis in liver fibrosis may related to hypoxia inducible factor 1alpha (HIF-1alpha). The underlying mechanism was further investigated by isolating and culturing murine primary LSECs. Hypoxia induced vascular endothelial growth factor A (VEGF-A), angiopoietin 2 (Ang-2), and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) elevated in LSECs were reduced by oroxylin A or acriflavine (ACF, an HIF-1alpha inhibitor), indicating HIF-1alpha involved the angiogenesis of LSECs. Additionally, interference with Yes-associated protein (YAP) significant downregulated the protein expression of HIF-1alpha and VEGF-A, while YAP plasmid exhibited an opposite effect. We next found that oroxylin A inhibited hypoxia-induced nuclear translocation of YAP, which may influence the accumulation of HIF-1alpha and subsequently decrease transcription of downstream target gene including VEGF-A and Ang-2, thereby exerting an anti-angiogenic activity. PMID- 28857295 TI - A protective role of IRF3 and IRF7 signalling downstream TLRs in the development of vein graft disease via type I interferons. AB - BACKGROUND: Toll like receptors (TLR) play an important role in vein graft disease (VGD). Interferon regulatory factors (IRF) 3 and 7 are the transcriptional regulators of type I interferons (IFN) and type I IFN responsive genes and are downstream factors of TLRs. Relatively little is known with regard to the interplay of IRFs and TLRs in VGD development. The aim of this study was to investigate the role of IRF3 and IRF7 signaling downstream TLRs and the effect of IRF3 and IRF7 in VGD. METHODS AND RESULTS: In vitro activation of TLR3 induced IRF3 and IRF7 dependent IFNbeta expression in bone marrow macrophages and vascular smooth muscle cells. Activation of TLR4 showed to regulate pro inflammatory cytokines via IRF3. Vein graft surgery was performed in Irf3-/- , Irf7-/- and control mice. After 14 days Irf3-/- vein grafts had an increased vessel wall thickness compared to both control (P = 0.01) and Irf7-/- (P = 0.02) vein grafts. After 28 days, vessel wall thickness increased in Irf3-/- (P = 0.0003) and Irf7-/- (P = 0.04) compared to control vein grafts and also increased in Irf7-/- compared to Irf3-/- vein grafts (P = 0.02). Immunohistochemical analysis showed a significant higher influx of macrophages after 14 days in Irf3 /- vein grafts and after 28 days in Irf7-/- vein grafts compared to control vein grafts. CONCLUSIONS: The present study is the first to describe a protective role of both IRF3 and IRF7 in VGD. IRFs regulate VGD downstream TLRs since Irf3-/- and Irf7-/- vein grafts show increased vessel wall thickening after respectively 14 and 28 days after surgery. PMID- 28857296 TI - Patient factors influencing symptom appraisal and subsequent adjustment to oesophageal cancer: A qualitative interview study. AB - Oesophageal cancer (EC) is characterised by vague symptoms and is often diagnosed at an advanced stage, leading to poor outcomes. Therefore, we aimed to investigate whether there might be any patient factors contributing to delay in EC diagnosis, and focused on the symptom appraisal and help-seeking strategies of people diagnosed with EC in the UK. Semi-structured interviews were conducted with 14 patients aged >18 years with localised EC at point of diagnosis. Purposive sampling was used to include patients from 1 to 9 months post diagnosis. Analysis of the interviews identified three main themes: Interpreting symptoms, Triggers to seeking help and Making sense of an unfamiliar cancer. Findings suggested that participants normalised symptoms or used previous health experiences as a means to interpret their symptoms. The majority of participants were not alarmed by their symptoms, mainly because they had very little knowledge of EC specific symptoms. Lack of knowledge also influenced participants' sense making of their diagnosis. The findings highlight that the process of symptom appraisal in EC is likely to be inaccurate, which may hinder early presentation and thus diagnosis. Public health campaigns communicating EC specific symptoms, however, could shorten the appraisal period and lead to earlier diagnosis. PMID- 28857297 TI - Cost-of-illness of psoriasis - results of a German cross-sectional study. AB - BACKGROUND: Though psoriasis poses a substantial chronic socio-economic burden, few studies have addressed the economic impact in Germany. OBJECTIVES: The objective was to evaluate the annual costs of psoriasis in Germany from the societal perspective. METHODS: A cross-sectional study was performed in randomly selected German dermatology practices and clinics in 2013/2014 using standardized questionnaires of illness-related costs. Costs were grouped by perspective and category as well as analysed by sex and age. Group differences were tested by non parametric tests. RESULTS: Complete data were obtained from 1158 patients in 132 centres. Annual average costs for patients with psoriasis: total costs ? 5543 +/- ? 8044, systemic treatment costs (paid by the statutory health insurances [SHI]) ? 3733 +/- ? 7322, out-of-pocket costs ? 224 +/- ? 406, total SHI costs ? 4940 +/ ? 7533, direct costs ? 5164 +/- ? 7581 and indirect costs ? 379 +/- ? 2087. Significant higher costs in male and significant lower costs in 65+-year-old patients were found. CONCLUSIONS: Psoriasis induces a considerable economic burden. Between 2003 and 2014, costs have markedly shifted from hospital, out-of pocket and indirect costs towards systemic drug costs. PMID- 28857298 TI - Cryptococcosis in patients with diabetes mellitus II in mainland China: 1993 2015. AB - Diabetes mellitus II (DM II) is a newly defined independent factor contributing to the morbidity and mortality of cryptococcosis. This retrospective case analysis aims to explore the epidemiology, clinical profile and strain characteristics of cryptococcosis in Chinese DM II patients. This study included 30 cases of cryptococcosis with DM II occurring from 1993 to 2015 in mainland China. The hospital-based prevalence of cryptococcosis in DM II was 0.21%. The mean age of the patients was 56.1 years (95% confidence interval: 51.5, 60.6), and 93% of the patients were older than 40 years. Sixty-two per cent of the patients experienced untreated or poorly controlled blood glucose before infection. Multilocus sequence typing analysis categorised all cultured strains as Cryptococcus neoformans and sequence type 5. Sixty-nine per cent of pulmonary cryptococcosis patients experienced misdiagnoses and treatment delays. Sixty per cent of cryptococcal meningitis patients received substandard antifungal therapy. The overall death rate was 33%. Considering the large population size of DM II patients in China, improved attention should be paid to the high prevalence of cryptococcosis as revealed by us. We also emphasised the importance of blood glucose control for infection prevention, especially among the elderly. PMID- 28857299 TI - European academy of dermatology and venereology European prurigo project: expert consensus on the definition, classification and terminology of chronic prurigo. AB - BACKGROUND: The term prurigo has been used for many decades in dermatology without clear definition, and currently used terminology of prurigo is inconsistent and confusing. Especially, itch-related prurigo remains unexplored regarding the epidemiology, clinical profile, natural course, underlying causes, available treatments and economic burden, although burdensome and difficult to treat. OBJECTIVE: To address these issues, the multicentre European Prurigo Project (EPP) was designed to increase knowledge on chronic prurigo (CPG). In the first step, European experts of the EADV Task Force Pruritus (TFP) aimed to achieve a consensus on the definition, classification and terminology of CPG. Additionally, procedures of the cross-sectional EPP were discussed and agreed upon. METHODS: Discussions and surveys between members of the TFP served as basis for a consensus conference. Using the Delphi method, consensus was defined as an agreement >=75% among the present members. RESULTS: Twenty-four members of the TFP participated in the consensus conference. Experts consented that CPG should be used as an umbrella term for the range of clinical manifestations (e.g. papular, nodular, plaque or umbilicated types). CPG is considered a distinct disease defined by the presence of chronic pruritus for >=6 weeks, history and/or signs of repeated scratching and multiple localized/generalized pruriginous skin lesions (whitish or pink papules, nodules and/or plaques). CPG occurs due to a neuronal sensitization to itch and the development of an itch-scratch cycle. CONCLUSION: This new definition and terminology of CPG should be implemented in dermatology to harmonize communication in the clinical routine, clinical trials and scientific literature. Acute/subacute forms of prurigo are separated entities, which need to be differentiated from CPG and will be discussed in a next step. In the near future, the cross-sectional EPP will provide relevant clinical data on various aspects of CPG leading to new directions in the scientific investigation of CGP. PMID- 28857300 TI - Ecological and physiological thermal niches to understand distribution of Chagas disease vectors in Latin America. AB - In order to assess how triatomines (Hemiptera, Reduviidae), Chagas disease vectors, are distributed through Latin America, we analysed the relationship between the ecological niche and the limits of the physiological thermal niche in seven species of triatomines. We combined two methodological approaches: species distribution models, and physiological tolerances. First, we modelled the ecological niche and identified the most important abiotic factor for their distribution. Then, thermal tolerance limits were analysed by measuring maximum and minimum critical temperatures, upper lethal temperature, and 'chill-coma recovery time'. Finally, we used phylogenetic independent contrasts to analyse the link between limiting factors and the thermal tolerance range for the assessment of ecological hypotheses that provide a different outlook for the geo epidemiology of Chagas disease. In triatomines, thermo-tolerance range increases with increasing latitude mainly due to better cold tolerances, suggesting an effect of thermal selection. In turn, physiological analyses show that species reaching southernmost areas have a higher thermo-tolerance than those with tropical distributions, denoting that thermo-tolerance is limiting the southern distribution. Understanding the latitudinal range along its physiological limits of disease vectors may prove useful to test ecological hypotheses and improve strategies and efficiency of vector control at the local and regional levels. PMID- 28857301 TI - Ouabain attenuates the oxidative stress induced by lipopolysaccharides in the cerebellum of rats. AB - Our study aimed to analyze the effect of ouabain administration on lipopolysaccharide (LPS)-induced changes in oxidative parameters, membrane lipid composition, and the activities of some important enzymes of the nervous system. The content of phospholipids, cholesterol, and gangliosides were analyzed in Wistar rats after intraperitoneal injection of ouabain (1.8 MUg/kg), LPS (200 MUg/kg), or saline. Oxidative parameters were also evaluated, including the activities of superoxide dismutase, catalase and glutathione peroxidase, the levels of glutathione and lipid peroxidation, as well as Na,K-ATPase activity and the level of glutamate transporter EAAT4. Administration of LPS resulted in increased oxidative stress, as evidenced by an increase in lipid peroxidation levels, glutathione peroxidase activity, decreased catalase activity and reduced glutathione levels. All changes recorded were attenuated by pretreatment with ouabain. Administration of ouabain plus LPS enhanced the total ganglioside content and EAAT4 levels, but failed to alter the Na,K-ATPase activity. Our data suggest a neuroprotective effect of ouabain against LPS-induced oxidative stress by promoting membrane lipid remodeling and increasing the expression of glutamate transporter EAAT4. Our results emphasize that the observed oxidative stress is not correlated with Na,K-ATPase, but with a possible ouabain-mediated effect on cellular signaling. The relevance of our results extends beyond LPS-induced changes in oxidative parameters, as nanomolar doses of ouabain might prove useful in neurodegenerative models. Further study of other cardenolides and related molecules, as well as the development of new molecules derived from ouabain, could also prove useful in the fight against the oxidative and/or general cell stress triggered by neuronal pathologies. PMID- 28857302 TI - Pyroglutamate-Modified Amyloid beta (11- 40) Fibrils Are More Toxic than Wildtype Fibrils but Structurally Very Similar. AB - The morphology, structure, and dynamics of mature amyloid beta (Abeta) fibrils formed by the Abeta variant, which is truncated at residue 11 and chemically modified by enzymatic pyroglutamate formation (pGlu11 -Abeta(11-40)), was studied along with the investigation of the toxicity of these Abeta variants to neurons and astrocytes. The fibrils of pGlu11 -Abeta (11-40) were more toxic than wildtype Abeta (1-40) and the longer pGlu3-Abeta (3-40) especially at higher concentration, whereas the overall morphology was quite similar. The secondary structure of pGlu11 -Abeta (11-40) fibrils shows the typical two beta-strands connected by a short turn as known for mature fibrils of Abeta (1-40) and also pGlu3 -Abeta (3-40). Further insights into tertiary contacts exhibit some similarities of pGlu11 -Abeta (11-40) fibrils with wildtype Abeta (1-40), but also a so far not described contact between Gly25 and Ile31 . This highlights the biological importance of chemical modifications on the molecular structure of Abeta. PMID- 28857303 TI - General Synthesis of Transition-Metal Oxide Hollow Nanospheres/Nitrogen-Doped Graphene Hybrids by Metal-Ammine Complex Chemistry for High-Performance Lithium Ion Batteries. AB - We present a general and facile synthesis strategy, on the basis of metal-ammine complex chemistry, for synthesizing hollow transition-metal oxides (Co3 O4 , NiO, CuO-Cu2 O, and ZnO)/nitrogen-doped graphene hybrids, potentially applied in high performance lithium-ion batteries. The oxygen-containing functional groups of graphene oxide play a prerequisite role in the formation of hollow transition metal oxides on graphene nanosheets, and a significant hollowing process occurs only when forming metal (Co2+ , Ni2+ , Cu2+ , or Zn2+ )-ammine complex ions. Moreover, the hollowing process is well correlated with the complexing capacity between metal ions and NH3 molecules. The significant hollowing process occurs for strong metal-ammine complex ions including Co2+ , Ni2+ , Cu2+ , and Zn2+ ions, and no hollow structures formed for weak and/or noncomplex Mn2+ and Fe3+ ions. Simultaneously, this novel strategy can also achieve the direct doping of nitrogen atoms into the graphene framework. The electrochemical performance of two typical hollow Co3 O4 or NiO/nitrogen-doped graphene hybrids was evaluated by their use as anodic materials. It was demonstrated that these unique nanostructured hybrids, in contrast with the bare counterparts, solid transition metal oxides/nitrogen-doped graphene hybrids, perform with significantly improved specific capacity, superior rate capability, and excellent capacity retention. PMID- 28857304 TI - Causes of hospital admission in beta-thalassemia (CHAT) in Lebanon from 1995 to 2015: A pilot retrospective study from a tertiary care center. PMID- 28857305 TI - The relationship of bilingualism to cognitive decline: The Australian Longitudinal Study of Ageing. AB - OBJECTIVES: We wished to clarify the link between bilingualism and cognitive decline, and examine whether improved executive function due to bilingualism may be a factor in preventing cognitive decline. METHODS: We used the Australian Longitudinal Study of Ageing which collected data on 2087 participants aged over 65 over 20 years. We compared baseline demographics, health, and social characteristics between bilingual and non-bilingual participants. We used linear mixed models analysis to explore the effect of bilingualism on MMSE score over time and linear regression to explore the effect of bilingualism on baseline MMSE scores, controlling for pre-specified potential confounders. RESULTS: Bilingual participants had lower baseline MMSE scores than the non-bilingual population (mean difference = -2.3 points; 95% confidence intervals = 1.56-2.90). This was fully explained by education and National Adult Reading Test scores (17.4; standard deviation [SD] =7.7 versus 28.1; SD = 8.2) which also partly explained baseline executive function test scores differences. Bilingual and non-bilingual participants did not differ in MMSE decline over time (-0.33 points, P = 0.31) nor on baseline tests of executive function (-0.26, P = 0.051). CONCLUSIONS: In this cohort, education rather than bilingualism was a predictor of MMSE score, and being bilingual did not protect from cognitive decline. We conclude that bilingualism is complex, and when it is not the result of greater educational attainment, it does not always protect from cognitive decline. Neuroprotective effects of bilingualism over time may be attributable to the precise patterns of language use but not to bilingualism per se. PMID- 28857306 TI - The effect of targeted therapy on recruited cancer stem cells in a head and neck carcinoma model. AB - OBJECTIVE: Head and neck cancers (HNC) are known for their repopulation ability driven by cancer stem cells (CSCs). While a small fraction of CSCs proliferates, there are quiescent CSCs that are long-lived and reside outside the cell cycle. Recruitment of quiescent CSCs into the cycle occurs as a response to cell loss and their proliferation may lead to treatment failure. Therefore, CSCs require a more targeted approach to be destroyed. An agent that sensitizes CSC response to treatment is all-trans-retinoic acid (ATRA). The aim of this work is to assess the impact of ATRA combined with radiotherapy on HNC and to analyse the interplay between these agents and cell recruitment. METHODS: An in silico model is employed to grow a HNC consisting of all cancer cell lineages, with biologically valid kinetic and dynamic parameters. The fate of both cycling and quiescent cancer stem cells is assessed. The Linear Quadratic model is used to simulate radiotherapy, while cellular recruitment and the effects of ATRA on cancer stem cells are modelled based on literature data. RESULTS: A Dose Enhancement Factor (DEF) was determined in order to undertake a quantitative assessment of the effect of ATRA on tumour control. Without recruitment, DEF for the tumour population is 1.06, indicating a slight radiosensitizing effect. Yet, when CSCs are being recruited, the dose enhancement factor is significantly greater (DEF = 1.89). Radiation-induced cell arrest and CSC sensitization by ATRA significantly decreases the dose required for CSC eradication in the cycling population. However, the tumour as a whole is not notably affected as the quiescent cells appear to dictate the shape of the survival curve. CONCLUSIONS: The model shows that ATRA exhibits a powerful effect on CSCs when combined with radiotherapy. However, the more radioresistant quiescent cell population should not be ignored, as it can be a potential threat to treatment outcome when cells are recruited into the cell cycle. PMID- 28857307 TI - Cell-type- and tissue-specific transcriptomes of the white spruce (Picea glauca) bark unmask fine-scale spatial patterns of constitutive and induced conifer defense. AB - Plant defenses often involve specialized cells and tissues. In conifers, specialized cells of the bark are important for defense against insects and pathogens. Using laser microdissection, we characterized the transcriptomes of cortical resin duct cells, phenolic cells and phloem of white spruce (Picea glauca) bark under constitutive and methyl jasmonate (MeJa)-induced conditions, and we compared these transcriptomes with the transcriptome of the bark tissue complex. Overall, ~3700 bark transcripts were differentially expressed in response to MeJa. Approximately 25% of transcripts were expressed in only one cell type, revealing cell specialization at the transcriptome level. MeJa caused cell-type-specific transcriptome responses and changed the overall patterns of cell-type-specific transcript accumulation. Comparison of transcriptomes of the conifer bark tissue complex and specialized cells resolved a masking effect inherent to transcriptome analysis of complex tissues, and showed the actual cell type-specific transcriptome signatures. Characterization of cell-type-specific transcriptomes is critical to reveal the dynamic patterns of spatial and temporal display of constitutive and induced defense systems in a complex plant tissue or organ. This was demonstrated with the improved resolution of spatially restricted expression of sets of genes of secondary metabolism in the specialized cell types. PMID- 28857308 TI - A novel splicing isoform of protein arginine methyltransferase 1 (PRMT1) that lacks the dimerization arm and correlates with cellular malignancy. AB - Methylation of arginine residues is an important modulator of protein function that is involved in epigenetic gene regulation, DNA damage response and RNA maturation, as well as in cellular signaling. The enzymes that catalyze this post translational modification are called protein arginine methyltransferases (PRMTs), of which PRMT1 is the predominant enzyme. Human PRMT1 has previously been shown to occur in seven splicing isoforms, which are differentially abundant in different tissues, and have distinct substrate specificity and intracellular localization. Here we characterize a novel splicing isoform which does not affect the amino-terminus of the protein like the seven known isoforms, but rather lacks exons 8 and 9 which encode the dimerization arm of the enzyme that is essential for enzymatic activity. Consequently, the isoform does not form catalytically active oligomers with the other endogenous PRMT1 isoforms. Photobleaching experiments reveal an immobile fraction of the enzyme in the nucleus, in accordance with earlier results from our laboratory that had shown a tight association of inhibited or inactivated PRMT1 with chromatin and the nuclear scaffold. Thus, it apparently is able to bind to the same substrates as catalytically active PRMT1. This isoform is found in a variety of cell lines, but is increased in those of cancer origin or after expression of the EMT-inducing transcriptional repressor Snail1. We discuss that the novel isoform could act as a modulator of PRMT1 activity in cancer cells by acting as a competitive inhibitor that shields substrates from access to active PRMT1 oligomers. PMID- 28857309 TI - Impact of the black triangle label on prescribing of new drugs in the United Kingdom: lessons for the United States at a time of deregulation. AB - PURPOSE: Newly approved novel drugs in Europe receive a black triangle label to promote pharmacovigilance. With growing momentum for earlier drug approvals and reliance on real-world evidence, we studied if the black triangle label promotes more judicious prescribing. METHODS: We examined whether general practitioners prescribed escitalopram, tadalafil, and vardenafil with a black triangle more cautiously than the same or similar drugs without a black triangle in The Health Improvement Network (UK). We performed interrupted time-series analyses to estimate changes in new prescription rates and nested case-control studies to compare characteristics of new users before and after removal of a black triangle. RESULTS: Prescribing rates to the 33 441 new users of these new drugs were highest shortly after initial approval and declined subsequently; there were no increases in rates of new prescriptions after a black triangle's removal (new prescriptions/million/month postlabel: escitalopram -1.5 [95% CI, -1.9 to -1.2]; tadalafil and vardenafil: -0.1 [95% CI, -0.6 to 0.4]). Among drugs in the same class, loss of a patent had more impact on prescribing rates than loss of a black triangle. People who began taking black triangle drugs were less likely to be young or to have multiple comorbidities or recent hospitalization compared with those starting the same drugs after the label's removal. However, these differences generally reflected secular trends seen also in similar, unlabeled medicines. CONCLUSIONS: Accelerated drug approvals could cause more uncertainty about drug effectiveness and safety, but specific labeling of newly approved medicines is unlikely to promote more judicious prescribing. PMID- 28857310 TI - Orotracheal manganese-enhanced MRI (MEMRI): An effective approach for lung tumor detection. AB - Lung cancer is a primary cause of cancer deaths worldwide. Timely detection of this pathology is necessary to delay or interrupt lung cancer progression, ultimately resulting in a possible better prognosis for the patient. In this context, magnetic resonance imaging (MRI) is especially promising. Ultra-short echo time (UTE) MRI sequences, in combination with gadolinium-based contrast agents, have indeed shown to be especially adapted to the detection of lung neoplastic lesions at submillimeter precision. Manganese-enhanced MRI (MEMRI) increasingly appears to be a possible effective alternative to gadolinium enhanced MRI. In this work, we investigated whether low-dose MEMRI can effectively target non-small-cell lung cancer in rodents, whilst minimizing the potential toxic effect of manganese. Both systemic and orotracheal administration modalities allowed the identification of tumors of submillimeter size, as confirmed by bioluminescence imaging and histology. Equivalent tumor signal enhancements and contrast-to-noise ratios were observed with orotracheal administration using 20 times lower doses compared with the more conventional systemic route. This finding is of crucial importance as it supports the observation that higher performances of contrast agents can be obtained using an orotracheal administration route when targeting lung diseases. As a consequence, lower concentrations of contrast media can be employed, reducing the dose and potential safety issues. The non-detectable accumulation of ionic manganese in the brain and liver following orotracheal administration observed in vivo is extremely encouraging with regard to the safety of the orotracheal protocol with low-dose Mn2+ administration. To our knowledge, this is the first time that a study has clearly allowed the high-precision detection of lung tumor and its contours via the synergic employment of a strongly T1 -weighted MRI UTE sequence and ionic manganese, an inexpensive contrast agent. Overall, these results support the growing interest in drug and contrast agent delivery via the airways to target and diagnose several diseases of the lungs. PMID- 28857311 TI - Engineered, highly reactive substrates of microbial transglutaminase enable protein labeling within various secondary structure elements. AB - Microbial transglutaminase (MTG) is a practical tool to enzymatically form isopeptide bonds between peptide or protein substrates. This natural approach to crosslinking the side-chains of reactive glutamine and lysine residues is solidly rooted in food and textile processing. More recently, MTG's tolerance for various primary amines in lieu of lysine have revealed its potential for site-specific protein labeling with aminated compounds, including fluorophores. Importantly, MTG can label glutamines at accessible positions in the body of a target protein, setting it apart from most labeling enzymes that react exclusively at protein termini. To expand its applicability as a labeling tool, we engineered the B1 domain of Protein G (GB1) to probe the selectivity and enhance the reactivity of MTG toward its glutamine substrate. We built a GB1 library where each variant contained a single glutamine at positions covering all secondary structure elements. The most reactive and selective variants displayed a >100-fold increase in incorporation of a recently developed aminated benzo[a]imidazo[2,1,5 cd]indolizine-type fluorophore, relative to native GB1. None of the variants were destabilized. Our results demonstrate that MTG can react readily with glutamines in alpha-helical, beta-sheet, and unstructured loop elements and does not favor one type of secondary structure. Introducing point mutations within MTG's active site further increased reactivity toward the most reactive substrate variant, I6Q GB1, enhancing MTG's capacity to fluorescently label an engineered, highly reactive glutamine substrate. This work demonstrates that MTG-reactive glutamines can be readily introduced into a protein domain for fluorescent labeling. PMID- 28857312 TI - Stable isotope discrimination factors and between-tissue isotope comparisons for bone and skin from captive and wild green sea turtles (Chelonia mydas). AB - RATIONALE: The ecological application of stable isotope analysis (SIA) relies on taxa- and tissue-specific stable carbon (Delta13 C) and nitrogen (Delta15 N) isotope discrimination factors, determined with captive animals reared on known diets for sufficient time to reflect dietary isotope ratios. However, captive studies often prohibit lethal sampling, are difficult with endangered species, and reflect conditions not experienced in the wild. METHODS: We overcame these constraints and determined the Delta13 C and Delta15 N values for skin and cortical bone from green sea turtles (Chelonia mydas) that died in captivity and evaluated the utility of a mathematical approach to predict discrimination factors. Using stable carbon (delta13 C values) and nitrogen (delta15 N values) isotope ratios from captive and wild turtles, we established relationships between bone stable isotope (SI) ratios and those from skin, a non-lethally sampled tissue, to facilitate comparisons of SI ratios among studies using multiple tissues. RESULTS: The mean (+/-SD) Delta13 C and Delta15 N values (0/00) between skin and bone from captive turtles and their diet (non-lipid-extracted) were 2.3 +/- 0.3 and 4.1 +/- 0.4 and 2.1 +/- 0.6 and 5.1 +/- 1.1, respectively. The mathematically predicted Delta13 C and Delta15 N values were similar (to within 10/00) to the experimentally derived values. The mean delta15 N values from bone were higher than those from skin for captive (+1.0 +/- 0.90/00) and wild (+0.8 +/- 1.00/00) turtles; the mean delta13 C values from bone were lower than those from skin for wild turtles (-0.6 +/- 0.90/00), but the same as for captive turtles. We used linear regression equations to describe bone vs skin relationships and create bone-to-skin isotope conversion equations. CONCLUSIONS: For sea turtles, we provide the first (a) bone-diet SI discrimination factors, (b) comparison of SI ratios from individual-specific bone and skin, and (c) evaluation of the application of a mathematical approach to predict stable isotope discrimination factors. Our approach opens the door for future studies comparing different tissues, and relating SI ratios of captive to wild animals. PMID- 28857313 TI - Perceptions of U.S. dermatology residency program directors regarding the adequacy of phototherapy training during residency. AB - BACKGROUND/PURPOSE: Phototherapy utilization has declined over the last 20 years despite its efficacy and cost-effectiveness. Adequacy of phototherapy training in residency may be a contributing factor. The purpose of this study was to evaluate perceptions of U.S. dermatology residency program directors (PDs) regarding the effectiveness of their programs' phototherapy training and what constitutes adequate phototherapy education. METHODS: A questionnaire was sent to PDs to assess phototherapy training within their program; aspects such as dedicated time, exposure to different modalities, and barriers to resident education were surveyed. We assessed the statistical association between these aspects and the perception by PDs that a program's training was adequate. Statistical testing was reported using Fisher's exact tests. RESULTS: A total of 42 PDs responded. Residency training in oral psoralen and ultraviolet A therapy (PUVA), home phototherapy, and excimer laser, respectively, is not provided in 19.0%, 31.0%, and 47.6% of programs. 38.1% of programs provide <=5 hours of phototherapy training over 3 years of training. 59.5% of PDs cited lack of curriculum time as the most common barrier to phototherapy education. 19.0% of PDs reported completely adequate phototherapy training, which was significantly associated with inclusion of faculty-led didactics, assigned reading, or hands-on clinical training in the curriculum. CONCLUSIONS: There is a mismatch between the resources devoted to phototherapy education and the need for dedicated training reported by PDs. Limited time is allocated to phototherapy training during dermatology residency, and a large majority of PDs do not feel that the phototherapy training offered is completely adequate. PMID- 28857314 TI - Factors influencing time to seeking medical advice and onset of treatment in women who are diagnosed with breast cancer in Serbia. AB - OBJECTIVE: Streamlining the diagnosis is a key factor in improving the treatment outcomes for breast cancer. The aim of this study was to determine factors influencing time to seeking medical advice and treatment onset in women who are diagnosed with breast cancer in Serbia. METHODS: The study was a multicenter, cross-sectional national survey, performed at 10 oncology centers in Serbia. Time intervals spent throughout the complex diagnostic pathway were evaluated using a validated questionnaire administered to women with breast cancer (n = 800). Total interval (TI) was determined using predefined time scales, including one referring to patient interval (PI), and several related to health care system interval (SI). RESULTS: Mean PI, SI, and TI were 4.5, 9.2, and 12.9 weeks, respectively; 20% of patients had a PI>12 weeks. Based on the multivariate regression model, longer PI was associated with perceived lack of time and personal disregard or trivialization of detected symptoms and signs. Women who were supported by family members or friends and had at least a secondary level education tended to have a shorter PI. Longer PI was correlated with a longer SI, while regular self-examination, having been diagnosed by an oncologist, and living in a major city were associated with shorter SI. CONCLUSIONS: Several factors, related to psychological, demographic, behavioral, and health system characteristics, determined both the time to seeking medical advice and treatment onset for breast cancer. These findings support review and refining of national strategies and policies to promote early detection, diagnosis, and treatment of breast cancer. PMID- 28857315 TI - Emerging Importance of Phytochemicals in Regulation of Stem Cells Fate via Signaling Pathways. AB - To reach ideal therapeutic potential of stem cells for regenerative medicine purposes, it is essential to retain their self-renewal and differentiation capacities. Currently, biological factors are extensively used for stemness maintaining and differentiation induction of stem cells. However, low stability, high cost, complicated production process, and risks associated with viral/endotoxin infection hamper the widespread use of biological factors in the stem cell biology. Moreover, regarding the modulation of several signaling cascades, which lead to a distinct fate, phytochemicals are preferable in the stem cells biology because of their efficiency. Considering the issues related to the application of biological factors and potential advantages of phytochemicals in stem cell engineering, there is a considerable increasing trend in studies associated with the application of novel alternative molecules in the stem cell biology. In support of this statement, we aimed to highlight the various effects of phytochemicals on signaling cascades involved in commitment of stem cells. Hence, in this review, the current trends in the phytochemicals-based modulation of stem cell fate have been addressed. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28857316 TI - Evolutionary modes of emergence of short interspersed nuclear element (SINE) families in grasses. AB - Short interspersed nuclear elements (SINEs) are non-autonomous transposable elements which are propagated by retrotransposition and constitute an inherent part of the genome of most eukaryotic species. Knowledge of heterogeneous and highly abundant SINEs is crucial for de novo (or improvement of) annotation of whole genome sequences. We scanned Poaceae genome sequences of six important cereals (Oryza sativa, Triticum aestivum, Hordeum vulgare, Panicum virgatum, Sorghum bicolor, Zea mays) and Brachypodium distachyon to examine the diversity and evolution of SINE populations. We comparatively analyzed the structural features, distribution, evolutionary relation and abundance of 32 SINE families and subfamilies within grasses, comprising 11 052 individual copies. The investigation of activity profiles within the Poaceae provides insights into their species-specific diversification and amplification. We found that Poaceae SINEs (PoaS) fall into two length categories: simple SINEs of up to 180 bp and dimeric SINEs larger than 240 bp. Detailed analysis at the nucleotide level revealed that multimerization of related and unrelated SINE copies is an important evolutionary mechanism of SINE formation. We conclude that PoaS families diversify by massive reshuffling between SINE families, likely caused by insertion of truncated copies, and provide a model for this evolutionary scenario. Twenty-eight of 32 PoaS families and subfamilies show significant conservation, in particular either in the 5' or 3' regions, across Poaceae species and share large sequence stretches with one or more other PoaS families. PMID- 28857317 TI - The impact of long work hours and shift work on cognitive errors in nurses. AB - AIM: Pilot study to examine the impact of long work hours and shift work on cognitive errors in nurses. BACKGROUND: Twelve-hour shifts are more commonly used in hospital settings and there is growing concern over the impact that extended and irregular work hours have on nurses' well-being and performance. METHOD: Twenty-eight nurses working different shifts (8-hr days and 12-hr rotation) participated in this study. Nurses were assessed at the beginning of four consecutive shifts using actigraphy, a sleep diary and an after work questionnaire. RESULTS: Nurses working 12-hr rotations had less total sleep time and less sleep efficiency than 8-hr day nurses. Twelve-hour rotation nurses also napped more than their counterparts. There were no differences between the two groups with respect to cognitive errors. CONCLUSIONS: Twelve-hour rotations have a negative effect on nurses' sleep patterns. There is no evidence indicating 12 hr rotations increased errors. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers can implement specific strategies, such as greater shift work flexibility and designated quiet time, to reduce the effects of disturbed sleep patterns in nurses. PMID- 28857318 TI - Liquid chromatography/mass spectrometry based detection and semi-quantitative analysis of INSL5 in human and murine tissues. AB - RATIONALE: Insulin-like peptide 5 (INSL5) is a hormone produced by enteroendocrine L-cells in the colon that has recently been implicated in the control of metabolic homeostasis. However, research into its physiology has been hindered by the reported unreliability of commercially available immunoassays and additional detection assays would benefit this emerging field. METHODS: Peptides from purified murine L-cells and homogenates from both human and mouse colonic tissues were extracted by precipitating larger proteins with acetonitrile. Untargeted liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses, followed by database searching, were used to detect and identify various INSL5 gene derived peptides and characterise their precise sequence. A similar approach was developed to quantify INSL5 levels in primary intestinal culture supernatants after purification and concentration by solid-phase extraction. RESULTS: Mass spectral analysis of purified enteroendocrine cells and tissue homogenates identified the exact sequence of A and B chains of INSL5 endogenously expressed in L-cells. Differences in the endogenously processed peptide and the Swissprot database entry were observed for murine INSL5, whereas the human sequence matched previous predictions from heterologous expression experiments. INSL5 was detected in the supernatant of human and mouse primary colonic cultures and concentrations increased after treatment with a known L-cell stimulus. CONCLUSIONS: The first LC/MS/MS-based method capable of the detection and semi-quantitative analysis of endogenous INSL5 using MS-based techniques has been demonstrated. The methodology will enable the identification of stimulants for INSL5 secretion from murine and human primary colonic epithelial cultures. PMID- 28857319 TI - Transcription factors-Intricate players of the bone morphogenetic protein signaling pathway. AB - Bone morphogenetic proteins (BMPs) are a family of growth factors, some of which are known by the name growth and differentiation factor (GDF). BMPs were discovered in the 1960s in an attempt to find factors capable of inducing bone formation. By the end of 1980s, several different BMPs had been found and to date, around 20 members are known. Together with TGFbeta, nodal, and activins, they comprise the TGFbeta superfamily. BMPs are known to regulate cell fate both in development and adult tissues, and as such they are also involved in many disease states. Understanding the impact of BMPs in these processes requires intimate knowledge of the regulation of the BMP signaling pathway. The intracellular BMP pathway has been studied extensively but the various transcription factors (TFs) necessary for the BMP-mediated gene expression changes have remained under less scrutiny. Most of the studies have focused on specific TFs in the context of differentiation or development. Varying cell types and BMPs have been used, but no large-scale studies have yet been performed. Here we aim to summarize the current knowledge on BMP pathway-related TFs, focusing on those involved in the canonical BMP signaling pathway through the SMAD proteins. PMID- 28857321 TI - Stability of an Aqueous Extract of Larrea divaricata Cav. during a Simulated Digestion Process. AB - Larrea divaricata Cav. (Zygophyllaceae) is a South American plant widely distributed in Argentina that is used in folk medicine to treat inflammatory diseases. The aqueous extract is known to have well-documented biological activities such as antitumour, immunomodulatory, antimicrobial, antiinflammatory and antioxidant. However, its stability in gastrointestinal fluids is unknown. The latter is an important factor to assure the bioavailability of plant extracts intended to be administered via the oral route. The aim of this work was to study the stability of a lyophilized aqueous extract of L. divaricata compressed as a pill. To this end, the main polyphenol compound found in the extract, that is, the nordihydroguaiaretic acid, the total polyphenols and flavonoids content and the antioxidant activity such as diphenylpicrylhydrazyl scavenger activity and reducing power were assayed after subjecting the extract to different incubation times in simulated digestive fluids. The HPLC and spectroscopic methods were employed. Although the levels of polyphenols and flavonoids decreased upon incubation in gastric and intestinal fluids, the extract maintained its antioxidant activity related to the presence of nordihydroguaiaretic acid. These results are promising and encourage the potential use of the extract by the oral route as a supplement or phytomedicine with antioxidant activity. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28857320 TI - Identification of heteromolecular binding sites in transcription factors Sp1 and TAF4 using high-resolution nuclear magnetic resonance spectroscopy. AB - The expression of eukaryotic genes is precisely controlled by interactions between general transcriptional factors and promoter-specific transcriptional activators. The fourth element of TATA-box binding protein-associated factor (TAF4), an essential subunit of the general transcription factor TFIID, serves as a coactivator for various promoter-specific transcriptional regulators. Interactions between TAF4 and site-specific transcriptional activators, such as Sp1, are important for regulating the expression levels of genes of interest. However, only limited information is available on the molecular mechanisms underlying the interactions between these transcriptional regulatory proteins. We herein analyzed the interaction between the transcriptional factors Sp1 and TAF4 using high-resolution solution nuclear magnetic resonance spectroscopy. We found that four glutamine-rich (Q-rich) regions in TAF4 were largely disordered under nearly physiological conditions. Among them, the first Q-rich region in TAF4 was essential for the interaction with another Q-rich region in the Sp1 molecule, most of which was largely disordered. The residues responsible for this interaction were specific and highly localized in a defined region within a range of 20-30 residues. Nevertheless, a detailed analysis of 13 C-chemical shift values suggested that no significant conformational change occurred upon binding. These results indicate a prominent and exceptional binding mode for intrinsically disordered proteins other than the well-accepted concept of "coupled folding and binding." PMID- 28857323 TI - Helping core medical training doctors achieve procedural competencies. PMID- 28857322 TI - New insights into structural organization and gene duplication in a 1.75-Mb genomic region harboring the alpha-gliadin gene family in Aegilops tauschii, the source of wheat D genome. AB - Among the wheat prolamins important for its end-use traits, alpha-gliadins are the most abundant, and are also a major cause of food-related allergies and intolerances. Previous studies of various wheat species estimated that between 25 and 150 alpha-gliadin genes reside in the Gli-2 locus regions. To better understand the evolution of this complex gene family, the DNA sequence of a 1.75 Mb genomic region spanning the Gli-2 locus was analyzed in the diploid grass, Aegilops tauschii, the ancestral source of D genome in hexaploid bread wheat. Comparison with orthologous regions from rice, sorghum, and Brachypodium revealed rapid and dynamic changes only occurring to the Ae. tauschii Gli-2 region, including insertions of high numbers of non-syntenic genes and a high rate of tandem gene duplications, the latter of which have given rise to 12 copies of alpha-gliadin genes clustered within a 550-kb region. Among them, five copies have undergone pseudogenization by various mutation events. Insights into the evolutionary relationship of the duplicated alpha-gliadin genes were obtained from their genomic organization, transcription patterns, transposable element insertions and phylogenetic analyses. An ancestral glutamate-like receptor (GLR) gene encoding putative amino acid sensor in all four grass species has duplicated only in Ae. tauschii and generated three more copies that are interspersed with the alpha-gliadin genes. Phylogenetic inference and different gene expression patterns support functional divergence of the Ae. tauschii GLR copies after duplication. Our results suggest that the duplicates of alpha-gliadin and GLR genes have likely taken different evolutionary paths; conservation for the former and neofunctionalization for the latter. PMID- 28857324 TI - Physical activity levels and hepatic steatosis: A longitudinal follow-up study in adults. AB - BACKGROUND AND AIM: This study aimed to evaluate the impact of physical activity (PA) on the course of hepatic steatosis (HS) in adults. METHODS: Hepatic steatosis status (ultrasonography) and PA levels were evaluated in 5860 subjects at baseline and after approximately 2.5 years (range: 19-50 months). At follow up, possible exposures to different PA levels were those who remained inactive, became inactive, became active, and remained active. After follow up, subjects were then classified according to the four possible states (outcomes): "remained without HS," "developed HS" (subjects without HS at baseline), "remained with HS," or "reverted HS." RESULTS: After multivariate adjustments, individuals without HS that became or remained physically active were less likely to develop HS compared with those who remained physically inactive (odds ratio = 0.75, P = 0.04 and 0.75, P = 0.03, respectively). Among those with HS at baseline, becoming and remaining physically active beneficially improved the HS status (odds ratio = 0.64, P = 0.01 and 0.66, P = 0.01, respectively). However, the significance was lost when adjusted for changes in body mass index. CONCLUSION: Higher levels of PA were associated with prevention and treatment of HS, with evidence of effect mediation by changes in body mass index. PMID- 28857326 TI - Mental disorder and victimisation in prison: Examining the role of mental health treatment. AB - BACKGROUND: There is evidence that people with mental disorders are at increased risk of victimisation in prison. It is unclear whether this risk of victimisation varies across types of disorders or symptoms and what role mental health treatment has on victimisation risk in this context. AIMS: To examine the relationship between specific mental disorders, psychiatric symptoms, and victimisation in prison and the effect of treatment for the disorders on victimisation risk. METHODS: Using a nationally-representative sample of prisoners, path analyses were conducted to examine the relationship between mental disorder and victimisation. The analyses also examined whether receiving mental health treatment in prison affected any such relationship. RESULTS: Victimisation risk varied with the type of mental disorder or symptoms. Depression, personality disorder, hopelessness, paranoia, and hallucinations were associated with increased victimisation risk. Psychotic illnesses were otherwise negatively associated with victimisation. Receiving mental health treatment in prison was associated with greater risk of victimisation there. Receiving treatment appeared to mediate the relationship between mental disorders, symptoms, and victimisation. CONCLUSIONS: The findings suggest that not all inmates with mental disorders are at an increased risk of victimisation. Further, mental health treatment in prison also appears to be a risk factor of victimisation. More research is needed to further elucidate the relationship between mental disorders, treatment, and victimisation. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28857325 TI - A versatile vector for mycobacterial protein production with a functional minimized acetamidase regulon. AB - Recombinant protein expression is a prerequisite for diverse investigations of proteins at the molecular level. For targets from Mycobacterium tuberculosis it is favorable to use M. smegmatis as an expression host, a species from the same genus. In the respective shuttle vectors, target gene expression is controlled by the complex tetra-cistronic acetamidase regulon. As a result, the size of those vectors is large, rendering them of limited use, especially when the target proteins are expressed from multi-cistronic operons. Therefore, in the current work we present a versatile new expression vector in which the acetamidase regulon has been minimized by deleting the two genes amiD and amiS. We assessed the functional properties of the resulting vector pMyCA and compared it with those of the existing vector pMyNT that contains the full-length acetamidase regulon. We analyzed the growth features and protein expression patterns of M. smegmatis cultures transformed with both vectors. In addition, we created mCherry expression constructs to spectroscopically monitor the expression properties of both vectors. Our experiments showed that the minimized vector exhibited several advantages over the pMyNT vector. First, the overall yield of expressed protein is higher due to the higher yield of bacterial mass. Second, the heterologous expression was regulated more tightly, offering an expression tool for diverse target proteins. Third, it is suitable for large multi-protein complexes that are expressed from multi-cistronic operons. Additionally, our results propose a new understanding of the regulation mechanism of the acetamidase regulon with the potential to construct more optimized vectors in the future. PMID- 28857327 TI - Manic episode occurring during investigational treatment with pan-class I phosphoinositide 3-kinase inhibitor in a patient with breast cancer. PMID- 28857328 TI - Different aspects of emotional intelligence of borderline personality disorder. AB - OBJECTIVES: The present study investigated deficiencies in different components of emotional intelligence in borderline personality disorder (BPD). METHOD: The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and the Emotional Quotient Inventory (EQ-i) were used to assess EI dimensions. BPD patients (N = 85; 69 women; M = 33.6 years) were compared with Cluster C personality disorder (PD) patients (N = 39; 23 women; M = 36.6 years) and nonpatients (N = 69; 44 women; M = 35.6 years). RESULTS: Compared to the Cluster C PD patients and the nonpatient group, BPD patients displayed only deficits in their ability to understand emotions as measured with the Mayer-Salovey-Caruso Emotional Intelligence Test. The Emotional Quotient Inventory only revealed deficits in stress management in BPD patients compared to Cluster C PD patients. CONCLUSIONS: Our findings suggest that BPD patients have the ability to regulate emotions effectively, but they subjectively experience deficits in emotion regulation and therefore may not use this ability when they need it. PMID- 28857329 TI - Anesthetic considerations for a novel anterior surgical approach to pediatric scoliosis correction. AB - BACKGROUND: Idiopathic scoliosis is a condition that may require surgical correction. Limitations of previous surgical modalities, however, created the need for novel methods of repair. One such technique, a newer form of anterolateral scoliosis correction, has shown considerable promise, which our center has had substantial experience performing. AIM: In this article, we present the case details of our first 105 patients for the purposes of describing the evolution and details of the anesthetic management and considerations for this procedure. METHODS: A retrospective review of medical records for 105 patients undergoing anterolateral instrumentation procedure for idiopathic scoliosis correction done at a single institution from May 2014 to June 2016 was performed. The details of perioperative management as well as surgical technique were reported for all patients. RESULTS: The mean age for patients was 14.8 years (range 10-18); the mean weight was 49.9 kg (range 25-82). Unilateral procedures were performed on 46.7%, with bilateral and hybrid procedures performed on 50.5% and 4.7%, respectively. The median number of levels corrected was 8 (interquartile range [IQR] 7-9) for unilateral, right 7 (IQR 6-7) and left 5 (IQR 4-5) for bilateral, and 4 (IQR 4-4.5) for hybrids. The average estimated blood loss (EBL) was 310 mL+/-138, with cell salvaged blood transfused in 61% of patients, and allogenic blood transfusion required in only two patients. CONCLUSIONS: The described anesthetic and analgesic management provides a framework for delivering perioperative care for this challenging procedure, which is gaining popularity as a modality for scoliosis correction. PMID- 28857331 TI - Ecological and phylogenetic variability in the spinalis muscle of snakes. AB - Understanding the origin and maintenance of functionally important subordinate traits is a major goal of evolutionary physiologists and ecomorphologists. Within the confines of a limbless body plan, snakes are diverse in terms of body size and ecology, but we know little about the functional traits that underlie this diversity. We used a phylogenetically diverse group of 131 snake species to examine associations between habitat use, sidewinding locomotion and constriction behaviour with the number of body vertebrae spanned by a single segment of the spinalis muscle, with total numbers of body vertebrae used as a covariate in statistical analyses. We compared models with combinations of these predictors to determine which best fit the data among all species and for the advanced snakes only (N = 114). We used both ordinary least-squares models and phylogenetic models in which the residuals were modelled as evolving by the Ornstein-Uhlenbeck process. Snakes with greater numbers of vertebrae tended to have spinalis muscles that spanned more vertebrae. Habitat effects dominated models for analyses of all species and advanced snakes only, with the spinalis length spanning more vertebrae in arboreal species and fewer vertebrae in aquatic and burrowing species. Sidewinding specialists had shorter muscle lengths than nonspecialists. The relationship between prey constriction and spinalis length was less clear. Differences among clades were also strong when considering all species, but not for advanced snakes alone. Overall, these results suggest that muscle morphology may have played a key role in the adaptive radiation of snakes. PMID- 28857330 TI - Increased habenular connectivity in opioid users is associated with an alpha5 subunit nicotinic receptor genetic variant. AB - BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive components of opioid dependence. METHODS: We studied habenular resting state functional connectivity with related brain structures, specifically the striatum. We compared abstinent psychiatric patients who use opioids (N = 51) to psychiatric patients who do not (N = 254) to identify an endophenotype of opioid use that focused on withdrawal avoidance and aversion rather than the more commonly examined craving aspects of relapse. RESULTS: We found that habenula striatal connectivity was stronger in opioid-using patients. Increased habenula striatum connectivity was observed in opioid-using patients with the low risk rs16969968 GG genotype, but not in patients carrying the high risk AG or AA genotypes. CONCLUSIONS: We propose that increased habenula-striatum functional connectivity may be modulated by the nicotinic receptor variant rs16969968 and may lead to increased opioid use. SCIENTIFIC SIGNIFICANCE: Our data uncovered a promising brain target for development of novel anti-addiction therapies and may help the development of personalized therapies against opioid abuse. (Am J Addict 2017;26:751-759). PMID- 28857332 TI - Landscape genomics of Colorado potato beetle provides evidence of polygenic adaptation to insecticides. AB - The ability of insect pests to rapidly and repeatedly adapt to insecticides has long challenged entomologists and evolutionary biologists. Since Crow's seminal paper on insecticide resistance in 1957, new data and insights continue to emerge that are relevant to the old questions about how insecticide resistance evolves: such as whether it is predominantly mono- or polygenic, and evolving from standing vs. de novo genetic variation. Many studies support the monogenic hypothesis, and current management recommendations assume single- or two-locus models. But inferences could be improved by integrating data from a broader sample of pest populations and genomes. Here, we generate evidence relevant to these questions by applying a landscape genomics framework to the study of insecticide resistance in a major agricultural pest, Colorado potato beetle, Leptinotarsa decemlineata (Say). Genome-environment association tests using genomic variation from 16 populations spanning gradients of landscape variables associated with insecticide exposure over time revealed 42 strong candidate insecticide resistance genes, with potentially overlapping roles in multiple resistance mechanisms. Measurements of resistance to a widely used insecticide, imidacloprid, among 47 L. decemlineata populations revealed heterogeneity at a small (2 km) scale and no spatial signature of origin or spread throughout the landscape. Analysis of nucleotide diversity suggested candidate resistance loci have undergone varying degrees of selective sweeps, often maintaining similar levels of nucleotide diversity to neutral loci. This study suggests that many genes are involved in insecticide resistance in L. decemlineata and that resistance likely evolves from both de novo and standing genetic variation. PMID- 28857333 TI - MRI assessment of the postprandial gastrointestinal motility and peptide response in healthy humans. AB - BACKGROUND: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. METHODS: Fifteen healthy volunteers (29.3+/-2.7 years and BMI 20.1+/-1.2 kg m-2 ) underwent baseline and postprandial MRI scans, symptom questionnaires, and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 [GLP-1], Polypeptide YY [PYY], Cholecystokinin [CCK]) at intervals for 270 minutes following a 400 g soup meal (204 kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility, and whole gut transit were measured from the MRI scans. KEY RESULTS: (mean+/-SEM) Small bowel motility index increased from fasting 39+/-3 arbitrary units (a.u.) to a maximum of 87+/-7 a.u. immediately after feeding. PYY increased from fasting 98+/-10 pg mL-1 to 149+/-14 pg mL-1 at 30 minutes and GLP-1 from fasting 15+/-3 MUg mL-1 to 22+/-4 MUg mL-1 . CCK increased from fasting 0.40+/ 0.06 pmol mL-1 to 0.94+/-0.1 pmol mL-1 . Gastric volumes declined with a T1/2 of 46+/-5 minute and the gallbladder contracted from a fasting volume of 19+/-2 mL-1 to 12+/-2 mL-1 . Small bowel water content increased from 39+/-2 mL-1 to 51+/-2 mL-1 postprandial. Fullness VAS score increased from 9+/-5 mm to 41+/-6 mm at 30 minutes postprandial. CONCLUSIONS AND INFERENCES: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response. PMID- 28857334 TI - Preventive effects of an intergenerational program on age-related hippocampal atrophy in older adults: The REPRINTS study. AB - OBJECTIVES: A growing body of literature indicates that social engagements, such as intergenerational programs, are effective strategies to improve a range of cognitive abilities. The present study examined whether the intergenerational program-REPRINTS-prevents age-related hippocampal atrophy. METHODS: After comprehensive baseline assessment, participants were allowed to decide whether to participate in the REPRINTS intervention or in the control group, which required only completion of assessments. REPRINTS participants engaged in group activities that involved reading picture books to children at kindergarten and elementary schools, once every 1 to 2 weeks. A follow-up assessment was conducted after 6 years. Two MRI scans were performed, one immediately after baseline assessment and the other after 6 years. Volumes of the hippocampus, thalamus, and caudate nucleus were derived from automated segmentation. The analysis included 17 REPRINTS and 42 control-group participants. RESULTS: There was no significant difference in any variable of participants' characteristics at baseline between the REPRINTS and control groups. Hippocampal volume significantly declined in the control group but was maintained in the REPRINTS group. No significant differences between groups in thalamus or caudate nucleus volume were observed. Although cognitive function was unaffected by the program, greater decreases in hippocampal volume were significantly correlated with greater decreases in cognitive performance scores. CONCLUSIONS: Our results suggest that the REPRINTS intergenerational program has protective effects on age-related hippocampal atrophy in older adults. These changes precede improvements in cognitive performance, suggesting the validity of the concept of brain plasticity in later life following social engagement. PMID- 28857335 TI - Comparison of a computed tomographic pulmonary trunk to aorta diameter ratio with echocardiographic indices of pulmonary hypertension in dogs. AB - There are limited criteria for the detection of pulmonary hypertension in dogs undergoing computed tomography (CT) for pulmonary disease. This retrospective analytical exploratory study compared a CT pulmonary trunk to aorta ratio with echocardiographic estimates of pulmonary hypertension. Dogs having both a contrast thoracic CT and echocardiogram were selected and maximal pulmonary trunk and descending aorta diameters were measured by two observers on a single transverse CT image. Computed tomographic diameter ratios were compared with the echocardiographic parameters of tricuspid regurgitation gradient, right ventricular acceleration time-to-ejection time ratio, pulmonary insufficiency gradient, and pulmonary artery to aorta diameter. A total of 78 dogs were sampled, with 44 dogs having one or more finding suggestive of pulmonary hypertension. A moderate positive correlation was shown between tricuspid regurgitation gradient and CT pulmonary trunk to aorta ratio (r = 0.61, P-value < 0.0001). Mean CT pulmonary trunk to aorta ratio of dogs with moderate (P = 0.0132) and severe (P < 0.0003) pulmonary hypertension were significantly higher than normal dogs. There was no significant difference in mean CT pulmonary trunk to aorta ratio between normal and mild pulmonary hypertension dogs (P = 0.4244). The intraclass correlation coefficient (0.72) showed good reproducibility of the ratio. Findings indicated that CT pulmonary trunk to aorta ratio is a reproducible and potentially useful method to predict moderate and severe pulmonary hypertension in dogs, but not mild pulmonary hypertension. In dogs undergoing thoracic CT for pulmonary disease, an increased ratio should prompt follow up echocardiography. PMID- 28857336 TI - Aerobic exercise training does not alter vascular structure and function in chronic obstructive pulmonary disease. AB - NEW FINDINGS: What is the central question of this study? Chronic obstructive pulmonary disease (COPD) is associated with endothelial dysfunction, arterial stiffness and systemic inflammation, which are linked to increased cardiovascular disease risk. We asked whether periodized aerobic exercise training could improve vascular structure and function in patients with COPD. What is the main finding and its importance? Eight weeks of periodized aerobic training did not improve endothelial function, arterial stiffness or systemic inflammation in COPD, despite improvements in aerobic capacity, blood pressure and dyspnoea. Short-term training programmes may not be long enough to improve vascular-related cardiovascular risk in COPD. Chronic obstructive pulmonary disease (COPD) has been associated with endothelial dysfunction and arterial stiffening, which are predictive of future cardiovascular events. Although aerobic exercise improves vascular function in healthy individuals and those with chronic disease, it is unknown whether aerobic exercise can positively modify the vasculature in COPD. We examined the effects of 8 weeks of periodized aerobic training on vascular structure and function and inflammation in 24 patients with COPD (age, 69 +/- 7 years; forced expiratory volume in 1 second as a percentage of predicted (FEV1 %pred), 68 +/- 19%) and 20 matched control subjects (age, 64 +/- 5 years; FEV1 %pred, 113 +/- 16%) for comparison. Endothelial function was measured using brachial artery flow-mediated dilatation, whereas central and peripheral pulse wave velocity, carotid artery intima-media thickness, carotid compliance, distensibility and beta-stiffness index were measured using applanation tonometry and ultrasound. Peak aerobic power (VO2 peak ) was measured using an incremental cycling test. Upper and lower body cycling training was performed three times per week for 8 weeks, and designed to optimize vascular adaptation by increasing and sustaining vascular shear stress. Flow-mediated dilatation was not increased in COPD patients (+0.15 +/- 2.27%, P = 0.82) or control subjects (+0.34 +/- 3.20%, P = 0.64) and was not different between groups (P = 0.68). No significant improvements in central pulse wave velocity (COPD, +0.30 +/- 1.79 m s-1 versus control subjects, -0.34 +/- 1.47 m s-1 ) or other markers of vascular structure or function were found within or between groups. The VO2 peak increased significantly in COPD and control subjects, and was greater in control subjects (1.6 +/- 1.4 versus 4.1 +/- 3.7 ml kg min-1 , P = 0.003), while blood pressure and dyspnoea were reduced in COPD patients (P < 0.05). These findings demonstrate that 8 weeks of aerobic training improved cardiorespiratory fitness and blood pressure in COPD but had little effect on other established markers of cardiovascular disease risk. PMID- 28857337 TI - Evidence-based injury prediction data for the water temperature and duration of exposure for clinically relevant deep dermal scald injuries. AB - Deep dermal burn injuries require extensive medical care; however, the water temperatures and durations of exposure that result in a severe scald injury are unknown. This study used a porcine burn model to investigate the time and temperature threshold for clinically relevant deep dermal injuries for both immersion (long duration) and spill/splash (short duration) scald events. Scald wounds were created on the flanks of anaesthetized juvenile large White pigs (27 kg). Acute tissue injury evaluations performed at 1 hour and days 1, 3, and 7 postburn (16 pigs) included: wound examination, biopsies, and laser Doppler imaging. Up to 20 burn combinations were tested including: 50-60 degrees C water for 1-10 minutes (immersion); and 60-90 degrees C water for 5 seconds (spill/splash). Burn conditions demonstrating mid-to-deep dermal damage histologically were followed for 21 days to assess time to reepithelialize (eight pigs). Histologically, depth of damage increased until day 3 postburn. Damage to >=75% of the depth of dermis was associated with burns taking longer than 3 weeks to fully reepithelialize. For spill/splash (5 seconds) scalds, water at >=75 degrees C showed damage to mid-dermis or deeper by day 3; however, only burns from water >=85 degrees C were not reepithelialized by day 21. For immersion scalds of equivalent duration, water at 55 degrees C caused significantly deeper dermal damage than 50 degrees C (p < 0.05) at day 3. Immersion scalds that were not fully reepithelialized by day 21 included 50 degrees C for >10 minutes, 55 degrees C for 5 minutes, 60 degrees C for 60 seconds, and 70 degrees C for > 15 seconds. This research provides valuable evidence-based injury prediction data, which can be used to inform future burn injury prevention guidelines/legislation to reduce the risk of severe scald injuries and support medicolegal opinions for cases where an inflicted mechanism of injury is alleged. PMID- 28857338 TI - Single nucleotide editing without DNA cleavage using CRISPR/Cas9-deaminase in the sea urchin embryo. AB - BACKGROUND: A single base pair mutation in the genome can result in many congenital disorders in humans. The recent gene editing approach using CRISPR/Cas9 has rapidly become a powerful tool to replicate or repair such mutations in the genome. These approaches rely on cleaving DNA, while presenting unexpected risks. RESULTS: In this study, we demonstrate a modified CRISPR/Cas9 system fused to cytosine deaminase (Cas9-DA), which induces a single nucleotide conversion in the genome. Cas9-DA was introduced into sea urchin eggs with sgRNAs targeted for SpAlx1, SpDsh, or SpPks, each of which is critical for skeletogenesis, embryonic axis formation, or pigment formation, respectively. We found that both Cas9 and Cas9-DA edit the genome, and cause predicted phenotypic changes at a similar efficiency. Cas9, however, resulted in significant deletions in the genome centered on the gRNA target sequence, whereas Cas9-DA resulted in single or double nucleotide editing of C to T conversions within the gRNA target sequence. CONCLUSIONS: These results suggest that the Cas9-DA approach may be useful for manipulating gene activity with decreased risks of genomic aberrations. Developmental Dynamics 246:1036-1046, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28857339 TI - Qualitative analyses of lived experience for residents in the Elderly Care Departments at the community health service centres in Southwestern China. AB - With its huge ageing population, China faces an enormous challenge for its elderly support and care. One of the proposed solutions was to diversify the elderly support systems. Towards this goal, setting up the Elderly Care Departments in the community health service centres is one of such new Chinese endeavour. This qualitative study was conducted among the residents enrolled in existing Elderly Care Departments established at the community health service centres in Chongqing, a Southwestern Chinese city, to evaluate the lived experience of the residents and to find strategies for improvement. Eighteen participants were recruited from the residents of the Elderly Care Departments of three community health service centres in the city. Data were collected through semi-structured in-depth individual interviews and were analysed utilising the Colaizzi's phenomenological method. Five main themes were identified: Safety and trust; Satisfaction and relief; Gratitude and mutual understanding; Complaints and helplessness; and Worries and apprehension. We found that set-up of the Elderly Care Departments at the community health service centres appeared to be consistent with the idea of integrated care and in general, the current running mode was able to provide the elderly with effective medical, nursing and other cares. The psychological and cultural services at these departments, however, need to be further enhanced. PMID- 28857340 TI - Associations between reduced telomere length, depressed mood, anhedonia, and irritability in prostate cancer patients: Further evidence for the presence of "male depression"? PMID- 28857341 TI - The multidimensional ionotropic receptors of Drosophila melanogaster. AB - Ionotropic receptors (IRs), which form ion channels, can be categorized into conserved 'antennal IRs', which define the first olfactory receptor family of insects, and species-specific 'divergent IRs', which are expressed in gustatory receptor neurones. These receptors are located primarily in cell bodies and dendrites, and are highly enriched in the tips of the dendritic terminals that convey sensory information to higher brain centres. Antennal IRs play important roles in odour and thermosensation, whereas divergent IRs are involved in other important biological processes such as taste sensation. Some IRs are known to play specific biological roles in the perception of various molecules; however, many of their functions have not yet been defined. Although progress has been made in this field, many functions and mechanisms of these receptors remain unknown. In this review, we provide a comprehensive summary of the current state of knowledge in this field. PMID- 28857342 TI - Relationship between physicians' perceived stigma toward depression and physician referral to psycho-oncology services on an oncology/hematology ward. AB - OBJECTIVE: This study was performed to identify relationships between physicians' perceived stigma toward depression and psycho-oncology service utilization on an oncology/hematology ward. METHODS: The study participants were 235 patients in an oncology/hematology ward and 14 physicians undergoing an internal medicine residency training program in Inha University Hospital (Incheon, South Korea). Patients completed the Patient Health Questionnaire-9 (PHQ-9), and residents completed the Perceived Devaluation-Discrimination scale that evaluates perceived stigma toward depression. A total PHQ-9 score of >=5 was defined as clinically significant depression. Physicians decided on referral on the basis of their opinions and those of their patients. The correlates of physicians' recommendation for referral to psycho-oncology services and real referrals psycho oncology services were examined. RESULTS: Of the 235 patients, 143 had PHQ-9 determined depression, and of these 143 patients, 61 received psycho-oncology services. Physicians recommended that 87 patients consult psycho-oncology services. Multivariate analyses showed that lower physicians' perceived stigma regarding depression was significantly associated with physicians' recommendation for referral, and that real referral to psycho-oncology services was significantly associated with presence of a hematologic malignancy and lower physicians' perceived stigma toward depression. CONCLUSION: Physicians' perceived stigma toward depression was found to be associated with real referral to psycho oncology services and with physician recommendation for referral to psycho oncology services. Further investigations will be needed to examine how to reduce physicians' perceived stigma toward depression. PMID- 28857343 TI - Efficacy of a surfactant-based wound dressing on biofilm control. AB - The aim of this study was to evaluate the efficacy of both a nonantimicrobial and antimicrobial (1% silver sulfadiazine-SSD) surfactant-based wound dressing in the control of Pseudomonas aeruginosa, Enterococcus sp, Staphylococcus epidermidis, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA) biofilms. Anti biofilm efficacy was evaluated in numerous adapted American Standards for Testing and Materials (ASTM) standard biofilm models and other bespoke biofilm models. The ASTM standard models employed included the Minimum biofilm eradication concentration (MBEC) biofilm model (ASTM E2799) and the Centers for Disease Control (CDC) biofilm reactor model (ASTM 2871). Such bespoke biofilm models included the filter biofilm model and the chamberslide biofilm model. Results showed complete kill of microorganisms within a biofilm using the antimicrobial surfactant-based wound dressing. Interestingly, the nonantimicrobial surfactant based dressing could disrupt existing biofilms by causing biofilm detachment. Prior to biofilm detachment, we demonstrated, using confocal laser scanning microscopy (CLSM), the dispersive effect of the nonantimicrobial surfactant-based wound dressing on the biofilm within 10 minutes of treatment. Furthermore, the non-antimicrobial surfactant-based wound dressing caused an increase in microbial flocculation/aggregation, important for microbial concentration. In conclusion, this nonantimicrobial surfactant-based wound dressing leads to the effective detachment and dispersion of in vitro biofilms. The use of surfactant-based wound dressings in a clinical setting may help to disrupt existing biofilm from wound tissue and may increase the action of antimicrobial treatment. PMID- 28857344 TI - Mild N-Alkylation of Amines with Alcohols Catalyzed by the Acetate Ru(OAc)2 (CO)(DiPPF) Complex. AB - The acetate complex Ru(OAc)2 (DiPPF) (2) obtained from Ru(OAc)2 (PPh3 )2 (1) and 1,1'-bis(diisopropylphosphino)ferrocene (DiPPF) reacts cleanly with formaldehyde affording Ru(OAc)2 (CO)(DiPPF) (3) in high yield. The monocarbonyl complex 3 (0.4 2 mol %) efficiently catalyzes the N-alkylation of primary and secondary alkyl and aromatic amines using primary alcohols ROH (R=Et, nPr, nBu, PhCH2 ) under mild reaction conditions (30-100 degrees C) with an alcohol/amine molar ratio of 10-100. Formation of the monohydride RuH(OAc)(CO)(DiPPF) (4) has been observed by reaction of 3 with iPrOH in the presence of NEt3 at RT through an equilibrium reaction. PMID- 28857345 TI - Basic overview of method validation in the clinical virology laboratory. AB - Diagnostic virology laboratories are an essential part of the health system and are often relied upon to provide information to clinicians that will inform clinical decision making. It is therefore imperative that diagnostic results produced in the laboratory are reliable. One way of ensuring quality results is by ensuring that all tests are either validated (for tests developed in-house) or verified (for commercial assays that are FDA-approved or CE-labeled). In the diagnostic virology laboratory, these processes can be complex as both qualitative and quantitative measurements for serological and molecular tests are routinely offered. While there are numerous guidelines governing quality assurance in the virology laboratory, all accrediting agencies would insist on tests being validated or verified prior to implementation without providing explicit guidance to the process. As there is no universal guideline on the optimal way to perform validation/verification experiments, this review will provide a basic overview of method validation/verification, specific for clinical virology laboratories, and includes explanation of statistical analysis and acceptance/rejection criteria. PMID- 28857346 TI - ZIC2 promotes viability and invasion of human osteosarcoma cells by suppressing SHIP2 expression and activating PI3K/AKT pathways. AB - Osteosarcoma is a malignant tumor of the skeletal system. The zinc finger transcription factor ZIC2 has been reported to be highly expressed in human cancers. The present study evaluated the effects of ZIC2 and the possible underlying mechanisms in the human osteosarcoma cells. The expression levels of ZIC2 in human fetal osteoblastic cell line (hFOB1.19), osteosarcoma cell lines (U 2OS, SaoS2, and MG63), normal bone tissue, and osteosarcoma tumor were analyzed by Western blot, and real-time quantitative RT-PCR (qRT-PCR). Osteosarcoma cells with either overexpressed ZIC2 or suppressed ZIC2 were analyzed to determine cell viability, colony formation, and cell invasion. The expressions of SHIP2 and PI3K/AKT signal pathway-related proteins were analyzed by Western blot and qRT PCR. We first showed that ZIC2 is highly expressed in osteosarcoma cells and tissues. Then we demonstrated that overexpression of ZIC2 promoted viability, migration, and invasion of osteosarcoma cells, whereas suppression of ZIC2 showed opposite effects. Furthermore, SHIP2 expression was negatively regulated by ZIC2. Importantly, ZIC2 overexpression activated the PI3K/AKT signal pathway; however, overexpressed SHIP2 inhibited these effects. Lastly, we showed that activation of the PI3K/AKT signal pathway is essential for the effects of ZIC2 on osteosarcoma cells, as the effects of ZIC2 on the osteosarcoma cells were reversed by a PI3K/AKT inhibitor. Overall, ZIC2 is highly expressed in osteosarcoma cells and tissues, and its overexpression promotes viability, invasion of osteosarcoma cells via SHIP2 suppression, and PI3K/AKT activation. Thus, ZIC2 can be considered as a novel drug target for osteosarcoma management. PMID- 28857347 TI - Improving functional outcome in bipolar disorder: A pilot study on metacognitive training. AB - BACKGROUND: Effective group psychological interventions in bipolar disorder are rare. In this study, we present "metacognitive training (MCT) for bipolar disorder"-an adaption of a group intervention that has proven effective in other severe psychiatric disorders. MCT is a structured, interactive approach that addresses cognitive biases, social cognition, and self-esteem. In this pilot study, we investigated psychosocial functioning as primary outcome measure, as well as the feasibility of MCT and its acceptance among bipolar patients. METHODS: Thirty-four outpatients with bipolar disorder were recruited. Inclusion criteria were euthymia and psychosocial functioning with a score >11 assessed by the Functional Assessment Short Test. The subjects received eight weekly MCT sessions. Before and after the intervention, psychosocial functioning, quality of life (QoL), and patient views were assessed. RESULTS: Patients improved significantly in global psychosocial functioning, with a large effect size from baseline to post-treatment. Over the intervention period, patient QoL improved significantly in terms of their physical health, however not for other QoL subdomains. Treatment adherence was 80%, and patients' appraisal of the training was positive. LIMITATIONS: As this study lacks a control group, it is not possible to ascertain whether the positive treatment effects are attributable to MCT. Additionally, it is unclear whether gains in psychosocial functioning would have been maintained long term. CONCLUSIONS: This pilot trial conclusively shows that MCT is feasible and provides preliminary evidence for both the acceptance and efficacy of MCT. Further studies with larger samples and control condition will be necessary to build on these findings. PMID- 28857348 TI - Critical Appraisal of Emergency Medicine Educational Research: The Best Publications of 2015. AB - OBJECTIVE: The objectives were to critically appraise the medical education research literature of 2015 and review the highest-quality quantitative and qualitative examples. METHODS: A total of 434 emergency medicine (EM)-related articles were discovered upon a search of ERIC, PsychINFO, PubMED, and SCOPUS. These were both quantitative and qualitative in nature. All were screened by two of the authors using previously published exclusion criteria, and the remaining were appraised by all authors using a previously published scoring system. The highest scoring articles were then reviewed. RESULTS: Sixty-one manuscripts were scored, and 10 quantitative and two qualitative papers were the highest scoring and are reviewed and summarized in this article. CONCLUSIONS: This installment in this critical appraisal series reviews 12 of the highest-quality EM-related medical education research manuscripts published in 2015. PMID- 28857349 TI - Factors that influence influenza vaccination rates among the elderly: nurses' perspectives. AB - AIMS: To explore which factors nurses perceive to help and hinder influenza vaccination rates among the elderly. BACKGROUND: Influenza-related illnesses and deaths have disproportionately high prevalence among the elderly. Vaccination is an effective tool to prevent complications. METHODS: Semistructured interviews were conducted with nurses focusing on barriers, facilitators and health care providers' roles in influencing patients to be vaccinated. Interviews were recorded, transcribed and thematically analysed. RESULTS: Nurses identified that the prevalent barriers were fear of the vaccine's side effects, feelings of good health and technical considerations. Facilitators included ease of access and encouragement from health providers, media and social networks. The health care team was influential in raising vaccination rates through direct recommendation, providing concrete information or leading by example. CONCLUSIONS: The health care team can influence patients to vaccinate. Investments in training nurses in the knowledge and skills needed to educate patients, and providing nurses with the necessary resources to engage patients in these discussions may be beneficial. Nurse managers can be instrumental in enhancing nurses' roles and actions to increase influenza vaccination rates among the elderly. IMPLICATIONS FOR NURSING MANAGEMENT: It is essential to reinforce the nurses' role in promoting vaccination among seniors. Given that nurses are the largest number of health professionals, their potential outreach to large numbers of people is strong. PMID- 28857350 TI - Analysing phase progression in Susan's case. AB - This study adds a phase-by-phase perspective to the case of Susan, with the aim of better understanding the processes of change in this therapeutic case. A team of 3 raters integrated the sequential phases of the Paradigmatic Complementarity Metamodel with a moment-by-moment tracking method-the Developmental Analysis of Psychotherapy Process method-to analyse this therapeutic process and clarify what happened throughout that may explain phase gains and how the therapist facilitated them. The results suggest that Susan evolved in accordance with the sequence of phases proposed by the Paradigmatic Complementarity Metamodel. We illustrate and explain this with therapeutic interactions representative of Susan's development within the evolving therapeutic process. This case study is the third of a series intended to contribute towards the optimization of clinical decisions in therapeutic processes by identifying markers of phase progression and assessing the value of the therapeutic interventions offered. PMID- 28857351 TI - MAPK kinase 10.2 promotes disease resistance and drought tolerance by activating different MAPKs in rice. AB - Mitogen-activated protein kinase (MAPK) cascades, with each cascade consisting of a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK) and a MAPK, have important roles in different biological processes. However, the signal transduction in rice MAPK cascades remains to be elucidated. We show that the structural non-canonical MAPKK, MPKK10.2, enhances rice resistance to Xanthomonas oryzae pv. oryzicola (Xoc), which causes bacterial streak disease, and increases rice tolerance to drought stress by phosphorylating and activating two MAPKs, MPK6 and MPK3, respectively. MPKK10.2-overexpressing (oe) plants showed enhanced resistance to both Xoc and drought, whereas MPKK10.2-RNA interference (RNAi) plants had increased sensitivity to both Xoc and drought. MPKK10.2 physically interacted with MPK6 and MPK3, and phosphorylated the two MAPKs in vivo. Transcriptionally modulating MPKK10.2 influenced MPK6 phosphorylation during rice-Xoc interaction, and MPKK10.2-oe/MPK6-RNAi double mutants showed increased sensitivity to Xoc. MPKK10.2-oe/MPK3-RNAi double mutants showed survival rates similar to those of control plants, although the survival rates of MPKK10.2 transgenic plants changed after drought stress. These results suggest that MPKK10.2 is a node involved in rice response to biotic and abiotic responses by functioning in the cross-point of two MAPK cascades leading to Xoc resistance and drought tolerance. PMID- 28857352 TI - Hip fracture risk and safety with alendronate treatment in the oldest-old. AB - BACKGROUND: There is high evidence for secondary prevention of fractures, including hip fracture, with alendronate treatment, but alendronate's efficacy to prevent hip fractures in the oldest-old (>=80 years old), the population with the highest fracture risk, has not been studied. OBJECTIVE: To investigate whether alendronate treatment amongst the oldest-old with prior fracture was related to decreased hip fracture rate and sustained safety. METHODS: Using a national database of men and women undergoing a fall risk assessment at a Swedish healthcare facility, we identified 90 795 patients who were 80 years or older and had a prior fracture. Propensity score matching (four to one) was then used to identify 7844 controls to 1961 alendronate-treated patients. The risk of incident hip fracture was investigated with Cox models and the interaction between age and treatment was investigated using an interaction term. RESULTS: The case and control groups were well balanced in regard to age, sex, anthropometrics and comorbidity. Alendronate treatment was associated with a decreased risk of hip fracture in crude (hazard ratio (HR) 0.62 (0.49-0.79), P < 0.001) and multivariable models (HR 0.66 (0.51-0.86), P < 0.01). Alendronate was related to reduced mortality risk (HR 0.88 (0.82-0.95) but increased risk of mild upper gastrointestinal symptoms (UGI) (HR 1.58 (1.12-2.24). The alendronate association did not change with age for hip fractures or mild UGI. CONCLUSION: In old patients with prior fracture, alendronate treatment reduces the risk of hip fracture with sustained safety, indicating that this treatment should be considered in these high-risk patients. PMID- 28857353 TI - Crystalline phases involved in the hydration of calcium silicate-based cements: Semi-quantitative Rietveld X-ray diffraction analysis. AB - Chemical comparisons of powder and hydrated forms of calcium silicate cements (CSCs) and calculation of alterations in tricalcium silicate (Ca3 SiO5 ) calcium hydroxide (Ca(OH)2 ) are essential for understanding their hydration processes. This study aimed to evaluate and compare these changes in ProRoot MTA, Biodentine and CEM cement. Powder and hydrated forms of tooth coloured ProRoot MTA, Biodentine and CEM cement were subjected to X-ray diffraction (XRD) analysis with Rietveld refinement to semi-quantitatively identify and quantify the main phases involved in their hydration process. Data were reported descriptively. Reduction in Ca3 SiO5 and formation of Ca(OH)2 were seen after the hydration of ProRoot MTA and Biodentine; however, in the case of CEM cement, no reduction of Ca3 SiO5 and no formation of Ca(OH)2 were detected. The highest percentages of amorphous phases were seen in Biodentine samples. Ettringite was detected in the hydrated forms of ProRoot MTA and CEM cement but not in Biodentine. PMID- 28857354 TI - Authorship in paediatric research conducted in low- and middle-income countries: parity or parasitism? AB - OBJECTIVES: Interest in global health has increased greatly in the past two decades. Concomitantly, the number and complexity of research partnerships between high-income (HIC) and low- and middle-income countries (LMICs) has grown. We aimed to determine whether there is authorship parity (equitable representation and author order) or parasitism (no authors from study countries) in paediatric research conducted in LMICs. METHODS: We reviewed all articles published from 2006 to 2015 in the four paediatric journals with the highest Eigenfactor scores. We limited our review to articles from LMICs and abstracted information on author affiliation and order, funding source and study design. We calculated Student's t-tests and chi-square using Fisher's exact test with Monte Carlo estimates. RESULTS: There were 24 169 articles published during the study period, and 1243 met inclusion criteria. Of those, 95.9% (n = 1,192) included at least one author affiliated with a LMIC. Among multicountry studies (n = 165), 40.4% did not include authors from every LMIC involved. Of the 9876 authors, most were affiliated with institutions from upper-middle-income countries (41.7%) and HICs (32.7%), with far fewer affiliated with lower middle-income (15.5%) and low income countries (5.4%) (P < 0.001). In articles from low-income countries, first and last authors from HICs were more common than authors with low-income country affiliations (P < 0.001). CONCLUSIONS: Authorship parasitism was rare overall but common in multicountry studies. In studies conducted in low-income countries, HIC authors more commonly occupied first and last author positions than authors from the study countries. Where LMIC authors make substantial contributions, researchers should strive for authorship parity. PMID- 28857355 TI - Galectin-1 from conditioned medium of three-dimensional culture of adipose derived stem cells accelerates migration and proliferation of human keratinocytes and fibroblasts. AB - Keratinocytes and fibroblasts cells play important roles in the skin-wound healing process and are the cell types activated by trauma. Activated cells participate in epithelialization, granulation, scar tissue formation, wound remodeling, and angiogenesis via a series of cellular activities including migration and proliferation. Previous studies reported that the conditioned medium (CM) of adipose-derived stem cells (ADSCs) stimulated the migration and proliferation of cell types involved in the skin wound healing process; however, these studies only show ADSC-CM effects that were obtained using 2-dimensional (2D) culture. Recently, 3-dimensional (3D) culture has been considered as a more physiologically appropriate system than 2D culture for ADSC cultures; therefore, ADSC-CM was collected from 3D culture (ADSC-CM-3D) and compared with ADSC-CM from 2D culture (ADSC-CM-2D) to investigate the effects on the migration and proliferation of human keratinocytes (HaCaTs) and fibroblasts. The migrations of the HaCaT cells and fibroblasts were significantly higher with ADSC-CM-3D compared with the 2D culture; similarly, the proliferation of HaCaT cells was also highly stimulated by ADSC-CM-3D. Proteomic analyses of the ADSC-CM revealed that collagens and actins were highly expressed in the 3D-culture system. Chitinase 3-like 1 (CHI3L1), tissue inhibitor of metalloproteinases (TIMP), and galectin-1 were specifically expressed only in ADSC-CM-3D. Especially, through antibody neutralization, galectin-1 in ADSC-CM-3D was found to be an important factor for the migration of human keratinocytes. Therefore, these results suggest that ADSC-CM-3D was more effective in the wound healing than ADSC-CM-2D, and galectin-1 in ADSC-CM-3D was could be a promising option for skin-wound healing. Furthermore, the differential expressions of several ADSC-CM proteins between the 2D- and 3D-culture systems may be used as basic information for the development of efficient wound-healing strategies. PMID- 28857356 TI - Different predictivity of fluid responsiveness by pulse pressure variation in children after surgical repair of ventricular septal defect or tetralogy of Fallot. AB - BACKGROUND: Pulse pressure variation derived from the varied pulse contour method is based on heart-lung interaction during mechanical ventilation. It has been shown that pulse pressure variation is predictive of fluid responsiveness in children undergoing surgical repair of ventricular septal defect. Right ventricle compliance and pulmonary vascular capacitance in children with tetralogy of Fallot are underdeveloped as compared to those in ventricular septal defect. We hypothesized that the difference in the right ventricle-pulmonary circulation in the two groups of children would affect the heart-lung interaction and therefore pulse pressure variation predictivity of fluid responsiveness following cardiac surgery. METHODS: Infants undergoing complete repair of ventricular septal defect (n=38, 1.05+/-0.75 years) and tetralogy of Fallot (n=36, 1.15+/-0.68 years) clinically presenting with low cardiac output were enrolled. Fluid infusion with 5% albumin or fresh frozen plasma was administered. Pulse pressure variation was recorded using pressure recording analytical method along with cardiac index before and after fluid infusion. Patients were considered as responders to fluid loading when cardiac index increased >=15%. Receiver operating characteristic curves analysis was used to assess the accuracy and cutoffs of pulse pressure variation to predict fluid responsiveness. RESULTS: The pulse pressure variation values before and after fluid infusion were lower in tetralogy of Fallot children than those in ventricular septal defect children (15.2+/-4.4% vs 19.3+/-4.4%, P<.001; 11.6+/-3.8 vs 15.4+/-4.3%, P<.001, respectively). In ventricular septal defect children, 27 were responders and 11 nonresponders. Receiver operating characteristic curve area was 0.89 (95% confidence interval, 0.77-1.01) and cutoff value 17.4% with a sensitivity of 0.89 and a specificity of 0.91. In tetralogy of Fallot children, 26 were responders and 10 were nonresponders. Receiver operating characteristic curve area was 0.79 (95% CI, 0.64-0.94) and cutoff value 13.4% with a sensitivity of 0.81 and a specificity of 0.80. CONCLUSION: Pulse pressure variation is predictive of fluid responsiveness in ventricular septal defect and tetralogy of Fallot patients following cardiac surgery. PMID- 28857357 TI - Aspergillus nidulans BapH is a RAB11 effector that connects membranes in the Spitzenkorper with basal autophagy. AB - Using affinity chromatography we identified the Aspergillus nidulans F-BAR-and-PH domain-containing protein BapH as a RabERAB11 effector. BapH localizes to the Spitzenkorper (SPK) in an F-actin- and Sec7-dependent manner, becoming cytosolic after inactivation of Trs120 in TRAPPII, the oligomeric GEF for RabERAB11 . Therefore, RabERAB11 contributes to the recruitment of BapH to secretory vesicles in vivo. BapH has a close homologue, SlmA, which is related to yeast Slm1p/Slm2p, localizes to eisosomes and does not bind RabERAB11 . bapHDelta, slmADelta and double bapHDelta slmADelta mutations do not affect growth, although slmADelta results in myriocin hypersensitivity. Both the PH and the F-BAR domain in BapH are necessary to recruit the protein to membranes, whereas its C-terminal moiety negatively regulates localization to the SPK. Strong overexpression of full length BapH or of BapH lacking the C-terminal moiety impairs growth. The tandemly duplicated PHBapH domain is recruited to the plasma membrane in a manner dependent on critical Lys residues in its 'noncanonical' lipid binding pocket, suggesting that it binds to biological membranes containing PtdIns(4,5)P2 . Ablation of BapH, or deletion of the PH or BAR domains critical for the SPK localization increases autophagy under nitrogen-replete conditions. Therefore, BapH localizing to SPK vesicles influences basal levels of autophagy. PMID- 28857358 TI - Hurthle cell carcinoma in an unattached thyroid lobe: A diagnostic challenge. PMID- 28857359 TI - Detection of tumor spread through airspaces by airway secretion cytology from resected lung cancer specimens. AB - It currently remains unclear whether tumor spread through airspaces (STAS) actually exist in vivo or are an artifact. The morphologies of STAS and tumor cell clusters in airway secretions collected from the segmental or lobar bronchus of resected lung adenocarcinomas and squamous cell carcinomas were compared among 48 patients. The EGFR status of tumor cell clusters in airway secretions was also compared with that of the main tumor in EGFR mutant adenocarcinomas. Tumor cell clusters were observed in the airway secretion cytology of ten patients (20.8%), and eight patients were adenocarcinoma (20.0% of adenocarcinoma). The morphology of STAS closely resembled that of tumor cell clusters detected in airway secretion cytology. The positive rates of airway secretion cytology were 83.3%, 100%, and 50% in papillary adenocarcinoma, micropapillary adenocarcinoma, and invasive mucinous adenocarcinoma, respectively. Among three EGFR mutant adenocarcinomas, the EGFR mutation subtypes of the main tumors in FFPE sections and tumor cell clusters in airway secretions were identical. These indicate that STAS may be detected in the airway secretion cytology. STAS is common in papillary or micropapillary adenocarcinoma and may spread as far as the segmental or lobar bronchus at the time of surgery. PMID- 28857360 TI - Type 1 diabetes incidence and prevalence trends in a cohort of Canadian children and youth. AB - BACKGROUND AND OBJECTIVE: Incidence rates of type 1 diabetes have long been on the rise across the globe, however, there is emerging evidence that the rate of rise may be slowing. The objective of this study was to describe trends in the incidence and prevalence of type 1 diabetes in a sample of Canadian children and youth. METHODS: Cases were extracted using linked administrative datasets and a validated diabetes case-finding definition. Incidence and prevalence trends were analyzed using the JoinPoint regression analysis program. RESULTS: A small increase in the incidence of type 1 diabetes was observed over the 11-year period from 2002-2003 to 2012-2013. Total incident cases per year ranged from 201 (2005 2006) to 250 (2007-2008). Total prevalent cases per year ranged from 1790 (2002 2003) to 2264 (2012-2013). Incidence was highest among children aged 5 to 14 years, and lowest in the youngest (1-4 years) and oldest (15-19 years) age brackets. The most significant increase in incidence was in children aged 10 to 14 years. Age-standardized prevalence increased significantly throughout the study period. CONCLUSION: These results are similar to data from the United States but differ from European data with respect to the annual percent change for incidence as well as age-specific incidence trends. In keeping with the low mortality rates associated with type 1 diabetes, the prevalence continues to rise. PMID- 28857363 TI - Impact of transmission cycles and vector competence on global expansion and emergence of arboviruses. AB - Arboviruses are transmitted between arthropod vectors and vertebrate host. Arboviral infection in mosquitoes is initiated when a mosquito feeds on a viremic host. Following ingestion of a viremic blood meal by mosquitoes, virus enters midgut along with the blood, infects and replicates in midgut epithelial cells, and then escapes to the hemocoel, from where it disseminates to various secondary organs including salivary glands. Subsequently, when mosquito bites another host, a new transmission cycle is initiated. The midgut and salivary glands act as anatomical barriers to virus infection and escape. These complex interactions between the virus and vector dictate the vector competence. Thus, vector competence reflects the success in overcoming different barriers within the vector. Along with these, other intrinsic factors like midgut microbiota and immune responses, extrinsic factors like temperature and humidity, and genetic factors like vector genotype and viral genotype have been discussed in this review. Recent advancement on novel molecular tools to study vector competence is also included. Different modes of arboviral transmission like horizontal, vertical, and venereal and how these play role in sustenance and emergence of arboviruses in nature are also discussed. These factors can be exploited to reduce the susceptibility of vectors for the viruses, so as to control arboviral diseases to certain extent. PMID- 28857361 TI - Modulation of VIPergic phenotype of enteric neurons by colonic biopsy supernatants from patients with inflammatory bowel diseases: Involvement of IL-6 in Crohn's disease. AB - BACKGROUND: Neuroplastic changes in the enteric nervous system (ENS) observed during IBD might participate in physiopathological processes. Vasoactive intestinal polypeptide has been shown to be involved in intestinal inflammation and barrier functions. We aimed to investigate the modulation of VIP expression in colonic biopsies of IBD patient, the ability of soluble factors from biopsies to reproduce in vitro these modulations and identify soluble factors responsible. METHODS: VIP and cytokines mRNA expressions were assessed in colonic biopsies of healthy subjects (HS) and IBD patients from inflamed (I) and non-inflamed areas (NI). Supernatants (SUP) of biopsies were applied to primary culture of ENS and VIP and cytokines mRNA expressions were assessed. The role of cytokines in SUP induced changes in VIP expression was evaluated. KEY RESULTS: VIP mRNA expression was lower in biopsies of patients with Crohn's disease (CD) than Ulcerative Colitis (UC) but unchanged as compared to HS. VIP mRNA and protein expression were lower in primary culture of ENS incubated with SUP-CD than with SUP-UC. Furthermore, in CD but not UC, SUP-I reduced VIP expression in the ENS as compared to SUP-NI. Next, IL-6 but not IL-5, IL-10, IL-17, IFN-gamma or TNF-alpha reduced VIP expression in the ENS. Finally, in CD, SUP-I incubated with anti-IL-6 antibody increased VIP expression as compared to SUP-I alone. CONCLUSIONS & INFERENCES: Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL-6 was identified as a putative soluble factor responsible in part for changes in VIP expression in CD. PMID- 28857362 TI - Diagnostic performance of endobronchial ultrasound-guided mediastinal lymph node sampling in early stage non-small cell lung cancer: A prospective study. AB - BACKGROUND AND OBJECTIVE: Standard nodal staging of lung cancer consists of positron emission tomography/computed tomography (PET/CT), followed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) if PET/CT shows mediastinal lymphadenopathy. Sensitivity of EBUS-TBNA in patients with N0/N1 disease by PET/CT is unclear and largely based on retrospective studies. We assessed the sensitivity of EBUS-TBNA in this setting. METHODS: We enrolled patients with proven or suspected lung cancer staged as N0/N1 by PET/CT and without metastatic disease (M0), who underwent staging EBUS-TBNA. Primary outcome was sensitivity of EBUS-TBNA compared with a composite reference standard of surgical stage or EBUS-TBNA stage if EBUS demonstrated N2/N3 disease. RESULTS: Seventy-five patients were included in the analysis. Mean tumour size was 3.52 cm (+/-1.63). Fifteen of 75 patients (20%) had N2 disease. EBUS-TBNA identified six while nine were only identified at surgery. Sensitivity of EBUS-TBNA for N2 disease was 40% (95% CI: 16.3-67.7%). CONCLUSION: A significant proportion of patients with N0/N1 disease by PET/CT had N2 disease (20%) and EBUS-TBNA identified a substantial fraction of these patients, thus improving diagnostic accuracy compared with PET/CT alone. Sensitivity of EBUS-TBNA however appears lower compared with historical data from patients with larger volume mediastinal disease. Therefore, strategies to improve EBUS-TBNA accuracy in this population should be further explored. PMID- 28857365 TI - Functional hemodynamic testing in pregnancy: recommendations of the International Working Group on Maternal Hemodynamics. AB - In the general population, functional hemodynamic testing, such as that during submaximal aerobic exercise and isometric handgrip, and the cold pressor test, has long been utilized to unmask abnormalities in cardiovascular function. During pregnancy, functional hemodynamic testing places additional demands on an already stressed maternal cardiovascular system. Dysfunctional responses to such tests in early pregnancy may predict the development of hypertensive disorders that develop later in gestation. For each of the above functional hemodynamic tests, these recommendations provide a description of the test, test protocol and equipment required, and an overview of the current understanding of clinical application during pregnancy. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28857366 TI - How do women's partners view perinatal mental health services? A qualitative meta synthesis. AB - OBJECTIVES: Perinatal mental health difficulties are prevalent among women and can adversely affect their partners too. There is also increasing recognition that a woman's partner can play a vital role in relation to her perinatal mental health and should be supported and involved in decisions about her care. Yet it is unclear how services are experienced by the partners of women with perinatal mental health difficulties. This study aimed to synthesize qualitative evidence of partners' views of perinatal mental health care. METHODS: A systematic search of 5 electronic databases identified 20 studies that met the inclusion criteria. The findings of these studies were synthesized using an approach based on meta ethnography. RESULTS: Six themes were identified, namely, the marginalization and neglect of women's partners, an unmet need for information, partners' ambivalence about involvement and support, practical barriers to involvement, views about support for women's partners, and the impact on partners of the care women received. CONCLUSIONS: Given the importance of women's partners in relation to perinatal mental health as well as to women's engagement with support and treatment outcomes, greater consideration should be given to their needs to ensure they feel well informed and involved in perinatal mental health care, rather than marginalized. However, professionals also need to challenge the barriers to involvement and support that women's partners face and consider the ways in which services may reinforce these barriers. PMID- 28857364 TI - Glycated hemoglobin: A powerful tool not used enough in primary care. AB - BACKGROUND: Glycated haemoglobin (HbA1c) is one of the most useful and relevant laboratory tests currently available. The aim of the actual research was to study the variability and appropriateness in the request of HbA1c in primary care, and differences between regions, to assess if there would be an opportunity to improve the request. METHODS: A cross-sectional study was conducted enrolling clinical Spanish laboratories. The number of HbA1c requested in 2014 by all general practitioners was reported by each participant. Test-utilization rate was expressed as tests per 1000 inhabitants. The index of variability was calculated, as the top decile divided by the bottom decile. HbA1c per 1000 inhabitants was compared between the different regions. To investigate whether HbA1c was appropriately requested to manage patients with diabetes, the real request was compared to the theoretically ideal number, according to prevalence of known diabetes mellitus in Spain and guideline recommendations. RESULTS: A total of 110 laboratories participated in the study, corresponding to a catchment area of 27 798 262 inhabitants (59.8% of the Spanish population) from 15 different autonomous communities (AACCs). 2 655 547 HbA1c were requested, a median of 93.9 (interquartile range (IQR): 33.4) per 1000 inhabitants. The variability index was 1.97. The HbA1c/1000 inhabitants was significantly different among the AACCs, ranging from 73.4 to 126.3. A total of 4 336 529 additional HbA1c would have been necessary to manage patients with diabetes according to guidelines, and 3 861 769 for diagnosis in asymptomatic patients. CONCLUSIONS: There was a high variability and significant differences between Spanish AACCs. Also a significant under request of HbA1c was observed in Primary Care in Spain. PMID- 28857367 TI - Circular dichroism spectroscopy and DFT calculations in determining absolute configuration and E/Z isomers of conjugated oximes. AB - The primary purpose of this work was to demonstrate the suitability of circular dichroism (CD) spectroscopy in stereochemical studies of alpha,beta-unsaturated oximes, with particular emphasis on determination of E and Z geometry of the oxime double bond. As models for this study, O-phenyl and O-triphenylmethyl (trityl) oximes of 4-hydroxy-2-methylcyclopent-2-en-1-one were selected. These model compounds differ in both absolute configuration at C4 carbon atom and E-Z configuration of the oxime double bond. The basic dichroic technique applied was electronic circular dichroism (ECD) assisted by quantum-chemical calculations and vibrational circular dichroism (VCD) for selected cases. Such an approach enabled effective implementation of both goals. Thus, we were able to associate the signs of Cotton effects in the range of 190-240 nm with the absolute configuration at C4 and within 240-300 nm with the E- or Z-geometry of the oxime double bond. Within this work, optical activity of the protecting trityl group was also studied towards formation of the propeller-shaped conformations by using the same combined CD/DFT methodology. As shown, the helical structure of the trityl group has a considerable influence on the ECD spectra. However, the MPM and PMP conformers of the trityl group are in fact almost equally populated in the conformational equilibrium, making it impossible to distinguish them. On the other hand, rotamers of the hydroxyl group at C4 show a decisive impact on the VCD spectra in both phenoxy and trityl oximes. PMID- 28857368 TI - Management of severe factor XI deficiency in cardiac surgery: A case report and review of the literature. PMID- 28857370 TI - Refining the role of endobronchial ultrasound transbronchial needle aspiration in lung cancer staging. PMID- 28857369 TI - Direct analysis of volatile organic compounds in foods by headspace extraction atmospheric pressure chemical ionisation mass spectrometry. AB - RATIONALE: The rapid screening of volatile organic compounds (VOCs) by direct analysis has potential applications in the areas of food and flavour science. Currently, the technique of choice for VOC analysis is gas chromatography/mass spectrometry (GC/MS). However, the long chromatographic run times and elaborate sample preparation associated with this technique have led a movement towards direct analysis techniques, such as selected ion flow tube mass spectrometry (SIFT-MS), proton transfer reaction mass spectrometry (PTR-MS) and electronic noses. The work presented here describes the design and construction of a Venturi jet-pump-based modification for a compact mass spectrometer which enables the direct introduction of volatiles for qualitative and quantitative analysis. METHODS: Volatile organic compounds were extracted from the headspace of heated vials into the atmospheric pressure chemical ionization source of a quadrupole mass spectrometer using a Venturi pump. Samples were analysed directly with no prior sample preparation. Principal component analysis (PCA) was used to differentiate between different classes of samples. RESULTS: The interface is shown to be able to routinely detect problem analytes such as fatty acids and biogenic amines without the requirement of a derivatisation step, and is shown to be able to discriminate between four different varieties of cheese with good intra and inter-day reproducibility using an unsupervised PCA model. Quantitative analysis is demonstrated using indole standards with limits of detection and quantification of 0.395 MUg/mL and 1.316 MUg/mL, respectively. CONCLUSIONS: The described methodology can routinely detect highly reactive analytes such as volatile fatty acids and diamines without the need for a derivatisation step or lengthy chromatographic separations. The capability of the system was demonstrated by discriminating between different varieties of cheese and monitoring the spoilage of meats. PMID- 28857371 TI - Reply to "Photoredox Catalysis: The Need to Elucidate the Photochemical Mechanism". PMID- 28857372 TI - Flexible Viologen-Based Porous Framework Showing X-ray Induced Photochromism with Single-Crystal-to-Single-Crystal Transformation. AB - A viologen-based Borromean entangled porous framework was found to be sensitive to both CuKalpha and MoKalpha X-ray sources, showing rapid photochromic response and recovery within one minute. The X-ray-induced photochromic process is accompanied by a reversible single-crystal-to-single-crystal (SC-SC) structural transformation, an unprecedented phenomenon for X-ray sensitive materials. The complex can be further processed into portable thin films for detecting the dose of the X-ray exposure. Moreover, the photochromism can occur over a broad temperature range of 100-333 K, both in the form of single crystals and thin films, making it a potential candidate for practical indoor and outdoor applications. PMID- 28857374 TI - Histology with immunohistochemistry of the fistula region in female anorectal malformation: Can it be used for neo-anus reconstruction? AB - AIM: Female anorectal malformation is characterised by communication to the exterior by a fistula. There are conflicting reports of the presence of normal anus in the fistula region. This study was undertaken to assess the histopathology and immunohistochemical correlation of the terminal portion of the fistula in female patients and suitability of fistula incorporation in the reconstruction of the neo-anus. METHODS: This prospective study included 13 patients of female anorectal malformation. Of these, seven had a vestibular fistula (VF), and the rest had an anterior ectopic anus (AEA). Histopathology of the fistula region was undertaken, along with immunohistochemistry. Various findings were evaluated. RESULTS: Of seven VF patients, four showed atrophic or disrupted internal sphincter smooth muscle, whereas the remaining three showed hypertropic internal sphincteric smooth muscle. Six patients showed hypertrophic nerve bundle. Five VF patients showed subepithelial fibrosis, and none of them showed ganglion cells. Of six patients of AEA, internal sphincteric smooth muscle was normal in five. It was hypertrophic in one patient. Transitional epithelium was present in four patients. All patients showed hypertrophic nerve bundle and aganglionosis. Subepithelial fibrosis was observed in six patients. CONCLUSION: The fistula region in VF and AEA patients appears to be an abnormal structure. Rather than preservation of the terminal fistulous region, resection followed by anoplasty may be a viable option. PMID- 28857373 TI - Effect of direct cold atmospheric plasma (diCAP) on microcirculation of intact skin in a controlled mechanical environment. AB - OBJECTIVE: The microcirculatory response of intact human skin to exposure with diCAP for different durations with a focus on the effect of implied mechanical pressure during plasma treatment was investigated. METHODS: Local relative hemoglobin, blood flow velocity, tissue oxygen saturation, and blood flow were monitored noninvasively for up to 1 hour in 1-2 mm depth by optical techniques, as well as temperature, pH values, and moisture before and after skin stimulation. The experimental protocol (N = 10) was set up to differentiate between pressure- and plasma-induced effects. RESULTS: Significant increases in microcirculation were only observed after plasma stimulation but not after pressure stimulus alone. For a period of 1 h after stimulation, local relative hemoglobin was increased by 5.1% after 270 seconds diCAP treatment. Tissue oxygen saturation increased by up to 9.4%, whereas blood flow was doubled (+106%). Skin pH decreased by 0.3 after 180 seconds and 270 seconds diCAP treatment, whereas skin temperature and moisture were not affected. CONCLUSIONS: diCAP treatment of intact skin notably enhances microcirculation for a therapeutically relevant period. This effect is specific to the plasma treatment and not an effect of the applied pressure. Prolonged treatment durations lead to more pronounced effects. PMID- 28857375 TI - The Wound-QoL questionnaire on quality of life in chronic wounds is highly reliable. AB - The Wound-QoL questionnaire has been tested in a previous study, indicating that the instrument is a reliable and valid measurement for the assessment of HRQoL in chronic wounds. The aim of this study was to examine the test-retest reliability of the Wound-QoL. Patients were asked to complete the Wound-QoL twice within 3-7 days. Next to descriptive statistics, internal consistency was determined. Test retest reliability was calculated with the intraclass correlation coefficient. The data showed ICCs between 0.79 and 0.86, which can be considered evidence of excellent reliability. Another indicator of very good reliability, high internal consistency of both global score, and subscale scores were found. The availability of the Wound-QoL provides a step forward in allowing measurement of the HRQoL in chronic wounds. The instrument is fit for use to measure outcomes in clinical trials and as well to assess treatment outcomes in routine practice. PMID- 28857376 TI - Preorganization and Cooperation for Highly Efficient and Reversible Capture of Low-Concentration CO2 by Ionic Liquids. AB - A novel strategy based on the concept of preorganization and cooperation has been designed for a superior capacity to capture low-concentration CO2 by imide-based ionic liquids. By using this strategy, for the first time, an extremely high gravimetric CO2 capacity of up to 22 wt % (1.65 mol mol-1 ) and excellent reversibility (16 cycles) have been achieved from 10 vol. % of CO2 in N2 when using an ionic liquid having a preorganized anion. Through a combination of quantum-chemical calculations and spectroscopic investigations, it is suggested that cooperative interactions between CO2 and multiple active sites in the preorganized anion are the driving force for the superior CO2 capacity and excellent reversibility. PMID- 28857377 TI - Stereoselective Synthesis of Z Fluoroalkenes through Copper-Catalyzed Hydrodefluorination of gem-Difluoroalkenes with Water. AB - A copper catalytic system was established for the stereoselective hydrodefluorination of gem-difluoroalkenes through C-F activation to synthesize various Z fluoroalkenes. H2 O is used as the hydrogen source for the fluorine acceptor moiety. This mild catalytic system shows good-functional group compatibility, accepting a range of carbonyls as precursors to the gem difluoroalkenes, including aliphatic, aromatic, and alpha,beta-unsaturated aldehydes and even ketones. It serves as a powerful synthetic method for the late stage modification of complex compounds. PMID- 28857379 TI - Metal-Containing Polymers as Light-Emitting and Light-Responsive Materials and Beyond. AB - Functional materials that respond to external stimuli are of major current interest. In particular, supramolecular systems that can interact with their surroundings, adapt to environmental changes and evolve with are even more fascinating, yet challenging. Combining the rich physico-chemical properties featured by metal centres with characteristics typical of classical organic polymers, metallopolymers or metallo-supramolecular polymers can be prepared, depending on their static versus dynamic structural features. Additionally, multiple and orthogonal functionalities can be encoded in their chemical structure affording materials with widespread potential applications to be employed as "smart" materials for advanced technologies. In this Concept article, selected examples of metal-containing polymers will be described demonstrating large potentialities of such systems for creating stimuli-responsive materials with special emphasis for those showing optical applications. PMID- 28857378 TI - SNARE proteins in membrane trafficking. AB - SNAREs are the core machinery mediating membrane fusion. In this review, we provide an update on the recent progress on SNAREs regulating membrane fusion events, especially the more detailed fusion processes dissected by well-developed biophysical methods and in vitro single molecule analysis approaches. We also briefly summarize the relevant research from Chinese laboratories and highlight the significant contributions on our understanding of SNARE-mediated membrane trafficking from scientists in China. PMID- 28857380 TI - The Rolling-Up of Oligophenylenes to Nanographenes by a HF-Zipping Approach. AB - Intramolecular aryl-aryl coupling is the key transformation in the rational synthesis of nanographenes and nanoribbons. In this respect the C-F bond activation was shown to be a versatile alternative enabling the synthesis of several unique carbon-based nanostructures. Herein we describe an unprecedentedly challenging transformation showing that the C-F bond activation by aluminum oxide allows highly effective domino-like C-C bond formation. Despite the flexible nature of oligophenylene-based precursors efficient regioselective zipping to the target nanostructures was achieved. We show that fluorine positions in the precursor structure unambiguously dictate the "running of the zipping-program" which results in rolling-up of linear oligophenylene chains around phenyl moieties yielding target nanographenes. The high efficiency of zipping makes this approach attractive for the synthesis of unsubstituted nanographenes which are difficult to obtain in pure form by other methods. PMID- 28857381 TI - Synergistic Effects between Atomically Dispersed Fe-N-C and C-S-C for the Oxygen Reduction Reaction in Acidic Media. AB - Various advanced catalysts based on sulfur-doped Fe/N/C materials have recently been designed for the oxygen reduction reaction (ORR); however, the enhanced activity is still controversial and usually attributed to differences in the surface area, improved conductivity, or uncertain synergistic effects. Herein, a sulfur-doped Fe/N/C catalyst (denoted as Fe/SNC) was obtained by a template sacrificing method. The incorporated sulfur gives a thiophene-like structure (C-S C), reduces the electron localization around the Fe centers, improves the interaction with oxygenated species, and therefore facilitates the complete 4 e- ORR in acidic solution. Owing to these synergistic effects, the Fe/SNC catalyst exhibits much better ORR activity than the sulfur-free variant (Fe/NC) in 0.5 m H2 SO4 . PMID- 28857382 TI - Nurse manager perspective of staff participation in unit level shared governance. AB - AIM: To examine the nurse manager perspective surrounding implementation of unit level shared governance in one Veterans Health Administration facility. BACKGROUND: Nursing shared governance is a formal model allowing nursing staff decision-making input into clinical practice, quality improvement, evidence-based practice and staff professional development. Unit level shared governance is a management process where decision authority is delegated to nursing staff at the unit level. METHODS: Convenience sampling was used to recruit ten nurse managers who participated in face-to-face semi-structured interviews. Data were analysed using content analysis and constant comparison techniques. Demographic data were described using descriptive statistics. RESULTS: The participants included seven female and three male nurse managers with seven Caucasian and three African American. Participant quotes were clustered to identify sub-themes that were then grouped into four global themes to describe unit level shared governance. The global themes were: (1) motivation, (2) demotivation, (3) recommendations for success, and (4) outcomes. CONCLUSION: These research findings resonate with previous studies that shared governance may be associated with increased nurse empowerment, self-management, engagement, and satisfaction. IMPLICATIONS FOR NURSING MANAGEMENT: These findings reflect the need for nurse managers to promote and recognize staff participation in unit level shared governance. PMID- 28857383 TI - A human serum-enriched medium formulation supports high viability and marker expression in primary melanocyte cultures from the outer root sheath and epidermis. AB - Formulating clinically relevant melanocyte cultivation media that maintain the balance between proliferation and maturation to functional melanocytes is a major experimental and regulatory challenge. Within the translation of human melanocytes from the outer root sheath of human hair follicle (HUMORS), we developed a melanocyte medium free of chemical mitogens, chemical melanogenesis enhancers and bovine products, enabling proliferation as well as melanotic differentiation. The formulation involved the replacement of bovine pituitary extract (BPE) and bovine serum (FBS) with human serum (HS) combined with ascorbic acid, CaCl2 , epinephrine, L-glutamine, insulin and fibroblast growth factor. The cultivation efficiency was characterized through proliferation and exertion of melanotic phenotype, gene and protein expression of melanotic markers and melanin content. Having established an application-directed BPE-free formulation, we then re-formulated a research-grade medium with BPE for purposes of even more effective in vitro cultivation, adjusted to specific requirements of HUMORS and normal human epidermal melanocytes (NHEM). PMID- 28857384 TI - Translation and validation of translation in cross-cultural research: Strategies used in a study of cervical cancer screening among ethnic minorities. AB - AIMS: A discussion of the challenges encountered during instrument translation and validation while researching cervical cancer screening among ethnic minorities and the strategies used to overcome them. BACKGROUND: Given the increasing ethnic and cultural diversity of populations in different countries, culturally sensitive instruments are needed to evaluate people's attitudes, perceptions, and health practices. Often, such instruments are lacking in the study population's language. DESIGN: Discussion paper. DATA SOURCES: The discussion is based on our previous experience including the challenges encountered in the translation process and in the semantic and content validation and the strategies used to overcome them. IMPLICATION FOR NURSING: Seeking help from community centres or translation agencies to use translators with a health care background and of the same cultural origins as the target participants is effective. Actively contacting potential experts through email addresses obtained from published research articles is another effective way to find suitable experts. Field testing of the study questionnaire is important in validation, as it uncovers difficulties that go beyond translation. CONCLUSION: Good planning and preparation before the translation and validation work begins is always required. Working closely with translators and experts through discussion is the key to success. PMID- 28857385 TI - Photoredox Catalysis: The Need to Elucidate the Photochemical Mechanism. AB - The photocatalytic mechanism reported in a recent Communication to produce the radical anion of pyrenes postulates a highly endergonic electron transfer process. An analysis of the thermodynamics is reported together with the proposal of an alternative thermodynamically feasible mechanism. PMID- 28857386 TI - Photoredox Imino Functionalizations of Olefins. AB - Shown herein is that polyfunctionalized nitrogen heterocycles can be easily prepared by a visible-light-mediated radical cascade process. This divergent strategy features the oxidative generation of iminyl radicals and subsequent cyclization/radical trapping, which allows the effective construction of highly functionalized heterocycles. The reactions proceed efficiently at room temperature, utilize an organic photocatalyst, use simple and readily available materials, and generate, in a single step, valuable building blocks that would be difficult to prepare by other methods. PMID- 28857387 TI - Profiling of glycan alterations in regrowing limb tissues of Cynops orientalis. AB - Glycans are known to play important roles in molecular recognition, cell-cell adhesion, molecular trafficking, receptor activation, and signal transduction during development and regeneration. Despite numerous investigations of regenerating salamander limbs, global analysis of the precise variation of glycans during the limb regeneration process has received little attention. Here, we have used lectin microarrays and lectin histochemistry to analyze the alterations and distribution of glycans during the early stages leading to blastema formation during Cynops orientalis limb regeneration in response to limb amputation. Compared with the control group, analysis at several time points (3, 7, and 14 days postamputation) using microarrays containing 37 lectins showed that limb tissues expressed significantly different complements of glycans recognized by 9 different lectins. Postamputation limb tissues showed higher expression of two glycan structures recognized by the lectins STL and LTL and lower expression of seven glycan structures recognized by PHA-E, MAL-I, SNA, UEA I, PHA-E + L, VVA, and GNA. We also observed significant changes in glycans specifically at 7 days postamputation, including higher binding capacity by WFA, GSL-I, and NPA and lower binding capacity by PNA, HHL, ConA, LCA, GSL-II, and PWM. Next, we validated our lectin microarray data using lectin histochemistry in limb tissues. Glycans recognized by STL and GNA showed similar changes in signal intensity to those found in the lectin microarrays, with STL staining in the cytoplasm and GNA in the cytoplasm and nucleus. Our findings are the first report of significant postamputation changes in glycans in limb tissues and suggest that those glycans perform potentially important functions during the early stages of C. orientalis limb regeneration. PMID- 28857388 TI - Metformin extended-release versus immediate-release: An international, randomized, double-blind, head-to-head trial in pharmacotherapy-naive patients with type 2 diabetes. AB - This international, randomized, double-blind trial (NCT01864174) compared the efficacy and safety of metformin extended-release (XR) and immediate-release (IR) in patients with type 2 diabetes. After a 4-week placebo lead-in, pharmacotherapy naive adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once-daily metformin XR 2000 mg or twice-daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: -0.93% vs -0.96%; -21.1 vs -20.6 mg/dL (-1.2 vs -1.1 mmol/L); -24.7 vs -27.1 mg/dL (-1.4 vs -1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once-daily dosing. PMID- 28857389 TI - Selenium and Selenocysteine in Protein Chemistry. AB - Selenocysteine, the selenium-containing analogue of cysteine, is the twenty-first proteinogenic amino acid. Since its discovery almost fifty years ago, it has been exploited in unnatural systems even more often than in natural systems. Selenocysteine chemistry has attracted the attention of many chemists in the field of chemical biology owing to its high reactivity and resulting potential for various applications such as chemical modification, chemical protein (semi)synthesis, and protein folding, to name a few. In this Minireview, we will focus on the chemistry of selenium and selenocysteine and their utility in protein chemistry. PMID- 28857390 TI - Challenges in measuring the effects of pharmacological interventions on cognitive and adaptive functioning in individuals with Down syndrome: A systematic review. AB - We systematically reviewed the measures used in pharmaceutical trials in children/adults with Down syndrome without dementia. Our purpose was to identify developmentally appropriate outcome measures capable of detecting changes in cognitive and adaptive functioning in this population. Eleven studies were included and used diverse outcome measures across the domains of language, memory, attention, behavior, and executive/adaptive functioning. Our results highlight the challenges in selecting measures capable of capturing improvements in pharmaceutical trials in individuals with DS. We offer suggestions to enhance future research, including: conducting studies with larger samples of participants with a range of developmental abilities; modifying existing/developing novel outcome measures; incorporating advances from related areas and DS observational studies; and considering alternative analytic techniques to characterize treatment effects. PMID- 28857391 TI - Estimated peak functional capacity: an accurate method for assessing change in peak oxygen consumption after cardiac rehabilitation? AB - OBJECTIVE: Cardiopulmonary exercise testing (CPET) is the 'gold standard' method of determining VO2peak . When CPET is unavailable, VO2peak may be estimated from treadmill or cycle ergometer workloads and expressed as estimated metabolic equivalents (METs). Cardiac rehabilitation (CR) programmes use estimated VO2peak (METs) to report changes in cardiorespiratory fitness (CRF). However, the accuracy of determining changes in VO2peak based on estimated functional capacity is not known. METHODS: A total of 27 patients with coronary heart disease (88.9% male; age 59.5 +/- 10.0 years, body mass index 29.6 +/- 3.8 kg m-2 ) performed maximal CPET before and after an exercise-based CR intervention. VO2peak was directly determined using ventilatory gas exchange data and was also estimated using the American College of Sports Medicine (ACSM) leg cycling equation. Agreement between changes in directly determined VO2peak and estimated VO2peak was evaluated using Bland-Altman limits of agreement (LoA) and intraclass correlation coefficients. RESULTS: Directly determined VO2peak did not increase following CR (0.5 ml kg-1 min-1 (2.7%); P = 0.332). Estimated VO2peak increased significantly (0.4 METs; 1.4 ml kg-1 min-1 ; 6.7%; P = 0.006). The mean bias for estimated VO2peak versus directly determined VO2peak was 0.7 ml kg-1 min-1 (LoA 4.7 to 5.9 ml kg-1 min-1 ). Aerobic efficiency (DeltaVO2 /DeltaWR slope) was significantly associated with estimated VO2peak measurement error. CONCLUSION: Change in estimated VO2peak derived from the ACSM leg cycling equation is not an accurate surrogate for directly determined changes in VO2peak . Our findings show poor agreement between estimates of VO2peak and directly determined VO2peak . Applying estimates of VO2peak to determine CRF change may over-estimate the efficacy of CR and lead to a different interpretation of study findings. PMID- 28857392 TI - Bioinspired Total Synthesis of (-)-Vescalin: A Nonahydroxytriphenoylated C Glucosidic Ellagitannin. AB - The first total synthesis of the 2,3,5-O-(S,R)-nonahydroxytriphenoylated (NHTP) C glucosidic ellagitannin (-)-vescalin was accomplished through a series of transformations mimicking the sequence of events leading to its biogenesis. The key steps of this synthesis encompass a Wittig-mediated ring opening of a glucopyranosic hemiacetal, a C-glucosidation event through a phenolic aldol-type reaction, and a Wynberg-Feringa-Yamada-type oxidative phenolic coupling, which forged the NHTP unit of (-)-vescalin. PMID- 28857393 TI - Comparing the acceptability of a positive psychology intervention versus a cognitive behavioural therapy for clinical depression. AB - There is growing evidence on the efficacy of positive psychology interventions (PPI) to treat clinical disorders. However, very few studies have addressed their acceptability. The present study aimed to analyse 2 key components of acceptability (i.e., client satisfaction and adherence to treatment) of a new PPI programme, the Integrative Positive Psychological Intervention for Depression (IPPI-D), in comparison to a standard cognitive behavioural therapy (CBT) programme in the treatment of clinical depression. One hundred twenty-eight women with a DSM-IV diagnosis of major depression or dysthymia were allocated to a 10 session IPPI-D or CBT group intervention condition. Results showed that both interventions were highly acceptable for participants. Attendance rates were high, and there were no significant differences between conditions. However, the IPPI-D condition showed significantly higher client satisfaction than the CBT condition. Moreover, acceptability did not differ based on participants' severity of symptoms, regardless of condition. These findings encourage further investigations of the applicability of PPI in clinical settings in order to broaden the range of acceptable and suitable therapies for depressed patients. Key Practitioner Message This study sheds light on the client satisfaction and adherence to a positive intervention. For participants, positive psychology interventions (PPI) may be more satisfactory than CBT as PPI are framed within a positive mental health model and, consequently, may reduce the risk of stigmatization Because acceptability of treatments and preferences may affect the efficacy of treatments, this study provides an excellent opportunity to offer professionals more therapeutic options to tailor treatments to clients' needs and expectations. PMID- 28857394 TI - Patterns of stress coping and depression among patients with head and neck cancer: A Japanese cross-sectional study. AB - OBJECTIVE: Patients with head and neck cancer (HNC) experience many stressful problems with breathing, eating, swallowing, and/or speaking. The aim of this study was to (a) identify the clusters of HNC patients based on their stress coping strategies and (b) evaluate the differences in clinical data and depression among the identified HNC patients' coping clusters. METHODS: We conducted a single-center, cross-sectional study with self-completed questionnaires for patients with HNC between April and August 2013. We measured stress coping (an abbreviated version of the COPE Inventory: Brief COPE) and depression (the Japanese version of the Beck Depression Inventory-II: BDI-II). RESULTS: Of the 116 patients who completed all the questionnaires, 81 (69.8%) participants were 60 to 79 years old and 105 (90.5%) were men. Cluster analysis based on the standardized z score of Brief COPE showed that patients were classified into 3 clusters, labeled "dependent coping," "problem-focused coping," and "resigned coping." The ANOVA revealed that depression (BDI score) was significantly higher in the dependent-coping cluster compared with the problem focused coping. CONCLUSIONS: This study indicates that patients with a dependent coping pattern may account for the largest HNC population and are likely to suffer from depression. Dependent coping includes smoking, drinking, seeking support, or engaging self-distraction. In the future, we should develop psychological intervention programs focused on coping strategies and enhancement of the support system for patients with HNC. PMID- 28857395 TI - HIV in retreat? PMID- 28857397 TI - Correct Modeling of Cisplatin: a Paradigmatic Case. AB - Quantum chemistry is a useful tool in modern approaches to drug and material design, but only when the adopted model reflects a correct physical picture. Paradigmatic is the case of cis-diaminodichloroplatinum(II), cis-[Pt(NH3 )2 Cl2 ], for which the correct simulation of the structural and vibrational properties measured experimentally still remains an open question. By using this molecule as a proof of concept, it is shown that state-of-the-art quantum chemical calculations and a simple model, capturing the basic physical flavors, a cis [Pt(NH3 )2 Cl2 ] dimer, can provide the accuracy required for interpretative purposes. The present outcomes have fundamental implications for benchmark studies aiming at assessing the accuracy of a given computational protocol. PMID- 28857396 TI - Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin-1 production. AB - Hyperphosphatemia is related to some pathologies, affecting vascular cell behavior. This work analyzes whether high concentration of extracellular phosphate induces endothelial senescence through up-regulation of endothelin-1 (ET-1), exploring the mechanisms involved. The phosphate donor beta glycerophosphate (BGP) in human endothelial cells increased ET-1 production, endothelin-converting enzyme-1 (ECE-1) protein, and mRNA expression, which depend on the AP-1 activation through ROS production. In parallel, BGP also induced endothelial senescence by increasing p16 expression and the senescence-associated beta-galactosidase (SA-beta-GAL) activity. ET-1 itself was able to induce endothelial senescence, increasing p16 expression and SA-beta-GAL activity. In addition, senescence induced by BGP was blocked when different ET-1 system antagonists were used. BGP increased ROS production at short times, and the presence of antioxidants prevented the effect of BGP on AP1 activation, ECE-1 expression, and endothelial senescence. These findings were confirmed in vivo with two animal models in which phosphate serum levels were increased: seven/eight nephrectomized rats as chronic kidney disease models fed on a high phosphate diet and aged mice. Both models showed hyperphosphatemia, higher levels of ET-1, and up-regulation in aortic ECE-1, suggesting a direct relationship between hyperphosphatemia and ET-1. Present results point to a new and relevant role of hyperphosphatemia on the regulation of ET-1 system and senescence induction at endothelial level, both in endothelial cells and aorta from two animal models. The mechanism involved showed a higher ROS production, which probably activates AP-1 transcription factor and, as a result, ECE-1 expression, increasing ET-1 synthesis, which in consequence induces endothelial senescence. PMID- 28857398 TI - Predictive value of serum markers for postacne scarring. AB - BACKGROUND: Postacne scarring is the main concern of many acne patients. Predicting the liability to scarring can alter the management protocols and help in preventing such disfigurement. METHODS: Sixty patients with moderate to severe acne vulgaris (according to Global Acne Grading system) were included, only 35 of them had postacne scars. A quantitative latex agglutination commercial kit was used to assess serum C-reactive protein (CRP) concentration by turbidimetry, while serum hepcidin concentration was assessed by a commercially available double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Patients with postacne scarring had significantly lower serum levels of hepcidin (P-value < .001) and significantly higher serum levels of CRP (P-value < .05). CONCLUSION: Serum levels of hepcidin and CRP are promising markers, which may be considered as objective tools to predict the possibility of postacne scarring. PMID- 28857399 TI - Status of wound management in Korea. AB - In spite of a period of intense economic, social, and political hardship following the Korean War, the Republic of Korea has made great strides in economic growth over the past half century, and also remarkable progress in the medical field. However, wound research has been slow to take off in South Korea. Meanwhile, as is the case in many countries in Western Europe and North America, South Korea is seeing a steady increase in its aged population. The growth in the geriatric population has in turn brought on more cases of chronic wounds. Though South Korea only began to recognize the importance of wound management in the early 2000s, it was fortunate enough to have sophisticated related industries, such as biotechnology and information technology, and brilliant, industrious, and eager wound researchers, contributing to rapid development of the field. The country has particular strengths in research for innovative cell-based treatments and products for managing wounds. Notwithstanding government policy ill-equipped to sufficiently support such advancement, better communication between experts and public officials will no doubt bring forth even more achievements in this very promising field. It is in this context that this article aims to summarize current wound management practices, research, training, product development, and government policies regarding wound management in South Korea as of the year 2017. PMID- 28857401 TI - Star-shaped Polymers through Simple Wavelength-Selective Free-Radical Photopolymerization. AB - Star-shaped polymers represent highly desired materials in nanotechnology and life sciences, including biomedical applications (e.g., diagnostic imaging, tissue engineering, and targeted drug delivery). Herein, we report a straightforward synthesis of wavelength-selective multifunctional photoinitiators (PIs) that contain a bisacylphosphane oxide (BAPO) group and an alpha-hydroxy ketone moiety within one molecule. By using three different wavelengths, these photoactive groups can be selectively addressed and activated, thereby allowing the synthesis of ABC-type miktoarm star polymers through a simple, highly selective, and robust free-radical polymerization method. The photochemistry of these new initiators and the feasibility of this concept were investigated in unprecedented detail by using various spectroscopic techniques. PMID- 28857400 TI - Predictive value of symptoms, signs and biomarkers on computed tomography pulmonary angiogram results. AB - BACKGROUND: Pulmonary embolism (PE) is associated with significant morbidity and mortality. PE is a heterogeneous entity that causes a wide variety of clinical presentations, making it imperative to establish which clinical symptoms, signs and biomarkers can influence the pretest probability of PE to aid clinicians and reduce over testing. AIM: To analyse the clinical parameters used by clinicians to order a computed tomography pulmonary angiogram (CTPA) and establish which were associated with the presence of PE. METHODS: Medical records of patients who underwent CTPA from December 2015 to March 2016 were extracted. Patient demographics, clinical symptoms, diagnostic and radiological results were analysed. RESULTS: The study included 150 CTPA studies. Of the studies, 25 were positive for PE and 125 were negative. There was no significant relationship between the presence or character of chest pain and a positive CTPA result (P = 0.216). Previous history of venous thromboembolism (VTE) (P < 0.0001), one or more risk factors for VTE and positive troponin (P < 0.002) were all predictive of PE. None of the patients with a negative D-dimer had a positive CTPA. CONCLUSION: This study supports the negative predictive value of the D-dimer for excluding PE and demonstrates that the strongest pretest predictors of PE in our population are a prior history of VTE, risk factors for VTE and elevated troponin. None of the parameters that often generate requests for CTPA, including vital signs or the presence of chest pain, was associated with the presence of PE in our study population. PMID- 28857402 TI - Thermally-Triggered Crystal Dynamics and Permanent Porosity in the First Heptatungstate-Metalorganic Three-Dimensional Hybrid Framework. AB - The hybrid compound [{Cu(cyclam)}3 (W7 O24 )]?15.5 H2 O (1) (cyclam=1,4,8,11 tetraaza-cyclotetradecane) was synthesized by reacting the {Cu(cyclam)}2+ complex with a tungstate source in water at pH 8. Compound 1 exhibits an unprecedented three-dimensional covalent structure built of heptatungstate clusters linked through metalorganic complexes in a POMOF-like framework that displays water filled channels. This dynamic architecture undergoes two sequential single crystal-to-single-crystal transformations upon thermal evacuation of water molecules to result in the partially dehydrated [{Cu(cyclam)}3 (W7 O24 )]?12 H2 O (2) and anhydrous [Cu(cyclam)]0.5 [{Cu(cyclam)}2.5 (W7 O24 )] (3) crystalline phases. These transitions are associated with cluster rotations and modifications in the CuII coordination geometries, which reduce the dimensionality of the original lattice to layered systems but preserving the porous nature. Phase 3 reverts to 2 upon exposure to ambient moisture, whereas the transition between 1 and 2 proved to be irreversible. The permanent microporosity of 3 was confirmed by gas sorption measurements (N2 , CO2 ), which reveal a system of parallel channels made of wide cavities connected through narrow necks that limit the adsorption process. This observation is in good agreement with Grand Canonical Monte Carlo simulations. PMID- 28857403 TI - In vivo chlorophyll fluorescence screening allows the isolation of a Chlamydomonas mutant defective for NDUFAF3, an assembly factor involved in mitochondrial complex I assembly. AB - The qualitative screening method used to select complex I mutants in the microalga Chlamydomonas, based on reduced growth under heterotrophic conditions, is not suitable for high-throughput screening. In order to develop a fast screening method based on measurements of chlorophyll fluorescence, we first demonstrated that complex I mutants displayed decreased photosystem II efficiency in the genetic background of a photosynthetic mutation leading to reduced formation of the electrochemical proton gradient in the chloroplast (pgrl1 mutation). In contrast, single mutants (complex I and pgrl1 mutants) could not be distinguished from the wild type by their photosystem II efficiency under the conditions tested. We next performed insertional mutagenesis on the pgrl1 mutant. Out of about 3000 hygromycin-resistant insertional transformants, 46 had decreased photosystem II efficiency and three were complex I mutants. One of the mutants was tagged and whole genome sequencing identified the resistance cassette in NDUFAF3, a homolog of the human NDUFAF3 gene, encoding for an assembly factor involved in complex I assembly. Complemented strains showed restored complex I activity and assembly. Overall, we describe here a screening method which is fast and particularly suited for the identification of Chlamydomonas complex I mutants. PMID- 28857404 TI - Polite, professional, practical: What drives caller 'satisfaction' with the New South Wales Quitline, Australia. AB - INTRODUCTION AND AIMS: Previous studies on smoking quitlines have focused on service effectiveness and usage, describing client characteristics, referral sources and service utilisation. There is a lack of qualitative research examining callers' perspectives on service quality. The analysis aimed to describe the factors which underpin quitline callers' descriptions of their satisfaction with the service. DESIGN AND METHODS: We conducted qualitative interviews with 46 callers to the NSW Quitline's English and multilingual lines. We used an iterative, inductive, thematic approach to identify common patterns within interviewees' descriptions of what informed their level of satisfaction with the service. RESULTS: Interviewees evaluated the Quitline service format (frequency, duration and convenience of call-backs), call content and advisor competence in terms of whether these components conveyed care, developed rapport and demonstrated a general professionalism (polite, reliable and convenient service). Satisfaction rested on callers finding advice and resources personally relevant and matching prior expectations, although many did not have an accurate idea of Quitline's services prior to calling. These themes were evident across age, gender, language background and quitting status. DISCUSSION AND CONCLUSIONS: 'Satisfaction' with Quitline is complex and not wholly dependent on achieving cessation. Evaluations emerged out of dynamic interactions between callers' preconceived notions and needs of smoking cessation services and the particular service experience of the caller. While callers' descriptions of the Quitline were predominantly positive, developing specialised modules for long-term smokers and those with a strong sense of personal responsibility for quitting may broaden the utility of the service. PMID- 28857405 TI - Assessment of the effectiveness of platelet rich fibrin in the treatment of Schneiderian membrane perforation. AB - BACKGROUND: The objective of this study is to evaluate the effect of Platelet rich fibrin (PRF) treatment of maxillary sinus membrane perforation on bone formation and new vascular supply and the success of dental implant survival rate. METHODS: The dataset for this retrospective study consists of patients who received sinus augmentation using the lateral wall technique. A total of 16 patients (20 sinuses) the patients without sinus membrane perforation (10 maxiller sinus area with sinus floor augmentation) and with Schneiderian perforation (10 maxiller sinus area repairing with PRF and augmented sinus floor area) were included in this study. The bone height was measured by comparing the preoperative and postoperative dental CBCT scans. Histological sections were evaluated for possible vasculogenesis augmented sinuses area. RESULTS: In both groups, it was observed that the possible vasculogenesis augmented sinuses area increased. Implant survival rates in both groups found that one hundred percent and any bone loss around implants were not observed. An apparent increase in alveolar bone height was observed and measured in CBCT scans. CONCLUSIONS: PRF can be considered as an alternative material for repairing sinus perforations because it is fully autogenous and easy manipulated. PMID- 28857406 TI - Trend of cardiovascular risk factors in the older Iranian population: 2002-2014. AB - AIM: Current study aimed to investigate the sex-stratified secular trend of cardiovascular disease risk factors among an older population in Iran during a median follow-up period of 8.76 years. METHODS: A total of 1490 participants (733 women) aged >=60 years were evaluated in four study phases of 2002-2005, 2005 2008, 2008-2011 and 2011-2014. The trends of cardiovascular disease risk factors for each sex were estimated using generalized estimating equations. RESULTS: The age-adjusted prevalence of diabetes, hypertension, central obesity, and chronic kidney disease at the baseline was 24%, 43%, 55%, and 32% in men and 31%, 57%, 60% and 53% in women, respectively, and had noticeable upward trend during the study period to reach 35%, 56%, 61% and 51% in men, and 42%, 71%, 74% and 67% in women, respectively. However, lipid profile parameters showed favorable trends. Despite the increasing trend in drug consumption, approximately 27% of women with diabetes and 37% of men with diabetes did not use antidiabetic medication, respectively; the results were 23% and 35% for hypertensive women and men, respectively. Among men, there was a decreasing trend towards low physical activity, from 40% at baseline to 26% at the most recent follow up. The prevalence of smoking remained steady throughout follow up. CONCLUSIONS: Despite the benefits of lipid lowering, the status of other risk factor profiles are often suboptimal in both sexes. There remains much room for improvement in risk factors management, particularly for hypertension, smoking and adiposity status, and a need for an intervention. Geriatr Gerontol Int 2018; 18: 130-137. PMID- 28857407 TI - Preparation and fabrication of a full-scale, sagittal-sliced, 3D-printed, patient specific radiotherapy phantom. AB - PURPOSE: Patient-specific 3D-printed phantoms have many potential applications, both research and clinical. However, they have been limited in size and complexity because of the small size of most commercially available 3D printers as well as material warping concerns. We aimed to overcome these limitations by developing and testing an effective 3D printing workflow to fabricate a large patient-specific radiotherapy phantom with minimal warping errors. In doing so, we produced a full-scale phantom of a real postmastectomy patient. METHODS: We converted a patient's clinical CT DICOM data into a 3D model and then sliced the model into eleven 2.5-cm-thick sagittal slices. The slices were printed with a readily available thermoplastic material representing all body tissues at 100% infill, but with air cavities left open. Each slice was printed on an inexpensive and commercially available 3D printer. Once the printing was completed, the slices were placed together for imaging and verification. The original patient CT scan and the assembled phantom CT scan were registered together to assess overall accuracy. RESULTS: The materials for the completed phantom cost $524. The printed phantom agreed well with both its design and the actual patient. Individual slices differed from their designs by approximately 2%. Registered CT images of the assembled phantom and original patient showed excellent agreement. CONCLUSIONS: Three-dimensional printing the patient-specific phantom in sagittal slices allowed a large phantom to be fabricated with high accuracy. Our results demonstrate that our 3D printing workflow can be used to make large, accurate, patient-specific phantoms at 100% infill with minimal material warping error. PMID- 28857408 TI - ACNM Fellows Inducted in 2017. PMID- 28857410 TI - Determinants of anemia among women and children in Nepal and Pakistan: An analysis of recent national survey data. AB - Anemia remains one of the most intractable public health challenges in South Asia. This paper analyzes individual-level and household-level determinants of anemia among children and women in Nepal and Pakistan. Applying multivariate modified Poisson models to recent national survey data, we find that the prevalence of anemia was significantly higher among women from the poorest households in Pakistan (adjusted prevalence ratio [95% CI]: 1.10 [1.04-1.17]), women lacking sanitation facilities in Nepal (1.22 [1.12-1.33]), and among undernourished women (BMI < 18.5 kg/m2 ) in both countries (Nepal: 1.10 [1.00 1.21] and Pakistan: 1.07 [1.02-1.13]). Similarly, children in both countries were more likely to be anemic if stunted (Nepal: 1.19 [1.09-1.30] and Pakistan: 1.10 [1.07-1.14]) and having an anemic mother (Nepal: 1.31 [1.20-1.42] and Pakistan: 1.21 [1.17-1.26]). Policies and programs need to target vulnerable and hard-to reach subpopulations who continue to bear a disproportionate burden of anemia. Covariates of poverty underpin rates of anemia among children and their mothers, but income growth alone will not suffice to resolve such deeply entrenched problems. Greater understanding of the relative role of various diet, health, sanitation, and educational factors by local context should guide investments to resolve anemia in tandem with stunting and maternal underweight. PMID- 28857409 TI - Practical implications for the quality assurance of modulated radiation therapy techniques using point detector arrays. AB - PURPOSE: Linac parameters potentially influencing the delivery quality of IMRT and VMAT plans are investigated with respect to threshold ranges, consequently to be considered in a linac based quality assurance procedure. Three commercially available 2D arrays are used to further investigate the influence of the measurement device. METHODS: Using three commercially available 2D arrays (Mx: MatriXXevolution , Oc: Octavius1500 , Mc: MapCHECK2), simple static measurements, measurements for MLC characterization and dynamic interplay of gantry movement, MLC movement and variable dose rate were performed. The results were evaluated with respect to each single array as well as among each other. RESULTS: Simple static measurements showed different array responses to dose, dose rate and profile homogeneity and revealed instabilities in dose delivery and profile shape during linac ramp up. Using the sweeping gap test, all arrays were able to detect small leaf misalignments down to +/-0.1 mm, but this test also demonstrated up to 15% dose deviation due to profile instabilities and fast accelerating leaves during linac ramp up. Tests including gantry rotation showed different stability of gantry mounts for each array. Including gantry movement and dose rate variability, differences compared to static delivery were smaller compared to dose differences when simultaneously controling interplay of gantry movement, leaf movement and dose rate variability. CONCLUSION: Linac based QA is feasible with the tested commercially available 2D arrays. Limitations of each array and the linac ramp up characteristics should be carefully considered during individual plan generation and regularly checked in linac QA. Especially the dose and dose profile during linac ramp up should be checked regularly, as well as MLC positioning accuracy using a sweeping gap test. Additionally, dynamic interplay tests including various gantry rotation speeds and angles, various leaf speeds and various dose rates should be included. PMID- 28857411 TI - Trajectories of serum hepatitis B surface antigen kinetics in patients with chronic hepatitis B receiving long-term nucleos(t)ide analogue therapy. AB - BACKGROUND & AIMS: The kinetics of serum hepatitis B surface antigen (HBsAg) levels during long-term nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients remains unclear. We investigated the patterns of serum HBsAg kinetics and their association with therapeutic outcomes in genotype B- or C infected CHB patients receiving long-term NA therapy. METHODS: We enrolled 329 treatment-naive CHB patients receiving NA therapy for >5 years to analyse the kinetic patterns by using group-based trajectory models (GBTMs). RESULTS: Most patients (82.4%) received entecavir therapy. The median treatment duration was 83.6 (68.5-89.7) months. The GBTMs revealed three groups for both the hepatitis B e antigen (HBeAg)-positive and -negative patients. The median annual decline in serum HBsAg levels during the first 5 years was significantly higher in Group 1 than in Groups 2 and 3 in HBeAg-positive (0.78 vs 0.10 vs 0.10 log10 IU/mL) and HBeAg-negative (0.71 vs 0.08 vs 0.09 log10 IU/mL) patients. HBsAg levels at the baseline and 12 months combined with an HBsAg decline from the baseline to 12 months of treatment predicted trajectory pattern 1 in HBeAg-positive (sensitivity, 77.8%; specificity, 99.1%; positive predictive value [PPV], 87.5%; and negative predictive value [NPV], 98.2%) and HBeAg-negative (sensitivity, 100%; specificity, 99.5%; PPV, 88.9%; and NPV, 100%) patients. The trajectory patterns were significantly associated with HBeAg loss in the HBeAg-positive patients and the achievement of HBsAg <100 IU/mL or HBsAg loss in HBeAg-positive and HBeAg-negative patients. CONCLUSIONS: The trajectory of serum HBsAg levels predicts HBsAg loss in CHB patients receiving long-term NA therapy. PMID- 28857412 TI - Epidemiological and clinical features of leptospirosis in a highly endemic area over three time periods. AB - OBJECTIVES: To present the features of human leptospirosis over three time periods (1970-1975; 2000-2005; 2010-2015), to compare the collected data and to determine whether the incidence, seasonal and spatial distribution, prevalence of presumptive infective serogroups and clinical features have changed over the last 50 years. METHODS: Epidemiological and clinical data obtained from patients hospitalised and treated in a well-known endemic focus of leptospirosis, Koprivnica-Krizevci County in Croatia, were analysed. RESULTS: We observed a steady decline in the overall incidence of leptospirosis and a change in the patient age distribution, with the age ratio changing in favour of middle-aged and older patients. Although leptospirosis was most frequently diagnosed in August in all time periods, the number of cases increased in autumn. The most prevalent serogroup during the first and the second time period was Icterohaemorrhagiae, while in the third time period, the serogroup Australis prevailed. We also noted an increase in the number of severe clinical manifestations. CONCLUSIONS: This retrospective research demonstrates a continuous decline in the incidence of human leptospirosis in Croatia. The pattern of disease has changed from predominantly mild clinical forms observed in children to more severe clinical forms observed in middle-aged to older patients, especially those working in agriculture. Additional epidemiological changes included an increase in the number of cases during the autumn months and changes in prevailing serogroups. Statistical analysis revealed a significant relationship between the severity of the clinical picture, patient age and presumed sources of infection. PMID- 28857413 TI - Frustrated Lewis Trios and Long-Range Hole Interactions: A Combined Structural and Theoretical Study of LB-AX3 ???LB and LB???AX3 ???LB (A=B, Al, Ga, In) Systems. AB - Herein, we present a theoretical study of systems with long-range Lewis acid-base interactions that involve a triel center and two electron donor species. These intermediate situations, between LB-AX3 and LB-AX3 -LB (LB=Lewis base, A=group 13 element), exist experimentally and their interaction topologies obey precise geometrical rules, such that they show a marked directionality and a clear dependence between the two A-LB distances. Despite the relatively long acid???base distances of up to 4 A, the interaction energies calculated at the M06-2X/aug-cc-pVTZ level are considerably large (5-25 kcal mol-1 ). A significant contribution to the interaction is related to the lone-pair-containing species that interacts with the pi hole of the acid center, as revealed by the natural bond order, atoms in molecules, and molecular electrostatic potential analyses. Remarkably, this n(N)->sigmaAl-N * interaction persists even at distances greater than the sum of the van der Waals radii. PMID- 28857414 TI - Predictive factors of rehospitalization for worsening heart failure and cardiac death within 1 year in octogenarians hospitalized for heart failure. AB - AIM: To investigate the predictive factors of cardiac events including rehospitalization for worsening heart failure (HF) and cardiac death within 1 year after hospital discharge in octogenarians hospitalized for HF. METHODS: We retrospectively analyzed in detail clinical data for patients aged >80 years who were admitted to Kochi University, Kochi, Japan, for acute decompensated HF in order to identify predictive factors for cardiac events within 1 year. RESULTS: A total of 67 patients (mean age of 85 +/- 4 years, 39 men) were included, and 28 patients (41.8%) had cardiac events. The patients with cardiac events were significantly older, had a lower prescription rate of beta-blockers at discharge and had a lower rate of arrhythmia as an exacerbating factor of HF than patients without cardiac events. When nutritional status was assessed by the controlling nutritional status (CONUT) score, patients in the cardiac events group had significant malnutrition (CONUT >=5). In addition, Kaplan-Meier analysis showed that patients with CONUT >=5 had a higher incidence of cardiac events than did those with a CONUT <5 (log-rank, P < 0.038). In logistic analysis, the independent determinants of the cardiac events within 1 year were malnutrition at moderate or severe levels by the CONUT score and no beta-blocker medication. CONCLUSIONS: In very elderly patients hospitalized for HF, malnutrition and no beta-blocker medication were predictors of rehospitalization for worsening HF or cardiac death within 1 year. These factors could be meaningful targets for improving the management of octogenarians with HF. Geriatr Gerontol Int 2018; 18: 101-107. PMID- 28857415 TI - Morphometric analysis of the maxillary root apex positions according to crowding severity. AB - OBJECTIVES: To determine differences in arch forms derived from the root apices locations between individuals with <2 mm maxillary crowding and controls. SETTING AND SAMPLE POPULATION: The Department of Orthodontics, Pusan National University. Cone-beam computed tomography (CBCT) images of 102 patients in the control group and 95 patients in the crowding group. MATERIALS AND METHODS: X, Y and Z coordinates of the tip of the crowns and the apex of the root of the maxillary teeth (except second molars) were determined on the CBCT images. The acquired three-dimensional (3D) coordinates were converted into two-dimensional (2D) coordinates via projection on the palatal plane, and the Procrustes analysis was employed to process the converted 2D coordinates. The mean shape of the arch form derived from the location of the tip of the crowns and the apex of the root was compared between groups using the statistical shape analysis. RESULTS: There was a statistically significant difference (P = .046) between the groups for the mean shape of the root apex arch form, but the difference was small and clinically irrelevant as it is minor compared to the degree of crowding. CONCLUSIONS: Maxillary arch from at the level of the maxillary apices only shows minor differences between crowded and non-crowded dentitions. PMID- 28857416 TI - Formation, Structure, and Composition of Methylaluminoxane. AB - The structurally ill-characterized methylaluminoxane (MAO) is the activator of choice in olefin polymerization catalysis. We have carried out large scale and systematic quantum chemical calculations to simulate the thermodynamics of its formation by controlled hydrolysis of trimethylaluminum (TMA), extending the studies up to 25 Al atoms, and thus, to the real size domain of MAO. In agreement with previous postulates on its structure, MAO is shown to favor cage-like structures, which commonly contain associated TMA, regardless of size or shape. The sites containing associated TMA are reactive, and explain the function of MAO as a catalyst activator. The compositions of MAOs show overall agreement with experiments, and exhibit structural transitions from chains to rings to sheets to eventually cages as a function of size. The most stable cage structure is obtained for a composition of (MeAlO)16 (Me3 Al)6 , which is in precise agreement with mass spectrometric studies of corresponding anions, and adapts a tubular molecular structure with a molecular weight of 1360 g mol-1 . Our mass spectrometric measurements enable detection of both major and minor anion species. PMID- 28857417 TI - Increased myoendothelial feedback is associated with increased connexin37 and IK1 channel expression in mesenteric arteries of diet-induced hyperhomocysteinemic mice. AB - OBJECTIVE: Previously, we found that diet-induced HHcy in mice caused decreased eNOS expression and signaling in mesenteric arteries, but greatly enhanced non NOS, non-prostacyclin-dependent vasodilation, which involves MEJ communication. To further assess whether HHcy enhances MEJ communication, this study examined endothelium-dependent attenuation of phenylephrine-induced vasoconstriction (myoendothelial feedback) and key molecules involved. METHODS: Myoendothelial feedback was examined in isolated mouse mesenteric arteries, after 6-weeks diet induced HHcy, using pressure myography. Gap junction (Cx37, Cx40, Cx43), NOS (eNOS, nNOS, iNOS), and potassium channel (IK1) protein expression were measured with immunoblots, and connexin mRNAs with real-time PCR. Contribution of nNOS + iNOS to vasomotor responses was assessed using the drug TRIM. RESULTS: Myoendothelial feedback was significantly (P < .05) enhanced in HHcy arteries compared to control, coincident with significantly greater Cx37 and IK1 protein and Cx37 mRNA. Cx43 protein, but not mRNA, was significantly less in HHcy, and Cx40 was not different. eNOS protein was significantly less in HHcy. nNOS and iNOS were not different. TRIM had little effect on vasomotor function. CONCLUSIONS: Diet-induced HHcy enhanced myoendothelial feedback, and increased Cx37 and IK1 expression may contribute. nNOS or iNOS did not upregulate to compensate for decreased eNOS, and they had little involvement in vasomotor function. PMID- 28857418 TI - An unusual case of an irretrievable hemodialysis catheter in a patient with end stage renal disease. AB - Hemodialysis catheters are associated with higher risks of complications compared to arteriovenous fistulas and grafts. Some common complications of dialysis catheters include infection, thrombus formation, central venous stenosis, and mechanical dysfunction. Rarely, catheters can become firmly adhered to a vessel wall. Catheter adhesion is a serious complication that can impact the delivery of safe and effective dialysis to affected patients. Adherent catheters commonly present insidiously with no overt diagnostic signs and symptoms or antecedent catheter malfunction. Prognosis is variable, but can be potentially fatal depending on the severity of adhesion, and sequelae of complications. There are no standardized methods of therapy and treatment strategies are anecdotally reported by interventional radiology, vascular, and cardiothoracic surgery. We hereby describe a case of hemodialysis catheter that has become firmly embedded within the superior vena cava wall. We review the available literature on the epidemiology, risk factors, long-term sequelae, and known management strategies of adherent catheters. The development of preventative measures will be of great importance given serious complications and limited treatment options. Clinical awareness and understanding of this rare condition is imperative to the prevention and management of adherent catheters. PMID- 28857419 TI - Bisphosphonate use and the risk of breast cancer: a meta-analysis of observational studies. AB - PURPOSE: To summarize current evidence of the association of bisphosphonate use with breast cancer risk, we used a systematic review and meta-analysis of observational studies to explore this issue. METHODS: A comprehensive search was conducted on PubMed, EMBASE, and the Cochrane Library. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: Bisphosphonate use was associated with a 16% lower breast cancer risk (pool RR0.84, 95%CI 0.77-0.90, n = 8). A protective effect of bisphosphonate was found in cohort studies (RR 0.85, 95%CI 0.80-0.90, n = 4) and case-control studies (RR 0.78, 95%CI 0.64-0.96, n = 4).We also found that the use of bisphosphonate resulted in a statistically significant reduction in all breast cancer risk (RR 0.87, 95%CI 0.81-0.93) and greater reduction in invasive breast cancer risk (RR 0.78, 95%CI 0.68-0.91) and contralateral breast cancer risk (RR, 0.41; 95% CI, 0.20-0.84).With respect to the type of bisphosphonate, we found that alendronate and etidronate resulted significant reduction in breast cancer risk. The short-term use of bisphosphonate (<1 y) led to nonsignificant change (RR 0.93, 95%CI 0.86-1.00), but a significant 26% reduction of breast cancer risk was noted with long-term use (>1 y) (RR 0.74, 95%CI 0.66-0.83). CONCLUSIONS: Our results supported bisphosphonate as being effective in preventing breast cancer, including invasive and contralateral breast cancer. Furthermore, the long-term use (>1 y) of bisphosphonate was more significant in lowering breast cancer risk. PMID- 28857420 TI - Single standard substance for the determination of nine volatile components in the distillate of Fructus Gardeniae and Radix Curcumae (an intermediate of Xingnaojing Injection). AB - Xingnaojing Injection is a traditional Chinese medicine extensively used for stroke and cerebral ischemia. For better in-process quality control of Xingnaojing Injection, a method for the analysis of its intermediate (i.e., the distillate of Fructus Gardeniae and Radix Curcumae) is needed to monitor and optimize the hydrodistillation extraction process. In this work, nine major volatile components in the intermediate were identified: isophorone, 4-methylene isophorone, curcumenone, curcumenol, curdione, curzerenone, furanodienone, curcumol, and germacrone. A quantitative analysis of multi-component with a single-marker method based on high-performance liquid chromatography with diode array detection was developed for the simultaneous determination of the nine components. In this method, only curdione was needed as the reference substance, and the other eight components were determined using their relative correction factors to curdione. In the method validation, good linearity (r > 0.9999), sensitivity, repeatability, and accuracy (recoveries within 95.3-105.4%) were shown. The repeatability and robustness of the relative correction factors were studied with different column temperatures, flow rates, detection wavelengths, columns, and instruments. In sample analyses, consistent results between the proposed method and the external standard method were shown. The proposed method provides a comprehensive and low-cost tool for the quality assessment of the intermediate of Xingnaojing Injection. PMID- 28857421 TI - Ethnicity predicts falls among community-dwelling older adults in Singapore. AB - AIM: The present study examined whether ethnicity independently predicted future falls among community-dwelling older Singaporeans, and whether ethnicity moderated the relationships between falls risk factors at baseline and falls at follow up. METHODS: Data from a longitudinal survey of older Singaporeans were used. Baseline assessment included handgrip strength, global cognitive function, mobility difficulties, health and psychosocial status. One-year retrospective falls information at follow up was the primary outcome. RESULTS: Final analysis included 1975 participants (mean age 73.6 +/- 6.2 years, 53% women). Indians, followed by Malays, had a higher risk of falling compared with Chinese at follow up. This association remained after controlling for falls risk factors. Self reported pain and poor global cognitive function imposed a substantial increment in the risk of falling among Malays compared with Chinese, but not Indians. CONCLUSION: Ethnicity was a significant predictor of future falls among older Singaporeans. Falls screening and intervention should take ethnicity into account to reach and support the appropriate target population. Geriatr Gerontol Int 2018; 18: 72-79. PMID- 28857422 TI - Four-Bits-Per-Cell Operation in an HfO2 -Based Resistive Switching Device. AB - The quadruple-level cell technology is demonstrated in an Au/Al2 O3 /HfO2 /TiN resistance switching memory device using the industry-standard incremental step pulse programming (ISPP) and error checking/correction (ECC) methods. With the highly optimistic properties of the tested device, such as self-compliance and gradual set-switching behaviors, the device shows 6sigma reliability up to 16 states with a state current gap value of 400 nA for the total allowable programmed current range from 2 to 11 uA. It is demonstrated that the conventional ISPP/ECC can be applied to such resistance switching memory, which may greatly contribute to the commercialization of the device, especially competitively with NAND flash. A relatively minor improvement in the material and circuitry may enable even a five-bits-per-cell technology, which can hardly be imagined in NAND flash, whose state-of-the-art multiple-cell technology is only at three-level (eight states) to this day. PMID- 28857423 TI - PIKfyve activity regulates reformation of terminal storage lysosomes from endolysosomes. AB - The protein complex composed of the kinase PIKfyve, the phosphatase FIG4 and the scaffolding protein VAC14 regulates the metabolism of phosphatidylinositol 3,5 bisphosphate, which serves as both a signaling lipid and the major precursor for phosphatidylinositol 5-phosphate. This complex is involved in the homeostasis of late endocytic compartments, but its precise role in maintaining the dynamic equilibrium of late endosomes, endolysosomes and lysosomes remains to be determined. Here, we report that inhibition of PIKfyve activity impairs terminal lysosome reformation from acidic and hydrolase-active, but enlarged endolysosomes. Our live-cell imaging and electron tomography data show that PIKfyve activity regulates extensive membrane remodeling that initiates reformation of lysosomes from endolysosomes. Altogether, our findings show that PIKfyve activity is required to maintain the dynamic equilibrium of late endocytic compartments by regulating the reformation of terminal storage lysosomes. PMID- 28857424 TI - A cross-cultural convergent parallel mixed methods study of what makes a cancer related symptom or functional health problem clinically important. AB - OBJECTIVE: In this study, we investigated what makes a symptom or functional impairment clinically important, that is, relevant for a patient to discuss with a health care professional (HCP). This is the first part of a European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group project focusing on the development of thresholds for clinical importance for the EORTC QLQ-C30 questionnaire and its corresponding computer-adaptive version. METHODS: We conducted interviews with cancer patients and HCPs in 6 European countries. Participants were asked to name aspects of a symptom or problem that make it clinically important and to provide importance ratings for a predefined set of aspects (eg, need for help and limitations of daily functioning). RESULTS: We conducted interviews with 83 cancer patients (mean age, 60.3 y; 50.6% men) and 67 HCPs. Participants related clinical importance to limitations of everyday life (patients, 65.1%; HCPs, 77.6%), the emotional impact of a symptom/problem (patients, 53.0%; HCPs, 64.2%), and duration/frequency (patients, 51.8%; HCPs, 49.3%). In the patient sample, importance ratings were highest for worries by partner or family, limitations in everyday life, and need for help from the medical staff. Health care professionals rated limitations in everyday life and need for help from the medical staff to be most important. CONCLUSIONS: Limitations in everyday life, need for (medical) help, and emotional impact on the patient or family/partner were found to be relevant aspects of clinical importance. Based on these findings, we will define anchor items for the development of thresholds for clinical importance for the EORTC measures in a Europe-wide field study. PMID- 28857425 TI - Strain-specific probiotic (microbial cell preparation) and omega-3 fatty acid in modulating quality of life and inflammatory markers in colorectal cancer patients: a randomized controlled trial. AB - AIM: Colorectal cancer patients on chemotherapy usually have elevated levels of inflammatory markers and experience numerous side effects from chemotherapy thereby leading to poor quality of life. Omega-3 fatty acid and microbial cell preparation (MCP) have been known to provide significant benefits in patients on chemotherapy. The aim of this study was to determine the effect of supplementation of omega-3 fatty acid and MCP in quality of life, chemotherapy side effects and inflammatory markers in colorectal cancer patients on chemotherapy. METHODS: A double-blind randomized study was carried out with 140 colorectal cancer patients on chemotherapy. Subjects were separated into two groups to receive either placebo or MCP [30 billion colony-forming unit (CFUs) per sachet] at a dose of two sachets daily for 4 weeks, and omega-3 fatty acid at a dose of 2 g daily for 8 weeks. Outcomes measured were quality of life, side effects of chemotherapy and levels of inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein. RESULTS: The supplementation with MCP and omega-3 fatty acid improved the overall quality of life and alleviated certain side effects of chemotherapy. The supplementation with MCP and omega-3 fatty acid also managed to reduce the level of IL-6 (P = 0.002). There was a significant rise in the placebo group's serum TNF-alpha (P = 0.048) and IL-6 (P = 0.004). CONCLUSION: The combined supplementation with MCP and omega-3 fatty acid may improve quality of life, reduce certain inflammatory biomarkers and relieve certain side effects of chemotherapy in colorectal patients on chemotherapy. PMID- 28857426 TI - CIT-9: A Fault-Free Gmelinite Zeolite. AB - A synthetic, fault-free gmelinite (GME) zeolite is prepared using a specific organic structure-directing agent (OSDA), cis-3,5-dimethylpiperidinium. The cis isomers align in the main 12-membered ring (MR) channel of GME. Trans-isomer OSDA leads to the small-pore zeolite SSZ-39 with the OSDA in its cages. Data from N2 physisorption and rotation electron diffraction provide evidence for the openness of the 12 MR channel in the GME 12*8*8 pore architecture and the absence of stacking faults, respectively. CIT-9 is hydrothermally stable when K+ -exchanged, while in the absence of exchange, the material transforms into an aluminous AFI zeolite. The process of this phase-change was followed by in situ variable temperature powder X-ray diffraction. CIT-9 has the highest Si/Al ratio reported for GME, and along with its good porosity, opens the possibility of using GME in a variety of applications including catalysis. PMID- 28857428 TI - Dose uncertainties associated with a set density override of unknown hip prosthetic composition. AB - The dosimetric uncertainties associated with radiotherapy through hip prostheses while overriding the implant to a set density within the TPS has not yet been reported. In this study, the uncertainty in dose within a PTV resulting from this planning choice was investigated. A set of metallic hip prosthetics (stainless steel, titanium, and two different Co-Cr-Mo alloys) were CT scanned in a water bath. Within the TPS, the prosthetic pieces were overridden to densities between 3 and 10 g/cm3 and irradiated on a linear accelerator. Measured dose maps were compared to the TPS to determine which density was most appropriate to override each metal. This was shown to be in disagreement with the reported literature values of density which was attributed to the TPS dose calculation algorithm and total mass attenuation coefficient differences in water and metal. The dose difference was then calculated for a set density override of 6 g/cm3 in the TPS and used to estimate the dose uncertainty beyond the prosthesis. For beams passing through an implant, the dosimetric uncertainty in regions of the PTV may be as high as 10% if the implant composition remains unknown and a set density override is used. These results highlight limitations of such assumptions and the need for careful consideration by radiation oncologist, therapist, and physics staff. PMID- 28857430 TI - Nonresolving macrophage-mediated inflammation in malignancy. AB - Tumors are populated with different cells of the immune system, each of which has the potential for pro- or antitumor functions. Macrophages are the numerically dominant type of myeloid cell in cancer and are suspected of having predominantly protumor functions. Key questions in cancer research concern the relationships between macrophages and anatomically different kinds of cancers, what specific properties of macrophages are involved in protumor functions and whether either macrophage numbers or functions can be modulated to enhance existing cancer therapies, for example, by reducing the immunosuppressive milieu such that anti tumor T cells can provoke antitumor immunity. Accordingly, several antimacrophage preclinical modalities have been attempted and revealed substantial clinical barriers to their use. Therefore, understanding and targeting the specific pathways associated with protumor functions of macrophages, rather than macrophages themselves is a promising approach for both basic research and therapeutic development. PMID- 28857429 TI - Tenascin-c renders a proangiogenic phenotype in macrophage via annexin II. AB - Tenascin-c is an extracellular matrix glycoprotein, the expression of which relates to the progression of atherosclerosis, myocardial infarction and heart failure. Annexin II acts as a cell surface receptor of tenascin-c. This study aimed to delineate the role of tenascin-c and annexin II in macrophages presented in atherosclerotic plaque. Animal models with atherosclerotic lesions were established using ApoE-KO mice fed with high-cholesterol diet. The expression of tenascin-c and annexin II in atherosclerotic lesions was determined by qRT-PCR, Western blot and immunohistochemistry analysis. Raw 264.7 macrophages and human primary macrophages were exposed to 5, 10 and 15 MUg/ml tenascin-c for 12 hrs. Cell migration as well as the proangiogenic ability of macrophages was examined. Additionally, annexin II expression was delineated in raw 264.7 macrophages under normal condition (20% O2 ) for 12 hrs or hypoxic condition (1% O2 ) for 6-12 hrs. The expression of tenascin-c and annexin II was markedly augmented in lesion aorta. Tenascin-c positively regulated macrophage migration, which was dependent on the expression of annexin II in macrophages. VEGF release from macrophages and endothelial tube induction by macrophage were boosted by tenascin-c and attenuated by annexin II blocking. Furthermore, tenascin-c activated Akt/NF kappaB and ERK signalling through annexin II. Lastly, hypoxia conditioning remarkably facilitates annexin II expression in macrophages through hypoxia inducible factor (HIF)-1alpha but not HIF-2alpha. In conclusion, tenascin-c promoted macrophage migration and VEGF expression through annexin II, the expression of which was modulated by HIF-1alpha. PMID- 28857431 TI - Cost-effectiveness of early intervention services for psychosis and fidelity to national policy implementation guidance. AB - AIM: Early intervention services (EIS) for psychosis are being implemented, internationally. It is important to learn from established examples and define the components and intensity of services that provide good value for money. This study aims to assess the cost-effectiveness of EIS according to how closely they adhered to the recommendations of the English Department of Health 2001 Policy Implementation Guide (PIG). METHODS: EIS from the National Eden Study were assessed using a measure of fidelity to the PIG that rated the presence or absence of 64 recommended items relating to team structure and practice. EIS were then classified into three groups: those with fidelity of 75-80%, 81-90% and 91 95%. Patient-level resource use and outcomes were measured 1 year following inception into the service; costs were calculated and combined with quality adjusted life years (QALYs) gained. RESULTS: At a threshold of L20 000 per QALY, the 81-90% fidelity group had a 56.3% likelihood of being the most cost-effective option followed by 75-80% fidelity at 35.8% and 91-95% fidelity group (7.9%). CONCLUSIONS: The results from England suggest that striving to maximize fidelity may not be warranted, but that dropping below a certain level of fidelity may result in inefficient use of resources. PMID- 28857427 TI - The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people. AB - OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-kappa, FLC-lambda, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case-control study was carried out within the EuroSIDA cohort, including 73 HIV positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels <= 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-kappa [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-lambda (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not <= 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-lambda emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-kappa, FLC-lambda and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention. PMID- 28857432 TI - Volumetric-modulated arc therapy and intensity-modulated radiation therapy treatment planning for prostate cancer with flattened beam and flattening filter free linear accelerators. AB - This study on patients with localized prostate cancer was set up to investigate valuable differences using flattened beam (FB) and flattening filter free (FFF) mode in the application of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). For ten patients, four different plans were calculated with Oncentra planning system of Elekta, using Synergy machines: IMRT and VMAT, with and without flattening filter. Homogeneity and conformity indexes, dose to the organs at risk, and measurements of peripheral dose and dosimetric plan verification including record of the delivery times were analyzed and statistically evaluated. The indexes for homogeneity and conformity (CTV and PTV) are either advantageous or not significantly different for FFF compared to FB with one minor exception. Regarding the doses to the organs at risk and the measured peripheral dose, equivalent or lower doses were delivered for FFF than with FB. Furthermore, the delivery times were significantly shorter for FFF. VMAT compared to IMRT reveals benefits or at least equivalent values. VMAT-FFF combines the most advantageous plan quality parameters with the shortest delivery times and reduced peripheral dose and is therefore recommended for the given equipment and cancer localization. PMID- 28857434 TI - Self-consciousness/Awareness and Bladder Sensations: Comparative Study of Overactive Bladder Patients and Healthy Volunteers. AB - OBJECTIVES: To explore differences in bladder sensations between patients with overactive bladder (OAB) and healthy volunteers by evaluating self-consciousness, self-awareness and affective complaints. METHODS: A prospective, observational study was performed comparing patients with OAB symptoms and healthy volunteers. During 3 days subjects filled out sensation-related bladder diaries (SR-BD), Self Consciousness Questionnaires (SCS), Self-Awareness Questionnaire (SSAS) and the Hospital Anxiety and Depression Scale (HADS). The SSAS was filled out at the second void of the first day. RESULTS: In total, 134 participants were included (66 volunteers and 68 patients). Patients had lower voided volumes (193 mL vs 270 mL, P < 0.05), higher urinary frequency (10.6 vs 6.6, P < 0.05) and higher urgency scores (2.0 vs 1.2, P < 0.05) than volunteers, while perceived bladder fullness was similar. The SCS scores were similar, but the SSAS score was significantly higher for OAB patients (53.6 vs 44.6, P < 0.05). OAB Patients had significantly higher scores for anxiety and depression according to the HADS. CONCLUSIONS: There were significant differences in SR-BD between volunteers and OAB patients. OAB patients had significantly higher self-awareness than volunteers, indicating that OAB patients may attribute different values to body signals. Future research is required to elaborate our knowledge on the perceived sensations and labeling of emotions in OAB. PMID- 28857433 TI - A review of nonstandardized applicators digitization in NucletronTM HDR procedures. AB - The major errors in HDR procedures were failures to enter the correct treatment distance, which could be caused by either entering wrong transmission lengths or imprecisely digitizing the dwelling positions. Most of those errors were not easily avoidable by enhancing the HDR management level because they were caused by implementations of nonstandardized applicators utilizing transmission tubes of different lengths in standard HDR procedures. We performed this comprehensive study to include all possible situations with different nonstandardized applicators that frequently occurred in HDR procedures, provide corresponding situations with standard applicator as comparisons, list all possible errors and in planning, clarify the confusions in offsets setting, and provide mathematical and quantitative solutions for each given scenarios. Training on HDR procedures with nonstandardized applicators are normally not included in most residential program for medical physics, thus this study could be meaningful in both clinical and educational purpose. At precision of 1 mm, our study could be used as the essential and practical reference for finding the correct treatment length as well as locating the accurate dwelling positions in any HDR procedure with nonstandardized applicators. PMID- 28857435 TI - Anesthesia-related and perioperative mortality: An audit of 8493 cases at a tertiary pediatric teaching hospital in South Africa. AB - AIM: This study aimed to quantify the incidence of anesthesia-related and perioperative mortality at a large tertiary pediatric hospital in South Africa. METHODS: This study included all children aged <18 years who died prior to discharge from hospital and within 30 days of their last anesthetic at the Red Cross War Memorial Children's Hospital between January 1, 2015 to December 31, 2015. A panel of three senior anesthetists reviewed each death to reach a consensus as to whether: (i) anesthesia caused the death; (ii) anesthesia may have contributed to or influenced the timing of death; or (iii) anesthesia was entirely unrelated to the death. RESULTS: There were 47 deaths within 30 days of anesthesia prior to discharge from hospital during this 12-month period. The in hospital mortality within 24 h of administration of anesthesia was 16.5 per 10 000 cases (95% confidence intervals [CI]=7.8-25.1) and within 30 days of administration of anesthesia was 55.3 per 10 000 cases (95% CI=39.5-71.2). Age under 1 year (OR 4.5; 95% CI=2.5-8.0, P=.012) and cardiac surgery and interventional cardiology procedures (OR 2.5; 95% CI=1.2-5.2, P<.01) were both independent predictors of increased risk of perioperative mortality. CONCLUSION: The overall 24-h and 30-day anesthesia-related and in-hospital perioperative mortality rates in our study are comparable with other similar studies from tertiary pediatric centers. PMID- 28857436 TI - Regioselective para-Carboxylation of Catechols with a Prenylated Flavin Dependent Decarboxylase. AB - The utilization of CO2 as a carbon source for organic synthesis meets the urgent demand for more sustainability in the production of chemicals. Herein, we report on the enzyme-catalyzed para-carboxylation of catechols, employing 3,4 dihydroxybenzoic acid decarboxylases (AroY) that belong to the UbiD enzyme family. Crystal structures and accompanying solution data confirmed that AroY utilizes the recently discovered prenylated FMN (prFMN) cofactor, and requires oxidative maturation to form the catalytically competent prFMNiminium species. This study reports on the in vitro reconstitution and activation of a prFMN dependent enzyme that is capable of directly carboxylating aromatic catechol substrates under ambient conditions. A reaction mechanism for the reversible decarboxylation involving an intermediate with a single covalent bond between a quinoid adduct and cofactor is proposed, which is distinct from the mechanism of prFMN-associated 1,3-dipolar cycloadditions in related enzymes. PMID- 28857437 TI - II3 V2 (II: Zn, Cd; V: P, As) Semiconductors: From Bulk Solids to Colloidal Nanocrystals. AB - II3 V2 semiconductors have become increasingly popular for a variety of applications including solar light harvesting, near-IR imaging, and low energy light detection. The bulk physical and electronic structure of these materials is highlighted, followed by an in-depth survey on progress in synthesizing these semiconductors as colloidal nanocrystals. Interestingly, no universal synthetic approach has yet been developed to access all compounds within this family. A discussion on how the complex crystal structure of these materials translates to small domain sizes will highlight current challenges in the characterization of II3 V2 nanocrystals. Finally, potential avenues for further research will be proposed as a way to advance this field towards greater utilization in light harvesting applications. PMID- 28857438 TI - Spectacle use after routine cataract surgery: a study from the Swedish National Cataract Register. AB - PURPOSE: To explore patients' obtaining and use of spectacles after routine cataract surgery. METHODS: The study included 1329 patients who underwent bilateral surgery with the second eye operated during March 2013 at 38 different clinics in Sweden. Five months after the second-eye surgery, patients completed a five-item questionnaire about their spectacle use preoperatively and postoperatively. The responses were linked to data from the registry on multiple variables including postoperative refraction, age and gender. RESULTS: Of the 387 patients who were advised by their surgeons to obtain distance spectacles postoperatively, most did so (77.3%, n = 299), while of the 691 patients who were not so advised, most did not obtain spectacles (78.9%, n = 545). Nevertheless, almost 50% of patients with both spherical and cylindrical errors exceeding 1 dioptre (D) did not obtain new distance spectacles postoperatively, while about 25% of patients with bilateral emmetropia (spherical error <0.5 D, cylinder <1 D) obtained new distance spectacles postoperatively. CONCLUSION: Patients' choices regarding obtaining and using new spectacles postoperatively are strongly correlated with advice given by the surgeon about the need for distance correction. The large difference between groups who were and were not advised to obtain spectacles for distance correction was only partially reflected in the postoperative refractive errors. Similarly, the patterns of preoperative spectacle use and gender or age differences did not explain this difference. PMID- 28857439 TI - Shprintzen-Goldberg syndrome associated with first cervical vertebra defects. PMID- 28857440 TI - Preschool children's response to behavioural parent training and parental predictors of outcome in routine clinical care. AB - OBJECTIVE: To investigate the effectiveness of behavioral parent training (BPT) for preschool children with disruptive behaviours and to explore parental predictors of response. METHODS: Parents of 68 preschool children, aged between 2.7 and 5.9 years, participated in BPT. We evaluated the changes in children's behaviour after BPT with a one group pretest-posttest design, using a waiting period for a double pretest. Outcome was based on parents' reports of the intensity and number of behaviour problems on the Eyberg Child Behavior Inventory. Predictor variables included parents' attention-deficit/hyperactivity disorder symptoms, antisocial behaviours, and alcohol use, and maternal parenting self-efficacy and disciplining. RESULTS: Mother-reported child behaviour problems did not change in the waiting period but improved significantly after BPT (d = 0.63). High levels of alcohol use by fathers and low levels of maternal ineffective disciplining were each associated with somewhat worse outcome. CONCLUSIONS: BPT under routine care conditions clearly improves disruptive behaviours in preschool children. Mothers who consider themselves as inadequate in disciplining and mothers whose partners do not consume high levels of alcohol report the largest improvements. PMID- 28857441 TI - Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis. AB - BACKGROUND: Despite many studies suggesting an association between human leukocyte antigen (HLA)-B*5801 and allopurinol-induced toxic epidermal necrolysis (TEN) and Stevens-Johnsons syndrome (SJS), the evidence of association in different populations and the degree of association remain uncertain. METHODS: The primary analysis was based on population-control studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR-), diagnostic odds ratios (DOR), and areas under summary receiver operating characteristic (SROC) curves (AUC) were calculated. RESULTS: In nine population-control studies, HLA-B*5801 was measured in 162 patients with allopurinol-induced TEN/SJS and 7372 patients without allopurinol-induced TEN/SJS. The pooled sensitivity, specificity, LR+, LR , DOR and AUC were 0.78 (95% CI = 0.71-0.85), 0.96 (95% CI = 0.96-0.97), 14.23 (95% CI = 7.89-25.63), 0.29 (95% CI = 0.16-0.54), 83.5 (95% CI = 50.7-137.4), and 0.97 (95% CI = 0.95-0.99), respectively. Subgroup analyses of the DORs for Chinese, Japanese, and Caucasian populations yielded similar findings for Chinese (196.1; 95% CI = 57.3-672.0), Japanese (78.8; 95% CI = 30.4-203.9), and Caucasian (58.4; 95% CI = 16.9-201.5) populations. Overall, HLA-B*5801 was associated with allopurinol-induced TEN/SJS in European and Japanese populations, but only had a 50-60% sensitivity (pooled sensitivity 56%), compared to the 80-100% sensitivity (pooled sensitivity 97%) observed in Korean, Thai, Sardinia Italian and Han Chinese populations. CONCLUSIONS: The present study reveals that allopurinol is the leading cause of TEN/SJS in many countries. In contrast to carbamazepine, which is ethnic/population specific, the HLA-B*5801 for detecting allopurinol induced TEN/SJS is universal. Screening of HLA-B*5801 may help patients to prevent the occurrence of allopurinol-induced TEN/SJS, especially in populations with a higher (>= 5%) risk allele frequency. PMID- 28857442 TI - cAMP response element-binding protein and Yes-associated protein form a feedback loop that promotes neurite outgrowth. AB - The cAMP response element-binding (CREB) protein is a member of the CREB/activating transcription factor family that is activated by various extracellular stimuli. It has been shown that CREB-dependent transcription stimulation plays a key role in neuronal differentiation and plasticity, but the underlying mechanisms remain largely elusive. Here, we show that Yes-associated protein (YAP) is a direct target induced by CREB upon retinoic acid (RA)-induced neurite outgrowth stimuli in N2a cells. Interestingly, YAP knockout using the CRISPR/Cas9 system inhibits neuronal differentiation and reduced neurite length. We further show that YAP could directly bind to CREB via its N-terminal region, and loss of YAP results in instability of phosphorylated CREB upon neurite outgrowth stimuli. Transient expression of YAP could largely restore CREB expression and neurite outgrowth in YAP knockout cells. Together, our results suggest that CREB and YAP form a positive feedback loop that is critical to maintain the stability of phosphorylated CREB and promote neurite outgrowth. PMID- 28857444 TI - Environmental vibrios represent a source of antagonistic compounds that inhibit pathogenic Vibrio cholerae and Vibrio parahaemolyticus strains. AB - With the overuse of antibiotics, many pathogens including Vibrio cholerae and Vibrio parahaemolyticus have evolved multidrug resistance making treatment more difficult. While understanding the mechanisms that underlie pathogenesis is crucial, knowledge of bacterial interactions of V. cholerae and V. parahaemolyticus could provide insight to their susceptibility outside of the human host. Based on previous work showing competition among environmental strains, we predict that marine-derived bacteria should inhibit Vibrio pathogens and may be a source of unique antibiotic compounds. We tested a collection of 3,456 environmental Vibrio isolates from diverse habitats against a panel of V. cholerae and V. parahaemolyticus, and identified 102 strains that inhibited the growth of these pathogens. Phylogenetic analysis revealed that 40 pathogen inhibiting strains were unique at the hsp60 gene sequence while 62 of the isolates were identical suggesting clonal groups. Genomic comparisons of ten strains revealed diversity even between clonal isolates and were identified as being closely related to known Vibrio crassostreae, Vibrio splendidus, and Vibrio tasmaniensis strains. Further analysis revealed multiple biosynthetic gene clusters within all sequenced genomes that encoded secondary metabolites with potential antagonistic activity. Thus, environmental vibrios represent a source of compounds that inhibit Vibrio pathogens. PMID- 28857443 TI - Metabolic and stress responses of Acinetobacter oleivorans DR1 during long-chain alkane degradation. AB - Acinetobacter oleivorans DR1 can utilize C12 -C30 alkanes as a sole carbon source but not short-chain alkanes (C6 , C10 ). Two copies of each alkB-, almA- and ladA type alkane hydroxylase (AH) are present in the genome of DR1 cells. Expression and mutational analyses of AHs showed that alkB1 and alkB2 are the major AH encoding genes under C12 -C30 , and the roles of other almA- and ladA genes are negligible. Our data suggested that AlkB1 is responsible for long-chain alkane utilization (C24 -C26 ), and AlkB2 is important for medium-chain alkane (C12 -C16 ) metabolism. Phylogenetic analyses revealed large incongruities between phylogenies of 16S rRNA and each AH gene, which implies that A. oleivorans DR1 has acquired multiple alkane hydroxylases through horizontal gene transfer. Transcriptomic and qRT-PCR analyses suggested that genes participating in the synthesis of siderophore, trehalose and poly 3-hydroxybutyrate (PHB) were expressed at much higher levels when cells used C30 than when used succinate as a carbon source. The following biochemical assays supported our gene expression analyses: (i) quantification of siderophore, (ii) measurement of trehalose and (iii) observation of PHB storage. Interestingly, highly induced both ackA gene encoding an acetate kinase A and pta gene encoding a phosphotransacetylase suggested unusual ATP synthesis during C30 alkane degradation, which was demonstrated by ATP measurement using the DeltaackA mutant. Impaired growth of the DeltaaceA mutant indicated that the glyoxylate shunt pathway is important when C30 alkane is utilized. Our data provide insight into long-chain alkane degradation in soil microorganisms. PMID- 28857445 TI - Contemporary antiplatelet therapy in acute coronary syndromes: are there differences in outcomes and discontinuation between clopidogrel and ticagrelor? AB - BACKGROUND/AIM: We studied clinical outcomes and discontinuation rates in a 'real world' population presenting with myocardial infarction treated with ticagrelor or clopidogrel. METHODS: Between January 2012 and May 2015, 992 patients with acute myocardial infarction undergoing invasive management and adequately pre treated with dual antiplatelet therapy were prospectively enrolled. Platelet aggregation was measured using the Multiplate analyser. Baseline characteristics, in-hospital outcomes and 1-year outcomes were collected. RESULTS: Patients treated with ticagrelor were younger and less likely to be diabetic, have a previous myocardial infarction or present with a ST-elevation myocardial infarction (all P < 0.05). Those treated with ticagrelor also had lower CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines; 20 +/- 9.4 vs 23 +/ 10.1, P < 0.0001) and GRACE (119 +/- 28 vs 126 +/- 32, P = 0.002) scores. High platelet reactivity was greatly reduced with ticagrelor compared to clopidogrel (16.1% vs 37.0%, respectively; P < 0.0001). Non-coronary artery bypass grafting related thrombolysis in myocardial infarction major and minor bleeding occurred at similar rates in those treated with ticagrelor and clopidogrel. Rates of drug discontinuation in those treated with ticagrelor and clopidogrel were similar in hospital (20.2% vs 16.2%, P = 0.18) and between discharge and 1 year (29.9% vs 27.9%, P = 0.63). However, discontinuation due to dyspnoea, (3.3% vs 0%, P < 0.0001) and discontinuation due to any possible drug-related adverse event (9.3% vs 2.2%, P = 0.0001) was more common in those treated with ticagrelor compared to clopidogrel CONCLUSION: Ticagrelor is paradoxically being used in lower-risk patients rather than those most likely to benefit. Ticagrelor was associated with similar rates of bleeding but higher discontinuation rates due to adverse effects compared to clopidogrel. PMID- 28857446 TI - Diagnostic accuracy of pre-treatment biopsy for grading cutaneous mast cell tumours in dogs. AB - Mast cell tumours (MCTs) are common tumours of the canine skin, and are estimated to represent up to 20% of all skin tumours in dogs. Tumour grade has a major impact on the incidence of local recurrence and metastatic potential. In addition to helping the clinician with surgical planning, knowledge of the tumour grade also assists in proper prognostication and client education. For pre-treatment biopsies to be useful, there must exist a high level of correlation between the histopathological grade obtained from the pre-treatment biopsy and the actual histopathological grade from the excisional biopsy. The aim of this study was to determine concordance of tumour grade between various biopsy techniques (wedge, punch, needle core) and the "gold standard" excisional biopsy method. We found an overall concordance rate of 96% based on the Patnaik grading system, and an overall concordance rate of 92% based on the Kiupel grading system. The accuracy of the various biopsy techniques (wedge, punch and needle core) when compared with excisional biopsy was 92%, 100% and 100%, respectively, based on the Patnaik grading system, and 90%, 95% and 100%, respectively, based on the Kiupel grading system. Of the cases with discordant results, the pre-treatment biopsies tended to underestimate the grade of the tumour. Based on these results, we conclude that pre-treatment biopsies are sufficiently accurate for differentiating low grade from high-grade MCTs, regardless of biopsy technique or tumour location. PMID- 28857447 TI - Perception of parents and self-reports of children regarding the impact of traumatic dental injury on quality of life. AB - BACKGROUND/AIM: Traumatic dental injuries occur frequently among young children. The aim of this study was to evaluate the impact of traumatic dental injuries on oral health-related quality of life (OHRQoL) in preschool children using the Scale of Oral Health Outcomes for 5-year-old children (SOHO-5). MATERIALS AND METHODS: This study involved 769 five-year-old children enrolled at public and private preschools. Two examiners underwent a training process which involved the determination of interexaminer and intra-examiner agreement (Kappa statistic) for all clinical conditions (K > 0.82). Descriptive statistics were performed, followed by Poisson regression analysis (alpha = 5%). RESULTS: The prevalence of the impact of oral problems on OHRQoL was 32.9% and 42.2% according to the parents/caregivers and children, respectively. Based on the children's self reports, the occurrence of two or more injured teeth (PR = 1.30; 95% CI: 1.04 1.64), toothache (PR = 1.68; 95% CI: 1.35-2.09), and a low level of parent's schooling (PR = 1.54; 95% CI: 1.24-1.91) exerted impacts on OHRQoL. For the reports of parents/caregivers, the occurrence of non-complicated TDI (PR = 0.66; 95% CI: 0.44-0.98), toothache (PR = 8.03; 95% CI: 5.92-10.88), and a low level of parent's schooling (PR = 1.60; 95% CI: 1.17-2.17) remained associated with the final model. CONCLUSIONS: The impact of oral problems on the OHRQoL of the preschool children was high. A greater number of injured teeth, the presence of toothache, and socioeconomic factors were associated with poorer OHRQoL, based on the reports of both the parents/caregivers and the children. The occurrence of non-complicated TDI was a protective factor for OHRQoL. PMID- 28857448 TI - Surgical and pharmacological reassignment: influence on transsexual cardiovascular risk profile. AB - BACKGROUND/AIM: To evaluate and stratify early cardiovascular risk of transsexuals who underwent pharmacological and/or surgical gender reassignment. METHODS: Fifty-six transsexuals were divided into two groups: group 1 - underwent gonadectomy (orchiectomy for transwomen and hystero-annessiectomy for transmen); group 2 - hormone replacement therapy alone. All participants underwent carotid artery intima-media thickness (C-IMT) and flow-mediated vasodilation (FMD) of brachial artery evaluations. RESULTS: FMD was lower in patients who had undergone gonadectomy compared with non-surgically treated patients (Group 1: 5.711 vs Group 2: 7.339, P < 0.0001). Mean C-IMT was higher in group 1 than group 2 (group 1: 0.733 vs group 2: 0.582). The duration of hormone therapy correlates positively with mean C-IMT (B = 0.001) and negatively with FMD (%) (B = - 0.007). CONCLUSIONS: Cardiovascular risk, which is expressed in terms of endothelial (FMD) and morphological (C-IMT) dysfunction, increases in subjects undergoing gonadectomy compared with those receiving cross-sex reassignment therapy alone. PMID- 28857449 TI - 3 D Porous Nickel-Cobalt Nitrides Supported on Nickel Foam as Efficient Electrocatalysts for Overall Water Splitting. AB - Exploring highly efficient and durable bifunctional electrocatalysts from earth abundant low-cost transition metals is central to obtaining clean hydrogen energy through large-scale electrolytic water splitting. Porous nickel-cobalt nitride nanosheets on macroporous Ni foam (NF) are synthesized through facile electrodeposition followed by a one-step annealing process in a NH3 atmosphere. The transformation from a metal hydroxide into a metal nitride could efficiently enhance the electrocatalytic performance for both the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Interestingly, the incorporation of nickel further boosts the catalytic activity of cobalt nitride. When used as bifunctional electrocatalysts, the obtained nickel-cobalt nitride electrocatalyst shows good stability and superior catalytic performance toward both HER and OER with low overpotentials of 0.29 and 0.18 V, respectively, to achieve a current density of 10 mA cm-2 . The good electrocatalytic performance was also evidenced by the fabrication of an electrolyzer for overall water splitting, which exhibits a high gas generation rate for hydrogen and oxygen with excellent stability during prolonged alkaline water electrolysis. The present work provides an efficient approach to prepare a 3 D interconnected porous nickel-cobalt nitride network with exposed inner active sites for overall water splitting. PMID- 28857450 TI - Screening, separation, and evaluation of xanthine oxidase inhibitors from Paeonia lactiflora using chromatography combined with a multi-mode microplate reader. AB - Natural products have become one of the most important resources for discovering novel xanthine oxidase inhibitors, which are commonly employed in the treatment of hyperuricemia and gout. However, to date, few reports exist regarding the use of monoterpene glycosides as xanthine oxidase inhibitors. Thus, we herein report the use of ultrafiltration coupled with liquid chromatography in the screening of monoterpene glycoside xanthine oxidase inhibitors from the extract of Paeonia lactiflora (P. lactiflora), and both high-performance counter-current chromatography and medium-pressure liquid chromatography were employed to separate the main constituents. Furthermore, the xanthine oxidase inhibitory activities and the mechanisms of inhibition of the isolated compounds were evaluated using a multi-mode microplate reader by Molecular Devices. As a result, three monoterpene glycosides were separated by combined high-performance counter current chromatography and medium-pressure liquid chromatography in purities of 90.4, 98.0, and 86.3%, as determined by liquid chromatography. These three compounds were identified as albiflorin, paeoniflorin, and 1-O-beta-? glucopyranosyl-8-O-benzoylpaeonisuffrone by electrospray ionization tandem mass spectrometry, and albiflorin and paeoniflorin were screened as potential xanthine oxidase inhibitors by ultrafiltration with liquid chromatography. The evaluation results of xanthine oxidase inhibitory activity corresponded with the screening results, as only albiflorin and paeoniflorin exhibited xanthine oxidase inhibitory activity. PMID- 28857451 TI - Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). AB - AIM: We evaluated the efficacy and safety of ertugliflozin, an SGLT2 inhibitor, in type 2 diabetes mellitus (T2DM) inadequately controlled (HbA1c, 7.0%-10.5%) with metformin monotherapy (>=1500 mg/d for >=8 weeks). METHODS: This was a double-blind, 26-week, multicentre study with ongoing 78-week extension (ClinicalTrials.gov identifier: NCT02033889). A total of 621 participants were randomized 1:1:1 to placebo, or ertugliflozin 5 or 15 mg/d. The primary endpoint was change from baseline at week 26 in HbA1c. Secondary efficacy endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight, systolic/diastolic blood pressure (SBP/DBP) and number of participants with HbA1c <7.0% (53 mmol/mol). Pre-specified adverse events (AEs) of special interest and percent change from baseline in bone mineral density (BMD) were also assessed at week 26. RESULTS: At week 26, the placebo-adjusted least-squares mean change from baseline HbA1c (8.1%) was -0.7% and -0.9% for ertugliflozin 5 and 15 mg, respectively (both P < .001), to final means of 7.3% and 7.2%, respectively. The odds of HbA1c <7.0% were significantly greater in both ertugliflozin groups vs placebo. Ertugliflozin significantly reduced FPG, body weight, SBP and DBP vs placebo. The incidence of genital mycotic infections was higher in the ertugliflozin groups (female subjects: placebo, 0.9%; ertugliflozin 5 mg, 5.5%; ertugliflozin 15 mg, 6.3% [P = .032]; male subjects: 0%; 3.1%; 3.2%, respectively), as was the incidence of urinary tract infections and symptomatic hypoglycaemia. The incidence of hypovolaemia AEs was similar across groups. Ertugliflozin had no adverse impact on BMD at week 26. CONCLUSIONS: Ertugliflozin added to metformin in patients with inadequately controlled T2DM improved glycaemic control, reduced body weight and BP, but increased the incidence of genital mycotic infections. PMID- 28857452 TI - Quantum molecular resonance technology in hard-to-heal extremity wounds: histological and clinical results. AB - Chronic wounds are commonly associated with high morbidity rates due to the patient's need of frequent dressing changes and repeated visits to the outpatient wound clinic. Furthermore, chronic wounds are often characterised by severe pain, which can cause significant disability to the patient. New technologies aim to develop an optimal device to reduce discomfort of the patient and to heal wounds. The device Rexon-age(r) is introduced for the first time in wound healing, and preliminary data on clinical and histological results are shown. From April 2014 to April 2015, 11 patients - 7 females and 4 males - were enrolled in the present study. The study was conducted at the Plastic and Reconstructive Institute of the Universita degli Studi di Torino, Citta della Salute e della Scienza of Torino, Italy. For histological characterisation, pre- and post-treatment biopsies on the wound bed were performed. Data regarding age, gender, weight, height, comorbidity, drug therapy and topical pre-treatment and dressings of the wound were collected as well. Moreover, local factors regarding the wound data were as follows: aetiology, time of the wound formation until first Rexon-age treatment, wound dimensions, wound bed, moisture, margins and anatomical region of the wound. A visual analogue scale (VAS) was used to monitor the pain before and after each treatment. Rexon-age treatment resulted in improvement in granulation tissue and wound contraction. Moreover, a significant reduction of pain was observed with the reduction of painkillers drug usage. Among these Rexon-age treated patients, three patients displayed 60-80% reduction in pain intensity, and two patients showed complete pain relief. In outpatient follow-up appointments, we registered long-term durability of pain relief. As assessed by histological analyses, post-treatment biopsies of all nine patients revealed a decreased amount of inflammatory cells and lower expression levels of metalloproteinases (e.g. MMP9). We observed increased capillary thrombosis as well as up-regulation of vascular endothelial growth factor (VEGF) expression. The current study presents the first evidence that Rexon-age-based therapy can significantly ameliorate and accelerate the healing process of chronic wounds. Although this study analysed only a small number of patients, we could consistently observe positive effects on both the clinical aspect of the lesions, which underwent size reduction and wound reactivation, and the quality of life of our patients due to long-term pain relief. PMID- 28857453 TI - Prior Endurance Training Enhances Beta-Adrenergic Signaling in Epidydimal Adipose from Mice Fed a High-Fat Diet. AB - OBJECTIVE: Adipose tissue beta-adrenergic signaling is attenuated in obesity and insulin resistance. It has been previously demonstrated that prior exercise training protects against short-term, high-fat diet (HFD)-induced weight gain and glucose intolerance. This study aimed to determine whether prior exercise training results in altered beta-adrenergic and lipolytic signaling in adipose tissue when challenged with a HFD. METHODS: Male C57BL/6J mice underwent 4 weeks of treadmill training (1 h/d, 5 d/wk). Twenty-four hours after the final bout of exercise, mice were fed a HFD (60% kcal lard) for 4 days. RESULTS: Serum fatty acids, beta-adrenergic signaling (phosphorylated ERK, hormone-sensitive lipase, and p38), and perilipin 1 content were greater in epididymal white adipose tissue (eWAT) from previously trained mice. These changes were not evident in eWAT from trained mice prior to the HFD and were not secondary to alterations in insulin responsiveness or catecholamine concentrations. CL 316,243-mediated increases in hormone-sensitive lipase phosphorylation and fatty acid accumulation in the media were greater in adipose tissue explants from previously trained mice fed a HFD. CONCLUSIONS: These findings suggest that previous training increases adipose tissue beta-adrenergic responsiveness to a short-term HFD. This may help to explain the protective effect of prior exercise training against the deleterious effects of a HFD. PMID- 28857454 TI - Anatomy education in occupational therapy curricula: Perspectives of practitioners in the United States. AB - The study of human anatomy is an integral component in the education of future occupational therapists, yet there is a paucity of research that explores the anatomy needs of students and new practitioners. As a follow up from a pilot study that surveyed a small cohort of practicing therapists, this article aimed to determine occupational therapy (OT) practitioners' views on anatomy course structure and content deemed important to include in OT curricula, entry level practitioners' anatomy knowledge, and application of anatomy in current practice. A Likert scale and free text questionnaire was distributed to practicing occupational therapists across the United States. Fifty-four percent of the participants in this cohort favored a standalone course, as compared to 94% in the pilot study group. Anatomy course content areas were comparable across groups. Systems identified as essential to cover in an OT anatomy course included skeletal, muscular, and nervous. Regions included the upper limb, thorax/trunk, head and neck, and lower limb. Seventy percent of participants in both groups felt that entry-level practitioners had adequate anatomy knowledge; 30% did not. Practice areas requiring anatomy knowledge included assessment of joint movement, muscle strength, pain, and functional mobility. Qualitative analysis of free text response data revealed the importance of anatomy knowledge in OT assessment and intervention strategies, determining the impact of injury or disease on occupational performance, client safety, and communication with other health care professionals and families. Anat Sci Educ 11: 243-253. (c) 2017 American Association of Anatomists. PMID- 28857455 TI - Pyruvate-Kinase-Coupled Glycosyltransferase Assays: Limitations, Struggles and Problem Resolution. AB - Enzyme assays involving coupled pyruvate kinase (PK) have been used for many years to monitor the activity of major classes of enzymes including glycosyltransferases. Numerous potent inhibitors have been discovered and kinetically characterized thanks to this technology. However, when inhibitors of these important enzymes are screened, PK inhibitors or activators are very often observed. In this study we report solutions to resolve the problems encountered either during the screening or during the kinetic characterization of glycosyltransferase inhibitors by means of PK-coupled assays. The enzyme under study-WaaC-is an important glycosyltransferase involved in the bacterial lipopolysaccharide (LPS) biosynthesis pathway. Firstly we showed that alternative kinases such as nucleoside 5-diphosphate kinase (NDPK), myokinase (MK), and ADPdependent hexokinase that catalyze similar reactions to PK are prone to the same troubles. Moreover, an ADP chemosensor was used as an alternative but the sensitivity was not sufficient to allow a proper screening. Finally, we found that a stepwise PK/luciferase assay resolved the problems encountered with PK inhibitors and that a WaaC HPLC assay allowed the identification of WaaC inhibitors acting as PK activators, thus allowing false positive and false negative results linked to the coupling to PK to be eliminated. PMID- 28857456 TI - Integration of Transcriptomic and Metabolomic Data Reveals Enhanced Steroid Hormone Biosynthesis in Mouse Uterus During Decidualization. AB - It has been long recognized that decidualization is accompanied by significant changes in metabolic pathways. In the present study, we used the GC-TOF-MS approach to investigate the global metabolite profile changes associated with decidualization of mouse uterus on day 8 of pregnancy. We identified a total of 20 differentially accumulated metabolites, of which nine metabolites were down regulated and 11 metabolites were up-regulated. As expected, seven differentially accumulated metabolites were involved in carbohydrate metabolism. We observed statistically significant changes in polyamines, putrescine and spermidine. Interestingly, the pantothenic acid, also known as vitamin B5 , was up-regulated. Finally, by integrating with transcriptomic data obtained by RNA-seq, we revealed enhanced steroid hormone biosynthesis during decidualization. Our study contributes to an increase in the knowledge on the molecular mechanisms of decidualization. PMID- 28857457 TI - Non-adherence to treatment of chronic wounds: patient versus professional perspectives. AB - The reasons for the non-adherence to treatment for wound healing are complex and fall into unintentional and intentional categories. This study explored intentional and unintentional non-adherence to treatment from patient/carer and health care professional perspectives. Patients with wounds receiving ALLEVYN Life dressings (n = 20) and patients not receiving ALLEVYN Life dressings who were deemed to be non-adherent to treatment regimes (n = 6) took part in semi structured interviews to explore their experiences of living with a wound, treatment and intentional and unintentional non-adherence. Three focus groups of health care professionals explored issues surrounding non-adherence to treatment regimes. Groups included nurses and doctors (n = 25). We found that relationships between participants and health care professionals varied in character across the groups. All participants expressed reasons for both intentional and unintentional adherence. Many reasons for intentional non-adherence are related to comfort and working the regime around patients' lives. Health care professionals considered the most common form of non-adherence to be unintentional. However, patients describe the most common form of non-adherence as being intentional. The relationship between patients and health care professionals varied in character between the groups. Discrepancies between professional and patient perspectives need to be reconciled and addressed to improve adherence to treatment regimes. PMID- 28857458 TI - Transparent Substrates Prepared From Different Amorphous Polymers Can Directly Modulate Primary Human B cell functions. AB - Manipulation of B cell functions such as antibody and cytokine secretion, is of clinical and biotechnological interest and can be achieved by soluble ligands activating cell surface receptors. Alternatively, the exposure to suitable solid substrates would offer the possibility to transiently induced cell signaling, since the signaling is interrupted when the cells are removed from the substrate. Cell/substrate interactions are mediated by physical valences such as, hydrogen bonds or hydrophobic forces on the substrate surface. Therefore, in this study B cells were cultivated on polymeric substrates, differing in their chemical composition and thus their capacity to undergo physical interactions. Activated B cells cultivated on polystyrene (PS) showed an altered cytokine response indicated by increased IL-10 and decreased IL-6 secretion. Interestingly, B cells cultivated on polyetherurethane (PEU), which has among all tested polymers the highest potential to form strong hydrogen bonds showed an impaired activation, which could be restored by re-cultivation on tissue culture polystyrene. The results indicate that B cell behavior can transiently be manipulated solely by interacting with polymeric surface, which could be explained by receptor activation mediated by physical interaction with the substrate or by altering the availability of the soluble stimulatory reagents by adsorption processes. PMID- 28857459 TI - Cobalt Doping To Boost the Electrochemical Properties of Ni@Ni3 S2 Nanowire Films for High-Performance Supercapacitors. AB - Metal sulfides have aroused great interest for energy storage. However, their low specific capacities and inferior rate capabilities hinder their practical applications. In this work, a facile cobalt-doping process is used to boost the electrochemical performance of Ni@Ni3 S2 core-sheath nanowire film electrodes for high-performance electrochemical energy storage. Co ions are doped successfully and uniformly into Ni3 S2 nanosheets through a facile ion-exchange process. The electrochemical properties of film electrodes are improved greatly, and an ultrahigh volumetric capacity (increased from 105 to 730 C cm-3 at 0.25 A cm-3 ) and excellent rate capability are obtained after Co is doped into Ni@Ni3 S2 core sheath nanowires. A hybrid asymmetric supercapacitor with Co-doped Ni@Ni3 S2 as the positive electrode and graphene-carbon nanotubes as the negative electrode is assembled and exhibits an ultrahigh volumetric capacitance of 142 F cm-3 (based on the total volume of both electrodes) at 0.5 A cm-3 and excellent cycling stability (only 3 % capacitance decrease after 5000 cycles). Moreover, the volumetric energy density can reach 44.5 mWh cm-3 , which is much larger than those of thin-film lithium batteries (1-10 mWh cm-3 ). These results may provide useful insights for the fabrication of high-performance film electrodes for energy-storage applications. PMID- 28857460 TI - Working memory and salivary brain-derived neurotrophic factor as developmental predictors of cocaine seeking in male and female rats. AB - Poor working memory is linked to future risk-taking behaviors. Lifelong risk of habitual drug use is highest in individuals who initiate use in early adolescence. We sought to determine in rats whether juvenile traits, specifically poor working memory and low salivary brain-derived neurotrophic factor (BDNF), are related to elevated cocaine taking and relapse in adolescence and adulthood. On postnatal day (P) 20, working memory was assessed using the novel object recognition task in male and female rats. Saliva was assayed at P20 for BDNF before cocaine self-administration on P28 [0.75 or 0.25 mg/kg/infusion for 30 days under a fixed-ratio (FR) 1 to FR5 schedule] and on P94 before relapse after 30-day abstinence in adulthood. A separate cohort of P28 male rats was assayed for object discrimination and BDNF in saliva and the medial prefrontal cortex and dorsolateral striatum. Novel object discrimination correlated positively with salivary BDNF on P20 and dorsolateral striatum levels, but negatively with medial prefrontal cortex BDNF in male rats. In female rats, P20 salivary BDNF negatively correlated with object discrimination. Salivary BDNF positively correlated across age in male rats. Male rats earned more cocaine (0.75 mg/kg) at FR5 and responded more at relapse than did female rats. These elevated relapse rates in male rats were significantly associated with P20 object discrimination and salivary BDNF. Relapse after 0.75 and 0.25 mg/kg in female rats correlated only with object discrimination. In conclusion, poor working memory and low salivary BDNF in juvenile male rats may represent biomarkers for later cocaine use. Further research is needed to identify biomarkers for risk in male rats. PMID- 28857461 TI - LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles. AB - Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. PMID- 28857462 TI - Polysulfide Coordination Clusters of the Lanthanides. AB - The reaction of [(DippForm)2 Ln(thf)2 ] with an excess of elemental sulfur in toluene resulted in the formation of the trinuclear polysulfide coordination clusters [(DippForm)3 Ln3 S12 ] (Ln=Sm, Yb; DippForm=N,N'-bis(2,6 diisopropylphenyl)formamidinate). These are the first f element coordination clusters (Lnn Sx ) with a larger polysulfide unit (n and x>2). The formation of the coordination clusters can be rationalized by the reductive cleavage of S8 with divalent lanthanides. PMID- 28857463 TI - Gastric bypass surgery does not increase the risk for sight-threatening diabetic retinopathy. AB - PURPOSE: To study the occurrence and level of diabetic retinopathy (DRP) before and after planned bariatric surgery and to investigate potential risk factors for deterioration of DRP. METHODS: The Scandinavian Obesity Surgery Registry (SOReg) was used to identify diabetic patients who underwent gastric bypass (GBP) surgery at three centres in Sweden during 2008-2010. Information regarding DRP screening was obtained from ophthalmological patient charts. Patients who had DRP screening before and after GBP surgery were included in the study. RESULTS: The survey included 117 patients. Mean age was 50 (SD 10) years, body mass index (BMI) 43 (SD 8) kg/m2 and HbA1c 64 (SD 18) mmol/mol before surgery. One year post-GBP, BMI was reduced to 31 (SD 6) kg/m2 . HbA1c was 43 (SD 10) mmol/mol, and in 66% (77/117) treatment for diabetes had been discontinued. Occurrence of DRP before GBP was as follows: no DRP 62%, mild 26%, moderate 10%, severe 0% and proliferative DRP 2%. No significant changes in occurrence of DRP after surgery were observed. Twelve patients (16%) developed mild DRP. In seven patients with pre-existing DRP, deterioration was observed and two of these patients required treatment for sight-threatening DRP. No association between preoperative BMI, HbA1c or reduction in HbA1c and worsening of DRP was found. CONCLUSION: In a majority of patients, no deterioration of DRP following GBP was observed. Screening for DRP before planned surgery is recommended for all diabetic patients about to undergo bariatric surgery to identify any pre-existing DRP. PMID- 28857464 TI - The effect of trypan blue treatment on autofluorescence of fixed cells. AB - Controlling background fluorescence remains an important challenge in flow cytometry, as autofluorescence can interfere with the detection of chromophores. Furthermore, experimental procedures can also affect cellular fluorescence in certain regions of the emission spectrum. In this work, the effects of fixation, permeabilization, and heating on cellular autofluorescence are analyzed in various spectral regions, along with the influence of trypan blue as a quenching dye for these treatments. The impact of these procedures on the staining of SK-BR 3 cells with a dim green fluorophore, a miniSOG (mini Singlet Oxygen Generator) flavoprotein in the form of the recombinant protein DARPin-miniSOG, is also evaluated. The data presented here indicate that fixation of certain types of cells leads to noticeable increase of the autofluorescence. Our results also suggest that trypan blue should be used as an autofluorescence quencher only with bright green emitters since it interferes with the fluorescent signal in a longer wavelength region of the spectrum and as a result causes reduction of the signal from dim green fluorescent agents. (c) 2017 International Society for Advancement of Cytometry. PMID- 28857465 TI - On the Dynamical Behavior of the Cysteine Dioxygenase-l-Cysteine Complex in the Presence of Free Dioxygen and l-Cysteine. AB - In this work, viable models of cysteine dioxygenase (CDO) and its complex with l cysteine dianion were built for the first time, under strict adherence to the crystal structure from X-ray diffraction studies, for all atom molecular dynamics (MD). Based on the CHARMM36 FF, the active site, featuring an octahedral dummy Fe(II) model, allowed us observing water exchange, which would have escaped attention with the more popular bonded models. Free dioxygen (O2 ) and l cysteine, added at the active site, could be observed being expelled toward the solvating medium under Random Accelerated Molecular Dynamics (RAMD) along major and minor pathways. Correspondingly, free dioxygen (O2 ), added to the solvating medium, could be observed to follow the same above pathways in getting to the active site under unbiased MD. For the bulky l-cysteine, 600 ns of trajectory were insufficient for protein penetration, and the molecule was stuck at the protein borders. These models pave the way to free energy studies of ligand associations, devised to better clarify how this cardinal enzyme behaves in human metabolism. PMID- 28857466 TI - Fractional ablative and nonablative radiofrequency for skin resurfacing and rejuvenation of Thai patients. AB - BACKGROUND: Fractional radiofrequency (RF) technology is often the preferable skin resurfacing treatment, especially among Asian patients. Second generation fractional RF technology has exclusive capability to produce separate biological responses (ablation, coagulation, or a combination of both) with 3 distinguished penetration depth programs. AIMS: The aim of this study was to evaluate the efficacy and safety of a fractional RF handpiece such as this, on the Thai population. METHODS: Fifty-five Thai patients were treated with a fractional RF handpiece. The clinical assessment included a pain score, satisfaction survey, physician assessment, a combined patient and physician's assessment of skin condition, and clinical photographic assessments. The wound healing response was evaluated according to 5-time points: immediately after applying a pulse, post 24 hours, post 7 days, post 1 month and post 8 weeks. RESULTS: The obtained patient satisfaction score was "very satisfied" among 74% of the patients, post 3 sessions. Positive correlation was found between patient satisfaction and the physician's assessment. The skin condition assessment showed an increase from an average of 4.2 to 7.9. All treated symptoms improved after each treatment and the clinical outcome lasted at least up to 3-5 months. No significant adverse events were recorded. The in vivo prospective study showed a dose-related response in the deepness of the coagulation injury. In addition, there was evidence for a progressive healing process beginning shortly after exposure and completed within a week. CONCLUSIONS: This study clinically and histologically supports the efficacy of fractional RF handpiece in question with a high safety profile. PMID- 28857467 TI - Impaired erythropoietin synthesis in chronic kidney disease is caused by alterations in extracellular matrix composition. AB - Renal fibrosis and anaemia are two of the most relevant events in chronic kidney disease. Fibrosis is characterized by the accumulation of extracellular matrix proteins in the glomeruli and tubular interstitium. Anaemia is the consequence of a decrease in erythropoietin production in fibrotic kidneys. This work analyses the possibility that the accumulation of abnormal collagens in kidney interstitium could be one of the mechanisms responsible for erythropoietin decreased synthesis. In renal interstitial fibroblast grown on collagen I, erythropoietin mRNA expression and HIF-2alpha protein decreased, whereas focal adhesion kinase protein (FAK) phosphorylation and proteasome activity increased, compared to cells grown on collagen IV. Proteasome inhibition or FAK inactivation in cells plated on collagen I restored erythropoietin and HIF-2alpha expression. FAK inhibition also decreased the collagen I-dependent proteasome activation. In a model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice, increased collagen I protein content and an almost complete disappearance of erythropoietin mRNA expression were observed in the ureteral ligated kidney with respect to the contralateral control. Interestingly, erythropoietin synthesis was recovered in obstructed mice treated with proteasome inhibitor. These data suggest that reduced kidney erythropoietin synthesis could be caused by the accumulation of abnormal extracellular matrix proteins. PMID- 28857468 TI - Effect of Thiolated Ligands in Au Nanowire Synthesis. AB - Thiolated ligands are seldom used as morphology-directing reagent in the synthesis of Au nanostructures due to their low selectivity toward the different facets. Recently, we developed a thiolated ligands-induced synthesis of nanowires where the selective Au deposition only occurs at the ligand-deficient Au substrate interface. Herein, the structural effect of thiolated ligands in this active surface growth is systematically investigated. It is revealed that their ability of rendering surface is closely related to the molecular structure. Ligands with aromatic backbones are capable of inducing nanowire formation, whereas those with aliphatic backbones cannot, likely because the former can pack better at short time scale of the rapid growth. The substituents of the ligands are critical for the colloidal stability of the final structure. It is further demonstrated that aromatic and aliphatic ligands could be mixed to turn on the continual lateral growth, leading to nanowires with tapered ends. The ligand generality in this growth mode also allows the creation of superhydrophobic surface, with the nanowire forest providing the nanoscale surface roughness and the hydrophobic ligand offering the surface property. These applications of the thiolated ligands in the nanosynthesis open a new approach for controlled synthesis of Au-based nanostructures with various morphologies and properties. PMID- 28857470 TI - Assessment of PlanIQ Feasibility DVH for head and neck treatment planning. AB - INTRODUCTION: Designing a radiation plan that optimally delivers both target coverage and normal tissue sparing is challenging. There are limited tools to determine what is dosimetrically achievable and frequently the experience of the planner/physician is relied upon to make these determinations. PlanIQ software provides a tool that uses target and organ at risk (OAR) geometry to indicate the difficulty of achieving different points for organ dose-volume histograms (DVH). We hypothesized that PlanIQ Feasibility DVH may aid planners in reducing dose to OARs. METHODS AND MATERIALS: Clinically delivered head and neck treatments (clinical plan) were re-planned (re-plan) putting high emphasis on maximally sparing the contralateral parotid gland, contralateral submandibular gland, and larynx while maintaining routine clinical dosimetric objectives. The planner was blinded to the results of the clinically delivered plan as well as the Feasibility DVHs from PlanIQ. The re-plan treatments were designed using 3-arc VMAT in Raystation (RaySearch Laboratories, Sweden). The planner was then given the results from the PlanIQ Feasibility DVH analysis and developed an additional plan incorporating this information using 4-arc VMAT (IQ plan). The DVHs across the three treatment plans were compared with what was deemed "impossible" by PlanIQ's Feasibility DVH (Impossible DVH). The impossible DVH (red) is defined as the DVH generated using the minimal dose that any voxel outside the targets must receive given 100% target coverage. RESULTS: The re-plans performed blinded to PlanIQ Feasibilty DVH achieved superior sparing of aforementioned OARs compared to the clinically delivered plans and resulted in discrepancies from the impossible DVHs by an average of 200-700 cGy. Using the PlanIQ Feasibility DVH led to additionalOAR sparing compared to both the re-plans and clinical plans and reduced the discrepancies from the impossible DVHs to an average of approximately 100 cGy. The dose reduction from clinical to re-plan and re-plan to IQ plan were significantly different even when taking into account multiple hypothesis testing for both the contralateral parotid and the larynx (P < 0.004 for all comparisons). No significant differences were observed between the three plans for the contralateral parotid when considering multiple hypothesis testing. CONCLUSIONS: Clinical treatment plans and blinded re-plans were found to suboptimally spare OARs. PlanIQ could aid planners in generating treatment plans that push the limits of OAR sparing while maintaining routine clinical target coverage goals. PMID- 28857469 TI - The NLPR3 inflammasome and obesity-related kidney disease. AB - Over the past decade, the prevalence of obesity has increased, accompanied by a parallel increase in the prevalence of chronic kidney disease (CKD). Mounting evidence suggests that high body mass index (BMI) and obesity are important risk factors for CKD, but little is known about the mechanisms of obesity-related kidney disease (ORKD). The NLRP3 inflammasome is a polyprotein complex that plays a crucial role in the inflammatory process, and numerous recent studies suggest that the NLRP3 inflammasome is involved in ORKD development and may serve as a key modulator of ORKD. Moreover, inhibiting activation of the NLRP3 inflammasome has been shown to attenuate ORKD. In this review, we summarize recent progress in understanding the link between the NLRP3 inflammasome and ORKD and discuss targeting the NLRP3 inflammasome as a novel therapeutic approach for ORKD. PMID- 28857472 TI - Dual-pH/Magnetic-Field-Controlled Drug Delivery Systems Based on Fe3 O4 @SiO2 Incorporated Salecan Graft Copolymer Composite Hydrogels. AB - Salecan is a water-soluble extracellular beta-glucan and has excellent physicochemical and biological properties for hydrogel preparation. In this study, a new pH/magnetic field dual-responsive hydrogel was prepared by the graft copolymerization of salecan with 4-pentenoic acid (PA) and N hydroxyethylacrylamide (HEAA) in the presence of Fe3 O4 @SiO2 nanoparticles for doxorubicin hydrochloride (DOX) release. Integration of Fe3 O4 @SiO2 nanoparticles in salecan-g-poly(PA-co-HEAA) copolymers afforded magnetic sensitivity to the original material. DOX-loaded hydrogels exhibited a clear capacity for pH/magnetic field dual-responsive controlled drug release. Lowering the pH to acidic conditions or introducing an external magnetic field caused an enhancement in DOX release. This salecan-g-poly(PA-co-HEAA)/Fe3 O4 @SiO2 composite hydrogel is a promising drug carrier for magnetically targeted drug delivery with enhanced DOX cytotoxicity against A549 cells. PMID- 28857471 TI - Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs. AB - Activation of the phosphoinositide 3-kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on-target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life-threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so-far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan-PI3K inhibitor. PMID- 28857473 TI - Genetic and environmental influences on cardiovascular risk factors and cognitive function: A Chinese twin aging study. AB - AIM: To explore the genetic and environmental influences on cardiovascular risk factors (CVRF) and cognitive function in the world's largest and rapidly aging Chinese population. METHODS: Cognitive function and CVRF, including body mass index, systolic blood pressure, diastolic blood pressure, pulse pressure, glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol were measured in 379 complete twin pairs. Univariate and bivariate twin models were fitted to estimate the genetic and environmental components in the variance and covariance of CVRF and cognition. RESULTS: Mild-to-high heritability was estimated for CVRF and cognition (0.27-0.74). Unique environmental factors showed low-to-moderate contributions (0.23-0.56). Only HDLC presented significant common environmental contribution (0.50). Bivariate analysis showed significantly negative genetic correlations (rG ) between cognition and systolic blood pressure (rG = -0.56), diastolic blood pressure (rG = -0.42), pulse pressure (rG = -0.45), and positive genetic correlations between cognition and total cholesterol (rG = 0.33), triglyceride (rG = 0.23) and HDLC (rG = 0.41). HDLC and cognition presented a unique environmental correlation (rE = -0.13), but in the opposite direction. CONCLUSIONS: Cognitive function was genetically related to systolic blood pressure, diastolic blood pressure, pulse pressure, total cholesterol, triglyceride and HDLC with a negative or positive direction. Cognition and HDLC might share part of a similar unique environmental factor. Geriatr Gerontol Int 2018; 18: 352-359. PMID- 28857474 TI - Association between serum vitamin D levels and neuropathic pain in rheumatoid arthritis patients: A cross-sectional study. AB - AIM: Recent literature suggests that neuropathic pain (NP) and vitamin D deficiency can occur concurrently in patients with rheumatoid arthritis (RA). This study aimed to examine the development of NP in patients with RA and the relationship between NP and vitamin D. METHODS: We used the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaire to evaluate NP in 93 patients with RA. Demographic and clinical data were obtained from patient files and interviews, and patients' serum vitamin D levels were recorded. Patients were requested to complete both the Short Form-36 survey and the Health Assessment Questionnaire. RESULTS: Seventy-five of the eligible patients were female (80.6%), and 31 (33.3%) were diagnosed with NP according to the LANSS. There was a negative correlation between vitamin D levels and the LANSS score (P = 0.001). The prevalence of NP was 5.8 times higher among patients with serum vitamin D levels below 20 ng/mL than in patients with vitamin D levels >= 30 ng/mL. Based on the area under curve (AUC) values, we found that serum levels of vitamin D were a good predictor of NP diagnoses in patients with RA (AUC = 0.71). CONCLUSION: We found that vitamin D deficiency was asssociated with increased NP in patients with RA. Although further research is needed to clarify the association between serum vitamin D levels and NP, our study raises awareness of the need to screen for vitamin D deficiency in RA patients with NP. PMID- 28857476 TI - Buchwald-Hartwig Amination of Nitroarenes. AB - The Buchwald-Hartwig amination of nitroarenes was achieved for the first time by using palladium catalysts bearing dialkyl(biaryl)phosphine ligands. These cross coupling reactions of nitroarenes with diarylamines, arylamines, and alkylamines afforded the corresponding substituted arylamines. A catalytic cycle involving the oxidative addition of the Ar-NO2 bond to palladium(0) followed by nitrite/amine exchange is proposed based on a stoichiometric reaction. PMID- 28857475 TI - Overexpression of IFITM3 predicts poor prognosis in stage IIA esophageal squamous cell carcinoma after Ivor Lewis esophagectomy. AB - BACKGROUND: Recent research has shown that IFITM3 plays an important role in the tumorigenesis of many malignancies. We investigated the clinicopathological variables and prognostic value of IFITM3 in stage IIA esophageal squamous cell carcinoma (ESCC) patients. METHODS: Immunohistochemistry and Western blot analysis were used to examine IFITM3 expression in tumor specimens. The relationships between IFITM3 expression and clinicopathological variables, as well as the five-year survival and recurrence status of patients, were analyzed. RESULTS: IFITM3 was aberrantly expressed in tumor tissue. Statistical analysis showed a close correlation of IFITM3 expression with T tumor status (P = 0.004). Additionally, IFITM3 overexpression, advanced T status, poor degree of differentiation, and large tumor size were not only associated with poor survival but were high lymphatic metastatic recurrence predictors in ESCC patients (P < 0.05). CONCLUSION: Our data indicated that IFITM3 overexpression may predict poor prognosis in stage IIA ESCC patients after Ivor Lewis esophagectomy. PMID- 28857477 TI - Human placenta mesenchymal stem cells promote axon survival following optic nerve compression through activation of NF-kappaB pathway. AB - Different damage factors are known to trigger cell death in the optic nerves. Use of mesenchymal stem cells is a possible treatments option for traumatic optic nerve injury due to their ability to secrete protective cytokines and recovery factors. In this study, we investigated the neuroprotective effects of human placenta-derived mesenchymal stem cells (hPMSCs) using an established optic nerve compression model and model of R28 cells that were exposed to hypoxia. Forty percent of axon death was seen in induced in vivo optic nerve injury model (p < .05), and 70% of R28 cells exposed to cobalt chloride (CoCl2 ), leading to hypoxia, underwent apoptosis (p < .05). After intravenous injection of hPMSCs into tail vein, there was 25% improvement of axon survival in vivo (p < .05). R28 cells incubated with hPMSCs after exposure to hypoxic condition resulted in 50% increased cell survival compared with R28 cells without hPMSC exposure (p < .05), suggesting the active release of multiple factors related to cell survival. In addition, we found that Nf-kappab protein mediates neuroprotection pathway via up regulation of target proteins regulated by hPMSCs. Therefore, we assert that Nf kappab was one of the mediator proteins in a recovery pathway induced by hPMSCs. In conclusion, these indicate that transactivation of Nf-kappab protein has a critical role in recovery mechanism by hPMSCs. We suggest that hPMSCs have abilities to recover neuronal damages by up-regulating the expression of genes associated with axon survival and can a better understanding of the possible role of hPMSCs in the treatment modalities of optic nerve injury. PMID- 28857478 TI - Metabolic interactions in cancer: cellular metabolism at the interface between the microenvironment, the cancer cell phenotype and the epigenetic landscape. AB - Metabolism is tied into complex interactions with cell intrinsic and extrinsic processes that go beyond the conversion of nutrients into energy and biomass. Indeed, metabolism is a central cellular hub that interconnects and influences the microenvironment, the cellular phenotype, cell signaling, and the (epi)genetic landscape. While these interactions evolved to support survival and function of normal cells, they are hijacked by cancer cells to enable cancer maintenance and progression. Thus, a mechanistic and functional understanding of complex metabolic interactions provides a basis for the discovery of novel metabolic vulnerabilities in cancer. In this review, we will summarize and provide context for the to-date discovered complex metabolic interactions by discussing how the microenvironment as well as the cellular phenotype define cancer metabolism, and how metabolism shapes the epigenetic state of cancer cells. Many of the studies investigating the crosstalk of metabolism with cell intrinsic and extrinsic processes have used integrative data analysis approaches at the interface between computational and experimental cancer research, and we will highlight those throughout the review. In conclusion, identifying and understanding complex metabolic interactions is a basis for deciphering novel metabolic vulnerabilities of cancer cells. WIREs Syst Biol Med 2018, 10:e1397. doi: 10.1002/wsbm.1397 This article is categorized under: Biological Mechanisms > Metabolism Physiology > Mammalian Physiology in Health and Disease. PMID- 28857480 TI - Principles for ethical treatment decision-making in veterinary oncology. AB - Many owners of companion animals with cancer are overwhelmed by having to choose the "right course of action." With the aim of reducing the burden on owners who are forced to act as surrogates for their animals, this work discusses principles that apply to ethical treatment decision-making for animal patients with cancer. Four principles frequently used for ethical decision-making in human medicine will be considered for their potential applicability in veterinary medicine. As a result of these considerations, preliminary guidelines are presented, along which a decision-making discussion can be held. The deliberate integration of the non maleficence and beneficence principles into the purely empirical facts of what is medically possible helps to maintain a moral perspective in specialized veterinary medicine. At the same time, such guidelines may contribute to individual decision-making in a way that animal patients neither have to endure unnecessarily severe side effects, nor that they are euthanized prematurely. PMID- 28857479 TI - Crystal structure of a lipase from Streptomyces sp. strain W007 - implications for thermostability and regiospecificity. AB - : MAS1 from marine Streptomyces sp. strain W007 belongs to the bacterial lipase I.7 subfamily and is characterized as a thermostable and nonregiospecific lipase. To shed light on the catalytic mechanism of MAS1, we determined its crystal structure with closed conformation in two crystal forms at 2.3 A resolution. MAS1 adopts the canonical alpha/beta hydrolase core fold with its catalytic triad being formed by S109, D200 and H232. Structural analysis and biochemical assays revealed that disulfide bonds and salt bridges play a vital role in the thermostability of MAS1. In addition, we discovered that the replacement of H108 with a tryptophan converts MAS1 from a nonregiospecific to an sn-1,3-specific lipase, suggesting the functional importance of the second position from the conserved pentapeptide motif in defining the regiospecificity of MAS1. Our present study provides insights into the molecular basis for the thermostability and regiospecificity of MAS1, and it may aid in the rational design of thermostable or regiospecific lipases for potential industrial applications. DATABASE: Structural data are available in the Protein Data Bank database under the accession numbers 5H6B and 5H6G. PMID- 28857481 TI - Fingerprint profiles of flavonoid compounds from different Psidium guajava leaves and their antioxidant activities. AB - Flavonoids are the main active components in Psidium guajava leaves and have many multi-physiological functions. In this study, the flavonoid compositions were identified in the Psidium guajava leaves samples using a high-performance liquid chromatography with time-of-flight electrospray ionization mass spectrometry method. A high-performance liquid chromatography fingerprint method, combined with chemometrics, was used to perform a quality assessment of the Psidium guajava leaves samples. The eight identified flavonoid compounds including rutin, isoquercitrin, quercetin-3-O-beta-d-xylopyranoside, quercetin-3-O-alpha-l arabinopyranoside, avicularin, quercitrin, quercetin, and kaempferol were used as the chemical markers. The antioxidant activity of 15 batches of samples was examined using three different methods, and the results revealed the Psidium guajava leaves samples that had higher contents of the flavonoid compounds, glycoside and aglycone, possessed the highest antioxidant capacities. Consequently, a combination of chromatographic fingerprints and chemometric analyses was used for a quality assessment of Psidium guajava leaf tea and its derived products, which can lay the foundation for the development of plant tea resources or other herbs. PMID- 28857483 TI - Intravitreal gas for symptomatic vitreomacular adhesion: a synthesis of the literature. AB - Symptomatic vitreomacular adhesion (sVMA) is defined as visual loss secondary to foveal damage from vitreomacular traction (VMT) and includes isolated VMT, impending macular hole (MH), and full-thickness MH with persisting vitreous attachment. Management options include pars plana vitrectomy (PPV), intravitreal ocriplasmin, intravitreal gas injection or observation. This synthesis of the literature aimed to assess the safety and efficacy of intravitreal gas for sVMA. Articles describing patients with VMT or MH treated with intravitreal expansile gas were selected by systematic literature review using MEDLINE, EMBASE, and the Cochrane Database of Controlled Trials (CENTRAL) up to September 2016. The main outcomes at 1 month and final review were logarithm of the minimum angle of resolution (logMAR) visual acuity (VA), anatomical success (absence of both VMT and MH, without PPV) and adverse events (AEs). The intended comparator was observation. Nine of 106 identified articles were eligible, and none were randomized controlled trials. The mean VA of 91 eyes improved from 0.55 (Snellen equivalent 6/21) to 0.48 (6/18) logMAR at 1 month and to 0.35 (6/13) logMAR at final review. The mean VA at final review, prior to a vitrectomy, was 0.42 (6/16). Anatomic success was 48% at 1 month and 57% at final review. The reported AEs comprised retinal detachment in two highly myopic eyes. Intravitreal gas injection can relieve sVMA. Larger controlled studies are needed to determine safety and efficacy relative to observation, ocriplasmin, or vitrectomy. PMID- 28857482 TI - Dopaminergic and behavioural changes in a loss-of-imprinting model of Cdkn1c. AB - The imprinted gene Cdkn1c is expressed exclusively from the maternally inherited allele as a consequences of epigenetic regulation. Cdkn1c exemplifies many of the functional characteristics of imprinted genes, playing a role in foetal growth and placental development. However, Cdkn1c also plays an important role in the brain, being key to the appropriate proliferation and differentiation of midbrain dopaminergic neurons. Using a transgenic model (Cdkn1cBACx1 ) with a twofold elevation in Cdkn1c expression that mimics loss-of-imprinting, we show that increased expression of Cdkn1c in the brain gives rise to neurobiological and behavioural changes indicative of a functionally altered dopaminergic system. Cdkn1cBACX1 mice displayed altered expression of dopamine system-related genes, increased tyrosine hydroxylase (Th) staining and increased tissue content of dopamine in the striatum. In addition, Cdkn1cBACx1 animals were hypersensitive to amphetamine as showed by c-fos expression in the nucleus accumbens. Cdkn1cBACX1 mice had significant changes in behaviours that are dependent on the mesolimbic dopaminergic system. Specifically, increased motivation for palatable food stuffs, as indexed on a progressive ratio task. In addition, Cdkn1cBACX1 mice displayed enhanced social dominance. These data show, for the first time, the consequence of elevated Cdkn1c expression on dopamine-related behaviours highlighting the importance of correct dosage of this imprinted gene in the brain. This work has significant relevance for deepening our understanding of the epigenetic factors that can shape neurobiology and behaviour. PMID- 28857484 TI - Bisphenol A Exposure Impairs Epididymal Development during the Peripubertal Period of Rats: Inflammatory Profile and Tissue Changes. AB - Bisphenol A (BPA) is a synthetic non-steroidal oestrogen used in the production of plastics. BPA can cause alterations in the endocrine system of human beings and animals at varied stages of development. During puberty, altered morphological, sexual behaviour and completion of the epididymal development occur. Therefore, this study aimed to evaluate the effects of BPA on epididymal development during the peripubertal period of rats. Male Wistar rats were treated with BPA via gavage at doses of 20 MUg/kg or 200 MUg/kg per day [post-natal day (PND] 36-66). The control group received the vehicles under the same conditions. Feed and water were provided ad libitum. On PND 67, the epididymis was removed, weighed, divided into caput/corpus and cauda sections. It was then used for sperm count determination; histopathological and stereological evaluation; inflammatory cell enzymatic profiling (myeloperoxidase activity - MPO; N-acetylglucosaminidase - NAG); immunohistochemistry for IL-6; and evaluation of superoxide anion levels and malondialdehyde (MDA). Exposure to BPA at 200 MUg/kg caused a significant increase of MPO activity and immunoreactivity to IL-6 (interleukin-6) as well as remodelling of tissue components in the caput/corpus and cauda regions of the epididymis. Under these experimental conditions, it is concluded that BPA alters post-natal epididymal development. PMID- 28857485 TI - Nonalcoholic fatty liver disease promotes hepatocellular carcinoma through direct and indirect effects on hepatocytes. AB - Hepatocellular carcinoma (HCC) is the sixth most frequent neoplasm and the second leading cause of cancer-related deaths worldwide. Nonalcoholic fatty liver disease (NAFLD), a common disorder in obese people, has been identified as an important risk factor for HCC. Following the increasing prevalence of obesity, it is expected that the contribution of NAFLD to HCC's incidence worldwide will grow. Recently, a number of studies have been published, which help us better understand cellular and molecular mechanisms of how NAFLD promotes hepatocarcinogensis. Inflammatory cytokines, ER stress and circadian dysregulation, which mediate hepatocyte injury and NAFLD progression, have been identified to promote malignant transformation of hepatocytes. Besides these 'intrinsic' effects, lipid dysregulation dramatically affects the liver local microenvironment. The reshaped immune environment has also been found to contribute to the NAFLD-mediated hepatocarcinogenesis. This review explores recent findings of both 'intrinsic' effects on hepatocytes and the role of the local environment in NAFLD-promoted HCC development. PMID- 28857486 TI - Educational priorities of students in the entrustable professional activity era. AB - BACKGROUND: The Association of American Medical Colleges (AAMC) guidelines on the entrustable professional activities (EPAs) expected of graduating medical students were recently published. Although perceptions of educators, residents and programme directors have been described, the voice of senior medical students is lacking. METHODS: A single-institution cross-sectional study of senior medical students was performed. Student perceptions were collected and compared with: (1) national guidelines (i.e. the 13 newly developed undergraduate EPAs); (2) resident expectations (i.e. through comparison with a recently published survey from >28 000 residents); and (3) institutional objectives. Descriptive statistics were performed. RESULTS: A total of 113 students participated. The top three EPA based educational priorities were 'recognising a patient requiring urgent/emergent care' (EPA10), 'performing procedures of a physician' (EPA12) and 'collaborating as an interprofessional' (EPA9). Over 80 per cent of students rated 'managing time efficiently' and 'communicating around care transitions' as very important pre-internship skills. Of the institutional objectives, 87 per cent rated 'recognising critically ill patients' and 'knowing when to ask for help' as the most important pre-internship skills. The voice of senior medical students is lacking CONCLUSIONS: Although the emphasis on knowing when to ask for help and communication around care transitions differed somewhat across stakeholders, educational priorities were shared by students, residents, educators and institutional objectives. These preliminary data support national assessments of perceptions and achievements of senior medical students to guide residency readiness in the EPA era. PMID- 28857487 TI - Improving the care of veterans: The role of nurse practitioners in team-based population health management. AB - BACKGROUND AND PURPOSE: Improving healthcare delivery for U.S. veterans is a national priority. The Veterans Health Administration (VHA) employs a variety of team-based, population health strategies to address critical issues in veterans' health including the effective management of chronic disease. Nurse practitioners (NPs) are integral members of the VHA patient care team with a substantial role to play in the organization and delivery of healthcare services for veterans. This report explores the contributions of NPs in team-based, population health strategies within the VHA. METHODS: This review of the literature examines peer reviewed articles published between 2006 and 2017 to explore the contributions of NPs in team-based, population health strategies within the VHA. Search words include veterans, VHA, NPs, population health, panel management, and chronic disease. CONCLUSIONS: NPs are vital members of the VHA primary care team; however, there is a dearth of available evidence reflecting the unique contribution of NPs within VHA team-based, population health management strategies. IMPLICATIONS FOR PRACTICE: The VHA adoption of full practice authority for NP practice provides NPs with an expanded capacity to lead improvements in veterans' health. Future research is needed to fully understand the unique role of the NP in the delivery of population health management strategies for veterans. PMID- 28857488 TI - Preliminary study of higher-order language and extralinguistic impairments in individuals with high clinical risk of psychosis and first episode of schizophrenia. AB - AIM: Higher-order language functions are associated with understanding indirect speech acts, lexical-semantic processes, the understanding and production of prosody, discourse production and comprehension. Only a few studies imply that language abnormalities may be present in individuals at ultra-high risk for psychosis (UHR) and first-episode of schizophrenia (FE). The purpose of this study was to test the presence of higher-order language dysfunctions in UHR and FE subjects using a standardized comprehensive test battery. METHODS: Twenty patients experiencing FE schizophrenia, 33 UHR individuals and 20 healthy controls (HC) took part in the study. Higher-order language and extralinguistic abilities were evaluated using the Right Hemisphere Language Battery (RHLB-PL). The battery consisted of tests covering the comprehension of implicit information, lexico-semantic processing, understanding humour, making inappropriate remarks and comments, understanding and explaining metaphors, understanding prosody and appropriateness of behaviour in communication settings. RESULTS: The UHR patients scored lower than HC when comprehending implicit information, discourse and in areas associated with the effectiveness of interpersonal communication; however, they scored higher than the FE participants in explanation of metaphors and processing language information in the context of general knowledge. The FE participants scored lower than healthy controls in comprehension of implicit information, explanation of metaphors, discourse understanding, processing language information in the context of general knowledge and effectiveness of interpersonal communication. CONCLUSIONS: The higher-order language dysfunctions mediated by the right hemisphere appear to be present in subjects at UHR of schizophrenia and those experiencing their FE. The results may play a crucial role in diagnostic processes. PMID- 28857489 TI - Restratification of survival prognosis of N1b papillary thyroid cancer by lateral lymph node ratio and largest lymph node size. AB - The current 7th TNM staging stratifies N1b papillary thyroid cancer (PTC) patients without distant metastasis into either stage I or stage IV merely by an age threshold (45 years). To date, no studies have adequately quantified the mortality risk of PTC patients with N1b disease. We hypothesized that incorporating lymph node (LN) factors into the staging system would better predict cancer-specific mortality (CSM). A total of 745 nonmetastatic PTC patients with N1b disease were enrolled. We identified factors related to LNs and cut-points using Cox regression and time-dependent ROC analysis. New prognostic groupings were derived based on minimal hazard differences for CSM among the groups stratified by LN risk and age, and prediction of CSM was assessed. Lateral lymph node ratio (LNR) and largest LN size were significant prognostic LN factors at cut-points of 0.3 and 3 cm. Without LN risk (lateral LNR >0.3 or largest LN size >3 cm), stage IV patients had prognosis [adjusted HR 1.10 (98% CI 0.19 6.20); P = 0.906] similar to stage I patients with LN risk. Patients were restratified into three prognostic groups: Group 1, <45 years without LN risk; Group 2, <45 years with LN risk or >=45 years without LN risk; and Group 3, >=45 with LN risk. This system had a lower log-rank P-value (<0.001 vs. 0.002) and higher C-statistics (0.80 vs. 0.71) than the 7th TNM. New prognostic grouping using lateral LNR and largest LN size predicts CSM accurately and distinguishes N1b patients with different prognosis. PMID- 28857491 TI - Gender differences in nurse practitioner salaries. AB - BACKGROUND AND PURPOSE: While male nurses have been shown to earn considerably more than female nurses, there is less evidence on gender disparities in salary among nurse practitioners (NPs). This study examines whether the gender gap in NP salaries persists after controlling for differences in work setting and demographic factors. METHODS: We analyzed the relationship between gender and salary (2011 pretax earnings) among 6591 NPs working as NPs at least 35 h per week, using the 2012 National Sample Survey of Nurse Practitioners. We first conducted bivariate regression analyses examining the relationship between gender and earnings, and then developed a multivariate model that controlled for individual differences in demographic and work characteristics. CONCLUSIONS: Male NPs earned $12,859 more than female NPs, after adjusting for individual differences in demographics and work characteristics. The gender gap was $7405 for recent NP graduates, and grew over time. Male NPs earned significantly more than female NPs across all clinical specialty areas. IMPLICATIONS FOR PRACTICE: The gender disparities in NP salaries documented here regardless of professional seniority or clinical area should spark healthcare organizations to conduct pay equity assessments of their employees' salaries to identify and ameliorate pay inequality. PMID- 28857490 TI - The acceleration of reproductive aging in Nrg1flox/flox ;Cyp19-Cre female mice. AB - Irregular menstrual cycles, reduced responses to exogenous hormonal treatments, and altered endocrine profiles (high FSH/high LH/low AMH) are observed in women with increasing age before menopause. In this study, because the granulosa cell specific Nrg1 knockout mice (gcNrg1KO) presented ovarian and endocrine phenotypes similar to older women, we sought to understand the mechanisms of ovarian aging and to develop a new strategy for improving fertility in older women prior to menopause. In the ovary of 6-month-old gcNrg1KO mice, follicular development was blocked in bilayer secondary follicles and heterogeneous cells accumulated in ovarian stroma. The heterogeneous cells in ovarian stroma were distinguished as two different types: (i) the LH receptor-positive endocrine cells and (ii) actin rich fibrotic cells expressing collagen. Both the endocrine and fibrotic cells disappeared following long-term treatment with a GnRH antagonist, indicating that the high levels of serum LH induced the survival of both cell types and the abnormal endocrine profile to reduce fertility. Moreover, follicular development to the antral stages was observed with reduced LH and the disappearance of the abnormal stromal cells. Mice treated with the GnRH antagonist regained normal, recurrent estrous cycles and continuously delivered pups for at least for 3 months. We conclude that endocrine and matrix alternations occur within the ovarian stroma with increasing age and that abolishing these alternations resets the cyclical release of LH. Thus, GnRH antagonist treatments might provide a new, noninvasive strategy for improving fertility in a subset of aging women before menopause. PMID- 28857492 TI - Identification of specific markers for amphetamine synthesised from the pre precursor APAAN following the Leuckart route and retrospective search for APAAN markers in profiling databases from Germany and the Netherlands. AB - alpha-Phenylacetoacetonitrile (APAAN) is one of the most important pre-precursors for amphetamine production in recent years. This assumption is based on seizure data but there is little analytical data available showing how much amphetamine really originated from APAAN. In this study, several syntheses of amphetamine following the Leuckart route were performed starting from different organic compounds including APAAN. The organic phases were analysed using gas chromatography-mass spectrometry (GC-MS) to search for signals caused by possible APAAN markers. Three compounds were discovered, isolated, and based on the performed syntheses it was found that they are highly specific for the use of APAAN. Using mass spectra, high resolution MS and nuclear magnetic resonance (NMR) data the compounds were characterised and identified as 2-phenyl-2 butenenitrile, 3-amino-2-phenyl-2-butenenitrile, and 4-amino-6-methyl-5 phenylpyrimidine. To investigate their significance, they were searched in data from seized amphetamine samples to determine to what extent they were present in illicitly produced amphetamine. Data of more than 580 cases from amphetamine profiling databases in Germany and the Netherlands were used for this purpose. These databases allowed analysis of the yearly occurrence of the markers going back to 2009. The markers revealed a trend that was in agreement with seizure reports and reflected an increasing use of APAAN from 2010 on. This paper presents experimental proof that APAAN is indeed the most important pre-precursor of amphetamine in recent years. It also illustrates how important it is to look for new ways to identify current trends in drug production since such trends can change within a few years. PMID- 28857493 TI - Al2 O3 Underlayer Prepared by Atomic Layer Deposition for Efficient Perovskite Solar Cells. AB - Perovskite solar cells, as an emergent technology for solar energy conversion, have attracted much attention in the solar cell community by demonstrating impressive enhancement in power conversion efficiencies. However, the high temperature and manually processed TiO2 underlayer prepared by spray pyrolysis significantly limit the large-scale application and device reproducibility of perovskite solar cells. In this study, lowtemperature atomic layer deposition (ALD) is used to prepare a compact Al2 O3 underlayer for perovskite solar cells. The thickness of the Al2 O3 layer can be controlled well by adjusting the deposition cycles during the ALD process. An optimal Al2 O3 layer effectively blocks electron recombination at the perovskite/fluorine-doped tin oxide interface and sufficiently transports electrons through tunneling. Perovskite solar cells fabricated with an Al2 O3 layer demonstrated a highest efficiency of 16.2 % for the sample with 50 ALD cycles (ca. 5 nm), which is a significant improvement over underlayer-free PSCs, which have a maximum efficiency of 11.0 %. Detailed characterization confirms that the thickness of the Al2 O3 underlayer significantly influences the charge transfer resistance and electron recombination processes in the devices. Furthermore, this work shows the feasibility of using a high band-gap semiconductor such as Al2 O3 as the underlayer in perovskite solar cells and opens up pathways to use ALD Al2 O3 underlayers for flexible solar cells. PMID- 28857494 TI - DRMDA: deep representations-based miRNA-disease association prediction. AB - Recently, microRNAs (miRNAs) are confirmed to be important molecules within many crucial biological processes and therefore related to various complex human diseases. However, previous methods of predicting miRNA-disease associations have their own deficiencies. Under this circumstance, we developed a prediction method called deep representations-based miRNA-disease association (DRMDA) prediction. The original miRNA-disease association data were extracted from HDMM database. Meanwhile, stacked auto-encoder, greedy layer-wise unsupervised pre-training algorithm and support vector machine were implemented to predict potential associations. We compared DRMDA with five previous classical prediction models (HGIMDA, RLSMDA, HDMP, WBSMDA and RWRMDA) in global leave-one-out cross validation (LOOCV), local LOOCV and fivefold cross-validation, respectively. The AUCs achieved by DRMDA were 0.9177, 08339 and 0.9156 +/- 0.0006 in the three tests above, respectively. In further case studies, we predicted the top 50 potential miRNAs for colon neoplasms, lymphoma and prostate neoplasms, and 88%, 90% and 86% of the predicted miRNA can be verified by experimental evidence, respectively. In conclusion, DRMDA is a promising prediction method which could identify potential and novel miRNA-disease associations. PMID- 28857496 TI - The Dark Side of the MedPhys Match. PMID- 28857495 TI - Identification of dysregulated lncRNAs profiling and metastasis-associated lncRNAs in colorectal cancer by genome-wide analysis. AB - The colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide, but the pathogenesis of CRC remains not well-known. Increasing studies have highlighted the critical roles of long noncoding RNAs (lncRNAs) in tumorigenesis and cancer cells metastasis, however, the expression pattern, biological roles of lncRNAs, and the mechanisms responsible for their function in CRC remain elusive. In this study, we performed a genome-wide comprehensive analysis of lncRNAs profiling and clinical relevance to identify novel lncRNAs for the further study in CRC. RNA sequencing and microarray data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were annotated and analyzed to find differentially expressed lncRNAs in CRC. Analysis of these datasets revealed that hundreds of lncRNAs expression are dysregulated in CRC tissues when compared with normal tissues. By genomic variation analyses, we identified that some of these lncRNAs dysregulation is associated with the copy number amplification or deletion. Moreover, many lncRNAs expression levels are significantly associated with CRC patients overall and recurrence-free survivals, such as H19, LEF1-AS1, and RP11-296E3.2. Furthermore, we identified one liver metastasis-associated lncRNA termed LUCAT1 in CRC by analyzing lncRNAs expression profiles in the CRC tissues from patients with liver metastasis compared with the CRC tissues without metastasis. Finally, loss-of-function assays determined that knockdown of LUCAT1 could impair CRC cells invasion. Taken together, aberrantly expressed lncRNAs may play critical roles in the development and liver metastasis of CRC, and our findings may provide useful resource for identification of novel biomarkers of CRC. PMID- 28857497 TI - Incidence and natural history of neonatal isolated ventricular septal defects: Do we know everything? A 6-year single-center Italian experience follow-up. AB - BACKGROUND: Despite ventricular septal defects (VSDs) are the most common congenital heart diseases (CHDs) in the neonatal period, their incidence and natural history are still debated and their follow-up and management strategies remain controversial. Our aim was to evaluate the incidence and natural history of isolated VSDs. METHODS: From January 1996 to December 2015 all neonates with a CHD suspicion were referred to the Cardiological Department of Grosseto Misericordia Hospital. Only newborns with confirmed isolated VSD were enrolled in this study and followed for 6 years. RESULTS: Our 343 newborns with an isolated VSD (incidence of 10.45/1000/births) account for 64% of all detected CHDs. VSDs location were as follows: muscular (73.8%), perimembranous (11.3%), inlet (1%), and outlet (0.8%). Of the located VSDs, 90% were small, 7.5% moderate, and 2.5% large, respectively. Spontaneous closure was observed in 96 (29.2%) of the VSD patients at 6-month, 198 (60.2%) at 1-year, 261 (79.3%) at 2-year, and in 302 (91.8%) at 6-year follow-up. Risk factors for defect persistence were a perimembranous location (P = .001; HR: 0.508, CI: 0.342-0.755), detection of multiple defects (P = .043; HR: 0.728, CI: 0.536-0.990), and male gender (P < .048; HR: 0.783, CI: 0.615-0.998), respectively. CONCLUSIONS: We here provide an incidence and natural history of neonatal isolated VSDs in a neonatal Caucasian population. These data may be useful for the development of expert consensus/standard recommendation guidelines for the follow-up and VSD management, data that are currently lacking. PMID- 28857499 TI - Controlled Synthesis of Hollow PbS-TiO2 Hybrid Structures through an Ion Adsorption-Heating Process and their Photocatalytic Activity. AB - Hollow hybrid nanostructures have received significant attention because of their unique structural features. This study reports a facile ion adsorption-heating method to fabricate hollow PbS-TiO2 hybrid particles. In this method, the TiO2 spheres used as a substrate material to grow PbS are aggregates of many small amorphous TiO2 particles, and each small particle is covered with thioglycolic acid ligands through Ti4+ -carboxyl coordination. When Pb2+ ions are added to a colloidal solution of these TiO2 spheres, these ions are adsorbed by sulfhydryl ( SH) groups to form metal thiolates, and the C-S bond is dissociated by heating to release S2- . The S2- ions react with Pb2+ ions to form PbS without additive sulfur sources. Additionally, the amorphous TiO2 spheres are transformed into the anatase phase during the heating process. As a result, the crystallization of TiO2 spheres along with the formation of PbS is simultaneously carried out by heating. During the heating process, owing to the Kirkendall effect of S2- diffusion and the Ostwald ripening effect of the crystallization of amorphous TiO2 spheres, PbS-TiO2 hollow hybrid structures can be obtained. The XRD and XPS characterizations proved the formation of anatase TiO2 and PbS. The TEM characterization confirmed the formation of hollow structures in the PbS-TiO2 hybrid sample. The photocatalytic activity of the hollow PbS-TiO2 hybrid spheres have been investigated for the degradation of Cr6+ under visible light. The results show that hollow PbS-TiO2 hybrid spheres exhibited the highest photocatalytic activity, in which almost all the Cr6+ was degraded after 140 min. PMID- 28857498 TI - Self-Regulatory Efficacy Encourages Exercise Persistence Despite Arthritis Flare Symptoms. AB - BACKGROUND: The study of exercise adherence during an arthritis flare is recommended by arthritis researchers. Studies to date have been correlational. METHODS: Social cognitions of exercising individuals with arthritis who consider exercise adherence under different levels of challenge of an arthritis flare were examined using an experimental design. Exercising individuals with differential self-regulatory efficacy for managing arthritis flare symptoms (SRE-flare) were randomly assigned to conditions where flare symptoms were perceived as either many or few. Individuals in each condition responded about the strength of their anticipated persistence to continue exercise, and their self-regulatory efficacy to use coping strategies to enable exercise. RESULTS: Higher SRE-flare individuals expressed significantly (a) greater persistence (Cohen's d = 1.17) and (b) more confidence to use their flare coping solutions (Cohen's d = 1.44). CONCLUSION: Main findings were as hypothesised. When exposed to the condition with more limiting flare symptoms (i.e. greater challenge), high SRE participants were the most confident in dealing with flare symptoms and exercising. Identifying lower SRE-flare individuals less likely to persist with exercise during arthritis flares may improve tailored exercise counselling. PMID- 28857500 TI - Chemical Composition, Enantiomeric Analysis, AEDA Sensorial Evaluation and Antifungal Activity of the Essential Oil from the Ecuadorian Plant Lepechinia mutica Benth (Lamiaceae). AB - This study describes the GC-FID, GC/MS, GC-O, and enantioselective GC analysis of the essential oil hydrodistilled from leaves of Lepechinica mutica (Lamiaceae), collected in Ecuador. GC-FID and GC/MS analyses allowed the characterization and quantification of 79 components, representing 97.3% of the total sample. Sesquiterpene hydrocarbons (38.50%) and monoterpene hydrocarbons (30.59%) were found to be the most abundant volatiles, while oxygenated sesquiterpenes (16.20%) and oxygenated monoterpenes (2.10%) were the minor components. In order to better characterize the oil aroma, the most important odorants, from the sensorial point of view, were identified by Aroma Extract Dilution Analysis (AEDA) GC-O. They were alpha-Pinene, beta-Phellandrene, and Dauca-5,8-diene, exhibiting the characteristic woody, herbaceus, and earthy odors, respectively. Enantioselective GC analysis of L. mutica essential oil revealed the presence of twelve couples and two enantiomerically pure chiral monoterpenoids. Their enantiomeric excesses were from a few percent units to 100%. Moreover, the essential oil exhibited moderate in vitro activity against five fungal strains, being especially effective against M. canis, which is a severe zoophilic dermatophyte causal agent of pet and human infections. PMID- 28857501 TI - Potential roles of neutrophils in regulating intestinal mucosal inflammation of inflammatory bowel disease. AB - Inflammatory bowel diseases (IBD), comprising of ulcerative colitis and Crohn's disease, are inflammatory disorders of the gastrointestinal tract characterized by chronically relapsing mucosal inflammation. Neutrophils, as the effector cells of acute inflammation, have long been reported to play a role in the maintenance of intestinal homeostasis and pathogenesis of IBD. At the early stage of mucosal inflammation in patients with IBD, neutrophils flood into intestinal mucosa, phagocytose pathogenic microbes, and promote mucosal healing and resolution of inflammation. However, large numbers of neutrophils infiltrating in the inflamed mucosa and accumulating in the epithelia cause damage of mucosal architecture, compromised epithelial barrier and production of inflammatory mediators. In this review we discuss the critical roles of neutrophils in modulating innate and adaptive immune responses in intestinal mucosa, and, importantly, clarify the potential roles of neutrophils related to their production of inflammatory mediators, transenthothelial and transepithelial migration into intestinal mucosa, and the underlying mechanisms in regulating mucosal inflammation of IBD. Moreover, we also describe a new subset of neutrophils (i.e., CD177+ neutrophils) and illustrate its protective role in modulating intestinal mucosal immune responses in IBD. PMID- 28857502 TI - Engineering Robustness of Microbial Cell Factories. AB - Metabolic engineering and synthetic biology offer great prospects in developing microbial cell factories capable of converting renewable feedstocks into fuels, chemicals, food ingredients, and pharmaceuticals. However, prohibitively low production rate and mass concentration remain the major hurdles in industrial processes even though the biosynthetic pathways are comprehensively optimized. These limitations are caused by a variety of factors unamenable for host cell survival, such as harsh industrial conditions, fermentation inhibitors from biomass hydrolysates, and toxic compounds including metabolic intermediates and valuable target products. Therefore, engineered microbes with robust phenotypes is essential for achieving higher yield and productivity. In this review, the recent advances in engineering robustness and tolerance of cell factories is described to cope with these issues and briefly introduce novel strategies with great potential to enhance the robustness of cell factories, including metabolic pathway balancing, transporter engineering, and adaptive laboratory evolution. This review also highlights the integration of advanced systems and synthetic biology principles toward engineering the harmony of overall cell function, more than the specific pathways or enzymes. PMID- 28857503 TI - Heme Biosynthetic Pathway is Functionally Linked to Adipogenesis via Mitochondrial Respiratory Activity. AB - OBJECTIVE: To investigate key enzymes of heme biosynthesis in human adipocytes and adipose tissue (AT). METHODS: Heme biosynthesis-related gene expression (ALAS1, ALAD, HMBS) was investigated in whole AT from humans (n = 178 and n = 75) and rats according to obesity status and during adipogenesis of human preadipocytes. The effects of aminotriazole (an ALAD inhibitor) and of ALAD knockdown were also studied. RESULTS: Consistent heme biosynthesis-related gene expression was detected in both subcutaneous AT (SAT) and visceral AT (VAT) and was significantly increased in SAT. ALAS1, ALAD, and HMBS mRNAs were positively associated with adipogenic gene expression in human AT and significantly decreased in subjects with obesity. These results were replicated in an independent cohort. Both SAT and VAT heme levels were positively correlated with ALAS1, ALAD, and HMBS mRNAs. ALAD and HMBS were mainly expressed in adipocytes and increased during differentiation of human adipocytes in parallel to adipogenic genes. In rats, high-fat diet-induced weight gain resulted in decreased Alad and Hmbs mRNAs in a similar way to what was observed with Adipoq. Aminotriazole administration or ALAD knockdown attenuated adipogenesis in parallel with decreased glucose uptake and impaired mitochondrial respiratory function during human adipocyte differentiation. CONCLUSIONS: Current data suggest a possible role of heme biosynthesis in human adipogenesis. PMID- 28857505 TI - Gray literature: An important resource in systematic reviews. AB - Systematic reviews aide the analysis and dissemination of evidence, using rigorous and transparent methods to generate empirically attained answers to focused research questions. Identifying all evidence relevant to the research questions is an essential component, and challenge, of systematic reviews. Gray literature, or evidence not published in commercial publications, can make important contributions to a systematic review. Gray literature can include academic papers, including theses and dissertations, research and committee reports, government reports, conference papers, and ongoing research, among others. It may provide data not found within commercially published literature, providing an important forum for disseminating studies with null or negative results that might not otherwise be disseminated. Gray literature may thusly reduce publication bias, increase reviews' comprehensiveness and timeliness, and foster a balanced picture of available evidence. Gray literature's diverse formats and audiences can present a significant challenge in a systematic search for evidence. However, the benefits of including gray literature may far outweigh the cost in time and resource needed to search for it, and it is important for it to be included in a systematic review or review of evidence. A carefully thought out gray literature search strategy may be an invaluable component of a systematic review. This narrative review provides guidance about the benefits of including gray literature in a systematic review, and sources for searching through gray literature. An illustrative example of a search for evidence within gray literature sources is presented to highlight the potential contributions of such a search to a systematic review. Benefits and challenges of gray literature search methods are discussed, and recommendations made. PMID- 28857504 TI - Persistent histone modifications at the BDNF and Cdk-5 promoters following extinction of nicotine-seeking in rats. AB - Drugs of addiction lead to a wide range of epigenetic changes at the promoter regions of genes directly implicated in learning and memory processes. We have previously shown that the histone deactylase inhibitor, sodium butyrate (NaB), accelerates the extinction of nicotine-seeking and provides resistance to relapse. Here, we explore the potential molecular mechanisms underlying this effect. Rats received intravenous nicotine or saline self-administration, followed by 6 days of extinction training, with each extinction session followed immediately by treatment with NaB or vehicle. On the last day of extinction, rats were killed and the medial ventral prefrontal cortex retained for chromatin immunoprecipitation and quantitative polymerase chain reaction (qPCR). A history of nicotine exposure significantly decreased H3K14 acetylation at the brain derived neurotrophic factor (BDNF) exon IV promoter, and this effect was abolished with NaB treatment. In contrast, nicotine self-administration alone, resulted in a significant decrease in histone methylation at the H3K27me3 and H3K9me2 marks in the promoter regions of BDNF exon IV and cyclin-dependent kinase 5 (Cdk-5). Quantitative PCR-identified changes in several genes associated with NaB treatment that were independent of nicotine exposure; however, an interaction of nicotine history and NaB treatment was detected only in the expression of BDNF IV and BDNF IX. Together these results suggest that nicotine self-administration leads to a number of epigenetic changes at both the BDNF and Cdk-5 promoters, and that these changes may contribute to the enhanced extinction of nicotine-seeking by NaB. PMID- 28857506 TI - Genetic susceptibility of lung cancer in Chinese population: An overview of systematic reviews and meta-analyses. AB - BACKGROUND: Genetic susceptibility of lung cancer has been widely studied for Chinese population, and meta-analysis of candidate gene association studies has also been performed for those genes. However, the overall evidence has not been well recognized. OBJECTIVE: To investigate genetic association for the risk of lung cancer in Chinese. METHOD: An overview of systematic reviews and meta analyses of candidate gene association studies for lung cancer in Chinese was performed up to August 10th , 2016. The AMSTAR tool was used to assess the quality of the included systematic reviews and meta-analyses. Bibliometric analysis was performed to analyze the characteristics of reviews. RESULTS: A total of 21 variants in 17 genes from 20 meta-analyses were included in this study. All 20 meta-analyses were published from 2011 to 2016. The quality scores of AMSTAR ranged from 3 to 7. All included genes were in the pathogenesis of lung cancer, such as the CYPs genes, GSTs genes, and base excision repair genes. Three polymorphisms were found to be associated with decreased risk of lung cancer for Chinese, 15 polymorphisms were found to be associated with increased risk of lung cancer for Chinese, but three polymorphisms were found to be not associated with lung cancer risk for Chinese. CONCLUSION: The current study supports the genetic risk factors of lung cancer for Chinese are more likely to be variants from genes that contribute to the etiology of lung cancer. PMID- 28857507 TI - Innovation of clinical trials in China: Commentary on the publication of "CONSORT extension for Chinese herbal medicine formulas 2017: Recommendations, explanation, and elaboration". PMID- 28857508 TI - Systemic TLR2 Antibody Application in Renal Ischaemia and Reperfusion Injury Decreases AKT Phosphorylation and Increases Apoptosis in the Mouse Kidney. AB - Acute kidney injury remains an important cause of renal dysfunction. In this context, Toll-like receptors have been demonstrated to play a critical role in the induction of innate and inflammatory responses. Among these, Toll-like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells (TECs) of the kidney and is also known to mediate ischaemia reperfusion (IR) injury. Adult male C57BL/6JRj mice were randomized into seven groups (n = 8): a non operative control group (CTRL) and six interventional groups in which mice were subjected to a 30 min. bilateral renal ischaemia. Immediately before reperfusion, mice were treated either with saline or with TLR2 antibody (clone T2.5) and harvested after ischaemia and reperfusion for 3, 24 and 48 hr. Analysed kidney homogenates of TLR2 antibody-treated mice displayed significantly decreased levels of TLR2 protein after 3 hr of IR compared to saline-treated mice. Accordingly, the degree of AKT phosphorylation was significantly decreased after 3 hr of IR compared to saline-treated animals. TUNEL staining revealed significantly higher apoptosis rates in TLR2 antibody-treated animals compared to saline-treated mice after 3 and 24 hr of IR. Further, a positive correlation between TLR2 protein expression and phosphorylation of AKT as well as a negative correlation with the number of TUNEL-positive cells could be observed. Inhibition of TLR2 and its signalling pathway by a single application of TLR2 antibody results in reduced phosphorylation of AKT and consecutively increased apoptosis. PMID- 28857509 TI - Fabrication of Lead-Free (CH3 NH3 )3 Bi2 I9 Perovskite Photovoltaics in Ethanol Solvent. AB - The toxicity of lead present in organohalide perovskites and the hazardous solvent systems used for their synthesis hinder the deployment of perovskite solar cells (PSCs). Herein, an environmentally friendly route toward bismuth based, lead-free (CH3 NH3 )3 Bi2 I9 perovskites that utilize ethanol as the solvent is described. Using this method, dense and homogeneous microstructures were obtained, compared to the porous, rough microstructures obtained using dimethylformamide. Photovoltaic performances were enhanced, with an open-circuit voltage of 0.84 V measured. PMID- 28857510 TI - Cell lines from diamondback moth exhibiting differential susceptibility to baculovirus infection and expressing midgut genes. AB - Six new cell lines were established from embryonic tissues of the diamondback moth, Plutella xylostella (L.). The cell lines showed differential characteristics, including growth in attachment or in suspension, susceptibility to a baculovirus infection and expression of genes involved in the glucosinolate detoxification pathway in P. xylostella larvae. Five of the cell lines grew attached to the culture flask and one cell line grew unattached as a suspension cell line. The cell lines had population doubling times ranging from 18 to 23 h. Among five of the P. xylostella cell lines examined for infection of a nucleopolyhedrovirus from Autographa californica, AcMNPV, four cell lines were highly susceptible to AcMNPV infection, but one was only semi-permissive to AcMNPV infection. The production of two recombinant proteins, a beta galactosidase of bacterial origin and a secreted alkaline phosphatase of eukaryotic origin, in the P. xylostella cell lines was examined in comparison with that in the cell line Sf9 which is commonly used for recombinant protein production. In the P. xylostella cell lines, expression of three important midgut genes involved in the glucosinolate detoxification pathway, including the glucosinolate sulfatase genes GSS1 and GSS2 and the sulfatase modifying factor gene SUMF1, was detected. The P. xylostella cell lines developed in this study could be useful in in vitro research systems for studying insec-virus interactions and complex molecular mechanisms in glucosinolate detoxification and insect-plant interactions. PMID- 28857511 TI - Considering technique of assessment and method for normalizing skeletal muscle mass. PMID- 28857513 TI - Novel Method Proposing Chemical Structures with Desirable Profile of Activities Based on Chemical and Protein Spaces. AB - Active molecules among numerous chemical structures in a chemical database can be searched easily by statistical prediction of compound-protein interactions. However, constructing a simple prediction model against one protein does not aid drug design, because detecting chemical structures that act similarly against multiple proteins is necessary for preventing side effects of the potential drug. To tackle this problem, we propose a new method that visualizes chemical and protein spaces. For simultaneous visualization of both spaces, we employ a counterpropagation neural network (CPNN) and develop a new visualization method named multi-input CPNN (MICPNN). In a case study of the kinase protein family, the MICPNN model predicted accurately the complex relationships between compounds and proteins. The proposed method identified chemical structures with promising activity against kinases. Our proposed method is also applicable to other protein families, such as G-protein coupled receptors, ion channels and transporters. PMID- 28857512 TI - Protein complex formation during denitrification by Pseudomonas aeruginosa. AB - The most efficient means of generating cellular energy is through aerobic respiration. Under anaerobic conditions, several prokaryotes can replace oxygen by nitrate as final electron acceptor. During denitrification, nitrate is reduced via nitrite, NO and N2 O to molecular nitrogen (N2 ) by four membrane-localized reductases with the simultaneous formation of an ion gradient for ATP synthesis. These four multisubunit enzyme complexes are coupled in four electron transport chains to electron donating primary dehydrogenases and intermediate electron transfer proteins. Many components require membrane transport and insertion, complex assembly and cofactor incorporation. All these processes are mediated by fine-tuned stable and transient protein-protein interactions. Recently, an interactomic approach was used to determine the exact protein-protein interactions involved in the assembly of the denitrification apparatus of Pseudomonas aeruginosa. Both subunits of the NO reductase NorBC, combined with the flavoprotein NosR, serve as a membrane-localized assembly platform for the attachment of the nitrate reductase NarGHI, the periplasmic nitrite reductase NirS via its maturation factor NirF and the N2 O reductase NosZ through NosR. A nitrate transporter (NarK2), the corresponding regulatory system NarXL, various nitrite (NirEJMNQ) and N2 O reductase (NosFL) maturation proteins are also part of the complex. Primary dehydrogenases, ATP synthase, most enzymes of the TCA cycle, and the SEC protein export system, as well as a number of other proteins, were found to interact with the denitrification complex. Finally, a protein complex composed of the flagella protein FliC, nitrite reductase NirS and the chaperone DnaK required for flagella formation was found in the periplasm of P. aeruginosa. This work demonstrated that the interactomic approach allows for the identification and characterization of stable and transient protein-protein complexes and interactions involved in the assembly and function of multi-enzyme complexes. PMID- 28857515 TI - Effects of FSTL1 on the proliferation and motility of breast cancer cells and vascular endothelial cells. AB - BACKGROUND: Treatments that prevent the motility of breast cancer cells and inhibit formation of new capillary vessels are urgently needed. FSTL1 is a secreted protein that has been implicated in maintaining the normal physiological function of the cardiovascular system, in addition to a variety of other biological functions. We investigated the role of FSTL1 in the proliferation and migration of breast cancer and vascular endothelial cells. METHODS: Human umbilical vein endothelial cells and human breast cancer BT-549 cells were used to test the effects of FSTL1 and the N-terminal domain of FSTL1. Immunofluorescence microscopy and 3-(4, 5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide, transwell invasion, and wound healing assays were conducted. RESULTS: Different doses of the N-terminal fragment of FSTL1 (FSTL-N) have variable effects on the migration of these cells. However, FSTL1 does not significantly affect tube formation in vitro from vascular endothelial cells. FSTL1-FL and FSTL1-N have modest effects on the invasion of breast cancer and vascular endothelial cells. Interestingly, FSTL1-FL, but not FSTL-N, modulates vascular endothelial cell polarization. CONCLUSION: FSTL1 modestly affects the proliferation of breast cancer cells and vascular endothelial cells. Our findings improve our understanding of the functions of FSTL1 in breast cancer development and angiogenesis. PMID- 28857514 TI - Genomic insights of Pannonibacter phragmitetus strain 31801 isolated from a patient with a liver abscess. AB - Pannonibacter phragmitetus is a bioremediation reagent for the detoxification of heavy metals and polycyclic aromatic compounds (PAHs) while it rarely infects healthy populations. However, infection by the opportunistic pathogen P. phragmitetus complicates diagnosis and treatments, and poses a serious threat to immunocompromised patients owing to its multidrug resistance. Unfortunately, genome features, antimicrobial resistance, and virulence potentials in P. phragmitetus have not been reported before. A predominant colony (31801) was isolated from a liver abscess patient, indicating that it accounted for the infection. To investigate its infection mechanism(s) in depth, we sequenced this bacterial genome and tested its antimicrobial resistance. Average nucleotide identity (ANI) analysis assigned the bacterium to the species P. phragmitetus (ANI, >95%). Comparative genomics analyses among Pannonibacter spp. representing the different living niches were used to describe the Pannonibacter pan-genomes and to examine virulence factors, prophages, CRISPR arrays, and genomic islands. Pannonibacter phragmitetus 31801 consisted of one chromosome and one plasmid, while the plasmid was absent in other Pannonibacter isolates. Pannonibacter phragmitetus 31801 may have a great infection potential because a lot of genes encoding toxins, flagellum formation, iron uptake, and virulence factor secretion systems in its genome. Moreover, the genome has 24 genomic islands and 2 prophages. A combination of antimicrobial susceptibility tests and the detailed antibiotic resistance gene analysis provide useful information about the drug resistance mechanisms and therefore can be used to guide the treatment strategy for the bacterial infection. PMID- 28857516 TI - Modeling of the hERG K+ Channel Blockage Using Online Chemical Database and Modeling Environment (OCHEM). AB - Human ether-a-go-go related gene (hERG) K+ channel plays an important role in cardiac action potential. Blockage of hERG channel may result in long QT syndrome (LQTS), even cause sudden cardiac death. Many drugs have been withdrawn from the market because of the serious hERG-related cardiotoxicity. Therefore, it is quite essential to estimate the chemical blockage of hERG in the early stage of drug discovery. In this study, a diverse set of 3721 compounds with hERG inhibition data was assembled from literature. Then, we make full use of the Online Chemical Modeling Environment (OCHEM), which supplies rich machine learning methods and descriptor sets, to build a series of classification models for hERG blockage. We also generated two consensus models based on the top-performing individual models. The consensus models performed much better than the individual models both on 5-fold cross validation and external validation. Especially, consensus model II yielded the prediction accuracy of 89.5 % and MCC of 0.670 on external validation. This result indicated that the predictive power of consensus model II should be stronger than most of the previously reported models. The 17 top performing individual models and the consensus models and the data sets used for model development are available at https://ochem.eu/article/103592. PMID- 28857518 TI - Diamond Open Access in the quest for interdisciplinarity and excellence. PMID- 28857517 TI - CISD2 enhances the chemosensitivity of gastric cancer through the enhancement of 5-FU-induced apoptosis and the inhibition of autophagy by AKT/mTOR pathway. AB - Gastric cancer (GC) is a prevalent upper gastrointestinal tumor characterized by high morbidity and mortality due to imperfect screening systems and the rapid development of resistance to 5-fluorouracil (5-FU). CDGSH iron sulfur domain 2 (CISD2) has been recently regarded as a candidate oncogene in several types of tumors. It is, therefore, necessary to investigate its biological function and clinical significance in gastric cancer. In this study, the down-regulated expression level of CISD2 in GC compared with adjacent normal tissues was evaluated by quantitative RT-PCR and Western blotting. An immunohistochemical analysis indicated that CISD2 expression in GC was significantly correlated with age (P = 0.002), Lauren's classification (P = 0.001), and differentiation (P = 0.049). Two cell lines, MKN1 and BGC823, were used to analyze the role of CISD2 in gastric carcinogenesis and response to 5-FU through CCK-8 assays, the RT-CES system, Transwell assays, flow cytometry, and confocal fluorescence microscopy. The overexpression of CISD2 resulted in reduced cellular growth and proliferation, inhibition of metastatic ability, and increased apoptosis. 5-FU treatment increased endogenous as well as exogenous overexpression of CISD2 in GC cells. Further investigation revealed that CISD2 enhanced sensitivity to 5-FU via an increase in apoptosis and inhibition of protective autophagy through the activation of the AKT/mTOR pathway. In conclusion, CISD2 is down-regulated in gastric cancer, and its effects on the inhibition of cellular proliferation, metastatic ability, and increased chemotherapy sensitivity are mediated by antagonism to 5-FU-induced autophagy through the AKT/mTOR pathway. PMID- 28857519 TI - Mortality and causes of death among Croatian male Olympic medalists. AB - AIM: To compare the overall and disease-specific mortality of Croatian male athletes who won one or more Olympic medals representing Yugoslavia from 1948 to 1988 or Croatia from 1992 to 2016, and the general Croatian male population standardized by age and time period. METHODS: All 233 Croatian male Olympic medalists were included in the study. Information on life duration and cause of death for the Olympic medalists who died before January 1, 2017, was acquired from their families and acquaintances. We asked the families and acquaintances to present medical documentation for the deceased. Data about the overall and disease-specific mortality of the Croatian male population standardized by age and time period were obtained from the Croatian Bureau of Statistics (CBS). Overall and disease-specific standard mortality ratios (SMR) with 95% confidence intervals (CI) were calculated to compare the mortality rates of athletes and general population. RESULTS: Among 233 Olympic medalists, 57 died before the study endpoint. The main causes of death were cardiovascular diseases (33.3%), neoplasms (26.3%), and external causes (17.6%). The overall mortality of the Olympic medalists was significantly lower than that of general population (SMR 0.73, 95% CI 0.56-0.94, P=0.013). Regarding specific causes of death, athletes' mortality from cardiovascular diseases was significantly reduced (SMR 0.61, 95% CI 0.38-0.93, P=0.021). CONCLUSIONS: Croatian male Olympic medalists benefit from lower overall and cardiovascular mortality rates in comparison to the general Croatian male population. PMID- 28857520 TI - A combination of levobupivacaine and lidocaine for paravertebral block in breast cancer patients undergoing quadrantectomy causes greater hemodynamic oscillations than levobupivacaine alone. AB - AIM: To test for differences in hemodynamic and analgesic properties in patients with breast cancer undergoing quadrantectomy with paravertebral block (PVB) induced with a solution of either one or two local anesthetics. METHOD: A prospective, single-center, randomized, double-blinded, controlled trial was conducted from June 2014 until September 2015. A total of 85 women with breast cancer were assigned to receive PVB with either 0.5% levobupivacaine (n=42) or 0.5% levobupivacaine with 2% lidocaine (n=43). Hemodynamic variables of interest included intraoperative stroke volume variation (SVV), mean arterial pressure, heart rate, cardiac output, episodes of hypotension, use of crystalloids, and use of inotropes. Analgesic variables of interest were time to block onset, duration of analgesia, and postoperative serial pain assessment using a visual analogue scale. RESULTS: Although the use of 0.5% levobupivacaine with 2% lidocaine solution for PVB decreased the mean time-to-block onset (14 minutes; P<0.001), it also caused significantly higher SVV values over the 60 minutes of monitoring (mean difference: 4.33; P<0.001). Furthermore, the patients who received 0.5% levobupivacaine with 2% lidocaine experienced shorter mean duration of analgesia (105 minutes; P=0.006) and more episodes of hypotension (17.5%; P=0.048) and received more intraoperative crystalloids (mean volume: 550 mL; P<0.001). CONCLUSION: The use of 0.5% levobupivacaine in comparison with 0.5% levobupivacaine with 2% lidocaine solution for PVB had a longer time-to-block onset, but it also reduced hemodynamic disturbances and prolonged the analgesic effect. PMID- 28857521 TI - IgM as a novel predictor of disease progression in secondary focal segmental glomerulosclerosis. AB - AIM: To determine the role of immunoglobulin M (IgM) deposits in clinical manifestations, disease outcome, and treatment response of idiopathic and secondary focal segmental glomerulosclerosis (FSGS). METHODS: Kidney biopsy specimens of 171 patients diagnosed with FSGS (primary and secondary) and 50 control patients were retrospectively included in the study. For each patient, clinical and outcome data were obtained and compared to morphological parameters, including immunofluorescence analysis of mesangial IgM and complement 3 (C3) deposits analyzed on kidney biopsy samples. RESULTS: There were significant positive correlations between IgM and C3 deposition in secondary FSGS (P<0.001) and between IgM and mesangial deposits detected by electron microscopy in secondary FSGS (P=0.015), which indicated that higher IgM deposition correlated with higher C3 deposition and mesangial deposits only in secondary FSGS. Patients with secondary FSGS and the deposition of IgM showed inferior renal outcomes at earlier time points in comparison with patients with negative IgM expression (P=0.022). CONCLUSIONS: We detected a positive correlation between IgM and C3 in secondary FSGS. The association between IgM deposition and worse renal outcome in secondary FSGS indicates that IgM may play a role in the progression of this disease. PMID- 28857522 TI - Validation of the Croatian version of CIVIQ quality of life questionnaire in patients with chronic venous disorders. AB - AIM: To test the psychometric properties of the Croatian version of the Chronic Venous Insufficiency Quality of Life (CIVIQ) Questionnaire and to assess the quality of life in patients with chronic venous disorders of all stages. METHODS: This cross-sectional study performed between 2014 and 2015 in a private family practice assessed the factorial validity, cross-sectional validity, and reliability of the Croatian CIVIQ 20-item questionnaire completed by 428 adult patients (78% women) with chronic venous disorders classified according to the Clinical-Etiologic-Anatomic-Pathophysiologic (CEAP) C classification as stages C1 C6. RESULTS: Median patient age was 52 years (5th-95th percentile, 30-77). The distribution according to the clinical stages of chronic venous disorders was as follows: C1 (n=78, 18%), C2 (n=192, 45%), C3 (n=53, 12%), C4 (n=44, 10%), C5 (n=13, 3%), and C6 (n=48, 11%). The CIVIQ-20 factorial structure was unstable, and six items were excluded from the analysis to test the psychometric properties of the shortened version (CIVIQ-14). CIVIQ-14 has three dimensions (physical, psychological, and pain). Internal consistency reliability is high for the entire CIVIQ-14 (Cronbach alpha=0.92) and for all CIVIQ-14 dimensions (alpha>=0.80). The median quality of life significantly decreased with higher CEAP C stages as follows: C1/C2 (86, 50-100); C3/C4 (75, 36-98); C5/C6 (67, 31-95) (P<0.001). Post hoc analysis showed a higher quality of life in C1/C2 than in other groups (P<0.001). CONCLUSION: The shortened CIVIQ-14 version is useful for assessing the quality of life in patients with chronic venous disorders in everyday clinical practice. To achieve a stable validated instrument, we recommend a cross-cultural validation of items that have loadings on more than one factor. PMID- 28857523 TI - Awareness and use of evidence-based medicine information among patients in Croatia: a nation-wide cross-sectional study. AB - AIM: To determine the use of evidence-based medicine (EBM) information and the level of awareness and knowledge of EBM among patients in Croatia. METHODS: A cross-sectional study was conducted among 987 patients in 10 family medicine practices in Croatia. Patients from both urban (n=496) and rural (n=482) areas were surveyed. A 27-item questionnaire was used to collect data about sources that patients searched for medical information, patient awareness and use of Cochrane systematic reviews and other EBM resources, and their demographic characteristics. RESULTS: Half of the patients searched for medical information from sources other than physician. Internet was the most common place they searched for information. Very few patients indicated using EBM sources for medical information; one fifth of patients heard of EBM and 4% of the patients heard of the Cochrane Collaboration. Patients considered physician's opinion as the most reliable source of medical information. A logistic regression model showed that educational level and urban vs rural residence were the predictors of awareness about EBM and systematic reviews (P<0.001 for both). CONCLUSION: Our finding that patients consider a physician's opinion to be the most reliable source of health-related information could be used for promotion of high-quality health information among patients. More effort should be devoted to the education of patients in rural areas and those with less formal education. New avenues for knowledge translation and dissemination of high-quality health information among patients are necessary. PMID- 28857524 TI - Concomitant occurrence of FXTAS and clinically defined sporadic inclusion body myositis: report of two cases. AB - This report describes unique presentations of inclusion body myositis (IBM) in two unrelated patients, one male and one female, with genetically and histologically confirmed fragile X-associated tremor/ataxia syndrome (FXTAS). We summarize overlapping symptoms between two disorders, clinical course, and histopathological analyses of the two patients with FXTAS and sporadic IBM, clinically defined per diagnostic criteria of the European Neuromuscular Centre. In case 1, a post-mortem analysis of available brain and muscle tissues is also described. Histopathological features (rimmed vacuoles) consistent with clinically defined IBM were detected in both presented cases. Postmortem testing in case 1 revealed the presence of an FMR1 premutation allele of 60 CGG repeats in both brain and skeletal muscle samples. Case 2 was a premutation carrier with 71 CGG repeats who had a son with FXS. Given that FXTAS is associated with immune mediated disorders among premutation carriers, it is likely that the pathogeneses of IBM and FXTAS are linked. This is, to our knowledge, the first report of these two conditions presenting together, which expands our understanding of clinical symptoms and unusual presentations in patients with FXTAS. Following detection of a premutation allele of the FMR1 gene, FXTAS patients with severe muscle pain should be assessed for IBM. PMID- 28857525 TI - Discourse, ethics, public health, abortion, and conscientious objection in Croatia. PMID- 28857526 TI - ["One-stop" Pediatric Surgery and its defense]. PMID- 28857527 TI - [Vesicoureteral reflux. Fundamentals of the current treatment]. PMID- 28857528 TI - [Benefits of magnetic resonance for the study of pectus excavatum in children: initial experience]. AB - INTRODUCTION/AIM OF THE STUDY: In patients with PE, cardiovascular alterations ensue as a result of the mediastinum compression caused by sternum impingement and is responsible of many of the symptoms. Anatomical and functional assessment is of the utmost importance for a comprehensive understanding of the disease and an adequate treatment plan. Our aim was to describe the use of magnetic resonance image (MRI) in the study of PE and whether it is comparable to imaging techniques. PATIENTS AND METHODS: A retrospective study of the first 10 patients in which an MRI was performed as part of PE assessment within august 2015-2016. PE indexes were evaluated: Haller, correction, asymmetry, as well as sternal rotation. An analysis of right ventricular function was carried out comparing echocardiogram and MRI. RESULTS: MRI scan on 10 patients showed the following findings: Haller index: inspiration: 3.75 (3.5-7.3) and expiration 4,9 (3.9 10.8), correction index of 24% (5-37%) and a sternal rotation of 12o (0-31o). The cardiovascular study showed a median ejection fraction of the right ventricle (EFRV) of 50% (38-64%), with 9 of the 10 patients under the normal value of 61% (54-71%). Echocardiographic findings underestimated functional alterations in all of the patients. CONCLUSION: This initial study suggests that the use of MRI as a test of choice in the evaluation of PE subject to surgical correction is feasible. Absence of radiation offers the capacity of a complete and dynamic anatomical as well as cardiovascular study. PMID- 28857529 TI - [Surgical treatment of tracheal stenosis. A 11-year report in a pediatric hospital]. AB - OBJECTIVES: To report our experience in the surgical treatment of patients having acquired and congenital tracheal stenosis. MATERIAL AND METHODS: Fifty eight patients with tracheal stenosis were surgically treated between July 2005 and May 2016, 29 were females and 29 were males. Thirty patients had acquired stenosis and 28 had congenital stenosis. RESULTS: Five to 12 rings were resected (median 5) in 26 patients, in 2 cartilage was grafted in the anterior wall, in another carinostomy was performed, and in the remaining, the trachea was replaced using an aortic cryopreserved graft. In those with congenital stenosis, 14 patients underwent slide technique; in eleven, 3 to 6 rings were resected (median 5); in 3 a patch was grafted in the anterior tracheal wall. Seven patients died: 2 with acquired stenosis and 5 with congenital stenosis. Global survival was 88% (28 of 30 patients with acquired stenosis and 23 of 28 with congenital). From 28 living patients operated on due to acquired stenosis, 26 are asymptomatic, one presents graft stenosis, and one has a stoma in the aortic graft. From 23 living patients operated on due to congenital stenosis, 20 remain asymptomatic and 3 have tracheal stents placed on. CONCLUSIONS: Surgical treatment of acquired stenosis is easier and presents less severe complications. Congenital stenosis often requires more than one procedure to control the disease, and presents a higher mortality rate. PMID- 28857530 TI - [Surgery in times of crisis: conservative treatment of pectus carinatum by static corset]. AB - INTRODUCTION: Dynamic compression system is the elective treatment for chondrogladiolar pectus carinatum. Nevertheless, its high cost poses a problem for its prescription in places where it is not subsidized. This article analyzes the experience of the Paediatric Plastic Surgery Service at a third grade hospital in the treatment of this deformity with a static compression system. MATERIALS AND METHODS: The study presents a descriptive, retrospective analysis of 30 patients with pectus carinatum treated with a static compression system. Furthermore, we describe the protocol of treatment used at our unit, and we analyse the satisfaction with bracing therapy, and its relation to therapeutic compliance. RESULTS: The study includes 28 boys and 2 girls. 93% of the patients presented a chondrogladiolar pectus carinatum. At the moment of finishing the study, 11 patients have completed the treatment, 14 still bracing, and 5 were lost in the follow-up. Satisfaction questionnaires were answered by 19 patients. CONCLUSION: Bracing therapy with static compression system is the treatment of choice for chondrogladiolar pectus carinatum in our unit, because of its effectiveness and lower price. Quality of life questionnaires show better marks in patients that are in the second phase of treatment. PMID- 28857531 TI - [When should gestation of a gastroschisis be terminated?] AB - OBJECTIVES: In gastroschisis pregnancies, a) to correlate prenatal ultrasound variables with postnatal outcome and b) to determine the ideal time for setting the delivery in order to achieve the best neonatal outcome. MATERIAL AND METHODS: Retrospective review (2000-2015) of all available gastroschisis whose prenatal findings could be correlated with the neonatal outcome. Two study groups have been defined according to the complications present after birth: favorable gastrosquisis and complicated. Prenatal variables were compared by groups using McWhitney or Chi tests as needed. RESULTS: Twenty-two gastroschisis fulfilled the requirement. Twelve cases had uneventful outcomes. Ten patients experienced complications, including death in five. In the complicated group there were 15 episodes of sepsis and 17 reoperations. Any single ultrasound parameter could predict a bad follow up. In thirteen cases, delivery was forced due to sudden changes on ultrasound bowel appearance. Nine of these patients had very good neonatal outcome. CONCLUSIONS: Finishing pregnancy when sudden changes on the fetal bowel were identified was the only strategy that leaded us to diminish the complication rate in gastroschisis. PMID- 28857532 TI - [Recurrence of uncomplicated intestinal intussusception. Can it be treated as an outpatient?] AB - OBJECTIVES: To estimate the recurrence rate of intussusception after successful enema reduction and to analyze the costs of hospital admission with the current management of this pathology. MATERIAL AND METHODS: A retrospective study over 5 years of 97 patients with confirmed diagnosis of intussusception was undertaken. Medical records were evaluated for patient demographic, clinical and radiological data. Patients with enema-reduced intussusception were selected and data respecting to timing and outcome of recurrences, and length of stay were analyzed. Recurrence was defined as a new episode of intussusception within 72 hours of the initial presentation. Costs were calculated using hospital-specific data. RESULTS: During the study period there were 81/97 children with successful enema reduction. Mean length of stay was 35 hours in the conservative treatment group. There were 8 episodes of recurrence, 5 of them within the first 24 hours (6.17%), for an overall recurrence rate of 9.88%. 7 children were treated by repeated enema and only one patient needed surgery for persistent illness. Assuming the overall recurrence rate of 9.88%, it would require hospitalizing 16 patients to identify a single recurrence with a cost of 1,723.75 ? per patient. CONCLUSIONS: Given the low recurrence rate for enema-reduced intussusception and the possibility of repeated enema for their treatment in most of recurrences, we strongly advocated for the outpatient management as a safe and cost-effective alternative. PMID- 28857533 TI - [Prophylactic thyroidectomy in RET proto-oncogen mutation]. AB - OBJECTIVE: Analysis of prophylactic thyroidectomy cases carried out in our Center in patients with RET gene mutations. MATERIAL AND METHODS: Retrospective study of 25 patients with RET proto-oncogene mutations subjected to prophylactic thyroidectomy between January 2000 and January 2016. Epidemiologic variables, surgical technique, histological results and follow-up were studied. RESULTS: Our sample consists of 25 patients, 15 males and 10 females. The range of age was from 7 months to 12 years old, with a median of 5 years old. We obtained 21 cases with NEM2A, from which 19 (76%) presented 634 mutation and 2 (8%) presented 611 mutation. Four cases were NEM2B, all with 918 mutation. Microscopical findings showed microcarcinoma, in situ carcinoma or medullary thyroid carcinoma in 16 patients (64%). Eight of them showed hyperplasia (32%) and 1 presented fibrosis (4%). The presence of elevated calcitonin was correlated with histologic alterations in 7 cases (43.7%), without significant differences (chi2 0.3; p 0.6). From 16 patients with carcinoma (13 NEM2A and 3 NEM2B), 10 were 5 years old or less at the moment of the surgery. A total thyroidectomy was performed in all patients. There were no intra or post-surgical complications. During the follow up of the patients, levels of calcitonin, calcium, parathormone, catecholamines and metanephrines were normal, except from one case. CONCLUSIONS: The study of RET proto-oncogene allows the identification of patients susceptible of performing a prophylactic thyroidectomy, which have to be carried out early, in an experienced centers. PMID- 28857534 TI - [Postural deformities of the skull. Advantages of protocolization in its treatment]. AB - INTRODUCTION: Since 2007, we have examined in our medical practice children with cranial deformities. The increasing demand and lack of professionals dedicated to it has forced us to assume the treatment of this disease. We present our experience. MATERIAL AND METHODS: Retrospective study of patients with cranial deformities treated from 2010 to 2015. We collected data as age at the first visit and at discharge, sequential measurements of the skull and cranial index, type of treatment prescribed (postural, orthosis or both) and consultation requested to other specialties. In the first stage (2010-2012), each surgeon prescribed the treatment he considered appropriate. Since November 2012 a protocol has been implemented, it includes guideline sheets for the surgeon and parents with information on postural therapy and graphs to record the measurements. RESULTS: We have treated 261 patients. Two were diagnosed with craniosynostosis. From the rest, only 151 possessed complete quantitative data and were included in the study with 105 men and 46 women and a mean age of 5.8 months (+/- 1.9 months). There were 23 pure brachycephaly, 126 mixed forms and 2 pure plagiocephaly. A significant disparity between observers' measurements was noticed. All patients underwent a protocolized postural treatment. In 36 patients who did not improve with postural treatment, cranial orthosis was prescribed with good response: 66.8% became mild forms. Those who maintained only postural treatment also improved to milder forms in 64.4%. CONCLUSIONS: The implementation of a protocol has enabled us to unify the care and follow-up of these patients. Cranial measurement techniques should be more precise and reproducible. Good postural treatment and empathy with the family reduce the use of orthosis in carefully selected cases. PMID- 28857536 TI - Food for thought. PMID- 28857535 TI - [Approach of the unilateral cleft lip with Meara's cheiloplasty technique]. AB - INTRODUCTION: Isolated cleft lip is the mildest form of the cleft lip and palate spectrum; however those patients are often treated with the same surgical techniques that are used for the more severe cases (advancement-rotation flaps, quadrangular flaps). Meara's cheiloplasty technique may be a less aggressive option for lip repair in isolated cleft lip or whenever the gap between labial segments is not wide. MATERIAL AND METHODS: All children that had their cleft lip repaired following Meara's cheiloplasty between May 2014 and December 2015 were retrospectively reviewed. Duration of the surgical procedure, time to hospital discharge and complications were noted. Aesthetic results were evaluated in terms of lip height and symmetry, nose shape and symmetry, and scar appearance. RESULTS: Thirteen patients underwent Meara's cheiloplasty during this period. The average age was 6.11 months (5 to 12 months). A primary rhinoplasty was done at the same time in case of nasal asymmetry. Duration of the lip repair averaged 85 minutes. Oral feeding was started 4 hours after the procedure; bottle-feeding was withheld for 2 weeks postoperatively, as our protocol recommends after other lip repair techniques. In all 13 cases the result was a symmetrical, adequately high upper lip and a well-balanced nose, except for one case of lip scar retraction that was solved with triamcinolone infiltration. There were no other intra or postoperative complications. CONCLUSIONS: Meara's cheiloplasty corrects small or moderate gap cleft lip (usually cleft lip without cleft alveolus). Benefits over other teccniques are a shorter procedure and less geometric, undulate flaps that produce a harmonic lip. PMID- 28857537 TI - Health foodies. Hospitals and clinics are getting into a new kind of "food service". PMID- 28857538 TI - TEMPO-Appended Metal-Organic Frameworks as Highly Active, Selective, and Reusable Catalysts for Mild Aerobic Oxidation of Alcohols. AB - Metal-organic frameworks (MOFs) decorated with stable organic radicals are highly promising materials for redox catalysis. Unfortunately however, the synthesis of chemically robust MOFs typically requires harsh solvothermal conditions, which are not compatible with organic radicals. Here, we describe the synthesis of two isoreticular families of stable, mixed component, zirconium MOFs with UiO-66 and UiO-67 structures and controlled amounts of covalently attached TEMPO radicals. The materials were obtained using a relatively low-temperature, HCl-modulated de novo method developed by Hupp and Farha and shown to contain large amounts of missing cluster defects, forming nanodomains of the reo phase with 8-connected clusters. In the extreme case of homoleptic UiO-67-TEMPO(100%), the material exists as an almost pure reo phase. Large voids due to missing clusters and linkers allowed these materials to accommodate up to 2 times more of bulky TEMPO substituents than theoretically predicted for the idealized structures and proved to be beneficial for catalytic activity. The TEMPO-appended MOFs were shown to be highly active and recyclable catalysts for selective aerobic oxidation of a broad range of primary and secondary alcohols under exceptionally mild conditions (room temperature, atmospheric pressure of air). The influence of various parameters, including the pore size and TEMPO content, on the catalytic activity was also comprehensively investigated. PMID- 28857539 TI - Interplay between pi-Bridges and Positions of Branched Alkyl Groups of Unsymmetrical D-A-D-pi-A Squaraines in Dye-Sensitized Solar Cells: Mode of Dye Anchoring and the Charge Transfer Process at the TiO2/Dye/Electrolyte Interface. AB - Far-red-absorbing squaraines possessing high molar absorptivity (>105 M-1 cm-1) are being attracted as high-efficiency chromophores in dye-sensitized solar cells (DSSCs). A series of donor-acceptor-donor-pi spacer-acceptor (D-A-D-pi-A) unsymmetrical squaraines, PSQ1-5, with indoline donor and squaric/cyanoacetic acid acceptor units, were designed for sensitized solar cells. For extending the absorption toward the near-infrared region (NIR) and controlling the orientation on the TiO2 surface, benzene (PSQ1 and PSQ2) and thiophene (PSQ3-5) pi-spacers and out-of-plane branched alkyl groups at the indoline that are away (PSQ1, PSQ3, and PSQ5) or near (PSQ2 and PSQ4) the anchoring group, respectively, were introduced. Dynamic aggregation tendency of PSQ1 and PSQ3 than that of their isomers systematically modulates the orientation on the TiO2 surface, which in turn enhances photovoltaic performance. Absorptance on a thin transparent TiO2 film shows a visible-to-NIR response with an onset around 800 nm for PSQ3-5. Although there is close resemblance in electrochemical redox levels, their high injection efficiency and recombination resistance differentiated their impact on the way of anchoring and the dihedral angle between D-A-D units and pi-spacers. DSSCs sensitized with PSQ5 achieved a PCE of 8.15% under simulated AM 1.5G illumination (100 mW cm-2), with the current density (Jsc) and open-circuit voltage (Voc) of 19.73 mA cm-2 and 630 mV, respectively. A clear comparison of the incident-photon-to-current conversion efficiency versus the light-harvesting efficiency correlates the structure-property relationship with Jsc obtained for PSQ dyes. Electrochemical impedance spectroscopy was carried out to examine the TiO2/dye/electrolyte interface for further confirmation of the enhanced PCE of top-sp3-alkylated PSQ5 over that of other dyes. PMID- 28857540 TI - Anion-Responsive Poly(ionic liquid)s Gating Membranes with Tunable Hydrodynamic Permeability. AB - Novel anion-responsive "intelligent" membranes with functional gates are fabricated by filling polyethersulfone microporous membranes with poly(ionic liquid)s (PILs) gels. The wetting properties of the PILs could be controlled by changing their counteranions (CAs), and thus, the filled PILs gel gates in the membrane pores could spontaneously switch from the "closed" state to the "open" one by recognizing the hydrophilic CAs in the environment and vice versa. As a result, the fluxes of the "intelligent" membranes could be tuned from a very low level (0 mL/m2.mmHg for Cl-, Br-, and BF4-) to a relatively high one (430 mL/m2.mmHg for TFSI). The anion-responsive gating behavior of the PILs filled membranes is fast, reversible, and reproducible. In addition, the "intelligent" membranes are sensitive to contact time and ion concentrations of the hydrophobic CA species. The proposed anion-responsive "intelligent" membranes are highly attractive for ion-recognizable chemical/biomedical separations and purifications. PMID- 28857541 TI - Enhanced X-Band Electromagnetic-Interference Shielding Performance of Layer Structured Fabric-Supported Polyaniline/Cobalt-Nickel Coatings. AB - Despite tremendous efforts, fabrication of lightweight conductive fabrics for high-performance X-band electromagnetic-interference (EMI) shielding remains a daunting technical challenge. We herein report an ingenious and efficient strategy to deposit polyaniline/cobalt-nickel (PANI/Co-Ni) coatings onto lyocell fabrics that involves consecutive steps of in situ polymerization and electroless plating. The PANI-Co-Ni ternary-component system successfully induced a synergistic effect from EM wave-absorption and EM wave-reflection and, moreover, upgraded the match level between magnetic loss and dielectric loss. By the judicious control of polymerization cycles and plating time, low-weight fabric supported PANI/Co-Ni composites (with PANI and Co-Ni loading of 2.86 and 3.99 mg.cm-2, respectively) were prepared, which displayed relatively high EMI shielding effectiveness (SE) (33.95-46.22 dB) when compared to their single peers (PANI-coated fabric and Co-Ni-coated fabric) or even the sum of them. Inspired by the so-called "1 + 1 > 2" phenomenon, here we demonstrated that there was an EMI SE enhancement effect in this conductive polymer/metal system that may be associated with interphase chemical and/or physical interactions. Further analysis revealed that this EMI SE enhancement effect was evident under circumstances of relatively low metal content and became weak with the increase of metal content. The mechanisms involved were interpreted through a series of fundamental measurements, including Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), and vector network analysis (VNA). The linkage between PANI and Co-Ni coatings was in the form of Co-N/Ni-N, which mimics the atomic configuration occurring in cobalt porphyrins. The Co-N/Ni N configuration strengthened the interphase adhesion and thus resulted in shielding fabrics with high durability for practical applications. PMID- 28857542 TI - Ion-Exchange-Induced Selective Etching for the Synthesis of Amino-Functionalized Hollow Mesoporous Silica for Elevated-High-Temperature Fuel Cells. AB - As differentiated from conventional synthetic processes, amino-functionalized hollow mesoporous silica (NH2-HMS) has been synthesized using a new and facile strategy of ion-exchange-induced selective etching of amino-functionalized mesoporous silica (NH2-meso-silica) by an alkaline solution. Nuclear magnetic resonance (NMR) spectroscopy and in situ time-resolved small-angle X-ray scattering (SAXS) reveal that ion-exchange-induced selective etching arises from the gradient distribution of OH- in the NH2-meso-silica nanospheres. Moreover, the ion-exchange-induced selective etching mechanism is verified through a successful synthesis of hollow mesoporous silica. After infiltration with phosphotungstic acid (PWA), PWA-NH2-HMS nanoparticles are dispersed in the poly(ether sulfone)-polyvinylpyrrolidone (PES-PVP) matrix, forming a hybrid PWA NH2-HMS/PES-PVP nanocomposite membrane. The resultant nanocomposite membrane with an optimum loading of 10 wt % of PWA-NH2-HMS showed an enhanced proton conductivity of 0.175 S cm-1 and peak power density of 420 mW cm-2 at 180 degrees C under anhydrous conditions. Excellent durability of the hybrid composite membrane fuel cell has been demonstrated at 200 degrees C. The results of this study demonstrated the potential of the facile synthetic strategy in the fabrication of NH2-HMS with controlled mesoporous structure for application in nanocomposite membranes as a technology platform for elevated-temperature proton exchange membrane fuel cells. PMID- 28857543 TI - Chameleonic Dye Adapts to Various Environments Shining on Macrocycles or Peptide and Polysaccharide Aggregates. AB - This work describes latent fluorescence particles (LFPs) based on a new environmentally sensitive carbazole compound aggregated in water and their use as sensors for probing various cavitands and the different stages of aggregating systems. Cyclodextrins (CDs), cucurbit[n]urils (CB[n], n = 6, 7, 8), and a resorcinarene capsule were used to study the dynamic nature of the LFPs. The fluorescence was dramatically enhanced by a proposed disaggregation-induced emission enhancement (DIEE) mechanism with specific features for CB[n]. Then, the aggregated states of the dipeptides Leu-Leu, Phe-Phe, and Fmoc-Leu-Leu (vesicles, crystals, fibers) were studied by fluorescence spectroscopy and confocal fluorescence microscopy thanks to the adaptive and emissive behavior of the LFPs, allowing us to study an interesting polymorphism phenomenon. The LFPs have then been used in the sensing of the aggregation of the polysaccharide alginate, for which distinct fluorescence turn-on is detected upon stepwise biopolymer assembly, and for amylose detection. The carbazole particles not only adapt to various environments but also display multicolor fluorescent signals. They can be used for the fast probing of the aggregation propensity of newly prepared molecules or biologically relevant compounds or to accelerate the discovery of new macrocycles or of self-assembling peptides in water. PMID- 28857544 TI - Identification of 5-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2 Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition. AB - Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT 0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 MUM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models. PMID- 28857545 TI - Photocatalytic Mechanism Regulation of Bismuth Oxyhalogen via Changing Atomic Assembly Method. AB - Exciton and carrier photocatalytic processes have been proved in bismuth oxyhalogen photocatalysts. But, there are no reports about how to regulate the different mechanisms to improve photocatalytic activity for different reaction. Here, we found that the photocatalytic mechanisms could be regulated by changing the assembly method of bismuth, oxygen, and halogen atoms. Reactive oxygen species (ROS) experimentals results concluded that solid solution BiOBr0.5I0.5 showed enhanced exciton photocatalytic process, and coupling 0.5BiOBr/0.5BiOI displayed improved carrier photocatalytic proces. This work promoted the understanding about solid solution and coupling for bismuth oxyhalogen. PMID- 28857546 TI - Antibacterial and Bioactive Coatings Based on Radio Frequency Co-Sputtering of Silver Nanocluster-Silica Coatings on PEEK/Bioactive Glass Layers Obtained by Electrophoretic Deposition. AB - Bioactive and antibacterial coatings on stainless steel substrates were developed and characterized in this study. Silver nanocluster-silica composite coatings of 60-150 nm thickness were deposited using radio frequency (RF) co-sputtering on PEEK/bioactive glass (BG) layers (of 80-90 MUm thickness) which had been electrophoretically deposited onto stainless steel. Two sputtering conditions were used by varying the deposition time (15 and 40 min); the resulting microstructure, composition, adhesion strength, in vitro bioactivity, and antibacterial activity were investigated. Scanning electron microscopy (SEM), X ray photoelectron spectroscopy (XPS), and energy dispersive spectroscopy (EDX) confirmed the presence of silver nanoclusters, which were homogeneously embedded in the silica matrix. The isoelectric point of the coatings and their charge at physiological pH were determined by zeta potential measurements. The presence of BG particles in the PEEK/BG layer allows the coatings to form apatite-like crystals upon immersion in simulated body fluid (SBF). Moreover, silver nanoclusters embedded in the silica matrix as a top layer provided an antibacterial effect against Escherichia coli and Staphylococcus carnosus. PMID- 28857547 TI - Deoxygenation of Palmitic and Lauric Acids over Pt/ZIF-67 Membrane/Zeolite 5A Bead Catalysts. AB - The deoxygenation of palmitic and lauric acids over 0.5 wt % Pt/ZIF-67 membrane/zeolite 5A bead catalysts is demonstrated. Almost complete conversion (% deoxygenation of >=95%) of these two fatty acids was observed over both fresh and recycled catalyst after a 2 h reaction time. The catalysts displayed high selectivity to pentadecane and undecane via decarboxylation reaction pathway even at low 0.5 wt % Pt loading. Selectivity to pentadecane and undecane as high as ~92% and ~94% was observed under CO2 atmosphere when palmitic and lauric acids were used respectively as reactants. Depending on the reaction gas atmosphere, two distinctive reaction pathways were observed: decarboxylation and hydrodeoxygenation. Specifically, it was found that decarboxylation reaction pathway was more favorable in the presence of helium and CO2, while hydrodeoxygenation pathway strongly competed against the decarboxylation pathway when hydrogen was employed during the deoxygenation reactions. Esters were identified as the key reaction intermediates leading to decarboxylation and hydrodeoxygenation pathways. PMID- 28857548 TI - Effect of BN Nanoparticles Loaded with Doxorubicin on Tumor Cells with Multiple Drug Resistance. AB - Herein we study the effect of doxorubicin-loaded BN nanoparticles (DOX-BNNPs) on cell lines that differ in the multidrug resistance (MDR), namely KB-3-1 and MDR KB-8-5 cervical carcinoma lines, and K562 and MDR i-S9 leukemia lines. We aim at revealing the possible differences in the cytotoxic effect of free DOX and DOX BNNP nanoconjugates on these types of cells. The spectrophotometric measurements have demonstrated that the maximum amount of DOX in the DOX-BNNPs is obtained after saturation in alkaline solution (pH 8.4), indicating the high efficiency of BNNPs saturation with DOX. DOX release from DOX-BNNPs is a pH-dependent and DOX is more effectively released in acid medium (pH 4.0-5.0). Confocal laser scanning microscopy has shown that the DOX-BNNPs are internalized by neoplastic cells using endocytic pathway and distributed in cell cytoplasm near the nucleus. The cytotoxic studies have demonstrated a higher sensitivity of the leukemia lines to DOX-BNNPs compared with the carcinoma lines: IC50(DOX-BNNPs) is 1.13, 4.68, 0.025, and 0.14 MUg/mL for the KB-3-1, MDR KB-8-5, K562, and MDR i-S9 cell lines, respectively. To uncover the mechanism of cytotoxic effect of nanocarriers on MDR cells, DOX distribution in both the nucleus and cytoplasm has been studied. The results indicate that the DOX-BNNP nanoconjugates significantly change the dynamics of DOX accumulation in the nuclei of both KB-3-1 and KB-8-5 cells. Unlike free DOX, the utilization of DOX-BNNPs nanoconjugates allows for maintaining a high and stable level of DOX in the nucleus of MDR KB-8-5 cells. PMID- 28857549 TI - Urease Inhibition in the Presence of N-(n-Butyl)thiophosphoric Triamide, a Suicide Substrate: Structure and Kinetics. AB - The nickel-dependent enzyme urease is a virulence factor for a large number of pathogenic and antibiotic-resistant bacteria, as well as a negative factor for the efficiency of soil nitrogen fertilization for crop production. The use of urease inhibitors to offset these effects requires knowledge, at a molecular level, of their mode of action. The 1.28 A resolution structure of the enzyme inhibitor complex obtained upon incubation of Sporosarcina pasteurii urease with N-(n-butyl)thiophosphoric triamide (NBPT), a molecule largely utilized in agriculture, reveals the presence of the monoamidothiophosphoric acid (MATP) moiety, obtained upon enzymatic hydrolysis of the diamide derivative of NBPT (NBPD) to yield n-butyl amine. MATP is bound to the two Ni(II) ions in the active site of urease using a MU2-bridging O atom and terminally bound O and NH2 groups, with the S atom of the thiophosphoric amide pointing away from the metal center. The mobile flap modulating the size of the active site cavity is found in the closed conformation. Docking calculations suggest that the interaction between urease in the open flap conformation and NBPD involves a role for the conserved alphaArg339 in capturing and orienting the inhibitor prior to flap closure. Calorimetric and spectrophotometric determinations of the kinetic parameters of this inhibition indicate the occurrence of a reversible slow inhibition mode of action, characterized, for both bacterial and plant ureases, by a very small value of the dissociation constant of the urease-MATP complex. No need to convert NBPT to its oxo derivative NBPTO, as previously proposed, is necessary for urease inhibition. PMID- 28857550 TI - Catalytic Hydride Transfer to CO2 Using Ru-NAD-Type Complexes under Electrochemical Conditions. AB - The catalytic performance of Ru-NAD-type complexes [Ru(tpy)(pbn)(CO)]2+ ([1]2+; tpy = 2,2';6',2"-terpyridine; pbn = 2-(pyridin-2-yl)benzo[b][1,5]naphthyridine) and the Ru-CO-bridged metallacycle [2]+ was investigated in the context of the electrochemical reduction of CO2 in H2O/CH3CN at room temperature. A controlled potential electrolysis of [1]2+ and [2]+ afforded formate (HCOO-) as the main product, under concomitant formation of minor amounts of CO and H2. Metallacycle [2]+ showed a higher selectivity toward the formation of HCOO- than [1]2+ (HCOO /CO for [1]2+, 2.7; HCOO-/CO for [2]+, 7). The generation of HCOO- via a catalytic hydride transfer from the NADH-type ligands of [1]2+ and [2]+ to CO2 was supported by the experimental results and a comparison with the reduction of CO2 catalyzed by [Ru(tpy)(bpy)(CO)]2+ under similar conditions. A mechanism for the catalytic reduction of CO2 by [1]2+ and [2]+ was proposed based on the experimental evidence. The thus-obtained results may help to expand the field of NADH-assisted reduction reactions. PMID- 28857551 TI - Sequence-Selective Formation of Synthetic H-Bonded Duplexes. AB - Oligomers equipped with a sequence of phenol and pyridine N-oxide groups form duplexes via H-bonding interactions between these recognition units. Reductive amination chemistry was used to synthesize all possible 3-mer sequences: AAA, AAD, ADA, DAA, ADD, DAD, DDA, and DDD. Pairwise interactions between the oligomers were investigated using NMR titration and dilution experiments in toluene. The measured association constants vary by 3 orders of magnitude (102 to 105 M-1). Antiparallel sequence-complementary oligomers generally form more stable complexes than mismatched duplexes. Mismatched duplexes that have an excess of H-bond donors are stabilized by the interaction of two phenol donors with one pyridine N-oxide acceptor. Oligomers that have a H-bond donor and acceptor on the ends of the chain can fold to form intramolecular H-bonds in the free state. The 1,3-folding equilibrium competes with duplex formation and lowers the stability of duplexes involving these sequences. As a result, some of the mismatch duplexes are more stable than some of the sequence-complementary duplexes. However, the most stable mismatch duplexes contain DDD and compete with the most stable sequence-complementary duplex, AAA.DDD, so in mixtures that contain all eight sequences, sequence-complementary duplexes dominate. Even higher fidelity sequence selectivity can be achieved if alternating donor acceptor sequences are avoided. PMID- 28857553 TI - Structural and Chemical Effects of the PtBu2 Bridge at Unsaturated Dimolybdenum Complexes Having Hydride and Hydrocarbyl Ligands. AB - A high-yield synthetic route for the preparation of the unsaturated anion [Mo2Cp2(MU-PtBu2)(MU-CO)2]- (2) was implemented, via two-electron reduction of the chloride complex [Mo2Cp2(MU-Cl)(MU-PtBu2)(CO)2] (1). Reaction of 2 with [NH4][PF6] led to the formation of the 30-electron complex [Mo2Cp2(H)(MU PtBu2)(CO)2] (3), in which the hydride ligand adopts an uncommon terminal disposition. DFT analysis of the electronic structure of 3 gave support to the presence of a M=M triple bond in this complex following from a sigma2delta2delta2 configuration, a view also supported by the high electron density accumulated at the corresponding Mo-Mo bond critical point. In contrast, reactions of 2 with IMe or ClCH2Ph gave the alkyl-bridged complexes [Mo2Cp2(MU-kappa1:eta2-CH2R)(MU PtBu2)(CO)2] (R = H (4a), Ph (4b)), which in solution display agostic Mo-H-C interactions. Decarbonylation of 4a took place rapidly under photochemical conditions to give the 30-electron complex [Mo2Cp2(MU-kappa1:eta2-CH3)(MU PtBu2)(MU-CO)] (7), with a stronger agostic coordination of its methyl ligand. In contrast, irradiation of 4b led to the formation of the benzylidyne derivative [Mo2Cp2(MU-CPh)(MU-PtBu2)(MU-CO)] (9), following from fast decarbonylation and dehydrogenation of the bridging benzyl ligand. Low-temperature photochemistry allowed for the NMR characterization of an intermediate preceding the hydrogen elimination, identified as the carbene hydride [Mo2Cp2(H)(MU-CHPh)(MU-PtBu2)(CO)] (10), a product which evolves slowly by H2 elimination to the benzylidyne derivative. Analogous dehydrogenation of the methyl ligand in 7 could be accomplished upon moderate heating, to yield the corresponding methylidyne derivative [Mo2Cp2(MU-CH)(MU-PtBu2)(MU-CO)] (9). A complete reaction mechanism accounting for these photochemical reactions was elaborated, based on the reaction intermediates identified experimentally and on extensive DFT calculations. Surprisingly, for both systems the C-H bond activation steps are relatively easy thermal processes occurring with modest activation energies after photochemical ejection of CO, with a rate-determining step involving the formation of agostic carbenes requiring also a strong structural reorganization of the central Mo2PC rings of these molecules. PMID- 28857552 TI - Precision Electrophile Tagging in Caenorhabditis elegans. AB - Adduction of an electrophile to privileged sensor proteins and the resulting phenotypically dominant responses are increasingly appreciated as being essential for metazoan health. Functional similarities between the biological electrophiles and electrophilic pharmacophores commonly found in covalent drugs further fortify the translational relevance of these small-molecule signals. Genetically encodable or small-molecule-based fluorescent reporters and redox proteomics have revolutionized the observation and profiling of cellular redox states and electrophile-sensor proteins, respectively. However, precision mapping between specific redox-modified targets and specific responses has only recently begun to be addressed, and systems tractable to both genetic manipulation and on-target redox signaling in vivo remain largely limited. Here we engineer transgenic Caenorhabditis elegans expressing functional HaloTagged fusion proteins and use this system to develop a generalizable light-controlled approach to tagging a prototypical electrophile-sensor protein with native electrophiles in vivo. The method circumvents issues associated with low uptake/distribution and toxicity/promiscuity. Given the validated success of C. elegans in aging studies, this optimized platform offers a new lens with which to scrutinize how on-target electrophile signaling influences redox-dependent life span regulation. PMID- 28857554 TI - Modification of Poly(propylene fumarate)-Bioglass Composites with Peptide Conjugates to Enhance Bioactivity. AB - Poly(propylene fumarate) (PPF) has been highlighted as one of the most promising materials for bone regeneration. Despite the promising advantages of using polymer scaffolds for biomedical applications, their inherent lack of bioactivity has limited their clinical application. In this study, PPF was successfully functionalized with Bioglass and a novel catechol-bearing peptide bioconjugate containing bioactive short peptide sequences of basic fibroblast growth factor, bone morphogenetic protein 2, and osteogenic growth peptide. The binding affinity was assessed to be around 110 nmol/cm2 with the Bioglass content at 10 wt %. Fluorescence imaging studies show that the catechol-bearing modular peptide binds preferentially to the Bioglass. A 4 week in vitro cell study using human mesenchymal stem cells showed that cell adhesion, spreading, proliferation, and osteogenic differentiation at both gene and protein levels were all improved by the introduction of peptides, demonstrating the potential approach of dually functionalized polymers for bone regeneration. PMID- 28857555 TI - Iron-Catalyzed Carboamination of Olefins: Synthesis of Amines and Disubstituted beta-Amino Acids. AB - Intermolecular carboamination of olefins with general alkyl groups is an unsolved problem. Diastereoselective carboamination of acyclic olefins represents an additional challenge in intermolecular carboaminations. We have developed a general alkylamination of vinylarenes and the unprecedented diastereoselective anti-carboamination of unsaturated esters, generating amines and unnatural beta amino acids. This alkylamination is enabled by difunctional alkylating reagents and the iron catalyst. Alkyl diacyl peroxides, readily synthesized from aliphatic acids, serve as both alkylating reagents and internal oxidizing agents. A computational study suggests that addition of a nitrile to the carbocation is the diastereoselectivity-determining step, and hyperconjugation is proposed to account for the highly diastereoselective anti-carboamination. PMID- 28857556 TI - Metal-Assisted Ligand-Centered Electrocatalytic Hydrogen Evolution upon Reduction of a Bis(thiosemicarbazonato)Cu(II) Complex. AB - In this study, we report the electrocatalytic behavior of the neutral, monomeric Cu(II) complex of diacetyl-bis(N-4-methyl-3-thiosemicarbazonato), CuL1, for metal assisted ligand-centered hydrogen evolution in acetonitrile and dimethylformamide. CuL1 displays a maximum turnover frequency (TOF) of 10 000 s-1 in acetonitrile and 5100 s-1 in dimethylformamide at an overpotential of 0.80 and 0.76 V, respectively. The rate law is first-order in catalyst and second-order in proton concentration. Gas analysis from controlled potential electrolysis confirms CuL1 as an electrocatalyst to produce H2 with a minimum Faradaic efficiency of 81% and turnover numbers as high as 73 while showing no sign of degradation over 23 h. The H2 evolution reaction (HER) was probed using deuterated acid, demonstrating a kinetic isotope effect of 7.54. A proton inventory study suggests one proton is involved in the rate-determining step. Catalytic intermediates were identified using 1H NMR, X-ray photoelectron, and UV visible spectroscopies. All catalytic intermediates in the proposed mechanism were successfully optimized using density functional theory calculations with the B3LYP functional and the 6-311g(d,p) basis set and support the proposed mechanism. PMID- 28857557 TI - Genetically Encoded Fluorescent Probe for Detecting Sirtuins in Living Cells. AB - Sirtuins are NAD+ dependent protein deacetylases, which are involved in many biological processes. We now report a novel genetically encoded fluorescent probe (EGFP-K85AcK) that responds to sirtuins in living cells. The probe design exploits a lysyl residue in EGFP that is essential for chromophore maturation, and is also an efficient deacetylation substrate for sirtuins. Analysis of activity in Escherichia coli DeltacobB revealed that the probe can respond to various human sirtuins, including SIRT1, SIRT2, SIRT3 and SIRT5. We also directly monitored SIRT1 and SIRT2 activity in HEK293T cells with an mCherry fusion of EGFP-K85AcK, and showed that this approach can be extended to other fluorescent proteins. Finally, we demonstrate that this approach can be used to examine the activity of sirtuins toward additional lysyl posttranslational modifications, and show that sirtuins can act as erasers of HibK modified proteins. PMID- 28857559 TI - Rational Design of in Vivo Tau Tangle-Selective Near-Infrared Fluorophores: Expanding the BODIPY Universe. AB - The elucidation of the cause of Alzheimer's disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 (306VQIVYK311) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Abeta-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly cost-effective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood-brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Abeta plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging. PMID- 28857558 TI - Vinblastine 20' Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance. AB - A series of 180 vinblastine 20' amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20' amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux. PMID- 28857560 TI - Multireference Density Functional Theory with Generalized Auxiliary Systems for Ground and Excited States. AB - To describe static correlation, we develop a new approach to density functional theory (DFT), which uses a generalized auxiliary system that is of a different symmetry, such as particle number or spin, from that of the physical system. The total energy of the physical system consists of two parts: the energy of the auxiliary system, which is determined with a chosen density functional approximation (DFA), and the excitation energy from an approximate linear response theory that restores the symmetry to that of the physical system, thus rigorously leading to a multideterminant description of the physical system. The electron density of the physical system is different from that of the auxiliary system and is uniquely determined from the functional derivative of the total energy with respect to the external potential. Our energy functional is thus an implicit functional of the physical system density, but an explicit functional of the auxiliary system density. We show that the total energy minimum and stationary states, describing the ground and excited states of the physical system, can be obtained by a self-consistent optimization with respect to the explicit variable, the generalized Kohn-Sham noninteracting density matrix. We have developed the generalized optimized effective potential method for the self consistent optimization. Among options of the auxiliary system and the associated linear response theory, reformulated versions of the particle-particle random phase approximation (pp-RPA) and the spin-flip time-dependent density functional theory (SF-TDDFT) are selected for illustration of principle. Numerical results show that our multireference DFT successfully describes static correlation in bond dissociation and double bond rotation. PMID- 28857561 TI - Identification of Missing Proteins in the Phosphoproteome of Kidney Cancer. AB - Identifying missing proteins (MPs) has been one of the critical missions of the Chromosome-Centric Human Proteome Project (C-HPP). Since 2012, over 30 research teams from 17 countries have been trying to search adequate and accurate evidence of MPs through various biochemical strategies. MPs mainly fall into the following classes: (1) low-molecular-weight (LMW) proteins, (2) membrane proteins, (3) proteins that contained various post-translational modifications (PTMs), (4) nucleic acid-associated proteins, (5) low abundance, and (6) unexpressed genes. In this study, kidney cancer and adjacent tissues were used for phosphoproteomics research, and 8962 proteins were identified, including 6415 phosphoproteins, and 44 728 phosphosites, of which 10 266 were unreported previously. In total, 75 candidate detections were found, including 45 phoshoproteins. GO analysis for these 75 candidate detections revealed that these proteins mainly clustered as membrane proteins and took part in nephron and kidney development. After rigorous screening and manual check, 9 of them were verified with the synthesized peptides. Finally, only one missing protein was confirmed. All mass spectrometry data from this study have been deposited in the PRIDE with identifier PXD006482. PMID- 28857562 TI - Intramolecular Nucleophilic Substitution of omega-Haloalkylphosphine Derivatives. AB - omega-Haloalkylphosphine derivatives undergo the intramolecular nucleophilic substitution reaction upon treatment with a strong base, yielding either cycloalkylphosphine derivatives or heterocyclic phosphine derivatives. The selectivity of the cyclization of (omega-haloalkyl)alkylarylphosphine derivatives depends strongly on the distance between the electrophilic and nucleophilic carbon atoms and the structure of the phosphorus moiety. The desymmetrization of dimethylphenylphosphine sulfide followed by haloalkylation and cyclization led to the enantiomerically enriched tertiary phosphine sulfide, possessing a cyclohexyl fragment at the phosphorus. PMID- 28857564 TI - Periodic Surface-Ring Pattern Formation for Hydroxyapatite Thin Films Formed by Biomineralization-Inspired Processes. AB - Surface morphology is a key factor that might significantly influence the properties of biomaterials. In this study, periodic surface-ring structures have been constructed for calcium phosphate thin films via biomineralization-inspired crystallization process. The patterned octacalcium phosphate crystals have been obtained on poly(2-hydroxyethyl methacrylate) (PHEMA) matrix in the presence of poly(acrylic acid) (PAA). The patterned surface morphologies of the crystal thin films could be tuned by the amount of PAA additives. In addition, the rapid and topotactic transformation to hydroxyapatite (HAP) thin films with surface-ring structures has also been achieved. This study may provide new strategy toward the design of functional calcium phosphate-based thin-film hybrids. PMID- 28857563 TI - Structure and Dynamics of Nonionic Surfactant Aggregates in Layered Materials. AB - The aggregation of surfactants on solid surfaces as they are adsorbed from solution is the basis of numerous technological applications such as colloidal stabilization, ore flotation, and floor cleaning. The understanding of both the structure and the dynamics of surfactant aggregates applies to the development of alternative ways of preparing hybrid layered materials. For this purpose, we study the adsorption of the triethylene glycol mono n-decyl ether (C10E3) nonionic surfactant onto a synthetic montmorillonite (Mt), an aluminosilicate clay mineral for organoclay preparation with important applications in materials sciences, catalysis, wastewater treatment, or as drug delivery. The aggregation mechanisms follow those observed in an analogous natural Mt, with the condensation of C10E3 in a bilayer arrangement once the surfactant self-assembles in a lamellar phase beyond the critical micelle concentration, underlining the importance of the surfactant state in solution. Solid-state 1H nuclear magnetic resonance (NMR) at fast magic-angle spinning (MAS) and high magnetic field combined with1H-13C correlation experiments and different types of 13C NMR experiments selectively probes mobile or rigid moieties of C10E3 in three different aggregate organizations: (i) a lateral monolayer, (ii) a lateral bilayer, and (iii) a normal bilayer. High-resolution 1H{27Al} CP-1H-1H spin diffusion experiments shed light on the proximities and dynamics of the different fragments and fractions of the intercalated surfactant molecules with respect to the Mt surface. 23Na and 1H NMR measurements combined with complementary NMR data, at both molecular and nanometer scales, precisely pointed out the location of the C10E3 ethylene oxide hydrophilic group in close contact with the Mt surface interacting through ion-dipole or van der Waals interactions. PMID- 28857565 TI - Fast Decorrelating Monte Carlo Moves for Efficient Path Sampling. AB - Many relevant processes in chemistry, physics, and biology are rare events from a computational perspective as they take place beyond the accessible time scale of molecular dynamics (MD). Examples are chemical reactions, nucleation, and conformational changes of biomolecules. Path sampling is an approach to break this time scale limit via a Monte Carlo (MC) sampling of MD trajectories. Still, many trajectories are needed for accurately predicting rate constants. To improve the speed of convergence, we propose two new MC moves, stone skipping and web throwing. In these moves, trajectories are constructed via a sequence of subpaths obeying superdetailed balance. By a reweighting procedure, almost all paths can be accepted. Whereas the generation of a single trajectory becomes more expensive, the reduced correlation results in a significant speedup. For a study on DNA denaturation, the increase was found to be a factor 12. PMID- 28857566 TI - Exploring Structural Parameters for Pretargeting Radioligand Optimization. AB - Pretargeting offers a way to enhance target specificity while reducing off-target radiation dose to healthy tissue during payload delivery. We recently reported the development of an 18F-based pretargeting strategy predicated on the inverse electron demand Diels-Alder reaction as well as the use of this approach to visualize pancreatic tumor tissue in vivo as early as 1 h postinjection. Herein, we report a comprehensive structure: pharmacokinetic relationship study of a library of 25 novel radioligands that aims to identify radiotracers with optimal pharmacokinetic and dosimetric properties. This investigation revealed key relationships between molecular structure and in vivo behavior and produced two lead candidates exhibiting rapid tumor targeting with high target-to-background activity concentration ratios at early time points. We believe this knowledge to be of high value for the design and clinical translation of next-generation pretargeting agents for the diagnosis and treatment of disease. PMID- 28857567 TI - Angle-Resolved HAXPES Investigation on the Chemical Origin of Adhesion between Natural Rubber and Brass. AB - Bulk sensitivity of hard X-ray photoelectron spectroscopy (HAXPES) makes this technique suitable for chemical state analysis of bulk and deeply buried interfaces of solid materials. HAXPES is employed in the present study to examine the chemical state of adhesive interfaces between natural rubber and copper-zinc alloy, i.e., brass, while maintaining the adhesion structure in order to understand the chemical mechanism of rubber-to-brass adhesion. Angle-resolved measurements allow to distinguish between chemical species in rubber and those at the adhesive interface. We specially focus on sulfur-containing species because metal sulfides at the interface have been suggested to be crucial for adhesion. Line-shape analysis of S 1s spectra reveals that the interface that exhibits a strong adhesive property is mainly composed of copper sulfides with a predominant amount of CuS. This type of the interfacial chemical state is obtained when a rubber-bonded brass sample is subjected to vulcanization at 170 degrees C for 10 min. However, prolonged vulcanization leads to a partial dissolution of CuS as well as accumulation of Zn species in the form of ZnO/Zn(OH)2 and ZnS, and as a result, adhesion strength is lowered. The present study paves the way for accurate and detailed discussion on the chemical state of deeply buried interfaces through bulk sensitive in-situ measurements. PMID- 28857568 TI - Solvation by Glycerol at Temperatures from 353 to 77 K: Its Solvatochromic Characterization and Use to Block the Molecular Structure of Conformationally Flexible Structures. AB - Glycerol is UV/vis spectroscopically characterized by using suitable solvatochromic polarity probes spanning a wide temperature range of 353 to 77 K. For the first time we find experimental evidence that, when the solvent preserves its internal structure in a broad range of temperatures, all solvatochromically derived solvent parameters (i.e., SP, SdP, SA, and SB) also maintain their values unchanged. On the basis of these solvatochromic measurements, it is shown that, below 180 K, glycerol efficiently blocks the molecular structure of conformationally flexible solutes. PMID- 28857569 TI - Total Synthesis of (+)-Aplykurodinone-1. AB - Starting from (R)-citronellic acid and (R)-seudenol, the total synthesis of (+) aplykurodinone-1, a highly degraded marine steroid, has been achieved in 11 steps and in 19% overall yield with excellent stereochemical control. In addition to the features such as an Ireland-Claisen rearrangement, an intramolecular carbonyl ene cyclization, and an intramolecular Michael addition, the present synthetic strategy is accomplished without the use of protecting groups. PMID- 28857570 TI - Domino Aza-Michael-ih-Diels-Alder Reaction to Various 3-Vinyl-1,2,4-triazines: Access to Polysubstituted Tetrahydro-1,6-naphthyridines. AB - A straightforward domino aza-Michael-inverse-electron-demand-hetero-Diels Alder/retro-Diels-Alder reaction between primary and secondary propargylamine derivatives and 3-vinyl-1,2,4-triazines is developed highlighting not only the uniqueness of this dual-heterocyclic platform but also a novel and unprecedented path to polysubstituted tetrahydro-1,6-naphthyridine scaffolds. PMID- 28857571 TI - Iridium-Catalyzed Asymmetric Hydrogenation of 2H-Chromenes: A Highly Enantioselective Approach to Isoflavan Derivatives. AB - A highly efficient (aS)-Ir/In-BiphPHOX-catalyzed asymmetric hydrogenation of substituted 2H-chromenes and substituted benzo[e][1,2]oxathiine 2,2-dioxides is described. A series of 2H-chromenes and benzo[e][1,2]oxathiine 2,2-dioxides were hydrogenated to give the target products in high yields (92-99%) with excellent enantioselectivities (up to 99.7% ee) using our catalytic system. This reaction provides a direct and efficient method for the construction of chiral benzo six membered oxygen-containing compounds. PMID- 28857572 TI - Asymmetric Polymersomes from an Oil-in-Oil Emulsion: A Computer Simulation Study. AB - Asymmetric vesicles are valuable for understanding and mimicking cell and practical biomedicine applications. Recently, a very straightforward methodology for fabricating asymmetric polymersome was developed by Lodge's group through the coassembly of polystyrene-b-poly(ethylene oxide) (PS-b-PEO) and polybutadiene-b poly(ethylene oxide) (PB-b-PEO) block copolymers at the interface of a polystyrene/polybutadiene/chloroform (PS/PB/CHCl3) emulsion. However, the in depth microscopic mechanism for the formation of asymmetric polymersomes remains unclear. To address this issue, in this article, the coassembly process for the formation of the asymmetric polymersomes in Asano's experimental system was systematically investigated by employing a dissipative particle dynamics (DPD) simulation. Our results definitely demonstrate the formation of the asymmetric polymersomes such as that in the experiments and that the bilayer formed through the folding and crossing of the PEO blocks. Besides, from the microscopic view, three stages can be discerned in the formation process: (1) the formation of micelles, (2) the micelle diffusion to the interface, and (3) the micelle rearrangement at the interface to form an asymmetric polymersome. Meanwhile, the incompatibility among PS, PB, and PEO is proven to be the main driving force for asymmetric polymersome formation. Moreover, the effects of the order of addition of copolymers and the volume fraction of PEO blocks on the structure of the asymmetric polymersomes are also investigated. We find that the formation process is affected severely by the order of addition, and adding PS-b-PEO first can make the asymmetric bilayer more perfect. Not only that, but perfect asymmetric polymersomes can be formed only when the volume fraction of PEO (fPEO) is greater than 0.55. We believe the present work can extend the knowledge of the self assembly of asymmetric polymersomes, especially with respect to the self-assembly mechanism. PMID- 28857573 TI - Achieving High Strength and Ductility in Magnesium Alloys via Densely Hierarchical Double Contraction Nanotwins. AB - Light-weight magnesium alloys with high strength are especially desirable for the applications in transportation, aerospace, electronic components, and implants owing to their high stiffness, abundant raw materials, and environmental friendliness. Unfortunately, conventional strengthening methods mainly involve the formation of internal defects, in which particles and grain boundaries prohibit dislocation motion as well as compromise ductility invariably. Herein, we report a novel strategy for simultaneously achieving high specific yield strength (~160 kN m kg-1) and good elongation (~23.6%) in a duplex magnesium alloy containing 8 wt % lithium at room temperature, based on the introduction of densely hierarchical {1011}-{1011} double contraction nanotwins (DCTWs) and full coherent hexagonal close-packed (hcp) particles in twin boundaries by ultrahigh pressure technique. These hierarchical nanoscaled DCTWs with stable interface characteristics not only bestow a large fraction of twin interface but also form interlaced continuous grids, hindering possible dislocation motions. Meanwhile, orderly aggregated particles offer supplemental pinning effect for overcoming latent softening roles of twin interface movement and detwinning process. The processes lead to a concomitant but unusual situation where double contraction twinning strengthens rather than weakens magnesium alloys. Those cutting-edge results provide underlying insights toward designing alternative and more innovative hcp-type structural materials with superior mechanical properties. PMID- 28857575 TI - Down-regulation of love feelings after a romantic break-up: Self-report and electrophysiological data. AB - Because remaining love feelings for an ex-partner are negatively associated with recovery from a romantic break-up, it may be helpful to decrease those love feelings. Love regulation is the use of behavioral or cognitive strategies to change the intensity of current feelings of romantic love. This study evaluated three regulation strategies: (1) negative reappraisal of the ex-partner, (2) reappraisal of love feelings, and (3) distraction. It was tested how these regulation strategies change love feelings for the ex-partner, valence of affect, and motivated attention for the ex-partner. Participants who were upset about a romantic break-up performed these regulation strategies before passively viewing a picture of their ex-partner, during which their electroencephalogram was recorded. Negative reappraisal decreased love feelings and made participants feel more unpleasant. Love reappraisal did not change how in love or pleasant/unpleasant participants felt. Distraction did not change love feelings but made participants feel more pleasant. This suggests that in the context of a romantic break-up, negative reappraisal is an effective love down-regulation strategy, whereas distraction is an effective positive emotion up-regulation strategy. Furthermore, all three strategies decreased motivated attention for the ex-partner, as indicated by a reduced amplitude of the late positive potential. This reduced motivated attention for the ex-partner could make it easier to deal with encounters of (reminders of) the ex-partner. Love regulation is a promising phenomenon with important everyday life and clinical implications. (PsycINFO Database Record PMID- 28857576 TI - An app-based blended intervention to reduce body dissatisfaction: A randomized controlled pilot study. AB - OBJECTIVE: As a common experience in the general population, dissatisfaction with one's body is associated with a variety of psychological problems and unhealthy behaviors, including the development of eating disorders. Therefore, the purpose of the present study was to develop and evaluate an app-based intervention to reduce body dissatisfaction. METHOD: Participants reporting elevated levels of body dissatisfaction were randomly allocated to an app-based intervention (n = 26) or to a wait list group (n = 27). The app-based intervention included a brief counseling session and 14 days of training with the Mindtastic Body Dissatisfaction app (MT-BD). The MT-BD app uses gamification strategies to systematically foster approach of functional and avoidance of dysfunctional stimuli. The primary outcome was body dissatisfaction as assessed with the Body Dissatisfaction scale of the Eating Disorder Inventory-2 (Garner, 1991). Secondary outcome measures included severity of eating disorder symptoms and depressive symptoms. RESULTS: Participants in the intervention group showed significantly greater reductions in body dissatisfaction compared to the wait list group (d = -0.62). The intervention group also showed greater reductions in eating disorder symptoms compared to the wait list group (d = -0.46). Reductions in body dissatisfaction and eating disorder symptoms were sustained at a 1-month follow-up. CONCLUSION: We found preliminary evidence that an app-based intervention may significantly reduce body dissatisfaction. Further research using larger samples and targeting clinical populations is necessary to evaluate the potential of interventions such as MT-BD. (PsycINFO Database Record PMID- 28857574 TI - Cognitive behavioral interventions for alcohol and drug use disorders: Through the stage model and back again. AB - Cognitive-behavioral therapy (CBT) approaches have among the highest level of empirical support for the treatment of drug and alcohol use disorders. As Psychology of Addictive Behaviors marks its 30th anniversary, we review the evolution of CBT for the addictions through the lens of the Stage Model of Behavioral Therapies Development. The large evidence base from Stage II randomized clinical trials indicates a modest effect size with evidence of relatively durable effects, but limited diffusion in clinical practice, as is the case for most empirically validated approaches for mental health and addictive disorders. Technology may provide a means for CBT interventions to circumvent the "implementation cliff" in Stages III-V by offering a flexible, low-cost, standardized means of disseminating CBT in a range of novel settings and populations. Moreover, returning to Stage I to reconnect clinical applications of CBT to recent developments in cognitive science and neuroscience holds great promise for accelerating understanding of mechanisms of action. It is critical that CBT not be considered as a static intervention, but rather 1 that constantly evolves and is refined through the stage model until the field achieves a maximally powerful intervention that addresses core features of the addictions. (PsycINFO Database Record PMID- 28857578 TI - Awe and humility. AB - Humility is a foundational virtue that counters selfish inclinations such as entitlement, arrogance, and narcissism (Tangney, 2000). We hypothesize that experiences of awe promote greater humility. Guided by an appraisal-tendency framework of emotion, we propose that when individuals encounter an entity that is vast and challenges their worldview, they feel awe, which leads to self diminishment and subsequently humility. In support of these claims, awe-prone individuals were rated as more humble by friends (Study 1) and reported greater humility across a 2-week period (Study 2), controlling for other positive emotions. Inducing awe led participants to present a more balanced view of their strengths and weaknesses to others (Study 3) and acknowledge, to a greater degree, the contribution of outside forces in their own personal accomplishments (Study 4), compared with neutral and positive control conditions. Finally, an awe inducing expansive view elicited greater reported humility than a neutral view (Study 5). We also elucidated the process by which awe leads to humility. Feelings of awe mediated the relationship between appraisals (perceptions of vastness and a challenge to one's world view) and humility (Study 4), and self diminishment mediated the relationship between awe and humility (Study 5). Taken together, these results reveal that awe offers one path to greater humility. (PsycINFO Database Record PMID- 28857579 TI - Some evidence for the usefulness of an optimal foraging theory perspective on goal conflict and goal facilitation. AB - Based on optimal foraging theory, we propose a metric that allows evaluating the goodness of goal systems, that is, systems comprising multiple goals with facilitative and conflicting interrelations. This optimal foraging theory takes into account expectancy and value, as well as opportunity costs, of foraging. Applying this approach to goal systems provides a single index of goodness of a goal system for goal striving. Three quasi-experimental studies (N = 277, N = 145, and N = 210) provide evidence for the usefulness of this approach for goal systems comprising between 3 to 10 goals. Results indicate that persons with a more optimized goal-system are more conscientious and open to new experience, are more likely to represent their goals in terms of means (i.e., adopt a process focus), and are more satisfied and engaged with their goals. Persons with a suboptimal goal system tend to switch their goals more often and thereby optimize their goal system. We discuss limitations as well as possible future directions of this approach. (PsycINFO Database Record PMID- 28857580 TI - Predictive validity of HCR-20, START, and static-99R assessments in predicting institutional aggression among sexual offenders. AB - Sexual offenders are at greater risk of nonsexual than sexual violence. Yet, only a handful of studies have examined the validity of risk assessments in predicting general, nonsexual violence in this population. This study examined the predictive validity of assessments completed using the Historical-Clinical-Risk Managment-20 Version 2 (HCR-20; Webster, Douglas, Eaves, & Hart, 1997), Short Term Assessment of Risk and Treatability (START; Webster, Martin, Brink, Nicholls, & Desmarais, 2009), and Static-99R (Hanson & Thornton, 1999) in predicting institutional (nonsexual) aggression among 152 sexual offenders in a large secure forensic state hospital. Aggression data were gathered from institutional records over 90-day and 180-day follow-up periods. Results support the predictive validity of HCR-20 and START, and to a lesser extent, Static-99R assessments in predicting institutional aggression among patients detained or civilly committed pursuant to the sexually violent predator (SVP) law. In general, HCR-20 and START assessments demonstrated greater predictive validity specifically, the HCR-20 Clinical subscale scores and START Vulnerability total scores-than Static-99R assessments across types of aggression and follow-up periods. (PsycINFO Database Record PMID- 28857577 TI - Sexual orientation differences in functional limitations, disability, and mental health services use: Results from the 2013-2014 National Health Interview Survey. AB - OBJECTIVES: The authors investigated sexual orientation differences in risk for mental health morbidity, functional limitations/disability, and mental health services use among adults interviewed in the nationally representative 2013-2014 National Health Interview Survey. METHOD: Respondents were 68,816 adults (67,152 heterosexual and 1,664 lesbian, gay, and bisexual [LGB] individuals), age 18 and older. Fully structured interviews assessed sexual orientation identity, health status, and services use. Using sex-stratified analyses while adjusting for demographic confounding, the authors compared LGB and heterosexual individuals for evidence of mental health-related impairments and use of mental health services. RESULTS: LGB adults, as compared to heterosexual adults, demonstrated higher prevalence of mental health morbidity and functional limitations. However, this varied by gender with LGB women evidencing elevated risk for both mental health and substance abuse (MHSA) and non-MHSA limitations. Among men, sexual orientation differences clustered among MHSA-related limitations. Overall, LGB adults were more likely than heterosexual adults to use services, with the source of functional limitations moderating these effects among men. CONCLUSION: MHSA related morbidity is a significant concern among LGB individuals and is associated with higher levels of functional limitations/disability. The findings highlight that LGB persons use MHSA-related treatment at higher rates than heterosexuals do, and, among men, are more likely to do so absent MHSA or non MHSA-related functional limitations. This presents a unique set of concerns within the integrated care setting, including the need to deliver culturally competent care sensitive to the context of probable sex differences among LGB individuals. (PsycINFO Database Record PMID- 28857581 TI - Bridging the gap between conventional and standardized competency to stand trial (CST) assessments: An examination of defendant answers to conventional CST questions. AB - Despite research suggesting that use of forensic assessment instruments of competency to stand trial (CST) can improve the integrity of forensic conceptualizations (Rogers & Johansson-Love, 2009), the majority of evaluators do not use these measures in CST evaluations (Nicholson & Norwood, 2000). The purpose of this study is to bridge the gap between competency evaluations based on a conventional interview and those conducted with the aid of a standardized forensic assessment instrument. To this end, we utilized an archival sample of 704 criminal defendants (543 males, 161 females) ordered to undergo evaluations of CST. In the overall sample, as well as in 2 comparison groups comprised of individuals with psychotic disorders and mental retardation, we coded evaluee responses to 45 conventional competency questions relating to factual understanding, rational understanding, and ability to cooperate with counsel. We present accuracy rates to these questions across competent and incompetent groups in an effort to provide information that can make conventional interviews more evidence-based. Using relative risk ratios, we also sought to identify the questions most associated with evaluator opinions of incompetency. Overall, the results indicated fairly consistent trends that questions relating to rational understanding and ability to cooperate with counsel were the most associated with competence. We discuss how the relative risk ratio findings and descriptive information can be used to make conventional competency interviews more objective and empirically based by providing evaluators with a normative reference point for commonly asked competency questions. (PsycINFO Database Record PMID- 28857582 TI - Supporting veterans' transitions from permanent supportive housing. AB - OBJECTIVES: Little research has assessed the nature of veterans' departures from permanent supportive housing (PSH), which may be of positive valence (e.g., moving into more independent housing). This study aimed to identify participants appropriate for "graduation" from PSH and how to support their transitions. METHOD: This mixed methods study used qualitative data from PSH program staff, 445 PSH participants' responses to a survey assessing their experiences and administrative records, and qualitative data from a subsample of 10 participants who graduated from the program. Participants were classified as "stayers" (retained in PSH for at least 600 days); "graduates" (exited with improvement in community integration); or "involuntary leavers" (exited for reasons of negative valence). Template analysis of qualitative data from PSH staff described graduation processes; qualitative data from participants were analyzed using a thematic analysis approach. The study compared veterans' characteristics using chi-square and analysis of variance (ANOVA) tests; a multinomial logistic regression assessed correlates of graduates' and involuntary leavers' exits from PSH. RESULTS: Approximately one half of participants who exited the program were graduates. Processes used by program staff to identify potential graduates varied. Participants' self-report of substance use and mental health problems was associated with involuntary leaver status. Frequency of case management, a trusting relationship between participant and case manager, and participants' receipt of compensation related to disability incurred during military service were associated with graduation. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: To support successful transitions from PSH, programs should focus on providing high quality case management that may respond flexibly to participants' varying recovery needs. (PsycINFO Database Record PMID- 28857583 TI - Neurophysiological traces of interpersonal pain: How emotional autobiographical memories affect event-related potentials. AB - The automatic, involuntary reactivation of disturbing emotional memories, for example, of interpersonal pain, causes psychological discomfort and is central to many psychopathologies. This study aimed at elucidating the automatic brain processes underlying emotional autobiographical memories by investigating the neurophysiological dynamics within the first second after memory reactivation. Pictures of different individualized familiar faces served as cues for different specific emotional autobiographical memories, for example, for memories of interpersonal pain and grievances or for memories of appreciation in interpersonal relationships. Nineteen subjects participated in a passive face viewing task while multichannel electroencephalogram was recorded. Analyses of event-related potentials demonstrated that emotional memories elicited an early posterior negativity and a stronger late positive potential, which tended to be particularly enhanced for painful memories. Source estimations attributed this stronger activation to networks including the posterior cingulate and ventrolateral prefrontal cortices. The findings suggest that the reactivation of emotional autobiographical memories involves privileged automatic attention at perceptual processing stages, and an enhanced recruitment of neural network activity at a postperceptual stage sensitive to emotional-motivational processing. (PsycINFO Database Record PMID- 28857584 TI - Even unpleasant reminders that you are an animal need not disgust you. AB - Three studies (Ns = 200, 400, 400) tested the hypothesis that we humans feel disgust when reminded of our animal nature. Participants verbally rated their disgust reaction to pictures of humans engaged in various unpleasant actions. For pictures of events that present danger or suffering, accompanied by an explicit and vivid reminder that animals face the same situation, participants reported fear and sadness rather than disgust. For pictures of events that present a norm violation, an explicit animal reminder (relative to a human picture alone) did not lead to a consequent increment in disgust. For pictures of events that present a physically disgusting contamination, an explicit animal reminder (relative to a human picture alone) led to a decrement in disgust. Thus, not all unpleasant animal reminders are disgusting. Some disgusting things may remind us of our animal nature, but they are not disgusting because they do so. (PsycINFO Database Record PMID- 28857585 TI - Self and informant report across the borderline personality disorder spectrum. AB - Individuals with borderline personality disorder (BPD) features may be unaware of or unwilling to report their own personality or maladaptive behaviors, which complicates the assessment of BPD. Informants who know the individuals with BPD features may be uniquely suited to aid in the personality assessment of these individuals. The present study analyzed the comparative ability of individuals (targets) and informants to report BPD features across the continuum of BPD severity. The sample consisted of 1387 targets, ages 55 to 65 (56% women), who were recruited for an epidemiological longitudinal study examining the effects of PDs on health and social functioning. Each target nominated an informant who provided information about the target's personality. Results indicated relatively low levels of agreement between perspectives and that informants reported BPD symptoms with more precision and at lower levels of BPD severity than targets. The benefits of including an informant perspective when measuring the BPD continuum are discussed; these benefits may include gains in reliability and improvement in the prediction of outcomes. (PsycINFO Database Record PMID- 28857586 TI - Relations between third grade teachers' depressive symptoms and their feedback to students, with implications for student mathematics achievement. AB - Recent studies have observed connections among teachers' depressive symptoms and student outcomes; however, the specific mechanisms through which teachers' mental health characteristics operate in the classroom remain largely unknown. The present study used student-level observation methods to examine the relations between third-grade teachers' (N = 32) depressive symptoms and their academic feedback to students (N = 310) and sought to make inferences about how these factors might influence students' mathematics achievement. A novel observational tool, the Teacher Feedback Coding System-Academic (TFCS-A), was used that assesses feedback across 2 dimensions-teacher affect and instructional strategy, which have been shown to be important to student learning. Multilevel exploratory factor analysis of TFCS-A data suggested 2 primary factors: positive feedback and neutral/negative feedback. Hierarchical linear modeling revealed that positive feedback was related to higher math achievement among students who began the year with weaker math skills and that teachers who reported more depressive symptoms less frequently provided this positive feedback. Results offer new information about a type of instruction that may be affected by teachers' depressive symptoms and inform efforts aimed at improving teachers' instructional interactions with students. (PsycINFO Database Record PMID- 28857587 TI - Factor structure and predictive validity of a homework motivation measure for use with middle school students with attention-deficit/hyperactivity disorder (ADHD). AB - Many students with attention-deficit/hyperactivity disorder (ADHD) exhibit deficits in motivation to pursue long-term goals. Students with ADHD have particular difficulty with motivation to complete homework-related tasks and often fail to complete assignments. Although these problems are common and may impact academic performance, no homework-motivation measures have been validated for use with students with ADHD. The primary goal of the present study was to evaluate the factor structure and predictive validity of a homework-motivation measure based upon the expectancy-value theory of achievement motivation. A sample of 285 middle school students with ADHD completed the measure, and confirmatory factor analysis was used to evaluate the proposed factor structure and associations with parent and teacher ratings of homework performance. A 2 factor structure emerged, and model fit was excellent. Further, student-rated ability-expectancy beliefs demonstrated significant associations with parent rated homework problems and performance and with teacher-rated homework performance and percentage of assignments turned in above and beyond ADHD symptoms. Future directions for studying the importance of motivation in students with ADHD are provided, with particular attention to the role that reward sensitivity may play in motivation. (PsycINFO Database Record PMID- 28857588 TI - Differential item functioning across race and ethnicity for the Emotional and Behavioral Screener. AB - The objective of this study was to assess the measurement invariance of items from the Emotional and Behavioral Screener (EBS) across racial and ethnic groups and assess the impact of differential item functioning (DIF) on test scores from the EBS. Participants were 4,856 first-grade students (49% female) who were diverse with regard to race and ethnicity (45% African American, 41% Hispanic/Latino, and 14% Caucasian). Classroom teachers rated each student on the EBS during the fall semester screening window. Item response theory modeling was combined with ordinal regression to investigate the presence and impact of differential item functioning across 3 race and ethnicity groups. The findings suggest that items from the EBS exhibit small to negligible levels of DIF, and the limited DIF that was present does not significantly impact overall scores. Researchers and practitioners can have confidence that scores from the EBS are relatively unaffected by test bias when measuring the emotional and behavioral risk of young students from African American, Hispanic/Latino, or Caucasian backgrounds. (PsycINFO Database Record PMID- 28857589 TI - The contribution of mastery experiences, performance feedback, and task effort to elementary-aged students' self-efficacy in writing. AB - Although intervention procedures exist for improving elementary-aged students' writing fluency skills, less is known about how their writing self-efficacy develops upon participating in these procedures. In this study, 117 second grade students participated in an evidence-based performance feedback writing intervention. Students reported higher levels of self-efficacy in their writing abilities after participating in the intervention than they did at baseline. Although their experiences with task mastery and positive feedback did not impact their writing self-efficacy, the effort they put forth during the intervention was a significant predictor. These results may provide initial guidance for the development of students' self-efficacy in the context of school-based interventions, and they have specific implications for how the performance feedback intervention procedures may be refined to more systematically target students' task effort in future research. (PsycINFO Database Record PMID- 28857590 TI - An empirical study of multidimensional fidelity of COMPASS consultation. AB - Consultation is essential to the daily practice of school psychologists (National Association of School Psychologist, 2010). Successful consultation requires fidelity at both the consultant (implementation) and consultee (intervention) levels. We applied a multidimensional, multilevel conception of fidelity (Dunst, Trivette, & Raab, 2013) to a consultative intervention called the Collaborative Model for Promoting Competence and Success (COMPASS) for students with autism. The study provided 3 main findings. First, multidimensional, multilevel fidelity is a stable construct and increases over time with consultation support. Second, mediation analyses revealed that implementation-level fidelity components had distant, indirect effects on student Individualized Education Program (IEP) outcomes. Third, 3 fidelity components correlated with IEP outcomes: teacher coaching responsiveness at the implementation level, and teacher quality of delivery and student responsiveness at the intervention levels. Implications and future directions are discussed. (PsycINFO Database Record PMID- 28857591 TI - Psychometric profile of an experimental Emergent Literacy Screener for preschoolers. AB - Home literacy activities influence children's emergent literacy progress and readiness for reading instruction. To help parents fulfill this opportunity, we developed a new Emergent Literacy Screener (ELS) and conducted 2 studies of its psychometric properties with independent prekindergarten samples. For Study 1 (n = 812, Mage = 54.4 months, 49.4% male, 46.1% white) exploratory factor analyses (EFA) supported a 5-factor structure. EFA and item calibration supported the removal of 10 items from the original 30 test items. The resultant 20-item ELS demonstrated good reliability (Cronbach's alpha = .83) and significant positive correlation, r = .50, p < .001 with a standardized emergent literacy measure, Get Ready to Read - Revised. For Study 2 (n = 959, Mage = 53.5 months, 52.3% male, 60.3% white), confirmatory factor analyses (CFA) supported a bifactor model, which captured direct effects of 5 specific subfactors and an overarching emergent literacy factor. Using a cut score of 15, the ELS demonstrated moderate sensitivity (.71) and specificity (.61). Negative predictive value was high, whereas positive predictive value was low. Overall the ELS demonstrated acceptable psychometric characteristics for use by parents of prekindergarten children, providing a promising new tool for universal emergent literacy screening and an opportunity to identify where children are in their emergent literacy development. Implications for further research and practice are discussed. (PsycINFO Database Record PMID- 28857592 TI - Case complexity as a guide for psychological treatment selection. AB - OBJECTIVE: Some cases are thought to be more complex and difficult to treat, although there is little consensus on how to define complexity in psychological care. This study proposes an actuarial, data-driven method of identifying complex cases based on their individual characteristics. METHOD: Clinical records for 1,512 patients accessing low- and high-intensity psychological treatments were partitioned in 2 random subsamples. Prognostic indices predicting post-treatment reliable and clinically significant improvement (RCSI) in depression (Patient Health Questionnaire-9; Kroenke, Spitzer, & Williams, 2001) and anxiety (Generalized Anxiety Disorder-7; Spitzer, Kroenke, Williams, & Lowe, 2006) symptoms were estimated in 1 subsample using penalized (Lasso) regressions with optimal scaling. A PI-based algorithm was used to classify patients as standard (St) or complex (Cx) cases in the second (cross-validation) subsample. RCSI rates were compared between Cx cases that accessed treatments of different intensities using logistic regression. RESULTS: St cases had significantly higher RCSI rates compared to Cx cases (OR = 1.81 to 2.81). Cx cases tended to attain better depression outcomes if they were initially assigned to high-intensity (vs. low intensity) interventions (OR = 2.23); a similar pattern was observed for anxiety but the odds ratio (1.74) was not statistically significant. CONCLUSIONS: Complex cases could be detected early and matched to high-intensity interventions to improve outcomes. (PsycINFO Database Record PMID- 28857593 TI - "Psychiatric disorders in smokers seeking treatment for tobacco dependence: Relations with tobacco dependence and cessation": Correction to Piper et al. (2010). AB - : Reports an error in "Psychiatric disorders in smokers seeking treatment for tobacco dependence: Relations with tobacco dependence and cessation" by Megan E. Piper, Stevens S. Smith, Tanya R. Schlam, Michael F. Fleming, Amy A. Bittrich, Jennifer L. Brown, Cathlyn J. Leitzke, Mark E. Zehner, Michael C. Fiore and Timothy B. Baker (Journal of Consulting and Clinical Psychology, 2010[Feb], Vol 78[1], 13-23). There was an error in the Method section in the World Mental Health Survey Initiative version of the CIDI subsection. The authors characterized one of the anxiety conditions analyzed as "panic disorder". However, this should have been labeled as "panic attacks", consequently making the occurrence rates and relations the authors reported actually pertain to panic attacks, social phobia, and generalized anxiety disorder. (The following abstract of the original article appeared in record 2010-00910-005.) Objective: The present research examined the relation of psychiatric disorders to tobacco dependence and cessation outcomes. METHOD: Data were collected from 1,504 smokers (58.2% women; 83.9% White; mean age = 44.67 years, SD = 11.08) making an aided smoking cessation attempt as part of a clinical trial. Psychiatric diagnoses were determined with the Composite International Diagnostic Interview structured clinical interview. Tobacco dependence was assessed with the Fagerstrom Test of Nicotine Dependence (FTND) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM). RESULTS: Diagnostic groups included those who were never diagnosed, those who had ever been diagnosed (at any time, including in the past year), and those with past-year diagnoses (with or without prior diagnosis). Some diagnostic groups had lower follow-up abstinence rates than did the never diagnosed group (ps < .05). At 8 weeks after quitting, strong associations were found between cessation outcome and both past-year mood disorder and ever diagnosed anxiety disorder. At 6 months after quitting, those ever diagnosed with an anxiety disorder (OR = .72, p = .02) and those ever diagnosed with more than one psychiatric diagnosis (OR = .74, p = .03) had lower abstinence rates. The diagnostic categories did not differ in smoking heaviness or the FTND, but they did differ in dependence motives assessed with the WISDM. CONCLUSION: Information on recent or lifetime psychiatric disorders may help clinicians gauge relapse risk and may suggest dependence motives that are particularly relevant to affected patients. These findings also illustrate the importance of using multidimensional tobacco dependence assessments. (PsycINFO Database Record PMID- 28857594 TI - "Meta-analysis of cognitive-behavioral treatments for adult ADHD": Correction to Knouse, Teller, and Brooks (2017). AB - : Reports an error in "Meta-analysis of cognitive-behavioral treatments for adult ADHD" by Laura E. Knouse, Jonathan Teller and Milan A. Brooks (Journal of Consulting and Clinical Psychology, 2017[Jul], Vol 85[7], 737-750). There were errors in Tables 1 and 2, Figures 2 and 3, and in related values reported in the abstract, Results, and Discussion section. These errors occurred because effect sizes from two studies comparing CBT to active control had been coded to represent better outcomes for the CBT group when, in these instances, outcomes for the control group were slightly better. However, because these effect sizes were not significantly different from zero, impact on calculated overall effect sizes for CBT treatment versus control was minimal. Calculations of pre-to-post effect sizes were not affected and the overall interpretation of the results remains unchanged. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-21394-001.) Objective: We conducted a meta-analysis of cognitive-behavioral treatment (CBT) studies for adult attention-deficit/hyperactivity disorder (ADHD), examining effects versus control and effects pre-to-post treatment to maximize the clinical and research utility of findings from this growing literature. METHOD: Eligible studies tested adults meeting criteria for Diagnostic and Statistical Manual of Mental Disorders ADHD as determined by interview or using a standardized rating scale and measured ADHD symptoms or related impairment at baseline and posttreatment. We analyzed data from 32 studies from published and unpublished sources available through December 2015. Effect size calculations included up to 896 participants. RESULTS: Using a random effects model, we found that CBTs had medium-to-large effects from pre- to posttreatment (self-reported ADHD symptoms: g = 1.00; 95% confidence interval [CI: 0.84, 1.16]; self-reported functioning g = .73; 95% CI [0.46, 1.00]) and small-to-medium effects versus control (g = .65; 95% CI [0.44, 0.86] for symptoms, .51; 95% CI [0.23, 0.79] for functioning). Effect sizes were heterogeneous for most outcome measures. Studies with active control groups showed smaller effect sizes. Neither participant medication status nor treatment format moderated pre-to-post treatment effects, and longer treatments were not associated with better outcomes. CONCLUSIONS: Current CBTs for adult ADHD show comparable effect sizes to behavioral treatments for children with ADHD, which are considered well-established treatments. Future treatment development could focus on identifying empirically supported principles of treatment-related change for adults with ADHD. We encourage researchers to report future findings in a way that is amenable to meta-analytic review. (PsycINFO Database Record PMID- 28857595 TI - Effectiveness of cognitive-behavioral therapy on quality of life, anxiety, and depressive symptoms among patients with inflammatory bowel disease: A multicenter randomized controlled trial. AB - OBJECTIVE: Inflammatory bowel disease (IBD) is characterized by a low level of quality of life (QoL) and a high prevalence of anxiety and depression, especially in patients with poor QoL. We examined the effect of IBD-specific cognitive behavioral therapy (CBT) on QoL, anxiety, and depression in IBD patients with poor mental QoL. METHOD: This study is a parallel-group multicenter randomized controlled trial. One hundred eighteen IBD patients with a low level of QoL (score <=23 on the mental health subscale of the Medical Outcomes Study Short Form 36 Health Survey [SF-36]) were included from 2 academic medical centers (Academic Medical Center Amsterdam, VU University Medical Centre Amsterdam) and 2 peripheral medical centers (Flevo Hospital, Slotervaart Hospital) in the Netherlands. Patients were randomized to an experimental group receiving CBT (n = 59) versus a wait-list control group (n = 59) receiving standard medical care for 3.5 months, followed by CBT. Both groups completed baseline and 3.5 months follow up assessments. The primary outcome was a self-report questionnaire and disease specific QoL (Inflammatory Bowel Disease Questionnaire [IBDQ]). Secondary outcomes were depression (Hospital Anxiety and Depression Scale-Depression Subscale [HADS-D], Center for Epidemiologic Studies Depression Scale [CES-D]), anxiety (HADS-Anxiety Subscale [HADS-A]) and generic QoL (SF-36). RESULTS: Data were analyzed both on intention to treat as well as on per protocol analysis (completed >=5 sessions). CBT had a positive effect on disease-specific-QoL (Cohen's d = .64 for IBDQ total score), depression (Cohen's d = .48 for HADS-D and .78 for CES-D), anxiety (Cohen's d = .58 for HADS-A), and generic QoL (Cohen's d = 1.08 for Mental Component Summary of the SF-36; all ps < .01). CONCLUSIONS: IBD-specific CBT is effective in improving QoL and in decreasing anxiety and depression in IBD patients with poor QoL. Clinicians should incorporate screening on poor mental QoL and consider offering CBT. (PsycINFO Database Record PMID- 28857596 TI - Should psychosocial safety climate theory be extended to include climate strength? AB - Psychosocial safety climate (PSC; climate for psychological health) is an organizational antecedent to work conditions articulated in the job demands resources model. We responded to calls for broader consideration of organizational climate in terms of both climate level and strength. We tested PSC level and strength as main and interactive predictors of work conditions, psychological health, and engagement. Using multilevel analysis and cross sectional data, the effects of unit-level PSC constructs were investigated in 21 hospital work units (n = 249 employees) in Australia. The correlation between PSC levels (measured at the unit mean) and PSC strength (measured as unit -1 * SD) was moderate and positive, suggesting that ceiling effects of PSC scores were not problematic. PSC level was a better predictor than PSC strength or their interactions for job demands (psychological and emotional demands), job resources (e.g., skill discretion and organizational support), and health (emotional exhaustion). For engagement, the interaction was significant-improving engagement, therefore, benefits from high levels of PSC and PSC strength within the work units. So, in answer to the research question regarding PSC theory extension, "it depends on the outcome." Research limitations are acknowledged, and the potential of the PSC model to guide the reduction of workplace psychosocial risk factors and the negative consequences is discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28857597 TI - A sorrow halved? A daily diary study on talking about experienced workplace incivility and next-morning negative affect. AB - Incivility by coworkers and customers can have detrimental consequences for employees' affective well-being at work. However, little is known about whether incivility also impairs employees' affect at home and how long these negative effects may last. In this diary study, we examine whether incivility by coworkers and customers is related to next-morning negative affect via negative affect at the end of the workday and at bedtime, and investigate different modes of social sharing (i.e., conversations about experienced mistreatment) as day-level moderators of this relationship. Daily diary data collected over 10 workdays (N = 113 employees) revealed that coworker incivility was indirectly related to bedtime negative affect via negative affect at the end of the workday, and customer incivility was indirectly related to next-morning negative affect via negative affect at the end of the workday and at bedtime. Although we found no moderating effect for conversations in an affective sharing mode (i.e., conversation partners provide comfort and consolation), the relationship between workplace incivility and employees' negative affect was buffered by conversations in a cognitive sharing mode (i.e., conversation partners suggest alternative explanations or reappraisal of uncivil behavior). In line with social sharing theory, our results suggest that talking about experienced mistreatment can, under specific circumstances, offset the negative relationship of uncivil coworker and customer behavior and employees' negative affect. This study advances current research on workplace incivility by studying negative affect 3 times a day and thus sheds light on the mechanism connecting workplace incivility and employees' affective well-being at home. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28857598 TI - Suicide attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia. AB - OBJECTIVE: Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. METHOD: This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. RESULTS: There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. CONCLUSIONS: The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record PMID- 28857599 TI - Genetic and environmental architecture of executive functions in midlife. AB - OBJECTIVE: Research on executive functions (EFs) has revealed evidence for general abilities that underlie performance across multiple EF tasks and domains. This Common EF factor is highly stable in adolescence through young adulthood, correlates with other important cognitive abilities, and is explained largely by genetic influences. However, little is known about Common EF beyond young adulthood. This study examines 3 hypotheses regarding the latent structure, genetic/environmental etiology, and cognitive correlates of Common EF in middle age. METHOD: We examined data from 1,284 middle-aged twins (51-60 years) in the Vietnam Era Twin Study of Aging who completed 7 neuropsychological measures of EFs, as well as measures of general cognitive ability and processing speed. RESULTS: Our confirmatory factor analysis indicated that Common EF explained variation across all 7 EF tasks. Inhibition and shifting were subsumed entirely under the Common EF factor, and there was an additional working memory span specific factor. Common EF was heritable in midlife (a2 = .46), with additional evidence for both shared environmental influences (c2 = .41) and nonshared environmental influences (e2 = .13). Higher Common EF was moderately associated with higher general cognitive ability, measured both in early adulthood and midlife, and faster processing speed in midlife. These correlations were primarily driven by shared genetic influences. CONCLUSIONS: These results support the hypothesis that Common EF captures similar EF abilities in midlife as in adolescence and young adulthood. However, environmental influences may explain a larger portion of variance in this construct as individuals age. (PsycINFO Database Record PMID- 28857601 TI - Phonological ambiguity modulates resolution of semantic ambiguity during reading: An fMRI study of Hebrew. AB - OBJECTIVES: The current fMRI study examined the role of phonology in the extraction of meaning from print in each hemisphere by comparing homophonic and heterophonic homographs (ambiguous words in which both meanings have the same or different sounds respectively, e.g., bank or tear). The analysis distinguished between the first phase, in which participants read ambiguous words without context, and the second phase in which the context resolves the ambiguity. METHOD: Native Hebrew readers were scanned during semantic relatedness judgments on pairs of words in which the first word was either a homophone or a heterophone and the second word was related to its dominant or subordinate meaning. RESULTS: In Phase 1 there was greater activation for heterophones in left inferior frontal gyrus (IFG), pars opercularis, and more activation for homophones in bilateral IFG pars orbitalis, suggesting that resolution of the conflict at the phonological level has abolished the semantic ambiguity for heterophones. Reduced activation for all ambiguous words in temporo-parietal regions suggests that although ambiguity enhances controlled lexical selection processes in frontal regions it reduces reliance on bottom-up mapping processes. After presentation of the context, a larger difference between the dominant and subordinate meaning was found for heterophones in all reading-related regions, suggesting a greater engagement for heterophones with the dominant meaning. CONCLUSIONS: Altogether these results are consistent with the prominent role of phonological processing in visual word recognition. Finally, despite differences in hemispheric asymmetry between homophones and heterophones, ambiguity resolution, even toward the subordinate meaning, is largely left lateralized. (PsycINFO Database Record PMID- 28857602 TI - The role of the medial prefrontal cortex in the generalization of conditioned fear. AB - OBJECTIVE: Fear generalization, the generalization of fear to innocuous stimuli, is a characteristic component of pathological anxiety. Neural models of fear generalization suggest the involvement of the medial prefrontal cortex (mPFC). However, conflicting empirical findings complicate our understanding of the role of the mPFC in pathological anxiety. To address important unanswered questions in this area, a detailed review and synthesis of results from human and nonhuman animal investigations of conditioned fear generalization was conducted. METHOD: Empirical articles were identified through March 2017 and selected if they used fear conditioning, measured fear generalization, and included a measure of activity in the mPFC or manipulation of mPFC functioning. RESULTS: In human cued fear conditioning, the ventral mPFC plays an important role in the inhibition of fear generalization, whereas dorsal mPFC is important for the activation of generalized fear. This pattern remains to be further investigated in nonhuman animal models. Nonhuman animal research suggests an interaction between the neural correlates of contextual fear generalization and timing, such that the mPFC appears to increase fear generalization at remote time points and reduce generalization at recent time points following acquisition. CONCLUSIONS: The literature suggests a key role for the mPFC in fear generalization, but empirical details vary depending on specific regions within the mPFC, the animal model used, and the timing of the generalization test. Further research is needed to elucidate the role of the mPFC in fear generalization, which could in turn facilitate more effective pharmacological interventions for pathological anxiety. (PsycINFO Database Record PMID- 28857603 TI - Action-matching biases in monkeys (Sapajus spp.) in a stimulus-response compatibility task: Evaluating experience-dependent malleability. AB - Stimulus-response (S-R) compatibility effects occur when observing certain stimuli facilitate the performance of a related response and interfere with performing an incompatible or different response. Using stimulus-response action pairings, this phenomenon has been used to study imitation effects in humans, and here we use a similar procedure to examine imitative biases in nonhuman primates. Eight capuchin monkeys (Sapajus spp.) were trained to perform hand and mouth actions in a stimulus-response compatibility task. Monkeys rewarded for performing a compatible action (i.e., using their hand or mouth to perform an action after observing an experimenter use the same effector) performed significantly better than those rewarded for incompatible actions (i.e., performing an action after observing an experimenter use the other effector), suggesting an initial bias for imitative action over an incompatible S-R pairing. After a predetermined number of trials, reward contingencies were reversed; that is, monkeys initially rewarded for compatible responses were now rewarded for incompatible responses, and vice versa. In this 2nd training stage, no difference in performance was identified between monkeys rewarded for compatible or incompatible actions, suggesting any imitative biases were now absent. In a 2nd experiment, 2 monkeys learned both compatible and incompatible reward contingencies in a series of learning reversals. Overall, no difference in performance ability could be attributed to the type of rule (compatible incompatible) being rewarded. Together, these results suggest that monkeys exhibit a weak bias toward action copying, which (in line with findings from humans) can largely be eliminated through counterimitative experience. (PsycINFO Database Record PMID- 28857604 TI - Kea (Nestor notabilis) decide early when to wait in food exchange task. AB - The ability to forego an immediate reward in favor of a bigger or better one at a later point has been linked with advanced cognitive skills, such as impulse control and forward-planning, and can be assessed by the classic food exchange paradigm. While the ability to perform in such tasks has long been regarded as an exclusive trait of humans and some mammals, that is, primates and dogs, in recent years some bird species have been found to perform similarly as primates. Here we test 10 captive kea (Nestor notabilis), using a food exchange paradigm standardized in earlier experiments, but adding the use of a container to hold the initial item. The subjects reached waiting times of up to 160 s. They also showed significantly different results depending on the difference in the preference level for the presented food items, as well as clearly nonrandom waiting times, displaying forward-planning and economic evaluation of the situation at hand. As in most other species, results were markedly better when exchanging for quality as opposed to quantity. These results provide further evidence for temporal discounting in birds and fit in with the data gained on corvids and parrots in recent years. (PsycINFO Database Record PMID- 28857605 TI - "I am going to groom you": Multiple forms of play fighting in gray mouse lemurs (Microcebus murinus). AB - Play fighting is a commonly reported form of play that involves competitive interactions that generally do not escalate to serious fighting. Although in many species what are competed over are the body targets that are bitten or struck in serious fighting, for many others, the competition can be over other forms of contact, such as sex, social grooming, and predation. In primates, the most detailed studies have been of species such as Old World monkeys, that engage in play fighting that simulates serious fighting, but reports of a number of others, especially among nocturnal prosimians, have noted that play fighting can also involve simulation of sex and grooming. The present study on captive born gray mouse lemurs (Microcebus murinus) provides a quantitative assessment of the relative engagement by juveniles in play fighting involving agonistic and amicable targets. About 80% of play fighting involves competing to groom or mount one another, with a minority involving competing to bite. That these forms of play fighting may be distinct from one another is suggested by the finding that attack on one target does not lead to counterattack on another. The findings are discussed in terms of the evolution and mechanisms underlying play fighting in primates and more widely among animals. (PsycINFO Database Record PMID- 28857600 TI - Advances in neurocognitive rehabilitation research from 1992 to 2017: The ascension of neural plasticity. AB - OBJECTIVE: The last 25 years have seen profound changes in neurocognitive rehabilitation that continue to motivate its evolution. Although the concept of nervous system plasticity was discussed by William James (1890), the foundation for experience-based plasticity had not reached the critical empirical mass to seriously impact rehabilitation research until after 1992. The objective of this review is to describe how the emergence of neural plasticity has changed neurocognitive rehabilitation research. METHOD: The important developments included (a) introduction of a widely available tool that could measure brain plasticity (i.e., functional MRI); (b) development of new structural imaging techniques that could define limits of and opportunities for neural plasticity; (c) deployment of noninvasive brain stimulation to leverage neural plasticity for rehabilitation; (d) growth of a literature indicating that exercise has positively impacts neural plasticity, especially for older persons; and (e) enhancement of neural plasticity by creating interventions that generalize beyond the boundaries of treatment activities. Given the massive literature, each of these areas is developed by example. RESULTS: The expanding influence of neural plasticity has provided new models and tools for neurocognitive rehabilitation in neural injuries and disorders, as well as methods for measuring neural plasticity and predicting its limits and opportunities. Early clinical trials have provided very encouraging results. CONCLUSION: Now that neural plasticity has gained a firm foothold, it will continue to influence the evolution of neurocognitive rehabilitation research for the next 25 years and advance rehabilitation for neural injuries and disease. (PsycINFO Database Record PMID- 28857606 TI - On the clock: Interval timing and overshadowing in domestic dogs (Canis familiaris). AB - Interval timing is an important skill that allows animals to approximate how much time has elapsed since a given event. Little, however, is known about interval timing in domestic dogs. In an initial experiment, dogs were trained to make an operant response on 30-s fixed intervals, with either a light or a tone + light compound signaling the beginning of the fixed interval. When dogs in the compound group were subsequently tested with nonreinforced 60-s tone-only probe trials, the dogs' rate of responding peaked near 30 s. When the same dogs were tested with light-only probes, however, no evidence of timing was found. In a second experiment, a bisection task was used in which dogs had to learn to approach 1 feeder when given an 8-s tone + light signal, and another feeder when given a 2-s tone + light signal. When subsequently tested at intermediate durations, psychophysical curves showed clear control of timing by the tone stimulus but not by the light stimulus. These findings clearly demonstrate that dogs are able to time fixed intervals and show the existence of an overshadowing effect, in which dogs are able to time a light cue presented alone but do not attend to the light when it is presented simultaneously with a tone. (PsycINFO Database Record PMID- 28857607 TI - Piagetian liquid conservation in grey parrots (Psittacus erithacus). AB - An understanding of Piagetian liquid conservation was investigated in four Grey parrots (Psittacus erithacus), their ages ranging from initially less than 1 year old to 18 years old. They were tested in several conditions: on the ability to choose between (a) identical containers filled with a greater or lesser quantity of a desirable liquid to see if they would reliably take the larger amount and (b) equal quantities of liquid that were visibly or invisibly transferred from identical to different-sized containers to examine their abilities with respect to conservation. Invisible transfers examined the extent to which birds chose based on perceptual evaluations of quantity and the effects of task order on their decisions. Adult birds succeeded on all or most aspects of the tests. As a chick (~6 months), 1 bird was unable or unwilling to choose between the smaller and larger quantities in the first stage of testing, but upon reaching juvenile status succeeded in all aspects of the tests. Grey parrots thus demonstrate some understanding of liquid conservation. (PsycINFO Database Record PMID- 28857608 TI - Proteomic alterations of fibroblasts induced by ovarian cancer cells reveal potential cancer targets. AB - The common spread pattern of ovarian cancer is peritoneal implantation. The growth of the shed ovarian cancer cells in the peritoneal cavity is closely related to the tumor microenvironment. Cancer-associated fibroblasts are vital in the tumor microenvironment. It is not clearly defined that the protein expression alters during the activating process of fibroblasts. This study detected the protein alterations in fibroblasts induced by ovarian cancer cells and explored the potential biological relevance through two-dimensional gel electrophoresis and mass spectrometry. Our data showed that the level of CENPE, BAG2, SOD2, GDI2, CORO1C, CFL1, DSTN, CALD1, PHGDH, PDHA1, AKR1B1, TST and TBCA proteins were significantly up-regulated in the fibroblasts co-cultured with ovarian cancer cells, whereas HSPB1, P4HB and VIM were significantlydown-regulated. However, only BAG2, SOD2 and CORO1C proteins were confirmed to be significantly increased by western blot analysis. The differentially expressed proteins were mainly involved in metabolic processes, cellular component organization, responses to stimulus, multicellular organismal processes, localization, protein depolymerization, cellular senescence and the mitotic pathway. These data demonstrated that fibroblasts had an altered protein expression pattern after being induced by ovarian cancer cells, and participated in multiple cell processes resulting in tumor progression. The differentially expressed proteins should be considered as targets for cancer treatment. PMID- 28857609 TI - Evaluation of the Flagging Performance of the Hematology Analyzer Sysmex XN Series on the Basis of "Q Values". AB - CONTEXT: - In the XN series of hematology analyzers (Sysmex, Kobe, Japan), the probability of the presence of abnormal cells is indicated by flags based on Q values. OBJECTIVE: - To evaluate the Q value performance of the Sysmex XN-20 modular analyzer. DESIGN: - The interinstrumental concordance, intrainstrumental precision, and diagnostic accuracy of Q values, with tested flags of "blasts/abnormal lymphocytes," "atypical lymphocytes," and "blasts," were investigated. RESULTS: - Absolute concordance rates in flagging between 2 analyzers ranged from 69.8% to 80.8%, and kappa values ranged from 0.43 to 0.61. In samples with absolute related cell counts lower than 100/MUL, the values ranged from 0.31 to 0.52. For intrainstrumental precision, standard deviations ranged from 4.8 to 23.9 for the blasts/abnormal lymphocytes, from 18.7 to 59.1 for the blasts, and from 11.0 to 23.0 for the atypical lymphocytes. Using a default Q value cutoff, diagnostic accuracy values based on the area under the curve, sensitivity, and specificity were, respectively, 0.910, 90.9%, and 72.2% for blasts/abnormal lymphocytes; 0.927, 84.9%, and 89.8% for blasts; and 0.865, 74.4%, and 84.9% for atypical lymphocytes. The diagnostic accuracy of Q values was much lower in samples with absolute related cell counts lower than 100/MUL than in those 100/MUL or higher. CONCLUSIONS: - Q values of the Sysmex XN-20 analyzer were found to be imprecise and irreproducible, especially with samples containing a small number of pathologic cells. Adjustments in the Q value threshold may help in the detection of these cells. PMID- 28857610 TI - Fast Track to Accreditation: An Implementation Review of College of American Pathologists and International Organization for Standardization 15189 Accreditation. AB - CONTEXT: - This review examines challenges and opportunities in preparing laboratories in a startup phase for accreditation by both the College of American Pathologists (CAP) and International Organization for Standardization (ISO) 15189 in an international setting as it relates to our experience at Cleveland Clinic Abu Dhabi Laboratory. It also discusses some of the strategies used in executing those projects and the added advantages in pursuing both types of accreditations. OBJECTIVES: - To share our experience with CAP and ISO 15189 accreditations in a startup international operation in relation to the challenges encountered and implementation strategy success factors. DATA SOURCES: - MEDLINE (PubMed) database was used to review this topic as well as peer-reviewed articles and World Health Organization publications on the topic. CONCLUSIONS: - Accreditation is a perfect means toward building quality medical laboratories in a diverse workforce environment and improving patient safety. Further, it establishes a strong foundation on which any new operation can build a sustainable quality improvement culture. Accreditations by CAP and/or ISO are among the most reputable and well-established accreditation systems that clinical laboratories could aim for. As a result of both accreditations offering synergistic and complementing features, we recommend that any laboratory seeking excellence in quality and performance should consider exploring both. Key elements to success include having dedicated project management and change management support while preparing for accreditation. Laboratories seeking accreditation in early operational stages may face a number of challenges; however, significant opportunities will also be present to optimize various operational components from the beginning. PMID- 28857611 TI - Bleeding risk of apixaban, dabigatran, and low-dose rivaroxaban compared with warfarin in Japanese patients with non-valvular atrial fibrillation: a propensity matched analysis of administrative claims data. AB - OBJECTIVES: There is scarce evidence comparing novel oral anticoagulants (NOACs) with warfarin in real-world settings in Japan. This study compared the risk of bleeding events among patients with non-valvular atrial fibrillation (NVAF) initiating treatment with NOACs versus warfarin. METHODS: A retrospective cohort study was conducted using a de-identified electronic health record based database of health claims and Diagnosis Procedure Combination data from 275 consenting hospitals in Japan. NVAF patients newly initiated on oral anticoagulants were eligible. Based on the first prescription, patients were assigned to 5/2.5 mg BID apixaban, 150/110 mg BID dabigatran, 15/10 mg QD rivaroxaban (approved dose lower in Japan compared to Western countries [20/15 mg QD]) or warfarin groups. One-to one propensity score matching (PSM) was used to balance patient characteristics between warfarin and each NOAC. Patients were followed up to 1 year post-first prescription. RESULTS: Among 38,662 eligible patients, a total of 5977, 5090, and 6726 matched pairs were identified for warfarin versus apixaban, warfarin versus dabigatran, and warfarin versus rivaroxaban, respectively after PSM. Compared to warfarin, apixaban (hazard ratio [HR] 0.586; 95% CI 0.421-0.815), dabigatran (HR 0.617; 0.425-0.895) and rivaroxaban (HR 0.693; 0.514-0.933) were associated with a significantly lower risk of major bleeding. The risk of any bleeding was significantly lower for apixaban (HR 0.782; 0.682-0.896), but not for dabigatran (HR 0.988; 0.860-1.135) or rivaroxaban (HR 0.938; 0.832-1.057) when comparing to warfarin. CONCLUSIONS: Among Japanese patients with NVAF, treatment with apixaban 5/2.5 mg BID was associated with a significantly lower risk of major bleeding and any bleeding when compared to warfarin. Treatment with dabigatran 150/110 mg BID or rivaroxaban 15/10 mg QD was associated with a significantly lower risk of major bleeding, but not any bleeding, than warfarin. The potential benefit of individual NOACs in real-world practice needs to be assessed further. PMID- 28857612 TI - Sign Language as Virus: Stigma and Relationality in Urban India. AB - Drawing upon ethnographic research conducted in urban locations in India, I consider the relationship between stigma and contagion in the context of deaf peoples' desires for and practices of communication in Indian Sign Language. If sign language can be considered or represented as a virus-and if it spreads between and among deaf people upon exposure-what might cure differentially look like, in a time when cochlear implantation and oral-based early intervention is increasingly becoming normalized? Considering the impact of stigma on multiple forms of relationality, I argue that sign language's viral potentiality lies in its ability to transform and create new relationships and worlds. PMID- 28857613 TI - Polyketides with different post-modifications from desert endophytic fungus Paraphoma sp. AB - Three new polyketides 4,6,8-trihydroxy-5-methyl-3,4-dihydronaphthalen-1(2H)-one (1), 5,7-dihydroxy-3-(1-hydroxyethyl)-3,4-dimethylisobenzofuran-1(3H)-one (2) and 1-(4-hydroxy-6-methoxy-1,7-dimethyl-3-oxo-1,3-dihydroisobenzofuran-1-yl) ethyl acetate (3) together with seven known analogues (4-10) were isolated from desert endophytic fungus Paraphoma sp. The structures of these compounds were elucidated by analysis of NMR data. The absolute configuration of (1-3) was established on the basis of CD experiments. The possible biosynthetic pathway of compounds (1 10) was suggested, which implied that these secondary metabolites might be originated from polyketide biosynthesis with different post-modification reactions. Compounds 2, and 5-8 were evaluated for bioactivities against plant pathogen A. solani, whereas none of them displayed any biological effects. In addition, compounds 1, 2 and 5-10 were also tested for cytotoxic activities against three human cancer cell lines (HepG2 cells, MCF-7 cells and Hela cells) without biological effects. PMID- 28857614 TI - Attitudes about when and how to treat patients with AL amyloidosis: an international survey. AB - The aim of this survey was to describe the treatment decision making of expert physicians in when and how to treat patients with AL amyloidosis. Fifty amyloid expert physicians completed the survey. Autologous stem cell transplant (ASCT) was considered the first line therapy, if medically feasible, by 73% of the physicians. Excluding ASCT, cyclophosphamide-bortezomib-dexamethasone regimen was the preferred strategy by 72%. Depending on organ involvement, the goal for treatment was CR for 27-35% and very good partial response (VGPR) for 65-72%. In the absence of organ progression but rising FLC, the factors that most influenced when to reinstitute therapy included: dFLC at diagnosis (35.2%); how sick the patient was at diagnosis (24.1%); and time to FLC rise (18.5%). For patients who achieved CR after first-line, in the presence of cardiac/renal progression, 37/42% of providers would consider starting clone directed therapy without evidence of a clone. These data would imply that the current definitions of hematologic progression do not match clinical judgment, clinical experience and a comprehensive evaluation of patient status. These disparities challenge the ability to design therapeutic trials for patients with relapsed/refractory disease. A consensus statement with the definition and validation of new hematologic progression criteria is required. PMID- 28857615 TI - Microbial transglutaminase in noodle and pasta processing. AB - Nowadays, there is an aggressive rate in consumption of noodles and pasta products throughout the world. Consumer acceptability and preference of these functional products can be promoted by the discovery of novel knowledge to improve their formulation and quality. The development of fortified-formulations for noodles and pasta products based on microbial transglutaminase (MTGase) can guarantee the shelf life extension with minimum quality losses. The current review focuses on recent trends and future prospects of MTGase utilization in the structural matrix of noodles and pasta products and represents the quality changes of cooking loss, texture, microstructure, color and sensory attributes of the MTGase-incorporated products. Digestibility, nutritional and health aspects of the MTGase-enriched formulations are also reviewed with a vision toward physical functions and safety outcomes of MTGases isolated from new microbial sources. The high potential of MTGase in developing commercial noodles and pasta products is successfully demonstrated. MTGase by modifying the crystallinity or molecular structure via covalent crosslinks between protein molecules strengthens the doughs stability and the textural characteristics of final products with the low- or high-protein flour. Compared with the control samples, the MTGase supplemented products indicate slower digestion rates and better sensory and cooking properties without any remarkable color instability. PMID- 28857616 TI - Adoptive cell therapy in multiple Myeloma. AB - INTRODUCTION: Recent breakthrough advances in Multiple Myeloma (MM) immunotherapy have been achieved with the approval of the first two monoclonal antibodies, elotuzumab and daratumumab. Adoptive cell therapy (ACT) represents yet another, maybe the most powerful modality of immunotherapy, in which allogeneic or autologous effector cells are expanded and activated ex vivo followed by their re infusion back into patients. Infused effector cells belong to two categories: naturally occurring, non-engineered cells (donor lymphocyte infusion, myeloma infiltrating lymphocytes, deltagamma T cells) or genetically- engineered antigen specific cells (chimeric antigen receptor T or NK cells, TCR-engineered cells). Areas covered: This review article summarizes our up-to-date knowledge on ACT in MM, its promises, and upcoming strategies to both overcome its toxicity and to integrate it into future treatment paradigms. Expert opinion: Early results of clinical studies using CAR T cells or TCR- engineered T cells in relapsed and refractory MM are particularly exciting, indicating the potential of long-term disease control or even cure. Despite several caveats including toxicity, costs and restricted availability in particular, these forms of immunotherapy are likely to once more revolutionize MM therapy. PMID- 28857617 TI - Recent advances and novel treatments for sphingolipidoses. AB - Sphingolipidoses are genetically inherited diseases in which genetic mutations lead to functional deficiencies in the enzymes needed for lysosomal degradation of sphingolipid substrates. As a consequence, nondegradable lipids enrich in the lysosomes and lead to fatal pathological phenotypes in affected individuals. In this review, different drug-based treatment strategies including enzyme replacement therapy and substrate reduction therapy are discussed. A special focus is on the concept of pharmacological chaperones, one of which recently acquired clinical approval within the EU. On the basis of the different limitations for each approach, possible future directions of research are discussed. PMID- 28857618 TI - The Home-Heart-Walk study, a self-administered walk test on perceived physical functioning, and self-care behaviour in people with stable chronic heart failure: A randomized controlled trial. AB - BACKGROUND: Adherence to self-care recommendations is associated with improved patient outcomes and improved quality of life for people living with heart failure. The Home-Heart-Walk (HHW) is an intervention to promote physical activity adapting the elements of a six minute walk test, a reliable and valid measure. This adaptation was designed to support self-monitoring of physical functioning and promote the self-care of people with heart failure. The primary outcome of the Home-Heart-Walk was perceived physical functioning and the secondary outcomes were six-minute walk test distance, health related quality of life, self-care behaviour, self-efficacy and physical activity level. METHODS: A multicentre randomized controlled trial. Participants ( N=132) were recruited from three academic hospitals in Sydney, Australia. Participants were randomized to either the Home-Heart-Walk group or the control group. Perceived physical functioning, health related quality of life, self-care behaviour, exercise self efficacy and physical activity level were measured at baseline and at three- and six-month follow-up. RESULTS: After adjusting for baseline scores, there were no statistically significant between-group differences in perceived physical functioning, six-minute walk test distance, health related quality of life and exercise self-efficacy at follow-up. The intervention group had improvement in self-care behaviour ( F(1,129) = 4.75, p = 0.031) and physical activity level ( U = 1713, z = -2.12, p = 0.034) at the six-month follow-up compared with the control group. CONCLUSION: The Home-Heart-Walk did not improve the perceived physical functioning of the intervention group. Although the feasibility and acceptability of this strategy to support self-monitoring and improve self-care behaviour was demonstrated, self-reported adherence was unreliable; newer technologies may offer better assessment of adherence. PMID- 28857619 TI - Evaluation of the performance of elastomeric pumps in practice: are we under delivering on chemotherapy treatments? AB - BACKGROUND AND AIMS: Elastomeric pumps are widely used to facilitate ambulatory chemotherapy, and studies have shown that they are safe and well received by patients. Despite these advantages, their end of infusion time can fluctuate significantly. The aim of this research was to observe the performance of these pumps in real practice and to evaluate patients' satisfaction. METHODS: This was a two-phase study conducted at three cancer units over 6 months. Phase-1 was an observational study recording the status of pumps at the scheduled disconnection time and noting remaining volume of infusion. Phase-2 was a survey of patients and their perception/satisfaction. Ethical approval was granted. RESULTS: A total of 92 cases were observed covering 50 cases disconnected at hospital and 42 disconnected at home. The infusion in 40% of hospital disconnection cases was slow, with patients arriving at hospital with unfinished pumps; 58% of these had an estimated remaining volume which exceeded 10 mL with 35% exceeded 20 mL. In 73% of these cases, and regardless of the remaining volume, the patient was disconnected and the pump was discarded. CONCLUSIONS: The performance of pumps varied, which affected nurse workload and patients' waiting-times. A smart system is an option to monitor the performance of pumps and to predict their accuracy. PMID- 28857620 TI - Active transcutaneous bone conduction implant: audiological results in paediatric patients with bilateral microtia associated with external auditory canal atresia. AB - OBJECTIVE: To describe, in terms of functional gain and word recognition, the audiological results of patients under 18 years of age implanted with the active bone conduction implant, BonebridgeTM. DESIGN: Retrospective case studies conducted by reviewing the medical records of patients receiving implants between 2014 and 2016 in the public health sector in Chile. STUDY SAMPLE: All patients implanted with the Bonebridge were included (N = 15). Individuals who had bilateral conductive hearing loss, secondary to external ear malformations, were considered as candidates. RESULTS: The average hearing threshold one month after switch on was 25.2 dB (95%CI 23.5-26.9). Hearing thresholds between 0.5 and 4 kHz were better when compared with bone conduction hearing aids. Best performance was observed at 4 kHz, where improvements to hearing were observed throughout the adaptation process. There was evidence of a significant increase in the recognition of monosyllables. CONCLUSIONS: The Bonebridge implant showed improvements to hearing thresholds and word recognition in paediatric patients with congenital conductive hearing loss. PMID- 28857621 TI - Analytical Approaches for Determining Chemical Oxygen Demand in Water Bodies: A Review. AB - Chemical oxygen demand (COD) is a critical analytical parameter for water quality assessment. COD represents the degree of organic pollution in water bodies. However, the standard analytical methods for COD are time-consuming and possess low oxidation efficiency, chloride interference, and severe secondary pollution. Works performed during the last two decades have resulted in several technologies, including modified standard methods (e.g., microwave-assisted method) and new technologies or methods (e.g., electro- and photo-oxidative methods based on advanced oxidation processes) that are less time-consuming, environment friendly, and more reliable. This review is devoted in analyzing the technical features of the principal methods described in the literature to compare their performances (i.e., measuring window, reliability, and robustness) and identify the advantages and disadvantages of each method. PMID- 28857622 TI - Supplementation of all trans retinoic acid ameliorates ethanol-induced endoplasmic reticulum stress. AB - CONTEXT: Molecular pathogenesis of chronic alcoholism is linked to increased endoplasmic reticulum stress. Ethanol is a competitive inhibitor of vitamin A metabolism and vitamin A supplementation aggravates existing liver problems. Hence, we probed into the impact of supplementation of all trans retinoic acid (ATRA), the active metabolite of vitamin A on ethanol-induced endoplasmic reticulcum stress. METHODS: Male Sprague-Dawley rats were divided into four groups - I: Control; II: Ethanol; III: ATRA; IV: ATRA + Ethanol. After 90 days the animals were sacrificed to study markers of lipid peroxidation in hepatic microsomal fraction and expression of ER stress proteins and apoptosis in liver. RESULTS AND CONCLUSION: Ethanol caused hepatic hyperlipidemia, enhanced microsomal lipid peroxidation, upregulated expression of unfolded protein response associated proteins and that of apoptosis. Ethanol also led to downregulation of retinoid receptors. ATRA supplementation reversed all these alterations indicating the decrease in ethanol-induced endoplasmic reticulum stress. PMID- 28857624 TI - ATS Core Curriculum 2017: Part III. Adult Critical Care Medicine. PMID- 28857623 TI - ATS Core Curriculum 2017: Part II. Pediatric Pulmonary Medicine. PMID- 28857626 TI - Introduction to the ATS Core Curriculum Series, 2017. PMID- 28857625 TI - ATS Core Curriculum 2017: Part IV. Adult Pulmonary Medicine. PMID- 28857627 TI - ATS Core Curriculum 2017: Part I. Adult Sleep Medicine. PMID- 28857628 TI - Correlation between allopregnanolone levels and depressive symptoms during late menopausal transition and early postmenopause. AB - OBJECTIVES: This observational, cross-sectional study included 140 women with climacteric symptoms. The aim of the study was to evaluate the correlation between the presence and severity of depressive symptoms and allopregnanolone levels in women during late menopausal transition and early postmenopause. METHODS: The study group was divided into two groups: 45 women in late menopausal transition and 95 early postmenopausal women. We evaluated Kupperman index, Hamilton scale and serum follicle-stimulating hormone, luteinizing hormone, 17beta-estradiol, prolactin, total testosterone, dehydroepiandrosterone sulfate and allopregnanolone levels. RESULTS: We found that serum allopregnanolone concentration was lower in early postmenopausal women compared to women in late menopausal transition; that there was a correlation between serum allopregnanolone levels in early postmenopausal women and time since last menstruation, intensity of climacteric symptoms, and intensity of depression symptoms and that there was a correlation between serum allopregnanolone levels and several depression symptoms presence (shallow sleep and symptoms of the digestive tract in women during late menopause transition; feelings of guilt, sleep disorders and general somatic symptoms in early postmenopausal women). CONCLUSION: We concluded that reproductive aging is characterized by a reduction of allopregnanolone circulating levels that correlate to Hamilton depression index in early postmenopause and presence of specific depressive symptoms during late menopausal transition and early postmenopause. PMID- 28857629 TI - High-intensity interval training acutely alters plasma adipokine levels in young overweight/obese women. AB - The aim of this study was to investigate the plasma adipokine responses to high intensity interval training (HIT) in overweight/obese women. Twelve women (age 21.7 +/- 3.8 years) completed a 19 days of HIT comprising six session of 4-6 repeats of a Wingate test (0.065 kg load/kg). Plasma adipokine levels were measured before exercise, and at 5 and 90 min after exercise on the first and the last training days. Adiponectin was higher at 5 min than 90 min post-exercise (11.7 +/- 7.3 and 10.5 +/- 5.8 ng/ml; p = .01) in the first exercise day. Leptin decreased 5 min after exercise (23.6 +/- 13.2 vs. baseline 27.8 +/- 14.4 ng/ml; p < .01) and remained depressed following 90 min (p < .01). The changes in adiponectin and leptin concentrations were similar on the first and last exercise days. No consistent effect was found on resistin concentration. Future studies are required to disclose the functional consequences of these alterations in plasma adipokine levels. PMID- 28857630 TI - Assessment of mTOR pathway molecules during implantation in rats. AB - Mammalian target of rapamycin (mTOR) is a member of the PI3K/Akt/mTOR signaling pathway that participates in cell growth, proliferation, protein synthesis, transcription, angiogenesis, apoptosis and autophagy. We investigated the role of mTOR and other signaling molecules in the rat uterus during implantation. Female pregnant rats were divided into three groups: embryonic days (ED) 4.5, 5.5 and 6.5 according to vaginal smears. Immunohistochemical staining of mTORC1, mTORC2, IGF1, PI3K, pAkt1/2/3, ERK1 and pERK1/2 was performed on formalin fixed, paraffin embedded uterine tissue samples. pAkt1/2/3 and ERK1 also were analyzed using western blotting. We found that PI3K/Akt/mTOR and ERK/pERK were increased during the implantation period. Different amounts of mTORC1, mTORC2, IGF1, PI3K, pAKT1/2/3, ERK1 and pERK1/2 were expressed in luminal epithelium, decidual cells, embryoblast and trophoblast cells during implantation. We suggest that mTOR and associated signaling molecules may participate in implantation. PMID- 28857631 TI - Practical implications of using real-world evidence (RWE) in comparative effectiveness research: learnings from IMI-GetReal. AB - In light of increasing attention towards the use of real-world evidence (RWE) in decision making in recent years, this commentary aims to reflect on the experiences gained in accessing and using RWE for comparative effectiveness research as a part of the Innovative Medicines Initiative GetReal Consortium and discuss their implications for RWE use in decision-making. PMID- 28857632 TI - Adherence, persistence, and discontinuation among Hispanic and African American patients with multiple sclerosis treated with fingolimod or glatiramer acetate. AB - OBJECTIVE: Few studies have examined compliance to disease-modifying therapies (DMTs) for multiple sclerosis (MS) in minority populations. This study compared adherence, discontinuation, and persistence for fingolimod (FTY) and glatiramer acetate (GA) initiators among Hispanic and African American patients with MS. METHODS: This retrospective claims data study examined Hispanic and African American adults with MS who initiated FTY or GA between September 1, 2010 and June 30, 2014. Outcomes (adherence, discontinuation, and persistence) were analyzed descriptively and with multivariable models, comparing FTY and GA cohorts within racial/ethnic groups. Adherence was assessed using medication possession ratio (MPR) and proportion of days covered (PDC). RESULTS: There were 171 patients in the Hispanic group (62 FTY, 109 GA) and 210 in the African American group (71 FTY, 139 GA). A larger proportion of GA initiators than FTY initiators were treatment-naive; other baseline characteristics were similar between cohorts. Hispanic FTY initiators had greater mean MPR, PDC, and persistence and less discontinuation than GA initiators. African American FTY initiators had greater mean PDC than GA initiators; other outcomes favored FTY but were not statistically significant. Multivariable analysis results were consistent with the unadjusted results, but differences between treatment cohorts were not statistically significant. CONCLUSIONS: Hispanic and African American patients with MS who initiated FTY had higher adherence than those who initiated GA, similar to the general MS population. These findings suggest that adherence should be considered in DMT selection, and racial/ethnic variations in MS disease course may not be primarily attributable to differences in DMT compliance. PMID- 28857633 TI - Practice makes perfect? The pedagogic value of online independent phonetic transcription practice for speech and language therapy students. AB - Accuracy of phonetic transcription is a core skill for speech and language therapists (SLTs) worldwide (Howard & Heselwood, 2002). The current study investigates the value of weekly independent online phonetic transcription tasks to support development of this skill in year one SLT students. Using a mixed methods observational design, students enrolled in a year one phonetics module completed 10 weekly homework activities in phonetic transcription on a stand alone tutorial site (WebFon (Bates, Matthews & Eagles, 2010)) and 5 weekly online quizzes (the 'Ulster Set' (Titterington, unpublished)). Student engagement with WebFon was measured in terms of the number of responses made to 'sparks' on the University's Virtual Learning Environment Discussion Board. Measures of phonetic transcription accuracy were obtained for the 'Ulster Set' and for a stand-alone piece of coursework at the end of the module. Qualitative feedback about experience with the online learning was gathered via questionnaire. A positive significant association was found between student engagement with WebFon and performance in the 'Ulster Set', and between performance in the 'Ulster Set' and final coursework. Students valued both online independent learning resources as each supported different learning needs. However, student compliance with WebFon was significantly lower than with the 'Ulster Set'. Motivators and inhibitors to engagement with the online resources were investigated identifying what best maximised engagement. These results indicate that while 'independent' online learning can support development of phonetic transcription skills, the activities must be carefully managed and constructively aligned to assessment providing the level of valance necessary to ensure effective engagement. PMID- 28857634 TI - Antiplatelets and profibrinolytic activity of Citrullus colocynthis in control and high-fat diet-induced obese rats: mechanisms of action. AB - The current study aimed to investigate the effect of Citrullus colocynthis (C. colocynthis) hydro-alcoholic extract on blood haemostasis in control and high-fat diet (HFD) induced obese rats. In control rats, the extract significantly enhanced bleeding time and plasma levels of tPA and significantly decreased plasma levels PAI-1 and serum levels of thromboxane B2 leading to inhibition of platelets aggregation. In HFD induced obese rats, similar effects were seen and the extract was also able to reverse HFD induced increases in fibrinogen and VWF. Searching for the mechanism, C. colocynthis acts by (1) inhibiting of food intake, (2) inhibiting the activity of pancreatic lipase, (3) decreasing levels of TNF-alpha and IL-6 and (4) decreasing circulatory levels of the prothrombotic adipokine, leptin and enhanced circulatory levels of the antithrombic adipokines and adiopnectin. In conclusion, C. colocynthis has antiplatelets and profibrinolytic activity in both control and HFD induced obese rats. PMID- 28857636 TI - The least worst option: user experiences of antipsychotic medication and lack of involvement in medication decisions in a UK community sample. AB - BACKGROUND: Treatment decision-making that fully involves service users is an aim across medicine, including mental health. AIM: To explore service users experiences of taking antipsychotic medication for psychotic disorders and their perceptions of decision-making about this. METHOD: Semi-structured interviews with 20 users of community mental health services, conducted by service user researchers and analysed using thematic analysis. RESULTS: Antipsychotic medication was perceived to have beneficial effects on symptoms and relapse risk, but adverse effects were prominent, including a global state of lethargy and demotivation. Weighing these up, the majority viewed antipsychotics as the least worst option. Participants were split between positions of "willing acceptance", "resigned acceptance" and "non-acceptance" of taking antipsychotics. Many felt their choices about medication were limited, due to the nature of their illness or pressure from other people. They commonly experienced their prescribing psychiatrist as not sufficiently acknowledging the negative impacts of medication on life quality and physical health concerns and described feeling powerless to influence decisions about their medication. CONCLUSION: The study highlights the complexity of agendas surrounding antipsychotic medication, including the pervasive influence of coercive processes and the challenges of implementing collaborative decision-making for people with serious mental health problems. PMID- 28857635 TI - Neural Correlates of Response Inhibition in Early Childhood: Evidence From a Go/No-Go Task. AB - We examined the neural correlates underlying response inhibition in early childhood. Five-year-old children completed a Go/No-go task with or without time pressure (Fast vs. Slow condition) while scalp EEG was recorded. On No-go trials where inhibition was required, the left frontal N2 and posterior P3 were enhanced relative to Go trials. Time pressure was detrimental to behavioral performance and modulated the early-occurring P1 component. The topography of ERPs related to response inhibition differed from patterns typically seen in adults, and may indicate a compensatory mechanism to make up for immature inhibition networks in children. PMID- 28857637 TI - Perceived Peer Behavior and Parental Support as Correlates of Marijuana Use: The Role of Age and Gender. AB - INTRODUCTION: Parental support and perceptions of peer behavior on substance use are well-studied, but precisely how their associations vary as a function of age, and how those age-specific patterns vary by gender, remain unknown components of the developmental process underlying substance use. METHODS: Using data from an 18-year longitudinal study of predominantly African-American students at high risk for high school dropout in Flint, Michigan (baseline average age = 14.8 years), we examined longitudinal associations between past 30-day marijuana use and three self-reported variables: perceived friend drug use, perceived friend aggression, parental support. We used varying-coefficient regression models to semiparametrically estimate how covariate effects on past 30-day marijuana use vary smoothly as a function of age; gender differences in these age-specific coefficient trajectories were also tested. RESULTS: In the unadjusted tests, the risk-enhancing effect of perceived friend drug use decreased with age in both genders, but the effect of perceived friend aggression varied only in females; in both cases, gender differences were not significant. In males, parental support had protective effects that decreased with age. The effect of both parental support differed in females, with less protective baseline effects and no evidence of age-variation. Adjusted models simultaneously including both friend and parental variables produced qualitatively similar results. CONCLUSIONS: Prevention strategies focusing on social exposures may be more effective if they are age- and gender-specific. In particular, interventions focusing on perceived peer behaviors may be more appropriate during adolescence, and those involving parental relationships may be more appropriate for males. PMID- 28857638 TI - Specificity of peptidases secreted by filamentous fungi. AB - Peptidases are enzymes that cleave peptide bonds, yielding proteins and peptides. Enzymes in this class also perform several other functions, regulating the activation or inactivation of target substrates via proteolysis. Owing to these functions, peptidases have been extensively used in industrial and biotechnological applications. Given their potential functions, it is important to optimize the use of these enzymes, which requires determination of the specificity of each peptidase. The peptidase specificity must be taken into account in choosing a peptidase to catalyze the available protein source within the desired application. The specificity of a peptidase defines the profile of enzyme-substrate interactions, and for this the catalytic site and the arrangement of the amino acid residues involved in peptide bond cleavage need to be known. The catalytic sites of peptidases may be composed of several subsites that interact with amino acid residues for proteolysis. Filamentous fungi produce peptidases with varying specificity, and here we provide a review of those reported to date and their potential applications. PMID- 28857639 TI - What helps in self-help? A qualitative exploration of interactions within a borderline personality disorder self-help group. AB - BACKGROUND: Self-help groups can have a large impact on individuals well-being and could reduce costs for healthcare services. Previous research supports the effectiveness of self-help groups, but explanations for this are lacking. Identifying the active ingredients which encourage positive change could inform effectiveness of these groups producing the best outcomes for members. AIM: This research investigated how members and facilitators of a borderline personality disorder self-help group (BPD SHG) interacted and made sense of their experiences in group meetings, to determine what aspects of interaction were helpful. METHOD: Naturalistic data was collected from 10 participants via audio recording and analysed using interpretative phenomenological analysis. RESULTS: Three emergent themes are discussed: humour, praise and experiential knowledge. CONCLUSION: These are suggested to be active ingredients which are critical for the effectiveness of this BPD SHG, with particular focus on the facilitator's contribution. PMID- 28857640 TI - Smoking Cessation Among Methadone-Maintained Patients: A Meta-Analysis. AB - BACKGROUND: Nicotine use disorder is highly prevalent among methadone maintenance patients with its tobacco-related problems. However, the treatment modalities for nicotine use disorder remain limited. OBJECTIVE: Our meta-analysis aims to examine the effectiveness of smoking cessation treatment in this group of patients. METHODS: A total of 1358 participants were recruited from 9 eligible studies, published from the start of studies in this field till Feb 2016, identified from PubMed, OVID, EMBASE and Google Scholar databases. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria. Pooled odd ratios or weighted mean difference was performed using random effects. RESULTS: The treatments for smoking cessation among MMT patients are behavioral and pharmacological therapies. Smoking cessation was better achieved with nicotine replacement therapy (NRT) especially with adjunctive behavioral therapy. The pooled odds ratio of smokers' abstinence of smoking by the end of the treatment between NRT and placebo group was 6.32 (95% CI = 1.18 to 33.75, p = 0.03) and is statistically significant. Any additional behavior therapy among MMT patients who received the smoking cessation pharmacotherapy as the primary treatment was not better than those who only received standard care (Odds ratio was 2.53, 95% CI = 0.75 to 8.56, p = 0.14). CONCLUSIONS: Although NRT is proven to be effective in smoking cessation, more studies are warranted to prove the effects of other pharmacotherapy in smoking cessation. PMID- 28857641 TI - Safety Events in High Risk Prehospital Neonatal Calls. AB - OBJECTIVE: The objective of this study was to quantify and characterize patient safety events during high-risk neonatal transports in the prehospital setting. METHOD: We conducted a retrospective chart review of all "lights and sirens" ambulance transports of neonates <=30 days old over a four-year period in a metropolitan area. Each case was independently reviewed for potential patient safety events that may have occurred in clinical assessment and decision making, resuscitation, airway management, fluid or medication administration, procedures performed, and/or equipment used. RESULTS: Twenty-six patients <=30 days old were transported by ambulance using lights and sirens during the four-year study period. Overall, safety events occurred in 19 patients and severe safety events (potentially causing permanent injury or harm, including death) occurred in ten. The incidence of safety events related to medication administrations was 90% (70% severe), resuscitation 64.7% (47.1% severe), procedures 64.7% (35.3% severe), fluid administration 50% (25% severe), clinical assessment and decision making 50% (30.8% severe), airway management 47.6% (28.6% severe), equipment use 25.5% (10.0% severe), and systems processes 19.2% (7.7% severe). CONCLUSIONS: High-risk neonatal calls are infrequent and prone to a high incidence of serious patient safety events. PMID- 28857642 TI - Cerebral hemodynamics in the different phases of migraine and cluster headache. AB - Headache is one of the most common ailments; migraine is one of the most prevalent and disabling neurological disorders and cluster headache presents as one of the most excruciating pain disorders. Both are complex disorder characterized by recurrent episodes of headache. A key feature is that various triggers can set off an attack providing the opportunity to explore disease mechanisms by experimentally inducing attacks. This review summarizes neuroimaging and hemodynamic studies in human in provoked and spontaneous attacks of migraine and cluster headache. Cerebral hemodynamics during different phases of the migraine attack demonstrate alterations in cerebral blood flow and perfusion, vessel caliber, cortical and sub-cortical function, underscoring that migraine pathophysiology is highly complex. Migraine attacks might begin in diencephalic and brainstem areas, whereas migraine aura is a cortical phenomenon. In cluster headache pathophysiology, the hypothalamus might also play a pivotal role, whereas the pattern of cerebral blood flood differs from migraine. For both disorders, alterations of arterial blood vessel diameter might be more an epiphenomenon of the attack than a causative trigger. Studying cerebral hemodynamics in provocation models are important in the search for specific biomarkers in the hope to discover future targets for more specific and effective mechanism-based anti-headache treatment. PMID- 28857643 TI - Opioid Prescribing in Rural Family Practices: A Qualitative Study. AB - BACKGROUND: Rural Tennessee, especially rural East Tennessee has seen a dramatic increase in rates of controlled drug prescriptions and controlled drug overdose deaths in recent years. However, little is known about the individual decisions to prescribe or continue prescriptions with relation to addiction concerns. OBJECTIVES: The purpose of this study was to learn more about what factors lead to physicians' prescribing control drugs for non-cancer pain through the use of focus groups. METHODS: A qualitative study, using focus groups, in five family medicine clinics in East Tennessee and Southwest Virginia. The investigators used a semi-structured interview guide designed to facilitate group discussions about prescription drug abuse and misuse. RESULTS: There were four main themes identified by the focus groups: (1) prescribers' changing prescribing patterns over time; (2) factors that influence controlled drug prescribing; (3) use and barriers to using state prescription drug monitoring programs (PDMPs); (4) prescribing controlled drugs to women of childbearing age. Each theme had several subthemes. CONCLUSIONS: The balance between treating the patient's symptoms and causing potential harm is a challenge. The patient's pain cannot be ignored, but the potential harm of opioid therapy is not taken lightly. As the public health concern of prescription drug abuse in rural Appalachia continues to spread, prescribers are aware of their connection to the problem, and ultimately the solution. PMID- 28857644 TI - Recombinant scorpion toxins: Focus on four-disulfide peptide blockers of Kv1 channels. AB - We have recently developed a simple and effective bioengineering approach to large-scale production of alpha-KTx, peptide toxins from scorpion venoms, that block voltage-gated potassium channels with high affinity and specificity. This approach was successfully approved for different peptides containing three disulfide bonds. To extend this method to production of peptide toxins with four disulfide bridges, in particular, maurotoxin and hetlaxin, appropriate conditions of a cleavage reaction with tobacco etch virus (TEV) protease need to be found. For this, the interplay between efficiency of TEV hydrolysis and sensitivity of the target peptides to disulfide reducing agents was studied, and optimized protocols of TEV cleavage reaction were worked out. Maurotoxin and hetlaxin were produced in a folded form avoiding in vitro renaturation step with yields of 14 and 12 mg/liter of culture, respectively. PMID- 28857645 TI - Distinct modifications of hippocampal glucocorticoid receptor phosphorylation and FKBPs by lipopolysaccharide in depressive female and male rats. AB - Inflammation plays a critical role in pathogenesis of depression and can affect the hypothalamic-pituitary-adrenal axis activity. Accordingly, in this study we investigated the role of hippocampal glucocorticoid receptor in mediating the effects of inflammation on behaviour of female and male Wistar rats. We studied the effects of lipopolysaccharide on the levels of glucocorticoid receptors and its co-chaperones FK506 binding protein 52 and FK506 binding protein 51, the levels of glucocorticoid receptor phospho-isoforms, pGR-232 and pGR-246, and glucocorticoid receptor up-stream kinases. In order to assess transcriptional activity of glucocorticoid receptor, we measured mRNA levels of several glucocorticoid receptor-regulated genes. We demonstrated that lipopolysaccharide induced depressive-like behaviour and elevated serum corticosterone in both sexes. However, it affected glucocorticoid receptor signalling in the nucleus of females and males differently - in females it elevated levels of glucocorticoid receptors, pGR-246 and FK506 binding protein 52, while in males it decreased levels of glucocorticoid receptor, both co-chaperons and pGR-246. Alterations in pGR-246 were associated with alterations of c-Jun N-terminal kinases. Altered nuclear levels of total glucocorticoid receptors and pGR-246 were accompanied by sex-specific reduction in brain-derived neurotrophic factor and cyclooxygenase-2 mRNA and sex-unspecific reduction in the expression of p11 and glucocorticoid receptor genes. These alterations may ultimately affect different glucocorticoid receptor -associated processes involved in depressive-like behaviour in males and females. PMID- 28857646 TI - Posttraumatic Stress, Coping Flexibility, and Risky Drinking Among Trauma-Exposed Male and Female College Students: The Mediating Effect of Delay of Gratification. AB - BACKGROUND: The co-occurence of posttraumatic stress (PTS) and risky drinking has been demonstrated in diverse populations, including college students. However, the mechanisms underlying this co-occurrence, as well as the protective factors that may reduce risky drinking among trauma-exposed college students have yet to be fully understood in the literature. OBJECTIVES: The present study builds upon self-regulation theories and previous empirical work to determine whether the effects of PTS and coping flexibility on risky drinking were mediated by delay of gratification among trauma-exposed college students. In addition, the potential moderating effect of gender on these relationships was examined. METHODS: Participants included 624 trauma-exposed college students (68.4% female) attending a public university in the southeast region of the United States. Data were collected through an online survey. The hypothesized model was examined using a multigroup structural equation modeling approach. RESULTS: As hypothesized, PTS had a significant, positive indirect effect on risky drinking through delay of gratification; however, the effect of PTS on delay of gratification was stronger for males than for females. Results also indicated that the indirect effect of coping flexibility on risky drinking through delay of gratification was significant and negative for males and females. Conclusions/Importance: The findings of this study suggest that delay of gratification might be an important mechanism underlying the co-occurrence of PTS and risky drinking. In addition, our results highlight the potential benefits of coping flexibility for college students coping with PTS. PMID- 28857647 TI - EMS Dispatches during Hurricanes Irene and Sandy in New Jersey. AB - BACKGROUND: Hurricanes Irene and Sandy heavily impacted New Jersey. Investigating EMS dispatch trends during these storms may allow us to prepare for future disasters. OBJECTIVES: Our objectives to characterize the types of EMS dispatches immediately before, during, and after landfall compared to a control period. METHODS: This retrospective study was conducted at a large EMS dispatch center that provides first responders, Basic Life Support (BLS), Advanced Life Support (ALS), and critical care transport services to an area with approximately 20 receiving hospitals including a Level I Trauma Center. At peak staffing, there are 8-10 ALS vehicles, 25 BLS vehicles, and 3 critical care transport vehicles deployed. We included of the day of landfall and seven days before and after. We compared dispatch data to a control period in 2010 that mirrored Hurricane Sandy the dates of. Descriptive statistics and two way ANOVA were used to assess dispatch, gender and age differences. RESULTS: We found Hurricane Sandy dispatches peaked 2 days after landfall. Both ALS and BLS had an increase in age in the post-Sandy period compared to the pre-Sandy (ALS 58.5 to 64.2, p = 0.005, ANOVA p = 0.078; BLS 47.4 to 56.3, p < 0.001, ANOVA p = 0.001). There were 17 "hurricane related" (loss of power related issues, oxygen supply depleted, evacuation) and 15 carbon monoxide dispatches in the post-Sandy period and none in the others, including peri-Irene. The average age of cardiac arrest dispatches was lower in the post-Irene group compared to pre-Irene (74.3 to 47.8, p = 0.023). There were no critical care requests before or after Hurricane Sandy, but there were 14 around Hurricane Irene and 10 surrounding the control period. CONCLUSIONS: Dispatch data can inform natural disaster planning. Education efforts can focus on geriatric patients, as well as resource distribution planning for an increase in geriatric populations. However, pattern variability between storms shows further study is needed to clarify exactly which resources should be utilized in order to maintain an ideal response to a natural disaster. PMID- 28857648 TI - Impact of clinical utility of MRD assessment with different techniques on survival in acute B lymphoblastic leukemia. AB - We investigated the impact of minimal residual disease (MRD) obtained from different approaches on the outcomes of 141 B lymphoblastic leukemia (B-ALL) patients. Among 169 samples with more than 5% blasts by morphology, 3.6% (6/169) were Flow-MRD negative. Of the 212 positive molecular-MRD samples from Ph+ ALL patients, 55 (25.9%) were Flow-MRD negative. Before consolidation or allogeneic stem cell transplantation (allo-HSCT), negative Flow-MRD was associated with improved survival (p = .019 and .041, respectively) for Ph- ALL patients, but not for Ph+ ALL (p = .111 and .812, respectively). There was no difference in overall survival (OS) by achievement of complete molecular response at complete remission (CR, p = .333 and .863, respectively). Our results indicated that the results of MRDs detected with different methods varied. Flow-MRD can be used as a reliable prognostic marker for Ph- ALL patients. MRD either by flow cytometry or quantitative reverse transcription-polymerase chain reaction (qRT-PCR) at CR did not affect OS or DFS for Ph+ ALL. PMID- 28857650 TI - Going global: do consumer preferences, attitudes, and barriers to using e-mental health services differ across countries? AB - BACKGROUND: e-Mental health services have the capacity to overcome barriers to care and reduce the unmet need for psychological services, particularly in developing countries. However, it is unknown how acceptable e-mental health interventions may be to these populations. AIMS: The purpose of the current study was to examine consumer attitudes and perceived barriers to e-mental health usage across four countries: Australia, Iran, the Philippines and South Africa. METHODS: An online survey was completed by 524 adults living in these countries, assessing previous contact with e-mental health services, willingness to use e mental health services, and perceived barriers and needs for accessing e-mental health services. RESULTS: Although previous contact with e-mental health services was low, the majority of respondents in each sample reported a willingness to try e-mental health services if offered. Barriers toward e-mental health usage were higher among the developing countries than Australia. The most commonly endorsed barriers concerned needing information and assurances regarding the programmes. CONCLUSIONS: Across countries, participants indicated a willingness to use e mental health programmes if offered. With appropriate research and careful implementation, e-mental health has the potential to be a valuable part of mental healthcare in developing countries. PMID- 28857649 TI - Immune responses to oral poliovirus vaccine in HIV-exposed uninfected Zimbabwean infants. AB - It remains uncertain whether HIV-exposed uninfected (HEU) infants have impaired responses to oral vaccines. We performed a cross-sectional study of 6-month-old infants recruited at birth to the ZVITAMBO trial in Zimbabwe between 1997-2001, before introduction of prevention of mother-to-child transmission interventions. We measured poliovirus-specific IgA to type 1-3 polio strains by semi quantitative capture ELISA in cryopreserved serum samples collected from 85 HEU and 101 HIV-unexposed infants at 6 months of age, one month after their last immunisation with trivalent OPV. Almost all infants were breastfed, with the majority in both groups mixed breastfed (70.6% HEU versus 71.3% HIV-unexposed). Median (IQR) vaccine titers for HEU and HIV-unexposed infants were 1592 (618 4896) vs. 1774 (711-5431) for Sabin 1 (P = 0.46); 1895 (810-4398) vs. 2308 (1081 4283) for Sabin 2 (P = 0.52); and 1798 (774-4192) vs. 2260 (996-5723) for Sabin 3 (P = 0.18). There were no significant differences in vaccine titers between HEU and HIV-unexposed infants, suggesting that vertical HIV exposure does not impact oral poliovirus vaccine immunogenicity. PMID- 28857651 TI - Gray matter structural networks are associated with cardiovascular risk factors in healthy older adults. AB - While recent 'big data' analyses discovered structural brain networks that alter with age and relate to cognitive decline, identifying modifiable factors that prevent these changes remains a major challenge. We therefore aimed to determine the effects of common cardiovascular risk factors on vulnerable gray matter (GM) networks in a large and well-characterized population-based cohort. In 616 healthy elderly (258 women, 60-80 years) of the LIFE-Adult-Study, we assessed the effects of obesity, smoking, blood pressure, markers of glucose and lipid metabolism as well as physical activity on major GM-networks derived using linked independent component analysis. Age, sex, hypertension, diabetes, white matter hyperintensities, education and depression were considered as confounders. Results showed that smoking, higher blood pressure, and higher glycated hemoglobin (HbA1c) were independently associated with lower GM volume and thickness in GM-networks that covered most areas of the neocortex. Higher waist to-hip ratio was independently associated with lower GM volume in a network of multimodal regions that correlated negatively with age and memory performance. In this large cross-sectional study, we found selective negative associations of smoking, higher blood pressure, higher glucose, and visceral obesity with structural covariance networks, suggesting that reducing these factors could help to delay late-life trajectories of GM aging. PMID- 28857652 TI - Safety testing of acellular pertussis vaccines: Use of animals and 3Rs alternatives. AB - The current test of acellular Bordetella pertussis (aP) vaccines for residual pertussis toxin (PTx) is the Histamine Sensitization test (HIST), based on the empirical finding that PTx sensitizes mice to histamine. Although HIST has ensured the safety of aP vaccines for years, it is criticized for the limited understanding of how it works, its technical difficulty, and for animal welfare reasons. To estimate the number of mice used worldwide for HIST, we surveyed major aP manufacturers and organizations performing, requiring, or recommending the test. The survey revealed marked regional differences in regulatory guidelines, including the number of animals used for a single test. Based on information provided by the parties surveyed, we estimated the worldwide number of mice used for testing to be 65,000 per year: ~48,000 by manufacturers and ~17,000 by national control laboratories, although the latter number is more affected by uncertainty, due to confidentiality policies. These animals covered the release of approximately 850 final lots and 250 in-process lots of aP vaccines yearly. Although there are several approaches for HIST refinement and reduction, we discuss why the efforts needed for validation and implementation of these interim alternatives may not be worthwhile, when there are several in vitro alternatives in various stages of development, some already fairly advanced. Upon implementation, one or more of these replacement alternatives can substantially reduce the number of animals currently used for the HIST, although careful evaluation of each alternative's mechanism and its suitable validation will be necessary in the path to implementation. PMID- 28857654 TI - Effects of antidepressant therapy on neural components of verbal working memory in depression. AB - Impairments in verbal working memory are evident in major depression. Verbal working memory is comprised of the components of encoding, maintenance and retrieval. Whether the neural impairments are expressed in specific components, and how pharmacological therapy could modify the neural correlates are not well understood. We investigated the neural correlates of verbal working memory components in depression using the Sternberg task in a longitudinal magnetic resonance imaging study. Serial scans were acquired in 23 patients (mean age 39.8 years) during an acute depressive episode and following 12 weeks of pharmacological therapy with duloxetine and in 22 matched healthy controls (mean age 39.1 years) at the same time points. A significant group by time interaction was evident during the long maintenance phase, extending from the left middle frontal to the middle temporal and caudate regions, in which there was reduced activation in healthy participants at the follow -up scan but there were no changes in patients. Persistent neural engagement during the maintenance phase following treatment was revealed in major depression. The findings emphasize that impairments in verbal working memory may be initiated in the maintenance phase in major depression in order to sustain performance. Further research with larger sample size and using randomized, placebo-controlled double-blind studies are required to confirm our results. PMID- 28857653 TI - Polo-like kinase 3, hypoxic responses, and tumorigenesis. AB - The cellular hypoxic response contributes to cell transformation and tumor progression. Hypoxia-inducible factor 1 (HIF-1) is a key transcription factor that mediates transcription of genes whose products are essential for cellular adaptation to hypoxia. The activity of HIF-1 is largely regulated by the abundance of its alpha subunit (HIF-1alpha), which is primarily regulated by an oxygen-dependent and ubiquitin/proteasome-mediated degradation process. The HIF 1alpha protein level is also regulated by protein kinases through phosphorylation. Polo-like kinase 3 (Plk3) is a serine/threonine protein kinase with a tumor suppressive function. Plk3 phosphorylates and destabilizes HIF 1alpha. Plk3 also phosphorylates and stabilizes PTEN, a known regulator of HIF 1alpha stability via the PI3K pathway. Our latest study showed that the Plk3 protein is suppressed by hypoxia or nickel treatment via the ubiquitin/proteasome system. We discovered that Seven in Absentia Homologue 2 (SIAH2) is the E3 ubiquitin ligase of Plk3 and that Plk3 in turn destabilizes SIAH2. Given the role of SIAH2 in promoting stability of HIF-1alpha, our work reveals a novel mutual regulatory mechanism between Plk3 and SIAH2, which may function to fine-tune the cellular hypoxic response. Here we discuss the role of Plk3 in the hypoxic response and tumorigenesis in light of these latest findings. PMID- 28857655 TI - Prevalence analysis of urinary incontinence after radical prostatectomy and influential preoperative factors in a single institution. AB - AIMS: To assess prevalence of urinary incontinence (UI) after radical prostatectomy (RP) and to analyze which preoperative characteristics of the patients have influence on UI. METHODS: Between 2002 and 2012, 746 consecutive patients underwent RP for clinically localized prostate cancer. We defined UI according to International Continence Society (ICS) definition: "the complaint of any involuntary leakage of urine" after 12 months of recovery, international consultation on incontinence questionnaire (ICIQ-SF) and pads/day was collected too. Clinical features and magnetic resonance imaging measurements were assessed. A multivariable logistic regression model predicting incontinence were built-in after adjust by cofounding factors and bootstrapping. RESULTS: About 172 (23%) of the patients were classified as incontinent according to the ICS definition. The mean value of the ICIQ-SF was 10.87 (+/-4). 17.8% of patients use at least one pad/day, 11.9% use more than one pad/day. The preoperative factors independently influential in UI are: age [OR: 1.055; CI 95% (1.006-1.107), p = .028], urethral wall thickness [OR: 5.03; CI 95% (1.11-22.8), p = .036], history of transurethral resection of the prostate [OR: 6.13; CI 95% (1.86-20.18), p = .003] and membranous urethral length [OR: 0.173; CI 95% (0.046-0.64), p = .009]. The predictive accuracy of the model is 78.7% and the area under the curve (AUC) value 71.7%. CONCLUSIONS: Urinary incontinence after radical prostatectomy has different prevalence depending on the definition. Age, prior transurethral resection of the prostate (TURP), membranous urethral length (MUL) and urethral wall thickness (UWT) were risk factors. PMID- 28857656 TI - Diaphragm reconstruction combined with thoraco-abdominal wall reconstruction after tumor resection. AB - BACKGROUND: Thoraco-abdominal wall resection including diaphragm resection results in a challenging surgical defect. Various methods have been used for diaphragm reconstruction. The aim of this study was to describe our methods of diaphragm and thoraco-abdominal wall reconstruction after combined resection of these anatomical structures. METHODS: Twenty-one patients underwent diaphragm resection at our institution between 1997 and 2015. We used a mesh or direct closure for diaphragm defect and a mesh for chest wall stabilization. A pedicled or free flap for soft tissue coverage was used when direct closure was not possible. RESULTS: Indications for resection were primary sarcoma (n = 14), cancer metastasis (n = 4), desmoid tumor (n = 2), and solitary fibrous tumor (n = 1). The median patient age was 58.9 years. The diaphragm was pulled to its original position and sutured directly (n = 15) or reconstructed with mesh (n = 6). Chest wall reconstructions were performed with a mesh (n = 14), mesh and a pedicled flap (n = 4), mesh and a free flap (n = 3). No perioperative mortality occurred. One-year and 5-year survival rates were 85.7 and 65.9%, respectively, while overall recurrence-free rates were 80.4 and 60.8%, respectively. CONCLUSIONS: We have described our surgical methods for the resection of tumors of the chest or abdominal wall, including our method of distal diaphragm resection with wide or clear surgical margins. The method is safe and the reconstructions provided adequate stability, as well as water-tight and air-tight closure of the chest cavity. There were no cases of paradoxical movement of the chest or of diaphragm or thoraco-abdominal hernia. PMID- 28857657 TI - Opioid system contribution to the antidepressant-like action of m-trifluoromethyl diphenyl diselenide in mice: A compound devoid of tolerance and withdrawal syndrome. AB - Animal and clinical researches indicate that the opioid system exerts a crucial role in the etiology of mood disorders and is a target for intervention in depression treatment. This study investigated the contribution of the opioid system to the antidepressant-like action of acute or repeated m-trifluoromethyl diphenyl diselenide administration to Swiss mice. m-Trifluoromethyl-diphenyl diselenide (50 mg/kg, intragastric) produced an antidepressant-like action in the forced swimming test from 30 min to 24 h after treatment. This effect was blocked by the u and delta-opioid receptor antagonists, naloxonazine (10 mg/kg, intraperitoneally) and naltrindole (3 mg/kg, intraperitoneally), and it was potentiated by a kappa-opioid receptor antagonist, norbinaltrophimine (1 mg/kg, subcutaneously ). Combined treatment with subeffective doses of m-trifluoromethyl diphenyl diselenide (10 mg/kg, intragastric) and morphine (1 mg/kg, subcutaneously) resulted in a synergistic antidepressant-like effect. The opioid system contribution to the m-trifluoromethyl-diphenyl diselenide antidepressant like action was also demonstrated in the modified tail suspension test, decreasing mouse immobility and swinging time and increasing curling time, results similar to those observed using morphine, a positive control. Treatment with m-trifluoromethyl-diphenyl diselenide induced neither tolerance to the antidepressant-like action nor physical signs of withdrawal, which could be associated with the fact that m-trifluoromethyl-diphenyl diselenide did not change the mouse cortical and hippocampal glutamate uptake and release. m Trifluoromethyl-diphenyl diselenide treatments altered neither locomotor nor toxicological parameters in mice. These findings demonstrate that m trifluoromethyl-diphenyl diselenide elicited an antidepressant-like action by direct or indirect MU and delta-opioid receptor activation and the kappa-opioid receptor blockade, without inducing tolerance, physical signs of withdrawal and toxicity. PMID- 28857659 TI - Cytocompatibility and biologic characteristics of synthetic scaffold materials of rabbit acellular vascular matrix combining with human-like collagen I. AB - Scaffold material provides a three-dimensional growing environment for seed cells in the research field of tissue engineering. In the present study, rabbit arterial blood vessel cells were chemically removed with trypsin and Triton X-100 to prepare rabbit acellular vascular matrix scaffold material. Observation by He&Masson staining revealed that no cellular components or nuclei existed in the vascular intima and media after decellularization. Human-like collagen I was combined with acellular vascular matrix by freeze-drying to prepare an acellular vascular matrix-0.25% human-like collagen I scaffold to compensate for the extracellular matrix loss during the decellularization process. We next performed a series of experiments to test the water absorbing quality, biomechanics, pressure resistance, cytotoxicity, and ultra-micro structure of the acellular vascular matrix composite material and natural rabbit artery and found that the acellular vascular matrix-0.25% human-like collagen I material behaved similarly to natural rabbit artery. In conclusion, the acellular vascular matrix-0.25% human-like collagen I composite material provides a new approach and lays the foundation for novel scaffold material research into tissue engineering of blood vessels. PMID- 28857658 TI - Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial. AB - BACKGROUND: Evidence suggests that anti-inflammatory medication may be effective in the treatment of depressive symptoms. In this study, we aimed to investigate whether minocycline added to treatment as usual (TAU) for 3 months in patients with treatment-resistant depression will lead to an improvement in depressive symptoms. METHODS: Multi-site, 12-week, double-blind, placebo-controlled, pilot trial of minocycline added to TAU for patients suffering from DSM-5 major depressive disorder, whose current episode has failed to respond to at least two antidepressants. The primary outcome measure was mean change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 12. Secondary measures were the Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder scale (GAD-7) and EuroQoL (EQ-5D) quality-of-life questionnaire. Side-effect checklists were also used. Minocycline was started at 100 mg once daily (OD) and increased to 200 mg after 2 weeks. RESULTS: A total of 41 participants were randomised, with 21 in the minocycline group and 20 in the placebo group. A large decrease in HAMD scores was observed in the minocycline group compared to the placebo group (standardised effect size (ES) -1.21, p < 0.001). CGI scores in the minocycline group also showed a large improvement compared with placebo (odds ratio (OR): 17.6, p < 0.001). PHQ-9, GAD-7 and EQ-5D total showed more moderate improvements (ES ~ 0.4-0.5). CONCLUSION: The findings indicate that adjunctive minocycline leads to improvement in symptoms of treatment-resistant depression. However, our findings require replication in a larger sample. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02263872, registered October 2014. PMID- 28857660 TI - Comparison between the univariate and multivariate analysis on the partial characterization of the endoglucanase produced in the solid state fermentation by Aspergillus oryzae ATCC 10124. AB - Endoglucanase production by Aspergillus oryzae ATCC 10124 cultivated in rice husks or peanut shells was optimized by experimental design as a function of humidity, time, and temperature. The optimum temperature for the endoglucanase activity was estimated by a univariate analysis (one factor at the time) as 50 degrees C (rice husks) and 60 degrees C (peanut shells), however, by a multivariate analysis (synergism of factors), it was determined a different temperature (56 degrees C) for endoglucanase from peanut shells. For the optimum pH, values determined by univariate and multivariate analysis were 5 and 5.2 (rice husk) and 5 and 7.6 (peanut shells). In addition, the best half-lives were observed at 50 degrees C as 22.8 hr (rice husks) and 7.3 hr (peanut shells), also, 80% of residual activities was obtained between 30 and 50 degrees C for both substrates, and the pH stability was improved at 5-7 (rice hulls) and 6-9 (peanut shells). Both endoglucanases obtained presented different characteristics as a result of the versatility of fungi in different substrates. PMID- 28857661 TI - Identification of novel RNA isoforms of LMNA. AB - The nuclear lamina is a proteinaceous meshwork situated underneath the inner nuclear membrane and is composed of nuclear lamin proteins, which are type-V intermediate filaments. The LMNA gene gives rise to lamin A and lamin C through alternative splicing. Mutations in LMNA cause multiple diseases known as laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disorder caused by a point mutation that activates a cryptic 5' splice site in exon 11, resulting in a 150 bp deletion in the LMNA mRNA and the production of the dominant lamin A isoform progerin. During RNA sequencing analysis of wild type and HGPS patient skin fibroblasts, we discovered two novel LMNA isoforms. LMNADelta447 and LMNADelta297 use an alternative 3' splice acceptor site in the 3' untranslated region, and either the HGPS cryptic 5' splice site in exon 11 or the wild type 5' splice site. Both isoforms are present at low levels in HGPS patient and wild type cells in multiple cell types. We validate and quantify the expression levels of these novel isoforms in HGPS and wild type fibroblasts. Overexpression of either LMNADelta447 or LMNADelta297 is not sufficient to induce the typical HGPS cellular disease phenotypes and no significant difference in the two isoforms were found between young and old fibroblasts. These results identify and characterize two novel RNA isoforms of LMNA produced through alternative splicing. PMID- 28857662 TI - Enhanced production of total flavones from Inonotus baumii by multiple strategies. AB - As one kind of important secondary metabolites produced by Inonotus baumii, flavones can be applied in food, medicine, and other industries due to their biological activities such as antioxidant, anticancer, and antibacterial activity. To enhance total flavone production in submerged fermentation of I. baumii, three different strategies, optimization of fermentation parameters by statistical designs including Plackett-Burman design and response surface methodology, addition of precursors and elicitors, and two-phase culture, were used. The production of total flavones (PTF) reached 1532.83 mg/L when the optimized medium was used. All precursors and elicitors can increase the PTF. The maximum PTF (2184.06 mg/L, up to 1.57-fold) was obtained with the addition of both AgNO3 and glutathione in fermentation media. Interestingly, when 0.5% (w/v) DM130 macroporous resin as adsorbent was added to fermentation broth on day 4 of culture, the highest production reached 2407.79 mg/L with this two-phase culture strategy. These methods can be further applied to large-scale industrial production and broaden the application of flavones. PMID- 28857664 TI - The role of pupil size in communication. Is there room for learning? AB - The eyes are extremely important for communication. The muscles around the eyes express emotional states and the size of the pupil signals whether a person is aroused and alert or bored and fatigued. Pupil size is an overlooked social signal, yet is readily picked up by observers. Observers mirror their own pupil sizes in response, which can influence social impressions. In a landmark study by Hess [1975. The role of pupil size in communication. Scientific American, 233(5), 110-119] it was shown that individuals with large pupils are perceived more positively than individuals with small pupils. In that behavioral study, participants were asked to draw pupils in line drawings of faces with empty irises and they drew large pupils in the happy face, and small ones in the angry face. The current study tested 579 participants (aged 4-80 years old) and extended this work by showing that this association between large (small) pupils and a positive (negative) impression develops over age and is absent in children. Several explanations for how individuals through interactions with close others learn that large pupils mean care, interest and attention and small pupils the opposite, are discussed. To conclude, this study shows that pupil size and emotion perception are intertwined but that their relationship develops over age. PMID- 28857663 TI - Extraction, purification, and biochemical characterization of serine protease from leaves of Abrus precatorius. AB - A protease from fresh leaves of Abrus precatorius was purified using two classical chromatography techniques: ion-exchange (DEAE-Sepharose) and Gel filtration (Sephadex G-75). The purified protease showed a molecular weight of ~ 28 kDa on sodium dodecyl sulfate polyacrylamide gel electrophoresis. The optimum pH and temperature for the purified protease was 8 and 40 degrees C, respectively. The purified protease was stable throughout a wide temperature range from 10 to 80 degrees C and pH from 2 to 12. Protease activity was inhibited in the presence of Co2+, Ni2+, Hg2+, and Zn2+ while its activity has increased in the presence of Ca2+ and Mg2+. The protease was highly specific to casein when compared to its specificity for gelatin, bovine serum albumin, hemoglobin, and defatted flour of Ricinodendron heudelotii. Its Vmax and Km determined using casein as a substrate were 94.34 U/mL and 349.07 ug/mL respectively. Inhibition studies showed that this purified protease was inhibited by both phenylmethane sulfonyl fluoride and aprotinin which are recognized as competitive inhibitors of serine proteases. PMID- 28857665 TI - Efficient bioconversion from acid hydrolysate of waste oleaginous yeast biomass after microbial oil extraction to bacterial cellulose by Komagataeibacter xylinus. AB - Biomass acid hydrolysate of oleaginous yeast Trichosporon cutaneum after microbial oil extraction was applied as substrate for bacterial cellulose (BC) production by Komagataeibacter xylinus (also named as Gluconacetobacter xylinus previously) for the first time. BC was synthesized in static culture for 10 days, and the maximum BC yield (2.9 g/L) was got at the 4th day of fermentation. Most carbon sources in the substrate (glucose, mannose, formic acid, acetic acid) can be utilized by K. xylinus. The highest chemical oxygen demand (COD) removal (40.7 +/- 3.0%) was obtained at the 6th day of fermentation, and then the COD increased possibly due to the degradation of BC. The highest BC yield on COD consumption was 38.7 +/- 4.0% (w/w), suggesting that this is one efficient bioconversion for BC production. The BC structure was affected little by the substrate by comparison with that generated in classical HS medium using field-emission scanning electron microscope (FE-SEM), Fourier transform infrared, and X-ray diffraction. Overall, this technology can both solve the issue of waste oleaginous yeast biomass and produce valuable biopolymer (BC). PMID- 28857667 TI - Spatiotemporal heterogeneity of tomato induced defense responses affects spider mite performance and behavior. AB - When feeding from tomato (Solanum lycopersicum), the generalist spider mite Tetranychus urticae induces jasmonate (JA)- and salicylate (SA)-regulated defense responses that hamper its performance. The related T. evansi, a Solanaceae specialist, suppresses these defenses, thereby upholding a high performance. On a shared leaf, T. urticae can be facilitated by T. evansi, likely via suppression of defenses by the latter. Yet, when infesting the same plant, T. evansi outcompetes T. urticae. Recently, we found that T. evansi intensifies suppression of defenses locally, i.e., at its feeding site, after T. urticae mites were introduced onto adjacent leaf tissue. This hyper-suppression is paralleled by an increased oviposition rate of T. evansi, probably promoting its competitive population growth. Here we present additional data that not only provide insight into the spatiotemporal dynamics of defense induction and suppression by mites, but that also suggest T. evansi to manipulate more than JA and SA defenses alone. PMID- 28857668 TI - MALAT1/miR-124/Capn4 axis regulates proliferation, invasion and EMT in nasopharyngeal carcinoma cells. AB - BACKGROUND: Long non-coding RNA MALAT1 (Metastasis-associated lung Adenocarcinoma transcript-1) has been demonstrated to play a critical role in the regulation of cancer progression and metastasis. However, little is known about MALAT1 in nasopharyngeal carcinoma (NPC) pathogenesis and progression. METHODS: Quantitative real-time PCR (qRT-PCR) was conducted to measure the expression of MALAT1, miR-124 and Capn4 mRNA in NPC cell lines. The protein level of Capn4 was examined by western blot analysis. Cell proliferation was detected by MTT assay, trypan blue exclusion method and colony formation analysis. Cell invasion was determined by transwell chamber assay. Expression of EMT-related proteins was detected by western blot. The potential targets of MALAT1 and miR-124 were verified by target prediction and luciferase reporter assay. RESULTS: MALAT1 and Capn4 were upregulated while miR-124 expression was downregulated in NPC cell lines. MALAT1 knockdown inhibited proliferation, invasion and EMT of NPC cells. Moreover, MALAT1 improved Capn4 expression by sponging miR-124. MALAT1 upregulation abated miR-124-induced repression on NPC cell proliferation, invasion and EMT. Furthermore, Capn4 overexpression reversed the inhibitory effect of MALAT1 silencing on proliferation, invasion and EMT of NPC cells. CONCLUSION: MALAT1 promoted proliferation, invasion and EMT of NPC cells through de-repressing Capn4 by sponging miR-124. The present study revealed a novel MALAT1/miR-124/Capn4 regulatory axis in NPC, contributing to a better understanding of the NPC pathogenesis and providing a promising therapeutic target for NPC therapy. PMID- 28857670 TI - Quantitative real-time PCR technique for the identification of E. coli residual DNA in streptokinase recombinant product. AB - Recombinant streptokinase is a biopharmaceutical which is usually produced in E. coli. Residual DNA as a contamination and risk factor may remain in the product. It is necessary to control the production procedure to exclude any possible contamination. The aim of the present study was to develop a highly specific and sensitive quantitative real-time PCR-based method to determine the amount of E. coli DNA in recombinant streptokinase. A specific primers and a probe was designed to detect all strains of E. coli. To determine the specificity, in addition to using NCBI BLASTn, 28 samples including human, bacterial, and viral genomes were used. The results confirmed that the assay detects no genomic DNA but E. coli's and the specificity was determined to be 100%. To determine the sensitivity and limit of detection of the assay, a 10-fold serial dilution (101 to 107 copies/uL) was tested in triplicate. The sensitivity of the test was determined to be 101 copies/uL or 35 fg/uL. Inter-assay and intra-assay were determined to be 0.86 and 1.69%, respectively. Based on the results, this assay can be used as an accurate method to evaluate the contamination of recombinant streptokinase in E. coli. PMID- 28857666 TI - Cancer vaccines: Enhanced immunogenic modulation through therapeutic combinations. AB - Therapeutic cancer vaccines have gained significant popularity in recent years as new approaches for specific oncologic indications emerge. Three therapeutic cancer vaccines are FDA approved and one is currently approved by the EMA as monotherapy with modest treatment effects. Combining therapeutic cancer vaccines with other treatment modalities like radiotherapy (RT), hormone therapy, immunotherapy, and/or chemotherapy have been investigated as a means to enhance immune response and treatment efficacy. There is growing preclinical and clinical data that combination of checkpoint inhibitors and vaccines can induce immunogenic intensification with favorable outcomes. Additionally, novel methods for identifying targetable neoantigens hold promise for personalized vaccine development. In this article, we review the rationale for various therapeutic combinations, clinical trial experiences, and future directions. We also highlight the most promising developments that could lead to approval of novel therapeutic cancer vaccines. PMID- 28857669 TI - Evaluation of extraction methods for the identification of proteins from date palm (Phoenix dactylifera L.) seed and flesh. AB - Date fruits are well known to be very nutritious. Nevertheless, the protein contents of the fruit, particularly the seed and flesh, are still understudied, largely due to their difficult physical characteristics. This study was conducted to compare three different protein extraction methods which were the trichloroacetic acid (TCA)-acetone (TCA-A), phenol (Phe), and TCA-acetone-phenol (TCA-A-Phe), and to perform proteomic analysis on date palm seed and flesh. Phe extraction method showed the highest protein yields for both seed (8.26 mg/g) and flesh (1.57 mg/g). Through sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Phe, and TCA-A-Phe extraction methods were shown to be efficient in removing interfering compounds and gave well-resolved bands over a wide range of molecular weights. Following liquid chromatography-tandem mass spectrometry analysis, about 50-64% of extracted proteins were identified with known functions including those involved in glycolysis, Krebs cycle, defense, and storage. Phe protein extraction method was proven to be the optimal method for date flesh and seed. PMID- 28857672 TI - Neurophysiological evidence (ERPs) for hemispheric processing of facial expressions of emotions: Evidence from whole face and chimeric face stimuli. AB - This study was designed to investigate the patterns of electrophysiological responses of early emotional processing at frontocentral sites in adults and to explore whether adults' activation patterns show hemispheric lateralization for facial emotion processing. Thirty-five adults viewed full face and chimeric face stimuli. After viewing two faces, sequentially, participants were asked to decide which of the two faces was more emotive. The findings from the standard faces and the chimeric faces suggest that emotion processing is present during the early phases of face processing in the frontocentral sites. In particular, sad emotional faces are processed differently than neutral and happy (including happy chimeras) faces in these early phases of processing. Further, there were differences in the electrode amplitudes over the left and right hemisphere, particularly in the early temporal window. This research provides supporting evidence that the chimeric face test is a test of emotion processing that elicits right hemispheric processing. PMID- 28857671 TI - Effect of Cuscuta campestris parasitism on the physiological and anatomical changes in untreated and herbicide-treated sugar beet. AB - The effects of field dodder on physiological and anatomical processes in untreated sugar beet plants and the effects of propyzamide on field dodder were examined under controlled conditions. The experiment included the following variants: N-noninfested sugar beet plants (control); I - infested sugar beet plants (untreated), and infested plants treated with propyzamide (1500 g a.i. ha 1 (T1) and 2000 g a.i. ha-1(T2)). The following parameters were checked: physiological-pigment contents (chlorophyll a, chlorophyll b, total carotenoids); anatomical -leaf parameters: thickness of epidermis, parenchyma and spongy tissue, mesophyll and underside leaf epidermis, and diameter of bundle sheath cells; petiole parameters: diameter of tracheid, petiole hydraulic conductance, xylem surface, phloem cell diameter and phloem area in sugar beet plants. A conventional paraffin wax method was used to prepare the samples for microscopy. Pigment contents were measured spectrophotometrically after methanol extraction. All parameters were measured: prior to herbicide application (0 assessment), then 7, 14, 21, 28 and 35 days after application (DAA). Field dodder was found to affect the pigment contents in untreated sugar beet plants, causing significant reductions. Conversely, reduction in the treated plants decreased 27% to 4% for chlorophyll a, from 21% to 5% for chlorophyll b, and from 28% to 5% for carotenoids (T1). Also, in treatment T2, reduction decreased in infested and treated plants from 19% to 2% for chlorophyll a, from 21% to 2% for chlorophyll b, from 23% to 3% for carotenoids and stimulation of 1% and 2% was observed 28 and 35 DAA, respectively. Plants infested (untreated) by field dodder had lower values of most anatomical parameters, compared to noninfested plants. The measured anatomical parameters of sugar beet leaves and petiole had significantly higher values in noninfested plants and plants treated with propyzamide than in untreated plants. Also, the results showed that propyzamide is an adequate herbicide for control of field dodder at the stage of early infestation. PMID- 28857673 TI - ASVAC2017: 6th Asian Vaccine Conference. PMID- 28857674 TI - Pelvic venous reflux in males with varicose veins and recurrent varicose veins. AB - Objectives To report on a male cohort with pelvic vein reflux and associated primary and recurrent lower limb varicose veins. Methods Full lower limb duplex ultrasonography revealed significant pelvic contribution in eight males presenting with bilateral lower limb varicose veins. Testicular and internal iliac veins were examined with either one or a combination of computed tomography, magnetic resonance venography, testicular, transabdominal or transrectal duplex ultrasonography. Subsequently, all patients received pelvic vein embolisation, prior to leg varicose vein treatment. Results Pelvic vein reflux was found in 23 of the 32 truncal pelvic veins and these were treated by pelvic vein embolisation. Four patients have since completed their leg varicose vein treatment and four are undergoing leg varicose vein treatments currently. Conclusion Pelvic vein reflux contributes towards lower limb venous insufficiency in some males with leg varicose veins. Despite the challenges, we suggest that pelvic vein reflux should probably be investigated and pelvic vein embolisation considered in such patients. PMID- 28857675 TI - Plant-Herbivore Interactions: A Case of an Extreme Generalist, the Two-Spotted Spider Mite Tetranychus urticae. AB - Plant-herbivore interactions evolved over long periods of time, resulting in an elaborate arms race between interacting species. While specialist herbivores evolved specific strategies to cope with the defenses of a limited number of hosts, our understanding of how generalist herbivores deal with the defenses of a plethora of diverse host plants is largely unknown. Understanding the interaction between a plant host and a generalist herbivore requires an understanding of the plant's mechanisms aimed at defending itself and the herbivore's mechanisms intended to counteract diverse defenses. In this review, we use the two-spotted spider mite (TSSM), Tetranychus urticae (Koch) as an example of a generalist herbivore, as this chelicerate pest has a staggering number of plant hosts. We first establish that the ability of TSSM to adapt to marginal hosts underlies its polyphagy and agricultural pest status. We then highlight our understanding of direct plant defenses against spider mite herbivory and review recent advances in uncovering mechanisms of spider mite adaptations to them. Finally, we discuss the adaptation process itself, as it allows TSSM to overcome initially effective plant defenses. A high-quality genome sequence and developing genetic tools, coupled with an ease of mite experimental selection to new hosts, make TSSM an outstanding system to study the evolution of host range, mechanisms of pest xenobiotic resistance and plant-herbivore interactions. In addition, knowledge of plant defense mechanisms that affect mite fitness are of practical importance, as it can lead to development of new control strategies against this important agricultural pest. In parallel, understanding mechanisms of mite counter adaptations to these defenses is required to maintain the efficacy of these control strategies in agricultural practices. PMID- 28857676 TI - Purification and characterization of cutinase from Bacillus sp. KY0701 isolated from plastic wastes. AB - A total of approximately 400 bacterial strains were isolated from 73 plastic wastes collected from 14 different regions. Nineteen isolates that form clear zones both on tributyrin and poly epsilon-caprolactone (PCL) agar, were identified based on 16S rRNA gene sequences. Among these, Bacillus sp. KY0701 that caused the highest weight loss of PCL films in minimal salt medium, was selected for cutinase production. The highest enzyme activity (15 U/mL) was obtained after 4 days of incubation at 50 degrees C, pH 7.0 and 200 rpm in a liquid medium containing 1.5% (w/v) apple cutin and 0.1% (w/v) yeast extract. The purified enzyme was stable at high temperatures (50-70 degrees C) and over a wide pH range (5.5-9.0). The relative activity of cutinase was at least 75% in the percent of various organic solvents. The apparent Km and Vmax values of the cutinase for p-nitrophenyl butyrate were 0.72 mM and 336.8 umol p nitrophenol/h/g, respectively. In addition, it showed high stability and compatibility with commercial detergents. These features of cutinase obtained from Bacillus sp. KY0701 make it a promising candidate for application in the detergent and chemical industries. In our best knowledge, this is the first report for cutinase production and characterization produced by a Bacillus strain. PMID- 28857677 TI - Is seasonal vaccination a contributing factor to the selection of influenza epidemic variants? AB - Influenza A/H3N2 viruses are the most common and virulent subtypes for humans. Antigenic drift, changes in antigenicity through the accumulation of mutations in the hemagglutinin (HA) gene is chiefly responsible for the continuing circulation of A/H3N2 viruses, resulting in frequent updates of vaccine strains based on new variant analyses. In humans, these drift-related mutations are considered to be primarily caused by the immune pressure elicited by natural infection. Whether or not the immune pressure elicited by vaccination (vaccine pressure) can have a certain effect on drift-related mutations is unclear. Recently, our findings suggested the possible effect of vaccine pressure on HA mutations by directly comparing amino acid differences from the corresponding vaccine strains between isolates from vaccinated and unvaccinated patients. It is possible that influenza vaccine pressure selects variants genetically distant from the vaccine strains. Considering the effect of vaccine pressure on HA mutations would contribute to further understanding the mechanism of antigenic drift, which would be helpful for predicting future epidemic viruses. PMID- 28857678 TI - Somali American female refugees discuss their attitudes toward homosexuality and the gay and lesbian community. AB - Minnesota is home to the largest population of Somalis in the USA - most arriving as refugees from the civil war in Somalia. As Somali Americans adjust to life in the USA, they are likely to undergo shifts in their belief systems - including changes in their attitudes toward gays and lesbians. We examined the attitudes of 29 Somali American women in the Minneapolis-St. Paul metropolitan area toward homosexuality via face-to-face, semi-structured interviews. Transcripts were translated, transcribed and analysed using an approach informed by grounded theory. Three major themes were identified: (1) Islamic prohibitions against homosexuality; (2) homosexuals exiled to a hidden community; and (3) community members exploring tolerance. Participants' attitudes toward homosexuality were heavily influenced by religious doctrines and cultural contexts. This is the first known study in the USA of Somali American attitudes toward gays and lesbians. As people mass migrate from nations with negative attitudes toward homosexuality to countries with more progressive attitudes toward varied sexual orientations, refugee attitudes about homosexuality will undergo change. Through research and education, we can better understand how to increase tolerance toward and opportunities for visibility among gay and lesbian refugees throughout the diaspora. PMID- 28857679 TI - Refining CVLT-II recognition discriminability indices to enhance the characterization of recognition memory changes in healthy aging. AB - The present study examined age-related differences on the four false-positive (FP) error subtypes found on the California Verbal Learning Test-Second Edition yes/no recognition memory trial and the influence of these subtypes on source and novel recognition discriminability (SoRD and NRD, respectively) index calculations. Healthy older (n = 55) adults generally made more FP errors than healthy young adults (n = 57). Accordingly, older adults performed worse than young adults on all SoRD and NRD indices. However, the manner in which FP error subtypes were incorporated into SoRD and NRD index calculations impacted the magnitudes of observed differences between and within the two age groups on SoRD and NRD indices. The present findings underline the importance of examining FP errors in assessments of recognition memory abilities, and using more refined indices of recognition discriminability to further elucidate the nature of age related recognition memory impairment. PMID- 28857680 TI - Cladribine versus fingolimod, natalizumab and interferon beta for multiple sclerosis. AB - OBJECTIVE: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon beta, fingolimod or natalizumab. METHODS: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ?1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. RESULTS: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results. CONCLUSION: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon beta and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab. PMID- 28857681 TI - Expression and purification of the extracellular domains of human glycoprotein VI (GPVI) and the receptor for advanced glycation end products (RAGE) from Rattus norvegicus in Leishmania tarentolae. AB - Glycosylation is one of the most complex post-translational modifications and may have significant influence on the proper function of the corresponding proteins. Bacteria and yeast are, because of easy handling and cost reasons, the most frequently used systems for recombinant protein expression. Bacteria generally do not glycosylate proteins and yeast might tend to hyperglycosylate. Insect cell- and mammalian cell-based expression systems are able to produce complex N glycosylation structures but are more complex to handle and more expensive. The nonpathogenic protozoa Leishmania tarentolae is an easy-to-handle alternative expression system for production of proteins requiring the eukaryotic protein folding machinery and post-translational modifications. We used and evaluated the system for the secretory expression of extracellular domains from human glycoprotein VI and the receptor for advanced glycation end products from rat. Both proteins were well expressed and homogeneously glycosylated. Analysis of the glycosylation pattern identified the structure as the conserved core pentasaccharide Man3GlcNac2. PMID- 28857682 TI - Assessing the potential of fatty acids produced by filamentous fungi as feedstock for biodiesel production. AB - Increased costs and limited availability of traditional lipid sources for biodiesel production encourage researchers to find more sustainable feedstock at low prices. Microbial lipid stands out as feedstock replacement for vegetable oil to convert fatty acid esters. In this study, the potential of three isolates of filamentous fungi (Mucor circinelloides URM 4140, M. hiemalis URM 4144, and Penicillium citrinum URM 4126) has been assessed as single-cell oil (SCO) producers. M. circinelloides 4140 had the highest biomass concentration with lipid accumulation of up to 28 wt% at 120 hr of cultivation. The profile of fatty acids revealed a high content of saturated (SFA) and monounsaturated fatty acids (MUFA), including palmitic (C16:0, 33.2-44.1 wt%) and oleic (C18:1, 20.7-31.2 wt%) acids, with the absence of polyunsaturated fatty acids (PUFA) having more than four double bonds. Furthermore, the predicted properties of biodiesel generated from synthesized SCOs have been estimated by using empirical models which were in accordance with the limits imposed by the USA (ASTM D6715), European Union (EN 14214), and Brazilian (ANP 45/2014) standards. These results suggest that the assessed filamentous fungus strains can be considered as alternative feedstock sources for high-quality biofuel production. PMID- 28857683 TI - How does health-promoting lifestyle relate to sexual function among women of reproductive age in Iran? AB - This study aimed to evaluate the relation between health-promoting lifestyle and sexual function among women of reproductive age. In this cross-sectional study, 1200 women were recruited randomly from 10 public health centers in Ahvaz, Iran. A demographic questionnaire, Health Promoting Lifestyle Profile 2 (HPLP2), and Female Sexual Function Index (FSFI) were used for data collection. The inclusion criteria were as follows: women aged 15-45 years, married, monogamous, and having basic literacy. Data were analyzed using Kruskal-Wallis test, chi-square test, Spearman correlation coefficient, and logistic regression. All aspects of sexual function showed a significant relationship with different dimensions of HPLP2, except for pain and physical activity ( p < 0.001). Women who had better self actualization were more likely to have better sexual function than other women (OR = 1.10, 95% CI: 1.06-1.14, p < 0.001). Other variables like responsibility, interpersonal relations and stress management also showed a significant correlation with sexual function. Results of this study showed that health promoting lifestyle dimensions are significantly related to all aspects of sexual function in women of reproductive age. Health policy makers should take lifestyle related factors of reproductive-aged women into account when seeking to improve the sexual wellbeing of this population. Further attention should also be given to assessing the direction of causality. PMID- 28857684 TI - 46. Jahrestagung Deutsche Gesellaft fur Angiologie - Gesellschaft fur Gefabetamedizin e. V. PMID- 28857685 TI - Enhanced degradation of metronidazole by heterogeneous sono-Fenton reaction coupled ultrasound using Fe3O4 magnetic nanoparticles. AB - Metronidazole (MNZ), one of the most commonly used nitroimidazole antibiotics in the world, poses a serious threat to human life and health. In this study, an enhanced sono-Fenton process for the degradation of MNZ is presented. The catalytic capacity of nano-Fe3O4 in systems comprising ultrasound + Fe3O4 + H2O2, and the influential parameters such as H2O2, nano-Fe3O4 doses and pH for the Sono Fenton process, was investigated. The results showed that the nano-Fe3O4 particles appeared to be roughly spherical in shape, with an average size of 10 20 nm. It was found that *OH radicals were rapidly generated due to the catalytic activity of the nano-Fe3O4. MNZ could be degraded within a wide pH range, from 3 to 9, and the degradation efficiencies were considerably enhanced by ultrasound. When the MNZ concentration was fixed at 20 mg/L, the nano-Fe3O4 dosage at 500 mg/L, the pH at 3 and the reaction temperature at 30 degrees C, the removal efficiencies of MNZ were above 98% after 5 h. It is indicated that Fe3O4 magnetic nanoparticles were synthesized as heterogeneous catalysts to effectively degrade MNZ, and the observed stability and recyclability demonstrated that nano-Fe3O4 was promising for the treatment of wastewater contaminated with antibiotics. PMID- 28857686 TI - Natalizumab during pregnancy and lactation. AB - BACKGROUND: Managing medication during pregnancy and lactation in multiple sclerosis (MS) patients needs to balance potential risks to the newborn with the substantial risks of ongoing disease activity. OBJECTIVE: To evaluate the potential transfer of natalizumab (NAT) into breast milk and into the serum of newborn babies in women who continued NAT treatment during pregnancy and lactation. METHODS: Serum samples of 11 mother-infant pairs and mother milk samples of a further 4 women were analyzed for free NAT using a HL60 cell-based fluorescence-activated cell sorting (FACS) assay. Two mother-baby pairs were analyzed for cell-bound NAT, very-late-antigen (VLA)-4 expression, and saturation with NAT on immune cells by FACS analysis. RESULTS: In the majority of the mother infant serum pairs (6/11) and in all breast milk samples, free NAT was detectable. Cell-bound NAT was measurable in both mother-baby pairs with significant higher levels in babies. VLA-4 expression seems to be higher in newborns. Saturation with NAT was comparable between newborns and mothers. CONCLUSION: NAT can pass placental barrier before delivery and into breast milk. Measurable NAT on neonatal lymphocytes may have functional impact. Further investigations are needed to clarify safety and risk of NAT exposure during pregnancy and lactation. PMID- 28857687 TI - 'There was a struggle between my instinct and my head': women's perception and experience of masturbation in contemporary Vietnam. AB - This paper investigates how masturbation, as one form of non-coital sexual practice, is interpreted and experienced by young married women in contemporary Vietnam. Data were collected through semi-structured interviews with 20 professional women aged 25-40 living in Hanoi. Thematic analysis suggests that by embracing the pursuit of pleasure and aspiring to achieve this goal, many women stake a claim for modernity by promoting the idea that they are no longer traditional in this particular domain of social life. However, wider social forces associated with traditional Vietnamese gender ideology and sexual values remain firmly rooted, impacting on their everyday lives as working wives and mothers, and stalling their pursuit of pleasure and thus 'wellbeing' in its fullest sense. Indeed, among participants in this study, sex was interpreted as being almost exclusively organised around penile-vaginal intercourse. Even when sex was conceptualised as involving more than penetration, penile-vaginal intercourse was still viewed as its most essential component, without which a sexual transaction could not be seen as complete. The normality of penetrative sex was sometimes coupled with the stigma and discrimination associated with other non-coital sexual practices, positioning women firmly within conventional discourses of naturalness and health in regard to sex. PMID- 28857688 TI - It Happened to Me: A Qualitative Analysis of Boys' Narratives About Child Sexual Abuse. AB - Previous research on children's narratives about sexual abuse written predominately by girls uncovered several themes, including: (a) memories of the abuse, (b) the disclosure and subsequent events, and (c) the healing journey and a meta-theme titled "fear and safety." This follow-up study explored how boys describe their life prior to, during, and after sexual abuse in the form of trauma narratives and if there are distinctive features of boys' experiences that differ from those of girls. Analysis of narratives written by males ages 3 to 17 (N = 19) found that boys ascribe to the same themes as the initial research but also have experiences and perspectives that are unique to being male survivors. This article focuses on the first two themes: memories of the abuse and the disclosure and subsequent events. Gender differences are discussed along with recommendations for prevention of male sexual abuse. PMID- 28857689 TI - Genomic Imprinting Is Implicated in the Psychology of Music. AB - Why do people sing to babies? Human infants are relatively altricial and need their parents' attention to survive. Infant-directed song may constitute a signal of that attention. In Prader-Willi syndrome (PWS), a rare disorder of genomic imprinting, genes from chromosome 15q11-q13 that are typically paternally expressed are unexpressed, which results in exaggeration of traits that reduce offspring's investment demands on the mother. PWS may thus be associated with a distinctive musical phenotype. We report unusual responses to music in people with PWS. Subjects with PWS ( N = 39) moved more during music listening, exhibited greater reductions in heart rate in response to music listening, and displayed a specific deficit in pitch-discrimination ability relative to typically developing adults and children ( N = 589). Paternally expressed genes from 15q11-q13, which are unexpressed in PWS, may thus increase demands for music and enhance perceptual sensitivity to music. These results implicate genomic imprinting in the psychology of music, informing theories of music's evolutionary history. PMID- 28857690 TI - Child Sexual Abuse Attributions Among Undergraduate Psychology Students in Singapore. AB - Experimental vignettes were used to investigate attributions relating to child sexual abuse with a focus on the degree of blame allocated to the family and to society, factors thought to be particularly relevant in a collectivist society. One hundred and sixty-two undergraduates in Singapore evaluated media reports describing a case of child sexual abuse. A 2 x 2 x 2 between-subjects design manipulated victim sex, perpetrator sex, and victim-perpetrator relationship. Participants rated the vignettes on degree of blame and prevention potential and rated the abusiveness of the case. Individualism and collectivism attitudes of the participants were also measured. While the highest blame ratings were attributed to perpetrators, significantly more blame was attributed to the family and to society than to the victim. The demonstration of the present attributions of blame to family and to society is a timely finding given recent recommendations to broaden approaches to child abuse prevention by moving away from a reliance on school based child protection programs, which leave the onus on the child to prevent and report abuse, toward a public health approach, which is particularly inclusive of parent and community education approaches . Allocation of some blame to victims, in spite of their status as children, while not a unique finding in victimology research, emphasizes the challenges still to be faced in encouraging the reporting of child sexual abuse. PMID- 28857691 TI - Exploring the Relationship Between Adverse Childhood Experiences and Hope. AB - To explore the relationship between adverse childhood experiences and hope, a convenience sample of caregivers bringing in children for medical investigation of child abuse at a regional child advocacy center were surveyed for adverse childhood experiences and dispositional hope. Hope in this sample had a significant negative correlation to the adverse childhood experiences subscale "abuse" (r = -.19; p < .05). The relationship between hope and the other adverse childhood experiences subscales "neglect" (r = -.14) and "dysfunctional family" (r = -.16) was not statistically significant. An analysis of variance was performed to determine if caregivers who have experienced both sexual and physical abuse (M = 29.67; SD = 15.96) have lower hope scores compared to those caregivers who have experienced neither physical nor sexual abuse (M = 42.64; SD = 18.44). This analysis (F (1, 84) = 5.28; p < 0.05) showed that caregivers who experienced both physical and sexual abuse scored significantly lower on hope compared to their counterparts who experienced no adverse events, with an estimated effect size of moderate strength (d = 0.70). Higher adverse childhood experiences scores are associated with lower hope. This result was especially true for those adult caregivers who reported experiencing both physical and sexual abuse when compared to adults who did not experience either form of child trauma. While the empirical literature continues to demonstrate the negative consequences of adverse childhood experiences across the life span, hope offers a compelling new line of inquiry in child maltreatment research especially for studies targeting prevention or intervention. PMID- 28857692 TI - Cultural adaptation of a supportive care needs measure for Hispanic men cancer survivors. AB - OBJECTIVE: Research with ethnic minority populations requires instrumentation that is cultural and linguistically relevant. The aim of this study was to translate and culturally adapt the Cancer Survivor Unmet Needs measure into Spanish. METHODS: We describe the iterative, community-engaged consensus-building approaches used to adapt the instrument for Hispanic male cancer survivors. We used an exploratory sequential mixed method study design. Methods included translation and back-translation, focus groups with cancer survivors (n = 18) and providers (n = 5), use of cognitive interview techniques to evaluate the comprehension and acceptability of the adapted instrument with survivors (n = 12), ongoing input from the project's community advisory board, and preliminary psychometric analysis (n = 84). RESULTS: The process emphasized conceptual, content, semantic, and technical equivalence. Combining qualitative and quantitative approaches offered a rigorous, systematic, and contextual approach to translation alone and supports the cultural adaptation of this measure in a purposeful and relevant manner. CONCLUSION: Our findings highlight the importance of going beyond translation when adapting measures for cross-cultural populations and illustrate the importance of taking culture, literacy, and language into consideration. PMID- 28857694 TI - In This Issue * September 15, 2017. PMID- 28857693 TI - Stroke while driving: Frequency and association with automobile accidents. AB - Background Cardiovascular events while driving have occasionally been reported. In contrast, there have been few studies on stroke while driving. Aim The objectives of this study were to (1) report the frequency of stroke while driving and (2) evaluate its association with automobile accidents. Methods Clinical data prospectively acquired between January 2011 and December 2016 on 2145 stroke patients (1301 with ischemic stroke, 585 with intracerebral hemorrhage, and 259 with subarachnoid hemorrhage) were reviewed to identify patients who sustained a stroke while driving. The ratio of driving to performing other activities was evaluated for each stroke type. Furthermore, the drivers' response to stroke was reviewed to understand how automobile accidents occurred. Results Among the 2145 patients, 85 (63 ischemic stroke, 20 intracerebral hemorrhage, and 2 subarachnoid hemorrhage) sustained a stroke while driving. The ratio of driving to performing other activities was significantly higher in ischemic stroke (4.8%) than in intracerebral hemorrhage (3.4%) or subarachnoid hemorrhage (0.8%). A majority of drivers either continued driving or pulled over to the roadside after suffering a stroke. However, 14 (16%) patients were involved in automobile accidents. In most patients, an altered mental status due to severe stroke was the presumed cause of the accident. Conclusion Stroke occurred while driving in 4.0% of all strokes and accidents occurred in 16% of these instances. PMID- 28857695 TI - Movement patterns of exhibition swine and associations of influenza A virus infection with swine management practices. AB - OBJECTIVE To identify the geographic distribution of exhibition swine in the Midwestern United States, characterize management practices used for exhibition swine, and identify associations between those practices and influenza A virus (IAV) detection in exhibition swine arriving at county or state agricultural fairs. DESIGN Cross-sectional survey. SAMPLE 480 swine exhibitors and 641 exhibition swine. PROCEDURES Inventories of swine exhibited at fairs in 6 selected Midwestern states during 2013 and of the total swine population (including commercial swine) in these regions in 2012 were obtained and mapped. In 2014, snout wipe samples were collected from swine on arrival at 9 selected fairs in Indiana (n = 5) and Ohio (4) and tested for the presence of IAV. Also at fair arrival, swine exhibitors completed a survey regarding swine management practices. RESULTS Contrary to the total swine population, the exhibition swine population was heavily concentrated in Indiana and Ohio. Many swine exhibitors reported attending multiple exhibitions within a season (median number, 2; range, 0 to 50), with exhibited swine often returned to their farm of origin. Rearing of commercial and exhibition swine on the same premises was reported by 13.3% (56/422) of exhibitors. Hosting an on-farm open house or sale was associated with an increased odds of IAV detection in snout wipe samples. CONCLUSIONS AND CLINICAL RELEVANCE The exhibition swine population was highly variable and differed from the commercial swine population in terms of pig density across geographic locations, population integrity, and on-farm management practices. Exhibition swine may be important in IAV transmission, and identified biosecurity deficiencies may have important public and animal health consequences. PMID- 28857697 TI - Isoniazid toxicosis in dogs: 137 cases (2004-2014). AB - OBJECTIVE To establish the minimum toxic dose of isoniazid in dogs, characterize the clinical signs and outcomes for dogs following isoniazid ingestion, and determine whether IV administration of pyridoxine to dogs with isoniazid toxicosis is protective against death. DESIGN Retrospective case series. ANIMALS 137 dogs with isoniazid toxicosis. PROCEDURES The electronic database of the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center was reviewed from January 2004 through December 2014 to identify dogs with isoniazid toxicosis. For each dog identified, information extracted from the medical record included signalment, estimated dose of isoniazid ingested, clinical signs, treatment, and outcome. Follow-up communication with pet owners or primary care veterinarians was performed when necessary to obtain missing information. RESULTS Clinical signs of isoniazid toxicosis were observed in 134 of 137 (98%) dogs and included seizures (n = 104), CNS signs without seizures (94), and gastrointestinal (41), cardiovascular (19), urogenital (4), and respiratory (1) abnormalities. Of the 87 dogs for which the outcome was available, 61 survived, 18 died, and 8 were euthanized. Probability of survival was positively associated with body weight and IV administration of pyridoxine and negatively associated with dose of isoniazid ingested and presence of seizures. Dogs that received pyridoxine IV were 29 times as likely to survive as dogs that did not receive pyridoxine IV. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated rapid diagnosis of isoniazid toxicosis and prompt treatment of affected dogs with pyridoxine and other supportive care were imperative for achieving a successful outcome. PMID- 28857696 TI - Theriogenology Question of the Month. PMID- 28857699 TI - Evaluation of the reasons for and outcomes of gastrointestinal tract surgery in pet pigs: 11 cases (2004-2015). AB - OBJECTIVE To evaluate the reasons for and outcomes of gastrointestinal tract surgery in pet pigs. DESIGN Retrospective case series. ANIMALS 11 pigs. PROCEDURES The medical record database of a teaching hospital was searched to identify pet pigs that underwent at least 1 celiotomy because of a possible gastrointestinal tract obstruction between 2004 and 2015. For each pig, information extracted from the medical record included history; signalment; clinical signs; physical examination, diagnostic imaging, and diagnostic test results; perioperative management; surgical diagnosis, duration, and procedures performed; postoperative complications; and outcome. Descriptive data were generated. RESULTS 11 pet pigs underwent 12 celiotomies during the study period. Five pigs with intestinal obstructions caused by foreign bodies survived to hospital discharge. Four pigs were euthanized during surgery: 2 because of extensive adhesions that prevented correction of an intestinal obstruction, 1 because of a perforated spiral colon, and 1 because of neoplasia. One pig with a fecal impaction in the spiral colon died during anesthetic recovery. A diagnosis was not achieved for 1 pig, which was euthanized after surgery because of a deteriorating clinical condition. For the pig that underwent 2 celiotomies, the first procedure was an enterotomy for removal of a foreign body, and the second was an intestinal bypass of a stricture caused by adhesions at the previous enterotomy site. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated prognosis was good for pet pigs following surgical removal of gastrointestinal foreign bodies; however, the presence or development of intra-abdominal adhesions appeared to adversely affect prognosis. PMID- 28857700 TI - Evaluation of the immunocrit method to detect failure of passively acquired immunity in dairy calves. AB - OBJECTIVE To evaluate the usefulness of serum immunocrit measurement to detect failure of passively acquired immunity (FPI) in dairy calves. DESIGN Diagnostic test evaluation. ANIMALS 249 female dairy calves (age, 2 to 6 days). PROCEDURES A blood sample was collected from each calf, and serum was harvested. Immunocrit was measured in serum samples by use of 55% ammonium sulfate solution and the standard technique. Serum IgG concentration was measured by means of radial immunodiffusion (reference standard), with FPI defined as a result < 1,000 mg/dL. The immunocrit value (cutpoint) that maximized both sensitivity and specificity of the method for detection of FPI was determined by construction of receiver operating characteristic curves, and likelihood ratios for positive and negative test results were calculated. RESULTS Immunocrit values were significantly correlated (rho = 0.71) with serum IgG concentration as measured by radial immunodiffusion. An immunocrit cutpoint of 11% was optimal for detection of FPI in the calves. Sensitivity and specificity of the immunocrit method at this cutpoint were 0.88 (95% confidence interval [CI], 0.79 to 0.97) and 0.51 (95% CI, 0.44 to 0.58), respectively. Likelihood ratios for positive and negative test results were 1.80 (95% CI, 1.51 to 2.14) and 0.23 (95% CI, 0.11 to 0.51), respectively. CONCLUSIONS AND CLINICAL RELEVANCE The immunocrit method was useful for identifying dairy calves with FPI and was simple and could be quickly performed. Because precipitation of immunoglobulins by ammonium sulfate is not species specific, the immunocrit method should be evaluated for detection of FPI in other veterinary species as well. PMID- 28857701 TI - What Is Your Diagnosis? Extraskeletal mesenchymal chondrosarcoma. PMID- 28857702 TI - What Is Your Neurologic Diagnosis? PMID- 28857704 TI - Letters to the Editor. PMID- 28857703 TI - Vascular stent placement for palliation of mass-associated chylothorax in two dogs. AB - CASE DESCRIPTION 2 dogs with chylothorax were identified to have cardiac mass lesions obstructing the return of venous blood from the cranial vena cava. Chylous effusion was presumed to have been a result of an increase in cranial vena cava pressure affecting flow of chyle through the thoracic duct. CLINICAL FINDINGS Both dogs had tachypnea and pleural effusion requiring therapeutic thoracocentesis. Fluid analysis confirmed chylothorax. A heart-base mass was identified via echocardiography in each dog, and CT-angiographic findings confirmed obstruction to venous return in the cranial vena cava in both dogs and compression of the pulmonary artery in 1 dog. TREATMENT AND OUTCOME Each dog was anesthetized, and self-expanding endovascular stents were placed with fluoroscopic guidance. In both dogs, the site of stent placement was the cranial vena cava, and in 1 dog, an additional stent was positioned in the pulmonary artery. Chylous effusion resolved successfully in both dogs after surgery, with postoperative survival times exceeding 6 months. Complications included periprocedural arrhythmias in both dogs and eventual obstruction of the stent with tumor extension and fluid reaccumulation in 1 dog. CLINICAL RELEVANCE Endovascular stent placement may provide a useful palliative treatment for chylothorax secondary to vascular compression by a heart-base mass in dogs. PMID- 28857705 TI - Pathology in Practice. Thrombotic meningoencephalitis (TME) in a calf. PMID- 28857707 TI - Comparison of clinical findings between dogs with suspected anaphylaxis and dogs with confirmed sepsis. AB - OBJECTIVE To compare clinical signs, laboratory test results, and imaging findings between dogs with suspected anaphylaxis and dogs with sepsis. DESIGN Retrospective case-case study. ANIMALS 10 dogs with suspected anaphylaxis and 22 dogs with confirmed sepsis that met the criteria for systemic inflammatory response syndrome. PROCEDURES Medical records for dogs in each group were reviewed and data extracted regarding signalment; reason for hospital admission; physical examination findings; results of CBC, serum biochemical analysis, coagulation testing, cytologic examination, and microbial culture; and imaging reports. RESULTS All dogs in the anaphylaxis group fulfilled the criteria for systemic inflammatory response syndrome. Dogs in both groups had gastrointestinal signs, lethargy, mentation change, and bleeding abnormalities. Dogs with suspected anaphylaxis had a significantly higher eosinophil count and serum alanine aminotransferase activity and lower blood pH than dogs with sepsis. Dogs with sepsis had a significantly higher band neutrophil count, serum globulins concentration, and serum alkaline phosphatase activity and lower serum glucose concentration. Dogs in both groups had intracavitary free fluid and ultrasonographic findings of thickened intestines, gas or fluid-filled intestines, and a thickened gallbladder wall. CONCLUSIONS AND CLINICAL RELEVANCE Clinical signs, laboratory values, and imaging findings may be similar in dogs with sepsis or anaphylaxis. Given the marked difference in prognosis and treatment, early differentiation is important. Anaphylaxis should be considered if a septic nidus cannot be identified, and supportive care should be considered for such patients. PMID- 28857708 TI - Pathology in Practice. Hereditary nephropathy (familial nephropathy) in an English Cocker Spaniel. PMID- 28857709 TI - Effect of Refurbishing Amalgam and Resin Composite Restorations After 12 Years: Controlled Clinical Trial. AB - OBJECTIVES: The aim of this study was to clinically evaluate posterior amalgam and resin composite restorations refurbished over a period of 12 years by investigating the influence of refurbishing on the survival of restorations and comparing their behaviors with respect to controls. METHODS AND MATERIALS: Thirty four patients were enrolled, ages 18 to 80 years, with 174 restorations, 48 restorations of resin composite (RC), and 126 restorations of amalgam (AM). Restorations with localized defects in anatomy, roughness, luster, or marginal staining that were clinically judged as suitable for refurbishing according to US Public Health Service (USPHS) Ryge criteria were assigned to group A-refurbishing (n=85; 67 AM, 18 RC)-or group B-control (n=89; 59 AM, 30 RC); the quality of the restorations was evaluated blindly according to the modified USPHS criteria. Two observers conducted evaluations at the initial state (k=0.74) and after one to five, 10, and 12 years (k=0.88). Wilcoxon, Friedman, and Mantel-Cox tests were performed to compare the groups, respectively. RESULTS: After 12 years, both groups experienced a similar decline, except for an evidently better performance in marginal adaptation in RC control (p=0.043) and in anatomy in AM refurbished (p=0.032). CONCLUSIONS: After 12 years, no difference was found in the clinical condition and longevity of the refurbished restorations compared to the control group. PMID- 28857710 TI - Microtensile Bond Strength of Resin-Modified Glass Ionomer Cement to Sound and Artificial Caries-Affected Root Dentin With Different Conditioning. AB - In this laboratory study, the microtensile bond strengths (MUTBS) of resin modified glass ionomer cement (RM-GIC) to sound and artificial caries-affected bovine root dentin (ACAD) using three different conditioning agents were evaluated after 24 hours and three months. The fractured interface was examined with a scanning electron microscope (SEM). Specimens were created on bovine root dentin that was embedded in epoxy resin. For the ACAD specimens, artificial carious lesions were created. The RM-GIC (Fuji II LC) was applied either directly (no treatment), after application of self conditioner, cavity conditioner, or 17% ethylenediamine tetraacetic acid (EDTA) applied for 60 seconds, on sound dentin and ACAD, then light cured. They were stored in artificial saliva for 24 hours or three months. Following this, the specimens were cut into sticks for the MUTBS test, and the failure mode of the debonded specimens was examined by using SEM. Pretest failures were excluded from the statistical analysis of the MUTBS values because of their high incidence in some groups. Results showed that the MUTBS values were significantly affected by the dentin substrate as well as the conditioning agent. Self conditioner provided the highest and most stable MUTBS values, while cavity conditioner showed stable MUTBS values on sound dentin. Both self conditioner and cavity conditioner had significantly higher MUTBS values than the no treatment groups. EDTA conditioning reduced the MUTBS after three months to sound dentin, while it showed 100% pretest failure with ACAD for both storage periods. PMID- 28857711 TI - Wear Evaluation of Prosthetic Materials Opposing Themselves. AB - The purpose of the present in vitro study was to compare the two-body wear resistance of a type 3 gold alloy (Aurocast8), two lithium disilicate glass ceramics (IPS e.max CAD and IPS e.max Press), a heat-pressed feldspathic porcelain (Cerabien ZR Press), an yttria-stabilized tetragonal zirconia polycrystal ceramic (Katana Zirconia ML), and three heat-cured composite resins (Ceram.X Universal, Enamel Plus Function, and Enamel Plus HRi) opposing antagonistic cusps made out of the same restorative materials. Ten 6-mm-thick samples and 10 cusp-shaped abraders were manufactured with each test material (n=10) according to standard laboratory procedures. All sample/antagonist pairs made out of the same material were subjected to a two-body wear test in a dual axis chewing simulator for up to 120,000 loading cycles. The total vertical wear (mm) and the total volumetric loss (mm3) for each sample/antagonist pair were calculated. Data were statistically analyzed using one-way analysis of variance tests. The total vertical wear for the gold alloy was not significantly different compared to Ceram.X Universal, Enamel Plus Function, IPS e.max CAD, and Cerabien ZR Press. Significantly increased wear values were observed for Enamel Plus HRi and IPS e.max Press. The lowest values for total vertical wear and volumetric loss were recorded on the monolithic zirconia. PMID- 28857712 TI - A novel drug interaction between busulfan and blinatumomab. AB - Busulfan is an alkylating agent used in pre-transplant conditioning for patients undergoing hematopoietic stem cell transplantation. Several factors contribute to variations in busulfan drug disposition including bioavailability, age, liver function, genetic polymorphisms, and concurrent administration of other drugs. Busulfan is metabolized by hepatic oxidation via the cytochrome P450 3A4 system as well as through conjugation with glutathione. Interactions with drugs such as phenytoin, itraconazole, and metronidazole have been reported to alter busulfan clearance and result in sub- or supra-therapeutic concentrations. We report a case of a clinically significant drug interaction between intravenous busulfan and the bifunctional T-cell engager, blinatumomab, observed through busulfan therapeutic drug monitoring. We found that busulfan clearance was reduced resulting in a higher area under the concentration-time curve when it was administered 48 h after blinatumomab. Repeat busulfan pharmacokinetic testing two weeks later demonstrated increased clearance of the drug and a 31% higher dose recommendation. Similar to other protein therapeutics, cytokine elevations during blinatumomab treatment can lead to cytochrome 3A4 suppression. We hypothesize that the increased busulfan levels observed could be related to a cytokine mediated CYP3A4 suppression. This represents a unique pharmacologic consideration in hematopoietic stem cell transplantation which would impact several drugs that undergo CYP3A4 metabolism, including calcineurin inhibitors, cyclophosphamide, sirolimus, and triazole antifungals. Additionally, this mechanism of CYP3A4 suppression may be relevant in treatments and disease states where cytokine levels are elevated such as haploidentical stem cell transplantation, graft versus-host disease, and use of chimeric antigen receptor T-cell therapy. PMID- 28857713 TI - Low-molecular-weight heparins for the prevention of recurrent venous thromboembolism in patients with cancer: A systematic literature review of efficacy and cost-effectiveness. AB - BACKGROUND: Patients with cancer have an elevated risk of venous thromboembolism. Importantly, patients with cancer, who have metastatic disease, renal insufficiency, or are receiving anticancer therapy, have an even higher risk of a recurrent event. Similarly, the risk of recurrent venous thromboembolism is higher than the risk of an initial event. To reduce the risk, extended duration of prophylaxis for up to six months with low-molecular-weight heparins such as dalteparin, enoxaparin, nadroparin, and tinzaparin is recommended by international guidelines. In this paper, the clinical and economic literature is reviewed to provide evidenced based recommendations based on clinical benefit and economic value. METHODS: A systematic review of major databases was conducted from January 1996 to October 2016 for randomized controlled trials evaluating the four distinct low-molecular-weight heparins against a vitamin K antagonists control group for the prevention of recurrent venous thromboembolism in patients with active cancer. This was then followed by the application of the National Institute of Health and Clinical Excellence guidance to assess the quality of all trials that met the inclusion criteria. Finally, the cost-effectiveness literature supporting the value proposition of each product was reviewed. RESULTS: Six randomized trials met the inclusion criteria. There were one, two, and three trials that compared dalteparin, tinzaparin, and enoxaparin to a vitamin K antagonists control group. However, there were no trials for nadroparin in the setting of secondary venous thromboembolism prevention. In addition, only the dalteparin and one of the tinzaparin trials were of high quality and adequately powered. Of the two studies, only the dalteparin trial reported a statistically significant benefit in terms of venous thromboembolism absolute risk reduction when compared to a vitamin K antagonists control group (HR = 0.48; p = 0.002). In addition, there was robust pharmacoeconomic data from Canada, the Netherlands, France, and Austria supporting the cost-effectiveness of dalteparin for this indication. There were no such studies for any of the other agents. CONCLUSIONS: The totality of high-quality clinical and cost-effectiveness data supports the use of dalteparin over other low-molecular-weight heparins for preventing recurrent venous thromboembolism in patients with cancer. PMID- 28857714 TI - Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia. AB - Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema. PMID- 28857715 TI - Predictive factors of flares in systemic lupus erythematosus patients: data from a multiethnic Latin American cohort. AB - Purpose The purpose of this paper is to determine the factors predictive of flares in systemic lupus erythematosus (SLE) patients. Methods A case-control study nested within the Grupo Latino Americano De Estudio de Lupus (GLADEL) cohort was conducted. Flare was defined as an increase >=4 points in the SLEDAI. Cases were defined as patients with at least one flare. Controls were selected by matching cases by length of follow-up. Demographic and clinical manifestations were systematically recorded by a common protocol. Glucocorticoid use was recorded as average daily dose of prednisone and antimalarial use as percentage of time on antimalarial and categorized as never (0%), rarely (>0-25%), occasionally (>25%-50%), commonly (?50%-75%) and frequently (?75%). Immunosuppressive drugs were recorded as used or not used. The association between demographic, clinical manifestations, therapy and flares was examined using univariable and multivariable conditional logistic regression models. Results A total of 465 cases and controls were included. Mean age at diagnosis among cases and controls was 27.5 vs 29.9 years, p = 0.003; gender and ethnic distributions were comparable among both groups and so was the baseline SLEDAI. Independent factors protective of flares identified by multivariable analysis were older age at diagnosis (OR = 0.929 per every five years, 95% CI 0.869-0.975; p = 0.004) and antimalarial use (frequently vs never, OR = 0.722, 95% CI 0.522 0.998; p = 0.049) whereas azathioprine use (OR = 1.820, 95% CI 1.309-2.531; p < 0.001) and SLEDAI post-baseline were predictive of them (OR = 1.034, 95% CI 1.005 1.064; p = 0.022). Conclusions In this large, longitudinal Latin American cohort, older age at diagnosis and more frequent antimalarial use were protective whereas azathioprine use and higher disease activity were predictive of flares. PMID- 28857716 TI - Chronic cutaneous lupus erythematosus presenting as atypical acneiform and comedonal plaque: case report and literature review. AB - Introduction Chronic cutaneous lupus erythematosus (CCLE) usually presents as characteristic erythematous patches and infiltrated coin-shaped plaques. However, there are some atypical clinical variants that may mimic other dermatological conditions. Haroon et al. reported in 1972 an unusual presentation of CCLE with hypertrophic follicular scars seen in acne vulgaris. Acneiform presentation is one of the most rarely reported and one of the most confusing, as it resembles a very common inflammatory skin disease. A brief review of the literature using PubMed found only nine other reports. Case report A 32-year-old woman presented with two-year pruritic infiltrated acneiform and comedonal eruption on the right chin treated as acne with isotretinoin without improvement. On examination the patient presented with erythematous-infiltrated plaque, papules, open comedones, pitting scars and hypopigmented atrophic scars on the right chin area and scalp hair loss. An incisional skin biopsy on the chin and scalp lesions was performed and the anatomopathological and immunofluorescence exam showed findings that are consistent with CCLE. Additional tests ruled out systemic involvement. The patient was treated with prednisone and chloroquine diphosphate with great improvement. After four years the lesion is stable, with some scarring. Discussion In a literature review we found nine other cases of acneiform presentation of lupus erythematosus: Three cases were systemic lupus erythematosus (SLE) and seven others were diagnosed as CCLE (including our patient). All three patients who had SLE tested positive for antinuclear antibodies (ANA), and only one patient with CCLE, had a low titer of positive ANA (1:80). Ages varied from 24 to 60 years old, with a median of 32 years old, the same as our patient's age and consistent with the literature. Seven were females and three were males, with a ratio of 2.3:1. Most cases, such as our patient, showed acneiform lesions mainly on the face, a common site of typical CCLE. The present case and literature review illustrates the need to expand the differential diagnosis of atypical acneiform and comedonal lesions. CCLE should be considered especially in a localized lesion, which can be itchy and does not improve with conventional treatment for acne vulgaris. PMID- 28857717 TI - Sustained complete renal remission is a predictor of reduced mortality, chronic kidney disease and end-stage renal disease in lupus nephritis. AB - Objective The objective of this paper is to identify the relationship between patients with lupus nephritis (LN) who achieve sustained complete renal remission (CR) and renal outcome and survival. Methods From a longitudinal cohort study we identified patients with LN with CR. We compared the outcomes of patients who achieved sustained CR for at least five years (Group A) with those less than five years (Group B). The outcomes were death, SLICC/ACR damage index (SDI), renal flare, end-stage renal disease (ESRD) or estimated glomerular filtration rate (eGFR) < 50 ml/min, and doubling of serum creatinine. Regression analyses were used to identify predictors of the outcomes. Results A total of 345 patients were identified, 132 patients in Group A and 213 patients in Group B. The duration of CR in Group A was 11.76 +/- 7.34 years but only 1.24 +/- 1.24 years in Group B ( p < 0.001). Death, increasing renal SDI, renal flare, renal transplantation, ESRD or eGFR < 50 ml/min, and doubling of serum creatinine in Group A were significantly lower than Group B. Multivariable analysis revealed that Group A patients were at a lower risk of death (hazard ratio (HR) = 0.20; 95% confidence interval (CI), 0.07-0.61; p = 0.004), increasing renal SDI (HR = 0.41; 95% CI, 0.21-0.76; p = 0.01), developing ESRD or eGFR < 50 ml/min (HR = 0.27; 95% CI, 0.12-0.61; p = 0.001), and doubling of serum creatinine (HR = 0.29; 95% CI, 0.14 0.61; p = 0.001) compared with Group B. Conclusion Sustained CR for at least five years is a predictor of better prognosis in patients with LN. PMID- 28857718 TI - Understanding systemic lupus erythematosus patients' desired outcomes and their perceptions of the risks and benefits of using corticosteroids. AB - Introduction The use of corticosteroids in systemic lupus erythematosus (SLE) patients requires difficult trade-offs between efficacy and risk of toxicity. This qualitative study examined SLE patients' most desired outcomes and their concerns with corticosteroid use in SLE treatment. Methods SLE patients with current/past experience with using corticosteroids were recruited from the clinics at the Johns Hopkins Lupus Center and the University of Maryland Medical Center. Five in-depth interviews ( N = 5) and four focus groups ( N = 15) were conducted during which discussions were transcribed and analyzed based on a grounded theory approach. Results We identified five major themes describing SLE patients' most desired outcomes: reduction in flares, maintenance of normal activities, minimization of treatment side effects, prevention of future organ damage, and finding a cure. Further, SLE patients reported these primary concerns with the adverse effects of corticosteroids: weight gain, organ damage (particularly bone-related damage), mood swings/irritability, sleep disturbances, and dental issues. Patients appeared to be more concerned with adverse effects that immediately affected their day-to-day lives. Conclusion Knowledge gained during this study better informs how patients view the benefits and risks of corticosteroids. This can facilitate discussions between physicians and patients as they work together to determine the appropriate use of corticosteroids. PMID- 28857720 TI - Application of aqueous biphasic systems as strategy to purify tannase from Aspergillus tamarii URM 7115. AB - The aims of the current study are to assess the influence of polyethylene glycol (PEG) concentration, molar mass, pH, and citrate concentrations on aqueous biphasic systems based on 24 factorial designs, as well as to check their capacity to purify tannase secreted by Aspergillus tamarii URM 7115. Tannase was produced through submerged fermentation at 26 degrees C for 67 h in Czapeck-Dox modified broth and added with yeast extract and tannic acid. The factorial design was followed to assess the influence of PEG molar mass (MPEG 600; 4,000 and 8,000 g/ mol), and PEG (CPEG 20.0; 22.0 and 24.0% w/w) and citrate concentrations (CCIT 15.0, 17.5, and 20.0%, w/w), as well as of pH (6.0, 7.0, and 8.0) on the response variables; moreover, partition coefficient (K), yield (Y), and purification factor (PF) were analyzed. The most suitable parameters to purify tannase secreted by A. tamarii URM 7115 through a biphasic system were 600 (g/mol) MPEG, 24% (w/w) CPEG, 15% (w/w) CCIT at pH 6.0 and they resulted in 6.33 enzyme partition, 131.25% yield, 19.80 purification factor and 195.08 selectivity. Tannase secreted by A. tamarii URM 7115 purified through aqueous biphasic systems composed of PEG/citrate can be used for industrial purposes, since it presents suitable purification factor and yield. PMID- 28857719 TI - A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy. AB - BACKGROUND: This randomized, double-blind, placebo-controlled study evaluated dose-response relationships of lisdexamfetamine dimesylate when used as augmentation for major depressive disorder in individuals exhibiting inadequate responses to antidepressant monotherapy. METHODS: Eligible adults (18-65 years) were assigned to antidepressant monotherapy (escitalopram or venlafaxine extended release) plus lisdexamfetamine dimesylate-matching placebo during an eight-week single-blind lead-in phase. Participants meeting randomization criteria were randomized (1:1:1:1:1) to eight weeks of lisdexamfetamine dimesylate (10, 30, 50, or 70 mg) or placebo while maintaining antidepressant therapy. Dose-responses for changes from augmentation baseline to week 16/early termination for Montgomery Asberg Depression Rating Scale total score (primary efficacy endpoint) and vital signs (systolic and diastolic blood pressure and pulse) were assessed using multiple comparisons procedures with modeling. RESULTS: For Montgomery-Asberg Depression Rating Scale total score change, no significant dose-responses were observed for any candidate dose-response curve (all p>0.10). In the dose-response evaluable population, least squares mean (90% confidence interval) treatment differences versus placebo for Montgomery-Asberg Depression Rating Scale total score change at week 16 were -1.4 (-3.9, 1.2), 0.1 (-2.5, 2.7), -0.7 (-3.4, 2.0), and -0.9 (-3.5, 1.6) with 10, 30, 50, and 70 mg lisdexamfetamine dimesylate, respectively. For all vital sign parameters, lisdexamfetamine dimesylate exhibited significant dose-responses for all candidate dose-response curves (all p<0.10), with increases observed as lisdexamfetamine dimesylate dose increased; a linear relationship provided the best fit. Mean+/-standard deviation changes from augmentation baseline for systolic and diastolic blood pressure and pulse at week 16/early termination were -0.7+/-9.90 and -0.3+/-7.24 mm Hg and 0.2+/-10.57 bpm with placebo and were 1.9+/-9.47 and 0.8+/-7.40 mm Hg and 3.6+/-9.74 bpm with lisdexamfetamine dimesylate (all doses combined). The safety and tolerability profile of lisdexamfetamine dimesylate was consistent with previous studies. CONCLUSIONS: Lisdexamfetamine dimesylate augmentation did not provide benefit over placebo in adults with inadequate responses to antidepressant monotherapy based on the assessed efficacy measures. PMID- 28857721 TI - Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: Prospective combination treatment for progressive disease? AB - BACKGROUND: Most multiple sclerosis (MS) patients succumb to a progressive phenotype. Continued lymphocyte activity in the brain, microglia-mediated injury, iron deposition, and oxidative stress are characteristics of progressive MS. OBJECTIVE: As minocycline and hydroxychloroquine have been shown to inhibit microglia, we evaluated their effects on other outcomes relevant for progression. METHODS: Medications were evaluated in culture and in mice with acute and chronic experimental autoimmune encephalomyelitis (EAE). RESULTS: Both medications individually reduced iron neurotoxicity and a combination effect was not observed. Hydroxyl radical scavenging activity was manifested by minocycline only. Minocycline reduced T-cell proliferation more prominently than hydroxychloroquine; an aggregate effect occurred at low but not high concentrations. B-cell proliferation was mitigated to a greater extent by hydroxychloroquine and an additive effect was not evident. In EAE, suboptimal doses of minocycline and hydroxychloroquine individually delayed onset of clinical signs, while their combination suppressed clinical manifestations until treatment was stopped. In Biozzi ABH mice, a model of progressive MS, the chronic phase was beneficially altered using the combination. CONCLUSION: While minocycline and hydroxychloroquine did not manifest additive effects in most culture assays, their combination at suboptimal doses in EAE unexpectedly exceeded their individual activity. Minocycline and hydroxychloroquine combined are candidate treatments for progressive MS. PMID- 28857722 TI - "She Got Spoilt": Perceptions of Victims of Child Sexual Abuse in Ghana. AB - International research has commented on social stigma as a key reason for nondisclosure of child sexual abuse. However, the actual components of this social stigma frequently remain unexplored. The present study deals with perceptions of consequences of child sexual abuse among professionals and laypeople in Ghana (N = 44), employing a bystander perspective. As a qualitative study using a grounded theory framework, it considers these consequences in light of their underlying beliefs about child and adolescent development, particularly in relation to gender-based expectations placed on girls and boys. Consequences of child sexual abuse could be divided into sexual health consequences, beliefs about "destroyed innocence" and beliefs about a "destroyed future," which were strongly related to the sexual nature of the violence perpetrated. These perceived consequences of child sexual abuse hold implications for what surviving child sexual abuse means on a social level. Implications for practice are discussed on the basis of the data analysis. PMID- 28857724 TI - A Case Study Approach to Reducing the Risks of Child Sexual Exploitation (CSE). AB - The risk of child sexual exploitation is a growing concern, both within community and child care settings. Within community services working with vulnerable young people, the risks of exploitation are pervasive and present a constant management problem for professionals. This makes the need for focused educational interventions within such settings all the more vital. This case study aims to describe the assessment, formulation, intervention, and outcomes of a young female considered to be at risk of sexual exploitation. It was hypothesised that, after completion of a psychoeducational group designed to enhance knowledge and skills around child sexual exploitation, positive outcomes would be seen in psychometric assessment, risk-taking behavior, and risk awareness. Results demonstrated no clinically significant change for measures of impulsivity, resourcefulness, or self-reported difficulties. A significant increase was seen for self-reported self-esteem, and all outcomes revealed a positive direction of change. Observational accounts of behavioral and attitudinal change produced more positive results, revealing an increase in prosocial behaviors and a reduction in risk-taking behaviors. Outcomes are discussed in relation to the individual's history and the residential care environment. Implications for future research and practice are outlined, and the study limitations are considered. PMID- 28857723 TI - Aquaporin-4 serostatus does not predict response to immunotherapy in neuromyelitis optica spectrum disorders. AB - BACKGROUND:: Debate exists about whether neuromyelitis optica spectrum disorder seronegative disease represents the same immune-mediated attack on astrocytic aquaporin-4 as in seropositive disease. OBJECTIVE:: We investigated whether response to common treatments for neuromyelitis optica spectrum disorder differed by serostatus, as assessed by change in annualized relapse rate. METHODS:: We performed a multicenter retrospective analysis of 245 patients with neuromyelitis optica spectrum disorder who were treated with either rituximab or mycophenolate mofetil as their first-line immunosuppressive treatment for disease prevention. Patients were followed for a minimum of 6 months following treatment initiation. RESULTS:: In those started on rituximab, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.81 and 1.93, respectively. On-treatment annualized relapse rates significantly declined to 0.32 (seropositive; p < 0.0001) and 0.12 (seronegative; p = 0.0001). In those started on mycophenolate mofetil, the pre-treatment annualized relapse rates for seropositive and seronegative patients were 1.79 and 1.45, respectively. On treatment annualized relapse rates declined to 0.29 (seropositive; p < 0.0001) and 0.30 (seronegative; p < 0.005). CONCLUSION:: In this international collaboration involving a large number of neuromyelitis optica spectrum disorder patients, treatment was effective regardless of serostatus. This suggests that treatment should not differ when considering these treatments. PMID- 28857725 TI - "I Am Not A Victim. I Am A Survivor": Resilience as a Journey for Female Survivors of Child Sexual Abuse. AB - This study was designed to expand our understanding of the positive aspects of coping and resilience in female survivors of child sexual abuse. Research questions focused on women's lived experiences of being survivors of child sexual abuse and how they have experienced resilience, developed healthy intimate relationships, and viewed themselves as sexual beings. Using a qualitative research lens of phenomenology, we captured the essence of survivors' experiences of resilience. Although each woman's experience was unique, similar patterns of processes and outcomes emerged as meaningful in their development of resilient and healthy sexuality and relationship functioning. However, participants emphasized resilience as a process or journey-recovery from trauma, reconceptualization of self, and development of healthy sexuality included deliberate efforts occurring over time. Implications for future research and practice using a positive lens of resilience are provided. PMID- 28857726 TI - Initial assessment of a novel delivery system (NuDELTM (r)) for the covered Cheatham-Platinum stent. AB - : Aims We sought to evaluate the first-in-man use of a new system for implantation of covered stents in patients with complex structural and CHD. Methods and results Retrospective data were collected of the first 13 NuDELTM delivery systems used in patients. The NuDELTM comprises a covered Cheatham Platinum stent mounted on a balloon-in-balloon and pre-loaded in a long delivery sheath. Data were collected from three centres in the United Kingdom and Ireland. A total of 13 covered stents were delivered via 12 NuDELTM delivery systems in 12 patients. Among them, six patients had coarctation of the aorta, five patients had right ventricular outflow tract stenosis, and one patient had severe stenosis of a Mustard systemic venous baffle. There were no complications, and all the stents were deployed in the desired position with satisfactory haemodynamic results. CONCLUSIONS: The development of a bespoke system of a pre-mounted, pre loaded covered stent may negate some of the technical challenges that complicate large-calibre stent deployment. Our preliminary results suggest that the NuDELTM system is a safe and effective means of covered stent deployment in challenging anatomy. PMID- 28857727 TI - Fungal endocarditis in paediatrics: a review of 192 cases (1971-2016). AB - BACKGROUND: The aims of this article were to review the published literature on fungal endocarditis in children and to discuss the aetiology and diagnosis, with emphasis on non-invasive methods and various treatment regimes. METHODS: We systematically reviewed published cases and case series of fungal endocarditis in children. We searched the literature, including PubMed and individual references for publications of original articles, single cases, or case series of paediatric fungal endocarditis, with the following keywords: "fungal endocarditis", "neonates", "infants", "child", and "cardiac vegetation". RESULTS: There have been 192 documented cases of fungal endocarditis in paediatrics. The highest number of cases was reported in infants (93/192, 48%) including 60 in neonates. Of the neonatal cases, 57 were premature with a median gestational age of 27 weeks and median birth weight of 860 g. Overall, 120 yeast - fungus that grows as a single cell - infections and 43 mould - fungus that grows in multicellular filaments, hyphae - infections were reported. With increasing age, there was an increased infection rate with moulds. All the yeast infections were detected by blood culture. In cases with mould infection, diagnosis was mainly established by culture or histology of emboli or infected valves after invasive surgical procedures. There have been a few recent cases of successful early diagnosis by non-invasive methods such as blood polymerase chain reaction (PCR) for moulds. The overall mortality for paediatric fungal endocarditis was 56.25%. The most important cause of death was cardiac complications due to heart failure. Among the various treatment regimens used, none of them was significantly associated with better outcome. CONCLUSIONS: Non-invasive methods such as PCR tests can be used to improve the chances of detecting and identifying the aetiological agent in a timely manner. Delays in the diagnosis of these infections may result in high mortality and morbidity. No significant difference was noted between combined surgical and medical therapy over exclusively combined medical therapy. PMID- 28857728 TI - Down syndrome and transposition of the great arteries. AB - There is an old adage in paediatric cardiology that, despite the high prevalence and wide spectrum of CHD, transposition of the great arteries does not occur in trisomy 21. We present a case of transposition of the great arteries, ventricular septal defect, and pulmonary stenosis in a patient with trisomy 21. PMID- 28857729 TI - A rapid echocardiographic screening protocol for rheumatic heart disease in Samoa: a high prevalence of advanced disease. AB - BACKGROUND: Echocardiography has been proposed as a method to screen children for rheumatic heart disease. The World Heart Federation has established guidelines for echocardiographic screening. In this study, we describe a rapid echocardiogram screening protocol according to the World Heart Federation guidelines in Samoa, endemic for rheumatic heart disease. METHODS: We performed echocardiogram screening in schoolchildren in Samoa between 2013 and 2015. A brief screening echocardiogram was performed on all students. Children with predefined criteria suspicious for rheumatic hear diseases were referred for a more comprehensive echocardiogram. Complete echocardiograms were classified according to the World Heart Federation guidelines and severity of valve disease. RESULTS: Echocardiographic screening was performed on 11,434 children, with a mean age of 10.2 years; 51% of them were females. A total of 558 (4.8%) children underwent comprehensive echocardiography, including 49 students who were randomly selected as controls. Definite rheumatic heart disease was observed in 115 students (10.0 per 1000): 92 students were classified as borderline (8.0 per 1000) and 23 with CHD. Advanced disease was identified in 50 students (4.4 per 1000): 15 with severe mitral regurgitation, five with severe aortic regurgitation, 11 with mitral stenoses, and 19 with mitral and aortic valve disease. CONCLUSIONS: We successfully applied a rapid echocardiographic screening protocol to a large number of students over a short time period - 28 days of screening over a 3-year time period - to identify a high prevalence of rheumatic heart disease. We also reported a significantly higher rate of advanced disease compared with previously published echocardiographic screening programmes. PMID- 28857730 TI - Reclassification of Phycicola gilvus (Lee et al. 2008) and Leifsonia pindariensis (Reddy et al. 2008) as Microterricola gilva comb. nov. and Microterricola pindariensis comb. nov. and emended description of the genus Microterricola. AB - The taxonomic positions of Microterricola viridarii JCM 15926T, Phycicola gilvus DSM 18319T and Leifsonia pindariensis JCM 15132T were re-examined. Phylogenetic analysis and 16S rRNA gene sequence similarities revealed that all three strains are closely related with each other and form a monophyletic cluster with high sequence similarity (99.2 -99.9 %). A dendrogram constructed based on the protein spectra generated by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy also displayed close clustering of these three strains. The fatty acid profiles of three strains were very similar to each other and contained branched fatty acids (anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0) as the predominant cellular fatty acids. The polar lipid profiles of the three stains were similar and consisted of diphosphatidylglycerol, phosphatidylglycerol and phosphatidylcholine as major polar lipids and an unknown lipid. Comparisons of morphological, chemotaxonomic and physiological data of Microterricola viridarii JCM 15926T, Leifsonia pindariensis JCM 15132T and Phycicola gilvus DSM 18319T are in agreement with the features of a common genus. DNA-DNA hybridization data generated during this study showed less than 70 % reassociation value with each other indicating that they are different at species level. Based on the present study, we conclude that Phycicola gilvus DSM 18319T and Leifsonia pindariensis JCM 15132T should be reclassified under the genus Microterricola, since this genus has the nomenclatural priority, and reclassified as Microterricolagilva comb. nov. (type strain SSWW-21T=DSM 18319T=KCTC 19185T=JCM 30550T) and Microterricolapindariensis comb. nov. (type strain PON10T=LMG 24222T=JCM 15132T=MTCC9128T). An emended description of the genus Microterricola is also presented. PMID- 28857731 TI - Terrimonas terrae sp. nov., isolated from the rhizosphere of a tomato plant. AB - A yellow, aerobic, Gram-stain-negative, non-motile, rod-shaped and non flagellated bacterial strain, designated T16R-129T, was isolated from the rhizosphere of a tomato plant collected at a farm located on Buyeo-gun of Chungcheongnam-do, South Korea. Strain T16R-129T grew at 15-40 degrees C and pH 7.0-9.0, and did not require NaCl for growth. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain T16R-129T clustered with members of the genus Terrimonas, and it shared highest similarity with Terrimonas arctica R9-86T (96.1 %), Terrimonas pekingensis QHT (95.9 %), Terrimonas lutea DYT (94.9 %), Terrimonas crocea M1-33108T (95.4 %) and Terrimonas rhizosphaerae CR94T (95.3 %). The major isoprenoid quinone was menaquinone 7 (MK-7). The major cellular fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. The polar lipids of strain T16R-129T were phosphatidylethanolamine, two unidentified aminolipids, two unidentified aminophospholipids and five unidentified polar lipids. The G+C content of the genomic DNA was 46.0 mol%. On the basis of data from this polyphasic taxonomic study, strain T16R-129T represents a novel species in the genus Terrimonas, for which the name Terrimonas terrae sp. nov. is proposed; the type strain is T16R-129T (=KACC 18787T=JCM 31603T). PMID- 28857732 TI - Molecular evidence for the absence of an association between Simkania negevensis and respiratory diseases. AB - Simkania negevensis has been implicated in respiratory diseases. This study aimed to unveil the aetiological role of this bacterium in community-acquired pneumonia (CAP) and bronchitis in Jordanian adults. Nasopharyngeal samples were collected from 98 CAP or bronchitis patients and 96 control individuals, and tested for Simkania nucleic acids using a PCR assay. The overall prevalence of the bacterial DNA in patients was markedly high and reached 57.1 %. Intriguingly, Simkania DNA was detected in 62.5 % of the nasopharyngeal swabs collected from apparently healthy controls (P>0.05). The DNA positivity in the bronchitis and CAP subgroups was 57.7 and 56.9 %, respectively, percentages that are approximately comparable to the DNA positivity assessed for the entire patient population. Simkania is most likely not a causative agent of CAP or bronchitis, despite its remarkable high prevalence. This organism, in the nasopharynx, is potentially harmless to the host and may coexist in a commensal relationship. PMID- 28857733 TI - Mycobacterium stephanolepidis sp. nov., a rapidly growing species related to Mycobacterium chelonae, isolated from marine teleost fish, Stephanolepis cirrhifer. AB - A previously undescribed rapidly growing, non-pigmented mycobacterium was identified based on biochemical and nucleic acid analyses, as well as growth characteristics. Seven isolates were cultured from samples collected from five thread-sail filefish (Stephanolepis cirrhifer) and two farmed black scraper (Thamnaconus modestus). Bacterial growth occurred at 15-35 degrees C on Middlebrook 7H11 agar. The bacteria were positive for catalase activity at 68 degrees C and urease activity, intermediate for iron uptake, and negative for Tween 80 hydrolysis, nitrate reduction, semi-quantitative catalase activity and arylsulfatase activity at day 3. No growth was observed on Middlebrook 7H11 agar supplemented with picric acid, and very little growth was observed in the presence of 5 % NaCl. alpha- and alpha'-mycolates were identified in the cell walls, and a unique profile of the fatty acid methyl esters and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiles of the protein and cell-wall lipids were acquired. Sequence analysis revealed that the seven isolates shared identical sequences for the 16S rRNA, rpoB, hsp65, recA and sodA genes. Phylogenetic analysis of the five gene sequences confirmed that the isolates were unique, but closely related to Mycobacterium chelonae. Antibiotic susceptibility testing revealed the minimum inhibitory concentration (MIC) of clarithromycin against this novel species was <0.25 ug ml-1, which was lower than that for Mycobacterium salmoniphilum. The hsp65 PCR restriction enzyme analysis pattern differed from those of M. chelonae and M. salmoniphilum. Based on these findings, the name Mycobacterium stephanolepidis sp. nov. is proposed for this novel species, with the type strain being NJB0901T (=JCM 31611T=KCTC 39843T). PMID- 28857734 TI - Low incidence of coaggregation amongst bacteria isolated from the upper respiratory tract in health and disease. AB - The nasal cavity harbours a commensal microbiota that reportedly provides colonization resistance against respiratory pathogens. Following the onset of chronic rhinosinusitis (CRS), a change in sinus microbiota composition is frequently reported in which atypical anaerobic and/or Gram-negative bacteria predominate. We have investigated pairwise interactions between respiratory bacteria isolated from healthy adults (n=3) and individuals exhibiting CRS (n=3). Antagonism was determined using a spot plate methodology and coaggregation scores were determined using a quantitative spectrophotometric assay. Obligate anaerobes were isolated from all CRS samples and exhibited inter-host growth inhibition of commensal nasal bacteria, including Corynebacterium spp. and Staphylococcus spp. Antagonism between bacteria isolated from healthy individuals was limited to corynebacterial-mediated inhibition of the staphylococci. The frequency of coaggregation was low overall (2/153 pairwise interactions). Antagonism of the nasal microbiota by respiratory pathogens may represent a competitive strategy in the sinus and warrants further investigation. PMID- 28857735 TI - Angustibacter speluncae sp. nov., isolated from a lava cave stalactite. AB - Gram-reaction-positive, strictly aerobic, motile coccoid- to rod-shaped actinobacteria, designated strains YC2-20T and YC2-19 were isolated from pieces of stalactites collected at the Yongcheon Cave in Jeju, Republic of Korea. The cells of orange-coloured colonies grew at 20-37 degrees C, pH 6-10 and in the absence of NaCl. In the neighbour-joining tree based on 16S rRNA gene sequences, the novel isolates formed a distant sublineage at the base of the radiation of the genus Angustibacter. The novel isolates shared identical 16S rRNA gene sequences to each other and revealed a 16S rRNA gene sequence similarity of 95.6 % to the closest relative, Angustibacter aerolatus and <95 % to other members of the family Kineosporiaceae. Albeit with a low similarity of 16S rRNA gene sequences and a distinct phylogenetic position, most of the chemotaxonomic characteristics were in agreement with those of the genus Angustibacter: meso diaminopimelic acid as the diagnostic diamino acid in the cell wall; MK-9(H4) as the major menaquinone; polar lipids including diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside; and a DNA G+C content of 73.1 mol%. On the basis of the phenotypic and phylogenetic distinctiveness, the novel isolates are considered to represent members of a novel species of the genus Angustibacter, for which the name Angustibacter speluncae sp. nov. is proposed, with type strain YC2-20T (=KCTC 39842T=DSM 103769T). PMID- 28857736 TI - Cryptosporangium eucalypti sp. nov., an actinomycete isolated from Eucalyptus camaldulensis roots. AB - A novel actinomycete, designated strain EURKPP3H10T, was isolated from surface sterilized roots of Eucalyptus camaldulensis Dehnh., collected from Kamphaengphet Silvicultural Research Station, Kamphaengphet province, Thailand. The taxonomic position of strain EURKPP3H10T was studied using a polyphasic approach. Phylogenetic evaluation based on 16S rRNA gene sequence analysis showed that strain EURKPP3H10T belongs to the genus Cryptosporangium, with the highest sequence similarity to Cryptosporangium cibodasense LIPI11-2-Ac046T (99.2 %). Colonies of strain EURKPP3H10T were orange yellow. Spherical sporangia with motile spores were observed. The strain contained meso-diaminopimelic acid and acofriose, arabinose, galactose, glucose, mannose, xylose and ribose in whole cell hydrolysates. The predominant menaquinones were MK-9(H8) and MK-9(H6). The major fatty acids were iso-C16 : 0, C17 : 1omega8c, C18 : 1omega9c and C17 : 0. The polar lipids of the strain were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol and unknown lipids. The DNA G+C content of the genomic DNA was 71.5 mol%. Based on comparative analysis of physiological, biochemical and chemotaxonomic data, including DNA-DNA hybridization, strain EURKPP3H10T represents a novel species of the genus Cryptosporangium, for which the name Cryptosporangium eucalypti sp. nov. is proposed. The type strain is EURKPP3H10T (=BCC 77605T=NBRC 111482T). PMID- 28857737 TI - Roseibium sediminis sp. nov., isolated from sea surface sediment. AB - A Gram-stain-negative, rod-shaped, facultatively aerobic strain, motile by a monotrichous (polar or lateral) flagellum, designated BSS09T, was isolated from surface sediment of the Bohai Sea, PR China. Growth was observed at 10-45 degrees C (optimum 32 degrees C), in the presence of 1.0-7.0 % (w/v) NaCl (optimum 4.0 %) and at pH 5.0-8.0 (optimum pH 6.0). Phylogenetic analysis, based on 16S rRNA gene sequences, revealed that strain BSS09T belonged to the genus Roseibium and showed the highest sequence similarity of 96.5 % to Roseibium hamelinense JCM 10544T. The significant dominant fatty acid was C18 : 1omega7c. The polar lipids comprised one phosphatidylcholine, one phosphatidylmonomethylethanolamine, one unidentified aminolipid, one phosphatidylglycerol, one phosphatidylethanolamine and one unidentified polar lipid. The major respiratory quinone was Q-10. The DNA G+C content of strain BSS09T was 57.1 mol%. On the basis of evidence from this polyphasic study, strain BSS09T is proposed to represent a novel species of the genus Roseibium, for which the name Roseibium sediminis sp. nov. is proposed. The type strain is BSS09T (=KCTC 52373T=MCCC 1K03201T). PMID- 28857738 TI - Detection of high levels of resistance to linezolid and vancomycin in Staphylococcus aureus. AB - Both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) are rapidly overcoming the current array of drugs. One hundred and fifty isolates from a hospital were studied for resistance towards linezolid and vancomycin. Fifty-four (36.0 %) isolates were MRSA. Both MRSA and MSSA showed high resistance towards linezolid when using the disc diffusion method, with the figures being 48.1 and 29.2 %, respectively. The figures for the E-test were 46.3 and 27.0 %, respectively. The vancomycin resistance was remarkable in MRSA (14.8 %), but relatively low in MSSA (3.1 %). The E-test results were 13.0 and 4.16 %, respectively. The cfr gene was detected in 78 % of linezolid-resistant isolates and the vanA operon was detected in 74 % of vancomycin-resistant isolates. This level of resistance against linezolid and vancomycin is unprecedented. These results are alarming and highlight the threat of non-treatable S. aureus strains. PMID- 28857739 TI - Association of codon 72 polymorphism of p53 with the severity of cervical dysplasia, E6-T350G and HPV16 variant lineages in HPV16-infected women. AB - PURPOSE: Polymorphic variability in the tumour-suppressor protein p53 at codon 72 has a considerable impact on cervical cancer development. The present study clarified the association between p53 codon 72 genotypes and the risk of cervical disease in Greek patients. We also examined whether the presence of specific p53 genotypes in combination with HPV16 variants or E6 T350G sequence variation can modify an individual's susceptibility to cervical disease. METHODOLOGY: The analysis of p53 genotypes was performed through PCR-RFLP. Sequence and phylogenetic tree analyses of the HPV16 E6 gene were also performed in order to identify HPV16 variants and T350G sequence variation.Results/Key findings. The outcomes of the present analysis revealed that women who are homozygous for the arg genotype are at a 4.17-fold higher risk of developing HPV16-associated HSIL+ (OR=4.17, 95 % CI:1.48-4.9, P=0.0049). Moreover, p53 arg/arg patients infected by an HPV16 prototype strain were associated with an increased risk of more severe lesions, while a significant relationship between the p53 arg/arg genotype in patients with T350G sequence variation and the risk of high-grade squamous intraepithelial lesions (HSILs) was revealed. CONCLUSION: The oncogenic potential of the virus is increased by the presence of the p53 arg/arg genotype in the Greek population in such a way that the specific protein interaction E6 (L83V) p53 (Arg-72) can modify an individual's susceptibility to cervical disease. PMID- 28857740 TI - A pilot randomised controlled trial of community-led ANtipsychotic Drug REduction for Adults with Learning Disabilities. AB - BACKGROUND: Data suggest that approximately 50,000 adults with learning disabilities (LDs) in England and Wales are currently prescribed antipsychotic medication. Illness in this population is common, including significant rates of challenging behaviour and mental illness, but there is particular concern over the use of antipsychotics prescribed for reasons other than the treatment of psychosis. Control of challenging behaviour is the primary reason why such medications are prescribed despite the absence of good evidence for any therapeutic effect for this purpose. OBJECTIVES: To assess the feasibility of recruitment and retention and to explore non-efficacy-based barriers to a blinded antipsychotic medication withdrawal programme for adults with LDs without psychosis compared with treatment as usual. A secondary objective was to compare trial arms regarding clinical outcomes. DESIGN: A two-arm individually randomised double-blind placebo-controlled drug reduction trial. SETTING: Recruitment was through community learning disability teams (CLDTs) in south Wales and south-west England. PARTICIPANTS: Adults with LDs who are prescribed risperidone for treatment of challenging behaviour with no known current psychosis or previous recurrence of psychosis following prior drug reduction. INTERVENTION: A double blind drug reduction programme leading to full withdrawal within 6 months. Treatment in the intervention group was gradually reduced over a 6-month period and then maintained at the same level for a further 3 months, still under blind conditions. In the control group, the baseline level of medication was maintained throughout the 9-month period. The blind was broken at 9 months, following final data collection. MAIN OUTCOME MEASURES: Feasibility outcomes were (1) the number and proportion of general practices/CLDTs that progressed from initial approach to recruitment of participants and (2) the number and proportion of recruited participants who progressed through the various stages of the study. Trial arms were also compared regarding clinical outcomes, the Modified Overt Aggression Scale, the Aberrant Behaviour Checklist, the Psychiatric Assessment Schedule for Adults with Developmental Disability checklist, the Antipsychotic Side-effect Checklist, the Dyskinesia Identification System Condensed User Scale, the Client Service Receipt Inventory, use of other interventions to manage challenging behaviour, use of as-required (pro re nata) medication and level of psychotropic medication use. RESULTS: Of the 22 participants randomised (intervention, n = 11; control, n = 11), 13 (59%) achieved progression through all four stages of reduction. Follow-up data at 6 and 9 months were obtained for 17 participants (intervention, n = 10; and control, n = 7; 77% of those randomised). There were no clinically important changes in participants' levels of aggression or challenging behaviour at the end of the study. There were no expedited safety reports. Four adverse events and one serious adverse event were reported during the trial. LIMITATIONS: Recruitment was challenging, which was largely a result of difficulty in identifying appropriate persons to consent and carer concerns regarding re-emergence of challenging behaviour. Reduced recruitment meant that the full trial became an exploratory pilot study. CONCLUSIONS: The results indicate that drug reduction is possible and safe. However, concerns about taking part were probably exacerbated by limited availability of alternative (behavioural) interventions to manage behaviour; therefore, focused support and alternative interventions are required. The results of the qualitative study provide important insights into the experiences of people taking part in drug reduction studies that should influence future trial development. FUTURE WORK: We recommend that further work focuses on support for practitioners, carers and patients in reducing antipsychotic medication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38126962. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 47. See the NIHR Journals Library website for further project information. PMID- 28857741 TI - In vivo experiments do not support the charge zipper model for Tat translocase assembly. AB - The twin-arginine translocase (Tat) transports folded proteins across the bacterial cytoplasmic membrane and the plant thylakoid membrane. The Tat translocation site is formed by substrate-triggered oligomerization of the protein TatA. Walther and co-workers have proposed a structural model for the TatA oligomer in which TatA monomers self-assemble using electrostatic 'charge zippers' (Cell (2013) 132: 15945). This model was supported by in vitro analysis of the oligomeric state of TatA variants containing charge-inverting substitutions. Here we have used live cell assays of TatA assembly and function in Escherichia coli to re-assess the roles of the charged residues of TatA. Our results do not support the charge zipper model. Instead, we observe that substitutions of charged residues located in the TatA amphipathic helix lock TatA in an assembled state, suggesting that these charged residues play a critical role in the protein translocation step that follows TatA assembly. PMID- 28857742 TI - Cation selectivity of the presequence translocase channel Tim23 is crucial for efficient protein import. AB - Virtually all mitochondrial matrix proteins and a considerable number of inner membrane proteins carry a positively charged, N-terminal presequence and are imported by the TIM23 complex (presequence translocase) located in the inner mitochondrial membrane. The voltage-regulated Tim23 channel constitutes the actual protein-import pore wide enough to allow the passage of polypeptides with a secondary structure. In this study, we identify amino acids important for the cation selectivity of Tim23. Structure based mutants show that selectivity is provided by highly conserved, pore-lining amino acids. Mutations of these amino acid residues lead to reduced selectivity properties, reduced protein import capacity and they render the Tim23 channel insensitive to substrates. We thus show that the cation selectivity of the Tim23 channel is a key feature for substrate recognition and efficient protein import. PMID- 28857743 TI - A quantitative theory of gamma synchronization in macaque V1. AB - Gamma-band synchronization coordinates brief periods of excitability in oscillating neuronal populations to optimize information transmission during sensation and cognition. Commonly, a stable, shared frequency over time is considered a condition for functional neural synchronization. Here, we demonstrate the opposite: instantaneous frequency modulations are critical to regulate phase relations and synchronization. In monkey visual area V1, nearby local populations driven by different visual stimulation showed different gamma frequencies. When similar enough, these frequencies continually attracted and repulsed each other, which enabled preferred phase relations to be maintained in periods of minimized frequency difference. Crucially, the precise dynamics of frequencies and phases across a wide range of stimulus conditions was predicted from a physics theory that describes how weakly coupled oscillators influence each other's phase relations. Hence, the fundamental mathematical principle of synchronization through instantaneous frequency modulations applies to gamma in V1 and is likely generalizable to other brain regions and rhythms. PMID- 28857744 TI - Dynamics of BMP signaling and distribution during zebrafish dorsal-ventral patterning. AB - During vertebrate embryogenesis, dorsal-ventral patterning is controlled by the BMP/Chordin activator/inhibitor system. BMP induces ventral fates, whereas Chordin inhibits BMP signaling on the dorsal side. Several theories can explain how the distributions of BMP and Chordin are regulated to achieve patterning, but the assumptions regarding activator/inhibitor diffusion and stability differ between models. Notably, 'shuttling' models in which the BMP distribution is modulated by a Chordin-mediated increase in BMP diffusivity have gained recent prominence. Here, we directly test five major models by measuring the biophysical properties of fluorescently tagged BMP2b and Chordin in zebrafish embryos. We found that BMP2b and Chordin diffuse and rapidly form extracellular protein gradients, Chordin does not modulate the diffusivity or distribution of BMP2b, and Chordin is not required to establish peak levels of BMP signaling. Our findings challenge current self-regulating reaction-diffusion and shuttling models and provide support for a graded source-sink mechanism underlying zebrafish dorsal-ventral patterning. PMID- 28857745 TI - Principles of cellular resource allocation revealed by condition-dependent proteome profiling. AB - Growing cells coordinate protein translation with metabolic rates. Central to this coordination is ribosome production. Ribosomes drive cell growth, but translation of ribosomal proteins competes with production of non-ribosomal proteins. Theory shows that cell growth is maximized when all expressed ribosomes are constantly translating. To examine whether budding yeast function at this limit of full ribosomal usage, we profiled the proteomes of cells growing in different environments. We find that cells produce excess ribosomal proteins, amounting to a constant ~8% of the proteome. Accordingly, ~25% of ribosomal proteins expressed in rapidly growing cells does not contribute to translation. Further, this fraction increases as growth rate decreases and these excess ribosomal proteins are employed when translation demands unexpectedly increase. We suggest that steadily growing cells prepare for conditions that demand increased translation by producing excess ribosomes, at the expense of lower steady-state growth rate. PMID- 28857746 TI - Purinergic regulation of brain catecholamine neurotransmission: In vivo electrophysiology and microdialysis study in rats. AB - It was previously reported that adenosine-2A (A2A) receptors interact with dopamine-2 (D2) receptors on a molecular level. The aim of the current study was to investigate the functional output of this interaction. In vivo microdialysis was used to assess the effects of an antagonist of A2A receptors, ZM 241385, and an antagonist of D2 receptors haloperidol, either alone or in combination, on brain catecholamine levels. It was found that ZM 241385 did not alter catecholamine levels by its own, but potentiated haloperidol-induced dopamine and norepinephrine release in the nucleus accumbens and prefrontal cortex, respectively. In vivo electrophysiology was used to assess the effect of an agonist (CGS 216820) and an antagonist (ZM 241385) of A2A receptors on the excitability of dopamine and norepinephrine neurons. It was found that CGS 216820 dose-dependently inhibited dopamine and norepinephrine neurons and ZM 241385 reversed this inhibition. In conclusion, those A2A receptors modulate brain catecholamine transmission, and this modulation is mediated, at least in part, via the regulation of excitability of norepinephrine and dopamine neurons. The ability of antagonists of A2A receptors to potentiate the effect of haloperidol on brain norepinephrine and dopamine levels may enhance its clinical efficacy as an antipsychotic drug. PMID- 28857747 TI - Investigation of cerebral venous outflow in microgravity. AB - OBJECTIVE: The gravitational gradient is the major component to face when considering the physiology of venous return, and there is a growing interest in understanding the mechanisms ensuring the heart filling, in the absence of gravity, for astronauts who perform long-term space missions. APPROACH: The purpose of the Drain Brain project was to monitor the cerebral venous outflow of a crew member during an experiment on the International Space Station (ISS), so as to study the compensatory mechanisms that facilitate this essential physiological action in subjects living in a microgravity environment. Such venous function has been characterized by means of a novel application of strain gauge plethysmography which uses a capacitive sensor. MAIN RESULTS: In this contribution, preliminary results of our investigation have been presented. In particular, comparison of plethysmography data confirmed that long duration spaceflights lead to a redistribution of venous blood volume, and showed interesting differences in the amplitude of cardiac oscillations measured at the level of the neck veins. SIGNIFICANCE: The success of the experiment has also demonstrated that thanks to its easy portability, non-invasiveness, and non operator dependence, the proposed device can be considered as a novel tool for use aboard the ISS. Further trials are now under way to complete the investigation on the drainage function of the neck veins in microgravity. PMID- 28857748 TI - Effects of fatigue and recovery on electromechanical delay during isokinetic muscle actions. AB - OBJECTIVE: To examine muscle-specific differences and the effects of fatigue and recovery on electromechanical delay (EMD) during maximal isokinetic muscle actions. APPROACH: Thirteen men performed maximal isokinetic knee extension muscle actions at 60 degrees s-1, pretest, posttest, and after 5 min of recovery from 25 maximal isokinetic knee extensions. The onsets of the electromyographic, mechanomyographic, and force signals were used to identify EMD measures from the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF). MAIN RESULTS: There were posttest increases in all EMD measures for all muscles that returned to pretest levels after 5 min of recovery. There were, however, no differences in EMD measures between the VL and VM. All EMD values from the RF were greater than the VL and VM. SIGNIFICANCE: These findings suggested muscle specific differences in EMD and that excitation-contraction coupling failure and increased compliance of the series elastic component occurred posttest, but subsided after 5 min of recovery. PMID- 28857749 TI - Direct means of obtaining CAVI0-a corrected cardio-ankle vascular stiffness index (CAVI)-from conventional CAVI measurements or their underlying variables. AB - OBJECTIVE: Cardio-ankle vascular index (CAVI) as measured using the VaSera device (CAVIVS, Fukuda Denshi), has been proposed as a stiffness index that does not depend on blood pressure. We have recently shown theoretically that CAVIVS still exhibits blood pressure dependence, and proposed the corrected index CAVI0. The present study aims to establish a method of calculating [Formula: see text] either (i) from VaSera-reported values of cardiac-brachial and brachial-ankle pulse transit times (tb and tba, respectively) and blood pressure, or (ii) directly from CAVIVS. To derive this method, the relationship among CAVIVS and its scale constants a and b, tb, tba, and blood pressure has to be established. APPROACH: From data of 497 subjects, eight candidate CAVI parameters were defined and calculated, containing all combinations of left or right tb/tba/blood pressure. Candidates were evaluated through correlation with measured left and right CAVIVS. Correlations were compared statistically. Once the correct candidates were determined, two constants (a and b) required for converting CAVIVS to CAVI0 were estimated through linear regression. MAIN RESULTS: Left and right CAVIVS are calculated using left and right tba; however, both left and right CAVIVS are calculated using right brachial blood pressures and right tb. Constants a and b for conversion of CAVIVS to CAVI0 were estimated to be 0.842 [0.836 0.848] and 0.753 [0.721 0.786] (mean [95%CI]), respectively. Equations to estimate CAVI0 from CAVIVS, and to directly calculate CAVI0 from the VaSera output are provided in this paper, as well as in a directly usable spreadsheet supplement. SIGNIFICANCE: Our results permit straightforward calculation of [Formula: see text] during a study, as well as retrospective estimation of [Formula: see text] from CAVIVS in already published studies or where the original transit time values are not available, paving the way for thorough comparison of CAVI0 to CAVIVS in clinical and research settings. Novelty and significance Cardio-ankle vascular index (CAVI) as measured using the VaSera device (CAVIVS, Fukuda Denshi), has been proposed as a blood pressure-independent arterial stiffness index. We have recently shown theoretically that CAVIVS still exhibits pressure dependence, and proposed a corrected index, CAVI0. In the present study, we derived equations to directly obtain CAVI0 using data from the VaSera device. Our results permit straightforward calculation of [Formula: see text] during a study, as well as retrospective estimation of [Formula: see text] from CAVIVS in already published studies, paving the way for thorough comparison of CAVI0 to CAVIVS in clinical and research settings. PMID- 28857750 TI - High-frequency electromechanical resonators based on thin GaTe. AB - Gallium telluride (GaTe) is a layered material, which exhibits a direct bandgap (~1.65 eV) regardless of its thickness and therefore holds great potential for integration as a core element in stretchable optomechanical and optoelectronic devices. Here, we characterize and demonstrate the elastic properties and electromechanical resonators of suspended thin GaTe nanodrums. We used atomic force microscopy to extract the Young's modulus of GaTe (average value ~39 GPa) and to predict the resonance frequencies of suspended GaTe nanodrums of various geometries. Electromechanical resonators fabricated from suspended GaTe revealed fundamental resonance frequencies in the range of 10-25 MHz, which closely match predicted values. Therefore, this study paves the way for creating a new generation of GaTe based nanoelectromechanical devices with a direct bandgap vibrating element, which can serve as optomechanical sensors and actuators. PMID- 28857751 TI - Single-nanowire, low-bandgap hot carrier solar cells with tunable open-circuit voltage. AB - Compared to traditional pn-junction photovoltaics, hot carrier solar cells offer potentially higher efficiency by extracting work from the kinetic energy of photogenerated 'hot carriers' before they cool to the lattice temperature. Hot carrier solar cells have been demonstrated in high-bandgap ferroelectric insulators and GaAs/AlGaAs heterostructures, but so far not in low-bandgap materials, where the potential efficiency gain is highest. Recently, a high open circuit voltage was demonstrated in an illuminated wurtzite InAs nanowire with a low bandgap of 0.39 eV, and was interpreted in terms of a photothermoelectric effect. Here, we point out that this device is a hot carrier solar cell and discuss its performance in those terms. In the demonstrated devices, InP heterostructures are used as energy filters in order to thermoelectrically harvest the energy of hot electrons photogenerated in InAs absorber segments. The obtained photovoltage depends on the heterostructure design of the energy filter and is therefore tunable. By using a high-resistance, thermionic barrier, an open circuit voltage is obtained that is in excess of the Shockley-Queisser limit. These results provide generalizable insight into how to realize high voltage hot carrier solar cells in low-bandgap materials, and therefore are a step towards the demonstration of higher efficiency hot carrier solar cells. PMID- 28857752 TI - Mental Health Stigma: so much progress and yet a long way to go - Introduction to special issue on stigma. PMID- 28857753 TI - Does Individual Stigma Predict Mental Health Funding Attitudes? Toward an Understanding of Resource Allocation and Social Climate. AB - BACKGROUND: The uneven progression of mental health funding in the United States, and the way that the funding climate seems to be influenced by local and regional differences, raises the issue of what factors, including stigma, may impact mental health funding decisions. Criticisms that mental health stigma research is too individually-focused have led researchers to consider how broader, macro level forms of stigma - such as structural stigma - intersect with micro-level forms of individual stigma. While some studies suggest that macro and micro stigma levels are distinct processes, other studies suggest a more synergistic relationship between structural and individual stigma. METHOD: Participants in the current study (N = 951; national, convenience sample of the U.S.) completed a hypothetical mental health resource allocation task (a measure of structural discrimination). We then compared participants' allocation of resources to mental health to participants' endorsement of negative stereotypes, beliefs about recovery and treatment, negative attributions, intended social distancing, microaggressions, and help-seeking (measures of individual stigma). RESULTS: Negative stereotyping, help-seeking self-stigma, and intended social distancing behaviors were weakly but significantly negatively correlated with allocating funds to mental health programs. More specifically, attributions of blame and anger were positively correlated to funding for vocational rehabilitation; attributions of dangerousness and fear were negatively correlated to funding for supported housing and court supervision and outpatient commitment; and attributions of anger were negatively correlated to funding for inpatient commitment and hospitalization. CONCLUSIONS: Individual stigma and sociodemographic factors appear to only partially explain structural stigma decisions. Future research should assess broader social and contextual factors, in addition to other beliefs and worldviews (e.g., allocation preference questionnaire, economic beliefs). PMID- 28857754 TI - Mental Illness Stigma Expressed by Police to Police. AB - OBJECTIVE: This paper describes mental health related stigma expressed by police to police using a newly developed 11-item Police Officer Stigma Scale and reports on the preliminary psychometric properties (factor structure and internal reliability) of this scale. METHOD: The scale used an indirect measurement approach adapted from the Perceived Devaluation and Discrimination Scale. Five themes appropriate to police culture were adapted and six additional items were added. Responses were rated on a 5-point agreement scale with an additional don't know option. Data were collected from officers attending a mandatory workshop (90.5% response). RESULTS: Exploratory factor analysis showed the scale to be unidimensional and internally reliable (Cronbach's alpha was 0.82). The most endorsed items pertained to avoiding disclosure to a supervisor/manager or to a colleague (85% agreement), that most officers would expect discrimination at work (62%), and that most officers would not want a supervisor or manager who had a mental illness (62%). CONCLUSIONS: Findings highlight that (a) Police-to-police mental illness stigma may be a particularly strong feature of police cultures; (b) police should be a focus for targeted anti-stigma interventions; and PMID- 28857755 TI - 'People with Problems, Not Patients with Illnesses': Using Psychosocial Frameworks to Reduce the Stigma of Psychosis. AB - BACKGROUND: Stigma and discrimination are major difficulties for people with psychosis. However, despite the dominance of biomedical ideology in public education and de-stigmatization efforts, there is substantial evidence that campaigns based on the "medical model" (such as the "mental illness is an illness like any other" approach) are not only ineffective, but can actually compound the problem. This paper considers the alternative role of psychosocial explanatory frameworks in promoting more tolerant and enlightened approaches to, and attitudes about, psychosis. DATA: A summary of theoretical and empirical research on the effectiveness of mental health anti-stigma campaigns is presented. CONCLUSIONS: There is a reasonably substantial evidencebase supporting the hypothesis that anti-stigma campaigns which frame psychosis as a meaningful response to adversity are effective. They are a more promising approach to "humanizing" people with complex mental health problems than strategies based on models of disease and disability. PMID- 28857756 TI - Explicit and Implicit Stigma of Mental Illness as Predictors of the Recovery Attitudes of Assertive Community Treatment Practitioners. AB - BACKGROUND: While explicit negative stereotypes of mental illness are well established as barriers to recovery, implicit attitudes also may negatively impact outcomes. The current study is unique in its focus on both explicit and implicit stigma as predictors of recovery attitudes of mental health practitioners. METHOD: Assertive Community Treatment practitioners (n = 154) from 55 teams completed online measures of stigma, recovery attitudes, and an Implicit Association Test (IAT). RESULTS: Three of four explicit stigma variables (perceptions of blameworthiness, helplessness, and dangerousness) and all three implicit stigma variables were associated with lower recovery attitudes. In a multivariate, hierarchical model, however, implicit stigma did not explain additional variance in recovery attitudes. In the overall model, perceptions of dangerousness and implicitly associating mental illness with "bad" were significant individual predictors of lower recovery attitudes. CONCLUSIONS: The current study demonstrates a need for interventions to lower explicit stigma, particularly perceptions of dangerousness, to increase mental health providers' expectations for recovery. The extent to which implicit and explicit stigma differentially predict outcomes, including recovery attitudes, needs further research. PMID- 28857757 TI - Violating Clan and Kinship Roles as Risk Factors for Suicide and Stigma among Lao Refugees: An Application of the Cultural Model of Suicide and "What Matters Most" Frameworks. AB - BACKGROUND: While Asian groups have immigrated worldwide, suicide risk models have neglected to integrate cultural components. This study incorporates how stigma associated with failure to uphold clan/kinship roles can increase suicide risk in highly-marginalized Lao-Americans. METHODS: One focus group with five Lao participants and 21 individual semi-structured interviews with community family members were conducted. Transcripts were coded via directed content analysis using the "What Matters Most" and Cultural Theory of Suicide frameworks. RESULTS: Violating role-expectations associated with youth, adults and older adults appears to be associated with risk for suicide. This suggests that the failure of adults to fulfill their roles might potentially threaten loss of "full personhood" and trigger stigma, thus potentially evoking greater suicide risk. CONCLUSION: Interventions would benefit from cultural considerations of fulfilling role-expectations and "personhood" to combat suicide and stigma within cultural communities. PMID- 28857758 TI - Greater Metacognition and Lower Fear of Negative Evaluation: Potential Factors Contributing to Improved Stigma Resistance among Individuals Diagnosed with Schizophrenia. AB - BACKGROUND: Stigma resistance, one's ability to block the internalization of stigma, appears to be a key domain of recovery. However, the conditions in which one is most likely to resist stigma have not been identified, and models of stigma resistance have yet to incorporate one's ability to consider the mind of others. The present study investigated the impact of the interaction between metacognition, or one's ability to form an integrated representation of oneself, others, and the world, and fear of negative evaluation on one's ability to resist stigma. METHODS: Narratives of encounters with stigma shared by 41 persons with schizophrenia or schizoaffective disorders were first coded for spontaneous expressions of fear of negative evaluation from others. Two-step cluster analyses were then conducted in order to test the hypothesis that metacognition and fearing negative evaluation from others are important, interacting pathways which contribute to resisting stigma. RESULTS: Those with high (n = 11; 26.8%), intermediate (n = 9; 22.0%), and low metacognition (n = 21; 51.2%) significantly differed on stigma resistance (F = 9.49, p<0.001) and the high metacognition group was most likely to resist stigma. Those with high and low metacognition did not express fear of negative evaluation, while those with intermediate metacognition did express fear of negative evaluation. PMID- 28857759 TI - Self-Stigma, Identity, and Co-Occurring Disorders. AB - BACKGROUND: A four stage regressive model that links public stigma to self-stigma is applied to mental illness and substance use disorder. We assess this four stage model in those with co-occurring disorders versus those who have mental illness or substance use disorder alone. METHOD: 366 people who self-identified as having either a mental illness or co-occurring mental illness with substance use disorder were recruited from MTurk and completed measures on identity and self-stigma. RESULTS: Higher group identity predicted lower selfstigma in those with mental illness while this effect was not present for participants with co occurring disorders. Limitations include that this study only looked at mental illness identity for those with both mental illness and substance use disorder; sample limitations are also discussed. CONCLUSIONS: Those with co-occurring disorders may identify more with certain groups over others. PMID- 28857760 TI - Different Roads Lead to Rome: Exploring Patterns of Change among Narrative Enhancement and Cognitive Therapy (NECT) Participants. AB - BACKGROUND: Narrative enhancement and cognitive therapy (NECT) is aimed at decreasing self-stigma and promoting recovery. The current study used a mixed methods approach to explore the process and mechanisms by which NECT affects self stigma and recovery. METHOD: Sixty-two participants with serious mental illness (SMI) and enrolled in NECT completed questionnaires assessing self-clarity, recovery, self-stigma, and hope before and after the intervention, and the two latter questionnaires also after completing two defined parts of the intervention. In addition, one group's transcriptions were qualitatively analyzed and compared with changes in quantitative measures. RESULTS: Quantitative analysis revealed a significant increase in self-clarity and a decrease in self stigma, which occurred early in the intervention. Qualitative analysis identified factors contributing to such changes. Limitations include lack of a comparison group, bias selection in the qualitative analysis and case record diagnoses. CONCLUSIONS: NECT was found to be effective in reducing self-stigma and improving self clarity and the mechanisms and process were identified. PMID- 28857761 TI - Poor Responders-Four Megadoses in Treating Vitamin-D Deficiency and Variable Outcome-A Prospective Interventional Study. PMID- 28857762 TI - Strangulation and Its Role in Multiple Causes of Death. AB - Forensic pathologists have a duty to determine the cause and manner of death and are bound by international guidelines in the completion of the death certificate. Sometimes, there are complex circumstances surrounding a death that cannot be captured in the structure of the death certificate and its requirement of listing only 1 cause of death per line. Cases may have multiple causes of death with comorbid medical conditions or inflicted injuries that equally contribute to the ultimate demise. Compared with other forms of homicide, autopsy evidence of strangulation will often be found with other life-threatening traumatic injuries. The Wayne County Medical Examiner's Office conducted a retrospective study of strangulation cases that came into the office from mid-2007 to the end of 2016. The purpose of the study was to examine patterns of injuries in strangulation cases and identify those with additional traumatic injuries of commensurate extent that required incorporation into the cause of death. A total of 43 strangulation cases were found, of which there were equal numbers of ligature and manual strangulations (19 each) and 5 cases in which the method was not specified, and decedents were divided: 63% female and 37% male. Fourteen of these cases were recognized to have multiple causes of death, where blunt force trauma was the most common additional cause, and the sex distribution weighed heavily toward the female (approximately 79%). PMID- 28857765 TI - Impact of Diuretic Therapy in the Treatment of Bronchopulmonary Dysplasia and Acute Kidney Injury in the Neonatal Population. AB - BACKGROUND: Diuretics are among the most frequently prescribed medications in the neonatal intensive care unit (NICU), despite minimal data regarding the safety and efficacy of their use in the neonatal population. Off-label diuretic therapy is used in preterm and full-term infants to both optimize kidney function and improve respiratory status. PURPOSE: This article examines the literature specific to the impact of diuretic therapy in the NICU and compares the benefits versus risks of utilization as they pertain to the prevention and treatment of renal and pulmonary dysfunction in this population. METHODS/SEARCH STRATEGY: A comprehensive literature search of online databases was performed, utilizing: CINAHL via EBSCO, PubMed, and ProQuest. Full-text, peer-reviewed, clinical trials, and review articles published in the English language between 2005 and 2015 were searched. FINDINGS/RESULTS: Diuretics rank as the seventh most frequently prescribed medication in the NICU. More than 8% of all NICU patients and 37% of infants born at less than 32 gestational weeks and weighing less than 1500 g are exposed to diuretics. Benefits include lung fluid resorption acceleration, improved urine output, fluid retention counteraction, and augmentation of physiologic weight loss. IMPLICATIONS FOR PRACTICE: Diuretics are currently utilized in the NICU at an alarming rate, without adequate clinical trials regarding their safety and efficacy of use. IMPLICATIONS FOR RESEARCH: Updated studies are needed regarding short- and long-term outcomes of diuretic use, as well as overall general outcome data regarding the impact and evaluation of diuretic usage in the NICU population. PMID- 28857763 TI - Competitive Antagonism of Anesthetic Action at the gamma-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy. AB - BACKGROUND: The authors characterized the gamma-aminobutyric acid type A receptor pharmacology of the novel etomidate analog naphthalene-etomidate, a potential lead compound for the development of anesthetic-selective competitive antagonists. METHODS: The positive modulatory potencies and efficacies of etomidate and naphthalene-etomidate were defined in oocyte-expressed alpha1beta3gamma2L gamma-aminobutyric acid type A receptors using voltage clamp electrophysiology. Using the same technique, the ability of naphthalene-etomidate to reduce currents evoked by gamma-aminobutyric acid alone or gamma-aminobutyric acid potentiated by etomidate, propofol, pentobarbital, and diazepam was quantified. The binding affinity of naphthalene-etomidate to the transmembrane anesthetic binding sites of the gamma-aminobutyric acid type A receptor was determined from its ability to inhibit receptor photoaffinity labeling by the site-selective photolabels [H]azi-etomidate and R-[H]5-allyl-1-methyl-5-(m trifluoromethyl-diazirynylphenyl) barbituric acid. RESULTS: In contrast to etomidate, naphthalene-etomidate only weakly potentiated gamma-aminobutyric acid evoked currents and induced little direct activation even at a near-saturating aqueous concentration. It inhibited labeling of gamma-aminobutyric acid type A receptors by [H]azi-etomidate and R-[H]5-allyl-1-methyl-5-(m-trifluoromethyl diazirynylphenyl) barbituric acid with similar half-maximal inhibitory concentrations of 48 MUM (95% CI, 28 to 81 MUM) and 33 MUM (95% CI, 20 to 54 MUM). It also reduced the positive modulatory actions of anesthetics (propofol > etomidate ~ pentobarbital) but not those of gamma-aminobutyric acid or diazepam. At 300 MUM, naphthalene-etomidate increased the half-maximal potentiating propofol concentration from 6.0 MUM (95% CI, 4.4 to 8.0 MUM) to 36 MUM (95% CI, 17 to 78 MUM) without affecting the maximal response obtained at high propofol concentrations. CONCLUSIONS: Naphthalene-etomidate is a very low-efficacy etomidate analog that exhibits the pharmacology of an anesthetic competitive antagonist at the gamma-aminobutyric acid type A receptor. PMID- 28857766 TI - Glucose Gel as a Treatment Strategy for Transient Neonatal Hypoglycemia. AB - BACKGROUND: Transient asymptomatic neonatal hypoglycemia (TANH) is common as infants transition from their mother's energy stores to their own. There is little evidence supporting the blood glucose threshold that indicates a need for treatment although sustained hypoglycemia has been correlated with negative neurodevelopmental consequences. Treatment of TANH includes a stepwise approach from supplemental enteral feedings, buccal glucose gel, intravenous dextrose infusion, and/or transfer to special care units including neonatal intensive care units. PURPOSE: The purpose of this evidence-based practice brief is to review current evidence on 40% buccal glucose gel administration as a treatment strategy for TANH. METHODS/SEARCH STRATEGY: CINAHL, Cochrane, Google Scholar, and PubMed were searched using the key words and restricted to English language over the last 7 years. FINDINGS/RESULTS: The use of buccal dextrose gel for TANH may reduce neonatal intensive care unit admissions, reduce hospital length of stay and cost, support the mother-infant dyad through reduced separation, support exclusive breastfeeding, and improve parental satisfaction without adverse neurodevelopmental consequences. IMPLICATIONS FOR PRACTICE: Timely collection of blood glucose levels following intervention is critical to support clinical decisions. Clinicians should offer family education regarding the rationale for serial glucose monitoring and treatment indications including buccal glucose administration. Clinical protocols can be revised to include use of buccal dextrose gel. IMPLICATIONS FOR RESEARCH: There is a need for rigorous long-term studies comparing treatment thresholds and neurodevelopmental outcomes among various treatment strategies for TANH. PMID- 28857767 TI - Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer. AB - Liposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN 38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC. PMID- 28857768 TI - Treatment with abiraterone in metastatic castration-resistant prostate cancer patients progressing after docetaxel: a retrospective study. AB - The aim of this study was to evaluate abiraterone's efficacy in Italian patients affected with metastatic prostate cancer progressing after treatment with docetaxel. We conducted a retrospective analysis of 60 patients. Prostate specific antigen (PSA) reduction in serum was the primary endpoint for evaluating the efficacy of abiraterone in combination with prednisone treatment, whereas reduced pain, safety, progression-free survival, response rate, and overall survival (OS) were secondary endpoints. A significant correlation was noticed between PSA response and OS. Further, the Index Bravais-Pearson (r) correlation allowed us to observe a significant negative interdependence between PSA response and reduction in pain of 0.57 (95% confidence interval: -0.30 to 0.80) (P=0.005). Meanwhile, regression analysis revealed that PSA levels are predictive of OS. There was a positive correlation with OS, which showed a value of R to 0.50 with a slope of 1.44 (P=0.0021). Abiraterone is a well-tolerated and effective treatment modality for patients affected with metastatic castration-resistant prostate cancer. The drug has a better tolerability profile, gives significant pain relief, and increases the survival rate. PMID- 28857769 TI - Robot-Assisted Training of Arm and Hand Movement Shows Functional Improvements for Incomplete Cervical Spinal Cord Injury. AB - OBJECTIVE: The aim of the study was to demonstrate the feasibility, tolerability, and effectiveness of robotic-assisted arm training in incomplete chronic tetraplegia. DESIGN: Pretest/posttest/follow-up was conducted. Ten individuals with chronic cervical spinal cord injury were enrolled. Participants performed single degree-of-freedom exercise of upper limbs at an intensity of 3-hr per session for 3 times a week for 4 wks with MAHI Exo-II. Arm and hand function tests (Jebsen-Taylor Hand Function Test, Action Research Arm Test), strength of upper limb (upper limb motor score, grip, and pinch strength), and independence in daily living activities (Spinal Cord Independence Measure II) were performed at baseline, end of training, and 6 mos later. RESULTS: After 12 sessions of training, improvements in arm and hand functions were observed. Jebsen-Taylor Hand Function Test (0.14[0.04]-0.21[0.07] items/sec, P = 0.04), Action Research Arm Test (30.7[3.8]-34.3[4], P = 0.02), American Spinal Injury Association upper limb motor score (31.5[2.3]-34[2.3], P = 0.04) grip (9.7[3.8]-12[4.3] lb, P = 0.02), and pinch strength (4.5[1.1]-5.7[1.2] lb, P = 0.01) resulted in significant increases. Some gains were maintained at 6 mos. No change in Spinal Cord Independence Measure II scores and no adverse events were observed. CONCLUSIONS: Results from this pilot study suggest that repetitive training of arm movements with MAHI Exo-II exoskeleton is safe and has potential to be an adjunct treatment modality in rehabilitation of persons with spinal cord injury with mild to moderate impaired arm functions. PMID- 28857770 TI - Effectiveness of a Group Physiotherapy Intervention in Nontraumatic, Inoperable Painful Shoulder: A Randomized Clinical Trial. AB - PURPOSE: The aim of the study was to assess the effectiveness of a group intervention in painful shoulder. DESIGN: This was a two-arm controlled clinical trial with a 5-wk follow-up and 1:1 allocation ratio with pretreatment and posttreatment assessments in a Spanish hospital in 2015-2016. This study comprised 74 patients with nontraumatic, inoperable painful shoulder. Patients were randomized into two groups: (1) in intervention, patients underwent group rehabilitation exercises supervised by a physical therapist and (2) in control, patients performed the same exercises as the intervention group but in their own home. The main variables were the differences preintervention and postintervention between scores on the visual analog scale, Constant-Murley scale, and Disabilities of the Arm, Shoulder and Hand scale. The mean differences in the main variables were compared between the two interventions (t test). Registration code is NCT02541279 (clinicaltrials.gov). RESULTS: Differences were found in favor of the intervention group: (1) visual analog scale = -0.1 (P = 0.723), (2) Constant-Murley = 4.1 (P = 0.085), and (3) Disabilities of the Arm, Shoulder and Hand = 14.7 (P < 0.001). CONCLUSIONS: Relevant improvements were obtained with our intervention in the Disabilities of the Arm, Shoulder and Hand scale. PMID- 28857771 TI - Clinical potential of oxytocin in autism spectrum disorder: current issues and future perspectives. AB - The effects of oxytocin on social cognition and behavior have recently attracted considerable attention. In particular, oxytocin has been proposed as a novel therapeutic for psychiatric disorders with social deficits such as autism spectrum disorders. This review provides a brief overview of behavioral and neural responses to oxytocin manipulations in humans and animal models. Although the differences in findings between human and animal studies should be interpreted carefully, shared behavioral phenotypes have been recognized, such as social bonding, social responses, and recognition and usage of social cues. Previous literature suggests that the neural effects of oxytocin in humans and animals overlap in the prefrontal, limbic, and paralimbic cortices. Oxytocin induced alterations in these regions may indicate a fundamental basis for how oxytocin modulates social behaviors and facilitate the discovery of new pharmaceutical targets for treating social deficits. PMID- 28857773 TI - Automatic assessment of blood pressure for Korotkoff sounds on the basis of human hearing threshold. AB - OBJECTIVE: In this study, to measure blood pressure (BP) on the basis of human hearing threshold, we proposed a method that detects the audible or inaudible Korotkoff sounds (K-sounds) using the equal loudness contour and automatically assesses the BP. METHODS: In this study, we detected the systolic period of K sounds using cuff pressure oscillation and then converted the K-sounds corresponding to the systolic interval into sound pressure levels (SPLs). Next, the systolic blood pressure (SBP) and diastolic blood pressure (DBP) were assessed by mapping the K-sounds, which were converted into SPLs on an equal loudness contour. RESULTS: To validate the accuracy of our proposed method, we compared it with the auscultatory method. The mean differences (mean+/-SD) in the SBP and DBP were 0.31+/-1.95 and 1.20+/-2.17 mmHg, respectively. For the SBP, the linear regression equation was y=0.98x+1.56 mmHg (where x and y represent the auscultatory and the proposed method, respectively), with a SE of estimate of 1.93 mmHg and a correlation coefficient of 0.99. For the DBP, the linear regression equation was y=1.01x-1.94 mmHg, with an SE of estimate of 2.18 mmHg and a correlation coefficient of 0.98. All P values were less than 0.0001 for both regressions. CONCLUSION: The auscultatory method of BP monitoring is sensitive to the observer's condition or environmental noise. To overcome these disadvantages, we used the human hearing threshold for objective SBP and DBP automatic assessment, and this method can be applicable to an automatic auscultatory method. PMID- 28857772 TI - A Randomized Double-Blind Placebo-Controlled Phase III Trial of Selegiline Monotherapy for Early Parkinson Disease. AB - BACKGROUND: In Japan, selegiline has been approved for combination therapy with levodopa for Parkinson disease (PD). We conducted a trial of selegiline monotherapy for early PD. METHODS: In this 12-week controlled phase III trial, a total of 292 subjects were randomized to receive placebo (n = 146) (full analysis set 140) or selegiline (n = 146) (full analysis set 139). The primary outcome measure was the change in the Unified Parkinson Disease Rating Scale part I + II + III total score from baseline to the final visit. Other secondary measures and a safety profile were evaluated. RESULTS: Selegiline monotherapy reduced the primary outcome measure by -6.26 +/- 7.86 compared with the placebo -3.14 +/- 6.98 (mean +/- SD, P = 0.0005 by analysis of covariance). There was no significant difference in the number of adverse events between the 2 groups (P > 0.05). CONCLUSIONS: Selegiline monotherapy reduced the total Unified Parkinson Disease Rating Scale part I + II + III score and was well tolerated in Japanese patients with early PD. PMID- 28857775 TI - Ex Vivo Lung Perfusion: Past, Present, and Future. AB - Lung transplant is the only therapy for several end-stage lung diseases; however, the number of donated lungs suitable for transplant is not sufficient, and hundreds of patients have died waiting for an organ. Ex vivo lung perfusion (EVLP) has emerged as a new technology with the potential of reconditioning human donor lungs previously unsuitable for transplantation. Since the first successful transplant of a lung treated using EVLP in the year 2000, multiple clinical trials have demonstrated, in several transplant centers around the word, the feasibility and the potential of EVLP to increase the total number of lungs available for transplant. PMID- 28857774 TI - Combined In Silico and In Vitro Approach Predicts Low Wall Shear Stress Regions in a Hemofilter that Correlate with Thrombus Formation In Vivo. AB - A major challenge in developing blood-contacting medical devices is mitigating thrombogenicity of an intravascular device. Thrombi may interfere with device function or embolize from the device to occlude distant vascular beds with catastrophic consequences. Chemical interactions between plasma proteins and bioengineered surface occur at the nanometer scale; however, continuum models of blood predict local shear stresses that lead to platelet activation or aggregation and thrombosis. Here, an iterative approach to blood flow path design incorporating in silico, in vitro, and in vivo experiments predicted the occurrence and location of thrombi in an implantable hemofilter. Low wall shear stress (WSS) regions identified by computational fluid dynamics (CFD) predicted clot formation in vivo. Revised designs based on CFD demonstrated superior performance, illustrating the importance of a multipronged approach for a successful design process. PMID- 28857776 TI - CHA2DS2-VASc score and exercise capacity of patients with coronary artery disease participating in cardiac rehabilitation programs. AB - BACKGROUND: Exercise based cardiac rehabilitation improves prognosis and quality of life in patients with coronary artery disease. We aimed to investigate whether the CHA2DS2-VASc score may be a predictor of improvement in exercise capacity in acute coronary syndrome (ACS) patients participating in a cardiac rehabilitation program. METHODS: Included were patients following a hospital admission due to ACS and were subsequently referred for an exercise based cardiac rehabilitation during 2010-2015. Participants were divided into three groups of low (1-2), intermediate (3) and high (4<=) CHA2DS2-VASc score. Exercise capacity was evaluated by a treadmill stress test at baseline and following 9 months. The primary endpoint was the percent of patients who achieved at least 25% improvement in exercise capacity. RESULTS: The 597 patients included in the study had a mean age of 65.5+/-9.3 years and consisted of 22.5% women. The primary endpoint of at least 25% improvement in exercise capacity following 9 months of cardiac rehabilitation occurred more frequently in patients in the high CHA2DS2 VASc group compared to the intermediate and low CHA2DS2-VASc score groups (47.3, 29.9 and 36.1% in the high, intermediate and low CHA2DS2-VASc score groups respectively, P=0.002). CONCLUSION: The CHA2DS2-VASc score may serve as a predictor of exercise capacity improvement. Its use for tailoring specific cardiac rehabilitation programs for ACS patients may yield further improvement in functional capacity and better utilization of resources. PMID- 28857777 TI - Barbed Ribbon Device for Progressive Tension Closure Reduces Seroma After Breast Reconstruction. AB - PURPOSE: Implant-based breast reconstruction is fraught with complications related to seroma formation. Soft tissue stabilization with progressive tension closure (PTC) has been shown to decrease seroma formation after various procedures but is less suitable for mastectomy flap stabilization. We evaluate the incidence of seroma in breast reconstruction using bioabsorbable barbed ribbon devices (BRDs) as a novel approach to PTC. METHODS: We performed a retrospective review of all patients whose mastectomy flaps were stabilized with BRDs. These patients were compared with consecutive patients who underwent mastectomy and reconstruction without progressive tension flap stabilization. Patient demographics and outcomes were recorded, including comorbidities, complications, presence of seroma, and total drain days. RESULTS: In the BRD-PTC group, there were 36 breasts compared with 56 in the nonstabilized control group. There were no significant differences in rate of tobacco use, age, or body mass index. We identified 11 seromas in the control group (19.6%) and none in the intervention group (P = 0.05). In the PTC group, drains were removed an average of 5 days sooner than those in controls (P = 0.006). CONCLUSION: Progressive tension stabilization of mastectomy flaps with BRD significantly reduces seroma formation and the duration for which closed suction drainage is required. PMID- 28857778 TI - Incidental lung cancers and positive computed tomography images in people living with HIV. AB - OBJECTIVE: Lung cancer screening with low-dose computed tomography (LDCT) of high risk groups in the general population is recommended by several authorities. This may not be feasible in people living with HIV (PLWHIV) due to higher prevalence of nodules. We therefore assessed the prevalence of positive computed tomography (CT) images and lung cancers in PLWHIV. DESIGN: The Copenhagen comorbidity in HIV infection (COCOMO) study is an observational, longitudinal cohort study. Single round LDCT was performed with subsequent clinical follow-up (NCT02382822). METHOD: Outcomes included histology-proven lung cancer identified by LDCT and positive CT images (noncalcified nodules) in the entire cohort and in the high risk group (>50 years of age and >30 pack-years). We also assessed the procedures and adverse events, and clinical factors associated with a positive CT image. RESULTS: LDCT was performed in 901 patients, including 113 at high risk for lung cancer. A positive image was found in 28 (3.1% of the entire cohort and 9.7% of the high-risk group). Nine patients (all in the high-risk group) had invasive procedures undertaken with no serious adverse events. Lung cancer (stages IA, IIA, and IIIA) was diagnosed in three patients from the high-risk group (2.7%). CD4 cell count less than 500 cells/MUl and CD4 nadir less than 200 cells/MUl were each independently associated with increased odds of a positive image odds ratio 2.32 [95% confidence interval: 1.01-5.13, P = 0.04] and odds ratio 2.63 [95% confidence interval: 1.13-6.66, P = 0.03]. CONCLUSION: Randomized LDCT screening trials in PLWHIV are nonexistent, but these findings are comparable with screening rounds from the general population in terms of prevalence of lung cancer and positive CT images. PMID- 28857779 TI - High levels of postmigration HIV acquisition within nine European countries. AB - OBJECTIVE: We aimed to estimate the proportion of postmigration HIV acquisition among HIV-positive migrants in Europe. DESIGN: To reach HIV-positive migrants, we designed a cross-sectional study performed in HIV clinics. METHODS: The study was conducted from July 2013 to July 2015 in 57 clinics (nine European countries), targeting individuals over 18 years diagnosed in the preceding 5 years and born abroad. Electronic questionnaires supplemented with clinical data were completed in any of 15 languages. Postmigration HIV acquisition was estimated through Bayesian approaches combining extensive information on migration and patients' characteristics. CD4 cell counts and HIV-RNA trajectories from seroconversion were estimated by bivariate linear mixed models fitted to natural history data. Postmigration acquisition risk factors were investigated with weighted logistic regression. RESULTS: Of 2009 participants, 46% were MSM and a third originated from sub-Saharan Africa and Latin America & Caribbean, respectively. Median time in host countries was 8 years. Postmigration HIV acquisition was 63% (95% confidence interval: 57-67%); 72% among MSM, 58 and 51% in heterosexual men and women, respectively. Postmigration HIV acquisition was 71% for Latin America and Caribbean migrants and 45% for people from sub-Saharan Africa. Factors associated with postmigration HIV acquisition among heterosexual women and MSM were age at migration, length of stay in host country and HIV diagnosis year and among heterosexual men, length of stay in host country and HIV diagnosis year. CONCLUSION: A substantial proportion of HIV-positive migrants living in Europe acquired HIV postmigration. This has important implications for European public health policies. PMID- 28857780 TI - MicroRNAs: novel tools to block gut inflammation in HIV? PMID- 28857781 TI - Dolutegravir and neuropsychiatric adverse events: a continuing debate. PMID- 28857782 TI - Eye compartmentalization of HIV replication and cataract risk in HIV-infected patients: is there a link? PMID- 28857783 TI - A critical review of biomarkers in kidney transplantation. AB - PURPOSE OF REVIEW: Improved long-term kidney allograft survival remains a critical goal in transplantation; the achievement of this, however, is highly dependent on the identification of biomarkers that can either predict or allow advance detection of patients at risk of allograft injury. The present review outlines the commonly used biomarkers in kidney transplantation, while also highlighting those currently under investigation, discussing their advantages and limitations. RECENT FINDINGS: Most of the approved biomarkers currently used in kidney transplantation capture antigen recognition or alloantibody production. However, tremendous progress has recently been made in the development of markers of other signaling pathways pertinent to the alloimmune response. Microarray gene sets that predict rejection or poor prognostic phenotypes have been identified in kidney biopsies (the 'molecular microscope diagnostic system' and the 'genomics of chronic allograft rejection' scores), peripheral blood (the 'kidney solid organ response test'), and urine (the '3-genes signature'). Strategies targeting serial measurements of urinary chemokines such as CXCL9 and CXCL10 also appear promising. SUMMARY: Although the range of biomarkers in current use is limited, there are many assays in the development and validation pipeline that appear promising but that have yet to reach mainstream clinical transplantation. The 'ideal biomarker' may eventually transpire to be the combination of several assays. PMID- 28857784 TI - Barriers to Primary Debulking Surgery for Advanced Ovarian Cancer in Latin America. AB - Ovarian cancer is gynecologic tumor with particularly high mortality because it is usually diagnosed in advanced stages. In Latin America and the Caribbean, it is the eighth most common malignancy in women, with an estimated 18,000 new cases and 11,500 deaths annually. Standard of care for women diagnosed with advanced ovarian cancer (AOC) is primary cytoreductive surgery followed by systemic chemotherapy using a combination of paclitaxel plus carboplatin. To pursue upfront surgery, highly specialized and well-trained gynecologic oncologists are required, in addition with well-equipped hospitals. Neoadjuvant chemotherapy (NACT) has been gaining greater acceptance in the past decade for patients with AOC. Two phase III randomized clinical trials have demonstrated that NACT is noninferior to primary cytoreductive surgery for women with stages III and IV epithelial ovarian cancer, and since publication of these results, NACT is more commonly used. Apart from medical reasons of inoperability and unresectability, there may be nonmedical barriers to upfront debulking surgery in clinical practice. These barriers include inadequate expertise of the surgeon, inadequate resources, and/or barriers to access. The aim of this article was to discuss patterns of care and barriers to upfront ovarian debulking surgery, as well as a possible shift toward overuse of NACT as the primary approach for patients with AOC (stages III and IV) in Latin America. PMID- 28857785 TI - Comparison of the laryngeal mask airway supreme and the i-gel in paralysed elderly patients: A randomised controlled trial. AB - BACKGROUND: The laryngeal mask airway supreme (LMA-S) and i-gel are both popular second-generation supraglottic airway devices that have been widely studied in surgical patients, but their differences in clinical performance in the elderly are not clear. OBJECTIVE: We compared the efficacy and safety of the LMA-S and i gel in anaesthetised and paralysed elderly patients. DESIGN: A randomised study. SETTING: Single-centre trial, study period January 2014 from to October 2016. PATIENTS: One hundred and six elderly patients who underwent urological or orthopaedic surgery with an expected duration less than 2 h. INTERVENTION: Patients were allocated to either the LMA-S (n = 53) or i-gel (n = 53) group. All insertions were performed in a standardised manner according to the manufacturers' instructions. MAIN OUTCOME MEASURES: Our primary endpoint was the rate of successful insertion at the first attempt. The adequacy of positive pressure ventilation and airway sealing, fibreoptic laryngoscopy grades and stability of airway maintenance during anaesthesia were also assessed. RESULTS: Although the rate of successful insertion at the first attempt was similar between the two groups (94.3 vs. 82.7%, P = 0.072), more patients required device manipulation during insertion with the LMA-S than the i-gel (42.3 vs. 18.9%, P = 0.011). Good fibreoptic laryngoscopy grades were significantly more common with the i-gel than the LMA-S (79.3 vs. 55.8%, P = 0.042), and peak inspiratory pressures were lower in the i-gel group both immediately after insertion and at the end of surgery. Leak pressures were significantly higher in the i-gel group than the LMA-S group, both immediately after insertion and at the end of surgery (25.8 vs. 23.0, P = 0.036; and 28.1 vs. 23.7, P < 0.001, respectively). CONCLUSION: Both the LMA-S and i-gel were used successfully and safely in elderly patients. However, the i-gel demonstrated better airway sealing than the LMA-S at insertion and during maintenance of anaesthesia. TRIAL REGISTRATION: NCT02026791 at clinicaltrial.gov. PMID- 28857786 TI - Dual-Task Walking Performance in Older Persons With Hearing Impairment: Implications for Interventions From a Preliminary Observational Study. AB - OBJECTIVES: Adults with "hearing loss" have an increased falls risks. There may be an association between hearing impairment and walking performance under dual task (DT) and triple-task (TT) conditions. The aim of this study was to identify DT and TT effects on walking speed, step length, and cadence in adults with hearing impairment, previous falls, and physical limitations. DESIGN: The observational study included 73 community-dwelling older people seeking audiology services. Data were collected on sociodemographic characteristics, previous falls, fear of falling, physical limitations, and walking performance under three task conditions. Differences between the task conditions (single task [ST], DT, and TT) and the hearing groups were analyzed with a two-way ANOVA with repeated measures. The influence of fall risks and limited physical functioning on walking under ST, DT, and TT conditions was analyzed with ANOVAs, with ST, DT, and TT performance as repeated measurement factor (i.e., walking speed, step length and Cadence * Previous falls, or short physical performance battery <12 * Hearing Groups). RESULTS: Walking speed was reduced accompanied by decreased step length and increased cadence in people with more severe hearing loss. Larger negative effects on DT and TT walking were found with increasing hearing loss (speed and cadence decreased with higher DT costs). Highest DT costs were found for the walking-manual conditions. These results were accompanied by small effects of older age and more comorbidities. CONCLUSIONS: This first screening data of walking performance under different conditions for people with hearing loss warrants the need for development and investigation of training interventions to improve walking abilities. DT training may be beneficial to enhance motor and cognitive flexibility and to reduce fall risks. PMID- 28857787 TI - Stability of Auditory Steady State Responses Over Time. AB - OBJECTIVES: Auditory steady state responses (ASSRs) are used in clinical practice for objective hearing assessments. The response is called steady state because it is assumed to be stable over time, and because it is evoked by a stimulus with a certain periodicity, which will lead to discrete frequency components that are stable in amplitude and phase over time. However, the stimuli commonly used to evoke ASSRs are also known to be able to induce loudness adaptation behaviorally. Researchers and clinicians using ASSRs assume that the response remains stable over time. This study investigates (1) the stability of ASSR amplitudes over time, within one recording, and (2) whether loudness adaptation can be reflected in ASSRs. DESIGN: ASSRs were measured from 14 normal-hearing participants. The ASSRs were evoked by the stimuli that caused the most loudness adaptation in a previous behavioral study, that is, mixed-modulated sinusoids with carrier frequencies of either 500 or 2000 Hz, a modulation frequency of 40 Hz, and a low sensation level of 30 dB SL. For each carrier frequency and participant, 40 repetitions of 92 sec recordings were made. Two types of analyses were used to investigate the ASSR amplitudes over time: with the more traditionally used Fast Fourier Transform and with a novel Kalman filtering approach. Robust correlations between the ASSR amplitudes and behavioral loudness adaptation ratings were also calculated. RESULTS: Overall, ASSR amplitudes were stable. Over all individual recordings, the median change of the amplitudes over time was -0.0001 MUV/s. Based on group analysis, a significant but very weak decrease in amplitude over time was found, with the decrease in amplitude over time around -0.0002 MUV/s. Correlation coefficients between ASSR amplitudes and behavioral loudness adaptation ratings were significant but low to moderate, with r = 0.27 and r = 0.39 for the 500 and 2000 Hz carrier frequency, respectively. CONCLUSIONS: The decrease in amplitude of ASSRs over time (92 sec) is small. Consequently, it is safe to use ASSRs in clinical practice, and additional correction factors for objective hearing assessments are not needed. Because only small decreases in amplitudes were found, loudness adaptation is probably not reflected by the ASSRs. PMID- 28857788 TI - Response: Letter to Article by Keswani SG, et al. The Future of Basic Science in Academic Surgery: Identifying Barriers to Success for Surgeon Scientists. Ann Surg 2017:265:1053-1059. PMID- 28857789 TI - Competency-Based Medical Education and the Ghost of Kuhn: Reflections on the Messy and Meaningful Work of Transformation. AB - The transition, if not transformation, to outcomes-based medical education likely represents a paradigm shift struggling to be realized. Paradigm shifts are messy and difficult but ultimately meaningful if done successfully. This struggle has engen dered tension and disagreements, with many of these disagreements cast as either-or polarities. There is little disagreement, however, that the health care system is not effectively achieving the triple aim for all patients. Much of the tension and polarity revolve around how more effectively to prepare students and residents to work in and help change a complex health care system.Competencies were an initial attempt to facilitate this shift by creating frameworks of essential abilities needed by physicians. However, implementation of competencies has proven to be difficult. Entrustable professional activities (EPAs) in undergraduate and graduate medical education and Milestones in graduate medical education are recent concepts being tried and studied as approaches to guide the shift to outcomes. Their primary purpose is to help facilitate implementation of an outcomes-based approach by creating shared mental models of the competencies, which in turn can help to improve curricula and assessment. Understanding whether and how EPAs and Milestones effectively facilitate the shift to outcomes has been and will continue to be an iterative and ongoing reflective process across the entire medical education community using lessons from implementation and complexity science. In this Invited Commentary, the author reflects on what got the community to this point and some sources of tension involved in the struggle to move to outcomes-based education. PMID- 28857790 TI - Critical Thoughts About the Core Entrustable Professional Activities in Undergraduate Medical Education. AB - The Core Entrustable Professional Activities for Entering Residency (Core EPAs) have taken a strong hold on undergraduate medical education (UME). This Perspective questions their value added and considers the utility of the Core EPAs along two separate dimensions: (1) the ways they change the content and focus of the goals of UME; and (2) the extent to which entrustable professional activity (EPA)-based assessment conforms to basic principles of measurement theory as practiced in the social sciences. Concerning content and focus, the author asks whether the 13 Core EPAs frame UME too narrowly, putting competencies into the background and overlooking certain aspirational, but important and measurable, objectives of UME. The author also discusses the unevenness of EPAs in terms of their breadth and their developmental status as core activities. Regarding measurement and assessment, the author raises concerns that the EPA metric introduces layers of inference that may cause distortions and hinder accuracy and rater agreement. In addition, the use of weak anchors and multidimensional scales is also of concern. The author concludes with a proposal for reframing the Core EPAs and Accreditation Council for Graduate Medical Education competencies into broadly defined sets of behaviors, referred to as "Tasks of Medicine," and calls for the development of a systematic and longitudinal research agenda. The author asserts that "slowing down when you should" applies to medical education as well as patient care, and calls for a reevaluation of the Core EPAs before further commitment to them. PMID- 28857791 TI - The High-Value Care Rounding Tool: Development and Validity Evidence. AB - Little is known about current practices in high-value care (HVC) bedside teaching. A lack of instruments for measuring bedside HVC behaviors confounds efforts to assess the impact of curricular interventions. The authors aimed to define observable HVC concepts by developing an instrument to measure the content and frequency of HVC discussions.The authors developed the HVC Rounding Tool in four iterative phases, using Messick's validity framework. Phases 1 and 2 were designed to collect evidence of content validity, Phases 3 and 4 to collect evidence of response process and internal structure. Phase 1 identified HVC topics within the literature. Phase 2 used a modified Delphi approach for construct definition and tool development. Through two rounds, the Delphi panel narrowed 16 HVC topics to 11 observable items, categorized into three domains (quality, cost, and patient values). Phase 3 involved rater training and creation of a codebook. Phase 4 involved three iterations of instrument piloting. Six trained raters, in pairs, observed bedside rounds during 148 patient encounters in 2016. Weighted kappas for each domain demonstrated improvement from the first to third iteration: Quality increased from 0.65 (95% CI 0.55-0.79) to 1.00, cost from 0.58 (95% CI 0.4-0.75) to 0.96 (95% CI 0.80-1.00), and patient values from 0.41 (95% CI 0.19-0.68) to 1.00. Percent positive agreement for all domains improved from 65.3% to 98.1%. This tool, the first with established validity evidence, addresses an important educational gap for measuring the translation of HVC from theoretical knowledge to bedside practice. PMID- 28857792 TI - Change in visceral adiposity is an independent predictor of future arterial pulse pressure. AB - OBJECTIVES: Pulse pressure (PP), a marker of arterial stiffness, and body composition are both risk factors for cardiovascular disease. Little is known about whether changes in body composition may be linked to future PP. We sought to determine whether change in amount of abdominal and thigh fat over 5 years predicted PP at 10 years. METHODS: Visceral fat as well as abdominal and thigh subcutaneous fat areas were measured by computed tomography at baseline and 5 years later in 284 Japanese Americans (mean age 49.3 years; 50.4% men) without hypertension, heart disease, and glucose-lowering medication use at baseline. PP at 10 years was calculated as the difference between SBP and DBP measured with a mercury sphygmomanometer. The association between change in fat at 5 years and arterial PP at 10 years, adjusted for baseline PP, was examined using linear regression analysis. MAIN RESULTS: Change in abdominal visceral fat area at 5 years was positively associated with 10-year PP independent of sex, 5-year change in BMI, and baseline age, BMI, PP, abdominal visceral fat, smoking status, alcohol consumption, physical activity, homeostasis model assessment insulin resistance, and fasting plasma glucose. There were no significant associations between baseline amounts or change in abdominal or thigh subcutaneous fat areas and future PP. CONCLUSION: The accumulation of abdominal visceral fat over time independently predicted future PP in Japanese Americans. PMID- 28857793 TI - Initiation and Termination of Massive Transfusion Protocols: Current Strategies and Future Prospects. AB - The advent of massive transfusion protocols (MTP) has had a significant positive impact on hemorrhaging trauma patient morbidity and mortality. Nevertheless, societal MTP guidelines and individual MTPs at academic institutions continue to circulate opposing recommendations on topics critical to MTPs. This narrative review discusses up-to-date information on 2 such topics, the initiation and termination of an MTP. The discussion for each begins with a review of the recommendations and supporting literature presented by MTP guidelines from 3 prominent societies, the American Society of Anesthesiologists, the American College of Surgeons, and the task force for Advanced Bleeding Care in Trauma. This is followed by an in-depth analysis of the main components within those recommendations. Societal recommendations on MTP initiation in hemorrhaging trauma patients emphasize the use of retrospectively validated massive transfusion (MT) prediction score, specifically, the Assessment of Blood Consumption and Trauma-Associated Severe Hemorrhage scores. Validation studies have shown that both scoring systems perform similarly. Both scores reliably identify patients that will not require an MT, while simultaneously overpredicting MT requirements. However, each scoring system has its unique advantages and disadvantages, and this review discusses how specific aspects of each scoring system can affect widespread applicability and statistical performance. In addition, we discuss the often overlooked topic of initiating MT in nontrauma patients and the specific tools physicians have to guide the MT initiation decision in this unique setting. Despite the serious complications that can arise with transfusion of large volumes of blood products, there is considerably less research pertinent to the topic of MTP termination. Societal recommendations on MTP termination emphasize applying clinical reasoning to identify patients who have bleeding source control and are adequately resuscitated. This review, however, focuses primarily on the recommendations presented by the Advanced Bleeding Care in Trauma's MTP guidelines that call for prompt termination of the algorithm-guided model of resuscitation and rapidly transitioning into a resuscitation model guided by laboratory test results. We also discuss the evidence in support of laboratory result-guided resuscitation and how recent literature on viscoelastic hemostatic assays, although limited, highlights the potential to achieve additional benefits from this method of resuscitation. PMID- 28857794 TI - Reductions in Average Lengths of Stays for Surgical Procedures Between the 2008 and 2014 United States National Inpatient Samples Were Not Associated With Greater Incidences of Use of Postacute Care Facilities. AB - BACKGROUND: Diagnosis-related group (DRG) based reimbursement creates incentives for reduction in hospital length of stay (LOS). Such reductions might be accomplished by lesser incidences of discharges to home. However, we previously reported that, while controlling for DRG, each 1-day decrease in hospital median LOS was associated with lesser odds of transfer to a postacute care facility (P = .0008). The result, though, was limited to elective admissions, 15 common surgical DRGs, and the 2013 US National Readmission Database. METHODS: We studied the same potential relationship between decreased LOS and postacute care using different methodology and over 2 different years. The observational study was performed using summary measures from the 2008 and 2014 US National Inpatient Sample, with 3 types of categories (strata): (1) Clinical Classifications Software's classes of procedures (CCS), (2) DRGs including a major operating room procedure during hospitalization, or (3) CCS limiting patients to those with US Medicare as the primary payer. RESULTS: Greater reductions in the mean LOS were associated with smaller percentages of patients with disposition to postacute care. Analyzed using 72 different CCSs, 174 DRGs, or 70 CCSs limited to Medicare patients, each pairwise reduction in the mean LOS by 1 day was associated with an estimated 2.6% +/- 0.4%, 2.3% +/- 0.3%, or 2.4% +/- 0.3% (absolute) pairwise reduction in the mean incidence of use of postacute care, respectively. These 3 results obtained using bivariate weighted least squares linear regression were all P < .0001, as were the corresponding results obtained using unweighted linear regression or the Spearman rank correlation. CONCLUSIONS: In the United States, reductions in hospital LOS, averaged over many surgical procedures, are not accomplished through a greater incidence of use of postacute care. PMID- 28857796 TI - Local Anesthetics Inhibit the Growth of Human Hepatocellular Carcinoma Cells. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapeutic options. Retrospective studies have shown that the administration of local anesthetics (LAs) during cancer surgery could reduce cancer recurrence. Besides, experimental studies reported that LAs could inhibit the growth of cancer cells. Thus, the purpose of this study was to investigate the effects of LAs on human HCC cells. METHODS: The effects of 2 LAs (lidocaine and ropivacaine) (10 to 10 M) were studied after an incubation of 48 hours on 2 HCC cell lines, namely HuH7 and HepaRG. Cell viability, cell cycle analysis, and apoptosis and senescence tests were performed together with unsupervised genome-wide expression profiling and quantitative real-time polymerase chain reaction for relevant genes. RESULTS: We showed that LAs decreased viability and proliferation of HuH7 cells (from 92% [P < .001] at 5 * 10 M to 40% [P = .02] at 10 M with ropivacaine and from 87% [P < .001] to 37% [P = .02] with lidocaine) and HepaRG progenitor cells (from 58% at 5 * 10 M [P < .001] to 29% at 10 M [P = .04] with lidocaine and 59% [P < .001] with ropivacaine 5 * 10 M) in concentration-dependent manner. LAs have no effect on well-differentiated HepaRG. Ropivacaine decreased the mRNA level of key cell cycle regulators, namely cyclin A2, cyclin B1, cyclin B2, and cyclin-dependent kinase 1, and the expression of the nuclear marker of cell proliferation MKI67. Lidocaine had no specific effect on cell cycle but increased by 10* the mRNA level of adenomatous polyposis coli (P < .01), which acts as an antagonist of the Wnt/beta-catenin pathway. Both LAs increased apoptosis in Huh7 and HepaRG progenitor cells (P < .01). CONCLUSIONS: The data demonstrate that LAs induced profound modifications in gene expression profiles of tumor cells, including modulations in the expression of cell cycle-related genes that result in a cytostatic effect and induction of apoptosis. PMID- 28857797 TI - A Comparison of Three Frailty Indices in Predicting Morbidity and Mortality After On-Pump Aortic Valve Replacement. AB - BACKGROUND: Aortic valve replacement is a high-risk surgery (3%-5%, 30-day mortality) performed on approximately 30,000 elderly patients a year in the United States. Currently, preoperative risk assessment is based on a composite of medical examination and a subjective evaluation for frailty ("eyeball test"). Objective frailty assessment using validated indices has the potential to improve risk stratification. The purpose of this study was to (1) establish whether frailty can predict 30-day mortality and composite morbidity in patients undergoing aortic valve replacement and (2) compare the predictive ability of 3 frailty indices in this population. METHODS: This study was a retrospective cohort study of 3088 patients 65 years old and older undergoing aortic valve replacement surgery (based on current procedure terminology codes) between the years 2006 and 2012 extracted from the American College of Surgeons National Surgical Quality Improvement Program database. Frailty was assessed using the modified frailty index, risk analysis index, and Ganapathi indices. Outcomes measured were 30-day mortality and composite morbidity (myocardial infarction, cardiac arrest, pulmonary embolism, pneumonia, reintubation, renal insufficiency, coma >24 hours, urinary tract infections, sepsis, deep vein thrombosis, deep wound surgical site infection, superficial site infection, and reoperation). RESULTS: Frailty was a better predictor of mortality than morbidity, and it was not markedly different among any of the 3 indices. Frailty was associated with an increased risk of 30-day mortality and longer lengths of stay. CONCLUSIONS: Frailty can predict mortality in patients undergoing aortic valve replacement. Choice of frailty index does not make a difference in this patient population. PMID- 28857800 TI - Outcomes in Patients Undergoing Cardiac Surgery Who Decline Transfusion and Received Erythropoietin Compared to Patients Who Did Not: A Matched Cohort Study. AB - BACKGROUND: Erythropoiesis-stimulating agents, such as erythropoietin (EPO), can be used to treat preoperative anemia. Some studies suggest an increased risk of mortality and thrombotic events, and use in cardiovascular surgery remains off label. This study compares outcomes in cardiac surgery patients declining blood transfusion who received EPO with a matched cohort who did not. METHODS: After institutional review board approval, we conducted a retrospective review of all patients who decline blood transfusion who underwent cardiac surgery and received EPO between January 1, 2004, and June 15, 2015, at a single institution. Control patients who did not receive EPO and were not transfused allogeneic red blood cells perioperatively were identified during the same period. Two controls were matched to each EPO patient using an optimal matching algorithm based on age, date of surgery, gender, operative procedure, and surgeon. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) and baseline characteristics remaining unbalanced in the matched cohorts were controlled for in assessing patient outcomes. The primary outcome was a composite of mortality and thrombotic events, and secondary outcomes included change in hemoglobin (Hb) from baseline to discharge, acute kidney injury (AKI), sternal wound infection, atrial fibrillation, time to extubation, intensive care unit, and hospital length of stay (LOS). RESULTS: Fifty-three patients who decline transfusion and received EPO were compared to 106 optimally matched control patients who did not receive EPO or red blood cell transfusion in the perioperative period. The median additive EuroSCORE was similar between the EPO and control group [6 (4, 9) vs 5 (3, 7), respectively; P = .39]. There was no difference in the primary outcome (P = .12) and mortality was zero in both groups. The EPO group had a higher mean preoperative Hb (13.91 g/dL vs 13.31; P = .02) and a smaller change in Hb from baseline (-2.65 vs -3.60; P = .001). The incidence of AKI (47.17% vs 41.51%; P = .49) was similar and there was no significant difference in all other outcomes, including time to extubation, hospital LOS, or intensive care unit LOS. CONCLUSIONS: In this retrospective matched cohort study of patients declining transfusion and receiving EPO matched to control patients, there were no clinically meaningful differences in the outcomes. PMID- 28857799 TI - Age at Exposure to Surgery and Anesthesia in Children and Association With Mental Disorder Diagnosis. AB - BACKGROUND: Animals exposed to anesthetics during specific age periods of brain development experience neurotoxicity, with neurodevelopmental changes subsequently observed during adulthood. The corresponding vulnerable age in children, however, is unknown. METHODS: An observational cohort study was performed using a longitudinal dataset constructed by linking individual-level Medicaid claims from Texas and New York from 1999 to 2010. This dataset was evaluated to determine whether the timing of exposure to anesthesia <=5 years of age for a single common procedure (pyloromyotomy, inguinal hernia, circumcision outside the perinatal period, or tonsillectomy and/or adenoidectomy) is associated with increased subsequent risk of diagnoses for any mental disorder, or specifically developmental delay (DD) such as reading and language disorders, and attention deficit hyperactivity disorder (ADHD). Exposure to anesthesia and surgery was evaluated in 11 separate age at exposure categories: <=28 days old, >28 days and <=6 months, >6 months and <=1 year, and 6-month age intervals between >1 year old and <=5 years old. For each exposed child, 5 children matched on propensity score calculated using sociodemographic and clinical covariates were selected for comparison. Cox proportional hazards models were used to measure the hazard ratio of a mental disorder diagnosis associated with exposure to surgery and anesthesia. RESULTS: A total of 38,493 children with a single exposure and 192,465 propensity score-matched children unexposed before 5 years of age were included in the analysis. Increased risk of mental disorder diagnosis was observed at all ages at exposure with an overall hazard ratio of 1.26 (95% confidence interval [CI], 1.22-1.30), which did not vary significantly with the timing of exposure. Analysis of DD and ADHD showed similar results, with elevated hazard ratios distributed evenly across all ages, and overall hazard ratios of 1.26 (95% CI, 1.20-1.32) for DD and 1.31 (95% CI, 1.25-1.37) for ADHD. CONCLUSIONS: Children who undergo minor surgery requiring anesthesia under age 5 have a small but statistically significant increased risk of mental disorder diagnoses and DD and ADHD diagnoses, but the timing of the surgical procedure does not alter the elevated risks. Based on these findings, there is little support for the concept of delaying a minor procedure to reduce long-term neurodevelopmental risks of anesthesia in children. In evaluating the influence of age at exposure, the types of procedures included may need to be considered, as some procedures are associated with specific comorbid conditions and are only performed at certain ages. PMID- 28857802 TI - Paravertebral Block Does Not Reduce Cancer Recurrence, but Is Related to Higher Overall Survival in Lung Cancer Surgery: A Retrospective Cohort Study. AB - BACKGROUND: Postoperative analgesic methods are suggested to have an impact on long-term prognosis after cancer surgery through opioid-induced immune suppression. We hypothesized that regional analgesia that reduces the systemic opioid requirement would be related to lower cancer recurrence and higher overall survival compared to intravenous patient-controlled analgesia (PCA) for lung cancer surgery. METHODS: Records for all patients who underwent open thoracotomy for curative resection of primary lung cancer between 2009 and 2013 in a tertiary care hospital were retrospectively analyzed. Patients were divided by postoperative analgesic methods: PCA (n = 574), thoracic epidural analgesia (TEA, n = 619), or paravertebral block (PVB, n = 536). Overall and recurrence-free survivals were compared among 3 analgesic methods via a multivariable Cox proportional hazard model and a log-rank test after adjusting confounding factors using propensity score matching (PSM). RESULTS: Analgesic method was associated with overall survival (P= .0015; hazard ratio against TEA [95% confidence intervals]: 0.58 [0.39-0.87] for PCA, 0.60 [0.45-0.79] for PVB). After confounder adjustment using PSM, PVB showed higher overall survival than PCA (log-rank P= .0229) and TEA (log-rank P= .0063) while PCA and TEA showed no difference (log rank P= .6). Hazard ratio for PVB was 0.66 [0.46-0.94] against PCA and 0.65 [0.48 0.89] against TEA after PSM. However, there was no significant association between the analgesic methods and recurrence-free survival (P= .5; log-rank P with PSM = .5 between PCA and TEA, .5 between PCA and PVB, .1 between TEA and PVB). CONCLUSIONS: Pain-control methods are not related to cancer recurrence. However, PVB may have a beneficial effect on overall survival of patients with lung cancer. PMID- 28857804 TI - Social Responsiveness Scale Assessment of the Preterm Behavioral Phenotype in 10 Year-Olds Born Extremely Preterm. AB - OBJECTIVE: To evaluate the correlates of a clinically significant high score on the Social Responsiveness Scale (SRS) in 10-year-old children who were born extremely preterm and who did not meet criteria for autism spectrum disorder (ASD). METHODS: After excluding 61 participants diagnosed with ASD, we grouped children by IQ < or >=85 and then compared the prevalence of neurocognitive and other deficits between those who had SRS total and component scores >=65 and their peers who had lower scores. RESULTS: Among children who had IQ >= 85, the prevalence of SRS total scores >=65 was 16% (n = 103/628), and among children who had IQ < 85, it was 27% (n = 40/148), higher than the 4% prevalence expected based on normative population data. Among children who had IQ >= 85, those who had high SRS scores more often than their peers had deficits in attention and executive function, and language and communication, and they were more often rated by their parents and teachers as having behavioral (e.g., attention-deficit hyperactivity disorder [ADHD]) and emotional (e.g., anxiety and depression) problems. CONCLUSION: Social Responsiveness Scale-defined social impairment was much more common in our cohort of 10-year-old children born extremely preterm than was expected based on general population norms. High SRS scores were characteristic of children who had intellectual, neurocognitive, language, and communication limitations, as well as deficits in behavior and emotion regulation. PMID- 28857805 TI - Precision Correction of Coagulopathy or Prothrombin Complex Concentrates?: Reversal Options for Dabigatran following Trauma. PMID- 28857806 TI - Reversing Dabigatran Anticoagulation with Prothrombin Complex Concentrate versus Idarucizumab as Part of Multimodal Hemostatic Intervention in an Animal Model of Polytrauma. AB - BACKGROUND: Although idarucizumab is the preferred treatment for urgent dabigatran reversal, it is not always available. Prothrombin complex concentrate (PCC) may be an alternative and, with bleeding in trauma, additional hemostatic therapy may be required. The authors investigated multimodal treatment in a preclinical polytrauma model. METHODS: Dabigatran etexilate (30 mg/kg twice daily) was given orally to 45 male pigs for 3 days. On day 4, animals received a dabigatran infusion before blunt liver injury and bilateral femur fractures. After injury, animals were randomized 1:1:1:1:1 to receive placebo (control), tranexamic acid (TXA; 20 mg/kg) plus human fibrinogen concentrate (FCH; 80 mg/kg) (TXA-FCH group), PCC (25 U/kg or 50 U/kg) plus TXA plus FCH (PCC25 and PCC50 groups), or 60 mg/kg idarucizumab (IDA) plus TXA plus FCH (IDA group). Animals were monitored for 240 min after trauma, or until death. RESULTS: The degree of injury was similar in all animals before intervention. Control and TXA-FCH animals had the highest total postinjury blood loss (3,652 +/- 601 and 3,497 +/- 418 ml) and 100% mortality (mean survival time 96 and 109 min). Blood loss was significantly lower in the PCC50 (1,367 +/- 273 ml) and IDA (986 +/- 144 ml) groups, with 100% survival. Thrombin-antithrombin levels and thrombin generation were significantly elevated in the PCC50 group. CONCLUSIONS: Idarucizumab may be considered the optimal treatment for emergency reversal of dabigatran anticoagulation. However, this study suggests that PCC may be similarly effective as idarucizumab and could therefore be valuable when idarucizumab is unavailable. (Anesthesiology 2017; 127:852-61). PMID- 28857807 TI - MAC Meeting MIGET: Leaps of Faith. PMID- 28857808 TI - Effect of Bronchoconstriction-induced Ventilation-Perfusion Mismatch on Uptake and Elimination of Isoflurane and Desflurane. AB - BACKGROUND: Increasing numbers of patients with obstructive lung diseases need anesthesia for surgery. These conditions are associated with pulmonary ventilation/perfusion (VA/Q) mismatch affecting kinetics of volatile anesthetics. Pure shunt might delay uptake of less soluble anesthetic agents but other forms of VA/Q scatter have not yet been examined. Volatile anesthetics with higher blood solubility would be less affected by VA/Q mismatch. We therefore compared uptake and elimination of higher soluble isoflurane and less soluble desflurane in a piglet model. METHODS: Juvenile piglets (26.7 +/- 1.5 kg) received either isoflurane (n = 7) or desflurane (n = 7). Arterial and mixed venous blood samples were obtained during wash-in and wash-out of volatile anesthetics before and during bronchoconstriction by methacholine inhalation (100 MUg/ml). Total uptake and elimination were calculated based on partial pressure measurements by micropore membrane inlet mass spectrometry and literature-derived partition coefficients and assumed end-expired to arterial gradients to be negligible. VA/Q distribution was assessed by the multiple inert gas elimination technique. RESULTS: Before methacholine inhalation, isoflurane arterial partial pressures reached 90% of final plateau within 16 min and decreased to 10% after 28 min. By methacholine nebulization, arterial uptake and elimination delayed to 35 and 44 min. Desflurane needed 4 min during wash-in and 6 min during wash-out, but with bronchoconstriction 90% of both uptake and elimination was reached within 15 min. CONCLUSIONS: Inhaled methacholine induced bronchoconstriction and inhomogeneous VA/Q distribution. Solubility of inhalational anesthetics significantly influenced pharmacokinetics: higher soluble isoflurane is less affected than fairly insoluble desflurane, indicating different uptake and elimination during bronchoconstriction. PMID- 28857809 TI - Learning Curve and Associated Morbidity of Minimally Invasive Esophagectomy: A Retrospective Multicenter Study. AB - OBJECTIVE: To investigate the morbidity that is associated with the learning curve of minimally invasive esophagectomy. BACKGROUND: Although learning curves have been described, it is currently unknown how much extra morbidity is associated with the learning curve of technically challenging surgical procedures. METHODS: Prospectively collected data were retrospectively analyzed of all consecutive patients undergoing minimally invasive Ivor Lewis esophagectomy in 4 European expert centers. The primary outcome parameter was anastomotic leakage. Secondary outcome parameters were operative time and textbook outcome ("optimal outcome"). Learning curves were plotted using weighted moving average and CUSUM analysis was used to determine after how many cases the plateau was reached. Learning associated morbidity was calculated with area under the curve analysis. RESULTS: This study included 646 patients. Three of the 4 hospitals reached the plateau of 8% anastomotic leakage. The length of the learning curve was 119 cases. The mean incidence of anastomotic leakage decreased from 18.8% during the learning phase to 4.5% after the plateau had been reached (P < 0.001). Thirty-six extra patients (10.1% of all patients operated on during the learning curve) experienced learning associated anastomotic leakage, that could have been avoided if patients were operated by surgeons who had completed the learning curve. The incidence of textbook outcome increased from 28% to 53% and the mean operative time decreased from 344 minutes to 270 minutes. CONCLUSIONS: A considerable number of 36 extra patients (10.1%) experienced learning associated anastomotic leakage. More research is urgently needed to investigate how learning associated morbidity can be reduced to increase patient safety during learning curves. PMID- 28857810 TI - Nationwide Procedural Trends for Renal Trauma Management. AB - OBJECTIVE: To characterize national trends in procedural management of renal trauma. BACKGROUND: Management of renal trauma has evolved to favor a more conservative approach. For patients requiring intervention, there is a paucity of information to characterize the nature of procedural therapy administered. METHODS: A retrospective cross-sectional analysis was performed using data contained within the National Trauma Data Bank. The National Trauma Data Bank is a voluntary data repository managed by the American College of Surgeons, containing data regarding trauma admissions at 747 level I to V trauma centers throughout the United States and Canada. Participants included any patient with renal trauma requiring intervention from 2002 to 2012. They were identified according to International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes, with codes 866.00 through 866.03 for blunt renal trauma, and codes 866.10 through 866.13 for penetrating trauma. Cases were separated into those requiring nephrectomy, renorrhaphy, or endovascular repair based on ICD-9 procedure code. The number of cases performed each year and yearly trends as measured by linear regression. RESULTS: A total of 4296 cases were reported during the study period. Of these cases, 2635 involved blunt trauma and 1661 involved penetrating injury. There was a significant increase in the percentage of cases managed by endovascular means for both blunt and penetrating trauma (R = 0.92, P < 0.01; and R = 0.86, P < 0.01, respectively). This was primarily at the expense of nephrectomy, with cases showing significant decline in both groups. CONCLUSIONS: National trends for procedural management of renal trauma are toward less invasive interventions. These trends suggest favorable change towards renal preservation and decreased morbidity, potentially facilitated, in part, by improved radiographic staging and endovascular techniques, and also increased provider awareness of the safety and value of conservative management. PMID- 28857811 TI - Biomarker-guided Intervention to Prevent Acute Kidney Injury After Major Surgery: The Prospective Randomized BigpAK Study. AB - OBJECTIVE: To determine the impact of renal biomarker-guided implementation of the Kidney Disease Improving Global Outcomes (KDIGO) care bundle on the incidence of acute kidney injury (AKI) after major noncardiac surgery in a single-center unblinded randomized clinical trial. BACKGROUND: Early optimization of volume status and discontinuation of nephrotoxic medication before the occurrence of AKI may be the crucial step to reduce preventable AKI. METHODS: The urinary biomarker triggered KDIGO care bundle (early optimization of fluid status, maintenance of perfusion pressure, discontinuation of nephrotoxic agents) was compared to standard intensive care unit (ICU) care in 121 patients with an increased AKI risk after major abdominal surgery that was determined by urinary biomarker (inhibitor of metalloproteinase-2 * insulin-like growth factor-binding protein 7) >0.3. Incidence of overall AKI, severity of AKI, length of stay, major kidney events at discharge, and cost effectiveness were evaluated. RESULTS: The overall stages of AKI were not statistically different between the 2 groups, but in patients with inhibitor of metalloproteinase-2 * insulin-like growth factor binding protein 7 values of 0.3 to 2.0 a subgroup analysis demonstrated a significantly reduced incidence of AKI 13/48 (27.1%) in the intervention group compared to control 24/50 (48.0%, P = 0.03). Incidence of moderate and severe AKI (P = 0.04), incidence of creatinine increase >25% of baseline value (P = 0.01), length of ICU, and hospital stay (P = 0.04) were significantly lower in the intervention group. Intervention was associated with cost reduction. There were no significant differences regarding renal replacement therapy, in-hospital mortality, or major kidney events at hospital discharge. CONCLUSIONS: Early biomarker-based prediction of imminent AKI followed by implementation of KDIGO care bundle reduced AKI severity, postoperative creatinine increase, length of ICU, and hospital stay in patients after major noncardiac surgery. PMID- 28857812 TI - Early Acute Mesenteric Ischemia: Many Rivers to Cross. PMID- 28857814 TI - Superspecialization and Clinical Trials on Surgical Site Infection: Is There a Bug in the System? PMID- 28857813 TI - Risk Factors and Mitigation Strategies for Pancreatic Fistula After Distal Pancreatectomy: Analysis of 2026 Resections From the International, Multi institutional Distal Pancreatectomy Study Group. AB - OBJECTIVE: To identify a clinical fistula risk score following distal pancreatectomy. BACKGROUND: Clinically relevant pancreatic fistula (CR-POPF) following distal pancreatectomy (DP) is a dominant contributor to procedural morbidity, yet risk factors attributable to CR-POPF and effective practices to reduce its occurrence remain elusive. METHODS: This multinational, retrospective study of 2026 DPs involved 52 surgeons at 10 institutions (2001-2016). CR-POPFs were defined by 2016 International Study Group criteria, and risk models generated using stepwise logistic regression analysis were evaluated by c statistic. Mitigation strategies were assessed by regression modeling while controlling for identified risk factors and treating institution. RESULTS: CR POPF occurred following 306 (15.1%) DPs. Risk factors independently associated with CR-POPF included: age (<60 yrs: OR 1.42, 95% CI 1.05-1.82), obesity (OR 1.54, 95% CI 1.19-2.12), hypoalbuminenia (OR 1.63, 95% CI 1.06-2.51), the absence of epidural anesthesia (OR 1.59, 95% CI 1.17-2.16), neuroendocrine or nonmalignant pathology (OR 1.56, 95% CI 1.18-2.06), concomitant splenectomy (OR 1.99, 95% CI 1.25-3.17), and vascular resection (OR 2.29, 95% CI 1.25-3.17). After adjusting for inherent risk between cases by multivariable regression, the following were not independently associated with CR-POPF: method of transection, suture ligation of the pancreatic duct, staple size, the use of staple line reinforcement, tissue patches, biologic sealants, or prophylactic octreotide. Intraoperative drainage was associated with a greater fistula rate (OR 2.09, 95% CI 1.51-3.78) but reduced fistula severity (P < 0.001). CONCLUSIONS: From this large analysis of pancreatic fistula following DP, CR-POPF occurrence cannot be reliably predicted. Opportunities for developing a risk score model are limited for performing risk-adjusted analyses of mitigation strategies and surgeon performance. PMID- 28857815 TI - Insurance Status, Not Race, Is Associated With Use of Minimally Invasive Surgical Approach for Rectal Cancer. PMID- 28857816 TI - Social Media as a Platform for Surgical Learning: Use and Engagement Patterns Among Robotic Surgeons. AB - : In response to technological advances and growing dispersion of surgical practice around the globe, social media platforms have emerged in recent years as channels for surgeons to share experiences, ask questions, and learn from one another. To better understand surgeons' engagement with these platforms, we analyzed data from a closed-membership Facebook group for robotic surgeons. Our analysis revealed that surgeons posted more frequently on midweek days, and further that text posts received significantly more comments, and significantly fewer "likes," than posts containing links, photos, or videos. We discuss the implications of these use and engagement patterns for the viability of social media platforms as tools for surgeons to learn vicariously from their peers' experiences and expertise. PMID- 28857817 TI - Obituary for Christophe Mariette. PMID- 28857818 TI - Response to: "Letter to the Editor for 'Low Versus Standard Urine Output Targets in Patients Undergoing Major Abdominal Surgery'". PMID- 28857820 TI - Effects of Intraoperative Fluid Management on Postoperative Outcome: What Is Our Limit in Fluid Therapy? PMID- 28857819 TI - Partial TIPE ALPPS for Perihilar Cancer. PMID- 28857822 TI - Impact of protease inhibitors on circulating PCSK9 levels in HIV-infected antiretroviral-naive patients from an ongoing prospective cohort. AB - OBJECTIVE: The study aims to assess the association between proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of LDL cholesterol (LDL-C) homeostasis, and HIV-related dyslipidaemia in a cohort of HIV-positive (HIV+) patients under protease inhibitors. METHODS: Plasma PCSK9 levels were measured in 103 HIV+ patients before and after initiating protease inhibitor-based antiretroviral therapy (ART), and in 90 HIV-negative controls matched for age and sex. PCSK9 was measured by ELISA. HIV+ patients who were not virologically suppressed at follow-up or were on lipid-lowering therapy were excluded. RESULTS: In HIV+ (median age 36 years; 77.7% men), PCSK9 levels did not increase after protease inhibitor exposure (median 14 months) (279.5 ng/ml before, 289.6 ng/ml after; P = 0.49) and were significantly elevated versus controls at all timepoints (adjusted P value before and after: <0.05). After protease inhibitor initiation, total cholesterol, LDL-C and HDL cholesterol levels increased, but LDL-C remained lower versus controls. At baseline, PCSK9 levels were positively associated with immunodeficiency and the severity of HIV disease [HIV-1 viral load (P = 0.01), CD4 T-cell count <200/MUl, P = 0.002], stage C HIV disease (P = 0.0002). In protease inhibitor-treated patients, PCSK9 levels were no longer associated with HIV-related factors but with total cholesterol (P = 0.0006), LDL C (P = 0.01), HDL cholesterol (P = 0.01), triglycerides (P = 0.05) and glycaemia (P = 0.006). CONCLUSION: PSCK9 levels are elevated in HIV+ patients. In ART-naive patients, the relationship between PCSK9 levels and infection severity suggests an effect of HIV disease. After initiating protease inhibitor-containing ART in virologically suppressed patients, PCSK9 levels were associated with dyslipidaemia similar to controls. PMID- 28857824 TI - Moderate levels of pre-therapy drug resistance (PDR) in a generalised epidemic: time for better first-line ART? AB - BACKGROUND: The WHO-recommended first-line antiretroviral therapy (ART) as a fixed dose combination (FDC) of efavirenz (EFV) and tenofovir disoproxil fumarate (TDF) with lamivudine (3TC) or emtricitabine (FTC) has been preferred in the large scale unprecedented ART roll out in Southern Africa. Models and recent reports suggest that pre-ARTHIV drug resistance (PDR) is increasing with high treatment coverage. METHOD: We therefore investigated PDR and any local transmission clusters in a setting where high treatment coverage was further enhanced by universal test and treat (UTT). Surveillance drug resistance mutations (SDRMs) were identified with an in-house PCR and population sequencing method and calibrated population resistance (CPR) tool. RESULTS: Of 60 patients, six (10%) had an SDRM mutation: five (8.3%) had nonnucleoside reverse transcriptase (NNRT) mutations, one had an nucleos(t)ide reverse transcriptase inhibitor mutation and none had protease inhibitor (PI) mutations. Phylogenetic analysis revealed no large transmission clusters. CONCLUSION: An increase to the current moderate PDR levels and the better tolerability and durability, may support a recent drive to avail FDC integrase strand transfer inhibitor (ISTI) based regimens as the new preferred first-line ART in the Southern African region for individual benefit and to contribute to limiting transmission of infection and drug resistant virus. PMID- 28857823 TI - Perceived and post-traumatic stress are associated with decreased learning, memory, and fluency in HIV-infected women. AB - OBJECTIVE: Psychological risk factors (PRFs) are associated with impaired learning and memory in HIV-infected (HIV+) women. We determined the dynamic nature of the effects of PRFs and HIV serostatus on learning and memory over time. DESIGN: Multi-center, prospective cohort study METHODS:: Every two years between 2009 and 2013 (3 times), 646 HIV+ and 300 demographically-similar HIV uninfected (HIV-) women from the Women's Interagency HIV Study completed neuropsychological (NP) testing and questionnaires measuring PRFs (perceived stress, post-traumatic stress disorder (PTSD) symptoms, depressive symptoms). Using mixed-effects regressions, we examined separate and interactive associations between HIV-serostatus and PRFs on performance over time. RESULTS: HIV+ and HIV- women had similar rates of PRFs. Fluency was the only domain where performance over time depended on the combined influence of HIV-serostatus and stress or PTSD (p's < 0.05); not depression. In HIV, higher stress and PTSD were associated with a greater cognitive decline in performance (p's < 0.05) versus lower stress and PTSD. Irrespective of time, performance on learning and memory depended on the combined influence of HIV-serostatus and stress or PTSD (p's <= 0.05). In the context of HIV, stress and PTSD were negatively associated with performance. Effects were pronounced on learning among HIV+ women without effective treatment or viral suppression. Regardless of time or HIV-serostatus, all PRFs were associated with lower speed, global NP, and executive function. CONCLUSIONS: More than depression, perceived stress and PTSD symptoms are treatment targets to potentially improve fluency, learning, and memory in women living with HIV particularly when HIV treatment is not optimal. PMID- 28857825 TI - Preferential susceptibility of Th9 and Th2 CD4+ T cells to X4-tropic HIV-1 infection. AB - OBJECTIVE: The functional polarization of CD4 T cells determines their antimicrobial effector profile, but may also impact the susceptibility to infection with HIV-1. Here, we analyzed the susceptibility of CD4 T cells with different functional polarization to infection with X4 and R5-tropic HIV-1. METHODS: CD4 T cells with a Th1, Th2, Th17, and Th9 polarization were subjected to in-vitro infection assays with X4, R5, or vesicular stomatitis virus-G protein pseudotyped HIV-1. In addition, we sorted differentially polarized CD4 T-cell subsets from individuals treated with antiretroviral therapy and analyzed the tropism of viral env sequences. RESULTS: Th9-polarized CD4 T cells and, to a lesser extent, Th2-polarized CD4 T cells expressed higher surface levels of CXCR4, and are more permissive to X4-tropic infection in vitro. In contrast, Th1 and Th17 CD4 T cells exhibited stronger surface expression of CCR5, and were more susceptible to infection with R5-tropic viruses. Correspondingly, the distribution of X4-tropic viral sequences in antiretroviral therapy-treated HIV-1 infected patients was biased toward Th9/Th2 cells, whereas R5-tropic sequences were more frequently observed in Th17 cells. CONCLUSION: CD4 T-cell polarization is associated with a distinct susceptibility to X4 and R5-tropic HIV-1 infection. PMID- 28857827 TI - Injecting drug use predicts active tuberculosis in a national cohort of people living with HIV. AB - OBJECTIVES: Tuberculosis (TB) is common in people living with HIV, leading to worse clinical outcomes including increased mortality. We investigated risk factors for developing TB following HIV diagnosis. DESIGN: Adults aged at least 15 years first presenting to health services for HIV care in England, Wales or Northern Ireland from 2000 to 2014 were identified from national HIV surveillance data and linked to TB surveillance data. METHODS: We calculated incidence rates for TB occurring more than 91 days after HIV diagnosis and investigated risk factors using multivariable Poisson regression. RESULTS: A total of 95 003 adults diagnosed with HIV were followed for 635 591 person-years; overall incidence of TB was 344 per 100 000 person-years (95% confidence interval 330-359). TB incidence was high for people who acquired HIV through injecting drugs [PWID; men 876 (696-1104), women 605 (365-945)] and black Africans born in high TB incidence countries [644 (612-677)]. The adjusted incidence rate ratio for TB amongst PWID was 4.79 (3.35-6.85) for men and 6.18 (3.49-10.93) for women, compared with MSM. The adjusted incidence rate ratio for TB in black Africans from high-TB countries was 4.27 (3.42-5.33), compared with white UK-born individuals. Lower time-updated CD4 cell count was associated with increased rates of TB. CONCLUSION: PWID had the greatest risk of TB; incidence rates were comparable with those in black Africans from high TB incidence countries. Most TB cases in PWID were UK-born, and likely acquired TB through transmission within the United Kingdom. Earlier HIV diagnosis and quicker initiation of antiretroviral therapy should reduce TB incidence in these populations. PMID- 28857828 TI - Time from HIV infection to virological suppression: dramatic fall from 2007 to 2016. AB - AIM: Time from HIV infection to virological suppression: dramatic fall from 2007 to 2016. OBJECTIVES: We examined the time from HIV infection to virological suppression in MSM who were first diagnosed at Melbourne Sexual Health Centre between 2007 and 2016. DESIGN: Retrospective cohort. METHODS: Date of infection was imputed from the testing history or serological evidence of recent infection (negative or indeterminate western blot) or baseline CD4 cell count. Date of virological suppression was determined using clinical viral load data. We analysed predictors of diagnosis with serological evidence of recent infection (logistic regression) and time from diagnosis to suppression and from infection to suppression (Cox regression) using demographic, clinical, and behavioral covariates. RESULTS: Between 2007 and 2016, the median time from HIV infection to diagnosis fell from 6.8 to 4.3 months (P = 0.001), from diagnosis to suppression fell from 22.7 to 3.2 months (P < 0.0001), and from infection to suppression fell from 49.0 to 9.6 months (P < 0.0001). Serological evidence of recent infection increased from 15.6 to 34.3% (P < 0.0001) of diagnoses. In the multivariate analyses, age, being recently arrived from a non-English speaking country, history of IDU, other sexually transmitted infections, and sexual risk were not associated with any of these measures. CONCLUSION: The duration of infectiousness in MSM diagnosed with HIV infection at Melbourne Sexual Health Centre in Victoria has fallen dramatically between 2007 and 2016 and the proportion diagnosed with serological evidence of recent infection has increased. This effect is observed across all population subgroups and marks a positive milestone for the treatment as prevention paradigm. PMID- 28857829 TI - Were we prepared for PrEP? Five years of implementation. PMID- 28857830 TI - Standout nurse leaders...What's in the research? PMID- 28857831 TI - Managing delirium behaviors with one-to-one sitters. PMID- 28857832 TI - "Stay interviews" to improve retention. PMID- 28857833 TI - Critical incidents in the ED. AB - Enhancing staff support with debriefing programs. PMID- 28857834 TI - Finding solutions or jumping to conclusions? PMID- 28857835 TI - Nurse leader emotional intelligence: How does it affect clinical nurse job satisfaction? PMID- 28857836 TI - Nursing Management Congress2017. PMID- 28857837 TI - Urgent care: A growing healthcare landscape. PMID- 28857838 TI - The power of networking. PMID- 28857839 TI - Different Patterns of Walking and Postprandial Triglycerides in Older Women. AB - PURPOSE: Although a single bout of continuous exercise (>=30 min) reduces postprandial triglyceride (TG), little evidence is available regarding the effect of multiple short (<=10 min) bouts of exercise on postprandial TG in individuals at increased risk for cardiovascular diseases. This study compared the effects of different patterns of walking on postprandial TG in postmenopausal, older women with hypertriglyceridemia. METHODS: Twelve inactive women (mean age +/- SD, 71 +/ 5 yr) with hypertriglyceridemia (fasting TG >=1.70 mmol.L) completed three, 1-d laboratory-based trials in a random order: 1) control, 2) continuous walking, and 3) multiple short bouts of walking. On the control trial, participants sat in a chair for 8 h. For the walking trials, participants walked briskly in either one 30-min bout in the morning (0900-0930 h) or twenty 90-s bouts over 8 h. Except for walking, both exercise trials mimicked the control trial. In each trial, participants consumed a standardized breakfast (0800 h) and lunch (1100 h). Venous blood samples were collected in the fasted state and at 2, 4, 6, and 8 h after breakfast. RESULTS: The serum TG incremental area under the curve was 35% and 33% lower on the continuous and multiple short bouts of walking trials than that on the control trial (8.2 +/- 3.1 vs 8.5 +/- 5.4 vs 12.7 +/- 5.8 mmol per 8 h.L, respectively; main effect of trial: effect size = 0.459, P = 0.001). CONCLUSIONS: Accumulating walking in short bouts limits postprandial TG in at risk, inactive older women with fasting hypertriglyceridemia. PMID- 28857840 TI - Voice rest after laryngeal surgery: what's the evidence? AB - PURPOSE OF REVIEW: This article aims to review previous research reports and to summarize current strategies for the optimal duration of voice rest and the effect of phonatory stimulation after phonomicrosurgery. RECENT FINDINGS: Voice rest is commonly recommended after laryngeal surgery to prevent worsening of vocal fold injuries. However, there are no established standard protocol for voice rest, and the type and duration of voice rest vary among clinicians. The most effective duration of voice rest is unknown. Recently, early vocal stimulation was recommended as a means to improve wound healing, on the basis of the basic and clinical researches. SUMMARY: It seems that early vocal stimulation may enhance the wound healing process in the vocal fold. More basic and clinical researches are warranted to investigate appropriate timing of initiation of stimulation, as well as the type and amount of stimulation that are available for human. PMID- 28857841 TI - Vocal fold leukoplakia: incidence, management, and prevention. AB - PURPOSE OF REVIEW: The purpose of this article is to provide an update on English language literature evaluating the current understanding of incidence, management, and prevention of vocal fold leukoplakia focusing on premalignancy. RECENT FINDINGS: Recent studies have continued to try to elucidate factors influencing recurrence and progression of dysplastic disease, though results vary. Although advanced diagnostic techniques have attempted to predict disease behavior, tissue diagnosis continues to be essential. Studies reinforce the necessity of removal of disease as the primary treatment, whereas use of photoangiolytic lasers via the ablative technique has increased, as has transition of some patients into the office-based settings for treatment. Although genetic and molecular testing may hold promise for predictive purposes, further study is necessary, and chemotherapy for recalcitrant disease continues to be an area of study with few case studies being reported. SUMMARY: Management of vocal fold leukoplakia continues to progress in terms of identification and treatment. Although many work to advance our knowledge in the field and push treatment strategies toward newer avenues, pathologic diagnosis, eradiation of disease on the basis of experience and skill, and close surveillance continue to be paramount. PMID- 28857842 TI - Relapsed/refractory acute myeloid leukemia: any progress? AB - PURPOSE OF REVIEW: Aim of this review was to focus on prognostic and predictive factors, standard and new treatment approaches, and on statistical considerations for future clinical trials in patients with relapsed/refractory acute myeloid leukemia (r/r-AML). RECENT FINDINGS: New prognostic molecular markers were identified in r/r-AML, FLT3-ITD, mutated IDH1, and biallelic CEBPA mutations. Intensive combination chemotherapy including gemtuzumab ozogamicin emerged as an effective salvage therapy in refractory AML. Timing of allo-HCT in r/r-AML may be oriented at the probability to achieve a response to intensive salvage therapy. Several new treatment approaches ranging from new and modified cytotoxic drugs to targeted approaches are in clinical development with first efficacy assessment in single-arm phase II studies. Their external validity may be considerably increased by using a novel design based on a matching approach. SUMMARY: FLT3 ITD, mutated IDH1, and biallelic CEBPA mutations are identified as prognostic molecular markers in r/r-AML. Timing of allo-HCT should be based on the probability to achieve a response to intensive salvage therapy. Several new approaches are currently evaluated and matching for controls may help to increase external validity. PMID- 28857843 TI - Altruistic nondirected kidney donation: attitudes, characteristics and ethical implications. AB - PURPOSE OF REVIEW: Altruistic nondirected kidney donation involves a person donating one of their kidneys to an unknown recipient. The donor's mental health and motives are frequently questioned. We want to highlight this topic and also encourage discussions about ethical implications. RECENT FINDINGS: The main topics are the mental health of altruistic nondirected kidney donors and the general attitude towards the practice of this form of donation as well as the willingness of the public to donate this way. Soliciting organ donation via social networks or financial support is debated extensively in the media. SUMMARY: There is a lack of studies on altruistic nondirected kidney donation. Most studies focus on related donors. Studies with larger samples should be performed on altruistic nondirected kidney donors to learn more about their motives and assess their mental health. PMID- 28857844 TI - The ethical challenges of uterus transplantation. AB - PURPOSE OF REVIEW: As the techniques of uterus transplantation have evolved, culminating in a birth in 2014, the ethical debate has been enriched by several considerations. Uterus transplantation raises issues because of its unique features of being temporary, nonlifesaving, experimental, and expensive, with established alternatives. RECENT FINDINGS: Uterus transplantation entails risks for the recipient related to multiple surgeries and immunosuppression, yet studies have shown that women see infertility as a distressing element in their lives, justifying the risks. The alternative of surrogacy has its own ethical issues, and adoption does not provide for genetic progeny. Although patient decisions are susceptible to inconsistent reasoning, misconception of risks or wishful thinking, a carefully drafted and clearly explained informed consent can represent a valid ethical response in balancing risks and benefits. There is no evidence of increased risks for children born from uterus transplant. For living donors, the risks of hysterectomy are known and can be explained to facilitate proper informed consent. Allocation of deceased donor organs needs to be determined, as guidelines for other organs cannot readily be applied. Cost is an issue, as the procedure is expensive and not covered by insurance. SUMMARY: In this rapidly advancing field, a strong ethical foundation is needed to guide regulations and legislation. PMID- 28857845 TI - Epilepsy and osteoporosis risk. AB - PURPOSE OF REVIEW: It is well-recognized that individuals with epilepsy have an increased risk of vertebral and nonvertebral fractures; this increased risk has been described to be secondary to an increased bone fragility and to an increased risk of falls. Osteoporosis is the most common bone disease which has been characterized by microarchitectural deterioration of trabecula and cortical bone mass with a decrease in bone mineral density and bone strength. Specific side effects of antiepileptic drugs (AEDs) on bone metabolism have been identified; recent research publications further characterized some of the specific side effects of AEDs on bone metabolism. It is the purpose of this review to describe recent advances on the knowledge of the effects of AEDs on bone metabolism and the cause of osteoporosis in the field of epilepsy. RECENT FINDINGS: Recent literature demonstrates that the increased risk of fractures in the epileptic patient population is likely multifactorial and includes seizure activity, injuries from falls, decreased bone strength, adverse effects from AEDs. Reviewed publications suggest that the mechanism of adverse effects on bone metabolism may differ among different AEDs. The impact of vitamin D deficiency or its metabolism in the epileptic population has also been a concern of several reviewed publications. SUMMARY: This is a review is of the recent epilepsy and osteoporosis literature published over the past 18 months, highlighting reports and studies concerning the cause, pathogenesis, and possible preventive measures and effects of AEDs on changes of bone metabolism, bone loss, and development of osteoporosis. In addition, we also reviewed articles focusing on issues of prevention and treatment of osteoporosis in individuals with epilepsy. We utilized the search engines of PubMed and Cochrane Reviews from January 2016 to June 2017. PMID- 28857846 TI - Utility of trabecular bone score in the evaluation of osteoporosis. AB - PURPOSE OF REVIEW: Trabecular bone score (TBS) is a lumbar spine dual-energy absorptiometry texture index which provides information on skeletal quality partially independent of bone mineral density (BMD). A body of work has emerged demonstrating the relationship between TBS and fracture risk, with lower TBS values associated with increased risk for osteoporotic fracture in postmenopausal women and older men. TBS is derived from standard DXA images; however, the information provided by TBS is complementary to that provided by BMD. In this article, we review the current state of TBS and its evolving role in the assessment and management of osteoporosis, with particular emphasis on the literature of the previous year. RECENT FINDINGS: TBS-adjusted The Fracture Risk Assessment tool (FRAX) probabilities enhance fracture risk prediction compared with conventional FRAX predictions. TBS has been found to better categorize fracture risk and assists in FRAX-based treatment decisions, particularly for patients close to an intervention threshold. However, change in lumbar spine TBS while undergoing antiresorptive treatment is not a useful indicator of antifracture effect. SUMMARY: Lumbar spine TBS is a recently developed image based software technique for skeletal assessment, complementary to conventional BMD, which has been shown to be clinically useful as a fracture risk prediction tool. PMID- 28857847 TI - Advances in treatment of glucocorticoid-induced osteoporosis. AB - PURPOSE OF REVIEW: The aim of this study is to summarize monitoring, prevention and treatment options of glucocorticoid-induced osteoporosis for patients on chronic glucocorticoid therapy. RECENT FINDINGS: Recent meta-analyses highlight the efficacy of bisphosphonate use in improving bone mineral density and in reducing vertebral fractures in the setting of long-term glucocorticoid use. A new study has now shown that alendronate also reduces the risk of hip fracture in glucocorticoid use. Emerging data indicate that teriparatide and denosumab also reduce the risk of osteoporotic fracture in glucocorticoid-induced osteoporosis. SUMMARY: Glucocorticoid use is a leading cause of secondary osteoporosis; however, patients at risk of glucocorticoid-induced osteoporosis are often not evaluated or treated in a timely manner. Patients on a dose equivalent of 2.5 mg prednisone or greater for 3 months or longer duration should have their fracture risk assessed. Those at moderate or high risk should start bisphosphonate therapy, or if contraindicated, a second-line agent such as teriparatide or denosumab. PMID- 28857848 TI - Nebulized Versus IV Amikacin as Adjunctive Antibiotic for Hospital and Ventilator Acquired Pneumonia Postcardiac Surgeries: A Randomized Controlled Trial. AB - OBJECTIVE: Nebulized antibiotics offer high efficacy due to significant local concentrations and safety with minimal blood levels. This study evaluates the efficacy and nephrotoxicity of nebulized versus IV amikacin in postcardiothoracic surgical patients with nosocomial pneumonia caused by multidrug-resistant Gram- negative bacilli. DESIGN: Prospective, randomized, controlled study on surgical patients divided into two groups. SETTING: Postcardiac surgery ICU. INTERVENTIONS: The first gtroup was administered IV amikacin 20 mg/kg once daily. The second group was prescribed amikacin nebulizer 400 mg twice daily. Both groups were co-administered IV piperacillin/tazobactam empirically. PATIENTS: Recruited patients were diagnosed by either hospital-acquired pneumonia or ventilator-associated pneumonia where 56 (42.1%) patients were diagnosed with hospital-acquired pneumonia, 51 (38.34%) patients were diagnosed with early ventilator-associated pneumonia, and 26 (19.54%) patients with late ventilator associated pneumonia. MEASUREMENTS AND MAIN RESULTS: Clinical cure in both groups assessed on day 7 of treatment was the primary outcome. Efficacy was additionally evaluated through assessing the length of hospital stay, ICU stay, days on amikacin, days on mechanical ventilator, mechanical ventilator-free days, days to reach clinical cure, and mortality rate. Lower nephrotoxicity in the nebulized group was observed through significant preservation of kidney function (p < 0.001). Although both groups were comparable regarding length of hospital stay, nebulizer group showed shorter ICU stay (p = 0.010), lower number of days to reach complete clinical cure (p = 0.001), fewer days on mechanical ventilator (p = 0.035), and fewer days on amikacin treatment (p = 0.022). CONCLUSION: Nebulized amikacin showed better clinical cure rates, less ICU stay, and fewer days to reach complete recovery compared to IV amikacin for surgical patients with nosocomial pneumonia. It is also a less nephrotoxic option associated with less deterioration in kidney function. PMID- 28857849 TI - Advanced Percutaneous Mechanical Circulatory Support Devices for Cardiogenic Shock. AB - OBJECTIVES: To review temporary percutaneous mechanical circulatory support devices for the treatment of cardiogenic shock, including current evidence, contraindications, complications, and future directions. DATA SOURCES: A MEDLINE search was conducted with MeSH terms: cardiogenic shock, percutaneous mechanical circulatory support, extracorporeal membrane oxygenation, Impella, and TandemHeart. STUDY SELECTION: Selected publications included randomized controlled trial data and observational studies describing experience with percutaneous mechanical circulatory support in cardiogenic shock. DATA EXTRACTION: Studies were chosen based on strength of association with and relevance to cardiogenic shock. DATA SYNTHESIS: Until recently, there were few options if cardiogenic shock was refractory to vasopressors or intra-aortic balloon pump counterpulsation. Now, several percutaneous mechanical circulatory support devices, including Impella (Abiomed, Danvers, MA), TandemHeart (CardiacAssist, Pittsburgh, PA), and extracorporeal membrane oxygenation, are more accessible. Compared with intra-aortic balloon pump, Impella provides greater hemodynamic support but no reduction in mortality. Similarly, TandemHeart improves hemodynamic variables but not survival. Comparative studies have been underpowered for mortality because of small sample size. Veno-arterial extracorporeal membrane oxygenation offers the advantage of biventricular circulatory support and oxygenation, but there are significant vascular complications. Comparative studies with extracorporeal membrane oxygenation have not been completed. Despite lack of randomized controlled data, there has been a substantial increase in use of percutaneous mechanical circulatory support. Several ongoing prospective studies with larger sample sizes may provide answers, and newer devices may become smaller, easier to insert, and more effective. CONCLUSIONS: Mortality from cardiogenic shock remains unacceptably high despite early coronary revascularization or other therapies. Although evidence is lacking and complications rates are high, improvements and experience with percutaneous mechanical circulatory support may offer the prospect of better outcomes. PMID- 28857850 TI - Interventions to Improve Hand Hygiene Compliance in the ICU: A Systematic Review. AB - OBJECTIVES: To synthesize the literature describing interventions to improve hand hygiene in ICUs, to evaluate the quality of the extant research, and to outline the type, and efficacy, of interventions described. DATA SOURCES: Systematic searches were conducted in November 2016 using five electronic databases: Medline, CINAHL, PsycInfo, Embase, and Web of Science. Additionally, the reference lists of included studies and existing review papers were screened. STUDY SELECTION: English language, peer-reviewed studies that evaluated an intervention to improve hand hygiene in an adult ICU setting, and reported hand hygiene compliance rates collected via observation, were included. DATA EXTRACTION: Data were extracted on the setting, participant characteristics, experimental design, hand hygiene measurement, intervention characteristics, and outcomes. Interventional components were categorized using the Behavior Change Wheel. Methodological quality was examined using the Downs and Black Checklist. DATA SYNTHESIS: Thirty-eight studies were included. The methodological quality of studies was poor, with studies scoring a mean of 8.6 of 24 (SD= 2.7). Over 90% of studies implemented a bundled intervention. The most frequently employed interventional strategies were education (78.9%), enablement (71.1%), training (68.4%), environmental restructuring (65.8%), and persuasion (65.8%). Intervention outcomes were variable, with a mean relative percentage change of 94.7% (SD= 195.7; range, 4.3-1155.4%) from pre to post intervention. CONCLUSIONS: This review demonstrates that best practice for improving hand hygiene in ICUs remains unestablished. Future research employing rigorous experimental designs, careful statistical analysis, and clearly described interventions is important. PMID- 28857851 TI - Antifungal Prevention of Systemic Candidiasis in Immunocompetent ICU Adults: Systematic Review and Meta-Analysis of Clinical Trials. AB - OBJECTIVES: The aim of this study was to identify the impact of antifungal prevention in critically ill immunocompetent adult patients on mortality and subsequent infection. DATA SOURCES: A systematic review and meta-analysis of randomized controlled trials comparing any antifungal use versus placebo to prevent candidiasis in ICU patients were performed. STUDY SELECTION: Searches were performed on PubMed, Embase, Scopus, main conference proceedings, and ClinicalTrials.gov, as well as reference lists. DATA EXTRACTION: The primary outcomes were mortality and invasive candidiasis. The secondary outcome was the rate of Candida albicans and nonalbicans strains after treatment. A random effect model was used, and sensitivity analysis was performed for both outcomes. Results are expressed as risk ratios and their 95% CIs. DATA SYNTHESIS: Nineteen trials (10 with fluconazole, four with ketoconazole, one with itraconazole, three with micafungin, and one with caspofungin) including 2,792 patients were identified. No individual trial showed a decreased mortality rate. Combined analysis showed that preventive antifungal did not decrease mortality (risk ratio, 0.88; 95% CI, 0.74-1.04; p = 0.14) but significantly decreased secondary fungal infections by 50% (risk ratio, 0.49; 95% CI, 0.35-0.68; p = 0.0001). No shift across nonalbicans strains was observed during treatment (risk ratio, 0.62; 95% CI, 0.19 1.97; p = 0.42). However, publication biases preclude any definite conclusions for prevention of infection. CONCLUSIONS: Antifungal prevention of systemic candidiasis in immunocompetent critically ill adults did not reduce mortality and may have decreased secondary fungal infection rates. However, significant publication bias was present. PMID- 28857852 TI - Effects of High-Flow Nasal Cannula on the Work of Breathing in Patients Recovering From Acute Respiratory Failure. AB - OBJECTIVES: High-flow nasal cannula is increasingly used in the management of respiratory failure. However, little is known about its impact on respiratory effort, which could explain part of the benefits in terms of comfort and efficiency. This study was designed to assess the effects of high-flow nasal cannula on indexes of respiratory effort (i.e., esophageal pressure variations, esophageal pressure-time product/min, and work of breathing/min) in adults. DESIGN: A randomized controlled crossover study was conducted in 12 patients with moderate respiratory distress (i.e., after partial recovery from an acute episode, allowing physiologic measurements). SETTING: Institut Universitaire de Cardiologie et de Pneumologie de Quebec, QC, Canada. SUBJECTS: Twelve adult patients with respiratory distress symptoms were enrolled in this study. INTERVENTIONS: Four experimental conditions were evaluated: baseline with conventional oxygen therapy and high-flow nasal cannula at 20, 40, and 60 L/min. The primary outcomes were the indexes of respiratory effort (i.e., esophageal pressure variations, esophageal pressure-time product/min, and work of breathing/min). Secondary outcomes included tidal volume, respiratory rate, minute volume, dynamic lung compliance, inspiratory resistance, and blood gases. MEASUREMENTS AND MAIN RESULTS: Esophageal pressure variations decreased from 9.8 (5.8-14.6) cm H2O at baseline to 4.9 (2.1-9.1) cm H2O at 60 L/min (p = 0.035). Esophageal pressure-time product/min decreased from 165 (126-179) to 72 (54-137) cm H2O * s/min, respectively (p = 0.033). Work of breathing/min decreased from 4.3 (3.5-6.3) to 2.1 (1.5-5.0) J/min, respectively (p = 0.031). Respiratory pattern variables and capillary blood gases were not significantly modified between experimental conditions. Dynamic lung compliance increased from 38 (24 64) mL/cm H2O at baseline to 59 (43-175) mL/cm H2O at 60 L/min (p = 0.007), and inspiratory resistance decreased from 9.6 (5.5-13.4) to 5.0 (1.0-9.1) cm H2O/L/s, respectively (p = 0.07). CONCLUSIONS: High-flow nasal cannula, when set at 60 L/min, significantly reduces the indexes of respiratory effort in adult patients recovering from acute respiratory failure. This effect is associated with an improvement in respiratory mechanics. PMID- 28857853 TI - Valproic Acid Combined With Postcardiac Arrest Hypothermic-Targeted Temperature Management Prevents Delayed Seizures and Improves Survival in a Rat Cardiac Arrest Model. AB - OBJECTIVES: High-dose valproic acid in combination with hypothermic-targeted temperature management has been reported to synergistically improve neurologic outcomes after cardiac arrest. This study investigated the potential synergistic mechanisms. DESIGN: Prospective, randomized, experimental study. SETTING: University research institution. SUBJECTS: Male Long Evans rats. INTERVENTION: Rats resuscitated from asphyxial cardiac arrest were randomized to one of the three groups: normothermic-targeted temperature management (37 degrees C +/- 1 degrees C), hypothermic-targeted temperature management (33 degrees +/- 1 degrees * 24 hr + placebo infusion), hypothermic-targeted temperature management plus high-dose valproic acid (300 mg/kg IV * 1 initiated 5 min post return of spontaneous circulation and infused over 20 min) (hypothermic-targeted temperature management + valproic acid). MEASUREMENTS AND MAIN RESULTS: Seventy two-hour survival was significantly greater with hypothermic-targeted temperature management + valproic acid, compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p < 0.05). Survival with good neurologic function, neurodegeneration, expression of HSP70, phosphorylation of Akt and Erk1/2 were not significantly different between hypothermic-targeted temperature management and hypothermic-targeted temperature management + valproic acid. The prevalence of seizures during the first 72-hour postcardiac arrest was significantly lower with hypothermic-targeted temperature management + valproic acid compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p = 0.01). CONCLUSIONS: High-dose valproic acid combined with hypothermic-targeted temperature management prevents postcardiac arrest seizures and improves survival. It remains to be determined if the mechanism of seizure prevention is through the antiepileptic effect of valproic acid or direct neuroprotection. Overall, the combination of high-dose valproic acid and hypothermic-targeted temperature management remains a promising strategy to improve cardiac arrest outcomes. PMID- 28857854 TI - Heparin-Free Prolonged Intermittent Hemodialysis Using Calcium-Free Citrate Dialysate in Critically Ill Patients. AB - OBJECTIVES: Critically ill patients who have a high risk of bleeding but require prolonged intermittent dialysis need a heparin-free easy-to-use alternative type of anticoagulation within the dialysis circuit. We assessed the safety and efficiency of heparin-free regional citrate anticoagulation of the dialysis circuit using a calcium-free citrate-containing dialysate, with calcium reinjected according to ionic dialysance. DESIGN: Prospective cohort study. SETTING: Critical care units. PATIENTS: Critically ill patients who required renal replacement therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 101 dialysis sessions were performed in 35 patients (mechanical ventilation n = 78; norepinephrine n = 13). Median duration of dialysis was 294 minutes (interquartile range, 240-300), and median ultrafiltration volume was 2.3 L (1-2.8). Urea and beta2-microglobulin reduction rates were 64.5% +/- 0.4% and 48% +/- 0.13%, respectively. Postfilter ionized calcium was 0.35 +/- 0.17 and 0.38 +/- 0.14 mmol/L at 1 and 3 hours, respectively, within the extracorporeal circuit. A major clotting event that led to premature termination of the session occurred in only three of 101 sessions. In these three cases, major catheter dysfunction occurred before clotting within the circuit. Prefilter ionized calcium remained within narrow ranges (before/after change +0.07 +/- 0.006 mmol/L), and total-to-ionized calcium ratio, a surrogate marker for citratemia, was unchanged. CONCLUSIONS: Dialysis anticoagulation with calcium-free citrate containing dialysate and calcium reinjection according to ionic dialysance is an easy-to-use, efficient, and inexpensive form of heparin-free regional anticoagulation. It allows prolonged hemodialysis sessions in critically ill patients without the need to systemically monitor ionized calcium. Furthermore, sessions can be safely extended according to the hemodynamic tolerance to ensure an adequate dose of dialysis and a negative water balance, a major point in patients with severe acute kidney disease. PMID- 28857855 TI - "It Was the Only Thing I Could Hold Onto, But...": Receiving a Letter of Condolence After Loss of a Loved One in the ICU: A Qualitative Study of Bereaved Relatives' Experience. AB - OBJECTIVES: Family members of patients who die in the ICU often remain with unanswered questions and suffer from lack of closure. A letter of condolence may help bereaved relatives, but little is known about their experience of receiving such a letter. The objective of the study was to understand bereaved family members' experience of receiving a letter of condolence. DESIGN: Qualitative study using interviews with bereaved family members who received a letter of condolence and letters written by these family members to the ICU team. This study was designed to provide insight into the results of a larger randomized, controlled, multicenter study. SETTING: Twenty-two ICUs in France. SUBJECTS: Family members who lost a loved one in the ICU and who received a letter of condolence. MEASUREMENTS AND MAIN RESULTS: Thematic analysis was used and was based on 52 interviews and 26 letters. Six themes emerged: 1) a feeling of support, 2) humanization of the medical system, 3) an opportunity for reflection, 4) an opportunity to describe their loved one, 5) continuity and closure, and 6) doubts and ambivalence. Possible difficulties emerged, notably the re-experience of the trauma, highlighting the absence of further support. CONCLUSIONS: This study describes the benefits of receiving a letter of condolence; mainly, it humanizes the medical institution (feeling of support, confirmation of the role played by the relative, supplemental information). However, this study also shows a common ambivalence about the letter of condolence's benefit. Healthcare workers must strive to adapt bereavement follow-up to each individual situation. PMID- 28857856 TI - Theoretical Modeling of Coagulation Management With Therapeutic Plasma or Prothrombin Complex Concentrate. AB - Prothrombin complex concentrates (PCCs) have been associated with a possible risk of thromboembolic complications, potentially attributable to an increased ratio of the plasma concentration of factor II (FII) to antithrombin (AT). We developed a mathematical model to examine the relationship between amounts of PCC or therapeutic plasma administered, and plasma levels of FII and AT. The model showed that PCC produces substantial increases in plasma levels of FII but only small changes in AT, increasing the FII:AT ratio. Therapeutic plasma was shown to have only modest effects on levels of FII or AT, unless high doses are used. PMID- 28857857 TI - Isoflurane Preconditioning Alleviated Murine Liver Ischemia and Reperfusion Injury by Restoring AMPK/mTOR-Mediated Autophagy. AB - BACKGROUND: Isoflurane has a pharmacological preconditioning effect against ischemia injury in the heart, kidney, and brain, but whether and how isoflurane preconditioning protects livers against ischemia and reperfusion (IR) injury is unclear. METHODS: Mice were randomly divided into an isoflurane preconditioning (ISO) group and control group, receiving 1.5% isoflurane or carrier gas for 40 minutes, respectively (n = 8/group). A partial warm liver IR model was used, and liver injury was evaluated. Primary hepatocytes were pretreated with 1.5% isoflurane for 2 hours before the induction of cell death by hydrogen peroxide. Cell death and survival were evaluated with the lactate dehydrogenase and cell counting kit-8 assay. Autophagy and regulatory molecules in stressed livers and hepatocytes were analyzed by Western blot (n = 6/group). An autophagy inhibitor (3-methyladenine [3-MA]) and 5' adenosine monophosphate-activated protein kinase (AMPK) inhibitor (dorsomorphin) were administered in vivo (n = 8/group) and in vitro (n = 6/group). RESULTS: Compared to that observed in the control group, mice in the ISO group showed reduced liver injury (alanine aminotransferase [ALT] levels, control versus ISO group, 8285 +/- 769 vs 4896 +/- 917 U/L, P < .001) and enhanced hepatocellular antiapoptosis in livers after IR. Furthermore, liver autophagy was restored by ISO as indicated by elevated LC3B II protein levels accompanied with increased p62 degradation. The in vitro study of primary hepatocytes also found that ISO effectively attenuated hepatocyte cell death induced by hydrogen peroxide. In addition, 3-MA pretreatment showed no significant influence in the control group, but abrogated the protective role of ISO both in stressed livers (ALT levels, phosphate-buffered saline + ISO versus 3 MA + ISO group, 5081 +/- 294 vs 8663 +/- 607 U/L, P < .001) and in hepatocytes. Finally, signaling pathway analysis demonstrated that AMPK was activated by ISO. Pretreatment with an AMPK inhibitor also abrogated liver protection by ISO (ALT levels, phosphate-buffered saline + ISO versus dorsomorphin [DOR] + ISO group, 5081 +/- 294 vs 8710 +/- 500 U/L, P < .001), with no significant effect in control mice. CONCLUSIONS: Our results indicate that isoflurane preconditioning attenuates liver IR injury via AMPK/mTOR-mediated hepatocellular autophagy restoration. Our findings provide a novel potential therapeutic strategy for managing liver IR injury. PMID- 28857859 TI - Fatty acids and macrophage functions: an update. PMID- 28857860 TI - Hyperlipidemia and cardiovascular disease with focus on familial hypercholesterolemia. PMID- 28857861 TI - Motion-Corrected Real-Time Cine Magnetic Resonance Imaging of the Heart: Initial Clinical Experience. AB - OBJECTIVES: Free-breathing real-time (RT) imaging can be used in patients with difficulty in breath-holding; however, RT cine imaging typically experiences poor image quality compared with segmented cine imaging because of low resolution. Here, we validate a novel unsupervised motion-corrected (MOCO) reconstruction technique for free-breathing RT cardiac images, called MOCO-RT. Motion-corrected RT uses elastic image registration to generate a single heartbeat of high-quality data from a free-breathing RT acquisition. MATERIALS AND METHODS: Segmented balanced steady-state free precession (bSSFP) cine images and free-breathing RT images (Cartesian, TGRAPPA factor 4) were acquired with the same spatial/temporal resolution in 40 patients using clinical 1.5 T magnetic resonance scanners. The respiratory cycle was estimated using the reconstructed RT images, and nonrigid unsupervised motion correction was applied to eliminate breathing motion. Conventional segmented RT and MOCO-RT single-heartbeat cine images were analyzed to evaluate left ventricular (LV) function and volume measurements. Two radiologists scored images for overall image quality, artifact, noise, and wall motion abnormalities. Intraclass correlation coefficient was used to assess the reliability of MOCO-RT measurement. RESULTS: Intraclass correlation coefficient showed excellent reliability (intraclass correlation coefficient >= 0.95) of MOCO RT with segmented cine in measuring LV function, mass, and volume. Comparison of the qualitative ratings indicated comparable image quality for MOCO-RT (4.80 +/- 0.35) with segmented cine (4.45 +/- 0.88, P = 0.215) and significantly higher than conventional RT techniques (3.51 +/- 0.41, P < 0.001). Artifact and noise ratings for MOCO-RT (1.11 +/- 0.26 and 1.08 +/- 0.19) and segmented cine (1.51 +/ 0.90, P = 0.088 and 1.23 +/- 0.45, P = 0.182) were not different. Wall motion abnormality ratings were comparable among different techniques (P = 0.96). CONCLUSIONS: The MOCO-RT technique can be used to process conventional free breathing RT cine images and provides comparable quantitative assessment of LV function and volume measurements to conventional segmented cine imaging while providing improved image quality and less artifact and noise. The free-breathing MOCO-RT reconstruction method may have considerable clinical utility in cardiac magnetic resonance imaging for patients with difficulty breath-holding. PMID- 28857862 TI - The International Home Care Nurse Association Annual Conference. PMID- 28857864 TI - Hypoglycemia in Diabetes Mellitus. AB - Hypoglycemia is a serious acute complication of diabetes treatment. Recognizing the risk factors and taking steps to prevent low blood glucose should be a part of self-management education for all people taking glucose-lowering medications. It is important for home care clinicians to evaluate their patient's understanding of hypoglycemia and the appropriate treatment options. PMID- 28857865 TI - Management of Heart Failure in a Rural Community. AB - In rural Western New York, hospitalizations of patients over 65 years of age with heart failure (HF) exceed state and national levels, demonstrating a need for improved management of older adult HF patients in rural communities. The aim of this project was to implement an evidence-based practice (EBP) guideline for HF management at a certified home health agency (CHHA). The objective was to increase CHHA interdisciplinary staff knowledge and to implement an EBP HF guideline to improve care and reduce hospital readmission rates. This quality improvement project used a quantitative descriptive study design, with a convenience sample of 60 CHHA interdisciplinary staff. A series of four 30-minute educational sessions were provided to the staff regarding the EBP HF guideline. Data were collected using pre- and posteducation testing to assess knowledge. A 3 month evaluation was completed to assess implementation along with readmission data pre- and postimplementation. Of the 60 interdisciplinary staff who received the EBP HF guideline education, 17 participants completed both the pretest and posttest. Results demonstrated a statistically significant increase in knowledge from the pretest (Md = 60.00%) to the posttest (Md = 80.00%) (p = .001). In the 3 month follow-up survey, 66% of the staff reported using the EBP HF guideline on "most" or "all" older adult HF patients. The organization had a 4.32% reduction in all-cause 30-day rehospitalizations from 11.39% to 7.07% following the implementation of the EBP HF guideline. PMID- 28857866 TI - Caregiving and Caregivers: An Important Part of the Healthcare Team. AB - As a home care and hospice consultant, I have written a newspaper column about caregiving in Sarasota County, Florida, a county with a median population age of 55 years (City-Data.com, n.d.) for many years. The following story is one of many I hear about every year. Sarah, an 86-year-old woman, has moved in with her adult daughter and son-in-law. My involvement began with a phone call from this very distraught couple who were trying to do the right thing and bring a family member into their home when it became obvious she was no longer safe on her own. This move did not occur with much forethought or planning; however, it soon became clear that Sarah was very demanding and difficult, and would not follow the doctor's recommendations nor theirs. The son and daughter-in-law work full time and have two children, ages 14 and 18, living at home. They related that, although Sarah had always been "prickly," her negative behaviors seemed magnified when she moved into their home. The last straw was when Sarah fired the aide they had hired to assist with her personal care. They knew they needed to regroup and develop a long-term plan that would be best for Sarah and her care needs. PMID- 28857867 TI - Factors Associated With Stability of Health Nursing Services for Children With Medical Complexity. AB - The objectives of our study are to: (1) identify the factors associated with lack of stable home healthcare nursing services for children with medical complexity, and (2) describe the implications of unstable home healthcare nursing for children, caregivers, nurses, and home healthcare agencies. We collected qualitative data in 20 semistructured in-depth interviews (15 English, 5 Spanish) with 26 primary caregivers of children with medical complexity, and 4 focus groups of 18 home healthcare nurses inquiring about their experiences about home healthcare nursing services for children with medical complexity. During an iterative analysis process, we identified recurrent themes related to stability of home healthcare nursing. Lack of stability in home healthcare nursing was common. These include: (1) not finding nurses to cover shifts, (2) nurse turnover, (3) nurses calling out frequently, and (4) nurses being fired by caregivers. Reasons for lack of stability of home healthcare nursing services were multifactorial and included: nurse-level, child-level, caregiver-level, residence-level, agency-level, and system-level factors. Lack of stable home healthcare nursing affected the well-being of children with medical complexity, and contributed to substantial caregiver burden. There were negative implications of unstable home healthcare services for nurses and home healthcare agencies as well. Lack of stable home healthcare nursing services is a major problem in the home care of children with medical complexity. Although some of the factors for unstable home healthcare nursing services are not modifiable, there are others that are potentially modifiable. Ensuring stable home healthcare nursing services will likely improve care of children and reduce caregiver burden. PMID- 28857868 TI - Patient Education: Painful Joints? Early Treatment for Rheumatoid Arthritis Is Key. PMID- 28857869 TI - Urinary Tract Infections. PMID- 28857870 TI - International Guidelines for Home Healthcare Nursing. PMID- 28857871 TI - Dispelling a Few Myths About ISMP. PMID- 28857872 TI - Hand Hygiene in the Home Setting: Technique Matters. PMID- 28857873 TI - A Day in the Life of a Home Health Wound Care Nurse. PMID- 28857874 TI - Is Your Agency Providing Maintenance Therapy? PMID- 28857875 TI - Keeping Patients at Home After Home Healthcare Discharge. PMID- 28857876 TI - Words You Never Want to Hear! PMID- 28857877 TI - Hypoglycemia in Diabetes Mellitus. PMID- 28857879 TI - From the Editor. PMID- 28857878 TI - Management of Heart Failure in a Rural Community. PMID- 28857880 TI - Competing Visions for Consumer Engagement in the Dawn of the Trump Administration. AB - Two different models of consumer engagement use largely the same language but represent 2 distinct paradigms: the first focuses on patients as partners in health care decision making and the second focuses on financial incentives/penalties for patients. While the 2 paradigms coexist to some degree, they have different implications particularly for populations with complex health and social needs. For these populations, financial barriers can undermine the ability to recognize and promote patients as partners in a system of integrated, coordinated care. We describe these 2 competing visions and their adoption to date and offer our assessment of future directions for consumer engagement. PMID- 28857881 TI - Commentary on "Refining Consumer Engagement Definitions and Strategies". PMID- 28857882 TI - Commentary on "Hwang et al". PMID- 28857884 TI - Commentary on "Competing Visions for Consumer Engagement in the Dawn of the Trump Administration". PMID- 28857883 TI - Commentary on "Competing Visions for Consumer Engagement in the Dawn of the Trump Administration". AB - In this commentary on Hwang, Garrett and Miller's piece, we explain how value based insurance design can help bring together both supporters and skeptics of the consumer-directed health care. Our commentary also notes the hazards that disruptive repeal-and-replace legislation might pose for consumer engagement efforts generally. PMID- 28857885 TI - Commentary on "Competing Visions for Consumer Engagement": Reaction. PMID- 28857886 TI - Perspectives on How to Engage Consumers in Health System Transformation. AB - While health care organizations and public programs have recently demonstrated an increased interest in engaging patients and consumers as part of the implementation of new programs and policies, there is little published to date to guide these organizations in how to best engage consumers. We turn to an unconventional source-health care consumer advocates-who have developed experience in the type of consumer outreach, engagement, and activation that could help inform health care organizations and policy makers in further defining and studying engagement. We share perspectives from the field of advocacy that we believe could be applicable to health care organizations and policy makers working to build patient and family engagement, particularly in organizational governance and policy. PMID- 28857887 TI - Reporting From the Front Lines: Implementing Oregon's Alternative Payment Methodology in Federally Qualified Health Centers. AB - Alternative payment models have been proposed as a way to facilitate patient centered medical home model implementation, yet little is known about how payment reform translates into changes in care delivery. We conducted site visits, observed operations, and conducted interviews within 3 Federally Qualified Health Center organizations that were part of Oregon's Alternative Payment Methodology demonstration project. Data were analyzed using an immersion-crystallization approach. We identified several care delivery changes during the early stages of implementation, as well as challenges associated with this new model of payment. Future research is needed to further understand the implications of these changes. PMID- 28857889 TI - Exercise Is an Adjuvant to Contemporary Dystrophy Treatments. AB - Duchenne muscular dystrophy is a lethal genetic disease of muscle wasting for which there is no cure. In healthy muscle, structure and function improve dramatically with exercise. In patients with dystrophy, little is known about the effects of exercise. As contemporary therapies rapidly progress and patients become more active, there is a need to understand the effects of exercise. PMID- 28857890 TI - Mechanical Coupling Between Muscle-Tendon Units Reduces Peak Stresses. AB - The presence of mechanical linkages between synergistic muscles and their common tendons may distribute forces among the involved structures. We review studies, using humans and other animals, examining muscle and tendon interactions and discuss the hypothesis that connections between muscle bellies and within tendons may serve as a mechanism to distribute forces and mitigate peak stresses. PMID- 28857892 TI - Evaluation and management of cytomegalovirus-associated congenital hearing loss. AB - PURPOSE OF REVIEW: The current article reviews the current literature related to congenital cytomegalovirus (CMV)-related hearing loss. The discussion will focus on the epidemiology, pathogenesis, and clinical presentation of human CMV infection as it pertains to hearing loss. Current methods of CMV diagnosis with a focus on the evolving trend toward broader neonatal screening protocols will also be explored. Discussion of medical, surgical, and audiologic management of the condition will also be addressed. RECENT FINDINGS: Much of the current research on this topic is focused on improving detection of CMV through screening programs. Some advances in understanding cochlear pathogenesis have also been made. SUMMARY: Congenital CMV infection remains an important cause of hearing loss in infants and children. Early detection of CMV infection can broaden treatment options and allow for improved hearing and language outcome for patients with CMV-associated sensorineural hearing loss. PMID- 28857894 TI - Outcomes of patients hospitalized with peptic ulcer disease diagnosed in acute upper endoscopy. AB - OBJECTIVES: The incidence and complications of peptic ulcer disease (PUD) have declined, but mortality from bleeding ulcers has remained unchanged. The aims of the current study were to evaluate the significance of PUD among patients admitted for acute upper endoscopy and to evaluate the survival of PUD patients. PATIENTS AND METHODS: In this prospective, observational cohort study, data on 1580 acute upper endoscopy cases during 2012-2014 were collected. A total of 649 patients were included with written informed consent. Data on patients' characteristics, living habits, comorbidities, drug use, endoscopy and short-term and long-term survival were collected. RESULTS: Of all patients admitted for endoscopy, 147/649 (23%) had PUD with the main symptom of melena. Of these PUD patients, 35% had major stigmata of bleeding (Forrest Ia-IIb) in endoscopy. Patients with major stigmata had significantly more often renal insufficiency, lower level of blood pressure with tachycardia and lower level of haemoglobin, platelets and ratio of thromboplastin time. No differences in drug use, Charlson comorbidity class, BMI, smoking or alcohol use were found. Of the PUD patients, 31% were Helicobacter pylori positive. The 30-day mortality was 0.7% (95% confidence interval: 0.01-4.7), 1-year mortality was 12.9% (8.4-19.5) and the 2 year mortality was 19.4% (13.8-26.8), with no difference according to major or minor stigmata of bleeding. Comorbidity (Charlson>1) was associated with decreased survival (P=0.029) and obesity (BMI>=30) was associated with better survival (P=0.023). CONCLUSION: PUD is still the most common cause for acute upper endoscopy with very low short-term mortality. Comorbidity, but not the stigmata of bleeding, was associated with decreased long-term survival. PMID- 28857895 TI - Cecal intubation time between cap-assisted water exchange and water exchange colonoscopy: a randomized-controlled trial. AB - BACKGROUND AND AIM: The water exchange (WE) method can decrease the discomfort of the patients undergoing colonoscopy. It also provides salvage cleansing and improves adenoma detection, but a longer intubation time is required. Cap assisted colonoscopy leads to a significant reduction in cecal intubation time compared with traditional colonoscopy with air insufflation. The aim of this study was to investigate whether combined cap-assisted colonoscopy and water exchange (CWE) could decrease the cecal intubation time compared with WE. PATIENTS AND METHODS: A total of 120 patients undergoing fully sedated colonoscopy at a regional hospital in southern Taiwan were randomized to colonoscopy with either CWE (n=59) or WE (n=61). The primary endpoint was cecal intubation time. RESULTS: The mean cecal intubation time was significantly shorter in CWE (12.0 min) compared with WE (14.8 min) (P=0.004). The volume of infused water during insertion was lower in CWE (840 ml) compared with WE (1044 ml) (P=0.003). The adenoma detection rate was 50.8 and 47.5% for CWE and WE, respectively (P=0.472). The Boston Bowel Preparation Scale scores were comparable in the two groups. Results from the multiple linear regression analysis indicated that WE with a cap, a higher degree of endoscopist's experience, a higher Boston Bowel Preparation Scale score, and a lower volume of water infused during insertion, without abdominal compression, without change of position, and without chronic laxative use, were significantly associated with a shorter cecal intubation time. CONCLUSION: In comparison with WE, CWE could shorten the cecal intubation time and required lower volume of water infusion during insertion without compromising the cleansing effect of WE. PMID- 28857896 TI - Viral hepatitis screening in transgender patients undergoing gender identity hormonal therapy. AB - BACKGROUND AND AIM: Viral hepatitis is a global health issue and can lead to cirrhosis, liver failure, and hepatocellular carcinoma. Guidelines for viral hepatitis screening in the transgender population do not exist. Transgender patients may be at higher risk for contracting viral hepatitis due to socioeconomic and behavioral factors. The aim of this study was to measure the quality of screening, prevalence, and susceptibility of viral hepatitis, and to identify barriers to screening in transgender patients undergoing gender identity hormonal therapy. METHODS: LGBTQ-friendly clinic visits from transgender patients older than 18 years in New York City from 2012 to 2015 were reviewed. RESULTS: Approximately 13% of patients were screened for any viral hepatitis on initial consultation. Screening rates for hepatitis C virus (HCV), hepatitis B virus (HBV), and hepatitis A virus (HAV) at any point were 27, 22, and 20%. HAV screening was performed in 28% of the female to male (FtM) patients and 16% of male to female (MtF) (P<0.05) patients. HBV screening was performed in 30% of FtM patients and 18% of MtF patients (P<0.05). Thirty-one percent of FtM, 24% of MtF, and 17% of genderqueer patients were tested for HCV (P>0.05). Prevalence of HCV, HBV, and HIV in FtM was 0, 0, and 0.44% and that in MtF was 1.78, 0.89, and 1.78%, respectively. Percentage of patients immune to hepatitis A in FtM and MtF subgroups were 55 and 47% (P>0.05). Percentage of patients immune to HBV in FtM and MtF subgroups were 54 and 48% (P>0.05). CONCLUSION: This study indicates a significant lack of hepatitis screening in the transgender population and a concerning proportion of patients susceptible to disease. PMID- 28857897 TI - MRI assessed pancreatic morphology and exocrine function are associated with disease burden in chronic pancreatitis. AB - BACKGROUND AND AIM: The aim of this study was to explore the association between morphological and functional secretin-stimulated MRI parameters with hospitalization, quality of life (QOL), and pain in patients with chronic pancreatitis (CP). PATIENTS AND METHODS: This prospective cohort study included 82 patients with CP. Data were obtained from clinical information, QOL, and pain as assessed by questionnaires (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and modified Brief Pain Inventory short form). Secretin-stimulated MRI morphological parameters included pancreatic gland volume, main pancreatic duct diameter, the modified Cambridge Classification of Duct Abnormality, apparent diffusion coefficient, fat signal fraction, and the pancreatic secretion volume as a functional parameter. The primary outcomes were time to first hospitalization related to the CP, as well as annual hospitalization frequency and duration. The secondary outcomes were pain severity, QOL, and pain interference scores. RESULTS: A main pancreatic duct diameter below 5 mm was associated with reduced time to first hospitalization (hazard ratio=2.06; 95% confidence interval: 1.02-4.17; P=0.043). Pancreatic secretion volume was correlated with QOL (r=0.31; P=0.0072) and pain interference score (r=-0.27; P=0.032), and fecal elastase was also correlated with QOL (r=0.28; P=0.017). However, functional and morphological findings were not related to pain intensity. CONCLUSION: Advanced pancreatic imaging techniques may be a highly sensitive tool for prognostication and monitoring of disease activity and its consequences. PMID- 28857898 TI - Prevalence of thiopurine S-methyltransferase gene polymorphisms in patients with inflammatory bowel disease from the island of Crete, Greece. AB - BACKGROUND: There is evidence that genotyping for the thiopurine S methyltransferase (TPMT) gene variants is useful for the prediction of response to thiopurine analogs (azathioprine and 6-mercaptopurine) in patients with inflammatory bowel disease (IBD). The aim of the present study was to determine the prevalence of TPMT gene polymorphisms in a genetic homogenous population of IBD patients in Crete and to correlate the results with adverse reactions to thiopurine drugs. PATIENTS AND METHODS: Genotyping for the most common TPMT variants TPMT*2, TPMT*3A, TPMT3*C, and TPMT*3B was performed using the PCR restriction fragment length polymorphism method in 223 consecutive IBD patients and 119 age-matched and sex-matched healthy controls. The hospital medical records were reviewed for thiopurine use in these patients and related adverse events. RESULTS: The prevalence of TPMT variants TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C was 1.8, 2.7, 1.3, and 1.8%, respectively. The G238C mutation was detected in four (1.8%) out of 223 patients, three (1.3%) patients were carriers of the G460A mutation, four (1.8%) of the A719G mutation, and six (2.7%) of both G460A and A719G mutations. In healthy controls, only one (0.8%) carried both the G460A and the A719G mutation, whereas TPMT*2, TPMT*3C, and TPMT*3B were not detected. None of the genotypes was homozygous. A statistically significant correlation between the presence of the G460A mutation and the development of leucopenia after the administration of thiopurines was observed (P=0.048). CONCLUSION: This study showed a lower frequency of total TPMT variants and a higher frequency of TPMT*3B in Cretan IBD patients compared with other Caucasian populations. The presence of the G460A mutation is associated with the development of leukopenia. PMID- 28857899 TI - Short article: Alcohol and substance use, race, and insurance status predict nontreatment for hepatitis C virus in the era of direct acting antivirals: a retrospective study in a large urban tertiary center. AB - OBJECTIVE: Direct acting antivirals (DAAs) have overcome many long-standing medical barriers to hepatitis C virus (HCV) treatment (i.e. host characteristics and medical contraindications) and treatment outcome disparities that were associated with interferon regimens. The public health and clinical benefit of current and forthcoming DAA discoveries will be limited if efforts are not made to examine racial, psychological, and socioeconomic factors associated with being treated with DAAs. This study examined racial, psychological, and socioeconomic factors that facilitate and inhibit patients receiving DAAs for HCV. PATIENTS AND METHODS: This was a single-center retrospective cohort study at a large urban tertiary center of patients (n=747) who were referred for evaluation and treatment of HCV. RESULTS: Sixty-eight percent of patients were non-Hispanic White, 31% were African American, and 1% were of other ethnicities. The majority of patients received treatment, but 29% (218/747) did not. Patients who were older [odds ratio (OR)=1.02, 95% confidence interval (CI): 1.01-1.04] and insured (OR=2.73, 95% CI: 1.12-6.97) were more likely to receive HCV treatment. Patients who were African American (OR=0.46, 95% CI: 0.46-1.06), used drugs (OR=0.09, 95% CI: 0.04-0.17), smoked (OR=0.55, 95% CI: 0.37-0.81), and used alcohol (OR=0.11, 95% CI: 0.06-0.20) were less likely to receive HCV treatment. CONCLUSION: Though DAAs have eliminated many historically, long-standing medical barriers to HCV treatment, several racial, psychological and socioeconomic barriers, and disparities remain. Consequently, patients who are African American, uninsured, and actively use drugs and alcohol will suffer from increased HCV-related morbidity and mortality in the coming years if deliberate public health and clinical efforts are not made to facilitate access to DAAs. PMID- 28857901 TI - Two Unique Cases of Ciprofloxacin-Associated Avulsion of Ligament and Tendon. AB - Ciprofloxacin is recognized to have a deleterious relationship with tendons, particularly Achilles tendinopathy, which makes up most case reports. Tendinopathy seems to occur because of induction of collagen-degrading enzymes causing damage and ischemia of the poorly vascularized regions preventing repair. The focus on the relationship of ciprofloxacin and the Achilles tendon leaves patients on fluoroquinolones with non-Achilles tendinopathy symptoms at risk of misdiagnosis. There have not been any documented instances of ligament damage with ciprofloxacin administration in the literature, although ligament and tendon compositions are similar and should have similar susceptibility. This report includes two cases, one presenting with right lateral thumb pain and a medical history of gastroenteritis treated with ciprofloxacin. Physical examination showed swelling of the right metacarpophalangeal joint and ultrasound confirmed disruption of the radial collateral ligament at insertion on first metacarpal; the second case is of a woman presenting with right hip pain in setting of chronic recurrent diverticulitis treated with ciprofloxacin. She received work-up for lumbar disc disease and spondylosis. After standard therapy with pharmacotherapy and physical therapy for radiculopathy failed, magnetic resonance imaging was performed showing near complete avulsion of the right hamstring tendons from the ischial tuberosity. PMID- 28857900 TI - Regression of liver fibrosis over a 24-week period after completing direct-acting antiviral therapy in patients with chronic hepatitis C receiving care within the national hepatitis C elimination program in Georgia: results of hepatology clinic HEPA experience. AB - OBJECTIVE: We assessed the impact of direct-acting antiviral (DAA) therapy on liver fibrosis regression measured by transient elastography (TE) in patients with chronic hepatitis C virus (HCV) infection. PATIENTS AND METHODS: A prospective cohort study was carried out in HCV monoinfected patients with advanced liver fibrosis or cirrhosis receiving interferon (IFN)-containing or IFN free DAA therapy. Liver stiffness (LS) score more than 14.5 kPa indicated LS defined cirrhosis. The primary outcome was improvement in liver stiffness measurement (LSM) at week 24 after treatment measured as (a) decrease in the median LS compared with baseline and (b) at least a 20% decrease in LSM compared with baseline. A multivariate logistic regression model was utilized to identify the factors associated with at least a 20% improvement in LSM. RESULTS: Of a total of 304 patients, 172 (56.6%) had LS-defined cirrhosis before treatment. LSM decreased from the baseline median value of 16.9 (interquartile range: 11.8-27.7) kPa to a post-treatment week 24 score of 11.9 (interquartile range: 8.2-20.9) kPa (P<0.0001). Of a total of 304 patients, 198 (65.1%) achieved at least a 20% reduction in LS. In multivariate logistic regression analysis, sustained virological response (SVR) was associated significantly with this reduction (P<0.0001). The addition of IFN to the treatment regimen had no impact on the decrease in LSM. Despite decreasing baseline LSM, more than half of the LS defined cirrhotic patients remained cirrhotic at week 24 after treatment. CONCLUSION: In patients with advanced fibrosis, pretreatment LS significantly reduced during DAA therapy. SVR was the only independent factor associated with the regression in LSM. However, irrespective of achieving SVR, liver damage still persisted in a substantial proportion of patients. Thus, early treatment of HCV infected patients can significantly prevent residual liver damage. PMID- 28857903 TI - Commentary on the Homburg Lung: Pro/Con of Miniaturized ECCO2R. PMID- 28857904 TI - In Vivo Evaluation of Physiologic Control Algorithms for Left Ventricular Assist Devices Based on Left Ventricular Volume or Pressure. AB - Turbodynamic left ventricular assist devices (LVADs) provide a continuous flow depending on the speed at which the pump is set, and do not adapt to the changing requirements of the patient. The limited adaptation of the pump flow (PF) to the amount of venous return can lead to ventricular suction or overload. Physiologic control may compensate such situations by an automatic adaptation of the PF to the volume status of the left ventricle. We evaluated two physiologic control algorithms in an acute study with eight healthy pigs. Both controllers imitate the Frank-Starling law of the heart and are based on a measurement of the left ventricular volume (LVV) or pressure (LVP), respectively. After implantation of a modified Deltastream DP2 blood pump as an LVAD, we tested the responses of the physiologic controllers to hemodynamic changes and compared them with the response of the constant speed (CS) mode. Both physiologic controllers adapted the pump speed (PS) such that the flow was more sensitive to preload and less sensitive to afterload, as compared with the CS mode. As a result, the risk for suction was strongly reduced. Five suction events were observed in the CS mode, one with the volume-based controller and none with the pressure-based controller. The results suggest that both physiologic controllers have the potential to reduce the number of adverse events when used in the clinical setting. PMID- 28857905 TI - Incidence of Cannula-Associated Deep Vein Thrombosis After Veno-Venous Extracorporeal Membrane Oxygenation. AB - Limited literature regarding the incidence of cannula-associated deep vein thrombosis (CaDVT) after veno-venous extracorporeal membrane oxygenation (VV ECMO) exists. The purpose of this study was to identify the incidence of post decannulation CaDVT and identify any associated risk factors. Forty-eight patients were admitted between August 2014 and January 2016 to the Lung Rescue Unit were included in the study. Protocolized anticoagulation levels (partial thromboplastin time [PTT] 45-55 seconds) and routine post decannulation DVT screening were in place during the study period. Forty-one (85.4%) patients had CaDVT. Of those with CaDVT, 31 (76%) patients were treated with full anti coagulation therapy. Thirty-four (76%) patients with right internal jugular (RIJ) cannulation had CaDVT at cannula site. Twenty-five (61%) patients had CaDVT in the lower extremity (18 associated right femoral vein cannulation and 7 left femoral vein cannulation). Eighteen (44%) patients had both upper and lower extremity CaDVT. Overall, patients with CaDVT tended to be older, have a higher body mass index (BMI), and on ECMO longer (p = NS). Mean PTT during time on ECMO between patients that did and did not have CaDVT did not differ. No clinical evidence of pulmonary embolism (PE) was seen. PMID- 28857906 TI - Lung Transplantation After 125 Days on ECMO for Severe Refractory Hypoxemia With No Prior Lung Disease. AB - Venovenous extracorporeal membrane oxygenation (ECMO) has become a viable and increasingly utilized option for the treatment of refractory hypoxemia in severe acute respiratory distress syndrome (ARDS). However, options are limited for ARDS patients who fail to wean from ECMO. The high rates of infection, presence of extrapulmonary end organ damage, intensive care unit-acquired weakness, and high short-term mortality associated with ARDS are all significant hurdles that make lung transplantation a difficult prospect to consider. However, ECMO support has been used as a bridge to transplant in patients with other underlying chronic lung diseases. Our case illustrates the successful use of lung transplantation for a patient with no previous lung disease who developed refractory ARDS requiring protracted ECMO support. The use of ambulatory ECMO with early institution of physical therapy is an essential component in preparing such patients for successful transplantation. PMID- 28857907 TI - Predicting Fluid Responsiveness in Critically Ill Patients by Using Combined End Expiratory and End-Inspiratory Occlusions With Echocardiography. AB - OBJECTIVES: First, we aimed at assessing whether fluid responsiveness is predicted by the effects of an end-expiratory occlusion on the velocity-time integral of the left ventricular outflow tract. Second, we investigated whether adding the effects of an end-inspiratory occlusion and of an end-expiratory occlusion on velocity-time integral can predict fluid responsiveness with similar reliability than end-expiratory occlusion alone but with a higher threshold, which might be more compatible with the precision of echocardiography. DESIGN: Diagnostic study. SETTING: Medical ICU. PATIENTS: Thirty mechanically ventilated patients in whom fluid administration was planned. INTERVENTIONS: A 15-second end expiratory occlusion and end-inspiratory occlusion, separated by 1 minute, followed by a 500-mL saline administration. MEASUREMENTS AND MAIN RESULTS: Pulse contour analysis-derived cardiac index and velocity-time integral were measured during the last 5 seconds of 15-second end-inspiratory occlusion and end expiratory occlusion and after fluid administration. End-expiratory occlusion increased velocity-time integral more in responders than in nonresponders to fluid administration (11% +/- 5% vs 3% +/- 1%, respectively; p < 0.0001), and end inspiratory occlusion decreased velocity-time integral more in responders than in nonresponders (12% +/- 5% vs 5% +/- 2%, respectively; p = 0.0002). When adding the absolute values of changes in velocity-time integral observed during both occlusions, velocity-time integral changed by 23% +/- 9% in responders and by 8% +/- 3% in nonresponders. Fluid responsiveness was predicted by the end-expiratory occlusion-induced change in velocity-time integral with an area under the receiver operating characteristic curve of 0.938 (0.785-0.989) and a threshold value of 5%. Fluid responsiveness was predicted by the sum of absolute values of changes in velocity-time integral during both occlusions with a similar reliability (area under the receiver operating characteristic curve = 0.973 [0.838-1.000]) but with a threshold of 13%. Both sensitivity and specificity were 93% (68-100%). CONCLUSIONS: If consecutive end-inspiratory occlusion and end expiratory occlusion change velocity-time integral is greater than or equal to 13% in total, fluid responsiveness is accurately predicted. This threshold is more compatible with the precision of echocardiography than that obtained by end expiratory occlusion alone. PMID- 28857908 TI - Physical Examination of the Knee: Meniscus, Cartilage, and Patellofemoral Conditions. PMID- 28857909 TI - Affective Adaptation to Repeated SIT and MICT Protocols in Insulin-Resistant Subjects. AB - INTRODUCTION: The aim of this study was to investigate affective responses to repeated sessions of sprint interval training (SIT) in comparison with moderate intensity continuous training (MICT) in insulin-resistant subjects. METHODS: Twenty-six insulin-resistant adults (age, 49 (4) yr; 10 women) were randomized into SIT (n = 13) or MICT (n = 13) groups. Subjects completed six supervised training sessions within 2 wk (SIT session, 4-6 * 30 s all-out cycling/4-min recovery; MICT session, 40-60 min at 60% peak work load). Perceived exertion, stress, and affective state were assessed with questionnaires before, during and after each training session. RESULTS: Perceived exertion, displeasure, and arousal were higher during the SIT compared with MICT sessions (all P < 0.01). These, however, alleviated similarly in response to SIT and MICT over the 6 d of training (all P < 0.05). SIT versus MICT exercise increased perceived stress and decreased positive affect and feeling of satisfaction acutely after exercise especially in the beginning of the intervention (all P < 0.05). These negative responses declined significantly during the training period: perceived stress and positive activation were no longer different between the training groups after the third, and satisfaction after the fifth training session (P > 0.05). CONCLUSIONS: The perceptual and affective responses are more negative both during and acutely after SIT compared with MICT in untrained insulin-resistant adults. These responses, however, show significant improvements already within six training sessions, indicating rapid positive affective and physiological adaptations to continual exercise training, both SIT and MICT. These findings suggest that even very intense SIT is mentally tolerable alternative for untrained people with insulin resistance. PMID- 28857910 TI - Should Oral Corticosteroids Be Used to Treat Demyelinating Optic Neuritis? PMID- 28857911 TI - The Economics of Residency Application Fees. PMID- 28857912 TI - In Reply to Maroongroge. PMID- 28857913 TI - The Emotional Domains of Empathy Matter, Too. PMID- 28857914 TI - In Reply to Quinn and Zelenski. PMID- 28857915 TI - A New Look at Medical Curricula. PMID- 28857916 TI - In Reply to Azer. PMID- 28857917 TI - Voting and the Role of Physicians. PMID- 28857918 TI - The Professional Educational Identity Across the Continuum of Medical Education. PMID- 28857919 TI - A Closer Look at Regional Medical Campuses. PMID- 28857920 TI - The Spider. PMID- 28857921 TI - A Tale of Two Cities: [Excerpt]. PMID- 28857922 TI - Commentary on an Excerpt From A Tale of Two Cities. PMID- 28857923 TI - Artist's Statement: Roger. PMID- 28857924 TI - Learning From Loss: What I Learned From the Death of My Grandfather. PMID- 28857925 TI - A Humanism of Disposition. PMID- 28857926 TI - Postpartum donor heart atrial tachycardia very late after orthotopic cardiac transplantation. PMID- 28857927 TI - Arrhythmogenic right-ventricular cardiomyopathy and cardiac microvascular disease: a rare association or a possible link? PMID- 28857928 TI - A second-degree atrioventricular block with double escape rhythm secondary to paroxysmal vagal hypertonia. PMID- 28857929 TI - Episodes of second-degree ventriculo-atrial block during ventricular tachycardia. PMID- 28857931 TI - Comparison of Machine Learning Algorithms for the Prediction of Preventable Hospital Readmissions. AB - A diverse universe of statistical models in the literature aim to help hospitals understand the risk factors of their preventable readmissions. However, these models are usually not necessarily applicable in other contexts, fail to achieve good discriminatory power, or cannot be compared with other models. We built and compared predictive models based on machine learning algorithms for 30-day preventable hospital readmissions of Medicare patients. This work used the same inclusion/exclusion criteria for diseases used by the Centers for Medicare and Medicaid Services. In addition, risk stratification techniques were implemented to study covariate behavior on each risk strata. The new models resulted in improved performance measured by the area under the receiver operating characteristic curve. Finally, factors such as higher length of stay, disease severity index, being discharged to a hospital, and primary language other than English were associated with increased risk to be readmitted within 30 days. In the future, better predictive models for 30-day preventable hospital readmissions can point to the development of systems that identify patients at high risk and lead to the implementation of interventions (e.g., discharge planning and follow up) to those patients, providing consistent improvement in the quality and efficiency of the healthcare system. PMID- 28857932 TI - The Cortical Bone Trajectory for Pedicle Screw Insertion. PMID- 28857933 TI - The Opioid Epidemic: Postoperative Pain Management Strategies in Orthopaedics. PMID- 28857934 TI - A Comprehensive Review of Stem-Cell Therapy. PMID- 28857935 TI - Post-Deepwater Horizon Oil Spill Exposure Patterns Among Children in Mobile County, Alabama. AB - OBJECTIVE: The aim of this study was to characterize environmental exposure from Deepwater Horizon oil spill among pre-K to fourth-grade children from six schools in Mobile County, Alabama. METHODS: A mail-in survey administered 11 months post oil spill to children's parents/caregivers elicited information on exposure related activities. Descriptive and multivariable analyses were performed. RESULTS: Overall, 180 children (coastal schools, 90; inland schools, 90) completed the survey. During the post-oil spill period, children in coastal schools were less likely to reduce their exposure-related activities, including fishing; eating and selling caught fish; visiting beaches; and parental participation in cleanup activities, than children in inland schools. Particularly, fishing and eating caught fish were significantly associated with the coastal group (odds ratio = 2.28; 95% confidence interval = 1.54 to 3.36). CONCLUSION: Proximity to the shoreline may serve as an indicator for potential exposure in oil spills among vulnerable populations including children. PMID- 28857936 TI - Brief Report: Radiofrequency Ablation Therapy for Anal Intraepithelial Neoplasia: Results From a Single-Center Prospective Pilot Study in HIV+ Participants. AB - BACKGROUND: HIV-positive individuals have high incidence of anal high-grade squamous intraepithelial lesions (HSIL) at the squamocolumnar junction (SCJ), which can progress to cancer. Focal radiofrequency ablation (RFA) treats HSIL, but metachronous recurrence remains high and may be improved with circumferential treatment. SETTING: The study was performed at a single center. METHODS: This was a prospective trial of circumferential anal RFA using Barrx 60 RFA focal catheters in participants with >=1 anal SCJ HSIL. The entire SCJ was ablated by RFA. Adverse events (AEs), symptoms, including pain, and quality of life were assessed. High-resolution anoscopy assessed recurrences at 3, 6, 9, and 12 months. Lesion site biopsies occurred at month 12. Recurrences were retreated with focal RFA. RESULTS: Ten male participants (9 HIV+), with a median 2 HSILs (range 2-8) each, enrolled. Median T-cell count and viral load were 730 cells/mcL and 38 copies/mL. Median duration of RFA treatment was 6.5 (5-13) minutes. Lesion persistence occurred in 4 participants (3 at 3 months, 1 at 6 months). Recurrence at a new site occurred in 1 participant at 3 months. No lesion persisted after retreatment. All participants were HSIL free and completely healed by 12 months. Two device-related mild AEs occurred in 1 participant each (thrombosed external hemorrhoid and soft anal scar; both resolved). No serious AEs occurred. CONCLUSION: Circumferential anal SCJ RFA produced total HSIL eradication with no more than 2 treatments. Circumferential RFA seems to be well tolerated with minimal pain and no serious AEs in HIV+ participants. CLINICALTRIALS.GOV:: NCT02189161. PMID- 28857938 TI - Polyalkylimide and Invasive Growth of Basal Cell Carcinoma of the Skin. PMID- 28857940 TI - The Next Turf War for Botulinum Toxin? PMID- 28857939 TI - Melasma Treatment With Combined Chemical Peels and a Novel Topical Agent Containing an Antiestrogen and a Vascular Endothelial Growth Factor Inhibitor. PMID- 28857941 TI - Triple Combination Therapy for Pincer Nail Deformity: Surgical Matricectomy, Thioglycolic Acid, and Anticonvex Sutures. AB - BACKGROUND: Pincer nail deformity (PND) is characterized by an excessive transverse curvature of the nail plate that increases along the longitudinal axis of the nail. Although many conservative and surgical techniques have been used in clinical practice, an established consensus for the correction of PND has not been present yet. OBJECTIVE: Aim of the technique described in this article is to provide to restore the suitable nail-matrix system curvature by a simplified and quick approach, which could be seen as a synthesis of conservative and surgical treatments described in the literature. MATERIALS AND METHODS: Nineteen cases of pincer nail of the great toe in 14 patients were analyzed. After softening nail plate with 5% thioglycolic acid solution for at least half an hour, surgical bilateral matricectomy and 2 anticonvex sutures with 1-0 polypropylene were performed to ensure proper nail plate shape. Besides demographic data, visual analog scale (VAS) score for pain, width index, height index, patient and surgeon satisfaction scores, operation time, and the day of painless return to the daily activities were investigated. RESULTS: A statistical significance was observed in VAS score for pain, width, and height indices between preoperative and postoperative values. CONCLUSION: This report gives acceptable outcomes with a combination of surgery and conservative treatments. PMID- 28857942 TI - Correlation Between Original Biopsy Pathology and Mohs Intraoperative Pathology. AB - BACKGROUND: The pathology observed on initial biopsy specimens for nonmelanoma skin cancer (NMSC), specifically the tumor subtype, weighs heavily into the selection of the treatment modality. Recognizing aggressive features on intraoperative Mohs micrographic surgery (MMS) frozen sections that were not indicated on initial biopsy reports is not uncommon. To date, there is limited data describing this discrepancy. OBJECTIVE: To investigate the frequency and nature of incongruity between the pathology seen in initial biopsies and intraoperative Mohs sections, providing information that will potentially impact skin cancer treatment and biopsy recommendations. METHODS: Retrospective chart review of cases of NMSC referred for MMS at the authors' institution over a 1 year period, recording changes between tumor subtypes observed at biopsy and those observed during MMS. RESULTS: Cases (50.5%) (n = 163) changed aggressiveness. Of these, 33% (n = 108) were more aggressive, whereas 17% (n = 55) were less aggressive. CONCLUSION: A substantial discrepancy was observed between preoperative biopsy and intraoperative pathology, including a significant portion tumors that became more aggressive. These results suggest that treatment modalities without margin control may not provide adequate treatment for a considerable number of NMSC based on preoperative tumor type alone. PMID- 28857943 TI - Visibility of Optic Nerve Head Structures With Spectral-domain and Swept-source Optical Coherence Tomography. AB - PURPOSE: To compare the visibility of deep optic nerve head (ONH) structures and the visible area of the anterior surface of the lamina cribrosa (ASLC) with spectral-domain optical coherence tomography (SD-OCT) and swept-source OCT (SS OCT). MATERIALS AND METHODS: In total, 33 glaucoma patients were imaged with SD OCT (Spectralis, 24 radial B-scans centered on the ONH) and SS-OCT (Atlantis, 12 radial and a horizontal and vertical raster scan pattern containing 5 lines each, centered on the ONH). One of the SS-OCT horizontal and vertical scans that was best matching with the horizontal and vertical scan lines with those of SD-OCT was selected. All B-scans were then exported and deidentified. An independent observer determined whether the posterior choroid, border tissue, anterior scleral canal opening, and LC insertion into the sclera were detectable in the matched scan lines. Bruch membrane opening (BMO) and ASLC were segmented manually in radial scans. The segmented points were combined into a single plane and a linear interpolation was used to define BMO and ASLC areas. RESULTS: The posterior choroid, border tissue, and anterior scleral canal opening were detectable in most patients (94% to 100%, 88% to 100%, and 76% to 100%, respectively) and were not different between SD-OCT and SS-OCT. The LC insertion detection rate was nonstatistically higher for SS-OCT compared with SD-OCT (58% to 85% vs. 42% to 73%; P>0.10). The mean (SD) ASLC visible area (percentage of the respective BMO area) was 124 (30%) with SD-OCT and 135 (32%) with SS-OCT (P<0.01). CONCLUSION: SD-OCT and SS-OCT had comparable detection rates of deep ONH structures; however, a larger area of ASLC was visible with SS-OCT. PMID- 28857944 TI - Volumetric Measurement of Optic Nerve Head Drusen Using Swept-Source Optical Coherence Tomography. AB - PURPOSE: To describe new software tools for quantifying optic nerve head drusen volume using 3-dimensional (3D) swept-source optical coherence tomography (SS OCT) volumetric scans. MATERIALS AND METHODS: SS-OCT was used to acquire raster volume scans of 8 eyes of 4 patients with bilateral optic nerve head drusen. The scans were manually segmented by 3 graders to identify the drusen borders, and thereafter total drusen volumes were calculated. Linear regression was performed to study the relationships between drusen volume, retinal nerve fiber layer thickness, and Humphrey visual field mean deviation. RESULTS: In the 8 study eyes, drusen volumes ranged between 0.24 to 1.05 mm. Visual field mean deviation decreased by ~20 dB per cubic millimeter increase in drusen volume, and the coefficient of correlation of the linear regression was 0.92. In this small patient series, visual field defects were detected when drusen volume was larger than about 0.2 mm. CONCLUSIONS: Software tools have been developed to quantify the size of OHND using SS-OCT volume scans. PMID- 28857945 TI - Can Adapted Motivational Interviewing Improve Uptake of Surgical or Laser Treatment for Glaucoma in Nigeria: Randomized Controlled Trial. AB - PURPOSE: To assess whether adapted motivational interviewing (MI) has any impact on the proportion of participants who subsequently underwent surgery or laser treatment for glaucoma. MATERIALS AND METHODS: A single site randomized controlled trial in Bauchi, Nigeria. Participants were new patients with a confirmed diagnosis of primary open-angle glaucoma in 1 or both eyes, where surgery or laser was recommended. Intervention was a session of MI adapted for glaucoma and the local context, using an interview guide based on local qualitative research. Participants were randomly allocated to intervention or usual care. Usual care was routine explanation by an ophthalmologist and an educational pamphlet. After the interview, a 12-item Working Alliance Inventory questionnaire was administered to patient-interviewer pairs to assess the collaborative relationship. RESULTS: Two hundred seventy-six glaucoma patients participated; 70% males. One hundred thirty-five (49%) were assigned to adapted MI and 141 to usual care. All received the intervention as allocated. Uptake (ie, the proportion who underwent treatment) of laser or surgery in the MI group was 52% compared with 45% in the usual care group (risk difference 7.2%; 95% confidence interval, -4.5% to 18.9%). Mean Working Alliance Inventory scores were 68.0 for interviewers and 68.5 for participants with a combined reliability coefficient of 93.9% (ie, high internal consistency and reliability). CONCLUSIONS: We observed only a small increase in the uptake of surgery or laser with MI compared with usual care which was not statistically significant. Although only 1 in 2 patients accepted surgery or laser in this trial, this is a much higher proportion than in other studies. PMID- 28857946 TI - Clinical Implications of Specific Features of the New Susanna Glaucoma Drainage Device. PMID- 28857947 TI - The Association of Chronic Topical Prostaglandin Analog Use With Meibomian Gland Dysfunction: Comment. PMID- 28857948 TI - Suppression of Oxidative Stress and Apoptosis in Electrically Stimulated Neonatal Rat Cardiomyocytes by Resveratrol and Underlying Mechanisms. AB - PURPOSE: We explored the effects of resveratrol on oxidative stress in cardiomyocytes subjected to rapid electrical stimulation (RES) and also investigated the underlying mechanisms. METHODS: Cultured ventricular myocytes of neonatal rat were subjected to RES at 4.0 Hz, with or without resveratrol, an NADPH oxidase inhibitor apocyanin (APO) or a Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor autocamtide-2-inhibitory peptide (AIP). Cell counts, to optimize resveratrol concentration, and angiotensin II content were evaluated. Reactive oxygen species (ROS), intracellular Ca in cardiomyocytes, and cardiomyocyte apoptosis were also assessed. Levels of methionine sulfoxide reductase A (MsrA), Nox, oxidative CaMKII (OX-CaMKII), and cleaved caspase-3 in cardiomyocytes were examined. RESULTS: Resveratrol treatment, as compared with APO and AIP, significantly decreased ROS levels, improved Ca amplitudes, and intracellular Ca transient decay rates, and inhibited cardiomyocyte apoptosis. Resveratrol also increased MsrA protein levels. In cardiomyocytes subjected to RES, after pretreatment with resveratrol or APO, protein levels of Nox4, Nox2, OX CaMKII, and cleaved caspase-3 were decreased. In comparison, with AIP pretreatment, only Nox2, OX-CaMKII, and cleaved caspase-3 were decreased. However, in the presence of dimethyl sulfoxide, a competitive inhibitor of MsrA function, a decrease in cleaved caspase-3 did not occur. CONCLUSIONS: Resveratrol decreased ROS, partially through the inhibition of NADPH oxidase activity and upregulation of MsrA expression. PMID- 28857949 TI - Immune-mediated necrotizing myopathy associated with statins: history and recent developments. AB - PURPOSE OF REVIEW: The use of statins has increased exponentially over the last 2 decades. Consequently, side effects have also increased, with muscle-related side effects commonly reported. RECENT FINDINGS: Although once thought to be only associated with self-limited direct myotoxicity, statins have recently been described in association with an autoimmune myopathy in association with antibodies directed against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate limiting enzyme in cholesterol synthesis and the pharmacologic target of statins. Since this discovery, various cohorts have been identified worldwide and highlight both similarities and differences among them. SUMMARY: Recent studies from different fields have revealed diverse aspects of anti-HMGCR-associated immune-mediated necrotizing myopathy (IMNM). HMGCR IMNM is a unique autoimmune disease characterized by a well defined environmental trigger (statins) and a strong association with a genetic risk factor (Human leukocyte antigen D related B 111 : 01). New diagnostic modalities have been established to confirm the presence of anti-HMGCR antibody and confirm the diagnosis of HMGCR IMNM. Clinical studies have shown that disease severity, as measured by muscle strength, as well as the rate of response to treatment have been associated with age at disease onset. Furthermore, a case series supported that intravenous immunoglobulin administration, perhaps even as monotherapy, may be a beneficial therapeutic intervention for selected patients. PMID- 28857950 TI - Effects of walking trainings on walking function among stroke survivors: a systematic review. AB - Physical function is often compromised as a result of stroke event. Although interventions propose different strategies that seek to improve stroke survivors' physical function, a need remains to evaluate walking training studies aimed at improving such physical function. The aim of this review was to assess the available literature that highlights the impact of walking training on enhancing walking for stroke survivors. We performed a systematic literature review of online databases - Google Scholar, PubMed, CINHAL, Cochrane Library, Scopus, and EBSCO - with the following inclusion criteria: manuscript published from 2005 to 2016, written in English, with treatment and control groups, for walking training studies aimed at improving physical function among stroke survivors. Findings indicated that walking speed, walking distance, and gait speed were the most used outcome variables for measuring improved physical function among stroke survivors. Importantly, proposed interventions involved either overground or treadmill walking trainings, if not both. Preserved locomotor improvements were not noted in all interventions at follow-up. Some interventions that used walking treadmill training augmented by auditory stimulations reported significant improvements in physical function compared with overground walking training augmented by auditory stimulations. The imperative to improve physical function among stroke survivors with physical impairment is paramount, as it allows survivors to be socially, emotionally, and physically more independent. In general, we note an insufficiency of research on the interaction between physical function and socialization among stroke survivors. PMID- 28857951 TI - Is There a Mismatch Between the Perspectives of Patients and Regulators on Healthcare Quality? A Survey Study. AB - OBJECTIVES: Internationally, healthcare quality regulators are criticized for failing to respond to patients' complaints. Patient involvement is, therefore, an important item on the policy agenda. However, it can be argued that there is a discrepancy between the patients' perspective and current regulatory approaches.This study examines whether a discrepancy exists between the perspectives of patients and regulators on healthcare quality. METHODS: A questionnaire was sent to 996 people who had registered a complaint with the Dutch Healthcare Inspectorate to measure expectations of and experiences with the Inspectorate. A taxonomy was used to classify their complaints into the clinical, relationship, or management domains. RESULTS: The response was 54%. More complaints about clinical issues (56%, P = 0.000) were investigated by the regulator than complaints about organizational (37%) and relational issues (51%). Patients with complaints about management issues less often indicated (13%, P = 0.002) that healthcare is improved by making their complaint than patients with complaints about clinical or relationship issues did (22%-23%). Patients who reported about relational issues with care providers attached more importance to issuing sanctions against the care provider than other patients (mean score 2.89 versus 2.62-2.68, P = 0.006). CONCLUSIONS: The predominant clinical approach taken by regulators does not match the patients' perspective of what is relevant for healthcare quality. In addition, patients seem to be more tolerant of what they perceive to be clinical or management errors than of perceived relational deficiencies in care providers. If regulators want to give patients a voice, they should expand their horizon beyond the medical framework. PMID- 28857952 TI - Communicating Patient Status: Comparison of Teaching Strategies in Prelicensure Nursing Education. AB - Research indicates that nurses lack adequate preparation for reporting patient status. This study compared 2 instructional methods focused on patient status reporting in the clinical setting using a randomized posttest-only comparison group design. Reporting performance using a standardized communication framework and student perceptions of satisfaction and confidence with learning were measured in a simulated event that followed the instruction. Between the instructional methods, there was no statistical difference in student reporting performance or perceptions of learning. Performance evaluations provided helpful insights for the nurse educator. PMID- 28857953 TI - Integrating Substance Use Content in an "Overcrowded" Nursing Curriculum. AB - Various factors have compelled nurse educators to address the lack of substance use-related content in nursing curriculum. Initiatives to add this content are often met with resistance because of an already crowded curriculum. This article describes a 4-phase process that guided the integration of this specialty content into a prelicensure nursing curriculum and a master's level advanced practice nursing curriculum. Lessons learned and recommendations from those experiences are provided to guide nurse educators undertaking similar efforts. PMID- 28857954 TI - Tips for a Successful Search for Nursing and Health Sciences Faculty. PMID- 28857955 TI - Nursing Students' Perceptions of Confidentiality, Accountability, and E Professionalism in Relation to Facebook. AB - This study examined nursing students' perceptions of confidentiality, accountability, and e-professionalism in relation to Facebook. All of the students were aware that posting patients' names and pictures of patients constituted a confidentiality breach. When comparing students based on educational status, there were differing opinions on whether employers should use Facebook profile information for hiring decisions. Nursing programs should provide current education, including clear and up-to-date policies, about social media use. PMID- 28857956 TI - Effect of Canine Play Interventions as a Stress Reduction Strategy in College Students. AB - Forty-eight students engaged with a therapy dog for 15 minutes during finals week to evaluate the effect on stress. Psychological (Perceived Stress Scale, visual analog scales) and physiologic stress (vital signs, salivary cortisol) measures were collected before and after the intervention. Paired t tests showed significant reductions in all psychological and physiologic measures except diastolic blood pressure. This supports animal-assisted therapy as an effective stress management strategy for nursing and other college students. PMID- 28857957 TI - The Clinical Instructor Program: Improving Self-efficacy for Nurse Educators. AB - The purpose of this study was to determine whether an online program, the Clinical Instructor Program (CIP), was helpful in improving feelings of efficacy for nurse clinicians in the role of clinical instructor. In addition, understanding of the clinical instructor role, knowledge of instructional content, and understanding of instructional strategies were evaluated before and after CIP participation. A primary finding of the study was that overall self efficacy significantly improved. PMID- 28857958 TI - Is there a role for a child life specialist during orthopedic cast room procedures? A prospective-randomized assessment. AB - : Pediatric anxiety during cast room procedures is common and various methods to manage distress may be used. Certified Child Life Specialists (CCLS) are formally trained professionals with proficiency in helping children during taxing events. The utilization of a CCLS has not been well documented in a pediatric orthopedic cast room. The aim of this study was to assess the impact of a CCLS in this setting through a prospective randomized trial. 86 children, age range 2-10 years, who underwent cast room procedures were randomized: group I (42 children) had a CCLS present during their procedure. Group II (44 children) did not have a CCLS present during their procedure. Procedures included cast removal/placement, fracture manipulation, and pin removal. We calculated change in heart rate as beats per min (bpm) during various stages of the visit and a subjective behavior score evaluating behaviors, score range -3 to 3. There was no significant difference in the demographics and age between groups. The mean behavior score for group I was 1.78 versus 1.04 in group II (P<0.001). The change in heart rate recorded showed an increase by 7.5 and 9.3 bpm in groups I and II, respectively (P=0.829). CCLS Therapy significantly affects the observed behavior score of children undergoing a procedure in a pediatric orthopedic cast room. A greater increase in heart rate was observed as a trend in those children treated in the absence of a CCLS. The presence of a CCLS appears to positively affect the cast room experience for children and their caregivers. LEVEL OF EVIDENCE: Level II - Therapeutic Randomized-Controlled Trial. PMID- 28857959 TI - Ovarian Torsion in a Pediatric Patient: The Importance of Repeat Imaging. AB - A previously healthy 10-year-old girl presented to the emergency department with a 1-day history of abdominal pain. She was afebrile with an elevated white blood cell count and a negative pelvic ultrasound. The pain resolved while in hospital, and the patient was discharged home. The patient returned 10 days later, and the pain now migrated from the left flank to the subumbilical region. The patient now had an elevated white blood cell count and C-reactive protein. On pelvic ultrasound, the patient had a large midline mass and a normal right ovary. The patient was taken to the operating room where she was found to have a torted and necrotic left ovary and fallopian tube, which were removed. There are few instances where pediatric ovarian torsion presents as intermittent episodes of abdominal pain. Emergency physicians should always have a high index of suspicion for ovarian torsion in any case of abdominal/pelvic pain in young girls with previous negative imaging. PMID- 28857960 TI - Novel Interprofessional Mentoring Intervention to Improve Spirometry in Primary Care: Uptake, Feedback, and Effects on Behavioral Intention. AB - INTRODUCTION: Little is known about the nature and effects of mentoring interventions on evidence-based clinician behaviors. We sought to design and evaluate a novel mentorship-based intervention to improve the usage of spirometry in primary care. METHODS: This was a prospective one-year study of a pragmatic intervention across Canadian primary care sites. We established mentor-mentee pods, each including physician and nurse/allied health mentors and mentees, and enabled communication through a secure online portal; email; telephone; teleconference; videoconference; fax; and/or in person. We measured (1) change in intention to perform spirometry (through a questionnaire based on the theory of planned behavior, administered before and after the intervention); (2) mentoring uptake; and (3) feedback/satisfaction. RESULTS: Twenty-five of 90 (28%) nurse/allied health and 23/68 (34%) physician mentees consented across seven sites. There were no statistically significant changes in behavioral intention after the intervention. Mentors logged 56.5 hours, with most preferred communication modalities being in person (6/11; 55%) and email (4/11; 36%). Mentees most commonly used email (9/18; 50%), followed by in-person communication (6/18; 33%). Mentees were highly satisfied with the experience, and most (89%) would participate in a similar program again. DISCUSSION: A mentorship-based intervention can successfully engage physicians, nurses, and allied health practitioners through multiple communication platforms. Email seems to be an important medium for this activity. Such interventions can be highly satisfying and may affect certain constructs underlying mentees' behavioral intentions. Such a program can be replicated across diseases, and future research should measure effects on behavior, patient outcomes, and the sustainability of effects. PMID- 28857961 TI - Using Patient-reported Outcome Measures to Improve Health Care: Time for a New Approach. PMID- 28857962 TI - Women's Awareness of and Responses to Messages About Breast Cancer Overdiagnosis and Overtreatment: Results From a 2016 National Survey. AB - BACKGROUND: Scientists, clinicians, and other experts aim to maximize the benefits of cancer screening while minimizing its harms. Chief among these harms are overdiagnosis and overtreatment. Although available data suggest that patient awareness of these harms is low, we know little about how patients respond to information about these phenomena. OBJECTIVES: Using the case of breast cancer screening, this study assesses women's awareness of and reactions to statements about overdiagnosis and overtreatment. METHODS: We draw on data from a 2016 population-based survey of US women aged 35-55 years that oversampled women of lower socioeconomic position (those living at or below 100% of federal poverty level) (N=429). RESULTS: Results showed that women's awareness of overdiagnosis (16.5%) and overtreatment (18.0%) was low, and women under age 40 were least likely to have heard about overdiagnosis. Most women did not evaluate statements about these harms positively: <1 in 4 agreed with and found statements about overdiagnosis and overtreatment to be believable, and even fewer evaluated them as strong arguments to consider in their own mammography decision making. Women with a recent mammogram history were particularly unconvinced by overdiagnosis and overtreatment arguments. CONCLUSIONS: A majority of women were unaware of 2 important harms of breast cancer screening: overdiagnosis and overtreatment. Most did not find statements about these harms to be believable and persuasive. Communication interventions, supported by evidence from health communication research, are necessary to improve patient understanding of screening's harms, promote informed decision making, and, in turn, ensure high-value care. PMID- 28857963 TI - Identifying Increased Risk of Readmission and In-hospital Mortality Using Hospital Administrative Data. PMID- 28857964 TI - Author Response for Identifying Increased Risk of Readmission and In-hospital Mortality Using Hospital Administrative Data: The AHRQ Elixhauser Comorbidity Index. PMID- 28857966 TI - Mini-open Lateral Retropleural Approach for Symptomatic Thoracic Disk Herniations. AB - BACKGROUND: Surgeries for symptomatic thoracic disk herniations (TDH) remain challenging. OBJECTIVE: A mini-open lateral retropleural approach is described and the clinical outcomes are reported. MATERIALS AND METHODS: A total of 23 patients underwent mini-open lateral retropleural diskectomy. Patients were placed in a lateral position. A 5-cm lateral incision was made followed by resection of the rib after careful dissection of its undersurface from the endothoracic fascia. The fascia was incised and separated from parietal pleura to widen the retropleural space. The rib head was removed followed by a pedicle resection below the TDH to expose the dura. A posterior partial corpectomy above and below the disk was performed to create a space ventral to the TDH, which was later dissected away from the dura and removed. RESULTS: Fourteen males and 9 females comprised the clinical cohort. Five presented with axial back pain, 7 with radicular pain and 11 with myelopathy. All but 2 disks were successfully removed. The mean blood loss was 214cc and the mean hospital stay was 5.3 days. There was no mortality or new neurological deficits. The mean follow-up was 15.4 months. CONCLUSIONS: Mini-open lateral retropleural approach is safe and effective to remove symptomatic TDH with minimal morbidities and fast patient recovery. PMID- 28857965 TI - Zoon Vulvitis Treated Successfully With Platelet-Rich Plasma: First Case Reported. PMID- 28857967 TI - The Timing of Surgery Affects Return to Work Rates in Patients With Degenerative Lumbar Stenosis in a Workers' Compensation Setting. AB - STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: The objective of this study is to determine how time to surgery affects outcomes for degenerative lumbar stenosis (DLS) in a workers' compensation (WC) setting. SUMMARY OF BACKGROUND DATA: WC subjects are known to be a clinically distinct population with variable outcomes following lumbar surgery. No study has examined the effect of time to surgery in this clinically distinct population. MATERIALS AND METHODS: A total of 227 Ohio WC subjects were identified who underwent primary decompression for DLS between 1993 and 2013. We allocated patients into 2 groups: those that received operative decompression before and after 1 year of symptom onset. Our primary outcome was, if patients were able to make a stable return to work (RTW). The authors classified subjects as RTW if they returned within 2 years after surgery and remained working for >6 months. RESULTS: The early cohort had a significantly higher RTW rate [50% (25/50) vs. 30% (53/117); P=0.01]. A logistic regression was performed to identify independent variables that predicted RTW status. Our regression model showed that time to surgery remained a significant negative predictor of RTW status (P=0.04; odds ratio, 0.48; 95% confidence interval, 0.23 0.91). Patients within the early surgery cohort cost on average, $37,332 less in total medical costs than those who opted for surgery after 1 year (P=0.01). Furthermore, total medical costs accrued over 3 years after index surgery was on average, $13,299 less when patients received their operation within 1 year after symptom onset (P=0.01). CONCLUSIONS: Overall, time to surgery had a significant impact on clinical outcomes in WC subjects receiving lumbar decompression for DLS. Patients who received their operation within 1 year had a higher RTW rate, lower medical costs, and lower costs accrued over 3 years after index surgery. The results presented can perhaps be used to guide surgical decision-making and provide predictive value for the WC population. PMID- 28857968 TI - Risk Factors and Management of Incidental Durotomy in Lumbar Interbody Fusion Surgery. AB - STUDY DESIGN: This is a retrospective study analysis. OBJECTIVE: In this retrospective study we evaluated risk factors for incidental durotomy and its impact on the postoperative course. SUMMARY OF BACKGROUND DATA: Lumbar interbody fusion (LIF) is increasingly applied for the treatment of degenerative instability. A known complication is incidental durotomy. MATERIALS AND METHODS: A cohort of 541 patients who underwent primary LIF surgery between 2005 and 2015 was analyzed. Previous lumbar surgery, age, surgeon's experience, intraoperative use of a microscope, and the number of operated levels were assessed and the risk for incidental durotomy was estimated using the Log-likelihood test and Wald test, respectively. The association of incidental durotomy and outcome parameters was analyzed using the quantile regression model. RESULTS: In 77 (14.2%) patients intraoperative cerebrospinal fluid (CSF) fistula was observed. Previous lumbar surgery (P<0.001), number of operated levels (P=0.03), and surgeon's experience (P=0.01) were significantly associated with incidental durotomy. Incidental durotomy was significantly associated with a prolonged bed rest (P<0.001), hospital stay (P=0.041), and an increased use of postoperative antibiotics (P<0.001). Eleven of 77 patients with incidental durotomy (14.3%) developed postoperative CSF fistula of whom 10 (91%) needed revision surgery for dural repair. CONCLUSIONS: We could identify important risk factors for incidental durotomy in LIF surgery. In patients who had undergone previous lumbar surgery and those with multilevel disease particular precaution is required. Furthermore, we were able to verify the morbidity associated with CSF fistula as shown by increased immobilization and follow-up surgeries for postoperative CSF fistula which emphasizes the importance to develop strategies to minimize the risk for incidental durotomy. PMID- 28857969 TI - Assessing Online Patient Education Readability for Spine Surgery Procedures. AB - BACKGROUND CONTEXT: Increased patient reliance on Internet-based health information has amplified the need for comprehensible online patient education articles. As suggested by the American Medical Association and National Institute of Health, spine fusion articles should be written for a 4th-6th-grade reading level to increase patient comprehension, which may improve postoperative outcomes. PURPOSE: The purpose of this study is to determine the readability of online health care education information relating to anterior cervical discectomy and fusion (ACDF) and lumbar fusion procedures. STUDY DESIGN: Online health education resource qualitative analysis. METHODS: Three search engines were utilized to access patient education articles for common cervical and lumbar spine procedures. Relevant articles were analyzed for readability using Readability Studio Professional Edition software (Oleander Software Ltd). Articles were stratified by organization type as follows: General Medical Websites (GMW), Healthcare Network/Academic Institutions (HNAI), and Private Practices (PP). Thirteen common readability tests were performed with the mean readability of each compared between subgroups using analysis of variance. RESULTS: ACDF and lumbar fusion articles were determined to have a mean readability of 10.7+/-1.5 and 11.3+/-1.6, respectively. GMW, HNAI, and PP subgroups had a mean readability of 10.9+/-2.9, 10.7+/-2.8, and 10.7+/-2.5 for ACDF and 10.9+/-3.0, 10.8+/-2.9, and 11.6+/-2.7 for lumbar fusion articles. Of 310 total articles, only 6 (3 ACDF and 3 lumbar fusion) were written for comprehension below a 7th-grade reading level. CONCLUSIONS: Current online literature from medical websites containing information regarding ACDF and lumbar fusion procedures are written at a grade level higher than the suggested guidelines. Therefore, current patient education articles should be revised to accommodate the average reading level in the United States and may result in improved patient comprehension and postoperative outcomes. PMID- 28857970 TI - Novel Technique for Sacral Alar-Iliac (S2AI) Fixation. AB - OBJECTIVE: To provide reasoning and steps for the placement of sacral alar-iliac (S2AI) screws for pelvic arthrodesis to aid osseous lumbosacral fusion. SUMMARY OF BACKGROUND DATA: Studies support lower rates of screw breakage and need for revision surgery or hardware removal for S2AI screws compared with traditional iliac bolts, as well as low rates of pseudoarthrosis and arthritis associated with this hardware placement. MATERIALS AND METHODS: A case video of S2AI placement demonstrates our operative technique and is accompanied by procedural description of surgical maneuvers. RESULTS AND SURGICAL TECHNIQUES: One patient underwent lumbosacral fusion surgery aided by S2AI-mediated pelvic fixation. CONCLUSIONS: The present technique utilizing S2AI screws provides for successful pelvic fixation to aid in lumbosacral fusion, with no need for subcutaneous tissue dissection and improved outcomes compared with traditional iliac bolts. PMID- 28857971 TI - State and Local Health Department Activities Related to Abortion: A Web Site Content Analysis. AB - CONTEXT: Recent legislation in states across the United States has required governmental health agencies to take on new and different roles in relation to abortion. While there has been media attention to health department roles in regulating abortion providers, there has been no systematic investigation of the range of activities in which state and local health departments are engaged. OBJECTIVE: To systematically investigate health department activities related to abortion. METHODS: We searched state health department Web sites of the 50 states and District of Columbia using key words such as "abortion" and "pregnancy termination". Two trained coders categorized 6093 documents using the 10 Essential Public Health Services (EPHS) framework. We then applied these methods to 671 local health department documents. SETTING: State and local health department Web sites. PARTICIPANTS: N/A. RESULTS: On average, states engaged in 5.1 of 10 Essential Services related to abortion. Most (76%-98%) state health departments engaged in activities to Monitor Health Status (EPHS1), Enforce Laws (EPHS6), and Evaluate Effectiveness, Accessibility, and Quality (EPHS9). Many (47%-69%) engaged in activities to Inform and Educate (EPHS3), Develop Policies (EPHS5), and Link to Services (EPHS7). A minority (4%-29%) engaged in activities to Diagnose and Investigate Health Problems (EPHS2), Mobilize Community Partnerships (EPHS4), and Assure Competent Workforce (EPHS8). No state engaged in Innovative Research (EPHS10). Few local health departments engaged in abortion related activities. CONCLUSIONS: While most state health departments engage in abortion-related activities, they appear to reflect what the law requires rather than the range of core public health activities. Additional research is needed to assess whether these services meet quality standards for public health services and determine how best to support governmental health agencies in their growing tasks. These findings raise important questions about the role of public health agencies and professionals in defining how health departments should be engaging with abortion. PMID- 28857972 TI - Are You Making an Impact? Evaluating the Population Health Impact of Community Benefit Programs. AB - CONTEXT: The Patient Protection and Affordable Care Act includes a change to the IRS 990 Schedule H, requiring nonprofit hospitals to submit a community health needs assessment every 3 years. Such health care entities are challenged to evaluate the effectiveness of community benefit programs addressing the health needs identified. OBJECTIVE: In an effort to determine the population health impact of community benefit programs in 1 hospital outreach department, researchers and staff conducted an impact evaluation to develop priority areas and overarching goals along with program- and department-level objectives. DESIGN: The longitudinal impact evaluation study design consists of retrospective and prospective secondary data analyses. SETTING: As an urban pediatric hospital, St Louis Children's Hospital provides an array of community benefit programs to the surrounding community. PARTICIPANTS: Hospital staff and researchers came together to form an evaluation team. Data from program evaluation and administrative data for analysis were provided by hospital staff. MAIN OUTCOME MEASURE: Impact scores were calculated by scoring objectives as met or unmet and averaged across goals to create impact scores that measure how closely programs meet the overarching departmental mission and goals. RESULTS: Over the 4-year period, there is an increasing trend in program-specific impact scores across all programs except one, Healthy Kids Express Asthma, which had a slight decrease in year 4 only. IMPLICATIONS: Current work in measuring and assessing the population health impact of community benefit programs is mostly focused on quantifying dollars invested into community benefit work rather than measuring the quality and impact of services. This article provides a methodology for measuring population health impact of community benefit programs that can be used to evaluate the effort of hospitals in providing community benefit. This is particularly relevant in our changing health care climate, as hospitals are being asked to justify community benefit and make meaningful contributions to population health. The Patient Protection and Affordable Care Act includes a change to the IRS 990 Schedule H, requiring nonprofit hospitals to submit a community health needs assessment every 3 years, and requires evaluation of program effectiveness; yet, it does not require any quantification of the impact of community benefit programs. The IRS Schedule H 990 policies could be strengthened by requiring an impact evaluation such as outlined in this article. CONCLUSION: As hospitals are being asked to justify community benefit and make meaningful contributions to population health, impact evaluations can be utilized to demonstrate the cumulative community benefit of programs and assess population health impact of community benefit programs. PMID- 28857973 TI - Partnerships: Collaboration Across the Healthcare Continuum. PMID- 28857974 TI - The Strategic Value of Affiliation Partnerships in Securing Future Relevance. AB - Finding the best route to navigate the changing landscape of healthcare has become an obsession for many organizations. Their quest to stay competitive, significant, and ultimately relevant is a continuous discovery process. Many hospitals and health systems have considered affiliations and partnerships as important tactical options. Partnerships can range from loose arrangements, such as nonequity collaborations and management agreements, to total affiliation, as in a merger and acquisition. Whichever option an organization decides to pursue, a comprehensive assessment is necessary to find the best partner-the right fit. Addressing the "why," "when," "how," and "with whom" questions is fundamental. Having the depth and breadth of resources to manage the discovery process is equally important.Learning from others who have experienced this journey is helpful, as is the support of industry experts. However, one task that cannot be delegated is discerning whether affiliation is right for an organization. That is the responsibility of an organization's leadership team, which must consider the dynamic forces in play when evaluating an affiliation partnership. Many of the suggested modalities revolve around how the affiliation partnership can provide a value proposition for the entities involved. Furthermore, inevitable challenges emerge when fiercely independent and successful organizations come together at different levels of need and readiness. Anticipating and providing for the potential exit of any member are matters that the partnership must accept and prepare for, and the ability to execute can make or break the trajectory toward a value proposition. A strong resolve to monitor, measure, calibrate, and recalibrate can give a partnership the agility to pivot toward relevance and sustainability.Stratus Healthcare applied principles of alignment and affiliation in creating the largest collaborative partnership of hospitals in the southeastern United States. Drawing from its affiliation partnership experience with Navicent Health and other member organizations, it has many lessons to share. PMID- 28857975 TI - Finding Like-Minded Partners to Span the Continuum of Care. AB - This is an era of profound industry transformation, characterized by such forces as acceleration away from inpatient-centered care and toward alternative payment models, rising rates of chronic disease, and an aging population. Add to this mix physician and nurse shortages and a newfound understanding that today's patients are informed consumers, and the reality becomes clear: Healthcare providers must be adaptable, agile, and innovative to survive. Sometimes, the best way forward in transformative times is collaboration with other like-minded organizations.For INTEGRIS, an integrated, not-for-profit health system based in Oklahoma City, Oklahoma, partnering has always been a part of the corporate culture and a vital strategy in fulfilling its mission to improve the health of the people and communities it serves. In earlier days, collaborations often took the form of partnerships with community organizations to go beyond the hospital's walls and reach deeply into the community to address the underlying health needs of its population.However, the concept of partnerships has expanded to meet today's strategic business needs. INTEGRIS, for example, evaluates most partnerships in terms of population health management and the system's continuum of care. Care settings are viewed as being of three distinct types: community-based, acute, and post-acute. When it comes to health-and, increasingly, wellness-the goal of the system is to connect patients to whatever service they need, at whatever stage of life, whether that service is fully or partly owned by INTEGRIS or provided through partner affiliations.This network of partnerships involves the patient, the community, physicians, other clinicians and providers, insurers, regional collaborators, and others. INTEGRIS's partnership strategies have evolved over the years, and its partnerships have produced synergy and alignment to decrease costs, increase revenue, and better serve customers with the right care, in the right setting, at the right time. PMID- 28857976 TI - What Comes Next? Exploring Collaboration Options. PMID- 28857977 TI - Providers Can Meet Community Health Needs as Independent Partners. PMID- 28857978 TI - Strategic Partnering to Gain Competencies for Future Healthcare Delivery. PMID- 28857979 TI - Coccidioidomycosis Involving Lungs and Skin: A Mimicker of Metastatic Disease. AB - Coccidioidomycosis is the major systemic mycoses, considered to be 1 of the most infectious fungal diseases. In symptomatic patients, the most common manifestation is pulmonary disease, but many other organs can be affected. Disseminated disease occurs in 1%-5% of all patients affected by coccidioidomycosis and can affect any organ, with the skin, central nervous system, and musculoskeletal system being reported as the most prevalent. Here, we report a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats. He was treated with various antibiotics for possible upper respiratory tract infection without symptomatic improvement. Computed tomography of the chest revealed numerous subcentimeter noncalcified pulmonary nodules scattered throughout both lungs with extensive mediastinal and bilateral hilar lymphadenopathy. The patient was referred to our hospital for further evaluation of suspected metastatic lung disease. Physical examination revealed an erythematous 1.2 cm nodule on his left medial eyebrow. Skin biopsy of the lesion revealed prominent squamous epithelial hyperplasia with basal keratinocytic atypia and associated mixed inflammatory infiltrate and scattered large thick-walled spherules containing variable-sized endospores, predominantly within the multinucleated giant cells. Special stain Periodic acid-Schiff tissue culture studies confirmed these to be Coccidioides immitis. After appropriate treatment with antifungal therapy for 5.5 months, his symptoms have improved with complete disappearance of lung nodules and a partially cavitated (1.1 * 1.1 cm) lesion in the left upper lung confirmed by follow-up chest computed tomography. With this report, the authors highlight disseminated coccidioidomycosis, a great mimicker of metastatic lung disease, which was diagnosed by skin biopsy, to ensure its prompt recognition and appropriate antifungal therapy. PMID- 28857980 TI - Perineurial Vascular Hamartoma. AB - Perineural vascular proliferations are extremely rare, and only a few cases have been reported in the literature, usually under the designation of "intraneural hemangioma." We report a case of a 28-year-old man with a nodule in the right palm of his hand that developed over an 8- to- 12-month period. Microscopic examination revealed a vascular proliferation growing within connective tissue and entrapping small nerve bundles. The features of the lesion are consistent with an unusual hamartomatous growth of small vessels and nerves rather than a hemangioma arising within a nerve. Clinical and histological details, and a discussion of the relevant literature on this unusual lesion, are provided. PMID- 28857981 TI - Toll-Like Receptor 7 Staining in Malignant Epithelial Tumors. AB - BACKGROUND: As important players of the innate immune system, Toll-like receptors (TLRs) and their role for tumorigenesis have been in the focus of research. In particular TLR7 is an interesting candidate, as TLR7 agonists are broadly used for the treatment of cutaneous tumors. However, data addressing the baseline expression of TLR7 in both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) on the protein level are lacking, while on the genomic level significantly elevated expression of TLR7 in SCC but not in BCC has been demonstrated. AIM: Our aim was to characterize the immunohistochemical staining pattern of TLR7 in SCC and BCC. Besides, we aimed to clarify if, in case of different TLR7 expression between SCC and BCC, TLR7 expression would help to define basosquamous carcinoma (BSC), a tumor entity sharing characteristics of both SCC and BCC. METHODS: We examined histopathological samples from 23 BCC, 4 BSC, and 24 SCC and characterized the expression of TLR7 by immunohistochemistry and immunofluorescence. RESULTS: We found that TLR7 was not expressed by the tumor tissue of SCC, BCC, and BSC, but by inflammatory cells located within the tumoral and/or peritumoral tissue. Whereas the overall expression of TLR7 did not differ between BCC and SCC (30.4% vs. 45.8%, respectively), we found that within the group of SCC, the well-differentiated SCC showed strong tumoral and/or peritumoral immunocellular TLR7 reactivity in contrast to the poorly differentiated SCC (73.33% vs. 11.1%, respectively). Besides, immunofluorescence double staining revealed the expression of TLR7 in immune cells closely interacting with T cells and natural killer cells. CONCLUSIONS: In contrast to genomic data, we did not find a general difference between baseline TLR7 expression of SCC and BCC on the protein level. Nevertheless, the expression of TLR7 by the inflammatory infiltrate associated with SCC may correlate with the degree of differentiation of SCC possibly indicating better outcome. PMID- 28857982 TI - Is Horizontal Mattress Suturing More Effective Than Simple Interrupted Suturing on Postoperative Complications and Primary Wound Healing After Impacted Mandibular Third Molar Surgery? AB - The aim of this clinical study was to compare the influence of 2 different suturing techniques on postoperative complications and wound healing after surgical extractions of impacted mandibular third molars. In this randomized split mouth study, 30 patients were examined in whom 60 consecutive surgical extractions of symmetrically positioned impacted mandibular third molars were performed. After the extractions, the surgical flaps were sutured with either the simple interrupted or horizontal mattress suturing technique. Postoperative swelling and trismus were recorded on the 2nd, 7th, and 10th days. Pain was recorded in a 7-day diary and wound dehiscence was recorded on the10th postoperative day. Statistical evaluation of data was made using Mann-Whitney U test and Pearson correlation. There were no statistical differences between the 2 suturing techniques in terms of postoperative pain, trismus, and swelling (P > 0.05). There was significantly less wound dehiscence in the horizontal mattress suturing group than in the simple interrupted suturing group (P: 0017). According to the results of this study, the horizontal mattress suturing technique is more effective than the simple interrupted suturing technique on wound healing after impacted mandibular third molar surgery, although it does not decrease the levels of pain, trismus, and swelling. PMID- 28857983 TI - Can Clinical Findings Predict Orbital Fractures and Treatment Decisions in Patients With Orbital Trauma? Derivation of a Simple Clinical Model. AB - The aim of this study was to determine the predictive value of 4 clinical signs (periorbital ecchymosis, periorbital emphysema, diplopia, and inferior orbital nerve hypoesthesia) for the diagnosis of orbital fractures (OFs) and the need for surgical treatment in patients with orbital trauma. The investigators designed and implemented a retrospective cohort study composed of patients with orbital trauma. The primary and secondary outcomes were respectively the diagnosis of OFs and the need for surgical treatment. Multivariable logistic regressions including the clinical signs, age, and causes of injury were used to determine the independent contribution of each clinical sign to the prediction of the outcomes and to obtain weights to compute OF and surgery scores. The outcomes were assessed by receiver-operating characteristic (ROC) curves, sensitivity, specificity, and positive and negative predictive values. A total of 912 patients were included. All clinical signs except periorbital ecchymosis were significantly associated with OFs and the need for surgical treatment (P < 0.001). The predictive power of each clinical sign taken separately was moderate for the 2 outcomes (area under ROC curve [AUC] <0.7). A better predictive value was found when all clinical signs were used together (AUC >0.7). Patients with an OF score >3 were likely to have an OF and patients with a surgery score <=2 were unlikely to have surgery.The present study demonstrated that our OF and surgery scores resulted in an effective model that allowed the stratification of patients with orbital trauma based on their risk of having OFs and risk of needing a surgical treatment. PMID- 28857984 TI - Levator Aponeurosis and Muller Muscle Plication Reinforced With Levator Sheath Advancement for Blepharoptosis Correction. AB - The authors innovated the levator aponeurosis and Muller muscle plication reinforced with levator sheath advancement (AMPSA) for blepharoptosis correction. The orbital septum was opened 1 mm above its fusion with the levator aponeurosis. The preaponeurotic fat was retracted and the thickened part of the levator sheath was identified. Two plication sutures were made: medial suture at the medial border of the pupil and lateral between the lateral border of the pupil and the lateral limbus. A needle with 6-0 nylon thread first bit the tarsal plate approximately 1 mm below its upper border, then bit the levator aponeurosis and the Muller muscle together at 3 to 6 mm above the upper border of the tarsal plate. The needle bit 1 to 3 mm of the thickened part of the levator sheath and the suture was tied. A total of 116 eyes were operated on using levator aponeurosis and Muller muscle plication (AMP), and 79 eyes using AMPSA. The mean follow-up period was 11.4 months. In the AMP group, the postoperative marginal reflex distance-1 (MRD-1) (3.8 +/- 0.2 mm) was significantly greater than the preoperative MRD-1 (2.7 +/- 0.3 mm) (P < 0.001). In the AMPSA group, the postoperative MRD-1 (3.5 +/- 0.3 mm) was also significantly greater than the preoperative MRD-1 (1.7 +/- 0.4 mm) (P < 0.001). The improvement in MRD-1 was greater in the AMPSA group (1.7 +/- 0.4 mm) than in the AMP group (1.1 +/- 0.3 mm) (P < 0.001). The difference in the MRD-1 outcome between AMPSA and AMP (0.6 mm) was obtained by advancing the thickened part of the levator sheath. AMPSA may be an effective procedure for correcting blepharoptosis. PMID- 28857985 TI - Does Septoplasty Improve Heart Functions of Patients With Septum Deviation in Terms of Echocardiography Findings? AB - OBJECTIVE: The authors aimed to determine pulmonary artery pressure and right heart functions in patients with nasal septum deviation (NSD) with echocardiography (EchoCG) and compare the postoperative changes of EchoCG parameters with preoperative findings. METHODS: Seventy-six patients who underwent septoplasty composed the study group. Average age of patients was 23.50 ranging between 18 and 48 years of age. There were 53 males (69.7%) and 23 females (30.3%). Mean pulmonary artery pressure, tricuspid annular-plane systolic excursion, right ventricular diameter, and e/a ratio were measured by EchoCG preoperatively and same parameters were reobtained 3 months after surgery. RESULTS: Mean pulmonary artery pressure reduced from 23.88 +/- 6.36 to 19.80 +/ 3.95 mm Hg and tricuspid annular-plane systolic excursion increased from 22.36 +/ 3.85 to 23.57+/-3.00 3 months after surgery. It represented statistically significant improvement at right heart functions postoperatively (P < 0.001). Although they were not statistically significant, there was also some improvement in right ventricular diameter and e/a ratio values postoperatively. CONCLUSION: Nasal septum deviation was associated with higher PAP values, which were improved after surgery. Although at a lower extent, a negative effect of NSD on right heart functions was also suspected. Thus, treatment of NSD without delay was proposed, not only to treat the nasal symptoms but possible future cardiovascular complications as well. PMID- 28857986 TI - Craniofacial and Dental Features in Six Children With Cherubism. AB - Cherubism is an autosomal-dominant benign bone disorder, characterized by fibro osseous lesions in the mandible and maxilla commonly caused by mutations in the SH3-binding protein 2-gene. The purpose of the authors' study was to analyze craniofacial and dental features of children diagnosed with cherubism, describe their treatment, and assess their dental age compared with norms for Finnish children. Six children were diagnosed, followed up and treated due to dental and skeletal disorders caused by cherubsim. The patients were followed up for an average of 91.5 months with emphasis on the skeletal changes and development of dentition. The treatment consisted of minor orthodontic treatment, dental extractions, and exposures. One patient underwent cosmetic mandibular surgery. All patients had lesions in the lower jaw and 5 of 6 patients had lesions in the maxilla as well. The patients were characterized by varying swelling of the jaws, premature loss of deciduous teeth in the affected area and widely spaced, displaced, un-erupted, or absent permanent teeth. The dental age was delayed at younger age but near to normal or even a little ahead at older age. Even though cherubism affects the jaws, jaw positions, and malocclusion, no common dentofacial proportions associated with the disease could be confirmed by cephalometric analysis. The surgical interventions did not provoke adverse reactions or local growth of the lesions. PMID- 28857987 TI - Surgical Tip for Prevention of Lip Injury During Orthognathic and Facial Bone Contouring Surgery. AB - Iatrogenic lip injury is a rather common complication after facial bone surgery, but is usually treated lightly by the surgeon compared with other more severe functional complications. However, these injuries can have permanent sequelae and can therefore be a reason for patient dissatisfaction, especially after cosmetic surgery. Intraoperative lip injuries during facial bone surgery are usually caused by heat-generating surgical instruments or forced traction on the operative fields. The authors have applied a special technical strategy using a hydrocolloid dressing material to avoid these intraoperative lip injuries. This method does not disturb the operative procedure itself, but efficiently prevents lip injuries and decreases surgical morbidities and postoperative swelling. PMID- 28857988 TI - Stability of Orbital Floor Fracture Fixation After Endoscope-Assisted Balloon Placement. AB - In recent years, endoscope-assisted balloon fixation using transantral and endonasal approaches has gained popularity as a minimally invasive treatment for orbital floor fractures. However, the optimal duration for balloon placement and the efficacy of the method have not been fully evaluated. The authors report their assessment of this method using postoperative and chronological measurements of the maxillary sinus volume.Fourteen patients with blowout fracture of the orbital floor who underwent reduction using endoscopic transantral and endonasal approaches followed by 6-week fixation with a balloon were evaluated. The volume of the maxillary sinus was measured for comparison using computed tomography at the time of balloon removal and 6 months after the surgery.The ratio of change in the maxillary sinus volume (maxillary sinus volume 6 months after surgery/maxillary sinus volume at balloon removal) for all subjects was 0.90 to 1.04 (0.96 +/- 0.44, mean +/- SD). No postoperative reduction in volume was detected, indicating satisfactory fixation. Postoperative computed tomography showed bone regeneration in the orbital floor in all patients in whom the fractured bone fragments were removed. No subjects had remaining enophthalmos greater than 2 mm.The postoperative change in the maxillary sinus volume was small, confirming the efficacy of 6-week balloon placement. This method was effective even in patients in whom fractured bone fragments were removed. Therefore, it is advisable to remove the fractured bone fragments if there is concern that the fragments will stray into the orbit due to inflation of the balloon. PMID- 28857989 TI - Albuminuria in Pediatric Patients With Adenotonsillar Hypertrophy. AB - The relationship between intermittent nocturnal hypoxia and albuminuria in pediatric patients with adenotonsillar hypertrophy was evaluated in this prospective study. Fifty children with grade 3 to 4 adenotonsillar hypertrophy scheduled for adenoidectomy and/or adenotonsillectomy were selected for study group. Fifteen patients with adenotonsillar grade 1 to 2 or adenotonsillectomized subjects in a similar range of sex, age, and body mass index scheduled for other surgeries were selected for control group. All children were monitored using finger pulse oximeter during the night before surgery. At the day of surgery, first morning urine samples were sent to the laboratory for analysis of albuminuria.Albuminuria was determined in 8 (16%) patients in study group and 1 (6.7%) patient in control group. This difference between groups was determined not to be statistically significant (P > 0.05). None of the pulse oximetry parameters was also found to be associated with albuminuria statistically (P > 0.05). However, the adenoid grade was observed to be associated with albuminuria (P = 0.011).This study revealed no relationship between albuminuria and intermittent hypoxia in children, although previous studies have reported that intermittent hypoxia causes albuminuria in adults. On the contrary, the adenoid grade was found to be in association with albuminuria. The reason seems to be unclear because of the lack of studies investigating albuminuria in children with adenotonsillar hypertrophy. However, inflammatory mediators arising from adenoid tissue may cause increase in renal capillary permeability and urine albumin excretion. PMID- 28857990 TI - Andy Gump Fracture of the Mandible in a Pediatric Patient. AB - The mandibular fractures in pediatric patients are rare, and they can need a fast and safe treatment. We present a case of a pediatric patient with "Andy Gump" fracture, resulting in a retrognathic mandible, distress to breathe, and functional discomfort to the patient caused by a cycling accident. The treatment was successful with the fast release of airway path and use of titanium plates to fix the fracture. PMID- 28857991 TI - Spontaneous Healing of Clodronate-Related Osteonecrosis of the Jaw. AB - Cases of medication-related osteonecrosis of the jaw (MRONJ) have been more commonly associated with aminobiphosphonate therapy than with alkylbiphosphonate treatment. Here, we report a case of MRONJ in a subject who received an alkylbiphosphonate, clodronate, for the treatment of osteoporosis, and discuss the pathogenic mechanisms of alkylbiphosphonates and the possible reasons for the spontaneous and rapid remission of MRONJ occurring in our patient. PMID- 28857992 TI - Solitary Frontal Sinus Fractures Compared to Multiple Facial Fractures, Energy Impact Dependency. AB - Frontal sinus fractures account for 2% to 15% of maxillofacial injuries. Up to 66% to 87% of the patients with frontal sinus fractures experience associated facial fractures. The majority of classifications used today categorize frontal sinus fractures depending on the integrity of the anterior table, posterior table, and the nasofrontal outflow. A retrospective study was performed, which included 24 patients diagnosed with frontal sinus fractures. Treatment in all patients consisted of open reduction and bone fixation. We analyzed population variables, injury etiology, fracture site, associated craniofacial injuries, surgical technique employed, handling of the nasofrontal duct, and postoperative complications. The most frequent etiology was falling accidents. Fifty-eight percent of the fractures involved both the anterior and posterior tables. Sixty six percent experienced associated facial fractures. Fifty percent of frontal sinus fractures were treated by open reduction internal fixation as the only treatment, 33.3% underwent sinus obliteration, and 16.6% were treated with cranialization. Frontal sinus fractures resulting from high-energy impact exhibited additional facial bone fractures in 100% of the cases, whereas fractures following low-energy impact showed involvement of additional facial fractures in only 27% of the cases. In this report, we suggest a modification to the anteroposterior classification of frontal sinus fractures. In addition to the involvement of the anterior and posterior walls and the degree of dislocation, high and low energy impact can direct us to the involvement of additional facial fractures and influence the surgical strategy. PMID- 28857993 TI - Surgical Treatment as a First Option of the Lower Eyelid Xanthelasma. AB - Xanthelasma palpebrarum represents yellowish plaques, which mostly appear near the inner cantus of the eyelid. In most patients, cosmetic reasons are the main purpose for their removal.The author presents a patient with a lower eyelid xanthelasma where surgical excision was used as a first treatment option. Cosmetic reasons, fast recovery, and possibility of a 1-stage procedure were the main requests of the patient for the removal of xanthelasma. Treatment and postrecovery period were routine.In the treatment of xanthelasma palpebrarum of the lower eyelids, it is necessary to consider surgical excision as a first treatment option. PMID- 28857994 TI - Lipoadenoma of the Submandibular Gland. AB - We report a case of an oncocytic lipoadenoma of the submandibular gland, which is a very rare benign tumor of the salivary gland. The patient was a 36-year-old man with a right submandibular mass measuring 29 * 1.3 * 1.2 cm. When the preoperative diagnostic tools were insufficient to rule out malignancy and for definite diagnosis, total removal of the gland was performed. Histopathologically, microscopic examination revealed a well-circumscribed tumor that is surrounded by a thin, fibrous capsule. The majority of the tumor consisted of adipocytes and normal components of salivary gland tissue. Oncocytic cells were observed only focally. Physicians should keep in mind that salivary glands may rarely exhibit this special tumor growth pattern. PMID- 28857995 TI - Transarterial Embolization and Transmucosal Sclerotherapy That Led to Successful Deliveries in a Patient With Symptomatic Arteriovenous Malformation of the Tongue. AB - Patients with arteriovenous malformations (AVMs) are at risk of significant hemorrhage and AVMs are especially difficult to manage in those desiring future pregnancy. Few patients with successful deliveries have been previously reported.The authors report an unusual case of AVM of the tongue in a pregnant woman who presented with massive pulsatile bleeding from a ruptured artery in the tongue in late gestation, this was thought to be caused by the changes in hormonal balance and the increase in cardiac output. The bleeding was controlled with transarterial embolization and transmucosal absolute ethanol sclerotherapy. Furthermore, her second and third deliveries were successfully managed.The authors managed symptomatic tongue AVM by combining transarterial embolization and transmucosal sclerotherapy, which was followed by successful deliveries. This patient supports the utility of transmucosal absolute ethanol sclerotherapy for tongue AVM and multidisciplinary medical care for a successful delivery. PMID- 28857996 TI - Effect of Suturation Plus Surgicel Application on Post-Tonsillectomy Bleeding and Pain. AB - OBJECTIVE: The aim of this study was to evaluate the effect of suturation (tonsillary fossa closure) plus Surgicel application on postoperative bleeding and pain after tonsillectomies performed using a classical dissection method. STUDY DESIGN: A prospective, randomized, double-blind, clinical trial was performed on 760 patients undergoing tonsillectomy or adenotonsillectomy during a 5-year period. METHODS: After excluding patients with hemorrhagic disorder, chronic disease, and peritonsillar abscess, both tonsils were removed via classic dissection technique (cold knife or blunt dissection) and then electrocauterized for hemostasis. The tonsillar fossa randomly assigned to the treatment protocol (Group 1) was closed by sutures, following Surgicel application. The other side was unaltered and acted as the control (Group 2). Pain was evaluated every day for 10 days postoperatively, and bleeding was reported at any time. RESULTS: A total of 760 patients (393 males, 367 females) between the ages of 4 and 35 years (mean age 13.46 +/- 7.98) were included in the study. Bleeding was observed in 31 patients: 8 from Group 1; and 23 from Group 2 (95% confidence interval [CI], P < 0.05). The average pain score was greater in Group 1 than in Group 2 on each postoperative day (95% CI, P < 0.05). CONCLUSION: Suturation plus Surgicel application increased pain levels while decreasing bleeding incidence during the postoperative period. PMID- 28857997 TI - Cervical Necrotizing Fasciitis of Odontogenic Origin and Hyperbaric Oxygen Therapy. AB - Necrotizing fasciitis (NF) is an infection of the soft tissues pathology with high mortality that spreads through the fascial planes and rarely seen in head and neck region. The cause of infection is often odontogenic problems. Broad spectrum antibiotics, surgical debridement, and hyperbaric oxygen therapy (HBO) are important for the treatment of disease. We report a case of cervical NF in a 33-year-old woman who was treated with rapid surgical debridement and simultaneous HBO. PMID- 28857998 TI - Differential Diagnosis of Intramuscular Schwannoma of the Craniocervical Region. AB - Schwannomas in the head and neck are a relatively common condition. However, intramuscular schwannomas in the craniocervical region are extremely rare. The preoperative consideration of schwannomas is very important to preserve adjacent circulation and nerve function during the surgery in this area. Moreover, the treatment and preoperative evaluation of this condition is not firmly established in the past literatures. The authors successfully managed the intramuscular schwannoma in the craniocervical region, and provide the differential diagnoses with appropriate treatments. PMID- 28857999 TI - Transnasal Endoscopic Resection of a Pleomorphic Adenoma Originate From Nasal Floor. AB - A 81-year-old female presented to our hospital frequent epistaxis. Nasal endoscopy showed a mass obstructing nasal cavity completely and occupying middle meatus. Magnetic resonance imaging was performed, an about 4.8 * 4 * 4.2 cm sized heterogeneous T2 high signal intensity and T1 enhancing mass mainly involving right nasal cavity with invasion of right hard palate with bony destruction. Therefore, the authors planned to do endoscopic mass excision, under general anesthesia for diagnosis and treatment. The authors removed the mass from lateral nasal wall, nasal roof, nasal septum, medial maxillary wall by piece-meal. Margins of mass were clear except the nasal floor. So, the authors did frozen biopsy to confirm the clear margin in nasal floor. Endoscopy enables better visualization of tumor margins, facilitating complete removal and avoiding excessive resection and following up using good visualization. PMID- 28858000 TI - Development and Psychometric Evaluation of the Speaking Up About Patient Safety Questionnaire. AB - OBJECTIVE: Speaking up about safety concerns by staff is important to prevent medical errors. Knowledge about healthcare workers' speaking up behaviors and perceived speaking up climate is useful for healthcare organizations (HCOs) to identify areas for improvement. The aim of this study was to develop a short questionnaire allowing HCOs to assess different aspects of speaking up among healthcare staff. METHODS: Healthcare workers (n = 523) from 2 Swiss hospitals completed a questionnaire covering various aspects of speak up-related behaviors and climate. Psychometric testing included descriptive statistics, correlations, reliabilities (Cronbach alpha), principal component analysis, and t tests for assessing differences in hierarchical groups. RESULTS: Principal component analysis confirmed the structure of 3 speaking up behavior-related scales, that is, frequency of perceived concerns (concern scale, alpha = 0.73), withholding voice (silence scale, alpha = 0.76), and speaking up (speak up scale, alpha = 0.85). Concerning speak up climate, principal component analysis revealed 3 scales (psychological safety, alpha = 0.84; encouraging environment, alpha = 0.74; resignation, alpha = 0.73). The final survey instrument also included items covering speaking up barriers and a vignette to assess simulated behavior. A higher hierarchical level was mostly associated with a more positive speak up related behavior and climate. CONCLUSIONS: Patient safety concerns, speaking up, and withholding voice were frequently reported. With this questionnaire, we present a tool to systematically assess and evaluate important aspects of speaking up in HCOs. This allows for identifying areas for improvement, and because it is a short survey, to monitor changes in speaking up-for example, before and after an improvement project. PMID- 28858001 TI - Prescribing Errors With Low-Molecular-Weight Heparins. AB - BACKGROUND: Low-molecular-weight heparins (LMWHs) are used in the prevention and treatment of venous thromboembolism (VTE). Bleeding is the primary major complication of LMWH therapy, which is associated with dose. The administration of appropriate dosages of LMWHs depends on the patient's risk of VTE, risk of bleeding, bodyweight, and renal function. Therefore, LMWH prescribing is prone to errors. However, no earlier study has explored the frequency of prescribing errors with LMWH. PURPOSE: The aim of the study was to determine the frequency and determinants of in-hospital LMWH-prescribing errors. METHODS: A cross sectional study was conducted to examine the frequency and determinants of LMWH prescribing errors between April and August 2014. We randomly selected 500 patients 18 years and older with at least one LMWH prescription during inpatient hospitalization. A prescribing error was a deviation from the internal hospital guidelines. Logistic regression estimated determinants of prescribing error. RESULTS: A prescribing error was present with 34% of all LMWH users. The most frequently recorded error was a dose that was not adjusted to body weight and/or renal function (85%). Prophylactic LMWH prescribing in medical wards was associated with a higher risk of prescribing error as compared with surgical wards. CONCLUSIONS: The frequency of prescribing errors was 34% in a tertiary care hospital. Being a patient with prophylactic LMWH use on a medical ward is a determinant for LMWH prescribing error. Interventions that will lead to better electronic recording of body weight and more awareness among medical doctors may reduce the total number of prescribing errors. PMID- 28858002 TI - Patient Recall of Informed Consent at 4 Weeks After Total Hip Replacement With Standardized Versus Procedure-Specific Consent Forms. AB - OBJECTIVES: Informed consent plays a pivotal role in the operative process, and surgeons have an ethical and legal obligation to provide patients with information to allow for shared decision-making. Unfortunately, patient recall after the consent process is frequently poor. This study aims to evaluate the effect of procedure-specific consent forms on patient's recall four weeks after total hip replacement (THR). METHODS: This is a prospective study using a posttest-only control group design. Sixty adult patients undergoing total hip replacement were allocated to be consented using either the generic or the surgery-specific consent form. Four weeks after surgery, a phone interview was conducted to assess patient's recall of risk of surgical complications. RESULTS: Patient demographic characteristics and educational attainment were similar in both groups. There was a statistically significant increase in the mean number of risks recalled in the study group at 1.43 compared with 0.67 in the control group (P = 0.0131). CONCLUSIONS: Consent is a complex process, and obtaining informed consent is far from straightforward. A statistically significant improvement in patient's recall with the use of procedure-specific consent forms was identified, and based on this, we would advocate their use. However, overall patient recall in both groups was poor. We believe that improving the quality of informed consent may require the sum of small gains, and the use of procedure-specific consent forms may aid in this regard. PMID- 28858003 TI - Refractive Status in Nepalese Pre-Term and Full-Term Infants Early in Life. AB - SIGNIFICANCE: This study suggests that pre-term infants, even without retinopathy of prematurity, are at risk for abnormal refractive development and informs the need for close monitoring of refractive error in such infants, regardless of their retinopathy of prematurity status. PURPOSE: The present study aims to investigate the refractive error trend in Nepalese pre-term infants without retinopathy of prematurity (ROP) in the first 6 months of life and explore the association of refractive error with birth weight (BW) and gestational age (GA). METHODS: Thirty-six pre-term infants without ROP and 40 full-term infants underwent cycloplegic retinoscopy at birth, term (for pre-term only), 3 months, and 6 months chronologically. Refractive status was classified into emmetropia (mean spherical equivalent refraction [SER] 0 to +3.00D), myopia (SER < 0.00D), and significant hyperopia (SER > +3.00D). Refractive parameters at various age points were compared between the pre-term and full-term infants using general linear model repeated measures ANOVA. RESULTS: At birth, the SER in the pre-term infants was +0.84 +/- 1.72D; however, there was a shift toward myopia at 6 months of age (SER = -0.33 +/- 1.95D). There was a significant difference in SER, astigmatism, and anisometropia between pre-term and full-term infants by 6 months of age (P < .01). Astigmatism and anisometropia showed an increasing trend with age in pre-term infants (P < .05 at 6 months) in contrast to a decreasing trend in full-term infants (P < 0.05 at 3 and 6 months). In pre-term infants, there was a statistically significant positive relationship between GA and SER (beta = 0.32, R = 17.6%, P < .05) but a negative relationship between BW and astigmatism (beta = -1.25, R = 20.6%, P < .01). CONCLUSIONS: Pre-term infants who do not develop ROP show a trend toward increasing myopia and demonstrate greater astigmatism and anisometropia than full-term infants in their first 6 months of life. PMID- 28858004 TI - Accommodative Behavior of Eyes Wearing Aspheric Single Vision Contact Lenses. AB - SIGNIFICANCE: Wearing aspheric contact lenses adds significant amounts of negative spherical aberration (SA). Also, when accommodated and converged to near targets, pupil size shrinks and SA shift from positive to more negative direction. Interestingly, in this study, pupil miosis was fully or partially able to compensate for the additional accommodation-induced negative SA. PURPOSE: The present study aims to examine the accommodative response characteristics of young eyes fit with aspheric single vision contact lenses (SVCLs) that add significant negative SA to the eye responding to a wide range of accommodation stimuli. METHODS: Using a Shack-Hartmann aberrometer, the accommodation behavior in eight young adult eyes (mean age and spherical equivalent is 27.25 +/- 2.05 years and 1.75 +/- 1.80D, respectively) was measured while subjects fixated binocularly and monocularly 20/40 letter E, which were moved from 2 m to 20 cm (0.5 to 5D) in 0.25D steps. Using natural pupils, refractive state was defined using three standard criteria: the dioptric power that (1) minimized the root mean square error (minRMS), (2) best-fit paraxial, and (3) provided the peak image quality (peak IQ). RESULTS: Wearing aspheric lenses with negative SA shifts the mean SA of the unaccommodated eyes from +0.05 MUm (eyes only) to -0.029 MUm (eyes + SVCL) and increases the negative SA for the eye + lens when accommodating from -0.029 to -0.07 MUm for natural pupils. Aberration changes with accommodation were attenuated by the accommodative pupil miosis, which reduced binocular viewing pupil diameters from 3.9 to 3.3 mm. This alteration of the typical SA levels by the aspheric SVCL did not prevent accurate accommodation (mean +/- standard deviation accommodative lag under binocular viewing were -0.08 +/- 0.12D, -0.38 +/- 0.12D, and -0.26 +/- 0.08D for paraxial, minRMS, and peak IQ, respectively). CONCLUSIONS: These data clearly show that aspheric contact lenses designed to correct some or all of the unaccommodated eye's positive SA do not interfere with accommodation. PMID- 28858005 TI - Preinflammatory Signs in Established Reusable and Disposable Contact Lens Wearers. AB - SIGNIFICANCE: Established reusable contact lens (CL) wearers show higher tear inflammatory cytokine concentrations and greater conjunctival metaplasia in the region covered by standard soft CLs. The balance of proinflammatory to anti inflammatory cytokines, but not individual tear cytokine concentrations, was associated with self-reported CL discomfort. PURPOSE: Daily disposable (DD) lenses are often used to improve CL discomfort, but the effect on ocular inflammatory responses has not been fully investigated. This study aimed to compare the concentrations of tear cytokines and conjunctival cell morphology in healthy habitual DD and reusable soft CL wearers. METHODS: Thirty-six established daily CL wearers, including 14 DD and 24 reusable wearers, were enrolled. Symptoms and ocular surface integrity were evaluated. The concentration of tear cytokines (interleukin 1beta [IL-1beta], IL-6, IL-10, IL-12(p70), IL-17A, and tumor necrosis factor alpha) were determined using Multiplex assays. The ratios of proinflammatory and anti-inflammatory cytokines were calculated. Impression cytology was performed on the conjunctiva, and goblet cell density and epithelial squamous metaplasia were quantified. Differences in variables by CL replacement schedules and the associations between variables were analyzed. RESULTS: Reusable CL wearers had higher concentrations (in pg/mL) of IL-1beta (26 +/- 7 vs. 16 +/- 11), IL-6 (42 +/- 14 vs. 25 +/- 20), IL-10 (83 +/- 23 vs. 49 +/- 36), IL-12(p70) (145 +/- 44 vs. 91 +/- 68), IL-17A (93 +/- 26 vs. 54 +/- 44), and tumor necrosis factor alpha (312 [171 to 468] vs. 189 [6 to 447]) (all P < .01) and greater conjunctival metaplasia in the region covered by CLs (0.7 [0.2 to 1.6] vs. 0.4 [0.04 to 1.2], P = .01) compared with DD wearers. There was a positive association between CL discomfort and ratios of IL-1beta to IL-10 and IL-12(p70) to IL-10 (rho = 0.42 and rho = 0.33, P < .05). CONCLUSIONS: Higher ocular inflammatory responses, as indicated by higher tear cytokine concentrations and higher conjunctival epithelial metaplasia, were found in reusable CL wearers than in DD CL wearers. The balance of proinflammatory and anti-inflammatory cytokines may be helpful to assess the inflammatory status of the eye. PMID- 28858007 TI - The management of sleep disorders in dementia: an update. AB - PURPOSE OF REVIEW: Sleep disorders in dementia cause distress and may lead to families being unable to care for someone with dementia at home. Recent Cochrane reviews found no interventions of proven effectiveness. There was no effect of light therapy and moderate evidence that melatonin was ineffective both given without knowledge of the patient's circadian rhythm. The current article updates this review by considering newer publications on interventions for sleep disorders or abnormalities of the sleep-wake cycle in people with dementia living in the community. RECENT FINDINGS: We searched electronically for new primary research, reviews and meta-analyses and identified 258 articles published between 15/12/2015 and 14/06/2017 on sleep and dementia; 43 of them on nonpharmacological or pharmacological treatments. Fifteen articles reported on the management of sleep disturbances in people with dementia, living at home. Those using pharmacological treatments (melatonin, psychotropic medications, donepezil, memantine) encompassed a meta-analysis, two double-blind RCTs, two uncontrolled trials, two population-based studies, and one case report. The studies of behavioural interventions comprised five uncontrolled trials, one case series, and one qualitative study. We also included three recent reviews on the management of sleep disturbances in Alzheimer's disease; pharmacotherapies for sleep disturbances in dementia, and dementia prevention, intervention and care. None of these found a treatment that showed definitive effectiveness, although there is preliminary work about nonpharmacological interventions, which can be built on. SUMMARY: Clinically effective, safe treatment of sleep disturbances in dementia remains an unresolved challenge. Given the importance of sleep and the many consequences of its disruption, well designed controlled trials are needed to determine acceptable and cost-effective treatment strategies that work for sleep disturbances. PMID- 28858008 TI - School start time effects on adolescent learning and academic performance, emotional health and behaviour. AB - PURPOSE OF REVIEW: The investigation of the relationship between the time of day that school begins and the effects it could have on students began in the mid 1990s. Since that time, many articles have been written either for the medical literature or the educational literature. This review is intended to bridge that gap by examining together the findings for both academic and health outcomes, exploring what we know and what is needed in further investigation. RECENT FINDINGS: Teens who are sleep deficient (defined as obtaining less than 8 h per night) because of early starting time for their school are much more likely to engage in risky behaviours, such as drug, cigarette and alcohol use, have significant feelings of depression, get lower grades and are at greater risk for car crashes. Many studies of academic performance and later school start time indicate benefits, although further research is needed to understand the related mechanisms that contribute to improvements in achievement. Recent research in adolescent sleep and outcomes is being shaped by not only measuring sleep duration, but also examining the timing in which sleep occurs. SUMMARY: Early school starting time for middle and high students has a clear, deleterious effect on their health and well being. Most recently, sleep deficit in teens is being viewed as a public health issue that needs a wider discussion about its impact and it necessitates improved public education about the sleep phase shift that occurs during adolescence. PMID- 28858009 TI - Sleep and memory: mechanisms and implications for psychiatry. AB - PURPOSE OF REVIEW: This review discusses current concepts on the relationship between sleep, memory formation and underlying neural refinements, with a particular focus on possible ways to use or modulate sleep in a targeted manner to augment psychiatric and psychotherapeutic treatments. RECENT FINDINGS: The most promising lines of research with regard to psychiatry and psychotherapy center on the targeted implementation or modulation of sleep to augment existing or create novel forms of treatment. SUMMARY: The modulation of sleep and interconnected neural plasticity processes provides a window of opportunity for developing novel treatments in psychiatry and psychotherapy. PMID- 28858010 TI - Is there a role for inhaled anticholinergic therapy in asthma management? AB - Anticholinergic therapy has long been a cornerstone of management of chronic obstructive pulmonary disease (COPD) but has not been included in treatment guidelines for asthma. In September 2015, tiotropium bromide was approved for use in adults with asthma; the indication has since been expanded to children ages 6 years and older. This article discusses appropriate patient selection and dosing, and the role of tiotropium bromide in asthma management. PMID- 28858011 TI - Diagnosing and managing scleroderma-related pulmonary arterial hypertension. AB - Scleroderma is an uncommon autoimmune disease of unknown cause that may affect any organ system in the body. Patients with scleroderma are prone to developing pulmonary complications, including pulmonary arterial hypertension (PAH), that are the leading cause of death in this population. This article describes scleroderma-related PAH and its diagnosis and management. PMID- 28858013 TI - Bone lymphoma with multiple negative bone biopsies. AB - This article describes a 71-year-old man with right knee pain, prerenal azotemia, hypercalcemia, and a mass in the distal femur. Although testing, including bone marrow biopsy, initially ruled out myeloma, an open surgical biopsy eventually confirmed the diagnosis as lymphoma involving the bone with classic histologic findings of mature B-cell neoplasm of germinal cell origin. PMID- 28858014 TI - The effects of obesity on pulmonary function in children. AB - The prevalence of obesity has risen rapidly in the United States in the past 20 years. Up to 25% of US children are obese, and obesity can be directly correlated with immediate and long-term health consequences. Pediatric obesity can harm multiple body systems and is a public health issue. This article focuses on how obesity affects a child's respiratory system, including pulmonary function, exercise intolerance, gas exchange, and airway musculature. PMID- 28858015 TI - PAs in primary care: Current status and workforce implications. AB - OBJECTIVES: Understanding the PA primary care workforce is an initial step toward greater use of primary care PAs in new healthcare delivery models. This study sought to describe primary care PA practice as it compares with PA practice in other specialties. METHODS: Data from two 2015 national American Academy of Physician Assistants surveys were analyzed using descriptive statistics. Statistically significant differences between primary care and specialty PAs were assessed using tests of column proportions and tests of column means. RESULTS: Compared with PAs in specialties, primary care PAs were older, saw more patients per week, and spent less time consulting with physicians. In addition, higher percentages were Hispanic, had a record of military service, and had plans to leave their specialty or retire. CONCLUSIONS: Primary care PAs appear to possess unique strengths; however, challenges to maintaining a primary care PA workforce are substantial. PMID- 28858016 TI - Female PAs-Where are we today? AB - As the physician assistant (PA) profession celebrates its 50th birthday, we can be proud of the gains our profession has accomplished. However, despite the positive reports of job satisfaction, a marked increase in female PA leaders, and overall gains in PA compensation, a significant wage gap remains between male and female PAs. The PA profession is flourishing but it is time female PAs are paid equitably. PMID- 28858017 TI - Urolithiasis and nephrolithiasis. PMID- 28858019 TI - What is causing this patient's headache? PMID- 28858018 TI - Naloxegol for managing opioid-induced constipation. AB - Naloxegol is a peripherally acting mu-opioid receptor antagonist for opioid induced constipation in adults with chronic noncancer pain. This drug's once daily oral formulation can be used as monotherapy and helps to decrease the constipating effects of opioid therapy; however, it has been associated with abdominal pain. PMID- 28858020 TI - Strength, humor, and hope. PMID- 28858021 TI - Primum non nocere. PMID- 28858022 TI - Lessons learned from an in-flight medical event. AB - Air transportation, although safe, exposes passengers to distinct physical, psychological, and physiological stressors that may be well tolerated in a healthy passenger but may trigger or exacerbate a medical event in a passenger with underlying medical problems. This article describes how a medical provider on the flight assisted with a medical emergency on a transatlantic flight. PMID- 28858023 TI - The officier de sante in 19th-century France: A PA prototype. AB - In 1803, shortly after the French Revolution, the French healthcare system was reorganized and a new independent medical officer, the officier de sante (health officer) was introduced. Qualifications included 3 years in a medical school (compared with 6 years for a physician) and an apprenticeship with a physician. Although somewhat independent, officiers de sante were limited in their scope of practice to general medicine, prescribing medications, and minor surgical procedures. Many were deployed to medically underserved areas. After almost a century of activity in a role not unlike physician assistants, the officiers de sante were abolished in 1892. Development of a more rigorous medical education and an adequate supply of physicians meant that physicians were better deployed throughout France, and were largely the reasons for abolishing this PA prototype. PMID- 28858025 TI - Chief PAs and diffusion of PA innovation. PMID- 28858027 TI - Dehydroepiandrosterone use in postmenopausal women: an androgenic option for managing sexual pain caused by vulvovaginal atrophy. PMID- 28858026 TI - In-utero cigarette smoke exposure and the risk of earlier menopause. AB - OBJECTIVE: Cigarette smoking is a risk factor for earlier menopause. Animal studies show that in-utero smoke exposure is toxic to developing ovaries. Our aim was to evaluate whether in-utero smoke exposed women reach menopause earlier compared with nonexposed women. METHODS: This is a cohort study within the Avon Longitudinal Study of Parents and Children. Participants included in this study were followed from 1991/1992 until 2010. Participant characteristics for the current analysis were obtained from obstetric records and from annual follow-up questionnaires. When not available, age at natural menopause was estimated by age at filling in the questionnaire minus 1 year. Cox proportional hazards modeling was used to estimate hazard ratios of menopause for in-utero exposed and nonexposed women. RESULTS: There were 695/2,852 postmenopausal women, of whom 466 had natural menopause, 117 had hormonal therapy, and 112 had surgical menopause. Age at natural menopause was 50.6 +/- 3.7 years. Of all participants, 20.2% (577/2,852) were exposed to smoke in-utero. Participants who were in-utero exposed but were not smokers did not have higher hazards of menopause (adjusted hazard ratio [HR] 0.92, 95% CI 0.72-1.18), whereas participants who were ever smokers (current or previous) and were in-utero exposed (adjusted HR 1.41, 95% CI 1.01-1.95) or were ever smokers but not exposed (adjusted HR 1.24, 95% CI 1.00 1.53) did have higher hazards of earlier menopause. CONCLUSIONS: In-utero smoke exposure was not associated with earlier menopause, but the effect of in-utero smoke exposure was modified by the smoking habits of the participants themselves increasing the risk for smokers who were in-utero exposed. PMID- 28858028 TI - Prevalence of sexual symptoms in relation to menopause in women in Asia: a systematic review. AB - OBJECTIVE: This systematic review of the literature was undertaken to investigate the prevalence of sexual symptoms in women in Asia in relation to their menopause status. METHODS: MEDLINE, EMBASE, PsycINFO, CINAHL, SCOPUS, and Google scholar were searched systematically for relevant population-based prevalence studies published between 1988 and 2016. The included studies were assessed for risk of bias using a risk-of-bias tool developed explicitly for the systematic review of prevalence studies. RESULTS: A total of 34 articles, comprising 24,743 women, were included. In Asia, diminished sexual desire appears to be highly prevalent amongst postmenopausal women. Vulvovaginal atrophy symptoms are common after menopause in some Asian countries, but are either less common or under-reported in other Asian countries. The review highlights the paucity of data pertaining to menopause and sexual well-being in Asia, and the lack of prevalence studies that have assessed sexual function using a validated questionnaire. Most of the included studies had a high risk of bias, especially in the four items that pertain to external validity. CONCLUSIONS: The available data, despite its limitations, suggests that after menopause, lowered sexual desire and vulvovaginal atrophy symptoms, including dryness, irritation, soreness, and dyspareunia, are common in women in Asia. The extent to which such symptoms cause women distress is not known. Studies of representative samples of premenopausal, perimenopausal, and postmenopausal women that use robustly translated and culturally appropriate validated questionnaires, and that collect detailed demographic data are still needed to determine the prevalence of sexual symptoms in relation to menopause in women in Asia. PMID- 28858029 TI - From the Editor. PMID- 28858030 TI - Why Follow JCRP and AACVPR on Twitter and Facebook? PMID- 28858031 TI - Coronary Artery Disease Patient Perspectives on Exercise Participation. AB - PURPOSE: Participation in exercise programs postmyocardial infarction is highly protective against future events and mortality. Unfortunately, uptake and maintenance of exercise participation has been documented as being low. This is thought to be due to a myriad of barriers. Qualitative research is a powerful tool to explain behaviors. We sought to summarize existing qualitative literature exploring patient perspectives of participation in exercise after a cardiac event. METHODS: We updated and built upon a previous systematic review and meta synthesis by identifying qualitative literature that was not previously captured. We used grounded formal theory to synthesize the qualitative findings in the selected literature. This process led to the development of a comprehensive conceptual framework for understanding the determinants of exercise participation. RESULTS: We found that external, internal, and cultural factors work together as umbrella themes to influence exercise initiation and continued participation in patients who have experienced a cardiac event. Internal factors expand into physical, cognitive, and emotional domains, which include fear, motivation, and mood. External factors include the domains of pragmatic and social considerations such as safety, accessibility, and social support networks. Cognitive and social domains were the most frequently cited factors influencing participation in exercise programs. CONCLUSIONS: The framework we outline allows for a more complete understanding of the factors that influence the exercise behaviors of patients with coronary artery disease. Cardiac rehabilitation programs should consider the key factors and capitalize on this knowledge, making these facilitators rather than barriers to exercise participation. PMID- 28858032 TI - Group Enrollment and Open Gym Format Decreases Cardiac Rehabilitation Wait Times. AB - PURPOSE: Wait times for the first cardiac rehabilitation (CR) session are inversely related to CR participation rates. We hypothesized that changing from individually scheduled appointments to a group enrollment and open gym format, in which patients were enrolled during group intake sessions and could arrive for subsequent CR sessions any time during open gym periods, would decrease wait times. METHODS: A total of 603 patients enrolled in CR at Vanderbilt University Medical Center from July 2012 to December 2014 were included in the study. We evaluated the effect of changing to a group enrollment and open gym format after adjusting for referral diagnosis, insurance status, seasonality, and other factors. We compared outcomes, including exercise capacity and quality of life, between the 2 groups. RESULTS: Patients in the group enrollment and open gym format had significantly lower average wait times than those receiving individual appointments (14.9 vs 19.5 days, P < .001). After multivariable adjustment, the new CR delivery model was associated with a 22% (3.7 days) decrease in average wait times (95% CI, 1.9-5.6, P < .001). Patients completing CR had equally beneficial changes in 6-minute walk distance and Patient Health Questionnaire scores between the 2 groups, although there was no significant difference in participation rates or the number of sessions attended. CONCLUSIONS: Implementation of a group enrollment and open gym format was associated with a significant decrease in wait times for first CR sessions. This CR delivery model may be an option for programs seeking to decrease wait times. PMID- 28858033 TI - Cardiorespiratory Responses to Short Bouts of Resistance Training Exercises in Individuals With Chronic Obstructive Pulmonary Disease: A COMPARISON OF EXERCISE INTENSITIES. AB - PURPOSE: Resistance training is recommended in pulmonary rehabilitation for people with chronic obstructive pulmonary disease (COPD); however, the acute cardiorespiratory responses to different intensities of resistance training are not known. We compared acute cardiorespiratory responses with high-intensity versus low-intensity resistance exercises in persons with COPD and healthy, matched controls. This research may assist in developing training parameters in COPD. METHODS: Participants (n = 10 per group) performed 1 set of 10 repetitions of leg extension and arm elevation at 2 intensities: 40% (low) and 80% (high) of 1-repetition maximum. Minute ventilation ((Equation is included in full-text article.)E), oxygen uptake ((Equation is included in full-text article.)O2), and heart rate (HR) data were collected continuously and expressed as absolute values and relative to values at (Equation is included in full-text article.)O2peak derived from a cardiopulmonary exercise test. Blood pressure, oxygen saturation, and rating of perceived exertion (RPE) were monitored before and after each set of exercises. RESULTS: Individuals with COPD showed similar (Equation is included in full-text article.)E, (Equation is included in full-text article.)O2, and HR with high- versus low-intensity exercises. RPE was higher after high- vs low intensity leg extension (4 +/- 1.4 vs 2 +/- 1, P < .005) and arm elevation (3 +/- 2 vs 1 +/- 1.4, P < .005). Compared with healthy participants, relative (Equation is included in full-text article.)O2, (Equation is included in full-text article.)E, and HR were higher in COPD (?40% vs 20% of the (Equation is included in full-text article.)O2peak; ?60% vs 20% of (Equation is included in full-text article.)Epeak; and ?80% vs 20% of HRpeak; all Ps <= .004). Absolute responses and RPE were similar between groups, irrespective of intensity and exercise. CONCLUSION: Immediate cardiorespiratory responses to an acute bout of resistance exercise appear to be independent of the exercise intensity in COPD. Although people with COPD are working closer to their (Equation is included in full-text article.)O2peak, their responses and RPE are comparable with healthy controls. PMID- 28858034 TI - AACVPR 32nd Annual Meeting Scientific Abstract Presentations. PMID- 28858036 TI - Altered regional homogeneity in patients with late monocular blindness: a resting state functional MRI study. AB - Many previous studies have demonstrated that the blindness patients have has functional and anatomical abnormalities in the visual and other vision-related cortex. However, changes in the brain function in late monocular blindness (MB) at rest are largely unknown. In this study, we investigated the underlying regional homogeneity (ReHo) of brain-activity abnormalities in patients with late MB and their relationship with clinical features. A total of 32 patients with MB (25 male and seven female) and 32 healthy controls (HCs) (25 male and seven female) closely matched in age, sex, and education underwent resting-state functional MRI scans. The ReHo method was used to assess local features of spontaneous brain activities. Patients with MB were distinguishable from HCs using the receiver operating characteristic curve. The relationship between the mean ReHo in brain regions and the behavioral performance was calculated using correlation analysis. Compared with HCs, patients with MB showed significantly decreased ReHo values in the right rectal gyrus, right cuneus, right anterior cingulate, and right lateral occipital cortex and increased ReHo values in the right inferior temporal gyrus, right frontal middle orbital, left posterior cingulate/precuneus, and left middle frontal gyrus. However, there was no significant relationship between the different mean ReHo values in the brain regions and the clinical features. Late MB involves abnormalities of the visual cortex and other vision-related brain regions, which may reflect brain dysfunction in these regions. PMID- 28858037 TI - Electroencephalogram characteristics during possession trances in healthy individuals. AB - Despite intensive studies on cerebral activity during trances involving tranquil arousal states, there are little data on physiological basis of naturally induced possession trances involving hyperarousal active states because of the difficulty of gathering data from participants within a natural cultural context in the field. We investigated the characteristics of electroencephalograms (EEGs) that were specific for naturally induced possession trances involving hyperarousal states in actual rituals. We measured the EEG signals of 12 healthy participants, seven with trance and five without trance, before, during, and after a dedicatory ritual drama in Bali, Indonesia, using a custom-modified field telemetry system. During trance, theta (4-7.5 Hz), alpha-1 (8-9.5 Hz), alpha-2 (10-12.5 Hz), and beta (13-30 Hz) signals were significantly increased compared with those during the control phases. Such findings were not observed in participants without trance when they performed similar movements in the rituals. The alpha-1 and alpha-2 signals tended to remain elevated for several minutes postritual compared with those recorded during the preritual resting state. These results suggest that spontaneous EEG patterns during possession trances may be related, at least in part, to the activation of the reward-generating neuronal system situated in deep-lying brain structures and deactivation of the cerebral cortex. PMID- 28858039 TI - Fulminant Haemophilus Influenzae Type a Infection in a 4-year-old with Previously Undiagnosed Asplenic Heterotaxy. AB - The post Hib-vaccine era has resulted in increased cases of invasive, non-Hib, Haemophilus influenzae infections. One of the encapsulated species, type a, displays the most similarity in virulence to type b. Our patient, a fully vaccinated 4-year-old female, with newly diagnosed asplenia in the setting of heterotaxy, had a prolonged hospital course with disseminated Haemophilus influenzae type a infection. PMID- 28858040 TI - Microbial Contamination on Touch Surfaces in Sick- and Well-Child Waiting Rooms in Pediatric Outpatient Facilities. AB - BACKGROUND: Healthcare-associated infections are a significant public health burden resulting in approximately 1.7 million infections each year. Much work is done to study the contributing factors in inpatient settings; however, little has been done to study outpatient facilities and their roles in healthcare-associated infections. While many pediatric outpatient offices utilize separated waiting areas for sick and well children to decrease the spread of disease, research has not been done to determine whether this practice is of benefit. In this study, we aimed to determine whether there is a difference in microbial burden between sick and well-child waiting areas and to identify surfaces with the highest levels of contamination. METHODS: Touch surfaces in waiting rooms were swabbed and surveyed for total microbial growth, staphylococcal growth and Gram-negative enteric bacterial growth. Selected bacteria were identified to screen for pathogenic organisms. Surfaces sampled included seats, tables, children's tables, children's seats, magazines and books. RESULTS: We found seats, children's seats and children's books to have the highest microbial burden. No conclusions can be made on the differences in microbial contamination in sick- and well-child waiting areas because of high variation. Streptococcus pyogenes was isolated as were several opportunistic pathogens. CONCLUSIONS: This study suggests the need for better cleaning practices by pediatric outpatient facilities, to include the disinfection of additional surfaces as well as more frequent and thorough cleaning. PMID- 28858041 TI - No Detection of Entamoeba Histolytica by Multiplex Polymerase Chain Reaction in Children With Acute Non-bloody Diarrhea in Guatemala. AB - Entamoeba histolytica is believed to be a ubiquitous cause of pediatric non bloody diarrhea. Using a multiplex polymerase chain reaction assay, we identified stool pathogens in 298 Guatemalan children presenting with acute, non-bloody diarrhea. Despite a high overall pathogen burden, we identified no cases of E. histolytica. Knowledge of local epidemiology is important to inform E. histolytica therapeutic strategies in low-income settings. PMID- 28858038 TI - Liver Fibrosis Quantification by Magnetic Resonance Imaging. AB - Liver fibrosis is a hallmark of chronic liver disease characterized by the excessive accumulation of extracellular matrix proteins. Although liver biopsy is the reference standard for diagnosis and staging of liver fibrosis, it has some limitations, including potential pain, sampling variability, and low patient acceptance. Hence, there has been an effort to develop noninvasive imaging techniques for diagnosis, staging, and monitoring of liver fibrosis. Many quantitative techniques have been implemented on magnetic resonance imaging (MRI) for this indication. The most widely validated technique is magnetic resonance elastography, which aims to measure viscoelastic properties of the liver and relate them to fibrosis stage. Several additional MRI methods have been developed or adapted to liver fibrosis quantification. Diffusion-weighted imaging measures the Brownian motion of water molecules which is restricted by collagen fibers. Texture analysis assesses the changes in the texture of liver parenchyma associated with fibrosis. Perfusion imaging relies on signal intensity and pharmacokinetic models to extract quantitative perfusion parameters. Hepatocellular function, which decreases with increasing fibrosis stage, can be estimated by the uptake of hepatobiliary contrast agents. Strain imaging measures liver deformation in response to physiological motion such as cardiac contraction. T1rho quantification is an investigational technique, which measures the spin-lattice relaxation time in the rotating frame. This article will review the MRI techniques used in liver fibrosis staging, their advantages and limitations, and diagnostic performance. We will briefly discuss future directions, such as longitudinal monitoring of disease, prediction of portal hypertension, and risk stratification of hepatocellular carcinoma. PMID- 28858042 TI - Yield of Anaerobic Blood Cultures in Pediatric Emergency Department Patients. AB - BACKGROUND: Anaerobic bacteremia is rare in children and current recommendations advocate against the routine use of anaerobic cultures in children. However, the incidence of anaerobic bacteremia and the utility of anaerobic blood cultures in children have not been assessed in recent years. Our pediatric emergency department (PED) policy still supports the use of both aerobic and anaerobic blood cultures in all cases of suspected bacteremia. This allowed us to re evaluate the yield of anaerobic cultures in PED settings. METHODS: Retrospective data of all blood cultures taken in the PED in a single tertiary center from 2002 to 2016 were collected. The incidence and characteristics of children with positive anaerobic blood cultures were assessed. Risk factors for anaerobic bacteremia were defined. RESULTS: Of the 68,304 blood culture sets taken during the study period, 971 (1.42%) clinically significant positive cultures were found. Pathogenic obligatory anaerobic bacteria were isolated in 33 (0.05%) cultures. The leading risk factors for anaerobic bacteremia were head and neck abscess and intra-abdominal infection. Of all the true positive cultures, 187 (22%) were only detected in the anaerobic culture and would have otherwise been missed. CONCLUSIONS: True anaerobic bacteremia is extremely rare in children admitted to the PED. Nevertheless, using anaerobic cultures may increase the overall yield of blood cultures. PMID- 28858043 TI - Clinical Manifestations of Cryptosporidiosis and Identification of a New Cryptosporidium Subtype in Patients From Sonora, Mexico. AB - The aim of this study was to identify the clinical manifestations of cryptosporidiosis and the distribution of Cryptosporidium spp. and subtypes in children in Sonora, Mexico. Two subtypes of C. parvum, including IIaA15G2R1 and IIcA5G3a, and 6 subtypes of Cryptosporidium hominis, including IaA14R3, IaA15R3, IbA12G3, IdA23, IeA11G3T3, and a new subtype IaA14R11, were identified. Cryptosporidium as an etiologic agent for acute gastroenteritis is discussed. PMID- 28858044 TI - Tonometry after Intrastromal Corneal Ring Segments for Keratoconus. AB - SIGNIFICANCE: Reliable intraocular pressure (IOP) measurement after intrastromal corneal ring segments (ICRS) implantation is a challenge because of altered corneal morphology. In this study, IOP is measured with four tonometers, compared with Goldmann applanation tonometry (GAT) values and the influence of corneal parameters is established. PURPOSE: This study compares IOP measurements made using different tonometers in patients implanted with ICRS and assesses the effects of central corneal thickness (CCT), corneal curvature, and corneal astigmatism on the IOP measurements obtained. METHODS: In this cross-sectional study, IOP was measured using three different tonometers in 91 eyes of 91 patients with corneal ectasia implanted at least 6 months previously with ICRS. The tonometers tested were the TonoPen XL, Pascal dynamic contour tonometer (DCT), and iCare Pro rebound tonometer. GAT measurements were used as reference. Agreement among the IOPs provided by the different tonometers and the influence of corneal variables on the IOP measurements obtained were assessed using the Bland-Altman method, intraclass correlation coefficients, and multiple linear regression analysis. RESULTS: Mean IOP differences were GAT versus TonoPen XL 0.8 +/- 3.07 mm Hg, GAT versus DCT -1.0 +/- 3.26 mm Hg, and GAT versus iCare Pro 0.8 +/- 2.92 mm Hg. Our multiple linear regression analysis identified CCT as a confounding factor affecting all the tonometer readings but DCT-IOP. CONCLUSIONS: In patients fitted with ICRS, IOP measurements made using the iCare Pro and TonoPen XL showed most agreement with GAT. Intraocular pressure measurements made by DCT were unaffected by corneal topographic factors though this procedure slightly overestimated GAT readings. PMID- 28858045 TI - Corneal Hysteresis Is Reduced in Obstructive Sleep Apnea Syndrome. AB - SIGNIFICANCE: To our knowledge, this is the first time a study looking at the association between corneal hysteresis (CH) and obstructive sleep apnea syndrome (OSAS) severity has been reported. We provide evidence that CH is lower in OSAS and speculate on the possible causes. PURPOSE: The present study aims to look at the association between CH and severity of OSAS, and whether CH could be another link between OSAS and the development of glaucoma. METHODS: This was a cross sectional, observational study at the University Malaya Medical Centre, Kuala Lumpur. Patients undergoing polysomnography for assessment of OSAS were recruited. We measured central corneal thickness (CCT) using optical biometry, and CH using ocular response analysis. Intraocular pressure (IOP) and Humphrey visual field (HVF) indices were also measured. The Apnea Hypopnea Index (AHI) divided patients into normal, mild, moderate, and severe OSAS categories. The normal and mild categories (47.9%) were then collectively called group 1, and the moderate and severe categories (52.1%) were called group 2. T tests, Pearson correlation tests, and general linear model analysis were performed, with P <.05 considered statistically significant. RESULTS: One eye each from 117 patients (75 men, 42 women) was included. Patients in group 2 had lower CH (9.8 +/- 1.4 vs. 10.3 +/- 1.1 mm Hg, P = .029), with unchanged estimated marginal means after correcting for age, sex, CCT, and IOP (P = .026). There were no statistically significant differences in IOP, CCT, or HVF indices between the two groups (all P > .05). CH correlated negatively with AHI (r = -0.229, P = .013) and positively with lowest oxygen saturation (r = 0.213, P = .022). CONCLUSIONS: CH is lower in moderate/severe OSAS than in normal/mild cases. This may be another link between OSAS and the development of glaucoma; further studies are indicated to determine the significance of this connection. PMID- 28858046 TI - 2015 Charles F. Prentice Medal Award Lecture: Neural Organization of Binocular Vision. AB - During a Research Career Development Award from the National Eye Institute, I spent a year at the University of Cambridge doing research with John Robson. The goal was to use a visual stimulation approach that had not been previously attempted, with the intention of exploring fundamental organization principles of the neural basis of binocular vision. The idea was to use sinusoidal gratings that drifted before both eyes such that the relative phase for one eye was fixed while that of the other was varied. This provided binocular stimuli of variable relative phase, i.e. retinal disparity, to enable testing of binocular response characteristics. We were able to obtain different types of disparity tuning functions for neurons in the primary visual cortex. This work, followed by extended investigations in Berkeley, provided basic information regarding response characteristics of simple and complex cells. We have also shown for monocular deprivation, an approximate model for human amblyopia, that many neurons remain connected to the deprived eye, as demonstrated with dichoptic activation. A selected portion of this work is described here. PMID- 28858047 TI - An Assessment of Stereovision Acquired in Adulthood. AB - SIGNIFICANCE: Increasing evidence indicates that childhood binocular vision disorders that lead to stereodeficiency may be treated in adulthood. Reports of patients who gain stereopsis as adults indicate that this achievement provides for a qualitatively different and dramatically improved sense of space and depth. PURPOSE: Increasing evidence suggests that stereopsis can be achieved in adult patients despite long-standing binocular disorders. We polled individuals who gained stereopsis as adults to ascertain their initial binocular disorders, the length of time they were stereodeficient, effective treatments, and the nature of their recovered stereovision. METHODS: A questionnaire was posted online and announced in a brief article in the journal Vision Development and Rehabilitation. RESULTS: Of the 63 responders, 56 (89%) reported strabismus and/or amblyopia, and 55 (87%) indicated that they had been stereodeficient for as long as they could remember. All but seven participants (89%) achieved stereovision through vision training or a combination of surgery and vision training, and many reported vivid visual changes. CONCLUSIONS: Despite childhood binocular disorders, patients may be able to achieve stereopsis following interventions in adulthood. This achievement provides for a qualitatively different and dramatically improved sense of space and depth. PMID- 28858048 TI - 2016 Glenn A. Fry Award Lecture: Mechanisms and Potential Treatments of Early Age Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in those older than 80 years. Understanding the mechanisms that cause this condition or its progression is critical for developing novel treatments. Here we summarize our studies evaluating the role of purine, adenosine triphosphate (ATP), in early AMD as well as photoreceptor loss and have also provided some insights to our investigations of a new laser treatment for those with early AMD. One of the receptors that are activated by ATP, P2X7, is expressed by neurons and immune cells and has a different function in each cell type. In neurons, P2X7 receptors form a ligand-gated ion channel, whereas on immune cells P2X7 receptors act as a scavenger receptor. These distinct functions have provided new insights to the mechanisms of AMD. On the one hand, high concentrations of ATP can cause photoreceptor death, most likely via stimulation of P2X7 receptors localized on photoreceptor terminals. On the other hand, P2X7 receptors mediate removal of dead and dying cells by monocytes. By understanding the fundamental cell biological changes that occur in patients and animal models of disease, we have uncovered mechanisms that may help us manage and treat patients in the future. PMID- 28858049 TI - Centration and Decentration of Contact Lenses during Peripheral Gaze. AB - SIGNIFICANCE: Varying amounts of peripheral defocus reported in previous studies are likely due to whether peripheral defocus is measured while turning the eyes or the head. Contact lenses (CLs) lag when viewing objects in peripheral gaze, so future studies ought to measure peripheral defocus while turning the head to measure defocus through the peripheral add power. PURPOSE: Soft multifocal CL peripheral defocus studies report varying results. To determine whether soft multifocal CL lag when turning the eyes could affect the measurement of peripheral defocus, we measured how much CLs move when looking in different gazes. METHODS: The distance between limbus and CL edge was measured with a slit lamp reticle magnifier. Centration was measured as the distance between CL edge and limbus at the superior, inferior, nasal, and temporal location of the CL while in primary gaze. Decentration of the CL equals the difference of the distance between the CL edge and limbus while looking centrally and 20 degrees in each direction. All measurements were performed while subjects wore habitual and Proclear Multifocal CL. RESULTS: The average +/- SD age of the 40 subjects was 27.8 +/- 8.4 years, 65% were female, and SE refractive error was -4.43 +/- 2.05 diopters. The soft multifocal CLs decentered 0.09 +/- 0.03 mm temporal (P = .006). The soft multifocal CLs lagged 0.49 +/- 0.28 mm while looking down (P < .001), 0.24 +/- 0.36 mm while looking up (P = .008), 0.58 +/- 0.20 mm while looking nasal (P < .001), and 0.35 +/- 0.21 mm while looking temporal (P < .001). CONCLUSIONS: Soft multifocal CLs center temporally in primary gaze, and they lag significantly while looking in every direction, but 0.50 mm or more when looking down or nasal, which could affect measurement of peripheral defocus when subjects turn their eyes instead of their head. PMID- 28858050 TI - Multicolor Scanning Laser Imaging in Diabetic Retinopathy. AB - SIGNIFICANCE: Diabetic retinopathy is a common cause of blindness in individuals younger than 60 years. Screening for retinopathy is undertaken using conventional color fundus photography and relies on the identification of hemorrhages, vascular abnormalities, exudates, and cotton-wool spots. These can sometimes be difficult to identify. PURPOSE: Multicolor scanning laser imaging, a new imaging modality, may have a role in improving screening outcomes, as well as facilitating treatment decisions. METHODS: Observational case series comprising two patients with known diabetes who were referred for further examination after color fundus photography revealed abnormal findings. Multicolor scanning laser imaging was undertaken. Features of retinal disease from each modality were compared. RESULTS: Multicolor scanning laser imaging provides superior visualization of retinal anatomy and pathology, thereby facilitating risk stratification and treatment decisions. CONCLUSIONS: Multicolor scanning laser imaging is a novel imaging technique offering the potential for improving the reliability of screening for diabetic retinopathy. Validation studies are warranted. PMID- 28858051 TI - Long-Term Changes in Jump Performance and Maximum Strength in a Cohort of National Collegiate Athletic Association Division I Women's Volleyball Athletes. AB - Kavanaugh, AA, Mizuguchi, S, Sands, WA, Ramsey, MW, and Stone, MH. Long-term changes in jump performance and maximum strength in a cohort of NCAA division I women's volleyball Athletes. J Strength Cond Res 32(1): 66-75, 2018-The purpose of this investigation was to quantify the magnitude of change in maximal strength and jumping abilities over approximately 1, 2, and 3 years of supervised sport and resistance training in National Collegiate Athletic Association (NCAA) division I women's volleyball athletes. This was an exploratory study on a cohort of women's volleyball athletes (n = 29) split into 3 groups based on the length of the time spent in a supervised resistance training program: group 1 (n = 11): 0.7 +/- 0.3 years, group 2 (n = 9): 1.6 +/- 0.2 years, and group 3 (n = 9): 2.4 +/- 0.6 years. Monitoring tests consisted of standing height (cm), body mass (kg), body fat (%), static jump height (SJH) and countermovement JH (CMJH) with 0 , 11-, and 20-kg loads (cm), and midthigh clean pull isometric peak force (IPF) and allometrically scaled IPF (IPFa) (N.kg). Increasing trends were observed for all variables from groups 1 to 2 to 3. Statistically greater improvements (p <= 0.05) with moderate to large effect sizes were found between groups 1 and 3 for SJH 0 (19.7%, d = 1.35), SJH 11 (23.8%, d = 1.23), SJH 20 (30.6%, d = 1.20), CMJH 11 (22.6%, d = 1.18), IPF (44.4%, d = 1.22), and IPFa (41.2%, d = 1.32). A combination of traditional resistance training exercises and weightlifting variations at various loads, in addition to volleyball practice, seem to be effective at increasing maximal strength by 44% and vertical JH by 20-30% in NCAA division I women's volleyball athletes after about 2.5 years of training. Furthermore, these characteristics can be improved in the absence of additional plyometric training outside normal volleyball-specific practice. PMID- 28858052 TI - Resistance training status and effectiveness of low frequency resistance training on upper-body strength and power in highly trained soccer players. AB - Soccer is classified as a contact/collision sport with many player-to-player duels. Winning these duels, shielding the ball or fending off an opponent requires upper-body strength and power. Therefore this study aimed, a) to examine the time-related effect of an upper-body RT on maximal strength and power changes in highly trained soccer players, b) to investigate if the resistance-training (RT) status influences these changes throughout a competitive season. Twenty eight soccer players participated in this study and were divided into an untrained (UG) and a trained (TG) group, according to their RT status. Both groups performed the same upper-body RT once a week, over 30 weeks. Maximal strength (1RM) and maximal power (MP) were assessed before, during and after the competitive season. Both groups significantly improved 1RM and MP over the entire competitive season, with a moderate (TG, 13%) to very large (UG, 21%) magnitude in 1RM and with a small (TG, 8%) to moderate (UG, 13%) magnitude in MP. After the initial 10 weeks of RT, UG presented significant and slightly (1RM) to moderately (MP) greater improvements than TG. For all other time intervals, the between groups changes in 1RM were rated as similar. For the last 20 weeks of the RT, the change in MP was significantly lower for UG compared to TG. One upper-body RT session per week will provide sufficient stimulus to enable an almost certain improvement in strength and power throughout a competitive season for all players disregarding their initial RT status. PMID- 28858053 TI - Time flies when you're at RPE13: How exercise intensity influences perception of time. AB - Previous studies have shown that there are some changes in our perception of time during exercise, but the relationship between intensity level and these perceptions is unclear. Therefore, the purpose of this study was to determine the effect of exercise intensity on prospective time estimations. Twenty-two trained runners (10 male, 12 female; age 25+/-6 years) participated in three 30-minute treadmill runs that were perceptually regulated at rating of perceived exertion (RPE) levels of 13 ("somewhat hard"), 15 ("hard") and 17 ("very hard"). Prospective time assessments, in which subjects estimated durations of 1, 3, 7 and 20 seconds, were obtained immediately before exercise, during (at 10 min. and 20 min.) and after exercise. A 3 (RPE) x 4 (timepoint) x 4 (estimated duration) repeated measures ANOVA was completed. There was a significant main effect of RPE level (p=.013). Post hoc tests revealed that time estimations at RPE17 were significantly lower than those at RPE13 (p=.021). The main effects of timepoint and estimated duration were not significant (both p>=.05), and no interactions were present. However, there was a trend for time estimations to decrease in all conditions as exercise progressed, with a rebound after cessation of exercise. This study showed a clear effect of exercise intensity on time perception. Specifically, the subjects perceived time to pass by more slowly as intensity increased. PMID- 28858054 TI - Using Microsensor Technology to Quantify Match Demands in Collegiate Women's Volleyball. AB - Vlantes, TG and Readdy, T. Using microsensor technology to quantify match demands in collegiate women's volleyball. J Strength Cond Res 31(12): 3266-3278, 2017-The purpose of this study was to quantify internal and external load demands of women's NCAA Division I collegiate volleyball competitions using microsensor technology and session rating of perceived exertion (S-RPE). Eleven collegiate volleyball players wore microsensor technology (Optimeye S5; Catapult Sports, Chicago, IL, USA) during 15 matches played throughout the 2016 season. Parameters examined include player load (PL), high impact PL, percentage of HI PL, explosive efforts (EEs), and jumps. Session rating of perceived exertion was collected 20 minutes postmatch using a modified Borg scale. The relationship between internal and external load was explored, comparing S-RPE data with the microsensor metrics (PL, HI PL, % HI PL, EEs, and jumps). The setter had the greatest mean PL and highest number of jumps of all positions in a 5-1 system, playing all 6 rotations. Playing 4 sets yielded a mean PL increase of 25.1% over 3 sets, whereas playing 5 sets showed a 31.0% increase in PL. A multivariate analysis of variance revealed significant differences (p < 0.01) across all position groups when examining % HI PL and jumps. Cohen's d analysis revealed large (>=0.8) effect sizes for these differences. Defensive specialists recorded the greatest mean S-RPE values over all 15 matches (886 +/- 384.6). Establishing positional load demands allows coaches, trainers, and strength and conditioning professionals to implement training programs for position-specific demands, creating consistent peak performance, and reducing injury risk. PMID- 28858055 TI - Thermoregulatory and Perceptual Effects of a Percooling Garment Worn Underneath an American Football Uniform. AB - Keen, ML, Miller, KC, and Zuhl, MN. Thermoregulatory and perceptual effects of a percooling garment worn underneath an American football uniform. J Strength Cond Res 31(11): 2983-2991, 2017-American football athletes are at the highest risk of developing exertional heat illness (EHI). We investigated whether percooling (i.e., cooling during exercise) garments affected perceptual or physiological variables in individuals exercising in the heat while wearing football uniforms. Twelve male participants (age = 24 +/- 4 year, mass = 80.1 +/- 8.5 kg, height = 182.5 +/- 10.4 cm) completed this cross-over, counterbalanced study. On day 1, we measured peak oxygen consumption (V[Combining Dot Above]O2). On days 2 and 3, participants wore percooling garments with (ICE) or without (CON) ice packs over the femoral and brachial arteries. They donned a football uniform and completed 3, 20-minute bouts of treadmill exercise at ~50% of peak V[Combining Dot Above]O2 (~33 degrees C, ~42% relative humidity) followed by a 10-minute rest period. Ice packs were replaced every 20 minutes. Rating of perceived exertion (RPE), thermal sensation, and thirst sensation were measured before and after each exercise bout. Environmental symptoms questionnaire (ESQ) responses and urine specific gravity (Usg) were measured pretesting and after the last exercise bout. V[Combining Dot Above]O2, change in heart rate (DeltaHR), and change in rectal temperature (DeltaTrec) were measured every 5 minutes. Sweat rate, sweat volume, and percent hypohydration were calculated. No interactions (F17,187 <= 1.6, p >= 0.1) or main effect of cooling condition (F1,11 <= 1.4, p >= 0.26) occurred for DeltaTrec, DeltaHR, thermal sensation, thirst, RPE, ESQ, or Usg. No differences between conditions occurred for sweat volume, sweat rate, or percent hypohydration (t11 <= 0.7, p >= 0.25). V[Combining Dot Above]O2 differed between conditions over time (F15,165 = 3.3, p < 0.001); ICE was lower than CON at 30, 55, and 70 minutes (p <= 0.05). It is unlikely that these garments would prevent EHI or minimize dehydration in football athletes. PMID- 28858056 TI - Putting Muscle Into Sports Analytics: Strength, Conditioning, and Ice Hockey Performance. AB - Kniffin, KM, Howley, T, and Bardreau, C. Putting muscle into sports analytics: strength, conditioning, and ice hockey performance. J Strength Cond Res 31(12): 3253-3259, 2017-Sports analytics is best known as the field of research that focuses on discovering slight but significant improvements within competitions; however, broader sets of athlete- and team-level data from outside competitions (e.g., strength and conditioning metrics) have been typically left out from such analyses. Given that strength and conditioning programs are perhaps the most common avenue through which people expect extra-competition progress to translate into within-competition performance, it is clear that strength and conditioning metrics warrant closer analytic attention. To illustrate this approach, we present a study of National Collegiate Athletic Association (NCAA) Division 1 Men's Ice Hockey players that integrates both (a) strength and conditioning metrics and (b) in-game performance measurements. Bivariate analyses show a significant positive correlation between bench press performance and points scored (r = 0.15), although multivariate analyses point to positive relationships between strength and conditioning measures and playing time as the more important finding. Although within-competition data are increasingly accessible for analytics research, the basic approach that we develop highlights the importance of considering extra-competition variables such as strength and conditioning metrics for understanding both coaching decisions regarding playing time and within-competition performance. We also discuss ways in which the integrated approach that we present offers potential applications for strength and conditioning professionals as well as players, coaches, and team managers. PMID- 28858057 TI - Effects of 6-Week Sprint-Strength and Agility Training on Body Composition, Cardiovascular, and Physiological Parameters of Male Field Hockey Players. AB - Sharma, HB and Kailashiya, J. Effects of 6-week sprint-strength and agility training on body composition, cardiovascular, and physiological parameters of male field hockey players. J Strength Cond Res 32(4): 894-901, 2018-Optimal physiological and cardiovascular characteristics are essential for optimal physical performance. Different types of training regimes affect these characteristics and lead to trainees' adaptation and changes in relevant parameters. In the present interventional study, we have evaluated the effects of 6-week sprint-strength and agility training on such parameters. Twenty-four young Indian national hockey players volunteered for this study. Body weight (BW), body mass index (BMI), percentage body fat, lean body mass (LBM), resting heart rate (rHR), resting blood pressure (rBP), resting double-product (rDP), P/power (using Running-based Anaerobic Sprint Test), vertical jump (VJ), seated shot put test (SP), ball-hitting speed (BS), Tm (505-agility test), and V[Combining Dot Above]O2max were measured, and changes (d) after specified training regime were studied. The training proved to be "short yet effective." Significant improvements after training were found in body composition, cardiovascular, aerobic, anaerobic, strength, agility, and performance-related parameters; but not in BW, BMI, P/LBM, SP/LBM, and V[Combining Dot Above]O2max/LBM. Change in VJ (dVJ) was associated with change in Tm (dTm); change in SP (dSP) with change in VO2max, which also related to change in rHR, rBP and rDP. Change in BS (dBS) was more among those with lower initial BW, BMI, and BF. dBS, along with change in VO2max/LBM, was more mainly among those with lower initial anaerobic-aerobic fitness. The findings will be useful for coaches, sports managers, players, and also for general population for better, individual, and sport-based designing of "short yet effective" training programs and monitoring of outcomes. Specific physiological parameter improvement-targeted training can also be designed based on this research. PMID- 28858058 TI - Resistance Training Is Associated With Higher Lumbar Spine and Hip Bone Mineral Density in Competitive Male Cyclists. AB - Mathis, SL, and Caputo, JL. Resistance training is associated with higher lumbar spine and hip bone mineral density in competitive male cyclists. J Strength Cond Res 32(1): 274-279, 2018-In contrast to other athletic activities, competitive cycling is associated with low areal bone mineral density (BMD). This investigation evaluated training and dietary factors associated with BMD in a sample of competitive male cyclists. Lumbar spine, total hip, femoral neck, and femoral trochanter BMD were measured with dual X-ray absorptiometry in 40 cyclists at the start of a cycling season. Participants reported weekly hours of cycling and weight training, years of competitive cycling experience, and completed a 1-day dietary recall to allow estimation of dietary calcium intake. Multivariable linear regression analyses revealed that weight training was associated with higher BMD of the lumbar spine (beta = 0.001, t = 2.88, p = 0.01), hip (beta = 0.002, t = 4.95, p < 0.001), femoral neck (beta = 0.002, t = 5.31, p < 0.001), and femoral trochanter (beta = 0.002, t = 4.31, p < 0.001). No other factor was a predictor of preseason BMD in this sample. These data emphasize the need for competitive male cyclists to participate in weight training to maintain or increase bone mass of the lumbar spine and hip. PMID- 28858059 TI - The relationship between repeated kicking performance and maximal aerobic capacity in elite junior Australian football. AB - Australian football (AF) is a physically demanding game, requiring players to engage in a range of anaerobic activities interspersed with prolonged aerobic exercise. Coupled, players have to perform a range of technical skills, the most fundamental of which being to effectively kick (dispose) the ball. The aim of this study was to ascertain the extent to which aerobic capacity influenced kicking performance in AF. Twenty four elite U18 players competing in the same U18 competition performed the Australian Football Kicking test (AFK) three times with the yo-yo IR2 completed twice (between each AFK), with no rest between all three AFKs. Linear mixed models (LMM) reported the extent to which kicking speed and accuracy scores were influenced by the level reached on the yo-yo IR2. Results indicated that players who recorded a higher level on the yo-yo IR2 produced a faster average kicking speed following each AFK (P <0.01), while for all players, kicking speed was faster and more accurate on their dominant kicking leg regardless of score on the yo-yo IR2 (P <0.01). The LMMs also reported that those who maintained kicking speeds following two yo-yo IR2 also had higher competition kicking efficiency than those who reported reduced kicking speeds. These results show that aerobically proficient U18 AF players who attain a relatively higher score on the yo-yo IR2 may be better equipped at preserving their kicking speed. Thus, coaches may wish to integrate both technical and aerobic drills in an attempt to preserve a player's capability to execute ball disposals with a high velocity. PMID- 28858060 TI - Reliability of Three Timing Systems Used to Time Short on Ice-Skating Sprints in Ice Hockey Players. AB - Bond, CW, Willaert, EM, Rudningen, KE, and Noonan, BC. Reliability of three timing systems used to time short on ice-skating sprints in ice hockey players. J Strength Cond Res 31(12): 3279-3286, 2017-Speed and acceleration are highly valued in ice hockey and frequently assessed using timing systems. Coaches must use reliable timing systems to assess these attributes, but many systems have not been thoroughly evaluated and the required number of sprint repetitions to obtain the coach's desired degree of reliability for a system may be impractical. This study aimed to compare the reliability of a single photocell (PC), a single laser with a microprocessor (LA), and a digital video camera (VC); and in doing so, evaluate the influence of completing additional sprint repetitions on each systems' reliability. We hypothesized that PC and LA would yield different times, have inferior reliability, and require a larger number of sprint repetitions to obtain the same degree of reliability compared with VC. Seventeen male ice hockey players completed 5 repetitions of a 9.15 m on ice-skating sprint timed simultaneously by PC, LA, and VC. The times obtained from VC were narrowly distributed around the mean compared with PC and LA and resulted in a mean sprint time approximately 0.05 and 0.07 second faster than PC and LA, respectively {PC: 1.74 second (95% confidence interval [1.72-1.76]); LA: 1.76 second [1.74-1.78]; VC: 1.69 second [1.67-1.70]}. When 2 sprint repetitions were completed, PC and LA typical error (TE) and smallest worthwhile difference (SWD) were 2.8- and 4.3 fold greater than VC, respectively. As more repetitions were completed, TE and SWD for PC and LA improved but remained approximately 2-fold greater than VC even when 5 repetitions were completed. With a smaller TE and SWD, VC was able to detect smaller "real" changes in a player's sprint performance over time compared with PC and LA. PMID- 28858061 TI - Evaluating the effects of under loaded and overloaded warm ups on subsequent swing velocity. AB - Several attempts to identify the optimal on deck procedure to enhance swing velocity in baseball have been made. However, inconsistent findings continue to constitute much of the body of literature. Additionally, the emergence of athlete monitoring in sport has led to the exploration of more sport specific tasks to potentially identify athlete fatigue and readiness to perform. Therefore, the purpose of this investigation was to examine three different bat weight warm up protocols on subsequent swing velocity and to examine the reliability of swing velocity measurements to allude to its potential a sport specific athlete monitoring metric. Thirty-two recreational male baseball players 20.3 +/- 2.0years, 179.6 +/- 7.1cm and 89.6+/- 11.1kg completed the study. Subjects completed three testing visits that included warming up with a control bat ([CB] 32in, 29oz), plastic bat ([PB] 31in, 6.4oz), or heavy bat ([HB] 32in, 57oz). Testing visits began with three CB swing trials followed by three intervention bat trials, then concluded with three additional CB swings. Swing velocity was assessed using visual 3D technology. Analyses of variance indicate that following the PB (26.6 +/- 2.0m/s) and CB interventions (26.2 +/- 1.7m/s) significantly faster (p<0.001) swing velocities were generated when compared to the traditional HB intervention (24.1 +/- 2.2m/s). When assessed for reliability, the average ICC was 0.681 and Chronbach's alpha was 0.95 indicating exceptional reliability. Congruent to previous research, this data bolsters the notion that warming up with a HB can hinder swing velocity. However, in contrast to previous research this data suggests that using a PB can increase swing velocity significantly. Furthermore, visual 3D can be designated as an exceptionally reliable device to measure swing velocity. PMID- 28858063 TI - Internal Repair of Very Large, Myopic and Recurrent Macular Holes by Creation of a Central Retinal Detachment and Silicone Oil Tamponade. PMID- 28858062 TI - RETINAL DETACHMENT SURGERY IN A PEDIATRIC POPULATION: Visual and Anatomic Outcomes. AB - PURPOSE: Pediatric retinal detachments (RDs) are unique in etiology, anatomy, and prognosis compared with the adult population. The mechanisms of pediatric RD include tractional (TRD), rhegmatogenous retinal detachment, traumatic, and other types, such as exudative or hemorrhagic. This study examined visual and anatomical outcomes of pediatric RD undergoing surgical repair at a single university referral center. METHODS: A retrospective consecutive case series of patients clinically diagnosed and undergoing surgery for RD between birth and 15 years of age from 2002 to 2013 at a single academic institution. RESULTS: A total of 206 patients (231 eyes) were included in this study, of which 25 (12%) had bilateral RD. Of those patients, 67 (29%) had TRD (retinopathy of prematurity, persistent fetal vasculature, or familial exudative vitreoretinopathy), 51 (22%) had rhegmatogenous retinal detachment (myopia, X-linked retinoschisis, or Stickler syndrome), 60 (26%) had traumatic RD, and 53 (23%) were due to other types of RD, such as Coats disease or coloboma. Presenting best-corrected visual acuity better than 20/200 correlated with better final best-corrected visual acuity (P < 0.0001). Anatomical success was strongly correlated with visual acuity outcome (P < 0.00001) and was significantly more likely in rhegmatogenous retinal detachment versus TRD (78% vs. 39%, P < 0.05). The rates of obtaining a final best-corrected visual acuity > 20/200 were poorer in TRD (10%) compared with rhegmatogenous retinal detachment (39%, P < 0.01) or traumatic RD (28%, P < 0.05). CONCLUSION: Visual and anatomical outcomes varied among categories of RD. Rhegmatogenous retinal detachments were associated with the best outcomes (anatomical success and globe conservation), whereas TRDs generally had poorer visual and anatomical outcomes. PMID- 28858064 TI - POSTOPERATIVE CHANGES AND PROGNOSTIC FACTORS OF VISUAL ACUITY, METAMORPHOPSIA, AND ANISEIKONIA AFTER VITRECTOMY FOR EPIRETINAL MEMBRANE. AB - PURPOSE: To investigate postoperative changes and prognostic factors of visual impairment after vitrectomy for unilateral epiretinal membrane. METHODS: A prospective observational study on 45 eyes from 45 patients with unilateral idiopathic epiretinal membrane who underwent vitrectomy. Visual parameters (best corrected visual acuity, metamorphopsia using M-CHARTS, and aniseikonia using the New Aniseikonia Test) and spectral domain optical coherence tomography parameters (macular retinal layer thickness and microstructure of the outer retina) were measured preoperatively and 6 and 12 months postoperatively. Statistical analyses included linear mixed-effects models for the longitudinal changes and prognostic factors of visual parameters. RESULTS: Best-corrected visual acuity and horizontal metamorphopsia improved significantly from 6 months after surgery (P < 0.001), whereas aniseikonia decreased significantly only at 12 months (P = 0.015). Vertical metamorphopsia remained unchanged. Preoperative inner nuclear layer thickness was significantly correlated with preoperative metamorphopsia. Besides baseline values, best-corrected visual acuity had no significant prognostic factors, but preoperative ellipsoid zone disruption had a negative direction of association with postoperative metamorphopsia (coefficients: -0.37 and -0.62, P = 0.015 and 0.006 for horizontal and vertical metamorphopsia, respectively), and preoperative horizontal metamorphopsia had a positive direction of association with postoperative aniseikonia (coefficient: 1.77, P = 0.002). CONCLUSION: After vitrectomy, postoperative changes and prognostic factors for unilateral epiretinal membrane differed for best-corrected visual acuity, metamorphopsia, and aniseikonia. PMID- 28858065 TI - Correspondence. PMID- 28858066 TI - Reply. PMID- 28858067 TI - Reply. PMID- 28858068 TI - Inflammatory Bowel Disease: Predictors and Causes of Early and Late Hospital Readmissions. AB - BACKGROUND AND AIMS: The rate of hospital readmission after discharge has been studied extensively in chronic conditions such as hepatic cirrhosis, diabetes mellitus, chronic obstructive pulmonary disease, and heart failure. Causative factors associated with hospital readmission have not been adequately investigated in patients with inflammatory bowel disease (IBD). We studied the rate, causes, and factors that predict readmissions at 1 month, 3 months, and 1 year in patients with IBD. METHODS: We performed a retrospective cohort study using the electronic medical record of a tertiary academic medical center, encompassing 3 large hospitals to identify patients discharged between January 2007 and December 2010 with a primary discharge diagnosis of either ulcerative colitis or Crohn's disease. The index admission was defined as the first unplanned admission during this period. Readmission was defined as unplanned admission (because of any cause) occurring within 1 week, 1 month, 3 months, and 1 year from the index admission. To identify factors predictive of readmissions, we compared social, demographic, and clinical features at the index admission of patients with readmission and those with no readmissions. Multivariate logistic regression analyses were performed to identify variables associated with 1-month, 3-month, and 1-year readmissions. RESULTS: A total of 439 index admissions with a primary discharge diagnosis of either ulcerative colitis or Crohn's disease were eligible for inclusion in the study. These patients accounted for a total of 785 admissions to the health system during the study period. The unplanned readmission rates were 5% at 1 week, 14% at 1 month, 23.7% at 3 months, and 39.2% at 1 year. The most common reasons for readmissions were IBD exacerbations, infections, and abdominal pain. On multivariate analysis, receiving total parenteral nutrition (odds ratio [OR] = 2.3; 95% confidence interval [CI], 1.22 4.30) and intensive care unit stay during index admission (OR = 3.61; 95% CI, 1.38-9.46) predicted both early and late readmissions, whereas sex, race, insurer, and outside hospital transfers predicted 1-year readmission. Receiving steroids (OR = 0.52; 95% CI, 0.23-1.15) at index admission was protective against 1-month readmission; being discharged on biologics (OR = 0.44; 95% CI, 0.19-1.02) was protective against 3-month readmission. CONCLUSIONS: Both early and late hospital readmissions are common in patients with IBD. Because frequent readmissions are indicators of poor quality of care, future prospective studies using larger cohorts of patients are needed to identify modifiable factors in patient care before discharge to improve quality of care, prevent readmissions, and consequently reduce health care costs. PMID- 28858069 TI - Comparison of Health Care Utilization and Costs Between Patients with Perianal Fistulizing Crohn's Disease Treated with Biologics with or Without Previous Seton Placement. AB - BACKGROUND: Fistulas are a common and often debilitating complication of Crohn's disease (CD). Tumor necrosis factor inhibitors and/or seton drainage are effective treatment options. We compared health care utilization and costs for patients with perianal CD who had setons placed before treatment with biologics versus those who did not. METHODS: Patients with CD (>=18 yr) were identified from the Truven Health MarketScan Database by ICD-9 code 555.x (January 1, 2006 March 31, 2015); those with external fistulas were identified by ICD-9 codes 565.1. Biological treatment and seton procedures were identified with the National Drug Codes or Current Procedural Terminology codes. Patients were grouped into 2 cohorts: seton before biological (SBB) treatment or no seton before biological (NSBB) treatment. RESULTS: SBB (N = 326) and NSBB (N = 1519) groups were similar in baseline age, sex, use of immunosuppressants and steroids, and comorbidity score. Baseline prevalence of asthma and cardiovascular disease, and use of antibiotics and 5-aminosalicylic acid were significantly greater in the SBB group versus the NSBB group. Baseline number of all-cause and fistula related hospitalizations were greater for the SBB group than in the NSBB group. However, during follow-up, the NSBB group required significantly more hospitalizations than the SBB group (all-cause: 0.41 versus 0.23; fistula related: 0.16 versus 0.07) and had significantly greater health care costs (all cause: $9711 versus $5514; fistula related: $4156 versus $1900). Results were confirmed in multivariate regressions adjusting for baseline characteristics and prescription drug use. CONCLUSIONS: Patients who had the setons placed before treatment with biologics used fewer health care resources and incurred lower health care costs compared with those who did not have the procedure. PMID- 28858070 TI - Anti-TNF-alpha Use During the Third Trimester of Pregnancy in Women with Moderate severe Inflammatory Bowel Disease and the Risk of Preterm Birth and Low Birth Weight. AB - BACKGROUND: Little knowledge exists about the association between anti-tumor necrosis factor-alpha (anti-TNF-alpha) therapy for inflammatory bowel disease during late pregnancy and adverse birth outcomes. We aimed to examine whether treatment with anti-TNF-alpha during the third trimester affected preterm birth and low birth weight (LBW), compared with women who discontinued anti-TNF-alpha therapy before the third trimester. METHODS: We identified a nationwide cohort of 219 women treated with anti-TNF-alpha during the pregnancy period and reviewed the medical records to extract clinical details. The exposed cohort (n = 113, 51.6%) constituted pregnancies exposed to anti-TNF-alpha during the third trimester, and the unexposed cohort (n = 106, 48.4%) constituted pregnancies with no anti-TNF-alpha during the third trimester. The association between anti-TNF alpha therapy in the third trimester and adverse birth outcomes was studied (1) in those women who had clinical disease activity during pregnancy and (2) in women who had no clinical disease activity during pregnancy. RESULTS: In women with disease activity, treated with anti-TNF-alpha during the third trimester, we found an adjusted odds ratio of 2.23 (95% confidence interval [CI], 0.80-6.20) for preterm birth and 1.16 (95% CI, 0.26-5.23) for LBW. Among women without disease activity, treated with anti-TNF-alpha therapy during the third trimester, we found an adjusted odds ratio of 3.36 (95% CI, 0.31-36.46) for preterm birth and 0.86 (95% CI, 0.05-14.95) for LBW. CONCLUSIONS: For anti-TNF-alpha therapy in the third trimester, we found no statistically significant increased risk of either LBW or preterm birth. PMID- 28858072 TI - Surgical Outcomes in Vedolizumab-Treated Patients with Ulcerative Colitis. AB - BACKGROUND: Surgical outcomes and pouch outcomes in the setting of vedolizumab remains poorly understood. We sought to determine the rate of 30-day postoperative surgical infectious complications and pouch-specific complications among patients with ulcerative colitis (UC) who received vedolizumab within 12 weeks of surgery. METHODS: A retrospective chart review between 5/1/2014 and 12/31/2016 of all adult patients with UC who underwent an abdominal operation was performed. Patients with UC who received vedolizumab within 12 weeks of their abdominal operation were compared with patients with UC on anti-TNFalpha treatment. RESULTS: Eighty-eight patients received vedolizumab and 62 received anti-TNFalpha within 12 weeks of surgery. More vedolizumab-treated patients had superficial surgical site infections (P = 0.047) and mucocutaneous separation at the ileostomy (P = 0.047), but there was no difference in the overall surgical infectious complication rate, deep space SSI, 30-day hospital readmission or return to the operating room. On univariate analysis of SSI among patients with UC, exposure to vedolizumab was not a significant predictor of SSI (P = 0.27), but steroids were predictive of SSI on univariate (P = 0.02) and multivariable analysis (P = 0.02). After ileal pouch anal anastomosis, there was a higher rate of intra-abdominal abscesses (31.3% versus 5.9%) and mucocutaneous separation (18.8% versus 0%) in the vedolizumab group compared with the anti-TNFalpha group, but statistical significance was not reached. CONCLUSIONS: Vedolizumab patients had significantly increased rates of superficial SSI, but not overall infectious complications. Among ileal pouch anal anastomosis patients, peripouch abscess rates were increased among vedolizumab-treated patients, but this did not reach statistical significance. Vedolizumab seems safe in the perioperative period for patients with UC. PMID- 28858071 TI - Efficacy of the Autoimmune Protocol Diet for Inflammatory Bowel Disease. AB - INTRODUCTION: Data suggest dietary modification can improve clinical responses in inflammatory bowel disease (IBD). The goal of this study was to determine the efficacy of an autoimmune protocol diet in patients with Crohn's disease and ulcerative colitis. METHODS: We enrolled adults with active IBD (Harvey-Bradshaw index >= 5 or partial Mayo score >=3 and erosions on endoscopy and/or elevated fecal calprotectin). For the autoimmune protocol, patients underwent 6-week elimination followed by 5-week maintenance phase. Clinical indices, laboratories, and biomarkers were assessed at baseline and weeks 6 and 11. Endoscopy was performed at study completion. RESULTS: The final cohort included 15 patients with IBD, with mean disease duration 19 years (SD 14.6) and active biological use in 7 (47%) patients. Nutrient repletion was initiated for deficiencies in vitamin D (n = 3) and iron (n = 6). From week 0 to weeks 6 and 11, mean partial Mayo score significantly improved from 5.8 (SD 1.2) to 1.2 (SD 2.0) and 1.0 (SD 2.0) for ulcerative colitis, and mean Harvey-Bradshaw index significantly improved from 7 (SD 1.5) to 3.6 (SD 2.1) and 3.4 (SD 2.6) for Crohn's disease. C-reactive protein did not significantly change during study. Mean fecal calprotectin improved from 471 (SD 562) to 112 (SD 104) at week 11 (P = 0.12). Among those with follow-up endoscopy at week 11 (n = 7), improvements were noted in simple endoscopic score for Crohn's disease (n = 1), Rutgeerts score (n = 1), and Mayo endoscopy subscore (n = 4). DISCUSSION: Dietary elimination can improve symptoms and endoscopic inflammation in patients with IBD. Randomized controlled trials are warranted. PMID- 28858073 TI - The Current Landscape and Lessons from Fecal Microbiota Transplantation for Inflammatory Bowel Disease: Past, Present, and Future. AB - Fecal microbiota transplantation (FMT) has changed the standard of care for Clostridium difficile infection. However, there is limited data focusing on efficacy and safety profile of FMT in patients with C. difficile infection with underlying inflammatory bowel disease (IBD), including the risk of IBD flare. Recently, there is also emerging evidence supporting the role of FMT to treat IBD including promising randomized trials in ulcerative colitis. However, with heterogeneity across these studies, the clinical application of this emerging therapy has yet to be fully elucidated. Here, we aim to review the current landscape of this rapidly developing field, mapping the efficacy and safety of FMT (1) to treat C. difficile infection in patients with IBD, (2) to treat underlying IBD, and (3) outline ongoing clinical trials and the future of the microbiome space. PMID- 28858074 TI - Efficacy of Combination Vedolizumab and Ustekinumab for Refractory Crohn's Disease. PMID- 28858075 TI - Concurrent radiotherapy for patients with metastatic melanoma and receiving anti programmed-death 1 therapy: a safe and effective combination. AB - A combination of immune-checkpoint inhibitors and radiation therapy (RT) represents a promising therapeutic strategy in part mediated by the abscopal effect, but clinical experience related to this combination remains scarce. Clinical data and patterns of treatment were retrospectively collected from all consecutive patients with metastatic melanoma and receiving programmed-death 1 (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and acute and delayed toxicities (graded according to Common Terminology Criteria for Adverse Events, v 4.3) were compared between patients receiving concurrent RT (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1 immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and December 2015 at our institution. Among these, 29% (n=17) received palliative RT for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions. Acute and late toxicity profiles were similar in the two groups. After a 10-month median follow-up, the objective response rate (complete or partial response) was significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%, P=0.02) and one complete responder after RT was compatible with an abscopal effect. The 6-month disease-free survival and overall survival rates for the NIR group versus the IR group were 49.7 versus 64.7% (P=0.32) and 58.8 versus 76.4% (P=0.42), respectively. We report here that the combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors. PMID- 28858076 TI - Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma. AB - Approximately 50% of all cutaneous melanomas harbor activating BRAF V600 mutations; among, these 10-30% carry the V600K mutation. Clinically, patients with V600K tumors experience distant metastases sooner and have an increased risk of relapse and shorter survival than patients with V600E tumors. Despite the clinical and other histopathological differences between these BRAF tumor subtypes, little is known about them at the genomic level. Herein, we systematically compared BRAF V600E and V600K skin cutaneous melanoma (SKCM) samples from the Cancer Genome Atlas (TCGA) for differential protein, gene, and microRNA expression genome-wide using the Mann-Whitney U-test. Our analyses showed that elements of energy-metabolism and protein-translation pathways were upregulated and that proapoptotic pathways were downregulated in V600K tumors compared with V600E tumors. We found that c-Kit protein and KIT gene expressions were significantly higher in V600K tumors than in V600E tumors, concurrent with significant downregulation of several KIT-targeting microRNAs (mir) including mir 222 in V600K tumors, suggesting KIT and mir-222 might be key genomic contributors toward the clinical differences observed. The relationship that we uncovered among KIT/c-Kit expression, mir-222 expression, and growth and prosurvival signals in V600 tumors is intriguing. We believe that the observed clinical aggressiveness of V600K tumors compared to V600E tumors may be attributable to the increased energy metabolism, protein translation and prosurvival signals compared with V600E tumors. If confirmed using larger numbers of V600K tumors, our results may prove useful for designing clinical management and targeted chemotherapeutical interventions for BRAF V600K-positive melanomas. Finally, the small sample size in V600K tumors is a major limitation of our study. PMID- 28858077 TI - Evaluation of the impact of statin therapy on the obesity paradox in patients with acute myocardial infarction: A propensity score matching analysis from the Korea Acute Myocardial Infarction Registry. AB - The phenomenon of obesity paradox after acute myocardial infarction (AMI) has been reported under strong recommendation of statin therapy. However, the impact of statin therapy on this paradox has not been investigated. This study investigated the impact of statin therapy on 1-year mortality according to obesity after AMI. A total of 2745 AMI patients were included from the Korea Acute Myocardial Infarction Registry after 1:4 propensity score matching analysis (n = 549 for nonstatin group and n = 2196 for statin group). Primary and secondary outcomes were all-cause and cardiac death, respectively. During 1-year follow-up, the incidence of all-cause (8.4% vs 3.7%) and cardiac (6.2% vs 2.3%) death was higher in nonstatin group than in statin (P < .001, respectively). In nonstatin group, the incidence of all-cause (7.2% vs 9.0%) and cardiac (5.5% vs 6.5%) death did not differ significantly between obese and nonobese patients. However, in statin group, obese patients had lower 1-year rate of all-cause (1.7% vs 4.8%) and cardiac (1.2% vs 2.9%) death (P < .05, respectively), and lower cumulative rates by Kaplan-Meier analysis of all-cause and cardiac death compared with nonobese patients (log-rank P < .05, respectively). The overall risk of all cause death was significantly lower in obese than in nonobese patients only in statin group (hazard ratio: 0.35; P = .001). After adjusting for confounding factors, obesity was independently associated with decreased risk of all-cause death in statin group. In conclusion, the greater benefit of statin therapy for survival in obese patients is further confirmation of the obesity paradox after AMI. PMID- 28858078 TI - Comparative analysis of diagnostic colonoscopy in symptomatic young adults from South Korea and the United States. AB - To date, not much is known about ethnic differences in the prevalence of colorectal neoplasia in symptomatic young patients with lower gastrointestinal symptoms. This study sought to compare diagnostic colonoscopic findings in symptomatic young patients from South Korea and the United States. Results from the first diagnostic colonoscopies in symptomatic 18- to 49-year-old patients were compared between the United States and Korean cohorts. The US cohort data were collected at Virginia Mason Medical Center in Seattle, Washington between January 2007 and January 2010, and the Korean cohort data were collected at 14 university hospitals in Korea between June 2006 and June 2015.The prevalence of advanced neoplasias was similar in both cohorts for bleeding and nonbleeding symptoms (P = .966 and P = .076, respectively). In a subgroup analysis for 40- to 49-year-old patients, the prevalence of advanced neoplasias was similar for bleeding symptoms; however, nonbleeding symptoms were significantly higher in the Korean cohort than in the US cohort (6.2% vs 2.6%, P < .001). In an age subgroup analysis for 18- to 39-year-old patients, the prevalence of advanced neoplasias was similar for bleeding and nonbleeding symptoms in both cohorts. Multivariate analysis showed that lower gastrointestinal symptoms were not associated with the risk of any type of advanced neoplasia in young Korean patients.Ethnic disparities in the prevalence of advanced neoplasia on diagnostic colonoscopy were not noticeable between Korean and US young patients. However, 40- to 49-year old patients with nonbleeding symptoms require more attention to detect advanced neoplasia in Korea than similarly aged patients in the United States. PMID- 28858079 TI - Laparoscopic vertical sleeve gastrectomy: A 5-year veterans affairs review. AB - The aim of this study was to evaluate the outcomes after laparoscopic sleeve gastrectomy (SG) in a VA population.SG has recently gained popularity as a definitive bariatric surgery procedure. Data are lacking on long-term outcomes, particularly in a Veterans Affairs population.We retrospectively reviewed 223 patients who underwent SG for morbid obesity between January 2009 and June 2014. Data on length of stay, complications, interval weight loss, comorbidities, and number of therapies preoperatively and at long-term follow-up were collected.There were 164 males and 59 females who underwent SG. The mean body mass index was 45.4 kg/m. Mean excess weight loss at 1 year was 62.9%, and 47.0% at 5 years. Weight loss continued until 12 to 18 months, when there was a nadir in weight loss (P < .001). There were 4 deaths and 4 staple-line leaks, with 3 deaths related to late cardiac events. One early death occurred in a very high risk patient. All staple-line leaks were managed nonoperatively. Of the 223 patients, 193 had hypertension, 137 diabetes, 158 hyperlipidemia, 119 obstructive sleep apnea (OSA), and 125 had gastroesophageal reflux disease. Preoperatively, patients were on a mean of 1.9 antihypertensive and 0.9 hyperlipidemic, anti reflux and oral hypoglycemic agents. Fifty percent of patients with diabetes were on insulin and 68% with OSA used continuous positive airway pressure/bilevel positive airway pressure (CPAP/BiPAP). We found significant absolute reductions in mean antihypertensive medications (-0.8), hyperlipidemic agents (-0.4), antireflux agents (-0.4), oral hypoglycemics (-0.6), insulin use (-25%), and use of CPAP/BiPAP (-55%) (all P < .001).Laparoscopic sleeve gastrectomy is a safe and effective bariatric surgery procedure, resulting in significant early weight loss up to 18 months and long-term improvement in all major obesity-related comorbid conditions. PMID- 28858080 TI - Comparative assessment of the efficacy and safety of acarbose and metformin combined with premixed insulin in patients with type 2 diabetes mellitus. AB - This study, a subgroup analysis of the data from the Organization Program of DiabEtes INsulIN ManaGement study, aimed to compare the efficacy and safety profiles of acarbose and metformin used in combination with premixed insulin.This analysis included 80 and 192 patients taking only 1 oral antidiabetic drug, classified into acarbose (treated with acarbose + insulin) and metformin groups (treated with metformin + insulin), respectively. The efficacy and safety data were analyzed for within- and between-group differences. The clinical trial registry number was NCT01338376.The percentage of patients who achieved target hemoglobin A1c (HbA1c) <7% in the acarbose and metformin groups were 38.75% and 30.73%, respectively, after a 16-week treatment. The average HbA1c levels in the acarbose and metformin groups were comparable at baseline and decreased significantly in both groups at the end of the study. All 7 blood glucose decreased significantly in both groups at endpoint compared with that at baseline. Insulin consumption was higher in the metformin group in terms of total daily amount and units/kg body weight. Incidences of hypoglycemia were similar in both groups. Body weight changed significantly in both groups from baseline to endpoint, but with no significant difference between the groups. Mean scores of Morisky Medication Adherence Scale improved in both groups at endpoint.Combination of insulin with acarbose or metformin could improve glycemic control in patients with type 2 diabetes mellitus. Acarbose and metformin were found to be comparable in terms of efficacy, weight gain, and incidence of hypoglycemia. PMID- 28858081 TI - Urachal mucinous adenocarcinoma with pseudomyxoma peritonei: A case report. AB - RATIONALE: Pseudomyxoma peritonei is an unusual clinical condition, and the appendix and ovaries are reported as the primary sites. PATIENT CONCERNS: A 44 year-old man who was reported a 3-month history of lower abdominal pain and distention, along with increased abdominal girth, was admitted with a palpable tender mass in the central lower abdomen. DIAGNOSIS: Ultrasonography showed a large well-circumscribed cystic-solid mass with lobulated margin, extending from the anterosuperior dome of the urinary bladder to the anterior abdominal wall. A computed tomography (CT) scan revealed a midline heterogeneous, hypodense, irregular polycystic-solid mass adjacent to the anterior wall of the abdomen and anterior to the dome of the urinary bladder. fluorodeoxyglucose positron-emission tomography/CT showed intense fluorodeoxyglucose uptake in the thickened wall of the mass. Intraperitoneal laparoscopic exploration also revealed a midline abdominal mass adjacent to the dome of the urinary bladder. Laparotomy showed that the mass originated from the dome of the urinary bladder and was disconnected with the urinary bladder lumen. The final histopathological diagnosis was urachal mucinous adenocarcinoma associated with high-grade pseudomyxoma peritonei. INTERVENTIONS: The patient underwent surgical cytoreductive procedure and the perioperative intraperitoneal chemotherapy. OUTCOMES: The patient made an uneventful recovery, and 7 months later had no recurrence. LESSONS: The urachus is a tubular structure, which extends medially from the apex of the bladder to the allantoid during fetal development, and it usually obliterates after birth. Urachal remnants can cause urachal carcinoma or bladder cancers. Pseudomyxoma peritonei originating from mucinous neoplasm of the urachus is extremely rare. PMID- 28858082 TI - Effects of arsenic trioxide on the expression of ezrin in hepatocellular carcinoma. AB - The aim of the study was to investigate the effects of arsenic trioxide (As2O3) treatment on the expression of ezrin and serum alpha-fetoprotein (AFP) levels in hepatocellular carcinoma (HCC).A total of 24 patients (20 males and 4 females) with resectable HCC were treated with venous injection of As2O3 for 14 days (10 mg/d) before surgery. The ezrin expression and serum AFP levels were assessed before and after treatment, respectively.The serum AFP levels were 325.5 ng/L before treatment and 278.6 ng/L after treatment, with statistical significant difference (Z = -2.360, P < .05). The expression of ezrin was negative, weak positive, and strong positive in 11, 7, and 6 cases, respectively, before As2O3 treatment, and 17, 5, 2 cases respectively after the treatment. The difference between the 2 groups was statistically significant (chi = 5.619, P < .05). Also, the results showed that there was a significant correlation between the high serum AFP level (AFP >= 500 ng/L) and high expression of ezrin (chi = 8.080, P < .05).As2O3 treatment can significantly downregulate the expression of ezrin in HCC. PMID- 28858083 TI - Robotic versus thoracoscopic lung resection: A systematic review and meta analysis. AB - BACKGROUND: Robotic video-assisted surgery (RVATS) has been reported to be equally effective to video-assisted surgery (VATS) in lung resection (pneumonectomy, lobectomy, and segmentectomy). Operation time, mortality, drainage duration, and length of hospitalization of patients undergoing either RVATS or VATS are compared in this meta-analysis. METHODS: A systematic research for articles meeting our inclusion criteria was performed using the PubMed database. Articles published from January 2011 to January 2016 were included. We used results of reported mortality, operation time, drainage duration, and hospitalization length for performing this meta-analysis. Mean difference and logarithmic odds ratio were used as summary statistics. RESULTS: Ten studies eligible were included into this analysis (5 studies for operation time, 3 studies for chest in tube days, 4 studies for length of hospitalization, and 6 studies for mortality). We were able to include 3375 subjects for RVATS and 58,683 subjects for VATS. Patients were mainly treated for lung cancer, metastatic foci, and benign lesions. We could not detect any difference between operation time; however, we found 2 trends showing that drainage duration and length of hospitalization are shorter for following RVATS than for following VATS. Mortality also is lower in patients undergoing RVATS. CONCLUSIONS: Therefore, we conclude that RVATS is a suitable minimal-invasive procedure for lung resection and suitable alternative to VATS. RVATS is as time-efficient as VATS and shows a trend to reduced hospital stay and drainage duration. More and better studies are required to provide reliable, unbiased evidence regarding the relative benefits of both methods. PMID- 28858084 TI - Diagnostic value of lactate, procalcitonin, ferritin, serum-C-reactive protein, and other biomarkers in bacterial and viral meningitis: A cross-sectional study. AB - There are many difficulties distinguishing bacterial from viral meningitis that could be reasonably solved using biomarkers. The aim of this study was to evaluate lactate, procalcitonin (PCT), ferritin, serum-CRP (C-reactive protein), and other known biomarkers in differentiating bacterial meningitis from viral meningitis in children.All children aged 28 days to 14 years with suspected meningitis who were admitted to Mofid Children's Hospital, Tehran, between October 2012 and November 2013, were enrolled in this prospective cross-sectional study. Children were divided into 2 groups of bacterial and viral meningitis, based on the results of cerebrospinal fluid (CSF) culture, polymerase chain reaction, and cytochemical profile. Diagnostic values of CSF parameters (ferritin, PCT, absolute neutrophil count [ANC], white blood cell count, and lactate) and serum parameters (PCT, ferritin, CRP, and erythrocyte sedimentation rate [ESR]) were evaluated.Among 50 patients with meningitis, 12 were diagnosed with bacterial meningitis. Concentrations of all markers were significantly different between bacterial and viral meningitis, except for serum (P = .389) and CSF (P = .136) PCT. The best rates of area under the receiver operating characteristic (ROC) curve (AUC) were achieved by lactate (AUC = 0.923) and serum CRP (AUC = 0.889). The best negative predictive values (NPV) for bacterial meningitis were attained by ANC (100%) and lactate (97.1%).The results of our study suggest that ferritin and PCT are not strong predictive biomarkers. A combination of low CSF lactate, ANC, ESR, and serum-CRP could reasonably rule out the bacterial meningitis. PMID- 28858085 TI - Evaluation of an interlaced triple procedure: penetrating keratoplasty, extracapsular cataract extraction, and nonopen-sky intraocular lens implantation. AB - To evaluate an interlaced triple procedure that involved penetrating keratoplasty (PKP), extracapsular cataract extraction (ECCE) using diathermy capsulotomy, and nonopen-sky intraocular lens (IOL) implantation.This retrospective study involved data from 34 patients who were diagnosed with severe corneal opacities and cataracts. These patients were divided into an interlaced procedure group (21 patients) and a traditional procedure group (13 patients). In the interlaced group, the method of continuous curvilinear capsulorhexis (CCC) was completed via diathermy capsulotomy. The donor corneal button was sutured at 8 positions (at equal intervals) using 10-0 nylon sutures, and the IOL was inserted into the capsular bag using a closed anterior chamber approach at the 10:30 to 12 o'clock positions between the sutures. In the traditional group, CCC was completed using side-port capsular forceps, and the IOL was implanted using an open anterior chamber approach.In the interlaced group, the CCC, open-sky, and total operation times were significantly shorter than in the traditional group (P < .05). Neither the best-corrected visual acuity (BCVA) nor corneal endothelial cell density was significantly different between the groups at 1 and 6 months after the operation.This interlaced triple procedure for the treatment of corneal diseases with cataracts appears to be feasible and practical. PMID- 28858086 TI - Association of croup with asthma in children: A cohort study. AB - Asthma and croup are common inflammatory airway diseases involving the bronchus in children. However, no study has reported the effects of urbanization, sex, age, and bronchiolitis on the association of croup and its duration with asthma development. We used the Taiwan Longitudinal Health Insurance Database (LHID) to perform this population-based cohort study; here, the cluster effect caused by hospitalization was considered to evaluate the association between croup and asthma development and the risk factors for asthma in children of different age groups. We evaluated children with croup aged <12 years (n = 1204) and age matched control patients (n = 140,887) by using Cox proportional hazards regression analysis within a hospitalization cluster. Of all 142,091 patients, 5799 (including 155 with croup [419 per 1000 person-y] and 5644 controls [106 per 1000 person-y]) had asthma during the 5-year follow-up period. During the 5-year follow-up period, the hazard ratios (HRs [95% CIs]) for asthma were 2.10 (1.81 2.44) in all children with croup, 2.13 (1.85-2.46) in those aged 0 to 5 years, and 2.22 (1.87-2.65) in those aged 6 to 12 years. Children with croup aged 7 to 9 years had a higher HR for asthma than did those in other age groups. Boys with croup had a higher HR for asthma. The adjusted HR for asthma was 1.78 times higher in children with croup living in urban areas than in those living in rural areas. In conclusion, our analyses indicated that sex, age, bronchiolitis, and urbanization level are significantly associated with croup and asthma development. According to our cumulative hazard rate curves, younger children with croup should be closely monitored for asthma development for at least 3 years. PMID- 28858087 TI - The influences of cognitive appraisal, physical injury, coping strategy, and forgiveness of others on PTSD symptoms in traffic accidents using hierarchical linear modeling. AB - The purpose of this study was to identify how physical injury, perceived threat, forgiveness of others, and problem-focused coping influence the change of posttraumatic stress disorder (PTSD) symptoms. One hundred twenty patients who had experienced a traumatic vehicle accident participated in 1 to 2 months after the accident; 70 of these people involved at 6 months after the accident. We used a hierarchical linear model analysis to verify the impacts of predictors on change of PTSD symptoms as time passed. The results showed that PTSD symptoms decreased over time, and greater perceived threat would worsen PTSD symptoms and more forgiveness would decrease PTSD symptoms. On the other hand problem-focused coping and physical injury severity were not significantly related to the PTSD symptoms. Specifically, greater perceived threat was found to be related with a deceleration of the decrease in PTSD symptoms, whereas greater forgiveness of others was associated with an acceleration of this decrease. However, problem focused coping and physical injury severity had no influence on the change rate of PTSD symptoms. Cognitive variable could be more important than physical injury to understand PTSD. In addition, forgiveness of other in a traumatic situation needs to be considered as one of coping strategies. PMID- 28858088 TI - Placental transmogrification of the lung: Case report and systematic review of the literature. AB - OBJECTIVE: Placental transmogrification of the lung (PTL) is rare cystic lesion. Thus, we summarized the characteristics of PTL to explore the strategy of diagnosis and treatment. METHODS: Two patients pathologically confirmed PTL were treated in our hospital. Retrospectively analysis was performed on such 2 cases and 34 cases of PTL reported in abroad. The basic information and clinical characteristics from each patient were gathered and analyzed. RESULTS: The imaging findings of 2 patients were the pulmonary solid mass with peripheral multiple pulmonary bullae. After the improvement of preoperative examination and the multidisciplinary discussion of thoracic surgery, respiration, imaging, and anesthesia, the possibility of benign pulmonary lesions was improved in all cases. Thoracoscopic lobectomy was carried out under general anesthesia, and the intraoperative frozen pathology showed bullae of lung. Ultimately, PTL was confirmed by paraffin pathological diagnosis. Both 2 PTL patients had satisfied recovery without obvious complications or imaging abnormalities. In addition, the literature review of 34 PTL cases from PubMed database was summarized between 1995 and 2015. A total of 36 patients were retrospectively analyzed in our study. The age of 34 cases ranged from 24 to 72 years (an average age of 45.6 +/- 13.5 years). Among these, 8 cases were no obvious symptoms. In addition, the other 25 cases had respiratory symptoms such as chest tightness, cough, and chest pain. Moreover, the mean size of pulmonary bulla was 6.5 +/- 5.5 cm. The size of the solid lesions in 23 cases was 3.3 +/- 3.4 cm (ranging from 0.5 to 15). The follow up period was 2 to 96 months (average 27.3 +/- 29.8 months). CONCLUSION: Early diagnosis and surgical operation of PTL should be performed as soon as possible. These lesions are best treated by minimally invasive surgery, so as to preserve more normal lung tissue and avoid the pneumonectomy. PMID- 28858089 TI - Adherence, tolerability, and outcome after 36 months of isoniazid-preventive therapy in 2 rural clinics of Swaziland: A prospective observational feasibility study. AB - Although efficacy of 36 months isoniazid preventive therapy (IPT) among HIV positive individuals has been proven in trial settings, outcome, tolerance, and adherence have rarely been evaluated in real-life settings.This is a prospective observational cohort study conducted in 2 primary care rural clinics in Swaziland.After negative tuberculosis symptom screening, patients either with the positive tuberculin skin test (TST) or after tuberculosis treatment were initiated on IPT for 144 weeks. In addition to routine clinic visits, adherence was assessed every semester.Of 288 eligible patients, 2 patients never started IPT (1 refusal, 1 contraindication), and 253 (87.8%), 234 (81.3%), and 228 (79.2%) were still on IPT after 48, 96, and 144 weeks, respectively (chiP = .01). Of 41 patients who interrupted IPT before 144 weeks, 21 defaulted (of which 17 also defaulted HIV care); 16 stopped because of adverse drug reactions; 2 were discontinued by clinicians' mistake and 1 because of TB symptoms. Five patients (1.7%) died of causes not related to IPT, 5 (1.7%) developed TB of which 2 were isoniazid-resistant, and 9 (3.1%) were transferred to another clinic. As an indicator of adherence, isoniazid could be detected in the urine during 86.3% (302/350) and 73.6% (248/337) of patient visits in the 2 clinics, respectively (chiP < .001).The routine implementation of IPT 36 months was feasible and good patient outcomes were achieved, with low TB incidence, good tolerance, and sustained adherence. PMID- 28858090 TI - Prenatal ultrasonic diagnosis of absent pulmonary valve syndrome: A case report. AB - RATIONALE: Absent pulmonary valve syndrome (APVS) is a rare congenital heart disease that is often associated with tetralogy of Fallot (TOF). Here, we report 2 cases of APVS associated with TOF diagnosed via fetal echocardiography and discuss their specific ultrasonographic characteristics. PATIENT CONCERNS: Two pregnant women with suspicion of fetal heart anomaly were referred from their local hospitals to our hospital for fetal malformation screening and detailed fetal echocardiography. Color and spectral Doppler flow imaging were utilized to evaluate the axis, size, situs, cardiac chambers, and both inflow and outflow tracts of the heart as well as the great arteries. Both cases had a severe dilatation of the pulmonary trunk and its branches and an absence or dysplasia of the pulmonary valve, which was associated with subaortic ventricular septal defect (VSD) with an overriding aorta. In addition, the fetus in case 1 showed a patent ductus arteriosus, and the fetus in case 2 showed arterial duct agenesis. Furthermore, color Doppler flow imaging showed a bi-directional multicolored flow signal in the pulmonary valve ring. DIAGNOSES: Both fetuses were diagnosed with APVS associated with TOF. INTERVENTIONS: No therapeutic intervention was performed. OUTCOMES: On the request of the pregnant women and their families, both fetuses were aborted. LESSONS: Although APVS is a rare congenital heart disease and often associated with TOF, it has an overall poor prognosis. Nowadays, it can be easily diagnosed via ultrasonography because of its typical ultrasonographic features, such as aneurysmal dilatation of pulmonary artery, massive regurgitation of the pulmonary valve, VSD, and an overriding aorta. Therefore, early fetal echocardiography screening should be performed for every fetus. PMID- 28858091 TI - Are programmed cell death 1 gene polymorphisms correlated with susceptibility to rheumatoid arthritis?: A meta-analysis. AB - BACKGROUND: Several studies investigated the relationship between programmed cell death 1 (PDCD1) gene polymorphisms and rheumatoid arthritis (RA) risk, but the results were controversial. To explore whether PDCD1 gene polymorphisms have an effect on RA risk, we conducted this meta-analysis to investigate the relationships between PDCD1 polymorphisms (rs36084323 [PD-1.1 G/A], rs11568821 [PD-1.3 G/A] and rs2227981 [PD-1.5 C/T]) and RA risk under 4 genetic models. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBLM) were systematically searched for all eligible case-control studies. The last search was updated on September 10, 2016. Studies were accessed using Newcastle-Ottawa Scale case control study (NOS), and the combined effect size was calculated using STATA software, version 12.0. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the association. Heterogeneity analysis and subgroup analysis were also performed. Sensitivity analysis and publication bias were also performed if necessary. RESULTS: This meta-analysis included 6 studies. The result demonstrated null association between rs36084323 (PD-1.1 G/A) polymorphism and RA susceptibility in all 4 genetic models. With regard to rs11568821 (PD-1.3 G/A), statistically significant association with RA risk was observed under allele model in Caucasians (allele model A vs G, OR = 1.19, 95% CI = 1.03-1.41). There was no significant association between rs2227981 (PD-1.5 C/T) polymorphism and RA risk. CONCLUSION: The present study suggests that mutant A allele in rs11568821 (PD-1.3 G/A) might increase the susceptibility to RA in Caucasians. PMID- 28858092 TI - Preoperative intravenous glucocorticoids can reduce postoperative acute pain following total knee arthroplasty: A meta-analysis. AB - BACKGROUND: The ability of preoperative intravenous glucocorticoids to control pain after total knee arthroplasty (TKA) has been examined in many studies, but it remains controversial. Therefore, we undertook a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of preoperative intravenous glucocorticoids for postoperative pain management after TKA. METHODS: We systematically searched RCTs from electronic databases, including PubMed, Embase, Web of Science, the Cochrane Library, the Chinese Wanfang Database, and the China National Knowledge Infrastructure database. The outcomes included visual analogue scale (VAS) scores at 6, 12, 24, 48, and 72 hours after TKA; the occurrence of postoperative nausea and vomiting (PONV); blood glucose at 6 and 24 hours after TKA; and the occurrence of infection. RESULTS: Of the identified studies, a total of 11 RCTs involving 1000 patients (glucocorticoids = 501, control = 499) were included in this meta-analysis. Compared with a placebo, preoperative intravenous glucocorticoids significantly reduced VAS scores at 6, 12, 24, and 48 hours, with decreases of 3.63 points, 6.81 points, 10.40 points, and 3.15 points, respectively, on a 110-point VAS. Moreover, intravenous glucocorticoids were associated with significant decreases of 19.4% and 16.8% in the occurrence of nausea and vomiting, respectively. However, intravenous glucocorticoids were also associated with increased blood glucose with no clinical importance at 6 hours after TKA. No significant difference was found in the occurrence of infection or in blood glucose at 24 hours after TKA. CONCLUSION: Preoperative intravenous glucocorticoids are an effective and safe method to reduce postoperative pain and PONV in patients following TKA. More studies are necessary to identify the optimal dose and type of glucocorticoids for maximal pain control. PMID- 28858093 TI - Surgical treatment of neovascular glaucoma with Ex-PRESS glaucoma shunt: Case report. AB - RATIONALE: Neovascular glaucoma (NVG) is one of the most aggressive types of glaucoma, and its abnormal fibrovascular tissue growth on the iris and trabecular meshwork may create difficulties to control the intraocular pressure (IOP) and perform the operation such as trabeculectomy. PATIENT CONCERNS: Ex-PRESS glaucoma shunt has been introduced to serve as one alternative operation for glaucoma, and is thought to have the potential advantage of being less traumatic than traditional trabeculectomy. The purpose of our study is to evaluate the efficacy and safety of primary Ex-PRESS implantation in eyes with NVG. DIAGNOSES AND INTERVENTIONS: This was a retrospective study of four patients with NVG in whom primary Ex-PRESS implantation was performed between January 2012 and October 2016. OUTCOMES: After a mean follow-up of 20.8 +/- 8.9 months (range, 15-34 months), three of four NVG patients (75.0%) receiving primary Ex-PRESS implantation had postoperative IOP under 21 mmHg without any antiglaucoma medication control at the last follow-up, but shunt reposition had been performed due to failed blebs or recurrent NVG. Besides, the best corrected visual acuity at the last follow-up was stabilized or improved in three of four NVG patients (75.0%), accompanied with the regression of iris neovascularization. Only one patient had self-resolved postoperative hyphema; otherwise, there were no other perioperative complications. LESSONS: Primary Ex-PRESS implantation might constitute a safe and alternative treatment for patients with NVG. In spite of the possible reoperations, the final outcomes were still shown effective after shunt reposition. PMID- 28858094 TI - Fatal acute hepatic failure in a family infected with the hepatitis A virus subgenotype IB: A case report. AB - RATIONALE: Hepatitis A viral infection is a well-known cause of subclinical or acute self-limited hepatitis. Few cases of hepatitis A virus (HAV)-associated acute liver failure (ALF) have been reported in low HAV endemic countries annually. PATIENTS CONCERNS: To investigate the possible factors that affected the severity of HAV infection, a family cluster infected with the HAV subgenotype IB strain, which is not common in Japan, was described. DIAGNOSES: This family consisted of five members who all were infected with HAV. INTERVENTIONS: Four of the five patients hospitalized except for an asymptomatic patient. OUTCOMES: Two of the five patients, men in their 50s and 60s, developed ALF, and one patient died. Various host factors, including sex (male), age, and a high bilirubin level, may affect the outcomes. Based on viral factors, HAV RNA was higher in the fatal case compared with others, and it decreased within a short period of time. The similarity of the nucleotide sequences was 99.9% among the HAV isolates based on an entire genomic sequence. Deletions and/or insertions on the HAV protein coding sequences that caused a frameshift were found in surviving cases but not in the fatal case. LESSONS: The rapid clearance of increased HAV and the absence of defective HAV might be closely associated with the onset of liver failure. PMID- 28858095 TI - The influence of inhaled corticosteroid discontinuation in children with well controlled asthma. AB - Asthma is a chronic inflammatory disease that requires adherence to both preventative and therapeutic interventions in disease management. Children with asthma are likely to discontinue inhaled corticosteroids (ICS), especially when symptoms are under control. We aimed to investigate the impact of ICS adherence in children whose symptoms were under control.The study is cohort study; 35 children with controlled asthma that had undergone 3 years of follow-up were included. Serum eosinophil count, serum total IgE (tIgE), and lung function (FEV1, FEV1/FVC, PEF, FEF20-75%, and PC20) were evaluated at the beginning and end of the follow-up.At baseline, patients in both the adherent and nonadherent groups were similar. After 3 years, the nonadherent group who had discontinued ICS had a decrease in FEV1 (P < .05), FEV1/FVC (P < .05), PEF (P < .05), and FEF20-75% (P < .05). The nonadherent group had no significant improvement in PC20 compared with their values at the beginning of the follow-up, whereas the adherent group had improvement in PC20. Furthermore, there was an increase in serum eosinophil (P < .001) and tIgE (P < .05) in the nonadherent compared with the adherent group.Despite good asthma control, airway hyperresponsiveness (AHR) was detected in a large proportion of children with asthma. ICS discontinuation affected lung function, serum eosinophil count, tIgE, and AHR. Adequate adherence is important in asthma management. The benefits of ICS and the influence of drug discontinuation despite good asthma control may encourage better adherence from patients. PMID- 28858096 TI - Fall prevalence in people with multiple sclerosis who use wheelchairs and scooters. AB - Falls are a serious health concern for persons with multiple sclerosis (PwMS) who use wheelchairs or scooters as their primary mode of mobility. Unfortunately, little is known about the fall prevalence and characteristics of this large segment of the multiple sclerosis (MS) community. The purpose of this study is to determine the prevalence and circumstances of falls in wheelchair and scooter users living with MS. Forty-four PwMS were recruited from research and medical centers in the United States and Asia. Participants completed a survey focusing on prevalence of falls, frequency of injurious falls, circumstances of the fall, and various quality of life indicators. A total of 44 individuals (32 females/11 males/1 not reported) aged 27 to 82 years (mean = 58 yrs) completed the survey. Seventy-five percent (n = 33) reported falling at least once in 6 months and 48% (n = 12) of those that fell sustained an injury. The majority (87.5%) of the falls occurred inside the home. Most individuals (76.7%; n = 33) reported concerns about falling and 65.9% (n = 29) limited their activities because of their concern of falling. Falls are prevalent in wheelchair and scooter users with MS. The observations highlight the need for interventions targeting this segment of the MS community. PMID- 28858097 TI - How frequent is osteogenesis imperfecta in patients with idiopathic osteoporosis?: Case reports. AB - RATIONALE: The term idiopathic osteoporosis itself is quite a non-specific disease label, which fails to address the etiological understanding. Bone mineral density alone is not a reliable parameter to detect patients at high risk of fracture. The diversity of the clinical phenotypes of discolored teeth, blueness of the sclera, back and joint pain, cardiovascular disease, Diabetes type II, hearing problems and a long list of orthopedic problems are have to be considered. PATIENTS CONCERNS: Our study has been designed in accordance with the clinical and radiological phenotype of eleven index cases with the provisional diagnosis of OI, which was followed by genotypic confirmation. This was followed by the invitation of siblings, parents, grandparents and other relatives to participate in the interviews, and to discuss the impact of the diagnosis. Proper collaboration with these families facilitated the process to identify other subjects with a history of fractures and other deformities/disabilities which were seemingly correlated to heritable connective tissue disorder. In total, 63 patients (27 children and 36 parents/grandparents and relatives) were enrolled in the study. Two groups of children were not included in our study. We excluded children with incomplete documentation and children who manifested de novo mutation. The term idiopathic osteoporosis (IOP) has been given to these families in other Institutes and was considered as a definite diagnosis. IOP was solely based on T scores, BMD and certain laboratory tests. Surprisingly, no single adult patient underwent clinical and or radiological phenotypic characterization. DIAGNOSES: A constellation of significant disease associations with osteoporotic fracture risk have been encountered. The index cases showed mutations in COL1A1 (17q21.31.q22) and COL1A2 (7q22.1), the genes encoding collagen type I. The phenotype/genotype confirmation in 11 children was the key factor to boost our research and to re-consult each family. Comprehensive clinical and radiological phenotypic documentation has been applied to most of other family subjects who principally received the diagnosis of IOP. INTERVENTIONS: All adult patients had normal serum calcium and only three patients showed an average of low serum phosphate of 0.7-0.61 mmol/l. Serumcrosslaps in six parents was in the average of (2.9-3.8 nM) and PTH levels were normal in all patients (the average showed 8.73 pg/ml). OUTCOMES: Our efforts to minimize and constrain the usage of the term idiopathic osteoporosis and to understand the sequence of pathological events that occurred in these families were emphasized. These efforts evolved into a remarkable and unique constellation of clinical findings. Strikingly, fracture represented a portion in a series of skeletal and extra-skeletal deformities and abnormalities which are all correlated to connective tissue disorder. This was achieved mainly through comprehensive phenotype/genotype confirmation, followed by scrutinizing the records of each family, clinical examination of the adults and revising the archives of our Hospitals and other Institutes. LESSONS: The sequence of diverse pathological events recorded within each family would be almost incomprehensible without a proper etiological understanding of the natural history of each child/family deformity that led to their occurrences. We wish to stress that, our current study is just an attempt to cover only a tiny fraction of the tip of the iceberg and to profoundly explore one of the most under estimated causes of idiopathic osteoporosis. PMID- 28858098 TI - Stepwise resection of the posterior ligamentous complex for stability of a thoracolumbar compression fracture: An in vitro biomechanical investigation. AB - To quantify the mechanical contribution of posterior ligamentous structures to the stability of thoracolumbar compression fractures.Twelve fresh human T11-L3 spinal specimens were harvested in this study. The 1/3 L1 vertebral body was resected in a wedged shape. After the preinjury had been created, the specimens were subjected to flexion-compression to create a fracture model. Resection of the ligaments was performed in a sequential manner from the bilateral facet capsule ligament (FCL), interspinous ligament, and supraspinous ligament (SSL) to the ligamentum flavum at the T12-L1 level. Then, for the intact specimen, fracture model, and ligament disruption steps, the range of motion (ROM) and neutral zone (NZ) of T12-L1 and L1-L2 were collected for each simulated movement.Sequential transection of the posterior ligamentous complex (PLC), ROM, and NZ were increased in all movements at the T12-L1 segment. In the flexion extension (FE), the ROM and NZ demonstrated significant increases after the fracture model and resection of SSL and LF. In lateral bending (LB), the ROM increased after the fracture and removal of the LF, while the NZ showed a slight increase. In axial rotation, the fracture model and removal of the LF resulted in a significant increase in the ROM, and the NZ showed a slight change after step reduction. For the L1-L2 segment, resection of the FCL led to an increased ROM in LB.With rupture of SSL or LF, the stability of the segment decreased significantly compared with the intact and fracture model, particularly in FE motion, the function of the PLC was considered to be incompetent. PMID- 28858099 TI - A novel classification of the anatomical variations of the first extensor compartment. AB - The presence of a septum in the first extensor compartment is closely associated with the pathophysiology of de Quervain disease, and affects the efficacy of corticosteroid injection and surgical release. This study aimed to examine the incidence and length of the first extensor compartment septum.Forty sides of the wrists in 20 cadavers were used. The presence of a septum in the first extensor compartment was examined. The septum length was recorded with the radial styloid process as the reference point.The anatomical variations of the first extensor compartment were classified into 3 types. Type I compartment was found in 7 sides in males (29.2%) versus 6 sides in females (37.5%, P = .733), type II was found in 6 sides in males (25%) versus 1 side in females (6.25%, P = .21), and type III was found in 11 sides in males (45.8%) versus 9 sides in females (56.25%, P = .56). There was no significant difference in the septum length between males and females (5.3 +/- 2.3 vs 4.8 +/- 1.1 mm, P = .54).The incidence of a septum in the first extensor compartment is approximately 50%. The mean septum length is 5 mm. Injection at 5 mm proximal to the radial styloid process has a great chance of delivering the steroids into both subcompartments. Exposure to 5 mm proximal to the radial styloid process can avoid the overlook of subcompartment and achieve adequate decompression of the first extensor compartment. PMID- 28858100 TI - Comparison of neuroendoscopic surgery and craniotomy for supratentorial hypertensive intracerebral hemorrhage: A meta-analysis. AB - BACKGROUND: In recent years, neuroendoscopy has been used as a method for treating intracerebral hemorrhages (ICHs). However, the efficacy and safety of neuroendoscopic surgery is still controversial compared with that of craniotomy. Our aim was to compare the outcomes of neuroendoscopic surgery and craniotomy in patients with supratentorial hypertensive ICH using a meta-analysis. METHODS: We searched on PubMed, EMBASE, and Cochrane Central Register of Controlled Trials to identify relevant studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Quality of eligible studies was evaluated and the related data were extracted by 2 reviewers independently. This study assessed clinical outcomes, evacuation rates, complications, operation time, and hospital stay for patients who underwent neuroendoscopic surgery (NE group) or craniotomy (craniotomy group). RESULTS: Meta-analysis included 1327 subjects from verified studies of acceptable quality. There was no significant heterogeneity between the included studies based on clinical outcomes. Compared with craniotomy, neuroendoscopic surgery significantly improved clinical outcomes in both randomized controlled studies (RCTs) group (relative risk: 0.62; 95% confidence interval [CI], 0.47-0.81, P < .001) and non-RCTs group (relative risk: 0.84; 95% CI: 0.75-0.95, P = .005); decreased the rate of death (relative risk: 0.53; 95% CI, 0.37-0.76, P < .001) in non-RCTs group but not in RCTs group (relative risk: 0.58; 95% CI, 0.26-1.29, P = .18); increased evacuation rates in non-RCTs group (standard mean differences: 0.75; 95% CI, 0.24-1.26, P = .004) and had a tendency of higher evacuation rates in RCTs group (standard mean differences: 1.34; 95% CI, 0.01-2.68, P = .05); reduced the total risk of complications in non-RCTs group (relative risk: 0.45; 95% CI, 0.25-0.83, P = .01) and RCTs group (relative risk: 0.37; 95% CI, 0.28-0.49, P < .001); reduced the operation time in non-RCTs group (standard mean differences: 3.26; 95% CI: 1.20 5.33, P < .001) and RCTs group (standard mean differences: 4.37; 95% CI: 3.32 5.41, P < .001). CONCLUSIONS: Our results suggested that the NE group showed better clinical outcomes than the craniotomy group for patients with supratentorial hypertensive ICH. Moreover, the patients who underwent neuroendoscopy had a higher evacuation rate, lower risk of complications, and shorter operation time compared with those that underwent a craniotomy. PMID- 28858101 TI - Usefulness of end-tidal carbon dioxide as an indicator of dehydration in pediatric emergency departments: A retrospective observational study. AB - Physician assessment of hydration status is one of the most important factors in the management of dehydration in the pediatric emergency department (ED). Overestimating dehydration may lead to overtreatment with intravenous fluids or unnecessary hospitalization, whereas underestimation may lead to delayed therapy and aggravation of symptoms. Various methods to estimate hydration status have been proposed, including use of physical findings, body weight, and laboratory results. These methods are subjective, invasive, or inappropriate for application in the ED. A few studies have investigated the use of end-tidal carbon dioxide (ETCO2) as an acidosis parameter in cases of gastroenteritis and diabetic ketoacidosis. We aimed to evaluate the usefulness of ETCO2 as an objective and noninvasive dehydration parameter for children.A retrospective observational study was conducted in the regional emergency center of a tertiary university hospital for a period of 1 year. We included patients from the ED whose primary diagnosis was acute gastroenteritis. Among these, we enrolled patients with recorded ETCO2 and bicarbonate concentration (HCO3) levels. We collected information of clinical characteristics, vital signs, clinical dehydration scale (CDS) scores, laboratory test results, and final disposition. Correlations between ETCO2 and HCO3 as well as CDS scores were analyzed.A total of 105 children were finally enrolled in the study. All participants underwent laboratory testing and were mildly to severely dehydrated, with mean serum HCO3 20.7 +/- 3.5 mmol/L. A total 95 (90.5%) patients had a CDS score <5, which is considered mild dehydration, and 10 (9.5%) patients had CDS >=5, considered moderate-to-severe dehydration. The mean ETCO2 level was 32.1 +/- 6.1 mmHg. Pearson correlation indicated a weak link between ETCO2 and HCO3 (correlation coefficient = 0.32), despite being statistically significant (P = .001). In addition, ETCO2 and CDS score showed a weak negative correlation (r = -0.20, P < .05).ETCO2 can be considered a simple, noninvasive parameter for identifying dehydration among patients in the pediatric ED. Though weak, ETCO2 showed a correlation with HCO3 level as well as CDS. In the future, a prospective study with a large number of pediatric patients is warranted. PMID- 28858102 TI - Prognostic value of KRAS codon 13 gene mutation for overall survival in colorectal cancer: Direct and indirect comparison meta-analysis. AB - BACKGROUND: The clinical significance of KRAS codon 13 mutation in patients with colorectal cancer (CRC) remains controversial. A systematic review and meta analysis is necessary for a more precise estimation of the predictive role of KRAS codon 13 mutations in CRC patients. METHODS: We performed a systematic search using the MEDLINE, EMBASE, and Cochrane library databases from January 2000 to November 2016. The prognostic value of KRAS codon 13 mutation for overall survival (OS) was investigated by measuring the hazard ratio (HR) and 95% confidence interval (CI). Data were analyzed with Review Manager Version 5.3 and the Canadian Agency for Drugs and Technologies in Health software. RESULTS: OS in CRC patients with KRAS codon 13 mutation was worse than that in CRC patients with KRAS wild-type (pooled HR = 1.37, 95% CI: 1.03-1.81, P = .03). Subgroup analysis of studies of enrolled CRC patients treated with antiepidermal growth factor receptor (EGFR) therapy showed no significant difference in OS associated with KRAS codon 13 mutation in comparison to KRAS wild-type (pooled HR = 1.57, 95% CI: 0.98-2.51, P = .06). In the indirect comparison, no statistically significant association was observed between codon 12 and 13 mutations for OS in CRC patients (pooled HR = 0.88, 95% CI: 0.65-1.20, P = .43). CONCLUSION: The current meta analysis suggests that Codon 13 mutation of KRAS gene seems to correlate with the OS of patients with CRC, but has similar OS to those with KRAS wild-type in patients receiving anti-EGFR therapy. No difference was detected in the OS of CRC patients with codon 13 mutation versus codon 12 mutation. PMID- 28858103 TI - Efficacy of nanoparticle albumin-bound paclitaxel regimens for relapsed small cell lung cancer: A retrospective analysis. AB - Although small cell lung cancer (SCLC) is initially sensitive to chemotherapy, it recurs in most cases. Standard regimens for salvage chemotherapy have not been established, and the prognosis of relapsed SCLC remains poor. In the present study, we investigated the clinical efficacy and safety of nanoparticle albumin bound paclitaxel (nab-paclitaxel) regimens for the treatment of relapsed SCLC.In this retrospective multicenter analysis, 14 patients (3 women and 11 men; median age 71 years) with relapsed SCLC received nab-paclitaxel alone or in combination with carboplatin between February 2013 and July 2014. The safety and efficacy of the regimens were evaluated.The response rates, disease control rates, and median overall survival for the total patient population were 36%, 64%, and 7.8 months, respectively. Response rates, disease control rates, and the median overall survival were 11%, 44%, and 4 months, respectively, in the monotherapy group; and 80%, 100%, and 10.6 months, respectively, in the combination therapy group. The most common adverse events were hematological toxicities such as neutropenia and anemia. Severe neutropenia appeared in some patients, although it was resolved by treatment in all. The most common nonhematological toxicity was anorexia (64%), followed by neurotoxicity and constipation. All nonhematological toxicities were mild and manageable.Our results suggest that chemotherapy with nab-paclitaxel regimens for relapsed SCLC exhibits moderate clinical efficacy and is well tolerated. Further clinical trials in relapsed SCLC patients are warranted. PMID- 28858104 TI - Oral and maxillofacial non-Hodgkin lymphomas: Case report with review of literature. AB - RATIONALE: Lymphomas take up about 14% of all head-neck malignancies, out of which 97% are non-Hodgkin lymphomas (NHL). The clinical courses, treatment responses, and prognoses of NHLs vary with different subtypes and anatomic sites. In the Chinese population (including the Taiwanese), head-neck NHLs are often seen with the tonsils, nasal cavity, nasal sinus, and the nasopharynx. However, oral NHLs are relatively rare. Delay of diagnosis is also often seen in clinical practice. Thus, we present 4 cases with delayed diagnosis of oral maxillofacial NHLs and discuss their clinical manifestations so as to draw a clue that can remind the doctors to take biopsies in time. PATIENT CONCERNS: Four cases, including 3 males and 1 female aged between 43 and 70 years old with oral lesions (ulcerations and/or masses) and accompanying cervical lymphadenopathies and/or skin erythemas presented to the Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China from January 2010 to January 2015. DIAGNOSES: The diagnoses of non-Hodgkin lymphomas were made by pathology, including nasal type extranodal NK/T-cell lymphoma, mycosis fungoides, subcutaneous panniculitis-like T-cell lymphoma, and extranodal marginal B-cell lymphoma of mucosa-associated lymphatic tissue. Their clinical courses until confirmed diagnosis varied between 2 months and 1 year and the follow-up/survival time from diagnosis ranged between 2 and 24 months. None of the biopsies was taken at the patients' initial medical consultations. INTERVENTIONS: Cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone (CHOP) and Rituximab, CHOP (R-CHOP) regimens were given to 2 (Cases 1 and 4) and 1 patient (Case 3), respectively. One patient refused further treatment. OUTCOMES: Two patients, including the one who refused treatment, died at 2-2.5 months from diagnosis. The other two patients survived until their last follow ups at 13 and 24 months from diagnosis, respectively. LESSONS: Oral lesions with aggressive growth patterns, multiple lymphadenopathies, and comorbid systemic skin lesions, elevated serum lactate dehydrogenase and poor response to medical therapies should warn the doctors of the possibility of malignancy and the necessity of biopsy. Excisional biopsy without sacrificing organs or functions should be preserved for patients whose pathological diagnoses cannot be established through aspiration or punch biopsy. PMID- 28858105 TI - Risk factors of periodontal disease in maintenance hemodialysis patients. AB - To explore the characteristics and relevant risk factors of periodontal disease (PD) among hemodialysis patients.Uremic patients on maintenance hemodialysis from November 2015 to March 2016 were retrospectively reviewed. Patients were divided into a PD group and a non-PD group. Demographic and laboratory data were collected and analyzed.In all, 136 uremic patients (79 males and 57 females, aged 50.8 +/- 15.3 years) on maintenance hemodialysis were included in this study. The incidence of PD increased with age. Hemodialysis patients most likely developed PD if they were male, smokers, or diabetic (P = .009, <.001, and <.001, respectively). Patients brushing their teeth twice daily had significantly less chance of developing PD as compared with those only brushing once daily (P < .001). Hemodialysis patients in the PD group had significantly higher levels of total cholesterol, high-sensitivity C-reactive protein, fasting blood glucose, and peripheral white blood cell counts, compared with the non-PD group (all P < .001). Logistic regression analysis revealed that diabetes, total cholesterol, high-sensitivity C-reactive protein, and peripheral white blood cell count were independent risk factors for developing PD, whereas teeth brushing twice daily and serum calcium were favorable factors for maintenance hemodialysis patients against PD.Identification of risk factors provides a theoretical basis for prevention and improvement of PD among maintenance hemodialysis patients. PMID- 28858106 TI - Robot-assisted internal mammary lymph chain excision for breast cancer: A case report. AB - RATIONALE: Understanding the status of internal mammary lymph nodes of breast cancer is critical in the accurate staging of breast cancer and the development of accurate therapeutic regimen for selected patients. Current techniques for dissection of internal mammary lymph node biopsy involve endoscopic or Traditional thoracic surgery, An important drawback of the current techniques is the great trauma caused by them. PATIENT CONCERNS: Da Vinci robotic surgery system (Intuitive Surgical Inc. Sunnyvale, CA) was used to perform the internal mammary lymph chain excision for a breast cancer patient with left internal mammary lymph node metastasis. DIAGNOSES: Positron emission tomography-computed tomography examination and Ultrasonography examination. INTERVENTIONS: In this paper, we introduce a Robot-assisted technique for dissection of internal mammary lymph node biopsy with only 3 small trocar ports. This technique reduces the incision size and considerably reduce the trauma. OUTCOMES: The operation lasted a duration of 1.5 hours. The operation was carried out smoothly with removal of 9 internal mammary lymph nodes in total. The amount of intra operative bleeding was less than 10 ml. The patient's postoperative recovery was fast. 11-month postoperative follow-up showed that the patient recovered well after surgery, no local recurrence or distant metastasis was found, and no obvious discomfort was reported. LESSONS: Robot-assisted excision of internal mammary lymph chain in breast cancer is a safe, effective and simple operation with minimal invasion. PMID- 28858107 TI - Comparison of the diagnostic accuracy of three current guidelines for the evaluation of asymptomatic pancreatic cystic neoplasms. AB - Asymptomatic pancreatic cysts are a common clinical problem but only a minority of these cases progress to cancer. Our aim was to compare the accuracy to detect malignancy of the 2015 American Gastroenterological Association (AGA), the 2012 International Consensus/Fukuoka (Fukuoka guidelines [FG]), and the 2010 American College of Radiology (ACR) guidelines.We conducted a retrospective study at 3 referral centers for all patients who underwent resection for an asymptomatic pancreatic cyst between January 2008 and December 2013. We compared the accuracy of 3 guidelines in predicting high-grade dysplasia (HGD) or cancer in resected cysts. We performed logistic regression analyses to examine the association between cyst features and risk of HGD or cancer.A total of 269 patients met inclusion criteria. A total of 228 (84.8%) had a benign diagnosis or low-grade dysplasia on surgical pathology, and 41 patients (15.2%) had either HGD (n = 14) or invasive cancer (n = 27). Of the 41 patients with HGD or cancer on resection, only 3 patients would have met the AGA guideline's indications for resection based on the preoperative cyst characteristics, whereas 30/41 patients would have met the FG criteria for resection and 22/41 patients met the ACR criteria. The sensitivity, specificity, positive predictive value, negative predictive value of HGD, and/or cancer of the AGA guidelines were 7.3%, 88.2%, 10%, and 84.1%, compared to 73.2%, 45.6%, 19.5%, and 90.4% for the FG and 53.7%, 61%, 19.8%, and 88% for the ACR guidelines. In multivariable analysis, cyst size >3 cm, compared to <=3 cm, (odds ratio [OR] = 2.08, 95% confidence interval [CI] = 1.11, 4.2) and each year increase in age (OR = 1.07, 95% CI = 1.03, 1.11) were positively associated with risk of HGD or cancer on resection.In patients with asymptomatic branch duct-intraductal papillary mucinous neoplasms or mucinous cystic neoplasms who underwent resection, the prevalence rate of HGD or cancer was 15.2%. Using the 2015 AGA criteria for resection would have missed 92.6% of patients with HGD or cancer. The more "inclusive" FG and ACR had a higher sensitivity for HGD or cancer but lower specificity. Given the current deficiencies of these guidelines, it will be important to determine the acceptable rate of false-positives in order to prevent a single true-positive. PMID- 28858108 TI - Effect of bone mineral density on lumbar discs in young adults: A case-control study. AB - Bone mineral density (BMD) might be a risk factor for lumbar disc herniation (LDH) in young adults, but there is not enough data concerning this effect. Several studies have been performed on elderly and osteoporotic patients. Thus, we aimed to investigate the effect of BMD on the etiopathogenesis of LDH in young adults.One hundred patients (mean age: 38.45 +/- 8.92 years; 50 men and 50 women) were enrolled this case-control study and classified into 2 groups, as follows. The case group (G-I) included 50 patients with symptomatic LDH who were hospitalized in the Physical Medicine and Rehabilitation Clinic, and the control group (G-II) included 50 patients with lower back pain but no finding of LDH detected using magnetic resonance imaging. Patients in the G-II were recruited among those admitted to the outpatient clinic at the time of the study, and whose age and sex were matched to those of the study group. Women in menopause were excluded from the study. BMD analysis by dual energy x-ray absorptiometry was performed in both groups.The mean values of the femur neck and lumbar spine BMD were 1.02 +/- 0.13 and 1.19 +/- 0.14 g/cm, respectively. There was no statistically significant relationship between BMD and LDH in this population.This result may mean that in a normal range, BMD does not exert a compressive load on the lumbar discs in young adults and therefore may not lead to LDH by this mechanism and the load. PMID- 28858109 TI - The effect of age and speed on foot and ankle kinematics assessed using a 4 segment foot model. AB - BACKGROUND: The effects of age and speed on foot and ankle kinematics in gait studies using foot models are not fully understood, whereas this can have significant influence. We analyzed these variables with the 4-segment Oxford foot model. METHODS: Twenty-one healthy subjects (aged 20-65 years) were recruited for gait analysis. The effect of speed on foot and ankle kinematics was assessed by comparing results during slow walking and fast walking. To assess the effect of age, a group of 13 healthy young adults (aged 20-24 years) were compared with a group of 8 older adults (aged 53-65 years). Also, the interaction between age and speed was analyzed. RESULTS: Regarding speed, there was a significant difference between forefoot/hindfoot motion in the sagittal plane (flexion/extension) during both loading- and push-off phase (P = .004, P < .001). Between hindfoot/tibia, there was a significant difference for all parameters except for motion in the sagittal plane (flexion/extension) during push-off phase (P = .5). Age did not significantly influence kinematics. There was no interaction between age and speed. CONCLUSION: Our analysis found that speed significantly influenced the kinematic outcome parameters. This was more pronounced in the ankle joint. In contrast, no significant differences were found between younger and older healthy subjects. PMID- 28858110 TI - Predictors of lymph nodes posterior to the right recurrent laryngeal nerve metastasis in patients with papillary thyroid carcinoma: A retrospective study. AB - The aim of this study was to identify the risk factors associated with lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) metastasis in patients with papillary thyroid carcinoma (PTC).A total of 81 PTC patients who underwent total/near-total thyroidectomy with LN-prRLN dissection in the Department of General Surgery at Guangdong General Hospital between June 2015 and August 2016 were assessed retrospectively. The relations of LN-prRLN metastasis with clinicopathologic characteristics of PTC were analyzed by univariate and multivariate logistic regression.The incidence of LN-prRLN metastasis in patients with PTC was 51.9% (42 of 81 cases). Univariate analysis showed that lateral LN metastasis (P = .005), VIa central LN metastasis (P = .000), pathologic tumor size (P = .000), capsular invasion (P = .002), and extrathyroidal invasion (P = .018) (P < .05) were significantly associated with the increased incidence of LN prRLN metastasis in PTC. No significant correlations were found between LN-prRLN metastasis and other variables such as gender (P = .056), age (P = .448), clinical N stage (cN) (P = .063), tumor location (P = .336), tumor site (P = .909), right tumor existence (P = .793), and multifocality (P = .381). Multivariate logistic regression analysis revealed that VIa central LN metastasis (OR: 4.490, P = .027) was independent risk factors of LN-prRLN metastasis in patients with PTC.LN-prRLN metastasis is often indentified in patients with PTC. VIa central LN metastasis is an independent predictors of LN-prRLN metastasis, which allow for selective LN-prRLN dissection in patients with PTC. PMID- 28858111 TI - Association of polymorphisms in TLR2 and TLR4 with asthma risk: An update meta analysis. AB - BACKGROUND: Several epidemiological studies have focused on the association between polymorphisms in toll-like receptors (TLRs) and asthma. However, the results remained inconclusive. METHODS: We systematically reviewed the database of PubMed, EMBASE, Web of Science, CNKI, and Google scholar for all related articles on TLR polymorphisms and asthma. We used the software STATA 12.0 to conduct the meta-analysis. The heterogeneity and publication bias were examined, respectively. RESULTS: Eighteen studies consisting of 3538 asthma cases and 4090 controls were selected into the meta-analysis. The pooled odds ratios (ORs) show that rs3804099 was associated with asthma in dominant model (OR = 1.51, 95% CI = 1.17-1.96, P = .002), and rs4986791 was associated with asthma in additive model (OR = 0.81, 95% CI = 0.64-1.02, P = .07) and dominant model (OR = 0.76, 95% CI = 0.60-0.97, P = .025). CONCLUSION: The combined results show that rs3804099 in TLR2 and rs4986791 in TLR4 were significantly associated with asthma risk. Polymorphisms in TLRs play important roles in asthma. PMID- 28858112 TI - Prescription of Chinese herbal products is associated with a decreased risk of invasive breast cancer. AB - The finding of a decrease in endometrial cancer incidence among breast cancer survivors following the use of Chinese herbal products (CHPs) has led to speculation that CHPs might play a role in breast cancer prevention.This study provides an overview of breast cancer incidence, comparing CHP users with those who do not use traditional Chinese medicine (TCM), referred to as non-TCM users. The results can provide information to clinicians for counseling women about the preventive use of TCM.A total of 184,386 women (20-79 years of age) were recruited from a nationwide 1-million-person representative sample of those covered by National Health Insurance in Taiwan and were followed from 1999 to 2012. A total of 1853 incidents of invasive breast cancer were diagnosed. The person-year approach with the Poisson assumption was used to estimate the incidence density rate. The age-specific hazard ratios of breast cancer in relation to either CHP or siwutang (SWT) use were calculated with multivariate Cox proportional hazard regression.More than 78% of patients had used a CHP at some point previously. The overall incidence density rate of breast cancer for non-TCM users was estimated at 1.73 per 10,000 patient-years. The corresponding values for CHP and SWT users were lower than those of the non-TCM group (CHP group = 0.85; SWT group = 0.63 per 10,000 patient-years). The covariate adjusted HRs for breast cancer were 0.57 (95% confidence interval [CI] 0.50-0.65) and 0.36 (95% CI 0.28-0.46) in women using CHPs and SWT, respectively. The findings were confirmed using propensity score matching.Consumption of CHPs reduces the incidence of invasive breast cancer. Although the mechanism of action of these products is unclear, their use as a preventive agent for breast cancer is appropriate for many women at an increased risk of breast cancer. PMID- 28858113 TI - Extraction of a dual-chamber pacemaker and inserting of a new automatic implantable cardioverter defibrillator: The easy procedure almost became catastrophic: a case report. AB - BACKGROUND: The cardiovascular illnesses are in the middle of the foremost reasons of death around the world. Deaths in Europe, from sudden cardiac death (SCD), reach nearby 700,000 individuals every year. In the United States, statistics point to the existence of nearly 1 million yearly deaths from cardiovascular sickness, of which 330,000 are the consequence of abrupt. The significance of automatic implantable cardioverter-defibrillator (ICD) has been proven in subjects with preceding myocardial infarction and stark systolic left ventricular dysfunction (secondary prevention). CASE PRESENTATION: In this case, we describe a female patient, 94 years old, with a dual-chamber pacemaker since 2014, normal functioning, and controlled hypertension. The patient was in use of bisoprolol 10 mg daily, hydrochlorothiazide 25 mg daily, and candesartan cilexetil 16 mg daily. She presented 2 episodes of syncope associated with the high ventricular rate (HVR), which characterizes sustained ventricular tachycardia (SVT) due to its instability, besides 1 episode of cardiorespiratory arrest. During an attempt to position the active monocoil shock lead in the right ventricle, there was perforation of the upper posterolateral wall of the right atrium, transfixing the pericardium and constituting a pericardial-pleural fistula with hemothorax formation in the right hemithorax. We chose to remove the electrodes and suture the left pocket. There was no cardiac tamponade or pericardial effusion, verified by a pericardial puncture. Thoracic drainage was introduced into the right hemithorax, and 3 L of blood were drained acutely with volume replacement and hemotransfusion. We maintained thoracic drainage in water seal. The ICD was implanted on the right side. CONCLUSION: So, in this case, we reported a rare complication during pacemakers or ICD implantation that is the pericardial-pleural fistula with hemothorax formation in the contralateral hemithorax. Despite the patient's advanced age, we had the dexterity and luck to save her life. PMID- 28858114 TI - Comparison of definitive chemoradiotherapy and radiotherapy alone in patients older than 75 years with locally advanced esophageal carcinoma: A retrospective cohort study. AB - The aim of this study was to evaluate the efficacy and acute toxicity of definitive chemoradiotherapy (CRT) and radiotherapy (RT) alone as initial treatment in patients aged 75 years and older with locally advanced esophageal squamous cell carcinoma (ESCC) who are not eligible for surgery.Between February 2009 and February 2015, 122 patients older than 75 years with locally advanced ESCC were retrospectively reviewed, in whom 52 patients allocated to the CRT group were treated with at least 2 cycles of platinum and 5-fluorouracil, 70 patients allocated to the RT group were treated with RT alone, all patients were received a total radiation dose of 54-66 Gy, with 1.8 or 2-Gy/fraction. Response rate (RR), progression-free survival (PFS), overall survival (OS), and acute toxicities were compared between the 2 different treatment groups.In the CRT group, the median PFS and OS were 15.3 and 24.6 months, while 10.6 and 19.4 months in the RT group (P = .008 and P = .018). The 1-year survival rates of the 2 groups were 78.8% versus 64.3% (P = .081), and the 2-year survival rates were 48.1% and 30.0% (P = .042), respectively. The objective RR was 55.8% in the CRT group with 18 complete response (CR) and 18.6% in the RT group with 13 CR. Acute toxicity in the CRT group was higher than in the RT group, especially the grade 3 to 4 acute toxicities.Compared with RT alone, definitive CRT in the treatment of locally advanced ESCC can prolong the survival time in elderly patients. Definitive CRT should be considered the first-treatment choice for elderly patients like the younger patients who are not eligible for surgery. PMID- 28858115 TI - Safety of catheter-directed thrombolysis for the treatment of acute lower extremity deep vein thrombosis: A systematic review and meta-analysis. AB - BACKGROUND: Despite established guidelines, catheter-directed thrombolysis (CDT) for the management of acute lower extremity deep vein thrombosis (DVT) should not be overstated because the risks of CDT are uncertain. We performed a meta analysis to comprehensively and quantitatively evaluate the safety of CDT for patients with acute lower extremity DVT. METHODS: Relevant databases, including PubMed, Embase, Cochrane, Ovid MEDLINE, and Scopus, were searched up to January 2017. The inclusion criteria were applied to select patients with acute lower extremity DVT treated by CDT or compared CDT with anticoagulation. In case series studies, the pooled estimates of safety outcomes for complications, pulmonary embolism (PE), and mortality were calculated across studies. In studies comparing CDT with anticoagulation, summary odds ratios (ORs) were calculated. RESULTS: Of the 1696 citations identified, 24 studies (6 comparing CDT with anticoagulation and 18 case series) including 9157 patients met the eligibility criteria. In the case series studies, the pooled risks of major, minor, and total complications were 0.03 (95% confidence interval [CI]: 0.02-0.04), 0.07 (95% CI: 0.05-0.08), and 0.09 (95% CI: 0.08-0.11), respectively; other pooled risk results were 0.00 for PE (95% CI: 0.00-0.01) and 0.07 for mortality (95% CI: 0.03-0.11). Our meta analysis of 6 studies comparing the risk of complications and PE related to CDT with those related to anticoagulation showed that CDT was associated with an increased risk of complications (OR = 4.36; 95% CI: 2.94-6.47) and PE (OR = 1.57; 95% CI: 1.37-1.79). CONCLUSION: Acute lower extremity DVT patients receiving CDT are associated with a low risk of complications. However, compared with anticoagulation, CDT is associated with a higher risk of complications and PE. Rare mortality related to thrombolytic therapy was reported. More evidence should be accumulated to prove the safety of CDT. PMID- 28858116 TI - Risk factors of mortality in bloodstream infections caused by Klebsiella pneumonia: A single-center retrospective study in China. AB - The prevalence of Klebsiella pneumonia bloodstream infections (KP-BSIs) is increasing worldwide. Few study reports focus on the KP-BSIs published in Mainland China over the previous years. This study aimed to describe the risk factors of mortality from KP-BSIs.A retrospective study was conducted in a teaching hospital in Shanghai, China, for a period of 4 years. Risk factors related to the patient mortality were analyzed using the binary logistic regression model.Of 104 patients with KP-BSIs, the overall 30-day mortality rate was 25%. The logistic regression analysis revealed that thrombocytopenia (TB) (odds ratio [OR]: 1.007, 95% confidence interval [CI]: 1.002-1.013), pancreaticobiliary tract (PBT) (OR: 4.059, 95% CI: 1.398-11.78), and intra abdominal infection (OR: 6.816, 95% CI: 1.806-25.716) were powerful risk factors leading to the mortality associated with KP-BSIs. Although prior antibiotic exposure, inappropriate empirical antibiotics, and inappropriate definitive antibiotics were not associated with mortality, multidrug-resistant (MDR) of KP BSIs in the present study was high in both survivors and nonsurvivors (67.9% and 88.5%, respectively).TB, PBT, and intra-abdominal infection caused significant mortality rates increase in KP-BSIs during the study period. PMID- 28858117 TI - Exacerbation of primary intestinal lymphangiectasia during late pregnancy and recovery after delivery: A case report and literature review. AB - RATIONALE: Primary intestinal lymphangiectasia (PIL) is a rare disease characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen. Main clinical features include intermittent diarrhea, hypoproteinemia. Scattered case reports suggested that PIL is compatible to pregnancy, but with increased complications. PATIENT CONCERNS: A 34-year-old woman with endoscopically diagnosed PIL presented to antenatal our clinic at 10 weeks into gestation. She reported strict adherence to low-fat/high-protein diet with medium-chain triglycerides (MCTs) supplementation. She was general well except for moderate edema and hypoalbuminemia. At 33 weeks, she developed diarrhea, nausea, and vomiting, with decreased fetal movements. One week later, she had an asthma attack. Nonstress test showed frequent variable deceleration. DIAGNOSES: The diagnosis of PIL was established endoscopically 8 years earlier. INTERVENTIONS: Hypoalbuminemia was corrected with intravenous albumin administration. She also received corticosteroid therapy to promote fetal lung maturation in anticipation to early termination of the pregnancy. OUTCOMES: A cesarean section was carried out at 34 weeks due to fetal distress. The baby girl was apparently healthy: weighing 2160 g, with an Apgar score of 9 at both 1 and 5 minutes. Symptoms dissipated rapidly after the delivery. The last follow-up visit at 15 months was unremarkable for both the mother and infant. LESSONS: PIL could be compatible with pregnancy, but requires strict adherence to dietary treatment, proper management of the symptoms (e.g., hypoalbuminemia), particularly during late gestation. PMID- 28858118 TI - An evaluation of medication appropriateness and frailty among residents of aged care homes in Malaysia: A cross-sectional study. AB - Aging is significantly associated with the development of comorbid chronic conditions. These conditions indicate the use of multiple medications, and are often warranted by clinical guidelines. The aim of the present study was to evaluate medication appropriateness and frailty among Malaysian aged care home residents with chronic disease. The participants were 202 elderly (>=65 years) individuals, a cross-sectional sample from 17 aged care homes. After ethics approval, each participant was interviewed to collect data on sociodemographics, frailty status (Groningen Frailty Indicator [GFI]), medication appropriateness (Medication Appropriateness Index (MAI), the 2015 Beers' criteria (Potentially Inappropriate Medication [PIM]), and 2014 STOPP criteria (Potentially Inappropriate Prescribing [PIP]). The findings show that 81% (n = 164) and 42% (n = 85) were taking medications for cardiovascular and central nervous system related conditions, respectively, and 34% were using medications for diabetes (n = 69). Each participant had a mean of 2.9 +/- 1.5 chronic diseases, with an average GFI score of 6.4 +/- 3.6. More than three-quarters of the participants (76%) were frail and polypharmacy was a factor in nearly half (48%); 41% and 36% were prescribed at least one PIP and PIM, respectively, whereas the average MAI score was 0.6 (range: 0-6). The number of medications used per participant correlated significantly and positively (0.21, P = .002) with GFI score. These findings reinforce the need for participants of aged care homes to receive periodic medication review aimed at minimizing morbidity associated with inappropriate pharmacotherapy. PMID- 28858119 TI - Flatfoot in the contralateral foot in patients with unilateral idiopathic clubfoot treated using the foot abduction brace. AB - While the foot abduction brace (FAB) plays an important role in the Ponseti method, the true function of the FAB in the treatment of idiopathic clubfoot remains unknown. In our clinical experience, we have noted that many patients with unilateral idiopathic clubfoot developed significant flatfoot in the contralateral foot during brace treatment. The purpose of this study was to investigate the natural history of the contralateral foot development during and after brace wear. We also discuss the effect of the FAB on the contralateral foot.We retrospectively reviewed 21 contralateral feet of 21 patients with unilateral idiopathic clubfoot who were treated using the Ponseti method and were conservatively followed up until the FAB was taken off (6 years of age or older). We evaluated flatfoot indicators of the contralateral foot on standing radiographs during and after brace wear and compared them against the normal reference ranges. We also evaluated the changes in the flatfoot indicators of the contralateral foot during and after brace wear.Although there was a significant difference in the flatfoot indicators between the contralateral foot and normal reference ranges during brace wear, there was no significant difference in the flatfoot indicators after brace wear. While there was no significant improvement in flatfoot indicators of the contralateral foot during brace wear, there was a significant improvement or a trend to improve after brace wear. There was no significant correlation between the contralateral flatfoot and original joint laxity.Significant flatfoot deformity was observed in the contralateral foot during brace wear. The contralateral flatfoot persisted during brace wear and improved to within normal reference ranges after brace wear. Our findings suggest that the FAB may influence the development of the contralateral foot, leading to the flatfoot. PMID- 28858120 TI - Effect of extracorporeal shock-wave therapy for treating patients with chronic rotator cuff tendonitis. AB - BACKGROUND: This study aimed to determine the efficacy and safety of extracorporeal shock-wave therapy (ESWT) for treating patients with chronic rotator cuff tendonitis (CRCT). METHODS: In this study, 84 patients with CRCT were randomly divided into intervention and control groups in a ratio of 1:1. Patients in the intervention group received ESWT, whereas those in the control group received placebo. The primary outcome was measured by Numeric Rating Scale (NRS). The secondary outcomes were measured by the Constant-Murley score (CMS), simple shoulder test (SST) score, and adverse events. RESULTS: Compared with placebo, ESWT showed greater efficacy in shoulder pain relief with regard to NRS score and shoulder function as measured by using CMS and SST score at 4 weeks (P < .05) and 8 weeks (P < .01) after treatment. However, no adverse events occurred in both groups. CONCLUSION: ESWT was efficacious and safe for treating patients with CRCT. PMID- 28858121 TI - Prognostic value of metabolic variables of [18F]FDG PET/CT in surgically resected stage I lung adenocarcinoma. AB - The objective of this study was to assess the prognostic value of metabolic tumor burden measured by positron emission tomography/computed tomography (PET/CT) in patients with stage I lung adenocarcinoma.We reviewed 127 consecutive patients with pathologically proven stage I lung adenocarcinoma who underwent pretreatment [18F]FDG PET/CT scans in our hospital from 2005 June to 2012 June. The maximum, mean, and peak standardized uptake value (SUVmax, SUVmean, and SUVpeak), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and computed tomography volume (CTV) were measured. The Kaplan-Meier and Cox proportional hazards model were used with age, gender, TNM stage, clinical stage, histological grade, nodule type, tumor size, and metabolic parameters to predict progression free survival (PFS). The cut-off point was determined through receiver-operating characteristic curve.In univariate analysis, the histological grade, nodule type, diameter (cut-off value of 2.0 cm), CTV (6.56 cm), SUVmax (3.25 g/mL), SUVmean (1.58 g/mL), SUVpeak (1.84 g/mL), MTV (4.80 cm), and TLG (10.40) were significantly associated with PFS (all P value < .05). Patients with poorly differentiated adenocarcinoma, solid nodule type, large size, and high metabolic tumor burden were associated with poor prognosis. In multivariate analysis, only histological grade was independent prognostic factors for progression with a P value of .005 (RR, 0.355; 95% CI, 0.173-0.728). Among 5 PET/CT metabolic parameters, only MTV was independent prognostic factors for progression with a P value of .031 (RR, 1.118; 95% CI, 1.010-1.237).Histological grade was an independent predictor for progression in patients with stage I lung adenocarcinoma. Among 5 PET/CT metabolic parameters, only MTV was an independent predictor for progression. PMID- 28858122 TI - Higher body weight and distant metastasis are associated with higher radiation exposure to the household environment from patients with thyroid cancer after radioactive iodine therapy. AB - There were insufficient data regarding radiation exposure to the household environment from patients with thyroid cancer who received radioactive iodine (RAI) therapy in Asia; we therefore performed the present study at the Chang Gung Memorial Hospital in Keelung, Taiwan.Patients with papillary or follicular thyroid cancer who received 3.7 GBq (100 mCi) RAI were enrolled in this prospective hospital-based study. The enrolled patients were asked to place a thermoluminescent dosimeter in the living room, bedroom, and bathroom of their houses for 4 weeks to measure radiation exposure to the household environment.A total of 43 patients (18 men and 25 women; mean age 51 +/- 13 years) who received 3.7 GBq (100 mCi) RAI completed the study. The mean value of total radiation exposure over 4 weeks from the patients to the bedroom, bathroom, and living room (eliminating the background radiation factor) was 0.446 +/- 0.304 (0.088-1.382) mSv. We divided the patients into 2 groups: those with more than and less than the mean value of total radiation exposure to the bedroom, bathroom, and living room. Factors associated with the higher amount of radiation exposure from the patients to the household environment were patient body weight (P = .025, univariate analysis; P = .037, multivariate analysis, odds ratio [95% confidence interval] 1.067 [1.004-1.134]) and distant metastases based on I post-therapy scanning (P = .041, univariate analysis; P = .058, multivariate analysis, odds ratio [95% confidence interval] 6.453 [0.938-44.369]); age, sex, body mass index, renal function, serum stimulated thyroglobulin level, and recombinant human thyroid-stimulating hormone use were not associated with the amount of radiation exposure from the patients to the household environment.Higher body weight and distant metastases may be the best predictors for higher radiation exposure to the household environment from patients with thyroid cancer after RAI therapy. PMID- 28858123 TI - Diabetes mellitus carries a risk of esophageal cancer: A meta-analysis. AB - BACKGROUND: Many studies have showed that diabetes mellitus (DM) might be a risk factor for certain types of cancers. However, there are still inconsistent results on the effects of DM on the risk of esophageal cancer (EC). The objective of this study is to investigate the association and to quantify the correlation between DM and EC by a meta-analysis. METHODS: The initial search identified 339 articles. Those publications that did not report the exact number of EC cases were removed. Finally, 13 meaningful studies were extracted from the databases of PubMed, MEDLINE, and Web of Science. All pooled analyses of risk ratios (RRs) and 95% confidence intervals (CIs) were assessed by a random-effect or fixed-effect model. Subgroup analysis was implemented on the basis of the sex or ethnicity. I value was used to assess heterogeneity, and funnel plot analysis was for publication bias. RESULTS: The result showed that there was a positive correlation between type 2 diabetes mellitus (T2DM) and EC risk (RR = 1.28, 95% CI: 1.12-1.47, P < .001). Subgroup analysis based on gender showed that male was an important risk factor for EC (RR = 1.53, 95% CI: 1.44-1.62, P < .001), but female was not (RR = 1.23, 95% CI: 0.41-3.69, P = .71). In addition, subgroup analysis based on ethnicity showed that DM was significantly correlated to EC in North America subjects (RR = 1.39, 95% CI: 1.31-1.47, P < .001), and in Europe subjects (RR = 1.37, 95% CI: 1.02-1.83, P = .04), whereas no correlation was found in Asian subjects (RR = 0.98, 95% CI: 0.50-1.95, P = .96). Furthermore, DM had a correlation to an increased risk of esophageal adenocarcinoma (EAC) (RR = 1.43, 95% CI: 1.35-1.51, P < .001). CONCLUSION: This meta-analysis indicates that DM is positively correlated to EC. However, the results should be interpreted with caution because of the limitations on potential clinical confounding factors in each study included in this meta-analysis. PMID- 28858124 TI - An injury mortality prediction based on the anatomic injury scale. AB - To determine whether the injury mortality prediction (IMP) statistically outperforms the trauma mortality prediction model (TMPM) as a predictor of mortality.The TMPM is currently the best trauma score method, which is based on the anatomic injury. Its ability of mortality prediction is superior to the injury severity score (ISS) and to the new injury severity score (NISS). However, despite its statistical significance, the predictive power of TMPM needs to be further improved.Retrospective cohort study is based on the data of 1,148,359 injured patients in the National Trauma Data Bank hospitalized from 2010 to 2011. Sixty percent of the data was used to derive an empiric measure of severity of different Abbreviated Injury Scale predot codes by taking the weighted average death probabilities of trauma patients. Twenty percent of the data was used to create computing method of the IMP model. The remaining 20% of the data was used to evaluate the statistical performance of IMP and then be compared with the TMPM and the single worst injury by examining area under the receiver operating characteristic curve (ROC), the Hosmer-Lemeshow (HL) statistic, and the Akaike information criterion.IMP exhibits significantly both better discrimination (ROC IMP, 0.903 [0.899-0.907] and ROC-TMPM, 0.890 [0.886-0.895]) and calibration (HL IMP, 9.9 [4.4-14.7] and HL-TMPM, 197 [143-248]) compared with TMPM. All models show slight changes after the extension of age, gender, and mechanism of injury, but the extended IMP still dominated TMPM in every performance.The IMP has slight improvement in discrimination and calibration compared with the TMPM and can accurately predict mortality. Therefore, we consider it as a new feasible scoring method in trauma research. PMID- 28858125 TI - Langerhans cell histiocytosis of the thyroid complicated by papillary thyroid carcinoma: A case report and brief literature review. AB - RATIONALE: Langerhans cell histiocytosis (LCH) involves mainly the skin and bone and rarely the thyroid. Meanwhile, papillary thyroid carcinoma (PTC) is the most common subtype of thyroid cancer. Both LCH and PTC could make the thyroid enlarged and hypermetabolic. The coincidence of these 2 events in a patient is rare, and this paper aimed to report such case. PATIENT CONCERNS: A 40-year-old man presented with polyuria and polydipsia for 5 years. The symptoms had been relieved well by drug therapy for >4 years, until the drugs could not control the symptoms anymore and an extensively enlarged thyroid gland was noticed. DIAGNOSES: Thyroid ultrasound showed a nodule with microcalcification in the upper right lobe, positron emission tomography/computer tomography scan demonstrated thyroid hypermetabolism, and fine needle aspiration (FNA) revealed PTC. Right lobectomy of the thyroid and cervical lymph node biopsy verified the diagnosis "LCH of the thyroid complicated by PTC." INTERVENTIONS: The ultrasound guided FNA biopsy was performed prior to right lobectomy of the thyroid and cervical lymph node biopsy. Postoperative histopathological examination confirmed the diagnosis, after which the patient received adjuvant chemotherapy. OUTCOMES: After 5 cycles of adjuvant chemotherapy, the patient had been followed up for 2 years. LCH was controlled satisfactorily and there was no significant sign of recurrence or metastasis of PTC. LESSONS: LCH of the thyroid complicated by PTC is rare. Thyroid involvement should always be considered in the differential diagnosis of LCH patients. Surgery for PTC followed by chemotherapy for LCH may be the suitable treatment. PMID- 28858126 TI - Classification and possible bacterial infection in outpatients with eczema and dermatitis in China: A cross-sectional and multicenter study. AB - Little is known about the classification and bacterial infection in outpatients with eczema and dermatitis in China.To investigate the prevalence of eczema and dermatitis in outpatients of dermatology clinics in China, examine classification and proportion of common types of dermatitis and the possible bacterial infection, and analyze the possible related factors.Outpatients with eczema or dermatitis from 39 tertiary hospitals of 15 provinces in mainland China from July 1 to September 30, 2014, were enrolled in this cross-sectional and multicenter study. Among 9393 enrolled outpatients, 636 patients (6.7%) were excluded because of incomplete information.The leading subtypes of dermatitis were unclassified eczema (35.5%), atopic dermatitis (13.4%), irritant dermatitis (9.2%), and widespread eczema (8.7%). Total bacterial infection rate was 52.3%, with widespread eczema, stasis dermatitis, and atopic dermatitis being the leading three (65.7%, 61.8%, and 61.4%, respectively). Clinically very likely bacterial infection has a significant positive correlation with disease duration, history of allergic disease, history of flexion dermatitis, and severe itching.Atopic dermatitis has become a common subtype of dermatitis in China. Secondary bacterial infection is common in all patients with dermatitis, and more attentions should be paid on this issue in other type of dermatitis apart from atopic dermatitis. PMID- 28858127 TI - Serum ghrelin, but not obestatin, is a potential predictor of acute pancreatitis severity. AB - The roles of ghrelin and obestatin in AP remain controversial.This study investigates the effects and the predictive value of serum ghrelin and obestatin levels in the early stage of AP.A total of 193 consecutive patients with AP and 24 healthy controls were included. Patients were divided into mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP), and severe acute pancreatitis (SAP) groups. Serum levels of ghrelin and obestatin were measured on the first, third, and fifth days of hospitalization. The predictive value of serum ghrelin and obestatin levels on the first day in AP was examined using receiver-operating characteristic (ROC) curves.On the first day of hospitalization, the mean serum ghrelin level was significantly lower in patients with AP than in controls (P < .01). The serum ghrelin concentration decreased with increasing AP severity and was lower in patients with SAP than in those with MAP and MSAP (P < .05). It increased gradually from the first to the fifth day after treatment. ROC curves demonstrated that the serum ghrelin level on the first day had some predictive value for AP severity (area under the ROC curve = 0.646), with an optimal cut-off value of 87.83 pg/mL. Logistic regression showed that the serum ghrelin level had independent predictive value for non-MAP (odds ratio = 10.94; 95% confidence interval, 5.08-23.55; P < .01). The serum obestatin level did not differ significantly between patients with AP and controls and had the limited predictive value for non-MAP (area under the ROC curve = 0.564). However, the serum obestatin concentration showed a "warning" effect regarding AP etiology; on the first day of treatment, it was significantly lower in patients with AP of hypertriglyceridemic etiology than in those with AP of biliary, alcohol-related, and other etiologies (P = .05, P = .031, and P = .029, respectively).Serum ghrelin and obestatin levels may be related to the progression of AP in the early stage. Only the serum ghrelin level is a potential predictor of AP severity in the early stage. Obestatin may be involved in the pathogenesis of AP caused by hypertriglyceridemia. PMID- 28858128 TI - Percutaneous transhepatic papilla balloon dilatation combined with a percutaneous transcystic approach for removing concurrent gallbladder stone and common bile duct stone in a patient with billroth II gastrectomy and acute cholecystitis: A case report. AB - BACKGROUND: A 61-year-old man presented with upper abdominal pain and jaundice. Abdominal computed tomography imaging revealed stones in the gallbladder and the common bile duct, with a thickening of the gallbladder wall and an obvious increase in the volume of the gallbladder. Initial treatment using endoscopic retrograde cholangiopancreatography failed due to the presence of surgically altered gastrointestinal anatomy. Stones in the gallbladder and common bile duct were subsequently removed concurrently via percutaneous transhepatic papilla balloon dilatation combined with a percutaneous transcystic approach. Liver function recovered rapidly, with total bilirubin and direct bilirubin levels decreasing to normal, with a concomitant improvement in hemoglobin and thrombocyte levels and resolution of the upper abdominal pain and jaundice. CONCLUSION: Percutaneous transhepatic papilla balloon dilatation, combined with a percutaneous transcystic approach, provided an effective alternative treatment for removing concurrent stones in the common bile duct and gallbladder in a patient with a previous Billroth II gastrectomy and presenting with an acute cholecystitis. PMID- 28858129 TI - Microscope-assisted anterior cervical discectomy and fusion combined with posterior minimally invasive surgery through tubular retractors for multisegmental cervical spondylotic myelopathy: A retrospective study. AB - This study aimed to investigate the clinical efficacy and outcome of combined microscope-assisted anterior cervical discectomy and fusion (ACDF) with posterior minimally invasive surgery through tubular retractors for patients with multisegmental cervical spondylotic myelopathy (MCSM).This retrospective study included 28 patients (19 males and 9 females) with multisegmental cervical spondylotic myelopathy, who underwent combined microscope-assisted ACDF with posterior minimally invasive surgery through tubular retractors in our single center between January 2012 and December 2016. The evaluated postoperative clinical outcomes were operation time, length of hospitalization, blood loss, levels of creatine phosphokinase isoenzyme MM (CPK-MM), Japanese Orthopedic Association (JOA) scores, visual analogue scale (VAS) scores, Cobb angle of C2 C7, and radiological assessments (included X-rays, computed tomography scans, and magnetic resonanceimaging images).The mean surgery time was 198.42 +/- 17.53 minutes, the average hospitalization length of hospital was 7.59 +/- 1.38 days, and the mean follow-up time was 13 +/- 2.45 months. On average, about 36.42 +/- 10.15 mL of blood was lost and CPK-MM increased to 331.75 +/- 23.15 IU/mL postoperatively (P < .001). The mean modified JOA scores increased from 8.21 +/- 0.69 preoperatively to 13.96 +/- 1.57 postoperatively (P < .001), whereas the mean VAS scores decreased from 6.64 +/- 1.28 preoperatively to 0.39 +/- 0.50 postoperatively (P < .001). Cobb angle of C2-C7 increased from 13.86 degrees +/- 5.69 degrees preoperatively to 14.10 degrees +/- 5.56 degrees postoperatively (P = .16).In conclusion, combined microscope-assisted ACDF with posterior minimally invasive surgery through tubular retractors appears to be a safe and effective treatment for patients with MCSM. PMID- 28858130 TI - Effect of bispectral index-guided anesthesia on consumption of anesthetics and early postoperative cognitive dysfunction after liver transplantation: An observational study. AB - The objective of this study was to summarize the incidence of postoperative cognitive dysfunction (POCD) after 7days following liver transplantation (LT), and to evaluate the effectiveness of bispectral index (BIS) guided anesthetic intervention in reducing POCD. Additional serum concentrations of S100beta and neuron-specific enolase (NSE) were detected during surgery to determine whether they were reliable predictors of POCD.Patients who underwent LT at Beijing YouAn Hospital Affiliated to Capital University of Medical Science from January 2014 to December 2015 were enrolled. BIS monitor was needed during surgery. Patients who underwent LT without BIS monitoring during August 2012 to December 2014 served as historical controls. A battery of 5 neuropsychological tests were performed and scored preoperatively and 7days after surgery. POCD was diagnosed by the method of one standard deviation (SD). The blood samples of BIS group were collected at 5 time points: just before induction of general anesthesia (T0), 60 minutes after skin incision (T1), 30 minutes after the start of the anhepatic phase (T2), 15 minutes after reperfusion of the new liver (T3), and at 24 hours after surgery (T4).A total of 33 patients were included in BIS group, and 27 in the control group. Mean arterial pressure was different between 2 groups at 30 minutes after the start of the anhepatic phase (P = .032). The dose of propofol using at anhepatic phase 30 min and new liver 15 min was lower in the BIS group than control group (0.042 +/- 0.021 vs. 0.069 +/- 0.030, P < .001; 0.053 +/- 0.022 vs. 0.072 +/- 0.020, P = .001). Five patients were diagnosed as having POCD after 7 days in the BIS group and the incidence of POCD was 15.15%. In the control group, 9 patients had POCD and the incidence of POCD was 33.33%. The incidence of POCD between 2 groups had no statistical difference (P = .089). S100beta increased at stage of anhepatic 30 minutes (T2) and new liver 15 minutes (T3) compared with the stage of before anesthesia (T0) (1.49 +/- 0.66 vs. 0.72 +/- 0.53, P < .001; 1.92 +/- 0.78 vs. 0.72 +/- 0.53, P < .001). NSE increased at stage of anhepatic 30 minutes (T2) and new liver 15 minutes (T3) compared with the stage of before anesthesia (T0) (5.80 +/- 3.03 vs. 3.58 +/- 3.24, P = .001; 10.04 +/- 5.65 vs. 3.58 +/- 3.24, P < .001). At 24 hours after surgery, S100beta had no difference compared to one before anesthesia (1.0 +/- 0.62 vs. 0.72 +/- 0.53, P = .075), but NSE still remained high (5.19 +/- 3.64 vs. 3.58 +/- 3.24, P = .043). There were no significant differences in the serum concentrations of S100beta between patients with and without POCD at 5 time points of operation (P > .05). But at 24 hours after surgery, NSE concentrations were still high of patients with POCD (8.14 +/- 3.25 vs. 4.81 +/- 3.50, P = .035).BIS-guided anesthesia can reduce consumption of propofol during anhepatic and new liver phase. Patients in BIS group seem to have a mild lower incidence of POCD compared to controls, but no statistical significant. The influence of BIS-guided anesthesia on POCD needs to be further confirmed by large-scale clinical study. S100beta protein and NSE are well correlative with neural injury, but NSE is more suitable for assessment of incidence of postoperative cognitive deficits after surgery. PMID- 28858131 TI - Recurrent bacteremia and liver abscess caused by Clostridium difficile: A case report. AB - RATIONALE: Clostridium difficile bacteremia (CDB) and liver abscess is a quite rare presentation of C. difficile infection. PATIENTS CONCERNS: A 74-year-old male with primary biliary cirrhosis and hepatocellular carcinoma who underwent transarterial chemoembolization (TACE) developed a high fever on post-TACE day 14. Intravenous ceftriaxone and following meropenem were administered, however, his clinical response was poor. On post-TACE day 24, 2 sets of blood culture were taken due to elevation of C-reactive protein levels. DIAGNOSIS: CDB, caused by bacterial translocation. INTERVENTIONS: Intravenous vancomycin and oral metronidazole were administered for two weeks. OUTCOMES: One month after recurrent CDB, the patient was re-admitted due to a liver abscess at the same site of TACE. C. difficile was isolated from the liver abscess and the patient received 6 weeks of oral metronidazole treatment. CDB and liver abscess have not recurred since completion of antibiotic treatment. LESSONS: The spore-forming ability of C. difficile may contributed to the recurrent CDB episodes and liver abscess formation in necrotic liver tissue following TACE, and long-term metronidazole therapy was considered to be effective to C. difficile liver abscess. PMID- 28858132 TI - A retrospective study on the effects of exclusive donor human milk feeding in a short period after birth on morbidity and growth of preterm infants during hospitalization. AB - The risks and benefits of feeding preterm formula (PF) versus donor human milk (DHM) in preterm infants are uncertain, and studies evaluating the efficacy of DHM to the morbidities and growth of preterm infants in the neonatal intensive care unit are confused by the need for milk fortification. We aimed to determine and compare the outcome of short-term morbidities in neonatal intensive care unit and growth between premature infants fed exclusively DHM only until a volume of 130 mL/kg/d of enteral feeding was achieved and infants fed with a PF mix after birth. The data of 132 infants with low birth weight of <1500 g and gestational age of less than 32 weeks were considered. Ninety infants were analyzed, of which 86 were discharged alive. The DHM group (n = 36) was made up of infants who were fed exclusively with DHM, whereas the PF group (n = 54) consisted of infants who were fed with a combination of PF and either DHM or human milk, until a volume of 130 mL/kg/d of enteral feeding was achieved. Once feeding in the DHM group progressed to volumes greater than 130 mL/kg/d, infants were fed fortified DHM and PF alternately. One infant (2.8%) in the DHM group had late-onset sepsis or necrotizing enterocolitis compared with 21 (38.9%) in the PF group (adjusted odds ratio 0.05, 95% confidence interval 0.01-0.41); 13 (36.1%) infants in the DHM group had bronchopulmonary dysplasia compared with 38 (70.4%) in the PF group (odds ratio 0.18, 95% confidence interval 0.05-0.41). Although the DHM group demonstrated a comparatively lower rate of weight gain, head circumference increment, and height increment from birth to the age at which an enteral feeding volume of 130 mL/kg/d was achieved, there were no significant differences in these values at 36 weeks' postmenstrual age between both groups. PMID- 28858133 TI - Kallmann syndrome with a Tyr113His PROKR2 mutation. AB - RATIONAL: Kallmann syndrome (KS) is a genetic gonadotropin-releasing hormone deficiency associated with hyposmia or anosmia and characterized by various modes of inheritance. PATIENT CONCERNS: A 16-year-old male did not reach puberty and was associated with hypogonadotropic hypogonadism and anosmia. His magnetic resonance imaging of brain revealed the absence of the olfactory bulb. DIAGNOSIS: His karyotype was 46 XY. Sanger sequencing of the KAL1 gene revealed no mutations. Diagnostic exome sequencing identified a prokineticin-receptor 2 (PROKR2) gene variant, c.337T > C (p.Tyr113His), previously reported to be a pathogenic mutation; we confirmed the presence of the mutation via Sanger sequencing of the coding exons of PROKR2. His apparently unaffected mother and sister, but not his father, were heterozygous for the PROKR2 Tyr113His mutation. LESSONS: This work advances our understanding of the role played by PROKR signaling and the mode of inheritance of the gene in patients with KS. PMID- 28858134 TI - Desflurane versus sevoflurane in pediatric anesthesia with a laryngeal mask airway: A randomized controlled trial. AB - BACKGROUND: Desflurane with a laryngeal mask airway may have advantages during ambulatory anesthesia. However, desflurane-induced airway irritability makes the use of desflurane challenging, especially in children. This study compared desflurane with sevoflurane maintenance anesthesia in terms of respiratory events and the emergence characteristics in children with a laryngeal mask airway. METHODS: This randomized controlled trial evaluated 200 children undergoing strabismus surgery allocated to desflurane or sevoflurane groups. After inducing anesthesia with sevoflurane and thiopental sodium 5 mg kg, the anesthetic agent was changed to desflurane in the desflurane group, whereas sevoflurane was continued in the sevoflurane group. Respiratory events, emergence time, recovery time, and emergence agitation were compared between the groups. RESULTS: The overall respiratory events did not differ between the groups. However, the incidence of mild desaturation (90% <= SpO2 < 97%) was significantly higher in the desflurane group (7%) than in the sevoflurane group (0%) (P = .007). Emergence was significantly faster in the desflurane group (6.6 +/- 3.9 vs 8.0 +/ 2.2 min, P = .003). The recovery time and emergence agitation in the postanesthesia care unit were comparable between groups. Laryngospasm developed in 5 children (1 in the sevoflurane group and 4 in the desflurane group, P = .365); of these, 4 patients were younger than 3 years. CONCLUSION: Desflurane maintenance anesthesia in children with a laryngeal mask airway shows a similar rate of overall respiratory events compared with sevoflurane anesthesia. However, anesthesiologists should be cautious of using desflurane in younger children concerning desaturation events during emergence. PMID- 28858135 TI - Stability study of dezocine in 0.9% sodium chloride solutions for patient controlled analgesia administration. AB - BACKGROUND: Dezocine, a mixed agonist/antagonist of opioid receptors, has been used in iv patient-controlled analgesia (PCA) pumps for postoperative pain control. The aim of this study was to investigate the physicochemical stability of dezocine solutions in 0.9% sodium chloride for injection for PCA administration. METHODS: Solutions of dezocine (0.3, 0.45, or 0.6 mg/mL in 0.9% sodium chloride for injection) were stored in polyolefin bags and glass bottles. Their stabilities at storage conditions of 4 degrees C for 14 days and 25 degrees C for 72 hours were studied. For all preparations, physical characteristics (including pH, color, and presence of precipitates) were evaluated. Each preparation of dezocine was also analyzed using a stability-indicating high performance liquid chromatography method. A solution was considered stable if it maintained at least 90% of its initial concentration. RESULTS: No notable changes in pH, color, or precipitation were observed in any of the prepared solutions over the testing period. All formulations maintained >97% of the initial dezocine concentration under the storage conditions evaluated. CONCLUSIONS: Dezocine solutions at 0.3, 0.45, or 0.6 mg/mL in 0.9% sodium chloride for PCA administration were stable for 72 hours at 25 degrees C and for 14 days at 4 degrees C when packaged in polyolefin bags or glass bottles and protected from light. PMID- 28858136 TI - Comparison of a curved forceps with a conventional straight forceps for nasogastric tube insertion under videolaryngoscopic guidance: A randomized, crossover manikin study. AB - BACKGROUND: Nasogastric tube (NGT) insertion is an easy procedure that can be routinely performed under general anesthesia. However, for difficult cases, there are limited insertion techniques available in routine clinical practice, considering the flexibility of NGTs. The SUZY curved forceps are designed for the removal of pharyngolaryngeal foreign bodies under guidance of the McGRATH MAC (McG) videolaryngoscope. Because McG enables clear visualization of the esophageal inlet, we hypothesized that the SUZY forceps can facilitate easier NGT insertion compared with the conventional Magill forceps under McG guidance and designed a randomized, crossover manikin study to test this hypothesis. MATERIALS AND METHODS: Ten anesthesiologists participated in this study. Each participant was instructed to insert an NGT using either the SUZY or the Magill forceps under McG guidance. Both types of forceps were used by each participant in a computer generated random order. The primary outcome measure was the number of "strokes" (1 stroke was defined by a specific sequence of participant actions) required to advance the NGT 30 cm from the starting point. Data are expressed as medians (interquartile ranges [ranges]). RESULTS: The number of strokes required for NGT insertion was fewer in the SUZY group than in the Magill group {7 [7.0-12.5 (5 14)] vs 16.5 [13.5-20.3 (7-22)]; P <.05}. The time required for NGT insertion was also lesser in the SUZY group than in the Magill group {15.4 [13.7-20.0 (7.0 38.3)] seconds vs 30.3 [22.0-42.3 (12.8-47.5) seconds]; P <.05}. CONCLUSIONS: The SUZY curved forceps facilitated NGT insertion more effectively than the Magill straight forceps under McG guidance. Our results suggest that NGT insertion using the SUZY forceps under McG guidance is a secure and easy procedure. PMID- 28858137 TI - Ectopic pancreatic tissue in the wall of the small intestine: Two rare case reports. AB - RATIONALE: Ectopic pancreas, which is a kind of rare congenital disease, forms during embryonic development. It can occur throughout the whole gastrointestinal tract, but has a low tendency to develop in the wall of the small intestine. It is easy for patients with ectopic pancreases to be misdiagnosed because the symptoms are untypical and can vary. PATIENT CONCERNS: In the present study, we reported two rare cases of ectopic pancreatic tissue in the wall of the small intestine, which presented with obvious abdominal pain and distention. DIAGNOSIS: The laboratory tests and computed tomography (CT) scans didn't reveal any evidence of ectopic pancreas. INTERVENTIONS: The two patients received small intestine masses resection and intestinal anastomosis. OUTCOMES: During surgery, an intestinal mass with a diameter of 4.0 cm was found in the first patient. An intestinal mass with a diameter of 0.8 cm, jejunum perforation, and diffuse peritonitis were found in the second patient. Histological analyses of the dissected intestinal masses confirmed them as ectopic pancreatic tissue. Interestingly, for the second patient, the intestinal perforation and diffuse peritonitis were not induced by the ectopic pancreas, but by a jujube pit that was found in the perforated site of the intestine. LESSONS: Our study demonstrated that an ectopic pancreas should be considered in cases of untypical abdominal symptoms with intestinal masses. PMID- 28858138 TI - Model-based meta-analysis of progression-free survival in non-Hodgkin lymphoma patients. AB - BACKGROUND: Non-Hodgkin lymphoma (NHL) is a group of lymphoproliferative malignancies with varying treatment responses and progression-free survival (PFS) times. The objective of this study was to quantify the effect of treatment and patient-population characteristics on PFS in patients with NHL. METHODS: A database was developed from 513 NHL clinical trials reported from 1993 to 2015. Summary-level PFS was obtained from 112 of these trials, which included 155 cohorts and 11,824 patients. Characteristics evaluated for their impact on PFS included cohort treatment, percentage of patients with each NHL subtype, percentage of patients with different numbers of prior treatments, percentage of subjects previously administered rituximab, performance status, disease stage, median age, and sex distribution. RESULTS: Rituximab, bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone combination)/CHOP like, and other nonchemotherapy drugs, aside from bortezomib, prolonged median PFS time 2 to 4-fold. Follicular lymphoma patients had 60% longer median PFS time than mantle cell lymphoma (MCL) patients, while diffuse large B-cell lymphoma patients had a median PFS time that was 25% of MCL patients. Patients who received <=1 prior treatment had median PFS times > 10-fold longer than patients who received >=2 prior treatments. The final model predicted the hazard ratio in 75% of the studies within 25% of the observed value and the observed median PFS time of 92% of the studies fell within the predicted 90% confidence intervals. CONCLUSIONS: The developed PFS model predicts the median PFS time and hazard ratio for specific populations and treatment combinations quantitatively and can potentially be extended to link short-term and long-term clinical outcomes. PMID- 28858139 TI - Platelet-Derived Microvesicles: A Potential Therapy for Trauma-Induced Coagulopathy. AB - Trauma patients are often affected by a hypocoagulable condition referred to as trauma-induced coagulopathy (TIC) for which few therapeutic options exist. One available treatment is fresh platelets transfusion, although it is not efficacious enough and has a number of limitations. Therefore, we reviewed the literature to propose an alternative therapy based on platelet-derived microvesicles (PMVs), which are cellular fragments surrounded by extracellular membrane and filled with cytoplasmic content. This concept is supported by a large number of studies in which the hypercoagulable role of PMVs has been demonstrated and associated with thrombosis-related conditions. The purpose of this review is to summarize what is currently known about PMVs and discuss whether a transfusion of isolated human PMVs could be used as a therapy for TIC. PMID- 28858140 TI - miRNA-214 Protects Sepsis-Induced Myocardial Injury. AB - Sepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. The underlying mechanisms associated with sepsis induced myocardial injury (SIMI) include impaired cardiac contractility, excessive cardiac inflammation, oxidative stress, cardiomyocyte apoptosis, and so on. SIMI is usually accompanied with dynamic changes of microRNAs (miRNAs) expression. And previous studies have shown that miR-214 plays a vital role in the protection of cardiomyocyte subjected to oxidative stress. In this study, we aimed to test whether miRNA-214 plays any roles in sepsis-induced myocardial injury. We performed quantitative real-time polymerase chain reaction in the septic mouse model induced by cecal ligation and puncture (CLP) and found the expression of miR-214 was upregulated. Then we transfected with the miRNA-214 precursor (pre-miR-214) to upregulate miR-214 expression and with the miR-214 inhibitor (anti-miR-214) to downregulate miR-214 expression respectively. Pre-miR 214 mouse model, anti-miR-214 mouse model, and wild-type mice were subjected to CLP or sham surgery. We observed that compared with control wild types, cardiac function, inflammatory response, the degree of myocardial injury, and myocyte apoptosis were remarkably alleviated in CLP-treated pre-miR-214 mice and aggravated in CLP-treated anti-miR-214 mice. Taken together, our study reveals that miR-214 has a protective effect in SIMI and thereby may provide a potential novel approach to treat SIMI. PMID- 28858141 TI - The Theory is Out There: The Use of ALPHA-2 Agonists in Treatment of Septic Shock. AB - The sympathetic nervous system plays an important role in the initial response to sepsis. This response enables the host to respond to invading pathogens; however, prolonged activation can become pathological. The potential for unregulated sympathetic tone to become detrimental in the septic patient has fueled interest in the role and impact of sympathetic manipulation, including the selective inhibition of sympathetic tone to return and augment vascular reactivity. While conventional understanding of alpha 2 agonists activity is depletion of sympathetic outflow, novel evidence suggests mitigation rather than depletion. The mechanism by which these agents exert these properties remains controversial and appears to be condition-specific. The hypothesis by which alpha agonists affect the pathology of sepsis is multifactorial, but includes influence on inflammatory regulation, coagulopathy, dynamic flow, as well as vascular responsiveness and integrity. Theory and basic science evidence supports the use of alpha agonists in the septic population. The clinical evidence shedding light on this topic is limited and confounded by intention or trial design. Future evidence should focus on adjuvant therapy in patients progressing to or at high risk of shock development. PMID- 28858142 TI - Neutrophil Activation During Septic Shock. AB - In addition to their well-known role as the cellular mediators of immunity, key other roles have been identified for neutrophils during septic shock. Importantly, neutrophils indeed play a critical role in the recently described immunothrombosis concept and in septic shock-induced coagulopathy. Septic shock is one of the most severe forms of infection, characterized by an inadequate host response to the pathogenic organism. This host response involves numerous defense mechanisms with an intense cellular activation, including neutrophil activation. Neutrophils are key cells of innate immunity through complex interactions with vascular cells and their activation may participate in systemic tissue damages. Their activation also leads to the emission of neutrophil extracellular traps, which take part in both pathogen circumscription and phagocytosis, but also in coagulation activation. Neutrophils thus stand at the interface between hemostasis and immunity, called immunothrombosis.The present review will develop a cellular approach of septic shock pathophysiology focusing on neutrophils as key players of septic shock-induced vascular cell dysfunction and of the host response, associating immunity and hemostasis. We will therefore first develop the role of neutrophils in the interplay between innate and adaptive immunity, and will then highlight recent advances in our understanding of immunothrombosis septic shock-induced coagulopathy. PMID- 28858144 TI - Exploring an Unknown Territory: "Sleeping Beauties" in the Nursing Research Literature. AB - BACKGROUND: Sleeping Beauties (SBs) are publications that are scarcely cited in the years immediately following publication but then suddenly become highly cited later. Such publications have unique citation patterns and can reveal important developments in the field in which they appear. OBJECTIVES: No holistic analysis of nursing SBs has been done yet. The aim of this study was to identify and analyze the SB phenomenon in the nursing research literature. METHOD: The corpus for the nursing SB identification was harvested from the Web of Science Core Collection (Thomas Reuters) for the period 1934-2015. Citation histories of 212,239 publications were screened. From those, 3,209 publications with more than 100 citations were selected for analysis. We used our own software and applied the van Raan (2004) and Baumgartner (2010) criteria for SBs-a 5-year sleeping period with at most 10 citations during that time, an average of at least five citations per year after the first 10 years, with at least 100 citations in total. The knowledge context for SBs was determined using citing papers. All citing papers were analyzed with the help of VOSviewer software. RESULTS: Nine publications were identified as SBs (prevalence of 0.004%). The length of sleep duration ranged from 5 to 10 years (M = 6.8, SD = 2.0), depth of sleep ranged from 0.2 to 0.8 citations (M = 0.6, SD = 0.2), and awake intensity ranged from 6.4 to 15.0 citations (M = 11.0, SD = 3.8). The average number of citations to SBs was 229. Most nursing SBs were produced in the United States (n = 8) from top institutions in journals with high-impact factors. Nursing SBs covered topics including resilience, sampling in qualitative research, metasynthesis, postoperative pain in children, dementia rating scales, care of patients with Alzheimer's disease, nursing theory related to fatigue mechanisms in cancer patients, and family participation during resuscitation. Nursing SBs were cited by authors from a large number of institutions and countries; the number of publications citing nursing SBs is growing exponentially and showing increasing and global interest in the research presented in them. DISCUSSION: This study demonstrated that SBs in nursing are similar to other scientific disciplines. Existence of SBs suggests that nursing knowledge accumulation is supported by research and professional processes similar to those that emerged in other academic disciplines. PMID- 28858143 TI - Facilitated Nurse Medication-Related Event Reporting to Improve Medication Management Quality and Safety in Intensive Care Units. AB - BACKGROUND: Medication safety presents an ongoing challenge for nurses working in complex, fast-paced, intensive care unit (ICU) environments. Studying ICU nurse's medication management-especially medication-related events (MREs)-provides an approach to analyze and improve medication safety and quality. OBJECTIVES: The goal of this study was to explore the utility of facilitated MRE reporting in identifying system deficiencies and the relationship between MREs and nurses' work in the ICUs. METHODS: We conducted 124 structured 4-hour observations of nurses in three different ICUs. Each observation included measurement of nurse's moment-to-moment activity and self-reports of workload and negative mood. The observer then obtained MRE reports from the nurse using a structured tool. The MREs were analyzed by three experts. RESULTS: MREs were reported in 35% of observations. The 60 total MREs included four medication errors and seven adverse drug events. Of the 49 remaining MREs, 65% were associated with negative patient impact. Task/process deficiencies were the most common contributory factor for MREs. MRE occurrence was correlated with increased total task volume. MREs also correlated with increased workload, especially during night shifts. DISCUSSION: Most of these MREs would not be captured by traditional event reporting systems. Facilitated MRE reporting provides a robust information source about potential breakdowns in medication management safety and opportunities for system improvement. PMID- 28858145 TI - Social Media Use and Sexual Risk Reduction Behavior Among Minority Youth: Seeking Safe Sex Information. AB - BACKGROUND: Sexual health is an important area of study-particularly for minority youth and youth living in disadvantaged neighborhoods. OBJECTIVES: The purpose of the research was to examine the sources of sexual health information associated with youth adopting sexual risk reduction behaviors. METHODS: Data collection took place in a small city in the Northeastern United States using cross sectional behavioral surveys and modified venue-based sampling. Participants included 249 African American and Latino youth aged 13-24. Participants reported their sources of information about contraception and human immunodeficiency virus/sexually transmitted disease, such as TV/movies, parents, social media; their intentions to have sex; and condom and contraception use during their last sexual activity. Social media use, past pregnancy experience, past sexual history, age, and gender were also measured. Standard tests of bivariate association (chi-square and F tests) were used to examine initial associations between sexual risk reduction behavior and exposure to sexual risk reduction information on social media. Logistic regression models were used to test multivariate relationships between information sources and sexual risk reduction behavior. RESULTS: Youth who were exposed to sexual health messages on social media were 2.69 times (p < .05) and 2.49 times (p < .08) more likely to have used contraception or a condom at last intercourse, respectively. Parents, schools, or traditional media as information sources were not significantly associated with contractive use or condom use at last intercourse. DISCUSSION: Youth sexual behavior is increasingly informed by social media messages. Health practitioners should utilize social media as an important health promotion tool. PMID- 28858146 TI - The Relationship Between Peripheral Artery Disease Symptomatology and Ischemia. AB - BACKGROUND: Fewer than half of individuals with peripheral artery disease (PAD) experience classic claudication, and the relationships between PAD typical or atypical symptom intensity, location, and description (classic or atypical) with ischemic changes have not previously been reported. OBJECTIVE: The primary purpose of this study was to evaluate the relationship between self-reported PAD symptom intensity and calf tissue ischemia measured using the tissue saturation index (TSI) during treadmill exercise. The location and descriptors of atypical PAD symptoms in the presence of calf tissue ischemia were also identified. METHODS: Adults with PAD with exercise-limiting ischemic symptoms were asked to (a) rate symptom intensity using a numerical rating scale (NRS) from 0 to 5 (0 = no pain, 1 = onset of pain, 5 = maximal pain), (b) provide symptom locations and descriptors, and (c) wear a near-infrared spectroscopy device to obtain calf TSI values during treadmill exercise. Multilevel models with TSI as the outcome variable were estimated during exercise and recovery. Covariates included were exercise time, recovery time, baseline TSI, exercise rating, recovery rating, ankle-brachial index (ABI), age, race, gender, body mass index, diabetes, neuropathy, and smoking. RESULTS: During three successive bouts of treadmill exercise for 40 participants (80% Caucasian men; average age = 68 years, SD = 9.2), the most rapid decline in TSI occurred between the start of exercise and symptom onset (when NRS = 1). The TSI nadir was often reached prior to report of maximum discomfort (when NRS = 5), and changes in TSI were related to exercise time (p < .001), baseline TSI (p < .001), exercise ratings (p < .001), and ABI (p < .05). During recovery, TSI increased steadily for most participants as pain eased. In the recovery model, changes in TSI were associated with recovery ratings (p < .001) and ABI (p < .03). Of 120 treadmill exercise tests, 69.2% were stopped due to discomfort in the calf with classic descriptors reported only half the time (55.4%). DISCUSSION: Exploratory analyses revealed ischemic symptoms extended beyond classic claudication locations and descriptors. Future research should evaluate changes in TSI relative to atypical locations and descriptors to improve understanding of the full range of ischemic symptoms experienced by individuals with PAD. PMID- 28858148 TI - Alcohol or Drug Use and Trauma Recidivism. AB - BACKGROUND: Alcohol, illicit drugs, and psychotropic medications are well-known causes of traumatic events. However, the association of each type of substance with trauma recidivism remains unclear. OBJECTIVES: The purpose of this study was to quantify the strength of associations between the type of substance detected in patients admitted for traumatic injury and trauma recidivism, defined as a documented history of past trauma. METHODS: The presence of alcohol and drugs (cannabis, cocaine, amphetamines, methamphetamines, benzodiazepines, opiates, methadone, barbiturates, and tricyclic antidepressants) was analyzed in 1,156 patients between 16 and 70 years old, hospitalized in a trauma hospital between November 2011 and March 2015. Their past trauma history was retrieved from the health information system, which included patient health histories since 1999. Multinomial logistic regression analysis was used to estimate the strength of the association between types of substances detected in current trauma patients and trauma recidivism (documented history of past trauma). RESULTS: At least one substance was detected in 521 patients (45.1%): only alcohol in 159 (13.7%), only cannabis in 62 (5.4%), only psychotropic medications/opioids in 145 (12.5%), only cocaine/amphetamines in 14 (1.2%), and a combination of these groups in 141 (12.2%). The consumption of alcohol, illicit drugs, and/or psychotropic medications was associated with increased recidivism in all substance groups; the adjusted odds ratio for multiple recidivism was 3.17 (95% CI [2.29, 4.39]). CONCLUSION: Patients who screened positive for alcohol, illicit drugs, and/or psychotropic medications had a higher frequency of past trauma history compared with patients with negative tests, independently of age, gender, or the presence of previous psychiatric disorders. PMID- 28858147 TI - Toward Meaningful Care Plan Clinical Decision Support: Feasibility and Effects of a Simulated Pilot Study. AB - BACKGROUND: Clinical decision support (CDS) tools-with easily understood and actionable information, at the point of care-are needed to help registered nurses (RNs) make evidence-based decisions. Not clear are the optimal formats of CDS tools. Thorough, preclinical testing is desirable to avoid costly errors associated with premature implementation in electronic health records. OBJECTIVE: The aims of this study were to determine feasibility of the protocol designed to compare multiple CDS formats and evaluate effects of numeracy and graph literacy on RN adoption of best practices and care planning time in a simulated environment. METHODS: In this pilot study, 60 RNs were randomly assigned to one of four CDS conditions (control, text, text + graph, and text + table) and asked to adjust the plan of care for two patient scenarios over three shifts. Fourteen best practices were identified for the two patients and sent as suggestions with evidence to the three CDS groups. Best practice adoption rates, care planning time, and their relationship to the RN's numeracy and graph literacy scores were assessed. RESULTS: CDS groups had a higher adoption rate of best practices (p < .001) across all shifts and decreased care planning time in shifts 2 (p = .01) and 3 (p = .02) compared with the control group. Higher numeracy and graph literacy were associated with shorter care planning times under text + table (p = .05) and text + graph (p = .01) conditions. No significant differences were found between the three CDS groups on adoption rate and care planning time. DISCUSSION: This pilot study shows the feasibility of our protocol. Findings show preliminary evidence that CDS improves the efficiency and effectiveness of care planning decisions and that the optimal format may depend on individual RN characteristics. We recommend a study with sufficient power to compare different CDS formats and assess the impact of potential covariates on adoption rates and care planning time. PMID- 28858149 TI - Conducting Clinically Based Intimate Partner Violence Research: Safety Protocol Recommendations. AB - BACKGROUND: Maintaining safety is of utmost importance during research involving participants who have experienced intimate partner violence (IPV). Limited guidance on safety protocols to protect participants is available, particularly information related to technology-based approaches to informed consent, data collection, and contacting participants during the course of a study. PURPOSE: The purpose of the article is to provide details on the safety protocol developed and utilized with women receiving care at an urban HIV clinic and who were taking part in an observational study of IPV, mental health symptoms, and substance abuse and their relationship to HIV treatment adherence. The protocol presents the technological strategies to promote safety and allow autonomy in participant decision-making throughout the research process, including Voice over Internet Protocol telephone numbers, and tablet-based eligibility screening and data collection. Protocols for management of participants at risk for suicide and/or intimate partner homicide that included automated high-risk messaging to participants and research staff and facilitated disclosure of risk to clinical staff based on participant preferences are discussed. DISCUSSION: Use of technology and partnership with clinic staff helped to provide an environment where research regarding IPV could be conducted without undue burden or risk to participants. Utilizing tablet-based survey administration provided multiple practical and safety benefits for participants. Most women who screened into high risk categories for suicide or intimate partner homicide did not choose to have their results shared with their healthcare providers, indicating the importance of allowing participants control over information sharing whenever possible. PMID- 28858150 TI - Effort-Reward Imbalance and Burnout Among ICU Nursing Staff: A Cross-Sectional Study. AB - BACKGROUND: Occupational stress is commonly observed among staff in intensive care units (ICUs). Sociodemographic, organizational, and job-related factors may lead to burnout among ICU health workers. In addition, these factors could modify the balance between efforts done and rewards perceived by workers; consequently, this imbalance could increase levels of emotional exhaustion and depersonalization and decrease a sense of personal accomplishment. OBJECTIVE: The purpose of this study was to analyze the relationship between effort-reward imbalance and burnout dimensions (emotional exhaustion, depersonalization, and personal accomplishment) among ICU nursing staff in a university hospital in Santiago, Chile. METHODS: A convenience sample of 36 registered nurses and 46 nurse aides answered the Maslach Burnout Inventory and Effort-Reward Imbalance Questionnaire and provided sociodemographic and work-related data. RESULTS: Age and effort-reward imbalance were significantly associated with emotional exhaustion in both registered nurses and nurse aides; age was negatively correlated with emotional exhaustion, whereas effort-reward imbalance was positively correlated. Age was negatively associated with depersonalization. None of the predictors were associated with personal accomplishment. DISCUSSION: This study adds valuable information about relationships of sociodemographic factors and effort-reward imbalance and their impact on dimensions of burnout, particularly on emotional exhaustion. PMID- 28858151 TI - Posterior Surgical Revision of Failed Fornix-based Trabeculectomy. AB - PURPOSE: To evaluate outcomes after revision of failed fornix-based trabeculectomy using a posterior conjunctival incision and mitomycin C. METHODS: Cases were identified using Current Procedural Terminology codes. Information from clinical records was analyzed retrospectively. Complete success was defined as intraocular pressure (IOP) <=16 mm Hg with no glaucoma medications and IOP reduction of >20% from preoperative levels. Qualified success was defined as IOP<=16 with or without medications and IOP reduction of >20%. Secondary outcomes included IOP, number of glaucoma medications used, visual acuity, and complications. RESULTS: Sixty eyes of 56 patients underwent surgical revision of failed trabeculectomy. The complete success rate at 1 year was 43.7%, declining to 41.7% at 2 years and all time points up to 5 years; qualified success rates were 68.9% at 1 year and at all subsequent time points. Mean IOP declined from 21.2+/-7.7 (SD) mm Hg preoperatively to 10.9+/-4.3 mm Hg at 1 year, to 10.5+/-3.8 mm Hg at 2 years, and to 9.9+/-4.6 mm Hg at 3 years. The mean number of glaucoma medications used fell from 2.5+/-0.5 preoperatively to 1.0+/-0.4 at 1 year, 0.9+/ 0.4 at 2 years, and 0.9+/-0.4 at 3 years. Complications included bleb leak in 3 eyes (5.0%), hypotony with choroidal detachment in 3 eyes (5.0%) and hyphema in 1 eye (1.7%). Eight eyes required additional glaucoma surgery. CONCLUSIONS: Surgical bleb revision with mitomycin C using a posterior incision in cases of failed fornix-based trabeculectomy can provide effective control of IOP. This conjunctiva-sparing procedure should be considered as a viable alternative to a tube shunt or repeat trabeculectomy. PMID- 28858152 TI - Prevalence and Associated Factors of Segmentation Errors in the Peripapillary Retinal Nerve Fiber Layer and Macular Ganglion Cell Complex in Spectral-domain Optical Coherence Tomography Images. AB - PURPOSE: To determine the prevalence of errors in segmentation of the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) boundary in spectral-domain optical coherence tomography (SDOCT) images, and to identify factors associated with the errors. MATERIALS AND METHODS: Peripapillary RNFL circle scans and macular 3-dimensional scans of consecutive cases imaged with SDOCT (RS-3000 Advance; Nidek, Gamagori, Japan) were retrospectively reviewed by a glaucoma specialist. Images with signal strength index (SSI)<6 were excluded. Threshold for segmentation failure was determined as 15 degrees in the RNFL scans and 1/24 of the scanned area in the GCC scans. Relationships between segmentation failure and clinical factors were statistically evaluated with univariable and multivariable analyses. RESULTS: This retrospective cross-sectional study included 207 eyes of 117 subjects (mean age, 58.5+/-16.5 y). Segmentation failure was found in 20.7% of the peripapillary RNFL scans, 16.6% of the 9 mm GCC scans, and 6.9% of the 6 mm GCC scans in SDOCT images. In multivariable logistic regression analyses, low SSI, large disc area, and disease type significantly correlated with RNFL segmentation failure, whereas SSI was the only baseline factor that was significantly associated with GCC segmentation failure. CONCLUSIONS: Although segmentation failure was common in both RNFL and GCC scans, it was less frequently observed in GCC scans. SSI, disc area, and disease type were significantly associated with segmentation failure. Predictive performance of baseline factors for failure was poor, underlining the importance of reviewing raw OCT images before using OCT parameters. PMID- 28858153 TI - Attenuation Coefficients From SD-OCT Data: Structural Information Beyond Morphology on RNFL Integrity in Glaucoma. AB - PURPOSE: The purpose of this study is to explore the attenuation coefficient (AC) of the retinal nerve fiber layer (RNFL) in spectral domain optical coherence tomography (OCT) images, in healthy eyes and eyes affected by glaucoma. To assess the relation between RNLF AC, disease severity, RNFL thickness, visual field sensitivity threshold, spatial location and age. PATIENTS AND METHODS: We analyzed peripapillary circle scans of a clinical OCT device (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) in 102 glaucoma patients and 90 healthy controls. The images were fully automatically converted into depth resolved AC images. Next, the median AC within the RNFL was calculated based on the Spectralis segmentation. We compared the RNFL AC between healthy, mild, moderate and advanced glaucomatous eyes and assessed the correlation with patient characteristics such as age and visual field sensitivity threshold (HFA, Carl Zeiss Meditec, Dublin, CA) in a generalized estimating equations (GEE) model. Finally, we explored the ability to discriminate between glaucomatous and healthy eyes by RNFL AC. RESULTS: Median RNFL AC decreased with increasing disease severity up to moderate glaucoma (P<0.001) in all 4 sectors around the optic nerve head. The largest relative decrease occurred in the nasal sector. The RNFL AC (AUC, 0.834+/-0.028) effectively discriminated healthy from glaucomatous eyes, although RNFL thickness (AUC, 0.975+/-0.013) performed even better (P<0.001). Prediction of visual field sensitivity improved significantly when RNFL thickness was augmented with RNFL AC as covariates (P<0.001). CONCLUSIONS: This study demonstrated that RNFL AC provides complementary information on the RNFL's health compared with RNFL thickness measurements alone. PMID- 28858154 TI - XEN-Baerveldt Implantation May Be Helpful to Avoid Late Corneal Complications. PMID- 28858155 TI - In Vivo Noninvasive Measurement of Young's Modulus of Elasticity in Human Eyes: A Feasibility Study. AB - PURPOSE: Abnormal ocular biomechanical properties may be important for understanding the risk of glaucoma. However, there are no clinical methods for measuring standard material properties in patients. In this feasibility study we demonstrated proof-of-principle for a novel method, ultrasound surface wave elastography (USWE), to determine the in vivo Young's modulus of elasticity of corneas in normal human eyes. METHODS: In total, 20 eyes of 10 healthy subjects (mean age, 51.4+/-7.2; +/-SD; range, 43 to 64 y) were studied. A spherical-tipped probe (3-mm diameter) was placed on closed eyelids and generated a gentle harmonic vibration at 100 Hz for 0.1 second. Wave speed propagation in the cornea was measured by USWE, and Young's modulus was calculated from the wave speed. Associations between Young's modulus and intraocular pressure (IOP), age, central corneal thickness, and axial length were explored by the Pearson correlation. Statistical significance was determined by using generalized estimating equation models to account for possible correlation between fellow eyes. RESULTS: Mean IOP was 12.8+/-2.7 mm Hg. Mean wave speed in the cornea was 1.82+/-0.10 m/s. Young's modulus of elasticity was 696+/-113 kPa and was correlated with IOP (r=0.57; P=0.004), but none of the other variables (P>0.1). CONCLUSIONS: USWE is a novel noninvasive technique for measuring ocular biomechanical properties. Corneal Young's modulus in normal eyes is associated with IOP, consistent with measurements in cadaver eyes. Further work is needed to determine elasticity in other ocular tissues, particularly the sclera, and if elasticity is altered in glaucoma patients. PMID- 28858156 TI - Comparison of Efficacy and Complications of Cyclophotocoagulation and Second Glaucoma Drainage Device After Initial Glaucoma Drainage Device Failure. AB - PURPOSE: Compare intraocular pressure (IOP) control and complication rates of a second glaucoma drainage device (GDD) to diode transscleral cyclophotocoagulation (TSCPC) following failure of an initial GDD. PATIENTS AND METHODS: Eyes with 1 GDD that required a second GDD or TSCPC for glaucoma control were included. Exclusion criteria were a cyclodestructive procedure before initial GDD, no light perception vision, or follow-up <1 year. Failure was defined as >=1 of (1) reoperation for lowering IOP; (2) explantation of second GDD; (3) persistent hypotony; (4) use of oral carbonic anhydrase inhibitor for lowering IOP in the study eye; or (5) loss of light perception. Reoperation for lowering IOP included additional GDD implantation or additional cyclodestruction, except if additional cyclodestruction was within 6 months of the initial session. RESULTS: A total of 75 eyes (35 in second GDD; 40 in TSCPC) were included (mean follow-up, 25.5 mo). Both procedures lowered IOP [-11.4 mm Hg (+/-13.6) for second GDD and -7.8 mm Hg (+/-11.8) for TSCPC groups] and decreased the number of IOP-lowering medications at the last visit. The second GDD group had significantly greater mean survival time [45.0 mo (+/-4.2)] than the TSCPC group [26.5 mo (+/-2.8)] but significantly more postoperative complications (60% of eyes) and non-IOP-related procedures (40% of eyes) than the TSCPC group (20% for postoperative complications and 18% for non-IOP-related procedures). CONCLUSIONS: Although both second procedures are efficacious in lowering IOP and number of IOP-lowering medications, TSCPC failed earlier, whereas a second GDD had significantly more complications. PMID- 28858157 TI - Primary Trabeculectomy Outcomes by Glaucoma Fellows in a Tertiary Hospital in Brazil. AB - PURPOSE: To examine outcomes of trabeculectomy with mitomycin C for uncontrolled glaucoma when performed by glaucoma trainee surgeons. MATERIALS AND METHODS: Retrospective case series of patients who underwent trabeculectomy with mitomycin C. Primary outcome was to assess the rate of failure, which was defined as intraocular pressure in 2 consecutive visits >18 or <5 mm Hg or intraocular pressure reduction <30% from baseline, additional glaucoma surgery, or loss of light perception. The secondary outcome was to investigate risk factors for failure and surgical complications. RESULTS: One hundred forty-three eyes from 126 glaucoma patients underwent primary trabeculectomy between 2013 and 2014 at University of Campinas. Mean follow-up time was 1.47+/-0.96 years. Kaplan-Meier analysis showed cumulative survival rates of 70.1%, 62.5%, and 57.8%, after 1, 2, and 3 years, respectively. Multivariate analysis with generalized estimating equations revealed that neovascular glaucoma [odd ratios (OR): 5.05, P=0.043], suture lysis (OR: 8.89, P=0.011), and early bleb leak (OR: 4.63, P=0.011) were risk factors for failure. CONCLUSIONS: A success rate of approximately 60% was obtained 3 years after primary trabeculectomy performed by trainees. Patients with neovascular glaucoma, who underwent suture lysis and who presented an early bleb leak had an increased risk for failure during follow-up. PMID- 28858160 TI - Evaluating the Quality of Life of Glaucoma Patients Using the State-Trait Anxiety Inventory. AB - PURPOSE: To evaluate anxiety felt by glaucoma patients. PATIENTS AND METHODS: In total, 472 glaucoma patients responded to a questionnaire on anxiety, subjective symptoms, and vision-related quality of life (VR-QOL) associated with glaucoma. Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI), state anxiety (STAI-State) subscale along with our novel questionnaire, assessing visual function and subjective symptoms, specialized for glaucoma. VR-QOL was evaluated using 5 subitems from the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). Adherence to ophthalmic antiglaucoma agents was confirmed. As indexes of visual function, corrected visual acuity (measured by eye chart), mean deviation (MD) score (measured with static perimetry), and 4 thresholds at the center of vision were determined. Stages were classified according to the Aulhorn Classification. From the STAI-State scores, the prevalence of anxiety in glaucoma patients was evaluated. We analyzed the correlation between the STAI-State and VFQ-25, anxiety, subjective symptoms, adherence, and visual function indexes. RESULTS: In total, 78% of glaucoma patients experienced at least an intermediate level of anxiety. The STAI-State correlated significantly with anxiety and subjective symptoms as measured by our novel questionnaire, particularly for questions "current anxiety about loss of vision" and "current anxiety in life" (r=0.468 and 0.500; both P<0.0001). However, STAI-State correlated weakly with VFQ-25, and not at all with visual function indexes and adherence. CONCLUSIONS: Many glaucoma patients feel anxiety. The STAI-State is correlated with the VR-QOL and anxiety in glaucoma patients, making it useful for understanding the anxiety present in glaucoma patients. PMID- 28858159 TI - Reproducibility of Optical Coherence Tomography Angiography Macular and Optic Nerve Head Vascular Density in Glaucoma and Healthy Eyes. AB - PURPOSE: Optical coherence tomography angiography (OCT-A) is a noninvasive technology that allows visualization of retinal blood vessels. It is important to determine reproducibility of measurements as low precision can impair its diagnostic capabilities. The purpose of this study is to determine intravisit and intervisit reproducibility of optic nerve head (ONH) and macular vessel density measurements with OCT-A. PATIENTS AND METHODS: Fifteen healthy volunteers and 14 glaucoma patients completed 2 OCT-A (AngioVue; Optovue Inc.) scanning sessions on each of 2 separate days to assess intravisit and intervisit reproducibility. A series of ONH and macula scans were acquired at each session. Vessel density (%), the proportion of vessel area over the total measurement area was calculated. Reproducibility was summarized using coefficients of variation (CV) and intraclass correlation coefficients calculated from variance component models. RESULTS: In healthy eyes, the CV of intravisit and intervisit global vessel density measures ranged from 1.8% to 3.2% in ONH scans and 2.5% to 9.0% in macular scans. In glaucoma eyes, the CV of intravisit and intervisit global vessel density measures ranged from 2.3% to 4.1% in ONH scans and 3.2% to 7.9% in macular scans. CVs were lower for global than sectorial measures. Global OCT-A ONH intraclass correlation measurements for the retinal nerve fiber layer in healthy eyes were lower (range: 0.65 to 0.85) than in glaucoma eyes (range: 0.89 to 0.94). Scan size did not make large differences in measurement CVs. CONCLUSIONS: Reproducibility of OCT-A ONH and macula vessel density measurements is good. Moreover, glaucoma patients have sparser vessel density with poorer reproducibility than healthy subjects. PMID- 28858161 TI - Expert Evaluation of Visual Field Decay in Glaucoma Correlates With the Fast Component of Visual Field Loss. AB - PURPOSE: To compare the assessment of serial visual fields (VFs) based on subjective expert evaluation with the fast and slow VF component rates determined with pointwise exponential regression (PER) and pointwise linear regression (PLR). MATERIALS AND METHODS: A total of 5272 VF examinations from 376 eyes diagnosed with open-angle glaucoma were included. Three glaucoma specialists assessed each VF qualitatively to evaluate progression status and the qualitative rate of progression. The rates of VF decay were determined with PER and PLR at each VF location, which were ranked according to the regression coefficient and partitioned into 2 groups (fast and slow). A mean rate for the fast and slow partitions was obtained based on the average of the regression coefficients in each partition. kappa-values were used to measure the agreement among the experts and the PER and PLR algorithms. RESULTS: The average baseline VF mean deviation for the study sample was -6.6 (+/-5.9) dB. The agreement of the likelihood of progression among the dichotomized experts' score and PER was moderate (kappa=0.41, P<0.01) and fair (kappa=0.39, P<0.01) for PLR. The agreement of the likelihood of progression among the 3 dichotomized experts' scores was fair (kappa=0.22, P<0.01). The agreement of the area of worsening among the dichotomized experts' score and PER and PLR were both moderate (kappa=0.48, P<0.01; kappa=0.46, P<0.01). The eyes flagged by experts as having "fast" progression rates had a higher average rates of decay for PER and PLR at -2.7 (+/ 4.1) %/year and -0.8 (+/-1.2) dB/year; eyes flagged as "slow" had lower rates of decay at -0.3 (+/-1.5) %/year and -0.1 (+/-0.5) dB/year. CONCLUSIONS: Expert qualitative evaluation of field series for change and rate of change correlate more closely with the fast component than with the slow component of VF decay. PMID- 28858158 TI - Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma. AB - Mitochondrial dysfunction may be an important, if not essential, component of human glaucoma. Using transcriptomics followed by molecular and neurobiological techniques, we have recently demonstrated that mitochondrial dysfunction within retinal ganglion cells is an early feature in the DBA/2J mouse model of inherited glaucoma. Guided by these findings, we discovered that the retinal level of nicotinamide adenine dinucleotide (NAD, a key molecule for mitochondrial health) declines in an age-dependent manner. We hypothesized that this decline in NAD renders retinal ganglion cells susceptible to damage during periods of elevated intraocular pressure. To replete NAD levels in this glaucoma, we administered nicotinamide (the amide of vitamin B3). At the lowest dose tested, nicotinamide robustly protected from glaucoma (~70% of eyes had no detectable glaucomatous neurodegeneration). At this dose, nicotinamide had no influence on intraocular pressure and so its effect was neuroprotective. At the highest dose tested, 93% of eyes had no detectable glaucoma. This represents a ~10-fold decrease in the risk of developing glaucoma. At this dose, intraocular pressure still became elevated but there was a reduction in the degree of elevation showing an additional benefit. Thus, nicotinamide is unexpectedly potent at preventing this glaucoma and is an attractive option for glaucoma therapeutics. Our findings demonstrate the promise for both preventing and treating glaucoma by interventions that bolster metabolism during increasing age and during periods of elevated intraocular pressure. Nicotinamide prevents age-related declines in NAD (a decline that occurs in different genetic contexts and species). NAD precursors are reported to protect from a variety of neurodegenerative conditions. Thus, nicotinamide may provide a much needed neuroprotective treatment against human glaucoma. This manuscript summarizes human data implicating mitochondria in glaucoma, and argues for studies to further assess the safety and efficacy of nicotinamide in human glaucoma care. PMID- 28858162 TI - Cost-effectiveness of Phacoemulsification Versus Combined Phacotrabeculectomy for Treating Primary Angle Closure Glaucoma. AB - PURPOSE: The purpose of this study is to compare the cost effectiveness of phacoemulsification and combined phacotrabeculectomy for lowering intraocular pressure (IOP) in primary angle closure glaucoma (PACG) eyes with coexisting cataract. METHODS: Real-life data of 2 previous randomized control trials that involved 51 medically uncontrolled PACG eyes and 72 medically controlled PACG eyes were utilized to calculate the direct cost of treatment. They were followed up for 2 years. Cost of preoperative assessments, surgical interventions, additional procedures for managing complications and maintenance of filtration, postoperative follow-up, and cost of medications were considered. Cost data of 3 different regions (The United States, People's Republic of China, and Hong Kong) were used for comparison. RESULTS: The corresponding average costs for treating 1 eye with newly diagnosed PACG by phacoemulsification alone and combined phacotrabeculectomy were US$3479 and US$2439 in the United States, US$1051 and US$861 in China, and US$6856 and US$12087 in Hong Kong. Surgical and medications costs were the 2 key contributors. Combined phacotrabeculectomy was more cost effective for IOP reduction when calculating with the United States and China cost data, but was less cost-effective when calculating with the Hong Kong cost data. The cost-effectiveness was insensitive to the costs of follow-up visit and investigations, the cost of surgical operations, and the cost of postoperative procedures, but sensitive to the cost fluctuation of medications. Furthermore, for the medically uncontrolled PACG group, phacoemulsification alone became more cost-effective when the cost of medication was reduced by >75%. CONCLUSIONS: Combined phacotrabeculectomy is a more cost-effective option for lowering IOP in PACG eyes with coexisting cataract, over a 2-year follow-up period. PMID- 28858163 TI - Collaboration, Knowledge, and Respect: The Perfect Combination to Benefit Patient Care. PMID- 28858164 TI - Mentoring: A Must for Nurses. PMID- 28858165 TI - Effect of Herbal Medicines During Surgery. PMID- 28858166 TI - Human Factors Validation of the AeroForm Tissue Expander System for Breast Reconstruction. AB - The tissue expansion process using traditional saline expanders is lengthy and uncomfortable. A new technology has been developed, providing a needle-free option implanted after a mastectomy, and is activated by a handheld remote control releasing small amounts (10 cc) of carbon dioxide from an internal reservoir. The expander is gradually filled with CO2 resulting in mechanical stretching of the overlying tissue. The AeroForm System has been evaluated in a series of clinical trials including a randomized, controlled U.S. study comparing the AeroForm System with saline expanders. Results demonstrated patients can safely and reliably dose and complete their expansions in half the time compared to saline expanders. A human factors validation study was conducted in 8 patients to evaluate whether patients could correctly use the device to complete their expansion at home. The sessions were recorded and data on performance, behavioral, and subjective measures were collected and analyzed and submitted to the FDA as part of the U.S. marketing approval. All 8 participants were successful in using the controller to deliver a simulated dose. Participants found the device easy to use and the training material provided adequate to understand use of the controller. For women who choose 2-stage breast reconstruction, a new safe and effective option is available for tissue expansion, offering a convenient and empowering alternative. The human factors validation study conducted confirmed the simplicity of the device and further validated that the device can be used safely and effectively for breast tissue expansion. PMID- 28858167 TI - Medical Aesthetics Training: Shifting to Collective Competence. AB - With increased demands for medical aesthetics procedures and the sudden profusion of newly licensed, and unlicensed, providers who are performing these medical aesthetics procedures also comes the responsibility to shift to collective competence. Collective competence refers to what occurs among professionals in action, emphasizing the sharing of experiences, knowledge, and perceptions among those who are providing services to the medical aesthetics client. Registered nurses and medical students are not taught to perform cosmetic procedures in basic nursing or medical programs and thus require a post-entry-level education to validate their competency. The current medical aesthetics apprenticeship training approach of see one, do one, and teach one focuses on teaching technical skills and thus does not sufficiently address the ever-changing health care context and the ambiguity in practitioner role. Recent scholars highlight that when health care failed or an error has been identified, it is rarely adduced to an individual's competence but rather is more likely to be a failure of the collective team. In this article, we are advocating for a change in how medical aesthetics practitioners are trained. In particular, it advocates creating opportunities within the curricula to train practitioners as a collective body, as opposed to providing training that focuses on the individual's competence and technical skills alone. PMID- 28858168 TI - Hyaluronidase: Understanding Its Properties and Clinical Application for Cosmetic Injection Adverse Events. AB - The recent global consensus on the management of cosmetic aesthetic injectable complications from hyaluronic acid (HA) has increased the focus on the use of hyaluronidase more than ever before (M. Signorini et al., 2016). A comprehensive knowledge of facial anatomy, including structural positioning of facial arteries and veins, and an extensive knowledge of HA products available for injection procedures, combined with best practice protocols, will assist to prevent adverse events. Despite the growing number of patients using cosmetic fillers for facial restoration, the incidents incidence of adverse events remains low. Indeed, the avoidance of complications through safe and effective injection practice remains the key to preventing the need to use hyaluronidase. PMID- 28858169 TI - Microneedling in Dermatology: A Review. PMID- 28858170 TI - Tissue Expansion: Do We Wait for Chemotherapy? PMID- 28858173 TI - Variations in hypertension awareness, treatment, and control among Ghanaian migrants living in Amsterdam, Berlin, London, and nonmigrant Ghanaians living in rural and urban Ghana - the RODAM study. AB - OBJECTIVES: Hypertension is a major burden among African migrants, but the extent of the differences in prevalence, treatment, and control among similar African migrants and nonmigrants living in different contexts in high-income countries and rural and urban Africa has not yet been assessed. We assessed differences in hypertension prevalence and its management among relatively homogenous African migrants (Ghanaians) living in three European cities (Amsterdam, London, and Berlin) and nonmigrants living in rural and urban Ghana. METHODS: A multicenter cross-sectional study was conducted among Ghanaian adults (n = 5659) aged 25-70 years. Comparisons between sites were made using prevalence ratios with adjustment for age, education, and BMI. RESULTS: The age-standardised prevalence of hypertension was 22 and 28% in rural Ghanaian men and women. The prevalence was higher in urban Ghana [men, 34%; adjusted prevalence ratio = 1.37, 95% confidence interval (CI), 1.10-1.70]; and much higher in migrants in Europe, especially in Berlin (men, 57%; prevalence ratio = 2.21, 1.78-2.73; women, 51%; prevalence ratio = 1.74, 1.45-2.09) than in rural Ghana. Hypertension awareness and treatment levels were higher in Ghanaian migrants than in nonmigrant Ghanaians. However, adequate hypertension control was lower in Ghanaian migrant men in Berlin (20%; prevalence ratio = 0.43 95%, 0.23-0.82), Amsterdam (29%; prevalence ratio = 0.59, 0.35-0.99), and London (36%; prevalence ratio = 0.86, 0.49-1.51) than rural Ghanaians (59%). Among women, no differences in hypertension control were observed. About 50% of migrants to 85% of rural Ghanaians with severe hypertension (Blood pressure > 180/110) were untreated. Antihypertensive medication prescription patterns varied considerably by site. CONCLUSION: Hypertension prevalence, awareness, and treatment levels were generally higher in African migrants, but blood pressure control level was lower in Ghanaian migrant men compared with their nonmigrant peers. Further work is needed to identify key underlying factors to support prevention and management efforts.Supplement Figure 1, http://links.lww.com/HJH/A831. PMID- 28858174 TI - Trends in Characteristics of Patients Listed for Liver Transplantation Will Lead to Higher Rates of Waitlist Removal Due to Clinical Deterioration. AB - BACKGROUND: Changes in the epidemiology of end-stage liver disease may lead to increased risk of dropout from the liver transplant waitlist. Anticipating the future of liver transplant waitlist characteristics is vital when considering organ allocation policy. METHODS: We performed a discrete event simulation to forecast patient characteristics and rate of waitlist dropout. Estimates were simulated from 2015 to 2025. The model was informed by data from the Organ Procurement and Transplant Network, 2003 to 2014. National data are estimated along with forecasts for 2 regions. RESULTS: Nonalcoholic steatohepatitis will increase from 18% of waitlist additions to 22% by 2025. Hepatitis C will fall from 30% to 21%. Listings over age 60 years will increase from 36% to 48%. The hazard of dropout will increase from 41% to 46% nationally. Wait times for transplant for patients listed with a Model for End-Stage Liver Disease (MELD) between 22 and 27 will double. Region 5, which transplants at relatively higher MELD scores, will experience an increase from 53% to 64% waitlist dropout. Region 11, which transplants at lower MELD scores, will have an increase in waitlist dropout from 30% to 44%. CONCLUSIONS: The liver transplant waitlist size will remain static over the next decade due to patient dropout. Liver transplant candidates will be older, more likely to have nonalcoholic steatohepatitis and will wait for transplantation longer even when listed at a competitive MELD score. There will continue to be significant heterogeneity among transplant regions where some patients will be more likely to drop out of the waitlist than receive a transplant. PMID- 28858175 TI - Fulminant type 1 diabetes after adjuvant ipilimumab therapy in cutaneous melanoma. PMID- 28858176 TI - Midterm Outcomes of 12 Renal Transplant Recipients Treated With Eculizumab to Prevent Atypical Hemolytic Syndrome Recurrence. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is an orphan disease with a high rate of recurrence after kidney transplantation. However, reports of successful prevention of posttransplant aHUS recurrence with eculizumab emerged a few years ago. To further delineate its optimal use, we describe the largest series of kidney transplant recipients treated with prophylactic eculizumab. METHODS: Twelve renal transplant recipients with aHUS-related end-stage renal disease received eculizumab: 10 from day 0 and 2 at the time of recurrence (days 6 and 25). Clinical and histological features, complement assessment, and free eculizumab measurements were analyzed. The median follow-up was 24.6 months. RESULTS: Five patients had failed at least 1 previous renal transplant from aHUS. A genetic mutation was identified in 9 patients, anti-H antibodies were found in 2. No patient demonstrated biological recurrence of thrombotic microangiopathy under treatment. Three antibody-mediated rejections (AMRs) occurred without detectable C5 residual activity. AMR was associated with subclinical thrombotic microangiopathy in 2 patients. One patient lost his graft after several complications, including AMR. One patient experienced posttransplant C3 glomerulonephritis. The last median serum creatinine was 128.2 +/- 40.8 MUmol/L. CONCLUSIONS: These data confirm that eculizumab is highly effective in preventing posttransplantation aHUS recurrence, yet may not fully block AMR pathogenesis. PMID- 28858178 TI - Organ Transplantation in Australia: Inequities in Access and Outcome for Indigenous Australians. PMID- 28858179 TI - Lung Retransplantation: Practical and Ethical Considerations Raised by the Hannover Protocol. PMID- 28858180 TI - Predictive approaches for post-therapy PET/CT in patients with extranodal natural killer/T-cell lymphoma: a retrospective study. AB - PURPOSE: The aim of this study was to assess the prognostic capacity of three methods of fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT analysis carried out after therapy in patients with extranodal natural killer/T-cell lymphoma (ENKTL). The three methods of PET/CT analysis included the International Harmonization Project (IHP) criteria, the Deauville five-point scale (5-PS), and standardized uptake value (SUV)-based assessment. PATIENTS AND METHODS: Fifty-nine patients diagnosed with ENKTL were enrolled. Each patient underwent three F-FDG PET/CT scans: (i) baseline, (ii) after two to four cycles of chemotherapy (early response assessment), and (iii) at the end of treatment (evaluation of the final response). Post-therapy F-FDG PET/CT results were determined on the basis of IHP criteria, 5-PS, and change in the maximum F-FDG uptake (DeltaSUVmax). IHP criteria, 5-PS, and DeltaSUVmax were then examined for their ability to predict progression-free survival (PFS) and overall survival (OS). RESULTS: Over a median follow-up of 25 months, 5-PS and DeltaSUVmax were significant predictors of PFS and OS. After multivariate analysis, 5-PS could predict PFS (P=0.008) and OS (P=0.002) independently. DeltaSUVmax was found to be an independent predictor of PFS (P=0.019), but not OS, and had a lower accuracy and positive predictive value than 5-PS. CONCLUSION: Post-therapy PET/CT analysis using the 5-PS is more able to predict survival than analysis with IHP or [INCREMENT]SUVmax in ENKTL patients. PMID- 28858181 TI - Double-Sided Mechanical Shocks Provoke Larger Seated Postural Reactions Compared With Single-Sided Mechanical Shocks. AB - STUDY DESIGN: Human volunteers were exposed experimentally to single-sided mechanical shocks (SSMS) and double-sided mechanical shocks (DSMS) while seated. OBJECTIVE: The aim of this study was to describe and contrast seated postural reactions due to SSMS or DSMS in healthy male adults. SUMMARY OF BACKGROUND DATA: Mechanical shocks to the body, caused when driving on irregular terrain, are suggested to be hazardous to the spine and may be associated with the reported musculoskeletal pain of the back and neck among professional drivers. However, very little is known about the characteristics of seated postural reactions and the biomechanical effects caused by mechanical shocks. METHODS: Twenty healthy male subjects (18-43 years old) were exposed while seated to 5 SSMS and 15 DSMS in lateral directions. The second acceleration in the DSMS was in the opposite direction to the first acceleration and was fast, medium, or slow depending on the speed of direction change. Surface electromyography (EMG) was recorded in muscles of the upper neck, trapezius, erector spinae, and external oblique, while kinematics were recorded with inertial sensors placed at the neck, trunk, and pelvis. Muscle activity was normalized to maximum voluntary contractions (MVCs). RESULTS: The EMG amplitudes were significantly higher (0.6-1%; P < 0.001) for the fast DSMS than all other shocks. Range of motion (ROM) of the neck and trunk was greater during the DSMS than the SSMS. Evoked muscle activity was less than 2% MVC in the trapezius, less than 10% MVC in the erector spinae and upper neck, while the activity exceeded 10% MVC in the external oblique muscles. CONCLUSION: Fast DSMS in lateral directions appear more demanding than SSMS, demonstrating augmented seated postural reactions. However, the present mechanical shocks employed did not seem to induce postural reactions with regard to ROM or muscle activity of a magnitude likely to cause musculoskeletal overload. LEVEL OF EVIDENCE: 4. PMID- 28858182 TI - Metabolic Syndrome and 30-Day Outcomes in Elective Lumbar Spinal Fusion. AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of this study was to evaluate the effect of metabolic syndrome (MetS) on 30-day morbidity and mortality following elective lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: MetS is a variable combination of hypertension, obesity, elevated fasting plasma glucose, and dyslipidemia.MetS has been associated with an increased risk of postoperative morbidity and mortality in multiple surgical settings. To our knowledge, the effect of MetS on 30-day outcomes following elective lumbar spinal fusion has not been well studied. METHODS: An analysis of ACS-NSQIP data was performed between 2006 and 2013. Patients undergoing elective posterior lumbar fusion were identified. Emergency procedures, infections, tumor cases, and revision surgeries were excluded. Patients were defined as having MetS if they had a history of hypertension requiring medication, diabetes, and a body mass index (BMI) >=30 kg/m. RESULTS: One thousand five hundred ninety (10.2%) patients with MetS were identified. A mild increase in major (P = 0.040) and minor complications (P = 0.003) in patients with MetS was noted. MetS was associated with increased rates of pulmonary complications (1.9% compared with 1.0%; P = 0.001), sepsis (1.7% compared with 0.9%; P = 0.005), and acute post-op renal failure (0.4% compared with 0%; P < 0.001). Multivariate analysis confirmed MetS to be an independent predictor of pulmonary complications [odds ratio (OR) 1.51; 95% confidence interval (95% CI 1.00-2.27); P = 0.048], sepsis (OR 1.56; 95% CI 1.01-2.42; P = 0.039), and acute postoperative renal failure (OR 6.95; 95% CI 2.23-21.67; P = 0.001). MetS status was associated with a mild increase in total hospital length of stay (4.38 compared with 3.81 days; P < 0.001). CONCLUSION: While MetS is a predictor of postoperative acute renal failure, it only slightly increases the risk of overall complications and is not associated with increased rates of 30-day reoperations or readmissions following elective lumbar fusion. LEVEL OF EVIDENCE: 3. PMID- 28858183 TI - Poorer Fusion Outcomes in Diabetic Cervical Spondylotic Myelopathy Patients Undergoing Single-level Anterior Cervical Discectomy and Fusion Does Not Compromise Functional Outcomes and Quality of Life. AB - STUDY DESIGN: Retrospective matched pair cohort study using prospectively collected registry data. OBJECTIVES: The aim of this study was to determine whether patients with DM have poorer patient-reported outcomes and poorer fusion rates after undergoing a single-level anterior cervical discectomy and fusion (ACDF) for cervical myelopathy. SUMMARY OF BACKGROUND DATA: ACDF remains the most common procedure in the treatment of cervical spondylotic myelopathy (CSM); however, there is a paucity of literature with regards to patient-reported outcome measures (PROMs), health-related quality-of-life (HRQOL) scores, and fusion rates post-ACDF in diabetic patients with CSM. METHODS: From 2002 to 2012, 29 diabetic patients were matched with 29 nondiabetic controls. Patient demographics, perioperative data, and validated spine-specific scores including the Numerical Pain Rating Scale on Neck Pain and Upper Limb Pain, American Academy of Orthopaedic Surgeons (AAOS) neck pain and disability scores, AAOS Neurogenic Symptoms Score, Neck Disability Index, Japanese Orthopaedic Association Cervical Myelopathy Score, and Short Form 36 Physical/Mental Component Summaries were recorded. Fusion rates based on Bridwell grading were assessed at 2 years. RESULTS: After matching, there were no significant preoperative differences in patient demographics, clinical outcomes, PROMs or HRQoL measures between the DM and control group (P > 0.05). There was no difference in either length of hospital stay (P = 0.92) or length of surgery (P = 0.92) between the two groups. At 2 years postoperatively, there were no significant differences between validated spine-specific scores, PROMs, HRQoL scores, satisfaction rates, or fulfilment of expectations between the two groups. Significant poorer Bridwell fusion grades were noted in the DM group at 2 years postoperatively (P < 0.05). Subgroup analysis within the DM group demonstrated that glycated hemoglobin levels had no impact on functional outcomes, fulfilment of expectations, or patient satisfaction at 2 years (P > 0.05). CONCLUSION: Despite poorer fusion outcomes following single-level ACDF for symptomatic CSM, there was no significant difference in validated spine outcome scores, PROMs, HRQoL measures, or satisfaction levels when compared to nondiabetic controls at short-term follow-up. LEVEL OF EVIDENCE: 3. PMID- 28858184 TI - Idiopathic Spinal Epidural Fat Accumulation Is Associated With Hyperlipidemia. AB - STUDY DESIGN: Single-center retrospective analysis of consecutively collected data. OBJECTIVE: To determine the clinical characteristics of idiopathic spinal epidural lipomatosis (SEL). SUMMARY OF BACKGROUND DATA: SEL is associated with the overt accumulation of nonencapsulated adipose tissue in the epidural space, leading to spinal cord or nerve root compression. The etiology of this condition is currently not completely understood. METHODS: Data of 166 male patients who underwent primary surgery for lumbar spinal canal stenosis (LSS) from May 2013 to February 2016 were retrospectively reviewed. Participants were divided into three groups based on the degree of epidural lipomatous lesion. Patient data of age at surgery, body mass index, prevalence of common noncommunicable diseases, blood tests, arteriosclerotic index, and preoperative clinical scores (assessed using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire) were evaluated. Multivariate analysis was performed to assess the potential associated factors for idiopathic SEL. RESULTS: Patients with LSS with severe SEL had a significantly higher body mass index and elevated serum levels of total cholesterol and triglyceride compared with those without SEL. Analysis of preoperative clinical scores revealed that patients with SEL experienced pain more frequently and showed less walking ability than did those without SEL. Multivariate analysis revealed that hyperlipidemia was significantly associated with idiopathic SEL (odds ratio = 3.74, 95% confidence interval = 1.31-10.64). CONCLUSION: Our data suggest that aberrant lipid metabolism is related to the pathogenesis of idiopathic SEL and that patients with LSS with idiopathic SEL have more severe pain than do those without SEL. LEVEL OF EVIDENCE: 3. PMID- 28858185 TI - Lumbar Spine Fusion Surgery in Solid Organ Transplant Recipients Is Associated With Increased Medical Complications and Mortality. AB - STUDY DESIGN: Retrospective database review. OBJECTIVE: To characterize the outcomes of solid organ transplant (SOT) patients after one- or two-level lumbar fusion surgery. SUMMARY OF BACKGROUND DATA: Over the past decade advances in SOT patients have improved graft survival. As such, this patient population is increasingly eligible for elective surgery such as lumbar fusion procedures to improve mobility and quality of life. However, the outcomes of spine surgery in this population are not well defined. METHODS: Data from the full 100% Medicare sample between 2005 and 2014 were used for the study. Patients were included if they had an elective one- or two-level lumbar spine fusion and previous history of renal, heart, liver, or lung SOT patients during this period. SOT patients were compared to non-SOT patients with respect to baseline characteristics, 90 day medical complications, 1-year rate of revision surgery, and 1-year mortality. RESULTS: There were 961 patients in the transplant cohort and 258,342 in the non SOT cohort. Seventy-seven percent of the SOT patients had prior renal transplant. SOT patients had a longer length of stay (P < 0.001), and a higher 30-day readmission rate compared to non-SOT patients (P = < 0.001). In addition, SOT patients experienced a 23.8% rate of 90-day postoperative major medical complications and 3.0%, 1-year mortality, significantly larger than respective rates in the control population (P < 0.001). One-year infection, revision surgery rates, and wound dehiscence were not significantly different between the two cohorts. CONCLUSION: Spine surgery is associated with significant medical complications and 1-year mortality in the SOT population. Although there may be a substantial benefit from lumbar fusion in the SOT population, judicious patient selection is of paramount importance. LEVEL OF EVIDENCE: 3. PMID- 28858186 TI - Commentary: Poorer Fusion Outcomes in Diabetic Cervical Spondylotic Myelopathy Patients. PMID- 28858187 TI - Commentary of Acute and Hyperacute Thoracolumbar Corpectomy for Traumatic Burst Fractures Using a Mini-open Lateral Approach. PMID- 28858188 TI - Spinal Deformities in Romantic Operas. AB - : The librettos of several of the most famous Romantic operas contain references to disease. These operas can serve as valuable sources of information regarding how spinal deformities were understood during the nineteenth century by physicians and lay persons alike. Original librettos of the operas "Rigoletto" (1851) by Giuseppe Verdi (1813-1901) and "La Esmeralda" (1836) by Louise Bertin (1805-1877) were analyzed. In both operas, spinal deformities of Rigoletto and Quasimodo are a central issue. In detail, Quasimodo could suffer from von Recklinghausen's neurofibromatosis, while Rigoletto could be affected by severe adolescent idiopathic scoliosis. The plays are an expression of the nineteenth century attitude toward deformity: the hunchbacks are ridiculed and excluded from the society due to their deformity. Thus, they are forced by society to act as ugly and evil beings. Although both Rigoletto and Quasimodo show an intense love, at the end of each opera, they are defeated by loss of this love. This is an evident sign that, despite its willingness to tackle the subject, nineteenth century society was not still ready to attribute success or human value to people affected by disabilities.Level of Evidence: 5. PMID- 28858189 TI - Sex-Related Differences in the Developmental Morphology of the Atlas: A Computed Tomography Study. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To elucidate sex-related differences in the age at synchondroses closure, the normative size of the atlas, and the ossification patterns of the atlas in Japanese children. SUMMARY OF BACKGROUND DATA: The atlas develops from three ossification centers during childhood. The anterior and posterior synchondroses, which are separate ossification centers, mimic fracture lines on computed tomography (CT). Sex related differences of age dependent morphological changes of the atlas in a large sample size have not been reported. METHODS: This study analyzed data of 688 subjects (449 boys) between 0 and 18 years old who underwent CT examination of the head and/or neck between January 2010 and July 2016. The age at synchondroses closure, anteroposterior outer, inner, and spinal canal widths of the atlas, and variations of the ossification centers were examined. RESULTS: Anterior synchondroses closed by 10 years in boys and by 7 years in girls. Significant earlier closure of anterior synchondroses was observed in girls than in boys (P < 0.05 at 4 and 5 years old). Posterior synchondrosis closed by 6 years in boys and by 5 years in girls. The outer, inner, and spinal canal widths increased up to 10 to 15 years in both sexes, although all three parameters in girls peaked 3 years earlier than those in boys. All parameters in boys were significantly larger than those in girls, except in the 10- to 12-year-old age category. Two or more ossification centers in the anterior arch were observed in 18.3% subjects, and 6% had midline ossification centers in the posterior arch of the atlas. CONCLUSION: Distinct sex-related differences in the age at anterior synchondroses closure and the size of the atlas were observed in Japanese children. Knowledge of morphological features of the atlas could help distinguish fractures from synchondroses. LEVEL OF EVIDENCE: 3. PMID- 28858190 TI - Performance on Balance Evaluation Systems Test (BESTest) Impacts Health-Related Quality of Life in Adult Spinal Deformity Patients. AB - STUDY DESIGN: Prospective single-center study. OBJECTIVE: Study investigates how dynamic balance performance complements 2D static radiographic measurements and demographics in terms of understanding health-related quality of life in adult spinal deformity (ASD) patients. SUMMARY OF BACKGROUND DATA: Recent insights suggest that demographic variables have a stronger impact on health-related quality of life than 2D radiographic spinopelvic parameters in ASD patients. METHODS: Nine healthy volunteers and 36 ASD patients following inclusion criteria were recruited. Demographics, Scoliosis Research Society Score-22r (SRS-22r), Oswestry Disability Index (ODI), Core Outcome Measures Index (COMI), 2D radiographic spinopelvic measurements, and performance on Balance Evaluation Systems Test (BESTest), and Trunk Control Measurement Scale (TCMS) were determined for each subject. Nonparametric tests, Spearman correlations, univariate, and stepwise-like linear multivariate regression analysis were performed. RESULTS: BESTest and TCMS had significant lower values in the ASD group versus the control group (P = 0.000). In the ASD group, Cumulative Illness Rating Scale (CIRS) correlated fair to ODI, COMI (0.441 >= r >= 0.383, P < 0.021) and to SRS-22-r (r = -0.335, P = 0.046), Mini Mental State Examination correlated fair to COMI (r = -0.352, P = 0.035), "Pelvic Incidence minus Lumbar Lordosis" correlated fair to ODI (r = 0.361, P = 0.031), BESTest correlated moderate to ODI and COMI (r <= -0.505; P <= 0.002), TCMS correlated fair to ODI (r = -0.356; P = 0.033). CIRS and BESTest were significant predictive variables for COMI based on univariate analysis in ASD patients. Multivariate regression analysis including demographics, 2D static radiographic parameters, and dynamic balance scales identified BESTest as single independent variable (P = 0.000) to predict COMI (adjusted R = 0.285) in ASD patients. CONCLUSION: BESTest has a higher potential than demographic and 2D radiographic spinopelvic parameters to predict quality of life in ASD patients. Further research is necessary to identify the impact of ASD on quality of life. LEVEL OF EVIDENCE: 3. PMID- 28858191 TI - Maximal Respiratory Muscle Strength and Vital Capacity in Children With Early Onset Scoliosis. AB - STUDY DESIGN: Descriptive cross-sectional study. OBJECTIVE: To measure respiratory muscle function in children with early onset scoliosis (EOS), determine the frequency of respiratory muscle weakness, and correlate these measures with vital capacity, body mass index, and Cobb angle. SUMMARY OF BACKGROUND DATA: Progressive restrictive respiratory disease is common among children with moderate to severe EOS. Reduced respiratory muscle strength is associated with the loss of lung function in adolescents and adults with scoliosis. We hypothesized that reduced inspiratory and expiratory respiratory muscle strength also occur in children with EOS and correlate with reduced vital capacity, poor nutritional status, and severity of the spine deformity. METHODS: We measured maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP), forced vital capacity (FVC), body mass index IBMI), and Cobb angle in 49 children with EOS but with no diagnosis of underlying muscle weakness. We measured these indices in 12 children serially over 18 months to see if abnormal respiratory muscle function was sustained. RESULTS: FVC averaged 51% (SD 21) of predicted norms with 26 subjects having an FVC <50% predicted. The mean MIP was 57% (SD 25) and the mean MEP was 53% (SD 23) of predicted norms. Thirteen (27%) of the group had MIP values >2SD below the age and sex-based norms. BMI ranged between 1% and 99% of age-based norms. Cobb angle averaged 59 degrees (SD27). MIP% and MEP% significantly correlated with FVC% (r =0.37, P = 0.01 and r = 0.52, P < 0.001 respectively)) but not with BMI or Cobb angle. Reduced MIP% and MEP% were sustained over 7 to 41 months. CONCLUSION: Respiratory muscle weakness is common and persistent in children with EOS and correlates with reductions in vital capacity. Mechanisms for abnormal respiratory function are unclear but must be determined to develop surgical treatment strategies that preserve respiratory muscle function in children with EOS throughout childhood. LEVEL OF EVIDENCE: 2. PMID- 28858192 TI - BLEB-RELATED ENDOPHTHALMITIS AFTER USE OF THE INVITRIA INJECTION GUIDE. AB - PURPOSE: To present the case of a patient who developed bleb-related endophthalmitis after an intravitreal injection using the InVitria injection guide, alongside a review of the literature on bleb-related endophthalmitis. METHODS: Our case is presented in context of the current literature on bleb related endophthalmitis. RESULTS: Bleb-related endophthalmitis occurs in up to 2% of eyes within 5 years of filtering glaucoma surgery. Risk factors include bleb leakage, use of anti-fibrinolytic agents, blepharitis, hypotony, and nasolacrimal duct obstruction. Our patient presented with a bleb leak and bleb-related endophthalmitis 2 weeks after an intravitreal injection using the InVitria injection guide. CONCLUSION: Injection guides can cause bleb trauma and resulting bleb leakage. They should be avoided in patients with filtering glaucoma surgery. PMID- 28858193 TI - UTILITY OF INTRAOPERATIVE OPTICAL COHERENCE TOMOGRAPHY IN ACUTE ENDOPHTHALMITIS. AB - PURPOSE: To evaluate the efficacy of intraoperative optical coherence tomography (OCT) during vitrectomy for acute endophthalmitis. METHODS: The intraoperative and postoperative images of an 87-year-old woman with acute endophthalmitis after uncomplicated cataract surgery were analyzed. RESULTS: At presentation, the vision of the patient was 20/2000, and the preoperative OCT was unable to obtain clear images because of vitreous opacities. Intraoperative OCT showed that the inner retinal layer was hyperreflective because of diffuse retinal edema. Cystic changes were also present in the retina. A fibrin-like epiretinal membrane that was connected to the hyperreflective inner retinal layer was detected, and the retinal microstructures were well preserved. Intravitreal injections of vancomycin and ceftazidime were given at the end of the surgery. Postoperative examination showed that the epiretinal membrane-like tissue disappeared on the OCT image 1 month after the surgery, and the vision improved to 20/30. CONCLUSION: Intraoperative OCT can be useful to examine the structural alterations of the retina in eyes with vitreous opacities that prevent preoperative OCT examinations. Evaluations of intraoperative OCT images can provide information on what surgical procedures are needed. PMID- 28858194 TI - Pharmacy blood pressure: a common, useful, and neglected out of office blood pressure measurement method. PMID- 28858195 TI - Caudal medullary and cervical spinal cord neurons in cardiovascular regulation. PMID- 28858196 TI - Lack of association between passive smoking and blood pressure, lipids, and fasting glucose. PMID- 28858197 TI - On aortic pressure waveforms and a happy or unhappy marriage between wave propagation and Windkessel models. PMID- 28858198 TI - Central diastolic pressure exponential decay constant and subendocardial flow supply. PMID- 28858199 TI - Propensity to calcification as a pathway to renal hypoxia in chronic kidney disease and in hypertension. PMID- 28858200 TI - Sympathomodulatory effects of sodium-glucose transporter-2 inhibitors in the kidneys and beyond. PMID- 28858201 TI - Aldoscore to predict postoperative atrial fibrillation after cardiac surgery: external validation in a Japanese cohort. PMID- 28858202 TI - Factitious hypertensive crises unraveled by Doppler ultrasound: potential limitations of oscillometric blood pressure assessment. PMID- 28858203 TI - Human Leukocyte Antigen Class I and Class II Polymorphisms and Serum Cytokine Profiles in Cervical Cancer. AB - Only a small proportion of women who are exposed to infection with high-risk human papillomavirus (HR-HPV) progress to persistent infection and develop cervical cancer (CC). The immune response and genetic background of the host may affect the risk of progression from a HR-HPV infection to lesions and cancer. However, to our knowledge, no studies has been conducted to evaluate the relationship between variability of human leukocyte antigens (HLA) genes and serum cytokine expression in this pathology. In the current study, we examined the associations of HLA alleles and haplotypes including Class I (HLA-A, -B and C) and II (HLA-DRB1, -DQA1 and -DQB1) with serum levels of cytokines interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), IL-10 and IL-17 as well as risks of HPV infections, lesions and CC among admixed Brazilian women. HLA polymorphisms were associated with an increased risk or protection from HPV, lesions and CC. Additionally, we demonstrated a potential association of a HLA class I haplotype (HLA-B*14-C*08) with higher IL-10 cytokine serum levels in cervical disease, suggesting an association between HLA class I and specific cytokines in cervical carcinogenesis. However, larger studies with detailed HPV types coupled with genetic data are needed to further evaluate the effects of HLA and CC by HPV genotype. PMID- 28858204 TI - Patient-Derived Orthotopic Xenograft (PDOX) Models of Melanoma. AB - Metastatic melanoma is a recalcitrant tumor. Although "targeted" and immune therapies have been highly touted, only relatively few patients have had durable responses. To overcome this problem, our laboratory has established the melanoma patient-derived orthotopic xenograft (PDOX) model with the use of surgical orthotopic implantation (SOI). Promising results have been obtained with regard to identifying effective approved agents and experimental therapeutics, as well as combinations of the two using the melanoma PDOX model. PMID- 28858205 TI - Impact of Novel Prebiotic Galacto-Oligosaccharides on Various Biomarkers of Colorectal Cancer in Wister Rats. AB - Colorectal cancer (CRC) is one of the leading causes of cancer deaths around the globe. Bioactive food ingredients such as prebiotics have protective potential in colon cancer. Data on galacto-oligosaccharides (GalOS) against CRC are very limited and GalOS used in this study have beta-1,6 and beta-1,3 as major glycosidic linkages and, to our best knowledge, were never used before against any cancer treatment. This study aims to investigate the protective role of novel GalOS against various biomarkers of CRC including aberrant crypt foci (ACF), bacterial enzymes and short chain fatty acids (SCFA) in a rodent model induced with 1,2-dimethylhydrazine dihydrochloride (DMH). Inulin group was taken as positive control in present study to compare novel GalOS protective effects. GalOS doses of 76-151 mg and inulin doses of 114 mg were given to different groups treated with DMH. Results showed that ACF formation was significantly (p <= 0.05) less in high dose GalOS group (27.3%). GalOS also had protective effects against DMH-induced body weight loss and showed higher level of cecal and fecal SCFA (acetate, propionate and butyrate). High doses of GalOS also resulted in significant (p <= 0.05) reduction of bacterial enzymatic activities. Increased populations of beneficial bacteria (bifidobacteria and lactobacilli) and decreased concentrations of harmful bacteria were observed in all prebiotics treatment groups. It can be concluded that novel GalOS exhibit robust protective activity against ACF formation in vivo. PMID- 28858206 TI - Erratum: Haraux, E., et al. Maternal Exposure to Domestic Hair Cosmetics and Occupational Endocrine Disruptors Is Associated with a Higher Risk of Hypospadias in the Offspring. Int. J. Environ. Res. Public Health 2016, 14, 27. AB - Due to an error during production, some data presented in Table 1 in the Experimental section of the published paper [1] were incorrect.[...]. PMID- 28858207 TI - X Chromosome Evolution in Cetartiodactyla. AB - The phenomenon of a remarkable conservation of the X chromosome in eutherian mammals has been first described by Susumu Ohno in 1964. A notable exception is the cetartiodactyl X chromosome, which varies widely in morphology and G-banding pattern between species. It is hypothesized that this sex chromosome has undergone multiple rearrangements that changed the centromere position and the order of syntenic segments over the last 80 million years of Cetartiodactyla speciation. To investigate its evolution we have selected 26 evolutionarily conserved bacterial artificial chromosome (BAC) clones from the cattle CHORI-240 library evenly distributed along the cattle X chromosome. High-resolution BAC maps of the X chromosome on a representative range of cetartiodactyl species from different branches: pig (Suidae), alpaca (Camelidae), gray whale (Cetacea), hippopotamus (Hippopotamidae), Java mouse-deer (Tragulidae), pronghorn (Antilocapridae), Siberian musk deer (Moschidae), and giraffe (Giraffidae) were obtained by fluorescent in situ hybridization. To trace the X chromosome evolution during fast radiation in specious families, we performed mapping in several cervids (moose, Siberian roe deer, fallow deer, and Pere David's deer) and bovid (muskox, goat, sheep, sable antelope, and cattle) species. We have identified three major conserved synteny blocks and rearrangements in different cetartiodactyl lineages and found that the recently described phenomenon of the evolutionary new centromere emergence has taken place in the X chromosome evolution of Cetartiodactyla at least five times. We propose the structure of the putative ancestral cetartiodactyl X chromosome by reconstructing the order of syntenic segments and centromere position for key groups. PMID- 28858209 TI - Understanding Animal Detection of Precursor Earthquake Sounds. AB - We use recent research to provide an explanation of how animals might detect earthquakes before they occur. While the intrinsic value of such warnings is immense, we show that the complexity of the process may result in inconsistent responses of animals to the possible precursor signal. Using the results of our research, we describe a logical but complex sequence of geophysical events triggered by precursor earthquake crustal movements that ultimately result in a sound signal detectable by animals. The sound heard by animals occurs only when metal or other surfaces (glass) respond to vibrations produced by electric currents induced by distortions of the earth's electric fields caused by the crustal movements. A combination of existing measurement systems combined with more careful monitoring of animal response could nevertheless be of value, particularly in remote locations. PMID- 28858210 TI - HPLC-HRMS Quantification of the Ichthyotoxin Karmitoxin from Karlodinium armiger. AB - Being able to quantify ichthyotoxic metabolites from microalgae allows for the determination of ecologically-relevant concentrations that can be simulated in laboratory experiments, as well as to investigate bioaccumulation and degradation. Here, the ichthyotoxin karmitoxin, produced by Karlodinium armiger, was quantified in laboratory-grown cultures using high-performance liquid chromatography (HPLC) coupled to electrospray ionisation high-resolution time-of flight mass spectrometry (HRMS). Prior to the quantification of karmitoxin, a standard of karmitoxin was purified from K. armiger cultures (80 L). The standard was quantified by fluorescent derivatisation using Waters AccQ-Fluor reagent and derivatised fumonisin B1 and fumonisin B2 as standards, as each contain a primary amine. Various sample preparation methods for whole culture samples were assessed, including six different solid phase extraction substrates. During analysis of culture samples, MS source conditions were monitored with chloramphenicol and valinomycin as external standards over prolonged injection sequences (>12 h) and karmitoxin concentrations were determined using the response factor of a closely eluting iturin A2 internal standard. Using this method the limit of quantification was 0.11 MUg.mL-1, and the limit of detection was found to be 0.03 MUg.mL-1. Matrix effects were determined with the use of K. armiger cultures grown with 13C-labelled bicarbonate as the primary carbon source. PMID- 28858208 TI - Inflammatory Diseases and Growth: Effects on the GH-IGF Axis and on Growth Plate. AB - This review briefly describes the most common chronic inflammatory diseases in childhood, such as cystic fibrosis (CF), inflammatory bowel diseases (IBDs), juvenile idiopathic arthritis (JIA), and intrauterine growth restriction (IUGR) that can be considered, as such, for the changes reported in the placenta and cord blood of these subjects. Changes in growth hormone (GH) secretion, GH resistance, and changes in the insulin-like growth factor (IGF) system are described mainly in relationship with the increase in nuclear factor-kappaB (NF kappaB) and pro-inflammatory cytokines. Changes in the growth plate are also reported as well as a potential role for microRNAs (miRNAs) and thus epigenetic changes in chronic inflammation. Many mechanisms leading to growth failure are currently known; however, it is clear that further research in the field is still warranted. PMID- 28858211 TI - CytoCluster: A Cytoscape Plugin for Cluster Analysis and Visualization of Biological Networks. AB - Nowadays, cluster analysis of biological networks has become one of the most important approaches to identifying functional modules as well as predicting protein complexes and network biomarkers. Furthermore, the visualization of clustering results is crucial to display the structure of biological networks. Here we present CytoCluster, a cytoscape plugin integrating six clustering algorithms, HC-PIN (Hierarchical Clustering algorithm in Protein Interaction Networks), OH-PIN (identifying Overlapping and Hierarchical modules in Protein Interaction Networks), IPCA (Identifying Protein Complex Algorithm), ClusterONE (Clustering with Overlapping Neighborhood Expansion), DCU (Detecting Complexes based on Uncertain graph model), IPC-MCE (Identifying Protein Complexes based on Maximal Complex Extension), and BinGO (the Biological networks Gene Ontology) function. Users can select different clustering algorithms according to their requirements. The main function of these six clustering algorithms is to detect protein complexes or functional modules. In addition, BinGO is used to determine which Gene Ontology (GO) categories are statistically overrepresented in a set of genes or a subgraph of a biological network. CytoCluster can be easily expanded, so that more clustering algorithms and functions can be added to this plugin. Since it was created in July 2013, CytoCluster has been downloaded more than 9700 times in the Cytoscape App store and has already been applied to the analysis of different biological networks. CytoCluster is available from http://apps.cytoscape.org/apps/cytocluster. PMID- 28858212 TI - Novel Molecular Targets for Chemoprevention in Malignancies of the Head and Neck. AB - Cancers of the head and neck region are among the leading causes of cancer related mortalities worldwide. Oral leukoplakia and erythroplakia are identified as precursor lesions to malignancy. Patients cured of an initial primary head and neck cancer are also susceptible to developing second primary tumors due to cancerization of their mucosal field. Multi-step acquisition of genetic mutations leading to tumorigenesis and development of invasive cancer has been previously described. Recently, whole exome sequencing of tumor specimens has helped to identify driver mutations in this disease. For these reasons, chemoprevention or the use of systemic or biologic agents to prevent carcinogenesis is an attractive concept in head and neck cancers. Nonetheless, despite extensive clinical research in this field over the past couple decades, no standard of care option has emerged. This review article reports on targeted interventions that have been attempted in clinical trials to date, and focuses on novel molecular pathways and drugs in development that are worthy of being tested for this indication as part of future endeavors. PMID- 28858213 TI - Recreational Exposure during Algal Bloom in Carrasco Beach, Uruguay: A Liver Failure Case Report. AB - In January 2015, a 20-month-old child and her family took part in recreational activities at Carrasco and Malvin beaches (Montevideo, Uruguay). An intense harmful algae bloom (HAB) was developing along the coast at that time. A few hours after the last recreational exposure episode, the family suffered gastrointestinal symptoms which were self-limited except in the child's case, who was admitted to hospital in Uruguay with diarrhea, vomiting, fatigue, and jaundice. The patient had increased serum levels of liver enzymes and bilirubin and five days later presented acute liver failure. She was referred to the Italian Hospital in Buenos Aires, being admitted with grade II-III encephalopathy and hepatomegaly and requiring mechanical respiratory assistance. Serology tests for hepatitis A, B, and C, Epstein-Barr virus, and cytomegalovirus were negative. Laboratory features showed anemia, coagulopathy, and increased serum levels of ammonium, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. Autoimmune Hepatitis Type-II (AH-II) was the initial diagnosis based on a liver kidney microsomal type 1 antibodies (LKM-1) positive result, and twenty days later a liver transplant was performed. The liver histopathology had indicated hemorrhagic necrosis in zone 3, and cholestasis and nodular regeneration, which were not characteristic of AH-II. LC/ESI-HRMS (liquid chromatography electrospray ionization high-resolution mass spectrometry) analysis of MCs in the explanted liver revealed the presence of Microsytin-LR (MC LR) (2.4 ng.gr-1 tissue) and [D-Leu1]MC-LR (75.4 ng.gr-1 tissue), which constitute a toxicological nexus and indicate a preponderant role of microcystins in the development of fulminant hepatitis. PMID- 28858214 TI - Membrane-Accelerated Amyloid-beta Aggregation and Formation of Cross-beta Sheets. AB - Amyloid- beta aggregates play a causative role in Alzheimer's disease. These aggregates are a product of the physical environment provided by the basic neuronal membrane, composed of a lipid bilayer. The intrinsic properties of the lipid bilayer allow amyloid- beta peptides to nucleate and form well-ordered cross- beta sheets within the membrane. Here, we correlate the aggregation of the hydrophobic fragment of the amyloid- beta protein, A beta 25 - 35 , with the hydrophobicity, fluidity, and charge density of a lipid bilayer. We summarize recent biophysical studies of model membranes and relate these to the process of aggregation in physiological systems. PMID- 28858215 TI - Stem Cell-Like Properties of CK2beta-down Regulated Mammary Cells. AB - The ubiquitous protein kinase CK2 has been demonstrated to be overexpressed in a number of human tumours. This enzyme is composed of two catalytic alpha or alpha' subunits and a dimer of beta regulatory subunits whose expression levels are probably implicated in CK2 regulation. Several recent papers reported that unbalanced expression of CK2 subunits is sufficient to drive epithelial to mesenchymal transition, a process involved in cancer invasion and metastasis. Herein, through transcriptomic and miRNA analysis together with comparison of cellular properties between wild type and CK2beta-knock-down MCF10A cells, we show that down-regulation of CK2beta subunit in mammary epithelial cells induces the acquisition of stem cell-like properties associated with perturbed polarity, CD44high/CD24low antigenic phenotype and the ability to grow under anchorage independent conditions. These data demonstrate that a CK2beta level establishes a critical cell fate threshold in the control of epithelial cell plasticity. Thus, this regulatory subunit functions as a nodal protein to maintain an epithelial phenotype and its depletion drives breast cell stemness. PMID- 28858216 TI - Stable Membrane-Association of mRNAs in Etiolated, Greening and Mature Plastids. AB - Chloroplast genes are transcribed as polycistronic precursor RNAs that give rise to a multitude of processing products down to monocistronic forms. Translation of these mRNAs is realized by bacterial type 70S ribosomes. A larger fraction of these ribosomes is attached to chloroplast membranes. This study analyzed transcriptome-wide distribution of plastid mRNAs between soluble and membrane fractions of purified plastids using microarray analyses and validating RNA gel blot hybridizations. To determine the impact of light on mRNA localization, we used etioplasts, greening plastids and mature chloroplasts from Zea mays as a source for membrane and soluble extracts. The results show that the three plastid types display an almost identical distribution of RNAs between the two organellar fractions, which is confirmed by quantitative RNA gel blot analyses. Furthermore, they reveal that different RNAs processed from polycistronic precursors show transcript-autonomous distribution between stroma and membrane fractions. Disruption of ribosomes leads to release of mRNAs from membranes, demonstrating that attachment is likely a direct consequence of translation. We conclude that plastid mRNA distribution is a stable feature of different plastid types, setting up rapid chloroplast translation in any plastid type. PMID- 28858217 TI - Relationship between Social Support Networks and Physical Functioning in Older Community-Dwelling Mexicans. AB - Some studies have demonstrated the relationship between social support networks (SSNs) and health status. In this sense, it has been considered that physical and mental functioning is a key indicator of the health in the age people. The aim of this study was to determine the association between social support networks and physical functioning. A cross-sectional study was carried out including a convenience sample of 150 older community-dwelling Mexicans. We assessed the familial, extra-familial and institutional SSNs; social contacts; the activities of daily living (ADL); the instrumental activities of daily living (IADLs); and physical functioning task (PFT) performance among study participants. Of the 150 older subjects, 53 reported living alone (35%), 113 (75%) reported having few SSNs, and 37 (25%) reported having enough SSNs. Persons with few familial SSNs were at increased odds of demonstrating dependence in at least one of the ADL (OR = 3.25, 95% CI 1.06-9.92, p < 0.05). Likewise, persons with few institutional SSNs and few social contacts were at increased odds of demonstrating dependence in at least one of the IADL (OR = 6.96, 95% CI 1.57-30.7, p < 0.01; OR = 5.02, 95% CI 1.44-17.5, p < 0.01, respectively). We also observed that having few extra familial SSNs and few social contacts were the main risk factors for PFT dependence, with ORs of 3.70 (95% CI 1.21-11.2, p < 0.05) and 3.85 (95% CI 1.10 13.5, p < 0.05), respectively. Our findings suggest that having few SSNs could be a significant risk factor for reduced physical functioning in older adults. PMID- 28858218 TI - A Novel Workflow to Enrich and Isolate Patient-Matched EpCAMhigh and EpCAMlow/negative CTCs Enables the Comparative Characterization of the PIK3CA Status in Metastatic Breast Cancer. AB - Circulating tumor cells (CTCs), potential precursors of most epithelial solid tumors, are mainly enriched by epithelial cell adhesion molecule (EpCAM) dependent technologies. Hence, these approaches may overlook mesenchymal CTCs, considered highly malignant. Our aim was to establish a workflow to enrich and isolate patient-matched EpCAMhigh and EpCAMlow/negative CTCs within the same blood samples, and to investigate the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutational status within single CTCs. We sequentially processed metastatic breast cancer (MBC) blood samples via CellSearch(r) (EpCAM based) and via ParsortixTM (size-based) systems. After enrichment, cells captured in ParsortixTM cassettes were stained in situ for nuclei, cytokeratins, EpCAM and CD45. Afterwards, sorted cells were isolated via CellCelectorTM micromanipulator and their genomes were amplified. Lastly, PIK3CA mutational status was analyzed by combining an amplicon-based approach with Sanger sequencing. In 54% of patients' blood samples both EpCAMhigh and EpCAMlow/negative cells were identified and successfully isolated. High genomic integrity was observed in 8% of amplified genomes of EpCAMlow/negative cells vs. 28% of EpCAMhigh cells suggesting an increased apoptosis in the first CTC-subpopulation. Furthermore, PIK3CA hotspot mutations were detected in both EpCAMhigh and EpCAMlow/negative CTCs. Our workflow is suitable for single CTC analysis, permitting-for the first time-assessment of the heterogeneity of PIK3CA mutational status within patient matched EpCAMhigh and EpCAMlow/negative CTCs. PMID- 28858219 TI - A Novel Impedance Biosensor for Measurement of Trans-Epithelial Resistance in Cells Cultured on Nanofiber Scaffolds. AB - Nanofibrous scaffolds provide high surface area for cell attachment, and resemble the structure of the collagen fibers which naturally occur in the basement membrane and extracellular matrix. A label free and non-destructive method of assessing the interaction of cell tissue and scaffolds aids in the ability to discern the effective quality and magnitude of any scaffold modifications. Impedance cell spectroscopy is a biosensing method that employs a functional approach to assessing the cell monolayer. The electrical impedance barrier function of a cell monolayer represents the level of restriction to diffusion of charged species between all adjacent cells across an entire contiguous cellular monolayer. The impedance signals from many individual paracellular pathways contribute to the bulk measurement of the whole monolayer barrier function. However, the scaffold substrate must be entirely porous in order to be used with electrochemical cell impedance spectroscopy (ECIS) and cells must be closely situated to the electrodes. For purposes of evaluating cell-scaffold constructs for tissue engineering, non-invasive evaluation of cell properties while seeded on scaffolds is critical. A Transwell-type assay makes a measurement across a semi-permeable membrane, using electrodes placed on opposing sides of the membrane immersed in fluid. It was found that by suspending a nanofiber scaffold across a Transwell aperture, it is possible to integrate a fully functional nanofiber tissue scaffold with the ECIS Transwell apparatus. Salivary epithelial cells were grown on the nanofiber scaffolds and tight junction formation was evaluated using ECIS measurements in parallel with immunostaining and confocal imaging. The trans-epithelial resistance increased coordinate with cell coverage, culminating with a cell monolayer, at which point the tight junction proteins assemble and strengthen, reaching the peak signal. These studies demonstrate that ECIS can be used to evaluate tight junction formation in cells grown on nanofiber scaffolds and on effects of scaffold conditions on cells, thus providing useful biological feedback to inform superior scaffold designs. PMID- 28858220 TI - A Hybrid Approach to Detect Driver Drowsiness Utilizing Physiological Signals to Improve System Performance and Wearability. AB - Driver drowsiness is a major cause of fatal accidents, injury, and property damage, and has become an area of substantial research attention in recent years. The present study proposes a method to detect drowsiness in drivers which integrates features of electrocardiography (ECG) and electroencephalography (EEG) to improve detection performance. The study measures differences between the alert and drowsy states from physiological data collected from 22 healthy subjects in a driving simulator-based study. A monotonous driving environment is used to induce drowsiness in the participants. Various time and frequency domain feature were extracted from EEG including time domain statistical descriptors, complexity measures and power spectral measures. Features extracted from the ECG signal included heart rate (HR) and heart rate variability (HRV), including low frequency (LF), high frequency (HF) and LF/HF ratio. Furthermore, subjective sleepiness scale is also assessed to study its relationship with drowsiness. We used paired t-tests to select only statistically significant features (p < 0.05), that can differentiate between the alert and drowsy states effectively. Significant features of both modalities (EEG and ECG) are then combined to investigate the improvement in performance using support vector machine (SVM) classifier. The other main contribution of this paper is the study on channel reduction and its impact to the performance of detection. The proposed method demonstrated that combining EEG and ECG has improved the system's performance in discriminating between alert and drowsy states, instead of using them alone. Our channel reduction analysis revealed that an acceptable level of accuracy (80%) could be achieved by combining just two electrodes (one EEG and one ECG), indicating the feasibility of a system with improved wearability compared with existing systems involving many electrodes. Overall, our results demonstrate that the proposed method can be a viable solution for a practical driver drowsiness system that is both accurate and comfortable to wear. PMID- 28858221 TI - Telemonitoring via Self-Report and Video Review in Community Palliative Care: A Case Report. AB - Continuous monitoring and management of a person's symptoms and performance status are critical for the delivery of effective palliative care. This monitoring occurs routinely in inpatient settings; however, such close evaluation in the community has remained elusive. Patient self-reporting using telehealth offers opportunities to identify symptom escalation and functional decline in real time, and facilitate timely proactive management. We report the case of a 57 year-old man with advanced non-small cell lung cancer who participated in a telehealth trial run by a community palliative care service. This gentleman was able to complete self-reporting of function and symptoms via iPad although at times he was reticent to do so. Self-reporting was perceived as a means to communicate his clinical needs without being a bother to the community palliative care team. He also participated in a videoconference with clinical staff from the community palliative care service and his General Practitioner. Videoconferencing with the nurse and GP was highly valued as an effective way to communicate and also because it eliminated the need for travel. This case report provides important information about the feasibility and acceptability of palliative care telehealth as a way to better manage clinical care in a community setting. PMID- 28858223 TI - Wireless Sensor Platform for Cultural Heritage Monitoring and Modeling System. AB - Results from three years of continuous monitoring of environmental conditions using a wireless sensor platform installed at The Cloisters, the medieval branch of the New York Metropolitan Museum of Art, are presented. The platform comprises more than 200 sensors that were distributed in five galleries to assess temperature and air flow and to quantify microclimate changes using physics-based and statistical models. The wireless sensor network data shows a very stable environment within the galleries, while the dense monitoring enables localized monitoring of subtle changes in air quality trends and impact of visitors on the microclimate conditions. The high spatial and temporal resolution data serves as a baseline study to understand the impact of visitors and building operations on the long-term preservation of art objects. PMID- 28858222 TI - Diurnal Changes in Distribution Characteristics of Salivary Cortisol and Immunoglobulin A Concentrations. AB - Salivary cortisol and secretory immunoglobulin A (S-IgA) are important biomarkers for environmental and public health research. The present study investigated the diurnal variations of these salivary biomarkers, with a focus on the change of distribution characteristics (i.e., skewness and kurtosis) of the concentrations. The participants in this study were 113 healthy young males. Salivary samples were collected in the morning (6:30-7:30 a.m.) and afternoon (1:00-4:00 p.m.). The skewness and kurtosis of salivary cortisol concentrations in afternoon samples (skewness = 1.06, kurtosis = 4.78) were significantly higher than those in morning samples (skewness = 0.49, kurtosis = 2.80). The differences in skewness and kurtosis of S-IgA concentrations were non-significant; however, the standard deviation and interquartile ranges for afternoon S-IgA concentrations were significantly smaller than those for morning S-IgA concentrations. Logarithmic transformation improved the distribution of afternoon cortisol values, making it an almost normal distribution, but the transformation showed no improvement in the distribution of morning cortisol or S-IgA values. The present study explored diurnal changes in the distribution characteristics of salivary cortisol and S-IgA. Consideration of a possible diurnal change in the distribution characteristics is needed when we compare the difference in these salivary biomarkers between different times of day. PMID- 28858224 TI - Genitalic Differentiations in Neoleucinodes elegantalis (Guenee) (Lepidoptera: Crambidae) Associated with Solanaceae Crops in Ecuador. AB - Neoleucinodes elegantalis (Guenee) is an oligophagous species of plants in the Solanaceae family that has a broad geographical distribution in the tropical zones of South America. It is the most important insect pest of naranjilla (Solanum quitoense Lamarck), a crop grown in threatened areas of the tropical old growth forest in Ecuador. In this study, two host-specific populations of N. elegantalis were collected from infested fruit of naranjilla and tree tomato (Solanum betaceum Cavanilles) in different locations. Sexually virgin adult insects (93 females and 103 males) were dissected to extract their genitalia to measure 12 morphological variables in females and six in males, resulting in six and four informative variables respectively. Using univariate and multivariate analysis of variance, it was found that the Solanaceous host was the main factor differentiating the area measurements of the seventh abdominal segment and ostium bursae in female genitalia, and cornuti length in male genitalia. Principal components generated with these measurements were employed in a logistic regression model for the classification of the Solanaceous host. Female genitalia of individuals from S. betaceum showed significantly larger ostium bursae relative to female genitalia from S. quitoense. For males, individuals collected from S. betaceum showed longer cornuti length than samples collected from S. quitoense. The results suggest genotypic differentiation according to the Solanaceous host or phenotypic plasticity in N. elegantalis. Further molecular and bio-geographical studies are needed to properly differentiate N. elegantalis populations that would help in the control of this pest. PMID- 28858225 TI - Thyroid Cancer Incidence around the Belgian Nuclear Sites, 2000-2014. AB - The present study investigates whether there is an excess incidence of thyroid cancer among people living in the vicinity of the nuclear sites in Belgium. Adjusted Rate Ratios were obtained from Poisson regressions for proximity areas of varying sizes. In addition, focused hypothesis tests and generalized additive models were performed to test the hypothesis of a gradient in thyroid cancer incidence with increasing levels of surrogate exposures. Residential proximity to the nuclear site, prevailing dominant winds frequency from the site, and simulated radioactive discharges were used as surrogate exposures. No excess incidence of thyroid cancer was observed around the nuclear power plants of Doel or Tihange. In contrast, increases in thyroid cancer incidence were found around the nuclear sites of Mol-Dessel and Fleurus; risk ratios were borderline not significant. For Mol-Dessel, there was evidence for a gradient in thyroid cancer incidence with increased proximity, prevailing winds, and simulated radioactive discharges. For Fleurus, a gradient was observed with increasing prevailing winds and, to a lesser extent, with increasing simulated radioactive discharges. This study strengthens earlier findings and suggests increased incidences in thyroid cancer around two of the four Belgian nuclear sites. Further analyses will be performed at a more detailed geographical level. PMID- 28858226 TI - Efficacy of Chlorantraniliprole in Controlling Structural Infestations of the Eastern Subterranean Termite in the USA. AB - Subterranean termites are the most economically important structural pests in the USA, and the eastern subterranean termite, Reticulitermes flavipes (Kollar) (Dictyoptera: Rhinotermitidae) is the most widely distributed species. Soil treatment with a liquid termiticide is a widely used method for controlling subterranean termites in structures. We assessed the efficacy of a nonrepellent termiticide, Altriset(r) (active ingredient: chlorantraniliprole), in controlling structural infestations of R. flavipes in Texas, North Carolina, and Ohio and determined the post-treatment fate of termite colonies in and around the structures. In all three states, microsatellite markers indicated that only one R. flavipes colony was infesting each structure. A single chlorantraniliprole treatment provided effective structural protection as there was no further evidence of termite activity in and on the majority of structures from approximately 1 month to 2 years post-treatment when the study concluded. Additionally, the treatment appeared to either severely reduce the infesting colony's footprint at monitors in the landscape or eliminate colony members from these monitors. A supplemental spot-treatment was conducted at one house each in Texas and North Carolina at 5 and 6 months post-treatment, respectively; no termites were observed thereafter in these structures and associated landscaping. The number of colonies found exclusively in the landscape (not attacking the structure) varied among the states, with the largest number of colonies in Texas (0-4) and North Carolina (0-5) as compared to 0-1 in Ohio, the most northern state. PMID- 28858228 TI - Health-Promoting Effects of Thymus herba-barona, Thymus pseudolanuginosus, and Thymus caespititius Decoctions. AB - Thymus herba-barona, Thymus pseudolanuginosus, and Thymus caespititius decoctions were screened for their phenolic constituents, along with their potential antioxidant, anti-inflammatory, and antibacterial activities. The total phenolic compounds in the extracts of the three plants ranged from 236.0 +/- 26.6 mgGAE/g (T. caespititus) to 293.0 +/- 30.5 mgGAE/g of extract (T. pseudolanuginosus), being particularly rich in caffeic acid derivatives, namely rosmarinic acid and its structural isomers, as well as flavones, such as luteolin-O-glucuronide. The T. pseudolanuginosus extract presented the best DPPH radical scavenging ability (EC50 = 10.9 +/- 0.7 ug/mL), a high reducing power (EC50 = 32.2 +/- 8.2 ug/mL), and effectively inhibited the oxidation of beta-carotene (EC50 = 2.4 +/- 0.2 ug/mL). The extracts also showed NO? scavenging activity close to that of ascorbic acid, and thus might be useful as anti-inflammatory agents. In addition, they exhibited antibacterial activity against gram-negative and gram-positive bacteria. Staphylococcus aureus strains were the most sensitive bacteria to thyme extracts, with minimum inhibitory concentration and minimum bactericidal concentration values in the range of 0.6-3.5 mg/mL. Overall, this work is an important contribution for the phytochemical characterization and the potential antioxidant, anti-inflammatory, and antimicrobial activities of these three Thymus species, which have been poorly explored. PMID- 28858229 TI - Gadolinium-Doped Gallic Acid-Zinc/Aluminium-Layered Double Hydroxide/Gold Theranostic Nanoparticles for a Bimodal Magnetic Resonance Imaging and Drug Delivery System. AB - We have developed gadolinium-based theranostic nanoparticles for co-delivery of drug and magnetic resonance imaging (MRI) contrast agent using Zn/Al-layered double hydroxide as the nanocarrier platform, a naturally occurring phenolic compound, gallic acid (GA) as therapeutic agent, and Gd(NO3)3 as diagnostic agent. Gold nanoparticles (AuNPs) were grown on the system to support the contrast for MRI imaging. The nanoparticles were characterized using techniques such as Hi-TEM, XRD, ICP-ES. Kinetic release study of the GA from the nanoparticles showed about 70% of GA was released over a period of 72 h. The in vitro cell viability test for the nanoparticles showed relatively low toxicity to human cell lines (3T3) and improved toxicity on cancerous cell lines (HepG2). A preliminary contrast property test of the nanoparticles, tested on a 3 Tesla MRI machine at various concentrations of GAGZAu and water (as a reference) indicates that the nanoparticles have a promising dual diagnostic and therapeutic features to further develop a better future for clinical remedy for cancer treatment. PMID- 28858227 TI - The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. AB - The deoxyribonucleic acid (DNA) damage response (DDR) is a major feature in the maintenance of genome integrity and in the suppression of tumorigenesis. PALB2 (Partner and Localizer of Breast Cancer 2 (BRCA2)) plays an important role in maintaining genome integrity through its role in the Fanconi anemia (FA) and homologous recombination (HR) DNA repair pathways. Since its identification as a BRCA2 interacting partner, PALB2 has emerged as a pivotal tumor suppressor protein associated to hereditary cancer susceptibility to breast and pancreatic cancers. In this review, we discuss how other DDR proteins (such as the kinases Ataxia Telangiectasia Mutated (ATM) and ATM- and Rad3-Related (ATR), mediators BRCA1 (Breast Cancer 1)/BRCA2 and effectors RAD51/DNA Polymerase eta (Poleta) interact with PALB2 to orchestrate DNA repair. We also examine the involvement of PALB2 mutations in the predisposition to cancer and the role of PALB2 in stimulating error-free DNA repair through the FA/HR pathway. PMID- 28858230 TI - A Smart Eddy Current Sensor Dedicated to the Nondestructive Evaluation of Carbon Fibers Reinforced Polymers. AB - This paper propose a new concept of an eddy current (EC) multi-element sensor for the characterization of carbon fiber-reinforced polymers (CFRP) to evaluate the orientations of plies in CFRP and the order of their stacking. The main advantage of the new sensors is the flexible parametrization by electronical switching that reduces the effort for mechanical manipulation. The sensor response was calculated and proved by 3D finite element (FE) modeling. This sensor is dedicated to nondestructive testing (NDT) and can be an alternative for conventional mechanical rotating and rectangular sensors. PMID- 28858231 TI - In situ Observation of Phase Transformation in MnAl(C) Magnetic Materials. AB - The phase transformation in two modes, including both displacive and massive growth of tau-phase from epsilon-MnAl(C), was observed by in situ transmission electron microscopy. The exact temperature range for different phase transformation modes was determined by magnetic measurements. The displacive growth of epsilon->tau in Mn54Al46 (or Mn54Al46C2.44) occurs at temperatures below 650 K (or 766 K), above which both modes coexist. One-third or less of the epsilon-phase can be transformed into tau-phase via displacive mode while the remaining two-thirds or more via massive mode. In bulk tau-phase, most tau nanocrystals formed via displacive mode are distributed in the matrix of large tau-grains that formed via massive mode. The typical massive growth rate of the tau-phase is 8-60 nm/s, while the displacive growth rate is low. A more complete understanding of the epsilon->tau phase transformations in the MnAl-based magnets was provided in this work, based on which the annealing process for epsilon->tau was optimized and thus high purity tau-phase with high saturation magnetization was obtained. PMID- 28858232 TI - Biofilm Producing Salmonella Typhi: Chronic Colonization and Development of Gallbladder Cancer. AB - Salmonella enterica subspecies enterica serovar Typhi is the aetiological agent of typhoid or enteric fever. In a subset of individuals, S. Typhi colonizes the gallbladder causing an asymptomatic chronic infection. Nonetheless, these asymptomatic carriers provide a reservoir for further spreading of the disease. Epidemiological studies performed in regions where S. Typhi is endemic, revealed that the majority of chronically infected carriers also harbour gallstones, which in turn, have been indicated as a primary predisposing factor for the onset of gallbladder cancer (GC). It is now well recognised, that S. Typhi produces a typhoid toxin with a carcinogenic potential, that induces DNA damage and cell cycle alterations in intoxicated cells. In addition, biofilm production by S. Typhi may represent a key factor for the promotion of a persistent infection in the gallbladder, thus sustaining a chronic local inflammatory response and exposing the epithelium to repeated damage caused by carcinogenic toxins. This review aims to highlight the putative connection between the chronic colonization by highly pathogenic strains of S. Typhi capable of combining biofilm and toxin production and the onset of GC. Considering the high risk of GC associated with the asymptomatic carrier status, the rapid identification and profiling of biofilm production by S. Typhi strains would be key for effective therapeutic management and cancer prevention. PMID- 28858233 TI - A Novel Organic Electrochemical Transistor-Based Platform for Monitoring the Senescent Green Vegetative Phase of Haematococcus pluvialis Cells. AB - The freshwater unicellular microalga Haematococcus pluvialis (H. pluvialis) has gained increasing attention because of its high-value metabolite astaxanthin, a super anti-oxidant. For the maximum astaxanthin production, a key problem is how to determine the senescent green vegetative phase of H. pluvialis cells to apply the astaxanthin production inducers. The conventional methods are time-consuming and laborious. In this study, a novel platform based on organic electrochemical transistor (OECT) was produced. A significant channel current change of OECTs caused by settled H. pluvialis cells on the poly(3,4-ethylenedioxythiophene): polystyrene sulfonate (PEDOT: PSS) film was recorded commencing from 75 min and a stationary stage was achieved at 120 min after the combined treatment of blue light irradiation and sodium bicarbonate solution additives, which indicate the onset and maturation of the senescent green vegetative phase, respectively. Therefore, the appropriate time point (120 min after sample loading) to apply astaxanthin production inducers was determined by as-fabricated OECTs. This work may assist to develop a real-time biosensor to indicate the appropriate time to apply inducers for a maximum astaxanthin production of H. pluvialis cells. PMID- 28858234 TI - A General Route for Growing Metal Sulfides onto Graphene Oxide and Exfoliated Graphite Oxide. AB - Graphene-based materials are elective materials for a number of technologies due to their unique properties. Also, semiconductor nanocrystals have been extensively explored due to their size-dependent properties that make them useful for several applications. By coupling both types of materials, new applications are envisaged that explore the synergistic properties in such hybrid nanostructures. This research reports a general wet chemistry method to prepare graphene oxide (GO) sheets decorated with nanophases of semiconductor metal sulfides. This method allows the in situ growth of metal sulfides onto GO by using metal dialkyldithiocarbamate complexes as single-molecule precursors. In particular, the role of GO as heterogeneous substrate for the growth of semiconductor nanocrystals was investigated by using Raman spectroscopic and imaging methods. The method was further extended to other graphene-based materials, which are easily prepared in a larger scale, such as exfoliated graphite oxide (EGO). PMID- 28858235 TI - Mini Review: Nanosheet Technology towards Biomedical Application. AB - The fabrication technique of ultrathin film (commonly known as nanosheets) has been significantly developed over the years. Due to the mechanical properties of nanosheets, such as high levels of adhesion and flexibility, this made nanosheets the ideal candidate in biomedical applications. In this review, innovative biomedical applications of nanosheets are discussed, which include, drug delivery, wound treatment, and functional nanosheets towards flexible biodevices, etc. Finally, the future outlook of nanosheet technology towards a biomedical application is discussed. PMID- 28858237 TI - Effect of Coiling Temperature on Microstructure, Properties and Resistance to Fish-Scaling of Hot Rolled Enamel Steel. AB - The microstructure, mechanical properties, and hydrogen permeation behavior of hot rolled enamel steel were investigated. Three coiling temperatures were adopted to gain different sizes of ferrite grain and TiC precipitates. The results show that a large number of interphase precipitates of nano-sized TiC can be obtained at coiling temperatures of 650 and 700 degrees C, while a few precipitates are found in experimental steel when coiling temperature is 600 degrees C. The yield strength and ultimate tensile strength decrease with increasing coiling temperature, while elongation increases. The experimental steel has the best resistance to fish-scaling at coiling temperature of 700 degrees C, due to the large quantities of nano-sized interphase precipitates of TiC. PMID- 28858236 TI - Non-Invasive Breast Cancer Diagnosis through Electrochemical Biosensing at Different Molecular Levels. AB - The rapid and accurate determination of specific circulating biomarkers at different molecular levels with non- or minimally invasive methods constitutes a major challenge to improve the breast cancer outcomes and life quality of patients. In this field, electrochemical biosensors have demonstrated to be promising alternatives against more complex conventional strategies to perform fast, accurate and on-site determination of circulating biomarkers at low concentrations in minimally treated body fluids. In this article, after discussing briefly the relevance and current challenges associated with the determination of breast cancer circulating biomarkers, an updated overview of the electrochemical affinity biosensing strategies emerged in the last 5 years for this purpose is provided highlighting the great potentiality of these methodologies. After critically discussing the most interesting features of the electrochemical strategies reported so far for the single or multiplexed determination of such biomarkers with demonstrated applicability in liquid biopsy analysis, existing challenges still to be addressed and future directions in this field will be pointed out. PMID- 28858238 TI - Force Transmission Modes of Non-Cohesive and Cohesive Materials at the Critical State. AB - This paper investigates the force transmission modes, mainly described by probability density distributions, in non-cohesive dry and cohesive wet granular materials by discrete element modeling. The critical state force transmission patterns are focused on with the contact model effect being analyzed. By shearing relatively dense and loose dry specimens to the critical state in the conventional triaxial loading path, it is observed that there is a unique critical state force transmission mode. There is a universe critical state force distribution pattern for both the normal contact forces and tangential contact forces. Furthermore, it is found that using either the linear Hooke or the non linear Hertz model does not affect the universe force transmission mode, and it is only related to the grain size distribution. Wet granular materials are also simulated by incorporating a water bridge model. Dense and loose wet granular materials are tested, and the critical state behavior for the wet material is also observed. The critical state strength and void ratio of wet granular materials are higher than those of a non-cohesive material. The critical state inter-particle distribution is altered from that of a non-cohesive material with higher probability in relatively weak forces. Grains in non-cohesive materials are under compressive stresses, and their principal directions are mainly in the axial loading direction. However, for cohesive wet granular materials, some particles are in tension, and the tensile stresses are in the horizontal direction on which the confinement is applied. The additional confinement by the tensile stress explains the macro strength and dilatancy increase in wet samples. PMID- 28858239 TI - Geometrical Characterisation of a 2D Laser System and Calibration of a Cross-Grid Encoder by Means of a Self-Calibration Methodology. AB - This article presents a self-calibration procedure and the experimental results for the geometrical characterisation of a 2D laser system operating along a large working range (50 mm * 50 mm) with submicrometre uncertainty. Its purpose is to correct the geometric errors of the 2D laser system setup generated when positioning the two laser heads and the plane mirrors used as reflectors. The non calibrated artefact used in this procedure is a commercial grid encoder that is also a measuring instrument. Therefore, the self-calibration procedure also allows the determination of the geometrical errors of the grid encoder, including its squareness error. The precision of the proposed algorithm is tested using virtual data. Actual measurements are subsequently registered, and the algorithm is applied. Once the laser system is characterised, the error of the grid encoder is calculated along the working range, resulting in an expanded submicrometre calibration uncertainty (k = 2) for the X and Y axes. The results of the grid encoder calibration are comparable to the errors provided by the calibration certificate for its main central axes. It is, therefore, possible to confirm the suitability of the self-calibration methodology proposed in this article. PMID- 28858241 TI - Preparation and Characterization of Novel Cationic Chitosan Derivatives Bearing Quaternary Ammonium and Phosphonium Salts and Assessment of Their Antifungal Properties. AB - Chitosan is an abundant and renewable polysaccharide, its derivatives exhibit attractive bioactivities and the wide applications in various biomedical fields. In this paper, two novel cationic chitosan derivatives modified with quaternary phosphonium salts were successfully synthesized via trimethylation, chloride acetylation, and quaternization with tricyclohexylphosphine and triphenylphosphine. The structures and properties of synthesized products in the reactions were characterized by FTIR spectroscopy, 1H-NMR, 31P-NMR, elemental and thermogravimetric analysis. The antifungal activities of chitosan derivatives against four kinds of phytopathogens, including Phomopsis asparagi, Watermelon fusarium, Colletotrichum lagenarium, and Fusarium oxysporum were tested using the radial growth assay in vitro. The results revealed that the synthesized cationic chitosan derivatives showed significantly improved antifungal efficiency compared to chitosan. It was reasonably suggested that quaternary phosphonium groups enabled the obviously stronger antifungal activity of the synthesized chitosans. Especially, the triphenylphosphonium-functionalized chitosan derivative inhibited the growth of Phomopsis asparagi most effectively, with inhibitory indices of about 80% at 0.5 mg/mL. Moreover, the data demonstrated that the substituted groups with stronger electron-withdrawing ability relatively possessed greater antifungal activity. The results suggest the possibility that cationic chitosan derivatives bearing quaternary phosphonium salts could be effectively employed as novel antifungal biomaterials for application in the field of agriculture. PMID- 28858240 TI - Toxicity Effects of Functionalized Quantum Dots, Gold and Polystyrene Nanoparticles on Target Aquatic Biological Models: A Review. AB - Nano-based products are widespread in several sectors, including textiles, medical-products, cosmetics, paints and plastics. Nanosafety and safe-by-design are driving nanoparticle (NP) production and applications through NP functionalization (@NPs). Indeed, @NPs frequently present biological effects that differ from the parent material. This paper reviews the impact of quantum dots (QDs), gold nanoparticles (AuNPs), and polystyrene-cored NPs (PSNPs), evidencing the role of NP functionalization in toxicity definition. Key biological models were taken into consideration for NP evaluation: Saccharomyces cerevisiae, fresh- (F) and saltwater (S) microalgae (Raphidocelis subcapitata (F), Scenedesmus obliquus (F) and Chlorella spp. (F), and Phaeodactylum tricornutum (S)), Daphnia magna, and Xenopus laevis. QDs are quite widespread in technological devices, and they are known to induce genotoxicity and oxidative stress that can drastically change according to the coating employed. For example, AuNPs are frequently functionalized with antimicrobial peptides, which is shown to both increase their activity and decrease the relative environmental toxicity. P-NPs are frequently coated with NH2- for cationic and COOH- for anionic surfaces, but when positively charged toxicity effects can be observed. Careful assessment of functionalized and non-functionalized NPs is compulsory to also understand their potential direct and indirect effects when the coating is removed or degraded. PMID- 28858242 TI - Effect of Processing Intensity on Immunologically Active Bovine Milk Serum Proteins. AB - Consumption of raw cow's milk instead of industrially processed milk has been reported to protect children from developing asthma, allergies, and respiratory infections. Several heat-sensitive milk serum proteins have been implied in this effect though unbiased assessment of milk proteins in general is missing. The aim of this study was to compare the native milk serum proteome between raw cow's milk and various industrially applied processing methods, i.e., homogenization, fat separation, pasteurization, ultra-heat treatment (UHT), treatment for extended shelf-life (ESL), and conventional boiling. Each processing method was applied to the same three pools of raw milk. Levels of detectable proteins were quantified by liquid chromatography/tandem mass spectrometry following filter aided sample preparation. In total, 364 milk serum proteins were identified. The 140 proteins detectable in 66% of all samples were entered in a hierarchical cluster analysis. The resulting proteomics pattern separated mainly as high (boiling, UHT, ESL) versus no/low heat treatment (raw, skimmed, pasteurized). Comparing these two groups revealed 23 individual proteins significantly reduced by heating, e.g., lactoferrin (log2-fold change = -0.37, p = 0.004), lactoperoxidase (log2-fold change = -0.33, p = 0.001), and lactadherin (log2-fold change = -0.22, p = 0.020). The abundance of these heat sensitive proteins found in higher quantity in native cow's milk compared to heat treated milk, renders them potential candidates for protection from asthma, allergies, and respiratory infections. PMID- 28858243 TI - Cooperation Techniques between LTE in Unlicensed Spectrum and Wi-Fi towards Fair Spectral Efficiency. AB - On the road towards 5G, a proliferation of Heterogeneous Networks (HetNets) is expected. Sensor networks are of great importance in this new wireless era, as they allow interaction with the environment. Additionally, the establishment of the Internet of Things (IoT) has incredibly increased the number of interconnected devices and consequently the already massive wirelessly transmitted traffic. The exponential growth of wireless traffic is pushing the wireless community to investigate solutions that maximally exploit the available spectrum. Recently, 3rd Generation Partnership Project (3GPP) announced standards that permit the operation of Long Term Evolution (LTE) in the unlicensed spectrum in addition to the exclusive use of the licensed spectrum owned by a mobile operator. Alternatively, leading wireless technology developers examine standalone LTE operation in the unlicensed spectrum without any involvement of a mobile operator. In this article, we present a classification of different techniques that can be applied on co-located LTE and Wi-Fi networks. Up to today, Wi-Fi is the most widely-used wireless technology in the unlicensed spectrum. A review of the current state of the art further reveals the lack of cooperation schemes among co-located networks that can lead to more optimal usage of the available spectrum. This article fills this gap in the literature by conceptually describing different classes of cooperation between LTE and Wi-Fi. For each class, we provide a detailed presentation of possible cooperation techniques that can provide spectral efficiency in a fair manner. PMID- 28858244 TI - Andrographolide Suppresses MV4-11 Cell Proliferation through the Inhibition of FLT3 Signaling, Fatty Acid Synthesis and Cellular Iron Uptake. AB - Background: Andrographolide (ADR), the main active component of Andrographis paniculata, displays anticancer activity in various cancer cell lines, among which leukemia cell lines exhibit the highest sensitivity to ADR. In particular, ADR was also reported to have reduced drug resistance in multidrug resistant cell lines. However, the mechanism of action (MOA) of ADR's anticancer and anti-drug resistance activities remain elusive. Methods: In this study, we used the MV4-11 cell line, a FLT3 positive acute myeloid leukemia (AML) cell line that displays multidrug resistance, as our experimental system. We first evaluated the effect of ADR on MV4-11 cell proliferation. Then, a quantitative proteomics approach was applied to identify differentially expressed proteins in ADR-treated MV4-11 cells. Finally, cellular processes and signal pathways affected by ADR in MV4-11 cell were predicted with proteomic analysis and validated with in vitro assays. Results: ADR inhibits MV4-11 cell proliferation in a dose- and time-dependent manner. With a proteomic approach, we discovered that ADR inhibited fatty acid synthesis, cellular iron uptake and FLT3 signaling pathway in MV4-11 cells. Conclusions: ADR inhibits MV4-11 cell proliferation through inhibition of fatty acid synthesis, iron uptake and protein synthesis. Furthermore, ADR reduces drug resistance by blocking FLT3 signaling. PMID- 28858245 TI - Molecular Cloning and Characterization of Carotenoid Pathway Genes and Carotenoid Content in Ixeris dentata var. albiflora. AB - Ixeris dentata var. albiflora is considered as a potential therapeutic agent against mithridatism, calculous, indigestion, pneumonia, hepatitis, and tumors as well as good seasoned vegetable in Far East countries. Phytoene synthase (PSY), phytoene desaturase (PDS) xi-carotene desaturase (ZDS), lycopene beta-cyclase (LCYB), lycopene epsilon-cyclase (LCYE), epsilon-ring carotene hydroxylase (CHXB), and zeaxanthin epoxidase (ZDS) are vital enzymes in the carotenoid biosynthesis pathway. We have examined these seven genes from I. dentata that are participated in carotenoid biosynthesis utilizing an Illumina/Solexa HiSeq 2000 platform. In silico analysis of the seven deduced amino acid sequences were revealed its closest homology with other Asteracea plants. Further, we explored transcript levels and carotenoid accumulation in various organs of I. dentata using quantitative real time PCR and high-performance liquid chromatography, respectively. The highest transcript levels were noticed in the leaf for all the genes while minimal levels were noticed in the root. The maximal carotenoid accumulation was also detected in the leaf. We proposed that these genes expressions are associated with the accumulation of carotenoids. Our findings may suggest the fundamental clues to unravel the molecular insights of carotenoid biosynthesis in various organs of I. dentata. PMID- 28858246 TI - Thirty Minutes of Hypobaric Hypoxia Provokes Alterations of Immune Response, Haemostasis, and Metabolism Proteins in Human Serum. AB - Hypobaric hypoxia (HH) during airline travel induces several (patho-) physiological reactions in the human body. Whereas severe hypoxia is investigated thoroughly, very little is known about effects of moderate or short-term hypoxia, e.g. during airline flights. The aim of the present study was to analyse changes in serum protein expression and activation of signalling cascades in human volunteers staying for 30 min in a simulated altitude equivalent to airline travel. After approval of the local ethics committee, 10 participants were exposed to moderate hypoxia (simulation of 2400 m or 8000 ft for 30 min) in a hypobaric pressure chamber. Before and after hypobaric hypoxia, serum was drawn, centrifuged, and analysed by two-dimensional gel electrophoresis (2-DIGE) and matrix-assisted laser desorption/ionization followed by time-of-flight mass spectrometry (MALDI-TOF). Biological functions of regulated proteins were identified using functional network analysis (GeneMania(r), STRING(r), and Perseus(r) software). In participants, oxygen saturation decreased from 98.1 +/- 1.3% to 89.2 +/- 1.8% during HH. Expression of 14 spots (i.e., 10 proteins: ALB, PGK1, APOE, GAPDH, C1QA, C1QB, CAT, CA1, F2, and CLU) was significantly altered. Bioinformatic analysis revealed an association of the altered proteins with the signalling cascades "regulation of haemostasis" (four proteins), "metabolism" (five proteins), and "leukocyte mediated immune response" (five proteins). Even though hypobaric hypoxia was short and moderate (comparable to an airliner flight), analysis of protein expression in human subjects revealed an association to immune response, protein metabolism, and haemostasis. PMID- 28858247 TI - Probiotic Supplementation in Preterm: Feeding Intolerance and Hospital Cost. AB - We hypothesized that giving the probiotic strain Lactobacillus reuteri (L. reuteri) DSM 17938 to preterm, formula-fed infants would prevent an early traumatic intestinal inflammatory insult modulating intestinal cytokine profile and reducing the onset of feeding intolerance. Newborn were randomly allocated during the first 48 h of life to receive either daily probiotic (108 colony forming units (CFUs) of L. reuteri DSM 17938) or placebo for one month. All the newborns underwent to gastric ultrasound for the measurement of gastric emptying time. Fecal samples were collected for the evaluation of fecal cytokines. Clinical data on feeding intolerance and weight gain were collected. The costs of hospital stays were calculated. The results showed that the newborns receiving L. reuteri DSM 17938 had a significant decrease in the number of days needed to reach full enteral feeding (p < 0.01), days of hospital stay (p < 0.01), and days of antibiotic treatment (p < 0.01). Statistically significant differences were observed in pattern of fecal cytokine profiles. The anti-inflammatory cytokine interleukin (IL)-10, was increased in newborns receiving L. reuteri DSM 17938. Pro-inflammatory cytokines: IL-17, IL-8, and tumor necrosis factor (TNF)-alpha levels were increased in newborns given placebo. Differences in the gastric emptying and fasting antral area (FAA) were also observed. Our study demonstrates an effective role for L. reuteri DSM 17938 supplementation in preventing feeding intolerance and improving gut motor and immune function development in bottle-fed stable preterm newborns. Another benefit from the use of probiotics is the reducing cost for the Health Care service. PMID- 28858248 TI - Evaluation of Rhamnetin as an Inhibitor of the Pharmacological Effect of Secretory Phospholipase A2. AB - Rhamnetin (Rhm), 3-O-methylquercetin (3MQ), and Rhamnazin (Rhz) are methylated derivatives of quercetin commonly found in fruits and vegetables that possess antioxidant and anti-inflammatory properties. Phospholipase A2 (PLA2) displays several important roles during acute inflammation; therefore, this study aimed at investigating new compounds able to inhibit this enzyme, besides evaluating creatine kinase (CK) levels and citotoxicity. Methylated quercetins were compared with quercetin (Q) and were incubated with secretory PLA2 (sPLA2) from Bothrops jararacussu to determine their inhibitory activity. Cytotoxic studies were performed by using the J774 cell lineage incubated with quercertins. In vivo tests were performed with Swiss female mice to evaluate decreasing paw edema potential and compounds' CK levels. Structural modifications on sPLA2 were made with circular dichroism (CD). Despite Q and Rhz showing greater enzymatic inhibitory potential, high CK was observed. Rhm exhibited sPLA2 inhibitory potential, no toxicity and, remarkably, it decreased CK levels. The presence of 3OH on the C-ring of Rhm may contribute to both its anti-inflammatory and enzymatic inhibition of sPLA2, and the methylation of ring A may provide the increase in cell viability and low CK level induced by sPLA2. These results showed that Rhm can be a candidate as a natural compound for the development of new anti-inflammatory drugs. PMID- 28858249 TI - Thermal Conductivity of a Nanoscale Yttrium Iron Garnet Thin-Film Prepared by the Sol-Gel Process. AB - The thermal conductivity of a nanoscale yttrium iron garnet (Y3Fe5O12, YIG) thin film prepared by a sol-gel method was evaluated using the ultrafast pump-probe technique in the present study. The thermoreflectance change on the surface of a 250 nm thick YIG film, induced by the irradiation of femtosecond laser pulses, was measured, and curve fitting of a numerical solution for the transient heat conduction equation to the experimental data was performed using the finite difference method in order to extract the thermal property. Results show that the film's thermal conductivity is 22-83% higher than the properties of bulk YIG materials prepared by different fabrication techniques, reflecting the microstructural characteristics and quality of the film. PMID- 28858251 TI - Insecticides for Suppression of Nylanderia fulva. AB - Nylanderia fulva (Mayr) is an invasive ant that is a serious pest in the southern United States. Pest control operators and homeowners are challenged to manage pest populations below acceptable thresholds. Contact and bait insecticides are key components of an Integrated Pest Management (IPM) strategy, however, little is known about their efficacy. In repellency and efficacy bioassays, N. fulva were not completely repelled by any insecticide tested, although fewer ants crossed a surface treated with Temprid(r). Few insecticides provided rapid control. Termidor(r) and Temprid(r) were the best performing with mean mortality of 100% in 13.4 and 19.0 days, respectively. In no-choice bait acceptance studies, it was shown that N. fulva generally had greater acceptance of carbohydrate-based ant baits (Advion(r), InTiceTM (gel), and InTiceTM (granular)). However, mortality was low for the InTiceTM baits in a 7-day bioassay. Maxforce(r) Ant Killer Bait Gel and Advance(r) 375A in the spring and Maxforce(r) Complete in the summer and fall required the fewest days to reach 100% mortality. Bait active ingredients that resulted in the highest mortality were hydramethylnon and fipronil. These data on the efficacy of commercially available contact and bait insecticides provide valuable information to manage this invasive pest. PMID- 28858252 TI - A Quantitative Evaluation of Drive Pattern Selection for Optimizing EIT-Based Stretchable Sensors. AB - Electrical Impedance Tomography (EIT) is a medical imaging technique that has been recently used to realize stretchable pressure sensors. In this method, voltage measurements are taken at electrodes placed at the boundary of the sensor and are used to reconstruct an image of the applied touch pressure points. The drawback with EIT-based sensors, however, is their low spatial resolution due to the ill-posed nature of the EIT reconstruction. In this paper, we show our performance evaluation of different EIT drive patterns, specifically strategies for electrode selection when performing current injection and voltage measurements. We compare voltage data with Signal-to-Noise Ratio (SNR) and Boundary Voltage Changes (BVC), and study image quality with Size Error (SE), Position Error (PE) and Ringing (RNG) parameters, in the case of one-point and two-point simultaneous contact locations. The study shows that, in order to improve the performance of EIT based sensors, the electrode selection strategies should dynamically change correspondingly to the location of the input stimuli. In fact, the selection of one drive pattern over another can improve the target size detection and position accuracy up to 4.7% and 18%, respectively. PMID- 28858250 TI - Solution NMR Studies of Mycobacterium tuberculosis Proteins for Antibiotic Target Discovery. AB - Tuberculosis is an infectious disease caused by Mycobacteriumtuberculosis, which triggers severe pulmonary diseases. Recently, multidrug/extensively drug resistant tuberculosis strains have emerged and continue to threaten global health. Because of the development of drug-resistant tuberculosis, there is an urgent need for novel antibiotics to treat these drug-resistant bacteria. In light of the clinical importance of M. tuberculosis, 2067 structures of M. tuberculsosis proteins have been determined. Among them, 52 structures have been solved and studied using solution nuclear magnetic resonance (NMR). The functional details based on structural analysis of M. tuberculosis using NMR can provide essential biochemical data for the development of novel antibiotic drugs. In this review, we introduce diverse structural and biochemical studies on M. tuberculosis proteins determined using NMR spectroscopy. PMID- 28858253 TI - Unique Roles of Gold Nanoparticles in Drug Delivery, Targeting and Imaging Applications. AB - Nanotechnology has become more and more potentially used in diagnosis or treatment of diseases. Advances in nanotechnology have led to new and improved nanomaterials in biomedical applications. Common nanomaterials applicable in biomedical applications include liposomes, polymeric micelles, graphene, carbon nanotubes, quantum dots, ferroferric oxide nanoparticles, gold nanoparticles (Au NPs), and so on. Among them, Au NPs have been considered as the most interesting nanomaterial because of its unique optical, electronic, sensing and biochemical properties. Au NPs have been potentially applied for medical imaging, drug delivery, and tumor therapy in the early detection, diagnosis, and treatment of diseases. This review focuses on some recent advances in the use of Au NPs as drug carriers for the intracellular delivery of therapeutics and as molecular nanoprobes for the detection and monitoring of target molecules. PMID- 28858254 TI - Identification of a Quality Marker (Q-Marker) of Danhong Injection by the Zebrafish Thrombosis Model. AB - Quality-marker (Q-marker) is an emerging concept to ensure the quality and batch to-batch consistency of Chinese medicine (CM). However, significant difficulties remain in the identification of Q-markers due to the unclear relationship between complex chemical compositions and the pharmacological efficacy of CM. In the present study, we proposed a novel strategy to identify the potential Q-marker of danhong injection (DHI) by an in vivo zebrafish thrombosis model. The anti thrombotic effects of DHI and its major constituents were evaluated by the zebrafish model of arachidonic acid (AA)-induced thrombosis. The results indicated that DHI can attenuate tail venous thrombus and recover the decrease of heart red blood cell (RBC) intensity in a dose-dependent manner. The result that DHI prevented the formulation of thrombosis in zebrafish was also validated in the zebrafish thrombosis model with green fluorescence protein (GFP)-labeled hemoglobin. The major components of DHI, namely danshen (DS) and honghua (HH), as well as the major chemical constituents of DHI, also exerted anti-thrombotic effects, among which rosmarinic acid (RA) and p-coumaric acid (pCA) showed moderate anti-thrombotic effects. This is the first time that pCA from HH has been found as an active compound exerting an anti-thrombotic effect in a dose dependent manner, whose IC50 value is approximately 147 MUg/mL. By analyzing 10 batches of normal DHI samples and five abnormal samples by high-performance liquid chromatography (HPLC), we found the contents of pCA and RA can be positively correlated to the anti-thrombotic effect of DHI, suggesting that pCA and RA could be potential Q-markers of DHI to ensure batch-to-batch consistency. Our findings illustrated that discovering major active compounds from CM by in vivo pharmacological models can be a useful approach to identifying Q-markers of CM, and in vivo pharmacological models can be a potential tool to evaluate batch to-batch consistency of CMs. PMID- 28858255 TI - Synthesis and Detailed Examination of Spectral Properties of (S) and (R) Higenamine 4'-O-beta-d-Glucoside and HPLC Analytical Conditions to Distinguish the Diastereomers. AB - Higenamine is a tetrahydroisoquinoline present in several plants that has beta adrenergic receptor agonist activity. Study of the biosynthesis of higenamine has shown the participation of norcoclaurine synthase, which controls the stereochemistry to construct the (S)-isomer. However, when isolated from nature, higenamine is found as the racemate, or even the (R)-isomer. We recently reported the isolation of higenamine 4'-O-beta-d-glucoside. Herein, its (R)- and (S) isomers were synthesized and compared to precisely determine the stereochemistry of the isolate. Owing to their similar spectral properties, determination of the stereochemistry based on NMR data was considered inappropriate. Therefore, a high performance liquid chromatography method was established to separate the isomers, and natural higenamine 4'-O-beta-d-glucoside was determined to be a mixture of isomers. PMID- 28858256 TI - New Antifeedant Grayanane Diterpenoids from the Flowers of Pieris formosa. AB - Three new grayanane diterpenoids, pierisoids C-E (1-3), as well as 10 known ones (4-13), were evaluated from the flowers of Pieris formosa, which is used as an insecticide in rural areas of China. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses. Significant antifeedant activity of 1, 3 and 10 against the beet armyworm (Spodoptera exigua) was found, indicating that these diterpenoids might also be involved in the plant defense against insect herbivores. PMID- 28858258 TI - Response of a Zn2TiO4 Gas Sensor to Propanol at Room Temperature. AB - In this study, three different compositions of ZnO and TiO2 powders were cold compressed and then heated at 1250 degrees C for five hours. The samples were ground to powder form. The powders were mixed with 5 wt % of polyvinyl butyral (PVB) as binder and 1.5 wt % carbon black and ethylene-glyco-lmono-butyl-ether as a solvent to form screen-printed pastes. The prepared pastes were screen printed on the top of alumina substrates containing arrays of three copper electrodes. The three fabricated sensors were tested to detect propanol at room temperature at two different concentration ranges. The first concentration range was from 500 to 3000 ppm while the second concentration range was from 2500 to 5000 ppm, with testing taking place in steps of 500 ppm. The response of the sensors was found to increase monotonically in response to the increment in the propanol concentration. The surface morphology and chemical composition of the prepared samples were characterized by Scanning Electron Microscopy (SEM) and X-Ray Diffraction (XRD). The sensors displayed good sensitivity to propanol vapors at room temperature. Operation under room-temperature conditions make these sensors novel, as other metal oxide sensors operate only at high temperature. PMID- 28858257 TI - Lamin B Receptor: Interplay between Structure, Function and Localization. AB - Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane, containing a hydrophilic N-terminal end protruding into the nucleoplasm, eight hydrophobic segments that span the membrane and a short, nucleoplasmic C-terminal tail. Two seemingly unrelated functions have been attributed to LBR. Its N terminal domain tethers heterochromatin to the nuclear periphery, thus contributing to the shape of interphase nuclear architecture, while its transmembrane domains exhibit sterol reductase activity. Mutations within the transmembrane segments result in defects in cholesterol synthesis and are associated with diseases such as the Pelger-Huet anomaly and Greenberg skeletal dysplasia, whereas no such harmful mutations related to the anchoring properties of LBR have been reported so far. Recent evidence suggests a dynamic regulation of LBR expression levels, structural organization, localization and function, in response to various signals. The molecular mechanisms underlying this dynamic behavior have not yet been fully unraveled. Here, we provide an overview of the current knowledge of the interplay between the structure, function and localization of LBR, and hint at the interconnection of the two distinct functions of LBR. PMID- 28858259 TI - Selective Removal of the Genotoxic Compound 2-Aminopyridine in Water using Molecularly Imprinted Polymers Based on Magnetic Chitosan and beta-Cyclodextrin. AB - To develop efficient materials with enhanced adsorption and selectivity for genotoxic 2-aminopyridine in water, based on magnetic chitosan (CTs) and beta cyclodextrin (beta-CD), the magnetic molecularly imprinted polymers (MMIPs) of Fe3O4-CTs@MIP and Fe3O4-MAH-beta-CD@MIP were synthesized by a molecular imprinting technique using 2-aminopyridine as a template. The selective adsorption experiments for 2-aminopyridine were performed by four analogues including pyridine, aniline, 2-amino-5-chloropyridine and phenylenediamine. Results showed the target 2-aminopyridine could be selectively adsorbed and quickly separated by the synthesized MMIPs in the presence of the above structural analogues. The coexisting ions including Na+, K+, Mg2+, Ca2+, Cl- and SO42- showed little effect on the adsorption of 2-aminopyridine. The maximum adsorption capacity of 2-aminopyridine on Fe3O4-CTs@MIP and Fe3O4-MAH-beta-CD@MIP was 39.2 mg.g-1 and 46.5 mg.g-1, respectively, which is much higher than values in previous reports. The comparison result with commercial activated carbon showed the obtained MMIPs had higher adsorption ability and selectivity for 2 aminopyridine. In addition, the synthesized MMIPs exhibited excellent performance of regeneration, which was used at least five times with little adsorption capacity loss. Therefore, the synthesized MMIPs are potential effective materials in applications for selective removal and analysis of the genotoxic compound aminopyridine from environmental water. PMID- 28858260 TI - Alkaloid Constituents of the Amaryllidaceae Plant Amaryllis belladonna L. AB - The plant family Amaryllidaceae is well-known for its unique alkaloid constituents, which exhibit a wide range of biological activities. Its representative, Amaryllis belladonna, has a geographical distribution covering mainly southern Africa, where it has significant usage in the traditional medicine of the native people. In this study, A. belladonna samples collected in Brazil were examined for alkaloid content. Alkaloid profiles of A. belladonna bulbs were generated by a combination of chromatographic, spectroscopic and spectrometric methods, including GC-MS and 2D NMR. In vitro screening against four different parasitic protozoa (Trypanosoma cruzi, T. brucei rhodesiense, Leishmania donovani and Plasmodium falciparum) was carried out using the A. belladonna crude methanol extract, as well as three of its alkaloid isolates. Twenty-six different Amaryllidaceae alkaloids were identified in the A. belladonna bulb samples, and three of them were isolated. Evidence for their respective biosynthetic pathways was afforded via their mass-spectral fragmentation data. Improved data for 1-O-acetylcaranine was provided by 2D NMR experiments, together with new 1H-NMR data for buphanamine. The crude extract and 3-O-acetylhamayne exhibited good antiprotozoal activity in vitro, although both with a high cytotoxic index. PMID- 28858261 TI - Voltammetric Study of Some 3-Aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide Derivatives with Anti-Tumor Activities. AB - The electrochemical properties of twenty 3-aryl-quinoxaline-2-carbonitrile 1,4-di N-oxide derivatives with varying degrees of cytotoxic activity were investigated in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. With one exception, the first reduction of these compounds was found to be reversible or quasireversible and is attributed to reduction of the N-oxide moiety to form a radical anion. The second reduction of the diazine ring was found to be irreversible. Compounds containing a nitro group on the 3-phenyl ring also exhibited a reduction process that may be attributed to that group. There was good correlation between molecular structure and reduction potential, with reduction being facilitated by an enhanced net positive charge at the electroactive site created by electron withdrawing substituents. Additionally, the reduction potential was calculated using two common basis sets, 6-31g and lanl2dz, for five of the test molecules. There was a strong correlation between the computational data and the experimental data, with the exception of the derivative containing the nitro functionality. No relationship between the experimentally measured reduction potentials and reported cytotoxic activities was evident upon comparison of the data. PMID- 28858262 TI - Heat Health Messages: A Randomized Controlled Trial of a Preventative Messages Tool in the Older Population of South Australia. AB - This study explores the efficacy of providing targeted information to older individuals to prevent adverse health outcomes during extreme heat. Participants >=65 years of age (n = 637) were recruited from previous population-based studies and randomized into intervention and control groups. The intervention group received evidence-based information leaflets and summarised "Beat the Heat" tips. Post summer 2013-2014, participants responded to questions about their behaviours and their health experiences. Chi square analysis and risk ratios (RR) were used to determine the difference in effects. Responses were received from 216 intervention subjects and 218 controls. Behaviour modification during extreme heat was similar in both groups except for significant increases in the use of cooling systems and the use of a wet cloth to cool the skin in the intervention group. Both actions were recommended in the information package. More people in the intervention group also claimed to have had adequate heat health information. After adjusting for confounders, the RR for self-reported heat stress experienced during summer 2014 indicated a 63% (RR 0.37; 95% CI: 0.22-0.63) reduction in the intervention group compared to the control group. Access to intensive prevention information may have contributed to this positive outcome, indicating the potential usefulness of targeted heat-health information for seniors. PMID- 28858263 TI - Collecting Evidence to Inform Salt Reduction Policies in Argentina: Identifying Sources of Sodium Intake in Adults from a Population-Based Sample. AB - The maximum content of sodium in selected processed foods (PF) in Argentina was limited by a law enacted in 2013. Data about intake of these and other foods are necessary for policy planning, implementation, evaluation, and monitoring. We examined data from the CESCAS I population-based cohort study to assess the main dietary sources among PF and frequency of discretionary salt use by sex, age, and education attainment, before full implementation of the regulations in 2015. We used a validated 34-item FFQ (Food Frequency Questionnaire) to assess PF intake and discretional salt use. Among 2127 adults in two Argentinean cities, aged 35 76 years, mean salt intake from selected PFs was 4.7 g/day, higher among male and low education subgroups. Categories of foods with regulated maximum limits provided near half of the sodium intake from PFs. Use of salt (always/often) at the table and during cooking was reported by 9% and 73% of the population, respectively, with higher proportions among young people. Reducing salt consumption to the target of 5 g/day may require adjustments to the current regulation (reducing targets, including other food categories), as well as reinforcing strategies such as education campaigns, labeling, and voluntary agreement with bakeries. PMID- 28858264 TI - Comparison of Chemical Profiles, Anti-Inflammatory Activity, and UPLC-Q-TOF/MS Based Metabolomics in Endotoxic Fever Rats between Synthetic Borneol and Natural Borneol. AB - Natural borneol (NB, called "Bingpian") is an important traditional Chinese medicine to restore consciousness, remove heat and relieve pain, all of which are inflammation-related diseases. Recently, due to the limited source of NB, synthetic borneol (SB) is widely used as a substitute for NB in clinics. However, little is known about the effects of SB instead of NB. Herein, the aim of the present study was to compare NB and SB on chemical profiles by gas chromatography mass spectrometer (GC-MS) analysis, anti-inflammatory activity in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) metabolomic approaches in endotoxic fever induced in rats. Results showed that, in total, 13 volatile components could be identified in NB and SB by GC-MS analysis, in which a significant difference between them still existed. The main constituents in SB were iso-borneol and borneol, while borneol contributes to 98.96% of the amount in NB. Additionally, both NB and SB exhibited remarkable anti-inflammatory effects to reduce the level of inflammatory factors including NO, TNF-alpha and IL-6 in LPS-induced RAW 264.7 macrophages, and lower the high body temperature in rats with endotoxic fever induced by LPS. Moreover, it seems that NB exhibited higher efficacy than SB. The unequal bioactive efficiency between NB and SB was also indicated by means of non-targeting metabolomics. Based on UPLC-Q-TOF/MS technology, 12 biomarkers in the serum of fever rats were identified. Pathway analysis revealed that the anti-fever effect of NB and SB was related to regulating the abnormal glycerophospholipid, linoleic acid and alpha linoleic acid metabolism pathways in the fever model. Results indicated that there was still a great difference between NB and SB involving chemical constituents, anti-inflammation activity and the ability to regulate the abnormal metabolism pathways of the fever model. Certainly, further studies are warranted to better understand the replacement rationale in medicinal application. PMID- 28858265 TI - Spatial Variability of Geriatric Depression Risk in a High-Density City: A Data Driven Socio-Environmental Vulnerability Mapping Approach. AB - Previous studies found a relationship between geriatric depression and social deprivation. However, most studies did not include environmental factors in the statistical models, introducing a bias to estimate geriatric depression risk because the urban environment was found to have significant associations with mental health. We developed a cross-sectional study with a binomial logistic regression to examine the geriatric depression risk of a high-density city based on five social vulnerability factors and four environmental measures. We constructed a socio-environmental vulnerability index by including the significant variables to map the geriatric depression risk in Hong Kong, a high density city characterized by compact urban environment and high-rise buildings. Crude and adjusted odds ratios (ORs) of the variables were significantly different, indicating that both social and environmental variables should be included as confounding factors. For the comprehensive model controlled by all confounding factors, older adults who were of lower education had the highest geriatric depression risks (OR: 1.60 (1.21, 2.12)). Higher percentage of residential area and greater variation in building height within the neighborhood also contributed to geriatric depression risk in Hong Kong, while average building height had negative association with geriatric depression risk. In addition, the socio-environmental vulnerability index showed that higher scores were associated with higher geriatric depression risk at neighborhood scale. The results of mapping and cross-section model suggested that geriatric depression risk was associated with a compact living environment with low socio-economic conditions in historical urban areas in Hong Kong. In conclusion, our study found a significant difference in geriatric depression risk between unadjusted and adjusted models, suggesting the importance of including environmental factors in estimating geriatric depression risk. We also developed a framework to map geriatric depression risk across a city, which can be used for identifying neighborhoods with higher risk for public health surveillance and sustainable urban planning. PMID- 28858266 TI - Kinases Involved in Both Autophagy and Mitosis. AB - Both mitosis and autophagy are highly regulated dynamic cellular processes and involve various phosphorylation events catalysed by kinases, which play vital roles in almost all physiological and pathological conditions. Mitosis is a key event during the cell cycle, in which the cell divides into two daughter cells. Autophagy is a process in which the cell digests its own cellular contents. Although autophagy regulation has mainly been studied in asynchronous cells, increasing evidence indicates that autophagy is in fact tightly regulated in mitosis. Here in this review, we will discuss kinases that were originally identified to be involved in only one of either mitosis or autophagy, but were later found to participate in both processes, such as CDKs (cyclin-dependent kinases), Aurora kinases, PLK-1 (polo-like kinase 1), BUB1 (budding uninhibited by benzimidazoles 1), MAPKs (mitogen-activated protein kinases), mTORC1 (mechanistic target of rapamycin complex 1), AMPK (AMP-activated protein kinase), PI3K (phosphoinositide-3 kinase) and protein kinase B (AKT). By focusing on kinases involved in both autophagy and mitosis, we will get a more comprehensive understanding about the reciprocal regulation between the two key cellular events, which will also shed light on their related therapeutic investigations. PMID- 28858267 TI - Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation. AB - Nuclear receptors such as the estrogen receptors (ERalpha and ERbeta) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A 4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERalpha and ERbeta isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC50 in MCF-7 cells of 187 nM, and binding affinity to ERalpha (IC50 = 19 nM) and ERbeta (IC50 = 229 nM) while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF 7 cells (IC50 = 5.7 nM) and binding affinity to ERalpha (IC50 = 15 nM) and ERbeta (IC50 = 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers. PMID- 28858268 TI - Fitness, Fatness and Active School Commuting among Liverpool Schoolchildren. AB - This study investigated differences in health outcomes between active and passive school commuters, and examined associations between parent perceptions of the neighborhood environment and active school commuting (ASC). One hundred-ninety four children (107 girls), aged 9-10 years from ten primary schools in Liverpool, England, participated in this cross-sectional study. Measures of stature, body mass, waist circumference and cardiorespiratory fitness (CRF) were taken. School commute mode (active/passive) was self-reported and parents completed the neighborhood environment walkability scale for youth. Fifty-three percent of children commuted to school actively. Schoolchildren who lived in more deprived neighborhoods perceived by parents as being highly connected, unaesthetic and having mixed land-use were more likely to commute to school actively (p < 0.05). These children were at greatest risk of being obese and aerobically unfit(p < 0.01). Our results suggest that deprivation may explain the counterintuitive relationship between obesity, CRF and ASC in Liverpool schoolchildren. These findings encourage researchers and policy makers to be equally mindful of the social determinants of health when advocating behavioral and environmental health interventions. Further research exploring contextual factors to ASC, and examining the concurrent effect of ASC and diet on weight status by deprivation is needed. PMID- 28858269 TI - A Review of Recent Advances towards the Development of (Quantitative) Structure Activity Relationships for Metallic Nanomaterials. AB - Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs). The extension of conventional (quantitative) structure-activity relationships ((Q)SARs) approach to nanotoxicology, i.e., nano-(Q)SARs, is a possible solution. The preliminary attempts of correlating ENMs' characteristics to the biological effects elicited by ENMs highlighted the potential applicability of (Q)SARs in the nanotoxicity field. This review discusses the current knowledge on the development of nano (Q)SARs for metallic ENMs, on the aspects of data sources, reported nano-(Q)SARs, and mechanistic interpretation. An outlook is given on the further development of this frontier. As concluded, the used experimental data mainly concern the uptake of ENMs by different cell lines and the toxicity of ENMs to cells lines and Escherichia coli. The widely applied techniques of deriving models are linear and non-linear regressions, support vector machine, artificial neural network, k nearest neighbors, etc. Concluded from the descriptors, surface properties of ENMs are seen as vital for the cellular uptake of ENMs; the capability of releasing ions and surface redox properties of ENMs are of importance for evaluating nanotoxicity. This review aims to present key advances in relevant nano-modeling studies and stimulate future research efforts in this quickly developing field of research. PMID- 28858270 TI - How Economic Analysis Can Contribute to Understanding the Links between Housing and Health. AB - An economic analysis of housing's linkages to health can assist policy makers and researchers to make better decisions about which housing interventions and policies are the most cost-beneficial. The challenge is to include cobenefits. The adoption in 2015 of the UN Sustainable Development Goals underscores the importance of understanding how policies interact, and the merit of comprehensively evaluating cobenefits. We explain our approach to the empirical assessment of such cobenefits in the housing and health context, and consider lessons from empirical economic appraisals of the impact of housing on health outcomes. Critical assumptions relating to cobenefits are explicitly examined. A key finding is that when wider policy outcome measures are included, such as mental health impacts and carbon emission reductions, it is important that effects of assumptions on outcomes are considered. Another is that differing values underlie appraisal, for example, the weight given to future generations through the discount rate. Cost-benefit analyses (CBAs) can better facilitate meaningful debate when they are based on explicit assumptions about values. In short, the insights drawn from an economic framework for housing-and-health studies are valuable, but nonetheless contingent. Given that housing interventions typically have both health and other cobenefits, and incorporate social value judgements, it is important to take a broad view but be explicit about how such interventions are assessed. PMID- 28858271 TI - [The relevance of Candida spp. in chronic periodontal disease]. AB - The aim of the study was to assess the correlation of Candida spp. incidence in periodontal tissues with various clinical manifestations of chronic periodontal disease (CPD). Ninety patients with CPD were included in the study in which Candida spp. was evaluated in periodontal pockets content and gingival biopsy material. In severe CPD more Candida spp. were seen in gingival biopsy than in periodontal pockets (p=0.0006). Candida spp. incidence and quantity correlated directly with the disease grade showing incidence increase from 40 to 73.3% and quantity increase from 0.8+/-0.18 do 3.6+/-0.49 lg CFU/ml in light and severe CPD, correspondingly Candida spp. had statistically significant association with cyanotic gingival color (p=0.0018), tongue plaque and swelling (r=0.0042), lip exfoliation (r=0.0030), periodontal pockets depth >5 mm (r=0.0030), oral mucosa hyperemia (r=0.0157), alveolar bone destruction >1/2 of root length (r=0.0157). These data prove the relevance of Candida spp. and mycological assessment of gingival biopsy in CPD patients. PMID- 28858272 TI - [Assessment of antibacterial efficacy of ozone therapy in treatment of caries at the white spot stage]. AB - : Effect on cariogenic flora is the key toremineralizing therapy efficacy in treatment of initial caries (at the white spot stage). Ozone in dentistry is used as a highly effective antibacterial agent. Treatment of white spot lesions with the ozone-air mixture leads to significant increase of efficacy in non-invasive treatment of initial caries. OBJECTIVE: clinical and microbiological assessment of antibacterial efficacy of ozone therapy in treatment of caries at the white spot stage. MATERIAL AND METHODS: The trial recruited 86 patients for non invasive treatment of caries at the white spot stage which included the complex of professional oral hygiene, medicamental treatment of white spot lesions with hydrogen peroxide 3% and chlorhexidinedigluconate 0,2%, treatment with the ozone air mixture and application of hydroxyapatite Sa2+. Material for microbiological study was received before the treatment, after the complex of professional oral hygiene and medicamental treatment of white spot lesions conducted as well as after the treatment with the ozone-air mixture. RESULTS: Before the treatment up to 16 kinds of microorganisms on the surface of white spot lesion were detected with the following shares: S. mutans (19.9%), S. salivarius (15.1%), S. epidermidis (8.7%), S. mitis (6.5%), Lactobacillus (6.5%) and different kinds of staphylococci (10.8%). After the complex of professional oral hygiene and medicamental treatment conducted decrease in number of cariogenic microorganisms was indicated as follows: S. mutans - from 1.105 to 1.104, S. salivarius - from 1.107 to 1.106, S. epidermidis - from 1.105 to 1.104, S. mitis - from 1.104 to 1.103, Lactobacillus - from 1.104 to 1.103. After the treatment of tooth enamel with the ozone-air mixture increase in microorganisms was not observed. The efficacy of ozone on cariogenic microorganisms exceeds significantly the efficacy of 3% hydrogen peroxide and 0,2% chlorhexidinedigluconate. CONCLUSION: It is strongly advisable to include ozone in protocol of non-invasive treatment of initial dental caries. PMID- 28858273 TI - [Microbiocenosis of subgingival biofilm and intestinal content in chronic periodontal disease in patients with metabolic syndrome]. AB - The aim of the study was to assess correlations of subgingival biofilm and intestinal microbiota in patients with chronic periodontal disease (CPD) and metabolic syndrome (MS). The study included 80 patients divided in 2 groups: 40 healthy individuals with no signs of periodontal disease and 40 patients with CPD and MS. Oral and intestinal microbial consortia compositions were revealed using deep sequencing libraries of 16S rDNA. The study showed than the qualitative composition of the intestinal microbiome in patients with CPD differ significantly from the microbiome of controls. Real-time PCR of subgingival microflora in CPD patients revealed high content of P. gingivalis, T. forsythia and T. denticola, while in intestinal microbiome dominated representatives of Enterobacteriaceae and Eubacteriaceae families with signs of intestinal dysbiosis mostly associated with the decrease of protective species. PMID- 28858274 TI - [Effectiveness of Paradontax toothpaste in patients undergoing orthodontic treatment]. AB - The purpose of this study was to determine the effectiveness of toothpaste Parodontax in patients undergoing orthodontic treatment. The results showed that fixed orthodontic appliances deteriorated oral hygiene, increased the viscosity of saliva and reduced mineralizing capacity of saliva (MCS). Use of Parodontax toothpaste based on sodium bicarbonate improved OHI-S, reduced the viscosity of saliva, increased MCS and normalized oral microbiota. PMID- 28858275 TI - [Botulinus toxin in complex treatment of myofacial pain syndrome]. AB - The aim of the study was to assess the efficacy of type A Botulinus toxin (BTA) in pain release by TMJ functional pain disorders. The study included 211 patients with TMJ functional pain disorder (20.4% males and 79.6% females; mean age 45.3 years). The patients underwent clinical examination and bioelectric activity assessment of masticatory muscles by electromyography (EMG). EMG specters of 20 healthy volunteers with intact dental arches served as a control. After examination BTA was injected in muscular pain trigger points. All patients had muscular hypertonus, unilateral in 88.6% and bilateral in 11.4%. EMG showed the decrease of masticatory muscle activity on affected side to mean values of 165+/ 20 mkV (30.0%, p<0.05) and on contralateral side to 460+/-31 mkV (89.6%, p>0.05). BTA injections in tensed muscles released significantly muscle-induced facial pain and improved quality of life. During 6 months follow up myofacial pain disorder relapse was seen in 3 patients. The results allow recommending BTA injection in muscular pain trigger points for treatment of myofacial pain syndrome and prolonged muscle relaxation. PMID- 28858276 TI - [Surgical treatment of patients with arteriovenous head and neck angiodisplasia]. AB - The aim of the study was to assess the results of surgical treatment in 74 patients with extensive arteriovenous angiodisplasia in the head and neck area. All patients underwent complex examination including ultrasound, CT and MRI with contrast and selective carotid angiography. The lesions excision was performed after endovascular embolization and soft tissue defects were restored by various methods selected according to prevalent vascular lesion type (arterial, arteriovenous, venous, capillary) and blood flow values (high flow, low flow, mixed). Good and satisfactory esthetic results were seen in 95.2% of cases, lesion relapse was detected in 4.8% of cases by 12-18 months follow-up. Endovascular embolization proved to decrease the intraoperative bleeding risk, prevent lesion relapse and minimize the size of the lesion improving the results of radical treatment. Local flap reconstruction usually results in good esthetic results. By local soft tissue deficiency distant free flaps or microsurgical complex flaps may be used. PMID- 28858277 TI - [Bone anchored auricular prosthesis for patients with grade III microtia]. AB - The aim of the study was to assess the effectivity of auricular prosthesis on intraosseous implants in patient with grade III microtia. The study included 7 patients (5 males and 2 females) aged 18 to 45 years with hemifacial microsomia and grade III microtia operated in Central Research Institute of Dentistry and Maxillofacial Surgery in 2013-2016. Number and position of intraosseous implants was determined by reverse planning based on CT representing hard and soft facial structures. Patients were followed-up for 6-36 months. Good esthetic results were obtained by minimally invasive surgical procedure and short post-op rehabilitation. However these results required meticulous virtual planning and manufacturing of surgical template. The described method promotes very fast medical and social rehabilitation of patients with severe microtia. PMID- 28858278 TI - [Cephalometry efficacy in orthodontic treatment planning: correlations of cephalometric values and their changes in the course of treatment]. AB - The aim of the study was to assess the efficacy of cephalometry in planning of orthodontic patients with teeth crowding (TC) and Angle Class I molar relationship (MR). Cephalometric values of 70 patients with TC and class I MR were analyzed before and after orthodontic treatment. Cephalometric study of correlations proved to be more relevant than comparing with mean values. In patients with TC and class I MR statistically significant were correlations with: facial profile (DN-A-B) and jaws relationship in anterio-posterior direction (DA N-B); DN-A-B and type of maxillary growth (DPn-Mp, DB); DB and maxillary incisors inclination (Dis-SpP); DPn-Mp and mandibular incisors inclination (Dii-Mp). These correlations depend on age, anomaly severity and orthodontic strategy. Cephalometry proved to be effective tool for orthodontic treatment planning, prognosis and modelling. PMID- 28858279 TI - [Dental health maintenance of military personnel under orthodontic treatment]. AB - The aim of the study was to estimate dental health of servicemen of young and middle age using PMA index, Schiller-Pisarev assay, iodic number of Svrakov, OHI S. Hundred and six servicemen were enrolled in the study: control group (n=35) with no orthodontic treatment and groups 2 (n=34) and 3 (n=37) group undergoing orthodontic treatment with bracket-systems. All patients had professional oral hygiene and received standard oral care recommendations. Group 3 participants additionally used dental foam (Splat, Russia) after meal. All patients were examined at baseline and 12 months later. In the presence of orthodontic appliances standard oral care products were not enough to maintain proper oral health. Dental foam improved both periodontal condition and OHI-S. PMID- 28858280 TI - [Legal aspects of providing medical care to patients with intolerance of dental materials]. AB - The paper presents an analysis of legal documents describing the legal side of dental care to patients with intolerance of dental materials (IDM). The features of dental treatment from the point of view of the risk of IDM are described with the examples of real court cases in precedent as well as the conditions for the onset of strict liability and exemption from liability in relation to the practice of treatment of patients with IDM. PMID- 28858281 TI - [Cytokine dysregulation in children with chronic catarrhal gingivitis living in polluted areas with fluoride and iodine deficiency]. AB - The aim of the research was to study the state of oral liquid immunity in children with chronic catarrhal gingivitis living in unfavorable environmental conditions. The study included 190 children with chronic catarrhal gingivitis (CCG): 110 children aged 7, 12 and 15 years and residing in ecologically unfavorable areas of Lviv region and 80 children living in 'conditionally clean' region which constituted comparison group. Children with CCG from polluted areas had increased content of pro-inflammatory cytokines and reduction of anti inflammatory cytokines compared to controls. The level of pro-inflammatory cytokines was age-depended in both groups but in children from ecologically unfavorable region this tendency was more pronounced. Thus, changes of indicators of interleukin spectrum in children with CCG depend not only on age and degree of severity of periodontium pathology but also on ecological living conditions. PMID- 28858282 TI - [Assessment of caries risk factors among school-age children by comparing EGOHID scores in Minsk and Moscow]. AB - The aim of the study was to assess the acceptability of the objective and subjective indicators for identification of oral diseases risk factors and the quality of dental care of school-aged children. The study included 200 school children of two age groups (12 and 15-year-old) surveyed in Minsk and Moscow cities using European global system of oral health indicators development (EGOHID). The modified WHO questionnaire was used to study behavioral habits of 15-year-old children. There were significant variations in the most indicators studied in different localities. An average DMFT of permanent teeth varied from 3.1 to 4.7 in 12-year-olds and from 5.5 to 6.5 in 15-year-olds. The prevalence of periodontal disease has reached 42%. The complex of objective and subjective evaluation of the teeth and gums status made it possible to reveal a number of risk factors. The majority of EGOHID indicators had shown satisfactory acceptability and specificity in assessing the risk factors and preliminary evaluation of a quality of dental care for school children. The EGOHID system is recommended for monitoring the preventive programs. PMID- 28858283 TI - [Oral biofilm: inductors of congenital immunity signal pathways]. PMID- 28858284 TI - [Mechanisms of tissue destruction in periodontal disease]. PMID- 28858285 TI - [Local enamel demineralization diagnostics and treatment]. AB - The article describes focal enamel demineralization - the most common disease of teeth hard tissues. Local and general factors of this pathological process advent and development were described. The main tools of focal enamel demineralization diagnostics and treatment were observed. The main role of enamel mesoporous structure in the remineralization therapy possibility was underlined. There are still a lot of questions in focal enamel demineralization diagnostics after publications analysis because of the existing methods subjectivity. The question of indications for different remineralization tools applications optimization depending on the focal enamel demineralization degree is still open. PMID- 28858286 TI - [Tissue engineering of the tooth: directions of development, achievements and unresolved problems]. PMID- 28858287 TI - Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. AB - Retroviral (RV) expression of genes of interest (GOIs) is an invaluable tool and has formed the foundation of cellular engineering for adoptive cell therapy in cancer and other diseases. However, monitoring of transduced T cells long term (weeks to months) in vivo remains challenging because of the low frequency and often poor durability of transduced T cells over time when transferred without enrichment. Traditional methods often require additional overnight in vitro culture after transduction. Moreover, in vitro-generated effector CD8+ T cells enriched by sorting often have reduced viability, making it difficult to monitor the fate of transferred cells in vivo. Here, we describe an optimized mouse CD8+ T-cell RV transduction protocol that uses simple and rapid Percoll density centrifugation to enrich RV-susceptible activated CD8+ T cells. Percoll density centrifugation is simple, can be done on the day of transduction, requires minimal time, has low reagent costs and improves cell recovery (up to 60%), as well as the frequency of RV-transduced cells (~sixfold over several weeks in vivo as compared with traditional methods). We have used this protocol to assess the long-term stability of CD8+ T cells after RV transduction by comparing the durability of T cells transduced with retroviruses expressing each of six commonly used RV reporter genes. Thus, we provide an optimized enrichment and transduction approach that allows long-term in vivo assessment of RV-transduced T cells. The overall procedure from T-cell isolation to RV transduction takes 2 d, and enrichment of activated T cells can be done in 1 h. PMID- 28858288 TI - Simultaneous lipid and content mixing assays for in vitro reconstitution studies of synaptic vesicle fusion. AB - This protocol describes reconstitution assays to study how the neurotransmitter release machinery triggers Ca2+-dependent synaptic vesicle fusion. The assays monitor fusion between proteoliposomes containing the synaptic vesicle SNARE synaptobrevin (with or without the Ca2+ sensor synaptotagmin-1) and proteoliposomes initially containing the plasma membrane SNAREs syntaxin-1 and soluble NSF attachment protein (SNAP)-25. Lipid mixing (from fluorescence de quenching of Marina-Blue-labeled lipids) and content mixing (from development of fluorescence resonance energy transfer (FRET) between phycoerythrin-biotin (PhycoE-Biotin) and Cy5-streptavidin trapped in the two proteoliposome populations) are measured simultaneously to ensure that true, nonleaky membrane fusion is monitored. This protocol is based on a method developed to study yeast vacuolar fusion. In contrast to other protocols used to study the release machinery, this assay incorporates N-ethylmaleimide sensitive factor (NSF) and alpha-SNAP, which disassemble syntaxin-1 and SNAP-25 heterodimers. As a result, fusion requires Munc18-1, which binds to the released syntaxin-1, and Munc13-1, which, together with Munc18-1, orchestrates SNARE complex assembly. The protocol can be readily adapted to investigation of other types of intracellular membrane fusion by using appropriate alternative proteins. Total time required for one round of the assay is 4 d. PMID- 28858289 TI - Production of tunable nanomaterials using hierarchically assembled bacteriophages. AB - Large-scale fabrication of precisely defined nanostructures with tunable functions is critical to the exploitation of nanoscience and nanotechnology for production of electronic devices, energy generators, biosensors, and bionanomedicines. Although self-assembly processes have been developed to exploit biological molecules for functional materials, the resulting nanostructures and functions are still very limited, and scalable synthesis is far from being realized. Recently, we have established a bacteriophage-based biomimetic process, called 'self-templating assembly'. We used bacteriophage as a nanofiber model system to exploit its liquid crystalline structure for the creation of diverse hierarchically organized structures. We have also demonstrated that genetic modification of functional peptides of bacteriophage results in structures that can be used as soft and hard tissue-regenerating materials, biosensors, and energy-generating materials. Here, we describe a comprehensive protocol to perform genetic engineering of phage, liter-scale amplification, purification, and self-templating assembly, and suggest approaches for characterizing hierarchical phage nanostructures using optical microscopy, atomic-force microscopy (AFM), and scanning electron microscopy (SEM). We also discuss sources of contamination, common mistakes during the fabrication process, and quality control measures to ensure reproducible material production. The protocol takes ~8-10 d to complete. PMID- 28858290 TI - Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. AB - Generation of precisely patterned neural cells from human pluripotent stem cells (hPSCs) is instrumental in developing disease models and stem cell therapies. Here, we provide a detailed 16-d protocol for obtaining high-purity ventral midbrain (VM) dopamine (DA) progenitors for intracerebral transplantation into animal models and for in vitro maturation into neurons. We have successfully transplanted such cells into the rat; however, in principle, the cells can be used for transplantation into any animal model, and the protocol is designed to also be compatible with clinical transplantation into humans. We show how to precisely set the balance of patterning factors to obtain specifically the caudal VM progenitors that give rise to DA-rich grafts. By specifying how to perform quality control (QC), troubleshooting and adaptation of the procedure, this protocol will facilitate implementation in different laboratories and with a variety of hPSC lines. To facilitate reproducibility of experiments and enable shipping of cells between centers, we present a method for cryopreservation of the progenitors for subsequent direct transplantation or terminal differentiation into DA neurons. This protocol is free of xeno-derived products and can be performed under good manufacturing practice (GMP) conditions. PMID- 28858291 TI - Epidemiology and Natural History of Primary Biliary Cholangitis in the Chinese: A Territory-Based Study in Hong Kong between 2000 and 2015. AB - OBJECTIVES: Studies on the epidemiology of primary biliary cholangitis (PBC) in the Chinese population are lacking. We aimed to determine the epidemiology of PBC in Hong Kong (HK) with a population of 7.3 million. METHODS: We retrieved data from the electronic database of the HK Hospital Authority, the only public healthcare provider in Hong Kong. PBC cases between 2000 and 2015 were identified by International Classification of Diseases (ICD)-9 code. We estimated the age /sex-adjusted incidence rate and prevalence of PBC, and analyzed the adverse outcomes (hepatocellular carcinoma (HCC), liver transplantation, and death). RESULTS: One thousand and sixteen PBC patients aged >=20 years were identified (female-to-male ratio 4:1; median age 60.6 years, interquartile range (IQR) 51.8 72.6 years; median follow-up 5.6 years, IQR 1.6-8.7 years). The average age/sex adjusted annual incidence rate and prevalence were 8.4 per million person-years and 56.4 per million, respectively. Between 2000 and 2015, the age/sex-adjusted annual incidence rate increased from 6.7 to 8.1 per million person-years (Poisson P=0.002), while age/sex-adjusted prevalence increased from 31.1 to 82.3 per million (Poisson P<0.001). Fifty patients developed HCC, and 49 underwent liver transplantation. Case fatality risk decreased from 10.8 to 6.4% (Poisson P=0.003). The 5- and 10-year overall survival rates were 81.5 and 78.3%, whereas the transplant-free survival rates were 78.0% and 74.3%, respectively. Increasing age, cirrhosis and being treatment-naive were associated with lower transplant free survival. CONCLUSIONS: There is a considerable increase in the incidence and prevalence of PBC in the Chinese population over the past 16 years, with significant morbidity and mortality. PMID- 28858292 TI - Endoscopic Drainage of >50% of Liver in Malignant Hilar Biliary Obstruction Using Metallic or Fenestrated Plastic Stents. AB - OBJECTIVES: Endoscopic drainage of complex hilar tumors has generally resulted in poor outcomes. Drainage of >50% of liver volume has been proposed as optimal, but not evaluated using long multifenestrated plastic stents (MFPS) or self-expanding metal stents (SEMS). We evaluated outcomes of endoscopic drainage of malignant hilar strictures using optimal strategy and stents, and determined factors associated with stent patency, survival, and complications. METHODS: Cross sectional study was conducted at an academic center over 5 years. MFPS (10 French or 8.5 French) or open-cell SEMS were used for palliation of unresectable malignant hilar strictures, with imaging-targeted drainage of as many sectors as needed to drain >50% of viable liver volume. Risk factors were evaluated using regression analysis. The cumulative risk was assessed using Kaplan-Meier analysis. RESULTS: 77 patients with malignant hilar biliary strictures (median Bismuth IV) underwent targeted stenting (41 MFPS and 36 SEMS). Comparing MFPS vs. SEMS, technical success (95.1 vs. 97.2%, P=0.64), clinical success (75.6 vs. 83.3%, P=0.40), frequency of multiple stents (23/41 vs. 25/36, P=0.19), survival and adverse events were similar, but stent patency was significantly shorter (P<0.0001). Factors associated with survival were Karnofsky score and serum bilirubin level at presentation. Outcomes were independent of Bismuth class with acceptable results in Bismuth III and IV. CONCLUSIONS: Endoscopic biliary drainage with MFPS or open-cell SEMS targeting >50% of viable liver resulted in effective palliation in patients with complex malignant hilar biliary strictures. Patency was shorter in the MFPS group, but similar survival and complications were found when comparing MFPS and SEMS group. PMID- 28858293 TI - Main active constituent identification in Guanxinjing capsule, a traditional Chinese medicine, for the treatment of coronary heart disease complicated with depression. AB - Guanxinjing capsules (GXJCs) are used in traditional Chinese medicine as a common therapy for coronary heart disease (CHD) complicated with depression. In this study, we aimed to identify the main active constituents in GXJCs and to investigate the mechanisms of GXJC action on CHD complicated with depression. The chemical constituent profile of the GXJC was identified by UHPLC-LTQ-Orbitrap assay, and oral bioavailability was evaluated to screen the GXJC drug-like chemical constituents. A total of 16 GXJC drug-like chemical constituents were identified. Then, putative targets of the GXJC drug-like chemical constituents were predicted using MedChem Studio, with 870 genes found to be the putative targets of these molecules. After that, a GXJC putative target-known CHD/depression therapeutic target network was constructed, and four topological features, including degree, betweenness, closeness and K-coreness, were calculated. According to the topological feature values of the GXJC putative targets, 14 main active constituents were identified because their corresponding putative targets had topological importance in the GXJC putative target-known CHD/depression therapeutic target network, which were defined as the candidate targets of GXJC against CHD complicated with depression. Functionally, these candidate targets were significantly involved in several CHD/depression-related pathways, including repairing pathological vascular changes, reducing platelet aggregation and inflammation, and affecting patient depression. This study identified a list of main active constituents of GXJC acting on CHD complicated with depression using an integrative pharmacology-based approach that combined active chemical constituent identification, drug target prediction and network analysis. This method may offer an efficient way to understand the pharmacological mechanisms of traditional Chinese medicine prescriptions. PMID- 28858294 TI - The ceramide pathway is involved in the survival, apoptosis and exosome functions of human multiple myeloma cells in vitro. AB - Multiple myeloma (MM) is characterized by the clonal proliferation of malignant plasma cells and refractoriness to traditional therapies. It has been shown that exosomes are involved in modulating the progression and the metastasis of cancers through microRNAs (miRs). Ceramide is a type of sphingolipid; the ceramide pathway of exosomal secretion has been shown to affect the apoptosis of cancer cells. But the role of this pathway in MM cell function, exosome function and miR regulation remains unknown. In this study, we showed that C6 ceramide (an exogenous ceramide supplement, 1.25-40 MUmol/L) dose-dependently inhibited the proliferation and promoted the apoptosis in human MM OPM2 cell line, which were associated with elevated caspase 3/9 and PARP cleavage. We also found that C6 ceramide (5-20 MUmol/L) dose-dependently stimulated exosome secretion and increased exosomal levels of tumor-suppressive miRs (miR 202, miR 16, miR 29b and miR 15a). Of note, exosomes from C6 ceramide-treated OPM2 cells could influence the proliferation and apoptosis of the recipient OPM2 cells, which correlated with increased tumor-suppressive exosomal miRs. In contrast, GW4869 (a ceramide inhibitor, 5-20 MUmol/L) exerted the opposite effects on the regulation of MM function, exosome secretion and miR levels in MM exosomes. However, exosomes from GW4869-treated OPM2 cells had no effect on these miRs and the survival of targeted OPM2 cells. Taken together, our findings reveal that the ceramide pathway modulates MM survival, probably directly via the caspase pathway and indirectly via exosomal miR mechanisms. PMID- 28858296 TI - CCN3 suppresses TGF-beta1-induced extracellular matrix accumulation in human mesangial cells in vitro. AB - Glomerular sclerosis is characterized by mesangial cell proliferation and progressive extracellular matrix (ECM) accumulation. CCN3 belongs to the CCN family of matrix proteins; increasing evidence suggests that CCN3 is an endogenous negative regulator of the ECM and fibrosis. However, the exact role of CCN3 in the accumulation of ECM remains unknown. The aim of the present study was to investigate the effects of CCN3 on TGF-beta1-induced production of ECM in human mesangial cells (HMCs) in vitro. Treatment with TGF-beta1 (0.5-2.0 ng/mL) suppressed the mRNA and protein expression of CCN3 in HMCs in dose- and time dependent manners. Furthermore, treatment with TGF-beta1 significantly increased the expression of the two markers of renal fibrosis, fibronectin (FN) and type I collagen (COLI), in HMCs. Moreover, treatment with TGF-beta1 significantly decreased the expression of metalloproteinase (MMP)-2 and MMP-9, and markedly increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1 in HMCs. Pretreatment of HMCs with exogenous CCN3 (5-500 ng/mL) or overexpression of CCN3 significantly attenuated TGF-beta1-induced changes in FN, COLI, MMP-2, MMP-9 and TIMP-1 in HMCs. These results suggest that CCN3 suppresses TGF-beta1-induced accumulation of ECM in HMCs. CCN3 may have potential as a novel therapeutic target for alleviating glomerulosclerosis. PMID- 28858297 TI - YL-0919, a dual 5-HT1A partial agonist and SSRI, produces antidepressant- and anxiolytic-like effects in rats subjected to chronic unpredictable stress. AB - YL-0919 has been identified as a novel dual 5-HT1A partial agonist and serotonin reuptake inhibitor. In the current study, we demonstrated that YL-0919 produced prominent antidepressant-like and anxiolytic-like effects in a chronic unpredictable stress (CUS) rat model. Male SD rats were exposed to CUS for 5 weeks; YL-0919 (1.25 and 2.5 mg/kg) or a positive control fluoxetine (Flx, 10 mg/kg) was orally administered daily. YL-0919 or Flx treatment significantly increased the sucrose preference rate, the locomotor activity in an open field test (OFT), the latency to feed in a novelty-suppressed feeding test (NSFT), and both the percentage of time spent in the open arms and the number of entries into the open arms in an elevated plus-maze test. YL-0919 or Flx treatment significantly suppressed the serum levels of ACTH and corticosterone in CUS exposed rats. Additionally, YL-0919 or Flx treatment significantly enhanced the levels of cAMP, the expression of phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of CUS-exposed rats. Similar to Flx, YL-0919 treatment significantly enhanced the dendritic complexity, and increased the number of dendritic nodes as well as the spine length and number of branch nodes in the hippocampal pyramidal neurons of CUS-exposed rats. Overall, our results reveal that YL-0919 suppresses the HPA axis and exerts antidepressant-like and anxiolytic-like effects in CUS-exposed rats, which are associated with the enhanced cAMP signaling and hippocampal dendritic complexity. PMID- 28858298 TI - Crystal structure-based comparison of two NAMPT inhibitors. AB - Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a novel strategy for cancer therapy, but only two inhibitors of NAMPT (FK866 and CHS828) have progressed into clinical trials. This study seeks to compare a novel potent NAMPT inhibitor, MS0, with a classical inhibitor FK866 in their biological activity and molecular binding mode, thereby contributing to future chemical optimization and a further understanding of the action mode of NAMPT inhibitors. The IC50 values of MS0 and FK866 in inhibition of recombinant human NAMPT activity were 9.08+/ 0.90 and 1.60+/-0.32 nmol/L, respectively. Consistently, FK866 exerted better antiproliferation in 6 human cancer cell lines (HepG2, A2780, 95-D, A549, U2OS and U266) than MS0 with IC50 values nearly 12-fold to 225-fold lower than those of MS0. Co-crystal structures of wild-type human NAMPT complexed with MS0 or FK866 were elucidated, which revealed that MS0 did not interact with Ser241. The hydrogen bond mediated by crystallographic water between MS0 and His191 or Val350 of NAMPT did not exist in FK866. Instead, FK866 exhibited hydrophobic interactions with Arg349. Based on the activity assays and crystal structure analyses, we elaborate the reason why the antiproliferation activity of MS0 was not as good as that of FK866, which would contributes to the current understanding of the mode of action of NAMPT inhibitors and will also contribute to further development of anticancer drugs in the future. PMID- 28858295 TI - Versatile effects of bacterium-released membrane vesicles on mammalian cells and infectious/inflammatory diseases. AB - Gram-negative bacterium-released outer-membrane vesicles (OMVs) and Gram-positive bacterium-released membrane vesicles (MVs) share significant similarities with mammalian cell-derived MVs (eg, microvesicles and exosomes) in terms of structure and their biological activities. Recent studies have revealed that bacterial OMVs/MVs could (1) interact with immune cells to regulate inflammatory responses, (2) transport virulence factors (eg, enzymes, DNA and small RNAs) to host cells and result in cell injury, (3) enhance barrier function by stimulating the expression of tight junction proteins in intestinal epithelial cells, (4) upregulate the expression of endothelial cell adhesion molecules, and (5) serve as natural nanocarriers for immunogenic antigens, enzyme support and drug delivery. In addition, OMVs/MVs can enter the systemic circulation and induce a variety of immunological and metabolic responses. This review highlights the recent advances in the understanding of OMV/MV biogenesis and their compositional remodeling. In addition, interactions between OMVs/MVs and various types of mammalian cells (ie, immune cells, epithelial cells, and endothelial cells) and their pathological/preventive effects on infectious/inflammatory diseases are summarized. Finally, methods for engineering OMVs/MVs and their therapeutic potential are discussed. PMID- 28858299 TI - Synthesis and in vitro biological evaluation of thiosulfinate derivatives for the treatment of human multidrug-resistant breast cancer. AB - Organosulfur compounds derived from Allium vegetables have long been recognized for various therapeutic effects, including anticancer activity. Allicin, one of the main biologically active components of garlic, shows promise as an anticancer agent; however, instability makes it unsuitable for clinical application. The aim of this study was to investigate the effect of stabilized allicin derivatives on human breast cancer cells in vitro. In this study, a total of 22 stabilized thiosulfinate derivatives were synthesized and screened for their in vitro antiproliferative activities against drug-sensitive (MCF-7) and multidrug resistant (MCF-7/Dx) human adenocarcinoma breast cancer cells. Assays for cell death, apoptosis, cell cycle progression and mitochondrial bioenergetic function were performed. Seven compounds (4b, 7b, 8b, 13b, 14b, 15b and 18b) showed greater antiproliferative activity against MCF-7/Dx cells than allicin. These compounds were also selective towards multidrug-resistant (MDR) cells, a consequence attributed to collateral sensitivity. Among them, 13b exhibited the greatest anticancer activity in both MCF-7/Dx and MCF-7 cells, with IC50 values of 18.54+/-0.24 and 46.50+/-1.98 MUmol/L, respectively. 13b altered cellular morphology and arrested the cell cycle at the G2/M phase. Additionally, 13b dose dependently induced apoptosis, and inhibited cellular mitochondrial respiration in cells at rest and under stress. MDR presents a significant obstacle to the successful treatment of cancer clinically. These results demonstrate that thiosulfinate derivatives have potential as novel anticancer agents and may offer new therapeutic strategies for the treatment of chemoresistant cancers. PMID- 28858300 TI - Development of a high-throughput fluorescence polarization assay for the discovery of EZH2-EED interaction inhibitors. AB - Aberrant activity of enhancer of zeste homolog 2 (EZH2) is associated with a wide range of human cancers. The interaction of EZH2 with embryonic ectoderm development (EED) is required for EZH2's catalytic activity. Inhibition of the EZH2-EED complex thus represents a novel strategy for interfering with the oncogenic potentials of EZH2 by targeting both its catalytic and non-catalytic functions. To date, there have been no reported high-throughput screening (HTS) assays for inhibitors acting at the EZH2-EED interface. In this study, we developed a fluorescence polarization (FP)-based HTS system for the discovery of EZH2-EED interaction inhibitors. The tracer peptide sequences, positions of fluorescein labeling, and a variety of physicochemical conditions were optimized. The high Z' factors (>0.9) at a variety of DMSO concentrations suggested that this system is robust and suitable for HTS. The minimal sequence requirement for the EZH2-EED interaction was determined by using this system. A pilot screening of an in-house compound library containing 1600 FDA-approved drugs identified four compounds (apomorphine hydrochloride, oxyphenbutazone, nifedipine and ergonovine maleate) as potential EZH2-EED interaction inhibitors. PMID- 28858301 TI - Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells. AB - Aldehyde dehydrogenase 2 (ALDH2) is a key mitochondrial enzyme in the metabolism of aldehydes and may have beneficial cardiovascular effects for conditions such as cardiac hypertrophy, heart failure, myocardial I/R injury, reperfusion, arrhythmia, coronary heart disease and atherosclerosis. In this study we investigated the role of ALDH2 in the progression of atherosclerosis and the underlying mechanisms, with a focus on endoplasmic reticulum (ER) stress. A clinical study was performed in 248 patients with coronary heart disease. The patients were divided into two groups according to their ALDH2 genotype. Baseline clinical characteristics and coronary angiography were recorded, and the coronary artery Gensini score was calculated. Serum levels of 4-hydroxy-2-nonenal (4-HNE) were detected. The clinical study revealed that the mutant ALDH2 genotype was an independent risk factor for coronary heart disease. ALDH2 gene polymorphism is closely associated with atherosclerosis and the severity of coronary artery stenosis. Serum levels of 4-HNE were significantly higher in patients with the mutant ALDH2 genotype than in patients with the wild-type ALDH2 genotype. As an in vitro model of atherosclerosis, rat smooth muscle cells (SMCs) were treated with oxygenized low-density lipoprotein (ox-LDL), which significantly elevated the levels of ER markers glucose-regulated protein78 (GRP78), protein kinase R like ER kinase (PERK), phosphorylated eukaryotic translation initiation factor alpha subunit (p-eIF2alpha), activating transcription factor-4 (ATF-4), CEBP homologous protein (CHOP) and 4-HNE in the cells. All the ox-LDL-induced responses were significantly attenuated in the presence of Alda-1 (an ALDH2 activating agent), and accentuated in the presence of daidzin (an ALDH2 inhibitor). Furthermore, pretreatment with ALDH2 activator Alda-1 significantly decreased ox-LDL-induced apoptosis. Similarly, overexpression of ALDH2 protected SMCs against ox-LDL-induced ER stress as well as ER stress-induced apoptosis. These findings suggest that ALDH2 may slow the progression of atherosclerosis via the attenuation of ER stress and apoptosis in smooth muscle cells. PMID- 28858302 TI - Proper-motion age dating of the progeny of Nova Scorpii AD 1437. AB - 'Cataclysmic variables' are binary star systems in which one star of the pair is a white dwarf, and which often generate bright and energetic stellar outbursts. Classical novae are one type of outburst: when the white dwarf accretes enough matter from its companion, the resulting hydrogen-rich atmospheric envelope can host a runaway thermonuclear reaction that generates a rapid brightening. Achieving peak luminosities of up to one million times that of the Sun, all classical novae are recurrent, on timescales of months to millennia. During the century before and after an eruption, the 'novalike' binary systems that give rise to classical novae exhibit high rates of mass transfer to their white dwarfs. Another type of outburst is the dwarf nova: these occur in binaries that have stellar masses and periods indistinguishable from those of novalikes but much lower mass-transfer rates, when accretion-disk instabilities drop matter onto the white dwarfs. The co-existence at the same orbital period of novalike binaries and dwarf novae-which are identical but for their widely varying accretion rates-has been a longstanding puzzle. Here we report the recovery of the binary star underlying the classical nova eruption of 11 March AD 1437 (refs 12, 13), and independently confirm its age by proper-motion dating. We show that, almost 500 years after a classical-nova event, the system exhibited dwarf-nova eruptions. The three other oldest recovered classical novae display nova shells, but lack firm post-eruption ages, and are also dwarf novae at present. We conclude that many old novae become dwarf novae for part of the millennia between successive nova eruptions. PMID- 28858304 TI - Molecular machines open cell membranes. AB - Beyond the more common chemical delivery strategies, several physical techniques are used to open the lipid bilayers of cellular membranes. These include using electric and magnetic fields, temperature, ultrasound or light to introduce compounds into cells, to release molecular species from cells or to selectively induce programmed cell death (apoptosis) or uncontrolled cell death (necrosis). More recently, molecular motors and switches that can change their conformation in a controlled manner in response to external stimuli have been used to produce mechanical actions on tissue for biomedical applications. Here we show that molecular machines can drill through cellular bilayers using their molecular scale actuation, specifically nanomechanical action. Upon physical adsorption of the molecular motors onto lipid bilayers and subsequent activation of the motors using ultraviolet light, holes are drilled in the cell membranes. We designed molecular motors and complementary experimental protocols that use nanomechanical action to induce the diffusion of chemical species out of synthetic vesicles, to enhance the diffusion of traceable molecular machines into and within live cells, to induce necrosis and to introduce chemical species into live cells. We also show that, by using molecular machines that bear short peptide addends, nanomechanical action can selectively target specific cell-surface recognition sites. Beyond the in vitro applications demonstrated here, we expect that molecular machines could also be used in vivo, especially as their design progresses to allow two-photon, near-infrared and radio-frequency activation. PMID- 28858306 TI - Pollution: US coal plans flout mercury convention. PMID- 28858305 TI - Very large release of mostly volcanic carbon during the Palaeocene-Eocene Thermal Maximum. AB - The Palaeocene-Eocene Thermal Maximum (PETM) was a global warming event that occurred about 56 million years ago, and is commonly thought to have been driven primarily by the destabilization of carbon from surface sedimentary reservoirs such as methane hydrates. However, it remains controversial whether such reservoirs were indeed the source of the carbon that drove the warming. Resolving this issue is key to understanding the proximal cause of the warming, and to quantifying the roles of triggers versus feedbacks. Here we present boron isotope data-a proxy for seawater pH-that show that the ocean surface pH was persistently low during the PETM. We combine our pH data with a paired carbon isotope record in an Earth system model in order to reconstruct the unfolding carbon-cycle dynamics during the event. We find strong evidence for a much larger (more than 10,000 petagrams)-and, on average, isotopically heavier-carbon source than considered previously. This leads us to identify volcanism associated with the North Atlantic Igneous Province, rather than carbon from a surface reservoir, as the main driver of the PETM. This finding implies that climate-driven amplification of organic carbon feedbacks probably played only a minor part in driving the event. However, we find that enhanced burial of organic matter seems to have been important in eventually sequestering the released carbon and accelerating the recovery of the Earth system. PMID- 28858308 TI - Astronomy: Cosmic exhumation. PMID- 28858311 TI - Multidisciplinarity: Philanthropy research is thriving. PMID- 28858312 TI - Brain surgery: Most lobotomies were done on women. PMID- 28858314 TI - In Retrospect: The inflammasome turns 15. PMID- 28858315 TI - Palaeoclimate: Volcanism caused ancient global warming. PMID- 28858313 TI - Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. AB - Induced pluripotent stem cells (iPS cells) are a promising source for a cell based therapy to treat Parkinson's disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD. PMID- 28858316 TI - Computational materials: Open data settled in materials theory. PMID- 28858317 TI - Fast automated analysis of strong gravitational lenses with convolutional neural networks. AB - Quantifying image distortions caused by strong gravitational lensing-the formation of multiple images of distant sources due to the deflection of their light by the gravity of intervening structures-and estimating the corresponding matter distribution of these structures (the 'gravitational lens') has primarily been performed using maximum likelihood modelling of observations. This procedure is typically time- and resource-consuming, requiring sophisticated lensing codes, several data preparation steps, and finding the maximum likelihood model parameters in a computationally expensive process with downhill optimizers. Accurate analysis of a single gravitational lens can take up to a few weeks and requires expert knowledge of the physical processes and methods involved. Tens of thousands of new lenses are expected to be discovered with the upcoming generation of ground and space surveys. Here we report the use of deep convolutional neural networks to estimate lensing parameters in an extremely fast and automated way, circumventing the difficulties that are faced by maximum likelihood methods. We also show that the removal of lens light can be made fast and automated using independent component analysis of multi-filter imaging data. Our networks can recover the parameters of the 'singular isothermal ellipsoid' density profile, which is commonly used to model strong lensing systems, with an accuracy comparable to the uncertainties of sophisticated models but about ten million times faster: 100 systems in approximately one second on a single graphics processing unit. These networks can provide a way for non-experts to obtain estimates of lensing parameters for large samples of data. PMID- 28858319 TI - Cassini's 13 years of stunning Saturn science - in pictures. PMID- 28858318 TI - Technology: Enlist blockchain to boost conservation. PMID- 28858320 TI - Keep on marching for science education. PMID- 28858321 TI - Closure of US coal study marks an alarming precedent. PMID- 28858322 TI - Scientists solve mystery of US Civil War submarine. PMID- 28858323 TI - Stop blocking postdocs' paths to success. PMID- 28858324 TI - US science envoy resigns in protest at Trump policies. PMID- 28858325 TI - Extreme weather events are the new normal. PMID- 28858326 TI - Dinosaur trio roosted together like birds. PMID- 28858327 TI - Alan Turing's notes, runaway salmon and illegal gold-mining. PMID- 28858328 TI - Europe's X-ray laser fires up. PMID- 28858329 TI - Legal threat exposes gaps in climate-change planning. PMID- 28858330 TI - Navigating the research-clinical interface in genomic medicine: analysis from the CSER Consortium. AB - PurposeThe Clinical Sequencing Exploratory Research (CSER) Consortium encompasses nine National Institutes of Health-funded U-award projects investigating translation of genomic sequencing into clinical care. Previous literature has distinguished norms and rules governing research versus clinical care. This is the first study to explore how genomics investigators describe and navigate the research-clinical interface.MethodsA CSER working group developed a 22-item survey. All nine U-award projects participated. Descriptive data were tabulated and qualitative analysis of text responses identified themes and characterizations of the research-clinical interface.ResultsSurvey responses described how studies approached the research-clinical interface, including in consent practices, recording results, and using a research versus clinical laboratory. Responses revealed four characterizations of the interface: clear separation between research and clinical care, interdigitation of the two with steps to maintain separation, a dynamic interface, and merging of the two. All survey respondents utilized at least two different characterizations. Although research has traditionally been differentiated from clinical care, respondents pointed to factors blurring the distinction and strategies to differentiate the domains.ConclusionThese results illustrate the difficulty in applying the traditional bifurcation of research versus clinical care to translational models of clinical research, including in genomics. Our results suggest new directions for ethics and oversight. PMID- 28858331 TI - Managing high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands on prostate biopsy. AB - Prostate biopsy is the gold standard for diagnosing prostate cancer and reliable pathological assessment is essential for guiding management. Research efforts over the past few years have aimed to establish a more universal approach to management according to pathological grading; however, high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands suspicious for carcinoma are two diagnoses without standardized follow-up and treatment pathways. Much of this uncertainty is due to limited evidence describing the subsequent rates of cancer and high-grade cancer when HGPIN or atypical glands are detected on initial biopsy. Fortunately, data from the past decade have shed light on these phenomena, and an improved understanding of the implications of the presence of HGPIN and atypical glands on prostate biopsy means that clinical recommendations can be made for the management of patients with these diagnoses. PMID- 28858333 TI - Prostate cancer: IGF2 imprinting loss promotes cancer. PMID- 28858332 TI - Infection: Proof of principle for effectiveness of a gonorrhoea vaccine. PMID- 28858334 TI - Prostate cancer: Mastering transcription: TMPRSS2-ERG and the cis-regulatory landscape. PMID- 28858335 TI - Prostate cancer: Stratifying salvage radiotherapy utility. PMID- 28858336 TI - Prostate cancer: Postdiagnosis statin use reduces mortality. PMID- 28858337 TI - Prostate cancer: Place your BETs. PMID- 28858339 TI - GUIDES: sgRNA design for loss-of-function screens. PMID- 28858340 TI - Structural biology: doors open at the European XFEL. PMID- 28858341 TI - Multielectrodes join the connectome. PMID- 28858342 TI - Pulsed-field gradient nuclear magnetic resonance measurements (PFG NMR) for diffusion ordered spectroscopy (DOSY) mapping. AB - While NMR is the most used analytical method for determining the molecular structure of isolated chemical entities, small compounds as well as macromolecules, its capability of analysing complex mixtures is less known. The advent of Diffusion Ordered SpectroscopY (DOSY) NMR has made diffusion experiments popular, enabling diffusion coefficients to be routinely measured and used to characterize chemical systems in solution. Indeed, since the translational diffusion coefficients of molecular species reflect their effective sizes and shapes, DOSY NMR allows the separation of the chemical entities present in multicomponent systems and, as in all diffusion NMR experiments, provides information on their intermolecular interactions as well as on their size and shape. The main aim of this review is to present an overview of the DOSY NMR mapping and its applications. The paper starts with a brief introduction to pulsed-field gradient (PFG) NMR and then focuses on the methodological procedures that can be used to perform good diffusion data acquisition and to obtain good quality DOSY maps. The second part describes, through selected literature examples, different applications of DOSY NMR to demonstrate the potential of the method for (i) unravelling the components of complex matrices comprising pharmaceuticals, dietary supplements, foods and beverages, and biological extracts, and (ii) probing intermolecular interactions and evaluating association constants between different hosts and guests, as well as estimating the sizes and molecular weights of molecular species. PMID- 28858338 TI - Data-analysis strategies for image-based cell profiling. AB - Image-based cell profiling is a high-throughput strategy for the quantification of phenotypic differences among a variety of cell populations. It paves the way to studying biological systems on a large scale by using chemical and genetic perturbations. The general workflow for this technology involves image acquisition with high-throughput microscopy systems and subsequent image processing and analysis. Here, we introduce the steps required to create high quality image-based (i.e., morphological) profiles from a collection of microscopy images. We recommend techniques that have proven useful in each stage of the data analysis process, on the basis of the experience of 20 laboratories worldwide that are refining their image-based cell-profiling methodologies in pursuit of biological discovery. The recommended techniques cover alternatives that may suit various biological goals, experimental designs, and laboratories' preferences. PMID- 28858343 TI - Comparison of indoor air sampling and dust collection methods for fungal exposure assessment using quantitative PCR. AB - Evaluating fungal contamination indoors is complicated because of the many different sampling methods utilized. In this study, fungal contamination was evaluated using five sampling methods and four matrices for results. The five sampling methods were a 48 hour indoor air sample collected with a ButtonTM inhalable aerosol sampler and four types of dust samples: a vacuumed floor dust sample, newly settled dust collected for four weeks onto two types of electrostatic dust cloths (EDCs) in trays, and a wipe sample of dust from above floor surfaces. The samples were obtained in the bedrooms of asthmatic children (n = 14). Quantitative polymerase chain reaction (qPCR) was used to analyze the dust and air samples for the 36 fungal species that make up the Environmental Relative Moldiness Index (ERMI). The results from the samples were compared by four matrices: total concentration of fungal cells, concentration of fungal species associated with indoor environments, concentration of fungal species associated with outdoor environments, and ERMI values (or ERMI-like values for air samples). The ERMI values for the dust samples and the ERMI-like values for the 48 hour air samples were not significantly different. The total cell concentrations of the 36 species obtained with the four dust collection methods correlated significantly (r = 0.64-0.79, p < 0.05), with the exception of the vacuumed floor dust and newly settled dust. In addition, fungal cell concentrations of indoor associated species correlated well between all four dust sampling methods (r = 0.68-0.86, p < 0.01). No correlation was found between the fungal concentrations in the air and dust samples primarily because of differences in concentrations of Cladosporium cladosporioides Type 1 and Epicoccum nigrum. A representative type of dust sample and a 48 hour air sample might both provide useful information about fungal exposures. PMID- 28858344 TI - NIR emission and luminescent sensing of a lanthanide-organic framework with Lewis basic imidazole and pyridyl sites. AB - A series of lanthanide-organic frameworks [Ln(Himdc)(ina)(H2O)]n (Ln = Eu 1a; Sm 1b; and Nd 1c, H3imdc = imidazole-4,5-dicarboxylic acid, Hina = isonicotinic acid) were synthesized under hydrothermal conditions. All compounds 1a-1c consist of a 3D microporous lanthanide carboxylate ([Eu(COO)3]n) framework and uncoordinated Lewis basic pyridyl and imidazole groups hung in the channels. The luminescence investigations show that the compound 1c displays an interesting NIR luminescence property. The compound 1a exhibits a good potential as a luminescent multi-responsive sensing material for Fe3+ ions and Cr2O72- anions. PMID- 28858345 TI - Hyperspectral depth-profiling with deep Raman spectroscopy for detecting chemicals in building materials. AB - Toxic chemicals inside building materials have long-term harmful effects on human bodies. To prevent secondary damage caused by the evaporation of latent chemicals, it is necessary to detect the chemicals inside building materials at an early stage. Deep Raman spectroscopy is a potential candidate for on-site detection because it can provide molecular information about subsurface components. However, it is very difficult to spectrally distinguish the Raman signal of the internal chemicals from the background signal of the surrounding materials and to acquire the geometric information of chemicals. In this study, we developed hyperspectral wide-depth spatially offset Raman spectroscopy coupled with a data processing algorithm to identify toxic chemicals, such as chemical warfare agent (CWA) simulants in building materials. Furthermore, the spatial distribution of the chemicals and the thickness of the building material were also measured from one-dimensional (1D) spectral variation. PMID- 28858346 TI - Response of the phytoplankton community to water quality in a local alpine glacial lake of Xinjiang Tianchi, China: potential drivers and management implications. AB - Eutrophication has become one of the most serious threats to aquatic ecosystems in the world. With the combined drivers of climate change and human activities, eutrophication has expanded from warm shallow lakes to cold-water lakes in relatively high latitude regions and has raised greater concerns over lake aquatic ecosystem health. A two-year field study was carried out to investigate water quality, phytoplankton characteristics and eutrophication status in a typical alpine glacial lake of Tianchi, a scenic area and an important drinking water source in the Xinjiang Autonomous Region of China, in 2014 and 2015. Clear seasonal and annual variations of nutrients and organic pollutants were found especially during rainy seasons. For the phytoplankton community, Bacillariophyta held the dominant position in terms of both species and biomass throughout the year, suggesting the dominant characteristics of diatoms in the phytoplankton structure in such a high-altitude cold-water lake. This was quite different from plain and warm lakes troubled with cyanobacterial blooming. Moreover, the dominant abundance of Cyclotella sp. in Tianchi might suggest regional warming caused by climate change, which might have profound effects on the local ecosystems and hydrological cycle. Based on water quality parameters, a comprehensive trophic level index TLI (Sigma) was calculated to estimate the current status of eutrophication, and the results inferred emerging eutrophication in Tianchi. Results from Canonical Correspondence Analysis (CCA) and correlation analysis of phytoplankton genera and physico-chemical variables of water indicated that abiotic factors significantly influenced the phytoplankton community and its succession in Tianchi Lake. These abiotic factors could explain 77.82% of the total variance, and ammonium was identified as the most discriminant variable, which could explain 41% of the total variance followed by TP (29%). An estimation of annual nutrient loadings to Tianchi was made, and the results indicated that about 212.97 t of total nitrogen and 32.14 t of total phosphorus were transported into Tianchi Lake annually. Human socio economic activities (runoff caused by historical overgrazing and increasing tourism) were identified as the most important contributors to Tianchi nutrient loadings. PMID- 28858347 TI - Small molecule-driven directional movement enabling pin-hole free perovskite film via fast solution engineering. AB - Organolead trihalide perovskite materials have been widely used as light absorbers in efficient photovoltaic cells. Solution engineering is a fast and effective method to fabricate perovskite films. Here, we report a fast precipitation of a pin-hole free perovskite film by small molecule-driven directed diffusion engineering. Solvent molecules diffuse easily and quickly by colliding with small molecules, e.g. helium. Fully compact perovskite films and highly efficient perovskite solar cells are achieved, and the devices show remarkable stability of ca. 90% original efficiency after more than 1000 hours of testing. The small molecule driving directed diffusion offers a promising fast precipitation of a perovskite film and highly efficient, stable perovskite solar cells. PMID- 28858348 TI - A Prussian blue anode for high performance electrochemical deionization promoted by the faradaic mechanism. AB - Desalination is a sustainable process that removes sodium and chloride ions from seawater. Herein, we demonstrate a faradaic mechanism to promote the capacity of capacitive deionization in highly concentrated salt water via an electrochemical deionization device. In this system, ion removal is achieved by the faradaic mechanism via a constant current operation mode, which is improved based on the constant voltage operation mode used in the conventional CDI operation. Benefiting from the high capacity and excellent rate performance of Prussian blue as an active electrochemical reaction material, the designed unit has revealed a superior removal capacity with an ultrafast ion removal rate. A high removal capacity of 101.7 mg g-1 has been obtained with proper flow rate and current density. To further improve the performance of the EDI, a reduced graphene oxide with nanopores and Prussian blue composite has been synthesized. The PB@NPG has demonstrated a high salt removal capacity of 120.0 mg g-1 at 1 C with an energy consumption of 6.76 kT per ion removed, which is much lower than most CDI methods. A particularly high rate performance of 0.5430 mg g-1 s-1 has been achieved at 40 C. The faradaic mechanism promoted EDI has provided a new insight into the design and selection of host materials for highly concentrated salt water desalination. PMID- 28858349 TI - Orientational ordering of water in extended hydration shells of cations is ion specific and is correlated directly with viscosity and hydration free energy. AB - Specific ion effects in aqueous solutions are investigated at the molecular, nanoscopic and macroscopic levels. Femtosecond elastic second harmonic scattering (fs-ESHS) is used here to assess the chemical effects of ions on molecular and nanoscopic length scales of water, probing changes in the charge distribution around ions as well as structural orientational order of water molecules in extended hydration shells. We measured >0.05 M electrolyte solutions with a series of chloride salts (LiCl, NaCl, KCl, CsCl, RbCl, NH4Cl, MgCl2, CaCl2, and SrCl2). Ion specificity is observed in both the local electronic anisotropy and the nanoscopic orientational ordering of water. Both observables are influenced more by cations with larger valencies and smaller sizes and follow a direct Hofmeister trend. These ion-induced structural changes in the hydrogen-bond network of water are strongly correlated with the viscosity B-coefficient and the Gibbs free energy of hydration of ions. Such a connection between the nanoscopic and macroscopic changes provides a possibility to construct a molecular model for specific ion effects in aqueous solutions. PMID- 28858350 TI - Full-colour carbon dots: integration of multiple emission centres into single particles. AB - The single particle emission behaviours of our previously reported excitation dependent full-colour carbon dots (F-C dots) have been analyzed by a single particle fluorescence imaging technique. The co-localization of the F-C dots excited with different wavelengths shows that single F-C dots can also be excited with multiple energies. The co-localization of the F-C dots that emit at different colour regions under the same excitation wavelength or different excitation wavelengths shows that single F-C dots have a broad emission band from blue to red, but the emission intensities in different colour regions vary from one particle to another. So this study concretely proves that the full colour emissions are single particle behaviours; they are different from the other type of excitation dependent full-colour emission carbon dots whose full-colour behaviour originates from the large heterogeneity in both particle size and the structures of the ensemble. Then the origination of the full-colour emission at the single dot level was further studied by comparing the emission properties of the F-C dots and the small molecular byproducts, and it is found that the emissions of the dozens of molecular byproducts can also cover the full visible regions. And the emission positions of F-C dots are very similar to those of the byproducts at the same excitations, but they show different lifetimes. So a mechanism for the full colour emissions of F-C dots is proposed to originate from the hybridization of multiple small emissive molecules on the emissive carbon cores. This single particle level understanding of full-colour emission properties will pave the way towards the development of single dot imaging or tracking. PMID- 28858351 TI - Controlled droplet microfluidic systems for multistep chemical and biological assays. AB - Droplet microfluidics is a relatively new and rapidly evolving field of science focused on studying the hydrodynamics and properties of biphasic flows at the microscale, and on the development of systems for practical applications in chemistry, biology and materials science. Microdroplets present several unique characteristics of interest to a broader research community. The main distinguishing features include (i) large numbers of isolated compartments of tiny volumes that are ideal for single cell or single molecule assays, (ii) rapid mixing and negligible thermal inertia that all provide excellent control over reaction conditions, and (iii) the presence of two immiscible liquids and the interface between them that enables new or exotic processes (the synthesis of new functional materials and structures that are otherwise difficult to obtain, studies of the functions and properties of lipid and polymer membranes and execution of reactions at liquid-liquid interfaces). The most frequent application of droplet microfluidics relies on the generation of large numbers of compartments either for ultrahigh throughput screens or for the synthesis of functional materials composed of millions of droplets or particles. Droplet microfluidics has already evolved into a complex field. In this review we focus on 'controlled droplet microfluidics' - a portfolio of techniques that provide convenient platforms for multistep complex reaction protocols and that take advantage of automated and passive methods of fluid handling on a chip. 'Controlled droplet microfluidics' can be regarded as a group of methods capable of addressing and manipulating droplets in series. The functionality and complexity of controlled droplet microfluidic systems can be positioned between digital microfluidics (DMF) addressing each droplet individually using 2D arrays of electrodes and ultrahigh throughput droplet microfluidics focused on the generation of hundreds of thousands or even millions of picoliter droplets that cannot be individually addressed by their location on a chip. PMID- 28858352 TI - Ultrafast structural dynamics of boron nitride nanotubes studied using transmitted electrons. AB - We investigate the ultrafast structural dynamics of multi-walled boron nitride nanotubes (BNNTs) upon femtosecond optical excitation using ultrafast electron diffraction in a transmission electron microscope. Analysis of the time-resolved (100) and (002) diffraction profiles reveals highly anisotropic lattice dynamics of BNNTs, which can be attributed to the distinct nature of the chemical bonds in the tubular structure. Moreover, the changes in (002) diffraction positions and intensities suggest that the lattice response of BNNTs to the femtosecond laser excitation involves a fast and a slow lattice dynamic process. The fast process with a time constant of about 8 picoseconds can be understood to be a result of electron-phonon coupling, while the slow process with a time constant of about 100 to 300 picoseconds depending on pump laser fluence is tentatively associated with an Auger recombination effect. In addition, we discuss the power-law relationship of a three-photon absorption process in the BNNT nanoscale system. PMID- 28858353 TI - Bio-inspired spider-web-like membranes with a hierarchical structure for high performance lithium/sodium ion battery electrodes: the case of 3D freestanding and binder-free bismuth/CNF anodes. AB - High gravimetric energy density and volumetric energy density energy storage devices are highly desirable due to the rapid development of electric vehicles, and portable and wearable electronic equipment. Electrospinning is a promising technology for preparing freestanding electrodes with high gravimetric and volumetric energy density. However, the energy density of the traditional electrospun electrodes is restricted by the low mass loading of active materials (e.g. 20%-30 wt%). Herein, a biomimetic strategy inspired by the phenomenon of the sticky spider web is demonstrated as a high performance anode, which simultaneously improves the gravimetric and volumetric energy density. Freestanding carbon nanofiber (CNF) membranes containing over 50 wt% of bismuth were prepared by electrospinning and subsequent thermal treatment. Membranes consisting of CNF network structures bonded tightly with active Bi cluster materials, resulting in excellent mechanical protection and a fast charge transport path, which are difficult to achieve simultaneously. The composite membrane delivers high reversible capacity (483 mA h g-1 at 100 mA g-1 after 200 cycles) and high rate performance (242 mA h g-1 at 1 A g-1) as a lithium-ion battery anode. For use as a sodium ion battery, the composite membrane also shows a high reversible specific capacity of 346 mA h g-1 and outstanding cycling performance (186 mA h g-1 at 50 mA g-1 after 100 cycles). This work offers a simple, low cost and eco-friendly method for fabricating free-standing and binder free composite electrodes with high loading used in LIBs and SIBs. PMID- 28858354 TI - Dynamic control over catalytic function using responsive bisthiourea catalysts. AB - Two novel bisthiourea molecular motor-based catalysts were designed and their dynamic control of activity and stereoselectivity in the Henry reaction using heat and light as external stimuli was investigated. Enantioselective organocatalysis studies established that a basic functional group is not required within the catalyst core to effect efficient dual stereocontrol, illustrating novel stimuli responsive organocatalysts. PMID- 28858355 TI - High thermal conductivity through simultaneously aligned polyethylene lamellae and graphene nanoplatelets. AB - The effect of simultaneous alignment of polyethylene (PE) lamellae and graphene nanoplatelets (GnP) on the thermal conductivity (k) of PE-GnP composites is investigated. Measurements reveal a large increase of 1100% in k of the aligned PE-GnP composite using 10 wt% GnPs relative to unoriented pure PE. The rate of increase of k with applied strain for the pure PE-GnP composite with 10 wt% GnP is found to be almost a factor of two higher than the pure PE sample, pointing to the beneficial effect of GnP alignment on k enhancement. Aligned GnPs are further found to be 3 times as effective in enhancing k as in the randomly oriented configuration. Enhancement in k is correlated with the alignment of PE lamellae and GnPs through wide-angle X-ray scattering and polarized Raman spectroscopy. At the maximum applied strain of 400% and using 10 wt% GnPs, a composite k of 5.9 W mK-1 is achieved. These results demonstrate the great potential of simultaneous alignment effects in achieving high k polymer composites. PMID- 28858356 TI - 2D reentrant auxetic structures of graphene/CNT networks for omnidirectionally stretchable supercapacitors. AB - Stretchable energy storage systems are essential for the realization of implantable and epidermal electronics. However, high-performance stretchable supercapacitors have received less attention because currently available processing techniques and material structures are too limited to overcome the trade-off relationship among electrical conductivity, ion-accessible surface area, and stretchability of electrodes. Herein, we introduce novel 2D reentrant cellular structures of porous graphene/CNT networks for omnidirectionally stretchable supercapacitor electrodes. Reentrant structures, with inwardly protruded frameworks in porous networks, were fabricated by the radial compression of vertically aligned honeycomb-like rGO/CNT networks, which were prepared by a directional crystallization method. Unlike typical porous graphene structures, the reentrant structure provided structure-assisted stretchability, such as accordion and origami structures, to otherwise unstretchable materials. The 2D reentrant structures of graphene/CNT networks maintained excellent electrical conductivities under biaxial stretching conditions and showed a slightly negative or near-zero Poisson's ratio over a wide strain range because of their structural uniqueness. For practical applications, we fabricated all solid-state supercapacitors based on 2D auxetic structures. A radial compression process up to 1/10th densified the electrode, significantly increasing the areal and volumetric capacitances of the electrodes. Additionally, vertically aligned graphene/CNT networks provided a plentiful surface area and induced sufficient ion transport pathways for the electrodes. Therefore, they exhibited high gravimetric and areal capacitance values of 152.4 F g-1 and 2.9 F cm-2, respectively, and had an excellent retention ratio of 88% under a biaxial strain of 100%. Auxetic cellular and vertically aligned structures provide a new strategy for the preparation of robust platforms for stretchable energy storage electrodes. PMID- 28858357 TI - Magnetic exchange force microscopy: theoretical analysis of induced magnetization reversals. AB - In magnetic exchange force microscopy a magnetic tip is scanned over the surface of a solid and an image representing the exchange interaction recorded. Sudden changes in the image corresponding to magnetization switching can be monitored as a function of the tip-surface distance thereby giving important information about the lifetime of metastable magnetic states and how it is affected by the exchange interaction. Here, theoretical calculations are carried out to study the tip surface interaction and determine the mechanism and rate of transitions in a magnetic exchange force microscopy experiment, and comparison made with reported experimental data on an Fe cluster interacting with an antiferromagnetic Fe overlayer on a W(001) surface. The activation energy was determined from calculations of minimum energy paths and the pre-exponential factor in the Arrhenius rate expression evaluated from harmonic transition state theory, extended to account for zero modes. A noncollinear extension of the Alexander Anderson model was used to describe the magnetic properties of an atomic scale representation of the system. The calculations reveal how the tip size, tip surface distance and magnetic field affect the lifetime of the magnetic states. PMID- 28858358 TI - Lipid nanodomains change ion channel function. AB - Signaling proteins and neurotransmitter receptors often associate with saturated chain and cholesterol-rich domains of cell membranes, also known as lipid rafts. The saturated chains and high cholesterol environment in lipid rafts can modulate protein function, but evidence for such modulation of ion channel function in lipid rafts is lacking. Here, using raft-forming model membrane systems containing cholesterol, we show that lipid lateral phase separation at the nanoscale level directly affects the dissociation kinetics of the gramicidin dimer, a model ion channel. PMID- 28858359 TI - 18O2 labeling experiments illuminate the oxidation of ent-kaurene in bacterial gibberellin biosynthesis. AB - Bacteria can produce gibberellin plant hormones. While the bacterial biosynthetic pathway is similar to that of plants, the individual enzymes are very distantly related and arose via convergent evolution. The cytochromes P450 (CYPs) that catalyze the multi-step oxidation of the alkane precursor ent-kaurene (1) to ent kauren-19-oic acid (5), are called ent-kaurene oxidases (KOs), and in plants are from the CYP701 family, and share less than 19% amino acid sequence identity with those from bacteria, which are from the phylogenetically distinct CYP117 family. Here the reaction series catalyzed by CYP117 was examined by 18O2 labeling experiments, the results indicate successive hydroxylation of 1 to ent-kauren-19 ol (2) and then ent-kauren-19,19-diol (3) and most likely an intervening dehydration to ent-kauren-19-al (4) prior to the concluding hydroxylation to 5. Accordingly, the bacterial and plant KOs converged on catalysis of the same series of reactions, despite their independent evolutionary origin. PMID- 28858360 TI - Influence of pi-bridge conjugation on the electrochemical properties within hole transporting materials for perovskite solar cells. AB - Hole transporting materials (HTMs) play an important role in most efficient perovskite solar cells (PSCs). In particular, donor-pi-bridge-donor type oligomers (D-pi-D) have been explored extensively as alternative and economical HTMs. In the present work, a series of triphenylamine-based derivatives as alternatives to the expensive Spiro-OMeTAD were explored by using first principles calculations combined with the Marcus theory. The electronic structures, optical properties and hole mobilities of all the molecules were investigated to reveal the relationship between their charge-transport properties and the pi-bridge conjugation. The HOMO levels decrease with the extension of the pi-bridge conjugation length, which may lead to higher open-circuit voltages. Moreover, we employed a quantum mechanical (QM) methodology to estimate the carrier mobility for organic crystals. Specifically, an orientation function MUPhi (V, lambda, r, theta, gamma; Phi) is first applied to quantitatively evaluate the overall carrier mobility of HTMs in PSCs. The theoretically calculated results validate that this model predicts the hole mobility of HTMs correctly. More importantly, it is revealed that enhancing the pi-bridge conjugation in HTMs can improve the hole mobility, which will definitely improve the performance of PSCs. We hope that our theoretical investigation will offer a reliable calculation method to estimate the charge-transport properties of novel HTMs applied in perovskite solar cells. PMID- 28858361 TI - Quantification of green fluorescent protein-(GFP-) tagged membrane proteins by capillary gel electrophoresis. AB - A fast and robust procedure for the quantification of GFP-tagged membrane proteins in cell homogenates was developed employing capillary gel electrophoresis coupled to laser-induced fluorescence detection (CGE-LIF). The new method was found to be highly sensitive and applicable to structurally diverse membrane proteins including synaptic vesicle protein 2A (SV2A), adenosine A2A receptor (A2AAR), and connexin 43 (Cx43). Quantification of SV2A and A2AAR using radioligand binding assays confirmed the results obtained with CGE-LIF. The CGE-LIF method showed significantly higher sensitivity as compared to fluorimetric measurement in a microplate. Importantly, CGE-LIF involves separation of the target proteins and their degradation products prior to quantification and thereby ensures specificity. We anticipate broad applicability of the method for any fluorophore-tagged protein. PMID- 28858362 TI - The acute effect of coffee on endothelial function and glucose metabolism following a glucose load in healthy human volunteers. AB - A diet rich in plant polyphenols has been suggested to reduce the incidence of cardiovascular disease and type 2 diabetes mellitus, in part, via improvements in endothelial function. Coffee is a rich source of phenolic compounds including the phenolic acid, chlorogenic acid (CGA). The aim of the study was to investigate the effect of coffee as a whole beverage on endothelial function, blood pressure and blood glucose concentration. Twelve healthy men and women were recruited to a randomised, placebo-controlled, cross-over study, with three treatments tested: (i) 18 g of ground caffeinated coffee containing 300 mg CGA in 200 mL of hot water, (ii) 18 g of decaffeinated coffee containing 287 mg CGA in 200 mL of hot water, and (iii) 200 mL of hot water (control). Treatment beverages were consumed twice, two hours apart, with the second beverage consumed simultaneously with a 75 g glucose load. Blood pressure was recorded and the finger prick glucose test was performed at time = 0 and then every 30 minutes up to 2 hours. Endothelial function, assessed using flow-mediated dilatation (FMD) of the brachial artery, was measured at 1 hour and a blood sample taken at 2 hours to measure plasma nitrate/nitrite and 5-CGA concentrations. The FMD response was significantly higher in the caffeinated coffee group compared to both decaffeinated coffee and water groups (P < 0.001). There was no significant difference in the FMD response between decaffeinated coffee and water. Blood glucose concentrations and blood pressure were not different between the three treatment groups. In conclusion, the consumption of caffeinated coffee resulted in a significant improvement in endothelial function, but there was no evidence for benefit regarding glucose metabolism or blood pressure. Although the mechanism has yet to be elucidated the results suggest that coffee as a whole beverage may improve endothelial function, or that caffeine is the component of coffee responsible for improving FMD. PMID- 28858363 TI - High surface coverage of a self-assembled monolayer by in situ synthesis of palladium nanodeposits. AB - Nascent metal|monolayer|metal devices have been fabricated by depositing palladium, produced through a CO-confined growth method, onto a self-assembled monolayer of an amine-terminated oligo(phenylene ethynylene) derivative on a gold bottom electrode. The high surface area coverage (85%) of the organic monolayer by densely packed palladium particles was confirmed by X-ray photoemission spectroscopy (XPS) and atomic force microscopy (AFM). The electrical properties of these nascent Au|monolayer|Pd assemblies were determined from the I-V curves recorded with a conductive-AFM using the Peak Force Tunneling AFM (PF-TUNATM) mode. The I-V curves together with the electrochemical experiments performed rule out the formation of short-circuits due to palladium penetration through the monolayer, suggesting that the palladium deposition strategy is an effective method for the fabrication of molecular junctions without damaging the organic layer. PMID- 28858364 TI - Shaping helical electrospun filaments: a review. AB - Nature abounds with helical filaments designed for specific tasks. For instance, some plants use tendrils to coil and attach to the surroundings, while Spiroplasma, a helical bacterium, moves by inverting the helical handedness along the filament axis. Therefore, developing methods to shape filaments on demand to exhibit a diversity of physical properties and shapes could be of interest to many fields, such as the textile industry, biomedicine or nanotechnology. Electrospinning is a simple and versatile technique that allows the production of micro and nanofibres with many different helical shapes. In this work, we review the different electrospinning procedures that can be used to obtain helical shapes similar to those found in natural materials. These techniques also demonstrate that the creation of helical shapes at the micro/nanoscale is not limited by the chirality of the building blocks at the molecular level, a finding which opens new horizons on filament shaping. PMID- 28858365 TI - Antioxidant and anti-inflammatory activities of Geranium robertianum L. decoctions. AB - Geranium robertianum L., commonly known as Herb Robert, is an herbaceous plant popularly known for its functional properties including antioxidant and anti inflammatory activities. In this study, the phenolic profile of leaf and stem decoctions of Geranium robertianum L. was elucidated by UHPLC-DAD-ESI-MSn analysis, and their antioxidant and anti-inflammatory potentials were assessed in vitro. Importantly, and envisaging the use of these extracts in human diets, the potential toxicity of bioactive concentrations was also addressed in macrophages and hepatocytes. Both extracts revealed high amounts of ellagitannins, although a slight prevalence of these compounds was observed in that originating from leaves. High radical scavenging activities against DPPH, ABTS+ and OH were observed either for the leaf or the stem extract, as well as good activities towards ferric reducing antioxidant power, lipid peroxidation and oxygen radical absorbance capacity. In addition, both extracts were very effective at scavenging NO, as measured in a chemical model, while only the stem extract was able to decrease the production of this radical by stimulated macrophages. On the other hand, none of the extracts was able to modulate the activity of lipoxygenase or the expression of the inducible nitric oxide synthase. Overall, these data allowed us to conclude that G. robertianum L. stem and leaf decoctions are particularly rich in tannins. The strong scavenging effects displayed by the stem extract suggest that its anti-inflammatory activity may partially result from its anti-radical capacities towards NO. PMID- 28858366 TI - Chiral phosphoric acid catalyzed enantioselective annulation of acyclic enecarbamates to in situ-generated ortho-quinone methides. AB - The first organocatalytic asymmetric reaction of acyclic enecarbamates with o quinone methides is disclosed. BINOL-based phosphoric acid catalysts were found to be suitable for the annulation reaction. With 10 mol% of the TRIP catalyst, high yields as well as excellent diastereo- and enantioselectivities are achieved for a variety of 2,3,4-trisubstituted chroman products. PMID- 28858367 TI - Silver nanocrystal-decorated polyoxometalate single-walled nanotubes as nanoreactors for desulfurization catalysis at room temperature. AB - Ultrathin nanocrystals generally provide a remarkable catalytic performance due to their high specific surface area and exposure of certain active sites. However, deactivation caused by growth and gathering limits the catalytic application of ultrathin nanocrystals. Here we report Ag nanocrystal-decorated polyoxometalate (Ag-POM) single-walled nanotubes assembled via a concise, surfactant-free soaking method as a new kind of well-defined core-sheath nanoreactor. The diameter of Ag nanocrystals inside polyoxometalate nanotubes can be controlled via simply adjusting the reactant concentration. Ag-POM provided outstanding oxidative desulfurization (ODS) catalytic performance for aromatic sulfocompounds at room temperature. It was suggested that Ag nanocrystals decorated on the inner surface played a key role in adjusting the electronic distribution and enhancing the catalytic activity. The as-prepared Ag-POM nanotubes are promising candidate catalysts with enhanced performance for practical catalytic applications in the gasoline desulfurization industry. PMID- 28858368 TI - Micro-mechanical, continuum-mechanical, and AFM-based descriptions of elasticity in open cylindrical micellar filaments. AB - We present theoretical and experimental descriptions of the elasticity of cylindrical micellar filaments using micro-mechanical and continuum theories, and atomic force microscopy. Following our micro-mechanical elasticity model for micellar filaments [M. Asgari, Eur. Phys. J. E: Soft Matter Biol. Phys., 2015, 38(9), 1-16], the elastic bending energy of hemispherical end caps is found. The continuum description of the elastic bending energy of a cylindrical micellar filament is also derived using constrained Cosserat rod theory. While the continuum approach provides macroscopic description of the strain energy of the micellar filament, the micro-mechanical approach has a microscopic view of the filament, and provides expressions for kinetic variables based on a selected interaction potential between the molecules comprising the filament. Our model predicts the dependence of the elastic modulus of the micellar filaments on their diameter, which agrees with previous experimental observations. Atomic force microscopy is applied to estimate the elastic modulus of the filaments using force volume analysis. The obtained values of elastic modulus yield the persistence length of micellar filaments on the same order of the previously reported values. Consistent with previous studies, our results indicate that semi flexible linear micelles have a relatively large local strain energy at their end points, which explains their tendency to fuse to minimize the number of end caps at relatively low total surfactant volume fractions. Also, the elastic modulus of micellar filaments was found to increase when the indentation frequency increases, a finding which agrees with previous rheological observations on the bulk shear modulus of micellar solutions. PMID- 28858369 TI - Bidirectional motion of filaments: the role of motor proteins and passive cross linkers. AB - In eukaryotic cells, motor proteins (MPs) bind to cytoskeletal filaments and move along them in a directed manner generating active stresses. During cell division a spindle structure of overlapping antiparallel microtubules forms whose stability and dynamics under the influence of MPs have been studied extensively. Although passive cross linkers (PCLs) are known to provide structural stability to a filamentous network, consequences of the interplay between ATP dependent active forces of MPs and passive entropic forces of PCLs on filamentous overlap remain largely unexplored. Here, we formulate and characterize a model to study this, using linear stability analysis and numerical integration. In the presence of PCLs, we find dynamic phase transitions with changing activity exhibiting regimes of stable partial overlap with or without oscillations, instability towards complete overlap, and stable limit cycle oscillations that emerge via a supercritical Hopf bifurcation characterized by an oscillation frequency determined by the MP and PCL parameters. We show that the overlap dynamics and stability depend crucially on whether both the filaments of an overlapping pair are movable or one is immobilized, having potential implications for in vivo and in vitro studies. PMID- 28858371 TI - 43rd Annual Meeting of the European Paediatric Ophthalmological Society (EPOS), 31 August-2 September 2017 | Oxford, UK. PMID- 28858370 TI - Intramolecular hydrogen bonding in conformationally semi-rigid alpha-acylmethane derivatives: a theoretical NMR study. AB - Conformational mobility is a core property of organic compounds, and conformational analysis has become a pervasive tool for synthetic design. In this work, we present experimental and computational (employing Density Functional Theory) evidence for unusual intramolecular hydrogen bonding interactions in a series of alpha-acylmethane derivatives, as well as a discussion of the consequences thereof for their NMR spectroscopic properties. PMID- 28858372 TI - Estimating Costs of Care Attributable to Cancer: Does the Choice of Comparison Group Matter? AB - OBJECTIVE: To compare alternative strategies for specifying cancer-free control cohorts for estimating cancer-attributable costs of care. DATA SOURCE, STUDY DESIGN, DATA EXTRACTION: Secondary data analysis of Surveillance, Epidemiology, and End Results data linked to Medicare claims among patients diagnosed with colorectal, lung, breast, and prostate cancers, 2007-2011. We estimated cancer attributable costs using three alternative reference cohorts: (1) noncancer Medicare patients individually matched by demographic characteristics, (2) noncancer patients individually matched on demographic factors and comorbidity score, (3) cancer patients as their own control, using prediagnosis costs. PRINCIPAL FINDINGS: Among 44,266 colorectal, 61,584 lung, 55,921 breast, and 67,733 prostate patients, mean total Medicare spending in the first year of diagnosis was $59,496, $54,261, $31,895, and $26,305, respectively. Estimates of cancer-attributable costs ranged from 79 percent to 82 percent of spending for colorectal, 76 percent-79 percent for lung, 65 percent-74 percent for breast, and 60 percent-75 percent for prostate cancers, depending on the reference cohort used. For all cancers, estimates were higher when patients were used as their own control, compared to demographic and comorbidity-matched controls. CONCLUSIONS: Choice of reference group can have a substantial impact on proportion of total costs attributed to cancer and should be clearly defined in analyses of the costs of cancer care. PMID- 28858373 TI - Electrolyte, acid-base, and hemoglobin oxygen affinity alterations following irradiation and storage of canine packed red blood cells. AB - BACKGROUND: Irradiation of RBC before transfusion is required to prevent transfusion-associated graft-versus-host disease for human patients undergoing hematopoietic stem cell transplantation. Additional applications for irradiated blood may exist in oncologic surgery. The effect of irradiation on canine packed RBC (pRBC) is unknown. OBJECTIVES: The aim of this study was to explore and characterize the in vitro electrolyte, acid-base, and oxygen-carrying capacity changes to pRBC immediately following irradiation and during storage. METHODS: Ten units of pRBC were irradiated using a linear accelerator. Concentration of potassium and glucose, percentage of free hemoglobin (fHb), hemoglobin oxygen saturation (sO2 ), total oxygen content, partial pressure of oxygen (pO2 ), the pO2 at which 50% of hemoglobin is saturated (p50), lactate, pH, and methemoglobin were measured before and following irradiation, and at 7 and 17 days post irradiation. RESULTS: In both irradiated and nonirradiated units, a significant decrease in pH and glucose, and a significant increase in lactate and potassium were noted. The pO2 , fHb, and the p50 value in both groups increased over the first 7 days. Immediately following irradiation, the pH was significantly lower, and the potassium, lactate, and fHb were significantly higher in irradiated units compared with controls. Small but significant differences were noted between irradiation status in pH, fHb, sO2 , total oxygen content, and p50 value at 7 days post irradiation. CONCLUSIONS: This hypothesis-generating study found irradiation and storage significantly altered in vitro properties of pRBC. The magnitude of these differences was small and the clinical impact of irradiation on pRBC may be negligible. PMID- 28858374 TI - PTEN allelic loss is an important mechanism in the late stage of development of oral leucoplakia into oral squamous cell carcinoma. AB - AIM: The aim of this study was to analyse allelic loss of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene and its protein immuno expression in dysplastic oral lesions and oral squamous cell carcinomas (OSCCs). METHODS AND RESULTS: Samples were collected from 153 patients [20 ranulas used as a control (C); 30 leucoplakias with mild dysplasia (MD); 30 leucoplakias with moderate to severe dysplasia (MSD); 73 oral squamous cell carcinoma (OSCC)]. PTEN protein expression was investigated using immunohistochemistry, and PTEN allelic loss was analysed by fluorescence in-situ hybridisation (FISH). Differences among groups were evaluated using the chi2 test. PTEN expression was higher in MSD (P = 0.002) and OSCC (P = 0.0259) compared with the C group; additionally, a higher expression was observed in MSD (P = 0.0035) and OSCC (P = 0.049) than MD. Regarding FISH analysis, a higher hemizygous (single copy) loss was observed in OSCC than in C (P = 0.0467) and in OSCC than in MD (P = 0.0175), as well as a higher homozygous deletion in OSCC compared with C (P = 0.0159) and OSCC than MD (P = 0.0145). CONCLUSION: The results of this work suggest that PTEN allelic loss is an important mechanism in the late stage of the development of oral potentially malignant lesions into oral cancer. PMID- 28858375 TI - Congenital Lymphocytic Choriomeningitis Virus: A Case of Prenatal Diagnosis. PMID- 28858376 TI - Effects of radio frequency and high pressure steam sterilisation on the colour and flavour of prepared Nostoc sphaeroides. AB - BACKGROUND: Nostoc sphaeroides has been used as a highly effective herbal medicine and dietary supplement for thousands of years. The desired dark green colour of fresh N. sphaeroides is converted into an undesirable dark brown during conventional high pressure (HP) steam sterilisation. Radio frequency (RF) sterilisation technology was used in this study to determine its effectiveness in sterilising N. sphaeroides and to achieve better preservation of natural colour and desirable flavour. Sterilisation was carried out using a 6 kW, 27 MHz RF instrument for 10, 20 and 30 min. The degree of microbial kill and the effects of RF sterilisation on colour and flavour were determined and compared with those obtained from HP steam (121 degrees C, 30 min) sterilisation. RESULTS: The effects of RF sterilisation on colour and flavour (measured using electronic nose) parameters were significantly lower than that in HP steam sterilisation. The RF sterilisation carried out for 20 min achieved logarithmic reduction of bacterial population and met China's national standard while preserving the colour and flavour better. CONCLUSION: Results of the present study indicated that application of RF sterilisation would improve the quality of sterilised N. sphaeroides and broaden its application in the food and health food industries. (c) 2017 Society of Chemical Industry. PMID- 28858378 TI - The nuclear pore complex: a strategic platform for regulating cell signaling. AB - Contents Summary 25 I Introduction 25 II. Structural organization of the NPC 26 III. The role of NPCs in immune signaling 26 IV. The role of NPCs in hormone signaling 28 V. Conclusions 29 Acknowledgements 29 References 29 SUMMARY: Nuclear pore complexes (NPCs) are fundamental components of the eukaryotic cell. They perforate the nuclear envelope and serve as highly selective transport gates that enable bi-directional macromolecule exchange between the nucleus and cytoplasm. Recent studies illustrate that the NPC is not a static structural channel but a flexible environment and strategic player during nuclear signaling. The constitutional and conformational dynamics of the NPC allow it to tailor nucleocytoplasmic transport activities and define specific signaling output in response to various cellular and environmental cues. In this Insight, we review the roles of NPC constituents in immune activation and hormone signaling in plants, and discuss the possible role of the NPC as a legitimate platform for regulating cell signaling. PMID- 28858377 TI - Effects of gamma-irradiation on cotyledon cell separation and pectin solubilisation in hard-to-cook cowpeas. AB - BACKGROUND: Cowpeas stored under high temperature and humidity develop the hard to-cook defect (HTC). This defect greatly increases cooking times and energy costs. To better understand the mechanisms involved in the HTC defect development, the effects of gamma-irradiation on cotyledon cellular structure and pectin solubility in two cowpea cultivars with different susceptibility to HTC defect were investigated. RESULTS: Gamma-irradiation decreased cotyledon cell wall thickness, increased cell size, and intercellular spaces in both cowpea cultivars and reduced cooking time of the less HTC susceptible cultivar. However, it did not reverse the HTC defect in the susceptible cultivar. Gamma-irradiation also increased the levels of cold water- and hot water-soluble pectin. The irradiation effects were thus mainly due to hydrolysis of pectin fractions in the cell walls. However, chelator-soluble pectin (CSP) solubility was not affected. CONCLUSION: As the cell wall changes brought about by gamma-irradiation were associated with pectin solubilisation, this supports the phytate-phytase-pectin theory as a major cause of the HTC defect. However, the non-reversal of the defect in HTC susceptible cowpeas and the absence of an effect on CSP indicate that other mechanisms are involved in HTC defect development in cowpeas, possibly the formation of alkali-soluble, ester bonded pectins. (c) 2017 Society of Chemical Industry. PMID- 28858379 TI - Hematologic reference intervals for wild Black vultures (Coragyps atratus). AB - BACKGROUND: The Black vulture (Coragyps atratus) is the most common species of vulture and is widespread in all America. The species feeds on rotting carcasses, and large groups are frequently seen in urban areas, concentrating especially on rubbish dumps. Although C atratus is a very common species in some areas, little is known about its health in the wild. OBJECTIVES: The aim of this study was to determine hematologic RIs of wild adult Black vultures. METHODS: Blood samples were obtained from 70 wild Black vultures captured in Sao Paulo, Brazil. Hematologic values were determined using conventional techniques applicable to birds. Reference intervals were determined using an Excel program with Reference Value Adviser (version 2.0). RESULTS: After statistical analysis, the following RIs were determined: HGB 8.5-12.5 g/dL, PCV 42.3-54.5%, MCV 203.2-402.6 fL, MCHC 17.4-26.2 g/dL, total solids 2.4-4.8 g/dL, RBC count 1.16-2.48 * 106 /MUL, WBC count 5.93-27.14 * 103 /MUL, heterophils 3.40-21.58 * 103 /MUL, lymphocytes 0.19 5.16 * 103 /MUL, eosinophils 0.0-3.07 * 103 /MUL, monocytes 0.0-1.49 * 103 /MUL, basophils 0.0-0.25 * 103 /MUL, and heterophil:lymphocyte ratio 1.3-36.9. Thrombocyte mean was 14.14 * 103 /MUL. CONCLUSIONS: Baseline hematologic data obtained in this study provide RIs that will be useful given that few studies have been carried out on the health of New World vultures. PMID- 28858380 TI - Facile Fabrication of Porous ZnS and ZnO Films by Coaxial Electrospinning for Highly Efficient Photodegradation of Organic Dyes. AB - Porous ZnS and ZnO nano-crystal films were fabricated via a three-step procedure. First, Zn(CH3 COO)2 /Silk Fibroin nanofiber mats were prepared by coaxial electrospinning. Second, Zn(CH3 COO)2 /Silk Fibroin mats were immersed in NaS solution to react with S2- to obtain ZnS/Silk Fibroin nanofiber mats. Finally, ZnO porous films were prepared by calcination of ZnS/Silk Fibroin composite mat at 600 degrees C in air atmosphere. When ZnS/Silk Fibroin mats were calcinated in nitrogen, ZnS/Carbon composite mats were obtained accordingly. The resulting porous films were fully characterized. The ZnO porous films were the aggregation of ZnO nano-crystal with hexagonal wurtzite structure. The seize of ZnO was estimated in the range of 10-20 nm. Both of the ZnS and ZnO nano-crystal films exhibited high photocatalytic activities for the photodegradation of Methylene blue and Rhodamine B. It was also found that ZnO porous films are better than ZnS/Carbon nanofiber mats. In addition, photocatalysis of a real wastewater sample from a printing and dyeing company was conducted. The ZnO porous films exhibited excellent performance to treat the real samples. Moreover, the porous ZnO nano-crystal photocatalyst could easily be recycled without notable loss of catalysis ability. PMID- 28858381 TI - 'Microcystic pattern' should be recognised as part of the morphological spectrum of solid-pseudopapillary neoplasm of the pancreas. AB - AIM: Solid pseudopapillary neoplasm (SPN) is an uncommon pancreatic tumour characterised by solid and pseudopapillary growth patterns. We have observed SPNs can show a microcystic pattern (microcystic SPN), which has been poorly described and may be confused with microcystic neoplasms. We conducted the present study to clarify the clinicopathological and immunohistochemical features of microcystic SPNs. METHODS AND RESULTS: We examined a consecutive series of 44 SPNs and 10 serous cystadenomas (SCAs), and classified them into 13 microcystic SPNs (29.5%) and 31 conventional SPNs (70.5%). Clinicopathological analysis, immunohistochemical staining and mucin histochemistry were performed. Clear cell change, hyalinised stroma and haemorrhage were observed significantly more frequently in the microcystic SPNs compared to the conventional SPNs. Immunohistochemically, the microcystic SPNs showed significantly lower frequencies of CD10 (0%) and CD56 expression (62%) compared to the conventional SPNs (87%; P < 0.001, 90%; P < 0.0085, respectively). There were no significant differences in other clinicopathological and immunohistochemical features between the two groups (i.e. the nuclear expression of beta-catenin, E-cadherin, progesterone receptor (PgR), lack of forkhead box (Fox)L2 and occasional oestrogen receptor (ER), AE1/AE3 expression). Microcystic SCAs lack such a characteristic immunophenotype. The myxoid stroma of microcystic SPNs contained hyaluronan revealed by Alcian blue stain with hyaluronidase digestion. CONCLUSION: We thus conclude that the microcystic pattern should be recognised as a part of the morphological spectrum of SPNs. Our findings may contribute to the correct diagnosis of the pancreatic neoplasms with the microcystic pattern. In addition, we speculate that stromal change caused by an accumulation of hyaluronan may contribute to the microcystic pattern of SPN. PMID- 28858382 TI - A 5-year randomized trial on the safety and efficacy of pimecrolimus in atopic dermatitis: a critical appraisal - comment. PMID- 28858383 TI - A Carrel patch technique for renal transplantation in cats. AB - OBJECTIVE: To evaluate the feasibility of a Carrel patch method in feline renal transplantation. STUDY DESIGN: Descriptive case series. ANIMALS: Nine healthy donor cats and 9 client recipient cats with chronic renal failure. METHODS: Renal transplantation was performed in 9 cats with chronic renal failure after collection of a donor's left kidney with a Carrel patch technique. A patch of donor aortic wall was removed with either 2 or 1 renal artery (ies) (n = 1 and 8 cats, respectively) central to the patch, with a cuff of tissue (<=1 mm) protruding from the base of the vessels. The Carrel patch was implanted in recipient cats with an end-to-side artery-to-aorta anastomosis, in a simple continuous pattern of 9-0 nylon. The renal vein and ureter were implanted as previously described. RESULTS: All donors and recipients survived surgery without vascular complication. CONCLUSION: The Carrel patch is a novel approach allowing the harvest of kidneys with multiple renal arteries. The technique also simplified the implant procedure, potentially decreasing the risks of bleeding and thrombosis. PMID- 28858385 TI - Pathological factors and prognosis of resected liver metastases of colorectal carcinoma: implications and proposal for a pathological reporting protocol. AB - Colorectal cancer is a leading cause of death worldwide. The liver is the most common site of distant metastases, and surgery is the only potentially curative treatment, although the recurrence rate following surgery is high. In order to define prognosis after surgery, many histopathological features have been identified in the primary tumour. In turn, pathologists routinely report specific findings to guide oncologists on the decision to recommend adjuvant therapy. In general, the pathological report of resected colorectal liver metastases is limited to confirmation of the malignancy and details regarding the margin status. Most pathological reports of a liver resection for colorectal liver metastasis lack information on other important features that have been reported to be independent prognostic factors. We herein review the evidence to support a more detailed pathological report of the resected liver specimen, with attention to: the number and size of liver metastases; margin size; the presence of lymphatic, vascular, perineural and biliary invasion; mucinous pattern; tumour growth pattern; the presence of a tumour pseudocapsule; and the pathological response to neoadjuvant chemotherapy. In addition, we propose a new protocol for the evaluation of colorectal liver metastasis resection specimens. PMID- 28858384 TI - Reduced Levels of mGlu2 Receptors within the Prelimbic Cortex Are Not Associated with Elevated Glutamate Transmission or High Alcohol Drinking. AB - BACKGROUND: A Grm2 cys407* stop codon mutation, which results in a loss of the metabotropic glutamate 2 (mGlu2) receptor protein, was identified as being associated with high alcohol drinking by alcohol-preferring (P) rats. The objectives of the current study were to characterize the effects of reduced levels of mGlu2 receptors on glutamate transmission and alcohol drinking. METHODS: Quantitative no-net-flux microdialysis was used to test the hypothesis that basal extracellular glutamate levels in the prelimbic (PL) cortex and nucleus accumbens shell (NACsh) will be higher in P than Wistar rats. A lentiviral-delivered short-hairpin RNA (shRNA)-mediated knockdown was used to test the hypothesis that reduced levels of mGlu2 receptors within the PL cortex will increase voluntary alcohol drinking by Wistar rats. A linear regression analysis was used to test the hypothesis that there will be a significant correlation between the Grm2 cys407* mutation and level of alcohol intake. RESULTS: Extracellular glutamate concentrations within the PL cortex (3.6 +/- 0.6 vs. 6.4 +/- 0.6 MUM) and NACsh (3.2 +/- 0.4 vs. 6.6 +/- 0.6 MUM) were significantly lower in female P than female Wistar rats. Western blot detected the presence of mGlu2 receptors in these regions of female Wistar rats, but not female P rats. Micro-infusion of shRNAs into the PL cortex significantly reduced local mGlu2 receptor levels (by 40%), but did not alter voluntary alcohol drinking in male Wistar rats. In addition, there was no significant correlation between the Grm2 mutation and alcohol intake in 36 rodent lines (r = 0.29, p > 0.05). CONCLUSIONS: Collectively, these results suggest a lack of association between the loss of mGlu2 receptors and glutamate transmission in the NACsh and PL cortex of female P rats, and between the level of mGlu2 receptors in the PL cortex and alcohol drinking of male Wistar rats. PMID- 28858386 TI - Ultrasonographic identification of the dorsal atlantoaxial ligament in dogs. AB - OBJECTIVE: To determine the ability to identify the dorsal atlantoaxial ligament during ultrasonographic examination of dogs. STUDY DESIGN: Canine cadaveric study. SAMPLE POPULATION: Canine cervical spines (n = 35). METHODS: Thirty-five canine cadavers with an estimated body weight of 6-35 kg were retrieved. Five cervical spines were dissected to assess the length and thickness of the dorsal atlantoaxial ligament and correlate ultrasound-guided injection of ink with anatomical dissection. Ultrasonographic evaluation of the dorsal atlantoaxial ligament was performed on 30 cadavers. The visibility of the dorsal atlantoaxial ligament in both the transverse and the sagittal planes was subjectively scored (0-3). RESULTS: The dorsal atlantoaxial ligament was detectable on ultrasonographic examination in all cadavers: 27/30 and 28/30 were graded as moderately visible (grade 2) or clearly visible (grade 3) in the sagittal and transverse view, respectively. Only 1/30 cadaver specimen of a large breed dog was graded as 1 (indistinct) in both the sagittal and transverse planes. None of the cadavers were graded as 0 (not visible) in any view. CONCLUSION: The dorsal atlantoaxial ligament can be identified in ultrasonographic examination of normal canine cadavers. Future studies on animals with clinical atlantoaxial instability/subluxation are needed to evaluate the role of this imaging technique in providing a safer diagnosis of this condition. CLINICAL RELEVANCE: Ultrasonographic examination of the dorsal atlantoaxial ligament could potentially provide a noninvasive and safe imaging technique that may contribute to the diagnosis of atlantoaxial instability/subluxation in dogs. PMID- 28858387 TI - Effect of Combination Therapy of Ezetimibe and Atorvastatin on Remnant Lipoprotein Versus Double Atorvastatin Dose in Egyptian Diabetic Patients. AB - A high level of remnant lipoprotein cholesterol (RLP-C) is a predominant feature in diabetic patients with atherosclerosis. This study aimed to investigate the effect of ezetimibe added to statin therapy compared to doubling standard statin dose. Sixty-five eligible patients were recruited then prospectively randomized to receive ezetimibe 10 mg/day plus their 40 mg daily atorvastatin dose (group 1) or atorvastatin 80 mg/day (group 2) for 3 months. Efficacy was evaluated using plasma levels of RLP-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL), percentage of brachial artery flow-mediated dilation, and lipid profile. Forty patients completed the study and provided efficacy data. Group 1 showed more reduction in RLP-C (45.7% vs 31.7%, P = .02), apolipoprotein B (28.5% vs 9.5%, P = .01), total cholesterol (34.7% vs 24.6%, P = .003), triglycerides (49% vs 24.4%, P = .000), non-HDL (49.3% vs 33%, P = .002), and low density lipoprotein cholesterol (49.6% vs 35.2%, P = .02) compared to group 2. Group 1 showed a greater increase in HDL (66% vs 35%, P = .002); and flow mediated dilation (30% vs 17%, P = .01) compared to group 2. It is concluded that adding ezetimibe 10 mg to atorvastatin 40 mg may be a better choice than doubling atorvastatin dose in improving RLPs, endothelial function, and lipid profile in diabetic cardiovascular patients who could not achieve their therapeutic treatment goals with the standard atorvastatin dose. PMID- 28858388 TI - Trends in the Types of Usual Sources of Care: A Shift from People to Places or Nothing at All. AB - OBJECTIVE: (1) To examine usual source of care (USC) trends across four categories (No USC, Person USC, Person, in Facility USC, and Facility USC), and (2) to determine whether USC types are associated with emergency department (ED) visits and hospital admissions. DATA SOURCE: 1996-2014 Medical Expenditure Panel Surveys. STUDY DESIGN: We stratified each USC category, by age, region, gender, poverty, insurance, race/ethnicity, and education and used regression to determine the characteristics associated with USC types, ED visits, and hospital admissions. PRINCIPAL FINDINGS: Those with No USC and Facility USCs increased 10 and 18 percent, respectively, while those with Person USCs decreased by 43 percent. Compared to those in the lowest income bracket, those in the highest income bracket were less likely to have a Facility USC. Among those with low incomes, individuals with No USC, Person, in Facility, and Facility USCs were more likely to have ED visits than those with Person USCs. CONCLUSIONS: A growing number are reporting facilities as their USCs or none at all. The impact of these trends is uncertain, although we found that some USC types are associated with ED visits and hospital admissions. Tracking USCs will be crucial to measuring progress toward enhanced care efficiency. PMID- 28858389 TI - Characterization of Physical and Mechanical Properties of Miscible Lactose-Sugars Systems. AB - Lactose-sugars systems were produced by spray drying. They were lactose, lactose glucose (4:1) mixtures, lactose-maltose (4:1) mixtures, lactose-sucrose (4:1) mixtures, lactose-trehalose (4:1) mixtures, and lactose-corn syrup solids (CSS) (4:1) mixtures. The physical characteristics, water sorption behavior, glass transition, and mechanical properties of miscible lactose-sugars systems were investigated. Lactose-glucose mixtures had larger particle size than other lactose-sugars systems after spray drying. The presence of glucose or sucrose in lactose-sugars mixtures decreased the glass transition temperatures of amorphous systems, while the presence of maltose and trehalose had only minor impact on the glass transition temperatures. Moreover, glucose accelerated the crystallization of amorphous system at 0.44 aw , but its presence delayed the loss of sorbed water at higher water activities (>=0.54 aw ). Mechanical property study indicated that glucose and sucrose in amorphous system could result in an increase of molecular mobility, while the presence of CSS could decrease the free volume and maintain the stiffness of the miscible systems. PMID- 28858390 TI - Non-destructive technique for determining the viability of soybean (Glycine max) seeds using FT-NIR spectroscopy. AB - BACKGROUND: The viability of seeds is important for determining their quality. A high-quality seed is one that has a high capability of germination that is necessary to ensure high productivity. Hence, developing technology for the detection of seed viability is a high priority in agriculture. Fourier transform near-infrared (FT-NIR) spectroscopy is one of the most popular devices among other vibrational spectroscopies. This study aims to use FT-NIR spectroscopy to determine the viability of soybean seeds. RESULTS: Viable and artificial ageing seeds as non-viable soybeans were used in this research. The FT-NIR spectra of soybean seeds were collected and analysed using a partial least-squares discriminant analysis (PLS-DA) to classify viable and non-viable soybean seeds. Moreover, the variable importance in projection (VIP) method for variable selection combined with the PLS-DA was employed. The most effective wavelengths were selected by the VIP method, which selected 146 optimal variables from the full set of 1557 variables. CONCLUSIONS: The results demonstrated that the FT-NIR spectral analysis with the PLS-DA method that uses all variables or the selected variables showed good performance based on the high value of prediction accuracy for soybean viability with an accuracy close to 100%. Hence, FT-NIR techniques with a chemometric analysis have the potential for rapidly measuring soybean seed viability. (c) 2017 Society of Chemical Industry. PMID- 28858391 TI - Pterocarpus santalinus L. Regulated Ultraviolet B Irradiation-induced Procollagen Reduction and Matrix Metalloproteinases Expression Through Activation of TGF beta/Smad and Inhibition of the MAPK/AP-1 Pathway in Normal Human Dermal Fibroblasts. AB - Ultraviolet light-induced reactive oxygen species (ROS) damage human skin and prematurely cause aging. A growing body of research is focusing on considering plants and plant-derived compounds as antiphotoaging therapeutic material. Pterocarpus santalinus L., as an Indian traditional medicine, possesses antidiabetic, anti-inflammatory and antioxidative effects. Here, we studied the antiphotoaging effects of ethanolic extract of P. santalinus L. heartwood (EPS) on ultraviolet radiation B (UVB)-irradiated normal human dermal fibroblasts (NHDFs). Results showed that EPS significantly inhibited the upregulation of matrix metalloproteinases and IL-6 caused by UVB irradiation, and suppressed UVB induced phosphorylation of extracellular signal-regulated kinase, Jun N-terminal kinase and p38, as well as the activation of AP-1 transcription factors. Further study indicated that UVB-induced production of MMP-1 and IL-6 could be inhibited by PD 98059 (an ERK inhibitor) and SP600125 (A JNK inhibitor), implied that EPS inhibited UVB-induced MMP-1 and IL-6 secretion by inactivating MAPK signaling pathway. In addition, EPS possessed an excellent antioxidant activity, which could increase cytoprotective antioxidants such as HO-1, NQ-O1 expression by facilitating the nuclear accumulation of Nrf2. Treatment of NHDFs with EPS also recovered UVB-induced procollagen type I reduction by activating TGF-beta/Smad pathway. These findings demonstrated that EPS had a potential effect against UVB induced skin photoaging. PMID- 28858392 TI - Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. AB - BACKGROUND: Locoregional extension of intrahepatic cholangiocarcinoma (ICC) at the time of diagnosis results in a low resectability rate and poor prognosis. The aim of this retrospective study was to assess the efficacy of neoadjuvant chemotherapy for locally advanced ICC. METHODS: All consecutive patients with ICC between 2000 and 2013 were included prospectively in a single-centre database and analysed retrospectively. Patients with locally advanced ICC considered as initially unresectable received primary chemotherapy, followed by surgery in those with secondary resectability. Results of patients who underwent surgery for locally advanced ICC were compared with those of patients with initially resectable ICC treated by surgery alone. RESULTS: A total of 186 patients were included in the study. Of 74 patients with locally advanced ICC, 39 (53 per cent) underwent secondary resection after a median of six chemotherapy cycles. Patients in this group were younger (P = 0.030) and had more advanced disease than those who had surgery alone, and presented more frequently with lymphadenopathy (P = 0.010) and vascular invasion (P = 0.010). Postoperative morbidity and mortality were no different between the groups. The median survival of patients who had surgery after chemotherapy was 24.1 months, and that of patients who had surgery alone was 25.7 months (P = 0.391). CONCLUSION: Patients with locally advanced ICC treated by surgery following neoadjuvant chemotherapy had similar short- and long term results to patients with initially resectable ICC who had surgery alone. Neoadjuvant chemotherapy as a first-line treatment for locally advanced ICC may be an effective downstaging option, facilitating secondary resectability in patients with initially unresectable disease. PMID- 28858393 TI - Optimizing perioperative lymphatic-venous anastomosis localization using transcutaneous vein illumination, isosulfan blue, and indocyanine green lymphangiography. PMID- 28858394 TI - Effect of Modafinil on Cognitive Function in Intensive Care Unit Patients: A Retrospective Cohort Study. AB - Modafinil therapy, a nonamphetamine cognition-enhancing agent, holds the potential to improve recovery from cognitive impairment after intensive care unit (ICU) admission. To date, however, there is a paucity of data on modafinil use in the ICU setting. The purpose of this study was to explore the role of modafinil for improvement in cognition in ICU patients. This retrospective cohort study evaluated a total of 60 ICU patients with any ventilatory support who started on modafinil during their ICU stay from January 1, 2010, to March 19, 2016. The requirements of opioids and sedatives, as well as the lowest and average scores of the Glasgow Coma Scale (GCS) and Riker Sedation-Agitation Scale (SAS), were recorded during 48 hours before and after the start of modafinil therapy in 6 hour periods. The average daily modafinil dose of 170 mg was given for a median duration of 9 days. Modafinil administration was associated with a small, nonsignificant increase in GCS by 0.34 points after controlling for age, baseline severity of illness, and changes in sedation and analgesia over time (95%CI, 0.34 to 0.73 points; P = .0743). No major modafinil-associated adverse effects were observed. Modafinil administration did not significantly improve cognitive function in ICU patients within 48 hours of initiation. However, because of lack of robust evidence, the impact of modafinil on overall patient outcomes in the ICU remains unclear and needs further investigation. PMID- 28858395 TI - Nicotinamide Adenine Dinucleotides Arrest Photoreduction of Class II DNA Photolyases in FADH State. AB - All light-sensitive members of the photolyase/cryptochrome family rely on FAD as catalytic cofactor. Its activity is regulated by photoreduction, a light triggered electron transfer process from a conserved tryptophan triad to the flavin. The stability of the reduced flavin depends on available external electron donors and oxygen. In this study, we show for the class II photolyase of Methanosarcina mazei, MmCPDII, that it utilizes physiologically relevant redox cofactors NADH and NADPH for the formation of the semiquinoid FAD in a light dependent reaction. Using redox-inert variants MmCPDII/W388F and MmCPDII/W360F, we demonstrate that photoreduction by NADH and NADPH requires the class II specific tryptophan cascade of MmCPDII. Finally, we confirmed that mutations in the tryptophan cascade can be introduced without any substantial structural disturbances by analyzing crystal structures of MmCPDII/W388F, MmCPDII/W360F and MmCPDII/Y345F. PMID- 28858396 TI - Histopathological and genetic review of phosphaturic mesenchymal tumours, mixed connective tissue variant. AB - AIMS: Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings. METHODS AND RESULTS: A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement. CONCLUSIONS: It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis. PMID- 28858397 TI - Model-Based Approach to Predict Adherence to Protocol During Antiobesity Trials. AB - Development of antiobesity drugs is continuously challenged by high dropout rates during clinical trials. The objective was to develop a population pharmacodynamic model that describes the temporal changes in body weight, considering disease progression, lifestyle intervention, and drug effects. Markov modeling (MM) was applied for quantification and characterization of responder and nonresponder as key drivers of dropout rates, to ultimately support the clinical trial simulations and the outcome in terms of trial adherence. Subjects (n = 4591) from 6 Contrave(r) trials were included in this analysis. An indirect-response model developed by van Wart et al was used as a starting point. Inclusion of drug effect was dose driven using a population dose- and time-dependent pharmacodynamic (DTPD) model. Additionally, a population-pharmacokinetic parameter- and data (PPPD)-driven model was developed using the final DTPD model structure and final parameter estimates from a previously developed population pharmacokinetic model based on available Contrave(r) pharmacokinetic concentrations. Last, MM was developed to predict transition rate probabilities among responder, nonresponder, and dropout states driven by the pharmacodynamic effect resulting from the DTPD or PPPD model. Covariates included in the models and parameters were diabetes mellitus and race. The linked DTPD-MM and PPPD-MM was able to predict transition rates among responder, nonresponder, and dropout states well. The analysis concluded that body-weight change is an important factor influencing dropout rates, and the MM depicted that overall a DTPD model driven approach provides a reasonable prediction of clinical trial outcome probabilities similar to a pharmacokinetic-driven approach. PMID- 28858398 TI - The missing, the short, and the long: Exploring the borderland between psychiatry and neurology. PMID- 28858399 TI - From "equal" to "unequal" combination of anterolateral thigh flap and fibula flap for extensive composite oromandibular defects. PMID- 28858400 TI - Evaluation of 389 patients following free-flap lower extremity reconstruction with respect to secondary refinement procedures. AB - INTRODUCTION: Primary functional and aesthetic results after free-flap salvage of lower extremities are occasionally suboptimal. The objective of this study was to identify predictors for secondary refinement procedures such as liposuction, dermolipectomy, or direct excision. In addition, patient-reported long-term satisfaction with the final reconstructive result was analyzed. PATIENTS AND METHODS: All patients undergoing free-flap lower extremity salvage between January 2011 and July 2015 were included in a comparative study. The patients of cohort 1 had no secondary refinement procedures, while those of cohort 2 had one or more procedures. The patient data, intraoperative characteristics, and postoperative course were reviewed. To assess the level of satisfaction, the patients were surveyed. RESULTS: Of the 389 patients included, 54 (13.9%) were identified with 1-3 secondary refinement procedures with an uneventful postoperative course. The most common procedure was surgical debulking (56.8%). The comparison of both cohorts revealed a statistical significance for patient's age (P < .01), gender (P = .02), ASA-score (P < .01), and localization (P < .01). Predictors for secondary refinement procedures were young age (<50 years), female gender, absence of comorbidities, and defects located at the feet or ankle. Overall patient satisfaction was negatively correlated with the number of secondary procedures performed. Patient-reported satisfaction with the overall (P < .01) and cosmetic (P = .02) result increased significantly with age. CONCLUSION: Secondary refinement procedures after successful free-flap lower extremity reconstruction are safe and not uncommon. Detailed information about the likelihood of secondary operations and the various techniques available should be part of the patient education to increase patient satisfaction and form realistic expectations. PMID- 28858402 TI - Fullerene Cluster Assisted Self-Assembly of Short DNA Strands into Semiconducting Nanowires. AB - Programmable, hierarchical assembly of DNA nanostructures with precise organisation of functional components have been demonstrated previously with tiled assembly and DNA origami. However, building organised nanostructures with random oligonucleotide strands remains as an elusive problem. Herein, a simple and general strategy, in which nanoclusters of a fullerene derivative act as stapler motifs in bringing ordered nanoscale assembly of short oligonucleotide duplexes into micrometre-sized nanowires, is described. In this approach, the fullerene derivative, by virtue of its amphiphilic structure and unique hydrophobic-hydrophilic balance, pre-assembles to form 3-5 nm sized clusters in a mixture of DMSO-phosphate buffer, which further assists the assembly of DNA strands. The optimum cluster size, availability of DNA anchoring motifs and the nature of the DNA strands controls the structure of these nanomaterials. Furthermore, horizontal conductivity measurements through conductive AFM confirmed the charge transport properties of these nanowires. The current strategy could be employed to organise random DNA duplexes and tiles into functional nanostructures, and hence, open up new avenues in DNA nanotechnology. PMID- 28858401 TI - Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection - clinicopathological and ultrastructural study. AB - AIMS: The pathogenesis, viral localization and histopathological features of Middle East respiratory syndrome - coronavirus (MERS-CoV) in humans are not described sufficiently. The aims of this study were to explore and define the spectrum of histological and ultrastructural pathological changes affecting various organs in a patient with MERS-CoV infection and represent a base of MERS CoV histopathology. METHODS AND RESULTS: We analysed the post-mortem histopathological findings and investigated localisation of viral particles in the pulmonary and extrapulmonary tissue by transmission electron microscopic examination in a 33-year-old male patient of T cell lymphoma, who acquired MERS CoV infection. Tissue needle biopsies were obtained from brain, heart, lung, liver, kidney and skeletal muscle. All samples were collected within 45 min from death to reduce tissue decomposition and artefact. Histopathological examination showed necrotising pneumonia, pulmonary diffuse alveolar damage, acute kidney injury, portal and lobular hepatitis and myositis with muscle atrophic changes. The brain and heart were histologically unremarkable. Ultrastructurally, viral particles were localised in the pneumocytes, pulmonary macrophages, renal proximal tubular epithelial cells and macrophages infiltrating the skeletal muscles. CONCLUSION: The results highlight the pulmonary and extrapulmonary pathological changes of MERS-CoV infection and provide the first evidence of the viral presence in human renal tissue, which suggests tissue trophism for MERS-CoV in kidney. PMID- 28858403 TI - Songs about cancer, gene expression, and the biochemistry of photosynthesis. AB - These three biology songs can be used for educational purposes to teach about biochemical concepts. They touch on three different topics: (1) cancer progression and germ cells, (2) gene expression, promoters, and repressors, and (3) electronegativity and the biochemical basis of photosynthesis. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):98-99, 2018. PMID- 28858405 TI - Development of high strength siloxane poly(urethane-urea) elastomers based on linked macrodiols for heart valve application. AB - Mixed macrodiol based siloxane poly(urethane-urea)s (SiPUU) having number average molecular weights in the range 87-129 kDa/mol were synthesized to give elastomers with high tensile and tear strengths required to fabricate artificial heart valves. Polar functional groups were introduced into the soft segment to improve the poor segmental compatibility of siloxane polyurethanes. This was achieved by linking alpha,omega-bis(6-hydroxyethoxypropyl) poly(dimethylsiloxane) (PDMS) or poly(hexamethylene oxide) (PHMO) macrodiols with either 4,4'-methylenediphenyl diisocyanate (MDI), hexamethylene diisocyanate (HDI) or isophorone diisocyanate (IPDI) prior to polyurethane synthesis. The hard segment was composed of MDI, and a 1:1 mixture of 1,3-bis(4-hydroxybutyl)-1,1,3,3-tetramethyldisiloxane and 1,2 ethylene diamine. We report the effect of urethane linkers in soft segments on properties of the SiPUU. PHMO linked with either MDI or IPDI produced SiPUU with the highest tensile and tear strengths. Linking PDMS hardly affected the tensile strength; however, the tear strength was improved. The stress-strain curves showed no plastic deformation region typically observed for conventional polyurethanes indicating good creep resistance. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1712-1720, 2018. PMID- 28858404 TI - Strong long-range temporal correlations of beta/gamma oscillations are associated with poor sustained visual attention performance. AB - Neuronal oscillations exhibit complex amplitude fluctuations with autocorrelations that persist over thousands of oscillatory cycles. Such long range temporal correlations (LRTC) are thought to reflect neuronal systems poised near a critical state, which would render them capable of quick reorganization and responsive to changing processing demands. When we concentrate, however, the influence of internal and external sources of distraction is better reduced, suggesting that neuronal systems involved with sustained attention could benefit from a shift toward the less volatile sub-critical state. To test these ideas, we recorded electroencephalography (EEG) from healthy volunteers during eyes-closed rest and during a sustained attention task requiring a speeded response to images deviating in their presentation duration. We show that for oscillations recorded during rest, high levels of alpha-band LRTC in the sensorimotor region predicted good reaction-time performance in the attention task. During task execution, however, fast reaction times were associated with high-amplitude beta and gamma oscillations with low LRTC. Finally, we show that reduced LRTC during the attention task compared to the rest condition correlates with better performance, while increased LRTC of oscillations from rest to attention is associated with reduced performance. To our knowledge, this is the first empirical evidence that 'resting-state criticality' of neuronal networks predicts swift behavioral responses in a sensorimotor task, and that steady attentive processing of visual stimuli requires brain dynamics with suppressed temporal complexity. PMID- 28858406 TI - Chemogenetic activation of the lateral hypothalamus reverses early life stress induced deficits in motivational drive. AB - Altered motivated behaviour is a cardinal feature of several neuropsychiatric conditions including mood disorders. One well-characterized antecedent to the development of mood disorders is exposure to early life stress (ELS). A key brain substrate controlling motivated behaviour is the lateral hypothalamus (LH). Here, we examined the effect of ELS on LH activation and the motivation to self administer sucrose. We tested whether chemogenetic activation of LH circuits could modify sucrose responding in ELS rats and examined the impact on LH cell populations. Male rat pups were maternally separated for 0 or 3 h on postnatal days 2-14. During adolescence, rats received bilateral injections of hM3D(Gq), the excitatory designer receptor exclusively activated by designer drugs, into LH. In adulthood, rats were trained to self-administer sucrose and tested under a progressive ratio schedule to determine their motivation for reward following injection with either vehicle or 5 mg/kg clozapine-N-oxide. Brains were processed for Fos-protein immunohistochemistry. ELS significantly suppressed lever responding for sucrose, indicating a long-lasting impact of ELS on motivation circuits. hM3D(Gq) activation of LH increased responding, normalizing deficits in ELS rats, and increased Fos-positive orexin and MCH cell numbers within LH. Our findings indicate that despite being susceptible to environmental stressors, LH circuits retain the capacity to overcome ELS-induced deficits in motivated behaviour. PMID- 28858407 TI - Neural correlates of food anticipatory activity in mice subjected to once- or twice-daily feeding periods. AB - In rodents, restricted food access to a limited period each day at a predictable time results in the appearance of food anticipatory activity (FAA). Two shorter periods of food access each day can result in two FAA bouts. In this study, we examine FAA under 12:12 and 18:6 photoperiods in mice (Mus musculus) with one or two food access periods per day and measure the activation of the suprachiasmatic, dorsomedial and arcuate nuclei by assaying Fos protein expression, while making use of tissue-type plasminogen activator knockout mice to assess the role of neural plasticity in adaptation to restricted feeding cycles. Long days were utilised to allow for temporal separation of two restricted feeding periods during the light phase. Mice fed twice per day generally divided FAA into two distinct bouts, with mice lacking tissue-type plasminogen activator showing reduced FAA. Increases in Fos expression in response to one restricted feeding period per day were seen in the dorsomedial and arcuate nuclei in both 12:12 and 18:6 conditions, with an increase seen in the SCN in only the 12:12 condition. These increases were eliminated or reduced in the two feeding time conditions (done in 18:6 only). Both activity patterns and Fos expression differed for single restricted feeding times between 18:6 and 12:12 photoperiods. Fos activation was lower during RF in 18:6 than 12:12 across all three brain regions, a pattern not reflective of changes in FAA. These data suggest that involvement of these regions in FAA may be influenced by photoperiodic context. PMID- 28858408 TI - Clinical characteristics of stroke occurring in the toilet: Are older adults more vulnerable? AB - AIM: While autonomic imbalance during defecation/micturition can cause hemodynamic instability, stroke occurring in the toilet has rarely been investigated. The objective of the present study was to clarify the frequency and clinical characteristics of toilet-related stroke. METHODS: Clinical data prospectively acquired between January 2011 and December 2015 on 1939 patients with acute stroke (1224 cerebral infarctions [CI], 505 intracerebral hemorrhages [ICH] and 210 subarachnoid hemorrhages [SAH]) were reviewed to identify patients with a toilet-related stroke. For each stroke type, the ratios of stroke occurring during defecation/micturition to those occurring during other activities were calculated. Subsequently, how patients with toilet-related stroke were brought to medical attention was investigated. Whether older patients (aged >65 years) had an elevated ratio of toilet-related stroke was investigated in each stroke type. RESULTS: A total of 108 patients (41 CI, 37 ICH and 30 subarachnoid hemorrhages) sustained a stroke in the toilet. The ratio of toilet related stroke was highest in subarachnoid hemorrhages (14.3%), followed by ICH (7.3%). Circadian differences existed among the three stroke types: toilet related CI were more likely to occur in the night-time than ICH. Patients with toilet-related CI were significantly more likely to sustain cardioembolic stroke. In all three stroke types, <40% of patients could call for help by themselves. Older patients showed a significantly higher proportion of toilet-related stroke in CI, but not in hemorrhagic strokes. CONCLUSIONS: The toilet is a closed space where stroke occurs disproportionately frequently. Effort to reduce the incidence of toilet-related strokes is warranted, as early patient detection is not always feasible. Geriatr Gerontol Int 2018; 18: 250-255. PMID- 28858409 TI - Nutritional supplementation for activities of daily living and functional ability of older people in residential facilities: A systematic review. AB - AIM: To review the best available evidence on nutritional supplementation for activities of daily living and functional ability of older people in residential facilities. METHODS: Electronic searches were carried out using CENTRAL, MEDLINE and EMBASE databases for the years 2006-2016. Randomized controlled trials and cluster-randomized controlled trials that examined the effects of nutrition interventions aimed at improving the energy or protein intake alone or both in combination were included. Two authors independently reviewed all potential studies for inclusion against the eligibility criteria. We reviewed studies for outcome relevance and methodological rigor. Any disagreement was resolved by discussion. RESULTS: A total of eight studies were included, containing four randomized controlled trials and four cluster-randomized controlled trials involving 698 participants. There was significant improvement in handgrip strength (mean difference 1.65 kg, 95% confidence interval 0.09-3.22 kg, P = 0.04), but no difference in activities of daily living (mean difference 2.06, 95% confidence interval -18.28-22.40, P = 0.84), balance (mean difference -1.10, 95% confidence interval -3.04-0.84, P = 0.27), gait velocity (mean difference 0.00, 95% confidence interval -0.03-0.03, P = 1.00) and death (RR 1.90, 95% confidence interval 0.61-5.99, P = 0.27). CONCLUSIONS: Nutritional intervention with older people in residential facilities was effective in improving handgrip strength, but did not significantly improve scores for activities of daily living, balance, gait velocity or preventing death. Further studies with larger sample sizes and of high quality are required to investigate appropriate intervention methods and specific target participants. Geriatr Gerontol Int 2018; 18: 197-210. PMID- 28858410 TI - Intentionally flawed manuscripts as means for teaching students to critically evaluate scientific papers. AB - As future scientists, university students need to learn how to avoid making errors in their own manuscripts, as well as how to identify flaws in papers published by their peers. Here we describe a novel approach on how to promote students' ability to critically evaluate scientific articles. The exercise is based on instructing teams of students to write intentionally flawed manuscripts describing the results of simple experiments. The teams are supervised by instructors advising the students during manuscript writing, choosing the 'appropriate' errors, monitoring the identification of errors made by the other team and evaluating the strength of their arguments in support of the identified errors. We have compared the effectiveness of the method with a journal club-type seminar. Based on the results of our assessment we propose that the described seminar may effectively complement the existing approaches to teach critical scientific thinking. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(1):22-30, 2018. PMID- 28858411 TI - Factors associated with cognitive function that cause a decline in the level of activities of daily living in Alzheimer's disease. AB - AIM: The principal aim of the present study was to clarify what type of cognitive decline results in a decrease in the ability to carry out activities of daily living (ADL) in patients with Alzheimer's disease (AD). METHODS: The participants comprised 1384 outpatients with mild AD. We used the Mini-Mental State Examination (MMSE) and Barthel Index (BI) as indicators of basic ADL, and the Lawton Index (LI) as an indicator of instrumental ADL (IADL). We then analyzed the relationships between MMSE and BI, as well as between MMSE and LI. We also carried out a logistic regression analysis with BI and LI subitems as dependent variables, and MMSE subitems as independent variables. RESULTS: For almost all BI and LI subitems, significantly high odds ratios (OR) were noted in MMSE "Copy the design shown" (e.g. dressing OR 3.66, toilet use OR 3.60 and transfers OR 2.80) and "Write a sentence" (e.g. ability to use telephone OR 5.24, laundry OR 2.60, grooming OR 2.50; P < 0.05). CONCLUSIONS: Visuospatial cognition had an important effect on the decrease in basic ADL and IADL. Furthermore, the subitems with minimal effect on the decrease of basic ADL and IADL differed. Therefore, it appears that specific activities have little effect on the maintenance of ADL and IADL, and that determining residual cognitive function and utilizing this as a means of compensating for decreased ADL is a useful strategy. Geriatr Gerontol Int 2018; 18: 50-56. PMID- 28858412 TI - Randomized, double-blind, placebo-controlled 8-week trial of the efficacy, safety, and tolerability of 5, 10, and 20 mg/day vortioxetine in adults with major depressive disorder. AB - AIM: This study assessed the efficacy and safety of vortioxetine in adults with major depressive disorder. METHODS: In this double-blind, placebo-controlled study, 600 patients with major depressive disorder were randomly assigned (1:1:1:1) to receive vortioxetine 5, 10, or 20 mg, or placebo once daily for 8 weeks. The primary end-point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 8, evaluated by the last observation-carried-forward method. Secondary end-points included response (>= 50% decrease in the MADRS total score from baseline) and remission (MADRS total score <= 10), Clinical Global Impression Scale-Improvement, and change from baseline in Sheehan Disability Scale. Adverse events were summarized. RESULTS: Vortioxetine failed to show significant differences from placebo in the primary end-point. Nominally significant improvements over placebo were observed for vortioxetine doses of 10 and 20 mg when the primary end-point was evaluated using the mixed model for repeated measures as the secondary analysis, and 10 mg in secondary measures of response and patient functioning. Vortioxetine was well tolerated. Nausea, constipation, dry mouth, dizziness, and insomnia each occurred at a >twofold higher rate than placebo. Discontinuation symptom scores were comparable between all groups after 1 and 2 weeks following withdrawal of the study drug. CONCLUSION: While vortioxetine failed to meet significance versus placebo in the primary efficacy analysis, there was evidence of efficacy for the 10- and 20-mg doses in secondary analyses. Vortioxetine was safe and well tolerated. Additional studies appear warranted. PMID- 28858413 TI - Decoding the microstructural correlate of diffusion MRI. AB - Diffusion imaging has evolved considerably over the past decade. While it provides valuable information about the structural connectivity at the macro- and mesoscopic scale, bridging the gap to the microstructure at the level of single nerve fibers poses an enormous challenge. This is particularly true for the human brain with its large size, its large white-matter volume and availability of histological techniques for studying human whole-brain sections and subsequent 3D reconstruction. Classic post-mortem techniques for studying the fiber architecture of the brain, such as myeloarchitectonic staining or dye tracing, are complemented by novel histological approaches, such as 3D polarized light imaging or optical coherence tomography, enabling unique insight into the fiber architecture from large fiber bundles within deep white matter to single nerve fibers in the cortex. The present review discusses the benefits and challenges of these latest developments in comparison with the classic techniques, with particular focus on the mutual exchange between in vivo and post-mortem diffusion imaging and post-mortem microstructural approaches for understanding the wiring of the brain across different scales. PMID- 28858414 TI - Association of intraocular pressure-related factors and retinal vessel diameter with optic disc rim area in subjects with and without primary open angle glaucoma. AB - IMPORTANCE: The data may support the notion that the intra-ocular pressure (IOP) related factors and vascular factors were implicated concurrently in glaucomatous optic nerve damage. BACKGROUND: To study the association of intraocular pressure (IOP)-related factors, IOP, trans-lamina cribrosa pressure difference (TLCPD), cerebrospinal fluid pressure (CSFP) and retinal vessel diameters (RVD), central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE) with neuro-retinal rim area (RA). DESIGN: A population-based, cross-sectional study. PARTICIPANTS: A total of 6830 people aged 30 years and over. METHODS: All participants underwent a comprehensive eye examination, fundus photograph-based measurements of RVD and Heidelberg retinal tomogram (HRT) measurement of optic disc. MAIN OUTCOME MEASURES: RA, CRAE, CRVE, IOP, body mass index (BMI), CSFP and TLCPD. RESULTS: Primary open-angle glaucoma (POAG) was diagnosed using two separate methods: 67 from expert consensus, and 125 from the International Society of Geographical and Epidemiologic Ophthalmology (ISGEO) classification. After excluding of those with high myopia or without gradable HRT images, 4194 non-glaucoma and 40 POAG were analysed for determinants of RA. On multivariable analysis determinants of reduced RA were POAG (P < 0.001), higher IOP (P = 0.03), higher refractive error (P < 0.01), longer axial length (P = 0.01), CRVE (P < 0.001), lower BMI (P = 0.015), older age (P < 0.001) smaller disc area (P < 0.001) and higher TLCPD (P = 0.03). When age and/or BMI were omitted from the model, reduced RA was also associated with lower CSFP (P < 0.001). CONCLUSIONS AND RELEVANCE: Reduced RA is associated with narrow CRVE and higher IOP or lower CSFP. The data supports the concurrent role of IOP-related and vascular factors in glaucomatous optic nerve damage. PMID- 28858416 TI - Response to: HCV viremic donors with hepatic bridging fibrosis: Are we ready to use their livers in the era of direct-acting antivirals? PMID- 28858415 TI - Effects of pair bonding on parental behavior and dopamine activity in the nucleus accumbens in male prairie voles. AB - Male parental care is a vital behavior for the development as well as the physical and mental well-being of the young. However, little is known about the neurochemical regulation of male parental behavior, mainly due to the lack of appropriate animal models. In this study, we used the socially monogamous male prairie vole (Microtus ochrogaster) to investigate the effect of pair-bonding experience on paternal behavior and dopamine (DA) signaling in the nucleus accumbens (NAcc) in the brain. We compared sexually naive males with males that were pair bonded with a female for two weeks. Our data showed that pair-bonded males displayed enhanced paternal behavior, particularly in pup licking/grooming, associated with increased DA type-1 receptor (D1R) protein expression in the NAcc, compared to sexually naive males. Site-specific brain microdialysis revealed a significant, but transient, increase in DA release in the NAcc associated with pup exposure in both groups of the males. Further, pharmacological blockade of D1R in the NAcc decreased pup licking/grooming in the pair-bonded males. Together, our data demonstrate that pair-bonding experience with a female facilitated male parental behavior via NAcc D1R mediation in male prairie voles. PMID- 28858417 TI - Changes of tooth color in middle and old age: A longitudinal study over a decade. AB - OBJECTIVE: To evaluate changes in tooth color for 2 age cohorts (younger cohort, YC: 1950-1952; older cohort, OC: 1930-1932) over a mean observation period of 8 years. MATERIAL AND METHODS: Sixty-one participants with 106 upper central incisors were subjected to baseline and follow-up examinations (YC: n = 46/OC: n = 15). International Commission on Illumination color coordinates of 1 or 2 unrestored test teeth for each participant were recorded by use of a spectrophotometer (VITA Easyshade 1) during both measurement times. Changes of color coordinates during the study period were evaluated by use of generalized linear mixed models with the variable "participant" as random effect. DeltaEab and E2000 color differences were calculated between baseline and follow-up. RESULTS: Significant changes in color coordinates were observed, with the exception of lightness in OC. The direction of the changes depended on the cohort. A decrease of lightness (value) was observed in YC (DeltaL = 4.0; P < .001) whereas in OC chroma increased (DeltaC = -3.3; P < .001). For both groups, a significant shift to more reddish tooth colors was observed. In almost all cases, color differences between baseline and follow-up exceeded the 50:50 acceptability thresholds for color differences (DeltaE = 2.7) in both YC (~90%) and OC (~80%). CONCLUSIONS: For both quinquagenarians and septuagenarians, clinically relevant changes in tooth color were observed after a decade; these could affect the long-term success of prosthetic restorations in terms of a satisfactory color match between natural teeth and dental prostheses. In contrast with the findings of cross-sectional studies, the changes were partially age group-specific. CLINICAL SIGNIFICANCE: Tooth color can change over a decade. When fixed dental prostheses are planned, one should consider that changes of tooth color could lead to mismatch between a restoration and adjacent teeth during the period in clinical service. PMID- 28858418 TI - Effect of access design on intracoronal bleaching of endodontically treated teeth: An ex vivo study. AB - OBJECTIVES: To determine the effect of access design on intracoronal bleaching with 35% carbamide peroxide on discolored teeth. MATERIALS AND METHODS: Forty-two intact maxillary central incisors were selected, sectioned and artificially stained using whole blood. Color measurements were performed with a spectrophotometer: before staining (T1), after staining (T2), at 7 (T3), and 14 (T4) days postbleaching. After T1, specimens were stratified and divided randomly into two groups according to access design (N = 20): G1: contracted endodontic cavity (CEC) access performed with a #848-010M bur and G2: traditional endodontic cavity (TEC) access done with a #1157 bur. Canals were obturated, a cervical barrier was placed and 35% carbamide peroxide was sealed in the chamber for 7 days and replaced at 7 days for an additional 7 days. Data were collected based on CIELAB-CIE1976 (L* a* b* ) system. Repeated measures SNK anova was used to evaluate the effects of access design and time on color change (DeltaE* ) and luminosity (L* ) (alpha < 0.05). RESULTS: For CEC, L* was significantly different at all times points (P < .05). For TEC, L* values were significantly different at all time points (P < .05) except for T0 and T4, which were similar (P > .05). There was no statistical difference for DeltaE* between CEC and TEC designs at any time point (P > .05). CONCLUSIONS: In general, teeth accessed with CEC or TEC designs showed statistically similar bleaching when using 35% carbamide peroxide. However, lightness values were only reestablished with bleaching through a TEC access design. CLINICAL SIGNIFICANCE: Despite the current trend to conserve tooth structure when performing endodontic access cavities, the use of conservative access designs for bleaching discolored maxillary central incisors affected the acceptability threshold when compared with a traditional access design. These smaller accesses might not be an alternative treatment option when internal bleaching in the esthetic zone is anticipated. PMID- 28858419 TI - Microscopic Insights on the Multiferroic Perovskite-Like [CH3 NH3 ][Co(COOH)3 ] Compound. AB - The characterization of the crystal structure, phase transitions, magnetic structure and dielectric properties has been carried out on [CH3 NH3 ][Co(COOH)3 ] (1) perovskite-like metal-organic compound through variable-temperature single crystal and powder neutron and X-ray diffraction and relative permittivity measurements. The paraelectric to antiferroelectric-like phase transition observed at around 90 K is triggered by a structural phase transition; the structural studies show a change from Pnma space group at RT (1A) to P21 /n space group at low temperature (1B). This phase transition involves the occurrence of small distortions in the framework and counterions. Neutron diffraction studies have shown a magnetic order showing spontaneous magnetization below 15 K, due to the occurrence of a non-collinear antiferromagnetic structure with a weak ferromagnetic component, mainly due to the single-ion anisotropy of the CoII ions. PMID- 28858420 TI - Photoswitchable Carbohydrate-Based Macrocyclic Azobenzene: Synthesis, Chiroptical Switching, and Multistimuli-Responsive Self-Assembly. AB - A one-pot O-alkylation mediated macrocyclization approach has been used for the synthesis of carbohydrate-based macrocyclic azobenzene. The synthesized macrocycle can be reversibly isomerized between E and Z isomers upon UV or visible irradiation with excellent photostability and thermal stability (t1/2 =51 days at 20 degrees C for the Z isomer). A chirality transfer from the chiral sugar unit to azobenzene was observed by circular dichroism (CD). DFT and TD-DFT calculations were performed to calculate the optimal geometry and the theoretical absorption and CD spectra. Comparison of the experimental CD spectra with the theoretical ones suggests that both E- and Z-macrocycles adopt preferentially P helicity for the azobenzene moiety. Furthermore, the macrocycle showed gelation ability in cyclohexane and ethanol with multistimuli-responsive behavior upon exposure to environmental stimuli including thermal-, photo-, and mechanical responses. Moreover, these organogels display temperature-dependent helical inversion, which can be tuned by a repeated heating-cooling procedure. PMID- 28858421 TI - Deceased donor uterus retrieval: A novel technique and workflow. AB - Uterus transplantation has proven successful when performed with a living donor. Subsequently, interest in the novel field of reproductive transplantation is growing. The procedure is still considered experimental, with fewer than 25 cases performed worldwide, and the techniques of both uterus procurement and transplantation are still developing. We detail a new approach to deceased donor uterus procurement. In contrast to reported techniques and our own initial experience, in which the deceased donor uterus was procured post cross-clamp and after other organs were procured, our approach now is to perform the uterus procurement prior to the procurement of other organs in a multiorgan donor and hence prior to cross-clamp. We describe our practical experience in developing and implementing the logistical workflow for deceased donor uterus procurement in a deceased multiorgan donor setting. PMID- 28858422 TI - Development and psychometric properties of the Basic Amputee Mobility Score for use in patients with a major lower extremity amputation. AB - AIM: To develop and examine the psychometric properties, including responsiveness and interrater reliability, of a new outcome measure for the evaluation of basic mobility activities after a major lower extremity amputation - The Basic Amputee Mobility Score (BAMS). METHODS: The four following essential activities were chosen through consensus meetings with experienced amputee physiotherapists: (i) supine in bed to sitting on the edge of the bed; (ii) bed to wheelchair transfer; (iii) indoor wheelchair mobility; and (iv) get up from a wheelchair to standing on the non-amputated leg. Each activity is scored from 0 to 2 (0 = not able to; 1 = able to with assistance/guiding; and 2 = independent), and cumulated to a 1-day BAMS score of 0-8. Validity and responsiveness were established in 106 consecutive in-hospital patients with a major dysvascular lower extremity amputation, while reliability and agreement were examined in an additional sample of 30 patients. RESULTS: The 30-day mortality risk was reduced by 88% (HR = 0.12, 95% CI 0.02-0.68) for those out of bed (BAMS >=2 points) at the first physiotherapy assessment, while BAMS scores improved between the first and the discharge assessment, with a standardized response mean of 1.3. Reliability assessments resulted in a weighted Kappa value of 0.98, a standard error of measurement of 0.32 and a minimal detectable change of 0.89 points. No systematic between-rater bias was seen (P = 0.3). CONCLUSIONS: The BAMS was feasible in all patients, and showed a large responsiveness, excellent interrater reliability and with a change of 1 point indicating a real change in performances. Geriatr Gerontol Int 2018; 18: 138-145. PMID- 28858423 TI - Raising quality whilst reducing cost in health care: A retrospective cohort study. AB - OBJECTIVE: The objective of this study was to investigate the relationship between cost and quality within the health care sector and to establish which factors could influence this relationship. The aim was to investigate the dynamics of the relationship, in order to improve the quality whilst reducing the cost. DESIGN: This is a retrospective cohort study, analysing quality, safety, and financial data from a 5-year period. SETTING: A publicly funded tertiary hospital. PARTICIPANTS: The dependent variable was cost saved, and the independent variables were patient safety, patient satisfaction, and clinical efficiency. MAIN OUTCOME MEASURES: Financial savings and quality domains. RESULTS: A statistically significant relationship between the variables was found. Multivariate analysis derived the equation Y = betaX1 + c, where Y is the cost saved, beta is the beta coefficient, X1 is the clinical efficiency, and c is a constant. R2 = 0.874 (coefficient of determination), which suggested that the cost saved by the unit varied due to clinical efficiency. Clinical efficiency accounted for 87.4% of the variation in the cost saved by the unit. CONCLUSIONS: The results indicated that, after the trade-off value, an improvement in the quality would result in reduced costs for the unit. Clinical efficiency of the services was found to be the key factor determining this relationship. Therefore, strategies to increase clinical efficiency, and thus overall quality, above the trade-off level could result in significant financial savings. Patient safety and patient experience were positively correlated with clinical efficiency. PMID- 28858424 TI - Association between potentially inappropriate medications and anxiety in Japanese older patients. AB - AIM: The use of potentially inappropriate medications (PIMs) for older patients is a major public health problem. However, there is little information regarding PIMs in Japanese primary care settings, and the association between psychological problems and PIMs is unknown. The present study was carried out to explore the prevalence of PIMs among older patients in a primary care setting in Tokyo, and to assess the association between PIMs and depression and anxiety. METHODS: A cross-sectional study in a Japanese outpatient clinic providing primary care was carried out. Data were collected from January 2016 to March 2016. A total of 740 patients aged >=65 years with chronic diseases were enrolled. Information regarding sociodemographic status, comorbidities, and prescription and psychological status was collected using a questionnaire that patients were required to complete, and by reviewing the patients' medical records. RESULTS: The Screening Tool of Older Person's Prescriptions criteria version 2 revealed PIM prescription for 32.3% of patients. Benzodiazepines, hypnotic Z-drugs and proton pump inhibitors accounted for a majority of PIMs. After adjusting for age, sex, comorbidities, estimated glomerular filtration rate and the number of medications, anxiety was identified as a predictor for PIMs. CONCLUSIONS: PIMs among older patients are common in Japanese primary care settings, and prescription of benzodiazepines or hypnotic Z-drugs and proton pump inhibitors was frequent as PIMs. PIMs might be associated with anxiety; therefore, their association should be focused on and addressed to reduce PIMs. Geriatr Gerontol Int 2017; 17: 2520-2526. PMID- 28858425 TI - An esthetic evaluation of unilateral canine substitution for a missing maxillary lateral incisor. AB - OBJECTIVES: The aim of this study is to determine whether variation in size, morphology, and color of a unilateral substituted maxillary canine has influence on the dentogingival attractiveness perceived by dental professionals and laypeople. MATERIALS AND METHODS: A frontal clinical photograph of a patient with unilateral canine substitution was used as standard picture. Five different series were created by modification of following parameters with a raster graphics editor (Photoshop CS 6): (1) width, (2) color, (3) gingival margin height, and (4) crown tip morphology of the substituted canine and (5) the gingival margin height of the neighboring first premolar. For each parameter, the photograph deviating the most from the standard photograph, was combined into a final series. Four groups of examiners (orthodontists, periodontists, dentists, and laypeople) were asked to rank the photographs from most to least attractive. RESULTS: One hundred seventy-four examiners ranked the photographs in order of attractiveness. Overall, a darker canine color (mean rank 4.36 +/- 1.03) and a more pronounced canine tip morphology (mean rank 3.47 +/- 1.11) were significantly ranked as most unattractive (P < .05). The gingival height of the neighboring premolar was ranked as least unattractive by all groups of examiners (mean rank 1.30 +/- 0.74). CONCLUSIONS: Darker canine color and a pronounced tip morphology of a substituted canine are rated as the most unattractive by dental professionals and laypeople. CLINICAL SIGNIFICANCE: The present study showed that the canine color and crown tip morphology are important parameters when considering unilateral canine substitution, both for professionals and laypeople. There is a general preference in favor of canines with a light color and a reduced incisal tip. PMID- 28858426 TI - Insights on the impact of diet-mediated microbiota alterations on immunity and diseases. AB - The intestinal tract is inhabited by a large and diverse community of bacteria collectively referred to as the gut microbiota. The intestinal microbiota is composed by 500-1000 distinct species, and alterations in its composition are associated with a variety of diseases including obesity, diabetes, and inflammatory bowel disease (IBD). Importantly, microbiota transplantation from diseased patients or mice (IBD, metabolic syndrome, etc.) to germ-free mice was found to be sufficient to transfer some aspects of disease phenotypes, indicating that altered microbiota is playing a direct role in those particular conditions. Moreover, it is now well admitted that the intestinal microbiota is involved in shaping and maturating the immune system, with for example the observation that germ-free animals harbor a poorly developed intestinal immune system and that some single bacteria species, such as segmented filamentous bacteria (SFB), are sufficient to induce the expansion of Th17 cells (CD4+ T helper cells producing IL-17). We will present herein an overview of the interactions occurring between the intestinal microbiota and the immune system, and we will discuss how a dietary-induced disruption of the intestinal environment may influence transplantation outcomes. PMID- 28858427 TI - Strengths and weaknesses of using SRTR data to shape the management of the HIV infected kidney transplant recipient. PMID- 28858428 TI - 2-Methoxypyridine as a Thymidine Mimic in Watson-Crick Base Pairs of DNA and PNA: Synthesis, Thermal Stability, and NMR Structural Studies. AB - The development of nucleic acid base-pair analogues that use new modes of molecular recognition is important both for fundamental research and practical applications. The goal of this study was to evaluate 2-methoxypyridine as a cationic thymidine mimic in the A-T base pair. The hypothesis was that including protonation in the Watson-Crick base pairing scheme would enhance the thermal stability of the DNA double helix without compromising the sequence selectivity. DNA and peptide nucleic acid (PNA) sequences containing the new 2-methoxypyridine nucleobase (P) were synthesized and studied by using UV thermal melting and NMR spectroscopy. Introduction of P nucleobase caused a loss of thermal stability of ~10 degrees C in DNA-DNA duplexes and ~20 degrees C in PNA-DNA duplexes over a range of mildly acidic to neutral pH. Despite the decrease in thermal stability, the NMR structural studies showed that P-A formed the expected protonated base pair at pH 4.3. Our study demonstrates the feasibility of cationic unnatural base pairs; however, future optimization of such analogues will be required. PMID- 28858429 TI - Energy imbalance and cancer: Cause or consequence? AB - Obesity has been an epidemic worldwide over the past decades and significantly increases the risk of developing a variety of deadly diseases including type 2 diabetes, cardiovascular diseases and many cancers. The relationship between obesity and type 2 diabetes and cardiovascular disease has been well documented. The drastically increased frequency of a number of cancers in obesity has attracted growing interest. On one hand, how increased adiposity promotes cancer development remains poorly understood, despite the fact that considerable epidemiological evidence has suggested links between them. On the other hand, however, numerous studies have shown that tumorigenesis leads to substantial weight loss in a large portion of cancer patients. Here, we summarize the recent advances on our understanding of the link between obesity and cancer development with a focus on the molecular mechanisms accounting for the rising cancer incidence in the context of obesity. In addition, we also discuss how cancer associated anorexia and cachexia causes weight loss. (c) 2017 IUBMB Life, 69(10):776-784, 2017. PMID- 28858430 TI - Social network confidants, duration of untreated psychosis and cannabis use in people with first episode psychosis: An exploratory study. AB - AIM: Reduced social network (SN) might be associated with a longer duration of untreated psychosis (DUP) in people with first episode psychosis (FEP). We aimed at exploring the specific role of SN confidants on DUP, taking into account cannabis misuse, which is known to influence DUP and might be associated with social functioning. METHODS: People with FEP recently referred to an inner London Early Intervention Service were assessed with standardized instruments exploring SN characteristics, DUP and cannabis misuse. RESULTS: Taking into account cannabis misuse, we found an association between confidants and DUP (P = 0.020), with the higher the number of confidants, the shorter the DUP. CONCLUSIONS: Confidants may provide access to, and perceptions of, social support and this may increase early engagement for people with FEP, reducing DUP and possibly improving outcomes. Future research should identify correlates of small networks of confidants, which could inform early detection community initiatives. PMID- 28858432 TI - Imaging lymphatics in human normal and lymphedema limbs-Usefulness of various modalities for evaluation of lymph and edema fluid flow pathways and dynamics. AB - The human lymphatic system morphology and function still remain largely unknown to clinicians and biologists. How does the lymphatic vascular system look like in comparison to the blood transport system, how does lymph flow, where does capillary filtrate accumulate in cases with lymphatic obstruction caused by inflammation, trauma, and cancer therapy, remain as basic questions. Visualization of the lymphatic pathways and dynamics of lymph flow, and in cases of obstruction, the localization of the capillary filtrate/edema fluid accumulation becomes indispensable. The contemporary methods only partly meet these requirements. Since the early 1950s of the 20th century only few specific clinical methods of imaging of limb lymphatics are being used in human clinic. Each of the applied modalities provides different images due to different physical chemistry and distribution of tracer, methods used for its detection in tissues, their sensitivity and specificity and clinical type of lymph vessel pathology. Here, the advantages and disadvantages of the most commonly used 3 methods of imaging: the iodinated oil X-ray, isotopic, and fluorescent lympangiographies are presented. The study is based on retrospective and recent collections of lymphangiograms from large cohorts of patients. Imaging of lymph nodes has not been included as it is requiring different interpretation compared with vessels. Composite evaluation of X-ray, isotopic, and fluorescent lymphographic images or, as it is practiced now the isotope and indocyanine green near infrared lymphographies, provide most clinically important information. Special attention was directed at methods enabling early diagnosis of imminent lymphedema especially in cases with cancer therapy-related lymphedema. Groups of typical images obtained with the 3 methods are presented. PMID- 28858431 TI - HLA-B*67:01:03, a HLA novel allele, identified in a Chinese platelet donor. AB - HLA-B*67:01:03 has one synonymous nucleotide change from HLA-B*67:01:02 at nucleotide 873 (codon 267 Proline). PMID- 28858433 TI - Getting to transplantation. PMID- 28858435 TI - In vivo multiphoton microscopy using a handheld scanner with lateral and axial motion compensation. AB - This paper reports a handheld multiphoton fluorescence microscope designed for clinical imaging that incorporates axial motion compensation and lateral image stabilization. Spectral domain optical coherence tomography is employed to track the axial position of the skin surface, and lateral motion compensation is realised by imaging the speckle pattern arising from the optical coherence tomography beam illuminating the sample. Our system is able to correct lateral sample velocities of up to approximately 65 MUm s-1 . Combined with the use of negative curvature microstructured optical fibre to deliver tunable ultrafast radiation to the handheld multiphoton scanner without the need of a dispersion compensation unit, this instrument has potential for a range of clinical applications. The system is used to compensate for both lateral and axial motion of the sample when imaging human skin in vivo. PMID- 28858434 TI - CD4+ CD28null T cells are not alloreactive unless stimulated by interleukin-15. AB - Proinflammatory, cytotoxic CD4+ CD28null T cells can be substantially expanded in patients with end-stage renal disease. These cells have been associated with the risk for rejection, but their alloreactive potential is unknown. CD4+ CD28null T cells were stimulated with HLA-mismatched antigen presenting cells in the absence/presence of exogenous cytokines. Alloreactive potential was evaluated based on proliferation, degranulation, cytotoxicity, and cytokine production. Further, their suppressive capacity was assessed by measuring inhibition of proliferating alloreactive CD28+ T cells. CD4+ CD28null T cells contained alloreactive (CD137+ ) T cells but did not proliferate in response to allogeneic stimulation, unless interleukin (IL)-15 was added. However, they could proliferate on stimulation with cytomegalovirus antigen without exogenous cytokines. IL-15 increased the frequency of proliferating alloreactive CD4+ CD28null T cells to 30.5% without inducing CD28 expression (P < .05). After allogeneic stimulation together with IL-15 and IL-21, frequency of degranulating CD107a+ CD4+ CD28null T cells increased significantly from 0.6% to 5.8% (P < .001). Granzyme B and perforin positivity remained similar, but production of interferon-gamma and tumor necrosis factor-alpha increased by the combination of IL-15 and IL-21 (P < .001 and P < .05, respectively). Finally, CD4+ CD28null T cells did not show significant suppression. Thus, CD4+ CD28null T cells represent a population with absent alloreactivity unless IL-15 is present. PMID- 28858436 TI - Genomic sequences of two novel HLA-C alleles, HLA-C*15:143 and HLA-C*07:109:02. AB - Two novel HLA-C alleles, C*07:109:02 and C*15:143, were characterized in two Spanish individuals. PMID- 28858438 TI - The argument against House Bill 1938. PMID- 28858439 TI - Adherence to infliximab therapy in inflammatory bowel disease patients in a real life setting. AB - OBJECTIVE: To assess adherence to infliximab (IFX) therapy in inflammatory bowel disease patients, to investigate reasons for non-adherence and to identify predictors for non-adherence. METHODS: This observational study was conducted in two French referral university hospitals between 1 September and 31 October, 2011. Patients were systematically asked if they had already delayed or missed an IFX perfusion since the beginning of the treatment and about the reasons for their non-adherence. RESULTS: Of the 162 included patients (121 Crohn's disease [CD], 41 ulcerative colitis), 87 (53.7%) reported a delay of at least one IFX injection and 14 (8.6%) missed at least one IFX perfusion since the beginning of the treatment. The overall non-adherence rate was 54.3%. Pooling all misses, the main reasons for non-adherence were pregnancy (33.3%), intentional non-adherence (20%) and forgetfulness (13.3%). Pooling all delays, the main reasons for non adherence were professional constraints (46.9%), infections (17.3%) and travels (14.3%). Perineal disease was associated with IFX delays (P = 0.0007, odds ratio 4.0), whereas active CD/UC was associated with IFX misses (P = 0.0258, OR = 5.4). CONCLUSIONS: The overall non-adherence rate for IFX use was 54.3%. Professional constraints and intentional non-adherence were the leading causes of non adherence. Perineal disease and active CD were negatively related to adherence. PMID- 28858440 TI - A Double-Blind, Placebo-Controlled Randomized Trial of Vilazodone in the Treatment of Posttraumatic Stress Disorder and Comorbid Depression. AB - Objective: To determine the efficacy, safety, and tolerability of vilazodone in the treatment of posttraumatic stress disorder (PTSD) with comorbid mild-to moderate depression. Methods: A 12-week randomized, double-blind, placebo controlled trial was conducted in adult outpatients who met DSM-IV criteria for PTSD with comorbid depression between February 2013 and September 2015. Participants were randomly assigned to receive vilazodone 40 mg/d or placebo, and outcome measures were obtained at scheduled visits. Primary outcome measures included change in PTSD symptoms from baseline to end of study as indexed by the Clinician-Administered PTSD Scale (CAPS) and PTSD Symptom Scale-Self-Report (PSS SR). Secondary outcome measures of anxiety, depression, and impairment were obtained, as well as biomarker assessment at baseline and end of study. Results: A total of 59 patients were randomly assigned to receive vilazodone (n = 29) or placebo (n = 30). Of those who were randomized, there were 25 completers in the vilazodone group and 22 completers in the placebo group. No significant differences were observed between the groups on any of the primary or secondary outcome measures. Vilazodone was generally well tolerated with few differences in the rate of adverse events between groups. Conclusions: Treatment with vilazodone 40 mg/d did not improve symptoms of PTSD and comorbid depression. Further investigation of the biological mechanisms underlying PTSD may lead to identification of improved therapeutic targets. Trial Registration: ClinicalTrials.gov identifier: NCT01715519. PMID- 28858442 TI - Introduction. PMID- 28858437 TI - Ageing with HIV: do comorbidities and polymedication drive treatment optimization? AB - OBJECTIVES: The aim of the study was to describe the ageing HIV-infected population (> 50 years old) and their current antiretroviral therapy (ART), comorbidities and coprescriptions in France in 2013 and to compare them to the younger population. METHODS: A retrospective analysis of a prospectively collected database was performed. The characteristics of patients receiving ART as well as their current ART and their numbers of comorbidities and comedications at the censoring date (1 July 2013) were compared between patients ageing with HIV infection, patients who seroconverted while ageing, and younger patients. RESULTS: We compared 10 318 ageing patients [median age 56 years; 25% interquartile range (IQR) 53-62 years] with 13 302 younger patients (median age 42 years; 25% IQR 36-47 years). The ageing patients were more frequently male than the younger patients (77 vs. 65%). Among the ageing patients, 7025 were diagnosed with HIV infection before 2000 and represented a distinct group, the 'experienced ageing' group, by comparison with the 'recently diagnosed ageing' group. Triple therapy containing a boosted protease inhibitor was used in 28.2% of the patients (vs. 39% and 36% of the younger and "recently diagnosed ageing" groups, respectively); a nonnucleoside reverse transcriptase inhibitor in 27% (vs. 33% and 38%, respectively), an integrase strand transfer inhibitor (INSTI) in 9% (vs. 7% and 9%, respectively), and another regimen (fewer or more than three drugs) in 35.8% (vs. 21% and 16.5%, respectively). "Experienced ageing" patients typically had one or more comorbidities (62.1%) and were receiving at least one comedication (71%). Central nervous system (CNS) agents (prescribed in 44.6% of the "experienced ageing" patients) and antilipidaemics (in 44.2%) were the most frequently prescribed comedications. INSTIs were used in 23% of the population and were used significantly more often in patients with comorbidities and coprescriptions. For all comparisons, P < 0.0001. CONCLUSIONS: In ageing HIV infected patients, especially those with a long history of HIV infection, comorbidities and coprescriptions are highly prevalent. PMID- 28858441 TI - The THINC-Integrated Tool (THINC-it) Screening Assessment for Cognitive Dysfunction: Validation in Patients With Major Depressive Disorder. AB - OBJECTIVE: To validate the THINC-integrated tool (THINC-it)-a freely available, patient-administered, computerized screening tool integrating subjective and objective measures of cognitive function in adults with major depressive disorder (MDD). METHODS: Subjects aged 18 to 65 years (n = 100) with recurrent MDD experiencing a major depressive episode of at least moderate severity were evaluated and compared to age-, sex-, and education-matched healthy controls (n = 100). Between January and June 2016, subjects completed the THINC-it, which includes variants of the Choice Reaction Time Identification Task (IDN), One-Back Test, Digit Symbol Substitution Test, Trail Making Test-Part B, and the Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D). RESULTS: The THINC-it required approximately 10 to 15 minutes for administration and was capable of detecting cognitive deficits in adults with MDD. A total of 44.4% of adults with MDD exhibited cognitive performance at >= 1.0 SD below that of healthy controls on standardized mean scores of the THINC-it. Concurrent validity of the overall tool, based on a calculated composite score, was acceptable (r = 0.539, P < .001). Concurrent validity of the component tests ranged from -0.083 (IDN) to 0.929 (PDQ-5-D). Qualitative survey results indicated that there was a high level of satisfaction and perceived value in administering the THINC-it regarding its impact on the appropriateness and quality of care being received. CONCLUSIONS: The THINC-it is a valid and sensitive tool for detecting cognitive dysfunction in adults with MDD that is free, easy to use, and rapidly administered. The THINC-it should be incorporated into the assessment and measurement of all patients with MDD, particularly among those with enduring functional impairment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02508493. PMID- 28858443 TI - Quality of Life, Functioning, and Depressive Symptom Severity in Older Adults With Major Depressive Disorder Treated With Citalopram in the STAR*D Study. AB - OBJECTIVE: Major depressive disorder (MDD) can substantially worsen patient reported quality of life (QOL) and functioning. Prior studies have examined the role of age in MDD by comparing depressive symptom severity or remission rates between younger and older adults. This study examines these outcomes before and after SSRI treatment. On the basis of prior research, we hypothesized that older adults would have worse treatment outcomes in QOL, functioning, and depressive symptom severity and that nonremitters would have worse outcomes. METHODS: A retrospective secondary data analysis was conducted from the National Institute of Mental Health-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (July 2001-September 2006). We analyzed data for 2,280 nonpsychotic adults with DSM-IV-TR-defined MDD who received citalopram monotherapy. Older adults were classified as adults aged 65 years and above. All subjects completed patient-reported QOL, functioning, and depressive symptom severity measures at entry and exit. Subjects included 106 older adults and 2,174 adults < 65. MDD remission status posttreatment was also determined. RESULTS: Both older adults and adults < 65 experienced significant improvements and medium to large treatment responses across QOL, functioning, and depressive symptom severity (P < .001). Older adults had smaller treatment effect sizes for all outcomes, particularly functioning. Conversely, mean change scores from entry to exit were equivalent across all outcomes. Remitters at exit had significantly better responses to treatment than nonremitters for the majority of outcomes. CONCLUSION: Findings suggest that older adults and younger adults have comparable treatment responses to citalopram monotherapy, with significant improvements in patient-reported depressive symptom severity, functioning, and QOL. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00021528. PMID- 28858445 TI - A Case Report of Biotin Treatment for Valproate-Induced Hair Loss. PMID- 28858444 TI - A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer's Disease. AB - OBJECTIVE: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. METHODS: Population pharmacokinetic pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [18F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. RESULTS: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P < .01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. CONCLUSIONS: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose. PMID- 28858446 TI - Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism: A Need for Further Analysis. PMID- 28858447 TI - Dr Brown and Colleagues Reply. PMID- 28858448 TI - Severity of Binge-Eating Disorder and Its Effects on Treatment Outcome. PMID- 28858449 TI - Dr Grilo Replies. PMID- 28858450 TI - Ketamine for Depression, 5: Potential Pharmacokinetic and Pharmacodynamic Drug Interactions. AB - Ketamine, administered in subanesthetic doses, is gaining recognition as an off label treatment for severe and even treatment-refractory depression. This article explores potential pharmacokinetic and pharmacodynamic drug interactions of relevance to the use of ketamine in depression. Sparse evidence suggests that ketamine will not induce clinically significant drug interactions except to the extent that these are predictable by its clinical actions. A small body of literature indicates that drugs that induce cytochrome P450 (CYP)2B6 and CYP3A4 will reduce exposure to ketamine and that drugs that inhibit these enzymes will increase exposure to ketamine. Common genetic polymorphisms of the CYP2B6 gene may also be associated with variations in the exposure to ketamine. However, the clinical implications of such variations in exposure have not been sufficiently studied. A very small number of reports and studies suggest that concurrent benzodiazepine medication may diminish the antidepressant benefits of ketamine. Likewise, a small body of literature suggests that drugs (such as lamotrigine) that inhibit glutamatergic signaling may reduce the adverse effects of ketamine; however, it is unknown whether these drugs also diminish the antidepressant effect. Data from clinical trials indicate that most conventional antidepressants can probably be combined with ketamine without compromising efficacy or increasing the adverse effect burden.. PMID- 28858451 TI - Why Food matters. Doctors need more training in nutrition if they are to prevent disease. PMID- 28858452 TI - RECIPE Rx. AB - As we started planning this issue on food and nutrition, we kepthearing about the importance of cooking. If physicians are going tobe credible when talking to patients about healthy eating, they oughtto know something about making a healthy meal, right? They mighteven want to share a recipe. We know many physicians and medicalstudents like to cook, and we thought it would be fun to find outwhat they are making. So we asked you to share your favorite healthyrecipes with us.The following are a few that we received. We'll post these andothers on our website (mnmed.org). Try them out and sharethem with your patients and colleagues. Also feel free tosend us your favorite. We'll add it to the collection. PMID- 28858453 TI - I eat too much butter. A day of bad eating becomes a wake-up call for healthier living. PMID- 28858454 TI - Ulipristal (Ella) for Emergency Contraception PMID- 28858455 TI - Assessment for Adverse Food Reactivity. A Clinician's Guide. AB - Patients frequently note adverse food reactions and report significant food restrictions as a result. Physiciansneed to consider the nutritional consequences and necessity of such voluntary dietary limitations. They alsoshould consider adverse food reactivity in their differential diagnosis for many frequently seen concerns. Thisarticle describes a three-step process for assessing a patient's potential for true adverse food reactivity. Readerswill note the significant contributions nutritionists and dieticians can offer as team members. PMID- 28858457 TI - Reimagining Nutrition Education in a Teaching Kitchen.Findings from a Pilot Study. AB - Students in U.S. medical schools spend little time learning about nutrition as it relates to health and disease.As a result, they lack important skills needed to care for themselves and their patients. To close this gap in theirknowledge, instructors from the University of Minnesota created a course, "Food Matters for Doctors," thatcombines didactic learning about practical topics related to food and nutrition with hands-on experience in thekitchen. They piloted the course in the spring of 2016. This article describes the course and changes in students'knowledge and abilities before and after completing it. PMID- 28858456 TI - Problems with the 2015 Dietary Guidelines for Americans.An Alternative. AB - The updated 2015 Dietary Guidelines for Americans, published in January 2016, have stirred muchcontroversy since the advisory report first appeared. Several important changes have been made, with somerecommendations having greater scientific evidence for their support than others. The focus of this reviewis to discuss specific recommendations from the 2015 Dietary Guidelines for Americans that lack soundscientific evidence; these include: 1) Allowing approximately half of all grains to be refined; 2) The continuedrecommendations for fat-free or low fat dairy and limitation of saturated fat intake to <10% of calories; 3)Sodium intake < 2,300 mg/day; and 4) Consumption of up to 27 g/day of "oils" (high in polyunsaturated fator monounsaturated fat). Based on our review, the aforementioned recommendations found in the updated2015 Dietary Guidelines for Americans may increase the incidence of cardiometabolic disease, diabetes,obesity, dyslipidemia, cardiovascular disease and possibly cancer. PMID- 28858459 TI - The Art of Listening. AB - Communication, once thought of as a soft skill for physicians, is now recognized as an essential skill. This articleasserts that listening is the foundation of good communication and that all physicians can become betterlisteners if they have the desire to improve and are intentional about how they approach listening. The authorsshare five strategies to help physicians improve their skills: listening with curiosity, reflective listening, empathiclistening, listening for discrepancies and listening in silence. PMID- 28858460 TI - Somali Cultural Competency among Students in One Minnesota MedicalSchool. AB - Minnesota has the largest Somali population in the United States. Thus, students in the state's medical schoolsare likely exposed to Somali patients during their training. We assessed baseline knowledge of and attitudesabout Somali patients among students at one medical school in the state. We then exposed those students to aneducational intervention and reassessed their knowledge and attitudes afterward. We found students' baselineknowledge was poor (65% of questions answered correctly, on average), but improved (80% answered correctly,on average) post-intervention. The majority of students also felt the quality of care they could provide Somalipatients would be compromised because of their lack of cultural understanding. Although the results were notstatistically significant due to low power, this study represents a meaningful attempt to assess students' baselineknowledge as well as a proof-of-concept intervention to highlight ways to improve cultural competency trainingin Minnesota's medical schools. PMID- 28858461 TI - Melanoma Sentinel-Node Metastasis. PMID- 28858462 TI - Lithium Use in Pregnancy and the Risk of Cardiac Malformations. PMID- 28858463 TI - Lithium Use in Pregnancy and the Risk of Cardiac Malformations. PMID- 28858464 TI - Myeloproliferative Neoplasms. PMID- 28858465 TI - Medical Assistance in Dying. PMID- 28858466 TI - Multilayered Magnetic Nanobeads for the Delivery of Peptides Molecules Triggered by Intracellular Proteases. AB - In this work, the versatility of layer-by-layer technology was combined with the magnetic response of iron oxide nanobeads to prepare magnetic mesostructures with a degradable multilayer shell into which a dye quenched ovalbumin conjugate (DQ OVA) was loaded. The system was specifically designed to prove the protease sensitivity of the hybrid mesoscale system and the easy detection of the ovalbumin released. The uptake of the nanostructures in the breast cancer cells was followed by the effective release of DQ-OVA upon activation via the intracellular proteases degradation of the polymer shells. Monitoring the fluorescence rising due to DQ-OVA digestion and the cellular dye distribution, together with the electron microscopy studying, enabled us to track the shell degradation and the endosomal uptake pathway that resulted in the release of the digested fragments of DQ ovalbumin in the cytosol. PMID- 28858467 TI - Transformative Nanomedicine of an Amphiphilic Camptothecin Prodrug for Long Circulation and High Tumor Uptake in Cancer Therapy. AB - We report a camptothecin (CPT) prodrug that was well formulated in solution and rapidly transformed into long-circulating nanocomplexes in vivo for highly efficient drug delivery and effective cancer therapy. Specifically, using a redox responsive disulfide linker, CPT was conjugated with an albumin-binding Evans blue (EB) derivative; the resulting amphiphilic CPT-ss-EB prodrug self-assembled into nanostructures in aqueous solution, thus conferring high solubility and stability. By binding CPT-ss-EB to endogenous albumin, the 80 nm CPT-ss-EB nanoparticles rapidly transformed into 7 nm albumin/prodrug nanocomplexes. CPT-ss EB was efficient at intracellular delivery into cancer cells, released intact CPT in a redox-responsive manner, and exhibited cytotoxicity as potent as CPT. In mice, the albumin/CPT-ss-EB nanocomplex exhibited remarkably long blood circulation (130-fold greater than CPT) and efficient tumor accumulation (30-fold of CPT), which consequently contributed to excellent therapeutic efficacy. Overall, this strategy of transformative nanomedicine is promising for efficient drug delivery. PMID- 28858469 TI - Dynamic Heterogeneous Multiscale Filtration Model: Probing Micro- and Macroscopic Filtration Characteristics of Gasoline Particulate Filters. AB - Motivated by high filtration efficiency (mass- and number-based) and low pressure drop requirements for gasoline particulate filters (GPFs), a previously developed heterogeneous multiscale filtration (HMF) model is extended to simulate dynamic filtration characteristics of GPFs. This dynamic HMF model is based on a probability density function (PDF) description of the pore size distribution and classical filtration theory. The microstructure of the porous substrate in a GPF is resolved and included in the model. Fundamental particulate filtration experiments were conducted using an exhaust filtration analysis (EFA) system for model validation. The particulate in the filtration experiments was sampled from a spark-ignition direct-injection (SIDI) gasoline engine. With the dynamic HMF model, evolution of the microscopic characteristics of the substrate (pore size distribution, porosity, permeability, and deposited particulate inside the porous substrate) during filtration can be probed. Also, predicted macroscopic filtration characteristics including particle number concentration and normalized pressure drop show good agreement with the experimental data. The resulting dynamic HMF model can be used to study the dynamic particulate filtration process in GPFs with distinct microstructures, serving as a powerful tool for GPF design and optimization. PMID- 28858468 TI - Real-Time Continuous Identification of Greenhouse Plant Pathogens Based on Recyclable Microfluidic Bioassay System. AB - The development of a real-time continuous analytical platform for the pathogen detection is of great scientific importance for achieving better disease control and prevention. In this work, we report a rapid and recyclable microfluidic bioassay system constructed from oligonucleotide arrays for selective and sensitive continuous identification of DNA targets of fungal pathogens. We employ the thermal denaturation method to effectively regenerate the oligonucleotide arrays for multiple sample detection, which could considerably reduce the screening effort and costs. The combination of thermal denaturation and laser induced fluorescence detection technique enables real-time continuous identification of multiple samples (<10 min per sample). As a proof of concept, we have demonstrated that two DNA targets of fungal pathogens (Botrytis cinerea and Didymella bryoniae) can be sequentially analyzed using our rapid microfluidic bioassay system, which provides a new paradigm in the design of microfluidic bioassay system and will be valuable for chemical and biomedical analysis. PMID- 28858470 TI - Occupational Respiratory Exposure to Platinum Group Metals: A Review and Recommendations. AB - Platinum group metals (PGMs) is a group of metals that include platinum, palladium, rhodium, ruthenium, iridium, and osmium. Occupational respiratory exposure to platinum has been reported since 1945, but studies investigating occupational exposure to palladium, rhodium, ruthenium, iridium, and osmium are scarce. This review provides a summation of the information available on the respiratory exposure to PGMs in various industrial settings, methods used to assess exposure, and the possible adverse health effects resulting from occupational exposure to PGMs. Of these effects, respiratory sensitization caused by soluble PGMs is of most importance. Metallic PGMs have not been shown to cause allergic reactions. This review reiterates that occupational respiratory exposure to PGMs is dependent on the type of industry where exposure takes place, the chemical form (soluble or insoluble) of the PGMs present in the workplace air, and the tasks performed by workers in the specific work areas. Sensitization to soluble platinum is associated with the degree of exposure to soluble platinum compounds, and the highest concentrations of soluble PGMs in workplace air have been reported for precious metals refineries where personal exposures frequently exceed the occupational exposure limit for soluble platinum (2 MUg/m3). Additionally, this review emphasizes that personal exposure monitoring is preferred over area monitoring when assessing workers' exposure to PGMs. The legislation applicable to occupational exposure to PGMs is also discussed, and it is highlighted that the occupational exposure limit for soluble platinum has remained unchanged, in most countries, since 1970 and that too few countries have classified PGM compounds as respiratory or skin sensitizers. Finally, recommendations are made to ensure that future investigations are comparable in terms of the type of exposure monitoring (personal or area) conducted, the type of tasks included in the exposure monitoring program, and the format in which results are reported. PMID- 28858471 TI - Enhanced Electronic Properties of SnO2 via Electron Transfer from Graphene Quantum Dots for Efficient Perovskite Solar Cells. AB - Tin dioxide (SnO2) has been demonstrated as an effective electron-transporting layer (ETL) for attaining high-performance perovskite solar cells (PSCs). However, the numerous trap states in low-temperature solution processed SnO2 will reduce the PSCs performance and result in serious hysteresis. Here, we report a strategy to improve the electronic properties in SnO2 through a facile treatment of the films with adding a small amount of graphene quantum dots (GQDs). We demonstrate that the photogenerated electrons in GQDs can transfer to the conduction band of SnO2. The transferred electrons from the GQDs will effectively fill the electron traps as well as improve the conductivity of SnO2, which is beneficial for improving the electron extraction efficiency and reducing the recombination at the ETLs/perovskite interface. The device fabricated with SnO2:GQDs could reach an average power conversion efficiency (PCE) of 19.2 +/- 1.0% and a highest steady-state PCE of 20.23% with very little hysteresis. Our study provides an effective way to enhance the performance of perovskite solar cells through improving the electronic properties of SnO2. PMID- 28858472 TI - Mechanical Detection and Imaging of Hyperbolic Phonon Polaritons in Hexagonal Boron Nitride. AB - Mid-infrared nanoimaging and spectroscopy of two-dimensional (2D) materials have been limited so far to scattering-type scanning near-field optical microscopy (s SNOM) experiments, where light from the sample is scattered by a metallic-coated atomic force microscope (AFM) tip interacting with the material at the nanoscale. These experiments have recently allowed imaging of plasmon polaritons in graphene as well as hyperbolic phonon polaritons in hexagonal boron nitride (hBN). Here we show that the high mechanical sensitivity of an AFM cantilever can be exploited for imaging hyperbolic phonon polaritons in hBN. In our imaging process, the lattice vibrations of hBN micrometer-sized flakes are locally enhanced by the launched phonon polaritons. These enhanced vibrations are coupled to the AFM tip in contact with the sample surface and recorded during scanning. Imaging resolution of Delta/20 is shown (Delta being the polaritonic fringes' separation distance), comparable to the best resolution in s-SNOM. Importantly, this detection mechanism is free from light background, and it is in fact the first photonless detection of phonon polaritons. PMID- 28858473 TI - Molecular-Targeted Immunotherapeutic Strategy for Melanoma via Dual-Targeting Nanoparticles Delivering Small Interfering RNA to Tumor-Associated Macrophages. AB - Tumor-associated macrophages (TAMs) are a promising therapeutic target for cancer immunotherapy. Targeted delivery of therapeutic drugs to the tumor-promoting M2 like TAMs is challenging. Here, we developed M2-like TAM dual-targeting nanoparticles (M2NPs), whose structure and function were controlled by alpha peptide (a scavenger receptor B type 1 (SR-B1) targeting peptide) linked with M2pep (an M2 macrophage binding peptide). By loading anti-colony stimulating factor-1 receptor (anti-CSF-1R) small interfering RNA (siRNA) on the M2NPs, we developed a molecular-targeted immunotherapeutic approach to specifically block the survival signal of M2-like TAMs and deplete them from melanoma tumors. We confirmed the validity of SR-B1 for M2-like TAM targeting and demonstrated the synergistic effect of the two targeting units (alpha-peptide and M2pep) in the fusion peptide (alpha-M2pep). After being administered to tumor-bearing mice, M2NPs had higher affinity to M2-like TAMs than to tissue-resident macrophages in liver, spleen, and lung. Compared with control treatment groups, M2NP-based siRNA delivery resulted in a dramatic elimination of M2-like TAMs (52%), decreased tumor size (87%), and prolonged survival. Additionally, this molecular-targeted strategy inhibited immunosuppressive IL-10 and TGF-beta production and increased immunostimulatory cytokines (IL-12 and IFN-gamma) expression and CD8+ T cell infiltration (2.9-fold) in the tumor microenvironment. Moreover, the siRNA carrying M2NPs down-regulated expression of the exhaustion markers (PD-1 and Tim 3) on the infiltrating CD8+ T cells and stimulated their IFN-gamma secretion (6.2 fold), indicating the restoration of T cell immune function. Thus, the dual targeting property of M2NPs combined with RNA interference provides a potential strategy of molecular-targeted cancer immunotherapy for clinical application. PMID- 28858474 TI - Hypotoxic and Rapidly Metabolic PEG-PCL-C3-ICG Nanoparticles for Fluorescence Guided Photothermal/Photodynamic Therapy against OSCC. AB - The development of agents for noninvasive photothermal/photodynamic therapies (PTT/PDT) against cancer remains challenging because most PTT agents cause side effects on normal tissues due to their high cytotoxicity and slow metabolism rate. We successfully synthesized an organic compound (C3), encapsulated in PEG PCL with indocyanine green (ICG), to form hybrid nanoparticles (PEG-PCL-C3-ICG NPs) for use as a new PPT/PDT agent to treat cancer with a single irradiation. Compared with conventional PPT agents, such as Au nanorods, C3 showed better photothermal conversion stability, lower cytotoxicity and a faster metabolic rate, ensuring promising PTT efficacy in eliminating tumors during in vivo application, while ICG was used as a PDT agent. With 808 nm laser irradiation at tumor sites, the PEG-PCL-C3-ICG NPs were able to simultaneously produce hyperthermia through C3 and produce reactive oxygen species as well as a fluorescence-guided effect through ICG to kill oral squamous cell carcinoma (OSCC) cells. The combination of these hypotoxic and metabolic hybrid nanoparticles with radiation therapy has potential for the future treatment of OSCC. PMID- 28858476 TI - Carbon Capture and Utilization in the Industrial Sector. AB - The fabrication and manufacturing processes of industrial commodities such as iron, glass, and cement are carbon-intensive, accounting for 23% of global CO2 emissions. As a climate mitigation strategy, CO2 capture from flue gases of industrial processes-much like that of the power sector-has not experienced wide adoption given its high associated costs. However, some industrial processes with relatively high CO2 flue concentration may be viable candidates to cost competitively supply CO2 for utilization purposes (e.g., polymer manufacturing, etc.). This work develops a methodology that determines the levelized cost ($/tCO2) of separating, compressing, and transporting carbon dioxide. A top-down model determines the cost of separating and compressing CO2 across 18 industrial processes. Further, the study calculates the cost of transporting CO2 via pipeline and tanker truck to appropriately paired sinks using a bottom-up cost model and geo-referencing approach. The results show that truck transportation is generally the low-cost alternative given the relatively small volumes (ca. 100 kt CO2/a). We apply our methodology to a regional case study in Pennsylvania, which shows steel and cement manufacturing paired to suitable sinks as having the lowest levelized cost of capture, compression, and transportation. PMID- 28858475 TI - Dysprosium-Modified Tobacco Mosaic Virus Nanoparticles for Ultra-High-Field Magnetic Resonance and Near-Infrared Fluorescence Imaging of Prostate Cancer. AB - The increasing prevalence of ultra-high-field magnetic resonance imaging (UHFMRI) in biomedical research and clinical settings will improve the resolution and diagnostic accuracy of MRI scans. However, better contrast agents are needed to achieve a satisfactory signal-to-noise ratio. Here, we report the synthesis of a bimodal contrast agent prepared by loading the internal cavity of tobacco mosaic virus (TMV) nanoparticles with a dysprosium (Dy3+) complex and the near-infrared fluorescence (NIRF) dye Cy7.5. The external surface of TMV was conjugated with an Asp-Gly-Glu-Ala (DGEA) peptide via a polyethylene glycol linker to target integrin alpha2beta1. The resulting nanoparticle (Dy-Cy7.5-TMV-DGEA) was stable and achieved a high transverse relaxivity in ultra-high-strength magnetic fields (326 and 399 mM-1 s-1 at 7 and 9.4 T, respectively). The contrast agent was also biocompatible (low cytotoxicity) and targeted PC-3 prostate cancer cells and tumors in vitro and in vivo as confirmed by bimodal NIRF imaging and T2-mapping UHFMRI. Our results show that Dy-Cy7.5-TMV-DGEA is suitable for multiscale MRI scanning from the cellular level to the whole body, particularly in the context of UHFMRI applications. PMID- 28858477 TI - Microemulsion-Based Soft Bacteria-Driven Microswimmers for Active Cargo Delivery. AB - Biohybrid cell-driven microsystems offer unparalleled possibilities for realization of soft microrobots at the micron scale. Here, we introduce a bacteria-driven microswimmer that combines the active locomotion and sensing capabilities of bacteria with the desirable encapsulation and viscoelastic properties of a soft double-micelle microemulsion for active transport and delivery of cargo (e.g., imaging agents, genes, and drugs) to living cells. Quasi monodisperse double emulsions were synthesized with an aqueous core that encapsulated the fluorescence imaging agents, as a proof-of-concept cargo in this study, and an outer oil shell that was functionalized with streptavidin for specific and stable attachment of biotin-conjugated Escherichia coli. Motile bacteria effectively propelled the soft microswimmers across a Transwell membrane, actively delivering imaging agents (i.e., dyes) encapsulated inside of the micelles to a monolayer of cultured MCF7 breast cancer and J744A.1 macrophage cells, which enabled real-time, live-cell imaging of cell organelles, namely mitochondria, endoplasmic reticulum, and Golgi body. This in vitro model demonstrates the proof-of-concept feasibility of the proposed soft microswimmers and offers promise for potential biomedical applications in active and/or targeted transport and delivery of imaging agents, drugs, stem cells, siRNA, and therapeutic genes to live tissue in in vitro disease models (e.g., organ-on-a chip devices) and stagnant or low-flow-velocity fluidic regions of the human body. PMID- 28858478 TI - Bisphenol AF and Bisphenol B Exert Higher Estrogenic Effects than Bisphenol A via G Protein-Coupled Estrogen Receptor Pathway. AB - Numerous studies have indicated estrogenic disruption effects of bisphenol A (BPA) analogues. Previous mechanistic studies were mainly focused on their genomic activities on nuclear estrogen receptor pathway. However, their nongenomic effects through G protein-coupled estrogen receptor (GPER) pathway remain poorly understood. Here, using a SKBR3 cell-based fluorescence competitive binding assay, we found six BPA analogues bound to GPER directly, with bisphenol AF (BPAF) and bisphenol B (BPB) displaying much higher (~9-fold) binding affinity than BPA. Molecular docking also demonstrated the binding of these BPA analogues to GPER. By measuring calcium mobilization and cAMP production in SKBR3 cells, we found the binding of these BPA analogues to GPER lead to the activation of subsequent signaling pathways. Consistent with the binding results, BPAF and BPB presented higher agonistic activity than BPA with the lowest effective concentration (LOEC) of 10 nM. Moreover, based on the results of Boyden chamber and wound-healing assays, BPAF and BPB displayed higher activity in promoting GPER mediated SKBR3 cell migration than BPA with the LOEC of 100 nM. Overall, we found two BPA analogues BPAF and BPB could exert higher estrogenic effects than BPA via GPER pathway at nanomolar concentrations. PMID- 28858479 TI - Functional Analysis of Cytochrome P450s Involved in Streptovaricin Biosynthesis and Generation of Anti-MRSA Analogues. AB - The streptovaricins, chemically related to the rifamycins, are highly effective antibacterial agents, particularly against mycobacteria. Herein, a bioassay guided investigation of Streptomyces spectabilis CCTCC M2017417 has led to the characterization of streptovaricins as potent compounds against methicillin resistant Staphylococcus aureus (MRSA). We identified the streptovaricin biosynthetic gene cluster from S. spectabilis CCTCC M2017417 based on genomic sequencing and bioinformatic analysis. Targeted in-frame deletion of five cytochrome P450 genes (stvP1-P5) resulted in the identification of four new streptovaricin analogues and revealed the functions of these genes as follows: stvP1, stvP4, and stvP5 are responsible for the hydroxylation of C-20, Me-24, and C-28, respectively. stvP2 is possibly involved in formation of the methylenedioxy bridge, and stvP3, a conserved gene found in the biosynthetic cluster for naphthalenic ansamycins, might be related to the formation of a naphthalene ring. Biochemical verification of the hydroxylase activity of StvP1, StvP4, and StvP5 was performed, and StvP1 showed unexpected biocatalytic specificity and promiscuity. More importantly, anti-MRSA studies of streptovaricins and derivatives revealed significant structure-activity relationships (SARs): The hydroxyl group at C-28 plays a vital role in antibacterial activity. The hydroxyl group at C-20 substantially enhances activity in the absence of the methoxycarbonyl side chain at C-24, which can increase the activity regardless of the presence of a hydroxyl group at C-20. The inner lactone ring between C-21 and C-24 shows a positive effect on activity. This work provides meaningful information on the SARs of streptovaricins and demonstrates the utility of the engineering of streptovaricins to yield novel anti-MRSA molecules. PMID- 28858480 TI - Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization. AB - Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of "telltale indicators" can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial cyclization reaction leading to either polymerization of the radical cation, elimination of a proton from or solvent trapping of that intermediate, or solvent trapping of the radical cation can be identified in the proton NMR spectrum of the crude reaction material. Such an NMR spectrum shows retention of the trapping group. The problems can be addressed by tuning the radical cation, altering the trapping group, or channeling the reactive intermediate down a radical pathway. Specific examples each are shown in this Account. Problems with the second oxidation step can be identified by poor current efficiency or general decomposition in spite of cyclic voltammetry evidence for a rapid cyclization. Solutions involve improving the oxidation conditions for the radical after cyclization by either the addition of a properly placed electron-donating group in the substrate or an increase in the concentration of electrolyte in the reaction (a change that stabilizes the cation generated from the second oxidation step). Problems with the final cation typically lead to overoxidation. Solutions to this problem require an approach that either slows down elimination side reactions or changes the reaction conditions so that the cation can be quickly trapped in an irreversible fashion. Again, this Account highlights these strategies along with the specific experimental protocols utilized. PMID- 28858481 TI - Engineering Isoprene Synthase Expression and Activity in Cyanobacteria. AB - Efforts to heterologously produce quantities of isoprene hydrocarbons (C5H8) renewably from CO2 and H2O through the photosynthesis of cyanobacteria face barriers, including low levels of recombinant enzyme accumulation compounded by their slow innate catalytic activity. The present work sought to alleviate the "expression level" barrier upon placing the isoprene synthase (IspS) enzyme in different fusion configurations with the cpcB protein, the highly expressed beta subunit of phycocyanin. Different cpcB*IspS fusion constructs were made, distinguished by the absence or presence of linker amino acids between the two proteins. Composition of linker amino acids was variable with lengths of 7, 10, 16, and 65 amino acids designed to test for optimal activity of the IspS through spatial positioning between the cpcB and IspS. Results showed that fusion constructs with the highly expressed cpcB gene, as the leader sequence, improved transgene expression in the range of 61 to 275-fold over what was measured with the unfused IspS control. However, the specific activity of the IspS enzyme was attenuated in all fusion transformants, possibly because of allosteric effects exerted by the leader cpcB fusion protein. This inhibition varied depending on the nature of the linker amino acids between the cpcB and IspS proteins. In terms of isoprene production, the results further showed a trade-off between specific activity and transgenic enzyme accumulation. For example, the cpcB*L7*IspS strain showed only about 10% the isoprene synthase specific-activity of the unfused cpcB IspS control, but it accumulated 254-fold more IspS enzyme. The latter more than countered the slower specific activity and made the cpcB*L7*IspS transformant the best isoprene producing strain in this work. Isoprene to biomass yield ratios improved from 0.2 mg g-1 in the unfused cpcB-IspS control to 5.4 mg g-1 in the cpcB*L7*IspS strain, a 27-fold improvement. PMID- 28858482 TI - Direct Electrochemical Bioconjugation on Metal Surfaces. AB - DNA has unique capabilities for molecular recognition and self-assembly, which have fostered its widespread incorporation into devices that are useful in science and medicine. Many of these platforms rely on thiol groups to tether DNA to gold surfaces, but this method is hindered by a lack of control over monolayer density and by secondary interactions between the nucleotide bases and the metal. In this work, we report an electrochemically activated bioconjugation reaction as a mild, reagent-free strategy to attach oligonucleotides to gold surfaces. Aniline-modified DNA was coupled to catechol-coated electrodes that were oxidized to o-quinones using an applied potential. High levels of coupling could be achieved in minutes. By changing the reaction time and the underlying catechol content, the final DNA surface coverage could be specified. The advantages of this method were demonstrated through the electrochemical detection of the endocrine disruptor bisphenol A, as well as the capture of living nonadherent cells on electrode surfaces by DNA hybridization. This method not only improves the attachment of DNA to metal surfaces but also represents a new direction for the site-specific attachment of biomolecules to device platforms. PMID- 28858483 TI - Monomeric and Dimeric Oxidomolybdenum(V and VI) Complexes, Cytotoxicity, and DNA Interaction Studies: Molybdenum Assisted C?N Bond Cleavage of Salophen Ligands. AB - Four novel dimeric bis-MU-imido bridged metal-metal bonded oxidomolybdenum(V) complexes [MoV2O2L'21-4] (1-4) (where L'1-4 are rearranged ligands formed in situ from H2L1-4) and a new mononuclear dioxidomolybdenum(VI) complex [MoVIO2L5] (5) synthesized from salen type N2O2 ligands are reported. This rare series of imido bridged complexes (1-4) have been furnished from rearranged H3L'1-4 ligands, containing an aromatic diimine (o-phenylenediamine) "linker", where Mo assisted hydrolysis followed by -C?N bond cleavage of one of the arms of the ligand H2L1-4 took place. A monomeric molybdenum(V) intermediate species [MoVO(HL'1-4)(OEt)] (Id1-4) was generated in situ. The concomitant deprotonation and dimerization of two molybdenum(V) intermediate species (Id1-4) ultimately resulted in the formation of a bis-MU-imido bridge between the two molybdenum centers of [MoV2O2L'21-4] (1-4). The mechanism of formation of 1-4 has been discussed, and one of the rare intermediate monomeric molybdenum(V) species Id4 has been isolated in the solid state and characterized. The monomeric dioxidomolybdenum(VI) complex [MoVIO2L5] (5) was prepared from the ligand H2L5 where the aromatic "linker" was replaced by an aliphatic diimine (1,2 diaminopropane). All the ligands and complexes have been characterized by elemental analysis, IR, UV-vis spectroscopy, NMR, ESI-MS, and cyclic voltammetry, and the structural features of 1, 2, 4, and 5 have been solved by X-ray crystallography. The DNA binding and cleavage activity of 1-5 have been explored. The complexes interact with CT-DNA by the groove binding mode, and the binding constants range between 103 and 104 M-1. Fairly good photoinduced cleavage of pUC19 supercoiled plasmid DNA was exhibited by all the complexes, with 4 showing the most promising photoinduced DNA cleavage activity of ~93%. Moreover, in vitro cytotoxic activity of all the complexes was evaluated by MTT assay, which reveals that the complexes induce cell death in MCF-7 (human breast adenocarcinoma) and HCT-15 (colon cancer) cell lines. PMID- 28858484 TI - An EXAFS Approach to the Study of Polyoxometalate-Protein Interactions: The Case of Decavanadate-Actin. AB - EXAFS and XANES experiments were used to assess decavanadate interplay with actin, in both the globular and polymerized forms, under different conditions of pH, temperature, ionic strength, and presence of ATP. This approach allowed us to simultaneously probe, for the first time, all vanadium species present in the system. It was established that decavanadate interacts with G-actin, triggering a protein conformational reorientation that induces oxidation of the cysteine core residues and oxidovanadium (VIV) formation. The local environment of vanadium's absorbing center in the [decavanadate-protein] adducts was determined, a V-SCys coordination having been verified experimentally. The variations induced in decavanadate's EXAFS profile by the presence of actin were found to be almost totally reversed by the addition of ATP, which constitutes a solid proof of decavanadate interaction with the protein at its ATP binding site. Additionally, a weak decavanadate interplay with F-actin was suggested to take place, through a mechanism different from that inferred for globular actin. These findings have important consequences for the understanding, at a molecular level, of the significant biological activities of decavanadate and similar polyoxometalates, aiming at potential pharmacological applications. PMID- 28858485 TI - Discovery of Small Molecules Targeting the Synergy of Cardiac Transcription Factors GATA4 and NKX2-5. AB - Transcription factors are pivotal regulators of gene transcription, and many diseases are associated with the deregulation of transcriptional networks. In the heart, the transcription factors GATA4 and NKX2-5 are required for cardiogenesis. GATA4 and NKX2-5 interact physically, and the activation of GATA4, in cooperation with NKX2-5, is essential for stretch-induced cardiomyocyte hypertrophy. Here, we report the identification of four small molecule families that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. A fragment-based screening, reporter gene assay, and pharmacophore search were utilized for the small molecule screening, identification, and optimization. The compounds modulated the hypertrophic agonist-induced cardiac gene expression. The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide (3, IC50 = 3 MUM), exhibited no activity on the protein kinases involved in the regulation of GATA4 phosphorylation. The identified and chemically and biologically characterized active compound, and its derivatives may provide a novel class of small molecules for modulating heart regeneration. PMID- 28858486 TI - Metabolism of N-Methyl-2-Pyrrolidone in Honey Bee Adults and Larvae: Exploring Age Related Differences in Toxic Effects. AB - In chronic feeding assays, the common agrochemical inert formulant N-methyl-2 pyrrolidone (NMP) is at least 20 times more toxic to honey bee larvae than to adults, but the underlying cause of this difference is unknown. In other taxa, NMP is primarily detoxified via a cytochrome P450 mediated pathway. Using a LC-MS method, putative cytochrome P450 metabolites of NMP were identified and quantified in adults and larvae following chronic exposure to NMP. Major differences in the identities and quantities of the generated metabolites were observed between adults and larvae. One major difference was the higher percentage of the administered NMP recovered as the parent compound in larvae compared to adults. To further explore the apparent difference in metabolic capacity, a spectrofluorometric method was used to compare general cytochrome P450 enzyme activity by monitoring the transformation of a 7-ethoxycoumarin substrate. Higher microsomal levels of 7-ethoxycoumarin-O-deethylase activity in adult fat bodies suggests that the higher percentage of unmetabolized NMP in larvae relative to adults may be due to lower cytochrome P450 enzyme activity in fat bodies. Taken together, these results suggest that larvae may be less able to detoxify xenobiotics encountered in diet than adults, and these findings will help inform future risk assessment. PMID- 28858487 TI - Enhanced Hydrogen Production from Sawdust Decomposition Using Hybrid-Functional Ni-CaO-Ca2SiO4 Materials. AB - A hybrid-functional material consisting of Ni as catalyst, CaO as CO2 sorbent, and Ca2SiO4 as polymorphic "active" spacer was synthesized by freeze-drying a mixed solution containing Ni, Ca and Si precursors, respectively, to be deployed during sawdust decomposition that generated gases mainly containing H2, CO, CO2 and CH4. The catalytic activity showed a positive correlation to the Ni loading, but at the expense of lower porosity and surface area with Ni loading beyond 20 wt %, indicating an optimal Ni loading of 20 wt % for Ni-CaO-Ca2SiO4 hybrid functional materials, which enables ~626 mL H2 (room temperature, 1 atm) produced from each gram of sawdust, with H2 purity in the product gas up to 68 vol %. This performance was superior over a conventional supported catalyst Ni-Ca2SiO4 that produced 443 mL H2 g-sawdust-1 under the same operating condition with a purity of ~61 vol %. Although the Ni-CaO bifunctional material in its fresh form generated a bit more H2 (~689 mL H2 g-sawdust-1), its cyclic performance decayed dramatically, resulting in H2 yield reduced by 62% and purity dropped from 73 to 49 vol % after 15 cycles. The "active" Ca2SiO4 spacer offers porosity and mechanical strength to the Ni-CaO-Ca2SiO4 hybrid-functional material, corresponding to its minor loss in reactivity over cycles (H2 yield reduced by only 7% and H2 purity dropped from 68 to 64 vol % after 15 cycles). PMID- 28858489 TI - Back-Donation in High-Valent d0 Metal Complexes: Does It Exist? The Case of NbV. AB - In the last years, some N-heterocyclic carbene (NHC) complexes of high-valent d0 transition-metal halides have been structurally characterized, showing a significant short distance between the carbene carbon and the cis-halide ligands (Clax). Some authors attributed this arrangement to a halide -> Ccarbene unusual "back-donation", whereas, according to others, the M-carbene bond is purely sigma. More, in general, the ability of d0 metal centers to provide back-donation to suitable ligands is still debated, and detailed bond analyses for this class of systems are missing in the literature. In this contribution, we analyze in detail the NbV-L bond within neutral, cationic, and anionic derivatives of NbCl5, with L = NHC, CO, CNH, and CN-. In [NbVCl6-x(NHC)x]x-1 complexes, with NHC being either a model carbene (1,3-dimethylimidazol-2-ylidene, IMe) or a realistic one [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, IPr], we demonstrate that the metal center is really capable of back-donation to the carbene ligand by a charge flux that involves the chloride in the trans position and, directly, the metal. In this case, a direct interaction between Clax and Ccarbene can be excluded, while if different pi-acceptor ligands, such as CO or CNH, are used (instead of NHC), the direct Clax -> L interligand interaction becomes predominant. PMID- 28858490 TI - Exploiting the 4-Phenylquinazoline Scaffold for the Development of High Affinity Fluorescent Probes for the Translocator Protein (TSPO). AB - The quinazoline class was exploited to search for a new translocator protein (TSPO) fluorescent probe endowed with improved affinity and residence time (RT). Computational studies on an "in-house" collection of quinazoline derivatives, featuring highly steric demanding groups at the amide nitrogen, suggested that, despite their molecular extension, these ligands are still easily lodged in the TSPO binding site. Binding assays supported this hypothesis, highlighting a low nanomolar/subnanomolar affinity of these ligands, together with a higher RT of the representative compound 11 with respect to our previously reported indole based fluorescent probe. Thanks to the amenability of the amide nitrogen atom to be substituted with bulky groups, we developed quinazoline-based imaging tools by fluorescently labeling the scaffold at this position. Probes with relevant TSPO affinity, favorable spectroscopic properties, and improved RT were identified. The results from fluorescence microscopy showed that these probes specifically labeled the TSPO at the mitochondrial level in the U343 cell line. PMID- 28858491 TI - Rapid, Sensitive, and Carryover Contamination-Free Loop-Mediated Isothermal Amplification-Coupled Visual Detection Method for 'Candidatus Liberibacter asiaticus'. AB - Huanglongbing is a devastating citrus disease, and 'Candidatus Liberibacter asiaticus' (Las) is the most prevalent huanglongbing-associated bacterium. Its field detection remains challenging. In this work, a visual, rapid, sensitive, and carryover contamination-free method was developed for field detection of Las. Leaf samples were treated with 500 MUL of 0.5 M sodium hydroxide solution for 3 min, and 50-fold dilutions were directly amplified by loop-mediated isothermal amplification. Then, a novel SYTO-9-based visual detection method was used to evaluate amplification results without uncapping operation. Negative samples remained colorless, while positive samples generated obvious green fluorescence, which could be easily distinguished by the naked eye with a mini-fluorescent emission cartridge developed originally. The proposed detection method could be accomplished within 40 min and is about 100 times more sensitive than conventional TaqMan polymerase chain reaction. The reliability of this method was also verified by analyzing practical samples. PMID- 28858492 TI - Cell-Surface Glyco-Engineering by Exogenous Enzymatic Transfer Using a Bifunctional CMP-Neu5Ac Derivative. AB - Cell-surface engineering strategies that permit long-lived display of well defined, functionally active molecules are highly attractive for eliciting desired cellular responses and for understanding biological processes. Current methodologies for the exogenous introduction of synthetic biomolecules often result in short-lived presentations, or require genetic manipulation to facilitate membrane attachment. Herein, we report a cell-surface engineering strategy that is based on the use of a CMP-Neu5Ac derivative that is modified at C-5 by a bifunctional entity composed of a complex synthetic heparan sulfate (HS) oligosaccharide and biotin. It is shown that recombinant ST6GAL1 can readily transfer the modified sialic acid to N-glycans of glycoprotein acceptors of living cells resulting in long-lived display. The HS oligosaccharide is functionally active, can restore protein binding, and allows activation of cell signaling events of HS-deficient cells. The cell-surface engineering methodology can easily be adapted to any cell type and is highly amenable to a wide range of complex biomolecules. PMID- 28858493 TI - Enantiospecific Solvolytic Functionalization of Bromochlorides. AB - Herein, we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. Arrays of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively, this work demonstrates that enantioenriched bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups. PMID- 28858494 TI - Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase. AB - Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold. From this structure-activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (kinact/KI > 105 M-1 min-1). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 MUM, representing a significant improvement over our previously reported "hit" NC9. PMID- 28858495 TI - Clarifying the Equilibrium Speciation of Periodate Ions in Aqueous Medium. AB - Equilibria of periodate ion were reinvestigated in aqueous solution by using potentiometric titration, UV and Raman spectroscopies, and gravimetry simultaneously at 0.5 M ionic strength and at 25.0 +/- 0.2 degrees C. Stepwise acid dissociation constants of orthoperiodic acid were found to be pK1 = 0.98 +/- 0.18, pK2 = 7.42 +/- 0.03, and pK3 = 10.99 +/- 0.02, as well as pK2 = 7.55 +/- 0.04 and pK3 = 11.25 +/- 0.03 in the presence of sodium nitrate and sodium perchlorate as background salts, respectively. pK1 cannot be determined unambiguously from our experiments in the presence of sodium perchlorate. The molar absorptivity spectrum of H4IO6- and H3IO62- was determined in the range of 215-335 nm, as major species of periodate present from slightly acidic to slightly alkaline conditions. The solubility of periodate decreases significantly under alkaline conditions, and it was determined to be (2.8 +/- 0.4) mM by gravimetry, under our experimental conditions. None of these studies gave any clear evidence for an ortho-meta equilibrium and the frequently invoked dimerization of periodate. All measurements can quantitatively be described by the presence of orthoperiodic acid and its three successive deprotonation steps. PMID- 28858496 TI - Characterization of the Fleeting Hydroxoiron(III) Complex of the Pentadentate TMC py Ligand. AB - Nonheme mononuclear hydroxoiron(III) species are important intermediates in biological oxidations, but well-characterized examples of synthetic complexes are scarce due to their instability or tendency to form MU-oxodiiron(III) complexes, which are the thermodynamic sink for such chemistry. Herein, we report the successful stabilization and characterization of a mononuclear hydroxoiron(III) complex, [FeIII(OH)(TMC-py)]2+ (3; TMC-py = 1-(pyridyl-2'-methyl)-4,8,11 trimethyl-1,4,8,11-tetrazacyclotetradecane), which is directly generated from the reaction of [FeIV(O)(TMC-py)]2+ (2) with 1,4-cyclohexadiene at -40 degrees C by H-atom abstraction. Complex 3 exhibits a UV spectrum with a lambdamax at 335 nm (epsilon ~ 3500 M-1 cm-1) and a molecular ion in its electrospray ionization mass spectrum at m/z 555 with an isotope distribution pattern consistent with its formulation. Electron paramagnetic resonance and Mossbauer spectroscopy show 3 to be a high-spin Fe(III) center that is formed in 85% yield. Extended X-ray absorption fine structure analysis reveals an Fe-OH bond distance of 1.84 A, which is also found in [(TMC-py)FeIII-O-CrIII(OTf)3]+ (4) obtained from the reaction of 2 with Cr(OTf)2. The S = 5/2 spin ground state and the 1.84 A Fe-OH bond distance are supported computationally. Complex 3 reacts with 1-hydroxy 2,2,6,6-tetramethylpiperidine (TEMPOH) at -40 degrees C with a second-order rate constant of 7.1 M-1 s-1 and an OH/OD kinetic isotope effect value of 6. On the basis of density functional theory calculations, the reaction between 3 and TEMPOH is classified as a proton-coupled electron transfer as opposed to a hydrogen-atom transfer. PMID- 28858497 TI - Direct Measurements of Gas/Particle Partitioning and Mass Accommodation Coefficients in Environmental Chambers. AB - Secondary organic aerosols (SOA) are a major contributor to fine particulate mass and wield substantial influences on the Earth's climate and human health. Despite extensive research in recent years, many of the fundamental processes of SOA formation and evolution remain poorly understood. Most atmospheric aerosol models use gas/particle equilibrium partitioning theory as a default treatment of gas aerosol transfer, despite questions about potentially large kinetic effects. We have conducted fundamental SOA formation experiments in a Teflon environmental chamber using a novel method. A simple chemical system produces a very fast burst of low-volatility gas-phase products, which are competitively taken up by liquid organic seed particles and Teflon chamber walls. Clear changes in the species time evolution with differing amounts of seed allow us to quantify the particle uptake processes. We reproduce gas- and aerosol-phase observations using a kinetic box model, from which we quantify the aerosol mass accommodation coefficient (alpha) as 0.7 on average, with values near unity especially for low volatility species. alpha appears to decrease as volatility increases. alpha has historically been a very difficult parameter to measure with reported values varying over 3 orders of magnitude. We use the experimentally constrained model to evaluate the correction factor (Phi) needed for chamber SOA mass yields due to losses of vapors to walls as a function of species volatility and particle condensational sink. Phi ranges from 1-4. PMID- 28858498 TI - A Unifying Synthesis Approach to the C18-, C19-, and C20-Diterpenoid Alkaloids. AB - The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C18, C19, and C20 families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C18 (weisaconitine D), one C19 (liljestrandinine), and three C20 (cochlearenine, paniculamine, and N-ethyl 1alpha-hydroxy-17-veratroyldictyzine) natural products from a common intermediate. PMID- 28858499 TI - A Role for 2-Methyl Pyrrole in the Browning of 4-Oxopentanal and Limonene Secondary Organic Aerosol. AB - Reactions of ammonia or ammonium sulfate (AS) with carbonyls in secondary organic aerosol (SOA) produced from limonene are known to form brown carbon (BrC) with a distinctive absorption band at 505 nm. This study examined the browning processes in aqueous solutions of AS and 4-oxopentanal (4-OPA), which has a 1,4-dicarbonyl structural motif present in many limonene SOA compounds. Aqueous reactions of 4 OPA with AS were found to produce 2-methyl pyrrole (2-MP), which was detected by gas chromatography. While 2-MP does not absorb visible radiation, it can further react with 4-OPA eventually forming BrC compounds. This was demonstrated by reacting 2-MP with 4-OPA or limonene SOA, both of which produced BrC with absorption bands at 475 and 505 nm, respectively. The formation of BrC in the reaction of 4-OPA with AS and ammonium nitrate was greatly accelerated by evaporation of the solution suggesting an important role of the dehydration processes in BrC formation. 4-OPA was also found to produce BrC in aqueous reactions with a broad spectrum of amino acids and amines. These results suggest that 4-OPA may be the smallest atmospherically relevant compound capable of browning by the same mechanism as limonene SOA. PMID- 28858500 TI - Development of Novel Chemical Probes for Examining Triplet Natural Organic Matter under Solar Illumination. AB - Excited triplet states of chromophoric dissolved organic matter (3CDOM*) are critical transient species in environmental photochemistry. In the present study, sorbic amine (2,4-hexadien-1-amine) and sorbic alcohol were employed as new probe molecules for triplet measurements and compared to the results measured from sorbic acid under identical conditions. Unlike sorbic acid, sorbic amine and sorbic alcohol were not directly photolyzed under solar irradiation. Photosensitized isomerization of the probes with the conjugated diene structure could yield four geometrical isomers. The separation and quantitative determination of the geometrical isomers were accomplished using HPLC and high resolution NMR analyses. When photoirradiated Suwannee River natural organic matter (SRNOM) was employed as a source of 3CDOM*, significantly different photosensitized isomerization rates were observed for the diverse charged probes. The bimolecular reaction rate constants between 3SRNOM* and the probes were calculated as (0.42 +/- 0.1) * 109 M-1 s-1 for sorbic acid, (1.1 +/- 0.1) * 109 M 1 s-1 for sorbic alcohol, and (5.2 +/- 0.4) * 109 M-1 s-1 for sorbic amine, respectively. The average apparent Phitriplet was (0.96 +/- 0.03)% based on an irradiation range of 290 to 400 nm. We developed highly selective and efficient probes for triplet determination and elucidated the different reaction behaviors of these conjugated dienes containing different charged substituents within the photochemical energy transfer process. PMID- 28858501 TI - Controlling the Compositional Chemistry in Single Nanoparticles for Functional Hollow Carbon Nanospheres. AB - Hollow carbon nanostructures have inspired numerous interests in areas such as energy conversion/storage, biomedicine, catalysis, and adsorption. Unfortunately, their synthesis mainly relies on template-based routes, which include tedious operating procedures and showed inadequate capability to build complex architectures. Here, by looking into the inner structure of single polymeric nanospheres, we identified the complicated compositional chemistry underneath their uniform shape, and confirmed that nanoparticles themselves stand for an effective and versatile synthetic platform for functional hollow carbon architectures. Using the formation of 3-aminophenol/formaldehyde resin as an example, we were able to tune its growth kinetics by controlling the molecular/environmental variables, forming resin nanospheres with designated styles of inner constitutional inhomogeneity. We confirmed that this intraparticle difference could be well exploited to create a large variety of hollow carbon architectures with desirable structural characters for their applications; for example, high-capacity anode for potassium-ion battery has been demonstrated with the multishelled hollow carbon nanospheres. PMID- 28858502 TI - Selective Degradation of Organic Pollutants Using an Efficient Metal-Free Catalyst Derived from Carbonized Polypyrrole via Peroxymonosulfate Activation. AB - Metal-free carbonaceous materials, including nitrogen-doped graphene and carbon nanotubes, are emerging as alternative catalysts for peroxymonosulfate (PMS) activation to avoid drawbacks of conventional transition metal-containing catalysts, such as the leaching of toxic metal ions. However, these novel carbocatalysts face relatively high cost and complex syntheses, and their activation mechanisms have not been well-understood. Herein, we developed a novel nitrogen-doped carbonaceous nanosphere catalyst by carbonization of polypyrrole, which was prepared through a scalable chemical oxidative polymerization. The defective degree of carbon substrate and amount of nitrogen dopants (i.e., graphitic nitrogen) were modulated by the calcination temperature. The product carbonized at 800 degrees C (CPPy-F-8) exhibited the best catalytic performance for PMS activation, with 97% phenol degradation efficiency in 120 min. The catalytic system was efficient over a wide pH range (2-9), and the reaction of phenol degradation had a relatively low activation energy (18.4 +/- 2.7 kJ mol 1). The nitrogen-doped carbocatalyst activated PMS through a nonradical pathway. A two-step catalytic mechanism was extrapolated: the catalyst transfers electrons to PMS through active nitrogen species and becomes a metastable state of the catalyst (State I); next, organic substrates are oxidized and degraded by serving as electron donors to reduce State I. The catalytic process was selective toward degradation of various aromatic compounds with different substituents, probably depending on the oxidation state of State I and the ionization potential (IP) of the organics; that is, only those organics with an IP value lower than ca. 9.0 eV can be oxidized in the CPPy-F-8/PMS system. PMID- 28858503 TI - Dermal Uptake of Benzophenone-3 from Clothing. AB - Benzophenone-3 (also known as BP-3 or oxybenzone) is added to sunscreens, plastics, and some coatings to filter UV radiation. The suspected endocrine disruptor BP-3 has been detected in the air and settled dust of homes and is expected to redistribute from its original sources to other indoor compartments, including clothing. Given its physical and chemical properties, we hypothesized that dermal uptake from clothing could contribute to the body burden of this compound. First, cotton shirts were exposed to air at an elevated concentration of BP-3 for 32 days; the final air concentration was 4.4 MUg/m3. Next, three participants wore the exposed shirts for 3 h. After 3 h of exposure, participants wore their usual clothing during the collection of urine samples for the next 48 h. Urine was analyzed for BP-3, a metabolite (BP-1), and six other UV filters. The rate of urinary excretion of the sum of BP-1 and BP-3 increased for all participants during and following the 3 h of exposure. The summed mass of BP-1 and BP-3 excreted during the first 24 h attributable to wearing exposed t-shirts were 12, 9.9, and 82 MUg for participants 1, 2, and 3, respectively. Analysis of these results, coupled with predictions of steady-state models, suggest that dermal uptake of BP-3 from clothing could meaningfully contribute to overall body burden. PMID- 28858504 TI - Energy Transfer in Microhydrated Uracil, 5-Fluorouracil, and 5-Bromouracil. AB - Experiment and theory are combined to study the interaction of low energy electrons with microhydrated uracil and its halogenated analogues 5-fluorouracil and 5-bromouracil. We report electron ionization (EI) and electron attachment (EA) mass spectra for the uracils with different degrees of hydration. Both EI and EA lead to evaporation of water molecules. The number of evaporated molecules serves as a measure of the energy transferred to the solvent. Upon EI, the amount of energy transferred to neighboring water molecules is similar for all three studied species. On the other hand, the energy transferred upon EA rises significantly from uracil to 5-fluorouracil and 5-bromouracil. 5-Bromouracil is the only studied molecule that undergoes dissociative electron attachment after hydration at the studied energy of 1.2 eV. Theoretical modeling of the energetics for the electron attachment process allows for setting the energy transferred to the solvent on the absolute scale. We discuss the importance of this energy for the radiosensitization. PMID- 28858505 TI - Synthesis of Intrinsically Blue-Colored bis-Nitronyl Nitroxide Peptidomimetic Templates and Their Conformational Preferences as Revealed by a Combined Spectroscopic Analysis. AB - The intrinsically blue-colored Ullman imidazolinyl nitronyl nitroxide (NN) mono radicals have found various applications, in particular as spin probes and organic magnetic materials. Here, we present the solution-phase synthesis, extensive characterization, and conformational analysis of the first peptidomimetics with two pendant, chiral nitronyl nitroxide free radical units. Two (R)-Aic(NN) residues, where Aic(NN) is 2-amino-5-nitronylnitroxide-indan-2 carboxylic acid, have been inserted at positions i and i+3 of the pentapeptide Boc-(R)-Aic(NN)-(Ala)2-(R)-Aic(NN)-Ala-OMe and the hexapeptide Boc-[Ala-(R) Aic(NN)-Ala]2-OMe as well. The two compounds were obtained in good yields and high purities. Thanks to a combination of several spectroscopic techniques (IR absorption, NMR, VCD, and EPR) we gained clear evidence that both compounds adopt a right-handed 310-helical conformation with both nitronyl nitroxide pendants positioned on the same side of the helix. This peptidomimetic/free radical system is a potentially excellent template for the preparation of a set of appropriate analogs with exciting applications in the area of host-guest organic chemistry, or to spectroscopically evaluate in-depth the intramolecular exchange interactions in this type of probe. PMID- 28858506 TI - Establishing Structure Property Relationship in Drug Partitioning into and Release from Niosomes: Physical Chemistry Insights with Anti-Inflammatory Drugs. AB - Understanding the physical chemistry underlying interactions of drugs with delivery formulations is extremely important in devising effective drug delivery systems. The partitioning and release kinetics of diclofenac sodium and naproxen from Brij 30 and Triton X-100 niosomal formulations have been addressed based on structural characterization, partitioning energetics, and release kinetics, thus establishing a relationship between structures and observed properties. Both the drugs partition in nonpolar regions of TX-100 niosomes via stacking of aromatic rings. The combined effects of interactions of the drugs with polar head groups and the rigidity of the niosome vesicles determine entry and partitioning of drugs into niosomes. The observed slower rate of release of the drugs from the drug encapsulated niosomes of TX-100 than those of Brij 30, suggest stable complexation of drugs in the nonpolar interior of the former. No release of drugs from the niosomes was observed until 24 h even upon varying pH conditions without SDS. However, SDS in drug loaded niosomes led to release of drugs in as early as 6 h. The sustained pattern of in vitro release kinetics of the drugs thus observed from our niosomal preparations suggest these vesicular systems to be promising for pharamaceutical applications as potential drug delivery vehicles. PMID- 28858507 TI - Epitaxial Nanoflag Photonics: Semiconductor Nanoemitters Grown with Their Nanoantennas. AB - Semiconductor nanostructures are desirable for electronics, photonics, quantum circuitry, and energy conversion applications as well as for fundamental science. In photonics, optical nanoantennas mediate the large size difference between photons and semiconductor nanoemitters or detectors and hence are instrumental for exhibiting high efficiency. In this work we present epitaxially grown InP nanoflags as optically active nanostructures encapsulating the desired characteristics of a photonic emitter and an efficient epitaxial nanoantenna. We experimentally characterize the polarized and directional emission of the nanoflag-antenna and show the control of these properties by means of structure, dimensions, and constituents. We analyze field enhancement and light extraction by the semiconductor nanoflag antenna, which yield comparable values to enhancement factors of metallic plasmonic antennas. We incorporated quantum emitters within the nanoflag structure and characterized their emission properties. Merging of active nanoemitters with nanoantennas at a single growth process enables a new class of devices to be used in nanophotonics applications. PMID- 28858509 TI - Trifluoromethanesulfonate Anion as Nucleophile in Organic Chemistry. AB - Although the triflate ion is not generally perceived as a nucleophile, many examples of its behavior as such exist in the literature. This Synopsis presents an overview of such reactions, in which triflate may be either a stoichiometric or catalytic nucleophile, leading to the suggestion that nucleophilic catalysis by triflate may be more common than generally accepted, albeit hidden by the typical reactivity of organic triflates which complicates their observation as intermediates. PMID- 28858510 TI - Water Librations in the Hydration Shell of Phospholipids. AB - The hydrophilic phosphate moiety in the headgroup of phospholipids forms strong hydrogen bonds with water molecules in the first hydration layer. Time-domain terahertz spectroscopy in a range from 100 to 1000 cm-1 reveals the influence of such interactions on rotations of water molecules. We determine librational absorption spectra of water nanopools in phospholipid reverse micelles for a range from w0 = 2 to 16 waters per phospholipid molecule. A pronounced absorption feature with maximum at 830 cm-1 is superimposed on a broad absorption band between 300 and 1000 cm-1. Molecular dynamics simulations of water in the reverse micelles suggest that the feature at 830 cm-1 arises from water molecules forming one or two strong hydrogen bonds with phosphate groups, while the broad component comes from bulk-like environments. This behavior is markedly different from water interacting with less polar surfaces. PMID- 28858508 TI - Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease. AB - Candidate drugs to counter intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) continue to represent a promising approach to mitigating the primary cause of the pathophysiology associated with sickle cell disease (SCD). One such compound is the naturally occurring antisickling agent, 5-hydroxymethyl 2-furfural (5-HMF), which has been studied in the clinic for the treatment of SCD. As part of our efforts to develop novel efficacious drugs with improved pharmacologic properties, we structurally modified 5-HMF into 12 ether and ester derivatives. The choice of 5-HMF as a pharmacophore was influenced by a combination of its demonstrated attractive hemoglobin modifying and antisickling properties, well-known safety profiles, and its reported nontoxic major metabolites. The derivatives were investigated for their time- and/or dose dependent effects on important antisickling parameters, such as modification of hemoglobin, corresponding changes in oxygen affinity, and inhibition of red blood cell sickling. The novel test compounds bound and modified Hb and concomitantly increased the protein affinity for oxygen. Five of the derivatives exhibited 1.5- to 4.0-fold higher antisickling effects than 5-HMF. The binding mode of the compounds with Hb was confirmed by X-ray crystallography and, in part, helps explain their observed biochemical properties. Our findings, in addition to the potential therapeutic application, provide valuable insights and potential guidance for further modifications of these (and similar) compounds to enhance their pharmacologic properties. PMID- 28858511 TI - Anchimerically Activated ProTides as Inhibitors of Cap-Dependent Translation and Inducers of Chemosensitization in Mantle Cell Lymphoma. AB - The cellular delivery of nucleotides through various pronucleotide strategies has expanded the utility of nucleosides as a therapeutic class. Although highly successful, the highly popular ProTide system relies on a four-step enzymatic and chemical process to liberate the corresponding monophosphate. To broaden the scope and reduce the number of steps required for monophosphate release, we have developed a strategy that depends on initial chemical activation by a sulfur atom of a methylthioalkyl protecting group, followed by enzymatic hydrolysis of the resulting phosphoramidate monoester. We have employed this ProTide strategy for intracellular delivery of a nucleotide antagonist of eIF4E in mantle cell lymphoma (MCL) cells. Furthermore, we demonstrated that chemical inhibition of cap-dependent translation results in suppression of c-Myc expression, increased p27 expression, and enhanced chemosensitization to doxorubicin, dexamethasone, and ibrutinib. In addition, the new ProTide strategy was shown to enhance oral bioavailability of the corresponding monoester phosphoramidate. PMID- 28858512 TI - Scalable Synthesis of a Key Intermediate for the Production of Pleuromutilin Based Antibiotics. AB - An improved synthesis of an eneimide, which is a useful precursor to pleuromutilin-based antibiotics, is reported. This synthesis proceeds in six steps and 17% overall yield (27% based on recovery of a key hydrindenone intermediate) and requires two fewer chromatography steps and five fewer days of reaction time than the previously reported route. The use of expensive, acutely toxic, and precious metal reagents or catalysts has been minimized. PMID- 28858513 TI - Useful Applications of Enantioselective (4 + 2)-Cycloaddition Reactions to the Synthesis of Chiral 1,2-Amino Alcohols, 1,2-Diamines, and beta-Amino Acids. AB - The scope of enantioselective (4 + 2)-cycloaddition reactions has been expanded to include reactive olefinic components that are equivalents of three inoperable and unstable ethylene derivatives: 1-hydroxy-2-aminoethylene, 1,2 diaminoethylene, and beta-aminoacrylic acid. In this way, a variety of otherwise unavailable functionalized (4 + 2)-cycloadducts have been synthesized from 1,3 dienes with high enantioselectivity (92-98%) and in good yields. The research leading up to this synthetic advance has also produced some surprising insights on reactivity and positional selectivity in catalytic enantioselective (4 + 2) cycloaddition. PMID- 28858514 TI - Copper-Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amides. AB - Cu2O/N,N'-bis(thiophen-2-ylmethyl)oxalamide is established to be an effective catalyst system for Goldberg amidation with inferior reactive (hetero)aryl chlorides, which have not been efficiently documented by Cu-catalysis to date. The reaction is well liberalized toward a variety of functionalized (hetero)aryl chlorides and a wide range of aromatic and aliphatic primary amides in good to excellent yields. Furthermore, the arylation of lactams and oxazolidinones is achieved. The present catalytic system also accomplished an intramolecular cross coupling product. PMID- 28858515 TI - Direct Access to 2,3,4,6-Tetrasubstituted Tetrahydro-2H-pyrans via Tandem SN2' Prins Cyclization. AB - A new, direct, and diastereoselective synthesis of activated 2,3,4,6 tetrasubstituted tetrahydro-2H-pyrans is described. In this reaction, iron(III) catalyzed an SN2'-Prins cyclization tandem process leading to the creation of three new stereocenters in one single step. These activated tetrahydro-2H-pyran units are easily derivatizable through CuAAC conjugations in order to generate multifunctionalized complex molecules. DFT calculations support the in situ SN2' reaction as a preliminary step in the Prins cyclization. PMID- 28858516 TI - Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib. AB - A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (1) is reported. The bicyclic pyrimidine 2 starting material was prepared via a nitrilase biocatalytic resolution, halogen-metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce alpha-aryl-beta-amino acid 3 in high yield and enantioselectivity. The API was assembled in a convergent manner through a late-stage amidation/deprotection/monohydrochloride salt formation sequence. PMID- 28858517 TI - Synthesis of Spirobidihydropyrazole through Double 1,3-Dipolar Cycloaddition of Nitrilimines with Allenoates. AB - The double 1,3-dipolar cycloaddition of allenoates with nitrilimines has been achieved under mild reaction conditions, affording a variety of spirobidihydropyrazoles in moderate to excellent yields with excellent diastereoselectivities. The reaction diastereoselectively constructs double dihydropyrazole moieties and two chiral centers including a spiro carbon center. PMID- 28858518 TI - Cnidimonins A-C, Three Types of Hybrid Dimer from Cnidium monnieri: Structural Elucidation and Semisynthesis. AB - Three pairs of racemic dimers, (+/-)-cnidimonins A-C (1-3), were isolated from the fruits of Cnidium monnieri. They represent novel hybrid-dimerization patterns of coumarin skeleton with structurally diverse units (flavonol, benzofuran, and chromone) via an unprecedented terminal chiral carbon of prenyl. The absolute configurations of the enantiomers were determined by electronic circular dichroism (ECD). To investigate their bioactivities in depth, (+/-)-cnidimonins A C (1-3) were synthesized. The racemic mixture (+/-)-1 exhibited stronger antiviral activity against HSV-1 (IC50: 1.23 MUM) than its corresponding optically pure enantiomers. PMID- 28858519 TI - Tumor Microenvironment Responsive Nanogel for the Combinatorial Antitumor Effect of Chemotherapy and Immunotherapy. AB - A biomimetic nanogel with tumor microenvironment responsive property is developed for the combinatorial antitumor effects of chemotherapy and immunotherapy. Nanogels are formulated with hydroxypropyl-beta-cyclodextrin acrylate and two opposite charged chitosan derivatives for entrapping anticancer drug paclitaxel and precisely controlling the pH responsive capability, respectively. The nanogel supported erythrocyte membrane can achieve "nanosponge" property for delivering immunotherapeutic agent interleukin-2 without reducing the bioactivity. By responsively releasing drugs in tumor microenvironment, the nanogels significantly enhanced antitumor activity with improved drug penetration, induction of calreticulin exposure, and increased antitumor immunity. The tumor microenvironment is remodeled by the combination of these drugs in low dosage, as evidenced by the promoted infiltration of immune effector cells and reduction of immunosuppressive factors. PMID- 28858520 TI - Catalytic Reductions and Tandem Reactions of Nitro Compounds Using in Situ Prepared Nickel Boride Catalyst in Nanocellulose Solution. AB - A mild and efficient method for the in situ reduction of a wide range of nitroarenes and aliphatic nitrocompounds to amines in excellent yields using nickel chloride/sodium borohydride in a solution of TEMPO-oxidized nanocellulose in water (0.01 wt %) is described. The nanocellulose has a stabilizing effect on the catalyst, which increases the turnover number and enables low loading of nickel catalyst (0.1-0.25 mol % NiCl2). In addition, two tandem protocols were developed in which the in situ formed amines were either Boc-protected to carbamates or further reacted with an epoxide to yield beta-amino alcohols in excellent yields. PMID- 28858521 TI - Gold(I)/Gold(III)-Catalyzed Selective Synthesis of N-Sulfonyl Enaminone Isomers from Sulfonamides and Ynones via Two Distinct Reaction Pathways. AB - Au-catalyzed chemoselective methods for synthesizing N-sulfonyl enaminones are developed. Two different isomers are obtained in a chemocontrolled manner by employing the different properties of Au(I) and Au(III) catalysts. Hydroamidation and proton-assisted carbonyl activation followed by Meyer-Schuster rearrangement are proposed as the working mechanisms for the reactions. A wide range of substrates afforded moderate to excellent yields and selectivities. These reactions represent the first examples of transition-metal-catalyzed enamine synthesis from sulfonamides and alkynes. PMID- 28858522 TI - Chemical Editing of Macrocyclic Natural Products and Kinetic Profiling Reveal Slow, Tight-Binding Histone Deacetylase Inhibitors with Picomolar Affinities. AB - Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules are highly important as tool compounds for probing these mechanisms as well as for the development of new medicines. Therefore, detailed mechanistic information and precise characterization of the chemical probes used to investigate the effects of HDAC enzymes are vital. We interrogated Nature's arsenal of macrocyclic nonribosomal peptide HDAC inhibitors by chemical synthesis and evaluation of more than 30 natural products and analogues. This furnished surprising trends in binding affinities for the various macrocycles, which were then exploited for the design of highly potent class I and IIb HDAC inhibitors. Furthermore, thorough kinetic investigation revealed unexpected inhibitory mechanisms of important tool compounds as well as the approved drug Istodax (romidepsin). This work provides novel inhibitors with varying potencies, selectivity profiles, and mechanisms of inhibition and, importantly, affords insight into known tool compounds that will improve the interpretation of their effects in biology and medicine. PMID- 28858523 TI - Combination of Poly[(2-dimethylamino)ethyl methacrylate] and Poly(beta-amino ester) Results in a Strong and Synergistic Transfection Activity. AB - This work reports an innovative and very effective gene delivery nanosystem, based on the combination of poly[(2-dimethylamino)ethyl methacrylate] (PDMAEMA) and poly(beta-amino ester) (PbetaAE) homopolymers, that has the capacity to efficiently deliver genetic material into target cells, even in the presence of serum. The best formulation, prepared with the combination PDMAEMA/4PbetaAE at the 25/1 nitrogen/phosphate (N/P) ratio, presented a 700-fold and 220-fold higher transfection activity than that obtained with branched polyethylenimine (PEI) based polyplexes and block copolymer-based polyplexes, respectively. This new nanocarrier revealed high transgene expression in different human cells, including hard-to-transfect normal human astrocytes. The polyplexes presented high protection of genetic material and reduced sizes, which are suitable physicochemical properties for in vivo applications. Overall, this study demonstrates that the combination of PDMAEMA and PbetaAE homopolymers resulted in a noticeable and synergistic effect in terms of transfection activity, without causing substantial toxicity, constituting a new platform for the development of gene delivery nanosystems. PMID- 28858524 TI - Reversible Dimerization of Polymeric Amphiphiles Acts as a Molecular Switch of Enzymatic Degradability. AB - Enzyme-responsive polymeric micelles have great potential as drug delivery systems due to the high selectivity and overexpression of disease-associated enzymes, which could be utilized to trigger the release of active drugs only at the target site. We previously demonstrated that enzymatic degradation rates of amphiphilic PEG-dendron hybrids could be precisely tuned by gradually increasing the hydrophobic to hydrophilic ratio. However, with the increase in hydrophobicity, the micelles rapidly became too stable and could not be degraded, as often encountered for many other amphiphilic assemblies. Here we address the challenge to balance between stability and reactivity of enzymatically degradable assemblies by utilizing reversible dimerization of diblock polymeric amphiphiles to yield jemini amphiphiles. This molecular transformation serves as a tool to control the critical micelle concentration of the amphiphiles in order to tune their micellar stability and enzymatic degradability. To demonstrate this approach, we show that simple dimerization of two polymeric amphiphiles through a single reversible disulfide bond significantly increased the stability of their micellar assemblies toward enzymatic degradation, although the hydrophilic to hydrophobic ratio was not changed. Reduction of the disulfide bond led to dedimerization of the polymeric hybrids and allowed their degradation by the activating enzyme. The generality of the approach is demonstrated by designing both esterase- and amidase-responsive micellar systems. This new molecular design can serve as a simple tool to increase the stability of polymeric micelles without impairing their enzymatic degradability. PMID- 28858525 TI - Kinetic Analysis of Enzymes Immobilized in Porous Film Arrays. AB - Measuring the catalytic activity of immobilized enzymes underpins development of biosensing, bioprocessing, and analytical chemistry tools. To expand the range of approaches available for measuring enzymatic activity, we report on a technique to probe activity of enzymes immobilized in porous materials in the absence of confounding mass transport artifacts. We measured reaction kinetics of calf intestinal alkaline phosphatase (CIAP) immobilized in benzophenone-modified polyacrylamide (BPMA-PAAm) gel films housed in an array of fluidically isolated chambers. To ensure kinetics measurements are not confounded by mass transport limitations, we employed Weisz's modulus (Phi), which compares observed enzyme catalyzed reaction rates to characteristic substrate diffusion times. We characterized activity of CIAP immobilized in BPMA-PAAm gels in a reaction limited regime (Phi ? 0.15 for all measurements), allowing us to isolate the effect of immobilization on enzymatic activity. Immobilization of CIAP in BPMA PAAm gels produced a ~2* loss in apparent enzyme-substrate affinity (Km) and ~200* decrease in intrinsic catalytic activity (kcat) relative to in-solution measurements. As estimating Km and kcat requires multiple steps of data manipulation, we developed a computational approach (bootstrapping) to propagate uncertainty in calibration data through all data manipulation steps. Numerical simulation revealed that calibration error is only negligible when the normalized root-mean-squared error (NRMSE) in the calibration falls below 0.05%. Importantly, bootstrapping is independent of the mathematical model, and thus generalizable beyond enzyme kinetics studies. Furthermore, the measurement tool presented can be readily adapted to study other porous immobilization supports, facilitating rational design (immobilization method, geometry, enzyme loading) of immobilized-enzyme devices. PMID- 28858526 TI - Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations. AB - The diastereoselectivities and rates of epoxidation (upon treatment with Cl3CCO2H then m-CPBA) of a range of cis- and trans-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ? OH > NBn2), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it. PMID- 28858527 TI - Family-wide Analysis of the Inhibition of Arf Guanine Nucleotide Exchange Factors with Small Molecules: Evidence of Unique Inhibitory Profiles. AB - Arf GTPases and their guanine nucleotide exchange factors (ArfGEFs) are major regulators of membrane traffic and organelle structure in cells. They are associated with a variety of diseases and are thus attractive therapeutic targets for inhibition by small molecules. Several inhibitors of unrelated chemical structures have been discovered, which have shown their potential in dissecting molecular pathways and blocking disease-related functions. However, their specificity across the ArfGEF family has remained elusive. Importantly, inhibitory responses in the context of membranes, which are critical determinants of Arf and ArfGEF cellular functions, have not been investigated. Here, we compare the efficiency and specificity of four structurally distinct ArfGEF inhibitors, Brefeldin A, SecinH3, M-COPA, and NAV-2729, toward six ArfGEFs (human ARNO, EFA6, BIG1, and BRAG2 and Legionella and Rickettsia RalF). Inhibition was assessed by fluorescence kinetics using pure proteins, and its modulation by membranes was determined with lipidated GTPases in the presence of liposomes. Our analysis shows that despite the intra-ArfGEF family resemblance, each inhibitor has a specific inhibitory profile. Notably, M-COPA is a potent pan-ArfGEF inhibitor, and NAV-2729 inhibits all GEFs, the strongest effects being against BRAG2 and Arf1. Furthermore, the presence of the membrane-binding domain in Legionella RalF reveals a strong inhibitory effect of BFA that is not measured on its GEF domain alone. This study demonstrates the value of family-wide assays with incorporation of membranes, and it should enable accurate dissection of Arf pathways by these inhibitors to best guide their use and development as therapeutic agents. PMID- 28858528 TI - Phospho-Priming Confers Functionally Relevant Specificities for Rad53 Kinase Autophosphorylation. AB - The vast majority of in vitro structural and functional studies of the activation mechanism of protein kinases use the kinase domain alone. Well-demonstrated effects of regulatory domains or allosteric factors are scarce for serine/threonine kinases. Here we use a site-specifically phosphorylated SCD1 FHA1-kinase three-domain construct of the serine/threonine kinase Rad53 to show the effect of phospho-priming, an in vivo regulatory mechanism, on the autophosphorylation intermediate and specificity. Unphosphorylated Rad53 is a flexible monomer in solution but is captured in an asymmetric enzyme:substrate complex in crystal with the two FHA domains separated from each other. Phospho priming induces formation of a stable dimer via intermolecular pT-FHA binding in solution. Importantly, autophosphorylation of unprimed and phospho-primed Rad53 produced predominantly inactive pS350-Rad53 and active pT354-Rad53, respectively. The latter mechanism was also demonstrated in vivo. Our results show that, while Rad53 can display active conformations under various conditions, simulation of in vivo regulatory conditions confers functionally relevant autophosphorylation. PMID- 28858530 TI - Exploring asthma in the workplace: A triangulation of perspectives from management, employees and people with asthma. AB - OBJECTIVE: People with asthma spend a significant amount of time in the workplace but little is known about the current state of disease management in such contexts. The aim of the current study is to explore the experiences, attitudes and perceptions of asthma across different stakeholders in the workplace to help inform potential recommendations for workplace asthma policies. METHOD: Using purposive and convenience sampling methods, in-depth semi-structured interviews were conducted in Australia with 5 human resource personnel, 10 employees with asthma and 10 employees without asthma. Interviews were guided by a schedule of questions focusing on attitudes and experiences of people with asthma in the workplace, which were audio recorded, transcribed verbatim and thematically analysed. RESULTS: Analysis of the qualitative dataset revealed three key themes: Beliefs and Attitudes about Asthma, Asthma Solutions in the Workplace and Workplace Obstacles. Findings suggest that employees with asthma experience problems managing their asthma at work and there is a lack of workplace support in relation to asthma emergency management. CONCLUSION: Key recommendations for workplace asthma policies have been made to provide better support for employees with asthma. However, further investigation into the experience of managing asthma is required in a wider variety of occupations and work experiences to inform the development of a workplace asthma policy. PMID- 28858529 TI - Soft Substrates Containing Hyaluronan Mimic the Effects of Increased Stiffness on Morphology, Motility, and Proliferation of Glioma Cells. AB - Unlike many other cancer cells that grow in tumors characterized by an abnormally stiff collagen-enriched stroma, glioma cells proliferate and migrate in the much softer environment of the brain, which generally lacks the filamentous protein matrix characteristic of breast, liver, colorectal, and other types of cancer. Glial cell-derived tumors and the cells derived from them are highly heterogeneous and variable in their mechanical properties, their response to treatments, and their properties in vitro. Some glioma samples are stiffer than normal brain when measured ex vivo, but even those that are soft in vitro stiffen after deformation by pressure gradients that arise in the tumor environment in vivo. Such mechanical differences can strongly alter the phenotype of cultured glioma cells. Alternatively, chemical signaling might elicit the same phenotype as increased stiffness by activating intracellular messengers common to both initial stimuli. In this study the responses of three different human glioma cell lines to changes in substrate stiffness are compared with their responses on very soft substrates composed of a combination of hyaluronic acid and a specific integrin ligand, either laminin or collagen I. By quantifying cell morphology, stiffness, motility, proliferation, and secretion of the cytokine IL-8, glioma cell responses to increased stiffness are shown to be nearly identically elicited by substrates containing hyaluronic acid, even in the absence of increased stiffness. PI3-kinase activity was required for the response to hyaluronan but not to stiffness. This outcome suggests that hyaluronic acid can trigger the same cellular response, as can be obtained by mechanical force transduced from a stiff environment, and demonstrates that chemical and mechanical features of the tumor microenvironment can achieve equivalent reactions in cancer cells. PMID- 28858531 TI - An update on cladribine for relapsing-remitting multiple sclerosis. AB - INTRODUCTION: Despite recent progress, currently available therapies for relapsing remitting multiple sclerosis (MS) are only partly effective, and their use is limited by tolerability and safety issues, as well as high cost. Cladribine was originally rejected by the regulatory authorities in both the European Union and USA in 2011, but in June 2017 the European Medical Agency recommended marketing authorization for treatment of aggressive relapsing MS. Areas covered: We provide an update on chemistry, mechanism of action, efficacy and safety of cladribine for the treatment of MS. Expert opinion: Cladribine is well tolerated, it is dosed orally in cycles of one year, the need for regular blood testing during treatment is likely limited, and the two-year efficacy data for treatment of relapsing MS are at least in the same range as the most efficient licensed treatments. The increased risk of malignancies reported in the pivotal trial seems to be caused by unexpectedly low numbers of malignancies in the placebo group. Cladribine could therefore be an alternative for many patients with relapsing remitting MS. The main caveat is the lack of long term efficacy and safety data. Currently there are insufficient data to guide further treatment of patients who have completed two treatment cycles of cladribine. PMID- 28858532 TI - Tinnitus: still 'A Ghost in the Machine' or a Darwinian survival phenomenon? AB - INTRODUCTION: The causation of tinnitus continues to intrigue. Despite the plethora of publications there is no definitive path available to concentrate our efforts, in alleviating the symptom. Several mechanical theories are available in standard tinnitus literature with varying empiricism. Purpose/aim of the study: To investigate a possible way forward. MATERIALS AND METHODS: Employing a forensic methodology ("crime scene analysis" technique) and utilizing available evidence from the related sciences, inductive and abstract reasoning, a pragmatic model incorporating the known features of tinnitus is available. RESULTS: A plausible evolutionary explanation of the origins and functions for the causation of tinnitus is offered with a possible link to its evasive nature, in our search for a cause. CONCLUSION: The functional value of tinnitus may be provided by our evolutionary history. It is possible that tinnitus was a protective adaptive phenomenon in earlier forms but in our current environment merely contributes to nuisance value. PMID- 28858533 TI - Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome. AB - Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with acute respiratory distress syndrome (ARDS), and that these variants would alter MAP3K1-mediated changes in inflammation and transcriptional regulation. To test this hypothesis, we genotyped single-nucleotide polymorphisms covering linkage disequilibrium bins in MAP3K1 in 306 subjects with ARDS from the ARDSNet FACTT (Fluid and Catheter Treatment Trial) study, and tested for associations between MAP3K1 single-nucleotide polymorphisms and ventilator-free days (VFDs) and mortality. We then validated these associations in a separate cohort of 241 patients with ARDS from Harborview Medical Center (Seattle, WA). We found the variant allele of rs832582 (MAP3K1906Val) was significantly associated with decreased VFDs using multivariate linear regression (-6.1 d, false discovery rate = 0.06) in the FACTT cohort. In the Harborview Medical Center cohort, subjects homozygous for MAP3K1906Val also had decreased VFDs (-15.1 d, false discovery rate < 0.01), and increased 28-day mortality (all subjects homozygous for the rare allele died). In whole blood stimulated with various innate immune agonists ex vivo, MAP3K1906Val was associated with increased IL-1beta, IL-6, IL 8, monocyte chemoattractant protein 1, and TNF-alpha production. Transcriptome analysis of whole blood stimulated with Toll-like receptor 4 agonist ex vivo demonstrated enrichment of inflammatory gene sets in subjects homozygous for MAP3K1906Val. Our findings show a robust association between the variant allele of rs832582 (MAP3K1906Val) and decreased VFDs in patients with ARDS and suggest that this variant may predispose individuals to a greater inflammatory response. PMID- 28858534 TI - Comments on "The Diagnostic Utility and Clinical Implications of Wrist MRI in the Pediatric Population". PMID- 28858535 TI - Implementation of Surgeon-Initiated Gene Expression Profile Testing (Onco type DX) Among Patients With Early-Stage Breast Cancer to Reduce Delays in Chemotherapy Initiation. AB - PURPOSE: Delays to adjuvant chemotherapy initiation in breast cancer may adversely affect clinical outcomes and patient satisfaction. We previously identified an association between genomic testing (Onco type DX) and delayed chemotherapy initiation. We sought to reduce the interval between surgery and adjuvant chemotherapy initiation by developing standardized criteria and workflows for Onco type DX testing. METHODS: Criteria for surgeon-initiated reflex Onco type DX testing, workflows for communication between surgeons and medical oncologists, and a streamlined process for receiving and processing Onco type DX requests in pathology were established by multidisciplinary consensus. Criteria for surgeon-initiated testing included patients <= 65 years old with T1cN0 (grade 2 or 3), T2N0 (grade 1 or 2), or T1/T2N1 (grade 1 or 2) breast cancer on final surgical pathology. Medical oncologists could elect to initiate Onco type testing for cases falling outside the criteria. We then examined 720 consecutive patients with breast cancer who underwent Onco type DX testing postoperatively between January 1, 2014 and November 28, 2016 and measured intervals between date of surgery, Onco type DX order date, result received date, and chemotherapy initiation date (if applicable) before and after intervention implementation. RESULTS: The introduction of standardized criteria and workflows reduced time between surgery and Onco type DX ordering, and time from surgery to receipt of result, by 7.3 days ( P < .001) and 6.3 days ( P < .001), respectively. The mean number of days between surgery and initiation of chemotherapy was also reduced by 6.4 days ( P = .004). CONCLUSION: Developing consensus on Onco type DX testing criteria and implementing streamlined workflows has led to clinically significant reductions in wait times to chemotherapy decision making and initiation. PMID- 28858537 TI - Anti-inflammatory treatments for mood disorders: Systematic review and meta analysis. AB - BACKGROUND: Recent studies suggest that anti-inflammatory medication may play a role in the treatment of mood disorders. AIMS: The purpose of this study was to determine the efficacy of anti-inflammatory drugs in patients with major depressive disorder and bipolar disorder. METHOD: The Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO and Clinicaltrials.gov were searched from inception until 15 April 2017 for completed and on-going randomized controlled trials of anti-inflammatory agents for major depressive disorder and bipolar disorder. Data from randomized controlled trials assessing the antidepressant and anti-manic effect of adjunctive mechanistically diverse anti inflammatory agents were pooled to determine standard mean differences (SMDs) compared with placebo and/or treatment as usual. RESULTS: Patients receiving anti inflammatory agents showed lower post-treatment depressive symptom scores compared with those receiving placebo with a standard mean difference of -0.71 (six randomized controlled trials, n=214, 95% CI -1.24 to -0.17, p=0.009). Anti inflammatory treatment was found to reduce post-treatment manic symptom scores with a standard mean difference of -0.72 (three randomized controlled trials, n=96, 95% CI -1.31 to -0.13, p=0.02). Anti-inflammatories did not show a statistically significant improvement in the secondary outcome measure (change in symptom scores from baseline to outcome). CONCLUSIONS: Further high quality trials are needed before making recommendations for the routine clinical use of anti-inflammatories in the treatment of mood disorders. PMID- 28858538 TI - Screening for Transplant Renal Artery Stenosis: Ultrasound-Based Stenosis Probability Stratification. AB - OBJECTIVE: The objective of our study was to evaluate which spectral Doppler ultrasound parameters are useful in patients with clinical concern for transplant renal artery stenosis (TRAS) and create mathematically derived prediction models that are based on these parameters. MATERIALS AND METHODS: The study subjects included 120 patients with clinical signs of renal dysfunction who had undergone ultrasound followed by angiography (either digital subtraction angiography or MR angiography) between January 2005 and December 2015. Five ultrasound variables were evaluated: ratio of highest renal artery velocity to iliac artery velocity, highest renal artery velocity, spectral broadening, resistive indexes, and acceleration time. Angiographic studies were categorized as either showing no stenosis or showing stenosis. Reviewers assessed the ultrasound examinations for TRAS using all five variables, which we refer to as the full model, and using a reduced number of variables, which we refer to as the reduced-variable model; sensitivities and specificities were generated. RESULTS: Ninety-seven patients had stenosis and 23 had no stenosis. The full model had a sensitivity and specificity of 97% and 91%, respectively. The reduced-variable model excluded the ratio and resistive index variables without affecting sensitivity and specificity. We applied cutoff values to the variables in the reduced-variable model, which we refer to as the simple model. Using these cutoff values, the simple model showed a sensitivity and specificity of 96% and 83%. The simple model was able to categorize patients into four risk categories for TRAS: low, intermediate, high, and very high risk. CONCLUSION: We propose a simple model that is based on highest renal artery velocity, distal spectral broadening, and acceleration time to classify patients into risk categories for TRAS. PMID- 28858539 TI - Radiographic Findings of Distressed Venous Stents and Inferior Vena Cava Filters: Clinical Implications. AB - OBJECTIVE: The objective of our study was to describe an association between the radiographic appearance of distressed intravascular implants and venous stenosis or occlusion and to determine the success of reparative endovascular procedures. MATERIALS AND METHODS: Seventy-eight patients with distressed stents or inferior vena cava (IVC) filters characterized by pursing (short-axis contracture), straightening, longitudinal contraction (long-axis contracture), or fracture were identified from retrospective review of a venous registry for the period from February 2004 to October 2016. Patients originally presented with superior vena cava (SVC) syndrome (n = 25), arm swelling (n = 16), iliocaval thrombosis (n = 21), and lower extremity deep venous thrombosis (n = 16), and stents were initially placed in 65 and filters in 13. Implants were located in the IVC (n = 24), subclavian vein (n = 16), brachiocephalic vein (n = 15), common iliac vein (n = 10), multiple veins (n = 4), axillary vein (n = 4), common femoral vein (n = 3), SVC (n = 1), and internal jugular vein (n = 1). Implants included Wallstents in 63 patients; Smart stents in two patients; and Celect Platinum, Denali, Greenfield, and Trapease IVC filters in two, three, two, and six patients, respectively. Venographic indication, distress type, time from initial normal placement to identification of distress, venographic finding (patent, mild stenosis, high-grade stenosis, or occlusion), treatment, revascularization outcome, and complications were recorded. RESULTS: The mean time to distress was 23 months. Fifty-two (67%) patients underwent venography for symptoms and 26 (33%) for surveillance. Forty-five (58%) implants were pursed; 19 (24%), straightened; nine (12%), contracted; and five (6%), fractured. Venography depicted 48 (62%) high-grade stenoses, 19 (24%) complete occlusions, and six (8%) mild stenoses. Of the 73 patients who underwent an intervention, 29 (40%) underwent angioplasty, 15 (21%) underwent angioplasty and stenting, 15 (21%) underwent sharp recanalization, and five (7%) underwent thrombolysis. Revascularization was successful in 67 (92%). Three minor complications occurred. CONCLUSION: Distressed intravascular implants are associated with high-grade venous stenosis or occlusion. Reparative interventions are usually technically successful. PMID- 28858540 TI - Isolated Main Pancreatic Duct Dilatation: CT Differentiation Between Benign and Malignant Causes. AB - OBJECTIVE: The purpose of this study is to retrospectively evaluate the differential CT features of isolated benign and malignant main pancreatic duct (MPD) dilatation and to investigate whether the diagnostic performance of radiologists can be improved with knowledge of these differential CT features. MATERIALS AND METHODS: Forty-one patients who had isolated MPD dilatation without any visible mass on CT from January 2000 to October 2016 were retrospectively enrolled in the study. Two radiologists reviewed CT images in consensus for the location, shape (smooth vs abrupt), length of transition, dilated pancreatic duct (PD) diameter, presence of duct penetrating sign, parenchymal atrophy, attenuation difference, associated pancreatitis, calcification, PD or common bile duct (CBD) enhancement, and perilesional cyst. The chi-square test, Fisher exact test, and t test were used to find the differential CT features of benign and malignant MPD dilatation. Two successive review sessions for differentiation between the two disease entities were then independently performed by three other reviewers with differing expertise, with the use of a 5-point confidence scale. The first session provided no information for differentiation; however, reviewers were aware of the results of univariate analyses in the second session. The diagnostic performance of the radiologists was evaluated using a pairwise comparison of ROC curves. RESULTS: A total of 19 benign and 22 malignant MPD dilatations were identified. In patients with benign MPD dilatation, transition areas were frequently located in the head (57.9% [11/19] vs 13.6% [3/22], p = 0.003) and showed significantly shorter (< 6.1 mm) (78.9% [15/19] vs 9.1% [2/22], p < 0.0001) and smooth transition (89.5% [17/19] vs 9.1% [2/22], p < 0.0001). Duct penetrating sign was exclusively observed in patients with benign MPD dilatation (73.7% [14/19] vs 0% [0/22], p < 0.0001). In contrast, malignant MPD dilatation frequently was accompanied by attenuation difference (63.6% [14/22] vs 10.5% [2/19], p = 0.001) and associated PD or CBD enhancement (36.4% [8/22] vs 0% [0/19], p = 0.003). The AUC values of three reviewers significantly increased from 0.653, 0.587, and 0.884 to 0.864, 0.964, and 0.908, respectively, with knowledge of significant CT features (p = 0.013, p < 0.0001, and p = 0.701, respectively). CONCLUSION: Distal, long (>= 6.1 mm), and abrupt transition, the absence of duct penetrating sign, and the presence of attenuation difference and PD or CBD enhancement were highly suggestive CT findings for differentiation of malignant from benign MPD dilatation. The diagnostic performance of radiologists with regard to differentiation was significantly improved with knowledge of these highly suggestive CT criteria. PMID- 28858541 TI - Risk Stratification Among Men With Prostate Imaging Reporting and Data System version 2 Category 3 Transition Zone Lesions: Is Biopsy Always Necessary? AB - OBJECTIVE: The objective of our study was to determine the clinical and MRI characteristics of clinically significant prostate cancer (PCA) (Gleason score >= 3 + 4) in men with Prostate Imaging Reporting and Data System version 2 (PI RADSv2) category 3 transition zone (TZ) lesions. MATERIALS AND METHODS: From 2014 to 2016, 865 men underwent prostate MRI and MRI/ultrasound (US) fusion biopsy (FB). A subset of 90 FB-naive men with 96 PI-RADSv2 category 3 TZ lesions was identified. Patients were imaged at 3 T using a body coil. Images were assigned a PI-RADSv2 category by an experienced radiologist. Using clinical data and imaging features, we performed univariate and multivariate analyses to identify predictors of clinically significant PCA. RESULTS: The mean patient age was 66 years, and the mean prostate-specific antigen density (PSAD) was 0.13 ng/mL2. PCA was detected in 34 of 96 (35%) lesions, 14 of which (15%) harbored clinically significant PCA. In univariate analysis, DWI score, prostate volume, and PSAD were significant predictors (p < 0.05) of clinically significant PCA with a suggested significance for apparent diffusion coefficient (ADC) and prostate specific antigen value (p < 0.10). On multivariate analysis, PSAD and lesion ADC were the most important covariates. The combination of both PSAD of 0.15 ng/mL2 or greater and an ADC value of less than 1000 mm2/s yielded an AUC of 0.91 for clinically significant PCA (p < 0.001). If FB had been restricted to these criteria, only 10 of 90 men would have undergone biopsy, resulting in diagnosis of clinically significant PCA in 60% with eight men (9%) misdiagnosed (false negative). CONCLUSION: The yield of FB in men with PI-RADSv2 category 3 TZ lesions for clinically significant PCA is 15% but significantly improves to 60% (AUC > 0.9) among men with PSAD of 0.15 ng/mL2 or greater and lesion ADC value of less than 1000 mm2/s. PMID- 28858542 TI - Detection of Myocardial Infarction Using Delayed Enhancement Dual-Energy CT in Stable Patients. AB - OBJECTIVE: The objective of our study was to explore whether delayed enhancement dual-energy CT (DECT) allows the detection of myocardial infarcts in stable patients. SUBJECTS AND METHODS: Patients with known or suspected coronary artery disease clinically referred for myocardial perfusion imaging using SPECT were prospectively included. All patients (n = 34) also underwent stress, rest, and delayed enhancement DECT on a DECT scanner. At SPECT, segments with myocardial infarction (MI) were defined as those with a summed rest score of >= 2 in two or more consecutive segments, and a diagnosis of MI was supported by wall motion abnormalities, clinical history, and ECG findings. RESULTS: Segments with MI were identified in 13 (38%), 15 (44%), and 14 (41%) patients using SPECT, perfusion CT, and delayed enhancement DECT, respectively. When combined SPECT and perfusion CT results were used as the reference standard, delayed enhancement DECT had a sensitivity, specificity, positive predictive value, and negative predictive value for the detection of MI of 91.7% (95% CI, 62-98%), 86.4% (95% CI, 65-97%), 78.6% (95% CI, 49-95%), and 95.0% (95% CI, 75-100%). At delayed enhancement DECT (40 keV), a signal attenuation higher than 161 HU had a sensitivity of 72% and a specificity of 79% for the detection of MI on a per-segment basis. The median signal attenuation of myocardial infarcts at 40 keV was 3.0 SDs (interquartile range, 1.3-4.0 SDs) above that of normal myocardium. CONCLUSION: In this study, delayed enhancement DECT allowed the detection of myocardial infarcts in stable patients. PMID- 28858543 TI - Differentiation of Acute Osteoporotic and Malignant Vertebral Fractures by Quantification of Fat Fraction With a Dixon MRI Sequence. AB - OBJECTIVE: The purpose of this study was to differentiate malignant compression fractures from acute osteoporotic compression fractures of the spine by use of a Dixon MRI sequence to quantify fat fraction (FF). MATERIALS AND METHODS: Forty four vertebral compression fractures were assessed with turbo spin-echo T1 weighted and six-echo Dixon sequences for FF quantification at 3-T MRI. The fractures were divided into malignant compression fractures (n = 24) and acute osteoporotic compression fractures (n = 20). Two radiologists independently measured quantitative parameters from ROIs in the fractures, including the T1 signal intensity of the fracture, the FF of the fracture, and the FF ratio (fracture FF divided by normal marrow FF). The mean values of the parameters were compared between the two groups, interobserver reliability between two radiologists was assessed, ROC curves were analyzed, and logistic regression analysis was performed. RESULTS: The fracture FF and FF ratio of malignant compression fractures were significantly lower than those of acute osteoporotic compression fractures (fracture FF, 2.73% vs 14.36% [p < 0.001]; FF ratio, 0.05 vs 0.22 [p < 0.001]). There was no difference in T1 signal intensity of the fracture. The ROC AUC of fracture FF was 0.98 and of FF ratio was 0.95. In logistic regression analysis, fracture FF remained a significant variable that could be used to independently differentiate malignant from acute osteoporotic compression fractures (odds ratio, 0.33; p < 0.005). CONCLUSION: FF and FF ratio obtained from FF maps obtained with a six-echo Dixon MRI sequence may be useful for differentiating acute osteoporotic compression fractures from malignant compression fractures. PMID- 28858544 TI - Evaluation of Selective Bundle Injury to the Anterior Cruciate Ligament: T2 Weighted Fast Spin-Echo 3-T MRI With Reformatted 3D Oblique Isotropic (VISTA) Versus 2D Technique. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic utility of oblique sagittal and oblique coronal 3D volume isotropic turbo spin-echo acquisition (VISTA) images with that of 2D fast spin-echo (FSE) T2-weighted images in the diagnosis of selective bundle tears of the anterior cruciate ligament (ACL). MATERIALS AND METHODS: This retrospective study included 56 patients who underwent 2D FSE and 3D VISTA 3-T MRI of the knee before arthroscopic procedures. Images obtained with the two sequences were interpreted by two musculoskeletal radiologists independently, and the results were analyzed with the surgical diagnosis as the reference. RESULTS: Among the 56 patients with suspected ACL injury, the arthroscopic records revealed 14 cases (25%) of complete tear, four cases (7%) of selective posterolateral bundle tear, and three cases (5%) of selective anteromedial bundle tear. The contrast-to-noise ratio between the ACL and joint fluid for 3D VISTA was 1.97 times as high as that for 2D FSE (p < 0.001). The entire width evaluation and margin sharpness scores for 2D FSE were significantly higher than those for 3D VISTA for both readers (p < 0.05). No significant differences were found in sensitivity, specificity, or accuracy of 2D FSE and 3D VISTA in the diagnosis of selective ACL tears (p > 0.05). CONCLUSION: The diagnostic utility of oblique sagittal and oblique coronal 3D VISTA sequences was similar to that of 2D FSE sequences in the MRI diagnosis of selective bundle tear of the ACL, but the image quality of 3D VISTA was inferior to that of 2D FSE. PMID- 28858545 TI - MRI of the Extensor Tendons of the Wrist. AB - OBJECTIVE: This article reviews the normal anatomy of the extensor tendons of the wrist as well as the clinical presentation and MRI appearances of common tendon abnormalities, such as tears, tenosynovitis, intersection syndromes, and associated or predisposing osseous findings. Treatment options are also discussed. CONCLUSION: We review the anatomy and normal MRI appearance of the clinically important dorsal extensor tendons of the wrist, in addition to the spectrum of abnormalities associated with these tendons. PMID- 28858546 TI - Opioid Use Disorder in Dental Patients: The Latest on How to Identify, Treat, Refer and Apply Laws and Regulations in Your Practice. AB - Opioid use disorder is a persistent problem in the United States and has become an important issue to medical and dental professionals. Americans are the largest users of opioids by a large margin. The importance of knowing how to identify, handle, refer, and treat patients with opioid use disorder cannot be understated. This article attempts to educate dental professionals on the current epidemiology of opioid use, explain the physiology of addiction, teach practitioners how to identify chronic opioid users, gives options for treating dental pain, establishes criteria for referring to an addiction specialist, and describes the laws, regulations, and resources available to practitioners. With this article, practitioners should have a greater understanding of the current problem of opioid use disorder and be able to develop a protocol for treating these patients. PMID- 28858536 TI - Serotonin and brain function: a tale of two receptors. AB - Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5 HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5 HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain's default response to adversity but that an improved ability to change one's situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important - and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5 HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes. PMID- 28858547 TI - Junctional Rhythm Preoperatively and During General Anesthesia for Oral and Maxillofacial Surgery. AB - We report a case of junctional rhythm that occurred both preoperatively and later during a portion of general anesthesia. A 19-year-old woman was scheduled to undergo bilateral sagittal split ramus osteotomy after being diagnosed with a jaw deformity. Preoperative electrocardiography (ECG) revealed a junctional rhythm with a slow heart rate (HR). At 90 minutes after anesthesia induction, local anesthesia with 10 mL of 1% lidocaine and 1:100,000 adrenaline was administered. A junctional rhythm appeared 15 minutes after the local anesthesia. We believe that the atrioventricular nodal pacemaker cells accelerated because of the increased sympathetic activity due to the adrenaline. On the preoperative ECG, the junctional rhythm with slow HR appeared as an escaped beat caused by slowing of the primary pacemaker. Therefore, we think that the preoperative junctional rhythm and the junctional rhythm that appeared during general anesthesia were due to different causes. Understanding the cause of a junctional rhythm could lead to more appropriate treatment. We therefore believe that identifying the cause of the junctional rhythm is important in anesthetic management. PMID- 28858548 TI - Squamous Papilloma Causing Airway Obstruction During Conscious Sedation. AB - Monitoring for respiratory depression is essential during conscious sedation. We report a case of a squamous papilloma as an unusual cause of intermittent partial airway obstruction in a 43-year-old man undergoing intravenous conscious sedation with midazolam. The Integrated Pulmonary Index (IPI) is an algorithm included in some commercially available monitors that constitutes a representation of 4 parameters: end-tidal carbon dioxide, respiratory rate, oxygen saturation, and pulse rate. We discuss the potential of the IPI as a monitoring tool during sedation. PMID- 28858549 TI - Submental Intubation in Cases of Panfacial Fractures: A Retrospective Study. AB - Surgical treatment of panfacial fractures usually requires intraoperative temporary occlusion of the teeth and simultaneous access to the nasal pyramid. In such cases, the standard method of airway management is to perform a tracheostomy, but this may be associated with a significant number of perioperative and late complications. This study aimed to determine if submental endotracheal intubation (SEI) is a viable alternative to tracheostomy, especially when short-term postoperative control of the airway is foreseen. This was an observational retrospective study, carried out between 2012 and 2014, which involved 32 consecutive patients who sustained panfacial fractures and were surgically treated during a 3-year period in a level I trauma center hospital. Only those who required SEI were included in the sample. Four cases were excluded because of incomplete registries, follow-up period less than 4 months after hospital discharge, or other unrelated complications. The medical charts of all patients involved in the sample were carefully reviewed in order to qualify and quantify perioperative and postoperative complications related to anesthetic management. We hypothesized that SEI would not interfere with the surgical procedures and would present less morbidity and reduced complication rates. Twenty-eight patients, 24 male and 4 female, met all the inclusion criteria. The mean age was 29.5 +/- 9.05 years (range, 18-56 years). The mean duration time of surgery was 8.07 +/- 4.0 hours (range, 4-16 hours). There were no perioperative complications. Postoperatively, only 1 patient (3.57%) experienced a cutaneous infection at the submental region, which was easily treated. Additionally, only 1 case (3.57%) of hypertrophic scar was reported. SEI appears to be a safe, simple, and effective technique of immediate perioperative airway management in selected cases of panfacial fractures. PMID- 28858550 TI - Preemptive Effect of Dexamethasone in Third-Molar Surgery: A Meta-Analysis. AB - The aim of the present study was to assess the effectiveness of preemptive dexamethasone in surgery of the lower third molars and to compare it with other oral anti-inflammatories. An electronic search was conducted for preemptive effects related to lower third-molar surgery in 3 separate databases. The variables pain, swelling, and trismus were assessed. Meta-analysis was used to calculate the pooled effect measures for mean and standard deviation values (95% confidence interval [CI]). Seven split-mouth clinical trials were selected. Two studies were included in the meta-analysis. Three studies showed a low risk of bias; 2 studies exhibited a moderate risk and 2 a high risk of bias. Dexamethasone was better than nonsteroidal anti-inflammatories for preemptive effectiveness. Meta-analysis for swelling confirmed better results for dexamethasone than for methylprednisolone after 2 days (95% CI = -1.28 to -0.38), 4 days (95% CI = -1.65 to -0.71), 7 days (95% CI = -1.42 to -0.71), and overall (95% CI = -1.25 to -0.72). Dexamethasone was better than methylprednisolone for mouth opening after 4 days (95% CI = 0.18 to 1.07). There is insufficient evidence through meta-analysis to conclude that dexamethasone is better than other nonsteroidal anti-inflammatories or methylprednisolone as a preemptive analgesic. The results of this meta-analysis suggest that dexamethasone is more effective than methylprednisolone for swelling and trismus. PMID- 28858551 TI - The Anesthetic Management for a Patient With Trisomy 13. AB - Trisomy 13 is a chromosomal disorder that occurs in complete or partial mosaic forms. It is characterized by central apnea, mental retardation, seizure and congenital heart disease. The survival of the patients with trisomy 13 is the majority dying before one month. Trisomy 13 is the worst life prognosis among all trisomy syndromes. It is reported the cause of death is central apnea. Special needs patients with mental retardation are recognized to have poorer oral health condition. Oral health related quality of life reflects daily activity and well being. Dental treatment under general anesthesia is sometimes an option for such patients. This patient had received ventricular septal defect closure surgery at 2-year-old. In addition, he had mental retardation and seizure. Dental treatment had been completed without any cerebral and cardiovascular events under non invasive monitoring with not only cardiac electric velocimetry, but also epileptogenic activity. In addition, postoperative respiratory condition was maintained stable in room air. PMID- 28858552 TI - Nitrous Oxide Inhalation Sedation Through a Nasal High-Flow System: The Possibility of a New Technique in Dental Sedation. AB - High-flow nasal cannula (HFNC) systems are increasingly used for patients with both acute and chronic respiratory failure because of the clinical effectiveness and patient comfort associated with their use. Recently, HFNC has been used not only as a respiratory support device, but also as a drug delivery system. HFNC is designed to administer heated and humidified inspiratory oxygen flows (100% relative humidity at 37 degrees C). Therefore, HFNC can provide high flows (up to 60 L/min) without discomfort. Moreover, HFNC improves oxygenation by exerting physiologic effects such as (a) dead-space washout and (b) moderate positive airway pressure. These characteristics and physiologic effects of HFNC may permit administration of high-flow nitrous oxide sedation while ensuring patient comfort and adequate sedative effect. PMID- 28858553 TI - Liposomal Bupivacaine Use in Third Molar Impaction Surgery: INNOVATE Study. AB - The analgesic efficacy and safety of liposomal bupivacaine (LB) in third molar extraction was evaluated in this phase 3, double-blind, placebo-controlled study of subjects undergoing bilateral third molar extraction. Subjects were randomized 2 : 1 to infiltration with LB (133 mg/10 mL) or placebo, and received opioid rescue medication as needed. Primary efficacy measure was cumulative area under the curve (AUC) of numeric rating scale (NRS) pain severity scores through 48 hours (AUC of NRS0-48) postsurgery. Other measures included AUC of NRS0-24, AUC of NRS0-72, and AUC of NRS0-96, and incidence of adverse events. There were 150 subjects in the primary efficacy population (n = 99 LB, n = 51 placebo) and 89 in the per-protocol population (n = 59 LB, n = 30 placebo). Least-squares mean for AUC of NRS0-48 was 172.3 LB versus 194.7 placebo (P = .227) in the primary efficacy population and 120.8 LB versus 183.3 placebo (P = .023) in the per protocol population. At all time points, between-group differences in AUC of NRS scores were significant in the per-protocol population (LB lower than placebo, P < .05) but not in the primary efficacy population. The adverse event profile was similar between groups. LB produced significantly lower cumulative pain scores versus placebo at all time points in the per-protocol analysis but not in the primary efficacy analysis because of protocol violations. This study indicates significant improvement in pain scores in the third molar model, but because of extensive protocol violations additional studies are warranted to demonstrate effectiveness. PMID- 28858555 TI - A Review of Current Literature of Interest to the Office-Based Anesthesiologist. PMID- 28858554 TI - Office-Based Anesthesia: Safety and Outcomes in Pediatric Dental Patients. AB - The number of children with caries requiring general anesthesia to achieve comprehensive dental care and the demand for dentist anesthesiologists to provide ambulatory anesthesia for these patients is increasing. No current published studies examine the safety and outcomes of ambulatory anesthesia performed by dentist anesthesiologists for dental procedures in pediatric patients, and there is no national requirement for reporting outcomes of these procedures. In 2010, the Society for Ambulatory Anesthesia Clinical Outcomes Registry was developed. This Web-based database allows providers of ambulatory anesthesia to track patient demographics and various outcomes of procedures. Our study is a secondary analysis of data collected in the registry over a 4-year period, 2010-2014. Of the 7041 cases reviewed, no cases resulted in serious complications, including death, anaphylaxis, aspiration, cardiovascular adverse events, or neurologic adverse events. Of the 7041 cases reviewed, 196 (3.0%) resulted in a predischarge or postdischarge adverse event. The predischarge adverse event occurring with the highest frequency was laryngospasm, occurring in 35 cases (0.50%). The postdischarge adverse event occurring with the highest frequency was nausea, reported by 99 patients (5.0%). This study provides strong clinical outcomes data to support the safety of office-based anesthesia as performed by dentist anesthesiologists in the treatment of pediatric dental patients. PMID- 28858556 TI - A Case With Deteriorating Palmoplantar Pustulosis and Hyperthyroidism After Simultaneous Bimaxillary Orthognathic Surgery. AB - A case of palmoplantar pustulosis and hyperthyroidism following orthognathic surgery is presented. Both diseases may have been related to allergic phenomena. PMID- 28858557 TI - Inner Wall Detachment of the Spiral Tube During Extubation: A Case Report. AB - We report a case of endotracheal tube malfunction, in which the inner surface of the tube peeled off during anesthesia. The patient, a 7-year-old boy, was under general anesthesia for the treatment of multiple dental caries. The damaged tube could have caused respiratory failure, putting the patient's life at risk. We speculate that the use of nitrous oxide was one of the contributing factors to the inner wall detachment. Several additional lessons can be learned from this incident in order to prevent tube-related trouble during an operation. PMID- 28858558 TI - Presidential Address: Parasitism and the Discovery of Veiled Secrets. PMID- 28858560 TI - Facultative Parasitism by the Bivalve Kurtiella pedroana in the Mole Crab Emerita analoga. AB - Evolutionary transitions to parasitism are rare. In this study, we documented a potential step toward parasitism in the commensal clam Kurtiella pedroana (Bivalvia: Galeommatoidea). Galeommatoideans are known commensals of various invertebrates, including crustaceans. Emerita analoga (Decapoda: Hippidae) is an abundant intertidal mole crab inhabiting Pacific coast beaches in North and South America. Mole crabs collected from Monterey Bay, California, were measured and examined externally and internally for associated molluscs. Out of the 520 mole crabs, 37 large female individuals harbored 49 clams (prevalence of 7.11% and mean intensity of 1.3). Forty-one ectocommensal clams were attached by their byssal threads to the inside of the gill chambers or to the lateroventral surfaces. However, our key finding was 8 clams that lacked byssal threads and were living in the hemocoel of 6 crabs. These internal clams were smaller than the ectocommensals. Because these internal clams lacked access to their normal food, we hypothesize they might have fed on hemolymph as would a parasite. Clam larvae have no obvious exit from the hemocoel, implying that endoparasitism is a dead-end for K. pedroana. Regardless, facultative parasitism in a free-living or an ectocommensal is uncommon and suggests a pathway to parasitism. PMID- 28858559 TI - More Is Meaningful: The Magnitude Effect in Intertemporal Choice Depends on Self Control. AB - Impulsivity is a variable behavioral trait that depends on numerous factors. For example, increasing the absolute magnitude of available choice options promotes farsighted decisions. We argue that this magnitude effect arises in part from differential exertion of self-control as the perceived importance of the choice increases. First, we demonstrated that frontal executive-control areas were more engaged for more difficult decisions and that this effect was enhanced for high magnitude rewards. Second, we showed that increased hunger, which is associated with lower self-control, reduced the magnitude effect. Third, we tested an intervention designed to increase self-control and showed that it reduced the magnitude effect. Taken together, our findings challenge existing theories about the magnitude effect and suggest that visceral and cognitive factors affecting choice may do so by influencing self-control. PMID- 28858561 TI - Differential losses to follow-up that are outcome-dependent can vitiate a clinical trial: Simulation results. AB - Loss to follow-up (LTFU) in clinical trials represents a potential threat to their soundness that may not be adequately recognized. We consider a log-rank test in a trial with two arms, experimental and control, and with a single unfavorable binary endpoint such as death. Commonly, one applies censoring to patients with LTFU. That approach is valid if LTFU is independent of outcome, but can lead to bias otherwise. Unfortunately, there is no statistical test for independence, so the legitimacy of the approach rests on unverifiable assumptions. For two cases, we evaluate the impact of the approach based on simulations that use reasonable models for outcome-dependent LTFU. In each case, LTFU in one arm disproportionately suppresses recognition of relatively early deaths or other outcomes, thus producing bias favoring that arm. The first case has extra LTFU in the experimental arm and the treatment has no benefit. The second case has extra LTFU in the control arm and the treatment is effective. The simulation results show severe inflation of Type I error in the first case and major loss of power in the second case. Remedies for LTFU are scarce but include avoiding it in the first place where possible. PMID- 28858562 TI - Evaluation of Kidney Stones with Reduced-Radiation Dose CT: Progress from 2011 2012 to 2015-2016-Not There Yet. AB - Purpose To determine if the use of reduced-dose computed tomography (CT) for evaluation of kidney stones increased in 2015-2016 compared with that in 2011 2012, to determine variability in radiation exposure according to facility for this indication, and to establish a current average radiation dose for CT evaluation for kidney stones by querying a national dose registry. Materials and Methods This cross-sectional study was exempt from institutional review board approval. Data were obtained from the American College of Radiology dose registry for CT examinations submitted from July 2015 to June 2016. Study descriptors consistent with single-phase unenhanced CT for evaluation of kidney stones and associated RadLex(r) Playbook identifiers (RPIDs) were retrospectively identified. Facilities actively submitting data on kidney stone-specific CT examinations were included. Dose metrics including volumetric CT dose index, dose length product, and size-specific dose estimate, when available, were reported, and a random effects model was run to account for clustering of CT examinations at facilities. A z-ratio was calculated to test for a significant difference between the proportion of reduced-radiation dose CT examinations (defined as those with a dose-length product of 200 mGy . cm or less) performed in 2015-2016 and the proportion performed in 2011-2012. Results Three hundred four study descriptors for kidney stone CT corresponding to data from 328 facilities that submitted 105 334 kidney stone CT examinations were identified. Reduced-dose CT examinations accounted for 8040 of 105 334 (7.6%) CT examinations, a 5.6% increase from the 1010 of 49 903 (2%) examinations in 2011-2012 (P < .001). Mean overall dose-length product was 689 mGy . cm (95% confidence interval: 667, 712), decreased from the mean of 746 mGy . cm observed in 2011-2012. Median facility dose-length product varied up to sevenfold, from less than 200 mGy . cm to greater than 1600 mGy . cm. Conclusion Use of reduced-radiation dose CT for evaluation of kidney stones has increased since 2011-2012, but remains low; variability of radiation dose according to facility continues to be wide. National mean CT radiation exposure for evaluation of renal colic during 2015 2016 decreased relative to 2011-2012 values, but remained well above what is reasonably achievable. (c) RSNA, 2017. PMID- 28858563 TI - Imaging Human Brain Perfusion with Inhaled Hyperpolarized 129Xe MR Imaging. AB - Purpose To evaluate the feasibility of directly imaging perfusion of human brain tissue by using magnetic resonance (MR) imaging with inhaled hyperpolarized xenon 129 (129Xe). Materials and Methods In vivo imaging with 129Xe was performed in three healthy participants. The combination of a high-yield spin-exchange optical pumping 129Xe polarizer, custom-built radiofrequency coils, and an optimized gradient-echo MR imaging protocol was used to achieve signal sensitivity sufficient to directly image hyperpolarized 129Xe dissolved in the human brain. Conventional T1-weighted proton (hydrogen 1 [1H]) images and perfusion images by using arterial spin labeling were obtained for comparison. Results Images of 129Xe uptake were obtained with a signal-to-noise ratio of 31 +/- 9 and demonstrated structural similarities to the gray matter distribution on conventional T1-weighted 1H images and to perfusion images from arterial spin labeling. Conclusion Hyperpolarized 129Xe MR imaging is an injection-free means of imaging the perfusion of cerebral tissue. The proposed method images the uptake of inhaled xenon gas to the extravascular brain tissue compartment across the intact blood-brain barrier. This level of sensitivity is not readily available with contemporary MR imaging methods. (c)RSNA, 2017. PMID- 28858564 TI - Atherosclerotic Plaque Tissue: Noninvasive Quantitative Assessment of Characteristics with Software-aided Measurements from Conventional CT Angiography. AB - Purpose To (a) evaluate whether plaque tissue characteristics determined with conventional computed tomographic (CT) angiography could be quantitated at higher levels of accuracy by using image processing algorithms that take characteristics of the image formation process coupled with biologic insights on tissue distributions into account by comparing in vivo results and ex vivo histologic findings and (b) assess reader variability. Materials and Methods Thirty-one consecutive patients aged 43-85 years (average age, 64 years) known to have or suspected of having atherosclerosis who underwent CT angiography and were referred for endarterectomy were enrolled. Surgical specimens were evaluated with histopathologic examination to serve as standard of reference. Two readers used lumen boundary to determine scanner blur and then optimized component densities and subvoxel boundaries to best fit the observed image by using semiautomatic software. The accuracy of the resulting in vivo quantitation of calcification, lipid-rich necrotic core (LRNC), and matrix was assessed with statistical estimates of bias and linearity relative to ex vivo histologic findings. Reader variability was assessed with statistical estimates of repeatability and reproducibility. Results A total of 239 cross sections obtained with CT angiography and histologic examination were matched. Performance on held-out data showed low levels of bias and high Pearson correlation coefficients for calcification (-0.096 mm2 and 0.973, respectively), LRNC (1.26 mm2 and 0.856), and matrix (-2.44 mm2 and 0.885). Intrareader variability was low (repeatability coefficient ranged from 1.50 mm2 to 1.83 mm2 among tissue characteristics), as was interreader variability (reproducibility coefficient ranged from 2.09 mm2 to 4.43 mm2). Conclusion There was high correlation and low bias between the in vivo software image analysis and ex vivo histopathologic quantitative measures of atherosclerotic plaque tissue characteristics, as well as low reader variability. Software algorithms can mitigate the blurring and partial volume effects of routine CT angiography acquisitions to produce accurate quantification to enhance current clinical practice. Clinical trial registration no. NCT02143102 (c) RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on September 15, 2017. PMID- 28858565 TI - A New Fire Hazard for MR Imaging Systems: Blankets-Case Report. AB - In this report, a case of fire in a positron emission tomography (PET)/magnetic resonance (MR) imaging system due to blanket combustion is discussed. Manufacturing companies routinely use copper fibers for blanket fabrication, and these fibers may remain within the blanket hem. By folding a blanket with these copper fibers within an MR imaging system, one can create an electrical current loop with a major risk of local excessive heating, burn injury, and fire. This hazard applies to all MR imaging systems. Hybrid PET/MR imaging systems may be particularly vulnerable to this situation, because blankets are commonly used for fluorodeoxyglucose PET to maintain a normal body temperature and to avoid fluorodeoxyglucose uptake in brown adipose tissue. (c) RSNA, 2017. PMID- 28858566 TI - A Bayesian adaptive design for cancer phase I trials using a flexible range of doses. AB - We present a Bayesian adaptive design for dose finding in cancer phase I clinical trials. The goal is to estimate the maximum tolerated dose (MTD) after possible modification of the dose range during the trial. Parametric models are used to describe the relationship between the dose and the probability of dose-limiting toxicity (DLT). We investigate model reparameterization in terms of the probabilities of DLT at the minimum and maximum available doses at the start of the trial. Trial design proceeds using escalation with overdose control (EWOC), where at each stage of the trial we seek the dose of the agent such that the posterior probability of exceeding the MTD of this agent is bounded by a feasibility bound. At any time during the trial, we test whether the MTD is below or above the minimum and maximum doses, respectively. If during the trial there is evidence that the MTD is outside the range of doses, we extend the range of doses and complete the trial with the planned sample size. At the end of the trial, a Bayes estimate of the MTD is proposed. We evaluate design operating characteristics in terms of safety of the trial design and efficiency of the MTD estimate under various scenarios and model misspecification. The methodology is further compared to the original EWOC design. We showed by comprehensive simulation studies that the proposed method is safe and can estimate the MTD more efficiently than the original EWOC design. PMID- 28858568 TI - New Guidelines on Noninvasive Ventilation. A Few Answers, and Several More Questions. PMID- 28858567 TI - Effect of Telemedicine Education and Telemonitoring on Continuous Positive Airway Pressure Adherence. The Tele-OSA Randomized Trial. AB - RATIONALE: Automated telemedicine interventions could potentially improve adherence to continuous positive airway pressure (CPAP) therapy. OBJECTIVES: Examining the effects of telemedicine-delivered obstructive sleep apnea (OSA) education and CPAP telemonitoring with automated patient feedback messaging on CPAP adherence. METHODS: This four-arm, randomized, factorial design clinical trial enrolled 1,455 patients (51.0% women; age, 49.1 +/- 12.5 yr [mean +/- SD]) referred for suspected OSA. Nine hundred and fifty-six underwent home sleep apnea testing, and 556 were prescribed CPAP. Two telemedicine interventions were implemented: 1) web-based OSA education (Tel-Ed) and 2) CPAP telemonitoring with automated patient feedback (Tel-TM). Patients were randomized to 1) usual care, 2) Tel-Ed added, 3) Tel-TM added, or 4) Tel-Ed and Tel-TM added (Tel-both). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was 90-day CPAP usage. Secondary endpoints included attendance to OSA evaluation, and change in Epworth Sleepiness Scale score. CPAP average daily use at 90 days was 3.8 +/- 2.5, 4.0 +/ 2.4, 4.4 +/- 2.2, and 4.8 +/- 2.3 hours in usual care, Tel-Ed, Tel-TM, and Tel both groups. Usage was significantly higher in the Tel-TM and Tel-both groups versus usual care (P = 0.0002 for both) but not for Tel-Ed (P = 0.10). Medicare adherence rates were 53.5, 61.0, 65.6, and 73.2% in usual care, Tel-Ed, Tel-TM, and Tel-both groups (Tel-both vs. usual care, P = 0.001; Tel-TM vs. usual care, P = 0.003; Tel-Ed vs. usual care, P = 0.07), respectively. Telemedicine education improved clinic attendance compared with no telemedicine education (show rate, 68.5 vs. 62.7%; P = 0.02). CONCLUSIONS: The use of CPAP telemonitoring with automated feedback messaging improved 90-day adherence in patients with OSA. Telemedicine-based education did not significantly improve CPAP adherence but did increase clinic attendance for OSA evaluation. Clinical trial registered with www.clinicaltrials.gov (NCT02279901). PMID- 28858569 TI - Food and Drug Administration Approval of Glutamine for Sickle Cell Disease: Success and Precautions in Glutamine Research. PMID- 28858571 TI - Challenges in Neurorestoration: A Special Issue for the 14th Annual American Society for Neural Therapy and Repair (ASNTR) Meeting. PMID- 28858570 TI - Global Initiative for Chronic Obstructive Lung Disease 2017 Classification and Lung Function Decline in Chronic Obstructive Pulmonary Disease. PMID- 28858572 TI - Abstracts for the 14th Annual Meeting of the American Society for Neural Therapy and Repair. PMID- 28858577 TI - Memorial to Dr. Hugo Osvaldo Jauregui 1934 - 2000. PMID- 28858591 TI - Introduction. PMID- 28858592 TI - Long-Term Culture of Japanese Human Embryonic Stem Cells in Feeder-Free Conditions. AB - Human pluripotent embryonic stem cells (hESCs) have great promise for research into human developmental biology, development of cell therapies for the treatment of diseases, toxicology, and drug discovery. Traditionally, undifferentiated hESCs are maintained on mouse embryonic fibroblasts (MEFs), which impede the clinical applications of hESCs. Here we have examined the long-term stability of the Japanese hESC line (KhES-1) in feeder-free culture. KhES-1 cells were cultured with MEF conditioned medium (CM) and different doses of basic fibroblast growth factor (bFGF) in six-well-plates of which the surface was coated with Matrigel. KhES-1 cells were maintained for at least 40 passages. In this culture system, the cells maintained stable proliferation rates and steadily expressed Oct-4, Nanog, and alkaline phosphatase. In addition, KhES-1 cells maintained without direct feeder contact formed embryonic bodies with expression of markers from the three germ layers. Here we demonstrated that Japanese human embryonic stem cells KhES-1 were cultured long term in a feeder-free method, while retaining pluripotency in vitro. PMID- 28858599 TI - Emerging Strategies in Neural Transplantation and Repair: A Special Issue Based on the Eighth Annual Conference. PMID- 28858600 TI - Human Umbilical Cord Blood Cells can be Induced to Express Markers for Neurons and Glia. AB - Rare cells are present in human umbilical cord blood that do not express the hematopoietic marker CD45 and in culture do not produce cells of hematopoietic lineage. These umbilical cord multipotent stem cells (UC-MC) behave as multilineage progenitor cells (stem cells) and can be expanded in tissue culture. Exposure to basic fibroblast growth factor (bFGF) and human epidermal growth factor (hEGF) for a minimum of 7 days in culture induces expression of neural and glial markers. Western immunoblots demonstrate expression of both beta-tubulin III and glial fibrillary acidic protein (GFAP). Immunocytochemistry of the cells showed intense labeling to both compounds on the intracellular cytoskeleton. The oligodendrocyte cell surface marker galactocerebroside (Gal-C) was present on most cells. Many cells show dual labeling, expressing both neuronal and glial markers. PMID- 28858601 TI - Tauroursodeoxycholic Acid Improves the Survival and Function of Nigral Transplants in a Rat Model of Parkinson's Disease. AB - There is accumulating evidence showing that the majority of cell death in neural grafts results from apoptosis when cells are implanted into the brain. Tauroursodeoxycholic acid (TUDCA), a taurine-conjugated hydrophilic bile acid, has been found to possess antiapoptotic properties. In the present study we have examined whether the supplementation of TUDCA to cell suspensions prior to transplantation can lead to enhanced survival of nigral grafts. We first conducted an in vitro study to examine the effects of TUDCA on the survival of dopamine neurons in serum-free conditions. The number of tyrosine hydroxylase (TH)-positive neurons in the TUDCA-treated cultures was significantly greater than that of control cultures 7 days in vitro. In addition, a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) assay showed that the number of apoptotic cells in the TUDCA-treated cultures was dramatically smaller than that in the control cultures. In the transplantation study, a 50 MUM concentration of TUDCA was added to the media when nigral tissue from Sprague-Dawley (SD) rats was trypsinized and dissociated. Two microliters of cell suspension containing TUDCA was then stereotaxically injected into the striatum of adult SD rats subjected to an extensive unilateral 6-hydroxydopamine lesion of the nigrastriatal dopamine pathway. At 2 weeks after transplantation, the rats that received a cell suspension with TUDCA exhibited a significant reduction in amphetamine-induced rotation scores when compared with pretransplantation value. There was a significant increase (approximately threefold) in the number of TH-positive cells in the neural grafts for the TUDCA treated group when compared with the controls 6 weeks postgrafting. The number of apoptotic cells was much smaller in the graft areas in the TUDCA-treated groups than in the control group 4 days after transplantation. These data demonstrate that pretreatment of the cell suspension with TUDCA can reduce apoptosis and increase the survival of grafted cells, resulting in an improvement of behavioral recovery. PMID- 28858603 TI - Long-Term Graft Function after Allogeneic Islet Transplantation. AB - Islet transplants are emerging as a viable option for the treatment of type 1 diabetes mellitus. From 1989 to 1995 we conducted a series of simultaneous islet kidney transplants in six uremic type 1 diabetic patients. We report two of these patients who have shown persistent islet graft function over many years. Two female patients with duration of diabetes of 27 and 37 years underwent simultaneous islet-kidney transplant under steroid- and cyclosporine-based immunosuppression. Freshly isolated islets were supplemented with cryopreserved islets from our low-temperature bank of frozen islets. A total islet mass of 9,866 and 15,061 islet equivalents/kg body weight, respectively, was transplanted into the liver through portal vein. Reasonable blood glucose control has been achieved for up to 6 years posttransplant in one patient, but there was minimum clinical benefit from the islet graft at 10 years. In contrast, sustained insulin secretion with nearly normal HbA1c at 13 years follow-up was observed in another patient, providing hope for improving long-term graft outcomes for islet transplant recipient. PMID- 28858605 TI - Using a Community Workshop Model to Initiate Policy, Systems, and Environmental Change That Support Active Living in Indiana, 2014-2015. AB - BACKGROUND: Engaging in regular physical activity reduces the likelihood of developing chronic diseases. A community's rates of physical activity are directly connected to its built environment characteristics, which correspondingly affect the chronic disease prevalence of its population. Community planning and design interventions can increase levels of physical activity and reduce chronic disease rates by identifying and removing environmental and policy barriers that may hinder active living. COMMUNITY CONTEXT: Community stakeholder groups of various sizes and in various settings in Indiana are beginning to make changes to their policies, systems, and environments to increase levels of physical activity for residents. METHODS: We conducted day-long active living workshops in cities and towns in Indiana to help organize and support public officials, community-based organizations, and advocates in their efforts to promote policy, system, and environmental (PSE) changes that lead to more active communities. OUTCOME: We found that following a consistent process of holding a community workshop and then conducting ongoing follow-up activities led to PSE changes within 1 year. Communities that hosted active living workshops created identifiable changes by supporting active living goals through policy adoption, the creation of new advisory committees, and new local funding allocations. INTERPRETATION: The collaborative approach in the workshop provides a successful model for communities to build capacity to implement PSE strategies that support active living. This method requires various community stakeholders to work closely together, using a shared approach to make changes that would be difficult to achieve if they were working independently. PMID- 28858604 TI - Spread of Canine Influenza A(H3N2) Virus, United States. AB - A canine influenza A(H3N2) virus emerged in the United States in February-March 2015, causing respiratory disease in dogs. The virus had previously been circulating among dogs in Asia, where it originated through the transfer of an avian-origin influenza virus around 2005 and continues to circulate. Sequence analysis suggests the US outbreak was initiated by a single introduction, in Chicago, of an H3N2 canine influenza virus circulating among dogs in South Korea in 2015. Despite local control measures, the virus has continued circulating among dogs in and around Chicago and has spread to several other areas of the country, particularly Georgia and North Carolina, although these secondary outbreaks appear to have ended within a few months. Some genetic variation has accumulated among the US viruses, with the appearance of regional-temporal lineages. The potential for interspecies transmission and zoonotic events involving this newly emerged influenza A virus is currently unknown. PMID- 28858606 TI - Improving Nutrition and Physical Activity Policies and Practices in Early Care and Education in Three States, 2014-2016. AB - The National Early Care and Education Learning Collaboratives (ECELC) project aims to facilitate best practices in nutrition, physical activity, screen time, and breastfeeding support and infant feeding among early care and education (ECE) programs across multiple states. The project uses a train-the-trainer approach with 5, in-person learning-collaborative sessions, technical assistance, and action planning. We describe the longitudinal practice-based evaluation of the project and assess whether ECE programs evaluated (n = 104) sustained changes in policies and practices 1 year after completing the project. The number of best practices increased from pre-assessment to post-assessment (P < .01) but did not change significantly from post-assessment to follow-up assessment. ECELC shows promise as an approach to incorporate professional development and training focused on improving best practices for environment-level child nutrition and physical activity, which is one strategy among many that are warranted for obesity prevention in young children. PMID- 28858607 TI - A Community-Based Marketing Campaign at Farmers Markets to Encourage Fruit and Vegetable Purchases in Rural Counties With High Rates of Obesity, Kentucky, 2015 2016. AB - Availability of farmers markets may increase fruit and vegetable consumption among rural residents of the United States. We conducted a community-based marketing campaign, Plate it Up Kentucky Proud (PIUKP), in 6 rural communities over 2 years to determine the association between exposure to the campaign and fruit and vegetable purchases, adjusted for Supplemental Nutrition Assistance Program recipient status. Logistic regression was used to examine the odds of the PIUKP campaign influencing purchases. Awareness of the PIUKP marketing campaign was significantly associated with a willingness to prepare fruits and vegetables at home. Using marketing strategies at farmers markets may be an effective way to improve fruit and vegetable purchases in rural communities. PMID- 28858608 TI - Correction: In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. PMID- 28858609 TI - Role of medial premotor areas in action language processing in relation to motor skills. AB - The literature reports that the supplementary motor area (SMA) and pre supplementary motor area (pre-SMA) are involved in motor planning and execution, and in motor-related cognitive functions such as motor imagery. However, their specific role in action language processing remains unclear. In the present study, we investigated the impact of repetitive transcranial magnetic stimulation (rTMS) over SMA and pre-SMA during an action semantic analogy task (SAT) in relation with fine motor skills (i.e., manual dexterity) and motor imagery abilities in healthy non-expert adults. The impact of rTMS over SMA (but not pre SMA) on reaction times (RT) during SAT was correlated with manual dexterity. Specifically, results show that rTMS over SMA modulated RT for those with lower dexterity skills. Our results therefore demonstrate a causal involvement of SMA in action language processing, as well as the existence of inter-individual differences in this involvement. We discuss these findings in light of neurolinguistic theories of language processing. PMID- 28858610 TI - Synthesis of a model trisaccharide for studying the interplay between the anti alpha-Gal antibody and the trans-sialidase reactions in Trypanosoma cruzi. AB - Trypanosoma cruzi, the etiologic agent of Chagas disease, is covered by a dense glycocalix mainly composed by glycoproteins called mucins which are also the acceptors of sialic acid in a reaction catalyzed by a trans-sialidase (TcTS). Sialylation of trypomastigote mucins protects the parasite from lysis by the anti alpha-Galp antibodies from serum. The TcTS is essential for the infection process since T. cruzi is unable to biosynthesize sialic acid. The enzyme specifically transfers it from a terminal beta-d-Galp unit in the host glycoconjugate to terminal beta-d-Galp units in the parasite mucins to construct the d NeuNAc(alpha2->3)beta-d-Galp motif. On the other hand, although galactose is the most abundant sugar in mucins of both, the infective trypomastigotes and the insect stage epimastigotes, alpha-d-Galp is only present in the infective stage whereas beta-d-Galf is characteristic of the epimastigote stage of the less virulent strains. Neither alpha-d-Galp nor d-Galf is acceptor of sialic acid. In the mucins, some of the oligosaccharides are branched with terminal beta-d-Galp units to be able to accept sialic acid in the TcTS reaction. Based on previous reports showing that anti alpha-Galp antibodies only partially colocalize with sialic acid, we have undertaken the synthesis of the trisaccharide alpha-d-Galp(1 >3)-[beta-d-Galp(1->6)]-d-Galp, the smallest structure containing both, the antigenic d-Galp(alpha1->3)-d-Galp unit and the sialic acid-acceptor beta-d-Galp unit. The trisaccharide was obtained as the 6-aminohexyl glycoside to facilitate further conjugation for biochemical studies. The synthetic approach involved the alpha-galactosylation at O-4 of a suitable precursor of the reducing end, followed by beta-galactosylation at O-6 of the same precursor and introduction of the 6-aminohexyl aglycone. The fully deprotected trisaccharide was successfully sialylated by TcTS using either 3'-sialyllactose or fetuin as donors. The product, 6-aminohexyl alpha-d-NeuNAc(2->3)-beta-d-Galp(1->6)-[alpha-d-Galp(1->3)] beta-d-Galp, was purified and characterized. PMID- 28858611 TI - The Tanenbaum Open Science Institute: Leading a Paradigm Shift at the Montreal Neurological Institute. AB - The Montreal Neurological Institute is adopting an Open Science Policy that will be enacted by the Tanenbaum Open Science Institute. The aim is to accelerate the generation of knowledge and novel effective treatments for brain disorders by freeing science. PMID- 28858612 TI - On the Integration of Space, Time, and Memory. AB - The hippocampus is famous for mapping locations in spatially organized environments, and several recent studies have shown that hippocampal networks also map moments in temporally organized experiences. Here I consider how space and time are integrated in the representation of memories. The brain pathways for spatial and temporal cognition involve overlapping and interacting systems that converge on the hippocampal region. There is evidence that spatial and temporal aspects of memory are processed somewhat differently in the circuitry of hippocampal subregions but become fully integrated within CA1 neuronal networks as independent, multiplexed representations of space and time. Hippocampal networks also map memories across a broad range of abstract relations among events, suggesting that the findings on spatial and temporal organization reflect a generalized mechanism for organizing memories. PMID- 28858614 TI - Closed-Loop Real-Time Imaging Enables Fully Automated Cell-Targeted Patch-Clamp Neural Recording In Vivo. AB - Targeted patch-clamp recording is a powerful method for characterizing visually identified cells in intact neural circuits, but it requires skill to perform. We previously developed an algorithm that automates "blind" patching in vivo, but full automation of visually guided, targeted in vivo patching has not been demonstrated, with currently available approaches requiring human intervention to compensate for cell movement as a patch pipette approaches a targeted neuron. Here we present a closed-loop real-time imaging strategy that automatically compensates for cell movement by tracking cell position and adjusting pipette motion while approaching a target. We demonstrate our system's ability to adaptively patch, under continuous two-photon imaging and real-time analysis, fluorophore-expressing neurons of multiple types in the living mouse cortex, without human intervention, with yields comparable to skilled human experimenters. Our "imagepatching" robot is easy to implement and will help enable scalable characterization of identified cell types in intact neural circuits. PMID- 28858613 TI - The Aging Navigational System. AB - The discovery of neuronal systems dedicated to computing spatial information, composed of functionally distinct cell types such as place and grid cells, combined with an extensive body of human-based behavioral and neuroimaging research has provided us with a detailed understanding of the brain's navigation circuit. In this review, we discuss emerging evidence from rodents, non-human primates, and humans that demonstrates how cognitive aging affects the navigational computations supported by these systems. Critically, we show 1) that navigational deficits cannot solely be explained by general deficits in learning and memory, 2) that there is no uniform decline across different navigational computations, and 3) that navigational deficits might be sensitive markers for impending pathological decline. Following an introduction to the mechanisms underlying spatial navigation and how they relate to general processes of learning and memory, the review discusses how aging affects the perception and integration of spatial information, the creation and storage of memory traces for spatial information, and the use of spatial information during navigational behavior. The closing section highlights the clinical potential of behavioral and neural markers of spatial navigation, with a particular emphasis on neurodegenerative disorders. PMID- 28858615 TI - Robotic Automation of In Vivo Two-Photon Targeted Whole-Cell Patch-Clamp Electrophysiology. AB - Whole-cell patch-clamp electrophysiological recording is a powerful technique for studying cellular function. While in vivo patch-clamp recording has recently benefited from automation, it is normally performed "blind," meaning that throughput for sampling some genetically or morphologically defined cell types is unacceptably low. One solution to this problem is to use two-photon microscopy to target fluorescently labeled neurons. Combining this with robotic automation is difficult, however, as micropipette penetration induces tissue deformation, moving target cells from their initial location. Here we describe a platform for automated two-photon targeted patch-clamp recording, which solves this problem by making use of a closed loop visual servo algorithm. Our system keeps the target cell in focus while iteratively adjusting the pipette approach trajectory to compensate for tissue motion. We demonstrate platform validation with patch-clamp recordings from a variety of cells in the mouse neocortex and cerebellum. PMID- 28858616 TI - Inferior Olivary TMEM16B Mediates Cerebellar Motor Learning. AB - Ca2+-activated ion channels shape membrane excitability and Ca2+ dynamics in response to cytoplasmic Ca2+ elevation. Compared to the Ca2+-activated K+ channels, known as BK and SK channels, the physiological importance of Ca2+ activated Cl- channels (CaCCs) in neurons has been largely overlooked. Here we report that CaCCs coexist with BK and SK channels in inferior olivary (IO) neurons that send climbing fibers to innervate cerebellar Purkinje cells for the control of motor learning and timing. Ca2+ influx through the dendritic high threshold voltage-gated Ca2+ channels activates CaCCs, which contribute to membrane repolarization of IO neurons. Loss of TMEM16B expression resulted in the absence of CaCCs in IO neurons, leading to markedly diminished action potential firing of IO neurons in TMEM16B knockout mice. Moreover, these mutant mice exhibited severe cerebellar motor learning deficits. Our findings thus advance the understanding of the neurophysiology of CaCCs and the ionic basis of IO neuron excitability. PMID- 28858617 TI - A Circuit Node that Integrates Convergent Input from Neuromodulatory and Social Behavior-Promoting Neurons to Control Aggression in Drosophila. AB - Diffuse neuromodulatory systems such as norepinephrine (NE) control brain-wide states such as arousal, but whether they control complex social behaviors more specifically is not clear. Octopamine (OA), the insect homolog of NE, is known to promote both arousal and aggression. We have performed a systematic, unbiased screen to identify OA receptor-expressing neurons (OARNs) that control aggression in Drosophila. Our results uncover a tiny population of male-specific aSP2 neurons that mediate a specific influence of OA on aggression, independent of any effect on arousal. Unexpectedly, these neurons receive convergent input from OA neurons and P1 neurons, a population of FruM+ neurons that promotes male courtship behavior. Behavioral epistasis experiments suggest that aSP2 neurons may constitute an integration node at which OAergic neuromodulation can bias the output of P1 neurons to favor aggression over inter-male courtship. These results have potential implications for thinking about the role of related neuromodulatory systems in mammals. PMID- 28858618 TI - Synaptic Mechanisms of Feature Coding in the Visual Cortex of Awake Mice. AB - The synaptic mechanisms of feature coding in the visual cortex are poorly understood, particularly in awake animals. The ratio between excitation (E) and inhibition (I) might be constant across stimulus space, controlling only the gain and timing of neuronal responses, or it might change, directly contributing to feature coding. Whole-cell recordings in L2/3 of awake mice revealed that the E/I ratio systematically declines with increasing stimulus contrast or size. Suppressing somatostatin (SOM) neurons enhanced the E and I underlying size tuning, explaining SOM neurons' role in surround suppression. These data imply that contrast and size tuning result from a combination of a changing E/I ratio and the tuning of total synaptic input. Furthermore, they provide experimental support in awake animals for the "Stabilized Supralinear Network," a model that explains diverse cortical phenomena, and suggest that a decreasing E/I ratio with increasing cortical drive could contribute to many different cortical computations. PMID- 28858619 TI - The Spatiotemporal Organization of the Striatum Encodes Action Space. AB - Activity in striatal direct- and indirect-pathway spiny projection neurons (SPNs) is critical for proper movement. However, little is known about the spatiotemporal organization of this activity. We investigated the spatiotemporal organization of SPN ensemble activity in mice during self-paced, natural movements using microendoscopic imaging. Activity in both pathways showed predominantly local but also some long-range correlations. Using a novel approach to cluster and quantify behaviors based on continuous accelerometer and video data, we found that SPN ensembles active during specific actions were spatially closer and more correlated overall. Furthermore, similarity between different actions corresponded to the similarity between SPN ensemble patterns, irrespective of movement speed. Consistently, the accuracy of decoding behavior from SPN ensemble patterns was directly related to the dissimilarity between behavioral clusters. These results identify a predominantly local, but not spatially compact, organization of direct- and indirect-pathway SPN activity that maps action space independently of movement speed. PMID- 28858620 TI - Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus. AB - Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT. PMID- 28858622 TI - Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. PMID- 28858623 TI - Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy. PMID- 28858621 TI - Specialized Representations of Value in the Orbital and Ventrolateral Prefrontal Cortex: Desirability versus Availability of Outcomes. AB - Advantageous foraging choices benefit from an estimation of two aspects of a resource's value: its current desirability and availability. Both orbitofrontal and ventrolateral prefrontal areas contribute to updating these valuations, but their precise roles remain unclear. To explore their specializations, we trained macaque monkeys on two tasks: one required updating representations of a predicted outcome's desirability, as adjusted by selective satiation, and the other required updating representations of an outcome's availability, as indexed by its probability. We evaluated performance on both tasks in three groups of monkeys: unoperated controls and those with selective, fiber-sparing lesions of either the OFC or VLPFC. Representations that depend on the VLPFC but not the OFC play a necessary role in choices based on outcome availability; in contrast, representations that depend on the OFC but not the VLPFC play a necessary role in choices based on outcome desirability. PMID- 28858624 TI - Ligand-Selective Wnt Receptor Complexes in CNS Blood Vessels: RECK and GPR124 Plugged In. AB - CNS angiogenesis and blood-brain barrier integrity are controlled by the canonical Wnt pathway. In this issue of Neuron, Cho et al. (2017) use advanced mouse genetics and biochemical experiments to unravel the ligand-specific association of membrane proteins GPR124 and RECK with Wnt receptor complexes. PMID- 28858625 TI - To Fight or Not to Fight. AB - In this issue of Neuron, Watanabe et al. (2017) uncover how octopamine, an invertebrate norepinephrine analog, modulates the neural pathways that bias Drosophila males toward aggression. PMID- 28858626 TI - Synapse-Specific Encoding of Fear Memory in the Amygdala. AB - Input specificity is a fundamental property of long-term potentiation (LTP), but it is not known if learning is mediated by synapse-specific plasticity. Kim and Cho (2017) now show that fear conditioning is mediated by synapse-specific LTP in the amygdala, allowing animals to discriminate stimuli that predict threat from those that do not. PMID- 28858627 TI - Urgent Commitment Issues. AB - Making a choice requires a combination of urgency, which provides the drive to act, and perceptual analysis, which identifies the most advantageous alternative. In behaving monkeys, Thura and Cisek (2017, in this issue of Neuron) map these processes onto separate brain structures with a complex interplay. PMID- 28858628 TI - A novel recombinant vaccine candidate comprising PBP2a and autolysin against Methicillin Resistant Staphylococcus aureus confers protection in the experimental mice. AB - The methicillin-resistant Staphylococcus aureus infection is a hot topic area in microbiology research. Here a novel vaccine candidate consisting of recombinant PBP2a and autolysin proteins were used. The proteins over expressed in E.coli BL21 (DE3) cells, and purified by the Ni-NTA affinity column and conjugated using EDAC and ADH as a linker and spacer, respectively. To investigate the immunogenicity and protective effects of recombinant proteins, 5 and 20MUg of proteins in various formulations were subcutaneously injected in different groups. Two booster vaccinations were carried out in three-week intervals and blood samples were collected three weeks after each injection. To evaluate the immune response, total IgG, IgG1, IgG2a, and IgG2b were analyzed. Immunization of mice with r-autolysin and r-autolysin-PBP2a mixture raised total IgGantibody. Additionally, both IgG1 and IgG2a responses induced. Opsonophagocytosis assay showed that anti r-PBP2a and r-autolysin IgG not only promoted phagocytosis of S.aureus, but also decreased the number of viable bacterial cells. Furthermore, survival rate of experimental mice increased in the bacteremia infection. Our results demonstrated that active vaccination with a mixture of r-PBP2a/r autolysin and conjugate form vaccine reduced the mortality rate and protected mice against lethal MRSA challenge as well as single proteins. PMID- 28858630 TI - Quantitative assessment of salivary oral bacteria according to the severity of dental caries in childhood. AB - This study aimed to assess differences in selected oral bacteria in children according to the severity of dental caries. One hundred and thirty-six children, 36-60 months old were divided into three groups according to caries status: caries-free (CF) (n=47), early childhood caries (ECC) (n=40) and severe-early childhood caries (S-ECC) (n=49). Saliva was collected for detection and quantification of selected oral streptococci, Actinomyces naeslundii, Lactobacillus spp., Bifidobacterium spp., and Scardovia wiggsiae by quantitative polymerase chain reaction. The results showed that the detection and quantitative levels of S. mutans, S. sobrinus, Bifidobacterium spp. and S. wiggsiae were significantly higher in S-ECC children compared to CF and ECC children, while for S. salivarius were significantly higher in CF compared to ECC and S-ECC children. There was no statistical difference among the clinical groups for S. mitis, S. oralis, A. naeslundii and Lactobacillus spp. levels and detection. S-ECC children had a lower monthly family income, started tooth brushing later and were breastfeed for a longer duration compared to CF children. S. mutans levels were positively correlated with S. wiggsiae and Bifidobacterium spp. levels, lower mother's education and child bottle-feeding before sleeping and negatively correlated with S. salivarius. It was concluded that in addition to S. mutans, other bacterial species, including bifidobacteria, Scardovia wiggsiae and S. sobrinus, are associated with severity of early childhood caries, although their role in the progress of dental caries remains unclear. PMID- 28858629 TI - Selective expression of the transcription elongation factor ELL3 in B cells prior to ELL2 drives proliferation and survival. AB - B cell activation is dependent on a large increase in transcriptional output followed by focused expression on secreted immunoglobulin as the cell transitions to an antibody producing plasma cell. The rapid transcriptional induction is facilitated by the release of poised RNA pol II into productive elongation through assembly of the super elongation complex (SEC). We report that a SEC component, the Eleven -nineteen Lysine-rich leukemia (ELL) family member 3 (ELL3) is dynamically up-regulated in mature and activated human B cells followed by suppression as B cells transition to plasma cells in part mediated by the transcription repressor PRDM1. Burkitt's lymphoma and a sub-set of Diffuse Large B cell lymphoma cell lines abundantly express ELL3. Depletion of ELL3 in the germinal center derived lymphomas results in severe disruption of DNA replication and cell division along with increased DNA damage and cell death. This restricted utilization and survival dependence reveal a key step in B cell activation and indicate a potential therapeutic target against B cell lymphoma's with a germinal center origin. PMID- 28858631 TI - Near-falls in people with Parkinson's disease: Circumstances, contributing factors and association with falling. AB - OBJECTIVES: To describe circumstances of near-falls among persons with Parkinson's disease (PD), assess factors associated with near-falling and assess whether near-falls in the first 6 months are associated with falling in the latter 6 months over one year of follow-up. MATERIALS AND METHODS: In the period August 2011-December 2012, 120 consecutive persons with PD, who denied having fallen in the past 6 months, were recruited at Clinical center of Serbia in Belgrade. Occurrence of falling and near-falls was followed for one year. RESULTS: A total of 31 persons with PD (25.8%) experienced near-falls, but did not fall. Of 42 fallers, 32 (76.2%) experienced near-falls. Tripping was the most common cause of near-falls among fallers, whereas postural instability was the most common in non-fallers. Regardless of falling experience, the most common manner to avoid fall was holding onto furniture or wall. After adjustment for multiple motor and non-motor PD features, more severe freezing of gait was associated with occurrence of near-falls over one year of follow-up (odds ratio [OR]=1.08, 95% confidence interval [CI] 1.01-1.16; p=0.043). Adjusted regression analysis did not show associations between near-falling in the first 6 months and falling in the latter 6 months of follow-up. CONCLUSION: Near-falls commonly occur in persons with PD. More severe freezing of gait appears to predispose near falling. Fall prevention programs focusing on balance maintenance when experiencing freezing of gait could potentially be useful in reduction of near falls. PMID- 28858632 TI - Widely spread corticospinal tracts lesions in a case of neuromyelitis optica. AB - Brain abnormalities have frequently been reported in neuromyelitis optica (NMO) patients, but corticospinal tract involvement has rarely been described. Here we review the case of a 56-year-old woman who presented with unusual MRI features involving the whole corticospinal tract, and summarize the clinical features, neuroimaging, and prognosis of the case. The patient presented with bilateral visual loss and developed progressive weakness in both lower limbs, and urinary incontinence 12days later. Brain MRI revealed T2-hyperintensities in the bilateral corticospinal tract (posterior limb of the internal capsule and cerebral peduncle), callosal lesions, and subcortical white matter lesions. Spinal cord MRI showed a longitudinally extensive lesion involving the cervical and lumbar regions. The patient showed minimal improvement after methylprednisolone therapy. Our case suggests that in a patient with NMO, involvement of the whole corticospinal tract with specific brain abnormalities on MRI is indicative of a poor prognosis. PMID- 28858633 TI - Effects of microvascular decompression on depression and anxiety in trigeminal neuralgia: A prospective cohort study focused on risk factors and prognosis. AB - OBJECTIVE: Patients with trigeminal neuralgia (TN) often develop a terrible fear of triggering pain, which may lead to depression and anxiety, exerting a negative effect on their quality of life. This study aimed to investigate the prevalence and risk factors of depression and anxiety in TN patients, and further to investigate the effects of microvascular decompression (MVD) on these psychiatric disorders. PATIENTS AND METHODS: A prospective cohort study was conducted, patients with TN who underwent MVD in our department between 2013 and 2015 were included. Visual analogue scale (VAS) score was used to measure the severity of pain. Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were used to evaluate depression and anxiety disorders before and 6-month after MVD. The clinical data of these patients were collected prospectively and statistically analyzed. RESULTS: A total of 128 study subjects comprising 70 women and 58 men with a mean age of 47.5+/-11.2years were included in this study. The mean VAS score was 7.7+/-1.5. Eighty-three patients (64.8%) had depression and 24 patients (18.8%) suffered anxiety. Multivariate logistic regression analysis revealed that female gender (OR=2.4, P=0.036), high pain intensity (OR=3.25, P=0.027) and ineffective medicine treatment (OR=1.89, P=0.041) were associated with depression, and female gender (OR=3.45, P=0.034) and high pain intensity (OR=2.88, P=0.022) were also associated with anxiety. There were significant improvements in depression and anxiety symptoms between pre- and postoperative responses. CONCLUSIONS: Depression and anxiety are prevalent in patients with idiopathic TN. Female gender, high pain intensity and ineffective medicine treatment are risk factors. MVD not only provides high pain-relief rate, but also leads to significant improvements in the depression and anxiety symptoms. PMID- 28858634 TI - Effect of diabetes mellitus on the quality and cytokine content of human semen. AB - The effects of diabetes mellitus (DM) on the quality and cytokine levels of human semen remain unknown. Sixty semen samples from 30 normal volunteers and 30 DM patients were assayed. The percentage of sperm progressive motility, sperm vitality, sperm survival rate, the rate of normal sperm morphology, semen volume, and semen pH and density of DM males were significantly lower than those of normal males (p<0.05). Moreover, semen interleukin (IL)-17 and IL-18 levels in DM males were significantly higher than those in normal males (p<0.05) and were positively correlated with blood glucose level and sperm DNA fragmentation index. DM increased blood glucose levels, consequently inducing the abnormal expression of IL-17 and IL-18. The abnormal expression of these cytokines in semen decreased semen quality and might lead to male infertility. PMID- 28858635 TI - Comparison of risk factors and perinatal outcomes in early onset and late onset preeclampsia: A cohort based study in Reunion Island. AB - Clinical differences, maternal risk factors and pregnancy outcomes of deliveries complicated by early- (delivery<34 weeks) and late-onset (delivery>=34 weeks) preeclampsia were studied in a cohort of women in Reunion Island during 15 years (period 2001-2015; N=62,230 pregnancies). The overall preeclampsia rate in singleton pregnancies was 2.37%. Early- and late-onset preeclampsia rates were 0.75% and 1.5% respectively, and the trend for each type of disease was stable over time. In both form of preeclampsia, smoking during pregnancy was a protective factor and associated risk factors were: older age, primiparity, pre existing diabetes, chronic hypertension, higher pre-pregnancy body mass index and obesity, infertility treatment, history of renal disease and hypercholesterolemia (all p<0.05). The rate of caesarean section, medically-induced delivery and impaired foetal and neonatal outcomes were significantly higher in preeclamptic women (all p<0.0001). When comparing early- versus late-onset preeclampsia, the only difference was the older maternal age in primiparae with early-onset preeclampsia (p=0.02), and the two groups of preeclamptic women were similar in terms of maternal risk factors, with the exception of higher rates of chronic hypertension in early-onset preeclampsia (p=0.02). Foetal and neonatal outcomes were evaluated after adjustment for gestational age at delivery and no difference was detected between early- and late-onset preeclamptic women. These analyses failed to identify a specific phenotype of preeclampsia in terms of predisposition or pre-existing risk factors for one form or another. Gestational age at delivery was the most important predictor for offspring outcome. PMID- 28858637 TI - Compensation of the magnetic force imaging by scanning directions. AB - It was found that the results of magnetic force microscope (MFM) imaging were different with the probe scanning directions. This paper studied the effect of scanning directions on the MFM imaging, and a method for the distortion compensation was proposed to reduce the errors. In the study, three different scanning directions with the angles of 0 degrees , 45 degrees and 90 degrees were used to measure the magnetic domain structures distributions of magnetic sample. The experimental results have shown that the scanning direction parallel to the magnetic domain structure will cause a minimum phase shift difference and lead to a structure distortion. A method for compensating the distortions was proposed. With this method, the distorted structures were corrected and the effect of scanning directions on the MFM imaging was significantly reduced. This work provides a way for the acquisition of the correct images of magnetic structures using an MFM and the improvement of imaging quality in a wide range of MFM applications. PMID- 28858636 TI - Damage-Associated molecular pattern markers HMGB1 and cell-Free fetal telomere fragments in oxidative-Stressed amnion epithelial cell-Derived exosomes. AB - Term labor in humans is associated with increased oxidative stress (OS) -induced senescence and damages to amnion epithelial cells (AECs). Senescent fetal cells release alarmin high-mobility group box 1 (HMGB1) and cell-free fetal telomere fragments (cffTF) which can be carried by exosomes to other uterine tissues to produce parturition-associated inflammatory changes. This study characterized AEC derived exosomes under normal and OS conditions and their packaging of HMGB1 and cffTF. Primary AECs were treated with either standard media or oxidative stress induced media (exposure to cigarette smoke extract for 48h). Senescence was determined, and exosomes were isolated and characterized. To colocalize HMGB1 and cffTF in amnion exosomes, immunofluorescent staining and in situ hybridization were performed, followed by confocal microscopy. Next generation sequencing (NGS) determined exosomal cffTF and other cell-free amnion cell DNA specificity. Regardless of condition, primary AECs produce exosomes with a classic size, shape, and markers. OS and senescence caused the translocation of HMGB1 and cffTF from AECs' nuclei to cytoplasm compared to untreated cells, which was inhibited by antioxidant N-acetyl cysteine (NAC). Linescans confirmed colocalization of HMGB1 and cffTF in exosomes were higher in the cytoplasm after CSE treatment compared to untreated AECs. NGS determined that besides cffTF, AEC exosomes also carry genomic and mitochondrial DNA, regardless of growth conditions. Sterile inflammatory markers HMGB1 and cffTF from senescent fetal cells are packaged inside exosomes. We postulate that this exosomal cargo can act as a fetal signal at term and can cause labor-associated changes in neighboring tissues. PMID- 28858638 TI - Upward social mobility and identity. AB - As psychological research on socioeconomic status (SES) continues to expand, greater attention should be devoted to the influence of social mobility and the dynamic and malleable aspects of SES on people's lives. Status-based identity describes how people's socioeconomic circumstances relate to their broader sense of self and the meaning that they make of their own SES. Such an approach allows for complex study of the challenges and consequences of a change in SES. Research related to status-based identity suggests that although social mobility is often considered a signifier of reduced inequality, upward social mobility may also exacerbate other forms of inequality by instigating a destabilizing sense of status uncertainty that impairs motivation and well-being for class migrants. PMID- 28858639 TI - Childhood trauma and psychosis: Beyond the association. AB - Childhood traumas have been extensively associated with the development of psychotic disorders. However, our understanding of processes underlying this relationship remains poor. In order to address this issue, we examined which specific aspects of childhood trauma are significantly associated with a first episode of psychosis. 109 patients with first episode of psychosis and 145 controls representative from general population were recruited in three centers in France. Child experiences of care and abuses allowed obtaining information about types of childhood trauma, age at first exposure, identity of perpetrator, and social support. Odds ratio were calculated for each of these aspects, adjusted for age, sex, and education. Sexual and physical abuses (OR=2.26 (1.19 4.32)), and separation from one or both parents (OR ranging from 1.94 to 3.17; all significant) are significantly associated with an increased risk to present a first episode of psychosis. Furthermore, separation from mother occurring before age of 4 (OR=5.96 (1.24-28.77)), and sexual and physical abuses perpetrated by someone other than parents (OR=4.61 (1.66-12.80)) were also associated with an increased risk of first episode of psychosis. Finally, social support was significantly associated with a decreased risk to develop psychotic disorders (OR ranging from 0.33 to 0.42; all significant). Together, these findings suggest that some but not all aspects of childhood trauma are related to a significant risk to develop a first episode of psychosis. PMID- 28858640 TI - A historical comparison of Australian lawyers' strategies for cross-examining child sexual abuse complainants. AB - Many child sexual abuse complainants find the adversarial trial process so distressing that they say they would never report abuse again. Their concerns stem largely from cross-examination, in which the lawyer acting for the accused attempts to discredit their evidence. We examined whether-and if so, how Australian defense lawyers' approaches to cross-examining child sexual abuse complainants have changed meaningfully over the past 60 years. To do this, we systematically evaluated cases that were prosecuted in the 1950s, comparing them to a matched set of cases from the turn of the twenty-first century. Despite the intervening law reforms designed to improve complainants' experience in court, we found that, relative to their historical counterparts, contemporary child complainants of sexual abuse are actually subjected to far lengthier cross examinations involving a much broader range of strategies and associated tactics. These findings have important implications for future legal practice and reform, and for the way in which these are evaluated. PMID- 28858641 TI - Knowledge and attitudes about epilepsy: A survey of high school students in Germany. AB - PURPOSE: Attitudes concerning epilepsy improved over the last few decades, but children with epilepsy still suffer from stigmatisation. Data about unaffected children's knowledge of and attitudes about epilepsy is scarce. METHODS: We developed a questionnaire regarding epilepsy for high school students attending 8th-10th grade. The survey was performed from October 2015 to March 2016 in 5 different federal states of Germany. RESULTS: 1092 students [mean age (Q25/75): 14.5 (14/15) years] participated. 542/1092 (50%) of the respondents knew that people could die from a seizure. 216/1092 (20%) thought emotional strain could cause epilepsy. Asked for measures they would perform in case of a seizure, 235/1092 (24%) participants would hold the person to the ground, and 182/1092 (19%) would put a solid object into the person's mouth. 28/1092 (3%) would not like to be friends with a person with epilepsy, and 237/1092 (22%) would not like to go on a date with a person with epilepsy. Answers of 342/1092 (31%) students of a school located nearby a specialised epilepsy centre differed in some questions. The latter students were more familiar with epilepsy and showed better knowledge concerning causes, symptoms and treatment of epilepsy. In a question about special characteristics of people with epilepsy, 63/342 (18%) [other schools: 52/750 (11%)] answered people with epilepsy were friendlier and 76/342 (22%) [other schools: 49/750 (11%)] answered they were more sociable compared to people without epilepsy. CONCLUSION: To improve knowledge and attitudes and reduce misconceptions further education seems necessary. PMID- 28858642 TI - Catalytic hydrogenation of CO2 over Pt- and Ni-doped graphene: A comparative DFT study. AB - Today, the global greenhouse effect of carbon dioxide (CO2) is a serious environmental problem. Therefore, developing efficient methods for CO2 capturing and conversion to valuable chemicals is a great challenge. The aim of the present study is to investigate the catalytic activity of Pt- or Ni-doped graphene for the hydrogenation of CO2 by a hydrogen molecule. To gain a deeper insight into the catalytic mechanism of this reaction, the reliable density functional theory calculations are performed. The adsorption energies, geometric parameters, reaction barriers, and thermodynamic properties are calculated using the M06-2X density functional. Two reaction mechanisms are proposed for the hydrogenation of CO2. In the bimolecular mechanism, the reaction proceeds in two steps, initiating by the co-adsorption of CO2 and H2 molecules over the surface, followed by the formation of a OCOH intermediate by the transfer of H atom of H2 toward O atom of CO2. In the next step, formic acid is produced as a favorable product with the formation of CH bond. In our proposed termolecular mechanism, however, H2 molecule is directly activated by the two pre-adsorbed CO2 molecules. The predicted activation energy for the formation of the OCOH intermediate in the bimolecular mechanism is 20.8 and 47.9kcalmol-1 over Pt- and Ni-doped graphene, respectively. On the contrary, the formation of the first formic acid in the termolecular mechanism is found as the rate-determining step over these surfaces, with an activation energy of 28.8 and 45.5kcal/mol. Our findings demonstrate that compared to the Ni-doped graphene, the Pt-doped surface has a relatively higher catalytic activity towards the CO2 reduction. These theoretical results could be useful in practical applications for removal and transformation of CO2 to value added chemical products. PMID- 28858643 TI - Exploring putative inhibitors of Death Associated Protein Kinase 1 (DAPK1) via targeting Gly-Glu-Leu (GEL) and Pro-Glu-Asn (PEN) substrate recognition motifs. AB - Recently, a new signaling complex Death Associated Protein Kinase 1 (DAPK1) N methyl-D-aspartate receptor subtype 2B (NMDAR2B or NR2B) engaged in the neuronal death cascade was identified and it was found that after stroke injury, N-methyl D-aspartate glutamate (NMDA) receptors interact with DAPK1 through NR2B subunit and lead to excitotoxicity via over-activation of NMDA receptors. An acute brain injury, such as stroke, is a serious life-threatening medical condition which occurs due to poor blood supply to the brain and further leads to neuronal cell death. During a stroke, activated DAPK1 migrates towards the extra-synaptic site and binds to NR2B subunit of NMDA receptor. It is this DAPK1-NR2B interaction that arbitrates the pathological processes like apoptosis, necrosis, and autophagy of neuronal cells observed in stroke injury, hence we aimed to inhibit this vital interaction to prevent neuronal damage. In the present study, using PubChem database, we applied an integrative approach of virtual screening and molecular dynamic simulations and identified a potential lead compound 11 that interrupts DAPK1-NR2B interaction by competing with both ATP and substrate for their binding sites on DAPK1. This inhibitor was found potent and considerably selective to DAPK1 as it made direct contact with the ATP binding sites as well as substrate recognition motifs: Gly-Glu-Leu (GEL) and Pro-Glu-Asn (PEN). Further in vitro and in vivo experiments are demanded to validate the efficacy of compound 11 nevertheless, it can be considered as suitable starting point for designing DAPK1 inhibitors. PMID- 28858644 TI - A computational theoretical model for radiofrequency ablation of tumor with complex vascularization. AB - Radiofrequency ablation (RFA) for liver tumors is a minimally invasive procedure that uses electrical energy and heat to destroy cancer cells. One of the critical factors that impedes its successful outcome is the thermal heat sink effects from complex vascular systems that give rise to incomplete destruction of the target tumor tissue, resulting in therapy failure. To better understand the thermal influence of the complex vascular system during RFA, this work proposes the employment of two 3D fractal tree-like branched networks to investigate which key factors of the tree-like vascular system impact heating process. A three dimensional finite difference analysis is employed to simulate the RFA treatment. Based on the data acquired from the measured experiments, the simulated results derived from combining the Pennes bioheat model and the boundary condition enforced immersed boundary method (IBM) have demonstrated close agreement with experimental data with a maximum discrepancy of +/-8.3%. We employed the orthogonal design approach to analyze 3 factors, namely, the blood vessel's volume, the average distance between probe center and the blood vessel system and the number of the selected part's branches at three different levels. Results have revealed that the distance between RFA probe and blood vessel plays a major role during the heating process compared with the other two factors. In addition, both the ablating rates and the volume of damaged tissue are slightly reduced with increasing number of blood vessel branches. PMID- 28858645 TI - Simulation study of the ionic mechanisms underlying Torsade de Pointes in a 2D cardiac tissue. AB - BACKGROUND: To understand the ionic mechanism behind the genesis of Torsade de Pointes (TdP) occurring with long QT syndrome 2 (LQTS2) in a remodelled transmural tissue. METHODS: The TP06 model is used to simulate the electrical activity of cells in a 2D transmural ventricular model. LQTS2 is realised by reducing the potassium current (IKr) to 0.5 in each cell. Each cell of the tissue is remodelled by increasing the conductance of calcium current (GCaL). The above two factors make the cells prone to early after depolarizations (EADs) development. The rise in GCaL that can develop a sustained TdP at normal pacing rate is determined from this study. A look at the calcium dynamics, sodium calcium exchanger current (INaCa) and slow delayed rectifier potassium current (IKs) distribution maps of the tissue helps us in analysing the mechanism of TdP generation. RESULTS: A TdP type pattern at normal pacing rate is generated when GCaL is more than 3.5 times the control parameter. From the M-cell island, an adequate number of cells spontaneously release calcium from their sarcoplasmic reticulum leading to increased intracellular calcium and inward sodium current through the sodium calcium exchanger current (INaCa). These contribute to the development of EADs which create a depolarising wavefront that triggers TdP in the tissue. When GCaL is less than 3.5 times the control value, premature ventricular complexes (PVC) occur interspersed between normal beats. CONCLUSION: Normal pacing rates can induce a multi focal TdP when sufficient number of M cells simultaneously undergo spontaneous calcium release (SCR) events. PMID- 28858646 TI - Inferring the effects of saliva on liquid bolus flow using computer simulation. AB - Computer simulation of liquid bolus flow is used to test the assumption that a slip boundary condition approximates a healthy swallow due to the presence of saliva lubricating the bolus. Six dynamic, 320-row area detector CT (ADCT) sequences of normal subjects swallowing thin, nectar, and honey-thick liquids are used in this work. The aerodigestive tract is segmented from the images in order to create a dynamic 3D geometry, which is subsequently used to drive a Smoothed Particle Hydrodynamics (SPH) fluid simulation of the bolus. The results show that the no-slip simulation, approximating no-lubrication, provides a closer match to the ADCT bolus images than the slip simulation, particularly in the oral phase. This finding suggests that the role of saliva in swallowing liquid boluses is not to lubricate the aerodigestive tract, and that there is another reason for its importance in normal swallowing of liquids. PMID- 28858647 TI - Hair segmentation using adaptive threshold from edge and branch length measures. AB - BACKGROUND: Non-invasive imaging techniques allow the monitoring of skin structure and diagnosis of skin diseases in clinical applications. However, hair in skin images hampers the imaging and classification of the skin structure of interest. Although many hair segmentation methods have been proposed for digital hair removal, a major challenge in hair segmentation remains in detecting hairs that are thin, overlapping, of similar contrast or color to underlying skin, or overlaid on highly-textured skin structure. METHODS: To solve the problem, we present an automatic hair segmentation method that uses edge density (ED) and mean branch length (MBL) to measure hair. First, hair is detected by the integration of top-hat transform and modified second-order Gaussian filter. Second, we employ a robust adaptive threshold of ED and MBL to generate a hair mask. Third, the hair mask is refined by k-NN classification of hair and skin pixels. RESULTS: The proposed algorithm was tested using two datasets of healthy skin images and lesion images respectively. These datasets were taken from different imaging platforms in various illumination levels and varying skin colors. We compared the hair detection and segmentation results from our algorithm and six other hair segmentation methods of state of the art. Our method exhibits high value of sensitivity: 75% and specificity: 95%, which indicates significantly higher accuracy and better balance between true positive and false positive detection than the other methods. PMID- 28858648 TI - Viscoelastic dynamic arterial response. AB - BACKGROUND: Arteries undergo large deformations under applied intraluminal pressure and may exhibit small hysteresis due to creep or relaxation process. The mechanical response of arteries depends, among others, on their topology along the arterial tree. Viscoelasticity of arterial tissues, which is the topic investigated in this study, is mainly a characteristic mechanical response of arteries that are located away from the heart and have increased smooth muscle cells content. METHODS: The arterial wall viscosity is simulated by adopting a generalized Maxwell model and the method of internal variables, as proposed by Bonet and Holzapfel et al. The total stresses consist of elastic long-term stresses and viscoelastic stresses, requiring an iterative procedure for their calculation. The cross-section of the artery is modeled as a circular ring, consisting of a single homogenized layer, under a time-varying blood pressure. Two different loading approximations for the aortic pressure vs time are considered. A novel numerical method is developed in order to solve the controlling integro-differential equation. RESULTS: A large number of numerical investigations are performed and typical response time-profiles are presented in pictorial form. Results suggest that the viscoelastic arterial response is mainly affected by the ratio of the relaxation time to the characteristic time of the response and by the pressure-time approximation. Numerical examples, based on data available in the literature, are conducted. CONCLUSIONS: The investigation presented in this study reveals the effect of each material parameter on the viscoelastic arterial response. Thus, a better understanding of the behavior of viscoelastic arteries is achieved. PMID- 28858649 TI - Magnetic chitosan/anaerobic granular sludge composite: Synthesis, characterization and application in heavy metal ions removal. AB - In present study, magnetic anaerobic granule sludge/chitosan (M-CS-AnGS) composite was synthesized and applied to remove Pb(II) and Cu(II) from aqueous solution. The physicochemical properties of prepared M-CS-AnGS were characterized by using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), Zeta potential analysis and X-ray photoelectron spectroscopy (XPS). The factors affecting adsorption performance in view of different sorbents, adsorbent dosage, pH value and contact time were conducted to obtain optimum conditions of Pb(II) and Cu(II) onto M-CS-AnGS. The adsorption kinetics of Pb(II) and Cu(II) were better fitted with pseudo-second-order kinetic mode and Langmuir isotherm. The maximum adsorption capacities for Pb(II) and Cu(II) were 97.97 and 83.65mg/g, respectively. According to FTIR, Zeta potential and XPS analysis, it was found that the adsorption mechanisms Pb(II) and Cu(II) onto M-CS AnGS were mainly caused by surface complexation and electrostatic attraction. In addition, M-CS-AnGS could be easily separated under an external magnetic field. The obtained result suggested that M-CS-AnGS composite could be used as a promising adsorbent for metal removal from aqueous solution. PMID- 28858650 TI - Surplus adsorption of bromide ion into pi-conjugated carbon nanospaces assisted by proton coadsorption. AB - Nanoporous carbons can preferentially adsorb bromide ions from an aqueous solution of alkali metal bromides, even on pi-conjugated surfaces. Our results show a new adsorption mechanism whereby coadsorption of protons enhances the adsorption of the anions onto the carbons. PMID- 28858651 TI - Synthesis of TiO2@g-C3N4 core-shell nanorod arrays with Z-scheme enhanced photocatalytic activity under visible light. AB - Novel rutile TiO2@g-C3N4 core-shell photocatalysts were synthesized by a facile saturated aqueous solution method. The composites were further characterized by using X-ray diffraction (XRD), high-resolution transmission microscopy (HRTEM), UV-visible light diffusion reflectance spectrometry (DRS), X-ray photoelectron spectroscopy (XPS) and so on. The results indicated that an ultrathin layer of g C3N4 was in-situ fabricated over the surface of rutile TiO2 nanorod. The rutile TiO2@ g-C3N4 core-shell structures showed much higher photo-current and photocatalytic activity for Rhodamine B (RhB) degradation under visible irradiation. The enhanced performance was attributed to the high separation efficiency of photo-induced carriers via a Z-scheme form. PMID- 28858652 TI - MnO2 nanotubes assembled on conductive graphene/polyester composite fabric as a three-dimensional porous textile electrode for flexible electrochemical capacitors. AB - A three-dimensional (3D) electrode material was successfully synthesized through a facile ZnO-assisted hydrothermal process in which vertical MnO2 nanotube arrays were in situ grown on the conductive graphene/polyester composite fabric. The morphology and structure of MnO2 nanotubes/graphene/polyester textile electrode were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The 3D electrode structure facilitates to achieve the maximum number of active sites for the pesudocapacitance redox reaction, fast electrolyte ion transportation and short ion diffusion path. The electrochemical measurements showed that the electrode possesses good capacitance capacity which reached 498F/g at a scan rate of 2mV/s in Na2SO4 electrolyte solution. The electrode also showed stable electrochemical performances under the conditions of long-term cycling, and mechanical bending and twisting. PMID- 28858653 TI - Facile fabrication of CNTs@C@MoSe2@Se hybrids with amorphous structure for high performance anode in lithium-ion batteries. AB - Amorphous MoSe2 and Se anchored on amorphous carbon coated multiwalled carbon nanotubes (CNTs@C@MoSe2@Se) have been synthesized by a facile solvothermal strategy. The one dimensional CNTs@C@MoSe2@Se can effectively buffer the volume variation, prohibit the aggregation and facilitate electron and ion transport throughout the electrode. Furthermore, the combination of MoSe2 and Se also provides buffer spaces for the volumetric change during cycling. Thus, the obtained CNTs@C@MoSe2@Se hybrids display the enhanced cycle stability and excellent high rate capacity. The reversible capacity of 1010mAhg-1 can be achieved after 100 cycles at the current density of 0.1Ag-1. Even after 500 cycles, a reversible capacity of 508mAhg-1 is still retained at 5Ag-1. PMID- 28858654 TI - Designing a high performance, stable spectroscopic biosensor for the binding of large and small molecules. AB - In the context of FTIR ATR-based sensors, the organic layer covering the ATR element has to be as stable as possible for optimal spectroscopic measurements. Previously, this self-assembled covering was considered stable after several hours under a PBS flux, probably due to a hydrophobic barrier, which prevents water penetration into the grafted network. Stability and reactivity, measured simultaneously using FTIR ATR, identify the limits of the previously used molecular construction. For the first time, surface etching of the previous functionalised Ge devices (Ge-PEG-NHS), a few minutes after BSA injection, was observed. It was concluded that the molecular chain deformation of Ge-PEG-NHS likely occurred when large molecules were bound. BSA loaded onto a Ge-PEG-NHS surface led to network deprotection, with the probable disruption of hydrogen bonds for single barrier-based networks. This, in turn, was presumably influenced by the random deposition of the NHS moiety on the PEG chain. A new functionalised germanium device, using a rapid three-step in situ procedure, provides an efficient robust network composed of two protective barriers, ideal for the binding of various sized molecules. The Ge-APS-PEG-NHS device has shown exceptional sensitivity with regards to BSA and ethanolamine target molecules while offering homogeneous NHS distribution. PMID- 28858655 TI - Highly sensitive and selective aptasensor for detection of adenosine based on fluorescence resonance energy transfer from carbon dots to nano-graphite. AB - In this article, a novel aptasensor was fabricated by modifying carbon dots (CDs) with adenosine aptamer (CDs-aptamer) for sensitive, selective and quantitative detection of adenosine (AD). When nano-graphite (NG) as an energy acceptor was added into the CDs-aptamer (energy donor) solution, the fluorescence of CDs aptamer was quenched due to fluorescence resonance energy transfer (FRET). When AD was present in the solution of CDs-aptamer/NG, the process of FRET was inhibited because of the specific combination between AD and AD aptamer. As a result, the fluorescence of CDs-aptamer was restored due to the dissociation of CDs-aptamer from NG and its change was proportional to the AD concentration. Under the optimized conditions, a linear range was found to be 2-50nM for the detection of AD with a detection limit of 0.63nM. Furthermore, the application of the proposed approach was demonstrated in real sample with satisfying results and it showed promise in diagnostic purpose. PMID- 28858656 TI - Achieving the interfacial polarization on C/Fe3C heterojunction structures for highly efficient lightweight microwave absorption. AB - Design of dielectric/magnetic heterostructure and multiple interfaces is a challenge for the microwave absorption. Thus, in this study, a novel C/Fe3C nanocomposites have been fabricated by annealing the precursors obtained by the facile chemical blowing of polyvinyl pyrrolidone (PVP) and Fe(NO3)3.9H2O. By changing the content of Fe(NO3)3.9H2O, the honeycomb-like structure with scads of pores and electromagnetic parameters could be successfully tailored. When the addition of Fe(NO3)3.9H2O is ranging from 1 to 2g, honeycomb-structured nanocomposites possess high performance microwave absorption when mixed with 90wt% paraffin. The minimal reflection loss is -37.4dB at 13.6GHz and effective bandwidth can reach to 5.6GHz when the thickness is 2.0mm, indicating its great potential in microwave absorbing field. Its outstanding microwave performance is tightly related to the porous structure and substantial interface such as carbon/air and carbon/Fe3C, which are in favor of the impedance matching and interfacial polarization. Thus, our study may provide a good reference for the facile synthesis of light-weight carbon-based nanocomposites with effective interfacial polarization. PMID- 28858657 TI - The classification of body dysmorphic disorder symptoms in male and female adolescents. AB - BACKGROUND: Body dysmorphic disorder (BDD) was categorised in DSM-5 within the newly created 'obsessive-compulsive and related disorders' chapter, however this classification remains subject to debate. Confirmatory factor analysis was used to test competing models of the co-occurrence of symptoms of BDD, obsessive compulsive disorder, unipolar depression, anxiety, and eating disorders in a community sample of adolescents, and to explore potential sex differences in these models. METHODS: Self-report questionnaires assessing disorder symptoms were completed by 3149 Australian adolescents. The fit of correlated factor models was calculated separately in males and females, and measurement invariance testing compared parameters of the best-fitting model between males and females. RESULTS: All theoretical models of the classification of BDD had poor fit to the data. Good fit was found for a novel model where BDD symptoms formed a distinct latent factor, correlated with affective disorder and eating disorder latent factors. Metric non-invariance was found between males and females, and the majority of factor loadings differed between males and females. Correlations between some latent factors also differed by sex. LIMITATIONS: Only cross sectional data were collected, and the study did not assess a broad range of DSM 5 defined eating disorder symptoms or other disorders in the DSM-5 obsessive compulsive and related disorders chapter. CONCLUSIONS: This study is the first to statistically evaluate competing models of BDD classification. The findings highlight the unique features of BDD and its associations with affective and eating disorders. Future studies examining the classification of BDD should consider developmental and sex differences in their models. PMID- 28858658 TI - Physical activity and suicidal ideation: A systematic review and meta-analysis. AB - BACKGROUND: A potential approach to suicide prevention that has not been closely examined, but which holds promise in terms of widespread dissemination without major side-effects, is physical activity (PA). This systematic review and meta analysis set out to: (a) explore associations between PA and suicidal ideation (SI) levels, and (b) investigate the effect of PA interventions on SI. METHODS: Major electronic databases were searched from inception up to 05/2017 to identify quantitative studies reporting an association between PA and SI. A quantitative correlates synthesis and random effects meta-analysis were conducted. RESULTS: Fourteen of 21 studies in adults (67%) (n = 130,737), 7/14 (50%) in adolescents (n = 539,170) and 2/3 (67%) in older adults (n = 50,745) found a significant negative association between PA- and SI-levels. Pooled adjusted meta-analysis of 14 effect sizes over eight studies and 80,856 people found that those who were "active" versus those who were "inactive" were less likely to have SI (OR = 0.87, 95%CI = 0.76-0.98). Additionally, meeting PA guidelines conferred a significant protective effect against SI (OR = 0.91, 95%CI = 0.51-0.99, P = 0.03; N studies = 3, n people = 122,395), while not meeting guidelines was associated with increased SI (OR = 1.16, 95%CI = 1.09-1.24, P < 0.001; N = 4, n = 78,860). Data from the intervention studies (N = 3, n = 121) was mixed and limited. LIMITATIONS: Our findings are based mainly on cross-sectional studies, while the majority of studies did not include a rigorous physical activity assessment. CONCLUSIONS: The current study suggests that higher PA levels are associated with lower SI. However, the associations observed need to be confirmed in prospective observational studies and controlled trials. PMID- 28858659 TI - Are self-report scales as effective as clinician rating scales in measuring treatment response in routine clinical practice? AB - OBJECTIVE: Recent treatment guidelines have suggested that outcome should be measured in routine clinical practice. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we compared three self-report scales of depressive symptoms and the two most widely used clinician administered scales in treatment studies in their sensitivity to change and evaluation of treatment response in depressed patients treated in routine practice. METHODS: At baseline and 4-month follow-up 153 depressed outpatients with DSM-IV MDD completed the Clinically Useful Depression Outcome Scale (CUDOS), Quick Inventory of Depressive Symptomatology-Self-report version (QIDS-SR), and Patient Health Questionnaire (PHQ-9). The patients were rated on the 17-item Hamilton Depression Rating Scale (HAMD) and the Montgomery-Asberg Depression Rating Scale (MADRS). On each scale treatment response was defined as a 50% or greater reduction in scores from baseline. RESULTS: While there were some differences in the percentage of patients considered to be responders on the different scales, a large effect size was found for each scale, with little variability amongst the scales. The level of agreement between the three self report scales and the clinician rating scales was approximately the same LIMITATIONS: The present study was conducted in a single clinical practice in which the majority of the patients were white, female, and had health insurance. DISCUSSION: When measuring outcome in clinical practice the magnitude of change in depressive symptoms is as great on self-report scales as on clinician rating scales. PMID- 28858660 TI - Amygdala-frontal connectivity predicts internalizing symptom recovery among inpatient adolescents. AB - BACKGROUND: The possibility of using biological measures to predict the trajectory of symptoms among adolescent psychiatric inpatients has important implications. This study aimed to examine emotion regulation ability (measured via self-report) and a hypothesized proxy in resting-state functional connectivity [RSFC] between the amygdala and frontal brain regions as baseline predictors of internalizing symptom recovery during inpatient care. METHODS: 196 adolescents (61% female; Mage = 15.20; SD = 1.48) completed the Achenbach Brief Problem Monitor (BPM) each week during their inpatient care. RSFC (n = 45) and self-report data of emotion regulation (n = 196) were collected at baseline. RESULTS: The average internalizing symptom score at admission was high (alpha0 = 66.52), exceeding the BPM's clinical cut off score of 65. On average, internalizing symptom scores declined significantly, by 0.40 points per week (p = 0.004). While self-reported emotion regulation was associated with admission levels of internalizing problems, it did not predict change in symptoms. RSFC between left amygdala and left superior frontal gyrus was significantly associated with the intercept-higher connectivity was associated with higher internalizing at admission-and the slope- higher connectivity was associated with a more positive slope (i.e., less decline in symptoms). RSFC between the right amygdala and the left superior frontal gyrus was significantly, positively correlated with the slope parameter. CONCLUSIONS: Results indicate the potential of biologically-based measures that can be developed further for personalized care in adolescent psychiatry. PMID- 28858661 TI - Skin permeability and transdermal delivery route of 50-nm indomethacin-loaded PLGA nanoparticles. AB - Recently, nano-seized systems for transdermal delivery have attracted attention. To efficiently deliver drugs to hair follicles, we focused on poly(DL-lactide-co glycolide) (PLGA) nanoparticles prepared using a combination of an antisolvent diffusion method with preferential solvation. The PLGA nanoparticles prepared using this method are suitable for iontophoresis because of their high surface charge number density. It has been reported that PLGA nanoparticles were delivered to hair follicles by applying iontophoresis, however research on PLGA nanoparticles with a size of less than 100nm was lacking. In this study, we prepared 50-nm and 100-nm PLGA nanoparticles. Indomethacin was used as a hydrophobic drug model and the nanoparticles were evaluated their skin permeability using the abdominal skin of a rat. Two hours after administration, the skin permeation indomethacin amounts of 50-nm and 100-nm PLGA nanoparticles with iontophoresis were significantly higher than those of passively diffused nanoparticles and indomethacin solution. Moreover, when iontophoresis was applied, the indomethacin concentration in the rat skin of 50-nm PLGA nanoparticles was 1.7 times higher than that of 100-nm PLGA nanoparticles. We also prepared coumarin-6-loaded 50-nm and 100-nm PLGA nanoparticles having surface characteristics equivalent to those of indomethacin-loaded PLGA nanoparticles to investigate transdermal delivery route of indomethacin-loaded PLGA nanoparticles. The 50-nm nanoparticles reached a deeper portion of the hair follicle when applying iontophoresis. Therefore, it was shown that this nanoparticle was useful for targeting to hair follicles. PMID- 28858662 TI - Surface engineering of organic nanoparticles for highly improved bioimaging. AB - Surface properties of nanoparticles (NPs) have a huge influence on their biological activities. In this work, we report to use mesoporous silica nanoshell surface to regulate the cellular internalization rate and intracellular fate of fluorescent organic NPs for highly improved cellular imaging. We systematically studied the internalization of the NPs into cells, the intracellular transport pathways, the excretion from cells, and very importantly, compared the results with those from various NPs with different surface properties. It was found that the silica nanoshell coating allow the NPs to achieve strikingly improved brightness in imaging (over ten-fold enhancement) and much higher delivery efficiency than other NPs. This was attributed to their unique non-clathrin- and non-caveolae-mediated pathways which enable them to enter cells very efficiently and quickly in the cellular internalization, as well as their low cellular excretion rate. This highly effective cellular imaging effect caused by silica surface coating is much desirable for applications in sensitive imaging and long term tracking of cells. PMID- 28858663 TI - Photoswitchable Janus glycodendrimer micelles as multivalent inhibitors of LecA and LecB from Pseudomonas aeruginosa. AB - The first example of the self-assembly and lectin binding properties of photoswitchable glycodendrimer micelles is reported. Light-addressable micelles were assembled from a library of 12 amphiphilic Janus glycodendrimers composed of variable carbohydrate head groups and hydrophobic tail groups linked to an azobenzene core. Spontaneous association in water gave cylindrical micelles with uniform size distribution as determined by dynamic light scattering (DLS) and small angle neutron scattering (SANS). Trans-cis photoisomerization of the azobenzene dendrimer core was used to probe the self-assembly behaviour and lectin binding properties of cylindrical micelles, revealing moderate-to-potent inhibition of lectins LecA and LecB from Pseudomonas aeruginosa. PMID- 28858664 TI - Fullerene-based amino acid ester chlorides self-assembled as spherical nano vesicles for drug delayed release. AB - Fullerenes with novel structures find numerous potential applications, particularly in the fields of biology and pharmaceutics. Among various fullerene derivatives, those exhibiting amphiphilic character and capable of self-assembly into vesicles are particularly interesting, being suitable for delayed drug release. Herein, we report the synthesis and self-assembly of biocompatible hollow nanovesicles with bilayer shells from amphiphilic functionalized fullerenes C60R5Cl (R=methyl ester of 4-aminobutyric/glutamic acid or phenylalanine). The thus prepared vesicles exhibit sizes of 80-135nm (depending on R) and can be used as delayed-release carriers of anti-cancer drugs such as 5 fluorouracil, cyclophosphamide, and cisplatin, with the time of 5-fluorouracil release from drug-containing vesicles exceeding that of non-encapsulated forms by a factor of three. We further reveal the effect of R on the loading amount and release rate/amount of vesicle-encapsulated drugs, demonstrating a potential pharmaceutical application of the prepared nanovesicles depending on the nature of R. PMID- 28858665 TI - Design considerations for a novel shape-memory-plate osteosynthesis allowing for non-invasive alteration of bending stiffness. AB - Biomechanical stimuli play a major role in fracture healing. Changing the fixation stiffness through the course of healing might accelerate bone healing and prevent healing complications. Shape memory alloy (SMA) based implants were developed to allow for non-invasive stiffness alteration during the fracture healing process. To gain a deeper understanding of the implant functionality based on the alloy characteristics and geometric design, the mechanical properties of different shape memory alloys where mechanically characterized. SMA bone plates were manufactured and the structural bending stiffness of the implants was determined at different temperatures and configurations. The temperature required for complete recovery of shape after deformation increased continuously with increasing pseudo-plastic deformation in SMA probes. Full recovery was observed at temperatures ranging from 38 degrees C to 52 degrees C after pseudo-plastic deformations ranging from 0.2% to 1.0% outer fibre strain, respectively. The small fragment inverse-dynamisation implants revealed bending stiffnesses ranging from 0.09Nm2 to 0.34Nm2 in the initial state and from 0.16Nm2 to 0.46Nm2 after shape alteration. Dependent on the design, a relative gain of the implant stiffness ranging from 18.8% to 115.0% could be observed. The large inverse-dynamisation implants revealed bending stiffnesses from 3.7Nm2 to 7.1Nm2 before and 4.1Nm2 to 12.6Nm2 after triggering the shape memory effect. Dependent on the design a gain in stiffness from 11.8% to 117.2% was observed. Warming the SMA implant to 40 degrees C for a short period of time, leads to a moderate increase in implant stiffness of up to 64.5%, while triggering the implant with 50 degrees C leads to a maximum increase in stiffness of up to 127.3%. The Nitinol shape memory bone plates have a huge potential for improving the treatment of long shaft fractures by allowing for the increase, decrease or incremental change of implant stiffness in fracture stabilization. However, the interaction between design, material properties, and manufacturing processes need to be carefully considered for each specific application to achieve optimum function of SMA-based, stiffness altering, fracture-fixation implants. PMID- 28858666 TI - Effect of alcohol stimulation on salivary pellicle formation on human tooth enamel surface and its lubricating performance. AB - This study was to investigate the salivary pellicle formation on the surface of human tooth enamel and its lubricating behavior under alcohol stimulation. Normal saliva and alcohol-stimulated saliva were collected from a young male volunteer after rinsing mouth with deionized water and different-concentration alcohol aqueous solution, respectively. Saliva-adsorption treatment was conducted in vitro on enamel surface to obtain salivary pellicle. Microscopic examinations and lubrication testing of salivary pellicle were performed by nanoscratch technology. Given that the pellicle lubricating properties are closely associated with its adhesion strength to substrates, the adhesion force between salivary pellicle and enamel was measured using an Atomic Force Microscopy. Compared with normal salivary pellicle, the salivary pellicle obtained from alcohol-stimulated saliva was not uniform anymore and even without any orderly multi-layer structure. Although alcohol stimulation improved the pellicle bonding to enamel surface, it caused the pellicle lubrication worse. In sum, the lubricating performance of salivary pellicle was more dependent on its orderly multi-layer structure from salivary protein self-assembly than its adhesion strength to enamel. PMID- 28858667 TI - The role of declarative and procedural metamemory in event-based prospective memory in school-aged children. AB - Prospective memory (PM) develops considerably during the primary school years (7 or 8years of age). Developmental changes have been mainly related to executive functions, although it has been recently suggested that PM would also potentially benefit from metamemory (MM). To date, only procedural MM, operationalized as performance predictions, has been investigated in relation to PM, whereas declarative MM has remained unexplored. Adults' performance has been shown to improve with predictions, but only in a resource-demanding (i.e., categorical) PM task rather than a more automatic (i.e., specific) one. The aim of the current investigation was to study whether PM performance of 7-year-old children (N=59) would benefit from performance predictions. Thus, half of the children predicted their performance and half of them received standard instructions for two PM tasks: one including categorical PM targets and one including specific ones. To investigate the processes underlying the retrieval of PM targets and the effect of predictions, we obtained measures for declarative MM, inhibitory control, and working memory (WM). Results revealed that children benefitted from performance predictions in the categorical PM task but not in the specific one. This advantage caused slower ongoing task response times, suggesting that strategic monitoring processes were enhanced. Moreover, PM performance was related to WM capacity and declarative MM. However, declarative MM mainly predicted PM advantage in the prediction group, showing that children with high MM knowledge benefitted especially from performance predictions. These findings are the first showing the important relation among procedural MM, declarative MM, and PM in school-aged children. PMID- 28858668 TI - Effects of Fe plaque and organic acids on metal uptake by wetland plants under drained and waterlogged conditions. AB - This study aims to assess the role of Fe plaque in metal uptake and translocation by different wetland plants and examine the effects of organic acids on metal detoxification in wetland plants. It was found that although exposed to a similar level of metals in rhizosphere soil solution, metal uptake by shoots of Cypercus flabelliformis and Panicum paludosum was greatly reduced, consequently leading to a better growth under flooded than under drained conditions. This may be related to the enhanced Fe plaque in the former, but due to the decreased root permeability in the latter under anoxic conditions. The Fe plaque on root surface has potential to sequester metals and then reduce metal concentrations and translocation in shoot tissues. However, whether the Fe plaque acts as a barrier to metal uptake and translocation may also be dependent on the root anatomy. Although metal tolerance in wetland plants mainly depends upon their metal exclusion ability, the higher-than-toxic-level of metal concentrations in some species indicates that internal metal detoxification might also exist. It was suggested that malic or citric acid in shoots of P. paludosum and C. flabelliformis may account for their internal detoxification for Zn. PMID- 28858669 TI - Allantoin contributes to the stress response in cadmium-treated Arabidopsis roots. AB - Ureides are nitrogen-rich compounds, derived from purine catabolism. A dual role for ureides, and for allantoin in particular, in both nitrogen recycling and the abiotic stress response has been recently identified. Previous work on the effect of allantoin on cadmium (Cd)-exposed Arabidopsis revealed that high concentration of allantoin in allantoinase-negative mutant (aln-3) leaves alleviates Cd toxicity via inducing antioxidant mechanisms in these plants. In the present study, we evaluate whether allantoin has a similar protective role in roots. Both wild type and aln-3 roots contain higher amounts of internal Cd compared to leaves. Likewise, aln-3 roots are more resistant to Cd, reflected in fresh and dry weight, and stimulated antioxidant enzyme activity, including superoxide dismutase (SOD) and catalase (CAT), resulting in lower reactive oxygen species concentration. In contrast with wild-type leaves, high levels of Cd in Col-0 roots reduces transcript abundance of uricase, leading to a significant decline in allantoin level of treated roots at 1000 and 1500 MUM CdCl2. This metabolite change is also accompanied by decreasing the activity of antioxidant enzymes (SOD and CAT). Additionally, contrary to wild-type leaves, root genotype has a significant effect on CAT activity under Cd treatment, suggesting the possible different sources of damage and oxidative stress response in these two tissues. PMID- 28858670 TI - Generalised inhibitory impairment to appetitive cues: From alcoholic to non alcoholic visual stimuli. AB - BACKGROUND: Prior research demonstrates that individuals who consume alcohol show diminished inhibitory control towards alcohol-related cues. However, such research contrasts predominantly alcoholic appetitive cues with non-alcoholic, non-appetitive cues (e.g., stationary items). As such, it is not clear whether it is specifically the alcoholic nature of the cues that influences impairments in inhibitory control or whether more general appetitive processes are at play. AIMS: The current study examined the hitherto untested assertion that the disinhibiting effects of alcohol-related stimuli might generalise to other appetitive liquid stimuli, but not to non-appetitive liquid stimuli. METHOD: Fifty-nine participants (Mage=21.63, SD=5.85) completed a modified version of the Stop Signal Task, which exposed them to visual stimuli of three types of liquids: Alcoholic appetitive (e.g., wine), non-alcoholic appetitive (e.g., water) and non appetitive (e.g., washing-up liquid). RESULTS: Consistent with predictions, Stop signal reaction time was significantly longer for appetitive (alcoholic, non alcoholic) compared to non-appetitive stimuli. Participants were also faster and less error-prone when responding to appetitive relative to non-appetitive stimuli on go-trials. There were no apparent differences in stop signal reaction times between alcoholic and non-alcoholic appetitive products. CONCLUSIONS: These findings suggest that decreases in inhibitory control in response to alcohol related cues might generalise to other appetitive liquids, possibly due to evaluative conditioning. Implications for existing research methodologies include the use of appetitive control conditions and the diversification of cues within tests of alcohol-related inhibitory control. PMID- 28858671 TI - Analysis of macrolide antibiotics in water by magnetic solid-phase extraction and liquid chromatography-tandem mass spectrometry. AB - Macrolides are one of the most commonly used families of antibiotics employed in human and veterinary treatment. These compounds are considered emerging contaminants with potential ecological and human health risks that could be present in surface water. This paper describes the development and application of a simple and efficient extraction procedure for the determination of tilmicosin; erythromycin, tylosin and erythromycin-H2O from water samples. Sample extraction was carried out using magnetic solid-phase extraction using oleate functionalized magnetic nanoparticles followed by LC-MS/MS analysis. The effects of several parameters on the extraction efficiency of MLs from water were evaluated. The recovery results obtained were >84% for most of the compounds, except for erytromycin. The LOD and LOQ values ranged from 11.5 to 26ngL-1 and from 34 to 77ngL-1, respectively. The selected method was applied to monitor these contaminants in water samples from different sources. Tilmicosin and tylosin were not detected in any of the samples, but erythromycin and erythromycin-H2O were found in 50% of the surface water samples at levels from 0.75). Correlations between instruments (Pearson's r = 0.51 to 0.77, p < 0.001) demonstrated good convergent validity. There was a medium to large effect (Cohen's d > 0.47) for mean differences in scores, for all instruments, between professions. CONCLUSIONS: This study found excellent internal consistency, test retest reliability and good convergent validity for the FABT, TSK-HC, and Back PAQ. Previously reported internal consistency, test-retest and convergent validity of the HC-PAIRS were confirmed, and test-retest reliability was excellent. There were significant scoring differences on each instrument between professions, and while both groups demonstrated fear avoidant beliefs, physiotherapist respondent scores indicated that as a group, they held fewer fear avoidant beliefs than osteopath respondents. PMID- 28858682 TI - Evaluation of a new generation platelet-derived hemostatic agent in a rabbit thrombocytopenic model. PMID- 28858683 TI - Upshaw-Schulman Syndrome: Novel homozygous missense mutation. PMID- 28858684 TI - What women want? A scoping survey on women's knowledge, attitudes and behaviours towards ovarian reserve testing and egg freezing. AB - OBJECTIVE: We aimed to investigate women's knowledge, attitudes and behaviours towards ovarian reserve testing and egg freezing for non-medical reasons in the general population. STUDY DESIGN: This was a cross-sectional survey study of 663 women aged 18-44 years which assessed female perception of ovarian reserve testing and oocyte cryopreservation. An online forum was used to deliver the survey through the use of two social media sites. Participants were recruited through the technique of "snowballing", whereby existing study subjects recruited others from among their acquaintances. The data collected was analyzed using SPSS to explore descriptive statistics and frequencies relating to the participants' knowledge, attitudes and behaviour towards the practices of ovarian reserve testing and oocyte cryopreservation. Categorical variables were analyzed using Chi-squared; a p-value of <0.05 was considered significant. RESULTS: A majority (60%) of women surveyed had knowledge of ovarian reserve testing. 64.8% would be interested in having testing performed. Younger women (<30 years of age) were more interested in checking their ovarian reserve (75.8% vs. 59.1%, p<0.0001). Single women were also more likely to be interested, (73.6% v's 62.1%, p=0.022). 89.7% of women surveyed were aware of oocyte cryopreservation. 72.2% agreed that they would consider freezing their eggs to preserve fertility. There was no significant difference in the numbers of single women compared to women in a relationship who would consider egg freezing to preserve fertility (75.7% v's 71.2%, p=0.347, or in younger (<30years) compared to older women, (74.7% v's 71.1%, p=0.387). A majority (62.1%) of study participants believed that it is a woman's right to postpone pregnancy for social reasons and to freeze her eggs, with no significant difference in options noted between younger and older women. CONCLUSIONS: Knowledge of ovarian reserve testing and oocyte cryopreservation for non-medical reasons were higher than in previous studies, possibly reflecting increasing awareness of these issues among the general public. Additionally, we demonstrated that the women, in our study, were very open to the use of these modern technologies in an attempt to avoid unintended childlessness. PMID- 28858685 TI - Laparoscopy during pregnancy: Case report and key points to improve laparoscopic management. AB - CASE REPORT: A 34-year-old woman in her 19th week of gestation was admitted to the Emergency Department of our hospital for acute abdominal pain. The patient was diagnosed with haemoperitoneum. Laparoscopy was performed and revealed acute bleeding from a crumbly superficial uterine vascular network. Haemostasis was achieved and both mother and foetus recovered well after surgery. A caesarean section was performed at 38 weeks, delivering a healthy newborn and revealing that the pregnancy had developed in a rudimentary hemiuterus. Laparoscopy during pregnancy is safe and feasible and can be performed in any trimestre of pregnancy with no differences in perinatal outcomes but, as intervention complexity increases with gestational age, laparoscopy during pregnancy should be performed by experienced surgeons To minimise surgical risk several recommendations should be taken into account: gravid patients should be positioned in a left-tilted supine position, trocar placement should be adjusted to uterine size and gas insuflattion of 10-15mmHg can be used. PMID- 28858686 TI - Nicotinic acetylcholine receptor alpha 7 stimulation dampens splenic myelopoiesis and inhibits atherogenesis in Apoe-/- mice. AB - BACKGROUND AND AIMS: Monocyte levels predict cardiovascular outcomes and play a causal role in atherogenesis. Monocytes can be produced in the spleen and track to the atherosclerotic lesion in significant numbers. The cholinergic system has been shown to have anti-inflammatory actions in the spleen. We aimed to explore whether therapeutic stimulation of the nicotinic acetylcholine receptor alpha 7 (nAChRalpha7) can suppress atherogenesis. METHODS: Apoe-/- mice were placed on a Western-type diet and treated with bi-daily injections of the nAChRalpha7 agonist GTS-21 or vehicle every 2-3 days for 8 weeks. RESULTS: GTS-21 caused a reduction in atherosclerosis in the aortic arch and proximal aorta. This also resulted in less plaque macrophages. Moreover, GTS-21 reduced the abundance of blood monocytes, which was caused by inhibition of inflammatory cytokines and extramedullary hematopoiesis in the spleen, along with splenic monocytes. CONCLUSIONS: Stimulation of nAChRalpha7 with GTS-21 reduced atherosclerosis, which was associated with dampened splenic myelopoiesis. PMID- 28858687 TI - Clinical epidemiology of tracheal invasion from thyroid cancer in Japanese population: Functional outcomes and effect of aging. AB - BACKGROUND: Although tracheal invasion from thyroid cancer is life-threatening, the epidemiology of its development remains unclear. This study aimed to determine the epidemiology (prevalence, incidence, and risk factors) and functional outcomes of tracheal invasion from thyroid cancer among Japanese patients who were eligible for full-layer tracheal resection. METHODS: Patients with thyroid cancer and with or without tracheal invasion were identified based on procedure codes using a large inpatient database that is maintained by a data vendor. The prevalence and incidence were estimated for each age and sex using Japanese volume of thyroidectomies and Japanese population data. We also explored whether a tumor-related tracheal defect was successfully reconstructed after full layer tracheal resection. RESULTS: Among the 8482 patients with thyroid cancer, the overall prevalence of tracheal invasion was 0.4-0.7%. The overall incidence of thyroid cancer was 12.0/100,000 persons, and the incidence of tracheal invasion was estimated to be 0.05-0.09/100,000 persons. The age distributions were noticeably different between thyroid cancer cases with and without tracheal invasion. The highest incidence was observed at ages of 70-79 years for thyroid cancer with tracheal invasion and 60-69 years for thyroid cancer without invasion. Approximately one-half of patients experienced long-term use of a tracheal tube and/or multiple operations for tracheal reconstruction. CONCLUSION: The peak incidence of tracheal invasion from thyroid cancer was observed at ages of >70years. In addition, conventional surgical management appears to be limited in its ability to reconstruct tracheal defects. PMID- 28858688 TI - Skill level constrains the coordination of posture and upper-limb movement in a pistol-aiming task. AB - The purpose of the experiment was to investigate whether skill level differentially organizes the coordination of the postural system and upper limb kinematics in a pistol-aiming task. Participants aimed an air-pistol at a target center in 30s trials as accurately as possible while standing on a force platform with shooting arm joint kinematics recorded. The novice group had greater motion of the pistol end point, arm joints and the center of pressure than the skilled group. Principal components analysis (PCA) showed that the skilled group required 2 components as opposed to the 3 components of the novice group to accommodate the variance. Coherence analysis in the 0-1Hz bandwidth revealed that the coupling between posture and upper-limb movement was stronger in the skilled than the novice group. The findings are consistent with the view that skill acquisition reduces the kinematic variables into a lower dimensional functional unit that in pistol-aiming is defined over the collective posture and upper-limb system. PMID- 28858689 TI - Ethanol levels in legally autopsied subjects: Analytical approach and epidemiological relevance in a prospective study in the touristic region of the Canary Islands (Spain). AB - The aim of this study was to analyze the presence of alcohol in individuals (137) that were subjected to a mandatory medico-legal autopsy in the Institute of Legal Medicine of Las Palmas (Canary Islands, Spain) during 2015. Blood and vitreous humor samples (232) were analyzed by gas chromatography. 46.0% of the individuals were positive for alcohol, being half of them tourists. Blood alcohol concentrations (BAC) was higher in men over 60 years (p = 0.041). 10.2% of the series died in a traffic accident, and victims had the highest proportion of positives to alcohol (64.3%) and the highest BAC (2.56 g/L, p = 0.048). The BAC:VHAC (alcohol in vitreous humor) ratio was higher among victims of traffic crashes (p = 0.036), suggesting a short elapsed interval between the alcohol intake and the fatal accident. The results of this study indicate that ethanol is still heavily involved in non-natural deaths. PMID- 28858690 TI - The influence of lake water alkalinity and humic substances on particle dispersion and lanthanum desorption from a lanthanum modified bentonite. AB - A 12 days laboratory study on potential desorption of Lanthanum (La) from a commercial La modified clay (Phoslock) was conducted using lake water from 17 Danish lakes with alkalinities between 0.02 and 3.7 meq L-1 and varying concentrations of DOC and humic acids (HA's). A similar study was conducted in artificial lake water with alkalinities from 0 to 2.5 meq L-1in order to exclude interference from dissolved HA's. To test if La in solution (FLa) was associated with fine particles, the water samples were filtered sequentially through three filter sizes (1.2 MUm, 0.45 MUm and 0.2 MUm), and finally, ultracentrifugation was used in an attempt to separate colloidal La from dissolved La. The study showed that higher FLa (up to 2.5 mg L-1 or 14% of the total La in the Phoslock) concentrations were found in soft water lakes compared to hard water lakes, probably due to dispersion of the clay at low alkalinities. In addition, this study showed that HA's seem to increase the FLa concentrations in soft water lakes, most likely through complexation of La retained in the Phoslock matrix. In summary, we conclude that elevated La concentrations in lake water after a Phoslock treatment should only be expected in soft water lakes rich in DOC and HA's. PMID- 28858692 TI - Modeling hepatitis virus infections and treatment strategies in humanized mice. AB - Hepatitis viruses cause chronic liver diseases such as fibrosis, cirrhosis and hepatocellular carcinomas that are difficult to treat and constitute a global health problem. Species-specific viral tropism has limited the usefulness of small animal models to study the impact of viral hepatitis. Immunodeficient mice grafted with human hepatocytes are susceptible to hepatitis viruses B, C, D and E (HBV, HCV, HDV and HEV), developing full viral life cycles, and delivering a means to investigate virus-host interactions and antiviral treatments. These chimeric humanized mouse models have been further grafted with humanized immune systems to decipher immune responses following hepatotropic viral infections, the ensuing pathophysiology, and to test novel therapeutic strategies. PMID- 28858691 TI - Pharmacological challenge studies with acute psychosocial stress. AB - Chronic stress is known to affect many psychiatric disorders, and studies of responses to acute stress may reveal processes that ultimately lead to maladaptive responses to chronic stress. Many studies have used simulated public speaking tasks to induce stress in the laboratory and, of interest to this review, the tasks have been used to assess the effects of both therapeutic and nonmedical drugs on stress reactivity. Here we review 38 studies that examined effects of single doses of drugs on subjective, cardiovascular and hormonal responses to an acute social stressor in healthy volunteers. Most studies have used the Trier Social Stress Test (TSST), or variations on it involving public speaking or mental arithmetic. Pharmacological studies with the TSST (ph-TSST) have been conducted for three main reasons: i) to determine the clinical effectiveness of psychiatric medications to reduce stress responses, ii) to investigate the neurochemical mechanisms involved in the stress response, and iii) to determine whether drugs of abuse relieve, or occasionally worsen, responses to acute stress. The review indicates that standard anxiolytic medications consistently reduce subjective responses to the TSST, whereas single doses of antidepressants produce mixed effects. Mechanistic studies indicate that several neurotransmitter systems are involved in the stress response, including serotonin, norepinephrine, GABA, glutamate, opioids, and endocannabinoids. Among drugs of abuse, alcohol and cannabinoids exert some stress-dampening effects, whereas caffeine, nicotine, and amphetamines tend to increase stress responses. Comparing outcome measures of the responses to stress, subjective ratings of anxiety are among the most sensitive indices of the stress response, with cortisol levels second and cardiovascular responses least sensitive. We conclude that the TSST is a valuable tool to study the clinical effectiveness of medications for stress-related disorders, and that it is important to use standardized procedures to enable comparisons across studies. PMID- 28858693 TI - Trends in average days' supply of opioid medications in Medicaid and commercial insurance. AB - OBJECTIVES: To calculate trends in adult average days' supply for six commonly prescribed opioids: hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tapentadol to assess whether physicians changed prescribing practices at the time of the intensifying epidemic. METHODS: We used 2005-2015 Truven Health MarketScan Commercial Claims and Encounters data to measure trends in opioid average days' supply among commercially insured individuals and 2005-2014 MarketScan Multi-State Medicaid data to measure trends in opioid average days' supply among Medicaid beneficiaries. RESULTS: For Medicaid, we found an increase in days' supply for all drugs except morphine. The largest percentage increase was for oxycodone, which increased 4.5days (37%). Opioid days' supply for individuals with commercial insurance exhibited similar but steeper trends. The largest increase was also for oxycodone, which increased 6days (56%). Between 2013 and 2015, when the opioid epidemic had begun to be widely publicized, there was no decline in the median days supplied for any of the opioids. CONCLUSIONS: Our results find that days' supply of opioids are increasing despite public health campaigns and media attention on the risks of opioid prescribing. More effective interventions to curb opioid prescribing are needed to reverse these trends. PMID- 28858694 TI - Recent cannabis use among Veterans in the United States: Results from a national sample. AB - BACKGROUND: Compared to civilians, little is known about cannabis use among Veterans in the general United States (US) population. This study aimed to examine the prevalence and correlates of recent medical and non-medical cannabis use among this important US sub-population. METHOD: Data came from the 2014 National Survey on Drug Use and Health. Bivariate and multivariable analyses were conducted that were weighted to account for the complex survey design. RESULTS: Approximately 9% of Veterans in the US reported past year cannabis use. Older, and female, Veterans had lower odds of past year cannabis use. Veterans who were unmarried, out of the work force, had greater functioning disability, nicotine dependence, heavy episodic alcohol use, alcohol use disorder, and drug use had greater odds of past year cannabis use. In states where medical cannabis was legal in 2014, approximately 41% of Veterans who used cannabis in the past year used medically. Those who used medically were older and less likely to engage in recent heavy episodic drinking or to meet criteria for alcohol abuse/dependence, compared to Veterans using non-medically. CONCLUSION: Compared to non-Veterans in the US general population, recent cannabis use was similar or slightly lower among Veterans. However, among those with past year use, the proportion of those using medically was more than double that of the general population. Because only non-medical cannabis use was associated with higher rates of heavy episodic alcohol use and alcohol use disorder, it may be important to address problematic alcohol consumption among this high-risk group. PMID- 28858695 TI - Interest in and reactions to genetic risk information: The role of implicit theories and self-affirmation. AB - RATIONALE: Implicit theories reflect core assumptions about whether human attributes are malleable or fixed: Incremental theorists believe a characteristic is malleable whereas entity theorists believe it is fixed. People with entity theories about health may be less likely to engage in risk-mitigating behavior. Spontaneous self-affirmation (e.g., reflecting on one's values when threatened) may lessen defensiveness and unhealthy behaviors associated with fixed beliefs, and reduce the likelihood of responding to health risk information with fixed beliefs. METHOD: Across two studies conducted in the US from 2012 to 2015, we investigated how self-affirmation and implicit theories about health and body weight were linked to engagement with genetic risk information. In Study 1, participants in a genome sequencing trial (n = 511) completed cross-sectional assessments of implicit theories, self-affirmation, and intentions to learn, share, and use genetic information. In Study 2, overweight women (n = 197) were randomized to receive genetic or behavioral explanations for weight; participants completed surveys assessing implicit theories, self-affirmation, self-efficacy, motivation, and intentions. RESULTS: Fixed beliefs about weight were infrequently endorsed across studies (10.8-15.2%). In Study 1, participants with stronger fixed theories were less interested in learning and using genetic risk information about medically actionable disease; these associations were weaker among participants higher in self-affirmation. In Study 2, among participants given behavioral explanations for weight, stronger fixed theories about weight were associated with lower motivation and intentions to eat a healthy diet. Among participants given genetic explanations, being higher in self-affirmation was associated with less fixed beliefs. CONCLUSION: Stronger health-related fixed theories may decrease the likelihood of benefiting from genetic information, but less so for people who self-affirm. PMID- 28858696 TI - Social support, flexible resources, and health care navigation. AB - Recent research has focused attention on the role of patients' and clinicians' cultural skills and values in generating inequalities in health care experiences. Yet, examination of how social structural factors shape people's abilities to build, refine, and leverage strategies for navigating the health care system have received less attention. In this paper I place focus on one such social structural factor, social support, and examine how social support operates as a flexible resource that helps people navigate the health care system. Using the case of families navigating pediatric cancer care this study combines in-depth interviews with parents of pediatric cancer patients (N = 80), direct observation of clinical interactions between families and physicians (N = 73), and in-depth interviews with pediatric oncologists (N = 8). Findings show that physicians assess parental visibility in the hospital, medical vigilance, and adherence to their child's treatment and use these judgments to shape clinical decision making. Parents who had help from their personal networks had more agility in balancing competing demands, and this allowed parents to more effectively meet institutional expectations for appropriate parental involvement in the child's health care. In this way, social support served as a flexible resource for some families that allowed parents to more quickly adapt to the demands of caring for a child with cancer, foster productive interpersonal relationships with health care providers, and play a more active role in their child's health care. PMID- 28858698 TI - Insomnia identity. AB - Insomnia identity refers to the conviction that one has insomnia, and this sleep complaint can be measured independently of sleep. Conventional wisdom predicts that sleep complaints are synchronous with poor sleep, but crossing the presence or absence of poor sleep with the presence or absence of insomnia identity reveals incongruity with expected patterns. This review of existing research on insomnia identity processes and influence finds that about one-fourth of the population are uncoupled sleepers, meaning there is an uncoupling of sleep and sleep appraisal, and daytime impairment accrues more strongly to those who endorse an insomnia identity. Research supports the conclusion that there is a cost to pathologizing sleep. Individuals claiming an insomnia identity, regardless of sleep status, are at greater risk for a range of sequelae including self-stigma, depression, suicidal ideation, anxiety, hypertension, and fatigue. A broad research agenda is proposed with hypotheses about the sources, clinical mechanisms, and clinical management of insomnia identity. PMID- 28858697 TI - Post-conflict struggles as networks of problems: A network analysis of trauma, daily stressors and psychological distress among Sri Lankan war survivors. AB - A growing body of literature indicates that the mental distress experienced by survivors of war is a function of both experienced trauma and stressful life events. However, the majority of these studies are limited in that they 1) employ models of psychological distress that emphasize underlying latent constructs and do not allow researchers to examine the unique associations between particular symptoms and various stressors; and 2) use one or more measures that were not developed for that particular context and thus may exclude key traumas, stressful life events and symptoms of psychopathology. The current study addresses both these limitations by 1) using a novel conceptual model, network analysis, which assumes that symptoms covary with each other not because they stem from a latent construct, but rather because they represent meaningful relationships between the symptoms; and 2) employing a locally developed measure of experienced trauma, stressful life problems and symptoms of psychopathology. Over the course of 2009 2011, 337 survivors of the Sri Lankan civil war were administered the Penn-RESIST Peradeniya War Problems Questionnaire (PRPWPQ). Network analysis revealed that symptoms of psychopathology, problems pertaining to lack of basic needs, and social problems were central to the network relative to experienced trauma and other types of problems. After controlling for shared associations, social problems in particular were the most central, significantly more so than traumatic events and family problems. Several particular traumatic events, stressful life events and symptoms of psychopathology that were central to the network were also identified. Discussion emphasizes the utility of such network models to researchers and practitioners determining how to spend limited resources in the most impactful way possible. PMID- 28858699 TI - Parent-child interactions in children with asthma and anxiety. AB - Anxiety disorders are highly prevalent in children with asthma yet very little is known about the parenting factors that may underlie this relationship. The aim of the current study was to examine observed parenting behaviours - involvement and negativity - associated with asthma and anxiety in children using the tangram task and the Five Minute Speech Sample (FMSS). Eighty-nine parent-child dyads were included across four groups of children (8-13 years old): asthma and anxiety, anxiety only, asthma only and healthy controls. Overall, results from both tasks showed that parenting behaviours of children with and without asthma did not differ significantly. Results from a subcomponent of the FMSS indicated that parents of children with asthma were more overprotective, or self sacrificing, or non-objective than parents of children without asthma, and this difference was greater in the non-anxious groups. The results suggest that some parenting strategies developed for parents of children with anxiety may be useful for parents of children with asthma and anxiety (e.g. strategies targeting involvement), however, others may not be necessary (e.g. those targeting negativity). PMID- 28858700 TI - Modulation of motor cortex excitability by paired peripheral and transcranial magnetic stimulation. AB - OBJECTIVE: Repetitive application of peripheral electrical stimuli paired with transcranial magnetic stimulation (rTMS) of M1 cortex at low frequency, known as paired associative stimulation (PAS), is an effective method to induce motor cortex plasticity in humans. Here we investigated the effects of repetitive peripheral magnetic stimulation (rPMS) combined with low frequency rTMS ('magnetic-PAS') on intracortical and corticospinal excitability and whether those changes were widespread or circumscribed to the cortical area controlling the stimulated muscle. METHODS: Eleven healthy subjects underwent three 10min stimulation sessions: 10HzrPMS alone, applied in trains of 5 stimuli every 10s (60 trains) on the extensor carpi radialis (ECR) muscle; rTMS alone at an intensity 120% of ECR threshold, applied over motor cortex of ECR and at a frequency of 0.1Hz (60 stimuli) and magnetic PAS, i.e., paired rPMS and rTMS. We recorded motor evoked potentials (MEPs) from ECR and first dorsal interosseous (FDI) muscles. We measured resting motor threshold, motor evoked potentials (MEP) amplitude at 120% of RMT, short intracortical inhibition (SICI) at interstimulus interval (ISI) of 2ms and intracortical facilitation (ICF) at an ISI of 15ms before and immediately after each intervention. RESULTS: Magnetic-PAS, but not rTMS or rPMS applied separately, increased MEP amplitude and reduced short intracortical inhibition in ECR but not in FDI muscle. CONCLUSION: Magnetic-PAS can increase corticospinal excitability and reduce intracortical inhibition. The effects may be specific for the area of cortical representation of the stimulated muscle. SIGNIFICANCE: Application of magnetic-PAS might be relevant for motor rehabilitation. PMID- 28858701 TI - Systems-level interference strategies to decipher host factors involved in bacterial pathogen interaction: from RNAi to CRISPRi. AB - Bacterial pathogen-host cell interactions involve an intricate interplay of multiple components from both partners. Systems level surveys have been used widely to profile host requirements for pathogen infection. Functional genomics, and more specifically genome-wide perturbation screens, constitute attractive methodologies to assess such host infectomes. Although these strategies have successfully identified numerous critical host factors, they may have failed in generating the high-quality data required for systems level analysis. This is the case for most RNA interference (RNAi) setups with their high propensity to off target effects (OTE). However, recent efforts to circumvent OTE in RNAi-based experiments as well as the emergence of alternative strategies will likely soon allow significant breakthrough in the systems level understanding of bacterial pathogen-host interactions. PMID- 28858702 TI - Large-scale projects in the amazon and human exposure to mercury: The case-study of the Tucurui Dam. AB - The Tucurui Dam is one of the largest dams ever built in the Amazon. The area is not highly influenced by gold mining as a source of mercury contamination. Still, we recently noted that one of the most consumed fishes (Cichla sp.) is possibly contaminated with methylmercury. Therefore, this work evaluated the mercury content in the human population living near the Tucurui Dam. Strict exclusion/inclusion criteria were applied for the selection of participants avoiding those with altered hepatic and/or renal functions. Methylmercury and total mercury contents were analyzed in hair samples. The median level of total mercury in hair was above the safe limit (10ug/g) recommended by the World Health Organization, with values up to 75ug/g (about 90% as methylmercury). A large percentage of the participants (57% and 30%) showed high concentrations of total mercury (>= 10ug/g and >= 20ug/g, respectively), with a median value of 12.0ug/g. These are among the highest concentrations ever detected in populations living near Amazonian dams. Interestingly, the concentrations are relatively higher than those currently shown for human populations highly influenced by gold mining areas. Although additional studies are needed to confirm the possible biomagnification and bioaccumulation of mercury by the dams in the Amazon, our data already support the importance of adequate impact studies and continuous monitoring. More than 400 hydropower dams are operational or under construction in the Amazon, and an additional 334 dams are presently planned/proposed. Continuous monitoring of the populations will assist in the development of prevention strategies and government actions to face the problem of the impacts caused by the dams. PMID- 28858703 TI - Tolerance and bioaccumulation of Cd and Cu in Sesuvium portulacastrum. AB - In order to investigate the tolerance and bioaccumulation of Cd and Cu in the halophyte Sesuvium portulacastrum, seedlings were hydroponically cultured for 30 days using the modified 1/2 Hoagland nutrient solution with different concentrations of Cd (0, 5, 10, 15, and 20mgL-1) and Cu (0, 2.5, 5, 7.5, and 10mgL-1). Afterwards, the seedling height, leaf area, biomass, and mineral element contents (Fe, Mg, Cu, and Zn) in the roots, stems and leaves were measured, and the tolerance index, bioconcentration factor (BCF), transportation index, and removal rate were calculated. The effects of salinity (00/00-300/00) on the growth and bioaccumulation ability of S. portulacastrum under combined Cu/Cd (5mgL-1) exposure were also determined. The results showed that, with an increasing Cd concentration, the biomass and seedling height of S. portulacastrum initially increased and then decreased. The highest leaf biomass and seedlings height was observed in the 10mgL-1 and 5mgL-1 Cd treatment group, respectively. Salinity did not affect the biomass of S. portulacastrum but decreased Cd concentration in roots and aboveground tissues and Cu concentration in roots of S. portulacastrum. Cu treatment significantly facilitated the absorption of Mg, Cu, and Zn in roots. With an increasing Cu concentration, the Mg and Fe contents increased in the leaves of S. portulacastrum. In comparison to the above-ground portions, the root showed a higher bioaccumulation ability of Cd and Cu, with the BCF of 341.5 and 211.9, respectively. The BCF and translocation factor (TF) values indicated that S. portulacastrum was not a hyperaccumulator for Cd and Cu, but could be used as a phytostablization plant in heavy metal contaminated coastal environments. PMID- 28858704 TI - Interactive effects of supplemental ultraviolet-B radiation and indole-3-acetic acid on Coleus forskohlii Briq.: Alterations in morphological-, physiological-, and biochemical characteristics and essential oil content. AB - Ultraviolet (UV)-B radiation and the growth hormone indole-3-acetic acid (IAA) have been known to cause various changes in plants at morphological and physiological levels as individual entities, but their interactive effects on the overall plant performance remain practically unknown. The present study was conducted under near-natural field conditions to evaluate the effects of supplemental (s)-UV-B (ambient+3.6kJm-2day-1) treatment alone, and in combination with two doses of IAA (200ppm and 400ppm) exogenously applied as foliar spray on various growth-, morphological-, physiological-, and biochemical parameters of an indigenous medicinal plant, Coleus forskohlii. Under s-UV-B, the plant growth and morphology were adversely affected (along with reductions in protein- and chlorophyll contents) with concomitant increase in secondary metabolites (as substantiated by an increase in the activities of various enzymes of the phenylpropanoid pathway) and cumulative antioxidative potential (CAP), suggesting the plant's capability of adaptive resilience against UV-B. The essential oil content of the plant was, however, compromised reducing its pharmaceutical value. IAA application at both doses led to a reversal in the effects caused by s-UV-B radiation alone; both the plant growth as well as the essential oil content improved, especially at the higher IAA dose, suggesting its ameliorative role against UV-B induced oxidative stress, and also in improving the plant's medicinal value. PMID- 28858705 TI - Effects of short- and long-term exposures to copper on lethal and reproductive endpoints of the harpacticoid copepod Tigriopus fulvus. AB - The long-term exposure provides a realistic measurement of the effects of toxicants on aquatic organisms. The harpacticoid copepod Tigriopus fulvus has a wide geographical distribution and is considered as an ideal model organism for ecotoxicological studies for its good sensitivity to different toxicants. In this study, acute, sub-chronic and chronic toxicity tests based on lethal and reproductive responses of Tigriopus fulvus to copper were performed. The number of moults during larval development was chosen as an endpoint for sub-chronic test. Sex ratio, inhibitory effect on larval development, hatching time, fecundity, brood number, nauplii/brood, total newborn production, etc, were calculated in the chronic test (28d). Lethal effect of copper to nauplii showed the LC50-48h of 310 +/- 72ugCu/L (mean +/- sd). It was observed a significant inhibition of larval development at sublethal copper concentrations, after 4 and 7 d. After 4d, the EC50 value obtained for the endpoint in "moult naupliar reduction" was of 55.8 +/- 2.5ugCu/L (mean +/- sd). The EC50 for the inhibition of naupliar development into copepodite stage, was of 21.7 +/- 4.4ugCu/L (mean +/ sd), after 7 days. Among the different traits tested, copper did not affect sex ratio and growth, while fecundity and total nauplii production were the most sensitive endpoints. The reproductive endpoints offer the advantage of being detectable at very low pollutant concentrations. PMID- 28858706 TI - Comparative investigation of toxicity and bioaccumulation of Cd-based quantum dots and Cd salt in freshwater plant Lemna minor L. AB - The purpose of this study was to determine the toxicity of two different sources of cadmium, i.e. CdCl2 and Cd-based Quantum Dots (QDs), for freshwater model plant Lemna minor L. Cadmium telluride QDs were capped with two coating ligands: glutathione (GSH) or 3-mercaptopropionic acid (MPA). Growth rate inhibition and final biomass inhibition of L. minor after 168-h exposure were monitored as toxicity endpoints. Dose-response curves for Cd toxicity and EC50168h values were statistically evaluated for all sources of Cd to uncover possible differences among the toxicities of tested compounds. Total Cd content and its bioaccumulation factors (BAFs) in L. minor after the exposure period were also determined to distinguish Cd bioaccumulation patterns with respect to different test compounds. Laser-Induced Breakdown Spectroscopy (LIBS) with lateral resolution of 200um was employed in order to obtain two-dimensional maps of Cd spatial distribution in L. minor fronds. Our results show that GSH- and MPA capped Cd-based QDs have similar toxicity for L. minor, but are significantly less toxic than CdCl2. However, both sources of Cd lead to similar patterns of Cd bioaccumulation and distribution in L. minor fronds. Our results are in line with previous reports that the main mediators of Cd toxicity and bioaccumulation in aquatic plants are Cd2+ ions dissolved from Cd-based QDs. PMID- 28858707 TI - Assessing potential release tendency of As, Mo and W in the tributary sediments of the Three Gorges Reservoir, China. AB - As the largest man-made reservoir in China, the Three Gorges Reservoir (TGR) has significant influence on national drinking water safety. The geochemical behavior of trace elements at the sediment-water interface (SWI) is still unknown. The mobilization characteristics of trace elements (As, Mo and W)-determined by diffusive gradients in thin films (DGT)-were studied to quantitatively calculate the release trends in the SWI in three typical tributaries and the mainstream of the TGR in the summer. The results showed that concentrations of DGT-labile As, Mo and W in the overlying water and sediment cores showed significant variations in the ranges of 0.05-50.90, 0.30-1.63 and 0.01-0.42MUgL-1, respectively. The apparent net diffusive fluxes were significantly positive in most sampling sites (77.8% for As, 88.8% for Mo and 66.6% for W), suggesting that the sediment was the source of these three elements. It was noteworthy that the maximum net diffusive fluxes of As and W were found in the upstream of Meixi tributary, which may be attributed to anthropogenic activities. In addition, As, Mo and W may be incorporated in Fe and Mn oxyhydroxides and these three elements simultaneously remobilized with Fe and Mn. PMID- 28858708 TI - The time-dependent stimulation of sodium halide salts on redox reactants, energy supply and luminescence in Vibrio fischeri. AB - The excess of halide ions (F-, Cl-, Br-, I-) can cause adverse effects. Earlier studies demonstrated time-dependent stimulations of organic salts with halide ions on photobacteria. Therefore, inorganic ones with halide ions (e.g., NaX, X=F , Cl-, Br-, I-) were assumed to cause similar effects. In the present study, Vibrio fischeri was exposed to NaX. Results showed that the contents of favin mono-nucleotide (FMN), nicotinamide adenine dinucleotide (NADH), and nicotinamide adenine dinucleotide phosphate (NADPH) were stimulated by NaX with a time dependent fashion. The maximum stimulations on FMN at 24h were 172%, 168%, 211% and 298% of the control (p<0.05) in NaF, NaCl, NaBr and NaI, respectively, with an order of NaF~NaCl Cu (63.13 +/- 31.72) > Cr (22.29 +/- 30.23) > Cd (14.54 +/- 4.28) > Ni (9.41 +/- 11.33) > Pb (2.22 +/- 1.33) > As (0.58 +/- 0.91) > Hg (0.04 +/- 0.06). Bioconcentration Factor (BCF) and Biota Sediment Accumulation Factor (BSAF) exhibited that C. gigas in the region are strong accumulators for Zn and Cd respectively. Thus, the present study proves to fulfill the gap in understanding the rate of bioaccumulation of metals in C. gigas which is regarded as the most sought after oyster species globally. PMID- 28858713 TI - Assessment of indoor air quality exposures and impacts on respiratory outcomes in River Rouge and Dearborn, Michigan. AB - Ambient air pollution is a public health issue which could potentially exacerbate pre-existing respiratory conditions and contribute to increases in asthma incidence. This study aims to address gaps in understanding how IAQ is impacted by outdoor air quality, which was done by sampling for indoor gaseous and particulate pollutants in residence and facilities near the sources of pollution. The study areas were selected due to non-attainment status with air quality standards, as well as demographic and socioeconomic status of those residing in these areas. Samples are obtained from five locations around the study areas. The sampling procedure involves active sampling methodologies for particulate matter (PM) and gases. Average volatile organic compounds (VOC) levels of 2.71 ppm were measured at a location, while the average particulate matter (PM) concentrations in three study locations were; 15,979 pt/cc, 9533 pt/cc, 5267 pt/cc respectively, which exceeded clean background environment level of 500-2000 pt/cc. All locations had average CO concentrations above 0.3 ppm, which is potentially associated with elevated asthma symptoms. Results demonstrated that facilities in the study area have increased levels of indoor air pollutants that potentially increase asthma and respiratory issues. The study concludes that particulate and gaseous pollutant levels in the study areas are a concerning human health issue. The study outcomes have significant implications for air quality exposure modeling and potential exposure mitigation strategies, which are expected to facilitate the implementation of public policies for improved human health conditions. PMID- 28858714 TI - The influence of environmental conditions on lead transfer from spent gunshot to sediments and water: Other routes for Pb poisoning. AB - Lead (Pb) from spent gunshot and fishing sinkers is recognized as the main source of Pb poisoning among waterfowl. It is also suspected to directly pollute water and sediments, but no appropriate, comprehensive evaluation of this issue has so far been carried out. An experiment on Pb pellets in microcosms (n = 160) with two sediment types (mud and gravel), three water pH values (4, 7 and 9) and two wind levels (wind and windless simulation) was therefore run. Substantial differences in Pb transfer (measured with ICP-OES) between sediment types and pH levels of water were observed. Simulated wind conditions were a significant factor only for some variables and circumstances. The strongest Pb deposit to water and sediments occurred in mud microcosms with water of pH value of 4. Median pellet erosion during the experiment differed little between sediment types. The experiment revealed that Pb transfer from spent gunshot to the environment occurs only in specific environmental conditions. PMID- 28858715 TI - Effects of chloride on PMS-based pollutant degradation: A substantial discrepancy between dyes and their common decomposition intermediate (phthalic acid). AB - A considerable effort has been devoted to elucidating the roles of chloride in oxidative degradation and chlorination of dyes. However, few investigations are available on kinetic analysis and transformation pathways of secondary degradation byproducts of dyes in saline wastewater treatment. Here the impact of chlorine on the degradation rate of phthalic acid, a typical dye degradation intermediate, by the Co2+/peroxymonosulfate (PMS) process was examined. Degradation efficiency, intermediate products, AOX (adsorbable organic halogen) formation and mineralization were considered. An overall negative impact was observed within the concentration of Cl- up to 100 mM, differing from the dual effect of chloride on dye degradation process as previously observed. The presence of high levels of Cl- led to a low production of AOX and a reduction of the formation of chlorinated by-products. The mineralization was also restrained when the Cl- concentration was increased. Degradation pathways for these processes are proposed. These findings provide valuable information about the degradation pathways of dyes and about the formation mechanism of chlorinated by products in industrial saline wastewater treatment. PMID- 28858716 TI - Assessment of toxic effects of magnetic particles used for lake restoration on Chlorella sp. and on Brachionus calyciflorus. AB - Laboratory tests, by following standardized Organization for Economic Co operation and Development (OECD) protocols, were run for evaluating the acute effects of iron magnetic microparticles (MPs), recently proposed for lake restoration, on Chlorella sp. (algal growth) and on the rotifer B. calyciflorus (mortality). In addition, the MPs potential indirect effects on rotifer egg bank were assessed by performing hatching rate test with B. calyciflorus cysts in contact with dissolved iron (Tot-Fedis). In the algal growth test, no inhibition occurred at the two lowest MPs concentrations (0.01 and 0.05 g l-1) which would correspond, considering the adsorption efficiency ratio (Phosphorus: MPs), to P concentrations lower than 0.94 mg P l-1, much higher than typical concentrations found in natural waters. For higher MPs dose (EC50 for Chlorella sp. was 0.15 g l 1), no nutrient limitations but high turbidity and Tot-Fedis values cause negative effects on algal growth. For the case of B. calyciflorus, LC50 was 1.63 g MPs l-1 (corresponding to 30.7 mg P l-1). When analyzing Tot-Fedis effect, the hatching rate of B. calyciflorus cysts was 100% for all treatments. To sum up our results for B. calyciflorus acute and chronic toxicity tests, it is extremely unlikely the mortality of adult organisms in contact with MPs as well as an affectation of the rotifer egg bank. In conclusion, it is expected that MPs addition in a real whole-lake application cause minor lethal and sublethal effects on both Chlorella sp. and B. calyciflorus. PMID- 28858717 TI - Can visible light impact litter decomposition under pollution of ZnO nanoparticles? AB - ZnO nanoparticles is one of the most used materials in a wide range including antibacterial coating, electronic device, and personal care products. With the development of nanotechnology, ecotoxicology of ZnO nanoparticles has been received increasing attention. To assess the phototoxicity of ZnO nanoparticles in aquatic ecosystem, microcosm experiments were conducted on Populus nigra L. leaf litter decomposition under combined effect of ZnO nanoparticles and visible light radiation. Litter decomposition rate, pH value, extracellular enzyme activity, as well as the relative contributions of fungal community to litter decomposition were studied. Results showed that long-term exposure to ZnO nanoparticles and visible light led to a significant decrease in litter decomposition rate (0.26 m-1 vs 0.45 m-1), and visible light would increase the inhibitory effect (0.24 m-1), which caused significant decrease in pH value of litter cultures, fungal sporulation rate, as well as most extracellular enzyme activities. The phototoxicity of ZnO nanoparticles also showed impacts on fungal community composition, especially on the genus of Varicosporium, whose abundance was significantly and positively related to decomposition rate. In conclusion, our study provides the evidence for negatively effects of ZnO NPs photocatalysis on ecological process of litter decomposition and highlights the contribution of visible light radiation to nanoparticles toxicity in freshwater ecosystems. PMID- 28858718 TI - Impact of salt-induced toxicity on growth and yield-potential of local wheat cultivars: oxidative stress and ion toxicity are among the major determinants of salt-tolerant capacity. AB - High salinity is a major constraint for wheat productivity in many countries, including Bangladesh. Here, we examined the effects of salt-induced toxicity on growth and production of 10 local wheat cultivars by analyzing physiological, biochemical and agronomical responses to identify the salt-tolerant attributes among the contrasting genotypes. Results of cluster analyses based on salt tolerance indices of plant growth-related and yield-contributing parameters, ionic balance (Na+, K+ and Na+/K+ ratio), and stress indicators (SPAD values and proline) revealed Gourab and Shatabdi as salt-sensitive, BARI Gom 27 and 28 as salt-tolerant and the other six examined varieties as moderately salt-tolerant cultivars. Hierarchical clustering and principle component analyses also demonstrated BARI Gom 27 and 28 as the highest salt-tolerant cultivars, especially in terms of Na+/K+ ratio and proline level. Additionally, lower accumulations of hydrogen peroxide and malondialdehyde, and higher activities of antioxidant enzymes catalase, peroxidase and ascorbate peroxidase in the salt tolerant BARI Gom 28 than in the salt-sensitive Gourab indicated reduced oxidative damage in BARI Gom 28 relative to that in Gourab. Collectively, our findings suggest that the optimum growth and yield of salt-tolerant cultivars are associated with decreased Na+/K+ ratio, increased proline level and reduced oxidative stress. Furthermore, BARI Gom 27 and 28 could be suggested as suitable cultivars for cultivation in salt-affected areas, and the contrasting salt responsive genotypes can be used as valuable genetic resources in breeding and dissection of molecular mechanisms underlying wheat adaptation to high salinity. PMID- 28858719 TI - Liposome-supported enzymatic peritoneal dialysis. AB - Compared to hemodialysis, peritoneal dialysis represents a more straightforward and less invasive alternative, though current solutions are not as effective. Herein, the feasibility of liposome-supported enzymatic peritoneal dialysis (LSEPD) is explored to increase the functionality of peritoneal dialysis for the model indication acute alcohol poisoning. Enzyme-loaded liposomes (E-Liposomes) containing alcohol metabolizing enzymes, alcohol oxidase and catalase, are developed and their in vitro and in vivo performances investigated. The E Liposomes outperform the free enzymes in stability, overcoming the thermal instability of alcohol oxidase and enhancing the in vitro ethanol elimination, which is further accelerated by hydrogen peroxide, due to the rapid generation of oxygen by catalase. Compared to the free enzymes, the E-Liposomes exhibit reduced systemic exposure and organ distribution. In a rodent ethanol intoxication model, LSEPD enhances ethanol metabolism as evidenced by an increased acetaldehyde production, ethanol's primary metabolite. In conclusion, LSEPD presents an innovative platform to temporarily enhance xenobiotic metabolism, in view of the improved enzyme stability and peritoneal retention. PMID- 28858720 TI - FRET-enabled monitoring of the thermosensitive nanoscale assembly of polymeric micelles into macroscale hydrogel and sequential cognate micelles release. AB - Thermosensitive "micellar hydrogel" is prepared based on poly(epsilon caprolactone-co- 1,4,8-trioxa[4.6]spiro-9-undecanone)-b-poly(ethylene glycol)- b poly(epsilon-caprolactone- co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) triblock copolymer. Fluorescence resonance energy transfer (FRET) is adopted to explore its assembly (formation) and disassembly (degradation) mechanism within the range of 10 nm. Results prove that the thermosensitive non-covalent aggregation of micelles facilitates the hydrogel formation and the sustained shedding of cognate micelles induces the hydrogel degradation, during which polymers are steadily incorporated in micelles without any micelle disassembly or reassembly. It is confirmed that using multiple-tags based imaging technology, such as FRET imaging, the fate of macro biodegradable materials in vitro and in vivo can be followed at a precise nano even molecular level. Such an unique hydrogel composed of nothing more than PECT micelles can act as not only an injectable nanomedicine reservoir by subcutaneous or peri-tissue administration, but also an advanced "combo" macroscale platform for co-delivery of multi-modal therapeutic agents. Our findings also indicate that biological stimuli (e.g., temperature, enzymes)-induced non-covalent micelle self-assembly may provide us an effective strategy to prepare a macroscale device from nanoscale subunits. PMID- 28858721 TI - Evolution of the degradation mechanism of pure zinc stent in the one-year study of rabbit abdominal aorta model. AB - In the present study, pure zinc stents were implanted into the abdominal aorta of rabbits for 12 months. Multiscale analysis including micro-CT, scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM) and histological stainings was performed to reveal the fundamental degradation mechanism of the pure zinc stent and its biocompatibility. The pure zinc stent was able to maintain mechanical integrity for 6 months and degraded 41.75 +/- 29.72% of stent volume after 12 months implantation. No severe inflammation, platelet aggregation, thrombosis formation or obvious intimal hyperplasia was observed at all time points after implantation. The degradation of the zinc stent played a beneficial role in the artery remodeling and healing process. The evolution of the degradation mechanism of pure zinc stents with time was revealed as follows: Before endothelialization, dynamic blood flow dominated the degradation of pure zinc stent, creating a uniform corrosion mode; After endothelialization, the degradation of pure zinc stent depended on the diffusion of water molecules, hydrophilic solutes and ions which led to localized corrosion. Zinc phosphate generated in blood flow transformed into zinc oxide and small amounts of calcium phosphate during the conversion of degradation microenvironment. The favorable physiological degradation behavior makes zinc a promising candidate for future stent applications. PMID- 28858722 TI - Comprehension and production of nouns and verbs in temporal lobe epilepsy. AB - Previous research on linguistic performance at the single-word level in patients with temporal lobe epilepsy (TLE) has mostly been limited to the comprehension and production of nouns, and findings have been inconsistent. Results are likewise limited and controversial regarding the lateralization of the epileptogenic focus. The present study investigates comprehension and production of nouns and verbs in patients with left and right TLE (12 in each group). We designed a comprehension (word-picture matching) test and a production (naming) test, matched on a range of psycholinguistic parameters for the two word classes. The results showed impaired verb comprehension in patients with left TLE and impaired noun and verb production in both groups of patients compared to the control group. Patients with left and right TLE differed significantly on verb comprehension and noun production, whereas verb production was equally impaired in the two groups of patients. These findings suggest difficulties with single word processing in patients with both left and right TLE, which are more prominent for verbs than for nouns in patients with left TLE. The verb production (action naming) test turned out to be the most effective tool for assessing linguistic difficulties at the single-word level in patients with TLE. PMID- 28858723 TI - Epigallocatechin-3-gallate inhibits TLR4 signaling through the 67-kDa laminin receptor and effectively alleviates acute lung injury induced by H9N2 swine influenza virus. AB - Epigallocatechin-3-gallate (EGCG) was found to inhibit the Toll-like receptor 4 (TLR4) pathway involved in influenza virus pathogenesis. Here, the effect of EGCG on TLR4 in an H9N2 virus-induced acute lung injury mouse model was investigated. BALB/c mice were inoculated intranasally with A/Swine/Hebei/108/2002 (H9N2) virus or noninfectious allantoic fluid, and treated with EGCG and E5564 or normal saline orally for 5 consecutive days. PMVECs were treated with EGCG or anti-67kDa laminin receptor (LR). Lung physiopathology, inflammation, oxidative stress, viral replication, and TLR4/NF-kappaB/Toll-interacting protein (Tollip) pathway in lung tissue and/or PMVECs were investigated. EGCG attenuated lung histological lesions, decreased lung W/D ratio, cytokines levels, and inhibited MPO activity and prolonged mouse survival. EGCG treatment also markedly downregulated TLR4 and NF-kappaB protein levels but Tollip expression was upregulated compared with that in untreated H9N2-infected mice (P<0.05). In PMVECs, anti-67LR antibody treatment significantly downregulated Tollip levels; however, the TLR4 and NF-kappaB protein levels dramatically increased compared with that in the EGCG-treated group (P<0.05). EGCG remarkably downregulated TLR4 protein levels through 67LR/Tollip, decreased MPO activity and inflammatory cytokine levels, supporting EGCG as a potential therapeutic agent for managing acute lung injury induced by H9N2 SIV. PMID- 28858724 TI - Alpha-Mangostin protects rat articular chondrocytes against IL-1beta-induced inflammation and slows the progression of osteoarthritis in a rat model. AB - Osteoarthritis (OA) is a joint disease characterized by inflammation and cartilage degradation. alpha-Mangostin (alpha-MG), which can be isolated from the fruit of the tropical evergreen tree Garcinia mangostana-L, is known to have anti inflammatory properties. The aim of the study was to investigate the use of alpha MG in the treatment of OA, using both rat chondrocytes and an OA rat model induced by destabilization of the medial meniscus (DMM). Rat chondrocytes were pretreated with alpha-MG (0, 1.25, 2.5, and 5.0MUg/ml for 24h) prior to stimulation with interleukin-1beta (IL-1beta) (10ng/ml for 24h). Nitric oxide (NO) production was determined using the Griess method and prostaglandin E2 (PGE2) was assessed using an enzyme-linked immunosorbent assay (ELISA). The expression of inducible nitric oxide synthase (INOS), cyclooxygenase-2 (COX-2), matrix metalloproteinase-3, -9, and -13 (MMP-3, MMP-9, and MMP-13), Collagen II, and Aggrecan were detected by both quantitative real-time PCR (qRT-PCR) and a western blot analysis. Nuclear factor-kappaB (NF-kappaB) signaling molecules were detected by western blot analysis. Detection of p65 nuclear translocation of NF kappaB was examined using immunofluorescence staining. The OA rats received intraperitoneal injections of alpha-MG (10mg/kg) or saline every other day. Hematoxylin and eosin and Safranin-O-Fast green staining were used to evaluate the severity of cartilage lesions up to 8weeks following surgery. alpha-MG inhibited the production of NO and PGE2. The elevated expression of INOS, COX-2, MMP-3, MMP-9, and MMP-13, and the degradation of Collagen II and Aggrecan, were reversed by alpha-MG in IL-1beta-stimulated chondrocytes. In addition, IL-1beta induced considerable phosphorylation of the NF-kB signaling pathway, which was inhibited by alpha-MG. Furthermore, the immunofluorescence staining demonstrated that alpha-MG could suppress IL-1beta-induced p65 nuclear translocation. In vivo, cartilage treated with alpha-MG showed attenuated degeneration and had low Osteoarthritis Research Society International (OARSI) scores compared with the control group. Taken together, these results show that alpha-MG has potential therapeutic value in the treatment of OA. PMID- 28858725 TI - Focus on the therapeutic efficacy of 3BNC117 against HIV-1: In vitro studies, in vivo studies, clinical trials and challenges. AB - 3BNC117, which was discovered in 2011, is a broadly neutralizing antibody (bNAb) and specifically neutralizes the human immunodeficiency virus type-1 (HIV-1) by targeting the CD4-binding site. This is the first comprehensive review that focuses on the role of 3BNC117 in the prevention of HIV-1 and acquired immune deficiency syndrome (AIDS). Briefly, 3BNC117 neutralizes many HIV/SHIV strains in vitro, blocks HIV-1 acquisition in animal models via a pre-exposure prophylaxis, alleviates HIV-1-associated viremia via a post-exposure therapeutic effect, prevents the establishment of latent HIV-1 reservoirs, and induces both humoral and cellular anti-HIV immune responses in vivo. The outcomes of Phase I and Phase IIa clinical trials in 2015 and 2016 showed the safety, tolerability, and therapeutic efficacy of 3BNC117 in HIV-1-infected human individuals. Nevertheless, anti-3BNC117 antibodies and HIV-1 strains resistant to 3BNC117 pose clinical challenges to immunotherapy with 3BNC117, so potential strategies for optimizing the potency of 3BNC117 are suggested here. Predictably, HIV-1 prevention and AIDS treatment will benefit from combinational immunotherapies with 3BNC117 and other pharmaceuticals (bNAbs, antiretroviral medicines, viral inducers, etc.) in the near future. PMID- 28858726 TI - Optimal retraining time for regaining functional fitness using multicomponent training after long-term detraining in older adults. AB - OBJECTIVES: Little is known about the optimal retraining time for regaining functional fitness through multicomponent training following long-term detraining in older adults. This study first investigated the time course of functional fitness changes during 12-month multicomponent training, 12-month detraining, and 9-month retraining in 18 older adults (68.33+/-3.46) and then determined the optimal retraining time for regaining the post-training functional fitness level after a 12-month detraining period. METHODS: Functional fitness, including lower and upper limb strength, lower and upper limb flexibility, aerobic endurance, and dynamic balance, was assessed at baseline, 12 months post-training, 12 months post-detraining, and 3, 6, and 9 months post-retraining. RESULTS: There were significant increases in all of the functional fitness components except upper limb flexibility at post-training and no significant decreases at post detraining. For lower and upper limb strength and lower limb flexibility, a 3 month period was required to regain the post-training condition. For aerobic endurance and dynamic balance, a retraining period >=9months was necessary to regain the post-training functional fitness condition. CONCLUSIONS: To regain the post-training condition of all functional fitness components, a retraining period >=9months was required. This information might be useful for health professionals to encourage older adults not to interrupt retraining until they regain their post-training functional fitness condition. PMID- 28858727 TI - Association between joint stiffness and health-related quality of life in community-dwelling older adults. AB - OBJECTIVE: This study aimed to examine the association between joint stiffness and health-related quality of life (HRQOL) in community-dwelling older adults. METHODS: Participants in this cross-sectional study were 530 Japanese community dwelling older adults (mean age, 73.9 years; women, 64.3%). Joint stiffness was assessed at the neck, low back, shoulder, elbow, hand or wrist, hip, knee, and ankle or feet; the duration of joint stiffness was also evaluated. We assessed HRQOL using the Short Form-12 (SF-12) and EuroQOL-5 Dimension (EQ-5D) questionnaires. We calculated the physical component summary scores (PCS) and mental component summary scores (MCS) from SF-12 and the EQ-5D index from EQ-5D. RESULTS: The prevalence of joint stiffness was 54.0%. Joint stiffness at two or more sites and at each site had a meaningful impact on PCS. Joint stiffness that lasted for 30min or more was meaningfully associated with low PCS and EQ-5D scores (PCS, 30-60min: beta=-6.122, P<0.05; >60min: beta=-5.962, P<0.01; EQ-5D index, 30-60min: beta=-0.068, P<0.01; >60min: beta=-0.070, P<0.01). Further, joint stiffness that lasted over 60min extended over MCS (MCS, >60min: beta= 3.212, P<0.05). CONCLUSIONS: Joint stiffness is associated with HRQOL. Assessing joint stiffness and intervention could be beneficial for HRQOL. PMID- 28858728 TI - A carbapenem antibiotic imipenem/cilastatin induces an oxidative stress-status and gonadotoxic effects in " wistar " rats. AB - Imipenem is a carbapenem antibiotic largely used to treat infection diseases. The present study was designed to investigate the effects of imipenem/cilastatin (IMP) on oxidative stress, antioxidant levels, testicular structure and sperm parameters in rats. Adult Wistar rats (84days old; N=8/group) were treated intraperitoneally with physiological serum containing 0mg/kg, 30mg/kg, 50mg/kg and 80mg/kg of IMP for one week. The results revealed that exposure to IMP especially at high doses, significantly decreased sexual organs weights (testis, epididymis, seminal vesicle and prostate), sperm characteristics (motility, viability and count) and plasma testosterone level while increased sperm abnormality. In addition, the testicular tissue level of lipid peroxidation (LPO) was significantly increased while the level of activities of superoxide dismutase (SOD), catalase (CAT) and glutathion peroxidase (GPx) decreased compared to the control group. Severe testicular lesions were recorded in the seminiferous tubules as well as a significant impairment in sperm characteristics. In conclusion, IMP induced an oxidative stress-status and histopathological changes in the testis and altered spermatogenesis in particular at both 50 and 80mg/kg dose-levels (p<0.001). PMID- 28858729 TI - Effect of zinc gluconate, sage oil on inflammatory patterns and hyperglycemia in zinc deficient diabetic rats. AB - BACKGROUND: The relationship between zinc homeostasis and pancreatic function had been established. In this study we aimed firstly to configure the inflammatory pattern and hyperglycemia in zinc deficient diabetic rats. Secondly to illustrate the effect of two selected agents namely Zinc gluconate and sage oil (Salvia Officinalis, family Lamiaceae). METHODS: Rats were fed on Zinc deficient diet, deionized water for 28days along with Zinc level check up at intervals to achieve zinc deficient state then rats were rendered diabetic through receiving one dose of alloxan monohydrate (120mg/kg) body weight, classified later into 5 subgroups. RESULTS: Treatment with sage oil (0.042mg/kg IP) and Zinc gluconate orally (150mg/kg) body weight daily for 8 weeks significantly reduced serum glucose, C reactive protein (CRP), Tumor necrosis factor alpha (TNF- alpha), interleukins-6 1 beta, inflammatory8 (IFN ou), pancreatic 1L1-beta along with an increase in serum Zinc and pancreatic Zinc transporter 8 (ZNT8). Histopathological results of pancreatic tissues showed a good correlation with the biochemical findings. CONCLUSIONS: Both sage oil and zinc gluconate induced an improvement in the glycemic and inflammatory states. This may be of value like the therapeutic agent for diabetes. PMID- 28858730 TI - Effect and Mechanism of Sophoridine to suppress Hepatocellular carcinoma in vitro and vivo. AB - AIM: The aim of this study is to explain effect and mechanism of Sophoridine to suppress Hepatocellular carcinoma in vitro and vivo. METHODS: In vitro experiment, the HepG2 cells were divided into 5 groups: 0MUg/mL Sophoridine treated group (0 MUg/mL group); 10MUg/mL matrine treated group (10MUg/mL group); 20MUg/mL matrine treated group (20MUg/mL group) and 10MUg/mL Paclitaxel treated group (Positive drug group). Measuring the cell proliferation of difference groups by MTS assay; evaluating cell apoptosis of difference by flow cytometry; the cell invasion and migration abilities of difference HepG2 cells were measured by transwell and wound healing testing; measuring the relative proteins expression in difference groups. In vovo experiment, the nude mice were divided into 5 groups: 0MUg/mL, 5MUg/mL, 10MUg/mL, 20MUg/mL and Positive drug groups, after executing, taking the tumor tissue from nude mice of difference groups, measuring the tumor volume and weight; evaluating the PTEN protein expression in tumor tissue by Immunohistochemistry (IHC). RESULTS: In the cell experiments, Compared with 0MUg/mL group, cell proliferation rates were significantly reduced, cell aopotosis were significantly increased and invasion and wound healing abilities were significantly decreased in marine treated groups with dose dependent (P<0.05, respectively). In the nude mice experiment, the tumor volume and weight of matrine treated groups were significantly decreased compared with 0 MUg/mL group with dose-dependent (P<0.05, respectively). And the PTEN protein expression of Sophoridine treated groups were significantly decreased compared with 0MUg/mL group with dose-dependent (P<0.05, respectively). CONCLUSION: Sophoridine had anti-cance effects to suppress HepG2 activities by regulation PTEN/PI3K/AKT, Caspase-3/-9 and MMP-2/-9 signaling pathway. PMID- 28858731 TI - LncRNA FEZF1-AS1 enhances epithelial-mesenchymal transition (EMT) through suppressing E-cadherin and regulating WNT pathway in non-small cell lung cancer (NSCLC). AB - OBJECTIVE: Recent discoveries verify that long non-coding RNAs (lncRNAs) are important functional regulators involved in non-small cell lung cancer (NSCLC) progression. However, long non-coding RNA FEZF1-AS1 was not been investigated in NSCLC so for. METHODS: We applied the quantitative real time polymerase chain reaction (qRT-PCR) assays to detect the expression of lncRNA FEZF1-AS1 in NSCLC tissues and adjacent normal tissues. Cell proliferation and invasion capacities were evaluated by MTT, colony formation, and cell invasion assays. Chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) methods demonstrated the association between lncRNA FEZF1-AS1 expression and E-cadherin. The relative protein expression levels were analyzed by western blot analysis. RESULTS: LncRNA FEZF1-AS1 was significantly up-regulated in NSCLC tissues compared with adjacent normal tissues. Higher lncRNA FEZF1-AS1 expression levels associated with lymph node metastasis, poor differentiation grade and advanced TNM stage. In vitro, we revealed that down-regulation of lncRNA FEZF1-AS1 inhibited cell proliferation and cell invasion capacities in NSCLC. Moreover, down-regulation of lncRNA FEZF1 AS1 suppressed cell epithelial-mesenchymal transition (EMT) process by increasing the expression of E-cadherin and ZO-1, whereas, decreasing the expression of Slug, Twist and Vimentin in NSCLC cells. Furthermore, we demonstrated lncRNA FEZF1-AS1 could epigenetically repress the expression of E-cadherin via binding with LSD1 and EZH2 in NSCLC cells. We also revealed that knockdown of lncRNA FEZF1-AS1 suppressed Wnt/beta-catenin signaling in NSCLC. CONCLUSION: These results demonstrated that lncRNA FEZF1-AS1 could function as a tumor promoting regulator in NSCLC, which may provide a target of treatment in NSCLC. PMID- 28858732 TI - Decreased expression of cytochrome p450 1B1 in non-small cell lung cancer. AB - Recent studies have associated oestrogen metabolism and cigarette smoking with their carcinogenic impact on the lungs. Compounds commonly found in tobacco smoke induce the activity of CYP1B1, the enzyme responsible for the synthesis of catecholic derivatives of oestrogens. During their redox transformations, these structures can release large amounts of reactive oxygen species or can form DNA adducts, which lead to the decomposition of genetic material. This process may illustrate the synergistic effect of oestrogenic activity and tobacco combustion on oestrogen-dependant lung cancer development. There is considerable evidence suggesting that the level of oestrogen in lung tumours is elevated. Therefore, by using reverse transcription, real-time PCR and Western Blot analysis, we evaluated the CYP1B1 status in tissues from 76 patients diagnosed with non-small cell lung cancer (NSCLC) to confirm whether potential overexpression of CYP1B1 may impact lung cancerogenesis induced by oestrogens. We found significantly lower levels of CYP1B1 transcripts (p=0.00001) and proteins (p=0.000085) in lung tumour material compared to corresponding, histopathologically unchanged tissues. We also analysed the association of CYP1B1 expression with gender, age and clinicopathological data of NSCLC patients. We observed lower amounts of CYP1B1 occurring in the middle stages of LC, regardless of gender, age or histological type of lung cancer. PMID- 28858733 TI - Quercetin attenuates the ischemia reperfusion induced COX-2 and MPO expression in the small intestine mucosa. AB - Quercetin, the active substance of tea, fruits and vegetables, exerts a broad spectrum of pharmacological activities and is considered to have potential therapeutic application. The present study was designed to investigate the beneficial effect of quercetin against experimental ischemia- reperfusion (IR) injury of the small intestine in rats. Quercetin was administrated intraperitoneally 30min before 1h ischemia of superior mesenteric artery with following reperfusion periods lasting 1, 4 and 24h. The male specific pathogen free Charles River Wistar rats were used (n=45). In acute phase, 4h after start of reperfusion, the quercetin induced a significant decrease in mucosal injury index (p<0.05) accompanied by a significant decrease in cyclooxygenase-2 (COX-2) expression in the epithelial lining of the intestinal villi in comparison with the control group (p<0.01). In the epithelium of the intestinal glands, COX-2 expression resulting from IR injury significantly increased regardless quercetin application (in control group p<0.001; in quercetin group p<0.05), but in quercetin group, significant decrease in it during 24h of reperfusion in a late phase of IR injury was detected (p<0.001). Based on morphology of COX-2 positive cells, the COX-2 positivity was found particularly in goblet cells of the intestinal villi epithelium and enteroendocrine cells respectively, in the glandular epithelium. We concluded that quercetin application attenuated mucosal damage from IR injury by inhibiting neutrophil infiltration which was demonstrated by a lower number of myeloperoxidase positive cells in the lamina propria during both phases of IR injury and the significant decrease in that in a late phase after 24h of reperfusion (p<0.05). PMID- 28858734 TI - Rosoloactone: A natural diterpenoid inducing apoptosis in human cervical cancer cells through endoplasmic reticulum stress and mitochondrial damage. AB - Natural diterpenoids have been previously reported to induce tumor cell apoptosis. We identified a diterpenoid metabolite as rosoloactone that was isolated from the endophytic fungus Trichothecium roseum and displayed significant antitumor activity in vitro. In this study, we report the antitumor effect of rosoloactone on human cervical cancer HeLa cells and its mechanism of action. Our data indicate that rosoloactone induces strong anti-proliferative and pro-apoptotic effects in human cervical cancer HeLa cells, leads to significant apoptotic morphological characteristics, and increases the number of Annexin V positive stained cells. These effects were associated with endoplasmic reticulum stress (ERS) and mitochondrial damage. More specifically, rosoloactone caused accumulation of misfolded or unfolded proteins in the ER lumen, leading to excessive ERS, as well as mitochondrial damage followed by release of cytochrome c into the cytosol, activation of caspase-9 and -3, and subsequent activation of mitochondria-mediated apoptosis. Furthermore, the effects of rosoloactone were likely accompanied by marked reactive oxygen species (ROS) production. Altogether our results showed that rosoloactone mediates pro-apoptotic effects in human cervical cancer HeLa cells likely via the activation of ERS-associated apoptosis and the mitochondria-mediated apoptotic pathway. PMID- 28858735 TI - Linarin suppresses glioma through inhibition of NF-kappaB/p65 and up-regulating p53 expression in vitro and in vivo. AB - Glioma is the most common form of malignant brain cancer with high mortality rate in human. Therefore, finding effective therapeutic strategy and revealing the underlying molecular mechanism is necessary. Plant-extracted flavonoid glycosides have been suggested to be bioactive compounds with pleiotropic functions, such as anti-cancer, anti-inflammatory, antioxidant and effects. Our study was attempted to explore the anti-cancer role of linarin (acacetin-7-O-beta-d-rutinoside) in glioma in vitro and in vivo. Nuclear factor kappa-B (NF-kappaB) activity is a common phenomenon in various cancers, resulting in abnormal cell proliferation, malignant transformation, or resistance to cell death. P53, an essential tumor suppressor, plays an important role in preventing tumor progression. Our data indicated that linarin suppressed glioma cell proliferation and migration by inducing apoptosis, which was through reducing cell cycle-related signals, including Survivin, p-Rb, and Cyclin D1, while promoting p21, Bax, Caspase-3 and poly (ADP-ribose) polymerase (PARP) activation. Also, we found that linarin reduced cellular proliferation of glioma was dependent on p53 up-regulation and Nuclear factor kappa-B (NF-kappaB)/p65-down-regulation, thereby inhibiting glioma cell growth. We further conformed the inhibitory effect of linarin in vivo using xenograft tumor model. Linarin significantly triggered apoptosis as well as the tumor growth in animals, accompanied with p53 increase and p65 decrease. Our data illustrated that linarin could be used as a promising candidate against glioma progression. PMID- 28858736 TI - The anti-invasive role of novel synthesized pyridazine hydrazide appended phenoxy acetic acid against neoplastic development targeting matrix metallo proteases. AB - Neoplastic metastasis is a major process where tumor cells migrate from the primary tumor and colonize at other parts of our body to form secondary tumor. Cancer incidences are rising and novel anti-neoplastic compounds with new mechanism of actions are essential for preventing cancer related deaths. In the current examination, a novel series of pyridazine analogues 6a-l was synthesized and evaluated against metastatic neoplastic cells. Experimental data postulated compound 6j has potential cytotoxic efficacy with prolonged activity against various cancer cells, including A549, HepG2, A498, CaSki and SiHa cells. Moreover, compound 6j arrests the A549 migration and invasions markedly by counteracting matrix metalloproteinase (MMP)-2 and MMP-9 expressions. Also, compound 6j proved its potentiality against Dalton's solid lymphoma progression in-vivo by abridging MVD and MMP expressions. Compound 6j interacts with MMP-2 and MMP-9 by H- bond in-silico, thereby down regulates the MMPs action in tumourigenesis. Altogether, we concluded that compound 6j down regulates MMP-2 and MMP-9 and thereby impairs metastatic cancer cell migration and invasions which can be translated into a potent anti-neoplastic agent. PMID- 28858737 TI - Ginkgo biloba L. leaf extract offers multiple mechanisms in bridling N methylnitrosourea - mediated experimental colorectal cancer. AB - In Egypt, colorectal cancer (CRC) is the 6th cancer in both gender and CRC rates are high in subjects under 40 years of age. This study goaled to determine the development of CRC using relevant biochemical markers and to elucidate the potent mechanism of Ginkgo biloba L. leaf extract in retrogression of experimental CRC. Adult male Sprague-Dawley rats were administered N-methylnitrosourea (N-MNU; 2mg in 0.5ml water/rat) intrarectally thrice a week for five weeks to induce CRC, followed by treatment with either 5-fluorouracil (5-FU; 12.5mg/kg, i.p.) or Ginkgo biloba L. leaf extract in a dose of 0.675 and 1.35g/kg, p.o. respectively. The developed tumor enhanced plasma TGF-beta, and Bcl2, serum EGF, CEA, CCSA, and MMP-7 significantly. Also, gene expression analysis showed significant upregulation of colonic beta-Catenin, K-ras and C-myc genes. Besides, immunohistochemical findings revealed significant increase in COX-2, cyclin D1 and survivin content in colon tissue. These data were further supported by the histological observations. Ginkgo biloba L. leaf extract-treated rats; particularly those treated with dose of 1.35g/kg, exhibited significant reduction in the aforementioned parameters and improvement in the histological organization of the colon tissue. The therapeutic effect of Ginkgo biloba L. leaf extract was comparable with that mediated by 5-FU. The current research proved that Ginkgo biloba L. leaf extract could suppress tumor cell proliferation, promote apoptosis, and mitigat inflammation in vivo. The amelioration of these key events might be linked with the inhibition of Wnt/beta-Catenin signaling module. The outcomes of the present investigation encourage the use of Ginkgo biloba L. leaf extract as a complementary and alternative therapeutic approach to abate CRC. PMID- 28858738 TI - Primary retroperitoneal mucinous cystadenoma. AB - Mucinous cystadenomas and carcinomas of the ovary are well-established and common tumors. However, Primary retroperitoneal mucinous cystadenomas (PRMCs) are very rare. We present a 50-year-old woman referred to our institution with history of intermittent abdominal pain and palpable mass in her left flank. On CT-scan an unilocular cystic mass with thin wall measuring 171*155*108mm in the retroperitoneum was shown. Patient underwent surgical excision of the tumor. The histopathology examination showed a cystic mass with a fibrous wall and an epithelium composed of a single layer of columnar cells with mucin vacuoles compatible with PRMC. PMID- 28858739 TI - Spontaneous non-traumatic mediastinal hematoma associated with oral anticoagulant therapy: A case report and literature review. AB - INTRODUCTION: Mediastinal hematoma is usually caused by thoracic trauma or a ruptured aortic aneurysm. Spontaneous non-traumatic mediastinal hematomas are rare but potentially life-threatening conditions that can occur in patients taking anticoagulants. PRESENTATION OF CASE: We report a case of 72-year-old man with a massive mediastinal hematoma associated with anticoagulant therapy. He had complained of acute chest discomfort and subsequent tarry diarrhea. Because he had been taking warfarin for paroxysmal atrial fibrillation, an upper gastrointestinal hemorrhage was initially suspected, but no bleeding was detected by upper endoscopy. A computed tomography scan revealed a massive posterior mediastinal hematoma and markedly compressed surrounding structures. The compression of the left atrium caused a congested lung and exacerbated respiratory and hemodynamic status despite conservative therapy. Therefore, we surgically removed the hematoma. Immediately after removal, the respiratory and hemodynamic conditions improved, and the postoperative course was uneventful. DISCUSSION: Spontaneous mediastinal hematoma is rare but can occur in patients who are administered anticoagulants regardless of the therapeutic level of anticoagulation. Although conservative therapy is commonly effective, active surgical intervention should be considered for cases in which the hematoma is symptomatic or conservative therapy is ineffective. CONCLUSION: To facilitate prompt and proper management, clinicians should be aware of this condition as a potential complication of anticoagulant therapy. PMID- 28858740 TI - Solid pseudopapillary tumor of the pancreas: Experience at a tertiary care centre of Northern India. AB - INTRODUCTION: Solid pseudopapillary tumor (SPT) of the pancreas is rare, accounting for 0.13-2.7% of all pancreatic tumors. It is unique, has low malignant potential and predominantly affects young women. Radiological and pathological studies have revealed that the tumor is quite different from other pancreatic tumors. But the cell origin of SPT and tumorigenesis are still enigmatic. Abdominal mass is the most common presenting symptom. Due to the paucity of the number of cases, the natural history of the disease is not fully understood. This study was undertaken to examine the clinico-pathological characteristics of the disease and to evaluate the outcome of surgical intervention in a tertiary referral care centre. MATERIALS AND METHODS: A retrospective analysis of all patients diagnosed and treated for SPN in our hospital over a period of 10 years (2005-2015) was carried out. A database of the characteristics of these patients was developed. In all, 11 patients were identified. A CT scan of the abdomen was performed in all the patients and the findings revealed a mass in the pancreas. The investigations performed included routine blood investigations, chest X-ray, CA-19-9 level and either an ultrasound or a CT Scan of the abdomen. RESULTS: During the time period of 10 years, of 349 patients with pancreatic malignancy admitted to our department, only 11 were diagnosed as having SPN (3.15%). Ten patients were women (90%) and one patient was a man (10%). The patients had a median age of 27.6 years (range 17-41). The most common symptoms were abdominal pain and dullness. Eight patients (72.7%) presented with abdominal pain or abdominal dullness and three patient (27%) were asymptomatic. All the 11 patients were taken up for surgery. Three patients underwent distal pancreatectomy with splenectomy, three patients underwent the total mass excision and one patient underwent total pancreatic resection. Three required extended distal pancreatectomy with splenectomy. One underwent spleen preserving distal pancreatectomy. CONCLUSION: SPT is rare, but treatable pancreatic tumor. While clinical signs and symptoms are relatively nonspecific, characteristic findings on imaging and histology separate these tumors from the more malignant pancreatic tumors. The prognosis is favorable even in the presence of distant metastasis. Although surgical resection is generally curative, a close follow-up is advised in order to diagnose a local recurrence or distant metastasis. PMID- 28858741 TI - A rare case report of patent vitellointestinal duct causing bowel obstruction in an adult. AB - INTRODUCTION: Patent vitellointestinal duct occurs in about 2% of the population which unusually leads to small intestinal obstruction associated with high morbidity and mortality. Here we are reporting an unusual case of patent vitellointestinal duct causing small intestinal obstruction in an adult patient. PRESENTATION OF CASE: A 22-year-old male without any medical illness presented as an emergency with a 3day hystory of abdominal pain, multiple episode of vomiting and abdominal distention. Distended abdomen and sign of peritonitis were found on abdominal examination. Abdominal X-rays revealed multiple small intestinal air fluid levels. A patent vitellointestinal duct extending from distal ileum to the posterior wall of the umbilicus was found causing closed loop ileal obstruction during laparotomy. Resection of a vitellointestinal duct along with gangrenous distal ileum and cecum with ileocolostomy was performed. He was discharged on the 8 th postoperative day. DISCUSSION: Diagnosing and management of cause of intestinal obstruction in patients without history of abdominal surgery is very challenging. Early resuscitation and timely surgical intervention of intestinal obstruction due to a rare patent vitellointestinal duct can be life-saving measure. CONCLUSION: The patent vitellointestinal duct is an uncommon entity in adults and moreover this disorder leading to intestinal obstruction is very rare. Surgeons should be aware of this infrequent cause of small bowel obstruction to allow for early diagnosis and to facilitate better patient outcomes. PMID- 28858742 TI - Postoperative disseminated intravascular coagulation in a pregnant patient with Blue Rubber Bleb Nevus Syndrome presenting with acute intestinal obstruction: Case report and literature review. AB - BACKGROUND: Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare condition which usually manifests as multiple hemangioma-like skin and gastrointestinal lesions. The latter often present with chronic bleeding. There is no consensus regarding the optimal management of such patients. Although rare, complications such as intestinal intussusception might occur, demanding surgical treatment. Postoperative complications such as coagulation disorders can increase morbidity and should be timely addressed. This is the first report of a life-threatening postoperative disseminated intravascular coagulation in such patients. The main objectives of this case report are to present diagnostic and treatment features of this condition and, more importantly, address the optimal management of postoperative disseminated intravascular coagulation. CASE PRESENTATION: Twenty five year-old female pregnant patient presents to the emergency department with colicky pain and oligohydramnios. After C-section, persistent symptoms and further investigation led to the diagnosis of intestinal intussusception. After surgical management she showed clinical and laboratory signs of disseminated intravascular coagulation (DIVC), which was corrected with transfusional therapy and intraperitoneal clot evacuation. After optimal management, she was discharged home. Sirolimus was initiated further improving her condition. CONCLUSION: This rare presentation of acute intestinal intussusception in a patient with Blue Rubber Bleb Nevus Syndrome was further complicated with postoperative coagulation disorder. Prompt surgical evaluation is essential especially when complications are suspected. Operative treatment might be necessary in the emergent setting. Close monitoring of infectious and coagulation parameters is essential in the postoperative period, and aggressive treatment should be timely initiated when disseminated intravascular coagulation is suspected. PMID- 28858743 TI - Quadruple primary urogenital cancers - A case report. AB - INTRODUCTION: Urogenital cancers are not an uncommon occurrence in daily practice. Prostate cancer is the second most frequent cancer in men, kidney cancer accounts for 2.4% of all cancers and bladder cancers represent 3.1% of cancers in both men and women [1]. However, the cases of a simultaneous development of all three cancers, including one with a neuroendocrine component, are very few and far between. PRESENTATION OF CASE: Our case report involves a case of a patient with prostate adenocarcinoma, clear-cell renal carcinoma, papillary renal carcinoma and small-cell bladder cancer. The patient was treated as if he had separate pathologies by a multidisciplinary team: surgical and oncological, performing radical cystoprostatectomy with left perifascial nephroureterectomy, right ureterostomy and adjuvant chemotherapy, with excellent outcome even four years after the initial diagnosis. DISCUSSION: The distinct features of this case are the occurence of four different malignancies of the urogenital system, the family history of colon cancer, the development of small cell carcinoma of the bladder, which is extremely rare and the good outcome, despite the quadruple malignancies and the aggresivity of the small-cell carcinoma. CONCLUSION: Mutiple primary malignancies are a relatively rare pathology, but should be considered as a possibility in patients who already had a second malignancy. Cases of patients with MPMs should be supervised by a multidisciplinary team and should be followed closely. PMID- 28858744 TI - Initial validation of a proxy indicator of functioning as a potential tool for establishing a clinically meaningful cocaine use outcome. AB - BACKGROUND: Establishing a non-abstinence cocaine use outcome as clinically meaningful has been elusive, in part due to the lack of association between cocaine use outcomes and meaningful indicators of long-term functioning. METHODS: Using data pooled across 7 clinical trials evaluating treatments for cocaine (N=718), a dichotomous indicator of functioning was created to represent a meaningful outcome ('problem-free functioning' - PFF), defined as the absence of problems across non-substance-related domains on the Addiction Severity Index. Its validity was evaluated at multiple time points (baseline, end-of-treatment, terminal follow-up) and used to explore associations with cocaine use. RESULTS: The percentage of participants meeting PFF criteria increased over time (baseline=18%; end-of-treatment=32%; terminal follow-up=37%). At each time point, ANOVAs indicated those who met PFF criteria reported significantly less distress on the Brief Symptom Inventory and less perceived stress on the Perceived Stress Scale. Generalized linear models indicated categorical indices of self-reported cocaine use at the end of treatment were predictive of the probability of meeting PFF criteria during follow-up (beta=-0.01, p<0.01; 95% CI: -0.008 to -0.003), with those reporting 0days or 1-4days ('occasional' use) in the final month of treatment showing an increased likelihood of achieving PFF. CONCLUSIONS: Initial validation of a proxy indicator of problem-free functioning demonstrated criterion validity and sensitivity to change over time. Frequency of cocaine use in the final month of treatment was associated with PFF during follow-up, with strongest associations between PFF and abstinence or 'occasional' use. PMID- 28858745 TI - Response of ecosystem productivity to dry/wet conditions indicated by different drought indices. AB - Various climatic and hydrological variables such as precipitation, soil moisture, stream flow, and water level can be used to assess drought conditions, however, the response of ecosystem productivity to such metrics is not very clear. In this study, we examined the sensitivity of GPP anomalies to five drought indicators: the Standardized Precipitation Index (SPI), the Standardized Precipitation Evapotranspiration Index (SPEI), Palmer Drought Severity Index (PDSI), deficit of soil moisture (DSM), and the difference between precipitation (P) and evapotranspiration (ET) (D(P-ET)). The global spatial distributions of drying and wetting trends from 2000 to 2014 determined by these five indices were similar. Additionally, the percent of drought-impacted areas decreased over the study period, indicating a reduction in drought conditions. GPP increased over the study period in the Northern Hemisphere (NH) but decreased in the Southern Hemisphere (SH), resulting in a net increase in global GPP. GPP anomalies were more sensitive to drought indices in the SH than in the NH. Among the five indices, GPP anomalies were most closely correlated with SPI in the NH (R=0.60, P<0.05) and SPEI in the SH (R=0.93, P<0.01). Regionally speaking, annual and seasonal GPP anomalies were most sensitive to DSM and PDSI, highlighting the importance of soil moisture observations to regional drought monitoring and assessment. The results of this study are important for evaluating the impacts of drought on ecosystem production and the global carbon cycle. PMID- 28858746 TI - Response to the comments on "Radiofrequency electromagnetic fields and some cancers of unknown etiology: An ecological study" by J. Gonzalez-Rubio, E. Arribas, R. Ramirez-Vazquez and A. Najera. Science of the Total Environment 599 600 (2017) 834-843. PMID- 28858747 TI - Soil cadmium uptake by cocoa in Honduras. AB - Cadmium (Cd) is a trace metal without essential biological functions that is toxic to plants, animals and humans at low concentrations. It occurs naturally in soils, but inputs from anthropogenic sources have increased soil Cd contents worldwide. Cadmium uptake by cocoa (Theobroma cacao L.) has recently attracted attention, after the European Union (EU) decided to bring into force values for maximum Cd concentrations in cocoa products that would be exceeded by current products of various provenances from Latin America. In order to identify factors governing Cd uptake by cocoa, we carried out a survey on 55 cocoa farms in Honduras in which we determined Cd concentrations in cocoa leaves, pod husks and beans and analysed their relationships to a variety of surrounding soil and site factors. Averaging 2.6+/-0.4mgkg-1, the concentrations of Cd were higher in the leaves than in the beans. With an average of 1.1+/-0.2mgkg-1, the bean Cd concentrations still exceeded the proposed EU limit, however. The bean Cd showed large differences between geological substrates, even though regional variations in 'total' soil Cd were comparably small and the average concentration was in the range of uncontaminated soils (0.25+/-0.02mgkg-1). As we found no influence of fertilizer application or vicinity to industrial sites, we conclude that the differences in soil Cd between sites were due to natural variation. Of all factors included here, DGT-available soil Cd was the best predictor of bean Cd (R2=0.5). When DGT was not considered, bean Cd was best predicted by 'total' soil Cd, pH and geology. The highest bean Cd concentrations were found on alluvial substrates. PMID- 28858748 TI - Impact of ambient temperature on clinical visits for cardio-respiratory diseases in rural villages in northwest China. AB - BACKGROUND: The association between temperature and cardio-respiratory disease in urban areas has been widely reported but there is limited information from populations living in rural areas that may be disproportionately affected by climate change. OBJECTIVES: To quantify the associations between daily temperature and clinical visits due to cardiovascular and/or respiratory disease in rural villages in the Ningxia Hui Autonomous Region, China over 2012-2015. METHODS: Daily data on clinical visits and weather conditions were collated from 203 villages. A quasi-Poisson regression with distributed lag non-linear model was used to examine the associations between daily temperature and clinical visits up to 28days, after controlling for potential confounders. RESULTS: Over three years, 158,733 and 1,272,212 clinical visits were recorded for cardiovascular and respiratory diseases, respectively. Both low and high temperatures were associated with an increased risk of clinical visits for cardiovascular-related conditions, whereas only low temperatures were associated with increased clinical visits related to respiratory illness. The cold effect on cardiovascular visits appeared at the lag 6th day and persisted until the 22nd day, resulting in a cumulative relative risk (RR) 1.55 (95% CI: 1.26-1.92), compared with the minimum-clinical visit temperature. The cold effect on respiratory visits appeared immediately and lasted over the lag 0-28days, with a cumulative RR 2.96 (2.74-3.21). Suboptimal temperature accounted for approximately 13% and 26% of clinic visits due to cardiovascular and respiratory disorders, respectively, with the majority of cases attributable to moderate - rather than extreme - cold temperature. CONCLUSIONS: In rural settings, sub optimal temperatures explained nearly one quarter of all clinical visits due to cardiovascular and respiratory diseases. Although extreme cold temperature had a stronger, more immediate, prolonged effect on respiratory disease than for cardiovascular disease, moderately cold temperatures accounted for most of the overall burden of clinical visits. PMID- 28858749 TI - Life-cycle consequences of internalising socio-environmental externalities of power generation. AB - Current national energy sectors are generally unsustainable. Within this context, energy policy-makers face the need to move from economy- to sustainability oriented schemes. Beyond the integration of the sustainability concept into energy policies through the implementation of techno-economic, environmental and/or social restrictions, other approaches propose the use of externalities based on life-cycle emissions- to deeply take into account sustainability in the design of the future energy system. In this sense, this work evaluates the consequences of internalising socio-environmental externalities associated with power generation. Besides the calculation of external costs of power generation technologies and their implementation in an energy systems optimisation model for Spain, the life-cycle consequences of this internalisation are explored. This involves the prospective analysis of the evolution of the sustainability indicators on which the externalities are founded, i.e. climate change and human health. For the first time, this is done by endogenously integrating the life cycle indicators into the energy systems optimisation model. The results show that the internalisation of externalities highly influences the evolution of the electricity production mix as well as the corresponding life-cycle profile, hastening the decarbonisation of the power generation system and thus leading to a significant decrease in life-cycle impacts. This effect is observed both when internalising only climate change externalities and when internalising additionally human health external costs. PMID- 28858750 TI - Estimation of spatial distribution of quorum sensing signaling in sequencing batch biofilm reactor (SBBR) biofilms. AB - Quorum sensing (QS) signaling, plays a significant role in regulating formation of biofilms in the nature; however, little information about the occurrence and distribution of quorum sensing molecular in the biofilm of carriers has been reported. In this study, distribution of QS signaling molecules (the acylated homoserine lactones-AHLs, and AI-2), extracellular polymeric substances (EPS) and the mechanical properties in sequencing batch biofilm reactor (SBBR) biofilms have been investigated. Using increased centrifugal force, the biofilms were detached into different fractions. The AHLs ranged from 5.2ng/g to 98.3ng/g in different fractions of biofilms, and N-decanoyl-dl-homoserine lactone (C10-HSL) and N-dodecanoyl-dl-homoserine lactone (C12-HSL) in the biofilms obtained at various centrifugal forces displayed significant differences (p<0.01). Interspecies communication signal autoinducer-2(AI-2) in the biofilms ranged from 79.2ng/g to 98.3ng/g. Soluble EPS and loosely bound EPS content in the different fractions of biofilms displayed significant positive relationship with the distribution of C12-HSL (r=0.86, p<0.05). Furthermore, 49.62% of bacteria in the biofilms were positively related with AHLs with 22.76% was significantly positively (p<0.05) related with AHLs. Biofilm adhesion and compliance was the strongest in the tightly-bound biofilm, the weakest in the supernatant/surface biofilm, which was in accordance with the distribution of C12 HSL(r=0.77, p<0.05) and C10-HSL(r=0.75, p<0.05), respectively. This study addressed on better understanding of possible methods for the improvement of wastewater bio-treatment through biofilm application. PMID- 28858751 TI - Quantification of menadione from plasma and urine by a novel cysteamine derivatization based UPLC-MS/MS method. AB - Menadione, as the crucial component of vitamin Ks, possessed significant nutritional and clinical values. However, there was still lack of favourable quantification strategies for it to date. For improvement, a novel cysteamine derivatization based UPLC-MS/MS method was presented in this work. The derivatizating reaction was proved non-toxic, easy-handling and high-efficient, which realized the MS detection of menadione under positive mode. Benefitting from the excellent sensitivity of the derivatizating product as well as the introduction of the stable isotope dilution technique, the quantification could be achieved in the range of 0.05-50.0ng/mL for plasma and urine matrixes with satisfied accuracy and precision. After analysis of the samples from healthy volunteers after oral administration of menadione sodium bisulfite tablets, the urinary free menadione was quantified for the very first time. We believe the progress in this work could largely promote the exploration of the metabolic mechanism of vitamin K in vivo. PMID- 28858752 TI - Determination of chlorpyrifos and its metabolites in cells and culture media by liquid chromatography-electrospray ionization tandem mass spectrometry. AB - A sensitive method to simultaneously quantitate chlorpyrifos, chlorpyrifos oxon and the detoxified product 3,5,6-trichloro-2-pyridinol (TCP) was developed using either liquid-liquid extraction for culture media samples, or protein precipitation for cell samples. Multiple reaction monitoring in positive ion mode was applied for the detection of chlorpyrifos and chlorpyrifos oxon, and selected ion recording in negative mode was applied to detect TCP. The method provided linear ranges from 5 to 500, 0.2-20 and 20-2000ng/mL for media samples and from 0.5-50, 0.02-2 and 2-200ng/million cells for CPF, CPO and TCP, respectively. The method was validated using selectivity, linearity, precision, accuracy, recovery, stability and dilution tests. All relative standard deviations (RSDs) and relative errors (REs) for QC samples were within 15% (except for LLOQ, within 20%). This method has been successfully applied to study the neurotoxicity and metabolism of chlorpyrifos in a human neuronal model. PMID- 28858753 TI - Development and validation of a new HPLC-DAD method for quantification of sofosbuvir in human serum and its comparison with LC-MS/MS technique: Application to a bioequivalence study. AB - Although for many analyses tandem mass spectrometry (LC-MS/MS) systems have significant advantage over the high-performance liquid chromatography with diode array detection (HPLC-DAD) however, the HPLC methods are easier, cheaper and more available to perform. As no published method is available for quantitative HPLC analysis of sofosbuvir (SOF), an orally administered anti-hepatitis drug in human serum, this study was aimed to evaluate applicability of the HPLC technique to quantify sofosbuvir and comparison of the two methods for analytical performance. Following extraction of the drug and an internal standard (Hexobarbital), same chromatographic conditions were used for both the systems. After the chromatographic separation on a reverse phase C18 column using a mobile phase consisting of water (containing formic acid 0.5mL/L) and acetonitrile (57:43; v/v) at a flow rate of 0.8mL/min, the eluate was introduced into a DAD detector set at 261nm, then passed through the mass spectrometry system in single ion monitoring mode (SIM). For UV and mass spectrometry detections the calibration curves were linear over a concentration range of 25-3200 and 10-3200ng/mL, respectively and the linearity was over 0.998 for both the systems. Lower limit of quantification (LLOQ) for mass spectrometry and DAD detections were 10 and 25ng/mL, respectively. In conclusion sensitivity of DAD detection is sufficient enough to determine concentrations down to 0.5% of Cmax which achieved in bioequivalence study of sofosbuvir and meet FDA requirements for these types of studies. PMID- 28858754 TI - Longitudinal association between air pollution exposure at school and cognitive development in school children over a period of 3.5 years. AB - INTRODUCTION: Recently, we showed that exposure to traffic-related air pollutants (TRAPs) at school was negatively associated with cognitive development, specifically working memory and inattentiveness, in primary schoolchildren during a course of 12 months. The persistence of such associations over longer periods remains as an open question. OBJECTIVE: To study the longitudinal association between TRAPs at school and cognitive development over a period of 3.5 years. METHODS: Indoor and outdoor levels of TRAPs (elemental carbon (EC), dioxide nitrogen (NO2), particulate matter (PM2.5) from traffic sources and ultrafine particles (UFP)) were measured at 39 schools across Barcelona during 2012/2013. Working memory, as a measure of cognitive development, was evaluated 4 times in 2012/2013 assessment and was re-evaluated one more time in 2015 using computerized n-back test (3-back d' as main outcome). Linear mixed effects models were used to test the association between TRAPs and 3-back d', adding child and school as random effects to account for the multilevel nature of the data, and school air pollutants levels (one at a time) as predictor. RESULTS: We found detrimental associations between all TRAPs and annual change in 3-back d' (working memory) (i.e. slower development of working memory in children attending schools with higher levels of air pollution). The associations (per one interquartile range increase in exposure) were strongest for outdoor NO2 (Coefficient (Coef) = - 4.22, 95% confidence interval (CI), - 6.22, - 2.22) and indoor UFP (Coef = - 4.12, 95%CI, - 5.68, - 1.83). These reductions were equivalent to - 20% (95%CI, - 30.1, - 10.7) and - 19.9% (95%CI, - 31.5, - 8.4) change in annual working memory development associated with one interquartile range increase in outdoor NO2 and indoor UFP, respectively. CONCLUSION: Our findings suggest the persistence of the negative association between TRAPs exposure at school and cognitive trajectory measured by n-back test over a period of 3.5 years. PMID- 28858755 TI - Calls to Florida Poison Control Centers about mercury: Trends over 2003-2013. AB - OBJECTIVE: The aim of this analysis was to contrast trends in exposure-report calls and informational queries (a measure of public interest) about mercury to the Florida Poison Control Centers over 2003-2013. MATERIALS AND METHODS: Poison control specialists coded calls to Florida Poison Control Centers by substance of concern, caller demographics, and whether the call pertained to an exposure event or was an informational query. For the present study, call records regarding mercury were de-identified and provided along with daily total number of calls for statistical analysis. We fit Poisson models using generalized estimating equations to summarize changes across years in counts of daily calls to Florida Poison Control Centers, adjusting for month. In a second stage of analysis, we further adjusted for the total number of calls each day. We also conducted analyses stratified by age of the exposed. RESULTS: There was an overall decrease over 2003-2013 in the number of total calls about mercury [Ratio per year: 0.89, 95% CI: (0.88, 0.90)], and calls about mercury exposure [Ratio per year: 0.84, 95% CI: (0.83, 0.85)], but the number of informational queries about mercury increased over this time [Ratio per year: 1.15 (95% CI: 1.12, 1.18)]. After adjusting for the number of calls of that type each day (e.g., call volume), the associations remained similar: a ratio of 0.88 (95% CI: 0.87, 0.89) per year for total calls, 0.85 (0.83, 0.86) for exposure-related calls, and 1.17 (1.14, 1.21) for informational queries. CONCLUSION: Although, the number of exposure-related calls decreased, informational queries increased over 2003-2013. This might suggest an increased public interest in mercury health risks despite a decrease in reported exposures over this time period. PMID- 28858756 TI - A spatio-temporal prediction model based on support vector machine regression: Ambient Black Carbon in three New England States. AB - Fine ambient particulate matter has been widely associated with multiple health effects. Mitigation hinges on understanding which sources are contributing to its toxicity. Black Carbon (BC), an indicator of particles generated from traffic sources, has been associated with a number of health effects however due to its high spatial variability, its concentration is difficult to estimate. We previously fit a model estimating BC concentrations in the greater Boston area; however this model was built using limited monitoring data and could not capture the complex spatio-temporal patterns of ambient BC. In order to improve our predictive ability, we obtained more data for a total of 24,301 measurements from 368 monitors over a 12 year period in Massachusetts, Rhode Island and New Hampshire. We also used Nu-Support Vector Regression (nu-SVR) - a machine learning technique which incorporates nonlinear terms and higher order interactions, with appropriate regularization of parameter estimates. We then used a generalized additive model to refit the residuals from the nu-SVR and added the residual predictions to our earlier estimates. Both spatial and temporal predictors were included in the model which allowed us to capture the change in spatial patterns of BC over time. The 10 fold cross validated (CV) R2 of the model was good in both cold (10-fold CV R2 = 0.87) and warm seasons (CV R2 = 0.79). We have successfully built a model that can be used to estimate short and long-term exposures to BC and will be useful for studies looking at various health outcomes in MA, RI and Southern NH. PMID- 28858757 TI - Association between perceptions of public drinking water quality and actual drinking water quality: A community-based exploratory study in Newfoundland (Canada). AB - Studying public perception on drinking water quality is crucial for managing of water resources, generation of water quality standards, and surveillance of the drinking-water quality. However, in policy discourse, the reliability of public perception concerning drinking water quality and associated health risks is questionable. Does the public perception of water quality equate with the actual water quality? We investigated public perceptions of water quality and the perceived health risks and associated with the actual quality of public water supplies in the same communities. The study was conducted in 45 communities of Newfoundland (Canada) in 2012. First, a telephone survey of 100 households was conducted to examine public perceptions of drinking water quality of their respective public sources. Then we extracted public water quality reports of the same communities (1988-2011) from the provincial government's water resources portal. These reports contained the analysis of 2091 water samples, including levels of Disinfection By-Products (DBPs), nutrients, metals, ions and physical parameters. The reports showed that colour, manganese, total dissolved solids, iron, turbidity, and DBPs were the major detected parameters in the public water. However, the majority of the respondents (>56%) were either completely satisfied or very satisfied with the quality of drinking water. Older, higher educated and high-income group respondents were more satisfied with water quality than the younger, less educated and low-income group respondents. The study showed that there was no association with public satisfaction level and actual water quality of the respective communities. Even, in the communities, supplied by the same water system, the respondents had differences in opinion. Despite the effort by the provincial government to make the water-test results available on its website for years, the study showed existing disconnectedness between public perception of drinking water quality and actual quality. We had little scope to explore the possible explanations, and hence further studies are required to verify the age, gender educational status and income differential about the satisfaction of public service like water supply. PMID- 28858758 TI - Livestock and poultry density and childhood cancer incidence in nine states in the USA. AB - BACKGROUND: Parental occupational and childhood exposures to farm animals have been positively associated with childhood brain tumors, whereas associations with childhood leukemia are equivocal. The developing immune system may be influenced by allergen, virus, or other exposures from animal sources, which may contribute to childhood cancer incidence. METHODS: Incident cancers (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], central nervous system [CNS], peripheral nervous system [PNS]) for children aged 0-4 diagnosed between 2003 and 2008 were obtained from nine National Cancer Institute Surveillance, Epidemiology and End Results (SEER) registries and were linked to U.S. Census of Agriculture data from 2002 and 2007 by county of diagnosis. Animal densities (animal units [AU]/km2; one animal unit is 1000 pounds of animal weight) were estimated for hogs, cattle, chickens (layers and broilers, separately), equine (horses, ponies, mules, burros, donkeys), goats, sheep, turkeys, and total animals. Animal density was examined in models as both continuous (AU per km2) and categorical variables (quartiles). Animal operation densities (per km2) by size of operation (cattle, hogs, chickens, sheep) were modeled continuously. Rate ratios and 95% confidence intervals were estimated using Poisson regression. RESULTS: We found positive associations between AML and broiler chicken densities (RRper 10AU/km2 = 1.14, 95% CI = 1.02-1.26). ALL rates increased with densities of hog operations (RRper operation/100km2 = 1.06, 95% CI = 1.02-1.11). PNS cancer rates were inversely associated with layer chicken density (RRper log of AU/km2 = 0.94, 95% CI = 0.89 0.99). No association was found between any cancer type and densities of cattle, equine, or goats. CONCLUSIONS: Although limited by the ecologic study design, some of our findings are novel and should be examined in epidemiological studies with individual level data. PMID- 28858759 TI - Effects of metal-rich particulate matter exposure on exogenous and endogenous viral sequence methylation in healthy steel-workers. AB - BACKGROUND: Inhaled particles have been shown to produce systemic changes in DNA methylation. Global hypomethylation has been associated to viral sequence reactivation, possibly linked to the activation of pro-inflammatory pathways occurring after exposure. This observation provides a rationale to investigate viral sequence (both exogenous and endogenous) methylation in association to metal-rich particulate matter exposure. To verify this hypothesis, we chose the Wp promoter of the Epstein-Barr Virus (EBV-Wp) and the promoter of the human endogenous-retrovirus w (HERV-w), respectively as a paradigm of an exogenous and an endogenous retroviral sequence, to be investigated by bisulfite PCR Pyrosequencing. We enrolled 63 male workers in an electric furnace steel plant, exposed to high level of metal-rich particulate matter. RESULTS: Comparing samples obtained in the first day of a work week (time 0-baseline, after 2 days off work) and the samples obtained after 3 days of work (time 1-post exposure), the mean methylation of EBV-Wp was significantly higher at baseline compared to post-exposure (meanbaseline = 56.7%5mC; meanpost-exposure = 47.9%5mC; p-value = 0.009), whereas the mean methylation of HERV-w did not significantly differ. Individual exposure to inhalable particles and metals was estimated based on measures in all working areas and time spent by the study subjects in each area. In a regression model adjusted for age, body mass index and smoking, PM and metal components had a positive association with EBV-Wp methylation (i.e. PM10: beta = 5.99, p-value < 0.038; nickel: beta = 17.82, p-value = 0.02; arsenic: beta = 13.59, p-value < 0.015). CONCLUSIONS: The difference observed comparing baseline and post-exposure samples may be suggestive of a rapid change in EBV methylation induced by air particles, while correlation between EBV methylation and PM/metal exposure may represent a more stable adaptive mechanism. Future studies investigating a larger panel of viral sequences could better elucidate possible mechanisms and their role in pro-inflammatory pathways leading to systemic health effects. PMID- 28858761 TI - Benefit of extending the dosing interval of olanzapine on schizophrenics during maintenance treatment. PMID- 28858760 TI - Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents. AB - INTRODUCTION: While studies have suggested that exposure to manganese (Mn) may be associated with neurodevelopment in school-age children, there is limited information on prenatal and postnatal Mn exposures and tremor or motor function in children. METHODS: We measured Mn levels in dentine of shed teeth, representing prenatal, early postnatal, and cumulative childhood exposure windows, from 195 children (predominantly right-handed, 92%) in Italy. Pursuit Aiming, Luria Nebraska Motor Battery, as well as Tremor and Sway system from Computerized Adaptive Testing System (CATSYS) were administered at 11-14 years old. We examined the relationships of tooth Mn (ln-transformed) with motor function using multivariable linear regressions and generalized additive models, adjusting for age, sex, and socioeconomic status index. Effect modification by sex was also examined. RESULTS: We found that higher prenatal Mn was associated with better body stability in boys in a number of sway tests (including mean sway, transversal sway, sagittal sway, sway area, and sway intensity), while Mn was associated with poorer performance in girls on all of these metrics (all p for Mn * sex interaction < 0.05). Higher prenatal Mn was also modestly associated with better hand/finger and eye-hand coordination in boys compared to girls in sex-stratified analyses, although interaction models did not reach statistical significance. For tremor, on the other hand, higher early postnatal Mn was associated with increased right-hand center frequency in girls (p for interaction < 0.01), but increased Mn level at the later postnatal period was associated with increased center frequency in boys (p for interaction = 0.01). CONCLUSIONS: This study, which used a direct measure of prenatal and childhood Mn exposure, suggested sex-specific critical windows of early life Mn exposure in relation to neuromotor function in adolescents. The sex-specific associations might be strongest with measures of whole body stability, for which the critical exposure window was during the prenatal period. PMID- 28858762 TI - Ultrasensitive electrochemiluminescence immunosensor for 5-hydroxymethylcytosine detection based on Fe3O4@SiO2 nanoparticles and PAMAM dendrimers. AB - An ultrasensitive sandwiched electrochemiluminescence (ECL) immunosensor was developed for 5-hydroxymethylcytosine (5hmC) detection in genomic DNA by using Fe3O4@SiO2 core-shell magnetic nanomaterial as a immobilization matrix for anti 5hmC antibody, PAMAM conjugated avidin and Ru(bpy)2(phen-5-NH2)(PF6)2 as signal amplification unit. Importantly, Fe3O4@SiO2 nanoparticles were verified to not only possess enormous surface for loading antibody by amido link, but also exhibit excellent bioactivity. With the dual signal amplification strategy, the ECL immunosensor showed wide detection range from 0.1 to 30nM with low detection limit of 0.047nM (S/N = 3). Based on the specific immunoreaction, the developed method also illustrated excellent detection selectivity. The fabricated immunosensor was also applied to detect the 5hmC in genomic DNA of cancer tissue, which indicated that the immunosensor possess potential applications in clinical detection. PMID- 28858763 TI - Electrochemical biosensors for Salmonella: State of the art and challenges in food safety assessment. AB - According to the recent statistics, Salmonella is still an important public health issue in the whole world. Legislated reference methods, based on counting plate methods, are sensitive enough but are inadequate as an effective emergency response tool, and are far from a rapid device, simple to use out of lab. An overview of the commercially available rapid methods for Salmonella detection is provided along with a critical discussion of their limitations, benefits and potential use in a real context. The distinguished potentialities of electrochemical biosensors for the development of rapid devices are highlighted. The state-of-art and the newest technologic approaches in electrochemical biosensors for Salmonella detection are presented and a critical analysis of the literature is made in an attempt to identify the current challenges towards a complete solution for Salmonella detection in microbial food control based on electrochemical biosensors. PMID- 28858764 TI - LuxS/AI-2 in Streptococcus agalactiae reveals a key role in acid tolerance and virulence. AB - LuxS-mediated autoinducer-2 (AI-2) directly or indirectly regulates important physiologic function in a variety of bacteria. We found a luxS homologue in the genome of Streptococcus agalactiae, an important pathogen of tilapia. To investigate the relationship between luxS/AI-2 and pathogenicity for tilapia, its bioluminescent activity, acid resistance, cell adherence, virulence, and regulation of virulence gene were evaluated. Compared with the wild-type strain, the bioluminescent activity lost in the luxS mutant, its resistance to acid (pH2.8) was significantly decreased 33.8 times, and furthermore, its adherence to the NGF-2 cell line was dramatically reduced 3 times in the mutant strain. The virulence of the mutant strain was decreased in the tilapia infection model, exogenous AI-2 molecule (7.4nM) and luxS gene complementation with plasmid could complement the deficiencies of function in the luxS mutant strain. These results showed that inactivation of luxS gene caused a significant decrease of bioluminance, acid resistance, cell adhesion, virulence to tilapia and transcription levels of many virulence genes in S. agalactiae. Expression of the known stress resistance factors DnaK and GroEL, relative regulator factors CovR/CovS and virulence factor cpsE verified above results. These findings suggest that luxS may be involved in the interruption of bacterial virulence and resistance to environmental factors. PMID- 28858765 TI - 1-Aryl-1H- and 2-aryl-2H-1,2,3-triazole derivatives blockade P2X7 receptor in vitro and inflammatory response in vivo. AB - Fifty-one 1,2,3-triazole derivatives were synthesized and evaluated with respect to P2X7 receptor (P2X7R) activity and its associated pore. These triazoles were screened in vitro for dye uptake assay and its cytotoxicity against mammalian cell types. Seven 1,2,3-triazole derivatives (5e, 6e, 8h, 9d, 9i, 11, and 12) potently blocked P2X7 receptor pore formation in vitro (J774.G8 cells and peritoneal macrophages). All blockers displayed IC50 value inferior to 500 nM, and they have low toxicity in either cell types. These seven selected triazoles inhibited P2X7R mediated interleukin-1 (IL-1beta) release. In particular, compound 9d was the most potent P2X7R blocker. Additionally, in mouse acute models of inflammatory responses induced by ATP or carrageenan administration in the paw, compound 9d promoted a potent blocking response. Similarly, 9d also reduced mouse LPS-induced pleurisy cellularity. In silico predictions indicate this molecule appropriate to develop an anti-inflammatory agent when it was compared to commercial analogs. Electrophysiological studies suggest a competitive mechanism of action of 9d to block P2X7 receptor. Molecular docking was performed on the ATP binding site in order to observe the preferential interaction pose, indicating that binding mode of the 9d is by interacting its 1,2,3-triazole and ether moiety with positively charged residues and with its chlorobenzene moiety orientated toward the apolar end of the ATP binding site which are mainly composed by the Ile170, Trp167 and Leu309 residues from alpha subunit. These results highlight 9d derivative as a drug candidate with potential therapeutic application based on P2X7 receptor blockade. PMID- 28858766 TI - Asymmetric synthesis of novel triazole derivatives and their in vitro antiviral activity and mechanism of action. AB - In this study, forty-four chiral triazole derivatives have been prepared via asymmetric synthesis, and which has been successfully characterized by typical spectroscopic techniques including 1H NMR, 13C NMR, EI-MS, elemental analysis and optical rotations. Their in vitro antiviral activities against EV71 and CVB3 were fully investigated in cell-based assays. It was observed that 13 synthetic triazole derivatives inhibited the CPE of EV71 on RD cells, with EC50S in the 5.3 15.9 MUg/ml range and corresponding SIs of 4.0-27.6, while 17 triazole derivatives showed antiviral activities against CVB3, with EC50S in the 4.7-15.1 MUg/ml range and the corresponding SIs of 3.7-14.5. In addition, in some cases, the respective enantiomers showed significantly selective inhibitory effect against EV71, most notably for the enantiomers 9(R) and 10(S), 42(R) and 43(S), which presented an obvious activity difference. The most potential molecules are the compounds 10 and 43 with S-configuration, and which exhibit good SI values compared with the control Ribavirin. PMID- 28858767 TI - Discovery of new MD2-targeted anti-inflammatory compounds for the treatment of sepsis and acute lung injury. AB - Myeloid differentiation 2 (MD2) is essential to the recognition of lipopolysaccharide (LPS) and the subsequent mediation of toll-like receptor 4 (TLR4)-dependent acute inflammatory disorders including sepsis and acute lung injury. Inhibitors targeting MD2 may provide an alternative means to subdue acute inflammatory diseases. In the present study, 39 bisaryl-1,4-dien-3-one compounds with 5-carbon connection chains were designed and synthesized as MD2 inhibitors based on the analysis of the molecular docking of xanthohumol to MD2. The compound-MD2 interactions were measured by cell-free assays including bis-ANS displacement and SPR, and the active compounds were further tested for MD2 inhibition and anti-inflammatory activities in LPS-challenged macrophages. The most active compound, 1f, was shown to have remarkable protective effects against sepsis shock and pulmonary inflammation. Collectively, we present evidence that bisaryl-1,4-dien-3-one is a new lead structure for the development of anti inflammatory agents targeting MD2. PMID- 28858768 TI - Making the most of person-centred education by integrating flipped and simulated teaching: An exploratory study. AB - Preparing a person-centred nursing workforce to work in diverse settings is a global health priority. Nursing students' first placement experience is a key transitional moment that shapes professional understanding and motivation to become a nurse. This paper reports the outcomes of combining flipped and simulated learning to enhance nursing students' understanding of person-centred care, the professional nursing role and preparation for placement. The study design was exploratory, the setting, an undergraduate nursing program in an Australian University. Participants included first year nursing students, academic tutors and clinical facilitators. Data collected via survey, semistructured interviews and focus group discussion were analysed descriptively and thematically. Over 90% of students surveyed considered the unit structure, content and resources prepared them well for placement. Pre-class preparation and simulated tutorial activities facilitated student engagement and knowledge translation. Students, tutors and clinical facilitators valued the person-centred approach. Tutors considered the unit materials and focus enhanced students' professional understanding. Clinical facilitators deemed students well-prepared for placement. These results from multiple perspectives, though limited, support combining the flipped classroom and person-centred simulation in nursing education as a strategy to prepare students for clinical placement, translate person-centred values into practice and promote professional understanding and role socialisation. PMID- 28858769 TI - Genetic and environmental contributions to children's prosocial behavior: brief review and new evidence from a reanalysis of experimental twin data. AB - Children's prosocial behaviors show considerable variability. Here we discuss the genetic and environmental contributions to individual differences in children's prosocial behavior. Twin research systematically shows, at least from the age of 3 years, a genetic contribution to individual differences in prosocial behavior, both questionnaire-based and observed. This finding is demonstrated across a wide variety of cultures. We discuss the possibility that different prosocial behaviors have different genetic etiologies. A re-analysis of past twin data shows that sharing and comforting are affected by overlapping genetic factors at age 3.5 years. In contrast, the association between helping and comforting is attributed to environmental factors. The few molecular genetic studies of children's prosocial behavior are reviewed, and we point out genome-wide and polygenic methods as a key future direction. Finally, we discuss the interplay of genetic and environmental factors, focusing on both gene*environment interactions and gene-environment correlations. PMID- 28858770 TI - The early emergence of sociomoral evaluation: infants prefer prosocial others. AB - Humans readily evaluate third-parties' prosocial and antisocial acts. Recent evidence reveals that this tendency emerges early in development-even preverbal infants selectively approach prosocial others and avoid antisocial ones. Rather than reflecting attraction toward or away from low-level characteristics of the displays or simple behavioral rules, infants are sensitive to characteristics of both the agents and recipients of prosocial and antisocial acts. Specifically, infants' preferences require that the recipients of positive and negative acts be social agents with clear unfulfilled goals, who have not previously harmed others. In addition, prosocial and antisocial agents must act intentionally, in the service of positive and negative goals. It is an open question whether these prosocial preferences reflect self-interested and/or moral concerns. PMID- 28858771 TI - How do social norms influence prosocial development? AB - Humans are both highly prosocial and extremely sensitive to social norms, and some theories suggest that norms are necessary to account for uniquely human forms of prosocial behavior and cooperation. Understanding how norms influence prosocial behavior is thus essential if we are to describe the psychology and development of prosocial behavior. In this article I review recent research from across the social sciences that provides (1) a theoretical model of how norms influence prosocial behavior, (2) empirical support for the model based on studies with adults and children, and (3) predictions about the psychological mechanisms through which norms shape prosocial behavior. I conclude by discussing the need for future studies into how prosocial behavior develops through emerging interactions between culturally varying norms, social cognition, emotions, and potentially genes. PMID- 28858772 TI - The influence of reputational concerns on children's prosociality. AB - While it is well known that reputational concerns promote prosociality in adults, their ontogenetic origins remain poorly understood. Here we review evidence suggesting that the first prosocial acts of young children are not aimed at gaining reputational credit. However, at approximately five years of age, children come to be concerned about their reputations, and their prosocial behaviors show the signature of self-promotional strategies: increased prosociality in public compared to private settings. In middle childhood, at around eight years of age, children acquire further abilities to control the image they project and start to reason explicitly about their reputation. We discuss potential social and cognitive factors-Partner Choice and Theory of Mind that contribute to the developmental emergence of self-presentational behavior. PMID- 28858773 TI - Sibling influences on prosocial behavior. AB - Sibling relationships are characterized by familiarity and emotional intensity. Alongside frequent shared play, sibling interactions feature complementary interactions (e.g. teaching, caregiving) reflecting age-related asymmetries in socio-cognitive skills. These aspects may underpin sibling influences on prosocial behavior: theoretical accounts of social influences on prosocial behavior highlight emotion sharing, goal alignment, the intrinsically rewarding nature of social interaction, and scaffolding of social norms. Taking a fine grained approach to prosocial behavior, we examine these processes in relation to sibling influences on children's comforting, sharing, and helping. Emergent themes include: developmental change in the nature of sibling influences on prosocial behavior, the need to consider sibling influences in the wider family context, and the importance of individual differences in the quality of sibling relationships. PMID- 28858774 TI - Comparison of older and younger novice driver crash rates: Informing the need for extended Graduated Driver Licensing restrictions. AB - BACKGROUND: Few previous studies have directly compared crash rates of older and younger novice drivers. To inform discussion about whether Graduated Driver Licensing (GDL) policies that are applied in the US for younger novice drivers should be applied to older novice drivers, we conducted a longitudinal study to examine overall, nighttime, and multiple passenger crash rates over the initial four years of licensure differ for novice drivers licensed at different ages. METHODS: Using data from the New Jersey Traffic Safety Outcomes (NJ-TSO) data warehouse, we selected all NJ drivers who obtained their initial intermediate driver's license from 2006 through 2014 and had at least one month of follow-up from the date of licensure to study end or death (n=1,034,835). Novice drivers were grouped based on age at licensure: age 17; 18-20; 21-24; and 25 or older. We estimated monthly rates for overall crashes (per 10,000 licensed drivers) as well as: late night crashes (11:01 p.m.-4:59 a.m.); early night crashes (9:00 p.m. 11:00 p.m.); and multiple passenger crashes (two or more passengers). Average monthly rates were calculated for specific relevant time periods and Poisson regression models were used to compare rates: (1) between novice driver groups with the same time since licensure; (2) over the first 48 months of licensure within each novice driver group; and (3) between same-aged 21-year-old drivers with varying lengths of licensure. RESULTS: Although initial (three months post licensure) overall crash rates of novice NJ drivers age 21 and older were higher than rates of same-aged experienced drivers, they were substantially lower than initial rates for 17- to 20-year-old novice drivers, who are licensed under GDL policies. Moreover, older novice drivers experience much less steep crash reductions over the first year of licensure than younger novice drivers. Nighttime crash rates among the 21- to 24-year old and aged 25 and older novice driver groups were stable over the first year of licensure. For novice drivers under age 21, early night crash rates declined rapidly over the course of licensure, while changes in late night crashes were much smaller. First-year multiple passenger crash rates were highest for drivers licensed at age 18-20, and novice driver groups experienced varying amounts of reduction in multiple passenger crashes over time. CONCLUSIONS: Study findings support NJ's current GDL policies for 17- to 20-year-old novice drivers and the potential for added benefits from beginning the nighttime restriction at 9:00 p.m. Conversely, there was a lack of compelling evidence for additional policies for drivers licensed at age 21-24 and no evidence to indicate a need for additional GDL policies for NJ novices aged 25 years and older. PMID- 28858775 TI - Driver braking behavior analysis to improve autonomous emergency braking systems in typical Chinese vehicle-bicycle conflicts. AB - Bicycling is one of the fundamental modes of transportation especially in developing countries. Because of the lack of effective protection for bicyclists, vehicle-bicycle (V-B) accident has become a primary contributor to traffic fatalities. Although AEB (Autonomous Emergency Braking) systems have been developed to avoid or mitigate collisions, they need to be further adapted in various conflict situations. This paper analyzes the driver's braking behavior in typical V-B conflicts of China to improve the performance of Bicyclist-AEB systems. Naturalistic driving data were collected, from which the top three scenarios of V-B accidents in China were extracted, including SCR (a bicycle crossing the road from right while a car is driving straight), SCL (a bicycle crossing the road from left while a car is driving straight) and SSR (a bicycle swerving in front of the car from right while a car is driving straight). For safety and data reliability, a driving simulator was employed to reconstruct these three scenarios and some 25 licensed drivers were recruited for braking behavior analysis. Results revealed that driver's braking behavior was significantly influenced by V-B conflict types. Pre-decelerating behaviors were found in SCL and SSR conflicts, whereas in SCR the subjects were less vigilant. The brake reaction time and brake severity in lateral V-B conflicts (SCR and SCL) was shorter and higher than that in longitudinal conflicts (SSR). The findings improve their applications in the Bicyclist-AEB and test protocol enactment to enhance the performance of Bicyclist-AEB systems in mixed traffic situations especially for developing countries. PMID- 28858776 TI - Associations between alcohol consumption patterns and attitudes towards alcohol interlocks. AB - BACKGROUND: Drink-driving and alcohol-related crashes are a significant problem globally. Alcohol interlocks are used to prevent drivers with a blood alcohol concentration above a pre-determined level from starting their vehicle, making the technology highly effective in preventing drink-drive episodes. While alcohol interlocks are commonly used in drink-drive offender groups, their broader use as a preventative road safety strategy is considered increasingly feasible. In this context it is important to understand attitudes towards the technology, and to investigate whether these attitudes vary according to alcohol consumption patterns as this influences the acceptability of a broad-based preventative alcohol interlock program. METHODS: A representative sample of 2994 Australian drivers participated in an online cross-sectional survey. Participants reported their alcohol consumption, drink-drive behaviour and attitudes towards the use of alcohol interlocks for personal use and for drink-drive offenders. RESULTS: Half of the sample stated that alcohol interlocks would be of use personally. Seventy four percent of high-risk drinkers (defined by an AUDIT score >=20) stated they would find the technology personally useful when compared to 49% of low-risk drinkers (AUDIT <=7). Overwhelmingly, more than 80% of participants agreed with the mandatory instalment of alcohol interlocks and compulsory clinical interventions for drink-drive offenders, with more low-risk drinkers supporting this than the high-risk drinkers. CONCLUSIONS: While there were mixed opinions regarding the perceived personal usefulness of alcohol interlocks, higher-risk drinkers were most likely to perceive interlocks as being of use for themselves. This high-risk group however, was less likely to provide support for clinical interventions and additional re-licensing requirements aimed at eliciting changes in drinking behaviour. These findings have important implications for drink-drive offender relicensing and the likely success of drink-driver education, and interventions aimed at curbing risky alcohol consumption. PMID- 28858777 TI - Trafficking patterns of NMDA and GABAA receptors in a Mg2+-free cultured hippocampal neuron model of status epilepticus. AB - An altered pattern of receptor trafficking is one of the pathophysiologic mechanisms of status epilepticus (SE). The gradual internalization of GABAA receptors (GABARs) occurs in both in vitro and in vivo models of SE and is thought to be a cause of decreased GABAergic inhibition. Unlike GABARs, little is known about alterations in NMDA receptor (NMDAR) trafficking during SE, even though increased activity of NMDARs is indispensable for the induction and maintenance of SE. Therefore, we aimed to simultaneously investigate the changes in the trafficking patterns of GABARs and NMDARs in an in vitro cultured hippocampal neuron model of SE. For induction of epileptiform discharges, hippocampal neurons were exposed to external medium without Mg2+. Biotinylation assay and immunofluorescence staining for GABAR beta2,3 and NMDAR NR1 subunits were performed to quantify and visualize surface GABARs and NMDARs, respectively. The frequency of spontaneous action potentials increased more than 4-fold after Mg2+-free induction. The level of surface GABARs decreased over time after Mg2+ free induction, dropping to approximately 50% of control levels an hour after Mg2+-free induction. By contrast, the trafficking of NMDARs to the surface was enhanced after a slight time lag, increasing by 30% of control levels an hour after Mg2+-free induction. Our data showed the changes of both NMDAR and GABAR trafficking during prolonged SE induced by a Mg2+-free extracellular environment and confirmed that this in vitro SE model is suitable for examining alterations in the receptor trafficking pattern by prolonged seizure activity. These results suggest that targeting of surface NMDAR could be a promising method in controlling benzodiazepine-resistant SE. PMID- 28858778 TI - Mode pair selection of circumferential guided waves for cumulative second harmonic generation in a circular tube. AB - The appropriate mode pairs of primary and double-frequency circumferential guided waves (CGWs) have been investigated and selected for generation of the cumulative second harmonics, which are applicable for quantitative assessment of damage/degradation in a circular tube. The selection criteria follow the requirements: the higher efficiency of cumulative second-harmonic generation (SHG) of primary CGW propagation, and the larger response sensitivity of cumulative SHG to material damage/degradation [characterized by variation in the third-order elastic (TOE) constants]. The acoustic nonlinearity parameter beta of CGW propagation and the change rate of normalized beta versus the TOE constants of tube material are, respectively, used to describe the efficiency of SHG and its response sensitivity to damage/degradation. Based on the selection criteria proposed, all the possible mode pairs of primary and double-frequency CGWs satisfying the phase velocity matching have been numerically examined. It has been found that there are indeed some mode pairs of CGW propagation with the larger values both of beta and the change rate of normalized beta versus the TOE constants. The CGW mode pairs found in this paper are of practical significance for quantitative assessment of damage/degradation in the circular tube. PMID- 28858780 TI - A Machine Learning Approach to Automated Gait Analysis for the Noldus Catwalk System. AB - OBJECTIVE: Gait analysis of animal disease models can provide valuable insights into in vivo compound effects and thus help in preclinical drug development. The purpose of this paper is to establish a computational gait analysis approach for the Noldus Catwalk system, in which footprints are automatically captured and stored. METHODS: We present a - to our knowledge - first machine learning based approach for the Catwalk system, which comprises a step decomposition, definition and extraction of meaningful features, multivariate step sequence alignment, feature selection, and training of different classifiers (gradient boosting machine, random forest, and elastic net). RESULTS: Using animal-wise leave-one out cross validation we demonstrate that with our method we can reliable separate movement patterns of a putative Parkinson's disease animal model and several control groups. Furthermore, we show that we can predict the time point after and the type of different brain lesions and can even forecast the brain region, where the intervention was applied. We provide an in-depth analysis of the features involved into our classifiers via statistical techniques for model interpretation. CONCLUSION: A machine learning method for automated analysis of data from the Noldus Catwalk system was established. SIGNIFICANCE: Our works shows the ability of machine learning to discriminate pharmacologically relevant animal groups based on their walking behavior in a multivariate manner. Further interesting aspects of the approach include the ability to learn from past experiments, improve with more data arriving and to make predictions for single animals in future studies. PMID- 28858779 TI - Smoothness of gait detects early alterations of walking in persons with multiple sclerosis without disability. AB - In people with Multiple Sclerosis (pwMS) with little or no signs of disability, early detection of walking impairments represents a challenging issue, as simple gait metrics (e.g. speed, cadence, stride length, etc.) may not significantly differ from those of healthy individuals. In this study, we aimed to assess the existence of possible differences in spatial-temporal parameters and smoothness of gait measures (assessed through Harmonic Ratio, HR) obtained from trunk accelerations between 50pwMS without disability (Expanded Disability Status Scale score =1) and 50 age-matched healthy controls. The results show no differences in terms of gait velocity, stride length, stance/swing and double support phases duration, while HR in the direction of motion was significantly lower in pwMS (2.92 vs. 3.67, p<0.001), thus indicating a less smooth gait. The study of trunk accelerations through calculation of HR represents a fast, non-intrusive technique that allows early identification of anomalies in gait patterns of pwMS in absence of disability. PMID- 28858781 TI - Epidermal Electrode Technology for Detecting Ultrasonic Perturbation of Sensory Brain Activity. AB - OBJECTIVE: We aim to demonstrate the in vivo capability of a wearable sensor technology to detect localized perturbations of sensory-evoked brain activity. METHODS: Cortical somatosensory evoked potentials (SSEPs) were recorded in mice via wearable, flexible epidermal electrode arrays. We then utilized the sensors to explore the effects of transcranial focused ultrasound, which noninvasively induced neural perturbation. SSEPs recorded with flexible epidermal sensors were quantified and benchmarked against those recorded with invasive epidural electrodes. RESULTS: We found that cortical SSEPs recorded by flexible epidermal sensors were stimulus frequency dependent. Immediately following controlled, focal ultrasound perturbation, the sensors detected significant SSEP modulation, which consisted of dynamic amplitude decreases and altered stimulus-frequency dependence. These modifications were also dependent on the ultrasound perturbation dosage. The effects were consistent with those recorded with invasive electrodes, albeit with roughly one order of magnitude lower signal-to noise ratio. CONCLUSION: We found that flexible epidermal sensors reported multiple SSEP parameters that were sensitive to focused ultrasound. This work therefore 1) establishes that epidermal electrodes are appropriate for monitoring the integrity of major CNS functionalities through SSEP; and 2) leveraged this technology to explore ultrasound-induced neuromodulation. The sensor technology is well suited for this application because the sensor electrical properties are uninfluenced by direct exposure to ultrasound irradiation. SIGNIFICANCE: The sensors and experimental paradigm we present involve standard, safe clinical neurological assessment methods and are thus applicable to a wide range of future translational studies in humans with any manner of health condition. PMID- 28858782 TI - Acoustical Emission Analysis by Unsupervised Graph Mining: A Novel Biomarker of Knee Health Status. AB - OBJECTIVE: To study knee acoustical emission patterns in subjects with acute knee injury immediately following injury and several months after surgery and rehabilitation. METHODS: We employed an unsupervised graph mining algorithm to visualize heterogeneity of the high-dimensional acoustical emission data, and then to derive a quantitative metric capturing this heterogeneity-the graph community factor (GCF). A total of 42 subjects participated in the studies. Measurements were taken once each from 33 healthy subjects with no known previous knee injury, and twice each from 9 subjects with unilateral knee injury: first, within seven days of the injury, and second, 4-6 months after surgery when the subjects were determined to start functional activities. Acoustical signals were processed to extract time and frequency domain features from multiple time windows of the recordings from both knees, and k-nearest neighbor graphs were then constructed based on these features. RESULTS: The GCF calculated from these graphs was found to be 18.5 +/- 3.5 for healthy subjects, 24.8 +/- 4.4 (p = 0.01) for recently injured, and 16.5 +/- 4.7 (p = 0.01) at 4-6 months recovery from surgery. CONCLUSION: The objective GCF scores changes were consistent with a medical professional's subjective evaluations and subjective functional scores of knee recovery. SIGNIFICANCE: Unsupervised graph mining to extract GCF from knee acoustical emissions provides a novel, objective, and quantitative biomarker of knee injury and recovery that can be incorporated with a wearable joint health system for use outside of clinical settings, and austere/under resourced conditions, to aid treatment/therapy. PMID- 28858783 TI - Molecularly Imprinted Polymer-Based Electrochemical Biosensor for Bone Loss Detection. AB - Serum C-terminal telopeptide of type I collagen (CTx-I) assays quantify the fragment of CTx-I released throughout the procedure of bone remodeling. CTx-I is a key bone turnover biomarker where any variation in the level of CTx-I can be an indication of increased bone resorption. This study focuses on a new strategy for the prognosis of bone loss by monitoring the concentration of CTx-I in serum. An interdigital capacitive sensor together with electrochemical impedance spectroscopy was employed to assess the dielectric properties of the test solution. Artificial antibodies have been prepared for CTx-I molecules using the molecular imprinting technique. The sensor was functionalized using the synthesized molecular imprinted polymer in order to introduce the selectivity of CTx-I biomarker to the sensor. Calibration experiments were performed using different known concentration of sample solutions. The proposed biosensor showed a good linear response between 0.1 and 2.5 ng/mL. The detection limit of 0.09 ng/mL was found, encompassing the normal reference ranges required for recognition of bone turnover. Unknown real serum samples obtained from sheep blood were analysed using the proposed biosensor. The validation of the suggested technique was done using enzyme-linked immunosorbent assay (ELISA). The developed biosensor exhibited a good correlation with ELISA. PMID- 28858784 TI - A Probabilistic Active Learning Algorithm Based on Fisher Information Ratio. AB - The task of labeling samples is demanding and expensive. Active learning aims to generate the smallest possible training data set that results in a classifier with high performance in the test phase. It usually consists of two steps of selecting a set of queries and requesting their labels. Among the suggested objectives to score the query sets, information theoretic measures have become very popular. Yet among them, those based on Fisher information (FI) have the advantage of considering the diversity among the queries and tractable computations. In this work, we provide a practical algorithm based on Fisher information ratio to obtain query distribution for a general framework where, in contrast to the previous FI-based querying methods, we make no assumptions over the test distribution. The empirical results on synthetic and real-world data sets indicate that this algorithm gives competitive results. PMID- 28858785 TI - Crafting GBD-Net for Object Detection. AB - The visual cues from multiple support regions of different sizes and resolutions are complementary in classifying a candidate box in object detection. Effective integration of local and contextual visual cues from these regions has become a fundamental problem in object detection. In this paper, we propose a gated bi directional CNN (GBD-Net) to pass messages among features from different support regions during both feature learning and feature extraction. Such message passing can be implemented through convolution between neighboring support regions in two directions and can be conducted in various layers. Therefore, local and contextual visual patterns can validate the existence of each other by learning their nonlinear relationships and their close interactions are modeled in a more complex way. It is also shown that message passing is not always helpful but dependent on individual samples. Gated functions are therefore needed to control message transmission, whose on-or-offs are controlled by extra visual evidence from the input sample. The effectiveness of GBD-Net is shown through experiments on three object detection datasets, ImageNet, Pascal VOC2007 and Microsoft COCO. Besides the GBD-Net, this paper also shows the details of our approach in winning the ImageNet object detection challenge of 2016, with source code provided on https://github.com/craftGBD/craftGBD. In this winning system, the modified GBD Net, new pretraining scheme and better region proposal designs are provided. We also show the effectiveness of different network structures and existing techniques for object detection, such as multi-scale testing, left-right flip, bounding box voting, NMS, and context. PMID- 28858786 TI - A Functional Regression Approach to Facial Landmark Tracking. AB - Linear regression is a fundamental building block in many face detection and tracking algorithms, typically used to predict shape displacements from image features through a linear mapping. This paper presents a Functional Regression solution to the least squares problem, which we coin Continuous Regression, resulting in the first real-time incremental face tracker. Contrary to prior work in Functional Regression, in which B-splines or Fourier series were used, we propose to approximate the input space by its first-order Taylor expansion, yielding a closed-form solution for the continuous domain of displacements. We then extend the continuous least squares problem to correlated variables, and demonstrate the generalisation of our approach. We incorporate Continuous Regression into the cascaded regression framework, and show its computational benefits for both training and testing. We then present a fast approach for incremental learning within Cascaded Continuous Regression, coined iCCR, and show that its complexity allows real-time face tracking, being 20 times faster than the state of the art. To the best of our knowledge, this is the first incremental face tracker that is shown to operate in real-time. We show that iCCR achieves state-of-the-art performance on the 300-VW dataset, the most recent, large-scale benchmark for face tracking. PMID- 28858787 TI - Foreground Segmentation with Tree-Structured Sparse RPCA. AB - Background subtraction is a fundamental video analysis technique that consists of creation of a background model that allows distinguishing foreground pixels. We present a new method in which the image sequence is assumed to be made up of the sum of a low-rank background matrix and a dynamic tree-structured sparse matrix. The decomposition task is then solved using our approximated Robust Principal Component Analysis (ARPCA) method which is an extension to the RPCA that can handle camera motion and noise. Our model dynamically estimates the support of the foreground regions via a superpixel generation step, so that spatial coherence can be imposed on these regions. Unlike conventional smoothness constraints such as MRF, our method is able to obtain crisp and meaningful foreground regions, and in general, handles large dynamic background motion better. To reduce the dimensionality and the curse of scale that is persistent in the RPCA-based methods, we model the background via Column Subset Selection Problem, that reduces the order of complexity and hence decreases computation time. Comprehensive evaluation on four benchmark datasets demonstrate the effectiveness of our method in outperforming state-of-the-art alternatives. PMID- 28858788 TI - Development of a Fluid Dynamic Model for Quantitative Contrast-Enhanced Ultrasound Imaging. AB - Contrast-enhanced ultrasound (CEUS) is a non-invasive imaging technique extensively used for blood perfusion imaging of various organs. This modality is based on the acoustic detection of gas-filled microbubble contrast agents used as intravascular flow tracers. Recent efforts aim at quantifying parameters related to the enhancement in the vascular compartment using time-intensity curve (TIC), and at using these latter as indicators for several pathological conditions. However, this quantification is mainly hampered by two reasons: first, the quantification intrinsically solely relies on temporal intensity variation, the explicit spatial transport of the contrast agent being left out. Second, the exact relationship between the acquired US-signal and the local microbubble concentration is hardly accessible. This paper introduces the use of a fluid dynamic model for the analysis of dynamic CEUS (DCEUS), in order to circumvent the two above-mentioned limitations. A new kinetic analysis is proposed in order to quantify the velocity amplitude of the bolus arrival. The efficiency of proposed methodology is evaluated both in-vitro, for the quantitative estimation of microbubble flow rates, and in-vivo, for the classification of placental insufficiency (control versus ligature) of pregnant rats from DCEUS. Besides, for the in-vivo experimental setup, we demonstrated that the proposed approach outperforms the performance of existing TIC-based methods. PMID- 28858789 TI - Sparse Recovery in Magnetic Resonance Imaging With a Markov Random Field Prior. AB - Recent research in compressed sensing of magnetic resonance imaging (CS-MRI) emphasizes the importance of modeling structured sparsity, either in the acquisition or in the reconstruction stages. Subband coefficients of typical images show certain structural patterns, which can be viewed in terms of fixed groups (like wavelet trees) or statistically (certain configurations are more likely than others). Wavelet tree models have already demonstrated excellent performance in MRI recovery from partial data. However, much less attention has been given in CS-MRI to modeling statistically spatial clustering of subband data, although the potentials of such models have been indicated. In this paper, we propose a practical CS-MRI reconstruction algorithm making use of a Markov random field prior model for spatial clustering of subband coefficients and an efficient optimization approach based on proximal splitting. The results demonstrate an improved reconstruction performance compared with both the standard CS-MRI methods and the recent related methods. PMID- 28858790 TI - Image Registration Based on Low Rank Matrix: Rank-Regularized SSD. AB - Similarity measure is a main core of image registration algorithms. Spatially varying intensity distortion is an important challenge, which affects the performance of similarity measures. Correlation among the pixels is the main characteristic of this distortion. Similarity measures such as sum-of-squared differences (SSD) and mutual information ignore this correlation; hence, perfect registration cannot be achieved in the presence of this distortion. In this paper, we model this correlation with the aid of the low rank matrix theory. Based on this model, we compensate this distortion analytically and introduce rank-regularized SSD (RRSSD). This new similarity measure is a modified SSD based on singular values of difference image in mono-modal imaging. In fact, image registration and distortion correction are performed simultaneously in the proposed model. Based on our experiments, the RRSSD similarity measure achieves clinically acceptable registration results, and outperforms other state-of-the art similarity measures, such as the well-known method of residual complexity. PMID- 28858791 TI - Selective Video Object Cutout. AB - Conventional video segmentation approaches rely heavily on appearance models. Such methods often use appearance descriptors that have limited discriminative power under complex scenarios. To improve the segmentation performance, this paper presents a pyramid histogram-based confidence map that incorporates structure information into appearance statistics. It also combines geodesic distance-based dynamic models. Then, it employs an efficient measure of uncertainty propagation using local classifiers to determine the image regions, where the object labels might be ambiguous. The final foreground cutout is obtained by refining on the uncertain regions. Additionally, to reduce manual labeling, our method determines the frames to be labeled by the human operator in a principled manner, which further boosts the segmentation performance and minimizes the labeling effort. Our extensive experimental analyses on two big benchmarks demonstrate that our solution achieves superior performance, favorable computational efficiency, and reduced manual labeling in comparison to the state of the art. PMID- 28858792 TI - Joint Machine Learning and Game Theory for Rate Control in High Efficiency Video Coding. AB - In this paper, a joint machine learning and game theory modeling (MLGT) framework is proposed for inter frame coding tree unit (CTU) level bit allocation and rate control (RC) optimization in high efficiency video coding (HEVC). First, a support vector machine-based multi-classification scheme is proposed to improve the prediction accuracy of CTU-level rate-distortion (R-D) model. The legacy "chicken-and-egg" dilemma in video coding is proposed to be overcome by the learning-based R-D model. Second, a mixed R-D model-based cooperative bargaining game theory is proposed for bit allocation optimization, where the convexity of the mixed R-D model-based utility function is proved, and Nash bargaining solution is achieved by the proposed iterative solution search method. The minimum utility is adjusted by the reference coding distortion and frame-level quantization parameter (QP) change. Finally, intra frame QP and inter frame adaptive bit ratios are adjusted to make inter frames have more bit resources to maintain smooth quality and bit consumption in the bargaining game optimization. Experimental results demonstrate that the proposed MLGT-based RC method can achieve much better R-D performances, quality smoothness, bit rate accuracy, buffer control results, and subjective visual quality than the other state-of-the art one-pass RC methods, and the achieved R-D performances are very close to the performance limits from the FixedQP method. PMID- 28858793 TI - Geometric Occlusion Analysis in Depth Estimation Using Integral Guided Filter for Light-Field Image. AB - Unlike traditional multi-view images, sampling in angular domain of light field images is distributed in different directions. Therefore, an angular sampling image (ASI), comprising of possible matching points extracted from each view, is available for each point. In this paper, we analyze the geometric relationship between ASIs and reference sub-aperture images, and then prove the occlusion boundary similarity. Based on the geometric relationship in extreme cases, we show that some points in ASI have higher reliability than other points for depth calculation. An integral guided filter is then built based on the sub-aperture image to predict occlusion probabilities in ASIs. The filter is independent of ASIs and has no requirement for high angular resolution so that it is easy to apply to the cost volume calculation. We integrate the filter into our depth estimation framework and other state-of-the-art depth estimation frameworks. Experimental results demonstrate that the proposed filter is more effective to occluded point detection in ASIs than other methods. Results from different data sets show that our method outperforms the existing state-of-the-art depth estimation methods, especially along occlusion boundaries. PMID- 28858794 TI - A Hybrid Data Association Framework for Robust Online Multi-Object Tracking. AB - Global optimization algorithms have shown impressive performance in data association-based multi-object tracking, but handling online data remains a difficult hurdle to overcome. In this paper, we present a hybrid data association framework with a min-cost multi-commodity network flow for robust online multi object tracking. We build local target-specific models interleaved with global optimization of the optimal data association over multiple video frames. More specifically, in the min-cost multi-commodity network flow, the target-specific similarities are online learned to enforce the local consistency for reducing the complexity of the global data association. Meanwhile, the global data association taking multiple video frames into account alleviates irrecoverable errors caused by the local data association between adjacent frames. To ensure the efficiency of online tracking, we give an efficient near-optimal solution to the proposed min-cost multi-commodity flow problem, and provide the empirical proof of its sub optimality. The comprehensive experiments on real data demonstrate the superior tracking performance of our approach in various challenging situations. PMID- 28858795 TI - Log-Euclidean Metrics for Contrast Preserving Decolorization. AB - This paper presents a novel Log-Euclidean metric inspired color-to-gray conversion model for faithfully preserving the contrast details of color image, which differs from the traditional Euclidean metric approaches. In the proposed model, motivated by the fact that Log-Euclidean metric has promising invariance properties such as inversion invariant and similarity invariant, we present a Log Euclidean metric-based maximum function to model the decolorization procedure. The Gaussian-like penalty function consisting of the Log-Euclidean metric between gradients of the input color image and transformed grayscale image is incorporated to better reflect the degree of preserving feature discriminability and color ordering in color-to-gray conversion. A discrete searching algorithm is employed to solve the proposed model with linear parametric and non-negative constraints. Extensive evaluation experiments show that the proposed method outperforms the state-of-the-art methods both quantitatively and qualitatively. PMID- 28858796 TI - Synergistic Instance-Level Subspace Alignment for Fine-Grained Sketch-Based Image Retrieval. AB - We study the problem of fine-grained sketch-based image retrieval. By performing instance-level (rather than category-level) retrieval, it embodies a timely and practical application, particularly with the ubiquitous availability of touchscreens. Three factors contribute to the challenging nature of the problem: 1) free-hand sketches are inherently abstract and iconic, making visual comparisons with photos difficult; 2) sketches and photos are in two different visual domains, i.e., black and white lines versus color pixels; and 3) fine grained distinctions are especially challenging when executed across domain and abstraction-level. To address these challenges, we propose to bridge the image sketch gap both at the high level via parts and attributes, as well as at the low level via introducing a new domain alignment method. More specifically, first, we contribute a data set with 304 photos and 912 sketches, where each sketch and image is annotated with its semantic parts and associated part-level attributes. With the help of this data set, second, we investigate how strongly supervised deformable part-based models can be learned that subsequently enable automatic detection of part-level attributes, and provide pose-aligned sketch-image comparisons. To reduce the sketch-image gap when comparing low-level features, third, we also propose a novel method for instance-level domain-alignment that exploits both subspace and instance-level cues to better align the domains. Finally, fourth, these are combined in a matching framework integrating aligned low-level features, mid-level geometric structure, and high-level semantic attributes. Extensive experiments conducted on our new data set demonstrate effectiveness of the proposed method. PMID- 28858797 TI - Zero-Shot Learning via Attribute Regression and Class Prototype Rectification. AB - Zero-shot learning (ZSL) aims at classifying examples for unseen classes (with no training examples) given some other seen classes (with training examples). Most existing approaches exploit intermedia-level information (e.g., attributes) to transfer knowledge from seen classes to unseen classes. A common practice is to first learn projections from samples to attributes on seen classes via a regression method, and then apply such projections to unseen classes directly. However, it turns out that such a manner of learning strategy easily causes projection domain shift problem and hubness problem, which hinder the performance of ZSL task. In this paper, we also formulate ZSL as an attribute regression problem. However, different from general regression-based solutions, the proposed approach is novel in three aspects. First, a class prototype rectification method is proposed to connect the unseen classes to the seen classes. Here, a class prototype refers to a vector representation of a class, and it is also known as a class center, class signature, or class exemplar. Second, an alternating learning scheme is proposed for jointly performing attribute regression and rectifying the class prototypes. Finally, a new objective function which takes into consideration both the attribute regression accuracy and the class prototype discrimination is proposed. By introducing such a solution, domain shift problem and hubness problem can be mitigated. Experimental results on three public datasets (i.e., CUB200-2011, SUN Attribute, and aPaY) well demonstrate the effectiveness of our approach. PMID- 28858798 TI - Convergence of Proximal Iteratively Reweighted Nuclear Norm Algorithm for Image Processing. AB - The nonsmooth and nonconvex regularization has many applications in imaging science and machine learning research due to its excellent recovery performance. A proximal iteratively reweighted nuclear norm algorithm has been proposed for the nonsmooth and nonconvex matrix minimizations. In this paper, we aim to investigate the convergence of the algorithm. With the Kurdyka-Lojasiewicz property, we prove the algorithm globally converges to a critical point of the objective function. The numerical results presented in this paper coincide with our theoretical findings. PMID- 28858799 TI - Anatomical-functional image fusion by information of interest in local Laplacian filtering domain. AB - A novel method for performing anatomical (MRI)-functional (PET or SPECT) image fusion is presented. The method merges specific feature information from input image signals of a single or multiple medical imaging modalities into a single fused image while preserving more information and generating less distortion. The proposed method uses a local Laplacian filtering based technique realized through a novel multi-scale system architecture. Firstly, the input images are generated in a multi-scale image representation and are processed using local Laplacian filtering. Secondly, at each scale, the decomposed images are combined to produce fused approximate images using a local energy maximum scheme and produce the fused residual images using an information of interest-based scheme. Finally, a fused image is obtained using a reconstruction process that is analogous to that of conventional Laplacian pyramid transform. Experimental results computed using individual multi-scale analysis-based decomposition schemes or fusion rules clearly demonstrate the superiority of the proposed method through subjective observation as well as objective metrics. Furthermore, the proposed method can obtain better performance, compared to the state-of-the-art fusion methods. PMID- 28858800 TI - Rate-Performance-Loss Optimization for Inter-Frame Deep Feature Coding From Videos. AB - With the explosion in the use of cameras in mobile phones or video surveillance systems, it is impossible to transmit a large amount of videos captured from a wide area into a cloud for big data analysis and retrieval. Instead, a feasible solution is to extract and compress features from videos and then transmit the compact features to the cloud. Meanwhile, many recent studies also indicate that the features extracted from the deep convolutional neural networks will lead to high performance for various analysis and recognition tasks. However, how to compress video deep features meanwhile maintaining the analysis or retrieval performance still remains open. To address this problem, we propose a high efficiency deep feature coding (DFC) framework in this paper. In the DFC framework, we define three types of features in a group-of-features (GOFs) according to their coding modes (i.e., I-feature, P-feature, and S-feature). We then design two prediction structures for these features in a GOF, including a sequential prediction structure and an adaptive prediction structure. Similar to video coding, it is important for P-feature residual coding optimization to make a tradeoff between feature bitrate and analysis/retrieval performance when encoding residuals. To do so, we propose a rate-performance-loss optimization model. To evaluate various feature coding methods for large-scale video retrieval, we construct a video feature coding data set, called VFC-1M, which consists of uncompressed videos from different scenarios captured from real-world surveillance cameras, with totally 1M visual objects. Extensive experiments show that the proposed DFC can significantly reduce the bitrate of deep features in the videos while maintaining the retrieval accuracy. PMID- 28858801 TI - Visual Tracking by Sampling in Part Space. AB - In this paper, we present a novel part-based visual tracking method from the perspective of probability sampling. Specifically, we represent the target by a part space with two online learned probabilities to capture the structure of the target. The proposal distribution memorizes the historical performance of different parts, and it is used for the first round of part selection. The acceptance probability validates the specific tracking stability of each part in a frame, and it determines whether to accept its vote or to reject it. By doing this, we transform the complex online part selection problem into a probability learning one, which is easier to tackle. The observation model of each part is constructed by an improved supervised descent method and is learned in an incremental manner. Experimental results on two benchmarks demonstrate the competitive performance of our tracker against state-of-the-art methods. PMID- 28858802 TI - Structure-Regularized Compressive Tracking With Online Data-Driven Sampling. AB - Being a powerful appearance model, compressive random projection derives effective Haar-like features from non-rotated 4-D-parameterized rectangles, thus supporting fast and reliable object tracking. In this paper, we show that such successful fast compressive tracking scheme can be further significantly improved by structural regularization and online data-driven sampling. Our major contribution is threefold. First, we find that superpixel-guided compressive projection can generate more discriminative features by sufficiently capturing rich local structural information of images. Second, we propose fast directional integration that enables low-cost extraction of feasible Haar-like features from arbitrarily rotated 5-D-parameterized rectangles to realize more accurate object localization. Third, beyond naive dense uniform sampling, we present two practical online data-driven sampling strategies to produce less yet more effective candidate and training samples for object detection and classifier updating, respectively. Extensive experiments on real-world benchmark data sets validate the superior performance, i.e., much better object localization ability and robustness, of the proposed approach over state-of-the-art trackers. PMID- 28858803 TI - Event Detection in Continuous Video: An Inference in Point Process Approach. AB - We propose a novel approach toward event detection in real-world continuous video sequences. The method: 1) is able to model arbitrary-order non-Markovian dependences in videos to mitigate local visual ambiguities; 2) conducts simultaneous event segmentation and labeling; and 3) is time-window free. The idea is to represent a video as an event stream of both high-level semantic events and low-level video observations. In training, we learn a point process model called a piecewise-constant conditional intensity model (PCIM) that is able to capture complex non-Markovian dependences in the event streams. In testing, event detection can be modeled as the inference of high-level semantic events, given low-level image observations. We develop the first inference algorithm for PCIM and show it samples exactly from the posterior distribution. We then evaluate the video event detection task on real-world video sequences. Our model not only provides competitive results on the video event segmentation and labeling task, but also provides benefits, including being interpretable and efficient. PMID- 28858804 TI - Unsupervised Hierarchical Dynamic Parsing and Encoding for Action Recognition. AB - Generally, the evolution of an action is not uniform across the video, but exhibits quite complex rhythms and non-stationary dynamics. To model such non uniform temporal dynamics, in this paper, we describe a novel hierarchical dynamic parsing and encoding method to capture both the locally smooth dynamics and globally drastic dynamic changes. It parses the dynamics of an action into different layers and encodes such multi-layer temporal information into a joint representation for action recognition. At the first layer, the action sequence is parsed in an unsupervised manner into several smooth-changing stages corresponding to different key poses or temporal structures by temporal clustering. The dynamics within each stage are encoded by mean-pooling or rank pooling. At the second layer, the temporal information of the ordered dynamics extracted from the previous layer is encoded again by rank-pooling to form the overall representation. Extensive experiments on a gesture action data set (Chalearn Gesture) and three generic action data sets (Olympic Sports, Hollywood2, and UCF101) have demonstrated the effectiveness of the proposed method. PMID- 28858805 TI - Optimal Couple Projections for Domain Adaptive Sparse Representation-Based Classification. AB - In recent years, sparse representation-based classification (SRC) is one of the most successful methods and has been shown impressive performance in various classification tasks. However, when the training data have a different distribution than the testing data, the learned sparse representation may not be optimal, and the performance of SRC will be degraded significantly. To address this problem, in this paper, we propose an optimal couple projections for domain adaptive SRC (OCPD-SRC) method, in which the discriminative features of data in the two domains are simultaneously learned with the dictionary that can succinctly represent the training and testing data in the projected space. OCPD SRC is designed based on the decision rule of SRC, with the objective to learn coupled projection matrices and a common discriminative dictionary such that the between-class sparse reconstruction residuals of data from both domains are maximized, and the within-class sparse reconstruction residuals of data are minimized in the projected low-dimensional space. Thus, the resulting representations can well fit SRC and simultaneously have a better discriminant ability. In addition, our method can be easily extended to multiple domains and can be kernelized to deal with the nonlinear structure of data. The optimal solution for the proposed method can be efficiently obtained following the alternative optimization method. Extensive experimental results on a series of benchmark databases show that our method is better or comparable to many state-of the-art methods. PMID- 28858806 TI - A Novel Nonlinear Dynamic Method for Stroke Rehabilitation Effect Evaluation Using EEG. AB - Evaluating the effect of stroke rehabilitation based on electroencephalogram (EEG) is still a challenging problem. This paper presents a novel nonlinear dynamic complexity method for the evaluation of stroke rehabilitation effect from EEG signal. Our method calculates the nonlinearly separable degree (NLSD) of EEG signal, and then employs an indicator, called mean nonlinearly separable complexity degree (Mean_NLSD), to efficiently and accurately evaluate therapy effect of stroke patients. This paper under twelve stimuli conditions on eleven patients and eleven control subjects indicates that in general Mean_NLSD is smaller at the lesion regions and that the Mean_NLSD of the control subjects is stochastic. Compared with conventional spectral methods, such as mean power spectral density (PSD), Mean_NLSD is more sensitive and robust. Overall Mean_NLSD may offer a promising approach to facilitate the evaluation of stroke rehabilitation effect. PMID- 28858807 TI - Bio-Inspired Adaptive Control for Active Knee Exoprosthetics. AB - On the quest to bring function of prosthetic legs closer to their biological counterparts, the intuitive interplay of their control with the user's impedance modulation is key. We present two control features to enable more physiological and more user-adaptive control of prosthetic legs: a neuromusculoskeletal impedance model ( ) including a reflexive component, and a human model reference adaptive controller ( ), which can be combined with the former. In stance-phase simulations, the allowed to control a prosthetic leg with physiological knee joint angle and moment. When perturbations were applied, the reduced the resulting root mean square error (RMSE) between simulated and physiological reference angle by 96%. In a pilot experiment with two unimpaired and one amputee subject, gait with the deviated more from a physiological reference than with a conventional visco-elastic impedance controller. Subjects, however, preferred the . When adding the to either of the two impedance controllers, the RMSE between the actual and the physiological reference angle was reduced by up to 54%. Subjects confirmed this finding and reported an easier stance-to-swing transition. Simulation and pilot experiment suggest that a reflex-based impedance controller combined with an adaptive controller may improve user-cooperative behavior of active knee exoprostheses. PMID- 28858808 TI - Using Inertial Sensors to Automatically Detect and Segment Activities of Daily Living in People With Parkinson's Disease. AB - Wearable sensors such as inertial measurement units (IMUs) have been widely used to measure the quantity of physical activities during daily living in healthy and people with movement disorders through activity classification. These sensors have the potential to provide valuable information to evaluate the quality of the movement during the activities of daily living (ADL), such as walking, sitting down, and standing up, which could help clinicians to monitor rehabilitation and pharmaceutical interventions. However, high accuracy in the detection and segmentation of these activities is necessary for proper evaluation of the quality of the performance within a given segment. This paper presents algorithms to process IMU data, to detect and segment unstructured ADL in people with Parkinson's disease (PD) in simulated free-living environment. The proposed method enabled the detection of 1610 events of ADL performed by nine community dwelling older adults with PD under simulated free-living environment with 90% accuracy (sensitivity = 90.8%, specificity = 97.8%) while segmenting these activities within 350 ms of the "gold-standard" manual segmentation. These results demonstrate the robustness of the proposed method to eventually be used to automatically detect and segment ADL in free-living environment in people with PD. This could potentially lead to a more expeditious evaluation of the quality of the movement and administration of proper corrective care for patients who are under physical rehabilitation and pharmaceutical intervention for movement disorders. PMID- 28858809 TI - Coevolutionary Structure-Redesigned-Based Bacterial Foraging Optimization. AB - This paper presents a Coevolutionary Structure-Redesigned-Based Bacteria Foraging Optimization (CSRBFO) based on the natural phenomenon that most living creatures tend to cooperate with each other so as to fulfill tasks more effectively. Aiming at lowering computational complexity while maintaining the critical search capability of standard bacterial foraging optimization (BFO), we employ a general loop to replace the nested loop and eliminate the reproduction step of BFO. Hence, the proposed CSRBFO only consists of two main steps: (1) chemotaxis and (2) elimination & dispersal. A coevolutionary strategy by which all bacteria can learn from each other and search for optima cooperatively is incorporated into the chemotactic step to accelerate convergence and facilitate accurate search. In the elimination & dispersal step, the three-stage evolutionary strategy with different learning methods for maintaining diversity is studied. An evaluation of the convergence status is then added to determine whether bacteria should move on to the next stage or not. The combination of coevolutionary strategy and convergence status evaluation is expected to balance exploration and exploitation. Experimental results comparing 7 well-known heuristic algorithms on 24 benchmark functions demonstrate that the proposed CSRBFO outperforms the comparison algorithms significantly in most of the cases. PMID- 28858810 TI - Optimizing Phylogenetic Queries for Performance. AB - The vast majority of phylogenetic databases do not support declarative querying using which their contents can be flexibly and conveniently accessed and the template based query interfaces they support do not allow arbitrary speculative queries. They therefore also do not support query optimization leveraging unique phylogeny properties. While a small number of graph query languages such as XQuery, Cypher, and GraphQL exist for computer savvy users, most are too general and complex to be useful for biologists, and too inefficient for large phylogeny querying. In this paper, we discuss a recently introduced visual query language, called PhyQL, that leverages phylogeny specific properties to support essential and powerful constructs for a large class of phylogentic queries. We develop a range of pruning aids, and propose a substantial set of query optimization strategies using these aids suitable for large phylogeny querying. A hybrid optimization technique that exploits a set of indices and "graphlet" partitioning is discussed. A "fail soonest" strategy is used to avoid hopeless processing and is shown to produce dividends. Possible novel optimization techniques yet to be explored are also discussed. PMID- 28858811 TI - Network clustering analysis using mixture exponential-family random graph models and its application in genetic interaction data. AB - MOTIVATION: Epistatic miniarrary profile (EMAP) studies have enabled the mapping of large-scale genetic interaction networks and generated large amounts of data in model organisms. It provides an incredible set of molecular tools and advanced technologies that should be efficiently understanding the relationship between the genotypes and phenotypes of individuals. However, the network information gained from EMAP cannot be fully exploited using the traditional statistical network models. Because the genetic network is always heterogeneous, for example, the network structure features for one subset of nodes are different from those of the left nodes. Exponentialfamily random graph models (ERGMs) are a family of statistical models, which provide a principled and flexible way to describe the structural features (e.g. the density, centrality and assortativity) of an observed network. However, the single ERGM is not enough to capture this heterogeneity of networks. In this paper, we consider a mixture ERGM (MixtureEGRM) networks, which model a network with several communities, where each community is described by a single EGRM. PMID- 28858812 TI - A Thermally Powered ISFET Array for On-Body pH Measurement. AB - Recent advances in electronics and electrochemical sensors have led to an emerging class of next generation wearables, detecting analytes in biofluids such as perspiration. Most of these devices utilize ion-selective electrodes (ISEs) as a detection method; however, ion-sensitive field-effect transistors (ISFETs) offer a solution with improved integration and a low power consumption. This work presents a wearable, thermoelectrically powered system composed of an application specific integrated circuit (ASIC), two commercial power management integrated circuits and a network of commercial thermoelectric generators (TEGs). The ASIC is fabricated in 0.35 m CMOS and contains an ISFET array designed to read pH as a current, a processing module which averages the signal to reduce noise and encodes it into a frequency, and a transmitter. The output frequency has a measured sensitivity of 6 to 8 kHz/pH for a pH range of 7-5. It is shown that the sensing array and processing module has a power consumption 6 W and, therefore, can be entirely powered by body heat using a TEG. Array averaging is shown to reduce noise at these low power levels to 104 V (input referred integrated noise), reducing the minimum detectable limit of the ASIC to 0.008 pH units. The work forms the foundation and proves the feasibility of battery-less, on-body electrochemical for perspiration analysis in sports science and healthcare applications. PMID- 28858813 TI - Tactile Morse Code Using Locational Stimulus Identification. AB - This research investigated several haptic interfaces designed to reduce mistakes in Morse code reception. Results concluded that a bimanual setup, discriminating dots/dashes by left/right location, reduced the amount of errors to only 56.6 percent of the errors compared to a unimanual setup that used temporal discrimination to distinguish dots and dashes. PMID- 28858814 TI - Evaluation of the Perceptual Characteristics of a Force Induced by Asymmetric Vibrations. AB - This paper describes the perceptual characteristics of a sense of a force induced by asymmetric vibration using a vibration speaker-type non-grounded haptic interface. We confirm that the vibration speaker generates a perceived force that pulls or pushes a user's hand in a particular direction when an asymmetric amplitude signal that is generated by inverting a part of a sine wave is input. In this paper, to verify the system with respect to various factors of force perception caused by asymmetric vibration, we conducted six experiments and the following results were obtained. (1) The force vector can be controlled by reversing the asymmetric waves. (2) By investigating the physical characteristics of the vibration, asymmetric vibration was confirmed. (3) The presentation of vibration in the shear direction on the finger pad is effective. (4) The point of subjective equality of the perceived force can be controlled by up to 0.43 N by changing the amplitude voltage of the input signals. (5) The minimum stimulation time required for force perception is 66.7 ms. (6) When the vibration is continuously presented for 40 to 50 s, the perceived force decreases because of adaptation. Hence, we confirmed that we can control both the direction and magnitude of the reaction force by changing the input signal of the vibration speaker. PMID- 28858815 TI - Using Directional Fibers to Locate Fixed Points of Recurrent Neural Networks. AB - We introduce mathematical objects that we call "directional fibers," and show how they enable a new strategy for systematically locating fixed points in recurrent neural networks. We analyze this approach mathematically and use computer experiments to show that it consistently locates many fixed points in many networks with arbitrary sizes and unconstrained connection weights. Comparison with a traditional method shows that our strategy is competitive and complementary, often finding larger and distinct sets of fixed points. We provide theoretical groundwork for further analysis and suggest next steps for developing the method into a more powerful solver. PMID- 28858816 TI - Sophisticated Merging Over Random Partitions: A Scalable and Robust Causal Discovery Approach. AB - Scalable causal discovery is an essential technology to a wide spectrum of applications, including biomedical studies and social network evolution analysis. To tackle the difficulty of high dimensionality, a number of solutions are proposed in the literature, generally dividing the original variable domain into smaller subdomains by computation intensive partitioning strategies. These approaches usually suffer significant structural errors when the partitioning strategies fail to recognize true causal edges across the output subdomains. Such a structural error accumulates quickly with the growing depth of recursive partitioning, due to the lack of correction mechanism over causally connected variables when they are wrongly divided into two subdomains, finally jeopardizing the robustness of the integrated results. This paper proposes a completely different strategy to solve the problem, powered by a lightweight random partitioning scheme together with a carefully designed merging algorithm over results from the random partitions. Based on the randomness properties of the partitioning scheme, we design a suite of tricks for the merging algorithm, in order to support propagation-based significance enhancement, maximal acyclic subgraph causal ordering, and order-sensitive redundancy elimination. Theoretical studies as well as empirical evaluations verify the genericity, effectiveness, and scalability of our proposal on both simulated and real-world causal structures when the scheme is used in combination with a variety of causal solvers known effective on smaller domains. PMID- 28858817 TI - Learning Low-Rank Decomposition for Pan-Sharpening With Spatial-Spectral Offsets. AB - Finding accurate injection components is the key issue in pan-sharpening methods. In this paper, a low-rank pan-sharpening (LRP) model is developed from a new perspective of offset learning. Two offsets are defined to represent the spatial and spectral differences between low-resolution multispectral and high-resolution multispectral (HRMS) images, respectively. In order to reduce spatial and spectral distortions, spatial equalization and spectral proportion constraints are designed and cast on the offsets, to develop a spatial and spectral constrained stable low-rank decomposition algorithm via augmented Lagrange multiplier. By fine modeling and heuristic learning, our method can simultaneously reduce spatial and spectral distortions in the fused HRMS images. Moreover, our method can efficiently deal with noises and outliers in source images, for exploring low-rank and sparse characteristics of data. Extensive experiments are taken on several image data sets, and the results demonstrate the efficiency of the proposed LRP. PMID- 28858818 TI - Optimal Classification of Respiratory Patterns From Manual Analyses Using Expectation-Maximization. AB - Manual scoring (MS) of cardiorespiratory signals is the gold standard method for the analysis of respiratory data in sleep laboratories. In MS, trained, expert scorers characterize respiratory patterns by scrolling through a data record and visually identifying patterns. However, MS is limited by high intra- and inter scorer variability and subjectivity. A strategy to mitigate this is to analyze the same respiratory data multiple times and generate a consensus. This consensus is generally determined by a majority vote (MV), where the most frequent pattern is selected as the true pattern. This paper presents expectation-maximization pattern sequence (EM-PSEQ), a novel method based on EM that estimates the true patterns optimally. A simulation study examined the accuracies of EM-PSEQ, MV, and individual scorers (IS) as a function of the number of analyses. Accuracy was measured with the Fleiss kappa statistic, and is reported as , where , the median value, is the expected accuracy, and , the 5th percentile value, gives the minimum accuracy for 95% confidence. IS accuracy remained constant at as the number of analyses increased. MV accuracy increased slowly with the number of analyses and plateaued at after five analyses. In contrast, EM-PSEQ accuracy improved quickly, reaching an almost perfect value of with four analyses, and perfect accuracy after 25 analyses. EM-PSEQ performed much better than either MV or IS, and required only modest computational effort. Consequently, we believe EM PSEQ will be a very valuable tool for clinical studies, as it can dramatically improve the accuracy of manual respiratory analysis with minimal additional cost. PMID- 28858819 TI - Machine Learning Approaches on Diagnostic Term Encoding With the ICD for Clinical Documentation. AB - This work focuses on data mining applied to the clinical documentation domain. Diagnostic terms (DTs) are used as keywords to retrieve valuable information from electronic health records. Indeed, they are encoded manually by experts following the International Classification of Diseases (ICD). The goal of this work is to explore the aid of text mining on DT encoding. From the machine learning (ML) perspective, this is a high-dimensional classification task, as it comprises thousands of codes. This work delves into a robust representation of the instances to improve ML results. The proposed system is able to find the right ICD code among more than 1500 possible ICD codes with 92% precision for the main disease (primary class) and 88% for the main disease together with the nonessential modifiers (fully specified class). The methodology employed is simple and portable. According to the experts from public hospitals, the system is very useful in particular for documentation and pharmacosurveillance services. In fact, they reported an accuracy of 91.2% on a small randomly extracted test. Hence, together with this paper, we made the software publicly available in order to help the clinical and research community. PMID- 28858820 TI - Hashing for Adaptive Real-Time Graph Stream Classification With Concept Drifts. AB - Many applications involve processing networked streaming data in a timely manner. Graph stream classification aims to learn a classification model from a stream of graphs with only one-pass of data, requiring real-time processing in training and prediction. This is a nontrivial task, as many existing methods require multipass of the graph stream to extract subgraph structures as features for graph classification which does not simultaneously satisfy "one-pass" and "real-time" requirements. In this paper, we propose an adaptive real-time graph stream classification method to address this challenge. We partition the unbounded graph stream data into consecutive graph chunks, each consisting of a fixed number of graphs and delivering a corresponding chunk-level classifier. We employ a random hashing function to compress the original node set of graphs in each chunk for fast feature detection when training chunk-level classifiers. Furthermore, a differential hashing strategy is applied to map unlimited increasing features (i.e., cliques) into a fixed-size feature space which is then used as a feature vector for stochastic learning. Finally, the chunk-level classifiers are weighted in an ensemble learning model for graph classification. The proposed method substantially speeds up the graph feature extraction and avoids unbounded graph feature growth. Moreover, it effectively offsets concept drifts in graph stream classification. Experiments on real-world and synthetic graph streams demonstrate that our method significantly outperforms existing methods in both classification accuracy and learning efficiency. PMID- 28858821 TI - A Decomposition-Based Many-Objective Evolutionary Algorithm With Two Types of Adjustments for Direction Vectors. AB - Decomposition-based multiobjective evolutionary algorithm has shown its advantage in addressing many-objective optimization problem (MaOP). To further improve its convergence on MaOPs and its diversity for MaOPs with irregular Pareto fronts (PFs, e.g., degenerate and disconnected ones), we proposed a decomposition-based many-objective evolutionary algorithm with two types of adjustments for the direction vectors (MaOEA/D-2ADV). At the very beginning, search is only conducted along the boundary direction vectors to achieve fast convergence, followed by the increase of the number of the direction vectors for approximating a more complete PF. After that, a Pareto-dominance-based mechanism is used to detect the effectiveness of each direction vector and the positions of ineffective direction vectors are adjusted to better fit the shape of irregular PFs. The extensive experimental studies have been conducted to validate the efficiency of MaOEA/D 2ADV on many-objective optimization benchmark problems. The effects of each component in MaOEA/D-2ADV are also investigated in detail. PMID- 28858822 TI - Fuzzy Sparse Autoencoder Framework for Single Image Per Person Face Recognition. AB - The issue of single sample per person (SSPP) face recognition has attracted more and more attention in recent years. Patch/local-based algorithm is one of the most popular categories to address the issue, as patch/local features are robust to face image variations. However, the global discriminative information is ignored in patch/local-based algorithm, which is crucial to recognize the nondiscriminative region of face images. To make the best of the advantage of both local information and global information, a novel two-layer local-to-global feature learning framework is proposed to address SSPP face recognition. In the first layer, the objective-oriented local features are learned by a patch-based fuzzy rough set feature selection strategy. The obtained local features are not only robust to the image variations, but also usable to preserve the discrimination ability of original patches. Global structural information is extracted from local features by a sparse autoencoder in the second layer, which reduces the negative effect of nondiscriminative regions. Besides, the proposed framework is a shallow network, which avoids the over-fitting caused by using multilayer network to address SSPP problem. The experimental results have shown that the proposed local-to-global feature learning framework can achieve superior performance than other state-of-the-art feature learning algorithms for SSPP face recognition. PMID- 28858823 TI - Asynchronous Dissipative Control for Fuzzy Markov Jump Systems. AB - The problem of asynchronous dissipative control is investigated for Takagi-Sugeno fuzzy systems with Markov jump in this paper. Hidden Markov model is introduced to represent the nonsynchronization between the designed controller and the original system. By the fuzzy-basis-dependent and mode-dependent Lyapunov function, a sufficient condition is achieved such that the resulting closed-loop system is stochastically stable with a strictly ( , , )- -dissipative performance. The controller parameter is derived by applying MATLAB to solve a set of linear matrix inequalities. Finally, we present two examples to confirm the validity and correctness of our developed approach. PMID- 28858824 TI - The Value of Traditional Ecological Knowledge for the Environmental Health Sciences and Biomedical Research. AB - BACKGROUND: Traditional Ecological Knowledge (TEK) is a term, relatively new to Western science, that encompasses a subset of traditional knowledge maintained by Indigenous nations about the relationships between people and the natural environment. The term was first shared by tribal elders in the 1980s to help raise awareness of the importance of TEK. TEK has become a construct that Western scientists have increasingly considered for conducting culturally relevant research with Tribal nations. OBJECTIVES: The authors aim to position TEK in relation to other emerging schools of thought, that is, concepts such as the exposome, social determinants of health (SDoH), and citizen science, and to explore TEK's relevance to environmental health research. This article provides examples of successful application of TEK principles in federally funded research when implemented with respect for the underlying cultural context and in partnership with Indigenous communities. DISCUSSION: Rather than treating TEK as an adjunct or element to be quantified or incorporated into Western scientific studies, TEK can instead ground our understanding of the environmental, social, and biomedical determinants of health and improve our understanding of health and disease. This article provides historical and recent examples of how TEK has informed Western scientific research. CONCLUSIONS: This article provides recommendations for researchers and federal funders to ensure respect for the contributions of TEK to research and to ensure equity and self-determination for Tribal nations who participate in research. https://doi.org/10.1289/EHP858. PMID- 28858825 TI - Erratum: "Genome-wide Association Study of Susceptibility to Particulate Matter Associated QT Prolongation". AB - [This corrects the article DOI: 10.1289/EHP347.]. PMID- 28858826 TI - Updated Global Estimates of Respiratory Mortality in Adults >=30Years of Age Attributable to Long-Term Ozone Exposure. AB - BACKGROUND: Relative risk estimates for long-term ozone (O3) exposure and respiratory mortality from the American Cancer Society Cancer Prevention Study II (ACS CPS-II) cohort have been used to estimate global O3-attributable mortality in adults. Updated relative risk estimates are now available for the same cohort based on an expanded study population with longer follow-up. OBJECTIVES: We estimated the global burden and spatial distribution of respiratory mortality attributable to long-term O3 exposure in adults >=30y of age using updated effect estimates from the ACS CPS-II cohort. METHODS: We used GEOS-Chem simulations (2*2.5o grid resolution) to estimate annual O3 exposures, and estimated total respiratory deaths in 2010 that were attributable to long-term annual O3 exposure based on the updated relative risk estimates and minimum risk thresholds set at the minimum or fifth percentile of O3 exposure in the most recent CPS-II analysis. These estimates were compared with attributable mortality based on the earlier CPS-II analysis, using 6-mo average exposures and risk thresholds corresponding to the minimum or fifth percentile of O3 exposure in the earlier study population. RESULTS: We estimated 1.04-1.23 million respiratory deaths in adults attributable to O3 exposures using the updated relative risk estimate and exposure parameters, compared with 0.40-0.55 million respiratory deaths attributable to O3 exposures based on the earlier CPS-II risk estimate and parameters. Increases in estimated attributable mortality were larger in northern India, southeast China, and Pakistan than in Europe, eastern United States, and northeast China. CONCLUSIONS: These findings suggest that the potential magnitude of health benefits of air quality policies targeting O3, health co-benefits of climate mitigation policies, and health implications of climate change-driven changes in O3 concentrations, are larger than previously thought. https://doi.org/10.1289/EHP1390. PMID- 28858827 TI - A Method for Identifying Prevalent Chemical Combinations in the U.S. Population. AB - BACKGROUND: Through the food and water they ingest, the air they breathe, and the consumer products with which they interact at home and at work, humans are exposed to tens of thousands of chemicals, many of which have not been evaluated to determine their potential toxicities. Furthermore, while current chemical testing tends to focus on individual chemicals, the exposures that people actually experience involve mixtures of chemicals. Unfortunately, the number of mixtures that can be formed from the thousands of environmental chemicals is enormous, and testing all of them would be impossible. OBJECTIVES: We seek to develop and demonstrate a method for identifying those mixtures that are most prevalent in humans. METHODS: We applied frequent itemset mining, a technique traditionally used for market basket analysis, to biomonitoring data from the 2009-2010 cycle of the continuous National Health and Nutrition Examination Survey (NHANES) to identify combinations of chemicals that frequently co-occur in people. RESULTS: We identified 90 chemical combinations consisting of relatively few chemicals that occur in at least 30% of the U.S. population, as well as three supercombinations consisting of relatively many chemicals that occur in a small but nonnegligible proportion of the U.S. population. CONCLUSIONS: We demonstrated how FIM can be used in conjunction with biomonitoring data to narrow a large number of possible chemical combinations down to a smaller set of prevalent chemical combinations. https://doi.org/10.1289/EHP1265. PMID- 28858828 TI - Arsenic and Obesity: A Comparison of Urine Dilution Adjustment Methods. AB - INTRODUCTION: A commonly used approach to adjust for urine dilution in analyses of biomarkers is to adjust for urinary creatinine. However, creatinine is a product of muscle mass and is therefore associated with body mass. In studies of urinary analytes and obesity or obesity-related outcomes, controlling for creatinine could induce collider stratification bias. We illustrate this phenomenon with an analysis of urinary arsenic. OBJECTIVE: We aimed to evaluate various approaches of adjustment for urinary dilution on the associations between urinary arsenic concentration and measures of obesity. METHODS: Using data from the National Health and Nutrition Examination Survey, we regressed body mass index (BMI) and waist-to-height ratios on urinary arsenic concentrations. We compared eight approaches to account for urine dilution, including standardization by urinary creatinine, osmolality, and flow rates, and inclusion of these metrics as independent covariates. We also used a recently proposed method known as covariate-adjusted standardization. RESULTS: Inverse associations between urinary arsenic concentration with BMI and waist-to-height ratio were observed when either creatinine or osmolality were used to standardize or as covariates. Not adjusting for dilution, standardizing or adjusting for urinary flow rate, and using covariate-adjusted standardization resulted in null associations observed between arsenic concentration in relation to BMI and waist to-height ratio. CONCLUSIONS: Our findings suggest that arsenic exposure is not associated with obesity, and that urinary creatinine and osmolality may be colliders on the causal pathway from arsenic exposure to obesity, as common descendants of hydration and body composition. In studies of urinary biomarkers and obesity or obesity-related outcomes, alternative metrics such as urinary flow rate or analytic strategies such as covariate-adjusted standardization should be considered. https://doi.org/10.1289/EHP1202. PMID- 28858829 TI - Toward Consistent Methodology to Quantify Populations in Proximity to Oil and Gas Development: A National Spatial Analysis and Review. AB - BACKGROUND: Higher risk of exposure to environmental health hazards near oil and gas wells has spurred interest in quantifying populations that live in proximity to oil and gas development. The available studies on this topic lack consistent methodology and ignore aspects of oil and gas development of value to public health-relevant assessment and decision-making. OBJECTIVES: We aim to present a methodological framework for oil and gas development proximity studies grounded in an understanding of hydrocarbon geology and development techniques. METHODS: We geospatially overlay locations of active oil and gas wells in the conterminous United States and Census data to estimate the population living in proximity to hydrocarbon development at the national and state levels. We compare our methods and findings with existing proximity studies. RESULTS: Nationally, we estimate that 17.6 million people live within 1,600m (~1 mi) of at least one active oil and/or gas well. Three of the eight studies overestimate populations at risk from actively producing oil and gas wells by including wells without evidence of production or drilling completion and/or using inappropriate population allocation methods. The remaining five studies, by omitting conventional wells in regions dominated by historical conventional development, significantly underestimate populations at risk. CONCLUSIONS: The well inventory guidelines we present provide an improved methodology for hydrocarbon proximity studies by acknowledging the importance of both conventional and unconventional well counts as well as the relative exposure risks associated with different primary production categories (e.g., oil, wet gas, dry gas) and developmental stages of wells. https://doi.org/10.1289/EHP1535. PMID- 28858830 TI - Exposure to Low Levels of Lead in Utero and Umbilical Cord Blood DNA Methylation in Project Viva: An Epigenome-Wide Association Study. AB - BACKGROUND: Early-life exposure to lead is associated with deficits in neurodevelopment and with hematopoietic system toxicity. DNA methylation may be one of the underlying mechanisms for the adverse effects of prenatal lead on the offspring, but epigenome-wide methylation data for low levels of prenatal lead exposure are lacking. OBJECTIVES: We investigated the association between prenatal maternal lead exposure and epigenome-wide DNA methylation in umbilical cord blood nucleated cells in Project Viva, a prospective U.S.-based prebirth cohort with relatively low levels of lead exposure. METHODS: Among 268 mother infant pairs, we measured lead concentrations in red blood cells (RBC) from prenatal maternal blood samples, and using HumanMethylation450 Bead Chips, we measured genome-wide methylation levels at 482,397 CpG loci in umbilical cord blood and retained 394,460 loci after quality control. After adjustment for batch effects, cell types, and covariates, we used robust linear regression models to examine associations of prenatal lead exposure with DNA methylation in cord blood at epigenome-wide significance level [false discovery rate (FDR)<0.05]. RESULTS: The mean [standard deviation (SD)] maternal RBC lead level was 1.22 (0.63) MUg/dL. CpG cg10773601 showed an epigenome-wide significant negative association with prenatal lead exposure (-1.4% per doubling increase in lead exposure; p=2.3*10-7) and was annotated to C-Type Lectin Domain Family 11, Member A (CLEC11A), which functions as a growth factor for primitive hematopoietic progenitor cells. In sex-specific analyses, we identified more CpGs with FDR<0.05 among female infants (n=38) than among male infants (n=2). One CpG (cg24637308), which showed a strong negative association with prenatal lead exposure among female infants (-4.3% per doubling increase in lead exposure; p=1.1*10-06), was annotated to Dynein Heavy Chain Domain 1 gene (DNHD1) which is highly expressed in human brain. Interestingly, there were strong correlations between blood and brain methylation for CpG (cg24637308) based on another independent set of samples with a high proportion of female participants. CONCLUSION: Prenatal low level lead exposure was associated with newborn DNA methylation, particularly in female infants. https://doi.org/10.1289/EHP1246. PMID- 28858832 TI - Synthesis and photodegradation studies of analogues of muscle relaxant 1,4 dihydropyridine compounds. AB - This paper describes the synthesis of 1,4-dihydropyridine compounds (DHPs) endowed with good muscle relaxant activity and stability to light. Six new condensed DHPs were synthesized by the microwave irradiation method. A long-chain ester moiety [2-(methacryloyloxy)ethyl] and various substituents on the phenyl ring were demonstrated to affect the muscle relaxant activity occurring in isolated rabbit gastric fundus smooth muscle strips. Forced photodegradation conditions were applied to the molecules according to the ICH rules. The degradation profile of the drugs was monitored by spectrophotometry coupled with the multivariate curve resolution technique. Formation of the oxidized pyridine derivative was observed for all the studied DHPs, except for one compound, which showed very fast degradation and formation of a second photo-product. Pharmacological tests on the molecules showed a good muscle relaxing effect, with a mechanism similar to that of nifedipine, however, proving to be more stable to light. PMID- 28858831 TI - Urinary Concentrations of Organophosphate Flame Retardant Metabolites and Pregnancy Outcomes among Women Undergoing in Vitro Fertilization. AB - BACKGROUND: Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have been conducted to evaluate effects on fertility and pregnancy outcomes. OBJECTIVES: We evaluated associations between urinary concentrations of PFR metabolites and outcomes of in vitro fertilization (IVF) treatment among couples recruited from an academic fertility clinic. METHODS: This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman. RESULTS: Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of SigmaPFR were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%). CONCLUSIONS: Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021. PMID- 28858833 TI - Influence of novel oral anticoagulants on anticoagulation care management. AB - Anticoagulation treatment was recently improved by the introduction of novel oral anticoagulants (NOACs). Using a combination of qualitative and quantitative methods, this study explores the effects of the introduction of NOACs on anticoagulation care in Slovenia. Face-to-face interviews with key stakeholders revealed evolvement and challenges of anticoagulation care from different perspectives. Obtained information was further explored through the analysis of nationwide data of drug prescriptions and realization of health care services. Simplified management of anticoagulation treatment with NOACs and their high penetration expanded the capacity of anticoagulation clinics, and consequentially the treated population increased by more than 50 % in the last 5 years. The main challenge concerned the expenditures for medicines, which increased approximately 10 times in just a few years. At the same time, the anticoagulation clinics and their core organisation were not affected, which is not expected to change, since they are vital in delivering high-quality care. PMID- 28858834 TI - Curcumin: Synthesis optimization and in silico interaction with cyclin dependent kinase. AB - Curcumin is a natural product with enormous biological potential. In this study, curcumin synthesis was revisited using different reaction solvents, a catalyst (n butylamine) and a water scavenger [(n-BuO)3B], to develop the optimal procedure for its rapid acquisition. During synthesis, solvent choice was found to be an important parameter for better curcumin yield and high purity. In a typical reaction, acetyl acetone was treated with boron trioxide, followed by condensation with vanillin in the presence of tri-n-butyl borate as water scavenger and n-butylamine as catalyst at 80 degrees C in ethyl acetate to afford curcumin. Moreover, curcumin was also extracted from turmeric powder and spectroscopic properties such as IR, MS, 1H NMR and 13C NMR with synthetic curcumin were established to identify any impurity. The purity of synthetic and extracted curcumin was also checked by TLC and HPLC-DAD. To computationally assess its therapeutic potential against cyclin dependent kinases (CDKs), curcumin was docked in different isoforms of CDKs. It was observed that it did not dock at the active sites of CDK2 and CDK6. However, it could enter into weak interactions with CDK4 protein. PMID- 28858835 TI - Transdermal delivery of tolterodine tartrate for overactive bladder treatment: In vitro and in vivo evaluation. AB - The purpose of the study was to develop a transdermal tolterodine tartrate (TT) patch and to analyse its efficacy for overactive bladder (OAB) treatment. Patches were prepared using various polymers and plasticizers via the solvent casting method. The patches were characterized for tensile strength, thickness, moisture content, modulus of elasticity and water absorption capacity. Differential scanning calorimetry and Fourier transform infrared analyses were also performed. To determine patch effectiveness, in vitro release, permeation and animal studies were performed. The patches showed satisfactory percentage of release, up to 89.9 %, and their mechanical properties included thickness (0.10-0.15 mm), tensile strength (4.62-9.98 MPa) and modulus of elasticity (20-29 MPa). There were no significant interactions between TT and other excipients. Animal studies indicated that the TT patch reduced the incidence of side effects; however, studies of longer duration are required to determine the effectiveness in treating OAB. PMID- 28858836 TI - Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3 triazole carrying benzothiazoles and fluorinated-1,2,4-triazole conjugates and their antimicrobial evaluation. AB - The present study describes an efficient and ecofriendly, ultrasound, one-pot click cycloaddition approach for the construction of a novel series of 1,4 disubstituted-1,2,3-triazoles tethered with fluorinated 1,2,4-triazole benzothiazole molecular conjugates. It involved three-component condensation of the appropriate bromoacetamide benzothiazole, sodium azide and 4-alkyl/aryl-5-(2 fluorophenyl)-3-(prop-2-ynylthio)-1,2,4-triazoles 4a-e through a Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction. This approach involves in situ generation of azidoacetamide benzothiazole, followed by condensation with terminal alkynes in the presence of CuSO4/Na-ascorbate in aqueous DMSO under both conventional and ultrasound conditions. Some of the designed 1,2,3-triazole conjugates 6a-o were recognized for their antimicrobial activity against some bacterial and fungal pathogenic strains. PMID- 28858837 TI - Pharmacokinetic studies and anticancer activity of curcumin-loaded nanostructured lipid carriers. AB - In order to investigate the potential of nanostructured lipid carriers for efficient and targeted delivery of curcumin, the pharmacokinetic parameters of curcumin-loaded nanostructured lipid carriers (Cur-NLC) were evaluated in rats after a single intraperitoneal dose of Cur-NLC. In addition, the anticancer activity of Cur-NLC against human lung adenocarcinoma A549 cells was verified by a cellular uptake study, and a cytotoxicity and apoptosis assay. Bioavailability of Cur-NLC was better than that of native curcumin (p > 0.01), as seen from the area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), mean residence time (MRT) and total plasma clearance (CLz/F). Cur-NLC has a more obvious lung-targeting property in comparison with native curcumin. Cur-NLC showed higher anticancer activity in vitro against A549 cells than native curcumin (IC50 value of 5.66 vs. 9.81 mg L-1, respectively). Meanwhile, Cur-NLC treated A549 cells showed a higher apoptosis rate compared to that of native curcumin. These results indicate that NLC is a promising system for the delivery of curcumin in the treatment of lung adenocarcinoma. PMID- 28858838 TI - Synthesis of thiophene and N-substituted thieno[3,2-d] pyrimidine derivatives as potent antitumor and antibacterial agents. AB - A novel series of carbamothioylamino-benzene-sulfonamide-thiophene-carboxylates 4a-c and thieno[3,2-d]pyrimidin-2-yl-amino-benzene-sulfonamides 5a-c were synthesized in a series of synthetic steps and were used as key intermediates for the synthesis of thienotriazolopyrimidine-benzene-sulfonamide derivatives 6a-c and 7a-c. Thieno[3,2-d]pyrimidinones (8 and 9) were also prepared. Compound 9 was used as an intermediate for the synthesis of imidazole/1,2,4-triazole and tetrazine functionalized thieno[3,2-d]pyrimidine derivatives (10-12). Pyrrole derivatives/pyrrolopyrimidine/pyrrolotriazolopyrimidine functionalized thiophenes (15-19) were also synthesized. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. Most of the newly synthesized compounds were evaluated for their in vitro activity against three human tumor cell lines, namely, liver cancer (HepG-2), colon cancer (HT-29) and lung cancer (NCI-H460), using doxorubicin as standard. Compounds 16 (GI50 = 0.02, 0.04 and 0.06 MUmol L-1, resp.) and 19b (GI50 = 0.02, 0.03 and 0.05 MUmol L-1, resp.) showed higher activity against all cell lines than doxorubicin. Most of the compounds were also screened for antibacterial activity using ciprofloxacin as standard drug. Compounds 4b and 6b, both containing benzenesulfonamide linked to N-, 10 bearing imidazole moiety, and 15 and 19b,c with a thiophene-2 carboxylic acid chain, exhibited high activity against Gram-positive and Gram negative bacteria. PMID- 28858839 TI - Axonal excitability and conduction alterations caused by levobupivacaine in rat. AB - In this study, effects of the long-acting amide-type local anesthetic levobupivacaine on axonal conduction and excitability parameters of the rat sciatic nerve were thoroughly examined both in vitro and in vivo. In order to deduce its effects on isolated nerve conduction, compound nerve action potential (CNAP) recordings were performed using the suction method over sciatic nerves of Wistar rats before and after administration of 0.05 % (1.7 mmol L-1) levobupivacaine. Levobupivacaine caused complete CNAP area and amplitude depression by blocking conduction in a time-dependent manner. To assess the influence of levobupivacaine on in vivo excitability properties, threshold tracking (TT) protocols were performed at sciatic nerves of rats injected with perineural 0.05 % (1.7 mmol L-1) levobupivacaine or vehicle alone. Charge duration TT results revealed that levobupivacaine increases the rheobase and decreases the strength-duration time constant, suggesting interference of the anesthetic with the opening of Na+ channels. Twenty and 40 % threshold electrotonus curves were found for both groups to follow the same paths, suggesting no significant effect of levobupivacaine on K+ channels for either the fastest or relatively slow conducting fibers. Current-threshold relationship results revealed no significant effect on axonal rectifying channels. However, according to the results of the recovery cycle protocol yielding the pattern of excitability changes following the impulse, potential deviation was found in the recovery characteristics of Na+ channels from the absolute refractory period. Consequently, conduction blockage caused by levobupivacaine may not be due to the passive (capacitive) properties of axon or the conductance of potassium channels but to the decrease in sodium channel conductance. PMID- 28858840 TI - Pharmacological activities of some triazinopyrazolothieno pyrimidine derivatives. AB - Triazinopyrazolothieno pyrimidine derivatives 1-5 were evaluated for their anti inflammatory, analgesic and anticancer activities and acute toxicity. Anti inflammatory activity of the compounds was studied using the carrageenan test. All tested compounds showed analgesic activity, 3-methoxycarbonyl-4,6-dimethyl-8 [(N-methylindolyl)methyl] pyrimido [5',4':4,5]thieno [3',2'-3,4]pyrazolo [5,1 c]triazine (4) showed activity comparable to that of diclofenac. Compounds 1-5 were also screened for anticancer activity on a human lung cancer cell line (A549) and a human prostate cancer cell line (DU145) using the MTT micro-cultured tetrazolium assay method. Compound 4 showed also significant anticancer activity against both cancer cell lines, comparable to that of doxorubicin. The most active compounds were tested for their acute toxicity and median lethal doses were evaluated. PMID- 28858841 TI - Development of a new HPLC method for wogonin in rat plasma: Compatibility of standard and test samples. AB - In the current paper, an HPLC/UV method was developed and validated for determination of wogonin in plasma. Considerable attention was paid to the preparation of standard samples and factors affecting drug distribution. A preparation procedure was devised to simulate the conditions the drug is expected to experience in vivo while pointing to the shortcomings of previously published methods. The method was validated according to the FDA regulations and showed to be highly efficient and capable of extracting the drug and IS from the plasma accurately and precisely within the specified range of 50-500 ng mL-1. Further, the standard sample preparation of this method can be used as a guideline for other methods, particularly when highly hydrophobic drugs with considerable protein binding are involved and could be valuable in the field of bioanalysis to improve the reliability of methods. PMID- 28858842 TI - The consequences of deglycosylation of recombinant intra-melanosomal domain of human tyrosinase. AB - Tyrosinase, a melanosomal glycoenzyme, catalyzes initial steps of the melanin biosynthesis. While glycosylation was previously studied in vivo, we present three recombinant mutant variants of human tyrosinase, which were obtained using multiple site-directed mutagenesis, expressed in insect larvae, purified and characterized biochemically. The mutagenesis demonstrated the reduced protein expression and enzymatic activity due to possible loss of protein stability and protein degradation. However, the complete deglycosylation of asparagine residues in vitro, including the residue in position 371, interrupts tyrosinase function, which is consistent with a melanin loss in oculocutaneous albinism type 1 (OCA1) patients. PMID- 28858843 TI - Using plasma exchange to successfully manage thyrotoxicosis in a patient with possible antithyroid drug-related thrombotic thrombocytopenic purpura. AB - OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic abnormalities, fever, and renal insufficiency. The association or co existence of thyrotoxicosis or antithyroid drugs with TTP has not been previously reported. Subject and Results. Herein, we present a 54-year-old female patient newly diagnosed with toxic multinodular goiter accompanying with TTP, possibly triggered by either thyrotoxicosis or antithyroid drugs. CONCLUSIONS: The present report is the first in the literature to demonstrate the co-existence of these two diseases and the use of plasma exchange as a modality to treat both conditions. PMID- 28858844 TI - Can regular moderate exercise lead to changes in miRNA-146a and its adapter proteins in the kidney of streptozotocin-induced diabetic male rats? AB - OBJECTIVE: The aim of this study was to assess whether microRNA-146a and its adapter proteins TNF receptor associated factor6 (TRAF6) and interleukin-1 receptor-associated kinase-1 (IRAK1) may be changed in the kidney of streptozotocin-induced diabetic rats, following regular moderate exercise. METHODS: Forty adult male Wistar rats were allocated randomly into four groups (n=10), including sedentary control (SC), sedentary diabetic (SD), healthy sixty day exercise (H60E), and diabetic sixty-day exercise (D60E) groups. Diabetes was induced by an intraperitoneal injection of 60 mg/kg streptozotocin. After 48 h, blood glucose levels >250 mg/dl was included to diabetic rats. After 2 days of diabetes induction, the exercise protocol began. Animals were exposed to 5 days of consecutive treadmill exercise for 60 min/day with the 22 m/min speed for 60 days. The kidneys of the rats were removed and microRNA was extracted from them using the miRCURYTM RNA isolation kit. RESULTS: In diabetic rats, statistical analysis revealed a significant decrease in miR-146a expression, non-significant decrease in IRAK1 mRNA expression, and non-significant increase in TRAF6 and NF kB mRNA expression compared to the SC group. Exercise led to a non-significant increase in the expression of miR-146a and NF-kB mRNA in the kidneys of the diabetic group as compared to the SD group, significant increase in TRAF6 and IRAK1 mRNA expression compared to the H60E group, and significant increase in TRAF6 mRNA expression compared to the SD group. CONCLUSION: The present data indicate that exercise might be able to help in the prevention in the diabetic nephropathy development. PMID- 28858845 TI - Bidirectional asymmetry in the neurovisceral communication for the cardiovascular control: New insights. AB - The cardiovascular control involves a bidirectional functional connection between the brain and heart. We hypothesize that this connection could be extended to other organs using endocrine and autonomic nervous systems (ANS) as communication pathways. This implies a neuroendocrine interaction controlling particularly the cardiovascular function where the enzymatic cascade of the renin-angiotensin system (RAS) plays an essential role. It acts not only through its classic endocrine connection but also the ANS. In addition, the brain is functionally, anatomically, and neurochemically asymmetric. Moreover, this asymmetry goes even beyond the brain and it includes both sides of the peripheral nervous and neuroendocrine systems. We revised the available information and analyze the asymmetrical neuroendocrine bidirectional interaction for the cardiovascular control. Negative and positive correlations involving the RAS have been observed between brain, heart, kidney, gut, and plasma in physiologic and pathologic conditions. The central role of the peptides and enzymes of the RAS within this neurovisceral communication, as well as the importance of the asymmetrical distribution of the various RAS components in the pathologies involving this connection, are particularly discussed. In conclusion, there are numerous evidences supporting the existence of a neurovisceral connection with multiorgan involvement that controls, among others, the cardiovascular function. This connection is asymmetrically organized. PMID- 28858846 TI - TLR4 polymorphisms seem not to be associated with prediabetes and type 2 diabetes but predispose to diabetic retinopathy; TLR4 polymorphisms in glucose continuum. AB - OBJECTIVES: Compared to type 1 diabetes, the role of the immune and autoimmune pathogenetic mechanisms is much less studied in the type 2 diabetes. Toll-like receptors 4 (TLR4) have a leading role in inflammation, insulin resistance, and vascular damage. This study aimed to analyze the relationship between the polymorphisms in TLR4 gene and different stages in the glucose continuum from prediabetes to the type 2 diabetes and chronic microvascular complications. MATERIALS AND METHODS: The study included 113 patients with the type 2 diabetes, 29 participants with prediabetes, and 28 controls. Polymerase chain reaction (PCR) was used for genotyping Asp299Gly and Thr399Ile polymorphism, followed by restriction analysis. RESULTS: The difference in the genotype frequency for both polymorphisms in patients with the type 2 diabetes or prediabetes compared to that in controls was not significant. Patients with heterozygous genotype of Asp299Gly polymorphism had a higher prevalence of diabetic retinopathy (42.9%) than participants with homozygous genotype (9.0%) (OR [95%CI]=7.61 [1.41-41.08]; p=0.018). No association was established for diabetic polyneuropathy and nephropathy. Prevalence of chronic diabetes complications was not related to Thr399Ile polymorphism. CONCLUSION: Our study demonstrates that Asp299Gly and Thr399Ile polymorphisms seem not to be associated with the type 2 diabetes and prediabetes but Asp299Gly may contribute to diabetic retinopathy predisposition. PMID- 28858847 TI - Pheochromocytoma, diagnosis and treatment: Review of the literature. AB - OBJECTIVE: We conducted an extensive review of the literature and tried to cite the most recent recommendations concerning the pheochromocytoma (PHEO). METHODS: Pub Med and Google Scholar databases were searched systematically for studies concerning pheochromocytomas (intra-adrenal paragangliomas) from 1980 until 2016. Bibliographies were searched to find additional articles. RESULTS: More than four times elevation of plasma fractionated metanephrines or elevated 24-h urinary fractionated metanephrines are keys to diagnosing pheochromocytoma. If the results are equivocal then we perform the clonidine test. If we have not done it already, we preferably do a CT scan and/or an MRI scan. The patient needs pre treatment with alpha1-blockers at least 10-14 days before operation. Alternatives or sometimes adjuncts are Calcium Channels Blockers and/or beta-Blockers. Several familial syndromes are associated with PHEO and genetic testing should be considered. CONCLUSIONS: The biggest problem for pheochromocytoma is to suspect it in the first place. Elevated metanephrines establish the diagnosis. With the proper preoperative preparation the risks during operation and the postoperative period are minimal. If there is a risk of the hereditable mutation, it is strongly suggested that all the patients with pheochromocytoma need clinical genetic testing. PMID- 28858848 TI - Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) may be superior to C-reactive protein (CRP) for predicting the occurrence of differentiated thyroid cancer. AB - OBJECTIVES: NLR (neutrophil-lymphocyte ratio) and PLR (platelet-lymphocyte ratio) are prognostic markers of differentiated thyroid cancers. In our study, we evaluated NLR, PLR and C-reactive protein (CRP) for predicting the occurence of differentiated thyroid cancer. This is the first study that compares NLR and PLR to C-reactive protein indifferantiated thyroid cancer not only papillary cancer but also folliculer cancer. METHODS: This study includes 51 papillary carcinoma, 42 papillary microcarcinoma and 31 folliculer carcinoma patients attending to our outpatient Endocrinology Clinic at Erzurum Region Training and Research Hospital between 2009 and 2014. The control group include 50 age, sex and body mass index matched healty subjects. Blood counts and CRP were measured at the day before surgery. Thyroglobulin was measured after 6 months of operation. RESULTS: There were positive correlations between tumor diameter, age, white blood cell (WBC) and thyroglobulin levels. There were also positive correlation between NLR, PLR and CRP levels. CONCLUSION: In our study, we found out that higher NLR and PLR was associated with higher levels of thyroglobulin which indicates worse survival. CRP levels were also associated with poorer tumor profile but the determining rate was lower according to ROC analysis. PMID- 28858849 TI - Neuroimaging-derived brain-age: an ageing biomarker? PMID- 28858850 TI - MortalityPredictors.org: a manually-curated database of published biomarkers of human all-cause mortality. AB - Biomarkers of all-cause mortality are of tremendous clinical and research interest. Because of the long potential duration of prospective human lifespan studies, such biomarkers can play a key role in quantifying human aging and quickly evaluating any potential therapies. Decades of research into mortality biomarkers have resulted in numerous associations documented across hundreds of publications. Here, we present MortalityPredictors.org, a manually-curated, publicly accessible database, housing published, statistically-significant relationships between biomarkers and all-cause mortality in population-based or generally healthy samples. To gather the information for this database, we searched PubMed for appropriate research papers and then manually curated relevant data from each paper. We manually curated 1,576 biomarker associations, involving 471 distinct biomarkers. Biomarkers ranged in type from hematologic (red blood cell distribution width) to molecular (DNA methylation changes) to physical (grip strength). Via the web interface, the resulting data can be easily browsed, searched, and downloaded for further analysis. MortalityPredictors.org provides comprehensive results on published biomarkers of human all-cause mortality that can be used to compare biomarkers, facilitate meta-analysis, assist with the experimental design of aging studies, and serve as a central resource for analysis. We hope that it will facilitate future research into human mortality and aging. PMID- 28858852 TI - Targeting NFkappaB signaling in GD2+ BCSCs. PMID- 28858851 TI - Epigenetic silencing of miR-338 facilitates glioblastoma progression by de repressing the pyruvate kinase M2-beta-catenin axis. AB - Glioblastoma is the most malignant type of brain tumor, and its high invasiveness and multiplication severely shortens patients' overall survival. The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. We used computational target gene prediction, in vitro cell culture, immunoblotting, quantitative real-time PCR, ATP measurements, luciferase reporter assays, wound healing assays, Transwell assays, RNA immunoprecipitation PCR, co immunoprecipitation, flow cytometry and tumor xenografts to study the regulation of the PKM2/beta-catenin axis in glioma. PKM2 was predicted to be a potential target of miR-338. MiR-338 was downregulated in high-grade gliomas due to hypermethylation of CpG islands in its promoter, and ectopic expression of miR 338 inhibited cell proliferation, invasion and ATP generation. MiR-338 inhibited PKM2 expression by binding to the 3' untranslated region of PKM2, which ultimately prevented binding of PKM2 to beta-catenin and reduced T-cell factor/lymphoid enhancer factor reporter gene transcriptional activity. MiR-338 also inhibited PKM2 expression, attenuated glioma growth and prolonged survival in an animal model. These results confirm that miR-338, a tumor suppressor, suppresses the PKM2/beta-catenin axis and is downregulated in glioblastoma. This provides a theoretical basis for glioma-targeting therapy. PMID- 28858853 TI - Performance of a SiPM based semi-monolithic scintillator PET detector. AB - A depth encoding PET detector module using semi-monolithic scintillation crystal single-ended readout by a SiPM array was built and its performance was measured. The semi-monolithic scintillator detector consists of 11 polished LYSO slices measuring 1 * 11.6 * 10 mm3. The slices are glued together with enhanced specular reflector (ESR) in between and outside of the slices. The bottom surface of the slices is coupled to a 4 * 4 SiPM array with a 1 mm light guide and silicon grease between them. No reflector is used on the top surface and two sides of the slices to reduce the scintillation photon reflection. The signals of the 4 * 4 SiPM array are grouped along rows and columns separately into eight signals. Four SiPM column signals are used to identify the slices according to the center of the gravity of the scintillation photon distribution in the pixelated direction. Four SiPM row signals are used to estimate the y (monolithic direction) and z (depth of interaction) positions according to the center of the gravity and the width of the scintillation photon distribution in the monolithic direction, respectively. The detector was measured with 1 mm sampling interval in both the y and z directions with electronic collimation by using a 0.25 mm diameter 22Na point source and a 1 * 1 * 20 mm3 LYSO crystal detector. An average slice based energy resolution of 14.9% was obtained. All slices of 1 mm thick were clearly resolved and a detector with even thinner slices could be used. The y positions calculated with the center of gravity method are different for interactions happening at the same y, but different z positions due to depth dependent edge effects. The least-square minimization and the maximum likelihood positioning algorithms were developed and both methods improved the spatial resolution at the edges of the detector as compared with the center of gravity method. A mean absolute error (MAE) which is defined as the probability-weighted mean of the absolute value of the positioning error is used to evaluate the spatial resolution. An average MAE spatial resolution of ~1.15 mm was obtained in both y and z directions without rejection of the multiple scattering events. The average MAE spatial resolution was ~0.7 mm in both y and z directions after the multiple scattering events were rejected. The timing resolution of the detector is 575 ps. In the next step, long rectangle detector will be built to reduce edge effects and improve the spatial resolution of the semi-monolithic detector. Thick detector up to 20 mm will be explored and the positioning algorithms will be further optimized. PMID- 28858854 TI - Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer. AB - Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r > 0.87 and p-values >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy. PMID- 28858855 TI - A new model for volume recombination in plane-parallel chambers in pulsed fields of high dose-per-pulse. AB - In order to describe the volume recombination in a pulsed radiation field of high dose-per-pulse this study presents a numerical solution of a 1D transport model of the liberated charges in a plane-parallel ionization chamber. In addition, measurements were performed on an Advanced Markus ionization chamber in a pulsed electron beam to obtain suitable data to test the calculation. The experiment used radiation pulses of 4 MUs duration and variable dose-per-pulse values up to about 1 Gy, as well as pulses of variable duration up to 308 [Formula: see text] at constant dose-per-pulse values between 85 mGy and 400 mGy. Those experimental data were compared to the developed numerical model and existing descriptions of volume recombination. At low collection voltages the observed dose-per-pulse dependence of volume recombination can be approximated by the existing theory using effective parameters. However, at high collection voltages large discrepancies are observed. The developed numerical model shows much better agreement with the observations and is able to replicate the observed behavior over the entire range of dose-per-pulse values and collection voltages. Using the developed numerical model, the differences between observation and existing theory are shown to be the result of a large fraction of the charge being collected as free electrons and the resultant distortion of the electric field inside the chamber. Furthermore, the numerical solution is able to calculate recombination losses for arbitrary pulse durations in good agreement with the experimental data, an aspect not covered by current theory. Overall, the presented numerical solution of the charge transport model should provide a more flexible tool to describe volume recombination for high dose-per-pulse values as well as for arbitrary pulse durations and repetition rates. PMID- 28858856 TI - Impact of fitting algorithms on errors of parameter estimates in dynamic contrast enhanced MRI. AB - Parameter estimation in dynamic contrast-enhanced MRI (DCE MRI) is usually performed by non-linear least square (NLLS) fitting of a pharmacokinetic model to a measured concentration-time curve. The two-compartment exchange model (2CXM) describes the compartments 'plasma' and 'interstitial volume' and their exchange in terms of plasma flow and capillary permeability. The model function can be defined by either a system of two coupled differential equations or a closed-form analytical solution. The aim of this study was to compare these two representations in terms of accuracy, robustness and computation speed, depending on parameter combination and temporal sampling. The impact on parameter estimation errors was investigated by fitting the 2CXM to simulated concentration time curves. Parameter combinations representing five tissue types were used, together with two arterial input functions, a measured and a theoretical population based one, to generate 4D concentration images at three different temporal resolutions. Images were fitted by NLLS techniques, where the sum of squared residuals was calculated by either numeric integration with the Runge Kutta method or convolution. Furthermore two example cases, a prostate carcinoma and a glioblastoma multiforme patient, were analyzed in order to investigate the validity of our findings in real patient data. The convolution approach yields improved results in precision and robustness of determined parameters. Precision and stability are limited in curves with low blood flow. The model parameter v e shows great instability and little reliability in all cases. Decreased temporal resolution results in significant errors for the differential equation approach in several curve types. The convolution excelled in computational speed by three orders of magnitude. Uncertainties in parameter estimation at low temporal resolution cannot be compensated by usage of the differential equations. Fitting with the convolution approach is superior in computational time, with better stability and accuracy at the same time. PMID- 28858857 TI - Maximum entropy analysis of polarized fluorescence decay of (E)GFP in aqueous solution. AB - The maximum entropy method (MEM) was used for the analysis of polarized fluorescence decays of enhanced green fluorescent protein (EGFP) in buffered water/glycerol mixtures, obtained with time-correlated single-photon counting (Visser et al 2016 Methods Appl. Fluoresc. 4 035002). To this end, we used a general-purpose software module of MEM that was earlier developed to analyze (complex) laser photolysis kinetics of ligand rebinding reactions in oxygen binding proteins. We demonstrate that the MEM software provides reliable results and is easy to use for the analysis of both total fluorescence decay and fluorescence anisotropy decay of aqueous solutions of EGFP. The rotational correlation times of EGFP in water/glycerol mixtures, obtained by MEM as maxima of the correlation-time distributions, are identical to the single correlation times determined by global analysis of parallel and perpendicular polarized decay components. The MEM software is also able to determine homo-FRET in another dimeric GFP, for which the transfer correlation time is an order of magnitude shorter than the rotational correlation time. One important advantage utilizing MEM analysis is that no initial guesses of parameters are required, since MEM is able to select the least correlated solution from the feasible set of solutions. PMID- 28858858 TI - Detection of large deletion in human BRCA1 gene in human breast carcinoma MCF-7 cells by using DNA-Silver Nanoclusters. AB - Here we describe a label-free detection strategy for large deletion mutation in breast cancer (BC) related gene BRCA1 based on a DNA-silver nanocluster (NC) fluorescence upon recognition-induced hybridization. The specific hybridization of DNA templated silver NCs fluorescent probe to target DNAs can act as effective templates for enhancement of AgNCs fluorescence, which can be used to distinguish the deletion of BRCA1 due to different fluorescence intensities. Under the optimal conditions, the fluorescence intensity of the DNA-AgNCs at emission peaks around 440 nm (upon excitation at 350 nm) increased with the increasing deletion type within a dynamic range from 1.0 * 10-10 to 2.4 * 10-6 M with a detection limit (LOD) of 6.4 * 10-11 M. In this sensing system, the normal type shows no significant fluorescence; on the other hand, the deletion type emits higher fluorescence than normal type. Using this nanobiosensor, we successfully determined mutation using the non-amplified genomic DNAs that were isolated from the BC cell line. PMID- 28858859 TI - Independent Risk Factors and 2-Year Outcomes of Acute Kidney Injury after Surgery for Congenital Heart Disease. AB - BACKGROUND: Data are limited regarding risk factors for acute kidney injury (AKI) following cardiac surgery in children with congenital heart disease (CHD). This observational study was performed to examine temporal trends in AKI incidence according to the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria, identify independent risk factors for AKI after cardiac surgery, and examine associations between AKI and long-term mortality. METHODS: We retrospectively evaluated 418 patients (259 males, 159 females; median age, 5 months) who underwent cardiac surgery for CHD between April 2007 and August 2013. Patients were followed up for 2 years. AKI was defined according to the pRIFLE criteria as >=25% decrease in estimated creatinine clearance. RESULTS: AKI developed postoperatively in 104 cases (24.9%). Approximately 80% belonged to the "Risk" category according to the pRIFLE criteria, and only 21 cases (5%) required renal replacement therapy (peritoneal dialysis in all cases). Multivariate analysis revealed 3 independent risk factors for onset of AKI: young age (<1 year), surgery in Risk Adjustment in Congenital Heart Surgery (RACHS-1) category >=4, and long cardiopulmonary bypass (CPB) time (>=90 min). Twenty-three patients (22%) with AKI died during the 2-year follow-up. In multivariate cox hazard regression analysis, the most significant contributor to risk of mortality was AKI. CONCLUSIONS: Postoperative AKI was strongly associated with young age, high RACHS-1 category, and prolonged CPB time. In addition, mortality rate was higher in patients who survived after recovery from AKI than in those without AKI, even among the lower pRIFLE categories. PMID- 28858860 TI - Minimal Gap Size and Dentin Wall Lesion Development Next to Resin Composite in a Microcosm Biofilm Model. AB - This in vitro study investigated the development of dentin wall lesions next to resin composite containing very small gap sizes using an in vitro biofilm model, and evaluated whether a relevant threshold for the gap size could be established. Microcosm biofilms were grown for 14 days within small interfacial gaps between dentin-resin composite discs under intermittent cariogenic challenge. The factor under study was gap size: samples were either restored with composite resin without adhesive procedure (no intentional gap; no bonding [NB] group) or with intentional gaps of 30, 60, or 90 um, or with complete adhesive procedure (no gap; bonding [B] group). Secondary caries wall lesion progression was measured in lesion depth (LD) and mineral loss (ML) using transversal wavelength independent microradiography at 3 locations: outer surface lesion and wall lesions at 200 and 500 um distance from gap entrance. Results from linear regression analysis showed that the presence of an intentional gap (30, 60, and 90 um) affected the secondary caries progression at 200 um from the gap entrance (p <= 0.013). The NB group did not show significant wall lesion development (ML and LD, p >= 0.529). At 500 um distance almost no wall caries development was observed. In conclusion, dentin wall lesions developed in minimal gap sizes, and the threshold for secondary wall lesion development was a gap of around 30 um in this microcosm biofilm model. PMID- 28858862 TI - Pancreas Cancer Precision Treatment Using Avatar Mice from a Bioinformatics Perspective. AB - Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death among solid malignancies. Unfortunately, PDAC lethality has not substantially decreased over the past 20 years. This aggressiveness is related to the genomic complexity and heterogeneity of PDAC, but also to the absence of an effective screening for the detection of early-stage tumors and a lack of efficient therapeutic options. Therefore, there is an urgent need to improve the arsenal of anti-PDAC drugs for an effective treatment of these patients. Patient derived xenograft (PDX) mouse models represent a promising strategy to personalize PDAC treatment, offering a bench testing of candidate treatments and helping to select empirical treatments in PDAC patients with no therapeutic targets. Moreover, bioinformatics-based approaches have the potential to offer systematic insights into PDAC etiology predicting putatively actionable tumor specific genomic alterations, identifying novel biomarkers and generating disease associated gene expression signatures. This review focuses on recent efforts to individualize PDAC treatments using PDX models. Additionally, we discuss the current understanding of the PDAC genomic landscape and the putative druggable targets derived from mutational studies. PDAC molecular subclassifications and gene expression profiling studies are reviewed as well. Finally, latest bioinformatics methodologies based on somatic variant detection and prioritization, in silico drug response prediction, and drug repositioning to improve the treatment of advanced PDAC tumors are also covered. PMID- 28858861 TI - Pathways to Brain Aging and Their Modifiers: Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS) Model - A Mini-Review. AB - In this mini-review, we survey the extant literature on brain aging, with the emphasis on longitudinal studies of neuroanatomy, including regional brain volumes and white matter microstructure. We assess the impact of vascular, metabolic, and inflammatory risk factors on the trajectories of change in regional brain volumes and white matter properties, as well as the relationships between neuroanatomical and physiological changes and their influence on cognitive performance. We examine these findings in the context of current biological theories of aging and propose the means of integrating noninvasive measures - spectroscopic indices of brain energy metabolism and regional iron deposits - as valuable proxies for elucidating the basic neurobiology of human brain aging. In a brief summary of the recent findings pertaining to age-related changes in the brain structure and their impact on cognition, we discuss the role of vascular, metabolic, and inflammatory risk factors in shaping the trajectories of change. Drawing on the extant biological theories of aging and mindful of the brain's role as a disproportionately voracious energy consumer in mammals, we emphasize the importance of the fundamental bioenergetic mechanisms as drivers of age-related changes in brain structure and function. We sketch out a model that builds on the conceptualization of aging as an expression of cumulative cellular damage inflicted by reactive oxygen species and ensuing declines in energy metabolism. We outline the ways and means of adapting this model, Free-Radical Induced Energetic and Neural Decline in Senescence (FRIENDS), to human aging and testing it within the constraints of noninvasive neuroimaging. PMID- 28858863 TI - Association of Plasminogen Activator Inhibitor-1 Gene Polymorphisms and Methylene Tetrahydrofolate Reductase Polymorphisms with Spontaneous Miscarriages. AB - AIM: The objective of this study was to investigate a possible correlation between the plasminogen activator inhibitor-1 (PAI-1) and methylene tetrahydrofolate reductase (MTHFR) polymorphisms and unexplained spontaneous miscarriages (SM). MATERIALS AND METHODS: PAI-1 polymorphisms were evaluated in 150 women with pregnancy in their history. One hundred women with a history of SM formed the study group and 50 women with normal pregnancies served as the control group. Also, the combination of PAI-1 and MTHFR polymorphisms were evaluated in 138 women out of a total of 150, which included 92 women with SM in their history compared to 46 women in the control group. For statistical analysis, chi2 test, Phi, and Cramer V tests were used; p < 0.05 was taken as a statistically significant result. RESULTS: Our findings show: (a) the correlation between SM and PAI-1 mutations reaches statistical significance (p = 0.026); (b) there was a statistically significant difference between heterozygous PAI-1 in women with only 1 SM compared to the control group (p = 0.047); (c) the comparison of combinations of both mutations, PAI-1 and MTHFR, with the control group demonstrates statistical significance in favor of women with SM and both mutations (p = 0.022). CONCLUSION: PAI-1 and MTHFR polymorphisms may play an important role in pregnancy complications because heterozygous PAI-1 mutations and a combination of both PAI-1 and MTHFR mutations might contribute to SM. PMID- 28858864 TI - Early Intervention with Infliximab Prevents Reoperation in Crohn's Disease: A Single-Center Retrospective Analysis. AB - BACKGROUND/AIMS: We aimed to evaluate the prognostic factors that can aid in the prevention of first and second surgeries in patients with Crohn's disease (CD). METHODS: The clinical records of 115 patients with CD whose disease onset was between January 1987 and July 2012 were retrospectively investigated. The cumulative rate of bowel resection for CD-related intestinal manifestations following onset until the first surgery and the cumulative rate of reoperation following the first to second surgeries were estimated using the Kaplan-Meier method, and the relationship to each factor was statistically analyzed using the log-rank test. The background factors that influenced the cumulative rate of the first surgery and reoperation were evaluated using univariate and multivariate analyses. RESULTS: The cumulative bowel resection rate was significantly higher in patients with ileocolitis-type CD (p = 0.0018) and in those with CD with smoking habits (p = 0.0315). And the cumulative reoperation rate was significantly higher in patients with ileocolitis-type CD (p = 0.0161) and those without early intervention with infliximab (p = 0.0161). CONCLUSIONS: Ileocolitis type CD and smoking habit might be initiating factors for bowel resection due to CD-related intestinal manifestations. Early intervention with infliximab likely prevents reoperation for CD recurrence. PMID- 28858865 TI - Prof. Dr. med. Dr. h.c. Michael Frotscher (1947-2017). PMID- 28858866 TI - Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases. AB - Compared to intravitreal injection, subretinal injection has more direct effects on the targeting cells in the subretinal space, which provides a new therapeutic method for vitreoretinal diseases, especially when gene therapy and/or cell therapy is involved. To date, subretinal delivery has been widely applied by scientists and clinicians as a more precise and efficient route of ocular drug delivery for gene therapies and cell therapies including stem cells in many degenerative vitreoretinal diseases, such as retinitis pigmentosa, age-related macular degeneration, and Leber's congenital amaurosis. However, clinicians should be aware of adverse events and possible complications when performing subretinal delivery. In the present review, the subretinal injection used in vitreoretinal diseases for basic research and clinical trials is summarized and described. Different methods of subretinal delivery, as well as its benefits and challenges, are also briefly introduced. PMID- 28858867 TI - Pretreatment Serum Carbohydrate Antigen 19-9 Concentration Is a Predictor of Survival of Patients Who Have Undergone Curative Resection of Stage IV Rectal Cancer. AB - BACKGROUND: To evaluate whether pretreatment carcinoembryonic antigen and carbohydrate antigen (CA)19-9 are useful predictors of survival in patients with stage IV rectal cancer who have undergone curative resection. METHODS: In this retrospective study, data on 73 patients who had undergone curative resection of stage IV rectal cancer were reviewed. Associations between various clinicopathological factors and survival outcomes were analyzed. RESULTS: According to univariate analysis, elevated pretreatment CA19-9 (p = 0.0028), R1 resection (p = 0.0318), and mucinous or poorly differentiated adenocarcinoma (p = 0.0228) were significantly associated with poor overall survival (OS), and lymph node metastasis (p = 0.0211) was significantly associated with poor disease-free survival (DFS). Multivariate analyses showed that elevated pretreatment serum CA19-9 concentration (hazard ratios [HR] 3.33; 95% CI 1.24-9.42; p = 0.0174) was an independent predictor for OS and lymph node metastasis (HR 2.26; 95% CI 1.15 4.82; p = 0.0164) was an independent predictor for DFS. Among 55 patients with recurrences after curative resection, the rate of complete resection of recurrences was significantly higher in patients with normal pretreatment CA19-9 than in those with elevated CA19-9 (p = 0.049). Post-recurrence survival was significantly worse in patients with elevated pretreatment CA19-9 than in those with normal CA19-9 (p = 0.0196). CONCLUSIONS: Pretreatment CA19-9 is good predictor of survival after curative resection of stage IV rectal cancer. PMID- 28858868 TI - Association between Testosterone and Mortality Risk among U.S. Males Receiving Dialysis. AB - BACKGROUND: Among the general population, low circulating testosterone levels are associated with higher risk of cardiovascular disease and death. While testosterone deficiency is common in dialysis patients, studies of testosterone and mortality in this population are ambiguous and overlapping. We hypothesized that lower testosterone levels are associated with higher mortality in male dialysis patients. METHODS: We examined a nationally representative cohort of male dialysis patients from a large US dialysis organization who underwent one or more total testosterone measurements from 1/2007 to 12/2011. The association between total testosterone categorized as quartiles and all-cause mortality was studied using Cox models adjusted for expanded case-mix and laboratory covariates. We also examined total testosterone as a continuous predictor of all cause mortality using restricted cubic splines. RESULTS: Among 624 male dialysis patients, 51% of patients demonstrated testosterone deficiency (total testosterone <300 ng/dL); median (IQR) total testosterone levels were 297 (190 424) ng/mL. In expanded case-mix + laboratory adjusted Cox analyses, we observed a graded association between lower testosterone levels and higher mortality risk (ref: quartile 3): adjusted hazard ratios (95% CI) 2.32 (1.33-4.06), 1.80 (0.99 3.28), and 0.68 (0.32-1.42) for Quartiles 1, 2, and 4, respectively. In adjusted spline analyses, the lower testosterone-higher mortality risk association declined with higher testosterone levels until the value reached a threshold of 400 ng/dL above which risk plateaued. CONCLUSION: Lower testosterone levels were independently associated with higher mortality risk in male dialysis patients. Further studies are needed to determine underlying mechanisms, and whether testosterone replacement ameliorates death risk in this population. PMID- 28858869 TI - Overexpression of a Laccase with Dye Decolorization Activity from Bacillus sp. Induced in Escherichia coli. AB - Laccases from bacteria have been widely studied in the past 2 decades due to the higher growth rate of bacteria and their excellent thermal and alkaline pH stability. In this study, a novel laccase gene was cloned from Bacillus sp., analyzed, and functionally expressed in Escherichia coli. The laccase was highly induced in the E. coli expression system with a maximum intracellular activity of 16 U mg-1 protein. The optimal temperature and pH of the purified laccase were 40 degrees C and 4.6, respectively, when ABTS (2,2'-azino-bis[3-ethylbenzothiazoline 6-sulfonate]) was used as the substrate. The purified laccase showed high stability in the pH range of 3.0-9.0, and retained more than 70% of its activity after 24 h of incubation at 40 degrees C with a pH value of 9.0. Furthermore, the enzyme exhibited extremely high temperature and ion metal tolerance. The half life of the purified laccase at 70 degrees C was 15.9 h. The purified laccase could efficiently decolorize 3 chemical dyes, especially in the presence of ABTS as a mediator. The high production of this laccase in E. coli and exceptional characteristics of the recombinant enzyme protein make it a promising candidate for industrial applications. PMID- 28858870 TI - The TLR2 Antagonist Staphylococcal Superantigen-Like Protein 3 Acts as a Virulence Factor to Promote Bacterial Pathogenicity in vivo. AB - Toll-like receptor (TLR) signaling is important in the initiation of immune responses and subsequent instigation of adaptive immunity. TLR2 recognizes bacterial lipoproteins and plays a central role in the host defense against bacterial infections, including those caused by Staphylococcus aureus. Many studies have demonstrated the importance of TLR2 in murine S. aureus infection. S. aureus evades TLR2 activation by secreting two proteins, staphylococcal superantigen-like protein 3 (SSL3) and 4 (SSL4). In this study, we demonstrate that antibodies against SSL3 and SSL4 are found in healthy individuals, indicating that humans are exposed to these proteins during S. aureus colonization or infection. To investigate the TLR2-antagonistic properties of SSL3 and SSL4, we compared the infection with wild-type and SSL3/4 knockout S. aureus strains in an intravenous murine infection model. Direct evaluation of the contribution of SSL3/4 to infection pathogenesis was hindered by the fact that the SSLs were not expressed in the murine system. To circumvent this limitation, an SSL3-overproducing strain (pLukM-SSL3) was generated, resulting in constitutive expression of SSL3. pLukM-SSL3 exhibited increased virulence compared to the parental strain in a murine model that was found to be TLR2 dependent. Altogether, these data indicate that SSL3 contributes to S. aureus virulence in vivo. PMID- 28858872 TI - 12th International Symposium on Resistance Arteries (ISRA 2017) Manchester, September 3-6, 2017: Abstracts. PMID- 28858871 TI - Unilateral Upper Lung Field Pulmonary Fibrosis Radiologically Consistent with Pleuroparenchymal Fibroelastosis after Thoracotomy: A New Disease Entity Related to Thoracotomy. AB - BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare bilateral idiopathic interstitial pneumonia defined by pleural-parenchymal involvement. In clinical practice, we encountered patients with upper lung field pulmonary fibrosis (Upper-PF), which was radiologically consistent with PPFE, but apparently limited to the unilateral lung. OBJECTIVES: The purpose of the study was to clarify the clinical characteristics in those patients. METHODS: We examined the medical records of all the consecutive patients from 2012 to 2016 to see whether there were patients having unilateral Upper-PF. RESULTS: We found 6 patients with unilateral Upper-PF. The most common symptom was dyspnea, and all patients had a low body mass index and severe restrictive pulmonary impairment. Notably, all patients had a history of thoracotomy for resecting lung or esophageal cancer, and the lesions were limited to the operated side. Dynamic breathing chest MRI showed an impaired thoracic movement in the operated side. Serial chest CT from prethoracotomy to the first visit was obtained in 5 patients: before thoracotomy, only a slight apical cap, defined as a wedge- and triangle-shaped opacity with broad pleural contact, was observed only in the operated side, but progressed into the lesion after a median of 8.4 years following thoracotomy. After the first visit, the unilateral lesion rapidly deteriorated in all patients. CONCLUSIONS: Unilateral Upper-PF had some characteristics in common with PPFE. Because the lesion was limited to the operated side, unilateral Upper-PF would be a new disease entity related to thoracotomy. Our results indicate that thoracotomy impairs thoracic movement in the operated side and subsequently triggers unilateral Upper-PF development, especially in patients with an apical cap. PMID- 28858873 TI - Circulating Triglycerides and the Association of Triglycerides with Dietary Intake Are Altered by Alpha-2-Heremans-Schmid Glycoprotein Polymorphisms. AB - BACKGROUND: Circulating fetuin-A (FetA) inhibits insulin receptor signaling and activates the toll-like receptor 4 proinflammatory cascade; thus, it may contribute to metabolic syndrome. Polymorphisms in alpha-2-Heremans-Schmid glycoprotein (AHSG), the gene which codes FetA, may influence metabolic syndrome progression in higher-risk ethnic groups. We aimed to identify whether individual variation in AHSG influences biomarkers of metabolic disease and obesity in young Mexican adults. METHODS: The participants were Mexican college applicants (18-25 years, n = 641). Dietary intake, anthropometric data, and blood for the analysis of biomarkers and genetics were collected. Single nucleotide polymorphisms (SNPs) in AHSG (rs2518136 and rs4917) were genotyped. RESULTS: Neither AHSG SNP was associated with body mass index (BMI) or waist circumference. rs4917 C allele carriers had lower triglycerides (TG) than T allele homozygotes (98.85 +/- 2.3 vs. 112.2 +/- 5.2 mg/dL, p = 0.0113). BMI was strongly associated with TG (p < 0.0001) regardless of genotype. The relationship between circulating TG and dietary intake of carbohydrates and saturated fat was significant in rs4917 CT allele heterozygotes only (p = 0.03 and p = 0.02, respectively). CONCLUSIONS: rs4917 T allele carriers had higher TG. This relationship was exaggerated in individuals with overweight and obesity. Dietary intake was significantly associated with TG in only those with heterozygosity at rs4917, suggesting that these individuals may be more susceptible to dietary interventions. PMID- 28858874 TI - Variants in Chemosensory Genes Are Associated with Picky Eating Behavior in Preschool-Age Children. AB - BACKGROUND/AIMS: Picky eating is prevalent among preschoolers and is associated with risk of both underweight and overweight. Although differences in taste perception may be due to genetic variation, it is unclear whether these variations are related to picky eating behavior. The aim of this study was to investigate the association of 6 single nucleotide polymorphisms (SNPs) in 5 candidate genes related to chemosensory perception with picky eating behavior and adiposity in a cohort of preschool-aged children. METHODS: Parents of 2- to 5 year-old non-Hispanic white preschoolers (n = 153) responded to survey questions on demographics, and information regarding their child's breastfeeding history and picky eating behavior. Height and weight were measured to calculate body mass index (BMI) z-scores using standard growth charts, and saliva was collected for genotyping. Generalized linear models were used to examine associations between picky eating behavior and BMI z-scores with genetic variation. RESULTS: When controlling for child age, sex, breastfed status, and parent education level, SNPs in TAS2R38 (rs713598) and CA6 (rs2274327) were associated with picky eating behavior in children. There was no association between SNPs and BMI z-scores. CONCLUSION: Genes related to chemosensory perception may play a role in children's picky eating behavior. PMID- 28858875 TI - Clinical Metabolomics and Glaucoma. AB - Glaucoma is one of the leading causes of irreversible blindness worldwide. However, there are no biomarkers that accurately help clinicians perform an early diagnosis or detect patients with a high risk of progression. Metabolomics is the study of all metabolites in an organism, and it has the potential to provide a biomarker. This review summarizes the findings of metabolomics in glaucoma patients and explains why this field is promising for new research. We identified published studies that focused on metabolomics and ophthalmology. After providing an overview of metabolomics in ophthalmology, we focused on human glaucoma studies. Five studies have been conducted in glaucoma patients and all compared patients to healthy controls. Using mass spectrometry, significant differences were found in blood plasma in the metabolic pathways that involve palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors. For nuclear magnetic resonance spectroscopy, a high glutamine glutamate/creatine ratio was found in the vitreous and lateral geniculate body; no differences were detected in the optic radiations, and a lower N acetylaspartate/choline ratio was observed in the geniculocalcarine and striate areas. Metabolomics can move glaucoma care towards a personalized approach and provide new knowledge concerning the pathophysiology of glaucoma, which can lead to new therapeutic options. PMID- 28858876 TI - Intracranial Hemorrhage in Patients Newly Diagnosed with Acute Myeloid Leukemia and Hyperleukocytosis. PMID- 28858877 TI - Rare Human Codons and HCMV Translational Regulation. AB - Restriction of protein synthesis characterizes human cytomegalovirus (HCMV) latency in the human host. In analyzing the molecular factors that hinder HCMV expression, the present study shows that HCMV genes frequently use 6 rare codons, i.e., GCG (Ala), CCG (Pro), CGT (Arg), CGC (Arg), TCG (Ser), and ACG (Thr). In some instances, the rare host codons are clustered along viral nucleotide sequences and represent the majority in sequences encoding short alanine and proline repeats. Given the positive correlation between codon usage, tRNA content, and protein production, the results support the hypothesis that HCMV usage of rare human codons might hinder HCMV protein synthesis, in this way leading to HCMV latency. PMID- 28858879 TI - Evaluation of the Macular Ganglion Cell-Inner Plexiform Layer and the Circumpapillary Retinal Nerve Fiber Layer in Early to Advanced Stages of Glaucoma: Correlation with Central Visual Function and Visual Field Indexes. PMID- 28858878 TI - A Retrospective Analysis of gammadelta T Cell Expression in Chronic Rhinosinusitis and Its Association with Recurrence of Nasal Polyps. AB - BACKGROUND/AIMS: To examine whether gammadelta T cell is expressed in the nasal mucosa of chronic rhinosinusitis (CRS) patients and its potential association with recurrence of nasal polyps. METHODS: Thirty-six patients with CRS with nasal polyps (CRSwNP) and 25 patients with CRS without nasal polyps (CRSsNP) were recruited. Twenty-six patients with other nasal diseases served as controls. The CRSwNP group was divided into the eosinophilic CRSwNP and noneosinophilic CRSwNP groups. The expression of gammadelta T cells was detected by immunohistochemistry. The expression of each subtype of gammadelta T cells was detected by using qRT-PCR. All patients underwent nasal endoscopy, and postoperative follow-up lasted over 12 months. CRS patients were evaluated by preoperative VAS scores of symptoms and nasal endoscopy Lund-Kennedy scores. RESULTS: The expression of gammadelta T cells in the CRSwNP groups was stronger than in the CRSsNP and the control group (p < 0.05, p < 0.05). The expression of Vgamma1+gammadelta T cells in the eosinophilic CRSwNP group was higher than that in the CRSsNP group and the control group (p < 0.05, p < 0.05). The expression of gammadelta T cells was associated with high rate of recurrence, tissue eosinophil infiltration, worse symptom score of nasal obstruction, and higher Lund-Kennedy score (all p < 0.05). CONCLUSIONS: Increased expression of gammadelta T cells in CRSwNP may be associated with recurrence of nasal polyps. PMID- 28858880 TI - The Histopathology of Urticaria Revisited-Clinical Pathological Study. AB - BACKGROUND: The classic histopathological findings of urticaria include dermal edema and a sparse perivascular infiltrate of neutrophils, eosinophils, macrophages, and lymphocytes. However, this pattern is inconsistently described. OBJECTIVE: To describe the histological and immunofluorescence characteristics of urticaria and to identify distinctive patterns. METHODS: A retrospective study was performed in which the medical files and biopsy specimens of 58 patients with acute and chronic classical urticaria were reviewed. Pathological parameters were quantified. RESULTS: We recognized 2 distinctive patterns of urticaria: lymphocyte and neutrophil predominant; the former was characterized by a perivascular location, whereas the latter was associated with an interstitial location and a denser infiltrate. Mast cells were relatively sparse, better demonstrated with special stains. Tryptase stain demonstrated more mast cells than Giemsa stain. Extravasated erythrocytes were present in 50% of the cases, but vasculitis was not observed. CONCLUSIONS: Histological findings in classical urticaria show a spectrum of findings from a sparse superficial perivascular to a deep perivascular and interstitial infiltrate. Distinctive groups based on the dominant cell type can be identified, accounting for the similarity to neutrophilic urticarial dermatosis. Lesions may have a purpuric appearance, but leukocytoclastic vasculitis is never present. PMID- 28858881 TI - Online Patient Resources for Gender Affirmation Surgery: An Analysis of Readability. AB - BACKGROUND: Gender affirmation surgery is an important treatment for patient with gender dysphoria. It consists of a series of complex procedures, and well informed patients have been shown to have better outcomes. However, there are no published data regarding the readability of currently available online patient recourses for gender affirmation surgery. This study aims at identifying the most popular online resources and evaluating the readability of these documents in the context of average literacy within the United States. METHODS: An online search with the terms "gender affirmation surgery," "gender reassignment surgery," "top surgery," and "bottom surgery" was performed. Location, cookies, and user account information was disabled before each search to avoid bias in the results. Readability assessment was performed using the 10 commonly used readability scales. RESULTS: The overall mean readability level was 13.4. The mean reading level was 14 (range, 7.6-17.0) for the search term "gender affirmation surgery," 14.2 (range, 11.9-16.7) for the search term "gender reassignment surgery," 13 (range, 8.9-17.5) for the search term "top surgery," and 12.6 (range, 7.1-15.0) for the search term "bottom surgery." There was no statistically significant difference between the search terms. CONCLUSIONS: Our findings demonstrate that the articles most commonly seen by patients who perform an Internet search for information on gender reassignment surgery are more difficult than the recommended readability level. PMID- 28858882 TI - Reconstruction of Anterolateral Thigh Defects Using Perforator-Based Propeller Flaps. AB - BACKGROUND: Usually, anterolateral thigh (ALT) defects with width more than 8 cm cannot be closed directly. Although several methods of using local flaps exist, flap mobility of these methods is limited. We introduced a perforator-based propeller flap for such reconstruction. Their maximal mobility, which minimizes their size, is their greatest advantage. In addition, we present our technical refinements including double-axes propeller flap, the use of indocyanine green real-time angiography, and supercharged propeller flap for safer flap transfer. PATIENTS AND METHODS: Seven patients underwent perforator-based propeller flap reconstruction of ALT defects. Flaps were designed cranial or caudal to the defect according to the perforator locations. To maximize mobility, flaps were designed so that the perforator was located at the periphery and closer to the defect. After rotating the flap to the defect, indocyanine green angiography was performed to determine the need for supercharge. RESULTS: In all cases, all flaps survived completely. Defect size ranged from 12 * 11 cm to 18 * 16 cm, and flap size ranged from 7 * 5 cm to 15 * 7 cm. The number of perforators in the flap was 1 in 3 cases and 2 in 4 cases. Supercharging was performed in 3 cases. Donor-site complications, including gait disturbance, were not observed. CONCLUSIONS: This method achieves ALT defect closure with minimal donor-site morbidity and can provide prompt and aesthetically acceptable results. Indocyanine green real-time angiography and supercharging technique are also useful for safer and reliable flap transfer. PMID- 28858883 TI - Nonincisional Conjoint Fascial Sheath Suspension: A Novel Technique for Minimally Invasive Blepharoptosis Correction. AB - BACKGROUND: Mild to moderate blepharoptosis, or ptosis, is relatively common among Asians, and it is not uncommon to offer ptosis correction at the time of double-eyelid surgery in this patient population. The traditional open approaches to ptosis correction are subject to scarring and prolonged recovery time, whereas the newer nonincisional approaches are marred by issues of incomplete correction or recurrence. This study describes a new nonincisional technique that overcomes the limitations of current methods by using conjoint fascial sheath (CFS) for suspension. METHODS: From January 2014 to April 2015, a retrospective review was conducted on 21 patients (41 eyelids) who underwent simultaneous nonincisional ptosis correction and double-eyelid surgery. All patients had either mild or moderate ptosis without excess skin hooding and excellent or good levator palpebrae function. RESULTS: Mild ptosis correction (1-loop CFS suspension) was performed in 25 eyelids, and moderate ptosis correction (2-loop CFS suspension) was performed in 16 eyelids. At 6 months of follow-up, 23 eyelids (56.1 %) improved to "normal" with overall improvement seen in 33 eyelids (80.0%). The mean marginal reflex distance 1 increased from 3.16 +/- 0.61 mm preoperatively to 4.11 +/- 0.61 mm postoperatively, which was statistically significant (P < 0.001). CONCLUSIONS: Mild to moderate ptosis correction with nonincisional CFS suspension technique is a safe and effective method that combines the benefits of nonincisional procedure with longevity and precision seen in the traditional open approaches. The procedure is easy to perform with minimal recovery time and high patient satisfaction and can be combined with nonincisional double-eyelid surgery. PMID- 28858884 TI - Evaluating the Impact of the Medical Education Partnership Initiative at the University of Zimbabwe College of Health Sciences Using the Most Significant Change Technique. AB - PROBLEM: In medical education, evaluating outcomes from programs intended to transform attitudes or influence career trajectories using conventional methods of monitoring is often difficult. To address this problem, the authors adapted the most significant change (MSC) technique to gain a more comprehensive understanding of the impact of the Medical Education Partnership Initiative (MEPI) program at the University of Zimbabwe College of Health Sciences. APPROACH: In 2014-2015, the authors applied the MSC to systematically examine the personal significance and level of positive transformation that individuals attributed to their MEPI participation. Interviews were conducted with 28 participants nominated by program leaders. The authors coded results inductively for prevalent themes in participants' stories and prepared profiles with representative quotes to place the stories in context. Stakeholders selected 9 themes and 18 stories to illustrate the most significant changes. OUTCOMES: Six themes (or outcomes) were expected, as they aligned with MEPI goals-becoming a better teacher, becoming a better clinician, increased interest in teaching, increased interest in research, new career pathways (including commitment to practice in Zimbabwe), and improved research skills. Three themes were unexpected increased confidence, expanded interprofessional networks, and improved interpersonal interactions. NEXT STEPS: The authors found the MSC to be a useful and systematic evaluation approach for large, complex, and transformative initiatives like MEPI. The MSC seemed to encourage participant reflection, support values inquiry by program leaders, and provide insights into the personal and cultural impacts of MEPI. Additional trial applications of the MSC technique in academic medicine are warranted. PMID- 28858885 TI - Recent perspectives on the role of nutraceuticals as cholesterol-lowering agents. AB - PURPOSE OF REVIEW: Reduction in circulating cholesterol is an important step in lowering cardiovascular risk. Although statins are the most frequently prescribed cholesterol-lowering medication, there remains a significant portion of patients who require alternative treatment options. Nutraceuticals are increasingly popular as cholesterol-lowering agents. Despite the lack of long-term trials evaluating their use on cardiovascular endpoints and mortality, several studies have demonstrated their potential cholesterol-lowering effects. The purpose of this review is to provide an update on the role of nutraceuticals as cholesterol lowering agents. The present review will focus on individual nutraceutical compounds, which have shown modest cholesterol-lowering abilities, as well as combination nutraceuticals, which may offer potential additive and/or synergistic effects. RECENT FINDINGS: Berberine, red yeast rice, and plant sterols have moderate potential as cholesterol-lowering agents. Combination nutraceuticals, including the proprietary formulation, Armolipid Plus, appear to confer additional benefit on plasma lipid profiles, even when taken with statins and other agents. SUMMARY: Although robust, long-term clinical trials to examine the effects of nutraceuticals on clinical outcomes are still required, their cholesterol-lowering ability, together with their reported tolerance and safety, offer a pragmatic option for lowering plasma cholesterol levels. PMID- 28858886 TI - State of the Science in Heart Failure Symptom Perception Research: An Integrative Review. AB - BACKGROUND: Heart failure (HF) is a common condition requiring self-care to maintain physical stability, prevent hospitalization, and improve quality of life. Symptom perception, a domain of HF self-care newly added to the Situation Specific Theory of HF Self-Care, is defined as a comprehensive process of monitoring and recognizing physical sensations and interpreting and labeling the meaning of the sensations. OBJECTIVE: The purpose of this integrative review was to describe the research conducted on HF symptom perception to further understanding of this new concept. METHOD: A literature search was conducted using 8 databases. The search term of HF was combined with symptom, plus symptom perception subconcepts of monitoring, somatic awareness, detection, recognition, interpretation, and appraisal. Only peer-reviewed original articles published in English with full-text availability were included. No historical limits were imposed. Study subjects were adults. Twenty-one studies met the inclusion criteria. Each study was categorized into either symptom monitoring or symptom recognition and interpretation. RESULTS: Although daily weighing and HF-related symptom-monitoring behaviors were insufficient in HF patients, use of a symptom diary improved HF self-care, symptom distress and functional class, and decreased mortality, hospital stay, and medical costs. Most HF patients had trouble recognizing an exacerbation of symptoms. Aging, comorbid conditions, and gradual symptom progression made it difficult to recognize and correctly interpret a symptom exacerbation. Living with others, higher education, higher uncertainty, shorter symptom duration, worse functional class, and an increased number of previous hospitalizations were positively associated with symptom recognition. CONCLUSIONS: Existing research fails to capture all of the elements in the theoretical definition of symptom perception. PMID- 28858887 TI - Psychometric Properties of the 9-item European Heart Failure Self-care Behavior Scale Using Confirmatory Factor Analysis and Rasch Analysis Among Iranian Patients. AB - BACKGROUND: The 9-item European Heart Failure Self-Care Behavior scale (EHFScB-9) is a self-reported questionnaire commonly used to capture the self-care behavior of people with heart failure (HF). OBJECTIVE: The aim of this study was to investigate the EHFScB-9's factorial structure and categorical functioning of the response scale and differential item functioning (DIF) across subpopulations in Iran. METHODS: Patients with HF (n = 380; 60.5% male; mean [SD] age, 61.7 [9.1] years) participated in this study. The median (interquartile range) of the duration of their HF was 6.0 (2.4-8.8) months. Most of the participants were in New York Heart Association classification II (NYHA II, 61.8%); few of them had left ventricular ejection fraction assessment (11.3%). All participants completed the EHFScB-9. Confirmatory factor analysis was used to test the factorial structure of the EHFScB-9; Rasch analysis was used to analyze categorical functioning and DIF items across 2 characteristics (gender and NYHA). RESULTS: The 2-factor structure ("adherence to regimen" and "consulting behavior") of the EHFScB-9 was confirmed, and the unidimensionality of each factor was found. Categorical functioning was supported for all items. No items displayed substantial DIF across gender (DIF contrast, -0.25-0.31). Except for item 3 ("Contact doctor or nurse if legs/feet are swollen"; DIF contrast, -0.69), no items displayed substantial DIF across NYHA classes (DIF contrast, -0.40 to 0.47). CONCLUSIONS: Despite the DIF displayed in 1 item across the NYHA classes, the EHFScB-9 demonstrated sound psychometric properties in patients with HF. PMID- 28858888 TI - Acceptability of an Opioid Relapse Prevention Text-message Intervention for Emergency Department Patients. AB - OBJECTIVE: To explore whether a text message-based relapse prevention intervention (Preventing and Interrupting Early Relapse [PIER]1) is acceptable to treatment-seeking adults with opioid use disorder (OUD) after Emergency Department (ED) discharge using mixed-methods design. METHODS: Adults seeking care in an urban ED for OUD (n = 20; mean age 22; 55% female; 75% white race) completed a baseline survey, and were invited to enroll in PIER1, which was delivered in 7-day blocks, with the option to re-enroll at the end of each block, up to 4 blocks. PIER1 included a morning "push" message focused on positive thinking, adaptive coping feedback tailored to twice-daily assessments of craving severity and contextual correlates of craving, and end-of-day feedback on daily opioid use and goal commitment. Participants were asked to complete a follow-up phone interview after the first 7 days of PIER1. Transcripts were thematically coded. RESULTS: Seventeen out of 20 participants enrolled in PIER1. In the first 7 days, response rates to text-message assessments averaged 30%. Ten out of 17 participants re-enrolled after 7 days. Main themes from follow-up interviews (n = 9) included ease of use, social connection, and self-empowerment. Participants desired more personalized support and the ability to communicate through text messaging with another person about their struggles. Event-level data suggest that higher craving severity increased risk of opioid lapses. CONCLUSIONS: In this mixed-methods intervention development study, we found conflicting evidence supporting an automated text-message intervention providing relapse prevention support for treatment-seeking individuals with OUD discharged from the ED. Qualitative feedback suggests that PIER1 could be useful and acceptability enhanced through personalized human support. PMID- 28858889 TI - Prescriptions Written for Opioid Pain Medication in the Veterans Health Administration Between 2000 and 2016. AB - OBJECTIVES: The purpose of this study was to identify national opioid pain medication (OPM) prescribing trends within the Veterans Health Administration (VA), and assess the impact of educational campaigns introduced in 2010 and 2013. METHODS: We created a national cohort that documents more than 21 million patient records and 97 million outpatient OPM prescriptions covering a 17-year period. We examined OPM prescriptions in emergency departments, outpatient clinics, and inpatient settings. RESULTS: The cohort accounted for 2.5 billion outpatient clinic visits, 18.9 million emergency department visits, and 12.4 million hospital admissions. The number of OPM prescriptions peaked in 2011, when they were provided during 5% of all outpatient visits and 15% of all emergency department visits. The morphine milligram equivalents (MMEs) peaked in 2014 at almost 17 billion in outpatient clinics and at 137 million in emergency departments. In 2016, OPM prescriptions were down 37% in outpatient clinics and 23% in emergency departments, and MMEs were down 30% in both settings. Prescriptions for hydrocodone and tramadol increased markedly between 2011 and 2015. OPM doses in inpatient settings continued to rise until 2015. CONCLUSIONS: We used a large national cohort to study trends in OPM prescriptions within the VA. Educational efforts to reduce the number of OPM prescriptions coincided with these reductions, but were initially associated with an increase in OPM dosage, an increase in the use of tramadol and hydrocodone, and an increase in the use of OPMs in inpatient settings. PMID- 28858890 TI - Fat-soluble micronutrients and metabolic syndrome. AB - PURPOSE OF REVIEW: Metabolic syndrome (MetS) is associated with increased risk of obesity, type 2 diabetes mellitus and cardiovascular diseases. MetS prevalence has been associated with diet inadequacy. Conversely, the cumulative incidence of MetS has been inversely associated with a Mediterranean-style diet that includes many different health-beneficial nutrients. Adherence to a Mediterranean-style diet could reduce or at least stabilize metabolic risk factors. RECENT FINDINGS: Low serum level of fat-soluble micronutrients, such as carotenoids, vitamin (vit) A, D and E, has been linked to MetS. Fat-soluble micronutrients could contribute to prevent MetS thanks to their antioxidant and anti-inflammatory properties (vit E, carotenoids) or to their central role as hormone regulators (vit D) and/or lipid metabolism and glucose homeostasis sensors (vit D and E). SUMMARY: This review summarizes recent epidemiological studies linking fat-soluble micronutrients to MetS and highlights new evidence on their mechanisms of actions. PMID- 28858891 TI - Recent advances on bioactivities of black rice. AB - PURPOSE OF REVIEW: Black rice has been consumed for centuries in Asian countries such as China, Korea or Japan. Nowadays, extracts and derivatives are considered as beneficial functional foods because of their high content in several bioactive molecules such as anthocyanins, other phenolics and terpenoids. The purpose of this review is to summarize and discuss recent developments on black rice bioactivities. RECENT FINDINGS: Some sterols and triterpenoids with potential anticancer properties already tested in vitro and in vivo have been isolated and identified from bran extracts of black rice. Protection against osteoporosis has been suggested for the first time for black rice extracts. Because of its antioxidant and anti-inflammatory properties, black rice also protects liver and kidney from injuries. One clinical study reported the interest of black rice in case of alcohol withdrawal. SUMMARY: Several advances have been recently achieved on the understanding of the potential biological effects of black rice and its derivatives. They further confirm that black rice should be considered as a promising source of health-promoting functional foods targeting a large set of noninfectious diseases. However, more clinical studies are needed to support the findings highlighted in this review. PMID- 28858893 TI - Button battery ingestion in children. AB - PURPOSE OF REVIEW: As the demand for small electronics continues to grow so does the risk of oesophageal ingestion of button batteries. These small but powerful sources of energy are ubiquitous in every household and when swallowed, especially in small children, have been shown to create significant injury in a short amount of time leading to long-term morbidity and possible death. This review highlights the latest findings regarding epidemiology, pathophysiology, diagnosis and management of ingested button batteries. RECENT FINDINGS: Updated epidemiology from the National Capital Poison Center, new bench research looking at injury patterns and possible mitigation strategies, updated ideas on management algorithms including the use of a trauma protocol, close-look second endoscopy and management of button batteries in the lower gastrointestinal tract are reviewed in this paper. SUMMARY: Despite advances in the understanding of injury mechanics and innovations leading to early diagnosis and improved management of button battery ingestion, parental and provider education remain the most important tools to keep children well tolerated from the sequelae of these potentially fatal events. Collaboration between healthcare experts, public health and industry is essential to find a safe answer to this ongoing threat. PMID- 28858894 TI - Multiple Sclerosis: Improved Detection of Active Cerebral Lesions With 3 Dimensional T1 Black-Blood Magnetic Resonance Imaging Compared With Conventional 3-Dimensional T1 GRE Imaging. AB - OBJECTIVES: The aim of this study was to assess the diagnostic accuracy of a modified high-resolution whole-brain three-dimensional T1-weighted black-blood sequence (T1-weighted modified volumetric isotropic turbo spin echo acquisition [T1-mVISTA]) in comparison to a standard three-dimensional T1-weighted magnetization-prepared rapid gradient echo (MP-RAGE) sequence for detection of contrast-enhancing cerebral lesions in patients with relapsing-remitting multiple sclerosis (MS). MATERIALS AND METHODS: After institutional review board approval and informed consent, 22 patients (8 men; aged 31.0 +/- 9.2 years) with relapsing remitting MS were included in this monocentric prospective cohort study.Contrast enhanced T1-mVISTA and MP-RAGE, both with 0.8 mm resolution, were performed in all patients. In a substudy of 12 patients, T1-mVISTA was compared with a T1 mVISTA with 1.0 mm resolution (T1-mVISTA_1.0). Reference lesions were defined by an experienced neuroradiologist using all available sequences and served as the criterion standard. T1-mVISTA, T1-mVISTA_1.0, and MP-RAGE sequences were read in random order 4 weeks apart. Image quality, visual contrast enhancement, contrast to-noise-ratio (CNR), diagnostic confidence, and lesion size were assessed and compared by Wilcoxon and Mann-Whitney U tests. RESULTS: Eleven of 22 patients displayed contrast-enhancing lesions. Visual contrast enhancement, CNR, and diagnostic confidence of contrast-enhancing MS lesions were significantly increased in T1-mVISTA compared with MP-RAGE (P < 0.001). Significantly more contrast-enhancing lesions were detected with T1-mVISTA than with MP-RAGE (71 vs 39, respectively; P < 0.001). With MP-RAGE, 25.6% of lesions were missed in the initial reading, whereas only 4.2% of lesions were missed with T1-mVISTA. Increase of the voxel volume from 0.8 mm to 1.0 mm isotropic in T1-mVISTA_1.0 did not affect the detectability of lesions, whereas scan time was decreased from 4:43 to 1:55 minutes. CONCLUSIONS: Three-dimensional T1-mVISTA improves the detection rates of contrast-enhancing cerebral MS lesions compared with conventional 3D MP-RAGE sequences by increasing CNR of lesions and might, therefore, be useful in patient management. PMID- 28858895 TI - Current review of prepubertal vaginal bleeding. AB - PURPOSE OF REVIEW: Prepubertal vaginal bleeding raises many concerns and evaluation and diagnosis may prove difficult for many providers. We aim to provide a comprehensive review and recent updates for those practitioners who care for these patients. RECENT FINDINGS: Prompt management in the case of prepubertal vaginal bleeding is indicated, especially to rule out malignancy or abuse. If a child is reluctant to undergo examination, or if the extent of injury or source of bleeding cannot be determined, examination under anesthesia and vaginoscopy is recommended. Use of vaginoscopy allows for clear visualization of the vagina and cervix without distorting hymenal anatomy, as well as diagnosis and removal of a foreign body and evaluation of mucosal damage caused. In the case of sexual abuse, providers specifically trained in pediatrics need to be present, and safety of the patient should always be ensured. SUMMARY: Careful history taking and targeted examination may lead to diagnosis in the case of prepubertal vaginal bleeding. However, in more difficult cases, practitioners should not hesitate to examine a patient in the operating room using general anesthesia to elicit the cause. Although sexual abuse and malignancy are always on the differential, most causes of bleeding are benign and easily treated. PMID- 28858896 TI - Evaluation and management of heavy menstrual bleeding in adolescents. AB - PURPOSE OF REVIEW: Heavy menstrual bleeding (HMB) is a common condition in women of reproductive age; however, adolescents with this issue present unique challenges in both diagnosis and management. Much of the research into this topic focuses on the adult population, with variable applicability to adolescents. There are currently no standard guidelines for the work up and treatment of adolescents with HMB. RECENT FINDINGS: Current research into this topic has explored the utilization of standardized protocols in the evaluation of HMB in adolescents, the efficacy of various hormonal, nonhormonal, and surgical treatment modalities, and the benefits of a multidisciplinary approach. Recent literature has focused on adolescents found to have an underlying bleeding disorder, recommending more comprehensive bleeding disorder work up to identify these patients in a timely manner and initiate effective treatment plans. SUMMARY: Providers in the primary care setting should be aware of the definitions for normal menses, and be able to recognize abnormal bleeding and HMB. Early recognition of HMB in adolescents can then lead to appropriate diagnosis of underlying disorders, and current research has proposed standard protocols to assist with the evaluation, ultimately leading to effective long-term management into adulthood.VIDEO ABSTRACT. PMID- 28858897 TI - Anesthetic Considerations for Patients Undergoing Bronchial Thermoplasty. AB - Bronchial thermoplasty (BT) is a novel, Food and Drug Administration-approved nondrug treatment for patients whose asthma remains uncontrolled despite traditional pharmacotherapy. BT involves application of controlled radiofrequency energy to reduce airway smooth muscle in large- and medium-sized airways. Although BT is often performed under general anesthesia, anesthetic management strategies for BT are poorly described. We describe the anesthetic management of 7 patients who underwent 19 BT treatments in a tertiary academic medical center. PMID- 28858898 TI - The Accuracy of a Handheld Ultrasound Device for Neuraxial Depth and Landmark Assessment: A Prospective Cohort Trial. AB - This study investigated the accuracy of a wireless handheld ultrasound with pattern recognition software that recognizes lumbar spine bony landmarks and measures depth to epidural space (Accuro, Rivanna Medical, Charlottesville, VA) (AU). AU measurements to epidural space were compared to Tuohy needle depth to epidural space (depth to loss of resistance at epidural placement). Data from 47 women requesting labor epidural analgesia were analyzed. The mean difference between depth to epidural space measured by AU versus needle depth was -0.61 cm (95% confidence interval, -0.79 to -0.44), with a standard deviation of 0.58 (95% confidence interval, 0.48-0.73). Using the AU-identified insertion point resulted in successful epidural placement at first attempt in 87% of patients, 78% without redirects. PMID- 28858899 TI - Patients Undergoing Cesarean Delivery After Exposure to Oxytocin During Labor Require Higher Postpartum Oxytocin Doses. AB - BACKGROUND: Experts recommend postpartum oxytocin to prevent uterine atony and hemorrhage, but oxytocin may be associated with dose-dependent adverse effects, and the correct dose of postpartum oxytocin has yet to be determined. The effective dose in 90% of patients (ED90) of oxytocin after cesarean delivery may be higher in patients exposed to oxytocin during labor compared to patients unexposed. We therefore undertook this study to compare postpartum oxytocin requirements in patients exposed to oxytocin prior to cesarean delivery versus those not exposed, when all were treated according to a specific institutional protocol. METHODS: In this retrospective chart review, we reviewed medical records of patients who underwent cesarean delivery under neuraxial anesthesia and noted demographic data, relevant comorbidities, and oxytocin exposure, infusion rate, and duration prior to delivery. Patients exposed to oxytocin before cesarean (OXY+ group) were compared to those not exposed (OXY- group). The primary outcome variable was highest infusion rate of postpartum oxytocin required per institutional protocol. Secondary outcomes included estimated blood loss, proportion of patients with postpartum hemorrhage, and proportions who received other uterotonic medications or red blood cell transfusion. RESULTS: OXY+ patients were more likely to be nulliparous and had higher estimated gestational age and neonatal weight than OXY- patients. They also had higher incidence of chorioamnionitis and lower incidence of multiple gestation. OXY+ patients required a high postpartum oxytocin infusion rate more often than OXY- patients (adjusted odds ratio 1.94 [95% confidence interval, 1.19-3.15; P = .008]). They also received other uterotonic agents more commonly. Estimated blood loss, hemorrhage rates, and transfusion rates did not differ between groups. CONCLUSIONS: Reported increases in the ED90 of postpartum oxytocin after oxytocin exposure during labor appear to be clinically significant. We have therefore altered our institutional protocol so that women preexposed to oxytocin routinely receive higher initial postpartum oxytocin infusion rates. PMID- 28858900 TI - Trends in the Prevalence of Intraoperative Adverse Events at Two Academic Hospitals After Implementation of a Mandatory Reporting System. AB - BACKGROUND: Anesthesia information management systems (AIMSs) have been effectively used to improve quality in anesthesia care, and have enabled the development of mandatory quality assurance (QA) reporting systems for adverse events (AEs). While this approach has been shown to increase event reporting over time, the long-term effect of such a system on quality is unknown. We investigated the trends in AE reporting over time after implementing AIMS-based mandatory reporting systems at 2 academic medical centers. METHODS: At Thomas Jefferson University Hospital, AEs were retrieved after implementation of a mandatory QA process in 2013. These AEs were categorized as preventable and unpreventable. The rates of overall preventable and unpreventable AEs were analyzed over time. At Vanderbilt University Medical Center, the rates of AEs were analyzed after establishing a mandatory QA process in 2002. Data were binned by quarter, and trends over time were analyzed using the Mann-Kendall test. RESULTS: At Thomas Jefferson University Hospital, over a period of 2 years after implementation of a mandatory QA process, the documented AE rate decreased from 1.23% to 0.64% (P < .0001). This decrease occurred primarily in the group of preventable AEs, which declined from 1.01% to 0.52% (P = .014). The rate of unpreventable AEs was unchanged, from 0.22% to 0.12% (P = .12). At Vanderbilt University Medical Center, over a 7-year period after implementation, the AE rate decreased from 4.20% to 1.36% (P < .0001). CONCLUSIONS: After implementation of a mandatory QA process at 2 academic medical centers, documented AE rates decreased significantly. The decrease observed in preventable AEs, with unchanged rates of unpreventable AEs, demonstrates that mandatory reporting of intraoperative AEs was followed by a reduction in preventable intraoperative AEs. If our findings are replicated at other institutions and are shown to have a stronger trend compared with institutions where the implementation was not conducted, or there was a change from preimplementation trends, adding mandatory perioperative outcomes reporting in the AIMS may represent a valuable method to improve the overall safety of anesthesia. PMID- 28858902 TI - Huntington Mice Demonstrate Diminished Pain Response in Inflammatory Pain Model. AB - BACKGROUND: Huntington disease (HD) affects the nervous system and leads to mental and motor dysfunction. Previous studies have shown that HD is caused by the exon 1 region of the huntingtin (HTT) gene having expanded CAG trinucleotide repeats. However, few studies have focused on the relationship between HD and pain. The purpose of this study is to investigate the relationship between HD and pain response. METHODS: We used clinical similar transgenic HD mice carrying a mutant HTT exon 1 containing 84 CAG trinucleotide repeats to evaluate the relationship between HD and pain. Inflammatory pain models were induced by either formalin or complete Freund adjuvant injection over the hind paw. Spinal cord, dorsal root ganglion, and paw skin tissues were harvested at the end of the behavioral inflammatory pain studies. Immunofluorescence assay, Western blotting, and enzyme-linked immunosorbent assay were used to identify changes in cells and cytokines. RESULTS: Our data demonstrate that preonset HD mice exhibited less pain behavior than wild-type (WT) mice in both young (n = 11 [WT], 13 [HD]) and aged (n = 8 [WT], 9 [HD]) mice. Western blotting and immunohistological examination of lumbar spinal cord tissue and dorsal root ganglion indicate less activation of glial cells and astrocytes in young HD mice (n = 6-7) compared to that in WT mice (n = 6-7). The production levels of tumor necrosis factor-alpha, interleukin-1beta, and substance P were also lower in young HD mice (n = 6-7). CONCLUSIONS: Our data demonstrate less pain behavior and pain-related cytokine response at the spinal cord level for HD mice compared to those for WT mice. Further studies are needed for determining the mechanism as to how mutant HTT leads to altered pain behavior and pain-related cytokine response. PMID- 28858903 TI - Understanding Infusion Pumps. AB - Infusion systems are complicated electromechanical systems that are used to deliver anesthetic drugs with moderate precision. Four types of systems are described-gravity feed, in-line piston, peristaltic, and syringe. These systems are subject to a number of failure modes-occlusion, disconnection, siphoning, infiltration, and air bubbles. The relative advantages of the various systems and some of the monitoring capabilities are discussed. A brief example of the use of an infusion system during anesthetic induction is presented. With understanding of the functioning of these systems, users may develop greater comfort. PMID- 28858904 TI - Tranexamic Acid Administration During On-Pump Cardiac Surgery: A Survey of Current Practices Among Canadian Anesthetists Working in Academic Centers. AB - BACKGROUND: Tranexamic acid (TXA) is commonly administered during on-pump cardiac surgery to minimize bleeding. However, an optimal dosing regimen has not been described, and recent studies suggest that higher doses may be associated with seizure. Little is known about current practice among cardiac anesthetists. METHODS: We contacted all academic anesthesia departments in Canada to identify cardiac anesthetists, who represent the majority of practitioners. This group constituted our sampling frame. Information regarding participant demographics, TXA dose, and administration details were obtained by electronic survey. Responses were analyzed descriptively. To compare dose, we assumed an 80-kg patient and 3 hours of infusion time. The Kruskal-Wallis test was used to compare average dose across provinces. RESULTS: Among 341 Canadian academic cardiac anesthetists, 234 completed the survey (68.2% response rate). Among respondents, 86.3% administer TXA to all patients; 13.7% administer it to some. Most (68.4%) administer an infusion after a bolus; other modes included infusion (4.7%), single bolus (13.2%), 2 or more boluses (12.0%), or another regimen (1.7%). The mean (standard deviation) dose given was 49 mg/kg (24), with a range from 10 to 100 mg/kg. The mean dose varied across provinces from 23 to 55 mg/kg (P = .001). CONCLUSIONS: TXA is given to nearly all patients undergoing on-pump cardiac surgery at academic hospitals in Canada. However, there is significant heterogeneity in practice between individuals and across provinces. Further research is needed to determine the TXA dose that maximizes efficacy and minimizes side effects. PMID- 28858905 TI - Electroencephalogram Abnormalities During Positional Changes in Brain Sagging Syndrome. AB - PURPOSE: Brain sagging after craniotomy and clipping of a ruptured aneurysm is a rare complication. Clinical and electrographic changes in patients with a final diagnosis of intracranial hypotension are not well described, and can be mistaken on rare occasions for other entities such as nonconvulsive status epilepticus. There may be resulting delay in the diagnosis and treatment of this potentially life-threatening disorder. METHODS: Case report and imaging. RESULTS: We present a case of intracranial hypotension in which concerning continuous electroencephalogram (cEEG) and quantitative EEG (qEEG) findings were noted during active sagging of the brain, which resolved with supine positioning. During upright seating, cEEG showed high-amplitude bilateral rhythmic 2-Hz slow wave activity, and bilateral increase of spectral delta power on qEEG, in association with neurologic decline in function. When placed in supine position, the cEEG and qEEG abnormalities resolved in conjunction with the recovery of neurologic function. CONCLUSIONS: Brain sagging can be diagnosed using simple maneuvers such as supine positioning. This case report describes changes seen in cEEG and qEEG monitoring that accompany these maneuvers, which may provide further evidence for the diagnosis of brain sagging. Thus, cEEG and qEEG monitoring may have a role in the early detection and treatment of brain sagging. PMID- 28858907 TI - Nucleoligands-repurposing G Protein-coupled Receptor Ligands to Modulate Nuclear localized G Protein-coupled Receptors in the Cardiovascular System. AB - There is significant evidence that internal pools of G protein-coupled receptors (GPCRs) exist and may be affected by both endogenous signaling molecules and hydrophobic pharmaceutical ligands, once assumed to only affect cell surface versions of these receptors. Here, we discuss evidence that the biology of nuclear GPCRs in particular is complex, rich, and highly interactive with GPCR signaling from the cell surface. Caging existing GPCR ligands may be an excellent means of further stratifying the phenotypic effects of known pharmacophores such as beta-adrenergic, angiotensin II, and type B endothelin receptor ligands in the cardiovascular system. We describe some synthetic strategies we have used to design ligands to go from in cellulo to in vivo experiments. We also consider how surface and intracellular GPCR signaling might be integrated and ways to dissect this. If they could be selectively targeted, nuclear GPCRs and their associated nucleoligands would represent a completely novel area for exploration by Pharma. PMID- 28858906 TI - Preparing the Patient for Enhanced Recovery After Surgery. PMID- 28858908 TI - Robotic-Assisted Radical Hysterectomy Results in Better Surgical Outcomes Compared With the Traditional Laparoscopic Radical Hysterectomy for the Treatment of Cervical Cancer. AB - OBJECTIVE: The aim of this study was to compare the surgical outcomes of robotic assisted radical hysterectomy (RRH) with traditional laparoscopic radical hysterectomy (TLRH) for the treatment of early-stage cervical cancer in a large retrospective cohort of a total of 933 patients. METHODS: We have enrolled 100 patients into the RRH and 833 patients into the TLRH group. The surgical outcomes include operating time, blood loss, transfusion rate, pelvic lymph node yield, hospitalization days, duration of bowel function recovery, catheter removal before and after 3 weeks, conversion to laparotomy, and intraoperative and postoperative complications. Follow-up results were also analyzed for all patients. RESULTS: Both groups have similar patient and tumor characteristics but patients with a larger lesion size were preferably enrolled in the TLRH treatment group. The treatment with RRH was generally superior to TLRH with respect to operating time, blood loss, length of hospitalization, duration of bowel function recovery, and postoperative complications. On follow-up of patients, there were no relapses reported in the RRH group compared with 4% of relapse cases and 2.9% of deaths because of metastasis in the TLRH group. No conversion of laparotomy occurred in the RRH group. No significant difference was found with respect to intraoperative complications and blood transfusion between both groups. CONCLUSIONS: The results from this study suggest that RRH is superior to TLRH with regard to surgical outcome and may pose a safe and feasible alternative to TLRH. The operating time and lymph node yield is acceptable. Our study is one of the largest single-center studies of surgical outcomes comparing RRH with TLRH during cervical cancer treatment and will significantly contribute to the safety of alternative treatment options for patients. Furthermore, the difference detected between TLRH and RRH group is further strengthened by the great expertise of the surgeon performing laparoscopic surgeries. PMID- 28858909 TI - Determinants of Sunburn and Sun Protection of Agricultural Workers During Occupational and Recreational Activities. AB - OBJECTIVE: The aim of this study was to identify determinants of occupational sunburn in agricultural workers and assess their occupational and recreational sun protection habits. METHODS: Specific surveys of agricultural workers in Switzerland and France were conducted (N = 1538). Multivariate logistic regressions identified occupational sunburn determinants. Occupational and recreational sun protection habits were estimated and correlated. RESULTS: One year occupational and recreational sunburn prevalences were 19.8% and 11.5%, respectively. Occupational sunburn increased with having a recent recreational sunburn, highly sensitive skin, young age, high perceived skin cancer risk, using sunscreen, and not wearing a hat. Correlation between protection habits during work and leisure was substantial (rs 0.5 to 0.7). Skin health knowledge was high and pro-tanning attitude moderate. CONCLUSION: Potentially modifiable sunburn determinants and suboptimal recreational and occupational sun protection practices were identified in agricultural workers. Refining and tailoring sun protection messages targeting the agricultural sector are needed. PMID- 28858911 TI - Less-invasive coronary artery bypass grafting international landscape and progress. AB - PURPOSE OF REVIEW: Less-invasive coronary artery bypass grafting (CABG) has evolved in multiple forms. Specifically noteworthy are recent technical refinement and reports of mid-term outcomes from well designed trials and observational studies in off-pump CABG, minimally invasive coronary artery bypass grafting (MICS CABG) and hybrid coronary revascularization (HCR). This review summarizes the historical evolution and recent development in less-invasive coronary artery bypass grafting. RECENT FINDINGS: A recent network meta-analysis of CABG with various degree of aortic manipulation demonstrated that no-touch technique may result in a significant reduction of postoperative stroke risk. A 5 year follow-up data of CORONARY study demonstrated that there was no significant difference in the rate of mortality, repeat revascularization, or primary composite outcome. The first multicenter observational study of HCR and PCI cohorts demonstrated that there was no significant difference in major adverse cardiac and cerebrovascular events at 12 months, with diverging event-free survival favoring HCR toward the end of the study period. SUMMARY: Less-invasive CABG continues to evolve in multiple forms. MICS CABG with the use of bilateral internal thoracic arteries preserves the sternum while allowing for a robust revascularization. HCR augments each form of less-invasive CABG, and is expected to play a larger role in the near future. PMID- 28858910 TI - Digital pathology in nephrology clinical trials, research, and pathology practice. AB - PURPOSE OF REVIEW: In this review, we will discuss (i) how the recent advancements in digital technology and computational engineering are currently applied to nephropathology in the setting of clinical research, trials, and practice; (ii) the benefits of the new digital environment; (iii) how recognizing its challenges provides opportunities for transformation; and (iv) nephropathology in the upcoming era of kidney precision and predictive medicine. RECENT FINDINGS: Recent studies highlighted how new standardized protocols facilitate the harmonization of digital pathology database infrastructure and morphologic, morphometric, and computer-aided quantitative analyses. Digital pathology enables robust protocols for clinical trials and research, with the potential to identify previously underused or unrecognized clinically useful parameters. The integration of digital pathology with molecular signatures is leading the way to establishing clinically relevant morpho-omic taxonomies of renal diseases. SUMMARY: The introduction of digital pathology in clinical research and trials, and the progressive implementation of the modern software ecosystem, opens opportunities for the development of new predictive diagnostic paradigms and computer-aided algorithms, transforming the practice of renal disease into a modern computational science. PMID- 28858912 TI - Compliance of Nurses and Hospitals With Ventilator-Associated Pneumonia Prevention Guidelines: A Middle Eastern Survey. AB - This study was a self-reported cross-sectional survey that investigated nurses' and hospitals' compliance with ventilator-associated pneumonia prevention guidelines and the barriers and factors that affect their level of compliance. A questionnaire was completed by 471 intensive care unit nurses from 16 medical centers in 3 Middle Eastern countries: Jordan, Egypt, and Saudi Arabia. The results show that both nurses and hospitals have insufficient compliance. Previous education, experience, and academic degree were all found to affect nurses' compliance. PMID- 28858913 TI - When nutrition and allergy collide: the rise of anaphylaxis to plant foods. AB - PURPOSE OF REVIEW: Interest in nutrition is increasing, but in the world of internet health gurus, whilst the nutritional benefits of fruits and vegetables are extolled, wheat is often vilified. This review will assess the positive nutritional effects of plant foods in relation to allergy prevention, the effectiveness of gluten-avoidance and the likelihood of anaphylaxis to fruits and vegetables. RECENT FINDINGS: Although the numbers of people who report gluten sensitivity is rising, hard evidence of mass sensitivity to gluten is scant. Also, the avoidance of wheat containing foods could lead to nutritional imbalance and effects on the gut microbiome. The evidence that fruits and vegetables have a protective effect on the development of allergy is inconsistent, although fruit juices may promote beneficial changes to gut microflora. Fruits and vegetables can cause severe allergic reactions, especially due to the presence of lipid transfer proteins, but this is not just a Mediterranean phenomenon, and not limited to peaches. SUMMARY: These findings emphasise the importance of a keeping an open mind about reported reactions to plant foods, to ensure the correct diagnosis is made and nutrition is optimised to prevent any adverse effects of avoidance on the gut microbiome. PMID- 28858915 TI - How to translate the new hospital-acquired and ventilator-associated pneumonia guideline to the bedside. AB - PURPOSE OF REVIEW: Hospital-acquired pneumonia and ventilator-associated pneumonia remain significant causes of morbidity, mortality, and financial burden in the United States and around the globe. Although guidelines for the management of patients with these conditions have been available for several years, implementation remains challenging. Here, we review the most common barriers faced by clinicians in implementing the current guidelines and offer suggestions for improved adherence. RECENT FINDINGS: Recent studies have identified barriers to the implementation of the guidelines regarding management of hospital-acquired and ventilator-associated pneumonia. The most common difficulties encountered are lack of awareness of the guidelines, practice variation among providers delivering care to affected patients, lack of antibiogram information, and lack of antibiotic stewardship programs. SUMMARY: Translating the current hospital acquired and ventilator-associated pneumonia guidelines to the bedside requires understanding of the current barriers affecting care of patients with these conditions. Adopting clinical guidelines facilitates the management of these patients and improves outcomes. Dissemination of the guidelines, provider education, antibiotic stewardship programs, access to local antibiogram information, audit and feedback, electronic tools and leadership commitment are likely to play important roles in guideline implementation. More studies on hospital-acquired and ventilator-associated pneumonia guideline implementation are necessary to identify the most effective interventions. PMID- 28858916 TI - Reducing catheter-associated urinary tract infections in the ICU. AB - PURPOSE OF REVIEW: Patients in the ICU are at higher risk for catheter-associated urinary tract infection (CAUTI) due to more frequent use of catheters and lower threshold for obtaining urine cultures. This review provides a summary of CAUTI reduction strategies that are specific to the intensive care setting. RECENT FINDINGS: The surveillance definition for CAUTI is imprecise and measures catheter-associated bacteriuria rather than true infection. Alternatives have been proposed, but CAUTI rates measured by this definition are currently required to be reported to the Centers for Medicare and Medicaid Services and high CAUTI rates can result in financial penalties. Although CAUTI may not directly result in significant patient harm, it has several indirect patient safety implications and CAUTI reduction has several benefits. Various bundles have been successful at reducing CAUTI both in individual institutions and on larger scales such as healthcare networks and entire states. SUMMARY: CAUTI reduction is possible in the ICU through a combination of reduced catheter usage, improved catheter care and stewardship of urine cultures. PMID- 28858914 TI - Neuropathic symptoms of the ocular surface: dryness, pain, and itch. AB - PURPOSE OF REVIEW: This review aims to describe the recent findings on epidemiology, pathophysiology, and management of neuropathic symptoms of the ocular surface, with a focus on potential similarities between sensations of dry eye, pain and itch. RECENT FINDINGS: A narrative review of the literature was undertaken. Key references from research in dry eye, neuropathic symptoms of the ocular surface, ocular pain and itch, as well as general references on itch and pain neurobiology were included. Recent findings suggest aspects of dry eye, chronic ocular pain and itch symptomatology are driven by neuropathic pain mechanisms involving peripheral and central sensitization processes. SUMMARY: Ocular dryness, pain, and itch are prevalent complaints with several of shared features. Multiple lines of evidence suggest that peripheral and central neuronal sensitization processes are involved in generating and maintaining ocular sensory symptoms. Research is warranted on the epidemiology of ocular sensations, molecular mechanisms involved in nociception and pruriception in the eye, electrophysiological alterations in animal models of eye conditions, and therapeutic modalities that can alleviate unpleasant ocular sensations. PMID- 28858917 TI - Why do we fail to deliver evidence-based practice in critical care medicine? AB - PURPOSE OF REVIEW: The use of evidence-based practices in clinical practice is frequently inadequate. Recent research has uncovered many barriers to the implementation of evidence-based practices in critical care medicine. Using a comprehensive conceptual framework, this review identifies and classifies the barriers to implementation of several major critical care evidence-based practices. RECENT FINDINGS: The many barriers that have been recently identified can be classified into domains of the consolidated framework for implementation research (CFIR). Barriers to the management of patients with acute respiratory distress syndrome (ARDS) include ARDS under-recognition. Barriers to the use of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility (ABCDE) bundle for mechanically ventilated patients and the sepsis bundle include patient-related, clinician-related, protocol-related, contextual-related, and intervention-related factors. Although these many barriers can be classified into all five CFIR domains (intervention, outer setting, inner setting, individuals, and process), most barriers fall within the individuals and inner setting domains. SUMMARY: There are many barriers to the implementation of evidence-based practice in critical care medicine. Systematically classifying these barriers allows implementation researchers and clinicians to design targeted implementation strategies, giving them the greatest chance of success in improving the use of evidence-based practice. PMID- 28858918 TI - Implementation of the Surviving Sepsis Campaign guidelines. AB - PURPOSE OF REVIEW: Early identification and appropriate management of sepsis improves outcomes. Despite convincing data showing the benefits of early recognition and treatment of sepsis and septic shock, implementation of such evidence-based therapy is suboptimal. This review describes methods that have been shown to improve bedside application of the evidence-based guidelines. RECENT FINDINGS: The Surviving Sepsis Campaign (SSC) has developed guidelines for the management of severe sepsis and septic shock. The initial SSC guidelines were published in 2004; as evidence continued to evolve, the guidelines were updated, with the most recent iteration published in 2016. Guidelines by themselves can take years to change clinical practice. To affect more rapid change, the SSC guidelines are filtered into bundles to impact behavior change in a simple and uniform way. SUMMARY: Implementation of the SSC bundles revolves around practice improvement measures. Hospitals that have successfully implemented these bundles have consistently shown improved outcomes and reductions in healthcare spending. Finally, the Centers for Medicare and Medicaid Services has approved SSC bundle compliance as a core measure, and hospitals in the United States are mandated to collect and report their data regularly to Centers for Medicare and Medicaid Services. PMID- 28858919 TI - Delayed Paleness After Hyaluronic Acid Filler Injection: A Warning Sign of Vascular Compromise. PMID- 28858920 TI - Measuring Cutaneous Lesions: Trends in Clinical Practice. AB - BACKGROUND: Knowing the size of a cutaneous lesion can be important for tracking its progression over time, selecting the proper treatment modality, surgical planning, determining prognosis, and accurate billing. However, providers vary in their consistency, accuracy, and methods of measuring cutaneous lesions. OBJECTIVE: To investigate the clinical practices of US dermatologists and dermatologic surgeons regarding how they determine the size of cutaneous lesions. MATERIALS AND METHODS: A survey was electronically distributed to members of the American Society for Dermatologic Surgery. RESULTS: Four hundred twenty-six dermatologists completed the online survey. When a lesion is suspected to be malignant, 85% of respondents obtained exact measurements most, if not all, of the time; however, only 8% did for benign lesions. Most providers determined lesion sizes themselves rather than delegating to staff. When performing visual estimation, approximately three-quarters believed that they were accurate to within 1 to 2 mm. The top reasons for obtaining exact measurements were for tracking atypical pigmented lesions, determining treatment pathways, and accurate billing. CONCLUSION: The majority of respondents believed that lesion size affected management decisions; however, the need for exact measurement remains controversial, particularly for benign lesions. Future studies may investigate whether taking exact versus estimated measurements has an effect on outcomes. PMID- 28858921 TI - A Novel Mohs Precision Tool. AB - BACKGROUND: Effective treatment by Mohs micrographic surgery requires preparation of high-quality slides. OBJECTIVE: To examine a novel tissue alignment device designed to address variability in tissue processing because of excessive sample trimming. MATERIALS AND METHODS: A device was designed to account for angular errors and unparalleled tissue embedding. A retrospective chart review was performed both with and without the use of the device over the course of a 4-year period (2012-2015). RESULTS: Between January 1, 2012, and June 10, 2014, before device implementation, mean number of stages per case was 1.65 (n = 3,680) and mean number of surgeries per day was 6.34 (n = 640). Between June 11, 2014, and October 02, 2015, with device implemented, the average number of stages per case between decreased to 1.58 (n = 2,562) and the number of daily surgeries increased to 7.05 (n = 358). This represents a significant decrease in number of stages per case by 0.07 stages (95% CI: -0.01 to -0.13, p = .02), as well as an increase in the number of cases per day by 0.71 cases (95% CI: 0.12-1.3, p < .01). CONCLUSION: Slide preparation using the novel alignment device may result in less tissue waste and more cases being performed daily. PMID- 28858922 TI - Videodermoscopy and Curettage: The Value of Simple Procedures During Mohs Surgery. AB - BACKGROUND: Mohs surgery (MS) is regarded as one of the most efficient surgical procedures for the treatment of skin tumors. OBJECTIVES: Delineating tumor margins accurately is important in limiting broad excisions during conventional surgery and in reducing the number of stages during Mohs procedure. METHODS: This study aimed to evaluate the role of 2 simple procedures, curettage and videodermoscopy (VDS), in determining margins during MS for the treatment of basal cell carcinoma (BCC) of the head and neck. RESULTS: The use of both procedures offered a good intraoperative margin definition and consequently small surgical defects in 197 patients affected by BCC. Recurrences in basal cell cancers, which included both primary and recurrent lesions, occurred less frequently than in the institution's previous experience, appearing in only 8 of 197 cases (approx. 4%). CONCLUSION: In the authors' experience, both VDS and curettage were found advantageous in delineating tumor margins while treating BCC with MS. PMID- 28858923 TI - Repair of 2 Nearby Cheek Defects. PMID- 28858924 TI - Validation and Application of the Webb and Rivera Score in the Academic Setting. PMID- 28858925 TI - Pulsed Dye Laser at Subpurpuric Settings for the Treatment of Pulsed Dye Laser Induced Ecchymoses in Patients With Port-Wine Stains. AB - BACKGROUND: Post-procedure purpura is a major complaint of patients with port wine stains (PWSs) treated with pulsed dye laser (PDL). OBJECTIVE: To assess the safety and efficacy of using PDL at nonpurpuric settings to treat ecchymoses that develop within PWSs after treatment with PDL. MATERIALS AND METHODS: Prospective, randomized, controlled study using 595-nm PDL for treatment of PWSs and laser induced ecchymoses. Port-wine stains were treated in entirety at baseline. Two days later, ecchymoses on randomly selected half of the lesion were re-treated with PDL at subpurpuric settings. Treatment series was repeated 4 to 8 weeks later, and follow-up was at 1 month. Reduction in bruising and PWS clearance were assessed. Three masked evaluators graded clinical improvement using a 4-point scale (1 = 1%-25% improvement, 2 = 26%-50% improvement, 3 = 51%-75% improvement, and 4 = 76%-100% improvement). RESULTS: Twenty adults with 21 PWSs on the head, trunk, and extremities were treated. After first treatment, reduction of bruising was graded a mean value of 2.43 for the treatment side, compared with 1.93 for the control side (p = .012); after the second treatment, 2.83 compared with 2.40 (p = .021). No significant adverse events occurred. CONCLUSION: Pulsed dye laser can be used safely and effectively to reduce treatment-induced purpura in patients with PWSs. PMID- 28858926 TI - A Prospective, Open-Label Study of Hyaluronic Acid-Based Filler With Lidocaine (VYC-15L) Treatment for the Correction of Infraorbital Skin Depressions. AB - BACKGROUND: Infraorbital skin depressions are one of the most troublesome facial areas for aesthetically aware patients. OBJECTIVE: Evaluate effectiveness and safety of Juvederm Volbella with Lidocaine (VYC-15L; Allergan plc, Dublin, Ireland) for correction of bilateral infraorbital depressions. METHODS: In this 12-month, prospective, uncontrolled, open-label study, subjects aged >=18 years with infraorbital depressions rated >=1 on the Allergan Infra-oRbital Scale (AIRS) received injections of VYC-15L with optional touch-up treatment on Day 14. The primary efficacy measure was >=1 AIRS grade improvement from baseline at month 1. RESULTS: Of 80 subjects initially treated with VYC-15L, 75 (94%) completed the study. All injections were intentionally deep, most using multiple microbolus technique. At 1 month, 99.3% of eyes achieved >=1 AIRS grade improvement. The responder rate (subjects with >=1 AIRS grade improvement in both eyes) was 99% at month 1, 92% at month 6, and 54% at month 12. Most injection site reactions (e.g., bruising, redness, irregularities/bumps) were mild and resolved by day 14. Late-onset mild to moderate edema was observed in 11% of eyes at month 6% and 4% of eyes at month 12. CONCLUSION: VYC-15L is effective and safe for the treatment of infraorbital depressions, with effectiveness lasting up to 12 months. PMID- 28858927 TI - Clinical and Histologic Evaluation of Ingenol Mebutate 0.015% Gel for the Cosmetic Improvement of Photoaged Skin. AB - BACKGROUND: No studies have examined the use of topical ingenol mebutate for improvement of photoaged skin. OBJECTIVE: To evaluate clinical results of ingenol mebutate gel applied to photoaged skin and to quantify improvement at 7, 30, and 60 days after application. MATERIALS AND METHODS: Twenty-five subjects were enrolled in the study. Picato (ingenol mebutate) (LEO Pharma, Parsippany, NJ) gel was applied to an area with a known actinic keratosis daily for 3 days. Subjects self-evaluated and were investigator evaluated on 6 characteristics on Days 7, 30, and 60 using an objective scale. The scale evaluated actinic keratosis, overall skin appearance, wrinkling, dyschromia, erythema, and texture. The subjects were also evaluated using the Griffiths' Photonumeric Photoaging Scale for overall improvement. RESULTS: Twenty-two subjects completed the clinical study and demonstrated statistically significant improvement by Day 60 in actinic keratosis, overall skin appearance, wrinkling, dyschromia, erythema, and texture (p < .05). CONCLUSION: Topical ingenol mebutate 0.015% gel produces cosmetic improvement of photoaged skin within 60 days of application. PMID- 28858928 TI - Marginal Mandibular Versus Pseudo-Marginal Mandibular Nerve Injury With Submandibular Deoxycholic Acid Injection. PMID- 28858929 TI - Pearly Facial Nodule as a Presentation of Late Metastasis of Retroperitoneal Leiomyosarcoma. PMID- 28858930 TI - Orifice Preserving Double Opposing Z-Plasty for Partial Split Ear Lobe Repair: A Review of 25 Cases. AB - BACKGROUND: Surgeons often come across split earlobe (SEL) deformities in their clinical practice which usually result from wearing heavy earrings for a long duration. It is of utmost importance to achieve a satisfactory repair with increased strength in one go. OBJECTIVE: To describe a strong repair for partial SEL with preservation of the orifice. MATERIALS AND METHODS: This study is a retrospective review of 25 patients (36 earlobes), who underwent repair of partial SEL deformity with an orifice preserving double opposing Z-plasty in the hospital, from January 2014 to June 2015. The duration of follow-up was 12 months. RESULTS: Adequate cosmetic results were obtained in all patients with no need for revision surgery due to recurrence or scar dehiscence. Patients did not report any difficulty in wearing earrings and were satisfied with the aesthetic outcome. CONCLUSION: The orifice preserving double opposing Z-plasty technique seems to offer an efficacious method of repair of partial SEL deformity with an acceptable scar. The technique is simple and reproducible with good aesthetic outcomes and minimal complications. PMID- 28858931 TI - Venous Treatment of Lipodermatosclerosis to Improve Ambulatory Function. PMID- 28858932 TI - Utilization of Topographical Mohs Micrographic Surgery Maps for Rapid Review of Clinicopathologic Characteristics of Nonmelanoma Skin Cancers of the Ear. AB - BACKGROUND: Nonmelanoma skin cancers (NMSCs) of the ear are considered high risk. Precise location of tumor sites is important when identifying surgical treatment sites. OBJECTIVE: Review precise locations and histopathologic subtypes of auricular NMSC treated with Mohs micrographic surgery (MMS) using a standardized topographical numbering system for rapid data extraction. MATERIALS AND METHODS: Using a MMS topographical number system, the author performed a retrospective chart review of 649 consecutive patients treated with MMS at Mayo Clinic for primary cutaneous basal cell carcinomas (BCCs) or squamous cell carcinomas (SCCs) of the ear. RESULTS: Nineteen percent of consecutively referred patients had NMSC of the ear. Fifty-four percent were SCC and 42% were BCC. The left superior helix was the most common auricular location treated with MMS. Fifty-three percent of BCC on the ear were nodular. Seventy percent SCC on the ears were well differentiated. Contrary to previous studies, basosquamous carcinoma had strong predilection for the posterior ear (80%). CONCLUSION: Higher incidence of auricular NMSC in men was confirmed with SCC being most common. Searching the medical record for specific topographical numbers allowed for rapid investigation of precise anatomic locations of NMSC. This technique may allow for focused research and rapid data extraction when anatomic location is the primary search criterion. PMID- 28858933 TI - Male Body Contouring. AB - BACKGROUND: Men are increasingly seeking out cosmetic procedures, especially minimally and noninvasive body-contouring procedures. OBJECTIVE: With the relative lack of scientific evidence related specifically to the use of body contouring procedures in men, there is a need for more education and scientific discussion in this growing group. MATERIALS AND METHODS: Understanding the male anatomy and aesthetics, and how body-contouring techniques and new modalities can be used in men, can lead to better outcomes. CONCLUSIONS: This review of body contouring in men emphasizes currently available literature and author experiences. PMID- 28858934 TI - Cutaneous Metastases of Melanoma Affecting Exclusively Skin Graft Donor and Receiving Sites: A Novel Clinical Presentation. PMID- 28858935 TI - Facial Soft Tissue Augmentation in Males: An Anatomical and Practical Approach. AB - BACKGROUND: Soft tissue augmentation is increasingly being performed to treat male facial aging. OBJECTIVE: To review anatomical consideration specific for the male face and define an approach to male soft tissue augmentation that creates harmonious and natural results. CONCLUSION: Addressing aesthetic concerns in the upper face, midface, and lower face should be performed in concert with a combinatorial and pan facial approach. Correct filler placement at different areas of concern is important to achieve desired and natural results. Dermal and subcutaneous fillers can be used successfully in the male patient to enhance facial features, correct volume loss, and improve features of aging. PMID- 28858936 TI - Pathologists' Use of Second Opinions in Interpretation of Melanocytic Cutaneous Lesions: Policies, Practices, and Perceptions. AB - BACKGROUND: Research examining the role of second opinions in pathology for diagnosis of melanocytic lesions is limited. OBJECTIVE: To assess current laboratory policies, clinical use of second opinions, and pathologists' perceptions of second opinions for melanocytic lesions. MATERIALS AND METHODS: Cross-sectional data collected from 207 pathologists in 10 US states who diagnose melanocytic lesions. The web-based survey ascertained pathologists' professional information, laboratory second opinion policy, use of second opinions, and perceptions of second opinion value for melanocytic lesions. RESULTS: Laboratory policies required second opinions for 31% of pathologists and most commonly required for melanoma in situ (26%) and invasive melanoma (30%). In practice, most pathologists reported requesting second opinions for melanocytic tumors of uncertain malignant potential (85%) and atypical Spitzoid lesions (88%). Most pathologists perceived that second opinions increased interpretive accuracy (78%) and protected them from malpractice lawsuits (62%). CONCLUSION: Use of second opinions in clinical practice is greater than that required by laboratory policies, especially for melanocytic tumors of uncertain malignant potential and atypical Spitzoid lesions. Quality of care in surgical interventions for atypical melanocytic proliferations critically depends on the accuracy of diagnosis in pathology reporting. Future research should examine the extent to which second opinions improve accuracy of melanocytic lesion diagnosis. PMID- 28858937 TI - Paramedian Forehead Flap Salvage Through Pedicle Full-Thickness Skin Graft. PMID- 28858938 TI - Pilot Study Examining the Safety and Efficacy of Calcium Hydroxylapatite Filler With Integral Lidocaine Over a 12-Month Period to Correct Temporal Fossa Volume Loss. AB - BACKGROUND: Age-related volume loss in the temporal fossae is due to thinning of the epidermis, loss of subcutaneous structural volume, and change in the bony architecture. Temporal concavities are important areas of 3-dimensional volume restoration. The temporal fossae is becoming an increasingly popular area for patients seeking soft tissue augmentation with injectable fillers such as calcium hydroxylapatite with integral lidocaine [CaHA (+)]. OBJECTIVE: This pilot study aims to define the safety, efficacy, technique, and patient-reported outcomes for injectable CaHA (+) to correct volume loss in the temporal fossae over a 12-month period. MATERIALS AND METHODS: This was a single-investigator, nonblinded study involving 20 participants. Participants received filler injection into their temporal fossae, with follow-up evaluations at Day 14, 6 weeks, and 3, 6, 9, and 12 months. RESULTS: CaHA (+) results in statistically significant improvement in temporal fossae appearance lasting up to 12 months. Subjects reported "moderate" global aesthetic improvement over the 12-month period. CONCLUSION: As the cosmetic field continues to advance, it is important for practitioners to have access to research regarding the efficacy and safety of injectables. These results show that CaHA (+) is an effective and safe option to correct temporal fossae volume loss associated with high patient satisfaction. PMID- 28858939 TI - Beyond Abdominal Pain: Pain Beliefs, Pain Affect, and Distress as Determinants of Quality of Life in Patients With Chronic Pancreatitis. AB - GOALS: To assess the relationship between pain, psychological processes, and quality of life (QOL) in chronic pancreatitis (CP). BACKGROUND: CP is a progressive inflammatory disorder of the pancreas characteristically resulting in abdominal pain and impairing QOL. Pain due to CP is poorly understood and frequently difficult to treat. This pain has historically been understood as a peripheral process originating from the pancreas itself, but a growing body of literature is revealing an important role offered by central influences. Viewed through the perspective of the biopsychosocial model of illness, cognitive variables strongly influence QOL. However, there is little understanding of variables that influence QOL in CP. STUDY: Patients with CP from the University of Alabama at Birmingham were administered a 165-question test battery which was comprised of questionnaires evaluating pain beliefs, disease-specific QOL, psychological distress, pain sensation, pain affect, and long-term suffering. RESULTS: Sixty-eight subjects completed the question battery between February 28, 2011 and January 16, 2014. Almost all (91.2%) reported taking pain medication. QOL was significantly associated with reported levels of pain intensity (r=-0.52, P<0.01) as well as perceived self-blame. CONCLUSIONS: The significant predictors of QOL impairment in CP are pain intensity and perceived self-blame for pain. Further research is needed to elucidate this relationship while also evaluating the effectiveness of systematic modification of these variables in an attempt to improve pain and QOL in CP. PMID- 28858940 TI - Fat-soluble Vitamin Deficiencies and Inflammatory Bowel Disease: Systematic Review and Meta-Analysis. AB - BACKGROUND: Vitamin deficiency is frequently associated with inflammatory bowel disease (IBD). Supplementation of vitamins could thus serve as an adjunctive therapy. The present meta-analysis reviews the deficiencies and alterations in serum fat-soluble vitamins (A, D, E, and K) reported in IBD patients. MATERIALS AND METHODS: PubMed database search was performed to identify all primary studies up to January 2015 that evaluated the serum concentrations of fat-soluble vitamin levels in IBD patients compared with healthy individuals. We estimated pooled mean differences between groups and estimated their relations with some compounding variables (age, disease duration, C-reactive protein, albumin), using a meta-regression analysis. RESULTS: Nineteen case-control studies met selection criteria. In patients with Crohn's disease (CD), vitamin A, D, E, K status was lower than in controls [D=212 MUg/L.92; 95% confidence interval (CI), 95.36 330.48 MUg/L, P=0.0002; D=6.97 nmol/L, 95% CI, 1.61-12.32 nmol/L, P=0.01; D=4.72 MUmol/L, 95% CI, 1.60-7.84 MUmol/L, P=0.003; D=1.46 ng/mL, 95% CI, 0.48-2.43 ng/mL, P=0.003, respectively]. Patients with ulcerative colitis had lower levels of vitamin A than controls (D=223.22 MUg/L, 95% CI, 44.32-402.12 MUg/L, P=0.01). Patients suffering from CD for a longer time had lower levels of vitamins A (95% CI=7.1-67.58 y, P=0.02) and K (95% CI, 0.09-0.71 y, P=0.02). Meta-regression analysis demonstrated statistically significant associations between the levels of inflammatory biomarkers: C-reactive protein (P=0.03, 95% CI, -9.74 to -0.6 mgl/L) and albumin (P=0.0003, 95% CI, 402.76-1361.98 g/dL), and vitamin A status in CD patients. CONCLUSION: Our meta-analysis shows that the levels of fat soluble vitamins are generally lower in patients with inflammatory bowel diseases and their supplementation is undoubtedly indicated. PMID- 28858941 TI - Regional and National Variations in Reasons for Gluten Avoidance. AB - BACKGROUND: Although studies have assessed the prevalence of celiac disease (CD), less is known about the prevalence of gluten avoidance because of nonceliac gluten sensitivity (GS). The avoidance of foods other than gluten is also understudied in these 2 groups. METHODS: Participants visiting a web site for information about a newly developed portable gluten detection device (Nima) were instructed to complete questions about food and gluten avoidance patterns. We assessed the relative proportion of CD and GS across world regions and United States (US) regions and determined the distribution of food avoidance patterns. RESULTS: CD was reported in 6474 respondents and GS in 2597 respondents. Within the United States, the majority of avoiders of gluten reported having CD (69.8%), with the highest ratio of CD to GS in the Northeast (CD: 74.3%; GS: 25.7%) and the lowest in the West (CD: 67.1%; GS: 32.9%) (P<0.0001). Compared with the United States, all other countries had lower proportions of GS, with the lowest in Argentina (CD: 94.7%; GS: 5.3%; P<0.0001). Food avoidances other than gluten were reported by 25% of respondents, with avoidance in all categories more common in GS than CD (P<0.0001). CONCLUSION: There is a significant difference in the relative rates of CD and GS within the United States and worldwide. Food avoidance other than gluten seems to be a more common component of GS than CD. Future research should focus on the causes of these international and US regional differences and the significance of other food avoidances. PMID- 28858942 TI - Colonoscopy in Patients With Postmyocardial Infarction Gastrointestinal Bleeding: A Nationwide Analysis. AB - GOALS: The goal of this study was to evaluate outcomes of colonoscopy in the setting of post myocardial infarction (MI) gastrointestinal bleeding (GIB) in a large population-based data set. BACKGROUND: The literature to substantiate the proposed safety of colonoscopy following an acute MI is limited. STUDY: The Nationwide Inpatient Sample (2007 to 2013) was utilized to identify all adult patients (age, 18 y or above) hospitalized with a primary diagnosis of ST elevation MI and receiving left heart catheterization (STEMI-C). The outcomes of patients with concomitant diagnosis of GIB receiving endoscopic intervention with esophagogastroduodenoscopy (EGD) or colonoscopy postcatheterization were compared with those who did not. Primary outcomes including mortality, length of stay, and hospital costs were evaluated with univariate and multivariate analysis. RESULTS: There were 131,752 patients with post-STEMI-C GIB (5.35% of all STEMI-C patients) and same admission colonoscopy was performed in 1599 patients (1.21%). Although the prevalence of post-STEMI-C GIB increased from 4.27% in 2007 to 5.87% in 2013 (P<0.001), patients receiving colonoscopy decreased from 1.42% to 1.09% (P<0.001) over the course of the study period. Multivariate analysis revealed that patients receiving no endoscopic intervention [odds ratio, 3.61; 95% confidence interval: 1.57, 8.31] or EGD alone (OR, 2.70; 95% confidence interval: 1.12, 6.49) have higher mortality compared with those receiving colonoscopy. CONCLUSIONS: Same admission colonoscopy performed for post-STEMI-C GIB was associated with lower mortality. However, despite increased incidence of GIB in these patients during the study period, a lower percentage of patients received colonoscopy. These results suggest that colonoscopy is safe but underutilized in this setting. PMID- 28858943 TI - Increased Risk of Mortality Associated With Pancreatic Exocrine Insufficiency in Patients With Chronic Pancreatitis. AB - BACKGROUND: Pancreatic exocrine insufficiency (PEI) is a common serious complication in chronic pancreatitis (CP); however, little is known about its effect on mortality in these patients. In this study, we assessed the mortality risk of PEI in patients with CP. STUDY: A prospective, longitudinal cohort study conducted in patients with CP under long-term follow-up. CP and PEI were diagnosed using pancreatic imaging and the C-labeled mixed triglyceride breath test, respectively. Multivariate analysis was performed to evaluate the impact of PEI and other clinical features on mortality risk. RESULTS: Patients (N=430) were analyzed (79.1% male; mean age, 47.8 y) during a mean follow-up of 8.6+/-4.6 years. PEI prevalence was 29.3% and mortality was 10.9%. Most frequent causes of death were cancer (40.4%), infection (21.3%), and acute cardiovascular event (14.9%). Multivariate analyses showed associations between increased mortality and presence of PEI [hazard ratio (HR), 2.59; 95% confidence interval (CI), 1.42 4.71; P<0.003], liver cirrhosis (HR, 3.87; 95% CI, 1.95-7.69; P<0.001), age at diagnosis (HR, 1.05; 95% CI, 1.03-1.09; P<0.001), toxic etiology of CP (HR, 3.11; 95% CI, 1.11-8.70; P<0.05) and respiratory comorbidity (HR, 2.19; 95% CI, 1.12 4.31; P<0.03). Nutritional markers were significantly lower in patients with PEI versus those without PEI (P<0.001) and in those who died versus survivors (P<0.001). CONCLUSIONS: PEI was a significant independent risk factor for mortality in patients with CP. These results support further research into the optimal treatment of PEI to reduce mortality in this population. PMID- 28858944 TI - Rate of Nonsurveillance and Advanced Hepatocellular Carcinoma at Diagnosis in Chronic Liver Disease. AB - AIMS: Ultrasound surveillance for hepatocellular carcinoma (HCC) is recommended in cirrhotic patients to allow early diagnosis. This study investigated risk factors for nonsurveillance and advanced HCC at diagnosis and their effect on survival. MATERIALS AND METHODS: Two hundred seventy HCC patients were included. Clinical data were collected from hospital databases. RESULTS: One hundred twenty eight (47.1%) patients had 6-monthly ultrasound surveillance before HCC diagnosis. Ninety-two (34.1%) patients had advanced HCC (multifocal or total diameter >=6 cm) at diagnosis. The nonsurveillance rate was significantly higher in nonalcoholic fatty liver disease (NAFLD) (79%) compared with other causes of chronic liver disease (31.6% to 58.1%, P<0.001). Nonrecognition of NAFLD was significantly higher (68.4%) compared with other causes of chronic liver disease (0% to 23.2%, P<0.001). In NAFLD HCC patients, 23.7% were noncirrhotic and smoking was significantly associated HCC in this noncirrhotic group (P=0.041). No surveillance for HCC was significantly associated with advanced HCC at diagnosis with an odds ratio (OR) of 8.1. Compared with nondrinkers, heavy alcohol consumption was significantly associated with advanced HCC (OR=7.6). In the surveillance group, diagnosis using computed tomography rather than magnetic resonance imaging was significantly associated with advanced HCC (OR=3.36). Patients without HCC surveillance had a significantly shorter median survival compared with those who had HCC surveillance (27.4 vs. 52.0 mo, P=0.0006). CONCLUSIONS: The lack of HCC surveillance is associated with advanced HCC at diagnosis and decreased survival. NAFLD patients with HCC have a significantly lower rate of diagnosis of chronic liver disease and HCC surveillance compared with the other causes of chronic liver disease. PMID- 28858945 TI - Impact of Insurance Status and Race on Outcomes in Nonvariceal Upper Gastrointestinal Hemorrhage: A Nationwide Analysis. AB - BACKGROUND AND GOALS: We examined the interaction between race, insurance, and important outcomes in nonvariceal upper gastrointestinal hemorrhage (NVUGIH). STUDY: Adults with NVUGIH were selected from the National Inpatient Sample. PRIMARY OUTCOME: in-hospital mortality. SECONDARY OUTCOMES: treatment modalities [esophagogastroduodenoscopy (EGD), early EGD, and endoscopic or radiologic therapy], and resource utilization (length of hospital stay and total hospitalization charges). RESULTS: Mortality was similar for Medicare and private insurance [adjusted odds ratios (aOR): 1.15 95% confidence interval (CI) 0.90 to 1.47), P=0.24], but higher for under/uninsured patients [aOR: 1.84 (CI: 1.42 to 2.40), P<0.01]. Compared with Medicare, patients with private insurance had more EGDs [aOR: 1.35 (CI: 1.23 to 1.48), P<0.01], early EGDs [aOR: 1.29 (CI: 1.21 to 1.38), P<0.01], and endoscopic [aOR: 1.19 (CI: 1.11 to 1.27), P<0.01], or radiologic therapy [aOR:1.35 (CI: 1.06 to 1.71), P=0.01]. Patients who were under/uninsured had less EGDs [aOR: 0.84 (CI: 0.76 to 0.91), P<0.01] or endoscopic therapy [aOR: 0.74 (CI: 0.68 to 0.81), P<0.01], but similar odds of early EGD [aOR: 0.95 (CI: 0.88 to 1.02), P=0.13] or radiologic therapy [aOR: 1.01 (CI: 0.75 to 1.37), P=0.75]. Compared with whites, blacks had lower [aOR: 0.73 (CI: 0.58 to 0.93), P=0.01] and Native Americans higher mortality [aOR: 2.60 (CI: 1.57 to 4.13), P<0.01]. Blacks were less likely [aOR: 0.86 (CI: 0.79 to 0.94), P<0.01] and Asians more likely [aOR: 1.24 (CI: 1.05 to 1.47), P=0.01] to have EGDs. Both blacks and Hispanics had lower, whereas Asians had higher early EGD rates. Patients with private insurance had lower total charges [adjusted mean difference: -$2761 (CI: -$4617 to -$906), P<0.01]. CONCLUSIONS: Insurance and race have independent effects on NVUGIH mortality, therapeutic modalities used, and resource utilization. Black and under/uninsured patients have the worst outcomes. PMID- 28858946 TI - Facts and Fantasies on Extraesophageal Reflux: A Gastroenterologist Perspective. AB - Gastroesophageal reflux disease encompasses a wide spectrum of disorders related to the reflux of gastric contents into the esophagus. Extraesophageal reflux (EER) may be suspected in patients with unexplained chronic cough, pharyngolaryngeal symptoms, and asthma. For physicians, suspected EER is challenging as there is currently no tool that can reliably make a definitive diagnosis. Endoscopic signs are not specific, pharyngeal and proximal reflux monitoring are not reliable, and if distal pH or pH-impedance monitoring can identify patients with abnormal reflux, they cannot predict the response to therapy. Controlled randomized trials have failed to reliably demonstrate any benefit of high-dose proton-pump inhibitors over placebo in patients with laryngeal symptoms, chronic cough, and asthma. Overall, the role of gastroesophageal reflux has been largely overestimated in patients with suspected EER. Especially when proton-pump inhibitors failed to improve symptoms, other diagnosis should be considered, such as functional laryngeal disorders which are probably much more prevalent in these patients than pathologic gastroesophageal reflux. PMID- 28858947 TI - Is Transcutaneous Endoscopic Necrosectomy Appropriate Method In Managing All Patients With Walled-off Pancreatic Necrosis That Extend Into the Paracolic Gutter. PMID- 28858948 TI - Promoting the use of Markovian simulation models to study outcomes of thrombectomy after acute ischemic stroke. PMID- 28858949 TI - ST-segment elevation acute myocardial infarction associated with hyperthyroidism: beware of coronary spasm! PMID- 28858950 TI - Integration of an Individual Simulation-Based Experience Into a Psychomotor Skills Course. PMID- 28858951 TI - Impact of Interactive Video Communication Versus Text-Based Feedback on Teaching, Social, and Cognitive Presence in Online Learning Communities. AB - A key element to online learning is the ability to create a sense of presence to improve learning outcomes. This quasi-experimental study evaluated the impact of interactive video communication versus text-based feedback and found a significant difference between the 2 groups related to teaching, social, and cognitive presence. Recommendations to enhance presence should focus on providing timely feedback, interactive learning experiences, and opportunities for students to establish relationships with peers and faculty. PMID- 28858952 TI - Substance Use Education in Schools of Nursing: A Systematic Review of the Literature. AB - The authors systematically reviewed the nursing literature for articles describing substance use disorders (SUDs) education in schools of nursing. Five literature databases were searched, producing 3107 retrieved articles, of which 12 were included in this review. A Medical Education Research Study Quality Instrument score was calculated for each study. The included studies demonstrated that teaching nursing students about SUDs produced a positive impact on their attitudes, knowledge, and skills. PMID- 28858953 TI - Misconceptions About Genomics Among Nursing Faculty and Students. AB - A comparison of 2 research studies revealed that nursing faculty and students share limited understanding and specific misconceptions about foundational genomic concepts. Mean scores on the Genomic Nursing Concept Inventory were 48% for faculty and 42% for students. Identifying misconceptions is important when designing educational strategies for students who will inevitably care for patients with genomic concerns. Common clinical scenarios requiring accurate interpretation of genomic terminology, gene function and expression, and genetic counseling principles are presented. PMID- 28858954 TI - Curricular Interventions to Promote Self-care in Prelicensure Nursing Students. AB - Personal self-care should be an expectation of the professional nursing role. This study evaluated self-care behaviors and perceptions of prelicensure nursing students after the integration of curricular interventions designed to promote self-care behaviors. Although few statistically significant changes were found, findings indicate that changes were beginning to occur and self-care behaviors were not declining: the curricular interventions are having a positive impact on self-care behaviors in nursing students. PMID- 28858955 TI - Variability in Acuity in Acute Care. AB - OBJECTIVE: This study was designed to describe variable acuity among 1 population of acute care patients. BACKGROUND: Acuity, defined as the individual patient need for nursing care, can inform level of care, nurse staffing, and the nurse-to patient assignment. Nurse-generated data in the electronic health record can be mined and analyzed for decision support. METHODS: This study used a descriptive, retrospective analysis of repeated measures of acuity generated from 28 739 nursing assessments of 405 consecutive subjects treated for heart failure (HF) in a 455-bed southern hospital. RESULTS: Patients treated for HF have variable care needs throughout the course of treatment. Univariate analysis of variance and post hoc analysis found that gender, age, type of unit, and length of stay (LOS) had a significant impact on acuity, P < .01, with a very small effect of less than 1%, indicating that acuity should be measured instead of assumed. Patients in medical-surgical and step-down units had highly variable acuity, ranging from ready to discharge to acuity levels consistent with critical care. Across the LOS, the mean acuity stabilized at 12 hours after admission, decreased until 88 hours, then increased steadily through discharge. CONCLUSIONS: Understanding the variability in acuity within an individual patient, or a specific patient population, will contribute to decision support levels of patient care, staffing, nurse-patient assignments, and the cost of care. Frequent, sequential, and real time measures of acuity may be valuable for tracking patient progress or measuring response to nursing interventions. PMID- 28858956 TI - Factors Facilitating Publication by Clinical Nurses in a Magnet(r) Hospital. AB - OBJECTIVE: This study examined the cognitive, behavioral, and environmental factors that facilitate publication by clinical nurses in Magnet(r) hospitals. BACKGROUND: The culture promoted by the Magnet Recognition Program(r) promotes nurses practicing in those settings to use, generate, and disseminate best practices. Successful and promising models of care and nursing practice are rarely disseminated beyond the organization where they are practiced. The questions persist: what barriers to writing for publication exist for clinical nurses, and how do we overcome them to advance emergent evidence? METHODS: A focused ethnographic, multiple-case study design examined 5 well-published nurses with high levels of dissemination occurring outside the Magnet organization where they were employed. RESULTS: Nurses in this study most often credited cognitive and behavioral factors for promoting publication. Although the organization encouraged peer-reviewed publication, there were limited environmental efforts to support efforts to publish in peer-reviewed journals by clinical nurses. CONCLUSIONS: The results of this case study call for more research on the multifaceted factors that promote publication by clinical nurses in the practice environment. Publication of research in peer-reviewed journals was supported by environmental influences of time to write, collaborative writing opportunities, and supportive and accurate guidance from editors. PMID- 28858957 TI - Addressing Occupational Fatigue in Nurses: Current State of Fatigue Risk Management in Hospitals, Part 2. AB - OBJECTIVE: The aim of this article is to describe the current state of fatigue risk management systems (FRMSs) to address nurse fatigue in hospitals. BACKGROUND: Little is known about the current state of FRMS implementation and adoption of national recommendations in nursing work systems. METHODS: This study used a sequential exploratory mixed-methods design including a survey of nurse leaders from across the United States. RESULTS: Adoption of evidence-based policies to address fatigue is both limited and variable depending on the policy. Nurse leaders indicate that while nurse fatigue is an important issue and has negative consequences, the social norms of fatigue have not allowed the elevation of this topic to trigger sweeping organizational change. CONCLUSIONS: This study provides a framework for implementation of FRMSs as an innovation, highlighting the critical role of nurse leaders in adoption and dissemination. Raising the visibility of fatigue across the organization is a critical 1st step. PMID- 28858958 TI - Chronic Uveitis Following Neodymium-Doped Yttrium Aluminum Garnet Laser Peripheral Iridotomy. AB - PURPOSE: Assessment of a chronic uveitis entity in nonuveitic patients following neodymium-doped yttrium aluminum garnet (Nd:YAG) laser peripheral iridotomy. METHODS: A 7-year retrospective observational case series of 5 patients that developed chronic uveitis following a Nd:YAG laser peripheral iridotomy treatment. RESULTS: Five eyes of 5 nonconsecutive patients had developed chronic anterior uveitis lasting >12 weeks. Four patients were female, with a mean age of 60.3 years (range, 48 to 83 y), and a mean follow-up duration of 8 months after initiation of treatment. CONCLUSIONS: Chronic anterior uveitis should be addressed as a possible risk in patients undergoing Nd:YAG laser iridotomies. A larger prospective study would be necessary in establishing and exploring the association between these 2 entities. PMID- 28858960 TI - Ahmed Valve Upstream Obstruction Caused by Fibrous Ingrowth: Surgical Approach. AB - Glaucoma secondary to penetrating keratoplasty can be challenging and multiple surgeries may be needed to control the intraocular pressure (IOP), including the use of glaucoma drainage implants. However, late failure of these drainage implant surgery is common, mostly because of excessive scarring or bleb encapsulation which may require further surgical intervention. We present a case of a young patient referred for advanced glaucoma secondary to penetrating keratoplasty and chronic uveitis. He presented with elevated IOP under maximal therapy, already with 2 failed trabeculectomies and a nonfunctional Ahmed Valve. As no bleb was seen overlying the plate of the valve, an exploratory surgical revision was scheduled. The cause for defective aqueous humour drainage was identified as a fibrovascular ingrowth into the valve's plate slit. We proceeded with removal of this membrane, as well as confirmation of patency with trypan blue and application of mitomycin C to prevent recurrence of the fibrous ingrowth. With a 6 month follow-up, a diffuse bleb exists over the plate, with IOP values within the target values for this patient (<16 mm Hg). This exploratory procedure identified an unusual cause for drainage device failure, as well as reporting its management without explanting the device. PMID- 28858962 TI - Drug-induced Myopia and Bilateral Angle Closure Secondary to Zolmitriptan. AB - PURPOSE: To describe a unique case of drug-induced transient myopia with angle closure glaucoma in a patient being treated with zolmitriptan for migraines. METHODS: A 42-year-old woman who had been using increasing amounts of zolmitriptan over the previous 12 months presented with an acute myopic shift and raised intraocular pressures (IOP) with anterior chamber shallowing. Clinical examination findings at presentation and at follow-up visits were reviewed. RESULTS: Initial examination revealed unaided visual acuities of 20/100 in the right eye and 20/125 in the left, with IOP measuring 34 mm Hg bilaterally. Zolmitriptan was ceased and the patient was commenced on topical antiglaucoma medication. Within 2 weeks, IOP had normalized, with deepening of the anterior chambers and complete resolution of her myopia. Her final recorded unaided visual acuities were 20/12.5 in the right eye and 20/16 in the left. When topical antiglaucoma medication was ceased the patient developed pressure-related headaches and selective laser trabeculoplasty was performed to minimize the need for long-term topical medication use. CONCLUSION: Idiosyncratic drug reactions resulting in ciliochoroidal effusion, secondary angle closure, and transient myopia are well described, but they have not been previously reported with zolmitriptan use. An awareness of the various potential causative agents is important, as findings are generally reversible if recognized early and if the offending drug is discontinued. PMID- 28858963 TI - IgG4-related disease in the eye and ocular adnexa. AB - PURPOSE OF REVIEW: IgG4-related disease is a multi-organ fibro-inflammatory disease with characteristic histopathology showing lymphoplasmacytic infiltration, increased IgG4+ plasma cells and elevated IgG4/IgG ratios (>40%). The lacrimal gland is the most common ocular site of involvement. Scleritis and intraocular involvement in IgG4-related ophthalmic disease (IgG4-ROD) have recently been reported. The purpose of this review is to describe orbital and intraocular IgG4-ROD with a focus on publications since 2016. RECENT FINDINGS: Case reports of scleritis and uveitis in IgG4-ROD have been described since 2012. Systemic prednisone is recommended as the first-line treatment, but immunosuppressive therapy may be required for steroid-sparing or in steroid resistant cases. High rates of systemic IgG4-RD involvement exist in patients with bilateral IgG4-ROD or if the lacrimal gland is involved. Rituximab is the most specific immune targeted therapy available with high rates of remission. SUMMARY: IgG4-ROD is an emerging cause of scleritis and uveitis and should be considered in any patient with multisystem inflammatory disease. New targeted immune therapies may improve outcomes and lead to clinical remission. PMID- 28858964 TI - Improvement through Small Cycles of Change: Lessons from an Academic Medical Center Emergency Department. AB - This article describes the experiences of a quality improvement team that used small cycles of change to improve the emergency department (ED) of an academic medical center. The role of EDs in the provision of healthcare continues to increase in importance. ED bottlenecks contribute to long waits and diminished outcomes for ED patients as well as more system-wide issues, such as inefficiencies in inpatient admission processes. The purpose of this "ED Operational Efficiency Project" was to reduce lengths of stay (LOS) for low acuity patients. The team used lean management techniques to both improve services and shift the ED culture to prioritize continuous quality improvement. The goal to reduce LOS by 30% was met as the result of several inter=related projects (or small cycles of change). Key lessons include monitoring metrics, communicating with teams and target populations, learning from initial failures, using small wins to increase momentum, and anchoring changes. PMID- 28858965 TI - Stepping Back to Move Forward: Evaluating the Effectiveness of a Diabetes Prevention Program Within a Large Integrated Healthcare Delivery System. AB - OBJECTIVE: To evaluate the short-term effectiveness of the Intermountain Healthcare (IH) Diabetes Prevention Program (DPP) for patients with prediabetes (preDM) deployed within primary care clinics. STUDY DESIGN: A quasi-experimental study design was used to deploy the DPP within the IH system to identify patients with preDM and target a primary goal of a 5% weight loss within 6-12 months of enrollment. STUDY POPULATION: Adults (aged 18-75 years) who met the American Diabetes Association criteria for preDM were included for study. Patients who attended DPP counseling between August 2013 and July 2014 were considered as the intervention (or DPP) group. The DPP group was matched using propensity scores at a 1:4 ratio with a control group of patients with preDM who did not participate in DPP. RESULTS: Of the 17,142 patients who met the inclusion criteria for preDM, 40% had an in-person office visit with their provider. On average, patients were 58 years old, and greater than 60% were women. Based on multivariate logistic regression, the DPP group was more likely to achieve a 5% weight loss within 6-12 months after enrollment (OR = 1.70; 95% CI = 1.29-2.25; p < .001) when compared with the no-DPP group. CONCLUSIONS: Diabetes Prevention Program-based lifestyle interventions demonstrated significant reduction in body weight and incident Type 2 diabetes mellitus when compared with nonenrollees. PMID- 28858966 TI - Using Technology to Support Data Analytics: A Chief Nursing Officer Accountability Scorecard. AB - Accountability for health system improvement is a requirement for nursing leadership in practice. However, to be accountable for organizational goals, nurse leaders need the tools to identify gaps in their microsystems of care. The purpose of this article was to provide a case study example of chief nursing officer (CNO) leadership in using a technology solution to develop a CNO accountability scorecard. This project highlights the HQ Essential for data analytics using an innovative technological approach to drive improvement at the front line of clinical care. PMID- 28858967 TI - Applying Decision Science to the Prioritization of Healthcare-Associated Infection Initiatives. AB - OBJECTIVES: Improving patient quality remains a top priority from the perspectives of both patient outcomes and cost of care. The continuing threat to patient safety has resulted in an increasing number of options for patient safety initiatives, making choices more difficult because of competing priorities. This study provides a proof of concept for using low-cost decision science methods for prioritizing initiatives. METHODS: Using multicriteria decision analysis, we developed a decision support model for aiding the prioritization of the four most common types of healthcare-associated infections: surgical site infections, central line-associated bloodstream infections, ventilator-associated events, and catheter-associated urinary tract infections. In semistructured interviews, we elicited structure and parameter values of a candidate model, which was then validated by six participants with different roles across three urban teaching and nonteaching hospitals in the Baltimore, Maryland area. RESULTS: Participants articulated the following structural attributes of concern: patient harm, monetary costs, patient mortality, reputational effects, and patient satisfaction. A quantitative decision-making model with an associated uncertainty report for prioritizing initiatives related to the four most common types of healthcare-associated infections was then created. CONCLUSIONS: A decision support methodology such as our proof of concept could aid hospital executives in prioritizing the quality improvement initiatives within their hospital, with more complete data. Because hospitals continue to struggle in improving quality of care with tighter budgets, a formal decision support mechanism could be used to objectively prioritize patient safety and quality initiatives. PMID- 28858968 TI - What Wait Time in a Soiled Pad Is Acceptable to Older Patients and Their Direct Caregivers? AB - PURPOSE: We sought to establish views on wait times and hypothesized that they may vary depending upon perspective, circumstance, and incontinence type. DESIGN: Cross-sectional, descriptive survey. SUBJECTS AND SETTING: Eligible patients were inpatients, 65 years and older, in a single tertiary acute care hospital. Eligible staff were regulated (licensed) and unregulated providers of direct care to patients. Patients may or may not have used absorbent continence products prior to their admission. METHODS: We examined views on acceptable and actual wait times of elderly acute care inpatients and their direct care providers (DCPs). Participants were asked about wait times for pads soiled with urine or feces during the day and at night. Differences between patients and DCPs and acceptable and actual wait times were compared. Factors associated with tolerance to the presence of urine or stool in absorptive products were analyzed by logistic regression. RESULTS: There was patient-provider mismatch for daytime urinary incontinence: 90% of patients but only 44% of DCPs reported urinary soiling more than 1 hour in the daytime as unacceptable (38.0 vs 85.0 minutes; P < .0001). A significant majority (80%-90%) of both groups reported short acceptable wait times for fecal incontinence (<15 minutes). The odds of being tolerant to any soiling were significantly higher in patients who were prior residents of care facilities (odds ratio [OR] = 6.2; 95% confidence interval [CI], 1.3-28.1; P = .019), previously used incontinence products (OR = 2.0; 95% CI, 1.0-3.8; P = .036), or used walking aids (OR = 4.0; 95% CI, 1.1-14.7; P = .039). Actual wait times were significantly longer than deemed acceptable by either patients or DCPs. CONCLUSIONS: There are significant gaps in patient provider perspectives on acceptable wait times in soiled incontinence products. Direct care providers need to take patient preference into account when managing continence. PMID- 28858969 TI - Obstructive sleep apnoea of mild severity: should it be treated? AB - PURPOSE OF REVIEW: To provide guidance in the management of mild obstructive sleep apnoea syndrome (OSAS) in the context of a very high prevalence, poor correlation with symptom profile, and lack of evidence that mild OSAS significantly contributes to comorbidity or early mortality. RECENT FINDINGS: Mild obstructive sleep apnoea defined by hourly frequency of apnoeas or hypopnoeas (AHI) between 5 and 15 affects up to 35% of the general adult population but is much less prevalent when associated daytime symptoms are included. The poor correlation between symptoms and AHI complicates diagnosis and reports that mild OSAS is not significantly associated with comorbidity casts doubt on clinical significance. The diagnosis is complicated by night-to-night variability and by underestimation of AHI in ambulatory sleep studies that do not include sleep assessment. Active management of mild OSAS can be symptom-driven and offers a broad range of options. Lifestyle measures may be sufficient in many cases and mandibular advancement devices or positional therapy may be more effective in mild OSAS. Sleepy patients with low AHI may warrant a trial of continuous positive airway pressure therapy to establish the relationship between sleep disordered breathing and symptoms. SUMMARY: Management of mild OSAS can focus on symptom relief to the individual patient. PMID- 28858970 TI - Lung transplantation in cystic fibrosis patients with difficult to treat lung infections. AB - PURPOSE OF REVIEW: In cystic fibrosis (CF) patients with end-stage pulmonary disease, lung transplantation (LTx) remains a life-extending therapy with good outcome in most patients. Despite early concern about chronic pretransplantation infections in the context of posttransplantation immunosuppression, typical CF associated organisms such as Pseudomonas aeruginosa turned out to be quite well manageable and associated with favorable outcomes in transplanted CF patients, even in patients with highly resistant strains. However, the situation is less evident with other pathogens. RECENT FINDINGS: Burkholderia cenocepacia is associated with reduced survival and regarded as a contraindication for LTx in most centers, other Burkholderia species are less problematic. Other resistant Gram-negative bacteria and methicillin-resistant staphylococcus aureus in CF patients are not regarded as a contraindication. Nontuberculous mycobacteria disease in CF patients does not preclude successful recovery after LTx, although postoperative complications can be expected in patients with Mycobacterium abscessus and specific management is indicated. Fungal species should be treated aggressively to limit morbidity after transplantation. SUMMARY: Despite its complexity, LTx is safe in most CF patients, with good outcomes if the pathogens that are present are identified and adequately treated. PMID- 28858971 TI - Effect of Family-Based Education on the Quality of Life of Persons With Type 2 Diabetes: A Randomized Clinical Trial. AB - BACKGROUND: Diabetes, a disease with increasing prevalence, requires comprehensive support from family members to ensure that sufferers are able to perform daily activities. The chronic nature of diabetes and its potential side effects impose high financial costs on patients and families, reduce their quality of life (QOL), and change the lifestyle of both patients and their families. PURPOSE: The aim of this study was to investigate the effects of a family-based training program on QOL in persons with Type 2 diabetes. METHODS: A randomized clinical trial was used to assess the effects of an educational program on QOL both before and after 12 weeks of training for the experimental group (40 patients and families) and of standard care for the control group (40 patients) at an endocrinology clinic in a hospital in Iran. A demographic and social questionnaire and the QOL questionnaire for patients with Type 2 diabetes were used for data collection. The study groups were selected using block randomization sampling, and results were analyzed using descriptive and inferential statistics. RESULTS: Both the experimental and control groups were homogeneousin terms of demographic characteristics and QOL before the intervention. The results of the mean score of patient QOL after the 12-week training program showed a significant difference between the scores for the two groups of patients in the physical, mental, social, economic, disease, and treatment dimensions. Moreover, the total score and QOL of the experimental group improved significantly after the patients' families had attended the training program. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Educating the families of patients was shown in this study to improve the QOL of the patient. The design of educational programs for nursing students must emphasize the role of the family in the care of chronic patients. PMID- 28858972 TI - Influence of Ankle Active Dorsiflexion Movement Guided by Inspiration on the Venous Return From the Lower Limbs: A Prospective Study. AB - BACKGROUND: Active ankle movement is recommended intervention for preventing deep vein thrombosis effectively and easily by promoting venous return from the lower limbs. The active ankle dorsiflexion and plantar flexion movement guided by deep breathing is considered the most effective method, although outstanding problems remain, including low patient compliance and difficult motion essentials. PURPOSE: The aims of this study were to compare the influence of different ankle active movements on venous return from the lower limbs and to suggest the optimal movement for preventing deep venous thrombosis in the lower limbs. METHODS: A self-controlled study on 130 subjects was undertaken. The femoral venous hemodynamics of the left femoral vein and changes in pulse oxygen saturation and heart rate were compared among the three states of quiescent, active ankle 30 degrees dorsiflexion movement, and active ankle 30 degrees dorsiflexion with active plantar 45 degrees flexion movement. The immediate master rates of the two ankle movements were examined before the study. RESULTS: The femoral venous hemodynamics of the left femoral vein were significantly higher in both movement states compared with the quiescent state. Moreover, no significant difference was found among the three states in terms of pulse oxygen saturation and heart rate. The immediate master rate was significantly higher in the active ankle 30 degrees dorsiflexion movement than in the active ankle 30 degrees dorsiflexion and active plantar 45 degrees flexion movement. Therefore, active ankle 30 degrees dorsiflexion movement guided by inspiration was found in this study to increase femoral venous hemodynamics, which heightened the immediate master rate but had no obvious influence on pulse oxygen saturation and heart rate. CONCLUSIONS: Active ankle 30 degrees dorsiflexion movement guided by inspiration effectively promotes venous return from the lower limbs and is a better method to prevent deep vein thrombosis of the lower limbs. PMID- 28858973 TI - An Evolutionary Route for the Moral Development of Nursing Students: A Constructivist Grounded Theory. AB - BACKGROUND: Developing moral competency is a main aim of educational systems, especially in healthcare-related disciplines. PURPOSE: The aim of this study was to explore the moral development process in nursing students. METHODS: This study used a constructivist grounded theory. Twenty-five semistructured, face-to-face interview with 22 participants were conducted to gather the data. The participants were nursing students and educators attending three nursing schools in Tehran. RESULTS: Moral development evolves within nursing students following a stepwise progression. Within each step or phase, students experience specific changes with regard to both their practical skills and their moral capabilities and competencies. Three main steps were identified: moral transition, moral reconstruction, and moral internalization. Techno-scientific competence, biomedical competence, and nursing competence are developed in each step, respectively. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Moral competency in nursing students develops along with their competency as nursing practitioners. To facilitate progress through each phase, it needs to be ensured that the learning experiences that students are exposed to during each consecutive year of study facilitate as much as possible the development of moral competence. PMID- 28858974 TI - Development Trajectories and Predictors of the Role Commitment of Nursing Preceptors. AB - BACKGROUND: The commitment of nursing preceptors to their role is an important driving force that supports their clinical teaching and affects teaching quality. Role commitment undergoes dynamic development and thus changes over time. Existing studies have utilized only cross-sectional study designs and have not analyzed the changes in commitment trajectories with related factors. PURPOSE: This study aimed to investigate the development trajectories of the commitment of preceptors and to examine the predictors between the trajectories of role commitment among nursing preceptors. METHODS: A single-group, repeated-measures design was adopted, and 59 participants completed the Commitment to the Preceptor Role Scale and the Preceptor's Perception of Support Scale. The latent class growth analysis method was used to estimate the trajectory class patterns. The Wilcoxon rank-sum test, a nonparametric method, was used to compare the differences in demographic characteristics between the trajectories of commitment among nursing preceptors. Predictors were examined using binary logistic regression analysis. RESULTS: The two-class model was the best-fitting model to describe the trajectories of nursing preceptor commitment. The two classes in this model were "low commitment," which accounted for 90.3% of all the participants, and "high commitment," which accounted for 9.7%. A significant difference was found between the two classes in terms of motivation for being a preceptor (p = .048). Neither demographic characteristics nor organizational support had a predictive effect on the trajectories of commitment development. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This study found a low level of role commitment among new preceptors. Moreover, internal motivation was found to be a significant factor affecting the trajectories of this commitment. Therefore, institutions should foster an appropriate environment to enhance the role identity of preceptors as well as cultivate and stimulate their commitment to this role. PMID- 28858975 TI - Development and Validation of a Fertility Intention Scale in Breast Cancer Survivors. AB - BACKGROUND: Evidence indicates that breast cancer survivors with reproductive concerns have a poorer quality of life than survivors without fertility concerns. There is a lack of reliable and valid assessments of fertility intention among breast cancer survivors. PURPOSE: The aim of this study was to develop and validate the Fertility Intention Scale (FIS) that is sensitive to the fertility intention of women with breast cancer. METHODS: A literature review and a qualitative study were conducted to generate the items in the scale. Content validity was evaluated by 15 experts, and face validity was assessed by 10 patients with cancer. Factor analysis was used to assess construct validity, and criterion validity was evaluated using two percentile items of fertility willingness. We developed and examined the validity and reliability of the FIS using a sample of 178 patients with breast cancer who had completed chemotherapy. RESULTS: The Cronbach's alpha calculated for the FIS (15 items) was .88. The factor analysis performed for the construct validity of the scale identified four factors that accounted for approximately 68.72% of the total variance. These four factors were pregnancy risk, disease control, social support, and happiness. There was a significant correlation between the total FIS and the level of desiring fertility preservation or pregnancy. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The FIS has acceptable reliability, content validity, and construct validity. This scale is appropriate for use in research and clinical practice settings to evaluate the risk-benefit perceptions of pregnancy in patients with breast cancer. PMID- 28858976 TI - Galectin-3 pharmacological inhibition attenuates early renal damage in spontaneously hypertensive rats. AB - BACKGROUND: The pharmacological blockade of galectin-3 (Gal-3), a beta galactoside-binding lectin, reduces renal impairment in acute kidney injury, hyperaldosteronism or nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in renal damage in spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: Gal-3 inhibition did not modify blood pressure levels in 30-week-old SHR. Kidney weight was higher in SHR, with no effect of MCP treatment (100 mg/kg/day in the drinking water). Plasma creatinine and albuminuria were slightly but significantly increased in SHR and reduced by MCP, as well as plasma and urinary neutrophil gelatinase associated lipocalin. In kidney from SHR, Gal-3 was upregulated, as well as the fibrotic markers (collagen type I, TGF-beta and connective tissue growth factor) and tubulointerstitial fibrosis. MCP treatment reduced Gal-3 levels and fibrosis. The epithelial-mesenchymal transition (EMT) molecules (fibronectin, alpha-smooth muscle actin and beta-catenin) were modified in SHR and normalized by Gal-3 inhibition. The inflammatory mediators (monocyte chemoattractant protein-1, osteopontin, cd68, cd80, cd44 and cd45) were elevated in SHR and attenuated by MCP. Renal damage markers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) were augmented in SHR and improved by MCP. In renal epithelial normal rat kidney-52E cells, Gal-3 treatment induced EMT markers, whereas Gal-3 silencing attenuated EMT. CONCLUSION: Gal-3 inhibition attenuated early renal damage in SHR as indicated by reduced albuminuria, improved renal function and decreased renal fibrosis, EMT and inflammation, independently of blood pressure levels. These data suggest that Gal-3 could be a potential therapeutic candidate for the prevention of early renal alterations in hypertension. PMID- 28858977 TI - The value of uromodulin as a new serum marker to predict decline in renal function. AB - BACKGROUND: Uromodulin is the most abundant protein in urine. Low uromodulin has been found associated with diabetes as well as with chronic kidney disease (CKD). Whether it also predicts a future decline in kidney function is not known. METHODS: We evaluated the association between serum uromodulin and kidney function in 529 patients and performed a genome-wide association study. Clinical parameters including renal function were determined at baseline and reassessed at a 4-year follow-up visit. RESULTS: Patients' serum uromodulin levels were highest associated with a polymorphism in the UMOD coding region and were significantly correlated with estimated glomerular filtration rate (eGFR) (r = 0.242, P < 0.001) and, in an inverse way, with the albumin-creatinine ratio (r = -0.120, P = 0.012). Serum uromodulin concentrations were significantly lower in patients with CKD (eGFR < 60 ml/min per 1.73 m) than in patients with normal kidney function (71.9 +/- 29.0 vs. 169.1 +/- 76.1 ng/ml, P < 0.001) and the same applied to patients with albuminuria (148.7 +/- 72.2 vs. 167.9 +/- 77.6 ng/ml, P = 0.008) or hypertension (160.9 +/- 74.0 vs. 181.8 +/- 87.8 ng/ml, P = 0.037). Prospectively, patients who developed CKD during the follow-up had significantly less uromodulin in serum than those who did not (126.8 +/- 42.3 vs. 180.2 +/- 79.1 ng/ml, P = 0.003). Serum uromodulin concentration was inversely associated with the development of CKD, even after adjustment for patients age, sex, genotype of the identified polymorphism, hypertension and diabetes status, and eGFR (odds ratio = 0.263, P = 0.019), and it significantly increased the performance of a prediction model for CKD (C-statistics 0.844 vs. 0.804, P = 0.049). CONCLUSION: The current study is the first evaluating the value of uromodulin in serum as a novel predictive biomarker for renal function and for the incidence of CKD. PMID- 28858978 TI - Microalbuminuria and plasma aldosterone levels in nondiabetic treatment-naive patients with hypertension. AB - OBJECTIVES: Identification of factors that contribute to urinary albumin losses in hypertensive nephropathy is crucial for prevention of renal deterioration. The aim of this study was to investigate the relationship of low-grade albuminuria with plasma aldosterone levels in treatment-naive hypertensive patients free of additional comorbidities that might affect renal function. METHODS: In 242 newly diagnosed patients with uncomplicated primary hypertension, we obtained duplicate 24-h urine collections for measurement of urinary albumin/creatinine ratio (UACR) and measured plasma aldosterone levels. Patients with diabetes, overt proteinuria (>300 mg/day), glomerular filtration rate less than 30 ml/min per 1.73 m, and previous renal diseases were excluded. RESULTS: Increasing UACR was associated with significantly and progressively higher blood pressure (BP), HDL-cholesterol, and plasma aldosterone levels, and with lower glomerular filtration. Microalbuminuria (30-300 mg/day) was detected in 41 (17%) of 242 hypertensive patients, and these patients had significantly higher BP and plasma aldosterone levels (178 +/- 113 vs. 128 +/- 84 pg/ml; P = 0.001), and lower glomerular filtration than patients without microalbuminuria. UACR was directly and independently correlated with BP and plasma aldosterone levels. In a logistic regression model, presence of microalbuminuria was associated with plasma aldosterone levels independently of glomerular filtration and demographic, anthropometric, and metabolic variables. CONCLUSION: In nondiabetic, treatment naive patients with hypertension, low-grade albuminuria is independently associated with elevated plasma aldosterone. These findings suggest a contribution of aldosterone to the early glomerular changes occurring in hypertensive nephropathy. PMID- 28858979 TI - MiR-195 modulates oxidative stress-induced apoptosis and mitochondrial energy production in human trophoblasts via flavin adenine dinucleotide-dependent oxidoreductase domain-containing protein 1 and pyruvate dehydrogenase phosphatase regulatory subunit. AB - OBJECTIVE: Preeclampsia is a severe pregnancy-specific syndrome defined as newly onset hypertension and proteinuria. Abnormal placental development has been generally accepted as the initial cause of the disorder. Recently, miR-195 was identified as one of the downregulated small RNAs in preeclamptic placentas. METHODS: The potential targets of miR-195 in human trophoblast cells were screened by isobaric tags for relative and absolute quantification-based mass spectrum analysis. Localization of miR-195 and its targets was examined by in situ hybridization and immunohistochemistry in human placenta. Real-time PCR, western blotting and luciferase assay were used for target validation. Apoptosis was accessed by Annexin V/PI costaining, whereas mitochondrial function by ATP measurement and tetramethylrhodamine ethyl ester fluorescence. RESULTS: Two mitochondria-associated proteins, flavin adenine dinucleotide-dependent oxidoreductase domain-containing protein 1 (FOXRED1) and pyruvate dehydrogenase phosphatase regulatory subunit (PDPR), were identified as targets of miR-195. Overexpression of miR-195 in HTR8/SVneo cells resulted in enhanced apoptosis, decreased mitochondrial membrane potential and cellular ATP content upon hydrogen peroxide stimulation. The effects could be partially rescued by FOXRED1 or PDPR. In preeclamptic patients, lowered circulating level of miR-195 were found at early-to-mid gestation and term pregnancy, and marked increase in FOXRED1 and PDPR expression were observed in the placenta when compared with gestational week matched controls. In addition, chronic hydrogen peroxide stimuli suppressed miR 195 expression in trophoblast cells. CONCLUSION: MiR-195 could suppress mitochondrial energy production via targeting FOXRED1 and PDPR, and lead to trophoblast cell apoptosis under oxidative stress. In preeclamptic placenta, lowered level of miR-195 might be induced by chorionic oxidative stress and subsequently form a compensation mechanism to defend the disturbed energy production and cell apoptosis upon oxidative stress. PMID- 28858980 TI - The predictive role of CHA2DS2-VASc score between venous thromboembolism and ischemic stroke: a large-scale cohort study. AB - PURPOSE: This study aimed to explore the predictive role of CHA2DS2-VASc score between venous thromboembolism (VTE) and ischemic stroke. METHODS: The current study was analyzed from the in-patient claims data of the Taiwan National Health Insurance Research Database. We identified the patients diagnosed with VTE (for Study 1) or ischemic stroke (for Study 2) from 1 January 2000 to 31 December 2011 to observe the occurrence of ischemic stroke (for Study 1) and VTE (for Study 2), respectively. We used the CHA2DS2-VASc score to evaluate the risk of ischemic stroke among VTE patients (for Study 1) and to measure the risk of VTE among ischemic stroke patients (for Study 2). The predictive ability of CHA2DS2-VASc score was assessed by C-statistics based on Cox-regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 56 996 patients with VTE (Study 1), whereas a total of 688 556 patients with ischemic stroke (Study 2) were identified. The C-statistics of the CHA2DS2-VASc score for predicting ischemic stroke among VTE patients and for predicting VTE events in patients with ischemic stroke were 0.71 [95% confidence interval (CI) = 0.70 0.72] and 0.61 (95% CI = 0.60-0.62), respectively. Furthermore, among VTE patients, the area under the curve of ROC of CHA2DS2-VASc score predictive of ischemic stroke was 0.66 (95% CI = 0.65-0.67), whereas the area under the curve of ROC of the score predictive of VTE was 0.55 (95% CI = 0.54-0.55) in patients with ischemic stroke. CONCLUSION: Our study is the first to concern the performance of CHA2DS2-VASc score in predicting the risk of ischemic stroke in VTE patients and the risk of VTE in ischemic stroke patients. Nevertheless, the performance of the score was modest, and the transportability of the score in these populations still needs to be defined. PMID- 28858981 TI - Individualizing treatment choices in the systolic blood pressure intervention trial. AB - BACKGROUND: Any treatment decision should be tailored to the individual patients' characteristics. A personalized approach aims to help better selecting the patients who are likely to benefit most from a treatment decision. In the systolic blood pressure intervention trial, intensive treatment reduced the rate of major cardiovascular events, but increased the rate of serious adverse events (SAEs). OBJECTIVES: To assess the trade-off between efficacy and safety to simultaneously quantify an individual patient's absolute benefit and absolute harm, helping clinicians making better therapeutic choices in daily practice. METHODS: Multivariable Poisson regression models were used to identify independent risk factors for: primary composite cardiovascular outcome and major SAEs = safety. Estimates from the models were used to quantify each individual risk. RESULTS: Subclinical cardiovascular disease, number of antihypertensive agents, current smoking, age, urine albumin-to-creatinine ratio, and serum creatinine were associated with increased risk of both primary outcome events and SAEs. Triglycerides were associated with increased primary outcome events only, and chronic kidney disease and female sex with SAEs only. The models were well calibrated and showed good performance (c-index for safety = 0.69 and c-index for efficacy = 0.72). For the primary outcome, there is a steep gradient in risk by fifths of the predicted model and a similar gradient exists for the safety outcome predicted model. Mortality within 1 year of an efficacy outcome (as assessed by the Kaplan-Meier method) was nearly three-fold higher than following a safety outcome (21.9 vs. 7.5%). If one judges the clinical importance of efficacy and safety outcomes based on their 1-year mortality, then there is a net benefit of intensive therapy for almost all patients. CONCLUSION: Antihypertensive treatment intensification is associated with lower cardiovascular event rates; however, it increases the risk of adverse events. However, having adverse events has less weight when it comes to therapeutic decisions and antihypertensive therapy intensification is beneficial for the great majority of patients included in the systolic blood pressure intervention trial. PMID- 28858983 TI - Effects of blood-pressure-lowering treatment on outcome incidence in hypertension. 11. Effects of total cardiovascular risk and achieved blood pressure: overview and meta-analyses of randomized trials. AB - BACKGROUND: In recent meta-analyses of blood pressure (BP)-lowering randomized controlled trials (RCTs), we have shown that in hypertensive patients with diabetes, but not in those without, relative risk reduction of cardiovascular outcomes for a standardized BP reduction is significantly smaller at progressively lower SBP values achieved by treatment. OBJECTIVES: Whether this feature is typical of diabetes or is common to all hypertensive patients at high very high cardiovascular risk is unknown. To clarify these points, we report a new set of meta-analyses, in which BP-lowering RCTs have been stratified in a double way, according to two levels of cardiovascular risk (below and above 5% cardiovascular death in 10 years) and three SBP levels attained by treatment (>=140, 130-139, and <130 mmHg). METHODS: The database consisted of 72 BP lowering RCTs including 260 210 patients, stratified in two ways (cardiovascular risk and achieved SBP) as indicated above. Risk ratios and 95% confidence intervals of six fatal and nonfatal cardiovascular outcomes and all-cause death were calculated (random effects model) for all patients and, separately, for those with and those without diabetes mellitus. Differences between treatment effects at different achieved SBP levels were evaluated by test of homogeneity or trend analysis. RESULTS: When all patients at higher cardiovascular risk were analyzed (46 RCTs, 182 248 patients), no significant difference could be found in the relative risk reduction of any outcome in response to a standard BP reduction at any level of achieved SBP. On the other hand, in patients at a high level of cardiovascular risk, the presence of diabetes (29 RCTs, 52 350 patients) was associated with a significantly smaller outcome benefit of a standardized BP lowering to SBP less than 130 mmHg, and the opposite was found in absence of diabetes (22 RCTs, 102 792 patients). Similar findings were obtained in lower cardiovascular risk patients, but the smaller number of trials and, particularly, events weakens the evidence they provide, particularly on lower risk patients with diabetes. CONCLUSION: A high level of cardiovascular risk is not in itself a restraint to target at SBP values less than 130 mmHg, if treatment is well tolerated. Though a high cardiovascular risk associated with diabetes is not an indication for aiming at SBP less than 130 mmHg, current evidence is that SBP values slightly below 130 mmHg are not associated with harm. PMID- 28858982 TI - Office, standardized and 24-h ambulatory blood pressure and renal function loss in renal transplant patients. AB - OBJECTIVES: Hypertension is a risk factor for renal function loss in kidney transplant patients but there are still no longitudinal studies focusing on the relationship between ambulatory blood pressure (BP) monitoring (ABPM) and the glomerular filtration rate (GFR) evolution over time in these patients. METHODS: In a cohort of 260 renal transplant patients, we investigated the longitudinal relationship between repeated office BP measurements and simultaneous GFR measurements (on average 35 paired measurements per patient) and the relationship between baseline ABPM with the same outcome measure (by linear mixed models). Furthermore, we tested the prediction power of baseline ABPM and standardized BP measurements for a combined renal end point (GFR loss >30%, end-stage kidney disease or death) over a 3.7 years follow-up. RESULTS: Longitudinal office BP measurements were inversely related with simultaneous GFR measurements and the same was true both for baseline daytime and night-time BP. (all P < 0.001). Baseline 24-h ABPM [hazard ratio (5 mmHg):1.11; 95% confidence interval 1.03 1.19] and night-time SBP [hazard ratio (5 mmHg):1.10; 95% confidence interval 1.03-1.17] predicted the combined renal end point and the predictive model based on night-time SBP provided a data-fit superior than that by daytime SBP. CONCLUSION: In renal transplant patients, daytime and night-time SBP predict the risk of GFR loss overtime, and among the various BP metrics, night-time BP is the strongest indicator of the risk of renal function loss. Optimization of BP control and interventions targeting night-time BP may afford renal benefits in transplant patients, a hypothesis that remains to be tested in a clinical trial. PMID- 28858984 TI - Effects of blood-pressure-lowering treatment on outcome incidence. 12. Effects in individuals with high-normal and normal blood pressure: overview and meta analyses of randomized trials. AB - BACKGROUND: It is currently unknown whether individuals with SBP/DBP values in the ranges 120-139/80-89 mmHg, usually defined as with prehypertension or high normal and normal blood pressure (BP), benefit from BP-lowering treatment and whether benefits in these individuals depend on the level of their cardiovascular risk. OBJECTIVES: Meta-analyzing all available data from randomized controlled trials (RCTs) about the effects on cardiovascular outcomes of BP-lowering treatment in individuals with normal or high-normal BP values in absence of baseline antihypertensive drugs and free from a recent myocardial infarction, left ventricular dysfunction and heart failure. METHODS: From an available database of BP-lowering RCTs updated to end 2016, RCTs were selected only including normotensive individuals or including both hypertensive and normotensive individuals but providing separate information in normotensive individuals. Risk ratios and 95% confidence intervals, and absolute risk reduction of cardiovascular outcomes and all deaths were calculated by a random effects model. RESULTS: We identified 24 RCTs providing data on 47 991 high normal or normal BP individuals. BP-lowering treatment was found to significantly reduce cardiovascular disease risk in these individuals, but risk reduction was limited to stroke. When RCTs were stratified according to total cardiovascular risk, no significant benefits were found in RCTs including individuals at low moderate risk (13 RCTs, 21 128 individuals), whereas a significant reduction in stroke risk (-60% to a SBP/DBP reduction of 10/5 mmHg) was found in RCTs including individuals at high-very high risk mostly because of symptomatic cardiovascular disease (11 RCTs, 26 863 individuals). In high-very high-risk normotensive individuals, BP-lowering treatment appeared to reduce stroke risk independently of the drug class used. CONCLUSION: Individuals with very high cardiovascular risk due to symptomatic cardiovascular disease should consider BP lowering treatment even when their BP is in the high-normal and normal range. PMID- 28858985 TI - Beyond solicitousness: a comprehensive review on informal pain-related social support. AB - Adults with chronic pain cite social support (SS) as an important resource. Research has mostly focused on general SS or pain-specific solicitousness, resulting in a limited understanding of the role of SS in pain experiences. Drawing on SS theoretical models, this review aimed to understand how pain related SS has been conceptualized and measured and how its relationship with pain experiences has been investigated. Arksey and O'Malley scoping review framework guided the study. A database search (2000-2015) was conducted in PsycINFO, CINAHL, MEDLINE, and EMBASE using a combination of subject headings/keywords on pain and SS; 3864 citations were screened; 101 full texts were assessed for eligibility; references of 52 papers were hand searched. Fifty three studies were included. Most studies were either a-theoretical or drew upon the operant conditioning model. There are several self-report measures and observational systems to operationalize pain-related SS. However, the Multidimensional Pain Inventory remains the most often used, accounting for the centrality of the concept of solicitousness in the literature. Most studies focused on individuals with chronic pain self-report of spousal pain-related SS and investigated its main effects on pain outcomes. Only a minority investigated the role of pain SS within the stress and coping process (as a buffer or mediator). Little is known about mediating pathways, contextual modulation of the effectiveness of SS exchanges, and there are practically no SS-based intervention studies. Drawing on general SS models, the main gaps in pain-related SS research are discussed and research directions for moving this literature beyond solicitousness are proposed. PMID- 28858987 TI - Pain-autonomic relationships: implications for experimental design and the search for an "objective marker" for pain. PMID- 28858986 TI - Sensory phenotype and risk factors for painful diabetic neuropathy: a cross sectional observational study. AB - Different sensory profiles in diabetic distal symmetrical sensory-motor polyneuropathy (DSPN) may be associated with pain and the responsiveness to analgesia. We aimed to characterize sensory phenotypes of patients with painful and painless diabetic neuropathy and to assess demographic, clinical, metabolic, and electrophysiological parameters related to the presence of neuropathic pain in a large cohort of well-defined DSPN subjects. This observational cross sectional multi-center cohort study (performed as part of the ncRNAPain EU consortium) of 232 subjects with nonpainful (n = 74) and painful (n = 158) DSPN associated with diabetes mellitus of type 1 and 2 (median age 63 years, range 21 87 years; 92 women) comprised detailed history taking, laboratory tests, neurological examination, quantitative sensory testing, nerve conduction studies, and neuropathy severity scores. All parameters were analyzed with regard to the presence and severity of neuropathic pain. Neuropathic pain was positively correlated with the severity of neuropathy and thermal hyposensitivity (P < 0.001). A minority of patients with painful DSPN (14.6%) had a sensory profile, indicating thermal hypersensitivity that was associated with less severe neuropathy. Neuropathic pain was further linked to female sex and higher cognitive appraisal of pain as assessed by the pain catastrophizing scale (P < 0.001), while parameters related to diabetes showed no influence on neuropathic pain with the exception of laboratory signs of nephropathy. This study confirms the value of comprehensive DSPN phenotyping and underlines the importance of the severity of neuropathy for the presence of pain. Different sensory phenotypes might be useful for stratification of patients with painful DSPN for analgesic treatment and drug trials. PMID- 28858988 TI - Venous Diverticula Causing Pulsatile Tinnitus Treated With Coil Embolization and Stent Placement With Resolution of Symptoms: Report of Two Cases and Review of the Literature. AB - OBJECTIVE: To report two cases of pulsatile tinnitus caused by complex venous diverticula with successful treatment via coil embolization and stent placement followed by complete resolution of symptoms. We also review the literature pertaining to venous diverticula causing pulsatile tinnitus treated using endovascular techniques. PATIENTS: Two women patients, aged 27 and 29 years, presented to our institution with 3-month histories of pulsatile tinnitus. In each case, non-invasive imaging and conventional digital subtraction angiography (DSA) confirmed the presence of a complex right transverse-sigmoid sinus junction diverticulum. INTERVENTION: Both patients underwent stent-assisted coil embolization of the venous diverticula. MAIN OUTCOME AND RESULTS: Clinical and DSA follow-up at 6 and 12 months confirmed resolution of symptoms with obliteration of the venous diverticulum. We also performed a PubMed database search for the period January 1995 through June 2016 using the terms pulsatile tinnitus, venous aneurysm/diverticulum, stent-assisted coil embolization, and endovascular treatment and identified reports of 14 additional patients treated using endovascular techniques. CONCLUSIONS: Venous sinus diverticula causing pulsatile tinnitus can be successfully treated with stent-assisted coil embolization with complete resolution of clinical symptoms. This is in concordance with 13 case reports in the literature involving 14 patients with venous sinus diverticula treated using endovascular techniques. PMID- 28858989 TI - Long-term Functioning of Allogeneic Islets in Subcutaneous Tissue Pretreated With a Novel Cyclic Peptide Without Immunosuppressive Medication. AB - BACKGROUND: There exists a need for a minimally invasive method of islet transplantation without immunosuppressive drugs for the treatment of type 1 diabetes. METHODS: In diabetic August Copenhagen Irish rats, an agarose rod containing the cyclic oligopeptide SEK-1005 (agarose-SEK rod) was implanted at 2 dorsal subcutaneous sites. Then these rods were removed, and 1500 islets of Langerhans isolated from Fischer 344 rats were transplanted into each of the pockets. RESULTS: Ten days after implantation of agarose-SEK rods, vascularized pockets were present. Nonfasting blood glucose levels confirmed long-term survival of the allogeneic islet grafts, without immunosuppressive therapy, in 8 of 10 recipients. Flow cytometry and gene expression analyses were performed to investigate the mechanisms underlying graft acceptance. Agarose-SEK rod implantation led to the formation of granulomatous tissue containing regulatory T cells that suppressed immune reactions against the allogeneic islet grafts. CONCLUSIONS: These results indicate that the use of an agarose-SEK rod to prevascularize a subcutaneous site may be a useful method for achieving successful allogeneic islet transplantation without immunosuppression. PMID- 28858990 TI - Mesenchymal Stromal Cell Therapy: After the Gold Rush. PMID- 28858991 TI - Yes Virginia, There Is a Future in Science. PMID- 28858992 TI - The genotypes and methylation of MAO genes as factors behind smoking behavior. AB - OBJECTIVE: Smoking dependence is the main cause for tobacco-related illnesses. The addiction-causing substance in tobacco, nicotine, acts through the dopamine pathway in the brain, causing several pleasurable experiences through cigarette smoking. Thus, both genetic and epigenetic factors related to dopamine metabolism may play an important role in influencing an individual's smoking behavior. MATERIALS AND METHODS: We studied the 1460 C/T variation and the variable number tandem repeat polymorphism in the MAOA gene and A/G variation in intron 13 in the MAOB gene together with four DNA methylation sites in both of these genes in relation to several smoking-related phenotypes in a study population of 1230 Whites of Russian origin. RESULTS: The genotypes studied were found to be associated with smoking status in women; the MAOB G variant allele was more prevalent in female smokers than nonsmokers [odds ratio (OR): 2.16, 95% confidence interval (CI): 1.08-4.33], whereas a reverse relation was observed for the MAOA 1460 T-variant allele (OR: 0.44, 95% CI: 0.21-0.91) and variable number tandem repeat low-activity alleles (OR: 0.49, 95% CI: 0.24-0.98). Moreover, the mean methylation values of the CpG sites studied in the MAOA gene were related to smoking behavior in women. Similarly, several methylation patterns in the MAOB gene were associated with a smoking history, with each CpG site showing a remarkable sex dependence. CONCLUSION: Smoking behavior seems to be related to the genetic and epigenetic profile of MAO genes, with considerable individual and sex-related differences. PMID- 28858994 TI - High plasma concentrations of dolutegravir in patients with ABCG2 genetic variants. AB - The ATP-binding cassette transporters B1 (ABCB1) and G2 (ABCG2) are both expressed in the intestine and known as efflux transporters of drugs. Dolutegravir was identified recently as a substrate of both ABCB1 and ABCG2. This study aimed to determine the relations between single-nucleotide polymorphisms of ABCB1 and ABCG2 genes and plasma dolutegravir concentrations. Plasma samples were obtained from 42 HIV-1-infected patients treated with dolutegravir-containing regimens 0.5-4 h after dolutegravir dosing. Plasma dolutegravir concentrations were measured by liquid chromatography-mass spectrometry. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotyping of allelic variants of ABCB1 1236 C>T (rs1128503), 2677 G>T/A (rs2032582), 3435 C>T (rs1045642), 4036 A>G (rs3842), and ABCG2 421 C>A (rs2231142) was performed using the TaqMan drug metabolism assays. None of the genotypes in ABCB1 1236 C>T, 2677 G>T/A, 3435 C>T, and 4036 A>G correlated with plasma dolutegravir concentration. In contrast, the mean peak plasma concentration of dolutegravir was significantly higher in the genotypes of ABCG2 421 AA (5002 ng/ml, n=3) compared with the genotypes of ABCG2 421 CC (2569 ng/ml, n=22) and ABCG2 421 CA (2479 ng/ml, n=17) (P=0.0005). The speculated peak level of plasma dolutegravir concentration was significantly higher in ABCG2 genetic variant holders, probably, at least in part, because of low expression levels of efflux transporters in the intestines associated with these genetic variants. PMID- 28858995 TI - From the Editor. PMID- 28858996 TI - Guest Editorial. PMID- 28858993 TI - PharmGKB summary: very important pharmacogene information for ABCG2. PMID- 28858997 TI - Virtually Integrated Care: A New Paradigm in Patient Care Delivery. AB - Current trends, including an aging population; the impact of the Affordable Care Act; increased complexity and acuity of patient needs; shorter hospital stays; and higher patient expectations have resulted in a significant demand for reconfiguration of the bedside nursing model. The health care system is further complicated by a shortage of highly trained nurses, challenging financial incentive models, and inefficient traditional staffing models. These challenges have increased the urgency for designing a more efficient, cost-effective care delivery model. One large national system is redefining how it cares for patients in the acute care setting in preparation for the Next Era. Catholic Health Initiatives is developing a new integrated model of care that combines advances in technology with a restructuring of nursing roles for significantly more efficient and effective care. The model is person-centered and allows team members to practice to the full extent of their education and training. The model emphasizes care from the right skill level, for the right patient need, at the right time. This article begins to describe the planning and implementation of the Virtually Integrated Care Team (VIC) pilot project on 2 medical-surgical units within the Catholic Health Initiatives system. PMID- 28858998 TI - An Integrative Review of 21st-Century Roles, Responsibilities, Characteristics, and Competencies of Chief Nurse Executives: A Blueprint for the Next Generation. AB - Executive nursing practice is experiencing "head-snapping change." Health care has transitioned from the managed care era to the disruptive innovation era. As chief nurse executives (CNEs) navigate evolving care delivery models, they must consider retooling their roles and responsibilities related to emergent models. This integrative review's purpose was to examine evidence for the roles, responsibilities, characteristics, and competencies of CNEs and system CNEs to better guide future generations of nurse executives. Ganong and Cooper's integrative review methodology was chosen to guide the evidence synthesis. Seventeen articles were identified that pertained to the clinical inquiry. The evidence is inconsistent for specific CNE roles, responsibilities, characteristics, and competencies due to many areas of overlap and an absence of definitions. The evidence does describe who CNEs are, what they do, and how they articulate executive practice. Embedding evidence regarding emerging roles, responsibilities, characteristics, and competencies into the personal journeys of nurse executives helps articulate shifting paradigms and the CNE's role in transforming health care. Review results have the potential to create a blueprint for the recruitment, development, and retention of the next generation of nurse executives. New knowledge for the ever-changing worlds of CNEs is needed by robust research studies and other evidence. PMID- 28858999 TI - Applying Bureaucratic Caring Theory and the Chronic Care Model to Improve Staff and Patient Self-Efficacy. AB - Patient activation and engagement can be powerful enablers for health outcomes that are just as important as staff engagement and satisfaction. The authors applied the Bureaucratic Caring Theory and the Chronic Care Model to a process improvement project designed to link activation, engagement, satisfaction, and health outcomes. Twenty-two adults with diabetes and 7 staff members caring for them participated in a 12-week process improvement project that incorporated a time-based element of longitudinal care with skill-based competencies to provide collaborative, team-based care to patients with type 2 diabetes. Patients completed satisfaction surveys at the end of their clinical encounters. Staff members completed satisfaction surveys pre- and postimplementation. The authors analyzed hemoglobin A1C levels pre- and postimplementation. As engagement and activation increased for both staff and patients, hemoglobin A1C levels decreased. The clinical implication is that the use of Bureaucratic Caring Theory may foster caring while broad application of the Chronic Care Model may improve self-efficacy, create healthier populations, and reduce health care costs. PMID- 28859000 TI - A New Tool for Quality: The Internal Audit. AB - As health care systems aspire to improve the quality and value for the consumers they serve, quality outcomes must be at the forefront of this value equation. As organizations implement evidence-based practices, electronic records to standardize processes, and quality improvement initiatives, many tactics are deployed to accelerate improvement and care outcomes. This article describes how one organization utilized a formal clinical audit process to identify gaps and/or barriers that may be contributing to underperforming measures and outcomes. This partnership between quality and audit can be a powerful tool and produce insights that can be scaled across a large health care system. PMID- 28859001 TI - Report From the Night Shift: How Administrative Supervisors Achieve Nurse and Patient Safety. AB - The administrative supervisor role (the nurse leader on the evening or night shift) has been present in hospitals for more than 100 years, but research is just commencing regarding how this leader achieves nurse and patient safety. This focused ethnographic study was conducted in 2 parts. The first part consisted of focus groups with night-shift staff nurses, held at 7 hospitals in the mid Atlantic region of the United States, with the objective of obtaining the staff nurses' perception of the supervisors' role. The second part consisted of interviews with 30 administrative supervisors, recruited nationally from 20 different states, to explore the supervisors' perspective on practices used to enhance safety. The focus group and interview transcripts were thematically analyzed, using an iterative, comparative method to identify codes and sort for patterns. The findings reveal that administrative supervisors "make it (whatever needs to be done) work" and achieve nurse and patient safety by building trust with the staff, doing rounds, educating, and providing support to the front line team. These shift leaders foster a culture of safety with their relationship oriented leadership style. By gaining further understanding about the administrative supervisor role, new workflow processes can be explored; specific continuing education programs can be developed; and additional research can be conducted. PMID- 28859002 TI - International Nursing: How Much Power Do Nurse Managers Have? AB - This study was conducted to explore issues of nurse managers' power and empowerment. Data were collected from nurse managers by way of a questionnaire consisting of background factors, work-related questions, and power-related questions at the unit and organization levels. The degree of empowerment was evaluated using 2 established instruments (CWEQ-II and Work Empowerment Questionnaire). The overall level of managers' personal power within their own units was relatively high. Nurse managers' perception of their power at an organizational level was found to be at a moderate level. Several factors related to an individual's professional background were correlated to power issues, both at the unit and organizational levels. Structural and psychological empowerment correlated with the overall level of power at a unit level and the overall level of power at an organizational level. Nurse managers self-reported their own general power at a unit level as high, which offers them possibilities to lead the development of nursing care in their units. Organizations may benefit more from nurse managers' leadership by more fully integrating them in the development processes of the entire organization. PMID- 28859003 TI - A Rural "Grow Your Own" Strategy: Building Providers From the Local Workforce. AB - Rural health care leaders are increasingly tasked with the responsibility of providing health access to 21% of the national population with only 10% of the provider workforce. Provider recruitment strategies offering loan repayment have had some success in the short term but are less impactful at creating a long-term retention rate, unless the providers have an existing connection to either the community in which they are working or rural health care. Responding to these data, a demonstration project and study has been underway in Colorado to test a rural focused "grow your own" advanced practice registered nurse (APRN) model. Phase 1 is designed to measure recruitment of RNs from inside rural communities to return to school and become primary care providers within those communities. Phase 2 will measure completion of education and phase 3 will measure retention rates in those communities. This article reports on phase 1 of the project, which is recruitment. The project offers stipend support with assistance in the school application process, educational support, clinical and job placement assistance, and monthly coaching. In addition, communities were asked to provide matching funds to support the APRN students with a goal of creating a self-sustaining model that will build a continuous pipeline of APRN providers. This strategy avoids the costly need to recruit and relocate providers who have no ties to the community. Thirty-four of 36 nurses (94%) responded to the study survey. Survey results suggested that the combination of financial, community, and employer support utilized in this model could serve to create a new and sustainable strategy for building a rural APRN provider workforce pipeline. The ultimate outcome has the potential to ensure that all people in rural areas have access to a high-quality, well-educated primary care provider. PMID- 28859004 TI - Effects of the Nurse Athlete Program on the Healthy Lifestyle Behaviors, Physical Health, and Mental Well-being of New Graduate Nurses. AB - Recognizing that transition from nursing student to point-of-care nurse can be a stressful time period in one's career. A pilot study at a large Midwestern medical center tested the preliminary effects of a health-oriented workshop, the Nurse Athlete, on new graduate nurses' healthy lifestyle beliefs, healthy lifestyle behaviors, depressive and anxiety symptoms, as well as health outcomes. The Nurse Athlete workshop, provided in partnership with Johnson & Johnson's Human Performance Institute (HPI), used materials from HPI's Corporate Athlete program. The 2-day workshop focuses on energy management through a comprehensive examination of goals and values in relation to one's spiritual, mental, emotional, and physical development and provides practical strategies to improve self-care. Eighty-eight new graduate nurses hired at the university's medical center were offered the opportunity to participate in the Nurse Athlete program and associated study. Sixty-nine percent of these new graduate nurses (n = 61) consented and participated in the program. There was a statistically significant decrease in the participants' weight and body mass index from baseline to the 6 month follow-up assessment, which resulted in small to medium positive effects for the Nurse Athlete program. There was also a significant decrease in body fat percentage across time, resulting in a large positive intervention effect. Statistically significant reductions in depressive symptoms were measured between baseline and 6 months. PMID- 28859005 TI - On-boarding the Middle Manager. AB - The trend of promoting clinical experts into management roles continues. New middle managers need a transitional plan that includes support, mentoring, and direction from senior leaders, including the chief nursing officer (CNO). This case study demonstrates how the CNO of one organization collaborated with a faculty member colleague to develop and implement a yearlong personalized on boarding program for a group of new nurse middle managers. PMID- 28859006 TI - Nurses to Their Nurse Leaders: We Need Your Help After a Failure to Rescue Patient Death. AB - The purpose of this study was to describe nurses' needs and how they are being met and not met after caring for surgical patients who died after a failure to rescue (FTR). A qualitative, phenomenologic approach was used for the interview and analysis framework. Methods to ensure rigor and trustworthiness were incorporated into the design. The investigator conducted semistructured 1:1 interviews with 14 nurses. Data were analyzed using Colaizzi's methods. Four themes were identified: (1) coping mechanisms are important; (2) immediate peer and supervisor feedback and support are needed for successful coping; (3) subsequent supervisor support is crucial to moving on; and (4) nurses desire both immediate support and subsequent follow-up from their nurse leaders after every FTR death. Nurses' needs after experiencing an FTR patient death across multiple practice areas and specialties were remarkably similar and clearly identified and articulated. Coping mechanisms vary and are not uniformly effective across different groups. Although most nurses in this study received support from their peers after the FTR event, many nurses did not receive the feedback and support that they needed from their nurse leaders. Immediate nurse leader support and follow-up debriefings should be mandatory after patient FTR deaths. Developing an understanding of nurses' needs after experiencing an FTR event can assist nurse leaders to better support nurses who experience FTR deaths. Insight into the environment surrounding FTR deaths also provides a foundation for future research aimed at improving patient safety and quality through an improved working environment for nurses. PMID- 28859007 TI - Developing Professional Practice and Ethics Engagement: A Leadership Model. AB - Nurse leaders are responsible for a practice environment that fosters safe, quality patient outcomes through excellence in nursing practice. This article describes a reflective practice intervention in the Cardiac Intensive Care Unit of an urban academic medical center led by the unit nursing director and the hospital's nurse ethicist. The twice monthly case-based discussions, called "Nursing Practice and Ethics Rounds," were attended by staff and unit managers (nurse director, assistant nurse director, and clinical educator) and were facilitated by the nurse ethicist. The purpose of this descriptive qualitative study was to identify nurses' perceptions of the rounds on individual practice, unit practice, and the practice of their peers. Two focus groups were conducted with nurses who attended 3 or more sessions. Staff reported that they felt valued; experienced a decrease in moral distress; and improved empathy with patients, families, and other staff members after the intervention. They also reported better understanding of ethical issues and language to better talk about them. The presence of nurse leaders was valued as affirming the importance of practice development and of witnessing the experience of staff nurses. Finally, the process of reflection was valued for the opportunity it provided to process emotional and intellectual aspects of challenging cases. PMID- 28859008 TI - Leveraging the Internet of Things to Transform Care Delivery. PMID- 28859009 TI - The Case for Bringing the Licensed Practical Nurse Back to the Hospital. AB - The expansion of the aging population, residential care facilities, and projected registered nurse shortages pose significant challenges to nurse staffing ratios. The licensed practical/vocational nursing role is now being reexamined, as acute care and long-term care facilities look at staffing models and patient safety. There is now a demand for an increase in the numbers of practical nurse education programs, which have been overlooked as a pipeline for professional nursing. Recruiting and educating practical nurses open a pathway for greater diversity in the nursing profession as well as improving patient health outcomes. PMID- 28859010 TI - The Effects of Implementing a Patient Acuity Tool on Nurse Satisfaction in a Pulmonary Medicine Unit. AB - In response to nurses' concerns of equity and satisfaction with patient assignments in a pulmonary medicine unit, a Patient Acuity Tool (PAT) was implemented. The impact of the PAT on nurse satisfaction and perceived equity of patient assignments was measured using a pre-/postsurvey design. Findings of the investigation indicate that a PAT supports nurse satisfaction and equity. In addition, qualitative data suggested that the PAT improved perceived professional autonomy and nurse-to-nurse communication. PMID- 28859011 TI - Construct Validation of the FMS: Relationship between a Jump-Landing Task and FMS Items. AB - Sports injuries and athletic performance are complex areas, which are characterized by manifold interdependencies. The landing error scoring system (LESS) is a valid screening tool to examine bilateral jump-landing mechanics. Whereas, the Functional Movement Screen (FMS) items are thought to operationalize flexibility and motor behaviour during low intense bodyweight patterns. The aim of the study was to explore possible interdependency of the diagnostic information of these screening tools. 53 athletes (age 23.3+/-2.1 yrs.) were tested in a sport scientific lab. In detail, 31 professional soccer players (3 Division) and 22 collegiate athletes were studied. Linear, partial correlational and cluster analysis were performed to examine possible trends. Generally, the sportsmen achieved a LESS score of 6.6+/-2 and a jumping height of 37+/-7.8cm. Partial correlational analysis indicates that trunk control (r=0.4; p<0.01) is moderately related to landing mechanics, which in turn was negatively related on LESS height (r=-0.67, p<0.01). In addition, clustering showed by trend, that a higher active straight leg raise (ASLR) score is related to better landing mechanics (ASLR score 1: LESS 6.9+/-1.8; n=15 vs. ASLR score 3: LESS 5.6+/-2.1; n=10). On the task-specific level, jump-landing mechanics were directly related to jumping performance in this cohort with poor mechanics. On unspecific analysis level, kinetic chain length (ASLR) and trunk control has been identified as potential moderator variables for landing mechanics, indicating that these parameter can limit landing mechanics and ought to be optimized within the individual's context. A potential cognitive strategy shift from internal (FMS) to external focus (LESS) as well as different muscle recruitment patterns are potential explanations for the non-significant linear relationship between the FMS and LESS data. PMID- 28859012 TI - Muscle power predicts bone strength in Division II athletes. AB - The relationship between muscle fitness measures and tibial bone strength in collegiate level athletes was investigated. Eighty-six Division II collegiate athletes (age: (18-29 years), height: 1.71 m (.09): mass: 66.7 kg (10.5) 56 female: 30 male) participated in this cross-sectional study. Maximum grip strength (GS), 1 repetition maximum leg press (1RM) and vertical jump peak power (PP) tests were measured. Cortical area (Ct.Ar), cortical bone mineral density (cBMD), moment of inertia (J) and bone strength (polar strength-strain index, SSIp) were measured using peripheral quantitative computed tomography (pQCT) at 50% tibia length. For each bone strength parameter, a hierarchical multiple regression (HMR) analysis was performed to examine the contribution of sex and the 3 muscle fitness parameters (muscle power, relative 1 repetition leg extensor strength and relative grip strength) to bone parameters. Vertical jump peak power explained 54-59% of the variance in bone strength parameters, and relative leg extensor and grip strength were not predictive of bone strength parameters. Muscle power correlated with bone mass and architecture variables but not cBMD values. Cortical bone mineral density (cBMD) was also not predicted by relative leg extensor strength or relative grip strength. Muscular fitness assessment, specifically peak power calculated from vertical jump height assessments provides a simple, objective, valid and reliable measure to identify and monitor bone strength in collegiate athletes. PMID- 28859013 TI - Efficacy of Compression Garments on Recovery From a Simulated Rugby Protocol. AB - Upton, CM, Brown, FC, and Hill, JA. Efficacy of compression garments on recovery from a simulated rugby protocol. J Strength Cond Res 31(11): 2977-2982, 2017-The aim of this study was to examine the efficacy of lower limb compression garments on recovery in club-level rugby players. Nineteen participants (age, 20.3 +/- 1.7 years, height, 184.2 +/- 7.5 cm, and body mass, 89.5 +/- 9.9 kg) completed a rugby-specific, muscle-damaging protocol before being assigned to a compression garment group (n = 10) or a SHAM ("recovery" drink) treatment (n = 9). The compression group wore the garments for 48 hours after exercise, whereas SHAM consumed a sweetened, low energy drink within an hour of protocol completion. Perceived muscle soreness (PMS), creatine kinase (CK), maximal voluntary isometric contraction (MVIC), and countermovement jump (CMJ) height were measured at baseline, post, 24, and 48 hours after exercise. Perceived muscle soreness was significantly lower in the compression group compared with the SHAM group at both 24 and 48 hours after exercise (p <= 0.05). The compression group was also subject to lower CK values than SHAM, as demonstrated by a significant time by group effect (p <= 0.05). There was no significant group effect for MVIC or CMJ (p > 0.05). Wearing compression garments after a rugby-specific, muscle-damaging protocol seems to reduce PMS and circulating concentrations of CK, suggesting improved recovery from muscle-damaging exercise. PMID- 28859014 TI - Comparisons in the Recovery Response From Resistance Exercise Between Young and Middle-Aged Men. AB - Gordon, JA III, Hoffman, JR, Arroyo, E, Varanoske, AN, Coker, NA, Gepner, Y, Wells, AJ, Stout, JR, and Fukuda, DH. Comparisons in the recovery response from resistance exercise between young and middle-aged men. J Strength Cond Res 31(12): 3454-3462, 2017-The purpose of this study was to compare the effects of a bout of high-volume isokinetic resistance exercise protocol (HVP) on lower-body strength and markers of inflammation and muscle damage during recovery between young and middle-aged adult men. Nineteen recreationally trained men were classified as either a young adult (YA: 21.8 +/- 2.0 years; 90.7 +/- 11.6 kg) or a middle-aged adult (MA: 47.0 +/- 4.4 years; 96.0 +/- 21.5 kg) group. The HVP consisted of 8 sets of 10 repetitions, with 1 minute of rest between each set, performed on an isokinetic dynamometer at 60 degrees .s. Maximal voluntary isometric contractions and isokinetic peak torque (PKT) and average torque (AVGT) (measured at 240 degrees and 60 degrees .s, respectively) were assessed at baseline (BL), immediately post (IP), 120 minutes, 24, and 48 hours after HVP. Blood was obtained at BL, IP, 30, 60, 120 minute, 24, and 48 hours after HVP to assess muscle damage and inflammation. All performance data were analyzed using repeated measures analysis of covariance, whereas all inflammatory and muscle damage markers were analyzed using a 2-way (time * group) repeated measures analysis of variance. Results revealed no between-group differences for PKT, AVGT, or rate of torque development at 200 ms (RTD200). No between-group differences in myoglobin, creatine kinase, C-reactive protein, or interleukin-6 were observed. Although BL differences in muscle performance were observed between YA and MA, no between-group differences were noted in performance recovery measures from high-volume isokinetic exercise in recreationally trained men. These results also indicate that the inflammatory and muscle damage response from high-volume isokinetic exercise is similar between recreationally trained, young, and middle-aged adult men. PMID- 28859015 TI - Characteristics and Risk Factors of Late-onset Bloodstream Infection Beyond 6 Months After Liver Transplantation in Children. AB - BACKGROUND: Bloodstream infection (BSI) is a major cause of morbidity and mortality after pediatric liver transplantation (LT). However, most studies have focused on BSI occurring within a few months after LT. In this study, we evaluated the characteristics of BSI occurring beyond 6 months after pediatric LT. METHODS: We conducted a retrospective cohort study at a pediatric LT center in Japan from November 2005 to March 2016. We evaluated the causative organisms and site of late-onset BSI in children <= 18 years of age. The risk factors for developing late-onset BSI and the associations of late-onset BSI with long-term outcomes were also evaluated. RESULTS: Three hundred forty cases of LT were evaluated. Thirty-eight BSI developed in 29 (9%) LT recipients. There were 42 organisms (nine Gram-positive cocci, 33 Gram-negative rods) isolated from the blood cultures of recipients with late-onset BSI. The most frequent sites of late onset BSI was intraabdominal infection (18/38; 47%). There were also 14 (39%) episodes with no apparent focus. In multivariate analysis, a prolonged operative time > 12 hours (odds ratio [OR] = 3.55; P = 0.04) and biliary stenosis (OR = 4.60; P = 0.006) were independent risk factors for developing late-onset BSI. Late-onset BSI was associated with increased retransplantation rate (P = 0.04) and mortality (P < 0.001). CONCLUSION: Late-onset BSI developed in 9% of recipients after pediatric LT. Gram-negative rods accounted for the majority of late-onset BSI as a consequence of abdominal infection, but the focus was often unclear. Prolonged operative time at LT and biliary stenosis were independent risk factors for developing late-onset BSI. PMID- 28859016 TI - Case of Infantile Legionella Pneumonia After Bathing in Reheated and Reused Water. AB - A 1-month-old girl developed respiratory failure due to bilateral interstitial pneumonia after bathing in reheated and reused water. A molecular test for sputum and an environmental culture detected Legionella pneumophila serotype 1. This is the first report of infantile legionellosis contracted from a bathtub at home. PMID- 28859017 TI - Potential Impact of Changes in the Schedule for Primary Diphtheria-Tetanus Toxoids-Pertussis Immunization as Control Strategy for Pertussis. AB - BACKGROUND: Pertussis is a vaccine-preventable respiratory disease that may cause death mainly in infants. The schedules for primary pertussis vaccination are set in each country by the local health authorities. Several different schedules meet World Health Organization recommendations, 2-4-6 months, 6-10-14 weeks, 2-3-4 months and 3-4-5 months being the most commonly used worldwide. In this work, we analyze the benefits of changing the vaccination schedule to control the disease. METHODS: We used an age-structured deterministic mathematical model for pertussis transmission to compute the incidences for the 4 above-mentioned schedules. Different vaccination coverages and vaccine effectiveness levels were considered. Immunization data from Argentina and Belgium were used. RESULTS: The highest reduction in incidence was obtained by adopting the 6-10-14 weeks schedule, reaching about a 36% reduction of 0-1-year incidence with respect to the 2-4-6 months schedule. We show the dependence of this reduction on both vaccine effectiveness and coverage. The severe pertussis incidence decreased significantly when the first dose of the 2-4-6 months schedule was accelerated to 6 weeks. Finally, we estimated that the communication campaign adopted in Flanders (Belgium) to improve compliance with the vaccine schedule could lead to a reduction of 16% in severe pertussis incidence and about 7% in total incidence in infants. CONCLUSIONS: Our work highlights the use of mathematical modeling to quantify the benefits of the existing vaccination schedules and the strategies that could be implemented to improve their compliance. Our results indicated that the 6-10-14 weeks is the best schedule option and that the Belgium vaccination campaign significantly reduced the incidence of severe cases. PMID- 28859018 TI - Analysis of Invasive Community-Acquired Methicillin-Susceptible Staphylococcus aureus Infections During a Period of Declining Community Acquired Methicillin Resistant Staphylococcus aureus Infections at a Large Children's Hospital. AB - BACKGROUND: The epidemiology of community acquired (CA) Staphylococcus aureus infections is changing in the United States. We investigated the current epidemiology of S. aureus infections at Texas Children's Hospital. METHODS: Patients with CA-S. aureus skin and soft tissue and invasive infections were retrospectively identified from January 1, 2007 to December 31, 2014. Invasive CA MSSA isolates were characterized by pulsed field gel electrophoresis, Spa typing, agr type and presence of lukSF-PV (pvl) genes. Medical records were reviewed. Statistical analyses included Fisher exact, chi for trend and Wilcoxon tests. RESULTS: CA-MRSA infections decreased by 60.4% (1461-578 infections) from 2007 to 2014 (P < 0.0001), while CA-MSSA infections averaged 550 infections annually. Invasive CA-MRSA infections decreased by 67.2% from 61 to 20 infections (P < 0.0001); invasive CA-MSSA averaged 44 infections annually. Among 296 invasive CA MSSA isolates, 74 (25%) isolates were USA300 and 88 (30%) were pvl+. USA300 declined among invasive CA-MSSA over time (P < 0.008). Musculoskeletal infections were most common (242/296, 82%); 52/242 (21.5%) isolates were USA300 and 62/242 (25.6%) pvl+. All 18 isolates from musculoskeletal infections with deep venous thrombosis and/or septic shock were pvl+ and 16/18 (88.9%) were USA300. Pneumonia isolates were mainly USA300 (8, 66.7%) and pvl+ (11, 91.7%). CONCLUSIONS: MSSA now cause the majority of invasive CA-S. aureus infections at our institution. Molecular analysis of invasive CA-MSSA isolates suggests strain diversity with USA300 on the decline and that disease presentations are to some extent strain specific. Changes in the CA-S. aureus epidemiology may, in part, be related to changes in immunity to the USA300 clone in the general population. PMID- 28859019 TI - Age-Specific Antibiotic Prescribing and Adherence to Guidelines in Pediatric Patients in Primary Care. AB - BACKGROUND: Most antibiotics in children are used to treat viral and self limiting conditions. This study aims to compare physicians' adherence to guidelines on antibiotic prescribing in fever and in ear and respiratory infections to children in different age groups in the Netherlands. METHODS: Data were used from the NIVEL Primary Care Database. For all pediatric episodes of fever, acute otitis media (AOM), streptococcal pharyngitis (strep throat), sinusitis, acute tonsillitis, acute bronchitis/bronchiolitis and pneumonia in 2012, we determined whether national guidelines were followed with regard to whether an antibiotic was prescribed, and the type of antibiotic. RESULTS: For diagnoses that generally do not require antibiotics, more prescriptions were found in adolescents' episodes compared with children 0-4 and 5-11 years of age, respectively, (bronchitis: 52.0% versus 42.4% and 42.7%, and fever: 16.8% versus 9.0% and 14.2%). The same was true for diagnoses that require antibiotics (strep throat: 76.5% versus 55.0% and 49.5%, pneumonia: 71.6% versus 60.2% and 69.8% and tonsillitis: 57.8% versus 54.8% and 49.7%), except for AOM (43.9% versus 52.4% and 39.6%). First-choice amoxicillin was prescribed more frequently in children 0 4 years of age than in age groups 5-11 and 11-17 years (AOM: 88.0% versus 83.2% and 81.8%, and pneumonia:74.7% versus 57.2% and 53.8%). First-choice narrow spectrum penicillins were prescribed more often in adolescents than in age groups 0-4 and 5-11 years (strep throat: 72.0% versus 63.6%, and 60.9% and tonsillitis: 67.9% versus 33.1 and 45.9%). CONCLUSIONS: Concerning adherence patterns include high antibiotic rates for bronchitis, particularly in adolescents, and underuse of narrow-spectrum penicillins in the 0-4 years group. PMID- 28859020 TI - Evaluation of 2-stage Treatment for Cervical Dorsal Rami Entrapment Syndrome: A Randomized, Controlled Trial. AB - OBJECTIVES: To evaluate the effectiveness of a 2-stage nonoperative treatment for patients with cervical dorsal rami entrapment syndrome. MATERIALS AND METHODS: The study included 66 patients diagnosed with cervical dorsal rami entrapment syndrome randomized to an experimental group (n=33) and control group (n=33). The experimental group was treated with additional diagnostic block if regular 2 weeks medication was not effective. The control group only received nonsteroidal anti-inflammatory drugs for 2 weeks. A visual analog scale (VAS) and pain treatment satisfaction scale (PTSS) were used to assess pain. Muscle power in the upper limbs was also assessed. The registration number of this study is ChiCTR IIR-15007565. RESULTS: The VAS scores of the experimental group were significantly lower at 2, 4, and 6 months after treatment compared with baseline and the VAS scores of the control group (all P<0.001). The PTSS scores of the experimental group were significantly higher at 2, 4, and 6 months after treatment compared with baseline and the PTSS scores of the control group (all P<0.001). Maximal muscle power after treatment was significantly greater in the experimental group compared with the control group for shoulder abduction (P<0.001), thumb pinch force (P=0.001), and grasp (P<0.001). CONCLUSIONS: The results suggest that the 2-stage treatment is effective for patients with cervical dorsal rami entrapment syndrome. PMID- 28859021 TI - Early Versus Delayed Initiation of Pharmacological Venous Thromboembolism Prophylaxis After an Intracranial Hemorrhage. AB - BACKGROUND: Intracranial hemorrhage (ICH) accounts for up to 20% of all strokes with and carries an approximate 50% 30-day mortality. The risk of venous thromboembolism (VTE) is markedly higher in patients with ICH compared with ischemic strokes, but the optimal time to initiate pharmacological prophylaxis is ill-defined. DESIGN: Retrospective analysis. SETTING: University-affiliated, tertiary care center. PATIENTS: Patients admitted for a nontraumatic ICH who received pharmacological VTE prophylaxis during their first 30 hospital days. RESULTS: Of the 793 patients evaluated, 400 were included [142 (35.5%) early]. Rebleeding event rates were similar for early versus late [8 (5.6%) vs. 13 (5.0%), P=0.80] and rates of hospital-acquired VTEs were not statistically different [1 (0.7%) vs. 8 (3.1%), P=0.17]. The median time from admission to the first dose of pharmacological prophylaxis was similar in patients who experienced rebleeding versus those that did not [74 h (range, 38 to 110.5 h) vs. 63 h (range, 45 to 90.5 h), P=0.69]. There was a longer median time from admission to the first dose of pharmacological prophylaxis in patients who developed a VTE during the initial hospitalization versus those who did not [108 h (range, 73.3 to 187 h) vs. 63 h (range, 44.5 to 90 h), P=0.005]. CONCLUSIONS: Initiation of early pharmacological prophylaxis in ICH patients did not appear to increase the risk of rebleeding nor decrease the risk of VTE. Among those patients who did develop VTE during hospitalization, there was a longer median time from admission to the first dose of pharmacological prophylaxis. PMID- 28859022 TI - Embolic Stroke of Undetermined Source in Latin America: A Review. AB - BACKGROUND: Stroke is a major health concern throughout Latin America. As elsewhere, no precise cause can be determined for a substantial portion of strokes. In 6 studies since 2010 in the region, 16% to 43% of ischemic strokes were identified as cryptogenic. The term embolic stroke of undetermined source (ESUS) has been proposed as more clinically useful and positively defined than the vague term cryptogenic. The epidemiology of ESUS in Latin America is largely unknown. REVIEW SUMMARY: This article aims to provide a description of the epidemiology of ESUS in Latin America and practical information regarding available diagnostic procedures and current guidelines. Atrial fibrillation (AF) is a significant risk factor for stroke, observed in approximately 10% of Mexican and Brazilian stroke patients. Previously unknown AF has been detected through extended monitoring in numerous studies of stroke patients, including 8% of patients in an Argentinian study, and is a possible contributing cause of ESUS. External or implantable outpatient cardiac monitoring has shown increased diagnostic yield for the detection of intermittent AF versus standard cardiac monitoring, but is infrequently used in Latin America. CONCLUSIONS: Undiagnosed AF is likely to contribute significantly to cryptogenic stroke and ESUS. Research is needed to continue evaluation of the optimum means of identifying clinically relevant occult AF. In view of the thromboembolic mechanism of ESUS, anticoagulant therapy may prove useful in prevention of recurrence. Ongoing trials are evaluating use of dabigatran, rivaroxaban, or apixaban versus aspirin for reducing the risk of recurrent stroke in patients with previous ESUS. PMID- 28859023 TI - Isolated Third Cranial Nerve Palsy Leading to the Diagnosis of Disseminated Burkitt Lymphoma: A Case Report and Literature Review. AB - INTRODUCTION: Dysfunction of the third cranial nerve can result from lesions anywhere along its course between the midbrain and the orbit. Lymphoma is a rare cause of isolated oculomotor nerve palsy (OMP), with only 19 cases reported in the literature. We describe a case of an isolated OMP leading to the diagnosis of disseminated Burkitt lymphoma (BL). CASE REPORT: A 37-year-old man presented with acute onset diplopia and right ptosis and was found to have a right pupillary sparing OMP. The diagnostic workout was unremarkable, including contrast-enhanced brain and orbital magnetic resonance imaging, MR angiography, exhaustive laboratory tests, and cerebrospinal fluid analysis. After a course of high-dose intravenous steroid therapy, the patient recovered almost completely. Three weeks after the discharge, he developed lumbar radicular pain and lower limbs weakness followed by the relapse of the right OMP. A second lumbar puncture revealed the presence of "small monomorphic lymphocytes," consistent with leptomeningeal lymphomatosis. A whole-body positron emission tomography scan disclosed a mediastinal mass, whose histopathologic "starry sky" appearance was pathognomonic for BL. CONCLUSIONS: Reviewing the literature, we were able to find only 3 cases of OMP as the presenting manifestation of BL, all occurring in patients with predisposing HIV infection.Our case of isolated OMP highlights some "red flags" for a lymphomatous etiology, including young age, a progressive course, a response to high-dose steroid therapy, and relapse upon steroid discontinuation; these cases require a comprehensive evaluation, including repeated cytological cerebrospinal fluid analysis and sensitive imaging techniques to detect a possible primary lesion. PMID- 28859024 TI - Spontaneous Resolution of Venous Aneurysms After Transarterial Embolization of a Variant Superior Sagittal Sinus Dural Arteriovenous Fistula: Case Report and Literature Review. AB - We present a rare case of dural arteriovenous fistula (DAVF) with subarachnoid hemorrhage and intraventricular hemorrhage due to its venous aneurysms. A 63-year old woman was admitted for a sudden loss of consciousness. Computed tomography angiograph, magnetic resonance imaging angiography, and digital subtraction angiography revealed a superior sagittal sinus DAVF. The fistula was fed by the left middle meningeal artery and left internal carotid artery, and was drained by a right vein of Trolard, the superficial Sylvian vein, deep Sylvian vein, and basal vein to the vein of Galen. The drainage veins were enlarged obviously with 3 aneurysmal venous malformations. There was a stenosis segment on the right basal vein. All the anatomic factors of direct cortical vein drainage, normal deep vein drainage, long tortuous drainage vein, outflow restriction, and multiple venous aneurysms, were contributed to the aggressive presentation of our case. Transarterial complete embolization of the fistula with balloon protection was successfully performed. Nine months later, a follow-up magnetic resonance imaging showed a complete disappearance of the 2 venous aneurysms located in the deep Sylvian vein and basal vein, and an obvious decrease in size of the venous aneurysm of the superficial Sylvian vein. This is the first report of a DAVF with 3 ballooned venous aneurysms and a spontaneous anatomy resolution of the venous aneurysms after the embolization of the fistula. At the same time, the clinical and radiologic characteristics of variant superior sagittal sinus DAVFs were summarized by review of the literatures reported previously. PMID- 28859025 TI - Seizures Induced by Exiting Water: A Unique Form of Reflex Epilepsy. AB - INTRODUCTION: Reflex epilepsies represent a form of epilepsy in which unique modes of seizure precipitation are characterized by endogenous or exogenous stimuli. Hot water epilepsy represents a subtype of reflex epilepsy in which seizure precipitation arises from the act of immersing the head with hot water. Bathing epilepsy represents another subtype of reflex epilepsy in which seizure precipitation arises from the immersion with water at lukewarm temperatures. CASE SERIES: We report on 2 boys with a unique form of bathing epilepsy characterized by the act of exiting out of water. The first patient had a family history significant for a brother with frontal lobe epilepsy. He underwent an evaluation in the epilepsy monitoring unit in which a reflex seizure was recorded while exiting the shower. This seizure was characterized by an ictal onset in the left frontal lobe and subsequent secondary generalization. The second patient initially had nonreflex seizures arising from the left temporal lobe and went on to develop reflex seizures upon exiting water. For both patients, the precipitation of seizures was independent of water or environmental temperature, exposure of specific body parts, or duration of water immersion. Both children experienced a sensation of coldness, followed by convulsive or atonic activity. CONCLUSIONS: Our cases represent a unique form of bathing epilepsy in which seizure precipitation is dependent upon exiting water. PMID- 28859026 TI - Reexpression of Prior Stroke Symptoms in Adults: When is a Mimic a Mimic? AB - A "stroke mimic" refers to any clinical condition that causes neurological symptoms clinically indistinguishable from a cerebral lesion that affects a vascular distribution, but is not caused by ischemia. One subtype of stroke mimic, termed stroke reexpression, is a form of mimicry in which previously recovered or improved stroke symptoms recur in the setting of a neurological disturbance (seizure, hypoperfusion state) or a systemic disturbance (toxic, metabolic, infectious). Many reports of stroke reexpression exist in the literature and are well known to clinicians, but there has been no consensus regarding terminology that has been published to date. The purpose of this review is to summarize several examples of stroke reexpression and propose simple, useful criteria for this clinical condition. PMID- 28859027 TI - Subarachnoid Hemorrhage Revealing Moyamoya Syndrome in a Patient With May-Hegglin Anomaly. AB - INTRODUCTION: Moyamoya syndrome is a rare progressive cerebrovascular occlusive disease for which several associated conditions have been described. CASE REPORT: We report the case of a 76-year-old woman with a history of May-Hegglin anomaly who presented with an isolated unusual diffuse headache. Initial laboratory investigations showed only thrombocytopenia (platelet count 95000/MUL). Unenhanced brain computed tomography scan revealed a small subarachnoid hemorrhage in the left frontal lobe. Computed tomography angiography showed occlusion of the terminal portion of the left internal carotid artery (ICA) and narrowing of the terminal portion of the right ICA with abnormal collateral vessels. Conventional angiography confirmed the tight stenosis of the extremity of the right ICA, and the occlusion of the left ICA, associated with an extensive collateral network consistent with moyamoya syndrome. No aneurysm was identified. CONCLUSIONS: The rarity of these 2 diseases makes a fortuitous association very unlikely. We thus concluded that this observation could be the first reported case of May-Hegglin anomaly as a cause of moyamoya syndrome. PMID- 28859028 TI - Sinusoidal Obstruction Syndrome During Chemotherapy of Pediatric Cancers and its Successful Management With Defibrotide. AB - Sinusoidal obstruction syndrome (SOS) is a life-threatening complication generally occurring after hematopoietic stem cell transplantation. SOS after standard dose chemotherapy in malignancies is rare. Between the year 1995 and 2016, 414 patients were diagnosed with acute lymphoblastic leukemia and 113 patients were diagnosed with Wilms tumor in our institution. Among these patients, 4 patients with acute lymphoblastic leukemia (0.96%) and 2 patients with Wilms tumor (1.7%) developed SOS during treatment. SOS behaves like a local disseminated intravascular coagulation. Defibrotide has proved to be effective in SOS. In this article, we report our experience with defibrotide in SOS. PMID- 28859029 TI - Very Long-term Sequelae After Nonradical Surgery Combined With Brachytherapy in an Infant With a Chemotherapy-resistant Rhabdomyosarcoma of the Tongue. AB - In 2003, van Grotel and colleagues reported an infant suffering a chemotherapy resistant eRMS of the tongue, that was treated with subtotal tumor resection and brachytherapy after major medical ethical discussions. As no long-term sequelae of such a procedure have been described, perspectives were uncertain at that time. Now, after 15 years, we describe hypoplasia of the mandibula, compromised dentation, osteopenia, neuropsychological deficits, and moderate speech impairment as the most prominent late effects. Also, mandibular cysts and basal cell carcinomas in the irradiated area, eventually led to the diagnosis Gorlin syndrome. PMID- 28859030 TI - Treatment of Refractory Infantile Hemangiomas and Pulmonary Hypertension With Sirolimus in a Pediatric Patient. AB - Infantile hemangioma is a benign vascular neoplasm that spontaneously involutes over time. Management, when needed, consists of medications, laser treatment and surgical excision. We describe a 3-year-old girl who presented shortly after birth with diffuse cutaneous hemangiomas, hepatosplenomegaly with liver lesions, anemia, and acute heart failure. She was diagnosed with hepatic and cutaneous infantile hemangioma based on skin biopsy. She developed progressive pulmonary hypertension with numerous pulmonary nodules suspicious for pulmonary arteriovenous malformations. She was started on sirolimus and had significant improvement in her pulmonary hypertension and liver lesions. This report supports prior studies that sirolimus is effective for vascular anomalies including IH refractory to conventional therapy. PMID- 28859031 TI - Immature Ovarian Teratoma: When to Give Adjuvant Therapy? AB - The question of giving or not adjuvant chemotherapy in pure ovarian immature teratomas (ITs) remains unsolved to date and illustrates differences in management between pediatric and adults oncologists. Because of the rarity of these tumors, this question has never been addressed through randomized trials. Standard of care for adult women with ovarian ITs is postoperative platinum based chemotherapy for all patients except FIGO stage IA, grade 1 tumors, whereas pediatric series concluded that surgery alone is curative for completely resected ovarian ITs, regardless of grade. Moreover the role of chemotherapy in incompletely resected tumors and its impact on the rate of malignant relapses needs to be better assessed. This emphasizes the urgent need for cooperation between adult and pediatric teams. PMID- 28859032 TI - Successful Reduced Intensity Conditioning Alternate Donor Stem Cell Transplant for Wiskott-Aldrich Syndrome. AB - There are very few reports of reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) with alternate donor for Wiskott-Aldrich syndrome (WAS) and there is no report of RIC with posttransplant cyclophosphamide (PTCy) in WAS. There is only 1 report of T cell receptor alphabeta and CD19-depleted haploidentical HSCT for WAS. Here we report successful outcome in 3 children with WAS who underwent successful RIC alternate donor HSCT of whom 2 (matched unrelated donor and T-cell replete haploidentical) received PTCy and 1 underwent T cell receptor alphabeta and CD19-depleted haploidentical HSCT. We modified conditioning used by Luznik for haploidentical HSCT by adding thiotepa 8 mg/kg and Campath or rabbit antithymoglobulin for 2 cases who received PTCy. In third case we gave fludarabine, thiotepa, and treosulfan-based conditioning. The mean duration of follow-up for these patients was 23.6 months posttransplant (range, 21 to 26 mo). All 3 patients are transfusion independent. Acute graft versus host disease (GVHD) grade I occurred in 1 and none had chronic GVHD. Chimerism of all 3 was fully donor (>95% donor) at D+30 and D+100 posttransplant. All are alive, healthy, and doing well. Our 3 cases highlight that with newer conditioning and GVHD prophylaxis approach alternate donor HSCT in WAS can become a safe and effective treatment option. PMID- 28859033 TI - Longitudinal Analysis of Echocardiographic Abnormalities in Children With Sickle Cell Disease. AB - BACKGROUND: Cardiac abnormalities have been described in echocardiograms of children with sickle cell disease (SCD). However, longitudinal studies investigating progression of echocardiographic abnormalities across the pediatric age spectrum in SCD are lacking. METHODS: A retrospective longitudinal analysis of 829 echocardiograms from pediatric patients with SCD at steady-state was performed. Left heart parameters included left ventricular end-systolic, end diastolic diameters, fractional shortening, and mass. Right ventricular pressure was estimated by tricuspid regurgitation gradient. Tricuspid regurgitation gradient >=25 mm Hg, a z-score >=2 for LV parameters and <=-2 for left ventricular fractional shortening were considered abnormal. RESULTS: Kaplan-Meier analysis revealed that echocardiographic abnormalities were detected by 5 years of age, and the cumulative incidence progressively increased throughout childhood. Age, male gender, HbSS and Sbeta thalassemia genotype, white blood cell count, platelet count, total bilirubin, admissions for pain crises and acute chest syndrome were positively, whereas hemoglobin was negatively associated with cardiac abnormalities. CONCLUSION: Cardiac abnormalities began early in childhood and progressively increased with age. Our study highlights the high cumulative incidence of cardiac abnormalities in children with SCD, which could represent a marker of disease severity. PMID- 28859034 TI - Six Weeks Versus 3 Months of Anticoagulant Treatment for Pediatric Central Venous Catheter-related Venous Thromboembolism. AB - OBJECTIVE: Central venous catheters (CVCs) are the single most important predisposing factor for the development of pediatric venous thromboembolism (VTE). Treatment recommendations suggest anticoagulation for the duration of 6 weeks to 3 months. This project investigated clinical outcomes associated with 6 weeks compared with 3 months of enoxaparin therapy following diagnosis of a CVC related VTE. METHODS: This retrospective cohort study enrolled patients aged 18 years and below treated with enoxaparin with/without unfractionated heparin for a radiologically confirmed CVC-related VTE. Patients were identified using the pharmacy database, radiologic imaging, and medical records. Patients were divided into 2 groups based on the duration of anticoagulation (6+1 or 12+/-2 wk) and data were analyzed using descriptive statistics. RESULTS: Seventy-four patients were included. Higher rates of complete thrombosis resolution were observed in children treated for 6 weeks at treatment cessation (39.4%) and long-term follow up (61.5%), compared with 3 months (11.8% and 9.0%, respectively). CONCLUSIONS: Six weeks of treatment for CVC-related VTE may provide noninferior clinical outcomes compared with 3 months of anticoagulation. An international randomized controlled trial (Kids-DOTT) is underway to explore the optimal duration of anticoagulation for acute-provoked VTE in children. This manuscript highlights that data from such studies is urgently needed. PMID- 28859035 TI - Giant Cell Tumor of the Ribs and Aneurysmal Bone Cyst Presenting With Hemothorax in a Child. AB - Giant cell tumor (GCT) is one of the most common tumors of bone and is the most common precursor of aneurysmal bone cysts (ABC). The clinical behavior of concurrent GCT and ABC can be very aggressive in children. GCT of the ribs, with or without ABC, is rarely seen in children. We report a case of an 8-year-old girl with GCT and associated ABC of the ribs who presented with sudden onset of chest pain and breathlessness due to a hemothorax. The patient was successfully treated by surgical resections and arterial embolization. She has remained well for 4 years after the initial surgery. PMID- 28859036 TI - Hemophagocytic Lymphohistiocytosis: A Dangerous Intruder in Pediatric Acute Lymphoblastic Leukemia. AB - Hemophagocytic lymphohistiocytosis (HLH) is a condition caused by a pathologic immune activation, which is responsible for its signs and symptoms. It may also appear as a secondary process caused by malignancy. Developing HLH during treatment for acute lymphoblastic leukemia (ALL) is extremely uncommon, but underdiagnosis may be fatal. Two patients with ALL on chemotherapy maintenance treatment who developed HLH triggered by infection are presented here. We emphasize the importance of being aware of this condition when a patient with ALL in complete remission presents with unexplained hepatomegaly, cytopenia, and fever. Early diagnosis and treatment may be lifesaving. PMID- 28859037 TI - Health-related Quality of Life and Associated Factors Among Thalassemia Major Patients, Southeast of Iran. AB - Low quality of life (QOL) is a feature that has been overlooked in thalassemia major (TM) patients. Our aim was to assess QOL in school-aged TM patients in Zabol city and surrounding rural areas in southeast of Iran. The study was performed in 2014. QOL was evaluated using Pediatric Quality of Life Inventory 4 (PedsQL4) questionnaire addressing physical, emotional, social, and educational, along with psychological health in 80 TM patients. Also, 80 age-matched and sex matched subjects without any chronic illness served as control group. Mean age of the patients was 11.7+/-4.1 years old. Total QOL scores was 51.4+/-13.3 in the patients. In comparison, mean value of total QOL score in controls was 91.1+/-3.3 (P<0.0001). Poor and moderate QOL were observed in 44.7% and 48.7% of the patients, respectively. Mean functioning scores for physical, emotional, social, educational, and psychological dimensions in the patients were 56.2+/-119, 69.6.4+/-23.3, 27.1+/-22.1, 52.3+/-18.1, and 48.9+/-11.8, respectively. The lowest level of QOL was related to the social field (81.3% with less than average score), while the highest QOL was related to the emotional aspect (58.8% with good QOL; >75 scores). Overall, female sex, poor compliance with chelation therapy, and residency in urban areas were significantly associated with poor QOL. In conclusion, providing a psychiatric health package seems to be essential for improving QOL in TM patients, especially in social field. PMID- 28859038 TI - Refractory LCH With Secondary Intracranial PNET: A Case Report and Review of Literature. AB - The occurrence of second malignant neoplasms in patients with Langerhans cell histiocytosis is infrequent but has been reported. Here we report the case of a child with refractory Langerhans cell histiocytosis who was treated with cladribine and later developed a secondary intracranial primitive neuroectodermal tumor. The possible association of cladribine with second neoplasm is further discussed. PMID- 28859039 TI - Clinical Profile and Outcome of Influenza A/H1N1 in Pediatric Oncology Patients During the 2015 Outbreak: A Single Center Experience from Northern India. AB - BACKGROUND: Owing to their immunocompromised status, childhood cancer patients on chemotherapy are at a greater risk for Influenza infection and its associated complications. There is limited data available on the clinical profile and outcome of Influenza A/H1N1 in this subset of patients. METHODS: A retrospective study was performed of Influenza A/H1N1 cases diagnosed between January 2015 to December 2015 in the in-patients of Pediatric Oncology unit of a tertiary care hospital from Northern India. RESULTS: In total, 16 children were diagnosed with laboratory confirmed H1N1. Most frequent symptoms were fever and cough. Oseltamivir was administered to all patients. Complications encountered were delay/interruption of antineoplastic therapy (9), need for respiratory support (5), and air leaks (1). Prolonged viral shedding was encountered in 50% of patients who were retested for H1N1 in their throat swabs. There were 2 deaths, 1 in a child of Acute Lymphoblastic Leukemia on induction therapy and another in a child with anaplastic Wilms tumor. CONCLUSIONS: Childhood cancer patients infected with Influenza A/H1N1 are at risk of serious illness and higher mortality. Delay of anticancer treatment is a concern in these infected children. Prompt initiation of antivirals and an optimum duration of treatment are warranted to reduce the morbidity and mortality. PMID- 28859040 TI - Successful Treatment of Recurrent Li-Fraumeni Syndrome-related Choroid Plexus Carcinoma. AB - The management of choroid plexus carcinoma (CPC) is challenging and multifaceted. Here, we discuss a 3-year-old girl with CPC and Li-Fraumeni syndrome who achieved full remission after surgery and chemotherapy, with radiation therapy spared. At recurrence, we used a novel, standard-dose cytotoxic chemotherapy regimen, focal proton radiation therapy, and targeted agents based on morphoproteomic analysis to achieve long-term survival. We highlight the rationale for our therapy at recurrence, as well as the risk-benefit analyses necessary in decision making for these patients. Our strategy may be effective in managing other patients with recurrent CPC and Li-Fraumeni syndrome. PMID- 28859041 TI - Case Report: Clinical Variation in Children With Thrombopoietin Receptor (C-MPL) Mutations: Report of 2 Cases. AB - Congenital amegakaryocytic thrombocytopenia (CAMT, MIM# 604498) is a rare congenital bone marrow failure syndrome which presents early in life with abnormal bleeding because of thrombocytopenia. Classically, megakaryocytes are decreased to absent in the bone marrow. The development of aplastic anemia early in childhood has led to the recommendation for early stem cell transplantation. Quantitative or loss-of-function mutations in the myeloproliferative leukemia gene (c-mpl), whose gene product functions as the thrombopoietin receptor, have been identified as causative for CAMT. Approximately 100 cases of CAMT are published in the medical literature. We describe 2 cases of CAMT who demonstrate disparate clinical courses, thereby highlighting phenotypic differences and increasing awareness of this clinical entity. PMID- 28859042 TI - Quality of Life Among Parents of Adolescent and Young Adult Brain Tumor Survivors. AB - We aimed to describe the quality of life (QOL) among parents of adolescent and young adult brain tumor survivors as well as parent, survivor, and diagnosis/treatment-related factors associated with adverse QOL. A cross sectional study of 28 parents of adolescent and young adult brain tumor survivors (who were on average 10 y postdiagnosis) was used to assess QOL. Parent QOL was measured using the Patient-Reported Outcomes Measurement Information System Global Health measure. Factors associated with adverse parent QOL were explored using logistic regression including: parent, survivor, and diagnosis/treatment related factors. Parent QOL was within the normal range; however, 40% scored below the clinical threshold of 0.5 SD below the mean for physical and mental health. Parent perceptions of greater family impact, survivor emotional/behavioral health problems, improved cognitive function, and recurrence were associated with adverse parent physical health. Parent anger/sorrow, uncertainty, survivor emotional/behavioral health problems, speech/language problems, and recurrence were associated with adverse parent mental health. Parental emotional resources and perceptions of improved survivor peer relationships were associated with greater parent physical and mental health. The impact of a brain tumor diagnosis and treatment on the QOL of parents may be significant. Interventions are needed to ensure that the needs of parents are met. PMID- 28859043 TI - Etiologies and Impact of Readmission Rates in the First 180 Days After Hematopoietic Stem Cell Transplantation in Children, Adolescents, and Young Adults. AB - INTRODUCTION: High rates of patients require readmission to the hospital within 6 months of hematopoietic stem cell transplantation (HSCT). We investigated the relationship between readmission rates and outcomes after HSCT in children, adolescents, and young adults (CAYA). MATERIALS AND METHODS: A retrospective analysis of patients (26 years or younger) treated with HSCT was conducted. RESULTS: A chart review of 435 CAYA who underwent HSCT from 2008 to 2015 revealed that 171 patients (39%) had at least 1 hospital readmission within 180 days of transplant; 87% received allogeneic and 13% received autologous HSCT. A total of 312 readmission events were reported. The median follow-up time was 31 months. Documented infection (n=99) and graft-versus-host disease complications (n=60) were the most common causes. Higher than 2 readmission rates were associated with lower overall survival (OS) (P=0.001) and disease-free survival (P<0.001) in patients who received allogeneic HSCT. These findings were not found in the autologous HSCT. In a multivariate analysis of those who received allogeneic HSCT, prior treatment with >=2 chemotherapy regimens (P=0.03) was independent predictor of lower OS. There were also trends noted toward lower OS for patients with documented infections at index admission or subsequent readmissions (P=0.09). CONCLUSIONS: More than 2 hospital readmissions within 6 months of allogeneic HSCT in CAYA, who are either heavily pretreated or had documented infections at index admission or subsequent readmissions adversely affected the outcomes. PMID- 28859044 TI - Vincristine, Irinotecan, and Bevacizumab in Relapsed Wilms Tumor With Diffuse Anaplasia. AB - The prognosis of relapsed Wilms tumor (WT) with diffuse anaplasia is dismal, therefore, novel therapeutic strategies need to be explored. We reported on 2 consecutive cases with relapsed anaplastic WT who presented a partial response after 2 courses of vincristine, irinotecan, and bevacizumab association. This regimen may have a role in the treatment of patients with anaplastic advanced WT. PMID- 28859045 TI - Mesenteric Primitive Myxoid Mesenchymal Tumor in a 7-Month-Old Boy. AB - Mesenteric tumors are rare, especially in the pediatric population. We present a case of a 7-month-old boy with an incidental abdominal mass identified as a Primitive Myxoid Mesenchymal Tumor of Infancy derived from the small bowel mesentery. This neoplasm is part of a spectrum of myofibroblastic lesions, with distinct clinical, morphologic, IHQ reactivity, and an aggressive clinical course. There is a paucity of evidence for the management of these tumors, and surgical resection remains the mainstay of treatment. PMID- 28859046 TI - Wiskott-Aldrich Syndrome Misdiagnosed as Immune Thrombocytopenic Purpura: A Case Report. AB - Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency characterized by various clinical phenotypes. We report the case of a 3-year-old immigrant boy presenting with persistent infant-onset thrombocytopenia treated for refractory immune thrombocytopenic purpura. Sequence analysis confirmed the diagnosis of WAS. The patient responded neither to IV infusions of immunoglobulin (Ig) nor a thrombopoietin receptor agonist and is currently planned for stem cell transplantation. Raised awareness is thus vital of this potentially misdiagnosed and lethal disorder. The diagnosis of WAS should be considered in all males with infant-onset immune thrombocytopenic purpura-like features, especially, if mean platelet volume is decreased (<7 fL) and good increment to platelet transfusions are evident. PMID- 28859047 TI - Childhood Blastic Plasmacytoid Dendritic Cell Neoplasm Mimicking Acute Rheumatic Fever: Report of an Unusual Clinical Presentation and Review of Literature. AB - BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is very rarely diagnosed in children with less than 50 cases in the literature. OBSERVATION: We report a case of childhood BPDCN who mimicked acute rheumatic fever at presentation. Majority of the reported childhood BPDCN received acute lymphoblastic leukemia-like chemotherapy with/without stem cell therapy, whereas those who received acute myeloid leukemia-like therapy predominantly succumbed to disease or sepsis. Overall 68% of the patients were alive and achieved complete remission with an overall prognosis slightly better in children compared with adults. CONCLUSIONS: The case is reported due to its unique unusual clinical presentation and its rarity in pediatric population. PMID- 28859048 TI - Nanomechanical Characteristics of Cervical Cancer and Cervical Intraepithelial Neoplasia Revealed by Atomic Force Microscopy. AB - BACKGROUND Understanding the biological features and developmental progress of cervical cancer is crucial for disease prevention. This study aimed to determine the nanomechanical signatures of cervical samples, ranging from cervicitis to cervical carcinomas, and to investigate the underlying mechanisms. MATERIAL AND METHODS Forty-five cervical biopsies at various pathological stages were subjected to atomic force microscopy (AFM) measurements. Cdc42 and collagen I were quantified using immunohistochemical staining to investigate their relationship with nanomechanical properties of cervical cancers and premalignant lesions. RESULTS We found that the lower elasticity peaks (LEPs) in the high grade squamous intraepithelial lesion (HSIL) group (21.24+/-3.83 kPa) and higher elasticity peaks (HEPs) in the cancer group (81.23+/-8.82 kPa) were upshifted compared with the control group (LEP at 8.51+/-0.18 kPa and HEP at 44.07+/-3.54 kPa). Furthermore, compared with the control [29.51+/-13.61 for cell division cycle 42 (Cdc42) expression and 28.61+/-17.65 for collagen I expression], immunohistochemical staining verified a significant increase of Cdc42 in the HSIL group (50.57+/-23.85) and collagen I (56.09+/-25.70) in the cancer group. In addition, using the Pearson correlation coefficient, Cdc42 expression tended to be positively correlated with LEP locations (r=0.63, P=0.012), while collagen I expression displayed a strong and positive correlation with HEP positions (r=0.88, P<0.001). CONCLUSIONS The nanomechanical properties of HSIL and cancer biopsies show unique features compared with controls, and these alterations are probably due to changes in cytoskeleton and extracellular matrix contents. PMID- 28859049 TI - Awareness, Beliefs, and Actions Concerning Zika Virus Among Pregnant Women and Community Members - U.S. Virgin Islands, November-December 2016. AB - As of May 2, 2017, the U.S. Virgin Islands (USVI), comprising St. Thomas, St. John, and St. Croix, had reported 1,021 probable or confirmed cases* of Zika virus disease in its population of approximately 100,000 (1); 222 symptomatic and asymptomatic pregnant women in the USVI had tested positive for Zika virus. In January 2016, USVI Department of Health (USVI DOH) initiated Zika response measures, including surveillance, vector control, and a communications program. Interventions included education and outreach, distribution of Zika prevention kits? to pregnant women in the USVI, and provision of free Zika virus laboratory testing and vector control services. In November 2016, USVI DOH staff members conducted interviews with convenience samples of community members and pregnant women to gather feedback about current and proposed interventions (2). Pregnant women reported taking a median of two actions to protect themselves from Zika, with repellent use being the most commonly reported action. Community members reported taking a median of one action and were supportive of several proposed vector control approaches. Whereas multiple pregnant women and community members reported hearing messages about the cause and consequences of Zika virus infections, few recalled messages about specific actions they could take to protect themselves. Integrating evaluation into response measures permits ongoing assessment of intervention effectiveness and supports improvement to serve the population's needs. PMID- 28859050 TI - Overdose Deaths Related to Fentanyl and Its Analogs - Ohio, January-February 2017. AB - Ohio is experiencing unprecedented loss of life caused by unintentional drug overdoses (1), with illicitly manufactured fentanyl (IMF) emerging as a significant threat to public health (2,3). IMF is structurally similar to pharmaceutical fentanyl, but is produced in clandestine laboratories and includes fentanyl analogs that display wide variability in potency (2); variations in chemical composition of these drugs make detection more difficult. During 2010 2015, unintentional drug overdose deaths in Ohio increased 98%, from 1,544 to 3,050.* In Montgomery County (county seat: Dayton), one of the epicenters of the opioid epidemic in the state, unintentional drug overdose deaths increased 40% in 1 year, from 249 in 2015 to 349 in 2016 (estimated unadjusted mortality rate = 57.7 per 100,000) (4). IMFs have not been part of routine toxicology testing at the coroner's offices and other types of medical and criminal justice settings across the country (2,3). Thus, data on IMF test results in the current outbreak have been limited. The Wright State University and the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory (MCCO/MVRCL) collaborated on a National Institutes of Health study of fentanyl analogs and metabolites and other drugs identified in 281 unintentional overdose fatalities in 24 Ohio counties during January-February 2017. Approximately 90% of all decedents tested positive for fentanyl, 48% for acryl fentanyl, 31% for furanyl fentanyl, and 8% for carfentanil. Pharmaceutical opioids were identified in 23% of cases, and heroin in 6%, with higher proportions of heroin-related deaths in Appalachian counties. The majority of decedents tested positive for more than one type of fentanyl. Evidence suggests the growing role of IMFs, and the declining presence of heroin and pharmaceutical opioids in unintentional overdose fatalities, compared with 2014-2016 data from Ohio and other states (3-5). There is a need to include testing for IMFs as part of standard toxicology panels for biological specimens used in the medical, substance abuse treatment, and criminal justice settings. PMID- 28859051 TI - QuickStats: Percentage* of Children Aged 6-17 Years Who Wear Glasses or Contact Lenses,? by Sex and Age Group - National Health Interview Survey, 2016S. PMID- 28859052 TI - Trends in Deaths Involving Heroin and Synthetic Opioids Excluding Methadone, and Law Enforcement Drug Product Reports, by Census Region - United States, 2006 2015. AB - Opioid overdose deaths quadrupled from 8,050 in 1999 to 33,091 in 2015 and accounted for 63% of drug overdose deaths in the United States in 2015. During 2010-2015, heroin overdose deaths quadrupled from 3,036 to 12,989 (1). Sharp increases in the supply of heroin and illicitly manufactured fentanyl (IMF) are likely contributing to increased deaths (2-6). CDC examined trends in unintentional and undetermined deaths involving heroin or synthetic opioids excluding methadone (i.e., synthetic opioids)* by the four U.S. Census regions during 2006-2015. Drug exhibits (i.e., drug products) obtained by law enforcement and reported to the Drug Enforcement Administration's (DEA's) National Forensic Laboratory Information System (NFLIS) that tested positive for heroin or fentanyl (i.e., drug reports) also were examined. All U.S. Census regions experienced substantial increases in deaths involving heroin from 2006 to 2015. Since 2010, the South and West experienced increases in heroin drug reports, whereas the Northeast and Midwest experienced steady increases during 2006-2015.? In the Northeast, Midwest, and South, deaths involving synthetic opioids and fentanyl drug reports increased considerably after 2013. These broad changes in the U.S. illicit drug market highlight the urgent need to track illicit drugs and enhance public health interventions targeting persons using or at high risk for using heroin or IMF. PMID- 28859053 TI - Notes from the Field: Fatal Yellow Fever in a Traveler Returning From Peru - New York, 2016. PMID- 28859054 TI - Notes from the Field: Lead Poisoning in an Infant Associated with a Metal Bracelet - Connecticut, 2016. PMID- 28859055 TI - Separase is a marker for prognosis and mitotic activity in breast cancer. AB - BACKGROUND: Cancer cell proliferation is a critical feature in classifying and predicting the outcome of breast carcinoma. Separase has a central role in cell cycle progression in unleashing sister-chromatids at anaphase onset. Abnormally functioning separase is known to lead to chromosomal instability. METHODS: The study comprises 349 breast carcinoma patients treated in Central Hospital of Central Finland. The prognostic value, role as a proliferation marker and regulatory interactions of separase are evaluated by immunohistochemical and double- and triple-immunofluorescence (IF) detections based on complete clinical data and >22-year follow-up of the patient material. RESULTS: In our material, abnormal separase expression predicted doubled risk of breast cancer death (P<0.001). Up to 11.3-year survival difference was observed when comparing patients with and without separase expressing cancer cell mitoses. Particularly, abnormal separase expression predicted impaired survival for luminal breast carcinoma (P<0.001, respectively). In multivariate analyses, abnormal separase expression showed independent prognostic value. The complex inhibitory interactions involving securin and cyclin B1 were investigated in double- and triple-IFs and revealed patient subgroups with aberrant regulation and expression patterns of separase. CONCLUSIONS: In our experience, separase is a promising and clinically applicable proliferation marker. Separase expression shows strong and independent prognostic value and could be developed into a biomarker for treatment decisions in breast carcinoma, particularly defining prognostic subgroups among luminal carcinomas. PMID- 28859056 TI - Persistent inequalities in 90-day colon cancer mortality: an English cohort study. AB - BACKGROUND: Variation in colon cancer mortality occurring shortly after diagnosis is widely reported between socio-economic status (SES) groups: we investigated the role of different prognostic factors in explaining variation in 90-day mortality. METHODS: National cancer registry data were linked with national clinical audit data and Hospital Episode Statistics records for 69 769 adults diagnosed with colon cancer in England between January 2010 and March 2013. By gender, logistic regression was used to estimate the effects of SES, age and stage at diagnosis, comorbidity and surgical treatment on probability of death within 90 days from diagnosis. Multiple imputations accounted for missing stage. We predicted conditional probabilities by prognostic factor patterns and estimated the effect of SES (deprivation) from the difference between deprivation specific average predicted probabilities. RESULTS: Ninety-day probability of death rose with increasing deprivation, even after accounting for the main prognostic factors. When setting the deprivation level to the least deprived group for all patients and keeping all other prognostic factors as observed, the differences between deprivation-specific averaged predicted probabilities of death were greatly reduced but persisted. Additional analysis suggested stage and treatment as potential contributors towards some of these inequalities. CONCLUSIONS: Further examination of delayed diagnosis, access to treatment and post-operative care by deprivation group may provide additional insights into understanding deprivation disparities in mortality. PMID- 28859057 TI - The prevalence of unmet needs in 625 women living beyond a diagnosis of early breast cancer. AB - BACKGROUND: There are over half a million women with a previous breast cancer diagnosis living in the UK. It is important to establish their level of unmet physical and psychosocial needs, as many are not routinely seen for follow-up under current models of care. METHODS: We conducted a retrospective analysis of early breast cancer survivors entering an Open Access Follow-Up (OAFU) programme in 2015. Unmet needs were assessed using the Holistic Needs Assessment (HNA) or extracted directly from the electronic patient record (EPR), when the HNA had not been completed. RESULTS: Six hundred and twenty-five patients were eligible. Sixty-one per cent of the survivors had at least one unmet need and 18% had ?5 needs. Consistently higher levels of unmet needs were identified using the formal HNA checklist as opposed to extraction from EPR (P<0.001). Physical and emotional needs were the most frequently reported (55 and 24% respectively). Patients receiving endocrine therapy and those who had received chemotherapy were more likely to report unmet needs (both P<0.001). CONCLUSIONS: Unmet physical and emotional needs are common in breast cancer survivors. It is vital that the services are available for these patients as they transition from hospital-based follow-up to patient-led self-management models of care. PMID- 28859060 TI - Rethinking apprenticeship. PMID- 28859058 TI - Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations. AB - BACKGROUND: The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. METHODS: In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. RESULTS: Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73-88%) (four patients with clinical complete response declined surgery). Twenty-four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05-1.03, P=0.055). CONCLUSIONS: This regimen was feasible and the primary study endpoint was met. For the first time using pre operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss. PMID- 28859061 TI - Is the New Zealand Early Warning Score useful following cardiac surgery? AB - AIMS: The rate of medical emergency team (MET) calling among post-cardiac surgery patients is unknown. We set out to determine what the call frequency would be if MET activation occurred in every instance that the early warning score (EWS) breached our local threshold, what the outcome was for these patients and what the calling rate might be if the proposed New Zealand EWS (NZEWS) system was implemented with 100% adherence. METHODS: The clinical records of 400 consecutive post-cardiac surgery patients were examined. The number of times a patient's EWS reached the threshold which mandated a call to the MET was determined, as was the actual rate of calling, the occurrence of inpatient death and re-admission to the intensive care unit (ICU). The rate of calling was then determined using the NZEWS, and with a routine modification to the heart rate score. RESULTS: There were 73 occasions (MET events) where the EWS reached the MET calling threshold. The MET was only called twice. There were no inpatient deaths and 12 ICU re admissions in the study cohort. Nine ICU re-admissions were preceded by a MET event, two by cardiac arrest and one had neither. Re-scoring with NZEWS yielded 53 events. Eight of the 12 ICU admissions were preceded by a NZEWS event. CONCLUSIONS: The rate of MET triggering EWS in patients post-cardiac surgery is high at 182/1,000 admissions. Using NZEWS could reduce the MET calling rate without significant risk to patient safety. PMID- 28859059 TI - Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies. AB - BACKGROUND: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity. METHODS: In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24 h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography. RESULTS: Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m-2 as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred. CONCLUSIONS: Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue. PMID- 28859062 TI - Media accounts of unintentional child injury deaths in New Zealand: a teachable moment? AB - AIM: To review media accounts of fatal child unintentional injury events reported in leading New Zealand newspapers for their completeness and potential to deliver evidence-based injury prevention messages. METHOD: Media accounts of fatal unintentional child (0-14 years) injury events in New Zealand's four largest newspapers between 2011 and 2015 were reviewed. Variables of interest included: date, mechanism of injury and victim details. The article prominence, presence of prevention messages and case ascertainment for the two leading causes of death (2011 to 2013 only) were evaluated. RESULTS: Two hundred and forty-two media accounts detailing 122 fatal child injury events (133 deaths) were located for the five-year period. The most common causes of injury were transport-related (56%) and drownings (21%). Only 20% (n=49) of accounts included clear prevention messages. Just over 33% of accounts included images and 66% were located within the first three pages. Case ascertainment in the media accounts was complete for all transport deaths and all but one drowning. CONCLUSION: The low frequency of prevention messages in the media accounts reviewed highlights a missed opportunity for the dissemination of prevention messages to the New Zealand public. The findings confirm the utility of these accounts as a timely source of fatal child injury information. PMID- 28859063 TI - BMI is a key risk factor for early periprosthetic joint infection following total hip and knee arthroplasty. AB - AIM: To identify patient and surgical risk factors that are associated with periprosthetic joint infection (PJI), especially whether obesity is a risk factor following total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: New Zealand Surgical Site Infection Improvement Programme data was analysed using deep infection within 90 days of the index procedure as the outcome. This was tested against surgical and patient factors for statistical associations in a multivariate model. RESULTS: A total of 10,690 primary THAs and 9,481 primary TKAs were recorded by the NZSSIIP between 2013 and 2015. Multivariate analysis showed statistically significant associations with deep infections for BMI (BMI >40kg/m2 OR 5.62, 95% CI 2.25-14.0), male gender (OR 1.7, 95% CI 1.05-2.74) and age greater than 75 for THAs (age <55 years OR 0.35, 95% CI 0.14-0.87). For TKAs, multivariate analysis showed statistically significant associations with deep infection for BMI (BMI >40kg/m2 OR 1.94, 95% CI: 0.63 5.70) and male gender (OR 2.96, 95% CI 1.51-5.80). CONCLUSIONS: These findings show that obesity is one of the most important modifiable patient factors in predicting PJI following THA and TKA. PMID- 28859064 TI - Mental health service use by Asians: a New Zealand census. AB - BACKGROUND: Asians are the third largest ethnic group in New Zealand. Little is known about their use of mental health services and the psychiatric diagnoses they receive in these services. AIM: To study rates of mental health service use and the prevalence of mental disorders in mental health services among New Zealand Asians compared to European, Maori and Pacific peoples. METHODS: Date from PRIMHD (Program for the Integration of Mental Health Data) was collected over a five-year period from 1 July 2008 to 30 June 2013. RESULTS: There were 229,874 individuals who had contact with mental health services. Asians were less likely to use mental health services compared to European, Maori or Pacific people. Asian clinical diagnoses were similar to other ethnic groups. The major differences were lower rates of substance-related disorders and personality disorders. CONCLUSION: Asians have low rates of mental health service utilisation. There is no evidence they are more severely ill when using mental health services. This suggests Asians may have lower prevalence rates of mental disorder than other ethnic groups in New Zealand. PMID- 28859065 TI - Estimated reduction in expenditure on hospital-acquired pressure injuries after an intervention for early identification and treatment. AB - AIM: An intervention designed to reduce numbers of hospital-acquired pressure injuries was delivered in Counties Manukau Health hospitals. An audit of a sample of patients was carried out to estimate the cost savings that would have been acquired across the district health board (DHB) due to a reduction in pressure injuries. METHOD: The pressure injury intervention was delivered from 2011 to 2015. A monthly prospective audit of patients with stages 1, 2, 3 and 4 pressure injuries was carried out. This involved a random sample of five patients per ward in all hospitals in Counties Manukau DHB. RESULTS: It was found that the annual estimated cost of treating pressure injuries in hospital patients was NZ$12,290,484 less in 2015 than in 2011. CONCLUSION: Implementation of strategies for managing hospital-acquired pressure injuries can lead to potentially large financial savings for hospitals, as well as reducing the burden of managing this difficult condition for patients and staff. PMID- 28859066 TI - The association between the first locating emergency ambulance being single crewed and cardiac arrest outcomes in New Zealand. AB - AIM: This study investigated the association between the first locating emergency ambulance being single crewed on outcomes following out-of-hospital cardiac arrest in New Zealand. METHOD: Using data from the St John cardiac arrest registry for the period of 1 October 2013 to 30 June 2015, cases were included if a resuscitation attempt was made and the patient was an adult. Logistic regression modelling was used to account for confounding factors. The primary outcome was survival to hospital discharge. RESULTS: A total of 2,347 cases were included. There was no difference in the rate of return of spontaneous circulation sustained to hospital handover in patients attended by either single crewed (27%) or double-crewed ambulances (32%); p=0.059. However, patients were significantly less likely to survive to hospital discharge when attended by single-crewed (12%) compared to double-crewed ambulances (17%) with an OR of 0.533, 95% confidence interval 0.320-0.888 and p=0.016. CONCLUSION: Patients had lower survival to hospital discharge outcomes when the first locating ambulance was single crewed than those where the first locating ambulance was double crewed. PMID- 28859067 TI - Bionic balance organs: progress in the development of vestibular prostheses. AB - The vestibular system is a sensory system that is critically important in humans for gaze and image stability as well as postural control. Patients with complete bilateral vestibular loss are severely disabled and experience a poor quality of life. There are very few effective treatment options for patients with no vestibular function. Over the last 10 years, rapid progress has been made in developing artificial 'vestibular implants' or 'prostheses', based on cochlear implant technology. As of 2017, 13 patients worldwide have received vestibular implants and the results are encouraging. Vestibular implants are now becoming part of an increasing effort to develop artificial, bionic sensory systems, and this paper provides a review of the progress in this area. PMID- 28859068 TI - The apprenticeship model of clinical medical education: time for structural change. AB - The apprenticeship model, which forms the backbone of the current medical education system, has a strong historical precedent (and indeed multiple strengths). It is, however, important to acknowledge that its application to modern medicine is far from perfect, particularly with the breadth and complexity of current hospital systems. Demands on clinician resources, the sheer volume of knowledge our trainees must amass, short attachments and rigorous assessment schedules are all major challenges to a relatively simplistic educational system. Identifying and addressing these vulnerabilities is essential to enhancing the educational experiences of both undergraduate medical students and junior doctors. PMID- 28859069 TI - Unusual cause of dilated cardiomyopathy in an adolescent girl. PMID- 28859070 TI - Sweet rebellion: a campaign for a sugar-sweetened beverage tax in New Zealand. PMID- 28859071 TI - Response to-Orbital fractures treated in Auckland from 2010-2015: review of patient outcomes. PMID- 28859072 TI - Response to-Better organ donation education. PMID- 28859073 TI - Bowel cancer screening. PMID- 28859074 TI - Open chromatin profiling identifies AP1 as a transcriptional regulator in oesophageal adenocarcinoma. AB - Oesophageal adenocarcinoma (OAC) is one of the ten most prevalent forms of cancer and is showing a rapid increase in incidence and yet exhibits poor survival rates. Compared to many other common cancers, the molecular changes that occur in this disease are relatively poorly understood. However, genes encoding chromatin remodeling enzymes are frequently mutated in OAC. This is consistent with the emerging concept that cancer cells exhibit reprogramming of their chromatin environment which leads to subsequent changes in their transcriptional profile. Here, we have used ATAC-seq to interrogate the chromatin changes that occur in OAC using both cell lines and patient-derived material. We demonstrate that there are substantial changes in the regulatory chromatin environment in the cancer cells and using this data we have uncovered an important role for ETS and AP1 transcription factors in driving the changes in gene expression found in OAC cells. PMID- 28859075 TI - Plantar pressures are elevated in people with longstanding diabetes-related foot ulcers during follow-up. AB - OBJECTIVE: High plantar pressures are implicated in the development of diabetes related foot ulcers. Whether plantar pressures remain high in patients with chronic diabetes-related foot ulcers over time is uncertain. The primary aim of this study was to compare plantar pressures at baseline and three and six months later in participants with chronic diabetes-related foot ulcers (cases) to participants without foot ulcers (controls). METHODS: Standardised protocols were used to measure mean peak plantar pressure and pressure-time integral at 10 plantar foot sites (the hallux, toes, metatarsals 1 to 5, mid-foot, medial heel and lateral heel) during barefoot walking. Measurements were performed at three study visits: baseline, three and six months. Linear mixed effects random intercept models were utilised to assess whether plantar pressures differed between cases and controls after adjusting for age, sex, body mass index, neuropathy status and follow-up time. Standardised mean differences (Cohen's d) were used to measure effect size. RESULTS: Twenty-one cases and 69 controls started the study and 16 cases and 63 controls completed the study. Cases had a higher mean peak plantar pressure at several foot sites including the toes (p = 0.005, Cohen's d = 0.36) and mid-foot (p = 0.01, d = 0.36) and a higher pressure time integral at the hallux (p<0.001, d = 0.42), metatarsal 1 (p = 0.02, d = 0.33) and mid-foot (p = 0.04, d = 0.64) compared to controls throughout follow up. A reduction in pressure-time integral at multiple plantar sites over time was detected in all participants (p<0.05, respectively). CONCLUSIONS: Plantar pressures assessed during gait are higher in diabetes patients with chronic foot ulcers than controls at several plantar sites throughout prolonged follow-up. Long term offloading is needed in diabetes patients with diabetes-related foot ulcers to facilitate ulcer healing. PMID- 28859076 TI - Developmental programming of somatic growth, behavior and endocannabinoid metabolism by variation of early postnatal nutrition in a cross-fostering mouse model. AB - BACKGROUND: Nutrient deprivation during early development has been associated with the predisposition to metabolic disorders in adulthood. Considering its interaction with metabolism, appetite and behavior, the endocannabinoid (eCB) system represents a promising target of developmental programming. METHODS: By cross-fostering and variation of litter size, early postnatal nutrition of CB6F1 hybrid mice was controlled during the lactation period (3, 6, or 10 pups/mother). After weaning and redistribution at P21, all pups received standard chow ad libitum. Gene expression analyses (liver, visceral fat, hypothalamus) were performed at P50, eCB concentrations were determined in liver and visceral fat. Locomotor activity and social behavior were analyzed by means of computer assisted videotracking. RESULTS: Body growth was permanently altered, with differences for length, weight, body mass index and fat mass persisting beyond P100 (all 3>6>10,p<0.01). This was paralleled by differences in hepatic IGF-I expression (p<0.01). Distinct gene expression patterns for key enzymes of the eCB system were observed in fat (eCB-synthesis: 3>6>10 (DAGLalpha p<0.05; NAPE-PLD p = 0.05)) and liver (eCB-degradation: 3>6>10 (FAAH p<0.05; MGL p<0.01)). Concentrations of endocannabinoids AEA and 2-AG in liver and visceral fat were largely comparable, except for a borderline significance for higher AEA (liver, p = 0.049) in formerly overfed mice and, vice versa, tendencies (p<0.1) towards lower AEA (fat) and 2-AG (liver) in formerly underfed animals. In the arcuate nucleus, formerly underfed mice tended to express more eCB-receptor transcripts (CB1R p<0.05; CB2R p = 0.08) than their overfed fellows. Open-field social behavior testing revealed significant group differences, with formerly underfed mice turning out to be the most sociable animals (p<0.01). Locomotor activity did not differ. CONCLUSION: Our data indicate a developmental plasticity of somatic growth, behavior and parameters of the eCB system, with long-lasting impact of early postnatal nutrition. Developmental programming of the eCB system in metabolically active tissues, as shown here for liver and fat, may play a role in the formation of the adult cardiometabolic risk profile following perinatal malnutrition in humans. PMID- 28859077 TI - Distinct roles and differential expression levels of Wnt5a mRNA isoforms in colorectal cancer cells. AB - The canonical Wnt/beta-catenin pathway is constitutively activated in more than 90% of colorectal cancer (CRC) cases in which beta-catenin contributes to CRC cell growth and survival. In contrast to the Wnt/beta-catenin pathway, the non canonical Wnt pathway can antagonize functions of the canonical Wnt/beta-catenin pathway. Wnt5a is a key factor in the non-canonical Wnt pathway, and it plays diverse roles in different types of cancers. It was shown that reintroducing Wnt5a into CRC cells resulted in inhibited cell proliferation and impaired cell motility. However, contradictory results were reported describing increased Wnt5a expression being associated with a poor prognosis of CRC patients. Recently, it was shown that the diverse roles of Wnt5a are due to two distinct roles of Wnt5a isoforms. However, the exact roles and functions of the Wnt5a isoforms in CRC remain largely unclear. The present study for the first time showed the ambiguous role of Wnt5a in CRC was due to the encoding of distinct roles of the various Wnt5a mRNA isoforms. A relatively high expression level of the Wnt5a-short (S) isoform transcript and a low expression level of the Wnt5a-long (L) isoform transcript were detected in CRC cell lines and specimens. In addition, high expression levels of the Wnt5a-S mRNA isoform and low expression levels of the Wnt5a-L mRNA isoform were significantly positively correlated with tumor depth of CRC patients. Furthermore, knockdown of the endogenous expression of the Wnt5a-S mRNA isoform in HCT116 cells drastically inhibited their growth ability by inducing apoptosis through induction of FASLG expression and reduction of TNFRSF11B expression. Moreover, reactivation of methylation inactivation of the Wnt5a-L mRNA isoform by treatment with 5-azacytidine (5-Aza) enhanced the siWnt5a S isoform's ability to induce apoptosis. Finally, we showed that the simultaneous reactivation of Wnt5a-L mRNA isoform and knockdown of Wnt5a-S mRNA isoform expression enhanced siWnt5a-S isoform-induced apoptosis and siWnt5a-L isoform regulated suppression of beta-catenin expression in vitro. High expression levels of the Wnt5a-S mRNA isoform and low expression levels of the Wnt5a-L mRNA isoform were significantly positively correlated with high mRNA levels of beta-catenin detection in vivo. Altogether, our study showed that, for the first time, different Wnt5a mRNA isoforms play distinct roles in CRC and can be used as novel prognostic markers for CRC in the future. PMID- 28859078 TI - The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene. AB - WAGR syndrome is characterized by Wilm's tumor, aniridia, genitourinary abnormalities and intellectual disabilities. WAGR is caused by a chromosomal deletion that includes the PAX6, WT1 and PRRG4 genes. PRRG4 is proposed to contribute to the autistic symptoms of WAGR syndrome, but the molecular function of PRRG4 genes remains unknown. The Drosophila commissureless (comm) gene encodes a short transmembrane protein characterized by PY motifs, features that are shared by the PRRG4 protein. Comm intercepts the Robo axon guidance receptor in the ER/Golgi and targets Robo for degradation, allowing commissural axons to cross the CNS midline. Expression of human Robo1 in the fly CNS increases midline crossing and this was enhanced by co-expression of PRRG4, but not CYYR, Shisa or the yeast Rcr genes. In cell culture experiments, PRRG4 could re-localize hRobo1 from the cell surface, suggesting that PRRG4 is a functional homologue of Comm. Comm is required for axon guidance and synapse formation in the fly, so PRRG4 could contribute to the autistic symptoms of WAGR by disturbing either of these processes in the developing human brain. PMID- 28859080 TI - PRRG4 function reveals that Robo trafficking is evolutionarily conserved. PMID- 28859079 TI - A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions. AB - Intracellular calcium cycling is a vital component of cardiac excitation contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-localisation of these two structures to form dyads within which calcium induced-calcium-release occurs. The organisation of these structures tightly controls intracellular calcium dynamics. In this study, we present a computational model of intracellular calcium cycling in three-dimensions (3-D), which incorporates high resolution reconstructions of these key regulatory structures, attained through imaging of tissue taken from the sheep left ventricle using serial block face scanning electron microscopy. An approach was developed to model the sarcoplasmic reticulum structure at the whole-cell scale, by reducing its full 3-D structure to a 3-D network of one-dimensional strands. The model reproduces intracellular calcium dynamics during control pacing and reveals the high-resolution 3-D spatial structure of calcium gradients and intracellular fluxes in both the cytoplasm and sarcoplasmic reticulum. We also demonstrated the capability of the model to reproduce potentially pro-arrhythmic dynamics under perturbed conditions, pertaining to calcium-transient alternans and spontaneous release events. Comparison with idealised cell models emphasised the importance of structure in determining calcium gradients and controlling the spatial dynamics associated with calcium-transient alternans, wherein the probabilistic nature of dyad activation and recruitment was constrained. The model was further used to highlight the criticality in calcium spark propagation in relation to inter-dyad distances. The model presented provides a powerful tool for future investigation of structure-function relationships underlying physiological and pathophysiological intracellular calcium handling phenomena at the whole-cell. The approach allows for the first time direct integration of high resolution images of 3-D intracellular structures with models of calcium cycling, presenting the possibility to directly assess the functional impact of structural remodelling at the cellular scale. PMID- 28859081 TI - Neurosyphilis in Africa: A systematic review. AB - INTRODUCTION: Neurological involvement is one of the most important clinical manifestations of syphilis and neurological disease occurs in both early and late syphilis. The impact of HIV co-infection on clinical neurosyphilis remains unclear. The highest prevalence of both syphilis and HIV is in Africa. Therefore it might be expected that neurosyphilis would be an important and not uncommon manifestation of syphilis in Africa and frequently occur in association with HIV co-infection; yet few data are available on neurosyphilis in Africa. The aim of this study is to review data on neurosyphilis in Africa since the onset of the HIV epidemic. METHODS: We searched the literature for references on neurosyphilis in Africa for studies published between the 1st of January 1990 and 15th February 2017. We included case reports, case series, and retrospective and prospective cohort and case-control studies. We did not limit inclusion based on the diagnostic criteria used for neurosyphilis. For retrospective and prospective cohorts, we calculated the proportion of study participants who were diagnosed with neurosyphilis according to the individual study criteria. Depending on the study, we assessed the proportion of patients with syphilis found to have neurosyphilis, and the proportion of patients with neurological syndromes who had neurosyphilis. Due to heterogeneity of data no formal pooling of the data or meta analysis was undertaken. RESULTS: Amongst patients presenting with a neurological syndrome, three studies of patients with meningitis were identified; neurosyphilis was consistently reported to cause approximately 3% of all cases. Three studies on stroke reported mixed findings but were limited due to the small number of patients undergoing CSF examination, whilst neurosyphilis continued to be reported as a common cause of dementia in studies from North Africa. Ten studies reported on cases of neurosyphilis amongst patients known to have syphilis. Studies from both North and Southern Africa continue to report cases of late stage syphilis, including tabes dorsalis and neurosyphilis, in association with ocular disease. DISCUSSION: This is the first systematic review of the literature on neurosyphilis in Africa since the beginning of the HIV epidemic. Neurosyphilis continues to be reported as a manifestation of both early and late syphilis, but the methodological quality of the majority of the included studies was poor. Future well-designed prospective studies are needed to better delineate the incidence and clinical spectrum of neurosyphilis in Africa and to better define interactions with HIV in this setting. PMID- 28859082 TI - Mouth-clicks used by blind expert human echolocators - signal description and model based signal synthesis. AB - Echolocation is the ability to use sound-echoes to infer spatial information about the environment. Some blind people have developed extraordinary proficiency in echolocation using mouth-clicks. The first step of human biosonar is the transmission (mouth click) and subsequent reception of the resultant sound through the ear. Existing head-related transfer function (HRTF) data bases provide descriptions of reception of the resultant sound. For the current report, we collected a large database of click emissions with three blind people expertly trained in echolocation, which allowed us to perform unprecedented analyses. Specifically, the current report provides the first ever description of the spatial distribution (i.e. beam pattern) of human expert echolocation transmissions, as well as spectro-temporal descriptions at a level of detail not available before. Our data show that transmission levels are fairly constant within a 60 degrees cone emanating from the mouth, but levels drop gradually at further angles, more than for speech. In terms of spectro-temporal features, our data show that emissions are consistently very brief (~3ms duration) with peak frequencies 2-4kHz, but with energy also at 10kHz. This differs from previous reports of durations 3-15ms and peak frequencies 2-8kHz, which were based on less detailed measurements. Based on our measurements we propose to model transmissions as sum of monotones modulated by a decaying exponential, with angular attenuation by a modified cardioid. We provide model parameters for each echolocator. These results are a step towards developing computational models of human biosonar. For example, in bats, spatial and spectro-temporal features of emissions have been used to derive and test model based hypotheses about behaviour. The data we present here suggest similar research opportunities within the context of human echolocation. Relatedly, the data are a basis to develop synthetic models of human echolocation that could be virtual (i.e. simulated) or real (i.e. loudspeaker, microphones), and which will help understanding the link between physical principles and human behaviour. PMID- 28859083 TI - Short-term effectiveness of a community health worker intervention for HIV infected pregnant women in Tanzania to improve treatment adherence and retention in care: A cluster-randomized trial. AB - INTRODUCTION: Community health workers (CHWs) are lay workers who have the potential to enhance services to prevent mother-to-child HIV transmission (PMTCT) and improve the health of women living with HIV infection. We conducted a cluster randomized trial of an intervention to integrate CHWs with 'Option B+' PMTCT services in Shinyanga Region, Tanzania. METHODS: The intervention was implemented for 11 months and included four integrated components: 1) formal linkage of CHWs to health facilities; 2) CHW-led antiretroviral therapy (ART) adherence counseling; 3) loss to follow-up tracing by CHWs; and 4) distribution of Action Birth Cards (ABCs), a birth planning tool. We cluster-randomized 32 facilities offering PMTCT services, within strata of size, to the intervention (n = 15) or comparison (standard of care, n = 17) groups. Intervention effectiveness was determined with a difference-in-differences strategy based on clinical and pharmacy data from HIV-infected postpartum women at baseline (births in 2014) and endline (births April-Oct 2015). The primary outcome was retention in care between 60 and 120 days postpartum. Secondary outcomes included ART initiation, timing of ART initiation (as measured by week of gestation), and ART adherence 90 days postpartum, measured using the medication possession ratio (MPR>=95%). RESULTS: Intervention and comparison facilities were similar at baseline. Data were collected from 1,152 and 678 mother-infant pairs at baseline and endline, respectively. There were no significant differences in retention in care, ART initiation, or timing of ART initiation between the intervention and control groups. Adherence (MPR>=95%) at 90 days postpartum was 11.3 percentage points higher in the intervention group in ITT analyses (95% CI: -0.7, 23.3, p = 0.06), though this effect was attenuated after adjusting for baseline imbalance (9.5 percentage points, 95% CI: -2.9, 22.0, p = 0.13). Among only sites that had the greatest fidelity to the intervention, however, we found a stronger effect on adherence (13.6 percentage points, 95% CI: 2.5, 24.6). CONCLUSIONS: Despite being feasible and acceptable, the CHW-based intervention did not have strong effects on most PMTCT indicators. CHW involvement in PMTCT programs may improve ART adherence among HIV-infected postpartum women, however, and success appears heavily dependent on program implementation. TRIAL REGISTRATION: Registry for International Development Impact Evaluations (RIDIE, ID 552553838b402) and ClinicalTrials.gov (NCT03058484). PMID- 28859084 TI - Regulation of myoblast differentiation by metabolic perturbations induced by metformin. AB - The metabolic perturbation caused by calorie restriction enhances muscle repair by playing a critical role in regulating satellite cell availability and activity in the muscles of young and old mice. To clarify the underlying mechanisms we asked whether myoblast replication and differentiation are affected by metformin, a calorie restriction-mimicking drug. C2C12, a mouse myoblast cell line, readily differentiate in vitro and fuse to form myotubes. However, when incubated with metformin, C2C12 slow their replication and do not differentiate. Interestingly, lower doses of metformin promote myogenic differentiation. We observe that metformin treatment modulates the expression of cyclins and cyclin inhibitors thereby inducing a cell cycle perturbation that causes a delay in the G2/M transition. The effect of metformin treatment is reversible since after drug withdrawal, myoblasts can re-enter the cell cycle and/or differentiate, depending on culture conditions. Myoblasts cultured under metformin treatment fail to up regulate MyoD and p21cip1, a key step in cell cycle exit and terminal differentiation. Although the details of the molecular mechanisms underlying the effect of the drug on myoblasts still need to be clarified, we propose that metformin negatively affects myogenic differentiation by inhibiting irreversible exit from the cell cycle through reduction of MyoD and p21cip1 levels. PMID- 28859085 TI - Plant microRNAs in larval food regulate honeybee caste development. AB - The major environmental determinants of honeybee caste development come from larval nutrients: royal jelly stimulates the differentiation of larvae into queens, whereas beebread leads to worker bee fate. However, these determinants are not fully characterized. Here we report that plant RNAs, particularly miRNAs, which are more enriched in beebread than in royal jelly, delay development and decrease body and ovary size in honeybees, thereby preventing larval differentiation into queens and inducing development into worker bees. Mechanistic studies reveal that amTOR, a stimulatory gene in caste differentiation, is the direct target of miR162a. Interestingly, the same effect also exists in non-social Drosophila. When such plant RNAs and miRNAs are fed to Drosophila larvae, they cause extended developmental times and reductions in body weight and length, ovary size and fecundity. This study identifies an uncharacterized function of plant miRNAs that fine-tunes honeybee caste development, offering hints for understanding cross-kingdom interaction and co evolution. PMID- 28859086 TI - Dengue, West Nile virus, chikungunya, Zika-and now Mayaro? PMID- 28859087 TI - Community effectiveness of indoor spraying as a dengue vector control method: A systematic review. AB - BACKGROUND: The prevention and control of dengue rely mainly on vector control methods, including indoor residual spraying (IRS) and indoor space spraying (ISS). This study aimed to systematically review the available evidence on community effectiveness of indoor spraying. METHODS: A systematic review was conducted using seven databases (PubMed, EMBASE, LILACS, Web of Science, WHOLIS, Cochrane, and Google Scholar) and a manual search of the reference lists of the identified studies. Data from included studies were extracted, analysed and reported. RESULTS: The review generated seven studies only, three IRS and four ISS (two/three controlled studies respectively). Two IRS studies measuring human transmission showed a decline. One IRS and all four ISS studies measuring adult mosquitoes showed a very good effect, up to 100%, but not sustained. Two IRS studies and one ISS measuring immature mosquitoes, showed mixed results. CONCLUSIONS: It is evident that IRS and also ISS are effective adulticidal interventions against Aedes mosquitoes. However, evidence to suggest effectiveness of IRS as a larvicidal intervention and to reduce human dengue cases is limited-and even more so for ISS. Overall, there is a paucity of studies available on these two interventions that may be promising for dengue vector control, particularly for IRS with its residual effect. PMID- 28859088 TI - The francophone network on neglected tropical diseases. PMID- 28859089 TI - Flavin monooxygenases regulate Caenorhabditis elegans axon guidance and growth cone protrusion with UNC-6/Netrin signaling and Rac GTPases. AB - The guidance cue UNC-6/Netrin regulates both attractive and repulsive axon guidance. Our previous work showed that in C. elegans, the attractive UNC 6/Netrin receptor UNC-40/DCC stimulates growth cone protrusion, and that the repulsive receptor, an UNC-5:UNC-40 heterodimer, inhibits growth cone protrusion. We have also shown that inhibition of growth cone protrusion downstream of the UNC-5:UNC-40 repulsive receptor involves Rac GTPases, the Rac GTP exchange factor UNC-73/Trio, and the cytoskeletal regulator UNC-33/CRMP, which mediates Semaphorin-induced growth cone collapse in other systems. The multidomain flavoprotein monooxygenase (FMO) MICAL (Molecule Interacting with CasL) also mediates growth cone collapse in response to Semaphorin by directly oxidizing F actin, resulting in depolymerization. The C. elegans genome does not encode a multidomain MICAL-like molecule, but does encode five flavin monooxygenases (FMO 1, -2, -3, -4, and 5) and another molecule, EHBP-1, similar to the non-FMO portion of MICAL. Here we show that FMO-1, FMO-4, FMO-5, and EHBP-1 may play a role in UNC-6/Netrin directed repulsive guidance mediated through UNC-40 and UNC 5 receptors. Mutations in fmo-1, fmo-4, fmo-5, and ehbp-1 showed VD/DD axon guidance and branching defects, and variably enhanced unc-40 and unc-5 VD/DD axon guidance defects. Developing growth cones in vivo of fmo-1, fmo-4, fmo-5, and ehbp-1 mutants displayed excessive filopodial protrusion, and transgenic expression of FMO-5 inhibited growth cone protrusion. Mutations suppressed growth cone inhibition caused by activated UNC-40 and UNC-5 signaling, and activated Rac GTPase CED-10 and MIG-2, suggesting that these molecules are required downstream of UNC-6/Netrin receptors and Rac GTPases. From these studies we conclude that FMO-1, FMO-4, FMO-5, and EHBP-1 represent new players downstream of UNC-6/Netrin receptors and Rac GTPases that inhibit growth cone filopodial protrusion in repulsive axon guidance. PMID- 28859090 TI - Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway. AB - Angiogenesis is a highly coordinated, extremely complex process orchestrated by multiple signaling molecules and blood flow conditions. While sprouting mode of angiogenesis is very well investigated, the molecular mechanisms underlying intussusception, the second mode of angiogenesis, remain largely unclear. In the current study two molecules involved in vascular growth and differentiation, namely endoglin (ENG/CD105) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) were examined to unravel their specific roles in angiogenesis. Down- respectively up-regulation of both molecules tightly correlates with intussusceptive microvascular growth. Upon ENG inhibition in chicken embryo model, formation of irregular capillary meshwork accompanied by increased expression of COUP-TFII could be observed. This dynamic expression pattern of ENG and COUP-TFII during vascular development and remodeling correlated with formation of pillars and progression of intussusceptive angiogenesis. Similar findings could be observed in mammalian model of acute rat Thy1.1 glomerulonephritis, which was induced by intravenous injection of anti Thy1 antibody and has shown upregulation of COUP-TFII in initial phase of intussusception, while ENG expression was not disturbed compared to the controls but decreased over the time of pillar formation. In this study, we have shown that ENG inhibition and at the same time up-regulation of COUP-TFII expression promotes intussusceptive angiogenesis. PMID- 28859091 TI - The effect of a movement-to-music video program on the objectively measured sedentary time and physical activity of preschool-aged children and their mothers: A randomized controlled trial. AB - Regular physical activity (PA) and the avoidance of prolonged sitting are essential for children's healthy growth, and for the physical and mental wellbeing of both children and adults. In the context of exercise, music may promote behavioral change through increased exercise adherence and participation. The purpose of this study was to determine whether a movement-to-music video program could reduce sedentary behavior (SB) and increase PA in mother-child pairs in the home environment. A randomized controlled trial was conducted in the Pirkanmaa region, Finland, in 2014-2016. The participants consisted of 228 mother child pairs (child age 5-7 years). The primary outcomes of interest were tri axial accelerometer-derived SB and PA, which were measured in weeks one (baseline), two, and eight in both the intervention and control groups. Further, the mothers and children in the intervention group used a movement-to-music video program from the beginning of week two to the end of week eight. Secondary outcomes included self-reported screen time. The statistical methods employed comprised an intention-to-treat and linear mixed effects model design. No statistically significant differences between groups were found in primary or secondary outcomes. Among the children in the control group, light PA decreased significantly over time and screen time increased from 89 (standard deviation, SD 37) to 99 (SD 41) min/d. Among mothers and children in the intervention group, no statistical differences were found. In supplementary analysis, the children who stayed at home instead of attending daycare/preschool had on average 25 (95% confidence interval, CI 19-30) min/d more sedentary time and 11 (95% CI 8-14) min/d less moderate-to-vigorous PA than those who were at daycare/preschool. The higher body mass index of mothers was related with 5 (95% CI 2-7) min/d more sedentary time and 1 (95% CI 0-2) min/d less moderate-to-vigorous PA. The movement-to-music video program did not change the objectively measured SB or PA of the mother-child pairs. However, mothers and children seemed to be more sedentary at home, and therefore interventions for decreasing SB and increasing PA should be targeted in the home environment. PMID- 28859092 TI - Seeing virtual while acting real: Visual display and strategy effects on the time and precision of eye-hand coordination. AB - Effects of different visual displays on the time and precision of bare-handed or tool-mediated eye-hand coordination were investigated in a pick-and-place-task with complete novices. All of them scored well above average in spatial perspective taking ability and performed the task with their dominant hand. Two groups of novices, four men and four women in each group, had to place a small object in a precise order on the centre of five targets on a Real-world Action Field (RAF), as swiftly as possible and as precisely as possible, using a tool or not (control). Each individual session consisted of four visual display conditions. The order of conditions was counterbalanced between individuals and sessions. Subjects looked at what their hands were doing 1) directly in front of them ("natural" top-down view) 2) in top-down 2D fisheye view 3) in top-down undistorted 2D view or 4) in 3D stereoscopic top-down view (head-mounted OCULUS DK 2). It was made sure that object movements in all image conditions matched the real-world movements in time and space. One group was looking at the 2D images with the monitor positioned sideways (sub-optimal); the other group was looking at the monitor placed straight ahead of them (near-optimal). All image viewing conditions had significantly detrimental effects on time (seconds) and precision (pixels) of task execution when compared with "natural" direct viewing. More importantly, we find significant trade-offs between time and precision between and within groups, and significant interactions between viewing conditions and manipulation conditions. The results shed new light on controversial findings relative to visual display effects on eye-hand coordination, and lead to conclude that differences in camera systems and adaptive strategies of novices are likely to explain these. PMID- 28859093 TI - Pulling MscL open via N-terminal and TM1 helices: A computational study towards engineering an MscL nanovalve. AB - There are great opportunities in the manipulation of bacterial mechanosensitive (MS) ion channels for specific and targeted drug delivery purposes. Recent research has shown that these ion channels have the potential to be converted into nanovalves through clever use of magnetic nanoparticles and magnetic fields. Using a combination of molecular dynamics (MD) simulations and the finite element (FE) modelling, this study investigates the theoretical feasibility of opening the MscL channel (MS channel of large conductance of E. coli) by applying mechanical force directly to its N-terminus. This region has already been reported to function as a major mechanosensor in this channel. The stress-strain behaviour of each MscL helix was obtained using all atom MD simulations. Using the same method, we simulated two models, the wild-type (WT) MscL and the G22N mutant MscL, both embedded in a POPE lipid bilayer. In addition to indicating the main interacting residues at the hydrophobic pore, their pairwise interaction energies were monitored during the channel gating. We implemented these inputs into our FE model of MscL using curve-fitting codes and continuum mechanics equations. In the FE model, the channel could be fully opened via pulling directly on the N-terminus and bottom of TM1 by mutating dominant van der Waals interactions in the channel pore; otherwise the stress generated on the channel protein can irreversibly unravel the N-secondary structure. This is a significant finding suggesting that applying force in this manner is sufficient to open an MscL nanovalve delivering various drugs used, for example, in cancer chemotherapy. More importantly, the FE model indicates that to fully operate an MscL nanovalve by pulling directly on the N-terminus and bottom of TM1, gain-of function (GOF) mutants (e.g., G22N MscL) would have to be employed rather than the WT MscL channel. PMID- 28859094 TI - Epithelial heparan sulfate regulates Sonic Hedgehog signaling in lung development. AB - The tree-like structure of the mammalian lung is generated from branching morphogenesis, a reiterative process that is precisely regulated by numerous factors. How the cell surface and extra cellular matrix (ECM) molecules regulate this process is still poorly understood. Herein, we show that epithelial deletion of Heparan Sulfate (HS) synthetase Ext1 resulted in expanded branching tips and reduced branching number, associated with several mesenchymal developmental defects. We further demonstrate an expanded Fgf10 expression and increased FGF signaling activity in Ext1 mutant lungs, suggesting a cell non-autonomous mechanism. Consistent with this, we observed reduced levels of SHH signaling which is responsible for suppressing Fgf10 expression. Moreover, reactivating SHH signaling in mutant lungs rescued the tip dilation phenotype and attenuated FGF signaling. Importantly, the reduced SHH signaling activity did not appear to be caused by decreased Shh expression or protein stability; instead, biologically active form of SHH proteins were reduced in both the Ext1 mutant epithelium and surrounding wild type mesenchymal cells. Together, our study highlights the epithelial HS as a key player for dictating SHH signaling critical for lung morphogenesis. PMID- 28859095 TI - Exacerbation of colon carcinogenesis by Blastocystis sp. AB - Colorectal cancer (CRC) is one the most commonly diagnosed cancers worldwide and the number is increasing every year. Despite advances in screening programs, CRC remains as the second leading cause of cancer deaths in the United States. Oxidative stress plays an important role in the molecular mechanisms of colorectal cancer (CRC) and has been shown to be associated with Blastocystis sp., a common intestinal microorganism. In the present study, we aimed to identify a role for Blastocystis sp. in exacerbating carcinogenesis using in vivo rat model. Methylene blue staining was used to identify colonic aberrant crypt foci (ACF) and adenomas formation in infected rats whilst elevation of oxidative stress biomarker levels in the urine and serum samples were evaluated using biochemical assays. Histological changes of the intestinal mucosa were observed and a significant number of ACF was found in Blastocystis sp. infected AOM-rats compared to the AOM-controls. High levels of urinary oxidative indices including advanced oxidative protein products (AOPP) and hydrogen peroxide were observed in Blastocystis sp. infected AOM-rats compared to the uninfected AOM-rats. Our study provides evidence that Blastocystis sp. has a significant role in enhancing AOM induced carcinogenesis by resulting damage to the intestinal epithelium and promoting oxidative damage in Blastocystis sp. infected rats. PMID- 28859096 TI - Disclosing 3' UTR cis-elements and putative partners involved in gene expression regulation in Leishmania spp. AB - To identify putative cis-elements involved in gene expression regulation in Leishmania, we previously conducted an in silico investigation to find conserved intercoding sequences (CICS) in the genomes of L. major, L. infantum, and L. braziliensis. Here, the CICS databank was explored to search for sequences that were present in the untranslated regions (UTRs) of groups of genes showing similar expression profiles during in vitro differentiation. Using a selectable marker as a reporter gene, flanked by either an intact 3' UTR or a UTR lacking the conserved element, the regulatory role of a CICS was confirmed. We observed that the pattern of modulation of the mRNA levels was altered in the absence of the CICS. We also identified putative CICS RNA-binding proteins. This study suggests that the publicly available CICS database is a useful tool for identifying regulatory cis-elements for Leishmania genes and suggests the existence of post-transcriptional regulons in Leishmania. PMID- 28859097 TI - Multiple stressors and the potential for synergistic loss of New England salt marshes. AB - Climate change and other anthropogenic stressors are converging on coastal ecosystems worldwide. Understanding how these stressors interact to affect ecosystem structure and function has immediate implications for coastal planning, however few studies quantify stressor interactions. We examined past and potential future interactions between two leading stressors on New England salt marshes: sea-level rise and marsh crab (Sesarma reticulatum) grazing driven low marsh die-off. Geospatial analyses reveal that crab-driven die-off has led to an order of magnitude more marsh loss than sea-level rise between 2005 and 2013. However, field transplant experimental results suggest that sea-level rise will facilitate crab expansion into higher elevation marsh platforms by inundating and gradually softening now-tough high marsh peat, exposing large areas to crab driven die-off. Taking interactive effects of marsh softening and concomitant overgrazing into account, we estimate that even modest levels of sea-level rise will lead to levels of salt marsh habitat loss that are 3x greater than the additive effects of sea-level rise and crab-driven die-off would predict. These findings highlight the importance of multiple stressor studies in enhancing mechanistic understanding of ecosystem vulnerabilities to future stress scenarios and encourage managers to focus on ameliorating local stressors to break detrimental synergisms, reduce future ecosystem loss, and enhance ecosystem resilience to global change. PMID- 28859098 TI - A comparative transcriptomic analysis reveals the core genetic components of salt and osmotic stress responses in Braya humilis. AB - Braya humilis is a member of the Euclidieae tribe within the family Brassicaceae. This species exhibits a broad range of adaptations to different climatic zones and latitudes as it has a distribution that ranges from northern Asia to the arctic-alpine regions of northern North America. In China, B. humilis is mainly found on the Qinghai-Tibetan Plateau (QTP) and in adjacent arid regions. In this study, we sequenced a sample from an arid region adjacent to the QTP using the Illumina platform generating a total of 46,485 highly accurate unigenes, of which 78.41% were annotated by BLASTing versus public protein databases. The B. humilis transcriptome is characterized by a high level of sequence conservation compared with its close relative, Arabidopsis thaliana. We also used reciprocal blast to identify shared orthologous genes between B. humilis and four other sequenced Brassicaceae species (i.e. A. thaliana, A. lyrata, Capsella rubella, and Thellungiella parvula). To enable precise characterization of orthologous genes, the early-diverging basal angiosperm Amborella trichopoda was also included. A total of 6,689 orthologous genes were identified before stricter criteria for the determination of e-values, amino acid hit lengths, and identity values was applied to further reduce this list. This led to a final list of 381 core orthologous genes for B. humilis; 39 out of these genes are involved in salt and osmotic stress responses and estimations of nonsynonymous/synonymous substitution ratios for this species and A. thaliana orthologs show that these genes are under purifying selection in B. humilis. Expression of six genes was detected in B. humilis seedlings under salt and osmotic stress treatments. Comparable expression patterns to their counterparts in Arabidopsis suggest that these orthologous genes are both sequence and functional conservation. The results of this study demonstrate that the environmental adaptations of B. humilis are mainly the results of preexisting genetic components. Future work will be required to characterize the expression patterns of these orthologous genes in natural populations and will provide further insights into the adaptive mechanisms underlying the wide range of B. humilis adaptations. PMID- 28859099 TI - Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells. AB - BACKGROUND: Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients. PURPOSE: In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC) cells. STUDY DESIGN: During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin. METHODS: The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR. RESULTS: The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on doxorubicin influx and efflux was mediated through downregulation of MDR1 treansporter in NSCLC cells. CONCLUSION: These findings suggested that acacetin augments the cytotoxicity of doxorubicin at lower concentrations in lung cancer cells. Their combination leads to more retention of doxorubicin in the cells by modulating drug trasporter and thus enhances its therapeutic potential. PMID- 28859100 TI - Synergistic rhizosphere degradation of gamma-hexachlorocyclohexane (lindane) through the combinatorial plant-fungal action. AB - Fungi are usually involved in degradation/deterioration of many anthropogenic wastes due to their verse enzyme secretions and adaptive capabilities. In this study, five dominant fungal strains were isolated from an aged lindane polluted site, they were all mixed (100 mg each) together with pent mushroom compost (SMC) and applied to lindane polluted soil (5 kg) at 10, 20, 30, 40% and control 0% (soil with no treatment), these were used to grow M. maximus Jacq for 3 months. To establish lindane degradation, deductions such as Degradation rate (K1), Half life (t1/2) and Degradation efficiency (DE) were made based on the analyzed lindane concentrations before and after the experiment. We also tested the presence and expressions of phosphoesterases (mpd and opd-A) and catechol 1,2 dioxygenases (efk2 and efk4) genes in the strains. The stains were identified as Aspergillus niger (KY693970); Talaromyces atroroseus (KY488464), Talaromyces purpurogenus (KY488468), Yarrowia lipolytica (KY488469) and Aspergillus flavus (KY693973) through morphological and molecular methods. Combined rhizospheric action of M. maximus and fungi speed up lindane degradation rate, initially detected lindane concentration of 45 mg/kg was reduced to 11.26, 9.34 and 11.23 mg/kg in 20, 30 and 40% treatments respectively making 79.76, 85.93 and 88.67% degradation efficiencies. K1 of 1.29 was recorded in control while higher K1 of 1.60, 1.96 and 2.18 /day were recorded in 20, 30 and 40% treatments respectively. The best t1/2 of 0.32 and 0.35 /day were recorded in 40 and 30% compared to control (0.54 /day). All the strains were also affirmed to possess the tested genes; opd was overexpressed in all the strains except KY693973 while mpd was overexpressed in KY693970, KY488464 but moderately expressed in KY488468, KY488469 and KY693973. However, efk genes were under-expressed in most of the strains except KY488469 and KY693973 which showed moderate expression of efk4. This work suggests that the synergistic association of the identified rhizospheric fungi and M. maximus roots could be used to remove lindane in soil at a limited time period and this combination could be used at large scale. PMID- 28859101 TI - Stakeholder perceptions of communication about vaccination in two regions of Cameroon: A qualitative case study. AB - BACKGROUND: Understanding stakeholders' (parents', communities' and health workers') perspectives of communication about childhood vaccination, including their preferences for its format, delivery and content, is an important step towards designing better communication strategies and ensuring more informed parents. Our objectives were to explore stakeholders' views, experiences and preferences for childhood vaccination communication in Cameroon. METHODS: In 2014, in the Central and North West Regions of Cameron, we gathered qualitative data for our case study using the following methods: semi structured interviews; observations and informal conversations during routine immunization clinics and three rounds of the National Polio Immunization Campaign; document analysis of reports and mass media communications about vaccination; and a survey of parents. We conducted a thematic analysis of the qualitative data to identify themes relating to views, experiences and perceptions of vaccination information and its delivery. Survey data were analysed using simple descriptive statistics. RESULTS: All of the parents interviewed felt that vaccinating their child was important, and trusted the information provided by health workers. However, many parents wanted more information. Parents did not always feel that they could ask questions during vaccination appointments. All participants felt that health workers and vaccination clinics were important sources of information. Social mobilisation activities such as door-to-door visits and announcements during religious services were important and accepted ways of communicating information, especially during vaccination campaigns. Information communicated through mass media and text messages was also seen as important. In general, stakeholders believed that more consistent messaging about routine vaccination through community channels would be helpful to remind parents of the importance of routine vaccination during ongoing rounds of vaccination campaigns against polio. CONCLUSIONS: This study confirms that parents regard information about childhood vaccination as important, but that health services need to be organized in ways that prioritize and facilitate communication, particularly about routine vaccination. PMID- 28859102 TI - Factors associated with last dental visit or not to visit the dentist by Brazilian adolescents: A population-based study. AB - OBJECTIVES: We investigated the factors associated with no dental visit within the last two years by adolescents in the state of Sao Paulo, Brazil, by using data from the Oral Health Conditions of Sao Paulo state population Project (SBSP 2015) conducted in 2015. METHODS: This was a cross-sectional epidemiological study with a representative sample of adolescents aged 15 to higher years residing in Sao Paulo State. The examiners were calibrated and dental visits were measured categorically as 1- Less than 1 year, 2- One to two years, 3 - Three years or more, 4- I have never visited the dentist. Based on the literature we dichotomized the outcome in two groups: response 1 plus 2 against response 3 plus 4. Then, Multilevel Poisson Regression (MPR) was used to estimate the prevalence ratios of last dental visit three years or had never been to a dentist by adolescents compared with those who had visited the dentist within the past two years, with contextual variables as the distal level; sociodemographic variables, mesial; and individual variables, proximal level. RESULTS: A high percentage of adolescents (84.9%) reported visiting the dentist in the last 2 years. Whereas, 626 (11.6%) had not visited the dentist for over 3 years and 188 (3.4%) had never been. A significantly higher proportion of females than males reported visiting the dentist in the past 2 years (p = 0.003). The oral and dental condition was reported as satisfactory by 4,350 respondents (80.6%), and when they accessed the health service, 2,286 (42.3%) went to the public service. Lower mean family income (1.62PR;95%CI;1.36-1.94); >= 1,000 inhabitant/Dental Surgeons (1.25PR;95%IC;1.03-1.56);male (1.26PR;95%CI; 1.11-1.43) non-Caucasian ethnicity (Mulatto:1.30PR;95%CI;1.13-1.50 and Black:1.58PR;95%CI;1.29-1.93); dissatisfaction with the oral health condition (1.20PR;95%CI;1.01-1.45),last visit to the public service versus private service (2.26PR; 95%CI;1.91-2.65) and presenting with periodontal disease in the form of dental calculus as the worst situation (1.38PR; 95%CI; 1.16-1.53) were associated with last visit to the dentist. CONCLUSIONS: A high proportion of adolescents had visited the dentist in the last two years. No dental visit within the last two years by adolescents were associated with contextual, health care system, sociodemographic, personal and oral health status, demonstrating that this is a complex phenomenon. Actions to promote regular dental visits by adolescents in Brazil should take these factors into consideration. PMID- 28859104 TI - Near-infrared fluorescence imaging and photodynamic therapy with indocyanine green lactosome has antineoplastic effects for hepatocellular carcinoma. AB - BACKGROUND: Anticancer agents and operating procedures have been developed for hepatocellular carcinoma (HCC) patients, but their prognosis remains poor. It is necessary to develop novel diagnostic and therapeutic strategies for HCC to improve its prognosis. Lactosome is a core-shell-type polymeric micelle, and enclosing labeling or anticancer agents into this micelle enables drug delivery. In this study, we investigated the diagnostic and therapeutic efficacies of indocyanine green (ICG)-loaded lactosome for near-infrared fluorescence (NIF) imaging and photodynamic therapy (PDT) for HCC. METHODS: The human HCC cell line HuH-7 was treated with ICG or ICG-lactosome, followed by PDT, and the cell viabilities were measured (in vitro PDT efficiency). For NIF imaging, HuH-7 cells were subcutaneously transplanted into BALB/c nude mice, followed by intravenous administration of ICG or ICG-lactosome. The transplanted animals were treated with PDT, and the antineoplastic effects were analyzed (in vivo PDT efficiency). RESULTS: PDT had toxic effects on HuH-7 cells treated with ICG-lactosome, but not ICG alone. NIF imaging revealed that the fluorescence of tumor areas in ICG lactosome-treated animals was higher than that of contralateral regions at 24 h after injection and thereafter. PDT exerted immediate and continuous phototoxic effects in the transplanted mice treated with ICG-lactosome. CONCLUSIONS: Our results demonstrate that ICG-lactosome accumulated in xenograft tumors, and that PDT had antineoplastic effects on these malignant implants. NIF imaging and PDT with ICG-lactosome could be useful diagnostic and/or therapeutic strategies for HCC. PMID- 28859103 TI - MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus. AB - Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus. PMID- 28859105 TI - Programmed cell death in Acanthamoeba castellanii Neff induced by several molecules present in olive leaf extracts. AB - Therapy against Acanthamoeba infections such as Granulomatous Amoebic Encephalitis (GAE) and Acanthamoeba Keratitis (AK), remains as an issue to be solved due to the existence of a cyst stage which is highly resistant to most chemical and physical agents. Recently, the activity of Olive Leaf Extracts (OLE) was demonstrated against Acanthamoeba species. However, the molecules involved in this activity were not identified and/or evaluated. Therefore, the aim of this study was to evaluate the activity of the main molecules which are present in OLE and secondly to study their mechanism of action in Acanthamoeba. Among the tested molecules, the observed activities ranged from an IC50 of 6.59 in the case of apigenine to an IC50 > 100 MUg/ml for other molecules. After that, elucidation of the mechanism of action of these molecules was evaluated by the detection of changes in the phosphatidylserine (PS) exposure, the permeability of the plasma membrane, the mitochondrial membrane potential and the ATP levels in the treated cells. Vanillic, syringic and ursolic acids induced the higher permeabilization of the plasma membrane. Nevertheless, the mitochondrial membrane was altered by all tested molecules which were also able to decrease the ATP levels to less than 50% in IC90 treated cells after 24 h. Therefore, all the molecules tested in this study could be considered as a future therapeutic alternative against Acanthamoeba spp. Further studies are needed in order to establish the true potential of these molecules against these emerging opportunistic pathogenic protozoa. PMID- 28859106 TI - Local inner ear application of dexamethasone in cochlear implant models is safe for auditory neurons and increases the neuroprotective effect of chronic electrical stimulation. AB - Dexamethasone (DEX) can reduce fibrous tissue growth as well as loss of residual hearing which may occur after cochlear implantation. Little is known about the effect of local inner ear DEX treatment on the spiral ganglion neurons (SGN), which are the target of the electrical stimulation with a cochlear implant (CI). Three different clinically relevant strategies of DEX-delivery into the inner ear were used. DEX was either eluted from the electrode carriers' silicone, released from a reservoir by passive diffusion, or actively applied using a pump based system. The effect of the locally applied DEX on SGN density, size and function was evaluated. DEX did not affect the SGN density compared to the relevant control groups. Simultaneously applied with chronic electrical stimulation (ES), DEX increased the neuroprotective effect of ES in the basal region and the hearing threshold tended to decrease. The EABR thresholds did not correlate with the relevant SGN density. When correlating the SGN number with fibrosis, no dependency was observed. DEX concentrations as applied in these animal models are safe for inner ear delivery in terms of their effect on SGN density. Additionally, DEX tends to improve the neuroprotective effect of chronic electrical stimulation by increasing the number of surviving neurons. This is an important finding in regard to clinical applications of DEX for local treatment of the inner ear in view of cochlear implantation and other applications. PMID- 28859107 TI - Evaluation of the cost-effectiveness of bovine brucellosis surveillance in a disease-free country using stochastic scenario tree modelling. AB - Surveillance systems of exotic infectious diseases aim to ensure transparency about the country-specific animal disease situation (i.e. demonstrate disease freedom) and to identify any introductions. In a context of decreasing resources, evaluation of surveillance efficiency is essential to help stakeholders make relevant decisions about prioritization of measures and funding allocation. This study evaluated the efficiency (sensitivity related to cost) of the French bovine brucellosis surveillance system using stochastic scenario tree models. Cattle herds were categorized into three risk groups based on the annual number of purchases, given that trading is considered as the main route of brucellosis introduction in cattle herds. The sensitivity in detecting the disease and the costs of the current surveillance system, which includes clinical (abortion) surveillance, programmed serological testing and introduction controls, were compared to those of 19 alternative surveillance scenarios. Surveillance costs included veterinary fees and laboratory analyses. The sensitivity over a year of the current surveillance system was predicted to be 91+/-7% at a design prevalence of 0.01% for a total cost of 14.9+/-1.8 million ?. Several alternative surveillance scenarios, based on clinical surveillance and random or risk-based serological screening in a sample (20%) of the population, were predicted to be at least as sensitive but for a lower cost. Such changes would reduce whole surveillance costs by 20 to 61% annually, and the costs for farmers only would be decreased from about 12.0 million ? presently to 5.3-9.0 million ? (i.e. 25-56% decrease). Besides, fostering the evolution of the surveillance system in one of these directions would be in agreement with the European regulations and farmers perceptions on brucellosis risk and surveillance. PMID- 28859109 TI - Assessing the population coverage of a health demographic surveillance system using satellite imagery and crowd-sourcing. AB - Remotely sensed data can serve as an independent source of information about the location of residential structures in areas under demographic and health surveillance. We report on results obtained combining satellite imagery, imported from Bing, with location data routinely collected using the built-in GPS sensors of tablet computers, to assess completeness of population coverage in a Health and Demographic Surveillance System in Malawi. The Majete Malaria Project Health and Demographic Surveillance System, in Malawi, started in 2014 to support a project with the aim of studying the reduction of malaria using an integrated control approach by rolling out insecticide treated nets and improved case management supplemented with house improvement and larval source management. In order to support the monitoring of the trial a Health and Demographic Surveillance System was established in the area that surrounds the Majete Wildlife Reserve (1600 km2), using the OpenHDS data system. We compared house locations obtained using GPS recordings on mobile devices during the demographic surveillance census round with those acquired from satellite imagery. Volunteers were recruited through the crowdcrafting.org platform to identify building structures on the images, which enabled the compilation of a database with coordinates of potential residences. For every building identified on these satellite images by the volunteers (11,046 buildings identified of which 3424 (ca. 30%) were part of the censused area), we calculated the distance to the nearest house enumerated on the ground by fieldworkers during the census round of the HDSS. A random sample of buildings (85 structures) identified on satellite images without a nearby location enrolled in the census were visited by a fieldworker to determine how many were missed during the baseline census survey, if any were missed. The findings from this ground-truthing effort suggest that a high population coverage was achieved in the census survey, however the crowd sourcing did not locate many of the inhabited structures (52.3% of the 6543 recorded during the census round). We conclude that using auxiliary data can play a useful role in quality assurance in population based health surveillance, but improved algorithms would be needed if crowd-sourced house locations are to be used as the basis of population databases. PMID- 28859108 TI - Obesity-associated metabolic syndrome spontaneously induces infiltration of pro inflammatory macrophage in synovium and promotes osteoarthritis. AB - OBJECTIVES: Epidemiological and experimental studies have established obesity to be an important risk factor for osteoarthritis (OA), however, the mechanisms underlying this link remains largely unknown. Here, we studied local inflammatory responses in metabolic-OA. METHODS: Wistar rats were fed with control diet (CD) and high-carbohydrate, high-fat diet (HCHF) for period of 8 and 16 weeks. After euthanasia, the knees were examined to assess the articular cartilage changes and inflammation in synovial membrane. Further IHC was conducted to determine the macrophage-polarization status of the synovium. In addition, CD and HCHF synovial fluid was co-cultured with bone marrow-derived macrophages to assess the effect of synovial fluid inflammation on macrophage polarisation. RESULTS: Our study showed that, obesity induced by a high-carbohydrate, high-fat (HCHF) diet is associated with spontaneous and local inflammation of the synovial membranes in rats even before the cartilage degradation. This was followed by increased synovitis and increased macrophage infiltration into the synovium and a predominant elevation of pro-inflammatory M1 macrophages. In addition, bone marrow derived macrophages, cultured with synovial fluid collected from the knees of obese rats exhibited a pro-inflammatory M1 macrophage phenotype. CONCLUSION: Our study demonstrate a strong association between obesity and a dynamic immune response locally within synovial tissues. Furthermore, we have also identified synovial resident macrophages to play a vital role in the inflammation caused by the HCHF diet. Therefore, future therapeutic strategies targeted at the synovial macrophage phenotype may be the key to break the link between obesity and OA. PMID- 28859110 TI - Junk food diet-induced obesity increases D2 receptor autoinhibition in the ventral tegmental area and reduces ethanol drinking. AB - Similar to drugs of abuse, the hedonic value of food is mediated, at least in part, by the mesostriatal dopamine (DA) system. Prolonged intake of either high calorie diets or drugs of abuse both lead to a blunting of the DA system. Most studies have focused on DAergic alterations in the striatum, but little is known about the effects of high calorie diets on ventral tegmental area (VTA) DA neurons. Since high calorie diets produce addictive-like DAergic adaptations, it is possible these diets may increase addiction susceptibility. However, high calorie diets consistently reduce psychostimulant intake and conditioned place preference in rodents. In contrast, high calorie diets can increase or decrease ethanol drinking, but it is not known how a junk food diet (cafeteria diet) affects ethanol drinking. In the current study, we administered a cafeteria diet consisting of bacon, potato chips, cheesecake, cookies, breakfast cereals, marshmallows, and chocolate candies to male Wistar rats for 3-4 weeks, producing an obese phenotype. Prior cafeteria diet feeding reduced homecage ethanol drinking over 2 weeks of testing, and transiently reduced sucrose and chow intake. Importantly, cafeteria diet had no effect on ethanol metabolism rate or blood ethanol concentrations following 2g/kg ethanol administration. In midbrain slices, we showed that cafeteria diet feeding enhances DA D2 receptor (D2R) autoinhibition in VTA DA neurons. These results show that junk food diet-induced obesity reduces ethanol drinking, and suggest that increased D2R autoinhibition in the VTA may contribute to deficits in DAergic signaling and reward hypofunction observed with obesity. PMID- 28859111 TI - Geographical variations in bacterial communities associated with soft coral Scleronephthya gracillimum. AB - Environmental impacts can alter relationships between a coral and its symbiotic microbial community. Furthermore, changes in the microbial community associated with increased seawater temperatures can cause opportunistic infections, coral disease and death. Interactions between soft corals and their associated microbes are not well understood. The species Scleronephthya gracillimum is distributed in tropical to temperate zones in coral assemblages along the Kuroshio Current region. In this study we collected S. gracillimum from various sites at different latitudes, and compared composition of their bacterial communities using Next Generation Sequencing. Coral samples from six geographically distinct areas (two sites each in Taiwan, Japan, and Korea) had considerable variation in their associated bacterial communities and diversity. Endozoicimonaceae was the dominant group in corals from Korea and Japan, whereas Mycoplasma was dominant in corals from Taiwan corals. Interestingly, the latter corals had lower relative abundance of Endozoicimonaceae, but greater diversity. These biogeographic differences in bacterial composition may have been due to varying environmental conditions among study locations, or because of host responses to prevailing environmental conditions. This study provided a baseline for future studies of soft coral microbiomes, and assessment of functions of host metabolites and soft coral holobionts. PMID- 28859113 TI - Unusual cohabitation and competition between Planktothrix rubescens and Microcystis sp. (cyanobacteria) in a subtropical reservoir (Hammam Debagh) located in Algeria. AB - Succession in bloom-forming cyanobacteria belonging to distant functional groups in freshwater ecosystems is currently an undescribed phenomenon. However in the Hammam Debagh reservoir (Algeria), P. rubescens and Microcystis sp. co-occur and sometimes proliferate. With the aim of identifying the main factors and processes involved in this unusual cohabitation, water samples were collected monthly from February 2013 to June 2015 at the subsurface at four sampling stations and along the entire water column at one sampling station. In addition, the composition of the cyanobacterial communities was estimated by Illumina sequencing of a 16S rRNA gene fragment from samples collected over one year (October 2013-November 2014). This molecular approach showed that the Hammam Debagh reservoir displays high species richness (89 species) but very low diversity due to the high dominance of Microcystis in this community. Furthermore, it appears that Planktothrix rubescens and Microcystis sp. coexisted (from September to January) but proliferated alternately (Spring 2015 for P. rubescens and Spring 2014 and Autumn 2014/2015 for Microcystis). The main factors and processes explaining these changes in bloom-forming species seem to be related to the variation in the depth of the lake during the mixing period and to the water temperatures during the winter prior to the bloom season in spring. PMID- 28859112 TI - Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development. AB - The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as "A Human Inflammation Model for Cancer Development". This novel concept has been built upon clinical, experimental, genomic, immunological and not least epidemiological studies. Only a few studies have described the development of MPNs by mathematical models, and none have addressed the role of inflammation for clonal evolution and disease progression. Herein, we aim at using mathematical modelling to substantiate the concept of chronic inflammation as an important trigger and driver of MPNs.The basics of the model describe the proliferation from stem cells to mature cells including mutations of healthy stem cells to become malignant stem cells. We include a simple inflammatory coupling coping with cell death and affecting the basic model beneath. First, we describe the system without feedbacks or regulatory interactions. Next, we introduce inflammatory feedback into the system. Finally, we include other feedbacks and regulatory interactions forming the inflammatory-MPN model. Using mathematical modeling, we add further proof to the concept that chronic inflammation may be both a trigger of clonal evolution and an important driving force for MPN disease progression. Our findings support intervention at the earliest stage of cancer development to target the malignant clone and dampen concomitant inflammation. PMID- 28859114 TI - Using King Vision video laryngoscope with a channeled blade prolongs time for tracheal intubation in different training levels, compared to non-channeled blade. AB - PURPOSE: It is generally accepted that using a video laryngoscope is associated with an improved visualization of the glottis. However, correctly placing the endotracheal tube might be challenging. Channeled video laryngoscopic blades have an endotracheal tube already pre-loaded, allowing to advance the tube once the glottis is visualized. We hypothesized that use of a channel blade with pre loaded endotracheal tube results in a faster intubation, compared to a curved Macintosh blade video laryngoscope. METHODS: After ethical approval and informed consent, patients were randomized to receive endotracheal Intubation with either the King Vision(r) video laryngoscope with curved blade (control) or channeled blade (channeled). Success rate, evaluation of the glottis view (percentage of glottic opening (POGO), Cormack&Lehane (C&L)) and intubating time were evaluated. RESULTS: Over a two-month period, a total of 46 patients (control n = 23; channeled n = 23) were examined. The first attempt success rates were comparable between groups (control 100% (23/23) vs. channeled 96% (22/23); p = 0.31). Overall intubation time was significantly shorter with control (median 40 sec; IQR [24-58]), compared to channeled (59 sec [40-74]; p = 0.03). There were no differences in glottis visualization between groups. CONCLUSION: Compared with the King Vision channeled blade, time for tracheal intubation was shorter with the control group using a non-channeled blade. First attempt success and visualization of the glottis were comparable. These data do not support the hypothesis that a channeled blade is superior to a curved video laryngoscopic blade without tube guidance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02344030. PMID- 28859115 TI - Development and validation of a rapid and robust method to determine visceral adipose tissue volume using computed tomography images. AB - BACKGROUND: Visceral adiposity is a risk factor for many chronic diseases. Existing methods to quantify visceral adipose tissue volume using computed tomographic (CT) images often use a single slice, are manual, and are time consuming, making them impractical for large population studies. We developed and validated a method to accurately, rapidly, and robustly measure visceral adipose tissue volume using CT images. METHODS: In-house software, Medical Executable for the Efficient and Robust Quantification of Adipose Tissue (MEERQAT), was developed to calculate visceral adipose tissue volume using a series of CT images within a manually identified region of interest. To distinguish visceral and subcutaneous adipose tissue, ellipses are drawn through the rectus abdominis and transverse abdominis using manual and automatic processes. Visceral and subcutaneous adipose tissue volumes are calculated by counting the numbers of voxels corresponding to adipose tissue in the region of interest. MEERQAT's ellipse interpolation method was validated by comparing visceral adipose volume from 10 patients' CT scans with corresponding results from manually delineated scans. Accuracy of visceral adipose quantification was tested using a phantom consisting of animal fat and tissues. Robustness of the method was tested by determining intra-observer and inter-observer coefficients of variation (CV). RESULTS: The mean difference in visceral adipose tissue volume between manual and elliptical delineation methods was -0.54 +/- 4.81%. In the phantom, our measurement differed from the known adipose volume by <= 7.5% for all scanning parameters. Mean inter-observer CV for visceral adipose tissue volume was 0.085, and mean intra-observer CV for visceral adipose tissue volume was 0.059. CONCLUSIONS: We have developed and validated a robust method of accurately and quickly determining visceral adipose tissue volume in any defined region of interest using CT imaging. PMID- 28859116 TI - The Sommersdorf mummies-An interdisciplinary investigation on human remains from a 17th-19th century aristocratic crypt in southern Germany. AB - Sommersdorf Castle (Bavaria, Germany) is a medieval castle complex which has been inhabited by the aristocratic family von Crailsheim. The deceased were entombed in a crypt located in the parapets underneath the castle's church, resulting in mummification of the bodies. Based on the family chronicle and oral history, identities have been ascribed to the mummies. The aim of the study is therefore to test the accuracy of the historical records in comparison to archaeological, anthropological and genetic data. Today, the crypt houses eleven wooden coffins from the 17th to 19th century AD. In ten of these, mummified and scattered human remains were found. Archive records were studied in order to identify names, ancestry, titles, occupation, date of birth and death, and place of interment of the individuals. The coffins were visually inspected and dated by typo chronology, and the mummified and scattered skeletal remains were subjected to a physical anthropological examination. In total, the crypt contains the remains of a minimum number of nine individuals, among them three adult males, five adult females and one infant. A detailed scientific examination, including prior conservation, ancient DNA analyses, and computed tomography (CT), was performed on five mummies. By means of the CT data age at death, sex, body height, pathologies, and anatomical variants were investigated. CT analysis further showed that the bodies were naturally mummified. Mitochondrial DNA analyses revealed that the tested individuals are not maternally related. In addition, health, living conditions and circumstances of death of the entombed individuals could be highlighted. Being confronted with the strengths, weaknesses and limitations of each methodological approach, probable identification was achieved in two cases. PMID- 28859118 TI - Tumor parameters predict the risk of side effects after ruthenium-106 plaque brachytherapy of uveal melanomas. AB - BACKGROUND: To report on radiation-related side effects and complications after ruthenium-106 plaque brachytherapy of uveal melanomas. METHODS: Medical records of 143 eyes with uveal melanoma, treated by ruthenium-106 brachytherapy between 1997 and 2012 at a single center, were analyzed. We evaluated the occurrence of radiation-related side effects on the anterior and posterior segment of the eye. The influence of patient, tumor and treatment parameters on outcome was analyzed by multivariate time to event analysis considering competing risks. RESULTS: The median overall follow-up was 37.9 months. After treatment, the estimated risk at 12, 24 and 48 months for developing anterior segment complications was 25.3%, 37.5% and 50.3% for cataract formation and 5.4%, 6.4% and 8.1% for secondary glaucoma, respectively. The estimated risk for the occurrence of posterior segment complications 12, 24 and 48 months after treatment was 3.1%, 6.7% and 18.3% for radiation retinopathy, 18.3%, 27.1% and 42.6% for radiation maculopathy and 16.5%, 21.0% and 32.8% for radiation neuropathy, respectively. The risk of an increase in retinal detachment after treatment was 14.7%, 14.7% and 17.4% at 12, 24 and 48 months, respectively. The risk of vitreous hemorrhage occurring after treatment was 6.2%, 8.1% and 12.7%, and the risk of tumor vasculopathy was 15.4%, 17.4% and 19.0%. Scleral necrosis was observed in one patient. CONCLUSION: Radiation-related side effects and complications are common among patients treated with ruthenium brachytherapy for uveal melanoma. However, the risk for those largely depends on individual tumor parameters. Before treatment, patients should be informed of their specific risks to develop various side effects. Patient information before treatment should cover not only general information about the treatment and possible complications and side effects but should also give details on the specific risks of the patient in her individual situation. This also includes elucidating the patient's individual resources and expectations and her willingness for long-term regular follow-up examinations and secondary adjunct treatments. PMID- 28859117 TI - Phosphorylation of STAT3 at Tyr705 regulates MMP-9 production in epithelial ovarian cancer. AB - Ovarian cancer's poor progression is closely associated with overexpression of matrix metalloproteinase 9 (MMP-9), which belongs to the class of enzymes believed to be involved in the degradation of extracellular matrix. However, the mechanisms underlying regulation of MMP-9 are not completely understood. STAT (signal transducer and activator of transcription) family of transcription factors is well known to be engaged in diverse cellular functions. Activation of STAT3 has been observed in a number of cancers, promoting tumorigenesis and metastasis via transcriptional activation of its target genes. In this study, we tested our hypothesis that STAT3 regulates MMP-9 gene expression in epithelial ovarian cancer. Using epithelial ovarian cancer cell lines as in vitro model, we show an abundance of phosphorylated STAT3 at Tyr705 (p-STAT3) in SKOV3 cell line. We further show that MMP-9 gene promoter was significantly enriched by p-STAT3, and IL-6 treatment led to a significant increase of MMP-9 at mRNA and protein levels, in addition to an association of p-STAT3 with MMP-9 gene. By using luciferase reporter assay, we determined that the STAT3 DNA responsive element of MMP-9 was sufficient to regulate transcriptional activity of a heterologous promoter. These results suggest that the phosphorylation of STAT3 regulates MMP-9 production in ovarian cancer, which might be responsible for its invasiveness and metastasis. PMID- 28859119 TI - Characteristics of the King-Devick test in the assessment of concussed patients in the subacute and later stages after injury. AB - Although the King-Devick (K-D) test has been used frequently in assessing sports related concussion early after injury, its characteristics over time after injury and in patients with prolonged persistent symptoms are unknown. The purpose of this paper was to: evaluate the ability of the K-D Test to distinguish patients seen early after concussion from those with symptoms persisting more than 3 months compared to controls, assess changes in the K-D test times over time after concussion, and determine the relationship of K-D times to the Stroop Color and Word Test scores. We performed cross-sectional comparisons of patients with recent concussive brain injury (acute group) and those with symptoms persisting more than 3 months to healthy controls on the K-D test, the Sports Concussion Assessment Tool 3 (SCAT3), and the Stroop Color and Word Test. Longitudinal comparisons of the acute group over time within the first month after injury were also made. Post-concussive syndrome (PCS) patients had significantly higher K-D times compared to controls (p = 0.01), while the acute group did not differ from controls(p = 0.33). K-D times at the second visit for the acute group were similar to those of controls (54.7 vs. 49.6, p = 0.31). While SCAT3 scores improved over time in the acute group, the K-D scores did not change between the first and second visit (55.2 vs. 54.7, p = 0.94). K-D scores correlated significantly with the Stroop scores for all three participant groups. The K-D test is likely useful very early after concussion in conjunction with baseline scores, and while scores in PCS patients remain elevated, they can be confounded by factors such as pre-morbid depression and medication use. High correlations with Stroop scores also suggest that performance on the K-D test can by proxy provide additional insight about cognitive function and predict performance on more cognitively demanding tasks. PMID- 28859120 TI - Semi-quantitative MALDI-TOF for antimicrobial susceptibility testing in Staphylococcus aureus. AB - Antibiotic resistant bacterial infections are a significant problem in the healthcare setting, in many cases requiring the rapid administration of appropriate and effective antibiotic therapy. Diagnostic assays capable of quickly and accurately determining the pathogen resistance profile are therefore crucial to initiate or modify care. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a standard method for species identification in many clinical microbiology laboratories and is well positioned to be applied towards antimicrobial susceptibility testing. One recently reported approach utilizes semi-quantitative MALDI-TOF MS for growth rate analysis to provide a resistance profile independent of resistance mechanism. This method was previously successfully applied to Gram-negative pathogens and mycobacteria; here, we evaluated this method with the Gram-positive pathogen Staphylococcus aureus. Specifically, we used 35 strains of S. aureus and four antibiotics to optimize and test the assay, resulting in an overall accuracy rate of 95%. Application of the optimized assay also successfully determined susceptibility from mock blood cultures, allowing both species identification and resistance determination for all four antibiotics within 3 hours of blood culture positivity. PMID- 28859121 TI - Economic impact and policy implications from urban shared transportation: The case of Pittsburgh's shared bike system. AB - During the last years the number of cities that have installed and started operating shared bike systems has significantly increased. These systems provide an alternative and sustainable mean of transportation to the city dwellers. Apart from the energy sustainability benefits, shared bike systems can have a positive effect on residents' health, air quality and the overall condition of the currently crumbling road network infrastructure. Anecdotal stories and survey studies have also identified that bike lanes have a positive impact on local businesses. In this study, driven by the rapid adoption of shared bike systems by city governments and their potential positive effects on a number of urban life facets we opt to study and quantify the value of these systems. We focus on a specific aspect of this value and use evidence from the real estate market in the city of Pittsburgh to analyze the effect on dwellers' properties of the shared bike system installed in the city in June 2015. We use quasi-experimental techniques and find that the shared bike system led to an increase in the housing prices (both sales and rental prices) in the zip codes where shared bike stations were installed. We further bring into the light potential negative consequences of this impact (i.e., gentrification) and discuss/propose two public policies that can exploit the impact of the system for the benefit of both the local government as well as the city dwellers. PMID- 28859122 TI - Effects of arachidonyl-2'-chloroethylamide (ACEA) on the protective action of various antiepileptic drugs in the 6-Hz corneal stimulation model in mice. AB - Accumulating evidence indicates that cannabinoid CB1 receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2'-chloroethylamide (ACEA-a selective cannabinoid CB1 receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (P<0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB1 receptor mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future. PMID- 28859123 TI - Prognostic significance of the co-expression of EGFR and HER2 in adenocarcinoma of the uterine cervix. AB - Prognostic factors and therapeutic targets are needed for the patients with cervical adenocarcinoma because they have a poor prognosis. Recently, co expression of multiple receptor tyrosine kinases (RTKs) has been found to be associated with aggressive biological behavior and poor prognosis of several types of malignancy. To evaluate the significance of the expression of multiple RTKs in uterine cervical cancers, we examined the expression profile of RTKs (EGFR, HER2 and c-Met) and the correlation of their expression with clinicopathological features and prognosis of patients with cervical adenocarcinomas. AIS and adenocarcinoma showed strong expression of a single RTK (EGFR, HER2 or c-Met) on the cell membrane in 41 (77.4%) of 53 cases. Twenty (46%) of the 43 adenocarcinoma cases were positive for double or triple RTKs (P = 0.034). Positivity for EGFR and double positivity for EGFR and HER2 (EGFR+/HER2+/c-Met+ and EGFR+/HER2+/c-Met-) were significantly correlated with lymph node metastasis (P = 0.010 for single and P = 0.013 for double) and UICC stage (P = 0.021 for single and P = 0.007 for double). Positivity for HER2 was significantly correlated with tumor size (P = 0.029). Relapse-free survival (RFS) was significantly shorter in patients who were double positive for EGFR and HER2. Our results suggest that EGFR and HER2 are potential therapeutic targets and that their co-expression is a prognostic factor for cervical adenocarcinoma. PMID- 28859124 TI - Effect of general anesthesia on neonatal aEEG-A cohort study of patients with non cardiac congenital anomalies. AB - INTRODUCTION: The aim of the current study was to determine the effect of general anesthesia on neonatal brain activity using amplitude-integrated EEG (aEEG). METHODS: A prospective cohort study of neonates (January 2013-December 2015), who underwent major neonatal surgery for non-cardiac congenital anomalies. Anesthesia was administered at the discretion of the anesthetist. aEEG monitoring was started six hours preoperatively until 24 hours after surgery. Analysis of classes of aEEG background patterns, ranging from continuous normal voltage to flat trace in six classes, and quantitative EEG-measures, using spontaneous activity transients (SATs) and interSATintervals (ISI), was performed. RESULTS: In total, 111 neonates were included (36 preterm/75 full-term), age at time of surgery was (median (range) 2 (0-32) days. During anesthesia depression of brain activity was seen, with background patterns ranging from flat trace to discontinuous normal voltage. In most patients brain activity was two background pattern classes lower during anesthesia. After cessation of anesthesia, recovery to preoperative brain activity occurred within 24 hours in 86% of the preterm and 96% of the term infants. Gestational age and the dose of sevoflurane were significantly associated with SAT-rate (F(2,68) = 9.288, p < 0.001) and ISI- durations during surgery (F(3,71) = 12.96, p < 0.001). Background pattern and quantitative EEG-values were not associated with brain lesions (chi2(4) = 2.086, ns). CONCLUSION: aEEG shows a variable reduction of brain activity in response to anesthesia in neonates with noncardiac congenital anomalies, with fast recovery after cessation of anesthesia. This reduction is related to gestational age and the dose of sevoflurane. The aEEG offers the opportunity to monitor the depth of anesthesia in the neonate. PMID- 28859125 TI - Searchable attribute-based encryption scheme with attribute revocation in cloud storage. AB - Attribute based encryption (ABE) is a good way to achieve flexible and secure access control to data, and attribute revocation is the extension of the attribute-based encryption, and the keyword search is an indispensable part for cloud storage. The combination of both has an important application in the cloud storage. In this paper, we construct a searchable attribute-based encryption scheme with attribute revocation in cloud storage, the keyword search in our scheme is attribute based with access control, when the search succeeds, the cloud server returns the corresponding cipher text to user and the user can decrypt the cipher text definitely. Besides, our scheme supports multiple keywords search, which makes the scheme more practical. Under the assumption of decisional bilinear Diffie-Hellman exponent (q-BDHE) and decisional Diffie Hellman (DDH) in the selective security model, we prove that our scheme is secure. PMID- 28859126 TI - Development of a real-time PCR for detection of Staphylococcus pseudintermedius using a novel automated comparison of whole-genome sequences. AB - Staphylococcus pseudintermedius is an opportunistic pathogen in dogs and cats and occasionally causes infections in humans. S. pseudintermedius is often resistant to multiple classes of antimicrobials. It requires a reliable detection so that it is not misidentified as S. aureus. Phenotypic and currently-used molecular based diagnostic assays lack specificity or are labour-intensive using multiplex PCR or nucleic acid sequencing. The aim of this study was to identify a specific target for real-time PCR by comparing whole genome sequences of S. pseudintermedius and non-pseudintermedius.Genome sequences were downloaded from public repositories and supplemented by isolates that were sequenced in this study. A Perl-script was written that analysed 300-nt fragments from a reference genome sequence of S. pseudintermedius and checked if this sequence was present in other S. pseudintermedius genomes (n = 74) and non-pseudintermedius genomes (n = 138). Six sequences specific for S. pseudintermedius were identified (sequence length between 300-500 nt). One sequence, which was located in the spsJ gene, was used to develop primers and a probe. The real-time PCR showed 100% specificity when testing for S. pseudintermedius isolates (n = 54), and eight other staphylococcal species (n = 43). In conclusion, a novel approach by comparing whole genome sequences identified a sequence that is specific for S. pseudintermedius and provided a real-time PCR target for rapid and reliable detection of S. pseudintermedius. PMID- 28859127 TI - Peptide B targets soluble guanylyl cyclase alpha1 and kills prostate cancer cells. AB - Among androgen-regulated genes, soluble guanylyl cyclase alpha1 (sGCalpha1) is significant in promoting the survival and growth of prostate cancer cells and does so independent of nitric oxide (NO) signaling. Peptides were designed targeting sGCalpha1 to block its pro-cancer functions and one peptide is discussed here. Peptide B-8R killed both androgen-dependent and androgen independent prostate cancer cells that expressed sGCalpha1, but not cells that do not express this gene. Peptide B-8R induced apoptosis of prostate cancer cells. Importantly, Peptide B-8R does not affect nor its cytotoxicity depend on NO signaling, despite the fact that it associates with sGCalpha1, which dimerizes with sGCbeta1 to form the sGC enzyme. Just as with a previously studied Peptide A 8R, Peptide B-8R induced elevated levels of reactive oxygen species (ROS) in prostate cancer cells, but using a ROS-sequestering agent showed that ROS was not responsible the cytotoxic activity of Peptide B-8R. Interestingly, Peptide B-8R induced elevated levels of p53 and phosphorylated p38, but neither of these changes is the cause of the peptide's cytotoxicity. Additional drugs were used to alter levels of iron levels in cells and these studies showed that Peptide B-8R activity does not depend on Ferroptosis. Thus, future work will be directed at defining the mechanism of cytotoxic action of Peptide B-8R against prostate cancer cells. PMID- 28859128 TI - Plasma microvesicle analysis identifies microRNA 129-5p as a biomarker of heart failure in univentricular heart disease. AB - Biomarkers of heart failure in adults have been extensively studied. However, biomarkers to monitor the progression of heart failure in children with univentricular physiology are less well understood. We proposed that as mediators of diverse pathophysiology, miRNAs contained within circulating microvesicles could serve as biomarkers for the presence and progression of heart failure in univentricular patients. To test this, we studied the association of heart failure with elevations in specific miRNAs isolated from circulating microvesicles in a cohort of children with univentricular heart disease and heart failure. We conducted a single site cross-sectional observational study of 71 children aged 1 month-7 years with univentricular heart disease and heart failure. We demonstrated that levels of miR129-5p isolated from plasma microvesicles were inversely related to the degree of clinical heart failure as assessed by Ross score. We then showed that miR129-5p levels are downregulated in HL1 cells and human embryonic stem cell-derived cardiomyocytes exposed to oxidative stress. We demonstrated that bone morphogenetic protein receptor 2, which has been implicated in the development of pulmonary vascular disease, is a target of miR129-5p, and conversely regulated in response to oxidative stress in cell culture. Levels of miR129-5p were inversely related to the degree of clinical heart failure in patients with univentricular heart disease. This study demonstrates that miR129-5p is a sensitive and specific biomarker for heart failure in univentricular heart disease independent of ventricular morphology or stage of palliation. Further study is warranted to understand the targets affected by miR129-5p with the development of heart failure in patients with univentricular physiology. PMID- 28859129 TI - Rhinovirus induction of fractalkine (CX3CL1) in airway and peripheral blood mononuclear cells in asthma. AB - Rhinovirus infection is associated with the majority of asthma exacerbations. The role of fractalkine in anti-viral (type 1) and pathogenic (type 2) responses to rhinovirus infection in allergic asthma is unknown. To determine whether (1) fractalkine is produced in airway cells and in peripheral blood leucocytes, (2) rhinovirus infection increases production of fractalkine and (3) levels of fractalkine differ in asthmatic compared to non-asthmatic subjects. Fractalkine protein and mRNA levels were measured in bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMCs) from non-asthmatic controls (n = 15) and mild allergic asthmatic (n = 15) subjects. Protein levels of fractalkine were also measured in macrophages polarised ex vivo to give M1 (type 1) and M2 (type 2) macrophages and in BAL fluid obtained from mild (n = 11) and moderate (n = 14) allergic asthmatic and non-asthmatic control (n = 10) subjects pre and post in vivo rhinovirus infection. BAL cells produced significantly greater levels of fractalkine than PBMCs. Rhinovirus infection increased production of fractalkine by BAL cells from non-asthmatic controls (P<0.01) and in M1-polarised macrophages (P<0.05), but not in BAL cells from mild asthmatics or in M2 polarised macrophages. Rhinovirus induced fractalkine in PBMCs from asthmatic (P<0.001) and healthy control subjects (P<0.05). Trends towards induction of fractalkine in moderate asthmatic subjects during in vivo rhinovirus infection failed to reach statistical significance. Fractalkine may be involved in both immunopathological and anti-viral immune responses to rhinovirus infection. Further investigation into how fractalkine is regulated across different cell types and into the effect of stimulation including rhinovirus infection is warranted to better understand the precise role of this unique dual adhesion factor and chemokine in immune cell recruitment. PMID- 28859130 TI - Molecular basis of surface anchored protein A deficiency in the Staphylococcus aureus strain Wood 46. AB - Protein A in Staphylococcus aureus is encoded by the spa (staphylococcal protein A) gene and binds to immunoglobulin (Ig). The S. aureus strain Wood 46 has been variously reported as protein A-deficient and/or spa negative and used as a control in animal models of staphylococcal infections. The results of this study indicate that Wood 46 has normal spa expression but transcribes very low levels of the srtA gene which encodes the sortase A (SrtA) enzyme. This is consistent with unique mutations in the srtA promoter. In this study, a low level of sortase A explains deficient anchoring of proteins with an LPXTG motif, such as protein A, fibrinogen-binding protein and fibronectin-binding proteins A and B on to the peptidoglycan cell wall. The activity of secreted protein A is an important consideration for use of Wood 46 in functional experiments and animal models. PMID- 28859132 TI - Suppression of cuelure attraction in male Queensland fruit flies provided raspberry ketone supplements as immature adults. AB - Tephritid fruit flies are amongst the most damaging insect pests of horticulture globally. Some of the key fruit fly species are managed using the sterile insect technique (SIT), whereby millions of sterile males are released to suppress reproduction of pest populations. Male annihilation technique (MAT), whereby sex specific lures are used to attract and kill males, is often used to reduce wild male numbers before SIT programs commence, providing released sterile males an increased numerical advantage. Overall program efficacy might be improved if MAT could be deployed simultaneously with SIT, continuously depleting fertile males from pest populations and replacing them with sterile males. However, such 'male replacement' requires a means of suppressing attraction of released sterile males to lures used in MAT. Previous studies have found that exposure of some fruit flies to lure compounds as mature adults can suppress subsequent response to those lures, raising the possibility of pre-release treatments. However, this approach requires holding flies until after maturation for treatment and then release. The present study takes a novel approach of exposing immature adult male Queensland fruit flies (Bactrocera tryoni, or 'Qfly') to raspberry ketone (RK) mixed in food, forcing these flies to ingest RK at ages far younger than they would naturally. After feeding on RK-supplemented food for two days after emergence, male Qflies exhibited a reduction in attraction to cuelure traps that lasted more than 20 days. This approach to RK exposure is compatible with current practises, in which Qflies are released as immature adults, and also yields advantages of accelerated reproductive development and increased mating propensity at young ages. PMID- 28859131 TI - Mouse models of human ocular disease for translational research. AB - Mouse models provide a valuable tool for exploring pathogenic mechanisms underlying inherited human disease. Here, we describe seven mouse models identified through the Translational Vision Research Models (TVRM) program, each carrying a new allele of a gene previously linked to retinal developmental and/or degenerative disease. The mutations include four alleles of three genes linked to human nonsyndromic ocular diseases (Aipl1tvrm119, Aipl1tvrm127, Rpgrip1tvrm111, RhoTvrm334) and three alleles of genes associated with human syndromic diseases that exhibit ocular phentoypes (Alms1tvrm102, Clcn2nmf289, Fkrptvrm53). Phenotypic characterization of each model is provided in the context of existing literature, in some cases refining our current understanding of specific disease attributes. These murine models, on fixed genetic backgrounds, are available for distribution upon request and may be useful for understanding the function of the gene in the retina, the pathological mechanisms induced by its disruption, and for testing experimental approaches to treat the corresponding human ocular diseases. PMID- 28859133 TI - An association of cognitive impairment with diabetes and retinopathy in end stage renal disease patients under peritoneal dialysis. AB - BACKGROUND: Diabetes and retinopathy have been considered as risk factors of cognitive impairment (CI) in previous studies. We investigated both of these two factors and their relationship with global and specific cognitive functions in end stage renal disease patients under peritoneal dialysis (PD). METHODS: In this multicenter cross-sectional study, 424 clinically stable patients were enrolled from 5 PD units, who performed PD for at least three months and completed fundoscopy examination if they had diabetes. Global cognitive function was measured using the Modified Mini-Mental State Examination (3MS), Trail-Making Test forms A and B for executive function, and subtests of the Battery for the Assessment of Neuropsychological Status for immediate and delayed memory, visuospatial skills, and language ability. RESULTS: PD Patients with DM and Retinopathy had significantly higher prevalence of CI, executive dysfunction, impaired immediate memory and visuospatial skill, compared with patients in non DM group. By multivariate logistic regression analyses, DM and retinopathy rather than DM only were significantly associated with increased risk for CI, executive dysfunction, impaired immediate memory and visuospatial skill, odds ratios(ORs) and 95% confidence intervals were 2.09[1.11,3.92], 2.89[1.55,5.37], 2.16 [1.15,4.06] and 2.37[1.32,4.22], respectively (all P < 0.05). CONCLUSIONS: Diabetic PD patients with retinopathy were at two times risk for overall cognitive impairment, executive dysfunction, impaired immediate memory and visuospatial skill as compared to non-diabetic PD patients. PMID- 28859134 TI - Are baboons learning "orthographic" representations? Probably not. AB - The ability of Baboons (papio papio) to distinguish between English words and nonwords has been modeled using a deep learning convolutional network model that simulates a ventral pathway in which lexical representations of different granularity develop. However, given that pigeons (columba livia), whose brain morphology is drastically different, can also be trained to distinguish between English words and nonwords, it appears that a less species-specific learning algorithm may be required to explain this behavior. Accordingly, we examined whether the learning model of Rescorla and Wagner, which has proved to be amazingly fruitful in understanding animal and human learning could account for these data. We show that a discrimination learning network using gradient orientation features as input units and word and nonword units as outputs succeeds in predicting baboon lexical decision behavior-including key lexical similarity effects and the ups and downs in accuracy as learning unfolds-with surprising precision. The models performance, in which words are not explicitly represented, is remarkable because it is usually assumed that lexicality decisions, including the decisions made by baboons and pigeons, are mediated by explicit lexical representations. By contrast, our results suggest that in learning to perform lexical decision tasks, baboons and pigeons do not construct a hierarchy of lexical units. Rather, they make optimal use of low-level information obtained through the massively parallel processing of gradient orientation features. Accordingly, we suggest that reading in humans first involves initially learning a high-level system building on letter representations acquired from explicit instruction in literacy, which is then integrated into a conventionalized oral communication system, and that like the latter, fluent reading involves the massively parallel processing of the low level features encoding semantic contrasts. PMID- 28859135 TI - Identification of miR-16 as an endogenous reference gene for the normalization of urinary exosomal miRNA expression data from CKD patients. AB - Chronic kidney disease (CKD) is a severe disorder with an increasing incidence worldwide. An early detection may help to prevent its progression and to minimize the risk of cardiovascular diseases as one of the major comorbidities. Recently, extracellular miRNAs like urinary exosomal miRNAs became of great interest as non invasive biomarkers which can be determined by RT-qPCR. But until now, there is no consensus regarding the normalization of miRNAs isolated from body fluids. The present study analyzed the miRNAs miR-16, miR-92a, miR-21, miR-124a and the small nuclear RNA RNU6B for their applicability as an endogenous reference gene in expression studies of exosomal miRNAs isolated from CKD patients. For this purpose, miRNA expression levels were determined by RT-qPCR after the isolation of urinary exosomes from 33 CKD patients and from 5 healthy controls. Expression data was analyzed with the normalization determination software NormFinder, BestKeeper, GeNorm and DeltaCt. Our results revealed an abundant expression of the four candidate miRNAs in urinary exosomes and no detectable expression of RNU6B. We identified miR-16 as the most stable endogenous reference gene in our data set, making it a suitable endogenous reference gene for miRNA studies of urinary exosomes derived from CKD patients. PMID- 28859136 TI - Integrated analysis of mRNA and miRNA expression profiling in rice backcrossed progenies (BC2F12) with different plant height. AB - Inter-specific hybridization and backcrossing commonly occur in plants. The use of progeny generated from inter-specific hybridization and backcrossing has been developed as a novel model system to explore gene expression divergence. The present study investigated the analysis of gene expression and miRNA regulation in backcrossed introgression lines constructed from cultivated and wild rice. High-throughput sequencing was used to compare gene and miRNA expression profiles in three progeny lines (L1710, L1817 and L1730), with different plant heights resulting from the backcrossing of introgression lines (BC2F12) and their parents (O. sativa and O. longistaminata). A total of 25,387 to 26,139 mRNAs and 379 to 419 miRNAs were obtained in these rice lines. More differentially expressed genes and miRNAs were detected in progeny/O. longistaminata comparison groups than in progeny/O. sativa comparison groups. Approximately 80% of the genes and miRNAs showed expression level dominance to O. sativa, indicating that three progeny lines were closer to the recurrent parent, which might be influenced by their parental genome dosage. Approximately 16% to 64% of the differentially expressed miRNAs possessing coherent target genes were predicted, and many of these miRNAs regulated multiple target genes. Most genes were up-regulated in progeny lines compared with their parents, but down-regulated in the higher plant height line in the comparison groups among the three progeny lines. Moreover, certain genes related to cell walls and plant hormones might play crucial roles in the plant height variations of the three progeny lines. Taken together, these results provided valuable information on the molecular mechanisms of hybrid backcrossing and plant height variations based on the gene and miRNA expression levels in the three progeny lines. PMID- 28859137 TI - A non-destructive DNA sampling technique for herbarium specimens. AB - Herbarium specimens are an important source of DNA for plant research but current sampling methods require the removal of material for DNA extraction. This is undesirable for irreplaceable specimens such as rare species or type material. Here I present the first non-destructive sampling method for extracting DNA from herbarium specimens. DNA was successfully retrieved from robust leaves and/or stems of herbarium specimens up to 73 years old. PMID- 28859138 TI - Inflammatory bowel disease and patterns of volatile organic compounds in the exhaled breath of children: A case-control study using Ion Molecule Reaction-Mass Spectrometry. AB - Inflammatory bowel diseases (IBD) profoundly affect quality of life and have been gradually increasing in incidence, prevalence and severity in many areas of the world, and in children in particular. Patients with suspected IBD require careful history and clinical examination, while definitive diagnosis relies on endoscopic and histological findings. The aim of the present study was to investigate whether the alveolar air of pediatric patients with IBD presents a specific volatile organic compounds' (VOCs) pattern when compared to controls. Patients 10 17 years of age, were divided into four groups: Crohn's disease (CD), ulcerative colitis (UC), controls with gastrointestinal symptomatology, and surgical controls with no evidence of gastrointestinal problems. Alveolar breath was analyzed by ion molecule reaction mass spectrometry. Four models were built starting from 81 molecules plus the age of subjects as independent variables, adopting a penalizing LASSO logistic regression approach: 1) IBDs vs. controls, finally based on 18 VOCs plus age (sensitivity = 95%, specificity = 69%, AUC = 0.925); 2) CD vs. UC, finally based on 13 VOCs plus age (sensitivity = 94%, specificity = 76%, AUC = 0.934); 3) IBDs vs. gastroenterological controls, finally based on 15 VOCs plus age (sensitivity = 94%, specificity = 65%, AUC = 0.918); 4) IBDs vs. controls, built starting from the 21 directly or indirectly calibrated molecules only, and finally based on 12 VOCs plus age (sensitivity = 94%, specificity = 71%, AUC = 0.888). The molecules identified by the models were carefully studied in relation to the concerned outcomes. This study, with the creation of models based on VOCs profiles, precise instrumentation and advanced statistical methods, can contribute to the development of new non-invasive, fast and relatively inexpensive diagnostic tools, with high sensitivity and specificity. It also represents a crucial step towards gaining further insights on the etiology of IBD through the analysis of specific molecules which are the expression of the particular metabolism that characterizes these patients. PMID- 28859140 TI - Data augmentation-assisted deep learning of hand-drawn partially colored sketches for visual search. AB - In recent years, image databases are growing at exponential rates, making their management, indexing, and retrieval, very challenging. Typical image retrieval systems rely on sample images as queries. However, in the absence of sample query images, hand-drawn sketches are also used. The recent adoption of touch screen input devices makes it very convenient to quickly draw shaded sketches of objects to be used for querying image databases. This paper presents a mechanism to provide access to visual information based on users' hand-drawn partially colored sketches using touch screen devices. A key challenge for sketch-based image retrieval systems is to cope with the inherent ambiguity in sketches due to the lack of colors, textures, shading, and drawing imperfections. To cope with these issues, we propose to fine-tune a deep convolutional neural network (CNN) using augmented dataset to extract features from partially colored hand-drawn sketches for query specification in a sketch-based image retrieval framework. The large augmented dataset contains natural images, edge maps, hand-drawn sketches, de colorized, and de-texturized images which allow CNN to effectively model visual contents presented to it in a variety of forms. The deep features extracted from CNN allow retrieval of images using both sketches and full color images as queries. We also evaluated the role of partial coloring or shading in sketches to improve the retrieval performance. The proposed method is tested on two large datasets for sketch recognition and sketch-based image retrieval and achieved better classification and retrieval performance than many existing methods. PMID- 28859139 TI - Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of IV laronidase for MPS I. METHODS: A systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including >= five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs. RESULTS: The selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant-NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 MUg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion. CONCLUSIONS: Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population. PMID- 28859142 TI - Evolutionary games, climate and the generation of diversity. AB - Environmental stochasticity and climate affect outcomes in evolutionary games, which can thereby affect biological diversity. Our maximum likelihood (ML) estimates of replicator dynamics for morph frequency data from control (25 years) and three experimentally perturbed populations (14 years) of side-blotched lizards yield a 3 * 3 payoff matrix in the generalized Rock-Paper-Scissors family; it has intransitive best replies, and each strategy is its own worst reply. ML estimates indicate significant interactive effects of density and temperature on morph frequency. Implied dynamics feature a powerful interior attractor and recover (for the first time) observed 4-5 year oscillations. Our evolutionary experiment on morph frequency confirms that oscillations are driven by frequency dependent selection, but climate entrains the cycles across the perturbed and control populations within 10 generations. Applying the model across the species range, we find that climate also accounts for morph fixation and mating system diversity, suggesting climate may similarly impact ecosystem diversity. PMID- 28859141 TI - Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure. AB - The main structural component of connective tissues is fibrillar, cross-linked collagen whose fibrillogenesis can be modulated by Small Leucine-Rich Proteins/Proteoglycans (SLRPs). Not all SLRPs' effects on collagen and extracellular matrix in vivo have been elucidated; one of the less investigated SLRPs is asporin. Here we describe the successful generation of an Aspn-/- mouse model and the investigation of the Aspn-/- skin phenotype. Functionally, Aspn-/- mice had an increased skin mechanical toughness, although there were no structural changes present on histology or immunohistochemistry. Electron microscopy analyses showed 7% thinner collagen fibrils in Aspn-/- mice (not statistically significant). Several matrix genes were upregulated, including collagens (Col1a1, Col1a2, Col3a1), matrix metalloproteinases (Mmp2, Mmp3) and lysyl oxidases (Lox, Loxl2), while lysyl hydroxylase (Plod2) was downregulated. Intriguingly no differences were observed in collagen protein content or in collagen cross-linking-related lysine oxidation or hydroxylation. The glycosaminoglycan content and structure in Aspn-/- skin was profoundly altered: chondroitin/dermatan sulfate was more than doubled and had an altered composition, while heparan sulfate was halved and had a decreased sulfation. Also, decorin and biglycan were doubled in Aspn-/- skin. Overall, asporin deficiency changes skin glycosaminoglycan composition, and decorin and biglycan content, which may explain the changes in skin mechanical properties. PMID- 28859143 TI - The effect of wool hydrolysates on squamous cell carcinoma cells in vitro. Possible implications for cancer treatment. AB - Squamous cell carcinoma of the skin is the second most common cutaneous malignancy. Despite various available treatment methods and advances in noninvasive diagnostic techniques, the incidence of metastatic cutaneous squamous cell carcinoma is rising. Deficiency in effective preventive or treatment methods of transformed keratinocytes leads to necessity of searching for new anticancer agents. The present study aims to evaluate the possibility of using wool hydrolysates as such agents. Commercially available compounds such as 5 fluorouracil, ingenol mebutate, diclofenac sodium salt were also used in this study. The process of wool degradation was based on chemical pre-activation and enzymatic digestion of wool. The effect of mentioned compounds on cell viability of squamous carcinoma cell line and healthy keratinocytes was evaluated. The obtained data show a significantly stronger effect of selected wool hydrolysates compared to commercial compounds (p<0.05) on viability of cells. The wool hydrolysates decreased squamous cell carcinoma cells viability by up to 67% comparing to untreated cells. These results indicate bioactive properties of wool hydrolysates, which affect the viability of squamous carcinoma cells and decrease their number. We hypothesize that these agents may be used topically for treatment of transformed keratinocytes in actinic keratosis and invasive squamous skin cancer in humans. PMID- 28859144 TI - The effects of sleep loss on young drivers' performance: A systematic review. AB - Young drivers (18-24 years) are over-represented in sleep-related crashes (comprising one in five fatal crashes in developed countries) primarily due to decreased sleep opportunity, lower tolerance for sleep loss, and ongoing maturation of brain areas associated with driving-related decision making. Impaired driving performance is the proximal reason for most car crashes. There is still a limited body of evidence examining the effects of sleep loss on young drivers' performance, with discrepancies in the methodologies used, and in the definition of outcomes. This study aimed to identify the direction and magnitude of the effects of sleep loss on young drivers' performance, and to appraise the quality of current evidence via a systematic review. Based on the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) approach, 16 eligible studies were selected for review, and their findings summarised. Next, critical elements of these studies were identified, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines augmented to rate those elements. Using those criteria, the quality of individual papers was calculated and the overall body of evidence for each driving outcome were assigned a quality ranking (from 'very low' to 'high-quality'). Two metrics, the standard deviation of lateral position and number of line crossings, were commonly reported outcomes (although in an overall 'low-quality' body of evidence), with significant impairments after sleep loss identified in 50% of studies. While speed-related outcomes and crash events (also with very low- quality evidence) both increased under chronic sleep loss, discrepant findings were reported under conditions of acute total sleep deprivation. It is crucial to obtain more reliable data about the effects of sleep loss on young drivers' performance by using higher quality experimental designs, adopting common protocols, and the use of consistent metrics and reporting of findings based on GRADE criteria and the PRISMA statement. Key words: Young drivers, sleep loss, driving performance, PRISMA, the GRADE, systematic review. PMID- 28859146 TI - Negative correlation of cortical thickness with the severity and duration of abdominal pain in Asian women with irritable bowel syndrome. AB - BACKGROUND & AIMS: Irritable bowel syndrome (IBS) manifests as chronic abdominal pain. One pathophysiological theory states that the brain-gut axis is responsible for pain control in the intestine. Although several studies have discussed the structural changes in the brain of IBS patients, most of these studies have been conducted in Western populations. Different cultures and sexes experience different pain sensations and have different pain responses. Accordingly, we aimed to identify the specific changes in the cortical thickness of Asian women with IBS and to compare these data to those of non-Asian women with IBS. METHODS: Thirty Asian female IBS patients (IBS group) and 39 healthy individuals (control group) were included in this study. Brain structural magnetic resonance imaging was performed. We used FreeSurfer to analyze the differences in the cortical thickness and their correlations with patient characteristics. RESULTS: The left cuneus, left rostral middle frontal cortex, left supramarginal cortex, right caudal anterior cingulate cortex, and bilateral insula exhibited cortical thinning in the IBS group compared with those in the controls. Furthermore, the brain cortical thickness correlated negatively the severity as well as duration of abdominal pain. CONCLUSIONS: Some of our findings differ from those of Western studies. In our study, all of the significant brain regions in the IBS group exhibited cortical thinning compared with those in the controls. The differences in cortical thickness between the IBS patients and controls may provide useful information to facilitate regulating abdominal pain in IBS patients. These findings offer insights into the association of different cultures and sexes with differences in cortical thinning in patients with IBS. PMID- 28859147 TI - The effects of poaching and habitat structure on anti-predator behavioral strategies: A guanaco population in a high cold desert as case study. AB - The effects of poaching on wildlife have been widely studied in conservation biology and can be heterogeneous, particularly on ungulates. These effects can be estimated through different methodologies whose use depends on several conditions such as Flight-initiation distance (FID). Our objectives were: 1- to evaluate whether poaching affects the FID and group structure of a guanaco (Lama guanicoe) population in a high cold desert in San Juan (Argentina); 2- to assess whether habitat structure (slope and vegetation cover) influences FID and group structure in this population. The study area included a site with poaching (unprotected area), and a site without poaching (protected area). We recorded 100 groups of guanacos: 70 in the protected and 30 in the unprotected area. FID and group size were greater in the unprotected than in the protected area, whereas proportions of group categories (with offspring, without offspring and solitary) were similar between areas. Besides, in relation to habitat structure, FID increased when vegetation cover decreased. On the other hand, FID and group size were not affected by slope. Our study shows that guanacos respond to poaching pressure as do other ungulate species, and that other factors such as vegetation cover also affect this behavior. Managers should be aware when interpreting FID due to its relation to habitat structure; the guanaco appears to assume greater risk (lower FID) in areas with high vegetation cover. PMID- 28859145 TI - Positively selected amino acid replacements within the RuBisCO enzyme of oak trees are associated with ecological adaptations. AB - Phylogenetic analysis by maximum likelihood (PAML) has become the standard approach to study positive selection at the molecular level, but other methods may provide complementary ways to identify amino acid replacements associated with particular conditions. Here, we compare results of the decision tree (DT) model method with ones of PAML using the key photosynthetic enzyme RuBisCO as a model system to study molecular adaptation to particular ecological conditions in oaks (Quercus). We sequenced the chloroplast rbcL gene encoding RuBisCO large subunit in 158 Quercus species, covering about a third of the global genus diversity. It has been hypothesized that RuBisCO has evolved differentially depending on the environmental conditions and leaf traits governing internal gas diffusion patterns. Here, we show, using PAML, that amino acid replacements at the residue positions 95, 145, 251, 262 and 328 of the RuBisCO large subunit have been the subject of positive selection along particular Quercus lineages associated with the leaf traits and climate characteristics. In parallel, the DT model identified amino acid replacements at sites 95, 219, 262 and 328 being associated with the leaf traits and climate characteristics, exhibiting partial overlap with the results obtained using PAML. PMID- 28859148 TI - Stellate ganglion block attenuates chronic stress induced depression in rats. AB - BACKGROUND: Stress is a significant factor in the etiology of depression. Stellate ganglion block (SGB) has been shown to maintain the stability of the autonomic system and to affect the neuroendocrine system, including the hypothalamic-pituitary-adrenal (HPA) axis. The objective of this study was to determine the antidepressant-like effects of SGB on the autonomic system and the HPA axis, apoptosis-related proteins, related spatial learning and memory impairment, and sensorimotor dysfunction. METHODS: Forty-eight Sprague Dawley rats were assigned to four experimental groups: control + saline (sham group), control + SGB (SGB group), unpredictable chronic mild stress (UCMS) + saline (UCMS group), and UCMS + SGB (UCSG group). Stress-induced effects and the function of SGB were assessed using measures of body weight, coat state, sucrose consumption, and behavior in open-field and Y-maze tests. Neuronal damage was assessed histologically using the hematoxylin-eosin (HE) staining method, while western blotting was used to investigate changes in the expression of apoptosis related proteins. Plasma corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), corticosterone (CORT), noradrenaline and adrenaline were measured to evaluate changes in the autonomic system and HPA axis. RESULTS: SGB treatment significantly improved sensorimotor dysfunction and spatial learning and memory impairment following UCMS. Moreover, UCMS significantly decreased body weight, sucrose preference and anti-apoptotic protein Bcl-2, and increased scores on measures of coat state, adrenal gland weight, levels of CORT, CRF, ACTH, noradrenaline and adrenaline, as well as increased neuronal loss, cell shrinkage, nuclear condensation, and the pro apoptotic protein Bax. These symptoms were attenuated by treatment with SGB. CONCLUSIONS: These findings suggest that SGB can attenuate depression-like behaviors induced by chronic stress. These protective effects appear to be due to an anti-apoptotic mechanism of two stress pathways-the autonomic system and the HPA axis. PMID- 28859149 TI - Biofilm formation of methicillin-resistant coagulase negative staphylococci (MR CoNS) isolated from community and hospital environments. AB - Methicillin-resistant coagulase negative staphylococci (MR-CoNS) are the major cause of infectious diseases because of their potential ability to form biofilm and colonize the community or hospital environments. This study was designed to investigate the biofilm producing ability, and the presence of mecA, icaAD, bap and fnbA genes in MR-CoNS isolates. The MR-CoNS used in this study were isolated from various samples of community environment and five wards of hospital environments, using mannitol salt agar (MSA) supplemented with 4 MUg/ml of oxacillin. The specie level of Staphylococcus haemolyticus, Staphylococcus epidermidis, Staphylococcus hominis and Staphylococcus warneri was identified by specific primers of groESL (S. haemolyticus), rdr (S. epidermidis) and nuc (S. hominis and S. warneri). The remainder isolates were identified by tuf gene sequencing. Biofilm production was determined using Congo red agar (CRA) and Microtiter plate (MTP) assay. The mecA and biofilm associated genes (icaAD, fnbA and bap) were detected using PCR method. From the 558 samples from community and hospital environments, 292 MR-CoNS were isolated (41 from community environments, and 251 from hospital environments). S. haemolyticus (41.1%) and S. epidermidis (30.1%) were the predominant species in this study. Biofilm production was detected in 265 (90.7%) isolates by CRA, and 260 (88.6%) isolates were detected by MTP assay. The staphylococci isolates derived from hospital environments were more associated with biofilm production than the community-derived isolates. Overall, the icaAD and bap genes were detected in 74 (29.5%) and 14 (5.6%) of all isolates from hospital environments. When tested by MTP, the icaAD gene from hospital environment isolates was associated with biofilm biomass. No association was found between bap gene and biofilm formation. The MR-CoNS isolates obtained from community environments did not harbor the icaAD and bap genes. Conversely, fnbA gene presented in MR-CoNS isolated from both community and hospital environments. The high prevalence of biofilm producing MR-CoNS strains demonstrated in this study indicates the persisting ability in environments, and is useful in developing prevention strategies countering the spread of MR-CoNS. PMID- 28859150 TI - The real world effect of omalizumab add on therapy for patients with moderate to severe allergic asthma: The ASTERIX Observational study. AB - BACKGROUND: Omalizumab is a non-steroidal medication indicated for the treatment of poorly controlled moderate-to-severe allergic asthmatics. This observational study examines the "real world" effectiveness of omalizumab in this population. METHODS: This is a one year open-label observational study that compared clinical outcomes including total oral corticosteroid use, exacerbation history, measures of quality of life and inflammation in patients with moderate-to-severe allergic asthma, who were prescribed omalizumab as part of their treatment with the year prior to therapy. RESULTS: A total of 99 patients were enrolled at 25 sites in Canada. During the study period, the mean total annual OCS dose was reduced from 2301.5 mg (prednisone equivalents) in the year prior to omalizumab to 1130.0 mg (p<0.0001). There was a 71% reduction in asthma exacerbations and 56% of patients on omalizumab remained exacerbation free when compared to the year prior to study entry. Associated with this was reduced health care utilization. There were significant improvements in the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life questionnaire (AQLQ) Patients with an elevated FeNO at baseline showed a better response to treatment. No new safety issues were identified during the study period. CONCLUSION: Our study demonstrates that in "real world" clinical practice, after initiating omalizumab, there is a reduction in total OCS use and exacerbation frequency in patients with moderate-to-severe allergic asthma. Patients on treatment reported improved asthma control and quality of life. FeNO may be a useful biomarker to identify patients who may benefit with omalizumab treatment. PMID- 28859151 TI - Solid-phase microextraction-based cuticular hydrocarbon profiling for intraspecific delimitation in Acyrthosiphon pisum. AB - Insect cuticular hydrocarbons (CHCs) play critical roles in reducing water loss and chemical communication. Species-specific CHC profiles have been used increasingly as an excellent character for species classification. However, considerably less is known about their potential for population delimitation within species. The aims of this study were to develop a solid-phase microextraction (SPME)-based CHC collection method and to investigate whether CHC profiles could serve as potential chemotaxonomic tools for intraspecific delimitation in Acyrthosiphon pisum. Optimization of fibers for SPME sampling revealed that 7 MUm polydimethylsiloxane (PDMS) demonstrated the most efficient adsorption of CHCs among five different tested fibers. SPME sampling showed good reproducibility with repeated collections of CHCs from a single aphid. Validation of SPME was performed by comparing CHC profiles with those from conventional hexane extractions. The two methods showed no qualitative differences in CHCs, although SPME appeared to extract relatively fewer short-chained CHCs. While CHC profiles of a given population differed among developmental stages, wing dimorphism types, and host plants, wingless adult aphids showed very low variance in relative proportions of individual CHC components. Reproducibility of CHC profiles was explored further to classify wingless adult morphs of A. pisum from five different geographic regions that showed no variation in mitochondrial COI gene sequences. Our results demonstrate that CHC profiles are useful in intraspecific delimitation in the field of insect chemotaxonomy. PMID- 28859152 TI - Elevated aminopeptidase N affects sperm motility and early embryo development. AB - Aminopeptidase N (APN) is a naturally occurring ectopeptidase present in mammalian semen. Previous studies have demonstrated that APN adversely affects male fertility through the alteration of sperm motility. This enzyme constitutes 0.5 to 1% of the seminal plasma proteins, which can be transferred from the prostasomes to sperms by a fusion process. In the present study, we investigated the molecular mechanism of action of APN and its role in regulating sperm functions and male fertility. In this in vitro study, epididymal mouse spermatozoa were incubated in a capacitating media (pH 7) containing 20 ng/mL of recombinant mouse APN for 90 min. Our results demonstrated that the supplementation of recombinant APN in sperm culture medium significantly increased APN activity, and subsequently altered motility, hyperactivated motility, rapid and medium swimming speeds, viability, and the acrosome reaction of mouse spermatozoa. These effects were potentially caused by increased toxicity in the spermatozoa. Further, altered APN activity in sperm culture medium affected early embryonic development. Interestingly, the effect of elevated APN activity in sperm culture medium was independent of protein tyrosine phosphorylation and protein kinase A activity. On the basis of these results, we concluded that APN plays a significant role in the regulation of several sperm functions and early embryonic development. In addition, increased APN activity could potentially lead to several adverse consequences related to male fertility. PMID- 28859153 TI - Clonality and distribution of clinical Ureaplasma isolates recovered from male patients and infertile couples in China. AB - Ureaplasma spp. have gained increasing recognition as pathogens in both adult and neonatal patients with multiple clinical presentations. However, the clonality of this organism in the male population and infertile couples in China is largely unknown. In this study, 96 (53 U. parvum and 43 U. urealyticum) of 103 Ureaplasma spp. strains recovered from genital specimens from male patients and 15 pairs of infertile couples were analyzed using multilocus sequence typing (MLST)/expanded multilocus sequence typing (eMLST) schemes. A total of 39 sequence types (STs) and 53 expanded sequence types (eSTs) were identified, with three predominant STs (ST1, ST9 and ST22) and eSTs (eST16, eST41 and eST82). Moreover, phylogenetic analysis revealed two distinct clusters that were highly congruent with the taxonomic differences between the two Ureaplasma species. We found significant differences in the distributions of both clusters and sub-groups between the male and female patients (P < 0.001). Moreover, 66.7% and 40.0% of the male and female partners of the infertile couples tested positive for Ureaplasma spp. The present study also attained excellent agreement of the identification of both Ureaplasma species between paired urine and semen specimens from the male partners (k > 0.80). However, this concordance was observed only for the detection of U. urealyticum within the infertile couples. In conclusion, the distributions of the clusters and sub-groups significantly differed between the male and female patients. U. urealyticum is more likely to transmit between infertile couples and be associated with clinical manifestations by the specific epidemic clonal lineages. PMID- 28859154 TI - The cost-effectiveness of PHQ screening and collaborative care for depression in New York City. AB - BACKGROUND: Depression is under-diagnosed and under-treated in most areas of the US. New York City is currently looking to close gaps in identifying and treating depression through the adoption of a screening and collaborative care model deployed throughout the city. METHODS: We examine the cost-effectiveness of universal two-stage screening with the 2- and 9-item Patient Health Questionnaires (PHQ-2 and PHQ-9) in New York City followed by collaborative care for those who screen positive. We conducted microsimulations on hypothetical adult participants between ages 20 and 70. RESULTS: The incremental cost effectiveness of the interventions over the average lifespan of a 20-year-old adult in NYC is approximately $1,726/QALY gained (95% plausible interval: cost saving, $10,594/QALY gained). CONCLUSIONS: Two-stage screening coupled with collaborative care for depression in the clinical setting appears to be significantly less expensive than most clinical preventive interventions, such as HIV screening in high-risk patients. However, effectiveness is dependent on the city's ability to manage scale up of collaborative care models. PMID- 28859155 TI - Cyclocarya paliurus extract activates insulin signaling via Sirtuin1 in C2C12 myotubes and decreases blood glucose level in mice with impaired insulin secretion. AB - Diabetes is caused by the lack of release or action of insulin. Some foods and supplements can compensate for this deficiency; thus, they can aid in the prevention or treatment of diabetes. The aim of this study was to investigate the effects of Cyclocarya paliurus extract (CPE) on insulin signaling and its capacity to correct hyperglycemia in the absence of insulin. To investigate the hypoglycemic effects of CPE, C2C12 cells were exposed to CPE (50 and 100 MUg/mL). CPE promoted 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2NBDG) uptake into the cells via translocation of glucose transporter 4 (Glut4) to the plasma membrane. In addition, CPE enhanced tyrosine phosphorylation of insulin receptor substrate and activated phosphatidylinositol 3-kinase and protein kinase B (Akt) via sirtuin1 in C2C12 cells. Moreover, we found that oral administration of CPE (1 g/kg) to streptozotocin-induced hyperglycemic mice produced a progressive decrease in plasma glucose levels at 1 h after single dosing. At that point, CPE significantly increased the expression of skeletal muscle membrane Glut4 and enhanced the phosphorylation of Akt. These results suggest that CPE exerts antidiabetic effects similar to those of insulin, and may be an oral therapeutic alternative for the management of diabetes. PMID- 28859156 TI - Longterm storage of post-packaged bread by controlling spoilage pathogens using Lactobacillus fermentum C14 isolated from homemade curd. AB - One potent lactic acid bacterial strain C14 with strong antifungal activity was isolated from homemade curd. Based on morphological as well as biochemical characters and 16S rDNA sequence homology the strain was identified as Lactobacillus fermentum. It displayed a wide antimicrobial spectrum against both Gram-positive and Gram-negative pathogenic bacteria, and also against number of food spoilage, plant and human pathogenic fungi. The cell free supernatant (CFS) of the strain C14 was also effective against the fungi tested. Inhibition of radial growth of Penicillium digitatum, Trichophyton rubrum and Mucor sp. was noticed in the presence of CFS of C14 even at low concentration (1%). More than 94.3 +/- 1.6% and 91.5 +/- 2.2% inhibition of conidial germination of P. digitatum and Mucor sp. were noticed in the presence of 10-fold-concentrated CFS of C14. Massive deformation of the fungal mycelia was observed by SEM studies, and losses of cellular proteins and DNA are also evident upon its treatment with C14. HPLC analysis revealed the presence of phenyl lactic acid, lactic acid along with some unidentified compounds in the antifungal extract. Challenge experiment showed immense potential of the strain C14 in preventing the spoilage of bread samples caused by Mucor sp. and Bacillus subtilis. The bread samples remained fresh upto 25 days even after inoculation with Mucor sp. (3.7 * 104 spores /ml) and B. subtilis (4.6 * 104 CFU /ml). Along with the antifungal properties, the isolated lactic acid bacterial strain also showed very good antioxidant activities. Unchanged level of liver enzymes serum glutamic pyruvic transaminase and serum glutamic oxaloacetic transaminase in albino mice upon feeding with C14 also suggested non-toxic nature of the bacterial isolate. PMID- 28859157 TI - Pseudophakic retinal detachment in young-aged patients. AB - OBJECTIVE: To investigate the incidence and risk factors for retinal detachment (RD) after cataract surgery or refractive lens exchange (RLE) in patients aged below 61 years. METHODS: Retrospective medical chart review of 7,886 patients (13,925 eyes) who underwent cataract surgery or RLE. Patients aged below 61 years were selected. Age, gender, axial length, follow-up times, and the occurrence of RD were recorded. Additional characteristics documented for RD cases were: history of RD, preexisting retinal findings, laser capsulotomy, status of macula at RD, date and details of RD. RESULTS: From a total of 421 patients (677 eyes) aged below 61 years 24 cases of RD were identified, resulting in an overall cumulative incidence per eyes of 3.55%. The mean follow-up time was 45 +/- 32.8 months. Ninety-two % of all RDs occurred within 3.6 years from surgery. Axial length had a significant effect on the risk of RD after cataract/ RLE surgery (HR = 1.42, P = 0.0001, 95% CI 1.19-1.69). The highest incidence of RD occurred in the subgroup of 25 to 28.9 mm axial length (10.2%). With an increase in age of ten years, the hazard of postoperative RD was not significantly increased by a factor of 1.50 (P = 0.286, 95% CI 0.71-3.15). The highest incidence of RD occurred in patients aged 50-54 years (5.39%). Compared to females, males had an almost twofold not significant risk of postoperative RD (HR = 1.96, P = 0.123, 95% CI 0.83-4.63). None of the RD cases had a history of RD. CONCLUSIONS: Axial length is a significant risk factor for pseudophakic RD. The need for cataract surgery or RLE should be carefully considered in patients with axial lengths between 25 and 29 mm, aged 50-54 years, in males, and in case of preexisting retinal findings. PMID- 28859159 TI - Correction: Insecticide resistance to permethrin and malathion and associated mechanisms in Aedes aegypti mosquitoes from St. Andrew Jamaica. AB - [This corrects the article DOI: 10.1371/journal.pone.0179673.]. PMID- 28859158 TI - Metabolic inhibition reduces cardiac L-type Ca2+ channel current due to acidification caused by ATP hydrolysis. AB - Metabolic stress evoked by myocardial ischemia leads to impairment of cardiac excitation and contractility. We studied the mechanisms by which metabolic inhibition affects the activity of L-type Ca2+ channels (LTCCs) in frog ventricular myocytes. Metabolic inhibition induced by the protonophore FCCP (as well as by 2,4- dinitrophenol, sodium azide or antimycin A) resulted in a dose dependent reduction of LTCC current (ICa,L) which was more pronounced during beta adrenergic stimulation with isoprenaline. ICa,L was still reduced by metabolic inhibition even in the presence of 3 mM intracellular ATP, or when the cell was dialysed with cAMP or ATP-gamma-S to induce irreversible thiophosphorylation of LTCCs, indicating that reduction in ICa,L is not due to ATP depletion and/or reduced phosphorylation of the channels. However, the effect of metabolic inhibition on ICa,L was strongly attenuated when the mitochondrial F1F0-ATP synthase was blocked by oligomycin or when the cells were dialysed with the non hydrolysable ATP analogue AMP-PCP. Moreover, increasing the intracellular pH buffering capacity or intracellular dialysis of the myocytes with an alkaline solution strongly attenuated the inhibitory effect of FCCP on ICa,L. Thus, our data demonstrate that metabolic inhibition leads to excessive ATP hydrolysis by the mitochondrial F1F0-ATP-synthase operating in the reverse mode and this results in intracellular acidosis causing the suppression of ICa,L. Limiting ATP break-down by F1F0-ATP-synthase and the consecutive development of intracellular acidosis might thus represent a potential therapeutic approach for maintaining a normal cardiac function during ischemia. PMID- 28859160 TI - IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton's jelly of the umbilical cord via JNK and Akt signaling pathways. AB - Mesenchymal stem cell (MSC)-mediated tissue engineering represents a promising strategy to address adipose tissue defects. MSCs derived from Wharton's jelly of the umbilical cord (WJCMSCs) may serve as an ideal source for adipose tissue engineering due to their abundance, safety profile, and accessibility. How to activate the directed differentiation potentials of WJCMSCs is the core point for their clinical applications. A thorough investigation of mechanisms involved in WJCMSC adipogenic differentiation is necessary to support their application in adipose tissue engineering and address shortcomings. Previous study showed, compared with periodontal ligament stem cells (PDLSCs), WJCMSCs had a weakened adipogenic differentiation potentials and lower expression of insulin-like growth factor binding protein 2 (IGFBP2). IGFBP2 may be involved in the adipogenesis of MSCs. Generally, IGFBP2 is involved in regulating biological activity of insulin like growth factors, however, its functions in human MSCs are unclear. Here, we found IGFBP2 expression was upregulated upon adipogenic induction, and that IGFBP2 enhanced adipogenic differentiation of WJCMSCs and BMSCs. Moreover, IGFBP2 increased phosphorylation of c-Jun N-terminal kinase (p-JNK) and p-Akt, and activated JNK or Akt signaling significantly promoted adipogenic differentiation of MSCs. Furthermore, inhibitor-mediated blockage of either JNK or Akt signaling dramatically reduced IGFBP2-mediated adipogenic differentiation. And the JNK inhibitor, SP600125 markedly blocked IGFBP2-mediated Akt activation. Moreover, IGFBP2 was negatively regulated by BCOR, which inhibited adipogenic differentiation of WJCMSCs. Overall, our results reveal a new function of IGFBP2, providing a novel insight into the mechanism of adipogenic differentiation and identifying a potential target mediator for improving adipose tissue engineering based on WJCMSCs. PMID- 28859161 TI - Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice. AB - Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice. PMID- 28859162 TI - Foods are differentially associated with subjective effect report questions of abuse liability. AB - OBJECTIVES: The current study investigates which foods may be most implicated in addictive-like eating by examining how nutritionally diverse foods relate to loss of control consumption and various subjective effect reports. Subjective effect reports assess the abuse liabilities of substances and may similarly provide insight into which foods may be reinforcing in a manner that triggers an addictive-like response for some individuals. DESIGN: Cross-sectional. SETTING: Online community. PARTICIPANTS: 507 participants (n = 501 used in analyses) recruited through Amazon MTurk. MEASUREMENTS: Participants (n = 501) self reported how likely they were to experience a loss of control over their consumption of 30 nutritionally diverse foods and rated each food on five subjective effect report questions that assess the abuse liability of substances (liking, pleasure, craving, averseness, intensity). Hierarchical cluster analytic techniques were used to examine how foods grouped together based on each question. RESULTS: Highly processed foods, with added fats and/or refined carbohydrates, clustered together and were associated with greater loss of control, liking, pleasure, and craving. The clusters yielded from the subjective effect reports assessing liking, pleasure, and craving were most similar to clusters formed based on loss of control over consumption, whereas the clusters yielded from averseness and intensity did not meaningfully differentiate food items. CONCLUSION: The present work applies methodology used to assess the abuse liability of substances to understand whether foods may vary in their potential to be associated with addictive-like consumption. Highly processed foods (e.g., pizza, chocolate) appear to be most related to an indicator of addictive-like eating (loss of control) and several subjective effect reports (liking, pleasure, craving). Thus, these foods may be particularly reinforcing and capable of triggering an addictive-like response in some individuals. Future research is warranted to understand whether highly processed foods are related to these indicators of abuse liability at a similar magnitude as addictive substances. PMID- 28859163 TI - Down-regulation of C35 decreased the cell viability and migration of breast ductal carcinoma cells. AB - BACKGROUND: Resistance to human epidermal growth factor receptor-2 (HER2) targeted therapies is common, and results in treatment failure and new tumor progression. C35 is over-expressed in many invasive breast cancer endogenously, and functions as an oncogene in breast cancer cell lines. METHODS: The current study aims to investigate effects of C35 on cell viability and migration of HER2 positive breast tumor cells and explore possible mechanisms. The protein expression of C35 in BT-474 breast ductal carcinoma cells was interfered by siRNAs. MTT assay was utilized to detect the viability of BT474 breast ductal carcinoma cells after transfection. The migration of BT474 breast ductal carcinoma cells was examined by cell wound scratch assay. RESULTS: In addition, the protein expression of C35, HER2, AKT and p-AKT in breast ductal carcinoma cells were detected by Western Blot. The protein expression of C35 was weaker in siRNA1 and siRNA2 groups compared with the control group. The relative expression ratio of C35 to beta-actin decreased significantly in siRNA2 and siRNA1 groups. When C35 expression was interfered by siRNA1 and siRNA2 for 48 h, the viability of BT474 breast ductal carcinoma cells decreased compared with the control group. In addition, the migration of breast ductal carcinoma cells decreased when C35 expression was interfered by siRNA1 for 24 h, and interfered by siRNA1 and siRNA2 for 48 h. PMID- 28859164 TI - TSS-Seq analysis of low pH-induced gene expression in intercalated cells in the renal collecting duct. AB - Metabolic acidosis often results from chronic kidney disease; in turn, metabolic acidosis accelerates the progression of kidney injury. The mechanisms for how acidosis facilitates kidney injury are not fully understood. To investigate whether low pH directly affects the expression of genes controlling local homeostasis in renal tubules, we performed transcription start site sequencing (TSS-Seq) using IN-IC cells, a cell line derived from rat renal collecting duct intercalated cells, with acid loading for 24 h. Peak calling identified 651 up regulated and 128 down-regulated TSSs at pH 7.0 compared with those at pH 7.4. Among them, 424 and 38 TSSs were >= 1.0 and <= -1.0 in Log2 fold change, which were annotated to 193 up-regulated and 34 down-regulated genes, respectively. We used gene ontology analysis and manual curation to profile the up-regulated genes. The analysis revealed that many up-regulated genes are involved in renal fibrosis, implying potential molecular mechanisms induced by metabolic acidosis. To verify the activity of the ubiquitin-proteasome system (UPS), a candidate pathway activated by acidosis, we examined the expression of proteins from cells treated with a proteasome inhibitor, MG132. The expression of ubiquitinated proteins was greater at pH 7.0 than at pH 7.4, suggesting that low pH activates the UPS. The in vivo study demonstrated that acid loading increased the expression of ubiquitin proteins in the collecting duct cells in mouse kidneys. Motif analysis revealed Egr1, the mRNA expression of which was increased at low pH, as a candidate factor that possibly stimulates gene expression in response to low pH. In conclusion, metabolic acidosis can facilitate renal injury and fibrosis during kidney disease by locally activating various pathways in the renal tubules. PMID- 28859165 TI - The peritubular reinforcement effect of porous dentine microstructure. AB - In the current study, we evaluate the equivalent stiffness of peritubular reinforcement effect (PRE) of porous dentine optimized by the thickness of peritubular dentine (PTD). Few studies to date have evaluated or quantitated the effect of PRE on composite dentine. The miscrostructure of porous dentine is captured by scanning electron microscope images, and then finite element modeling is used to quantitate the deformation and stiffness of the porous dentine structure. By optimizing the radius of PTD and dentine tubule (DT), the proposed FE model is able to demonstrate the effect of peritubular reinforcement on porous dentine stiffness. It is concluded that the dentinal equivalent stiffness is reduced and degraded with the increase of the radius of DT (i.e., porosity) in the certain ratio value of Ep/Ei and certain radius of PTD, where Ep is the PTD modulus and Ei is the intertubular dentine modulus. So in order to ensure the whole dentinal equivalent stiffness is not loss, the porosity should get some value while the Ep/Ei is certain. Thus, PTD prevents the stress concentration around DTs and reduces the risk of DTs failure. Mechanically, the overall role of PTD appears to enhance the stiffness of the dentine composite structure. These results provide some new and significant insights into the biological evolution of the optimal design for the porous dentine microstructure. These findings on the biological microstructure design of dentine materials are applicable to other engineering structural designs aimed at increasing the overall structural strength. PMID- 28859166 TI - Primate lentiviruses use at least three alternative strategies to suppress NF kappaB-mediated immune activation. AB - Primate lentiviruses have evolved sophisticated strategies to suppress the immune response of their host species. For example, HIV-2 and most simian immunodeficiency viruses (SIVs) use their accessory protein Nef to prevent T cell activation and antiviral gene expression by downmodulating the T cell receptor CD3. This Nef function was lost in HIV-1 and other vpu-encoding viruses suggesting that the acquisition of Vpu-mediated NF-kappaB inhibition reduced the selection pressure for inhibition of T cell activation by Nef. To obtain further insights into the modulation of NF-kappaB activity by primate lentiviral accessory factors, we analyzed 32 Vpr proteins from a large panel of divergent primate lentiviruses. We found that those of SIVcol and SIVolc infecting Colobinae monkeys showed the highest efficacy in suppressing NF-kappaB activation. Vpr-mediated inhibition of NF-kappaB resulted in decreased IFNbeta promoter activity and suppressed type I IFN induction in virally infected primary cells. Interestingly, SIVcol and SIVolc differ from all other primate lentiviruses investigated by the lack of both, a vpu gene and efficient Nef mediated downmodulation of CD3. Thus, primate lentiviruses have evolved at least three alternative strategies to inhibit NF-kappaB-dependent immune activation. Functional analyses showed that the inhibitory activity of SIVolc and SIVcol Vprs is independent of DCAF1 and the induction of cell cycle arrest. While both Vprs target the IKK complex or a factor further downstream in the NF-kappaB signaling cascade, only SIVolc Vpr stabilizes IkappaBalpha and inhibits p65 phosphorylation. Notably, only de-novo synthesized but not virion-associated Vpr suppressed the activation of NF-kappaB, thus enabling NF-kappaB-dependent initiation of viral gene transcription during early stages of the replication cycle, while minimizing antiviral gene expression at later stages. Our findings highlight the key role of NF-kappaB in antiviral immunity and demonstrate that primate lentiviruses follow distinct evolutionary paths to modulate NF-kappaB dependent expression of viral and antiviral genes. PMID- 28859167 TI - Up to 52 administrations of macrocyclic ionic MR contrast agent are not associated with intracranial gadolinium deposition: Multifactorial analysis in 385 patients. AB - PURPOSE: To determine whether multiple repeated administrations of gadolinium based macrocyclic ionic MR contrast agent (MICA) are associated with intracranial gadolinium deposition and identify the predisposing factors for deposition in various clinical situations. MATERIALS AND METHODS: In this institutional review board-approved retrospective study, 385 consecutive patients who underwent MICA enhanced MR imaging were enrolled. The dentate nucleus-to-pons (DN/P) and globus pallidus-to-thalamus (GP/Th) signal intensity (SI) ratios on unenhanced T1 weighted images were recorded by 2 independent readers and averaged. The mean DN/P and GP/Th SI ratio difference between the last and the first examinations were tested using the one-sample t-test. Student's t-test and stepwise regression analysis were used to identify the predisposing factors for deposition based on the number of administrations, time interval, hepatic and renal function, magnetic field strength, and chemo- or radiation therapy. RESULTS: The mean DN/P SI ratio difference was not different from zero (P = .697), even in patients with >=20 administrations (n = 33). Only patients with abnormal renal function showed an increase in the mean DN/P SI ratio difference (P = .019). The mean DN/P SI ratio difference was not associated with any predisposing factors. However, the mean GP/Th SI ratio difference showed decrease (P < .001), which was associated with age (P = .007), number of administrations (P = .01) and number of radiation therapy sessions (P = .022) on multivariate analysis. CONCLUSION: Multiple repeated administrations of MICA were not associated with increased T1 signal intensity in deep brain nuclei suggestive of Gd deposition in patients with normal renal function. PMID- 28859170 TI - Correction: Physical activity domains and risk of gastric adenocarcinoma in the MCC-Spain case-control study. AB - [This corrects the article DOI: 10.1371/journal.pone.0179731.]. PMID- 28859169 TI - The replication initiator protein of a geminivirus interacts with host monoubiquitination machinery and stimulates transcription of the viral genome. AB - Geminiviruses constitute a group of plant viruses, with a ssDNA genome, whose replication in the nucleus of an infected cell requires the function of geminivirus-encoded replication initiator protein (Rep). Our results suggest that monoubiquitinated histone 2B (H2B-ub) promotes tri-methylation of histone 3 at lysine 4 (H3-K4me3) on the promoter of Chilli leaf curl virus (ChiLCV). We isolated homologues of two major components of the monoubiquitination machinery: UBIQUITIN-CONJUGATING ENZYME2 (NbUBC2) and HISTONE MONOUBIQUITINATION1 (NbHUB1) from N. benthamiana. ChiLCV failed to cause disease in NbUBC2-, and NbHUB1 silenced plants, at the same time, H2B-ub and H3-K4me3 modifications were decreased, and the occupancy of RNA polymerase II on the viral promoter was reduced as well. In further investigations, Rep protein of ChiLCV was found to re localize NbUBC2 from the cytoplasm to the nucleoplasm, like NbHUB1, the cognate partner of NbUBC2. Rep was observed to interact and co-localize with NbHUB1 and NbUBC2 in the nuclei of the infected cells. In summary, the current study reveals that the ChiLCV Rep protein binds the viral genome and interacts with NbUBC2 and NbHUB1 for the monoubiquitination of histone 2B that subsequently promotes trimethylation of histone 3 at lysine 4 on ChiLCV mini-chromosomes and enhances transcription of the viral genes. PMID- 28859171 TI - Elucidating the function of the prion protein. PMID- 28859168 TI - P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria. AB - A complete understanding of the mechanisms underlying the acquisition of protective immunity is crucial to improve vaccine strategies to eradicate malaria. However, it is still unclear whether recognition of damage signals influences the immune response to Plasmodium infection. Adenosine triphosphate (ATP) accumulates in infected erythrocytes and is released into the extracellular milieu through ion channels in the erythrocyte membrane or upon erythrocyte rupture. The P2X7 receptor senses extracellular ATP and induces CD4 T cell activation and death. Here we show that P2X7 receptor promotes T helper 1 (Th1) cell differentiation to the detriment of follicular T helper (Tfh) cells during blood-stage Plasmodium chabaudi malaria. The P2X7 receptor was activated in CD4 T cells following the rupture of infected erythrocytes and these cells became highly responsive to ATP during acute infection. Moreover, mice lacking the P2X7 receptor had increased susceptibility to infection, which correlated with impaired Th1 cell differentiation. Accordingly, IL-2 and IFNgamma secretion, as well as T-bet expression, critically depended on P2X7 signaling in CD4 T cells. Additionally, P2X7 receptor controlled the splenic Tfh cell population in infected mice by promoting apoptotic-like cell death. Finally, the P2X7 receptor was required to generate a balanced Th1/Tfh cell population with an improved ability to transfer parasite protection to CD4-deficient mice. This study provides a new insight into malaria immunology by showing the importance of P2X7 receptor in controlling the fine-tuning between Th1 and Tfh cell differentiation during P. chabaudi infection and thus in disease outcome. PMID- 28859172 TI - Financial forecasts accuracy in Brazil's social security system. AB - Long-term social security statistical forecasts produced and disseminated by the Brazilian government aim to provide accurate results that would serve as background information for optimal policy decisions. These forecasts are being used as support for the government's proposed pension reform that plans to radically change the Brazilian Constitution insofar as Social Security is concerned. However, the reliability of official results is uncertain since no systematic evaluation of these forecasts has ever been published by the Brazilian government or anyone else. This paper aims to present a study of the accuracy and methodology of the instruments used by the Brazilian government to carry out long term actuarial forecasts. We base our research on an empirical and probabilistic analysis of the official models. Our empirical analysis shows that the long-term Social Security forecasts are systematically biased in the short term and have significant errors that render them meaningless in the long run. Moreover, the low level of transparency in the methods impaired the replication of results published by the Brazilian Government and the use of outdated data compromises forecast results. In the theoretical analysis, based on a mathematical modeling approach, we discuss the complexity and limitations of the macroeconomic forecast through the computation of confidence intervals. We demonstrate the problems related to error measurement inherent to any forecasting process. We then extend this exercise to the computation of confidence intervals for Social Security forecasts. This mathematical exercise raises questions about the degree of reliability of the Social Security forecasts. PMID- 28859173 TI - Vitamin D supplementation to palliative cancer patients shows positive effects on pain and infections-Results from a matched case-control study. AB - BACKGROUND: We previously showed an association between low vitamin D levels and high opioid doses to alleviate pain in palliative cancer patients. The aim of this case-controlled study was to investigate if vitamin D supplementation could improve pain management, quality of life (QoL) and decrease infections in palliative cancer patients. METHODS: Thirty-nine palliative cancer patients with levels of 25-hydroxyvitamin D < 75 nmol/L were supplemented with vitamin D 4000 IE/day, and were compared to 39 untreated, matched "control"-patients from a previous study at the same ward. Opioid doses, antibiotic consumption and QoL scores measured with the Edmonton Symptom Assessment Scale (ESAS) were monitored. The primary endpoint was the change from baseline after 1 and 3 months compared between the groups using linear regression with adjustment for a potential cofounding factor. RESULTS: After 1 month the vitamin D treated group had a significantly decreased fentanyl dose compared to the untreated group with a difference of 46 MUg/h; 95% CI 24-78, which increased further at 3 months to 91 MUg/h; 95% CI 56-140 MUg/h. The ESAS QoL-score improved in the Vitamin D group the first month; -1.4; 95% CI -2.6 - (-0.21). The vitamin D-treated group had significantly lower consumption of antibiotics after 3 months compared to the untreated group, the difference was -26%; 95%CI -0.41%-(-0.12%). Vitamin D was well tolerated by all patients and no adverse events were reported. CONCLUSION: Vitamin D supplementation to palliative cancer patients is safe and improvement in pain management is noted as early as 1 month after treatment. Decreased infections are noted 3 months after vitamin D treatment. The results from this pilot-study have been used for the power-calculation of a future randomized, placebo-controlled, double-blind study called "Palliative-D" that will start in Nov 2017 and will include 254 palliative cancer patients. PMID- 28859174 TI - Whole-loop mitochondrial DNA D-loop sequence variability in Egyptian Arabian equine matrilines. AB - BACKGROUND: Egyptian Arabian horses have been maintained in a state of genetic isolation for over a hundred years. There is only limited genetic proof that the studbook records of female lines of Egyptian Arabian pedigrees are reliable. This study characterized the mitochondrial DNA (mtDNA) signatures of 126 horses representing 14 matrilines in the Egyptian Agricultural Organization (EAO) horse breeding program. FINDINGS: Analysis of the whole D-loop sequence yielded additional information compared to hypervariable region-1 (HVR1) analysis alone, with 42 polymorphic sites representing ten haplotypes compared to 16 polymorphic sites representing nine haplotypes, respectively. Most EAO haplotypes belonged to ancient haplogroups, suggesting origin from a wide geographical area over many thousands of years, although one haplotype was novel. CONCLUSIONS: Historical families share haplotypes and some individuals from different strains belonged to the same haplogroup: the classical EAO strain designation is not equivalent to modern monophyletic matrilineal groups. Phylogenetic inference showed that the foundation mares of the historical haplotypes were highly likely to have the same haplotypes as the animals studied (p > 0.998 in all cases), confirming the reliability of EAO studbook records and providing the opportunity for breeders to confirm the ancestry of their horses. PMID- 28859175 TI - Correction: Transcriptomic analysis to uncover genes affecting cold resistance in the Chinese honey bee (Apis cerana cerana). AB - [This corrects the article DOI: 10.1371/journal.pone.0179922.]. PMID- 28859176 TI - Comparison of peripapillary vessel density between preperimetric and perimetric glaucoma evaluated by OCT-angiography. AB - PURPOSE: To determine peripapillary vessel density in eyes with perimetric glaucoma (PG) or preperimetric glaucoma (PPG) compared to normal controls using optical coherence tomography-angiography (OCT-A). METHODS: We recruited 13 patients with unilateral perimetric normal-tension glaucoma (NTG) and fellow preperimetric NTG showing only inferotemporal retinal nerve fiber layer (RNFL) defect in red-free RNFL photography in both eyes. We also enrolled 9 healthy controls. Using OCT-A, radial peripapillary capillary densities at inferotemporal and superotemporal regions were evaluated. Paired comparison of peripapillary vessel density was performed for PG eye, PPG eye, and normal eye. RESULTS: A total of 26 eyes of the 13 patients with unilateral PG and fellow PPG eyes and 18 eyes of 9 normal controls were analyzed. Vessel densities at the whole peripapillary region and inferotemporal region in PG eyes were significantly lower than those in PPG eyes (P = 0.001, P<0.001, respectively). Comparison between PPG and normal eyes showed no significant difference in the whole peripapillary region or the inferotemporal region (P = 0.654, P = 0.174, respectively). There was no significant (P = 0.288) difference in vessel density at superotemporal region among the three types of eyes (PG eye, PPG eye, and normal eye). CONCLUSION: PPG eyes and normal eyes were found to have the similar densities of peripapillary microvasculature at the area with nerve fiber layer defect, whereas in PG eye, there was a significant decrease in vessel density at the area of RNFL thinning. This provides evidence that microvascular compromise in the retina might be a secondary change to nerve fiber layer degeneration in the pathogenesis of NTG. PMID- 28859177 TI - Correction: Methodological approach to the ex vivo expansion and detection of T. cruzi-specific T cells from chronic Chagas disease patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0178380.]. PMID- 28859178 TI - Directed evolution provides insight into conformational substrate sampling by SrtA. AB - The Sortase family of transpeptidases are found in numerous gram-positive bacteria and involved in divergent physiological processes including anchoring of surface proteins to the cell wall as well as pili assembly. As essential proteins, sortase enzymes have been the focus of considerable interest for the development of novel anti-microbials, however, more recently their function as unique transpeptidases has been exploited for the synthesis of novel bio conjugates. Yet, for synthetic purposes, SrtA-mediated conjugation suffers from the enzyme's inherently poor catalytic efficiency. Therefore, to identify SrtA variants with improved catalytic efficiency, we used directed evolution to select a catalytically enhanced SrtA enzyme. An analysis of improved SrtA variants in the context of sequence conservation, NMR and x-ray crystal structures, and kinetic data suggests a novel mechanism for catalysis involving large conformational changes that delivers substrate to the active site pocket. Indeed, using DEER-EPR spectroscopy, we reveal that upon substrate binding, SrtA undergoes a large scissors-like conformational change that simultaneously translates the sort-tag substrate to the active site in addition to repositioning key catalytic residues for esterification. A better understanding of Sortase dynamics will significantly enhance future engineering and drug discovery efforts. PMID- 28859179 TI - The calcium binding properties and structure prediction of the Hax-1 protein. AB - Hax-1 is a protein involved in regulation of different cellular processes, but its properties and exact mechanisms of action remain unknown. In this work, using purified, recombinant Hax-1 and by applying an in vitro autoradiography assay we have shown that this protein binds Ca2+. Additionally, we performed structure prediction analysis which shows that Hax-1 displays definitive structural features, such as two alpha-helices, short beta-strands and four disordered segments. PMID- 28859180 TI - Long-term Outcome of Speech Intelligibility in Maxillary Dental Rehabilitation with Full Dentures: A Prospective Study Using Automatic Speech Quantification. AB - AIMS: Complete maxillary edentulism and prosthetic rehabilitation with removable full dentures are known to affect speech intelligibility. The aim of this study was to prospectively investigate the long-term effect of time on speech intelligibility in patients being rehabilitated with newly fabricated full maxillary dentures. MATERIALS AND METHODS: Speech was recorded in a group of 14 patients (male = 9, female = 5; mean age +/- standard deviation [SD] = 66.14 +/- 7.03 years) five times within a mean period of 4 years (mean +/- SD: 47.50 +/- 18.16 months; minimum/maximum: 24/68 months) and in a control group of 40 persons with healthy dentition (male = 30, female = 10; mean age +/- SD = 59 +/- 12 years). All 14 participants had their inadequate removable full maxillary dentures replaced with newly fabricated dentures. Speech intelligibility was measured by means of a polyphone-based speech recognition system that automatically computed the percentage of accurately spoken words (word accuracy [WA]) at five different points in time: 1 week prior to prosthetic maxillary rehabilitation (both with and without inadequate dentures in situ) and at 1 week, 6 months, and a mean of 48 months after the insertion of newly fabricated full maxillary dentures. RESULTS: Speech intelligibility of the patients significantly improved after 6 months of adaptation to the new removable full maxillary dentures (WA = 66.93% +/- 9.21%) compared to inadequate dentures in situ (WA = 60.12% +/- 10.48%). After this period, no further significant change in speech intelligibility was observed. After 1 week of adaptation, speech intelligibility of the rehabilitated patients aligned with that of the control group (WA = 69.79% +/- 10.60%) and remained at this level during the examination period of 48 months. CONCLUSION: The provision of new removable full maxillary dentures can improve speech intelligibility to the level of a healthy control group on a long term basis. PMID- 28859181 TI - Clinical Application of Newly Developed Custom-made Mouthpiece for Scuba Diving. AB - PURPOSE: To describe a method for customizing scuba diving mouthpieces, to examine their usability, and to assess divers' satisfaction with their use. MATERIALS AND METHODS: A rational method for fabricating custom-made mouthpieces for scuba diving was developed. Twenty scuba divers agreed to use a custom-made mouthpiece for at least 4 weeks. After mouthpiece use, participants completed an 11-item questionnaire. RESULTS: Custom-made mouthpieces had significantly lower scores for all items on the questionnaire except uncomfortable sensation, indicating that they were more comfortable than ready-made mouthpieces. CONCLUSION: It can be concluded that these novel custom-made mouthpieces for scuba diving offer greater comfort than ready-made mouthpieces. PMID- 28859182 TI - Evaluation of a New Ultrasonic Insert for Prosthodontic Preparation. AB - PURPOSE: This paper describes a new ultrasonic instrument (tipholder DB1 with crown prep tip inserts) designed to optimize prosthodontic margin repositioning and finishing. MATERIALS AND METHODS: The insert movement was assessed, and it was demonstrated that tipholder DB1 provides its inserts with an elliptical-like movement, making the entire insert surface able to cut. Then, 20 extracted teeth were prepared using tipholder DB1, sonic instruments, and traditional drills. Dental surface roughness produced using each of the three tools was measured using a roughness tester. Results were compared using univariate analysis of variance and Bonferroni post hoc test. RESULTS: The roughness produced using tipholder DB1 with crown prep insert presented no statistically significant differences compared to the roughness produced using sonic instruments and traditional drills. CONCLUSION: Tipholder DB1 with crown prep inserts is a promising treatment for margin repositioning and finishing. PMID- 28859183 TI - Association Between Patient Value Systems and Physician and Practice Attributes Available Online. AB - Importance: The relative value of facial plastic surgeon personal and practice attributes is relevant to the broader health care system because of increasing out-of-pocket expenses to patients. Objective: To determine the relative value of specific facial plastic surgeon personal and practice attributes available online from the perspective of patients. Design, Setting, and Participants: This study consisted of an electronic survey sent to patients by email using choice-based conjoint analysis; surveys were sent between December 2015 and March 2016. Participants had agreed to join email registries to be sent email surveys and promotions at 3 private facial plastic and reconstructive surgery practices. The following surgeon personal and practice attributes and levels were compared: (1) outcome transparency (above average, average, not available); (2) surgical training affiliations (US News and World Reports rankings); (3) online rating site scores (2 [poor], 3, or 4 [excellent] stars); and (4) price ($1*, $2*, and $3* [* = $1500; average cost was set at $2*]). Main Outcomes and Measures: The relative importance of outcome transparency, surgical training affiliations, online rating scores, and price to prospective patients. Results: Overall, 291 patients participated for a completion rate of 68%. Outcome transparency was the most valued attribute (attribute utility range = 141; attribute importance = 35.2%). Price was the least valued attribute (attribute utility range = 58.59; attribute importance = 15.1%). Assuming top-tier affiliations and 4-star ratings, share of market (SOM) was 75.5% for surgeons with above-average outcome transparency priced at $3* compared with those surgeons with no outcomes available priced at $1*. Holding price constant at $2*, surgeons with middle-tier affiliations and 2-star online ratings but above average outcomes achieved 48.4% SOM when compared with those surgeons with top-tier affiliations and 4-star online ratings without available outcomes. Conclusions and Relevance: Facial plastic surgery patients most value surgeons who publish outcomes. Moreover, they are willing to discount poor rating scores and lower-ranked institutional affiliations when outcome transparency is high. This study demonstrates that outcome transparency is crucial in facial plastic surgery markets. Level of Evidence: NA. PMID- 28859184 TI - A Dual Approach to Understanding Facial Perception Before and After Blepharoplasty. AB - Importance: Blepharoplasty consistently ranks among the most common facial plastic surgery procedure sought by both men and women. Despite the popularity of blepharoplasty, there has been little research focused on quantifying how eyelid surgery changes facial perceptions. Objectives: To quantify the effect of blepharoplasty on facial perceptions and measure patient-reported ratings of fatigue before and after surgery to compare observer and patient perceptions. Design, Setting, and Participants: A web-based survey experiment was conducted from January to February 2017, featuring photographs of female patients before and after blepharoplasty. Observers were randomly shown independent images of each patient and asked to rate perceived age, attractiveness, health, and energy level. Respondents saw only preoperative or postoperative photographs of each patient to reduce bias due to priming. Patient-reported outcomes were also collected. Main Outcomes and Measures: A multivariate mixed effects regression model was used to quantify the changes in each domain after surgery. Ordinal rank change was calculated to provide a measure of clinical effect size across the domains. To analyze patient-reported outcomes, a Kruskal-Wallis test followed by Mann-Whitney tests were performed to determine if there were differences in patient-perceived tiredness based on operative status. Results: A total of 401 participants (243 women, 152 men, and 6 not specified; mean age 25.9 years [range, 18-73 years]) successfully completed the survey and evaluated before-and after photographs of 10 female patients (mean age, 59.8 years). The multivariable mixed effects model revealed that individuals are perceived as appearing significantly younger (-1.04 years; 95% CI, -1.70 to -0.37 years) and more attractive (coefficient, 4.92; 95% CI, 3.91-5.93) after blepharoplasty. Ratings of perceived health (coefficient, 4.33; 95% CI, 3.28-5.37) and energy level (coefficient, 9.83; 95% CI, 8.51-11.16) also improved significantly. After undergoing blepharoplasty, patients had significantly improved ratings of energy level compared with those who had not undergone blepharoplasty. Conclusions and Relevance: This is the first study, to date, aimed at quantifying the perceptions of facial aesthetic changes following blepharoplasty. The data demonstrate that individuals are rated as appearing more youthful, attractive, and healthy following blepharoplasty. Furthermore, both patients and casual observers perceived a significant improvement in energy level following blepharoplasty, a meaningful finding as the appearance of fatigue is a chief concern of the patients before they undergo blepharoplasty. Level of Evidence: NA. PMID- 28859186 TI - Achieving Active Surveillance for Thyroid Cancer-Not a Euphemism for Watching a Ticking Time Bomb. PMID- 28859185 TI - Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial. AB - Importance: The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL. Objective: To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL. Design, Setting, and Participants: A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston. Interventions: The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 * 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles. Main Outcomes and Measures: The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate. Results: Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03). Conclusions and Relevance: The combination of inotuzumab with low-intensity mini HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates. Trial Registration: clinicaltrials.gov Identifier: NCT01371630. PMID- 28859187 TI - Profound Vision Loss After a Traumatic Work Injury. PMID- 28859188 TI - Medication and Cognitive Behavioral Therapy for Pediatric Anxiety Disorders: No Need for Anxiety in Treating Anxiety. PMID- 28859189 TI - Trends in Adult Cancer-Related Emergency Department Utilization: An Analysis of Data From the Nationwide Emergency Department Sample. AB - Importance: The emergency department (ED) is used to manage cancer-related complications among the 15.5 million people living with cancer in the United States. However, ED utilization patterns by the population of US adults with cancer have not been previously evaluated or described in published literature. Objective: To estimate the proportion of US ED visits made by adults with a cancer diagnosis, understand the clinical presentation of adult patients with cancer in the ED, and examine factors related to inpatient admission within this population. Design, Setting, and Participants: Nationally representative data comprised of 7 survey cycles (January 2006-December 2012) from the Nationwide Emergency Department Sample were analyzed. Identification of adult (age >=18 years) cancer-related visits was based on Clinical Classifications Software diagnoses documented during the ED visit. Weighted frequencies and proportions of ED visits among adult patients with cancer by demographic, geographic, and clinical characteristics were calculated. Weighted multivariable logistic regression was used to examine the associations between inpatient admission and key demographic and clinical variables for adult cancer-related ED visits. Main Outcomes and Measures: Adult cancer-related ED utilization patterns; identification of primary reason for ED visit; patient-related factors associated with inpatient admission from the ED. Results: Among an estimated 696 million weighted adult ED visits from January 2006 to December 2012, 29.5 million (4.2%) were made by a patient with a cancer diagnosis. The most common cancers associated with an ED visit were breast, prostate, and lung cancer, and most common primary reasons for visit were pneumonia (4.5%), nonspecific chest pain (3.7%), and urinary tract infection (3.2%). Adult cancer-related ED visits resulted in inpatient admissions more frequently (59.7%) than non-cancer-related visits (16.3%) (P < .001). Septicemia (odds ratio [OR], 91.2; 95% CI, 81.2-102.3) and intestinal obstruction (OR, 10.94; 95% CI, 10.6-11.4) were associated with the highest odds of inpatient admission. Conclusions and Relevance: Consistent with national prevalence statistics among adults, breast, prostate, and lung cancer were the most common cancer diagnoses presenting to the ED. Pneumonia was the most common reason for adult cancer-related ED visits with an associated high inpatient admission rate. This analysis highlights cancer-specific ED clinical presentations and the opportunity to inform patient and system-directed prevention and management strategies. PMID- 28859190 TI - Comparative Effectiveness and Safety of Cognitive Behavioral Therapy and Pharmacotherapy for Childhood Anxiety Disorders: A Systematic Review and Meta analysis. AB - Importance: Childhood anxiety is common. Multiple treatment options are available, but existing guidelines provide inconsistent advice on which treatment to use. Objectives: To evaluate the comparative effectiveness and adverse events of cognitive behavioral therapy (CBT) and pharmacotherapy for childhood anxiety disorders. Data Sources: We searched MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and SciVerse Scopus from database inception through February 1, 2017. Study Selection: Randomized and nonrandomized comparative studies that enrolled children and adolescents with confirmed diagnoses of panic disorder, social anxiety disorder, specific phobias, generalized anxiety disorder, or separation anxiety and who received CBT, pharmacotherapy, or the combination. Data Extraction and Synthesis: Independent reviewers selected studies and extracted data. Random-effects meta-analysis was used to pool data. Main Outcomes and Measures: Primary anxiety symptoms (measured by child, parent, or clinician), remission, response, and adverse events. Results: A total of 7719 patients were included from 115 studies. Of these, 4290 (55.6%) were female, and the mean (range) age was 9.2 (5.4-16.1) years. Compared with pill placebo, selective serotonin reuptake inhibitors (SSRIs) significantly reduced primary anxiety symptoms and increased remission (relative risk, 2.04; 95% CI, 1.37-3.04) and response (relative risk, 1.96; 95% CI, 1.60-2.40). Serotonin-norepinephrine reuptake inhibitors (SNRIs) significantly reduced clinician-reported primary anxiety symptoms. Benzodiazepines and tricyclics were not found to significantly reduce anxiety symptoms. When CBT was compared with wait-listing/no treatment, CBT significantly improved primary anxiety symptoms, remission, and response. Cognitive behavioral therapy reduced primary anxiety symptoms more than fluoxetine and improved remission more than sertraline. The combination of sertraline and CBT significantly reduced clinician-reported primary anxiety symptoms and response more than either treatment alone. Head-to-head comparisons were sparse, and network meta-analysis estimates were imprecise. Adverse events were common with medications but not with CBT and were not severe. Studies were too small or too short to assess suicidality with SSRIs or SNRIs. One trial showed a statistically nonsignificant increase in suicidal ideation with venlafaxine. Cognitive behavioral therapy was associated with fewer dropouts than pill placebo or medications. Conclusions and Relevance: Evidence supports the effectiveness of CBT and SSRIs for reducing childhood anxiety symptoms. Serotonin norepinephrine reuptake inhibitors also appear to be effective based on less consistent evidence. Head-to-head comparisons between various medications and comparisons with CBT represent a need for research in the field. PMID- 28859191 TI - Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers During Active Surveillance. AB - Importance: Active surveillance of low-risk papillary thyroid cancer (PTC) is now an accepted alternative to immediate surgery, but experience with this approach outside of Japan is limited. The kinetics (probability, rate, and magnitude) of PTC tumor growth under active surveillance have not been well defined. Objective: To describe the kinetics of PTC tumor growth during active surveillance. Design, Setting, and Participants: Cohort study of 291 patients undergoing active surveillance for low-risk PTC (intrathyroidal tumors <=1.5 cm) with serial tumor measurements via ultrasonography at a tertiary referral center in the United States. Intervention: Active surveillance. Main Outcomes and Measures: The cumulative incidence, rate, and magnitude of the change in tumor diameter or volume, as well as associations with patient and tumor characteristics. Results: Of the 291 patients, 219 (75.3%) were women; mean (SD) age was 52 (15) years. During a median (range) active surveillance of 25 (6-166) months, growth in tumor diameter of 3 mm or more was observed in 11 of 291 (3.8%) patients, with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during active surveillance. In all cases, 3 dimensional measurements of tumor volume allowed for earlier identification of growth (median, 8.2 months; range, 3-46 months before increase in tumor diameter). In multivariable analysis, both younger age at diagnosis (hazard ratio per year, 0.92; 95% CI, 0.87-0.98; P = .006) and risk category at presentation (hazard ratio for inappropriate, 55.17; 95% CI, 9.4-323.19; P < .001) were independently associated with the likelihood of tumor growth. Of the tumors experiencing volume growth, kinetics demonstrated a classic exponential growth pattern, with a median doubling time of 2.2 years (range, 0.5-4.8 years; median r2 = 0.75; range, 0.42-0.99). Conclusions and Relevance: The rates of tumor growth during active surveillance in a US cohort with PTCs measuring 1.5 cm or less were low. Serial measurement of tumor volumes may facilitate early identification of tumors that will continue to grow and thereby inform the timing of surveillance imaging and therapeutic interventions. PMID- 28859192 TI - Measurement of Intraocular Pressure by Patients With Glaucoma. AB - Importance: The ability of patients to measure their own intraocular pressure (IOP) would allow more frequent measurements and better appreciation of peak IOP and IOP fluctuation. Objective: To examine whether patients with glaucoma can perform self-tonometry using a rebound tonometer and examine patient acceptability. Design, Setting, and Participants: An observational study in which IOP was assessed using Goldmann applanation tonometry and a rebound tonometer. Consecutive patients were provided with a patient information sheet and those consenting to take part in the study received standardized self-tonometry training and were then instructed to measure their own IOP under observation. This study was conducted at a glaucoma clinic at a university hospital from March 1, 2016, to December 30, 2016, and included both eyes of 100 patients with glaucoma or ocular hypertension. Main Outcomes and Measures: The percentage of patients who could successfully perform self-tonometry. Complete success was defined by a good technique and an IOP reading within 5 mm Hg of that obtained by a clinician using the same device. A 3-item questionnaire was used to examine perceptions of self-tonometry among patients. Results: Among the 100 patients, the mean (SD) age was 67.5 (10.9) years (53% female). A total 73 of 100 patients (73%) met the complete success criteria. An additional 6 patients could use the device but had IOP readings greater than 5 mm Hg different from those obtained by the clinician. On average, IOP by the rebound tonometer was 2.66 mm Hg lower than Goldmann applanation tonometry (95% limits of agreement, -3.48 to 8.80 mm Hg). The IOPs with the rebound tonometer were similar whether obtained by self tonometry or investigator, with excellent reproducibility with an intraclass correlation coefficient of 0.903 (95% CI, 0.867-0.928). A total of 56 of 79 successful or partially successful patients (71%) felt self-tonometry was easy, with 73 of 79 (92%) reporting self-tonometry to be comfortable, and a similar number happy to perform self-tonometry in the future. Conclusions and Relevance: Most patients could perform self-tonometry and the method was acceptable to patients. Self-tonometry has the potential to improve patient engagement, while also providing a more complete picture of IOP changes over time. PMID- 28859193 TI - Validity of Surrogate End Points for Prostate Cancer. PMID- 28859194 TI - Validity of Surrogate End Points for Prostate Cancer-Reply. PMID- 28859195 TI - Population-Based Incidence of Strabismus: Why Is It Important? PMID- 28859196 TI - Strabismus Incidence in a Danish Population-Based Cohort of Children. AB - Importance: To our knowledge, there have been few population-based studies of strabismus incidence conducted. Our population-based study provides valuable data for health services planning and identifying research needs. Objective: To determine the incidence and age distribution of strabismus, overall and by subtype, among children 7 years or younger. Design, Setting, and Participants: This population-based cohort study was conducted with data from 96 842 children enrolled in the Danish National Birth Cohort. Main Outcomes and Measures: Age specific incidence and cumulative incidence and median age at the detection of strabismus, overall and by subtype. Results: The study cohort included 96 842 children born between 1996 and 2008 who are predominantly Caucasian and is composed of approximately 30% of births in Denmark, with a boy-girl ratio of 51:49. Overall, 1309 cases of strabismus were identified in the cohort. We found an overall cumulative strabismus incidence of 2.56% (95% CI, 2.42-2.69) at 7 years. The overall incidence was similar among boys and girls. Two hundred sixteen participants (16.5%) (95% CI, 14.5-18.6) had congenital esotropia, 177 (13.5%) (95% CI, 11.7-15.5) had fully accommodative esotropia, 252 (19.3%) (95% CI, 17.1-21.5) had partially accommodative esotropia, and 181 (13.8%) (95% CI, 12.0-15.8) had exotropia. The esotropia:exotropia ratio was 5.4:1 (95% CI, 3.4:1 to 7.5:1). Age-specific incidence curves for congenital esotropia, fully accommodative esotropia, partially accommodative esotropia, and all exotropia revealed interactions between strabismus subtype and age, suggesting that the different subtypes had different age-specific patterns of incidence (P < .001 for all comparisons between pairs of curves). The median age at detection for the 4 subtypes was 0, 32.0, 26.1, and 16.6 months, respectively. Conclusions and Relevance: In a national, population-based cohort study, we found a cumulative incidence of strabismus consistent with those reported in smaller European and American cohorts, but a somewhat higher esotropia:exotropia ratio than those that, to our knowledge, are typically reported by English and American studies. Patterns of incidence by age differed for different strabismus subtypes, indicating differences in age at onset and thereby implying differences in the underlying etiology. PMID- 28859198 TI - Home Tonometry-Can We? Should We? PMID- 28859197 TI - Rare Genetic Variants in Age-Related Macular Degeneration. PMID- 28859199 TI - Mise en Place. PMID- 28859200 TI - Measuring the Cost of Quality Measurement: A Missing Link in Quality Strategy. PMID- 28859201 TI - Characterization of Head-Trunk Coordination Deficits After Unilateral Vestibular Hypofunction Using Wearable Sensors. AB - Importance: Individuals with vestibular hypofunction acutely restrict head motion to reduce symptoms of dizziness and nausea. This restriction results in abnormal decoupling of head motion from trunk motion, but the character, magnitude, and persistence of these deficits are unclear. Objective: To use wearable inertial sensors to quantify the extent of head and trunk kinematic abnormalities in the subacute stage after resection of vestibular schwannoma (VS) and the particular areas of deficit in head-trunk motion. Design, Setting, and Participants: This cross-sectional observational study included a convenience sample of 20 healthy adults without vestibular impairment and a referred sample of 14 adults 4 to 8 weeks after resection of a unilateral VS at a university and a university hospital outpatient clinic. Data were collected from November 12, 2015, through November 17, 2016. Exposures: Functional gait activities requiring angular head movements, including items from the Functional Gait Assessment (FGA; range, 1-30, with higher scores indicating better performance), the Timed Up & Go test (TUG; measured in seconds), and a 2-minute walk test (2MWT; measured in meters). Main Outcomes and Measures: Primary outcomes included peak head rotation amplitude (in degrees), peak head rotation velocity (in degrees per second), and percentage of head-trunk coupling. Secondary outcomes were activity and participation measures including gait speed, FGA score, TUG time, 2MWT distance, and the Dizziness Handicap Inventory score (range, 0-100, with higher scores indicating worse performance). Results: A total of 34 participants (14 men and 20 women; mean [SD] age, 39.3 [13.6] years) were included. Compared with the 20 healthy participants, the 14 individuals with vestibular hypofunction demonstrated mean (SD) reduced head turn amplitude (84.1 degrees [15.5 degrees ] vs 113.2 degrees [24.4 degrees ] for FGA-3), reduced head turn velocities (195.0 degrees /s [75.9 degrees /s] vs 358.9 degrees /s [112.5 degrees /s] for FGA-3), and increased head trunk coupling (15.1% [6.5%] vs 5.9% [5.8%] for FGA-3) during gait tasks requiring angular head movements. Secondary outcomes were also worse in individuals after VS resection compared with healthy individuals, including gait speed (1.09 [0.27] m/s vs 1.47 [0.22] m/s), FGA score (20.5 [3.6] vs 30.0 [0.2]), TUG time (10.9 [1.7] s vs 7.1 [0.8] s), 2MWT (164.8 [37.6] m vs 222.6 [26.8] m), and Dizziness Handicap Inventory score (35.4 [20.7] vs 0.1 [0.4]). Conclusions and Relevance: With use of wearable sensors, deficits in head-trunk kinematics were characterized along with a spectrum of disability in individuals in the subacute stage after VS surgery compared with healthy individuals. Future research is needed to fully understand how patterns of exposure to head-on-trunk movements influence the trajectory of recovery of head-trunk coordination during community mobility. PMID- 28859202 TI - Phenotype Characteristics of Patients With Age-Related Macular Degeneration Carrying a Rare Variant in the Complement Factor H Gene. AB - Importance: Rare variants in the complement factor H (CFH) gene and their association with age-related macular degeneration (AMD) have been described. However, there is limited literature on the phenotypes accompanying these rare variants. Phenotypical characteristics could help ophthalmologists select patients for additional genetic testing. Objective: To describe the phenotypical characteristics of patients with AMD carrying a rare variant in the CFH gene. Design, Setting, and Participants: In this cross-sectional study, we searched the genetic database of the department of ophthalmology at the Radboudumc (tertiary ophthalmologic referral center) and the European Genetic Database for patients with AMD with a rare genetic variant in the CFH gene. Patient recruitment took place from March 30, 2006, to February 18, 2013, and data were analyzed from November 30, 2015, to May 8, 2017. Phenotypical features on fundus photographs of both eyes of patients were graded by 2 independent reading center graders masked for carrier status. Main Outcomes and Measures: Differences in phenotypical characteristics between rare variant carriers and noncarriers were analyzed using univariable generalized estimated equations logistic regression models accounting for intereye correlation. Results: Analyses included 100 eyes of 51 patients with AMD carrying a CFH variant (mean [SD] age, 66.7 [12.1] years; 64.7% female) and 204 eyes of 102 age-matched noncarriers (mean [SD] age, 67.1 [11.8] years; 54.9% female). Carrying a rare pathogenic CFH variant was associated with larger drusen area (odds ratio range, 6.98 [95% CI, 2.04-23.89] to 18.50 [95% CI, 2.19-155.99]; P = .002), presence of drusen with crystalline appearance (odds ratio, 3.24; 95% CI, 1.24-8.50; P = .02), and drusen nasal to the optic disc (odds ratio range, 4.03 [95% CI, 1.70-9.56] to 7.42 [95% CI, 0.65-84.84]; P = .003). Conclusions and Relevance: Identification of rare CFH variant carriers may be important for upcoming complement-inhibiting therapies. Patients with an extensive drusen area, drusen with crystalline appearance, and drusen nasal to the optic disc are more likely to have a rare variant in the CFH gene. However, it is not likely that carriers can be discriminated from noncarriers based solely on phenotypical characteristics from color fundus images. Therefore, ophthalmologists should consider genetic testing in patients with these phenotypic characteristics in combination with other patient characteristics, such as early onset, cuticular drusen on fluorescein angiography, and family history of AMD. PMID- 28859204 TI - [Physical Activity and Cancer]. AB - The value of physical activity in cancer prevention and therapy has been increasingly recognised during the last twenty years. Many patients suffer from a loss of physical performance and a decline in quality of life - with fatigue, anxiety and depression as a direct result of their disease and therapy. Since the 1990 s, there has been a substantial increase in scientific evidence demonstrating the positive effects of physical activity in cancer patients. This article presents an overview of the most important studies investigating the effects of physical activity for breast, colon, and prostate cancer. PMID- 28859203 TI - Applying Item Response Theory to the Development of a Screening Adaptation of the Goldman-Fristoe Test of Articulation-Second Edition. AB - Purpose: Item response theory (IRT) is a psychometric approach to measurement that uses latent trait abilities (e.g., speech sound production skills) to model performance on individual items that vary by difficulty and discrimination. An IRT analysis was applied to preschoolers' productions of the words on the Goldman Fristoe Test of Articulation-Second Edition (GFTA-2) to identify candidates for a screening measure of speech sound production skills. Method: The phoneme accuracies from 154 preschoolers, with speech skills on the GFTA-2 ranging from the 1st to above the 90th percentile, were analyzed with a 2-parameter logistic model. Results: A total of 108 of the 232 phonemes from stimuli in the sounds-in words subtest fit the IRT model. These phonemes, and subgroups of the most difficult of these phonemes, correlated significantly with the children's overall percentile scores on the GFTA-2. Regression equations calculated for the 5 and 10 most difficult phonemes predicted overall percentile score at levels commensurate with other screening measures. Conclusions: These results suggest that speech production accuracy can be screened effectively with a small number of sounds. They motivate further research toward the development of a screening measure of children's speech sound production skills whose stimuli consist of a limited number of difficult phonemes. PMID- 28859205 TI - Acute Abdomen Syndrome Due To Spontaneous Intraperitoneal Bladder Rupture Following Vaginal Delivery. AB - We report a rare case of spontaneous intraperitoneal bladder rupture following normal vaginal delivery without concomitant uterine rupture. Key diagnostic clinical features were acute renal failure, new-onset ascites and bowel ileus with urosepsis. Laparotomy and bladder repair with omentum patch were performed with no adverse outcome reported. PMID- 28859206 TI - Beta-Blockers and Evidence-Based Guidelines for the Pharmacological Management of Acute Methamphetamine-Related Disorders and Toxicity. PMID- 28859207 TI - Hashimoto's Thyroiditis is an Important Risk Factor of Papillary Thyroid Microcarcinoma in Younger Adults. AB - The association between autoimmune thyroid disease and thyroid cancer remains unclear. We performed a matched case-control study to assess the association between Hashimoto's thyroiditis and papillary thyroid microcarcinoma (PTMC). A total of 927 PTMC cases and 927 age- and gender- matched controls selected from the same population were recruited. Odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the strength of the association between Hashimoto's thyroiditis and PTMC. Conditional logistic regression analysis was carried out, and stratified analyses by age, gender and types of thyroid antibodies were also performed. Hashimoto's thyroiditis was significantly associated with increased risk of PTMC (OR=1.87, 95% CI 1.49-2.34, p<0.001). Stratified analysis by thyroid antibodies also found obvious associations of PTMC risk with TPOAb positivity (OR=1.58, p=0.001) and TGAb positivity (OR=2.35, p<0.001). Stratified analyses by age showed that the association between Hashimoto's thyroiditis and PTMC risk was more significant in younger adults aged between 18 and 30 years (OR=11.48, p<0.001). Further stratified analyses by thyroid antibodies also found that the associations of PTMC risk with TPOAb positivity or TGAb positivity were more significant in younger adults aged between 18 and 30, and the ORs were 8.27 (p<0.001) and 12.71 (p<0.001), respectively. This study suggests an obvious relationship between Hashimoto's thyroiditis and PTMC risk, and Hashimoto's thyroiditis is an important risk of PTMC in younger adults. PMID- 28859208 TI - Height Increment and Laboratory Profile of Boys Treated With Aromatase Inhibitors With or Without Growth Hormone. AB - Aromatase inhibitors (AIs) have been used to recover height loss due to their capacity to delay growth plate closure. Long-term studies describing final heights are needed to determine the efficacy and safety profiles of these drugs for the treatment of impaired growth. This study aims to identify the therapeutic efficiency of AIs in improve growth and to describe potential adverse effects during treatment. Retrospective data analysis of 96 adolescents, among which 22 patients already attained near-final height, were followed at outpatient clinics of two referral centers. Patients were all in puberty and present idiopathic decrease in predicted adult height. Patients were treated with Anastrozole (ANZ: 1 mg/day) or Letrozole (LTZ: 2.5 mg/day) with/without recombinant human growth hormone (0.05 mg/kg/day) for 1.0 to 3.5 years (2.1+/-1.2 years). Height gain, body mass index, lipid, liver enzyme, gonadotropins and testosterone levels were described before and at the end of treatment. Predicted adult height (PAH) and NF height were compared with the TH. The height SDS (adjusted to bone age) significantly increased (p<0.05) in all groups [0.8+/-0.7 (ANZ), 0.7+/-0.7 (ANZ+GH), 0.3+/-0.5 (LTZ), and 1.2+/-0.8 (LTZ+GH)]; the latter group exhibited the highest increment of PAH and growth recovery to the TH (p<0.004). No significant side effects were observed. AI treatment, especially when used in association with GH was able to improve growth and the attainment of familial target height. PMID- 28859209 TI - Follicle Viability after Vitrification of Bovine Ovarian Tissue. AB - Purpose The present study aimed to evaluate the impact of vitrification on the viability of follicles using a three-dimensional (3D) in vitro culture. Methods Bovine ovarian tissue samples (n = 5) obtained from slaughterhouses were utilized. The cortex was cut into small fragments of 2 * 3 * 0.5 mm using a tissue slicer. From these fragments, secondary follicles were first isolated by mechanical and enzymatic methods, then encapsulated in alginate gel and individually cultured for 20 days. Additional fragments of the same ovarian tissue were vitrified in a solution containing 25% glycerol and 25% ethylene glycol. After warming, the follicles underwent the same follicular isolation process that was performed for the fresh follicles. Results A total of 61 follicles were isolated, 51 from fresh ovarian tissue, and 10 from vitrified tissue. After the culture, the vitrified and fresh follicles showed 20% and 43.1% survival rates respectively (p = 0.290), with no significant differences. At the end of the culture, there were no significant differences in follicular diameter between the vitrified (422.93 +/- 85.05 um) and fresh (412.99 +/- 102.55 um) groups (p = 0.725). Fresh follicles showed higher mean rate of antrum formation when compared with vitrified follicles (47.1% and 20.0% respectively), but without significant difference (p = 0.167). Conclusions The follicles were able to develop, grow and form antrum in the 3D system after vitrification, despite the lower results obtained with the fresh tissue. PMID- 28859210 TI - Oral Desensitization to Penicillin for the Treatment of Pregnant Women with Syphilis: A Successful Program. AB - Gestational syphilis is a prevalent disease in Brazil and other low and medium income countries. Desensitization to penicillin is recommended for pregnant women with syphilis who are allergic to beta-lactams. This is a descriptive study utilizing outpatient medical records from 2011 to 2015 from a mother and child hospital that is part of the national healthcare system in the South of Brazil, which performs an average of 3,600 birth assistances per year. All cases of pregnant women with syphilis and presumptive diagnosis of beta-lactam allergy during the study period were included. The patients referred for desensitization originated from the hospital prenatal care service, as well as from municipal/state antenatal care services. Oral desensitization was performed in the obstetric emergency room, and adult and pediatric intensive care units were available at all times. Ten patients underwent desensitization during the period of study. Personal history of urticaria was the most common reaction that demanded desensitization. All patients tolerated the procedure well, and showed no adverse reactions. We report a successful program of oral desensitization. None of the patients presented adverse reactions or complications, a fact that corroborates the feasibility and safety of the desensitization protocol. Oral administration of penicillin comes at a low cost, and optimizes the use of time and resources. PMID- 28859212 TI - MOG Spectrum Disorders and Role of MOG-Antibodies in Clinical Practice. AB - Myelin oligodendrocyte glycoprotein (MOG) antibodies (abs) are present in one third of all children with an acute demyelinating syndrome (ADS). MOG-abs can be found in acute disseminated encephalomyelitis (ADEM), transverse myelitis, isolated optic neuritis (ON), or recurrent demyelinating diseases, such as multiphasic neuromyelitis optica spectrum disorders (NMOSD) without aquaporin-4 (AQP4) abs or multiphasic ADEM (MDEM), but rarely in children who subsequently develop multiple sclerosis (MS). The presence of MOG-abs is age dependent with the highest seropositivity rates found in young children and an episode of ADEM, whereas older children with MOG-abs present with ON, myelitis, or brainstem symptoms. MOG-abs, initially thought to be associated with a benign disease course, are found in a substantial proportion of children with relapsing episodes associated with high and persisting MOG-ab titers. This review describes, in particular, the increasing spectrum of phenotypes associated with MOG-abs with a focus on clinical characteristics, radiological features, and therapeutic aspects. PMID- 28859213 TI - ? PMID- 28859214 TI - [Injuries in the Schoolyard: An Analysis of Individual and Contextual Factors]. AB - AIMS OF THE STUDY: Injuries of children and adolescents rank among the most immediate problems in public health in Germany. Alongside accidents in the household and during leisure time, the school is of great importance. However, there are significant gaps in knowledge about the causes of school injuries. This is the starting point of this article, which analyses individual and contextual factors that influence the occurrence of injuries in schools and deals explicitly with injuries happening in the schoolyard. METHOD: The data foundation is the second wave of the panel study "Gesundheitsverhalten und Unfallgeschehen im Schulalter" (Health Behavior and Occurrence of Accidents at School Age) (GUS). Following a random sampling of secondary general education schools in 11 German states, 10089 pupils aged 11-13 years from 138 schools were surveyed within their respective classes via a standardized electronic questionnaire. Alongside accidents and injuries, the questionnaire covers a wide range of topics including health and recreational behavior and also surveys information about the schools. The factors influencing schoolyard accidents are analyzed using multivariate, logistic multilevel-models. RESULTS: In the second wave, 5.8% of the pupils reported at least one injury happening in the schoolyard in the last 12 months that had to be treated by a doctor. Correlations with these schoolyard accidents were found for individual factors such as gender (female, OR=0.53), experiences of bullying (OR=1.68), sleeping problems (OR=1.07) and individual athletic activity (OR=1.03). Although the variance is primarily tied to the individual level, certain contextual variables also proved influential: Schools, in which the overall condition is rated better by the pupils, also have a lower overall risk of injuries (OR=0.60). CONCLUSIONS: According to these results, preventive measures may target the individual as well as the contextual level: prevention of bullying should be a focus in the light of these findings, but at the same time, also the condition of the schools should be taken into consideration. PMID- 28859215 TI - 1'-Acetoxychavicol Acetate Increases Proteasome Activity by Activating cAMP-PKA Signaling. AB - Protein degradation systems are critical pathways for the maintenance of protein homeostasis. The age-dependent attenuation of the proteasome activity contributes to age-related neurodegenerative processes. The molecule 1'-acetoxychavicol acetate (ACA) is naturally obtained from the rhizomes and seeds of Zingiberaceae plants, such as Languas galangal and Alpinia galangal, and exhibits anti carcinogenic effects. Recently, we have shown that ACA protected the age-related learning and memory impairments in senescence-accelerated mice and maintained cognitive performance. Therefore, we here examined the effects of ACA on the protein degradation systems and cell protection against neurotoxicity in differentiated PC12 cells. ACA increased proteasome activity in PC12 cells. Increased proteasome activity occurred during the initial stages of ACA treatment and lasted at least 9 h. The activity returned to control levels within 24 h. The increase in proteasome activity by ACA was suppressed by H-89, which is a cAMP dependent protein kinase A inhibitor. ACA increased the adenylate cyclase activity and therefore the intracellular cAMP levels. Furthermore, ACA recovered the initial cell viability, which was reduced after the addition of the amyloid beta-protein fragment to neuronally differentiated PC12 cells. The effects of ACA on amyloid toxicity were reduced after treatment with MG132, a proteasome inhibitor. These results demonstrated a neuroprotective effect of ACA via activation of cAMP/cAMP-dependent protein kinase A signaling in neuronally differentiated PC12 cells. PMID- 28859216 TI - Evaluating the Multitarget Effects of Combinations through Multistep Clustering of Pharmacological Data: the Example of the Commercial Preparation Iberogast. AB - Herbal combination preparations are widely used in traditional herbal medicine and are even established as modern evidence-based herbal medicinal products. The rationale behind such combinations is often questioned and assessing the contribution of each of the combination partners to overall activity is challenging. STW 5 (Iberogast) is such a combination with confirmed clinical efficacy in functional gastrointestinal disorders. It consists of nine plant extracts responsible for its multitarget function in these multifactorial diseases with their heterogeneous and overlapping pathomechanisms. This makes the combination an ideal candidate for the use of the newly described method of stepwise cluster analysis, a standardized procedure to transfer heterogeneous pharmacological data, from different models, into effect size categories. This allows for a stepwise cluster formation starting from the level of single tests up to the level of different pathomechanisms involved in the development of a certain disease, in this case functional dyspepsia subtypes and irritable bowel syndrome. In the current article, an overview on the pharmacological data on STW 5 and its single components is provided. The data are further analyzed using stepwise cluster formation, resulting in a summary of the different modes of action of STW 5 along with an evaluation of the contribution of the single constituents to the overall multitarget effects of the herbal combination preparation. PMID- 28859217 TI - Effects of dietary coated cysteamine hydrochloride on pork color in finishing pigs. AB - BACKGROUND: Coated cysteamine hydrochloride (CC) was applied as a feed additive in animal production. The influence and the mechanisms of CC used as a feed additive in promoting meat quality in finishing pigs were investigated. RESULTS: Dietary CC supplementation increased (P < 0.05) the a* and H* values and reduced (P < 0.05) the L* value in the longissimus dorsi muscles at 48 h postmortem (P < 0.05). The deoxymyoglobin content was enhanced (P < 0.05) and the metmyoglobin and malondialdehyde contents were reduced (P < 0.05) in pigs fed the dietary CC. Pigs fed a dietary CC of 0.035 g kg-1 had a lower cooking loss (P < 0.05) and a higher a* (24 h) value in the longissimus dorsi muscles than pigs on control treatment. The messenger RNA expression of superoxide dismutase 1 was upregulated (P < 0.05) in the longissimus dorsi. CONCLUSION: Dietary supplementation with CC could improve antioxidant status and delay meat discoloration by improving glutathione levels and antioxidase activity after longer chill storage (for 48 h after slaughter). Dietary supplementation with CC at 0.035 g kg-1 may promote the stability of pork color by reducing oxidation. (c) 2017 Society of Chemical Industry. PMID- 28859218 TI - Incidence of early anxiety aggravation in trials of selective serotonin reuptake inhibitors in depression. AB - OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) may aggravate anxiety and agitation during the first days of treatment but the frequency of such reactions remains unknown. METHOD: We analysed patient-level data from placebo controlled trials of sertraline, paroxetine or citalopram in depressed adults. Somatic anxiety, psychic anxiety and psychomotor agitation as assessed using the Hamilton Depression Rating Scale (HDRS) were analysed in all trials (n = 8262); anxiety-related adverse events were analysed in trials investigating paroxetine and citalopram (n = 5712). RESULTS: After one but not two weeks, patients on an SSRI were more likely than those on placebo to report enhanced somatic anxiety (adjusted risk 9.3% vs. 6.7%); likewise, mean rating of somatic anxiety was higher in the SSRI group. In contrast, patients receiving an SSRI were less likely to report aggravation of psychic anxiety (adjusted risk: 7.0% vs. 8.5%) with mean rating of psychic anxiety and agitation being lower in the SSRI group. The adverse event 'nervousness' was more common in patients given an SSRI (5.5% vs. 2.5%). Neither aggravation of HDRS-rated anxiety nor anxiety-related adverse events predicted poor antidepressant response. CONCLUSION: Whereas an anxiety reducing effect of SSRIs is notable already during the first week of treatment, these drugs may also elicit an early increase in anxiety in susceptible subjects that however does not predict a poor subsequent response to treatment. PMID- 28859219 TI - Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B. AB - : Relapses are observed in most hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients who discontinue treatment with nucleos(t)ide analogues (NAs); however, the rates of relapse vary widely among studies, and whether all patients with relapse need retreatment is unclear. The aim of this study was to assess the impact of different definitions on the rates of posttreatment relapse and therefore on the probability of retreatment in patients who have discontinued effective long-term NA therapy. In total, 130 HBeAg-negative chronic hepatitis B patients without cirrhosis and before NA treatment were included. All had on therapy virological remission for >=24 months and close follow-up for >=12 months after stopping NA treatment or until retreatment, which started on stringent predefined criteria. Relapses rates based on several predetermined definitions of virological and perhaps biochemical criteria were assessed. The median duration of therapy was 60 months and the median duration of on-therapy virological remission was 43 months. During a median off-NAs follow-up of 15 months, no patient experienced liver decompensation or died. Cumulative relapse rates were 2%-49%, 4%-73%, 11%-82%, and 16%-90% at 3, 6, 12, and 24 months, respectively, whereas cumulative retreatment rates were 15%, 22%, and 40% at 6, 12, and 24 months, respectively, after discontinuation of NA therapy. No patient characteristic was independently associated with the probability of relapse based on at least two definitions or of retreatment. CONCLUSION: In HBeAg-negative chronic hepatitis B patients who discontinue NA therapy, the definition of relapse has a great impact on off-NAs relapse rates and potentially on the probability of retreatment. Regardless of definition, off-NAs relapses cannot be easily predicted by patient characteristics. A substantial proportion of such patients may not require retreatment if stringent criteria are adopted. (Hepatology 2017). PMID- 28859220 TI - Projections of primary liver cancer to 2030 in 30 countries worldwide. AB - : Primary liver cancer (PLC) is the sixth most common cancer worldwide and the second most common cause of cancer death. Future predictions can inform health planners and raise awareness of the need for cancer control action. We predicted the future burden of PLC in 30 countries around 2030. Incident cases of PLC (International Classification of Diseases, Tenth Revision, C22) were obtained from 30 countries for 1993-2007. We projected new PLC cases to 2030 using age period-cohort models (NORDPRED software). Age-standardized incidence rates per 100,000 person-years were calculated by country and sex. Increases in new cases and rates of PLC are projected in both sexes. The largest increases in rates are, among men, in Norway (2.9% per annum), US whites (2.6%), and Canada (2.4%) and, among women, in the United States (blacks 4.0%), Switzerland (3.4%), and Germany (3.0%). The projected declines are in China, Japan, Singapore, and parts of Europe (e.g., Estonia, Czech Republic, Slovakia). A 35% increase in the number of new cases annually is expected compared to 2005. This increasing burden reflects both increasing rates (and the underlying prevalence of risk factors) and demographic changes. Japan is the only country with a predicted decline in the net number of cases and annual rates by 2030. CONCLUSION: Our reporting of a projected increase in PLC incidence to 2030 in 30 countries serves as a baseline for anticipated declines in the longer term through the control of hepatitis B virus and hepatitis C virus infections by vaccination and treatment; however, the prospect that rising levels of obesity and its metabolic complications may lead to an increased risk of PLC that potentially offsets these gains is a concern. (Hepatology 2017). PMID- 28859221 TI - Optical coherence tomography for the investigation of frontal fibrosing alopecia. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) is a cicatricial alopecia that affects the frontotemporal hairline, eyebrows and body hair. OCT is a non invasive imaging technique useful in understanding skin architecture and vascularization. OBJECTIVE: To describe structural and vascular findings in FFA using OCT. METHODS: This was a case-control study conducted from the months of December 2016-February 2017. The study was IRB approved and conducted at the University of Miami Hospital outpatient dermatology hair and nail clinic in Miami, FL. Four patients with biopsy proven FFA, and three healthy age and sex matched controls participated. OCT scans were taken on cicatricial alopecic band, inflammatory hairline, eyebrow, uninvolved scalp, facial papules, glabellar red dots and arm. The same body regions were evaluated in controls. RESULTS: Patients and controls were women aged 42-66. Results reveal epidermal thickness is increased in the inflammatory hairline (0.13 mm) and decreased in the alopecic band (0.08 mm) compared to controls (0.10 mm). Attenuation coefficient increased the inflammatory hairline and decreased in the alopecic band compared to controls. Vascular flow in the alopecic band is decreased compared to inflammatory scalp and controls in the superficial levels, but increased at deeper levels as compared to controls. Inflammatory tissue is consistently more vascular at all levels (P < 0.01). Vascular flows in each stage are significantly different than one another (P < 0.01). CONCLUSIONS: Increased vascular flow of the deep plexus in cicatricial stages can be a consequence of superficial tissue ischaemia or fibrosis. It is difficult to establish if the increased flow in the inflammatory stage is due to neovascularization as seen in other ischaemic diseases or is the result of the inflammatory response. OCT may be a useful non invasive tool in imaging FFA. Not only can the technology assist in monitoring disease activity in a non-invasive manner, but it may elucidate new pathophysiologic findings. PMID- 28859222 TI - Therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis. AB - : Patients with hepatocellular carcinoma (HCC) who are listed for liver transplantation (LT) are often treated while on the waiting list with locoregional therapy (LRT), which is aimed at either preventing progression of HCC or reducing the measurable disease burden of HCC in order to receive increased allocation priority. We aimed to synthesize evidence regarding the effectiveness of LRT in the management of patients with HCC who were on the LT waitlist. We conducted a comprehensive search of multiple databases from 1996 to April 25, 2016, for studies that enrolled adults with cirrhosis awaiting LT and treated with bridging or down-staging therapies before LT. Therapies included transcatheter arterial chemoembolization, transarterial radioembolization, ablation, and radiotherapy. We included both comparative and noncomparative studies. There were no randomized controlled trials identified. For adults with T1 HCC and waiting for LT, there were only two nonrandomized comparative studies, both with a high risk of bias, which reported the outcome of interest. In one series, the rate of dropout from all causes at 6 months in T1 HCC patients who underwent LRT was 5.3%, while in the other series of T1 HCC patients who did not receive LRT, the dropout rate at median follow-up of 2.4 years and the progression rate to T2 HCC were 30% and 88%, respectively. For adults with T2 HCC awaiting LT, transplant with any bridging therapy showed a nonsignificant reduction in the risk of waitlist dropout due to progression (relative risk [RR], 0.32; 95% confidence interval [CI], 0.06-1.85; I2 = 0%) and of waitlist dropout from all causes (RR, 0.38; 95% CI, 0.060-2.370; I2 = 85.7%) compared to no therapy based on three comparative studies. The quality of evidence is very low due to high risk of bias, imprecision, and inconsistency. There were five comparative studies which reported on posttransplant survival rates and 10 comparative studies which reported on posttransplant recurrence, and there was no significant difference seen in either of these endpoints. For adults initially with stage T3 HCC who received LRT, there were three studies reporting on transplant with any down-staging therapy versus no downstaging, and this showed a significant increase in 1-year (two studies, RR, 1.11; 95% CI, 1.01-1.23) and 5 year (1 study, RR, 1.17; 95% CI, 1.03-1.32) post-LT survival rates for patients who received LRT. The quality of evidence is very low due to serious risk of bias and imprecision. CONCLUSION: In patients with HCC listed for LT, the use of LRT is associated with a nonsignificant trend toward improved waitlist and posttransplant outcomes, though there is a high risk of selection bias in the available evidence. (Hepatology 2018;67:381-400). PMID- 28859223 TI - How does role transition affect the experience of trainee Advanced Clinical Practitioners: Qualitative evidence synthesis. AB - BACKGROUND: Advanced Clinical Practitioners have been developed to address current and future gaps in the medical workforce. Insight into problems associated with Advanced Clinical Practitioner transition may help present and future trainees adapt to their changing and demanding health environment. AIMS: To identify potential problems experienced by trainee Advanced Clinical Practitioners during transition and what the implications might be for workforce planning. DESIGN: A qualitative evidence synthesis to examine the issue of role transition for Advanced Clinical Practitioners. DATA SOURCES: The electronic databases accessed (1997-2016) were MEDLINE, EMBASE, CINAHL, BNI, AMED and PubMed and also included Researchgate, thesis publications, hand searching and NHS staffing reports. REVIEW METHODS: Eleven studies were identified between 1997 - 2016. Thematic synthesis was undertaken, creating codes, descriptive and analytical themes. Quality appraisal of individual studies was conducted using the tool of Walsh and Downe. FINDINGS: Six analytical themes were identified that addressed the key issues of transition discussed in the 11 articles and which were directly related to the proposed research project: experience of change, orientation to role, mentorship, clinical skills, clinical supervision and Masters' level education. CONCLUSIONS: Findings from all 11 articles were similar. Where these six themes were ignored, there was often either a failure to reach expected goals or resignation from the role. Future employers must ensure that they establish a comprehensive orientation and education programme to be certain that qualified Advanced Clinical Practitioners are suitably prepared for their role in health care. PMID- 28859224 TI - Reply. PMID- 28859225 TI - Widespread brain distribution and activity following i.c.v. infusion of anti-beta secretase (BACE1) in nonhuman primates. AB - BACKGROUND AND PURPOSE: The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. I.c.v. delivery is a promising route to the brain; however, it is unclear how efficiently antibodies delivered i.c.v. penetrate the cerebrospinal spinal fluid (CSF)-brain barrier and distribute throughout the brain parenchyma. EXPERIMENTAL APPROACH: We evaluated the pharmacokinetics and pharmacodynamics of an inhibitory monoclonal antibody against beta-secretase 1 (anti-BACE1) following continuous infusion into the left lateral ventricle of healthy adult cynomolgus monkeys. KEY RESULTS: Animals infused with anti-BACE1 i.c.v. showed a robust and sustained reduction (~70%) of CSF amyloid-beta (Abeta) peptides. Antibody distribution was near uniform across the brain parenchyma, ranging from 20 to 40 nM, resulting in a ~50% reduction of Abeta in the cortical parenchyma. In contrast, animals administered anti-BACE1 i.v. showed no significant change in CSF or cortical Abeta levels and had a low (~0.6 nM) antibody concentration in the brain. CONCLUSION AND IMPLICATIONS: I.c.v. administration of anti-BACE1 resulted in enhanced BACE1 target engagement and inhibition, with a corresponding dramatic reduction in CNS Abeta concentrations, due to enhanced brain exposure to antibody. PMID- 28859226 TI - Viral persistence, liver disease, and host response in a hepatitis C-like virus rat model. AB - : The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity, and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus from wild rats (Rattus norvegicus), RHV-rn1; acquired the complete viral genome sequence; and developed an infectious reverse genetics system. RHV-rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5' and 3' untranslated regions. We used site-directed and random mutagenesis to determine that only the first of the two microRNA-122 seed sites in the viral 5' untranslated region is required for viral replication and persistence in rats. Next, we used the clone-derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV-rn1 possesses several HCV-defining hallmarks: hepatotropism, propensity to persist, and the ability to induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation, and macrovesicular and microvesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct-acting antiviral therapy, sofosbuvir, effectively suppresses chronic RHV-rn1 infection in rats. CONCLUSION: We developed RHV-rn1 infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV-related viral persistence, immunity, and pathogenesis. (Hepatology 2018). PMID- 28859227 TI - Transmembrane BAX Inhibitor motif-containing 1, a novel anti-inflammatory approach for nonalcoholic steatohepatitis treatment. PMID- 28859229 TI - Mesenchymal stem cells for hepatitis B patients with acute on chronic liver failure-are we there? PMID- 28859228 TI - Performance characteristics of vibration-controlled transient elastography for evaluation of nonalcoholic fatty liver disease. AB - : Vibration-controlled transient elastography estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), which are noninvasive assessments of hepatic fibrosis and steatosis, respectively. However, prior vibration-controlled transient elastography studies reported high failure rates in patients with nonalcoholic fatty liver disease. We examined the performance characteristics of the FibroScan 502 Touch with two probes, medium (M+) and extra large (XL+), in patients with nonalcoholic fatty liver disease in a multicenter setting. A total of 1,696 exams were attempted in 992 patients (body mass index, 33.6 +/- 6.5 kg/m2 ) with histologically confirmed nonalcoholic fatty liver disease. Simultaneous assessment of LSM and CAP was performed using the FibroScan 502 Touch with an automatic probe selection tool. Testing was conducted twice in patients by either a single operator (87%) or two operators (13%). Failure was defined as the inability to obtain a valid examination. An examination was considered unreliable if LSM interquartile range/median was >30%. Significant disagreement between two readings was defined as >95% limits of agreement between two readings. A total of 1,641 examinations yielded valid results with a failure rate of 3.2% (55/1,696). The proportion of unreliable scans for LSM was 3.9%. The proportion of unreliable scans with operator experience in the top quartile (>=59 procedures) was significantly lower than that in the lower three quarters combined (1.6% versus 4.7%, P = 0.02 by Fisher's exact test). The significant disagreement between first and second readings for LSM and CAP when obtained back to back was 18% and 11%, respectively. CONCLUSION: Vibration-controlled transient elastography for estimation of LSM and CAP can be successfully deployed in a multicenter setting with low failure (3.2%) and high reliability (>95%) rates and high reproducibility. (Hepatology 2018;67:134-144). PMID- 28859230 TI - Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure. AB - : Hyperammonemia has been associated with intracranial hypertension and mortality in patients with acute liver failure (ALF). We evaluated the effect of renal replacement therapy (RRT) on serum ammonia level and outcomes in ALF. This was a multicenter cohort study of consecutive ALF patients from the United States ALF Study Group registry between January 1998 and December 2016. First, we studied the association of ammonia with hepatic encephalopathy (HE) and 21-day transplant free survival (TFS; n = 1,186). Second, we studied the effect of RRT on ammonia for the first 3 days post study admission (n = 340) and on 21-day TFS (n = 1,186). Higher admission (n = 1,186) median ammonia level was associated with grade 3-4 HE (116 vs. 83 MUmol/L) and mortality at day 21 attributed to neurological (181 vs. 90 MUmol/L) and all causes (114 vs. 83 MUmol/L; P < 0.001 for all). Among 340 patients with serial ammonia levels, 61 (18%) were on continuous RRT (CRRT), 59 (17%) were on intermittent RRT (IRRT), and 220 (65%) received no RRT for the first 2 days. From days 1 to 3, median ammonia decreased by 38%, 23%, and 19% with CRRT, IRRT, and no RRT, respectively. Comparing to no RRT use, whereas ammonia reduction with CRRT was significant (P = 0.007), with IRRT it was not (P = 0.75). After adjusting for year of enrollment, age, etiology, and disease severity, whereas CRRT (odds ratio [OR], 0.47 [95% confidence interval {CI}, 0.26-0.82]) was associated with reduction in 21-day transplant-free all-cause mortality, IRRT (OR, 1.68 [95% CI, 1.04-2.72]) was associated with an increase. CONCLUSION: In a large cohort of ALF patients, hyperammonemia was associated with high-grade HE and worse 21-day TFS. CRRT was associated with a reduction in serum ammonia level and improvement of 21-day TFS. (Hepatology 2017). PMID- 28859231 TI - Retrospective 8-year analysis of negative pressure wound therapy in dermatosurgery: a single-centre experience. AB - BACKGROUND: Negative pressure wound therapy (NPWT) is an established treatment modality in dermatologic surgery, but proof of evidence for efficacy is inconclusive. PURPOSE: To evaluate patient characteristics, treatment modalities and outcomes in a single dermatosurgery centre with NPWT applied over chronic and acute surgical wounds. METHODS: Of all surgical patients between 2008 and 2015, we selected those who were treated and hospitalized due to NPWT for treatment of acute and chronic wounds. The medical records of 188 patients were retrospectively evaluated and statistically calculated. RESULTS: Method of surgical defect closure depends significantly on localization of the surgical defect, cardiovascular comorbidity and age. Hence, outcome depends significantly on the surgical situation that indexes NPWT, the underlying diagnosis and the vacuum system used, but is not associated with distinct treatment modalities or gender of the patients. Hospitalization significantly depends on the vacuum system used, surgical situation that indexes NPWT and underlying diagnoses. CONCLUSION: NPWT has a fixed role in distinct, well-defined clinical indications in dermatosurgery as the treatment of acute surgical wounds, fixation of skin grafts and treatment of skin substitutes, as well as an important treatment option for refractory, superinfected chronic wounds in dermatologic patients. PMID- 28859232 TI - Pregnancy in Wilson's disease: Management and outcome. AB - : Wilson's disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634-4.982]). Birth defects occurred in 7 of 209 (3%) live births. CONCLUSION: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy naive patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (Hepatology 2018;67:1261-1269). PMID- 28859233 TI - Imaging for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. AB - : Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for noninvasive diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one over the other, we synthesized evidence regarding the relative performance of CT, extracellular contrast-enhanced MRI, and gadoxetate-enhanced MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy versus follow-up with the same versus alternative imaging is best for CT-indeterminate or MRI-indeterminate liver nodules in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016, for studies comparing CT with extracellular contrast-enhanced MRI or gadoxetate-enhanced MRI in adults with cirrhosis and suspected HCC. Two reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14 reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity (0.82 versus 0.66) and lower negative likelihood ratio (0.20 versus 0.37) for MRI over CT. The specificities of MRI versus CT (0.91 versus 0.92) and the positive likelihood ratios (8.8 versus 8.1) were not different. All three modalities performed better for HCCs >=2 cm. Performance was poor for HCCs <1 cm. No studies examined whether adults with cirrhosis and an indeterminate nodule are best evaluated using biopsy, repeated imaging, or alternative imaging. Concerns about publication bias, inconsistent study results, increased risk of bias, and clinical factors precluded support for exclusive use of either gadoxetate-enhanced or extracellular contrast-enhanced MRI over CT. CONCLUSION: CT, extracellular contrast-enhanced MRI, or gadoxetate enhanced MRI could not be definitively preferred for HCC diagnosis in patients with cirrhosis; in patients with cirrhosis and an indeterminate mass, there were insufficient data comparing biopsy to repeat cross-sectional imaging or alternative imaging. (Hepatology 2018;67:401-421). PMID- 28859234 TI - Side Chain Engineering on Medium Bandgap Copolymers to Suppress Triplet Formation for High-Efficiency Polymer Solar Cells. AB - Suppression of carrier recombination is critically important in realizing high efficiency polymer solar cells. Herein, it is demonstrated difluoro-substitution of thiophene conjugated side chain on donor polymer can suppress triplet formation for reducing carrier recombination. A new medium bandgap 2D-conjugated D-A copolymer J91 is designed and synthesized with bi(alkyl-difluorothienyl) benzodithiophene as donor unit and fluorobenzotriazole as acceptor unit, for taking the advantages of the synergistic fluorination on the backbone and thiophene side chain. J91 demonstrates enhanced absorption, low-lying highest occupied molecular orbital energy level, and higher hole mobility, in comparison with its control polymer J52 without fluorination on the thiophene side chains. The transient absorption spectra indicate that J91 can suppress the triplet formation in its blend film with n-type organic semiconductor acceptor m-ITIC (3,9-bis(2-methylene-(3-(1,1-dicyanomethylene)-indanone)-5,5,11,11-tetrakis(3 hexylphenyl)-dithieno[2,3-d:2,3'-d']-s-indaceno[1,2-b:5,6-b']-dithiophene). With these favorable properties, a higher power conversion efficiency of 11.63% with high VOC of 0.984 V and high JSC of 18.03 mA cm-2 is obtained for the polymer solar cells based on J91/m-ITIC with thermal annealing. The improved photovoltaic performance by thermal annealing is explained from the morphology change upon thermal annealing as revealed by photoinduced force microscopy. The results indicate that side chain engineering can provide a new solution to suppress carrier recombination toward high efficiency, thus deserves further attention. PMID- 28859235 TI - Twinned Growth of Metal-Free, Triazine-Based Photocatalyst Films as Mixed Dimensional (2D/3D) van der Waals Heterostructures. AB - Design and synthesis of ordered, metal-free layered materials is intrinsically difficult due to the limitations of vapor deposition processes that are used in their making. Mixed-dimensional (2D/3D) metal-free van der Waals (vdW) heterostructures based on triazine (C3 N3 ) linkers grow as large area, transparent yellow-orange membranes on copper surfaces from solution. The membranes have an indirect band gap (Eg,opt = 1.91 eV, Eg,elec = 1.84 eV) and are moderately porous (124 m2 g-1 ). The material consists of a crystalline 2D phase that is fully sp2 hybridized and provides structural stability, and an amorphous, porous phase with mixed sp2 -sp hybridization. Interestingly, this 2D/3D vdW heterostructure grows in a twinned mechanism from a one-pot reaction mixture: unprecedented for metal-free frameworks and a direct consequence of on-catalyst synthesis. Thanks to the efficient type I heterojunction, electron transfer processes are fundamentally improved and hence, the material is capable of metal free, light-induced hydrogen evolution from water without the need for a noble metal cocatalyst (34 umol h-1 g-1 without Pt). The results highlight that twinned growth mechanisms are observed in the realm of "wet" chemistry, and that they can be used to fabricate otherwise challenging 2D/3D vdW heterostructures with composite properties. PMID- 28859236 TI - Oral appliances for managing sleep bruxism in adults: a systematic review from 2007 to 2017. AB - The review focuses on the last decade of research regarding the use of various oral appliances (OAs) in the management of sleep bruxism (SB) in adults. Sixteen (n = 16) papers of 641 identified citations involving 398 participants were included in the review. Of them, seven were randomised controlled trials (RCTs), seven were uncontrolled before-after studies and two were crossover trials. Analysis of the included articles revealed a high variability of study designs and findings. Generally, the risk of bias was low-to-unclear for RCTs and high for crossover studies, whilst the before-after studies exhibited several structural limitations. Nine studies used polysomnography/polygraphy/electromyography for SB diagnosis, whilst others were based on history taking and clinical examination. Most of them featured small samples and were short term. Of the studies using objective SB evaluations, eight showed positive results for almost every type of OA in reducing SB activity, with a higher decrease for devices that are designed to provide a certain extent of mandibular advancement. Among the studies using a subjective SB evaluation, one demonstrated a significant reduction in SB activity, and additional two showed a myorelaxant effect of OA in SB patients. Although many positive studies support the efficiency of OA treatment for SB, accepted evidence is insufficient to support its role in the long-term reduction of SB activity. Further studies with larger samples and sufficient treatment periods are needed to obtain more acknowledgements for clinical application. PMID- 28859237 TI - Cystathionine beta-synthase is required for body iron homeostasis. AB - : Cystathionine beta-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide. In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 pathway used in the regulatory systems of hydrogen sulfide and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knockout (CBS-/- ) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen, and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron overload is the reduced iron usage due to suppressed erythropoiesis, which is consistent with an increase in interleukin-6 and reduced expression of erythropoietin. Importantly, in the liver, absence of CBS caused both a reduction in the transcriptional factor nuclear factor erythroid 2-related factor-2 and an up regulation of hepcidin that led to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS overexpressing adenovirus into CBS mutant mice could partially reverse the iron related phenotype. CONCLUSION: Our findings point to a critical role of CBS in iron homeostasis of the body, and the liver in particular; it is likely that a hemochromatosis-like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway but also of those related to CBS. (Hepatology 2018;67:21-35). PMID- 28859239 TI - Rendering Photoreactivity to Ceria: The Role of Defects. AB - The photoreactivity of ceria, a photochemically inert oxide with a large band gap, can be increased to competitive values by introducing defects. This previously unexplained phenomenon has been investigated by monitoring the UV induced decomposition of N2 O on well-defined single crystals of ceria by using infrared reflection-absorption spectroscopy (IRRAS). The IRRAS data, in conjunction with theory, provide direct evidence that reducing the ceria(110) surface yields high photoreactivity. No such effects are seen on the (111) surface. The low-temperature photodecomposition of N2 O occurs at surface O vacancies on the (110) surface, where the electron-rich cerium cations with a significantly lowered coordination number cause a local lowering of the huge band gap (ca. 6 eV). The quantum efficiency of strongly reduced ceria(110) surfaces in the photodecomposition of N2 O amounts to 0.03 %, and is thus comparable to that reported for the photooxidation of CO on rutile TiO2 (110). PMID- 28859238 TI - Lipocalin 2 negatively regulates cell proliferation and epithelial to mesenchymal transition through changing metabolic gene expression in colorectal cancer. AB - Lipocalin 2 (LCN2), a member of the lipocalin superfamily, plays an important role in oncogenesis and progression in various types of cancer. However, the expression pattern and functional role of LCN2 in colorectal cancer (CRC) is still poorly understood. The purpose of the present study was to investigate whether LCN2 is associated with proliferation and the epithelial-mesenchymal transition (EMT) in CRC and to elucidate the underlying signaling pathways. LCN2 was preferentially expressed in CRC cells compared to normal tissues. However, LCN2 expression was significantly lower in metastatic or advanced-stage CRC than in non-metastatic or early stage CRC. Knockdown of LCN2 using small interfering RNA (siRNA) in CRC cells expressing a high level of LCN2 induced cell proliferation and a morphological switch from an epithelial to mesenchymal state. Furthermore, downregulation of LCN2 in CRC cells increased cell migration and invasion involved in the regulation of EMT markers. Knockdown of LCN2 also induced glucose consumption and lactate production, accompanied by an increase in energy metabolism-related genes. Taken together, our findings indicated that LCN2 negatively modulated proliferation, EMT and energy metabolism in CRC cells. Accordingly, LCN2 may be a candidate metastasis suppressor and potential therapeutic target in CRC. PMID- 28859240 TI - Rocking-Chair Ammonium-Ion Battery: A Highly Reversible Aqueous Energy Storage System. AB - Aqueous rechargeable batteries are promising solutions for large-scale energy storage. Such batteries have the merit of low cost, innate safety, and environmental friendliness. To date, most known aqueous ion batteries employ metal cation charge carriers. Here, we report the first "rocking-chair" NH4 -ion battery of the full-cell configuration by employing an ammonium Prussian white analogue, (NH4 )1.47 Ni[Fe(CN)6 ]0.88 , as the cathode, an organic solid, 3,4,9,10-perylenetetracarboxylic diimide (PTCDI), as the anode, and 1.0 m aqueous (NH4 )2 SO4 as the electrolyte. This novel aqueous ammonium-ion battery demonstrates encouraging electrochemical performance: an average operation voltage of ca. 1.0 V, an attractive energy density of ca. 43 Wh kg-1 based on both electrodes' active mass, and excellent cycle life over 1000 cycles with 67 % capacity retention. Importantly, the topochemistry results of NH4+ in these electrodes point to a new paradigm of NH4+ -based energy storage. PMID- 28859242 TI - Selective release of miRNAs via extracellular vesicles is associated with house dust mite allergen-induced airway inflammation. AB - BACKGROUND: MicroRNAs (miRNAs) may facilitate cell-to-cell communication via extracellular vesicles (EVs). The biological roles of miRNAs in EVs on allergic airway inflammation are unclear. METHODS: Airway-secreted EVs (AEVs) were isolated from bronchoalveolar lavage fluid (BALF) of control and house-dust mite (HDM) allergen-exposed HDM-sensitized mice. The expression of miRNAs in AEVs or miRNAs and mRNAs in lung tissue was analysed using miRNA microarray. RESULTS: The amount of AEV increased 8.9-fold in BALF from HDM-exposed mice compared with that from sham-control mice. HDM exposure resulted in significant changes in the expression of 139 miRNAs in EVs and 175 miRNAs in lung tissues, with 54 miRNAs being common in both samples. Expression changes of these 54 miRNAs between miRNAs in AEVs and lung tissues after HDM exposure were inversely correlated. Computational analysis revealed that 31 genes, including IL-13 and IL-5Ra, are putative targets of the miRNAs up-regulated in AEVs but down-regulated in lung tissues after HDM exposure. The amount of AEV in BALF after HDM exposure was diminished by treatment with the sphingomyelinase inhibitor GW4869. The treatment with GW4869 also decreased Th2 cytokines and eosinophil counts in BALFs and reduced eosinophil accumulation in airway walls and mucosa. CONCLUSION: These results indicate that selective sorting of miRNA including Th2 inhibitory miRNAs into AEVs and increase release to the airway after HDM exposure would be involved in the pathogenesis of allergic airway inflammation. PMID- 28859243 TI - Ultrafast Charge Transfer and Upconversion in Zinc beta-Tetraaminophthalocyanine Functionalized PbS Nanostructures Probed by Transient Absorption Spectroscopy. AB - We functionalize PbS nanocrystals with the organic semiconductor Zn beta tetraaminophthalocyanine to design a nanostructured solid-state material with frequent organic-inorganic interfaces. By transient absorption and fluorescence spectroscopy, we investigate the optoelectronic response of this hybrid material under near-infrared excitation to find efficient charge transfer from the nanocrystals to the molecules. We demonstrate that the material undergoes cooperative sensitization of two nanocrystals followed by photon upconversion and singlet emission of the organic semiconductor. The upconversion efficiency resembles that of comparable systems in solution, which we attribute to the large amount of interfaces present in this solid-state film. We anticipate that this synthetic strategy has great prospects for increasing the open-circuit voltage in PbS nanocrystal-based solar cells. PMID- 28859241 TI - miR-125b-1 and miR-378a are predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. AB - Many clinical trials of peptide vaccines have been conducted. However, these vaccines have provided clinical benefits in only a small fraction of patients. The purpose of the present study was to explore microRNAs (miRNAs) as novel predictive biomarkers for the efficacy of vaccine treatment against colorectal cancer. First, we carried out microarray analysis of pretreatment cancer tissues in a phase I study, in which peptide vaccines alone were given. Candidate miRNAs were selected by comparison of the better prognosis group with the poorer prognosis group. Next, we conducted microarray analysis of cancer tissues in a phase II study, in which peptide vaccines combined with chemotherapy were given. Candidate miRNAs were further selected by a similar comparison of prognosis. Subsequently, we carried out reverse-transcription PCR analysis of phase II cases, separating cancer tissues into cancer cells and stromal tissue using laser capture microdissection. Treatment effect in relation to overall survival (OS) and miRNA expression was analyzed. Three miRNA predictors were negatively associated with OS: miR-125b-1 in cancer cells (P = 0.040), and miR-378a in both cancer cells (P = 0.009) and stromal cells (P < 0.001). Multivariate analysis showed that expression of miR-378a in stromal cells was the best among the three predictors (HR, 2.730; 95% CI, 1.027-7.585; P = 0.044). In conclusion, miR-125b-1 and miR-378a expression might be considered as novel biomarkers to predict the efficacy of vaccine treatment against colorectal cancer. PMID- 28859244 TI - Significance of human papillomavirus positivity in sinonasal squamous cell carcinoma. AB - BACKGROUND: The role of human papillomavirus (HPV) in sinonasal squamous cell carcinoma (SNSCC) is not well understood. METHODS: The National Cancer Database was queried for cases of SNSCC with known HPV status. Demographics, socioeconomic variables, TNM stage, histology, grade, treatment modalities, and overall survival (OS) through 5 years were compared between HPV-positive and HPV-negative tumors. Cox proportional hazard regression analyses were performed. RESULTS: Seven hundred seventy (770) cases were identified; 526 were HPV-negative (68.3%) and 244 (31.7%) were HPV-positive. Patients with HPV-positive tumors were younger (58.0 vs 63.7 years, p < 0.0001). Nasal cavity (49.4%) tumors were more likely to be HPV-positive (p < 0.05) than maxillary (18.8%), ethmoid (18.8%), and frontal (18.2%) sinus tumors. Large cell nonkeratinizing (42.4%), papillary (42.1%), and basaloid (56.5%) tumors were more likely than keratinizing (25.2%) tumors to be HPV-positive (p < 0.05). Well-differentiated (grade I) tumors (9.0%) were less likely than higher grade tumors to be HPV-positive (p < 0.05). Gender, race, facility type, insurance type, median income, education level, Charlson-Deyo comorbidity score, overall stage, T stage, N stage, M stage, tumor size, treatment modality, surgical approach, and surgical margins did not vary by HPV status (p >= 0.05). HPV-positive tumors had higher OS than HPV-negative tumors (p < 0.0001). At 5 years, OS was 68.1% and 51.5% for HPV-positive and HPV-negative tumors, respectively. On multivariate analyses, HPV positivity remained a favorable prognostic factor (hazard ratio, 0.49; 95% confidence interval, 0.34 0.70). CONCLUSION: HPV positivity is more common in nasal cavity SCC and nonkeratinizing SNSCC. It is also a favorable prognostic factor in SNSCC. Future studies on SNSCC should take HPV positivity into consideration. PMID- 28859245 TI - Comparison of the effect of aerosolized fibrin sealant and biodegradable synthetic polyurethane foam on hemostasis and wound healing after endoscopic sinus surgery: a prospective randomized study. AB - BACKGROUND: Use of absorbable packing materials after functional endoscopic sinus surgery (FESS) is associated with increased patient comfort and a lack of need for packing removal. Different materials may induce different patterns of mucosal healing and hemostasis. This study investigated the effect of fibrin sealant (FS; Tisseel) or biodegradable synthetic polyurethane foam (Nasopore(r) ) packing on hemostasis and wound healing after FESS. METHODS: This prospective randomized controlled trial included 35 consecutive patients who underwent bilateral FESS for chronic rhinosinusitis. The patients were randomized to receive FS through aerosol spraying on 1 side and Nasopore packing on the opposite side. They were followed at 1, 2, 4, 8, and 12 weeks after surgery. Endoscopically visible packing material, crusting, adhesion, bleeding, granulation tissue formation, frontal sinus patency, and adverse effects were assessed. Subjective symptoms related to nasal packing were evaluated by using questionnaires quantified with a visual analogue scale. RESULTS: No significant differences were found between the FS-treated side and the Nasopore-packed side with respect to postoperative bleeding, adhesion, or frontal sinus patency. However, crusting and granulation were significantly lower in FS-treated nostrils (p < 0.01). The patients' satisfaction and willingness to reuse the material were not significantly different between FS and Nasopore. There were no allergic reactions to either material. CONCLUSION: FS and Nasopore were equally successful in achieving hemostasis and patient satisfaction after FESS. However, our results suggest that differential mucosal healing patterns may be induced by alternative absorbable hemostatic materials. FS-treated sides showed more optimal healing patterns than Nasopore-packed sides. PMID- 28859246 TI - Systematic Review of Cyberbullying Interventions for Youth and Parents With Implications for Evidence-Based Practice. AB - BACKGROUND: Cyberbullying is a new risk factor for the well-being of pediatric populations. Consequences of cyberbullying include both physical and mental health concerns such as depression, anxiety, and somatic concerns. Adolescents who have been victims of cyberbullying and developed secondary symptoms are often recommended to visit a healthcare provider to obtain effective, evidence-based treatment. To date, no interventions exist in the healthcare setting for adolescents who are victims of cyberbullying. AIMS: The purpose of this project is to review interventional studies on cyberbullying that have components for adolescents who have been involved with cyberbullying and their parents and to provide recommendations on effective intervention components with the goal of guiding clinical practice. METHODS: A systematic review was conducted using the Institute of Medicine guidelines. A comprehensive electronic literature search was completed targeting interventions of cyberbullying in any setting. No date limits were used. Literature was searched in MEDLINE, Cumulative Index of Nursing and Allied Health Literature (CINAHL), PubMed, Communication and Mass Media Complete, Education Information Resource Center (ERIC), and PsycINFO databases. The following search terms were applied "cyberbullying" + "intervention" or "treatment" or "therapy" or "program." Only articles with a pediatric population were selected for review. RESULTS: Seventeen cyberbullying intervention programs in 23 articles were found to meet the search criteria. The most frequently used intervention components included education on cyberbullying for the adolescent, coping skills, empathy training, communication and social skills, and digital citizenship. Parent education on cyberbullying was also found to be important and was included in programs with significant outcomes. LINKING EVIDENCE TO ACTION: As youth present to healthcare providers with symptoms related to cyberbullying, effective interventions are needed to guide evidence-based practice. This review supports educating the individual youth and parent on cyberbullying and teaching the youth skills in communication and social, empathy, coping with cyberbullying, and digital citizenship. PMID- 28859247 TI - The effect of solvation processes on amino acid- and peptide-silica stationary phases. AB - The surface excess adsorption isotherms of water, acetonitrile, and methanol from binary hydro-organic mobile phases were investigated on nine home-made stationary phases with chemically bonded amino acids, dipeptides, and tripeptides using the dynamic minor disturbance method. The stationary phases were modified by the following amino acids: glycine, alanine, phenylalanine, leucine, and aspartic acid. We investigated the influence of the type of immobilized amino acids, in particular their different side chains, on the solvent adsorption. The interpretation of solvation phenomena shows significant accumulation of investigated solvents on the adsorbent surface according to their hydrophilic or hydrophobic properties. Moreover, the accumulated amount was dependent on the length and type of amino acid sequences bonded to the silica surface. Stationary phases with bonded amino acids and peptides show stronger water and acetonitrile adsorption in contrast to the stationary phase modified with aminopropyl groups-a support for the synthesis. The comparison of water and acetonitrile adsorption as well as a data obtained with the two-site adsorption model reveal and confirm the heterogeneity of chemically bonded phases. As a consequence of performed investigations, the classification of tested stationary phases for the potential usage in particular high-performance liquid chromatography mode was also accomplished. PMID- 28859248 TI - Allergic FcepsilonRI- and pseudo-allergic MRGPRX2-triggered mast cell activation routes are independent and inversely regulated by SCF. AB - While allergic mast cell (MC) degranulation occurs by FcepsilonRI aggregation and varies in strength among subjects, the analogous pseudo-allergic route was recently uncovered to proceed via MRGPRX2. Here, we examine interindividual variability in skin MC responses to FcepsilonRI triggering vs those evoked by MRGPRX2. While population-based variability is comparable between the routes, FcepsilonRI- and MRGPRX2-stimulated pathways are completely independent from each other, and responsiveness to one has therefore no predictive value for the other. Conversely, degranulation triggered by compound 48/80 is highly correlated to the process elicited by substance P. MRGPRX2 mRNA shows pronounced population-based variability (coefficient of variation 102.9%). Surprisingly, stem cell factor (SCF) as the MC-supportive mediator par excellence potently inhibits pseudo allergic degranulation, while it simultaneously promotes allergic stimulation via FcepsilonRI. We conclude that SCF can have selective MC-dampening functions. Clinically, the data imply that subjects highly reactive in one pathway are not automatically hyper-responsive in terms of the alternative route. PMID- 28859249 TI - The evolving professional identity of the clinical research nurse: A qualitative exploration. AB - AIMS AND OBJECTIVES: To examine the perspectives of CRNs in the UK on their professional role identity, in order to inform the professional practice of Clinical Research Nursing. BACKGROUND: Clinical research nurses (CRN) make a significant contribution to healthcare research within the UK and internationally. However, lack of clarity about their role, and scope of practice renders their contribution within the profession and in the minds of the wider public invisible. This has implications in terms of promoting the role nurses play not only in terms of recruitment, retention, and care of research participants but also as research leaders of the future. DESIGN: Exploratory qualitative design using thematic analysis conducted within a realist paradigm. RESULTS: Participants viewed the positive aspects of their identity 'as agents of change' who were fundamental to the clinical research process. Resourcefulness and the ability to guide members of the research team were valued as key to job satisfaction. Successful navigation through the complexity of advice, support, management and leadership tasks related to their role in caring for research patients were role affirming and generated a sense of pride. However, lack of recognition, clarity of the role and career development opportunities within an identified structure undermined the CRN identity and optimism about progression in the future. Participants reported feeling invisible to colleagues within the clinical community, isolated and excluded from wider nursing groups. CONCLUSIONS: The study describes UK CRN practice, highlighting the positive benefits and challenges associated with the role, including the need to support professional and career development to maximise their research contribution. RELEVANCE TO CLINICAL PRACTICE: This study provides nurses, health care and research organisations and academic nursing educators with a broadened understanding of the professional role, identity and context of clinical research nursing practice in the United Kingdom, with recommendations to improve its professional efficiency and recognition. PMID- 28859250 TI - Light-induced regulation of ligand-gated channel activity. AB - : The control of ligand-gated receptors with light using photochromic compounds has evolved from the first handcrafted examples to accurate, engineered receptors, whose development is supported by rational design, high-resolution protein structures, comparative pharmacology and molecular biology manipulations. Photoswitchable regulators have been designed and characterized for a large number of ligand-gated receptors in the mammalian nervous system, including nicotinic acetylcholine, glutamate and GABA receptors. They provide a well equipped toolbox to investigate synaptic and neuronal circuits in all-optical experiments. This focused review discusses the design and properties of these photoswitches, their applications and shortcomings and future perspectives in the field. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 28859251 TI - Comparative sperm protein profiling in bulls differing in fertility and identification of phosphatidylethanolamine-binding protein 4, a potential fertility marker. AB - This study aimed to identify sperm proteomic signatures regulating sperm functions and fertility by: (i) comparing the sperm electrophoretic protein profiles and identifying the differentially abundant proteins among breeding bulls differing in fertility status and (ii) elucidating the possible role of one of the identified novel proteins, PEBP4 on sperm function and fertility. The grouping of bulls as fertile (n = 6) and low fertile (n = 6) was performed based on bull fertility index and infertile (n = 6) based on semen rejection rate (>33%). The sperm motility, fructolysis index, acrosomal reaction, intracellular calcium levels, and seminal plasma fructose and calcium levels were studied among fertility groups. The differentially expressed sperm proteins observed in single- and two-dimensional gel electrophoresis (2DE) were identified using Nano-LC MS/MS. In the fertile bulls, the expression levels of calmodulin (CALM1), spermadhesinZ13 (SPADH2), and phosphatidylethanolamine-binding protein 4 (PEBP4) were significantly (p < 0.05) higher than in other fertility groups. In bovine, expression of PEBP4 a novel seminal protein was not observed in spermatozoa of infertile bulls. When the bulls were grouped based on the presence (n = 8) or absence (n = 10) of PEBP4 protein in spermatozoa, a positive significant (p < 0.05) association of this protein with the percentage of motile, type-A spermatozoa, and sperm fructose uptake was observed. Further, PEBP4 was localized in elongated spermatids, Leydig cells, excurrent duct system, and principal piece of spermatozoa. These findings suggest a crucial role for the PEBP4 protein in spermiogenesis, epididymal sperm maturation, and sperm motility. This first study in bovine indicates the positive association of PEBP4 in regulating sperm maturation, functions, and fertility and could be a potential marker for predicting semen quality and fertility. PMID- 28859252 TI - Open access database of raw ultrasonic signals acquired from malignant and benign breast lesions. AB - PURPOSE: The aim of this paper is to provide access to a database consisting of the raw radio-frequency ultrasonic echoes acquired from malignant and benign breast lesions. The database is freely available for study and signal analysis. ACQUISITION AND VALIDATION METHODS: The ultrasonic radio-frequency echoes were recorded from breast focal lesions of patients of the Institute of Oncology in Warsaw. The data were collected between 11/2013 and 10/2015. Patients were examined by a radiologist with 18 yr' experience in the ultrasonic examination of breast lesions. The set of data includes scans from 52 malignant and 48 benign breast lesions recorded in a group of 78 women. For each lesion, two individual orthogonal scans from the pathological region were acquired with the Ultrasonix SonixTouch Research ultrasound scanner using the L14-5/38 linear array transducer. All malignant lesions were histologically assessed by core needle biopsy. In the case of benign lesions, part of them was histologically assessed and another part was observed over a 2-year period. DATA FORMAT AND USAGE NOTES: The radio-frequency echoes were stored in Matlab file format. For each scan, the region of interest was provided to correctly indicate the lesion area. Moreover, for each lesion, the BI-RADS category and the lesion class were included. Two code examples of data manipulation are presented. The data can be downloaded via the Zenodo repository (https://doi.org/10.5281/zenodo.545928) or the website http://bluebox.ippt.gov.pl/~hpiotrzk. POTENTIAL APPLICATIONS: The database can be used to test quantitative ultrasound techniques and ultrasound image processing algorithms, or to develop computer-aided diagnosis systems. PMID- 28859253 TI - Flow features and device-induced blood trauma in CF-VADs under a pulsatile blood flow condition: A CFD comparative study. AB - In this study, the flow features and device-associated blood trauma in 4 clinical ventricular assist devices (VADs; 2 implantable axial VADs, 1 implantable centrifugal VAD, and 1 extracorporeal VAD) were computationally analyzed under clinically relevant pulsatile flow conditions. The 4 VADs were operated at fixed pump speed at a mean rate of 4.5 L/min. Mean pressure difference, wall shear stress, volume distribution of scalar shear stress (SSS), and shear-induced hemolysis index (HI) were derived from the flow field of each VAD and were compared. The computationally predicted mean pressure difference across the 3 implantable VADs was ~70 mmHg, and the extracorporeal VAD was ~345 mmHg, which matched well with their reported pressure-flow curves. The axial VADs had higher mean wall shear stress and SSS compared with the centrifugal VADs. However, the residence time of the centrifugal VADs was much longer compared with the axial VADs because of the large volume of the centrifugal VADs. The highest SSS was observed in one axial VAD, and the longest exposure time was observed in 1 centrifugal VAD. These 2 VADs generated the highest HI. The shear-induced HI varied as a function of flow rate within each cardiac cycle. At fixed pump speed, the HI was greatest at low flow rate due to longer exposure time to shear stress compared with at high flow rate. Subsequently, we hypothesize that to reduce the risk of blood trauma during VAD support, shear stress magnitude and exposure time need to be minimized. PMID- 28859254 TI - What impact does nursing care left undone have on patient outcomes? Review of the literature. AB - AIMS AND OBJECTIVES: Systematic review of the impact of missed nursing care on outcomes in adults, on acute hospital wards and in nursing homes. BACKGROUND: A considerable body of evidence supports the hypothesis that lower levels of registered nurses on duty increase the likelihood of patients dying on hospital wards, and the risk of many aspects of care being either delayed or left undone (missed). However, the direct consequence of missed care remains unclear. DESIGN: Systematic review. METHODS: We searched Medline (via Ovid), CINAHL (EBSCOhost) and Scopus for studies examining the association of missed nursing care and at least one patient outcome. Studies regarding registered nurses, healthcare assistants/support workers/nurses' aides were retained. Only adult settings were included. Because of the nature of the review, qualitative studies, editorials, letters and commentaries were excluded. PRISMA guidelines were followed in reporting the review. RESULTS: Fourteen studies reported associations between missed care and patient outcomes. Some studies were secondary analyses of a large parent study. Most of the studies used nurse or patient reports to capture outcomes, with some using administrative data. Four studies found significantly decreased patient satisfaction associated with missed care. Seven studies reported associations with one or more patient outcomes including medication errors, urinary tract infections, patient falls, pressure ulcers, critical incidents, quality of care and patient readmissions. Three studies investigated whether there was a link between missed care and mortality and from these results no clear associations emerged. CONCLUSIONS: The review shows the modest evidence base of studies exploring missed care and patient outcomes generated mostly from nurse and patient self-reported data. To support the assertion that nurse staffing levels and skill mix are associated with adverse outcomes as a result of missed care, more research that uses objective staffing and outcome measures is required. RELEVANCE TO CLINICAL PRACTICE: Although nurses may exercise judgements in rationing care in the face of pressure, there are nonetheless adverse consequences for patients (ranging from poor experience of care to increased risk of infection, readmissions and complications due to critical incidents from undetected physiological deterioration). Hospitals should pay attention to nurses' reports of missed care and consider routine monitoring as a quality and safety indicator. PMID- 28859256 TI - Editorial: Clinical Trials in Raynaud's Phenomenon: A Spoonful of Sugar (Pill) Makes the Medicine Go Down (in Flames). PMID- 28859255 TI - A review of the literature on symptom clusters in studies that included oncology patients receiving primary or adjuvant chemotherapy. AB - AIMS AND OBJECTIVES: To summarise the current state of knowledge of symptom clusters research from studies that included, as part of their sample, patients who were receiving primary or adjuvant chemotherapy. BACKGROUND: Since the concept of a symptom cluster was first introduced into the oncology literature in 2001, only four comprehensive reviews of symptom clusters research in oncology patients were identified that provide insights into this important concept in symptom management research. DESIGN: A comprehensive review of the literature. METHODS: A comprehensive literature search was conducted for the years 2000 to 2016. Only 19 studies met the inclusion criteria for this literature review. These studies were evaluated in terms of the symptom assessment instruments used; the statistical analysis methods used; the symptom dimension(s) used to create the symptom cluster(s); the number and types of symptom clusters identified; and whether the specific symptom clusters changed over time. RESULTS: The number of symptom clusters identified ranged from one-seven. The majority of the studies used some type of factor analysis to create the symptom clusters. The most common symptom dimension used to create the clusters was symptom severity. A "gastrointestinal symptom cluster" was the most common symptom cluster identified. Across the eight longitudinal studies, for half of these studies the symptom clusters remained relatively stable over time. CONCLUSIONS: Additional research is needed in oncology patients to address the assessment of symptom clusters, the specific nature of symptom clusters and whether symptom clusters change over time. PMID- 28859259 TI - Mass-spectrometry-based lipidomics. AB - Lipids, which have a core function in energy storage, signalling and biofilm structures, play important roles in a variety of cellular processes because of the great diversity of their structural and physiochemical properties. Lipidomics is the large-scale profiling and quantification of biogenic lipid molecules, the comprehensive study of their pathways and the interpretation of their physiological significance based on analytical chemistry and statistical analysis. Lipidomics will not only provide insight into the physiological functions of lipid molecules but will also provide an approach to discovering important biomarkers for diagnosis or treatment of human diseases. Mass spectrometry-based analytical techniques are currently the most widely used and most effective tools for lipid profiling and quantification. In this review, the field of mass-spectrometry-based lipidomics was discussed. Recent progress in all essential steps in lipidomics was carefully discussed in this review, including lipid extraction strategies, separation techniques and mass-spectrometry-based analytical and quantitative methods in lipidomics. We also focused on novel resolution strategies for difficult problems in determining C=C bond positions in lipidomics. Finally, new technologies that were developed in recent years including single-cell lipidomics, flux-based lipidomics and multiomics technologies were also reviewed. PMID- 28859260 TI - Reply. PMID- 28859258 TI - Lupus-Associated Functional Polymorphism in PNP Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is frequently characterized by activation of the type I interferon (IFN) pathway. We previously observed that a missense single-nucleotide polymorphism (rs1049564) in the purine nucleoside phosphorylase (PNP) gene was associated with high levels of IFN in SLE. PNP is a key enzyme involved in purine metabolism. In this study, we performed functional follow-up of this polymorphism in human cells. METHODS: Type I IFN was measured in patient sera, using a reporter cell assay. Structural modeling of the PNP variant was performed using PyMOL software. PNP messenger RNA (mRNA) and protein levels and type I IFN-induced gene expression were measured in lymphoblastoid cell lines with known PNP rs1049564 genotypes. The cell cycle was assayed using flow cytometry. RESULTS: Structural modeling indicated no major disruption in folding related to rs1049564. We observed that homozygous rs1049564 TT lymphoblastoid cells had decreased PNP mRNA expression and protein levels, and that cells with the TT genotype had reduced PNP enzymatic activity even when the amount of PNP was controlled. Cells with the TT genotype had a 2-fold increase in S-phase block as compared with cells with the homozygous CC phenotype. The S phase block could be pharmacologically reversed with hypoxanthine and adenosine, supporting the notion that relative PNP deficiency is the cause of the S-phase block. Type I IFN-induced transcripts were increased in a dose-response manner related to the rs1049564 T allele, at both baseline and after type I IFN stimulation. CONCLUSION: The PNP rs1049564 T allele is a loss-of-function variant that induces S-phase block and IFN pathway activation in lymphocytes. The S-phase block could be rescued in our in vitro experiments, suggesting the potential for personalized treatment. PMID- 28859257 TI - Cytomegalovirus infection management in solid organ transplant recipients across European centers in the time of molecular diagnostics: An ESGICH survey. AB - BACKGROUND: Scant information is available about how transplant centers are managing their use of quantitative molecular testing (QNAT) assays for active cytomegalovirus (CMV) infection monitoring in solid organ transplant (SOT) recipients. The current study was aimed at gathering information on current practices in the management of CMV infection across European centers in the era of molecular testing assays. METHODS: A questionnaire-based cross-sectional survey study was conducted by the European Study Group of Infections in Immunocompromised Hosts (ESGICH) of the Society of Clinical Microbiology and Infectious Diseases (ESCMID). The invitation and a weekly reminder with a personal link to an Internet service provider (https://es.surveymonkey.com/) was sent to transplant physicians, transplant infectious diseases specialists, and clinical virologists working at 340 European transplant centers. RESULTS: Of the 1181 specialists surveyed, a total of 173 responded (14.8%): 73 transplant physicians, 57 transplant infectious diseases specialists, and 43 virologists from 173 institutions located at 23 different countries. The majority of centers used QNAT assays for active CMV infection monitoring. Most centers preferred commercially available real-time polymerase chain reaction (RT-PCR) assays over laboratory-developed procedures for quantifying CMV DNA load in whole blood or plasma. Use of a wide variety of DNA extraction platforms and RT-PCR assays was reported. All programs used antiviral prophylaxis, preemptive therapy, or both, according to current guidelines. However, the centers used different criteria for starting preemptive antiviral treatment, for monitoring systemic CMV DNA load, and for requesting genotypic assays to detect emerging CMV-resistant variants. CONCLUSIONS: Significant variation in CMV infection management in SOT recipients still remains across European centers in the era of molecular testing. International multicenter studies are required to achieve commutability of CMV testing and antiviral management procedures. PMID- 28859261 TI - Long-term survival following the development of heart failure in an elderly hypertensive population. AB - BACKGROUND: Available data on the prognosis of heart failure (HF) patients are predominantly limited to patients diagnosed at time of hospitalization. AIMS: To describe the long-term survival of incident HF patients and identify clinical characteristics associated with mortality. METHODS: The Second Australian National Blood Pressure Study (ANBP2) randomized 6083 hypertensive subjects aged 65-84 years to angiotensin-converting enzyme (ACE) inhibitor or thiazide diuretic based therapy and followed them for a median of 4.1 years. One hundred forty-five participants who developed HF and 5938 who remained free from HF during the trial period were followed for a median of 6.7 years during a posttrial follow-up. RESULTS: Three quarters, 110 (76%) of HF patients had died at the end of the follow-up. The five- and ten-year survival rates following HF diagnosis during the trial period were 37% and 15%, respectively, in men, compared with 60% and 33%, respectively, in women. In non-heart failure participants, the five- and ten year survival rates, following enrollment into the study, were 92% and 76%, respectively. Mortality following HF diagnosis increased with advancing age (HR = 1.09, 95% CI: 1.04-1.33). In addition, male gender and preexisting diabetes were predictive of mortality, while ACE inhibitor-based therapy for the initial trial was associated with 39% decrease (HR = 0.61, 95% CI: 0.41-0.91) in mortality compared with a thiazide diuretic-based regimen. CONCLUSIONS: Long-term survival in elderly HF patients is poor, especially in men. Mortality in HF patients increased progressively with advancing age, while allocation to the ACE inhibitor based regimen for the initial trial significantly improved HF outcome. PMID- 28859262 TI - Earliest Phase of Systemic Sclerosis Typified by Increased Levels of Inflammatory Proteins in the Serum. AB - OBJECTIVE: Patients with definite systemic sclerosis (SSc) who lack fibrotic features can be stratified into an intermediate stage of disease severity between preclinical/early SSc (EaSSc) and fibrotic subsets (limited cutaneous SSc [lcSSc] and diffuse cutaneous SSc [dcSSc]). The aim of the present study was to molecularly characterize nonfibrotic SSc and EaSSc on the basis of a broad panel of serum markers of inflammation and tissue damage, in order to increase the knowledge of the pathophysiologic mechanisms underlying SSc progression before the development of fibrosis. METHODS: An 88-plex immunoassay was performed in serum samples from a discovery cohort composed of 21 patients with EaSSc (meeting the LeRoy and Medsger criteria), 15 with nonfibrotic SSc (meeting the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria, without skin or lung fibrosis), and 11 healthy controls. Analyte concentrations that were consistently significantly different at the exploratory P value threshold of 0.1 were selected for replication analysis in a larger group composed of 47 patients with EaSSc, 48 with nonfibrotic SSc, and 43 healthy controls, as well as 51 patients with lcSSc and 35 with dcSSc. The value of the replicated molecules in predicting SSc progression (at a family-wise error rate of 0.05) was tested. RESULTS: Based on the results of the explorative analysis, 16 molecules were selected for testing in the replication set. The results showed that CXCL10, CXCL11, tumor necrosis factor receptor type II (TNFRII), and chitinase 3-like protein 1 levels were significantly increased in patients with EaSSc and those with nonfibrotic SSc as compared to healthy controls. The disease in patients with high concentrations of CXCL10 and TNFRII was also characterized by a faster rate of progression from EaSSc and from nonfibrotic SSc to worse disease stages. CONCLUSION: SSc patients with preclinical/early SSc and those with established, yet nonfibrotic, disease exhibit clear molecular alterations that are associated with faster rates of disease evolution. These data open novel avenues for disease interception in SSc. PMID- 28859263 TI - Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma. AB - BACKGROUND: Recent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to facilitate selection of patients most likely to derive the greatest clinical benefit from therapy. METHODS: Data from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16-week inhaled corticosteroid (ICS) dose-stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils <300/MUL [low] vs >=300/MUL [high]) and baseline markers of asthma severity (emergency asthma treatment in prior year, asthma hospitalization in prior year, forced expiratory volume in 1 second [FEV1 ; FEV1 <65% vs >=65% predicted], inhaled beclomethasone dipropionate dose [<600 vs >=600 MUg/day], and long-acting beta agonist [LABA] use [yes/no]). RESULTS: Adults/adolescents (N = 1071) were randomized to receive either omalizumab (n = 542) or placebo (n = 529). In the 16 week ICS dose-stable phase, rates of exacerbations requiring >=3 days of systemic corticosteroid treatment were 0.066 and 0.147 with omalizumab and placebo, respectively, representing a relative rate reduction in omalizumab-treated patients of 55% (95% CI, 32%-70%; P = .002). For patients with eosinophils >=300/MUL or with more severe asthma, this rate reduction was significantly more pronounced. CONCLUSION: In patients with allergic asthma, baseline blood eosinophil levels and/or clinical markers of asthma severity predict response to omalizumab. PMID- 28859264 TI - Adefovir-induced Fanconi syndrome associated with osteomalacia. AB - Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The pathophysiology of drug-induced Fanconi syndrome is unclear. Here we report the case of a 36-year-old woman who presented with pain in multiple bones and proteinuria. She had a 7-year history of taking adefovir at 10 mg/day for chronic hepatitis B. Three years previously she had received surgery for a nontraumatic right femur neck fracture, after which she continued to complain of pain in multiple bones, and proteinuria, glycosuria, and phosphaturia were noted. The findings of a light-microscope examination of a renal biopsy sample were normal, but mitochondrial damage of the proximal tubules was evident in electron microscopy. Western blot analysis revealed that the level of serum fibroblast growth factor 23 (FGF23) was lower than in normal controls. After 2 months of treatment, hypophosphatemia and proximal tubular dysfunction were reversed, and serum FGF23 had normalized. This case suggests that direct mitochondrial damage in proximal tubules can cause drug-induced Fanconi syndrome associated with osteomalacia. PMID- 28859265 TI - Preface. PMID- 28859266 TI - Optimization of human, animal, and environmental health by using the One Health approach. AB - Emerging diseases are increasing burdens on public health, negatively affecting the world economy, causing extinction of species, and disrupting ecological integrity. One Health recognizes that human, domestic animal, and wildlife health are interconnected within ecosystem health and provides a framework for the development of multidisciplinary solutions to global health challenges. To date, most health-promoting interventions have focused largely on single-sector outcomes. For example, risk for transmission of zoonotic pathogens from bush-meat hunting is primarily focused on human hygiene and personal protection. However, bush-meat hunting is a complex issue promoting the need for holistic strategies to reduce transmission of zoonotic disease while addressing food security and wildlife conservation issues. Temporal and spatial separation of humans and wildlife, risk communication, and other preventative strategies should allow wildlife and humans to co-exist. Upstream surveillance, vaccination, and other tools to prevent pathogen spillover are also needed. Clear multi-sector outcomes should be defined, and a systems-based approach is needed to develop interventions that reduce risks and balance the needs of humans, wildlife, and the environment. The ultimate goal is long-term action to reduce forces driving emerging diseases and provide interdisciplinary scientific approaches to management of risks, thereby achieving optimal outcomes for human, animal, and environmental health. PMID- 28859267 TI - Evolution, global spread, and pathogenicity of highly pathogenic avian influenza H5Nx clade 2.3.4.4. AB - Novel subtypes of Asian-origin (Goose/Guangdong lineage) H5 highly pathogenic avian influenza (HPAI) viruses belonging to clade 2.3.4, such as H5N2, H5N5, H5N6, and H5N8, have been identified in China since 2008 and have since evolved into four genetically distinct clade 2.3.4.4 groups (A-D). Since 2014, HPAI clade 2.3.4.4 viruses have spread rapidly via migratory wild aquatic birds and have evolved through reassortment with prevailing local low pathogenicity avian influenza viruses. Group A H5N8 viruses and its reassortant viruses caused outbreaks in wide geographic regions (Asia, Europe, and North America) during 2014-2015. Novel reassortant Group B H5N8 viruses caused outbreaks in Asia, Europe, and Africa during 2016-2017. Novel reassortant Group C H5N6 viruses caused outbreaks in Korea and Japan during the 2016-2017 winter season. Group D H5N6 viruses caused outbreaks in China and Vietnam. A wide range of avian species, including wild and domestic waterfowl, domestic poultry, and even zoo birds, seem to be permissive for infection by and/or transmission of clade 2.3.4.4 HPAI viruses. Further, compared to previous H5N1 HPAI viruses, these reassortant viruses show altered pathogenicity in birds. In this review, we discuss the evolution, global spread, and pathogenicity of H5 clade 2.3.4.4 HPAI viruses. PMID- 28859268 TI - Development and trial of vaccines against Brucella. AB - The search for ideal brucellosis vaccines remains active today. Currently, no licensed human or canine anti-brucellosis vaccines are available. In bovines, the most successful vaccine (S19) is only used in calves, as adult vaccination results in orchitis in male, prolonged infection, and possible abortion complications in pregnant female cattle. Another widely deployed vaccine (RB51) has a low protective efficacy. An ideal vaccine should exhibit a safe profile as well as enhance protective efficacy. However, currently available vaccines exhibit one or more major drawbacks. Smooth live attenuated vaccines suffer shortcomings such as residual virulence and serodiagnostic interference. Inactivated vaccines, in general, confer relatively low levels of protection. Recent developments to improve brucellosis vaccines include generation of knockout mutants by targeting genes involved in metabolism, virulence, and the lipopolysaccharide synthesis pathway, as well as generation of DNA vaccines, mucosal vaccines, and live vectored vaccines, have all produced varying degrees of success. Herein, we briefly review the bacteriology, pathogenesis, immunological implications, candidate vaccines, vaccinations, and models related to Brucella. PMID- 28859269 TI - Optimized clade 2.3.2.1c H5N1 recombinant-vaccine strains against highly pathogenic avian influenza. AB - A/Puerto Rico/8/34 (PR8)-derived recombinant viruses have been used for seasonal flu vaccines; however, they are insufficient for vaccines against some human fatal H5N1 highly pathogenic avian influenza (HPAI) viruses (HPAIV) due to low productivity. Additionally, the polymerase basic 2 (PB2) protein, an important mammalian-pathogenicity determinant, of PR8 possesses several mammalian pathogenic mutations. We previously reported two avian PB2 genes (01310 and 0028) related to efficient replication in embryonated chicken eggs (ECEs) and nonpathogenicity in BALB/c mice. In this study, we generated PR8-derived H5N1 recombinant viruses harboring hemagglutinin (attenuated) and neuraminidase genes of a clade 2.3.2.1c H5N1 HPAIV (K10-483), as well as the 01310 or 0028 PB2 genes, and investigated their replication and immunogenicity. Compared with a control virus harboring six internal PR8 genes (rK10-483), the recombinant viruses possessing the 01310 and 0028 PB2 genes showed significantly higher replication efficiency in ECEs and higher antibody titers in chickens. In contrast to rK10 483, none of the viruses replicated in BALB/c mice, and all showed low titers in Madin-Darby canine kidney cells. Additionally, the recombinant viruses did not induce a neutralization antibody but elicited decreased protective immune responses against K10-483 in mice. Thus, the highly replicative and mammalian nonpathogenic recombinant H5N1 strains might be promising vaccine candidates against HPAI in poultry. PMID- 28859270 TI - Effect of the fourth nucleotide at the 3' end of neuraminidase and matrix viral genomic RNA on the pathogenicity of influenza virus A/PR/8/34. AB - Twelve nucleotides located at the 3' end of viral genomic RNA (vRNA) are conserved among influenza A viruses (IAV) and have a promoter function. Hoffmann's 8-plasmid reverse genetics vector system introduced mutations at position 4, C nucleotide (C4) to U nucleotide (U4), of the 3' ends of neuraminidase (NA) and matrix (M) vRNAs of wild-type A/PR/8/34 (PR8). This resulted in a constellation of C4 and U4 vRNAs coding for low (polymerases) and relatively high (all others) copy number proteins, respectively. U4 has been reported to increase promoter activity in comparison to C4, but the constellation effect on the replication efficiency and pathogenicity of reverse genetics PR8 (rgPR8) has not been fully elucidated. In the present study, we generated 3 recombinant viruses with C4 in the NA and/or M vRNAs and rgPR8 by using reverse genetics and compared their pathobiological traits. The mutant viruses showed lower replication efficiency than rgPR8 due to the low transcription levels of NA and/or M genes. Furthermore, C4 in the NA and/or M vRNAs induced lower PR8 virus pathogenicity in BALB/c mice. The results suggest that the constellation of C4 and U4 among vRNAs may be one of the multigenic determinants of IAV pathogenicity. PMID- 28859271 TI - Influence of vaccine potency and booster administration of foot-and-mouth disease vaccines on the antibody response in calves with maternal antibodies. AB - Foot-and-mouth disease is one of the most important viral diseases of cloven hoofed animals. Mass vaccination is an effective method to control the disease and is frequently utilized in endemic regions. Sufficient protection of young animals is important in mass vaccination campaigns. Maternal antibodies negatively affect the success of vaccination. Hence, determination of the optimal vaccination age is crucial for the uninterrupted protection of young animals. This study was performed to identify the effect of vaccine potency and booster administration on serum neutralizing antibody titers of calves with different levels of maternal antibodies. Calves (n = 111) on a state farm were used in this study. Oil adjuvant foot-and-mouth disease vaccines with 3 PD50 and 6 PD50 potencies were used with or without booster administration. Serum samples were collected each month up to day 120 postvaccination. Virus neutralization tests were used to measure the serum neutralizing antibody titers and estimate the protection period by using pre-determined cut-off values for protection. The results revealed that a vaccination with a 6 PD50 potency vaccine, preferably followed by a booster dose, should be used to overcome maternal immunity for incessant protection. PMID- 28859272 TI - Immune responses in pigs and cattle vaccinated with half-volume foot-and-mouth disease vaccine. AB - With the current commercial foot-and-mouth disease vaccine, inoculating twice increases the formation of denatured meat due to granuloma or residual adjuvant at the injection site in pigs, resulting in economic loss. Therefore, we investigated protective antibody levels after reducing the amount of adjuvant in the vaccine. Field applicability of the experimental vaccine, made with a new adjuvant ISA 201, was tested by vaccinating farm animals with half-volume doses (1 mL/animal) of commercial vaccine and monitoring their immunogenicity. Among pigs, the group that received a half-volume dose showed similar or higher titers of structural protein antibody and neutralizing antibody than those receiving the standard dose (2 mL). In pigs, the durable effects of antibody titer of the reduced vaccine volume did not diminish up to the time of slaughter. Among cattle, boosting with a second 1 mL vaccine increased virus neutralizing antibody for the protective effects. The boosting effects were more marked in cattle than in pigs. The immune responses differed between species with the effect of the half-volume vaccination being lower in cattle than in pigs. In conclusion, the immune response to the half-volume vaccine was similar to that from the standard volume vaccine in pigs, but not in cattle. PMID- 28859273 TI - Establishment of minimal positive-control conditions to ensure brain safety during rapid development of emergency vaccines. AB - With the increase in international human and material exchanges, contagious and infectious epidemics are occurring. One of the effective methods of epidemic inhibition is the rapid development and supply of vaccines. Considering the safety of the brain during vaccine development is very important. However, manuals for brain safety assays for new vaccines are not uniform or effective globally. Therefore, the aim of this study is to establish a positive-control protocol for an effective brain safety test to enhance rapid vaccine development. The blood-brain barrier's tight junctions provide selective defense of the brain; however, it is possible to destroy these important microstructures by administering lipopolysaccharides (LPSs), thereby artificially increasing the permeability of brain parenchyma. In this study, test conditions are established so that the degree of brain penetration or brain destruction of newly developed vaccines can be quantitatively identified. The most effective conditions were suggested by measuring time-dependent expressions of tight junction biomarkers (zonula occludens-1 [ZO-1] and occludin) in two types of mice (C57BL/6 and ICR) following exposure to two types of LPS (Salmonella and Escherichia). In the future, we hope that use of the developed positive-control protocol will help speed up the determination of brain safety of novel vaccines. PMID- 28859274 TI - Associations between maternal exposure to incense burning and blood pressure during pregnancy. AB - Incense burning is a popular practice in Asian and Arabic countries. Previous studies show that incense burning was associated with increased risks of adverse outcomes among non-pregnant population. However, very few studies explored its health effects among pregnant women, who are more susceptible to environmental stressor. We aimed to examine the association between incense burning at home and hypertensive disorders as well as blood pressure levels during pregnancy, using data from 10,563 pregnant women recruited in Born in Guangzhou Cohort Study, China between January 2013 and December 2015. Information on frequency and duration of exposure to incense burning were collected at early and late pregnancy using questionnaire. Data on outcome variables, including hypertensive disorders diagnosis and blood pressure levels at the final antenatal visit before delivery, were extracted from medical records. We used Poisson regression model and general linear model to examine the associations between incense exposure and the outcomes. We found incense use at early pregnancy was not significantly associated with outcomes. Pregnant women who frequently smelled the incense burning at late pregnancy was associated with higher risk of hypertensive disorders (relative risk, 1.84; 95% confidence interval, 1.14-2.98) and higher levels of blood pressure (1.6mmHg increase of systolic blood pressure; 95% confidence interval, 0.4-2.8mmHg) before delivery, compared to those did not burn incense. These associations tended to more evident among women without active and passive smoking. We did not observe significant dose-response relationship between exposure duration and the risk of hypertensive disorders. We firstly reported exposure to incense burning was associated with the risk of hypertensive disorders and blood pressure levels during pregnancy. Given hypertensive disorders in pregnancy are well-established risk factors for a variety of adverse outcomes and the incense burning is a modifiable factor, our finding may have important public health significance. PMID- 28859275 TI - Investigation of triclosan contamination on microbial biomass and other soil health indicators. AB - Triclosan (TCS) is an antimicrobial compound found in personal care products, and consequently in greywater. After its release to the environment, it continues its antimicrobial action on indigenous microbial communities. Little is known about the environmental impacts of high levels of TCS, which may occur due to accumulation following long-term greywater application to soil. Soil microcosms were established using a silty clay loam and augmented with a range of TCS concentrations ranging from 500 to 7500 mg kg-1. Samples were analysed for substrate-induced respiration, microbial biomass and sulphatase activity. The soil augmented with the lowest concentration of TCS (500 mg kg-1) significantly decreased microbial biomass, with a calculated EC20 of 195 mg kg-1. Substrate induced respiration indicated that the soil microbial community was impacted for all TCS concentrations; however, the community showed potential to recover over time. Sulphatase activity was less sensitive to TCS and was significantly impacted at high concentrations of TCS (>2500 mg kg-1). It is likely that TCS has selective toxicity for more susceptible microbes when introduced into the soil environment. At high levels, TCS could overwhelm TCS-degrading soil microbes. PMID- 28859276 TI - Characterization of a lactose-responsive promoter of ATP-binding cassette (ABC) transporter gene from Lactobacillus acidophilus 05-172. AB - A novel lactose-responsive promoter of the ATP-binding cassette (ABC) transporter gene Lba1680 of Lactobacillus acidophilus strain 05-172 isolated from a traditionally fermented dairy product koumiss was characterized. In L. acidophilus 05-172, expression of Lba1680 was induced by lactose, with lactose induced transcription of Lba1680 being 6.1-fold higher than that induced by glucose. This is in contrast to L. acidophilus NCFM, a strain isolated from human feces, in which expression of Lba1680 and Lba1679 is induced by glucose. Both gene expression and enzyme activity assays in L. paracasei transformed with a vector containing the inducible Lba1680 promoter (PLba1680) of strain 05-172 and a heme-dependent catalase gene as reporter confirmed that PLba1680 is specifically induced by lactose. Its regulatory expression could not be repressed by glucose, and was independent of cAMP receptor protein. This lactose-responsive promoter might be used in the expression of functional genes in L. paracasei incorporated into a lactose-rich environment, such as dairy products. PMID- 28859277 TI - Absolute quantification of Aggregatibacter actinomycetemcomitans in patients carrying haplotypes associated with susceptibility to chronic periodontitis: multifaceted evaluation with periodontitis covariants. AB - This study aimed to evaluate the association between haplotypes in the interleukin 8 (IL8) and IL4 genes previously associated to chronic periodontitis (CP) and the levels of Aggregatibacter actinomycetemcomitans (A.a.) in subgingival sites of patients with and without CP. Moreover, multifaceted evaluations were made to search associations among patients' genetic background with the A.a. levels and previous clinical/immunological/microbiological findings. Subgingival sites (n = 596) of 104 patients were divided into susceptible to CP by the IL8 haplotype ATC/TTC (IL8+); non-susceptible to CP by the IL8 AGT/TTC (IL8-); susceptible to CP by the IL4 TCI/CCI (IL4+); protection against CP by the IL4 TTD/CTI (IL4-). Subgingival biofilm samples from diseased and healthy sites of CP patients and from control sites of health patients were obtained for absolute quantification of A.a. by quantitative real-time polymerase chain reaction. For diseased sites, samples were collected before and 45 days after periodontal treatment. The IL4 but not the IL8 haplotypes were associated with levels of A.a. (in both periods). After periodontal treatment, higher levels of A.a. were found in subgingival sites of (IL4-) patients, and higher levels of IL-4 were associated with deeper probing pockets in these same patients. Significant correlations were found among genetic (patients carrying IL8 or IL4 haplotypes), microbiological and immunological data showing the interrelationship of different factors in the CP. PMID- 28859278 TI - The transcriptome of the endometrium and placenta is associated with pregnancy development but not lactation status in dairy cows. AB - Infertility in lactating dairy cows is explained partially by the metabolic state associated with high milk production. The hypothesis was that lactating and nonlactating cows would differ in endometrial and placental transcriptomes during early pregnancy (day 28 to 42) and this difference would explain the predisposition for lactating cows to have embryonic loss at that time. Cows were either milked or not milked after calving. Reproductive [endometrium (caruncular and intercaruncular) and placenta] and liver tissues were collected on day 28, 35, and 42 of pregnancy. The hypothesis was rejected because no effect of lactation on mRNA abundance within reproductive tissues was found. Large differences within liver demonstrated the utility of the model to test an effect of lactation on tissue gene expression. Major changes in gene expression in reproductive tissues across time were found. Greater activation of the transcriptome for the recruitment and activation of macrophages was found in the endometrium and placenta. Changes in glucose metabolism between day 28 and 42 included greater mRNA abundance of rate-limiting genes for gluconeogenesis in intercaruncular endometrium and evidence for the establishment of aerobic glycolysis (Warburg effect) in the placenta. Temporal changes were predicted to be controlled by CSF1, PDGFB, TGFB1, and JUN. Production of nitric oxide and reactive oxygen species by macrophages was identified as a mechanism to promote angiogenesis in the endometrium. Reported differences in pregnancy development for lactating vs. nonlactating cows could be explained by systemic glucose availability to the conceptus and appeared to be independent of the endometrial and placental transcriptomes. PMID- 28859279 TI - The superovulated environment, independent of embryo vitrification, results in low birthweight in a mouse model. AB - Epidemiological studies suggest that babies born following in vitro fertilization (IVF) and fresh embryo transfer are of lower birthweight than babies born following frozen embryo transfer, although the mechanism responsible for this phenotype is not known. We developed a novel mouse model that isolates the independent effects of embryo freezing and the superovulated environment, which cannot be performed in humans. We transferred blastocysts that had been vitrified and warmed, mixed with with fresh blastocysts, into individual pseudopregnant recipients produced by either natural mating or mating following injection with equine chorionic gonadotropin and human chorionic gonadotropin and hCG (superovulation). We found that superovulation of the recipient dams led to significantly lower fetal weight at term while blastocyst vitrification had no significant effect on fetal weight (1.43 +/- 0.24 g fresh-natural, 1.30 +/- 0.28 g vitrified-natural vs. 1.09 +/- 0.20 fresh-superovulated, 0.93 +/- 0.23 g vitrified-superovulated, P < 0.0001). Doppler ultrasound revealed increased median umbilical artery resistance in the placentae of near-term dams exposed to superovulation compared to naturally mated dams (0.927 vs 0.904, P = 0.02). Additionally, placental microvascular density was lower in superovulated compared to naturally mated dams (1.24 * 10-3 vessel/micron vs 1.46 * 10-3 vessels/micron, P = 0.046). Gene expression profiling suggested alterations in fetal genes involved in glucorticoid regulation. These results suggest a potential mechanism for altered birthweight following superovulation in our model and may have implications for human IVF. PMID- 28859280 TI - Subfertility in bulls carrying a nonsense mutation in transmembrane protein 95 is due to failure to interact with the oocyte vestments. AB - In a recent genome-wide association study, 40 Fleckvieh bulls with exceptionally poor fertility were found to be homozygous for a nonsense mutation in the transmembrane protein 95 (TMEM95) encoding gene. Ejaculates from these individuals exhibited normal sperm concentration, morphology, viability, and motility. However, only 1.7% of inseminations resulted in pregnancies. The aim of this study was to examine the effect of this mutation in TMEM95 on bovine sperm function in vitro. Sperm from homozygous (mt/mt) males had lower in vitro fertility than sperm from wild-type (wt/wt) or heterozygous (wt/mt) bulls (P < 0.01). In addition, early embryo division was affected in the mt/mt group (P < 0.01). This translated into a lower (P < 0.01) blastocyst rate at day 8. Fluorescent staining revealed that TMEM95 is lost after the acrosome reaction. This led us to hypothesize that TMEM95 might be involved in events that lead to sperm-oocyte interaction. After fertilization, a lower number (P < 0.01) of sperm from mt/mt bulls bound to the zona pellucida (ZP). Sperm from mt/mt bulls were also less able to penetrate oocytes with no ZP (P< 0.01). However, when sperm from these animals were injected into mouse oocytes, they could decondense as successfully as sperm from wt/wt bulls. No differences between genotypes were observed in the ability of sperm to retain motility in an ex vivo oviduct, or in the percentage of sperm exhibiting markers for capacitation and acrosomal reaction. These results suggest that fertilization failure in mt/mt bulls is due to the inability of their sperm to interact with the oocyte vestments. PMID- 28859281 TI - A delayed sperm penetration of cumulus layers by disruption of acrosin gene in rats. AB - Acrosin, the trypsin-like serine protease in the sperm acrosome, was long viewed as a key enzyme required for zona pellucida penetration to fertilize eggs. However, gene disruption experiments in mice surprisingly showed that acrosin disrupted males were fertile. Thus, the acrosin was considered to be not an essential enzyme for fertilization in mice. However, the involvement of acrosin in fertilization has been suggested in various species such as rat, bull, and pig. Moreover, it has been reported that serine protease (including acrosin) activity in mice is significantly weaker compared to other species, including rats. We analyzed the role of acrosin by disrupting the rat acrosin gene. It was found that, unlike in mice, acrosin was almost the sole source of serine protease in rat spermatozoa. Nevertheless, the acrosin-disrupted males were not infertile. However, the litter size from acrosin-disrupted males was decreased compared to heterozygous mutant rats. Further investigation using an in vitro fertilization system revealed that the acrosin-disrupted spermatozoa possessed an equal ability to penetrate the zona pellucida with wild-type spermatozoa, but the cumulus cell dispersal was slower compared to wild-type and heterozygous spermatozoa. This delay was presumed to be the cause of the small litter size of acrosin-disrupted male rats. PMID- 28859282 TI - A neurokinin 3 receptor-selective agonist accelerates pulsatile luteinizing hormone secretion in lactating cattle. AB - Pulsatile gonadotropin-releasing hormone (GnRH) secretion, which is indispensable for follicular development, is suppressed in lactating dairy and beef cattle. Neurokinin B (NKB) neurons in the arcuate nucleus of the hypothalamus are considered to play an essential role in generating the pulsatile mode of GnRH/luteinizing hormone (LH) secretion. The present study aimed to clarify the role of NKB-neurokinin 3 receptor (NK3R) signaling in the pulsatile pattern of GnRH/gonadotropin secretion in postpartum lactating cattle. We examined the effects of the administration of an NK3R-selective agonist, senktide, on gonadotropin secretion in lactating cattle. The lactating cattle, at approximately 7 days postpartum, were intravenously infused with senktide (30 or 300 nmol/min) or vehicle for 24 h. The administration of 30 or 300 nmol/min senktide significantly increased LH pulse frequency compared to in the control group during 0-4 or 20-24 h after infusion, respectively. Moreover, LH and follicle-stimulating hormone levels were gradually increased by 300 nmol/min administration of senktide during the 0-4-h sampling period. Ultrasonography of the ovaries was performed to identify the first postpartum ovulation in senktide administered lactating cattle. The interval from calving to first postpartum ovulation was significantly shorter in the 300 nmol/min senktide-administered group than in the control group. Taken together, these findings suggest that senktide infusion elicits an increase in LH pulse frequency that may stimulate follicular development and, in turn, induce the first postpartum ovulation in lactating cattle. PMID- 28859283 TI - Plasma anti-Mullerian hormone profile in heifers from birth through puberty and relationship with puberty onset. AB - The current study aimed to define the plasma profile of anti-Mullerian hormone (AMH) and follicle stimulating hormone (FSH) in heifers during postnatal life until achieving puberty, as defined by plasma progesterone (P4) profile, to demonstrate a relationship between AMH and age of puberty onset. Blood samples collected from 11 Japanese Black female calves within 1 week after birth (W 0) and then biweekly until the sixth week after puberty (WP 6) were assayed for AMH, FSH, and P4. The heifers were classified into two groups based on age of puberty onset: <=42 weeks (early puberty group; EP, n = 4) and >=44 weeks (late puberty group; LP, n = 7). Minimal plasma AMH concentration occurring at W 0 gradually increased to its peak level by W 10 (fourfold higher than W 0; P < 0.01) before gradually declining to a steady plateau 6 weeks before puberty (WP -6). The AMH peak was preceded by a significant rise in plasma FSH at W 4, W 6, and W 8 compared with W 0. Plasma AMH at W 16 positively correlated with WP 4 and WP 6 (r = 0.69 and 0.71, respectively; P < 0.05). Overall plasma AMH and FSH was significantly higher and lower in EP compared with LP, respectively. In conclusion, heifers exhibit a characteristic plasma AMH profile during postnatal life, such that plasma AMH at an early prepubertal age could be a biomarker for precocious puberty and postpubertal AMH levels. PMID- 28859284 TI - Understanding avian egg cuticle formation in the oviduct: a study of its origin and deposition. AB - The cuticle is a unique invisible oviduct secretion that protects avian eggs from bacterial penetration through gas exchange pores. Despite its importance, experimental evidence is lacking for where, when, and what is responsible for its deposition. By using knowledge about the ovulatory cycle and oviposition, we have manipulated cuticle deposition to obtain evidence on these key points. Cuticle deposition was measured using staining and spectrophotometry. Experimental evidence supports the location of cuticle deposition to be the shell gland pouch (uterus), not the vagina, and the time of deposition to be within the final hour before oviposition. Oviposition induced by arginine vasotocin or prostaglandin, the penultimate and ultimate factors for the induction of oviposition, produces an egg with no cuticle; therefore, these factors are not responsible for cuticle secretion. Conversely, oviposition induced by GNRH, which mimics the normal events of ovulation and oviposition, results in a normal cuticle. There is no evidence that cuticle deposition differs at the end of a clutch and, therefore, there is no evidence that the ovulatory surge of progesterone affects cuticle deposition. Overall, the results demonstrate that the cuticle is a specific secretion and is not merely an extension of the organic matrix of the shell. Cuticle deposition was found to be reduced by an environmental stressor, and there is no codependence of the deposition of pigment and cuticle. Defining the basic facts surrounding cuticle deposition will help reduce contamination of hen's eggs and increase understanding of the strategies birds use to protect their eggs. PMID- 28859285 TI - Bovine lineage specification revealed by single-cell gene expression analysis from zygote to blastocyst. AB - Preimplantation embryos undergo zygotic genome activation and lineage specification resulting in three distinct cell types in the late blastocyst. The molecular mechanisms underlying this progress are largely unknown in bovines. Here, we sought to analyze an extensive set of regulators at the single-cell level to define the events involved in the development of the bovine blastocyst. Using a quantitative microfluidics approach in single cells, we analyzed mRNA levels of 96 genes known to function in early embryonic development and maintenance of stem cell pluripotency in parallel in 384 individual cells from bovine preimplantation embryos. The developmental transitions can be distinguished by distinctive gene expression profiles and we identified NOTCH1, expressed in early developmental stages, while T-box 3 (TBX3) and fibroblast growth factor receptor 4 (FGFR4), expressed in late developmental stages. Three lineages can be segregated in bovine expanded blastocysts based on the expression patterns of lineage-specific genes such as disabled homolog 2 (DAB2), caudal type homeobox 2 (CDX2), ATPase H+/K+ transporting non-gastric alpha2 subunit (ATP12A), keratin 8 (KRT8), and transcription factor AP-2 alpha (TFAP2A) for trophectoderm; GATA binding protein 6 (GATA6) and goosecoid homeobox (GSC) for primitive endoderm; and Nanog homeobox (NANOG), teratocarcinoma-derived growth factor 1 (TDGF1), and PR/SET domain 14 (PRDM14) for epiblast. Moreover, some lineage specific genes were coexpressed in blastomeres from the morula. The commitment to trophectoderm and inner cell mass lineages in bovines occurs later than in the mouse, and KRT8 might be an earlier marker for bovine trophectoderm cells. We determined that TDGF1 and PRDM14 might play pivotal roles in the primitive endoderm and epiblast specification of bovine blastocysts. Our results shed light on early cell fate determination in bovine preimplantation embryos and offer theoretical support for deriving bovine embryonic stem cells. PMID- 28859286 TI - Persistence of risk factors associated with maternal cardiovascular disease following aberrant inflammation in rat pregnancy. AB - Introduction: Pre-eclampsia is associated with increased risk of subsequent cardiovascular and metabolic disease in the affected mothers. While aberrant inflammation contributes to the pathophysiology of pre-eclampsia, it is unclear whether maternal inflammation contributes to the increased risk of disease. Here, we determined the effect of aberrant inflammation in pregnancy on cardiovascular and metabolic disease risk factors. Methods: Wistar rats were administered low doses of lipopolysaccharide (LPS) on gestational days (GD) 13.5-16.5 to induce inflammation. Controls included pregnant rats treated with saline and nonpregnant rats treated with LPS or saline. We previously showed that LPS-treated pregnant rats exhibit key features of pre-eclampsia. Echocardiographic parameters, heart weight, blood pressure, blood lipids, pulse-wave velocity, and glucose tolerance, were assessed at 16 weeks postpartum. Messenger RNA levels of transcription factors associated with cardiac growth were measured in left ventricular tissue; histone modifications and global DNA methylation were determined in hearts and livers at GD 17.5 and at 16 weeks postpartum. Results: Compared with saline treated pregnant rats and nonpregnant rats treated with LPS or saline, LPS treated pregnant rats exhibited left ventricular hypertrophy and increased blood cholesterol and low-density lipoprotein levels at 16 weeks postdelivery. LPS treated rats had increased left ventricular mRNA levels of hypertrophy-associated transcription factors at GD 17.5 and increased levels of modified histones in hearts and livers at GD 17.5 and 16 weeks postpartum. Other parameters remained unchanged. Conclusion: Aberrant inflammation during pregnancy results in persistent alterations in maternal physiological parameters and epigenetic modifications that could contribute to the pathophysiology of cardiovascular disease. PMID- 28859287 TI - Analysis of cysteine-X-cysteine motif chemokine ligands 9, 10, and 11, their receptor CXCR3, and their possible role on the recruitment of immune cells at the maternal-conceptus interface in pigs. AB - Chemokines play critical roles in the establishment and maintenance of pregnancy in animals. Cysteine-X-cysteine motif chemokine ligand 9 (CXCL9), CXCL10, and CXCL11 are involved in recruiting immune cells by binding to their shared receptor, CXC receptor 3 (CXCR3), in a variety of tissues. This study examined the expression and regulation of chemokines CXCL9, CXCL10, and CXCL11, their receptor CXCR3, and their role at the maternal-conceptus interface in pigs. The endometrium expressed CXCL9, CXCL10, CXCL11, and CXCR3 stage specifically during pregnancy, with the greatest abundance on Day 15 of pregnancy. It was noted that their expression was primarily localized to stromal cells, endothelial cells, or vascular smooth muscle cells in the endometrium. Interferon-gamma increased the abundance of CXCL9, CXCL10, CXCL11 mRNAs, but not CXCR3, in endometrial explants. Furthermore, recombinant CXCL9 (rCXCL9), rCXCL10, and rCXCL11 proteins increased migration of cultured peripheral blood mononuclear cells (PBMCs) in a dose dependent manner. Recombinant CXCL9 and rCXCL10 caused migration of CD4+, CD8+, CD4+CD8+ T cells, and natural killer (NK) cells, and rCXCL11 increased migration of CD4+ T and NK cells in PBMCs. The present study demonstrated that interferon gamma-induced CXCL9, CXCL10, and CXCL11, and their receptor CXCR3 were expressed in the uterus in stage- and cell-type specific manners and increased the migration of T and NK cells, which showed the greatest endometrial infiltration on Day 15 of pregnancy. These results suggest that CXCL9, CXCL10, and CXCL11 may play an important role in the recruitment of immune cells into the endometrium during the implantation period in pigs. PMID- 28859288 TI - The long and short of translational control in male germ cells. PMID- 28859289 TI - A New Chapter for Biology of Reproduction. PMID- 28859291 TI - Relevance of Spatial Heterogeneity of Immune Infiltration for Predicting Risk of Recurrence After Endocrine Therapy of ER+ Breast Cancer. AB - Background: Despite increasing evidence supporting the clinical utility of immune infiltration in the estrogen receptor-negative (ER-) subtype, the prognostic value of immune infiltration for ER+ disease is not well defined. Methods: Quantitative immune scores of cell abundance and spatial heterogeneity were computed using a fully automated hematoxylin and eosin-stained image analysis algorithm and spatial statistics for 1178 postmenopausal patients with ER+ breast cancer treated with five years' tamoxifen or anastrozole. The prognostic significance of immune scores was compared with Oncotype DX 21-gene recurrence score (RS), PAM50 risk of recurrence (ROR) score, IHC4, and clinical treatment score, available for 963 patients. Statistical tests were two-sided. Results: Scores of immune cell abundance were not associated with recurrence-free survival. In contrast, high immune spatial scores indicating increased cell spatial clustering were associated with poor 10-year, early (0-5 years), and late (5-10 years) recurrence-free survival (Immune Hotspot: LR-chi2 = 14.06, P < .001, for 0-10 years; LR-chi2 = 6.24, P = .01, for 0-5 years; LR-chi2 = 7.89, P = .005, for 5-10 years). The prognostic value of spatial scores for late recurrence was similar to that of IHC4 and RS in both populations, but was not as strong as other tests in comparison for recurrence across 10 years. Conclusions: These results provide a missing link between tumor immunity and disease outcome in ER+ disease by examining tumor spatial architecture. The association between spatial scores and late recurrence suggests a lasting memory of protumor immunity that may impact disease progression and evolution of endocrine treatment resistance, which may be exploited for therapeutic advances. PMID- 28859290 TI - Racial Differences in PAM50 Subtypes in the Carolina Breast Cancer Study. AB - Background: African American breast cancer patients have lower frequency of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative disease and higher subtype-specific mortality. Racial differences in molecular subtype within clinically defined subgroups are not well understood. Methods: Using data and biospecimens from the population-based Carolina Breast Cancer Study (CBCS) Phase 3 (2008-2013), we classified 980 invasive breast cancers using RNA expression-based PAM50 subtype and recurrence (ROR) score that reflects proliferation and tumor size. Molecular subtypes (Luminal A, Luminal B, HER2-enriched, and Basal-like) and ROR scores (high vs low/medium) were compared by race (blacks vs whites) and age (<=50 years vs > 50 years) using chi-square tests and analysis of variance tests. Results: Black women of all ages had a statistically significantly lower frequency of Luminal A breast cancer (25.4% and 33.6% in blacks vs 42.8% and 52.1% in whites; younger and older, respectively). All other subtype frequencies were higher in black women (case-only odds ratio [OR] = 3.11, 95% confidence interval [CI] = 2.22 to 4.37, for Basal-like; OR = 1.45, 95% CI = 1.02 to 2.06, for Luminal B; OR = 2.04, 95% CI = 1.33 to 3.13, for HER2-enriched). Among clinically HR+/HER2- cases, Luminal A subtype was less common and ROR scores were statistically significantly higher among black women. Conclusions: Multigene assays highlight racial disparities in tumor subtype distribution that persist even in clinically defined subgroups. Differences in tumor biology (eg, HER2-enriched status) may be targetable to reduce disparities among clinically ER+/HER2- cases. PMID- 28859292 TI - Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis. AB - Aims: Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide and results from an obstruction in the blood supply to a region of the heart. In an attempt to replenish oxygen and nutrients to the deprived area, affected cells release signals to promote the development of new vessels and confer protection against MI. However, the mechanisms underlying the growth of new vessels in an ischaemic scenario remain poorly understood. Here, we show that cardiomyocytes subjected to ischaemia release exosomes that elicit an angiogenic response of endothelial cells (ECs). Methods and results: Exosomes secreted by H9c2 myocardial cells and primary cardiomyocytes, cultured either in control or ischaemic conditions were isolated and added to ECs. We show that ischaemic exosomes, in comparison with control exosomes, confer protection against oxidative-induced lesion, promote proliferation, and sprouting of ECs, stimulate the formation of capillary-like structures and strengthen adhesion complexes and barrier properties. Moreover, ischaemic exosomes display higher levels of metalloproteases (MMP) and promote the secretion of MMP by ECs. We demonstrate that miR-222 and miR-143, the relatively most abundant miRs in ischaemic exosomes, partially recapitulate the angiogenic effect of exosomes. Additionally, we show that ischaemic exosomes stimulate the formation of new functional vessels in vivo using in ovo and Matrigel plug assays. Finally, we demonstrate that intramyocardial delivery of ischaemic exosomes improves neovascularization following MI. Conclusions: This study establishes that exosomes secreted by cardiomyocytes under ischaemic conditions promote heart angiogenesis, which may pave the way towards the development of add-on therapies to enhance myocardial blood supply. PMID- 28859293 TI - Impaired calcium homeostasis is associated with sudden cardiac death and arrhythmias in a genetic equivalent mouse model of the human HRC-Ser96Ala variant. AB - Aims: The histidine-rich calcium-binding protein (HRC) Ser96Ala variant has previously been identified as a potential biomarker for ventricular arrhythmias and sudden cardiac death in patients with idiopathic dilated cardiomyopathy. Herein, the role of this variant in cardiac pathophysiology is delineated through a novel mouse model, carrying the human mutation in the homologous mouse position. Methods and results: The mouse HRC serine 81, homologous to human HRC serine 96, was mutated to alanine, using knock-in gene targeting. The HRC Ser81Ala mice presented increased mortality in the absence of structural or histological abnormalities, indicating that early death may be arrhythmia related. Indeed, under stress-but not baseline-conditions, the HRC-Ser81Ala mice developed ventricular arrhythmias, whilst at the cardiomyocyte level they exhibited increased occurrence of triggered activity. Cardiac contraction was decreased in vivo, ex vivo, and in vitro. Additionally, Ca2+ transients and SR Ca2+ load were both reduced suggesting that cytosolic Ca2+ overload is not the underlying proarrhythmic mechanism. Interestingly, total SR Ca2+ leak was increased in HRC-Ser81Ala cardiomyocytes, without an increase in Ca2+ spark and wave frequency. However, Ca2+ wave propagation was significantly slower and the duration of the associated Na/Ca exchange current was increased. Moreover, action potential duration was also increased. Notably, Ca2+/Calmodulin kinase II (CaMKII) phosphorylation of the ryanodine receptor was increased, whilst KN-93, an inhibitor of CaMKII, reduced the occurrence of arrhythmias. Conclusions: The homologous mutation Ser81Ala in HRC in mice, corresponding to Ser96Ala in humans, is associated with sudden death and depressed cardiac function. Ventricular arrhythmias are related to abnormal Ca2+ cycling across the SR. The data further support a role for CaMKII with the perspective to treat arrhythmias through CaMKII inhibition. PMID- 28859294 TI - CCAAT/enhancer-binding protein delta promotes intracellular lipid accumulation in M1 macrophages of vascular lesions. AB - Aims: Lipid homeostasis is reprogrammed in the presence of inflammation, which results in excessive lipid accumulation in macrophages, and leads to the formation of lipid-laden foam cells. We aimed to link an inflammation-responsive transcription factor CCAAT/enhancer-binding protein delta (CEBPD) with polarized macrophages and dissect its contribution to lipid accumulation. Methods and results: We found that CEBPD protein colocalized with macrophages in human and mouse (C57BL/6, Apoe-/-) atherosclerotic plaques and that Cebpd deficiency in bone marrow cells suppressed atherosclerotic lesions in hyperlipidemic Apoe-/- mice. CEBPD was responsive to modified low-density lipoprotein (LDL) via the p38MAPK/CREB pathway, and it promoted lipid accumulation in M1 macrophages but not in M2 macrophages. CEBPD up-regulated pentraxin 3 (PTX3), which promoted the macropinocytosis of LDL, and down-regulated ATP-binding cassette subfamily A member 1 (ABCA1), which impaired the intracellular cholesterol efflux in M1 macrophages. We further found that simvastatin (a HMG-CoA reductase inhibitor) could target CEBPD to block lipid accumulation in a manner not directly related to its cholesterol-lowering effect in M1 macrophages. Conclusion: This study underscores how CEBPD functions at the junction of inflammation and lipid accumulation in M1 macrophages. Therefore, CEBPD-mediated lipid accumulation in M1 macrophages could represent a new therapeutic target for the treatment of cardiovascular diseases. PMID- 28859295 TI - Melatonin as a cardioprotective therapy following ST-segment elevation myocardial infarction: is it really promising? Reply. PMID- 28859296 TI - Human induced pluripotent stem cell-derived vascular smooth muscle cells: differentiation and therapeutic potential. AB - Cardiovascular diseases remain the leading cause of death worldwide and current treatment strategies have limited effect of disease progression. It would be desirable to have better models to study developmental and pathological processes and model vascular diseases in laboratory settings. To this end, human induced pluripotent stem cells (hiPSCs) have generated great enthusiasm, and have been a driving force for development of novel strategies in drug discovery and regenerative cell-therapy for the last decade. Hence, investigating the mechanisms underlying the differentiation of hiPSCs into specialized cell types such as cardiomyocytes, endothelial cells, and vascular smooth muscle cells (VSMCs) may lead to a better understanding of developmental cardiovascular processes and potentiate progress of safe autologous regenerative therapies in pathological conditions. In this review, we summarize the latest trends on differentiation protocols of hiPSC-derived VSMCs and their potential application in vascular research and regenerative therapy. PMID- 28859298 TI - ROCK as a molecular bond connecting coronary microvascular and cardiac remodelling. PMID- 28859297 TI - Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced glycation endproducts. AB - Aims: Medin is a common amyloidogenic protein in humans that accumulates in arteries with advanced age and has been implicated in vascular degeneration. Medin's effect on endothelial function remains unknown. The aims are to assess medin's effects on human arteriole endothelial function and identify potential mechanisms underlying medin-induced vascular injury. Methods and results: Ex vivo human adipose and leptomeningeal arterioles were exposed (1 h) to medin (0.1, 1, or 5 uM) without or with FPS-ZM1 [100 uM, receptor for advanced glycation endproducts (RAGE)-specific inhibitor] and endothelium-dependent function (acetylcholine dilator response) and endothelium-independent function (dilator response to nitric oxide donor diethylenetriamine NONOate) were compared with baseline control. Human umbilical vein endothelial cells were exposed to medin without or with FPS-ZM1 and oxidative and nitrative stress, cell viability, and pro-inflammatory signaling measures were obtained. Medin caused impaired endothelial function (vs. baseline response: -45.2 +/- 5.1 and -35.8 +/- 7.9% in adipose and leptomeningeal arterioles, respectively, each P < 0.05). Dilator response to NONOate was not significantly changed. Medin decreased arteriole and endothelial cell nitric oxide production, increased superoxide production, reduced endothelial cell viability, proliferation, and migration. Medin increased gene and protein expression of interleukin-6 and interleukin-8 via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB). Medin induced endothelial dysfunction and oxidative stress were reversed by antioxidant polyethylene glycol superoxide dismutase and by RAGE inhibitor FPS-ZM1. Conclusions: Medin causes human microvascular endothelial dysfunction through oxidative and nitrative stress and promotes pro-inflammatory signaling in endothelial cells. These effects appear to be mediated via RAGE. The findings represent a potential novel mechanism of vascular injury. PMID- 28859299 TI - Bioactive lipids in aortic valve stenosis-a possible link to atherosclerosis? PMID- 28859301 TI - From drugs to devices and back again: chemical vagal nerve stimulation for the treatment of heart failure. PMID- 28859302 TI - Future strategies for acute cardioprotection: 'melatonin as promising therapy'. PMID- 28859300 TI - Etv2 as an essential regulator of mesodermal lineage development. AB - The 'master regulatory factors' that position at the top of the genetic hierarchy of lineage determination have been a focus of intense interest, and have been investigated in various systems. Etv2/Etsrp71/ER71 is such a factor that is both necessary and sufficient for the development of haematopoietic and endothelial lineages. As such, genetic ablation of Etv2 leads to complete loss of blood and vessels, and overexpression can convert non-endothelial cells to the endothelial lineage. Understanding such master regulatory role of a lineage is not only a fundamental quest in developmental biology, but also holds immense possibilities in regenerative medicine. To harness its activity and utility for therapeutic interventions, it is essential to understand the regulatory mechanisms, molecular function, and networks that surround Etv2. In this review, we provide a comprehensive overview of Etv2 biology focused on mouse and human systems. PMID- 28859303 TI - Context-dependent signalling in platelets in vascular diseases: ROCK2 around thrombosis. PMID- 28859304 TI - Tilting at the tilted protease balance in arterial aneurysmal disease. PMID- 28859305 TI - Cardiovascular benefits and risks of testosterone replacement: another warning? PMID- 28859306 TI - IL-10 reprogramming of metabolism in macrophages through mitophagy. PMID- 28859307 TI - Arthritis is inhibited in Borrelia-primed and infected interleukin-17A-deficient mice after administration of anti-gamma-interferon, anti-tumor necrosis factor alpha and anti-interleukin-6 antibodies. AB - The role that cytokines play in the induction of Lyme arthritis is gradually being delineated. We showed previously that severe arthritis developed in a T cell-driven murine model, even in mice lacking interleukin-17A (IL-17A) and administered anti-gamma-interferon (IFN-gamma) antibody. Increased levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), two pro inflammatory cytokines, were detected in cultures of popliteal lymph node cells obtained from these mice. We hypothesized that concomitantly administered anti-IL 6, anti-TNF-alpha and anti-IFN-gamma antibodies would inhibit the development of arthritis in IL-17A-deficient mice. Our results showed that swelling of the hind paws and histopathological changes consistent with arthritis were significantly reduced in IL-17A-deficient mice that administered the three anti-cytokine antibodies. These results suggest that treatment with multiple anti-cytokine antibodies can abrogate the induction of Lyme arthritis in mice. PMID- 28859308 TI - Integration host factor is important for biofilm formation by Salmonella enterica Enteritidis. AB - Salmonella enterica Enteritidis forms biofilms and survives in agricultural environments, infecting poultry and eggs. Bacteria in biofilms are difficult to eradicate compared to planktonic cells, causing serious problems in industry and public health. In this study, we evaluated the role of ihfA and ihfB in biofilm formation by S. enterica Enteritidis by employing different microbiology techniques. Our data indicate that ihf mutant strains are impaired in biofilm formation, showing a reduction in matrix formation and a decrease in viability and metabolic activity. Phenotypic analysis also showed that deletion of ihf causes a deficiency in curli fimbriae expression, cellulose production and pellicle formation. These results show that integration host factor has an important regulatory role in biofilm formation by S. enterica Enteritidis. PMID- 28859310 TI - Detection of misidentifications of species from the Burkholderia cepacia complex and description of a new member, the soil bacterium Burkholderia catarinensis sp. nov. AB - The correct identification of bacteria from the Burkholderia cepacia complex (Bcc) is crucial for epidemiological studies and treatment of cystic fibrosis infections. However, genome-based identification tools are revealing many controversial Bcc species assignments. The aim of this work is to re-examine the taxonomic position of the soil bacterium B. cepacia 89 through polyphasic and genomic approaches. recA and 16S rRNA gene sequence analysis positioned strain 89 inside the Bcc group. However, based on the divergence score of seven concatenated allele sequences, and values of average nucleotide identity, and digital DNA:DNA hybridization, our results suggest that strain 89 is different from other Bcc species formerly described. Thus, we propose to classify Burkholderia sp. 89 as the novel species Burkholderia catarinensis sp. nov. with strain 89T (=DSM 103188T = BR 10601T) as the type strain. Moreover, our results call the attention to some probable misidentifications of Bcc genomes at the National Center for Biotechnology Information database. PMID- 28859309 TI - Artificial opsonin enhances bacterial phagocytosis, oxidative burst and chemokine production by human neutrophils. AB - Here, we describe the application of an 'artificial opsonin' to stimulate the innate immune response against Gram-positive bacteria. The artificial opsonin comprises a poly(L-lysine)-graft-poly(ethylene glycol) backbone displaying multiple copies of vancomycin and human IgG-Fc. The vancomycin targets bacteria by recognizing d-Ala-d-Ala-terminated peptides present in the bacterial cell wall. The human IgG-Fc antibody fragments serve as phagocyte recognition moieties that recognize the Fcgamma cell surface receptors expressed by professional human phagocytes. Staphylococcus epidermidis RP62A, a biofilm-forming, methicillin resistant strain, was utilized to investigate the effects of opsonization on phagocytosis, oxidative burst and IL-8 chemokine production by human neutrophils. Results show that opsonization of S. epidermidis RP62A with the artificial opsonin resulted in an ~2-fold increase in neutrophil phagocytosis. Analysis of the cell supernatant found a 2- to 3-fold increase in neutrophil IL-8 secretion. The neutrophil oxidative burst was investigated using the oxidation-sensitive fluorophore dihydrorhodamine-123. Bacterial opsonization resulted in a 20% increase in fluorescence intensity, indicating a significant increase in the production of reactive oxygen species by the neutrophils. These studies suggest that artificial opsonins may be a novel immunostimulation therapeutic strategy to control infections caused by Gram-positive bacteria, particularly those that are known to be immune evasive and/or antibiotic resistant. PMID- 28859311 TI - Design, synthesis and antiviral evaluation of novel heteroarylcarbothioamide derivatives as dual inhibitors of HIV-1 reverse transcriptase-associated RNase H and RDDP functions. AB - In the continuous effort to identify new HIV-1 inhibitors endowed with innovative mechanisms, the dual inhibition of different viral functions would provide a significant advantage against drug-resistant variants. The HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) is the only viral-encoded enzymatic activity that still lacks an efficient inhibitor. We synthesized a library of 3,5-diamino-N-aryl-1H-pyrazole-4-carbothioamide and 4-amino-5-benzoyl N-phenyl-2-(substituted-amino)-1H-pyrrole-3-carbothioamide derivatives and tested them against RNase H activity. We identified the pyrazolecarbothioamide derivative A15, able to inhibit viral replication and both RNase H and RNA dependent DNA polymerase (RDDP) RT-associated activities in the low micromolar range. Docking simulations hypothesized its binding to two RT pockets. Site directed mutagenesis experiments showed that, with respect to wt RT, V108A substitution strongly reduced A15 IC50 values (12.6-fold for RNase H inhibition and 4.7-fold for RDDP), while substitution A502F caused a 9.0-fold increase in its IC50 value for RNase H, not affecting the RDDP inhibition, reinforcing the hypothesis of a dual-site inhibition. Moreover, A15 retained good inhibition potency against three non-nucleoside RT inhibitor (NNRTI)-resistant enzymes, confirming a mode of action unrelated to NNRTIs and suggesting its potential as a lead compound for development of new HIV-1 RT dual inhibitors active against drug resistant viruses. PMID- 28859312 TI - Phase variation of DNA methyltransferases and the regulation of virulence and immune evasion in the pathogenic Neisseria. AB - The pathogenic Neisseria provide textbook examples of phase variation: the high frequency, random and reversible switching of gene expression. Typically, phase variable gene expression is observed in genes required for the expression of surface proteins and carbohydrate structures. All Neisseria gonorrhoeae and N. meningitidis strains also express phase variable DNA methyltransferases that are components of DNA restriction-modification systems. Phase variation of these DNA methyltransferases (Mod) alters global DNA methylation patterns. The change in DNA methylation due to phase variation events alters expression of a regulon of genes, called a phasevarion, and results in differentiation of the population into cells with two distinct phenotypes. For example, in N. meningitidis switching of the modA11 phasevarion alters expression of immunogenic outer membrane proteins such as lactoferrin-binding protein, and also modulates sensitivity to ceftazidime and ciprofloxacin. The modD1 phasevarion is associated with hypervirulent meningococcal clonal complexes. In N. gonorrhoeae, modA13 phasevarion switching generates differentiation into cells that display enhanced biofilm formation and enhanced intracellular survival. Phasevarions are ubiquitous in pathogenic Neisseria and modulate expression of numerous genes. These systems have the potential to impact all studies on vaccine development and pathobiology in the pathogenic Neisseria. PMID- 28859313 TI - Autotrophic microbial arsenotrophy in arsenic-rich soda lakes. AB - A number of prokaryotes are capable of employing arsenic oxy-anions as either electron acceptors [arsenate; As(V)] or electron donors [arsenite; As(III)] to sustain arsenic-dependent growth ('arsenotrophy'). A subset of these microorganisms function as either chemoautotrophs or photoautotrophs, whereby they gain sufficient energy from their redox metabolism of arsenic to completely satisfy their carbon needs for growth by autotrophy, that is the fixation of inorganic carbon (e.g. HCO3-) into their biomass. Here we review what has been learned of these processes by investigations we have undertaken in three soda lakes of the western USA and from the physiological characterizations of the relevant bacteria, which include the critical genes involved, such as respiratory arsenate reductase (arrA) and the discovery of its arsenite-oxidizing counterpart (arxA). When possible, we refer to instances of similar process occurring in other, less extreme ecosystems and by microbes other than haloalkaliphiles. PMID- 28859315 TI - Salmonella enterica serovar Typhi siderophore production is elevated and Fur inactivation causes cell filamentation and attenuation in macrophages. AB - Salmonella enterica serovars Typhi and Typhimurium are two closely related bacteria causing different types of infection in humans. Iron acquisition is considered essential for virulence. Siderophores are important iron chelators and production of enterobactin and salmochelins by these serovars was quantified. Overall, Salmonella Typhi produced higher levels of siderophores than Salmonella Typhimurium. The role of the global regulator Fur, involved in iron homeostasis, present and conserved in both these serovars, was then investigated. Deletion of the fur gene led to distinct phenotypes in these serovars. Defective growth in iron-rich and iron-limiting conditions and formation of filamentous cells was only observed in the S. Typhi fur mutant. Furthermore, Fur was required for optimal motility in both serovars, but motility was more reduced for the fur mutant of S. Typhi compared to S. Typhimurium. During interaction with human cultured macrophages, Fur was more important for S. Typhi, as the fur mutant had severe defects in uptake and survival. Globally, these results demonstrate that Fur differentially affects the physiology and the virulence phenotypes of the two strains and is more critical for S. Typhi growth, morphology, motility and interaction with host cells than it is for S. Typhimurium. PMID- 28859314 TI - The role of multispecies social interactions in shaping Pseudomonas aeruginosa pathogenicity in the cystic fibrosis lung. AB - Pseudomonas aeruginosa is a major pathogen in the lungs of cystic fibrosis (CF) patients. However, it is now recognised that a diverse microbial community exists in the airways comprising aerobic and anaerobic bacteria as well as fungi and viruses. This rich soup of microorganisms provides ample opportunity for interspecies interactions, particularly when considering secreted compounds. Here, we discuss how P. aeruginosa-secreted products can have community-wide effects, with the potential to ultimately shape microbial community dynamics within the lung. We focus on three well-studied traits associated with worsening clinical outcome in CF: phenazines, siderophores and biofilm formation, and discuss how secretions can shape interactions between P. aeruginosa and other commonly encountered members of the lung microbiome: Staphylococcus aureus, the Burkholderia cepacia complex, Candida albicans and Aspergillus fumigatus. These interactions may shape the evolutionary trajectory of P. aeruginosa while providing new opportunities for therapeutic exploitation of the CF lung microbiome. PMID- 28859316 TI - Gut microbiome composition is associated with cardiac disease in zoo-housed western lowland gorillas (Gorilla gorilla gorilla). AB - Cardiac disease is a leading cause of mortality in zoo-housed western lowland gorillas (Gorilla gorilla gorilla). The gut microbiome is associated with cardiac disease in humans and similarly the gut microbiome may be associated with cardiac diseases in close relatives of humans, such as gorillas. We assessed the relationship between cardiac disease and gut bacterial composition in eight zoo housed male western lowland gorillas (N = 4 with and N = 4 without cardiac disease) utilizing 16S rRNA gene analysis on the Illumina MiSeq sequencing platform. We found bacterial composition differences between gorillas with and without cardiac disease. Bacterial operational taxonomic units from phyla Bacteroidetes, Spirochaetes, Proteobacteria and Firmicutes were significant indicators of cardiac disease. Our results suggest that further investigations between diet and cardiac disease could improve the management and health of zoo housed populations of this endangered species. PMID- 28859317 TI - Diauxic growth of Fibrobacter succinogenes S85 on cellobiose and lactose. AB - Fibrobacter succinogenes rapidly colonizes the preruminant calf rumen and becomes a dominant cellulolytic bacterium in the rumen after weaning. Although F. succinogenes actively degrades cellulose in the rumen, it seems that there is no or little of its substrate, cellulose, in the rumen of preweaned calves. We thus evaluated the ability of F. succinogenes to utilize lactose, a main sugar of milk, with or without the presence of cellobiose. We grew F. succinogenes S85 on media containing 2.5% lactose combined with 0%-0.2% cellobiose or a medium with 0.2% cellobiose but without lactose. The generation times on the 0.2% cellobiose medium and the 2.5% lactose medium were 1.9 and 16.2 h, respectively. The bacterium showed rapid growth on cellobiose and diauxic growth on the lactose media containing 0.05%-0.2% cellobiose. Moreover, the production of beta galactosidase was low in the presence of 0.1%-0.2% cellobiose. Since the beta galactosidase contained a signal peptide and a Por secretion system C-terminal sorting domain, we speculate that the beta-galactosidase would be secreted from the bacterial cells by the Por secretion system. Our data indicate the possibility that F. succinogenes could colonize preruminant calf rumen, consuming the lactose present in cow milk. PMID- 28859318 TI - Effect of the RNA pyrophosphohydrolase RppH on envelope integrity in Escherichia coli. AB - The bacterial enzyme RppH initiates mRNA decay by removing pyrophosphate from 5? triphosphorylated mRNA. Escherichia coli RppH has promiscuous substrate specificity, but relatively few transcripts are affected by loss of RppH. The phenotypic analysis of the rppH mutant is required for understanding the physiological role of RppH, but the phenotype of the rppH mutant has not yet been determined. In this study, we provide several phenotypes of the rppH mutant associated with envelope integrity. Through phenotype analysis and drug susceptibility testing, we found that the rppH mutant is sensitive to a variety of chemicals including antibiotics, and is also significantly sensitive to envelope stresses, such as osmotic stress, ethanol and sodium dodecyl sulfate. All phenotypes of the rppH mutant were caused by loss of its enzymatic activity. The rppH mutant exhibited increased envelope permeability, compared to wild-type cells. In contrast, an increase of RppH activity significantly inhibited the growth of wild-type cells under low-temperature conditions. In conclusion, various phenotypes of the rppH mutant propose that RppH is associated with regulation of envelope integrity. PMID- 28859319 TI - Autophagy participates in the unfolded protein response in Toxoplasma gondii. AB - Environmental and genetic perturbations of endoplasmic reticulum (ER) function can lead to the accumulation of unfolded proteins. In these conditions, eukaryotic cells can activate a complex signaling network called the unfolded protein response (UPR) to reduce ER stress and restore cellular homeostasis. Autophagy, a degradation and recycling process, is part of this response. The parasitic protist Toxoplasma gondii is known to be able to activate the UPR upon ER stress, and we now show that this pathway leads to autophagy activation, supporting the idea of a regulated function for canonical autophagy as part of an integrated stress response in the parasites. PMID- 28859320 TI - Role of PatS and cell type on the heterocyst spacing pattern in a filamentous branching cyanobacterium. AB - Cell differentiation is one of the marks of multicellular organisms. Terminally specialised nitrogen-fixing cells, termed heterocysts, evolved in filamentous cyanobacteria more than 2 Gya. The development of their spacing pattern has been thoroughly investigated in model organisms such as Anabaena sp. PCC 7120. This paper focuses on the more complex, branching cyanobacterium Mastigocladus laminosus (Stigonematales). Contrary to what has been previously published, a heterocyst spacing pattern is present in M. laminosus but it varies with the age of the culture and the morphology of the cells. Heterocysts in young, narrow trichomes were more widely spaced (~14.8 cells) than those in old, wide trichomes (~9.4 cells). Biochemical and transgenic experiments reveal that the heterocyst spacing pattern is affected by the heterocyst inhibitor PatS. Addition of the pentapeptide RGSGR (PatS-5) to the growth medium and overexpression of patS from Anabaena sp. PCC 7120 in M. laminosus resulted in the loss of heterocyst differentiation under nitrogen deprivation. Bioinformatics investigations indicated that putative PatS sequences within cyanobacteria are highly diverse, and fall into two main clades. Both are present in most branching cyanobacteria. Despite its more complex, branching phenotype, M. laminosus appears to use a PatS based pathway for heterocyst differentiation, a property shared by Anabaena/Nostoc. PMID- 28859321 TI - Course-based undergraduate research experiences in molecular biosciences patterns, trends, and faculty support. AB - Inquiry-driven learning, research internships and course-based undergraduate research experiences all represent mechanisms through which educators can engage undergraduate students in scientific research. In life sciences education, the benefits of undergraduate research have been thoroughly evaluated, but limitations in infrastructure and training can prevent widespread uptake of these practices. It is not clear how faculty members can integrate complex laboratory techniques and equipment into their unique context, while finding the time and resources to implement undergraduate research according to best practice guidelines. This review will go through the trends and patterns in inquiry-based undergraduate life science projects with particular emphasis on molecular biosciences-the research-aligned disciplines of biochemistry, molecular cell biology, microbiology, and genomics and bioinformatics. This will provide instructors with an overview of the model organisms, laboratory techniques and research questions that are adaptable for semester-long projects, and serve as starting guidelines for course-based undergraduate research. PMID- 28859322 TI - The secretion signal peptide of the cyanobacterial extracellular protein HesF is located at its C-terminus. AB - Cyanobacteria are photosynthetic prokaryotes, capable of sustaining their growth by converting sunlight into chemical energy by fixing CO2 into organic matter. The cyanobacterium Anabaena sp. PCC 7120 is also capable of fixing atmospheric nitrogen, a metabolic process that occurs in specialized cells, the heterocysts. During the process of heterocyst differentiation, drastic morphological changes occur to prepare the future differentiated cell to accommodate the nitrogen fixation metabolism, which is a highly O2-sensitive process. Recently, we identified an unknown extracellular protein (termed HesF) in Anabaena sp. PCC 7120 and found it to be required for the proper deposition of the polysaccharide layers in the heterocyst cell wall. HesF is a non-classical type I secretion system (T1SS)-dependent secreted substrate, and its secretion signal remained elusive. Here, we report that the secretion signal of HesF is located in its C terminus. We present evidence that a heterologous reporter protein fused with HesF's secretion signal could be successfully expressed in heterocysts and secreted to the extracellular medium, following hesF's native regulation. This represents the first time that the secretion signal of a cyanobacterial T1SS dependent substrate is identified, and demonstrates the feasibility of using cyanobacteria for selected protein expression and secretion. PMID- 28859323 TI - Unusual tense bullae on the legs of a woman with rheumatoid arthritis. PMID- 28859324 TI - Vasodilation is not the only approach to the management of cutaneous ulceration in systemic sclerosis. PMID- 28859325 TI - Drivers of patient global assessment in patients with rheumatoid arthritis who are close to remission: an analysis of 1588 patients. AB - Objectives: ACR/EULAR Boolean remission in RA is frequently not obtained solely due to a patient global assessment (PGA) >1/10 (a condition often designated as near-remission). This study aimed to assess which domains of impact could explain an elevated PGA in near-remission patients. Methods: We performed an ancillary analysis of data from three cross-sectional studies in patients with established RA. Three disease activity states were defined: remission (tender and swollen joint counts, CRP and PGA all ?1), near-remission (tender and swollen joint counts, and CRP are all <=1 but PGA >1) and non-remission. Physical and psychological domains were assessed using the RA Impact of Disease 0-10 (numeric rating scale) as explanatory factors of PGA. Univariable and multivariable linear regression analyses were performed to explain PGA. Results: A total of 1588 patients (79.1% females) were analysed. The mean disease duration was 13.0 years (s.d. 9.8) and the 28-joint DAS with four variables was 3.2 (s.d. 1.4). Near remission [mean PGA 3.6 (s.d. 1.9)] was more frequent (19.1%) than remission (12.3%). Scores of RA Impact of Disease domains were similar in near-remission and non-remission patients. In near-remission, PGA was explained (R2adjusted = 0.55) by pain (beta = 0.29), function (beta = 0.23), physical well-being (beta = 0.19) and fatigue (beta = 0.15). Conclusion: Near-remission was more frequent than remission. These patients, despite having no signs of significant inflammation, report an impact of disease similar to the non-remission patients. PGA in near-remission seems to be driven by physical rather than psychological domains. Selecting the best therapy for these patients requires a better understanding of the meaning of PGA, both globally and in individual patients. PMID- 28859326 TI - Similar efficacy and safety of initial COBRA-light and COBRA therapy in rheumatoid arthritis: 4-year results from the COBRA-light trial. AB - Objective: To assess the efficacy and safety of initial COBRA-light vs COBRA therapy in RA patients after a 4-year follow-up period. Methods: In the COBRA light trial, 162 consecutive patients with recent-onset RA were randomized to either COBRA-light (prednisolone and MTX) or COBRA therapy (prednisolone, MTX and SSZ) for 1 year. After 1 year, treatment was continued without protocol, and adjusted by the treating physician according to clinical judgement, preferably with a treat-to-target strategy. Four years after trial initiation, all patients were invited to participate in the COBRA-light extension study, in which patients were interviewed and physically examined, patient reported outcomes were assessed, radiographs were made and clinical records were examined for comorbidities and medication use. Results: In the extension study, 149 out of 162 (92%) original trial patients participated: 72 COBRA-light and 77 COBRA patients. Initial COBRA-light and COBRA therapy showed similar effect on disease activity, physical functioning, radiological outcome and Boolean remission over the 4-year follow-up period. In addition, both treatment groups showed similar survival and major comorbidities, although the power to detect differences was limited. Besides protocolled differences in prednisolone, MTX and SSZ use, the use of other synthetic and biologic DMARDs and intra-articular and intramuscular glucocorticoid injections was similar in both treatment groups over the 4-year period. Conclusion: Early RA patients initially treated with COBRA-light or COBRA therapy had similar efficacy and safety outcomes over a 4-year follow-up period. PMID- 28859327 TI - Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis. AB - Objectives: To analyse the association between female hormonal factors and the development of systemic autoimmunity associated with RA in women at increased risk for RA, namely first-degree relatives of patients with RA (RA-FDRs). Methods: In an ongoing cohort study of RA-FDRs, we analysed all women with available ACPA status. The primary outcome was ACPA positivity. The predictors of interest were female hormonal factors, such as oral contraceptives, breastfeeding, post-menopausal status, early post-menopausal period and total number of ovulatory years. Results: A total of 768 female RA-FDRs were analysed, of which 42 (5%) had developed ACPA positivity. ACPA-positive women were older (52 vs 44 years, P = 0.001). Hormonal factors significantly and independently associated with the presence of ACPA were the post-menopausal (P < 0.001) and the early post-menopausal periods (P = 0.040). Conclusions: In women at increased risk of RA, characteristic systemic autoimmunity was associated with menopause, suggesting that the acute decline in ovarian function might contribute to the development of autoimmunity associated with RA and potentially to the increased risk of RA in women. PMID- 28859328 TI - Are interferon-related biomarkers advantageous for monitoring disease activity in systemic lupus erythematosus? A longitudinal benchmark study. AB - Objective: To determine the clinical value of six traditional and three IFN related biomarkers in monitoring disease activity (DA) in SLE. Methods: Prospective longitudinal study of IFNalpha, IFNgamma-inducible protein 10 (IP-10) and sialic acid-binding Ig-like lectin 1 (SIGLEC1) vs antibodies against dsDNA (ELISA and Farr radioimmunoassay), dsDNA-complexed nucleosomes (anti-dsDNA-NcX: ELISA), nucleosomes (ANuA: ELISA) and complement C3/C4 for correlation with DA (measured by BILAG 2004 index) in 26 SLE patients (77 visits). Optimal upper and lower longitudinal thresholds for the biomarkers and their accuracies for reflecting clinically relevant changes in DA (flares and remission) were determined by receiver operating characteristic and Youden index analysis. Results: Increases in IP-10, SIGLEC1 and ANuA to + 101.6 pg/ml, +5.01 relative mean fluorescence intensity and +16.20 IU/ml above the calculated upper longitudinal threshold significantly reflected lupus flares, with a sensitivity and specificity of 50 and 95% for IP-10, 83 and 90% for SIGLEC1 and 58 and 95% for ANuA. Decreases in anti-dsDNA (ELISA), IFNalpha and anti-dsDNA (Farr assay) to - 64.7 IU/ml, -16.69 pg/ml and -3.3 IU/ml below lower longitudinal thresholds, respectively, best reflected remission, with sensitivity and specificity of 75 and 95%, 62 and 90%, and 75 and 90%, respectively. Conclusion: IP-10, SIGLEC1 and ANuA emerged as advantageous biomarkers for monitoring disease activity. This is the first study in SLE that provides longitudinal biomarker thresholds and test accuracies for SLE flares and remitting disease. In the context of IFN-directed therapies, chemokines and fluorescence-activated cell sorting-based IFN biomarkers for monitoring SLE activity should be further studied. PMID- 28859329 TI - Familial Mediterranean fever in children and adolescents: factors for colchicine dosage and predicting parameters for dose increase. AB - Objectives: The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future. Methods: Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA. Results: The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease. Conclusion: Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future. PMID- 28859331 TI - Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome. Dr. Hannah Cohen about the results of the RAPS trial (Lancet Haematol 2016; 3: e426-36). PMID- 28859330 TI - Ultrasound cut-off values for intima-media thickness of temporal, facial and axillary arteries in giant cell arteritis. PMID- 28859332 TI - Biology of Microglia in the Developing Brain. AB - Microglia exist in different morphological forms in the developing brain. They show a small cell body with scanty cytoplasm with many branching processes in the grey matter of the developing brain. However, in the white matter such as the corpus callosum where the unmyelinated axons are loosely organized, they appear in an amoeboid form having a round cell body endowed with copious cytoplasm rich in organelles. The amoeboid cells eventually transform into ramified microglia in the second postnatal week when the tissue becomes more compact with the onset of myelination. Microglia serve as immunocompetent macrophages that act as neuropathology sensors to detect and respond swiftly to subtle changes in the brain tissues in pathological conditions. Microglial functions are broadly considered as protective in the normal brain development as they phagocytose dead cells and sculpt neuronal connections by pruning excess axons and synapses. They also secrete a number of trophic factors such as insulin-like growth factor-1 and transforming growth factor-beta among many others that are involved in neuronal and oligodendrocyte survival. On the other hand, microglial cells when activated produce a plethora of molecules such as proinflammatory cytokines, chemokines, reactive oxygen species, and nitric oxide that are implicated in the pathogenesis of many pathological conditions such as epilepsy, cerebral palsy, autism, and perinatal hypoxic-ischemic brain injury. Although many studies have investigated the origin and functions of the microglia in the developing brain, in-depth in vivo studies along with analysis of their transcriptome and epigenetic changes need to be undertaken to elucidate their full potential be it protective or neurotoxic. This would lead to a better understanding of their roles in the healthy and diseased developing brain and advancement of therapeutic strategies to target microglia-mediated neurotoxicity. PMID- 28859333 TI - alpha-Synucleinopathy in the Human Amygdala in Parkinson Disease: Differential Vulnerability of Somatostatin- and Parvalbumin-Expressing Neurons. AB - Olfactory dysfunction and emotional impairment are nonmotor symptoms in Parkinson disease (PD). These symptoms might be correlated with the appearance of Lewy bodies and neurites (ubiquitin and alpha-synuclein aggregates) in the amygdala (Braak stage 3). alpha-Synucleinopathy in the amygdala has been studied only occasionally, and no data on cell types involved are available. This work aimed to analyze alpha-synuclein expression in the basolateral, central, and cortical amygdaloid nuclei in 5 PD patients (Braak stages 3-5) and 5 controls. Expression of somatostatin and parvalbumin as well as its colocalization with alpha synuclein was quantified under confocal microscopy. alpha-synuclein expression did not differ significantly between the central and other nuclei. The density of somatostatin was significantly decreased in the basolateral and central complex. The density of parvalbumin was significantly diminished in the basolateral complex. Parvalbumin-positive cells colocalized frequently with alpha-synuclein (68.44%), whereas, somatostatin-positive cells colocalized only occasionally (6.98%). These data revealed the differential vulnerability among interneuron populations in the human amygdala and could help to explain nonmotor symptoms such as anhedonia in PD. PMID- 28859334 TI - SOD1G93A Mutant Mice Develop a Neuroinflammation-Independent Dendropathy in Excitatory Neuronal Subsets of the Olfactory Bulb and Retina. AB - Nonmotor neuron-related pathology is a feature of amyotrophic lateral sclerosis (ALS), both in patients and in animal models. There is emerging evidence that sensory systems (olfaction and vision) are affected in humans. Here, we asked whether such sensory neuropathology is recapitulated in the superoxide dismutase 1 (SOD1G93A) mouse model of ALS. Neuronal vacuolization in olfaction and vision pathways was assessed in tissue sections from presymptomatic and symptomatic disease stages, and compared to wild type. In both, the olfactory bulb and retina, vacuolization started around postnatal day 60, and vacuole sizes increased until disease end-stage. Notably, vacuolization was largely restricted to the external plexiform layer of the olfactory bulb and to the inner plexiform layer of the retina. In both layers, hSOD1-immunoreactive vacuoles localized to dendrites of excitatory neurons. Downstream olfaction and vision pathway fiber tracts and relay stations did not display obvious vacuolization. Finally, on a morphological level, there was no evidence for an activation of astrocytes and microglia in the 2 affected areas. Thus, we identified a new pathology hallmark in SOD1G93A ALS mice: a glutamatergic sensory neuron dendropathy restricted to olfactory bulb mitral cells and retinal ganglionic cells. PMID- 28859335 TI - A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade. AB - Mutations in FIG4, coding for a phosphoinositol(3,5) bisphosphate 5' phosphatase and involved in vesicular trafficking and fusion, have been shown causing a recessive form of Charcot-Marie-Tooth (CMT). We have identified a novel intronic mutation in the FIG4 in a wheel-chair bound patient presenting with a severe form of CMT4J and provide a longitudinal study. Investigations indicated a demyelinating sensorimotor polyneuropathy with diffuse active denervation and severe axonal loss. Genetic testing revealed that the patient is heterozygous for 2 FIG4 mutations, p.I41T and a T > G transversion at IVS17-10, the latter predicted to cause a splicing defect. FIG4 was severely diminished in patient's fibroblasts indicating loss-of-function. Consistent with FIG4's function in phosphoinositol homeostasis and vesicular trafficking, fibroblasts contained multiple large vacuoles and vesicular organelles were abnormally dispersed. FIG4 deficiency has implications for turnover of membrane proteins. The transient receptor cation channel, TRPV4, accumulated at the plasma membrane of patient's fibroblasts due to slow turnover. Knocking down Fig4 in murine cultured motor neurons resulted in vacuolation and cell death. Inhibiting TRPV4 activity significantly preserved viability, although not correcting vesicular trafficking. In conclusion, we demonstrate a new FIG4 intronic mutation and, importantly, a functional interaction between FIG4 and TRPV4. PMID- 28859337 TI - Amygdala TDP-43 Pathology in Frontotemporal Lobar Degeneration and Motor Neuron Disease. AB - TDP-43-positive inclusions are present in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) including amyotrophic lateral sclerosis. Behavioral abnormalities, one of the chief symptoms of FTLD, could be, at least partly, related to amygdala pathology. We examined TDP-43 inclusions in the amygdala of patients with sporadic FTLD/MND (sFTLD/MND), FTLD/MND with mutation of the C9ORF72 (FTLD/MND-C9) and FTLD with mutation of the progranulin (FTLD-GRN). TDP-43 inclusions were common in each one of these subtypes, which can otherwise be distinguished on topographical and genetic grounds. Conventional and immunological stainings were performed and we quantified the numerical density of inclusions on a regional basis. TDP-43 inclusions in amygdala could be seen in 10 out of 26 sFTLD/MND cases, 5 out of 9 FTLD/MND-C9 cases, and all 4 FTLD-GRN cases. Their numerical density was lower in FTLD/MND-C9 than in sFTLD/MND and FTLD-GRN. TDP-43 inclusions were more numerous in the ventral region of the basolateral nucleus group in all subtypes. This contrast was apparent in sporadic and C9-mutated FTLD/MND, while it was less evident in FTLD GRN. Such differences in subregional involvement of amygdala may be related to the region-specific neuronal connections that are differentially affected in FTLD/MND and FTLD-GRN. PMID- 28859336 TI - Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma. AB - Pediatric adamantinomatous craniopharyngioma (ACP) is a highly solid and cystic tumor, often causing substantial damage to critical neuroendocrine structures such as the hypothalamus, pituitary gland, and optic apparatus. Paracrine signaling mechanisms driving tumor behavior have been hypothesized, with IL-6R overexpression identified as a potential therapeutic target. To identify potential novel therapies, we characterized inflammatory and immunomodulatory factors in ACP cyst fluid and solid tumor components. Cytometric bead analysis revealed a highly pro-inflammatory cytokine pattern in fluid from ACP compared to fluids from another cystic pediatric brain tumor, pilocytic astrocytoma. Cytokines and chemokines with particularly elevated concentrations in ACPs were IL-6, CXCL1 (GRO), CXCL8 (IL-8) and the immunosuppressive cytokine IL-10. These data were concordant with solid tumor compartment transcriptomic data from a larger cohort of ACPs, other pediatric brain tumors and normal brain. The majority of receptors for these cytokines and chemokines were also over-expressed in ACPs. In addition to IL-10, the established immunosuppressive factor IDO-1 was overexpressed by ACPs at the mRNA and protein levels. These data indicate that ACP cyst fluids and solid tumor components are characterized by an inflammatory cytokine and chemokine expression pattern. Further study regarding selective cytokine blockade may inform novel therapeutic interventions. PMID- 28859339 TI - Pathologic Involvement of Glutamatergic Striatal Inputs From the Cortices in TAR DNA-Binding Protein 43 kDa-Related Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. AB - In frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), recent studies have presumed relationships between cognitive declines and striatal dysfunctions. The striatum contributes to socio-cognitive functions by receiving glutamatergic inputs from the cerebral cortices. However, the vulnerability of these cortico-striatal inputs is unclear in these diseases. This study aimed to evaluate the glutamatergic inputs to the striatum from the cerebral cortices in patients with sporadic TDP-43-related FTLD (FTLD-TDP) and ALS (ALS-TDP). We examined 46 consecutively autopsied patients (31 FTLD-TDP and 15 ALS patients) and 10 normal controls. The axon terminals of the glutamatergic cortico-striatal projection neurons were quantified at the striatum using antivesicular glutamate transporter-1 (VGLUT-1) immunohistochemistry. In results, all FTLD-TDP patients displayed marked depletion of VGLUT-1-positive axon terminals in the caudate head and putamen. Particularly, the patients with type C pathology showed a severe loss. The nondemented ALS patients displayed loss of VGLUT-1-positive axon terminals in the putamen, but those were relatively spared in the caudate head. Confocal microscopy revealed TDP-43 aggregations within VGLUT-1-positive axon terminals in a subset of the patients. Our results indicate marked involvement of glutamatergic striatal inputs from the cerebral cortices in association with socio-cognitive declines in a disease spectrum of TDP-43 proteinopathy. PMID- 28859340 TI - Rewiring Microbiology and Infection. PMID- 28859338 TI - Human Brain Abnormalities Associated With Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder. AB - Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental problem, but neuropathologic descriptions are rare and focused on the extreme abnormalities. We conducted a retrospective survey (1980-2016) of autopsies on 174 individuals with prenatal alcohol exposure or an FASD diagnosis. Epidemiologic details and neuropathologic findings were categorized into 5 age groups. Alcohol exposure was difficult to quantify. When documented, almost all mothers smoked tobacco, many abused other substances, and prenatal care was poor or nonexistent. Placental abnormalities were common (68%) in fetal cases. We identified micrencephaly (brain weight <5th percentile) in 31, neural tube defects in 5, isolated hydrocephalus in 6, corpus callosum defects in 6 (including some with complex anomalies), probable prenatal ischemic lesions in 5 (excluding complications of prematurity), minor subarachnoid heterotopias in 4, holoprosencephaly in 1, lissencephaly in 1, and cardiac anomalies in 26 cases. The brain abnormalities associated with prenatal alcohol exposure are varied; cause-effect relationships cannot be determined. FASD is likely not a monotoxic disorder. The animal experimental literature, which emphasizes controlled exposure to ethanol alone, is therefore inadequate. Prevention must be the main societal goal, however, a clear understanding of the neuropathology is necessary for provision of care to individuals already affected. PMID- 28859341 TI - Evaluating the Clinical Burden and Mortality Attributable to Antibiotic Resistance: The Disparity of Empirical Data and Simple Model Estimations. AB - Given the proliferation of cataclysmic predictions about antibiotic resistance, cases of which are estimated to amount to 12500 per year in France, we herein decided to compare the empirical clinical microbiology data from our institution with estimates and predictions from 10 major international scientific articles and reports. The analysis of 7 years of antibiotic resistance data from 10 bacterial species and genera of clinical interest from our institution identified no deaths that were directly attributable to extremely drug-resistant bacteria. By comparing our observations to the 10 articles and reports studied herein, we concluded that their results lack empirical data. Interventions are urgently needed to significantly reduce both mortality and the healthcare costs associated with bacterial infections, including the implementation of local and national laboratory data-based surveillance systems for the routine surveillance of antibiotic resistance that would be helpful for a better understanding of how to manage antibiotic-resistant bacteria in the future. PMID- 28859342 TI - Developing Research in Infectious and Tropical Diseases in Africa: The Paradigm of Senegal. AB - Infectious diseases represent one of the greatest potential barriers to achievement of the third Sustainable Development Goals in African countries and around the world because they continue to pose major public health challenges. The surveillance of infectious diseases has recently assumed greater importance in most African countries, both because of the emergence of infectious diseases and because strains of pathogens that cause tuberculosis, malaria, cholera, dysentery, and pneumonia have developed resistance to common and inexpensive antimicrobial drugs. However, data on the pathogen-specific causes of infectious diseases are limited. Developing research in infectious and tropical diseases in Africa is urgently needed to better describe the distribution of pathogen-borne diseases and to know which pathogens actually cause fever. This research is critical for guiding treatment and policies in Africa. More effective diagnostics are also needed for these diseases, which often are misdiagnosed or diagnosed too late. A comprehensive review of this type of research is presented here. PMID- 28859343 TI - Place of International Congresses in the Diffusion of Knowledge in Infectious Diseases. AB - Through digital resources, physicians, microbiologists, and researchers around the world can stay up-to-date with the newest developments in their field and are therefore less dependent on medical congresses as a provider of knowledge and education. The role of the medical congress in spreading knowledge in the face of this changing environment needs to be reexamined. The result is a new paradigm that thinks about the dissemination of medical knowledge and discovery as ongoing conversations between professionals and their extended networks, rather than activities that happen only during the congress. Even though the tools we use to deliver information and knowledge are rapidly evolving, there is confidence in the lasting value of meetings for medical professionals. Medical congresses are environments uniquely conducive to generating new ideas and solutions to problems. As organizers explore new ways of sharing knowledge globally, it is crucial that the high quality of medical congresses be maintained. PMID- 28859344 TI - Viruses in the 21st Century: From the Curiosity-Driven Discovery of Giant Viruses to New Concepts and Definition of Life. AB - The curiosity-driven discovery of giant DNA viruses infecting amoebas has triggered an intense debate about the origin, nature, and definition of viruses. This discovery was delayed by the current paradigm confusing viruses with small virions. Several new definitions and concepts have been proposed either to reconcile the unique features of giant viruses with previous paradigms or to propose a completely new vision of the living world. I briefly review here how several other lines of research in virology converged during the last 2 decades with the discovery of giant viruses to change our traditional perception of the viral world. This story emphasizes the power of multidisciplinary curiosity driven research, from the hospital to the field and the laboratory. Notably, some philosophers have now also joined biologists in their quest to make sense of the abundance and diversity of viruses and related capsidless mobile elements in the biosphere. PMID- 28859345 TI - Basic Sciences Fertilizing Clinical Microbiology and Infection Management. AB - Basic sciences constitute the most abundant sources of creativity and innovation, as they are based on the passion of knowing. Basic knowledge, in close and fertile contact with medical and public health needs, produces distinct advancements in applied sciences. Basic sciences play the role of stem cells, providing material and semantics to construct differentiated tissues and organisms and enabling specialized functions and applications. However, eventually processes of "practice deconstruction" might reveal basic questions, as in de-differentiation of tissue cells. Basic sciences, microbiology, infectious diseases, and public health constitute an epistemological gradient that should also be an investigational continuum. The coexistence of all these interests and their cross-fertilization should be favored by interdisciplinary, integrative research organizations working simultaneously in the analytical and synthetic dimensions of scientific knowledge. PMID- 28859346 TI - Data Science Priorities for a University Hospital-Based Institute of Infectious Diseases: A Viewpoint. AB - Automation of laboratory tests, bioinformatic analysis of biological sequences, and professional data management are used routinely in a modern university hospital-based infectious diseases institute. This dates back to at least the 1980s. However, the scientific methods of this 21st century are changing with the increased power and speed of computers, with the "big data" revolution having already happened in genomics and environment, and eventually arriving in medical informatics. The research will be increasingly "data driven," and the powerful machine learning methods whose efficiency is demonstrated in daily life will also revolutionize medical research. A university-based institute of infectious diseases must therefore not only gather excellent computer scientists and statisticians (as in the past, and as in any medical discipline), but also fully integrate the biologists and clinicians with these computer scientists, statisticians, and mathematical modelers having a broad culture in machine learning, knowledge representation, and knowledge discovery. PMID- 28859347 TI - A Hospital-Based Committee of Moral Philosophy to Revive Ethics. AB - The Mediterranee Infection Foundation's primary goal is supporting a research hospital for the treatment of infectious diseases in Marseille. The main objective of this innovative center is to understand the mechanisms of contagion and face them. The Foundation will include a committee on moral philosophy that will accompany and supervise biomedical research. This is not a conventional ethics committee, frequently giving rise to a board's bureaucratic excesses, which might slow down creative biomedical clinical research without necessarily restricting abuses. Moral philosophy, however, can handle contemporary biomedical issues. In all its diversity, this discipline is able to enrich the debate on medical issues, thanks to many philosophical currents such as deontological ethics and consequentialism. The purpose of this committee is therefore to advance reflection on the bioethical issues encountered in biomedical research in infectious diseases, while respecting the precepts of moral philosophy. PMID- 28859348 TI - Building an Intelligent Hospital to Fight Contagion. AB - The idea of building hospitals to fight contagion was born with the lazarettos. At the time when the microorganisms were not yet known, the mechanisms of transmission of contagion were already well apprehended. Based on the same knowledge but thanks to new technologies, such hospitals have now been built downtown, next to the most highly performing technological plateau. Regrouping patient care, diagnostics, research, and development, the University Hospital Institute Mediterranee Infection building offers a wonderful tool to contain and understand contagion, in a well-designed setting, creating excellent working conditions that are attractive for interested scientists. PMID- 28859349 TI - From Expert Protocols to Standardized Management of Infectious Diseases. AB - We report here 4 examples of management of infectious diseases (IDs) at the University Hospital Institute Mediterranee Infection in Marseille, France, to illustrate the value of expert protocols feeding standardized management of IDs. First, we describe our experience on Q fever and Tropheryma whipplei infection management based on in vitro data and clinical outcome. Second, we describe our management-based approach for the treatment of infective endocarditis, leading to a strong reduction of mortality rate. Third, we report our use of fecal microbiota transplantation to face severe Clostridium difficile infections and to perform decolonization of patients colonized by emerging highly resistant bacteria. Finally, we present the standardized management of the main acute infections in patients admitted in the emergency department, promoting antibiotics by oral route, checking compliance with the protocol, and avoiding the unnecessary use of intravenous and urinary tract catheters. Overall, the standardization of the management is the keystone to reduce both mortality and morbidity related to IDs. PMID- 28859350 TI - Many More Microbes in Humans: Enlarging the Microbiome Repertoire. AB - The proportion of cultured microorganisms is dramatically lower than those predicted to be involved in colonization, acute, or chronic infections. We report our laboratory's contribution to promoting culture methods. As a result of using culturomics in our clinical microbiology laboratories (including amoeba co culture and shell-vial culture) and through the use of matrix-assisted laser desorption/ionization-time-of-flight and the 16S rRNA gene for identification, we cultured 329 new bacterial species. This is also the first time that 327 of species have been isolated from humans, increasing the known human bacterial repertoire by 29%. We isolated 4 archaeal species for the first time from human, including 2 new species. Of the 100 isolates of giant viruses, we demonstrated the human pathogenicity of Mimivirus in pneumonia and Marseillevirus in diverse clinical situations. From sand flies, we isolated most of the known Phlebovirus strains that potentially cause human infections. Increasing the repertoire of human-associated microorganisms through culture will allow us to test pathogenicity models with viable microorganisms. PMID- 28859351 TI - New Laboratory Tools for Emerging Bacterial Challenges. AB - Since its creation, the Mediterranee-Infection foundation has aimed at optimizing the management of infectious diseases and surveying the local and global epidemiology. This pivotal role was permitted by the development of rational sampling, point-of-care tests, and extended automation as well as new technologies, including mass spectrometry for colony identification, real-time genomics for isolate characterization, and the development of versatile and permissive culture systems. By identifying and characterizing emerging microbial pathogens, these developments provided significant breakthroughs in infectious diseases. PMID- 28859352 TI - New Approaches to Prevent Healthcare-Associated Infection. AB - Healthcare-associated infection (HCAI) in hospitals mainly results from unsolved but well-identified causes such as hand hygiene, overuse of catheters, and to a lesser extent, the airborne transmission of infectious agents caused by the misuse of respiratory precautions. The aims of the Institut Hospitalo Universitaire Mediterranee Infection are to develop new approaches to fight HCAIs. Among them, new technologies that allow for the traceability of care and good practices reminders have been developed concomitantly to an anthropological approach, facilitating acceptability by healthcare workers. While the automated continuous monitoring system is validated and commercially available, some other technologies are still under clinical evaluation or in the early development phase. Quorum sensing-based biotechnologies are developed with the aims to fight against wound colonization. PMID- 28859353 TI - Medical Entomology: A Reemerging Field of Research to Better Understand Vector Borne Infectious Diseases. AB - In the last decade, the Chikungunya and Zika virus outbreaks have turned public attention to the possibility of the expansion of vector-borne infectious diseases worldwide. Medical entomology is focused on the study of arthropods involved in human health. We review here some of the research approaches taken by the medical entomology team of the University Hospital Institute (UHI) Mediterranee Infection of Marseille, France, with the support of recent or representative studies. We propose our approaches to technical innovations in arthropod identification and the detection of microorganisms in arthropods, the use of arthropods as epidemiological or diagnostic tools, entomological investigations around clinical cases or within specific populations, and how we have developed experimental models to decipher the interactions between arthropods, microorganisms, and humans. PMID- 28859354 TI - Ultraconserved Sequences Associated with HoxD Cluster Have Strong Repression Activity. AB - Increase in the complexity of organisms during evolution strongly correlates with the increase in the noncoding DNA content of their genomes. Although a gradual increase in the proportion of repetitive DNA elements along with increasing complexity is known, most of the noncoding components of the genome remain uncharacterized. A nonrepetitive but highly conserved noncoding component of the genome in vertebrates, called ultraconserved DNA sequences, constitutes up to 5% of the human genome. The function of most of the ultraconserved DNA elements is not well known. One such ultraconserved stretch of DNA has been identified upstream of the HoxD cluster in vertebrates. We analyzed the function of these elements in different cell lines and zebrafish. Our results suggest that these ultraconserved sequences work as repressor elements. This is the first report which reveals the repressor function of ultraconserved sequences and implicates their role in the regulation of developmental genes. PMID- 28859355 TI - Whole-Genome Sequence of the Anaerobic Isosaccharinic Acid Degrading Isolate, Macellibacteroides fermentans Strain HH-ZS. AB - The ability of micro-organisms to degrade isosaccharinic acids (ISAs) while tolerating hyperalkaline conditions is pivotal to our understanding of the biogeochemistry associated within these environs, but also in scenarios pertaining to the cementitious disposal of radioactive wastes. An alkalitolerant, ISA degrading micro-organism was isolated from the hyperalkaline soils resulting from lime depositions. Here, we report the first whole-genome sequence, ISA degradation profile and carbohydrate preoteome of a Macellibacteroides fermentans strain HH-ZS, 4.08 Mb in size, coding 3,241 proteins, 64 tRNA, and 1 rRNA. PMID- 28859356 TI - Quantitation of spatial and temporal variability of biomarkers for Barrett's Esophagus. AB - Chemoprevention and risk-stratification studies in Barrett's esophagus (BE) rely on biomarkers but the variability in their temporal and spatial expression is unknown. If such variability exists, it will impact sampling techniques and sample size calculations. Specimens from three levels of biopsies over two serial endoscopies in nondysplastic BE patients were analyzed for aneuploidy, proliferation markers (Ki67, Mcm2), and cell cycle markers (cyclin A and cyclin D1). A modification of the image cytometry technique, where cytokeratin staining automatically distinguished epithelial and stromal cells, measured aneuploidy on whole tissue sections. Other biomarkers were studied by immunohistochemistry. Coefficient of variability (SD/mean) was calculated; a value <10% indicated low variability. A total of 120 specimens (20 subjects each with three biopsy levels at two time points) from nondysplastic BE patients (71 +/- 8.8 years, all Caucasian, 90% males, C5.1M7.5 +/- 3.4 cm) were analyzed. The mean interval between endoscopies was 32.8 +/- 8.4 months. Aneuploidy had a spatial variability of 6.8% at visit 1 (mean diploid index: 1.1 +/- 0.09) and 7.9% at visit 2 (mean diploid index: 1.1 +/- 0.06) and a temporal variability of 7.0-8.1% for the three levels. For other biomarkers, the spatial variability ranged from ~5 to 30% at visit 1 and 11-92% at visit 2 and the temporal variability ranged from 0 to 77%. To conclude, of all the biomarkers, only aneuploidy had both spatial and temporal variability of <10%. Spatial and temporal variability were biomarker dependent and could be as high as 90% even without progression. These data will be useful to design chemoprevention and risk-stratification studies in BE. PMID- 28859357 TI - Review of antireflux procedures for proton pump inhibitor nonresponsive gastroesophageal reflux disease. AB - Up to 40% of patients with gastroesophageal reflux disease (GERD) report persistent symptoms despite proton pump inhibitor (PPI) therapy. This review outlines the evidence for surgical and endoscopic therapies for the treatment of PPI nonresponsive GERD. A literature search for GERD therapies from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 2928 unique citations. Of those, 45 unique articles specific to surgical and endoscopic therapies for PPI nonresponsive GERD were reviewed. Laparoscopic fundoplication (n = 19) provides symptomatic and physiologic relief out to 10 years, though efficacy wanes with time. Magnetic sphincter augmentation (n = 6) and transoral incisionless fundoplication (n = 9) improve symptoms in PPI nonresponders and may offer fewer side effects than fundoplication, though long-term follow-up is lacking. Radiofrequency energy delivery (n = 8) has insufficient evidence for routine use in treating PPI nonresponsive GERD. Electrical stimulator implantation (n = 1) and endoscopic mucosal surgery (n = 2) are newer therapies under evaluation for the treatment of GERD. Laparoscopic fundoplication remains the most proven therapeutic approach. Newer antireflux procedures such as magnetic sphincter augmentation and transoral incisionless fundoplication offer alternatives with varying degrees of success, durability, and side effect profiles that may better suit individual patients. Larger head-to-head comparison trials are needed to better characterize the difference in symptom response and side effect profiles. PMID- 28859359 TI - Abdominal diameter index is a stronger predictor of prevalent Barrett's esophagus than BMI or waist-to-hip ratio. AB - Abdominal obesity is associated with gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE). Increased body mass index (BMI) and waist-to-hip ratio (WHR) have been associated with BE. Abdominal diameter index (ADI, sagittal abdominal diameter divided by thigh circumference) was previously shown to be a more accurate predictor of incident cardiovascular disease compared to other measurements. Our aim is to examine whether abdominal diameter index was a more accurate predictor of prevalent BE compared to other anthropometric measurements. We conducted a case-control study of patients presenting to our institution. Our study population was consecutive Caucasian men with a known history of BE, and we recruited control patients who had GERD without BE. Both groups completed a questionnaire about demographics, smoking, and medications and underwent a series of anthropometric body measurements using standardized measuring tools. BMI, waist-to-hip ratio, and abdominal diameter index were calculated. Thirty-one BE patients and 27 control patients were recruited. The BE cohort were older and had a higher rate of hiatal hernia. The mean abdominal diameter index for patients with BE was 0.65 +/- 0.07 and without BE was 0.60 +/- 0.07 (p = 0.01). The predictive value of abdominal diameter index was analyzed using a receiver operator characteristic (ROC) curve and was a more powerful predictor of BE than waist-to-hip ratio or BMI (AUROC = 0.70 vs. 0.60 vs. 0.52, respectively). Using a cut-point abdominal diameter index value of 0.60, abdominal diameter index had a sensitivity of 77.4% and a specificity of 63.0% for the presence of BE. When controlling for age, smoking status, and BMI, an abdominal diameter index >=0.60 was a significant independent risk factor for BE (OR = 5.7, 95% CI = 1.29-25.4). In this pilot study, the abdominal diameter index appears to be a more powerful predictor of the presence of BE than BMI and waist-to-hip ratio and remained the only significant predictor of BE in multivariate analysis. We propose further validation of abdominal diameter index before inclusion in future prediction tools for BE. PMID- 28859358 TI - A review of medical therapy for proton pump inhibitor nonresponsive gastroesophageal reflux disease. AB - Up to 40% of patients report persistent gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy. This review outlines the evidence for medical therapy for PPI nonresponsive GERD. A literature search for GERD therapies from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 2928 unique citations. Of those, 40 unique articles specific to the impact of PPI metabolizer genotype on PPI response and the use adjunctive medical therapies were identified. Thirteen articles reported impacts on CYP genotypes on PPI metabolism demonstrating lower endoscopic healing rates in extensive metabolizers; however, outcomes across genotypes were more uniform with more CYP independent PPIs rabeprazole and esomeprazole. Twenty-seven publications on 11 adjunctive medications showed mixed results for adjunctive therapies including nocturnal histamine-2 receptor antagonists, promotility agents, transient lower esophageal sphincter relaxation inhibitors, and mucosal protective agents. Utilizing PPI metabolizer genotype or switching to a CYP2C19 independent PPI is a simple and conservative measure that may be useful in the setting of incomplete acid suppression. The use of adjunctive medications can be considered particularly when the physiologic mechanism for PPI nonresponse is suspected. Future studies using adjunctive medications with improved study design and patient enrollment are needed to better delineate medical management options before proceeding to antireflux interventions. PMID- 28859360 TI - Targeted next-generation sequencing of commonly mutated genes in esophageal adenocarcinoma patients with long-term survival. AB - Survival of patients with esophageal adenocarcinoma remains poor and individual differences in prognosis remain unexplained. This study investigated whether gene mutations can explain why patients with high-risk (pT3-4, pN+) esophageal adenocarcinoma survive past 5 years after esophagectomy. Six long-term survivors (LTS) (>=5 years survival without recurrence) and six short-term survivors (STS) (<2 years survival due to recurrence) who underwent resection without neoadjuvant therapy for high-risk esophageal adenocarcinoma were included. Targeted next generation sequencing of 16 genes related to esophageal adenocarcinoma was performed. Mutations were compared between the LTS and STS and described in comparison with literature. A total of 48 mutations in 10 genes were identified. In the LTS, the median number of mutated genes per sample was 5 (range: 0-5) and the samples together harbored 22 mutations in 8 genes: APC (n = 1), CDH11 (n = 2), CDKN2A (n = 2), FAT4 (n = 5), KRAS (n = 1), PTPRD (n = 1), TLR4 (n = 8), and TP53 (n = 2). The median number of mutated genes per sample in the STS was 4 (range: 1-8) and in total 26 mutations were found in six genes: CDH11 (n = 5), FAT4 (n = 7), SMAD4 (n = 1), SMARCA4 (n = 1), TLR4 (n = 7), and TP53 (n = 5). CDH11, CDKN2A, FAT4, TLR4, and TP53 were mutated in at least 2 LTS or STS, exceeding mutation rates in literature. Mutations across the LTS and STS were found in 10 of the 16 genes. The results warrant future studies to investigate a larger range of genes in a larger sample size. This may result in a panel with prognostic genes, to predict individual prognosis and to select effective individualized therapy for patients with esophageal adenocarcinoma. PMID- 28859361 TI - BNIP3 induces apoptosis and protective autophagy under hypoxia in esophageal squamous cell carcinoma cell lines: BNIP3 regulates cell death. AB - Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), a pro-apoptosis protein regulated by the methylation status of its promoter, has been implicated in inducing autophagy. However, the roles of BNIP3 and BNIP3-induced autophagy under hypoxia remain uncertain in esophageal squamous cell carcinoma (ESCC). Two esophageal squamous cancer cell lines, CAES17 and KYSE140, were selected on the basis of the expression and methylation status of BNIP3 to investigate the features of BNIP3 under hypoxia. Hypoxia increased cell death and the expression of BNIP3, whose promoter status was lower methylation, in a time-dependent manner. BNIP3 knockdown by RNA interference downregulated cell death. These studies demonstrated that the exposure of ESCC cells to hypoxia increased the autophagic punctate distribution of MDC staining and GFP-LC3 and that autophagy rate could be inhibited by BNIP3-siRNA. In addition, under hypoxia, cells transfected with BNIP3-siRNA exhibited a lower apoptosis rate than the control, and the apoptosis induced by BNIP3 exhibited a caspase-independent manner. Furthermore, the administration of the autophagic inhibitor 3-methyladenine (3 MA) could augment BNIP3-induced cell apoptosis and death, suggesting that autophagy plays a protective role under hypoxia. Together, our studies indicated that BNIP3 exerts prodeath effects through the induction of caspase-independent apoptosis under hypoxia in ESCC, though BNIP3-induced autophagy acting as a survival mechanism. PMID- 28859362 TI - Comparative study of radiotherapy plus erlotinib versus chemoradiotherapy for elderly patients with esophageal cancer: a propensity score-matched analysis. AB - This study compared the efficiency and safety of radiotherapy plus erlotinib with concurrent chemoradiotherapy (CCRT) based on paclitaxel plus cisplatin in elderly esophageal cancer patients. The eligible patients were retrospectively enrolled at Wenzhou Medical University cancer center from January 2005 to December 2011. Propensity score matching generated a matched cohort (1:1) composed from radiotherapy plus erlotinib and CCRT groups. The efficiency and safety were compared between two groups. Multivariable analysis was used to identify significant prognostic factors. Thirty-four patients treated with radiotherapy plus erlotinib were matched with patients who received CCRT. Radiotherapy plus erlotinib group showed better treatment compliance compared with the CCRT group (91.2% vs. 67.6%, hazard ratio [HR] 0.202, 95% confidence interval [CI] 0.051 0.809; P = .016). No significant overall response rate differences were found between the two groups (88.2% vs. 79.4%, HR 0.514, 95% CI 0.135-1.952; P = .323). The 5-year overall survival (OS) rate was 23.5% vs. 19.2% for patients treated with CCRT or radiotherapy plus erlotinib (HR 1.008, 95% CI 0.574-1.768; P = .979). The 5-year progression-free survival (PFS) rate was 16.8% versus 17.1% for patients treated with CCRT or radiotherapy plus erlotinib, respectively (HR 0.978, 95% CI 0.576-1.662; P = .934). The rate of severe hematologic toxicities in the CCRT group was significantly higher than that in the radiotherapy plus erlotinib group (HR 4.306, 95% CI 1.066-17.389; P = .031). Late toxicities were similar between radiotherapy plus erlotinib group and the CCRT group. Multivariate analysis showed that T stage (HR 1.730, 95% CI 1.062-2.816; P = .028), M stage (HR 2.859, 95% CI 1.407-5.811; P = .004), and complete response (HR 2.154, 95% CI 1.190-3.901; P = .011) were independent prognostic factors associated with OS. In conclusion, the present study suggested radiotherapy plus erlotinib should be a preferable modality compared with CCRT, with similar survival outcomes but better treatment compliance and less toxicities. PMID- 28859363 TI - Appropriate timing for surgery after neoadjuvant chemoradiation for esophageal cancer. AB - Optimal interval between neoadjuvant chemoradiotherapy (CRT) and surgery is not elucidated for esophageal squamous carcinoma. The aim of this study is to evaluate the impact of this time interval on patient outcome. Patients treated with neoadjuvant CRT followed by surgery between 2002 and 2009 were analyzed. Patients were divided into two groups based on the median interval to surgery (64 days): A 64 days (n = 53). A second analysis was performed by re-classifying patients into three interval groups: A* <= 40 days (n = 16); B* 41-80 days (n = 60); C* > 80 days (n = 31). Operative outcome, pathological data, and long-term survival were analyzed. One hundred and seven (n = 107) patients were analyzed. Five patients (9.4%) in group B had an anastomotic leak compared with no leakage from group A (P < 0.021). The complete pathological response was comparable in groups A and B (35% vs. 24.5%, p = 0.23). R0 was significantly lower in group A* (A*: 56.3%, B*: 90%, C*: 74.2%, P = 0.006). In patients with R0 resection, 5-year survival was significantly better in group A than B (71.7% vs. 51%, P = 0.032) and in group A* (A* 100% vs. B* 60.2% & C* 48.3%; A* vs. B*, P = 0.036; A* vs. C*, P = 0.019). Complete pathological response was an independent predictor of survival. Early surgery with R0 resection following neoadjuvant CRT may lead to a better outcome. Further prospective studies are still necessary to provide better insight into the issue. At present, timing of surgery should be individualized and performed at the earliest opportunity. PMID- 28859364 TI - Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction. AB - The aim of this prospective cohort study is to analyze the impact of supplemental home enteral nutrition (HEN) post-esophageal cancer surgery on nutritional parameters, quality of life (QL), and patient satisfaction. A systematic review reported that over 60% of patients lose >10% of both body weight and BMI by 6 months after esophagectomy. Enteral feeding (EF) is increasingly a modern standard postoperatively; however, the impact of extended HEN postdischarge has not been systematically studied. One hundred forty-nine consecutive patients [mean age 62 +/- 9, 80% male,76% adenocarcinoma, 66% on multimodal protocols, and 69% with BMI >= 25 kg/m2] were studied. Jejunal EF commenced day 1 postoperatively, and supplemental overnight HEN (764 kcal; 32g protein) continued on discharge for a planned further 4 weeks. Weight, BMI, and body composition analysis (bioimpedance analysis) were measured at baseline, preoperatively and at 1, 3, and 6 months, along with the EORTC QLQ-C30/OES18 QL measures. A patient satisfaction questionnaire addressed eight key items in relation to HEN (max score 100/item). Median (range) total duration of EF was 49 days (28-96). Overall compliance was 96%. At 6 months, compared with preoperatively, 58 (39%) patients lost >10% weight, with median (IQR) loss of 6.8 (4-9) kg, and 62 (41%) patients lost >10% BMI. Lean body mass and body fat were significantly (p < 0.001) decreased. Mean global QL decreased (p < 0.01) from 82 to 72. A high mean satisfaction score (>70 +/- 11/100) was reported, >80 for practical training, activities of daily living, pain, anxiety, recovery and impact on caregivers, with lower scores for appetite (33 +/- 24) and sleep (63 +/- 30). Supplemental HEN for a minimum of one month postdischarge is associated with high compliance and patient satisfaction. Weight and BMI loss may still be substantial, however this may be less than published literature, in addition the impact on HR-QL may be attenuated. HEN has both subjective and objective rationale and merits further validation toward optimizing nutritional recovery and overall wellbeing. PMID- 28859365 TI - Incidence of brain metastasis from esophageal cancer. AB - We investigated whether the incidence of brain metastasis (BM) from primary esophageal and esophagogastric cancer is increasing. A single-institution retrospective review identified 583 patients treated from January 1997 to January 2016 for stages I through IV cancer of the esophagus and esophagogastric junction (follow-up, >=3 months). Collected data included demographic information, date and staging at primary diagnosis, histologic subtype, treatment regimen for primary lesion, date of BM diagnosis, presence or absence of central nervous system symptoms, presence or absence of extracranial disease, treatment regimen for intracranial lesions, and date of death. The overall cohort included 495 patients (85%) with adenocarcinoma and 82 (14%) with squamous cell carcinoma (492 [84%] were male; median age at diagnosis, 68 years [range: 26-90 years]). BM was identified in 22 patients (3.8%) (median latency after primary diagnosis, 11 months). Among patients with BM, the primary histology was adenocarcinoma in 21 and squamous cell carcinoma in 1 (P = 0.30). BM developed in 12 who were initially treated for locally advanced disease and in 10 stage IV patients who presented with distant metastases. Overall survival (OS) after BM diagnosis was 18% at 1 year (median, 4 months). No difference in OS after BM diagnosis was observed in patients initially treated for localized disease compared to patients who presented with stage IV disease; however, OS was superior for patients who initially had surgical resection compared to patients treated with whole brain radiotherapy or stereotactic radiosurgery alone (1-year OS, 67% vs. 0%; median OS, 13.5 vs. 3 months; P = 0.003). The incidence of BM is low in patients with esophageal cancer. Outcomes were poor overall for patients with BM, but patients who underwent neurosurgical resection had improved survival. PMID- 28859366 TI - Variation by stage in the effects of prediagnosis weight loss on mortality in a prospective cohort of esophageal cancer patients. AB - Cancer cachexia is increasingly recognized as a poor prognostic marker for various tumor types. Weight loss in esophageal cancer is multifactorial, as patients with bulky tumors also have reduced ability to eat. We aimed to investigate the relationship between prediagnosis weight loss and mortality in esophageal cancer and to determine whether these associations vary with tumor stage. We conducted a prospective cohort study of esophageal cancer patients at two tertiary centers. We recorded baseline patient characteristics including medications, smoking, body mass index, and weight loss in the year prior to diagnosis, and collected data on treatment and outcomes. We used Cox regression modeling to determine the associations between percent weight loss and outcomes. The main outcome of interest was all-cause mortality; secondary endpoints were esophageal cancer-specific mortality and development of metastases. We enrolled 134 subjects, the majority of whom had adenocarcinoma (82.1%); median percent weight loss was 4.7% (IQR: 0%-10.9%). Increasing percent weight loss was not associated with all-cause mortality (ptrend = 0.36). However, there was evidence of significant interaction by tumor stage (p = 0.02). There was a strong and significant association between prediagnosis weight loss and mortality in patients with T stages 1 or 2 (adjusted HR 8.26 for highest versus lowest tertile, 95%CI 1.11-61.5, ptrend = 0.03) but not for T stages 3 or 4 (ptrend = 0.32). Body mass index one year prior to diagnosis was not associated with mortality. Prediagnosis weight loss was associated with increased all-cause mortality only in patients with early stage esophageal cancer. This suggests that tumor-related cachexia can occur early in esophageal cancer and represents a poor prognostic marker. PMID- 28859368 TI - Surgical strategy of esophageal resection and reconstruction for aortoesophageal fistula. AB - Aortoesophageal fistula is a critical and life-threatening disease. The cardiovascular strategy for graft replacement has been widely discussed. However, the surgical strategy of esophageal resection and reconstruction for aortoesophageal fistula has rarely been discussed. The objective of this study is to establish a surgical strategy and procedure of esophageal resection and reconstruction for aortoesophageal fistula. Eleven patients with aortoesophageal fistula who underwent aortic graft replacement and esophagectomy between 2008 and 2015 at Kobe University Hospital were enrolled in this study. Patient characteristics, operative methods, and clinical outcomes were obtained by retrospective chart review. All 11 patients underwent graft replacement, esophagectomy, and omental wrapping. Ten esophagectomies were simultaneously accomplished in the same operative field as aortic graft replacement. Seven patients underwent subtotal esophagectomy from a left thoracotomy, and three patients underwent upper hemiesophagectomy from a median sternotomy. The other patient underwent staged esophagectomy from a right thoracotomy. Seven of 11 patients (63.6%) successfully underwent staged esophageal reconstruction. Pedicled jejunal transfer with supercharge and superdrainage were performed in six patients, and ileocecal reconstruction was performed in one patient. Median survival time in the patients with esophageal reconstruction was 21 months while that in the patients without esophageal reconstruction was 10 months. Six of 7 patients (85.7%) who underwent esophageal reconstructions were alive. Our surgical strategy for aortoesophageal fistula, which includes simultaneous graft replacement and esophagectomy in the same operative field and staged reconstruction by pedicled jejunal transfer to ensure omental wrapping, is feasible and promising. PMID- 28859367 TI - Failure of neoadjuvant chemotherapy for resectable esophageal squamous cell carcinoma. AB - Neoadjuvant treatment has become standard care for patients with resectable esophageal cancer. However, some patients cannot undergo surgery or curative resection because of disease progression during neoadjuvant treatment. The aim of this study is to identify the pretreatment characteristics of patients in whom neoadjuvant treatment failed. The study enrolled 231 patients who underwent chemotherapy with cisplatin and 5-fluorouracil (CF) as neoadjuvant therapy for T1N1-3 or T2-3 any-N esophageal squamous cell carcinoma (ESCC). Of these patients, 201 (87.0%) underwent curative resection (R0) and 30 (13.0%) could not undergo curative resection; 19 patients (8.2%) underwent incomplete resection (R1 or R2), and 11 patients (4.8%) could not undergo surgery because of disease progression. We compared clinical characteristics and survival between patients who underwent curative resection (curative group) and those who could not undergo curative resection (noncurative group) to determine the factors predicting noncurative treatment. The noncurative group had significantly worse disease specific survival than the curative group (P < 0.001). All patients in the noncurative group had cT3 tumors. In 141 patients with cT3 tumors, those in the noncurative group were more likely to have higher serum SCC antigen concentration (P = 0.021), location of the main tumor in the upper to the middle third of the esophagus (P = 0.071), intramural metastases (P < 0.001), advanced N category (P = 0.016), and bulky lymph node metastases (P = 0.060). Multivariate logistic regression analysis identified location of the main tumor in the upper to the middle third of the esophagus (P = 0.047), intramural metastases (P = 0.002), and nodal metastases (N1, P = 0.014; N2, P = 0.015, respectively) as independent predictors of treatment failure in patients with cT3 tumors. Neoadjuvant CF therapy alone may not be effective for patients with cT3 tumors accompanied by these risk factors, and the efficacy of alternative strategies, such as triplet chemotherapy or chemoradiotherapy, should be evaluated. PMID- 28859369 TI - Precision GERD management for the 21st century. AB - The highly heterogeneous nature of gastroesophageal reflux disease (GERD), together with the multiplicity of available diagnostic and therapeutic options (lifestyle, pharmacologic, endoscopic and surgical) available today call for a new approach that funnels the multidimensionality of the disease into precise and effective algorithms - reviewed herein- aimed at improving clinical outcomes. PMID- 28859370 TI - Management of recurrent tracheoesophageal fistula after esophageal atresia and follow-up. AB - Recurrent tracheoesophageal fistula (rTEF) is a complex complication after the repair of esophageal atresia (EA) and remains a challenge because of difficulties in preoperative management and the substantial rates of mortality and morbidity after reoperation. By reviewing a single institution's experience in the management of rTEF and assessing the outcome, we aimed to provide an optimal approach for managing rTEF and to evaluate growth and feeding problems after reoperations. The medical records of 35 patients with rTEF treated at a single institution from June 2012 to December 2015 were reviewed, and follow-up data were collected from all survivors. The diagnosis of rTEF was made using a modified esophagram in 32 of 35 patients. Before reoperation, all patients received continuous aspiration to prevent reflux and aspiration pneumonia by placing two nasogastric tubes at the level of the fistula and into the stomach, and they received enteral nutrition through a jejunal feeding tube. Thirty-five patients received a total of 41 reoperations, including 12 operations of fistula resection, 28 reanastomosis, and 1 esophageal replacement. The incidence of postoperative anastomotic leak (AL), anastomotic stricture (AS), and repeat recurrences was 40.0%, 17.1%, and 11.4%, respectively. The mortality rate was 8.6%. All survivors achieved full oral intake. Mid-term follow-up (median of 18 months) revealed that 7 (21.9%) presented prolonged meal time, 6 (18.8%) had feeding refusal, 8 (25.0%) experienced coughing during feeding, and 7 (21.9%) had vomiting during feeding. According to the growth data, 5 survivors (15.6%) presented with growth retardation, including stunting (n = 1), wasting (n = 2), and underweight (n = 2). The modified esophagram is an effective and reliable method for diagnosing rTEF. Optimized preoperative management and surgical techniques lead to a satisfactory outcome. Nevertheless, nutritional evaluation and feeding guidance by a nutritionist after reoperation are recommended. PMID- 28859371 TI - Treatment strategies in recurrent esophageal or junctional cancer. AB - Little evidence is available about survival rates in patients with recurrent disease after potentially curative surgery for esophageal or junctional cancer. Only in limited occasions, potentially curative salvage strategies are available. The aim of this study is to analyze survival rates and patterns of dissemination, and to identify independent prognostic factors in a consecutive series of patients who develop recurrent esophageal or junctional cancer. Between 1994 and 2015, patients who developed disease recurrence after neoadjuvant chemo(radio)therapy followed by radical esophagectomy for esophageal or junctional cancer were retrospectively analyzed. The Kaplan-Meier estimates were performed to calculate and compare overall survival between patients with different patterns of dissemination and to compare between different treatment strategies. Furthermore, univariate and multivariate Cox-regression analyses were performed to identify independent prognostic factors for post recurrence survival. In this study, we included 219 patients. The median overall survival of all included patients was 3.2 months (range: 0.0-101.1 months). The median overall survival in patients with exclusively locoregional recurrence (n = 23, 10.8%) was 4.9 months (range: 0.1- 55.6) and 2.9 months (range: 0.0-101.1) in patients who had distant metastases (n = 189, 89.2%), P = 0.003. Patients who received treatment aimed at complete tumor eradication (n = 28, 13.7%) had a median overall survival of 13.6 months (range: 1.1-101.1) and palliative treated patients (n = 94, 46.1%) of 4.7 months (range: 0.3-25.6), P < 0.001. In a selected group of patients survival of more than 20 months was achieved. Univariate and multivariate Cox-regression analysis showed that a higher age at the diagnosis of recurrent disease (hazard ratio: 1.087, P <= 0.001), an irradical resection of the primary tumor (hazard ratio: 3.355, P = < 0.001), the number of positive lymph nodes after neoadjuvant therapy (hazard ratios: ypN2 = 1.724 (P = 0.024) and ypN3 = 2.082 (P = 0.028) and the presence of a single hematogenous distant metastases (hazard ratio: 2.281, P = 0.003) or more than one hematogenous distant metastasis (hazard ratio: 2.385, P = 0.005) were associated with a shorter postrecurrence survival. The prognosis of patients who develop recurrent esophageal or junctional cancer is poor. In a selected group of patients however relatively long survival can be achieved. This offers new perspectives to improve treatment strategies and survival rates. PMID- 28859372 TI - On the stability of nucleoside diphosphate glucose metabolites: implications for studies of plant carbohydrate metabolism. AB - Nucleoside diphosphate sugars (NDP-sugars) are the substrates for biosynthesis of oligo- and polysaccharides, such as starch and cellulose, and are also required for biosynthesis of nucleotides, ascorbic acid, several cofactors, glycoproteins and many secondary metabolites. A controversial study that questions the generally accepted pathway of ADP-glucose and starch synthesis in plants is based, in part, on claims that NDP-sugars are unstable at alkaline pH in the presence of Mg2+ and that this instability can lead to unreliable results from in vitro assays of enzyme activities. If substantiated, this claim would have far reaching implications for many published studies that report on the activities of NDP-sugar metabolizing enzymes. To resolve this controversy, we investigated the stability of UDP- and ADP-glucose using biophysical, namely nuclear magnetic resonance (NMR), and highly specific enzymatic methods. Results obtained with both techniques indicate that NDP-sugars are not as unstable as previously suggested. Moreover, their calculated in vitro half-lives are significantly higher than estimates of their in planta turnover times. This indicates that the physico-chemical stability of NDP-sugars has little impact on their concentrations in vivo and that NDP-sugar levels are determined primarily by the relative rates of enzymatic synthesis and consumption. Our results refute one of the main arguments for the controversial pathway of starch synthesis from imported ADP-glucose produced by sucrose synthase in the cytosol. PMID- 28859373 TI - Phenotyping of field-grown wheat in the UK highlights contribution of light response of photosynthesis and flag leaf longevity to grain yield. AB - Improving photosynthesis is a major target for increasing crop yields and ensuring food security. Phenotyping of photosynthesis in the field is critical to understand the limits to crop performance in agricultural settings. Yet, detailed phenotyping of photosynthetic traits is relatively scarce in field-grown wheat, with previous studies focusing on narrow germplasm selections. Flag leaf photosynthetic traits, crop development, and yield traits were compared in 64 field-grown wheat cultivars in the UK. Pre-anthesis and post-anthesis photosynthetic traits correlated significantly and positively with grain yield and harvest index (HI). These traits included net CO2 assimilation measured at ambient CO2 concentrations and a range of photosynthetic photon flux densities, and traits associated with the light response of photosynthesis. In most cultivars, photosynthesis decreased post-anthesis compared with pre-anthesis, and this was associated with decreased Rubisco activity and abundance. Heritability of photosynthetic traits suggests that phenotypic variation can be used to inform breeding programmes. Specific cultivars were identified with traits relevant to breeding for increased crop yields in the UK: pre-anthesis photosynthesis, post anthesis photosynthesis, light response of photosynthesis, and Rubisco amounts. The results indicate that flag leaf longevity and operating photosynthetic activity in the canopy can be further exploited to maximize grain filling in UK bread wheat. PMID- 28859374 TI - Vitamin B1 diversity and characterization of biosynthesis genes in cassava. AB - Vitamin B1, which consists of the vitamers thiamin and its phosphorylated derivatives, is an essential micronutrient for all living organisms because it is required as a metabolic cofactor in several enzymatic reactions. Genetic diversity of vitamin B1 biosynthesis and accumulation has not been investigated in major crop species other than rice and potato. We analyzed cassava germplasm for accumulation of B1 vitamers. Vitamin B1 content in leaves and roots of 41 cassava accessions showed significant variation between accessions. HPLC analyses of B1 vitamers revealed distinct profiles in cassava leaves and storage roots, with nearly equal relative levels of thiamin pyrophosphate and thiamin monophosphate in leaves, but mostly thiamin pyrophosphate in storage roots. Unusually, the cassava genome has two genes encoding the 4-amino-2-methyl-5 hydroxymethylpyrimidine phosphate synthase, THIC (MeTHIC1 and MeTHIC2), both of which carry a riboswitch in the 3'-UTR, as well as the adenylated thiazole synthase, THI1 (MeTHI1a and MeTHI1b). The THIC and THI1 genes are expressed at very low levels in storage roots compared with the accumulation of vitamin B1, indicating only limited biosynthesis de novo therein. In leaves, vitamin B1 content is negatively correlated with THIC and THI1 expression levels, suggesting post-transcriptional regulation of THIC by the riboswitch present in the 3'-UTR of the THIC mRNA and regulation of THI1 by promoter activity or alternative post transcriptional mechanisms. PMID- 28859375 TI - Filamentous sieve element proteins are able to limit phloem mass flow, but not phytoplasma spread. AB - In Fabaceae, dispersion of forisomes-highly ordered aggregates of sieve element proteins-in response to phytoplasma infection was proposed to limit phloem mass flow and, hence, prevent pathogen spread. In this study, the involvement of filamentous sieve element proteins in the containment of phytoplasmas was investigated in non-Fabaceae plants. Healthy and infected Arabidopsis plants lacking one or two genes related to sieve element filament formation-AtSEOR1 (At3g01680), AtSEOR2 (At3g01670), and AtPP2-A1 (At4g19840)-were analysed. TEM images revealed that phytoplasma infection induces phloem protein filament formation in both the wild-type and mutant lines. This result suggests that, in contrast to previous hypotheses, sieve element filaments can be produced independently of AtSEOR1 and AtSEOR2 genes. Filament presence was accompanied by a compensatory overexpression of sieve element protein genes in infected mutant lines in comparison with wild-type lines. No correlation was found between phloem mass flow limitation and phytoplasma titre, which suggests that sieve element proteins are involved in defence mechanisms other than mechanical limitation of the pathogen. PMID- 28859376 TI - Natural variation in Arabidopsis thaliana reveals shoot ionome, biomass, and gene expression changes as biomarkers for zinc deficiency tolerance. AB - Zinc (Zn) is an essential nutrient for plants, with a crucial role as a cofactor for many enzymes. Approximately one-third of the global arable land area is Zn deficient, leading to reduced crop yield and quality. To improve crop tolerance to Zn deficiency, it is important to understand the mechanisms plants have adopted to tolerate suboptimal Zn supply. In this study, physiological and molecular aspects of traits related to Zn deficiency tolerance were examined in a panel of 19 Arabidopsis thaliana accessions. Accessions showed a larger variation for shoot biomass than for Zn concentration, indicating that they have different requirements for their minimal Zn concentration required for growth. Accessions with a higher tolerance to Zn deficiency showed an increased expression of the Zn deficiency-responsive genes ZIP4 and IRT3 in comparison with Zn deficiency sensitive accessions. Changes in the shoot ionome, as a result of the Zn treatment of the plants, were used to build a multinomial logistic regression model able to distinguish plants regarding their Zn nutritional status. This set of biomarkers, reflecting the A. thaliana response to Zn deficiency and Zn deficiency tolerance, can be useful for future studies aiming to improve the performance and Zn status of crop plants grown under suboptimal Zn concentrations. PMID- 28859377 TI - DORNROSCHEN, DORNROSCHEN-LIKE, and PUCHI redundantly control floral meristem identity and organ initiation in Arabidopsis. AB - The biphasic floral transition in Arabidopsis thaliana involves many redundant intersecting regulatory networks. The related AP2 transcription factors DORNROSCHEN (DRN), DORNROSCHEN-LIKE (DRNL), and PUCHI individually execute well characterized functions in diverse developmental contexts, including floral development. Here, we show that their combined loss of function leads to synergistic floral phenotypes, including reduced floral merosity in all whorls, which reflects redundant functions of all three genes in organ initiation rather than outgrowth. Additional loss of BLADE-ON-PETIOLE1 (BOP1) and BOP2 functions results in the complete conversion of floral meristems into secondary inflorescence shoots, demonstrating that all five genes define an essential regulatory network for establishing floral meristem identity, and we show that their functions converge to regulate LEAFY expression. Thus, despite their largely discrete spatiotemporal expression domains in the inflorescence meristem and early floral meristem, PUCHI, DRN, and DRNL interdependently contribute to cellular fate decisions. Auxin might represent one potential non-cell-autonomous mediator of their gene functions, because PUCHI, DRN, and DRNL all interact with auxin transport and biosynthesis pathways. PMID- 28859378 TI - Relationship of leaf oxygen and carbon isotopic composition with transpiration efficiency in the C4 grasses Setaria viridis and Setaria italica. AB - Leaf carbon and oxygen isotope ratios can potentially provide a time-integrated proxy for stomatal conductance (gs) and transpiration rate (E), and can be used to estimate transpiration efficiency (TE). In this study, we found significant relationships of bulk leaf carbon isotopic signature (delta13CBL) and bulk leaf oxygen enrichment above source water (Delta18OBL) with gas exchange and TE in the model C4 grasses Setaria viridis and S. italica. Leaf delta13C had strong relationships with E, gs, water use, biomass, and TE. Additionally, the consistent difference in delta13CBL between well-watered and water-limited plants suggests that delta13CBL is effective in separating C4 plants with different availability of water. Alternatively, the use of Delta18OBL as a proxy for E and TE in S. viridis and S. italica was problematic. First, the oxygen isotopic composition of source water, used to calculate leaf water enrichment (Delta18OLW), was variable with time and differed across water treatments. Second, water limitations changed leaf size and masked the relationship of Delta18OLW and Delta18OBL with E. Therefore, the data collected here suggest that delta13CBL but not Delta18OBL may be an effective proxy for TE in C4 grasses. PMID- 28859379 TI - Water content, adenylate kinase, and mitochondria drive adenylate balance in dehydrating and imbibing seeds. AB - Water and life are inexorably linked, but some organisms are capable of losing almost all cellular water to enter a non-metabolic state of anhydrobiosis. This raises intriguing questions about how energy metabolism is managed during such transitions. Here, we have investigated adenylate metabolism during seed imbibition and drying using intact or fragmented pea (Pisum sativum L.) seeds. AMP was confirmed as the major adenylate stored in dry seeds, and normal adenylate balance was rapidly restored upon rehydration of the tissues. Conversely, re-drying of fully imbibed seeds reversed the balance toward AMP accumulation. The overall analysis, supported by in vitro enzyme mimicking experiments, shows that during tissue dehydration, when oxidative phosphorylation is no longer efficient because of decreasing water content, the ATP metabolic demand is met by adenylate kinase, resulting in accumulation of AMP. During seed imbibition, adenylate balance is rapidly restored from the AMP stock by the concerted action of adenylate kinase and mitochondria. The adenylate balance in orthodox seeds, and probably in other anhydrobiotes, appears to be simply driven by water content throughout the interplay between ATP metabolic demand, adenylate kinase, and oxidative phosphorylation, which requires mitochondria to be energetically efficient from the onset of imbibition. PMID- 28859380 TI - Actin fringes of polar cell growth. AB - The eukaryotic actin cytoskeleton is a highly dynamic framework that is involved in many biological processes, such as cell growth, division, morphology, and motility. G-actin polymerizes into microfilaments that associate into bundles, patches, and networks, which, in turn, organize into higher order structures that are fundamental for the course of important physiological events. Actin rings are an example for such higher order actin entities, but this term represents an actually diverse set of subcellular structures that are involved in various processes. This review especially sheds light on a crucial type of non constricting ring-like actin networks, and categorizes them under the term 'actin fringe'. These 'actin fringes' are visualized as highly dynamic and yet steady structures in the tip of various polarized growing cells. The present comprehensive overview compares the actin fringe characteristics of rapidly elongating pollen tubes with several related actin arrays in other cell types of diverse species. The current state of knowledge about various actin fringe functions is summarized, and the key role of this structure in the polar growth process is discussed. PMID- 28859381 TI - Endoplasmic reticulum and Golgi apparatus: old friends, novel intimate relationships. PMID- 28859382 TI - Evaluation of treatment pattern and symptom control in patients with gastroesophageal reflux disease: multihospital questionnaire survey on the current situation in Korea. AB - Proton pump inhibitors (PPIs) are the most effective treatment for gastroesophageal reflux disease (GERD); however, a considerable number of patients fail to respond to PPI therapy and complain of nocturnal heartburn and sleep disturbance. The aims of this study are to evaluate the treatment pattern of GERD-related medications and their efficacy in relieving nocturnal heartburn. A total of 334 patients with GERD receiving PPI therapy within 6 months were enrolled in a multihospital questionnaire survey from January, 2014 to March, 2015. GERD symptoms and patients' satisfaction were assessed by patient questionnaires, and treatment patterns of GERD-related medications were assessed by investigators. Among the 334 patients, 95.8% used PPI once daily and 58.6% used a half-dose of PPI. The PPI treatment pattern was changed in 26.6% of all patients, of those, 54% of the patients doubled the PPI dose, and 29.2% of the patients switched to another PPI. Approximately 60.3% of all patients were prescribed more than three GERD-related medications. The overall satisfaction rate was 61.8%, and 32.2% of patients experienced nocturnal heartburn and sleep disturbance. In the extended-release PPI group, there were fewer nocturnal symptoms compared with the conventional PPI group (10% vs. 33.7%, respectively, P = 0.027). The use of more than three medications was inversely associated with patients' satisfaction (OR = 0.355, 95% CI; 0.197-0.642, P = 0.001). Most patients were prescribed adjunctive medications other than PPIs; however, patients' satisfaction was inversely associated with multiple drugs. Patients' satisfaction was superior in extended-release PPIs than conventional PPIs for the relief of nocturnal heartburn in Korean patients. PMID- 28859383 TI - Effect of alginate in patients with GERD hiatal hernia matters. AB - Alginate-based formulations are frequently used as add-on proton pump inhibitor (PPI) therapy to help control of heartburn and regurgitation. There are limited data regarding the mechanisms and effects of alginate-based formulations. We aimed to evaluate the effects of the sodium alginate intake and its likely temporal relations on intraesophageal reflux events by MII-pH in patients with and without hiatal hernia (HH). Fifty GERD patients (18 with HH, 32 without HH) with heartburn or regurgitation once a week or more common were included. After combined multichannel intraluminal impedance and pH-metry (MII-pH) had been performed, all patients were asked to eat the same standard meal (double cheeseburger, 1 banana, 100 g regular yoghurt, and 200 mL water with total energy value of 744 kcal: 37.6% of carbohydrates, 21.2% of proteins, and 41.2% of lipids) during two consecutive days. On separate random two consecutive days, all patients took 10 mL of sodium alginate (GA; Gaviscon Advance; Reckitt Benckiser Healthcare, Hull, UK) or 10 mL of water, 30 minutes after the refluxogenic meal. After eating refluxogenic meal, patients were examined 1/2 hour for basal conditions, 1 hour in upright, and 1 hour in supine positions. Alginate significantly decreased acid reflux after intake at the first hour in comparison to water in patients with HH (6.1 vs. 13.7, P = 0.004) and without HH (3.5 vs. 5.5, P = 0.001). Weakly acid reflux were increased at the first hour in patients with HH (3.4 vs. 1.3, P = 0.019) and without HH (1.7 vs. 5, P = 0.02) compared to water. There was no distinctive effect of alginate on the height of proximal migration of reflux events in patients with HH and without HH. Alginate decreases acid reflux events within a limited time period, especially at the first hour both in patients with and without HH. Alginate has no effect on the height of reflux events along the esophagus both in patients with and without HH. PMID- 28859384 TI - Symptom association latency during ambulatory reflux monitoring: a review of 1445 symptoms. AB - To determine the optimal time window of symptom association in GERD patient, a 2 minute time window is nonapplicable for all gastroesophageal reflux (GERD) symptoms and 5 minutes remains an arbitrary choice. Symptom association analysis is a critical component in pH-impedance (imp) testing. Symptom index (SI) and symptom association probability (SAP) are the two widely accepted methods. Both were introduced in the preimpedance era and initially tested in patients with typical GERD symptoms. We reviewed ambulatory pH-imp studies of (294) patients referred for evaluation of possible GERD symptoms from January 2012 to August 2015. Patients with heartburn (HB), regurgitation (Reg), cough, and throat clearing (TC) alone or in combination were reviewed. The analysis time windows were separated into five intervals (0-1, 1-2, 2-3, 3-4, 4-5 minutes) to explore the frequency of symptom occurrence in each window. The SI was then calculated and contrasted to the usual 5-minute window; similar calculations were made to SAP 2-minute windows. Secondary analysis was performed to test whether symptoms due to acid reflux have a different time perception than non-acid. Overall, there were 1445 total symptoms preceded by impedance detected reflux. Frequency analysis showed that (34.7%- 86.7%) of symptoms occurred in the first minute after onset of the reflux. chi2 showed a significant association between SI with 1 minute and SAP for heartburn (P <= 0.0001) and regurgitation (P = 0.0003). There was also a significant association between cough with 2-minute window and SAP (P = 0.025). There was no significant association between TC at 1-, 2-, 3-, and 4-minute time windows and SAP. There was no evidence of increased frequency of positive reflux to symptoms over time. There was also no significant difference in time window in relation to acid or nonacid reflux. It seems doubtful that a universal time window can be applied to all GERD symptoms to calculate symptom association. PMID- 28859385 TI - Operative and survival outcomes in a series of 100 consecutive cases of robot assisted transhiatal esophagectomies. AB - Robotic-assisted transhiatal esophagectomy (RATE) is a technically complex procedure with potential for improved postoperative outcomes. In this report, we describe our experience with RATE in a large case series. A retrospective review was conducted to collect clinical, outcomes, and survival data for 100 consecutive patients with esophageal cancer (n = 98) and benign (n = 2) conditions undergoing RATE between March 2007 and December 2014. Progression-free (PFS) and overall (OS) survival were estimated using the Kaplan-Meier curves with comparisons by log-rank tests. Median operative time and estimated blood loss were 264 minutes and 75 mL, respectively. Median intensive care unit stay was 1 day and median length of hospital stay was 8 days. Postoperative complications commonly observed were nonmalignant pleural effusion (38%) and recurrent laryngeal nerve injury (33%); 30 day mortality rate was 2%. Median number of lymph nodes removed during RATE was 17 and R0 resection was achieved in 97.8% patients. At the end of the median follow-up period of 27.7 months, median PFS was 41 months and median OS was 54 months. 1-year and 3-year PFS rates were 82% (95% CI, 75%-89%) and 53% (95% CI, 42%-62%), respectively, and OS rates were 95% (95% CI, 91%-99%) and 57% (95% CI, 46%-67%). In our experience, RATE is an effective and safe oncologic surgical procedure in a carefully selected group of patients with acceptable operative time, minimal blood loss, standard postoperative morbidity and adequate PFS and OS profiles. PMID- 28859386 TI - Validation of EORTC QLQ-OES18 for Chinese patients with esophageal cancer. AB - The aim of this study is to evaluate the reliability, validity, and acceptability of the Chinese version of the EORTC QLQ-OES18 in patients with esophageal cancer. The questionnaire was translated according to the guideline of the EORTC. One hundred and forty-nine patients with esophageal cancer from Tianjin Medical University Cancer Institute and Hospital completed the Karnofsky performance scale (KPS) and the simplified Chinese EORTC QLQ-C30/OES18 scales during July 2013 to January 2014. The results were statistically analyzed by Cronbach's alpha coefficient, Spearman correlation test with multiple strengthen analysis, and Wilcoxon Rank Sum test. The internal consistency (Cronbach's alpha coefficient) of all four scales (dysphagia, eating, reflux, and pain) was 0.689-0.822, which were satisfactory or near satisfactory. The absolute values of correlation of each scale between EORTC QLQ-OES18 and EORTC QLQ-C30 were 0.002-0.750 while there was no significant difference between groups divided by KPS scores. We confirmed the Chinese version of EORTC QLQ-OES18 appears to be a reliable, valid, and acceptable instrument for measuring the health-related quality of life of patients with esophageal cancer in mainland China. PMID- 28859387 TI - Perioperative outcomes of single-port mediastinoscope-assisted transhiatal esophagectomy for thoracic esophageal cancer. AB - We developed an en bloc lymphadenectomy method in the upper mediastinum with a single-port mediastinoscopic cervical approach. This study was designed to evaluate the safety and efficacy of single-port mediastinoscope-assisted transhiatal esophagectomy for thoracic esophageal cancer. The perioperative outcomes of 60 patients with thoracic esophageal cancer who underwent this operation between March 2014 and June 2016 were retrospectively analyzed. The upper mediastinal dissection including lymphadenectomy along the left recurrent laryngeal nerve, using a left cervical approach, was performed with a single-port mediastinoscopic technique, which was used to improve the visibility and handling in the deep mediastinum around the aortic arch. The lymphadenectomy along the right recurrent laryngeal nerve was performed under direct vision using a right cervical approach. Bilateral cervical approaches were followed by hand-assisted laparoscopic transhiatal esophagectomy with en bloc lymphadenectomy in the middle and lower mediastinum. Tumors were mainly located in the middle thoracic esophagus (n = 33), and most tumors were squamous cell carcinoma (n = 58). Pretreatment diagnoses were stage I, 19; II, 13; III, 24; IV, 4. Preoperative chemotherapy was performed for 40 patients. The median operation time and blood loss were 363 minutes and 235 mL, respectively. There were two patients who underwent conversion to thoracotomy. Perioperative complications were evaluated and graded according to the Clavien-Dindo (CD) and the Esophagectomy Complications Consensus Group (ECCG) classifications. Postoperatively, pneumonia was observed in four patients (CD, Grade II, 2; Grade IIIb, 2), although vocal cord palsy was more frequent (ECCG, Type I, 12; Type III, 8). The median number of thoracic lymph nodes resected was 21, and the R0 resection rate was 95%. Single-port mediastinoscope-assisted transhiatal esophagectomy is feasible, in terms of perioperative outcomes, for a radical surgery for thoracic esophageal cancer, although its safety needs to be further demonstrated. PMID- 28859388 TI - Postoperative pain management after esophagectomy: a systematic review and meta analysis. AB - Effective pain management after esophagectomy is essential for patient comfort, early recovery, low surgical morbidity, and short hospitalization. This systematic review and meta-analysis aims to determine the best pain management modality focusing on the balance between benefits and risks. Medline, Embase, and the Cochrane library were systematically searched to identify all studies investigating different pain management modalities after esophagectomy in relation to primary outcomes (postoperative pain scores at 24 and 48 hours, technical failure, and opioid consumption), and secondary outcomes (pulmonary complications, nausea and vomiting, hypotension, urinary retention, and length of hospital stay). Ten studies investigating systemic, epidural, intrathecal, intrapleural and paravertebral analgesia involving 891 patients following esophagectomy were included. No significant differences were found in postoperative pain scores between systemic and epidural analgesia at 24 (mean difference (MD) 0.89; 95% confidence interval (CI) -0.47-2.24) and 48 hours (MD 0.15; 95%CI -0.60-0.91), nor described for systemic and other regional analgesia. Also, no significant differences in pulmonary complication rates were identified between systemic and epidural analgesia (relative risk (RR) 1.69; 95%CI 0.86 3.29), or between systemic and paravertebral analgesia (RR 1.49; 95%CI 0.31 7.12). Technical failure ranged from 17% to 22% for epidural analgesia. Sample sizes were too small to draw inferences on opioid consumption, the risk of nausea and vomiting, hypotension, urinary retention, and length of hospital stay when comparing the different pain management modalities including systemic, epidural, intrathecal, intrapleural, and paravertebral analgesia. This systematic review and meta-analysis shows no differences in postoperative pain scores or pulmonary complications after esophagectomy between systemic and epidural analgesia, and between systemic and paravertebral analgesia. Further randomized controlled trails are warranted to determine the optimal pain management modality after esophagectomy. PMID- 28859389 TI - Impacts of treatments on the quality of life among esophageal squamous cell carcinoma patients. AB - This study aims to investigate the effects of treatments on the quality of life for patients with esophageal squamous cell carcinoma patients diagnosed at early and late stages. From a medical center in central Taiwan, patients who had been diagnosed with esophageal squamous cell carcinoma from February 2007 and March 2011 were recruited. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Oesophageal 18 (QLQ-OES18), quality of life scores for 105 esophageal squamous cell carcinoma patients were obtained and assessed. Multivariate analysis was performed on the quality of life scores after stratification by cancer stage. Among early-stage esophageal squamous cell carcinoma patients, those received only surgery (S-only) performed better in physical and social functioning compared with patients who underwent surgery and concurrent chemoradiotherapy (S+CCRT) (beta = 9.0, P = 0.03; beta = 12.1, P = 0.04, respectively). For those that received only concurrent chemoradiotherapy (CCRT-only), they performed worse in role and emotional functioning relative to S+CCRT patients (beta = -17.2, P = 0.02; beta = -15.7, P = 0.05, respectively). Among late-stage patients, CCRT-only treatment gave insignificantly better global health status and functional scale scores and less severe symptoms compared to the S+CCRT option. Better functional scores and less aggravated symptoms are observed in early-stage esophageal squamous cell carcinoma patients who received surgery-only treatment relative to those that underwent both surgery and chemoradiotherapy. For late-stage esophageal cancer patients, the measured difference of quality of life is not significant between CCRT-only and S+CCRT treatments. PMID- 28859390 TI - Prognostic relevance of serial endoscopic ultrasound after chemoradiation in esophageal cancer. AB - The objective of this study is the feasibility of sequential endoscopic and endosonographic measurement of locoregional tumor load for the prediction of tumor recurrence in patients after neoadjuvant or definitive chemoradiotherapy, treated in curative intent for locally advanced esophageal carcinoma. In 67 patients with esophageal cancer, serial endoscopic ultrasound was performed before and after neoadjuvant (25) or definitive (42) chemoradiotherapy. Rate of complete endoscopic and endosonographic tumor response, reduction in tumor length or circumferential tumorous extension, maximal tumor thickness, lymph node size, and endosonographic uT- and uN-stage shift was measured. Results were correlated with tumor recurrence rate. After chemoradiotherapy, endosonography revealed a complete response of the primary tumor in 27 patients, and complete resolution of suspicious lymph nodes in 24 patients. According to uTN-stage, 43 patients showed a therapeutic response, with stage shift to a lower tumor stage. In patients with macroscopic residual disease, mean tumor thickness decreased from 13 to 9 mm, with nine patients presenting with a decrease of >50%. Mean tumor length decreased from 5.6 to 4.6 cm, with 10 patients showing a decrease of >50%. Mean lymph node size decreased from 14.5 to 12 mm, with four patients having a reduction in size of >50%. Tumor response was generally more pronounced after definitive than after neoadjuvant chemoradiotherapy. During follow-up, 33 patients developed a tumor recurrence. None of the endoscopic and endosonographic parameter analyzed was predictive for patient's prognosis, irrespective of the kind of chemoradiotherapy (neoadjuvant or definitive). Sequential measurement of locoregional tumor load with endoscopic ultrasound before and after chemoradiotherapy is not suitable for the prediction of tumor recurrence risk. PMID- 28859391 TI - Esophagogastric junction outflow obstruction is often associated with coexistent abnormal esophageal body motility and abnormal bolus transit. AB - Currently, the diagnosis of esophageal motility disorders is in part based upon a hierarchical algorithm in which abnormalities of the esophagogastric junction (EGJ) is prioritized. An important metric in evaluating the EGJ is the integrated relaxation pressure (IRP). Patients who do not have achalasia but are found to have an elevated IRP are diagnosed with EGJ outflow obstruction. It has been our observation that a subset of these patients also has a second named motility disorder and may also have abnormal bolus transit. The aim of this study is to determine the frequency of abnormal body motility and or abnormal bolus movement in patients with EGJ outflow obstruction. Further, in an effort to evaluate the potential clinical value in measuring bolus transit as a complement to esophageal manometry, specifically in patients with EGJ outflow obstruction, we analyzed the presenting symptoms of these patients. A total of 807 patients with a mean age of 53 years completed esophageal function testing with impedance monitoring and high resolution manometry between January 2012 and October 2016. There were 74 patients with achalasia who were excluded from the study. Of the remaining 733 patients, 138 (19%) had an elevated IRP and were given a diagnosis of EGJ outflow obstruction. Among these patients, 56 (40%) were diagnosed with an abnormal motility pattern to liquids (ineffective esophageal motility = 28, distal esophageal spasm = 19, Jackhammer = 6), of which 44 (76%) had abnormal bolus transit to liquids, viscous, or both. In contrast, there were 82 patients with EGJ outflow obstruction and normal esophageal motility, of which 33 (40%) had abnormal bolus transit. Patients with preserved esophageal motility and EGJ outflow obstruction were then evaluated. Of the 733 patients, 299 (40%) had intact esophageal motility. Of the 299 patients with normal esophageal motility, 56 patients had an elevated IRP, of which 16 (28%) had abnormal bolus transit. There were 243 (33%) patients with intact esophageal motility and normal IRP. Of these, 56 (23%) patients had abnormal bolus transit. Among patients with abnormal bolus transit, the two most commonly presenting symptoms were dysphagia and heartburn. A substantial percentage of patients with EGJ outflow obstruction have abnormal esophageal body motility and or abnormal bolus transit. The clinical implications of EGJ outflow obstruction need to be further elucidated as current criteria do not allow for the description of other abnormalities in esophageal motility and bolus transit among patients who are given the diagnosis of EGJ outflow obstruction. PMID- 28859392 TI - Long-term wireless pH monitoring of the distal esophagus: prolonging the test beyond 48 hours is unnecessary and may be misleading. AB - Wireless pH monitoring of the esophagus has been widely used to detect GERD for more than a decade. It is generally well tolerated and accepted by patients, but it is still unclear whether prolonging a recording beyond the usual 48 hours can improve the test's diagnostic value. The aim of this study is to examine the diagnostic yield of 96-hour pH monitoring vis-a-vis 24- and 48-hour tests, and to ascertain whether any gain in diagnostic terms was of genuine clinical utility. Patients with suspected GERD underwent 4-day PPI-off wireless pH monitoring of the distal esophagus. The capsule was inserted under endoscopic control, 6 cm above the squamocolumnar junction. Average acid exposure time was calculated after 24, 48, and 96 hours of recording. Ninety-nine patients completed the 96 hour test, and formed the study sample. The wireless test method was used in 42 patients (42.4%) unable to tolerate the traditional pH-monitoring catheter, and in 57 (57.6%) with a previous negative pH study despite symptoms suggestive of GERD. On complete analysis, 47 patients (47.5%) had a pathological test result: 19 patients within the first 24 hours (19.2%, 24 hour group); another 16 after 48 hours (+16.2%, 48 hour group), and a further 12 (+12.1%, 96 hour group) only after 96 hours of monitoring. All 47 patients with an abnormal acid exposure were offered and accepted surgery (10 patients) or medical therapy (37 patients). Clinical follow-up was obtained in all patients with a positive Bravo test result after a median 67 months (IQR: 38-98) using a validated symptom questionnaire. A good outcome after fundoplication or medical therapy was achieved in 73.7% of patients in the 24 hour group, in 62.5% of those in the 48 hour group, and in only 25% of those in the 96 hour group, P = 0.02. Long-term wireless pH monitoring enables an increase in the diagnostic yield over traditional 24- and 48-hour pH studies, but prolonging the test may constitute an unwanted bias and prompt the recruitment of more complex patients, in whom the outcome of surgical or medical therapy may prove less than satisfactory. These findings should be taken into account when establishing the guidelines for assessing GERD with such long-term pH monitoring methods. PMID- 28859393 TI - Open peroral endoscopic myotomy (O-POEM) for the treatment of achalasia. AB - With the development of endoscopic interventions and inspired by the success of peroral endoscopic myotomy (POEM) for the treatment of achalasia, we investigated an old method of direct peroral endoscopic myotomy without a submucosal tunnel for the treatment of achalasia, which we call open peroral endoscopic myotomy (O POEM). In this study, Clinical success was achieved in the patient after O-POEM. A reduction of LES pressure, Eckardt score, and a timed barium esophagogram were observed during follow-up. There were no severe complications and no recurrences during two months of follow-up. Therefore, open peroral endoscopic myotomy is a feasible and effective endoscopic treatment modality for achalasia. However, long term outcomes of O-POEM requires further follow-up. PMID- 28859394 TI - Esophageal achalasia: a risk factor for carcinoma. A systematic review and meta analysis. AB - Achalasia of the cardia is associated with an increased risk of esophageal carcinoma. The real burden of achalasia at the malignancy genesis is still a controversial issue. Therefore, there are no generally accepted recommendations on follow-up evaluation for achalasia patients. This study aims to estimate the risk of esophageal adenocarcinoma and squamous cell carcinoma in achalasia patients. We searched for association between carcinoma and esophageal achalasia in databases up to January 2017 to perform a systematic review and meta-analysis. A total of 1,046 studies were identified from search strategy, of which 40 were selected for meta-analysis. A cumulative number of 11,978 esophageal achalasia patients were evaluated. The incidence of squamous cell carcinoma was 312.4 (StDev 429.16) cases per 100,000 patient-years at risk. The incidence of adenocarcinoma was 21.23 (StDev 31.6) cases per 100,000 patient-years at risk. The prevalence for esophageal carcinoma was 28 carcinoma cases in 1,000 esophageal achalasia patients (CI 95% 2, 39). The prevalence for squamous cell carcinoma was 26 cases in 1,000 achalasia patients (CI 95% 18, 39) and for adenocarcinoma was 4 cases in 1,000 achalasia patients (CI 95% 3, 6).The absolute risk increase for squamous cell carcinoma was 308.1 and for adenocarcinoma was 18.03 cases per 100,000 patients per year. To the best of our knowledge, this is the first meta-analysis estimating the burden of achalasia as an esophageal cancer risk factor. The high increased risk rate for cancer in achalasia patients points to a strict endoscopic surveillance for these patients. Also, the increased risk for developing adenocarcinoma in achalasia patients suggests fundoplication after myotomy, to avoid esophageal reflux and Barret esophagus, a known risk factor for adenocarcinoma. PMID- 28859395 TI - Association of high-dose postoperative opioids with recurrence risk in esophageal squamous cell carcinoma: reinterpreting ERAS protocols for long-term oncologic surgery outcomes. AB - Esophageal squamous cell carcinoma (ESCC) is associated with a poor prognosis and high postoperative recurrence rate. Although postoperative opioid use has been associated with cancer recurrence, its relevance in ESCC has not been determined. Therefore, this study investigated whether high-dose postoperative opioid use was associated with recurrence risk in patients with ESCC. For this retrospective analysis, the medical records of patients who were diagnosed with ESCC and who underwent surgery between January 2006 and December 2010 in the National Cancer Center, Korea were evaluated. Total opioid administration over a 10-day period, from during surgery to postoperative day 9, was calculated. A cutoff value was determined using receiver operating characteristic curve analysis, and patients were classified into the high-use and low-use groups. The primary and secondary outcomes of the study were freedom from recurrence and overall survival, respectively. After propensity score matching, the effect of opioid use on freedom from recurrence and overall survival was evaluated using the Kaplan-Meier method. The final analysis set included 258 patients. The cumulative opioid dose cutoff point was 1783.5 mg of oral morphine. High-dose postoperative opioid use was a significant factor affecting recurrence (Hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.583-2.954; P < 0.0001). In contrast, postoperative opioid use was not associated with death (HR, 1.274; 95% CI, 0.922-1.761; P = 0.1422). In patients with ESCC, compared with low-dose opioid use, high-dose intraoperative and postoperative opioid use was significantly associated with an increased risk of recurrence. However, opioid dosage did not affect overall survival. PMID- 28859396 TI - Whole greater than the parts: integrated esophageal centers (IEC) and advanced training in esophageal diseases. AB - An integrated esophageal center (IEC) is a multidisciplinary team with expertise, skill, range, and facilities necessary to achieve optimal outcomes in patients with esophageal diseases efficiently and expeditiously. Within IEC, patients presenting with esophageal symptoms undergo a detailed clinical, functional and structural evaluation of their esophagus prior to implementation of tailored medical, endoscopic or surgical therapy. Serving as a core, the IEC clinical practice also supports research and innovation in esophageal diseases as well as public and physician education. Referrals to the unit may be primary, either from primary care or self-initiated, or secondary from other specialty practices, to reassess patients who have previously failed therapies and to manage complex or complicated cases. The fundamental goals of the IEC are to provide value for patients with esophageal diseases, streamlining complex diagnostic investigations and expediting therapies aiming at reducing costs while improving clinical outcomes, and to accelerate knowledge generation through robust interaction and cross-training across disciplines. The organization of the IEC goes beyond traditional academic and clinical silos and involves a director and administrative team coordinating faculty and fellows from both medical and surgical disciplines and supported by other clinical lines, such as radiology, pathology, etc., while it interfaces with physicians, the public, basic, translational and clinical research groups, and related industry partners. PMID- 28859397 TI - Peer advice giving from posttreatment to newly diagnosed esophageal cancer patients. AB - The benefits of peer support in cancer care include the sharing of information and experience, supporting adjustment by providing an illness trajectory which cancer patients can use to prepare for their own cancer journey. Information from peers is prioritized by esophageal cancer patients, yet the content of this experiential information is not well understood. The purpose of this study is to understand the content of peer advice giving from posttreatment to newly diagnosed esophageal cancer patients. Esophageal cancer survivors (n = 23) at median 67-months postdiagnosis completed a single open-ended survey item which asked for advice they would give to individuals newly diagnosed with esophageal cancer on how to cope emotionally with the cancer journey (including adjusting to life after treatment). Transcripts were assessed using qualitative content analysis, with five categories of advice identified: social support, psychological approach, realistic expectations, support from healthcare professionals and self-care. The categories of advice reported were distinct from information needs prioritized by clinicians. This study demonstrates that experiential information is accessible and has the potential to identify neglected information and supportive care needs, and may have a potential use in delivery of psychological support to newly diagnosed patients. PMID- 28859398 TI - Component analysis of enhanced recovery pathways for esophagectomy. AB - The objective of this systematic review is to identify key components of enhanced recovery protocols (ERP) that lead to improved length of hospital stay (LOS) following esophagectomy. Relevant electronic databases were searched for studies comparing clinical outcome from esophagectomy followed by a conventional pathway versus ERP. Relevant outcome measures were compared and metaregression was performed to identify the key ERP components associated with reduced in LOS. Thirteen publications were included, ERP was associated with no changes in in hospital mortality, total complications, anastomotic leak, or pulmonary complications compared with a conventional pathway, however LOS was reduced in the ERP group. Metaregression identified that immediate extubation was associated with reduced LOS (OR = -0.51, 95%CI -0.77 to -0.25; P < 0.01). Several postoperative factors were associated with a significant reduction in length of hospital stay, and in order of most important were (i) gastrograffin swallow <=5 days (OR = -4.27, 95%CI -4.50 to -4.03); (ii) mobilization on postoperative day <=1 (OR = -2.49, 95%CI -2.63 to -2.34); (iii) removal of urinary catheter <=2 days (OR = -0.99, 95%CI -1.15 to -0.84); (iv) oral intake with at least sips of fluid <=1 day (OR = -0.96, 95%CI -1.24 to -0.68); (v) enteral diet with feeding jejunostomy or gastrostomy <= 1 day (OR = -0.57, 95%CI -0.80 to -0.35) and (vi) epidural removal <= 4 days (OR = -0.17, 95%CI -0.27 to -0.07). Several core ERP components and principles appear to be associated with LOS reduction. These elements should form a part of the core ERP for the specialty, while surgical teams incorporate other elements through an iterative process. PMID- 28859399 TI - Microvesicles released during the interaction between Trypanosoma cruzi TcI and TcII strains and host blood cells inhibit complement system and increase the infectivity of metacyclic forms of host cells in a strain-independent process. AB - Extracellular vesicles, whether microvesicles (MVs) or exosomes, shed by pathogens transfer virulence factors and biomolecules to host cells, thereby altering the host's susceptibility to infection. We have previously demonstrated that MV release is increased during the interaction between the infective forms of Trypanosoma cruzi and host cells. MVs confer parasite resistance to complement mediated lysis and enhance parasite invasion. In this study, we show that differences exist in the levels of MVs released during the interaction between metacyclic trypomastigotes of different T. cruzi strains (with varied sensitivity to complement-mediated lysis, namely sensitive G strain TcI and resistant Y strain TcII) and host cells. MVs produced during the interaction between TcII parasites and host cells increased parasite resistance to complement lysis from 50% to 80% and parasite invasion was increased to over 50%. MVs purified during the interaction between TcI parasites and host cells have a stronger effect, doubling complement resistance and parasite invasion. The complement-mediated lysis assays showed that all MVs inhibit mainly the lectin pathway. Interestingly, MVs derived from parasites of one class did not alter complement resistance and the invasion process of parasites from the other class. This is the first description of MVs from T. cruzi with strain-dependent phenotypic effects. PMID- 28859400 TI - Association between peripheral gammadelta T cell subsets and disease progression of severe fever with thrombocytopenia syndrome virus infection. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by SFTS virus. The cellular immune responses during SFTS virus infection have not been fully understood. This study examined the association between circulating gammadelta T cell subsets and clinical outcome of SFTS patients from China. A total of 101 hospitalized SFTS patients and 28 healthy controls were enrolled. Peripheral blood was collected, and lymphocyte subgroups and gammadelta T cell frequencies were evaluated by flow cytometry analysis. Their association with patients' outcome was also investigated. Starting from Week 1, the Vdelta1 cells of patients were increased to significantly higher level at Month 3 after disease onset than the controls (P < 0.05), followed by a decrease to the normal level in Year 1. In contrast, the Vdelta2 cells displayed significant lower level than the controls from Week 2 to Year 1. On Week 2, the Vdelta2 cells demonstrated a significant decrease in the severe patients than both the mild and controls (P < 0.05). The adverse disease progression is accompanied by the reduction of Vdelta2 cells, suggesting the key role of Vdelta2 cells in the disease progression. PMID- 28859401 TI - Do Bar-Headed Geese Train for High Altitude Flights? AB - SYNOPSIS: Exercise at high altitude is extremely challenging, largely due to hypobaric hypoxia (low oxygen levels brought about by low air pressure). In humans, the maximal rate of oxygen consumption decreases with increasing altitude, supporting progressively poorer performance. Bar-headed geese (Anser indicus) are renowned high altitude migrants and, although they appear to minimize altitude during migration where possible, they must fly over the Tibetan Plateau (mean altitude 4800 m) for much of their annual migration. This requires considerable cardiovascular effort, but no study has assessed the extent to which bar-headed geese may train prior to migration for long distances, or for high altitudes. Using implanted loggers that recorded heart rate, acceleration, pressure, and temperature, we found no evidence of training for migration in bar headed geese. Geese showed no significant change in summed activity per day or maximal activity per day. There was also no significant change in maximum heart rate per day or minimum resting heart rate, which may be evidence of an increase in cardiac stroke volume if all other variables were to remain the same. We discuss the strategies used by bar-headed geese in the context of training undertaken by human mountaineers when preparing for high altitude, noting the differences between their respective cardiovascular physiology. PMID- 28859402 TI - How Do We Measure the Cost of Whole-Organism Performance Traits? AB - SYNOPSIS: Whole-organism performance traits, such as maximal speed and endurance capacity are undoubtedly costly, but we know little about how or when all of the costs associated with performance are paid to individuals or how to measure them. To understand how performance traits might be involved in trade-offs with other life-history traits it is critical to determine the development, production, and maintenance costs of performance traits, as well as how each of these changes with increased or decreased use of the performance trait. We discuss the advantages and disadvantages of several potential phenotypic measures of dynamic whole-organism performance that may be used in life-history studies, including direct performance measures; metabolic rates; ecological cost of transport; and changes in metabolic rate after training. We use the first approach, direct performance measures, to show trade-offs between endurance capacity and several traditional life history variables in phrynosomatid lizards. The largest problem currently in determining the costs of performance traits and how those costs might lead to life-history trade-offs is that there are estimates of performance costs in very few taxa, and when there are, those species typically are not studied with respect to "traditional" life-history traits. PMID- 28859403 TI - Plasmodium Infections in Natural Populations of Anolis sagrei Reflect Tolerance Rather Than Susceptibility. AB - SYNOPSIS: Parasites can represent formidable selection pressures for hosts, but the cost of infection is sometimes difficult to demonstrate in natural populations. While parasite exploitation strategies may, in some instances, actually inflict low costs on their hosts, the response of hosts to infection is also likely to determine whether or not these costs can be detected. Indeed, costs of infection may be obscured if infected individuals in the wild are those that are the most tolerant, rather than the most susceptible, to infection. Here we test this hypothesis in two natural populations of Anolis sagrei, one of the most common anole lizard of the Bahamas. Plasmodium parasites were detected in > 7% of individuals and belonged to two distinct clades: P. mexicanum and P. floriensis. Infected individuals displayed greater body condition than non infected ones and we found no association between infection status, stamina, and survival to the end of the breeding season. Furthermore, we found no significant difference in the immuno-competence (measured as a response to phytohemagglutinin challenge) of infected versus non-infected individuals. Taken together, our results suggest that the infected individuals that are caught in the wild are those most able to withstand the cost of the infection and that susceptible, infected individuals have been removed from the population (i.e., through disease induced mortality). This study highlights the need for caution when interpreting estimates of infection costs in natural populations, as costs may appear low either when parasites exploitation strategies truly inflict low costs on their hosts or when those costs are so high that susceptible hosts are removed from the population. PMID- 28859404 TI - Ecology of Exercise in Wild Fish: Integrating Concepts of Individual Physiological Capacity, Behavior, and Fitness Through Diverse Case Studies. AB - SYNOPSIS: Wild animals maximize fitness through certain behaviors (e.g., foraging, mating, predator avoidance) that incur metabolic costs and often require high levels of locomotor activity. Consequently, the ability of animals to achieve high fitness often relies on their physiological capacity for exercise (aerobic scope) and/or their ability to acquire and utilize energy judiciously. Here, we explore how environmental factors and physiological limitations influence exercise and metabolism in fish while foraging, migrating to spawning grounds, and providing parental care. We do so with three case studies that use a number of approaches to studying exercise in wild fish using biologging and biotelemetry platforms. Bonefish (Albula vulpes) selectively use shallow water tropical marine environments to forage when temperatures are near optimal for aerobic scope and exercise capacity. Bonefish energy expenditure at upper thermal extremes is maximal while activity levels diminish, likely caused by reduced aerobic scope. Pacific salmon (Oncorhynchus spp.) reproductive migrations frequently involve passage through hydraulically challenging areas, and their ability to successfully pass these regions is constrained by their physiological capacity for exercise. Aerobic scope and swim performance are correlated with migration difficulty among sockeye salmon (O. nerka) populations; however, depletion of endogenous energy stores can also limit migration success. In another example, male smallmouth bass (Micropterus dolomieu) allocate a significant amount of energy to nest-guarding behaviors to protect their developing brood. Smallmouth bass body size, endogenous energy reserves, and physiological state influence nest-guarding behaviors and reproductive success. We suggest that in some scenarios (e.g., bonefish foraging, Pacific salmon dam passage) metabolic capacity for exercise may be the strongest determinant of biological fitness, while in others (e.g., long distance salmon migration, smallmouth bass parental care) energy stores may be more important. Interactions among environmental and ecological factors, fish behavior, and fish physiology offer important avenues of mechanistic inquiry to explain ecological dynamics and demonstrate how exercise is fundamental to the ecology of fish. PMID- 28859405 TI - Parasites and Host Performance: Incorporating Infection into Our Understanding of Animal Movement. AB - SYNOPSIS: Studies of animal locomotion and movement largely assume that individuals are healthy and performing to the best of their abilities in ways which are adapted to their survival. However, wild animals face numerous ecological challenges that can compromise their health, reduce their performance capacity, impair their movement abilities and, ultimately, lower their fitness. By diverting resources and increasing host energetic demands, parasites, bacteria, and viruses (hereafter parasites) can dramatically influence the ways in which their hosts allocate energy to movement. Yet, the role of parasites in influencing animal locomotor performance and movement remains relatively unexplored, perhaps because animals often hide outward signs of sickness, and parasites tend to be small and inconspicuous to researchers. Here, we review how parasite infection can alter host locomotor performance via impacts on host morphology and physiology. We also give examples of behavioral strategies that some hosts employ to help overcome the disadvantages imposed by infection. Finally, we discuss how parasites can lead to both increased and decreased host movement patterns, either as an adaptive strategy for the host or due to manipulation by the parasite. The dynamic interplay between host movement (such as migration and dispersal) and infection has profound consequences for population and ecosystem-level processes that are influenced by movement. Acknowledging the important functional role played by parasites in driving the evolution of host locomotor performance and behavior is a critical step toward developing a comprehensive understanding of the causes and consequences of animal movement. PMID- 28859406 TI - Of Uberfleas and Krakens: Detecting Trade-offs Using Mixed Models. AB - SYNOPSIS: All animals experience performance trade-offs as they complete tasks such as capturing prey, defending territories, acquiring mates, and escaping predators. Why then, is it so hard to detect performance trade-offs at the whole organismal level? Why do we sometimes even obtain positive correlations between two performance traits that are predicted to be negatively associated? Here we explore two plausible explanations. First, most analyses are based on individual maximal values (i.e., personal best), which could introduce a bias in the correlation estimates. Second, phenotypic correlations alone may be poor indicators of a trade-off when contrasting processes occur at the among- versus within-individual levels. One such scenario is the "big houses big cars" model developed in life-history theory to explain the existence of "uberfleas" that are superior in all regards (because they acquire more resources than others). We highlight that the exact opposite scenario might occur for performance trade offs, where among-individual trade-offs may be masked by within-individual changes in physical condition. One of the best ways to test among these alternative scenarios is to collect repeated pairs of performance traits and analyze them using multivariate mixed models (MMMs). MMMs allow straightforward and simultaneous examination of trait correlations at the among- and within individual levels. We use a simple simulation tool (SQuID package in R) to create a population of Krakens, a mythical giant squid-like sea creature whose morphology generates a performance trade-off between swimming speed and strength or ability to sink ships. The simulations showed that using individual maximum values introduces a bias that is particularly severe when individuals differ in the number of repeated samples (ntrial). Finally, we show how MMMs can help detect performance (or any other type of) trade-offs and offer additional insights (e.g., help detect plasticity integration). We hope researchers will adopt MMMs when exploring trade-offs in whole-animal performances. PMID- 28859407 TI - Systems Biology of Phenotypic Robustness and Plasticity. AB - SYNOPSIS: Gene regulatory networks, cellular biochemistry, tissue function, and whole body physiology are imbued with myriad overlapping and interacting homeostatic mechanisms that ensure that many phenotypes are robust to genetic and environmental variation. Animals also often have plastic responses to environmental variables, which means that many different phenotypes can correspond to a single genotype. Since natural selection acts on phenotypes, this raises the question of how selection can act on the genome if genotypes are decoupled from phenotypes by robustness and plasticity mechanisms. The answer can be found in the systems biology of the homeostatic mechanisms themselves. First, all such mechanisms operate over a limited range and outside that range the controlled variable changes rapidly allowing natural selection to act. Second, mutations and environmental stressors can disrupt homeostatic mechanisms, exposing cryptic genetic variation and allowing natural selection to act. We illustrate these ideas by examining the systems biology of four specific examples. We show how it is possible to analyze and visualize the roles of specific genes and specific polymorphisms in robustness in the context of large and realistic nonlinear systems. We also describe a new method, system population models, that allows one to connect causal dynamics to the variable outcomes that one sees in biological populations with large variation. PMID- 28859408 TI - Fuel Use in Mammals: Conserved Patterns and Evolved Strategies for Aerobic Locomotion and Thermogenesis. AB - SYNOPSIS: Effective aerobic locomotion depends on adequate delivery of oxygen and an appropriate allocation of metabolic substrates. The use of metabolic substrates during exercise follows a predictive pattern of lipid and carbohydrate oxidation that is similar in lowland native cursorial mammals. We have found that in two highland lineages of mice (Phyllotis and Peromyscus) the fuel use pattern is shifted to a greater reliance on carbohydrates compared to their lowland conspecifics and congenerics. However, there is variation between lineages in the importance of phenotypic plasticity in the expression of this metabolic phenotype. Moreover, this metabolic phenotype is independent of running aerobic capacity and can also be independent of thermogenic capacity. For example, wild caught mice from a highland population of deer mice (Peromyscus maniculatus) housed in warm normoxic laboratory conditions maintain higher maximum cold induced oxygen consumption in acute hypoxia than lowland congenerics, but shivering and non-shivering thermogenesis is supported by high rates of lipid oxidation. This is reflected in the consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius of highland deer mice compared to lowlanders, which are resistant to hypoxia acclimation. While a fixed trait in muscle aerobic capacity may reflect the pervasive and unremitting low PO2 at high altitudes, muscle capacities for substrate oxidation may be more flexible to match appropriate substrate use with changing energetic demands. How shivering thermogenesis and locomotion potentially interact in the matching of muscle metabolic capacities to appropriate substrate use is unclear. Perhaps it is possible that shivering serves as "training" to ensure muscles have the capacity to support locomotion or visa-versa. PMID- 28859410 TI - Does the Treadmill Support Valid Energetics Estimates of Field Locomotion? AB - SYNOPSIS: Quantifying animal energy expenditure during locomotion in the field is generally based either on treadmill measurements or on estimates derived from a measured proxy. Two common proxies are heart rate (fH) and dynamic body acceleration (accelerometry). Both fH and accelerometry have been calibrated extensively under laboratory conditions, which typically involve prompting the animal to locomote on a treadmill at different speeds while simultaneously recording its rate of oxygen uptake (Vo2) and the proxy. Field estimates of Vo2 during locomotion obtained directly from treadmill running or from treadmill calibrated proxies make assumptions about similarities between running in the field and in the laboratory. The present study investigated these assumptions, focusing on humans as a tractable species. First we investigated experimentally if and how the rate of energy expenditure during treadmill locomotion differs to that during field locomotion at the same speeds, with participants walking and running on a treadmill, on tarmac, and on grass, while wearing a mobile respirometry system. Vo2 was substantially higher during locomotion in both of the field conditions compared with on a level treadmill: 9.1% on tarmac and 17.7% on grass. Second, we included these data in a meta-analysis of previous, related studies. The results were influenced by the studies excluded due to particulars of the experiment design, suggesting that participant age, the surface type, and the degree of turning during field locomotion may influence by how much treadmill and field locomotion Vo2 differ. Third, based on our experiments described earlier, we investigated the accuracy of treadmill-calibrated accelerometry and fH for estimating Vo2 in the field. The mean algebraic estimate errors varied between 10% and 35%, with the fH associated errors being larger than those derived from accelerometry. The mean algebraic errors were all underestimates of field Vo2, by around 10% for fH and varying between 0% and 15% for accelerometry. Researchers should question and consider how accurately a treadmill-derived proxy calibration of Vo2 will estimate Vo2 during terrestrial locomotion in free-living animals. PMID- 28859409 TI - The Ecology of Exercise: Mechanisms Underlying Individual Variation in Behavior, Activity, and Performance: An Introduction to Symposium. AB - SYNOPSIS: Wild animals often engage in intense physical activity while performing tasks vital for their survival and reproduction associated with foraging, avoiding predators, fighting, providing parental care, and migrating. In this theme issue we consider how viewing these tasks as "exercise"-analogous to that performed by human athletes-may help provide insight into the mechanisms underlying individual variation in these types of behaviors and the importance of physical activity in an ecological context. In this article and throughout this issue, we focus on four key questions relevant to the study of behavioral ecology that may be addressed by studying wild animal behavior from the perspective of exercise physiology: (1) How hard do individual animals work in response to ecological (or evolutionary) demands?; (2) Do lab-based studies of activity provide good models for understanding activity in free-living animals and individual variation in traits?; (3) Can animals work too hard during "routine" activities?; and (4) Can paradigms of "exercise" and "training" be applied to free-living animals? Attempts to address these issues are currently being facilitated by rapid technological developments associated with physiological measurements and the remote tracking of wild animals, to provide mechanistic insights into the behavior of free-ranging animals at spatial and temporal scales that were previously impossible. We further suggest that viewing the behaviors of non-human animals in terms of the physical exercise performed will allow us to fully take advantage of these technological advances, draw from knowledge and conceptual frameworks already in use by human exercise physiologists, and identify key traits that constrain performance and generate variation in performance among individuals. It is our hope that, by highlighting mechanisms of behavior and performance, the articles in this issue will spur on further synergies between physiologists and ecologists, to take advantage of emerging cross-disciplinary perspectives and technologies. PMID- 28859411 TI - Epigenetic Potential as a Mechanism of Phenotypic Plasticity in Vertebrate Range Expansions. AB - SYNOPSIS: During range expansions, organisms are often exposed to multiple pressures, including novel enemies (i.e., predators, competitors and/or parasites) and unfamiliar or limited resources. Additionally, small propagule sizes at range edges can result in genetic founder effects and bottlenecks, which can affect phenotypic diversity and thus selection. Despite these obstacles, individuals in expanding populations often thrive at the periphery of a range, and this success may be mediated by phenotypic plasticity. Increasing evidence suggests that epigenetic mechanisms may underlie such plasticity because they allow for more rapid phenotypic responses to novel environments than are possible via the accumulation of genetic variation. Here, we review how molecular epigenetic mechanisms could facilitate plasticity in range-expanding organisms, emphasizing the roles of DNA methylation and other epigenetic marks in the physiological regulatory networks that drive whole-organism performance. We focus on the hypothalamic-pituitary-adrenal (HPA) axis, arguing that epigenetically mediated plasticity in the regulation of glucocorticoids in particular might strongly impact range expansions. We hypothesize that novel environments release and/or select for epigenetic potential in HPA variation and hence organismal performance and ultimately fitness. PMID- 28859412 TI - Introduction to the Symposium: Integrative Life-History of Whole-Organism Performance. AB - SYNOPSIS: A strong case can be made for whole-organism performance traits (i.e., dynamic, ecologically relevant traits whose expression is shaped by underlying morphological factors) as being the ultimate integrative traits. This is not only because they capture the output of multiple lower levels of biological organization, but also because they are directly relevant to individual fitness in multiple ecological contexts, and are in many cases important proximate determinants of survival and/or reproductive success. But although many ecological and evolutionary phenomena can be examined through the lens of performance (and vice-versa), performance research has been surprisingly slow to incorporate concepts from the large and important field of life-history evolution. Such a synthesis is necessary, because shifts in resource allocation strategies can have implications for these highly ecologically relevant, functional traits, whose expression may trade-off against fecundity, immune function, or longevity, among other key life-history traits. The papers in this symposium showcase many of the ways in which life-history strategies can have direct consequences for the expression, maintenance, and evolution of whole organism performance (and at least one case where they may not). By approaching the issue of life-history trade-offs from a number of diverse perspectives, this symposium reveals the scope for future explicit integration of life-history techniques with those of whole-organism performance studies for a more complete understanding of multivariate phenotypic evolution. PMID- 28859413 TI - Locomotion, Energetics, Performance, and Behavior: A Mammalian Perspective on Lizards, and Vice Versa. AB - SYNOPSIS: Animals are constrained by their abilities and by interactions with environmental factors, such as low ambient temperatures. These constraints range from physical impossibilities to energetic inefficiencies, and may entail trade offs. Some of the constraints related to locomotion and activity metabolism can be illustrated through allometric comparisons of mammals and lizards, as representative terrestrial vertebrate endotherms and ectotherms, respectively, because these lineages differ greatly in aerobic metabolic capacities, resting energetic costs, and thermoregulatory patterns. Allometric comparisons are both useful and unavoidable, but "outlier" species (unusual for their clade) can also inform evolutionary scenarios, as they help indicate extremes of possible adaptation within mammalian and saurian levels of organization. We compared mammals and lizards for standard metabolic rate (SMR), maximal oxygen consumption during forced exercise (VO2max), net (incremental) cost of transport (NCT), maximal aerobic speed (MAS), daily movement distance (DMD), daily energy expenditure (DEE) during the active season, and the ecological cost of transport (ECT = percentage of DEE attributable to locomotion). (Snakes were excluded because their limbless locomotion has no counterpart in terrestrial mammals.) We only considered lizard SMR, VO2max, NCT, MAS, and sprint speed data if measured at 35-40 degrees C. On average, MAS is ~7.4-fold higher in mammals, whereas SMR and VO2max are ~6-fold greater, but values for all three of these traits overlap (or almost overlap) between mammals and lizards, a fact that has not previously been appreciated. Previous studies show that sprint speeds are similar for smaller mammals and lizards, but at larger sizes lizards are not as fast as some mammals. Mammals move ~6-fold further each day than lizards, and DMD is by far the most variable trait considered here, but their NCT is similar. Mammals exceed lizards by ~11.4-fold for DEE. On average for both lineages, the ECT is surprisingly low, somewhat higher for lizards, and positively allometric. If a lizard and mammal of 100 g body mass were both to move their entire DMD at their MAS, they could do so in ~21 and 17 min, respectively, thus de-emphasizing the possible importance of time constraints. We conclude that ecological-energetic constraints related to locomotion are relatively more likely to occur in large, carnivorous lizards. Overall, our comparisons support the idea that the (gradual) evolution of mammalian endothermy did not necessarily require major changes in locomotor energetics, performance, or associated behaviors. Instead, we speculate that the evolution of thermoregulatory responses to low temperatures (e.g., shivering) may have been a key and "difficult" step in this transition. PMID- 28859414 TI - Physiological and Biomechanical Mechanisms of Distance Specific Human Running Performance. AB - SYNOPSIS: Running events range from 60-m sprints to ultra-marathons covering 100 miles or more, which presents an interesting diversity in terms of the parameters for successful performance. Here, we review the physiological and biomechanical variations underlying elite human running performance in sprint to ultramarathon distances. Maximal running speeds observed in sprint disciplines are achieved by high vertical ground reaction forces applied over short contact times. To create this high force output, sprint events rely heavily on anaerobic metabolism, as well as a high number and large cross-sectional area of type II fibers in the leg muscles. Middle distance running performance is characterized by intermediates of biomechanical and physiological parameters, with the possibility of unique combinations of each leading to high-level performance. The relatively fast velocities in mid-distance events require a high mechanical power output, though ground reaction forces are less than in sprinting. Elite mid-distance runners exhibit local muscle adaptations that, along with a large anaerobic capacity, provide the ability to generate a high power output. Aerobic capacity starts to become an important aspect of performance in middle distance events, especially as distance increases. In distance running events, VO2max is an important determinant of performance, but is relatively homogeneous in elite runners. VO2 and velocity at lactate threshold have been shown to be superior predictors of elite distance running performance. Ultramarathons are relatively new running events, as such, less is known about physiological and biomechanical parameters that underlie ultra-marathon performance. However, it is clear that performance in these events is related to aerobic capacity, fuel utilization, and fatigue resistance. PMID- 28859415 TI - Performance Tradeoffs, Ontogenetic Conflict, and Multisport Athletes: How is an Ironman Triathlete Like a Frog? AB - SYNOPSIS: Life-history theory is a cornerstone of modern evolutionary biology that addresses myriad phenomena ranging from demography and population structure to the evolution of aging and senescence. Trade-offs may arise in a number of contexts, from allocation-based (e.g., egg size vs. egg number) to genomic conflicts (e.g., intralocus sexual conflict in which genes that perform well in males perform poorly in females). Here we test for performance tradeoffs in human athletes. We show that in Ironman triathletes, swimming performance trades off with cycling and running performance. The tradeoff appears to be plastic, in that only highly trained athletes experience the tradeoff. We then investigate whether wood frogs (Rana sylvatica) experience similar locomotor performance tradeoffs, to ask whether the divergent environments experienced by tadpoles and frogs leads to ontogenetic conflict (tradeoffs over development). We show that although swimming and jumping performance are positively correlated, antagonistic natural selection may still favor alternative adaptive optima in the two life history stages. However, "adaptive decoupling" of the life stages during metamorphosis may resolve ontogenetic conflict and facilitate independent adaptation to both environments. Thus, whereas performance tradeoffs are general in both systems, the unique selective environment of amphibians has favored the evolution of mechanisms to alleviate the costs of those tradeoffs. PMID- 28859416 TI - Does Hormonal Pleiotropy Shape the Evolution of Performance and Life History Traits? AB - SYNOPSIS: Hormonal pleiotropy occurs when a part of the endocrine system (e.g., hormone concentrations) influences the expression of two or more phenotypes. Although hormonal pleiotropy may have similar evolutionary consequences as genetic pleiotropy, most conceptual and empirical work on its putative evolutionary consequences to date has focused on identifying whether the different components of an endocrine axis (titer, receptor expression, etc.) that affect trait expression are themselves able to evolve independently from one another. This is important because if these different components evolve together, the expression of two traits affected by the same hormone may be yoked and evolve non-independently. Here, we first describe methodological approaches used to identify how hormonal pleiotropy could cause the co-evolution of performance and life history traits. We then focus on a similar but less studied concept about how hormonal pleiotropy can affect phenotypic responses to selection. If the expression of two traits is affected by the same hormone, the magnitude of the phenotypic response to selection may be exacerbated or retarded compared to the absence of this hormonal pleiotropy. We use classical concepts from quantitative genetics to discuss an approach for identifying whether hormonal pleiotropy has such evolutionary consequences using data collected from longitudinal studies of wild animals. We develop a simple quantitative genetics model to derive predictions about the conditions under which hormonal pleiotropy would affect the response to selection. We focus on performance and life history traits and how the effects of hormonal pleiotropy on the evolution of these traits depend upon the genetic correlations between the hormone and traits as well as the direction and strength of selection on the two traits. Finally, we review the literature for examples that have estimated these model parameters to characterize the studies that have or have not found support for these model predictions. PMID- 28859417 TI - Predicting Life-History Trade-Offs with Whole-Organism Performance. AB - SYNOPSIS: Whole-organism performance traits are key intermediaries between the organism and the environment. Because performance traits are energetically costly to both build and maintain, performance will compete with other life-history traits over a limited pool of acquired energetic resources at any given time, potentially leading to trade-offs in performance expression. Although these trade offs can have important implications for organismal fitness we currently lack a conceptual framework for predicting both where trade-offs might be expected, and which traits may be especially prone to trade-offs with other fitness-related life-history traits. We propose such a framework based on an estimate of the energetic requirements of locomotion in vertebrates, the ecological cost of transport. By analyzing existing data on mammalian energetic budgets and life history, we found that species with higher costs of locomotion also tended to be those with "slow" life histories that invest relatively less in current reproduction than "fast" life-history species. We discuss the potential implications of ectothermy for masking such relationships, and how this framework might be expanded upon in the future. PMID- 28859418 TI - Merging the "Morphology-Performance-Fitness" Paradigm and Life-History Theory in the Eagle Lake Garter Snake Research Project. AB - SYNOPSIS: The morphology-performance-fitness paradigm for testing selection on morphological traits has seen decades of successful application. At the same time, life-history approaches using matrix methods and perturbation studies have also allowed the direct estimate of selection acting on vital rates and the traits that comprise them. Both methodologies have been successfully applied to the garter snakes of the long-term Eagle Lake research project to reveal selection on morphology, such as color pattern, number of vertebrae, and gape size; and life-history traits such as birth size, growth rates, and juvenile survival. Here we conduct a reciprocal transplant study in a common laboratory environment to study selection on morphology and life-history. To place our results in the ecomorphology paradigm, we measure performance outcomes (feeding rates, growth, insulin-like growth factor 1 titers) of morphological variation (body size, condition) and their fitness consequences for juvenile survival-a trait that has large fitness sensitivities in these garter snake populations, and therefore is thought to be subject to strong selection. To better merge these two complementary theories, we end by discussing our findings in a nexus of morphology-performance-fitness-life history to highlight what these approaches, when combined, can reveal about selection in the wild. PMID- 28859419 TI - Complex Reproductive Traits and Whole-Organism Performance. AB - SYNOPSIS: Arnold's 1983 path-analytic paradigm, considering "morphology, performance, and fitness," has been elaborated in several ways. For example, current versions recognize the level of "behavior" (including aspects of motivation) as a filter between performance abilities (only measurable if motivation is maximal) and fitness components. Performance abilities constrain behavior, but behavioral choices may shield performance from selection. Conceptual and empirical issues remain, such as the extent to which individual variation in lower-level subordinate traits (e.g., circulating hormone concentrations) might directly affect behavior, growth rates, sexual maturation, etc., rather than having effects only through paths involving some aspect of performance. Moreover, empirical studies have yet to encompass more than a few possible paths in a given system, in part because life-history researchers rarely communicate with those focused on performance. Most life-history studies ponder trade-offs associated with reproductive effort, but studies of locomotor performance (e.g., maximal sprint speed) have rarely considered trade-offs with reproduction. This lack of connection is surprising because both life history (e.g., clutch size) and locomotor performance (e.g., locomotor stamina) traits require allocation of energy and other resources, so trade-offs between these trait types may be expected. These perspectives and cultures could be bridged by a focus on the ability of organisms to perform components of reproductive biology (e.g., lactation performance could be studied in animals maximally "motivated" by manipulation of litter size or endocrine function). Alternatively, one could study impacts of reproduction on performance, as when bats and live-bearing fishes lose maneuverability during gestation. We also consider sperm performance in the context of the paradigm and illustrate that the paradigm can easily be utilized as a frame-work within which to consider key aspects of sperm biology. PMID- 28859420 TI - Physiological Trade-Offs in Lizards: Costs for Individuals and Populations. AB - SYNOPSIS: The immune system is a critical component of health and fitness, whereby organisms must maintain sufficient health to survive to reproduce. Because of the key role of immunity in an organism's fitness, the use of immunological indices is widespread. However, there is a paucity of empirical support for the best way to interpret immunological data, and the internal energetic state of the organism, as well as the external environmental pressures it faces, are often not considered concurrently. A stronger immune response is not always beneficial to the organism; a more attenuated response may ultimately lead to improved fitness if the animal incurs fewer performance costs on competing systems, especially reproduction. Additionally, the external pressures animals encounter (such as anthropogenic disturbance) must be considered along with the animal's internal state. A synthesis of results addressing resource allocation between the immune and reproductive systems is presented using a well studied organism, the side-blotched lizard, from a combination of field and laboratory studies under varying environmental conditions. Specifically, experiments involving specific immune, reproductive, metabolic, and performance costs in a laboratory setting are discussed, as well as associated demographic trade-offs between survival and reproductive success, demonstrating essential links between immunity and the population. PMID- 28859421 TI - Evidence and Feasibility of Implementing an Integrated Wellness Program in Northeast Georgia. AB - Evidence for the connection between physical and mental health is growing, as is interest in providing a holistic, mind-body approach to improving mental health and wellness. A needs assessment in northeast Georgia identified several regional health priorities, including mental health and substance abuse, access to care, and cardiovascular health. The study's purpose is threefold: to (1) review evidence for integrated mind-body wellness services, (2) explore the feasibility of implementing wellness services in a small mental health agency serving northeast Georgia, and (3) conduct a brief survey assessing interest in a wellness program. The literature search identified articles within the past 10 years with these key words: "yoga," "mental health," "wellness program," "complementary alternative medicine," "tai chi," "mindfulness," "meditation," and "nutrition." The survey was distributed to the agency's affiliates. The literature review identified strong evidence for an integrated mind-body wellness program that includes yoga, tai chi, mindfulness meditation, and nutrition education. Among 73 survey respondents, 86 percent indicated interest in wellness services, and 85 percent agreed that wellness services are important to mental health and well-being. Authors suggest a model to incorporate a holistic wellness program to complement mental health services and help facilitate physical and mental health. PMID- 28859422 TI - Can't We Just Get Some Help? Providing Innovative Care to Children in Acute Psychiatric Crisis. PMID- 28859423 TI - A Comparison of Compliance and Noncompliance in Breast Cancer Screening among African American Women. AB - African American women are more likely to be diagnosed with late stage breast cancer, due in part to low participation in screening procedures. The purpose of this study was to explore the differences among African American women who were compliant and noncompliant with standard mammography screening recommendations. The study participants were African American women (N = 599) over the age of 40 with no history of cancer, who were recruited to attend a local community health event. Findings revealed that 78 percent of the women reported having had a mammogram within the past year, whereas 22 percent had not. The most commonly reported reasons given by those who did not have a mammogram in the past year were that they simply did not think to do so, or that they were not told to do so by their doctor. Women who reported that they did not have a mammogram last year were significantly less likely to have health insurance, to have had a clinical breast exam at their last checkup, to have had their breasts examined by their doctor at least once per year, or to have previously had a mammogram. There were no group differences in the number of visits to a doctor during the past 12 months. The article concludes with a discussion of the implications for health care professionals and suggestions for future research. PMID- 28859424 TI - Age Differences in Health Literacy: Do Younger Korean Adults Have a Higher Level of Health Literacy than Older Korean Adults? AB - The purpose of this study was to investigate the level of health literacy of adults living in South Korea and identify factors associated with health literacy in different age groups. Using a quota sampling method, authors recruited 1,000 Korean adults age 20 years and older. Health literacy was measured by using three items selected from a 16-question self-report health literacy measure. In accordance with Andersen's behavioral model, predisposing, enabling, and need factors were included in the multiple regression model. Age differences were found in health literacy levels; specifically, lower health literacy was associated with older age. For the 20 through 44-year age group, health literacy was positively associated with having private health insurance and higher self rated health status. For the 45 through 64 and the 65 and over age groups, education was positively associated with health literacy. For the oldest age group, gender also had a positive association with health literacy. Lower levels of depression were significantly linked to a higher level of health literacy across all ages. This study illustrates ways to increase health literacy among different age groups and prioritizes target intervention groups in an effort to reduce health disparities. PMID- 28859425 TI - Invisible Illness Increases Risk of Suicidal Ideation: The Role of Social Workers in Preventing Suicide. PMID- 28859426 TI - A Bipartisan Obamacare Repair Plan. PMID- 28859427 TI - What's Next for Health Care Reform under the Trump Administration? PMID- 28859428 TI - Determining the Seasonality of Respiratory Syncytial Virus in the United States: The Impact of Increased Molecular Testing. AB - Background: In the United States, the seasonality of respiratory syncytial virus (RSV) has traditionally been defined on the basis of weeks during which antigen based tests detect RSV in >10% of specimens (hereafter, the "10% threshold"). Because molecular testing has become more widely used, we explored the extent of polymerase chain reaction (PCR)-based RSV testing and its impact on determining the seasonality of RSV. Methods: We assessed antigen- and PCR-based RSV reports submitted to the National Respiratory and Enteric Virus Surveillance System during July 2005-June 2015. To characterize RSV seasons by using PCR-based reports, we assessed the traditional 10% threshold; subsequently, we developed 3 methods based on either PCR-based detections or the percentage of positive test results. Results: The annual number of PCR-based reports increased 200-fold during 2005-2015, while the annual number of antigen-based reports declined. The weekly percentage of specimens positive for RSV by PCR was less than that for antigen-detection tests; accordingly, the 10% threshold excluded detections by PCR and so was imprecise for characterizing RSV seasons. Among our PCR-specific approaches, the most sensitive and consistent method captured 96%-98% of annual detections within a season, compared with 82%-94% captured using the traditional method. Conclusions: PCR-based reports are increasingly relevant for RSV surveillance and determining the seasonality of RSV. These PCR-specific methods provide a more comprehensive understanding of RSV trends, particularly in settings where testing and reporting are most active. Diagnostic practices will vary by locality and should be understood before choosing which method to apply. PMID- 28859429 TI - Gametocytemia and Attractiveness of Plasmodium falciparum-Infected Kenyan Children to Anopheles gambiae Mosquitoes. AB - It has been suggested that Plasmodia manipulate their vertebrate hosts to enhance parasite transmission. Using a dual-choice olfactometer, we investigated the attraction of Anopheles gambiae to 50 Kenyan children (aged 5-12 years) who were naturally infected with Plasmodium falciparum or noninfected controls. Microscopic gametocyte carriers attracted almost 2 times more mosquitoes than children who were parasite free, harbored asexual stages, or had gametocytes at submicroscopic densities. By using highly sensitive stage-specific molecular methods to detect P. falciparum, we show that gametocytes-and not their noninfectious asexual progenitors-induce increased attractiveness of humans to mosquitoes. Our findings therefore support the parasite host manipulation hypothesis. PMID- 28859430 TI - Robust Antibody and Cytokine Response to Hepatitis B Vaccine Among Not-in Treatment Patients With Chronic Hepatitis C: An Open-Label Control Study in China. AB - Background: Hepatitis B vaccine is an effective measure to prevent hepatitis B virus infection. Whether chronic hepatitis C virus (HCV) infection decreases humoral and cell-mediated immunity responses to hepatitis B vaccination is still controversial. Methods: Patients with chronic HCV infection who were not in treatment and healthy controls, matched at a 1:2 ratio for community, sex, and age (within 5 years), were identified from a community-based screening. All participants received 3 doses of hepatitis B vaccine. Antibody to hepatitis B surface antigen was tested 1 month after the third vaccine dose and was compared between 2 groups. Spot-forming cells (SFCs) of interferon gamma and interleukin 2, 4, 5, and 6 were counted by means of enzyme-linked immunospot, and SFC counts were compared between the 2 groups. Results: The rates of nonresponse and low, normal, and high response were 3.80%, 10.13%, 45.57%, and 40.50% respectively, in the HCV group, and the corresponding rates in the healthy control group were 1.26%, 10.13%, 39.24%, and 49.37% (all P > .05). There were no significant differences in SFC counts between the 2 groups for interferon gamma or interleukin 2, 4, or 5 (all P > .05). Conclusions: This study provided preliminary evidence of the good immunogenicity and safety of hepatitis B vaccination among patients in China with chronic hepatitis C who are not in treatment. Clinical Trials Registration: NCT 02898922. PMID- 28859431 TI - Different Challenges in Eliminating HPV16 Compared to Other Types: A Modeling Study. AB - Background: Human papillomavirus (HPV) vaccination is still not reaching many high-risk populations. HPV16/18 vaccines offer cross-protection against other types, for example, HPV45. Both direct vaccine efficacy and indirect herd protection contribute to vaccination effectiveness. Methods: We used a dynamic transmission model, calibrated to cervical screening data from Italy, to estimate vaccination effectiveness against HPV16 and HPV45 infection, assuming for HPV45 either 95% or lower cross-protection. Results: Basic reproductive number was smaller (2.1 vs 4.0) and hence vaccine effectiveness and herd protection stronger for HPV45 than for HPV16. The largest difference in the reduction of infection prevalence in women <35 years old was found at 70% coverage in girls-only vaccination programs (99% vs 83% for total protection for HPV45 and HPV16, respectively, mainly owing to stronger herd protection, ie, 37% vs 16%). In gender-neutral vaccination, the largest difference was at 40% coverage (herd protection, 54% vs 28% for HPV16 and HPV45, respectively). With >=80% coverage, even 50% cross-protection would reduce HPV45 by >=94%. Conclusions: The characteristics of individual high-risk HPV types strongly influence herd protection and determine the level of coverage and cross-protection required to reduce or eliminate the infection through HPV vaccination. HPV16 infection and related cancers are the most difficult to eliminate. PMID- 28859433 TI - Cerebrospinal Fluid Leukotriene B4 and Soluble Tumor Necrosis Factor Receptor II Levels and Treatment Outcome in Tuberculous Meningitis. PMID- 28859432 TI - Naturally Acquired Immunity Against Rotavirus Infection and Gastroenteritis in Children: Paired Reanalyses of Birth Cohort Studies. AB - Background: Observational studies in socioeconomically distinct populations have yielded conflicting conclusions about the strength of naturally acquired immunity against rotavirus gastroenteritis (RVGE), mirroring vaccine underperformance in low-income countries. We revisited birth cohort studies to understand naturally acquired protection against rotavirus infection and RVGE. Methods: We reanalyzed data from 200 Mexican and 373 Indian children followed from birth to 2 and 3 years of age, respectively. We reassessed protection against RVGE, decomposing the incidence rate into the rate of rotavirus infection and the risk of RVGE given infection, and tested for serum antibody correlates of protection using regression models. Results: Risk for primary, secondary, and subsequent infections to cause RVGE decreased per log-month of age by 28% (95% confidence interval [CI], 12%-41%), 69% (95% CI, 30%-86%), and 64% (95% CI, -186% to 95%), respectively, in Mexico City, and by 10% (95% CI, -1% to 19%), 51% (95% CI, 41% 59%) and 67% (95% CI, 57%-75%), respectively, in Vellore. Elevated serum immunoglobulin A and immunoglobulin G titers were associated with partial protection against rotavirus infection. Associations between older age and reduced risk for RVGE or moderate-to-severe RVGE given infection persisted after controlling for antibody levels. Conclusions: Dissimilar estimates of protection against RVGE may be due in part to age-related, antibody-independent risk for rotavirus infections to cause RVGE. PMID- 28859434 TI - Reply to Neeradi et al and Dhawan and Sankhyan. PMID- 28859435 TI - Predictors of Mortality in Patients With Tuberculous. PMID- 28859436 TI - Prevalence of Drug-Resistant Minority Variants in Untreated HIV-1-Infected Individuals With and Those Without Transmitted Drug Resistance Detected by Sanger Sequencing. AB - Minority variant human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations are associated with an increased risk of virological failure during treatment with NNRTI-containing regimens. To determine whether individuals to whom variants with isolated NNRTI associated drug resistance were transmitted are at increased risk of virological failure during treatment with a non-NNRTI-containing regimen, we identified minority variant resistance mutations in 33 individuals with isolated NNRTI associated transmitted drug resistance and 49 matched controls. We found similar proportions of overall and nucleoside reverse transcriptase inhibitor-associated minority variant resistance mutations in both groups, suggesting that isolated NNRTI-associated transmitted drug resistance may not be a risk factor for virological failure during treatment with a non-NNRTI-containing regimen. PMID- 28859437 TI - SLC44A4 mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. PMID- 28859438 TI - Pharmacokinetics of once-daily dolutegravir and ritonavir-boosted darunavir in HIV patients: the DUALIS study. PMID- 28859439 TI - Trimethoprim/sulfamethoxazole versus vancomycin in the treatment of healthcare/ventilator-associated MRSA pneumonia: a case-control study-authors' response. PMID- 28859440 TI - Quantification of the risk of liver injury associated with flucloxacillin: a UK population-based cohort study. AB - Background: Flucloxacillin is an established cause of liver injury. Despite this, there are a lack of published data on both the strength of association after adjusting for potential confounders, and the absolute incidence among different subgroups of patients. Objectives: To assess the relative and absolute risks of liver injury following exposure to flucloxacillin and identify subgroups at potentially increased risk. Methods: A cohort study between 1 January 2000 and 1 January 2012 using the UK Clinical Practice Research Datalink, including 1 046 699 people with a first prescription for flucloxacillin (861 962) or oxytetracycline (184 737). Absolute risks of experiencing both symptom-defined (jaundice) and laboratory-confirmed liver injury within 1-45 and 46-90 days of antibiotic initiation were estimated. Multivariable logistic regression was used to estimate 1-45 day relative effects. Results: There were 183 symptom-defined cases (160 prescribed flucloxacillin) and 108 laboratory-confirmed cases (102 flucloxacillin). The 1-45 day adjusted risk ratio for laboratory-confirmed injury was 5.22 (95% CI 1.64-16.62) comparing flucloxacillin with oxytetracycline use. The 1-45 day risk of laboratory-confirmed liver injury was 8.47 per 100 000 people prescribed flucloxacillin (95% CI 6.64-10.65). People who received consecutive flucloxacillin prescriptions had a 1-45 day risk of jaundice of 39.00 per 100 000 (95% CI 26.85-54.77), while those aged >70 receiving consecutive prescriptions had a risk of 110.57 per 100 000 (95% CI 70.86-164.48). Conclusions: The short-term risk of laboratory-confirmed liver injury was >5-fold higher after a flucloxacillin prescription than an oxytetracycline prescription. The risk of flucloxacillin-induced liver injury is particularly high within those aged >70 and those who receive multiple flucloxacillin prescriptions. The stratified risk estimates from this study could help guide clinical care. PMID- 28859441 TI - Baicalein acts as a nephroprotectant that ameliorates colistin-induced nephrotoxicity by activating the antioxidant defence mechanism of the kidneys and down-regulating the inflammatory response. AB - Background: Nephrotoxicity is the major adverse effect patients experience during colistin therapy. The development of effective nephroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. Objectives: To investigate the nephroprotective effect of baicalein, a component of the root of Scutellaria baicalensis, against colistin-induced nephrotoxicity using a mouse model. Methods: C57BL/6 mice were randomly divided into the following groups: control, baicalein 100 mg/kg/day (administered orally), colistin (18 mg/kg/day administered intraperitoneally) and colistin (18 mg/kg/day) plus baicalein (25, 50 and 100 mg/kg/day). After 7 day treatments, histopathological damage, the markers of renal functions, oxidative stress and inflammation were examined. The expressions of Nrf2, HO-1 and NF kappaB mRNAs were also further examined using quantitative RT-PCR examination. Results: Baicalein co-administration markedly attenuated colistin-induced oxidative and nitrative stress, apoptosis, the infiltration of inflammatory cells, and caused decreases in IL-1beta and TNF-alpha levels (all P < 0.05 or 0.01) in the kidney tissues. Baicalein co-administration up-regulated expression of Nrf2 and HO-1 mRNAs and down-regulated the expression of NF-kappaB mRNA, compared with those in the colistin alone group. Conclusions: To the best of our knowledge, this is the first study demonstrating the protective effect of baicalein on colistin-induced nephrotoxicity and apoptosis by activating the antioxidant defence mechanism in kidneys and down-regulating the inflammatory response. Our study highlights that oral baicalein could potentially ameliorate nephrotoxicity in patients undergoing polymyxin therapy. PMID- 28859442 TI - Emerging multidrug resistance in community-associated Staphylococcus aureus involved in skin and soft tissue infections and nasal colonization. AB - Background: Staphylococcus aureus is a major pathogen causing significant morbidity and mortality worldwide. The emergence of MDR S. aureus strains in the community setting has major implications in disease management. However, data regarding the occurrence and patterns of MDR community-associated S. aureus sub clones is limited. Objectives: To use whole-genome sequences to describe the diversity and distribution of resistance mechanisms among community-associated S. aureus isolates. Methods: S. aureus isolates from skin and soft tissue infections (SSTIs) and nasal colonization were collected from patients within 10 primary care clinics from 2007 to 2015. The Illumina Miseq platform was used to determine the genome sequences for 144 S. aureus isolates. Phylogenetic and bioinformatics analyses were performed using in silico tools. The resistome was assembled and compared with the phenotypically derived antibiogram. Results: Approximately one third of S. aureus isolates in the South Texas primary care setting were MDR. A higher proportion of SSTI isolates were MDR in comparison with nasal colonization isolates. Individuals with MDR S. aureus SSTIs were more likely to be African American and obese. Furthermore, S. aureus populations are able to acquire and lose antimicrobial resistance genes. USA300 strains were differentiated by a stable chromosomal mutation in gyrA conferring quinolone resistance. The resistomes were highly predictive of antimicrobial resistance phenotypes. Conclusions: These findings highlight the high prevalence and epidemiological factors associated with MDR S. aureus strains in the community setting and demonstrate the utility of next-generation sequencing to potentially quicken antimicrobial resistance detection and surveillance for targeted interventions. PMID- 28859443 TI - Imbalance in mitochondrial dynamics and apoptosis in pregnancies among HIV infected women on HAART with obstetric complications. AB - Background: HIV infection and HAART trigger genetic and functional mitochondrial alterations leading to cell death and adverse clinical manifestations. Mitochondrial dynamics enable mitochondrial turnover and degradation of damaged mitochondria, which may lead to apoptosis. Objectives: To evaluate markers of mitochondrial dynamics and apoptosis in pregnancies among HIV-infected women on HAART and determine their potential association with obstetric complications. Methods: This controlled, single-site, observational study without intervention included 26 HIV-infected pregnant women on HAART and 18 control pregnancies and their newborns. Maternal PBMCs and neonatal cord blood mononuclear cells (CBMCs) were isolated at the first trimester of gestation and at delivery. The placenta was homogenized at 5% w/v. Mitochondrial dynamics, fusion events [mitofusin 2 (Mfn2)/beta-actin] and fission events [dynamin-related protein 1 (Drp1/beta actin)] and apoptosis (caspase 3/beta-actin) were assessed by western blot analysis. Results: Obstetric complications were significantly more frequent in pregnancies among HIV-infected women [OR 5.00 (95% CI 1.21-20.70)]. Mfn2/beta actin levels in PBMCs from controls significantly decreased during pregnancy (202.13 +/- 57.45%), whereas cases maintained reduced levels from the first trimester of pregnancy and no differences were observed in CBMCs. Mfn2/beta-actin and Drp1/beta-actin contents significantly decreased in the placenta of cases. Caspase 3/beta-actin levels significantly increased during pregnancy in PBMCs of cases (50.00 +/- 7.89%), remaining significantly higher than in controls. No significant differences in caspase 3/beta-actin content of neonatal CBMCs were observed, but there was a slight increased trend in placenta from cases. Conclusions: HIV- and HAART-mediated mitochondrial damage may be enhanced by decreased mitochondrial dynamics and increased apoptosis in maternal and placental compartments but not in the uninfected fetus. However, direct effects on mitochondrial dynamics and implication of apoptosis were not demonstrated in adverse obstetric outcomes. PMID- 28859444 TI - Evaluation of combinations of putative anti-biofilm agents and antibiotics to eradicate biofilms of Staphylococcus aureus and Pseudomonas aeruginosa. AB - Objectives: To evaluate potential anti-biofilm agents for their ability to enhance the activity of antibiotics for local treatment of localized biofilm infections. Methods: Staphylococcus aureus and Pseudomonas aeruginosa in vitro biofilm models were developed. The putative antibiotic enhancers N acetylcysteine, acetylsalicylic acid, sodium salicylate, recombinant human deoxyribonuclease I, dispersin B, hydrogen peroxide and Johnson's Baby Shampoo (JBS) were tested for their anti-biofilm activity alone and their ability to enhance the activity of antibiotics for 7 or 14 days, against 5 day old biofilms. The antibiotic enhancers were paired with rifampicin and clindamycin against S. aureus and gentamicin and ciprofloxacin against P. aeruginosa. Isolates from biofilms that were not eradicated were tested for antibiotic resistance. Results: Antibiotic levels 10* MIC and 100* MIC significantly reduced biofilm, but did not consistently eradicate it. Antibiotics at 100* MIC with 10% JBS for 14 days was the only treatment to eradicate both staphylococcal and pseudomonal biofilms. Recombinant human deoxyribonuclease I significantly reduced staphylococcal biofilm. Emergence of resistance of surviving isolates was minimal and was often associated with the small colony variant phenotype. Conclusions: JBS enhanced the activity of antibiotics and several other promising anti-biofilm agents were identified. Antibiotics with 10% JBS eradicated biofilms produced by both organisms. Such combinations might be useful in local treatment of localized biofilm infections. PMID- 28859446 TI - OXA-427, a new plasmid-borne carbapenem-hydrolysing class D beta-lactamase in Enterobacteriaceae. AB - Objectives: To describe a novel plasmid-borne class D carbapenemase (CHDL) named OXA-427 identified in several Enterobacteriaceae clinical isolates from nine patients in one Belgian hospital. Methods: OXA-427-producing isolates were analysed by an electrochemical imipenem hydrolysis method (BYG Carba test), Carba NP test, conventional phenotypic assays and by molecular methods (PCR, whole sequencing of the OXA-427-encoding plasmid and cloning). The antimicrobial resistance profile of OXA-427 was analysed by expression of the cloned gene in Escherichia coli DH10B and J53. Results: Eleven OXA-427-producing Enterobacteriaceae isolates of various species were identified from clinical specimens of nine patients between March 2012 and June 2014. OXA-427 shares only 22%-29% amino acid identity with OXA-48-like enzymes and other acquired CHDL (e.g. OXA-23, -24/40 and -58 of Acinetobacter spp.). Conversely, it appeared closely related to the chromosomal class D beta-lactamase of Aeromonas media, Aeromonas hydrophila and Aeromonas sobria (99%, 89% and 77% of identity, respectively). When expressed in E. coli, OXA-427 hydrolysed imipenem and conferred resistance to extended-spectrum cephalosporins (mostly ceftazidime), penicillins including temocillin, and reduced susceptibility to carbapenems. The blaOXA-427 gene was located in a 45 kb resistance island on a 177 kb IncA/C plasmid. Conclusions: OXA-427 is a novel CHDL most closely related to chromosomal class D beta-lactamase of A. media WS. It confers resistance to penicillins, ceftazidime and aztreonam and in some instances to carbapenems. OXA-427, which is not detectable by classical molecular tests, caused a protracted outbreak in one university hospital over a 2 year period. PMID- 28859445 TI - Social and professional influences on antimicrobial prescribing for doctors-in training: a realist review. AB - Background: Antimicrobial resistance has led to widespread implementation of interventions for appropriate prescribing. However, such interventions are often adopted without an adequate understanding of the challenges facing doctors-in training as key prescribers. Methods: The review followed a realist, theory driven approach to synthesizing qualitative, quantitative and mixed-methods literature. Consistent with realist review quality standards, articles retrieved from electronic databases were systematically screened and analysed to elicit explanations of antimicrobial prescribing behaviours. These explanations were consolidated into a programme theory drawing on social science and learning theory, and shaped though input from patients and practitioners. Results: By synthesizing data from 131 articles, the review highlights the complex social and professional dynamics underlying antimicrobial prescribing decisions of doctors in-training. The analysis shows how doctors-in-training often operate within challenging contexts (hierarchical relationships, powerful prescribing norms, unclear roles and responsibilities, implicit expectations about knowledge levels, uncertainty about application of knowledge in practice) where they prioritize particular responses (fear of criticism and individual responsibility, managing one's reputation and position in the team, appearing competent). These complex dynamics explain how and why doctors-in-training decide to: (i) follow senior clinicians' prescribing habits; (ii) take (or not) into account prescribing aids, advice from other health professionals or patient expectations; and (iii) ask questions or challenge decisions. This increased understanding allows for targeted tailoring, design and implementation of antimicrobial prescribing interventions. Conclusions: This review contributes to a better understanding of how antimicrobial prescribing interventions for doctors-in-training can be embedded more successfully in the hierarchical and inter-professional dynamics of different healthcare settings. PMID- 28859447 TI - HIV-1 non-group M phenotypic susceptibility to integrase strand transfer inhibitors. AB - Objectives: To determine natural phenotypic susceptibility of non-group M HIV-1 to integrase strand transfer inhibitors (INSTIs) in a large panel of 39 clinical strains from groups O, N and P and to identify genotypic polymorphisms according to susceptibility levels. Methods: Susceptibility to raltegravir, elvitegravir and dolutegravir was evaluated in 36 HIV-1/O, 2 HIV-1/N and 1 HIV-1/P strains plus an HIV-1/M reference strain. IC50 values were determined after 3 days, and fold changes (FCs) were calculated relative to the HIV-1/M strain. Genotypic polymorphism was determined by amplification of codons 19-263 of the integrase; the natural occurrence of resistance-associated mutations was analysed using the main resistance algorithms and the IAS-USA list. VESPA analysis of the strain sequences was used to determine a signature pattern associated with higher FC. Results: Similar IC50 results were observed for the three drugs. Based on the value for the HIV-1/M reference strain, the data showed FC values <2.5 for raltegravir and dolutegravir, whereas the distribution for elvitegravir was heterogeneous, with FC > 10 for six strains (15%). Analysis of the non-M integrase sequences showed a high level of polymorphism without a major genotypic impact; it also revealed mutations that may be associated with the highest FC values obtained for elvitegravir. Conclusions: Our phenotypic data showed that non-M strains are globally susceptible to the three currently used INSTIs, but the impact of the high FC values observed for some strains with elvitegravir needs to be explored. Clinical data are now needed to confirm these phenotypic results. PMID- 28859448 TI - MASTER: a model to improve and standardize clinical breakpoints for antimicrobial susceptibility testing using forecast probabilities. AB - Objectives: The procedure for setting clinical breakpoints (CBPs) for antimicrobial susceptibility has been poorly standardized with respect to population data, pharmacokinetic parameters and clinical outcome. Tools to standardize CBP setting could result in improved antibiogram forecast probabilities. We propose a model to estimate probabilities for methodological categorization errors and defined zones of methodological uncertainty (ZMUs), i.e. ranges of zone diameters that cannot reliably be classified. The impact of ZMUs on methodological error rates was used for CBP optimization. Methods: The model distinguishes theoretical true inhibition zone diameters from observed diameters, which suffer from methodological variation. True diameter distributions are described with a normal mixture model. The model was fitted to observed inhibition zone diameters of clinical Escherichia coli strains. Repeated measurements for a quality control strain were used to quantify methodological variation. Results: For 9 of 13 antibiotics analysed, our model predicted error rates of < 0.1% applying current EUCAST CBPs. Error rates were > 0.1% for ampicillin, cefoxitin, cefuroxime and amoxicillin/clavulanic acid. Increasing the susceptible CBP (cefoxitin) and introducing ZMUs (ampicillin, cefuroxime, amoxicillin/clavulanic acid) decreased error rates to < 0.1%. ZMUs contained low numbers of isolates for ampicillin and cefuroxime (3% and 6%), whereas the ZMU for amoxicillin/clavulanic acid contained 41% of all isolates and was considered not practical. Conclusions: We demonstrate that CBPs can be improved and standardized by minimizing methodological categorization error rates. ZMUs may be introduced if an intermediate zone is not appropriate for pharmacokinetic/pharmacodynamic or drug dosing reasons. Optimized CBPs will provide a standardized antibiotic susceptibility testing interpretation at a defined level of probability. PMID- 28859449 TI - Erratum to: "New dimensions for extracorporeal circulation [Interact CardioVasc Thorac Surg (2017) 24(4):479-481]". PMID- 28859450 TI - eComment. Noonan syndrome and biventricular hypertrophic obstructive cardiomyopathy. PMID- 28859452 TI - Letter: Results of the ANSWER Trial Using the PulseRider for the Treatment of Broad-Necked, Bifurcation Aneurysms. PMID- 28859453 TI - Comparison of Complications, Trends, and Costs in Endoscopic vs Microscopic Pituitary Surgery: Analysis From a US Health Claims Database. AB - BACKGROUND: Microsurgical and endoscopic techniques are commonly utilized surgical approaches to pituitary pathologies. There are limited data comparing these 2 procedures. OBJECTIVE: To evaluate postoperative complications, associated costs, and national and regional trends of microscopic and endoscopic techniques in the United States employing a nationwide database. METHODS: The Truven MarketScan database 2010 to 2014 was queried and Current Procedural Terminology codes identified patients that underwent microscopic and/or endoscopic transsphenoidal pituitary surgery. International Classification of Diseases codes identified postoperative complications. Adjusted logistic regression and matched propensity analysis evaluated independent odds for complications. RESULTS: Among 5886 cases studied, 54.49% were microscopic and 45.51% endoscopic. The commonest surgical indications were benign pituitary tumors. Annual trends showed increasing utilization of endoscopic techniques vs microscopic procedures. Postoperative complications occurred in 40.04% of cases, including diabetes insipidus (DI; 16.90%), syndrome of inappropriate antidiuretic hormone (SIADH; 2.02%), iatrogenic hypopituitarism (1.36%), fluid/electrolyte abnormalities (hypoosmolality/hyponatraemia [5.03%] and hyperosmolality/hypernatraemia [2.48%]), and cerebrospinal fluid (CSF) leaks (CSF rhinorrhoea [4.42%] and other CSF leak [6.52%]). In our propensity-based model, patients that underwent endoscopic surgery were more likely to develop DI (odds ratio [OR] = 1.48; 95% confidence interval [CI] = 1.28-1.72), SIADH (OR = 1.53; 95% CI = 1.04-2.24), hypoosmolality/hyponatraemia (OR = 1.17; 95% CI = 1.01 1.34), CSF rhinorrhoea (OR = 2.48; 95% CI = 1.88-3.28), other CSF leak (OR = 1.59; 95% CI = 1.28-1.98), altered mental status (OR = 1.46; 95% CI = 1.01-2.60), and postoperative fever (OR = 4.31; 95% CI = 1.14-16.23). There were no differences in hemorrhagic complications, ophthalmological complications, or bacterial meningitis. Postoperative complications resulted in longer hospitalization and increased healthcare costs. CONCLUSION: Endoscopic approaches are increasingly being utilized to manage sellar pathologies relative to microsurgery. Postoperative complications occur in both techniques with higher incidences observed following endoscopic procedures. PMID- 28859454 TI - Subcutaneous Solar Cells Harvest Energy for Pulse Generation. PMID- 28859455 TI - 3K3A-Activated Protein C and Implanted Neural Stem Cells Stimulate Repair and Functional Recovery After Ischemic Stroke. PMID- 28859456 TI - Colony Stimulating Factor-1 Receptor Inhibitors-A 4 for 1 Deal in the Desire to Improve Glioma Radiotherapy. PMID- 28859457 TI - Diffuse Midline Gliomas: Closer to a Cure? PMID- 28859458 TI - From Nodes to Networks: Can Virtual Resections Predict Neurosurgical Outcomes in Focal Epilepsy? PMID- 28859459 TI - From the Bottom Up: The Role of Sacral Pattern Generators in Modulating Rostral Lumbar Flexor Motor Neurons. PMID- 28859460 TI - Intracranial Electroencephalography for Alzheimer's. PMID- 28859461 TI - Randomized Trial for Short-Term Radiation Therapy With Temozolomide in Elderly Patients With Glioblastoma. PMID- 28859462 TI - Sustained Benefit of Endovascular Therapy in Acute Ischemic Stroke. PMID- 28859463 TI - Neuroanatomical Interpretation of the Painting Starry Night by Vincent van Gogh. AB - Gogh, Vincent Van (1853-1890). The Starry Night. Saint Remy, June 1889. Oil on canvas, 29 * 36 1/4" (73.7 * 92.1 cm). Acquired through the Lillie P. Bliss Bequest. The Museum of Modern Art. Digital Image (c) The Museum of Modern Art/Licensed by SCALA/Art Resource, NY. PMID- 28859464 TI - How to Proceed in the Disease Concept Debate? A Pragmatic Approach. AB - In the traditional philosophical debate over different conceptual analyses of "disease," it is often presupposed that "disease" is univocally definable and that there are clear boundaries which distinguish this univocal category "disease" from the category of "nondisease." In this paper, I will argue for a shift in the discussion on the concept of "disease" and propose an alternative, pragmatic approach that is based on the conviction that "disease" is not a theoretical concept but a practical term. I develop a view on which our use of the term "disease" is determined by two interacting factors, namely, value-laden considerations about the (un)desirabilty of certain states and discoveries of cause(s) which is/are explanatorily relevant. I show how these factors interact with regard to a taxonomy of kinds of diseases. This pragmatic approach will not lead me to a final definition of "disease," but will result in a more realistic description of the way we build, use, apply, and change our concept of "disease." Meanwhile, it is useful as a basis for critical reflection on disease-labeling in medicine. PMID- 28859465 TI - Progress in Defining Disease: Improved Approaches and Increased Impact. AB - In a series of recent papers, I have made three arguments about how to define "disease" and evaluate and apply possible definitions. First, I have argued that definitions should not be seen as traditional conceptual analyses, but instead as proposals about how to define and use the term "disease" in the future. Second, I have pointed out and attempted to address a challenge for dysfunction-requiring accounts of disease that I call the "line-drawing" problem: distinguishing between low-normal functioning and dysfunctioning. Finally, I have used a dysfunction-requiring approach to argue that some extremely prevalent conditions, such as high blood pressure, high cholesterol, and ductal carcinoma in situ, are not diseases, but instead are risk factors. Four of the papers in this issue directly engage my previous work. In this commentary, I applaud the advances these authors make, address points of disagreement, and make suggestions about where the discussion should go next. PMID- 28859466 TI - Prevalence of thyroid nodules and their associated clinical parameters: a large scale, multicenter-based health checkup study. AB - Background/Aims: We evaluated the prevalence and characteristics of thyroid nodules detected by thyroid ultrasound (US) at health checkups and the associated clinical parameters. METHODS: A total of 72,319 subjects who underwent thyroid US at three health checkup centers in Korea from January 2004 to December 2010 were included in this study. The correlations between the presence of thyroid nodules and other clinical parameters were analyzed. RESULTS: The prevalence of thyroid nodules and cysts was 34.2% (n = 24,757). Thyroid nodules were more prevalent in women and older age groups. Among the subjects with thyroid nodules with size information (n = 24,686), 18,833 (76.3%) had nodules measuring <= 1.0 cm. Women and older age groups showed higher proportion of larger nodules. Percentage of women, age, body mass index (BMI), waist circumference, body fat composition, blood pressure, and the level of fasting glucose, total cholesterol, and low density lipoprotein cholesterol were higher in the subjects with thyroid nodules compared to those without nodules. The prevalence of metabolic syndrome and overt/subclinical thyrotoxic state was higher in the subjects with thyroid nodules. In the multivariable logistic regression analysis, women, age, BMI, metabolic syndrome, and thyrotoxicosis were independently associated with the presence of thyroid nodules. Conclusions: The high prevalence of thyroid nodules in people who underwent thyroid US at a health checkup suggests that increased detection of thyroid nodules resulted in an increased prevalence in the general population. However, metabolic disturbances may also have contributed to the increase in thyroid nodule prevalence in Korea. PMID- 28859467 TI - Transradial versus transfemoral intervention in ST-segment elevation myocardial infarction patients in Korean population. AB - Background/Aims: Transradial intervention (TRI) is becoming the preferred method over transfemoral intervention (TFI) because TRI is associated with lower incidence of major bleeding and vascular complications. However, there has been limited published data regarding the clinical outcomes of TRI versus TFI in Korean patients with ST-elevation myocardial infarction (STEMI). METHODS: A total of 689 consecutive STEMI patients who underwent primary percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) from January to December of 2009 at nine university hospitals were enrolled in this study. Mid-term angiographic and 12-month cumulative clinical outcomes of the TRI group (n = 220, 31.9%) were compared to those of the TFI group (n = 469, 28.1%). RESULTS: After propensity score matching, in-hospital complications and the 12-month major clinical outcomes during follow-up in the two groups were similar to each other. However, the incidence rates of repeat revascularization (6.4% vs. 0.5%, p = 0.003), target vessel revascularization (6.4% vs. 0.5%, p = 0.003), and major adverse cardiac events (MACE; 11.6% vs. 4.6%, p = 0.018) in the TFI group were higher than those in the TRI group during the 12-month of follow-up. Conclusions: In our study, TRI in STEMI patients undergoing primary PCI with DESs was associated with lower incidence of access site hematoma, 12-month repeat revascularization, and MACE compared to TFI. Therefore, TRI might play an important role in reducing bleeding complications while improving major clinical outcomes in STEMI patients undergoing primary PCI with DESs. PMID- 28859468 TI - Clinical and microbiological factors associated with early patient mortality from methicillin-resistant Staphylococcus aureus bacteremia. AB - Background/Aims: Methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) is a major bloodstream infection with a high mortality rate. Identification of factors associated with early mortality in MRSAB patients would be useful for predicting prognosis and developing new therapeutic options. Methods: A prospective cohort of MRSAB patients was examined between August 2008 and June 2011. Early and late mortality was defined as death within 2 and 28 days of blood culture, respectively. The clinical and microbiological characteristics in the early and late mortality and survival groups were compared. Risk factors associated with severe sepsis or septic shock were also investigated. Results: A total of 385 adult MRSAB patients whose S. aureus isolates were available were enrolled; of these patients, 25 patients (6.5%) and 50 (13%) died early and late, respectively. Compared with both the late-mortality group and the survival group, severe sepsis or septic shock was a statistically significant independent risk factor associated with early mortality. Rapidly or ultimately fatal McCabe and Jackson classification (adjusted odds ratio [aOR], 1.94; 95% confidence interval [CI], 1.25 to 3.02) and pneumonia (aOR, 2.04; 95% CI, 1.03 to 4.02) were independently associated with severe sepsis or septic shock. A vancomycin minimum inhibitory concentration (MIC) >= 1.5 MUg/mL was associated with a reduced incidence of severe sepsis or septic shock (aOR, 0.53; 95% CI, 0.34 to 0.84). Conclusions: Severity of illness seems to be the most important risk factor associated with early mortality in MRSAB. Although vancomycin MIC was not independently associated with early mortality, reduced vancomycin susceptibility appears to be linked to reduced disease severity. PMID- 28859469 TI - Histologically confirmed nonbacterial thrombotic endocarditis in a febrile leukemic patient. PMID- 28859470 TI - Medication nonadherence in Korean patients with rheumatoid arthritis: the importance of belief about medication and illness perception. AB - BACKGROUND/AIMS: To investigate medication nonadherence in Korean patients with rheumatoid arthritis (RA) and analyze related factors. METHODS: A total of 292 patients with RA participated in this study. Medication nonadherence, intentional or unintentional, was gauged via self-reported questionnaire. Patient perceptions of illness, treatment beliefs, and moods were measured via Brief Illness Perception Questionnaire, Beliefs about Medicines Questionnaire, and Patient Health Questionnaire-2, respectively. Demographic and clinical data were also collected. Multinomial regression analysis was used to assess the impact of demographic, clinical, and psychological factors on medication nonadherence. RESULTS: The medication nonadherence rate was 54.1% (intentional, 21.6%; unintentional, 32.5%). Intentional nonadherence was reported most often in patients treated daily drugs (nonsteroidal anti-inflammatory drugs and/or disease modifying antirheumatic drugs) (24.2%), and unintentional nonadherence was highest in patients receiving methotrexate (33.3%) (p = 0.872). In univariate analysis, beliefs in necessity and concerns of medication differed significantly in adherent and nonadherent patients (intentional or unintentional). When controlling for other factors that may impact medication nonadherence, less belief in necessity of medication (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.68 to 0.95) and greater emotional response to disease (OR, 1.19; 95% CI, 1.01 to 1.40) were important predictors of intentional nonadherence. CONCLUSIONS: Medication nonadherence is common in Korean patients with RA. Less belief in necessity of medication and greater emotional response to disease were identified as key factors prompting intentional nonadherence. These factors may be strategically targeted to improve medication adherence rates and subsequent clinical outcomes. PMID- 28859471 TI - Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors. AB - Purpose: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. Materials and Methods: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort. Results: A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Doselimiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD >= 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer). Conclusion: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers. PMID- 28859472 TI - Fish consumption, mercury exposure, and the risk of cholesterol profiles: findings from the Korea National Health and Nutrition Examination Survey 2010 2011. AB - In this study, the associations between mercury (Hg) exposure and cholesterol profiles were analyzed, and increased Hg levels and cholesterol profiles according to the amount of fish consumption were evaluated. Data on levels of blood Hg, the frequency of fish consumption, total blood cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), and triglyceride (TG) in 3951 adults were obtained from the Korea National Health and Nutrition Examination Survey 2010-2011 database. To compare the distribution for each log-transformed indicator, Student's t-test and analysis of variance were carried out, and the groups were classified according to the frequency of fish consumption through linear regression analysis; the association between Hg level and cholesterol profiles in each group was analyzed. The blood Hg levels (arithmetic mean, median, and geometric mean) for all target participants were 4.59, 3.66, and 3.74 ug/L, respectively. The high cholesterol group, low HDL-C group, and high TG group showed a statistically and significantly higher blood Hg level than the low-risk group. In both sexes, as the frequency of fish consumption increased, blood Hg level also increased, but TC, HDL-C, LDL-C, and TG did not show a similar trend. Increased blood Hg level showed a significant association with increased TC and LDL-C. This statistical significance was maintained in the group with less frequent fish consumption (<4 times per month), but the group with frequent fish consumption (>8 times per month) did not show a similar trend. The results of this study suggest that fish consumption increases the level of Hg exposure, and that as the level of Hg exposure increases, the levels of cholesterol profiles increase. However, this study also suggests that the levels of cholesterol profiles in those with frequent fish consumption can be diminished. PMID- 28859473 TI - Reactivity of Cork Extracts with (+)-Catechin and Malvidin-3-O-glucoside in Wine Model Solutions: Identification of a New Family of Ellagitannin-Derived Compounds (Corklins). AB - The aim of this study was to evaluate the reactivity of phenolic compounds extracted from cork stoppers to wine model solutions with two major wine components, namely, (+)-catechin and malvidin-3-O-glucoside. Besides the formation of some compounds already described in the literature, these reactions also yielded a new family of ellagitannin-derived compounds, named herein as corklins. This new family of compounds that were found to result from the interaction between ellagitannins in alcoholic solutions and (+)-catechin were structurally characterized by mass spectroscopy, nuclear magnetic resonance, and computational methods. PMID- 28859474 TI - Aggregated Single-Walled Carbon Nanotubes Absorb and Deform Dopamine-Related Proteins Based on Molecular Dynamics Simulations. AB - Single-walled carbon nanotubes (SWCNTs) have attracted considerable attention owing to their applications in various fields such as biotechnology and biomedicine. Recently, aggregated SWCNTs have shown more significant effects on the treatment of methamphetamine addiction (Nat. Nanotech. 2016, 11, 613). However, the mechanisms underlying these actions are unclear. By using all-atom molecular dynamics simulations, we investigate the effects of single and aggregated SWCNTs (single-(10,10)CNT, aggregated-7-(10,10)CNTs, and single (35,35)CNT with the same diameter as that of the aggregated one) on the activity of dopamine-related proteins [tyrosine hydroxylase (TyrOH) and dopamine transporter (DAT), which are related to the synthesis and transport of dopamine, respectively]. We find that both TyrOH and DAT can adsorb onto these SWCNTs. For TyrOH, the aggregated-7-(10,10)CNTs mainly affect the conformation of the active site of the protein, and hence, they are more effective in inhibiting the expression of TyrOH. For DAT, our results suggest that the aggregated-7 (10,10)CNTs allow DAT to maintain an outward-facing conformation and hence are favorable to the reuptake of dopamine. The binding of a dopamine reuptake inhibitor, [3H]-WIN35,428, to DAT is significantly disrupted by aggregated-7 (10,10)CNTs and hence improve the ability to transport dopamine. Our results provide the dynamic interactions of proteins with single/aggregated SWCNTs, which illustrate the mechanism of aggregated SWCNTs for the treatment of drug addiction. PMID- 28859476 TI - Investigation of the Effects of Sodium Dicarboxylates on the Crystal Habit of Calcium Sulfate alpha-Hemihydrate. AB - The effects of disodium malonate, disodium succinate, disodium glutarate, and disodium adipate on the crystal habit of calcium sulfate alpha-hemihydrate (CaSO4.0.5H2O, alpha-CSH) were studied using experimental studies and molecular dynamics simulations. The calculation and experimental results provided insight into the mechanism of the interaction between the additives mentioned above and the different faces of alpha-CSH that dominate the morphology of alpha-CSH. The calculation results indicated that the formation of high-aspect-ratio alpha-CSH, namely, calcium sulfate alpha-hemihydrate whiskers (alpha-CSH whiskers), in aqueous solution was due to the interaction between liquid water and side faces of the alpha-CSH crystal, which inhibits the growth of alpha-CSH along the radial direction. However, when a trace amount of crystal habit modifier, such as disodium succinate or disodium glutarate, was added to the aqueous solution, the growth rates along the directions normal to the {0 0 1} and {1 1 4} faces were considerably inhibited. Thus, alpha-CSH crystals with a low aspect ratio were synthesized using a hydrothermal method. In addition, the calculation methodology used in this work could provide a powerful tool for selecting suitable crystal habit modifiers for preparing alpha-CSH and other inorganic crystals. PMID- 28859475 TI - Identification of SLIRP as a G Quadruplex-Binding Protein. AB - The guanine quadruplex (G4) structure in DNA is a secondary structure motif that plays important roles in DNA replication, transcriptional regulation, and maintenance of genomic stability. Here, we employed a quantitative mass spectrometry-based approach to profile the interaction proteomes of three well defined G4 structures derived from the human telomere and the promoters of cMYC and cKIT genes. We identified SLIRP as a novel G4-interacting protein. We also demonstrated that the protein could bind directly with G4 DNA with Kd values in the low nanomolar range and revealed that the robust binding of the protein toward G4 DNA requires its RRM domain. We further assessed, by using CRISPR-Cas9 introduced affinity tag and ChIP-Seq analysis, the genome-wide occupancy of SLIRP, and showed that the protein binds preferentially to G-rich DNA sequences that can fold into G4 structures. Together, our results uncovered a novel cellular protein that can interact directly with G4 DNA, which underscored the complex regulatory networks involved in G4 biology. PMID- 28859477 TI - Adsorption and Phase Behavior of Pure/Mixed Alkanes in Nanoslit Graphite Pores: An iSAFT Application. AB - The prediction of fluid phase behavior in nanoscale pores is critical for shale gas/oil development. In this work, we use a molecular density functional theory (DFT) to study the effect of molecular size and shape on partitioning to graphite nanopores as a model of shale. Here, interfacial statistical associating fluid theory (iSAFT) is applied to model alkane (C1 - C8) adsorption/desorption/phase behavior in graphite slit pores for both pure fluids and mixtures. The pure component parameters were fit to the bulk saturated liquid density and vapor pressure data in selected temperature ranges. The potential of interaction between the fluid and graphite is modeled with a Steele 10-4-3 potential that is fit to the potential of mean force from single-molecule simulations. Good agreement is found between theory and molecular simulation for the density distributions of pure components in slit pores. The critical properties of methane, ethane, and their mixtures as well as the shift in bubble point and dew point densities were studied, showing good agreement with simulation. The competitive adsorption of mixtures of normal and branched alkanes in graphite pores was also studied. Heavier components more strongly adsorb up to the point that the entropic penalty due to confinement reduces adsorption. PMID- 28859478 TI - Computationally Mapping pKa Shifts Due to the Presence of a Polyelectrolyte Chain around Whey Proteins. AB - Experimental studies have shown the formation of soluble complexes in the pure repulsive Coulombic regime even when the net charges of the protein and the polyelectrolyte have the same sign ( De Kruif et al. Curr. Opin. Colloid Interface Sci. 2004 , 9 , 340 ; De Vries et al. J. Chem. Phys. 2003 , 118 , 4649 ; Grymonpre et al. Biomacromolecules 2001 , 2 , 422 ; Hattori et al. Langmuir 2000 , 16 , 9738 ). This attractive phenomenon has often been described as "complexation on the wrong side of pI". While one theory assumes the existence of "charged patches" on the protein surface from ion-dipole interactions, thus allowing a polyelectrolyte to bind to an oppositely heterogeneous charged protein region, another theoretical view considers the induced-charge interactions to be the dominant factor in these complexations. This charge regulation mechanism can be described by proton fluctuations resulting from mutual rearrangements of the distributions of the charged groups, due to perturbations of the acid-base equilibrium. Using constant-pH Monte Carlo simulations and several quantitative and visual analysis tools, we investigate the significance of each of these interactions for two whey proteins, alpha-lactalbumin (alpha-LA) and lysozyme (LYZ). Through physical chemistry parameters, free energies of interactions, and the mapping of amino acid pKa shifts and polyelectrolyte trajectories, we show the charge regulation mechanism to be the most important contributor in protein polyelectrolyte complexation regardless of pH, dipole moment, and protein capacitance in a low salt regime. PMID- 28859479 TI - Effect of Adsorbed Alcohol Layers on the Behavior of Water Molecules Confined in a Graphene Nanoslit: A Molecular Dynamics Study. AB - With the rapid development of a two-dimensional (2D) nanomaterial, the confined liquid binary mixture has attracted increasing attention, which has significant potential in membrane separation. Alcohol/water is one of the most common systems in liquid-liquid separation. As one of the most focused systems, recent studies have found that ethanol molecules were preferentially adsorbed on the inner surface of the pore wall and formed an adsorbed ethanol layer under 2D nanoconfinement. To evaluate the effect of the alcohol adsorption layer on the mobility of water molecules, molecular simulations were performed to investigate four types of alcohol/water binary mixtures confined under a 20 A graphene slit. Residence times of the water molecules covering the alcohol layer were in the order of methanol/water < ethanol/water < 1-propanol/water < 1-butanol/water. Detailed microstructural analysis of the hydrogen bonding (H-bond) network elucidated the underlying mechanism on the molecular scale in which a small average number of H-bonds between the preferentially adsorbed alcohol molecules and the surrounding water molecules could induce a small degree of damage to the H-bond network of the water molecules covering the alcohol layer, resulting in the long residence time of the water molecules. PMID- 28859480 TI - Self-Assembled DNA Generated Electric Current Biosensor for HER2 Analysis. AB - We have developed a new DNA self-assembly amplification technology that generates electric current for electrochemical biosensing. The new technology was used for detection of human epidermal growth factor receptor 2 (HER2). In our technology, an aptamer was utilized both as a ligand for recognition and as a signal generating reporter. The aptasensor is based on a sandwich format and a DNA primer on a HER2 aptamer initiates auxiliary DNA self-assembled on the electrode to form a long one-dimensional DNA. The resulting DNA is then reacted with molybdate to generate electrochemical current. The sensitivity of the aptasensor with DNA self-assembly was greater than that of the aptasensor without DNA self assembly due to the extended length of the DNA strand. Aptasensor analysis of HER2 in serum of breast cancer patients and healthy individuals is highly correlated (R2 = 0.9924) with ELISA measurements, with a p value of 1.37 * 10-7. The analysis of HER2 in serum (confirmed by ELISA) suggests that HER2 levels in breast cancer patients are much higher than healthy individuals. For HER2 positive patients, the levels are higher than those of HER2 negative patients. After surgery, there is a drop of HER2 levels in serum, suggesting potential clinical applications of the new self-assembled DNA electric current generating biosensor. Unlike proteins, DNA is easily amplifiable. The DNA signal amplification method presented here enables effective current generation, which can find wide range of biomedical applications for protein detection. PMID- 28859481 TI - Dissolution Kinetics of Hot Compressed Oxide Glasses. AB - The chemical durability of oxide glasses is an important property for a wide range of applications and can in some cases be tuned through composition optimization. However, these possibilities are relatively limited because around 3/5 of the atoms in most oxide glasses are oxygens. An alternative approach involves post-treatment of the glass. In this work, we focus on the effect of hot compression on dissolution kinetics because it is known to improve, for example, elastic moduli and hardness, whereas its effect on chemical durability is poorly understood. Specifically, we study the bulk glass dissolution rate of phosphate, silicophosphate, borophosphate, borosilicate, and aluminoborosilicate glasses, which have been compressed at 0.5, 1.0, and 2.0 GPa at the glass transition temperature (Tg). We perform weight loss and supplementary modifier leaching measurements of bulk samples immersed in acid (pH 2) and neutral (pH 7) solutions. Compression generally improves the chemical durability as measured from weight loss, but the effect is highly composition- and pressure-dependent. As such, we show that the dissolution mechanisms depend on the topological changes induced by permanent densification, which in turn are a function of the changes in the number of nonbridging oxygens and the network cross-linking. We also demonstrate a direct relationship between the chemical durability and the number of chemical topological constraints per atom (nc) acting within the molecular network. PMID- 28859482 TI - Comprehensive Analysis of Acylcarnitine Species in db/db Mouse Using a Novel Method of High-Resolution Parallel Reaction Monitoring Reveals Widespread Metabolic Dysfunction Induced by Diabetes. AB - Acylcarnitines are exerting a variety of biological functions depending on the differences in lengths, saturation levels, and conjugation groups, which to a great extent contribute to the challenges of acylcarnitines quantifications due to various kinds of isomers. Here, we describe a novel method by using high resolution parallel reaction monitoring (PRM) liquid chromatography-tandem mass spectrometry (LC-MS/MS). Both reversed-phase and normal-phase column were used in order to get accurate, reliable, widespread quantification of acylcarnitines, and without tedious sample preparation procedure. The method provided the most comprehensive acylcarnitine profile with high-resolution MS and MS/MS confirmation to date. A total of 117 acylcarnitines were detected from plasma and urine samples. The application of targeted profiling of acylcarnitines in db/m+ control and db/db diabetic mice indicated incomplete amino acid and fatty acid oxidation on diabetic mice. Interestingly, the reduction of medium odd-numbered chain acylcarnitines in urine samples was first observed between db/m+ and db/db mice. The high-resolution PRM method makes it possible to monitor the widespread metabolic changes of the acylcarnitines in response to stimuli. Besides, the accurate MS and MS/MS spectra data of the 117 acylcarnitines could be used as mass spectrometric resources for the identification of acylcarnitines. PMID- 28859483 TI - Interaction of a synthetic antimicrobial peptide with a model bilayer platform mimicking bacterial membranes. AB - Tethered bimolecular lipid membranes are solid supported membrane systems, which provide a versatile model platform for the study of many membrane related processes. Here, such an architecture has been used to study the interaction of the small synthetic antimicrobial peptide, V4, with membranes of various mixed lipid compositions, including membranes containing bacterial lipids. By investigating the binding of the peptide using a range of surface analytical techniques such as surface plasmon resonance and surface plasmon field-enhanced fluorescence spectroscopy as well as electrochemical impedance spectroscopy, a clear preference of the peptide for negatively charged membranes over zwitterionic ones has been shown. Additionally, the interactions seemed to indicate a cooperative behavior for the peptide binding to a membrane. PMID- 28859484 TI - Factors associated with intention to be tested for HIV among men who have sex with men in a country with a very low HIV prevalence. AB - This study examined factors associated with the intention to take an HIV test among men who have sex with men (MSM) in South Korea. An internet website-based survey was conducted among users of the only and largest online MSM website between 20 July 2016, and 20 August 2016. A total of 2915 participants completed the survey and answered questions related to sociodemographic information, health behaviors, sexual behaviors, and HIV testing history. Of these, 2587 (88.7%) participants responded as having an intention to take an HIV test. A multivariable logistic regression analysis revealed the following as having reduced the intention to undergo HIV testing: very good subjective health status and no sexual interactions during the last 6 months (Adjusted odds ratios [AOR] 0.45 and 0.54, respectively). In contrast, increased intention to take an HIV test was associated with being 20-29 years old, 30-39 years old, not paying or receiving money for sex, having a history of HIV testing, and taking an HIV test once per 12 months (AOR 2.64, 2.13, 1.54, 1.81, and 2.17, respectively). In conclusion, HIV testing among MSM in this study was associated with age, subjective health status, sex(es) of one's sexual partner(s) during the last 6 months, sexual risk behaviors, HIV testing history, and undergoing regular HIV testing. PMID- 28859485 TI - Randomized Controlled Trial Comparing Three Different Modalities of Lithotrites for Intracorporeal Lithotripsy in Percutaneous Nephrolithotomy. AB - PURPOSE: To compare the efficiency (stone fragmentation and removal time) and complications of three models of intracorporeal lithotripters in percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: Prospective, randomized controlled trial at nine centers in North America from 2009 to 2016. Patients were randomized to one of three lithotripter devices: the Cyberwand, a dual-probe ultrasonic device; the Swiss Lithoclast Select, a combination pneumatic and ultrasonic device; and the StoneBreaker, a portable pneumatic device powered by CO2 cartridges. Since the StoneBreaker lacks an ultrasonic component, it was used with the LUS-II ultrasonic lithotripter to allow fair comparison with combination devices. RESULTS: Two hundred seventy patients were enrolled, 69 were excluded after randomization. Two hundred one patients completed the study: 71 in the Cyberwand group, 66 in the Lithoclast Select group, and 64 in the StoneBreaker group. The baseline patient characteristics of the three groups were similar. Mean stone surface area was smaller in the StoneBreaker group at 407.8 mm2 vs 577.5 mm2 (Lithoclast Select) and 627.9 mm2 (Cyberwand). The stone clearance rate was slowest in the StoneBreaker group at 24.0 mm2/min vs 28.9 mm2/min and 32.3 mm2/min in the Lithoclast Select and Cyberwand groups, respectively. After statistically adjusting for the smaller mean stone in the StoneBreaker group, there was no difference in the stone clearance rate among the three groups (p = 0.249). Secondary outcomes, including complications and stone-free rates, were similar between the groups. CONCLUSIONS: The Cyberwand, Lithoclast Select, and the StoneBreaker lithotripters have similar adjusted stone clearance rates in PCNL for stones >2 cm. The safety and efficacy of these devices are comparable. PMID- 28859486 TI - An appraisal of practice guidelines for smoking cessation in people with severe mental illness. AB - OBJECTIVE: To review the quality of current smoking cessation guidelines that include recommendations for people with severe mental illness. METHODS: A systematic search of scientific databases, central government health authority websites, psychiatry peak bodies, guideline clearing houses and Google was undertaken for relevant smoking cessation guidelines. Three reviewers independently assessed guideline quality using the AGREE II (Appraisal of Guidelines for REsearch and Evaluation II) instrument. Two reviewers extracted recommendations specific to smokers with severe mental illness. RESULTS: Thirteen guidelines met the inclusion criteria. Seven guidelines scored ?60% in at least four domains. Median scores for 'Editorial independence', 'Rigour of development', 'Stakeholder Involvement' and 'Applicability' were less than 60%. The highest median scores were for 'Scope and purpose' (87%, 69-96%) and 'Clarity of presentation' (87%, 56-98%). 'Editorial independence' (33.3%, 0-86%) and 'Rigour of development' (54%, 11-92%) had the lowest median domain scores. The guidelines varied greatly in their recommendations but the majority recommended nicotine replacement therapy, bupropion or varenicline as first-line pharmacotherapy, along with behavioural support. CONCLUSION: Many guidelines did not adequately report their methods or the competing interests of the authors. Future guidelines development may benefit from more specifically addressing AGREE II criteria and the needs of smokers with severe mental illness. PMID- 28859487 TI - Policy responses to problematic video game use: A systematic review of current measures and future possibilities. AB - BACKGROUND AND AIMS: Empirical research into problematic video game playing suggests that overuse might cause functional and psychological impairments for a minority of gamers. Therefore, the need for regulation in the case of video games (whether governmental or self-imposed) has arisen but has only been implemented in a few countries around the world, and predominantly in Asia. This paper provides a systematic review of current and potential policies addressing problematic gaming. METHODS: After conducting a systematic search in the areas of prevention, treatment, and policy measures relating to problematic Internet and video game use, papers were selected that targeted problematic gaming policies (N = 12; six in English and six in Korean). These papers served as the basis of this review. RESULTS: Policies were classified into three major groups: (i) policy measures limiting availability of video games (e.g., shutdown policy, fatigue system, and parental controls), (ii) measures aiming to reduce risk and harm (e.g., warning messages), and (iii) measures taken to provide help services for gamers. Beyond the attempt to classify the current and potential policy measures, the authors also tried to evaluate their efficiency theoretically and (if data were available) empirically. DISCUSSION AND CONCLUSIONS: Overall, it appears that although several steps have been taken to address problematic video game playing, most of these steps were not as effective as expected, or had not been evaluated empirically for efficacy. The reason for this may lie in the fact that the policies outlined only addressed or influenced specific aspects of the problem instead of using a more integrative approach. PMID- 28859488 TI - Psychometric Properties of the Persian Adaptation of Mini-Cog Test in Iranian Older Adults. AB - The aim of this study was to assess the psychometric properties of the Mini-Cog in Iranian older adults. It was a cross-sectional study; 50 older people with dementia and 50 without dementia who matched for age, gender, and education entered the study. The diagnostic and statistical manual of mental disorders criteria for dementia were used as gold standard. A battery of scales included the abbreviated mental test score (AMTS), the Geriatric Depression Scale, and the Mini-Cog was performed. Validity and reliability of the Mini-Cog determined using the Pearson product-moment correlation coefficient (Pearson's r), Cronbach's alpha, and Receiver Operating Characteristic (ROC) curve analysis. The Persian version of Mini-Cog showed a good inter-rater reliability ( K = 0.76, p < .01) and a positive concurrent validity ( r = 0.39, p < .01) with the AMTS. The sensitivity and specificity were 88% and 62.8%, respectively, using the original cutoff point of 2. The findings showed that the Persian version of Mini-Cog have an acceptable sensitivity, specificity, and substantial overall agreement with the AMTS. PMID- 28859489 TI - Role of Sex, Socioeconomic Status, and Emotional Support in Predicting Aging Perception Among Older Adults. AB - Self-perception is found to be a central predictive factor in experiencing successful aging. The aim of this study was to explore the role of sex, socioeconomic status, and emotional support in elders' aging perception. A cross sectional design was used with 300 older aged participants recruited from 23 clinics and health centers in Qazvin, Iran. Data were collected included questions to elicit demographic information and Barker's aging perception questionnaire. Exploratory multiple linear regression showed that the level of emotional support (beta: -12.10; 95% CI: [-20.72, -3.48]), socioeconomic status (beta: 2.84; 95% CI: [0.25, 5.43]), and women (beta: -4.34; 95% CI: [-6.91, 1.77]) were associated with aging perception among elders. Educational level and marital status did not significantly contribute to the variance of AP. Findings revealed that aging perception was related to individual differences as well as social and emotional factors. Researchers, health-care professionals, and elders may benefit from thinking about old age as an inevitable life stage. PMID- 28859490 TI - Diagnostic Utility of the Shortened Version of the Wisconsin Card Sorting Test in Patients With Sporadic Late Onset Alzheimer Disease. AB - BACKGROUND: The classic version of the Wisconsin Card Sorting Test (WCST) consists of correctly sorting 128 cards according to changing sorting criteria. Its application is costly in terms of the time employed, with all the negative consequences this entails (decrease in motivation, frustration, and fatigue). METHOD: The main objective of this study was to test the usefulness of the shortened version of the WCST as compared to the full test by analyzing the equivalence between the two decks comprising the full 128-card version on a sample of patients diagnosed with sporadic late onset Alzheimer disease (SLOAD) and to check its clinical usefulness. RESULTS: The variables showed equivalence between the two decks and their ability to differentiate between the control group (CG) and the Alzheimer disease (AD) group. CONCLUSION: The scores obtained suggest equivalence between decks and that the application of only the first deck is sufficient. PMID- 28859491 TI - Analysis of Accessory Pudendal Artery Transection on Erections During Robot Assisted Radical Prostatectomy. AB - PURPOSE: To compare the recovery of erections and potency following the transection of accessory pudendal arteries (APAs) in men undergoing robot assisted radical prostatectomy (RARP) compared with men with normal vascular anatomy. MATERIALS AND METHODS: A total of 880 consecutive patients who underwent RARP from January 1, 2007 to December 31, 2014 were included with prospectively collected data in cross-sectional analysis. Erectile function (EF) was assessed preoperatively and postoperatively at 3, 6, 12, and 24 months using the International Index of Erectile Function (IIEF)-5, a percent erection fullness compared to preoperative status, and two Expanded Prostate Cancer Index (EPIC) questions: (1) are erections firm enough for penetration and (2) are they satisfactory? RESULTS: Two hundred thirty-one (33.1%) men had APAs transected. There were no significant differences in baseline demographics or clinical characteristics in men with or without APAs transected. Multivariate analyses demonstrated that age (confidence interval [95% CI]: 0.94, 0.99) and baseline IIEF-5 (95% CI: 1.15, 1.26) strongly correlated with recovery of erections and potency. Transection of APAs was not a significant predictor of erectile dysfunction (ED). CONCLUSION: Good surgical technique dictates the preservation of APAs. However, when preservation is questioned, we found that APA transection had no measurable effect on recovery of erections or potency regardless of age, preoperative ED, or number of APAs transected. PMID- 28859492 TI - Retzius-Sparing Robotic-Assisted Laparoscopic Radical Prostatectomy: A Safe Surgical Technique with Superior Continence Outcomes. AB - PURPOSE: To report early operative outcomes and assess continence in 100 consecutive patients who underwent Retzius-sparing robotic-assisted laparoscopic radical prostatectomy (RALP). MATERIALS AND METHODS: This was a prospective, single-center, consecutive case series of 100 and 100 patients undergoing a Retzius-sparing and a conventional RALP, respectively, by a single surgeon between March 2015 and April 2017. RESULTS: Baseline patient characteristics were similar between the two groups. The Retzius-sparing approach required significantly less console time (120.0 minutes vs 144.0 minutes, p < 0.001). There were no differences between intra- and post-operative complication rates, and hospital length of stay was similar in the two groups. Incidence of positive surgical margins was nonsignificantly different between the two groups, with 17% and 13% of pT2 patients and 49% and 48% of pT3 patients in the Retzius-sparing and conventional groups, respectively. Patients in the Retzius-sparing group had significantly superior rates of achieving post-operative urinary continence (log rank test: p < 0.001), with 20% of patients continent within the first month, compared with 8% of patients in the conventional group. The mean number of pads per day needed at 3, 6, 9, and 12 months post-operatively was also significantly lower in the Retzius-sparing group. CONCLUSIONS: Retzius-sparing RALP requires shorter console time, is oncologically safe, and leads to significantly superior continence outcomes compared with conventional RALP. PMID- 28859493 TI - Characterizing the histopathology of natural co-infection with Marek's disease virus and subgroup J avian leucosis virus in egg-laying hens. AB - Marek's disease virus (MDV) and avian leucosis virus (ALV) are known to cause tumours in egg-laying hens. Here, we investigated the aetiology of tumours in a flock of egg-laying hens vaccinated against MDV. We carried out gross pathology and histopathological examinations of the diseased tissues, identified virus antigen and sequenced viral oncogenes to elucidate the cause of death in 21-22 week-old hens. At necropsy, diseased hens had distinctly swollen livers, spleens, and proventriculus, and white tumour nodules in the liver. The spleen and liver had been infiltrated by lymphoid tumour cells, while the proventriculus had been infiltrated by both lymphoid tumour cells and myeloblastic cells. Subtype J ALV (ALV-J) and MDV were widely distributed in the proventricular gland cells, and the lymphoid tumour cells in the liver and the spleen. In addition, positive ALV J signals were also observed in parts of the reticular cells in the spleen. MDV and ALV-J antigens were observed in the same foci of the proventricular gland cells; however, the two antigens were not observed in the same foci from the spleen and liver. The amino acid sequence of the AN-1 (the representative liver tumour tissue that was positive for both ALV-J and MDV) Meq protein was highly similar to the very virulent MDV QD2014 from China. Compared to the ALV-J HPRS 103 reference strain, 10 amino acids (224-CTTEWNYYAY-233) were deleted from the gp85 protein of AN-1. We concluded that concurrent infection with MDV and ALV-J contributed to the tumorigenicity observed in the flock. PMID- 28859494 TI - Development of a method for determining binaural sensitivity to temporal fine structure. AB - OBJECTIVE: To develop and evaluate a test of the ability to process binaural temporal-fine-structure (TFS) information. The test was intended to provide a graded measure of TFS sensitivity for all listeners. DESIGN: Sensitivity to TFS was assessed at a sensation level of 30 dB using the established TFS-LF test at centre frequencies of 250, 500 and 750 Hz, and using the new TFS-AF test, in which the interaural phase difference (IPD) was fixed and the frequency was adaptively varied. IPDs varied from 30 to 180 degrees . STUDY SAMPLE: Nine young (19-25 years) and 23 older (47-84 years) listeners with normal hearing over the tested frequency range. RESULTS: For the young listeners, thresholds on the TFS AF test did not improve significantly with repeated testing. The rank-ordering of performance across listeners was independent of the size of the IPD, and moderate to-strong correlations were observed between scores for the TFS-LF and TFS-AF tests. Older listeners who were unable to complete the TFS-LF test were all able to complete the TFS-AF test. CONCLUSIONS: No practice effects and strong correlations with an established test of binaural TFS sensitivity make the TFS-AF test a good candidate for the assessment of supra-threshold binaural processing. PMID- 28859495 TI - Comparison of treatment adherence outcome among PLHIV enrolled in economic strengthening program with community control. AB - Economic strengthening (ES) interventions are increasingly promoted to support the economic well-being and food security of people living with HIV (PLHIV) in resource poor settings. This study aims to assess the impact of ES interventions in Ethiopia designed to address poverty and food insecurity on antiretroviral treatment (ART) adherence. A comparative cross-sectional design was employed to compare treatment adherence between food insecure PLHIV benefitting from the ES project of WFP Ethiopia to food insecure PLHIV not participating in ES. Using the visual analogue scale (VAS) to measure ART adherence, only 9.9% of the ES group reported less than 95% adherence compared to 25.9% of the comparison group. Controlling for socio-economic and demographic variables using logistic regression models, engagement in ES activities increased the likelihood of having 95% or greater ART adherence by a factor of 2.4 and 5.6 respectively (as measured by VAS and ACTG approaches) compared to those PLHIV that were not engaged in ES. The findings of the study suggest that engagement in ES contributes to improved ART adherence among food insecure PLHIV. If further studies validate this result, ES should be adopted as a key strategy to improve HIV treatment adherence in resource poor settings where adherence is an issue of concern. PMID- 28859496 TI - The Effect of Physician Specialty Obtaining Access for Percutaneous Nephrolithotomy on Perioperative Costs and Outcomes. AB - OBJECTIVE: To evaluate the impact of the specialty (urologist vs radiologist) of the physician obtaining percutaneous renal access (RA) on perioperative outcomes, complications, and costs of percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: We used data from a national hospital discharge database to identify patients undergoing PCNL between 2003 and 2015. Procedure codes related to RA were linked to physician specialty. We examined patient demographics, Charlson comorbidity index, postoperative complications, length of stay (LOS), and direct hospital costs, as well as hospital and surgeon characteristics stratified by specialty of the physician obtaining RA. A multivariable regression model was created adjusting for potential confounders. RESULTS: We identified 40,501 patients undergoing PCNL between 2003 and 2015. Urologists obtained access in 17.0% of cases. RA by urologists was associated with a lower 90-day complication rate (5.0% vs 8.3%, p < 0.001) and lower rates of prolonged hospitalization >=4 days (22.5% vs 42.1%, p < 0.001). On multivariable analysis, RA by urologists was associated with lower rates of any complication (Clavien 1-5) (odds ratios [OR] 0.70, p <= 0.001), shorter LOS (OR 0.67, p < 0.001), and lower direct hospital costs (OR 0.65, p < 0.001). CONCLUSION: In the United States, radiologists obtain percutaneous RA in the majority of PCNLs. Access by urologists is associated with lower overall complications, shorter hospitalizations, and lower direct hospital costs. Coding errors and absence of stone complexity information may limit the cogency of our findings and requires further investigation. PMID- 28859497 TI - First report of coexistence of AmpC beta-lactamase genes in Klebsiella pneumoniae strains isolated from burn patients. AB - Klebsiella spp. are among the most frequently isolated bacteria from burn wounds. These organisms are among the most important opportunistic pathogens, causing hospital-acquired and healthcare-associated infections worldwide. Limited information is available about prevalence of AmpC-producing Klebsiella pneumoniae from burn patients. Therefore, the aim of this study was to determine the characterization of AmpC beta-lactamase among K. pneumoniae isolated from burn patients. Samples were collected from wound specimens of patients with burn injury from a burn hospital in Tehran during 18 months (March 2015 to August 2016). For phenotypic detection of AmpC beta-lactamase, disk diffusion method with cefoxitin was used for screening, AmpC disk test and boronic acid inhibitor based method were used as confirmatory tests. Polymerase chain reaction (PCR) was performed to screen all isolates with AmpC genes including ACCM, DHAM, EBCM, FOXM, MOXM, and CITM. Finally, PCR products were validated using sequencing. During this study, 102 isolates of K. pneumoniae were collected. Among these isolates, 52.9% suspected as AmpC producer by disk agar diffusion cefoxitin screening method. By confirmatory phenotypic methods, 19.6% of isolates considered as AmpC producer. Molecular analysis revealed 43.1% of cefoxitin resistant isolates harbored at least one of the AmpC genes including CITM (22.5%), EBCM (21.5%), DHAM (7.8%), and FOXM (0.98%). In addition, 5.8% of isolates harbored two AmpC genes and 2.9% harbored three AmpC genes. In conclusion, K. pneumoniae is becoming a serious problem in burn patients. Accurate and precise methods and guidelines should be designed for detection of antibiotic-resistant mechanisms. Our data showed the high rate of AmpC beta lactamase among K. pneumoniae isolated from burn patients, which limit the treatment options. Therefore, the results of this study can provide evidence to help for appropriate treatment of burn patients. PMID- 28859498 TI - Influence of human milk oligosaccharides on adherence of bifidobacteria and clostridia to cell lines. AB - Adhesion of gut bacteria to the intestinal epithelium is the first step in their colonization of the neonatal immature gut. Bacterial colonization of the infant gut is influenced by several factors, of which the most important are the mode of delivery and breast-feeding. Breast-fed infants ingest several grams of human milk oligosaccharides (HMOs) per day, which can become receptor decoys for intestinal bacteria. The most abundant intestinal bacteria in vaginally delivered infants are bifidobacteria, whereas infants born by cesarean section are colonized by clostridia. The influence of HMOs on the adhesion of five strains of intestinal bacteria (three bifidobacterial strains and two clostridial strains) to mucus-secreting and non-mucus-secreting human epithelial cells was investigated. Bifidobacterium bifidum 1 and Bifidobacterium longum displayed almost the same level of adhesion in the presence and absence of HMOs. By contrast, adhesion of Clostridium butyricum 1 and 2 decreased from 14.41% to 6.72% and from 41.54% to 30.91%, respectively, in the presence of HMOs. The results of this study indicate that HMOs affect bacterial adhesion and are an important factor influencing bacterial colonization of the gut. Adhesion of the tested bacteria correlates with their ability to autoaggregate. PMID- 28859499 TI - Prevalence and molecular typing of methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin gene. AB - Panton-Valentine leukocidin (pvl) toxin is an important virulence factor of Staphylococcus aureus. The main genes are coa and spa for distinguishing and typing of S. aureus isolates. The aim of this study was to investigate antibiotic resistance, presence of mecA and pvl genes, as well as epidemiological typing of these isolates according to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in clinical sample isolated from Rasht city, Iran. A total of 250 clinical samples have been isolated from different hospitals. First, isolates of S. aureus were identified through microbiological methods and their antibiotic sensitivity was determined by disk diffusion agar based on a standard method of Clinical and Laboratory Standards Institute. DNA was extracted by boiling and presence of pvl and mecA genes was investigated by PCR using specific primers. To type these isolates, amplification of fragments of coa and spa genes was done and restriction enzyme digestion pattern was determined by PCR RFLP method. Among the 250 samples, 50 isolates belonged to S. aureus and results of antibiotic sensitivity showed that 68% (34 samples) of isolates were methicillin resistant. Frequency of mecA and pvl genes among S. aureus isolates were 60% (30 samples) and 20% (10 samples). The PCR of coa gene showed three patterns whereas that of spa gene showed two patterns for enzyme digestion. Result of PCR-RFLP using HaeIII enzymes for coa gene and Bsp1431 for spa gene showed three patterns for enzyme digestion. Recent studies indicated increase in the resistance of S. aureus to different antibiotics, which is a serious problem in the treatment of infections resulting from S. aureus in this region. The result of PCR of pvl showed high frequency of this gene in this region, and coa and spa typing by PCR-RFLP was a useful tool for typing of S. aureus isolates. PMID- 28859500 TI - Emergence of NDM-1 among carbapenem-resistant Klebsiella pneumoniae in Iraqi hospitals. AB - Carbapenems are the last drugs of choice apart from colistin against serious infections caused by Gram-negative bacteria. However, there are increasing number of reports indicating prevailing emergence of metallo-beta-lactamase (MBL) producing clinical isolates worldwide and among them New Delhi MBL (NDM) is the most prevalent one. This study reports NDM-1 for the first time among Klebsiella pneumoniae from hospitalized patients in Baghdad, Iraq. Fifty-five clinical isolates of K. pneumoniae resistant to carbapenem were investigated from burned wounds, sputum, and blood samples. The susceptibility to different antibiotics was tested by VITEK-2 system. All strains were multidrug-resistant and they showed nine different antimicrobial-resistant patterns (A-I) and the most effective antibiotic on these strains was levofloxacin (85.45%). The phenotypic detection of carbapenemases by MASTDISCS D70C revealed 29 (52.73%) strains were MBL-producing, out of 55 were carbapenem-resistant K. pneumoniae strains. The blaNDM-1 and other MBL genes were detected by conventional PCR and the result showed 37 (67.27%) strains positive for blaNDM-1 gene and only 5 (9.1%) strains harbored blaIMP gene, while all strains were negative for blaVIM, blaSIM, blaGIM, and blaSPM genes. Our results showed the coexistence of both blaNDM-1 and blaIMP genes in three strains of K. pneumoniae, while indicated widespread NDM-1 in Baghdad, Iraq. Hence, it is necessary to follow proper infection control practices and physicians should be aware of the patients with such risk factors. PMID- 28859501 TI - Is there a hormonal regulation of phagocytosis at unicellular and multicellular levels? A critical review. AB - Phagocytosis is an ancient cell function, which is similar at unicellular and multicellular levels. Unicells synthesize, store, and secrete multicellular (mammalian) hormones, which influence their phagocytosis. Amino acid hormones, such as histamine, serotonin, epinephrine, and melatonin stimulate phagocytosis, whereas peptide hormones, such as adrenocorticotropic hormone (ACTH), insulin, opioids, arginine vasopressin, and atrial natriuretic peptide decreased it, independently on their chemical structure or function in multicellulars. Macrophage phagocytosis of multicellulars is also stimulated by amino acid hormones, such as histamine, epinephrine, melatonin, and thyroid hormones, however, the effect of peptide hormones is not uniform: prolactin, insulin, glucagon, somatostatin, and leptin have positive effects, whereas ACTH, human chorionic gonadotropin, opioids, and ghrelin have negative ones. Steroid hormones, such as estrogen, hydrocortisone, and dexamethasone are stimulating macrophage phagocytosis, whereas progesterone, aldosterone, and testosterone are depressing it. Considering the data and observations there is not a specific phagocytosis hormone, or a hormonal regulation of phagocytosis neither unicellular, nor multicellular level, however, hormones having specific functions in multicellulars also influence phagocytosis at both levels universally (in unicellulars) or individually (in macrophages). Nevertheless, the hormonal influence cannot be neglected, as phagocytosis (as a function) is rather sensitive to minute dose of hormones and endocrine disruptors. The hormonal influence of phagocytosis by macrophages can be deduced to the events at unicellular level. PMID- 28859502 TI - Drug Treatments for ADHD Reduce Risk of Substance Use Disorders. PMID- 28859503 TI - The Character Heads by Franz Messerschmidt: An Example of Art Therapy. PMID- 28859505 TI - Challenges in Treating Undocumented Immigrants. PMID- 28859506 TI - How Can We Encourage Medical Student Interest in Psychiatric Careers? PMID- 28859507 TI - Association Between Low Barometric Pressure and Completed Suicides. PMID- 28859508 TI - An Unexpected Sight in the Rearview Mirror. PMID- 28859509 TI - Tele-Operating an Android Robot to Promote the Understanding of Facial Expressions and to Increase Facial Expressivity in Individuals With Autism Spectrum Disorder. PMID- 28859510 TI - On the Road to Physiological Models of Brain Function in ADHD. PMID- 28859511 TI - Why Are Innovative Drugs Failing in Phase III? PMID- 28859512 TI - New Genetic Discoveries in Anorexia Nervosa: Implications for the Field. PMID- 28859513 TI - CORRECTION. PMID- 28859515 TI - The Percentage of Continuous Subcutaneous Insulin Infusion Usage Among Adult Type 1 Diabetes Mellitus Patients in Japan: A Cross-Sectional Study at National Hospital Organization Hospitals. PMID- 28859516 TI - Novel In-Shoe Exoskeleton for Offloading of Forefoot Pressure for Individuals With Diabetic Foot Pathology. AB - INTRODUCTION: Infected diabetic foot ulcers are the leading cause of lower limb amputation. This study evaluated the ability of in-shoe exoskeletons to redirect forces outside of body and through an exoskeleton as an effective means of offloading plantar pressure, the major contributing factor of ulceration. METHODS: We compared pressure in the forefoot and hind-foot of participants (n = 5) shod with novel exoskeleton footwear. Plantar pressure readings were taken during a 6-m walk at participant's self-selected speed, and five strides were averaged. Results were taken with Achilles exotendon springs disengaged as a baseline, followed by measurements taken with the springs engaged. RESULTS: When springs were engaged, all participants demonstrated a decrease in forefoot pressure, averaging a 22% reduction ( P < .050). Patient feedback was universally positive, preferring the exotendon springs to be engaged and active. CONCLUSIONS: Offloading is standard of care for reducing harmful plantar pressure, which may lead to foot ulcers. However, current offloading modalities are limited and have issues. This proof-of-concept study proposed a novel offloading approach based on an exoskeleton solution. Results suggest that when the novel exoskeletons were deployed in footwear and exotendon springs engaged, force was successfully transferred from the lower leg through the exoskeleton-enabled shoe to ground, reducing load on the forefoot. The results need to be confirmed in a larger sample. Another study is warranted to examine the effectiveness of this offloading to prevent diabetic foot ulcer, while minimizing gait alteration in daily physical activities. PMID- 28859517 TI - A Novel Approach for Meniscal Regeneration Using Kartogenin-Treated Autologous Tendon Graft. AB - BACKGROUND: The meniscus is one of the most commonly injured parts of the body, and meniscal healing is difficult. HYPOTHESIS: Kartogenin (KGN) induces tendon stem cells (TSCs) to differentiate into cartilage cells in vitro and form meniscus-like tissue in vivo. A damaged meniscus can be replaced with a KGN treated autologous tendon graft. STUDY DESIGN: Controlled laboratory study. METHODS: In the in vitro experiments, TSCs were isolated from rabbit patellar tendons and cultured with various concentrations of KGN, from 0 to 1000 uM. The effect of KGN on the chondrogenesis of TSCs in vitro was investigated by histochemical staining and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The in vivo experiments were carried out on 6 New Zealand White rabbits by removing a meniscus from the rabbit knee and implanting an autologous tendon graft treated with KGN or saline. The meniscus formation in vivo was examined by histological analysis and immune staining. RESULTS: The proliferation of TSCs was promoted by KGN in a concentration dependent manner. Both histochemical staining and qRT-PCR showed that the chondrogenic differentiation of TSCs was increased with KGN concentration. After 3 months of implantation, the tendon graft treated with KGN formed a meniscus like tissue with a white and glistening appearance, while the saline-treated tendon graft retained tendon-like tissue and appeared yellowish and unhealthy. Histochemical staining showed that after 3 months of implantation, the KGN treated tendon graft had a structure similar to that of normal meniscus. Many cartilage-like cells and fibrocartilage-like tissues were found in the KGN treated tendon graft. However, no cartilage-like cells were found in the saline treated tendon graft after 3 months of implantation. Furthermore, the KGN-treated tendon graft was positively stained by both anti-collagen type I and type II antibodies, but the saline-treated tendon graft was not stained by collagen type II. CONCLUSION: The findings indicated that KGN can induce the differentiation of TSCs into cartilage-like cells in vitro and in vivo. The results suggest that KGN treated tendon graft may be a good substitute for meniscal repair and regeneration. CLINICAL RELEVANCE: This study revealed the direct effects of KGN on the chondrogenic differentiation of TSCs in vitro and in vivo. A KGN-treated autologous tendon graft induced formation of a meniscus-like tissue in vivo. This study provides a new cartilage regenerating technology for the treatment of damaged meniscus. PMID- 28859518 TI - Socioeconomic indicators as predictors of smoking cessation among Spanish Speaking Mexican Americans. AB - OBJECTIVE: Smoking-related illnesses are the leading cause of death among Latinos, and within this ethnic group, Mexican Americans are the largest subgroup in the U.S. Understanding the factors associated with successful smoking cessation could inform interventions for this population. Although socioeconomic status (SES) is a powerful predictor of cessation outcomes in the general U.S. population, it has generally been a poor predictor of quitting smoking among Latinos. Within a sample of Spanish-speaking Mexican Americans (n = 199), this study examined a broad array of objective and subjective indicators of SES (i.e. income, education, employment, subjective social status, financial strain, insurance status) as predictors of smoking cessation. DESIGN: Data for the current study came from a longitudinal cohort study examining the pathways linking the social determinants of health with smoking cessation. Generalized estimating equation modeling examined the association of each predictor variable with smoking abstinence across quit day, and the 3 and 26-weeks post-quit time points. RESULTS: Results indicated that both low financial strain and insurance status predicted an increased likelihood of abstinence when controlling for covariates in the intention-to-treat analyses (p = .02 and p = .01, respectively). However, these models only approached significance in the multiple imputation analyses (all ps > .05). Other indicators of SES (i.e. income, education, employment) that have been predictive of cessation in other populations were not predictive of abstinence in this sample. CONCLUSIONS: These findings suggest that SES may indeed influence smoking cessation among Spanish speaking Mexican Americans similarly to its influence in other populations, but that capturing the construct of SES may require assessing a broader range of SES indicators. Specifically, low financial strain and having insurance predicted a greater likelihood of achieving smoking abstinence, whereas other indicators of SES (i.e. income, education) were not predictive. PMID- 28859519 TI - Intraoperative measurement of pressure gradient in median arcuate ligament syndrome as a rationale for radical surgical approach. AB - BACKGROUND: Median arcuate ligament syndrome (MALS) describes clinical symptoms in patients with stenosis of the celiac artery due to external compression by the ligament. There is an ongoing debate, whether sole release of the median arcuate ligament warrants long-term relief of the symptoms. MATERIALS AND METHODS: Eight patients diagnosed with MALS underwent open surgical treatment beginning with the release of the ligament. Systemic pressure and pressure in the left gastric artery were measured before and after division of the median arcuate ligament and release of the celiac artery. In patients with persistent gradient above 15 mm Hg after the release a PTFE bypass was performed. RESULTS: After the release, the pressure gradient decreased from 66 +/- 19 to 48 +/- 14 mm Hg (p = .001) and therefore in all patients either an aorto-celiac bypass (n = 6) or aorto-hepatic bypass (n = 2) was created. Consequently, the gradient decreased to 7 +/- 2 mm Hg (p = .0001). One month postoperatively, three patients were free of symptoms and the rest reported relief of symptoms. CONCLUSIONS: Release of the celiac artery resulted in insufficient decrease of pressure gradient, which was achieved by bypassing the segment with favorable mid-term outcome. We believe that the effect of the release should always be assessed to decide on subsequent treatment. PMID- 28859520 TI - The downfall of TBA-354 - a possible explanation for its neurotoxicity via mass spectrometric imaging. AB - 1. TBA-354 was a promising antitubercular compound with activity against both replicating and static Mycobacterium tuberculosis (M.tb), making it the focal point of many clinical trials conducted by the TB Alliance. However, findings from these trials have shown that TBA-354 results in mild signs of reversible neurotoxicity; this left the TB Alliance with no other choice but to stop the research. 2. In this study, mass spectrometric methods were used to evaluate the pharmacokinetics and spatial distribution of TBA-354 in the brain using a validated liquid chromatography tandem-mass spectrometry (LCMS/MS) and mass spectrometric imaging (MSI), respectively. Healthy female Sprague-Dawley rats received intraperitoneal (i.p.) doses of TBA-354 (20 mg/kg bw). 3. The concentrationtime profiles showed a gradual absorption and tissue penetration of TBA-354 reaching the Cmax at 6 h post dose, followed by a rapid elimination. MSI analysis showed a time-dependent drug distribution, with highest drug concentration mainly in the neocortical regions of the brain. 4. The distribution of TBA-354 provides a possible explanation for the motor dysfunction observed in clinical trials. These results prove the importance of MSI as a potential tool in preclinical evaluations of suspected neurotoxic compounds. PMID- 28859521 TI - The Importance of Purpose in Whole Health and Well-Being. PMID- 28859522 TI - Be Careful and Pay Attention. PMID- 28859524 TI - Conflicts of Interest. PMID- 28859523 TI - Early Intervention for Children With Autism Spectrum Disorder in Low-Resource Countries. PMID- 28859525 TI - Influence of essential oils in diet and life-stage on gut microbiota and fillet quality of rainbow trout (Oncorhynchus mykiss). AB - Developing fish farming to meet the demands of food security and sustainability in the 21st century will require new farming systems and improved feeds. Diet and microbe interactions in the gut is an important variable with the potential to make a significant impact on future fish farming diets and production systems. It was monitored the gut microbiota of farmed rainbow trout using 16S rRNA profiling over 51 weeks during standard rearing conditions and feeding diet with supplementation of an essential oils (MixOil) mixture from plants (at a concentration in diet of 200 mg/kg). Gut microbiota 16S rRNA profiling indicated that the fish gut was dominated by Actinobacteria, Proteobacteria, Bacteroidetes and Firmicutes. Although the dietary supplementation with MixOil had no impact on either the composition or architecture of gut microbiota, significant changes in alpha and beta diversity and relative abundance of groups of gut bacteria were evident during growth stages on test feeds, especially upon prolonged growth on finishing feed. Fish fillet quality to guarantee palatability and safety for human consumption was also evaluated. Significant differences within the gut microbiota of juvenile and adult trout under the same rearing conditions were observed, The addition of essential oil blend affected some physicochemical characteristics of trout fillets, including their resistance to oxidative damage and their weight loss (as liquid loss and water holding capacity) during the first period of storage, that are two important parameters related to product shelf life and susceptibility to spoilage. The results highlighted the need for further studies concern dietary microbiome modulation at different life stages and its influence on animal health, growth performance and final product quality. PMID- 28859526 TI - Increase in DNA methylation in patients with amyotrophic lateral sclerosis carriers of not fully penetrant SOD1 mutations. AB - OBJECTIVE: More than 180 different superoxide dismutase 1 (SOD1) mutations have been described to date in amyotrophic lateral sclerosis (ALS) patients, including not completely penetrant ones leading to phenotypic heterogeneity among carriers. We collected DNA samples from five ALS families with not fully penetrant SOD1 mutations (p.Asn65Ser, p.Gly72Ser, p.Gly93Asp, and p.Gly130_Glu133del) searching for epigenetic differences among ALS patients, asymptomatic/paucisymptomatic carriers and non-carrier family members. METHODS: Global DNA methylation levels (5-methylcytosine levels) were determined in blood DNA samples with an enzyme linked immunosorbent assay (ELISA), and the methylation analysis of SOD1, FUS, TARDBP and C9orf72 genes was performed using Methylation-Sensitive High Resolution Melting (MS-HRM) technique. RESULTS: Global DNA methylation levels were significantly higher in blood DNA of ALS patients than in asymptomatic/paucisymptomatic carriers or family members non-carriers of SOD1 mutations, and a positive correlation between global DNA methylation levels and disease duration (months) was observed. SOD1, FUS, TARDBP and C9orf72 gene promoters were demethylated in all subjects. CONCLUSIONS: The present study suggests that global changes in DNA methylation might contribute to the ALS phenotype in carriers of not fully penetrant SOD1 mutations, thus reinforcing the role of epigenetic factors in modulating the phenotypic expression of the disease. PMID- 28859527 TI - Unique relations between post-traumatic stress disorder symptoms and patient functioning in type 2 diabetes. AB - This study examined reported post-traumatic stress disorder symptoms in adults with poorly controlled type 2 diabetes who had no history of psychiatric diagnosis or treatment ( n = 184, MHbA1c = 9.13%, standard deviation = 1.68). Participants reported moderate to severe intensity of post-traumatic stress disorder symptoms ( M = 19.17, SD = 17.58). Together, depressive and post traumatic stress disorder symptoms accounted for 10-40 percent of the variance in type 2 diabetes outcomes; post-traumatic stress disorder symptoms were associated with elevated diabetes distress and more frequent exercise and self-blood glucose testing (unique R2 ~ 3%). Post-traumatic stress disorder symptoms may be overlooked in type 2 diabetes among patients without formal psychiatric diagnoses, and warrant increased attention. PMID- 28859528 TI - The interpretation of static positional nystagmus in a balance clinic. AB - OBJECTIVE: To review the current criteria for the interpretation of positional nystagmus (PN). DESIGN: Videonystagmography data on PN was collected for 90 patients presenting for balance testing with a history of vertigo or imbalance (excluding those diagnosed with benign paroxysmal positional vertigo). These were compared to normative data from 90 asymptomatic subjects. A literature review was carried out regarding threshold criteria for clinically significant PN. These were evaluated using the data collected. STUDY SAMPLE: Clinic group: 90 patients; 37 male, 53 female. Age range 15-82 years. Normative group: Ninety subjects; 31 male, 59 female. Age range 21-79 years. RESULTS: PN was seen in 75.6% of the clinic group and in 50% of the normative group. The prevalence of nystagmus of slow phase velocity (SPV) > 3 degrees /s was significantly higher in the clinic group than the normative group. The maximum SPV recorded in each position was greater from the clinic group than the normative group. CONCLUSIONS: This study supports the use of normative thresholds for SPV for both horizontal and vertical PN. A normative threshold of >3 degrees /s for horizontal and >7 degrees /s for vertical nystagmus is proposed. PMID- 28859529 TI - Calculating the first-order kinetics of three coupled, reversible processes. AB - Calculation of the concentration-time profile in four consecutive, well-mixed compartments that are connected by diffusional transport is a frequently occurring problem for chemists and engineers. Mathematically this is equivalent to many other problems such as the concentration profiles of a parent compound and its three consecutive reaction products resulting from reversible first-order kinetics. Here we present an analytical solution to this problem implemented in a Microsoft Excel spreadsheet (available for download) and we discuss various examples of how this simple-to-use tool can be applied to very different scenarios from various fields of science. PMID- 28859531 TI - Hearing disorder from music; a neglected dysfunction. AB - CONCLUSION: Music-induced acute acoustic trauma is not inevitably linked to hearing dysfunction as validated by conventional pure tone audiometry. Tinnitus is often in combination with hyperacusis. Our results point at 'silent hearing loss' as the underlying pathology, having afferent nerve terminal damage rather than hair cell loss as the structural correlate. OBJECTIVES: Exposure to loud music is one of the most common causes of acute acoustic trauma, which adolescents and teenagers experience by voluntary exposure to loud music of sound levels up to 110 dB(A). METHODS: The clinical and psychophysical data of 104 consecutive patients with music-induced hearing disorder (MIHD) were analyzed to construct individual hearing and tinnitus profiles. In all cases, tinnitus was the presenting symptom. RESULTS: Hearing abilities were normal in about two thirds of the tinnitus patients. Tinnitus was experienced most often as a high frequency tone (83%). The Tinnitus Handicap Inventory (THI) scores ranged from 0 to 94 with an average score of 43.1. Visual analog scales (VAS) were used to assess tinnitus loudness (average 42.4) and annoyance (average 54.2), and tinnitus awareness was estimated (average 60.3). All VAS values correlated strongly with the THI. Hyperacusis was present in 65% and 71% of the patients reported sleeping disorders. PMID- 28859532 TI - European Society for Gene and Cell Therapy-Inaugural Learned Society in the Field Worldwide: A Vision on Its Birth, Life, and Prospects for Sustainability. PMID- 28859533 TI - Comparison of bolus versus continuous infusion of propofol for procedural sedation: a meta-analysis. AB - OBJECTIVE: To compare the efficacy and safety of bolus infusion versus continuous infusion for propofol sedation. METHODS: We searched OVID-MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, Koreamed, and Kmbase databases to identify all randomized controlled trials that compared bolus infusion with continuous infusion for propofol sedation. We evaluated propofol dose used, procedure, sedation, and recovery time. The incidences of respiratory and cardiovascular complications were also evaluated. RESULTS: A total of 12 studies of 963 patients were included. The required propofol dose was significantly higher in continuous infusion compared with bolus infusion (standardized mean difference [SMD]: -0.44; 95% confidence interval [CI]: -0.71 to -0.16; I2 = 84%). Sedation time was significantly longer in continuous infusion compared with bolus infusion (mean difference [MD]: -8.58 min; 95% CI: -15.13 to -2.03; I2 = 44%). The recovery time and incidences of desaturation, airway intervention, hypotension, and bradycardia were comparable between bolus and continuous infusion. CONCLUSIONS: Propofol sedation by continuous infusion required a higher dose of propofol compared with bolus infusion, but the recovery time and frequency of complications were similar. PMID- 28859536 TI - Physician-assisted death should be available to people with MS - Commentary. PMID- 28859534 TI - Larvicidal and pupicidal evaluation of silver nanoparticles synthesized using Aquilaria sinensis and Pogostemon cablin essential oils against dengue and zika viruses vector Aedes albopictus mosquito and its histopathological analysis. AB - Mosquitoes pose a threat to humans and animals, causing millions of deaths every year. Vector control by effective eco-friendly pesticides of natural origin is a serious issue that requires urgent attention. The employment of green-reducing extracts for nanoparticles biosynthesis in a rapid and single-step process represents a promising strategy. In this study, silver nanoparticles (AgNPs) were biofabricated using an essential oil of Aquilaria sinensis (AsEO) and Pogostemonis Herba essential oil of Pogostemon cablin (PcEO) in one step and cost effective manner. UV-vis spectrophotometry, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, X ray diffraction analysis and energy-dispersive X-ray spectroscopy were used to confirm the AgNPs formation and their biophysical characterization. The larvicidal and pupicidal toxicity of AsEO, PcEO and biosynthesized AgNPs were evaluated against larvae and pupae of the dengue and Zika virus vector Aedes albopictus. Compared to the tested essential oils, the biofabricated AgNPs showed the highest toxicity against larvae and pupae of Ae.albopictus. In particular, the LC50 values of AsEO ranged from 44.23 (I) to 166 (pupae), LC50 values of PcEO ranged from 32.49 (I) to 90.05(IV), LC50 values of AsEO-AgNPs from 0.81 (I) to 1.12 (IV) and LC50 values of PcEO-AgPNs from 0.85 (I) to 1.19 (IV). Furthermore, histological analysis of the midgut cells of the control and treated larvae exhibited that the epithelial cells and brush border were highly affected by the fabricated AgNPs compared to the essential oils (AsEO and PcEO). Overall, the A. sinensis and P. cablin essential oils fabricated AgNPs have a potential of application as a biopesticide for mosquito control through safer and cost effective approach. PMID- 28859537 TI - Nutrients removal from the secondary effluents of municipal domestic wastewater by Oscillatoria tenuis and subsequent co-digestion with pig manure. AB - Batch experiments were carried out to investigate the performance of Oscillatoria tenuis to remove nitrogen, phosphorus and chemical oxygen demand (COD) from secondary effluents of municipal domestic wastewater. Meanwhile the potential of biogas production by collected O. tenuis co-digested with pig manure was also investigated. O. tenuis had a biomass productivity of 150 mg L-1 d-1, a removal rate of [Formula: see text] (96.1%), total phosphorus (82.9%) and COD (92.6%) within 7 d at an aeration rate of 1.0 L/min. The biochemical methane potential (BMP) test for O. tenuis fermented with pig manure was evaluated at three different ratios. The cumulative methane yield was 183 mL CH4/gVSadd at a mixing ratio (MR) of 3.0, 191 mL CH4/gVSadd at a MR of 2.0 and 84 mL CH4/gVSadd at a MR of 1.0. The maximum methane yield appeared at the ratio of 2.0. Meanwhile, acid-, alkali- and thermal-pretreatments were applied to raw microalgae biomass to promote biogas production. The highest methane productivity (256 mL CH4/gVSadd) was achieved by the thermal-pretreatment at 120 degrees C, which was about 1.5 times higher than the non-pretreatment group (191 mL CH4/g VSadd). PMID- 28859538 TI - Synergistic effects of polymer adsorbents on the performance of bilirubin hemoperfusion. AB - Neonatal hyperbilirubinemia (jaundice) is a common disease with high incidence. Currently, the clinical inefficiency of adult bilirubin hemoperfusion medical adsorbent is a major technical barrier for the application of hemoperfusion treatment to rescue the severe neonatal jaundice. Based on the well-known principle of synergistic effects, a series of customized bilirubin polymeric compounds, comprised of one or more of the following components (glycidyl methacrylate, sodium acrylate, methacrylic acid isooctyl, hexamethylene diamine, albumin), were designed and fabricated based on molecular design. Their adsorption performances upon bilirubin were investigated and compared under the same conditions, and the compound with the highest adsorption performance was then subject to preliliminary safety assessments and compared with a commercial one (BS330). The results showed that positive synergistic effects appeared on the adsorption performance to adsorb bilirubin based on this study, and the one comprised of glycidyl methacrylate+sodium acrylate+methacrylic acid isoocty+hexamethylene diamine+albumin possesses the highest adsorption performance as well as outome clinical acceptable medical safety assessments, and its adsorption efficiency was up to 46% while the commerical one's was about 26% under the same conditions. This study sheds a new light on how to design and develop hemoperfusion bilirubin adsorbents with good overall clinical performance, as well as providing a novel idea and experimental referrences for future related topics. PMID- 28859530 TI - Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. AB - Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism's response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic-pituitary-gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life. PMID- 28859539 TI - Physician-assisted death should be available to people with MS - YES. PMID- 28859540 TI - Physician-assisted death should be available to people with MS - No. PMID- 28859543 TI - The relationship between microRNAs and the STAT3-related signaling pathway in cancer. AB - MicroRNAs are non-coding RNAs that regulate gene expression by targeting messenger RNA molecules in 3' untranslated region. Mounting evidence indicates that microRNAs regulate several factors to influence various biological activities that are related to carcinogenesis, including signal transducer and activator of transcription 3, which is a transcription factor that also acts as an oncogene. MicroRNAs influence signal transducer and activator of transcription 3 either by directly targeting or via other pathway components upstream or downstream of signal transducer and activator of transcription 3 such as Janus kinases, members of the suppressor of cytokine signaling family, and other genes that regulate cell proliferation, apoptosis, migration, invasion, and epithelial mesenchymal transition. However, signal transducer and activator of transcription 3 activation changes the pattern of expression of microRNAs and mediates tumorigenesis. Moreover, the relationship between signal transducer and activator of transcription 3 and microRNAs varies among different kinds of cancers. A specific microRNA may act as an oncogene or tumor suppressor in different cancers, and microRNAs also directly or indirectly regulate signal transducer and activator of transcription 3 via pathways in the same cancers. In this review, we focus on the reciprocal regulation and roles of microRNAs and signal transducer and activator of transcription 3 in cancer, as well as describe current research progress on this relationship. A better understanding of this relationship may facilitate in the identification of targets for clinical therapeutics. PMID- 28859545 TI - Acute cardiorespiratory, perceptual and enjoyment responses to high-intensity interval exercise in adolescents. AB - This study aimed to examine adolescents' acute cardiorespiratory and perceptual responses during high-intensity interval exercise (HIIE) and enjoyment responses following HIIE and work-matched continuous moderate intensity exercise (CMIE). Fifty-four 12- to 15-year olds (27 boys) completed 8 * 1-min cycling at 90% peak power with 75-s recovery (HIIE) and at 90% of the gas exchange threshold (CMIE). Absolute oxygen uptake ([Formula: see text]), percentage of maximal [Formula: see text] (%[Formula: see text]), heart rate (HR), percentage of maximal HR (%HRmax) and ratings of perceived exertion (RPE) were collected during HIIE. Enjoyment was measured using the physical activity enjoyment scale (PACES) following HIIE and CMIE. Boys elicited higher absolute [Formula: see text] during HIIE work (p < .01, effect size (ES) > 1.22) and recovery (p < .02, ES > 0.51) intervals but lower %[Formula: see text] during HIIE recovery intervals compared to girls (p < .01, ES > 0.67). No sex differences in HR and %HRmax were evident during HIIE and 48 participants attained >=90% HRmax. Boys produced higher RPE at intervals 6 (p = .004, ES = 1.00) and 8 (p = .003, ES = 1.00) during HIIE. PACES was higher after HIIE compared with CMIE (p = .003, ES = 0.58). Items from PACES "I got something out of it", "It's very exciting" and "It gives me a strong feeling of success" were higher after HIIE (all p < .01, ES > 0.32). The items "I feel bored" and "It's not at all interesting" were higher after CMIE (all p < .01, ES > 0.46). HIIE elicits a maximal cardiorespiratory response in most adolescents. Greater enjoyment after HIIE was due to elevated feelings of reward, excitement and success and may serve as a strategy to promote health in youth. PMID- 28859546 TI - MicroRNA-34a induces transdifferentiation of glioma stem cells into vascular endothelial cells by targeting Notch pathway. AB - The function of microRNA-34a (miR-34a) in transdifferentiation of glioma stem cells (GSCs) into vascular endothelial cells (VECs) was explored by focusing on Notch ligand Delta-like 1 (Dll1). MiR-34a mimics was transfected into CD133 + glioma cell U251. The angiogenesis feature of miR-34a transfected U251 cells was investigated and the expressions of CD31, CD34, Vwf, Notch 1, and Dll1 were quantified. Length of branching vessel-like structures in the miR-34a transfected U251 cells was significantly higher than control cells. The VEC feature of miR 34a overexpressed U251 cells was further confirmed by the expressions of CD31, CD34, and vWF. Transfection of miR-34a decreased the expression of Notch 1 and Dll1. Furthermore, the miR-34a overexpression-enhanced tube formation of GSCs was suppressed when the decreased expression of Dll1 was restored. The current study highlighted the potential of miR-34a as an inducer in GSCs' transdifferentiation into VECs by targeting Dll1. PMID- 28859547 TI - Fast start-up of anammox process with mixed activated sludge and settling option. AB - In this study, successful start-up of the anaerobic ammonium oxidation (anammox) process in a sequencing batch reactor (SBR) was achieved by seeding mixed activated sludge which included aerobic sludge, anaerobic sludge, simultaneous partial nitrification, anammox and denitrification (SNAD) sludge, and anammox sludge with low activity at a 2200:2100:5:2 volume ratio. On day 15, the effective anammox activity was attained in SBR, with the specific total nitrogen removal rate (SRR) of 0.214 gNg-1 VSSd-1. The total nitrogen removal rate (NRR) increased to 230 gNm-3 d-1 by gradually reducing the setting time to 10 min. With the nitrogen loading rate (NLR) up to 506 gNm-3 d-1, the total NRR of the SBR reached 433 gNm-3 d-1 during stationary phase. Candidatus Brocadia was detected as predominant functional microbes in the anammox SBR. The results demonstrated the feasibility of seeding mixed activated sludge to start-up an anammox SBR by settling option. PMID- 28859548 TI - Recovery of 3-Iodothyronamine and Derivatives in Biological Matrixes: Problems and Pitfalls. AB - BACKGROUND: Difficulties have been reported in quantitating 3-iodothyronamine (T1AM) in blood or serum, and tentatively attributed to problems in extraction or other pre-analytical steps. For this reason, even cell culture experiments have often be performed with unphysiological protein-free media. The aim of this study was to evaluate the recovery of exogenous T1AM added to a standard cell culture medium, namely Dulbecco's minimum essential medium (DMEM) supplemented with fetal bovine serum (FBS), and to other biological matrixes. METHODS: Cell culture media (Krebs-Ringer buffer, DMEM, FBS, DMEM + FBS, used either in the absence or in the presence of NG108-15 cells) and other biological matrixes (rat brain and liver homogenates, human plasma, and blood) were spiked with T1AM and/or deuterated T1AM (d4-T1AM) and incubated for times ranging from 0 to 240 minutes. Samples were then extracted using a liquid/liquid method and analyzed using liquid chromatography coupled to mass spectrometry in order to assay T1AM and its metabolites, namely 3-iodothyroacetic acid (TA1), thyronamine, thyroacetic acid, N-acetyl-T1AM, and T1AM esters. RESULTS: In FBS-containing buffers, T1AM decreased exponentially over time, with a half-life of 6-17 minutes, depending on FBS content, and after 60 minutes, it averaged 0-10% of the baseline. T1AM metabolites were not detected, except for minimum amounts of TA1. Notably, d4 T1AM decreased over time at a much lower rate, reaching 50-70% of the baseline at 60 minutes. These effects were completely abolished by protein denaturation and partly reduced by semicarbazide. In the presence of cells, T1AM concentration decreased virtually to 0 within 60 minutes, but TA1 accumulated in the incubation medium, with quantitative recovery. Spontaneous decrease in T1AM concentration with isotopic difference was confirmed in rat organ homogenates and human blood. CONCLUSIONS: These results suggest binding and sequestration of T1AM and/or its aldehyde derivative by blood and tissue proteins, with significant isotope effects. These issues might account for the technical problems complicating the analytical assays of endogenous T1AM. PMID- 28859550 TI - Optimization and mechanisms for biodecoloration of a mixture of dyes by Trichosporon akiyoshidainum HP 2023. AB - Trichosporon akiyoshidainum HP2023 is a basidiomycetous yeast isolated from Las Yungas rainforest (Tucuman, Argentina) and selected based on its outstanding textile-dye-decolorizing ability. In this work, the decolorization process was optimized using Reactive Black 5 as dye model. Lactose and urea were chosen as carbon and nitrogen sources through a one-at-time approach. Afterwards, factorial designs were employed for medium optimization, leading to the formulation of a simpler optimized medium which contains in g L-1: lactose 10, yeast extract 1, urea 0.5, KH2PO4 1 and MgSO4 1. Temperature and agitation conditions were also optimized. The optimized medium and incubation conditions for dye removal were extrapolated to other dyes individually and a mixture of them. Dye removal process happened through both biosorption and biodegradation mechanisms, depending primarily on the dye structure. A positive relation between initial inoculum and dye removal rate and a negative relation between initial dye concentration and final dye removal percentages were found. Under optimized conditions, T. akiyoshidainum HP2023 was able to completely remove a mixture of dyes up to a concentration of 300 mg L-1, a concentration much higher than those expected in real effluents. PMID- 28859549 TI - Traumatic Brain Injury in hTau Model Mice: Enhanced Acute Macrophage Response and Altered Long-Term Recovery. AB - Traumatic brain injury (TBI) induces widespread neuroinflammation and accumulation of microtubule associated protein tau (MAPT): two key pathological features of tauopathies. This study sought to characterize the microglial/macrophage response to TBI in genomic-based MAPT transgenic mice in a Mapt knockout background (called hTau). Two-month-old hTau and age-matched control male and female mice received a single lateral fluid percussion TBI or sham injury. Separate groups of mice were aged to an acute (3 days post-injury [DPI]) or chronic (135 DPI) post-injury time point. As judged by tissue immunostaining for macrophage markers, microglial/macrophage response to TBI was enhanced at 3 DPI in hTau mice compared with control TBI and sham mice. However, MAPT phosphorylation increased in hTau mice regardless of injury group. Flow cytometric analysis revealed distinct populations of microglia and macrophages within all groups at 135 DPI. Unexpectedly, microglial reactivity was significantly reduced in hTau TBI mice compared with all other groups. Instead, hTau TBI mice showed a persistent macrophage response. In addition, TBI enhanced MAPT pathology in the temporal cortex and hippocampus of hTau TBI mice compared with controls 135 DPI. A battery of behavioral tests revealed that TBI in hTau mice resulted in compromised use of spatial search strategies to complete a water maze task, despite lack of motor or visual deficits. Collectively, these data indicate that the presence of wild-type human tau alters the microglial/macrophage response to a single TBI, induces delayed, region-specific MAPT pathology, and alters cognitive recovery; however, the causal relationship between these events remains unclear. These results highlight the potential significance of communication between MAPT and microglia/macrophages following TBI, and emphasize the role of neuroinflammation in post-injury recovery. PMID- 28859551 TI - Fractionating controlled memory processes and recall of context in recognition memory: a case report. AB - Recollection has been described as both a recognition memory judgment requiring cognitive control and the ability to retrieve contextual information about a prior occurrence. At the core of this article is the question whether or not these two subcomponents of recollection are dissociable in amnesia. In three experiments, we explored the influence of exclusion task instructions on performance in a single case (CJ), with the view to understand the relative contributions of control and source memory to recognition memory decisions. First, contrasting findings were obtained between tasks requiring strategic control or source reports. Second, even though CJ displayed some residual source memory relative to the ability to strategically control this information, his source memory capacity was time-limited. Our findings resonate with the novel proposal that recollection draws heavily upon working memory resources, and provide an example of how amnesic patients might utilize residual working memory capacity to solve episodic memory tasks. PMID- 28859552 TI - Treatment of landfill leachate with combined biological and chemical processes: changes in the dissolved organic matter and functional groups. AB - Leachates contain complicated and hazardous substances that need multiple treatment processes to meet the discharge standards. Few studies have considered the changes in different fractions, based on their molecular weight (MW), of dissolved organic matter, during the different treatment processes. In this study, we investigated the application of a biological method, using sequencing batch reactors, and a chemical method, using the electro-Fenton oxidation process, in combination. The combined treatment, and the electro-Fenton process alone, was applied to a landfill leachate. Samples taken at various points during the treatment processes were fractionated according to their MW using ultra membranes; this divided the samples into their less biodegradable constituents (0.45 MUm: >10 kDa MW), their bio-refractory constituents (10-1 kDa MW) and their biodegradable constituents (<1 kDa MW). The dominant contributors to the chemical oxygen demand (COD) in the raw leachate comprised the biodegradable constituents (79% of total COD). The COD was reduced to 33.6% and 18.5% of its original levels, by the electro-Fenton process alone and the combined treatment, respectively. Based on the absorption intensities in the Fourier transform infrared (FTIR) spectra, the functional groups in the raw leachate were reduced by the biological treatment, but changed by the electro-Fenton process. PMID- 28859553 TI - Thyroid Nodule Diagnostic Markers in the Face of the New NIFTP Category: Time for a Reset? AB - BACKGROUND: Current thyroid molecular tests are specifically designed for the differential diagnosis of nodules with indeterminate or suspicious fine-needle aspiration (FNA) cytology. SUMMARY: However, their clinical validity faces challenges from both variation among institutions in cancer prevalence and, most recently, the new category of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The latter diagnosis was previously classified as malignant. Relevant to this, all molecular panels on the market today were originally tested and validated within the context of these entities being considered malignant. CONCLUSION: This review examines possible effects of the NIFTP reclassification as a precancerous lesion on the original validation studies and, investigates the effect of the significant reported variability in thyroid cancer prevalence on the performance of these tests. PMID- 28859554 TI - Effects of Ecballium elaterium on brain in a rat model of sepsis-associated encephalopathy. AB - Despite recent advances in antibiotic therapy, sepsis remains a major clinical challenge in intensive care units. Here we examined the anti-inflammatory and antioxidant effects of Ecballium elaterium (EE) on brain, and explored its therapeutic potential in an animal model of sepsis-associated encephalopathy (SAE) [induced by cecal ligation and puncture (CLP)]. Thirty rats were divided into three groups of 10 each: control, sepsis, and treatment. Rats were subjected to CLP except for the control group, which underwent laparatomy only. The treatment group received 2.5 mg/kg EE while the sepsis group was administered by saline. Twenty-four hours after laparotomy, animals were sacrificied and the brains were removed. Brain homogenates were prepared to assess interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), total antioxidant capacity (TAC), and total oxidant status (TOS). Brain tissue sections were stained by hematoxylin and eosin (H&E) to semi-quantitatively examine the histopathologic changes such as neuron degeneration, pericellular/perivascular edema and inflammatory cell infiltration in the cerebral cortex. We found a statistically significant reduction in brain tissue homogenate levels of TNF alpha 59.5 +/- 8.4/50.2 +/- 6.2 (p = 0.007) and TOS 99.3 +/- 16.9/82.3 +/- 7.8 (p = 0.01) in rats treated with EE; although interleukin 6 levels were increased in the treatment group compared to the sepsis group, this was not statistically significant. Neuronal damage (p = 0.00), pericellular/perivascular edema and inflammatory cell infiltration (p = 0.001) were also significantly lower in the treatment group compared to those in the sepsis group. These data suggest that Ecballium elaterium contains some components that exert protective effects against SAE in part by attenuating accumulation of proinflammatory cytokines, which may be important contributors to its anti-inflammatory effects during sepsis. PMID- 28859555 TI - Child and Adolescent Disposition Model: An Examination of the Temperament Factor Structure Within Early Childhood. AB - Lahey and Waldman proposed a temperament theory of conduct disorder (CD). Critical is the hypothesized temperament structure in which three relatively uncorrelated temperament dimensions (i.e., negative emotionality, daring, prosociality) central to CD are theorized to emerge in early childhood. The validity of this hypothesized factor structure in early childhood is unknown. The current study seeks to fill this gap by examining Lahey and Waldman's hypothesized temperament structure utilizing a Canadian sample ( n = 283) of preschoolers. Confirmatory factor analyses (CFAs) were performed to compare the hypothesized relatively uncorrelated temperament structure with two alternative models (i.e., correlated three-factor and single-factor structure). The CFA indicated that the temperament dimensions are present in early childhood and are relatively uncorrelated consistent with previous work at later developmental stages. Of importance, the findings highlighted key gender differences observable at 3 and 4 years of age. The theoretical implications are discussed. PMID- 28859556 TI - The perceptions of first nation participants in a community oral health initiative. AB - The Children's Oral Health Initiative (COHI) is a federally funded community based preventive dental program for children and their caregivers living in geographically isolated Canadian Aboriginal communities. The goal of the program is to improve access to preventive dental services for children of 0-7 years of age. It utilises community health workers in collaboration with dental therapists to promote and deliver the program. Almost half of the province of Manitoba's (n=27) First Nations communities have implemented COHI since 2005. The objective of this investigation was to explore the opinions of COHI from the perspective of community members whose children had participated in the program. Purposeful selection identified caregivers of enrolled children for a semi-structured interview. The targeted caregivers had children who met at least one of the following criteria: (1) 0-2 years old; (2) 5-7 years old; (3) had two or more children either currently or formerly enrolled in COHI. Six open-ended questions guided the interview process. Content analysis was used to code transcripts and identify themes. One hundred and forty-one interviews were completed in 13 communities. Participants defined good oral health as the absence of dental cavities, which reflects a Western biomedical model of disease. The local, community-based nature of COHI was viewed as essential to its success in increasing access to preventive dental services and improving children and caregivers' oral health knowledge and behaviours. In conclusion, a local, community-based oral health prevention programme is perceived as having a beneficial effect on children and caregivers' oral health knowledge and behaviours. However, oral health preventive messages need to be further integrated into traditional Aboriginal holistic models of wellness. PMID- 28859557 TI - Pneumoencephalography in the workup of neuropsychiatric illnesses: a historical perspective. AB - Throughout history, neurosurgical procedures have been fundamental in advancing neuroscience; however, this has not always been without deleterious side effects or harmful consequences. While critical to the progression of clinical neuroscience during the early 20th century, yet, at the same time, poorly tolerated by patients, pneumoencephalography is one such procedure that exemplifies this juxtaposition. Presented herein are historical perspectives and reflections on the role of the pneumoencephalography in the diagnosis and treatment of neuropsychiatric illnesses. PMID- 28859558 TI - The early argument for prefrontal leucotomy: the collision of frontal lobe theory and psychosurgery at the 1935 International Neurological Congress in London. AB - The pathophysiology of mental illness and its relationship to the frontal lobe were subjects of immense interest in the latter half of the 19th century. Numerous studies emerged during this time on cortical localization and frontal lobe theory, drawing upon various ideas from neurology and psychiatry. Reflecting the intense interest in this region of the brain, the 1935 International Neurological Congress in London hosted a special session on the frontal lobe. Among other presentations, Yale physiologists John Fulton and Carlyle Jacobsen presented a study on frontal lobectomy in primates, and neurologist Richard Brickner presented a case of frontal ablation for olfactory meningioma performed by the Johns Hopkins neurosurgeon Walter Dandy. Both occurrences are said to have influenced Portuguese neurologist Egas Moniz (1874-1955) to commence performing leucotomies on patients beginning in late 1935. Here the authors review the relevant events related to frontal lobe theory leading up to the 1935 Neurological Congress as well as the extent of this meeting's role in the genesis of the modern era of psychosurgery. PMID- 28859559 TI - The origins and persistence of psychosurgery in the state of Iowa. AB - Neurosurgery for the treatment of psychological disorders has a checkered history in the United States. Prior to the advent of antipsychotic medications, individuals with severe mental illness were institutionalized and subjected to extreme therapies in an attempt to palliate their symptoms. Psychiatrist Walter Freeman first introduced psychosurgery, in the form of frontal lobotomy, as an intervention that could offer some hope to those patients in whom all other treatments had failed. Since that time, however, the use of psychosurgery in the United States has waxed and waned significantly, though literature describing its use is relatively sparse. In an effort to contribute to a better understanding of the evolution of psychosurgery, the authors describe the history of psychosurgery in the state of Iowa and particularly at the University of Iowa Department of Neurosurgery. An interesting aspect of psychosurgery at the University of Iowa is that these procedures have been nearly continuously active since Freeman introduced the lobotomy in the 1930s. Frontal lobotomies and transorbital leukotomies were performed by physicians in the state mental health institutions as well as by neurosurgeons at the University of Iowa Hospitals and Clinics (formerly known as the State University of Iowa Hospital). Though the early technique of frontal lobotomy quickly fell out of favor, the use of neurosurgery to treat select cases of intractable mental illness persisted as a collaborative treatment effort between psychiatrists and neurosurgeons at Iowa. Frontal lobotomies gave way to more targeted lesions such as anterior cingulotomies and to neuromodulation through deep brain stimulation. As knowledge of brain circuits and the pathophysiology underlying mental illness continues to grow, surgical intervention for psychiatric pathologies is likely to persist as a viable treatment option for select patients at the University of Iowa and in the larger medical community. PMID- 28859560 TI - Topectomy versus leukotomy: J. Lawrence Pool's contribution to psychosurgery. AB - Surgery of the mind has a rather checkered past. Though its history begins with the prehistoric trephination of skulls to allow "evil spirits" to escape, the early- to mid-20th century saw a surge in the popularity of psychosurgery. The 2 prevailing operations were topectomy and leukotomy for the treatment of certain mental illnesses. Although they were modified and refined by several of their main practitioners, the effectiveness of and the ethics involved with these operations remained controversial. In 1947, Dr. J. Lawrence Pool and the Columbia Greystone Associates sought to rigorously investigate the outcomes of specific psychosurgical procedures. Pool along with R. G. Heath and John Weber believed that nonexcessive bifrontal cortical ablation could successfully treat certain mental illnesses without the undesired consequences of irreversible personality changes. They conducted this investigation at the psychiatric hospital at Greystone Park near Morristown, New Jersey. Despite several encouraging findings of the Columbia-Greystone project, psychosurgery practices began to decline significantly in the 1950s. The uncertainty of results and ethical debates related to side effects made these procedures unpopular. Further, groups such as the National Association for the Advancement of Colored People and the American Civil Liberties Union condemned the use of psychosurgery, believing it to be an inhumane form of treatment. Today, there are strict guidelines that must be adhered to when evaluating a patient for psychosurgery procedures. It is imperative for the neurosurgery community to remember the history of psychosurgery to provide the best possible current treatment and to search for better future treatments for a particularly vulnerable patient population. PMID- 28859561 TI - Psychosurgery, ethics, and media: a history of Walter Freeman and the lobotomy. AB - At the peak of his career, Walter J. Freeman II was a celebrated physician and scientist. He served as the first chairman of the Department of Neurology at George Washington University and was a tireless advocate of surgical treatment for mental illness. His eccentric appearance, engaging personality during interviews, and theatrical demonstrations of his surgical techniques gained him substantial popularity with local and national media, and he performed more than 3000 prefrontal and transorbital lobotomies between 1930 and 1960. However, poor patient outcomes, unfavorable portrayals of the lobotomy in literature and film, and increased regulatory scrutiny contributed to the lobotomy's decline in popularity. The development of antipsychotic medications eventually relegated the lobotomy to rare circumstances, and Freeman's reputation deteriorated. Today, despite significant advancements in technique, oversight, and ethical scrutiny, neurosurgical treatment of mental illness still carries a degree of social stigma. This review presents a historical account of Walter Freeman's life and career, and the popularization of the lobotomy in the US. Additionally, the authors pay special attention to the influence of popular literature and film on the public's perception of psychosurgery. Aided by an understanding of this pivotal period in medical history, neurosurgeons are poised to confront the ethical and sociological questions facing psychosurgery as it continues to evolve. PMID- 28859562 TI - Editorial. London 1935: the frontal lobe, insanity, and a brain surgery. PMID- 28859563 TI - Editorial. The Kluver-Bucy syndrome and the golden age of localization. PMID- 28859564 TI - Dr. Robert G. Heath: a controversial figure in the history of deep brain stimulation. AB - The history of psychosurgery is filled with tales of researchers pushing the boundaries of science and ethics. These stories often create a dark historical framework for some of the most important medical and surgical advancements. Dr. Robert G. Heath, a board-certified neurologist, psychiatrist, and psychoanalyst, holds a debated position within this framework and is most notably remembered for his research on schizophrenia. Dr. Heath was one of the first physicians to implant electrodes in deep cortical structures as a psychosurgical intervention. He used electrical stimulation in an attempt to cure patients with schizophrenia and as a method of conversion therapy in a homosexual man. This research was highly controversial, even prior to the implementation of current ethics standards for clinical research and often goes unmentioned within the historical narrative of deep brain stimulation (DBS). While distinction between the modern practice of DBS and its controversial origins is necessary, it is important to examine Dr. Heath's work as it allows for reflection on current neurosurgical practices and questioning the ethical implication of these advancements. PMID- 28859565 TI - Neuroplasticity and the brain connectome: what can Jean Talairach's reflections bring to modern psychosurgery? AB - Contrary to common psychosurgical practice in the 1950s, Dr. Jean Talairach had the intuition, based on clinical experience, that the brain connectome and neuroplasticity had a role to play in psychosurgery. Due to the remarkable progress of pharmacology at that time and to the technical limits of neurosurgery, these concepts were not put into practice. Currently, these concepts are being confirmed by modern techniques such as neuroimaging and computational neurosciences, and could pave the way for therapeutic innovation in psychiatry. Psychosurgery commonly uses a localizationist approach, based on the idea that a lesion to a specific area is responsible for a deficit opposite to its function. To psychosurgeons such as Walter Freeman, who performed extensive lesions causing apparently inevitable deficit, Talairach answered with clinical data: complex psychic functions cannot be described that simply, because the same lesion does not provoke the same deficit in different patients. Moreover, cognitive impairment did not always follow efficacious psychosurgery. Talairach suggested that selectively destructing part of a network could open the door to a new organization, and that early psychotherapy could encourage this psychoplasticity. Talairach did not have the opportunity to put these concepts into practice in psychiatric diseases because of the sudden availability of neuroleptics, but connectomics and neuroplasticity gave rise to major advances in intraparenchymal neurosurgery, from epilepsy to low-grade glioma. In psychiatry, alongside long-standing theories implicating focal lesions and diffuse pathological processes, neuroimaging techniques are currently being developed. In mentally healthy individuals, combining diffusion tensor imaging with functional MRI, magnetoencephalography, and electroencephalography allows the determination of a comprehensive map of neural connections in the brain on many spatial scales, the so-called connectome. Ultimately, global neurocomputational models could predict physiological activity, behavior, and subjective feeling, and describe neuropsychiatric disorders. Connectomic studies comparing psychiatric patients with controls have already confirmed the early intuitions of Talairach. As a striking example, massive dysconnectivity has been found in schizophrenia, leading some authors to propose a "dysconnection hypothesis." Alterations of the connectome have also been demonstrated in obsessive-compulsive disorder and depression. Furthermore, normalization of the functional dysconnectivity has been observed following clinical improvement in several therapeutic interventions, from psychotherapy to pharmacological treatments. Provided that mental disorders result from abnormal structural or functional wiring, targeted psychosurgery would require that one be able: 1) to identify the pathological network involved in a given patient; 2) to use neurostimulation to safely create a reversible and durable alteration, mimicking a lesion, in a network compatible with neuroplasticity; and 3) to predict which functional lesion would result in adapted neuronal plasticity and/or to guide neuronal plasticity to promote recovery. All these conditions, already suggested by Talairach, could now be achievable considering modern biomarkers and surgical progress. PMID- 28859566 TI - History of psychosurgery at Sainte-Anne Hospital, Paris, France, through translational interactions between psychiatrists and neurosurgeons. AB - Sainte-Anne Hospital is the largest psychiatric hospital in Paris. Its long and fascinating history began in the 18th century. In 1952, it was at Sainte-Anne Hospital that Jean Delay and Pierre Deniker used the first neuroleptic, chlorpromazine, to cure psychiatric patients, putting an end to the expansion of psychosurgery. The Department of Neuro-psychosurgery was created in 1941. The works of successive heads of the Neurosurgery Department at Sainte-Anne Hospital summarized the history of psychosurgery in France. Pierre Puech defined psychosurgery as the necessary cooperation between neurosurgeons and psychiatrists to treat the conditions causing psychiatric symptoms, from brain tumors to mental health disorders. He reported the results of his series of 369 cases and underlined the necessity for proper follow-up and postoperative re education, illustrating the relative caution of French neurosurgeons concerning psychosurgery. Marcel David and his assistants tried to follow their patients closely postoperatively; this resulted in numerous publications with significant follow-up and conclusions. As early as 1955, David reported intellectual degradation 2 years after prefrontal leucotomies. Jean Talairach, a psychiatrist who eventually trained as a neurosurgeon, was the first to describe anterior capsulotomy in 1949. He operated in several hospitals outside of Paris, including the Sarthe Psychiatric Hospital and the Public Institution of Mental Health in the Lille region. He developed stereotactic surgery, notably stereo electroencephalography, for epilepsy surgery but also to treat psychiatric patients using stereotactic lesioning with radiofrequency ablation or radioactive seeds of yttrium-90. The evolution of functional neurosurgery has been marked by the development of deep brain stimulation, in particular for obsessive-compulsive disorder, replacing the former lesional stereotactic procedures. The history of Sainte-Anne Hospital's Neurosurgery Department sheds light on the initiation-yet fast reconsideration-of psychosurgery in France. This relatively more prudent attitude toward the practice of psychosurgery compared with other countries was probably due to the historically strong collaboration between psychiatrists and neurosurgeons in France. PMID- 28859567 TI - The hypothalamus at the crossroads of psychopathology and neurosurgery. AB - The neurosurgical endeavor to treat psychiatric patients may have been part of human history since its beginning. The modern era of psychosurgery can be traced to the heroic attempts of Gottlieb Burckhardt and Egas Moniz to alleviate mental symptoms through the ablation of restricted areas of the frontal lobes in patients with disabling psychiatric illnesses. Thanks to the adaptation of the stereotactic frame to human patients, the ablation of large volumes of brain tissue has been practically abandoned in favor of controlled interventions with discrete targets. Consonant with the role of the hypothalamus in the mediation of the most fundamental approach-avoidance behaviors, some hypothalamic nuclei and regions, in particular, have been selected as targets for the treatment of aggressiveness (posterior hypothalamus), pathological obesity (lateral or ventromedial nuclei), sexual deviations (ventromedial nucleus), and drug dependence (ventromedial nucleus). Some recent improvements in outcomes may have been due to the use of stereotactically guided deep brain stimulation and the change of therapeutic focus from categorical diagnoses (such as schizophrenia) to dimensional symptoms (such as aggressiveness), which are nonspecific in terms of formal diagnosis. However, agreement has never been reached on 2 related issues: 1) the choice of target, based on individual diagnoses; and 2) reliable prediction of outcomes related to individual targets. Despite the lingering controversies on such critical aspects, the experience of the past decades should pave the way for advances in the field. The current failure of pharmacological treatments in a considerable proportion of patients with chronic disabling mental disorders is reminiscent of the state of affairs that prevailed in the years before the early psychosurgical attempts. This article reviews the functional organization of the hypothalamus, the effects of ablation and stimulation of discrete hypothalamic regions, and the stereotactic targets that have most often been used in the treatment of psychopathological and behavioral symptoms; finally, the implications of current and past experience are presented from the perspective of how this fund of knowledge may usefully contribute to the future of hypothalamic psychosurgery. PMID- 28859568 TI - A brief note on the history of psychosurgery in Japan. AB - In Japan, there has been no neurosurgical treatment for psychiatric disorders since the 1970s. Even deep brain stimulation (DBS) has not been studied or used for psychiatric disorders. Neurosurgery for psychiatric disorders has been thwarted by social taboos for many years, and psychiatrists today seem to simply ignore modern developments and therapies offered by neurosurgery such as DBS. As a result, most patients and their families do not know such "last-resort" options exist. Historically, as in other countries, frontal lobotomies were widely performed in Japan in the 1940s and 1950s, and some Japanese neurosurgeons used stereotactic methods for the treatment of psychiatric disorders until the 1960s. However, in the 1960s and 1970s such surgical treatments began to receive condemnation based on political judgment, rather than on medical and scientific evaluation. Protest campaigns at the time hinged on the prevailing political beliefs, forming a part of the new "left" movement against leading authorities across a wide range of societal institutions including medical schools. Finally, the Japanese Society for Psychiatry and Neurology banned the surgical treatment for psychiatric disorders in 1975. Even today, Japan's dark history continues to exert an enormous negative influence on neurosurgery for psychiatric disorders. PMID- 28859569 TI - Introduction. Neurosurgery, psychiatry, and function: the history of altering behavior, thought, and function through neurosurgery. PMID- 28859570 TI - Sanger Brown and Edward Schafer before Heinrich Kluver and Paul Bucy: their observations on bilateral temporal lobe ablations. AB - Fifty years before a report on the complete bitemporal lobectomy syndrome in primates, known as the Kluver-Bucy syndrome, was published, 2 talented investigators working at the University College in London, England-neurologist Sanger Brown and physiologist Edward Schafer-also made this discovery. The title of their work was "An investigation into the functions of the occipital and temporal lobes of the monkey's brain," and it involved excisional brain surgery in 12 monkeys. They were particularly interested in the then-disputed primary cortical locations relating to vision and hearing. However, following extensive bilateral temporal lobe excisions in 2 monkeys, they noted peculiar behavior including apparent loss of memory and intelligence resembling "idiocy." These investigators recognized most of the behavioral findings that later came to be known as the Kluver-Bucy syndrome. However, they were working within the late 19th-century framework of cerebral cortical localizations of basic motor and sensory functions. Details of the Brown and Schafer study and a glimpse of the neurological thinking of that period is presented. In the decades following the pivotal work of Kluver and Bucy in the late 1930s, in which they used a more advanced neurosurgical technique, tools of behavioral observations, and analysis of brain sections after euthanasia, investigators have elaborated the full components of the clinical syndrome and the extent of their resections. Other neuroscientists sought to isolate and determine the specific temporal neocortical, medial temporal, and deep limbic structures responsible for various visual and complex behavioral deficits. No doubt, Kluver and Bucy's contribution led to a great expansion in attention given to the limbic system's role in action, perception, emotion, and affect-a tide that continues to the present time. PMID- 28859571 TI - Exploring the brain through posterior hypothalamus surgery for aggressive behavior. AB - Neurological surgery offers an opportunity to study brain functions, through either resection or implanted neuromodulation devices. Pathological aggressive behavior in patients with intellectual disability is a frequent condition that is difficult to treat using either supportive care or pharmacological therapy. The bulk of the laboratory studies performed throughout the 19th century enabled the formulation of hypotheses on brain circuits involved in the generation of emotions. Aggressive behavior was also studied extensively. Lesional radiofrequency surgery of the posterior hypothalamus, which peaked in the 1970s, was shown to be an effective therapy in many reported series. As with other surgical procedures for the treatment of psychiatric disorders, however, this therapy was abandoned for many reasons, including the risk of its misuse. Deep brain stimulation (DBS) offers the possibility of treating neurological and psychoaffective disorders through relatively reversible and adaptable therapy. Deep brain stimulation of the posterior hypothalamus was proposed and performed successfully in 2005 as a treatment for aggressive behavior. Other groups reported positive outcomes using target and parameter settings similar to those of the original study. Both the lesional and DBS approaches enabled researchers to explore the role of the posterior hypothalamus (or posterior hypothalamic area) in the autonomic and emotional systems. PMID- 28859572 TI - The Genetic Diversity of the Americas. AB - The history of the Americas involved the encounter of millions of Native Americans, Europeans, and Africans. A variable admixture of these three continental groups has taken place throughout the continent, influenced by demography and a range of social factors. This variable admixture has had a major influence on the genetic makeup of populations across the continent. Here, we summarize the demographic history of the region, highlight some social factors that affected historical admixture, and review major patterns of ancestry across the Western Hemisphere based on genetic data. PMID- 28859573 TI - Recent Advancements in DNA Damage-Transcription Crosstalk and High-Resolution Mapping of DNA Breaks. AB - Until recently, DNA damage arising from physiological DNA metabolism was considered a detrimental by-product for cells. However, an increasing amount of evidence has shown that DNA damage could have a positive role in transcription activation. In particular, DNA damage has been detected in transcriptional elements following different stimuli. These physiological DNA breaks are thought to be instrumental for the correct expression of genomic loci through different mechanisms. In this regard, although a plethora of methods are available to precisely map transcribed regions and transcription start sites, commonly used techniques for mapping DNA breaks lack sufficient resolution and sensitivity to draw a robust correlation between DNA damage generation and transcription. Recently, however, several methods have been developed to map DNA damage at single-nucleotide resolution, thus providing a new set of tools to correlate DNA damage and transcription. Here, we review how DNA damage can positively regulate transcription initiation, the current techniques for mapping DNA breaks at high resolution, and how these techniques can benefit future studies of DNA damage and transcription. PMID- 28859574 TI - Cognitive Dysfunctions in Intellectual Disabilities: The Contributions of the Ras MAPK and PI3K-AKT-mTOR Pathways. AB - The Ras-MAPK and PI3K-AKT-mTOR signaling cascades were originally identified as cancer regulatory pathways but have now been demonstrated to be critical for synaptic plasticity and behavior. Neurodevelopmental disorders arising from mutations in these pathways exhibit related neurological phenotypes, including cognitive dysfunction, autism, and intellectual disability. The downstream targets of these pathways include regulation of transcription and protein synthesis. Other disorders that affect protein translation include fragile X syndrome (an important cause of syndromal autism), and other translational regulators are now also linked to autism. Here, we review how mechanisms of synaptic plasticity have been revealed by studies of mouse models for Ras-MAPK, PI3K-AKT-mTOR, and translation regulatory pathway disorders. We discuss the face validity of these mouse models and review current progress in clinical trials directed at ameliorating cognitive and behavioral symptoms. PMID- 28859575 TI - Variation in cell surface characteristics and extracellular polymeric substances during the biodegradation of monocyclic and heterocyclic aromatic hydrocarbons in single and multi-substrate systems. AB - The variation in surface characteristics and the composition of extracellular polymeric substances (EPS) of bacterial cells during biodegradation of single and multi-aromatic hydrocarbons was investigated in the present study. The maximum cell surface hydrophobicity (CSH) of 80.1% was observed during the degradation of toluene. Bacterial cells acquired more negative surface charge with an increase in CSH and vice versa. Proteins constituted the major fraction of EPS during biodegradation of benzene and toluene with protein/carbohydrate ratio varying between 2.19 and 3.1. Carbohydrates constituted the major fraction of EPS in the presence of pyridine. A significant variation in cell surface characteristics was observed in multi-substrate systems involving heterocyclic and monocyclic aromatic hydrocarbons. An increase in EPS production (62.89 mg/g) did not facilitate enhanced degradation of hydrophobic substrates in multi-substrate system involving benzothiophene, benzofuran, benzene and toluene. Under toxic conditions, especially at higher concentration of target pollutants, a significant increase in concentration of polysaccharides was observed compared to proteins. PMID- 28859576 TI - Optimization of the enhanced membrane coagulation reactor for sewage concentration efficiency and energy recovery. AB - The application of an enhanced membrane coagulation reactor (E-MCR) for sewage concentration and energy recovery through anaerobic digestion (AD) was investigated. The results show that the addition of powder-activated carbon (PAC) and polyaluminum chloride (PACl) enhanced the sewage concentration efficiency and minimized the membrane fouling. The reactor was operated for 100 d with 70 d without severe fouling. The flux of 6 L/(m2 h) with sludge retention time of 2 d recorded a long-term stable performance and recovered concentrates with about 6000-9800 mg/L of chemical oxygen demand (COD) values. The concentrate was used as feed for AD using a continuous stirred tank reactor. The results show that at a thermophilic temperature of 35 degrees C, a high biogas yield was achieved at 20 and 30 d hydraulic retention time (HRT). Meanwhile, biogas yields of 10, 220, and 295 mL/(gCOD) were achieved at 10, 20, and 30 d HRT, respectively. The addition of PAC/PACl and the low flux condition enhanced the concentration efficiency and minimized the membrane fouling during the long-term operation. Thus, with the optimization of the operation, E-MCR becomes a promising option for sewage concentration and energy recovery. PMID- 28859577 TI - Single-Cell Sequencing Technologies for Cardiac Stem Cell Studies. AB - Today with the rapid advancements in stem cell studies and the promising potential of using stem cells in clinical therapy, there is an increasing demand for in-depth comprehensive analysis on individual cell transcriptome and epigenome, as they play critical roles in a number of cell functions such as cell differentiation, growth, and reprogramming. The development of single-cell sequencing technologies has helped in revealing some exciting new perspectives in stem cells and regenerative medicine research. Among the various potential applications, single-cell analysis for cardiac stem cells (CSCs) holds tremendous promises in understanding the mechanisms of heart development and regeneration, which might light up the path toward cell therapy for cardiovascular diseases. This review briefly highlights the recent progresses in single-cell sequencing analysis technologies and their applications in CSC research. PMID- 28859578 TI - Quality Improvement Initiative to Reduce Pediatric Intensive Care Unit Noise Pollution With the Use of a Pediatric Delirium Bundle. AB - OBJECTIVES: Noise pollution in pediatric intensive care units (PICU) contributes to poor sleep and may increase risk of developing delirium. The Environmental Protection Agency (EPA) recommends <45 decibels (dB) in hospital environments. The objectives are to assess the degree of PICU noise pollution, to develop a delirium bundle targeted at reducing noise, and to assess the effect of the bundle on nocturnal noise pollution. METHODS: This is a QI initiative at an academic PICU. Thirty-five sound sensors were installed in patient bed spaces, hallways, and common areas. The pediatric delirium bundle was implemented in 8 pilot patients (40 patient ICU days) while 108 non-pilot patients received usual care over a 28-day period. RESULTS: A total of 20,609 hourly dB readings were collected. Hourly minimum, average, and maximum dB of all occupied bed spaces demonstrated medians [interquartile range] of 48.0 [39.0-53.0], 52.8 [48.1-56.2] and 67.0 [63.5-70.5] dB, respectively. Bed spaces were louder during the day (10AM to 4PM) than at night (11PM to 5AM) (53.5 [49.0-56.8] vs. 51.3 [46.0-55.3] dB, P < 0.01). Pilot patient rooms were significantly quieter than non-pilot patient rooms at night (n=210, 45.3 [39.7-55.9]) vs. n=1841, 51.2 [46.9-54.8] dB, P < 0.01). The pilot rooms compliant with the bundle had the lowest hourly nighttime average dB (44.1 [38.5-55.5]). CONCLUSIONS: Substantial noise pollution exists in our PICU, and utilizing the pediatric delirium bundle led to a significant noise reduction that can be perceived as half the loudness with hourly nighttime average dB meeting the EPA standards when compliant with the bundle. PMID- 28859579 TI - Understanding the Cost of a New Integrated Care Model to Serve CMHC Patients Who Have Serious Mental Illness. AB - People with serious mental illness, such as schizophrenia and bipolar disorder, experience premature mortality, often from cardiovascular disease (CVD). Unfortunately, people with serious mental illness typically are not screened or treated for CVD risk factors despite national guideline recommendations. Access to primary preventive care in community mental health settings has the potential to reduce early mortality rates in this population. The authors review best practices for developing an integrated care model for people with serious mental illness by considering economic feasibility and sustainability from the perspective of a community mental health clinic (CMHC). A process-mapping approach was used to gather information on clinic costs (staff roles, responsibilities, time, and salary) of serving 544 patients at one CMHC. The estimated annual cost of the model was measurable and modest, at $74 per person, suggesting that this model may be financially feasible. PMID- 28859581 TI - Telehealth Delivery of Mental Health Services: An Analysis of Private Insurance Claims Data in the United States. AB - OBJECTIVE: This study characterizes telehealth claims for mental health and substance abuse (MH/SA) services by using national private claims data. METHODS: Telehealth-related mental health service claims were identified with private claims data from 2009 to 2013. These data-provided by the Health Care Cost Institute-included claims from Aetna, Humana, and UnitedHealth for more than 50 million individuals per year. RESULTS: In 2009-2013, there were 13,480 MH/SA telehealth provider claims out of 3,986,159 claims, with the majority of telehealth claims submitted by psychiatrists. For telehealth services, there was a decreasing trend for average reimbursements ($54.61 in 2009 to $43.28 in 2013). Average reimbursements for telehealth claims were half those for nontelehealth claims. Reimbursements for nine of the top 10 telehealth services were lower in 2015 dollars than for the same services provided during face-to-face treatment. CONCLUSIONS: Widespread adoption and use of costly telehealth technologies for mental health services may be limited by low reimbursements for telehealth services. PMID- 28859580 TI - Simulated Effects of Policies to Reduce Diabetes Risk Among Adults With Schizophrenia Receiving Antipsychotics. AB - OBJECTIVE: Second-generation antipsychotics increase the risk of diabetes and other metabolic conditions among individuals with schizophrenia. Although metabolic testing is recommended to reduce this risk, low testing rates have prompted concerns about negative health consequences and downstream medical costs. This study simulated the effect of increasing metabolic testing rates on ten-year prevalence rates of prediabetes and diabetes (diabetes conditions) and their associated health care costs. METHODS: A microsimulation model (N=21,491 beneficiaries) with a ten-year time horizon was used to quantify the impacts of policies that increased annual testing rates in a Medicaid population with schizophrenia. Data sources included California Medicaid data, National Health and Nutrition Examination Survey data, and the literature. In the model, metabolic testing increased diagnosis of diabetes conditions and diagnosis prompted prescribers to switch patients to lower-risk antipsychotics. Key inputs included observed diagnoses, prescribing rates, annual testing rates, imputed rates of undiagnosed diabetes conditions, and literature-based estimates of policy effectiveness. RESULTS: Compared with 2009 annual testing rates, ten-year outcomes for policies that achieved universal testing reduced exposure to higher risk antipsychotics by 14%, time to diabetes diagnosis by 57%, and diabetes prevalence by .6%. These policies were associated with higher spending because of testing and earlier treatment. CONCLUSIONS: The model showed that policies promoting metabolic testing provided an effective approach to improve the safety of second-generation antipsychotic prescribing in a Medicaid population with schizophrenia; however, the policies led to additional costs at ten years. Simulation studies are a useful source of information on the potential impacts of these policies. PMID- 28859582 TI - Adverse Childhood Experiences and the Risk of Criminal Justice Involvement and Victimization Among Homeless Adults With Mental Illness. AB - OBJECTIVE: Exposure to adverse childhood experiences (ACEs) is highly prevalent among homeless individuals and is associated with negative consequences during homelessness. This study examined the effect of ACEs on the risk of criminal justice involvement and victimization among homeless individuals with mental illness. METHODS: The study used baseline data from a demonstration project (At Home/Chez Soi) that provided Housing First and recovery-oriented services to homeless adults with mental illness. The sample was recruited from five Canadian cities and included participants who provided valid responses on an ACEs questionnaire (N=1,888). RESULTS: Fifty percent reported more than four types of ACE, 19% reported three or four types, 19% reported one or two, and 12% reported none. Rates of criminal justice involvement and victimization were significantly higher among those with a history of ACEs. For victimization, the association was significant for all ten types of ACE, and for justice involvement, it was significant for seven types. Logistic regression models indicated that the effect of cumulative childhood adversity on the two outcomes was significant regardless of sociodemographic factors, duration of homelessness, and psychiatric diagnosis, with one exception: the relationship between cumulative childhood adversity and criminal justice involvement did not remain significant when the analysis controlled for a diagnosis of posttraumatic stress disorder and substance dependence. CONCLUSIONS: Findings support the need for early interventions for at risk youths and trauma-informed practice and violence prevention policies that specifically target homeless populations. PMID- 28859583 TI - Relationship Between Psychiatric-Service Consumers' and Providers' Goal Concordance and Consumers' Personal Goal Attainment. AB - OBJECTIVE: This study tested concordance between consumers' and providers' reports of personal goal setting and its relationship to self-reported goal attainment. METHODS: Data are from the Israeli Psychiatric Rehabilitation Patient Reported Outcome Measurement project. Consumers (N=2,885) and the providers who were most knowledgeable about their care indicated two domains from a list of ten in which consumers had set goals during the previous year. Consumers reported on goal attainment in each domain. RESULTS: A total of 2,345 consumers (82%) reported a personal goal. Overall, consumer-provider concordance reached 54%. Concordance was greatest in the employment (76%), housing (71%), and intimate relationship (52%) domains and lowest in family relationships (23%) and finances (15%). For most domains, concordance was less than 50%. On average, 75% of consumers reported having achieved their goals. Consumer-provider concordance was associated with goal attainment (p<.001). CONCLUSIONS: These findings emphasize the importance of agreed-upon goals and call for conceptualizing goal setting as an interpersonal process central to recovery. PMID- 28859584 TI - Impact of Physician Follow-Up Care on Psychiatric Readmission Rates in a Population-Based Sample of Patients With Schizophrenia. AB - OBJECTIVE: The study evaluated the association between physician follow-up within 30 days after hospital discharge and psychiatric readmission within the subsequent 180 days. METHODS: Among inpatients with schizophrenia who were discharged between 2007 and 2012 in Ontario (N=19,132), those who had a 30-day follow-up visit with a primary care physician (PCP) only, a psychiatrist only, or both were compared with a no-follow-up group. The primary outcome was psychiatric readmission in the subsequent 180 days. Secondary analyses stratified the sample on the basis of readmission risk at discharge. RESULTS: About 65% of patients had follow-up care within 30 days postdischarge. Psychiatric readmission rates were similar among patients with any physician follow-up and significantly lower than among those with no follow-up (26%): PCP only: 22%; adjusted hazard ratio [aHR]=.88, 95% confidence interval [CI]=.81-.96; psychiatrist only, 22%; aHR=.84, CI=.77-.90; both, 21%, aHR=.82, CI=.75-.90). In stratified analyses, 66% of patients were in the category at highest risk of psychiatric readmission, and the effect of follow-up with any physician was significant for these patients, compared with high-readmission risk patients with no follow-up, who had a 29% readmission rate (PCP only, 20% readmission rate, aHR=.85, CI=.77-.94; psychiatrist only, 29%, aHR=.84, CI=.77-.92; both, 17%, aHR=.81, CI=.73-.90). DISCUSSION: Timely physician follow-up was associated with reduced risk of psychiatric readmissions, with the greatest reduction among patients at high risk of readmission. Because more than one-third of patients had no physician visit within 30 days postdischarge, improving physician follow-up may help reduce psychiatric readmission rates. PMID- 28859585 TI - Prevalence of Serious Emotional Disturbance Among U.S. Children: A Meta-Analysis. AB - OBJECTIVE: Prevalence estimates of child psychiatric disorders with severe impairment vary widely, and there is a critical need for precise estimates to inform clinical practice and policy in the United States. This study presents a systematic review and meta-analysis of population-based U.S. studies estimating the prevalence of youths with serious emotional disturbance (SED), as defined by the Substance Abuse and Mental Health Services Administration. METHODS: Studies were identified through searches of the MEDLINE and PsycINFO databases and nine prior reviews. Two raters evaluated 423 full-text articles, and studies were included if they assessed psychopathology and functional impairment among community samples of youths (age <=18) in the United States via structured interviews or standardized, nationally normed rating scales and if they reported point to 12-month prevalence estimates. Prevalence estimates of SED with domain specific and global impairment were extracted, along with study characteristics and case definitions. Random-effects meta-analysis was used to calculate pooled prevalence estimates; metaregression analyses tested predictors of heterogeneity. RESULTS: Twelve studies met inclusion criteria. The pooled prevalence of SED with domain-specific impairment was 10.06% (95% confidence interval [CI]=8.60%-11.51%, N=32,015); prevalence of SED with global impairment was 6.36% (CI=5.78%-6.93%, N=38,939). Prevalence estimates did not differ by study or sample characteristic, including representativeness of the sample (national versus regional), assessment method (taxonomic versus quantitative), or time frame (12 versus <12 months). CONCLUSIONS: These estimates of SED are sufficiently precise to meaningfully guide clinical decision making, mental health policy, and consideration of child psychiatry workforce needs in the United States. PMID- 28859586 TI - Evaluating the Implementation of Home-Based Videoconferencing for Providing Mental Health Services. AB - OBJECTIVE: The Veterans Health Administration (VHA) has recently implemented video-to-home (V2H) telehealth as part of a strategy to improve access to mental health treatment. Implementation research of this modality is needed, given that V2H telehealth transforms the traditional face-to-face delivery of mental health services. To address this need, V2H implementation was evaluated by examining barriers and facilitators that were associated with level of staff V2H experience and factors that differentiated facilities with various levels of V2H performance. METHODS: Semistructured interviews with VHA personnel (N=33) from three facilities were conducted. The facilities were selected by overall number of mental health V2H visits during fiscal year (FY) 2015 as well as by growth in number of visits from FY 2014 through FY 2015. Factors influencing implementation were identified through qualitative analyses that contrasted responses by groups of participants with three different levels of V2H experience (no experience, limited experience, most experience) as well as three facilities that differed in V2H productivity (high visit count, high visit growth, and low visit count and low visit growth). RESULTS: Providers seemed to encounter different barriers and facilitators depending on their level of experience with V2H. Site-level analyses illustrated the importance of logistical support, especially for providers who are newly adopting the technology. Other factors that differentiated the facilities were also identified and described. CONCLUSIONS: Key factors related to implementation of V2H telehealth pertained to provider buy-in and logistical support. Facility-level strategies that address these factors may enhance provider progression from nonuse to sustained use. PMID- 28859587 TI - First-Episode Psychosis and the Criminal Justice System: Using a Sequential Intercept Framework to Highlight Risks and Opportunities. AB - In first-episode psychosis there is a heightened risk of aggression and subsequent criminal justice involvement. This column reviews the evidence pointing to these heightened risks and highlights opportunities, using a sequential intercept model, for collaboration between mental health services and existing diversionary programs, particularly for patients whose behavior has already brought them to the attention of the criminal justice system. Coordinating efforts in these areas across criminal justice and clinical spheres can decrease the caseload burden on the criminal justice system and optimize clinical and legal outcomes for this population. PMID- 28859588 TI - September 2017 Letter to the Editor-in-Chief. AB - Letter to the Editor-in-Chief of JOSPT as follows: "Clinically Meaningful Outcome Measures in Patients With Shoulder Problems" with Authors' Response J Orthop Sports Phys Ther 2017;47(9):693-695. doi:10.2519/jospt.2017.0205. PMID- 28859589 TI - Predicting Low Back Pain Outcomes: Suggestions for Future Directions. AB - Chronic low back pain (LBP) is a common and costly musculoskeletal pain condition, and effective treatment of LBP represents a significant goal of physical therapists. Establishing a targeted track of treatment for patients with LBP at high risk for chronicity that is focused on modifiable prognostic factors could have significant personal and societal benefit. Such an approach would require that clinicians accurately predict the patients who are at an elevated risk of developing chronic LBP in the early stages of the condition. In this Viewpoint, we consider the strengths and limitations of existing literature and propose suggestions that may lead to the development of parsimonious, cost effective, and accurate predictive models of LBP chronicity. J Orthop Sports Phys Ther 2017;47(9):588-592. doi:10.2519/jospt.2017.0607. PMID- 28859590 TI - Neural Mobilization: Treating Nerve-Related Musculoskeletal Conditions. AB - Physical therapists often assess and treat patients whose pain and disability stem from impaired mobility of the peripheral nervous system. Neural mobilization is a movement-based therapy, applied manually or via exercise. The nerve is mobilized relative to adjacent structures, with the aim of reducing symptoms through mechanisms that may be mechanical or neurophysiologic. A new systematic review published in the September 2017 issue of JOSPT includes 40 studies of neural mobilization in various neuromusculoskeletal conditions. The available evidence suggests that neural mobilization can be considered when treating certain nerve-related musculoskeletal conditions. J Orthop Sports Phys Ther 2017;47(9):616. doi:10.2519/jospt.2017.0509. PMID- 28859591 TI - Assessing Implementation Readiness and Success of an e-Resource to Improve Prelicensure Physical Therapy Workforce Capacity to Manage Rheumatoid Arthritis. AB - Study Design Prospective within-subject, cross-sectional, between-group, nested qualitative designs within an implementation science framework. Background Physical therapy is recommended for rheumatoid arthritis (RA) care, yet prelicensure RA curriculum time remains limited. Objectives To determine readiness for, and success of, implementing an e-learning tool, Rheumatoid Arthritis for Physiotherapists e-Learning (RAP-eL), within the prelicensure physical therapy curriculum. Methods All physical therapy students in a 1-year cohort in 2014 had RAP-eL embedded in their curriculum. Rheumatoid Arthritis for Physiotherapists e-Learning is an online platform that delivers RA disease information with translation to clinical practice. Implementation readiness, determined by acceptability of RAP-eL to students, was evaluated using focus groups (n = 23). Implementation success was measured using quantitative data from a previously validated questionnaire, including changes in students' self reported confidence in knowledge (out of 45) and skills (out of 40) in managing RA after 4 weeks of access to RAP-eL, retention of learning over 14 months, and differences in workforce readiness between students in the cohort who had access to RAP-eL and a historical control cohort. Results Acceptability of RAP-eL was confirmed from qualitative data, demonstrating implementation readiness. Short term improvements were observed in RA knowledge (mean difference, 16.6; 95% confidence interval [CI]: 15.7, 17.6) and RA skills (mean difference, 14.9; 95% CI: 13.9, 15.9; n = 137). Retention was demonstrated after 14 months (P<.001; n = 62). Students in the 1-year cohort who had RAP-eL embedded in the curriculum scored significantly higher on knowledge (mean difference, 3.6; 95% CI: 1.3, 5.9) and skills (mean difference, 3.3; 95% CI: 0.9, 5.7; n = 62) compared to those without RAP-eL (n = 36). Rheumatoid Arthritis for Physiotherapists e-Learning remains embedded in the curriculum. Conclusion This study demonstrated both readiness and success of the sustainable implementation of RAP-eL within a prelicensure physical therapy curriculum. J Orthop Sports Phys Ther 2017;47(9):652-663. doi:10.2519/jospt.2017.7281. PMID- 28859592 TI - Dr Abbott Leaves JOSPT to Focus on Research Program. AB - The Board of Directors of JOSPT(r), Inc, d/b/a Movement Science Media (MSM), has accepted the resignation of J. Haxby Abbott, PhD, DPT, FNZCP, as Editor-in-Chief (EIC) of the Journal of Orthopaedic & Sports Physical Therapy, effective December 31, 2017. Dr Abbott is leaving JOSPT to focus on his research program and to spend time with his young family. The Board expects to appoint an interim EIC and to begin a search for Dr Abbott's successor. J Orthop Sports Phys Ther 2017;47(9):587. doi:10.2519/jospt.2017.47.9.587. PMID- 28859593 TI - September 2017 Corrigendum. AB - Corrections to an article published in the May 2017 issue of JOSPT: Peterson S, Denninger T, Porter S. Physical therapist clinical reasoning and action for individuals with undiagnosed lower extremity tumors: a report of 3 cases. J Orthop Sports Phys Ther 2017;47(9):696. doi:10.2519/jospt.2017.47.9.696. PMID- 28859594 TI - September 2017 New Products. AB - A selection of products and developments of interest to JOSPT readers. J Orthop Sports Phys Ther 2017;47(9):698. doi:10.2519/jospt.2017.47.9.698. PMID- 28859595 TI - C6 Spinous Process Fracture in a Young Adult. AB - A 21-year-old male military academy cadet developed acute posterior neck pain after performing multiple sets of overhead shoulder presses and resting the bar on his lower neck and shoulders. He presented to a direct-access physical therapy clinic. Due to the acute onset and focal nature of pain in the setting of repetitive weightlifting, the physical therapist ordered radiographs of the cervical spine, which revealed a C6 spinous process fracture. J Orthop Sports Phys Ther 2017;47(8):578. doi:10.2519/jospt.2017.7277. PMID- 28859596 TI - Cervical Myelopathy Presenting as Bilateral Upper Extremity Weakness. AB - A 57-year-old man with insidious onset of progressive bilateral upper extremity weakness was referred to physical therapy by his primary care physician. Following examination, the physical therapist referred the patient back to his primary care physician with a request for cervical magnetic resonance imaging (MRI) and neurology consultation. Cervical radiographs demonstrated multilevel degenerative changes, while cervical spine MRI revealed compressive myelopathy, significant spinal canal stenosis, and severe spondylosis J Orthop Sports Phys Ther 2017;47(9):691. doi:10.2519/jospt.2017.7287. PMID- 28859597 TI - Enhanced efficiency of swine wastewater treatment by the composite of modified zeolite and a bioflocculant enriched from biological sludge. AB - A high-ammonia-resistant strain was firstly isolated from activated sludge and applied to harvest a bioflocculant from a swine wastewater. Enhancement of swine wastewater treatment was investigated by a composite of the harvested bioflocculant and a zeolite modified by integrating calcinations with MgO at 400 degrees C. Results have demonstrated that 71.8% of Chemical Oxygen Demand (COD), 54.5% of ammonia, and 81.2% of turbidity can be removed from the swine wastewater by the bioflocculant alone. Results have also demonstrated that 73.4% of ammonia could be removed from the swine wastewater by the modified zeolite alone, while almost no COD was removed. Thus, the bioflocculant and modified zeolite were used simultaneously to enhance swine wastewater treatment, and response surface methodology (RSM) was employed to optimize the treatment process. Under the optimal treatment conditions of bioflocculant of 12 mg/L, modified zeolite of 8 g/L, pH of 7.5, and agitation speed of 200 r/min, obtained by the RSM, 88.6% of COD, 85.8% of ammonia, and 95.5% of turbidity could be removed from swine wastewater, which were significantly improved compared with that by the bioflocculant or modified zeolite alone. The use of the composite exerted advantages of the bioflocculant and modified zeolite, and provided a feasible way to improve pollutants' removal from wastewaters. PMID- 28859599 TI - Child Neuropsychology. PMID- 28859600 TI - Two Cases of Popliteal Cystic Adventitial Disease Treated With Excision and Primary Bypass Graft: A Review of the Literature. AB - Cystic adventitial disease (CAD) is a rare vascular pathology which predominantly affects peripheral vessels of young otherwise healthy males. Much debate exists regarding its exact etiology. It is characterized by a collection of mucinous material within the adventitial wall layer of the affected vessel, resulting in arterial stenosis and rapidly progressive calf claudication. Treatment is primarily surgical, although radiological interventions have been reported. Its rarity makes evidence-based surgical or radiological management difficult. With this in mind, we report two cases of popliteal artery CAD treated successfully with primary excision and bypass grafting. We analyzed all literature published on CAD since first reported in 1947 and we propose an algorithm for appropriate management pathways. PMID- 28859602 TI - Corrigendum. AB - Sayler KA, Bigelow T, Koster LG, Swenson S, Bounds C, Hernandez F, Wisely SM. Development of a rapid, simple, and specific real-time PCR assay for detection of pseudorabies viral DNA in domestic swine herds. J Vet Diagn Invest 2017;29:522 528. (Original doi:10.1177/1040638717706593). In the article titled "Development of a rapid, simple, and specific real-time PCR assay for detection of pseudorabies viral DNA in domestic swine herds" by Katherine A. Sayler et al., the Acknowledgements section, should read as follows: We thank all of the researchers who provided isolates or DNA samples of PRV, including C Romero at the University of Florida, College of Veterinary Medicine (U.S.); A Moreno at the Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna (Italy); S Verpoest at the CODA-CERVA Veterinary and Agrochemical Research Center (Belgium); A Steinrigl at the Austrian Agency for Health and Food Safety GmbH, Institute for Veterinary Disease Control (Austria); Z Dirbakova at the State Veterinary and Food Institute, Veterinary Institute in Zvolen (Slovakia); T Muller at the Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health (Germany); and F Ruiz-Fons and D Gonzalez-Barrio at the Instituto de Investigacion en Recursos Cinegeticos (IREC) (Spain). PMID- 28859603 TI - Effects of constraint-induced movement therapy for lower limbs on measurements of functional mobility and postural balance in subjects with stroke: a randomized controlled trial. AB - : Abstrato Background: Constraint-induced movement therapy (CIMT) is suggested to reduce functional asymmetry between the upper limbs after stroke. However, there are few studies about CIMT for lower limbs. OBJECTIVE: To examine the effects of CIMT for lower limbs on functional mobility and postural balance in subjects with stroke. METHODS: A 40-day follow-up, single-blind randomized controlled trial was performed with 38 subacute stroke patients (mean of 4.5 months post-stroke). Participants were randomized into: treadmill training with load to restraint the non-paretic ankle (experimental group) or treadmill training without load (control group). Both groups performing daily training for two consecutive weeks (nine sessions) and performed home-based exercises during this period. As outcome measures, postural balance (Berg Balance Scale - BBS) and functional mobility (Timed Up and Go test - TUG and kinematic parameters of turning - Qualisys System of movement analysis) were obtained at baseline, mid-training, post-training and follow-up. RESULTS: Repeated-measures ANOVA showed improvements after training in postural balance (BBS: F = 39.39, P < .001) and functional mobility, showed by TUG (F = 18.33, P < .001) and by kinematic turning parameters (turn speed: F = 35.13, P < .001; stride length: F = 29.71, P < .001; stride time: F = 13.42, P < .001). All these improvements were observed in both groups and maintained in follow-up. CONCLUSIONS: These results suggest that two weeks of treadmill gait training associated to home-based exercises can be effective to improve postural balance and functional mobility in subacute stroke patients. However, the load addition was not a differential factor in intervention. PMID- 28859604 TI - Diagnosis, Management, and Outcome of Aortitis at a Single Center. AB - BACKGROUND: Aortitis is a rare condition with inflammatory or infectious etiology that can be difficult to diagnose due to the highly variable clinical presentation and nonspecific symptoms. However, current literature on the diagnosis, management, and prognosis of aortitis is extremely scarce. METHODS: We retrospectively reviewed all patients' charts who were diagnosed with giant cell arteritis, Takayasu arteritis, or noninfectious aortitis presenting at a single center between January 1, 2009, and April 17, 2015. Data collected included demographics, medical history, comorbidities, laboratory and imaging data, management, and outcome. RESULTS: Among the included 15 patients presenting with aortitis at our center, 53% were diagnosed with Takayasu arteritis, 33% with idiopathic inflammatory aortitis, and 13% with giant cell arteritis. All patients received steroid treatment, 67% received adjunctive immunosuppressants or immunomodulators, and 33% underwent interventional procedures. Based on clinical presentation and laboratory and imaging findings at the last follow-up visit for each patient, 67% showed improvement, 27% had no change in disease activity, and 7% had a progression of the disease. CONCLUSIONS: Takayasu arteritis was found to be more common than idiopathic inflammatory aortitis and giant cell arteritis among our 15 cases diagnosed with aortitis. All patients received medical therapy and 33% received interventional procedures, leading to 67% improvement of disease activity or related complications. This article also offers a comprehensive review of the diagnosis, management, and outcome of aortitis, supplementing the very limited literature on this disease. PMID- 28859605 TI - The role of increased body mass index in outcomes of sepsis: a systematic review and meta-analysis. AB - BACKGROUND: The role of increased body mass index (BMI) in sepsis is controversial. We aimed to evaluate the associations between overweight (25 kg/m2 < BMI <= 29.9 kg/m2), obese (30 kg/m2 < BMI <= 39.9 kg/m2) and morbidly obese (BMI > 40 kg/m2) BMIs and outcomes in septic patients. METHODS: We searched the PubMed, Embase, Web of Science, Cochrane Library and ClinicalTrials.gov databases for studies published by December 1, 2016. Electronic database searches yielded 3713 articles, eight of which were included in this meta-analysis. Data were independently extracted by two reviewers, and a third reviewer participated in making decisions as needed. We used Review Manager to conduct the analysis, and the outcomes were reported with odds ratios (ORs) or mean differences (MDs). The primary outcome was mortality, and the secondary outcome was length of stay (LOS) in the intensive care unit (ICU) or the hospital. RESULTS: Data from eight studies involving a total of 9696 patients were pooled in our final analysis. Compared with patients with normal BMI (18.5 kg/m2 < BMI <= 24.9 kg/m2), patients with BMI >= 25 kg/m2 exhibited decreased mortality (OR 0.81; 95% confidence interval (CI), 0.74-0.89, P < 0.0001). In subgroup analysis, compared with normal weight patients, overweight patients had lower mortality (OR 0.87; 95% CI 0.77 0.97, P = 0.02), whereas obese (OR 0.89, 95% CI 0.72-1.10, P = 0.29) and morbidly obese (OR 0.64, 95% CI 0.38-1.08, P = 0.09) patients did not exhibit significantly reduced mortality. CONCLUSIONS: In sepsis cases, overweight, but not obesity or morbid obesity, was associated with lower mortality. Further prospective studies are needed to clarify this relationship. PMID- 28859606 TI - No increase in small-solute transport in peritoneal dialysis patients treated without hypertonic glucose for fifty-four months. AB - BACKGROUND: Glucose is widely used as an osmotic agent in peritoneal dialysis (PD), but exerts untoward effects on the peritoneum. The potential protective effect of a reduced exposure to hypertonic glucose has never been investigated. METHODS: The cohort of PD patients attending our center which tackled the challenge of a restricted use of hypertonic glucose solutions has been prospectively followed since 1992. Small-solute transport was assessed using an equivalent of the glucose peritoneal equilibration test after 6 months, and then every year. Study was stopped on July 1st, 2008, before use of biocompatible solutions. Repeated measures in patients treated with PD for 54 months were analyzed by using (1) the slopes of the linear regression for D4/D0 ratios over time computed for each individual, and (2) a linear mixed model. RESULTS: In the study period, 44 patients were treated for a total of 2376 months, 2058 without hypertonic glucose. There was one episode of peritoneal infection every 18 patient-months. The mean of slopes of the linear regression for D4/D0 ratios was found to be significantly positive (Student's test, p < .001) and the results of the mixed model reflected a similar significant increase for D4/D0 ratios over time. These results reflected a significant decrease of small-solute transport. CONCLUSION: In this large series, minimizing the use of hypertonic glucose solutions was associated in patients on long term PD with an overall decrease of small-solute transport within 54 months, despite a high rate of peritoneal infection. PMID- 28859607 TI - Suitability of saliva for Tuberculosis diagnosis: comparing with serum. AB - BACKGROUND: In the search for fast, simple and better ways for diagnosis of tuberculosis (TB), there is need to discover and evaluate new biomarkers that are found in samples other than sputum to determine their effectiveness. This study examined the utility of saliva vis-a-vis serum by evaluating levels of biomarkers found in saliva and serum from TB suspects. METHODS: Study enrolled tuberculosis suspects. Sputum MGIT was used as the gold standard for active TB. Quantiferon gold-In tube assay was done to identify exposure to Mycobacterium tuberculosis (M.tb). Multiplex assay was run for 10 markers using a 10 plex customized kit from Bio-Rad Laboratories. RESULTS: There was a significant difference between saliva and serum marker levels. Saliva had significantly higher levels of GM-CSF and VEGF. Serum had higher levels of MIP-1a, b, TNF-a, G-CSF and IFN-g. Serum levels of IL-6, VEGF and TNF-a were significantly different between participants with active TB disease and those with other respiratory diseases. CONCLUSION: Salivary TB biomarkers are worth the search to evaluate their ability to differentiate between TB disease states for generation of a non invasive point of care test for TB diagnosis. PMID- 28859608 TI - Refining the South Asian Origin of the Romani people. AB - BACKGROUND: Recent genetic studies based on genome-wide Single Nucleotide Polymorphism (SNP) data further investigated the history of Roma and suggested that the source of South Asian ancestry in Roma originates most likely from the Northwest region of India. METHODS: In this study, based also on genome-wide SNP data, we attempted to refine these findings using significantly larger number of European Roma samples, an extended dataset of Indian groups and involving Pakistani groups into the analyses. Our Roma data contained 179 Roma samples. Our extended Indian data consisted of 51 distinct Indian ethnic groups, which provided us a higher resolution of the population living on the Indian subcontinent. We used in this study principal component analysis and other ancestry estimating methods for the study of population relationships, several formal tests of admixture and an improved algorithm for investigating shared IBD segments in order to investigate the main sources of Roma ancestry. RESULTS: According to our analyses, Roma showed significant IBD sharing of 0.132 Mb with Northwest Indian ethnic groups. The most significant IBD sharings included ethnic groups of Punjab, Rajasthan and Gujarat states. However, we found also significant IBD sharing of 0.087 Mb with ethnic groups living in Pakistan, such as Balochi, Brahui, Burusho, Kalash, Makrani, Pashtun and Sindhi. CONCLUSION: Our results show that Northwest India could play an important role in the South Asian ancestry of Roma, however, the origin of Romani people might include the area of Pakistan as well. PMID- 28859609 TI - Development of quality indicators for non-small cell lung cancer care: a first step toward assessing and improving quality of cancer care in China. AB - BACKGROUND: Large gap exists between clinical practice and recommended care and large room exists for the improvement of care quality for non-small cell lung cancer (NSCLC) in China. Results of some studies have shown that assessment of care quality can help to make improvement and the development of quality indicators is deemed as the initial and most essential part. Yet there is no such an indicators system specifically suitable for Chinese health care system. The goal of the study is to set up a group of Chinese quality indicators for NSCLC care and make it the first step towards the improvement of NSCLC care quality in China. METHODS: We constructed a new indicator framework based on the characteristics of NSCLC care and the nature of Chinese health care system. Under the new framework, potential indicators were collected and a 3-round modified Delphi process was conducted by a national multi-disciplinary Expert Panel to develop a set of indicators until they reached the final consensus. RESULTS: A new indicator framework (structure, process, communication, management of symptoms or treatment toxicity and outcome) was developed. Seventy four indicators were extracted from guidelines and relevant literatures as potential indicators; 43 indicators plus 1 suggested indicator were remained after the discussion of Round 1; questionnaires of Round 2 were rated by Expert Panel and 19 indicators met the inclusion criteria and entered Round 3; 2 of the eliminated indicators in Round 2 were retrieved by the Expert Panel at the in-person meeting (Round 3). Therefore, 21 indicators got the final consensus of the Expert Panel. CONCLUSIONS: Guided by the new indicator structure, a set of indicators suitable for Chinese healthcare system was developed and can be utilized to measure and improve the care quality of non-small cell lung cancer. PMID- 28859610 TI - Jump step - a community based participatory approach to physical activity & mental wellness. AB - BACKGROUND: There is a physical inactivity pandemic around the world despite the known benefits of engaging in physical activity. This is true for individuals who would receive notable benefits from physical activity, in particular those with mood disorders. In this study, we explored the factors that facilitate and impede engagement in physical activity for individuals with a mood disorder. The intent was to understand the key features of a community based physical activity program for these individuals. METHODS: We recruited and interviewed 24 participants older than 18 with Major Depressive Disorder or Bipolar II. The interviews were conducted by peer researchers. The interviews were transcribed and analyzed using NVivo 10TM. Thematic analysis was used to analyze the data. RESULTS: The facilitators to physical activity include being socially connected with family and friends, building a routine in daily life, and exposure to nature. The barriers to physical activity include the inability to build a routine owing to a mood disorder, and high cost. The ideal exercise program comprises a variety of light-to-moderate activities, offers the opportunity to connect with other participants with a mood disorder, and brings participants to nature. The average age of our participants was 52 which could have influenced the preferred level of intensity. CONCLUSION: The individuals in this study felt that the key features of a physical activity program for individuals with a mood disorder must utilize a social network approach, take into account the preferences of potential participants, and incorporate nature (both green and blue spaces) as a health promotion resource. PMID- 28859611 TI - Transcript profiling of genes expressed during fibre development in diploid cotton (Gossypium arboreum L.). AB - BACKGROUND: Cotton fibre is a single cell and it is one of the best platforms for unraveling the genes express during various stages of fibre development. There are reports devoted to comparative transcriptome study on fiber cell initiation and elongation in tetraploid cultivated cotton. However, in the present investigation, comparative transcriptome study was made in diploid cultivated cotton using isogenic fuzzy-lintless (Fl) and normal fuzzy linted (FL) lines belong to Gossypium arboreum, diploid species at two stages, 0 and 10 dpa (days post anthesis), using Affymetrix cotton GeneChip genome array. RESULT: Scanning electron microscopy (SEM) analysis uncovered the occurrence of few fibre cell initials in the Fl line as compared to many in Normal FL at -2 and 0 dpa. However, at 10 dpa there were no fibre cells found elongated in Fl but many elongated cells were found in FL line. Up-regulation of transcription factors, AP2-EREBP, C2H2, C3H, HB and WRKY was observed at 0 dpa whereas in 10 dpa transcription factors, AP2-EREBP, AUX/IAA, bHLH, C2H2, C3H, HB, MYB, NAC, Orphans, PLATZ and WRKY were found down regulated in Fl line. These transcription factors were mainly involved in metabolic pathways such as phytohormone signaling, energy metabolism of cell, fatty acid metabolism, secondary metabolism and other signaling pathways and are related directly or indirectly in fiber development. Quantitative real-time PCR was performed to check fold up or down regulation of these genes and transcription factors (TFs) down regulated in mutants as compared to normal at 0 and 10 dpa. CONCLUSION: This study elucidates that the up-regulation of transcription factors like AP2-EREBP, C2H2, C3H, HB, WRKY and phytohormone signaling genes at 0 dpa and their down-regulation at the 10 dpa might have constrain the fibre elongation in fuzzy-lintless line. Along with this the down-regulation of genes involved in synthesis of VLCFA chain, transcripts necessary for energy and cell wall metabolism, EXPANSINs, arabinogalactan proteins (AGPs), tubulin might also be the probable reason for reduced growth of fibres in the Fl. Plant receptor-like kinases (RLKs), Leucine Rich Repeats) LRR- family protein and signal transduction coding for mitogen activated protein kinase (MAPK) cascade, have been engaged in coordination of cell elongation and SCW biosynthesis, down-regulation of these might loss the function leads to reduced fibre growth. PMID- 28859612 TI - Differential expression of estrogen receptor subtypes and variants in ovarian cancer: effects on cell invasion, proliferation and prognosis. AB - BACKGROUND: Due to the presence of both classical estrogen receptor (ERalpha) and another ER subtype (ERbeta) in ovarian cancer, hormonal treatment is an attractive option. However, response to tamoxifen in ovarian cancer is modest. The presence of ERbeta variants further complicated the issue. We have recently shown that specifically targeting ER subtypes using selective ER modulators showed opposing functions of ER subtypes on cell growth. In the present study, the clinical significance of ERalpha and ERbeta variants (beta1, beta2 and beta5) and the functional effects of ERbeta2 and ERbeta5 in ovarian cancer was investigated. METHODS: ERalpha, ERbeta1, ERbeta2 and ERbeta5 expression were evaluated by immunohistochemistry in 106 ovarian cancer tissues. The association between ERs expression and clinicopathological parameters or prognosis was analyzed. Ectopic expression of ERbeta2 and ERbeta5 followed by functional assays were performed in ovarian cancer cell lines in order to detect their effects on cell invasion and proliferation. RESULTS: We found significantly higher nuclear (n)ERalpha and nERbeta5 and lower cytoplasmic (c)ERalpha expression in advanced cancers. Significantly lower ERbeta1 expression was also detected in high grade cancers. Significant loss of nERalpha and cERbeta2 expression were observed in clear cell histological subtypes. Higher nERbeta5 and lower cERbeta5 expression were associated with serous/clear cell subtypes, poor disease-free and overall survival. Positive cERalpha and higher cERbeta1 expression were significantly associated with better disease-free and overall survival. Furthermore, we found nERbeta5 as an independent prognostic factor for overall survival. Functionally, overexpression of ERbeta5 enhanced ovarian cancer cell migration, invasion and proliferation via FAK/c-Src activation whereas ERbeta2 induced cell migration and invasion. CONCLUSIONS: Since tamoxifen binds to both ERalpha and ERbeta1 which appear to bear opposing oncogenic roles, the histotypes-specific expression pattern of ERs indicates that personalized treatment for women based on ERs expression using selective estrogen receptor modulators may improve response rate. This study also suggests nERbeta5 as a potential prognostic marker and therapeutic target in ovarian cancer. PMID- 28859613 TI - Clinical care given to victims of sexual assault at Kadoma General Hospital, Zimbabwe: a secondary data analysis, 2016. AB - BACKGROUND: Despite the guidelines for managing sexual assault being in place, victims of sexual assault attended to at Kadoma General Hospital consistently raised complaints related to the quality of care offered. Medicolegal data for sexual assault has been collected at the hospital since 2012. However, no analysis had been done regardless of complaints having been raised. We analysed the dataset to determine the quality of clinical care offered to sexual assault victims. METHODS: A retrospective cross-sectional study based on secondary data was conducted. Epi. Info 7 software was used to analyse data and generate frequencies, measures of central tendency and proportions. RESULTS: We analysed 474 medical affidavits completed between January 2014 and July 2016. Thirty percent of the victims sought care within 72 h of the sexual assault. Baseline HIV testing was done in 23 (22%) and follow-up HIV test done in 2 (2%) of the victims. Post Exposure Prophylaxis for HIV was administered to 18 (51%), emergency contraception 9 (69%) and forensic evidence gathered in six (5%) of victims presenting within the prescribed 72 h of the sexual assault. Prophylactic antibiotics were given to 156 (33%). There were no documented counselling sessions for all victims whilst follow up care was given to 47 (10%) victims. CONCLUSION: Suboptimal clinical care was given to victims of sexual assault during the period 2014-2016. These findings suggest possible delayed presentation by victims of sexual assault as well as suboptimal administration of prophylaxis by health care workers. We recommend adherence to guidelines in managing sexual assault. Further research to determine factors for delayed presentation among sexual assault victims and quality of care provided to them is recommended. PMID- 28859614 TI - Characterization of mechanisms underlying degradation of sclerotia of Sclerotinia sclerotiorum by Aspergillus aculeatus Asp-4 using a combined qRT-PCR and proteomic approach. AB - BACKGROUND: The biological control agent Aspergillus aculeatus Asp-4 colonizes and degrades sclerotia of Sclerotinia sclerotiorum resulting in reduced germination and disease caused by this important plant pathogen. Molecular mechanisms of mycoparasites underlying colonization, degradation, and reduction of germination of sclerotia of this and other important plant pathogens remain poorly understood. RESULTS: An RNA-Seq screen of Asp-4 growing on autoclaved, ground sclerotia of S. sclerotiorum for 48 h identified 997 up-regulated and 777 down-regulated genes relative to this mycoparasite growing on potato dextrose agar (PDA) for 48 h. qRT-PCR time course experiments characterized expression dynamics of select genes encoding enzymes functioning in degradation of sclerotial components and management of environmental conditions, including environmental stress. This analysis suggested co-temporal up-regulation of genes functioning in these two processes. Proteomic analysis of Asp-4 growing on this sclerotial material for 48 h identified 26 up-regulated and 6 down-regulated proteins relative to the PDA control. Certain proteins with increased abundance had putative functions in degradation of polymeric components of sclerotia and the mitigation of environmental stress. CONCLUSIONS: Our results suggest co temporal up-regulation of genes involved in degradation of sclerotial compounds and mitigation of environmental stress. This study furthers the analysis of mycoparasitism of sclerotial pathogens by providing the basis for molecular characterization of a previously uncharacterized mycoparasite-sclerotial interaction. PMID- 28859615 TI - Identification of predictive markers of the therapeutic effect of eribulin chemotherapy for locally advanced or metastatic breast cancer. AB - BACKGROUND: The recently developed reagent, eribulin mesylate (eribulin), is a microtubule dynamics inhibitor with a mechanism of action that differs from those of taxanes and vinca alkaloids. This drug is considered to be a promising chemotherapeutic agent for the treatment of locally advanced or metastatic breast cancer (MBC). In this study, we investigated if variables such as tumor expression of beta-tubulin class III, glutathione S-transferase pi (GSTP) 1 or transducin-like enhancer of split (TLE) 3 might act as predictive factors on the therapeutic effect of eribulin chemotherapy. METHODS: The subjects included 52 patients with MBC who underwent chemotherapy with eribulin. The expression levels of Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor (HER) 2, Ki67, beta-tubulin class III, GSTP-1 and TLE-3 were evaluated using immunostaining employing needle biopsy specimens. RESULTS: Patients with TLE3-negative tumors displayed significantly poorer outcomes regarding progression-free survival than patients with TLE3-positive tumors when prognosis within the group of patients with triple-negative breast cancer (TNBC) lesions was analyzed (p = 0.011, log-rank). In contrast, no such difference in prognosis was found in a comparison of TLE-3 positive/negative patients in the group of all patients (p = 0.433, log-rank) or of patients with non-TNBC lesions (p = 0.659, log-rank). Based on a univariate analysis of 22 TNBC cases, a better progression-free survival correlated significantly with a positive TLE3 expression in the tumor (p = 0.025). A multivariate logistic regression analysis including 22 patients with TNBC also showed that a positive TLE3 expression significantly correlated with a better progression-free survival (p = 0.037). CONCLUSIONS: Our findings suggest that TLE3 is a useful marker for predicting the therapeutic effect of eribulin chemotherapy for TNBC. PMID- 28859616 TI - Molecular characterization of hepatitis B virus in Vietnam. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major public health problem globally. HBV genotypes and subgenotypes influence disease transmission, progression, and treatment outcome. A study was conducted among treatment naive chronic HBV patients in southern Vietnam to determine the genotypes and subgenotypes of HBV. METHODS: A prospective, exploratory study was conducted among treatment naive chronic HBV patients attending at the Hospital for Tropical Diseases, in Ho Chi Minh City, Vietnam during 2012, 2014 and 2016. HBV DNA positive samples (systematically selected 2% of all treatment naive chronic patients during 2012 and 2014, and 8% of all treatment naive chronic patients during 2016) were subjected to whole genome sequencing (WGS) either by Sanger or Illumina sequencing. WGS was used to define genotype, sub-genotype, recombination, and the prevalence of drug resistance and virulence-associated mutations. RESULTS: One hundred thirty five treatment naive chronic HBV patients including 18 from 2012, 24 from 2014, and 93 from 2016 were enrolled. Of 135 sequenced viruses, 72.6% and 27.4% were genotypes B and C respectively. Among genotype B isolates, 87.8% and 12.2% were subgenotypes B4 and B2 respectively. A G1896A mutation in the precore gene was present in 30.6% of genotype B isolates. The genotype C isolates were all subgenotype C1 and 78.4% (29/37) of them had at least one basal core promoter (BCP) mutation. A1762T and G1764 T mutations and a double mutation (A1762T and G1764 T) in the BCP region were significantly more frequent in genotype C1 isolates (p < 0.001). CONCLUSION: HBV genotype B including subgenotype B4 is predominant in southern Vietnam. However, one fourth of the chronic HBV infections were caused by subgenotype C1. PMID- 28859617 TI - Factors associated with attrition in a longitudinal online study: results from the HaBIDS panel. AB - BACKGROUND: Knowing about predictors of attrition in a panel is important to initiate early measures against loss of participants. We investigated attrition in both early and late phase of an online panel with special focus on preferences regarding mode of participation. METHODS: We used data from the HaBIDS panel that was designed to investigate knowledge, attitudes, and practice regarding infections in the German general population. HaBIDS was divided into two phases: an initial phase when some participants could choose their preferred mode of participation (paper-and-pencil or online) and an extended phase when participants were asked to become members of an online panel that was not limited regarding its duration (i.e. participants initially preferring paper questionnaires switched to online participation). Using competing risks regression, we investigated two types of attrition (formal withdrawal and discontinuation without withdrawal) among online participants, separately for both phases. As potential predictors of attrition, we considered sociodemographic characteristics, physical and mental health as well as auxiliary information describing the survey process, and, in the extended phase, initial mode preference. RESULTS: In the initial phase, higher age and less frequent Internet usage predicted withdrawal, while younger age, higher stress levels, delay in returning the consent form, and need for receiving reminder emails predicted discontinuation. In the extended phase, only need for receiving reminder emails predicted discontinuation. Numbers of withdrawal in the extended phase were too small for analysis. Initial mode preference did not predict attrition in the extended phase. Besides age, there was no evidence of differential attrition by sociodemographic factors in any phase. CONCLUSIONS: Predictors of attrition were similar in both phases of the panel, but they differed by type of attrition (withdrawal vs. discontinuation). Sociodemographic characteristics only played a minor role for both types of attrition. Need for receiving a reminder was the strongest predictor of discontinuation in any phase, but no predictor of withdrawal. We found predictors of attrition, which can be identified already in the early phase of a panel so that countermeasures (e.g. special incentives) can be taken. PMID- 28859618 TI - Evaluation of noise hazard during the holmium laser enucleation of prostate. AB - BACKGROUND: To evaluate noise hazard during holmium laser enucleation of the prostate (HoLEP), we designed a study to detect such a risk in this procedure. METHODS: This study was conducted over a 12-month period on 223 patients with benign prostatic hyperplasia (BPH), 121 of whom underwent HoLEP while those remaining underwent transurethral resection of the prostate (TURP). A sound level meter was used to detect the exposure of surgeons to noise. The recordings used were in accordance with the standards set by the Occupational Safety and Health Administration (OSHA) and the United States E nvironmental Protection A gency . Moreover, each of the 43 surgeons participating in a BPH discussion conference answered the questionnaire on the influence of noise, and 33 surgeons in our department volunteered for blood pressure monitoring post-surgically. RESULTS: The sound level produced by a high-powered holmium laser emitter during HoLEP was 67.37 +/- 0.13 dB, which was significantly higher than the sound heard during TURP (46.41 +/- 0.29 dB, P < 0.01). The 65-70 dB noise during HoLEP was proved to be a safe level in accordance with the OSHA standards. However, this level was considerably greater than the stated 55 dB. Moreover, it exceeded the normal communication protective level of 60 dB. In the analysis of responses from the surgeons, the HoLEP group obtained an average score that reflected disturbance caused by the laser emitter and an increase in average systolic pressure relative to that in the TURP group. CONCLUSIONS: The noise level during HoLEP is within hearing conservation levels. However, the noise disturbs intrateam communication and concentration during surgery. Some surgeons may experience discomfort post surgically, but no significant difference among the groups is indicated. The findings suggest that measures should be taken to address the noise caused by the laser emitter during HoLEP. PMID- 28859619 TI - Analysis of DNA methylation in chondrocytes in rats with knee osteoarthritis. AB - BACKGROUND: Knee osteoarthritis (KOA) is a degenerative knee disease commonly found in the ageing population. DNA methylation works with histone acetylation to participate in aging. Alterations of DNA methylation may involve the joint chondrocyte degeneration in KOA. The aim of this study is to detect DNA methylation changes in chondrocytes of rats with KOA. METHODS: The rat KOA model was established with the Hulth method (n = 10), while rats receiving sham operation served as the control (n = 10). At 16 weeks after modeling, the knee joint tissue was collected from half of the rats in each group for Micro-CT scanning, Haematoxylin& Eosin (HE) staining, ABH/OG staining, immunohistochemistry for Bax, Bcl-2 and Fas, and TUNNEL staining. Meanwhile, the articular cartilage was collected from the other half to detect promoter methylation in target genes with the MethylTarget approach. RESULTS: Micro-CT scanning, HE staining, ABH/OG staining, immunohistochemistry, and TUNNEL staining all showed more severe cartilage injury in the KOA group than in the control group, indicating successful establishment of KOA model. The methylation rate in the KOA group was significantly decreased for C/ebpalpha-2 (within a CpG island 452 bp to the initiation codon on chromosome 1 91,363,511), Cdk2 (within a CpG island -55 bp to the initiation codon on chromosome 7 3,132,362), Bak1 (within a CpG island 6452 bp to the initiation codon on chromosome 20 5,622,277), and Fas (within a CpG island on the entire chromosome 1 gene), compared with the sham group (P = 0.005, 0.008, 0.022 and 0.027, respectively). CONCLUSION: The chondrocyte apoptosis and significantly reduced methylation levels of C/ebpalpha 2, Cdk2, Bak1, and Fas may participate in the pathogenesis of KOA. However, the exact mechanisms remain to be determined. PMID- 28859620 TI - Orthonome - a new pipeline for predicting high quality orthologue gene sets applicable to complete and draft genomes. AB - BACKGROUND: Distinguishing orthologous and paralogous relationships between genes across multiple species is essential for comparative genomic analyses. Various computational approaches have been developed to resolve these evolutionary relationships, but strong trade-offs between precision and recall of orthologue prediction remains an ongoing challenge. RESULTS: Here we present Orthonome, an orthologue prediction pipeline, designed to reduce the trade-off between orthologue capture rates (recall) and accuracy of multi-species orthologue prediction. The pipeline compares sequence domains and then forms sequence similar clusters before using phylogenetic comparisons to identify inparalogues. It then corrects sequence similarity metrics for fragment and gene length bias using a novel scoring metric capturing relationships between full length as well as fragmented genes. The remaining genes are then brought together for the identification of orthologues within a phylogenetic framework. The orthologue predictions are further calibrated along with inparalogues and gene births, using synteny, to identify novel orthologous relationships. We use 12 high quality Drosophila genomes to show that, compared to other orthologue prediction pipelines, Orthonome provides orthogroups with minimal error but high recall. Furthermore, Orthonome is resilient to suboptimal assembly/annotation quality, with the inclusion of draft genomes from eight additional Drosophila species still providing >6500 1:1 orthologues across all twenty species while retaining a better combination of accuracy and recall than other pipelines. Orthonome is implemented as a searchable database and query tool along with multiple-sequence alignment browsers for all sets of orthologues. The underlying documentation and database are accessible at http://www.orthonome.com . CONCLUSION: We demonstrate that Orthonome provides a superior combination of orthologue capture rates and accuracy on complete and draft drosophilid genomes when tested alongside previously published pipelines. The study also highlights a greater degree of evolutionary conservation across drosophilid species than earlier thought. PMID- 28859621 TI - NAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity. AB - BACKGROUND: N-acetyltransferase 10 (NAT10) is a histone acetyltransferase which is involved in a wide range of cellular processes. Recent evidences indicate that NAT10 is involved in the development of human cancers. Previous study showed that NAT10 acetylates the tumor suppressor p53 and regulates p53 activation. As Tp53 gene is frequently mutated in hepatocellular carcinoma (HCC) and associates with the occurrence and development of HCC, the relationship between NAT10 and HCC was investigated in this study. METHODS: Immunohistochemistry (IHC) and western blot analysis were performed to evaluate the NAT10 expression in HCC. Immunoprecipitation experiments were performed to verify the interaction of NAT10 with mutant p53 and Mdm2. RNA interference and Western blot were applied to determine the effect of NAT10 on mutant p53. Cell growth curve was used to examine the effect of NAT10 on HCC cell proliferation. RESULTS: NAT10 was upregulated in HCC and increased NAT10 expression was correlated with poor overall survival of the patients. NAT10 protein levels were significantly correlated with p53 levels in human HCC tissues. Furthermore, NAT10 increased mutant p53 levels by counteracting Mdm2 action in HCC cells and promoted proliferation in cells carrying p53 mutation. CONCLUSION: Increased NAT10 expression levels are associated with shortened patient survival and correlated with mutant p53 levels. NAT10 upregulates mutant p53 level and might enhance its tumorigenic activity. Hence, we propose that NAT10 is a potential prognostic and therapeutic candidate for p53-mutated HCC. PMID- 28859622 TI - Neonatal alloimmune thrombocytopenia caused by anti-HPA antibodies in pregnant Chinese women: a study protocol for a multicentre, prospective cohort trial. AB - BACKGROUND: Neonatal alloimmune thrombocytopenia (NAIT), caused by maternal antibodies raised against alloantigens carried on foetal platelets, is a very common haematological abnormality in newborns worldwide. However, baseline data on NAIT in China are lacking. Therefore, this study seeks to explore the incidence of alloantibody against the human platelet antigen (HPA) in pregnant women and its associations with NAIT in China. METHODS: A multicentre, prospective cohort study design will be used, and 55,497 pregnant women will be recruited for the first screening of the anti-HPA antibody at 12 to 28 weeks of gestational age. Subjects who are positive in the first screening for the anti HPA antibody will be included in the exposure group. Re-tests of the antibody titre, antigen-specificity and genotyping of HPA and HLA will be conducted during admission. A ratio of 1:1 paired individuals with the same ethnicity and parity but testing negative for the anti-HPA antibody will be randomly selected to be included in the non-exposure group. NAIT will be diagnosed in the newborns on day one of the birth. The HPA of the neonates in the exposure group will also be genotyped by sequencing. Associations of maternal HLA with the occurrence of the anti-HPA antibody and correlation of the severity of NAIT with the titre of the anti-HPA antibody will be further analysed. DISCUSSION: The study is expected to provide baseline data on NAIT in China. Besides, we hope to find out a population who expresses particular HLA molecules has significant higher risk of HPA alloimmunization in Chinese individuals. We also hope to find a Chinese-specific cut-off antibody titre for the prediction of the severity of NAIT and to provide a means to evaluate the necessity of antenatal treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02934906 (date registered: 13.10.2016). PMID- 28859623 TI - Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs. AB - BACKGROUND: microRNAs (miRNAs) are essential to the regulation of gene expression in eukaryotes, and improper expression of miRNAs contributes to hundreds of diseases. Despite the essential functions of miRNAs, the evolutionary dynamics of how they are integrated into existing gene regulatory and functional networks is not well understood. Knowledge of the origin and evolutionary history a gene has proven informative about its functions and disease associations; we hypothesize that incorporating the evolutionary origins of miRNAs into analyses will help resolve differences in their functional dynamics and how they influence disease. RESULTS: We computed the phylogenetic age of miRNAs across 146 species and quantified the relationship between human miRNA age and several functional attributes. Older miRNAs are significantly more likely to be associated with disease than younger miRNAs, and the number of associated diseases increases with age. As has been observed for genes, the miRNAs associated with different diseases have different age profiles. For example, human miRNAs implicated in cancer are enriched for origins near the dawn of animal multicellularity. Consistent with the increasing contribution of miRNAs to disease with age, older miRNAs target more genes than younger miRNAs, and older miRNAs are expressed in significantly more tissues. Furthermore, miRNAs of all ages exhibit a strong preference to target older genes; 93% of validated miRNA gene targets were in existence at the origin of the targeting miRNA. Finally, we find that human miRNAs in evolutionarily related families are more similar in their targets and expression profiles than unrelated miRNAs. CONCLUSIONS: Considering the evolutionary origin and history of a miRNA provides useful context for the analysis of its function. Consistent with recent work in Drosophila, our results support a model in which miRNAs increase their expression and functional regulatory interactions over evolutionary time, and thus older miRNAs have increased potential to cause disease. We anticipate that these patterns hold across mammalian species; however, comprehensively evaluating them will require refining miRNA annotations across species and collecting functional data in non human systems. PMID- 28859624 TI - Living kidney transplantation between brothers with unrecognized renal amyloidosis as the first manifestation of familial Mediterranean fever: a case report. AB - BACKGROUND: Familial Mediterranean fever is an autosomal recessive disease characterized by recurrent episodes of fever and polyserositis and by the onset of reactive amyloid-associated amyloidosis. Amyloidosis due to familial Mediterranean fever can lead to end-stage renal disease, culminating in kidney transplantation for some patients. In this study, we report the clinical outcome of two brothers with familial Mediterranean fever who were the inadvertent donor and recipient, respectively, of a kidney. Subsequently, they were diagnosed with renal amyloidosis secondary to familial Mediterranean fever and were successfully treated with anakinra and colchicine. CASE PRESENTATION: Two brothers with familial Mediterranean fever and renal amyloidosis were the inadvertent donor and recipient, respectively, of a kidney. The recipient had presented recurrent acute febrile episodes of familial Mediterranean fever, developed nephrotic syndrome secondary to amyloidosis and needed bilateral nephrectomy and chronic dialysis. His elder brother, in apparent good health, donated his left kidney to his brother. Immediately after the kidney transplantation, both the donor and recipient presented massive proteinuria, impaired renal function and elevated serum amyloid A levels. Biopsies of the brothers' kidneys showed amyloidosis. Genetic studies thereafter revealed a homozygous variant for the MEFV gene (NM_000243.2.c.2082G > A; p.M694I) in both brothers. At this point, both the donor and recipient were treated with colchicine and anakinra, resulting in improved renal function, decreased proteinuria, undetectable serum amyloid A levels and stable renal function at 62 months of follow-up and no major adverse effects. CONCLUSIONS: In familial Mediterranean fever, analyses of the MEFV gene should be performed in potential live kidney donors from a direct family member (either between siblings or between parents and children). In addition, genetic studies are required when consanguinity is suspected between members involved in the living transplant. Finally, anakinra could be a safe adjuvant therapy combined with colchicine for patients with familial Mediterranean fever and amyloidosis, including those with successful kidney transplantation. PMID- 28859625 TI - Plasticity first: molecular signatures of a complex morphological trait in filamentous cyanobacteria. AB - BACKGROUND: Filamentous cyanobacteria that differentiate multiple cell types are considered the peak of prokaryotic complexity and their evolution has been studied in the context of multicellularity origins. Species that form true branching filaments exemplify the most complex cyanobacteria. However, the mechanisms underlying the true-branching morphology remain poorly understood despite of several investigations that focused on the identification of novel genes or pathways. An alternative route for the evolution of novel traits is based on existing phenotypic plasticity. According to that scenario - termed genetic assimilation - the fixation of a novel phenotype precedes the fixation of the genotype. RESULTS: Here we show that the evolution of transcriptional regulatory elements constitutes a major mechanism for the evolution of new traits. We found that supplementation with sucrose reconstitutes the ancestral branchless phenotype of two true-branching Fischerella species and compared the transcription start sites (TSSs) between the two phenotypic states. Our analysis uncovers several orthologous TSSs whose transcription level is correlated with the true-branching phenotype. These TSSs are found in genes that encode components of the septosome and elongasome (e.g., fraC and mreB). CONCLUSIONS: The concept of genetic assimilation supplies a tenable explanation for the evolution of novel traits but testing its feasibility is hindered by the inability to recreate and study the evolution of present-day traits. We present a novel approach to examine transcription data for the plasticity first route and provide evidence for its occurrence during the evolution of complex colony morphology in true-branching cyanobacteria. Our results reveal a route for evolution of the true-branching phenotype in cyanobacteria via modification of the transcription level of pre-existing genes. Our study supplies evidence for the 'plasticity-first' hypothesis and highlights the importance of transcriptional regulation in the evolution of novel traits. PMID- 28859626 TI - Isolation of ripening-related genes from ethylene/1-MCP treated papaya through RNA-seq. AB - BACKGROUND: Since papaya is a typical climacteric fruit, exogenous ethylene (ETH) applications can induce premature and quicker ripening, while 1 methylcyclopropene (1-MCP) slows down the ripening processes. Differential gene expression in ETH or 1-MCP-treated papaya fruits accounts for the ripening processes. To isolate the key ripening-related genes and better understand fruit ripening mechanisms, transcriptomes of ETH or 1-MCP-treated, and non-treated (Control Group, CG) papaya fruits were sequenced using Illumina Hiseq2500. RESULTS: A total of 18,648 (1-MCP), 19,093 (CG), and 15,321 (ETH) genes were detected, with the genes detected in the ETH-treatment being the least. This suggests that ETH may inhibit the expression of some genes. Based on the differential gene expression (DGE) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, 53 fruit ripening-related genes were selected: 20 cell wall-related genes, 18 chlorophyll and carotenoid metabolism-related genes, four proteinases and their inhibitors, six plant hormone signal transduction pathway genes, four transcription factors, and one senescence associated gene. Reverse transcription quantitative PCR (RT-qPCR) analyses confirmed the results of RNA-seq and verified that the expression pattern of six genes is consistent with the fruit senescence process. Based on the expression profiling of genes in carbohydrate metabolic process, chlorophyll metabolism pathway, and carotenoid metabolism pathway, the mechanism of pulp softening and coloration of papaya was deduced and discussed. We illustrate that papaya fruit softening is a complex process with significant cell wall hydrolases, such as pectinases, cellulases, and hemicellulases involved in the process. Exogenous ethylene accelerates the coloration of papaya changing from green to yellow. This is likely due to the inhibition of chlorophyll biosynthesis and the alpha-branch of carotenoid metabolism. Chy-b may play an important role in the yellow color of papaya fruit. CONCLUSIONS: Comparing the differential gene expression in ETH/1 MCP-treated papaya using RNA-seq is a sound approach to isolate ripening-related genes. The results of this study can improve our understanding of papaya fruit ripening molecular mechanism and reveal candidate fruit ripening-related genes for further research. PMID- 28859627 TI - Genetics of depressive symptoms in adolescence. AB - BACKGROUND: Despite many attempts to understand the genetic architecture of depression, little progress has been made. The majority of these studies, however, have been carried out in adults and do not account for the potential influence of development. METHODS: The Avon Longitudinal Study of Parents and Children (ALSPAC) is a longitudinal pregnancy cohort which recruited participants between April 1991 and December 1992. Analyses were replicated in two independent European cohorts. Genome-wide complex trait analysis (GCTA) software was used to investigate SNP-heritability (h2SNP) of depression across adolescence, the role of puberty was investigated by stratifying these estimates according to pubertal onset. Genome-wide association studies were performed to identify genetic variants associated with depression at different stages of development. RESULTS: Heritability was estimated between the ages of 11 and 18 with sample sizes ranging from 3289 to 5480. Heritability was low with an apparent peak was found at age 13 (h2 = 0.17, p = 0.006). Confidence intervals around these estimates suggest an upper-bound to h2SNP of around 30%. A variant located on chromosome 7 was found to be associated with depressive symptoms at age 13 in ALSPAC (rs138191010: beta = 0.142, p = 2.51 * 10-8), although this was not replicated. CONCLUSIONS: Although power is a potential limitation, the observed patterns provide interesting hypotheses surrounding the heritability of depression at different developmental stages. We found substantially lower estimates for depressive symptoms at age 11 (0.07) compared to those previously estimated in adults (0.21). We also found a peak in heritability at age 13. These findings suggest environmental factors are likely to be more important in the aetiology of depressive symptoms in early adolescence than in adulthood. PMID- 28859628 TI - Assessment of thoracic ultrasound in complementary diagnosis and in follow up of community-acquired pneumonia (cap). AB - BACKGROUND: Chest X-ray (CXR) is the primary diagnostic tool for community acquired pneumonia (CAP). Some authors recently proposed that thoracic ultrasound (TUS) could valuably flank or even reliably substitute CXR in the diagnosis and follow-up of CAP. We investigated the clinical utility of TUS in a large sample of patients with CAP, to challenge the hypothesis that it may be a substitute for CXR. METHODS: Out of 645 consecutive patients with a CXR-confirmed CAP diagnosed in the emergency room of our hospital over a three-years period, 510 were subsequently admitted to our department of Internal Medicine. These patients were evaluated by TUS by a well-trained operator who was blinded of the initial diagnosis. TUS scans were performed both at admission and repeated at day 4-6th and 9-14th during stay. RESULTS: TUS identified 375/510 (73.5%) of CXR-confirmed lesions, mostly located in posterior-basal or mid-thoracic areas of the lungs. Pleural effusion was detected in 26.9% of patients by CXR and in 30.4% by TUS. TUS documented the change in size of the consolidated areas as follows: 6.3 +/- 3.4 cm at time 0, 2.5 +/- 1.8 at 4-6 d, 0.9 +/- 1.4 at 9-14 d. Out of the 12 patients with delayed CAP healing, 7 of them turned out to have lung cancer. CONCLUSIONS: TUS allowed to detect lung consolidations in over 70% of patients with CXR-confirmed CAP, but it gave false negative results in 26.5% of cases. Our longitudinal results confirm the role of TUS in the follow-up of detectable lesions. Thus, TUS should be regarded as a complementary and monitoring tool in pneumonia, instead of a primary imaging modality. PMID- 28859629 TI - Developing a decision tool to identify patients with personality disorders in need of highly specialized care. AB - BACKGROUND: Current guidelines recommend referral to highly specialized care for patients with severe personality disorders. However, criteria for allocation to highly specialized care are not clearly defined. The aim of the present study was to develop a decision tool that can support clinicians to identify patients with a personality disorder in need of highly specialized care. METHODS: Steps taken to develop a decision tool were a literature search, concept mapping, a meeting with experts and a validation study. RESULTS: The concept mapping method resulted in six criteria for the decision tool. The model used in concept mapping provided a good fit (stress value = 0.30) and reasonable reliability (rho = 0.49). The bridging values were low, indicating homogeneity. The decision tool was subsequently validated by enrolling 368 patients from seven centers. A multilevel model with a Receiver Operating Characteristic Curve (ROC) was applied. In this way, an easily implementable decision tool with relatively high sensitivity (0.74) and specificity (0.69) was developed. CONCLUSIONS: A decision tool to identify patients with personality disorders for highly specialized care was developed using advanced methods to combine the input of experts with currently available scientific knowledge. The tool appeared to be able to accurately identify this group of patients. Clinicians can use this decision tool to identify patients who are in need of highly specialized treatment. PMID- 28859630 TI - Disability and ageing in China and India - decomposing the effects of gender and residence. Results from the WHO study on global AGEing and adult health (SAGE). AB - BACKGROUND: China and India are the world's two most populous countries. Although their populations are growing in number and life expectancies are extending they have different trajectories of economic growth, epidemiological transition and social change. Cross-country comparisons can allow national and global insights and provide evidence for policy and decision-making. The aim of this study is to measure and compare disability in men and women, and in urban and rural dwellers in China and India, and assess the extent to which social and other factors contribute to the inequalities. METHODS: National samples of adults aged 50 to 79 years in China (n = 11,694) and India (n = 6187) from the World Health Organization (WHO) longitudinal Study on global AGEing and adult health (SAGE) Wave 1 were analysed. Stratified multiple linear regressions were undertaken to assess disability differences by sex and residence, controlling for other biological and socioeconomic determinants of disability. Oaxaca-Blinder decomposition partitioned the two-group inequalities into explained and unexplained components. RESULTS: In both countries women and rural residents reported more disability. In India, the gender inequality is attributed to the distribution of the determinants (employment, education and chronic conditions) but in China about half the inequality is attributed to the same. In India, more than half of the urban rural inequality is attributed to the distribution of the determinants (education, household wealth) compared with under 20% in China. CONCLUSIONS: Education and employment were important drivers of these measured inequalities. Overall inequalities in disability among older adults in China and India were shaped by gender and residence, suggesting the need for policies that target women and rural residents. There is a need for further research, using both qualitative and quantitative methods, to question and challenge entrenched practices and institutions and grasp the implications of global economic and social changes that are impacting on population health and ageing in China and India. PMID- 28859631 TI - QNB: differential RNA methylation analysis for count-based small-sample sequencing data with a quad-negative binomial model. AB - BACKGROUND: As a newly emerged research area, RNA epigenetics has drawn increasing attention recently for the participation of RNA methylation and other modifications in a number of crucial biological processes. Thanks to high throughput sequencing techniques, such as, MeRIP-Seq, transcriptome-wide RNA methylation profile is now available in the form of count-based data, with which it is often of interests to study the dynamics at epitranscriptomic layer. However, the sample size of RNA methylation experiment is usually very small due to its costs; and additionally, there usually exist a large number of genes whose methylation level cannot be accurately estimated due to their low expression level, making differential RNA methylation analysis a difficult task. RESULTS: We present QNB, a statistical approach for differential RNA methylation analysis with count-based small-sample sequencing data. Compared with previous approaches such as DRME model based on a statistical test covering the IP samples only with 2 negative binomial distributions, QNB is based on 4 independent negative binomial distributions with their variances and means linked by local regressions, and in the way, the input control samples are also properly taken care of. In addition, different from DRME approach, which relies only the input control sample only for estimating the background, QNB uses a more robust estimator for gene expression by combining information from both input and IP samples, which could largely improve the testing performance for very lowly expressed genes. CONCLUSION: QNB showed improved performance on both simulated and real MeRIP-Seq datasets when compared with competing algorithms. And the QNB model is also applicable to other datasets related RNA modifications, including but not limited to RNA bisulfite sequencing, m1A-Seq, Par-CLIP, RIP-Seq, etc. PMID- 28859632 TI - Case report of anti-N-methyl-D-aspartate receptor encephalitis in a middle-aged woman with a long history of major depressive disorder. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease involving antibodies against the NR1 subunits of NMDARs. The disease shows variable clinical presentation, and involves new-onset acute psychotic symptoms, making it difficult to differentiate from major depressive disorder with psychotic symptoms. Potential associations between this autoimmune disorder and onset or progression of major depressive disorder remains unclear. CASE PRESENTATION: We present a rare case of a patient who had both major depressive disorder and anti-NMDAR encephalitis and in whom the encephalitis initially went undetected. The patient had been suffering from depressive disorder for more than 6 years without any treatment, when she was hospitalized for new-onset psychotic symptoms. She was initially diagnosed only with major depressive disorder with psychotic symptoms, but antipsychotics did not alleviate symptoms and the patient's psychiatric course began to fluctuate rapidly. Anti NR1 IgG autoantibodies were detected in cerebrospinal fluid, and the combination of immunotherapy and antipsychotics proved more effective than antipsychotics alone. The patient was then also diagnosed with anti-NMDAR encephalitis. CONCLUSIONS: Our case suggests that clinicians should consider anti-NMDAR encephalitis when a patient with depressive disorder shows sudden fluctuations in psychiatric symptoms. It also highlights the need for research into possible relationships between anti-NMDAR encephalitis and major depressive disorder. PMID- 28859633 TI - Identification of a methyltransferase catalyzing the final step of methyl anthranilate synthesis in cultivated strawberry. AB - BACKGROUND: Methyl anthranilate (MA) contributes an attractive fruity note to the complex flavor and aroma of strawberry (Fragaria spp.), yet it is rare in modern cultivars. The genetic basis for its biosynthesis has not been elucidated. Understanding the specific genes required for its synthesis could allow the development of gene/allele-specific molecular markers to speed breeding of flavorful strawberries. RESULTS: Ripe fruits from individuals in an F1 population resulting from a cross between a MA producer and a non-producer were examined using a bulk-segregant transcriptome approach. MA producer and non-producer transcriptomes were compared, revealing five candidate transcripts that strictly co-segregated with MA production. One candidate encodes an annotated methyltransferase. MA levels are lower when this transcript is suppressed with RNAi, and bacterial cultures expressing the protein produced MA in the presence of anthranilic acid. Frozen fruit powders reconstituted with anthranilic acid and a methyl donor produced MA only if the transcript was detected in the fruit powder. A DNA-based molecular marker was developed that segregates with the MA producing gene variant. CONCLUSIONS: These analyses indicate that the methyltransferase, now noted ANTHRANILIC ACID METHYL TRANSFERASE (FanAAMT), mediates the ultimate step of MA production in cultivated strawberry. Identification of this gene and its associated molecular marker may hasten breeding efforts to introduce this important volatile into modern cultivars. PMID- 28859634 TI - Erratum to: Validation of verbal autopsy: determination of cause of deaths in Malaysia 2013. PMID- 28859635 TI - Hair cortisol concentrations correlate negatively with survival in a wild primate population. AB - BACKGROUND: Glucocorticoid hormones are known to play a key role in mediating a cascade of physiological responses to social and ecological stressors and can therefore influence animals' behaviour and ultimately fitness. Yet, how glucocorticoid levels are associated with reproductive success or survival in a natural setting has received little empirical attention so far. Here, we examined links between survival and levels of glucocorticoid in a small, short-lived primate, the grey mouse lemur (Microcebus murinus), using for the first time an indicator of long-term stress load (hair cortisol concentration). Using a capture mark-recapture modelling approach, we assessed the effect of stress on survival in a broad context (semi-annual rates), but also under a specific period of high energetic demands during the reproductive season. We further assessed the power of other commonly used health indicators (body condition and parasitism) in predicting survival outcomes relative to the effect of long-term stress. RESULTS: We found that high levels of hair cortisol were associated with reduced survival probabilities both at the semi-annual scale and over the reproductive season. Additionally, very good body condition (measured as scaled mass index) was related to increased survival at the semi-annual scale, but not during the breeding season. In contrast, variation in parasitism failed to predict survival. CONCLUSION: Altogether, our results indicate that long-term increased glucocorticoid levels can be related to survival and hence population dynamics, and suggest differential strength of selection acting on glucocorticoids, body condition, and parasite infection. PMID- 28859636 TI - Development of duplex PCR for differential detection of goatpox and sheeppox viruses. AB - BACKGROUND: Clinically, sheeppox and goatpox have the same symptoms and cannot be distinguished serologically. A cheaper and easy method for differential diagnosis is important in control of this disease in endemic region. METHODS: A duplex PCR assay was developed for the specific differential detection of Goatpox virus (GTPV) and Sheeppox virus (SPPV), using two sets of primers based on viral E10R gene and RPO132 gene. RESULTS: Nucleic acid electrophoresis results showed that SPPV-positive samples appear two bands, and GTPV-positive samples only one stripe. There were no cross-reactions with nucleic acids extracted from other pathogens including foot-and-mouth disease virus, Orf virus. The duplex PCR assay developed can specially detect SPPV or GTPV present in samples (n = 135) collected from suspected cases of Capripox. CONCLUSIONS: The duplex PCR assay developed is a specific and sensitive method for the differential diagnosis of GTPV and SPPV infection, with the potential to be standardized as a detection method for Capripox in endemic areas. PMID- 28859637 TI - Q&A: Where did the Neanderthals go? AB - Genomic evidence has demonstrated that humans and Neanderthals interbred. Today, the genomes of most individuals outside Africa contain 2-3% Neanderthal DNA. However, it is still hotly debated why the Neanderthals went extinct and if humans contributed to the Neanderthal extinction. In this Q&A we explore what genomic data might have to say about this issue. PMID- 28859638 TI - Should DNA sequence be incorporated with other taxonomical data for routine identifying of plant species? AB - BACKGROUND: A variety of plants in Acanthaceae have long been used in traditional Thai ailment and commercialised with significant economic value. Nowadays medicinal plants are sold in processed forms and thus morphological authentication is almost impossible. Full identification requires comparison of the specimen with some authoritative sources, such as a full and accurate description and verification of the species deposited in herbarium. Intake of wrong herbals can cause adverse effects. Identification of both raw materials and end products is therefore needed. METHODS: Here, the potential of a DNA-based identification method, called Bar-HRM (DNA barcoding coupled with High Resolution Melting analysis), in raw material species identification is investigated. DNA barcode sequences from five regions (matK, rbcL, trnH-psbA spacer region, trnL and ITS2) of Acanthaceae species were retrieved for in silico analysis. Then the specific primer pairs were used in HRM assay to generate unique melting profiles for each plants species. RESULTS: The method allows identification of samples lacking necessary morphological parts. In silico analyses of all five selected regions suggested that ITS2 is the most suitable marker for Bar-HRM in this study. The HRM analysis on dried samples of 16 Acanthaceae medicinal species was then performed using primer pair derived from ITS2 region. 100% discrimination of the tested samples at both genus and species level was observed. However, two samples documented as Clinacanthus nutans and Clinacanthus siamensis were recognised as the same species from the HRM analysis. Further investigation reveals that C. siamensis is now accepted as C. nutans. CONCLUSIONS: The results here proved that Bar-HRM is a promising technique in species identification of the studied medicinal plants in Acanthaceae. In addition, molecular biological data is currently used in plant taxonomy and increasingly popular in recent years. Here, DNA barcode sequence data should be incorporated with morphological characters in the species identification. PMID- 28859639 TI - Longitudinal study of Senecavirus a shedding in sows and piglets on a single United States farm during an outbreak of vesicular disease. AB - BACKGROUND: The study highlights the shedding pattern of Senecavirus A (SVA) during an outbreak of vesicular disease in a sow farm from the South-central Minnesota, USA. In this study, 34 individual, mixed parity sows with clinical signs of vesicular lesions and 30 individual piglets from 15 individual litters from sows with vesicular lesions were conveniently selected for individual, longitudinal sampling. Serum, tonsil, rectal, and vesicular swabs were collected on day1 post outbreak, and then again at 1, 2, 3, 4, 6, and 9 weeks post outbreak. Samples were tested at the University of Minnesota Veterinary Diagnostic Laboratory for SVA via Real Time Polymerase Chain Reaction (RT-PCR) RESULTS: In sows, vesicular lesions had the highest concentration of SVA, but had the shortest duration of detection lasting only 2 weeks. Viremia was detected for 1 week post outbreak, and quickly declined thereafter. SVA was detected at approximately the same frequency for both tonsil and rectal swabs with the highest percentage of SVA positive samples detected in the first 6 weeks post outbreak. In suckling piglets, viremia quickly declined 1 week post outbreak and was prevalent in low levels during the first week after weaning (4 weeks post outbreak) and was also detected in piglets that were co-mingled from a SVA negative sow farm. Similar to sows, SVA detection on rectal and tonsil swabs in piglets lasted approximately 6 weeks post outbreak. CONCLUSION: The study illustrates the variation of SVA shedding patterns in different sample types over a 9 week period in sows and piglets, and suggests the potential for viral spread between piglets at weaning. PMID- 28859640 TI - Evaluation of infectious diseases and clinical microbiology specialists' preferences for hand hygiene: analysis using the multi-attribute utility theory and the analytic hierarchy process methods. AB - BACKGROUND: Hand hygiene is one of the most effective attempts to control nosocomial infections, and it is an important measure to avoid the transmission of pathogens. However, the compliance of healthcare workers (HCWs) with hand washing is still poor worldwide. Herein, we aimed to determine the best hand hygiene preference of the infectious diseases and clinical microbiology (IDCM) specialists to prevent transmission of microorganisms from one patient to another. METHODS: Expert opinions regarding the criteria that influence the best hand hygiene preference were collected through a questionnaire via face-to-face interviews. Afterwards, these opinions were examined with two widely used multi criteria decision analysis (MCDA) methods, the Multi-Attribute Utility Theory (MAUT) and the Analytic Hierarchy Process (AHP). RESULTS: A total of 15 IDCM specialist opinions were collected from diverse private and public hospitals located in Izmir, Turkey. The mean age of the participants was 49.73 +/- 8.46, and the mean experience year of the participants in their fields was 17.67 +/- 11.98. The findings that we obtained through two distinct decision making methods, the MAUT and the AHP, suggest that alcohol-based antiseptic solution (ABAS) has the highest utility (0.86) and priority (0.69) among the experts' choices. CONCLUSION: In conclusion, the MAUT and the AHP, decision models developed here indicate that rubbing the hands with ABAS is the most favorable choice for IDCM specialists to prevent nosocomial infection. PMID- 28859641 TI - A streamlined method for analysing genome-wide DNA methylation patterns from low amounts of FFPE DNA. AB - BACKGROUND: Formalin fixed paraffin embedded (FFPE) tumor samples are a major source of DNA from patients in cancer research. However, FFPE is a challenging material to work with due to macromolecular fragmentation and nucleic acid crosslinking. FFPE tissue particularly possesses challenges for methylation analysis and for preparing sequencing-based libraries relying on bisulfite conversion. Successful bisulfite conversion is a key requirement for sequencing based methylation analysis. METHODS: Here we describe a complete and streamlined workflow for preparing next generation sequencing libraries for methylation analysis from FFPE tissues. This includes, counting cells from FFPE blocks and extracting DNA from FFPE slides, testing bisulfite conversion efficiency with a polymerase chain reaction (PCR) based test, preparing reduced representation bisulfite sequencing libraries and massively parallel sequencing. RESULTS: The main features and advantages of this protocol are: An optimized method for extracting good quality DNA from FFPE tissues. An efficient bisulfite conversion and next generation sequencing library preparation protocol that uses 50 ng DNA from FFPE tissue. Incorporation of a PCR-based test to assess bisulfite conversion efficiency prior to sequencing. CONCLUSIONS: We provide a complete workflow and an integrated protocol for performing DNA methylation analysis at the genome-scale and we believe this will facilitate clinical epigenetic research that involves the use of FFPE tissue. PMID- 28859642 TI - Dental caries status and its associated factors among 5-year-old Hong Kong children: a cross-sectional study. AB - BACKGROUND: This study investigated dental caries status and its associated factors among 5-year-old children in Hong Kong. METHOD: This cross-sectional survey was conducted in 2016. It comprised a questionnaire survey and a clinical examination. Kindergarten children aged 5 were recruited using a multistage sampling method. Parents of the participating children were asked about their children's demographic information, sugary snacking behaviours, and oral health related behaviours and about their own oral health knowledge. One trained dentist performed oral examinations on the children. Caries experience was measured using the dmft index. The relationships between the dmft scores and background information, sugary snacking behaviours, oral health-related behaviours and parental dental knowledge were studied using a zero-inflated negative binomial (ZINB) regression analysis. RESULTS: A total of 570 children were invited to participate, and 501 completed the oral examination (response rate: 88%). The prevalence of dental caries was 55%, and the mean dmft score was 2.7 +/- 3.7. Decayed teeth (dt) constituted 93% of caries experience. ZINB analysis found that children who visited a dentist, who were taken care of primarily by grandparents and whose parental dental knowledge levels were moderate had higher dmft scores. Children who ate sugary snacks more than twice daily, had irregular dental attendance and lived in low-income families had a significantly higher chance of having dental caries. CONCLUSIONS: Dental caries was prevalent among 5-year-old Hong Kong children, and most of the decayed teeth were untreated. The caries prevalence of the children was related to their frequency of sugary snack intake, dental attendance and socio-economic background. PMID- 28859643 TI - Presence of transient hydronephrosis immediately after surgery has a limited influence on renal function 1 year after ileal neobladder construction. AB - BACKGROUND: Urinary tract obstruction and postoperative hydronephrosis are risk factor for renal function deterioration after orthotopic ileal neobladder construction. However, reports of relationship between transient hydronephrosis and renal function are limited. We assess the influence of postoperative transient hydronephrosis on renal function in patients with orthotopic ileal neobladder construction. METHODS: Between January 2006 and June 2013, we performed radical cystectomy in 164 patients, and 101 received orthotopic ileal neobladder construction. This study included data available from 64 patients with 128 renal units who were enrolled retrospectively. The hydronephrosis grade of each renal unit scored 0-4. The patients were divided into 4 groups according to the grade of hydronephrosis: control, low, intermediate, and high. The grade of postoperative hydronephrosis was compared with renal function 1 month and 1 year after surgery. RESULTS: There were no significant differences in renal function before surgery between groups. One month after surgery, the presence of hydronephrosis was significantly associated with decreased renal function. However, 1 year after urinary diversion hydronephrosis grades were improved significantly, and renal function was comparable between groups. Postoperative hydronephrosis at 1 month had no significant influence on renal function 1 year after ileal neobladder construction. Limitations include retrospective design, short follow-up periods, and a sample composition. CONCLUSIONS: The presence of transient hydronephrosis immediately after surgery may have limited influence on renal function 1 year after ileal neobladder construction. PMID- 28859644 TI - Predictive value of C-reactive protein in patients treated with sunitinib for metastatic clear cell renal cell carcinoma. AB - BACKGROUND: Sunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making. METHODS: In the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded. RESULTS: Median PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival. CONCLUSION: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies. PMID- 28859645 TI - Effects of acupoint-stimulation for the treatment of primary dysmenorrhoea compared with NSAIDs: a systematic review and meta-analysis of 19 RCTs. AB - BACKGROUND: Primary dysmenorrhoea (PD), defined as painful menses in women with normal pelvic anatomy, is one of the most common gynaecological syndromes. Acupoint-stimulation could potentially be an effective intervention for PD. Our aim was to determine the effectiveness of acupoint-stimulation compared with Non Steroidal Anti-Inflammatory Drugs (NASIDs) in the treatment of PD. METHODS: Six databases were searched to December 2014. Sixteen studies involving 1679 PD patients were included. We included randomized controlled trials that compared acupoint-stimulation with NASIDs for the treatment of PD. The main outcomes assessed were clinical effectiveness rate, symptom score, visual analogue score, variation in peripheral blood prostaglandin F2alpha (PGF2alpha) and side effects. All analyses were performed using Comprehensive Meta-Analysis statistical software. RESULTS: (1) The total efficacy was better than control group: odds ratio = 5.57; 95% confidence interval (95% CI) = 3.96, 7.83; P < 0.00001; (2) The effect of intervention was positive in relieving the severity of PD symptoms: mean difference (MD) = 2.99; 95%CI = 2.49, 3.49; P < 0.00001; (3) No statistical difference existed between two groups in terms of a reduction in the VAS: MD = 1.24; 95%CI = -3.37, 5.85; P = 0.60; (4) The effect of intervention on the variation in peripheral blood PGF2alpha between two groups was positive: MD = 7.55; 95%CI = 4.29,10.82; P < 0.00001; (5) The side effects of control groups was more than the acupoint-stimulation group: OR = 0.03; 95%CI =0.00,0.22; P = 0.0005. CONCLUSIONS: According to this article, acupoint-stimulation can relieve pain effectively in the treatment of PD and offers advantages in increasing the overall effectiveness. PMID- 28859647 TI - Blob-ology and biology of cryo-EM: an interview with Helen Saibil. AB - Helen Saibil is Bernal Professor of Structural Biology at Birkbeck, University of London. After undergraduate work at McGill University, Canada, Helen moved to London for her PhD at Kings College. After stints at CEA Grenoble and the University of Oxford, she moved to Birkbeck where her lab studies the operation of macromolecular machinery-including molecular chaperones, protein folding/misfolding, and host cell interactions with pathogens. Helen is a Fellow of the Royal Society, Fellow of the Academy of Medical Sciences, and an Honorary Member of both the British Biophysical Society and the Royal Microscopical Society. She talked to us about the background, recent developments, and future prospects in cryo-electron microscopy. PMID- 28859646 TI - Decision aids for second-line palliative chemotherapy: a randomised phase II multicentre trial. AB - BACKGROUND: There is increasing recognition of the delicate balance between the modest benefits of palliative chemotherapy and the burden of treatment. Decision aids (DAs) can potentially help patients with advanced cancer with these difficult treatment decisions, but providing detailed information could have an adverse impact on patients' well-being. The objective of this randomised phase II study was to evaluate the safety and efficacy of DAs for patients with advanced cancer considering second-line chemotherapy. METHODS: Patients with advanced breast or colorectal cancer considering second-line treatment were randomly assigned to usual care (control group) or usual care plus a DA (intervention group) in a 1:2 ratio. A nurse offered a DA with information on adverse events, tumour response and survival. Outcome measures included patient-reported well being (primary outcome: anxiety) and quality of the decision-making process and the resulting choice. RESULTS: Of 128 patients randomised, 45 were assigned to the control group and 83 to the intervention group. Median age was 62 years (range 32-81), 63% were female, and 73% had colorectal cancer. The large majority of patients preferred treatment with chemotherapy (87%) and subsequently commenced treatment with chemotherapy (86%). No adverse impact on patients' well being was found and nurses reported that consultations in which the DAs were offered went well. Being offered the DA was associated with stronger treatment preferences (3.0 vs. 2.5; p=0.030) and increased subjective knowledge (6.7 vs. 6.3; p=0.022). Objective knowledge, risk perception and perceived involvement were comparable between the groups. CONCLUSIONS: DAs containing detailed risk information on second-line palliative treatment could be delivered to patients with advanced cancer without having an adverse impact on patient well-being. Surprisingly, the DAs only marginally improved the quality of the decision-making process. The effectiveness of DAs for palliative treatment decisions needs further exploration. TRIAL REGISTRATION: Netherlands Trial Registry (NTR): NTR1113 (registered on 2 November 2007). PMID- 28859649 TI - The integration of blended learning into an occupational therapy curriculum: a qualitative reflection. AB - BACKGROUND: This paper presents a critical reflection of the integration of Blended Learning (BL) into an undergraduate occupational therapy curriculum which was delivered through Problem Based Learning (PBL). METHOD: This is a qualitative reflection of a Participatory Action Research (PAR) study using Brookfield's model for critical reflection of an educator's practice. The model uses four 'lenses' through which to focus enquiry: Lens 1) our autobiography as a learner of practice; Lens 2) our learners' eyes; Lens 3) our colleagues' experiences; and Lens 4) the theoretical literature. Grounded theory analysis was applied to the data. RESULTS: The factors that contributed to successful integration of technology and e-Learning into an existing curriculum, the hurdles that were navigated along the way, and how these influenced decisions and innovation are explored. The core categories identified in the data were "drivers of change" and "outcomes of BL integration". Key situations and pivotal events are highlighted for their role in the process that led to the project maturing. Each lens reflects the successes and hurdles experienced during the study. CONCLUSION: Brookfield's model provides an objective method of reflection which showed that despite the hurdles, e-Learning was successfully integrated into the curriculum. PMID- 28859648 TI - Engaging patients and families to create a feasible clinical trial integrating palliative and heart failure care: results of the ENABLE CHF-PC pilot clinical trial. AB - BACKGROUND: Early palliative care (EPC) is recommended but rarely integrated with advanced heart failure (HF) care. We engaged patients and family caregivers to study the feasibility and site differences in a two-site EPC trial, ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers). METHODS: We conducted an EPC feasibility study (4/1/14-8/31/15) for patients with NYHA Class III/IV HF and their caregivers in academic medical centers in the northeast and southeast U.S. The EPC intervention comprised: 1) an in-person outpatient palliative care consultation; and 2) telephonic nurse coach sessions and monthly calls. We collected patient- and caregiver-reported outcomes of quality of life (QOL), symptom, health, anxiety, and depression at baseline, 12- and 24-weeks. We used linear mixed-models to assess baseline to week 24 longitudinal changes. RESULTS: We enrolled 61 patients and 48 caregivers; between site demographic differences included age, race, religion, marital, and work status. Most patients (69%) and caregivers (79%) completed all intervention sessions; however, we noted large between-site differences in measurement completion (38% southeast vs. 72% northeast). Patients experienced moderate effect size improvements in QOL, symptoms, physical, and mental health; caregivers experienced moderate effect size improvements in QOL, depression, mental health, and burden. Small-to-moderate effect size improvements were noted in patients' hospital and ICU days and emergency visits. CONCLUSIONS: Between site demographic, attrition, and participant-reported outcomes highlight the importance of intervention pilot-testing in culturally diverse populations. Observations from this pilot feasibility trial allowed us to refine the methodology of an in-progress, full-scale randomized clinical efficacy trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT03177447 (retrospectively registered, June 2017). PMID- 28859650 TI - Conditional cash transfers and the creation of equal opportunities of health for children in low and middle-income countries: a literature review. AB - INTRODUCTION: Conditional Cash Transfers (CCTs) have been largely used in the world during the past decades, since they are known for enhancing children's human development and promoting social inclusion for the most deprived groups. In other words, CCTs seek to create life chances for children to overcome poverty and exclusion, thus reducing inequality of opportunity. The main goal of the present article is to identify studies capable of showing if CCTs create equality of opportunity in health for children in low and middle-income countries. METHODOLOGY: Comprehensive literature searches were conducted in the Academic Search Complete (EBSCO), PubMed/Medline, Scopus and Web of Science electronic bibliographic databases. Relevant studies were searched using the combination of key words (either based on Medical Subject Headings (MeSH) terms or free text terms) related to conditional cash transfers, child health and equality of opportunity. An integrative research review was conducted on 17 quantitative studies. RESULTS: The effects of CCTs on children's health outcomes related to Social Health Determinants were mostly positive for immunization rates or vaccination coverage and for improvements in child morbidity. Nevertheless, the effects of CCTs were mixed for the child mortality indicators and biochemical or biometric health outcomes. CONCLUSIONS: The present literature review identified five CCTs that provided evidence regarding the creation of health opportunities for children under 5 years old. Nevertheless, cash transfers alone or the use of conditions may not be able to mitigate poverty and health inequalities in the presence of poor health services. PMID- 28859651 TI - Video-based feedback as a method for training rural healthcare workers to manage medical emergencies: a pilot study. AB - BACKGROUND: Video-based feedback has been shown to aid knowledge retention, skills learning and improve team functionality. We explored the use of video based feedback and low fidelity simulation for training rural healthcare workers along the Thailand-Myanmar border and Papua New Guinea (PNG) to manage medical emergencies effectively. METHODS: Twenty-four study participants were recruited from three Shoklo Malaria Research Unit clinics along the Thailand-Myanmar border and eight participants from Kudjip Nazarene Hospital, PNG. The teams were recorded on video managing a simulated medical emergency scenario and the video was used to aid feedback and assess performance using Observed Structured Clinical Examination (OSCE) scoring and Team Emergency Assessment Measure (TEAM) questionnaire. The process was repeated post-feedback at both sites and at 6 weeks at the Thailand-Myanmar border site. Thailand-Myanmar border participants' individual confidence levels and baseline knowledge (using OSCE scoring) were assessed before team assessment and feedback at week 1 and repeated post-feedback and at 6 weeks. Focus group discussions (FGD) were held at each Thailand-Myanmar border clinic at week 1 (8 participants at each clinic). RESULTS: Individual paired tests of OSCE scores showed significant improvement post-feedback at week 1 (p < 0.001) and week 6 (p < 0.001) compared to baseline OSCE scores. There was a trend for increased team OSCE scores compared to baseline at week 1 (p = 0.068) and week 6 (p = 0.109) although not significant. Thailand-Myanmar border TEAM scores demonstrated improvement post-feedback mainly in leadership, teamwork and task management which was sustained up to week 6. PNG showed an improvement mainly in teamwork and task management. The global rating of the teams' non technical performance at both sites improved post feedback and at week 6 on the Thailand-Myanmar border site. Self-rated confidence scores by Thailand-Myanmar border participants increased significantly from baseline following training at week 1 (p = 0.020), and while higher at 6 weeks follow up than at baseline, this was not significant (p = 0.471). The FGD revealed majority of participants felt that watching the video recording of their performance and the video-based feedback contributed most to their learning. CONCLUSION: Video-assisted feedback resulted in an improvement in clinical knowledge, confidence and quality of teamwork for managing medical emergencies in two low resource medical facilities in South East Asia and the South Pacific. PMID- 28859652 TI - Ready for goal setting? Process evaluation of a patient-specific goal-setting method in physiotherapy. AB - BACKGROUND: Patient participation and goal setting appear to be difficult in daily physiotherapy practice, and practical methods are lacking. An existing patient-specific instrument, Patient-Specific Complaints (PSC), was therefore optimized into a new Patient Specific Goal-setting method (PSG). The aims of this study were to examine the feasibility of the PSG in daily physiotherapy practice, and to explore the potential impact of the new method. METHODS: We conducted a process evaluation within a non-controlled intervention study. Community-based physiotherapists were instructed on how to work with the PSG in three group training sessions. The PSG is a six-step method embedded across the physiotherapy process, in which patients are stimulated to participate in the goal-setting process by: identifying problematic activities, prioritizing them, scoring their abilities, setting goals, planning and evaluating. Quantitative and qualitative data were collected among patients and physiotherapists by recording consultations and assessing patient files, questionnaires and written reflection reports. RESULTS: Data were collected from 51 physiotherapists and 218 patients, and 38 recordings and 219 patient files were analysed. The PSG steps were performed as intended, but the 'setting goals' and 'planning treatment' steps were not performed in detail. The patients and physiotherapists were positive about the method, and the physiotherapists perceived increased patient participation. They became aware of the importance of engaging patients in a dialogue, instead of focusing on gathering information. The lack of integration in the electronic patient system was a major barrier for optimal use in practice. Although the self-reported actual use of the PSG, i.e. informing and involving patients, and client-centred competences had improved, this was not completely confirmed by the objectively observed behaviour. CONCLUSION: The PSG is a feasible method and tends to have impact on increasing patient participation in the goal-setting process. However, its full potential for shared goal setting has not been utilized yet. More implementation effort is needed to achieve the required behaviour change and a truly client-centred attitude, to make physiotherapists totally ready for shared goal setting. PMID- 28859653 TI - Retroperitoneal laparoscopic partial nephrectomy with segmental renal artery clamping for cancer of the left upper calyx: a case report. AB - BACKGROUND: Currently, the standard treatment for renal pelvis carcinoma is radical nephroureterectomy with bladder cuff excision. To describe the feasibility of retroperitoneal laparoscopic partial nephrectomy with segmental renal artery clamping for cancer of renal pelvis, we report this special case for the first time. CASE PRESENTATION: A 67-year-old woman received this operation. Preoperative ureteroscopy revealed a papillary neoplasm with a pedicle in the upper calyx of the left kidney. After entering the retroperitoneal space and dissociating the renal artery and renal vein, the target artery was clamped beyond the final bifurcation before entering the parenchyma. After incision of the left renal parenchyma and exposure of the upper calyceal neck, the tumor was found confined to the upper calyx. Thereafter, the renal calyx and parenchyma were sutured successively after complete resection of the neoplasm. Postoperative pathological examination confirmed that the Grade I papillary carcinoma was confined to the mucosal layer. Thus far, there is no evidence of recurrence during the follow-up period for more than 42 months after surgery. CONCLUSIONS: Retroperitoneal laparoscopic partial nephrectomy with segmental renal artery clamping of the kidney provides a feasible treatment modality for noninvasive tumors that are limited to the calyx. PMID- 28859654 TI - Perceptions of Mexican women regarding barriers in mental Heath Services in primary care. AB - BACKGROUND: The recent mental health care reforms in Mexico call for the regular evaluation of the services provided. This involves analyzing the opinions of those who utilize them on a daily basis, particularly women, since they are the main health service users. This study explores the barriers to mental health care perceived by a group of women attending primary care centers. METHOD: A qualitative methodological approach was chosen. The participants were purposively selected, using the snowball technique. Semi-structured interviews were analyzed using the thematic analysis. RESULTS: Three sets of factors representing barriers to care were identified in the participants' discourse. The first is linked to systemic barriers such as a lack of familiarity with the way the service operates, and irregularities in the consultations and appointment schedules that are not always geared to women's needs. The second concerns the social stigma associated with emotional and/or mental disorders and their care while the third involves the characteristics of psychologists and their professional work. CONCLUSIONS: In order to overcome some of the barriers identified, users should be given information on the work of mental health professionals, which would help dispel certain misconceptions and sensitize them to the importance of this type of treatment in achieving overall health. There is also a need to make psychologists aware of the living conditions and socio-cultural context of the women who attend these health facilities. PMID- 28859655 TI - Management of large renal stones: laparoscopic pyelolithotomy versus percutaneous nephrolithotomy. AB - BACKGROUND: Percutaneous nephrolithotomy (PCNL) remains the standard procedure for large (>=2 cm) renal calculi; however, laparoscopic pyelolithotomy (LPL) can be used as an alternative management procedure. The aim of present study was to compare LPL and PCNL in terms of efficacy and safety for the management of large renal pelvic stones. METHODS: A literature search was performed in Jan 2016 using electronic databases (Cochrane Central Register of Controlled Trials, Medline, and EMBASE) to identify relevant studies for the meta-analysis. Only comparative studies investigating LPL versus PCNL were included. Effect sizes were estimated by pooled odds ratio (ORs) and mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Five randomized and nine non-randomized studies were identified for analysis, involving a total of 901 patients. Compared with PCNL, LPL provided a significantly higher stone-free rate (OR 3.94, 95% CI 2.06-7.55, P < 0.001), lower blood transfusion rate (OR 0.28, 95% CI 0.13-0.61, P = 0.001), lower bleeding rate (OR 0.20, 95% CI 0.06-0.61, P = 0.005), fewer hemoglobin decrease(MD -0.80, 95% CI -0.97 to -0.63, P < 0.001), less postoperative fever (OR 0.38, 95% CI 0.21-0.68; P = 0.001), and lower auxiliary procedure rate (OR 0.24, 95% CI 0.12-0.46, P < 0.001) and re-treatment rate (OR 0.20, 95% CI 0.07 0.55, P = 0.002). However, LPL had a longer operative time and hospital stay. There were no significant differences in conversion to open surgery and prolonged urine leakage rates between LPL and PCNL. CONCLUSIONS: Our present findings suggest that LPL is a safe and effective approach for management of patients with large renal stones. However, PCNL still suitable for most cases and LPL can be used as an alternative management procedure with good selection of cases. PMID- 28859656 TI - Blood lead level is associated with non-alcoholic fatty liver disease in the Yangtze River Delta region of China in the context of rapid urbanization. AB - BACKGROUND: China has undergone rapid urbanization in the past three decades. We aimed to report blood lead level (B-Pb) in the most rapidly urbanized Yangtze River Delta Region of China, and explore the association B-Pb and non-alcoholic fatty liver disease (NAFLD). METHODS: Our data source was the SPECT-China study. We enrolled 2011 subjects from 6 villages in the Yangtze River Delta Region. Lead was measured by atomic absorption spectrometry. According to abdominal ultrasound, residents were divided into normal and NAFLD groups. RESULTS: In total, 824 (41.0%) were diagnosed with NAFLD. Medians (interquartile range) of B Pb were 5.29 MUg/dL (3.60-7.28) [0.25 MUmol/L (0.17-0.35)] for men and 4.49 MUg/dL (2.97-6.59) [0.22 MUmol/L (0.14-0.32)] for women. In both genders, the NAFLD group had significantly greater B-Pb than normal group (both P < 0.001). The prevalence of NAFLD significantly increased with increasing B-Pb quartiles in men (P for trend = 0.032) and women (P for trend = 0.001). Residents in Shanghai had significantly greater B-Pb (P < 0.001) and a higher prevalence of NAFLD (P < 0.001). Compared with women in the lowest quartile of BLL, OR of NAFLD in women in the highest quartile was 1.613 (95%CI 1.082-2.405) (P for trend = 0.019) after multivariable adjustment. In men, this association showed marginal significance (OR 2.168, 95%CI 0.989-4.750, P for trend = 0.063). CONCLUSION: B-Pb in Chinese residents in the Yangtze River Delta Region were much higher than in developed countries. Elevated B-Pb was associated with an increased risk of NAFLD, especially in women. PMID- 28859657 TI - FTO associations with obesity and telomere length. AB - This review examines the biology of the Fat mass- and obesity-associated gene (FTO), and the implications of genetic association of FTO SNPs with obesity and genetic aging. Notably, we focus on the role of FTO in the regulation of methylation status as possible regulators of weight gain and genetic aging. We present a theoretical review of the FTO gene with a particular emphasis on associations with UCP2, AMPK, RBL2, IRX3, CUX1, mTORC1 and hormones involved in hunger regulation. These associations are important for dietary behavior regulation and cellular nutrient sensing via amino acids. We suggest that these pathways may also influence telomere regulation. Telomere length (TL) attrition may be influenced by obesity-related inflammation and oxidative stress, and FTO gene-involved pathways. There is additional emerging evidence to suggest that telomere length and obesity are bi-directionally associated. However, the role of obesity risk-related genotypes and associations with TL are not well understood. The FTO gene may influence pathways implicated in regulation of TL, which could help to explain some of the non-consistent relationship between weight phenotype and telomere length that is observed in population studies investigating obesity. PMID- 28859658 TI - The effect of socioeconomic disadvantage on prescription of guideline-recommended medications for patients with acute coronary syndrome: systematic review and meta analysis. AB - BACKGROUND: There are varying data on whether socioeconomic status (SES) affects the treatment in patients with acute coronary syndrome (ACS). Our aim was to obtain a reliable estimate of the effect of SES on discharge prescription of medications following an ACS through systematic review and meta-analysis. METHODS: Medline, EMBASE and Global Health were searched systematically on 6th April 2016. Studies were eligible if the participants had ACS and reported the rate/odds of guideline-recommended ACS medications prescription (aspirin, antiplatelet, beta blocker, angiotensin co-enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and statin) at discharge stratified by SES. A meta analysis was performed to pool the estimates, comparing the prescription ratio (PR) between the lowest and the highest SES groups. RESULTS: Of 252 articles found from the search, seven met the eligibility criteria and it included 41,462 (20,986 from the lowest SES group) patients. We found that the individual/neighbourhood level SES did not affect the prescription of aspirin (PR (95% CI): 0.97 (0.91, 1.03)), but for beta blocker and statin, the lowest SES group were disadvantaged (0.84 (0.73, 0.94), 0.80 (0.62, 0.98), respectively). In contrast, ACEi were prescribed more often to the lowest individual/neighbourhood level SES group than the highest (1.13 (1.05, 1.22)). Although the risk of bias was low, there was considerable heterogeneity between the studies. CONCLUSIONS: Despite the recommendations to close the treatment gap, the rate of prescription of guideline-recommended medications in managing ACS is significantly different between patients with the lowest and the highest groups. A solution is needed to provide equitable care across the SES groups. PROSPERO REGISTRY: Systematic review registration no.: CRD42016048503. Registered 28 September 2016. PMID- 28859659 TI - Few opportunities to influence decisions regarding the care and treatment of an older hospitalized family member: a qualitative study among family members. AB - BACKGROUND: The drive towards patient involvement in health services has been increasingly promoted. The World Health Organisation emphasizes the family's perspective in comprehensive care. Internationally there is an increased emphasis on what patients and their family tell about the hospital experiences. However, current literature does not adequately address the question of participation experiences among relatives of older hospitalized family members. There is a paucity of research with a generational perspective on relatives' opportunities to exert influence. The aim of the study was to explore relatives' experiences of opportunities to participate in decisions about the care and treatment of older hospitalized family members and whether there are different experiences of influence to the relatives' age. METHODS: This was an explorative study applying individual qualitative interviews. The interviews were analysed following hermeneutic methodological principles. Two Norwegian geriatric wards participated: one at a university hospital and one at a local hospital. Twelve participants, six women and six men, were purposively selected. The relatives were aged from 36 to 88 (mean age 62) and were spouses, children and/or children in-law of patients. RESULTS: The relatives' experienced opportunities to exert influence were distributed along a continuum ranging from older relatives being reactive waiting for an initiative from health professionals, to younger adults being proactive securing influence. Older "invisible" carers appeared to go unnoticed by the health professionals, establishing few opportunities to influence decisions. The middle-aged relatives also experienced limited influence, but participated when the hospital needed it. However, limited participation seemed to have less impact on their lives than in the older relatives. Middle-aged relatives and younger adults identified strategies in which visibility was the key to increasing the odds of gaining participation. The exceptional case seemed to be some older carers' experiences of influencing decisions with the help of professionals. CONCLUSIONS: Our findings suggest that experiences of influence were limited regardless of age. However, the results indicated that participation among relatives decrease with age while vulnerability for not having influence seemed to increase with age. The problem of patient choice most clearly manifested among the older carers, which might indicate that the relatives' age sets terms for opportunities to participate. PMID- 28859660 TI - Early- versus late-onset Alzheimer's disease in clinical practice: cognitive and global outcomes over 3 years. AB - BACKGROUND: Whether age at onset influences Alzheimer's disease (AD) progression and the effectiveness of cholinesterase inhibitor (ChEI) therapy is not clear. We aimed to compare longitudinal cognitive and global outcomes in ChEI-treated patients with early-onset Alzheimer's disease (EOAD) versus late-onset Alzheimer's disease (LOAD) in clinical practice. METHODS: This 3-year, prospective, observational, multicentre study included 1017 participants with mild to moderate AD; 143 had EOAD (age at onset < 65 years) and 874 had LOAD (age at onset >= 65 years). At baseline and semi-annually, patients were assessed using cognitive, global and activities of daily living (ADL) scales, and the dose of ChEI was recorded. Potential predictors of decline were analysed using mixed effects models. RESULTS: Six-month response to ChEI therapy and long-term prognosis in cognitive and global performance were similar between the age-at onset groups. However, deterioration was significantly faster when using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) over 3 years in participants with EOAD than in those with LOAD; hence, prediction models for the mean ADAS-Cog trajectories are presented. The younger cohort had a larger proportion of homozygote apolipoprotein E (APOE) epsilon4 allele carriers than the older cohort; however, APOE genotype was not a significant predictor of cognitive impairment in the multivariate models. A slower rate of cognitive progression was related to initiation of ChEIs at an earlier stage of AD, higher ChEI dose and fewer years of education in both groups. In LOAD, male sex, better instrumental ADL ability and no antipsychotic drug use were additional protective characteristics. The older patients received a lower ChEI dose than the younger individuals during most of the study period. CONCLUSIONS: Although the participants with EOAD showed a faster decline in ADAS-Cog, had a longer duration of AD before diagnosis, and had a higher frequency of two APOE epsilon4 alleles than those with LOAD, the cognitive and global responses to ChEI treatment and the longitudinal outcomes after 3 years were similar between the age-at-onset groups. A higher mean dose of ChEI and better cognitive status at the start of therapy were independent protective factors in both groups, stressing the importance of early treatment in adequate doses for all patients with AD. PMID- 28859661 TI - Triple synchronous primary lung cancer: a case report and review of the literature. AB - BACKGROUND: Multiple primary lung cancer may present in synchronous or metachronous form. Synchronous multiple primary lung cancer is defined as multiple lung lesions that develop at the same time, whereas metachronous multiple primary lung cancer describes multiple lung lesions that develop at different times, typically following treatment of the primary lung cancer. Patients with previously treated lung cancer are at risk for developing metachronous lung cancer, but with the success of computed tomography and positron emission tomography, the ability to detect both synchronous and metachronous lung cancer has increased. CASE PRESENTATION: We present a case of a 63-year-old Hispanic man who came to our hospital for evaluation of chest pain, dry cough, and weight loss. He had recently been diagnosed with adenocarcinoma in the right upper lobe, with a poorly differentiated carcinoma favoring squamous cell cancer based on bronchoalveolar lavage of the right lower lobe for which treatment was started. Later, bronchoscopy incidentally revealed the patient to have an endobronchial lesion that turned out to be mixed small and large cell neuroendocrine lung cancer. Our patient had triple synchronous primary lung cancers that histologically were variant primary cancers. CONCLUSIONS: Triple synchronous primary lung cancer management continues to be a challenge. Our patient's case suggests that multiple primary lung cancers may still occur at a greater rate than can be detected by high-resolution computed tomography. PMID- 28859662 TI - Chronic pain in Gaucher disease: skeletal or neuropathic origin? AB - BACKGOUND: Pain is one of the most disabling symptoms of Gaucher disease. It is referred by the majority of Gaucher patients and often persists despite long-term enzyme replacement treatment. It has been mainly considered as nociceptive pain secondary to skeletal involvement but it is described even in the absence of bone disease without a clear explanation. In the last years an increasing number of reports have described the presence of neurological manifestation in Gaucher type 1 patients, including subclinical large fibre neuropathy. In our Gaucher clinic we have observed the recurrence of painful symptoms in a group of type 1 Gaucher patients even after a long-term enzyme replacement therapy. METHODS: A cross sectional study was designed to investigate the pathophysiology of pain in a cohort of 25 Gaucher patients (13 females, 12 males). Twenty-two patients received enzyme replacement therapy for a period of time ranging from 10 to >20 years, while three were new diagnosis. Pain was classified as bone or neurologic related on the basis of anamnestic data, clinical and electrophysilogical examinations. Intensity and quality of pain were recorded by Douleur Neuropathique en 4 questionnaire and Neuropathic Pain Symptom Inventory. Neuroalgological evaluation, quantitative sensory testing, nerve conduction studies and evaluation of epidermal nerve fibres density were performed. Comorbidities for peripheral neuropathy were excluded. RESULTS: Thirteen patients complained of pain suggestive of neuropathic origin with proximal patchy distribution, six manifested severe pain paroxysmal, nine pinprick hypoesthesia and 17 thermal hypoesthesia. At quantitative sensory testing, all of them showed high cold thresholds with errata sensation (burning instead of cold), paradoxical heat sensation and mechanic hypoesthesia; three patients showed pressure pain hyperalgesia. Epidermal denervation was present in 19 patients, 12 of them with non-length dependent pattern. CONCLUSIONS: These results confirm the role of peripheral neuropathy in Gaucher pain and demonstrate that skin denervation is as a constitutive feature of the disorder. In addition, they further confirm the existence of a continuum Gaucher phenotype, and provide a new interpretation of pain origin that should be considered for an appropriate disease management and to avoid unnecessary dose escalations of enzyme therapy. PMID- 28859663 TI - Sparse conserved under-methylated CpGs are associated with high-order chromatin structure. AB - BACKGROUND: Whole-genome bisulfite sequencing (WGBS) is the gold standard for studying landscape DNA methylation. Current computational methods for WGBS are mainly designed for gene regulatory regions with multiple under-methylated CpGs (UMCs), such as promoters and enhancers. RESULTS: To reliably predict the functional importance of single isolated UMCs across the genome, which is usually not achievable using traditional methods, we develop a multi-sample-based method. We identified 9421 sparse conserved under-methylated CpGs (scUMCs) from 31 high quality methylomes, which are enriched in distal interacting anchor regions co occupied by multiple chromatin-loop factors and are flanked by highly methylated CpGs. Moreover, cell lineage-specific scUMCs are associated with essential developmental genes, regulators of cell differentiation, and chromatin remodeling enzymes. Dynamic methylation levels of scUMCs correlate with the intensity of chromatin interactions and binding of looping factors as well as patterns of gene expression. CONCLUSIONS: We introduce an innovative computational method for the identification of scUMCs, which are novel epigenetic features associated with high-order chromatin structure, opening new directions in the study of the inter relationships between DNA methylation and chromatin structure. PMID- 28859664 TI - Synergistic effects of aerobic exercise and cognitive training on cognition, physiological markers, daily function, and quality of life in stroke survivors with cognitive decline: study protocol for a randomized controlled trial. AB - BACKGROUND: Aerobic exercise and cognitive training have been effective in improving cognitive functions; however, whether the combination of these two can further enhance cognition and clinical outcomes in stroke survivors with cognitive decline remains unknown. This study aimed to determine the treatment effects of a sequential combination of aerobic exercise and cognitive training on cognitive function and clinical outcomes. METHODS/DESIGN: Stroke survivors (n = 75) with cognitive decline will be recruited and randomly assigned to cognitive training, aerobic exercise, and sequential combination of aerobic exercise and cognitive training groups. All participants will receive training for 60 minutes per day, 3 days per week for 12 weeks. The aerobic exercise group will receive stationary bicycle training, the cognitive training group will receive cognitive based training, and the sequential group will first receive 30 minutes of aerobic exercise, followed by 30 minutes of cognitive training. The outcome measures involve cognitive functions, physiological biomarkers, daily function and quality of life, physical functions, and social participation. Participants will be assessed before and immediately after the interventions, and 6 months after the interventions. Repeated measures of analysis of variance will be used to evaluate the changes in outcome measures at the three assessments. DISCUSSION: This trial aims to explore the benefits of innovative intervention approaches to improve the cognitive function, physiological markers, daily function, and quality of life in stroke survivors with cognitive decline. The findings will provide evidence to advance post-stroke cognitive rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02550990 . Registered on 6 September 2015. PMID- 28859665 TI - Left atrial thrombus due to transseptal catheterization simulating solid mass of right atrium. AB - BACKGROUND: Transseptal catheterization has been popularized through ongoing advances in percutaneous procedures, but related complications are known to occur. CASE PRESENTATION: A 72 year-old female was admitted with left-sided weakness. In the course of various exams, a rounded and smooth-surfaced solid mass of right atrium was identified. However, a septal aneurysm associated with left atrial mural thrombus was evident intraoperatively. Given that percutaneous transseptal mitral valvotomy had been done 7 years previously, a causal relationship is likely. CONCLUSIONS: Prior cardiac intervention should be considered in patients presenting with mass lesions of interatrial septum. PMID- 28859666 TI - A systematic review of interventions to increase awareness of mental health and well-being in athletes, coaches and officials. AB - BACKGROUND: The aim of the current study was to conduct a systematic review determining the effect of sport-specific mental health awareness programs to improve mental health knowledge and help-seeking among sports coaches, athletes and officials. The second aim was to review the study quality and to report on the validity of measures that were used to determine the effectiveness of programs. METHODS: Sport-specific mental health awareness programs adopting an experimental or quasi-experimental design were included for synthesis. Six electronic databases were searched: PsycINFO, MEDLINE (OVID interface), Scopus, Cochrane, CINAHL and SPORTDiscus. Each database was searched from its year of inception to October 2016. Risk of bias was assessed using the Cochrane and QATSQ tools. RESULTS: Ten studies were included from the 1216 studies retrieved: four comprising coaches or service providers, one with officials, four with athletes, and one involved a combination of coaches and athletes. A range of outcomes was used to assess indices of mental health awareness and well-being. Mental health referral efficacy was improved in six studies, while three reported an increase in knowledge about mental health disorders. However, seven studies did not report effect sizes for their outcomes, limiting clinically meaningful interpretations. Furthermore, there was substantial heterogeneity and limited validity in the outcome measures of mental health knowledge and referral efficacy. Seven studies demonstrated a high risk of bias. CONCLUSIONS: Further, well-designed controlled intervention studies are required. Researchers, practitioners and policy makers should adhere to available methodological guidance and apply the psychological theory of behaviour change when developing and evaluating complex interventions. TRIAL REGISTRATION: PROSPERO CRD42016040178. PMID- 28859667 TI - Young adult non-smokers' exposure to real-world tobacco marketing: results of an ecological momentary assessment pilot study. AB - BACKGROUND: The aims of this pilot study were to assess and characterize non current smoking young adults' exposure to tobacco marketing through an ecological momentary assessment protocol. METHODS: Ecological momentary assessment (EMA) consists of repeated measurement of momentary phenomena and is well-suited to capture sporadic experiences in the real-world, such as exposure to tobacco marketing. EMA has the potential to capture detailed information about real-world marketing exposures in ways that reduce recall bias and increase ecological validity. In this study, young adults (n = 31; ages 18-25) responded to random prompts regarding their momentary exposure to tobacco marketing via text messages on their smartphones for 14 days (n = 1798 observations). Unadjusted and adjusted analyses were conducted using multilevel logistic regression to assess the odds of exposure accounting for correlation of multiple repeated measures within individuals while controlling for variability between individuals. RESULTS: Respondents reported, on average, two momentary exposures to tobacco advertising in the 14-day study period. In adjusted analyses, African-American (aOR 3.36; 95% CI 1.07, 10.54) and Hispanic respondents (aOR 5.08; 95% CI 1.28, 20.13) were more likely to report exposure to tobacco advertising. Respondents were also more likely to report exposure when also exposed to others using tobacco products and when they were at stores compared with at home (aOR 14.82; 95% CI 3.61, 60.88). CONCLUSION: Non-smoking young adults report exposure to tobacco marketing particularly at the point-of-sale, with the highest likelihood of exposure among African-American and Hispanic young people. EMA protocols can be effective in assessing the potential impact of point-of-sale tobacco marketing on young adults. PMID- 28859668 TI - Cerebrospinal fluid CXCL13 as a diagnostic marker of neuroborreliosis in children: a retrospective case-control study. AB - BACKGROUND: Lyme neuroborreliosis (LNB) is a frequent manifestation of Lyme disease in children and its current diagnosis has limitations. The elevation of the chemokine CXCL13 in the cerebrospinal fluid (CSF) of adult patients with LNB has been demonstrated and suggested as a new diagnostic marker. Our aim was to evaluate this marker in the CSF of children with suspected LNB and to determine a CXCL13 cut-off concentration that would discriminate between LNB and other central nervous system (CNS) infections. METHODS: For this single-center retrospective case-control study we used a diagnostic-approved ELISA to measure CXCL13 concentrations in the CSF of 185 children with LNB suspicion at presentation. Patients were classified into definite LNB (cases), non-LNB (controls with other CNS affections), and possible LNB. A receiver-operating characteristic curve was generated by comparison of cases and controls. RESULTS: CXCL13 was significantly elevated in the CSF of 53 children with definite LNB (median 774.7 pg/ml) compared to 91 control patients (median 4.5 pg/ml, p < 0.001). A cut-off of 55 pg/ml resulted in a sensitivity of 96.7% and a specificity of 98.1% for the diagnosis of definite LNB and the test exhibited a diagnostic odds ratio of 1525.3. Elevated CSF CXCL13 levels were also detected in three controls with viral meningitis (enterovirus n = 1, varicella-zoster virus n = 2) while other CNS affections such as idiopathic facial palsy did not lead to CXCL13 elevation. Of the 41 patients with possible LNB, 27% had CXCL13 values above the cut-off of 55 pg/ml (median 16.7 pg/ml). CONCLUSIONS: CSF CXCL13 is highly elevated in children during early LNB as previously shown in adults. CXCL13 is a highly sensitive and specific marker that helps to differentiate LNB from other CNS affections in children. PMID- 28859669 TI - Epigenetic silencing of miR-493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1). AB - BACKGROUND: The potential mechanisms regarding how methylation of microRNA(miRNA) CpG Island could regulate cancer cell chemo-resistance remains unclear. This study aims to explore the epigenetic dysregulation mechanism of miRNA-493 and the ability to modulate lung cancer cell chemotherapy resistance. METHODS: Real-time quantitative PCR (qRT-PCR) and In situ hybridization (ISH) were used to analyze the expression of miR-493 in lung cancer cell lines and tumor tissue, respectively. Bisulfite sequencing PCR (BSP) was used to exam the promoter CpG Island of miR-493. The effect of miR-493 on chemosensitivity was evaluated by cell viability assays, apoptosis assays and in vivo experiment. The DNA damage was measured by gamma-H2AX immunofluorescence. Luciferase reporter assay was used to assess the target genes of miR-493. Expression of target proteins and downstream molecules were analyzed by Western blot. RESULTS: miR-493 is silenced in resistant lung cancer cell due to the aberrant DNA methylation. Enforced expression of miR-493 in lung cancer cells promotes chemotherapy sensitivity to cisplatin through impairing the DNA damage repair and increasing the cells apoptosis in vitro and in vivo. Furthermore, we identify that TCRP1 is a direct functional target of miR-493. Ectopic expression of TCRP1 attenuated increased apoptosis in miR-493-overexpressing lung cancer cells upon cisplatin treatment. Meanwhile, miR-493 level is negatively correlated with TCRP1 expression in lung cancer patients and TCRP1 expression were correlated with poor survival. CONCLUSIONS: Our results highlight that hyper-methylation of miR-493CpG island might play important roles in the development of lung cancer chemo-resistance by targeting TCRP1, which might be used as a potential therapeutic target in preventing the chemo-resistance of lung cancer. PMID- 28859670 TI - Selective suppression of the JNK-MMP2/9 signal pathway by tetramethylpyrazine attenuates neuropathic pain in rats. AB - BACKGROUND: Activated astrocytes release matrix metalloproteinase-2/9 (MMP-2/9) to induce central sensitization and maintain neuropathic pain. However, the mechanisms involved in the activation of MMP-2/9 on astrocytes during pain remain poorly understood. Meanwhile, there is a lack of effective treatment to inhibit the activation of MMP-2/9 on astrocytes. In this study, we aim to investigate the effect of tetramethylpyrazine (TMP), a natural compound with analgesic effects but unknown mechanisms, on MMP-2/9 in neuropathic pain. METHODS: The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 6). Cell signaling was assayed using western blotting (n = 6) and immunohistochemistry (n = 5). The astrocyte cell line C8-D1A was cultured to investigate the in vitro effects. RESULTS: TMP significantly attenuated the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain, inhibited the activation of astrocytes, and decreased the expression of MMP-2/9. Furthermore, our results indicated that TMP could selectively suppress JNK activity but had no notable effects on ERK and p38. Our study also revealed that the effect of TMP may be dependent on the inhibition of TAK1. CONCLUSIONS: Inhibition of astrocyte activation in the spinal cord by tetramethylpyrazine may have utility in the treatment of CCI-induced neuroinflammation, and our results further implicate JNK-MMP-2/9 as a novel target for the attenuation of neuropathic pain. PMID- 28859671 TI - The structure of the Brassica napus seed microbiome is cultivar-dependent and affects the interactions of symbionts and pathogens. AB - BACKGROUND: Although the plant microbiome is crucial for plant health, little is known about the significance of the seed microbiome. Here, we studied indigenous bacterial communities associated with the seeds in different cultivars of oilseed rape and their interactions with symbiotic and pathogenic microorganisms. RESULTS: We found a high bacterial diversity expressed by tight bacterial co occurrence networks within the rape seed microbiome, as identified by llumina MiSeq amplicon sequencing. In total, 8362 operational taxonomic units (OTUs) of 40 bacterial phyla with a predominance of Proteobacteria (56%) were found. The three cultivars that were analyzed shared only one third of the OTUs. The shared core of OTUs consisted mainly of Alphaproteobacteria (33%). Each cultivar was characterized by having its own unique bacterial structure, diversity, and proportion of unique microorganisms (25%). The cultivar with the lowest bacterial abundance, diversity, and the highest predicted bacterial metabolic activity rate contained the highest abundance of potential pathogens within the seed. This data corresponded with the observation that seedlings belonging to this cultivar responded more strongly to the seed treatments with bacterial inoculants than other cultivars. Cultivars containing higher indigenous diversity were characterized as having a higher colonization resistance against beneficial and pathogenic microorganisms. Our results were confirmed by microscopic images of the seed microbiota. CONCLUSIONS: The structure of the seed microbiome is an important factor in the development of colonization resistance against pathogens. It also has a strong influence on the response of seedlings to biological seed treatments. These novel insights into seed microbiome structure will enable the development of next generation strategies combining both biocontrol and breeding approaches to address world agricultural challenges. PMID- 28859672 TI - Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS. AB - BACKGROUND: Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. METHODS: One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. RESULTS: Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. CONCLUSION: Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. TRIAL REGISTRATION: EudraCT Number: 2009-011234-99 . Registered 23 June 2009. PMID- 28859674 TI - Identifying research priorities for effective retention strategies in clinical trials. AB - BACKGROUND: The failure to retain patients or collect primary-outcome data is a common challenge for trials and reduces the statistical power and potentially introduces bias into the analysis. Identifying strategies to minimise missing data was the second highest methodological research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs) and is important to minimise waste in research. Our aim was to assess the current retention practices within the UK and priorities for future research to evaluate the effectiveness of strategies to reduce attrition. METHODS: Seventy-five chief investigators of NIHR Health Technology Assessment (HTA)-funded trials starting between 2009 and 2012 were surveyed to elicit their awareness about causes of missing data within their trial and recommended practices for improving retention. Forty-seven CTUs registered within the UKCRC network were surveyed separately to identify approaches and strategies being used to mitigate missing data across trials. Responses from the current practice surveys were used to inform a subsequent two round Delphi survey with registered CTUs. A consensus list of retention research strategies was produced and ranked by priority. RESULTS: Fifty out of seventy five (67%) chief investigators and 33/47 (70%) registered CTUs completed the current practice surveys. Seventy-eight percent of trialists were aware of retention challenges and implemented strategies at trial design. Patient initiated withdrawal was the most common cause of missing data. Registered CTUs routinely used newsletters, timeline of participant visits, and telephone reminders to mitigate missing data. Whilst 36 out of 59 strategies presented had been formally or informally evaluated, some frequently used strategies, such as site initiation training, have had no research to inform practice. Thirty-five registered CTUs (74%) participated in the Delphi survey. Research into the effectiveness of site initiation training, frequency of patient contact during a trial, the use of routinely collected data, the frequency and timing of reminders, triggered site training and the time needed to complete questionnaires was deemed critical. Research into the effectiveness of Christmas cards for site staff was not of critical importance. CONCLUSION: The surveys of current practices demonstrates that a variety of strategies are being used to mitigate missing data but with little evidence to support their use. Six retention strategies were deemed critically important within the Delphi survey and should be a primary focus of future retention research. PMID- 28859675 TI - Mycobacterium malmoense pulmonary infection in France: a case report. AB - BACKGROUND: Mycobacterium malmoense infections have frequently been reported in northern Europe since the late 1970s. Factors accounting for this geographically localized epidemiology remain poorly understood. CASE PRESENTATION: We report the case of a 54-year old man concomitantly diagnosed with non-small cell lung carcinoma and M. malmoense pulmonary infection. We present detailed clinical, microbiological and radiological elements strongly arguing for M. malmoense true pathogenicity. Since M. malmoense infection has rarely been reported in France, we also provide elements of the epidemiological investigation and a literature review of potential acquisition and transmission pathways of M. malmoense. We detail therapeutic interventions and subsequent favorable evolution. CONCLUSION: Mycobacterium malmoense is a recognized respiratory pathogen for which routes of infection need to be better investigated. PMID- 28859673 TI - Multiple therapeutic effect of endothelial progenitor cell regulated by drugs in diabetes and diabetes related disorder. AB - BACKGROUND: Reduced levels of endothelial progenitor cells (EPCs) counts have been reported in diabetic mellitus (DM) patients and other diabetes-related disorder. EPCs are a circulating, bone marrow-derived cell population that appears to participate in vasculogenesis, angiogenesis and damage repair. These EPC may revert the damage caused in diabetic condition. We aim to identify several existing drugs and signaling molecule, which could alleviate or improve the diabetes condition via mobilizing and increasing EPC number as well as function. MAIN BODY: Accumulated evidence suggests that dysregulation of EPC phenotype and function may be attributed to several signaling molecules and cytokines in DM patients. Hyperglycemia alone, through the overproduction of reactive oxygen species (ROS) via eNOS and NOX, can induce changes in gene expression and cellular behavior in diabetes. Furthermore, reports suggest that EPC telomere shortening via increased oxidative DNA damage may play an important role in the pathogenesis of coronary artery disease in diabetic patients. In this review, different type of EPC derived from different sources has been discussed along with cell-surface marker. The reduced number and immobilized EPC in diabetic condition have been mobilized for the therapeutic purpose via use of existing, and novel drugs have been discussed. Hence, evidence list of all types of drugs that have been reported to target the same pathway which affect EPC number and function in diabetes has been reviewed. Additionally, we highlight that proteins are critical in diabetes via polymorphism and inhibitor studies. Ultimately, a lucid pictorial explanation of diabetic and normal patient signaling pathways of the collected data have been presented in order to understand the complex signaling mystery underlying in the diseased and normal condition. CONCLUSION: Finally, we conclude on eNOS-metformin-HSp90 signaling and its remedial effect for controlling the EPC to improve the diabetic condition for delaying diabetes-related complication. Altogether, the review gives a holistic overview about the elaborate therapeutic effect of EPC regulated by novel and existing drugs in diabetes and diabetes-related disorder. PMID- 28859676 TI - Abundance and distribution of sylvatic dengue virus vectors in three different land cover types in Sarawak, Malaysian Borneo. AB - BACKGROUND: Mosquito-borne dengue virus (DENV) is maintained in a sylvatic, enzootic cycle of transmission between canopy-dwelling non-human primates and Aedes mosquitoes in Borneo. Sylvatic DENV can spill over into humans living in proximity to forest foci of transmission, in some cases resulting in severe dengue disease. The most likely vectors of such spillover (bridge vectors) in Borneo are Ae. albopictus and Ae. niveus. Borneo is currently experiencing extensive forest clearance. To gauge the effect of this change in forest cover on the likelihood of sylvatic DENV spillover, it is first necessary to characterize the distribution of bridge vectors in different land cover types. In the current study, we hypothesized that Ae. niveus and Ae. albopictus would show significantly different distributions in different land cover types; specifically, we predicted that Ae. niveus would be most abundant in forests whereas Ae. albopictus would have a more even distribution in the landscape. RESULTS: Mosquitoes were collected from a total of 15 sites using gravid traps and a backpack aspirator around Kampong Puruh Karu, Sarawak, Malaysian Borneo, where sylvatic DENV spillover has been documented. A total of 2447 mosquitoes comprising 10 genera and 4 species of Aedes, were collected over the three years, 2013, 2014 and 2016, in the three major land cover types in the area, homestead, agriculture and forest. Mosquitoes were identified morphologically, pooled by species and gender, homogenized, and subject to DNA barcoding of each Aedes species and to arbovirus screening. As predicted, Ae. niveus was found almost exclusively in forests whereas Ae. albopictus was collected in all land cover types. Aedes albopictus was significantly (P = 0.04) more abundant in agricultural fields than forests. Sylvatic DENV was not detected in any Aedes mosquito pools, however genomes of 14 viruses were detected using next generation sequencing. CONCLUSIONS: Land cover type affects the abundance and distribution of the most likely bridge vectors of sylvatic DENV in Malaysia Borneo. Conversion of forests to agriculture will likely decrease the range and abundance of Ae. niveus but enhance the abundance of Ae. albopictus. PMID- 28859677 TI - Engagement of public and private medical facilities in tuberculosis care in Myanmar: contributions and trends over an eight-year period. AB - BACKGROUND: As part of the WHO End TB strategy, national tuberculosis (TB) programs increasingly aim to engage all private and public TB care providers. Engagement of communities, civil society organizations and public and private care provider is the second pillar of the End TB strategy. In Myanmar, this entails the public-public and public-private mix (PPM) approach. The public public mix refers to public hospital TB services, with reporting to the national TB program (NTP). The public-private mix refers to private general practitioners providing TB services including TB diagnosis, treatment and reporting to NTP. The aim of this study was to assess whether PPM activities can be scaled-up nationally and can be sustained over time. METHODS: Using 2007-2014 aggregated program data, we collected information from NTP and non-NTP actors on 1) the number of TB cases detected and their relative contribution to the national case load; 2) the type of TB cases detected; 3) their treatment outcomes. RESULTS: The total number of TB cases detected per year nationally increased from 133,547 in 2007 to 142,587 in 2014. The contribution of private practitioners increased from 11% in 2007 to 18% in 2014, and from 1.8% to 4.6% for public hospitals. The NTP contribution decreased from 87% in 2007 to 77% in 2014. A similar pattern was seen in the number of new smear (+) TB cases (31% of all TB cases) and retreatment cases, which represented 7.8% of all TB cases. For new smear (+) TB cases, adverse outcomes were more common in public hospitals, with more patients dying, lost to follow up or not having their treatment outcome evaluated. Patients treated by private practitioners were more frequently lost to follow up (8%). Adverse treatment outcomes in retreatment cases were particularly common (59%) in public hospitals for various reasons, predominantly due to patients dying (26%) or not being evaluated (10%). In private clinics, treatment failure tended to be more common (8%). CONCLUSIONS: The contribution of non-NTP actors to TB detection at the national level increased over time, with the largest contribution by private practitioners involved in PPM. Treatment outcomes were fair. Our findings confirm the role of PPM in national TB programs. To achieve the End TB targets, further expansion of PPM to engage all public and private medical facilities should be targeted. PMID- 28859678 TI - Does the applied polytrauma definition notably influence outcome and patient population? - a retrospective analysis. AB - BACKGROUND: Although the term "polytrauma" has been in use for decades, no generally accepted definition exists. The aim of this study was to demonstrate that different polytrauma definitions applied to a specific patient population result in diverse subgroups of individuals, who in turn present a varying outcome. METHODS: All patients (>=18 years) treated at our level I trauma center within a time period of three years were classified according to 11 selected polytrauma definitions and included in our study, if they were rated "polytraumatized" by at least one of these definitions. All patients, who met the criteria of a certain definition, were combined to the relevant definition positive group, thus resulting in 11 patient subgroups. Their demographic data (number of patients, mean patient age, mean Injury Severity Score value, median number of ventilator days, median length of stay at the intensive care unit and at the hospital, mortality rate and odds ratio) were statistically compared. RESULTS: Three hundred seventy-five patients (73% male) with a mean age of 47 years met the inclusion criteria and were allocated to the relevant subgroups; their patient number varied from 55 to 346 and their mean Injury Severity Score value ranged from 4 to 75. Not surprisingly, all examined parameters were subject to variations. Whereas most definition-positive groups showed a mortality rate of about 21% to 30%, 18% of the individuals, who met the criteria according to Blacker, and 40% of the polytrauma victims according to Schalamon died. The Pape 1-, Schalamon-, and Berlin-positive groups presented a significant odds ratio with regard to mortality that considerably exceeded 1. DISCUSSION: A polytrauma definition can only be a reliable tool in classifying trauma victims if it provides a significant odds ratio with regard to mortality that considerably exceeds 1 and if it succeeds in capturing patients with multiple severe injuries and a higher mortality rate without reducing the number of polytraumatized patients to a not representatively small number. CONCLUSIONS: Solely the Berlin definition resulted in a patient number reflecting clinical reality, thus enabling a transparent evaluation of treatment results provided by different institutions and allowing objective comparison of published studies. PMID- 28859679 TI - Social ecological correlates of workplace sedentary behavior. AB - BACKGROUND: To identify social ecological correlates of objectively measured workplace sedentary behavior. METHODS: Participants from 24 worksites - across academic, industrial, and government sectors - wore an activPAL-micro accelerometer for 7-days (Jan-Nov 2016). Work time was segmented using daily logs. Sedentary behavior outcomes included time spent sitting, standing, in light intensity physical activity (LPA, stepping cadence <100 steps/min), and in prolonged sitting bouts (>30 min). Outcomes were standardized to an 8 h work day. Two electronic surveys were completed to derive individual (job type and work engagement), cultural (lunch away from the desk, walking at lunch and face-to face interaction), physical (personal printer and office type) and organizational (sector) factors. Mixed-model analyses with worksite-level clustering were performed to examine multi-level associations. Secondary analyses examined job type and sector as moderators of these associations. All models were adjusted for age, race/ethnicity and gender. RESULTS: Participants (N = 478; 72% female; age: 45.0 +/- 11.3 years; 77.8% non-Hispanic white) wore the activPAL-micro for 90.2 +/- 15.5% of the reported workday. Walking at lunch was positively associated with LPA (5.0 +/- 0.5 min/8 h, P < 0.001). Regular face-to-face interaction was negatively associated with prolonged sitting (-11.3 +/- 4.8 min/8 h, P < 0.05). Individuals in private offices sat more (20.1 +/- 9.1 min/8 h, P < 0.05), stood less (-21.5 +/- 8.8 min/8 h, P < 0.05), and engaged in more prolonged sitting (40.9 +/- 11.2 min/8 h, P < 0.001) than those in public office space. These associations were further modified by job type and sector. CONCLUSIONS: Work specific individual, cultural, physical and organizational factors are associated with workplace sedentary behavior. Associations vary by job type and sector and should be considered in the design of workplace interventions to reduce sedentary behavior. TRIAL REGISTRATION: Clinical trial No. NCT02566317 ; Registered Sept 22nd 2015. PMID- 28859680 TI - Prevalence of human pegivirus-1 and sequence variability of its E2 glycoprotein estimated from screening donors of fetal stem cell-containing material. AB - BACKGROUND: Human pegivirus-1 (HPgV-1) is a member of the Flaviviridae family whose genomic organization and mode of cellular entry is similar to that of hepatitis C virus (HCV). The E2 glycoprotein of HPgV-1 is the principle mediator in the virus-cell interaction and as such harbors most of HPgV-1's antigenic determinants. HPgV-1 persists in blood cell precursors which are increasingly used for cell therapy. METHODS: We studied HPgV-1 prevalence in a large cohort of females donating fetal tissues for clinical use. PCR was used for screening and estimation of viral load in viremic plasma and fetal samples. Sequence analysis was performed for portions of the 5'-untranslated and E2 regions of HPgV-1 purified from donor plasmas. Sequencing was followed by phylogenetic analysis. RESULTS: HPgV-1 was revealed in 13.7% of plasmas, 5.0% of fetal tissues, 5.4% of chorions, exceeding the prevalence of HCV in these types of samples. Transmission of HPgV-1 occurred in 25.8% of traceable mother-chorion-fetal tissues triads. For HPgV-1-positive donors, a high viral load in plasma appears to be a prerequisite for transmission. However, about one third of fetal samples acquired infection from non-viremic individuals. Sequencing of 5'-untranslated region placed most HPgV-1 samples to genotype 2a. At the same time, a portion of E2 sequence provided a much weaker support for this grouping apparently due to a higher variability. Polymorphisms were detected in important structural and antigenic motifs of E2. CONCLUSION: HPgV-1 is efficiently transmitted to fetus at early embryonic stages. A high variability in E2 may pose a risk of generation of pathogenic subtypes. Although HPgV-1 is considered benign and no longer tested mandatorily in blood banks, the virus may have adversary effects at target niches if delivered with infected graft upon cell transplantation. This argues for the necessity of HPgV-1 testing of cell samples aimed for clinical use. PMID- 28859681 TI - Factors affecting affect cardiovascular health in Indonesian HIV patients beginning ART. AB - BACKGROUND: We present a small longitudinal study of how demographic factors and persistent burdens of HIV and cytomegalovirus (CMV) influence cardiovascular health in young adults beginning ART in an inner-city clinic in Jakarta, Indonesia. METHODS: ART-naive HIV patients [n = 67; aged 31 (19 to 48) years] were enrolled in the JakCCANDO Project. Echocardiography and carotid Doppler ultrasonography were performed before ART (V0) and after 3, 6, and 12 months (V3 12). Antibodies reactive with CMV lysate or IE-1 protein were assessed at each timepoint and CMV DNA was identified at V0. RESULTS: Markers of adverse cardiovascular prognosis [left ventricular mass index, ejection fraction and carotid intimal media thickness (cIMT)] were similar to healthy controls, but increased at V12. Internal diameters of the carotid arteries and systolic blood pressure correlated with HIV disease severity at V0, but cardiac parameters and cIMT did not. E/A ratios (left ventricular diastolic function) were lower in patients with CMV DNA at V0, but this effect waned by V6. Levels of antibody reactive with CMV IE-1 correlated inversely with CD4 T cell counts at V0, and levels at V6-V12 correlated directly with the right cIMT. CONCLUSIONS: Overall the severity of HIV disease and the response to ART have only subtle effects on cardiovascular health in this young Asian population. CMV replication before ART may have a transient effect on cardiac health, whilst antibody reactive with CMV IE-1 may mark a high persistent CMV burden with cumulative effects on the carotid artery. PMID- 28859682 TI - Early detection of neuropathy in leprosy: a comparison of five tests for field settings. AB - BACKGROUND: Early detection and treatment of neuropathy in leprosy is important to prevent disabilities. A recent study showed that the Nerve Conduction Studies (NCS) and Warm Detection Thresholds (WDT) tests can detect leprosy neuropathy the earliest. These two tests are not practical under field conditions, however, because they require climate-controlled rooms and highly trained staff and are expensive. We assessed the usefulness of alternative test methods and their sensitivity and specificity to detect neuropathy at an early stage. METHODS: Through a literature search we identified five alternative devices that appeared user-friendly, more affordable, portable and/or battery-operated: the Neuropad(r), VibratipTM, NC-Stat(r)DPNCheckTM, NeuroQuick and the Thermal Sensibility Tester (TST), assessing respectively sweat function, vibration sensation, nerve conduction, cold sensation and warm sensation. In leprosy patients in Bangladesh, the posterior tibial and sural nerves that tested normal for the monofilament test and voluntary muscle test were assessed with the NCS and WDT as reference standard tests. The alternative devices were then tested on 94 nerves with abnormal WDT and/or NCS results and on 94 unaffected nerves. Sensitivity and specificity were the main outcomes. RESULTS: The NeuroQuick and the TST showed very good sensitivity and specificity. On the sural nerve, the NeuroQuick had both a sensitivity and a specificity of 86%. The TST had a sensitivity of 83% and a specificity of 82%. Both the NC-Stat(r)DPNCheckTM and VibratipTM had a high specificity (88% and 100%), but a low sensitivity (16% and 0%). On the posterior tibial nerve, the NeuroQuick and the TST also showed good sensitivity, but the sensitivity was lower than for the sural nerve. The Neuropad(r) had a sensitivity of 56% and a specificity of 61%. CONCLUSIONS: The NeuroQuick and TST are good candidates for further field-testing for reliability and reproducibility. The feasibility of production on a larger scale should be examined. PMID- 28859683 TI - Psychosocial and career outcomes of peer mentorship in medical resident education: a systematic review protocol. AB - BACKGROUND: Many medical residents lack ready access to social and emotional supports that enable them to successfully cope with the challenges associated with medical residency. This absence of support has been shown to lead to high levels of burnout, decreased mental wellbeing, and difficulty mastering professional competencies in this population. While there is emerging evidence that peer mentoring can be an important source of psychosocial and career-related support for many individuals, the extent of the evidence regarding the benefits of peer mentorship in medical residency education has not yet been established. We describe a protocol for a systematic review to assess the effects of peer mentoring on medical residents' mental wellbeing, social connectedness, and professional competencies. METHODS: Studies included in this review will be those that report on peer-mentoring relationships among medical residents. Quantitative, qualitative, and mixed-methods studies will be eligible for inclusion. No date or language limits will be applied. We will search EMBASE, MEDLINE, PsychINFO, Web of Science, Scopus, ERIC, Education Research Complete, and Academic Research Complete databases to identify relevant studies. Two authors will independently assess all abstracts and full-text studies for inclusion and study quality and extract study data in duplicate. DISCUSSION: This is the first systematic review to explicitly explore the role of peer mentoring in the context of medical residency education. We anticipate that the findings from this review will raise awareness of the benefits and challenges associated with peer-mentoring relationships, further the development and implementation of formal peer-mentoring programs for medical residents, and, through identifying gaps in the existing literature, inform future research efforts. SYSTEMATIC REVIEW REGISTRATION: This protocol has not been registered in PROSPERO or any other publicly accessible registry. PMID- 28859684 TI - Sex differences in thermal detection and thermal pain threshold and the thermal grill illusion: a psychophysical study in young volunteers. AB - BACKGROUND: Sex-related differences in human thermal and pain sensitivity are the subject of controversial discussion. The goal of this study in a large number of subjects was to investigate sex differences in thermal and thermal pain perception and the thermal grill illusion (TGI) as a phenomenon reflecting crosstalk between the thermoreceptive and nociceptive systems. The thermal grill illusion is a sensation of strong, but not necessarily painful, heat often preceded by transient cold upon skin contact with spatially interlaced innocuous warm and cool stimuli. METHODS: The TGI was studied in a group of 78 female and 58 male undergraduate students and was evoked by placing the palm of the right hand on the thermal grill (20/40 degrees C interleaved stimulus). Sex-related thermal perception was investigated by a retrospective analysis of thermal detection and thermal pain threshold data that had been measured in student laboratory courses over 5 years (776 female and 476 male undergraduate students) using the method of quantitative sensory testing (QST). To analyse correlations between thermal pain sensitivity and the TGI, thermal pain threshold and the TGI were determined in a group of 20 female and 20 male undergraduate students. RESULTS: The TGI was more pronounced in females than males. Females were more sensitive with respect to thermal detection and thermal pain thresholds. Independent of sex, thermal detection thresholds were dependent on the baseline temperature with a specific progression of an optimum curve for cold detection threshold versus baseline temperature. The distribution of cold pain thresholds was multi-modal and sex-dependent. The more pronounced TGI in females correlated with higher cold sensitivity and cold pain sensitivity in females than in males. CONCLUSIONS: Our finding that thermal detection threshold not only differs between the sexes but is also dependent on the baseline temperature reveals a complex processing of "cold" and "warm" inputs in thermal perception. The results of the TGI experiment support the assumption that sex differences in cold-related thermoreception are responsible for sex differences in the TGI. PMID- 28859685 TI - An umbrella review of the literature on the effectiveness of psychological interventions for pain reduction. AB - BACKGROUND: Psychological interventions are widely implemented for pain management and treatment, but their reported effectiveness shows considerable variation and there is elevated likelihood for bias. METHODS: We summarized the strength of evidence and extent of potential biases in the published literature of psychological interventions for pain treatment using a range of criteria, including the statistical significance of the random effects summary estimate and of the largest study of each meta-analysis, number of participants, 95% prediction intervals, between-study heterogeneity, small-study effects and excess significance bias. RESULTS: Thirty-eight publications were identified, investigating 150 associations between several psychological interventions and 29 different types of pain. Of the 141 associations based on only randomized controlled trials, none presented strong or highly suggestive evidence by satisfying all the aforementioned criteria. The effect of psychological interventions on reducing cancer pain severity, pain in patients with arthritis, osteoarthritis, rheumatoid arthritis, breast cancer, fibromyalgia, irritable bowel syndrome, self-reported needle-related pain in children/adolescents or with chronic musculoskeletal pain, chronic non-headache pain and chronic pain in general were supported by suggestive evidence. CONCLUSIONS: The present findings reveal the lack of strong supporting empirical evidence for the effectiveness of psychological treatments for pain management and highlight the need to further evaluate the established approach of psychological interventions to ameliorate pain. PMID- 28859686 TI - The genetic variation of Angiostrongylus cantonensis in the People's Republic of China. AB - BACKGROUND: The People's Republic of China (P.R. China) is the presumptive home range of the rat lungworm Angiostrongylus cantonensis, a major aetiological agent of human eosinophilic meningitis. We present a study of the genetic variation of A. cantonensis in P.R. China. Our aim was to deepen the current knowledge pertaining to its origin and global spread from a molecular perspective. METHODS: Adult A. cantonensis were collected in the frame of a national survey and identified based on morphological criteria. Polymerase chain reaction (PCR) was employed to amplify the target DNA sequences (cytochrome c oxidase subunit I (cox1), nicotinamide adenine dinucleotide dehydrogenase subunit 1 (nad1) and internal transcribed spacer (ITS)). The PCR product of cox1 was directly submitted to sequencing, while clone sequencing was used for nad1 and ITS. The identity of the samples was verified by comparing the sequences to those of accepted A. cantonensis specimens. The specific composition of substitutions in each gene was analysed, and the genotypes were compared based on the complete cox1, nad1 and ITS genes. RESULTS: We characterised the complete mitochondrial genes cox1 and nad1 of 130 specimens and obtained 357 nuclear sequences containing two complete ITS (ITS1 and ITS2) and 5.8S rRNA of the same samples. All specimens were genetically confirmed as A. cantonensis. Two major groups (i.e. I and II) were identified according to the phylogeny of cox1 sequences. Group I could be further categorised into six distinct clades. Almost half of the specimens (47.7%) belong to the clade Ia and 22.3% to the group II. The former was widely distributed across the study region. A variable number of repeat units in three microsatellites was observed, resulting in considerable length variation in ITS. Intragenomic variation of ITS sequences was found in a large proportion of the samples. Genotyping showed a striking difference between mitochondrial DNA and ITS. CONCLUSIONS: Our results demonstrate that A. cantonensis is the only rat lungworm species in P.R. China and shows high genetic diversity. Results of diversity and genotyping of A. cantonensis can be impacted by the sequencing strategy and biomarker. Although ITS may be a valuable marker for interspecific identification, it is not suitable for studying the intraspecific variation of A. cantonensis due to its high intragenomic variation and current challenges for direct sequencing. PMID- 28859687 TI - Healthcare professionals' views of the enhanced recovery after surgery programme: a qualitative investigation. AB - BACKGROUND: The Enhanced Recovery After Surgery (ERAS) programme is an approach to the perioperative care of patients which aims to improve outcomes and speed up recovery after surgery. Although the evidence base appears strong for this programme, the implementation of ERAS has been slow. This study aimed to gain an understanding of the facilitating factors and challenges of implementing the programme with a view to providing additional contextual information to aid implementation. The study had a particular focus on the nutritional elements as these have been highlighted as important. METHODS: The study employed qualitative research methods, guided by the Normalisation Process Theory (NPT) to explore the experiences and opinions of 26 healthcare professionals from a range of disciplines implementing the programme. RESULTS: This study identified facilitating factors to the implementation of ERAS: alignment with evidence based practice, standardising practice, drawing on the evidence base of other specialties, leadership, teamwork, ERAS meetings, patient involvement and education, a pre-operative assessment unit, staff education, resources attached to obtaining The Commissioning for Quality and Innovation (CQUIN) money, the ward layout, data collection and feedback, and adapting the care pathway. A number of implementation challenges were also identified: resistance to change, standardisation affecting personalised patient care, the buy-in of relevant stakeholders, keeping ERAS visible, information provision to patients, resources, palatability of nutritional drinks, aligning different ward cultures, patients going to non-ERAS departments, spreading the programme within the hospital, differences in health issue, and utilising a segmental approach. CONCLUSIONS: The findings presented here provide useful contextual information from diverse surgical specialties to inform healthcare providers when implementing ERAS in practice. Addressing the challenges and utilising the facilitating factors identified in this study, could speed up the rate at which ERAS is adopted, implemented and embedded. PMID- 28859688 TI - A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes. AB - BACKGROUND: Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease. METHODS: Gene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs). RESULTS: We identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the "atypical" molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor. CONCLUSIONS: Our study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease. PMID- 28859689 TI - Remote sensing measurements of sea surface temperature as an indicator of Vibrio parahaemolyticus in oyster meat and human illnesses. AB - BACKGROUND: Vibrio parahaemolyticus (Vp) is a naturally occurring bacterium found in marine environments worldwide. It can cause gastrointestinal illness in humans, primarily through raw oyster consumption. Water temperatures, and potentially other environmental factors, play an important role in the growth and proliferation of Vp in the environment. Quantifying the relationships between environmental variables and indicators or incidence of Vp illness is valuable for public health surveillance to inform and enable suitable preventative measures. This study aimed to assess the relationship between environmental parameters and Vp in British Columbia (BC), Canada. METHODS: The study used Vp counts in oyster meat from 2002-2015 and laboratory confirmed Vp illnesses from 2011-2015 for the province of BC. The data were matched to environmental parameters from publicly available sources, including remote sensing measurements of nighttime sea surface temperature (SST) obtained from satellite readings at a spatial resolution of 1 km. Using three separate models, this paper assessed the relationship between (1) daily SST and Vp counts in oyster meat, (2) weekly mean Vp counts in oysters and weekly Vp illnesses, and (3) weekly mean SST and weekly Vp illnesses. The effects of salinity and chlorophyll a were also evaluated. Linear regression was used to quantify the relationship between SST and Vp, and piecewise regression was used to identify SST thresholds of concern. RESULTS: A total of 2327 oyster samples and 293 laboratory confirmed illnesses were included. In model 1, both SST and salinity were significant predictors of log(Vp) counts in oyster meat. In model 2, the mean log(Vp) count in oyster meat was a significant predictor of Vp illnesses. In model 3, weekly mean SST was a significant predictor of weekly Vp illnesses. The piecewise regression models identified a SST threshold of approximately 14oC for both model 1 and 3, indicating increased risk of Vp in oyster meat and Vp illnesses at higher temperatures. CONCLUSION: Monitoring of SST, particularly through readily accessible remote sensing data, could serve as a warning signal for Vp and help inform the introduction and cessation of preventative or control measures. PMID- 28859690 TI - Targeted anti-staphylococcal therapy with endolysins in atopic dermatitis and the effect on steroid use, disease severity and the microbiome: study protocol for a randomized controlled trial (MAAS trial). AB - BACKGROUND: Atopic dermatitis (AD) is associated with reduced skin microbial diversity and overgrowth of Staphylococcus (S.) aureus. However, the importance of S. aureus colonisation in the complex pathogenesis remains unclear and studies on the effect of anti-staphylococcal therapy in non-infected AD show contradictory results. Long-term interventions against S. aureus might be needed to restore the microbial balance, but carry the risk of bacterial resistance induction. Staphefekt, an engineered bacteriophage endolysin, specifically kills S. aureus leaving other skin commensals unharmed. Bacterial resistance towards endolysins has not been reported, nor is it expected, which allows us to study its effect as long-term anti-staphylococcal treatment in non-infected AD. METHODS: This is a multi-centre, placebo-controlled, double-blinded and randomized superiority trial with a parallel group design. A total of 100 participants, aged 18 years or older, diagnosed with moderate to severe AD and using a topical corticosteroid in the weeks before enrolment are included in the study. The study is executed in the Erasmus MC University Medical Centre Rotterdam in collaboration with the Havenziekenhuis Rotterdam. After a 2-week run in period to standardize the corticosteroid use with triamcinolone acetonide 0.1% cream, participants will be randomized to either treatment with Staphefekt in a cetomacrogol-based cream or a placebo for 12 weeks, followed by an 8-week follow up period. The primary objective is to assess the difference in the need for corticosteroid co-therapy between the Staphefekt and the placebo group, measuring the number of days per week of corticosteroid cream (triamcinolone) use. Secondary outcomes include the difference in use of corticosteroid cream measured in grams, differences in clinical efficacy, quality of life (QoL), microbial composition (includi23ng S. aureus) between the Staphefekt and the placebo group, and the safety and tolerability. DISCUSSION: The results of this trial will provide data about the effect of long-term anti-staphylococcal therapy with Staphefekt on corticosteroid use, clinical symptoms and QoL in patients with moderate to severe AD. Additional data about growth characteristics of the skin microbiome, including S. aureus, will give insight into the role of the microbiome as a factor in the pathophysiology of AD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02840955 . Registered on 11 July 2016. PMID- 28859691 TI - Effect of oregano essential oil and benzoic acid supplementation to a low-protein diet on meat quality, fatty acid composition, and lipid stability of longissimus thoracis muscle in pigs. AB - BACKGROUND: Consumers are becoming increasingly interested in food containing appropriately high concentration of intramuscular fat (IMF) and polyunsaturated fatty acids (PUFA). The supplementation of feed with antioxidants decreases degradation of lipids in muscles thereby enhances nutritional and sensory properties of meat. Two experiments were conducted to determine the effects of adding oregano essential oil (OEO) and benzoic acid (BA) to low-protein, amino acid-supplemented diets on meat quality, sensory profile, fatty acid composition, and lipid oxidation of longissimus thoracis (LT) muscle in pigs. METHODS: In Exp. 1, 21 barrows were housed in metabolism cages and randomly allotted to 1 of 3 diets. The three diets were normal protein diet (NPD), medium protein diet (MPD) and low protein diet (LPD) with 1% and 2% less than NPD, respectively. In Exp. 2, 36 barrows were randomly divided into three experimental groups, namely, NPD, LPD, and identical LPD supplemented with blends of OEO (250 mg/kg feed) and BA (1000 mg/kg feed) (LPOB) groups. RESULTS: No significant effects of diets on meat quality were observed in Exp. 1. The b*45min, tenderness, and IMF content in LPD muscle were higher than those in NPD and LPOB muscle. The LT muscle in LPD group contained a higher percentage of oleic acid (C18:1n-9) and a lower percentage of linoleic acid (C18:2n-6) than those in NPD group. Dietary LPOB improved oxidative stability, total superoxide dismutase, and glutathione peroxidase but decreased drip loss in LT muscle. CONCLUSIONS: These findings suggest that growing finishing pigs fed with a low-protein, amino acid-supplemented diet show a high content of intramuscular fat in the longissimus thoracis muscle. Dietary LPOB enhances the anti-oxidative status by improving antioxidative capacity but deteriorates the sensory attributes by decreasing IMF content of meat. PMID- 28859692 TI - Fourteen simple-sequence repeats newly developed for population genetic studies in Prosopis africana (Fabaceae-Mimosoideae). AB - BACKGROUND: There is very limited genetic knowledge in Prosopis africana, an important sub-Saharan multi-purpose tree species. Availability of highly polymorphic genetic markers would be helpful for future genetic work. FINDINGS: Leaf samples from 15 trees were used to develop simple sequence repeat (SSR) markers. Size-selected fragments from genomic DNA were enriched for repeats and the library was analyzed on an Illumina MiSeq platform. Fourteen SSRs were selected and applied in two Burkinabe populations (40 adult trees each). The number of alleles varied from 4 to 20, evenness (effective number of alleles/observed number of alleles) averaged to 0.54 and unbiased heterozygosity ranged from 0.305 to 0.925 over all loci and populations. Null alleles were not detected. CONCLUSIONS: Due to the high level of polymorphism and lack of null alleles the developed SSRs can be effectively employed in population genetic studies. PMID- 28859693 TI - Comprehensive analysis for genetic diagnosis of Dystrophinopathies in Japan. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common disease in children caused by mutations in the DMD gene, and DMD and Becker muscular dystrophy (BMD) are collectively called dystrophinopathies. Dystrophinopathies show a complex mutation spectrum. The importance of mutation databases, with clinical phenotypes and protein studies of patients, is increasingly recognized as a reference for genetic diagnosis and for the development of gene therapy. METHODS: We used the data from the Japanese Registry of Muscular Dystrophy (Remudy) compiled during from July 2009 to March 2017, and reviewed 1497 patients with dystrophinopathies. RESULTS: The spectrum of identified mutations contained exon deletions (61%), exon duplications (13%), nonsense mutations (13%), small deletions (5%), small insertions (3%), splice-site mutations (4%), and missense mutations (1%). Exon deletions were found most frequently in the central hot spot region between exons 45-52 (42%), and most duplications were detected in the proximal hot spot region between exons 3-25 (47%). In the 371 patients harboring a small mutation, 194 mutations were reported and 187 mutations were unreported. CONCLUSIONS: We report the largest dystrophinopathies mutation dataset in Japan from a national patient registry, "Remudy". This dataset provides a useful reference to support the genetic diagnosis and treatment of dystrophinopathy. PMID- 28859694 TI - Usefulness of interferon-gamma release assay for the diagnosis of sputum smear negative pulmonary and extra-pulmonary TB in Zhejiang Province, China. AB - BACKGROUND: Quick diagnosis of smear-negative pulmonary tuberculosis (TB) and extra-pulmonary TB are urgently needed in clinical diagnosis. Our research aims to investigate the usefulness of the interferon-gamma release assay (IGRA) for the diagnosis of smear-negative pulmonary and extra-pulmonary TB. METHODS: We performed TB antibody and TB-IGRA tests on 389 pulmonary TB patients (including 120 smear-positive pulmonary TB patients and 269 smear-negative pulmonary TB patients), 113 extra-pulmonary TB patients, 81 patients with other pulmonary diseases and 100 healthy controls. Blood samples for the TB-Ab test and the TB IGRA were collected, processed, and interpreted according to the manufacturer's protocol. RESULTS: The detection ratio of smear-positive pulmonary TB patients and smear-negative pulmonary TB patients were 90.8% (109 of 120) and 89.6% (241 of 269), respectively. There was no statistically significant difference of its performance between these two sample sets (P > 0.05). The detection ratio of positive TB patients and extra-pulmonary TB patients were 90.0% (350 of 389) and 87.6% (99 of 113), respectively, which was not significantly different (P > 0.05). CONCLUSIONS: In this work, the total detection ratio using TB-IGRA was 89.4%, therefore TB-IGRA has diagnostic values in smear-negative pulmonary TB and extra-pulmonary TB diagnosis. PMID- 28859695 TI - Learning Microbial Community Structures with Supervised and Unsupervised Non negative Matrix Factorization. AB - BACKGROUND: Learning the structure of microbial communities is critical in understanding the different community structures and functions of microbes in distinct individuals. We view microbial communities as consisting of many subcommunities which are formed by certain groups of microbes functionally dependent on each other. The focus of this paper is on methods for extracting the subcommunities from the data, in particular Non-Negative Matrix Factorization (NMF). Our methods can be applied to both OTU data and functional metagenomic data. We apply the existing unsupervised NMF method and also develop a new supervised NMF method for extracting interpretable information from classification problems. RESULTS: The relevance of the subcommunities identified by NMF is demonstrated by their excellent performance for classification. Through three data examples, we demonstrate how to interpret the features identified by NMF to draw meaningful biological conclusions and discover hitherto unidentified patterns in the data. Comparing whole metagenomes of various mammals, (Muegge et al., Science 332:970-974, 2011), the biosynthesis of macrolides pathway is found in hindgut-fermenting herbivores, but not carnivores. This is consistent with results in veterinary science that macrolides should not be given to non-ruminant herbivores. For time series microbiome data from various body sites (Caporaso et al., Genome Biol 12:50, 2011), a shift in the microbial communities is identified for one individual. The shift occurs at around the same time in the tongue and gut microbiomes, indicating that the shift is a genuine biological trait, rather than an artefact of the method. For whole metagenome data from IBD patients and healthy controls (Qin et al., Nature 464:59-65, 2010), we identify differences in a number of pathways (some known, others new). CONCLUSIONS: NMF is a powerful tool for identifying the key features of microbial communities. These identified features can not only be used to perform difficult classification problems with a high degree of accuracy, they are also very interpretable and can lead to important biological insights into the structure of the communities. In addition, NMF is a dimension-reduction method (similar to PCA) in that it reduces the extremely complex microbial data into a low-dimensional representation, allowing a number of analyses to be performed more easily-for example, searching for temporal patterns in the microbiome. When we are interested in the differences between the structures of two groups of communities, supervised NMF provides a better way to do this, while retaining all the advantages of NMF-e.g. interpretability and a simple biological intuition. PMID- 28859696 TI - A systematic review of evidence for fitness-to-drive among people with the mental health conditions of schizophrenia, stress/anxiety disorder, depression, personality disorder and obsessive compulsive disorder. AB - BACKGROUND: Limited evidence exists regarding fitness-to-drive for people with the mental health conditions of schizophrenia, stress/anxiety disorder, depression, personality disorder and obsessive compulsive disorder (herein simply referred to as 'mental health conditions'). The aim of this paper was to systematically search and classify all published studies regarding driving for this population, and then critically appraise papers addressing assessment of fitness-to-drive where the focus was not on the impact of medication on driving. METHODS: A systematic search of three databases (CINAHL, PSYCHINFO, EMBASE) was completed from inception to May 2016 to identify all articles on driving and mental health conditions. Papers meeting the eligibility criteria of including data relating to assessment of fitness-to-drive were critically appraised using the American Academy of Neurology and Centre for Evidence-Based Medicine protocols. RESULTS: A total of 58 articles met the inclusion criteria of driving among people with mental health conditions studied, and of these, 16 contained data and an explicit focus on assessment of fitness-to-drive. Assessment of fitness-to-drive was reported in three ways: 1) factors impacting on the ability to drive safely among people with mental health conditions, 2) capability and perception of health professionals assessing fitness-to-drive of people with mental health conditions, and 3) crash rates. The level of evidence of the published studies was low due to the absence of controls, and the inability to pool data from different diagnostic groups. Evidence supporting fitness-to-drive is conflicting. CONCLUSIONS: There is a relatively small literature in the area of driving with mental health conditions, and the overall quality of studies examining fitness-to-drive is low. Large-scale longitudinal studies with age matched controls are urgently needed in order to determine the effects of different conditions on fitness-to-drive. PMID- 28859697 TI - O'Connor et al. systematic review regarding animal feeding operations and public health: critical flaws may compromise conclusions. AB - In this comment, we summarize several scientific concerns with the recently published systematic review from O'Connor and colleagues that examined the relationship between proximity to animal-feeding operations and health of individuals in nearby communities. The authors utilized a bias tool not designed for environmental health research, erroneously excluded important studies, and incorrectly interpreted others. As a result, the conclusions drawn in the review misrepresent the evidence from the published literature, limiting its value to policymakers, researchers, and the public. PMID- 28859698 TI - Validated HPLC-DAD Method for the Simultaneous Determination of Six Selected Drugs Used in the Treatment of Glaucoma. AB - This work presents a simple, sensitive, and generic HPLC-diode-array detection method for the simultaneous determination of six drugs prescribed for the treatment of open-angle glaucoma and ocular hypertension. The investigated drugs include brimonidine tartarate (BMN), acetazolamide (AZA), brinzomaide (BZA), dorzolamide HCl (DZA), levobunolol HCl (LVB), and timolol maleate (TIM). Efficient chromatographic separation was achieved using a Thermo Hypersil BDS C18 column (4.6 * 250 mm, 5 um) with a mobile phase consisting of phosphate buffer pH 5 and acetonitrile in a ratio of 78 + 22. The flow rate was 1 mL/min, and quantification was based on measuring peak areas at 298 nm for TIM and 254 nm for the other drugs. Peaks were perfectly resolved, with retention times at 3.06, 3.87, 4.53, 5.78, 7.31, and 10.78 min for BMN, AZA, DZA, TIM, LVB, and BZA respectively. The developed method was validated according to International Conference on Harmonization guidelines with respect to system suitability, linearity, ranges, accuracy, precision, robustness, and LODs and LOQs. The proposed method showed good linearity in the ranges of 2-80, 2.5-100, 2.5-100, 5 200, 3.75-150, and 1.75-70 ug/mL for BMN, AZA, DZA, TIM, LVB, and BZA, respectively. LODs were 0.20-1.01 MUg/mL for the analyzed compounds. Applicability of the proposed method to real-life situations was assessed through the analysis of five different pharmaceutical formulations, and satisfactory results were obtained. PMID- 28859699 TI - Method Modification for the Atlas Listeria Environmental LE Detection Assay Using FoodChek Actero Listeria Enrichment Media and Half-Fraser Media for the Detection of Listeria spp. from Environmental Surfaces. AB - Two candidate method modifications for the Atlas Listeria Environmental LE Detection Assay were compared with the U.S. Department of Agriculture (USDA)-Food Safety and Inspection Service Microbiology Laboratory Guidebook 8.09 (MLG 8.09) method for detection of Listeria spp. on stainless steel, polyvinyl chloride (PVC), and sealed concrete surfaces. For LE candidate method 1, samples were enriched in FoodChek Actero Listeria Enrichment Media [ALEM; Performance Tested MethodSM (PTM) 111201] at 35 +/- 2 degrees C for 18 to 24 h and evaluated for a range of analytical sample volumes. For LE candidate method 2, the current Roka PTM using 90 mL of Half-Fraser broth for enrichment at 35 +/- 2 degrees C was evaluated at 24 h with a reduced sample volume. These comparisons were made in multiple studies across the three environmental surfaces. Within each method and study, a total of 5 samples were uninoculated, 20 samples were inoculated with Listeria spp. at a low level to target fractional positivity, and 5 samples were inoculated with Listeria spp. at a high level to approach a probability of detection of 1. Inclusivity and exclusivity studies were also conducted for the LE method in combination with Half-Fraser and ALEM. The Atlas Listeria Environmental LE Detection Assay detected all 50 inclusive organisms, including 25 strains of L. monocytogenes and 5 strains of each of the other five common species of Listeria (L. innocua, L. welshimeri, L. ivanovii, L. seeligeri, and L. grayi) and none of the 30 exclusive organisms across all media and with both 200 and 2000 uL sample volumes. For the LE candidate method 1 studies, no significant differences were observed within the Roka ALEM method at 18, 20, or 24 h and for both the 200 and 2000 uL sample volumes as compared with the paired culture outcome. However, the ALEM method performed significantly better as compared with the unpaired reference method for sealed concrete and stainless steel. For the LE candidate method 2 studies, no significant differences were observed within the Roka HF method at 24 h for the 200 and 2000 uL samples as compared with the paired culture outcomes and unpaired reference method outcomes across the surfaces. The independent laboratory studies observed no significant differences in performance between the USDA/MLG 8.09 reference method and candidate methods 1 or 2, respectively, across the evaluated parameters. Overall, the candidate method 1 modification parameters and candidate method 2 sample parameters for the Atlas Listeria Environmental LE Detection Assay were statistically equivalent to or better than the reference method for detection of Listeria spp. on stainless steel, PVC, and sealed concrete surfaces, providing greater flexibility in method application for end users. PMID- 28859701 TI - RNA sequencing and pathway analysis identify tumor necrosis factor alpha driven small proline-rich protein dysregulation in chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder in which many pathways contribute to end-organ disease. Small proline-rich proteins (SPRR) are polypeptides that have recently been shown to contribute to epithelial biomechanical properties relevant in T-helper type 2 inflammation. There is evidence that genetic polymorphism in SPRR genes may predict the development of asthma in children with atopy and, correlatively, that expression of SPRRs is increased under allergic conditions, which leads to epithelial barrier dysfunction in atopic disease. METHODS: RNAs from uncinate tissue specimens from patients with CRS and control subjects were compared by RNA sequencing by using Ingenuity Pathway Analysis (n = 4 each), and quantitative polymerase chain reaction (PCR) (n = 15). A separate cohort of archived sinus tissue was examined by immunohistochemistry (n = 19). RESULTS: A statistically significant increase of SPRR expression in CRS sinus tissue was identified that was not a result of atopic presence. SPRR1 and SPRR2A expressions were markedly increased in patients with CRS (p < 0.01) on RNA sequencing, with confirmation by using real-time PCR. Immunohistochemistry of archived surgical samples demonstrated staining of SPRR proteins within squamous epithelium of both groups. Pathway analysis indicated tumor necrosis factor (TNF) alpha as a master regulator of the SPRR gene products. CONCLUSION: Expression of SPRR1 and of SPRR2A is increased in mucosal samples from patients with CRS and appeared as a downstream result of TNF alpha modulation, which possibly resulted in epithelial barrier dysfunction. PMID- 28859702 TI - Promotion of olfactory receptor neuron differentiation of olfactory neuroepithelial cells by using chitosan solution. AB - BACKGROUND: Olfactory dysfunction significantly influences patients' quality of life. Chitosan has been reported to support neuron and Schwann cell growth and even leads to orient axonal growth. However, researchers have yet to explore whether chitosan solution can promote differentiation of olfactory receptor neurons of the olfactory neuroepithelium and be used for treating olfactory dysfunction. OBJECTIVE: To evaluate the effect of chitosan solution on the differentiation of olfactory neuroepithelial cells. METHOD: Olfactory neuroepithelial cells were isolated from embryonic day 17 of Wistar rats and then cultured with and without soluble chitosan for 9 days. The concentration of chitosan solution was set at 0.1 mg/mL. The effects of treatment were assessed by immunocytochemistry and Western blot after culturing. RESULTS: The morphologic analysis indicated that olfactory neuroepithelial cells treated with chitosan exhibited bipolar shape with asymmetric processes. In addition, from days 3 to 9, the expression level of betaIII tubulin gradually reduced, but the expression level of olfactory marker protein significantly rose at day 9 in the chitosan groups (p < 0.05). Importantly, chitosan-treated olfactory neuroepithelial cells expressed more signal transduction apparatuses, olfactory neuron specific-G protein and adenylate cyclase 3, than those without chitosan treatment at day 9. Western blot analysis also further confirmed the results (p < 0.05). CONCLUSION: Experimental results revealed that soluble chitosan promoted differentiation of olfactory neuroepithelial cells based on its role in olfactory receptor neuron differentiation, neurite outgrowth, and signal transduction apparatus expressions. PMID- 28859704 TI - An update on the epidemiology of aspirin-exacerbated respiratory disease. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a disorder of nasal polyposis, asthma, and hypersensitivity respiratory reactions when on systemic cyclooxygenase 1 blockade. METHODS: AERD warrants specific evaluation as an endotype of asthma and chronic sinus disease due to unique therapeutic opportunities. Currently, aspirin therapy is uniquely beneficial as an anti inflammatory therapy in AERD, with multiple additional therapies currently in early to late clinical studies, which might also show exceptional benefit in AERD. RESULTS: Yet, given the lack of a simple diagnostic test, opportunities to identify patients with AERD are still frequently neglected. CONCLUSION: Identifying the prevalence and population characteristics necessary to determine appropriate candidates in whom to perform diagnostic aspirin challenge remains critically important and was the purpose of this article. PMID- 28859703 TI - Sinus bacteriology in patients with cystic fibrosis or primary ciliary dyskinesia: A systematic review. AB - BACKGROUND: A correlation exists between the microbial flora of the upper and lower airways in patients with cystic fibrosis (CF) or with primary ciliary dyskinesia (PCD). The sinuses can function as a bacterial reservoir where gram negative bacteria adapt to the airways and repeatedly are aspirated to and colonize the lungs according to the theory of the united (unified) airways. Whereas the pattern of bacterial flora in the lower airways has been extensively studied, the upper airways have drawn limited attention. OBJECTIVE: Our aim was to review the literature that reported bacterial flora in the sinuses and nasal cavities of patients with CF or PCD. METHODS: A number of medical literature data bases were systematically searched between January 1960 and July 2016. We applied the following inclusion criteria: a minimum of one case of PCD (or Kartagener syndrome) or CF, and microbiology analyses from the nose or paranasal sinuses. RESULTS: We included 46 studies (1823 patients) from 16 countries. Staphylococcus aureus was found in 30% of the noses and sinuses of patients with CF. Other common bacteria found included Pseudomonas aeruginosa, coagulase negative staphylococci, and Haemophilus influenzae. In PCD, H. influenzae was the most common bacteria (28%), followed by Streptococcus pneumoniae and P. aeruginosa. If studies that included nonsurgical swab and blowing samples were excluded, then P. aeruginosa was the most common bacterium in patients with CF (34%) and in patients with PCD (50%), followed by S. aureus and H. influenza. CONCLUSION: S. aureus, P. aeruginosa, coagulase negative staphylococci, and H. influenzae dominated in the upper airways of patients with CF. In patients with PCD, H. influenzae, S. pneumoniae, and P. aeruginosa dominated. When studies that included swab and blowing samples were excluded, P. aeruginosa was the most common bacterium in both groups. Direct comparisons among the studies were restricted due to very heterogeneous methods, and a better standardization of procedures and outcomes is needed. PMID- 28859705 TI - Immunoglobulin G4 sinusitis in association with aspirin-exacerbated respiratory disease. AB - BACKGROUND: Immunoglobulin G4 (IgG4) related disease is a systemic inflammatory disease characterized by tumor-like tissue infiltration with IgG4 positive (IgG4+) plasma cells. Aspirin-exacerbated respiratory disease (AERD) is defined as asthma, chronic rhinosinusitis with nasal polyposis, and hypersensitivity to cyclooxygenase-1 inhibitors. OBJECTIVE: We described a case of a non-smoking 61 year-old male with prior NSAID sensitivity who presented with a 1-year history of left eye proptosis associated with chronic nasal symptoms, ultimately identified as concurrent AERD and IgG4 sinusitis. METHODS: The patient was evaluated in the clinic and diagnosed by using clinical, radiographic, and surgical biopsy findings. RESULTS: Although initial concern was greatest for malignancy, a biopsy specimen confirmed the presence of a dense lymphoplasmacytic infiltrate and storiform fibrosis, associated with increased IgG4+ plasma cells. Therefore, IgG4 related disease (RD) was identified in this patient with AERD. CONCLUSION: Shared type II inflammation may be responsible for the coexistence of IgG4-RD and AERD as observed in our patient. Health care workers must be cognizant of the simultaneous presentation of both IgG4-RD and AERD. PMID- 28859706 TI - Outcomes of sinonasal squamous cell carcinoma with and without association of inverted papilloma: A multi-institutional analysis. AB - INTRODUCTION: Sinonasal squamous cell carcinoma (SCC) accounts for <1% of all malignancies but represents 70% of sinonasal cancer. Up to 10% of SCCs are associated with inverted papilloma (IPSCC). Studies that compare patients, treatment, and outcomes of SCC and IPSCC are absent in the literature. METHODS: A retrospective review of patients with SCC and those with IPSCC at Cleveland Clinic and Indiana University from 1995 to 2015. The records were analyzed for demographics, tumor characteristics, treatment, and outcomes. RESULTS: The study comprised 117 patients with SCC, of whom, 29 had IPSCC. The mean age at diagnosis was similar: 63 and 64 years for patients with SCC and patients with IPSCC, respectively; with female patients representing 36% and 34%, respectively (p > 0.99).Smokers represented 64% of the patients with SCC and 55% of patients with IPSCC (p = 0.3); excessive alcohol intake was noted in 16% of the patients with SCC and 21% of the patients with IPSCC (p = 0.56).The maxillary sinus was most commonly involved, followed by the nasal cavity (51% versus 35% SCC, 45% versus 38% IPSCC). Frontal ethmoid and sphenoid sinuses contained primary tumors only in patients with SCC. Upfront treatment was surgery in 84% of patients with SCC and 97% of patients with IPSCC (p = 0.18); 68 and 55% received radiation, respectively, and 25 and 21% received chemotherapy, respectively.Overall survival averaged 5.5 and 3.4 years for patients with SCC and patients with IPSCC, respectively (p = 0.12); disease-free survival was 4.8 and 2.9 years, respectively (p = 0.18). Nodal metastasis was more likely in patients with SCC (18 versus 0%; p = 0.02). When divided into high- and low-stage disease: more common nodal metastases were demonstrated in high-stage SCC than in low-stage disease (p = 0.03). Overall survival was decreased between high- and low-grade disease but not when subdivided between SCC and IPSCC. CONCLUSION: Although SCC with and without IP association are considered different diseases, their demographics and outcomes seem similar. Nodal metastasis was noted to be higher in the SCC cohort, which may indicate different tumor biology. Further study is warranted. PMID- 28859707 TI - Quality-of-life outcomes in patients who underwent subcutaneous immunotherapy and sublingual immunotherapy in a real-world clinical setting. AB - OBJECTIVE: To compare changes in quality of life (QOL) that resulted from sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) in a real world clinical setting. BACKGROUND: SLIT is established as a viable alternative to SCIT for the treatment of allergic rhinitis. Although comparative trials are increasingly available, few studies have examined QOL outcomes between these two treatments. METHODS: One hundred and five participants who underwent immunotherapy for airborne allergies were enrolled in this prospective, single center study. Forty participants completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at initiation of therapy, after 6 months, and after 1 year of therapy. Only patients with complete time points were included in the ultimate analysis. Twenty-nine of these participants underwent SCIT and 11 underwent SLIT. The effects of age, sex, and asthma history were also examined. RESULTS: The participants in both groups demonstrated improvements in QOL regarding allergic rhinoconjunctivitis over the study period. However, the change in the RQLQ score from both baseline to 6 months and baseline to 1 year was only statistically significant in the SCIT group (p = 0.002, 6 months and 1 year). The participants in the SCIT group also demonstrated statistically significant improvement from baseline to 1 year in the specific domains of practical and emotional functioning, nasal symptoms, non-nasal/eye symptoms, and sleep. After 1 year, both SCIT and SLIT demonstrated a minimally important difference from baseline in the overall RQLQ score. Age <35 years in the SCIT group had a significant positive impact on QOL improvement (p = 0.038). CONCLUSION: Although improvements in QOL were noted in both groups, changes in overall scores and the majority of domains only achieved statistical significance in the SCIT group. A small study population and difficulties adhering to immunotherapy dosing schedules in the SLIT group may be contributing factors. PMID- 28859708 TI - The effect of olfactory training on the odor threshold in patients with traumatic anosmia. AB - BACKGROUND: Olfactory training is a novel intervention that has been used to treat olfactory dysfunction. This study attempted to investigate the effect of olfactory training in patients with traumatic anosmia. METHODS: Patients with a clear history of anosmia after experiencing a head injury and whose phenyl ethyl alcohol (PEA) odor detection thresholds were -1 after steroid and zinc treatment were included. The patients were randomly divided into two groups, with patients in one group given a bottle of PEA and those in another group given a bottle of mineral oil for 3-month olfactory training. All the patients were followed up with a PEA threshold test and the traditional Chinese version of the University of Pennsylvania Smell Identification Test (UPSIT-TC). Magnetic resonance imaging was performed to measure the volume of the olfactory bulbs. Any patient whose PEA threshold result was below -1.01 or whose UPSIT-TC score increased four or more points was considered to have shown improvement in their olfactory function. RESULTS: Forty-two patients received PEA olfactory training, whereas 39 received olfactory training with mineral oil. The improvement of PEA thresholds function was observed in 10 patients within the PEA group and in 2 patients in the mineral oil group. The frequency of improvement of threshold within the PEA group was significantly higher than that of the mineral oil group. Neither olfactory bulb volume nor UPSIT-TC score was significantly different between the two groups. CONCLUSION: Our results showed that olfactory training with PEA can improve PEA odor threshold levels in patients with traumatic anosmia. PMID- 28859709 TI - Erratum. PMID- 28859710 TI - The effect of closed septorhinoplasty on nasal functions and on external and internal nasal valves: A prospective study. AB - BACKGROUND: Because nasal function and shape are so closely intertwined, quantitative assessments can better define their relationship and how they are affected by septorhinoplasty. OBJECTIVE: The aim of this prospective study was to perform an analysis of the nasal airflow resistances and a three-dimensional (3D) evaluation of the soft-tissue changes after closed septorhinoplasty. METHODS: Before surgery (T0) and 6 months after closed septorhinoplasty (T1), 30 patients underwent symptoms evaluation by means of the Italian version of the Nasal Obstruction Symptom Evaluation scale, endoscopic fiberoptic nasal examination, and visual analog scale for subjective assessment of nasal obstruction. Nasal airflow resistances were investigated with active anterior active rhinomanometry. A 3D laser scanner was used to evaluate facial soft-tissues, with specific nasal points and angles. RESULTS: Subjective nasal obstruction decreased. Anterior active rhinomanometry demonstrated a reduction in total inspiratory and expiratory resistances between T0 and T1 but without statistical significance. The significance was still absent after decongestion, excluding turbinate hypertrophy as a cause of failed objective amelioration of nasal resistance. Facial laser scanning showed statistically significant reduction of the superior nasal width and superior alar angle, and a weak negative correlation between the superior alar angle and nasal resistances. CONCLUSION: The absence of objective reduction of nasal airflow resistances could be the result of concurrent surgery on nasal septum and nasal valve. In particular, the ameliorating effect on nasal airflow resistances is counterbalanced by the worsening effect of the narrowing of nasal valve. PMID- 28859711 TI - Primary endoscopic endonasal dacryocystorhinostomy for pediatric nasolacrimal duct obstruction: A systematic review. AB - BACKGROUND: Epiphora secondary to nasolacrimal duct obstruction is common in the pediatric age group. The mainstay treatment among these young patients has been conservative. Once epiphora becomes recalcitrant, however, an external or an endonasal approach is considered. OBJECTIVE: Endoscopic dacryocystorhinostomy (EDCR) entails creating an opening from the lacrimal sac directly into the nasal cavity to counteract nasolacrimal duct obstruction. We reviewed the literature to determine the effectiveness and the safety of primary EDCR to treat pediatric nasolacrimal duct obstruction. METHOD: A literature search was conducted by using a number of medical literature data bases for the period from 1995 to 2016. The following search words were used either individually or in combination: epiphora, nasolacrimal duct obstruction, endoscopic dacryocystorhinostomy, powered endoscopic dacryocystorhinostomy, laser-assisted endoscopic dacryocystorhinostomy, children, congenital, acquired, presaccal obstruction, and postsaccal obstruction. In addition, a few articles were identified based on the experience and information provided by the senior authors (B.A., S.H., D.Y.W.). The search was conducted over a 1-month period (January 2017). Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews of Interventions were followed when possible. RESULTS: Only 10 original clinical research articles were selected based on our objectives and selection criteria. All the studies were at level of evidence III: nonrandomized and noncomparative prospective or retrospective case series. Altogether, 313 patients with ages that ranged from 4 months to 18 years were enrolled. A total of 352 EDCRs were performed that were either single sided (n = 313) or bilateral (n = 39). The most common causes of the obstruction were classified as congenital, followed by idiopathic, and then acquired. A meta analysis was not performed because of the heterogeneity of the patient groups and variability of the methods used to measure outcomes. CONCLUSION: Analysis of the results indicated that EDCR was an effective, safe therapeutic approach to treating nasolacrimal duct obstruction in pediatric patients. It should be considered as an alternative procedure to external dacryocystorhinostomy after a failed conservative treatment. PMID- 28859712 TI - Long-term olfactory outcome after nasoseptal flap reconstructions in midline skull base surgery. AB - BACKGROUND: The nasoseptal flap (NSF) is a universally used surgical technique to cover defects of the skull base after extended sinonasal surgery. Long-term follow-up of complications, sequelae, and smell function is largely unknown. OBJECTIVE: The main objective of this study was to investigate monorhinal olfaction after transsphenoidal skull base surgery. METHODS: Patients who underwent skull base surgery for midline lesions (craniopharyngioma and pituitary tumors) by using a NSF, also referred to as the Haddad flap, were assessed for their long-term outcome. Endoscopic examination was conducted and the bilateral "Sniffin' Sticks" test was performed before surgery. Each side was tested separately in the postoperative follow-up consultation. RESULTS: Twenty patients were included in the study. No flap failures were observed. One anterior perforation and one small posterior septal perforation were found during long term follow-up. None of the patients had nasal breathing impairment, whereas two patients had nose bleeds. A significant decrease in olfactory function was observed on the flap donor side in four patients (20%) compared with that observed in one patient (5%) on the opposite side. CONCLUSION: NSF reconstructions for midline lesions were efficient and safe in the long term. Olfactory impairment on the donor side was frequently encountered. Although subclinical, these findings justified a monorhinal smell testing before surgery, which possibly prevented bilateral smell impairment in patient with preexisting single-sided olfactory loss. PMID- 28859714 TI - Utility of intraoperative frozen sections in surgical decision making for acute invasive fungal rhinosinusitis. PMID- 28859713 TI - Draf III frontal sinus surgery: "How I do it". AB - BACKGROUND: The Draf III approach to the frontal sinus can be used during revision endoscopic sinus surgery for chronic rhinosinusitis and to provide access for tumor resection, mucoceles, and repair of cerebrospinal fluid leaks. OBJECTIVE: To describe a simple and safe way to perform a Draf III approach by using the "outside-in" approach. METHODS: By using a 0 degrees endoscope and a single 15 degrees , 5-mm, coarse diamond burr, the main steps of the procedure are the following: (1) elevation of the mucosal flaps and creation of the septal window, (2) drilling out the frontal beak, (3) creation of neo-ostium and removal of the interfrontal septum, (4) joining the neo-ostium with the frontal recesses, (5) smoothing off the cavity and lowering of the "frontal T," and (6) use of mucosal flaps and grafts to cover exposed bone. CONCLUSION: This approach is a quick and easy way to perform a Draf III, and reduces operative time and minimizes complications. PMID- 28859715 TI - Insomnia in Pregnancy Is Associated With Depressive Symptoms and Eating at Night. AB - STUDY OBJECTIVES: Deterioration in sleep quality seems to be a natural consequence of physical changes during pregnancy. It is still unclear if insomnia in pregnancy is associated with the same factors as chronic insomnia in the general population. The aim of this study was to explore the determinants of insomnia during pregnancy. METHODS: The study included 266 women (mean age: 30.6 +/- 5 years, weeks of pregnancy: 36 [interquartile range 32-38]) recruited at the Department of Gynecology and Obstetrics, Medical University of Warsaw. The assessment of variables was performed using the Athens Insomnia Scale (AIS), Beck Depression Inventory (BDI), Regestein Hyperarousal Scale (HS), Epworth Sleepiness Scale (ESS), General Practice Physical Activity Questionnaire, and a semi structured interview about different sleep disorders. RESULTS: Almost 40% of the women in our study received a diagnosis of insomnia based on AIS cutoff scores. The between-group analyses indicated that HS score, BDI score, eating at night, legs tingling, nightmares, snoring, and myoclonus differentiated the groups of individuals with insomnia from those without insomnia. Other variables were not significantly different between the groups. We divided individuals with insomnia in terms of insomnia duration: 49% developed insomnia at least 1 year before the study onset and 39.6% during pregnancy. For further analyses we used only the women in whom insomnia developed during pregnancy. Logistic regression confirmed that depressive symptoms (BDI) and eating at night were significant predictors of insomnia in pregnancy. CONCLUSIONS: Depressive symptoms and night eating are key factors related to insomnia developed during pregnancy. PMID- 28859716 TI - Non-REM Sleep Instability in Children With Primary Monosymptomatic Sleep Enuresis. AB - STUDY OBJECTIVES: Sleep enuresis is one of the most common sleep disturbances in childhood. Parental perception of deeper sleep in children with sleep enuresis is not confirmed by objective studies. However, evidence of disturbed sleep has been demonstrated by questionnaire, actigraphy, and polysomnographic studies, but no neurophysiological correlation with low arousability has been found. The goal of this study was to analyze the sleep microstructure of children with sleep enuresis using cyclic alternating pattern (CAP) analysis. METHODS: Forty-nine children were recruited, 27 with enuresis (19 males and 8 females, mean age 9.78 years, 2.52 standard deviation) and 22 normal control patients (11 males and 11 females, mean age 10.7 years, 3.43 standard deviation); all subjects underwent clinical evaluation followed by a full-night polysomnographic recording. Psychiatric, neurological, respiratory, and renal diseases were excluded. RESULTS: No differences in sex, age, and apnea-hypopnea index were noted in the patients with enuresis and the control patients. Sleep stage architecture in children with sleep enuresis showed a decrease in percentage of stage N3 sleep. CAP analysis showed an increase in CAP rate in stage N3 sleep and in phase A1 index during stage N3 sleep in the sleep enuresis group, but also a significant reduction of A2% and A3% and of phases A2 and A3 indexes, supporting the concept of decreased arousability in patients with sleep enuresis. The decrease of phase A2 and A3 indexes in our patients might reflect the impaired arousal threshold of children with sleep enuresis. Sleep fragmentation might result in a compensatory increase of slow wave activity (indicated by the increase of CAP rate in stage N3 sleep) and may explain the higher arousal threshold (indicated by a decrease of phase A2 and A3 indexes) linked to an increased sleep pressure. CONCLUSIONS: The findings of this study indicate the presence of a significant disruption of sleep microstructure (CAP) in children with sleep enuresis, supporting the hypothesis of a higher arousal threshold. PMID- 28859717 TI - Omega-3 Index and Obstructive Sleep Apnea: A Cross-Sectional Study. AB - STUDY OBJECTIVES: Erythrocyte levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omega-3 Index) were previously found to be associated with obstructive sleep apnea (OSA) at very low levels (< 5.0%) in only one epidemiologic study. OSA has comorbidities, such as arterial hypertension, heart failure, or major depression, also associated with a low Omega-3 Index. These comorbidities can be improved by increasing intake of EPA and DHA, and thus the Omega-3 Index, preferably to its target range of 8% to 11%. Symptoms of OSA might improve by increasing the Omega-3 Index, but more research is needed. METHODS: In our sleep laboratory, 357 participants with OSA were recruited, and data from 315 participants were evaluated. Three categories of OSA (none/ mild, moderate, severe) were defined based on apnea-hypopnea index. Anthropometrics and lifestyle characteristics (smoking, alcohol, fish intake, omega-3 supplementation) were recorded. Erythrocyte fatty acid compositions were assessed with the HS-Omega-3 Index methodology. RESULTS: The mean Omega-3 Index in all 3 categories of OSA was 5.7%, and no association with OSA was found. There were more male participants with severe OSA (79.7%, P = .042) than females, and participants with severe OSA had a significantly higher body mass index (32.11 +/- 6.39 kg/m2, P = .009) than participants with mild or moderate OSA. Lifestyle characteristics were not significantly different. CONCLUSIONS: In contrast to our hypothesis, an Omega-3 Index of 5.7% was not associated with OSA severity. Previously, an Omega-3 Index < 5.0% was associated. Although our results suggest aiming for an Omega-3 Index > 5.7% in an intervention trial with EPA and DHA in OSA, comorbidities of OSA suggest a target range of 8% to 11%. PMID- 28859719 TI - Sleep-Related Rhythmic Movement Disorder and Obstructive Sleep Apnea in Five Adult Patients. AB - ABSTRACT: Sleep-related rhythmic movements (SRRMs) are typical in infancy and childhood, where they usually occur at the wake-to-sleep transition. However, they have rarely been observed in adults, where they can be idiopathic or associated with other sleep disorders including sleep apnea. We report a case series of 5 adults with sleep-related rhythmic movement disorder, 4 of whom had a previous history of SRRMs in childhood. SRRMs mostly occurred in consolidated sleep, in association with pathological respiratory events, predominantly longer ones, especially during stage R sleep, and recovered in 1 patient with continuous positive airway pressure therapy. We hypothesize that sleep apneas may act as a trigger of rhythmic motor events through a respiratory-related arousal mechanism in genetically predisposed subjects. PMID- 28859718 TI - Sleep Duration and Sleep Patterns in Chinese University Students: A Comprehensive Meta-Analysis. AB - STUDY OBJECTIVES: This meta-analysis aimed to determine duration and patterns of sleep in Chinese university students. METHODS: English (PubMed, PsycINFO, Embase) and Chinese (SinoMed, Wan Fang Database, and Chinese National Knowledge Infrastructure) databases were systematically and independently searched from their inception until August 16, 2016. Data on sleep duration and sleep patterns of tertiary student population in eligible studies were extracted and pooled using random-effects models. RESULTS: A total of 57 studies with 82,055 university students were included in the meta-analysis. Pooled mean sleep duration was 7.08 h/d (95% confidence interval [CI]: 6.84 to 7.32 h/d). The percentage of students with sleep duration shorter than 6 h/d and 7 h/d (short sleep) was 8.4% (95% CI: 5.7% to 12.3%) and 43.9% (95% CI: 36.9% to 51.1%), respectively. In contrast, the percentage of students with sleep duration longer than 8 hours and 9 hours (long sleep) was 18.3% and 5.7%, respectively. The pooled mean bedtime was at 12:51 am. The percentage of university students who fall asleep after midnight was 23.8%. The percentage of students with sleep latency more than 30 minutes was 25.5%. The pooled mean wake-up time was at 8:04 am on weekdays and on weekends. CONCLUSIONS: Short sleep duration and unhealthy sleep patterns were found to be common among Chinese university students. PMID- 28859720 TI - Sleep Overnight Monitoring for Apnea in Patients Hospitalized with Heart Failure (SOMA-HF Study). AB - INTRODUCTION: Sleep-disordered breathing (SDB) is highly prevalent in hospitalized patients with congestive heart failure (CHF) and the condition is diagnosed and treated in only a minority of these patients. Portable monitoring (PM) is a screening option, but due to costs and the expertise required, many hospitals may find it impractical to implement. We sought to test the utility of an alternative approach for screening hospitalized CHF patients for SDB, high resolution pulse oximetry (HRPO). METHODS: We conducted a prospective controlled trial of 125 consecutive patients admitted to the hospital with CHF. Simultaneous PM and HRPO for a single night was performed. All but one patient were monitored on breathing room air. The HRPO-derived ODI (oxygen desaturation index) was compared with PM-derived respiratory event index (REI) using both receiver operator characteristic (ROC) curve analysis and a Bland-Altman plot. RESULTS: Of 105 consecutive CHF patients with analyzable data, 61 (58%) were males with mean age of 64.9 +/- 15.1 years and mean body mass index of 30.3 +/- 8.3 kg/m2. Of the 105 patients, 10 (9.5%) had predominantly central sleep apnea (central events > 50% of the total events), although central events were noted in 42 (40%) of the patients. The ROC analysis showed an area under the curve of 0.89 for REI > 5 events/h. The Bland-Altman plot showed acceptable agreement with 95% limits of agreement between -28.5 to 33.7 events/h and little bias. CONCLUSIONS: We conclude that high-resolution pulse oximetry is a simple and cost-effective screening tool for SDB in CHF patients admitted to the hospital. Such screening approaches may be valuable for large-scale implementation and for the optimal design of interventional trials. PMID- 28859721 TI - CPAP Treats Enuresis in Adults With Obstructive Sleep Apnea. AB - ABSTRACT: Enuresis, or "bedwetting," in children is associated with obstructive sleep apnea (OSA), and often resolves with treatment of OSA. However, it is poorly understood whether a similar relationship exists in adults. We describe a case series of 5 adult patients in whom OSA was diagnosed by laboratory polysomnography, who presented with enuresis that resolved after treatment with continuous positive airway pressure (CPAP). All cases occurred in the setting of obesity, in addition to other known risk factors for urinary incontinence and enuresis. OSA was diagnosed as severe in all but one case, which was mild. One patient noted recurrence of enuresis that coincided with malfunction of his CPAP machine. There is growing evidence that CPAP therapy may alleviate OSA and enuresis in adults with both conditions. Clinicians should routinely ask about enuresis in patients suspected of having OSA. A systematic study of the association between enuresis and OSA in adults is warranted. PMID- 28859722 TI - Validation of a New System Using Tracheal Body Sound and Movement Data for Automated Apnea-Hypopnea Index Estimation. AB - STUDY OBJECTIVES: The current gold standard for assessment of obstructive sleep apnea is the in-laboratory polysomnography. This approach has high costs and inconveniences the patient, whereas alternative ambulatory systems are limited by reduced diagnostic abilities (type 4 monitors, 1 or 2 channels) or extensive setup (type 3 monitors, at least 4 channels). The current study therefore aims to validate a simplified automated type 4 monitoring system using tracheal body sound and movement data. METHODS: Data from 60 subjects were recorded at the University Hospital Ulm. All subjects have been regular patients referred to the sleep center with suspicion of sleep-related breathing disorders. Four recordings were excluded because of faulty data. The study was of prospective design. Subjects underwent a full-night screening using diagnostic in-laboratory polysomnography and the new monitoring system concurrently. The apnea-hypopnea index (AHI) was scored blindly by a medical technician using in-laboratory polysomnography (AHIPSG). A unique algorithm was developed to estimate the apneahypopnea index (AHIest) using the new sleep monitor. RESULTS: AHIest strongly correlates with AHIPSG (r2 = .9871). A mean +/- 1.96 standard deviation difference between AHIest and AHIPSG of 1.2 +/- 5.14 was achieved. In terms of classifying subjects into groups of mild, moderate, and severe sleep apnea, the evaluated new sleep monitor shows a strong correlation with the results obtained by polysomnography (Cohen kappa > 0.81). These results outperform previously introduced similar approaches. CONCLUSIONS: The proposed sleep monitor accurately estimates AHI and diagnoses sleep apnea and its severity. This minimalistic approach may address the need for a simple yet reliable diagnosis of sleep apnea in an ambulatory setting. CLINICAL TRIAL REGISTRATION: Trial name: Validation of a new method for ambulant diagnosis of sleep related breathing disorders using body sound; URL: https://drks-neu.uniklinik freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011195; Identifier: DRKS00011195. PMID- 28859723 TI - Improving PTSD Symptoms and Preventing Progression of Subclinical PTSD to an Overt Disorder by Treating Comorbid OSA With CPAP. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) and posttraumatic stress disorder (PTSD) are common in United States veterans. These conditions often coexist and symptoms overlap. Previous studies reported improvement in PTSD symptoms with continuous positive airway pressure (CPAP) therapy for comorbid OSA but its effect has not been assessed in a non-PTSD cohort. We have prospectively assessed the effect of CPAP therapy on clinical symptom improvement as a function of CPAP compliance levels among PTSD and non-PTSD veterans. METHODS: Veterans in whom OSA was newly diagnosed were enrolled in our study (n = 192). Assignment to PTSD and non-PTSD cohorts was determined by chart review. Each patient completed the military version of the PTSD Checklist (PCL), Epworth Sleepiness Scale (ESS), and reported nightmare frequency (NMF) at baseline and 6 months after CPAP therapy. CPAP adherence was objectively documented from machine compliance data. RESULTS: We had complete data for 177 veterans (PTSD n = 59, non-PTSD n = 118) for analysis. The mean ages were 51.24 years in the PTSD cohort and 52.36 years in the non-PTSD cohort (P = .30). In the PTSD cohort, the mean total PCL score (baseline = 66.06, post-CPAP = 61.27, P = .004, d = -0.34) and NMF (baseline = 4.61, post-CPAP = 1.49, P = .0001, d = -0.51) decreased after 6 months of CPAP treatment. Linear regression analysis showed that the CPAP compliance was the only significant predictor for these changes among veterans with PTSD (PCL score: P = .033, R2 = .65; NMF; P = .03, R2 = .61). Further analysis by CPAP compliance quartiles in this cohort (Q1 = 0% to 25%, Q2 = 26% to 50%, Q3 = 51% to 75%, Q4 > 75%) revealed that mean total PCL score declined in Q2 (change = -3.91, P = .045, d = 0.43), Q3 (change = -6.6, P = .002, d = 0.59), and Q4 (change = -7.94, P = .037, d = 0.49). In the non-PTSD cohort, the PCL score increased despite CPAP therapy in lower CPAP compliance quartiles Q1 (change = 8.71, P = .0001, d = 0.46) and Q2 (change = 4.51, P = .046, d = 0.27). With higher CPAP compliance (in Q3 and Q4) in this cohort, the mean total PCL scores slightly improved with CPAP but they were not statistically significant (P > .05). CONCLUSIONS: CPAP treatment reduces total PCL score and NMF in veterans with PTSD and OSA. Those with overt PTSD respond to even lower CPAP compliance, whereas non-PTSD patients require higher compliance to achieve any symptom improvement. Poor CPAP compliance results in increased PCL score in non-PTSD veterans and may lead to overt PTSD if the OSA remains undertreated. COMMENTARY: A commentary on this article appears in this issue on page 1121. PMID- 28859724 TI - Meeting ACGME and ABMS Quality Improvement Requirements in a Sleep Medicine Fellowship Program. AB - STUDY OBJECTIVES: To describe a sustainable program of teaching and implementing quality improvement (QI) in a 12-month sleep medicine fellowship. METHODS: We created a QI curriculum based on Accreditation Council for Graduate Medical Education (ACGME) and American Board of Medical Specialty (ABMS) Part IV Maintenance of Certification (MOC) requirements for QI. Two program faculty with prior QI training volunteered to mentor fellows. Our institution's central QI office houses QI experts who teach QI across the health system. One of these experts, referred to as the "QI consultant," helped us adapt QI teaching materials to include 4 online modules and 5 group sessions. Fellows worked in teams to complete 2 data-guided QI cycles. RESULTS: The curriculum required 29 hours for fellows, 18 hours for faculty, and 55 hours for the QI consultant; now that teaching materials have been created, the QI consultant's involvement will decrease over time. Post-curriculum surveys showed that fellows' knowledge of QI concepts increased, as did their confidence performing QI activities. Fellows' QI projects objectively improved timeliness and quality of care for patients. Sleep medicine fellows and QI faculty mentors evaluated the curriculum positively. The curriculum met ACGME requirements for QI, and fellows and mentoring faculty received ABMS Part IV MOC credit upon completion of the curriculum. CONCLUSIONS: A QI curriculum can successfully be implemented into a 12-month sleep medicine fellowship to increase sleep medicine fellows' QI knowledge and confidence, meet ACGME and MOC requirements, and contribute to care of patients with sleep disorders. PMID- 28859725 TI - What Can Tweets Tell Us About a Person's Sleep? PMID- 28859726 TI - Retaining HIV-positive patients in HIV care: a personalised approach for those at risk of loss to follow-up at an inner city sexual health service. AB - In 2013 a personalised approach to follow-up of HIV patients who had withdrawn from HIV care was taken at RPA Sexual Health, a Sydney metropolitan sexual health service. HIV patients were telephoned, sent text messages, emailed and sent letters multiple times where applicable. With this intervention 20 of 23 people who had withdrawn from HIV care re-engaged. Since that time, active follow-up of all people diagnosed with HIV has resulted in only 2% of HIV patients at RPA Sexual Health being lost to follow-up. PMID- 28859727 TI - Private sex workers' engagement with sexual health services: an online survey. AB - This study examined where private sex workers (PSW) present for sexual health services, disclosure, services received, and their satisfaction with care. An online anonymous survey was conducted via SurveyMonkey (surveymonkey.com). Among the 53 participants, 42% attended a sexual health clinic, 24% attended a general practitioner (GP) and 34% attended both. Participants attending GPs were less likely to be offered a throat swab and opportunities for cervical screening, contraception and vaccination were often missed in both service models. Participants attending GPs were less likely to disclose sex work and were less satisfied. Better awareness of the sexual health needs of PSWs is important in GP services. PMID- 28859728 TI - Stigma associated with sexually transmissible infection testing in an online testing environment: examining the perspectives of youth in Vancouver, Canada. AB - : Background Online sexually transmissible infection (STI) testing is increasingly available and has shown promising results across different settings. However, evidence on how stigma associated with STI testing may be experienced by youth in the context of these online services is limited. METHODS: A convenience sample of 71 youth (aged 15-24 years) both male and female was engaged through online and offline recruitment strategies in Vancouver, Canada. Through semistructured and exploratory interviews, participants were asked about their perceptions of stigma associated with STI testing in an online testing environment. Data were analysed using a thematic analysis approach. RESULTS: Youth came from a diverse set of sociodemographic backgrounds and most (n=46, 65%) had previously accessed STI testing in clinic-based settings. Participants' perceptions pointed to the benefits of online testing for reducing the external stigma despite the potential persistence of internalised stigma. Notions of hegemonic masculinity and emphasised femininity were also present in the participants' descriptions of the role of gender in accessing online STI testing. CONCLUSIONS: Online STI testing could potentially ameliorate the experiences of participants in regards to the stigma associated with STI testing; however, participants' internalised feelings of shame and stigma around testing for STI may continue to persist. Our findings underscore the need to revisit and re evaluate existing STI testing services to provide less anxiety-inducing testing environments for youth. PMID- 28859729 TI - Factors influencing uptake of pre-exposure prophylaxis: some qualitative insights from an intervention study of men who have sex with men in China. AB - BACKGROUND: Pre-exposure prophylaxis (PrEP) is a biomedical approach for preventing the acquisition of HIV in populations at substantial risk for HIV. However, its uptake among men who have sex with men (MSM) is low in China. The study aimed to identify factors that might influence MSM's uptake and use of PrEP. METHODS: In-depth interviews were conducted with 32 self-identified MSM from a PrEP intervention study evaluating daily oral tenofovir disoproxil fumarate (TDF) to prevent HIV infection. Of these men, 11 were presently using the 'TDF' group; 8 from the 'change-over' group (i.e. initially used PrEP but subsequently quitted); and 13 from the non-user group. Data were analysed using thematic approach. RESULTS: Perception of low HIV risk, mistrust of the national PrEP program, and concerns of side effects were the main reasons for not wanting to use PrEP. Also, lack of main sexual partner's support, difficulties in adhering to the daily TDF regimen, and the inconvenient schedules in securing the medicine were the major reasons for not wanting to use or quitting the use of PrEP. On the other hand, perceived high HIV risk, beliefs in efficacy of PrEP, and worries of transmitting HIV to families were the major motives for PrEP uptake. CONCLUSIONS: Findings suggest that PrEP implementation strategies should first address issues including but not limited to accurate self-assessment of HIV risk, mistrust and limited knowledge about medical trials and PrEP, and ease of accessing PrEP. PMID- 28859731 TI - Acne Keloidalis Nuchae-Is the Barber Really to Blame? PMID- 28859730 TI - A multi-method study of health behaviours and perceived concerns of sexual minority females in Mumbai, India. AB - BACKGROUND: This multi-method study explores the perceived health status and health behaviours of sexual minority (i.e. self-identifying with a sexual identity label other than heterosexual) females (i.e. those assigned female at birth who may or may not identify as women) in Mumbai, India, a population whose health has been generally absent in scientific literature. METHODS: Using community-based participatory research approaches, this study is a partnership with The Humsafar Trust (HST). HST is India's oldest and largest LGBT-advocacy organisation. An online survey targeted towards sexual minority females was conducted (n=49), with questions about sexual identity, perceived health and wellbeing, physical and mental healthcare access and experiences, and health behaviours (including substance use). Additionally, photo-elicitation interviews in which participants' photos prompt interview discussion were conducted with 18 sexual minority females. RESULTS: Sexual minority females face obstacles in health care, mostly related to acceptability and quality of care. Their use of preventative health screenings is low. Perceived mental health and experiences with care were less positive than that for physical health. Participants in photo elicitation interviews described bodyweight issues and caretaking of family members in relation to physical health. Substance use functioned as both a protective and a risk factor for their health. CONCLUSION: Our findings point to a need for more resources for sexual minority females. Education on screening guidelines and screening access for sexual minority females would also assist these individuals in increasing their rates of preventative health. PMID- 28859732 TI - Emperipolesis, Proposed Mechanism for a Unique Intercellular Interaction: The Defective Phagocytosis Hypothesis. PMID- 28859733 TI - Hidradenitis Suppurativa and Concomitant Down Syndrome: Literature Review of Other Associated Mucocutaneous Manifestations in Adults. AB - This contribution describes hidradenitis suppurativa (HS) occurring in Down disease that presented with morphology conforming to an overlap of stages 1 and 2 of the Hurley staging system, namely the formation of solitary or multiple isolated abscesses without scarring or sinus tracts, recurrent abscesses, and single or multiple widely separated lesions with sinus tract formation, occupying apocrine sweat gland-bearing areas: the inner thighs, groin, and buttocks. The lesions were bilateral and symmetrical, of rare occurrence. In addition, the clinical and pathognomonic features of several other concomitant diseases are defined and reviewed; these include elastosis perforans serpiginosa, fissured tongue/macroglossia, syringomas, palmoplantar keratodermas, cheilitis, xerosis, atopic dermatitis, seborrheic dermatitis, vitiligo, cutis marmorata, and alopecia areata. PMID- 28859734 TI - Analysis of Sebaceous Neoplasms for DNA Mismatch Repair Proteins in Muir-Torre Syndrome. AB - Muir-Torre syndrome is a rare genodermatosis inherited most frequently in an autosomal dominant fashion. Current criteria for its diagnosis include at least one sebaceous tumor and an underlying visceral malignancy. Muir-Torre syndrome is strongly associated with a germline mutation in DNA mismatch repair genes. We report two patients with a history of colorectal carcinoma who presented with sebaceous neoplasms on the face and trunk. Immunohistochemical staining of the sebaceous neoplasms demonstrated absence of mismatch repair proteins MSH2 and MSH6. Genetic studies confirmed deletions in the MSH2 gene, and a diagnosis of Lynch syndrome was made. Immunohistochemical staining for mismatch repair genes MLH1, MSH2, MSH6 and PMS2 may aid in the diagnosis of Muir-Torre syndrome in cases where there is high suspicion. Genetic testing is an important final step in the confirmation of Muir-Torre syndrome. PMID- 28859735 TI - Molecular Variations in Histologic Subtypes of Basal Cell Carcinoma. AB - There are many molecular variations in the histologic subtypes of basal cell carcinoma (BCC); Ki67 and Bcl-2 expression differs among them and might relate to their prognostic features. The clinically notable friability and its histologic counterpart, retraction, are dependent on cell-cell adhesion and basement membrane characteristics, which may be altered in different ways depending on the tumor morphology and phenotype. Finally, we discuss the pathogenesis of BCCs and recent molecular advances with a review of new and upcoming molecular-based therapeutics. PMID- 28859737 TI - Techniques for Optimizing Surgical Scars, Part 1: Wound Healing and Depressed/Atrophic Scars. AB - Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three part review. In part 1, an overview of the importance of preoperative planning, intraoperative technique, and pathophysiology of wound healing is followed by a discussion of scar revision options for depressed/atrophic scars. Scar revision options for these scars include dermabrasion, needling and subcision, punch excision and grafts, fillers, nonablative fractional lasers, ablative and fractional ablative lasers, and platelet-rich plasma (PRP). This review examines the scar revision outcomes for each technique, discusses potential adverse effects, and highlights the importance of further studies to optimize postsurgical scar revision. PMID- 28859738 TI - Fading Signals: How Long Does Antigenicity in Immunohistochemical Staining Last? PMID- 28859739 TI - Brodalumab (Siliq(r)): A Treatment for Plaque Psoriasis. PMID- 28859740 TI - Telangiectasia Macularis Eruptiva Perstans Revisited. PMID- 28859741 TI - On Lanolin Allergy and the Approach to Its Diagnosis. PMID- 28859742 TI - Diffuse Papular Eruption of the Face and Eyelids. AB - A 68-year-old Caucasian woman presented with a 1-month history of a facial and neck eruption (Figure 1A). Her face was covered with 3-mm monomorphic, pink, shiny, papules and rare pustules on an erythematous background. The eruption extended down the neck, her conjunctivae were injected, and her lid margins were inflamed. She had no history of rosacea. PMID- 28859743 TI - Demodicosis Treatment with Systemic Ivermectin. AB - A 23-year-old white man presented to our dermatology department complaining of pruriginous and erythematous papulopustules on the right cheek that had developed 6 months previously. He had a history of chronic blepharitis, complicated by a recurrent hordeolum that had been treated with warm compresses and topical antibiotic ointment (chloramphenicol) for approximately 2 years. The patient had oily skin and atopy (allergic rhinitis) and did not experience photosensitivity or flushing or have previous exposure to immunosuppressants or topical/systemic corticosteroids. PMID- 28859744 TI - Neutrophilic Eccrine Hidradenitis in an HIV-Infected Patient. AB - A 35-year-old man presented with a 2-day history of a maculopapular pruritic eruption that had affected his general state of health and was accompanied by chills. The patient had been diagnosed with HIV in 2008, and was undergoing treatment with a combination of emcitrabine/tenofovir plus nevirapine. He had a current viral load of 1,558,160 copies/mL and a lymphocyte count CD4+ count of 230/mm3. Physical examination revealed an eruption involving the face, nape of the neck, chest, abdomen, extremities, palms, and soles. This was characterized by erythematous papules approximately 2 mm in diameter coalescing on the palms and soles, where they formed plaques (Figures 1 and 2). PMID- 28859745 TI - Cutaneous Rosai-Dorfman Disease. AB - A 48-year-old Hispanic man presented with a nodule on the right cheek. The lesion had started as a papule 4 months previously that had slowly enlarged and then plateaued at its present size. The nodule was asymptomatic, and the patient denied bleeding, draining, or preceding trauma. Review of systems was negative for fevers, weight loss, night sweats, lymphadenopathy, or other skin findings. Past medical history was significant only for type 2 diabetes mellitus, hyperlipidemia, and hypertension. PMID- 28859746 TI - Oxalosis in a Patient with Livedo Reticularis. AB - A 27-year-old man with terminal renal failure requiring peritoneal dialysis for the past 2 years was referred to the dermatologist for evaluation of red violaceous macular skin lesions consistent with livedo reticularis. These lesions had appeared suddenly on his legs (Figure 1). He had first experienced recurrent nephrolithiasis at the age of 14. Results from urine analysis and abdominal ultrasound revealed chronic kidney failure. Because the patient had a sister with similar findings, primary hyperoxaluria (PH) was suspected and genetic testing was performed in all members of his family. The results confirmed PH type 1 (PH1) in both our patient and his sister, who had died 8 years after the establishment of the diagnosis. A biopsy of the livedo reticularis lesions revealed deposits of a yellowish brown crystalline material within the lumen and the media of medium vessels in the hypodermis associated with a histiocytic giant cell reaction (Figure 2a). There was no evidence of extravascular calcium deposition in the sections examined. The deposits were intensely birefringent under polarized light, and classic speculated crystals of oxalate salts were observed (Figure 2b). No focal epidermal or superficial dermal necrosis was seen. On the basis of the histopathologic findings, the diagnosis of oxalate crystal-induced vascular disease was established. The patient subsequently developed complications including pancreatitis and peritonitis. He underwent hemodialysis until a combined liver-kidney transplant could be performed. PMID- 28859747 TI - Auricular Hemosiderosis in a Diabetic Patient. AB - A 74-year-old Caucasian man with poorly controlled diabetes and hypertension was seen in the dermatology clinic for treatment of a nodular basal cell carcinoma on his right temple. He had poorly controlled diabetes for decades and had been insulin dependent for 20 to 25 years. He had not been on any anticoagulation therapy in the past or present and had no history of a hematologic disorder. He was retired and did woodworking as a hobby. During a routine presurgical head and neck skin examination, he was noted to have macular bluegray dyspigmentation of the central portion of the anterior portion of his ear lobes, bilaterally (Figure 1). He had first noticed this color change approximately 2 years ago and thought the pigmentation was darkening. It was not symptomatic. A punch biopsy was obtained. PMID- 28859748 TI - Isotretinoin and Surgical Extraction for Adult-Onset Nevus Comedonicus. AB - We present a case of postmenopausal-onset nevus comedonicus in a 58-year-old white woman with no relevant medical history. Two years before presentation, the patient had had a solitary red nodule, measuring 3.8 cm wide, on the mid lateral region of her left thigh. This progressed to a large area, 11.4 cm wide and 14 cm long, of multiple pruritic and painful red nodules, cysts, and deep open comedones extending across the lateral part of the left thigh, with less severe segmental extension to the lateral aspect of the left leg. PMID- 28859749 TI - Transient Reactive Eruptive Lymphangiectasia Following Partial Vulvectomy for Chronic Acquired Lymphangioma. AB - A 64-year-old white woman was originally diagnosed with histiocytic lymphoma in 1977. She had bilateral lymph node biopsies of the groin, chemotherapy, and radiation therapy after her diagnosis had been confirmed pathologically. She was treated with prednisone and vincristine. PMID- 28859750 TI - Acquired Idiopathic True Transverse Leukonychia. AB - A 34-year-old man from Djibouti presented with a 14-year history of relapsing and remitting transverse white bands on the fingernails with sparing of the toenails. Examination revealed several transverse, white bands following the contour of the lunula on seven of his fingernails that did not fade upon compression of the digits (Figure). There was no onycholysis. No other skin lesions were noted. The patient reported having lived for 4 years (2000-2004) in a house that had well water as its primary water supply. This 4-year period was a stressful point in our patient's life. During that time, he had been a student at university. He had had no reported occupational exposure to arsenic. He reported being a cigarette smoker since 1996 but denied any illicit drug use or alcohol consumption. His past medical history was significant for hepatitis A infection, but he denied any history of systemic illness, including renal disease, heart disease, and lung disease. He denied any family history of leukonychia. He denied any trauma or participation in activities that require excessive use of his hands, and also denied manipulation of the cuticles. The patient's liver function tests, lipid panel, complete blood count, and urinalysis were all within normal limits. A blood test revealed normal arsenic levels. Histologic examination of the nail plate showed segmental parakeratosis, with no evidence of fungal organisms upon PAS staining. PMID- 28859751 TI - Tuberous Sclerosis Complex: Unusual Presentation in an Adult Patient. PMID- 28859752 TI - Anticoagulation in Patients with Pseudoxanthoma Elasticum. PMID- 28859753 TI - European Academy of Dermatology and Venereology (EADV) membership is worthwhile for Spanish dermatologists. PMID- 28859754 TI - Evolution of Functional Mitral Regurgitation and Prognosis in Medically Managed Heart Failure Patients With Reduced Ejection Fraction. AB - OBJECTIVES: The purpose of this study was to assess whether medical management may alter the severity of functional mitral regurgitation (FMR) and its prognosis in patients who have heart failure with reduced ejection fraction (HFrEF). BACKGROUND: FMR in patients who have HFrEF is associated with a worse prognosis. It is uncertain to what extent medical management may alter the severity of FMR and its prognosis. METHODS: The extent of FMR was assessed at baseline and after a median follow-up period of 50 months in 163 consecutive HFrEF patients (left ventricular ejection fraction <40%). Severe FMR was defined as mitral regurgitation (MR) grade 3-4. All of the patients received the maximal tolerable doses of their heart failure (HF) medications. Major adverse cardiac events were defined as a composite of all-cause death and the need for heart transplantation or hospitalization for HF and/or malignant arrhythmias. RESULTS: A total of 50 (31%) patients had severe MR at baseline. During the follow-up period, 38% of the severe FMR patients showed an improvement to nonsevere FMR (MR grade <3), whereas 18% of the nonsevere FMR patients developed severe FMR despite optimal HF treatment. Cox regression analysis revealed that the presence of sustained severe FMR or worsening of FMR was the most important independent prognostic determinant with an adjusted odds ratio of 2.5 (95% confidence interval: 1.5 to 4.3, major adverse cardiac events 83% vs. 43%). In addition, those patients showed a 13% increase in left ventricular end-diastolic volume index (LVEDVI), whereas the patients with improvement in their severe MR showed a 2% decrease in LVEDVI (p = 0.01). CONCLUSIONS: Severe FMR was successfully treated with medication in almost 40% and was associated with prevention of left ventricular adverse remodeling and with an improved long-term prognosis. PMID- 28859756 TI - No Fun at All. PMID- 28859755 TI - Guideline-Directed Medical Therapy for Secondary Mitral Regurgitation: More Questions Than Answers! PMID- 28859757 TI - America and Apple Pie: How Do We Change the American Health Care System? PMID- 28859758 TI - Adoption of Sacubitril/Valsartan Must Take Into Account Different Heart Failure Patient Types. PMID- 28859759 TI - Reply: Adoption of Sacubitril/Valsartan Must Take Into Account Different Heart Failure Patient Types. PMID- 28859760 TI - When clomiphene is no longer available.... PMID- 28859761 TI - Quand le clomiphene ne sera plus offert.... PMID- 28859762 TI - Excerpts from the World Medical Literature. PMID- 28859763 TI - Extraits de la litterature medicale mondiale. PMID- 28859764 TI - No. 347-Obstetric Management at Borderline Viability. AB - OBJECTIVE: The primary objective of this guideline was to develop consensus statements to guide clinical practice and recommendations for obstetric management of a pregnancy at borderline viability, currently defined as prior to 25+6 weeks. INTENDED USERS: Clinicians involved in the obstetric management of women whose fetus is at the borderline of viability. TARGET POPULATION: Women presenting for possible birth at borderline viability. EVIDENCE: This document presents a summary of the literature and a general consensus on the management of pregnancies at borderline viability, including maternal transfer and consultation, administration of antenatal corticosteroids and magnesium sulfate, fetal heart rate monitoring, and considerations in mode of delivery. Medline, EMBASE, and Cochrane databases were searched using the following keywords: extreme prematurity, borderline viability, preterm, pregnancy, antenatal corticosteroids, mode of delivery. The results were then studied, and relevant articles were reviewed. The references of the reviewed studies were also searched, as were documents citing pertinent studies. The evidence was then presented at a consensus meeting, and statements were developed. VALIDATION METHODS: The content and recommendations were developed by the consensus group from the fields of Maternal-Fetal Medicine, Neonatology, Perinatal Nursing, Patient Advocacy, and Ethics. The quality of evidence was rated using criteria described in the Grading of Recommendations Assessment, Development and Evaluation methodology framework (reference 1). The Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. METHODS: The quality of evidence was rated using the criteria described in the Grading of Recommendations, Assessment, Development, and Evaluation methodology framework. The interpretation of strong and weak recommendations is described later. The Summary of Findings is available upon request. BENEFITS, HARMS, AND COSTS: A multidisciplinary approach should be used in counselling women and families at borderline viability. The impact of obstetric interventions in the improvement of neonatal outcomes is suggested in the literature, and if active resuscitation is intended, then active obstetric interventions should be considered. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Obstetricians and Gynaecologists of Canada and the Women and Babies Program at Sunnybrook Health Sciences Centre. RECOMMENDATIONS: PMID- 28859765 TI - ? PMID- 28859766 TI - No. 348-Joint SOGC-CCMG Guideline: Update on Prenatal Screening for Fetal Aneuploidy, Fetal Anomalies, and Adverse Pregnancy Outcomes. AB - OBJECTIVE: To review the available prenatal screening options in light of the recent technical advances and to provide an update of previous guidelines in the field of prenatal screening. INTENDED USERS: Health care providers involved in prenatal screening, including general practitioners, obstetricians, midwives, maternal fetal medicine specialists, geneticists, and radiologists. TARGET POPULATION: All pregnant women receiving counselling and providing informed consent for prenatal screening. EVIDENCE: Published literature was retrieved through searches of Medline, PubMed, and the Cochrane Library in and prior to March 2016 using an appropriate controlled vocabulary (prenatal diagnosis, amniocentesis, chorionic villi sampling, non-invasive prenatal screening) and key words (prenatal screening, prenatal genetic counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English and published from January 1985 to May 2016. Searches were updated on a regular basis and incorporated in the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical speciality societies. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to determine whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. PMID- 28859767 TI - ? PMID- 28859768 TI - No. 233-Antibiotic Therapy in Preterm Premature Rupture of the Membranes. AB - OBJECTIVE: To review the evidence and provide recommendations on the use of antibiotics in preterm premature rupture of the membranes (PPROM). OUTCOMES: Outcomes evaluated include the effect of antibiotic treatment on maternal infection, chorioamnionitis, and neonatal morbidity and mortality. EVIDENCE: Published literature was retrieved through searches of Medline, EMBASE, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary and key words (PPROM, infection, and antibiotics). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and new material incorporated in the guideline to July 2008. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: Guideline implementation should assist the practitioner in developing an approach to the use of antibiotics in women with PPROM. Patients will benefit from appropriate management of this condition. VALIDATION: This guideline has been reviewed and approved by the Infectious Diseases Committee and the Maternal Fetal Medicine Committee of the SOGC, and approved by the Executive and Council of the SOGC. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS: PMID- 28859769 TI - ? PMID- 28859770 TI - No. 245-Alcohol Use and Pregnancy Consensus Clinical Guidelines. AB - OBJECTIVE: To establish national standards of care for the screening and recording of alcohol use and counselling on alcohol use of women of child-bearing age and pregnant women based on the most up-to-date evidence. EVIDENCE: Published literature was retrieved through searches of PubMed, CINAHL, and the Cochrane Library in May 2009 using appropriate controlled vocabulary (e.g., pregnancy complications, alcohol drinking, prenatal care) and key words (e.g., pregnancy, alcohol consumption, risk reduction). Results were restricted to literature published in the last five years with the following research designs: systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment (HTA) and HTA-related agencies, national and international medical specialty societies, clinical practice guideline collections, and clinical trial registries. Each article was screened for relevance and the full text acquired if determined to be relevant. The evidence obtained was reviewed and evaluated by the members of the Expert Workgroup established by the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. VALUES: The quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). SPONSOR: The Public Health Agency of Canada and the Society of Obstetricians and Gynaecologists of Canada. ENDORSEMENT: These consensus guidelines have been endorsed by the Association of Obstetricians and Gynecologists of Quebec; the Canadian Association of Midwives; the Canadian Association of Perinatal, Women's Health and Neonatal Nurses (CAPWHN); the College of Family Physicians of Canada; the Federation of Medical Women of Canada; the Society of Rural Physicians of Canada; and Motherisk. SUMMARY STATEMENTS: RECOMMENDATIONS. PMID- 28859771 TI - ? PMID- 28859772 TI - No. 247-Antibiotic Prophylaxis in Obstetric Procedures. AB - OBJECTIVE: To review the evidence and provide recommendations on antibiotic prophylaxis for obstetrical procedures. OUTCOMES: Outcomes evaluated include need and effectiveness of antibiotics to prevent infections in obstetrical procedures. EVIDENCE: Published literature was retrieved through searches of Medline and The Cochrane Library on the topic of antibiotic prophylaxis in obstetrical procedures. Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and articles published from January 1978 to June2009 were incorporated in the guideline. Current guidelines published by the American College of Obstetrics and Gynecology were also incorporated. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The evidence obtained was reviewed and evaluated by the Infectious Diseases Committee of the Society of Obstetricians and Gynaecologists of Canada under the leadership of the principal authors, and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: Implementation of this guideline should reduce the cost and harm resulting from the administration of antibiotics when they are not required and the harm resulting from failure to administer antibiotics when they would be beneficial. SUMMARY STATEMENTS: RECOMMENDATIONS. PMID- 28859773 TI - ? PMID- 28859774 TI - No. 248-Guidelines for the Evaluation and Treatment of Recurrent Urinary Incontinence Following Pelvic Floor Surgery. AB - OBJECTIVE: To provide general gynaecologists and urogynaecologists with clinical guidelines for the management of recurrent urinary incontinence after pelvic floor surgery. OPTIONS: Evaluation includes history and physical examination, multichannel urodynamics, and possibly cystourethroscopy. Management includes conservative, pharmacological, and surgical interventions. OUTCOMES: These guidelines provide a comprehensive approach to the complicated issue of recurrent incontinence that is based on the underlying pathophysiological mechanisms. EVIDENCE: Published opinions of experts, and evidence from clinical trials where available. VALUES: The quality of the evidence is rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table). RECOMMENDATIONS: PMID- 28859775 TI - ? PMID- 28859776 TI - No. 246-Pelvic Examinations by Medical Students. PMID- 28859777 TI - ? PMID- 28859778 TI - ? PMID- 28859779 TI - No. 262-Prenatal Screening for and Diagnosis of Aneuploidy in Twin Pregnancies. AB - OBJECTIVE: To provide a Canadian consensus document with recommendations on prenatal screening for and diagnosis of fetal aneuploidy (e.g., Down syndrome and trisomy 18) in twin pregnancies. OPTIONS: The process of prenatal screening and diagnosis in twin pregnancies is complex. This document reviews the options available to pregnant women and the challenges specific to screening and diagnosis in a twin pregnancy. OUTCOMES: Clinicians will be better informed about the accuracy of different screening options in twin pregnancies and about techniques of invasive prenatal diagnosis in twins. EVIDENCE: PubMed and Cochrane Database were searched for relevant English and French language articles published between 1985 and 2010, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis, twin gestation). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. Searches were updated on a regular basis and incorporated in the guideline to August 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: There is a need for specific guidelines for prenatal screening and diagnosis in twins. These guidelines should assist health care providers in the approach to this aspect of prenatal care of women with twin pregnancies. SUMMARY STATEMENTS: RECOMMENDATIONS. PMID- 28859780 TI - ? PMID- 28859781 TI - No. 261-Prenatal Screening for Fetal Aneuploidy in Singleton Pregnancies. AB - OBJECTIVE: To develop a Canadian consensus document on maternal screening for fetal aneuploidy (e.g., Down syndrome and trisomy 18) in singleton pregnancies. OPTIONS: Pregnancy screening for fetal aneuploidy started in the mid 1960s, using maternal age as the screening test. New developments in maternal serum and ultrasound screening have made it possible to offer all pregnant patients a non invasive screening test to assess their risk of having a fetus with aneuploidy to determine whether invasive prenatal diagnostic testing is necessary. This document reviews the options available for non-invasive screening and makes recommendations for Canadian patients and health care workers. OUTCOMES: To offer non-invasive screening for fetal aneuploidy (trisomy 13, 18, 21) to all pregnant women. Invasive prenatal diagnosis would be offered to women who screen above a set risk cut-off level on non-invasive screening or to pregnant women whose personal, obstetrical, or family history places them at increased risk. Currently available non-invasive screening options include maternal age combined with one of the following: (1) first trimester screening (nuchal translucency, maternal age, and maternal serum biochemical markers), (2) second trimester serum screening (maternal age and maternal serum biochemical markers), or (3) 2-step integrated screening, which includes first and second trimester serum screening with or without nuchal translucency (integrated prenatal screen, serum integrated prenatal screening, contingent, and sequential). These options are reviewed, and recommendations are made. EVIDENCE: Studies published between 1982 and 2009 were retrieved through searches of PubMed or Medline and CINAHL and the Cochrane Library, using appropriate controlled vocabulary and key words (aneuploidy, Down syndrome, trisomy, prenatal screening, genetic health risk, genetic health surveillance, prenatal diagnosis). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to August 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment- related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The previous Society of Obstetricians and Gynaecologists of Canada guidelines regarding prenatal screening were also reviewed in developing this clinical practice guideline. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: This guideline is intended to reduce the number of prenatal invasive procedures done when maternal age is the only indication. This will have the benefit of reducing the numbers of normal pregnancies lost because of complications of invasive procedures. Any screening test has an inherent false- positive rate, which may result in undue anxiety. It is not possible at this time to undertake a detailed cost-benefit analysis of the implementation of this guideline, since this would require health surveillance and research and health resources not presently available; however, these factors need to be evaluated in a prospective approach by provincial and territorial initiatives. RECOMMENDATIONS: PMID- 28859782 TI - Cardiovascular Risk Following Fertility Therapy: Systematic Review and Meta Analysis. AB - BACKGROUND: The longer term cardiovascular effects of fertility therapy are unknown. OBJECTIVES: The aim of this study was to summarize data linking fertility therapy with subsequent cardiovascular outcomes. METHODS: We systematically searched published reports for studies addressing the question "does fertility therapy increase the risk of longer term cardiovascular outcomes?" We included: 1) human studies; 2) case control, cohort, or randomized designs with 3) exposure to fertility therapy and 4) cardiovascular outcomes clearly reported; 5) presence of comparison group; 6) minimum 1-year follow-up; and 7) adjustment for age. Two independent reviewers screened abstracts, titles, and full texts, and assessed study quality. We used the DerSimonian and Laird random-effects models to pool hazard ratios (HRs) with 95% confidence intervals (CIs) of the following outcomes: acute cardiac event; stroke; venous thromboembolism; hypertension; and diabetes mellitus, comparing women who received fertility therapy with those who did not. RESULTS: Six observational studies met inclusion criteria including 41,910 women who received fertility therapy and 1,400,202 women who did not. There was no increased risk of a cardiac event (pooled HR: 0.91; 95% CI: 0.67 to 1.25; I2 = 36.6%), or diabetes mellitus (pooled HR: 0.93; 95% CI: 0.87 to 1.001; I2 = 0%). Results were not pooled for hypertension (I2 = 95.0%) and venous thromboembolism (I2 = 82.3%). There was a trend toward higher risk of stroke (pooled HR: 1.25; 95% CI: 0.96 to 1.63; I2 = 0%). CONCLUSIONS: The small number of studies and significant heterogeneity precludes definitive reassurance about the longer term cardiovascular safety of these treatments, particularly stroke. Future studies are needed to address ongoing knowledge gaps in this area. PMID- 28859783 TI - Fertility Therapy and Long-Term Cardiovascular Risk: Raising More Questions Than Answers? PMID- 28859784 TI - Outcomes of Cardiac Resynchronization Therapy With or Without Defibrillation in Patients With Nonischemic Cardiomyopathy. AB - BACKGROUND: Recent studies have cast doubt on the benefit of cardiac resynchronization therapy (CRT) with defibrillation (CRT-D) versus pacing (CRT-P) for patients with nonischemic cardiomyopathy (NICM). Left ventricular myocardial scar portends poor clinical outcomes. OBJECTIVES: The aim of this study was to determine whether CRT-D is superior to CRT-P in patients with NICM either with (+) or without (-) left ventricular midwall fibrosis (MWF), detected by cardiac magnetic resonance. METHODS: Clinical events were quantified in patients with NICM who were +MWF (n = 68) or -MWF (n = 184) who underwent cardiac magnetic resonance prior to CRT device implantation. RESULTS: In the total study population, +MWF emerged as an independent predictor of total mortality (adjusted hazard ratio [aHR]: 2.31; 95% confidence interval [CI]: 1.45 to 3.68), total mortality or heart failure hospitalization (aHR: 2.02; 95% CI: 1.32 to 3.09), total mortality or hospitalization for major adverse cardiac events (aHR: 2.02; 95% CI: 1.32 to 3.07), death from pump failure (aHR: 1.95; 95% CI: 1.11 to 3.41), and sudden cardiac death (aHR: 3.75; 95% CI: 1.26 to 11.2) over a maximum follow up period of 14 years (median 3.8 years [interquartile range: 2.0 to 6.1 years] for +MWF and 4.6 years [interquartile range: 2.4 to 8.3 years] for -MWF). In separate analyses of +MWF and -MWF, total mortality (aHR: 0.23; 95% CI: 0.07 to 0.75), total mortality or heart failure hospitalization (aHR: 0.32; 95% CI: 0.12 to 0.82), and total mortality or hospitalization for major adverse cardiac events (aHR: 0.30; 95% CI: 0.12 to 0.78) were lower after CRT-D than after CRT-P in +MWF but not in -MWF. CONCLUSIONS: In patients with NICM, CRT-D was superior to CRT-P in +MWF but not -MWF. These findings have implications for the choice of device therapy in patients with NICM. PMID- 28859785 TI - Selecting Patients With Nonischemic Dilated Cardiomyopathy for ICDs: Myocardial Function, Fibrosis, and What's Attached? PMID- 28859787 TI - New Pharmacological Target to Treat Ischemic Mitral Regurgitation: Thinking Outside the Box. PMID- 28859789 TI - Traumatic Brains and Broken Hearts: Mending the Donor Shortage in Cardiac Transplantation. PMID- 28859788 TI - Outcomes After Transplantation of Donor Hearts With Improving Left Ventricular Systolic Dysfunction. AB - BACKGROUND: Left ventricular systolic dysfunction (LVSD) accounts for almost 25% of nonacceptance of potential donor hearts. Previous smaller, single-center studies showed that LVSD following brain death may be transient, and such hearts can be successfully resuscitated with resolution of LVSD, then transplanted. OBJECTIVES: This study evaluated outcomes of donor hearts with LVSD on initial transthoracic echocardiogram (TTE) that resolved during donor management. METHODS: We reviewed echocardiograms of all cardiac donors in the United Network of Organ Sharing database that were transplanted from January 1, 2007, to September 30, 2015, and identified 472 donor hearts with LVSD (left ventricular ejection fraction [LVEF] <=40%) on initial TTE that resolved (LVEF >=50%) during donor management on a subsequent TTE. These patients comprised the improved donor LVEF group. These were compared with donor hearts with normal LVEF (LVEF >=55%) on the initial TTE for recipient mortality, cardiac allograft vasculopathy (CAV), and primary graft failure (PGF). RESULTS: There was no significant difference in recipient mortality at 30 days, 1 year, 3 years, and 5 years of follow-up, nor any difference in rates of PGF at 90 days and CAV at 5 years between recipients of donor hearts with improved LVEF and recipients of donor hearts with initially normal LVEF. Post-transplant length of stay was also similar between the 2 groups. Using propensity scores, 461 transplants in the improved-donor LVEF group were matched to 461 transplants in the normal-donor LVEF group. There was no significant difference in PGF at 90 days or recipient mortality after up to 5 years of follow-up. CONCLUSIONS: In the largest analysis of donor hearts with transient LVSD, we found that such hearts can be successfully resuscitated and transplanted without increasing recipient mortality, CAV, or PGF. These results underscore the importance of appropriate donor management and should help to increase utilization of donor hearts with transient LVSD. PMID- 28859786 TI - Effect of Losartan on Mitral Valve Changes After Myocardial Infarction. AB - BACKGROUND: After myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth, but counterproductive leaflet thickening and fibrosis augment mitral regurgitation (MR), doubling heart failure and mortality. MV fibrosis post-MI is associated with excessive endothelial-to-mesenchymal transition (EMT), driven by transforming growth factor (TGF)-beta overexpression. In vitro, losartan-mediated TGF-beta inhibition reduces EMT of MV endothelial cells. OBJECTIVES: This study tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF beta inhibition. METHODS: The study assessed 17 sheep, including 6 sham-operated control animals and 11 with apical MI and papillary muscle retraction short of producing MR; 6 of the 11 were treated with daily losartan, and 5 were untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by using three dimensional echocardiography at baseline and at 60 +/- 6 days, and excised leaflets were analyzed by histopathology and flow cytometry. RESULTS: Post-MI LV dilation and tethering were comparable in the losartan-treated and untreated LV constraint sheep. Telemetered sensors (n = 6) showed no significant losartan induced changes in arterial pressure. Losartan strongly reduced leaflet thickness (0.9 +/- 0.2 mm vs. 1.6 +/- 0.2 mm; p < 0.05; 0.4 +/- 0.1 mm sham animals), TGF beta, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 +/- 12.0% vs. 51.6 +/- 11.7% alpha-smooth muscle actin-positive endothelial cells, p < 0.05; 7.2 +/- 3.5% sham animals), cellular proliferation, collagen deposition, endothelial cell activation (vascular cell adhesion molecule-1 expression), neovascularization, and cells positive for cluster of differentiation (CD) 45, a hematopoietic marker associated with post-MI valve fibrosis. Leaflet area increased comparably (17%) in constrained and losartan treated sheep. CONCLUSIONS: Profibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth. Understanding the cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR. PMID- 28859790 TI - Ivabradine in Children With Dilated Cardiomyopathy and Symptomatic Chronic Heart Failure. AB - BACKGROUND: Heart rate reduction as a therapeutic target has been investigated in adults with heart failure (HF). Ivabradine has shown promising efficacy, but has not been evaluated in children. Currently, treatment recommendations for chronic pediatric HF are based mainly on chronic HF guidelines for adults. OBJECTIVES: The authors explored the dose-response relationship of ivabradine in children with dilated cardiomyopathy and symptomatic chronic HF. The primary endpoint was >=20% reduction in heart rate from baseline without inducing bradycardia or symptoms. METHODS: This was a randomized, double-blind, placebo-controlled, phase II/III study with 12 months of follow-up. Children (n = 116) receiving stable HF therapy were randomized to either ivabradine or placebo. After an initial titration period, the dose was adjusted to attain the primary endpoint. Left ventricular function (echocardiography), clinical status (New York Heart Association functional class or Ross class), N-terminal pro-B-type natriuretic peptide, and quality of life (QOL) were assessed. RESULTS: The primary endpoint was reached by 51 of 73 children taking ivabradine (70%) versus 5 of 41 taking placebo (12%) at varying doses (odds ratio: 17.24; p < 0.0001). Between baseline and 12 months, there was a greater increase in left ventricular ejection fraction in patients taking ivabradine than placebo (13.5% vs. 6.9%; p = 0.024). New York Heart Association functional class or Ross class improved more with ivabradine at 12 months than placebo (38% vs. 25%; p = 0.24). There was a trend toward improvement in QOL for ivabradine versus placebo (p = 0.053). N-terminal pro-B type natriuretic peptide levels decreased similarly in both groups. Adverse events were reported at similar frequencies for ivabradine and placebo. CONCLUSIONS: Ivabradine safely reduced the resting heart rate of children with chronic HF and dilated cardiomyopathy. Ivabradine's effect on heart rate was variable, highlighting the importance of dose titration. Ivabradine treatment improved left ventricular ejection fraction, and clinical status and QOL showed favorable trends. (Determination of the efficacious and safe dose of ivabradine in paediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure from ages 6 months to 18 years; ISRCTN60567801). PMID- 28859791 TI - Does Lowering Heart Rate Improve Outcomes in Children With Dilated Cardiomyopathy and Chronic Heart Failure? PMID- 28859792 TI - How Medicine Has Changed the End of Life for Patients With Cardiovascular Disease. AB - Advances in medicine have changed how patients experience the end of life. With longer life spans, there has also been an increase in years lived with disability. The clustering of illnesses in the last years of life is particularly pronounced in patients with cardiovascular disease. At the end of life, patients with cardiovascular disease are more symptomatic, less likely to die at home, and less likely to receive high-quality palliative care. Social determinants have created widening disparities in end-of-life care. The increasing complexity and duration of care have resulted in an epidemic of caregiver burden. Modern medical care has also resulted in new ethical challenges, for example, those related to deactivation of cardiac devices, such as pacemakers, defibrillators, and mechanical circulatory support. Recommendations to improve end-of-life care for patients with cardiovascular disease include optimizing metrics to assess quality, ameliorating disparities, enhancing education and research in palliative care, overcoming disparities, and innovating palliative care delivery and reimbursement. PMID- 28859794 TI - Outcomes in Guideline-Based Versus Off-Guideline Primary Prevention Implantable Cardioverter-Defibrillator Recipients. PMID- 28859795 TI - Meta-Analyses on DAPT Length: Chasing the Calm After the (Perfect) Storm. PMID- 28859793 TI - Optimizing Cholesterol Treatment in Patients With Muscle Complaints. AB - Statins are highly effective for preventing cardiovascular events by reducing low density lipoprotein cholesterol (LDL-C). However, many patients taking statins report muscle-related symptoms that prevent the use of guideline recommended doses. Patients with reported intolerance to statins have a high risk of cardiovascular events. Clinical strategies that optimize cardiovascular risk reduction through LDL-C lowering need to be applied in patients experiencing intolerable side effects that they attribute to statins. In this paper, the authors review definitions of statin intolerance, propose algorithms to better define statin intolerance, and describe approaches to optimize cardiovascular risk reduction among individuals reporting statin-associated muscle symptoms. PMID- 28859796 TI - Dual Antiplatelet Therapy and Bleeding-Related Deaths. PMID- 28859797 TI - Reply: Meta-Analyses on DAPT Length: Chasing the Calm After the (Perfect) Storm. PMID- 28859798 TI - TAVR and Stroke Prevention: Importance of Cerebral Embolic Protection Device Data. PMID- 28859800 TI - Correction. PMID- 28859799 TI - Reply: TAVR and Stroke Prevention: Importance of Cerebral Embolic Protection Device Data. PMID- 28859801 TI - Correction. PMID- 28859802 TI - Combination of physico-chemical entrapment and crosslinking of low activity laccase-based biocathode on carboxylated carbon nanotube for increasing biofuel cell performance. AB - New laccase-based catalysts to improve oxygen reduction reactions (ORR) are described, and enzymatic biofuel cells (EBCs) adopting these catalysts were developed. These new catalysts are synthesized by combining laccase, poly(ethylenimine) and carbon nanotubes, with attachment of selected elements using the crosslinker, glutaraldehyde (GA). Several characterization approaches are implemented to evaluate catalytic electron transfer in both the absence and presence of mediators and their effects on glucose/O2 biofuel cell performance. [CNT/Lac/PEI/Lac]/GA shows that the best electron transfer rate constants (ks) achieved, in the presence as well as the absence of a mediator, are 8.6 and 1.8s 1. Additionally, [CNT/Lac/PEI/Lac]/GA results in high performance of Maximum Power Density with a value of 0.2mWcm-2. Its relative stability can be maintained up to 83.76% with relative efficiency up to 84.73%, while CNT/Lac gives the lowest performance levels. This indicates that GA induces an improvement in catalytic activity by (i) increasing the amount of immobilized laccase and (ii) strengthening interaction between laccase and PEI. Therefore, it induces excellent redox reactivity, promoting the ORR, and glucose/O2 biofuel cell performance. The effect of pH on catalytic activity is also measured, with pH 5 being optimal. PMID- 28859803 TI - Coupling xylitol dehydrogenase with NADH oxidase improves l-xylulose production in Escherichia coli culture. AB - Escherichia coli expressing NAD-dependent xylitol-4-dehydrogenase (XDH) from Pantoea ananatis and growing on glucose or glycerol converts xylitol to the rare sugar l-xylulose. Although blocking potential l-xylulose consumption (l xylulosekinase, lyxK) or co-expression of the glycerol facilitator (glpF) did not significantly affect l-xylulose formation, co-expressing XDH with water-forming NADH oxidase (NOX) from Streptococcus pneumoniae increased l-xylulose formation in shake flasks when glycerol was the carbon source. Controlled batch processes at the 1L scale demonstrated that the final equilibrium l-xylulose/xylitol ratio was correlated to the intracellular NAD+/NADH ratio, with 69% conversion of xylitol to l-xylulose and a yield of 0.88g l-xylulose/g xylitol consumed attained for MG1655/pZE12-xdh/pCS27-nox growing on glycerol. NADH oxidase was less effective at improving l-xylulose formation in the bioreactor than in shake flasks, likely as a result of an intrinsic maximum NAD+/NADH and l xylulose/xylitol equilibrium ratio being attained. Intermittently feeding carbon source was ineffective at increasing the final l-xylulose concentration because introduction of carbon source was accompanied by a reduction in NAD+/NADH ratio. A batch process using 12g/L glycerol and 22g/L xylitol generated over 14g/L l xylulose after 80h, corresponding to 65% conversion and a yield of 0.89g l xylulose/g xylitol consumed. PMID- 28859804 TI - Fungal BVMOs as alternatives to cyclohexanone monooxygenase. AB - FAD-dependent Baeyer-Villiger monooxygenases (BVMOs) have proven to be useful biocatalysts in the selective and specific oxygenation of various ketones. Despite the cloning, heterologous expression and characterization of close to 80 members of this enzyme family, some sub-groups of BVMOs still remain underrepresented and their evolutionary relationship uncertain. Until recently, very few fungal BVMOs have been described. Our previous investigations into BVMOs from the fungus Aspergillus flavus, yielded very little activity on simple cyclic ketones. Here we report on another four BVMOs from A. flavus that are more closely related to cyclohexanone monooxygenase (CHMO) from Acinetobacter sp. NCIMB 9871. Evolutionary analysis with other characterized BVMOs show their closest relationship to be with either cycloalkanone monooxygenase (CAMO) or 2 oxo-Delta3-4,5,5-trimethylcyclopentenylacetyl-coenzyme A monooxygenase (OTEMO). The OTEMO-related BVMOAFL706 and BVMOAFL334 were heterologously expressed in E. coli, purified and shown to be able to convert a range of cyclic and substituted cyclic ketones. Of the unsubstituted cyclic ketones, cyclohexanone showed the highest conversion with maximum turnover frequencies reaching 4.3s-1 for BVMOAFL706. Unlike CHMOacinet, and many of the closely related BVMOs, no substrate inhibition was observed with cyclohexanone to a concentration of up to 30mM, creating the possibility for applications requiring high substrate loading. Aliphatic ketones were also readily converted with excellent regioselectivity. Similar to CHMOacinet, acetophenones were not converted and the oxidation of rac cis-bicyclo[3.2.0]hept-2-en-6-one occurs enantiodivergently, with the (1R,5S) isomer converted to the "normal" lactone and the (1S,5R) isomer to the "abnormal" lactone. PMID- 28859805 TI - Pathway engineering of Enterobacter aerogenes to improve acetoin production by reducing by-products formation. AB - Enterobacter aerogenes was metabolically engineered for acetoin production. To remove the pathway enzymes that catalyzed the formation of by-products, the three genes encoding a lactate dehydrogenase (ldhA) and two 2,3-butanediol dehydrogenases (budC, and dhaD), respectively, were deleted from the genome. The acetoin production was higher under highly aerobic conditions. However, an extracellular glucose oxidative pathway in E. aerogenes was activated under the aerobic conditions, resulting in the accumulation of 2-ketogluconate. To decrease the accumulation of this by-product, the gene encoding a glucose dehydrogenase (gcd) was also deleted. The resulting strain did not produce 2-ketogluconate but produced significant amounts of acetoin, with concentration reaching 71.7g/L with 2.87g/L/h productivity in fed-batch fermentation. This result demonstrated the importance of blocking the glucose oxidative pathway under highly aerobic conditions for acetoin production using E. aerogenes. PMID- 28859806 TI - CO2-H2O based pretreatment and enzyme hydrolysis of soybean hulls. AB - The high carbohydrate content of soybean hull makes it an attractive biorefinery resource. But hydrolyzing its complex structure requires concerted enzyme activities, at least cellulase, xylanase, pectinase and alpha-galactosidase. Effective pretreatment that generates minimal inhibitory products is important to facilitate enzymatic hydrolysis. Combined CO2-H2O pretreatment and enzymatic hydrolysis by Aspergillus niger and Trichoderma reesei enzyme broths was studied here. The pretreatment was evaluated at 80 degrees C-180 degrees C temperature and 750psi-1800psi pressure, with fixed moisture content (66.7%) and pretreatment time (30min). Ground hulls without and with different pretreatments were hydrolyzed by enzyme at 50 degrees C and pH 4.8 and compared for glucose, xylose, galactose, arabinose, mannose and total reducing sugar release. CO2-H2O pretreatment at 1250psi and 130 degrees C was found to be optimal. Compared to the unpretreated hulls hydrolyzed with 2.5-fold more enzyme, this pretreatment improved glucose, xylose, galactose, arabinose and mannose releases by 55%, 35%, 105%, 683% and 52%, respectively. Conversions of 97% for glucose, 98% for xylose, 41% for galactose, 59% for arabinose, 87% for mannose and 89% for total reducing sugar were achieved with Spezyme CP at 18FPU/g hull. Monomerization of all carbohydrate types was demonstrated. At the optimum pretreatment condition, generation of inhibitors acetic acid, furfural and hydroxymethylfurfural (HMF) was negligible, 1.5mg/g hull in total. The results confirmed the effective CO2 H2O pretreatment of soybean hulls at much lower pressure and temperature than those reported for biomass of higher lignin contents. The lower pressure requirement reduces the reactor cost and makes this new pretreatment method more practical and economical. PMID- 28859807 TI - Construction and functional analysis of a whole-cell biocatalyst based on CYP108N7. AB - Cytochrome P450 enzymes are versatile biocatalysts with great potential in biotechnology. A new bacterial P450 was identified from the genome of Rhodococcus wratislaviensis NBRC 100605 and annotated as CYP108N7. The enzyme accepted the ferredoxin and ferredoxin reductase from spinach as surrogate redox partners for improved electron transfer efficiency. It was heterologous expressed in Escherichia coli together with the redox partners and a glucose dehydrogenase which supplied the reduced cofactor NADPH. The resulting whole-cell biocatalyst catalyzed a variety of reactions including sulfoxidation, epoxidation, hydroxylation, demethylation and dehalogenation. Remarkable stereoselectivity was observed in asymmetric sulfoxidation reaction, which could deliver chiral sulfoxides with >99% ee from thioanisole and derivatives. PMID- 28859808 TI - Enzyme-based processing of soybean carbohydrate: Recent developments and future prospects. AB - Soybean is well known for its high-value oil and protein. Carbohydrate is, however, an underutilized major component, representing almost 26-30% (w/w) of the dried bean. The complex soybean carbohydrate is not easily hydrolyzable and can cause indigestibility when included in food and feed. Enzymes can be used to hydrolyze the carbohydrate for improving soybean processing and value of soybean products. Here the enzyme-based processing developed for the following purposes is reviewed: hydrolysis of different carbohydrate-rich by/products from soybean processing, improvement of soybean oil extraction, and increase of nutritional value of soybean-based food and animal feed. Once hydrolyzed into fermentable sugars, soybean carbohydrate can find more value-added applications and further improve the overall economics of soybean processing. PMID- 28859809 TI - Selenium nanoparticle-enriched biomass of Yarrowia lipolytica enhances growth and survival of Artemia salina. AB - Controlling disease outbreaks is a major challenge in aquaculture farms and conventional methods are often ineffective. Nutritional supplementation and probiotic preparations help in reducing severity of such infections. The generally regarded as safe yeast (Yarrowia lipolytica) was used in the current study. A marine strain of Y. lipolytica exhibited tolerance towards sodium selenite and formed cell associated selenium nanoparticles (SeNPs). The synthesized nanoparticles were characterized by UV-vis spectroscopy, X-ray diffraction (XRD) and Field Emission Scanning Electron Microscope (FE-SEM) observations. Fourier transform infra-red (FTIR) spectroscopy indicated the role of carboxylic and amine groups in the synthesis of nanoparticles. This SeNP enriched biomass was used as feed for the model aquaculture system, Artemia salina and compared with normal feed, baker's yeast (Saccharomyces cerevisiae). A. salina fed with SeNP-enriched biomass, showed increased survival rates (96.66%) as compared to those fed with S. cerevisiae (60.0%). The size of the larvae fed with SeNP-enriched biomass of Y. lipolytica was also found to be larger. Additionally, larval groups fed with SeNP-enriched biomass were better protected (70.0% survival) against V. harveyi infection when compared with groups fed with S. cerevisiae (24.44%). This combination of selenium in the nanoparticle form associated with the biomass of Y. lipolytica has potential application in improving health of aquaculture species in farms. PMID- 28859810 TI - Global substitution of hemeproteins with noncanonical amino acids in Escherichia coli with intact cofactor maturation machinery. AB - Global substitution of canonical amino acids (cAAs) with noncanonical (ncAAs) counterparts in proteins whose function is dependent on post-translational events such as cofactor binding is still a methodically challenging and difficult task as ncAA insertion generally interferes with the cofactor biosynthesis machinery. Here, we report a technology for the expression of fully substituted and functionally active cofactor-containing hemeproteins. The maturation process which yields an intact cofactor is timely separated from cAA->ncAA substitutions. This is achieved by an optimised expression and fermentation procedure which includes pre-induction of the heme cofactor biosynthesis followed by an incorporation experiment at multiple positions in the protein sequence. This simple strategy can be potentially applied for engineering of other cofactor containing enzymes. PMID- 28859811 TI - Engineering Escherichia coli for poly-(3-hydroxybutyrate) production guided by genome-scale metabolic network analysis. AB - Poly-(3-hydroxybutyrate) (P3HB) is a promising biodegradable plastic synthesized from acetyl-CoA. One important factor affecting the P3HB production cost is the P3HB yield. Through flux balance analysis of an extended genome-scale metabolic network of E. coli, we found that the introduction of non-oxidative glycolysis pathway (NOG), a previously reported pathway enabling complete carbon conservation, can increase the theoretical carbon yield from 67% to 89%, equivalent to the theoretical mass yield from 0.48g P3HB/g glucose to 0.64g P3HB/g glucose. Based on this analysis result, we introduced phosphoketolase and enhanced the NOG pathway in E. coli. The mass yield in the engineered strain was increased from 0.16g P3HB/g glucose to 0.24g P3HB/g glucose. We further overexpressed pntAB to enhance the NADPH availability and down-regulated TCA cycle to divert more acetyl-CoA toward P3HB. The final construct accumulated 5.7g/L P3HB and reached a carbon yield of 0.43 (a mass yield of 0.31g P3HB/g glucose) in shake flask cultures in shake flask cultures. The introduction of NOG pathway could also be useful for improving yields of many other biochemicals derived from acetyl-coA. PMID- 28859812 TI - Improved stability of immobilized lipases via modification with polyethylenimine and glutaraldehyde. AB - Phospholipase Lecitase Ultra (LU) and lipase from Thermomyces lanuginosus (TLL) have been immobilized under conditions that favor either enzyme crowding or enzyme dispersion. Highly loaded LU was more stable than low loaded biocatalyst under all studied conditions. Using TLL, the results depended on the inactivation conditions, e.g., crowding was positive at pH 5 and negative at pH 7. Then, all preparations were treated with glutaraldehyde (Glu), polyethyleneimine (PEI) or sequentially with Glu and PEI. These treatments may permit to stabilize the physically immobilized lipases by avoiding enzyme desorption via intermolecular crosslinking. Moreover, immobilizing a second enzyme on the lipase-glutaraldehyde PEI has been proposed as a strategy without risks of PEI desorption by incubation in high ion strength solutions. The treatments altered the enzyme activity slightly but produced significant enzyme stabilization. This enzyme stabilization was more significant when using the highly loaded preparations, where intermolecular crosslinking was easier to obtain. SDS-PAGE analyses confirmed that crowded enzyme preparations were intermolecular crosslinked using Glu plus PEI, but some molecules still remained non-crosslinked. In general, PEI treatment was the most effective in increasing enzyme stability, while glutaraldehyde had a milder stabilization effect. PMID- 28859813 TI - Impact of orientation of carbohydrate binding modules family 22 and 6 on the catalytic activity of Thermotoga maritima xylanase XynB. AB - Xylanase XynB of the hyperthermophile Thermotoga maritima, which belongs to glycoside hydrolase family 10 (GH10), does not have an associated carbohydrate binding module (CBM) in the native state. CBM6 and CBM22 from a thermophile Clostridium thermocellum were fused to the catalytic domain of XynB (XynB-C) to determine the effects on activity and other properties. XynB-B22C and XynB-CB22, produced by fusing CBM22 to the N- and C-terminal of XynB-C, showed 1.7- and 3.24 fold increase in activity against the insoluble birchwood xylan, respectively. Similarly, CBM6 when attached to the C-terminal of XynB-C resulted in 2.0-fold increase in activity, whereas its attachment to the N-terminal did not show any increase of activity. XynB-B22C and XynB-CB22 retained all the activity, whereas XynB-B6C and XynB-CB6 lost 17 and 11% of activity, respectively, at 60 degrees C for 4h. Thermostability data and the secondary structure contents obtained by molecular modelling are in agreement with the data from circular dichroism analysis. Molecular modelling analysis showed that the active site residues of the catalytic domain and the binding residues of CBM6 and CBM22 were located on the surface of molecule, except XynB-B6C, where the binding residues were found somewhat buried. In the case of XynB-CB22, the catalytic and the binding residues seem to be located favorably adjacent to each other, thus showing higher increase in activity. This study shows that the active site residues of the catalytic domain and the binding residues of the CBM are arranged in a unique fashion, not reported before. PMID- 28859814 TI - Overexpressing key component genes of the secretion pathway for enhanced secretion of an Aspergillus niger glucose oxidase in Trichoderma reesei. AB - Vast interest exists in developing T. reesei for production of heterologous proteins. Although rich genomic and transcriptomic information has been uncovered for the T. reesei secretion pathway, little is known about whether engineering its key components could enhance expression of a heterologous gene. In this study, snc1, a v-SNARE gene, was first selected for overexpression in T. reesei. In engineered T. reesei with additional copies of snc1, the Aspergillus niger glucose oxidase (AnGOD) was produced to a significantly higher level (2.2-fold of the parental strain). hac1 and bip1, two more component genes in the secretion pathway, were further tested for overexpression and found to be also beneficial for AnGOD secretion. The overexpression of one component gene more or less affected the expression of the other two genes, suggesting a complex regulating mechanism. Our study demonstrates the potential of engineering the secretion pathway for enhancing heterologous gene production in T. reesei. PMID- 28859815 TI - Direct rate assessment of laccase catalysed radical formation in lignin by electron paramagnetic resonance spectroscopy. AB - Laccases (EC 1.10.3.2) catalyse removal of an electron and a proton from phenolic hydroxyl groups, including phenolic hydroxyls in lignins, to form phenoxy radicals during reduction of O2. We employed electron paramagnetic resonance spectroscopy (EPR) for real time measurement of such catalytic radical formation activity on three types of lignin (two types of organosolv lignin, and a lignin rich residue from wheat straw hydrolysis) brought about by two different fungal laccases, derived from Trametes versicolor (Tv) and Myceliophthora thermophila (Mt), respectively. Laccase addition to suspensions of the individual lignin samples produced immediate time and enzyme dose dependent increases in intensity in the EPR signal with g-values in the range 2.0047-2.0050 allowing a direct quantitative monitoring of the radical formation and thus allowed laccase enzyme kinetics assessment on lignin. The experimental data verified that the laccases acted upon the insoluble lignin substrates in the suspensions. When the action on the lignin substrates of the two laccases were compared on equal enzyme dosage levels (by activity units on syringaldazine) the Mt laccase exerted a significantly faster radical formation than the Tv laccase on all three types of lignin substrates. When comparing the equal laccase dose rates on the three lignin substrates the enzymatic radical formation rate on the wheat straw lignin residue was consistently higher than those of the organosolv lignins. The pH temperature optimum for the radical formation rate in organosolv lignin was determined by response surface methodology to pH 4.8, 33 degrees C and pH 5.8, 33 degrees C for the Tv laccase and the Mt laccase, respectively. The results verify direct radical formation action of fungal laccases on lignin without addition of mediators and the EPR methodology provides a new type of enzyme assay of laccases on lignin. PMID- 28859817 TI - JAMDA Maintains Excellent Impact Factor. PMID- 28859816 TI - Improvement of enzyme activity and soluble expression of an alkaline protease isolated from oil-polluted mud flat metagenome by random mutagenesis. AB - A new protease gene (pro1437)was separated from an oil-polluted Mud flat metagenomic library. Pro1437 belongs to a peptidase M48 superfamily according to the results of sequence analysis, and it showed very low identities compared to other known proteases or peptidases. The error-prone PCR was used to introduce random mutations and improve the expression of pro1437. After two rounds of mutagenesis and screening, a mutant (Pro2T21) with a 6.6-fold higher activity and a 4.8-fold higher expression level than Pro1437 was obtained. Sequence analysis found three amino acid substitutions (A54V, L192H, F224L) in Pro2T21. 3D structure modelling analysis indicated A54V and L192H probably played a crucial role in the improvement of enzymatic activity and soluble expression level of Pro2T21. Furthermore, Pro2T21opti displayed a 5.8-fold higher expression level than the wild type under optimal pH 8.0 at 50 degrees C after codon-optimization. Also, Pro2T21opti represented robust compatibility with several popular laundry detergents, and blood stains on white cloth pieces were completely washed away when endogenous protease-inactivated Tide and Pro2T21opti were used together. Therefore, Pro2T21opti has great potential for use as an additive in detergents after further study. PMID- 28859818 TI - What Works to Improve and Manage Fecal Incontinence in Care Home Residents Living With Dementia? A Realist Synthesis of the Evidence. AB - The prevalence of fecal incontinence (FI) in care homes is estimated to range from 30% to 50%. There is limited evidence of what is effective in the reduction and management of FI in care homes. Using realist synthesis, 6 potential program theories of what should work were identified. These addressed clinician-led support, assessment, and review; the contribution of teaching and support for care home staff on how to reduce and manage FI; addressing the causes and prevention of constipation; how cognitive and physical capacity of the resident affects outcomes; how the potential for recovery, reduction, and management of FI is understood by those involved; and how the care of people living with dementia and FI is integral to the work patterns of the care home and its staff. Dementia was a known risk factor for fecal incontinence (FI), but how it affected uptake of different interventions or the dementia specific continence and toileting skills staff require, were not addressed in the literature. There was a lack of dementia-specific evidence on continence aids. Most care home residents with FI will be doubly incontinent; there is, therefore, limited value in focusing solely on FI or single causes, such as constipation. Medical and nursing support for continence care is an important resource, but it is unhelpful to create a distinction between what is continence care and what is personal or intimate care. Prompted toileting is an approach that may be particularly beneficial for some residents. Valuing the intimate and personal care work unqualified and junior staff provide to people living with dementia and reinforcement of good practice in ways that are meaningful to this workforce are important clinician led activities. Providing dementia-sensitive continence care within the daily work routines of care homes is key to helping to reduce and manage FI for this population. PMID- 28859819 TI - Responsiveness of the full-length and short form of The Older Persons and Informal Caregivers Survey. PMID- 28859821 TI - Erratum to "Visual activation of extra-striate cortex in the absence of V1 activation" [Neuropsychologia 48/14 (2010) 4148-4154]. PMID- 28859822 TI - Erratum to "Failures of sustained attention in life, lab, and brain: Ecological validity of the SART" [Neuropsychologia 48 (9) (2010) 2564-2570]. PMID- 28859823 TI - Erratum to: "Orbital prefrontal cortex volume correlates with social cognitive competence" by Powell, J.L. et al. [Neuropsychologia 48 (12) (2010) 3554-3562]. PMID- 28859824 TI - REMOVED: Investigating misophonia: A review of the literature, clinical implications and research agenda reflecting current neuroscience and emotion research perspectives. AB - This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been removed at the request of the authors due to errors in the author list. PMID- 28859825 TI - Multi-modal discriminative dictionary learning for Alzheimer's disease and mild cognitive impairment. AB - BACKGROUND AND OBJECTIVE: The differentiation of mild cognitive impairment (MCI), which is the prodromal stage of Alzheimer's disease (AD), from normal control (NC) is important as the recent research emphasis on early pre-clinical stage for possible disease abnormality identification, intervention and even possible prevention. METHODS: The current study puts forward a multi-modal supervised within-class-similarity discriminative dictionary learning algorithm (SCDDL) we introduced previously for distinguishing MCI from NC. The proposed new algorithm was based on weighted combination and named as multi-modality SCDDL (mSCDDL). Structural magnetic resonance imaging (sMRI), fluorodeoxyglucose (FDG) positron emission tomography (PET) and florbetapir PET data of 113 AD patients, 110 MCI patients and 117 NC subjects from the Alzheimer's disease Neuroimaging Initiative database were adopted for classification between MCI and NC, as well as between AD and NC. RESULTS: Adopting mSCDDL, the classification accuracy achieved 98.5% for AD vs. NC and 82.8% for MCI vs. NC, which were superior to or comparable with the results of some other state-of-the-art approaches as reported in recent multi modality publications. CONCLUSIONS: The mSCDDL procedure was a promising tool in assisting early diseases diagnosis using neuroimaging data. PMID- 28859826 TI - An Alzheimers disease related genes identification method based on multiple classifier integration. AB - BACKGROUND AND OBJECTIVE: Alzheimers disease (AD) is a fatal neurodegenerative disease and the onset of AD is insidious. Full understanding of the AD-related genes (ADGs) has not been completed. The National Center for Biotechnology Information (NCBI) provides an AD dataset of 22,283 genes. Among these genes, 71 genes have been identified as ADGs. But there may still be underlying ADGs that have not yet been identified in the remaining 22,212 genes. This paper aims to identify additional ADGs using machine learning techniques. METHODS: To improve the accuracy of ADG identification, we propose a gene identification method through multiple classifier integration. First, a feature selection algorithm is applied to select the most relevant attributes. Second, a two-stage cascading classifier is developed to identify ADGs. The first stage classification task is based on the relevance vector machine and, in the second stage, the results of three classifiers, support vector machine, random forest and extreme learning machine, are combined through voting. RESULTS: According to our results, feature selection improves accuracy and reduces training time. Voting based classifier reduces the classification errors. The proposed ADG identification system provides accuracy, sensitivity and specificity at levels of 78.77%, 83.10% and 74.67%, respectively. Based on the proposed ADG identification method, potentially additional ADGs are identified and top 13 genes (predicted ADGs) are presented. CONCLUSIONS: In this paper, an ADG identification method for identifying ADGs is presented. The proposed method which combines feature selection, cascading classifier and majority voting leads to higher specificity and significantly increases the accuracy and sensitivity of ADG identification. Potentially new ADGs are identified. PMID- 28859827 TI - GEEORD: A SAS macro for analyzing ordinal response variables with repeated measures through proportional odds, partial proportional odds, or non proportional odds models. AB - BACKGROUND AND OBJECTIVE: A SAS macro, GEEORD, has been developed for the analysis of ordinal responses with repeated measures through a regression model that flexibly allows the proportional odds assumption to apply (or not) separately for each explanatory variable. METHODS AND RESULTS: Previously utilized in an analysis of a longitudinal orthognathic surgery clinical trial by Preisser et al. [1,2], the basis of GEEORD is the generalized estimating equations (GEE) method for cumulative logits models described by Lipsitz et al. [3]. The macro extends the capabilities for modeling correlated ordinal data of GEECAT, a SAS macro that allows the user to model correlated categorical response data [4]. The macro applies to independent ordinal responses as a special case. APPLICATIONS AND CONCLUSIONS: Examples are provided to demonstrate the convenient application of GEEORD to two different datasets. The macro's features are illustrated in fitting models to ordinal response variables in univariate and repeated measures settings; this includes the capacity to fit the non proportional odds model, the partial proportional odds model, and the proportional odds model. The macro additionally provides relevant tests of the proportional odds assumption. PMID- 28859828 TI - Liver vessel segmentation and identification based on oriented flux symmetry and graph cuts. AB - BACKGROUND AND OBJECTIVE: Accurate segmentation of liver vessels from abdominal computer tomography angiography (CTA) volume is very important for liver-vessel analysis and living-related liver transplants. This paper presents a novel liver vessel segmentation and identification method. METHODS: Firstly, an anisotropic diffusion filter is used to smooth noise while preserving vessel boundaries. Then, based on the gradient symmetry and antisymmetry pattern of vessel structures, optimal oriented flux (OOF) and oriented flux antisymmetry (OFA) measures are respectively applied to detect liver vessels and their boundaries, and further to slenderize vessels. Next, according to vessel geometrical structure, a centerline extraction measure based on height ridge traversal and leaf node line-growing (LNLG) is proposed for the extraction of liver-vessel centerlines, and an intensity model based on fast marching is integrated into graph cuts (GCs) for effective segmentation of liver vessels. Finally, a distance voting mechanism is applied to separate the hepatic vein and portal vein. RESULTS: The experiment results on abdominal CTA images show that the proposed method can effectively segment liver vessels, achieving an average accuracy, sensitivity, and specificity of 97.7%, 79.8%, and 98.6%, respectively, and has a good performance on thin-vessel extraction. CONCLUSIONS: The proposed method does not require manual selection of the centerlines and vessel seeds, and can effectively segment liver vessels and identify hepatic vein and portal vein. PMID- 28859829 TI - Multi-model-based interactive authoring environment for creating shareable medical knowledge. AB - OBJECTIVE: Technologically integrated healthcare environments can be realized if physicians are encouraged to use smart systems for the creation and sharing of knowledge used in clinical decision support systems (CDSS). While CDSSs are heading toward smart environments, they lack support for abstraction of technology-oriented knowledge from physicians. Therefore, abstraction in the form of a user-friendly and flexible authoring environment is required in order for physicians to create shareable and interoperable knowledge for CDSS workflows. Our proposed system provides a user-friendly authoring environment to create Arden Syntax MLM (Medical Logic Module) as shareable knowledge rules for intelligent decision-making by CDSS. METHODS AND MATERIALS: Existing systems are not physician friendly and lack interoperability and shareability of knowledge. In this paper, we proposed Intelligent-Knowledge Authoring Tool (I-KAT), a knowledge authoring environment that overcomes the above mentioned limitations. Shareability is achieved by creating a knowledge base from MLMs using Arden Syntax. Interoperability is enhanced using standard data models and terminologies. However, creation of shareable and interoperable knowledge using Arden Syntax without abstraction increases complexity, which ultimately makes it difficult for physicians to use the authoring environment. Therefore, physician friendliness is provided by abstraction at the application layer to reduce complexity. This abstraction is regulated by mappings created between legacy system concepts, which are modeled as domain clinical model (DCM) and decision support standards such as virtual medical record (vMR) and Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT). We represent these mappings with a semantic reconciliation model (SRM). RESULTS: The objective of the study is the creation of shareable and interoperable knowledge using a user friendly and flexible I-KAT. Therefore we evaluated our system using completeness and user satisfaction criteria, which we assessed through the system- and user centric evaluation processes. For system-centric evaluation, we compared the implementation of clinical information modelling system requirements in our proposed system and in existing systems. The results suggested that 82.05% of the requirements were fully supported, 7.69% were partially supported, and 10.25% were not supported by our system. In the existing systems, 35.89% of requirements were fully supported, 28.20% were partially supported, and 35.89% were not supported. For user-centric evaluation, the assessment criterion was 'ease of use'. Our proposed system showed 15 times better results with respect to MLM creation time than the existing systems. Moreover, on average, the participants made only one error in MLM creation using our proposed system, but 13 errors per MLM using the existing systems. CONCLUSION: We provide a user-friendly authoring environment for creation of shareable and interoperable knowledge for CDSS to overcome knowledge acquisition complexity. The authoring environment uses state of-the-art decision support-related clinical standards with increased ease of use. PMID- 28859830 TI - Social network Analysis-based classifier (SNAc): A case study on time course gene expression data. AB - BACKGROUND AND OBJECTIVES: Social Network Analysis is an attractive approach to model and analyze complex networks. In recent years, several bioinformatics related networks have been modeled and analyzed thoroughly using social network analysis. The objective of this study is to build a social network analysis based classifier for time sequential data. METHODS: In this work, we model a genomic time sequential data as a 'social' network of interactions. We define interactions as similarity of patients' measurements. Using this 'genomic social network', we develop a classification model called Social Network Analysis-based Classifier. RESULTS: We conducted some experiments to demonstrate how the developed Social Network Analysis-based Classifier outperforms traditional classifiers by effectively classifying a time sequential genomic dataset. Best achieved accuracy is 64.51% and best f-measure is 78.34%. CONCLUSIONS: Our study emphasized Social Network Analysis-based Classifier Model as a powerful technique for analyzing a time sequential dataset. Eventually, the plan is to develop and evolve the Social Network Analysis-based Classifier model into a general classifier. PMID- 28859831 TI - Automatic reconstruction of the muscle architecture from the superficial layer fibres data. AB - BACKGROUND AND OBJECTIVE: Physiological cross-sectional area (PCSA) of a muscle plays a significant role in determining the force contribution of muscle fascicles to skeletal movement. This parameter is typically calculated from the lengths of muscle fibres selectively sampled from the superficial layer of the muscle. However, recent studies have found that the length of fibres in the superficial layer often differs significantly (p < 0.5) from the length of fibres in the deep layer. As a result, PCSA estimation is inaccurate. In this paper, we propose a method to automatically reconstruct fibres in the whole volume of a muscle from those selectively sampled on the superficial layer. METHODS: The method performs a centripetal Catmull-Rom interpolation of the input fibres within the volume of a muscle represented by its 3D surface model, automatically distributing the fibres among multiple heads of the muscle and shortening the deep fibres to support large attachment areas with extremely acute angles. RESULTS: Our C++ implementation runs in a couple of seconds on commodity hardware providing realistic results for both artificial and real data sets we tested. CONCLUSIONS: The fibres produced by the method can be used directly to determine the personalised mechanical muscle functioning. Our implementation is publicly available for the researchers at https://mi.kiv.zcu.cz/. PMID- 28859832 TI - A novel and robust Bayesian approach for segmentation of psoriasis lesions and its risk stratification. AB - BACKGROUND AND OBJECTIVE: The need for characterization of psoriasis lesion severity is clinically valuable and vital for dermatologists since it provides a reliable and precise decision on risk assessment. The automated delineation of lesion is a prerequisite prior to characterization, which is challenging itself. Thus, this paper has two major objectives: (a) design of a segmentation system which can model by learning the lesion characteristics and this is posed as a Bayesian model; (b) develop a psoriasis risk assessment system (pRAS) by crisscrossing the blocks which drives the fundamental machine learning paradigm. METHODS: The segmentation system uses the knowledge derived by the experts along with the features reflected by the lesions to build a Bayesian framework that helps to classify each pixel of the image into lesion vs. BACKGROUND: Since this lesion has several stages and grades, hence the system undergoes the risk assessment to classify into five levels of severity: healthy, mild, moderate, severe and very severe. We build nine kinds of pRAS utilizing different combinations of the key blocks. These nine pRAS systems use three classifiers (Support Vector Machine (SVM), Decision Tree (DT) and Neural Network (NN)) and three feature selection techniques (Principal Component Analysis (PCA), Fisher Discriminant Ratio (FDR) and Mutual Information (MI)). The two major experiments conducted using these nine systems were: (i) selection of best system combination based on classification accuracy and (ii) understanding the reliability of the system. This leads us to computation of key system performance parameters such as: feature retaining power, aggregated feature effect and reliability index besides conventional attributes like accuracy, sensitivity, specificity. RESULTS: Using the database used in this study consisted of 670 psoriasis images, the combination of SVM and FDR was revealed as the optimal pRAS system and yielded a classification accuracy of 99.84% using cross-validation protocol. Further, SVM FDR system provides the reliability of 99.99% using cross-validation protocol. CONCLUSIONS: The study demonstrates a fully novel model of segmentation embedded with risk assessment. Among all nine systems, SVM-FDR produced best results. Further, we validated our pRAS system with automatic segmented lesions against manually segmented lesions showing comparable performance. PMID- 28859833 TI - Massively parallel simulator of optical coherence tomography of inhomogeneous turbid media. AB - BACKGROUND AND OBJECTIVE: An accurate and practical simulator for Optical Coherence Tomography (OCT) could be an important tool to study the underlying physical phenomena in OCT such as multiple light scattering. Recently, many researchers have investigated simulation of OCT of turbid media, e.g., tissue, using Monte Carlo methods. The main drawback of these earlier simulators is the long computational time required to produce accurate results. We developed a massively parallel simulator of OCT of inhomogeneous turbid media that obtains both Class I diffusive reflectivity, due to ballistic and quasi-ballistic scattered photons, and Class II diffusive reflectivity due to multiply scattered photons. METHODS: This Monte Carlo-based simulator is implemented on graphic processing units (GPUs), using the Compute Unified Device Architecture (CUDA) platform and programming model, to exploit the parallel nature of propagation of photons in tissue. It models an arbitrary shaped sample medium as a tetrahedron based mesh and uses an advanced importance sampling scheme. RESULTS: This new simulator speeds up simulations of OCT of inhomogeneous turbid media by about two orders of magnitude. To demonstrate this result, we have compared the computation times of our new parallel simulator and its serial counterpart using two samples of inhomogeneous turbid media. We have shown that our parallel implementation reduced simulation time of OCT of the first sample medium from 407 min to 92 min by using a single GPU card, to 12 min by using 8 GPU cards and to 7 min by using 16 GPU cards. For the second sample medium, the OCT simulation time was reduced from 209 h to 35.6 h by using a single GPU card, and to 4.65 h by using 8 GPU cards, and to only 2 h by using 16 GPU cards. Therefore our new parallel simulator is considerably more practical to use than its central processing unit (CPU)-based counterpart. CONCLUSIONS: Our new parallel OCT simulator could be a practical tool to study the different physical phenomena underlying OCT, or to design OCT systems with improved performance. PMID- 28859834 TI - Two new computational methods for data analysis: A social network analysis-based classifier and the GEEORD SAS module. PMID- 28859835 TI - Corrigendum to "PKC? and PKCbeta cooperate functionally in CD3-induced de novo IL 2 mRNA transcription" [Immunol. Lett. 151 (1-2) (2013) 31-38)]. PMID- 28859836 TI - Corrigendum to "Coronin 1 is dispensable for leukocyte recruitment and liver injury in concanavalin A-induced hepatitis" [Immunol. Lett. 153 (1-2) (2013) 62 70]. PMID- 28859837 TI - Safety of diabetes drugs in patients with heart failure. AB - Heart failure (HF) and diabetes mellitus are 2 clinical conditions that often coexist, particularly in patients older than 65 years. Diabetes mellitus promotes the development of HF and confers a poorer prognosis. Hypoglycaemic agents (either by their mechanism of action, hypoglycaemic action or adverse effects) can be potentially dangerous for patients with HF. In this study, we performed a review of the available evidence on the safety of diabetes drugs in HF, focused on the main observational and experimental studies. Recent studies on cardiovascular safety have evaluated, although as a secondary objective, the impact of new hypoglycaemic agents on HF, helping us understand the neutrality, risks and potential benefits of these agents. PMID- 28859838 TI - Far from the Lonely Crowd: The Trenchant Techno-Cynicism of Mr. Robot. AB - Mr. Robot is a television drama with an unusually techno-cynical premise, tying cybersecurity to the contemporary malaise of social alienation and political disengagement. Weary of consumer capitalism, the show's youthful protagonists seek a more authentic sense of belonging by exploiting the vulnerability of a global economic system that depends critically on creaking technological infrastructures. A remarkable display of iconoclasm for commercial entertainment, Mr. Robot suggests rising discontentment with the commodification of friendship through consumer electronics, but it may also offer media enterprises a model for how to profit from that discontentment in the future. PMID- 28859839 TI - Learning from professionals: Exploring cognitive rehabilitation strategies for the definition of the functional requirements of a telerehabilitation platform. AB - In the past few years, the advances in Information and Communication Technology (ICT) led to the development of platforms and applications that aim to support cognitive rehabilitation therapy that contributes to extend patients' treatment at home. In our research we adopted the Human Centered Approach to design a cognitive rehabilitation platform that is able to provide tools and features tailored to the professional needs and strategies and also able to engage patients in their treatment process. In order to explore the clinicians' point of view on the neuropsychological intervention strategies, we applied two different techniques often used in human factors research: the Critical Decision Method to study professionals' strategies with a descriptive perspective, and the Hierarchical Task Analysis to analyze the processes with a normative view. The results of our research showed that the hybrid approach adopted allowed us to have a better focus on the cognitive rehabilitation process and on the professionals' decision making mechanism. This led to a better understanding of functional requirements for supporting clinician's strategic decision making, in terms of personalization of treatments, cognitive exercises settings and feedback customization. In conclusion, our research highlights the value of the CDM to focus deeply on which functionalities professionals require from a cognitive telerehabilitation system and allowed us to design more precisely clinician patients interactions inside the system compared to prescriptive methods currently used. Our study offers contribution to the comprehension of the rehabilitation processes, suggesting the positive impacts of an "extended" clinic treatment by adopting a flexible and adaptable tool. PMID- 28859840 TI - Corrigendum to "Lung ultrasound predicts decompensation in heart failure outpatients: Another piece to the puzzle but still an incomplete picture" [Int. J. Cardiol. 240 (2017) 324-325]. PMID- 28859841 TI - Use of statins and adverse outcomes in patients with atrial fibrillation: An analysis from the EURObservational Research Programme Atrial Fibrillation (EORP AF) general registry pilot phase. AB - BACKGROUND: Despite oral anticoagulation being highly effective in reducing stroke and thromboembolism, patients with atrial fibrillation (AF) still have a significant residual excess in mortality risk. Additional management strategies are needed to reduce the mortality risk seen in AF patients. METHODS: Ancillary analysis from the EURObservational Research Programme Atrial Fibrillation (EORP AF) General Pilot Registry, to evaluate 1-year outcomes in AF patients according to statin use at baseline. RESULTS: Of 2636 patients, 1286 (48.8%) patients used statins at baseline. Patients prescribed statins had more comorbidities. At 1 year follow-up, logistic regression analysis adjusted for AF type, symptomatic status and CHA2DS2-VASc score demonstrated that statin use was inversely associated with CV death (odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.30-0.82, p<0.0001), all-cause death (OR: 0.52, 95% CI: 0.37-0.73, p<0.0001) and the composite outcome of CV death/any thromboembolic event/bleeding (OR: 0.71, 95% CI: 0.52-0.98, p<0.0001). Similar findings were observed for 'high risk' subgroups including the elderly, primary prevention and high thromboembolic risk AF patients. Survival analysis showed that statins prescribed patients had a lower risk of all-cause death at follow-up (p=0.0433). Multivariate Cox regression analysis found that statin use remained independently associated with a lower risk for all-cause death (hazard ratio [HR]: 0.61, 95% CI: 0.42-0.88, p=0.0077). CONCLUSIONS: Statin use in AF patients was associated with improved outcomes, with an independent association with a lower risk of all-cause death at 1-year follow-up. PMID- 28859842 TI - Freestanding emergency departments can help fill the gap in trauma care. PMID- 28859843 TI - Anterior subcutaneous internal fixation of the pelvis - what rod-to-bone distance is anatomically optimal? AB - INTRODUCTION: Anterior fixation of the pelvis using subcutaneous supra-acetabular pedicle screw internal fixation (INFIX) has proven to be a useful tool by avoiding the downsides of external fixation in patients where open fixation is not suited. The purpose of this study was to find a rod-to-bone distance for the INFIX that allows for minimal hazard to the inguinal neuro-vascular structures and, at the same time, as little as possible interference with the soft tissues of the proximal thigh when the patient is sitting. METHODS: An INFIX was applied to 10 soft-embalmed cadaver pelvises with three different rod-to-bone distances. With each configuration, the relations of the rod to the neuro-vascular and the muscular surroundings were measured in supine and sitting position. RESULTS: Except for the femoral artery, vein and nerve, all investigated anatomical structures of the groin were under compression with a rod-to-bone distance of 1cm. With a rod-to-bone distance of 2cm most of the anatomical structures were safe in supine position, although less than with 3cm. With hip flexion some structures got under compression, especially the lateral femoral cutaneous nerve (LFCN, 80%) and the anterior cutaneous branches of the femoral nerve (ACBFN, 35%). With a rod-to-bone distance of 3cm almost all anatomical structures were safe in supine position, while with hip flexion most superficial structures of the proximal thigh got under compression, especially the LFCN (75%) and the ACBFN (60%). CONCLUSIONS: Aiming for a rod-to-bone distance of 2cm is the safest way with regard to compression of the femoral neuro-vascular bundle and at the same time leads to the least compression of more superficial structures like the LFCN, the ACBFN, or the sartorius and the rectus femoris muscles in sitting position. PMID- 28859844 TI - Risk factors for achilles tendon rupture: A matched case control study. AB - PURPOSE: The purpose of this study was to elucidate whether body mass index (BMI), activity level, and other risk factors predispose patients to Achilles tendon ruptures. MATERIALS AND METHODS: A retrospective review of 279 subjects was performed (93 with Achilles tendon rupture, matched 1:2 with 186 age/sex matched controls with ankle sprains). Demographic variables and risk factors for rupture were tabulated and compared. RESULTS: The rupture group mean BMI was 27.77 (95% CI, 26.94-28.49), and the control group mean BMI was 26.66 (95% CI, 26.06-27.27). These populations were found to be statistically equivalent (p=0.047 and p<0.001 by two one-sided t-test). A significantly higher proportion of those suffering ruptures reported regular athletic activity at baseline (74%) versus controls (59%, p=0.013). CONCLUSION: There was no clinically significant difference found in BMI between patients with ruptures and controls. Furthermore, it was found that patients who sustained ruptures were also more likely to be active at baseline than their ankle sprain counterparts. PMID- 28859845 TI - Guide wire insertion for percutaneous LC2 screws in acetabular and pelvic ring fixation using a transpedicular working cannula. AB - Closed reduction and percutaneous screw fixation (CRIF) of iliac crescent fractures and fractures of the anterior column of the acetabulum has become an established method in the treatment of these injuries. After reduction, safe insertion of a guide wire is a key step during this procedure. We present a technique that can facilitate introducing the guide wire under fluoroscopic guidance and allow for decreased radiation exposure. PMID- 28859846 TI - The influence of the hips position on measurements of posterior tilt in a valgus impacted femoral neck fracture. AB - INTRODUCTION: Lateral radiographs are important for the evaluation of Garden I and II femoral neck fractures. These fractures appear undisplaced in the anteroposterior view, but posterior tilt of the femoral head may still be present in the lateral view. The influence of posterior tilt is, however, debated, which could be caused by the use of non-standardized cross-table radiographs in the conflicting reports. The aim of this bone-model study was therefore to evaluate the influence of the hips position on measurements of posterior tilt. MATERIALS AND METHODS: We generated models of a Garden I-II femoral neck fracture and the non-injured contralateral femur from CT reconstructions with a 3D-printer. Lateral radiographs of the models were obtained in positions ranging from 90 degrees internal rotation (IR) to 90 degrees external rotation (ER) and 0-80 degrees flexion. Two investigators independently measured posterior tilt on 27 lateral radiographs obtained from each model. RESULTS: The inter-tester ICC was 0.91 (0.84-0.94), standard error of measurement (SEM) 2.6, and minimal detectable change (MDC) 7.2. The median (range) posterior tilt for the fracture model was 21.9 degrees (5.0, 33.8) and 23.6 degrees (2.2, 28.6) for observer 1 and observer 2, respectively. The corresponding posterior tilt within the range of 10 degrees IR to 40 degrees ER and 0 to 30 degrees flexion of the fracture model, was 27.3 degrees (24.0, 33.8) and 26.3 degrees (24.8, 28.6). DISCUSSION: The range of posterior tilt measurements for positions of the proximal femur restricted from 10 degrees IR to 40 degrees ER and 0 to 30 degrees flexion, was above the MDC for observer 1, and below the MDC for observer 2. These findings indicate that rotation and flexion affect measurements of posterior tilt, but the influence may be negligible for positions of the injured extremity that are clinically relevant during cross-table lateral radiographs. A larger study that accounts for variations in anatomy and fracture displacement is required to confirm these findings. PMID- 28859847 TI - Estimating oil pollution risk in environmentally sensitive areas of petrochemical terminals based on a stochastic numerical simulation. AB - This paper presents a method based on the oceanic current model and the oil spill model to evaluate the pollution risk of sensitive resources when oil spills occur. Moreover, this study proposes a novel impact index based on the risk theory to improve the risk assessment accuracy. The impact probability and the first impact time of the oil spill are calculated through a stochastic numerical simulation. The risk assessment content is enriched by establishing an impact model that considers the impact of sensitive index and spillage. Finally, the risk score of sensitive resources in an oil spill accident is visualized for formulating a scientific and effective protection priority order in a contamination response strategy. This study focuses on integrating every possible impact factor that plays a role in risk assessment and helps to provide a better theoretical support for protecting sensitive resources. PMID- 28859848 TI - Chronic in vivo nitric oxide deficiency impairs cardiac functional recovery after ischemia in female (but not male) mice. AB - Nitric oxide (NO) is an important regulator of cardiac function and plays a key role in ischemic cardioprotection. The role of chronic NO deficiency in coordinating ischemic vulnerability in female myocardium has not been established. The aim of this study was to determine the influence of chronic in vivo NO synthase inhibition in modulating ex vivo ischemia-reperfusion responses in female hearts (relative to males). Mice were subjected to l-NAME (l-NG Nitroarginine-methyl-ester) treatment in vivo for 8weeks. Cardiac fibrotic, inflammatory and cardiomyocyte Ca2+ handling related gene expression changes were assessed. Hearts were Langendorff-perfused, subjected to 20min global ischemia with 45min reperfusion. In response to this moderate ex vivo ischemic insult, hearts derived from l-NAME treated female animals exhibited increased incidence of reperfusion arrhythmias, diastolic abnormality and reduced contractile recovery in reperfusion. This differential response was observed even though baseline performance of hearts from l-NAME treated animals was not different to vehicle controls, myocardial inflammatory and fibrotic indices were similar in males and females and the systolic blood pressure effect of l-NAME administration was equivalent in both sexes. Evaluation of a subgroup of mice with cardiomyocyte specific mineralocorticoid receptor deletion suggests involvement of this receptor in NO-deficiency mediated responses. To examine underlying pre-disposing mechanisms, expression of a panel of candidate genes encoding proteins involved in electromechanical homeostasis (particularly relevant to ischemic challenge) was evaluated in normoxic myocardial tissues from the l-NAME- and vehicle-treated animals. Analysis revealed that l-NAME treatment in females selectively regulated expression of genes related directly and indirectly to cardiomyocyte Ca2+ handling in a manner consistent with destabilization of Ca2+ homeostasis and arrhythmogenesis. Our investigation provides new insight into the role of sustained decrease in NO bioavailability in determining distinctive female cardiac vulnerability to ischemic challenge. PMID- 28859849 TI - Comparative analysis of the immune responses induced by native versus recombinant versions of the ASP-based vaccine against the bovine intestinal parasite Cooperia oncophora. AB - The protective capacities of a native double-domain activation-associated secreted protein (ndd-ASP)-based vaccine against the cattle intestinal nematode Cooperia oncophora has previously been demonstrated. However, protection analysis upon vaccination with a recombinantly produced antigen has never been performed. Therefore, the aim of the current study was to test the protective potential of a Pichia-produced double-domain ASP (pdd-ASP)-based vaccine against C. oncophora. Additionally, we aimed to compare the cellular and humoral mechanisms underlying the vaccine-induced responses by the native (ndd-ASP) and recombinant vaccines. Immunisation of cattle with the native C. oncophora vaccine conferred significant levels of protection after an experimental challenge infection, whereas the recombinant vaccine did not. Moreover, vaccination with ndd-ASP resulted in a higher proliferation of CD4-T cells both systemically and in the small intestinal mucosa when compared with animals vaccinated with the recombinant antigen. In terms of humoral response, although both native and recombinant vaccines induced similar levels of antibodies, animals vaccinated with the native vaccine were able to raise antibodies with greater specificity towards ndd-ASP in comparison with antibodies raised by vaccination with the recombinant vaccine, suggesting a differential immune recognition towards the ndd-ASP and pdd-ASP. Finally, the observation that animals displaying antibodies with higher percentages of recognition towards ndd-ASP also exhibited the lowest egg counts suggests a potential relationship between antibody specificity and protection. PMID- 28859850 TI - IL-4/5 signalling plays an important role during Litomosoides sigmodontis infection, influencing both immune system regulation and tissue pathology in the thoracic cavity. AB - Approximately 100 million people suffer from filarial diseases including lymphatic filariasis (elephantiasis), onchocerciasis (river blindness) and loiasis. These diseases are amongst the most devastating of the neglected tropical diseases in terms of social and economic impact. Moreover, many infection-induced immune mechanisms in the host, their relationship to disease related symptoms and the development of pathology within the site of infection remain unclear. To improve on current drug therapies or vaccines, further studies are necessary to decipher the mechanisms behind filaria-driven immune responses and pathology development, and thus the rodent model of Litomosoides sigmodontis can be used to unravel host-filaria interactions. Interestingly, BALB/c mice develop a patent state (release of microfilariae, the transmission life-stage, into the periphery) when exposed to L. sigmodontis. Thus, using this model, we determined levels of host inflammation and pathology development during a L. sigmodontis infection in vivo for the first known time. Our study reveals that after 30days p.i., inflammation and pathology began to develop in infected wild type BALB/c mice between the lung and diaphragm, close to the site of infection - the thoracic cavity. Interestingly, infected IL-4Ralpha/IL-5-/- BALB/c mice had accentuated inflammation of the pleural lung and pleural diaphragm, and higher parasite burdens. Corresponding to the pleural inflammation, levels of IP-10, MIP 1alpha, MIP-1beta, MIP-2 and RANTES were significantly elevated in the thoracic cavity fluid of infected IL-4Ralpha/IL-5-/- mice compared with wild type controls. Moreover, upon L. sigmodontis antigen stimulation, IFN-gamma and IL-17A secretions by cells isolated from draining lymph nodes of IL-4Ralpha/IL-5-/- mice were significantly elevated, whereas secretion of IL-5, IL-13 and IL-10 was reduced. Elevated filaria-specific IFN-gamma secretion was also observed in spleen-derived CD4+ T cell co-cultures from IL-4Ralpha/IL-5-/- mice. In summary, this study unravels the essential role of IL-4/IL-5 signalling in controlling immunity against filarial infections and demonstrates the requirement of this pathway for the host to control ensuing pathology and inflammation. PMID- 28859851 TI - Association of imaging abnormalities of the subcallosal septal area with Alzheimer's disease and mild cognitive impairment. AB - AIM: To evaluate the use the distance between the adjacent septal nuclei as a surrogate marker of septal area atrophy seen in Alzheimer's disease (AD). MATERIALS & METHODS: Interseptal distance (ISD) was measured, blind to clinical details, in 250 patients who underwent computed tomography (CT) of the brain at University Hospital of Wales. Clinical details including memory problem history were retrieved. An ISD cut-off value that discriminated those with and without memory symptoms was sought. ISD measurements were also made in 20 AD patients. To test both the method and the defined cut-off, measurements were then made in an independent cohort of 21 mild cognitive impairment (MCI) patients and 45 age matched healthy controls, in a randomised and blinded fashion. RESULTS: ISD measurement was achieved in all patients. In 28 patients with memory symptoms, the mean ISD was 5.9 mm compared with 2.3 mm in those without overt symptoms (p=0.001). The optimum ISD cut-off value was 4 mm (sensitivity 85.7% and specificity 85.8%). All AD patients had an ISD of >4 mm (mean ISD= 6.1 mm). The mean ISD for MCI patients was 3.84 mm compared with 2.18 mm in age-matched healthy controls (p=0.001). Using a 4 mm cut-off correctly categorised 10 mild cognitive impairment patients (47.6%) and 38 healthy controls (84.4%). CONCLUSION: ISD is a simple and reliable surrogate measurement for septal area atrophy, applicable to CT and magnetic resonance imaging (MRI). It can be used to help select patients for further investigation. PMID- 28859852 TI - Initial radiofrequency ablation failure for hepatocellular carcinoma: repeated radiofrequency ablation versus transarterial chemoembolisation. AB - AIM: To compare the long-term therapeutic outcomes of repeated radiofrequency ablation (RFA) with that of transarterial chemoembolisation (TACE) in patients with local tumour progression (LTP) after initial RFA treatment for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. Between July 2006 and February 2012, 713 patients underwent RFA for single HCC as a first-line treatment. Fifty-eight patients who showed LTP as initial tumour recurrence post-RFA treatment were included. Patients were treated with either repeated RFA (n=33) or TACE (n=25). TACE was performed as an alternative therapeutic option when repeated RFA was not feasible based on the planning ultrasonography. Recurrence-free and overall survival rates were estimated using the Kaplan-Meier method. Prognostic factors for outcomes were evaluated using the Cox proportional hazards model. RESULTS: Both groups did not show significant differences in terms of baseline characteristics, with the exception being the proportion of subphrenic tumours (p=0.031). The RFA and TACE groups did not differ significantly in their 5-year recurrence-free and overall survival rates (17% versus 10.7% and 72.7% versus 51.9%, respectively, with all p values >0.05). In addition, multivariate analyses revealed that type of treatment was not associated with recurrence-free or overall survival in patients with post RFA LTP. CONCLUSION: TACE is an effective treatment, comparable to repeated RFA, in patients with LTP after initial RFA when repeated RFA is not feasible. PMID- 28859854 TI - Erratum. PMID- 28859853 TI - Ultrasound carpal tunnel syndrome: additional criteria for diagnosis. AB - AIM: To define the usefulness of the cross-sectional area (CSA) of the median nerve distal to the carpal tunnel in addition to other established common parameters in the diagnosis of carpal tunnel syndrome (CTS). MATERIALS AND METHODS: Forty-four wrists from 24 symptomatic CTS patients and 32 wrists from 17 asymptomatic volunteers were evaluated by ultrasound. The CSA of the median nerve was measured at four pre-selected levels, i.e., proximal, inlet, outlet, and distal to the carpal tunnel. The flattening ratio, intraneural vascularity, neural fasciculation, and retinacular palmar bowing were also assessed. RESULTS: Significant differences were found between the CTS and control groups for median nerve CSA proximal and distal (p<0.001) to the tunnel as well as retinacular bowing (p<0.001). Using the receiver operating characteristic (ROC) curve, the sensitivity, specificity, and accuracy of using a cut-off of >14 mm2 of CSA proximal and distal to the tunnel were 75%, 87.5%, 86.8% and 63.6%, 100%, 78.9%, respectively. Using either CSA proximal or distal to the tunnel or bowing retinaculum at the outlet >1 mm yielded a sensitivity, specificity, and accuracy of 100%, 84.3% and 93.4%, respectively. CONCLUSION: The median nerve CSA proximal and distal to the carpal tunnel and bowing of the retinaculum at the outlet are helpful in diagnosis of CTS. PMID- 28859855 TI - Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis. AB - BACKGROUND & AIMS: Obesity-induced nonalcoholic fatty liver disease (NAFLD) develops, in part, via excess insulin-stimulated hepatic de novo lipogenesis, which increases, paradoxically, in patients with obesity-induced insulin resistance. Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) terminates insulin signaling by dephosphorylating Akt; levels of PHLPP2 are reduced in livers from obese mice. We investigated whether loss of hepatic PHLPP2 is sufficient to induce fatty liver in mice, mechanisms of PHLPP2 degradation in fatty liver, and expression of genes that regulate PHLPP2 in livers of patients with NAFLD. METHODS: C57BL/6J mice (controls), obese db/db mice, and mice with liver-specific deletion of PHLPP2 (L-PHLPP2) fed either normal chow or high-fat diet (HFD) were analyzed for metabolic phenotypes, including glucose tolerance and hepatic steatosis. PHLPP2-deficient primary hepatocytes or CRISPR/Cas9-mediated PHLPP2-knockout hepatoma cells were analyzed for insulin signaling and gene expression. We performed mass spectrometry analyses of liver tissues from C57BL/6J mice transduced with Ad-HA-Flag-PHLPP2 to identify posttranslational modifications to PHLPP2 and proteins that interact with PHLPP2. We measured levels of mRNAs by quantitative reverse transcription polymerase chain reaction in liver biopsies from patients with varying degrees of hepatic steatosis. RESULTS: PHLPP2-knockout hepatoma cells and hepatocytes from L PHLPP2 mice showed normal initiation of insulin signaling, but prolonged insulin action. Chow-fed L-PHLPP2 mice had normal glucose tolerance but hepatic steatosis. In HFD-fed C57BL/6J or db/db obese mice, endogenous PHLPP2 was degraded by glucagon and PKA-dependent phosphorylation of PHLPP2 (at Ser1119 and Ser1210), which led to PHLPP2 binding to potassium channel tetramerization domain containing 17 (KCTD17), a substrate-adaptor for Cul3-RING ubiquitin ligases. Levels of KCTD17 mRNA were increased in livers of HFD-fed C57BL/6J or db/db obese mice and in liver biopsies patients with NAFLD, compared with liver tissues from healthy control mice or patients without steatosis. Knockdown of KCTD17 with small hairpin RNA in primary hepatocytes increased PHLPP2 protein but not Phlpp2 mRNA, indicating that KCTD17 mediates PHLPP2 degradation. KCTD17 knockdown in obese mice prevented PHLPP2 degradation and decreased expression of lipogenic genes. CONCLUSIONS: In mouse models of obesity, we found that PHLPP2 degradation induced lipogenesis without affecting gluconeogenesis. KCTD17, which is up regulated in liver tissues of obese mice and patients with NAFLD, binds to phosphorylated PHLPP2 to target it for ubiquitin-mediated degradation; this increases expression of genes that regulate lipogenesis to promote hepatic steatosis. Inhibitors of this pathway might be developed for treatment of patients with NAFLD. PMID- 28859857 TI - An ex vivo experiment to reproduce a forward fall leading to fractured and non fractured radii. AB - Forward falls represent a risk of injury for the elderly. The risk is increased in elderly persons with bone diseases, such as osteoporosis. However, half of the patients with fracture were not considered at risk based on bone density measurement (current clinical technique). We assume that loading conditions are of high importance and should be considered. Real loading conditions in a fall can reach a loading speed of 2m/s on average. The current study aimed to apply more realistic loading conditions that simulate a forward fall on the radius ex vivo. Thirty radii from elderly donors (79y.o.+/-12y.o., 15 males, 15 females) were loaded at 2m/s using a servo-hydraulic testing machine to mimic impact that corresponds to a fall. Among the 30 radii, 14 had a fracture after the impact, leading to two groups (fractured and non-fractured). Surfacic strain fields were measured using stereovision and allow for visualization of fracture patterns. The average maximum load was 2963+/-1274N. These experimental data will be useful for assessing the predictive capability of fracture risk prediction methods such as finite element models. PMID- 28859856 TI - Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells. AB - BACKGROUND & AIMS: The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia. METHODS: Primary enteric glial cultures were generated from the VillinCre:Men1FL/FL:Sst-/- mice or C57BL/6 mice (controls), with or without inhibition of gastric acid by omeprazole. Primary enteric glial cells from C57BL/6 mice were incubated with gastrin and separated into nuclear and cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or inhibit protein kinase A (a family of enzymes whose activity depends on cellular levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures using an ELISA. Immunoprecipitation with menin or ubiquitin was used to demonstrate post-translational modification of menin. Primary glial cells were incubated with leptomycin b and MG132 to block nuclear export and proteasome activity, respectively. We obtained human duodenal, lymph node, and pancreatic gastrinoma samples, collected from patients who underwent surgery from 1996 through 2007 in the United States or the United Kingdom. RESULTS: Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas. CONCLUSIONS: MEN1 associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae. PMID- 28859858 TI - Obesity and spinal loads; a combined MR imaging and subject-specific modeling investigation. AB - Epidemiological studies have identified obesity asa possible risk factor for low back disorders. Biomechanical models can help test such hypothesis and shed light on the mechanism involved. A novel subject-specific musculoskeletal-modelling approach is introduced to estimate spinal loads during static activities in five healthy obese (BMI>30kg/m2) and five normal-weight (200.05). Heavier subjects did not necessarily have larger muscle moment arms (e.g., they were larger in 64kg (BMI=20.7kg/m2) subject than 78kg (BMI=24.6kg/m2) subject) or greater T1-L5 trunk weight (e.g., the 97kg (BMI=31kg/m2) subject had similar trunk weight as 109kg (BMI=33.3kg/m2) subject). Obese individuals had in average greater spinal loads than normal-weight ones but heavier subjects did not necessarily have greater spinal loads (117kg (BMI=40.0kg/m2) subject had rather similar L5-S1 compression as 105kg (BMI=34.7kg/m2) subject). Predicted L4-L5 intradiscal pressures for the normal weight subjects ranged close to the measured values (R2=0.85-0.92). Obese individuals did not necessarily have greater IDPs than normal-weight ones. PMID- 28859859 TI - Letter to the Editor regarding 'How symmetric are metal-on-metal hip resurfacing patients during gait? Insights for the rehabilitation'. PMID- 28859860 TI - Visual reminders of death enhance nociceptive-related cortical responses and event-related alpha desynchronisation. AB - Previous research suggests that prompting individuals to think on their own mortality affects their perception of painful somatic stimuli and related brain activity. Grounded on the assumption that reminders of mortality may recruit threat-defence mechanisms similar to the ones activated by painful nociceptive stimuli, we hypothesize that the effects exerted by linguistic reminders of death on pain perception and brain activity would be elicited by passive observation of death-related pictures vs. more generic threat-related pictures. Results showed an increase of the laser evoked P2 amplitude and oscillatory theta activity when participants observed death-related images. However, no change in pain ratings was found. Moreover, observation of death-related content was linked to increased oscillatory alpha desynchronisation but not to variations of visual evoked potentials amplitude. Our findings indicate that pairing potentially noxious stimuli with death-related images exerts a preferential modulation of nociceptive and visual cortical representations. PMID- 28859861 TI - Patient-Reported Outcome Measures in Pruritus: A Systematic Review of Measurement Properties. AB - This review aims to systematically evaluate studies on the measurement properties of patient-reported outcome measures in pruritus, especially for use in clinical trials. Validation studies on instruments were identified based on a PubMed literature search. The consensus-based standards for the selection of health status measurement instruments checklist was used to evaluate the studies' methodological quality, and the consensus-based standards for the selection of health status measurement instruments criteria were used to synthesize the instruments' measurement properties. Twenty-three studies were included, which contain 37 examinations of reliability and/or validity for 23 different outcome measures. The methodological quality of reliability and validity evidence was moderate for six outcome measures; for these measures, psychometric property rating was adequate too, making them suitable for use in clinical trials. Itch severity scale, itchy quality of life, numerical rating scale-6, numerical rating scale-11, visual analog scale (horizontal), and verbal numerical rating scale-4 are currently the most appropriate patient-reported outcome measures with regard to overall reliability and validity. PMID- 28859862 TI - The promise of signal transduction in genetically driven sarcomas of the nerve. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome. Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas arising from peripheral nerve sheaths, and the most commonly lethal feature associated with NF1. The hallmark of NF1 and NF1-related MPNST is the loss of neurofibromin expression. Loss of neurofibromin is considered a tumor promoting event, and leads to constitutive activation of RAS and its downstream effectors. However, RAS activation alone is not sufficient for MPNST formation, and additional tumor suppressors and signaling pathways have been implicated in tumorigenesis of MPNST. Taking advantage of the rapid development of novel therapeutics targeting key molecular pathways across all cancer types, the best in-class modulators of these pathways can be assessed in pre-clinical models and translated into clinical trials for patients with MPNST. Here, we describe the genetic changes and molecular pathways that drive MPNST formation and highlight the promise of signal transduction to identify therapies that may treat these tumors more effectively. PMID- 28859863 TI - Catechol-O-Methyltransferase gene (val158met) polymorphisms and anxious symptoms in early childhood: The roles of hypothalamus-pituitary-adrenal axis reactivity and life stress. AB - Individual differences in hypothalamus-pituitary-adrenal (HPA) axis reactivity to stress (measured via salivary cortisol) have been widely implicated in the etiology of internalizing problems such as depression and anxiety. Literature suggests that stress during early childhood is an important source of contextual risk although its effects may be moderated by polymorphisms of neurotransmitter genes. The COMT val158met is one such polymorphism, and literature documents its link to internalizing problems. To extend these findings, and to better understand the role of this polymorphism in developmental risk, we investigated links between the val158met polymorphism and early-age cortisol response. Additionally, we investigated whether cortisol reactivity mediated the link between COMT and emerging internalizing symptoms. The study was conducted in a community sample of 409 preschoolers. Saliva samples were collected pre-stress task (baseline) and every 10min post-stress task for one-hour to asses cortisol response. Child anxious and depressive symptoms were tabulated based on parent reports. Markers of early childhood stress included marital discord, socio economic status and the UCLA Life Stress Interview. Findings indicated that the val158met polymorphism is associated with childhood cortisol response (p<0.05). A gene-environment interaction between val158met and life stress also predicted child anxiety symptoms (p<0.01). Finally, cortisol response mediated the main effect of val158met on child anxiety symptoms (pathway ps<0.05). Analyses suggest that COMT val158met moderates the influence of early life stress on preschool-age symptoms of anxiety. Additionally, cortisol reactivity acts as a mechanistic mediator of the main-effect of COMT genotype on child anxious symptoms. PMID- 28859864 TI - Impaired decision making under risky conditions in the acute phase of Graves' thyroitoxicosis. AB - The patients with Graves' thyroitoxicosis often complain that they have neuropsychiatric symptoms and impaired cognitive function. Decision making is important and complex process involving the interaction and integration of a series of cognitive components. In the 31 newly diagnosed patients with Graves' thyroitoxicosis and 30 healthy controls, we used the Hamilton Anxiety Rating Scale (HAMD), Hamilton Depression Rating Scale (HAMD) and The Game of Dice Task (GDT) to assess the emotion and decision making under risky conditions. The patients with Graves' disease had higher score on HAMA and HAMD, and had poorer performance in GDT than healthy controls. A negative correlation was found between utilization of negative feedback and score of HAMA in the patients with Graves' disease. Our findings in Graves' disease might be association with the extensive brain disorders including prefrontal cortex and the limbic system, and dopamine dysfunction. PMID- 28859865 TI - Ischemic stroke damages the intestinal mucosa and induces alteration of the intestinal lymphocytes and CCL19 mRNA in rats. AB - The immunoreaction has a pivotal effect on ischemic stroke. It has been demonstrated that intestinal lymphocytes infiltrate into the brain and aggravate tissue injury after stroke. However, less attention has been paid to the influence on the intestinal immunology as well as morphology. Here, we utilized a rat permanent middle cerebral artery occlusion (MCAO) model to investigate the influences on intestinal mucosa, lymphocytes of the gut-associated lymphoid tissue (GALT), and the intestinal expression of CCL25 mRNA and CCL19 mRNA of stroke. Rats were randomly divided into stroke, sham, and control groups. Stroke and sham groups were further divided into interval groups of 6h, 12h, and 24h after surgery. Intestinal pathophysiological changes were observed by hematoxylin eosin (H&E) staining. The lymphocyte numbers were detected by flow cytometry. The expression of CCL25 mRNA and CCL19 mRNA was tested with the PCR technique. We found significant necrosis and shedding of the epithelium after stroke. Moreover, the lesion aggravated with time. In addition, there was a significant increase of T lymphocytes in Peyer's patches (PPs), especially at 12h and 24h after stroke, while no differences in the number of B lymphocytes and the intraepithelial lymphocytes (IELs) were found. The data displayed no alteration of CCL25 mRNA expression. In contrast, an upregulation of CCL19 mRNA expression was detected at 6h after stroke. This study showed that ischemic stroke significantly damaged the intestinal epithelium and activated intestinal immunity. PMID- 28859866 TI - Association of KIBRA polymorphism with risk of Alzheimer's disease: Evidence based on 20 case-control studies. AB - Kidney and brain expressed protein (KIBRA) has been demonstrated to play an important role in episodic memory by genome-wide association study (GWAS). Since memory impairment is a typical clinical feature of AD, KIBRA has been considered to be a candidate gene for AD. Previous case-control association studies on KIBRA SNP rs17070145 have yielded inconsistent results. Thus, this study aimed to assess the risk of KIBRA polymorphism for sporadic AD via meta-analysis. A total of 7 articles including 20 case-control studies were included in this study. Results showed that rs17070145 had a significant association with AD risk in the homozygote comparison model (OR=1.23; 95%CI=1.07, 1.41), and the dominant model (OR=1.14; 95%CI=1.02, 1.26). In the subgroup analysis by ethnicity, an increased risk was detected in the homozygote comparison model and the dominant model among Caucasians, as well as in the homozygote comparison model and recessive model among Asians. Notably, in the subgroup analysis by age, a borderline increased risk was detected in the Old subgroup under the dominant model (OR=1.19; 95%CI=1.00, 1.43), but not in the Young subgroup. Results of the present meta analysis indicated that KIBRA polymorphism rs17070145 might increase the risk of sporadic AD, especially among Caucasians, Asians and elders. PMID- 28859867 TI - Tanshinone IIA attenuates nerve transection injury associated with nerve regeneration promotion in rats. AB - Tanshinone IIA (Tan IIA) is the major pharmacological constituent of Salvia miltiorrhiza Bunge (Danshen) for the therapeutic purpose of preventing ischemic injury and treating cerebrovascular disease. The aim of the present study was to explore the potential neuroprotective effects of Tan IIA in sciatic nerve transection injury. We investigated the possible beneficial effects of Tan IIA in promoting nerve regeneration after nerve transection injury in rats. Nerve transection injury was induced in male Sprague-Dawley rats by left sciatic nerve transection. After neuroanastomosis, the rats were intraperitoneally (IP) injected with 6mg/kg, 15mg/kg, or 40mg/kg Tan IIA once daily for 12 weeks; the vehicle and positive control groups were injected with normal saline and mecobalamin (MeCbl, 100MUg/kg), respectively. Axonal regeneration and functional recovery were evaluated by a range of morphological and functional measures 12 weeks after neuroanastomosis. The administration of 15mg/kg and 40mg/kg Tan IIA and MeCbl achieved better axonal regeneration with significant restoration of motor function as well as a marked decrease in Fluoro-Gold (FG)-labeled neurons and increased nerve regeneration. At 12 weeks post-surgery, 40mg/kg Tan IIA showed a better neuroprotective effect than 15mg/kg Tan IIA and MeCbl. There were no statistical differences between the 15mg/kg Tan IIA and MeCbl groups or the control and 6mg/kg Tan IIA groups. Our findings demonstrate that Tan IIA can alleviate nerve injury and promote nerve regeneration in a sciatic nerve transection model in rats, providing supportive evidence for Tan IIA as an effective potential therapeutic remedy for peripheral nerve injury. PMID- 28859868 TI - Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease. AB - BACKGROUND & AIMS: Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids. METHODS: We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients' samples, we investigated the effects of PGE2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration. RESULTS: At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P < .0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 +/- 4.8 ng/mL) compared with plasma collected before treatment (17.7 +/- 4.5 ng/mL; P = .0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P = .0012). AD/ACLF plasma protein binding to PGE2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P < .0001). Circulating levels of PGE2, lipopolysaccharide, and inflammatory or anti inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group. CONCLUSIONS: Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma mediated immune dysfunction by binding and inactivating PGE2. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793). PMID- 28859869 TI - Conservatism predicts lapses from vegetarian/vegan diets to meat consumption (through lower social justice concerns and social support). AB - Lapses from vegetarian and vegan (i.e., veg*n) food choices to meat consumption are very common, suggesting that sustaining veg*nism is challenging. But little is known about why people return to eating animals after initially deciding to avoid meat consumption. Several potential explanatory factors include personal inconvenience, meat cravings, awkwardness in social settings, or health/nutrition concerns. Here we test the degree to which political ideology predicts lapsing to meat consumption. Past research demonstrates that political ideology predicts present levels of meat consumption, whereby those higher in right-wing ideologies eat more animals, even after controlling for their hedonistic liking of meat (e.g., Dhont & Hodson, 2014). To what extent might political ideology predict whether one has lapsed from veg*n foods back to meat consumption? In a largely representative US community sample (N = 1313) of current and former veg*ns, those higher (vs. lower) in conservatism exhibited significantly greater odds of being a former than current veg*n, even after controlling for age, education, and gender. This ideology-lapsing relation was mediated (i.e., explained) by those higher (vs. lower) in conservatism: (a) adopting a veg*n diet for reasons less centered in justice concerns (animal rights, environment, feeding the poor); and (b) feeling socially unsupported in their endeavor. In contrast, factors such as differential meat craving or lifestyle inconvenience played little mediational role. These findings demonstrate that ideology and justice concerns are particularly relevant to understanding resilience in maintaining veg*n food choices. Implications for understanding why people eat meat, and how to develop intervention strategies, are discussed. PMID- 28859870 TI - The Natural History of Erectile Dysfunction After Prostatic Radiotherapy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Erectile dysfunction (ED) after treatment for prostate cancer with radiotherapy (RT) is well known, and pooled estimates of ED after RT will provide more accurate patient education. AIM: To systematically evaluate the natural history of ED in men with previous erectile function after prostate RT and to determine clinical factors associated with ED. METHODS: We performed a review of the PubMed and Medline, Embase, Cochrane Library, and Web of Science databases in April 2016 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports included a measurement of ED before and after prostate RT. Two hundred seventy-eight abstracts were screened and 105 publications met the criteria for inclusion. Only men with known erectile function before RT were included in the analysis. OUTCOME: ED after RT of the prostate. RESULTS: In total, 17,057 men underwent brachytherapy (65%), 8,166 men underwent external-beam RT (31%), and 1,046 men underwent both (4%). Seven common instruments were used to measure ED, including 23 different cutoffs for ED. The Sexual Health Inventory for Men (SHIM) was used in 31 studies (30%). Pooled estimates of SHIM-confirmed ED (score <10-17) suggested the prevalence of ED after RT is 34% of men (95% CI = 0.29-0.39) at 1 year and 57% (95% CI = 0.53 0.61) at 5.5 years. Compared with brachytherapy, studies of the two types of radiation increased the proportion of new-onset ED found by 12.3% of studies (95% CI = 2.3-22.4). For every 10% who were lost to follow-up, the proportion of ED reported increased by 2.3% (95% CI = 0.03-4.7). CLINICAL IMPLICATIONS: ED is common regardless of RT modality and increases during each year of follow-up. Using the SHIM, ED is found in approximately 50% patients at 5 years. STRENGTHS AND LIMITATIONS: The strengths of this systematic review include strict inclusion criteria of studies that measured baseline erectile function, no evidence for large effect size bias, and a large number of studies, which allow for modeling techniques. However, all data included in this analysis were observational, which leaves the possibility that residual confounding factors increase the rates of ED. CONCLUSION: Definitions and measurements of ED after RT vary considerably in published series and could account for variability in the prevalence of reported ED. Loss to follow-up in studies could bias the results to overestimate ED. Gaither TW, Awad MA, Osterberg EC, et al. The Natural History of Erectile Dysfunction After Prostatic Radiotherapy: A Systematic Review and Meta-Analysis. J Sex Med 2017;14:1071-1078. PMID- 28859871 TI - "Stiction Syndrome": Non-Operative Management of Patients With Difficult AMS 700 Series Inflation. AB - INTRODUCTION: Static friction (stiction) is a mechanical phenomenon in which a state of increased resistance exists across a control valve mechanism. AIM: To present a strategy for non-operative management of inflatable penile prosthesis (IPP) cases with pump malfunction from pump valve stiction. METHODS: All patients had American Medical Systems (AMS; Minnetonka, MN, USA) 700 series Momentary Squeeze IPPs with transient pump malfunction owing to pump valve stiction after extended periods of device inactivity. MAIN OUTCOME MEASURES: Our evolving non operative management experience with the "forced deflation" maneuver is described. This technique has successfully prevented the need for surgical pump replacement. Of patients with IPP who were instructed to inflate and deflate daily to prevent stiction recurrence, none have re-presented with difficult inflation. RESULTS: Of 306 patients receiving the AMS 700 series IPP at our institution from 2007 through 2015, 6 (1.9%) presented with difficulty activating the Momentary Squeeze pump (from 2011 through 2015). Four additional patients were referred from outside institutions with the same complaint. All patients (10 of 10, 100%) presented after a prolonged period of inactivity (minimum = 6 weeks) during which the IPP was not cycled and remained stagnant. Although the initial four patients (40%) underwent surgical exploration with pump mobilization and replacement, the six most recent patients (60%) were successfully instructed in the forced deflation maneuver in the office, which enabled the device to cycle normally thereafter. CONCLUSION: Device inactivity, for as little as 6 weeks, can predispose to Momentary Squeeze pump valve malfunction; and a regimen of daily IPP cycling could prevent stiction-related malfunction. Our findings should encourage practitioners to attempt conservative management of patients with "stiction syndrome" whenever possible, thereby avoiding unnecessary surgery. Kavoussi NL, Viers BR, VanDyke ME, et al. "Stiction Syndrome": Non-Operative Management of Patients With Difficult AMS 700 Series Inflation. J Sex Med 2017;14:1079-1083. PMID- 28859872 TI - Different Characteristics of the Female Sexual Function Index in a Sample of Sexually Active and Inactive Women. AB - BACKGROUND: The Female Sexual Function Index (FSFI) is a widely used measurement tool to assess female sexual function along the six dimensions of desire, arousal, lubrication, orgasm, satisfaction, and pain. However, the structure of the questionnaire is not clear, and several studies have found high correlations among the dimensions, indicating that a common underlying "sexual function" factor might be present. AIM: To investigate whether female sexual function is best understood as a multidimensional construct or, alternatively, whether a common underlying factor explains most of the variance in FSFI scores, and to investigate the possible effect of the common practice of including sexually inactive women in studies using the FSFI. METHODS: The sample consisted of 508 women: 202 university students, 177 patients with endometriosis, and 129 patients with polycystic ovary syndrome. Participants completed the FSFI, and confirmatory factor analyses were used to test the underlying structure of this instrument in the total sample and in samples including sexually active women only. OUTCOMES: The FSFI is a multidimensional self-report questionnaire composed of 19 items. RESULTS: Strong positive correlations were found among five of the six original factors on the FSFI. Confirmatory factor analyses showed that in the total sample items loaded mainly on the general sexual function factor and very little variance was explained by the specific factors. However, when only sexually active women were included in the analyses, a clear factor structure emerged, with items loading on their six specific factors, and most of the variance in FSFI scores was explained by the specific factors, rather than the general factor. University students reported higher scores, indicating better functioning compared with the patient samples. CLINICAL TRANSLATION: The reliable and valid assessment of female sexual function can contribute to better understanding, prevention, and treatment of different sexual difficulties and dysfunctions. STRENGTHS AND LIMITATIONS: This study provides a rigorous statistical test of the structure of the FSFI and an explicit decision rule for categorizing sexually inactive women. Limitations include a lack of control over the circumstances of data collection. CONCLUSION: This study supports the use of the FSFI as a multidimensional measurement of female sexual function but highlights the need to establish clear decision rules for the inclusion or exclusion of sexually active and inactive respondents. Hevesi K, Meszaros V, Kovi Z, et al. Different Characteristics of the Female Sexual Function Index in a Sample of Sexually Active and Inactive Women. J Sex Med 2017;14:1133-1141. PMID- 28859873 TI - A 10-Year Interval Study About the Sexual Life and Attitudes of Korean Women: The Korean Internet Sexuality Survey (KISS) 2014, Part 2. AB - BACKGROUND: Many studies on sexual attitudes and behavior have been performed to improve sexual health. AIM: To evaluate changing trends in Korean female sexual life and attitudes in an internet-based survey at 10-year intervals. METHODS: The survey was targeted toward 20- to 59-year-old women who were asked to complete the questionnaire only if they were sexually active. The survey contained 110 questions about demographic statistics, sexual life, and attitudes that were crafted based on the 2004 study. OUTCOMES: Results of the 2004 study vs those of the 2014 study. RESULTS: In total, 516 women participated in the study; the questionnaire response rate was 16.0%. The mean frequency of intercourse (FOI) per month was 3.46 +/- 2.56 in 2014 vs 5.34 +/- 3.84 in 2004. Women in their 20s and 30s in 2014 reported a lower mean FOI than those in 2004. There was no significant difference in the mean FOI in 2004 vs 2014 for women who in their 40s. Risk factors for lower FOI were being older, being single, and having dyspareunia. Most Korean women had positive attitudes toward sex (3.2 +/- 0.6 of 5) and considered it as important (3.3 +/- 0.7 of 5) as those surveyed in 2004. However, women 20 to 39 years old had less positive attitudes toward sex than in the past decade. Women in their 40s were more active and had more conversations with their partners. Of women using contraceptives, 63.8% were found to use less effective methods, such as intercourse withdrawal and the fertility awareness method. CLINICAL IMPLICATIONS: Assessment of changing trends in Korean female sexual life, attitudes, and contraceptive methods could help to establish proper national sexual education programs and campaigns. STRENGTHS AND LIMITATIONS: This study was not a cohort study, because subjects in the 2014 were not identical to those in the 2004 study. Nevertheless, we applied the same inclusion and exclusion criteria for this internet survey, a suitable tool to evaluate the sex life of women, which is often considered a sensitive and private issue in Asian culture. CONCLUSIONS: Compared with the 2004 survey, young Korean women had fewer sexual relationships and had a less positive attitude toward sex. In addition, many women used less effective methods of contraception. Park J, Min B, Shin H, et al. A 10-Year Interval Study About the Sexual Life and Attitudes of Korean Women: The Korean Internet Sexuality Survey (KISS) 2014, Part 2. J Sex Med 2017;14:1142-1151. PMID- 28859874 TI - Biochemical Analysis of Four Missense Mutations in the HSD17B3 Gene Associated With 46,XY Disorders of Sex Development in Egyptian Patients. AB - BACKGROUND: Mutations in the HSD17B3 gene are associated with a 46,XY disorder of sexual development (46,XY DSD) as a result of low testosterone production during embryogenesis. AIM: To elucidate the molecular basis of the disorder by chemically analyzing four missense mutations in HSD17B3 (T54A, M164T, L194P, G289S) from Egyptian patients with 46,XY DSD. METHODS: Expression plasmids for wild-type 17beta-hydroxysteroid hydrogenase type 3 (17beta-HSD3) and mutant enzymes generated by site-directed mutagenesis were transiently transfected into human HEK-293 cells. Protein expression was verified by western blotting and activity was determined by measuring the conversion of radiolabeled Delta4 androstene-3,17-dione to testosterone. Application of a homology model provided an explanation for the observed effects of the mutations. OUTCOMES: Testosterone formation by wild-type and mutant 17beta-HSD3 enzymes was compared. RESULTS: Mutations T54A and L194P, despite normal protein expression, completely abolished 17beta-HSD3 activity, explaining their severe 46,XY DSD phenotype. Mutant M164T could still produce testosterone, albeit with significantly lower activity compared with wild-type 17beta-HSD3, resulting in ambiguous genitalia or a microphallus at birth. The substitution G289S represented a polymorphism exhibiting comparable activity to wild-type 17beta-HSD3. Sequencing of the SRD5A2 gene in three siblings bearing the HSD17B3 G289S polymorphism disclosed the homozygous Y91H mutation in the former gene, thus explaining the 46,XY DSD presentations. Molecular modeling analyses supported the biochemical observations and predicted a disruption of cofactor binding by mutations T54A and M164T and of substrate binding by L196P, resulting in the loss of enzyme activity. In contrast, the G289S substitution was predicted to disturb neither the three dimensional structure nor enzyme activity. CLINICAL TRANSLATION: Biochemical analysis of mutant 17beta-HSD3 enzymes is necessary to understand genotype phenotype relationships. STRENGTHS AND LIMITATIONS: Biochemical analysis combined with molecular modeling provides insight into disease mechanism. However, the stability of mutant proteins in vivo cannot be predicted by this approach. CONCLUSION: The 17beta-HSD3 G289S substitution, previously reported in other patients with 46,XY DSD, is a polymorphism that does not cause the disorder; thus, further sequence analysis was required and disclosed a mutation in SRD5A2, explaining the cause of 46,XY DSD in these patients. Engeli RT, Tsachaki M, Hassan HA, et al. Biochemical Analysis of Four Missense Mutations in the HSD17B3 Gene Associated With 46,XY Disorders of Sex Development in Egyptian Patients. J Sex Med 2017;14:1165-1174. PMID- 28859875 TI - Intravenous Preload of Mesenchymal Stem Cells Rescues Erectile Function in a Rat Model of Cavernous Nerve Injury. PMID- 28859877 TI - The effect of stimulus strength on binocular rivalry rate in healthy individuals: Implications for genetic, clinical and individual differences studies. AB - Binocular rivalry (BR) occurs when conflicting images concurrently presented to corresponding retinal locations of each eye stochastically alternate in perception. Anomalies of BR rate have been examined in a range of clinical psychiatric conditions. In particular, slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) to improve power in large-scale genome wide association studies. Examining the validity of BR rate as a BD endophenotype however requires large-scale datasets (n=1000s to 10,000s), a standardized testing protocol, and optimization of stimulus parameters to maximize separation between BD and healthy groups. Such requirements are indeed relevant to all clinical psychiatric BR studies. Here we address the issue of stimulus optimization by examining the effect of stimulus parameter variation on BR rate and mixed-percept duration (MPD) in healthy individuals. We aimed to identify the stimulus parameters that induced the fastest BR rates with the least MPD. Employing a repeated-measures within-subjects design, 40 healthy adults completed four BR tasks using orthogonally drifting grating stimuli that varied in drift speed and aperture size. Pairwise comparisons were performed to determine modulation of BR rate and MPD by these stimulus parameters, and individual variation of such modulation was also assessed. From amongst the stimulus parameters examined, we found that 8cycles/s drift speed in a 1.5 degrees aperture induced the fastest BR rate without increasing MPD, but that BR rate with this stimulus configuration was not substantially different to BR rate with stimulus parameters we have used in previous studies (i.e., 4cycles/s drift speed in a 1.5 degrees aperture). In addition to contributing to stimulus optimization issues, the findings have implications for Levelt's Proposition IV of binocular rivalry dynamics and individual differences in such dynamics. PMID- 28859876 TI - Genetics-based manipulation of adipose tissue sympathetic innervation. AB - There is renewed interest in leveraging the thermogenic capacity of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) to improve energy balance and prevent obesity. In addition to these effects on energy expenditure, both BAT and WAT secrete large numbers of hormones and cytokines that play important roles in maintaining metabolic health. Both BAT and WAT are densely innervated by the sympathetic nervous system (SNS) and this innervation is crucial for BAT thermogenesis and WAT browning, making it a potentially interesting target for manipulating energy balance and treatment of obesity and metabolic disease. Peripheral neuromodulation in the form of electrical manipulation of the SNS and parasympathetic nervous system (PSNS) has been used for the management of pain and many other conditions, but progress is hampered by lack of detailed knowledge of function-specific neurons and nerves innervating particular organs and tissues. Therefore, the goal of the National Institutes of Health (NIH) Common Fund project "Stimulating Peripheral Activity to Relieve Conditions (SPARC)" is to comprehensively map both anatomical and neurochemical aspects of the peripheral nervous system in animal model systems to ultimately guide optimal neuromodulation strategies in humans. Compared to electrical manipulation, neuron specific opto- and chemogenetic manipulation, now being extensively used to decode the function of brain circuits, will further increase the functional specificity of peripheral neuromodulation. PMID- 28859878 TI - The adaptiveness of a queuing strategy shaped by social experiences during adolescence. AB - Social experiences during adolescence profoundly influence behavioural and endocrine phenotypes. A key question is whether these environmentally induced changes can adjust the individual to prevailing environmental conditions. Previous work shows that male guinea pigs living in pairs from early adolescence are more aggressive and exhibit distinctly higher cortisol responses than males living in large mixed-sex colonies. In environments with limited numbers of competitors, the high-aggressive phenotype of pair-housed males (PMs) leads to more dominant positions and higher reproductive success compared with colony housed males (CMs) and thus represents an adaptation to this situation. Here we tested whether CMs, conversely, are better adapted to the complex social life in large groups. For that purpose, pairs of one PM and one CM were placed into large mixed-sex colonies during late adolescence. During the initial days, PMs displayed significantly more aggressive behaviour than CMs. Nevertheless, PMs and CMs achieved only low dominance ranks and did not reproduce at that time. Simultaneously, PMs showed marked increases in testosterone and cortisol as well as substantial reductions in body weight, whereas CMs coped with the situation in a non-stressful way. A few days later, however, PMs changed their high-aggressive strategy to a low-aggressive queuing strategy and could no longer be distinguished from CMs. As a consequence, PMs and CMs did not differ in numbers of sired offspring. In summary, these results demonstrate that adolescence is a sensitive phase not only for adapting to current environmental conditions but also for readjusting phenotypic development when the actual environment deviates from earlier predictions. PMID- 28859879 TI - Nematophagous fungi combinations reduce free-living stages of sheep gastrointestinal nematodes in the field. AB - Gastrointestinal nematodes (GIN) can reduce or limit sheep production. Currently there is a clear deficiency in the action of drugs for the control of these parasites. Nematophagous fungi are natural enemies of GIN. Fungal combinations have potential for reducing GIN populations. The aim of this study was to evaluate the efficiency combinations of nematophagous fungi in sodium alginate matrix pellets for the biological control agents of gastrointestinal sheep nematode parasites in the field. The nematophagous fungi (0.2mg of fungus per kg of body weight), Arthrobotrys conoides, A. robusta, Duddingtonia flagrans, and Monacrosporium thaumasium were used. The treated groups were administered mycelium combinations in the following combinations: group 1 (D. flagrans+A. robusta); group 2 (M. thaumasium+A. conoides). The control group did not receive any fungal pellets. We used three groups with eight Santa Ines sheep each. Each animal was treated with approximately 1g of pellet per 10kg of live weight. During the experimental period, we evaluated: number of eggs per gram of feces (EPG), infective larvae (L3) per kg of dry matter, larvae recovered from coprocultures, packed cell volume, total plasma protein concentration of sheep, and environmental conditions. Group 2 EPG (M. thaumasium+A. conoides) differed from the control group in September and October. The number of L3/kg of dry matter recovered from animals of groups 1 and 2 at distances of 0-20 and 20-40cm from the fecal pats was lower than the control group. The packed cell volume and total plasma proteins of treated animals were similar to those of the control group. The combination of treatment groups (D. flagrans+A. robusta and M. thaumasium+A. conoides) reduced the number of L3/kg of pasture. Therefore, treatment of nematophagous fungal combinations have the potential to manage free living stages of GIN in sheep. PMID- 28859880 TI - Cathepsin O is involved in the innate immune response and metamorphosis of Antheraea pernyi. AB - Cathepsins are key members of mammalian papain-like cysteine proteases that play an important role in the immune response. In this study, a fragment of cDNA encoding cathepsin O proteinase (ApCathepsin O) was cloned from Antheraea pernyi. It contains an open reading frame of 1170bp and encodes a protein with 390 amino acid residues, including a conserved I29 inhibitor domain and a peptidase C1A (clan CA of cysteine proteases, papain family C1 subfamily) domain. Comparison with other previously reported cathepsin O proteins showed identity ranging from 45% to 79%. Quantitative real-time PCR (qRT-PCR) and Western blot analysis revealed that ApCathepsin O was highly expressed in the fat body; furthermore, the high expression during the pupal stage indicated that it might be involved during metamorphosis. After exposure to four different heat-killed pathogens (Escherichia coli, Beauveria bassiana, Micrococcus luteus, and A. pernyi nucleopolyhedrovirus), the expression levels of ApCathepsin O mRNA significantly increased and showed variable expression patterns. This indicates that ApCathepsin O is potentially involved in the innate immune system of A. pernyi. Interestingly, ApCathepsin O expression was upregulated after 20-hydroxyecdysone (20E) injection, which suggested that it might be regulated by 20E. In conclusion, ApCathepsin O is a protease that may play an important role in the innate immune response and metamorphosis of A. pernyi. PMID- 28859881 TI - Correction. PMID- 28859882 TI - Congruence Between Latent Class and K-Modes Analyses in the Identification of Oncology Patients With Distinct Symptom Experiences. AB - CONTEXT: Risk profiling of oncology patients based on their symptom experience assists clinicians to provide more personalized symptom management interventions. Recent findings suggest that oncology patients with distinct symptom profiles can be identified using a variety of analytic methods. OBJECTIVES: The objective of this study was to evaluate the concordance between the number and types of subgroups of patients with distinct symptom profiles using latent class analysis and K-modes analysis. METHODS: Using data on the occurrence of 25 symptoms from the Memorial Symptom Assessment Scale, that 1329 patients completed prior to their next dose of chemotherapy (CTX), Cohen's kappa coefficient was used to evaluate for concordance between the two analytic methods. For both latent class analysis and K-modes, differences among the subgroups in demographic, clinical, and symptom characteristics, as well as quality of life outcomes were determined using parametric and nonparametric statistics. RESULTS: Using both analytic methods, four subgroups of patients with distinct symptom profiles were identified (i.e., all low, moderate physical and lower psychological, moderate physical and higher Psychological, and all high). The percent agreement between the two methods was 75.32%, which suggests a moderate level of agreement. In both analyses, patients in the all high group were significantly younger and had a higher comorbidity profile, worse Memorial Symptom Assessment Scale subscale scores, and poorer QOL outcomes. CONCLUSION: Both analytic methods can be used to identify subgroups of oncology patients with distinct symptom profiles. Additional research is needed to determine which analytic methods and which dimension of the symptom experience provide the most sensitive and specific risk profiles. PMID- 28859883 TI - Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents. AB - Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7 dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin 1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE2-, PGF2alpha-, and AMPA-induced allodynia, while both pregabalin and duloxetine alleviated only PGE2-induced allodynia in mice. Similarly, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These findings suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain. Accordingly, pharmacological LPA5 antagonists are attractive development candidates for potential novel pain therapies. PMID- 28859884 TI - A network of insulin peptides regulate glucose uptake by astrocytes: Potential new druggable targets for brain hypometabolism. AB - Astrocytes are major players in brain glucose metabolism, supporting neuronal needs on demand through mechanisms that are not yet entirely clear. Understanding glucose metabolism in astrocytes is therefore of great consequence to unveil novel targets and develop new drugs to restore brain energy balance in pathology. Contrary to what has been held for many years, we now present evidence that insulin, in association with the related insulin-like growth factor I (IGF-I) modulates brain glucose metabolism through a concerted action on astrocytes. Cooperativity of insulin and IGF-I relies on the IGF-I receptor (IGF-IR), that acts as a scaffold of Glucose Transporter 1 (GluT1) regulating its activity by retaining it in the cytoplasm or, in response to a concerted action of insulin and IGF-I, translocating it to the cell membrane. Regulated translocation of GluT1 to the cell membrane by IGF-IR involves an intricate repertoire of protein protein interactions amenable to drug modulation, particularly by interfering with IGF-IR/GluT1 interactions. We propose that this mechanism accounts for a substantial proportion of basal and regulated glucose uptake by astrocytes as GluT1 is the major glucose transporter in these brain cells. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 28859885 TI - Case studies on genetically modified organisms (GMOs): Potential risk scenarios and associated health indicators. AB - Within the frame of the EU-funded MARLON project, background data were reviewed to explore the possibility of measuring health indicators during post-market monitoring for potential effects of feeds, particularly genetically modified (GM) feeds, on livestock animal health, if applicable. Four case studies (CSs) of potential health effects on livestock were framed and the current knowledge of a possible effect of GM feed was reviewed. Concerning allergenicity (CS-1), there are no case-reports of allergic reactions or immunotoxic effects resulting from GM feed consumption as compared with non-GM feed. The likelihood of horizontal gene transfer (HGT; CS-2) of GMO-related DNA to different species is not different from that for other DNA and is unlikely to raise health concerns. Concerning mycotoxins (CS-3), insect-resistant GM maize may reduce fumonisins contamination as a health benefit, yet other Fusarium toxins and aflatoxins show inconclusive results. For nutritionally altered crops (CS-4), the genetic modifications applied lead to compositional changes which require special considerations of their nutritional impacts. No health indicators were thus identified except for possible beneficial impacts of reduced mycotoxins and nutritional enhancement. More generally, veterinary health data should ideally be linked with animal exposure information so as to be able to establish cause effect relationships. PMID- 28859888 TI - Postnatal development of GABAergic interneurons and perineuronal nets in mouse temporal cortex subregions. AB - In human neuropsychiatric disorders, there are functional and anatomical abnormalities of GABAergic interneurons in each temporal cortex subregion. Furthermore, accumulation of amyloid-beta is observed in the temporal cortex in the early stages of Alzheimer's disease. Each subregion of the temporal cortex has an important role in coordinating the input and output of the hippocampus. When subregions of the temporal cortex are impaired, memory and learning ability decrease. GABAergic interneurons control excitatory neurons, forming the cortico cortical and cortico-hippocampal networks. However, in temporal cortex subregions, details of the distribution and developmental processes of GABAergic interneurons and perineuronal nets (PNNs) have not been elucidated. Here we examined the development of GABAergic interneurons and PNNs in mouse temporal cortex subregions. Results indicate that temporal cortex GABAergic interneurons have developmental stages different to those of the primary sensory cortex. In addition, the density of PNNs in the temporal cortex is lower than that in the sensory cortex. Furthermore, we found that the Wisteria floribunda agglutinin reactive extracellular matrix molecule is present in the upper level of layer 1 of the temporal cortex. These results support the idea that mouse temporal cortex subregions develop differently from other cortical regions and have region specific characteristics after maturation. The present study results suggested that the structure of the temporal cortex is significantly different from the sensory cortex and that temporal cortex may be highly vulnerable to neuropsychiatric and neurodegenerative disorders. PMID- 28859889 TI - Development of a metal/chelate polyhydroxyethylmethacrylate monolith capillary for selective depletion of immunoglobulin G from human plasma for proteomics. AB - In this study, we report the development of a new poly HEMA (HEMA-co-DEGDA-co DATD) monolith capillary functionalized with "IDA-Cu (II) complex". Of the two tested crosslinkers (methylene bisacrylamide (MBAAm) and diethylene glycol diacrylate (DEGDA)), presence of DEGDA has enhanced the monolith rigidity. Structural assembly of these monoliths are organized with highly interconnected large globule like structures and dominated by macropore region. Iminodiacetic acid (IDA) immobilization was performed using two chemical approaches (i. aldehyde - secondary amine reaction and ii. epoxy - sec. amine reaction). FT-IR analysis confirmed successful IDA immobilization in both cases. For the first time, a reaction of sec. amine ligand with aldehyde functional material was successfully reported. Overall, the Cu (II)-IDA monolith capillary showed good permeability (3.05*10 -13m2), high IgG adsorption capacity and reusablilty even after 5 consecutive adsorption-desorption cycles. The amount of protein (IgG/HSA) adsorbed on Cu (II)-IDA monolith prepared via the two chemistries is almost similar. Using this affinity monolith capillary, we selectively depleted ~95% of IgG from human plasma (dilution of 1:16). PMID- 28859886 TI - Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression. AB - Atrazine, a herbicide used on agricultural crops is widely applied in the Midwestern United States as well as other areas of the globe. Atrazine frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. Previous studies have reported morphological, hormonal, and molecular alterations due to developmental and adulthood atrazine exposure; however, studies examining epigenetic alterations are limited. In this study, the effects of atrazine exposure on DNA methyltransferase (DNMT) activity and kinetics were evaluated. Global DNA methylation levels and dnmt expression in zebrafish larvae exposed to 0, 3, or 30 parts per billion (ppb) atrazine throughout embryogenesis was then assessed. Results indicate that atrazine significantly decreased the activity of maintenance DNMTs and that the inhibition mechanism can be described using non-competitive Michaelis-Menten kinetics. Furthermore, results show that an embryonic atrazine exposure decreases global methylation levels and the expression of dnmt4 and dnmt5. These findings indicate that atrazine exposure can decrease the expression and activity of DNMTs, leading to decreased DNA methylation levels. PMID- 28859887 TI - RIFM fragrance ingredient safety assessment, p-(2,2-dimethoxyethyl)toluene, CAS Registry Number 42866-91-1. PMID- 28859890 TI - Comprehensive determination of flavouring additives and nicotine in e-cigarette refill solutions. Part II: Gas-chromatography-mass spectrometry analysis. AB - Flavouring compounds are an essential part of e-liquid products for cigarettes. In general, they are regarded as safe for ingestion, but they may have unrecognized risks when they are inhaled. In some cases, manufactures do not currently abide by the Tobacco Products Directive (2014/40/EU) and do not declare the detailed contents of e-liquids on their labels. To help evaluate the health impact of flavouring substances, there is a need for comprehensive approaches to determine their concentrations in e-liquids. For this purpose, a GC-EI-MS method was developed and validated for the simultaneous determination of 46 commonly used flavour additives in e-liquids. The proposed method performed well in terms of the key validation parameters: accuracy (84-113%), inter-/intra-day precision: 0.1-10% and 1-11%, respectively, and sensitivity (limit of detection: 3-87ng/mL). The sample preparation step was based on a simple "dilute & shoot" approach. This study is a complementary method to the LC-MS/MS procedure described in Part I. Both approaches are suitable for the comprehensive determination of 88 flavouring compounds and nicotine and can be used as tools for the rapid evaluation of the quality and safety of e-cigarette products. PMID- 28859891 TI - Dispersive micro solid phase extraction (DMSPE) using polymer anion exchange (PAX) as the sorbent followed by UPLC-MS/MS for the rapid determination of four bisphenols in commercial edible oils. AB - The present work presents a novel and rapid analytical method for the simultaneous analysis of bisphenol A (BPA), bisphenol B (BPB), bisphenol F (BPF) and bisphenol S (BPS) in edible oil based on dispersive micro solid phase extraction (DMSPE) for the first time followed by isotope dilution-ultra high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The edible oil sample was dispersed by n-hexane and extracted with ammoniated methanol-water solution. Then the target analytes were dispersedly absorbed using the polymer anion exchange (PAX) as the sorbent and eluted by acidic methanol. After that, four bisphenols were separated on a C18 column by gradient elution with methanol and 0.05% ammonium hydroxide in water as mobile phase, detected by MS/MS under multiple reactions monitoring (MRM) mode and quantified by internal standard method. The PAX amounts, adsorption time, concentrations of formic acid in the elution solvent and volume of elution solvent for the DMSPE technique were optimized. The limit of detection and quantitation (LOD and LOQ), matrix effect, recovery and precision of the developed method were investigated. Results indicated that BPS and the rest three bisphenols displayed excellent linearity in the concentration ranges of 0.1-50MUg/L and 0.5-250MUg/L, respectively, with correlation coefficients (R2) all larger than 0.998. Achieved MLODs (S/N=3) varied between 0.1-0.4MUg/kg for all bisphenols. The mean recoveries at three spiked levels in edible oil were in the range of 87.3-108%. Intra-day precision (n=6) and inter-day precision (n=5) were <9% and <11%, respectively. This method is of rapid-and-simple pretreatment, accurate and sensitive, and suitable for the simultaneous determination of bisphenols in edible oil. PMID- 28859892 TI - Fistulous Complications following Radical Cystectomy for Bladder Cancer: Analysis of a Large Modern Cohort. AB - PURPOSE: Fistula formation is a rare and poorly described complication following radical cystectomy with urinary diversion. We sought to identify patients who experienced any type of fistulous complication and we analyzed risk factors for formation as well as management outcomes. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent radical cystectomy for bladder cancer at our institution. Patients who experienced any fistula were identified. Risk factors, management strategies and outcomes were analyzed. Patients underwent initial conservative treatment and those in whom this treatment failed underwent surgical repair. Univariable and multivariable analyses were performed to identify predictors of fistula formation as well as the need for surgical repair. RESULTS: Of the 1,041 patients 31 (3.0%) experienced fistula formation. Median time to fistula presentation was 31 days. Enterodiversion was the most common fistula type, noted in 54.8% of patients, followed by enterocutaneous and diversion cutaneous treatment in 29.0% and 12.9%, respectively. On multivariable analyses a history of radiation therapy (OR 3.1, p = 0.03) and an orthotopic neobladder (OR 3.1, p = 0.04) were predictors of fistula formation. Conservative management was successful in 41.9% of cases. There were no predictors of failed conservative management. Of patients who required surgical repair success was achieved in 94.4% at a single operation. CONCLUSIONS: Fistulas are rare after radical cystectomy and they are most common between the urinary diversion and the small bowel. A history of radiation therapy and a orthotopic neobladder are risk factors for formation. When required, surgical repair is generally successful at a single operation. PMID- 28859893 TI - Predictors of Long-Term Survival after Renal Cancer Surgery. AB - PURPOSE: Renal cancer surgery can adversely impact long-term function and survival. We evaluated predictors of chronic kidney disease 5 years and nonrenal cancer mortality 10 years after renal cancer surgery. MATERIALS AND METHODS: We analyzed the records of 4,283 patients who underwent renal cancer surgery from 1997 to 2008. Radical and partial nephrectomy were performed in 46% and 54% of patients, respectively. Cumulative probability ordinal modeling was used to predict chronic kidney disease status 5 years after surgery and multivariable logistic regression was used to predict nonrenal cancer mortality at 10 years. Relevant patient, tumor and functional covariates were incorporated, including the preoperative glomerular filtration rate (A), the new baseline glomerular filtration rate after surgery (B) and the glomerular filtration rate loss related to surgery (C), that is C = A - B. In contrast, partial or radical nephrectomy was not used in the models due to concerns about strong selection bias associated with the choice of procedure. RESULTS: Multivariable modeling established the preoperative glomerular filtration rate and the glomerular filtration rate loss related to surgery as the most important predictors of the development of chronic kidney disease (Spearman rho = 0.78). Age, gender and race had secondary roles. Significant predictors of 10-year nonrenal cancer mortality were the preoperative glomerular filtration rate, the new baseline glomerular filtration rate, age, diabetes and heart disease (all p <0.05). Multivariable modeling established age and the preoperative glomerular filtration rate as the most important predictors of 10-year nonrenal cancer mortality (c-index 0.71) while the glomerular filtration rate loss related to surgery only changed absolute mortality estimates 1% to 3%. CONCLUSIONS: Glomerular filtration rate loss related to renal cancer surgery, whether due to partial or radical nephrectomy, influences the risk of chronic kidney disease but it may have less impact on survival. In contrast, age and the preoperative glomerular filtration rate, which reflects general health status, are more robust predictors of nonrenal cancer mortality, at least in patients with good preoperative function or mild chronic kidney disease. PMID- 28859894 TI - The Prevalence and Impact of Urinary Marker Testing in Patients with Bladder Cancer. AB - PURPOSE: Novel urinary tumor markers for bladder cancer may permit early detection and improved oncologic outcomes but data on use is limited. We sought to identify trends in the application of urinary markers and long-term outcomes of urinary tumor marker use in patients with bladder cancer. MATERIALS AND METHODS: Data from the SEER (Surveillance, Epidemiology and End Results)-Medicare database from 2001 to 2011 were used to identify a cohort of 64,450 patients with bladder cancer who underwent urinary marker testing with UroVysion(r) fluorescence in situ hybridization, or the NMP22(r) or BTA Stat(r) test. We assessed the prevalence of urinary marker testing and urine cytology. Characteristics of patients who did and did not undergo urinary marker testing were analyzed by the chi-square test. Urinary marker testing predictors were analyzed with a multivariable logistic regression model and Cox proportional hazards were used to determine unadjusted cancer specific and overall mortality risks. RESULTS: The rate of urinary marker testing increased from 17.8% to a peak of 28.2% during the study years (p <0.0001). Predictors of marker use included female gender, younger age and lower Charlson score. Overall and cancer specific survival improved on Kaplan-Meier and Cox proportional hazards analyses with urinary marker testing. CONCLUSIONS: Increased urinary marker testing was documented over all stages and grades of bladder cancer, and in certain patient and provider variables. This increase may have contributed to improved overall and cancer specific survival. Additional investigation is necessary to further characterize this benefit. PMID- 28859896 TI - HIV-1 mutates to adapt in fluxing environments. AB - Human immunodeficiency virus type 1 (HIV-1) is specifically adapted for replication, persistence, transmission, and survival in humans. HIV-1 is highly mutable in nature, and well responds to a variety of environmental pressures by altering its genome sequences. In this review, we have described experimental evidence that demonstrates this phantasmagoric property of HIV-1. PMID- 28859895 TI - Construction and comparison of different source neuraminidase candidate vaccine strains for human infection with Eurasian avian-like influenza H1N1 virus. AB - Human infections with Eurasian avian-like swine influenza H1N1 viruses have been reported in China in past years. One case resulted in death and others were mild case. In 2016, the World Health Organization recommended the use of A/Hunan/42443/2015(H1N1) virus to construct the first candidate vaccine strain for Eurasian avian-like swine influenza H1N1 viruses. Previous reports showed that the neuraminidase of A/Puerto Rico/8/34(H1N1) might improve the viral yield of reassortant viruses. Therefore, we constructed two reassortant candidate vaccine viruses of A/Hunan/42443/2015(H1N1) by reverse genetic technology, with (6+2) and (7+1) gene constitution, respectively. The (6+2) virus had hemagglutinin and neuraminidase from A/Hunan/42443/2015, and the (7+1) one had hemagglutinin from A/Hunan/42443/2015, while all the other genes were from A/Puerto Rico/8/34. Our data revealed that although the neuraminidase of the (7+1) virus was from high yield A/Puerto Rico/8/34, the hemagglutination titer and the hemagglutinin protein content of the (7+1) virus was not higher than that of the (6+2) virus. Both of the (7+1) and (6+2) viruses reached a similar level to that of A/Puerto Rico/8/34 at the usual harvest time in vitro. Therefore, both reassortant viruses are potential candidate vaccine viruses, which could contribute to pandemic preparedness. PMID- 28859897 TI - New Assessment Table for Establishing Severity in Psoriasis. PMID- 28859898 TI - The effect of dietary antioxidants and exercise training on the escape performance of Southern Corroboree frogs. AB - Escape-response behaviour is essential to ensure an individual's survival during a predator attack, however, these behaviours are energetically costly and may cause oxidative stress. Oxidative stress can be reduced by supplementing an individual's diet with exogenous antioxidants or through regular moderate exercise training, which stimulates the upregulation of the endogenous antioxidant system. Two studies have tested the simultaneous effects of dietary antioxidant supplementation and exercise training on animal escape-response behaviour. The present study investigated the effects of dietary carotenoids and exercise training on the escape-response behaviour of Southern Corroboree frogs. Frogs were fed either a carotenoid-supplemented or unsupplemented diet and were exposed to repeated escape-response trials (training) for five consecutive weeks. Carotenoid-supplemented individuals outperformed unsupplemented individuals in initial hopping speed, length of the first hop and hopping distance, however, the performance of frogs in each treatment group became statistically similar after training. Within treatment groups, exercise training significantly improved the hopping speed of unsupplemented frogs, with speeds almost doubling between training weeks one and five. By contrast, exercise training did not significantly improve the hopping speed of carotenoid-supplemented frogs. Our results provide some of the first evidence that exercise training improves escape performance, and that dietary antioxidants may inhibit training-induced benefits. PMID- 28859899 TI - Combination of using prodrug-modified cationic liposome nanocomplexes and a potentiating strategy via targeted co-delivery of gemcitabine and docetaxel for CD44-overexpressed triple negative breast cancer therapy. AB - : In this study, novel prodrug-modified cationic liposome nanocomplexes (Combo NCs) were reported for gemcitabine (GEM) and docetaxel (DTX) co-delivery. This nanoplatform exhibited multiple favorable characteristics, such as a 'green' fabrication with a one-step chemical reaction, appropriate size (~200nm) and distribution (PDI<0.2), low zeta potential (-31.1mv), high drug-loading efficiency (9.3% GEM plus 3.1% DTX, wt%) and pH and enzymatic dual-stimulus responsive release properties. Immunofluorescence and cellular uptake studies showed that Combo NCs efficiently targeted overexpressed CD44 in MDA-MB-231 carcinoma. In vitro studies revealed that Combo NCs played a critical role in the synergistic induction of cytotoxicity, apoptosis and inhibition of wound healing. Combo NCs were confirmed to exhibit great potency for increasing S phase arrest and remodeling the CDA and dCK balance by decreasing the mRNA expression of CDA down to 0.09-fold and increasing the mRNA expression of dCK by 1.36-fold, remarkably increasing the dCK/CDA ratio to 15.3-fold compared with the blank control. The biodistribution results obtained in vivo revealed an effective accumulation in tumor foci. All of these advantages of Combo NCs contributed to their remarkable anti-tumor efficacy without systemic toxicity as well as their apoptosis-enhancing and anti-proliferative capacities, as determined by TUNEL and Ki67 immunohistochemistry in vivo. Consequently, such a rationally contemplated co-delivery system demonstrated the promising potential of clinical applications for triple-negative breast cancer therapy. STATE OF SIGNIFICANCE: The Combo NCs were innovatively applied for co-delivery of hydrophilic GEM and hydrophobic DTX. The ester bond linking and shielding effect of HA-GEM made the carriers achieve synchronous release properties, which was determined in in vitro release study. Due to the HA modification, the vectors own great potency for positive targeting to CD44 overexpressed triple-negative breast cancer cells MDA-MB-231. Cytotoxicity and apoptosis studies confirmed the targeting effect and synergism between two drugs. Interestingly, we found in cell cycle study, drug combinations (free combination or Combo NCs) didn't show a rise in G2M phase, which was significantly higher when treated DTX alone. We further discovered the role of DTX in combinations may involve in modulating GEM associated enzymes thus enhancing the efficacy of GEM. Consequently, this nanoplatform provided a novel solution for achieving targeted co-delivery and potentiating effect in cancer therapy. PMID- 28859900 TI - Inclusion complex from cyclodextrin-grafted hyaluronic acid and pseudo protein as biodegradable nano-delivery vehicle for gambogic acid. AB - : beta-Cyclodextrin can form inclusion complex with a series of guest molecules including phenyl moieties, and has gained considerable popularity in the study of supramolecular nanostructure. In this study, a biodegradable nanocomplex (HA(CD) 4Phe4 nanocomplex) was developed from beta-cyclodextrin grafted hyaluronic acid (HA) and phenylalanine based poly(ester amide). The phenylalanine based poly(ester amide) is a biodegradable pseudo protein which provides the encapsulation capacity for gambogic acid (GA), a naturally-derived chemotherapeutic which has been effectively employed to treat multidrug resistant tumor. The therapeutic potency of free GA is limited due to its poor solubility in water and the lack of tumor-selective toxicity. The nanocomplex carrier enhanced the solubility and availability of GA in aqueous media, and the HA component enabled the targeted delivery to tumor cells with overexpression of CD44 receptors. In the presence of hyaluronidase, the release of GA from the nanocomplex was significantly accelerated, due to the enzymatic biodegradation of the carrier. Compared to free GA, GA-loaded nanocomplex exhibited improved cytotoxicity in MDA-MB-435/MDR multidrug resistant melanoma cells, and induced enhanced level of apoptosis and mitochondrial depolarization, at low concentration of GA (1-2uM). The nanocomplex enhanced the therapeutic potency of GA, especially when diluted in physiological environment. In addition, suppressed matrix metalloproteinase activity was also detected in MDA-MB-435/MDR cells treated by GA-loaded nanocomplex, which demonstrated its potency in the inhibition of tumor metastasis. The in vitro data suggested that HA(CD)-4Phe4 nanocomplex could provide a promising alternative in the treatment of multidrug resistant tumor cells. STATEMENT OF SIGNIFICANCE: Gambogic acid (GA), naturally derived from genus Garcinia trees, exhibited significant cytotoxic activity against multiple types of tumors with resistance to traditional chemotherapeutics. Unfortunately, the poor solubility of GA in conventional pharmaceutical solvents and non-targeted distribution in normal tissues greatly limited its therapeutic potency. To overcome the challenges, we develop a nanoplatform from the supramolecular assembly of beta-cyclodextrin grafted hyaluronic acid (HA) and phenylalanine based pseudo protein. The pseudo protein in the nanocomplex provided the hydrophobic interaction and loading capacity for GA, while the HA component targeted the overexpressed CD44 receptor and improved the selective endocytosis in multidrug resistant melanoma cells. The supramolecular nanocomplex provide a promising platform for the delivery of hydrophobic chemotherapeutics to improve the bioavailability and efficiency. PMID- 28859901 TI - Use of hydrogel scaffolds to develop an in vitro 3D culture model of human intestinal epithelium. AB - : The human intestinal cell lines: Caco-2 and HT29-MTX cells have been used extensively in 2D and 3D cell cultures as simple models of the small intestinal epithelium in vitro. This study aimed to investigate the potential of three hydrogel scaffolds to support the 3D culture of Caco-2 and HT29-MTX cells and critically assess their use as scaffolds to stimulate villi formation to model a small intestinal epithelium in vitro. Here, alginate, l-pNIPAM, and l-pNIPAM-co DMAc hydrogels were investigated. The cells were suspended within or layered on these hydrogels and maintained under static or dynamic culture conditions for up to 21days. Caco-2 cell viability was increased when layered on the synthetic hydrogel scaffolds, but reduced when suspended within the synthetic hydrogels. In contrast, HT29-MTX cells remained viable when suspended within or layered on all 3D cultures. Interestingly, cells cultured in and on the alginate hydrogel scaffolds formed multilayer spheroid structures, whilst the cells layered on synthetic hydrogels formed villus-like structures. Immunohistochemistry staining demonstrated positive expression of enterocyte differentiation markers and goblet cell marker. In conclusion, l-pNIPAM hydrogel scaffolds supported both cell lines and induced formation of villus-like structures when cells were layered on and cultured under dynamic conditions. The ability of the l-pNIPAM to recapitulate the 3D structure and differentiate main cell types of human intestinal villi may deliver a potential alternative in vitro model for studying intestinal disease and for drug testing. STATEMENT OF SIGNIFICANCE: Forty percent of hospital referrals are linked to disorders of the digestive tract. Current studies have utilised animal models or simple cultures of isolated cells which do not behave in the same manner as human intestine. Thus new models are required which more closely mimic the behaviour of intestinal cells. Here, we tested a number of scaffolds and conditions to develop a cell culture model which closely represents the 3D environment seen within the human small intestine. We successfully created structures seen within the intestine which have not previously been possible with other culture models. These models could be used to investigate tissue engineering, drug discovery, and used asan alternative to in vivo animal models in drug toxicity studies. PMID- 28859903 TI - Bazedoxifene and raloxifene protect neocortical neurons undergoing hypoxia via targeting ERalpha and PPAR-gamma. AB - Selective estrogen receptor modulators (SERMs) such as bazedoxifene and raloxifene are recognized to mainly act via estrogen receptors (ERs), but there is no study examining the involvement of PPAR-gamma in their actions, especially in neurons undergoing hypoxia. Little is also known about age-dependent actions of the SERMs on neuronal tissue challenged with hypoxia. In this study, bazedoxifene and raloxifene protected neocortical cells against hypoxia at early and later developmental stages. Both SERMs evoked caspase-3-independent neuroprotection and increased protein levels of ERalpha (66 and 46 kDa isoforms) and PPAR-gamma. In addition, bazedoxifene enhanced expression of ERalpha regulated Cyp19a1 mRNA. Using double siRNA silencing, for the first time we demonstrated a key role of ERalpha and PPAR-gamma in the neuroprotective action of the SERMs in neocortical neurons undergoing hypoxia. This study provides prospects for the development of a new therapeutic strategies against hypoxic brain injury that selectively target ERalpha and/or PPAR-gamma. PMID- 28859902 TI - Nitric oxide releasing hydrogel promotes endothelial differentiation of mouse embryonic stem cells. AB - : Transplantation of endothelial cells (ECs) holds great promise for treating various kinds of ischemic diseases. However, the major challenge in ECs-based therapy in clinical applications is to provide high quality and enough amounts of cells. In this study, we developed a simple and efficient system to direct endothelial differentiation of mouse embryonic stem cells (ESCs) using a controllable chitosan nitric oxide (NO)-releasing hydrogel (CS-NO). ESCs were plated onto the hydrogel culture system, and the expressions of differentiation markers were measured. We found that the expression of Flk-1 (early ECs marker) and VE-cadherin (mature ECs marker) increased obviously under the controlled NO releasing environment. Moreover, the Flk-1 upregulation was accompanied by the activation of the phospho-inositide-3 kinase (PI3K)/Akt signaling. We also found that in the presence of the PI3K inhibitor (LY294002), the endothelial commitment of ESCs was abolished, indicating the importance of Akt phosphorylation in the endothelial differentiation of ESCs. Interestingly, in the absence of NO, the activation of Akt phosphorylation alone by using AKT activator (SC-79) did not profoundly promote the endothelial differentiation of ESCs, suggesting an interdependent relationship between NO and the Akt phosphorylation in driving endothelial fate specification of ESCs. Taken together, we demonstrated that NO releasing in a continuous and controlled manner is a simple and efficient method for directing the endothelial differentiation of ESCs without adding growth factors. STATEMENT OF SIGNIFICANCE: Fascinating data continues to show that artificial stem cell niche not only serve as a physical supporting scaffold for stem cells proliferation, but also as a novel platform for directing stem cell differentiation. Because of the lack of proper microenvironment for generating therapeutic endothelial cells (ECs) in vitro, the source of ECs for transplantation is the major limitation in ECs-based therapy to clinical applications. The current study established a feeder cell-free, 2-dimensional culture system for promoting the differentiation processes of embryonic stem cells (ESCs) committed to the endothelial lineage via using a nitric oxide (NO) controlled releasing hydrogel (CS-NO). Notably, the NO releasing from the hydrogel could selectively up-regulate Flk-1 (early ECs marker) and VE-cadherin (mature ECs marker) in the absence of growth factors, which was of crucial importance in the endothelial differentiation of ESCs. In summary, the current study proposes a simple and efficient method for directing the endothelial differentiation of ESCs without extra growth factors. PMID- 28859904 TI - Bisphenol A decreases progesterone synthesis by disrupting cholesterol homeostasis in rat granulosa cells. AB - Bisphenol A (BPA) is an endocrine disruptor used in a variety of consumer products. Exposure to BPA leads to alterations in steroidogenesis of ovarian granulosa cells. Here, we analyzed the mechanism by which BPA alters progesterone biosynthesis in immature rat granulosa cells. BPA increased expression of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme and 3beta-hydroxysteroid dehydrogenase in granulosa cells; however, BPA prevented the basal and the FSH-induced progesterone production. BPA caused sequestration of cholesterol to the perinuclear area, as evident by the Filipin staining. BPA decreased mRNA expression of ATP binding cassette transporter-A1 (Abca1) and increased level of sterol regulatory element binding protein 1. Addition of exogenous cell-permeable cholesterol restored the effect of BPA on Abca1 and Star mRNA expression and partially reversed BPA's effect on progesterone production. These results indicate that exposure to BPA disrupts cholesterol homeostasis leading to decreased progesterone production in immature rat granulosa cells. PMID- 28859905 TI - Atrazine suppresses FSH-induced steroidogenesis and LH-dependent expression of ovulatory genes through PDE-cAMP signaling pathway in human cumulus granulosa cells. AB - Atrazine (ATR) alters female reproductive functions in different animal species. Here, we analyzed whether ATR disturbs steroidogenic and ovulatory processes in hormone-stimulated human cumulus granulosa cells and mechanism of its action. Results showed that treatment of human cumulus granulosa cells with 20 MUM ATR for 48 h resulted in lower FSH-stimulated estradiol and progesterone production. ATR reduced mRNA levels of aromatase (CYP19A1), steroidogenic acute regulatory protein (STAR) and luteinizing hormone/choriogonadotropin receptor (LHCGR). Addition of hCG 48 h after FSH and ATR treatment did not trigger maximal expression of the ovulatory genes amphiregulin (AREG) and epiregulin (EREG). Mechanistic experiments showed that ATR activated cPDE and decreased cAMP level. Addition of total PDE and specific PDE4 inhibitors, IBMX and rolipram, prevented ATR's action on CYP19A1 and STAR mRNA expression in FSH-stimulated human cumulus granulosa cells. This study suggests that ATR alters steroidogenesis and ovulatory process in human cumulus granulosa cells jeopardizing female reproduction. PMID- 28859906 TI - A systematic linguistic profile of spontaneous narrative speech in pre symptomatic and early stage Huntington's disease. AB - Cognitive decline accompanying the clinically more salient motor symptoms of Huntington's disease (HD) has been widely noted and can precede motor symptoms onset. Less clear is how such decline bears on language functions in everyday life, though a small number of experimental studies have revealed difficulties with the application of rule-based aspects of language in early stages of the disease. Here we aimed to determine whether there is a systematic linguistic profile that characterizes spontaneous narrative speech in both pre-manifest and/or early manifest HD, and how it is related to striatal degeneration and neuropsychological profiles. Twenty-eight early-stage patients (19 manifest and 9 gene-carriers in the pre-manifest stage), matched with 28 controls, participated in a story-telling task. Speech was blindly scored by independent raters according to fine-grained linguistic variables distributed over 5 domains for which composite scores were computed (Quantitative, Fluency, Reference, Connectivity, and Concordance). Voxel-based morphometry (VBM) was used to link specific brain degeneration patterns to loci of linguistic decline. In all of these domains, significant differences were observed between groups. Deficits in Reference and Connectivity were seen in the pre-manifest stage, where no other neuropsychological impairment was detected. Among HD patients, there was a significant positive correlation only between the values in the Quantitative domain and gray matter volume bilaterally in the putamen and pallidum. These results fill the gap of qualitative data of spontaneous narrative speech in HD and reveal that HD is characterized by systematic linguistic impairments leading to dysfluencies and disorganization in core domains of grammatical organization. This includes the referential use of noun phrases and the embedding of clauses, which mediate crucial dimensions of meaning in language in its normal social use. Moreover, such impairment is seen prior to motor symptoms onset and when standardized neuropsychological test profiles are otherwise normal. PMID- 28859907 TI - Release, Recycle, Rebuild: Cell-Wall Remodeling, Autodegradation, and Sugar Salvage for New Wall Biosynthesis during Plant Development. AB - Plant cell walls contain elaborate polysaccharide networks and regulate plant growth, development, mechanics, cell-cell communication and adhesion, and defense. Despite conferring rigidity to support plant structures, the cell wall is a dynamic extracellular matrix that is modified, reorganized, and degraded to tightly control its properties during growth and development. Far from being a terminal carbon sink, many wall polymers can be degraded and recycled by plant cells, either via direct re-incorporation by transglycosylation or via internalization and metabolic salvage of wall-derived sugars to produce new precursors for wall synthesis. However, the physiological and metabolic contributions of wall recycling to plant growth and development are largely undefined. In this review, we discuss long-standing and recent evidence supporting the occurrence of cell-wall recycling in plants, make predictions regarding the developmental processes to which wall recycling might contribute, and identify outstanding questions and emerging experimental tools that might be used to address these questions and enhance our understanding of this poorly characterized aspect of wall dynamics and metabolism. PMID- 28859908 TI - Author Reply. PMID- 28859909 TI - Editorial Comment. PMID- 28859910 TI - Numerical solution of non-linear dual-phase-lag bioheat transfer equation within skin tissues. AB - This paper deals with numerical modeling and simulation of heat transfer in skin tissues using non-linear dual-phase-lag (DPL) bioheat transfer model under periodic heat flux boundary condition. The blood perfusion is assumed temperature dependent which results in non-linear DPL bioheat transfer model in order to predict more accurate results. A numerical method of line which is based on finite difference and Runge-Kutta (4,5) schemes, is used to solve the present non linear problem. Under specific case, the exact solution has been obtained and compared with the present numerical scheme, and we found that those are in good agreement. A comparison based on model selection criterion (AIC) has been made among non-linear DPL models when the variation of blood perfusion rate with temperature is of constant, linear and exponential type with the experimental data and it has been found that non-linear DPL model with exponential variation of blood perfusion rate is closest to the experimental data. In addition, it is found that due to absence of phase-lag phenomena in Pennes bioheat transfer model, it achieves steady state more quickly and always predict higher temperature than thermal and DPL non-linear models. The effect of coefficient of blood perfusion rate, dimensionless heating frequency and Kirchoff number on dimensionless temperature distribution has also been analyzed. The whole analysis is presented in dimensionless form. PMID- 28859911 TI - Global dynamics of a mathematical model for the possible re-emergence of polio. AB - Motivated by studies warning about a possible re-emergence of poliomyelitis in Europe, we analyse a compartmental model for the transmission of polio describing the possible effect of unvaccinated people arriving to a region with low vaccination coverage. We calculate the basic reproduction number, and determine the global dynamics of the system: we show that, depending on the parameters, one of the two equilibria is globally asymptotically stable. The main tools applied are Lyapunov functions and persistence theory. We illustrate the analytic results by numerical examples, which also suggest that in order to avoid the risk of polio re-emergence, vaccinating the immigrant population might result insufficient, and also the vaccination coverage of countries with low rates should be increased. PMID- 28859912 TI - Establishment of nasal breathing should be the ultimate goal to secure adequate craniofacial and airway development in children. PMID- 28859913 TI - Quality of human milk expressed in a human milk bank and at home. AB - OBJECTIVE: To evaluate the quality of the human milk expressed at home and at a human milk bank. METHODS: This a retrospective, analytical, and observational study, performed by assessing titratable acidity records and the microbiological culture of 100 human milk samples expressed at home and at a human milk bank, in 2014. For the statistical analysis, generalized estimating equations (GEE) and the chi-squared test were used. RESULTS: When comparing the two sample groups, no significant difference was found, with 98% and 94% of the samples being approved among those collected at the milk bank and at home, respectively. No main interaction effect between local and titratable acidity records (p=0.285) was observed, and there was no statistically significant difference between the expected and observed values for the association between the collection place and the microbiological culture results (p=0.307). CONCLUSIONS: The quality of human milk expressed at home and at the milk bank are in agreement with the recommended standards, confirming that the expression of human milk at home is as safe as expression at the human milk bank, provided that the established hygiene, conservation, storage, and transport standards are followed. PMID- 28859914 TI - There is an association between disease location and gestational age at birth in newborns submitted to surgery due to necrotizing enterocolitis. AB - OBJECTIVES: To evaluate if there are differences regarding disease location and mortality of necrotizing enterocolitis, according to the gestational age at birth, in newborns submitted to surgery due to enterocolite. METHODS: A historical cohort study of 198 newborns submitted to surgery due to necrotizing enterecolitis in a tertiary hospital, from November 1991 to December 2012. The newborns were divided into different categories according to gestational age (<30 weeks, 30-33 weeks and 6 days, 34-36 weeks and 6 days, and >=37 weeks), and were followed for 60 days after surgery. The inclusion criterion was the presence of histological findings of necrotizing enterocolitis in the pathology. Patients with single intestinal perforation were excluded. RESULTS: The jejunum was the most commonly affected site in extremely premature infants (p=0.01), whereas the ileum was the most commonly affected site in premature infants (p=0.002), and the colon in infants born at term (p<0.001). With the increasing gestational age, it was observed that intestinal involvement decreased for the ileum and the jejunum (decreasing from 45% to 0% and from 5% to 0%, respectively), with a progressive increase in colon involvement (0% to 84%). Total mortality rate was 45.5%, and no statistical difference was observed in the mortality at different gestational ages (p=0.287). CONCLUSIONS: In newborns submitted to surgery due to necrotizing enterocolitis, the disease in extremely preterm infants was more common in the jejunum, whereas in preterm infants, the most affected site was the ileum, and in newborns born close to term, it was the colon. No difference in mortality was observed according to the gestational age at birth. PMID- 28859915 TI - Viral bronchiolitis in young infants: new perspectives for management and treatment. AB - OBJECTIVE: The aim of this review was to address advances in management and treatment of acute viral bronchiolitis in infants. SOURCES: A systematic review search was made including all articles published in English between 2010 and 2017, and available in the electronic databases PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) and specialized register of the Acute Respiratory Infections Group (Cochrane review group). The following MESH terms in English were included, using different Boolean operators for the search strategy: "bronchiolitis, viral," "diagnosis," "epidemiology," "etiology," "therapy," "virology," "prevention and control," "respiratory syncytial virus, human." Additional filters were used. SUMMARY OF FINDINGS: Few effective interventions are recommended for the management of RSV bronchiolitis in young infants. The main goal is to ensure an adequate oxygen supplementation and fluid balance whenever deemed necessary. Hypertonic saline nebulization is helpful only for hospitalized infants. Numerous antiviral drugs and specific vaccines for RSV are under evaluation and foretell advances in disease management in the near future. CONCLUSION: A number of promising new technologies are advancing in the field. Until new interventions became feasible, early detection and modification of preventable risk factors is essential to improve outcomes. PMID- 28859916 TI - The effect of type of afferent feedback timed with motor imagery on the induction of cortical plasticity. AB - A peripherally generated afferent volley that arrives at the peak negative (PN) phase during the movement related cortical potential (MRCP) induces significant plasticity at the cortical level in healthy individuals and chronic stroke patients. Transferring this type of associative brain-computer interface (BCI) intervention into the clinical setting requires that the proprioceptive input is comparable to the techniques implemented during the rehabilitation process. These consist mainly of functional electrical stimulation (FES) and passive movement induced by an actuated orthosis. In this study, we compared these two interventions (BCIFES and BCIpassive) where the afferent input was timed to arrive at the motor cortex during the PN of the MRCP. Twelve healthy participants attended two experimental sessions. They were asked to perform 30 dorsiflexion movements timed to a cue while continuous electroencephalographic (EEG) data were collected from FP1, Fz, FC1, FC2, C3, Cz, C4, CP1, CP2, and Pz, according to the standard international 10-20 system. MRCPs were extracted and the PN time calculated. Next, participants were asked to imagine the same movement 30 times while either FES (frequency: 20Hz, intensity: 8-35mAmp) or a passive ankle movement (amplitude and velocity matched to a normal gait cycle) was applied such that the first afferent inflow would coincide with the PN of the MRCP. The change in the output of the primary motor cortex (M1) was quantified by applying single transcranial magnetic stimuli to the area of M1 controlling the tibialis anterior (TA) muscle and measuring the motor evoked potential (MEP). Spinal changes were assessed pre and post by eliciting the TA stretch reflex. Both BCIFES and BCIpassive led to significant increases in the excitability of the cortical projections to TA (F(2,22)=4.44, p=0.024) without any concomitant changes at the spinal level. These effects were still present 30min after the cessation of both interventions. There was no significant main effect of intervention, F(1,11)=0.38, p=0.550, indicating that the changes in MEP occurred independently of the type of afferent inflow. An afferent volley generated from a passive movement or an electrical stimulus arrives at the somatosensory cortex at similar times. It is thus likely that the similar effects observed here are strictly due to the tight coupling in time between the afferent inflow and the PN of the MRCP. This provides further support to the associative nature of the proposed BCI system. PMID- 28859917 TI - Clinical usefulness of postoperative C-reactive protein/albumin ratio in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Patients' prognoses have been predicted by the preoperative inflammation-based score, but predicting a patient's risk for operative load remains challenging. This study investigates the usefulness of the postoperative C-reactive protein/albumin (CRP/Alb) ratio in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: This study retrospectively assessed 142 patients who underwent pancreatic resection for PDAC between 2004 and 2014. The time at which perioperative CRP/Alb ratio most influences the prognosis was identified, and the correlations among the perioperative CRP/Alb ratio, clinicopathological factors, and patient outcomes were investigated. RESULTS: Among the perioperative CRP/Alb ratios, only a high CRP/Alb ratio at postoperative day 14 (POD14) was significantly associated with shorter overall survival (OS) and relapse-free survival (RFS). High CRP/Alb ratio at POD 14 was related to high BMI, large amount of intraoperative bleeding, and the presence of complications. Finally, high CRP/Alb at POD14 was an independent prognostic factor of poor OS and RFS. CONCLUSIONS: The CRP/Alb ratio at POD14 is a useful predictive marker of surgical invasion, biological reaction, and prognosis in PDAC patients. PMID- 28859918 TI - Vital sign based shock scores are poor at triaging South African trauma patients. AB - BACKGROUND: Traumatic shock cannot be diagnosed by a single physiological measurement and a number of vital sign based combined shock scores (CSS) have been proposed to identify and triage trauma patients with shock. This audit uses data from a prospectively entered electronic trauma registry to compare the ability of these CSS to predict in-hospital mortality, need for surgery, need for blood transfusion and ICU admission. MATERIALS AND METHODS: The data used in the study was obtained from the Hybrid Electronic Medical Record (HEMR) in Pietermaritzburg from January 2012-September 2015. The calculated scores (Systolic Blood Pressure [SBP], Mean Arterial Pressure [MAP], Shock Index [SI], Modified Shock Index [MSI] and Shock Index multiplied by Age [SIA]) were plotted against each outcome parameter and the inflection points at which they started to increase, for each parameter, was determined and compared. RESULTS: A total of 8793 patients met the inclusion criteria. After the datasets with missing data were removed, a total of 7623 patients were available for analyses. There was a slightly higher incidence of blunt trauma (46%) compared to penetrating trauma (43%). Area under the Receiver Operating Curves (AUROC) for prediction of mortality revealed the MSI and SIA performed best, with values of 0.69 and 0.70, respectively. In both the 'need for ICU' prediction as well as the 'need for blood transfusion' prediction, MSI performed best with scores of 0.73 and 0.79, respectively. None of the parameters performed well in the 'need for surgery' prediction. None of the CSS parameters reached a 'good predictor capability' score of 0.8. CONCLUSION: The currently available vital sign based scores (SBP, MAP, SI, MSI, SIA) used in the prediction of shock severity and triage are not good predictors of mortality, need for ICU, need for theatre or need for blood transfusion in our population where half the trauma is penetrating and there are long pre-hospital delays. Our data suggests that none of the proposed CSS's are capable of reliably and accurately identifying and categorizing shock states in South African trauma patients. PMID- 28859919 TI - Nationwide analysis of adrenocortical carcinoma reveals higher perioperative morbidity in functional tumors. AB - BACKGROUND: Current adrenalectomy outcomes for functional adrenocortical carcinoma (ACC) remain unclear. This study examines nationwide in-hospital post adrenalectomy outcomes for ACC. METHODS: A retrospective analysis of the Nationwide Inpatient Sample database (2006-2011) to identify unilateral adrenalectomy patients for functional or nonfunctional ACC was performed. Patient demographics, comorbidities and postoperative outcomes were evaluated by t-test, Chi-square and multivariate regression. RESULTS: Of 2199 patients who underwent adrenalectomy, 87% had nonfunctional and 13% had functional ACC (86% hypercortisolism, 16% hyperaldosteronism, 4% hyperandrogenism). Functional ACC patients had significantly more comorbidities, and experienced certain postoperative complications more frequently including wound issues, adrenocortical insufficiency and acute kidney injury with longer hospital stay compared to nonfunctional ACC (P < 0.01). On multivariate analysis, functional ACC was an independent prognosticator for wound complications (28.1, 95%CI 4.59 176.6). CONCLUSION: Patients with functional ACC manifest significant comorbidities with certain in-hospital complications. Such high-risk patients require appropriate preoperative medical optimization prior to adrenalectomy. PMID- 28859920 TI - Sponsoring surgeons: An investigation on the influence of the da Vinci robot. AB - INTRODUCTION: The integrity of the medical literature about robotic surgery remains unclear despite wide-spread adoption. We sought to determine if payment from Intuitive Surgical Incorporated (ISI) affected quality of the research produced by surgeons. METHODS: Publicly available financial data from the CMS website regarding the top-20 earners from ISI for 2015 was gathered. Studies conducted by these surgeons were identified using PubMed. Inclusion criteria consisted of publications about the da Vinci(r) robot on patient outcomes. The primary outcome of our study was if the study conclusion was positive/equivocal/negative towards the robot. Secondary outcomes included authorship, sponsorship, study controls, and disclosure. RESULTS: The top earners received $3,296,844 in 2015, with a median of $141,959. Sub-specialties included general surgery (55%), colorectal (20%), thoracic (15%), and obstetrics/gynecology (10%). Of the 37 studies, there was 1 RCT, with observational studies comprising the rest. The majority of the studies (n = 16, 43%) had no control population, with 11 (30%) comparing to same institution/surgeon, Though ISI sponsored only 6 (16%) studies, all with positive conclusions, 27 (73%) studies had positive conclusions for robot use, 9 (24%) equivocal, and only 1 (3%) negative. Overall, 13 earners had lead authorship and 11 senior. CONCLUSION: This initial pilot study highlights a potential bias as current literature published by benefactors demonstrates low quality and highly positive conclusions towards approval of the robot. This substantiates the need for a large, systematic review of the potential influence of sponsoring surgeons on medical literature. PMID- 28859921 TI - Greater hypertrophy can be achieved with associating liver partition with portal vein ligation for staged hepatectomy compared to conventional staged hepatectomy, but with a higher price to pay? AB - BACKGROUND: Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) and conventional staged hepatectomy (CSH) are options for patients with unresectable liver tumors due to insufficient future liver remnant (FLR). METHODS: A retrospective comparison of clinical data, liver volumetry and surgical outcomes between 10 ALPPS and 29 CSH patients was performed. RESULTS: Patient demographics and disease characteristics were similar between both groups. ALPPS induced superior FLR growth (ALPPS vs. CSH, 48.1% (IQR 39.4-96.9%) vs. 11.8% (IQR 4.3-41.9%), p = 0.013). However, post-operative day 5 international normalized ratio (INR) (ALPPS vs. CSH, 1.6 (IQR 1.5-1.8) vs. 1.4 (IQR 1.3-1.6), p = 0.015) and rate of post-hepatectomy liver failure (ALPPS vs. CSH, 25 vs. 0%, p = 0.032) was higher in the ALPPS group. 90-day mortality (ALPPS vs. CSH, 12.5% vs. 0%, p = 0.320) was similar in both groups. CONCLUSION: ALPPS was superior in inducing FLR growth but associated with increased post hepatectomy liver failure compared to CSH. PMID- 28859922 TI - The role of multiorgan procurement for abdominal transplant in general surgery resident education. AB - BACKGROUND: To assess the impact of participation of multiorgan procurement (MP) by general surgery (GS) residents on surgical knowledge and skills, a prospective cohort study of GS residents during transplant surgery rotation was performed. METHODS: Before and after participation in MPs, assessment of knowledge was performed by written pre and post tests and surgical skills by modified Objective Structured Assessment of Technical Skill (OSATS) score. Thirty-nine residents performed 84 MPs. RESULTS: Significant improvement was noted in the written test scores (63.3% vs 76.7%; P < 0.001). Better surgical score was associated with female gender (15.4 vs 13.3, P = <0.01), prior MP experience (16.2 vs 13.7, P = 0.03), and senior level resident (15.1 vs 13.0, P = 0.03). Supraceliac aortic dissection (P = 0.0017) and instrument handling (P = 0.041) improved with more MP operations. CONCLUSIONS: Participation in MP improves residents' knowledge of abdominal anatomy and surgical technique. PMID- 28859923 TI - Proper Choice of Donor Site Veins for Patients Undergoing Free Radial Forearm Flap Reconstruction for the Defects of Head and Neck. AB - PURPOSE: The purpose of this study was to analyze the reliability of the deep venous drainage system of the free radial forearm flap. MATERIALS AND METHODS: The authors implemented a retrospective cohort study and enrolled patients admitted for the evaluation and management of head and neck tumors with radial forearm flap reconstruction. The primary predictor variables were the donor site veins, including the deep, dual, and superficial venous drainage systems. The primary outcome measurement was the incidence of venous compromise. Potential confounders included patient demographics, history of chemotherapy with or without radiotherapy, defect sites, and the recipient artery and vein. The chi2 test and logistic regression analysis were used for statistical analysis. RESULTS: The final study population consisted of 520 patients (mean age, 54 years) who underwent head and neck soft tissue reconstruction using the free radial forearm flap. Patients with the deep system (odds ratio [OR] = 0.251; 95% confidence interval [CI], 0.108-0.581) or dual system (OR = 0.197; 95% CI, 0.064 0.605) had a markedly lower risk of venous compromise than those with the superficial system. The overall incidence of inadequate outflow was 2.5% (5 of 204) when the deep system was used alone and 8.9% (19 of 212) when the superficial system was used alone (P = .004). CONCLUSIONS: Patients with the deep venous drainage system had a statistically lower risk of venous compromise. This study recommends using the deep system as a drainage vein for the free radial forearm flap. PMID- 28859924 TI - The Use of Platelet-Rich Fibrin for Immediate Closure of Acute Oroantral Communications: An Alternative Approach. AB - Currently, the buccal advancement flap, palatal rotational flap, and buccal fat pad techniques are frequently used to close an oroantral communication (OAC). In this study, platelet-rich fibrin (PRF) clots were used for immediate closure of acute OACs after extraction of posterior maxillary molars. Acute oroantral perforations larger than 3 mm in diameter in 21 patients were treated uneventfully using PRF clots. None of the patients had systemic diseases or symptoms of sinus disease. After tooth extraction, the diagnosis of acute OAC was examined by the Valsalva maneuver (compressing the nostrils with the fingers and then blowing out air). After detection of an air leak, a modified ball burnisher instrument 3 mm in diameter was used to determine whether the perforation was larger than 3 mm. The postextraction socket of the tooth was cleaned with sterile physiologic saline solution and the cavity was filled with PRF. PRF clots were sutured to the gingiva to prevent them from migrating to the sinus and for stabilization. On the seventh day of follow-up, healthy granulation tissue was observed; during the third week of follow-up, epithelialized oral mucosa was detected at the extraction site in all cases. The use of PRF enables the closure of OACs without primary flap closure or any other surgical interventions. Thus, the use of PRF for immediate closure of acute OACs will make the treatment of OACs less traumatic and easier and will eliminate the need for special surgical expertise. PMID- 28859925 TI - Effect of Resveratrol on Critical-Sized Calvarial Defects of Diabetic Rats: Histometric and Gene Expression Analysis. AB - PURPOSE: This study investigated the influence of resveratrol (RESV) on the repair of bone critical defects in calvaria of animals with induced diabetes mellitus (DM). MATERIAL AND METHODS: One hundred rats were divided into 5 groups: induced DM + RESV administration (DM + RESV; n = 20); induced DM plus placebo solution administration (DM + PLAC; n = 20); induced DM plus insulin therapy (DM + INS; n = 20); induced DM plus administration of RES and INS (DM + RESV + INS; n = 20); and nondiabetic controls (NDM; n = 20). DM was induced by intraperitoneal injection of streptozotocin 50 mg/kg 3 days before the surgical procedures. Two critical calvarial defects were created in each animal at the start of the study (day 0). Treatments were administered from day 0 to day 30 of the experiment, when animals were euthanized. One defect was processed for histometric analysis to measure closure of the bone defect. The tissue of the other defect was analyzed for quantification of bone morphogenetic protein-2 (BMP-2), osteopontin, osteoprotegerin, receptor activator of nuclear factor-kappaB ligand, runt-related transcription factor-2, osterix (Osx), beta-catenin, lipoprotein receptor-related protein-5, and dikkop-1 mRNA by quantitative polymerase chain reaction. RESULTS: Histometric results showed that the DM + RESV, DM + RESV + INS, and NDM groups exhibited greater closure of the bone defects compared with the PLAC- or INS treated groups (P < .05). Diabetic animals treated with RESV plus INS showed higher levels of BMP-2 and Osx; Osx also was positively increased in animals treated with INS alone (P < .05). CONCLUSIONS: The use of RESV, regardless of the presence of INS, positively influenced bone repair in animals with induced DM. Further, the combination of INS plus RESV was necessary for the modulation of BMP 2 gene expression. PMID- 28859926 TI - Impact of Accurate 30-Day Status on Operative Mortality: Wanted Dead or Alive, Not Unknown. AB - BACKGROUND: Risk-adjusted operative mortality is the most important quality metric in cardiac surgery for determining The Society of Thoracic Surgeons (STS) Composite Score for star ratings. Accurate 30-day status is required to determine STS operative mortality. The goal of this study was to determine the effect of unknown or missing 30-day status on risk-adjusted operative mortality in a regional STS Adult Cardiac Surgery Database cooperative and demonstrate the ability to correct these deficiencies by matching with an administrative database. METHODS: STS Adult Cardiac Surgery Database data were submitted by 27 hospitals from five hospital systems to the Texas Quality Initiative (TQI), a regional quality collaborative. TQI data were matched with a regional hospital claims database to resolve unknown 30-day status. The risk-adjusted operative mortality observed-to-expected (O/E) ratio was determined before and after matching to determine the effect of unknown status on the operative mortality O/E. RESULTS: TQI found an excessive (22%) unknown 30-day status for STS isolated coronary artery bypass grafting cases. Matching the TQI data to the administrative claims database reduced the unknowns to 7%. The STS process of imputing unknown 30-day status as alive underestimates the true operative mortality O/E (1.27 before vs 1.30 after match), while excluding unknowns overestimates the operative mortality O/E (1.57 before vs 1.37 after match) for isolated coronary artery bypass grafting. CONCLUSIONS: The current STS algorithm of imputing unknown 30-day status as alive and a strategy of excluding cases with unknown 30-day status both result in erroneous calculation of operative mortality and operative mortality O/E. However, external validation by matching with an administrative database can improve the accuracy of clinical databases such as the STS Adult Cardiac Surgery Database. PMID- 28859927 TI - A nonlinear poroelastic theory of solid tumors with glycosaminoglycan swelling. AB - Mechanics plays a crucial role in the growth, development, and therapeutics of tumors. In this paper, a nonlinear poroelastic theory is established to describe the mechanical behaviors of solid tumors. The free-swollen state of a tumor is chosen as the reference state, which enables us to avoid pursuing a dry and stress-free state that is hard to achieve for living tissues. Our results reveal that the compression resistance of a tumor is primarily attributed to glycosaminoglycan (GAG) swelling, and the compactness of cell aggregates is found to affect tumor consolidation. Over-expressed GAGs and dense cell aggregates can stiffen the tumor, a remodeling mechanism that makes the tumor with higher elastic modulus than its surrounding host tissues. Glycosaminoglycan chains also influence the transient mechanical response of the tumor by modulating the tissue permeability. The theoretical results show good agreement with relevant experimental observations. This study may not only deepen our understanding of tumorigenesis but also provide cues for developing novel anticancer strategies. PMID- 28859928 TI - Response to the Letter to the Editor. PMID- 28859929 TI - Cutaneous and renal vasodilatory response to local pressure application: A comparative study in mice. AB - BACKGROUND AND AIM: We have reported a novel relationship involving mechanical stimulation and vasodilation in rodent and human skin, referred to as pressure induced vasodilation (PIV). It is unknown whether this mechanism exists in kidney and reflects the microcirculation in deep organs. Therefore, we compared the skin and kidney PIV to determine whether their changes were similar. METHODS: In anesthetized mice fed a normal salt-diet, laser Doppler flux (LDF) signals were measured when an increase in local pressure was applied to the surface of the head skin with the rate of 2.2Pa/s (1mmHg/min) and to the left kidney with a rate of 4.4Pa/s (2mmHg/min). The mechanism underlying renal PIV was also investigated. The skin and kidney PIV were also compared during salt load (4% NaCl diet). RESULTS: The kidney had higher baseline LDF and vascular conductance compared to those of the skin. Pressure application increased the LDF in the kidney as well as in the skin with a comparable maximal magnitude (about 25% from baseline value), despite different kinetics of PIV evolution. As we previously reported in the skin, the kidney PIV response was mediated by the activation of transient receptor potential vanilloid type 1 channels, the release of calcitonin gene related peptide, and the participation of prostaglandins and nitric oxide. In the absence of hypertension, high salt intake abolished the cutaneous PIV response and markedly impaired the renal one. CONCLUSION: PIV response in the mouse kidney results from a neuro-vascular interaction. Despite some differences between the skin and the kidney PIV, the similarities in their response and signaling mechanisms suggest that the cutaneous microcirculation could reflect, in part, the microcirculation of the renal cortex. PMID- 28859930 TI - Novel secolignans from Peperomia dindygulensis and their inhibitory activities on JAK-STAT signaling pathways. AB - Nineteen secolignans (1-19), including five new ones (1-5), were isolated from the whole plant of Peperomia dindygulensis. Their structures including stereochemistry were determined by spectroscopic methods, in particular NMR and electronic CD (ECD) analysis. All the isolates were evaluated for their inhibitory activities against IFN-gamma/STAT1 as well as IL-6/STAT3 signaling pathway by the method of Luciferase assay. Six 2-methene type secolignans (1, 2, 6-9) exhibited significant inhibitory activities against JAK-STAT pathways with the IC50 values both lower than 10MUM. PMID- 28859931 TI - Isoindolinone-containing meroterpenoids with alpha-glucosidase inhibitory activity from mushroom Hericium caput-medusae. AB - Hericium caput-medusae is an edible and medicinal mushroom closely relative to H. erinaceus. According to our detailed chemical investigation, two novel isoindolinone-containing meroterpene dimers, caputmedusins A (1) and B (2), as well as nine analogues, caputmedusins C-K (3-11), were isolated from the fermentation broth of H. caput-medusae. Their structures were elucidated by analyses of 1D and 2D NMR spectroscopic methods. The absolute configurations of 1 4 were speculated based on the specific optical rotation and biogenetic consideration. The absolute configurations of 10 and 11 were rationalized by the calculation of 1H NMR chemical shifts. Caputmedusins A-C (1-3) showed moderate inhibitory activity against alpha-glucosidase with the IC50 values of 39.2, 36.2 and 40.8MUM, respectively. PMID- 28859933 TI - Evaluation of high dose volumetric CT to reduce inter-observer delineation variability and PTV margins for prostate cancer radiotherapy. AB - PURPOSE: The aim was to determine whether the enhanced soft tissue contrast provided by high-dose volumetric CT (HDVCT) can reduce inter-observer variability in delineating prostate compared to helical conventional CT (CCT) scans and 3T MRI scans for patients undergoing radical prostate cancer radiotherapy. Secondly, to quantify the potential PTV reduction with decreased inter-observer variability. MATERIALS AND METHODS: A 320 slice volumetric CT scanner was used. The wide-detector coverage of 16cm enabled volumetric image acquisition of prostate gland in one rotation. Three imaging studies were performed on ten patients. CCT and HDVCT were performed consecutively at the same coordinate system followed by MRI. Five radiation oncologists delineated the prostate. RESULTS: The inter-observer variability is 2.0+/-0.6, 1.9+/-0.4 and 1.8+/-0.4mm for CCT, HDVCT and MR respectively with the maximum at the apex region. Comparing inter-observer difference variability between CCT and HDVCT with MR indicates that observers have larger variations in contouring using CCT than HDVCT especially at apex. Jaccard index of HDVCT is significantly higher than CCT with a mean difference of 0.03 (p=0.011). Both MRI and HDVCT provide the opportunity for a 2mm PTV margin reduction at the apex compared to CCT. CONCLUSION: Inter observer variability in delineation remains an important source of systematic error. HDCTV for treatment planning reduces this error without recourse to MRI and permits a PTV reduction of 2mm at the apex. The margins required to account for residual error with any imaging modality are still greater than are used in typical current practice. PMID- 28859932 TI - The role of radical radiotherapy in the management of malignant pleural mesothelioma: A systematic review. AB - Malignant pleural mesothelioma (MPM) is a devastating disease with limited treatment options and a dismal prognosis. Attempts to employ radical radiotherapy in this disease have been limited by the complex shape of the pleura and the dose restrictions necessitated by the close proximity of radiosensitive structures. Recent shifts towards a 'lung sparing' surgical approach in MPM have further heightened these challenges. The aim of this systematic review is to assess recent advances in radiotherapy planning and delivery, to ascertain how these developments have impacted on the feasibility of delivering photon-based, high dose radiotherapy with radical intent in MPM. Three electronic databases were searched and a total of 249 articles reviewed. The challenge of generating high quality, practice-defining data for diseases such as MPM was highlighted by the identification of just two randomised studies. Much of the literature consisted of low quality, retrospective data with small cohorts and inconsistent reporting on radiotherapy techniques and dosimetry. Nevertheless, a number of prospective phase II studies were identified to suggest that radical doses of radiotherapy can be delivered safely after a lung sparing procedure in MPM, reporting encouraging survival data and acceptable levels of toxicity. PMID- 28859934 TI - Acacia nilotica leaf improves insulin resistance and hyperglycemia associated acute hepatic injury and nephrotoxicity by improving systemic antioxidant status in diabetic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acacia nilotica (L.) Delile is used as a traditional anti-diabetic remedy in Bangladesh, Pakistan, Egypt, Nigeria and is mentioned in Ayurveda as well. AIM: The objective of the study was to evaluate the ethnomedicinal claim of A. nilotica leaf (ANL) extract for its efficiency in ameliorating diabetic complications. MATERIALS AND METHODS: ANL was orally administrated (50 and 200mg/kg) to alloxanized mice (blood glucose > 200mg/dL) for 20d. Parameters of glucose metabolism, hepatotoxicity, hyperlipidemia and nephrotoxicity were measured with emphasis on elevated oxidative stress. ANL was chemically characterized using GC-MS. Further, docking studies were employed to predict molecular interactions. RESULTS: ANL lowered (65%, P< 0.001) systemic glucose load in diabetic mice, which was otherwise 398% higher than control. ANL lowered (35%) insulin resistance, without any significant effect on insulin sensitivity (P> 0.05). Anti-hyperglycemic properties of ANL was further supported by lowering of HbA1c (34%; P< 0.001) and improved glucose utilization (OGTT). Overall diabetic complications were mitigated as reflected by lowered hepatic (ALT, AST) and renal (creatinine, BUN) injury markers and normalization of dyslipidemia. Elevated systemic oxidative stress was lowered by increased catalase and peroxidase activities in liver, kidney and skeletal muscle, resulting in 32% decrease of serum MDA levels. Apart from high phenolic and flavonoid content, tocopherol, catechol and beta-sitosterol, identified in ANL, demonstrated substantial binding affinity with Nrf2 protein (5FNQ) reflecting possible crosstalk with intracellular antioxidant defense pathways. CONCLUSION: The present study revealed the potentials of A. nilotica to alleviate diabetes related systemic complications by limiting oxidative stress which justified the ethnopharmacological antidiabetic claim. PMID- 28859935 TI - Recurrence of urinary tract infections and development of urinary-specific antibiogram for kidney transplant recipients. AB - OBJECTIVES: Urinary tract infection (UTI) recurrence and antimicrobial resistance remain a common problem in kidney transplant recipients. Whilst the use of annual institutional antibiograms may help guide appropriate empirical antibiotic selection, these non-disease specific antibiograms do not always account for patient-specific risk factors or disease-specific resistance patterns. This study determined the frequency of UTI recurrence during the first year after kidney transplantation as well as differences in antimicrobial susceptibility between an institutional antibiogram and the disease-specific antibiogram for patients following kidney transplantation. METHODS: In this study, adult patients with at least one UTI during an inpatient admission within 1 year post kidney transplantation were evaluated. A disease-specific antibiogram for UTIs in kidney transplant recipients was prepared based on culture results and was compared with the annual institutional antibiograms. RESULTS: Of 299 kidney transplants performed during the study period, 66 subjects meet the study inclusion criteria, of whom 47% had two or more UTIs within the first year after kidney transplant. In comparison with the institutional antibiogram, Escherichia coli isolated from urine samples from kidney transplant recipients were significantly more resistant to trimethoprim/sulfamethoxazole, ceftriaxone, cefepime, ciprofloxacin and gentamicin (P<0.0001). CONCLUSIONS: Multiple UTIs are common in kidney transplant recipients during the first year post-transplantation. E. coli urinary isolates were significantly more resistant to multiple antibiotic drug classes in this patient population compared with the general hospital population. Antimicrobial stewardship programmes at transplant centres should consider producing disease specific antibiograms specifically for transplant recipients to improve empirical antibiotic selection guidance. PMID- 28859936 TI - Corrigendum to "3T MRI in paediatrics: Challenges and clinical applications" [Eur. J. Radiol. 68 (2) (2008) 309-319]. PMID- 28859937 TI - Voriconazole-loaded nanostructured lipid carriers (NLC) for drug delivery in deeper regions of the nail plate. AB - Voriconazole-loaded nanostructured lipid carriers (VOR-NLC) were developed and drug penetration evaluated in porcine hooves in vitro. Synergistic effect of urea (Ur), selected among other known chemical enhancers according to hoof hydration potential, was also evaluated. VOR-NLC presented a high encapsulation efficiency (74.52+/-2.13%), approximate mean diameter of 230nm and were positively charged (+27.32+/-2.74mV). Stability studies indicated they were stable under refrigeration (4+/-2 degrees C) for up to 150days. SEM images revealed hooves treated with VOR-NLC and VOR-NLC-Ur suffered a disturbance on the surface depicting high roughness and porosity. Permeation data showed a substantial VOR amount retained in superficial hooves sections independent of the formulation used (2.42+/-0.26; 2.52+/-0.36 and 2.41+/-0.60MUg/cm2 for unloaded VOR, VOR-NLC and VOR-NLC-Ur, respectively, p>0.05). Still, successive extractions, revealed the amount of VOR retained in deeper regions was significantly higher when VOR NLC or VOR-NLC-Ur was used (0.17+/-0.04, 0.47+/-0.14 and 0.36+/-0.07MUg/cm2 for unloaded VOR, VOR-NLC and VOR-NLC-Ur, respectively, p<0.05). Such results indicate NLC are promising formulations for the management of onychomycosis. Further studies in diseased nail plates are necessary. PMID- 28859938 TI - A novel multi-tiered experimental approach unfolding the mechanisms behind cyclodextrin-vitamin inclusion complexes for enhanced vitamin solubility and stability. AB - This study was conducted to provide a mechanistic account for understanding the synthesis, characterization and solubility phenomena of vitamin complexes with cyclodextrins (CD) for enhanced solubility and stability employing experimental and in silico molecular modeling strategies. New geometric, molecular and energetic analyses were pursued to explicate experimentally derived cholecalciferol complexes. Various CD molecules (alpha-, beta-, gamma-, and hydroxypropyl beta-) were complexed with three vitamins: cholecalciferol, ascorbic acid and alpha-tocopherol. The Inclusion Efficiency (IE%) was computed for each CD-vitamin complex. The highest IE% achieved for a cholecalciferol complex was for 'betaCDD3-8', after utilizing a unique CD:cholecalciferol molar synthesis ratio of 2.5:1, never before reported as successful. 2HPbetaCD cholecalciferol, gammaCD-cholecalciferol and alpha-tocopherol inclusion complexes (IC's) reached maximal IE% with a CD:vitamin molar ratio of 5:1. The results demonstrate that IE%, thermal stability, concentration, carrier solubility, molecular mechanics and intended release profile are key factors to consider when synthesizing vitamin-CD complexes. Phase-solubility data provided insights into the design of formulations with IC's that may provide analogous oral vitamin release profiles even when hydrophobic and hydrophilic vitamins are co incorporated. Static lattice atomistic simulations were able to validate experimentally derived cholecalciferol IE phenomena and are invaluable parameters when approaching formulation strategies using CD's for improved solubility and efficacy of vitamins. PMID- 28859939 TI - Relationships between response surfaces for tablet characteristics of placebo and API-containing tablets manufactured by direct compression method. AB - In this study, we evaluated the correlation between the response surfaces for the tablet characteristics of placebo and active pharmaceutical ingredient (API) containing tablets. The quantities of lactose, cornstarch, and microcrystalline cellulose were chosen as the formulation factors. Ten tablet formulations were prepared. The tensile strength (TS) and disintegration time (DT) of tablets were measured as tablet characteristics. The response surfaces for TS and DT were estimated using a nonlinear response surface method incorporating multivariate spline interpolation, and were then compared with those of placebo tablets. A correlation was clearly observed for TS and DT of all APIs, although the value of the response surfaces for TS and DT was highly dependent on the type of API used. Based on this knowledge, the response surfaces for TS and DT of API-containing tablets were predicted from only two and four formulations using regression expression and placebo tablet data, respectively. The results from the evaluation of prediction accuracy showed that this method accurately predicted TS and DT, suggesting that it could construct a reliable response surface for TS and DT with a small number of samples. This technique assists in the effective estimation of the relationships between design variables and pharmaceutical responses during pharmaceutical development. PMID- 28859940 TI - Downstream drug product processing of itraconazole nanosuspension: Factors influencing tablet material properties and dissolution of compacted nanosuspension-layered sugar beads. AB - There has been limited research done on the downstream processing of nanosuspensions into solid oral dosage forms. This paper demonstrates the bead layering process with a layering level at 150% and 240%, as well as the selection and justification of the outer phase excipients for tabletability and disintegrating properties. In a previous study, an itraconazole nanosuspension stabilised by SDS and HPMC E5 was layered onto sugar beads with coating polymer HPMC VLV. In the current study, compression studies with these layered beads utilising the small bead size at 150% or 240% layering levels with outer phase cushioning excipients MCC, copovidone or isomalt were performed. Other excipients such as co-compressed crospovidone-PEG 4000; DCP functioning as a disintegrant; and HPC as a binder was also added. Target output variables were achieved with a balance between an adequate tensile strength and fast dissolution rate with a release of 99.0% (+/-1.0% SD) within 10min, which is in accordance with the FDA guidance for dissolution testing. The results show that the compaction of nanosuspension-layered beads is a suitable process for processing an itraconazole nanosuspension into a solid dosage form such as a compacted tablet without compromising on drug release. PMID- 28859941 TI - Very low LDL-cholesterol concentrations achieved: which target is next? PMID- 28859943 TI - Population screening and intervention for vascular disease in Danish men (VIVA): a randomised controlled trial. AB - BACKGROUND: Abdominal aortic aneurysm is the only cardiovascular disease targeted by population screening. In this study, we test the effect of screening and subsequent intervention for abdominal aortic aneurysm, peripheral arterial disease, and hypertension combined. METHODS: In this randomised controlled trial, we randomly allocated (1:1) all men aged 65-74 years living in the Central Denmark Region to screening for abdominal aortic aneurysm, peripheral arterial disease, and hypertension, or to no screening. We based allocation on computer generated random numbers from 1 to 100 in blocks of 1067 to 4392, stratified by 19 municipalities. Only the non-screening group and the investigator assessing outcomes were masked. We invited participants who were found to have abdominal aortic aneurysm or peripheral arterial disease back for confirmation and eventual initiation of relevant pharmacological therapy. We further offered participants with abdominal aortic aneurysm annual control or surgical repair. We referred participants with suspected hypertension to their general practitioner. The primary outcome was all-cause mortality, assessed 5 years after randomisation, analysed in all randomly allocated participants except for those who had incorrect person identification numbers. This trial is registered at ClinicalTrials.gov, number NCT00662480. FINDINGS: Between Oct 8, 2008, and Jan 11, 2011, we randomly allocated 50 156 participants, with 25 078 (50%) each in the screening and non-screening groups. Four (<1%) participants in the screening group were lost to follow-up. After a median follow-up of 4.4 years (IQR 3.9 4.8), 2566 (10.2%) of 25 074 participants in the screening group and 2715 (10.8%) of 25 078 in the non-screening group had died. This finding resulted in a significant hazard ratio of 0.93 (95% CI 0.88-0.98; p=0.01), an absolute risk reduction of 0.006 (0.001-0.011), and a number needed to invite of 169 (89-1811). Incidences of diabetes (3995 per 100 000 person-years in the screening group vs 4129 per 100 000 person-years in the non-screening group), intracerebral haemorrhage (146 vs 140), renal failure (612 vs 649), cancer (3578 vs 3719), or 30 day mortality after cardiovascular surgery (44.57 vs 39.33) did not differ between groups. INTERPRETATION: The observed reduction of mortality risk from abdominal aortic aneurysm, peripheral arterial disease, and hypertension has never been seen before in the population screening literature and can be linked primarily to initiation of pharmacological therapy. Health policy makers should consider implementing combined screening whether no screening or isolated abdominal aortic aneurysm screening is currently offered. FUNDING: The 7th European Framework Programme, Central Denmark Region, Viborg Hospital, and the Danish Council for Independent Research. PMID- 28859945 TI - Catheter-based renal denervation for treatment of hypertension. PMID- 28859946 TI - Population-based screening for vascular disease. PMID- 28859944 TI - Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. AB - BACKGROUND: Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS: SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS: Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5.5 mm Hg (95% CI 9.1 to -2.0; p=0.0031), 24-h DBP -4.8 mm Hg (-7.0 to -2.6; p<0.0001), office SBP 10.0 mm Hg (-15.1 to -4.9; p=0.0004), and office DBP -5.3 mm Hg (-7.8 to -2.7; p=0.0002). No significant changes were seen in the sham-control group: 24-h SBP 0.5 mm Hg (95% CI -3.9 to 2.9; p=0.7644), 24-h DBP -0.4 mm Hg (-2.2 to 1.4; p=0.6448), office SBP -2.3 mm Hg (-6.1 to 1.6; p=0.2381), and office DBP -0.3 mm Hg (-2.9 to 2.2; p=0.8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5.0 mm Hg (95% CI -9.9 to -0.2; p=0.0414), 24-h DBP -4.4 mm Hg (-7.2 to -1.6; p=0.0024), office SBP -7.7 mm Hg (-14.0 to -1.5; p=0.0155), and office DBP -4.9 mm Hg (-8.5 to -1.4; p=0.0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION: Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING: Medtronic. PMID- 28859942 TI - A multifaceted intervention to improve treatment with oral anticoagulants in atrial fibrillation (IMPACT-AF): an international, cluster-randomised trial. AB - BACKGROUND: Oral anticoagulation is underused in patients with atrial fibrillation. We assessed the impact of a multifaceted educational intervention, versus usual care, on oral anticoagulant use in patients with atrial fibrillation. METHODS: This study was a two-arm, prospective, international, cluster-randomised, controlled trial. Patients were included who had atrial fibrillation and an indication for oral anticoagulation. Clusters were randomised (1:1) to receive a quality improvement educational intervention (intervention group) or usual care (control group). Randomisation was carried out centrally, using the eClinicalOS electronic data capture system. The intervention involved education of providers and patients, with regular monitoring and feedback. The primary outcome was the change in the proportion of patients treated with oral anticoagulants from baseline assessment to evaluation at 1 year. The trial is registered at ClinicalTrials.gov, number NCT02082548. FINDINGS: 2281 patients from five countries (Argentina, n=343; Brazil, n=360; China, n=586; India, n=493; and Romania, n=499) were enrolled from 48 clusters between June 11, 2014, and Nov 13, 2016. Follow-up was at a median of 12.0 months (IQR 11.8-12.2). Oral anticoagulant use increased in the intervention group from 68% (804 of 1184 patients) at baseline to 80% (943 of 1184 patients) at 1 year (difference 12%), whereas in the control group it increased from 64% (703 of 1092 patients) at baseline to 67% (732 of 1092 patients) at 1 year (difference 3%). Absolute difference in the change between groups was 9.1% (95% CI 3.8-14.4); odds ratio of change in the use of oral anticoagulation between groups was 3.28 (95% CI 1.67 6.44; adjusted p value=0.0002). Kaplan-Meier estimates showed a reduction in the secondary outcome of stroke in the intervention versus control groups (HR 0.48, 95% CI 0.23-0.99; log-rank p value=0.0434). INTERPRETATION: A multifaceted and multilevel educational intervention, aimed to improve use of oral anticoagulation in patients with atrial fibrillation and at risk for stroke, resulted in a significant increase in the proportion of patients treated with oral anticoagulants. Such an intervention has the potential to improve stroke prevention around the world for patients with atrial fibrillation. FUNDING: Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. PMID- 28859948 TI - The impact of IMPACT-AF. PMID- 28859947 TI - Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. AB - BACKGROUND: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9). METHODS: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2.2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633. FINDINGS: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4395 (17%) patients achieved concentrations of 2.6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L; p=0.0012 for the primary endpoint, p=0.0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events. INTERPRETATION: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0.2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2.2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations. FUNDING: Amgen. PMID- 28859949 TI - Probability, management, and long-term outcomes of biliary complications after hepatic artery thrombosis in liver transplant recipients. AB - BACKGROUND: Hepatic artery thrombosis after liver transplantation is a devastating complication associated with ischemic cholangiopathy that can occur even after successful revascularization. This study explores long-term outcomes after hepatic artery thrombosis in adult liver transplantation recipients, focusing on the probability, risk factors, and resolution of ischemic cholangiopathy. METHODS: A retrospective chart review of 1,783 consecutive adult liver transplantations performed between 1995 and 2014 identified 44 cases of hepatic artery thrombosis (2.6%); 10 patients underwent immediate retransplantation, and 34 patients received nontransplant treatments, involving revascularization (n = 19) or expectant nonrevascularization management (n = 15). RESULTS: The 1-year graft survival after nontransplant treatment was favorable (82%); however, 16 of the 34 patients who received a nontransplant treatment developed ischemic cholangiopathy and required long-term biliary intervention. A Cox regression model showed that increased serum transaminase and bilirubin levels at the time of hepatic artery thrombosis diagnosis, but not nonrevascularization treatment versus revascularization, were risk factors for the development of ischemic cholangiopathy. Ischemic cholangiopathy in revascularized grafts was less extensive with a greater likelihood of resolution within 5-years than that in nonrevascularized grafts (100% vs 17%). Most liver abscesses without signs of liver failure also were reversible. Salvage retransplantation after a nontransplant treatment was performed in 8 patients with a 1-year survival rate equivalent to immediate retransplantation (88% vs 80%). CONCLUSION: Selective nontransplant treatments for hepatic artery thrombosis resulted in favorable graft survival. Biliary intervention can resolve liver abscess and ischemic cholangiopathy that developed in revascularized grafts in the long-term; salvage retransplantation should be considered for ischemic cholangiopathy in nonrevascularized grafts because of a poor chance of resolution. PMID- 28859950 TI - Fortune cookie red and blood orange. PMID- 28859951 TI - A palpable pancreatic duct. PMID- 28859952 TI - Predictors of post-colonoscopy emergency department use. AB - BACKGROUND AND AIMS: Unplanned hospital visits within 7 days of colonoscopy were recently proposed as a quality measure. It is unknown whether patient, procedure, or endoscopist characteristics predict post-colonoscopy emergency department (ED) visits. Our aim was to determine the incidence and relatedness of ED visits within 7 days of colonoscopy and to identify predictors of post-colonoscopy ED use. METHODS: In this retrospective, single-center, cohort study, we evaluated outpatient colonoscopies performed at a tertiary academic medical center or affiliated facility between January 2008 and September 2013. We determined the incidence of ED visits within 7 days of colonoscopy and the relatedness of the ED visit to the procedure. We assessed for independent factors associated with ED use within 7 days using logistic regression analysis. RESULTS: We reviewed 50,319 colonoscopies performed on 44,082 individuals (47% male, median age 59 years) by 40 endoscopists. There were 382 (0.76%) ED visits after colonoscopy, of which 68% were related to the procedure. On multivariate analysis, recent ED visit (odds ratio [OR], 16.60; 95% confidence interval [CI], 12.83-21.48; P < .001), EMR (OR, 4.69; 95% CI, 2.82-7.79; P < .001), number of medication classes (OR, 1.18; 95% CI, 1.11-1.26; P < .001), endoscopist adenoma detection rate (ADR) (OR, 1.14; 95% CI, 1.01-1.29; P = .029), and white race (OR, 0.77; 95% CI, 0.62-0.97; P = .028) were identified as independent variables associated with ED visits after colonoscopy. CONCLUSIONS: Increased patient complexity, higher endoscopist ADR, and EMR were associated with increased ED use after colonoscopy. Patients at high risk for an unplanned hospital visit within 7 days should be targeted for quality improvement efforts to reduce adverse events and cost. PMID- 28859954 TI - Optimization of conditions for decolorization of azo-based textile dyes by multiple fungal species. AB - Wastewater from textile industries contains azo dye residues that negatively affect most environmental systems. The biological treatment of these wastes is the best option due to safety and cost concerns. Here we isolated and identified 19 azo dye-degrading fungi and optimized conditions resulting in enhanced degradation. The fungi belonged to five species of Aspergillus and a single Lichtheimia sp. All fungi were evaluated for their ability to decolorize 20 azo dyes. While the most easily transformable azo dye was direct violet (decolorization ranged from 71.1 to 93.3%), the most resistant to decolorization was fast green azo dye. The greatest degradation potential of azo dyes (direct violet and methyl red) was optimized using the most promising four fungal strains and changing media glucose concentration, nitrogen source, and micronutrients. Biomass, lignin peroxidase, and laccases production were also determined in the optimization studies. The decolorization of both azo dyes by the four fungal strains was greatly enhanced by glucose supplementation. The fungal strains were not able to produce lignin peroxidases in the absence of organic nitrogen source. Both yeast extract and casamino acid supplementation enhanced decolorization of direct violet and methyl red dyes and production of lignin peroxidase by the fungal strains. In contrast, the laccases were absent in the similar medium enriched with the same organic nitrogen sources. PMID- 28859953 TI - A prospective comparison of live and video-based assessments of colonoscopy performance. AB - BACKGROUND AND AIMS: Colonoscopy performance is typically assessed by a supervisor in the clinical setting. There are limitations of this approach, however, because it allows for rater bias and increases supervisor workload demand during the procedure. Video-based assessment of recorded procedures has been proposed as a complementary means by which to assess colonoscopy performance. This study sought to investigate the reliability, validity, and feasibility of video-based assessments of competence in performing colonoscopy compared with live assessment. METHODS: Novice (<50 previous colonoscopies), intermediate (50-500), and experienced (>1000) endoscopists from 5 hospitals participated. Two views of each colonoscopy were videotaped: an endoscopic (intraluminal) view and a recording of the endoscopist's hand movements. Recorded procedures were independently assessed by 2 blinded experts using the Gastrointestinal Endoscopy Competency Assessment Tool (GiECAT), a validated procedure-specific assessment tool comprising a global rating scale (GRS) and checklist (CL). Live ratings were conducted by a non-blinded expert endoscopist. Outcomes included agreement between live and blinded video-based ratings of clinical colonoscopies, intra-rater reliability, inter-rater reliability and discriminative validity of video-based assessments, and perceived ease of assessment. RESULTS: Forty endoscopists participated (20 novices, 10 intermediates, and 10 experienced). There was good agreement between the live and video-based ratings (total, intra-class correlation [ICC] = 0.847; GRS, ICC = 0.868; CL, ICC = 0.749). Intra-rater reliability was excellent (total, ICC = 0.99; GRS, ICC = 0.99; CL, ICC = 0.98). Inter-rater reliability between the 2 blinded video-based raters was high (total, ICC = 0.91; GRS, ICC = 0.918; CL, ICC = 0.862). GiECAT total, GRS, and CL scores differed significantly among novice, intermediate, and experienced endoscopists (P < .001). Video-based assessments were perceived as "fairly easy," although live assessments were rated as significantly easier (P < .001). CONCLUSIONS: Video-based assessments of colonoscopy procedures using the GiECAT have strong evidence of reliability and validity. In addition, assessments using videos were feasible, although live assessments were easier. PMID- 28859955 TI - Human placentophagy: a review. AB - Placentophagy or placentophagia, the postpartum ingestion of the placenta, is widespread among mammals; however, no contemporary human culture incorporates eating placenta postpartum as part of its traditions. At present, there is an increasing interest in placentophagy among postpartum women, especially in the United States. The placenta can be eaten raw, cooked, roasted, dehydrated, or encapsulated or through smoothies and tinctures. The most frequently used preparation appears to be placenta encapsulation after steaming and dehydration. Numerous companies offer to prepare the placenta for consumption, although the evidence for positive effects of human placentophagy is anecdotal and limited to self-reported surveys. Without any scientific evidence, individuals promoting placentophagy, especially in the form of placenta encapsulation, claim that it is associated with certain physical and psychosocial benefits. We found that there is no scientific evidence of any clinical benefit of placentophagy among humans, and no placental nutrients and hormones are retained in sufficient amounts after placenta encapsulation to be potentially helpful to the mother postpartum. In contrast to the belief of clinical benefits associated with human placentophagy, the Centers for Disease Control and Prevention recently issued a warning due to a case in which a newborn infant developed recurrent neonatal group B Streptococcus sepsis after the mother ingested contaminated placenta capsules containing Streptococcus agalactiae. The Centers for Disease Control and Prevention recommended that the intake of placenta capsules should be avoided owing to inadequate eradication of infectious pathogens during the encapsulation process. Therefore, in response to a woman who expresses an interest in placentophagy, physicians should inform her about the reported risks and the absence of clinical benefits associated with the ingestion. In addition, clinicians should inquire regarding a history of placenta ingestion in cases of postpartum maternal or neonatal infections such as group B Streptococcus sepsis. In conclusion, there is no professional responsibility on clinicians to offer placentophagy to pregnant women. Moreover, because placentophagy is potentially harmful with no documented benefit, counseling women should be directive: physicians should discourage this practice. Health care organizations should develop clear clinical guidelines to implement a scientific and professional approach to human placentophagy. PMID- 28859957 TI - Morphology of the spermathecae of twelve species of Triatominae (Hemiptera, Reduviidae) vectors of Chagas disease. AB - Trypanosoma cruzi, the etiological agent of Chagas disease, is transmitted by triatomines that have been described in a large number of studies. Most of those studies are related to external morphology and taxonomy, but some biochemical, genetic and physiological studies have also been published. There are a few publications in the literature about the internal organs of Triatominae, for instance the spermathecae, which are responsible for storing and maintaining the viability of the spermatozoids until the fertilization of the oocytes. This work aims to study the spermathecae of twelve species of triatomines obtained from the Triatominae Insectarium of the Faculty of Pharmaceutical Sciences, UNESP, Araraquara, using optical microscopy and scanning electron microscopy. The spermathecae of the twelve species studied showed three morphological patterns: a) P. herreri sn, P. lignarius, P. megistus, Triatoma brasiliensis, T. juazeirensis, T. sherlocki and T. tibiamaculata have spermathecae with a thin initial portion and an oval-shaped final portion; b) R. montenegrensis, R. nasutus, R. neglectus, R. pictipes and R. prolixus have tubular and winding spermathecae; c) T. infestans has oval spermathecae. In addition to the three morphological patterns, it was noted that each of the twelve species has particular features that differentiate them. PMID- 28859956 TI - Modulation of transmission success of Plasmodium falciparum gametocytes (sexual stages) in various species of Anopheles by erythrocytic asexual stage parasites. AB - During malaria infection, a small proportion of erythrocytic asexual stages undergo sexual differentiation. Male and female gametocytes ingested in the blood meal initiate the sexual development of malaria parasites in the mosquito midgut. During blood feeding on a host, a mosquito ingests, in addition to mature gametocytes, host immune factors present in the blood, as well as large excess of erythrocytic asexual stages. In the current study we addressed the impact of the presence of large excess of asexual stages, hitherto not known or even suspected to influence, on the infectivity of gametocytes in the mosquito. Asexual stages resulted in a dose-dependent inhibition of infectiousness of gametocytes, and some of this could be explained by the presumed effect of hemozoin and other unknown asexual-stage components on the mosquito immune system, affecting survival and maturation of parasites in the mosquito midgut. Interactions between asexual and sexual stages, maturity and ratio of male and female gametocytes, host immune factors and mosquito innate immune factors are some of the variables that determine the infectiousness of gametocytes in the mosquitoes and ultimately malaria transmission success. Understanding of determinants affecting malaria transmission will be critical to approaches directly targeting the transmission process for malaria elimination. PMID- 28859958 TI - Understanding Giardia infections among rural communities using the one health approach. AB - The epidemiology of giardiasis in rural villages in Peninsular Malaysia was examined in the context of the One Health triad that encompasses humans, animals and environment (i.e. river water). A cross-sectional study was carried out among five rural communities in Malaysia to determine the prevalence of Giardia duodenalis in humans, animals and river water. Fecal samples collected from humans and animals were examined by light microscopy. Water was sampled from the rivers adjacent to the target communities and investigated for the occurrence of Giardia cysts. The isolated cysts were further genotyped targeting the glutamate dehydrogenase and triosephosphate isomerase genes. The overall prevalence of G. duodenalis was 6.7% (18/269) and 4.7% (8/169) among humans and animals, respectively. Giardia cysts (mean concentration range: 0.10-5.97 cysts/L) were also found in adjacent rivers at four out of the five villages examined. At Kemensah and Kuala Pangsun, Giardia cysts were isolated from humans [rate: 3.7% each (of 54 each)], animals [rates: 6.3% (of 62) and 11.3% (of 16), respectively] and river water [average concentration of 9 samples each: 0.83+/-0.81 and 5.97+/ 7.00, respectively]. For both villages at Pos Piah and Paya Lebar, 12.2% (of 98) and 6.1% (of 33) of collected human samples were infected, respectively whilst none of the collected animals samples in these villages were found to be positive. The river water samples of these two villages were also contaminated (average concentration: 0.20+/-0.35 (of 9) and 0.10+/-0.19 (of 3), respectively). In conclusion, Giardia cysts were simultaneously observed in the human-animal environment (i.e., river water) interfaces in at least two of five studied communities highlighting a vital need to improve understanding on the interplay of transmission dynamics, the role of infected humans and animals in contaminating the water sources and the role of water as a vehicle of disease transmission in these communities. Indeed, this study illustrates the One Health approach which is to recognize that the optimal health of humans are interconnected with the well-being of animals and their environment. PMID- 28859959 TI - First confirmed report of outbreak of theileriosis/anaplasmosis in a cattle farm in Henan, China. AB - Tick-borne diseases (TBDs) impose a significant constraint to livestock production world widely. In this paper, we presented a case of TBD in a cattle farm in Henan, China. 35 blood samples (7 samples sent by veterinarian, 28 samples gathered by our colleagues) were collected from ill, surviving and asymptomatic cattle and microscopic observation and PCR assays were conducted to characterize the pathogens. Genus Ixodes feeding on these cattle were collected and identified. Theileria annulata-like and Anaplasma marginale-like pathogens were observed in the blood smears stained with Giemsa staining under microscope. Furthermore, 5 out of 7 cattle blood samples were found to be positive for T. annulata by PCR. In the 28 blood specimens, three were positive for T. annulata, while A. marginale DNA was detected in nine blood DNA samples. Besides, 56 ticks feeding on cattle were collected from this farm and were all identified as Rhipisephalus microplus, meanwhile, 10 of them were found to be positive for A. marginale. In addition, phylogenetic analysis of the msp4 gene sequences of A. marginale obtained in this study showed that the isolate from cattle (KX840009) fell in the same clade with that of R. microplus (KX904527), sharing 100% similarity. To the best of our knowledge, this is the first confirmed report of outbreak of theileriosis/anaplasmosis in cattle farms in Henan, China. PMID- 28859961 TI - Modeling mosquito-borne diseases in complex urban environments. PMID- 28859960 TI - Molecular detection of Trypanosoma cruzi in acai pulp and sugarcane juice. AB - Chagas disease, caused by Trypanosoma cruzi affects about 6-8 million people worldwide. Although transmission by triatomine insects has been controlled, other means of transmission maintain the infection. These forms of transmission are responsible for introducing Chagas disease in other non-endemic countries of the world. Thus, Chagas disease, nowadays is a worldwide health problem. In Brazil, acai pulp and sugarcane juice have been associated with Chagas disease outbreaks. The difficulties in isolation of the parasite from foods are hampering source tracking which could allow the confirmation of an implicated food commodity in these outbreak investigations. To address this scientific gap, we evaluated the performance of real-time PCR (qPCR) for detecting T. cruzi in acai pulp and sugarcane juice. All experiments were performed with acai pulp and sugarcane juice samples contaminated with different concentrations of T. cruzi. In assays with qPCR, the results showed that the ideal procedure for T. cruzi identification in acai pulp and sugarcane juice consisted of: i. centrifugation; ii. DNA extraction with a commercial kit for stool matrix; and iii. qPCR using a specific molecular marker for T. cruzi. The seeding in LIT medium of experimentally contaminated foods was effective in detecting the parasitic load by qPCR. The efficacy of qPCR was also verified testing food samples crushed with infected Triatomines. In conclusion, this methodology can be used to perform rapid diagnosis in outbreaks, facilitating measures in disease control. PMID- 28859962 TI - How do seasonality and host traits influence the distribution patterns of parasites on juveniles and adults of Columba livia? AB - Parasites may influence host fitness and consequently exert a selective pressure on distinct phenotypes of the host population. This pressure can result in an evolutionary response, maintaining only individuals with certain traits in the population. The present study was aimed at identifying the morphological characteristics of juveniles and adults of Columba livia that may influence the distribution patterns of lice, Pseudolynchia canariensis and Haemoproteus columbae and how the populations of these parasites vary throughout the seasons of the year. Between July 2012 and July 2014, 377 specimens of C. livia were captured. We observed a significant increase in the mean intensities of infestation by pigeon flies and lice, as well as in species richness of ectoparasites during the warmest seasons, suggesting a reproductive synchrony between ectoparasites and host species. Bill length, body mass, and body length did not affect the infestation levels of ectoparasites on adults and juveniles of C. livia with three distinct plumage colors. In juveniles, plumage color affected only the mean intensity of infestation by lice, with Spread individuals as the most infested. This indicates that melanin in feathers was not an effective barrier against ectoparasites. PMID- 28859963 TI - In Vitro Effects of Amino Alcohols on Echinococcus granulosus. AB - Cystic echinococcosis is a globally distributed zoonotic disease, which is caused by the larval stage of Echinococcosus granulosus sensu lato. The chemotherapy of the disease is limited to the use of benzimidazoles. Recently, mefloquine and its analogues, aminoalcohol-carbazole, and some amino alcohol derivatives were reported to display inhibitory effects on parasites. Here, the activities of 130 amino alcohol compounds against E. granulosus were tested on protoscoleces and germinal cells at a concentration of 20 MUg/ml over a period of three days. As a result, sixteen compounds totally were effective against both protoscoleces and germinal cells, and their IC50 and LC50 were also calculated respectively. Then effects of the most active compounds were observed on metacestodes over 14 days in vitro. Although the structure of active compounds were variable, hydroxyl and amino groups connected by two carbon atoms are held in common as the key feature of these compounds. The further investigation on metacestodes incubated with these active compounds revealed that the effects of JF16 and BTB4 were comparable to that of mefloquine and mebendazole. In addition, the ultrastructure alternations induced by these compounds on E. granulosus were confirmed by scanning electron microscopy and transmission electron microscopy observations. In conclusion, amino alcohols were a class of compounds with efficacy against E. granulosus. The most effective compounds JF16 and BTB4 indicated that their basic structure would be useful in the synthesis of new compound for the treatment of echinococcosis. However, their in vivo efficacy and toxicity need to be carefully evaluated in the future. PMID- 28859964 TI - In vitro and clinical evaluation of optical tooth whitening toothpastes. AB - OBJECTIVES: To measure tooth whitening effects delivered immediately after brushing with silica-based toothpastes containing either blue covarine or a combination of blue covarine and FD&C Blue No. 1 in vitro and in vivo. METHODS: Salivary pellicle coated human extracted teeth were brushed with either a slurry of a toothpaste containing blue covarine (BC) or a formulation containing a matched level of blue covarine and FD&C Blue No.1 (BC+D). The colour of the specimens were measured in vitro using a colorimeter, before and after brushing and changes in CIELAB and tooth Whiteness Index (WIO) values calculated. In a double-blind cross-over clinical study, subjects brushed with BC toothpaste, a toothpaste containing increased levels of blue covarine (BC+) or BC+D toothpaste and tooth colour changes were measured with a digital image analysis system. RESULTS: The in vitro study demonstrated that BC+D gave a significantly (p=0.002) greater change in WIO value than BC. Clinical results showed that BC, BC+ and BC+D gave a significant increase in WIO (p<0.0001) from baseline. The WIO change was significantly greater when brushing with BC+D toothpaste than with either toothpaste BC (p<0.0001) or BC+ (p<0.05). CONCLUSIONS: Toothpastes containing blue covarine or a combination of blue covarine and FD&C Blue No. 1 gave a statistically significant improvement in tooth whiteness immediately after brushing in both in vitro and clinical studies. In addition, the toothpaste containing both blue covarine and FD&C Blue No. 1 gave statistically significant greater tooth whitening from baseline than the blue covarine containing toothpastes. CLINICAL SIGNIFICANCE: The silica-based toothpastes containing blue covarine or a combination of blue covarine and FD&C Blue No. 1 evaluated in the current study gave significant tooth whitening benefits immediately after one brush. PMID- 28859965 TI - Comparison of the newer preventive therapies on remineralisation of enamel in vitro. AB - OBJECTIVES: To investigate in vitro the effect of MI Paste, MI Paste Plus and 2800ppm fluoride (F) toothpaste (TP) on the remineralisation of enamel subsurface lesions and to compare these to the effect of 1450ppm and 0ppm F toothpastes. METHODS: Enamel subsurface lesions were created in bovine enamel slabs (n=120) which were assigned randomly to five groups; (1) 0ppm F TP, (2) 1450ppm F TP, (3) 2800ppm F TP, (4) 1450ppm F TP+MI Paste (Tooth Mousse-TM,10% w/v CPP-ACP) and (5) 1450ppm F TP+MI Paste Plus (Tooth Mousse Plus,10% w/v CPP-ACP, 900ppm F as 0.2% w/w sodium fluoride). The enamel slabs were subjected to a pH cycling regimen for 21days. Quantitative Light-induced Fluorescence (QLF) images were taken and analysed. Data analysis was carried out using one way ANOVA. RESULTS: In all groups, both DeltaF (percentage fluorescence loss) and DeltaQ (DeltaF times the area) values improved significantly within the same group after the treatment. In addition, the mean difference in DeltaF of the non-fluoride control group was significantly lower than all other groups but not for the 2800ppm F- group. Whereas the mean difference in DeltaQ of the non-fluoride control of group was significantly lower when compared with all other groups (p<0.05). CONCLUSIONS: Both MI Paste and MI Paste Plus when used in conjunction with 1450ppm F did not show a significant increase in efficacy for the remineralisation of bovine enamel subsurface lesions in the model used in this study. CLINICAL SIGNIFICANCE: Newer preventive agents such as MI paste and MI paste plus are advocated as promoting remineralisation when used in addition to routine oral care. This in vitro study shows that they may have a limited value in promoting remineralisation over and above that of 1450ppm F toothpaste used twice a day. PMID- 28859966 TI - Relative distribution and biological characterization of CXCL4L1 isoforms in platelets from healthy donors. AB - CXCL4L1, a platelet-derived ELR-negative CXC chemokine, is a powerful angiostatic and anti-tumoral chemokine. We developed a mass spectrometric assay for the detection of different natural CXCL4L1 isoforms. Using this assay, we identified 4 different CXCL4L1 isoforms in the supernatant of thrombin-stimulated platelets from healthy volunteers: the classical isoform CXCL4L1(1-70), CXCL4L1(-4-70), which probably arises through alternative signal peptide removal and two COOH terminally truncated isoforms CXCL4L1(1-69) and CXCL4L1(-4-69). CXCL4L1(1-70) was the most abundant isoform, whereas CXCL4L1(-4-70) was detected in 50% of the platelet preparations. Since alterations to the NH2-terminus of chemokines can have severe biological consequences, we investigated the impact of the extension with 4 NH2-terminal amino acids on the biological activity of CXCL4L1. In vitro, CXCL4L1(-4-70) was as potent as CXCL4L1(1-70) in inhibiting signal transduction and migration of human microvascular endothelial cells towards vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). In a FITC-conjugated dextran cell permeability assay, both splice variants showed a strong but comparable anti-permeable effect upon VEGF stimulation of the endothelial cell monolayer. In vivo angiogenesis induced by FGF-2 was equally reduced by CXCL4L1(1-70) and CXCL4L1(-4-70). In chemotaxis assays with CXCR3A transfected cells the CXCL4L1 isoforms both induced migration from 125ng/ml onward. Finally, CXCL4L1(1-70) and CXCL4L1(-4-70) showed the same affinity for heparin. In conclusion, the investigated biological activities of CXCL4L1 are not influenced by the four extra NH2-terminal residues present in the alternatively spliced isoform CXCL4L1(-4-70). Therefore, our results suggest that both isoforms equally interact with the CXCR3A and CXCR3B receptor. PMID- 28859967 TI - A Jak2-selective inhibitor potently reverses the immune suppression by modulating the tumor microenvironment for cancer immunotherapy. AB - Small molecule therapeutics can be potent tools for cancer immunotherapy. They may be devised to target the tumor associated macrophages (TAMs) and regulatory T cells (Treg), which are major immunosuppressive cells in the tumor microenvironment. The infiltration and functionalization of these cells, which essentially promote tumor development, are mediated by the hyper-activation of the Jak-STAT3 signaling pathway. Here, we demonstrated that compound 9#, a novel inhibitor of Jak2, could suppress Jak2-STAT3 signaling in macrophages (peritoneal macrophages and THP-1 cells) and direct the macrophages toward the pro inflammatory (M1-like) phenotype. When tested in ex vivo TAM culture and in vivo tumor models, compound 9# could reverse the phenotype of TAM from M2- to M1-type by promoting IL-12 expression. Further study suggested that compound 9# also inhibited the induction of Treg both in vitro and in vivo via blockage of Jak2 signaling. Finally, compound 9# potently increased the frequency and anti-tumor activity of CD4+ and CD8+ T lymphocytes, leading to effective suppression of tumor growth. Taken together, our findings indicated that compound 9# could be a potential candidate of small molecule therapeutics for cancer immunotherapy. PMID- 28859969 TI - Non-singleton colors are not attended faster than categories, but they are encoded faster: A combined approach of behavior, modeling and ERPs. AB - The visual system is able to detect targets according to a variety of criteria, such as by categorical (letter vs digit) or featural attributes (color). These criteria are often used interchangeably in rapid serial visual presentation (RSVP) studies but little is known about how rapidly they are processed. The aim of this work was to compare the time course of attentional selection and memory encoding for different types of target criteria. We conducted two experiments where participants reported one or two targets (T1, T2) presented in lateral RSVP streams. Targets were marked either by being a singleton color (red letter among black letters), being categorically distinct (digits among letters) or non singleton color (target color letter among heterogeneously colored letters). Using event related potential (ERPs) associated with attention and memory encoding (the N2pc and the P3 respectively), we compared the relative latency of these two processing stages for these three kinds of targets. In addition to these ERP measures, we obtained convergent behavioral measures for attention and memory encoding by presenting two targets in immediate sequence and comparing their relative accuracy and proportion of temporal order errors. Both behavioral and EEG measures revealed that singleton color targets were attended much more quickly than either non-singleton color or categorical targets, and there was very little difference between attention latencies to non-singleton color and categorical targets. There was however a difference in the speed of memory encoding for non-singleton color and category latencies in both behavioral and EEG measures, which shows that encoding latency differences do not always mirror attention latency differences. PMID- 28859968 TI - Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure. AB - Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca2+/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca2+-ATPase 2a axis and Na+-Ca2+ exchanger function in Ca2+ extrusion. This resulted in reduced sarcoplasmic reticulum Ca2+ content, diastolic Ca2+ overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C mediated delayed rectifier K+ current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure. PMID- 28859970 TI - Aging does not affect integration times for the perception of depth from motion parallax. AB - To successfully navigate throughout the world, observers must rapidly recover depth information. One depth cue that is especially important for a moving observer is motion parallax. To perceive unambiguous depth from motion parallax, the visual system must integrate information from two different proximal signals, retinal image motion and a pursuit eye movement. Previous research has shown that aging affects both of these necessary components for motion parallax depth perception, but no research has yet investigated how aging affects the mechanism for integrating motion and pursuit information to recover depth from motion parallax. The goal of the current experiment was to assess the integration time required by older adults to process depth information. In four psychophysical conditions, younger and older observers made motion and depth judgments about stationary or translating random-dot stimuli. Stimulus presentations in all four psychophysical conditions were followed by a high-contrast pattern mask, and minimum stimulus presentation durations (stimulus-to-mask onset asynchrony, or SOA) were measured. These SOAs reflect the minimum neural processing time required to make motion and motion parallax depth judgments. Pursuit latency was also measured. The results revealed that, after accounting for age-related delays in motion processing and pursuit onset, older and younger adults required similar temporal intervals to combine retinal image motion with an internal pursuit signal for the perception of depth. These results suggest that the mechanism for motion and pursuit integration is not affected by age. PMID- 28859971 TI - Enzyme-linked immunosorbent assay of relaxin-like gonad-stimulating peptide in the starfish Patiria (Asterina) pectinifera. AB - A relaxin-like gonad-stimulating peptide (RGP) from starfish Patiria (Asterina) pectinifera is the first identified invertebrate gonadotropin for final gamete maturation. Recently, we succeeded in obtaining specific antibodies against P. pectinifera RGP (PpeRGP). In this study, the antibodies were used for the development of a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for the measurement of PpeRGP. A biotin-conjugated peptide that binds to peroxidase-conjugated streptavidin is specifically detectable using 3,3',5,5' tetramethylbenzidine (TMB)/hydrogen peroxide as a substrate; therefore, biotin conjugated RGP (biotin-PpeRGP) was synthesized chemically. Similarly to PpeRGP, synthetic biotin-PpeRGP bound to the antibody against PpeRGP. In binding experiments with biotin-PpeRGP using wells coated with the antibody, a displacement curve was obtained using serial concentrations of PpeRGP. The ELISA system showed that PpeRGP could be measured in the range 0.01-10pmol per 50ul assay buffer. On the contrary, the B-chains of PpeRGP, Asterias amurensis RGP, Aphelasterias japonica RGP, and human relaxin showed minimal cross-reactivity in the ELISA, except that the A-chain of PpeRGP affected it slightly. These results strongly suggest that this ELISA system is highly specific and sensitive with respect to PpeRGP. PMID- 28859972 TI - Increased oxytocin-monomeric red fluorescent protein 1 fluorescent intensity with urocortin-like immunoreactivity in the hypothalamo-neurohypophysial system of aged transgenic rats. AB - To visualize oxytocin in the hypothalamo-neurohypophysial system, we generated a transgenic rat that expresses the oxytocin-monomeric red fluorescent protein 1 (mRFP1) fusion gene. In the present study, we examined the age-related changes of oxytocin-mRFP1 fluorescent intensity in the posterior pituitary (PP), the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) of transgenic rats. The mRFP1 fluorescent intensities were significantly increased in the PP, the SON and the PVN of 12-, 18- and 24-month-old transgenic rats in comparison with 3-month-old transgenic rats. Immunohistochemical staining for urocortin, which belongs to the family of corticotropin-releasing factor family, revealed that the numbers of urocortin-like immunoreactive (LI) cells in the SON and the PVN were significantly increased in 12-, 18- and 24-month-old transgenic rats in comparison with 3-month-old transgenic rats. Almost all of urocortin-LI cells co exist mRFP1-expressing cells in the SON and the PVN of aged transgenic rats. These results suggest that oxytocin content of the hypothalamo-neurohypophysial system may be modulated by age-related regulation. The physiological role of the co-existence of oxytocin and urocortin in the SON and PVN of aged rats remains unclear. PMID- 28859973 TI - Histamine and Toll-like receptor ligands synergistically induce endothelial cell gap formation by the extrinsic coagulating pathway. PMID- 28859975 TI - Astrotactin 1-derived peptide: A new skin-penetrating peptide against inflammatory skin diseases. PMID- 28859974 TI - Novel signal transducer and activator of transcription 1 mutation disrupts small ubiquitin-related modifier conjugation causing gain of function. AB - BACKGROUND: Sumoylation is a posttranslational reversible modification of cellular proteins through the conjugation of small ubiquitin-related modifier (SUMO) and comprises an important regulator of protein function. OBJECTIVE: We sought to characterize the molecular mechanism of a novel mutation at the SUMO motif on signal transducer and activator of transcription 1 (STAT1). METHODS: STAT1 sequencing and functional characterization were performed in transfection experiments by using immunoblotting and immunoprecipitation in STAT1-deficient cell lines. Transcriptional response and target gene activation were also investigated in PBMCs. RESULTS: We identified a novel STAT1 mutation (c.2114A>T, p.E705V) within the SUMO motif (702IKTE705) in a patient with disseminated Rhodococcus species infection, Norwegian scabies, chronic mucocutaneous candidiasis, hypothyroidism, and esophageal squamous cell carcinoma. The mutation is located in the tail segment and is predicted to disrupt STAT1 sumoylation. Immunoprecipitation experiments performed in transfected cells confirmed absent STAT1 sumoylation for E705V, whereas it was present in wild-type (WT) STAT1 cells, as well as the loss-of-function mutants L706S and Y701C. Furthermore, stimulation with IFN-gamma led to enhanced STAT1 phosphorylation, enhanced transcriptional activity, and target gene expression in the E705V-transfected compared with WT-transfected cells. Computer modeling of WT and mutant STAT1 molecules showed variations in the accessibility of the phosphorylation site Y701, which corresponded to the loss-of-function and gain-of-function variants. CONCLUSION: This is the first report of a mutation in the STAT1 sumoylation motif associated with clinical disease. These data reinforce sumoylation as a key posttranslational regulatory modification of STAT1 and identify a novel mechanism for gain-of-function STAT1 disease in human subjects. PMID- 28859976 TI - Structural and mechanistic comparison of the Cyclopropane Mycolic Acid Synthases (CMAS) protein family of Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a chronic disease caused by the bacillus Mycobacterium tuberculosis(Mtb) and remains a leading cause of mortality worldwide. The bacteria has an external wall which protects it from being killed, and the enzymes involved in the biosynthesis of the cell wall components have been proposed as promising targets for future drug development efforts. Cyclopropane Mycolic Acid Synthases (CMAS) constitute a group of ten homologous enzymes which belong to the mycolic acid biosynthesis pathway. These enzymes have S-adenosyl-l methionine (SAM) dependent methyltransferase activity with a peculiarity, each one of them has strong substrate selectivity and reaction specificity, being able to produce among other things cyclopropanes or methyl-alcohol groups from the lipid olefin group. How each CMAS processes its substrate and how the specificity and selectivity are encoded in the protein sequence and structure, is still unclear. In this work, by using a combination of modeling tools, including comparative modeling, docking, all-atom MD and QM/MM methodologies we studied in detail the reaction mechanism of cmaA2, mmaA4, and mmaA1 CMAS and described the molecular determinants that lead to different products. We have modeled the protein-substrate complex structure and determined the free energy pathway for the reaction. The combination of modeling tools at different levels of complexity allows having a complete picture of the CMAS structure-activity relationship. PMID- 28859977 TI - Lowering the concentration affects the migration and viability of intracerebroventricular-delivered human mesenchymal stem cells. AB - Due to their widely known therapeutic benefits, mesenchymal stem cells have been proposed as a novel treatment option for a wide range of diseases including Alzheimer's disease. To maximize these benefits, critical factors such as delivery route, cell viability, and cell migration must be accounted for. Out of the various delivery routes to the brain, the intracerebroventricular (ICV) route stands out due to the widespread distribution that can occur via cerebrospinal fluid flow. The major objective of this present study was to observe how altering cell concentration influences the migration and viability of human umbilical cord blood derived-mesenchymal stem cells (hUCB-MSCs), delivered via ICV injection, in the brains of wild-type (WT) mice. C3H/C57 WT mice were divided into three groups and were injected with 1 * 105 hUCB-MSCs suspended in varying volumes: high (3 MUl), middle (5 MUl), and low (7 MUl) concentrations, respectively. Lowering the concentration increased the migratory capabilities and elevated the viability of hUCB-MSCs. These results suggest that cell concentration can affect the physiological state of hUCB-MSCs, and thus the extent of therapeutic efficacy that can be achieved. PMID- 28859978 TI - Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) suppresses STING-mediated DNA sensing pathway through inducing mitochondrial fission. AB - Besides its important role in innate immune response to DNA virus infection, the regulatory function of STING in autoimmunity and cancer is emerging. Recently, multiple mechanisms regulating the activity of the STING pathway have been revealed. Previous study showed that carbonyl cyanide 3-chlorophenylhydrazone (CCCP), the protonophore, inhibited STING-mediated IFN-beta production via disrupting mitochondrial membrane potential (MMP). However, how MMP dissipation leads to the suppression of the STING pathway remains unknown. Here, we show that CCCP inhibits activation of STING and its downstream signaling molecules, TBK1 and IRF3, but not STING translocation to the perinuclear region. We found that CCCP impairs the interaction between STING and TBK1 and concomitantly triggers mitochondria fission. Importantly, the knockout of the crucial mitochondria fission regulator Drp1 restored the STING activity, indicating that CCCP down modulates the STING pathway through DRP1-mediated mitochondria fragmentation. Our findings highlight the coupling of the STING signaling platform to mitochondria dynamics. PMID- 28859979 TI - Bortezomib, a proteasome inhibitor, alleviates atopic dermatitis by increasing claudin 1 protein expression. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease. Many studies investigating AD pathogenesis and its therapy have been conducted but none have been successful. One of the causes of AD is dysfunction of tight junctions through reduction of claudin 1 expression in the epidermal barrier of the skin. In the present study, we investigated the role of bortezomib (BTZ) in the restoration of the reduced expression of claudin 1. Immunoblot and immunofluorescence analyses revealed that BTZ increased the protein expression level of claudin 1 in the human keratinocyte cell line HaCaT, thereby forming paracellular barriers. Furthermore, repeated application of BTZ alleviated atopic symptoms on the backs and ears of 2, 4-dinitrochlorobenzene (DNCB)-induced AD mice, and led to the formation of normal tight junctions in the epidermal barrier of DNCB-induced mice skin. Taken together, these results demonstrate that BTZ induced claudin 1 expression may be a valuable therapeutic approach for AD. PMID- 28859980 TI - Phase separation in necrotic cells. AB - Necrotic cells are known to develop characteristic membrane blebs. We measured protein concentration within necrotic blebs and found that it can be reduced by as much as twenty-fold compared to the main cell body (CB). These results raise two questions: 1. Why do proteins vacate the bleb? 2. How can osmotic equilibrium be maintained between the bleb and CB? Our photobleaching and ultracentrifugation experiments indicate extensive protein aggregation. We hypothesize that protein aggregation within the CB shifts the chemical equilibrium and draws proteins out of the bleb; at the same time, aggregation reduces the effective molar concentration of protein in the CB, so that osmotic equilibrium between high protein CB and low-protein necrotic blebs becomes possible. PMID- 28859981 TI - Clump-passaging-based efficient 3D culture of human pluripotent stem cells under chemically defined conditions. AB - Large-scale production of human pluripotent stem cells (hPSCs) in an efficient and safe manner is crucial to the successful application of hPSCs in biomedical research and regenerative medicine. Three-dimensional culture methods for hPSCs have been extensively studied using single-cell passaging approaches; however, these techniques have been challenged by the induction of massive cell death and accumulation of genomic abnormalities. In this work, we developed and optimized a novel, simple clump-passaging method for in vitro hPSCs 3-dimensional (3D) culture that can be exploited for large-scale production. Fully grown hPSC spheroids were dissociated into smaller-sized spheroid clumps by simple treatment with enzyme-free dissociation buffer, and clumped hPSCs were inoculated and maintained for 3D suspension culture. Our clump-passaging method effectively increased the hPSCs survival rate after subculture and supported scalable hPSCs 3D expansion. We also tested and selected chemically defined media formulations that are suitable for 3D culture and commercially available. Overall, our clump passaging and expansion method demonstrated high survival and expansion rates for hPSC spheroids compared with conventional methods and may also have the advantage of maintaining genomic stability. PMID- 28859982 TI - Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer. AB - Interleukin-17 (IL-17), a pleiotropic proinflammatory cytokine, is reported to be significantly generated by a distinct subset of CD4+ T-cells, upgrading cancer elicited inflammation and preventing cancer cells from immune surveillance. T helper (Th)17 cells produced from naive CD4+ T cells have recently been renowned and generally accepted, gaining eminence in cancer studies and playing the effective role in context of cancer. Th17 cells are the main source of IL-17 secreting cells, It was found that other cell types produced this cytokine as well, including Group 3 innate lymphoid cells (ILC3), deltagammaT cells, invariant natural killer T (iNKT) cells, lymphoid-tissue inducer (LTi)-like cells and Natural killer (NK) cells. Th17-associated cytokines give impetus to tumor progression, or inducing angiogenesis and metastasis. This review demonstrates an understanding on how the pro- or antitumor function of Th17 cells and IL-17 may change cancer progression, leading to the appearance of complex and pivotal biologic activities in tumor. PMID- 28859983 TI - GABRB2 plays an important role in the lymph node metastasis of papillary thyroid cancer. AB - BACKGROUND: Thyroid cancer is a common malignant tumor of the endocrine system. Its incidence has increased continuously worldwide for the past three decades. With advanced sequencing technology, we discovered that GABRB2 gene is overexpressed in tumor tissues and closely associated with vertebrate nervous systems. However, its role in cancer remains unclear. METHODS: We conducted a massively parallel whole transcriptome resequencing and a comprehensive analysis of matched papillary thyroid carcinoma (PTC) tumors and normal tissues in 19 patients. Results showed that GABRB2 expression was significantly upregulated in thyroid cancer. Forty-five pairs of tumors and normal tissues were subjected to reverse transcription polymerase chain reaction to validate previous findings. The specific functions of GABRB2 in PTC cell lines (BCPAP, TPC1, and KTC-1) transfected with small interfering RNA were determined through cell colony formation, Cell Counting Kit-8, Transwell migration, Transwell invasion, and apoptosis assays. The effect of DNA demethylation on this gene was also examined. RESULTS: GABRB2 was remarkably overexpressed in primarily sequenced PTC tumors and validation cohort (T: N = 4.94 +/- 3.43:0.83 +/- 1.71, P < 0.001), and this observation was consistent with that in the TCGA cohort (T: N = 38.92 +/- 35.53:0.30 +/- 0.55, P < 0.001). GABRB2 overexpression was correlated with lymph node metastasis in both cohorts (P < 0.01). In vitro experiments revealed that GABRB2 downregulation significantly inhibited the colony formation, migration, and invasion of the three PTC cell lines. CONCLUSION: GABRB2 plays important tumorigenic functions and acts as a novel oncogene in PTC. PMID- 28859984 TI - Epstein-Barr virus-encoded latent membrane protein 1 induces epithelial to mesenchymal transition by inducing V-set Ig domain containing 4 (VSIG4) expression via NF-kB in renal tubular epithelial HK-2 cells. AB - The epithelial to mesenchymal transition (EMT), a hallmark of chronic kidney disease, is a key event in the conversion from tubular epithelial cells to myofibroblasts in renal fibrosis. Epstein-Barr virus (EBV) is a gamma-herpes oncovirus associated with chronic kidney disease. However, the relationship between EBV and the EMT process in renal tubular epithelial cells is not well understood. Among EBV-latent genes, EBV-encoded latent membrane protein 1 (LMP1) induces EMT by regulating a variety of molecules in EBV-induced oncogenic transformation. In this study, we investigated EBV-encoded LMP1 and EMT process markers in human proximal tubule epithelial cell line HK-2. LMP1 overexpression induces cell morphological changes via the epithelial to mesenchymal process in HK-2 cells, and these changes accelerate cell proliferation, cell motility, and invasion. Furthermore, VSIG4 upregulation by EBV-LMP1 induced LMP1-mediated EMT, cell motility, and invasion. VSIG4 upregulation by LMP1 was regulated at the transcriptional level via the NF-kB signaling axis. These results suggest that EBV-encoded LMP1 regulates EMT through the NF-kB-VSIG4 axis in HK-2 cells, and VSIG4 is a potential target in EBV-induced chronic kidney diseases. PMID- 28859985 TI - The normal trachea is cleaned by MUC5B mucin bundles from the submucosal glands coated with the MUC5AC mucin. AB - To understand the mucociliary clearance system, mucins were visualized by light, confocal and electron microscopy, and mucus was stained by Alcian blue and tracked by video microscopy on tracheal explants of newborn piglets. We observed long linear mucus bundles that appeared at the submucosal gland openings and were transported cephalically. The mucus bundles were shown by mass spectrometry and immunostaining to have a core made of MUC5B mucin and were coated with MUC5AC mucin produced by surface goblet cells. The transport speed of the bundles was slower than the airway surface liquid flow. We suggest that the goblet cell MUC5AC mucin anchors the mucus bundles and thus controls their transport. Normal clearance of the respiratory tree of pigs and humans, both rich in submucosal glands, is performed by thick and long mucus bundles. PMID- 28859986 TI - KRIBB11 accelerates Mcl-1 degradation through an HSF1-independent, Mule-dependent pathway in A549 non-small cell lung cancer cells. AB - The Bcl-2 family protein, Mcl-1 is known to have anti-apoptotic functions, and depletion of Mcl-1 by cellular stresses favors the apoptotic process. Moreover, Mcl-1 levels are frequently increased in various cancer cells, including non small cell lung cancer (NSCLC), and is implicated in resistance to conventional chemotherapy and in cancer metastasis. In this study, we demonstrated that KRIBB11 accelerates the proteasomal degradation of Mcl-1 in the NSCLC cell line, A549. While KRIBB11 is an inhibitor of HSF1, we found that KRIBB11 induced Mcl-1 degradation in an HSF1-independent manner. Furthermore, this process was triggered via increase ubiquitination by the E3 ligase, Mule, rather than via de ubiquitination by USP9X. Additionally, we found that Mcl-1 levels were only transiently reduced by KRIBB11: Mcl-1 levels were gradually restored as KRIBB11 activity diminished. However, we found that this effect was blocked in BIS (Bcl-2 interacting cell death suppressor, also called BAG3)-depleted cells, and that BIS prevents Mcl-1 from undergoing HSP70-driven proteasomal degradation, through an interaction with HSP70. Taken together, our results suggest that targeting Mcl-1 with KRIBB11 treatment, while simultaneously downregulating BIS, could be a therapeutic strategy in NSCLC. PMID- 28859987 TI - On the efficient bio-incorporation of 5-hydroxy-tryptophan in recombinant proteins expressed in Escherichia coli with T7 RNA polymerase-based vectors. AB - Biosynthetic incorporation of non-canonic amino acids is an attractive strategy to introduce new properties in recombinant proteins. Trp analogs can be incorporated in recombinant proteins replacing regular Trp during protein translation into a Trp-auxotrophic cell host. This straightforward method however, is limited to few analogs recognized and accepted by the cellular protein production machinery. 5-hydroxy-tryptophan (5OH-Trp) can be bio incorporated using E. coli as expression host however; we have experienced very low incorporation yields - amount of protein containing regular Trp/amount of protein containing the Trp analog - during expressions of 5OH-Trp labeled proteins. Furthermore, this low incorporation yield were verified especially when the widely-used vectors based on the T7 RNA polymerase were used. Testing different 5OH-Trp incorporation protocols we verified that in these T7-based systems, the production of the T7 RNA polymerase is driven by the same elements - lac promoter/IPTG - as the target protein. Consequently, the bio-incorporation of the 5OH-Trp residues also occurs in this crucial enzyme, but, the produced T7 RNA polymerase labeled with 5OH-Trp is inactive or much less active. In the present work, we describe an efficient method to overcome this mentioned problem and bio incorporate 5OH-Trp in proteins expressed in E. coli., using vectors based on the T7 RNA polymerase-T7 promoter. The two-step induction protocol here described showed incorporation efficiencies of 5OH-Trp higher than 90%. PMID- 28859990 TI - Immune discrepancies during in vitro granuloma formation in response to Cutibacterium (formerly Propionibacterium) acnes infection. AB - Cutibacterium (formerly Propionibacterium) acnes is involved in chronic/low-grade pathologies such as sarcoidosis or prosthetic joint infection (PJI). In these diseases, granulomatous structures are frequently observed. In this study, we induced a physiological granulomatous reaction in response to different well characterized clinical C. acnes isolates in order to investigate the cellular process during granuloma formation. Three C. acnes isolates selected according to their origin (PJI, sarcoidosis and acne) were typed by MLST. All C. acnes isolates generated granulomatous structures in our experimental conditions. The bacterial burden was better controlled by granulomas induced by the sarcoidosis C. acnes isolate. The PJI C. acnes isolate, belonging to CC36, promoted the recruitment of CD8+ lymphocytes inside the granuloma. In contrast, the acne and sarcoidosis C. acnes isolates, belonging to phylotypes IA1/CC18 and IA2/CC28, respectively, generated a higher number of granulomas and promoted the recruitment of CD4+ lymphocytes inside the granuloma. Our results provide new evidence supporting the role of C. acnes in the development of sarcoidosis and new explanations concerning the mechanisms underlying PJI due to C. acnes. PMID- 28859989 TI - Repeatedly measured material and behavioral factors changed the explanation of socioeconomic inequalities in all-cause mortality. AB - OBJECTIVES: We examined whether using repeatedly measured material and behavioral factors contributed differently to socioeconomic inequalities in all-cause mortality compared to one baseline measurement. STUDY DESIGN AND SETTING: Data from the Dutch prospective GLOBE cohort were linked to mortality register data (1991-2013; N = 4,851). Socioeconomic position was measured at baseline by educational level and occupation. Material factors (financial difficulties, housing tenure, health insurance) and behavioral factors (smoking, leisure time physical activity, sports participation, and body mass index) were self-reported in 1991, 1997, and 2004. Cox proportional hazards regression and bootstrap methods were used to examine the contribution of baseline-only and time-varying risk factors to socioeconomic inequalities in mortality. RESULTS: Men and women in the lowest educational and occupational groups were at an increased risk of dying compared to the highest groups. The contribution of material factors to socioeconomic inequalities in mortality was smaller when multiple instead of baseline-only measurements were used (25%-65% vs. 49%-93%). The contribution of behavioral factors was larger when multiple measurements were used (39%-51% vs. 19%-40%). CONCLUSION: Inclusion of time-dependent risk factors contributes to understanding socioeconomic inequalities in mortality, but careful examination of the underlying mechanisms and suitability of the model is required. PMID- 28859988 TI - Cytoskeletal remodeling via Rho GTPases during oxidative and thermal stress in Caenorhabditis elegans. AB - Biological systems are highly sensitive to changes in their environment. Indeed, the molecular basis of the environmental stress response suggests that the specialized stress responses share more commonalities than previously believed. Here, we used the nematode C. elegans to gain insight into the role of Rho signaling during two common environmental challenges, oxidative and thermal stress. In response to heat shock (HS), wild type (N2) worms demonstrated reduced viability which was rescued by genetic suppression of CDC42 and RHO-1. Visualization of F-actin by phalloidin-rhodamine underscored a strict correlation between the levels of F-actin following GTPase suppression and survival. Additionally, genetic ablation of OSG-1, a Guanine Nucleotide Exchange Factor (GEF) previously implicated in oxidative stress, was associated with constitutively lower levels of F-actin and increased mortality. However, upon an oxidative insult F-actin stability decreased in N2 worms, a rescue of this affect was observed in OSG-1 null worms, consistent with the resistance exhibited by these worms to oxidative stress (OS). Together these data suggest that during conditions of thermal or oxidative stress Rho signaling promotes vulnerability by altering actin dynamics. Thus, the stability of the actin cytoskeleton, in part through a conserved mechanism mediated by Rho signaling, is a crucial factor for the cell's survival to environmental challenges. PMID- 28859991 TI - 1alpha,25-Dihydroxyvitamin D3 promotes osteogenesis by promoting Wnt signaling pathway. AB - Diabetes mellitus (DM) remarkably affects bone metabolism and causes multiple skeletal disorders, which are associated with the increased oxidative stress that activates Forkhead family of transcription factors (FoxOs). 1alpha,25-Dihydroxy vitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D, plays a potential role in the prevention of glucose tolerance. However, its mechanism of action in high glucose-induced energy disorders remains unclear. In vitro study shows that 1,25(OH)2D3 promotes osteogenesis in high glucose-induced oxidative stress mainly results from increased osteoblasts proliferation and decreased apoptosis. Cells treated with 1,25(OH)2D3 exhibit an increased osteogenic differentiation capacity and an elevated level of osteogenic phenotype (i.e. alkaline phosphatase, collagen 1, osteocalcin, and osteopontin). We also found that the effect of 1,25(OH)2D3 on osteogenesis is achieved by FoxO1 inactivation and nuclear exclusion through PI3K/Akt pathway in a time- and dose-dependent manner. Moreover, the diversion of beta-catenin from FoxO1- to Wnt/TCF4-mediated transcription was indirectly promoted by the inactivation of FoxO1. These data together reveals that the activated Wnt/beta-catenin signaling is involved in the regulatory action of 1,25(OH)2D3 on osteogenesis in oxidative stress. This study also provides a novel understanding of the effect of 1,25(OH)2D3 on skeleton in oxidative stress condition. PMID- 28859992 TI - Survey on the knowledge of cochlear implant indication in the treatment of hearing loss in Spain. AB - INTRODUCTION: This study aims to analyse the knowledge of cochlear implant (CI) candidacy criteria of otorhinolaryngology specialists in Spain, and from the results, consider whether it is necessary to implement training measures aimed at improving knowledge in this area. MATERIAL AND METHODS: A questionnaire was designed for measuring the level of knowledge of cochlear implant candidacy criteria (CI) in people with hearing loss. The questionnaire collected the demographic data of the respondents and their knowledge on the conventional and emergency indications for CI, technical characteristics of CI and results in the implanted population. RESULTS: A total of 222 Spanish specialists in otorhinolaryngology answered the questionnaire (10.29% of the sample surveyed). CONCLUSIONS: The 50% of all respondents showed a medium-high knowledge about CI. Epidemiological data suggest that a high percentage of adults with postlocutive deafness and candidates for a CI are not referred for treatment. The lack of knowledge about the criteria for the indication of CI by otorhinolaryngology specialists may contribute to inadequate guidance of patients who are potential candidates for CI. The greatest shortcomings are found in the most emergency indications for a CI. Among otorhinolaryngology professionals, the greatest knowledge about CI is found in those who work in tertiary hospitals in the areas of otology and otoneurology, either in the public or private sector. This study suggests that training on CI should be increased for otorhinolaryngology professionals, especially for general otorhinolaryngologists. PMID- 28859993 TI - On ciprofloxacin concentration in chronic rhinosinusitis. AB - OBJECTIVE: Considering that all the evidence indicates that chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are distinct entities, the aim of this study was to compare the concentrations obtained in plasma and in sinonasal mucosa with oral and nasal topical ciprofloxacin, in patients with and without nasal polyps, without evaluating the effectiveness of the use of an antibiotic. METHODS: Prospective clinical study with single-blind randomization. The population consisted of patients with chronic rhinosinusitis with eligible for endonasal surgery, over 18 years old. It took place between January 2010 and December 2014. A single preoperative dose of ciprofloxacin (oral or nasal topic- spray, gel or drops) was given and samples of plasma and nasal mucosa (inferior turbinate, middle turbinate, ethmoid and maxillary sinus) were collected prior to surgery. The plasma and mucosal ciprofloxacin concentrations were assayed with high performance liquid chromatography (HPLC) with fluorescence detection (FD). RESULTS: The oral ciprofloxacin achieved better mucosal concentrations but had a significant plasmatic expression in all patients. None of the topical formulations achieved measurable ciprofloxacin plasmatic levels. Among the topical formulations, the gel had the best mucosal results, despite the existence of polyposis. PMID- 28859994 TI - Maxillary hydatid cyst. PMID- 28859995 TI - Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy. AB - Traumatic brain injury (TBI) is an increasingly important issue among veterans, athletes and the general public. Difficulties with sleep onset and maintenance are among the most commonly reported symptoms following injury, and sleep debt is associated with increased accumulation of beta amyloid (Abeta) and phosphorylated tau (p-tau) in the interstitial space. Recent research into the glymphatic system, a lymphatic-like metabolic clearance mechanism in the central nervous system (CNS) which relies on cerebrospinal fluid (CSF), interstitial fluid (ISF), and astrocytic processes, shows that clearance is potentiated during sleep. This system is damaged in the acute phase following mTBI, in part due to re localization of aquaporin-4 channels away from astrocytic end feet, resulting in reduced potential for waste removal. Long-term consequences of chronic dysfunction within this system in the context of repetitive brain trauma and insomnia have not been established, but potentially provide one link in the explanatory chain connecting repetitive TBI with later neurodegeneration. Current research has shown p-tau deposition in perivascular spaces and along interstitial pathways in chronic traumatic encephalopathy (CTE), pathways related to glymphatic flow; these are the main channels by which metabolic waste is cleared. This review addresses possible links between mTBI-related damage to glymphatic functioning and physiological changes found in CTE, and proposes a model for the mediating role of sleep disruption in increasing the risk for developing CTE related pathology and subsequent clinical symptoms following repetitive brain trauma. PMID- 28859998 TI - Long-term behavioral sensitization to apomorphine is independent of conditioning and increases conditioned pecking, but not preference, in pigeons. AB - When rodents are given a free choice between a variable option and a constant option, they may prefer variability. This preference is even sometimes increased following repeated administration of a dopamine agonist. The present study was the first to examine preference for variability under the systemic administration of a dopamine agonist, apomorphine (Apo), in birds. Experiment 1 tested the drug free preference and the propensity to choose of pigeons for a constant over a variable delay. It appeared that they preferred and decided more quickly to peck at the optimal delay option. Experiment 2 assessed the effects of a repeated injection of Apo on delay preference, in comparison with previous control tests within the same individuals. Apo treatment might have decreased the number of pecks at the constant option across the different experimental phases, but failed to induce a preference for the variable option. In Experiment 3, two groups of pigeons (Apo-sensitized and saline) were used in order to avoid inhomogeneity in treatments. They had to choose between a 50% probability option and a 5-s delay option. Conditioned pecking and the propensity to choose were higher in the Apo sensitized pigeons, but, in each group, the pigeons showed indifference between the two options. This experiment also showed that long-term behavioral sensitization to Apo can occur independently of a conditioning process. These results suggest that Apo sensitization can enhance the attractiveness of conditioned cues, while having no effect on the development of a preference for variable-delay and probabilistic schedules of reinforcement. PMID- 28859996 TI - Nicotine and networks: Potential for enhancement of mood and cognition in late life depression. AB - Late-life depression is characterized by both lower mood and poor cognitive performance, symptoms that often do not fully respond to current antidepressant medications. Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine may serve as a novel therapeutic approach for this population. Both preclinical and preliminary clinical studies suggest that nAChR agonists can improve depressive behavior in animal models and improve mood in depressed individuals. Substantial literature also supports that nAChR agonists benefit cognitive performance, particularly in older populations. These potential benefits may be mediated by the effects of nAChR stimulation on neural network function and connectivity. Functional neuroimaging studies detail effects of nAChR agonists on the default mode network, central-executive network, and salience network that may oppose or reverse network changes seen in depression. We propose that, given the existent literature and the clinical presentation of late-life depression, nicotine or other nAChR agonists may have unique therapeutic benefits in this population and that clinical trials examining nicotine effects on mood, cognition, and network dynamics in late-life depression are justified. PMID- 28859999 TI - Socially dominant mice in C57BL6 background show increased social motivation. AB - A series of behavioral tests measuring social dominance, social motivation, and non-social motivation are examined in adult male C57BL6 mice. By using the well known tube dominance test to determine social dominance and rank, we find that, in the absence of competition for resource and mating, group-housed mouse cage mates display stable and mostly linear and transitive social hierarchies. Mice with top and bottom social ranks are subjected to a three-chamber social interaction test to measure social motivation. The top ranked mice spend more time interacting with a stranger mouse than the bottom ranked mice, suggesting that social dominance may positively influence social motivation. When subjected to a novel environment, mice with different social ranks show similar locomotion and exploring activity in the open field test, suggesting no detectable difference in certain aspects of non-social motivation. These results demonstrate a behavioral correlation between social dominance and social motivation. PMID- 28859997 TI - Treatment resistant depression: A multi-scale, systems biology approach. AB - An estimated 50% of depressed patients are inadequately treated by available interventions. Even with an eventual recovery, many patients require a trial and error approach, as there are no reliable guidelines to match patients to optimal treatments and many patients develop treatment resistance over time. This situation derives from the heterogeneity of depression and the lack of biomarkers for stratification by distinct depression subtypes. There is thus a dire need for novel therapies. To address these known challenges, we propose a multi-scale framework for fundamental research on depression, aimed at identifying the brain circuits that are dysfunctional in several animal models of depression as well the changes in gene expression that are associated with these models. When combined with human genetic and imaging studies, our preclinical studies are starting to identify candidate circuits and molecules that are altered both in models of disease and in patient populations. Targeting these circuits and mechanisms can lead to novel generations of antidepressants tailored to specific patient populations with distinctive types of molecular and circuit dysfunction. PMID- 28860000 TI - Pre-Engraftment Bloodstream Infections after Allogeneic Hematopoietic Cell Transplantation: Impact of T Cell-Replete Transplantation from a Haploidentical Donor. AB - Bloodstream infections (BSIs) are frequent and important infectious complications after hematopoietic cell transplantation (HCT). The aim of this study was to analyze the incidence, risk factors, and outcome of pre-engraftment BSIs after allogeneic HCT. We retrospectively analyzed data from 553 consecutive patients who underwent HCT between 2010 and 2016. Sixty percent of the patients received T cell-replete unmanipulated haploidentical bone marrow with high-dose post transplantation cyclophosphamide. The BSI rate was 30%; among isolated 213 pathogens, 54% were Gram-positive, 43% were Gram-negative, and 3% were fungi. Independent risk factors for pre-engraftment BSI were transplantation from a haploidentical donor or from cord blood (P < .001), active disease (P = .002), age (P = .04), and myeloproliferative disorders or aplastic anemia (P < .001). Transplantation from a haploidentical donor was an independent risk factor for both Gram-positive and Gram-negative BSI. The 7-day mortality after any BSI was 5% (9 of 178), and in multivariate analysis, BSI etiology was the sole risk factor, with increased mortality in carbapenem-resistant Gram-negative BSI (P < .001). Nonrelapse mortality at day +60 after HCT was 3.8% (21 of 553); independent predictors were active disease (P = .045), year of HCT (P = .027), nonengraftment (P = .001), and pre-engraftment BSI (P < .001), with significantly higher risk in BSI due to Gram-negative pathogens compared with Gram-positive pathogens, and BSI due to carbapenem-resistant Gram-negative pathogens compared with susceptible pathogens. Pre-engraftment BSI is a frequent complication after HCT from a haploidentical donor or cord blood. Because the negative impact of pre engraftment BSI on 60-day nonrelapse mortality was caused mainly by carbapenem resistant Gram-negative pathogens, particular attention should be given to appropriate empiric therapy and management of patients at high risk for Gram negative BSI. PMID- 28860001 TI - Immune-Mediated Hematopoietic Failure after Allogeneic Hematopoietic Stem Cell Transplantation: A Common Cause of Late Graft Failure in Patients with Complete Donor Chimerism. AB - Late graft failure (LGF) without evidence of residual recipient cells is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-SCT) and often requires stem cell infusion from the same donor when the patient fails to respond to conventional therapies. We screened the peripheral blood (PB) of 14 patients who developed donor-type LGF at 2 to 132 months after allo-SCT for the presence of the markers for immune-mediated bone marrow (BM) failure. Increased glycosylphosphatidyl inositol-anchored protein-deficient (GPI AP-) leukocytes, which accounted for .009% to 0.147% of the total granulocytes, were detected in 5 patients (severe aplastic anemia, n = 2; follicular lymphoma, n = 1; acute lymphoblastic leukemia, n = 1; myelodysplastic syndromes; n = 1) and 4.7% to 81.2% HLA-allele-lacking leukocytes (HLA-LLs) were detected in 2 patients (acute myelogenous leukemia, n = 1; and myelodysplastic syndromes, n = 1). Three of the 5 patients with increased GPI-AP- leukocytes were treated with antithymocyte globulin (ATG), and 2 patients achieved transfusion independence. These results suggest that immune mechanisms that are similar to acquired aplastic anemia underlie condition of approximately one-half of the patients with donor-type LGF, and that in patients with increased GPI-AP- cells, donor-derived hematopoiesis may be restored by ATG therapy alone without donor stem cell infusion. PMID- 28860002 TI - Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation: A Comparison of Eculizumab Therapy and Conventional Therapy. AB - We report the results of a single-center analysis of a cohort of 39 patients treated between 1997 and 2016 for transplantion-associated thrombotic microangiopathy. We evaluated 2 subgroups of patients: 24 patients treated between 1997 and 2014 who received conventional therapy and 15 patients treated with the complement-inhibiting monoclonal antibody eculizumab between 2014 and 2016. The conventional therapy group was treated predominantly with defibrotide alone or in combination with plasmapheresis or rituximab. Despite an initial response rate of 61%, only 4 patients (16%) were long-term survivors, 2 of whom had a low-risk thrombotic microangiopathy without multiorgan damage. Progression of thrombotic micorangiopathy and bacterial/fungal infections contributed equally to treatment failure. The overall response rate in the eculizumab group was significantly higher, at 93%. In addition, we were able to stop eculizumab treatment in 5 patients (33%), all of whom had high-risk thrombotic microangiopathy, due to sustained recovery. Despite the very good response in the eculizumab-treated group, we did not observe a significant improved overall survival, due primarily to a high rate of infection-related mortality (70%). Therefore, further studies are needed to identify the optimal therapeutic management approach for transplantation-associated thrombotic microangiopathy to improve its dismal outcome. PMID- 28860003 TI - Sleep restriction induced energy, methylation and lipogenesis metabolic switches in rat liver. AB - Sleep curtailment is ubiquitous in modern day society. Sleep debt is associated with maladaptive physiological changes that can lead to cardiometabolic and neuropsychiatric pathologies. Recent literature has shown the effects of sleep restriction (SR) on systemic metabolic profiles in biofluids, implying that tissue-specific metabolomes are impacted by SR. To test this hypothesis, we assessed hepatic metabolic profiles of rats after 5days of SR using UPLC-MS based metabolomics analysis and gene expression analysis. Our data suggests distinctive effects of SR on the liver metabolic profile of rats compared to forced-activity control animals. We observed specific impacts of SR on NAD metabolism through NAD accumulation and upregulation of Nampt, the rate determining step of NAD salvage. Additional multi-omic changes were observed in methionine metabolism, with an elevated SAM:SAH ratio under SR. This effect on one carbon metabolism is indicative of increased methylation potential. Changes in TCA cycle intermediates and ATP-citrate lyase (Acly) gene expression were observed that may be related to altered circulatory lipid profiles previously reported documenting the chrono metabolic connection. Taken together with previous investigations, these observations are consistent with a model of decreased TCA activity with concomitant increase in lipogenesis induced by SR. These tissue-specific mechanistic insights into metabolic effects of SR provide a springboard to future metabolic intervention studies. PMID- 28860004 TI - LOX-1: A potential target for therapy in atherosclerosis; an in vitro study. AB - Pro-inflammatory signal generated from the interaction of oxLDL with its cognate receptor LOX-1 has been attenuated successfully by a novel combination siRNA (siLOX-1Omega) targeting unique regions of Homo sapien LOX-1 mRNA. Signalling via LOX-1R was studied in a potentially pro-atherogenic arena recreated in a metabolic, pulse-chase set up. An initial pulse of oxLDL (20MUg/mL;5h) was chased (without oxLDL) on a temporal scale upto 72h. Our study shows that the pro inflammatory signal generated via oxLDL-LOX-1R interaction was mediated in two rungs, an initial sustained increase in LOX-1R expression up to 12h, and a renewal after 48h. TNF-alpha acted as a primary mediator of LOX-1R signalling, presumably also stimulating CD40 and MMP-9. Both TNF-alpha and IL-6 were involved in the second rung of LOX-1R signalling; maximum secretion of both was detected at 48h. Our study suggests a temporal sustenance of LOX-1R signalling by pro inflammatory cytokines even on withdrawal of oxLDL. Also, siLOX-1Omega successfully abated LOX-1R expression along with its signalling intermediates, NO and NF-kB. Overall, LOX-1 signalling and the crucial role of cytokines in sustaining it is reported. Attenuation of this receptor may be of therapeutic value in atherosclerosis. PMID- 28860005 TI - Hypoxia decrease expression of cartilage oligomeric matrix protein to promote phenotype switching of pulmonary arterial smooth muscle cells. AB - Extracellular matrix proteins play important roles in the development of pulmonary hypertension(pH). However, the role of Cartilage oligomeric matrix protein (COMP) in the development of hypoxia-induced pH is largely unknown. We tested the hypothesis that COMP deficiency induced by hypoxia leads to the phenotype switching of pulmonary arterial smooth muscle cells (PASMCs). The expression of COMP decreased in a chronic hypoxia rat pH model (P<0.05) and in PASMCs under hypoxia (3%O2) (P<0.05). The expressions of differentiated marker proteins reduced in the pulmonary arteries from 5 month old COMP-/- mice and in PASMCs under hypoxia or with the siRNA of COMP treatment under normoxia, but increased in PASMCs with adenovirus-increased COMP under hypoxia. The absorbance of cell counting kit-8 at 450nm and the expressions of proliferating cell nuclear antigen (PCNA) and osteopontin increased in PASMCs with the siRNA of COMP under normoxia (P<0.05). PCNA and osteopontin decreased in PASMCs with adenovirus increased COMP under hypoxia (P<0.05). Additionally, the expression of bone morphogenetic protein receptor 2 (BMPR2) was reduced in COMP-/- mice (P<0.01). Both mRNA and protein levels of bone morphogenetic protein 2 (BMP2) were lower in PASMCs with the siRNA of COMP (P<0.05). The protein level of BMP2 could be reversed by adenovirus-increased COMP under hypoxia (P<0.05). These data suggest that COMP could normally have a protective role against PASMC phenotype switching and maintain BMP2/BMPR2 signaling, and these protective actions could be lost as a result of hypoxia promoting a depletion of COMP. PMID- 28860006 TI - Combining a symptom index, CA125 and HE4 (triple screen) to detect ovarian cancer in women with a pelvic mass. AB - OBJECTIVES: To assess a simple algorithm of CA125, HE4 and Symptom Index to predict ovarian cancer in women with a pelvic mass. METHODS: This was a prospective study of women referred to a gynecologic oncology clinic for surgical evaluation of a pelvic mass. Preoperatively, women completed a SI and had serum markers drawn. Results were correlated with pathology. A triple screen was considered positive if at least 2 of the 3 markers were abnormal (positive SI, CA125>=35U/mL, HE4>=140pmol/L). RESULTS: 218 patients enrolled in the study. 66 patients (30%) had ovarian or fallopian tube cancer (97% epithelial), 124 (57%) had benign masses, 17 (8%) had borderline tumors, and 11 (5%) had metastatic disease. The SI, CA125 and HE4 were positive in 87.9%, 74.2% and 60.6% of ovarian cancer patients, respectively. Of the 112 women with a positive SI 58 (52%) had ovarian cancer and 75 (67%) had non-benign masses. Excluding borderline and metastatic cancers the sensitivity of the triple screen was 79%; specificity 91%, PPV 83% and NPV 89%. CA125 alone had a sensitivity, specificity, PPV and NPV of 79%, 76%, 63% and 87% respectively. Requiring only one of the three tests to be abnormal resulted in a sensitivity of 97% but specificity dropped to 50%. CONCLUSIONS: An algorithm using SI, CA125 and HE4 has good performance statistics for predicting cancer in women with pelvic masses. The triple screen has higher specificity and PPV than CA125 alone but similar sensitivity and NPV for predicting ovarian cancer. PMID- 28860007 TI - Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. AB - Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are well-known leading causes of HCC. However, the mechanism of the induction of HCC by these virus is still being debated. This review will focus on the current knowledge of the pathogenesis of HBV- and HCV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC. It is well established that the recruitment of certain number and type of immune cells to liver is essential for the resolution of HBV and HCV infection and the prevention of subsequent chronic persistent infection. However, in case that the immune response do not completely clear virus, persistent chronic infection occurs, and the perpetual immune response may contribute to chronic damages of the liver. Such chronic inflammatory damages further harm hepatocytes, but not hepatic progenitor cells (HPCs). Thus, following chronic damages, HPCs are activated and their dysregulated proliferation ensures survival in the hostile environment, contributing to the tumorigenesis of HCC. Furthermore, accumulating evidence also provides a strong link between HPCs and human hepatocellular carcinoma. Collectively, these findings support a notion that immune response is involved in liver damage during hepatitis virus infection, and the activation and dysregulated differentiation of hepatic progenitor cells promote the tumorigenesis of human hepatocellular carcinoma. PMID- 28860008 TI - A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing. AB - TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimized, high through-put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four 10-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reverse-phase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF kappaB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing. PMID- 28860009 TI - Evolution of ribosomal internal transcribed spacers in Deuterostomia. AB - Sequences of ribosomal internal transcribed spacers (ITSs) are of great importance to molecular phylogenetics and DNA barcoding, but remain unstudied in some large taxa of Deuterostomia. We have analyzed complete ITS1 and ITS2 sequences in 62 species from 16 Deuterostomia classes, with ITS sequences in 24 species from 11 classes initially obtained using unannotated contigs and raw read sequences. A general tendency for both ITS length and GC-content increase from interior to superior Deuterostomia taxa, a uniform GC-content in both ITSs within the same species, thymine content decrease in sense DNA sequences of both ITSs are shown. A possible role of GC-based gene conversion in Deuterostomia ITS evolutionary changes is hypothesized. The first example of non-LTR retrotransposon insertion into ITS sequence in Deuterostomia is described in turtle Geochelone nigra. The roles of mobile genetic element insertions in the evolution of ITS sequences in some Sauropsida taxa are discussed as well. PMID- 28860010 TI - Conserved genomic collinearity as a source of broadly applicable, fast evolving, markers to resolve species complexes: A case study using the lichen-forming genus Peltigera section Polydactylon. AB - Synteny can be maintained for certain genomic regions across broad phylogenetic groups. In these homologous genomic regions, sites that are under relaxed purifying selection, such as intergenic regions, could be used broadly as markers for population genetic and phylogenetic studies on species complexes. To explore the potential of this approach, we found 125 Collinear Orthologous Regions (COR) ranging from 1 to >10kb across nine genomes representing the Lecanoromycetes and Eurotiomycetes (Pezizomycotina, Ascomycota). Twenty-six of these COR were found in all 24 eurotiomycete genomes surveyed for this study. Given the high abundance and availability of fungal genomes we believe this approach could be adopted for other large groups of fungi outside the Pezizomycotina. Asa proof of concept, we selected three Collinear Orthologous Regions (COR1b, COR3, and COR16), based on synteny analyses of several genomes representing three classes of Ascomycota: Eurotiomycetes, Lecanoromycetes, and Lichinomycetes. COR16, for example, was found across these three classes of fungi. Here we compare the resolving power of these three new markers with five loci commonly used in phylogenetic studies of fungi, using section Polydactylon of the cyanolichen-forming genus Peltigera (Lecanoromycetes) - a clade with several challenging species complexes. Sequence data were subjected to three species discovery and two validating methods. COR markers substantially increased phylogenetic resolution and confidence, and highly contributed to species delimitation. The level of phylogenetic signal provided by each of the COR markers was higher than the commonly used fungal barcode ITS. High cryptic diversity was revealed by all methods. As redefined here, most species represent lineages that have relatively narrower, and more homogeneous biogeographical ranges than previously understood. The scabrosoid clade consists of ten species, seven of which are new. For the dolichorhizoid clade, twenty-two new species were discovered for a total of twenty-nine species in this clade. PMID- 28860011 TI - The relationship between chronic health conditions and outcome following out-of hospital ventricular fibrillation cardiac arrest. AB - INTRODUCTION: The cumulative burden of chronic health conditions could contribute to out-of-hospital cardiac arrest (OHCA) physiology and response to attempted resuscitation. Yet little is known about how chronic health conditions influence prognosis. We evaluated the relationship between cumulative comorbidity and outcome following ventricular fibrillation OHCA using 3 different scales. METHODS: We performed a cohort investigation of persons >=18years who suffered non-traumatic OHCA and presented with ventricular fibrillation between January 1, 2007 and December 31, 2013 in a metropolitan emergency medical service (EMS) system. Chronic conditions were ascertained from EMS reports. The primary relationship between cumulative comorbidity and outcome (survival to hospital discharge) used the Charlson Index and two other scales. Analyses used logistical regression (LR), multiple imputation and inverse probability weighting. RESULTS: During the study period 1166/1488 potential patients were included. The median Charlson Index was 1 (25th-75th%: 0-2). Overall survival was 43.9%. Comorbidity was associated with a dose-dependent decrease in the likelihood of survival. ompared to Charlson Score of 0, the odds ratio of survival was 0.68 (0.48-0.96) for Charslon of 1, 0.49 (0.35-0.69) for Charlson of 2, and 0.43 (0.30-0.61) for Charlson of >=3 after adjustment for Utstein predictors using multivariable LR. This inverse comorbidity-survival association was similar for the other 2 scales and was observed for different clinical outcomes (admission to hospital, functional survival, 30-day survival, and 1-year survival). CONCLUSION: Based on these results, cumulative comorbidity can help explain survival variability and improve prognostic accuracy. Whether information about cumulative comorbidity or specific health conditions can inform resuscitation care is unknown though the results suggest comorbidity may influence acute pathophysiology and treatment response. PMID- 28860012 TI - Continuous versus intermittent neuromuscular blockade in patients during targeted temperature management after resuscitation from cardiac arrest-A randomized, double blinded, double dummy, clinical trial. AB - AIM OF THE STUDY: Current guidelines recommend targeted temperature management to improve neurological outcome after cardiac arrest. Evidence regarding an ideal sedative/analgesic regimen including skeletal muscle paralysis is limited. METHODS: Patients were randomized to either a continuous administration of rocuronium (continuous-NMB-group) or to a continuous administration of saline supplemented by rocuronium bolus administration if demanded (bolus-NMB-group). The primary outcome was the number of shivering episodes. Secondary outcomes included survival and neurological status one year after cardiac arrest, time to awakening, length of stay as well as required cumulative dose of rocuronium, midazolam and fentanyl. RESULTS: Sixty-three patients (32 continuous-NMB-group; 31 bolus-NMB-group) were enrolled. Differences in baseline characteristics were not significant. Shivering episodes were detected in 94% of the patients in the bolus-NMB-group compared to 25% of the patients receiving continuous rocuronium infusion (p<0.01). The continuous-NMB-group received significant lower doses of midazolam (4.3+/-0.8mg/kg vs. 5.1+/-0.9mg/kg, p<0.01) and fentanyl (62+/-14MUg/kg vs. 71+/-7MUg/kg, p<0.01), but higher cumulative doses of rocuronium (7.8+/ 1.8mg/kg vs. 2.3+/-1.6mg/kg, p<0.01). Earlier awakening (2 [IQR 2;3] vs. 4 [IQR 2;7.5] days, p=0.04) and decreased length of stay at the ICU (6 [IQR 3;5.9] vs. 10 [IQR 5;15] days, p=0.03) were observed in the continuous-NMB-group. There were no significant differences in survival and quality of life 12 months after cardiac arrest. CONCLUSIONS: Continuous neuromuscular blockade during the first day after resuscitation reduced shivering, midazolam and fentanyl requirement, time to awakening and discharge from intensive care unit. There were no differences in overall survival, cooling rate and time to target temperature. PMID- 28860013 TI - CPR mass training during an international sport competition: An evaluation of CPR skills in children. PMID- 28860014 TI - Feasibility and safety of intact cord resuscitation in newborn infants with congenital diaphragmatic hernia (CDH). AB - BACKGROUND: Starting resuscitation before clamping the umbilical cord at birth may progressively increase pulmonary blood flow while umbilical venous blood flow is still contributing to maintenance of oxygenation and left ventricle preload. OBJECTIVE: To evaluate the feasibility, safety, and effects of intact cord resuscitation (ICR) on cardiorespiratory adaptation at birth in newborn infants with CDH. STUDY DESIGN: Prospective, observational, single-center pilot study. METHODS: Physiologic variables and outcomes were collected prospectively in 40 consecutive newborn infants with an antenatal diagnosis of isolated CDH. RESULTS: Infants were managed with immediate cord clamping (ICC group) from 1/2012 to 5/2014 or the cord was clamped after initiation of resuscitation maneuvers (ICR group) from 6/2014 to 4/2016 (20 in each group). Ante- and postnatal markers of CDH severity were similar between groups. Resuscitation before cord clamping was possible for all infants in the ICR group. No increase in maternal or neonatal adverse events was observed during the period of ICR. The pH was higher and the plasma lactate concentration was significantly lower at one hour after birth in the ICR than in the ICC group (pH=7.17+/-0.1 vs 7.08+/-0.2; lactate=3.6+/-2.3 vs 6.6+/-4.3mmol/l, p<0.05). Mean blood pressure was significantly higher in the ICR than in the ICC group at H1 (52+/-7.7 vs 42+/-7.5mmHg), H6 (47+/-3.9 vs 40+/ 5.6mmHg) and H12 (44+/-2.9 vs 39+/-3.3mmHg) (p<0.05). CONCLUSION: Commencing resuscitation and initiating ventilation while the infant is still attached to the placenta is feasible in infants with CDH. The procedure may support the cardiorespiratory transition at birth in infants with CDH. PMID- 28860015 TI - State-wide reduction in in-hospital cardiac complications in association with the introduction of a national standard for recognising deteriorating patients. AB - AIM: To examine whether introducing a national standard to improve the recognition of and response to clinical deterioration, was associated with a reduction in cardiovascular events in the hospital environment. METHOD: Interrupted time series was used to analyse the trajectories of monthly complication rates for 4.69 million admissions in 218 hospitals. Trajectory slopes determined for the "baseline period" (1 July 2007-30 June 2010) and the "Intervention period" (1 January 2013-30 June 2014) were compared (slope ratio). RESULTS: Before the intervention, complication rates due to arrhythmias were increasing, acute coronary syndrome (ACS) and all-cause mortality decreasing, but were constant for cardiac arrest and heart failure and pulmonary oedema. Analysis of the overall data suggested reduction in the rate of cardiac and ACS complications after the intervention, but no significant change in overall hospital mortality. Analysis by age category showed significant reductions in monthly rate trajectories in the 80 plus years age group for cardiac arrest (slope ratio 0.983, 95% CI: 0.972-0.994) and ACS (0.989, 95% CI: 0.981-0.997) complications. Slope ratios indicating reduced monthly rates were seen in females for cardiac arrest (0.985, 95% CI: 0.977-0.994), ACS (0.991, 95% CI: 0.984-0.998) and heart failure (0.993, 95% CI: 0.986-1.000) complications. There were also significant reductions in cardiac arrest (0.983, 95% CI: 0.969-0.996), ACS (0.991, 95% CI: 0.982-1.000) and arrhythmia (0.996, 95% CI: 0.994-0.998) complications for surgical patients. CONCLUSIONS: Introduction of a national standard for deteriorating hospitalised patients was associated with a reduction in the rates of in-hospital cardiac arrests and acute coronary syndromes in acute hospitals. Greatest benefit was seen in the elderly, female and surgical patients. PMID- 28860016 TI - Hyperarousal during sleep in untreated, major depressed subjects with prodromal insomnia: A polysomnographic study. AB - In primary insomnia, specific dynamics of hyperarousal are evident during the night. Similarly, in major depression, many elements also favor of the presence of hyperarousal. Thus, it would be interesting to investigate if hyperarousal presents the same dynamic in major depression. Polysomnographic data from 30 healthy controls, 66 patients with major depression and prodromal insomnia, and 86 primary insomnia sufferers recruited from the sleep laboratory database were studied for whole night and thirds of the night. Insomnia sufferers and patients with depression exhibit a similar polysomnographic pattern both for whole night (increased sleep latency and WASO and reduced SWS and REM) and thirds of night (increased WASO at first and last thirds, reduced SWS in first third, and reduced in REM in first and last third). No alterations were detected during the second third of the night. Just as in primary insomnia, the hyperarousal phenomenon is found mainly in major depression with prodromal insomnia during the sleep-onset period and the first and last thirds of the night, but lesser during the second third of the night. These specific dynamics of hyperarousal may aid in the understanding of the particular relationship between insomnia and depression. PMID- 28860017 TI - Comparing two schizophrenia-specific quality of life instruments in institutionalized people with schizophrenia. AB - Clinical health professionals may have difficulties to select appropriate schizophrenia-specific Quality of life (QoL) instruments because of the limited information regarding their psychometric properties. Two widely used schizophrenia-specific QoL instruments (Schizophrenia Quality of Life Scale Revision 4 [SQLS-R4] and Lancashire Quality of Life Profile [LQOLP]) were compared in institutionalized people with schizophrenia, and useful recommendations for clinical health professionals were provided. Participants (n = 100) filled out the two instruments twice. Test-retest reliability, internal consistency, and confirmatory factor analyses (CFAs) were conducted. Both SQLS-R4 domains (r = 0.573-0.731) and LQOLP domains (r = 0.303-0.778) had good test retest reliability. However, the objective QoL domains in the LQOLP showed lower internal consistency (alpha = 0.219-0.617) than its subjective QoL domains (alpha = 0.532-0.947) and the SQLS-R4 domains (alpha = 0.768-0.939). The CFAs with two correlated underlying instruments constructs and two correlated underlying QoL traits (viz., Physical and Psychosocial QoL) performed the best data-model fit (CFI = 0.990, RMSEA = 0.039, SRMR = 0.039), which supported the validity of both instruments. Although both SQLS-R4 and LQOLP were valid and reliable, using SQLS R4 on institutionalized people seemed to be more psychometrically solid than using the LQOLP. PMID- 28860018 TI - Comparison of In-Hospital Outcomes of Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Obese (Body Mass Index >= 30 Kg/M2) Patients. AB - The comparative outcomes of transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement (SAVR) in obese (body mass index >= 30 kg/m2) patients are underexplored. Nationwide Inpatient Sample database was queried from 2011 to 2014, and those who underwent TAVI or SAVR with obesity were identified. A complete case analysis with multivariate analysis was performed to adjust for the difference in underlying co-morbidities. We identified a total of 12,525 patients (989 TAVI and 11,536 SAVR). TAVI patients were elderly, more women, and had higher co-morbidity burden represented by a higher Deyo's modification of Charlson's score. Inpatient mortality was similar between the 2 groups (2.6% vs 3.2%, p = 0.21). TAVI patients had less hemorrhage requiring transfusion (8.5% vs 18%, p < 0.01), cardiac complication (7.3% vs 14%, p < 0.01), respiratory complication (1.3% vs 3.9%, p < 0.01), postop sepsis (1.0% vs 3.2%, p < 0.01), acute myocardial infarction (2.5% vs 5.5%, p < 0.01), acute kidney injury (18% vs 22%, p < 0.001), and nonroutine discharge (62% vs 67%, p < 0.001). Conversely, vascular complication (5.6% vs 4.5%, p = 0.04), new pacemaker (13% vs 5.4%, p < 0.001), and use of extracorporeal oxygen membrane (1.1% vs 0.3%, p = 0.002) were observed more frequently in TAVI patients. The median hospital cost was higher in TAVI ($50,957 vs $44,977, p = 0.004), whereas TAVI patients had a significantly shorter hospital stay (median 7.4 vs 10 days, p < 0.001). TAVI portended similar in-hospital mortality and less certain perioperative complications. In TAVI, the medical cost was higher, but the length of stay was shorter and nonroutine discharge was less frequent. PMID- 28860019 TI - Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. AB - Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce HbA1c, blood pressure, and weight in patients with type 2 diabetes. To investigate the effect of renal function on reductions in these parameters with the SGLT2 inhibitor empagliflozin, we assessed subgroups by baseline estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease) in pooled data from five 24 week trials of 2286 patients with type 2 diabetes randomized to empagliflozin or placebo. Reductions in HbA1c with empagliflozin versus placebo significantly diminished with decreasing baseline eGFR. Reductions in systolic blood pressure (SBP) with empagliflozin were maintained in patients with lower eGFR. The mean placebo-corrected changes from baseline in systolic blood pressure at week 24 with empagliflozin were -3.2 (95% confidence interval -4.9,-1.5) mmHg, -4.0 ( 5.4, -2.6) mmHg, -5.5 (-7.6, -3.4) mmHg, and -6.6 (-11.4, -1.8) mmHg in patients with an eGFR of 90 or more, 60 to 89, 30 to 59, and under 30 ml/min/1.73m2, respectively. Similar trends were observed for diastolic blood pressure. Weight loss with empagliflozin versus placebo tended to be attenuated in patients with a lower eGFR. Results were consistent in a 12-week ambulatory blood pressure monitoring trial in 823 patients with type 2 diabetes and hypertension. Thus, unlike HbA1c reductions, systolic blood pressure and weight reductions with empagliflozin are generally preserved in patients with chronic kidney disease. PMID- 28860020 TI - Triplex High-Resolution Melting Assay for the Simultaneous Assessment of IFNL3 rs12979860, ABCB11 rs2287622, and RNF7 rs16851720 Genotypes in Chronic Hepatitis C Patients. AB - Chronic hepatitis C (CHC) is a leading cause of liver disease. Despite the improved efficacy of new antivirals, their high costs preclude their adoption in resource-limited settings, where CHC prevalence is highest. We developed a triplex high-resolution melting assay for the simultaneous assessment of three genetic polymorphisms related to the response to treatment and development of advanced fibrosis in CHC: IFNL3 rs12979860, ABCB11 rs2287622, and RNF7 rs16851720. We validated the assay in clinical samples from 130 CHC patients treated with classic therapy. The assay showed excellent reproducibility and 100% accuracy, sensitivity, and specificity against the gold standard Sanger sequencing. When added to routine examination data, genotype information significantly improved their performance for prediction of advanced liver fibrosis and sustained virological response (P = 0.041 and P = 0.011, respectively). Correspondingly, the full models had area under the receiver operating characteristic curve values of 0.842 (95% CI, 0.773-0.911) and 0.921 (95% CI, 0.870-0.972) and integrated discrimination improvements of 7.5% (95% CI, 2.5%-12.5%; P = 0.003) and 11.5% (95% CI, 5.8%-17.2%; P < 0.001), respectively. This is the first report on a diagnostic test for simultaneous genotyping of IFNL3, ABCB11, and RNF7 in CHC patients. Reliable and inexpensive, the assay should provide useful information for the clinical management of CHC, like identification of patients at risk of rapid disease progression or with high chances of response to classic therapy. PMID- 28860022 TI - Paths to Open Access: An update from Acta Materialia, Inc. PMID- 28860023 TI - Understanding pregnancy outcomes using epidemiology and health services research. PMID- 28860021 TI - Disruption of fibronectin matrix affects type IV collagen, fibrillin and laminin deposition into extracellular matrix of human trabecular meshwork (HTM) cells. AB - Fibronectin fibrils are a major component of the extracellular matrix (ECM) of the trabecular meshwork (TM). They are a key mediator of the formation of the ECM which controls aqueous humor outflow and contributes to the pathogenesis of glaucoma. The purpose of this work was to determine if a fibronectin-binding peptide called FUD, derived from the Streptococcus pyogenes Functional Upstream Domain of the F1 adhesin protein, could be used to control fibronectin fibrillogenesis and hence ECM formation under conditions where its expression was induced by treatment with the glucocorticoid dexamethasone. FUD was very effective at preventing fibronectin fibrillogenesis in the presence or absence of steroid treatment as well as the removal of existing fibronectin fibrils. Disruption of fibronectin fibrillogenesis by FUD also disrupted the incorporation of type IV collagen, laminin and fibrillin into the ECM. The effect of FUD on these other protein matrices, however, was found to be dependent upon the maturity of the ECM when FUD was added. FUD effectively disrupted the incorporation of these other proteins into matrices when added to newly confluent cells that were forming a nascent ECM. In contrast, FUD had no effect on these other protein matrices if the cell cultures already possessed a pre-formed, mature ECM. Our studies indicate that FUD can be used to control fibronectin fibrillogenesis and that these fibrils play a role in regulating the assembly of other ECM protein into matrices involving type IV collagen, laminin, and fibrillin within the TM. This suggests that under in vivo conditions, FUD would selectively disrupt fibronectin fibrils and de novo assembly of other proteins into the ECM. Finally, our studies suggest that targeting fibronectin fibril assembly may be a viable treatment for POAG as well as other glaucomas involving excessive or abnormal matrix deposition of the ECM. PMID- 28860024 TI - Perinatal legislative policies and health outcomes. AB - Perinatal epidemiology examines the variation and determinants of pregnancy outcomes from a maternal and neonatal perspective. However, improving public and population health also requires the translation of this evidence base into substantive public policies. Assessing the impact of such public policies requires sufficient data to include potential confounding factors in the analysis, such as coexisting medical conditions and socioeconomic status, and appropriate statistical and epidemiological techniques. This review will explore policies addressing three areas of perinatal medicine-elective deliveries prior to 39 weeks' gestation; perinatal regionalization; and mandatory paid maternity leave policies-to illustrate the challenges when assessing the impact of specific policies at the patient and population level. Data support the use of these policies to improve perinatal health, but with weaker and less certain effect sizes when compared to the initial patient-level studies. Improved data collection and epidemiological techniques will allow for improved assessment of these policies and the identification of potential areas of improvement when translating patient-level studies into public policies. PMID- 28860025 TI - Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder. AB - BACKGROUND & AIM: Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality. METHODS: A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Pathologic, virologic and immunologic investigations were carried out on biopsied skin lesion, and peripheral blood mononuclear cells between the 2nd and 3rd round of antiviral treatment and biopsied liver. RESULTS: Remission of T-LPD was observed upon antiviral treatment, and the patient remained in complete remission after achieving SVR. The T cell analysis showed large CD30(+) lymphocytes surrounding the blood vessels within the CD8(+) T cell infiltrate. HEV was detected within dermal microvascular endothelial cells using immunofluorescence staining, in situ hybridisation and electron microscopy. Infiltrating T cells mostly comprised memory CD8(+) T cells with a tissue-resident memory T cell phenotype. Overall, 98% of extracted T cells were CD8(+) T cells with aVbeta signature skewed towards Vbeta4 and with an oligoclonal profile. T cell clones from T-LPD were more like T cells in the liver than T cells in the blood [odds ratio=4.55, (3.70-5.60), p<0.0001]. No somatic mutations were found in the T-LPD exomes. CONCLUSION: HEV has an extra-hepatic tissue tropism in humans, including dermal endothelium, and can induce CD30(+) T-LPD that is sensitive to antivirals. LAY SUMMARY: Hepatitis E virus (HEV) has an extra-hepatic tissue tropism and should be added to the list of viruses associated with lymphoproliferative disorders. As such, HEV should be part of the laboratory workup of any lymphoproliferation, particularly those of the T cell phenotype that involve the skin. In the context of HEV-associated cutaneous T cell lymphoproliferative disorders, antiviral treatment could be considered a first-line treatment instead of chemotherapy. PMID- 28860026 TI - Isotope-dilution liquid chromatography-tandem mass spectrometry for sensitive quantification of human insulin in serum using derivatization-technique. AB - An isotope-dilution mass spectrometry (IDMS) method for measuring insulin levels in human serum was developed using C-terminal-derivatization method coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The carboxyl groups of Glu-C-cleavage products were derivatized with 1-(2-pyrimidinyl)piperazine to increase MS/MS sensitivity and IDMS quantification, resulting in increases in LC MS/MS peak areas of derivatized Glu-C-cleavage products of human insulin by ~23 (A5-17 peptide) to 49-fold(B14-21 peptide), respectively, as compared with results observed in the absence of derivatization. Separation was achieved on a C18 column by gradient elution at 0.3 mL/min, with a mobile phase composed of 0.1% formic acid in acetonitrile and water. Validation studies of target peptides (B1-13 peptide and B14-21 peptide) revealed a linear response in the range of 0.05 ng/mL to 10 ng/mL (regression coefficient, r2 = 0.9987 and 0.9988, respectively), a relative standard deviation within and between days of <8.6%, and spike and recovery test results indicating mean recoveries ranging from 100.2% to 106.6%. Comparison with an established commercial immunoassay showed high correlation (r2 = 0.9943 and 0.9944, B1-13 peptide and B14-21 peptide, respectively) at serum concentrations of between 0.20 ng/mL and 1.51 ng/mL. These findings suggested that this IDMS-based approach was able to quantify human serum insulin with high sensitivity and precision in the reference interval and indicated a potential for determining serum-insulin reference-measurement procedures to allow traceable measurement. PMID- 28860027 TI - Preparation of wool follicles for proteomic studies. AB - A variety of techniques were applied to wool follicles stored in William's E culture medium to optimise the extraction of keratin and keratin associated proteins (KAPs). A time course study indicated that the maximum storage time for live skin in this buffer at 20 degrees C was 24 h, after which degradative loss of protein became significant. Maceration of the skin for 10 min followed by reciprocal action shaking for 14 h had a detrimental effect on keratin extractability. The best approach involved using a Dounce homogeniser as this resulted in the highest amount of Type I and II keratins and KAPs. PMID- 28860028 TI - Dissociative amnesia: Disproportionate retrograde amnesia, stressful experiences and neurological circumstances. AB - Dissociative amnesias have been reported in neurological episodes mild enough to not cause any visible lesions on morphological examination. Disproportionate retrograde amnesia with or without identity loss happens in the context of psychological trauma (known or not). In metabolic imaging studies, some authors have reported functional alterations, particularly in the bilateral hippocampus, right temporal regions and inferolateral prefrontal cortex, despite normal morphological imaging. To avoid the presumption of an organic, psychogenic or mixed origin for such changes, De Renzi et al. suggested the term 'functional amnesia' to describe the condition. Patients have sometimes recovered during events similar to those preceding the amnesia in either a spectacular fashion or never. Also, in some cases, distraction or sedation may trigger the start of recovery. During psychotherapy, one patient remembered seeing a car on fire when he was a boy, and his amnesia started when his house was on fire. This suggests control by the frontal cortex, with repression blocking amnesic traces in the new emotional and biological context. PMID- 28860029 TI - Pediatric conjunctival melanoma arising from a compound nevus. AB - We present a rare case of conjunctival melanoma in a 9-year-old girl who presented with a conjunctival lesion of the left eye, growth of which was documented by patient photographs. Examination showed a raised pigmented lesion at the temporal limbus, with fine surrounding vessels. Enhanced depth imaging optical coherence tomography showed no invasion into the sclera. The patient underwent excisional biopsy, and histopathology revealed conjunctival melanoma arising from a nevus with malignant cells that stained positively with markers HMB-45 and Ki-67. Systemic workup was negative for metastatic disease. Conjunctival nevi are the most common melanocytic conjunctival lesions in children and generally demonstrate physiologic growth during adolescence. Thus, there may be a greater risk of misdiagnosis of conjunctival melanoma in a child. PMID- 28860030 TI - Long-term evaluation of two reoperation groups for intermittent exotropia. AB - PURPOSE: To evaluate the effect of initial postoperative deviation on subsequent reoperation in patients with intermittent exotropia and to compare the clinical factors and surgical outcomes between the two surgical failure groups. METHODS: The medical records of patients who underwent reoperation after failed primary surgery for intermittent exotropia at a single center were reviewed retrospectively. Patients with recurrent intermittent exotropia and consecutive esotropia were considered surgical failures. Various clinical factors were compared between these two groups, including age at surgery, interval between surgeries, stereoacuity, spherical equivalent, office control, surgical type, presence of neurologic disease, amblyopia and other strabismus, and postoperative angles of deviation. RESULTS: Of the 3,406 patients who underwent surgery for intermittent exotropia, 139 patients met inclusion criteria. Of these, 125 (3.8%) underwent reoperation for recurrent intermittent exotropia; 14 (0.4%), for consecutive esotropia. On postoperative day 1 the intermittent exotropia group showed esodeviation at distance fixation of 2Delta +/- 4Delta; the esotropia group, esodeviation of 5Delta +/- 4Delta. The intermittent exotropia group showed a significant progression of exodeviation from 2 months postoperatively (all P < 0.005). In the esotropia group, the amount of esodeviation significantly improved in postoperative months 2 and 6 (P = 0.024 and 0.013) then further worsened after 6 months. The interval between the first and second surgeries was 64 +/- 28 months in the exotropia group and 55 +/- 36 months in the esotropia group, a significant difference (P = 0.003). CONCLUSIONS: Initial postoperative overcorrection following primary surgery for intermittent exotropia may not predict long-term success. Careful monitoring for consecutive esotropia is needed 6 months postoperatively, and annual check-ups are recommended for all patients with under- and overcorrections for a period of at least 5 years after surgery. PMID- 28860031 TI - Acute Myocardial Infarction and Stress Cardiomyopathy Are Not Mutually Exclusive. AB - BACKGROUND: Stress cardiomyopathy is a transient cardiac syndrome characterized by reversible left ventricular systolic dysfunction precipitated by emotional or physiologic stress. The presence of obstructive coronary artery disease has been noted in stress cardiomyopathy. METHODS: We describe 3 case reports of patients with acute coronary syndrome and transient wall motion abnormalities not usually seen in the distribution of coronary artery disease. RESULTS: In these 3 cases of acute myocardial infarction, the distribution of the culprit coronary occlusion was not concordant with the territory of transient wall motion abnormality. Follow-up demonstrated resolution of the wall motion abnormalities without intervention in these territories. CONCLUSION: We believe that the physiologic stress of the acute coronary syndrome may have precipitated the stress cardiomyopathy as presented by these patients. This is the first demonstration that stress cardiomyopathy may be precipitated by acute coronary syndrome. PMID- 28860032 TI - Dietary Patterns and Long-Term Survival: A Retrospective Study of Healthy Primary Care Patients. AB - BACKGROUND: Dietary patterns are related to mortality in selected populations with comorbidities. We studied whether dietary patterns are associated with long term survival in a middle-aged, healthy population. METHODS: In this observational cohort study at the Cooper Clinic preventive medicine center (Dallas, Tex), a volunteer sample of 11,376 men and women with no history of myocardial infarction or stroke completed a baseline dietary assessment between 1987 and 1999 and were observed for an average of 18 years. Proportional hazard regressions, including a tree-augmented model, were used to assess the association of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern, Mediterranean dietary pattern, and individual dietary components with mortality. The primary outcome was all-cause mortality. The secondary outcome was cardiovascular mortality. RESULTS: Mean baseline age was 47 years. Each quintile increase in the DASH diet score was associated with a 6% lower adjusted risk for all-cause mortality (P < .02). The Mediterranean diet was not independently associated with all-cause or cardiovascular mortality. Solid fats and added sugars were the most predictive of mortality. Individuals who consumed >34% of their daily calories as solid fats had the highest risk for all-cause mortality. CONCLUSIONS: The DASH dietary pattern was associated with significantly lower all cause mortality over approximately 2 decades of follow-up in a middle-aged, generally healthy population. Added solid fat and added sugar intake were the most predictive of all-cause mortality. These results suggest that promotion of a healthy dietary pattern should begin in middle age, before the development of comorbid risk factors. PMID- 28860033 TI - Hospital-Associated Hypernatremia Spectrum and Clinical Outcomes in an Unselected Cohort. AB - BACKGROUND: Although hypernatremia is associated with adverse outcomes, most studies examined selected populations. METHODS: Discharge data of 19,072 unselected hospitalized adults were analyzed. The crude relationship between serum sodium [Na+] and mortality defined hypernatremia as serum [Na+] >142 mEq/L. Patients with community-acquired hypernatremia or hospital-acquired hypernatremia were compared with normonatremic patients (admission [Na+] 138-142 mEq/L) regarding in-hospital mortality, length of stay, and discharge disposition. Patients with community-acquired hypernatremia whose hypernatremia worsened during hospitalization were compared with those without aggravation. RESULTS: Community-acquired hypernatremia occurred in 21% of hospitalized patients and was associated with an adjusted odds ratio (OR) of 1.67 (95% confidence interval [CI], 1.38-2.01) for in-hospital mortality and 1.44 (95% CI, 1.32-1.56) for discharge to a short-/long-term care facility and an adjusted 10% (95% CI, 7-13) increase in length of stay. Hospital-acquired hypernatremia developed in 25.9% of hospitalized patients and was associated with an adjusted OR of 3.17 (95% CI, 2.45-4.09) for in-hospital mortality and 1.45 (95% CI, 1.32-1.59) for discharge to a facility, and an adjusted 49% (95% CI, 44-53) increase in length of stay. Hospital-aggravated hypernatremia developed in 11.7% of patients with community acquired hypernatremia and was associated with greater risk of in-hospital mortality (adjusted OR, 1.84; 95% CI, 1.32-2.56) and discharge to a facility (adjusted OR, 2.14; 95% CI, 1.71-2.69), and an adjusted 16% (95% CI, 7-27) increase in length of stay. CONCLUSIONS: The hypernatremia spectrum in unselected hospitalized patients is independently associated with increased in-hospital mortality and heightened resource consumption. PMID- 28860034 TI - An Unsuspected Zoonotic Infection Presenting as Sepsis. PMID- 28860035 TI - Acute Myocarditis Due to Mushroom Ingestion. PMID- 28860036 TI - Effect of chlorination by-products on the quantitation of microcystins in finished drinking water. AB - Microcystins are toxic peptides that can be produced by cyanobacteria in harmful algal blooms (HABs). Various analytical techniques have been developed to quantify microcystins in drinking water, including liquid chromatography tandem mass spectrometry (LC/MS/MS), enzyme linked immunosorbent assay (ELISA), and oxidative cleavage to produce 2-methyl-3-methoxy-4-phenylbutyric acid (MMPB) with detection by LC/MS/MS, the "MMPB method". Both the ELISA and MMPB methods quantify microcystins by detecting a portion of the molecule common to most microcystins. However, there is little research evaluating the effect of microcystin chlorination by-products potentially produced during drinking water treatment on analytical results. To evaluate this potential, chlorinated drinking water samples were fortified with various microcystin congeners in bench-scale studies. The samples were allowed to react, followed by a comparison of microcystin concentrations measured using the three methods. The congener specific LC/MS/MS method selectively quantified microcystins and was not affected by the presence of chlorination by-products. The ELISA results were similar to those obtained by LC/MS/MS for most microcystin congeners, but results deviated for a particular microcystin containing a variable amino acid susceptible to oxidation. The concentrations measured by the MMPB method were at least five-fold higher than the concentrations of microcystin measured by the other methods and demonstrate that detection of MMPB does not necessarily correlate to intact microcystin toxins in finished drinking water. PMID- 28860037 TI - The adult foraging assay (AFA) detects strain and food-deprivation effects in feeding-related traits of Drosophila melanogaster. AB - We introduce a high-resolution adult foraging assay (AFA) that relates pre- and post-ingestive walking behavior to individual instances of food consumption. We explore the utility of the AFA by taking advantage of established rover and sitter strains known to differ in a number of feeding-related traits. The AFA allows us to effectively distinguish locomotor behavior in Fed and Food-Deprived (FD) rover and sitter foragers. We found that rovers exhibit more exploratory behavior into the center of an arena containing sucrose drops compared to sitters who hug the edges of the arena and exhibit thigmotaxic behavior. Rovers also discover and ingest more sucrose drops than sitters. Sitters become more exploratory with increasing durations of food deprivation and the number of ingestion events also increases progressively with prolonged fasting for both strains. AFA results are matched by strain differences in sucrose responsiveness, starvation resistance, and lipid levels, suggesting that under the same feeding condition, rovers are more motivated to forage than sitters. These findings demonstrate the AFA's ability to effectively discriminate movement and food ingestion patterns of different strains and feeding treatments. PMID- 28860038 TI - Functional complement activity is decisive for the development of chronic synovitis, osteophyte formation and processes of cell senescence in zymosan induced arthritis. AB - Synovial inflammation plays a critical role in the symptoms and structural progression of arthritis which leads to irreversible damage of the adjacent cartilage and bone. Activation of complement system is strongly implicated as a factor in the pathogenesis of chronic synovitis in human rheumatoid arthritis (RA). In this study, we show that the depletion of functional complement activity at the time of the initiation of zymosan-induced arthritis, significantly reduced the expression of TGF-beta1/3, BMP2 and pSmad2 and decreased the number of Sudan Black B positive cells in the synovium. Also, the excessive synthesis of proteoglycans and glycosaminoglycans was diminished. The appearance of apoptotic and senescent cells among the adherent bone marrow cells cultivated in vitro was not observed in complement depleted mice. Therefore, the lack of functional complement prevented the development of chronic synovitis, osteophyte formation and the generation of pathologic senescent arthritic cells. PMID- 28860039 TI - The use of BirA-BAP system to study the effect of US2 and US11 on MHC class I heavy chain in cells. AB - Biotinylation has been extensively used for antibody tagging, affinity-based purification, and in protein/DNA-protein interaction studies. Here we describe the use of biotinylation to study the turn-over of proteins in cells. We use the prokaryotic biotin ligase (BirA) to biotinylate the human leukocyte antigen (HLA) A2 (A2) heavy chain (HC), which was engineered to contain a biotin acceptor peptide (BAP). Controlled availability of biotin in combination with visualization using streptavidin-conjugated peroxidase made it possible to detect biotinylated BAP-A2. Further, we exploited the effects of human cytomegalovirus (HCMV) unique short (US) proteins US2 and US11 on the turn-over of BAP-A2 HC. The full-length BAP-A2 HC and its mutants lacking either the cytosolic tail (tail less) or both the transmembrane and cytosolic regions (soluble) were expressed via recombinant adenoviruses (rAd). The effect of US2, US11 and a control HCMV protein US9, also expressed via rAd, on each of the BAP- A2 forms was assessed. Experiments using this system showed that US2 and US11 cause proteasome-mediated degradation of full-length BAP-A2 HC but only US2 could cause degradation of tail less BAP-A2. The results demonstrate that the technique of biotinylation can be used to study protein turn-over in cells. PMID- 28860040 TI - Protein energy malnutrition alters mucosal IgA responses and reduces mucosal vaccine efficacy in mice. AB - Oral vaccine responsiveness is often lower in children from less developed countries. Childhood malnutrition may be associated with poor immune response to oral vaccines. The present study was designed to investigate whether protein energy malnutrition (PEM) impairs B cell immunity and ultimately reduces oral vaccine efficacy in a mouse model. Purified isocaloric diets containing low protein (1/10 the protein of the control diet) were used to determine the effect of PEM. PEM increased both nonspecific total IgA and oral antigen-specific IgA in serum without alteration of gut permeability. However, PEM decreased oral antigen specific IgA in feces, which is consistent with decreased expression of polymeric Immunoglobulin receptor (pIgR) in the small intestine. Of note, polymeric IgA was predominant in serum under PEM. In addition, PEM altered B cell development status in the bone marrow and increased the frequency of IgA-secreting B cells, as well as IgA secretion by long-lived plasma cells in the small intestinal lamina propria. Moreover, PEM reduced the protective efficacy of the mucosally administered cholera vaccine and recombinant attenuated Salmonella enterica serovar Typhimurium vaccine in a mouse model. Our results suggest that PEM can impair mucosal immunity where IgA plays an important role in host protection and may partly explain the reduced efficacy of oral vaccines in malnourished subjects. PMID- 28860041 TI - Enhanced TH2-like peripheral adaptive immune responses in Juvenile-onset Recurrent Respiratory Papillomatosis (JORRP). AB - BACKGROUND: Defects in the adaptive immune response to human papillomavirus-6 and -11 are among the most important mechanisms for Juvenile-onset Recurrent Respiratory Papillomatosis (JORRP) development. However, the percentage of CD8+ T cells and peripheral TH1/TH2 immune responses in Juvenile-onset Recurrent Respiratory Papillomatosis is still not well addressed due to limited sample sizes. METHODS: Twenty-three patients who were diagnosed with JORRP and underwent surgical intervention at the Beijing TongRen Hospital from October 2015 to March 2016 were enrolled in our study. The CD8+ T cells and CD4+ T cells in periphery blood were measured by flow cytometry. Intracellular staining was also performed to determine IFN-gamma and IL-4 secretion by CD8+ T cells and CD4+ T cells. Serum IFN-gamma and IL-4 levels were measured by ELISA. RESULTS: We found that the proportions of CD4+ and CD8+ T cells in peripheral blood of JORRP patients were comparable to that of healthy controls. Moreover, after PMA stimulation, there was no significant change in IFN-gamma secretion by either CD4+ or CD8+ T cells. The secretion of IL-4 but not IFN-gamma by CD4+ T cells was increased, and the serum IL-4 levels were elevated in JORRP patients. CONCLUSION: We conclude that only TH2 responses were enhanced but that the TH1 responses did not change in the peripheral immunity of JORRP patients. PMID- 28860043 TI - Circumferential Trabeculotomy Versus Conventional Angle Surgery: Comparing Long term Surgical Success and Clinical Outcomes in Children With Primary Congenital Glaucoma. AB - PURPOSE: This study compares the long-term efficacy of circumferential trabeculotomy to that of conventional angle surgeries in primary congenital glaucoma (PCG), as judged by glaucoma and visual outcomes. DESIGN: Retrospective observational case series. METHODS: Setting: Emory Eye Center, Atlanta, Georgia. STUDY POPULATION: This was a single-institution retrospective study involving children with PCG who underwent circumferential trabeculotomy, standard trabeculotomy, or goniotomy with >=2-year follow-up. MAIN OUTCOME MEASURES: Postoperative success (intraocular pressure [IOP] < 22 mm Hg +/- glaucoma medications, without glaucoma progression/additional IOP-lowering surgery), Snellen-equivalent visual acuity (VA), and IOP at last follow-up. Kaplan-Meier method estimated the probability of glaucoma control vs time postoperatively, and values were compared between angle surgery cohorts using Wilcoxon signed rank tests, Mann-Whitney U tests, and Fisher exact tests. RESULTS: Included were 58 eyes (33 children) after circumferential trabeculotomy and 42 eyes (27 children) after standard trabeculotomy/goniotomy, with mean follow-up of 7.2 +/- 4.0 and 8.2 +/- 4.5 years, respectively. Postoperative success at last follow-up in the circumferential vs conventional cohorts was 81% (47 of 58 eyes) vs 31% (13 of 42 eyes) (P < .0001). At last follow-up, the circumferential cohort had better median VA than the conventional cohort (20/30 (interquartile range [IQR] 20/25 to 20/70) vs 20/70 (IQR 20/40 to 20/200), P = .009), required fewer glaucoma medications (0.55 +/- 1.2 vs 1.61 +/- 1.51, P < .0001), had lower IOP in first operated eye (15.2 +/- 3.6 vs 18.2 +/- 7.0, P = .048), and had comparable incidence of devastating complications (P = .065). CONCLUSIONS: In this retrospective study, circumferential trabeculotomy afforded better long-term success and visual outcomes than conventional angle surgery for children with PCG. PMID- 28860042 TI - Optical Coherence Tomography Angiography and Ultra-widefield Fluorescein Angiography for Early Detection of Adolescent Sickle Retinopathy. AB - PURPOSE: Based on standard screening techniques, sickle retinopathy reportedly occurs in 10% of adolescents with sickle cell disease (SCD). We performed a prospective, observational clinical study to determine if ultra-widefield fluorescein angiography (UWFA), spectral-domain optical coherence tomography (SD OCT), and optical coherence tomography angiography (OCT-A) detect more-frequent retinopathy in adolescents with SCD. DESIGN: Cross-sectional study. METHODS: Setting: Institutional. SUBJECTS: Sixteen adolescents with SCD, aged 10-19 years (mean age 14.9 years), and 5 age-equivalent controls (mean age 17.4 years). OBSERVATION PROCEDURES: Examinations including acuity, standard slit-lamp biomicroscopy, UWFA, SD-OCT, and OCT-A were performed. MAIN OUTCOME MEASURES: Sickle retinopathy defined by biomicroscopic changes, Goldberg stages I-V, Penman scale, flow void on OCT-A, or macular thinning on SD-OCT. RESULTS: While 22 of 32 SCD eyes (68.8%) had retinopathy on biomicroscopy, by UWFA 4 of 24 (16.7%) SCD eyes had peripheral arterial occlusion (Goldberg I), and 20 of 24 eyes (83.3%) had peripheral arteriovenous anastomoses (Goldberg II) in addition. No patients had Goldberg stages III-V. By SD-OCT and OCT-A, thinning of the macula and flow voids in both the superficial and deep retinal capillary plexus were found in 6 of 30 (20%) eyes. CONCLUSIONS: All 24 eyes with adequate UWFA studies demonstrated sickle retinopathy. SD-OCT and OCT-A, which have not been previously reported in the adolescent population, detected abnormal macular thinning and flow abnormalities undetected by biomicroscopy. These findings suggest that pediatric sickle retinopathy may be more prevalent than previously suspected. If these findings are confirmed with larger cross-sectional and prospective analyses, these approaches may enhance early screening for sickle retinopathy. PMID- 28860044 TI - Clinical Implications of Direct Immunofluorescence Findings in Patients With Ocular Mucous Membrane Pemphigoid. AB - PURPOSE: To examine the clinical implications of positive or negative direct immunofluorescence biopsies (DIF) in patients with clinically typical ocular mucous membrane pemphigoid (MMP). DESIGN: Retrospective cohort study. METHODS: The study population was patients with clinically typical ocular MMP disease with documented DIF results who were followed for at least 1 year at the Duke University multidisciplinary ocular MMP clinic. Data were collected by chart review and included patient demographics, clinical examination findings, and history of autoimmune disease and/or malignancy, as well as topical, systemic, and surgical treatments received. Main outcome measures included MMP Disease Area Index, Foster stages, proportion legally blind, duration of follow-up, and use of systemic immunosuppression and ocular procedures in treatment. RESULTS: In multivariable analysis restricted to 55 patients, patients with negative and positive biopsies were similar in the outcome measures; however, positive-biopsy patients were more likely to be treated with systemic immunosuppression and were followed for longer at our clinic. Patients with isolated ocular disease were also more likely to have negative biopsies compared to those who also had extraocular disease. Patients who had conjunctival biopsies were more likely to have a negative direct immunofluorescence result than patients with biopsies from other sites. CONCLUSIONS: We encourage clinicians and patients to consider treatment with systemic immunosuppression even in the absence of diagnosis confirmation by DIF. Furthermore, this study supports current standard of care to pursue a nonocular biopsy of normal-appearing, perilesional skin or oral mucosa when possible. PMID- 28860045 TI - The Effect of Pulsing on Transverse Ultrasound Efficiency and Chatter. AB - PURPOSE: To evaluate the effects of micropulse, long pulse, and continuous ultrasound on transverse ultrasound using Abbott Medical Optics' (AMO) WhiteStar Signature Pro with the Ellips FX handpiece. DESIGN: In vitro laboratory study. METHODS: This study was conducted at the John A. Moran Eye Center Laboratory, University of Utah, Salt Lake City, Utah, USA. Porcine lenses were hardened in formalin for 2 hours and equilibrated in basic salt solution (BSS) over a 24-hour period. The lenses were then cubed in 2.0 * 2.0-mm pieces. These pieces were stored in BSS until the time of experimentation. The AMO WhiteStar Signature Pro machine (Abbott Medical Optics) with the Ellips FX handpiece and a 0.9-mm bent Dewey tip with a 30-degree bevel (Microsurgical Technology Inc) were used for phacoemulsification. Three runs of 20 lenses each were performed, measuring efficiency and chatter. Transverse ultrasound varied in the 3 runs and included continuous, 6 ms on/off micropulse, and 50 ms on/off long pulse. RESULTS: Micropulse was more efficient than long pulse by 43% (P = .00003) and continuous by 42% (P = .000387). There were also less chatter events with micropulse than with long-pulse and continuous ultrasound. However, this difference did not reach significance. CONCLUSION: The 6 ms on and 6 ms off micropulse transverse 3 dimensional ultrasound is more efficient and produces fewer chatter events than both long-pulse and continuous ultrasound. PMID- 28860046 TI - Preoperative Bevacizumab Administration in Proliferative Diabetic Retinopathy Patients Undergoing Vitrectomy: A Randomized and Controlled Trial Comparing Interval Variation. AB - PURPOSE: To assess the optimal interval of preoperative intravitreal bevacizumab (IVB) administration in diabetic subjects undergoing pars plana vitrectomy (PPV) for severe manifestations of active proliferative diabetic retinopathy (PDR). DESIGN: Randomized clinical trial. METHODS: One hundred and fifty-six patients with PDR-related complications requiring PPV were prospectively randomized into 1 of 2 treatment groups: Group A received IVB (2.5 mg/0.1 mL) 1-3 days before PPV, while Group B received IVB (2.5 mg/0.1 mL) 5-10 days before PPV. The primary outcome was best-corrected visual acuity (BCVA) at 6 months follow-up. Secondary outcome measures were intraoperative surgery time, intraoperative complications, postoperative complications, and incidence of unplanned PPV at 6 months follow up. RESULTS: One hundred and twenty-five subjects underwent PPV and completed the 6-month follow-up interval. Group B patients had better final BCVA (P = .033) and were less likely to have a postoperative complication (P = .018) when compared to Group A patients. The mean difference in final BCVA between groups was 0.22 logMAR (95% confidence interval: 0.02-0.43, P = .017). Group A was 3.90 (95% confidence interval: 1.08-17.31, P = .046) times more likely to have a loss of 1 or more logMAR lines of final BCVA when compared to Group B. There were no significant differences among the treatment groups with regard to baseline features, intraoperative surgery time, intraoperative complications, and incidence of unplanned PPV during the study interval. CONCLUSIONS: This randomized clinical trial demonstrated better postoperative outcomes at 6 months when subjects received preoperative IVB 5-10 days before PPV compared to 1-3 days for the treatment of PDR-related complications. PMID- 28860047 TI - From fish to frogs and beyond: Impact and host range of emergent ranaviruses. AB - Ranaviruses are pathogens of ectothermic vertebrates, including amphibians. We reviewed patterns of host range and virulence of ranaviruses in the context of virus genotype and postulate that patterns reflect significant variation in the historical and current host range of three groups of Ranavirus: FV3-like, CMTV like and ATV-like ranaviruses. Our synthesis supports previous hypotheses about host range and jumps: FV3s are amphibian specialists, while ATVs are predominantly fish specialists that switched once to caudate amphibians. The most recent common ancestor of CMTV-like ranaviruses and FV3-like forms appears to have infected amphibians but CMTV-like ranaviruses may circulate in both amphibian and fish communities independently. While these hypotheses are speculative, we hope that ongoing efforts to describe ranavirus genetics, increased surveillance of host species and targeted experimental assays of susceptibility to infection and/or disease will facilitate better tests of the importance of hypothetical evolutionary drivers of ranavirus virulence and host range. PMID- 28860048 TI - Editorial introduction to "Ranaviruses and other members of the family Iridoviridae: Their place in the virosphere," a special emphasis section of Virology. PMID- 28860049 TI - Tests for autoimmunity: a Luddite analysis. PMID- 28860050 TI - A Prospective Study to Evaluate Sexual Dysfunction and Enlargement of Seminal Vesicles in Sexually Active Men Treated for Benign Prostatic Hyperplasia by Alpha blockers. AB - OBJECTIVE: To evaluate sexual dysfunction and enlargement of seminal vesicles in sexually active men who were treated by alpha1-blockers for benign prostatic hyperplasia and its possible clinical application. MATERIALS AND METHODS: This is a prospective cohort study from January 2015 to December 2016. We enrolled sexually active men above the age of 40 years having moderate to severe lower urinary tract symptoms (LUTS). We excluded patients with a history of prostate surgery, suspicious digital rectal examination findings, a serum prostate specific antigen of >4 ng/dL, and a history of medication with anticholinergic, cholinergic, and diuretic agents. Patients were divided into groups A, B, and C based on the prescription of silodosin 8 mg, tamsulosin 0.4 mg, or alfuzosin 10 mg orally once for LUTS and at 4 and 12 weeks. RESULTS: The mean age was 54.8 years (41-68 years). Twelve weeks of treatment with silodosin, tamsulosin, and alfuzosin resulted in a significant improvement in the total International Prostate Symptom Score and the quality of life score (P <.001). The baseline erectile function scores were 26.4, 27.6, and 28.1, and the baseline overall satisfaction (OS) (International Index of Erectile Function [IIEF]-OS) scores were 7.1, 8.3, and 8.6 among groups A, B, and C, respectively. After 12 weeks of alpha1-blockers, the IIEF-erectile function scores were 24.0, 24.7, and 26.2, and the IIEF-OS scores were 6.4, 7.8, and 7.9. All 3 groups demonstrated a statistically significant enlargement of seminal vesicles after 12 weeks' treatment, most significant in group A patients (7.65-14.11 cc, P <.001). CONCLUSION: Alpha-blockers as silodosin, tamsulosin, and alfuzosin are a safe and effective tool in benign prostatic hyperplasia for improving LUTS and the quality of life. Loss of seminal emission with alpha-blockers appears as the cause of seminal vesicle enlargement. The exact mechanism of these findings needs further clinical and experimental research. PMID- 28860051 TI - An Unusual Right-sided Suprarenal Accessory Spleen Misdiagnosed as an Atypical Pheochromocytoma. AB - Compared with left suprarenal splenosis, a right suprarenal accessory spleen is more likely to be misdiagnosed as an adrenal tumor because of its extreme rarity. Especially when splenosis mimics an atypical pheochromocytoma, preoperative diagnosis may become more difficult and elusive. Herein we report the case of a female patient with a right suprarenal mass, which was suspected to be an atypical pheochromocytoma based on a history of the classic triad and positive somatostatin receptor scintigraphy, but histopathology suggested a final diagnosis of right suprarenal splenosis. PMID- 28860052 TI - Management of Bilateral Undescended Bilobed Testes and Review of the Literature. AB - Polyorchidism is a rare anomaly of testicular development. Particularly, a bilobed testis is an extremely rare congenital malformation, which is thought to be a variant expression of polyorchidism. Only 5 cases of bilobed testis have been reported in the literature to date. This report is of bilateral, undescended, bilobed testes in a 15-month-old boy who has multiple other malformations of possible genetic etiology. PMID- 28860054 TI - Detection of contactin-2 in cerebrospinal fluid (CSF) of patients with Alzheimer's disease using Fluorescence Correlation Spectroscopy (FCS). AB - OBJECTIVES: Alzheimer's disease (AD) is the most common cause of dementia in the world. As many AD biomarkers occur at rather low abundances in CSF or blood, techniques of very high sensitivity and accuracy are important as diagnostic tools in the clinic. Here, we aimed to provide proof of concept of the use of a single molecule detection technique, Fluorescence Correlation Spectroscopy (FCS) for detection of novel candidate biomarkers for AD. DESIGN AND METHODS: FCS detects the diffusion times of the antigen-antibody complexes in highly diluted sample solutions, thus eliminating the need of large sample volumes and allows estimating the concentration of the target antigen. We developed a FCS set-up for contactin-2, a neuronal cell adhesion molecule and a ligand of beta-secretase 1 (BACE1) and amyloid precursor protein (APP), the latter proteins being important players in AD. With this method, we investigated whether contactin-2 concentrations are changed after delayed storage and in patients with Alzheimer's disease. RESULTS: The FCS set-up for measuring contactin-2 in CSF had a lower limit of quantification (LLOQ) of 0.2ng/ml and intra- and inter-assay coefficients of variation (CVs) of 12.2% and 14.6% respectively. Contactin-2 levels were stable up to one week storage of CSF (n=3) at RT and 4 degrees C. Further, contactin-2 levels were similar in probable AD patients (n=34, p=0.27) compared to patients with subjective cognitive decline (SCD) (n=11). CONCLUSIONS: FCS is a sensitive tool, which can be used for detecting biomarkers in the clinical setting using very low sample volumes (10MUl) and can measure proteins in their native conformations in the body fluid. PMID- 28860055 TI - Novel and environmental friendly approach; Impact of Neem (Azadirachta indica) gum nano formulation (NGNF) on Helicoverpa armigera (Hub.) and Spodoptera litura (Fab.). AB - The future of this study was to prepare a natural pesticide which will not harm the environment and yet control pests. Neem gum nano formulation (NGNF), a novel biopesticide prepared from the Neem gum extract (Azadirachta indica) (NGE) was evaluated for its antifeedant, larvicidal and pupicidal activities against Helicoverpa armigera (Hub.) and Spodoptera litura (Fab.) at 100ppm. The NGNF showed significant (100%) antifeedant, larvicidal and pupicidal activities against H. armigera and S. litura. The LC50 values of 10.20, 12.49 and LC90 values of 32.68, 36.68ppm on H. armigera and S. litura, respectively at 100ppm. The NGNF treatments showed differences in the activities of detoxifying enzymes, carboxylesterases, glucosidases and glutathione S-transferases in the larval gut. Earthworm toxicity illustrated that 6.25ppm of chemical insecticides (cypermethrin) varied widely in their contact toxicities compared to 100ppm of NGNF and control in both contact filter paper and artificial soil test. The NGNF were characterized and confirmed by FTIR, XRD, SEM and EDX analysis. Ten compounds were identified from the Neem gum extract (NGE) by Gas Chromatography Mass Spectrometry (GC-MS) analysis. The major compounds were fatty acids like Hexadecanoic acid, oleic acid, and ricinoleic acid. NGNF could be used as an agent to prepare novel bio-pesticides formulations. PMID- 28860053 TI - Blood-brain barrier-adapted precision medicine therapy for pediatric brain tumors. AB - Targeted chemotherapeutics provide a promising new treatment option in neuro oncology. The ability of these compounds to penetrate the blood-brain barrier is crucial for their successful incorporation into patient care. "CNS Targeted Agent Prediction" (CNS-TAP) is a multi-institutional and multidisciplinary translational program established at the University of Michigan for evaluating the central nervous system (CNS) activity of targeted therapies in neuro oncology. In this report, we present the methodology of CNS-TAP in a series of pediatric and adolescent patients with high-risk brain tumors, for which molecular profiling (academic and commercial) was sought and targeted agents were incorporated. Four of five of the patients had potential clinical benefit (partial response or stable disease greater than 6 months on therapy). We further describe the specific drug properties of each agent chosen and discuss characteristics relevant in their evaluation for therapeutic suitability. Finally, we summarize both tumor and drug characteristics that impact the ability to successfully incorporate targeted therapies into CNS malignancy management. PMID- 28860056 TI - Preparation of chitosan-collagen-alginate composite dressing and its promoting effects on wound healing. AB - The present study aimed to prepare a composite dressing composed of collagen, chitosan, and alginate, which may promote wound healing and prevent from seawater immersion. Chitosan-collagen-alginate (CCA) cushion was prepared by paintcoat and freeze-drying, and it was attached to a polyurethane to compose CCA composite dressing. The swelling, porosity, degradation, and mechanical properties of CCA cushion were evaluated. The effects on wound healing and seawater prevention of CCA composite dressing were tested by rat wound model. Preliminary biosecurity was tested by cytotoxicity and hemocompatibility. The results revealed that CCA cushion had good water absorption and mechanical properties. A higher wound healing ratio was observed in CCA composite dressing treated rats than in gauze or chitosan treated ones. On the fifth day, the healing rates of CCA composite dressing, gauze, and chitosan were 48.49%+/-1.07%, 28.02%+/-6.4%, and 38.97%+/ 8.53%, respectively. More fibroblast and intact re-epithelialization were observed in histological images of CCA composite dressing treated rats, and the expressions of EGF, bFGF, TGF-beta, and CD31 increased significantly. CCA composite dressing showed no significant cytotoxicity, and favorable hemocompatibility. These results suggested that CCA composite dressing could prevent against seawater immersion and promote wound healing while having a good biosecurity. PMID- 28860057 TI - Characterization and immunomodulatory activity of polysaccharides from the stems and leaves of Abelmoschus manihot and a sulfated derivative. AB - BACKGROUND: Abelmoschus manihot (Linn.) Medicus is a traditional herbal medicine whose flowers, stems and leaves exhibit widely pharmacological activities. However, only the flowers have long been used as medicine while the stems and leaves were mainly discarded and burned, which undoubtedly caused enormous waste of these resources and serious environment pollution. Many researches have indicated that bioactivities of polysaccharides were significantly improved after sulfation. The aim of this study was to investigate the characterization and immunomodulatory activity of polysaccharides from stems and leaves of A. manihot and a sulfated derivative. RESULTS: A mixed neutral polysaccharide (SLAMP-a) and two acidic polysaccharides (SLAMP-c and SLAMP-d) were obtained from stems and leaves of A. manihot by DEAE-cellulose chromatography. SLAMP-a was a water insoluble mixture while its sulfated derivative (S-SLAMP-a3), prepared with aminosulfonic acid, was a homogeneous polysaccharide with excellent solubility. The average molecular weights of S-SLAMP-a3, SLAMP-c and SLAMP-d were 1044.2kDa, 477.8kDa and 264.2kDa respectively. SLAMP-a and its sulfate mainly contained glucose, and SLAMP-c and SLAMP-d were both composed of mannose, rhamnose, glucuronic acid, glucose, galactose, and arabinose. In vitro study indicated that S-SLAMP-a3, SLAMP-c and SLAMP-d exhibited significant immunomodulatory activity, while SLAMP-a showed little effects. CONCLUSION: SLAMP-c and SLAMP-d from A. manihot stems and leaves could be explored as immunomodulatory agents, which would provide a way to utilize these enormously discarded resources and avoid massive waste. Additionally, the neutral polysaccharide, SLAMP-a, could also be developed after sulfation, suggesting that these disused resources would be further used effectively. PMID- 28860058 TI - Arabinogalactan from edible jambo fruit induces different responses on cytokine secretion by THP-1 macrophages in the absence and presence of proinflammatory stimulus. AB - Syzygium jambos is an Indo-Malaian found in many tropical countries and it is mainly composed of carbohydrates. Fraction PF-WSP and SF-WSP were obtained by aqueous extraction followed by Fehling's treatment. Monosaccharide analysis showed that fraction PF-WSP has a high content of uronic acids (90%) and fraction SF-WSP presented mainly galactose (39.1%) and arabinose (34.2%), as neutral sugars and 9% of galacturonic acid. The presence of type II arabinogalactan in SF WSP was evidenced by methylation analysis and 13C/1H HSQC NMR experiments. Immunomodulating properties of SF-WSP was investigated. It decreases THP-1 macrophage viability at the highest concentration tested (200MUg/mL). We then tested non-cytotoxic concentrations of SF-WSP on THP-1 cytokine production in the presence and absence of LPS. The results showed that SF-WSP increased TNF-alpha, IL-1beta and IL-10 secretion in a concentration-dependent manner as well as attenuated the inflammatory response induced by LPS at the highest concentration (100MUg/mL). These results contribute to elucidate the effects of fruit pectic polysaccharides on immune cells. PMID- 28860059 TI - Absence of differences among low, middle, and high molecular weight hyaluronan in activating murine immune cells in vitro. AB - Hyaluronan (HA) effects on immune response are suggested to be dependent on HA molecular weight (MW), as low MW HA should activate immune cells in contrast to high MW HA. However, some current studies do not support this conception and emphasize the importance of the form of preparation of HA, particularly with respect to its purity and origin. We compared the activation of mouse immune cells by HA samples (100kDa, 500kDa, and 997kDa) prepared from HA originating from rooster comb, and HA samples (71kDa, 500kDa, and 1000kDa) prepared from pharmacological grade HA originating from Streptococcus equi. Interestingly, in contrast to established theory, only middle and high MW HA originating from rooster comb induced the production of tumor necrosis factor-alpha by macrophages and in whole blood. Further, all tested preparations of HA failed to induce the expression of inducible nitric oxide synthase, the production of nitric oxide, or the expression of cyclooxygenase 2 in macrophages and splenocytes. Importantly, all HA samples originating from rooster comb were found to be contaminated by endotoxin (up to 1.23EU/ml). Hence, low MW HA did not reveal itself to have significantly higher immunostimulatory activity compared to HA of higher MW. PMID- 28860060 TI - Heteroprotein complex coacervates of ovalbumin and lysozyme: Formation and thermodynamic characterization. AB - The formation of heteroprotein coacervates obtained by the interaction of ovalbumin (Ova) and lysozyme (Lys) was investigated using turbidimetric analysis and the zeta potential at different protein ratios, pH values and concentrations of NaCl. The complexes were formed over a wide pH range with a 1:1 (Ova:Lys) ratio and the highest turbidity was observed at pH 7.5, which optimal biopolymer interactions occurring. The addition of NaCl disfavored formation, even at low concentrations, and suppressed it at 300mM. The complex coacervate formation occurred in the region between the isoelectric points (pI) of the proteins, predominantly by electrostatic interactions but with participation of hydrogen bonds. The structures formed had an average size of ~2MUm, which was well above the isolated proteins, and microscopic analysis revealed that the complexes had a globular structure. The interaction was exothermic and spontaneous with a favorable entropic and unfavorable entropic contribution during interaction. PMID- 28860061 TI - Effect of sulfated galactan from Porphyra haitanensis on H2O2-induced premature senescence in WI-38 cells. AB - Porphyran sulfated galactan extracted from red algae Porphyra haitanensis is a sulfated polysaccharide, which possesses excellent activities. In the present study, WI-38 cells were treated with H2O2 to induce premature senescence and then the protection of porphyran against aging in vitro and associated molecular mechanisms were investigated. The protection occurred in a dose-dependent manner, offering an optimal efficacy starting at 10MUg/mL. The proportion of SA-beta-gal positive cells in porphyran group decreases from 53% to 23% in the cultures at 30 PDs. Porphyran has been detected specifically reducing SAHF-like foci formation in senescent cells. In addition, porphyran significantly affected the p53-p21 pathways in H2O2-treated WI-38 cells. Our data suggest the promising role of porphyran as an attractive and bio-safe agent with the potential to retard senescence and attenuate senescence-related diseases. PMID- 28860062 TI - Effects of the molecular weight and protein and sulfate content of Chlorella ellipsoidea polysaccharides on their immunomodulatory activity. AB - We investigated the effects of the protein and sulfate content, as well as the molecular weight (Mw), of green alga Chlorella ellipsoidea polysaccharides on their immunomodulatory activity. The deproteinized (DP1-3), desulfated (DS1-3), and hydrolyzed (DH1-3) derivatives of C. ellipsoidea polysaccharides were prepared by enzymatic hydrolysis, desulfation, and acid hydrolysis, respectively, of differing durations, resulting in preparations containing various amounts of proteins (2.41%-8.97%), sulfates (1.36%-4.89%), and Mw (51.5-193.4kDa). The DH1-3 induced production of nitric oxide (NO) by RAW264.7 cells, decreased as the Mw of DH1-3 decreased. In addition, the sulfate content and Mw of DS1-3 affected the release of NO. However, lower protein content did not affect DP1-3-induced NO release and cytokine mRNA expression in RAW264.7 cells. Based on a multiple regression analysis of the effects of protein content, sulfate content, and Mw, on NO release, we found that Mw was a key factor for the stimulation of RAW264.7 cells, as it affected cytokine production, and activation of the nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways. Therefore, the Mw of C. ellipsoidea polysaccharides played an important role in their immunomodulatory activities. PMID- 28860063 TI - Production of a thermostable 1,3-1,4-beta-glucanase mutant in Bacillus subtilis WB600 at a high fermentation capacity and its potential application in the brewing industry. AB - 1,3-1,4-beta-glucanase was an important biotechnological aid in the brewing industry. In a previous research, a Bacillus BglTO mutant (BglTO) with high tolerance towards high temperature and low-pH conditions was constructed and expressed in Escherichia coli. However, E. coli was not a suitable host for enzyme production in food industry. Therefore, the present work aimed to achieve the high-level expression of BglTO in Bacillus subtilis WB600 and to test its effect in Congress mashing. The beta-glucanase mutant was successfully expressed in B. subtilis WB600 and favorable plasmid segregation and structural stability were observed. The maximal extracellular activity of beta-glucanase in recombinant B. subtilis WB600 reached 4840.4UmL-1 after cultivation condition optimization, which was 1.94-fold higher than that before optimization. The fermentation capacity of recombinant B. subtilis reached 242.02UmL-1h-1, which was the highest among all reported beta-glucanases. The addition of BglTO in Congress mashing significantly reduced the filtration time and viscosity of mash by 29.7% and 12.3%, respectively, which was superior to two commercial enzymes. These favorable properties indicated that B. subtilis WB600 was a suitable host for production of BglTO, which was promising for application in the brewing industry. PMID- 28860064 TI - Revalorization of selected municipal solid wastes as new precursors of "green" nanocellulose via a novel one-pot isolation system: A source perspective. AB - In the present work, four types of newly chosen municipal solid wastes (Panax ginseng, spent tea residue, waste cotton cloth, and old corrugated cardboard) were studied as the promising sources for nanocellulose, which has efficiently re engineered the structure of waste products into highly valuable nanocellulose materials. The nanocellulose was produced directly via a facile one-pot oxidative hydrolysis process by using H2O2/Cr(NO3)3 solution as the bleaching agent and hydrolysis medium under acidic condition. The isolated nanocellulose products were well-characterized in terms of chemical composition, product yield, morphological structure and thermal properties. The study has found that the crystallinity index of the obtained nanocellulose products were significantly higher (62.2-83.6%) than that of its starting material due to the successive elimination of lignin, hemicellulose and amorphous regions of cellulose, which were in good agreement with the FTIR analysis. The evidence of the successful production of nanocellulose was given by TEM observation which has revealed the fibril widths were ranging from 15.6 to 46.2nm, with high cellulose content (>90%), depending on the cellulosic origin. The physicochemical properties of processed samples have confirmed that the isolation of high purity nanocellulose materials from different daily spent products is possible. The comparative study can help to provide a deep insight on the possibility of revalorizing the municipal solid wastes into nanocellulose via the simple and versatile one-pot isolation system, which has high potential to be used in commercial applications for sustainable development. PMID- 28860065 TI - Chitosan extracted from Aspergillus flavus shows synergistic effect, eases quorum sensing mediated virulence factors and biofilm against nosocomial pathogen Pseudomonas aeruginosa. AB - The biological methods for extraction of chitosan were used as alternative procedures for chemical methods In biological methods, the chitosan was extracted from A. flavus by using of Lactobacillus paracasei for demineralization and Bacillus subtilis for deproteinization. The yield of extracted chitosan reached to 53.8%, pH was 7.8 and complete solubility in 1% acitic acid. Purified chitosan had the ability to reduce the biofilm forming capacity of P. aeruginosa clearly visible in light microscopic staining and scanning electron microscopy. The QS dependent phenotype and QS regulated gene expression was significantly reduced in the influence of chitosan. A significant decrease in biofilm formation was seen in the presence of chitosan. The chitosan treatment showed a decrease in the expression of lasR and rhlR genes. Same time production of pyocyanin and proteases was also inhibited in dose dependent manner. Chitosan led to increasing antimicrobial activity of antibiotics and had synergism effect, thus chitosan may be a useful adjuvant agent for the treatment of many bacterial infections in combination with antibiotics. PMID- 28860066 TI - Novel peptide MT23 for potent penetrating and selective targeting in mouse melanoma cancer cells. AB - Cell-penetrating peptides (CPPs) have a great potential for intracellular delivery of cell-impermeable biological macromolecules in clinical therapy. However, their lack of cell and tissue specificity remains the primary limitation for their clinical development as drug delivery vehicles. In this study, based on phage display and an in silico approach, we found a novel CPP-MT23 with mouse melanoma cell specificity, it can only enter B16 melanoma cancer cells and without any cytotoxicity, Moreover, MT23 showed higher penetration efficiency based on fluorescence microcopy and quantitative assay, and it has capability for mediating functional Apoptin into cells in vitro or in vivo. Moreover, MT23 Apoptin can significantly inhibit tumor growth and induce the cell apoptosis in B16 tumor bearing mice. To sum up, all the results implicated that MT23 has the potential to deliver exogenous therapeutic proteins for further use and it also expected to lay the foundation for developing human melanoma cancer cell specific CPP. PMID- 28860068 TI - Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats. AB - We have recently reported that a short course of morphine, starting 10days after sciatic chronic constriction injury (CCI), prolonged the duration of mechanical allodynia for months after morphine ceased. Maintenance of this morphine-induced persistent sensitization was dependent on spinal NOD-like receptor protein 3 (NLRP3) inflammasomes-protein complexes that proteolytically activate interleukin 1beta (IL-1beta) via caspase-1. However, it is still unclear how NLRP3 inflammasome signaling is maintained long after morphine is cleared. Here, we demonstrate that spinal levels of the damage associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and biglycan are elevated during morphine-induced persistent sensitization in male rats; that is, 5weeks after cessation of morphine dosing. We also show that HMGB1 and biglycan levels are at least partly dependent on the initial activation of caspase-1, as well as Toll like receptor 4 (TLR4) and the purinergic receptor P2X7R-receptors responsible for priming and activation of NLRP3 inflammasomes. Finally, pharmacological attenuation of the DAMPs HMGB1, biglycan, heat shock protein 90 and fibronectin persistently reversed morphine-prolonged allodynia. We conclude that after peripheral nerve injury, morphine treatment results in persistent DAMP release via TLR4, P2X7R and caspase-1, which are involved in formation/activation of NLRP3 inflammasomes. These DAMPs are responsible for maintaining persistent allodynia, which may be due to engagement of a positive feedback loop, in which NLRP3 inflammasomes are persistently activated by DAMPs signaling at TLR4 and P2X7R. PMID- 28860067 TI - A novel role for osteopontin in macrophage-mediated amyloid-beta clearance in Alzheimer's models. AB - Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115+ monocytes (MoBM) curbs amyloid beta-protein (Abeta) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated Abeta clearance. Here, we found extensive OPN upregulation along with reduction of vascular and parenchymal Abeta burden in cortices and hippocampi of GA-immunized ADtg mice. Treatment combining GA with blood-grafted MoBM further increased OPN levels surrounding residual Abeta plaques. In brains from AD patients and ADtg mice, OPN was also elevated and predominantly expressed by infiltrating GFP+- or Iba1+-CD45high monocyte-derived macrophages engulfing Abeta plaques. Following GA immunization, we detected a significant increase in a subpopulation of inflammatory blood monocytes (CD115+CD11b+Ly6Chigh) expressing OPN, and subsequently, an elevated population of OPN-expressing CD11b+Ly6C+CD45high monocyte/macrophages in the brains of these ADtg mice. Correlogram analyses indicate a strong linear correlation between cerebral OPN levels and macrophage infiltration, as well as a tight inverse relation between OPN and Abeta-plaque burden. In vitro studies corroborate in vivo findings by showing that GA directly upregulates OPN expression in BM-derived macrophages (MFBM). Further, OPN promotes a phenotypic shift that is highly phagocytic (increased uptake of Abeta fibrils and surface scavenger receptors) and anti inflammatory (altered cell morphology, reduced iNOS, and elevated IL-10 and Abeta degrading enzyme MMP-9). Inhibition of OPN expression in MFBM, either by siRNA, knockout (KOOPN), or minocycline, impairs uptake of Abeta fibrils and hinders GA's neuroprotective effects on macrophage immunological profile. Addition of human recombinant OPN reverses the impaired Abeta phagocytosis in KOOPN-MFBM. This study demonstrates that OPN has an essential role in modulating macrophage immunological profile and their ability to resist pathogenic forms of Abeta. PMID- 28860069 TI - GeRNet: a gene regulatory network tool. AB - Gene regulatory networks (GRNs) are crucial in every process of life since they govern the majority of the molecular processes. Therefore, the task of assembling these networks is highly important. In particular, the so called model-free approaches have an advantage modeling the complexities of dynamic molecular networks, since most of the gene networks are hard to be mapped with accuracy by any other mathematical model. A highly abstract model-free approach, called rule based approach, offers several advantages performing data-driven analysis; such as the requirement of the least amount of data. They also have an important ability to perform inferences: its simplicity allows the inference of large size models with a higher speed of analysis. However, regarding these techniques, the reconstruction of the relational structure of the network is partial, hence incomplete, for an effective biological analysis. This situation motivated us to explore the possibility of hybridizing with other approaches, such as biclustering techniques. This led to incorporate a biclustering tool that finds new relations between the nodes of the GRN. In this work we present a new software, called GeRNeT that integrates the algorithms of GRNCOP2 and BiHEA along a set of tools for interactive visualization, statistical analysis and ontological enrichment of the resulting GRNs. In this regard, results associated with Alzheimer disease datasets are presented that show the usefulness of integrating both bioinformatics tools. PMID- 28860070 TI - INDEX: Incremental depth extension approach for protein-protein interaction networks alignment. AB - : High-throughput methods have provided us with a large amount of data pertaining to protein-protein interaction networks. The alignment of these networks enables us to better understand biological systems. Given the fact that the alignment of networks is computationally intractable, it is important to introduce a more efficient and accurate algorithm which finds as large as possible similar areas among networks. This paper proposes a new algorithm named INDEX for the global alignment of protein-protein interaction networks. INDEX has multiple phases. First, it computes topological and biological scores of proteins and creates the initial alignment based on the proposed matching score strategy. Using networks topologies and aligned proteins, it then selects a set of high scoring proteins in each phase and extends new alignments around them until final alignment is obtained. Proposing a new alignment strategy, detailed consideration of matching scores, and growth of the alignment core has led INDEX to obtain a larger common connected subgraph with a much greater number of edges compared with previous methods. Regarding other measures such as edge correctness, symmetric substructure score, and runtime, the proposed algorithm performed considerably better than existing popular methods. Our results show that INDEX can be a promising method for identifying functionally conserved interactions. AVAILABILITY: The INDEX executable file is available at https://github.com/a mir/index/. PMID- 28860071 TI - Circadian clock as possible protective mechanism to pollution induced keratinocytes damage. AB - Ozone is among the most toxic environmental stressors to which we are continuously exposed. Due to its critical location, skin is one of the most susceptible tissues to oxidative stress damaging effect of ozone. An increasing collection of data suggests a significant role of circadian system in regulation of cellular response to oxidative stress. However, the molecular mechanism linking circadian clock and antioxidant pathway it is not completely understood. Here we investigated a possible protective role of entrained circadian clock to ozone induced damage in keratinocytes, the main cellular component of human epidermis. Our results showed that, clock-synchronized keratinocytes compared to arrhythmic ones exhibited a more efficient antioxidant response, attested by a faster activation of the master antioxidant regulatory factor NRF2. Moreover, analysis of clock gene expression profiles reveals a more rapid induction of the cardinal clock gene Bmal1 in entrained cells. Based on these findings, we suppose that an adequate coordination of circadian system and antioxidant pathway might be essential to maintain homeostasis in the skin. Alteration of metabolic pathways occurred in neurological diseases or in irregular schedule of life activity could negatively influence tissue gene expression programs and associated organ physiology via its effect on the circadian system. PMID- 28860072 TI - Oral delivery of a therapeutic gene encoding glucagon-like peptide 1 to treat high fat diet-induced diabetes. AB - The number of people suffering from insulin-independent type 2 diabetes mellitus (T2DM) is ever increasing on a yearly basis. Current anti-diabetic medications often result in adverse weight gain and hypoglycemic episodes. Hypoglycemia can be avoided with glucagon-like peptide (GLP)-1 receptor agonists, which are expensive and require daily injections that may result immune activation. This study demonstrates the use of non-viral vector based oral delivery of GLP-1 gene through enterohepatic recycling pathways of bile acids. Oral administration of the plasmid DNA (pDNA) encoding GLP-1 decreased diabetic glucose levels to the normoglycemic range with significant weight reduction in a high-fat diet (HFD) induced diabetic mouse model and a genetically engineered T2DM rat model. This novel oral GLP1 delivery system is an attractive alternative to treat late-stage T2DM conditions that require repeated insulin injection and can potentially minimize the occurrence of hypoglycemic anomalies. PMID- 28860073 TI - miR-92a regulates coelomocytes apoptosis in sea cucumber Apostichopus japonicus via targeting Aj14-3-3zeta in vivo. AB - miR-92a, a well-documented oncogene, was previously found to be differentially expressed in diseased sea cucumber Apostichopus japonicus by high-throughput sequencing. In this study, we identified Aj14-3-3zeta as a novel target of miR 92a in this species and investigated their regulatory roles in vivo. The negative expression profiles between miR-92a and Aj14-3-3zeta protein were detected in both LPS-exposed primary coelomocytes and Vibrio splendidus-challenged sea cucumbers. Over-expression of miR-92a by injection of miR-92a agomir significantly depressed the mRNA and protein expression of Aj14-3-3zeta and promoted coelomocytes apoptosis with 5.04-fold increase in vivo, which was consistent with those from siRNA-mediated Aj14-3-3zeta knockdown assay. In contrast, miR-92a antagomir significantly elevated the mRNA and protein expression of Aj14-3-3zeta and decreased coelomocytes apoptosis. Taken together, our result confirmed that miR-92a is involved in apoptotic signaling pathway regulation perhaps via targeting Aj14-3-3zeta in sea cucumbers, which will enhance our understanding of miR-92a regulatory roles in sea cucumber pathogenesis. PMID- 28860074 TI - Hepatopancreas transcriptome analysis of Chinese mitten crab (Eriocheir sinensis) with white hepatopancreas syndrome. AB - White hepatopancreas is a syndrome that has recently emerged in aquaculture of Chinese mitten crab (Eriocheir sinensis). High lethality of the disease caused large economic loss, which drew considerable attention of fish farmers and scientific researchers. In this study, hepatopancreas reference transcriptome was de novo assembled and differential expression analysis was conducted between white hepatopancreas and normal (yellow) hepatopancreas of E. sinensis. A total of 90,687 transcripts were assembled, and 27,387 were annotated. Transcriptomic comparison revealed 69 differentially expressed genes between individuals featuring white hepatopancreas and yellow hepatopancreas. Genes associated with immune response and cell death, include thioredoxin-related transmembrane protein 1, hemocytin, methuselah-like 1, and E3 ubiquitin-protein ligase, and they were up-regulated, whereas titin and 5-formyltetrahydrofolate cyclo-ligase, which are genes related to cell proliferation, were down-regulated in E. sinensis with white hepatopancreas syndrome. Our study provides novel insights into genetic causes of formation and novel gene markers for detection of white hepatopancreas syndrome in aquaculture of E. sinensis. PMID- 28860075 TI - CpG ODN 1668 induce innate and adaptive immune responses in rock bream (Oplegnathus fasciatus) against rock bream iridovirus (RBIV) infection. AB - Rock bream iridovirus (RBIV) causes severe mass mortalities in rock bream in Korea. CpG ODN 1668 showed promise as immunoprotective agents against RBIV infection in rock bream. In this study, we assessed innate/adaptive-related gene expression patterns in RBIV-infected rock bream with and without CpG ODN 1668 administration to determine important immune defense related factors that may affect fish survival. In the CpG ODN 1668+virus-injected group, virus copies were more than 7.4- to 790591-fold lower than in the virus-injected group at 4 d (8.79 * 104 and 6.58 * 105/MUl, respectively), 7 d (5.30 * 102 and 2.29 * 107/MUl, respectively) and 10 dpi (7.79 * 101 and 6.16 * 107/MUl, respectively). Furthermore, in the CpG ODN 1668+virus-injected group, significantly higher levels of MyD88 (6 h, 1 d, 4 d and 7 dpi), IL1beta (1 d, 2 d and 7 dpi) and perforin/granzyme (1 dpi) expression were observed, whereas these genes were not significantly expressed in the virus-injected group at that time points. Mx, ISG15 and PKR were significantly highly expressed at 4 d and 7 dpi and reduced when low viral loads at 10 dpi in the CpG ODN 1668+virus-injected group. Conversely, in the virus-injected group, Mx, ISG15 and PKR expression were significantly higher than the control group until 10 dpi. However, MHC class I, CD8, Fas, Fas ligand and caspases (3, 8 and 9) expression levels showed no statistically significant differences between virus- and CpG ODN 1668+virus injected group. In summary, CpG ODN 1668 administration in fish induces innate immune response or cell death pathway, which could be a major contributing factor to effective fish control over viral transcription on 4 d to 10 dpi. Expression of MyD88, IL1beta, perforin and granzyme-related immune gene response is critical factor for inhibition of RBIV replication. PMID- 28860076 TI - The antiviral role of heat shock protein 27 against red spotted grouper nervous necrosis virus infection in sea perch. AB - Heat shock protein 27 (HSP27), functioning as a stress induced protective protein, has been reported to participate in various biological processes, including apoptosis, thermal protection, and virus infection. In this study, a HSP27-like gene from the seawater fish sea perch, designated as LjHSP27, was characterized. The 1361 bp full-length cDNA of LjHSP27 encoded a 221 amino acid protein containing a conserved alpha-crystallin domain, two variable amino- and carboxy-terminal extensions, a WD/EPF motif, two serine phosphorylation sites, and two putative actin binding regions. Phylogenetic analysis showed that LjHSP27 shared the closest genetic relationship with HSP27 of the Asian seabass Lates calcarifer. LjHSP27 mRNA was ubiquitously expressed in all tissues examined, but significantly up-regulated in spleen and kidney and down-regulated in brain post red spotted grouper nervous necrosis virus (RGNNV) infection. In vitro, LjHSP27 transcript was remarkably reduced post RGNNV infection, but rapidly increased after polyinosinic-polycytidylic acid treatment. Up-regulation and down regulation of LjHSP27 inhibited and promoted RGNNV replication in cultured LJB cells, respectively. Luciferase assay indicated that LjHSP27 could enhance the promoter activities of zebrafish interferon (IFN)1 and IFN3, suggesting its potential role in innate immune responses. Moreover, overexpression of LjHSP27 inhibited RGNNV-induced apoptosis, as indicated by the up-regulation of anti apoptotic genes and down-regulation of pro-apoptotic genes, while KNK437 caused down-regulation of LjHSP27 dramatically led to opposite results, suggesting that LjHSP27 might exert its anti-RGNNV activities by regulating the apoptosis signaling pathway. Our results would provide a new insight into the underlying molecular mechanism of HSP and RGNNV interaction. PMID- 28860077 TI - The CS algorithm: A novel method for high frequency oscillation detection in EEG. AB - BACKGROUND: High frequency oscillations (HFOs) are emerging as potentially clinically important biomarkers for localizing seizure generating regions in epileptic brain. These events, however, are too frequent, and occur on too small a time scale to be identified quickly or reliably by human reviewers. Many of the deficiencies of the HFO detection algorithms published to date are addressed by the CS algorithm presented here. NEW METHOD: The algorithm employs novel methods for: 1) normalization; 2) storage of parameters to model human expertise; 3) differentiating highly localized oscillations from filtering phenomena; and 4) defining temporal extents of detected events. RESULTS: Receiver-operator characteristic curves demonstrate very low false positive rates with concomitantly high true positive rates over a large range of detector thresholds. The temporal resolution is shown to be +/-~5ms for event boundaries. Computational efficiency is sufficient for use in a clinical setting. COMPARISON WITH EXISTING METHODS: The algorithm performance is directly compared to two established algorithms by Staba (2002) and Gardner (2007). Comparison with all published algorithms is beyond the scope of this work, but the features of all are discussed. All code and example data sets are freely available. CONCLUSIONS: The algorithm is shown to have high sensitivity and specificity for HFOs, be robust to common forms of artifact in EEG, and have performance adequate for use in a clinical setting. PMID- 28860078 TI - Removing eye blink artefacts from EEG-A single-channel physiology-based method. AB - BACKGROUND: EEG signals are often contaminated with artefacts, particularly with large signals generated by eye blinks. Deletion of artefact can lose valuable data. Current methods of removing the eye blink component to leave residual EEG, such as blind source component removal, require multichannel recording, are computationally intensive, and can alter the original EEG signal. NEW METHOD: Here we describe a novel single-channel method using a model based on the ballistic physiological components of the eye blink. This removes the blink component, leaving uncontaminated EEG largely unchanged. Processing time allows its use in real-time applications such as neurofeedback training. RESULTS: Blink removal had a success rate of over 90% recovered variance of original EEG when removing synthesised eye blink components. Fronto-lateral sites were poorer (~80%) than most other sites (92-96%), with poor fronto-polar results (67%). COMPARISONS WITH EXISTING METHODS: When compared with three popular independent component analysis (ICA) methods, our method was only slightly (1%) better at frontal midline sites but significantly (>20%) better at lateral sites with an overall advantage of ~10%. CONCLUSIONS: With few recording channels and real-time processing, our method shows clear advantages over ICA for removing eye blinks. It should be particularly suited for use in portable brain-computer-interfaces and in neurofeedback training. PMID- 28860079 TI - Automated touch sensing in the mouse tapered beam test using Raspberry Pi. AB - BACKGROUND: Rodent models of neurological disease such as stroke are often characterized by motor deficits. One of the tests that are used to assess these motor deficits is the tapered beam test, which provides a sensitive measure of bilateral motor function based on foot faults (slips) made by a rodent traversing a gradually narrowing beam. However, manual frame-by-frame scoring of video recordings is necessary to obtain test results, which is time-consuming and prone to human rater bias. NEW METHOD: We present a cost-effective method for automated touch sensing in the tapered beam test. Capacitive touch sensors detect foot faults onto the beam through a layer of conductive paint, and results are processed and stored on a Raspberry Pi computer. RESULTS: Automated touch sensing using this method achieved high sensitivity (96.2%) as compared to 'gold standard' manual video scoring. Furthermore, it provided a reliable measure of lateralized motor deficits in mice with unilateral photothrombotic stroke: results indicated an increased number of contralesional foot faults for up to 6days after ischemia. COMPARISON WITH EXISTING METHOD: The automated adaptation of the tapered beam test produces results immediately after each trial, without the need for labor-intensive post-hoc video scoring. It also increases objectivity of the data as it requires less experimenter involvement during analysis. CONCLUSIONS: Automated touch sensing may provide a useful adaptation to the existing tapered beam test in mice, while the simplicity of the hardware lends itself to potential further adaptations to related behavioral tests. PMID- 28860080 TI - Rituximab desensitization in three patients with severe rituximab allergy. AB - Rituximab is a chimeric monoclonal antibody that targets CD20 positive B cells and has a positive effect on both overall and progression-free survival in B-cell lymphoid malignancies. Combination rituximab with chemotherapy treatment provide survival improvement. Although rituximab is an important treatment option in hematological malignancies, the risk of allergic reactions is high. These reactions are usually IgE-mediated and can be varied in regard of severity from urticaria to anaphylaxis. It is an option to interrupt the treatment and ommit rituximab therapy who had allergic reactions. Drug desensitization is another option and successful results have been reported by applying desensitization to such reactions. Drug desensitization alters the immune response to induce a state of temporary clinical tolerance to the allergic drug by giving gradual increasing of doses of drug at fixed time intervals. Herein, we present 3 cases successfully treated with rituximab desensitization. The cases were using rituximab with the diagnosis of Burkitt lymphoma, follicular lymphoma, and marginal zone lymphoma, respectively. Two cases had grade 2 and 1 case had grade 3 systemic allergic reaction with rituximab. There was no known allergy history in all 3 cases. All patients tolerated the desensitization protocol. The subsequent treatments of the patients were also given by desensitization protocol. A total of 12 desensitizations were administered to 3 cases. No severe or life-threating reactions were observed in subsequent applications. To date applying desensitization protocols ensure rituximab treatment safely. Rituximab desensitization can be performed at trained allergy centers, and it may be an appropriate option for rituximab allergic patients. PMID- 28860081 TI - Clinical decision-making: heuristics and cognitive biases for the ophthalmologist. AB - Diagnostic errors have a significant impact on health care outcomes and patient care. The underlying causes and development of diagnostic error are complex with flaws in health care systems, as well as human error, playing a role. Cognitive biases and a failure of decision-making shortcuts (heuristics) are human factors that can compromise the diagnostic process. We describe these mechanisms, their role with the clinician, and provide clinical scenarios to highlight the various points at which biases may emerge. We discuss strategies to modify the development and influence of these processes and the vulnerability of heuristics to provide insight and improve clinical outcomes. PMID- 28860082 TI - Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma. AB - Glioblastoma is one of the most aggressive malignant primary brain cancer in adults. To date, surgery, radiotherapy and current pharmacological treatments are not sufficient to manage this pathology that has a high mortality rate (median survival 12-15months). Recently, anticancer multi-targeted compounds have attracted much attention with the aim to obtain new drugs able to hit different biological targets that are involved in the onset and progression of the disease. Here, we report the synthesis of novel memantine-derived drugs (MP1-10) and their potential antitumor activities in human U87MG glioblastoma cell line. MP1-10 were synthetized joining memantine, which is a NMDA antagonist, to different histone deacetylase inhibitors to obtain one molecule with improved therapeutic efficacy. Biological results indicated that MP1 and MP2 possessed more potent anti proliferative effects on U87MG cells than MP3-10 in a dose-dependent manner. MP1 and MP2 induced significant cell death by apoptosis characterized by apoptotic morphological changes in Hoechst staining. Both drugs also exhibited non genotoxic and only mild cytotoxic effects in human whole blood cells. However, only MP1, showing good chemico-physical properties (solubility, LogP) and enzymatic stabilities in gastric and intestinal fluids, can be considered a suitable candidate for in vivo pharmacokinetic studies. PMID- 28860083 TI - Fluorescence spectroscopy in the visible range for the assessment of UVB radiation effects in hairless mice skin. AB - Ultraviolet (UV) radiation may induce skin alterations as observed in photoaging. Some recognized modifications are epidermal hyperplasia, amorphous deposition of degraded elastic fibers and reduction in the number of collagen fibers. They alter the tissue biochemical properties that can be interrogated by steady state fluorescence spectroscopy (SSFS). In this study, we monitored the changes in endogenous fluorescence emission from hairless mice skin during a protocol of photoaging using UVB irradiation. To perform the fluorescence spectroscopy, it was used a violet laser (408nm) to induce the native fluorescence that is emitted in the visible range. Under 408nm excitation, the emission spectrum showed bands with peaks centered around 510, 633 and 668nm for irradiated and control groups. A relative increase of the fluorescence at 633nm emission on the flank was observed with time when compared to the ventral skin at the same animal and the non-irradiated control group. We correlated the emission at 633nm with protoporphyrin IX (PpIX), and our hypothesis is that the PpIX metabolism in the photoaged and aged skin are different. PpIX fluorescence intensity in the photoaged skin is higher and more heterogeneous than in the aged skin. Notwithstanding, more spectroscopic and biochemistry studies investigating the 510 and 633nm emission are needed to confirm this hypothesis. PMID- 28860084 TI - High-density genetic mapping identifies the genetic basis of a natural colony morphology mutant in the root rot pathogen Armillaria ostoyae. AB - Filamentous fungi exhibit a broad spectrum of heritable growth patterns and morphological variations reflecting the adaptation of the different species to distinct ecological niches. But also within species, isolates show considerable variation in growth rates and other morphological characteristics. The genetic basis of this intraspecific variation in mycelial growth and morphology is currently poorly understood. By chance, a growth mutant in the root rot pathogen Armillaria ostoyae was discovered. The mutant phenotype was characterized by extremely compact and slow growth, as well as shorter aerial hyphae and hyphal compartments in comparison to the wildtype phenotype. Genetic analysis revealed that the abnormal phenotype is caused by a recessive mutation, which segregates asa single locus in sexual crosses. In order to identify the genetic basis of the mutant phenotype, we performed a quantitative trait locus (QTL) analysis. A mapping population of 198 haploid progeny was genotyped at 11,700 genome-wide single nucleotide polymorphisms (SNPs) making use of double digest restriction site associated DNA sequencing (ddRADseq). In accordance with the genetic analysis, a single significant QTL was identified for the abnormal growth phenotype. The QTL confidence interval spans a narrow, gene dense region of 87kb in the A. ostoyae genome which contains 37 genes. Overall, our study reports the first high-density genetic map for an Armillaria species and shows its successful application in forward genetics by resolving the genetic basis of a mutant phenotype with a severe defect in hyphal growth. PMID- 28860085 TI - First de novo whole genome sequencing and assembly of the pink-footed goose. AB - Annotated genomes can provide new perspectives on the biology of species. We present the first de novo whole genome sequencing for the pink-footed goose. In order to obtain a high-quality de novo assembly the strategy used was to combine one short insert paired-end library with two mate-pair libraries. The pink-footed goose genome was assembled de novo using three different assemblers and an assembly evaluation was subsequently performed in order to choose the best assembler. For our data, ALLPATHS-LG performed the best, since the assembly produced covers most of the genome, while introducing the fewest errors. A total of 26,134 genes were annotated, with bird species accounting for virtually all BLAST hits. We also estimated the substitution rate in the pink-footed goose, which can be of use in future demographic studies, by using a comparative approach with the genome of the chicken, the mallard and the swan goose. A substitution rate of 1.38*10-7 per nucleotide per generation was obtained when comparing the genomes of the two closely-related goose species (the pink-footed and the swan goose). Altogether, we provide a valuable tool for future genomic studies aiming at particular genes and regions of the pink-footed goose genome as well as other bird species. PMID- 28860086 TI - Assessing the Impact of Charge Variants on Stability and Viscosity of a High Concentration Antibody Formulation. AB - Characterizing molecular charge variants or isoforms is essential for understanding safety, potency, and bioavailability of antibody therapeutics. However, there is little information on how they influence stability and viscosity-properties governing immunogenicity and delivery. To bridge this gap, we studied antibody stability as a function of charge variant content generated via bioreactor process. We were able to systematically vary acidic variant levels as a function of bioreactor harvest time. Importantly, we do not observe any impact on aggregation behavior of a formulated antibody at high protein concentration as a function of acidic variant level. Furthermore, we confirm that acidic variants enriched using fractionation do not influence viscosity, colloidal or conformational stability. Interestingly, variants with the most acidic isoelectric points contribute disproportionately to formulation color. We discuss our findings in context of antibody manufacturing processes that may yield increased charge variant content. PMID- 28860087 TI - Pro-excitatory alterations in sodium channel activity facilitate subiculum neuron hyperexcitability in temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is a common form of adult epilepsy involving the limbic structures of the temporal lobe. Subiculum neurons act to provide a major output from the hippocampus and consist of a large population of endogenously bursting excitatory neurons. In TLE, subiculum neurons are largely spared, become hyperexcitable and show spontaneous epileptiform activity. The basis for this hyperexcitability is unclear, but is likely to involve alterations in the expression levels and function of various ion channels. In this study, we sought to determine the importance of sodium channel currents in facilitating neuronal hyperexcitability of subiculum neurons in the continuous hippocampal stimulation (CHS) rat model of TLE. Subiculum neurons from TLE rats were hyperexcitable, firing a higher frequency of action potentials after somatic current injection and action potential (AP) bursts after synaptic stimulation. Voltage clamp recordings revealed increases in resurgent (INaR) and persistent (INaP) sodium channel currents and pro-excitatory shifts in sodium channel activation and inactivation parameters that would facilitate increases in AP generation. Attenuation of INaR and INaP currents with 4,9-anhydro-tetrodotoxin (4,9-ah TTX; 100nM), a toxin with increased potency against Nav1.6 channels, suppressed neuronal firing frequency and inhibited AP bursting induced by synaptic stimulation in TLE neurons. These findings support an important role of sodium channels, particularly Nav1.6, in facilitating subiculum neuron hyperexcitability in TLE and provide further support for the importance of INaR and INaP currents in establishing epileptiform activity of subiculum neurons. PMID- 28860088 TI - Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit. AB - The entorhinal cortex (EC) is affected early in Alzheimer's disease, an illness defined by a co-occurrence of tau and amyloid-related pathologies. How the co occurrence of these pathologies in the EC affects the hippocampal circuit remains unknown. Here we address this question by performing electrophysiological analyses of the EC circuit in mice that express mutant human amyloid precursor protein (hAPP) or tau (hTau), or both in the EC. We show that the alterations in the hippocampal circuit are divergent, with hAPP increasing but hTau decreasing neuronal/circuit excitability. Most importantly, mice co-expressing hAPP and hTau show that hTau has a dominant effect, dampening the excitatory effects of hAPP. Additionally, compensatory synaptic downscaling, in response to increased excitability in EC was observed in subicular neurons of hAPP mice. Based on simulations, we propose that EC interneuron pruning can account for both EC hyperexcitability and subicular synaptic downscaling found in mice expressing hAPP. PMID- 28860090 TI - The secreted Candida albicans protein Pra1 disrupts host defense by broadly targeting and blocking complement C3 and C3 activation fragments. AB - Candida albicans the most frequently isolated clinical fungal pathogen can cause local as well as systemic and life-threatening infections particularly in immune compromised individuals. A better and more detailed understanding how C. albicans evades human immune attack is therefore needed for identifying fungal immune evasive proteins and develop new therapies. Here, we identified Pra1, the pH regulated C. albicans antigen as a hierarchical complement inhibitor that targets C3, the central human complement component. Pra1 cleaved C3 at a unique site and further inhibited effector function of the activation fragments. The newly formed C3a-like peptide lacked the C-terminal arginine residue needed for C3a-receptor binding and activation. Moreover, Pra1 also blocked C3a-like antifungal activity as shown in survival assays, and the C3b-like molecule formed by Pra1 was degraded by the host protease Factor I. Pra1 also bound to C3a and C3b generated by human convertases and blocked their effector functions, like C3a antifungal activity shown by fungal survival, blocked C3a binding to human C3a receptor expressing HEK cells, activation of Fura2-AM loaded cells, intracellular Ca2+ signaling, IL-8 release, C3b deposition, as well as opsonophagocytosis and killing by human neutrophils. Thus, upon infection C. albicans uses Pra1 to destroy C3 and to disrupt host complement attack. In conclusion, candida Pra1 represents the first fungal C3-cleaving protease identified and functions as a fungal master regulator of innate immunity and as a central fungal immune-escape protein. PMID- 28860089 TI - Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions. AB - The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from. At present, an effective treatment is available for only one form of NCL. Evidence of NCL has been documented in over 20 canine breeds and in mixed breed dogs. To date, 12 mutations in 8 different genes orthologous to the human NCL genes have been found to underlie NCL in a variety of dog breeds. A Dachshund model with a null mutation in one of these genes is being utilized to investigate potential therapeutic interventions, including enzyme replacement and gene therapies. Demonstration of the efficacy of enzyme replacement therapy in this model led to successful completion of human clinical trials of this treatment. Further research into the other canine NCLs, with in-depth characterization and understanding of the disease processes, will likely lead to the development of successful therapeutic interventions for additional forms of NCL, for both human patients and animals with these disorders. PMID- 28860092 TI - High serum adipocyte fatty acid binding protein level as a potential biomarker of aortic arterial stiffness in hypertensive patients with metabolic syndrome. AB - BACKGROUND: The adipocyte-fatty-acid-binding protein (A-FABP) has been implicated in arterial stiffness, metabolic syndrome (MetS), and cardiovascular disease. We aimed to determine the relationship among serum A-FABP concentration, cardiometabolic risk factors, and central arterial stiffness in a hypertensive population. METHODS: Fasting blood samples and baseline characteristics were obtained from 110 hypertensive patients. Serum A-FABP concentrations were determined by enzyme immunoassay kit. High arterial stiffness was defined as carotid-femoral pulse wave velocity values >10m/s via the SphygmoCor system. RESULTS: Patients with MetS and high arterial stiffness accounted for 67.3% and 42.7% of the study population, respectively. Serum A-FABP was positively associated with MetS and high arterial stiffness (P=0.006 and P<0.001, respectively). Multivariable stepwise linear regression analysis of the significant variables of arterial stiffness revealed that logarithmically transformed A-FABP (log-A-FABP, beta=0.278, P=0.002) was positively correlated arterial stiffness in hypertensive patients. Subgroup analysis revealed that log A-FABP (beta=0.327, P=0.003), age (beta=0229, P=0.032), and triglyceride (beta=0.307, P=0.004) were significantly positively correlated with arterial stiffness in hypertensive patients with MetS. CONCLUSIONS: Elevated A-FABP concentration could be a predictor for MetS and arterial stiffness in hypertensive patients. PMID- 28860091 TI - A quantitative study of neurochemically defined populations of inhibitory interneurons in the superficial dorsal horn of the mouse spinal cord. AB - Around a quarter of neurons in laminae I-II of the dorsal horn are inhibitory interneurons. These play an important role in modulating somatosensory information, including that perceived as pain or itch. Previous studies in rat identified four largely non-overlapping neurochemical populations among these cells, defined by expression of galanin, neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) or parvalbumin. The galanin cells were subsequently shown to coexpress dynorphin. Several recent studies have used genetically modified mice to investigate the function of different interneuron populations, and it is therefore important to determine whether the same pattern applies in mouse, and to estimate the relative sizes of these populations. We show that the neurochemical organization of inhibitory interneurons in mouse superficial dorsal horn is similar to that in the rat, although a larger proportion of these neurons (33%) express NPY. Between them, these four populations account for ~75% of inhibitory cells in laminae I-II. Since ~25% of inhibitory interneurons in this region belong to a novel calretinin-expressing type, our results suggest that virtually all inhibitory interneurons in superficial dorsal horn can be assigned to one of these five neurochemical populations. Although our main focus was inhibitory neurons, we also identified a population of excitatory dynorphin expressing cells in laminae I-II that are largely restricted to the medial part of the mid-lumbar dorsal horn, corresponding to glabrous skin territory. These findings are important for interpretation of studies using molecular-genetic techniques to manipulate the functions of interneuron populations to investigate their roles in somatosensory processing. PMID- 28860093 TI - TGF-beta1 enhances phagocytic removal of neuron debris and neuronal survival by olfactory ensheathing cells via integrin/MFG-E8 signaling pathway. AB - Olfactory ensheathing cells (OECs) have been shown to be a leading candidate in cell therapies for central nervous system (CNS) injuries and neurodegenerative diseases. Rapid clearance of neuron debris can promote neuronal survival and axonal regeneration in CNS injuries and neurodegenerative diseases. The phagocytic removal of neuron debris by OECs has been shown to contribute to neuronal outgrowth. However, the precise molecular and cellular mechanisms of phagocytic removal of neuron debris by OECs have not been explored. In this study, we found that OECs secreted anti-inflammatory cytokine transforming growth factor beta1 (TGF-beta1) during the phagocytic removal of neuron debris. TGF beta1 enhanced phagocytic activity of OECs through regulating integrin/MFG-E8 signaling pathway. In addition, TGF-beta1 shifted OECs towards a flattened shape with increased cellular area, which might also be involved in the enhancement of phagocytic activity of OECs. Furthermore, the removal of neuron debris by OECs affected neuronal survival and outgrowth. TGF-beta1 enhanced the clearance of neuron debris by OECs and increased neuronal survival. These results reveal the role and mechanism of TGF-beta1 in enhancing the phagocytic activity of OECs, which will update the understanding of phagocytosis of OECs and improve the therapeutic use of OECs in CNS injuries and neurodegenerative diseases. PMID- 28860094 TI - Quality of Life and Work Capacity Are Unrelated to Approach or Complications After Pituitary Surgery. AB - OBJECTIVE: Endoscopic pituitary surgery has shown favorable clinical outcomes. Less is known about the impact of surgical approaches on health-related quality of life (HRQoL) and work capacity. The present study was undertaken to compare transsphenoidal microscope-assisted surgery with endoscopic transsphenoidal surgery regarding preoperative and surgical factors for the final outcome of HRQoL and work capacity. METHODS: In a retrospective study of patients operated on for pituitary adenoma, outcome was compared between those operated on before and after transition with endoscopic surgery at our department. Data were gathered via patient questionnaires and patients' files. RESULTS: After exclusions, 235 patients were included (99 microsurgical and 136 endoscopic). Frequency of complications was similar but tumor size was significantly larger in the endoscopic group. Complications did not affect HRQoL or work capacity. HRQoL was not affected by surgical technique but showed an overall trend toward lower values compared with the general population. Sick leave, return to work frequency, and permanent sick leave were not affected by surgical technique. Female gender was a factor for lower ratings in all outcome variables. CONCLUSIONS: Surgical technique does not influence HRQoL or work capacity in this long-term follow-up although both are decreased compared with the general population. We conclude that fully endoscopic pituitary surgery, despite including larger tumors, bears the same risk for complications as microsurgery. In addition, females have a greater risk for decrease in HRQoL and work ability. This factor should be taken into account when informing patients and appreciating expectations of treatment. PMID- 28860095 TI - Effectiveness of Exercise Programs in Ankylosing Spondylitis: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To assess the effectiveness of exercise programs on disease activity and function in ankylosing spondylitis (AS) by a systematic review and meta analysis of randomized controlled trials (RCTs). DATA SOURCES: Medline via PubMed and Cochrane Library. STUDY SELECTION: Reports of RCTs examining the effectiveness of exercise programs for AS published up to May 2017. DATA EXTRACTION: Outcomes were evolution of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) after the completion of exercise programs. Modalities of exercise were compared and the use of biologic therapy was reported. DATA SYNTHESIS: After screening 190 abstracts, we selected 26 reports for detailed evaluation and finally investigated 8 trials that assessed a home-based exercise program (2/8), swimming (1/8), Pilates training (1/8), or supervised exercises (4/8), for a total of 331 patients with AS. Four trials included patients receiving antitumor necrosis factor therapy. All trials except one showed a decrease in BASDAI and BASFI with exercise. The weighted mean difference was -0.90 (95% confidence interval, -1.52 to -0.27; I2=69%; P=.005) for the BASDAI and -0.72 (95% confidence interval, 1.03 to -0.40; I2=0%; P<.00001) for the BASFI in favor of exercise programs. CONCLUSIONS: Despite the small number of patients and the heterogeneity of exercise programs in the RCTs included in this meta-analysis, its results support the potential of exercise programs to improve disease activity and body function in AS. PMID- 28860097 TI - Effectiveness of Conservative, Surgical, and Postsurgical Interventions for Trigger Finger, Dupuytren Disease, and De Quervain Disease: A Systematic Review. AB - OBJECTIVES: To provide an evidence-based overview of the effectiveness of conservative and (post)surgical interventions for trigger finger, Dupuytren disease, and De Quervain disease. DATA SOURCES: Cochrane Library, Physiotherapy Evidence Database, PubMed, Embase, and CINAHL were searched to identify relevant systematic reviews and randomized controlled trials (RCTs). DATA SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted the data and assessed the methodologic quality. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results. Two reviews (trigger finger and De Quervain disease) and 37 randomized controlled trials (RCTs) (trigger finger: n=8; Dupuytren disease: n=14, and De Quervain disease: n=15) were included. The trials reported on oral medication (Dupuytren disease), physiotherapy (De Quervain disease), injections and surgical treatment (trigger finger, Dupuytren disease, and De Quervain disease), and other conservative (De Qervain disease) and postsurgical treatment (Dupuytren disease). Moderate evidence was found for the effect of corticosteroid injection on the very short term for trigger finger, De Quervain disease, and for injections with collagenase (30d) when looking at all joints, and no evidence was found when looking at the PIP joint for Dupuytren disease. A thumb splint as additive to a corticosteroid injection seems to be effective (moderate evidence) for De Quervain disease (short term and midterm). For Dupuytren disease, use of a corticosteroid injection within a percutaneous needle aponeurotomy in the midterm and tamoxifen versus a placebo before or after a fasciectomy seems to promising (moderate evidence). We also found moderate evidence for splinting after Dupuytren surgery in the short term. CONCLUSIONS: In recent years, more and more RCTs have been conducted to study treatment of the aforementioned hand disorders. However, more high-quality RCTs are still needed to further stimulate evidence-based practice for patients with trigger finger, Dupuytren disease, and De Quervain disease. PMID- 28860096 TI - Association Between Therapy Intensity and Discharge Outcomes in Aged Medicare Skilled Nursing Facilities Admissions. AB - OBJECTIVES: To determine the association between therapy intensity and discharge outcomes for aged Medicare skilled nursing facilities (SNFs) fee-for-service beneficiaries and to determine the association between therapy intensity and time to community discharge. DESIGN: Retrospective observational design. SETTING: SNFs. PARTICIPANTS: Aged Medicare fee-for-service beneficiaries (N=311,338) in 3605 SNFs. INTERVENTIONS: The total minutes of physical therapy, occupational therapy, and speech therapy per day were divided into intensity groups: high (>=60min); medium-high (45-<60min); medium-low (30-<45min); and low (<30min). MAIN OUTCOME MEASURES: Four discharge outcomes-community, hospitalization, permanent placement, and death-were examined using a multivariate competing hazards model. For those associated with community discharge, a Poisson multivariate model was used to determine whether length of stay differed by intensity. RESULTS: High intensity therapy was associated with more community discharges in comparison to the remaining intensity groups (hazard ratio, .84, .68, and .433 for medium-high, medium-low, and low intensity groups, respectively). More hospitalizations and deaths were found as therapy intensity decreased. Only high intensity therapy was associated with a 2-day shorter length of stay (incident rate ratio, .95). CONCLUSIONS: High intensity therapy was associated with desirable discharge outcomes and may shorten SNF length of stay. Despite growing reimbursements to SNFs for rehabilitation services, there may be desirable benefits to beneficiaries who receive high intensity therapy. PMID- 28860098 TI - Monocyte chemoattractant protein 1 released from macrophages induced by hepatitis C virus promotes monocytes migration. AB - Hepatitis C Virus (HCV) infection usually progress to chronic liver disease and shows a significant increase in total monocyte/macrophages numbers in the liver. Monocyte chemoattractant protein-1 (MCP-1) plays a role in the recruitment of monocytes to the liver. In this study we found that MCP-1 were up-regulated in macrophages cultured with cell-culture derived infectious HCV particles (HCVcc) and promoted the migration of monocytes. IL1beta, IL6 and TNFalpha were factors that induced MCP-1 expression, which were up-regulated in macrophages induced by HCV. Long-term of HCV incubation induced apoptosis of macrophages. Finally, we observed the effect of HCV infected macrophages on nearby liver cells. Huh7 cells continuously co-cultured with monocyte/macrophages displayed increased expression of pro-inflammatory cytokines and the morphology of Huh7 cells were greatly changed. Taken together, our study provides more information for the role of monocyte/macrophages in HCV related chronic liver disease. PMID- 28860099 TI - Analysis of stress factors associated with KHV reactivation and pathological effects from KHV reactivation. AB - Koi herpesvirus (KHV) is a highly pathogenic virus of common carp and koi. KHV becomes latent in recovered koi or exposed koi without symptoms, and the latent infection can reactivate under stress conditions. KHV reactivation from latency often occurs when water temperature rapidly rises above 17 degrees C. Dissolved O2 is lower at >=17 degrees C than at non-stress temperatures <=15 degrees C. To determine whether reduced dissolved O2 level has a role in KHV reactivation during temperature stress, KHV reactivation was investigated in KHV latently infected koi (KHV+ koi) under stress temperatures by maintaining dissolved O2 consistent with the O2 level at 15 degrees C. There was no significant difference in the amount of reactivated virus between KHV+ koi maintained with and without O2 supplementation during temperature stress. Both handling and sampling were found to be stressful to koi and can contribute to KHV reactivation from latency. There was an increase in KHV genome within white blood cells (WBC) during KHV reactivation, which is about 3-4 fold higher than the amount of KHV genome detectable in WBC during the latency stage. At day 15 post-temperature stress (PTS), inflammation and necrosis were observed in multiple tissues, especially in the gills, eye, intestine, skin and kidney. KHV DNA was also detectable in multiple tissues on days 6, 9 and 15 PTS. Following day 3 PTS, the plasma cortisol levels were higher than that observed in koi before temperature stress, suggesting that KHV reactivation is associated with physiological stress in KHV+ koi. PMID- 28860100 TI - A polymerase chain reaction assay for detection of virulent and attenuated strains of duck plague virus. AB - Sequence analysis of duck plague virus (DPV) revealed that there was a 528bp (B fragment) deletion within the UL2 gene of DPV attenuated vaccine strain in comparison with field virulent strains. The finding of gene deletion provides a potential differentiation test between DPV virulent strain and attenuated strain based on their UL2 gene sizes. Thus we developed a polymerase chain reaction (PCR) assay targeting to the DPV UL2 gene for simultaneous detection of DPV virulent strain and attenuated strain, 827bp for virulent strain and 299bp for attenuated strain. This newly developed PCR for DPV was highly sensitive and specific. It detected as low as 100fg of DNA on both DPV virulent and attenuated strains, no same size bands were amplified from other duck viruses including duck paramyxovirus, duck tembusu virus, duck circovirus, Muscovy duck parvovirus, duck hepatitis virus type I, avian influenza virus and gosling plague virus. Therefore, this PCR assay can be used for the rapid, sensitive and specific detection of DPV virulent and attenuated strains affecting ducks. PMID- 28860101 TI - Development and application of a recombinant M protein-based indirect ELISA for the detection of porcine deltacoronavirus IgG antibodies. AB - Porcine deltacoronavirus (PDCoV) is a recently identified coronavirus in the genus Deltacoronavirus that can cause enteric disease including diarrhea, vomiting, dehydration and mortality in neonatal piglets. Serological assays to detect anti-PDCoV antibodies are presently limited to certain laboratories and geographic regions. In this study, a recombinant M protein-based indirect enzyme linked immunosorbent assay (PDCoV-rM ELISA) was developed and utilized to determine the prevalence of anti-PDCoV IgG in Hebei province. The PDCoV-rM ELISA showed no cross-reaction with antisera against transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), porcine rotavirus (PRV), porcine circovirus 2 (PCV2), classical swine fever virus (CSFV) or porcine reproductive and respiratory syndrome virus (PRRSV). The diagnostic sensitivity was 90.6% and the diagnostic specificity was 93.3%. A total of 871 serum samples collected in Hebei from January 2015 to October 2016 were checked for presence of antibodies against PDCoV using the novel PDCoV-rM ELISA. Anti-PDCoV IgG antibodies were detected in 11% (96/871) of the samples and in 25% (10/40) of the investigated farms. The data suggest that PDCoV has a low seroprevalence in pig population in Hebei province, China. PMID- 28860102 TI - Amyloid and membrane complexity: The toxic interplay revealed by AFM. AB - Lipid membranes play a fundamental role in the pathological development of protein misfolding diseases. Several pieces of evidence suggest that the lipid membrane could act as a catalytic surface for protein aggregation. Furthermore, a leading theory indicates the interaction between the cell membrane and misfolded oligomer species as the responsible for cytotoxicity, hence, for neurodegeneration in disorders such as Alzheimer's and Parkinson's disease. The definition of the mechanisms that drive the interaction between pathological protein aggregates and plasma membrane is fundamental for the development of effective therapies for a large class of diseases. Atomic force microscopy (AFM) has been employed to study how amyloid aggregates affect the cell physiological properties. Considerable efforts were spent to characterize the interaction with model systems, i.e., planar supported lipid bilayers, but some works also addressed the problem directly on living cells. Here, an overview of the main works involving the use of the AFM on both model system and living cells will be provided. Different kind of approaches will be presented, as well as the main results derived from the AFM analysis. PMID- 28860103 TI - DrosAfrica: Building an African biomedical research community using Drosophila. AB - The impact that research has on shaping the future of societies is perhaps as significant as never before. One of the problems for most regions in Africa is poor quality and quantity of research-based education, as well as low level of funding. Hence, African researchers produce only around one percent of the world's research. We believe that research with Drosophila melanogaster can contribute to changing that. As seen before in other places, Drosophila can be used as a powerful and cost-effective model system to scale-up and improve both academia and research output. The DrosAfrica project was founded to train and establish a connected community of researchers using Drosophila as a model system to investigate biomedical problems in Africa. Since founding, the project has trained eighty scientists from numerous African countries, and continues to grow. Here, we describe the DrosAfrica project, its conception and its mission. We also give detailed insights into DrosAfrica's approaches to achieve its aims, as well as future perspectives, and opportunities beyond Africa. PMID- 28860104 TI - Valsalva-induced elevation of intracranial pressure selectively decouples deoxygenated hemoglobin concentration from neuronal activation and functional brain imaging capability. AB - During neuronal activation, neurovascular coupling leads to a local decrease of deoxygenated hemoglobin concentration (deoxy-Hb) and thus forms the basis of many functional brain mapping methods. In animals, an elevated intracranial pressure (ICP) can attenuate or even reverse this deoxy-Hb signaling. To study the effect of an elevated ICP on functional brain imaging in humans, we used different breathing tasks to modify ICP and analyzed the resulting effect on neurovascular coupling in the motor cortex. Functional near-infrared spectroscopy (fNIRS) was performed on 45 subjects during alternating conditions of finger tapping and resting state combined with four different breathing maneuvers (normal breathing (NB), breath holding without Valsalva maneuver (BH), Valsalva maneuver with 15 mm Hg forced expiratory pressure against resistance (V15) and Valsalva maneuver with 35 mm Hg forced expiratory pressure against resistance (V35)) in randomized order. With escalation of breathing tasks the median amplitude of the functional deoxy-Hb decrease during finger tapping became smaller. In contrast, functional oxygenated hemoglobin concentration (oxy-Hb) and total hemoglobin concentration (total-Hb) responses did not show a significant alteration. The functional oxy-Hb map evoked by finger tapping withstood Valsalva challenges while the functional deoxy-Hb map identified the correct motor cortex in normal breathing conditions only and did not reveal a functional contrast during Valsalva maneuvers. In summary, we conclude that during ICP elevation, deoxy-Hb is not a reliable basis for functional brain imaging. This suggests that the validity of BOLD fMRI during increased ICP might be impaired. PMID- 28860105 TI - Ascertaining the Value of Noninvasive Measures Obtained Using Color Duplex Ultrasound and Central Aortic Pressure Monitoring During the Management of Cerebral Arteriovenous Malformation Resection: Protocol for a Prospective, Case Control Pilot Study. AB - BACKGROUND: Dramatic hemodynamic changes occur upon removal of an arteriovenous malformation of the brain (bAVM) with a number of potentially serious perioperative complications, such as intracranial hemorrhage and venous occlusive hypertensive syndrome. As these complications largely occur in the postoperative inpatient period, a rapid, repeatable noninvasive investigation to serially monitor relevant intracranial hemodynamics may be of benefit. Though, transcranial Doppler (TCD) and transcranial color duplex (TCCD) are techniques used and available to provide hemodynamic measurements postoperatively, the time course of hemodynamic sequences following bAVM resection remains uncertain. OBJECTIVE: This is a prospective, case control pilot study conducted in participants having elective bAVM resection surgery. METHODS: Each participant will undergo a preoperative color duplex ultrasound (CDU) of the bilateral extracranial carotid arteries, a CDU of the circle of Willis including the bAVM vessels, and a central aortic pressure measurement, repeated daily, postoperatively, for a 2-week period. RESULTS: Patient accrual has commenced with anticipation of first results in 2018. CONCLUSIONS: This protocol aims to strengthen the work of previous authors by providing documentation of the time course of hemodynamic changes following bAVM resection. The protocol is designed to determine whether noninvasive technology, including CDU imaging of the extracranial carotid and intracranial arteries in the form of TCCD along with central aortic pressure measurements, can determine whether there are any hemodynamically significant prognostic markers that may provide insight into the process of vessel remodeling, including insight into venous changes following bAVM resection. PMID- 28860106 TI - Web-Based Mindfulness Interventions for People With Physical Health Conditions: Systematic Review. AB - BACKGROUND: Mindfulness-based interventions (MBIs) are becoming increasingly popular for helping people with physical health conditions. Expanding from traditional face-to-face program delivery, there is growing interest in Web-based application of MBIs, though Web-based MBIs for people with physical health conditions specifically have not been thoroughly reviewed to date. OBJECTIVE: The objective of this paper was to review Web-based MBIs for people with physical health conditions and to examine all outcomes reported (eg, efficacy or effectiveness for physical changes or psychological changes; feasibility). METHODS: Databases PubMed, PsycINFO, Science Direct, CINAHL Plus, and Web of Science were searched. Full-text English papers that described any Web-based MBI, examining any outcome, for people with chronic physical health conditions were included. Randomized, nonrandomized, controlled, and uncontrolled trials were all included. Extracted data included intervention characteristics, population characteristics, outcomes, and quality indicators. Intervention characteristics (eg, synchronicity and guidance) were examined as potential factors related to study outcomes. RESULTS: Of 435 publications screened, 19 published papers describing 16 studies were included. They examined Web-based MBIs for people with cancer, chronic pain or fibromyalgia, irritable bowel syndrome (IBS), epilepsy, heart disease, tinnitus, and acquired brain injury. Overall, most studies reported positive effects of Web-based MBIs compared with usual care on a variety of outcomes including pain acceptance, coping measures, and depressive symptoms. There were mixed results regarding the effectiveness of Web-based MBIs compared with active control treatment conditions such as cognitive behavioral therapy. Condition-specific symptoms (eg, cancer-related fatigue and IBS symptoms) targeted by treatment had the largest effect size improvements following MBIs. Results are inconclusive regarding physical variables. CONCLUSIONS: Preliminary evidence suggests that Web-based MBIs may be helpful in alleviating symptom burden that those with physical health conditions can experience, particularly when interventions are tailored for specific symptoms. There was no evidence of differences between synchronous versus asynchronous or facilitated versus self directed Web-based MBIs. Future investigations of Web-based MBIs should evaluate the effects of program adherence, effects on mindfulness levels, and whether synchronous or asynchronous, or facilitated or self-directed interventions elicit greater improvements. PMID- 28860107 TI - Project Stronger Together: Protocol to Test a Dyadic Intervention to Improve Engagement in HIV Care Among Sero-Discordant Male Couples in Three US Cities. AB - BACKGROUND: An estimated one- to-two-thirds of new human immunodeficiency virus (HIV) infections among US men who have sex with men (MSM) occur within the context of primary partnerships. Despite this fact, there remains a lack of prevention interventions that focus on male sero-discordant dyads. Interventions that provide male couples with skills to manage HIV risk, and to support each other towards active engagement in HIV prevention and care, are urgently needed. OBJECTIVE: The objective of this paper is to describe the protocol for an innovative dyadic intervention (Stronger Together) that combines couples' HIV testing and dyadic adherence counseling to improve treatment adherence and engagement in care among HIV sero-discordant male couples in the United States. METHODS: The research activities involve a prospective randomized controlled trial (RCT) of approximately 165 venue- and clinic-recruited sero-discordant male couples (330 individuals: 165 HIV sero-negative and 165 HIV sero-positive). Couples randomized into the intervention arm receive couples' HIV counseling and testing plus dyadic adherence counseling, while those randomized to the control arm receive individual HIV counseling and testing. The study takes place in three cities: Atlanta, GA (study site Emory University); Boston, MA (study site The Fenway Institute); and Chicago, IL (study site Ann & Robert H. Lurie Children's Hospital of Chicago). Cohort recruitment began in 2015. Couples are followed prospectively for 24 months, with study assessments at baseline, 6, 12, 18, and 24 months. RESULTS: Stronger Together was launched in August 2014. To date, 160 couples (97% of the target enrollment) have been enrolled and randomized. The average retention rate across the three sites is 95%. Relationship dissolution has been relatively low, with only 13 couples breaking up during the RCT. Of the 13 couples who have broken up, 10 of the 13 HIV-positive partners have been retained in the cohort; none of these HIV-positive partners have enrolled new partners into the RCT. CONCLUSIONS: The intervention offers a unique opportunity for sero-discordant couples to support each other towards common HIV management goals by facilitating their development of tailored prevention plans via couples based HIV testing and counseling, as well as problem-solving skills in Partner Strategies to Enhance Problem-solving Skills (STEPS). TRIAL REGISTRATION: ClinicalTrials.gov NCT01772992; https://clinicaltrials.gov/ct2/show/NCT01772992 (Archived by WebCite at http://www.webcitation.org/6szFBVk1R). PMID- 28860108 TI - Smartphone Ownership Among US Adult Cigarette Smokers: 2014 Health Information National Trends Survey (HINTS) Data. AB - BACKGROUND: Despite increasing interest in smartphone apps as a platform for delivery of tobacco cessation interventions, no previous studies have evaluated the prevalence and characteristics of smokers who can access smartphone-delivered interventions. OBJECTIVE: To guide treatment development in this new platform and to evaluate disparities in access to smartphone-delivered interventions, we examined associations of smartphone ownership with demographics, tobacco use and thoughts about quitting, other health behaviors, physical and mental health, health care access, and Internet and technology utilization using a nationally representative sample of US adult smokers. METHODS: Data were from the National Cancer Institute's 2014 Health Information National Trends Survey 4 (HINTS 4), Cycle 4. This mailed survey targeted noninstitutionalized individuals aged 18 years or older using two-stage stratified random sampling. For this analysis, we restricted the sample to current smokers with complete data on smartphone ownership (n=479). RESULTS: Nearly two-thirds (weighted percent=63.8%, 248/479) of smokers reported owning a smartphone. Those who were younger (P<.001), employed (P=.002), never married (P=.002), and had higher education (P=.002) and income (P<.001) had the highest rates of ownership. Smartphone owners did not differ from nonowners on frequency of smoking, recent quit attempts, or future plans to quit smoking, although they reported greater belief in the benefits of quitting (P=.04). Despite being equally likely to be overweight or obese, smartphone owners reported greater fruit and vegetable consumption (P=.03) and were more likely to report past-year efforts to increase exercise (P=.001) and to lose weight (P=.02). No differences in health care access and utilization were found. Smartphone owners reported better physical and mental health in several domains and higher access to and utilization of technology and the Internet, including for health reasons. CONCLUSIONS: Smartphone ownership among smokers mirrors many trends in the general population, including the overall rate of ownership and the association with younger age and higher socioeconomic status. Apps for smoking cessation could potentially capitalize on smartphone owners' efforts at multiple health behavior changes and interest in communicating with health care providers via technology. These data also highlight the importance of accessible treatment options for smokers without smartphones in order to reach smokers with the highest physical and mental health burden and prevent worsening of tobacco-related health disparities as interventions move to digital platforms. PMID- 28860109 TI - Health as a "global public good": creating a market for pandemic risk. PMID- 28860110 TI - Polyarthralgia in a young woman. PMID- 28860112 TI - Risk factors for falls in older patients with cancer. AB - OBJECTIVES: A rising number of patients with cancer are older adults (65 years of age and older), and this proportion will increase to 70% by the year 2020. Falls are a common condition in older adults. We sought to assess the prevalence and risk factors for falls in older patients with cancer. METHODS: This is a single site, retrospective cohort study. Patients who were receiving cancer care underwent a comprehensive geriatric assessments, including cognitive, functional, nutritional, physical, falls in the prior 6 months and comorbidity assessment. Vitamin D and bone densitometry were performed. ANALYSIS: Descriptive statistics and multivariable logistic regression. RESULTS: A total of 304 patients aged 65 or above were enrolled in this study. The mean age was 78.4+/-6.9 years. They had haematological, gastrointestinal, urological, breast, lung and gynaecological cancers. A total of 215 patients with available information about falls within the past 6 months were included for final analysis. Seventy-seven (35.8%) patients had at least one fall in the preceding 6 months. Functional impairment (p=0.048), frailty (p<0.001), dementia (p=0.021), major depression (p=0.010) and low social support (p=0.045) were significantly associated with the fall status in the univariate analysis. Multivariate logistic regression analysis identified frailty and functional impairment to be independent risk factors for falls. CONCLUSIONS: Falls are common in older patients with cancer and lead to adverse clinical outcomes. Major depression, functional impairment, frailty, dementia and low social support were risk factors for falls. Heightened awareness and targeted interventions can prevent falls in older patients with cancer. PMID- 28860113 TI - Physiologically Based Pharmacokinetic Model of the CYP2D6 Probe Atomoxetine: Extrapolation to Special Populations and Drug-Drug Interactions. AB - Physiologically based pharmacokinetic (PBPK) modeling of drug disposition and drug-drug interactions (DDIs) has become a key component of drug development. PBPK modeling has also been considered as an approach to predict drug disposition in special populations. However, whether models developed and validated in healthy populations can be extrapolated to special populations is not well established. The goal of this study was to determine whether a drug-specific PBPK model validated using healthy populations could be used to predict drug disposition in specific populations and in organ impairment patients. A full PBPK model of atomoxetine was developed using a training set of pharmacokinetic (PK) data from CYP2D6 genotyped individuals. The model was validated using drug specific acceptance criteria and a test set of 14 healthy subject PK studies. Population PBPK models were then challenged by simulating the effects of ethnicity, DDIs, pediatrics, and renal and hepatic impairment on atomoxetine PK. Atomoxetine disposition was successfully predicted in 100% of healthy subject studies, 88% of studies in Asians, 79% of DDI studies, and 100% of pediatric studies. However, the atomoxetine area under the plasma concentration versus time curve (AUC) was overpredicted by 3- to 4-fold in end stage renal disease and hepatic impairment. The results show that validated PBPK models can be extrapolated to different ethnicities, DDIs, and pediatrics but not to renal and hepatic impairment patients, likely due to incomplete understanding of the physiologic changes in these conditions. These results show that systematic modeling efforts can be used to further refine population models to improve the predictive value in this area. PMID- 28860114 TI - Notum coordinates synapse development via extracellular regulation of Wingless trans-synaptic signaling. AB - Synaptogenesis requires orchestrated communication between pre- and postsynaptic cells via coordinated trans-synaptic signaling across the extracellular synaptomatrix. The first Wnt signaling ligand discovered, Drosophila Wingless (Wg; Wnt1 in mammals), plays crucial roles in synaptic development, regulating synapse architecture as well as functional differentiation. Here, we investigate synaptogenic functions of the secreted extracellular deacylase Notum, which restricts Wg signaling by cleaving an essential palmitoleate moiety. At the glutamatergic neuromuscular junction (NMJ) synapse, we find that Notum secreted from the postsynaptic muscle acts to strongly modulate synapse growth, structural architecture, ultrastructural development and functional differentiation. In Notum null flies, we find upregulated extracellular Wg ligand and nuclear trans synaptic signal transduction, as well as downstream misregulation of both pre- and postsynaptic molecular assembly. Structural, functional and molecular synaptogenic defects are all phenocopied by Wg overexpression, suggesting that Notum acts solely by inhibiting Wg trans-synaptic signaling. Moreover, these synaptic development phenotypes are suppressed by genetically correcting Wg levels in Notum null mutants, indicating that Notum normally functions to coordinate synaptic structural and functional differentiation via negative regulation of Wg trans-synaptic signaling in the extracellular synaptomatrix. PMID- 28860116 TI - Analysis of nationwide trends and outcomes of percutaneous endoscopic gastrostomy (PEG) tube placement in hospitalized patients with cancer over a 13-year period. PMID- 28860115 TI - Afadin orients cell division to position the tubule lumen in developing renal tubules. AB - In many types of tubules, continuity of the lumen is paramount to tubular function, yet how tubules generate lumen continuity in vivo is not known. We recently found that the F-actin-binding protein afadin is required for lumen continuity in developing renal tubules, though its mechanism of action remains unknown. Here, we demonstrate that afadin is required for lumen continuity by orienting the mitotic spindle during cell division. Using an in vitro 3D cyst model, we find that afadin localizes to the cell cortex adjacent to the spindle poles and orients the mitotic spindle. In tubules, cell division may be oriented relative to two axes: longitudinal and apical-basal. Unexpectedly, in vivo examination of early-stage developing nephron tubules reveals that cell division is not oriented in the longitudinal (or planar-polarized) axis. However, cell division is oriented perpendicular to the apical-basal axis. Absence of afadin in vivo leads to misorientation of apical-basal cell division in nephron tubules. Together, these results support a model whereby afadin determines lumen placement by directing apical-basal spindle orientation, resulting in a continuous lumen and normal tubule morphogenesis. PMID- 28860117 TI - Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function. AB - Hereditary spastic paraplegias (HSPs) are characterized by spasticity and weakness of the lower limbs, resulting from length-dependent axonopathy of the corticospinal tracts. In humans, the HSP-related atlastin genes ATL1-ATL3 catalyze homotypic membrane fusion of endoplasmic reticulum (ER) tubules. How defects in neuronal Atlastin contribute to axonal degeneration has not been explained satisfactorily. Using Drosophila, we demonstrate that downregulation or overexpression of Atlastin in motor neurons results in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability. Broad expression in the nervous system is required to rescue the atlastin-null Drosophila mutant (atl2 ) phenotype. Importantly, both spontaneous release and the reserve pool of synaptic vesicles are affected. Additionally, axonal secretory organelles are abnormally distributed, whereas presynaptic proteins diminish at terminals and accumulate in distal axons, possibly in lysosomes. Our findings suggest that trafficking defects produced by Atlastin dysfunction in motor neurons result in redistribution of presynaptic components and aberrant mobilization of synaptic vesicles, stressing the importance of ER-shaping proteins and the susceptibility of motor neurons to their mutations or depletion. PMID- 28860118 TI - Bringing the analysis of animal orientation data full circle: model-based approaches with maximum likelihood. AB - In studies of animal orientation, data are often represented as directions that can be analyzed using circular statistical methods. Although several circular statistical tests exist to detect the presence of a mean direction, likelihood based approaches may offer advantages in hypothesis testing - especially when data are multimodal. Unfortunately, likelihood-based inference in animal orientation remains rare. Here, we discuss some of the assumptions and limitations of common circular tests and report a new R package called CircMLE to implement the maximum likelihood analysis of circular data. We illustrate the use of this package on both simulated datasets and an empirical example dataset in Chinook salmon (Oncorhynchus tshawytscha). Our software provides a convenient interface that facilitates the use of model-based approaches in animal orientation studies. PMID- 28860119 TI - Strategies of ionoregulation in the freshwater nymph of the mayfly Hexagenia rigida. AB - This study investigated ionoregulatory strategies used by freshwater (FW) nymphs of the mayfly Hexagenia rigida Like other FW organisms, H. rigida nymphs maintain hemolymph ion levels (in mmol l-1: Na+ ~102; Cl- ~84; K+ ~6; pH ~7.35) far in excess of their surroundings. This appears to be accomplished by the combined actions of the alimentary canal, Malpighian tubules (MTs) and tracheal gills. The alimentary canal contributes in a region-specific manner, a view supported by: (1) spatial differences in the activity of basolateral Na+/K+-ATPase (NKA) and apical V-type H+-ATPase (VA) and (2) region-specific Na+ and K+ flux rates. Both indicate a prominent role for the hindgut (rectum) in K+ reabsorption. MTs also exhibit region-specific differences in Na+ and K+ flux rates that are coupled with an organized but tortuous architecture. NKA and VA activities were highest in MTs versus all other organs examined. Tracheal gills were found to be sites of Na+ uptake, but no difference in Na+ uptake was found between gills taken from different regions of the abdomen or spatially along individual gills. This is likely because each gill exhibited a dense population of NKA and/or VA immunoreactive cells (putative ionocytes). Data provide new insight into how FW mayfly nymphs regulate salt and water balance using the alimentary canal, MTs and tracheal gills as well as the first direct evidence that tracheal gills acquire ions from FW. PMID- 28860120 TI - Early gametogenesis in the Pacific oyster: new insights using stem cell and mitotic markers. AB - While our knowledge of bivalve gametogenesis has progressed in recent times, more molecular markers are needed in order to develop tissue imaging. Here, we identified stem cell and mitotic markers to further characterize oyster early gametogenesis, mainly through immunofluorescence microscopy. Intense alkaline phosphatase activity, a non-specific marker for stem cells, was detected on the outer edge of the gonad ducts at the post-spawning stage, suggesting an abundance of undifferentiated cells very early during the sexual cycle. This observation was confirmed using an antibody against Sox2, a transcription factor specific for stem or germline cells, which labeled cells in the gonad duct inner mass and ciliated epithelium early during the initial oyster sexual cycle. Moreover, Vasa, a cytoplasmic marker for germline cells, was also detected in the gonad acini and duct cells, thus confirming that germline cells were abundant early on. In addition, the binding of the minichromosome maintenance MCM6 protein to chromatin indicated the gonad acini and duct cells were engaged in the cell cycle. DNA replication was indeed confirmed by an abundant in vivo incorporation of BrdU into the duct cell chromatin. Finally, proliferation of acini and duct cells was demonstrated by the chromatin-bound Ser10-phosphorylated histone H3, a mitotic marker. The markers for the cell cycle and mitosis used here thus indicate that acini and duct cells were already actively dividing early during the oyster sexual cycle. In addition, together with the stem cell markers, these data reveal that the epithelium delimiting the duct outer edge contains a dynamic population of undifferentiated cells. PMID- 28860121 TI - NAD Synthesis Pathway Interference Is a Viable Therapeutic Strategy for Chondrosarcoma. AB - Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD+ synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2-mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored. Eleven chondrosarcoma cell lines were treated with NAMPT inhibitors, in which the effect on cell viability, colony formation, and 3D collagen invasion was assessed. The expression level of NAMPT and NAPRT transcripts in chondrosarcoma cells was determined by qRT-PCR. Methylation of the NAPRT promoter was evaluated using a previously published dataset of genome-wide methylation. In addition, a methylation dataset was used to determine methylation of the NAPRT promoter in 20 IDH1/2-mutated cartilage tumors. Chondrosarcoma cells showed a dose-dependent decrease in cell viability, 3D collagen invasion, and colony formation upon treatment with NAMPT inhibitors, in which nearly half of the cell lines demonstrated absolute IC50s in the low nanomolar range. Increasing IC50s correlated to increasing NAPRT expression levels and decreasing NAPRT promoter methylation. No correlation between IDH1/2 mutation status and sensitivity for NAMPT inhibitors was observed. Strikingly, higher methylation of the NAPRT promoter was observed in high-grade versus low-grade chondrosarcomas. In conclusion, this study identified NAMPT as a potential target for treatment of chondrosarcoma.Implications: Chondrosarcoma patients, especially those of high histologic grade with lower expression and hypermethylation of NAPRT, may benefit from inhibition of the NAD synthesis pathway. Mol Cancer Res; 15(12); 1714-21. (c)2017 AACR. PMID- 28860122 TI - Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth. AB - BACKGROUND: Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. METHODS: We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6 phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. RESULTS: Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. CONCLUSIONS: Exercise induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart. PMID- 28860123 TI - Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus. AB - BACKGROUND: The vascular complications of diabetes mellitus are the major causes of morbidity and mortality among people with diabetes. Circular RNAs are a class of endogenous noncoding RNAs that regulate gene expression in eukaryotes. In this study, we investigated the role of circular RNA in retinal vascular dysfunction induced by diabetes mellitus. METHODS: Quantitative polymerase chain reactions, Sanger sequencing, and Northern blots were conducted to detect circular HIPK3 (circHIPK3) expression pattern on diabetes mellitus-related stresses. MTT (3-[4,5 dimethythiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assays, EdU (5-ethynyl-2' deoxyuridine) incorporation assays, Transwell migration assays, and Matrigel assays were conducted to detect the role of circHIPK3 in retinal endothelial cell function in vitro. Retinal trypsin digestion, vascular permeability assays, and ELISA assays were conducted to detect the role of circHIPK3 in retinal vascular dysfunction in vivo. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were conducted to reveal the mechanism of circHIPK3-mediated retinal vascular dysfunction. RESULTS: circHIPK3 expression was significantly upregulated in diabetic retinas and retinal endothelial cells following stressors related to diabetes mellitus. circHIPK3 silencing or overexpressing circHIPK3 changed retinal endothelial cell viability, proliferation, migration, and tube formation in vitro. circHIPK3 silencing in vivo alleviated retinal vascular dysfunction, as shown by decreased retinal acellular capillaries, vascular leakage, and inflammation. circHIPK3 acted as an endogenous miR-30a-3p sponge to sequester and inhibit miR-30a-3p activity, which led to increased vascular endothelial growth factor-C, FZD4, and WNT2 expression. Ectopic expression of miR-30a-3p mimicked the effect of circHIPK3 silencing on vascular endothelial phenotypes in vivo and in vitro. CONCLUSIONS: The circular RNA circHIPK3 plays a role in diabetic retinopathy by blocking miR-30a function, leading to increased endothelial proliferation and vascular dysfunction. These data suggest that circular RNA is a potential target to control diabetic proliferative retinopathy. PMID- 28860124 TI - Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease. AB - Niemann-Pick type C (NPC) disease is an inherited, progressive neurodegenerative disorder principally caused by mutations in the NPC1 gene. NPC disease is characterized by the accumulation of unesterified cholesterol in the late endosomes (LE) and lysosomes (Ly) (LE/Ly). Vorinostat, a histone deacetylase inhibitor (HDACi), restores cholesterol homeostasis in fibroblasts derived from NPC patients; however, the exact mechanism by which Vorinostat restores cholesterol level is not known yet. In this study, we performed comparative proteomic profiling of the response of NPC1I1061T fibroblasts to Vorinostat. After stringent statistical criteria to filter identified proteins, we observed 202 proteins that are differentially expressed in Vorinostat-treated fibroblasts. These proteins are members of diverse cellular pathways including the endomembrane dependent protein folding-stability-degradation-trafficking axis, energy metabolism, and lipid metabolism. Our study shows that treatment of NPC1I1061T fibroblasts with Vorinostat not only enhances pathways promoting the folding, stabilization and trafficking of NPC1 (I1061T) mutant to the LE/Ly, but alters the expression of lysosomal proteins, specifically the lysosomal acid lipase (LIPA) involved in the LIPA->NPC2->NPC1 based flow of cholesterol from the LE/Ly lumen to the LE/Ly membrane. We posit that the Vorinostat may modulate numerous pathways that operate in an integrated fashion through epigenetic and post-translational modifications reflecting acetylation/deacetylation balance to help manage the defective NPC1 fold, the function of the LE/Ly system and/or additional cholesterol metabolism/distribution pathways, that could globally contribute to improved mitigation of NPC1 disease in the clinic based on as yet uncharacterized principles of cellular metabolism dictating cholesterol homeostasis. PMID- 28860126 TI - Incidence, Demographics, and Clinical Characteristics of Diabetes of the Exocrine Pancreas (Type 3c): A Retrospective Cohort Study. AB - OBJECTIVE: This study was conducted to describe the incidence of diabetes following pancreatic disease, assess how these patients are classified by clinicians, and compare clinical characteristics with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Primary care records in England (n = 2,360,631) were searched for incident cases of adult-onset diabetes between 1 January 2005 and 31 March 2016. We examined demographics, diabetes classification, glycemic control, and insulin use in those with and without pancreatic disease (subcategorized into acute pancreatitis or chronic pancreatic disease) before diabetes diagnosis. Regression analysis was used to control for baseline potential risk factors for poor glycemic control (HbA1c >=7% [53 mmol/mol]) and insulin requirement. RESULTS: We identified 31,789 new diagnoses of adult-onset diabetes. Diabetes following pancreatic disease (2.59 [95% CI 2.38-2.81] per 100,000 person-years) was more common than type 1 diabetes (1.64 [1.47-1.82]; P < 0.001). The 559 cases of diabetes following pancreatic disease were mostly classified by clinicians as type 2 diabetes (87.8%) and uncommonly as diabetes of the exocrine pancreas (2.7%). Diabetes following pancreatic disease was diagnosed at a median age of 59 years and BMI of 29.2 kg/m2. Diabetes following pancreatic disease was associated with poor glycemic control (adjusted odds ratio, 1.7 [1.3-2.2]; P < 0.001) compared with type 2 diabetes. Insulin use within 5 years was 4.1% (3.8-4.4) with type 2 diabetes, 20.9% (14.6-28.9) with diabetes following acute pancreatitis, and 45.8% (34.2-57.9) with diabetes following chronic pancreatic disease. CONCLUSIONS: Diabetes of the exocrine pancreas is frequently labeled type 2 diabetes but has worse glycemic control and a markedly greater requirement for insulin. PMID- 28860125 TI - Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials. AB - OBJECTIVE: We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) >=1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants. RESEARCH DESIGN AND METHODS: Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 <1.00 OGTTs with an incident Index60 >=1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND-) concomitant Index60 >=1.00. Incident Index60 >=1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS-) concomitant dysglycemia. RESULTS: The cumulative incidence for type 1 diabetes was greater after IND/DYS- than after DYS/IND- (P < 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND- (P < 0.001), whereas within the Index60 <1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS- did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS- than for DYS/IND- (P < 0.001). Hazard ratios (HRs) of DYS/IND- with age and 30- to 0-min C-peptide were positive (P < 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P < 0.001 for both). In contrast, HRs of IND/DYS- and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P < 0.01 for all]). CONCLUSIONS: The findings suggest that incident dysglycemia without Index60 >=1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 >=1.00, appear better suited as prediagnostic end points. PMID- 28860127 TI - Haptoglobin 1-1 Genotype Modulates the Association of Glycemic Control With Hippocampal Volume in Elderly Individuals With Type 2 Diabetes. AB - Recent evidence suggests that glycemic control is associated with cognitive function in older patients with type 2 diabetes who are carriers of the haptoglobin (Hp) 1-1 genotype compared with noncarriers. We assessed whether poor glycemic control in Hp 1-1 carriers is more strongly associated with smaller hippocampal volume than in noncarriers. Hippocampal volume was generated from high-resolution structural T1 MRI obtained for 224 participants (28 Hp 1-1 carriers [12.5%] and 196 noncarriers [87.5%]) from the Israel Diabetes and Cognitive Decline (IDCD) study, who had a mean (SD) number of years in the Maccabi Healthcare Services (MHS) registry of 8.35 (2.63) and a mean (SD) HbA1c level of 6.66 (0.73)% [49 mmol/mol]. A stronger negative association between right hippocampal volume and HbA1c was found in patients with the Hp 1-1 genotype, with a 0.032-mL decrease in right hippocampal volume per 14% increase in HbA1c (P = 0.0007) versus a 0.009-mL decrease in Hp 1-1 noncarriers (P = 0.047), after adjusting for total intracranial volume, age, sex, follow-up years in the registry, and cardiovascular factor (interaction, P = 0.025). This indicates that 29.66% of the total variance in right hippocampal volume is explained by HbA1c levels among Hp 1-1 carriers and that 3.22% is explained by HbA1c levels among Hp 1-1 noncarriers. Our results suggest that the hippocampus of Hp 1-1 carriers may be more vulnerable to the insults of poor glycemic control. PMID- 28860129 TI - World Bank's financing, priorities, and lending structures for global health. PMID- 28860128 TI - Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans. AB - Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 +/- 2.2 years, BMI 25.1 +/- 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 MUg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ~30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF's development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM. PMID- 28860130 TI - How does oestradiol influence the AVT/IT system in female round gobies during different reproductive phases? AB - In this in vitro gradient perfusion study, we determined whether there is a functional relationship between oestradiol and the arginine vasotocin/isotocin (AVT/IT) system in the female round goby (Neogobius melanostomus). Brain explants were perfused in medium supplemented with 17beta-oestradiol (E2) at doses mimicking the plasma levels of this hormone in nature during the spawning-capable phase and regressing phase. We aimed to establish which pathway, genomic or non genomic, is involved in this mechanism in different reproductive phases. For this purpose, brain explants were perfused in medium supplemented with Fulvestrant (ICI 182.780) or Actinomycin D (Act D) separately or in combination with E2 The contents of AVT and IT in the perfusion media were determined using high performance liquid chromatography (HPLC) with fluorescence and UV detection. During the spawning-capable phase, the effect of E2 on AVT release is mediated through oestrogen receptors (ERs) via both genomic and non-genomic pathways, while IT release is mediated through ERs via a genomic pathway only. In the regressing phase, release of both nonapeptides is mediated through ERs via a genomic pathway. This is the first study to present a feasible mechanism of oestradiol action on the AVT/IT system in female fish during different phases of the reproductive cycle. PMID- 28860132 TI - Parent-Child Interaction Therapy: A Meta-analysis. AB - CONTEXT: Parent-child interaction therapy (PCIT) is effective at reducing children's externalizing behavior. However, modifications are often made to PCIT, and it is not known whether these impact effectiveness. OBJECTIVE: To systematically review and meta-analyze the effects of PCIT on child externalizing behaviors, considering modifications, study design, and bias. DATA SOURCES: We searched PubMed, PsycINFO, Education Resources Information Center, Sociological Abstracts, and A+ Education. STUDY SELECTION: We selected randomized controlled or quasi-experimental trials. DATA EXTRACTION: We analyzed child externalizing and internalizing behaviors, parent stress, parent-child interactions, PCIT format, and study design and/or characteristics. RESULTS: We included 23 studies (1144 participants). PCIT was superior to control for reducing child externalizing (standardized mean difference [SMD]: -0.87, 95% confidence interval [CI]:-1.17 to -0.58). PCIT studies that required skill mastery had significantly greater reductions in externalizing behavior than those that did not (Mastery: SMD: -1.09, 95% CI: -1.44 to -0.73; Nonmastery: SMD: -0.51,95% CI: -0.85 to 0.17, P = .02). Compared with controls, PCIT significantly reduced parent-related stress (mean difference [MD]: -6.98, 95% CI: -11.69 to -2.27) and child-related stress (MD: -9.87, 95% CI: -13.64 to -6.09). Children in PCIT were observed to be more compliant to parent requests (SMD: 0.89, 95% CI: 0.50 to 1.28) compared with controls. PCIT effectiveness did not differ depending on session length, location (academic versus community settings), or child problems (disruptive behaviors only compared with disruptive behavior and other problems). LIMITATIONS: Results for parent-child observations were inconsistently reported, reducing the ability to pool important data. CONCLUSIONS: PCIT has robust positive outcomes across multiple parent-reported and observed parent-child interaction measures, and modifications may not be required even when implemented in diverse populations. PMID- 28860131 TI - CLASP1 regulates endothelial cell branching morphology and directed migration. AB - Endothelial cell (EC) branching is critically dependent upon the dynamic nature of the microtubule (MT) cytoskeleton. Extracellular matrix (ECM) mechanosensing is a prominent mechanism by which cytoskeletal reorganization is achieved; yet how ECM-induced signaling is able to target cytoskeletal reorganization intracellularly to facilitate productive EC branching morphogenesis is not known. Here, we tested the hypothesis that the composition and density of the ECM drive the regulation of MT growth dynamics in ECs by targeting the MT stabilizing protein, cytoplasmic linker associated protein 1 (CLASP1). High-resolution fluorescent microscopy coupled with computational image analysis reveal that CLASP1 promotes slow MT growth on glass ECMs and promotes short-lived MT growth on high-density collagen-I and fibronectin ECMs. Within EC branches, engagement of either high-density collagen-I or high-density fibronectin ECMs results in reduced MT growth speeds, while CLASP1-dependent effects on MT dynamics promotes elevated numbers of short, branched protrusions that guide persistent and directed EC migration. PMID- 28860134 TI - Nortitz GH, Murphy NA, NEUROMOTOR SCREENING EXPERT PANEL. Motor Delays: Early Identification and Evaluation. Pediatrics. 2013;131(6). Available at: www.pediatrics.org/cgi/content/full/131/6/e2016. PMID- 28860133 TI - Prescribing Antidepressants for Adolescents With Major Depression. PMID- 28860136 TI - Lewis, CW, Jacob LS, Lehmann CU, AAP SECTION ON ORAL HEALTH. The Primary Care Pediatrician and the Care of Children With Cleft Lip and/or Cleft Palate. Pediatrics. 2017;139(5):e20170628. PMID- 28860135 TI - Formula Feeding Exposure Not Homogenous. PMID- 28860137 TI - Author's Response. PMID- 28860138 TI - Universal health coverage, health systems strengthening, and the World Bank. PMID- 28860139 TI - Access to decision aids is important for evidence based medicine. PMID- 28860140 TI - Lens power in Iranian schoolchildren: a population-based study. AB - AIMS: To evaluate lens power (LP) in schoolchildren aged 6-12 years. METHODS: This cross-sectional study was conducted in Shahroud, northeast Iran. The students were selected through random cluster sampling and underwent the measurements of biometry, uncorrected and corrected visual acuity, non cycloplegic and cycloplegic refraction. The LP was calculated using the Bennett formula. RESULTS: Of 6624 invited children, 5620 (84.8%) participated in the study and data of 4870 children were finally analysed. The mean age of the participants was 9.7 years and 2277 participants (46.02%) were girls. The mean LPs were 22.86 dioptres (D) in total study population, 23.91 D in 6 and 22.10 D in 12-year-old children. The mean LP was higher in girls than boys (23.48 D vs 22.34 D), in rural children than urban children (23.17 D vs 22.83 D) and in children with hyperopia (23.25 D) than children with myopia or emmetropia (22.64 D and 22.86 D, respectively). In the multiple linear regression model, lens thickness (beta=1.59, p<0.001), anterior chamber depth (beta=2.21, p<0.001) and female sex (beta=0.016, p=0.015) were associated with an increase in the LP, while axial length (AL) (beta=-4.41, p<0.001), corneal power (CP) (beta=-1.47, p<0.001), spherical equivalent (SE) (beta=-1.50, p<0.001) and age (beta=-0.005, p=0.001) were associated with a decrease in the LP. AL and sex had the highest and lowest impact on LP, respectively. CONCLUSION: LP decreased with age between 6 and 12 years and was associated with a shorter AL, deeper ACD, higher SE, thicker lens and lower CP. PMID- 28860141 TI - World Bank and the Global Financing Facility. PMID- 28860142 TI - Novel therapeutic roles for surfactant-inositols and -phosphatidylglycerols in a neonatal piglet ARDS model: a translational study. AB - The biological and immune-protective properties of surfactant-derived phospholipids and phospholipid subfractions in the context of neonatal inflammatory lung disease are widely unknown. Using a porcine neonatal triple-hit acute respiratory distress syndrome (ARDS) model (repeated airway lavage, overventilation, and LPS instillation into airways), we assessed whether the supplementation of surfactant (S; poractant alfa) with inositol derivatives [inositol 1,2,6-trisphosphate (IP3) or phosphatidylinositol 3,5-bisphosphate (PIP2)] or phosphatidylglycerol subfractions [16:0/18:1-palmitoyloleoyl phosphatidylglycerol (POPG) or 18:1/18:1-dioleoyl-phosphatidylglycerol (DOPG)] would result in improved clinical parameters and sought to characterize changes in key inflammatory pathways behind these improvements. Within 72 h of mechanical ventilation, the oxygenation index (S+IP3, S+PIP2, and S+POPG), the ventilation efficiency index (S+IP3 and S+POPG), the compliance (S+IP3 and S+POPG) and resistance (S+POPG) of the respiratory system, and the extravascular lung water index (S+IP3 and S+POPG) significantly improved compared with S treatment alone. The inositol derivatives (mainly S+IP3) exerted their actions by suppressing acid sphingomyelinase activity and dependent ceramide production, linked with the suppression of the inflammasome nucleotide-binding domain, leucine-rich repeat containing protein-3 (NLRP3)-apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-caspase-1 complex, and the profibrotic response represented by the cytokines transforming growth factor-beta1 and IFN-gamma, matrix metalloproteinase (MMP)-1/8, and elastin. In addition, IkappaB kinase activity was significantly reduced. S+POPG and S+DOPG treatment inhibited polymorphonuclear leukocyte activity (MMP-8 and myeloperoxidase) and the production of interleukin-6, maintained alveolar-capillary barrier functions, and reduced alveolar epithelial cell apoptosis, all of which resulted in reduced pulmonary edema. S+DOPG also limited the profibrotic response. We conclude that highly concentrated inositol derivatives and phosphatidylglycerol subfractions in surfactant preparations mitigate key inflammatory pathways in inflammatory lung disease and that their clinical application may be of interest for future treatment of the acute exudative phase of neonatal ARDS. PMID- 28860143 TI - IL-8 mediates idiopathic pulmonary fibrosis mesenchymal progenitor cell fibrogenicity. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease, but the mechanisms driving progression remain incompletely defined. We previously reported that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs), which serve as a cell of origin for IPF fibroblasts. Proliferating IPF MPCs are located at the periphery of fibroblastic foci in an active cellular front at the interface between the myofibroblast-rich focus core and adjacent normal alveolar structures. Among a large set of genes that distinguish IPF MPCs from their control counterparts, we identified IL-8 as a candidate mediator of IPF MPC fibrogenicity and driver of fibrotic progression. IPF MPCs and their progeny displayed increased steady-state levels of IL-8 and its cognate receptor CXCR1 and secreted more IL-8 than did controls. IL-8 functioned in an autocrine manner promoting IPF MPC self-renewal and the proliferation and motility of IPF MPC progeny. Secreted IL-8 also functioned in a paracrine manner stimulating macrophage migration. Analysis of IPF lung tissue demonstrated codistribution of IPF MPCs with activated macrophages in the active cellular front of the fibroblastic focus. These findings indicate that IPF MPC-derived IL-8 is capable of expanding the mesenchymal cell population and recruiting activated macrophages cells to actively evolving fibrotic lesions. PMID- 28860144 TI - IPF lung fibroblasts have a senescent phenotype. AB - The mechanisms of aging that are involved in the development of idiopathic pulmonary fibrosis (IPF) are still unclear. Although it has been hypothesized that the proliferation and activation of human lung fibroblasts (hLFs) are essential in IPF, no studies have assessed how this process works in an aging lung. Our goal was to elucidate if there were age-related changes on primary hLFs isolated from IPF lungs compared with age-matched controls. We investigated several hallmarks of aging in hLFs from IPF patients and age-matched controls. IPF hLFs have increased cellular senescence with higher expression of beta galactosidase, p21, p16, p53, and cytokines related to the senescence-associated secretory phenotype (SASP) as well as decreased proliferation/apoptosis compared with age-matched controls. Additionally, we observed shorter telomeres, mitochondrial dysfunction, and upon transforming growth factor-beta stimulation, increased markers of endoplasmic reticulum stress. Our data suggest that IPF hLFs develop senescence resulting in a decreased apoptosis and that the development of SASP may be an important contributor to the fibrotic process observed in IPF. These results might change the existing paradigm, which describes fibroblasts as aberrantly activated cells, to a cell with a senescence phenotype. PMID- 28860145 TI - The respiratory tract microbial biogeography in alcohol use disorder. AB - Individuals with alcohol use disorders (AUDs) are at an increased risk of pneumonia and acute respiratory distress syndrome. Data of the lung microbiome in the setting of AUDs are lacking. The objective of this study was to determine the microbial biogeography of the upper and lower respiratory tract in individuals with AUDs compared with non-AUD subjects. Gargle, protected bronchial brush, and bronchoalveolar lavage specimens were collected during research bronchoscopies. Bacterial 16S gene sequencing and phylogenetic analysis was performed, and the alterations to the respiratory tract microbiota and changes in microbial biogeography were determined. The microbial structure of the upper and lower respiratory tract was significantly altered in subjects with AUDs compared with controls. Subjects with AUD have greater microbial diversity [ P < 0.0001, effect size = 16 +/- 1.7 observed taxa] and changes in microbial species relative abundances. Furthermore, microbial communities in the upper and lower respiratory tract displayed greater similarity in subjects with AUDs. Alcohol use is associated with an altered composition of the respiratory tract microbiota. Subjects with AUDs demonstrate convergence of the microbial phylogeny and taxonomic communities between distinct biogeographical sites within the respiratory tract. These results support a mechanistic pathway potentially explaining the increased incidence of pneumonia and lung diseases in patients with AUDs. PMID- 28860146 TI - IL-17 in the lung: the good, the bad, and the ugly. AB - The IL-17 family of cytokines has emerged over the last two decades as a pleiotropic group of molecules that function in a wide variety of both beneficial and detrimental (pathological) processes, mainly in mucosal barrier tissue. The beneficial effects of IL-17 expression are especially important in the lung, where exposure to foreign agents is abundant. IL-17A plays an important role in protection from both extracellular bacteria and fungi, as well as viruses that infect cells of the mucosal tracts. IL-17 coregulated cytokines, such as IL-22, are involved in maintaining epithelial cell homeostasis and participate in epithelial cell repair/regeneration following inflammatory insults. Thus, the IL 17/IL-22 axis is important in both responding to, and recovering from, pathogens. However, aberrant expression or overexpression of IL-17 cytokines contributes to a number of pathological outcomes, including asthma, pneumonitis, and generation or exacerbation of pulmonary fibrosis. This review covers the good, bad, and ugly aspects of IL-17 in the lung. PMID- 28860147 TI - Blockade of extracellular heat shock protein 90alpha by 1G6-D7 attenuates pulmonary fibrosis through inhibiting ERK signaling. AB - Pulmonary fibrosis is characterized by lung fibroblast activation and ECM deposition and has a poor prognosis. Heat shock protein 90 (Hsp90) participates in organ fibrosis, and extracellular Hsp90alpha (eHsp90alpha) promotes fibroblast activation and migration. This study aimed to investigate whether a selective anti-Hsp90alpha monoclonal antibody, 1G6-D7, could attenuate lung fibrosis and whether 1G6-D7 presents a protective effect by inactivating the profibrotic pathway. Our results showed that eHsp90alpha was increased in mice with BLM induced pulmonary fibrosis and that 1G6-D7 attenuated inflammation and collagen deposition in the lung. TGF-beta1 induced eHsp90alpha secretion, concomitantly promoting HFL-1 activation and ECM synthesis. 1G6-D7-mediated inhibition of eHsp90alpha significantly blocked these effects, meanwhile inhibiting downstream profibrotic pathways such as ERK, Akt, and P38. Human recombinant (hr)Hsp90alpha mimicked the effects of TGF-beta1, by activating profibrotic pathways and by upregulating LRP-1. Moreover, ERK inhibition effectively blocked the effect of (hr)Hsp90alpha. In conclusion, 1G6-D7 significantly protects against BLM-induced pulmonary fibrosis by ameliorating fibroblast activation and ECM production, which may be through blocking ERK signaling. Our results suggest a safer molecular therapy, 1G6-D7, in pulmonary fibrosis. PMID- 28860149 TI - Climate change, weather and road deaths. AB - In 2015, a 7% increase in road deaths per population in the USA reversed the 35 year downward trend. Here I test the hypothesis that weather influenced the change in trend. I used linear regression to estimate the effect of temperature and precipitation on miles driven per capita in urbanizedurbanised areas of the USA during 2010. I matched date and county of death with temperature on that date and number of people exposed to that temperature to calculate the risk per persons exposed to specific temperatures. I employed logistic regression analysis of temperature, precipitation and other risk factors prevalent in 2014 to project expected deaths in 2015 among the 100 most populous counties in the USA. Comparison of actual and projected deaths provided an estimate of deaths expected without the temperature increase. PMID- 28860148 TI - Targeting plasminogen activator inhibitor-1 in tetracycline-induced pleural injury in rabbits. AB - Elevated active plasminogen activator inhibitor-1 (PAI-1) has an adverse effect on the outcomes of intrapleural fibrinolytic therapy (IPFT) in tetracycline induced pleural injury in rabbits. To enhance IPFT with prourokinase (scuPA), two mechanistically distinct approaches to targeting PAI-1 were tested: slowing its reaction with urokinase (uPA) and monoclonal antibody (mAb)-mediated PAI-1 inactivation. Removing positively charged residues at the "PAI-1 docking site" (179RHRGGS184->179AAAAAA184) of uPA results in a 60-fold decrease in the rate of inhibition by PAI-1. Mutant prourokinase (0.0625-0.5 mg/kg; n = 12) showed efficacy comparable to wild-type scuPA and did not change IPFT outcomes ( P > 0.05). Notably, the rate of PAI-1-independent intrapleural inactivation of mutant uPA was 2 times higher ( P < 0.05) than that of the wild-type enzyme. Trapping PAI-1 in a "molecular sandwich"-type complex with catalytically inactive two chain urokinase with Ser195Ala substitution (S195A-tcuPA; 0.1 and 0.5 mg/kg) did not improve the efficacy of IPFT with scuPA (0.0625-0.5 mg/kg; n = 11). IPFT failed in the presence of MA-56A7C10 (0.5 mg/kg; n = 2), which forms a stable intrapleural molecular sandwich complex, allowing active PAI-1 to accumulate by blocking its transition to a latent form. In contrast, inactivation of PAI-1 by accelerating the active-to-latent transition mediated by mAb MA-33B8 (0.5 mg/kg; n = 2) improved the efficacy of IPFT with scuPA (0.25 mg/kg). Thus, under conditions of slow (4-8 h) fibrinolysis in tetracycline-induced pleural injury in rabbits, only the inactivation of PAI-1, but not a decrease in the rate of its reaction with uPA, enhances IPFT. Therefore the rate of fibrinolysis, which varies in different pathologic states, could affect the selection of PAI-1 inhibitors to enhance fibrinolytic therapy. PMID- 28860150 TI - Enduring enrolments in West Virginia's Medicaid programme due to severe injury. AB - OBJECTIVE: To assess frequency, duration and costs of Medicaid conversions that occur when severe injury causes patients to enrol in Medicaid to pay their hospital bills. Once enrolled, Medicaid pays all their medical bills, not simply their injury bill. DATA SOURCES: 2000-2005 West Virginia Medicaid claims data and 2000-2006 eligibility data for new enrollees under the age of 65. To model national costs, published Medicaid conversion rates across 14 states for 2003 and 2008 Healthcare Cost and Utilization Program Nationwide Inpatient Sample data. METHODS: We identified enrollees who had hospital inpatient claims for injury within 30 days of enrolment, then tabulated eligibility duration and payments by year and in aggregate. For those with open-ended eligibility, we assumed future annual claims payments would equal average payments in eligibility years 5-6. We multiplied the mean payments data adjusted to national prices with the estimated conversions nationally. RESULTS: Overall, 5.4% of hospitalised patients with injury in West Virginia converted to Medicaid, with 17% of conversions on Medicaid 7 years post injury. In 2010 dollars, Medicaid payments averaged $93 900 per conversion for non-injury medical care before the age of 65. Conversions added an estimated $87 in payments for non-injury care to governments' medical payments per medically treated injury in the USA. They added 14% to governments' gunshot and assault medical payments, 7.5% to its road crash medical payments and 6% to its total injury medical payments. CONCLUSIONS: These findings increase the rationale for governments to partner in injury prevention efforts. PMID- 28860153 TI - CQC's plans to revamp GP inspections will not reduce bureaucracy, says royal college. PMID- 28860151 TI - Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair. AB - Phagocytosis after myocardial infarction (MI) is a prerequisite to cardiac repair. Recruited monocytes clear necrotic cardiomyocytes and differentiate into cardiac macrophages. Some studies have linked apoptotic cell receptors on cardiac macrophages to tissue repair; however, the contribution of precursor monocyte phagocytic receptors, which are the first to interact with the cardiac parenchyma, is unclear. The scavenger receptor cluster of differentiation (CD)36 protein was detected on cardiac Ly6cHI monocytes, and bone marrow-derived Cd36 was essential for both early phagocytosis of dying cardiomyocytes and for smaller infarct sizes in female and male mice after permanent coronary ligation. Cd36 deficiency led to reduced expression of phagocytosis receptor Mertk and nuclear receptor Nr4a1 in cardiac macrophages, the latter previously shown to be required for phagocyte survival. Nr4a1 was required for phagocytosis-induced Mertk expression, and Nr4a1 protein directly bound to Mertk gene regulatory elements. To test the overall contribution of the Cd36-Mertk axis, MI was induced in Cd36-/ Mertk-/- double-knockout mice and led to increases in myocardial rupture. These data implicate monocyte CD36 in the mitigation of early infarct size and transition to Mertk-dependent macrophage function. Increased myocardial rupture in the absence of both Cd36 and Mertk underscore the physiologic significance of phagocytosis during tissue injury.-Dehn, S., Thorp, E. B. Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1 dependent mechanisms of cardiac repair. PMID- 28860152 TI - Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation induced osteoporosis. AB - Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by gammaH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. PMID- 28860154 TI - Etiolated Stem Branching Is a Result of Systemic Signaling Associated with Sucrose Level. AB - The potato (Solanum tuberosum) tuber is a swollen stem. Sprouts growing from the tuber nodes represent loss of apical dominance and branching. Long cold storage induces loss of tuber apical dominance and results in secondary branching. Here, we show that a similar branching pattern can be induced by short heat treatment of the tubers. Detached sprouts were induced to branch by the heat treatment only when attached to a parenchyma cylinder. Grafting experiments showed that the scion branches only when grafted onto heat- or cold-treated tuber parenchyma, suggesting that the branching signal is transmitted systemically from the bud base parenchyma to the grafted stem. Exogenous supply of sucrose (Suc), glucose, or fructose solution to detached sprouts induced branching in a dose-responsive manner, and an increase in Suc level was observed in tuber parenchyma upon branching induction, suggesting a role for elevated parenchyma sugars in the regulation of branching. However, sugar analysis of the apex and node after grafting showed no distinct differences in sugar levels between branching and nonbranching stems. Vacuolar invertase is a key enzyme in determining the level of Suc and its cleavage products, glucose and fructose, in potato parenchyma. Silencing of the vacuolar invertase-encoding gene led to increased tuber branching in combination with branching-inducing treatments. These results suggest that Suc in the parenchyma induces branching through signaling and not by excess mobilization from the parenchyma to the stem. PMID- 28860155 TI - Protoplast Swelling and Hypocotyl Growth Depend on Different Auxin Signaling Pathways. AB - Members of the TRANSPORT INHIBITOR RESPONSE1/AUXIN SIGNALING F-BOX PROTEIN (TIR1/AFB) family are known auxin receptors. To analyze the possible receptor function of AUXIN BINDING PROTEIN1 (ABP1), an auxin receptor currently under debate, we performed different approaches. We performed a pharmacological approach using alpha-(2,4-dimethylphenylethyl-2-oxo)-indole-3-acetic acid (auxinole), alpha-(phenylethyl-2-oxo)-indole-3-acetic acid (PEO-IAA), and 5 fluoroindole-3-acetic acid (5-F-IAA) to discriminate between ABP1- and TIR1/AFB mediated processes in Arabidopsis (Arabidopsis thaliana). We used a peptide of the carboxyl-terminal region of AtABP1 as a tool. We performed mutant analysis with the null alleles of ABP1, abp1-c1 and abp1-TD1, and the TILLING mutant abp1 5 We employed Coimbra, an accession that exhibits an amino acid exchange in the auxin-binding domain of ABP1. We measured either volume changes of single hypocotyl protoplasts or hypocotyl growth, both at high temporal resolution. 5-F IAA selectively activated the TIR1/AFB pathway but did not induce protoplast swelling; instead, it showed auxin activity in the hypocotyl growth test. In contrast, PEO-IAA induced an auxin-like swelling response but no hypocotyl growth. The carboxyl-terminal peptide of AtABP1 induced an auxin-like swelling response. In the ABP1-related mutants and Coimbra, no auxin-induced protoplast swelling occurred. ABP1 seems to be involved in mediating rapid auxin-induced protoplast swelling, but it is not involved in the control of rapid auxin-induced growth. PMID- 28860156 TI - Seasonal Regulation of Petal Number. AB - Four petals characterize the flowers of most species in the Brassicaceae family, and this phenotype is generally robust to genetic and environmental variation. A variable petal number distinguishes the flowers of Cardamine hirsuta from those of its close relative Arabidopsis (Arabidopsis thaliana), and allelic variation at many loci contribute to this trait. However, it is less clear whether C. hirsuta petal number varies in response to seasonal changes in environment. To address this question, we assessed whether petal number responds to a suite of environmental and endogenous cues that regulate flowering time in C. hirsuta We found that petal number showed seasonal variation in C. hirsuta, such that spring flowering plants developed more petals than those flowering in summer. Conditions associated with spring flowering, including cool ambient temperature, short photoperiod, and vernalization, all increased petal number in C. hirsuta Cool temperature caused the strongest increase in petal number and lengthened the time interval over which floral meristems matured. We performed live imaging of early flower development and showed that floral buds developed more slowly at 15 degrees C versus 20 degrees C. This extended phase of floral meristem formation, coupled with slower growth of sepals at 15 degrees C, produced larger intersepal regions with more space available for petal initiation. In summary, the growth and maturation of floral buds is associated with variable petal number in C. hirsuta and responds to seasonal changes in ambient temperature. PMID- 28860157 TI - How transcription circuits explore alternative architectures while maintaining overall circuit output. AB - Transcription regulators bind to cis-regulatory sequences and thereby control the expression of target genes. While transcription regulators and the target genes that they regulate are often deeply conserved across species, the connections between the two change extensively over evolutionary timescales. In this review, we discuss case studies where, despite this extensive evolutionary rewiring, the resulting patterns of gene expression are preserved. We also discuss in silico models that reach the same general conclusions and provide additional insights into how this process occurs. Together, these approaches make a strong case that the preservation of gene expression patterns in the wake of extensive rewiring is a general feature of transcription circuit evolution. PMID- 28860158 TI - Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock. AB - Collinear regulation of Hox genes in space and time has been an outstanding question ever since the initial work of Ed Lewis in 1978. Here we discuss recent advances in our understanding of this phenomenon in relation to novel concepts associated with large-scale regulation and chromatin structure during the development of both axial and limb patterns. We further discuss how this sequential transcriptional activation marks embryonic stem cell-like axial progenitors in mammals and, consequently, how a temporal genetic system is further translated into spatial coordinates via the fate of these progenitors. In this context, we argue the benefit and necessity of implementing this unique mechanism as well as the difficulty in evolving an alternative strategy to deliver this critical positional information. PMID- 28860161 TI - Erratum. PMID- 28860160 TI - Abro1 maintains genome stability and limits replication stress by protecting replication fork stability. AB - Protection of the stalled replication fork is crucial for responding to replication stress and minimizing its impact on chromosome instability, thus preventing diseases, including cancer. We found a new component, Abro1, in the protection of stalled replication fork integrity. Abro1 deficiency results in increased chromosome instability, and Abro1-null mice are tumor-prone. We show that Abro1 protects stalled replication fork stability by inhibiting DNA2 nuclease/WRN helicase-mediated degradation of stalled forks. Depletion of RAD51 prevents the DNA2/WRN-dependent degradation of stalled forks in Abro1-deficient cells. This mechanism is distinct from the BRCA2-dependent fork protection pathway, in which stable RAD51 filament formation prevents MRE11-dependent degradation of the newly synthesized DNA at stalled forks. Thus, our data reveal a new aspect of regulated protection of stalled replication forks that involves Abro1. PMID- 28860164 TI - The endothelium in hypoxic pulmonary vasoconstriction. AB - Hypoxic pulmonary vasoconstriction (HPV) in combination with hypercapnic pulmonary vasoconstriction redistributes pulmonary blood flow from poorly aerated to better ventilated lung regions by an active process of local vasoconstriction. Impairment of HPV results in ventilation-perfusion mismatch and is commonly associated with various lung diseases including pneumonia, sepsis, or cystic fibrosis. Although several regulatory pathways have been identified, considerable knowledge gaps persist, and a unifying concept of the signaling pathways that underlie HPV and their impairment in lung diseases has not yet emerged. In the past, conceptual models of HPV have focused on pulmonary arterial smooth muscle cells (PASMC) acting as sensor and effector of hypoxia in the pulmonary vasculature. In contrast, the endothelium was considered a modulating bystander in this scenario. For an ideal design, however, the oxygen sensor in HPV should be located in the region of gas exchange, i.e., in the alveolar capillary network. This concept requires the retrograde propagation of the hypoxic signal along the endothelial layer of the vascular wall and subsequent contraction of PASMC in upstream arterioles that is elicited via temporospatially tightly controlled endothelial-smooth muscle cell crosstalk. The present review summarizes recent work that provides proof-of-principle for the existence and functional relevance of such signaling pathway in HPV that involves important roles for connexin 40, epoxyeicosatrienoic acids, sphingolipids, and cystic fibrosis transmembrane conductance regulator. Of translational relevance, implication of these molecules provides for novel mechanistic explanations for impaired ventilation/perfusion matching in patients with pneumonia, sepsis, cystic fibrosis, and presumably various other lung diseases. PMID- 28860165 TI - Influence of nutrient ingestion on amino acid transporters and protein synthesis in human skeletal muscle after sprint exercise. AB - Nutrient ingestion is known to increase the exercise-induced stimulation of muscle protein synthesis following resistance exercise. Less is known about the effect of nutrients on muscle protein synthesis following sprint exercise. At two occasions separated by 1 mo, 12 healthy subjects performed three 30-s sprints with 20-min rest between bouts. In randomized order, they consumed a drink with essential amino acids and maltodextrin (nutrient) or flavored water (placebo). Muscle biopsies were obtained 80 and 200 min after the last sprint, and blood samples were taken repeatedly during the experiment. Fractional synthetic rate (FSR) was measured by continuous infusion of l-[2H5]phenylalanine up to 200 min postexercise. The mRNA expression and protein expression of SNAT2 were both 1.4 fold higher ( P < 0.05) after nutrient intake compared with placebo at 200 min postexercise. Phosphorylated Akt, mammalian target of rapamycin (mTOR), and p70S6k were 1.7- to 3.6-fold higher ( P < 0.01) 80 min after the last sprint with nutrient ingestion as compared with placebo. In addition, FSR was higher ( P < 0.05) with nutrients when plasma phenylalanine (FSRplasma) was used as a precursor but not when intracellular phenylalanine (FSRmuscle) was used. Significant correlations were also found between FSRplasma on the one hand and plasma leucine and serum insulin on the other hand in the nutrient condition. The results show that nutrient ingestion induces the expression of the amino acid transporter SNAT2 stimulates Akt/mTOR signaling and most likely the rate of muscle protein synthesis following sprint exercise. NEW & NOTEWORTHY There is limited knowledge regarding the effect of nutrients on muscle protein synthesis following sprint as compared with resistance exercise. The results demonstrate that nutrient ingestion during repeated 30-s bouts of sprint exercise induces expression of the amino acid transporter SNAT2 and stimulates Akt/mTOR signaling and most likely the rate of muscle protein synthesis. Future studies to explore the chronic effects of nutritional ingestion during sprint exercise sessions on muscle mass accretion are warranted. PMID- 28860159 TI - Physiological/pathological ramifications of transcription factors in the unfolded protein response. AB - Numerous environmental, physiological, and pathological insults disrupt protein folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications. PMID- 28860163 TI - Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD. AB - Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid beta-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP activated protein kinase signaling pathway. PMID- 28860166 TI - Effects of anti-inflammatory (NSAID) treatment on human tendinopathic tissue. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat tendinopathy, but evidence for this treatment is lacking, and little is known regarding effects of NSAIDs on human tendinopathic tendon. This study investigated the effects of NSAID treatment (ibuprofen) on human tendinopathic tendon, with changes in gene expression as the primary outcome, and tendon pain, function, and blood flow as secondary outcomes. Twenty-six adults (16 men, 10 women), diagnosed with chronic Achilles tendinopathy, were randomized to 1-wk treatment with ibuprofen (600 mg *3/day) (n = 13) or placebo (n = 13) (double blinded). Ibuprofen content in blood, visual analog scale score for tendon pain at rest and activity, Victorian Institute of Sports Assessment-Achilles (VISA-A) scores for tendon function, tendon thickness (with ultrasonography), and color Doppler were measured before and 1 h after treatment. After the last posttreatment test, a full-width tendon biopsy was taken from the affected area. Real-time-RT-PCR was used to assess expression of collagen I, collagen III, transforming growth factor (TGF-beta) isoforms, cyclooxygenase-2 (COX-2), angiopoietin-like 4 (ANGPTL4), and cyclic AMP-dependent transcription factor (ATF3) in tendon tissue. Expression of collagens and TGF-beta isoforms showed relatively low variation and was unaffected by ibuprofen treatment. Further, no changes were seen in tendon thickness or VISA-A score. The placebo treatment reduced the color Doppler (in tendon plus surrounding tissue) compared with the ibuprofen group and also increased the perception of pain at rest. In conclusion, there was no indication that short-term ibuprofen treatment affects gene expression in human chronic tendinopathic tendon or leads to any clear changes in tendon pain or function.NEW & NOTEWORTHY Nonsteroidal anti-inflammatory drugs are widely used in the treatment of tendinopathy, but little is known of the effects of these drugs on tendon tissue. We find that 1 wk of ibuprofen treatment has no effect on gene expression of collagen and related growth factors in adult human tendinopathic tendon in vivo (in spite of relatively low levels of variation in gene expression), suggesting that tendinopathic cells are not responsive to ibuprofen. PMID- 28860168 TI - Glucose transport across lagomorph jejunum epithelium is modulated by AMP activated protein kinase under hypoxia. AB - The gastrointestinal epithelium possesses adaptation mechanisms to cope with huge variations in blood flow and subsequently oxygenation. Since sufficient energy supply is crucial under hypoxic conditions, glucose uptake especially must be regulated by these adaptation mechanisms. Therefore, we investigated glucose transport under hypoxic conditions. Jejunal epithelia of rabbits were incubated in Ussing chambers under short-circuit current conditions. Hypoxia was simulated by gassing with 1% O2 instead of 100% O2. The activity of sodium-coupled glucose transporter-1 (SGLT-1) was assessed by measuring the increase of short circuit current ( Isc) after the addition of 2 mM glucose to the mucosal buffer solution. We observed decreased activity of SGLT-1 after hypoxia compared with control conditions. To investigate underlying mechanisms, epithelia were exposed to agonists and antagonists of AMP-activated protein kinase (AMPK) before assessment of SGLT-1-mediated transport and the pAMPK/AMPK protein ratio. Preincubation with the antagonist restored SGLT-1 activity under hypoxic conditions to the level of control conditions, indicating an involvement of AMPK in the downregulation of SGLT-1 activity under hypoxia, which was confirmed in Western blot analysis of pAMPK/AMPK. Transepithelial flux studies using radioactively labeled glucose, ortho-methyl-glucose, fructose, and mannitol revealed no changes after hypoxic incubation. Therefore, we could exclude a decreased transepithelial glucose transport rate and increased paracellular conductance under hypoxia. In conclusion, our study hints at a decreased activity of SGLT-1 under hypoxic conditions in an AMPK-dependent manner. However, transepithelial transport of glucose is maintained. Therefore, we suggest other transport mechanisms, especially glucose transporter 1 and/or 2 to substitute SGLT-1 under hypoxia. NEW & NOTEWORTHY To our knowledge, this is the first approach to simulate hypoxia and study its effects in the jejunal epithelium using the Ussing chamber technique. We were able show that AMPK plays a role in the downregulation of SGLT-1 and that there seems to be an upregulation of other glucose transport mechanisms in the apical membrane of lagomorph jejunum epithelium under hypoxia, securing the epithelial energy supply and thus integrity. PMID- 28860169 TI - Creatine ( methyl-d3) dilution in urine for estimation of total body skeletal muscle mass: accuracy and variability vs. MRI and DXA. AB - A noninvasive method to estimate muscle mass based on creatine ( methyl-d3) (D3 creatine) dilution using fasting morning urine was evaluated for accuracy and variability over a 3- to 4-mo period. Healthy older (67- to 80-yr-old) subjects ( n = 14) with muscle wasting secondary to aging and four patients with chronic disease (58-76 yr old) fasted overnight and then received an oral 30-mg dose of D3-creatine at 8 AM ( day 1). Urine was collected during 4 h of continued fasting and then at consecutive 4- to 8-h intervals through day 5. Assessment was repeated 3-4 mo later in 13 healthy subjects and 1 patient with congestive heart failure. Deuterated and unlabeled creatine and creatinine were measured using liquid chromatography-tandem mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by whole body MRI and 24-h urine creatinine, and lean body mass (LBM) was measured by dual-energy X-ray absorptiometry (DXA). D3-creatinine urinary enrichment from day 5 provided muscle mass estimates that correlated with MRI for all subjects ( r = 0.88, P < 0.0001), with less bias [difference from MRI = -3.00 +/- 2.75 (SD) kg] than total LBM assessment by DXA, which overestimated muscle mass vs. MRI (+22.5 +/- 3.7 kg). However, intraindividual variability was high with the D3-creatine dilution method, with intrasubject SD for estimated muscle mass of 2.5 kg vs. MRI (0.5 kg) and DXA (0.8 kg). This study supports further clinical validation of the D3-creatine method for estimating muscle mass. NEW & NOTEWORTHY Measurement of creatine ( methyl-d3) (D3-creatine) and D3 creatinine excretion in fasted morning urine samples may be a simple, less costly alternative to MRI or dual-energy X-ray absorptiometry (DXA) to calculate total body muscle mass. The D3-creatine enrichment method provides estimates of muscle mass that correlate well with MRI, and with less bias than DXA. However, intraindividual variability is high with the D3-creatine method. Studies to refine the spot urine sample method for estimation of muscle mass may be warranted. PMID- 28860167 TI - Measuring high-altitude adaptation. AB - High altitudes (>8,000 ft or 2,500 m) provide an experiment of nature for measuring adaptation and the physiological processes involved. Studies conducted over the past ~25 years in Andeans, Tibetans, and, less often, Ethiopians show varied but distinct O2 transport traits from those of acclimatized newcomers, providing indirect evidence for genetic adaptation to high altitude. Short-term (acclimatization, developmental) and long-term (genetic) responses to high altitude exhibit a temporal gradient such that, although all influence O2 content, the latter also improve O2 delivery and metabolism. Much has been learned concerning the underlying physiological processes, but additional studies are needed on the regulation of blood flow and O2 utilization. Direct evidence of genetic adaptation comes from single-nucleotide polymorphism (SNP)-based genome scans and whole genome sequencing studies that have identified gene regions acted upon by natural selection. Efforts have begun to understand the connections between the two with Andean studies on the genetic factors raising uterine blood flow, fetal growth, and susceptibility to Chronic Mountain Sickness and Tibetan studies on genes serving to lower hemoglobin and pulmonary arterial pressure. Critical for future studies will be the selection of phenotypes with demonstrable effects on reproductive success, the calculation of actual fitness costs, and greater inclusion of women among the subjects being studied. The well characterized nature of the O2 transport system, the presence of multiple long resident populations, and relevance for understanding hypoxic disorders in all persons underscore the importance of understanding how evolutionary adaptation to high altitude has occurred.NEW & NOTEWORTHY Variation in O2 transport characteristics among Andean, Tibetan, and, when available, Ethiopian high altitude residents supports the existence of genetic adaptations that improve the distribution of blood flow to vital organs and the efficiency of O2 utilization. Genome scans and whole genome sequencing studies implicate a broad range of gene regions. Future studies are needed using phenotypes of clear relevance for reproductive success for determining the mechanisms by which naturally selected genes are acting. PMID- 28860171 TI - Additive effects of heating and exercise on baroreflex control of heart rate in healthy males. AB - This study assessed the additive effects of passive heating and exercise on cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV). Twelve healthy young men (25 +/- 1 yr, 23.8 +/- 0.5 kg/m2) randomly underwent two experimental sessions: heat stress (HS; whole body heat stress using a tube-lined suit to increase core temperature by ~1 degrees C) and normothermia (NT). Each session was composed of a preintervention rest (REST1); HS or NT interventions; postintervention rest (REST2); and 14 min of cycling exercise [7 min at 40%HRreserve (EX1) and 7 min at 60%HRreserve (EX2)]. Heart rate and finger blood pressure were continuously recorded. cBRS was assessed using the sequence (cBRSSEQ) and transfer function (cBRSTF) methods. HRV was assessed using the indexes standard deviation of RR intervals (SDNN) and root mean square of successive RR intervals (RMSSD). cBRS and HRV were not different between sessions during EX1 and EX2 (i.e., matched heart rate conditions: EX1 = 116 +/- 3 vs. 114 +/- 3 and EX2 = 143 +/- 4 vs. 142 +/- 3 beats/min but different workloads: EX1 = 50 +/- 9 vs. 114 +/- 8 and EX2 = 106 +/- 10 vs. 165 +/- 8 W; for HS and NT, respectively; P < 0.01). However, when comparing EX1 of NT with EX2 of HS (i.e., matched workload conditions but with different heart rates), cBRS and HRV were significantly reduced in HS (cBRSSEQ = 1.6 +/- 0.3 vs. 0.6 +/- 0.1 ms/mmHg, P < 0.01; SDNN = 2.3 +/- 0.1 vs. 1.3 +/- 0.2 ms, P < 0.01). In conclusion, in conditions matched by HR, the addition of heat stress to exercise does not affect cBRS and HRV. Alternatively, in workload-matched conditions, the addition of heat to exercise results in reduced cBRS and HRV compared with exercise in normothermia. NEW & NOTEWORTHY The present study assessed cardiac baroreflex sensitivity during the combination of heat and exercise stresses. This is the first study to show that prior whole body passive heating reduces cardiac baroreflex sensitivity and autonomic modulation of heart rate during exercise. These findings contribute to the better understanding of the role of thermoregulation on cardiovascular regulation during exercise. PMID- 28860170 TI - Effects of vehicle microdialysis solutions on cutaneous vascular responses to local heating. AB - Microdialysis is a minimally invasive technique often paired with laser Doppler flowmetry to examine cutaneous microvascular function, yet presents with several challenges, including incompatibility with perfusion of highly lipophilic compounds. The present study addresses this methodological concern, with an emphasis on the independent effects of commonly used vehicle dialysis solutions to improve solubility of pharmacological agents with otherwise low aqueous solubility. Four microdialysis fibers were placed in the ventral forearm of eight subjects (4 men, 4 women; 25 +/- 1 yr) with sites randomized to serve as 1) control (lactated Ringer's), 2) Sodium carbonate-bicarbonate buffer administered at physiological pH [SCB-HCl; pH 7.4, achieved via addition of hydrochloric acid (HCl)], 3) 0.02% ethanol, and 4) 2% dimethyl sulfoxide (DMSO). After baseline (34 degrees C), vehicle solutions were administered throughout a standardized local heating protocol to 42 degrees C. Laser Doppler flowmetry provided an index of blood flow. Cutaneous vascular conductance was calculated and normalized to maximum (%CVCmax, sodium nitroprusside and 43 degrees C local heat). The SCB-HCl solution increased baseline %CVCmax (control: 9.7 +/- 0.8; SCB-HCl: 21.5 +/- 3.5%CVCmax; P = 0.03), but no effects were observed during heating or maximal vasodilation. There were no differences with perfusion of ethanol or DMSO at any stage of the protocol ( P > 0.05). These data demonstrate the potential confounding effects of some vehicle dialysis solutions on cutaneous vascular function. Notably, this study provides evidence that 2% DMSO and 0.02% ethanol are acceptable vehicles with no confounding local vascular effects to a standardized local heating protocol at the concentrations presented. NEW & NOTEWORTHY This study examined the independent effects of common vehicle solutions on cutaneous vascular responses. A basic buffer (SCB-HCl) caused baseline vasodilation; 2% DMSO and 0.02% ethanol had no effects. This highlights the need for considering potential confounding effects of solubilizing solutions when combined with low aqueous soluble pharmacological agents. Importantly, DMSO and ethanol do not appear to influence cutaneous vascular function during baseline or local heating at the concentrations studied, allowing their use without confounding effects. PMID- 28860172 TI - The effect of inert gas choice on multiple breath washout in healthy infants: differences in lung function outcomes and breathing pattern. AB - The detrimental effects on breathing pattern during multiple breath inert gas washout (MBW) have been described with different inhaled gases [100% oxygen (O2) and sulfur hexafluoride (SF6)] but detailed comparisons are lacking. N2- and SF6 based tests were performed during spontaneous quiet sleep in 10 healthy infants aged 0.7-1.3 yr using identical hardware. Differences in breathing pattern pre and post 100% O2 and 4% SF6 exposure were investigated, and the results obtained were compared [functional residual capacity (FRC) and lung clearance index (LCI)]. During 100% O2 exposure. mean inspiratory flow ("respiratory drive") decreased transiently by mean (SD) 28 (9)% ( P < 0.001), and end-tidal CO2 (carbon dioxide) increased by mean (SD) 0.3 (0.4)% units ( P < 0.05) vs. air breathing prephase. During subsequent N2 washin (i.e., recovery phase), the pattern of change reversed. No significant effect on breathing pattern was observed during SF6 testing. In vitro testing confirmed that technical artifacts did not explain these changes. Mean (SD) FRC and LCI in vivo were significantly higher with N2 vs. SF6 washout: 216 (33) vs. 186 (22) ml ( P < 0.001) and 8.25 (0.85) vs. 7.55 (0.57) turnovers ( P = 0.021). Based on these results, SF6 based MBW is the preferred methodology for tests in this age range. NEW & NOTEWORTHY Inert gas choice for multiple breath inert gas washout (MBW) in infants has important consequences on both breathing pattern during test performance and the functional residual capacity and lung clearance index values obtained. Data suggest the detrimental effect of breathing pattern of 100% O2 and movement of O2 across the alveolar capillary membrane, with direct effects on MBW outcomes. SF6 MBW during infancy avoids this and can be further optimized by addressing the sources of technical artifact identified in this work. PMID- 28860173 TI - Single passive leg movement assessment of vascular function: contribution of nitric oxide. AB - Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol 123: 1468-1476, 2017. First published August 31, 2017; doi:10.1152/japplphysiol.00533.2017.-The assessment of passive leg movement (PLM) induced leg blood flow (LBF) and vascular conductance (LVC) is a novel approach to assess vascular function that has recently been simplified to only a single PLM (sPLM), thereby increasing the clinical utility of this technique. As the physiological mechanisms mediating the robust increase in LBF and LVC with sPLM are unknown, we tested the hypothesis that nitric oxide (NO) is a major contributor to the sPLM-induced LBF and LVC response. In nine healthy men, sPLM was performed with and without NO synthase inhibition by intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA). Doppler ultrasound and femoral arterial pressure were used to determine LBF and LVC, which were characterized by the peak change (DeltaLBFpeak and DeltaLVCpeak) and area under the curve (LBFAUC and LVCAUC). l-NMMA significantly attenuated DeltaLBFpeak [492 +/- 153 (l-NMMA) vs. 719 +/- 238 (control) ml/min], LBFAUC [57 +/- 34 (l NMMA) vs. 147 +/- 63 (control) ml], DeltaLVCpeak [4.7 +/- 1.1 (l-NMMA) vs. 8.0 +/- 3.0 (control) ml.min-1.mmHg-1], and LVCAUC [0.5 +/- 0.3 (l-NMMA) vs. 1.6 +/- 0.9 (control) ml/mmHg]. The magnitude of the NO contribution to LBF and LVC was significantly correlated with the magnitude of the control responses ( r = 0.94 for DeltaLBFpeak, r = 0.85 for LBFAUC, r = 0.94 for DeltaLVCpeak, and r = 0.95 for LVCAUC). These data establish that the sPLM-induced hyperemic and vasodilatory response is predominantly (~65%) NO-mediated. As such, sPLM appears to be a promising, simple, in vivo assessment of NO-mediated vascular function and NO bioavailability. NEW & NOTEWORTHY Passive leg movement (PLM), a novel assessment of vascular function, has been simplified to a single PLM (sPLM), thereby increasing the clinical utility of this technique. However, the role of nitric oxide (NO) in mediating the robust sPLM hemodynamic responses is unknown. This study revealed that sPLM induces a hyperemic and vasodilatory response that is predominantly NO-mediated and, as such, appears to be a promising simple, in vivo, clinical assessment of NO-mediated vascular function and, therefore, NO bioavailability. PMID- 28860174 TI - UBC-Nepal Expedition: acute alterations in sympathetic nervous activity do not influence brachial artery endothelial function at sea level and high altitude. AB - Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g., shear stress) associated with increased SNA as a consequence of exposure to HA. We hypothesized that 1) at rest, SNA would be elevated and FMD would be reduced at HA compared with sea-level (SL); and 2) at SL and HA, FMD would be reduced when SNA was acutely increased, and elevated when SNA was acutely decreased. Using a novel, randomized experimental design, brachial artery FMD was assessed at SL (344 m) and HA (5,050 m) in 14 participants during mild lower-body negative pressure (LBNP; -10 mmHg) and lower body positive pressure (LBPP; +10 mmHg). Blood pressure (finger photoplethysmography), heart rate (electrocardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (Duplex ultrasound) were recorded during LBNP, control, and LBPP trials. Muscle SNA was recorded (via microneurography) in a subset of participants (n = 5). Our findings were 1) at rest, SNA was elevated (P < 0.01), and absolute FMD was reduced (P = 0.024), but relative FMD remained unaltered (P = 0.061), at HA compared with SL; and 2) despite significantly altering SNA with LBNP (+60.3 +/- 25.5%) and LBPP (-37.2 +/ 12.7%) (P < 0.01), FMD was unaltered at SL (P = 0.448) and HA (P = 0.537). These data indicate that acute and mild changes in SNA do not directly influence brachial artery FMD at SL or HA.NEW & NOTEWORTHY The role of the sympathetic nervous system on endothelial function remains unclear. We used lower-body negative and positive pressure to manipulate sympathetic nervous activity at sea level and high altitude and measured brachial endothelial function via flow mediated dilation. We found that acutely altering sympathetic nervous activity had no effect on endothelial function. PMID- 28860175 TI - Skeletal muscle contractile properties in a novel murine model for limb girdle muscular dystrophy 2i. AB - Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin related protein and aberrant alpha-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. Therefore, we quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle of a novel model of LGMD2i. Normalized maximal twitch force, tetanic force, and power were significantly smaller in P448L mice, compared with sex-matched, wild-type mice. These differences were consistent with the replacement of contractile fibers by passive tissue. The shape of the active force-length relationships were similar in both groups, regardless of sex, consistent with an intact sarcomeric structure in P448L mice. Passive force length curves normalized to maximal isometric force were steeper in P448L mice, and passive elements contribute disproportionately more to total contractile force in P448L mice. Sex differences were mostly noted in the force-velocity curves, as normalized values for maximal and optimal velocities were significantly slower in P448L males, compared with wild-type, but not in P448L females. This suggests that the dystrophic phenotype, which may include possible changes in cross-bridge kinetics and fiber-type proportions, progresses more quickly in P448L males. These results together indicate that active force and power generation are compromised in both sexes of P448L mice, while passive forces increase. More importantly, the results identified several functional markers of disease pathophysiology that could aid in developing and assessment of novel therapeutics for LGMD2i and possibly other dystroglycanopathies as well. NEW & NOTEWORTHY Comprehensive assessments of muscle contractile function have, until now, never been performed in an animal model for any dystroglycanopathy. This study suggests that skeletal muscle contractile properties are significantly compromised in a recently developed model for limb-girdle muscular dystrophy 2i, the P448L mouse. It further identifies novel pathological markers of muscle function that are suitable for developing therapeutics and for better understanding of disease pathogenesis. PMID- 28860177 TI - Effect of zileuton on osteoporotic bone and its healing, expression of bone, and brain genes in rats. AB - Estrogen deficiency and aging are associated with osteoporosis, impaired bone healing, and lower cognitive performance. Close functional and physical connections occur between bone and the central nervous system. An anti inflammatory drug, zileuton (which is an inhibitor of arachidonate 5 lipoxygenase), is known to have a positive effect on bone tissue repair and brain ischemia. We studied the effect of zileuton on osteopenic bone and its healing and on the genes considered to be crucial for the cross talks between bone and brain. Three-month-old Sprague-Dawley rats were ovariectomized or left untreated. After 8 wk, bilateral metaphyseal tibia osteotomy with plate osteosynthesis was performed in all rats. Ovariectomized rats were fed with food containing zileuton (1, 10, or 100 mg/kg body wt) for 5 wk. In tibiae, bone volume, callus and cortical volume, and gene expression of osteocalcin and alkaline phosphatase were enhanced by zileuton (10 or 100 mg); biomechanical properties and bone density were not changed. In femur, zileuton enlarged cortical volume distal and trabecular volume proximal, decreasing their density. The expression level of brain Sema3a, known to regulate bone mass positively, was downregulated after ovariectomy. In contrast, bone Sema4d, a negative regulator of bone mass, was upregulated in the tibia callus after ovariectomy, whereas zileuton treatment (10 or 100 mg) resulted in reverse effects. Here, we describe for the first time the expression of Rbbp4 mRNA and its increase in tibia after ovariectomy. Zileuton caused downregulation of Rbbp4 in the hippocampus and had an effect on bone healing, changed the expression of genes involved in cross talk between bones and brain, and may be a potent drug for further examination in estrogen deficiency related dysfunction(s). NEW & NOTEWORTHY Zileuton, a 5-lipoxygenase inhibitor, increased bone volume, callus and cortical volume in osteotomized tibia, and trabecular and cortical volume in femur. Although the expression of Sema3a (positively regulating bone mass) in brain was downregulated and Sema4d (negatively regulating bone mass) was upregulated in tibia callus after ovariectomy, zileuton could counteract these effects. Rbbp4 (involved in age related memory loss) was increased in tibia callus after ovariectomy. PMID- 28860178 TI - Can more appropriate support and services be provided for people who attend the emergency department frequently? National Health Service staff views. AB - BACKGROUND: Interventions designed to help Emergency Department (ED) staff manage frequent attenders are labour-intensive and only benefit a small sample of frequent attenders. We aimed to use the in-depth knowledge of health professionals with experience of working with ED frequent attenders to understand the challenges of managing this group of patients and their opinions on providing more appropriate support. METHODS: Semi-structured interviews were conducted with medical and nursing ED staff, mental health liaison nurses and general practitioners (GPs). Interviews covered the following: definitions and experiences of treating frequent attenders and thoughts on alternative service provision. Vignettes of frequent attenders were used to elicit discussions on these topics. Thematic analysis of transcribed interviews was undertaken. RESULTS: Twelve health professionals were interviewed. Three groups of frequent attenders were identified: people with long-term physical conditions, mental health problems and health-related anxiety. Underlying reasons for attendance differed between the groups, highlighting the need for targeted interventions. Suggested interventions included improving self-management of long-term physical conditions; creating a 'go-to' place away from the ED for patients experiencing a mental health crisis; increasing the provision of mental health liaison services; and for patients with health-related anxiety, the role of the GP in the patients' care pathway was emphasised, as were the benefits of providing additional training for ED staff to help identify and support this group. CONCLUSION: Interventions to address frequent attendance should focus on redirection to and liaison with more appropriate services, located on the hospital site or in the community, tailored to each identified patient group. PMID- 28860176 TI - Shifting gears: dynamic muscle shape changes and force-velocity behavior in the medial gastrocnemius. AB - When muscles contract, they bulge in thickness or in width to maintain a (nearly) constant volume. These dynamic shape changes are tightly linked to the internal constraints placed on individual muscle fibers and play a key functional role in modulating the mechanical performance of skeletal muscle by increasing its range of operating velocities. Yet to date we have a limited understanding of the nature and functional implications of in vivo dynamic muscle shape change under submaximal conditions. This study determined how the in vivo changes in medial gastrocnemius (MG) fascicle velocity, pennation angle, muscle thickness, and subsequent muscle gearing varied as a function of force and velocity. To do this, we obtained recordings of MG tendon length, fascicle length, pennation angle, and thickness using B-mode ultrasound and muscle activation using surface electromyography during cycling at a range of cadences and loads. We found that that increases in contractile force were accompanied by reduced bulging in muscle thickness, reduced increases in pennation angle, and faster fascicle shortening. Although the force and velocity of a muscle contraction are inversely related due to the force-velocity effect, this study has shown how dynamic muscle shape changes are influenced by force and not influenced by velocity.NEW & NOTEWORTHY During movement, skeletal muscles contract and bulge in thickness or width. These shape changes play a key role in modulating the performance of skeletal muscle by increasing its range of operating velocities. Yet to date the underlying mechanisms associated with muscle shape change remain largely unexplored. This study identified muscle force, and not velocity, as the mechanistic driving factor to allow for muscle gearing to vary depending on the contractile conditions during human cycling. PMID- 28860179 TI - Fewer REBOA complications with smaller devices and partial occlusion: evidence from a multicentre registry in Japan. AB - BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) performed by emergency physicians has been gaining acceptance as a less invasive technique than resuscitative thoracotomy. OBJECTIVE: To evaluate access-related complications and duration of occlusions during REBOA. METHODS: Patients with haemorrhagic shock requiring REBOA, from 18 hospitals in Japan, included in the DIRECT-IABO Registry were studied. REBOA-related characteristics were compared between non-survivors and survivors at 24 hours. 24-Hour survivors were categorised into groups with small (<=8 Fr), large (>=9 Fr) or unusual sheaths (oversized or multiple) to assess the relationship between the sheath size and complications. Haemodynamic response, occlusion duration and outcomes were compared between groups with partial and complete REBOA. RESULTS: Between August 2011 and December 2015, 142 adults undergoing REBOA were analysed. REBOA procedures were predominantly (94%) performed by emergency medicine (EM) physicians. The median duration of the small sheath (n=53) was 19 hours compared with 7.5 hours for the larger sheaths (P=0.025). Smaller sheaths were more likely to be removed using external manual compression (96% vs 45%, P<0.001). One case of a common femoral artery thrombus (large group) and two cases of amputation (unusual group) were identified. Partial REBOA was carried out in more cases (n=78) and resulted in a better haemodynamic response than complete REBOA (improvement in haemodynamics, 92% vs 70%, P=0.004; achievement of stability, 78% vs 51%, P=0.007) and allowed longer occlusion duration (median 58 vs 33 min, P=0.041). No statistically significant difference in 24-hour or 30-day survival was found between partial and complete REBOA. CONCLUSION: In Japan, EM physicians undertake the majority of REBOA procedures. Smaller sheaths appear to have fewer complications despite relatively prolonged placement and require external compression on removal. Although REBOA is a rarely performed procedure, partial REBOA, which may extend the occlusion duration without a reduction in survival, is used more commonly in Japan. PMID- 28860180 TI - Circadian Regulation and Diurnal Variation in Gas Exchange. PMID- 28860181 TI - A Major Advance in Plastid Transformation. PMID- 28860182 TI - Double pathology in a woman with worsening dysphagia. PMID- 28860183 TI - Single-Step qPCR and dPCR Detection of Diverse CRISPR-Cas9 Gene Editing Events In Vivo. AB - Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated protein 9 (Cas9)-based technology is currently the most flexible means to create targeted mutations by recombination or indel mutations by nonhomologous end joining. During mouse transgenesis, recombinant and indel alleles are often pursued simultaneously. Multiple alleles can be formed in each animal to create significant genetic complexity that complicates the CRISPR-Cas9 approach and analysis. Currently, there are no rapid methods to measure the extent of on-site editing with broad mutation sensitivity. In this study, we demonstrate the allelic diversity arising from targeted CRISPR editing in founder mice. Using this DNA sample collection, we validated specific quantitative and digital PCR methods (qPCR and dPCR, respectively) for measuring the frequency of on-target editing in founder mice. We found that locked nucleic acid (LNA) probes combined with an internal reference probe (Drop-Off Assay) provide accurate measurements of editing rates. The Drop-Off LNA Assay also detected on-target CRISPR-Cas9 gene editing in blastocysts with a sensitivity comparable to PCR-clone sequencing. Lastly, we demonstrate that the allele-specific LNA probes used in qPCR competitor assays can accurately detect recombinant mutations in founder mice. In summary, we show that LNA-based qPCR and dPCR assays provide a rapid method for quantifying the extent of on-target genome editing in vivo, testing RNA guides, and detecting recombinant mutations. PMID- 28860184 TI - A Bimolecular Fluorescence Complementation Tool for Identification of Protein Protein Interactions in Candida albicans. AB - Investigation of protein-protein interactions (PPI) in Candida albicans is essential for understanding the regulation of the signal transduction network that triggers its pathogenic lifestyle. Unique features of C. albicans, such as its alternative codon usage and incomplete meiosis, have enforced the optimization of standard genetic methods as well as development of novel approaches. Since the existing methods for detection of PPI are limited for direct visualization of the interacting complex in vivo, we have established a bimolecular fluorescence complementation (BiFC) assay in C. albicans, a powerful technique for studying PPI. We have developed an optimized set of plasmids that allows for N- and C-terminal tagging of proteins with split yeast-enhanced monomeric Venus fragments, so that all eight combinations of fusion orientations can be analyzed. With the use of our BiFC assay we demonstrate three interaction complexes in vivo, which were also confirmed by two-hybrid analysis. Our Candida optimized BiFC assay represents a useful molecular tool for PPI studies and shows great promise in expanding our knowledge of molecular mechanisms of protein functions. PMID- 28860185 TI - Genomic Relatedness Strengthens Genetic Connectedness Across Management Units. AB - Genetic connectedness refers to a measure of genetic relatedness across management units (e.g., herds and flocks). With the presence of high genetic connectedness in management units, best linear unbiased prediction (BLUP) is known to provide reliable comparisons between estimated genetic values. Genetic connectedness has been studied for pedigree-based BLUP; however, relatively little attention has been paid to using genomic information to measure connectedness. In this study, we assessed genome-based connectedness across management units by applying prediction error variance of difference (PEVD), coefficient of determination (CD), and prediction error correlation r to a combination of computer simulation and real data (mice and cattle). We found that genomic information ([Formula: see text]) increased the estimate of connectedness among individuals from different management units compared to that based on pedigree ([Formula: see text]). A disconnected design benefited the most. In both datasets, PEVD and CD statistics inferred increased connectedness across units when using [Formula: see text]- rather than [Formula: see text]-based relatedness, suggesting stronger connectedness. With r once using allele frequencies equal to one-half or scaling [Formula: see text] to values between 0 and 2, which is intrinsic to [Formula: see text] connectedness also increased with genomic information. However, PEVD occasionally increased, and r decreased when obtained using the alternative form of [Formula: see text] instead suggesting less connectedness. Such inconsistencies were not found with CD. We contend that genomic relatedness strengthens measures of genetic connectedness across units and has the potential to aid genomic evaluation of livestock species. PMID- 28860186 TI - Heat shock protein 47 and 65-kDa FK506-binding protein weakly but synergistically interact during collagen folding in the endoplasmic reticulum. AB - Collagen is the most abundant protein in the extracellular matrix in humans and is critical to the integrity and function of many musculoskeletal tissues. A molecular ensemble comprising more than 20 molecules is involved in collagen biosynthesis in the rough endoplasmic reticulum. Two proteins, heat shock protein 47 (Hsp47/SERPINH1) and 65-kDa FK506-binding protein (FKBP65/FKBP10), have been shown to play important roles in this ensemble. In humans, autosomal recessive mutations in both genes cause similar osteogenesis imperfecta phenotypes. Whereas it has been proposed that Hsp47 and FKBP65 interact in the rough endoplasmic reticulum, there is neither clear evidence for this interaction nor any data regarding their binding affinities for each other. In this study using purified endogenous proteins, we examined the interaction between Hsp47, FKBP65, and collagen and also determined their binding affinities and functions in vitro Hsp47 and FKBP65 show a direct but weak interaction, and FKBP65 prefers to interact with Hsp47 rather than type I collagen. Our results suggest that a weak interaction between Hsp47 and FKBP65 confers mutual molecular stability and also allows for a synergistic effect during collagen folding. We also propose that Hsp47 likely acts as a hub molecule during collagen folding and secretion by directing other molecules to reach their target sites on collagens. Our findings may explain why osteogenesis imperfecta-causing mutations in both genes result in similar phenotypes. PMID- 28860187 TI - Analysis of DNA binding by human factor xeroderma pigmentosum complementation group A (XPA) provides insight into its interactions with nucleotide excision repair substrates. AB - Xeroderma pigmentosum (XP) complementation group A (XPA) is an essential scaffolding protein in the multiprotein nucleotide excision repair (NER) machinery. The interaction of XPA with DNA is a core function of this protein; a number of mutations in the DNA-binding domain (DBD) are associated with XP disease. Although structures of the central globular domain of human XPA and data on binding of DNA substrates have been reported, the structural basis for XPA's DNA-binding activity remains unknown. X-ray crystal structures of the central globular domain of yeast XPA (Rad14) with lesion-containing DNA duplexes have provided valuable insights, but the DNA substrates used for this study do not correspond to the substrates of XPA as it functions within the NER machinery. To better understand the DNA-binding activity of human XPA in NER, we used NMR to investigate the interaction of its DBD with a range of DNA substrates. We found that XPA binds different single-stranded/double-stranded junction DNA substrates with a common surface. Comparisons of our NMR-based mapping of binding residues with the previously reported Rad14-DNA crystal structures revealed similarities and differences in substrate binding between XPA and Rad14. This includes direct evidence for DNA contacts to the residues extending C-terminally from the globular core, which are lacking in the Rad14 construct. Moreover, mutation of the XPA residue corresponding to Phe-262 in Rad14, previously reported as being critical for DNA binding, had only a moderate effect on the DNA-binding activity of XPA. The DNA-binding properties of several disease-associated mutations in the DBD were investigated. These results suggest that for XPA mutants exhibiting altered DNA-binding properties, a correlation exists between the extent of reduction in DNA-binding affinity and the severity of symptoms in XP patients. PMID- 28860188 TI - Discovery of a highly selective chemical inhibitor of matrix metalloproteinase-9 (MMP-9) that allosterically inhibits zymogen activation. AB - Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets. PMID- 28860189 TI - The major histocompatibility complex class I immunopeptidome of extracellular vesicles. AB - Extracellular vesicles (EVs) are released by most cell types and have been associated with multiple immunomodulatory functions. MHC class I molecules have crucial roles in antigen presentation and in eliciting immune responses and are known to be incorporated into EVs. However, the MHC class I immunopeptidome of EVs has not been established. Here, using a small-scale immunoisolation of the antigen serotypes HLA-A*02:01 and HLA-B*27:05 expressed on the Epstein-Barr virus transformed B cell line Jesthom and MS of the eluted peptides from both cells and EVs, we identified 516 peptides that bind either HLA-A*02:01 or HLA-B*27:05. Of importance, the predicted serotype-binding affinities and peptide-anchor motifs did not significantly differ between the peptide pools isolated from cells or EVs, indicating that during EV biogenesis, no obvious editing of the MHC class I immunopeptidome occurs. These results, for the first time, establish EVs as a source of MHC class I peptides that can be used for the study of the immunopeptidome and in the discovery of potential neoantigens for immunotherapies. PMID- 28860190 TI - Insights into the localization and function of myomaker during myoblast fusion. AB - Multinucleated skeletal muscle fibers form through the fusion of myoblasts during development and regeneration. Previous studies identified myomaker (Tmem8c) as a muscle-specific membrane protein essential for fusion. However, the specific function of myomaker and how its function is regulated are unknown. To explore these questions, we first examined the cellular localization of endogenous myomaker. Two independent antibodies showed that whereas myomaker does localize to the plasma membrane in cultured myoblasts, the protein also resides in the Golgi and post-Golgi vesicles. These results raised questions regarding the precise cellular location of myomaker function and mechanisms that govern myomaker trafficking between these cellular compartments. Using a synchronized fusion assay, we demonstrated that myomaker functions at the plasma membrane to drive fusion. Trafficking of myomaker is regulated by palmitoylation of C terminal cysteine residues that allows Golgi localization. Moreover, dissection of the C terminus revealed that palmitoylation was not sufficient for complete fusogenic activity suggesting a function for other amino acids within this C terminal region. Indeed, C-terminal mutagenesis analysis highlighted the importance of a C-terminal leucine for function. These data reveal that myoblast fusion requires myomaker activity at the plasma membrane and is potentially regulated by proper myomaker trafficking. PMID- 28860191 TI - Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes. AB - Preservation of insulin-secreting beta-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and beta-cell apoptosis in vitro In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 weeks to female nonobese diabetic (NOD) mice, beginning at 3 weeks of age, followed by twice-weekly injections until age 25 weeks, protects the animals from diabetes. The preservation of beta-cells was because of a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing additional evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased numbers of apoptotic beta-cells compared with those treated with vehicle or low dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced beta-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent beta-cell death with the long-term goal of limiting the progression of type 1 diabetes. PMID- 28860192 TI - Improving the thermal stability of cellobiohydrolase Cel7A from Hypocrea jecorina by directed evolution. AB - Secreted mixtures of Hypocrea jecorina cellulases are able to efficiently degrade cellulosic biomass to fermentable sugars at large, commercially relevant scales. H. jecorina Cel7A, cellobiohydrolase I, from glycoside hydrolase family 7, is the workhorse enzyme of the process. However, the thermal stability of Cel7A limits its use to processes where temperatures are no higher than 50 degrees C. Enhanced thermal stability is desirable to enable the use of higher processing temperatures and to improve the economic feasibility of industrial biomass conversion. Here, we enhanced the thermal stability of Cel7A through directed evolution. Sites with increased thermal stability properties were combined, and a Cel7A variant (FCA398) was obtained, which exhibited a 10.4 degrees C increase in Tm and a 44-fold greater half-life compared with the wild-type enzyme. This Cel7A variant contains 18 mutated sites and is active under application conditions up to at least 75 degrees C. The X-ray crystal structure of the catalytic domain was determined at 2.1 A resolution and showed that the effects of the mutations are local and do not introduce major backbone conformational changes. Molecular dynamics simulations revealed that the catalytic domain of wild-type Cel7A and the FCA398 variant exhibit similar behavior at 300 K, whereas at elevated temperature (475 and 525 K), the FCA398 variant fluctuates less and maintains more native contacts over time. Combining the structural and dynamic investigations, rationales were developed for the stabilizing effect at many of the mutated sites. PMID- 28860193 TI - Structural and functional insights into the interaction between the Cas family scaffolding protein p130Cas and the focal adhesion-associated protein paxillin. AB - The Cas family scaffolding protein p130Cas is a Src substrate localized in focal adhesions (FAs) and functions in integrin signaling to promote cell motility, invasion, proliferation, and survival. p130Cas targeting to FAs is essential for its tyrosine phosphorylation and downstream signaling. Although the N-terminal SH3 domain is important for p130Cas localization, it has also been reported that the C-terminal region is involved in p130Cas FA targeting. The C-terminal region of p130Cas or Cas family homology domain (CCHD) has been reported to adopt a structure similar to that of the focal adhesion kinase C-terminal focal adhesion targeting domain. The mechanism by which the CCHD promotes FA targeting of p130Cas, however, remains unclear. In this study, using a calorimetry approach, we identified the first LD motif (LD1) of the FA-associated protein paxillin as the binding partner of the p130Cas CCHD (in a 1:1 stoichiometry with a Kd ~4.2 MUm) and elucidated the structure of the p130Cas CCHD in complex with the paxillin LD1 motif by X-ray crystallography. Of note, a comparison of the CCHD/LD1 complex with a previously solved structure of CCHD in complex with the SH2-containing protein NSP3 revealed that LD1 had almost identical positioning of key hydrophobic and acidic residues relative to NSP3. Because paxillin is one of the key scaffold molecules in FAs, we propose that the interaction between the p130Cas CCHD and the LD1 motif of paxillin plays an important role in p130Cas FA targeting. PMID- 28860194 TI - The bacterial arginine glycosyltransferase effector NleB preferentially modifies Fas-associated death domain protein (FADD). AB - The inhibition of host innate immunity pathways is essential for the persistence of attaching and effacing pathogens such as enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium during mammalian infections. To subvert these pathways and suppress the antimicrobial response, attaching and effacing pathogens use type III secretion systems to introduce effectors targeting key signaling pathways in host cells. One such effector is the arginine glycosyltransferase NleB1 (NleBCR in C. rodentium) that modifies conserved arginine residues in death domain-containing host proteins with N acetylglucosamine (GlcNAc), thereby blocking extrinsic apoptosis signaling. Ectopically expressed NleB1 modifies the host proteins Fas-associated via death domain (FADD), TNFRSF1A-associated via death domain (TRADD), and receptor interacting serine/threonine protein kinase 1 (RIPK1). However, the full repertoire of arginine GlcNAcylation induced by pathogen-delivered NleB1 is unknown. Using an affinity proteomic approach for measuring arginine-GlcNAcylated glycopeptides, we assessed the global profile of arginine GlcNAcylation during ectopic expression of NleB1, EPEC infection in vitro, or C. rodentium infection in vivo NleB overexpression resulted in arginine GlcNAcylation of multiple host proteins. However, NleB delivery during EPEC and C. rodentium infection caused rapid and preferential modification of Arg117 in FADD. This FADD modification was extremely stable and insensitive to physiological temperatures, glycosidases, or host cell degradation. Despite its stability and effect on the inhibition of apoptosis, arginine GlcNAcylation did not elicit any proteomic changes, even in response to prolonged NleB1 expression. We conclude that, at normal levels of expression during bacterial infection, NleB1/NleBCR antagonizes death receptor induced apoptosis of infected cells by modifying FADD in an irreversible manner. PMID- 28860195 TI - Hypothyroidism induced by loss of the manganese efflux transporter SLC30A10 may be explained by reduced thyroxine production. AB - SLC30A10 and SLC39A14 are manganese efflux and influx transporters, respectively. Loss-of-function mutations in genes encoding either transporter induce hereditary manganese toxicity. Patients have elevated manganese in the blood and brain and develop neurotoxicity. Liver manganese is increased in patients lacking SLC30A10 but not SLC39A14. These organ-specific changes in manganese were recently recapitulated in knockout mice. Surprisingly, Slc30a10 knockouts also had elevated thyroid manganese and developed hypothyroidism. To determine the mechanisms of manganese-induced hypothyroidism and understand how SLC30A10 and SLC39A14 cooperatively mediate manganese detoxification, here we produced Slc39a14 single and Slc30a10/Slc39a14 double knockout mice and compared their phenotypes with that of Slc30a10 single knockouts. Compared with wild-type controls, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had higher manganese levels in the blood and brain but not in the liver. In contrast, Slc30a10 single knockouts had elevated manganese levels in the liver as well as in the blood and brain. Furthermore, SLC30A10 and SLC39A14 localized to the canalicular and basolateral domains of polarized hepatic cells, respectively. Thus, transport activities of both SLC39A14 and SLC30A10 are required for hepatic manganese excretion. Compared with Slc30a10 single knockouts, Slc39a14 single and Slc30a10/Slc39a14 double knockouts had lower thyroid manganese levels and normal thyroid function. Moreover, intrathyroid thyroxine levels of Slc30a10 single knockouts were lower than those of controls. Thus, the hypothyroidism phenotype of Slc30a10 single knockouts is induced by elevated thyroid manganese, which blocks thyroxine production. These findings provide new insights into the mechanisms of manganese detoxification and manganese-induced thyroid dysfunction. PMID- 28860197 TI - Cooperation between hearing and vision in people with cochlear implants. PMID- 28860196 TI - Conformational dynamics are a key factor in signaling mediated by the receiver domain of a sensor histidine kinase from Arabidopsis thaliana. AB - Multistep phosphorelay (MSP) cascades mediate responses to a wide spectrum of stimuli, including plant hormonal signaling, but several aspects of MSP await elucidation. Here, we provide first insight into the key step of MSP-mediated phosphotransfer in a eukaryotic system, the phosphorylation of the receiver domain of the histidine kinase CYTOKININ-INDEPENDENT 1 (CKI1RD) from Arabidopsis thaliana We observed that the crystal structures of free, Mg2+-bound, and beryllofluoridated CKI1RD (a stable analogue of the labile phosphorylated form) were identical and similar to the active state of receiver domains of bacterial response regulators. However, the three CKI1RD variants exhibited different conformational dynamics in solution. NMR studies revealed that Mg2+ binding and beryllofluoridation alter the conformational equilibrium of the beta3-alpha3 loop close to the phosphorylation site. Mutations that perturbed the conformational behavior of the beta3-alpha3 loop while keeping the active-site aspartate intact resulted in suppression of CKI1 function. Mechanistically, homology modeling indicated that the beta3-alpha3 loop directly interacts with the ATP-binding site of the CKI1 histidine kinase domain. The functional relevance of the conformational dynamics observed in the beta3-alpha3 loop of CKI1RD was supported by a comparison with another A. thaliana histidine kinase, ETR1. In contrast to the highly dynamic beta3-alpha3 loop of CKI1RD, the corresponding loop of the ETR1 receiver domain (ETR1RD) exhibited little conformational exchange and adopted a different orientation in crystals. Biochemical data indicated that ETR1RD is involved in phosphorylation-independent signaling, implying a direct link between conformational behavior and the ability of eukaryotic receiver domains to participate in MSP. PMID- 28860198 TI - Neanderthals and Denisovans as biological invaders. PMID- 28860199 TI - Hold the salt: Freshwater origin of primary plastids. PMID- 28860200 TI - Acute hepatitis A infection after hepatitis A immunity in a HIV-positive individual. AB - Hepatitis A is a self-limiting infection caused by the hepatitis A virus (HAV), transmitted predominantly by the faecal-oral route including some sexual practices. Outbreaks are commonly reported in the men who have sex with men (population. Previous exposure is thought to provide life-long immunity against subsequent infections with the development of an HAV IgG response. This paper reports a case of acute Hepatitis A infection, despite evidence of a previously positive Hepatitis A IgG results in an HIV-positive individual. PMID- 28860201 TI - Mental health impacts of flooding: a controlled interrupted time series analysis of prescribing data in England. AB - BACKGROUND: There is emerging evidence that people affected by flooding suffer adverse impacts on their mental well-being, mostly based on self-reports. METHODS: We examined prescription records for drugs used in the management of common mental disorder among primary care practices located in the vicinity of recent large flood events in England, 2011-2014. A controlled interrupted time series analysis was conducted of the number of prescribing items for antidepressant drugs in the year before and after the flood onset. Pre-post changes were compared by distance of the practice from the inundated boundaries among 930 practices located within 10 km of a flood. RESULTS: After control for deprivation and population density, there was an increase of 0.59% (95% CI 0.24 to 0.94) prescriptions in the postflood year among practices located within 1 km of a flood over and above the change observed in the furthest distance band. The increase was greater in more deprived areas. CONCLUSIONS: This study suggests an increase in prescribed antidepressant drugs in the year after flooding in primary care practices close to recent major floods in England. The degree to which the increase is actually concentrated in those flooded can only be determined by more detailed linkage studies. PMID- 28860202 TI - Letter to the Editor: CD8+ T cells as a source for transfer factor in understanding the immunology of leprosy and HIV. PMID- 28860203 TI - CD8+ T cell dialyzable extract activity is dependent on TCR and MHC-I. PMID- 28860204 TI - Editorial: The nose knows. PMID- 28860205 TI - Editorial: Searching for definitive evidence of the role of eosinophils in lung disease: are we there yet? PMID- 28860206 TI - Protecting unauthorized immigrant mothers improves their children's mental health. AB - The United States is embroiled in a debate about whether to protect or deport its estimated 11 million unauthorized immigrants, but the fact that these immigrants are also parents to more than 4 million U.S.-born children is often overlooked. We provide causal evidence of the impact of parents' unauthorized immigration status on the health of their U.S. citizen children. The Deferred Action for Childhood Arrivals (DACA) program granted temporary protection from deportation to more than 780,000 unauthorized immigrants. We used Medicaid claims data from Oregon and exploited the quasi-random assignment of DACA eligibility among mothers with birthdates close to the DACA age qualification cutoff. Mothers' DACA eligibility significantly decreased adjustment and anxiety disorder diagnoses among their children. Parents' unauthorized status is thus a substantial barrier to normal child development and perpetuates health inequalities through the intergenerational transmission of disadvantage. PMID- 28860207 TI - PAF1 regulation of promoter-proximal pause release via enhancer activation. AB - Gene expression in metazoans is regulated by RNA polymerase II (Pol II) promoter proximal pausing and its release. Previously, we showed that Pol II-associated factor 1 (PAF1) modulates the release of paused Pol II into productive elongation. Here, we found that PAF1 occupies transcriptional enhancers and restrains hyperactivation of a subset of these enhancers. Enhancer activation as the result of PAF1 loss releases Pol II from paused promoters of nearby PAF1 target genes. Knockout of PAF1-regulated enhancers attenuates the release of paused Pol II on PAF1 target genes without major interference in the establishment of pausing at their cognate promoters. Thus, a subset of enhancers can primarily modulate gene expression by controlling the release of paused Pol II in a PAF1-dependent manner. PMID- 28860208 TI - Nanophotonic rare-earth quantum memory with optically controlled retrieval. AB - Optical quantum memories are essential elements in quantum networks for long distance distribution of quantum entanglement. Scalable development of quantum network nodes requires on-chip qubit storage functionality with control of the readout time. We demonstrate a high-fidelity nanophotonic quantum memory based on a mesoscopic neodymium ensemble coupled to a photonic crystal cavity. The nanocavity enables >95% spin polarization for efficient initialization of the atomic frequency comb memory and time bin-selective readout through an enhanced optical Stark shift of the comb frequencies. Our solid-state memory is integrable with other chip-scale photon source and detector devices for multiplexed quantum and classical information processing at the network nodes. PMID- 28860209 TI - The Drosophila embryo at single-cell transcriptome resolution. AB - By the onset of morphogenesis, Drosophila embryos consist of about 6000 cells that express distinct gene combinations. Here, we used single-cell sequencing of precisely staged embryos and devised DistMap, a computational mapping strategy to reconstruct the embryo and to predict spatial gene expression approaching single cell resolution. We produced a virtual embryo with about 8000 expressed genes per cell. Our interactive Drosophila Virtual Expression eXplorer (DVEX) database generates three-dimensional virtual in situ hybridizations and computes gene expression gradients. We used DVEX to uncover patterned expression of transcription factors and long noncoding RNAs, as well as signaling pathway components. Spatial regulation of Hippo signaling during early embryogenesis suggests a mechanism for establishing asynchronous cell proliferation. Our approach is suitable to generate transcriptomic blueprints for other complex tissues. PMID- 28860211 TI - Excess all-cause mortality before age 30 in childhood onset type 1 diabetes: data from the Brecon Group Cohort in Wales. AB - BACKGROUND: Long-term outcomes in young people with type 1 diabetes continue to be of interest, and may help evaluate the effects of changes to the clinical care of children that have occurred in recent decades. AIMS: To identify mortality and its causes before age 30 years in patients developing type 1 diabetes before age 15 years. METHODS: Since 1995, paediatricians in Wales have compiled a prospective register of incident cases of type 1 diabetes occurring before age 15 years in Wales (the Brecon Cohort). Their subsequent mortality rates were compared with mortality in the general populations of Wales and England using the patient-years exposure method. Causes of death were ascertained from death certificates and from clinicians. RESULTS: The standardised mortality ratio for young people with type 1 diabetes in Wales was 2.91 with no clear evidence of improvement or worsening of mortality risk over time. Most deaths occurred between ages 15 and 30 years although at a slightly younger age than in the general population. There were more deaths with increasing age at diagnosis of diabetes. Ketoacidosis remains the most common cause of death before age 30 years. Hypoglycaemia was difficult to ascertain with certainty but also caused some deaths. In this age group, chronic complications of diabetes were not a cause of mortality. CONCLUSIONS: Despite the developments in clinical care in recent years, the mortality risk for people developing type 1 diabetes in childhood remains high in young adult life before the onset of chronic complications. PMID- 28860210 TI - Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS. AB - Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high risk MDS to investigate the safety and cell kinetics of the T cells. The WT1 specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519. PMID- 28860212 TI - Angioarchitectures and Hemodynamic Characteristics of Posterior Communicating Artery Aneurysms and Their Association with Rupture Status. AB - BACKGROUND AND PURPOSE: Intracranial aneurysms originating at the posterior communicating artery are known to have high rupture risk compared with other locations. We tested the hypothesis that different angioarchitectures (ie, branch point configuration) of posterior communicating artery aneurysms are associated with aneurysm hemodynamics, which in turn predisposes aneurysms to rupture. MATERIALS AND METHODS: A total of 313 posterior communicating artery aneurysms (145 ruptured, 168 unruptured) were studied with image-based computational fluid dynamics. Aneurysms were classified into different angioarchitecture types depending on the location of the aneurysm with respect to parent artery bifurcation. Hemodynamic characteristics were compared between ruptured and unruptured aneurysms, as well as among aneurysms with different angioarchitectures. RESULTS: Angioarchitecture was associated with rupture (P = .003). Ruptured aneurysms had higher, more concentrated, and more oscillatory wall shear stress distributions (maximum wall shear stress, P < .001; shear concentration index, P < .001; mean oscillatory shear index, P < .001), stronger and more concentrated inflow jets (represented as Q, P = .01; inflow concentration index, P < .001), and more complex and unstable flow patterns (vortex core length, P < .001; proper orthogonal decomposition entropy, P < .001) compared with unruptured aneurysms. These adverse conditions were more common in aneurysms with bifurcation-type angioarchitectures compared with those with lateral or sidewall angioarchitectures. Interestingly, ruptured aneurysms also had lower normalized mean wall shear stress (P = .02) and minimum wall shear stress (P = .002) than unruptured aneurysms. CONCLUSIONS: High-flow intrasaccular hemodynamic characteristics, commonly found in bifurcation-type angioarchitectures, are associated with the posterior communicating artery aneurysm rupture status. These characteristics include strong and concentrated inflow jets, concentrated regions of elevated wall shear stress, oscillatory wall shear stress, lower normalized wall shear stress, and complex and unstable flow patterns. PMID- 28860213 TI - [18F]-Sodium Fluoride PET MR-Based Localization and Quantification of Bone Turnover as a Biomarker for Facet Joint-Induced Disability. AB - Our aim was to prospectively evaluate the relationship between low back pain related disability and quantitative measures from [18F]-sodium fluoride ([18F] NaF) MR imaging. Six patients with facetogenic low back pain underwent dynamic [18F]-NaF PET/MR imaging. PET metrics were correlated with clinical measures and MR imaging grading of lumbar facet arthropathy. A significant positive correlation was observed between maximum facet joint uptake rate and clinical disability (P < .05). These data suggest that dynamic [18F]-NaF PET may serve as a useful biomarker for facetogenic disability. PMID- 28860214 TI - Brain Temperature Is Increased During the First Days of Life in Asphyxiated Newborns: Developing Brain Injury Despite Hypothermia Treatment. AB - BACKGROUND AND PURPOSE: Therapeutic hypothermia is the current treatment for neonates with hypoxic-ischemic encephalopathy. It is believed to work by decreasing the brain temperature and reducing the baseline metabolism and energy demand of the brain. This study aimed to noninvasively assess brain temperature during the first month of life in neonates with hypoxic-ischemic encephalopathy treated with hypothermia. MATERIALS AND METHODS: Neonates with hypoxic-ischemic encephalopathy treated with hypothermia and healthy neonates were enrolled prospectively. MR imaging was used to identify the presence and extent of brain injury. MR imaging multivoxel spectroscopy was used to derive brain temperatures in the basal ganglia and white matter at different time points during the first month of life. Brain temperature measurements were compared between neonates with hypoxic-ischemic encephalopathy and healthy neonates. RESULTS: Forty-three term neonates with hypoxic-ischemic encephalopathy treated with hypothermia had a total of 74 spectroscopy scans, and 3 healthy term neonates had a total of 9 spectroscopy scans during the first month of life. Brain temperatures were lower in neonates with hypoxic-ischemic encephalopathy during hypothermia, compared with the healthy neonates (respectively, on day 1 of life: basal ganglia, 38.81 degrees C +/- 2.08 degrees C, and white matter, 39.11 degrees C +/- 1.99 degrees C; and on days 2-3 of life: basal ganglia, 38.25 degrees C +/- 0.91 degrees C, and white matter, 38.54 degrees C +/- 2.79 degrees C). However, neonates with hypoxic-ischemic encephalopathy who developed brain injury had higher brain temperatures during hypothermia (respectively, on day 1 of life: basal ganglia, 35.55 degrees C +/- 1.31 degrees C, and white matter, 37.35 degrees C +/- 2.55 degrees C; and on days 2-3 of life: basal ganglia, 35.20 degrees C +/- 1.15 degrees C, and white matter, 35.44 degrees C +/- 1.90 degrees C) compared with neonates who did not develop brain injury (respectively, on day 1 of life: basal ganglia, 34.46 degrees C +/- 1.09 degrees C, and white matter, 33.97 degrees C +/ 1.42 degrees C; and on days 2-3 of life: basal ganglia, 33.90 degrees C +/- 1.34 degrees C, and white matter, 33.07 degrees C +/- 1.71 degrees C). Also, brain temperatures tended to remain slightly higher in the neonates who developed brain injury around day 10 of life and around 1 month of age. CONCLUSIONS: Therapeutic hypothermia using current guidelines decreased the brain temperature of neonates with hypoxic-ischemic encephalopathy during the first days of life but did not prevent an early increase of brain temperature in neonates with hypoxic-ischemic encephalopathy who developed brain injury despite this treatment. PMID- 28860215 TI - American Society of Functional Neuroradiology-Recommended fMRI Paradigm Algorithms for Presurgical Language Assessment. AB - INTRODUCTION: Functional MR imaging is increasingly being used for presurgical language assessment in the treatment of patients with brain tumors, epilepsy, vascular malformations, and other conditions. The inherent complexity of fMRI, which includes numerous processing steps and selective analyses, is compounded by institution-unique approaches to patient training, paradigm choice, and an eclectic array of postprocessing options from various vendors. Consequently, institutions perform fMRI in such markedly different manners that data sharing, comparison, and generalization of results are difficult. The American Society of Functional Neuroradiology proposes widespread adoption of common fMRI language paradigms as the first step in countering this lost opportunity to advance our knowledge and improve patient care. LANGUAGE PARADIGM REVIEW PROCESS: A taskforce of American Society of Functional Neuroradiology members from multiple institutions used a broad literature review, member polls, and expert opinion to converge on 2 sets of standard language paradigms that strike a balance between ease of application and clinical usefulness. ASFNR RECOMMENDATIONS: The taskforce generated an adult language paradigm algorithm for presurgical language assessment including the following tasks: Sentence Completion, Silent Word Generation, Rhyming, Object Naming, and/or Passive Story Listening. The pediatric algorithm includes the following tasks: Sentence Completion, Rhyming, Antonym Generation, or Passive Story Listening. DISCUSSION: Convergence of fMRI language paradigms across institutions offers the first step in providing a "Rosetta Stone" that provides a common reference point with which to compare and contrast the usefulness and reliability of fMRI data. From this common language task battery, future refinements and improvements are anticipated, particularly as objective measures of reliability become available. Some commonality of practice is a necessary first step to develop a foundation on which to improve the clinical utility of this field. PMID- 28860216 TI - Arterial Spin-Labeling Perfusion MR Imaging Demonstrates Regional CBF Decrease in Idiopathic Normal Pressure Hydrocephalus. AB - BACKGROUND AND PURPOSE: Regional cerebral blood flow has previously been studied in patients with idiopathic normal pressure hydrocephalus with imaging methods that require an intravenous contrast agent or expose the patient to ionizing radiation. The purpose of this study was to assess regional CBF in patients with idiopathic normal pressure hydrocephalus compared with healthy controls using the noninvasive quantitative arterial spin-labeling MR imaging technique. A secondary aim was to compare the correlation between symptom severity and CBF. MATERIALS AND METHODS: Differences in regional cerebral perfusion between patients with idiopathic normal pressure hydrocephalus and healthy controls were investigated with pseudocontinuous arterial spin-labeling perfusion MR imaging. Twenty-one consecutive patients with idiopathic normal pressure hydrocephalus and 21 age- and sex-matched randomly selected healthy controls from the population registry were prospectively included. The controls did not differ from patients with respect to selected vascular risk factors. Twelve different anatomic ROIs were manually drawn on coregistered FLAIR images. The Holm-Bonferroni correction was applied to statistical analyses. RESULTS: In patients with idiopathic normal pressure hydrocephalus, perfusion was reduced in the periventricular white matter (P < .001), lentiform nucleus (P < .001), and thalamus (P < .001) compared with controls. Cognitive function in patients correlated with CBF in the periventricular white matter (r = 0.60, P < .01), cerebellum (r = 0.63, P < .01), and pons (r = 0.71, P < .001). CONCLUSIONS: Using pseudocontinuous arterial spin labeling, we could confirm findings of a reduced perfusion in the periventricular white matter, basal ganglia, and thalamus in patients with idiopathic normal pressure hydrocephalus previously observed with other imaging techniques. PMID- 28860218 TI - Reply. PMID- 28860217 TI - Comparison of Clinical Outcomes of Intracranial Aneurysms: Procedural Rupture versus Spontaneous Rupture. AB - BACKGROUND AND PURPOSE: Procedural rupture of an intracranial aneurysm is a devastating complication in endovascular treatment. The purpose of this study was to evaluate the clinical outcomes of patients with procedural rupture of unruptured saccular intracranial aneurysms compared with those with spontaneously ruptured aneurysms. MATERIALS AND METHODS: A retrospective review was performed for 1340 patients with 1595 unruptured saccular intracranial aneurysms that underwent endovascular coil embolization between February 2010 and December 2014. The clinical outcomes of patients with procedural rupture of unruptured saccular intracranial aneurysms were compared with those of 198 patients presenting with spontaneously ruptured aneurysms. RESULTS: In this series, procedural rupture developed in 19 patients (1.4% per patient and 1.2% per aneurysm), and the morbidity related to procedural rupture was 26.3% (95% confidence interval, 8.5% 61.4%) with no mortality. Hunt and Hess scale grades and hospitalization days of patients with procedural rupture were equivalent to those of patients presenting with spontaneous aneurysm rupture. Subsequent treatment procedures after hemorrhage (including lumbar drainage, extraventricular drainage, decompressive craniectomy, and permanent shunt) showed no difference between the 2 groups. The hemorrhage volumes were smaller in the procedural-rupture group (P = .03), and the endovascular vasospasm therapies tended to be more frequently required in the spontaneous aneurysm-rupture group (P = .08). At postictus 6 months, the proportion of modified Rankin Scale scores of >=2 were lower in the procedural rupture group (5.3% versus 26.8%, P = .049). In multivariate analysis, spontaneous aneurysm rupture was a significant risk factor for worse clinical outcome (OR = 14.9; 95% CI, 1.2-193.1; P = .039). CONCLUSIONS: This study showed better clinical outcomes in the procedural-rupture group. Even though there is a potential chance of aneurysm rupture during treatment, the clinical outcomes after procedural bleeds seem to be more favorable than those of spontaneous rupture. PMID- 28860219 TI - Radiomics Approach Fails to Outperform Null Classifier on Test Data. PMID- 28860220 TI - Interleukin-18 Enhances Vascular Calcification and Osteogenic Differentiation of Vascular Smooth Muscle Cells Through TRPM7 Activation. AB - OBJECTIVE: Vascular calcification (VC) is an important predictor of cardiovascular morbidity and mortality. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is a key mechanism of VC. Recent studies show that IL 18 (interleukin-18) favors VC while TRPM7 (transient receptor potential melastatin 7) channel upregulation inhibits VC. However, the relationship between IL-18 and TRPM7 is unclear. We questioned whether IL-18 enhances VC and osteogenic differentiation of VSMCs through TRPM7 channel activation. APPROACH AND RESULTS: Coronary artery calcification and serum IL-18 were measured in patients by computed tomographic scanning and enzyme-linked immunosorbent assay, respectively. Primary rat VSMCs calcification were induced by high inorganic phosphate and exposed to IL-18. VSMCs were also treated with TRPM7 antagonist 2 aminoethoxy-diphenylborate or TRPM7 small interfering RNA to block TRPM7 channel activity and expression. TRPM7 currents were recorded by patch-clamp. Human studies showed that serum IL-18 levels were positively associated with coronary artery calcium scores (r=0.91; P<0.001). In VSMCs, IL-18 significantly decreased expression of contractile markers alpha-smooth muscle actin, smooth muscle 22 alpha, and increased calcium deposition, alkaline phosphatase activity, and expression of osteogenic differentiation markers bone morphogenetic protein-2, Runx2 (runt-related transcription factor 2), and osteocalcin (P<0.05). IL-18 increased TRPM7 expression through ERK1/2 (extracellular signal-regulated kinase 1/2) signaling activation, and TRPM7 currents were augmented by IL-18 treatment. Inhibition of TRPM7 channel by 2-aminoethoxy-diphenylborate or TRPM7 small interfering RNA prevented IL-18-enhanced osteogenic differentiation and VSMCs calcification. CONCLUSIONS: These findings suggest that coronary artery calcification is associated with increased IL-18 levels. IL-18 enhances VSMCs osteogenic differentiation and subsequent VC induced by beta-glycerophosphate via TRPM7 channel activation. Accordingly, IL-18 may contribute to VC in proinflammatory conditions. PMID- 28860221 TI - Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity. AB - OBJECTIVE: Cholesterol efflux capacity (CEC) has emerged as a biomarker of coronary artery disease risk beyond plasma high-density lipoprotein (HDL) cholesterol (HDL-C) level. However, the determinants of CEC are incompletely characterized. We undertook a large-scale family-based population study to identify clinical, biochemical, and HDL particle parameter determinants of CEC, characterize reasons for the discordancy with HDL-C, quantify its heritability, and assess its stability over 10 to 12 years. APPROACHES AND RESULTS: CEC was quantified in 1988 individuals from the GRAPHIC (Genetic Regulation of Arterial Pressure of Humans in the Community) cohort, comprising individuals from 2 generations from 520 white nuclear families. Serum lipid and lipoprotein levels were determined by ultracentrifugation or nuclear magnetic resonance and HDL particle size and number quantified by nuclear magnetic resonance. Ninety unrelated individuals had repeat CEC measurements in samples collected after 10 to 12 years. CEC was positively correlated with HDL-C (R=0.62; P<0.0001). Among clinical and biochemical parameters, age, systolic blood pressure, alcohol consumption, serum albumin, triglycerides, phospholipids, and lipoprotein(a) were independently associated with CEC. Among HDL particle parameters, HDL particle number, particle size, and apolipoprotein A-II level were independently associated with CEC. Serum triglyceride level partially explained discordancy between CEC and HDL-C. CEC measurements in samples collected 10 to 12 years apart were strongly correlated (r=0.73; P<0.0001). Heritability of CEC was 0.31 (P=3.89*10-14) without adjustment for HDL-C and 0.13 (P=1.44*10-3) with adjustment. CONCLUSIONS: CEC is a stable trait over time, is influenced by specific clinical, serum, and HDL particle parameters factors beyond HDL-C, can be maintained in persons with a low plasma HDL-C by elevated serum triglyceride level, and is modestly independently heritable. PMID- 28860222 TI - Variability in Total Cholesterol Is Associated With the Risk of End-Stage Renal Disease: A Nationwide Population-Based Study. AB - OBJECTIVE: Recent data suggest that visit-to-visit variability of cholesterol is associated with cardiovascular events. We evaluated the role of lipid variability as a determinant of end-stage renal disease (ESRD). APPROACH AND RESULTS: Using nationally representative data from the Korean National Health Insurance System, 8 493 277 subjects who were free of ESRD and who underwent >=3 health examinations during 2005 to 2010 were followed to the end of 2015. Total cholesterol (TC) variability was measured using the coefficient of variation, SD, and the variability independent of the mean. The primary outcome was the development of ESRD, defined as a combination of the relevant disease code and the initiation of renal replacement therapy. There were 11 247 cases of ESRD during a median follow-up of 6.1 years. There was a graded association between a higher TC variability and incident ESRD. In the multivariable adjusted model, the hazard ratios and 95% confidence intervals comparing the highest versus lowest quartiles of coefficient of variation of TC were 2.66 (95% confidence interval, 2.52-2.82). The results were consistent when the variability of TC was modeled using SD and variability independent of the mean and were independent of preexisting chronic kidney disease. CONCLUSIONS: Increasing TC variability was associated with an increasing incidence of ESRD. PMID- 28860223 TI - Differentiation and Application of Induced Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells. AB - Vascular smooth muscle cells (VSMCs) play a role in the development of vascular disease, for example, neointimal formation, arterial aneurysm, and Marfan syndrome caused by genetic mutations in VSMCs, but little is known about the mechanisms of the disease process. Advances in induced pluripotent stem cell technology have now made it possible to derive VSMCs from several different somatic cells using a selection of protocols. As such, researchers have set out to delineate key signaling processes involved in triggering VSMC gene expression to grasp the extent of gene regulatory networks involved in phenotype commitment. This technology has also paved the way for investigations into diseases affecting VSMC behavior and function, which may be treatable once an identifiable culprit molecule or gene has been repaired. Moreover, induced pluripotent stem cell derived VSMCs are also being considered for their use in tissue-engineered blood vessels as they may prove more beneficial than using autologous vessels. Finally, while several issues remains to be clarified before induced pluripotent stem cell derived VSMCs can become used in regenerative medicine, they do offer both clinicians and researchers hope for both treating and understanding vascular disease. In this review, we aim to update the recent progress on VSMC generation from stem cells and the underlying molecular mechanisms of VSMC differentiation. We will also explore how the use of induced pluripotent stem cell-derived VSMCs has changed the game for regenerative medicine by offering new therapeutic avenues to clinicians, as well as providing researchers with a new platform for modeling of vascular disease. PMID- 28860224 TI - NHS plans to spend L100m on recruiting overseas GPs. PMID- 28860225 TI - Is cardiovascular risk reduction therapy effective in South Asian, Chinese and other patients with diabetes? A population-based cohort study from Canada. AB - OBJECTIVES: Guidelines recommend ACE inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs) and diuretics in all patients with diabetes mellitus. However, the effectiveness of these agents in South Asian and Chinese populations is unknown. We sought to determine whether ACEi, ARB, CCB and diuretics are associated with reduced mortality in South Asian, Chinese and other patients with diabetes. DESIGN: Population-based cohort study using administrative health databases. SETTING: Province of British Columbia, Canada (2006-2013). PARTICIPANTS: Patients aged >=35 years with incident diabetes. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was all-cause mortality for each medication class compared with untreated patients within each ethnicity. Treatment effect was assessed using inverse probability of treatment weighted Cox proportional hazards models. Medication adherence effect on mortality was also evaluated. RESULTS: 208 870 patients (13 755 South Asian, 22 871 Chinese, 172 244 other Canadian) were included. ACEi reduced mortality in other patients (HR=0.88, 0.84-0.91), but power was insufficient to evaluate for benefit in Chinese and South Asian patients. ARB and diuretics reduced mortality in Chinese (ARB HR=0.64, 0.50-0.82; diuretics HR=0.77, 0.62-0.96) and other patients (ARB HR=0.69, 0.64-0.74; diuretics HR=0.66, 0.63-0.69) compared with untreated patients. No mortality benefit was observed among South Asians for any drug class or for CCB among all ethnicities. Higher medication adherence was associated with lower mortality for other patients only (HR=0.79, 0.72-0.86). CONCLUSIONS: Effectiveness of cardiovascular risk reduction therapy on mortality varies considerably by ethnicity. Further study is needed to evaluate the mortality benefit of antihypertensive agents in South Asians. Inclusion of these ethnic groups in future clinical trials is essential to examine for differential responses. PMID- 28860226 TI - Early detection of perceived risk among users of a UK travel health website compared with internet search activity and media coverage during the 2015-2016 Zika virus outbreak: an observational study. AB - OBJECTIVES: The Zika virus (ZIKV) outbreak in the Americas in 2015-2016 posed a novel global threat due to the association with congenital malformations and its rapid spread. Timely information about the spread of the disease was paramount to public health bodies issuing travel advisories. This paper looks at the online interaction with a national travel health website during the outbreak and compares this to trends in internet searches and news media output. METHODS: Time trends were created for weekly views of ZIKV-related pages on a UK travel health website, relative search volumes for 'Zika' on Google UK, ZIKV-related items aggregated by Google UK News and rank of ZIKV travel advisories among all other pages between 15 November 2015 and 20 August 2016. RESULTS: Time trends in traffic to the travel health website corresponded with Google searches, but less so with media items due to intense coverage of the Rio Olympics. Travel advisories for pregnant women were issued from 7 December 2015 and began to increase in popularity (rank) from early January 2016, weeks before a surge in interest as measured by Google searches/news items at the end of January 2016. CONCLUSIONS: The study showed an amplification of perceived risk among users of a national travel health website weeks before the initial surge in public interest. This suggests a potential value for tools to detect changes in online information seeking behaviours for predicting periods of high demand where the routine capability of travel health services could be exceeded. PMID- 28860227 TI - The relationship between school type and academic performance at medical school: a national, multi-cohort study. AB - OBJECTIVES: Differential attainment in school examinations is one of the barriers to increasing student diversity in medicine. However, studies on the predictive validity of prior academic achievement and educational performance at medical school are contradictory, possibly due to single-site studies or studies which focus only on early years' performance. To address these gaps, we examined the relationship between sociodemographic factors, including school type and average educational performance throughout medical school across a large number of diverse medical programmes. METHODS: This retrospective study analysed data from students who graduated from 33 UK medical schools between 2012 and 2013. We included candidates' demographics, pre-entry grades (adjusted Universities and Colleges Admissions Service tariff scores) preadmission test scores (UK Clinical Aptitude Test (UKCAT) and Graduate Medical School Admissions Test (GAMSAT)) and used the UK Foundation Programme's educational performance measure (EPM) decile as an outcome measure. Logistic regression was used to assess the independent relationship between students' background characteristics and EPM ranking. RESULTS: Students from independent schools had significantly higher mean UKCAT scores (2535.1, SD=209.6) than students from state-funded schools (2506.1, SD=224.0, p<0.001). Similarly, students from independent schools came into medical school with significantly higher mean GAMSAT scores (63.9, SD=6.9) than students from state-funded schools (60.8, SD=7.1, p<0.001). However, students from state-funded schools were almost twice as likely (OR=2.01, 95% CI 1.49 to 2.73) to finish in the highest rank of the EPM ranking than those who attended independent schools. CONCLUSIONS: This is the first large-scale study to examine directly the relationship between school type and overall performance at medical school. Our findings provide modest supportive evidence that, when students from independent and state schools enter with similar pre-entry grades, once in medical school, students from state-funded schools are likely to outperform students from independent schools. This evidence contributes to discussions around contextualising medical admission. PMID- 28860228 TI - Anterior transversalis fascia approach versus preperitoneal space approach for inguinal hernia repair in residents in northern China: study protocol for a prospective, multicentre, randomised, controlled trial. AB - INTRODUCTION: Many surgical techniques have been used to repair abdominal wall defects in the inguinal region based on the anatomic characteristics of this region and can be categorised as 'tension' repair or 'tension-free' repair. Tension-free repair is the preferred technique for inguinal hernia repair. Tension-free repair of inguinal hernia can be performed through either the anterior transversalis fascia approach or the preperitoneal space approach. There are few large sample, randomised controlled trials investigating the curative effects of the anterior transversalis fascia approach versus the preperitoneal space approach for inguinal hernia repair in patients in northern China. METHODS AND ANALYSIS: This will be a prospective, large sample, multicentre, randomised, controlled trial. Registration date is 1 December 2016. Actual study start date is 6 February 2017. Estimated study completion date is June 2020. A cohort of over 720 patients with inguinal hernias will be recruited from nine institutions in Liaoning Province, China. Patient randomisation will be stratified by centre to undergo inguinal hernia repair via the anterior transversalis fascia approach or the preperitoneal approach. Primary and secondary outcome assessments will be performed at baseline (prior to surgery), predischarge and at postoperative 1 week, 1 month, 3 months, 1 year and 2 years. The primary outcome is the incidence of postoperative chronic inguinal pain. The secondary outcome is postoperative complications (including rates of wound infection, haematoma, seroma and hernia recurrence). ETHICS AND DISSEMINATION: This trial will be conducted in accordance with the Declaration of Helsinki and supervised by the institutional review board of the Fourth Affiliated Hospital of China Medical University (approval number 2015-027). All patients will receive information about the trial in verbal and written forms and will give informed consent before enrolment. The results will be published in peer-reviewed journals or disseminated through conference presentations. TRIAL REGISTRATION NUMBER: NCT02984917; preresults. PMID- 28860229 TI - Development and validation of hospital information system-generated indicators of the appropriateness of oral anticoagulant prescriptions in hospitalised adults: the PACHA study protocol. AB - INTRODUCTION: The appropriateness of oral anticoagulant prescriptions is a major challenge to improve quality and safety of care. As indicators of the appropriateness of oral anticoagulant prescriptions are lacking, the aim of the study is to develop and validate a panel of such indicators, in hospitalised adults, from the hospital information system of two university hospitals in France. METHODS AND ANALYSIS: The study will be carried out in four steps: (1) a literature review to identify indicators of the appropriateness of oral anticoagulant prescriptions and their conditions of appropriateness; (2) a Delphi consensus method to assess the potential utility and operational implementation of the selected indicators; (3) techniques of medical data search to implement indicators from the hospital information system and; (4) a cross-sectional study to assess the ability of indicators to detect inappropriate oral anticoagulant prescriptions, performance of medical data search techniques for tracking or retrieving information and the ability of tools to be transferred into other institutions. The fourth step will include up to 80 patient hospital stays for each indicator, depending on the prevalence of inappropriate prescriptions estimated in interim analyses. ETHICS AND DISSEMINATION: This work addresses the current lack of quality indicators of the appropriateness of oral anticoagulant prescriptions. We aim to develop and validate such indicators for integrating them into hospital clinical practice, as part of a structured approach to improve quality and safety of care. As each hospital information system is different, we will propose tools transferable to other healthcare institutions to allow an automated construction of these indicators. The PACHA study protocol was approved by institutional review boards and ethics committees (CPP Sud-Ouest et Outre Mer III-DC 2016/119; CPP Ile-de-France II-CDW_2016_0014). REGISTRATION DETAILS: Clinical Trial.gov registration: NCT02898090. PMID- 28860230 TI - Predictors of discharge destination from acute care in patients with traumatic brain injury. AB - INTRODUCTION: Many studies have assessed the predictors of morbidity/mortality of patients with traumatic brain injury (TBI) in acute care. However, with the increasing rate of survival after TBI, more attention has been given to discharge destinations from acute care as an important measure of clinical priorities. This study describes the design of a systematic review compiling and synthesising studies on the prognostic factors of discharge settings from acute care in patients with TBI. METHODS AND ANALYSIS: This systematic review will be conducted on peer-reviewed studies using seven databases including Medline/Medline in Process, Embase, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, PsycINFO, CINAHL and Supplemental PubMed. The reference list of selected articles and Google Scholar will also be reviewed to determine other relevant articles. This study will include all English language observational studies that focus on adult patients with TBI in acute care settings. The quality of articles will be assessed by the Quality in Prognostic Studies tool. ETHICS AND DISSEMINATION: The results of this review will provide evidence that may guide healthcare providers in making more informed and timely discharge decisions to the next level of care for patient with TBI. Also, this study will provide valuable information to address the gaps in knowledge for future research. TRIAL REGISTRATION NUMBER: Trial registration number (PROSPERO) is CRD42016033046. PMID- 28860231 TI - Ultraviolet B Exposure Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Expanding CD4+Foxp3+ Regulatory T Cells. AB - BACKGROUND: Pathogenic immune responses are known to play an important role in abdominal aortic aneurysm (AAA) development. Ultraviolet B (UVB) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of UVB irradiation on experimental AAA. METHODS AND RESULTS: We used an angiotensin II-induced AAA model in apolipoprotein E-deficient mice fed a high-cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m2 UVB once weekly for 6 weeks (UVB irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of AAA formation at 16 weeks. Overall, 93% of angiotensin II-infused mice developed AAA, with 60% mortality possibly because of aneurysm rupture. UVB irradiation significantly decreased the incidence (66%) and mortality (29%) of AAA (P=0.004 and P=0.006, respectively). UVB-irradiated mice had significantly smaller diameter AAA (P=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of CD4+Foxp3+ regulatory T cells and decreased effector CD4+CD44highCD62Llow T cells in para-aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of UVB treatment, demonstrating a critical role of regulatory T cells. CONCLUSIONS: Our data suggest that UVB-dependent expansion of regulatory T cells has beneficial effects on experimental AAA and may provide a novel strategy for the treatment of AAA. PMID- 28860233 TI - Modeling mixed-lineage-rearranged leukemia initiation in CD34+ cells: a "CRISPR" solution. PMID- 28860234 TI - Complete Genome Sequence of Salmonella enterica Lytic Bacteriophage LPST10, Isolated in China. AB - Bacteriophage LPST10 was isolated from Wuhan, China. Lytic activity was demonstrated against multiple Salmonella enterica serovars, including Salmonella enterica serovar Typhimurium strains. This bacteriophage has a 47,657-bp double stranded DNA genome encoding 87 putative coding sequences. PMID- 28860235 TI - Whole-Genome Sequence of the 1,4-Dioxane-Degrading Bacterium Mycobacterium dioxanotrophicus PH-06. AB - We report here the complete genome sequence of Mycobacterium dioxanotrophicus PH 06, which is capable of using 1,4-dioxane as a sole source of carbon and energy. The reported sequence will enable the elucidation of this novel metabolic pathway and the development of molecular biomarkers to assess bioremediation potential at contaminated sites. PMID- 28860236 TI - Draft Genome Sequence of Solibacillus kalamii, Isolated from an Air Filter Aboard the International Space Station. AB - We report here the draft genome of Solibacillus kalamii ISSFR-015, isolated from a high-energy particulate arrestance filter aboard the International Space Station. The draft genome sequence of this strain contains 3,809,180 bp with an estimated G+C content of 38.61%. PMID- 28860237 TI - Draft Genome Sequence of Photorhabdus luminescens HIM3 Isolated from an Entomopathogenic Nematode in Agricultural Soils. AB - In this work, we report the draft genome sequence of Photorhabdus luminescens strain HIM3, a symbiotic bacterium associated with the entomopathogenic nematode Heterorhabditis indica MOR03, isolated from soil sugarcane in Yautepec, Morelos, Mexico. These bacteria have a G+C content of 42.6% and genome size of 5.47 Mb. PMID- 28860238 TI - Genome Sequences of 30 Escherichia coli O157:H7 Isolates Recovered from a Single Dairy Farm and Its Associated Off-Site Heifer-Raising Facility. AB - Cattle are the primary reservoir of Escherichia coli O157:H7, the most frequently isolated serotype of enterohemorrhagic E. coli infections among humans in North America. To evaluate the diversity of E. coli O157:H7 isolates within a single dairy herd, the genomes of 30 isolates collected over a 7-year period were sequenced. PMID- 28860239 TI - Corrected Genome Sequence of Acinetobacter baumannii Strain AB0057, an Antibiotic Resistant Isolate from Lineage 1 of Global Clone 1. AB - Extensively antibiotic-resistant Acinetobacter baumannii isolate AB0057 recovered in the United States in 2004 was one of the first global clone 1 isolates to be completely sequenced. Here, the complete 4.05-Mb genome sequence (chromosome and one plasmid) has been revised using Illumina HiSeq data and targeted sequencing of PCR products. PMID- 28860232 TI - Self-Care for the Prevention and Management of Cardiovascular Disease and Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association. AB - Self-care is defined as a naturalistic decision-making process addressing both the prevention and management of chronic illness, with core elements of self-care maintenance, self-care monitoring, and self-care management. In this scientific statement, we describe the importance of self-care in the American Heart Association mission and vision of building healthier lives, free of cardiovascular diseases and stroke. The evidence supporting specific self-care behaviors such as diet and exercise, barriers to self-care, and the effectiveness of self-care in improving outcomes is reviewed, as is the evidence supporting various individual, family-based, and community-based approaches to improving self-care. Although there are many nuances to the relationships between self-care and outcomes, there is strong evidence that self-care is effective in achieving the goals of the treatment plan and cannot be ignored. As such, greater emphasis should be placed on self-care in evidence-based guidelines. PMID- 28860240 TI - Genome Sequence of Roseovarius sp. Strain MCTG156(2b) Isolated from a Phytoplankton Net Trawl on the Scottish West Coast. AB - Roseovarius sp. strain MCTG156(2b) was isolated from a phytoplankton net sample collected on the west coast of Scotland and was selected based on its ability to degrade polycyclic aromatic hydrocarbons. Here, we present the genome sequence of this strain, which is 5,113,782 bp, with 5,142 genes and an average G+C content of 60.7%. PMID- 28860242 TI - Complete Genome Sequence of Systemically Disseminated Sequence Type 8 Staphylococcal Cassette Chromosome mec Type IVl Community-Acquired Methicillin Resistant Staphylococcus aureus. AB - Staphylococcus aureus JH4899, a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolate collected from a patient with systematically disseminated infection, is classified as sequence type 8 and carries the staphylococcal cassette chromosome mec type IVl (SCCmecIVl). It produces TSST-1, SEC, a newly discovered enterotoxin (SE1), and epidermal cell differentiation inhibitor A (EDIN-A). Here, we present the complete genome sequence of the chromosome and a plasmid harboring the se1 and ednA genes. PMID- 28860241 TI - Draft Genome Sequence of an Obligate Psychrophilic Yeast, Candida psychrophila NRRL Y-17665T. AB - Candida psychrophila is an obligate psychrophilic yeast classified into the family Debaryomycetaceae (Saccharomycotina). Here, we report the draft genome sequence of the type strain, NRRL Y-17665. The genome sequence is 11.2 Mb long and codes for 5,827 predicted proteins. PMID- 28860243 TI - Complete Genome Sequence of Frog virus 3, Isolated from a Strawberry Poison Frog (Oophaga pumilio) Imported from Nicaragua into the Netherlands. AB - Frog virus 3 was isolated from a strawberry poison frog (Oophaga pumilio) imported from Nicaragua via Germany to the Netherlands, and its complete genome sequence was determined. Frog virus 3 isolate Op/2015/Netherlands/UU3150324001 is 107,183 bp long and has a nucleotide similarity of 98.26% to the reference Frog virus 3 isolate. PMID- 28860244 TI - Whole-Genome Sequence of Streptococcus tigurinus Strain osk_001, Isolated from Postmortem Material. AB - Streptococcus tigurinus was recently described as a novel species, and some strains are highly virulent. We detected S. tigurinus in infected tissue sampled by necropsy. In order to characterize and confirm the virulence of this species, whole-genome sequencing of the pure cultured bacterium was performed. We found that the strain has specific and unique genetic elements contained in highly virulent strains of S. tigurinus. PMID- 28860245 TI - Draft Genome Sequence of the Phytopathogenic Fungus Fusarium euwallaceae, the Causal Agent of Fusarium Dieback. AB - Here, we report the genome of Fusarium euwallaceae strain HFEW-16-IV-019, an isolate obtained from Kuroshio shot hole borer (a Euwallacea sp.). These beetles were collected in Tijuana, Mexico, from elm trees showing typical symptoms of Fusarium dieback. The final assembly consists of 287 scaffolds spanning 48,274,071 bp and 13,777 genes. PMID- 28860246 TI - Complete Genome Sequence of Lumpy Skin Disease Virus Isolate SERBIA/Bujanovac/2016, Detected during an Outbreak in the Balkan Area. AB - The lumpy skin disease virus (LSDV) isolate SERBIA/Bujanovac/2016 consists of 150,661 nucleotides and has a 99.95% nucleotide identity with the Neethling Warmbaths LW strain isolated in South Africa in 1999. This is the first complete LSDV genome determined in Serbia and also in the Balkan area. PMID- 28860247 TI - Whole-Genome Sequence of Bacillus cereus AR156, a Potential Biocontrol Agent with High Soilborne Disease Biocontrol Efficacy and Plant Growth Promotion. AB - Bacillus cereus AR156 was originally isolated from the forest soil of Zhenjiang, a city in China. To shed new light on the molecular mechanisms underlying the biological control of soilborne pathogens, the whole genome of this strain was sequenced. Here, we report the draft genome sequence of this strain, consisting of a single circularized contig measuring 5.66 Mb, with an average GC content of 35.5% and 5,367 open reading frames. PMID- 28860248 TI - Complete Genome Sequences of Two Swiss Hepatitis E Virus Isolates from Human Stool and Raw Pork Sausage. AB - We present here the full-length genome sequences of two hepatitis E virus genotype 3 (HEV-3) isolates from a human stool sample from a patient with acute hepatitis and a raw sausage containing pig liver. Sequence analysis implies that Swiss HEV isolates may form a novel subgroup of HEV-3 viruses. PMID- 28860249 TI - Draft Genome Sequences of Sphingomonas mucosissima DSM 17494 and Sphingomonas dokdonensis DSM 21029. AB - Sphingomonas mucosissima and Sphingomonas dokdonensis are Gram-negative chemoheterotrophic strictly aerobic rods or cocci. The genomes (3.453 Mb and 3.587 Mb, respectively) contain 3,279 and 3,329 predicted protein-encoding genes, respectively. The genome of S. dokdonensis harbors a 90-kb plasmid. PMID- 28860250 TI - Draft Genome Sequence of Methanothermobacter sp. Strain EMTCatA1, Reconstructed from the Metagenome of a Thermophilic Electromethanogenesis-Catalyzing Biocathode. AB - A draft genome of Methanothermobacter sp. strain EMTCatA1 was reconstructed from a metagenome of a thermophilic electromethanogenic biocathode. This genome will provide information about methanogens catalyzing methanogenesis at the biocathodes. PMID- 28860251 TI - Whole-Genome Sequence of Chlamydia abortus Strain GN6 Isolated from Aborted Yak Fetus. AB - The obligate intracellular Gram-negative bacterium Chlamydia abortus is one of the causative agents of abortion and fetal loss in sheep, goats, and cattle in many countries. It also affects the reproductivity of yaks (Bos grunniens). This study reports the whole-genome sequence of Chlamydia abortus strain GN6, which was isolated from aborted yak fetus in Qinghai-Tibetan Plateau, China. PMID- 28860252 TI - Whole-Genome Sequences of Brucella melitensis Strain QY1, Isolated from Sheep in Gansu, China. AB - The facultative intracellular Gram-negative bacterium Brucella melitensis causes brucellosis in domestic and wild mammals, and it is a dominant pathogen responsible for human disease. This study reports the whole-genome sequencing of B. melitensis strain QY1, isolated from sheep suffering from abortion and arthritis in 2015 in Gansu, China. PMID- 28860253 TI - Draft Genome Sequences of the Oomycete Pilasporangium apinafurcum Strains JCM 30513 and JCM 30514, Formerly Classified as Pythium apinafurcum. AB - Pilasporangium apinafurcum, formerly classified as Pythium apinafurcum, is a unique oomycete that infects plants asymptomatically. Here, we present the draft genome sequences of two variants of P. apinafurcum, JCM 30513 and JCM 30514, isolated from uncultivated field soil in Wakayama Prefecture, Japan. PMID- 28860254 TI - Complete Genome Sequence of Mesorhizobium ciceri bv. biserrulae WSM1497, an Efficient Nitrogen-Fixing Microsymbiont of the Forage Legume Biserrula pelecinus. AB - We report here the complete genome sequence of Mesorhizobium ciceri bv. biserrulae strain WSM1497, the efficient nitrogen-fixing microsymbiont and commercial inoculant in Australia of the forage legume Biserrula pelecinus The genome consists of 7.2 Mb distributed across a single chromosome (6.67 Mb) and a single plasmid (0.53 Mb). PMID- 28860255 TI - Whole-Genome Sequence and Methylome Analysis of the Freshwater Colorless Sulfur Bacterium Thioflexothrix psekupsii D3. AB - In this report, we announce the availability of a whole-genome sequence and methylome analysis of Thioflexothrix psekupsii strain D3. PMID- 28860256 TI - Complete Genome Sequence of Vibrio sp. Strain 2521-89, a Close Relative of Vibrio cholerae Isolated from Lake Water in New Mexico, USA. AB - Vibrio sp. strain 2521-89 is an environmental isolate from lake water in New Mexico, USA. Average nucleotide identity, in silico DNA-DNA hybridization, and core genome single-nucleotide polymorphism (SNP)-based phylogenetic analysis suggest that this may be a potentially novel species that is closely related to Vibrio cholerae. PMID- 28860257 TI - High-Quality Draft Genome Sequences for Four Drug-Resistant or Outbreak Associated Shigella sonnei Strains Generated with PacBio Sequencing and Whole Genome Maps. AB - Drug-resistant Shigella sonnei poses a clinical and public health challenge. We report here the high-quality draft whole-genome sequences of four outbreak associated S. sonnei isolates; three were resistant to two or more antibiotics, and one was resistant to streptomycin only. PMID- 28860258 TI - Complete Genome Sequence of the Pathogenic Vibrio vulnificus Type Strain ATCC 27562. AB - Vibrio vulnificus has the highest death rate and economic burden per case of any foodborne pathogen in the United States. A complete genome sequence of the type strain promotes comparative analyses with other clinical and environmental isolates, improving our understanding of this important human pathogen and successful environmental organism. PMID- 28860259 TI - Complete Genome Sequence of Nectarine stem pitting-associated virus, Isolated from Prunus persica in Cheongdo County, South Korea. AB - We report here the first complete genome sequence of a South Korean isolate of Nectarine stem pitting-associated virus (NSPaV) from peach and compare it with previously described complete NSPaV genome sequences. The highest whole-genome nucleotide sequence identity was 95.3% with GenBank accession no. KT273409 (NSPaV) from the United States. PMID- 28860260 TI - Whole-Genome Sequence of Streptococcus agalactiae Strain S13, Isolated from a Fish Eye from a Nile Tilapia Farm in Southern Brazil. AB - Streptococcus agalactiae is an important pathogen to world aquaculture due to its high mortality rates in fish farms and consequent economic losses. Our study presents the complete genome sequence of strain S13, isolated from a tilapia farm outbreak in southern Brazil. PMID- 28860261 TI - Complete Genome Sequence of Bacillus velezensis GQJK49, a Plant Growth-Promoting Rhizobacterium with Antifungal Activity. AB - Bacillus velezensis GQJK49 is a plant growth-promoting rhizobacterium with antifungal activity, which was isolated from Lycium barbarum L. rhizosphere. Here, we report the complete genome sequence of B. velezensis GQJK49. Twelve gene clusters related to its biosynthesis of secondary metabolites, including antifungal and antibacterial antibiotics, were predicted. PMID- 28860262 TI - Complete Genome Sequences of Two Pseudomonas aeruginosa Strains Isolated from Children with Bacteremia. AB - Two Pseudomonas aeruginosa strains isolated from children with bacteremia in Mexico City were sequenced using PacBio RS-II single-molecule real-time (SMRT) technology. The strains consist of a 7.0- to 7.4-Mb chromosome, with a high content of mobile elements, and variation in the genetic content of class 1 integron In1409. PMID- 28860263 TI - Genome Sequence of Rhizobium esperanzae Type Strain CNPSo 668, Isolated from Phaseolus vulgaris Nodules in Mexico. AB - Rhizobium esperanzae CNPSo 668T is a nitrogen-fixing symbiont of Phaseolus vulgaris isolated from Mexican soils. Its genome is estimated at 6,294,057 bp, with 6,219 coding sequences (CDSs) showing higher similarity (92.9%) with Rhizobium etli Three copies of the regulatory nodD, in addition to other nodulation genes, should define its host specificity. PMID- 28860264 TI - Adaptive servo ventilation for central sleep apnoea in heart failure: SERVE-HF on treatment analysis. AB - This on-treatment analysis was conducted to facilitate understanding of mechanisms underlying the increased risk of all-cause and cardiovascular mortality in heart failure patients with reduced ejection fraction and predominant central sleep apnoea randomised to adaptive servo ventilation versus the control group in the SERVE-HF trial.Time-dependent on-treatment analyses were conducted (unadjusted and adjusted for predictive covariates). A comprehensive, time-dependent model was developed to correct for asymmetric selection effects (to minimise bias).The comprehensive model showed increased cardiovascular death hazard ratios during adaptive servo ventilation usage periods, slightly lower than those in the SERVE-HF intention-to-treat analysis. Self-selection bias was evident. Patients randomised to adaptive servo ventilation who crossed over to the control group were at higher risk of cardiovascular death than controls, while control patients with crossover to adaptive servo ventilation showed a trend towards lower risk of cardiovascular death than patients randomised to adaptive servo ventilation. Cardiovascular risk did not increase as nightly adaptive servo ventilation usage increased.On-treatment analysis showed similar results to the SERVE-HF intention-to-treat analysis, with an increased risk of cardiovascular death in heart failure with reduced ejection fraction patients with predominant central sleep apnoea treated with adaptive servo ventilation. Bias is inevitable and needs to be taken into account in any kind of on-treatment analysis in positive airway pressure studies. PMID- 28860267 TI - Vascular remodelling in the pulmonary circulation after major lung resection. PMID- 28860268 TI - Implementation of Xpert MTB/RIF in 22 high tuberculosis burden countries: are we making progress? PMID- 28860266 TI - Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-year follow-up results from two prospective multicentre studies. AB - Bronchial thermoplasty is an endoscopic therapy for severe asthma. The previously reported, randomised sham-controlled AIR2 (Asthma Intervention Research 2) trial showed a significant reduction in severe asthma exacerbations, emergency department visits and hospitalisations after bronchial thermoplasty. More "real world" clinical outcome data is needed.This article compares outcomes in bronchial thermoplasty subjects with 3 years of follow-up from the ongoing, post market PAS2 (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma) study with those from the AIR2 trial.279 subjects were treated with bronchial thermoplasty in the PAS2 study. We compared the first 190 PAS2 subjects with the 190 bronchial thermoplasty-treated subjects in the AIR2 trial at 3 years of follow-up. The PAS2 subjects were older (mean age 45.9 versus 40.7 years) and more obese (mean body mass index 32.5 versus 29.3 kg.m-2) and took higher doses of inhaled corticosteroids (mean dose 2301 versus 1961 MUg.day-1). More PAS2 subjects had experienced severe exacerbations (74% versus 52%) and hospitalisations (15.3% versus 4.2%) in the 12 months prior to bronchial thermoplasty. At year 3 after bronchial thermoplasty, the percentage of PAS2 subjects with severe exacerbations, emergency department visits and hospitalisations significantly decreased by 45%, 55% and 40%, respectively, echoing the AIR2 results.The PAS2 study demonstrates similar improvements in asthma control after bronchial thermoplasty compared with the AIR2 trial despite enrolling subjects who may have had poorer asthma control. PMID- 28860265 TI - Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. AB - Noninvasive mechanical ventilation (NIV) is widely used in the acute care setting for acute respiratory failure (ARF) across a variety of aetiologies. This document provides European Respiratory Society/American Thoracic Society recommendations for the clinical application of NIV based on the most current literature.The guideline committee was composed of clinicians, methodologists and experts in the field of NIV. The committee developed recommendations based on the GRADE (Grading, Recommendation, Assessment, Development and Evaluation) methodology for each actionable question. The GRADE Evidence to Decision framework in the guideline development tool was used to generate recommendations. A number of topics were addressed using technical summaries without recommendations and these are discussed in the supplementary material.This guideline committee developed recommendations for 11 actionable questions in a PICO (population-intervention-comparison-outcome) format, all addressing the use of NIV for various aetiologies of ARF. The specific conditions where recommendations were made include exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary oedema, de novo hypoxaemic respiratory failure, immunocompromised patients, chest trauma, palliation, post-operative care, weaning and post-extubation.This document summarises the current state of knowledge regarding the role of NIV in ARF. Evidence-based recommendations provide guidance to relevant stakeholders. PMID- 28860270 TI - Clinical screening of oropharyngeal dysphagia: standard of care. PMID- 28860271 TI - How effective is bronchial thermoplasty for severe asthma in clinical practice? PMID- 28860272 TI - Clinical screening of oropharyngeal dysphagia: standard of care. PMID- 28860273 TI - SERVE-HF on-treatment analysis: does the on-treatment analysis SERVE its purpose? PMID- 28860274 TI - WDR91 is a Rab7 effector required for neuronal development. AB - Early-to-late endosome conversion, which is essential for delivery of endosomal cargoes to lysosomes, requires switching of early endosome-specific Rab5 and PtdIns3P to late endosome-specific Rab7 and PtdIns(3,5)P2 In this study, we identify the WD40-repeat protein WDR91 as a Rab7 effector that couples Rab switching with PtdIns3P down-regulation on endosomes. Loss of WDR91 greatly increases endosomal PtdIns3P levels, arresting endosomes at an intermediate stage and blocking endosomal-lysosomal trafficking. WDR91 is recruited to endosomes by interacting with active guanosine triphosophate-Rab7 and inhibits Rab7-associated phosphatidylinositol 3-kinase activity. In mice, global Wdr91 knockout causes neonatal death, whereas brain-specific Wdr91 inactivation impairs brain development and causes postnatal death. Mouse neurons lacking Wdr91 accumulate giant intermediate endosomes and exhibit reduced neurite length and complexity. These phenotypes are rescued by WDR91 but not WDR91 mutants that cannot interact with Rab7. Thus, WDR91 serves as a Rab7 effector that is essential for neuronal development by facilitating endosome conversion in the endosome-lysosome pathway. PMID- 28860276 TI - DNA damage-induced immune response: Micronuclei provide key platform. AB - DNA damage-induced activation of the cytoplasmic DNA sensor cGAS influences the outcome of infections, autoinflammation, and cancer. Recent studies by Harding et al. (2017. Nature. http://dx.doi.org/10.1038/nature23470), Mackenzie et al. (2017. Nature. http://dx.doi.org/10.1038/nature23449), and Bartsch et al. (2017. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddx283) demonstrate a role for micronuclei formation in DNA damage-induced immune activation. PMID- 28860275 TI - 14-3-3 regulation of Ncd reveals a new mechanism for targeting proteins to the spindle in oocytes. AB - The meiotic spindle is formed without centrosomes in a large volume of oocytes. Local activation of crucial spindle proteins around chromosomes is important for formation and maintenance of a bipolar spindle in oocytes. We found that phosphodocking 14-3-3 proteins stabilize spindle bipolarity in Drosophila melanogaster oocytes. A critical 14-3-3 target is the minus end-directed motor Ncd (human HSET; kinesin-14), which has well-documented roles in stabilizing a bipolar spindle in oocytes. Phospho docking by 14-3-3 inhibits the microtubule binding activity of the nonmotor Ncd tail. Further phosphorylation by Aurora B kinase can release Ncd from this inhibitory effect of 14-3-3. As Aurora B localizes to chromosomes and spindles, 14-3-3 facilitates specific association of Ncd with spindle microtubules by preventing Ncd from binding to nonspindle microtubules in oocytes. Therefore, 14-3-3 translates a spatial cue provided by Aurora B to target Ncd selectively to the spindle within the large volume of oocytes. PMID- 28860278 TI - Deconstructing the Doctor. PMID- 28860277 TI - DC2 and KCP2 mediate the interaction between the oligosaccharyltransferase and the ER translocon. AB - In metazoan organisms, the STT3A isoform of the oligosaccharyltransferase is localized adjacent to the protein translocation channel to catalyze co translational N-linked glycosylation of proteins in the endoplasmic reticulum. The mechanism responsible for the interaction between the STT3A complex and the translocation channel has not been addressed. Using genetically modified human cells that are deficient in DC2 or KCP2 proteins, we show that loss of DC2 causes a defect in co-translational N-glycosylation of proteins that mimics an STT3A-/- phenotype. Biochemical analysis showed that DC2 and KCP2 are responsible for mediating the interaction between the protein translocation channel and the STT3A complex. Importantly, DC2- and KCP2-deficient STT3A complexes are stable and enzymatically active. Deletion mutagenesis revealed that a conserved motif in the C-terminal tail of DC2 is critical for assembly into the STT3A complex, whereas the lumenal loop and the N-terminal cytoplasmic segment are necessary for the functional interaction between the STT3A and Sec61 complexes. PMID- 28860279 TI - The polypharmacy challenge: time for a new script? PMID- 28860269 TI - Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: an international case-cohort study. AB - We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts.A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (kappaw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first choice diagnoses of IPF and were compared using the C-index.A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (kappaw=0.65, IQR 0.53-0.72, p<0.0001) than academic physicians (kappaw=0.56, IQR 0.45-0.65, p<0.0001) or physicians with access to multidisciplinary team (MDT) meetings (kappaw=0.54, IQR 0.45-0.64, p<0.0001). The prognostic accuracy of academic physicians with >20 years of experience (C index=0.72, IQR 0.0-0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70-0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72-0.75).Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts. PMID- 28860280 TI - Pharmacists working in general practice: can they help tackle the current workload crisis? PMID- 28860281 TI - What occupational medicine offers to primary care. PMID- 28860283 TI - Pharmacists' perceptions of their emerging general practice roles in UK primary care: a qualitative interview study. PMID- 28860282 TI - Acute kidney injury in primary care: where are we now and where are we going? PMID- 28860284 TI - Clinical relevance of thrombocytosis in primary care. PMID- 28860285 TI - Authors' response. PMID- 28860286 TI - Child not brought to appointment. PMID- 28860287 TI - Improving together: a new quality framework for GP clusters in Scotland. PMID- 28860288 TI - Helpful strategies for GPs seeing patients with MUPS. PMID- 28860289 TI - Viewpoint: Domperidone and breastfeeding. PMID- 28860290 TI - The Clinical Research Network: get involved and expand your portfolio. PMID- 28860291 TI - Professor Richard Scott: celebrating the first professor of general practice in the world. PMID- 28860292 TI - Bad Medicine: Evidence-based health care? PMID- 28860293 TI - Yonder: Welfare advice, pelvic floor training, telephone consultations, and the surprise question. PMID- 28860294 TI - Gordon Square Gardens: a hidden history: A Haven Close to the College. PMID- 28860295 TI - Books: The Pioppi Diet: A 21-Day Lifestyle Plan: It's Not Just a Diet: It's a Lifestyle. PMID- 28860296 TI - Books: The Health Gap: The Challenge of an Unequal World: Unjust Sense. PMID- 28860297 TI - Thoughts on GPs and social workers. PMID- 28860298 TI - Ills, pills, and skills: developing the clinical skills of pharmacists in general practice. PMID- 28860299 TI - The ethics of setting national antibiotic policies using financial incentives. PMID- 28860300 TI - Improving public health information for patients: shared decision making and influenza vaccination. PMID- 28860301 TI - Vitamin D supplementation for women before and during pregnancy: an update of the guidelines, evidence, and role of GPs and practice nurses. PMID- 28860302 TI - Cryptosporidium outbreaks: identification, diagnosis, and management. PMID- 28860305 TI - MSF criticises India's decision to grant pneumococcal vaccine patent to Pfizer. PMID- 28860303 TI - Conservation of tRNA mimicry in the 5'-untranslated region of distinct HIV-1 subtypes. AB - Human tRNALys3 serves as the primer for reverse transcription in human immunodeficiency virus type-1 (HIV-1) and anneals to the complementary primer binding site (PBS) in the genome. All tRNALys isoacceptors interact with human lysyl-tRNA synthetase (hLysRS) and are selectively packaged into virions. tRNALys3 must be released from hLysRS in order to anneal to the PBS, and this process is proposed to be facilitated by the interaction of hLysRS with a tRNA like element (TLE) first identified in the HIV-1 5'-untranslated region (5'-UTR) of the subtype B NL4-3 virus. However, a significant subset of HIV-1 strains represented by the MAL isolate possess a different secondary structure in this region of the genome. Thus, to establish the conservation of this mechanism for primer targeting and release, we investigated the subtype A-like 5'-UTR of the MAL isolate. hLysRS bound to a 229-nt MAL RNA containing the PBS domain with high affinity (Kd = 47 nM), and to a 98-nt truncated construct with ~10-fold reduced affinity. These results resemble previous studies using analogous NL4-3-derived RNAs. However, in contrast to studies with NL4-3, no binding was observed to smaller stem-loop elements within the MAL PBS domain. The tertiary structure of the 98-nt construct was analyzed using small-angle X-ray scattering, revealing remarkable global structural similarity to the corresponding NL4-3 PBS/TLE region. These results suggest that the tRNA-like structure within the 5'-UTR is conserved across distinct HIV-1 subtypes and that hLysRS recognition of the MAL isolate is likely not conferred by specific sequence elements but by 3D structure. PMID- 28860306 TI - The Hemoglobinopathies: An Empowering Era of Human Genetics in the Clinic and the Laboratory. PMID- 28860304 TI - Multiple miRNAs jointly regulate the biosynthesis of ecdysteroid in the holometabolous insects, Chilo suppressalis. AB - The accurate rise and fall of active hormones is important for insect development. The ecdysteroids must be cleared in a timely manner. However, the mechanism of suppressing the ecdysteroid biosynthesis at the right time remains unclear. Here, we sequenced a small RNA library of Chilo suppressalis and identified 300 miRNAs in this notorious rice insect pest. Microarray analysis yielded 54 differentially expressed miRNAs during metamorphosis development. Target prediction and in vitro dual-luciferase assays confirmed that seven miRNAs (two conserved and five novel miRNAs) jointly targeted three Halloween genes in the ecdysteroid biosynthesis pathway. Overexpression of these seven miRNAs reduced the titer of 20-hydroxyecdysone (20E), induced mortality, and retarded development, which could be rescued by treatment with 20E. Comparative analysis indicated that the miRNA regulation of metamorphosis development is a conserved process but that the miRNAs involved are highly divergent. In all, we present evidence that both conserved and lineage-specific miRNAs have crucial roles in regulating development in insects by controlling ecdysteroid biosynthesis, which is important for ensuring developmental convergence and evolutionary diversity. PMID- 28860307 TI - Fifty years in human genetics--a career retrospective. PMID- 28860309 TI - Erratum. PMID- 28860308 TI - Erratum. PMID- 28860311 TI - Meet the First Authors. PMID- 28860310 TI - Earmarking for global health: benefits and perils of the World Bank's trust fund model. PMID- 28860312 TI - Untangle a Broken Heart via Janus Kinase 1. PMID- 28860313 TI - Smooth Muscle Differentiation Control Comes Full Circle: The Circular Noncoding RNA, circActa2, Functions as a miRNA Sponge to Fine-Tune alpha-SMA Expression. PMID- 28860314 TI - Dynamic Regulation of the Subunit Composition of BK Channels in Smooth Muscle. PMID- 28860315 TI - The Endless Summer: Thermoneutrality Prevents Monocytosis and Reduces Atherosclerosis. PMID- 28860316 TI - Pearl Quijada: Enthusiastic Drive From Coast to Coast. PMID- 28860317 TI - The Myofilament Field Revisited in the Age of Cellular and Molecular Biology. PMID- 28860318 TI - Reducing the Global Burden of Cardiovascular Disease, Part 1: The Epidemiology and Risk Factors. AB - Current global health policy goals include a 25% reduction in premature mortality from noncommunicable diseases by 2025. In this 2-part review, we provide an overview of the current epidemiological data on cardiovascular diseases (CVD), its risk factors, and describe strategies aimed at reducing its burden. In part 1, we examine the global epidemiology of cardiac conditions that have the greatest impact on CVD mortality; the predominant risk factors; and the impact of upstream, societal health determinants (eg, environmental factors, health policy, and health systems) on CVD. Although age-standardized mortality from CVD has decreased in many regions of the world, the absolute number of deaths continues to increase, with the majority now occurring in middle- and low-income countries. It is evident that multiple factors are causally related to CVD, including traditional individual level risk factors (mainly tobacco use, lipids, and elevated blood pressure) and societal level health determinants (eg, health systems, health policies, and barriers to CVD prevention and care). Both individual and societal risk factors vary considerably between different regions of the world and economic settings. However, reliable data to estimate CVD burden are lacking in many regions of the world, which hampers the establishment of nationwide prevention and management strategies. A 25% reduction in premature CVD mortality globally is feasible but will require better implementation of evidence based policies (particularly tobacco control) and integrated health systems strategies that improve CVD prevention and management. In addition, there is a need for better health information to monitor progress and guide health policy decisions. PMID- 28860319 TI - Reducing the Global Burden of Cardiovascular Disease, Part 2: Prevention and Treatment of Cardiovascular Disease. AB - In this second part of a 2-part series on the global burden of cardiovascular disease, we review the proven, effective approaches to the prevention and treatment of cardiovascular disease. We specifically review the management of acute cardiovascular diseases, including acute coronary syndromes and stroke; the care of cardiovascular disease in the ambulatory setting, including medical strategies for vascular disease, atrial fibrillation, and heart failure; surgical strategies for arterial revascularization, rheumatic and other valvular heart disease, and symptomatic bradyarrhythmia; and approaches to the prevention of cardiovascular disease, including lifestyle factors, blood pressure control, cholesterol-lowering, antithrombotic therapy, and fixed-dose combination therapy. We also discuss cardiovascular disease prevention in diabetes mellitus; digital health interventions; the importance of socioeconomic status and universal health coverage. We review building capacity for conduction cardiovascular intervention through strengthening healthcare systems, priority setting, and the role of cost effectiveness. PMID- 28860321 TI - TPO for ITP in pregnancy. PMID- 28860320 TI - Cross-Species Y Chromosome Function Between Malaria Vectors of the Anopheles gambiae Species Complex. AB - Y chromosome function, structure and evolution is poorly understood in many species, including the Anopheles genus of mosquitoes-an emerging model system for studying speciation that also represents the major vectors of malaria. While the Anopheline Y had previously been implicated in male mating behavior, recent data from the Anopheles gambiae complex suggests that, apart from the putative primary sex-determiner, no other genes are conserved on the Y. Studying the functional basis of the evolutionary divergence of the Y chromosome in the gambiae complex is complicated by complete F1 male hybrid sterility. Here, we used an F1 * F0 crossing scheme to overcome a severe bottleneck of male hybrid incompatibilities that enabled us to experimentally purify a genetically labeled A. gambiae Y chromosome in an A. arabiensis background. Whole genome sequencing (WGS) confirmed that the A. gambiae Y retained its original sequence content in the A. arabiensis genomic background. In contrast to comparable experiments in Drosophila, we find that the presence of a heterospecific Y chromosome has no significant effect on the expression of A. arabiensis genes, and transcriptional differences can be explained almost exclusively as a direct consequence of transcripts arising from sequence elements present on the A. gambiae Y chromosome itself. We find that Y hybrids show no obvious fertility defects, and no substantial reduction in male competitiveness. Our results demonstrate that, despite their radically different structure, Y chromosomes of these two species of the gambiae complex that diverged an estimated 1.85 MYA function interchangeably, thus indicating that the Y chromosome does not harbor loci contributing to hybrid incompatibility. Therefore, Y chromosome gene flow between members of the gambiae complex is possible even at their current level of divergence. Importantly, this also suggests that malaria control interventions based on sex-distorting Y drive would be transferable, whether intentionally or contingent, between the major malaria vector species. PMID- 28860322 TI - CDK9 inhibition for ATL therapy. PMID- 28860323 TI - Traffic lights for ruxolitinib. PMID- 28860324 TI - Balancing the yin and yang of SINE. PMID- 28860325 TI - Allogeneic transplant: does age still matter? PMID- 28860326 TI - Coexistence of multiple myeloma and Paget disease of bone. PMID- 28860327 TI - Lacrimal gland and extensive subcutaneous tissue involvement by mantle cell lymphoma. PMID- 28860328 TI - Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood brain barrier. AB - Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS. PMID- 28860330 TI - Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy. AB - Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of alpha-synuclein; therefore, MSA is included in the category of alpha-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively. It is increasingly recognised, however, that clinical and pathological features of MSA are broader than previously considered.In this review, we aim to describe recent advances in neuropathology of MSA from a review of the literature and from information derived from review of nearly 200 definite MSA cases in the Mayo Clinic Brain Bank. In light of these new neuropathological findings, GCIs and neuronal cytoplasmic inclusions play an important role in clinicopathological correlates of MSA. We also focus on clinical diagnostic accuracy and differential diagnosis of MSA as well as candidate biomarkers. We also review some controversial topics in MSA. Cognitive impairment, which has been a non-supporting feature of MSA, is considered from both clinical and pathological perspectives. The cellular origin of alpha-synuclein in GCI and a 'prion hypothesis' are discussed. Finally, completed and ongoing clinical trials targeting disease modification, including immunotherapy, are summarised. PMID- 28860329 TI - Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A. AB - BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. METHODS: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. RESULTS: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. CONCLUSIONS: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A. PMID- 28860332 TI - Negative-Pressure Ventilation in Pediatric Acute Respiratory Failure. AB - BACKGROUND: The objective of this work was to describe the use of negative pressure ventilation (NPV) in a heterogeneous critically ill, pediatric population. METHODS: A retrospective chart review was conducted of all patients admitted to a pediatric ICU with acute respiratory failure supported with NPV from January 1, 2012 to May 15, 2015. RESULTS: Two hundred thirty-three subjects at a median age of 15.5 months were supported with NPV for various etiologies, most commonly bronchiolitis (70%). Median (interquartile range) duration of support was 18.7 (8.7-34.3) h. The majority were NPV responders (70%), defined as not needing escalation to any form of positive-pressure ventilation. In non responders, escalation occurred at a median (interquartile range) of 6.9 (3.3 16.6) h. More NPV non-responders had upper-airway obstruction (P = .02), and fewer had bronchiolitis (P = .008) compared with responders. A bedside scoring system developed on these data was 98% specific in predicting NPV failure by 4 h after NPV start (area under the curve 0.759, 95% CI 0.675-0.843, P < .001). Complications from NPV were rare (3%); however, delayed enteral nutrition (33%) and continuous intravenous sedation use (51%) in children while receiving NPV were more frequent. The annual percentage of pediatric ICU admissions requiring intubation declined by 28% in the 3 y after NPV introduction, compared with the 3 y prior. CONCLUSIONS: NPV is a noninvasive respiratory support for pediatric acute respiratory failure from all causes with few complications and a 70% response rate. Children receiving NPV often required intravenous sedation for comfort, and one third received delayed enteral nutrition. Those who required escalation from NPV worsened within 6 h; this may be predictable with a bedside scoring system. PMID- 28860331 TI - The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance. AB - Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines. PMID- 28860334 TI - Acute pulmonary embolism and multiple pulmonary nodules mimicking metastatic disease. PMID- 28860333 TI - Using hyperpolarized 129Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis. AB - BACKGROUND: Assessing functional impairment, therapeutic response and disease progression in patients with idiopathic pulmonary fibrosis (IPF) continues to be challenging. Hyperpolarized 129Xe MRI can address this gap through its unique capability to image gas transfer three-dimensionally from airspaces to interstitial barrier tissues to red blood cells (RBCs). This must be validated by testing the degree to which it correlates with pulmonary function tests (PFTs) and CT scores, and its spatial distribution reflects known physiology and patterns of disease. METHODS: 13 healthy individuals (33.6+/-15.7 years) and 12 patients with IPF (66.0+/-6.4 years) underwent 129Xe MRI to generate three dimensional quantitative maps depicting the 129Xe ventilation distribution, its uptake in interstitial barrier tissues and its transfer to RBCs. For each map, mean values were correlated with PFTs and CT fibrosis scores, and their patterns were tested for the ability to depict functional gravitational gradients in healthy lung and to detect the known basal and peripheral predominance of disease in IPF. RESULTS: 129Xe MRI depicted functional impairment in patients with IPF, whose mean barrier uptake increased by 188% compared with the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores but strongly with PFTs. Barrier uptake and RBC transfer both correlated significantly with diffusing capacity of the lungs for carbon monoxide (r=-0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated most strongly (r=0.94, p<0.01). RBC transfer exhibited significant anterior posterior gravitational gradients in healthy volunteers, but not in IPF, where it was significantly impaired in the basal (p=0.02) and subpleural (p<0.01) lung. CONCLUSIONS: Hyperpolarized129Xe MRI is a rapid and well-tolerated exam that provides region-specific quantification of interstitial barrier thickness and RBC transfer efficiency. With further development, it could become a robust tool for measuring disease progression and therapeutic response in patients with IPF, sensitively and non-invasively. PMID- 28860335 TI - Activation mechanisms of the E3 ubiquitin ligase parkin. AB - Monogenetic, familial forms of Parkinson's disease (PD) only account for 5-10% of the total number of PD cases, but analysis of the genes involved therein is invaluable to understanding PD-associated neurodegenerative signaling. One such gene, parkin, encodes a 465 amino acid E3 ubiquitin ligase. Of late, there has been considerable interest in the role of parkin signaling in PD and in identifying its putative substrates, as well as the elucidation of the mechanisms through which parkin itself is activated. Its dysfunction underlies both inherited and idiopathic PD-associated neurodegeneration. Here, we review recent literature that provides a model of activation of parkin in the setting of mitochondrial damage that involves PINK1 (PTEN-induced kinase-1) and phosphoubiquitin. We note that neuronal parkin is primarily a cytosolic protein (with various non-mitochondrial functions), and discuss potential cytosolic parkin activation mechanisms. PMID- 28860336 TI - A ligand divided: antagonist, agonist and analog control. AB - Inhibiting receptor tyrosine kinases has been a cornerstone of cancer therapeutics for decades. Treatment strategies largely involve small-molecule kinase inhibitors and monoclonal antibodies. For receptors activated by constitutively dimeric ligands, another potential mechanism of inhibition exists: developing monomeric ligands that prevent receptor dimerization. In a recent issue of the Biochemical Journal, Zur et al. [Biochem. J. (2017) 474, 2601-2617] describe the details of creating such an inhibitor directed toward the macrophage colony-stimulating factor receptor, c-FMS. In the process of teasing apart the ligand dimer, they also uncover a potential cryptic regulatory mechanism in this receptor subfamily. PMID- 28860337 TI - From B to A: making an essential cofactor in a human parasite. AB - Trypanosomatids are parasitic eukaryotic organisms that cause human disease. These organisms have complex lifestyles; cycling between vertebrate and insect hosts and alternating between two morphologies; a replicating form and an infective, nonreplicating one. Because trypanosomatids are one of the few organisms that do not synthesize the essential cofactor, heme, these parasites sequester the most common form, heme B, from their hosts. Once acquired, the parasites derivatize heme B to heme A by two sequential enzyme reactions. Although heme C is found in many cytochrome c and c1 proteins, heme A is the cofactor of only one known protein, cytochrome c oxidase (CcO). In a recent issue of the Biochemical Journal, Merli et al. [Biochem. J. (2017) 474, 2315-2332] demonstrate that the final step in the synthesis of heme A by heme A synthase (TcCox15) and the subsequent activity of CcO are essential for infectivity and replication of Trypanosoma cruzi. PMID- 28860338 TI - HIF1A is a critical downstream mediator for hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by overwhelming immune activation. A steroid and chemotherapy-based regimen remains as the first-line of therapy but it has substantial morbidity. Thus, novel, less toxic therapy for HLH is urgently needed. Although differences exist between familial HLH (FHL) and secondary HLH (sHLH), they have many common features. Using bioinformatic analysis with FHL and systemic juvenile idiopathic arthritis, which is associated with sHLH, we identified a common hypoxia inducible factor 1A (HIF1A) signature. Furthermore, HIF1A protein levels were found to be elevated in the lymphocytic choriomeningitis virus infected Prf1-/- mouse FHL model and the CpG oligodeoxynucleotide-treated mouse sHLH model. To determine the role of HIF1A in HLH, a transgenic mouse with an inducible expression of HIF1A/ARNT proteins in hematopoietic cells was generated, which caused lethal HLH-like phenotypes: severe anemia, thrombocytopenia, splenomegaly, and multi-organ failure upon HIF1A induction. Mechanistically, these mice show type 1 polarized macrophages and dysregulated natural killler cells. The HLH-like phenotypes in this mouse model are independent of both adaptive immunity and interferon-gamma, suggesting that HIF1A is downstream of immune activation in HLH. In conclusion, our data reveal that HIF1A signaling is a critical mediator for HLH and could be a novel therapeutic target for this syndrome. PMID- 28860339 TI - Treatment outcome in a population-based, 'real-world' cohort of patients with chronic myeloid leukemia. AB - Evaluations of the 'real-world' efficacy and safety of tyrosine kinase inhibitors in patients with chronic myeloid leukemia are scarce. A nationwide, population based, chronic myeloid leukemia registry was analyzed to evaluate (deep) response rates to first and subsequent treatment lines and eligibility for a treatment cessation attempt in adults diagnosed between January 2008 and April 2013 in the Netherlands. The registry covered 457 patients; 434 in chronic phase (95%) and 15 (3%) in advanced disease phase. Seventy-five percent of the patients in chronic phase were treated with imatinib and 25% with a second-generation tyrosine kinase inhibitor. At 3 years 44% of patients had discontinued their first-line treatment, mainly due to intolerance (21%) or treatment failure (19%). At 18 months 73% of patients had achieved a complete cytogenetic response and 63% a major molecular response. Deep molecular responses (MR4.0 and MR4.5) were achieved in 69% and 56% of patients, respectively, at 48 months. All response milestones were achieved faster in patients treated upfront with a second generation tyrosine kinase inhibitor, but ultimately patients initially treated with imatinib also reached similar levels of responses. The 6-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 31%. Our findings show that in a 'real-world' setting the long-term outcome of patients treated with tyrosine kinase inhibitors is excellent and the conditions for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients. PMID- 28860340 TI - Impact of hospital experience on the quality of tyrosine kinase inhibitor response monitoring and consequence for chronic myeloid leukemia patient survival. PMID- 28860341 TI - Targeting metabolism and survival in chronic lymphocytic leukemia and Richter syndrome cells by a novel NF-kappaB inhibitor. AB - IT-901 is a novel and selective NF-kappaB inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells (CLL) with IT-901 effectively interrupts NF-kappaB transcriptional activity. CLL cells exposed to the drug display elevated mitochondrial reactive oxygen species, which damage mitochondria, limit oxidative phosphorylation and ATP production, and activate intrinsic apoptosis. Inhibition of NF-kappaB signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-kappaB-driven expression of molecules involved in cell-cell contacts and immune responses, essential elements in creating a pro leukemic niche. The consequence is that accessory cells do not protect CLL cells from IT-901-induced apoptosis. In this context, IT-901 shows synergistic activity with ibrutinib, arguing in favor of combination strategies. IT-901 is also effective in primary cells from patients with Richter syndrome (RS). Its anti tumor properties are confirmed in xenograft models of CLL and in RS patient derived xenografts, with documented NF-kappaB inhibition and significant reduction of tumor burden. Together, these results provide pre-clinical proof of principle for IT-901 as a potential new drug in CLL and RS. PMID- 28860342 TI - CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. AB - CUDC-907 is a first-in-class, oral small molecule inhibitor of both HDAC (class I and II) and PI3K (class Ialpha, beta, and delta) enzymes, with demonstrated anti tumor activity in multiple pre-clinical models, including MYC-driven ones. In this report, we present the safety and preliminary activity results of CUDC-907, with and without rituximab, in patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL), with a particular focus on those with MYC-altered disease. Thirty-seven DLBCL patients were enrolled, 14 with confirmed MYC-altered disease. Twenty-five patients received monotherapy treatment, and 12 received the combination of CUDC-907 with rituximab. CUDC-907 monotherapy and combination demonstrated similar safety profiles consisting primarily of Grade 1/2 hematologic and gastrointestinal events. The most frequently reported Grade >=3 treatment-related events were thrombocytopenia, neutropenia, diarrhea, fatigue, and anemia. Eleven responses (5 complete responses and 6 partial responses) were reported, for a response rate of 37% (11 out of 30) in evaluable patients [30% (11 out of 37) including all patients]. The objective response rate in evaluable MYC-altered DLBCL patients was 64% (7 out of 11; 4 complete responses and 3 partial responses), while it was 29% (2 out of 7) in MYC unaltered, and 17% (2 out of 12) in those with unknown MYC status. Median duration of response was 11.2 months overall; 13.6 months in MYC-altered patients, 6.0 months in MYC unaltered, and 7.8 months in those with MYC status unknown. The tolerable safety profile and encouraging evidence of durable anti-tumor activity, particularly in MYC-altered patients, support the continued development of CUDC-907 in these populations of high unmet need. (clinicaltrials.gov identifier: 01742988). PMID- 28860343 TI - Antigen receptor sequencing of paired bone marrow samples shows homogeneous distribution of acute lymphoblastic leukemia subclones. AB - In B-cell precursor acute lymphoblastic leukemia, the initial leukemic cells share the same antigen receptor gene rearrangements. However, due to ongoing rearrangement processes, leukemic cells with different gene rearrangement patterns can develop, resulting in subclone formation. We studied leukemic subclones and their distribution in the bone marrow and peripheral blood at diagnosis. Antigen receptor gene rearrangements (IGH, IGK, TRG, TRD, TRB) were analyzed by next-generation sequencing in seven paired bone marrow samples and five paired bone marrow-peripheral blood samples. Background-thresholds were defined, which enabled identification of leukemic gene rearrangements down to very low levels. Paired bone marrow analysis showed oligoclonality in all 7 patients and up to 34 leukemic clones per patient. Additional analysis of evolutionary-related IGH gene rearrangements revealed up to 171 leukemic clones per patient. Interestingly, overall 86% of all leukemic gene rearrangements, including small subclones, were present in both bone marrow samples (range per patient: 72-100%). Paired bone marrow-peripheral blood analysis showed that 83% of all leukemic gene rearrangements in bone marrow were also found in peripheral blood (range per patient: 81-100%). Remarkably, in the paired bone marrow samples and paired bone marrow-peripheral blood samples the vast majority of leukemic gene rearrangements had a similar frequency (<5-fold frequency difference) (96% and 96% of leukemic rearrangements, respectively). Together, these results indicate that B-cell precursor acute lymphoblastic leukemia is generally highly oligoclonal. Nevertheless, the vast majority of leukemic clones, even the minor antigen receptor-defined subclones, are homogeneously distributed throughout the bone marrow and peripheral blood compartment. PMID- 28860344 TI - The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma. AB - Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunostaining, cell cycle and short interfering ribonucleic acid studies. Filanesib showed in vitro, ex vivo, and in vivo synergy with pomalidomide plus dexamethasone treatment. Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and was shown to be mediated by the impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, the triple combination increased the activation of the proapoptotic protein BAX, which has previously been associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone, and supported the initiation of a recently activated trial being conducted by the Spanish Myeloma group which is investigating this combination in relapsed myeloma patients. PMID- 28860345 TI - Co-occurrence of CRLF2-rearranged and Ph+ acute lymphoblastic leukemia: a report of four patients. PMID- 28860346 TI - Severe bradycardia associated with crizotinib. PMID- 28860347 TI - Why diets fail: eating more, moving less. PMID- 28860348 TI - Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections. AB - INTRODUCTION: Patients with cirrhosis have a high risk of sepsis, which confers a poor prognosis. The systemic inflammatory response syndrome (SIRS) criteria have several limitations in cirrhosis. Recently, new criteria for sepsis (Sepsis-3) have been suggested in the general population (increase of Sequential Organ Failure Assessment (SOFA) >=2 points from baseline). Outside the intensive care unit (ICU), the quick SOFA (qSOFA (at least two among alteration in mental status, systolic blood pressure <=100 mm Hg or respiratory rate >=22/min)) was suggested to screen for sepsis. These criteria have never been evaluated in patients with cirrhosis. The aim of the study was to assess the ability of Sepsis 3 criteria in predicting in-hospital mortality in patients with cirrhosis and bacterial/fungal infections. METHODS: 259 consecutive patients with cirrhosis and bacterial/fungal infections were prospectively included. Demographic, laboratory and microbiological data were collected at diagnosis of infection. Baseline SOFA was assessed using preadmission data. Patients were followed up until death, liver transplantation or discharge. Findings were externally validated (197 patients). RESULTS: Sepsis-3 and qSOFA had significantly greater discrimination for in-hospital mortality (area under the receiver operating characteristic (AUROC)=0.784 and 0.732, respectively) than SIRS (AUROC=0.606) (p<0.01 for both). Similar results were observed in the validation cohort. Sepsis-3 (subdistribution HR (sHR)=5.47; p=0.006), qSOFA (sHR=1.99; p=0.020), Chronic Liver Failure Consortium Acute Decompensation score (sHR=1.05; p=0.001) and C reactive protein (sHR=1.01;p=0.034) were found to be independent predictors of in-hospital mortality. Patients with Sepsis-3 had higher incidence of acute-on-chronic liver failure, septic shock and transfer to ICU than those without Sepsis-3. CONCLUSIONS: Sepsis-3 criteria are more accurate than SIRS criteria in predicting the severity of infections in patients with cirrhosis. qSOFA is a useful bedside tool to assess risk for worse outcomes in these patients. Patients with Sepsis-3 and positive qSOFA deserve more intensive management and strict surveillance. PMID- 28860349 TI - High prevalence of hepatitis E virus in semen of infertile male and causes testis damage. PMID- 28860351 TI - Oesophageal cancer incidence in 20-year follow-up in a population-based sample of 12 000 middle-age men with or without Helicobacter pylori infection in Finland. PMID- 28860350 TI - Identification of distinct mutational patterns and new driver genes in oesophageal squamous cell carcinomas and adenocarcinomas. AB - OBJECTIVES: Oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance. DESIGN: Previously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures. The biological functions of novel SMGs were investigated using cell line and xenograft models. We further performed whole-genome bisulfite sequencing and chromatin immunoprecipitation (ChIP)-seq to characterise epigenetic alterations. RESULTS: OSCC and OAC displayed nearly mutually exclusive sets of driver genes, indicating that they follow independent developmental paths. The combined sample size allowed the statistical identification of a number of novel subtype-specific SMGs, mutational signatures and prognostic biomarkers. Particularly, we identified a novel mutational signature similar to Catalogue Of Somatic Mutations In Cancer (COSMIC)signature 16, which has prognostic value in OSCC. Two newly discovered SMGs, CUL3 and ZFP36L2, were validated as important tumour-suppressors specific to the OSCC subtype. We further identified their additional loss-of function mechanisms. CUL3 was homozygously deleted specifically in OSCC and other squamous cell cancers (SCCs). Notably, ZFP36L2 is associated with super-enhancer in healthy oesophageal mucosa; DNA hypermethylation in its super-enhancer reduced active histone markers in squamous cancer cells, suggesting an epigenetic inactivation of a super-enhancer-associated SCC suppressor. CONCLUSIONS: These data comprehensively contrast differences between OSCC and OAC at both genomic and epigenomic levels, and reveal novel molecular features for further delineating the pathophysiological mechanisms and treatment strategies for these cancers. PMID- 28860352 TI - Factors Contributing to the Antiviral Effectiveness of Tenofovir. AB - Over 1 million people in the United States are living with human immunodeficiency virus (HIV), which may progress to AIDS. The use of antiviral therapy has successfully controlled the rate of viral growth in patients. Antiviral agents improve the quality of life and reduce the potential for spreading HIV; HIV is currently considered a chronic disease provided patients are compliant with their antiviral medications. Tenofovir is a nucleoside transcriptase inhibitor that prevents viral replication and is approved for treatment of HIV and chronic hepatitis B infection. Tenofovir is an antiretroviral drug used alone and in combination with other nucleoside reverse-transcriptase inhibitor agents to lower viral load in HIV patients. Tenofovir is administered as a prodrug to increase bioavailability. The prodrug forms of tenofovir are tenofovir disoproxil fumarate, approved in 2001, and tenofovir alafenamide, approved in 2016. Tenofovir is extensively used in controlling HIV, as it is administered once daily, allowing for good compliance. This minireview discusses the impact of food, age, and drug transporters on tenofovir absorption and clearance. The changes in dosing that are needed in the presence of renal impairment, which is a common occurrence with HIV chronic disease progression, will also be discussed. The potential special conditions occurring with fixed-combination doses containing tenofovir will also be reviewed, including the use of cobicistat, a cytochrome P450 3A4 inhibitor. The short review also addresses some newer preparations using niosomes to improve tenofovir absorption and delivery to the target cells. PMID- 28860353 TI - Histone Deacetylase Inhibitors Relax Mouse Aorta Partly through Their Inhibitory Action on L-Type Ca2+ Channels. AB - Histone deacetylase (HDAC) inhibitors modulate acetylation/deacetylation of histone and nonhistone proteins. They have been widely used for cancer treatment. However, there have been only a few studies investigating the effect of HDAC inhibitors on vascular tone regulation, most of which employed chronic treatment with HDAC inhibitors. In the present study, we found that two hydroxamate-based pan-HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), could partially but acutely relax high extracellular K+-contracted mouse aortas. SAHA and TSA also attenuated the high extracellular K+-induced cytosolic Ca2+ rise and inhibited L-type Ca2+ channel current in whole-cell patch-clamp. These data demonstrate that SAHA could inhibit L-type Ca2+ channels to cause vascular relaxation. In addition, SAHA and TSA dose dependently relaxed the arteries precontracted with phenylephrine. The relaxant effect of SAHA and TSA was greater in phenylephrine-precontracted arteries than in high K+-contracted arteries. Although part of the relaxant effect of SAHA and TSA on phenylephrine precontracted arteries was related to L-type Ca2+ channels, both agents could also induce relaxation via a mechanism independent of L-type Ca2+ channels. Taken together, HDAC inhibitors SAHA and TSA can acutely relax blood vessels via their inhibitory action on L-type Ca2+ channels and via another L-type Ca2+ channel independent mechanism. PMID- 28860354 TI - Comment on "Active sites for CO2 hydrogenation to methanol on Cu/ZnO catalysts". AB - Kattel et al (Reports, 24 March 2017, p. 1296) report that a zinc on copper (Zn/Cu) surface undergoes oxidation to zinc oxide/copper (ZnO/Cu) during carbon dioxide (CO2) hydrogenation to methanol and conclude that the Cu-ZnO interface is the active site for methanol synthesis. Similar experiments conducted two decades ago by Fujitani and Nakamura et al demonstrated that Zn is attached to formate rather than being fully oxidized. PMID- 28860355 TI - Response to Comment on "Active sites for CO2 hydrogenation to methanol on Cu/ZnO catalysts". AB - In their Comment on the our recent Report, Nakamura et al argue that our x-ray photoelectron spectroscopy (XPS) analysis was affected by the presence of formate species on the catalyst surface. This argument is not valid because the reactant gases were evacuated at temperatures from 525 to 575 kelvin, conditions under which formate is not stable on the catalyst surface. An analysis of the XPS results obtained after exposing zinc oxide/copper (111) [ZnO/Cu(111)] surfaces to hydrogen (H2) and mixtures of carbon dioxide (CO2)/H2 show an absence of carbon (C) 1s signal, no asymmetries in the oxygen (O) 1s peak, and a Zn:O intensity close to 1:1. Thus, the most active phase of these catalysts contained a ZnO-Cu interface. PMID- 28860357 TI - Measuring and managing bias. PMID- 28860356 TI - Island biogeography: Taking the long view of nature's laboratories. AB - Islands provide classic model biological systems. We review how growing appreciation of geoenvironmental dynamics of marine islands has led to advances in island biogeographic theory accommodating both evolutionary and ecological phenomena. Recognition of distinct island geodynamics permits general models to be developed and modified to account for patterns of diversity, diversification, lineage development, and trait evolution within and across island archipelagos. Emergent patterns of diversity include predictable variation in island species area relationships, progression rule colonization from older to younger land masses, and syndromes including loss of dispersability and secondary woodiness in herbaceous plant lineages. Further developments in Earth system science, molecular biology, and trait data for islands hold continued promise for unlocking many of the unresolved questions in evolutionary biology and biogeography. PMID- 28860359 TI - How an ocean climate cycle favored Harvey. PMID- 28860360 TI - Hurricane Harvey provides lab for U.S. forecast experiments. PMID- 28860361 TI - Anti-inflammatory prevents heart attacks. PMID- 28860362 TI - Science suffers as China plugs holes in Great Firewall. PMID- 28860363 TI - Toxic algae may be culprit in mysterious dinosaur deaths. PMID- 28860364 TI - India's dark matter quest. PMID- 28860365 TI - Reports raise concerns about France's nuclear waste tomb. PMID- 28860366 TI - The case of the macho crocs. PMID- 28860367 TI - Atomic bonding. PMID- 28860368 TI - A molecular dance to cleaner air. PMID- 28860369 TI - Glia put visual map in sync. PMID- 28860370 TI - Finding a new purpose for old drugs. PMID- 28860371 TI - The architecture of transcription elongation. PMID- 28860372 TI - Enzymes make light work of hydrocarbon production. PMID- 28860373 TI - Sounding out optical phonons. PMID- 28860374 TI - Howard Eichenbaum (1947-2017). PMID- 28860375 TI - Influence, integrity, and the FDA: An ethical framework. PMID- 28860376 TI - Intelligent design endangers education. PMID- 28860377 TI - Scientists need social media influencers. PMID- 28860378 TI - Yachay's promise. PMID- 28860379 TI - NextGen VOICES: Science and human rights call for submissions. PMID- 28860380 TI - Glia relay differentiation cues to coordinate neuronal development in Drosophila. AB - Neuronal birth and specification must be coordinated across the developing brain to generate the neurons that constitute neural circuits. We used the Drosophila visual system to investigate how development is coordinated to establish retinotopy, a feature of all visual systems. Photoreceptors achieve retinotopy by inducing their target field in the optic lobe, the lamina neurons, with a secreted differentiation cue, epidermal growth factor (EGF). We find that communication between photoreceptors and lamina cells requires a signaling relay through glia. In response to photoreceptor-EGF, glia produce insulin-like peptides, which induce lamina neuronal differentiation. Our study identifies a role for glia in coordinating neuronal development across distinct brain regions, thus reconciling the timing of column assembly with that of delayed differentiation, as well as the spatiotemporal pattern of lamina neuron differentiation. PMID- 28860382 TI - An algal photoenzyme converts fatty acids to hydrocarbons. AB - Although many organisms capture or respond to sunlight, few enzymes are known to be driven by light. Among these are DNA photolyases and the photosynthetic reaction centers. Here, we show that the microalga Chlorella variabilis NC64A harbors a photoenzyme that acts in lipid metabolism. This enzyme belongs to an algae-specific clade of the glucose-methanol-choline oxidoreductase family and catalyzes the decarboxylation of free fatty acids to n-alkanes or -alkenes in response to blue light. Crystal structure of the protein reveals a fatty acid binding site in a hydrophobic tunnel leading to the light-capturing flavin adenine dinucleotide (FAD) cofactor. The decarboxylation is initiated through electron abstraction from the fatty acid by the photoexcited FAD with a quantum yield >80%. This photoenzyme, which we name fatty acid photodecarboxylase, may be useful in light-driven, bio-based production of hydrocarbons. PMID- 28860381 TI - beta2-Adrenoreceptor is a regulator of the alpha-synuclein gene driving risk of Parkinson's disease. AB - Copy number mutations implicate excess production of alpha-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the beta2-adrenoreceptor (beta2AR) is a regulator of the alpha-synuclein gene (SNCA). beta2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the beta2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a beta2AR antagonist correlated with increased risk. beta2AR activation protected model mice and patient-derived cells. Thus, beta2AR is linked to transcription of alpha-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies. PMID- 28860384 TI - Global climatic drivers of leaf size. AB - Leaf size varies by over a 100,000-fold among species worldwide. Although 19th century plant geographers noted that the wet tropics harbor plants with exceptionally large leaves, the latitudinal gradient of leaf size has not been well quantified nor the key climatic drivers convincingly identified. Here, we characterize worldwide patterns in leaf size. Large-leaved species predominate in wet, hot, sunny environments; small-leaved species typify hot, sunny environments only in arid conditions; small leaves are also found in high latitudes and elevations. By modeling the balance of leaf energy inputs and outputs, we show that daytime and nighttime leaf-to-air temperature differences are key to geographic gradients in leaf size. This knowledge can enrich "next-generation" vegetation models in which leaf temperature and water use during photosynthesis play key roles. PMID- 28860383 TI - The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. AB - The intestinal microbiota has been identified as an environmental factor that markedly affects energy storage and body-fat accumulation in mammals, yet the underlying mechanisms remain unclear. Here we show that the microbiota regulates body composition through the circadian transcription factor NFIL3. Nfil3 transcription oscillates diurnally in intestinal epithelial cells, and the amplitude of the circadian oscillation is controlled by the microbiota through group 3 innate lymphoid cells, STAT3 (signal transducer and activator of transcription 3), and the epithelial cell circadian clock. NFIL3 controls expression of a circadian lipid metabolic program and regulates lipid absorption and export in intestinal epithelial cells. These findings provide mechanistic insight into how the intestinal microbiota regulates body composition and establish NFIL3 as an essential molecular link among the microbiota, the circadian clock, and host metabolism. PMID- 28860385 TI - A microtubule-organizing center directing intracellular transport in the early mouse embryo. AB - The centrosome is the primary microtubule-organizing center (MTOC) of most animal cells; however, this organelle is absent during early mammalian development. Therefore, the mechanism by which the mammalian embryo organizes its microtubules (MTs) is unclear. We visualize MT bridges connecting pairs of cells and show that the cytokinetic bridge does not undergo stereotypical abscission after cell division. Instead, it serves as scaffold for the accumulation of the MT minus-end stabilizing protein CAMSAP3 throughout interphase, thereby transforming this structure into a noncentrosomal MTOC. Transport of the cell adhesion molecule E cadherin to the membrane is coordinated by this MTOC and is required to form the pluripotent inner mass. Our study reveals a noncentrosomal form of MT organization that directs intracellular transport and is essential for mammalian development. PMID- 28860387 TI - The stories behind a CV. PMID- 28860386 TI - Structural basis of the redox switches in the NAD+-reducing soluble [NiFe] hydrogenase. AB - NAD+ (oxidized form of NAD:nicotinamide adenine dinucleotide)-reducing soluble [NiFe]-hydrogenase (SH) is phylogenetically related to NADH (reduced form of NAD+):quinone oxidoreductase (complex I), but the geometrical arrangements of the subunits and Fe-S clusters are unclear. Here, we describe the crystal structures of SH in the oxidized and reduced states. The cluster arrangement is similar to that of complex I, but the subunits orientation is not, which supports the hypothesis that subunits evolved as prebuilt modules. The oxidized active site includes a six-coordinate Ni, which is unprecedented for hydrogenases, whose coordination geometry would prevent O2 from approaching. In the reduced state showing the normal active site structure without a physiological electron acceptor, the flavin mononucleotide cofactor is dissociated, which may be caused by the oxidation state change of nearby Fe-S clusters and may suppress production of reactive oxygen species. PMID- 28860388 TI - What is the optimal level of expectation? PMID- 28860389 TI - All interventions differ, although some are more different than others. PMID- 28860390 TI - Contemporary acetabular fracture surgery: treading water or swimming upstream? AB - In the time since Letournel popularised the surgical treatment of acetabular fractures, more than 25 years ago, there have been many changes within the field, related to patients, surgical technique, implants and post-operative care. However, the long-term outcomes appear largely unchanged. Does this represent stasis or have the advances been mitigated by other negative factors? In this article we have attempted to document the recent changes within the surgery of patients with a fracture involving the acetabulum, outline contemporary management, and identify the major problem areas where further research is most needed. Cite this article: Bone Joint J 2017;99-B:1125-31. PMID- 28860391 TI - The mucopolysaccharidoses: advances in medical care lead to challenges in orthopaedic surgical care. AB - The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders with clinical manifestations relevant to the orthopaedic surgeon. Our aim was to review the recent advances in their management and the implications for surgical practice. The current literature about MPSs is summarised, emphasising orthopaedic complications and their management. Recent advances in the diagnosis and management of MPSs include the recognition of slowly progressive, late presenting subtypes, developments in life-prolonging systemic treatment and potentially new indications for surgical treatment. The outcomes of surgery in these patients are not yet validated and some procedures have a high rate of complications which differ from those in patients who do not have a MPS. The diagnosis of a MPS should be considered in adolescents or young adults with a previously unrecognised dysplasia of the hip. Surgeons treating patients with a MPS should report their experience and studies should include the assessment of function and quality of life to guide treatment. Cite this article: Bone Joint J 2017;99-B:1132-9. PMID- 28860392 TI - Factors affecting the potential for posterior bony impingement after total hip arthroplasty. AB - AIMS: Our aim was to evaluate the radiographic characteristics of patients undergoing total hip arthroplasty (THA) for the potential of posterior bony impingement using CT simulations. PATIENTS AND METHODS: Virtual CT data from 112 patients who underwent THA were analysed. There were 40 men and 72 women. Their mean age was 59.1 years (41 to 76). Associations between radiographic characteristics and posterior bony impingement and the range of external rotation of the hip were evaluated. In addition, we investigated the effects of pelvic tilt and the neck/shaft angle and femoral offset on posterior bony impingement. RESULTS: The range of external rotation and the ischiofemoral length were significantly lower, while femoral anteversion, the ischial ratio, and ischial angle were significantly higher in patients with posterior bony impingement compared with those who had implant impingement (p < 0.05). The range of external rotation positively correlated with ischiofemoral length (r = 0.49, p < 0.05), and negatively correlated with ischial length (r = -0.49, p < 0.05), ischial ratio (r =- 0.49, p < 0.05) and ischial angle (r = -0.55, p < 0.05). The range of external rotation was lower in patients with posterior pelvic tilt (p < 0.05) and in those with a high offset femoral component (p < 0.05) due to posterior bony impingement. CONCLUSION: Posterior bony impingement after THA is more likely in patients with a wider ischium and a narrow ischiofemoral space. A high femoral offset and posterior pelvic tilt are also risk factors for this type of impingement. Cite this article: Bone Joint J 2017;99-B:1140-6. PMID- 28860393 TI - Mild or moderate renal insufficiency does not increase circulating levels of cobalt and chromium in patients with metal-on-metal hip arthroplasty. AB - AIMS: To determine whether there is any association between glomerular filtration rate (GFR) and blood cobalt (Co) and chromium (Cr) levels in patients with metal on-metal (MoM) hip arthroplasty. PATIENTS AND METHODS: We identified 179 patients with a unilateral 36 mm diameter head as part of a stemmed Summit-Pinnacle MoM hip arthroplasty. GFR was calculated using the Modification of Diet in Renal Disease formula. RESULTS: Normal renal function (GFR >= 90 ml/min/1.73 m2) was seen in 74 patients. Mild renal insufficiency (GFR 60 to 89 ml/min/1.73 m2) was seen in 90 patients and moderate renal insufficiency (GFR 30 to 59 ml/min/1.73 m2) in 15. There was no statistical difference in Co and Cr levels between patients with normal renal function and those with mild or moderate renal insufficiency. No correlation was seen between creatinine and blood metal ion levels or between GFR and blood metal ion levels. Linear regression analysis did not show any association between Co and Cr levels and GFR. CONCLUSION: We did not find any association between GFR and blood metal ion levels. Consequently, the accumulation of Co and Cr in blood due to renal insufficiency does not seem to be a major risk in patients with mild or moderate renal insufficiency. Cite this article Bone Joint J 2017;99-B:1147-52. PMID- 28860394 TI - Does tantalum exhibit any intrinsic antimicrobial or antibiofilm properties? AB - AIMS: Tantalum (Ta) trabecular metal components are increasingly used to reconstruct major bone defects in revision arthroplasty surgery. It is known that some metals such as silver have antibacterial properties. Recent reports have raised the question regarding whether Ta components are protective against infection in revision surgery. This laboratory study aimed to establish whether Ta has intrinsic antibacterial properties against planktonic bacteria, or the ability to inhibit biofilm formation. MATERIALS AND METHODS: Equal-sized pieces of Ta and titanium (Ti) acetabular components were sterilised and incubated with a low dose inoculum of either Staphylococcus (S.) aureus or S. epidermidis for 24 hours. After serial dilution, colony forming units (cfu) were quantified on Mueller-Hinton agar plates. In order to establish whether biofilms formed to a greater extent on one material than the other, these Ta and Ti pieces were then washed twice, sonicated and washed again to remove loosely adhered planktonic bacteria. They were then re-incubated for 24 hours prior to quantifying the number of cfu. All experiments were performed in triplicate. RESULTS: More than 1x108 cfu/ml were observed in both the Ta and Ti experiments. After washing and sonication, more than 2x107 cfu/ml were observed for both Ta and Ti groups. The results were the same for both S. aureus and S. epidermidis. CONCLUSION: Compared with Ti controls, Ta did not demonstrate any intrinsic antibacterial activity or ability to inhibit biofilm formation. Hence, intrinsic antimicrobial properties of Ta do not account for the previously observed reduction in the frequency of subsequent infections when Ta was used in revision procedures. Cite this article: Bone Joint J 2017;99-B:1153-6. PMID- 28860395 TI - No difference in time-dependent improvement in functional outcome following closing wedge versus opening wedge high tibial osteotomy: a randomised controlled trial with two-year follow-up. AB - AIMS: The aim of this prospective randomised study was to compare the time course of clinical improvement during the first two years following a closing or opening wedge high tibial osteotomy (HTO). It was hypothesised that there would be no differences in clinical outcome between the two techniques. PATIENTS AND METHODS: Between 2007 and 2013, 70 consecutive patients were randomly allocated to undergo either a closing or opening wedge HTO. All patients had medial compartment osteoarthritis (OA), and were aged between 30 years and 60 years. They were evaluated by independent investigators pre-operatively and at three and six months, and one and two years post-operatively using the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Oxford Knee Score (OKS), the Lysholm score, the Tegner activity score, the University of California, Los Angeles (UCLA) activity scale and range of movement (ROM). RESULTS: There were no significant differences at any time between the two techniques for any clinical outcome score (p > 0.05). The mean scores for all the systems, except UCLA and Tegner, significantly improved until six months post-operatively (p < 0.001). For some scores, the improvement continued until one and two years. CONCLUSION: This prospective randomised study suggests that there are no differences in the time course of the clinical improvement between the closing and opening wedge techniques for HTO during the first two post-operative years. Patients can expect continued improvement in physical function for between six months and one year after HTO regardless of the technique used. Cite this article: Bone Joint J 2017;99-B:1157-66. PMID- 28860396 TI - Early patient-reported outcomes versus objective function after total hip and knee arthroplasty: a prospective cohort study. AB - AIMS: The purpose of this study was to assess early physical function after total hip or knee arthroplasty (THA/TKA), and the correlation between patient-reported outcome measures, physical performance and actual physical activity (measured by actigraphy). PATIENTS AND METHODS: A total of 80 patients aged 55 to 80 years undergoing THA or TKA for osteoarthritis were included in this prospective cohort study. The main outcome measure was change in patient reported hip or knee injury and osteoarthritis outcome score (HOOS/KOOS) from pre-operatively until post operative day 13 (THA) or 20 (TKA). Secondary measures were correlations to objectively assessed change in physical performance (paced-walk, chair-stand, stair-climb tests) at day 14 (THA) or 21 (TKA) and actual physical activity (actigraphy) measured at day 12 and 13 (THA) or 19 and 20 (TKA). RESULTS: Patients reported improved physical function (HOOS or KOOS) pre-operatively until day 13 (THA) or 20 (TKA) with a mean difference of 7 (95% confidence interval (CI) 1 to 13, p = 0.033) and 6 (95% CI 1 to 12, p = 0.033) percentage points, respectively. By contrast, objectively assessed physical function and activity declined, with no correlations between subjective and objective assessments for either THA or TKA patients (r2 <= 0.16, p >= 0.314). CONCLUSIONS: Early improvement in patient-reported physical function after THA/TKA does not correlate with objectively assessed function, and patient reported outcomes should not be used as the only measure of recovery. Cite this article: Bone Joint J 2017;99-B:1167-75. PMID- 28860397 TI - Diagnosis of prosthetic joint infection with alpha-defensin using a lateral flow device: a multicentre study. AB - AIMS: The purpose of this current multicentre study is to analyse the presence of alpha-defensin proteins in synovial fluid using the Synovasure lateral flow device and to determine its diagnostic reliability and accuracy compared with the prosthetic joint infection (PJI) criteria produced by the Musculoskeletal Infection Society (MSIS). PATIENTS AND METHODS: A cohort of 121 patients comprising 85 total knee arthroplasties and 36 total hip arthroplasties was prospectively evaluated between May 2015 and June 2016 in three different orthopaedic centres. The tests were performed on patients with a chronically painful prosthesis undergoing a joint aspiration in a diagnostic pathway or during revision surgery. RESULTS: Based on the MSIS criteria, 34 patients (28%) would have had a PJI, and 87 patients had no PJI. Testing with the lateral flow device had a sensitivity of 97.1% (95% confidence intervals (CI) 84.5 to 99.9) and a specificity of 96.6% (95% CI 90.3 to 99.2). The positive predictive value was 91.7% (95% CI 77.7% to 98.3), and the negative predictive value was 98.8% (95% CI 93.6 to 99.9). Receiver operator characteristics analysis demonstrated an area under the curve for the Synovasure test of 0.97 (95% CI 0.93 to 1.00). CONCLUSION: Our findings suggest that the Synovasure test has an excellent diagnostic performance to confirm or reject the diagnosis of a PJI. The results are promising for the care of the painful or problematic knee and hip joint arthroplasty and the test should be considered as part of the diagnostic toolbox for PJIs. Cite this article: Bone Joint J 2017;99-B:1176-82. PMID- 28860398 TI - Revision anatomical reconstruction of the lateral ligaments of the ankle augmented with suture tape for patients with a failed Brostrom procedure. AB - AIMS: The aim of this prospective study was to evaluate the intermediate-term outcomes after revision anatomical ankle ligament reconstruction augmented with suture tape for a failed modified Brostrom procedure. PATIENTS AND METHODS: A total of 30 patients with persistent instability of the ankle after a Brostrom procedure underwent revision augmented with suture tape. Of these, 24 patients who were followed up for more than two years were included in the study. There were 13 men and 11 women. Their mean age was 31.8 years (23 to 44). The mean follow-up was 38.5 months (24 to 56) The clinical outcome was assessed using the Foot and Ankle Outcome Score (FAOS) and the Foot and Ankle Ability Measure (FAAM) score. The stability of the ankle was assessed using stress radiographs. RESULTS: The mean FAOS and FAAM scores improved significantly to 87.5 (73 to 94) and 85.1 (70 to 95) points at final follow-up, respectively (p < 0.001). The mean angle of talar tilt and anterior talar translation improved significantly to 2.8 degrees (0 degrees to 6 degrees ) and 4.1 mm (2 to 7) at final follow-up, respectively (p < 0.001). Side to side comparison in stress radiographs at final follow-up showed no significant difference. The revision failed in one patient who underwent a further revision using allograft tendon. CONCLUSION: The revision modified Brostrom procedure augmented with suture tape is an effective form of treatment for recurrent instability of the ankle following a failed Brostrom procedure. This technique provides reliable stability and satisfactory clinical outcomes at intermediate-term follow-up. Cite this article: Bone Joint J 2017;99 B:1183-9. PMID- 28860399 TI - Effect of pre-operative expectations on the outcomes following total shoulder arthroplasty. AB - AIMS: Few studies have evaluated the relationship between patients' pre-operative expectations and the outcome of orthopaedic procedures. Our aim was to determine the effect of expectations on the outcome after primary anatomical total shoulder arthroplasty (TSA). We hypothesised that patients with greater expectations would have better outcomes. PATIENTS AND METHODS: Patients undergoing primary anatomical TSA completed the Hospital for Special Surgery's Shoulder Expectations Survey pre-operatively. The American Shoulder and Elbow Surgeons (ASES), Shoulder Activity Scale (SAS), Short-Form-36 (SF-36), and visual analogue scale (VAS) for pain, fatigue, and general health scores were also collected pre-operatively and two years post-operatively. Pearson correlations were used to assess the relationship between the number of expectations and the outcomes. Differences in outcomes between those with higher and lower levels of expectations for each expectation were assessed by independent samples t-test. Multivariable linear regression analysis was used to control for potential confounding factors. RESULTS: A total of 67 patients were evaluated two years post-operatively. Most parameters of outcome improved significantly from baseline and most patients were satisfied. A greater number of expectations was associated with a significantly greater improvement in the ASES score (p = 0.02). In the multivariable analysis, a greater number of expectations was an independent predictor of better ASES, VAS and SF-36 scores, as well as improvements in ASES and VAS pain scores (p < 0.05). Greater expectations for many specific expectation questions were significantly associated with better outcomes (p < 0.05). CONCLUSION: TSA is a successful procedure with significant improvements in outcome, and greater pre-operative expectations are associated with better outcomes. Cite this article: Bone Joint J 2017;99-B:1190-6. PMID- 28860400 TI - Mid-term outcomes of 77 modular radial head prostheses. AB - AIMS: Radial head arthroplasty (RHA) may be used in the treatment of non reconstructable radial head fractures. The aim of this study was to evaluate the mid-term clinical and radiographic results of RHA. PATIENTS AND METHODS: Between 2002 and 2014, 77 RHAs were implanted in 54 men and 23 women with either acute injuries (54) or with traumatic sequelae (23) of a fracture of the radial head. Four designs of RHA were used, including the Guepar (Small Bone Innovations (SBi)/Stryker; 36), Evolutive (Aston Medical; 24), rHead RECON (SBi/Stryker; ten) or rHead STANDARD (SBi/Stryker; 7) prostheses. The mean follow-up was 74.0 months (standard deviation (sd) 38.6; 24 to 141). The indication for further surgery, range of movement, mean Mayo Elbow Performance (MEP) score, quick Disabilities of the Arm, Shoulder and Hand (quickDASH) score, osteolysis and positioning of the implant were also assessed according to the design, and acute or delayed use. RESULTS: The mean MEP and quickDASH scores were 90.2 (sd 14; 45 to 100), and 14.0 points (sd 12; 1.2 to 52.5), respectively. There were no significant differences between RHA performed in acute or delayed fashion. There were 30 re-operations (19 with, and 11 without removal of the implant) during the first three post operative years. Painful loosening was the primary indication for removal in 14 patients. Short-stemmed prostheses (16 mm to 22 mm in length) were also associated with an increased risk of painful loosening (odds ratio 3.54 (1.02 to 12.2), p = 0.045). Radiocapitellar instability was the primary indication for re operation with retention of the implant (5). The overall survival of the RHA, free from re-operation, was 60.8% (sd 5.7%) at ten years. CONCLUSION: Bipolar and press-fit RHA gives unsatisfactory mid-term outcomes in the treatment of acute fractures of the radial head or their sequelae. The outcome may vary according to the design of the implant. The rate of re-operation during the first three years is predictive of the long-term survival in tight-fitting RHAs. Cite this article: Bone Joint J 2017;99-B1197-1203. PMID- 28860401 TI - Venous thromboembolism in adult elective spinal surgery: a tertiary centre review of 2181 patients. AB - AIMS: To evaluate the incidence of primary venous thromboembolism (VTE), epidural haematoma, surgical site infection (SSI), and 90-day mortality after elective spinal surgery, and the effect of two protocols for prophylaxis. PATIENTS AND METHODS: A total of 2181 adults underwent 2366 elective spinal procedures between January 2007 and January 2012. All patients wore anti-embolic stockings, mobilised early and were kept adequately hydrated. In addition, 29% (689) of these were given low molecular weight heparin (LMWH) while in hospital. SSI surveillance was undertaken using the Centers for Disease Control and Prevention criteria. RESULTS: In patients who only received mechanical prophylaxis, the incidence of VTE was 0.59% and that of SSI 2.1%. In patients who were additionally given LMWH, the incidence of VTE was 0% and that of SSI 0.7%. The unadjusted p-value was 0.04 for VTE and 0.01 for SSI. There were no cases of epidural haematoma or 90-day mortality in either group. When adjusted for case mix, LMWH remained a significant factor (p = 0.006) for VTE, but not for SSI. CONCLUSION: A peri-operative protocol involving mechanical anti-embolism stockings, adequate hydration, and early post-operative mobilisation is effective in significantly reducing the incidence of VTE. The addition of LMWH is safe in patients at higher risk of developing VTE. Cite this article: Bone Joint J 2017;99-B:1204-9. PMID- 28860402 TI - Sliding hip screw versus the Targon PFT nail for trochanteric hip fractures: a randomised trial of 400 patients. AB - AIMS: To compare the outcomes for trochanteric fractures treated with a sliding hip screw (SHS) or a cephalomedullary nail. PATIENTS AND METHODS: A total of 400 patients with a trochanteric hip fracture were randomised to receive a SHS or a cephalomedullary nail (Targon PFT). All surviving patients were followed up to one year from injury. Functional outcome was assessed by a research nurse blinded to the implant used. RESULTS: Recovery of mobility, as assessed by a mobility scale, was superior for those treated with the intramedullary nail compared with the SHS at eight weeks, three and nine months (p-values between 0.01 and 0.04), the difference at six and 12 months was not statistically significant (p = 0.15 and p = 0.18 respectively). The mean difference was around 0.4 points (0.3 to 0.5) on a nine point scale. Surgical time for the nail was four minutes less than that for the SHS (p < 0.001). Fracture healing complications were similar for the two groups. There were no statistically significant differences between implants for any other recorded outcomes including the need for post-operative blood transfusion, wound healing complications, general medical complications, hospital stay or mortality. CONCLUSION: This study confirms the findings of a previous study that both methods of treatment produce similar results, although intramedullary fixation does result in marginally improved regain of mobility in comparison with the SHS. Cite this article: Bone Joint J 2017;99-B:1210-15. PMID- 28860403 TI - Surgery for a fracture of the hip within 24 hours of admission is independently associated with reduced short-term post-operative complications. AB - AIMS: We aimed to characterise the effect of expeditious hip fracture surgery in elderly patients within 24 hours of admission on short-term post-operative outcomes. PATIENTS AND METHODS: Patients age 65 or older that underwent surgery for closed femoral neck and intertrochanteric hip fractures were identified from the American College of Surgeons National Surgical Quality Improvement Program between 2011 and 2014. Multivariable propensity-adjusted logistic regressions were performed to determine associations between early surgery within 24 hours and post-operative complications, controlling for selection bias in patients undergoing early surgery based on observable characteristics. RESULTS: A total of 26 051 patients were included in the study; 5921 (22.7%) had surgery within 24 hours of admission, while 20 130 (77.3%) patients had surgery after 24 hours. Propensity-adjusted multivariable logistic regressions demonstrated that surgery within 24 hours was independently associated with lower odds of respiratory complications including pneumonia, failure to extubate, or reintubation (odds ratio (OR) 0.78, 95% confidence interval (CI) 0.67 to 0.90), and extended length of stay (LOS) defined as >= 6 days (OR 0.84, 95% CI 0.78 to 0.90). CONCLUSION: In elderly patients with hip fractures, early surgery within 24 hours of admission is independently associated with less pulmonary complications including pneumonia, failure to extubate, and reintubation, as well as shorter LOS. Cite this article: Bone Joint J 2017;99-B:1216-22. PMID- 28860404 TI - The changing face of fractures of the hip in Northern Ireland: a 15-year review. AB - AIMS: We reviewed all patients who sustained a fracture of the hip and were treated in Northern Ireland over a period of 15 years to identify trends in incidence, the demographics of the patients, the rates of mortality, the configuration of the fracture and the choice of implant. PATIENTS AND METHODS: Since 01 January 2001 data about every fracture of the hip sustained in an adult have been collected centrally in Northern Ireland. All adults with such a fracture between 2000 and 2015 were included in the study. Temporal changes in their demographics, the mode of treatment, and outcomes including mortality were analysed. RESULTS: The incidence of fractures of the hip, in Northern Ireland, rose from 54 in 100 000 in 2000 to 86 in 100 000 in 2015. If these trends continue, we predict this rising to 128 in 100 000 in 2030. We found that these patients are becoming older and increasingly frail, as assessed by the American Association of Anesthesiology grade. Complex extracapsular fractures have become more common since 2009, which may explain the increased use of cephalomedullary nails. Despite increasing frailty, the 30-day and 12-month rates of mortality fell significantly (p = 0.002 and 0.001, respectively). CONCLUSION: Fractures of the hip are becoming more common and more complex in an aging, increasingly frail population. We expect these trends to continue. This will place an increasing economic and clinical strain on healthcare systems. Forward planning is essential to put systems in place that can deal with the increasing demand. Cite this article: Bone Joint J 2017;99-B:1223-31. PMID- 28860405 TI - The use of an anterior pelvic internal fixator to treat disruptions of the anterior pelvic ring: a report of technique, indications and complications. AB - AIMS: The anterior pelvic internal fixator is increasingly used for the treatment of unstable, or displaced, injuries of the anterior pelvic ring. The evidence for its use, however, is limited. The aim of this paper is to describe the indications for its use, how it is applied and its complications. PATIENTS AND METHODS: We reviewed the case notes and radiographs of 50 patients treated with an anterior pelvic internal fixator between April 2010 and December 2015 at a major trauma centre in the United Kingdom. The median follow-up time was 38 months (interquartile range 24 to 51). RESULTS: Three patients were excluded from the analysis leaving 47 patients with complete follow-up data. Of the 47 patients, 46 achieved radiological union and one progressed to an asymptomatic nonunion. Of the remaining patients, 45 required supplementary posterior fixation with percutaneous iliosacral screws, 2 of which required sacral plating. The incidence of injury to the lateral femoral cutaneous nerve (LFCN) was 34%. The rate of infection was 2%. There were no other significant complications. Without this treatment, 44 patients (94%) would have needed unilateral or bilateral open reduction and plate fixation extending laterally to the hip joint. CONCLUSION: The anterior pelvic internal fixator reduces the need for extensive open surgery and is a useful addition to the armamentarium for the treatment of anterior pelvic injuries. It is associated with injury to the LFCN in a third of patients. Cite this article: Bone Joint J 2017;99-B.1232-6. PMID- 28860406 TI - Vascularised fibular grafts for reconstruction of extremity bone defects after resection of bone and soft-tissue tumours : a single institutional study of 49 patients. AB - AIMS: The aims of this study were to analyse the long-term outcome of vascularised fibular graft (VFG) reconstruction after tumour resection and to evaluate the usefulness of the method. PATIENTS AND METHODS: We retrospectively reviewed 49 patients who had undergone resection of a sarcoma and reconstruction using a VFG between 1988 and 2015. Their mean follow-up was 98 months (5 to 317). Reconstruction was with an osteochondral graft (n = 13), intercalary graft (n = 12), inlay graft (n = 4), or resection arthrodesis (n = 20). We analysed the oncological and functional outcome, and the rate of bony union and complications. RESULTS: Five- and ten-year overall survival rates were 89% and 86%, respectively. Local recurrence occurred in two patients. Eight patients developed pulmonary metastases. Bone union was achieved in 44 patients (90%). Fracture occurred in six patients (12%), infection in three (6%), and nonunion in five (10%). The mean Musculoskeletal Tumor Society (MSTS) scores were as follows: osteochondral graft 70%; intercalary graft 73%; inlay graft 89%; and resection arthrodesis 83%. CONCLUSION: Although associated with a relatively high rate of complications, each reconstruction method is useful, with a high rate of successful limb salvage and a good long-term functional outcome. Cite this article: Bone Joint J 2017;99-B:1237-43. PMID- 28860407 TI - Is it safe to preserve the deltoid when resecting the proximal humerus for a primary malignant bone tumour? A comparative study. AB - AIMS: Resection of the proximal humerus for the primary malignant bone tumour sometimes requires en bloc resection of the deltoid. However, there is no information in the literature which helps a surgeon decide whether to preserve the deltoid or not. The aim of this study was to determine whether retaining the deltoid at the time of resection would increase the rate of local recurrence. We also sought to identify the variables that persuade expert surgeons to choose a deltoid sparing rather than deltoid resecting procedure. PATIENTS AND METHODS: We reviewed 45 patients who had undergone resection of a primary malignant tumour of the proximal humerus. There were 29 in the deltoid sparing group and 16 in the deltoid resecting group. Imaging studies were reviewed to assess tumour extension and soft-tissue involvement. The presence of a fat rim separating the tumour from the deltoid on MRI was particularly noted. The cumulative probability of local recurrence was calculated in a competing risk scenario. RESULTS: There was no significant difference (adjusted p = 0.89) in the cumulative probability of local recurrence between the deltoid sparing (7%, 95% confidence interval (CI) 1 to 20) and the deltoid resecting group (26%, 95% CI 8 to 50). Patients were more likely to be selected for a deltoid sparing procedure if they presented with a small tumour (p = 0.0064) with less bone involvement (p = 0.032) and a continuous fat rim on MRI (p = 0.002) and if the axillary nerve could be identified (p = 0.037). CONCLUSION: A deltoid sparing procedure can provide good local control after resection of the proximal humerus for a primary malignant bone tumour. A smaller tumour, the presence of a continuous fat rim and the identification of the axillary nerve on pre-operative MRI will persuade surgeons to opt for a deltoid resecting procedure. Cite this article: Bone Joint J 2017;99-B:1244-9. PMID- 28860408 TI - Late presentation of developmental dysplasia of the hip : a 15-year observational study. AB - AIMS: Despite the presence of screening programmes, infants continue to present with late developmental dysplasia of the hip (DDH), the impact of which is significant. The aim of this study was to assess infants with late presenting dislocation of the hip despite universal clinical neonatal and selective ultrasound screening. PATIENTS AND METHODS: Between 01 January 1997 to 31 December 2011, a prospective, longitudinal study was undertaken of a cohort of 64 670 live births. Late presenting dislocation was defined as presentation after three months of age. Diagnosis was confirmed by ultrasound and plain radiography. Patient demographics, referral type, reason for referral, risk factors (breech presentation/strong family history) and clinical and radiological findings were recorded. RESULTS: There were 31 infants with an irreducible dislocation of the hip, an incidence of 0.48 (95% confidence interval (CI) 0.34 to 0.68) per 1000 live births. Of these, 18 (0.28 (95% CI 0.17 to 0.44) per 1000 live births; 58%) presented late. All infants had a documented normal newborn clinical examination and no abnormality reported in the six to eight week check. Of the 18 late presenting cases 72% (n = 13) had no risk factors: 16 were referred by GPs and two were late due to administrative issues (missed appointments). The mean time to diagnosis was 62.4 weeks (19 to 84). CONCLUSION: Despite universal clinical neonatal and selective ultrasound screening, late cases of irreducible hip dislocation still occur. We recommend an update of the national screening programme for DDH, a review of training and education of healthcare professionals involved in the physical examination of neonates and infants, and the addition of a further assessment after the six to eight week check. Cite this article: Bone Joint J 2017;99-B:1250-5. PMID- 28860409 TI - Effects of multilevel surgery on a flexed knee gait in adults with cerebral palsy. AB - AIMS: A flexed knee gait is common in patients with bilateral spastic cerebral palsy and occurs with increased age. There is a risk for the recurrence of a flexed knee gait when treated in childhood, and the aim of this study was to investigate whether multilevel procedures might also be undertaken in adulthood. PATIENTS AND METHODS: At a mean of 22.9 months (standard deviation 12.9), after single event multi level surgery, 3D gait analysis was undertaken pre- and post operatively for 37 adult patients with bilateral cerebral palsy and a fixed knee gait. RESULTS: There was a significant improvement of indices and clinical and kinematic parameters including extension of the hip and knee, reduction of knee flexion at initial contact, reduction of minimum and mean knee flexion in the stance phase of gait, improved range of movement of the knee and a reduction of mean flexion of the hip in the stance phase. Genu recurvatum occurred in two patients (n = 3 legs, 4%) and an increase of pelvic tilt (> 5 degrees ) was found in 12 patients (n = 23 legs, 31%). CONCLUSION: Adult patients with bilateral cerebral palsy and a flexed knee gait benefit from multilevel surgery including hamstring lengthening. The risk of the occurence of genu recurvatum and increased pelvic tilt is lower than has been previously reported in children. Cite this article: Bone Joint J 2017;99-B:1256-64. PMID- 28860410 TI - Next-Generation Sequencing for Patients with Sarcoma: A Single Center Experience. AB - BACKGROUND: Sarcomas comprise over 50 subtypes of mesenchymal cancers. For the majority of sarcomas, the driver mutations remain unknown. In this article, we describe our experience with a targeted next-generation sequencing (NGS) platform in clinic patients. MATERIALS AND METHODS: We retrospectively analyzed results of NGS using 133 tumor samples from patients diagnosed with a variety of sarcomas that were analyzed with targeted NGS covering over 400 cancer-related genes (405 DNA, 265 RNA) on a commercially available platform. RESULTS: An average of two gene alterations were identified per tumor sample (range 0-14), and a total of 342 DNA mutations were detected. Eight-eight percent of samples had at least one detected mutation. The most common mutations were in the cell cycle, including TP53 (n = 35), CDKN2A/B (n = 23), and RB1 (n = 19). Twenty-seven PI3-kinase pathway alterations were observed, including PTEN (n = 14), PIK3Ca (n = 4), TSC1 (n = 1), TSC2 (n = 3), STK11 (n = 1), mTOR (n = 3), and RICTOR (n = 2). There were 75 mutations in genes that are targetable with existing drugs (excluding KIT in gastrointestinal stromal tumor) that would allow enrollment onto clinical trials. In general, the estimated tumor mutation burden was low, in particular for those with disease-defining gene fusions or genetic alterations. Microsatellite instability (MSI) data were available for 50 patients, and all were MSI stable. CONCLUSION: Our study describes a single-center experience with targeted NGS for patients with sarcoma. Mutations were readily detected and 75 (representing 40% of patients) were testable for therapeutic effect using existing drugs within the confines of a clinical trial. These data indicate that targeted NGS is a useful tool in potentially routing patients to mutation specific clinical trials. Further study will be required to determine if these mutations are clinically meaningful drug targets in sarcoma. IMPLICATIONS FOR PRACTICE: The sarcomas are a heterogenous family of over 50 different mesenchymal tumors. Current practice for metastatic disease involves systemic chemotherapy or nonspecific kinase inhibitors such as pazopanib. Sarcomas typically lack the classic kinase alterations seen in many carcinomas. The role of next-generation sequencing in sarcoma clinical practice remains undefined. PMID- 28860411 TI - Improved Detection of Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasms. AB - BACKGROUND: Recent work has demonstrated early shedding of circulating epithelial cells (CECs) from premalignant intraductal papillary mucinous neoplasms (IPMNs). However, the potential use of CECs as a "liquid biopsy" for patients with IPMNs has been limited by antigen dependence of CEC isolation devices and the lack of robust detection biomarkers across CEC phenotypes. MATERIALS AND METHODS: We utilized a negative depletion microfluidic platform to purify CECs from contaminating leukocytes and coupled this platform with immunofluorescence, RNA in situ hybridization, and RNA sequencing (RNA-seq) detection and enumeration. RESULTS: Using established protein (EpCAM, cytokeratins) and novel noncoding RNA (HSATII, cytokeratins) biomarkers, we detected CECs in 88% of patients bearing IPMN lesions. RNA-seq analysis for MUC genes confirm the likely origin of these CECs from pancreatic lesions. CONCLUSION: Our findings increase the sensitivity of detection of these cells and therefore could have clinical implications for cancer risk stratification. IMPLICATIONS FOR PRACTICE: This work describes a high sensitivity platform for detection of epithelial cells shed from preneoplastic lesions at high risk of malignant transformation. Further research efforts are underway to define the transcriptional programs that might allow discrimination between circulating cells released from tumors that will become malignant and cells released from tumors that will not. After further refinement, this combination of technologies could be deployed for monitoring and early detection of patients at high risk for developing new or recurrent pancreatic malignancies. PMID- 28860412 TI - Outcomes of Advanced Gastric Cancer Patients Treated with at Least Three Lines of Systemic Chemotherapy. AB - BACKGROUND: Second-line therapy has consistently demonstrated survival benefit if compared with best supportive care; however, there is limited evidence whether further lines of treatment may improve the prognosis of advanced gastric cancer (AGC) patients. MATERIALS AND METHODS: Starting from a real-world cohort of 868 AGC patients, we retrospectively analyzed baseline parameters, tumor characteristics, and treatment data of those treated with at least three lines. Categorical features were described through cross-tables and chi-square test. We explored the impact of treatment intensity and progression-free survival (PFS) experienced in previous lines on PFS and overall survival in third-line by uni- and multivariate Cox regression models and described by Kaplan-Meier estimator plot with log-rank test. RESULTS: Overall, 300 patients were included in the analysis. The most common site of primary tumor was gastric body; 45.3% of cancers had an intestinal histotype, 14% were human epidermal growth receptor 2 positive. In third-line, 45.7% of patients received a single-agent chemotherapy, 49.7% a combination regimen. Patients who had experienced a first-line PFS >=6.9 months had a better prognosis compared with those who had achieved a shorter one. Consistently, a second-line PFS >=3.5 months positively influenced the prognosis. Patients receiving a third-line combination regimen had better outcomes compared with those treated with a single-agent chemotherapy. CONCLUSION: Our real-world study confirms that selected AGC patients may receive third-line treatment. Longer PFS in previous lines or a more intense third-line treatment positively influenced prognosis. Further efforts are warranted to define the best therapeutic sequences, and to identify the optimal candidate for treatment beyond second-line. IMPLICATIONS FOR PRACTICE: The benefit of third-line treatment to advanced gastric cancer patients is controversial. This study depicts a real scenario of the clinical practice in Italy, confirming that a non-negligible proportion of patients receive a third-line therapy. Longer progression-free survival in previous treatment lines or higher third-line treatment intensity positively influenced prognosis. Including a large number of real-world patients, this study provides information on third-line treatment from the daily clinical practice; moreover, its results help in defining the best therapeutic sequence and offer some hints to select the optimal candidate for treatment beyond second line. PMID- 28860413 TI - The transcriptome of CDK4/6 inhibition. PMID- 28860415 TI - T2-relaxation time increases in lumbar intervertebral discs after 21d head-down tilt bed-rest. AB - OBJECTIVES: Spaceflight back pain and intervertebral disc (IVD) herniations cause problems in astronauts. Purpose of this study was to assess changes in T2 relaxation-time through MRI measurements before and after head-down tilt bed rest, a spaceflight analog. METHODS: 8 men participated in the bed-rest study. Subjects remained in 6 degrees head down tilt bed-rest in two campaigns of 21 days, and received a nutritional intervention (potassium bicarbonate 90 mmol/d) in a cross-over design. MRI measurements were performed 2 days before bed-rest, as well as one and five days after getting up. Image segmentation and data analysis were conducted for the IVDs Th12/L1 to L5/S1. RESULTS: 7 subjects, average age of 27.6 (SD 3.3) years, completed the study. Results showed a significant increase in T2-time in all IVDs (p?0.001), more pronounced in the nucleus pulposus than in the annulus fibrosus (p?0.001). Oral potassium bicarbonate did not show an effect (p=0.443). Pfirrmann-grade correlated with the T2-time (p?0.001). CONCLUSIONS: 6 degrees head-down tilt bed-rest leads to a T2 time increase in lumbar IVDs. Oral potassium bicarbonate supplementation does not have an effect on IVD T2-time. PMID- 28860416 TI - Estrogen-progestin therapy causes a greater increase in spinal bone mineral density than estrogen therapy - a systematic review and meta-analysis of controlled trials with direct randomization. AB - OBJECTIVE: To assess whether progesterone (P4) or osteoblast P4 receptor-acting progestin (P) contributed to estrogen (E) therapy-related increased areal bone mineral density (BMD) in randomized controlled trials (RCT) with direct randomization to estrogen (ET) or estrogen-progestin (EPT) therapy. METHODS: Systematic literature searches in biomedical databases identified RCT with direct randomization and parallel estrogen doses that measured spinal BMD change/year. Cyclic P4/P was included in this random effects meta-analysis only if for >= half the number of E-days. RESULTS: Searches yielded 155 publications; five met inclusion criteria providing eight dose-parallel ET-EPT comparisons in 1058 women. Women averaged mid-50 years, ?five years into menopause and took conjugated equine E daily at 0.625 mg with/without 2.5 mg medroxyprogesterone acetate (MPA). The weighted mean EPT minus ET percentage difference in spinal BMD change was +0.68%/year (95% CI 0.38, 0.97%) (P=0.00001). This result was highly heterogeneous (I2=81%) but this may reflect the small number of studies. CONCLUSION: Estrogen with an osteoblast P4R-acting progestin (EPT) in these five published RCT provides Level 1 evidence that MPA caused significantly greater annual percent spinal BMD gains than the same dose of ET. These data have implications for management of vasomotor symptoms and potentially for osteoporosis treatment in menopausal women. PMID- 28860417 TI - Exercise for osteoporosis: how to navigate between overeagerness and defeatism. AB - Osteoporosis and associated fractures remain a common and costly health problem. Public fears about rare side effects of efficacious drug treatments for osteoporosis have contributed to decreased prescription and compliance. Exercise and physical activity-based interventions have long been proposed as an alternative treatment for osteoporosis. However despite compelling evidence from experimental studies in animals and from observational studies in humans, the use of exercise to improve bone mass in clinical practice does not seem to be justifiable by current human interventional studies. In this perspective, we summarise the available evidence in support of exercise on bone mass. We review the modest effects observed in current exercise trials, and propose a number of factors which may contribute to these discrepancies. We also highlight the successful application of exercise to attenuating or even partially reversing bone loss in musculoskeletal disuse. We then propose how collaboration between basic science and clinical partners, and consideration of factors such as exercise modality, exercise intensity and participation motivation could improve exercise efficacy. PMID- 28860418 TI - Pantoprazole, a proton pump inhibitor, does not prevent botulinum toxin induced disuse osteopenia in mice. AB - OBJECTIVES: Pantoprazole is a proton pump inhibitor that has been shown to inhibit bone resorption. The aim of the study was to investigate whether pantoprazole can prevent development of botulinum toxin (BTX)-induced disuse osteopenia in mice. METHODS: Forty-eight 16-week-old female C57BL/6J mice were randomized into 4 groups (n=12): Base, Ctrl, BTX, and BTX+Pan. The Base group was euthanized at study start. The BTX and BTX+Pan groups were immobilized by injections with BTX in one hind limb. The BTX+Pan group was injected i.p. daily with 100 mg pantoprazole per kg bodyweight. The mice were euthanized after 3 weeks of treatment. The skeletal status was investigated by DEXA, uCT, mechanical testing, dynamic bone histomorphometry, and RT-qPCR. The bone sites investigated were tibia, femur, L5 vertebra, and humerus. RESULTS: Injections of BTX induced a pronounced and significant loss of bone density, microstructure, and strength in the immobilized hind limb. Furthermore, the localized intramuscular injections of BTX lead to a slight loss of bone and bone strength at the L5 vertebra and humerus. Treatment with pantoprazole did not have any bone protective or deleterious effects. CONCLUSION: Pantoprazole was unable to prevent the development of BTX induced disuse osteopenia in skeletally mature female C57BL/6J mice. PMID- 28860419 TI - Effect of quadriceps and hamstrings muscle cooling on standing balance in healthy young men. AB - OBJECTIVE: The present study compared the effect of quadriceps and hamstring muscle cooling on standing balance in healthy young men. METHODS: Thirty healthy young men (18-30 years) participated in the study. The participants were randomly assigned to three groups (n=10 each): quadriceps cooling (QC), hamstring cooling (HC), or control group (no cooling). Participants in the QC and HC groups received 20 minutes of cooling using a cold pack (gel pack), placed on the anterior thigh (from the apex of the patella to the mid-thigh) and the posterior thigh (from the base of the popliteal fossa to the mid-thigh), respectively. Balance score including unilateral stance was measured at baseline and immediately after the application of the cold pack. RESULTS: No significant difference in the balance score was noted in any group after the application of the cold pack (p?0.05). Similarly, no significant differences in post-test balance score were noted among the three groups (p?0.05). CONCLUSIONS: Cooling of the quadriceps and hamstring muscles has no immediate effect on standing balance in healthy young men. However, longitudinal studies are warranted to investigate the long-term effects of cooling these muscles on standing balance. PMID- 28860420 TI - Baseline mineralizing surface determines the magnitude of the bisphosphonate effect on cortical bone mineralization in postmenopausal osteoporotic patients. AB - PURPOSE: To determine the effect of short- or long-term bisphosphonate treatment on cortical bone mineralization density distribution (BMDD). METHODS: BMDD was assessed by quantitative backscatter electron imaging in postmenopausal osteoporosis: in paired transiliac biopsy samples (n=36) at baseline and after 3 years risedronate treatment from a clinical study, in transiliac biopsy samples from patients who were treated with either risedronate (n=31) or alendronate (n=68) for 3 to 7 years from an observational study. Outcomes were related to premenopausal reference data (n=73) and to histomorphometric mineralizing surface per bone surface (MS/BS). RESULTS: In the clinical study, patients with lower (below cohort median) MS/BS had normal cortical CaMean at baseline. After 3 years risedronate, their CaMean was not different versus baseline but increased versus reference (+2.9%, p=0.003). Among the groups of the observational study, CaMean did not exceed reference level, was similar for alendronate versus risedronate and similar between 3 to 5 years versus longer than 5 years treatment duration. CONCLUSION: Baseline bone mineralizing surface appears to be important for the effect of bisphosphonate on cortical bone mineralization. In patients with lower baseline MS/BS, level of mineralization after treatment can exceed reference level. Whether this is beneficial in the long-term is unknown. PMID- 28860414 TI - Mechanical basis of bone strength: influence of bone material, bone structure and muscle action. AB - This review summarises current understanding of how bone is sculpted through adaptive processes, designed to meet the mechanical challenges it faces in everyday life and athletic pursuits, serving as an update for clinicians, researchers and physical therapists. Bone's ability to resist fracture under the large muscle and locomotory forces it experiences during movement and in falls or collisions is dependent on its established mechanical properties, determined by bone's complex and multidimensional material and structural organisation. At all levels, bone is highly adaptive to habitual loading, regulating its structure according to components of its loading regime and mechanical environment, inclusive of strain magnitude, rate, frequency, distribution and deformation mode. Indeed, the greatest forces habitually applied to bone arise from muscular contractions, and the past two decades have seen substantial advances in our understanding of how these forces shape bone throughout life. Herein, we also highlight the limitations of in vivo methods to assess and understand bone collagen, and bone mineral at the material or tissue level. The inability to easily measure or closely regulate applied strain in humans is identified, limiting the translation of animal studies to human populations, and our exploration of how components of mechanical loading regimes influence mechanoadaptation. PMID- 28860421 TI - Relationship of body anthropometric measures with skeletal muscle mass and strength in a reference cohort of young Finnish women. AB - OBJECTIVES: 1) To study if limb length explains variability in appendicular and total muscle mass better than height and 2) if muscle mass adjusted for limb length rather than height correlates better with grip and knee extension strength. METHODS: 400 healthy women aged 20-40 were recruited as a reference population. Body composition, limb length, grip strength and knee extension strength were measured. New relative muscle mass indexes were computed by adjusting upper limb muscle mass for upper limb length (ULRSMI) and lower limb muscle mass for lower limb length (LLRSMI). RESULTS: Height correlated strongest with all muscle mass measures. Height had the highest R2 values for predicting variability in appendicular skeletal muscle mass (0.33), upper limb skeletal muscle mass (0.20), lower limb skeletal muscle mass (0.34) and total skeletal muscle mass (0.36). Correlation of relative skeletal muscle mass index (RSMI) with grip and knee extension strength (r=0.47 and 0.43) was higher when compared with correlation of ULRSMI and LLRSMI with these measures. CONCLUSION: Compared to limb length, height correlates better with regional and total muscle mass. Muscle mass adjusted for height correlates better with grip strength and knee strength when compared with muscle mass adjusted for limb length. PMID- 28860422 TI - Intertester and intratester reliability of a movement control test battery for patients with knee osteoarthritis and controls. AB - OBJECTIVES: To develop a test battery of movement control (MC) tests and assess its intertester and intratester reliability. METHODS: 29 subjects with knee OA with mean age of 64.7 (SD 8.7) years and 12 controls without either knee pain or previous diagnosis of OA (mean age 36.6 (SD 16.2) years) were included. Two experienced physiotherapists rated the filmed test performance of six MC tests blinded to the patients and to each other on 3-point scale as correct, incorrect or failed. Weighted kappa coefficient (wK) with 95% confidence interval (95%CI) and the percentage of agreement were calculated for each test. RESULTS: One-leg stance, one-leg squat 30 degrees and step down tests showed moderate to excellent inter- and intratester reliability with wK ranging between 0.43-0.85 for intertester and 0.51-0.80 for intratester reliability. The reliability of the 90 degrees squat test, small squat and step up tests was poor (wK ranging between 0.09-0.50). CONCLUSIONS: One-leg stance test, one-leg squat 30 degrees and step down test are reliable in the subjects with knee OA and controls. Further studies are needed to evaluate the discriminative validity of the reliable tests. PMID- 28860423 TI - Prevalence of sarcopenia in a population of nursing home residents according to their frailty status: results of the SENIOR cohort. AB - OBJECTIVE: To investigate the relationship between frailty and sarcopenia, by evaluating the prevalence of sarcopenia among frail, pre-frail and robust elderly nursing home residents in Belgium. METHODS: This is an analysis of baseline data collected from the SENIOR (Sample of Elderly Nursing home Individuals: an Observational Research) cohort. All subjects received a sarcopenia evaluation, based on the definition proposed by the European Working Group on Sarcopenia in Older People (EWGSOP). The frailty evaluation was primarily based on FRIED's definition but also on 9 other operational definitions. RESULTS: A total of 662 subjects (73.1% of women) were included in this analysis (mean age: 83.2+/-8.99 years). The prevalence of sarcopenia was 38.1% whereas the prevalence of frail and pre-frail persons was respectively 24.7% and 61.4%. Among frail, pre-frail and robust subjects, respectively 47%, 38.9% and 16.3% were diagnosed sarcopenic. The prevalence of sarcopenia according to ten different operational definitions of frailty ranged between 32.8 % (i.e. Frail scale Status and Frailty Index) and 47% (i.e. Fried definition). CONCLUSION: This research highlights that over a third of nursing home residents are sarcopenic and the percentage is almost 50% among frail subjects; those latter constitute about 1 in 4 of the population of nursing home residents studied here. PMID- 28860424 TI - Prolonging disuse in aged mice amplifies cortical but not trabecular bones' response to mechanical loading. AB - OBJECTIVE: Short-term neurectomy-induced disuse (SN) has been shown to restore load responses in aged mice. We examined whether this restoration was further enhanced in both cortical and trabecular bone by simply extending the SN. METHODS: Following load:strain calibration, tibiae in female C57BL/J6 mice at 8, 14 and 20 weeks and 18 months (n=8/group) were loaded and bone changes measured. Effects of long-term SN examined in twenty-six 18 months-old mice, neurectomised for 5 or 100 days with/without subsequent loading. Cortical and trabecular responses were measured histomorphometrically or by micro-computed tomography. RESULTS: Loading increased new cortical bone formation, elevating cross-sectional area in 8, 14 and 20 week-old (p ?0.05), but not 18 month-old aged mice. Histomorphometry showed that short-term SN reinstated load-responses in aged mice, with significant 33% and 117% increases in bone accrual at 47% and 37%, but not 27% of tibia length. Cortical responses to loading was heightened and widespread, now evident at all locations, following prolonged SN (108, 167 and 98% at 47, 37 and 27% of tibial length, respectively). In contrast, loading failed to modify trabecular bone mass or architecture. CONCLUSIONS: Mechanoadaptation become deficient with ageing and prolonging disuse amplifies this response in cortical but not trabecular bone. PMID- 28860425 TI - Marked expression of TNF receptors in human peritendinous tissues including in nerve fascicles with axonal damage - Studies on tendinopathy and tennis elbow. AB - BACKGROUND: The peritendinous connective tissues can have importance in chronic tendon pain. Recently cytokine TNF-alpha has been suggested to be involved in tendinopathic processes. It is not known how TNF-alpha and its receptors TNFR1 and TNFR2 are expressed in peritendinous tissues. METHODS: The objective for this study was to immunohistochemically evaluate the expression patterns of these in the peritendinous tissue located between the plantaris and Achilles tendons and the one located superficially to the extensor origin at the elbow region for patients with tendinopathy/tennis elbow. RESULTS: The nerve fascicles were of two types, one type being homogenously stained for the nerve markers betaIII-tubulin and neurofilament and the other showing deficits for these suggesting features of axonal damage. Much more distinct TNFR1/TNFR2 immunoreactions were seen for the latter nerve fascicles. TNFR1 was seen in axons, TNFR2 mainly in Schwann cells. TNFR1 and particularly TNFR2 were seen in walls of parts of blood vessels. The dispersed cells showed frequently TNFR1 and TNFR2 immunoreactivity. DISCUSSION: These findings suggest that TNF-alpha can be related to degenerative events but also attempts for healing concerning the nerve structures. The marked expression of the TNF-alpha system in the peritendinous tissue suggests an impact of TNF alpha in tendinopathy/tennis elbow. PMID- 28860426 TI - Experience with jumping mechanography in children with cerebral palsy. AB - OBJECTIVES: Jumping mechanography provides robust motor function indicators among healthy children. The aim of the study was to assess the reproducibility and validity of jumping mechanography conducted as single two-legged jump (S2LJ) in children with cerebral palsy (CP). METHODS: 215 S2LJ investigations from a sample of 75 children with CP were eligible for evaluation. For the estimation of the reproducibility, only the baseline set of data per patient were used. Gross motor function was evaluated by the Gross Motor Function Measure (GMFM-66). In 135 S2LJ investigations, GMFM-66 was assessed within a week in the same child. This data was used for validity assessment. RESULTS: Coefficients of variation for the main outcome parameters ranged between 6.15-9.71%, except for jump height (CV%=27.3%). The intraclass correlation coefficients for peak velocity (Vmax) and peak power relative to body weight (Pmax/mass) was 0.927 and 0.931. Vmax and Pmax/mass were also the test parameters with the strongest correlation to the GMFM-66 score (?0.7). CONCLUSIONS: S2LJ assessed in the present study provided reproducible outcome measures particularly for Vmax and Pmax/mass in children with CP. Further, Vmax and Pmax/mass showed the strongest correlation with the GMFM-66 score and seem to be the most relevant evaluation criteria. PMID- 28860427 TI - Feasibility and acceptability of using jumping mechanography to detect early components of sarcopenia in community-dwelling older women. AB - OBJECTIVE: To determine the feasibility and acceptability of using peak power and force, measured by jumping mechanography (JM), to detect early age-related features of sarcopenia in older women. METHODS: Community-dwelling women aged 71 87 years were recruited into this cross-sectional study. Physical function tests comprised the short physical performance battery (SPPB), grip strength and, if SPPB score>=6, JM. JM measured peak weight-adjusted power and force from two footed jumps and one-legged hops respectively. Questionnaires assessed acceptability. RESULTS: 463 women were recruited; 37(8%) with SPPB?6 were ineligible for JM. Of 426 remaining, 359(84%) were able to perform >=1 valid two footed jump, 300(70%) completed >=1 valid one-legged hop. No adverse events occurred. Only 14% reported discomfort. Discomfort related to JM performance, with inverse associations with both power and force (p?0.01). Peak power and force respectively explained 8% and 10% of variance in SPPB score (13% combined); only peak power explained additional variance in grip strength (17%). CONCLUSIONS: Peak power and force explained a significant, but limited, proportion of variance in SPPB and grip strength. JM represents a safe and acceptable clinical tool for evaluating lower-limb muscle power and force in older women, detecting distinct components of muscle function, and possibly sarcopenia, compared to those evaluated by more established measures. PMID- 28860428 TI - [Current Status and Future Perspectives of SCRUM-Japan]. AB - SCRUM-Japan was launched as a nation-wide genome screening consortium for recruiting patients to 35 sponsor-/investigator- initiated registration trials in collaboration with 15 pharmaceutical companies and 240 hospitals. During the first period between February 2015 and March 2017, a total of 4,805 patients have been enrolled. Genomic profiling of each cancer were analyzed and newdrug applications of label expansion are in preparation based on the results of several registration studies including investigator-initiated trial of vandetanib for RET fusion gene positive non-small cell lung cancer. In addition, on-time clinical-genome data sharing with industries and academic institutions and prospective cohort registry for new drug evaluation as a historical control data have already initiated, which will facilitate new agent development in Japan. In the second period started from April 2017, new studies using cutting-edge liquid biopsy and immune-genome panel for precision medi- cine will start soon. These efforts are attempted towards a leading group for innovative clinical/translations researches in the world. PMID- 28860429 TI - [The Overview of Two Programs to Support Cancer Survivor's Advocacy by CancerNet Japan]. AB - In 2016, the Cancer Control Act was revised, with emphasis on support for people living with cancer, the public's understanding of cancer patients, continuation of employment of cancer patients and cancer education, etc, was added. In order to make policies effective, it is necessary for society to listen to the voices of cancer survivor and to know the current situation of issues they face on. We, CancerNet Japan have been supporting cancer patients through the 2 projects "Breast cancer Experienced Coordinator(BEC)Training Course", started in 2007 and "Over Cancer Together(OCT)Campaign", started in 2013. We have educated the knowledge and skills that are required for cancer survivor to utilize their experiences. There are more than 400 graduates who have completed each 2 courses. Some engaged in consultation support activities as a peer supporter in hospitals and areas, other serve as local cancer promotion committee members, and give lecture activities. These 2 projects that have supported cancer survivorship were to support the process of enhancing advocacy, cancer survivor gaining correct knowledge, standing with their own power, disseminating their own experiences and issues based on it, and taking actions to resolve. PMID- 28860431 TI - [Survivor support by Pancreatic Cancer Action Network Japan - Double Survivors by 2020]. AB - In order to double the number of pancreatic cancer survivors, we need to develop early detection tool and new therapies that control stage IV metastatic disease. Pancreatic cancer survivors are slowly increasing and we would appreciate welcoming them to the cancer survivor community. PMID- 28860430 TI - [Now and the Future of Survivorship Support of Cancer Control in Japan]. AB - Based on the Cancer Control Act approved in June 2006 and the National Cancer Control Plan, cancer control promotion council including cancer patients in Ministry of Health, Labor and Welfare(MHLW)has discussed about cancer survivorship from the viewpoint of the reduction of economic burden on cancer patients and supporting cancer patients to be independent and MHLW has taken measures especially in the employment support for cancer patients. On the other hand, cancer survivorship is a theme related to general living of cancer patients after cancer diagnosis. In order to promote measures on cancer survivorship in Japan, not only the employment support for cancer patients but also the research and support for multifaceted areas are needed. PMID- 28860432 TI - [Maggie's Tokyo's Human Support the Meaning of Where Now ? And Cancer Journey]. AB - The landscape architect Maggie Jencks felt that she wanted a place to "get herself back" when her breast cancer recurred and was told that she only had a few months remaining. Mr. Charles Jencks, her husband who fulfilled her wishes, opened the first "Maggie's Cancer Caring Centre" in Edinburgh in 1996. Masako Akiyama, the chief of Maggie's Tokyo found out about Maggie's Centre when she listened to a presentation from Andrew Anderson, the director of Maggie's Edinburgh, at an International Nursing Seminar in 2008. Masako Akiyama realized that support to "get back ones own power" is one of the important things. In addition, she felt that providing a "place" and "support" to patients and their families were predominant elements. When someone is diagnosed with cancer, the person gets a great shock and feels loneliness. Suddenly the person feels tomorrow will not come, every day becomes uncertain. These feelings affect their whole life such as enrollment, employment, loss of role, and change. They also affect people such as family, friends, colleagues, besides the person. Due to changes in treatment, the existential troubles that have been prolonged after the completion of the initial treatment appear. Cancer survivorship is called "Cancer journey"in the Maggie's flow. The cancer journey suddenly starts, when a person is diagnosed with cancer", without direction or a plan. Additionally, the "heart"is often left behind. To undertake the cancer journey, there are a lot of forks in the road that cannot turn back and they are urged to choose their path. "Where now ?"is a phrase in a pamphlet from Maggie's Centre, and the phrase shows that staff of Maggie's Centre can help cancer patient to recognize where they are in their Cancer journey. The Maggie's Centre has 2 important pillars: "building/environment"and "human support". As a "homely place" between hospital and my house, the building is "a healing space". Human support is provided free of charge and patients and families can stop by without reservation. Experienced cancer specialists and medical staff are always available. Unlike previous supportive methods for patients such as giving information and helping to solve problems, Maggie's emphasizes the 3 points of "snuggling up to each individual", "equal footing" and "to cherish their likeness empowerment". By talking to Maggie's medical professionals, patients and families can find their "heart" and regain their original strength. PMID- 28860433 TI - [Thorax/Lung and Mediastinum, Pleura: Cancer Immunotherapy for Lung Cancer - The Beginning of a New Era in the Treatment of Lung Cancer]. PMID- 28860434 TI - [I. History of Immunotherapy and Cancer Vaccine for Lung Cancer]. PMID- 28860435 TI - [II. Overview and Future Outlook of Immune Cell Therapy for Lung Cancer]. PMID- 28860436 TI - [III. Immune Checkpoint Inhibitor as a Standard Treatment against Lung Cancer]. PMID- 28860437 TI - [IV. Development and Future Perspective of Immune Checkpoint Blockade Therapy]. PMID- 28860438 TI - [New Treatment Options for Renal Cell Carcinoma - Efficacy and Safety of Immune Checkpoint Inhibitors]. AB - In addition to chemotherapy for advanced renal cell carcinoma(RCC), molecular targeted drugs such as tyrosine kinase inhibitors(TKI)and mTOR inhibitors have been clinically introduced, and they have contributed to improved progression free survival(PFS)and overall survival(OS). However, complete response over a long period are rarely obtained with these drugs, and there are many cases of recurrence and progression. The anti-PD-1 antibody nivolumab, an immune checkpoint inhibitor, has approved for the indication of "Unresectable or metastatic RCC" in Japan, based on the phase III study results for advanced RCC with previous TKI treatment. The nivolumab response indicates the possibility of a sustained treatment effect for a long period of time, but also suggests the tendency to take time to develop the effect. Regarding safety, immune-related adverse events(irAEs)with a profile that may be different from those of conventional drugs, and in addition to fully understanding these features, we need to be familiar with how to manage irAEs. PMID- 28860439 TI - [Comparison between Primary Debulking Surgery and Neo-Adjuvant Chemotherapy Followed by Interval Debulking Surgery for Patients with Stage III-IV Ovarian Cancer]. AB - The current standard treatment for advanced ovarian cancer is primary debulking surgery(PDS). We may expect a good prognosis if complete debulking(no visible residual tumor)is possible. However, if complete surgery is not possible owing to the location of the tumor or poor performance status, neo-adjuvant chemotherapy(NAC)could be an alternative option. Interval debulking surgery(IDS)can be planned after NAC to try and achieve complete debulking surgery. We reviewed stage III and IV epithelial ovarian cancers treated at Kansai Rosai Hospital between January 2012 and January 2016. Fifty-one cases (PDS: 22 cases, NAC-IDS: 29 cases)were enrolled in our analysis. Progression-free survival(PFS), overall survival(OS), the successful complete surgery rate, and the contents and complications of the surgery were compared between the PDS and NAC-IDS groups. There was no significant difference in PFS and OS between the 2 groups(PFS: p=0.467, OS: p=0.685). Blood loss was larger in the PDS group(p=0.013). Patients in the NAC-IDS group were likely to be able to eventually achieve complete surgery(p=0.016). NAC followed by IDS is one of the effective treatment options for advanced ovarian cancers. PMID- 28860440 TI - [A Retrospective Analysis of Systematic Lymphadenectomy for Loco Regional(pT1)Epithelial Ovarian Cancer]. AB - BACKGROUND: The incidence of lymph node metastasis in pT1 epithelial ovarian cancer is between 5% and 21%. Most cases with lymph node metastasis are those of serous carcinoma; it is relatively rare in mucinous carcinoma. Therefore, there is a recent trend to omit systematic lymphadenectomy in early stage mucinous carcinoma. The purpose of this study was to verify whether the omission of systematic lymphadenectomy in mucinous carcinoma is oncologically safe. METHODS: We reviewed all pT1 epithelial ovarian cancer cases that were treated in our hospital between January 2002 and December 2015. RESULTS: Fiftynine cases of pT1 epithelial ovarian cancer were included. The overall rate of lymph node metastasis was 6.8%(4 in 59). It was 6.5%(2 in 31)in clear cell carcinoma and 22.2%(2 in 9)in mucinous carcinoma. CONCLUSION: According to our study, lymph node metastasis in pT1 mucinous carcinoma has a rate of 22.2% and some affected cases were not detected by presurgery imaging studies. Therefore, we need to be careful about the omission of systematic lymphadenectomy in mucinous carcinoma. PMID- 28860441 TI - [A Case of Merkel Cell Carcinoma Complicated with Severe Thrombocytopenia Treated with Carboplatin/Etoposide Regimen after Surgery]. AB - Thrombocytopenia is often caused by myelosuppression during chemotherapy. However, when platelet transfusions are required, pathological conditions such as idiopathic thrombocytopenic purpura(ITP)and thrombotic thrombocytopenic purpura( TTP)also occur. We report a case of Merkel cell carcinoma complicated with severe thrombocytopenia treated with carboplatin/etoposide regimen after surgery. The patient's platelet count did not increase in spite of platelet transfusions. However, the platelet count increased after steroid treatment was chosen under the diagnosis of ITP. Subsequent examinations revealed that the patient had HLA antibody, which caused the platelet transfusion refractoriness. When the platelet count does not increase in spite of platelet transfusions during chemotherapy, the possibility that the platelet transfusion refractoriness is due to the presence of HLA antibody should be considered. PMID- 28860442 TI - [Effective BiRd Therapy after the Addition of Clarithromycin for Lenalidomide and Dexamethasone Resistant Multiple Myeloma Ineligible for Stem Cell Transplantation]. AB - BiRd combination therapy, which comprises clarithromycin(CAM: Biaxin(r)), lenalidomide(LEN: Revlimid(r)), and dexamethasone( DEX), is a highly effective treatment for newly diagnosed symptomatic multiple myeloma(MM). However, its efficacy against recurrent myeloma refractory to LEN and DEX combination therapy(Rd therapy)remains unclear. In this study, we retrospectively analyzed the data of 7 patients(4 men and 3 women, median age of 76 years)with MM, who had clarithromycin added to their Rd regimen. In all patients, the starting dose of clarithromycin was 400 mg daily and the median number of prior therapies was 3(range, 1-4). Patients received a median of 9 cycles of Rd(range, 6-27 cycles)for a median duration of 8 months. Then, patients received a median of 14 cycles of BiRd(range 2-36 cycles). One patient showed partial response(PR), which was the best response, while the others showed stable disease(SD). Our results demonstrated that the addition of clarithromycin to Rd could overcome resistance to Rd and lead to durable responses, without exacerbating hematological or non hematological toxicities. Thus, BiRd therapy may represent a therapeutic option for symptomatic MM resist- ant to Rd therapy. PMID- 28860443 TI - [Efficacy and Safety of Lenvatinib for Unresectable Anaplastic Thyroid Cancer]. AB - The 208 trial showed that lenvatinib has a significant antitumor effect on unresectable anaplastic thyroid cancer(ATC). Herein, we present a retrospective review of data from 7 patients with unresectable ATC who received lenvatinib in our hospital between May 2015 and October 2016. Two patients were men and 5 were women. The median age was 78(range, 72-85)years, and 1 patient had Stage IV A disease, 1 had Stage IV B, and 5 had Stage IV C at diagnosis, respectively. Three patients experienced a partial response and 1 patient experienced stable disease. The response rate was 43%, and the disease control rate was 57%. The median progression-free survival(PFS)was 4.1(range, 1.1-12.2)months. Grade 3 and Grade 4 gastrointestinal hemorrhage were observed in 2patients and Grade 3 anorexia was observed in 1 patient. Further clinical research seems to be needed to establish a treatment strategy involving lenvatinib for ATC. PMID- 28860444 TI - [Nearly Complete Response after Second-Line Therapy with Nab-Paclitaxel Monotherapy in a Patient with Recurrent Advanced Non-Small Cell Lung Cancer]. AB - A 62-year-old woman was diagnosed with stage IV lung adenocarcinoma. After resection of a metastatic brain tumor, she had received first-line chemotherapy consisting of 6 courses of carboplatin and pemetrexed, then 14 courses of maintenance therapy of pemetrexed until disease progression. As second-line treatment, she was administered nanoparticle albuminbound paclitaxel(nab paclitaxel)monotherapy. A nearly complete response(nearly CR)has been maintained for 3 years without any severe adverse events. Although there is insufficient evidence for the use of nab-paclitaxel monotherapy as second-line chemotherapy, it could be an effective treatment option for patients with recurrent advanced non-small cell lung cancer. PMID- 28860445 TI - [Efficacy of GC Therapy for the Patient of iTNBC with Resistance to TAC Therapy]. AB - We report a case of TNBC treated effectively with a platinum-based regimen after developing resistance to anthracycline and taxane-based neoadjuvant chemotherapy(NAC). A 59-year-old woman with a right breast mass and high fever visited our clinic and was diagnosed as having inflammatory triple negative breast cancer(iTNBC). She was treated with NAC of docetaxel, doxorubicin, and cyclophosphamide(TAC)using pegfilgrastim. After 5 courses of TAC, the therapy failed and the disease progressed. Thus, a combination regimen of gemcitabine and carboplatin(GC)was administered. The treatment was successful, and the patient underwent a curative operation after 6 courses of the GC therapy. PMID- 28860446 TI - Translation and cross-cultural adaptation of the ASAS Health Index and ASAS Environmental Factors Item Set into European Portuguese Language. AB - OBJECTIVE: There is a lack of outcome measures to assess the impact of axial spondyloarthritis (axSpA) on health, function and quality of life. The Assessment of SpondyloArthritis International Society (ASAS) group developed the ASAS Health Index (ASAS-HI) and the ASAS Environmental Factors Item Set (ASAS-EF) to measure functioning and health across all aspects of health that are typically affected and relevant for patients with axSpA, based on the International Classification of Functioning, Disability and Health (ICF). The aim of this paper was to describe the translation and cross-cultural adaptation of both questionnaires into European Portuguese among patients with radiographic and non-radiographic axial SpA (nr-axSpA) and test the conceptual equivalence of the translated version in the Portuguese context. MATERIAL AND METHODS: The ASAS-HI and ASAS-EF were firstly translated into European Portuguese and then back-translated into English, following forward-backward procedure. After the review of the Portuguese version by an expert committee, the field test with cognitive debriefing involved a sample of 10 axSpA patients with different gender, age, disease duration, and educational background. RESULTS: Minor difficulties arose from the translation process of the ASAS-HI. The EF Item Set offered more difficulties indicating that concepts underlying the contextual factors may be more culture-dependent. A total of 10 patients with axSpA [8 males, mean age of 41.4 (+/-13.7)] participated in the field test. Cognitive debriefing showed that items of the ASAS-HI and EF Item Set of the Portuguese version are clear, relevant, understandable and easy to complete. As a result of cognitive debriefing, the wording of four items had to be changed to avoid misunderstandings or unintended interpretations, and a new response option "not applicable" was added to two items of the ASAS-HI to improve appropriateness. CONCLUSIONS: The resulting Portuguese version of the ASAS-HI and ASAS-EF showed acceptable linguistic validity and has potential for use in both clinical practice and research settings. Nevertheless, before European Portuguese versions can be fully implemented, its psychometric properties (validity and reliability) need to be evaluated. PMID- 28860447 TI - Recurrent Cardiovascular Events Despite Antiplatelet Therapy in a Patient with Polycythemia Vera and Accelerated Platelet Turnover. AB - BACKGROUND Clopidogrel is commonly used in the prevention and treatment of cardiovascular events. However, despite clopidogrel treatment, some patients experience recurrent ischemic events. CASE REPORT We present the case of a 58 year-old man with polycythemia vera and concomitant thrombocytosis who suffered 6 episodes of cerebral infarctions and 1 myocardial infarction, despite treatment with clopidogrel. Following his last ischemic event, the antiplatelet therapy was intensified from initially clopidogrel monotherapy to dual antiplatelet therapy with aspirin 75 mg once daily and ticagrelor 90 mg twice daily. Since then, no cardiovascular event has been reported. CONCLUSIONS This case report illustrates that insufficient platelet inhibition with clopidogrel monotherapy in a patient with thrombocytosis may be associated with recurrent arterial thrombosis. The exact reasons for the insufficient platelet inhibition are not known, but a plausible explanation may be an accelerated platelet turnover reflected by an increased number of immature platelets in this patient. PMID- 28860448 TI - Expression of Thyroid Hormone Responsive SPOT 14 Gene Is Regulated by Estrogen in Chicken (Gallus gallus). AB - Thyroid hormone responsive spot 14 (THRSP) is a small nuclear protein that responds rapidly to thyroid hormone. It has been shown that THRSP is abundant in lipogenic tissues such as liver, fat and the mammary gland in mammals. The THRSP gene acts as a key lipogenic activator and can be activated by thyroid hormone triiodothyronine (T3), glucose, carbohydrate and insulin. Here we report that chicken THRSP is also abundant in lipogenic tissues including the liver and the abdominal fat, and its expression levels increased with sex maturation and reached the highest level at the peak of egg production. Structure analysis of the THRSP gene indicates that there is a conscious estrogen response element (ERE) located in the -2390 - -2402 range of the gene promoter region. Further studies by ChIP-qPCR proved that the ERalpha interacts with the putative ERE site. In addition, THRSP was significantly upregulated (P < 0.05) when chickens or chicken primary hepatocytes were treated with 17beta-estradiol in both the in vivo and in vitro conditions. We therefore conclude that THRSP is directly regulated by estrogen and is involved in the estrogen regulation network in chicken. PMID- 28860449 TI - Reduced age-associated brain changes in expert meditators: a multimodal neuroimaging pilot study. AB - Aging is associated with progressive cerebral volume and glucose metabolism decreases. Conditions such as stress and sleep difficulties exacerbate these changes and are risk factors for Alzheimer's disease. Meditation practice, aiming towards stress reduction and emotion regulation, can downregulate these adverse factors. In this pilot study, we explored the possibility that lifelong meditation practice might reduce age-related brain changes by comparing structural MRI and FDG-PET data in 6 elderly expert meditators versus 67 elderly controls. We found increased gray matter volume and/or FDG metabolism in elderly expert meditators compared to controls in the bilateral ventromedial prefrontal and anterior cingulate cortex, insula, temporo-parietal junction, and posterior cingulate cortex /precuneus. Most of these regions were also those exhibiting the strongest effects of age when assessed in a cohort of 186 controls aged 20 to 87 years. Moreover, complementary analyses showed that these changes were still observed when adjusting for lifestyle factors or using a smaller group of controls matched for education. Pending replication in a larger cohort of elderly expert meditators and longitudinal studies, these findings suggest that meditation practice could reduce age-associated structural and functional brain changes. PMID- 28860450 TI - Indirect genetic effects: a key component of the genetic architecture of behaviour. AB - Behavioural ecology research increasingly focuses on why genetic behavioural variation can persist despite selection. Evolutionary theory predicts that directional selection leads to evolutionary change while depleting standing genetic variation. Nevertheless, evolutionary stasis may occur for traits involved in social interactions. This requires tight negative genetic correlations between direct genetic effects (DGEs) of an individual's genes on its own phenotype and the indirect genetic effects (IGEs) it has on conspecifics, as this could diminish the amount of genetic variation available to selection to act upon. We tested this prediction using a pedigreed laboratory population of Mediterranean field crickets (Gryllus bimaculatus), in which both exploratory tendency and aggression are heritable. We found that genotypes predisposed to be aggressive (due to DGEs) strongly decreased aggressiveness in opponents (due to IGEs). As a consequence, the variance in total breeding values was reduced to almost zero, implying that IGEs indeed greatly contribute to the occurrence of evolutionary stasis. IGEs were further associated with genetic variation in a non social behaviour: explorative genotypes elicited most aggression in opponents. These key findings imply that IGEs indeed represent an important overlooked mechanism that can impact evolutionary dynamics of traits under selection. PMID- 28860451 TI - Bi-directional plasticity: Rotifer prey adjust spine length to different predator regimes. AB - Numerous prey organisms, including many rotifers, exhibit inducible defensive plasticity, such as spines, in response to predators. Here, we test the hypothesis that prey modify their defence response to different predator sizes with a bi-directional adjustment in spine length. First, we show experimentally, that large-sized predators induce a reduction in prey spine length. Second, we conducted a complementary field monitoring study showing that the spine length of the prey rotifer Keratella cochlearis changed in opposite directions, in response to the shift in dominance between small-sized and large-sized predators. Third, in order to test the generality of our novel findings, we conducted a meta analysis covering a wide array of rotifer prey taxa, strengthening the conclusions from our experimental and field studies. Hence, by combining evidence from experiments and studies in the field with a meta-analysis, we, for the first time, demonstrate that rotifer prey distinguish between predators and adjust their protective spine length accordingly, i.e. rapidly adjust spine length to escape either below or above the dominant predator's gape size window. In a broader perspective, our conclusions advance our knowledge on observed spatial and temporal variations in protective morphologies among prey organisms. PMID- 28860452 TI - Optical spin noise spectra of Rb atomic gas with homogeneous and inhomogeneous broadening. AB - We study the optical spin noise spectra of Rb atomic gas with different broadening mechanisms. The first is homogeneous broadening using 250 Torr nitrogen buffer gas, while the other mechanism is inhomogeneous broadening via the Doppler effect without buffer gas. Spin noise signals are measured by the typical spin noise spectroscopy geometry (single-pass geometry) and the saturated absorption spectroscopy geometry (double-pass geometry). In the homogeneously broadened system, the line shape of the optical spin noise spectra shows a pronounced dip that vanishes at the center of the band in both geometries. In the inhomogeneously broadened system, however, a peak in the single-pass geometry and a dip in the double-pass geometry at the band center are observed. The difference between the optical spin noise spectra from these two systems arises from their different level-broadening mechanisms. PMID- 28860453 TI - Phenology-dependent variation in the non-structural carbohydrates of broadleaf evergreen species plays an important role in determining tolerance to defoliation (or herbivory). AB - Two broadleaf evergreen canopy species (Schima superba and Engelhardia roxburghiana) with different phenologies in a subtropical region of southern China were used to determine the influence of leaf phenology on the impact of an insect pest attack. S. superba regenerates its leaves in February, while E. roxburghiana regenerates its leaves in May. The moth Thalassodes quadraria attacked the two broadleaf evergreen species in March to April, and the newly produced leaves were removed for S. superba but not for E. roxburghiana. The young trees were artificially defoliated to imitate an insect pest attack during March 2014. Nonstructural carbohydrate (NSC) and growth measurements and a retrospective analysis based on the radial growth of mature trees were conducted in January 2015. The results showed that NSC concentrations decreased in S. superba during canopy rebuilding, and the subsequent defoliation severely inhibited leaf and shoot growth, prevented NSC restoration in roots and stem xylem, and caused high mortality. The insect outbreaks reduced the radial growth of S. superba. In contrast, E. roxburghiana experienced less growth retardation, lower mortality, and normal radial growth. Thus, taking phenology-dependent variation in NSCs into consideration, defoliation and insect pest outbreaks more negatively impacted S. superba than E. roxburghiana. PMID- 28860454 TI - The Synthesis of Hybrid Gold-Silicon Nano Particles in a Liquid. AB - We show that the laser ablation method can be efficiently employed for the synthesis of silicon nanoparticles (NP), which are characterized by a strong resonant optical response in the visible spectral range. A single layer composed of silicon NPs has been deposited from the colloidal solution generated by laser ablation. The formation of hybrid silicon-gold NPs as a result of the laser action on a mixed colloidal solution is observed. These hybrid NPs are characterized by broadening of the near-field photoluminescence spectra compared to pure silicon NPs. These results may be used for the realization of functional metasurfaces consisting of randomly distributed resonant NPs. PMID- 28860455 TI - Age differences in brain signal variability are robust to multiple vascular controls. AB - A host of studies support that younger, better performing adults express greater moment-to-moment blood oxygen level-dependent (BOLD) signal variability (SDBOLD) in various cortical regions, supporting an emerging view that the aging brain may undergo a generalized reduction in dynamic range. However, the exact physiological nature of age differences in SDBOLD remains understudied. In a sample of 29 younger and 45 older adults, we examined the contribution of vascular factors to age group differences in fixation-based SDBOLD using (1) a dual-echo BOLD/pseudo-continuous arterial spin labeling (pCASL) sequence, and (2) hypercapnia via a computer-controlled gas delivery system. We tested the hypothesis that, although SDBOLD may relate to individual differences in absolute cerebral blood flow (CBF), BOLD cerebrovascular reactivity (CVR), or maximum BOLD signal change (M), robust age differences in SDBOLD would remain after multiple statistical controls for these vascular factors. As expected, our results demonstrated that brain regions in which younger adults expressed higher SDBOLD persisted after comprehensive control of vascular effects. Our findings thus further establish BOLD signal variability as an important marker of the aging brain. PMID- 28860456 TI - The paradox of highly effective sofosbuvir-based combination therapy despite slow viral decline: can we still rely on viral kinetics? AB - High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy. PMID- 28860457 TI - Prognostic performance of three lymph node staging schemes for patients with Siewert type II adenocarcinoma of esophagogastric junction. AB - The prognostic performance of different lymph node staging schemes for adenocarcinoma of esophagogastric junction (AEG) remains controversial. The objective of the present study was to compare the prognostic efficacy of the number of lymph node metastases (LNMs), the positive lymph node ratio (LNR) and the log odds of positive lymph nodes (LODDS). Patients diagnosed with Siewert type II AEG were included from the Surveillance, Epidemiology, and End Results database. Harrell's C-index statistic, Schemper's proportion of explained variation (PEV), the Akaike information criterion (AIC) and restricted cubic spine analyses were adopted to assess the predictive accuracy of LNM, LNR and LODDS. A total of 1302 patients with post-surgery Siewert type II AEG were included. LNM, LNR and LODDS all showed significant prognostic value in the multivariate Cox regression analyses. LODDS performed higher predictive accuracy than LNM and LNR, with relatively higher C-index, higher Schemper's PEV value and lower AIC value. For patients with no nodes involved, LODDS still performed significantly discriminatory utility. LODDS showed more accurate prognostic performance than LNM and LNR for post-surgery Siewert type II AEG, and it could help to detect survival heterogeneity for patients with no positive lymph nodes involved. PMID- 28860458 TI - Intracellular Chloride Regulation in AVP+ and VIP+ Neurons of the Suprachiasmatic Nucleus. AB - Several reports have described excitatory GABA transmission in the suprachiasmatic nucleus (SCN), the master pacemaker of circadian physiology. However, there is disagreement regarding the prevalence, timing, and neuronal location of excitatory GABA transmission in the SCN. Whether GABA is inhibitory or excitatory depends, in part, on the intracellular concentration of chloride ([Cl-]i). Here, using ratiometric Cl- imaging, we have investigated intracellular chloride regulation in AVP and VIP-expressing SCN neurons and found evidence suggesting that [Cl-]i is higher during the day than during the night in both AVP+ and VIP+ neurons. We then investigated the contribution of the cation chloride cotransporters to setting [Cl-]i in these SCN neurons and found that the chloride uptake transporter NKCC1 contributes to [Cl-]i regulation in SCN neurons, but that the KCCs are the primary regulators of [Cl-]i in SCN neurons. Interestingly, we observed that [Cl-]i is differentially regulated between AVP+ and VIP+ neurons-a low concentration of the loop diuretic bumetanide had differential effects on AVP+ and VIP+ neurons, while blocking the KCCs with VU0240551 had a larger effect on VIP+ neurons compared to AVP+ neurons. PMID- 28860460 TI - Architecture for Directed Transport of Superparamagnetic Microbeads in a Magnetic Domain Wall Routing Network. AB - Directed transport of biological species across the surface of a substrate is essential for realizing lab-on-chip technologies. Approaches that utilize localized magnetic fields to manipulate magnetic particles carrying biological entities are attractive owing to their sensitivity, selectivity, and minimally disruptive impact on biomaterials. Magnetic domain walls in magnetic tracks produce strong localized fields and can be used to capture, transport, and detect individual superparamagnetic microbeads. The dynamics of magnetic microbead transport by domain walls has been well studied. However, demonstration of more complex functions such as selective motion and sorting using continuously driven domain walls in contiguous magnetic tracks is lacking. Here, a junction architecture is introduced that allows for branching networks in which superparamagnetic microbeads can be routed along dynamically-selected paths by a combination of rotating in-plane field for translation, and a pulsed out-of-plane field for path selection. Moreover, experiments and modeling show that the select field amplitude is bead-size dependent, which allows for digital sorting of multiple bead populations using automated field sequences. This work provides a simple means to implement complex routing networks and selective transport functionalities in chip-based devices using magnetic domain wall conduits. PMID- 28860459 TI - Association of the PLCB1 gene with drug dependence. AB - Genetic factors involved in the susceptibility to drug addiction still remain largely unknown. MiRNAs seem to play key roles in the drug-induced plasticity of the brain that likely drives the emergence of addiction. In this work we explored the role of miRNAs in drug addiction. With this aim, we selected 62 SNPs located in the 3'UTR of target genes that are predicted to alter the binding of miRNA molecules and performed a case-control association study in a Spanish sample of 735 cases (mainly cocaine-dependent subjects with multiple drug dependencies) and 739 controls. We found an association between rs1047383 in the PLCB1 gene and drug dependence that was replicated in an independent sample (663 cases and 667 controls). Then we selected 9 miRNAs predicted to bind the rs1047383 region, but none of them showed any effect on PLCB1 expression. We also assessed two miRNAs binding a region that contains a SNP in linkage disequilibrium with rs1047383, but although one of them, hsa-miR-582, was found to downregulate PLCB1, no differences were observed between alleles. Finally, we explored the possibility that PLCB1 expression is altered by cocaine and we observed a significant upregulation of the gene in the nucleus accumbens of cocaine abusers and in human dopaminergic-like neurons after cocaine treatment. Our results, together with previous studies, suggest that PLCB1 participates in the susceptibility to drug dependence. PMID- 28860461 TI - mHealth Intervention is Effective in Creating Smoke-Free Homes for Newborns: A Randomized Controlled Trial Study in China. AB - Mobile-phone-based smoking cessation intervention has been shown to increase quitting among smokers. However, such intervention has not yet been applied to secondhand smoke (SHS) reduction programs that target smoking parents of newborns. This randomized controlled trial, undertaken in Changchun, China, assessed whether interventions that incorporate traditional and mobile-phone based education will help create smoke-free homes for infants and increase quitting among fathers. The results showed that the abstinence rates of the fathers at 6 months (adjusted OR: 3.60, 95% CI: 1.41-9.25; p = 0.008) and 12 months (adjusted OR: 2.93, 95% CI: 1.24-6.94; p = 0.014) were both significantly increased in the intervention group compared to the control. Mothers of the newborns in the intervention group also reported reduced exposure to SHS at 12 months (adjusted OR: 0.53, 95% CI: 0.29-0.99; p = 0.046). The findings suggest that adding mHealth interventions to traditional face-to-face health counseling may be an effective way to increase male smoking cessation and reduce mother and newborn SHS exposure in the home. PMID- 28860462 TI - Development of gold nanoparticle-aptamer-based LSPR sensing chips for the rapid detection of Salmonella typhimurium in pork meat. AB - A non-labeled, portable plasmonic biosensor-based device was developed to enable the ultra-sensitive and selective detection of Salmonella typhimurium in pork meat samples. Specifically, a plasmonic sensor, using the self-assembly of gold nanoparticles (AuNPs) to achieve a regulated diameter of 20 nm for the AuNP monolayers, was used to conduct high-density deposition on a transparent substrate, which produced longitudinal wavelength extinction shifts via a localized surface plasmon resonance (LSPR) signal. The developed aptamers conjugated to the LSPR sensing chips revealed an ultra-sensitive upper limit of detection (LOD) of approximately 104 cfu/mL for S. typhimurium in pure culture under the optimal assay conditions, with a total analysis time of 30-35 min. When the LSPR sensing chips were applied on artificially contaminated pork meat samples, S. typhimurium in the spiked pork meat samples was also detected at an LOD of 1.0 * 104 cfu/mL. The developed method could detect S. typhimurium in spiked pork meat samples without a pre-enrichment step. Additionally, the LSPR sensing chips developed against S. typhimurium were not susceptible to any effect of the food matrix or background contaminant microflora. These findings confirmed that the developed gold nanoparticle-aptamer-based LSPR sensing chips could facilitate sensitive detection of S. typhimurium in food samples. PMID- 28860463 TI - Decision-making in primary onset middle-age type 2 diabetes mellitus: a BOLD-fMRI study. AB - Although type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for dementia, the neural mechanisms that underlying cognitive impairment in T2DM remain unclear. We used functional magnetic resonance imaging (fMRI) during a computerized version of the Iowa Gambling Task to investigate the neural basis of decision making at the initial onset stage of T2DM. Eighteen newly diagnosed middle-aged T2DM patients, with no previous diabetic treatment history, and 18 matched controls were recruited. Results indicated that T2DM patients made more disadvantageous decisions than controls. Compared to healthy subjects, T2DM patients showed decreased activation in the ventral medial prefrontal cortex (VMPFC), orbitofrontal cortex (OFC) and anterior cingulate cortex, and increased activity in the dorsolateral prefrontal cortex, posterior cingulate cortex, insula and occipital lobes. IGT performance positively correlated with changes in brain activation in the VMPFC and OFC in both groups. Moreover, poor glycemic control was associated with decision-making function both in behavioral and brain activity in the VMPFC and OFC in patients. Conclusively, T2DM patients may suffer from weaknesses in their prefrontal cortex functions that lead to poorer decision making under ambiguity, at least as assessed by the IGT. PMID- 28860464 TI - Characterization of a core region in the A2UCOE that confers effective anti silencing activity. AB - We have previously shown that reliability of the A2UCOE in driving transgene expression can be attributed to its resistance to DNA methylation, and its ability to confer this property to linked regulatory sequences. In order to gain a better understanding of how resistance to DNA methylation from the A2UCOE is conferred, and whether the anti-silencing effect from the A2UCOE is confined within a core region, we evaluated the anti-silencing effect of different sub domains. We found that maximal epigenetic regulatory activity was contained within a 455 bp element derived from the CBX3 region when tested in the context of a lentiviral vector in murine embryonic stem (ES) cells and human inducible pluripotent stem (iPS) cells. This region possessed an active chromatin signature, and operated effectively in cis to protect linked heterologous regulatory elements from methylation, thereby conferring stable transgene expression. Defined UCOE elements may be particularly useful for use in vectors where gene expression is desired in methylation-prone chromatin environments such as those encountered in pluripotent stem cells. PMID- 28860465 TI - Damaged fiber tracts of the nucleus basalis of Meynert in Parkinson's disease patients with visual hallucinations. AB - Damage to fiber tracts connecting the nucleus basalis of Meynert (NBM) to the cerebral cortex may underlie the development of visual hallucinations (VH) in Parkinson's disease (PD), possibly due to a loss of cholinergic innervation. This was investigated by comparing structural connectivity of the NBM using diffusion tensor imaging in 15 PD patients with VH (PD + VH), 40 PD patients without VH (PD - VH), and 15 age- and gender-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) of pathways connecting the NBM to the whole cerebral cortex and of regional NBM fiber tracts were compared between groups. In PD + VH patients, compared to controls, higher MD values were observed in the pathways connecting the NBM to the cerebral cortex, while FA values were normal. Regional analysis demonstrated a higher MD of parietal (p = 0.011) and occipital tracts (p = 0.027) in PD + VH, compared to PD - VH patients. We suggest that loss of structural connectivity between the NBM and posterior brain regions may contribute to the etiology of VH in PD. Future studies are needed to determine whether these findings could represent a sensitive marker for the hypothesized cholinergic deficit in PD + VH patients. PMID- 28860466 TI - Single, but not dual, attention facilitates statistical learning of two concurrent auditory sequences. AB - When we are exposed to a novel stimulus sequence, we can learn the sequence by extracting a statistical structure that is potentially embedded in the sequence. This mechanism is called statistical learning, and is considered a fundamental and domain-general process that is innate in humans. In the real-world environment, humans are inevitably exposed to auditory sequences that often overlap with one another, such as speech sound streams from multiple speakers or entangled melody lines generated by multiple instruments. The present study investigated how single and dual attention modulates brain activity, reflecting statistical learning when two auditory sequences were presented simultaneously. The results demonstrated that the effect of statistical learning had more pronounced neural activity when listeners paid attention to only one sequence and ignored the other, rather than paying attention to both sequences. Biased attention may thus be an essential strategy when learners are exposed to multiple information streams. PMID- 28860467 TI - Control of Early Flame Kernel Growth by Multi-Wavelength Laser Pulses for Enhanced Ignition. AB - The present contribution examines the impact of plasma dynamics and plasma-driven fluid dynamics on the flame growth of laser ignited mixtures and shows that a new dual-pulse scheme can be used to control the kernel formation process in ways that extend the lean ignition limit. We perform a comparative study between (conventional) single-pulse laser ignition (lambda = 1064 nm) and a novel dual pulse method based on combining an ultraviolet (UV) pre-ionization pulse (lambda = 266 nm) with an overlapped near-infrared (NIR) energy addition pulse (lambda = 1064 nm). We employ OH* chemiluminescence to visualize the evolution of the early flame kernel. For single-pulse laser ignition at lean conditions, the flame kernel separates through third lobe detachment, corresponding to high strain rates that extinguish the flame. In this work, we investigate the capabilities of the dual-pulse to control the plasma-driven fluid dynamics by adjusting the axial offset of the two focal points. In particular, we find there exists a beam waist offset whereby the resulting vorticity suppresses formation of the third lobe, consequently reducing flame stretch. With this approach, we demonstrate that the dual-pulse method enables reduced flame speeds (at early times), an extended lean limit, increased combustion efficiency, and decreased laser energy requirements. PMID- 28860468 TI - Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection. AB - Changes in cervico-vaginal microbiota with Lactobacillus depletion and increased microbial diversity facilitate human papillomavirus (HPV) infection and might be involved in viral persistence and cancer development. To define the microbial Community State Types (CSTs) associated with high-risk HPV-persistence, we analysed 55 cervico-vaginal samples from HPV positive (HPV+) women out of 1029 screened women and performed pyrosequencing of 16S rDNA. A total of 17 samples from age-matched HPV negative (HPV-) women were used as control. Clearance or Persistence groups were defined by recalling women after one year for HPV screening and genotyping. A CST IV subgroup, with bacterial genera such as Gardnerella, Prevotella, Megasphoera, Atopobium, frequently associated with anaerobic consortium in bacterial vaginosis (BV), was present at baseline sampling in 43% of women in Persistence group, and only in 7.4% of women in Clearance group. Atopobium genus was significantly enriched in Persistence group compared to the other groups. Sialidase-encoding gene from Gardnerella vaginalis, involved in biofilm formation, was significantly more represented in Persistence group compared to the other groups. Based on these data, we consider the CST IV BV as a risk factor for HPV persistence and we propose Atopobium spp and sialidase gene from G. vaginalis as microbial markers of HPV-persistence. PMID- 28860469 TI - Prolonged AT1R activation induces CaV1.2 channel internalization in rat cardiomyocytes. AB - The cardiac L-type calcium channel is a multi-subunit complex that requires co assembling of the pore-forming subunit CaV1.2 with auxiliary subunits CaValpha2delta and CaVbeta. Its traffic has been shown to be controlled by these subunits and by the activation of various G-protein coupled receptors (GPCR). Here, we explore the consequences of the prolonged activation of angiotensin receptor type 1 (AT1R) over CaV1.2 channel trafficking. Bioluminescence Resonance Energy Transfer (BRET) assay between beta-arrestin and L-type channels in angiotensin II-stimulated cells was used to assess the functional consequence of AT1R activation, while immunofluorescence of adult rat cardiomyocytes revealed the effects of GPCR activation on CaV1.2 trafficking. Angiotensin II exposure results in beta-arrestin1 recruitment to the channel complex and an apparent loss of CaV1.2 immunostaining at the T-tubules. Accordingly, angiotensin II stimulation causes a decrease in L-type current, Ca2+ transients and myocyte contractility, together with a faster repolarization phase of action potentials. Our results demonstrate that prolonged AT1R activation induces beta-arrestin1 recruitment and the subsequent internalization of CaV1.2 channels with a half dose of AngII on the order of 100 nM, suggesting that this effect depends on local renin-angiotensin system. This novel AT1R-dependent CaV1.2-trafficking modulation likely contributes to angiotensin II-mediated cardiac remodeling. PMID- 28860470 TI - Pathogenic lineage of Perkinsea associated with mass mortality of frogs across the United States. AB - Emerging infectious diseases such as chytridiomycosis and ranavirus infections are important contributors to the worldwide decline of amphibian populations. We reviewed data on 247 anuran mortality events in 43 States of the United States from 1999-2015. Our findings suggest that a severe infectious disease of tadpoles caused by a protist belonging to the phylum Perkinsea might represent the third most common infectious disease of anurans after ranavirus infections and chytridiomycosis. Severe Perkinsea infections (SPI) were systemic and led to multiorganic failure and death. The SPI mortality events affected numerous anuran species and occurred over a broad geographic area, from boreal to subtropical habitats. Livers from all PCR-tested SPI-tadpoles (n = 19) were positive for the Novel Alveolate Group 01 (NAG01) of Perkinsea, while only 2.5% histologically normal tadpole livers tested positive (2/81), suggesting that subclinical infections are uncommon. Phylogenetic analysis demonstrated that SPI is associated with a phylogenetically distinct clade of NAG01 Perkinsea. These data suggest that this virulent Perkinsea clade is an important pathogen of frogs in the United States. Given its association with mortality events and tendency to be overlooked, the potential role of this emerging pathogen in amphibian declines on a broad geographic scale warrants further investigation. PMID- 28860471 TI - High-throughput analysis of N-glycans using AutoTip via glycoprotein immobilization. AB - Analysis of a large number of samples requires an efficient, rapid and reproducible method. Automation is an ideal approach for high-throughput sample preparation. Multi-plexing sample preparation via a 96-well plate format becomes popular in recent years; however, those methods lack specificity and require several cleanup steps via chromatography purification. To overcome these drawbacks, a chemoenzymatic method has been developed utilizing protein conjugation on solid-phase. Previously, sample preparation was successfully performed in a snap-cap spin-column (SCSC) format. However, sample preparation using SCSC is time-consuming and lacks reproducibility. In this work, we integrated the chemoenzymatic technique in a pipette tip (AutoTip) that was operated by an automated liquid handler. We established a multi-step protocol involving protein immobilization, sialic acid modification, and N-glycan release. We first optimized our automated protocol using bovine fetuin as a standard glycoprotein, and then assessed the reproducibility of the AutoTip using isobaric tags for relative N-linked glycan quantification. We then applied this methodology to profile N-glycans from 58 prostate cancer patient urine samples, revealing increased sialyation on urinary N-glycans derived from prostate cancer patients. Our results indicated AutoTip has applications for high-throughput sample preparation for studying the N-linked glycans. PMID- 28860473 TI - Experiments support an improved model for particle transport in fluidized beds. AB - The upwards flow of particles in an Upflow Bubbling Fluidized Bed (UBFB) is studied experimentally and modelled from pressure drop considerations and energy loss equations. For Geldart group A powders tested, the upward solid flux, G s , in the tube can be expressed in terms of the applied superficial gas velocity, the free fall (terminal) velocity of the particles during their hindered settling, KU t , the pressure exerted at the base of the conveyor tube, and the tube length. The model expression [Formula: see text] can be used for design purposes, with K, the correction factor for hindered settling of the particles, approximately equal to 0.1 at high G s -values, but a function of the solids fraction in the upward conveying. The energy efficiency of the system increases with increasing U and Gs. The model equation was tentatively applied to predict the effects of particle size, tube length and operation in Circulating Fluidized Bed mode. It is demonstrated that the UBFB is an efficient and flexible way of transporting particles upwards, with limited particle attrition or tube erosion due to the low gas velocity applied. PMID- 28860472 TI - Transferrin-navigation Nano Artificial Antibody Fluorescence Recognition of Circulating Tumor Cells. AB - Specific recognition of circulating tumor cells (CTCs) is of great significance for cancer diagnosis and personalized therapy. The antibodies and aptamer are commonly used for recognition of CTCs, but they often suffer from low stability and high cost. Therefore, chemically stable and low-cost artificial recognition elements are still highly demanded. Herein, we prepared nano artificial antibody based on molecular imprinting and applied for fluorescence recognition of CTCs. Surface imprinting was employed to construct a transferrin (TRA)-imprinted layer on the surface of rhodamine doped silica nanoparticles. Take advantage of the specific interaction between TRA and TRA receptor (overexpressed on cancer cells), the as-prepared TRA-imprinted artificial antibody was allowed for specific targeting cancer cells mediated by TRA. And the average recognition efficiency of the artificial antibody for the cancer cells was 88% through flow cytometry. Finally, the nano artificial antibody was successfully applied to specific identify mimetic CTCs, under the same conditions, the recognition ability of artificial antibody for CTCs was 8 times higher than the white blood cells. PMID- 28860474 TI - Field-free manipulation of magnetization alignments in a Fe/GaAs/GaMnAs multilayer by spin-orbit-induced magnetic fields. AB - We investigate the process of selectively manipulating the magnetization alignment in magnetic layers in the Fe/GaAs/GaMnAs structure by current-induced spin-orbit (SO) magnetic field. The presence of such fields manifests itself through the hysteretic behavior of planar Hall resistance observed for two opposite currents as the magnetization in the structure switches directions. In the case of the Fe/GaAs/GaMnAs multilayer, hystereses are clearly observed when the magnetization switches direction in the GaMnAs layer, but are negligible when magnetization transitions occur in Fe. This difference in the effect of the SO field in the two magnetic layers provides an opportunity to control the magnetization in one layer (in the presence case in GaMnAs) by a current, while the magnetization in the other layer (i.e., Fe) remains fixed. Owing to our ability to selectively control the magnetization in the GaMnAs layer, we are able to manipulate the relative spin configurations in our structure between collinear and non-collinear alignments simply by switching the current direction even in the absence of an external magnetic field. PMID- 28860477 TI - One-pot preparation of nanoporous Ag-Cu@Ag core-shell alloy with enhanced oxidative stability and robust antibacterial activity. AB - Metallic core-shell nanostructures have inspired prominent research interests due to their better performances in catalytic, optical, electric, and magnetic applications as well as the less cost of noble metal than monometallic nanostructures, but limited by the complicated and expensive synthesis approaches. Development of one-pot and inexpensive method for metallic core-shell nanostructures' synthesis is therefore of great significance. A novel Cu network supported nanoporous Ag-Cu alloy with an Ag shell and an Ag-Cu core was successfully synthesized by one-pot chemical dealloying of Zr-Cu-Ag-Al-O amorphous/crystalline composite, which provides a new way to prepare metallic core-shell nanostructures by a simple method. The prepared nanoporous Ag-Cu@Ag core-shell alloy demonstrates excellent air-stability at room temperature and enhanced oxidative stability even compared with other reported Cu@Ag core-shell micro-particles. In addition, the nanoporous Ag-Cu@Ag core-shell alloy also possesses robust antibacterial activity against E. Coli DH5alpha. The simple and low-cost synthesis method as well as the excellent oxidative stability promises the nanoporous Ag-Cu@Ag core-shell alloy potentially wide applications. PMID- 28860475 TI - Long-term PGC1beta overexpression leads to apoptosis, autophagy and muscle wasting. AB - Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1alpha) and its splice variant PGC1alpha4 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1beta, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1beta in the skeletal muscle, we have found that PGC1beta progressively decreases skeletal muscle mass predominantly associated with loss of type 2b fast-twitch myofibers. Paradoxically, PGC1beta represses the ubiquitin-proteolysis degradation pathway genes resulting in ubiquitinated protein accumulation in muscle. However, PGC1beta overexpression triggers up-regulation of apoptosis and autophagy genes, resulting in robust activation of these cell degenerative processes, and a concomitant increase in muscle protein oxidation. Concurrently, PGC1beta up-regulates apoptosis and/or autophagy transcriptional factors such as E2f1, Atf3, Stat1, and Stat3, which may be facilitating myopathy. Therefore, PGC1beta activation negatively affects muscle mass over time, particularly fast-twitch muscles, which should be taken into consideration along with its known aerobic effects in the skeletal muscle. PMID- 28860476 TI - Quantifying perinatal transmission of Hepatitis B viral quasispecies by tag linkage deep sequencing. AB - Despite full immunoprophylaxis, mother-to-child transmission (MTCT) of Hepatitis B Virus still occurs in approximately 2-5% of HBsAg positive mothers. Little is known about the bottleneck of HBV transmission and the evolution of viral quasispecies in the context of MTCT. Here we adopted a newly developed tag linkage deep sequencing method and analyzed the quasispecies of four MTCT pairs that broke through immunoprophylaxis. By assigning unique tags to individual viral sequences, we accurately reconstructed HBV haplotypes in a region of 836 bp, which contains the major immune epitopes and drug resistance mutations. The detection limit of minor viral haplotypes reached 0.1% for individual patient sample. Dominance of "a determinant" polymorphisms were observed in two children, which pre-existed as minor quasispecies in maternal samples. In all four pairs of MTCT samples, we consistently observed a significant overlap of viral haplotypes shared between mother and child. We also demonstrate that the data can be potentially useful to estimate the bottleneck effect during HBV MTCT, which provides information to optimize treatment for reducing the frequency of MTCT. PMID- 28860478 TI - Antagonistic interaction between jasmonic acid and cytokinin in xylem development. AB - Developmental flexibility under stress conditions largely relies on the interactions between hormones that mediate stress responses and developmental processes. In this study, we showed that the stress hormone jasmonic acid (JA) induces formation of extra xylem in the roots of wild-type Arabidopsis thaliana (Col-0). JA signaling mutants such as coronatine insensitive1-1 and jasmonate resistant1-1 did not form extra xylem in response to JA, but the JA biosynthesis mutant oxophytodienoate-reductase3 did form extra xylem. These observations suggested that the JA response promotes xylem development. To understand the mechanism, we examined the regulatory interaction between JA and cytokinin, a negative regulator of xylem development. JA treatment reduced cytokinin responses in the vasculature, and exogenous cytokinin nullified the effect of JA on formation of extra xylem. A time-course experiment showed that suppression of cytokinin responses by JA does not occur rapidly, but the JA-mediated xylem phenotype is tightly linked to the suppression of the cytokinin response. Further analysis of arabidopsis histidine phosphotransfer protein6-1 and myc2-3 mutants revealed that the JA-responsive transcription factor MYC2 regulates the expression of AHP6 in response to JA and expression of AHP6 is involved in the JA mediated xylem phenotype. PMID- 28860479 TI - De novo design of antibody complementarity determining regions binding a FLAG tetra-peptide. AB - Computational antibody engineering efforts to date have focused on improving binding affinities or biophysical characteristics. De novo design of antibodies binding specific epitopes could greatly accelerate discovery of therapeutics as compared to conventional immunization or synthetic library selection strategies. Here, we employed de novo complementarity determining region (CDR) design to engineer targeted antibody-antigen interactions using previously described in silico methods. CDRs predicted to bind the minimal FLAG peptide (Asp-Tyr-Lys-Asp) were grafted onto a single-chain variable fragment (scFv) acceptor framework. Fifty scFvs comprised of designed heavy and light or just heavy chain CDRs were synthesized and screened for peptide binding by phage ELISA. Roughly half of the designs resulted in detectable scFv expression. Four antibodies, designed entirely in silico, bound the minimal FLAG sequence with high specificity and sensitivity. When reformatted as soluble antigen-binding fragments (Fab), these clones expressed well, were predominantly monomeric and retained peptide specificity. In both formats, the antibodies bind the peptide only when present at the amino-terminus of a carrier protein and even conservative peptide amino acid substitutions resulted in a complete loss of binding. These results support in silico CDR design of antibody specificity as an emerging antibody engineering strategy. PMID- 28860480 TI - Discovery of human-like L-asparaginases with potential clinical use by directed evolution. AB - L-asparaginase is a chemotherapy drug used to treat acute lymphoblastic leukemia (ALL). The main prerequisite for clinical efficacy of L-asparaginases is micromolar KM for asparagine to allow for complete depletion of this amino acid in the blood. Since currently approved L-asparaginases are of bacterial origin, immunogenicity is a challenge, which would be mitigated by a human enzyme. However, all human L-asparaginases have millimolar KM for asparagine. We recently identified the low KM guinea pig L-asparaginase (gpASNase1). Because gpASNase1 and human L-asparaginase 1 (hASNase1) share ~70% amino-acid identity, we decided to humanize gpASNase1 by generating chimeras with hASNase1 through DNA shuffling. To identify low KM chimeras we developed a suitable bacterial selection system (E. coli strain BW5Delta). Transforming BW5Delta with the shuffling libraries allowed for the identification of several low KM clones. To further humanize these clones, the C-terminal domain of gpASNase1 was replaced with that of hASNase1. Two of the identified clones, 63N-hC and 65N-hC, share respectively 85.7% and 87.1% identity with the hASNase1 but have a KM similar to gpASNase1. These clones possess 100-140 fold enhanced catalytic efficiency compared to hASNase1. Notably, we also show that these highly human-like L-asparaginases maintain their in vitro ALL killing potential. PMID- 28860481 TI - Increased expression of Siglec-9 in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a common inflammatory lung disease. Sialic acid-binding immunoglobulin-type lectins 9 (Siglec-9) is predominantly expressed on innate immune cells and has been shown to exert regulatory effect on immune cells through glycan recognition. Soluble Siglec-9 (sSiglec-9), the extracellular region of Siglec-9, might fulfill its function partly by competitive inhibiting siglec-9 binding to its ligands; however, the role of Siglec-9 and sSiglec-9 in the pathogenesis COPD remain largely unknown. In this study, we showed that Siglec-9 expression in alveolar and peripheral blood neutrophil were increased in COPD patients by immunofluorescence and flow cytometry, respectively. Plasma levels of sSiglelc-9 were elevated in COPD patients by ELISA. In vitro, Siglec-9 expression and/or sSiglelc-9 levels were up regulated by cigarette smoke extract (CSE), lipopolysaccharide (LPS), some cytokines, and dexamethasone (DEX). Recombinant sSiglce-9 increased oxidative burst in neutrophil and enhanced neutrophil chemotaxis toward IL-8 independent on CXCR1 and CXCR2 expression, but it did not affect neutrophil apoptosis or secretions of inflammatory cytokines. In conclusion, Siglec-9 was complementarily increased to induce a negative feedback loop to limit neutrophil activation in COPD, sSiglce-9 enhanced neutrophil ROS and chemotaxis toward IL-8 likely via competitively inhibiting ligands binding to Siglec-9. PMID- 28860482 TI - Circadian Clock Model Supports Molecular Link Between PER3 and Human Anxiety. AB - Generalized anxiety and major depression have become increasingly common in the United States, affecting 18.6 percent of the adult population. Mood disorders can be debilitating, and are often correlated with poor general health, life dissatisfaction, and the need for disability benefits due to inability to work. Recent evidence suggests that some mood disorders have a circadian component, and disruptions in circadian rhythms may even trigger the development of these disorders. However, the molecular mechanisms of this interaction are not well understood. Polymorphisms in a circadian clock-related gene, PER3, are associated with behavioral phenotypes (extreme diurnal preference in arousal and activity) and sleep/mood disorders, including seasonal affective disorder (SAD). Here we show that two PER3 mutations, a variable number tandem repeat (VNTR) allele and a single-nucleotide polymorphism (SNP), are associated with diurnal preference and higher Trait-Anxiety scores, supporting a role for PER3 in mood modulation. In addition, we explore a potential mechanism for how PER3 influences mood by utilizing a comprehensive circadian clock model that accurately predicts the changes in circadian period evident in knock-out phenotypes and individuals with PER3-related clock disorders. PMID- 28860484 TI - Biocomposite nanofiber matrices to support ECM remodeling by human dermal progenitors and enhanced wound closure. AB - Cell-based therapies have recently been the focus of much research to enhance skin wound healing. An important challenge will be to develop vehicles for cell delivery that promote survival and uniform distribution of cells across the wound bed. These systems should be stiff enough to facilitate handling, whilst soft enough to limit damage to newly synthesized wound tissue and minimize patient discomfort. Herein, we developed several novel modifiable nanofibre scaffolds comprised of Poly (epsilon-caprolactone) (PCL) and gelatin (GE). We asked whether they could be used as a functional receptacle for adult human Skin-derived Precursor Cells (hSKPs) and how naked scaffolds impact endogenous skin wound healing. PCL and GE were electrospun in a single facile solvent to create composite scaffolds and displayed unique morphological and mechanical properties. After seeding with adult hSKPs, deposition of extracellular matrix proteins and sulphated glycosaminoglycans was found to be enhanced in composite grafts. Moreover, composite scaffolds exhibited significantly higher cell proliferation, greater cell spreading and integration within the nanofiber mats. Transplantation of acellular scaffolds into wounds revealed scaffolds exhibited improvement in dermal-epidermal thickness, axonal density and collagen deposition. These results demonstrate that PCL-based nanofiber scaffolds show promise as a cell delivery system for wound healing. PMID- 28860483 TI - Selective LRRK2 kinase inhibition reduces phosphorylation of endogenous Rab10 and Rab12 in human peripheral mononuclear blood cells. AB - Genetic variation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with risk of familial and sporadic Parkinson's disease (PD). To support clinical development of LRRK2 inhibitors as disease-modifying treatment in PD biomarkers for kinase activity, target engagement and kinase inhibition are prerequisite tools. In a combined proteomics and phosphoproteomics study on human peripheral mononuclear blood cells (PBMCs) treated with the LRRK2 inhibitor Lu AF58786 a number of putative biomarkers were identified. Among the phospho-site hits were known LRRK2 sites as well as two phospho-sites on human Rab10 and Rab12. LRRK2 dependent phosphorylation of human Rab10 and human Rab12 at positions Thr73 and Ser106, respectively, was confirmed in HEK293 and, more importantly, Rab10-pThr73 inhibition was validated in immune stimulated human PBMCs using two distinct LRRK2 inhibitors. In addition, in non-stimulated human PBMCs acute inhibition of LRRK2 with two distinct LRRK2 inhibitor compounds reduced Rab10-Thr73 phosphorylation in a concentration-dependent manner with apparent IC50's equivalent to IC50's on LRRK2-pSer935. The identification of Rab10 phosphorylated at Thr73 as a LRRK2 inhibition marker in human PBMCs strongly support inclusion of assays quantifying Rab10-pThr73 levels in upcoming clinical trials evaluating LRRK2 kinase inhibition as a disease-modifying treatment principle in PD. PMID- 28860485 TI - Predicting hidden bulk phases from surface phases in bilayered Sr3Ru2O7. AB - The ability to predict hidden phases under extreme conditions is not only crucial to understanding and manipulating materials but it could also lead to insight into new phenomena and novel routes to synthesize new phases. This is especially true for Ruddlesden-Popper perovskite phases that possess interesting properties ranging from superconductivity and colossal magnetoresistance to photovoltaic and catalytic activities. In particular, the physical properties of the bilayer perovskite Sr3Ru2O7 at the surface are intimately tied to the rotation and tilt of the RuO6 octahedra. To take advantage of the extra degree of freedom associated with tilting we have performed first principles hybrid density functional simulations of uniaxial pressure applied along the c-axis of bulk Sr3Ru2O7 where we find that the octahedra become tilted, leading to two phase transitions. One is a structural transition at [Formula: see text]1.5 GPa, and the other is from a ferromagnetic (FM) metal to an antiferromagnetic (AFM) insulator at [Formula: see text]21 GPa whose AFM spin configuration is different from the AFM state near the FM ground state. PMID- 28860486 TI - A systematic analysis of orphan cyclins reveals CNTD2 as a new oncogenic driver in lung cancer. AB - As lung cancer has increased to the most common cause of cancer death worldwide, prognostic biomarkers and effective targeted treatments remain lacking despite advances based on patients' stratification. Multiple core cyclins, best known as drivers of cell proliferation, are commonly deregulated in lung cancer where they may serve as oncogenes. The recent expansion of the cyclin family raises the question whether new members might play oncogenic roles as well. Here, we investigated the protein levels of eight atypical cyclins in lung cancer cell lines and formalin-fixed and paraffin-embedded (FFPE) human tumors, as well as their functional role in lung cancer cells. Of the new cyclins evaluated, CNTD2 was significantly overexpressed in lung cancer compared to adjacent normal tissue, and exhibited a predominant nuclear location. CNTD2 overexpression increased lung cancer cell viability, Ki-67 intensity and clonogenicity and promoted lung cancer cell migration. Accordingly, CNTD2 enhanced tumor growth in vivo on A549 xenograft models. Finally, the analysis of gene expression data revealed a high correlation between elevated levels of CNTD2 and decreased overall survival in lung cancer patients. Our results reveal CNTD2 as a new oncogenic driver in lung cancer, suggesting value as a prognostic biomarker and therapeutic target in this disease. PMID- 28860487 TI - Identification of pyrrolopyrimidine derivative PP-13 as a novel microtubule destabilizing agent with promising anticancer properties. AB - Despite the emergence of targeted therapies and immunotherapy, chemotherapy remains the gold-standard for the treatment of most patients with solid malignancies. Spindle poisons that interfere with microtubule dynamics are commonly used in chemotherapy drug combinations. However, their troublesome side effects and the emergence of chemoresistance highlight the need for identifying alternative agents. We performed a high throughput cell-based screening and selected a pyrrolopyrimidine molecule (named PP-13). In the present study, we evaluated its anticancer properties in vitro and in vivo. We showed that PP-13 exerted cytotoxic effects on various cancer cells, including those resistant to current targeted therapies and chemotherapies. PP-13 induced a transient mitotic blockade by interfering with both mitotic spindle organization and microtubule dynamics and finally led to mitotic slippage, aneuploidy and direct apoptotic death. PP-13 was identified as a microtubule-targeting agent that binds directly to the colchicine site in beta-tubulin. Interestingly, PP-13 overcame the multidrug-resistant cancer cell phenotype and significantly reduced tumour growth and metastatic invasiveness without any noticeable toxicity for the chicken embryo in vivo. Overall, PP-13 appears to be a novel synthetic microtubule inhibitor with interesting anticancer properties and could be further investigated as a potent alternative for the management of malignancies including chemoresistant ones. PMID- 28860489 TI - Prognostic Significance of Elevated Cholestatic Enzymes for Fibrosis and Hepatocellular Carcinoma in Hospital Discharged Chronic Viral Hepatitis Patients. AB - Chronic viral hepatitis (CVH) is the root cause of liver fibrosis and subsequent hepatocellular carcinoma (HCC). We conducted a cross-sectional, observational study based on medical records and primary data collection from patients with CVH who were admitted in five hospitals across China between February and September 2013 to determine the prevalence of elevated cholestatic enzymes (ALP and/or GGT above ULN) in discharged Chinese patients with CVH as a primary outcome and secondarily evaluated the relationship of these enzymes with fibrosis and disease severity. Majority of the patients (56%) had cholestatic enzyme elevation at discharge, with high prevalence of liver fibrosis (37.6% vs. 20.1%, p < 0.001) and cirrhosis (Child-Pugh B: 56.9% vs. 48.7%; Child-Pugh C: 17.4% vs. 12.5%; p < 0.001) in addition to significantly higher odds of liver fibrosis (OR 1.54; p = 0.024) and a trend towards higher odds of moderate-to-severe cirrhosis (OR 1.24; p = 0.317) compared to those who had normal enzyme levels. Elevated cholestatic enzyme levels serve as important prognosticators of liver fibrosis in CVH patients. Therefore, pre-discharge testing of cholestatic enzymes is recommended to identify CVH patients and provide prophylactic care. PMID- 28860488 TI - Assessment of selected media supplements to improve F/HN lentiviral vector production yields. AB - The development of lentiviral-based therapeutics is challenged by the high cost of current Good Manufacturing Practices (cGMP) production. Lentiviruses are enveloped viruses that capture a portion of the host cell membrane during budding, which then constitutes part of the virus particle. This process might lead to lipid and protein depletion in the cell membrane and affect cell viability. Furthermore, growth in suspension also causes stresses that can affect virus production yields. To assess the impact of these issues, selected supplements (Cholesterol Lipid Concentrate, Chemically Defined Lipid Concentrate, Lipid Mixture 1, Gelatin Peptone N3, N-Acetyl-L-Cysteine and Pluronic F-68) were assayed in order to improve production yields in a transient transfection production of a Sendai virus F/HN-pseudotyped HIV-1-based third generation lentiviral vector in FreeStyle 293 (serum-free media) in suspension. None of the supplements tested had a significant positive impact on lentiviral vector yields, but small non-significant improvements could be combined to increase vector production in a cell line where other conditions have been optimised. PMID- 28860490 TI - Organic carbon budget for the eastern boundary of the North Atlantic subtropical gyre: major role of DOC in mesopelagic respiration. AB - Transports of suspended particulate (POCsusp) and dissolved (DOC) organic carbon are inferred from a box-model covering the eastern boundary of the North Atlantic subtropical gyre. Corresponding net respiration rates (R) are obtained from a net organic carbon budget that is based on the transport estimates, and includes both vertical and lateral fluxes. The overall R in the mesopelagic layer (100-1500 m) is 1.6 +/- 0.4 mmol C m-2 d-1. DOC accounts for up to 53% of R as a result of drawdown of organic carbon within Eastern North Atlantic Central Water (ENACW) that is entrained into sinking Mediterranean Overflow Water (MOW) that leads to formation of Mediterranean water (MW) at intermediate depths (~900 m). DOC represents 90% of the respired non-sinking organic carbon. When converted into oxygen units, the computed net respiration rate represents less than half the oxygen utilization rates (OUR) reported for the mesopelagic waters of the subtropical North Atlantic. Mesoscale processes in the area, not quantified with our approach, could account in part for the OUR differences observed between our carbon budget and other published studies from the North Atlantic, although seasonal or interannual variability could also be responsible for the difference in the estimates. PMID- 28860491 TI - Influence of Pregnancy History on the Vaginal Microbiome of Pregnant Women in their First Trimester. AB - Pregnancy permanently alters maternal anatomy, physiology and immunity. We evaluated if the vaginal microbiome differed between women with a first or subsequent conception. Relative abundance of bacteria in the vaginal microbiome in first trimester pregnant women, 52 with their first known conception, 26 with a prior spontaneous or induced abortion but no deliveries and 77 with at least one prior birth, was determined by classifying DNA sequences from the V1-V3 region of bacterial 16 S rRNA genes. Lactobacillus crispatus was the numerically most abundant bacterium in 76.4% of women with a first conception, 50.0% with only a prior spontaneous or scheduled abortion and 22.2% with a prior birth (p <= 0.01). L. iners was the most abundant bacterium in 3.8% of women with a first conception as compared to 19.2% (p = 0.03) and 20.8% (p = 0.03) in those with a prior abortion or birth, respectively. Gardnerella as the most abundant bacterial genus increased from 3.8% in women with a first conception to 15.4% and 14.3% in those with a prior abortion or birth, respectively (p > 0.05). L. iners dominance was also associated with a history of spontaneous abortion (p <= 0.02). The composition of the vaginal microbiome and its influence on pregnancy outcome varies with pregnancy history. PMID- 28860492 TI - Rapid removal of Pb(II) from aqueous solution using branched polyethylenimine enhanced magnetic carboxymethyl chitosan optimized with response surface methodology. AB - In this study, branched polyethylenimine (PEI) enhanced magnetic carboxymethyl chitosan (MCMC-PEI) was synthesized and applied as adsorbent for the rapid removal of Pb(II) from aqueous solution. The successful synthesis of the adsorbent was proved by scanning electron microscope (SEM), Fourier transform infrared spectrum (FTIR) and X-ray powder diffraction (XRD). Simultaneously, the effect of the parameters such as initial concentration, adsorbent mass and pH of the solution on the removal of Pb(II) was studied by using response surface methodology (RSM). And central composite design (CCD), which is a widely used form of RSM, was employed in the experimental design procedure. The adsorption results revealed that the adsorption process could reach equilibrium rapidly within 10 min. Furthermore, the adsorption kinetic data could be well described by pseudo-second order model. The maximum adsorption capacity was 124.0 mg/g according to the Langmuir-Freundlich model, which fitted the adsorption isotherm of Pb(II) better than Langmuir model and Freundlich model, respectively. Thermodynamic studies (DeltaG < 0, DeltaH < 0, DeltaS > 0) implied a spontaneous and exothermic process in nature. Meanwhile, the fabricated adsorbent exhibited excellent reusability. Therefore, the excellent adsorption property of MCMC-PEI made it a promising application in water treatment. PMID- 28860493 TI - CXCR3 plays a critical role for host protection against Salmonellosis. AB - CXCR3 and its ligands are heavily associated with inflammation and have been implicated in numerous inflammatory diseases. CXCR3 plays an important role in recruiting pro-inflammatory cells, specifically neutrophils, in a model of sterile colitis whereby CXCR3-/- mice showed an attenuated course of colitis with markedly reduced host-tissue damage in the inflamed caecum. The role of CXCR3 during infectious colitis, however, is unclear and therefore in this study, we investigated the role of CXCR3 in the regulation of the immune response during acute and chronic gastrointestinal infection, using a murine model of Salmonella enterica serovar Enteritidis. During acute infection with Salmonella, we observed significantly increased Salmonella loading in the caecum and dissemination to the spleen and liver in CXCR3-/- mice, but not in Wt counterparts. During chronic infection, increased pathological features of inflammation were noted in the spleen and liver, with significantly increased levels of apoptosis in the liver of CXCR3-/- mice, when compared to Wt counterparts. In addition, compromised intestinal IgA levels, CD4+ helper T cells and neutrophil recruitment were observed in CXCR3-/- challenged with Salmonella, when compared to Wt counterparts. Our data suggests that CXCR3 is a key molecule in host intestinal immunity against Salmonellosis via regulating neutrophils chemotaxis. PMID- 28860494 TI - Novel quinolone chalcones targeting colchicine-binding pocket kill multidrug resistant cancer cells by inhibiting tubulin activity and MRP1 function. AB - Agents targeting colchicine-binding pocket usually show a minimal drug-resistance issue, albeit often associated with high toxicity. Chalcone-based compounds, which may bind to colchicine-binding site, are found in many edible fruits, suggesting that they can be effective drugs with less toxicity. Therefore, we synthesized and examined 24 quinolone chalcone compounds, from which we identified ((E)-3-(3-(2-Methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR 17) and ((E)-6-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H) one) (CTR-20) as promising leads. In particular, CTR-20 was effective against 65 different cancer cell lines originated from 12 different tissues, largely in a cancer cell-specific manner. We found that both CTR-17 and CTR-20 reversibly bind to the colchicine-binding pocket on beta-tubulin. Interestingly however, both the CTRs were highly effective against multidrug-resistant cancer cells while colchicine, paclitaxel and vinblastine were not. Our study with CTR-20 showed that it overcomes multidrug-resistance through its ability to impede MRP1 function while maintaining strong inhibition against microtubule activity. Data from mice engrafted with the MDA-MB-231 triple-negative breast cancer cells showed that both CTR-17 and CTR-20 possess strong anticancer activity, alone or in combination with paclitaxel, without causing any notable side effects. Together, our data demonstrates that both the CTRs can be effective and safe drugs against many different cancers, especially against multidrug-resistant tumors. PMID- 28860495 TI - miR-96 attenuates status epilepticus-induced brain injury by directly targeting Atg7 and Atg16L1. AB - Status epilepticus (SE) can cause brain damage and lead to neural dysfunction. Developing novel targets for SE therapy and diagnosis is important and necessary. Previously, we found several differentially expressed microRNAs (miRNAs) in the developing hippocampus following SE, including the autophagy-related miR-96. In the present study, we employed immunofluorescence staining and Western blot analysis to assess the expression of autophagy-related 7 (Atg7) and Atg16L1 and the status of autophagosome formation in the hippocampus of immature rats with SE. Additional in vivo intervention was also performed to investigate the potential therapeutic function of miR-96 in developing rats with SE. We found that Atg7 and Atg16L1 were up-regulated in the neurons after SE, together with an increase in autophagosome formation. Meanwhile, overexpression of miR-96 significantly prevented brain damage in SE rats by inhibiting Atg7 and Atg16L1 expression and autophagosome formation in the hippocampus. Furthermore, Rapamycin negated miR-96 mediated brain injury attenuation through inducing autophagosome formation. Our study indicates that miR-96 might be a potential target for therapy of pediatric SE. PMID- 28860496 TI - Nanoindentation Induced Deformation and Pop-in Events in a Silicon Crystal: Molecular Dynamics Simulation and Experiment. AB - Silicon has such versatile characteristics that the mechanical behavior and deformation mechanism under contact load are still unclear and hence are interesting and challenging issues. Based on combined study using molecular dynamics simulations and experiments of nanoindentation on Si(100), the versatile deformation modes, including high pressure phase transformation (HPPT), dislocation, median crack and surface crack, were found, and occurrence of multiple pop-in events in the load-indentation strain curves was reported. HPPTs are regard as the dominant deformation mode and even becomes the single deformation mode at a small indentation strain (0.107 in simulations), suggesting the presence of a defect-free region. Moreover, the one-to-one relationship between the pop-in events and the deformation modes is established. Three distinct mechanisms are identified to be responsible for the occurrence of multiple pop-in events in sequence. In the first mechanism, HPPTs from Si-I to Si II and Si-I to bct5 induce the first pop-in event. The formation and extrusion of alpha-Si outside the indentation cavity are responsible for the subsequent pop-in event. And the major cracks on the surface induces the pop-in event at extreme high load. The observed dislocation burst and median crack beneath the transformation region produce no detectable pop-in events. PMID- 28860497 TI - Is there a frontier in sensitivity with Lossy mode resonance (LMR) based refractometers? AB - A tin dioxide thin layer has been studied in order to improve the sensitivity of lossy mode resonances (LMR) based sensors. The effects of the thin film thickness and the polarization of light in a SnO2 coated D-shaped single mode optical fiber have been evaluated. The optimization of such parameters in the fabrication of refractometers have led to an unprecedented sensitivity of over one million nanometers per refractive index unit (RIU), which means a sensitivity below 10-9 RIU with a pm resolution detector. This achievement is a milestone for the development of new high sensitivity devices and opens the door to new industrial applications, such as gear oil degradation, or biomedical devices where previous devices could not provide enough sensitivity. PMID- 28860498 TI - Rapid Fabrication of Graphene Field-Effect Transistors with Liquid-metal Interconnects and Electrolytic Gate Dielectric Made of Honey. AB - Historically, graphene-based transistor fabrication has been time-consuming due to the high demand for carefully controlled Raman spectroscopy, physical vapor deposition, and lift-off processes. For the first time in a three-terminal graphene field-effect transistor embodiment, we introduce a rapid fabrication technique that implements non-toxic eutectic liquid-metal Galinstan interconnects and an electrolytic gate dielectric comprised of honey. The goal is to minimize cost and turnaround time between fabrication runs; thereby, allowing researchers to focus on the characterization of graphene phenomena that drives innovation rather than a lengthy device fabrication process that hinders it. We demonstrate characteristic Dirac peaks for a single-gate graphene field-effect transistor embodiment that exhibits hole and electron mobilities of 213 +/- 15 and 166 +/- 5 cm 2/V.s respectively. We discuss how our methods can be used for the rapid determination of graphene quality and can complement Raman Spectroscopy techniques. Lastly, we explore a PN junction embodiment which further validates that our fabrication techniques can rapidly adapt to alternative device architectures and greatly broaden the research applicability. PMID- 28860499 TI - Neuroblastoma patient-derived xenograft cells cultured in stem-cell promoting medium retain tumorigenic and metastatic capacities but differentiate in serum. AB - Cultured cancer cells serve as important models for preclinical testing of anti cancer compounds. However, the optimal conditions for retaining original tumor features during in vitro culturing of cancer cells have not been investigated in detail. Here we show that serum-free conditions are critical for maintaining an immature phenotype of neuroblastoma cells isolated from orthotopic patient derived xenografts (PDXs). PDX cells could be grown either as spheres or adherent on laminin in serum-free conditions with retained patient-specific genomic aberrations as well as tumorigenic and metastatic capabilities. However, addition of serum led to morphological changes, neuronal differentiation and reduced cell proliferation. The epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were central for PDX cell proliferation and MYCN expression, and also hindered the serum-induced differentiation. Although serum induced a robust expression of neurotrophin receptors, stimulation with their cognate ligands did not induce further sympathetic differentiation, which likely reflects a block in PDX cell differentiation capacity coupled to their tumor genotype. Finally, PDX cells cultured as spheres or adherent on laminin responded similarly to various cytotoxic drugs, suggesting that both conditions are suitable in vitro screening models for neuroblastoma-targeting compounds. PMID- 28860500 TI - Adaptation of soil nitrifiers to very low nitrogen level jeopardizes the efficiency of chemical fertilization in west african moist savannas. AB - The moist savanna zone covers 0.5 * 106 km2 in West Africa and is characterized by very low soil N levels limiting primary production, but the ecology of nitrifiers in these (agro)ecosystems is largely unknown. We compared the effects of six agricultural practices on nitrifier activity, abundance and diversity at nine sites in central Ivory Coast. Treatments, including repeated fertilization with ammonium and urea, had no effect on nitrification and crop N status after 3 to 5 crop cycles. Nitrification was actually higher at low than medium ammonium level. The nitrifying community was always dominated by ammonia oxidizing archaea and Nitrospira. However, the abundances of ammonia oxidizing bacteria, AOB, and Nitrobacter increased with fertilization after 5 crop cycles. Several AOB populations, some affiliated to Nitrosospira strains with urease activity or adapted to fluctuating ammonium levels, emerged in fertilized plots, which was correlated to nitrifying community ability to benefit from fertilization. In these soils, dominant nitrifiers adapted to very low ammonium levels have to be replaced by high-N nitrifiers before fertilization can stimulate nitrification. Our results show that the delay required for this replacement is much longer than ever observed for other terrestrial ecosystems, i.e. > 5 crop cycles, and demonstrate for the first time that nitrifier characteristics jeopardize the efficiency of fertilization in moist savanna soils. PMID- 28860501 TI - In vivo immune interactions of multipotent stromal cells underlie their long lasting pain-relieving effect. AB - Systemic infusion of bone marrow stromal cells (BMSCs), a major type of multipotent stromal cells, produces pain relief (antihyperalgesia) that lasts for months. However, studies have shown that the majority of BMSCs are trapped in the lungs immediately after intravenous infusion and their survival time in the host is inconsistent with their lengthy antihyperalgesia. Here we show that long lasting antihyperalgesia produced by BMSCs required their chemotactic factors such as CCL4 and CCR2, the integrations with the monocytes/macrophages population, and BMSC-induced monocyte CXCL1. The activation of central mu-opioid receptors related to CXCL1-CXCR2 signaling plays an important role in BMSC produced antihyperalgesia. Our findings suggest that the maintenance of antihypergesia can be achieved by immune regulation without actual engraftment of BMSCs. In the capacity of therapeutic use of BMSCs other than structural repair and replacement, more attention should be directed to their role as immune modulators and subsequent alterations in the immune system. PMID- 28860502 TI - Bi-directional and shared epigenomic signatures following proton and 56Fe irradiation. AB - The brain's response to radiation exposure is an important concern for patients undergoing cancer therapy and astronauts on long missions in deep space. We assessed whether this response is specific and prolonged and is linked to epigenetic mechanisms. We focused on the response of the hippocampus at early (2 weeks) and late (20-week) time points following whole body proton irradiation. We examined two forms of DNA methylation, cytosine methylation (5mC) and hydroxymethylation (5hmC). Impairments in object recognition, spatial memory retention, and network stability following proton irradiation were observed at the two-week time point and correlated with altered gene expression and 5hmC profiles that mapped to specific gene ontology pathways. Significant overlap was observed between DNA methylation changes at the 2 and 20-week time points demonstrating specificity and retention of changes in response to radiation. Moreover, a novel class of DNA methylation change was observed following an environmental challenge (i.e. space irradiation), characterized by both increased and decreased 5hmC levels along the entire gene body. These changes were mapped to genes encoding neuronal functions including postsynaptic gene ontology categories. Thus, the brain's response to proton irradiation is both specific and prolonged and involves novel remodeling of non-random regions of the epigenome. PMID- 28860503 TI - The First Call Note Plays a Crucial Role in Frog Vocal Communication. AB - Vocal Communication plays a crucial role in survival and reproductive success in most amphibian species. Although amphibian communication sounds are often complex consisting of many temporal features, we know little about the biological significance of each temporal component. The present study examined the biological significance of notes of the male advertisement calls of the Emei music frog (Babina daunchina) using the optimized electroencephalogram (EEG) paradigm of mismatch negativity (MMN). Music frog calls generally contain four to six notes separated approximately by 150 millisecond intervals. A standard stimulus (white noise) and five deviant stimuli (five notes from one advertisement call) were played back to each subject while simultaneously recording multi-channel EEG signals. The results showed that the MMN amplitude for the first call note was significantly larger than for that of the others. Moreover, the MMN amplitudes evoked from the left forebrain and midbrain were typically larger than those from the right counterpart. These results are consistent with the ideas that the first call note conveys more information than the others for auditory recognition and that there is left-hemisphere dominance for processing information derived from conspecific calls in frogs. PMID- 28860504 TI - Small molecule-based lineage switch of human adipose-derived stem cells into neural stem cells and functional GABAergic neurons. AB - Cellular reprogramming using small molecules (SMs) without genetic modification provides a promising strategy for generating target cells for cell-based therapy. Human adipose-derived stem cells (hADSCs) are a desirable cell source for clinical application due to their self-renewal capacity, easy obtainability and the lack of safety concerns, such as tumor formation. However, methods to convert hADSCs into neural cells, such as neural stem cells (NSCs), are inefficient, and few if any studies have achieved efficient reprogramming of hADSCs into functional neurons. Here, we developed highly efficient induction protocols to generate NSC-like cells (iNSCs), neuron-like cells (iNs) and GABAergic neuron like cells (iGNs) from hADSCs via SM-mediated inhibition of SMAD signaling without genetic manipulation. All induced cells adopted morphological, molecular and functional features of their bona fide counterparts. Electrophysiological data demonstrated that iNs and iGNs exhibited electrophysiological properties of neurons and formed neural networks in vitro. Microarray analysis further confirmed that iNSCs and iGNs underwent lineage switch toward a neural fate. Together, these studies provide rapid, reproducible and robust protocols for efficient generation of functional iNSCs, iNs and iGNs from hADSCs, which have utility for modeling disease pathophysiology and providing cell-therapy sources of neurological disorders. PMID- 28860505 TI - Endolysin LysEF-P10 shows potential as an alternative treatment strategy for multidrug-resistant Enterococcus faecalis infections. AB - Phage-derived lysins can hydrolyse bacterial cell walls and show great potential for combating Gram-positive pathogens. In this study, the potential of LysEF-P10, a new lysin derived from a isolated Enterococcus faecalis phage EF-P10, as an alternative treatment for multidrug-resistant E. faecalis infections, was studied. LysEF-P10 shares only 61% amino acid identity with its closest homologues. Four proteins were expressed: LysEF-P10, the cysteine, histidine dependent amidohydrolase/peptidase (CHAP) domain (LysEF-P10C), the putative binding domain (LysEF-P10B), and a fusion recombination protein (LysEF-P10B-green fluorescent protein). Only LysEF-P10 showed highly efficient, broad-spectrum bactericidal activity against E. faecalis. Several key functional residues, including the Cys-His-Asn triplet and the calcium-binding site, were confirmed using 3D structure prediction, BLAST and mutation analys. We also found that calcium can switch LysEF-P10 between its active and inactive states and that LysEF-P10B is responsible for binding E. faecalis cells. A single administration of LysEF-P10 (5 MUg) was sufficient to protect mice against lethal vancomycin resistant Enterococcus faecalis (VREF) infection, and LysEF-P10-specific antibody did not affect its bactericidal activity or treatment effect. Moreover, LysEF-P10 reduced the number of Enterococcus colonies and alleviated the gut microbiota imbalance caused by VREF. These results indicate that LysEF-P10 might be an alternative treatment for multidrug-resistant E. faecalis infections. PMID- 28860506 TI - Differences in characteristics of glucose intolerance between patients with NAFLD and chronic hepatitis C as determined by CGMS. AB - Glucose intolerance frequently develops in accordance with the progression of chronic liver disease. However, differences in the characteristics of glucose intolerance between patients with nonalcoholic fatty liver disease (NAFLD) and those with chronic hepatitis C (C-CH) remain incompletely understood. To clarify these differences, patients with NAFLD (n = 37) and C-CH (n = 40) were evaluated with a continuous glucose monitoring system (CGMS). In the patients with NAFLD, Maximum blood glucose concentration and blood glucose swings were significantly correlated with hepatic fibrosis markers. In the patients with C-CH, however, those two CGMS parameters were negatively correlated with the serum albumin (ALB) concentration. Furthermore, in the patients with C-CH with an ALB concentration of <=4.0 g/dl, those two CGMS parameters were negatively correlated with the ALB concentration with greater statistical significance. In conclusion, obvious differences in the characteristics of glucose intolerance between patients with NAFLD and those with C-CH were clarified. In patients with NAFLD, glucose intolerance gradually progressed in accordance with the progression of hepatic fibrosis. In those with C-CH, glucose intolerance suddenly developed upon the appearance of hypoalbuminaemia. PMID- 28860507 TI - A Two-Step Growth Pathway for High Sb Incorporation in GaAsSb Nanowires in the Telecommunication Wavelength Range. AB - Self-catalyzed growth of axial GaAs1-xSbx nanowire (NW) arrays with bandgap tuning corresponding to the telecommunication wavelength of 1.3 um poses a challenge, as the growth mechanism for axial configuration is primarily thermodynamically driven by the vapor-liquid-solid growth process. A systematic study carried out on the effects of group V/III beam equivalent (BEP) ratios and substrate temperature (Tsub) on the chemical composition in NWs and NW density revealed the efficacy of a two-step growth temperature sequence (initiating the growth at relatively higher Tsub = 620 degrees C and then continuing the growth at lower Tsub) as a promising approach for obtaining high-density NWs at higher Sb compositions. The dependence of the Sb composition in the NWs on the growth parameters investigated has been explained by an analytical relationship between the effective vapor composition and NW composition using relevant kinetic parameters. A two-step growth approach along with a gradual variation in Ga-BEP for offsetting the consumption of the droplets has been explored to realize long NWs with homogeneous Sb composition up to 34 at.% and photoluminescence emission reaching 1.3 um at room temperature. PMID- 28860508 TI - Targeted metabolome profiling by dual-probe microdialysis sampling and treatment using Gardenia jasminoides for rats with type 2 diabetes. AB - Diabetes causes a variety of end-stage organ complications, including diabetic nephropathy. Metabolomics offers an approach for characterizing biofluid metabolic changes, but studies focusing on diabetic nephropathy are limited due to the loss of tissue-specific metabolic information. A microdialysis application for the sampling of intact endogenous metabolites has been developed, utilizing two probes simultaneously inserted into the kidney tissues and jugular vein of rats with type 2 diabetes. The comprehensive and quantitative analysis of 20 diagnostic biomarkers closely realated to type 2 diabetes and its complications were performed. Results indicated that amino acid and nucleotide levels were lower in diabetic rats, revealing that the metabolic pathways of amino acid, as well as purine and pyrimidine, were disturbed. Targeted metabolomics using mass spectrometry was performed to find potential therapeutic biomarkers and related metabolic pathways of Gardenia jasminoides (G. jasminoides) for treating diabetes. Results suggested that seven biomarkers in the kidney and five biomarkers in the blood were related to G. jasminoides. In addition, the marked perturbations of pathways were regulated after treatment with G. jasminoides, including amino acid metabolism and purine metabolism. These biomarkers and metabolic pathways provided new understanding for molecular mechanisms of G. jasminoides for treating diabetes and its complications. PMID- 28860509 TI - Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate. AB - Lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) are highly prevalent in older men, having a profound impact on patient quality of life. Current therapeutics for BPH/LUTS target neurogenic smooth muscle tone, but response is unpredictable and many patients fail to respond. Spontaneous myogenic tone is another component of smooth muscle contractility that is uncharacterized in human prostate. To better understand and improve the predictability of patient response, we defined myogenic contractility using human prostate specimens and examined the effect of existing therapeutics. We show that myogenic activity is present in the human prostate with the frequency of contractions in transition zone (TZ) specimens from BPH diagnosed patients approximately 160% greater than matched controls. alpha1-adrenoreceptor antagonists (Tamsulosin) and PDE5 inhibitors (Sildenafil) both significantly reduced myogenic contractile parameters, including frequency, with notable interpatient variability. Tamsulosin was more effective in older patients (R2 = 0.36, p < 0.01) and men with larger prostate volumes (R2 = 0.41, p < 0.05), while Sildenafil was more effective in younger men (R2 = 0.45, p < 0.05). As myogenic tone is significantly increased in BPH, therapeutics targeting this mechanism used with reference to patient characteristics could improve clinical outcomes and better predict patient response. PMID- 28860511 TI - InGaP (GaInP) mesa p-i-n photodiodes for X-ray photon counting spectroscopy. AB - In this paper, for the first time an InGaP (GaInP) photon counting X-ray photodiode has been developed and shown to be suitable for photon counting X-ray spectroscopy when coupled to a low-noise charge-sensitive preamplifier. The characterisation of two randomly selected 200 MUm diameter and two randomly selected 400 MUm diameter In0.5Ga0.5P p+-i-n+ mesa photodiodes is reported; the i layer of the p+-i-n+ structure was 5 MUm thick. At room temperature, and under illumination from an 55Fe radioisotope X-ray source, X-ray spectra were accumulated; the best spectrometer energy resolution (FWHM) achieved at 5.9 keV was 900 eV for the 200 MUm In0.5Ga0.5P diameter devices at reverse biases above 5 V. System noise analysis was also carried out and the different noise contributions were computed. PMID- 28860510 TI - A functional IL1RL1 variant regulates corticosteroid-induced sST2 expression in ulcerative colitis. AB - The ST2/IL33 signalling pathway has been associated with ulcerative colitis (UC). ST2, encoded by the IL1RL1 gene, is expressed as both a membrane-anchored receptor (ST2L) activated by IL33 and as a soluble receptor (sST2) with anti inflammatory properties. In UC patients, sST2 is further increased by corticosteroid treatment; however, the glucocorticoid-mediated molecular regulation remains unknown. We therefore tested whether genetic variants in the IL1RL1 distal promoter are involved in UC and affect glucocorticoid-mediated ST2 expression. Serum ST2 levels and genetic variants in the IL1RL1 distal promoter were examined by ELISA and PCR sequencing in UC patients receiving corticosteroids. Glucocorticoid-mediated ST2 production was evaluated in intestinal mucosa cultures. Molecular regulation of glucocorticoid-mediated ST2 was assessed by RT-qPCR, ChIP assay and luciferase reporter assay. Dexamethasone effect on ST2 transcript expression was analyzed in leukocytes and related to IL1RL1 variants. Sequencing of a distal IL1RL1 promoter region demonstrated that SNPs rs6543115(C) and rs6543116(A) are associated with increased sST2 in UC patients on corticosteroids. Dexamethasone up-regulated sST2 transcription through interaction with the glucocorticoid-response element (GRE) carrying rs6543115(C) variant. Our data indicate that IL1RL1 SNPs rs6543115(C) confer susceptibility to UC and is contained in the GRE, which may modulate glucocorticoid-induced sST2 expression. PMID- 28860512 TI - Regulation of androgen receptor signaling by ubiquitination during folliculogenesis and its possible dysregulation in polycystic ovarian syndrome. AB - Although chronic hyperandrogenism suppresses antral follicular development, a phenomenon often observed in polycystic ovarian syndrome (PCOS), whether and how deregulation of androgen receptor (AR) signaling is involved, is not well understood. In the present study, we examined the role of ring finger protein 6 (RNF6) in AR ubiquitination and the possible dysregulation in the expression and actions of growth differentiation factor 9 (GDF9) and kit-ligand (Kitlg) in a chronic androgenized PCOS rat model. 5alpha-dihydrotestosterone (DHT) treatment in vivo inhibited antral follicle growth, a response mediated through increased RNF6 content, suppressed K63- but increased K48-linked AR ubiquitination as well as the mRNA expression and content of soluble KIT-L (sKitlg) and content of GDF9. These androgenic responses were attenuated by gonadotropin treatment in vivo. Growth of antral follicles from DHT-treated rats in vitro was significantly slower when compared to those of control but was significantly enhanced by exogenous GDF9, suggesting the DHT-induced antral follicular growth arrest is in part the results of GDF9 suppression. Our findings indicate how hyperandrogenism modulates RNF6 content and subsequently AR ubiquitination, resulting in antral follicle growth arrest in a chronically androgenized PCOS rat model. PMID- 28860513 TI - Reservoir Computing Beyond Memory-Nonlinearity Trade-off. AB - Reservoir computing is a brain-inspired machine learning framework that employs a signal-driven dynamical system, in particular harnessing common-signal-induced synchronization which is a widely observed nonlinear phenomenon. Basic understanding of a working principle in reservoir computing can be expected to shed light on how information is stored and processed in nonlinear dynamical systems, potentially leading to progress in a broad range of nonlinear sciences. As a first step toward this goal, from the viewpoint of nonlinear physics and information theory, we study the memory-nonlinearity trade-off uncovered by Dambre et al. (2012). Focusing on a variational equation, we clarify a dynamical mechanism behind the trade-off, which illustrates why nonlinear dynamics degrades memory stored in dynamical system in general. Moreover, based on the trade-off, we propose a mixture reservoir endowed with both linear and nonlinear dynamics and show that it improves the performance of information processing. Interestingly, for some tasks, significant improvements are observed by adding a few linear dynamics to the nonlinear dynamical system. By employing the echo state network model, the effect of the mixture reservoir is numerically verified for a simple function approximation task and for more complex tasks. PMID- 28860514 TI - Delay discounting is associated with the fractional amplitude of low-frequency fluctuations and resting-state functional connectivity in late adolescence. AB - As a component of self-regulation, delay discounting (DD) refers to an individual's tendency to prefer smaller-but-sooner rewards over larger-but-later rewards and plays an essential role in many aspects of human behavior. Although numerous studies have examined the neural underpinnings of DD in adults, there are far fewer studies focusing on the neurobiological correlates underlying DD in adolescents. Here, we investigated the associations between individual differences in DD and the fractional amplitude of low-frequency fluctuations (fALFF) and resting-state functional connectivity (RSFC) in 228 high school students using resting-state functional magnetic resonance imaging (RS-fMRI). At the regional level, we found an association between higher DD and greater fALFF in the dorsal anterior cingulate cortex (dACC), which is involved in conflict monitoring and strategy adaptation. At the connectivity level, DD was positively correlated with the RSFC between the dACC and the left dorsolateral prefrontal cortex (DLPFC), a critical functional circuit in the cognitive control network. Furthermore, these effects persisted even after adjusting for the influences of general intelligence and trait impulsivity. Overall, this study reveals the fALFF and RSFC as the functional brain basis of DD in late adolescents, aiding to strengthen and corroborate our understanding of the neural underpinnings of DD. PMID- 28860515 TI - Activation of the peripheral immune system regulates neuronal aromatase in the adult zebra finch brain. AB - Estradiol provision via neural aromatization decreases neuro-inflammation and degeneration, but almost nothing is known about the interactions between the peripheral immune system and brain aromatase. Given the vulnerability of the CNS we reasoned that brain aromatization may protect circuits from the threats of peripheral infection; perhaps shielding cells that are less resilient from the degeneration associated with peripheral infection or trauma. Lipopolysaccharide (LPS) or vehicle was administered peripherally to adult zebra finches and sickness behavior was recorded 2 or 24 hours later. The central transcription of cytokines and aromatase was measured, as were telencephalic aromatase activity and immunoreactive aromatase (24 hour time point only). Two hours post LPS, sickness-like behaviors increased, the transcription of IL-1beta was higher in both sexes, and TNFalpha was elevated in females. 24 hours post-LPS, the behavior of LPS birds was similar to controls, and cytokines had returned to baseline, but aromatase mRNA and activity were elevated in both sexes. Immunocytochemistry revealed greater numbers of aromatase-expressing neurons in LPS birds. These data suggest that the activation of the immune system via peripheral endotoxin increases neuronal aromatase; a mechanism that may rapidly generate a potent anti neuroinflammatory steroid in response to peripheral activation of the immune system. PMID- 28860516 TI - Indirect immobilized Jagged1 suppresses cell cycle progression and induces odonto/osteogenic differentiation in human dental pulp cells. AB - Notch signaling regulates diverse biological processes in dental pulp tissue. The present study investigated the response of human dental pulp cells (hDPs) to the indirect immobilized Notch ligand Jagged1 in vitro. The indirect immobilized Jagged1 effectively activated Notch signaling in hDPs as confirmed by the upregulation of HES1 and HEY1 expression. Differential gene expression profiling using an RNA sequencing technique revealed that the indirect immobilized Jagged1 upregulated genes were mainly involved in extracellular matrix organization, disease, and signal transduction. Downregulated genes predominantly participated in the cell cycle, DNA replication, and DNA repair. Indirect immobilized Jagged1 significantly reduced cell proliferation, colony forming unit ability, and the number of cells in S phase. Jagged1 treated hDPs exhibited significantly higher ALP enzymatic activity, osteogenic marker gene expression, and mineralization compared with control. Pretreatment with a gamma-secretase inhibitor attenuated the Jagged1-induced ALP activity and mineral deposition. NOTCH2 shRNA reduced the Jagged1-induced osteogenic marker gene expression, ALP enzymatic activity, and mineral deposition. In conclusion, indirect immobilized Jagged1 suppresses cell cycle progression and induces the odonto/osteogenic differentiation of hDPs via the canonical Notch signaling pathway. PMID- 28860518 TI - Persistent anomalies of the extratropical Northern Hemisphere wintertime circulation as an initiator of El Nino/Southern Oscillation events. AB - Climates across both hemispheres are strongly influenced by tropical Pacific variability associated with the El Nino/Southern Oscillation (ENSO). Conversely, extratropical variability also can affect the tropics. In particular, seasonal mean alterations of near-surface winds associated with the North Pacific Oscillation (NPO) serve as a significant extratropical forcing agent of ENSO. However, it is still unclear what dynamical processes give rise to year-to-year shifts in these long-lived NPO anomalies. Here we show that intraseasonal variability in boreal winter pressure patterns over the Central North Pacific (CNP) imparts a significant signature upon the seasonal-mean circulations characteristic of the NPO. Further we show that the seasonal-mean signature results in part from year-to-year variations in persistent, quasi-stationary low pressure intrusions into the subtropics of the CNP, accompanied by the establishment of persistent, quasi-stationary high-pressure anomalies over high latitudes of the CNP. Overall, we find that the frequency of these persistent extratropical anomalies (PEAs) during a given winter serves as a key modulator of intraseasonal variability in extratropical North Pacific circulations and, through their influence on the seasonal-mean circulations in and around the southern lobe of the NPO, the state of the equatorial Pacific 9-12 months later. PMID- 28860517 TI - The EAL-domain protein FcsR regulates flagella, chemotaxis and type III secretion system in Pseudomonas aeruginosa by a phosphodiesterase independent mechanism. AB - The second messenger c-di-GMP regulates the switch between motile and sessile bacterial lifestyles. A general feature of c-di-GMP metabolism is the presence of a surprisingly large number of genes coding for diguanylate cyclases and phosphodiesterases, the enzymes responsible for its synthesis and degradation respectively. However, the physiological relevance of this apparent redundancy is not clear, emphasizing the need for investigating the functions of each of these enzymes. Here we focused on the phosphodiesterase PA2133 from Pseudomonas aeruginosa, an important opportunistic pathogen. We phenotypically characterized P. aeruginosa strain K overexpressing PA2133 or its inactive mutant. We showed that biofilm formation and motility are severely impaired by overexpression of PA2133. Our quantitative proteomic approach applied to the membrane and exoprotein fractions revealed that proteins involved in three processes were mostly affected: flagellar motility, type III secretion system and chemotaxis. While inhibition of biofilm formation can be ascribed to the phosphodiesterase activity of PA2133, down-regulation of flagellar, chemotaxis, and type III secretion system proteins is independent of this enzymatic activity. Based on these unexpected effects of PA2133, we propose to rename this gene product FcsR, for Flagellar, chemotaxis and type III secretion system Regulator. PMID- 28860519 TI - Dopaminergic Modulation of Biological Motion Perception in patients with Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder pathologically characterized by a selective loss of dopaminergic neurons in the substantia nigra. In previous studies, greater attention was paid to impairments in motor disturbances in contrast to impairments of cognitive function in PD that was often ignored. In present study, a duration discrimination paradigm was used to assess global and local biological motion (BM) perception in healthy controls(HCs) and PD patients with and without dopamine substitution treatment (DST). Biological motion sequences and inanimate motion sequences (inverted BM sequences) were sequentially presented on a screen. Observers were required to verbally make a 2-alternative forced-choice to indicate whether the first or second interval appeared longer. The stimuli involved global and local BM sequences. Statistical analyses were conducted on points of subjective equality (PSE). We found significant differences between untreated PD patients and HCs as well as differences between global and local BM conditions. PD patients have a deficit in both global and local BM perception. Nevertheless, these two BM conditions can be improved under DST. Our data indicates that BM perception may be damaged in PD patients and dopaminergic medication is conducive to maintain the BM perception in PD patients. PMID- 28860520 TI - Metagenomic evidence of stronger effect of stylo (legume) than bahiagrass (grass) on taxonomic and functional profiles of the soil microbial community. AB - Plants are key determinants of soil microbial community (SMC). Legumes and grasses are distinct groups in various ecosystems; however, how they differentially shape SMC structure and functioning has yet to be explored. Here, we investigate SMC in soils grown with stylo (legume) or bahiagrass (grass). Soil metagenomic sequencing indicates that Archaea was more abundant in unplanted soils than in planted soils, and that stylo selected higher abundance of fungi than bahiagrass. When the stylo soils enriched Streptomyces, Frankia, Mycobacterium and Amycolatopsis, the bahiagrass soils enriched Sphingomonas and Sphingobium. NMDS reveals that the legume shaped SMC more greatly than the grass (P < 0.004). SMC functional profiles (KEGG and CAZy) were also greatly altered by plants with the legume being more effective (P < 0.000 and P < 0.000). The abundant microbial taxa contributed to the main community functions, with Conexibacter, Sphingomonas, and Burkholderia showing multifunctionality. Moreover, soil chemical property showed much higher direct effect on SMC structure and functional profiles than soil extracts, although the soil total nitrogen and some compounds (e.g. heptadecane, 1-pentadecyne and nonanoic acid) in soil extracts were best correlated with SMC structure and functional profiles. These findings are the first to suggest that legume species shape SMC more greatly than grass species. PMID- 28860521 TI - The Value of Coastal Wetlands for Flood Damage Reduction in the Northeastern USA. AB - As exposure to coastal hazards increases there is growing interest in nature based solutions for risk reduction. This study uses high-resolution flood and loss models to quantify the impacts of coastal wetlands in the northeastern USA on (i) regional flood damages by Hurricane Sandy and (ii) local annual flood losses in Barnegat Bay in Ocean County, New Jersey. Using an extensive database of property exposure, the regional study shows that wetlands avoided $625 Million in direct flood damages during Hurricane Sandy. The local study combines these models with a database of synthetic storms in Ocean County and estimates a 16% average reduction in annual flood losses by salt marshes with higher reductions at lower elevations. Together, the studies quantify the risk reduction ecosystem services of marsh wetlands. Measuring these benefits in collaboration with the risk modelling industry is crucial for assessing risk accurately and, where appropriate, aligning conservation and risk reduction goals. PMID- 28860522 TI - Vacancies, disorder-induced smearing of the electronic structure, and its implications for the superconductivity of anti-perovskite MgC0.93Ni2.85. AB - The anti-perovskite superconductor MgC0.93Ni2.85 was studied using high resolution x-ray Compton scattering combined with electronic structure calculations. Compton scattering measurements were used to determine experimentally a Fermi surface that showed good agreement with that of our supercell calculations, establishing the presence of the predicted hole and electron Fermi surface sheets. Our calculations indicate that the Fermi surface is smeared by the disorder due to the presence of vacancies on the C and Ni sites, but does not drastically change shape. The 20% reduction in the Fermi level density-of-states would lead to a significant (~70%) suppression of the superconducting T c for pair-forming electron-phonon coupling. However, we ascribe the observed much smaller T c reduction at our composition (compared to the stoichiometric compound) to the suppression of pair-breaking spin fluctuations. PMID- 28860524 TI - Entropy spikes as a signature of Lifshitz transitions in the Dirac materials. AB - We demonstrate theoretically that the characteristic feature of a 2D system undergoing N consequent Lifshitz topological transitions is the occurrence of spikes of entropy per particle s of a magnitude +/-ln2/(J - 1/2) with 2 <= J <= N at low temperatures. We derive a general expression for s as a function of chemical potential, temperature and gap magnitude for the gapped Dirac materials. Inside the smallest gap, the dependence of s on the chemical potential exhibits a dip-and-peak structure in the temperature vicinity of the Dirac point. The spikes of the entropy per particles can be considered as a signature of the Dirac materials. These distinctive characteristics of gapped Dirac materials can be detected in transport experiments where the temperature is modulated in gated structures. PMID- 28860523 TI - Type 3 inositol 1,4,5-trisphosphate receptor is dispensable for sensory activation of the mammalian vomeronasal organ. AB - Signal transduction in sensory neurons of the mammalian vomeronasal organ (VNO) involves the opening of the canonical transient receptor potential channel Trpc2, a Ca2+-permeable cation channel that is activated by diacylglycerol and inhibited by Ca2+-calmodulin. There has been a long-standing debate about the extent to which the second messenger inositol 1,4,5-trisphosphate (InsP3) and type 3 InsP3 receptor (InsP3R3) are involved in the opening of Trpc2 channels and in sensory activation of the VNO. To address this question, we investigated VNO function of mice carrying a knockout mutation in the Itpr3 locus causing a loss of InsP3R3. We established a new method to monitor Ca2+ in the endoplasmic reticulum of vomeronasal sensory neurons (VSNs) by employing the GFP-aequorin protein sensor erGAP2. We also performed simultaneous InsP3 photorelease and Ca2+ monitoring experiments, and analysed Ca2+ dynamics, sensory currents, and action potential or field potential responses in InsP3R3-deficient VSNs. Disruption of Itpr3 abolished or minimized the Ca2+ transients evoked by photoactivated InsP3, but there was virtually no effect on sensory activation of VSNs. Therefore, InsP3R3 is dispensable for primary chemoelectrical transduction in mouse VNO. We conclude that InsP3R3 is not required for gating of Trpc2 in VSNs. PMID- 28860525 TI - Glucocorticoids are lower at delivery in maternal, but not cord blood of obese pregnancies. AB - Glucocorticoids are vital for lung maturation. We previously showed that cortisol is lower in obese pregnancy. Whether this is maintained at delivery is unknown but is clinically relevant as maternal and cord blood cortisol levels are correlated and offspring of obese are more likely to need neonatal respiratory support. We hypothesized that glucocorticoids are lower in maternal and cord blood at delivery in obese pregnancies. Glucocorticoids (cortisol and corticosterone) and their inactive versions (cortisone and 11 dehydrocorticosterone) were measured by LC-MS/MS in maternal and cord plasma from 259 Caucasian women at delivery (BMI 18-55 kg/m2). Analyses adjusted for labour status, delivery mode, offspring gender, birthweight and gestational age. Cortisol and corticosterone were significantly higher in maternal than cord blood. Inactive versions were significantly higher in cord than maternal blood. Increased maternal BMI associated with lower maternal cortisol, corticosterone and 11-dehydrocorticosterone. Despite significant positive correlations between maternal and cord blood glucocorticoid levels, increased maternal BMI was not associated with lower cord blood glucocorticoid levels. Conditions at delivery may overcome any potential negative effects of low maternal glucocorticoids on the fetus in the short-term. This may not preclude the longer-term effects of fetal exposure to lower glucocorticoid levels during obese pregnancy. PMID- 28860526 TI - An ab initio study on noble gas inserted halogenated acetylene: HNgCCX (Ng = Kr and Xe; X = halogen). AB - Although HNgCCX (Ng = Kr and Xe; X = F and Cl) have been identified in cryogenic matrices, similar Br and I analogues have not been prepared so far. In this paper, the nature of HNgCCX (Ng = Kr and Xe; X = F, Cl, Br and I) have been investigated by ab initio methods. The main characteristic absorption peak of HNgCCX is the v H-Ng, which decreases as X varies from F to I. Moreover, the H-Xe bond is stronger than the H-Kr bond. The v C=C and v C-X exhibit red- and blue shift characters, respectively, especially the C-X bond is abnormal blue-shift halogen bond. AIM results show that the H-Ng bond is essentially covalent bond and the covalent character of H-Xe bond is underestimated, and the trend of the covalent character is C-Cl > C-Br > C-F > C-I. Although HNgCCX is instable thermodynamically with respect to Ng + HCCX, it is kinetically stable with respect to the two-/three-body channels due to the relatively larger energy barriers. The three-body channels of HNgCCX is the main decomposition channel, and the kinetically stability of HXeCCX is more than its Kr analogues. This study is helpful for the preparation of new HNgCCX in cryogenic matrices. PMID- 28860527 TI - Relationship between fraction of exhaled nitric oxide and airway morphology assessed by three-dimensional CT analysis in asthma. AB - Fraction of exhaled nitric oxide (FeNO) provides information about chronic inflammation in asthma. However, its relationship with structural changes in the airways is unknown. We aimed to evaluate the correlation between computer-based airway changes and FeNO in patients with asthma. The wall area (WA) and airway inner luminal area (Ai) of the third- to sixth-generation bronchi were measured using three-dimensional computed tomography in asthmatic patients. Each value was corrected by body surface area (BSA). Relationships between FeNO and WA/BSA and Ai/BSA were evaluated. Forty-one clinically stable patients with asthma were evaluated. FeNO was significantly correlated with WA/BSA of the third-, fourth-, fifth- and sixth-generation bronchi (Spearman correlation coefficient (rho) = 0.326, p = 0.041; rho = 0.356, p = 0.025; rho = 0.496, p = 0.002; and rho = 0.529, p < 0.001, respectively). The correlation with sixth-generation bronchi was significantly greater than with the third-generation bronchi (p = 0.047). Partial rank correlation analysis indicated FeNO was significantly correlated with WA/BSA of the sixth-generation bronchi, independent from confounding factors of Ai/BSA, age, duration of asthma, dose of inhaled corticosteroid, blood eosinophil percentage, and blood IgE (rho = 0.360, p = 0.034). In contrast, there was no correlation between FeNO and Ai/BSA. FeNO correlates with bronchial wall thickening in asthma patients. Measurement of FeNO may be useful to detect airway remodeling in asthma. PMID- 28860528 TI - Pupillary responses to light are not affected by narrow irido-corneal angles. AB - Chromatic pupillometry is an emerging method for evaluating ocular health that relies upon the differential stimulation of rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs). Although it has been investigated in conditions affecting the outer or inner retina, there is a paucity of studies in conditions where the anterior chamber of the eye is affected. Primary angle closure suspects (PACS) are defined as eyes with narrow anterior chamber angles and intact retina. PACS patients are at risk of developing primary angle closure glaucoma and are prophylactically treated by performing laser peripheral iridotomy (LPI). Here we evaluated pupillary responses to monchromatic lights in 18 PACS before and after LPI, and compared the results with those of 36 age matched controls who had gonioscopically open angles. Dose response curves for pupillary constriction were similar between PACS patients and controls (p = 0.98 for blue and 0.90 for red light) and within subjects pre- and post-LPI (p = 0.58 for blue and 0.20 for red light). Baseline-adjusted pupillary constriction responses to blue and red lights were similar in controls and PACS, and not altered after LPI. Our findings suggest that narrow irido-corneal angles and LPI do not influence pupillary responses in PACS. PMID- 28860529 TI - Distribution of hybrid entanglement and hyperentanglement with time-bin for secure quantum channel under noise via weak cross-Kerr nonlinearity. AB - We design schemes to generate and distribute hybrid entanglement and hyperentanglement correlated with degrees of freedom (polarization and time-bin) via weak cross-Kerr nonlinearities (XKNLs) and linear optical devices (including time-bin encoders). In our scheme, the multi-photon gates (which consist of XKNLs, quantum bus [qubus] beams, and photon-number-resolving [PNR] measurement) with time-bin encoders can generate hyperentanglement or hybrid entanglement. And we can also purify the entangled state (polarization) of two photons using only linear optical devices and time-bin encoders under a noisy (bit-flip) channel. Subsequently, through local operations (using a multi-photon gate via XKNLs) and classical communications, it is possible to generate a four-qubit hybrid entangled state (polarization and time-bin). Finally, we discuss how the multi photon gate using XKNLs, qubus beams, and PNR measurement can be reliably performed under the decoherence effect. PMID- 28860530 TI - Low-molecular-weight organic acids correlate with cultivar variation in ciprofloxacin accumulation in Brassica parachinensis L. AB - To understand the mechanism controlling cultivar differences in the accumulation of ciprofloxacin (CIP) in Chinese flowering cabbage (Brassica parachinensis L.), low-molecular-weight organic acids (LMWOAs) secreted from the roots of high- and low-CIP cultivars (Sijiu and Cutai, respectively) and their effects on the bioavailability of CIP in soil were investigated. Significant differences in the content of LMWOAs (especially maleic acid) between the two cultivars played a key role in the variation in CIP accumulation. Based on the Freundlich sorption coefficient (K f ) and distribution coefficient (K d ), the presence of LMWOAs reduced the CIP sorption onto soil particles, and higher concentrations of LMWOAs led to less CIP sorption onto soil. On the other hand, LMWOAs enhanced CIP desorption by lowering the solution pH, which changed the surface charge of soil particles and the degree of CIP ionization. LMWOAs promoted CIP desorption from soil by breaking cation bridges and dissolving metal cations, particularly Cu2+. These results implied that the LMWOAs (mainly maleic acid) secreted from Sijiu inhibited CIP sorption onto soil and improved CIP desorption from soil to a greater extent than those secreted from Cutai, resulting in higher bioavailability of CIP and more uptake and accumulation of CIP in the former. PMID- 28860531 TI - Ultra-broad Mid-IR Supercontinuum Generation in Single, Bi and Tri Layer Graphene Nano-Plasmonic waveguides pumping at Low Input Peak Powers. AB - This article presents four different plasmonic structures using Graphene which yielded an efficient plasmonic mode with low loss for Supercontinuum(SC) generation. At an operating wavelength of 1550 nm in these structures, we generated a multi-octave broadband SC spectrum ranging from 1.5 um-25 um at a low input peak power of 1 W. Due to pumping in the anomalous dispersion region with two Zero Dispersion Wavelengths (ZDWs) and the process of cross phase modulation with soliton fission, red-shifted dispersive waves were generated which led to large broadening from 1.5 um-25 um. Two other Supercontinua ranging from 1-10 um and 0.85-2.2 um also at low input peak powers of 2 W and 0.1 W respectively were generated. These three supercontinua are useful for applications in the fields of biomedical sensors, spectroscopy, fluorescence lifetime imaging and in the design of many other new optical devices. Furthermore, we have also discussed our results on behaviour of Graphene as a metal, even without the negative real value of dielectric constant. PMID- 28860532 TI - Revealing the mystery of metabolic adaptations using a genome scale model of Leishmania infantum. AB - Human macrophage phagolysosome and sandfly midgut provide antagonistic ecological niches for Leishmania parasites to survive and proliferate. Parasites optimize their metabolism to utilize the available inadequate resources by adapting to those environments. Lately, a number of metabolomics studies have revived the interest to understand metabolic strategies utilized by the Leishmania parasite for optimal survival within its hosts. For the first time, we propose a reconstructed genome-scale metabolic model for Leishmania infantum JPCM5, the analyses of which not only captures observations reported by metabolomics studies in other Leishmania species but also divulges novel features of the L. infantum metabolome. Our results indicate that Leishmania metabolism is organized in such a way that the parasite can select appropriate alternatives to compensate for limited external substrates. A dynamic non-essential amino acid motif exists within the network that promotes a restricted redistribution of resources to yield required essential metabolites. Further, subcellular compartments regulate this metabolic re-routing by reinforcing the physiological coupling of specific reactions. This unique metabolic organization is robust against accidental errors and provides a wide array of choices for the parasite to achieve optimal survival. PMID- 28860533 TI - Predicting the Ionic Product of Water. AB - We present a first-principles calculation and mechanistic characterization of the ion product of liquid water (K W ), based on Quantum Cluster Equilibrium (QCE) theory with a variety of ab initio and density functional methods. The QCE method is based on T-dependent Boltzmann weighting of different-sized clusters and consequently enables the observation of thermodynamically less favored and therefore low populated species such as hydronium and hydroxide ions in water. We find that common quantum chemical methods achieve semi-quantitative accuracy in predicting K W and its T-dependence. Dominant ion-pair water clusters of the QCE equilibrium distribution are found to exhibit stable 2-coordinate buttress-type motifs, all with maximally Grotthus-ordered H-bond patterns that successfully prevent recombination of hydronium and hydroxide ions at 3-coordinate bridgehead sites. We employ standard quantum chemistry techniques to describe kinetic and mechanistic aspects of ion-pair formation, and we obtain NBO-based bonding indices to characterize other electronic, structural, spectroscopic, and reactive properties of cluster-mediated ionic dissociation. PMID- 28860534 TI - Genomic and transcriptomic analyses reveal differential regulation of diverse terpenoid and polyketides secondary metabolites in Hericium erinaceus. AB - The lion's mane mushroom Hericium erinaceus is a famous traditional medicinal fungus credited with anti-dementia activity and a producer of cyathane diterpenoid natural products (erinacines) useful against nervous system diseases. To date, few studies have explored the biosynthesis of these compounds, although their chemical synthesis is known. Here, we report the first genome and tanscriptome sequence of the medicinal fungus H. erinaceus. The size of the genome is 39.35 Mb, containing 9895 gene models. The genome of H. erinaceus reveals diverse enzymes and a large family of cytochrome P450 (CYP) proteins involved in the biosynthesis of terpenoid backbones, diterpenoids, sesquiterpenes and polyketides. Three gene clusters related to terpene biosynthesis and one gene cluster for polyketides biosynthesis (PKS) were predicted. Genes involved in terpenoid biosynthesis were generally upregulated in mycelia, while the PKS gene was upregulated in the fruiting body. Comparative genome analysis of 42 fungal species of Basidiomycota revealed that most edible and medicinal mushroom show many more gene clusters involved in terpenoid and polyketide biosynthesis compared to the pathogenic fungi. None of the gene clusters for terpenoid or polyketide biosynthesis were predicted in the poisonous mushroom Amanita muscaria. Our findings may facilitate future discovery and biosynthesis of bioactive secondary metabolites from H. erinaceus and provide fundamental information for exploring the secondary metabolites in other Basidiomycetes. PMID- 28860535 TI - Ecological and functional adaptations to water management in a semiarid agroecosystem: a soil metaproteomics approach. AB - Climate change models point to a decrease in water availability in semiarid areas that would compromise the maintenance of sustainable agriculture. Here, we used a grapefruit agroecosystem model to evaluate the responses of the active soil microbial community - as a microbial subset directly involved in soil functionality- undergoing strategies to cope with the low water availability in south-east Spain. For this purpose, we tested the impacts of: (i) water quality: transfer-water from a river (TW) or reclaimed-water from a wastewater-treatment plant (RW); and (ii) water quantity: continuous optimal amount of water or reduced irrigation (RDI) in the temporal frame when the crop is less sensitive; and their interactions. Metaproteomics revealed that the phylogenetic diversity of the active community and its functional diversity were lowered in soils with RW. RDI lowered soil respiration and functional diversity while the phylogenetic diversity remained constant. The reestablishment of full irrigation after RDI led to a recovery of soil respiration that was accompanied by an enhanced abundance of resilient bacterial populations. Bacterial populations displayed molecular mechanisms against water stress that have been conserved evolutionarily in plants. Protein-based studies shed light on ecological and functional mechanisms that govern the adaptive responses of soil microbial communities to climate change friendly water management. PMID- 28860536 TI - Optical absorbing origin of chiroptical activity in planar plasmonic metasurfaces. AB - As a significant characteristic of many biomolecules, chemical substances, and artificial nanostructures, chirality conduce different types of optical interactions with the spin angular momentum of the impinging light field. Although, chiral arrangement and spatial phase retardation are the key factors for obtaining chirality in three-dimensional (3D) structures, the origin of chirality in the feasible planar structures has not been thoroughly addressed. Here using an intuitive and simple analytical approach, called cross hybridization model, the essence and properties of the optical chirality of individual planar nanostructures are unveiled. In order to fundamentally address this chirality in terms of circular dichroism (CD), the chiroptical response of a simple dimer composed of the lossy nanoblocks in L-shape arrangement are investigated based on the provided optical interaction and loss effects. The theoretical findings, adequately supported by the numerical calculations, reveal that chiroptical activity occurs predominantly due to handedness-dependent absorption or heating loss in a nanostructured metasurface. PMID- 28860537 TI - Deswelling and deformation of microgels in concentrated packings. AB - Increasing the particle density of a suspension of microgel colloids above the point of random-close packing, must involve deformations of the particle to accommodate the increase in volume fraction. By contrast to the isotropic osmotic deswelling of soft particles, the particle-particle contacts give rise to a non homogeneous pressure, raising the question if these deformations occur through homogeneous deswelling or by the formation of facets. Here we aim to answer this question through a combination of imaging of individual microgels in dense packings and a simple model to describe the balance between shape versus volume changes. We find a transition from shape changes at low pressures to volume changes at high pressures, which can be explained qualitatively with our model. Whereas contact mechanics govern at low pressures giving rise to facets, osmotic effects govern at higher pressures, which leads to a more homogeneous deswelling. Our results show that both types of deformation play a large role in highly concentrated microgel suspensions and thus must be taken into account to arrive at an accurate description of the structure, dynamics and mechanics of concentrated suspensions of soft spheres. PMID- 28860538 TI - SIRT1 rs10823108 and FOXO1 rs17446614 responsible for genetic susceptibility to diabetic nephropathy. AB - SIRT1 and FOXO1 play an important role in the pathogenesis of diabetic nephropathy (DN). However, the association between genetic polymorphisms and susceptibility to type 2 DN (T2DN) has not been explored. In this study, a total of 1066 patients with type 2 diabetes mellitus (T2DM) (413 without and 653 with DN) were enrolled. The genotypes of three htSNPs (rs3818292, rs4746720, rs10823108) within SIRT1 and two htSNPs (rs2721068, rs17446614) in FOXO1 were determined by PCR-RFLP. HbA1C, LDL, HDL, TC, and TG levels were also examined. SIRT1 rs10823108 AA genotype was significantly associated with a decreased risk of DN (OR = 0.60, 95%CI: 0.38-0.97), while GA genotype (OR = 1.77, 95%CI: 1.33 2.35) and AA genotype (OR = 2.32, 95%CI: 1.25-4.34) of FOXO1 rs17446614 was associated with an increased T2DN risk. The interactions among rs1744 6614, BMI and duration of diabetes (OR: 2.63, 95%CI: 1.23-4.31) were also observed. Subsequent haplotype analysis revealed that two haplotype defined by AC (OR: 1.50, 95%CI: 1.15-1.94) and AT (OR: 1.79, 95%CI: 1.06-2.80) within FOXO1 gene may increase the risk of T2DN. In conclusion, genetic variant rs10823108 in SIRT1 and variant rs17446614 in FoxO1 may contribute to the risk of DN in T2DM patients. PMID- 28860539 TI - Hypoxia induces cancer-associated cAMP/PKA signalling through HIF-mediated transcriptional control of adenylyl cyclases VI and VII. AB - Hypoxia is a phenomenon often arising in solid tumours, linked to aggressive malignancy, bad prognosis and resistance to therapy. Hypoxia-inducible factor-1 has been identified as a key mediator of cell and tissue adaptation to hypoxic conditions through transcriptional activation of many genes involved in glucose metabolism and other cancer-related processes, such as angiogenesis, cell survival and cell invasion. Cyclic adenosine 3'5'-monophosphate is one of the most ancient and evolutionarily conserved signalling molecules and the cAMP/PKA signalling pathway plays an important role in cellular adaptation to hypoxia. We have investigated possible new mechanisms behind hypoxic activation of the cAMP/PKA pathway. For the first time, we have shown that hypoxia induces transcriptional up-regulation of the system of adenylyl cyclases, enzymes responsible for cAMP production, in a panel of carcinoma cell lines of various origin. Our data prove functional relevance of the hypoxic increase of adenylyl cyclases VI and VII at least partially mediated by HIF-1 transcription factor. We have identified adenylyl cyclase VI and VII isoforms as mediators of cellular response to hypoxia, which led to the elevation of cAMP levels and enhanced PKA activity, with an impact on cell migration and pH regulation. PMID- 28860540 TI - The global view of mRNA-related ceRNA cross-talks across cardiovascular diseases. AB - Competing endogenous RNA (ceRNA) have received wide attention because they are a novel way to regulate genes through sharing microRNAs (miRNAs) that are crucial for complex processes in many diseases. However, no systematic analysis of ceRNA mechanism in cardiovascular disease (CVD) is known. To gain insights into the global properties of ceRNAs in multi-CVDs, we constructed the global view of mRNA related ceRNA cross-talk in eight major CVDs from ~2,800 samples. We found common features that could be used to uncover similarities among different CVDs and highlighted a common core ceRNA network across CVDs. Comparative analysis of hub ceRNAs in each network revealed three types of hubs, which might play key roles in diverse biological processes. Importantly, by combining CVD-related pathway genes with ceRNA-ceRNA interactions, common modules that might exert functions in specific mechanisms were identified. In addition, our study investigated a potential mechanistic linkage between pathway cross-talk and ceRNA cross-talk. In summary, this study uncovered and systematically characterized global properties of mRNA-related ceRNA cross-talks across CVDs, which may provide a new layer for exploring biological mechanisms and shed new light on cardiology. PMID- 28860541 TI - Functional validation of novel MKS3/TMEM67 mutations in COACH syndrome. AB - COACH syndrome is an autosomal recessive developmental disorder, a subtype of Joubert syndrome and related disorders, characterized by cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Although mutations in TMEM67 (transmembrane protein 67)/MKS3 (Meckel-Gruber syndrome, type 3) were reported to cause COACH syndrome, this causality has not verified by functional studies. In a 20-year-old Korean man, we found cerebellar ataxia, isolated elevation in serum gamma-glutamyl transpeptidase (gamma-GTP) activity, oligophrenia, the molar tooth sign (MTS) in the brain MR images and congenital hepatic fibrosis (CHF). Two novel compound heterozygous mutations were found in TMEM67 in the patient: i) missense mutation (c.395 G > C and p.Gly132Ala) in exon 3, and ii) deletion in exon 26 (c.2758delT and p.Tyr920ThrfsX40). Western blotting showed that the p.Tyr920ThrfsX40 mutation accelerates turnover of the TMEM67 protein. Although wild-type human TMEM67 RNA rescued phenotypes of zebrafish embryos injected with anti-sense oligonucleotide morpholinos against tmem67, the two human TMEM67 RNAs individually harboring the two mutations did not. Finally, Wnt signaling, but not Hedgehog signaling, was suppressed in tmem67 morphants. To the best of our knowledge, this is the first report verifying the causality between COACH syndrome and TMEM67, which will further our understanding of molecular pathogenesis of the syndrome. PMID- 28860542 TI - Genetic association study of common variants in TGFB1 and IL-6 with developmental dysplasia of the hip in Han Chinese population. AB - Developmental dysplasia of the hip (DDH) is a congenital or developmental deformation or misalignment of the hip joint that is affected by environmental and genetic factors. Recently, polymorphisms in both TGFB1 and IL-6 have been identified as being significantly associated with hip osteoarthritis in Caucasians. In this study, we conducted a case-control study involving 4,206 Han Chinese individuals to investigate the effects of TGFB1 and IL-6 on the disease status and severity of DDH. A total of 32 single-nucleotide polymorphisms (SNPs) were selected to ensure coverage of the two genetic loci. We found SNP rs1800470 in TGFB1 (OR = 1.255, P = 0.0004) and rs1800796 (OR = 0.84, P = 0.0228) in IL-6 to be significantly associated with DDH in this cohort. Further haplotype-based analysis replicated this significant result. Another SNP in IL-6, rs1800796, showed a marginally significant association with DDH. As a non-synonymous SNP, rs1800470 alters the amino acid sequence of the polypeptide encoded by TGFB1; however, bioinformatics analyses revealed that this SNP has limited functional significance. No significant results were obtained in an association study focusing on the severity of DDH and epistasis analysis. Our findings support an important role for TGFB1 in the risk of DDH. Further research is needed to validate the weak association between rs1800796 in IL-6 and DDH. PMID- 28860543 TI - Spatial complexity of carcass location influences vertebrate scavenger efficiency and species composition. AB - Scavenging plays an important role in shaping communities through inter- and intra-specific interactions. Although vertebrate scavenger efficiency and species composition is likely influenced by the spatial complexity of environments, heterogeneity in carrion distribution has largely been disregarded in scavenging studies. We tested this hypothesis by experimentally placing juvenile bird carcasses on the ground and in nests in trees to simulate scenarios of nestling bird carrion availability. We used cameras to record scavengers removing carcasses and elapsed time to removal. Carrion placed on the ground was scavenged by a greater diversity of vertebrates and at > 2 times the rate of arboreal carcasses, suggesting arboreal carrion may represent an important resource to invertebrate scavengers, particularly in landscapes with efficient vertebrate scavenging communities. Nonetheless, six vertebrate species scavenged arboreal carcasses. Rat snakes (Elaphe obsolete), which exclusively scavenged from trees, and turkey vultures (Cathartes aura) were the primary scavengers of arboreal carrion, suggesting such resources are potentially an important pathway of nutrient acquisition for some volant and scansorial vertebrates. Our results highlight the intricacy of carrion-derived food web linkages, and how consideration of spatial complexity in carcass distribution (i.e., arboreal) may reveal important pathways of nutrient acquisition by invertebrate and vertebrate scavenging guilds. PMID- 28860544 TI - An Investigation on Attributes of Ambient Temperature and Diurnal Temperature Range on Mortality in Five East-Asian Countries. AB - Interest in the health effects of extremely low/high ambient temperature and the diurnal temperature range (DTR) on mortality as representative indices of temperature variability is growing. Although numerous studies have reported on these indices independently, few studies have provided the attributes of ambient temperature and DTR related to mortality, concurrently. In this study, we aimed to investigate and compare the mortality risk attributable to ambient temperature and DTR. The study included data of 63 cities in five East-Asian countries/regions during various periods between 1972 and 2013. The attributable risk of non-accidental death to ambient temperature was 9.36% (95% confidence interval [CI]: 8.98-9.69%) and to DTR was 0.59% (95% CI: 0.53-0.65%). The attributable cardiovascular mortality risks to ambient temperature (15.63%) and DTR (0.75%) are higher than the risks to non-accidental/respiratory-related mortality. We verified that ambient temperature plays a larger role in temperature-associated mortality, and cardiovascular mortality is susceptible to ambient temperature and DTR. PMID- 28860545 TI - 1alpha,20S-Dihydroxyvitamin D3 Interacts with Vitamin D Receptor: Crystal Structure and Route of Chemical Synthesis. AB - 1alpha,20S-Dihydroxyvitamin D3 [1,20S(OH)2D3], a natural and bioactive vitamin D3 metabolite, was chemically synthesized for the first time. X-ray crystallography analysis of intermediate 15 confirmed its 1alpha-OH configuration. 1,20S(OH)2D3 interacts with the vitamin D receptor (VDR), with similar potency to its native ligand, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] as illustrated by its ability to stimulate translocation of the VDR to the nucleus, stimulate VDRE-reporter activity, regulate VDR downstream genes (VDR, CYP24A1, TRPV6 and CYP27B1), and inhibit the production of inflammatory markers (IFNgamma and IL1beta). However, their co-crystal structures revealed differential molecular interactions of the 20S-OH moiety and the 25-OH moiety to the VDR, which may explain some differences in their biological activities. Furthermore, this study provides a synthetic route for the synthesis of 1,20S(OH)2D3 using the intermediate 1alpha,3beta diacetoxypregn-5-en-20-one (3), and provides a molecular and biological basis for the development of 1,20S(OH)2D3 and its analogs as potential therapeutic agents. PMID- 28860546 TI - Telemonitoring in fasting individuals with Type 2 Diabetes Mellitus during Ramadan: A prospective, randomised controlled study. AB - We determined the impact of a remote blood glucose telemonitoring program with feedback in type 2 diabetes mellitus patients fasting during Ramadan compared to conventional self-monitoring method. A twelve-week cluster randomised study, with 85 participants who wish to fast for at least 15 days during Ramadan was conducted. Self-measurement and transmission of blood glucose results were performed six times daily during Ramadan. Results were transmitted to a secure website for review with feedback from case manager if necessary. The control group received usual care. The main outcome was the number of participants experiencing hypoglycaemia during Ramadan and at the end of the study. During Ramadan, the number of participants reporting hypoglycaemia was significantly lower in the telemonitoring group [Odds ratio (OR): 0.186, 95% confidence interval: 0.04-0.936; p = 0.04]. Similarly, the proportion of participants reporting symptomatic hypoglycaemia at the end of the study was significantly lower in the telemonitoring group (OR: 0.257, 95% CI: 0.07-0.89; p = 0.03). A reduction of 1.07% in glycated haemoglobin levels was observed in the telemonitoring group compared to 0.24% in the control group (p < 0.01). Overall, telemonitoring was a useful adjunct to reduce the risk of hypoglycaemia during Ramadan with no deterioration in glycaemic control. PMID- 28860547 TI - Elevated mean platelet volume predicts poor prognosis in colorectal cancer. AB - Altered mean platelet volume (MPV) is implicated in several malignancies. However, the clinicopathological significance and prognostic value of MPV in colorectal cancer (CRC) is still elusive. The purpose of this study was to elucidate the predictive significance of MPV in CRC. The retrospective study recruited 509 consecutive CRC patients between January 2009 and December 2009. The relationships between MPV and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of MPV. Of the 509 CRC patients, high MPV levels were detected in 150 (29.5%) patients. Elevated MPV was associated with tumor differentiation (p < 0.001). Patients with increased MPV had poor overall survival compared with those with normal level (60.0% vs. 83.6%, log-rank test, p = 0.035). Cox regression analysis showed that MPV was an independent prognostic factor in CRC (HR = 1.452, 95% CI = 1.118-1.884, p = 0.005). In conclusion, MPV is easily available in routine blood test. Elevated MPV might act as a marker of prognosis and therapeutic target for CRC. PMID- 28860548 TI - Valley filter and valve effect by strong electrostatic potentials in graphene. AB - We report a theoretical study on the valley-filter and valley-valve effects in the monolayer graphene system by using electrostatic potentials, which are assumed to be electrically controllable. Based on a lattice model, we find that a single extremely strong electrostatic-potential barrier, with its strength exceeding the hopping energy of electrons, will significantly block one valley but allow the opposite valley flowing in the system, and this is dependent on the sign of the potential barrier as well as the flowing direction of electrons. In a valley-valve device composed of two independent potential barriers, the valley valve efficiency can even amount to 100% that the electronic current is entirely prohibited or allowed by reversing the sign of one of potential barriers. The physics origin is attributed to the valley mixing effect in the strong potential barrier region. Our findings provide a simple electric way of controlling the valley transport in the monolayer graphene system. PMID- 28860549 TI - High-performance metal mesh/graphene hybrid films using prime-location and metal doped graphene. AB - We introduce high-performance metal mesh/graphene hybrid transparent conductive layers (TCLs) using prime-location and metal-doped graphene in near-ultraviolet light-emitting diodes (NUV LEDs). Despite the transparency and sheet resistance values being similar for hybrid TCLs, there were huge differences in the NUV LEDs' electrical and optical properties depending on the location of the graphene layer. We achieved better physical stability and current spreading when the graphene layer was located beneath the metal mesh, in direct contact with the p GaN layer. We further improved the contact properties by adding a very thin Au mesh between the thick Ag mesh and the graphene layer to produce a dual-layered metal mesh. The Au mesh effectively doped the graphene layer to create a p-type electrode. Using Raman spectra, work function variations, and the transfer length method (TLM), we verified the effect of doping the graphene layer after depositing a very thin metal layer on the graphene layers. From our results, we suggest that the nature of the contact is an important criterion for improving the electrical and optical performance of hybrid TCLs, and the method of doping graphene layers provides new opportunities for solving contact issues in other semiconductor devices. PMID- 28860550 TI - The fight against overweight and obesity in school children: Public policy in Mexico. AB - Excess weight in schoolchildren is a serious health problem in Mexico. In 2010, the government established General Guidelines for Dispensing or Distribution of Foods and Beverages at School Food Establishments (SFEs) in Elementary Schools with the objective of stopping the epidemic of overweight and obesity. This study aimed to evaluate compliance with the Guidelines during two academic years. With a sample of 39 schools already randomly selected, we carried out a follow-up study. The research team recorded foods and beverages available at schools in two academic years, and compared their nutritional characteristics to those established in the Guidelines. At the schools in both stages of the study, we found broad availability of energy-dense foods not allowed in the SFEs. Vegetables, fruits, and plain water accounted for less than 7 per cent of the foods and drinks. We observed no changes between stages in the compliance the Guidelines. PMID- 28860551 TI - Odorant-odorant metabolic interaction, a novel actor in olfactory perception and behavioral responsiveness. AB - In the nasal olfactory epithelium, olfactory metabolic enzymes ensure odorant clearance from the olfactory receptor environment. This biotransformation of odorants into deactivated polar metabolites is critical to maintaining peripheral sensitivity and perception. Olfactory stimuli consist of complex mixtures of odorants, so binding interactions likely occur at the enzyme level and may impact odor processing. Here, we used the well-described model of mammary pheromone induced sucking-related behavior in rabbit neonates. It allowed to demonstrate how the presence of different aldehydic odorants efficiently affects the olfactory metabolism of this pheromone (an aldehyde too: 2-methylbut-2-enal). Indeed, according to in vitro and ex vivo measures, this metabolic interaction enhances the pheromone availability in the epithelium. Furthermore, in vivo presentation of the mammary pheromone at subthreshold concentrations efficiently triggers behavioral responsiveness in neonates when the pheromone is in mixture with a metabolic challenger odorant. These findings reveal that the periphery of the olfactory system is the place of metabolic interaction between odorants that may lead, in the context of odor mixture processing, to pertinent signal detection and corresponding behavioral effect. PMID- 28860552 TI - Identification of amino acid residues involved in the dRP-lyase activity of human Pol iota. AB - Besides X-family DNA polymerases (first of all, Pol beta) several other human DNA polymerases from Y- and A- families were shown to possess the dRP-lyase activity and could serve as backup polymerases in base excision repair (Pol iota, Rev1, Pol gamma and Pol theta). However the exact position of the active sites and the amino acid residues involved in the dRP-lyase activity in Y- and A- family DNA polymerases are not known. Here we carried out functional analysis of fifteen amino acid residues possibly involved in the dRP-lyase activity of human Pol iota. We show that substitutions of residues Q59, K60 and K207 impair the dRP lyase activity of Pol iota while residues in the HhH motif of the thumb domain are dispensable for this activity. While both K60G and K207A substitutions decrease Schiff-base intermediate formation during dRP group cleavage, the latter substitution also strongly affects the DNA polymerase activity of Pol iota, suggesting that it may impair DNA binding. These data are consistent with an important role of the N-terminal region in the dRP-lyase activity of Pol iota, with possible involvement of residues from the finger domain in the dRP group cleavage. PMID- 28860553 TI - RNA-seq analysis of apical meristem reveals integrative regulatory network of ROS and chilling potentially related to flowering in Litchi chinensis. AB - Litchi is an important woody fruit tree. Floral initiation in litchi is triggered by low temperatures. However, defective flowering is a major challenge for litchi production in times of climate change and global warming. Previous studies have shown that the reactive oxygen species (ROS) generated by methyl viologen dichloride hydrate (MV) promotes flowering. In this study, potted trees were transferred to growth chambers for low-temperature (LT), medium-temperature (MT), and high-temperature (HT) treatments. Trees at MT were subjected to ROS treatment to promote flowering, and those at LT were induced to flower. RNA-sequencing was applied to obtain a global transcriptome of the apical meristem and reveal potential gene networks controlling the transformation from vegetative meristems (VM) into inflorescence meristems (IM). We assembled 73,117 unigenes with a mean size of 790 bp and 11741 unigenes were identified as both chilling and ROS responsive genes (CRRGs), of which 48 were identified as flowering-related CRRGs, 59 were plant hormone signal transduction CRRGs, and 146 were plant hormone biosynthesis-related CRRGs. Genes co-expression network analysis indicated inner relationships, suggesting that ROS and chilling promotes the VM to IM transition through a regulatory gene network of transcription factors, hormones, and flowering regulators. PMID- 28860554 TI - Transcriptome analysis reveals the host selection fitness mechanisms of the Rhizoctonia solani AG1IA pathogen. AB - Rhizoctonia solani AG1IA is a major generalist pathogen that causes sheath blight. Its genome, which was the first to be sequenced from the Rhizoctonia genus, may serve as a model for studying pathogenic mechanisms. To explore the pathogen-host fitness mechanism of sheath-blight fungus, a comprehensive comparative transcriptome ecotype analysis of R. solani AG1IA isolated from rice, soybean and corn during infection was performed. Special characteristics in gene expression, gene ontology terms and expression of pathogenesis-associated genes, including genes encoding secreted proteins, candidate effectors, hydrolases, and proteins involved in secondary metabolite production and the MAPK pathway, were revealed. Furthermore, as an important means of pathogenic modulation, diverse alternative splicing of key pathogenic genes in Rhizoctonia solani AG1IA during infections of the abovementioned hosts was uncovered for the first time. These important findings of key factors in the pathogenicity of R. solani AG1IA ecotypes during infection of various hosts explain host preference and provide novel insights into the pathogenic mechanisms and host-pathogen selection. Furthermore, they provide information on the fitness of Rhizoctonia, a severe pathogen with a wide host range. PMID- 28860555 TI - Chloride Channels are Involved in the Development of Atrial Fibrillation - A Transcriptomic and proteomic Study. AB - ABSTARCT: Electrical and structural remodeling processes are contributors to the self-perpetuating nature of atrial fibrillation (AF). However, their correlation has not been clarified. In this study, human atrial tissues from the patients with rheumatic mitral valve disease in either sinus rhythm or persistent AF were analyzed using a combined transcriptomic and proteomic approach. An up-regulation in chloride intracellular channel (CLIC) 1, 4, 5 and a rise in type IV collagen were revealed. Combined with the results from immunohistochemistry and electron microscope analysis, the distribution of type IV collagen and effects of fibrosis on myocyte membrane indicated the possible interaction between CLIC and type IV collagen, confirmed by protein structure prediction and co-immunoprecipitation. These results indicate that CLICs play an important role in the development of atrial fibrillation and that CLICs and structural type IV collagen may interact on each other to promote the development of AF in rheumatic mitral valve disease. PMID- 28860556 TI - The Tomato DOF Daily Fluctuations 1, TDDF1 acts as flowering accelerator and protector against various stresses. AB - Adaptation to environmental changes is an important fitness trait for crop development. Photoperiod is an essential factor in seasonal control of flowering time. Sensing of day-length requires an interaction between the Photoperiod and the endogenous rhythms that is controlled by plant circadian clock. Thus, circadian clock is a critical regulator and internal molecular time-keeping mechanism, controlling key agricultural traits in crop plants such as the ability to adjust their growth and physiology to anticipate diurnal environmental changes. Here, we describe the gene Tomato Dof Daily Fluctuations 1 (TDDF1), which is involved in circadian regulation and stress resistance. Large daily oscillations in TDDF1 expression were retained after transferring to continuous dark (DD) or light (LL) conditions. Interestingly, overexpressing TDDF1 induce early flowering in tomato through up-regulation of the flowering-time control genes, moreover, by protein-protein interaction with the floral inducer SFT gene. Notably, overexpressing TDDF1 in tomato was associated with chlorophyll overaccumulation by up-regulating the related biosynthetic genes. TDDF1 expression results in improved drought, salt, various hormones stress tolerance alongwith resistance to late blight caused by Phytophthora infestans. This study can be a distinctive strategy to improve other economically important crops. PMID- 28860557 TI - Differential Cortical Gray Matter Deficits in Adolescent- and Adult-Onset First Episode Treatment-Naive Patients with Schizophrenia. AB - The current study aimed to explore age-variant trait differences of cortical gray matter volume (GMV) in a unique sample of first-episode and treatment-naive patients with schizophrenia. A total of 158 subjects, including 26 adolescent onset patients and 49 adult-onset patients as well as 83 age- and gender-matched controls were scanned using a 3T MRI scanner. Voxel-based morphometry (VBM) following Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL) was used to explore group differences between patients and controls in regional GMV. We found that patients with schizophrenia had decreased GMV in the left parietal postcentral region that extended to the left frontal regions, the right middle temporal gyrus, the occipital lobe and the right cerebellum posterior pyramis. Further analysis showed a distinct pattern of gray matter alterations in adolescent-onset patients compared with both healthy controls and adult-onset patients. Relative to healthy controls, adolescent-onset patients showed GMV alterations in the left parietal postcentral gyrus, parahippocampal gyrus and right cerebellum posterior pyramis, while GMV deficits in adult-onset patients were focused on the cingulo-fronto-temporal module and right occipital regions. Our study identified differential cortical gray matter deficits between adolescent- and adulthood-onset patients with schizophrenia, which suggests that the cortical abnormalities in schizophrenia are likely adjusted by the developmental community structure of the human brain. PMID- 28860558 TI - Development and validation of a multivariate predictive model for rheumatoid arthritis mortality using a machine learning approach. AB - We developed and independently validated a rheumatoid arthritis (RA) mortality prediction model using the machine learning method Random Survival Forests (RSF). Two independent cohorts from Madrid (Spain) were used: the Hospital Clinico San Carlos RA Cohort (HCSC-RAC; training; 1,461 patients), and the Hospital Universitario de La Princesa Early Arthritis Register Longitudinal study (PEARL; validation; 280 patients). Demographic and clinical-related variables collected during the first two years after disease diagnosis were used. 148 and 21 patients from HCSC-RAC and PEARL died during a median follow-up time of 4.3 and 5.0 years, respectively. Age at diagnosis, median erythrocyte sedimentation rate, and number of hospital admissions showed the higher predictive capacity. Prediction errors in the training and validation cohorts were 0.187 and 0.233, respectively. A survival tree identified five mortality risk groups using the predicted ensemble mortality. After 1 and 7 years of follow-up, time-dependent specificity and sensitivity in the validation cohort were 0.79-0.80 and 0.43-0.48, respectively, using the cut-off value dividing the two lower risk categories. Calibration curves showed overestimation of the mortality risk in the validation cohort. In conclusion, we were able to develop a clinical prediction model for RA mortality using RSF, providing evidence for further work on external validation. PMID- 28860559 TI - Genome-wide identification and characterization of TCP transcription factor genes in upland cotton (Gossypium hirsutum). AB - TCP proteins are plant-specific transcription factors (TFs), and perform a variety of physiological functions in plant growth and development. In this study, 74 non-redundant TCP genes were identified in upland cotton (Gossypium hirsutum L.) genome. Cotton TCP family can be classified into two classes (class I and class II) that can be further divided into 11 types (groups) based on their motif composition. Quantitative RT-PCR analysis indicated that GhTCPs display different expression patterns in cotton tissues. The majority of these genes are preferentially or specifically expressed in cotton leaves, while some GhTCP genes are highly expressed in initiating fibers and/or elongating fibers of cotton. Yeast two-hybrid results indicated that GhTCPs can interact with each other to form homodimers or heterodimers. In addition, GhTCP14a and GhTCP22 can interact with some transcription factors which are involved in fiber development. These results lay solid foundation for further study on the functions of TCP genes during cotton fiber development. PMID- 28860560 TI - Effect of non-linearity of a predictor on the shape and magnitude of its receiver operating-characteristic curve in predicting a binary outcome. AB - Area under a receiver-operating-characteristic (AUROC) curve is widely used in medicine to summarize the ability of a continuous predictive marker to predict a binary outcome. This study illustrated how a U-shaped or inverted U-shaped continuous predictor would affect the shape and magnitude of its AUROC curve in predicting a binary outcome by comparing the ROC curves of the worst first 24 hour arterial pH values of 9549 consecutive critically ill patients in predicting hospital mortality before and after centering the predictor by its mean or median. A simulation dataset with an inverted U-shaped predictor was used to assess how this would affect the shape and magnitude of the AUROC curve. An asymmetrical U-shaped relationship between pH and hospital mortality, resulting in an inverse-sigmoidal ROC curve, was observed. The AUROC substantially increased after centering the predictor by its mean (0.611 vs 0.722, difference = 0.111, 95% confidence interval [CI] 0.087-0.135), and was further improved after centering by its median (0.611 vs 0.745, difference = 0.133, 95%CI 0.110-0.157). A sigmoidal-shaped ROC curve was observed for an inverted U-shaped predictor. In summary, a non-linear predictor can result in a biphasic-shaped ROC curve; and centering the predictor can reduce its bias towards null predictive ability. PMID- 28860561 TI - Short Chain Fatty Acids Enhance Aryl Hydrocarbon (Ah) Responsiveness in Mouse Colonocytes and Caco-2 Human Colon Cancer Cells. AB - Aryl hydrocarbon receptor (AhR) ligands are important for gastrointestinal health and play a role in gut inflammation and the induction of T regulatory cells, and the short chain fatty acids (SCFAs) butyrate, propionate and acetate also induce similar protective responses. Initial studies with butyrate demonstrated that this compound significantly increased expression of Ah-responsive genes such as Cyp1a1/CYP1A1 in YAMC mouse colonocytes and Caco-2 human colon cancer cell lines. Butyrate synergistically enhanced AhR ligand-induced Cyp1a1/CYP1A1 in these cells with comparable enhancement being observed for 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) and also microbiota-derived AhR ligands tryptamine, indole and 1,4 dihydroxy-2-naphthoic acid (DHNA). The effects of butyrate on enhancing induction of Cyp1b1/CYP1B1, AhR repressor (Ahrr/AhRR) and TCDD-inducible poly(ADP ribose)polymerase (Tiparp/TiPARP) by AhR ligands were gene- and cell context dependent with the Caco-2 cells being the most responsive cell line. Like butyrate and propionate, the prototypical hydroxyamic acid-derived histone deacetylase (HDAC) inhibitors Panobinostat and Vorinostat also enhanced AhR ligand-mediated induction and this was accompanied by enhanced histone acetylation. Acetate also enhanced basal and ligand-inducible Ah responsiveness and histone acetylation, demonstrating that acetate was an HDAC inhibitor. These results demonstrate SCFA-AhR ligand interactions in YAMC and Caco-2 cells where SCFAs synergistically enhance basal and ligand-induced expression of AhR responsive genes. PMID- 28860562 TI - The effect of body mass index and physical activity on hypertension among Chinese middle-aged and older population. AB - Few studies have been conducted to explore the independent and combined associations of body mass index (BMI) and physical activity with risk of hypertension in Chinese population. A cross-sectional study of 5291 individuals (aged >= 40 years) selected using multi-stage sampling method was conducted from October 2013 to December 2015. In the present analysis, 55.64% of the participants were women, and the mean age of participants was 55.37 +/- 10.56. Compared with individuals in normal group, the risks of hypertension were nearly double in overweight subjects (odds ratio [OR] 1.77, 95% confidence interval [CI] 1.53-2.05) and more than three times higher in obese subjects (3.23, 2.62-4.13). Multi-adjusted odds for hypertension associated with low, moderate, and high physical activity were 1.44 (1.17-1.86), 1.40 (1.09-1.79) and 1.000, respectively. In comparison with normal weight subjects who reported high levels of physical activity, subjects who reported both low levels of physical activity and obesity showed the highest risk of hypertension (5.89, 3.90-8.88). In conclusion, both elevated BMI and reduced physical activity appear to play an important role in the risk of hypertension among Chinese middle-aged and older population. The risk of hypertension associated with overweight and obesity can be reduced considerably by increased physical activity levels. PMID- 28860563 TI - PIK3CA exon9 mutations associate with reduced survival, and are highly concordant between matching primary tumors and metastases in endometrial cancer. AB - Mutations of the phosphoinositide-3-kinase (PI3K) catalytic subunit alpha gene (PIK3CA) are frequent in endometrial cancer. We sequenced exon9 and exon20 of PIK3CA in 280 primary endometrial cancers to assess the relationship with clinicopathologic variables, patient survival and associations with PIK3CA mRNA and phospho-AKT1 by gene expression and protein data, respectively. While PIK3CA mutations generally had no impact on survival, and were not associated with clinicopathological variables, patients with exon9 charge-changing mutations, providing a positive charge at the substituted amino acid residue, were associated with poor survival (p = 0.018). Furthermore, we characterized PIK3CA mutations in the metastatic setting, including 32 patients with matched primary tumors and metastases, and found a high level of concordance (85.7%; 6 out of 7 patients), suggesting limited heterogeneity. PIK3CA mRNA levels were increased in metastases compared to the primary tumors (p = 0.031), independent of PIK3CA mutation status, which rather associated with reduced PIK3CA mRNA expression. PIK3CA mutated tumors expressed higher p-AKT/AKT protein levels, both within primary (p < 0.001) and metastatic lesion (p = 0.010). Our results support the notion that the PI3K signaling pathway might be activated, both dependent- and independently of PIK3CA mutations, an aspect that should be considered when designing PIK3 pathway targeting strategies in endometrial cancer. PMID- 28860564 TI - Differential effects of antidepressant treatment on long-range and short-range functional connectivity strength in patients with major depressive disorder. AB - ABSTARCT: Although we have some basic understanding of the neurochemical mechanisms of the antidepressants, the network-level effect of antidepressant treatment is still not fully understood. This study was conducted to investigate the effects of antidepressant on functional brain networks of patients with major depressive disorder (MDD). We performed resting-state fMRI scans on 20 first episode drug-naive MDD patients at baseline and after escitalopram medication for 8 weeks. Twenty healthy controls also received MRI scans with an 8-week interval. The graph theory indices, long- and short-range functional connectivity strength (FCS), were computed to characterize the brain connectivity. The analysis of covariance was conducted on FCS maps of patients and controls to obtain the interaction effect of group and time, which indicate treatment-related effect. Following treatment, increased long-range FCS in the bilateral posterior cingulate cortex/precuneus and right thalamus in MDD patients at baseline were reduced. Meanwhile, increased short-range FCS in the bilateral ventromedial prefrontal cortex and left amygdala in patients were reduced, while reduced short range FCS in the right parahippocampal gyrus was increased. Results suggest that the brain regions associated with negative emotional processing and regulation, and self-referential function could be modulated by escitalopram treatment; long- and short-range FCS are differentially affected by antidepressant. PMID- 28860565 TI - Interleukin-6-dependent growth in a newly established plasmablastic lymphoma cell line and its therapeutic targets. AB - Plasmablastic lymphoma (PBL) is a rare, highly aggressive subtype of non-Hodgkin lymphoma with plasma-cell differentiation occurring typically in immune suppressed patients such as those with AIDS. This study reports the establishment and characterization of a new cell line, PBL-1, derived from a patient with AIDS associated PBL. Morphological assessment of PBL-1 indicated plasma-cell differentiation with a CD20(-) CD38(+) CD138(+) immunophenotype and IgH/c-myc translocation. The cell line harbours Epstein-Barr virus, but a 52.7-kbp length defect was identified in its genome, resulting in no expression of viral microRNAs encoded in the BamHI-A Rightward Transcript region. Importantly, supplementation of culture medium with >5 ng/mL of interleukin-6 (IL-6) was required for PBL-1 growth. Starvation of IL-6 or addition of tocilizumab, an inhibitory antibody for the IL-6 receptor, induced apoptosis of PBL-1. Transduction of IL-6 into PBL-1 by lentivirus vector induced autologous growth without IL-6 supplementation of culture medium. These data indicate the IL-6 dependency of PBL-1 for proliferation and survival. mTOR inhibitors induced cell death effectively, suggesting mTOR in the IL-6 signalling pathway is a potential therapeutic target for PBL. This established PBL cell line will be a useful tool to further understand the pathophysiology of PBL and aid the future development of PBL treatment. PMID- 28860566 TI - Targeting cholesterol homeostasis in lung diseases. AB - Macrophages are critical to organ structure and function in health and disease. To determine mechanisms by which granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling normally maintains surfactant homeostasis and how its disruption causes pulmonary alveolar proteinosis (PAP), we evaluated lipid composition in alveolar macrophages and lung surfactant, macrophage-mediated surfactant clearance kinetics/dynamics, and cholesterol-targeted pharmacotherapy of PAP in vitro and in vivo. Without GM-CSF signaling, surfactant-exposed macrophages massively accumulated cholesterol ester-rich lipid-droplets and surfactant had an increased proportion of cholesterol. GM-CSF regulated cholesterol clearance in macrophages in constitutive, dose-dependent, and reversible fashion but did not affect phospholipid clearance. PPARgamma-agonist therapy increased cholesterol clearance in macrophages and reduced disease severity in PAP mice. Results demonstrate that GM-CSF is required for cholesterol clearance in macrophages, identify reduced cholesterol clearance as the primary macrophage defect driving PAP pathogenesis, and support the feasibility of translating pioglitazone as a novel pharmacotherapy of PAP. PMID- 28860568 TI - Condensation Mechanism of Hydrocarbon Field Formation. AB - Petroleum geology explains how hydrocarbon fluids are generated, but there is a lack of understanding regarding how oil is expelled from source rocks and migrates to a reservoir. To clarify the process, the multi-layer Urengoy field in Western Siberia was investigated. Based on this example, we have identified an alternative mechanism of hydrocarbon field formation, in which oil and gas accumulations result from the phase separation of an upward hydrocarbon flow. There is evidence that the flow is generated by the gases released by secondary kerogen destruction. This study demonstrates that oil components are carried by the gas flow and that when the flow reaches a low-pressure zone, it condenses into a liquid with real oil properties. The transportation of oil components in the gas flow provides a natural explanation for the unresolved issues of petroleum geology concerning the migration process. The condensation mechanism can be considered as the main process of oil field formation. PMID- 28860567 TI - The novel link between planar mobius aromatic and third order nonlinear optical properties of metal-bridged polycyclic complexes. AB - Metal-bridged polcyclic aromatic complexes, exhibiting unusual optical effects such as near-infrared photoluminescence with particularly large Stokes shifts, long lifetimes and aggregation enhancement, have been established as unique "carbonloong chemistry". Herein, the electronic structures, aromaticities, absorption spectra and third order nonlinear optical (NLO) responses of metal bridged polcyclic aromatic complexes (M = Fe, Re, Os and Ir) are investigated using the density functional theory computations. It is found that the bridge head metal can stabilize and influence rings, thus creating pi-, sigma- and metalla-aromaticity in an extended, pi-conjugated framework. Interestingly, metal radius greatly influence the bond, aromaticity, liner and third order NLO properties, which reveals useful information to develop new applications of metal regulatory mechanism in NLO materials field. Significantly, the novel relationship between the aromaticity and third order NLO response has firstly been proposed, that the metal-bridged polycyclic complex with larger aromaticity will exhibit larger third order nonlinear optical response. It is our expectation that the novel link between aromaticity and NLO response could provide valuable information for scientists to develop the potential NLO materials on the basis of metal-bridged polycyclic complexes. PMID- 28860569 TI - An intra-population analysis of the indris' song dissimilarity in the light of genetic distance. AB - The increasing interest in the evolution of human language has led several fields of research to focus on primate vocal communication. The 'singing primates', which produce elaborated and complex sequences of vocalizations, are of particular interest for this topic. Indris (Indri indri) are the only singing lemurs and emit songs whose most distinctive portions are "descending phrases" consisting of 2-5 units. We examined how the structure of the indris' phrases varied with genetic relatedness among individuals. We tested whether the acoustic structure could provide conspecifics with information about individual identity and group membership. When analyzing phrase dissimilarity and genetic distance of both sexes, we found significant results for males but not for females. We found that similarity of male song-phrases correlates with kin in both time and frequency parameters, while, for females, this information is encoded only in the frequency of a single type. Song phrases have consistent individual-specific features, but we did not find any potential for advertising group membership. We emphasize the fact that genetic and social factors may play a role in the acoustic plasticity of female indris. Altogether, these findings open a new perspective for future research on the possibility of vocal production learning in these primates. PMID- 28860571 TI - Understanding stability diagram of perpendicular magnetic tunnel junctions. AB - Perpendicular magnetic tunnel junctions (MTJ) with a bottom pinned reference layer and a composite free layer (FL) are investigated. Different thicknesses of the FL were tested to obtain an optimal balance between tunneling magnetoresistance (TMR) ratio and perpendicular magnetic anisotropy. After annealing at 400 degrees C, the TMR ratio for 1.5 nm thick CoFeB sublayer reached 180% at room temperature and 280% at 20 K with an MgO tunnel barrier thickness corresponding to the resistance area product RA = 10 OhmMUm2. The voltage vs. magnetic field stability diagrams measured in pillar-shaped MTJs with 130 nm diameter indicate the competition between spin transfer torque (STT), voltage controlled magnetic anisotropy (VCMA) and temperature effects in the switching process. An extended stability phase diagram model that takes into account all three effects and the effective damping measured independently using broadband ferromagnetic resonance technique enabled the determination of both STT and VCMA coefficients that are responsible for the FL magnetization switching. PMID- 28860570 TI - CXCL12 overexpression promotes the angiogenesis potential of periodontal ligament stem cells. AB - Periodontal ligament stem cells (PDLSCs) are a major source of mesenchymal stem cells (MSCs) in adults and are effective for tissue engineering, like promoting angiogenesis and bone regeneration. CXCL12 has been reported to be involved in the recruitment and engraftment of MSCs in wound sites. However, whether CXCL12 potentiates the angiogenesis of PDLSCs is not clear. In this experiment, we transduced PDLSCs with CXCL12, and evaluated the angiogenesis potential of CXCL12 modified PDLSCs through in vitro and in vivo studies. The results showed that CXCL12 overexpression significantly stimulated the gene and protein expressions of bFGF, VEGF, SCF and PLGF in PDLSCs; CXCL12 gene modified PDLSCs formed longer capillary-like structure; Moreover, in vivo transplanted PDLSCs transduced with CXCL12 could significantly promote bone tissue repair and angiogenesis in a rat critical-sized calvarial bone defect model. Taken together, our study confirmed that CXCL12 can enhance the angiogenesis potential of PDLSCs, which are crucial in the repair and regeneration of bone tissue. PMID- 28860572 TI - Forming-less and Non-Volatile Resistive Switching in WOX by Oxygen Vacancy Control at Interfaces. AB - Resistive switching devices are recognized as candidates for next-generation memory devices in that they can replace conventional memory devices. In these devices, a WOX film deposited by RF magnetron sputtering with a significant number of oxygen vacancies exhibits a resistive switching property and does not involve the use of a forming process. The resistive switching mechanism involves the hopping of electrons through the sub-band states of the oxygen vacancies in E field-driven electromigration. X-ray photoemission spectroscopy, ultra-violet photoemission spectroscopy, and transmission electron microscopy-electron energy loss spectroscopy were performed to analyze local variations in the O-vacancies and in the electronic band structure of a WOX thin film. The band structure is responsible for the correlation between the motion of the electrons under the interface effect at the electrodes with the change in the resistance and the bias polarity dependence of the I-V property of the device. The optimized metal insulator-metal structure (Pt/WOX/Au), which has an asymmetric electrode and many oxygen vacancies, gives rise to excellent resistive-switching properties with a high on/off ratio on the order of 105 times, a low set voltage of <0.34 V, and a uniform DC cyclic performance in the order of 1500 cycles at room temperature. These specifications can be further adopted for application to non-volatile memory-device applications. PMID- 28860573 TI - Full-field 3D shape measurement of discontinuous specular objects by direct phase measuring deflectometry. AB - ABSTARCT: With the advent of intelligent manufacturing, phase measuring deflectometry (PMD) has been widely studied for the measurement of the three dimensional (3D) shape of specular objects. However, existing PMDs cannot measure objects having discontinuous specular surfaces. This paper presents a new direct PMD (DPMD) method that measures the full-field 3D shape of complicated specular objects. A mathematical model is derived to directly relate an absolute phase map to depth data, instead of the gradient. Two relevant parameters are calibrated using a machine vision-based method. On the basis of the derived model, a full field 3D measuring system was developed. The accuracy of the system was evaluated using a mirror with known positions along an accurate translating stage. The 3D shape of a monolithic multi-mirror array having multiple specular surfaces was measured. Experimental results show that the proposed DPMD method can obtain the full-field 3D shape of specular objects having isolated and/or discontinuous surfaces accurately and effectively. PMID- 28860574 TI - Involvement of mTOR-autophagy in the selection of primitive mesenchymal stem cells in chitosan film 3-dimensional culture. AB - Mesenchymal stem cells (MSCs) in conventional monolayer culture are heterogeneous and contain a significant portion of senescent cells. MSCs cultured on chitosan film form 3-dimenional spheres, increase in stemness and differentiation capability; however, the underlying mechanisms remain elusive. We first demonstrate chitosan film culture induces apoptosis at 2 days, with specificity in late senescent cells. Especially in senescent cells, chitosan film culture activates mTOR, which activates S6K/S6/4E-BP1 to enhance fibronection synthesis and peripheral dead cell attachment, and phosphorylates ULK1 at S757 to further inactivate ULK1, LC3A and autophagy, thereby inducing apoptosis. Combination of chitosan film culture with mTOR inhibition prevents peripheral dead cell attachment, thereby further increasing pluripotent gene expression, in vitro osteogenesis and in vivo bone formation. These data successfully figure out the role of mTOR signaling in chitosan film culture and develop a method by combination of rapamycin treatment for promoting stemness and differentiation capability in MSCs. PMID- 28860575 TI - Towards large-scale in free-standing graphene and N-graphene sheets. AB - One of the greatest challenges in the commercialization of graphene and derivatives is production of high quality material in bulk quantities at low price and in a reproducible manner. The very limited control, or even lack of, over the synthesis process is one of the main problems of conventional approaches. Herein, we present a microwave plasma-enabled scalable route for continuous, large-scale fabrication of free-standing graphene and nitrogen doped graphene sheets. The method's crucial advantage relies on harnessing unique plasma mechanisms to control the material and energy fluxes of the main building units at the atomic scale. By tailoring the high energy density plasma environment and complementarily applying in situ IR and soft UV radiation, a controllable selective synthesis of high quality graphene sheets at 2 mg/min yield with prescribed structural qualities was achieved. Raman spectroscopy, scanning electron microscopy, high resolution transmission electron microscopy, X ray photoelectron spectroscopy and Near Edge X-ray-absorption fine-structure spectroscopy were used to probe the morphological, chemical and microstructural features of the produced material. The method described here is scalable and show a potential for controllable, large-scale fabrication of other graphene derivatives and promotes microwave plasmas as a competitive, green, and cost effective alternative to presently used chemical methods. PMID- 28860576 TI - PD-L1 expression in lung cancer and its correlation with driver mutations: a meta analysis. AB - Although many studies have addressed the prognostic value of programmed cell death-ligand 1 (PD-L1) expression in lung cancer, the results remain controversial. A systematic search of the PubMed, EMBASE, and Cochrane Library databases was performed to identify the correlation between PD-L1 expression and driver mutations and overall survival (OS). This meta-analysis enrolled a total of 11,444 patients for 47 studies, and the pooled results showed that increased PD-L1 expression was associated with poor prognosis (HR = 1.40, 95% CI: 1.19 1.65, P < 0.001). In subgroup analysis stratified according to histology types, the pooled results demonstrated that increased PD-L1 expression was an unfavorable prognostic factor for non-small cell lung cancer (NSCLC) (HR = 1.26, 95% CI: 1.05-1.52, P = 0.01) and pulmonary lymphoepithelioma-like carcinoma (LELC) (HR = 3.04, 95% CI: 1.19-7.77, P = 0.02), rather than small cell lung cancer (SCLC) (HR = 0.62, 95% CI: 0.27-1.39, P = 0.24). The pooled ORs indicated that PD-L1 expression was associated with gender, smoking status, histology, differentiation, tumour size, lymph nodal metastasis, TNM stage and EGFR mutation. However, PD-L1 expression was not correlated with ALK rearrangement and KRAS mutations. PMID- 28860577 TI - Humans with latent toxoplasmosis display altered reward modulation of cognitive control. AB - Latent infection with Toxoplasma gondii has repeatedly been shown to be associated with behavioral changes that are commonly attributed to a presumed increase in dopaminergic signaling. Yet, virtually nothing is known about its effects on dopamine-driven reward processing. We therefore assessed behavior and event-related potentials in individuals with vs. without latent toxoplasmosis performing a rewarded control task. The data show that otherwise healthy young adults with latent toxoplasmosis show a greatly diminished response to monetary rewards as compared to their non-infected counterparts. While this selective effect eliminated a toxoplasmosis-induced speed advantage previously observed for non-rewarded behavior, Toxo-positive subjects could still be demonstrated to be superior to Toxo-negative subjects with respect to response accuracy. Event related potential (ERP) and source localization analyses revealed that this advantage during rewarded behavior was based on increased allocation of processing resources reflected by larger visual late positive component (LPC) amplitudes and associated activity changes in the right temporo-parietal junction (BA40) and left auditory cortex (BA41). Taken together, individuals with latent toxoplasmosis show superior behavioral performance in challenging cognitive control situations but may at the same time have a reduced sensitivity towards motivational effects of rewards, which might be explained by the presumed increase in dopamine. PMID- 28860580 TI - Cancer: Ironing it out. PMID- 28860579 TI - Stable multi-GeV electron accelerator driven by waveform-controlled PW laser pulses. AB - The achievable energy and the stability of accelerated electron beams have been the most critical issues in laser wakefield acceleration. As laser propagation, plasma wave formation and electron acceleration are highly nonlinear processes, the laser wakefield acceleration (LWFA) is extremely sensitive to initial experimental conditions. We propose a simple and elegant waveform control method for the LWFA process to enhance the performance of a laser electron accelerator by applying a fully optical and programmable technique to control the chirp of PW laser pulses. We found sensitive dependence of energy and stability of electron beams on the spectral phase of laser pulses and obtained stable 2-GeV electron beams from a 1-cm gas cell of helium. The waveform control technique for LWFA would prompt practical applications of centimeter-scale GeV-electron accelerators to a compact radiation sources in the x-ray and gamma-ray regions. PMID- 28860581 TI - FDA OKs first in vitro route to expanded approval. PMID- 28860582 TI - Deal watch: IL-2 focus switches to stimulating Tregs. PMID- 28860583 TI - FDA approves first-in-class cancer metabolism drug. PMID- 28860584 TI - FDA rejects first-in-class osteoporosis drug. PMID- 28860585 TI - Biotechnology: CRISPR-Cas becoming more human. PMID- 28860586 TI - Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. PMID- 28860587 TI - Nigel Blackburn. PMID- 28860588 TI - Synthetic lethality screens point the way to new cancer drug targets. PMID- 28860589 TI - Diabetes drug shows promise in Parkinson disease. PMID- 28860590 TI - Distinct clinical features between acute and chronic progressive parenchymal neuro-Behcet disease: meta-analysis. AB - Neuro-Behcet's disease (NBD) is subcategorized into parenchymal-NBD (P-NBD) and non-parenchymal-NBD types. Recently, P-NBD has been further subdivided into acute P-NBD (A-P-NBD) and chronic progressive P-NBD (CP-P-NBD). Although an increasing number of studies have reported the various clinical features of A-P-NBD and CP-P NBD over the last two decades, there was a considerable inconsistency. Two investigators systematically searched four electrical databases to detect studies that provided sufficient data to assess the specific characteristics of A-P-NBD and CP-P-NBD. All meta-analysis was carried out by employing the random-model generic inverse variance method. We included 11 reports consisted of 184 A-P-NBD patients and 114 CP-P-NBD patients. While fever (42% for A-P-NBD, 5% for CP-P NBD, p < 0.001, I2 = 93%) was more frequently observed in A-P-NBD cases; sphincter disturbances (9%, 34%, P = 0.005, I2 = 87%), ataxia (16%, 57%, P < 0.001, I2 = 92%), dementia (7%, 61%, P < 0.001, I2 = 97%), confusion (5%, 18%, P = 0.04, I2 = 76%), brain stem atrophy on MRI (4%, 75%, P < 0.001, I2 = 98%), and abnormal MRI findings in cerebellum (7%, 54%, P = 0.02, I2 = 81%) were more common in CP-P-NBD. Cerebrospinal fluid cell count (94/mm3, 11/mm3, P = 0.009, I2 = 85%) was higher in A-P-NBD cases. We demonstrated that A-P-NBD and CP-P-NBD had clearly different clinical features and believe that these data will help future studies investigating P-NBD. PMID- 28860591 TI - Experimental methods for the Palaeolithic dry distillation of birch bark: implications for the origin and development of Neandertal adhesive technology. AB - The destructive distillation of birch bark to produce tar has recently featured in debates about the technological and cognitive abilities of Neandertals and modern humans. The abilities to precisely control fire temperatures and to manipulate adhesive properties are believed to require advanced mental traits. However, the significance given to adhesive technology in these debates has quickly outgrown our understanding of birch bark tar and its manufacture using aceramic techniques. In this paper, we detail three experimental methods of Palaeolithic tar production ranging from simple to complex. We recorded the fuel, time, materials, temperatures, and tar yield for each method and compared them with the tar known from the Palaeolithic. Our results indicate that it is possible to obtain useful amounts of tar by combining materials and technology already in use by Neandertals. A ceramic container is not required, and temperature control need not be as precise as previously thought. However, Neandertals must have been able to recognize certain material properties, such as adhesive tack and viscosity. In this way, they could develop the technology from producing small traces of tar on partially burned bark to techniques capable of manufacturing quantities of tar equal to those found in the Middle Palaeolithi c archaeological record. PMID- 28860592 TI - Learning performance is linked to procedural memory consolidation across both sleep and wakefulness. AB - We investigated whether learning performance in a procedural finger tapping task before nocturnal sleep would predict performance gains after sleep in 60 young adults. Gains were defined as change in correctly tapped digit sequences between learning (12 trials ad minist er ed in the evening) and retesting (3 trials administere d in the morning after sleep). The same task was also administered to a separate wake group (N = 54 young adults), which learned in the morning and was retested in the evening. Learning performance was determined by either using the average performance on the last three learning trials or the a verage performance on the best three learning trials. Our results demonstrated an inverse association between learning performance and gains in procedural skill, i.e., good learners exhibited smaller performance gains across both wakefulness and sleep than poor learners. Regardless of learning performance, gains in finger tapping skills were greater after sleep than daytime wakefulness. Importantly, some of our findings were influenced by how learning performance was estimated. Collectively, these results suggest that learning performance and the method through which it is estimated may influence performance gains in finger tapping skills across both sleep and wakefulness. PMID- 28860593 TI - Prerequisites for the acquisition of mammalian pathogenicity by influenza A virus with a prototypic avian PB2 gene. AB - The polymerase of avian influenza A virus (AIV) is a heterotrimer composed of PB2, PB1, and PA. PB2 plays a role in overcoming the host barrier; however, the genetic prerequisites for avian PB2 to acquire mammalian pathogenic mutations have not been well elucidated. Previously, we identified a prototypic avian PB2 that conferred non-replicative and non-pathogenic traits to a PR8-derived recombinant virus when it was used to infect mice. Here, we demonstrated that key amino acid mutations (I66M, I109V, and I133V, collectively referred to as MVV) of this prototypic avian PB2 increase the replication efficiency of recombinant PR8 virus carrying the mutated PB2 in both avian and mammalian hosts. The MVV mutations caused no weight loss in mice, but they did allow replication in infected lungs, and the viruses acquired fatal mammalian pathogenic mutations such as Q591R/K, E627K, or D701N in the infected lungs. The MVV mutations are located at the interfaces of the trimer and are predicted to increase the strength of this structure. Thus, gaining MVV mutations might be the first step for AIV to acquire mammalian pathogenicity. These results provide new insights into the evolution of AIV in birds and mammals. PMID- 28860594 TI - SIRT6 promotes osteogenic differentiation of mesenchymal stem cells through BMP signaling. AB - SIRT6 has been identified as an H3K9 deacetylase and a critical regulator of genome stability, telomere integrity, and metabolic homeostasis. Sirt6-deficient mice displayed dramatic phenotypes including profound lymphopenia, loss of subcutaneous fat, lordokyphosis and low bone marrow density. Here, we report that SIRT6 regulates osteogenic differentiation independent of its deacetylase activity in vitro. Further mechanistic studies showed that SIRT6 involves the cell fate determination by modulating bone morphogenetic protein (BMP) signaling. Unexpectedly, this modulation depends upon P300/CBP-associated factor (PCAF). In addition, we observed impaired SIRT6 expression in bone marrow mesenchymal stem cells and in bone sections of ovariectomized mice. Taken together, our present study provide new insights into mechanisms of SIRT6-regulated MSC function beyond its H3K9 deacetylase activity. PMID- 28860595 TI - Intestinal stem cells contribute to the maturation of the neonatal small intestine and colon independently of digestive activity. AB - The murine intestine, like that of other mammalians, continues to develop after birth until weaning; however, whether this occurs in response to an intrinsic developmental program or food intake remains unclear. Here, we report a novel system for the allotransplantation of small intestine and colon harvested from Lgr5 EGFP-IRES-CreERT2/+; Rosa26 rbw/+ mice immediately after birth into the subrenal capsule of wild-type mice. By histological and immunohistochemical analysis, the developmental process of transplanted small intestine and colon was shown to be comparable with that of the native tissues: mature intestines equipped with all cell types were formed, indicating that these organs do not require food intake for development. The intestinal stem cells in transplanted tissues were shown to self-renew and produce progeny, resulting in the descendants of the stem cells occupying the crypt-villus unit of the small intestine or the whole crypt of the colon. Collectively, these findings indicate that neonatal intestine development follows an intrinsic program even in the absence of food stimuli. PMID- 28860596 TI - MAPK1 of Leishmania donovani interacts and phosphorylates HSP70 and HSP90 subunits of foldosome complex. AB - MAP kinases (MAPK) are the most downstream kinases in signal transduction cascades and regulate critical cellular activities such as cell proliferation, differentiation, mortality, stress response, and apoptosis. The Leishmania donovani MAPK1 (LdMAPK1) is involved in parasite viability and drug resistance, but its substrates have not been identified yet. Aiming to identify the possible targets(s) of LdMAPK1, we sought to isolate interacting partners by co immunoprecipitation, gel electrophoresis and mass spectrometry. Out of fifteen analyzed protein bands, four were identified as subunits of the HSP90 foldosome complex, namely HSP 90, HSP70, STI and SGT. Western blot analysis not only confirmed that LdMAPK1 interacts with HSP70 and HSP90 but also demonstrated that MAPK1 abundance modulates their expression. The interaction is sensitive to treatment with AMTZD, a competitive ERK inhibitor. MAPK1 also displayed kinase activity with HSP90 or HSP70 as substrates. By phosphorylating HSPs in the foldosome complex, MAPK1 may regulate the stability and activity of the foldosome which in turn plays a pivotal role in the parasitic life cycle of L. donovani. Our study therefore implicates LdMAPK1 in the post-translational modification and possibly the regulation of heat shock proteins. Conversely, HSP90 and HSP70 are identified as the first substrates of LdMAPK1. PMID- 28860597 TI - Trichel pulse in various gases and the key factor for its formation. AB - We confirm in this paper that Trichel pulse of negative corona is a common phenomenon that can occur in various gases rather than only in electronegative gases as considered in the last 70 years since G W Trichel firstly reported. Trichel pulse is exactly a mode transition between low-current Townsend and high current normal glow regime, two pulseless stages of negative corona with different operating conditions and ion flux threshold. The rising of the pulse corresponds to the breakdown and formation of temporal glow discharge, the decay corresponds to the destroy of temporal sheath, and the interval (or repetition frequency of pulses) is determined by the re-building of the positive ion cloud to enhance significantly the local electric field for glow discharge to form again. The positive ions play a predominant role for the pulse formation and the mode transition, while the negative ions in electronegative gas are not necessary even if they affect greatly the pulsing process. PMID- 28860598 TI - Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin dependent diabetes, optic nerve atrophy and medullary degeneration. AB - Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5 KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1 ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS. PMID- 28860599 TI - Development and validation of a risk prediction model for end-stage renal disease in patients with type 2 diabetes. AB - The aim of this study is to develop a prediction model for ESRD in patients with type 2 diabetes. A retrospective cohort study was conducted, consisting of 24,104 Chinese patients with type 2 diabetes. We adopted the procedures proposed by the Framingham Heart Study to develop a prediction model for ESRD. Participants were randomly assigned to the derivation and validation sets at a 2:1 ratio. The Cox proportional hazard regression model was used for model development. A total of 813 and 402 subjects (5.06% and 5.00%, respectively) developed ESRD in the derivation and validation sets over a mean follow-up period of 8.3 years. The risk-scoring systems included age, gender, age of diabetes onset, combined statuses of blood pressure and anti-hypertensive medication use, creatinine, variation in HbA1c, variation in systolic blood pressure, diabetes retinopathy, albuminuria, anti-diabetes medications, and combined statuses of hyperlipidemia and anti-hyperlipidemia medication use. The area under curves of 3-year, 5-year, and 8-year ESRD risks were 0.90, 0.86, and 0.81 in the derivation set, respectively. This risk score model can be used as screening for early prevention. The risk prediction for 3-year, 5-year, and 8-year period demonstrated good predictive accuracy and discriminatory ability. PMID- 28860600 TI - Cranial biomechanics in basal urodeles: the Siberian salamander (Salamandrella keyserlingii) and its evolutionary and developmental implications. AB - Developmental changes in salamander skulls, before and after metamorphosis, affect the feeding capabilities of these animals. How changes in cranial morphology and tissue properties affect the function of the skull are key to decipher the early evolutionary history of the crown-group of salamanders. Here, 3D cranial biomechanics of the adult Salamandrella keyserlingii were analyzed under different tissue properties and ossification sequences of the cranial skeleton. This helped unravel that: (a) Mechanical properties of tissues (as bone, cartilage or connective tissue) imply a consensus between the stiffness required to perform a function versus the fixation (and displacement) required with the surrounding skeletal elements. (b) Changes on the ossification pattern, producing fontanelles as a result of bone loss or failure to ossify, represent a trend toward simplification potentially helping to distribute stress through the skull, but may also imply a major destabilization of the skull. (c) Bone loss may be originated due to biomechanical optimization and potential reduction of developmental costs. (d) Hynobiids are excellent models for biomechanical reconstruction of extinct early urodeles. PMID- 28860601 TI - CDC42 expression is altered by dioxin exposure and mediated by multilevel regulations via AhR in human neuroblastoma cells. AB - Emerging evidence has shown that dioxin causes dysregulation of microRNAs (miRs) in a variety of tissues or cells. However, little is known about dioxin effects on neuronal miRs expression. In the present study, 277 differentially expressed miRs were identified by miRs microarray analysis in 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD, at 10-10 M) treated SK-N-SH neuroblastoma cells. Among them, 53 miRs exhibited changes of more than 0.4-fold. Consistent with the microarray data, we verified the induction effect of TCDD on hsa-miR-608 expression, which is a primate-specific miR associated with brain functions. Bioinformatics analysis showed involvement of hsa-miR-608 in cytoskeleton organization, in which one of the hsa-miR-608 target genes, Cell Division Cycle 42 (CDC42), might play a role. We also confirmed induction of CDC42 expression by TCDD in SK-N-SH cells. TCDD induced the expression of CDC42 mRNA in hsa-miR-608 inhibitor transfected cells more obviously than in control cells, suggesting involvement of both transcriptional and post-transcriptional mechanisms in the TCDD-induced CDC42 regulation. Furthermore, CH223191, an antagonist of the aryl hydrocarbon receptor (AhR), counteracted TCDD-induced hsa-miR-608 and CDC42 expression. These results indicated that AhR not only mediates transcriptional induction of CDC42, but also hsa-miR-608-induced post-transcriptional regulation of CDC42 in dioxin treated neuroblastoma cells. PMID- 28860603 TI - Response of soil microbial community to application of biochar in cotton soils with different continuous cropping years. AB - The bacterial community in soils of cotton that have continuously been cropped for 2 years, 6 years, 11 years and 14 years and treated with biochar (B0, 0 t.ha 1; B1, 12.5 t.ha-1; and B2, 20 t.ha-1) was investigated using next-generation sequencing. Of the 45 bacterial genera (relative abundance ratio of genera greater than 0.3%), 21 genera were affected (p < 0.05) by the biochar treatment, whereas 20 genera were affected by the continuous cropping. Between the soils that have been continuously cropped for 2 years and 14 years, 12 different genera were significantly observed (p < 0.05), and 6 genera belonged to the phylum Acidobacteria. The relative abundance of Sphingomonas and Pseudomonas in the biochar-treated soils was significantly higher than that in the soil without biochar treatment (p < 0.05), and the relative abundance of Sphingomonas and Pseudomonas in soils that have been continuously cropped for 2 years and 6 years was significantly higher than that in the soils continuously cropped for 11 years and 14 years (p < 0.05). The results suggest that the biochar application has a significant impact on the soil bacterial community, which may improve the microbial diversity of continuous cropping systems in cotton soils. PMID- 28860602 TI - Gene expression analysis of whole blood RNA from pigs infected with low and high pathogenic African swine fever viruses. AB - African swine fever virus (ASFV) is a macrophage-tropic virus responsible for ASF, a transboundary disease that threatens swine production world-wide. Since there are no vaccines available to control ASF after an outbreak, obtaining an understanding of the virus-host interaction is important for developing new intervention strategies. In this study, a whole transcriptomic RNA-Seq method was used to characterize differentially expressed genes in pigs infected with a low pathogenic ASFV isolate, OUR T88/3 (OURT), or the highly pathogenic Georgia 2007/1 (GRG). After infection, pigs infected with OURT showed no or few clinical signs; whereas, GRG produced clinical signs consistent with acute ASF. RNA-Seq detected the expression of ASFV genes from the whole blood of the GRG, but not the OURT pigs, consistent with the pathotypes of these strains and the replication of GRG in circulating monocytes. Even though GRG and OURT possess different pathogenic properties, there was significant overlap in the most upregulated host genes. A small number of differentially expressed microRNAs were also detected in GRG and OURT pigs. These data confirm previous studies describing the response of macrophages and lymphocytes to ASFV infection, as well as reveal unique gene pathways upregulated in response to infection with GRG. PMID- 28860604 TI - Epigenetic Regulation of PLIN 1 in Obese Women and its Relation to Lipolysis. AB - Increased adipocyte lipolysis links obesity to insulin resistance. The lipid droplet coating-protein Perilipin participates in regulation of lipolysis and is implicated in obesity. In the present study we investigate epigenetic regulation of the PLIN1 gene by correlating PLIN1 CpG methylation to gene expression and lipolysis, and functionally evaluating PLIN1 promoter methylation. PLIN1 CpG methylation in adipocytes and gene expression in white adipose tissue (WAT) was quantified in two cohorts by array. Basal lipolysis in WAT explants and adipocytes was quantified by measuring glycerol release. CpG-methylation of the PLIN1 promoter in adipocytes from obese women was higher as compared to never obese women. PLIN1 promoter methylation was inversely correlated with PLIN1 mRNA expression and the lipolytic activity. Human mesenchymal stem cells (hMSCs) differentiated in vitro into adipocytes and harboring methylated PLIN1 promoter displayed decreased reporter gene activity as compared to hMSCs harboring unmethylated promoter. Treatment of hMSCs differentiated in vitro into adipocytes with a DNA methyltransferase inhibitor increased levels of PLIN1 mRNA and protein. In conclusion, the PLIN1 gene is epigenetically regulated and promoter methylation is inversely correlated with basal lipolysis in women suggesting that epigenetic regulation of PLIN1 is important for increased adipocyte lipolysis in insulin resistance states. PMID- 28860605 TI - Proteome-wide acetylation dynamics in human cells. AB - Protein acetylation plays a critical role in biological processes by regulating the functions and properties of proteins. Thus, the study of protein acetylation dynamics is critical for understanding of how this modification influences protein stability, localization, and function. Here we performed a comprehensive characterization of protein acetylation dynamics using mass spectrometry (MS) based proteomics through utilization of 13C-glucose or D3-acetate, which are metabolized into acetyl-coA, labeling acetyl groups through subsequent incorporation into proteins. Samples were collected at eight time points to monitor rates and trends of heavy acetyl incorporation. Through this platform, we characterized around 1,000 sites with significantly increasing acetylation trends, which we clustered based on their rates of acetylation. Faster rates were enriched on proteins associated with chromatin and RNA metabolism, while slower rates were more typical on proteins involved with lipid metabolism. Among others, we identified sites catalyzed at faster rates with potential critical roles in protein activation, including the histone acetyltransferase p300 acetylated in its activation loop, which could explain self-acetylation as an important feedback mechanism to regulate acetyltransferases. Overall, our studies highlight the dynamic nature of protein acetylation, and how metabolism plays a central role in this regulation. PMID- 28860606 TI - Effect of cortisol diurnal rhythm on emotional memory in healthy young adults. AB - Few studies have investigated the relationship between cortisol diurnal rhythm and cognitive function in healthy young adults, especially for emotional memory. To address this deficiency, this study examined the effect of diurnal cortisol slope (DCS) and heart rate variability (HRV) on emotional memory. Participants included healthy volunteers (44 men and 23 women; mean age 20.60 yrs). Participants were shown emotionally arousing slides and were asked to return to the laboratory one week later where they were given a "surprise" memory test to examine their emotional memory retention. Participants were asked to collect saliva samples at four time points (08:00, 11:00, 15:00, and 20:00) on the experimental days; these samples were used to calculate the DCS. Moreover, HRV was measured during the experiment. The multiple linear regression analysis revealed that declarative memory ability, sleep duration, and the DCS were the final significant determinants for emotional memory enhancement (B = -20.41, 0.05, -48.20, ps < 0.05), with participants having flatter cortisol slopes showing reduced or absent emotional memory enhancement. These findings are discussed in reference to the possible effects of diurnal rhythm mechanisms of the hypothalamus-pituitary-adrenal axis and the autonomic nervous system on emotional memory. PMID- 28860607 TI - Myeloperoxidase is not a good biomarker for preeclampsia prediction. AB - Myeloperoxidase is a proinflammatory enzyme found to be increased in patients with established preeclampsia but never investigated before the disease onset. Here we examined myeloperoxidase concentration and activity in plasma and urine samples from pregnant women who remained normotensive throughout pregnancy and those who developed preeclampsia in order to assess its potential to predict this disorder. Our sample consisted of 30 cases who developed preeclampsia (14 severe and 16 mild) and 57 controls who remained healthy throughout pregnancy, derived from the Brazilian Ribeirao Preto and Sao Luis prenatal cohort (BRISA). Myeloperoxidase concentration were assessed using a commercial ELISA kit and enzymatic activity through tetramethylbenzidine oxidation. No statistical differences were found in myeloperoxidase levels nor activity between plasma or urine samples from controls, severe and mild cases. Myeloperoxidase did not seem to have a potential application for preeclampsia prediction. PMID- 28860608 TI - FMISO-PET-derived brain oxygen tension maps: application to glioblastoma and less aggressive gliomas. AB - Quantitative imaging modalities for the analysis of hypoxia in brain tumors are lacking. The objective of this study was to generate absolute maps of tissue ptO2 from [18F]-FMISO images in glioblastoma and less aggressive glioma patients in order to quantitatively assess tumor hypoxia. An ancillary objective was to compare estimated ptO2 values to other biomarkers: perfusion weighted imaging (PWI) and tumor metabolism obtained from 1H-MR mono-voxel spectroscopy (MRS). Ten patients with glioblastoma (GBM) and three patients with less aggressive glioma (nGBM) were enrolled. All patients had [18F]-FMISO and multiparametric MRI (anatomic, PWI, MRS) scans. A non-linear regression was performed to generate ptO2 maps based on normal appearing gray (NAGM) and white matter (NAWM) for each patient. As expected, a marked [18F]-FMISO uptake was observed in GBM patients. The ptO2 based on patient specific calculations was notably low in this group (4.8 +/- 1.9 mmHg, p < 0.001) compared to all other groups (nGBM, NAGM and NAWM). The rCBV was increased in GBM (1.4 +/- 0.2 when compared to nGBM tumors 0.8 +/- 0.4). Lactate (and lipid) concentration increased in GBM (27.8 +/- 13.8%) relative to nGBM (p < 0.01). Linear, nonlinear and ROC curve analyses between ptO2 maps, PWI-derived rCBV maps and MRS-derived lipid and lactate concentration strengthens the robustness of our approaches. PMID- 28860609 TI - A promising azeotrope-like mosquito repellent blend. AB - Topical repellents play a key role in reducing the outdoor transmission of mosquito-borne diseases by reducing human-vector contact. Excellent repellents are available, but there is always room for improvement. This article reports on a particularly effective binary repellent blend of ethyl butylacetylaminopropionate and nonanoic acid. A composition containing 25 mol% of the acid exhibits negative pseudo-azeotrope behaviour at 50 degrees C, meaning that the liquid vapour pressure is lower than that of the parent compounds and evaporation occurs without a change in the liquid composition. In tests performed using the South African Medical Research Council's cup-on-arm procedure, this mixture provided better protection for a longer time than the "gold standard of mosquito repellents", namely N,N-diethyl-m-toluamide, commonly known as DEET. PMID- 28860610 TI - Association of leukocyte telomere length and the risk of age-related hearing impairment in Chinese Hans. AB - Age-related hearing loss (ARHI) is the most common sensory disorder in the elderly. Although telomere attrition has been shown as a determinant in the pathobiology of various age-related diseases, it remains unknown whether telomere length is associated with ARHI. We hypothesized that decreased leukocyte telomere length (LTL) increased the risk of ARHI. Thus, we measured LTL of 666 ARHI and 43 controls by an established quantitative PCR technique. Four audiogram shape subtypes of ARHI, including "flat shape (FL)", "2-4 kHz abrupt loss (AL) shape", "8 kHz dip (8D) shape" and "sloping shape (SL)" could be identified among the cases using K-means cluster analysis. Longer LTL was associated with the reduced incidence of ARHI (adjusted OR = 0.550, 95% CI: 0.420-0.721, P < 0.0001 for all the ARHI; 0.498, 0.318-0.780, P = 0.0023 for FL subgroup; 0.428, 0.292-0.628, P < 0.0001 for AL subgroup; 0.552, 0.399-0.764, P = 0.0003 for mSL subgroup). Subjects in the highest tertile of LTL were at less risk for ARHI than those in the lowest and middle tertiles (OR for ARHI: 0.327, 95% CI 0.170-0.629, P = 0.0008). There was a descending trend of LTL as the degree of pure tone threshold average (PTA) aggravated. These results suggest that telomere attrition may be involved in the progression of ARHI. PMID- 28860611 TI - Impact of Immunosuppression on the Metagenomic Composition of the Intestinal Microbiome: a Systems Biology Approach to Post-Transplant Diabetes. AB - Solid organ transplantation (SOT) outcomes have continued to improve, although long-term use of immunosuppressants can lead to complications such as diabetes, compromising post-transplant outcomes. In this study, we have characterized the intestinal microbiome (IM) composition at the metagenomic level in the context of hyperglycemia induced by immunosuppressants. Sprague-Dawley rats were subjected to doses of tacrolimus and sirolimus that reliably induce hyperglycemia and an insulin-resistant state. Subsequent exposure to probiotics resulted in reversal of hyperglycemia. 16S rRNA and metagenomic sequencing of stool were done to identify the bacterial genes and pathways enriched in immunosuppression. Bacterial diversity was significantly decreased in sirolimus-treated rats, with 9 taxa significantly less present in both immunosuppression groups: Roseburia, Oscillospira, Mollicutes, Rothia, Micrococcaceae, Actinomycetales and Staphylococcus. Following probiotics, these changes were reversed to baseline. At the metagenomic level, the balance of metabolism was shifted towards the catabolic side with an increase of genes involved in sucrose degradation, similar to diabetes. Conversely, the control rats had greater abundance of anabolic processes and genes involved in starch degradation. Immunosuppression leads to a more catabolic microbial profile, which may influence development of diabetes after SOT. Modulation of the microbiome with probiotics may help in minimizing adverse long-term effects of immunosuppression. PMID- 28860612 TI - Unraveling variations of crystalline cellulose induced by ionic liquid and their effects on enzymatic hydrolysis. AB - Ionic liquid (IL) is one of the pretreatment processes gaining considerable interests to remove the native recalcitrance of lignocellulose. But the cellulose crystalline transformation during the pretreatment and their correlations with enzymatic digestibility have not been fully elucidated. Microcrystalline cellulose (Avicel) and holocellulose, which have differential sources and original crystallinity, were respectively pretreated with 1-butyl-3 methylimidazolium chloride ([C4min]Cl). Cellulose crystalline variations as well as chemical and morphological changes were determined. Crystallinity of different materials was proved to influence the effects of pretreatment and following enzymatic digestibility. Recrystallized cellulose Ibeta was revealed from slight initial cellulose Ialpha of Avicel, which was accomplished via formation of intermediate paracrystalline phases. The conversion yield of IL pretreated Avicel displayed no obvious changes, mainly resulted from initial high crystalline order and the recrystallization behavior. Recalcitrance of holocellulose was destroyed during cellulose allomorph transformation and hemicelluloses extraction, contributing to significant increase of glucose yield up to 92.20%. Explicit comprehension on cellulose supramolecular structure may help provide more efficient process for bioconversion after IL pretreatment. PMID- 28860613 TI - The stem cell regulator PEDF is dispensable for maintenance and function of hematopoietic stem cells. AB - Pigment epithelium derived factor (PEDF), a ubiquitously expressed 50 kDa secreted glycoprotein, was recently discovered to regulate self-renewal of neural stem cells and have a supportive effect on human embryonic stem cell growth. Here, we analyzed expression of PEDF in the murine hematopoietic stem cell (HSC) compartments and found that PEDF is highly expressed in primary long-term HSCs. Therefore, we characterized the hematopoietic system in a knockout mouse model for PEDF and using this model we surprisingly found that PEDF is dispensable for HSC regulation. PEDF knockout mice exhibit normal hematopoiesis in steady state conditions and the absence of PEDF lead to normal regeneration capacity in a serial competitive transplantation setting. Additionally, PEDF-deficient cells exhibit unaltered lineage distribution upon serial transplantations. When human cord blood stem and progenitor cells were cultured in media supplemented with recombinant PEDF they did not show changes in growth potential. Taken together, we report that PEDF is not a critical regulatory factor for HSC function during regeneration in vivo or growth of human stem/progenitor cells in vitro. PMID- 28860614 TI - Efficient laser-driven proton acceleration from cylindrical and planar cryogenic hydrogen jets. AB - We report on recent experimental results deploying a continuous cryogenic hydrogen jet as a debris-free, renewable laser-driven source of pure proton beams generated at the 150 TW ultrashort pulse laser Draco. Efficient proton acceleration reaching cut-off energies of up to 20 MeV with particle numbers exceeding 109 particles per MeV per steradian is demonstrated, showing for the first time that the acceleration performance is comparable to solid foil targets with thicknesses in the micrometer range. Two different target geometries are presented and their proton beam deliverance characterized: cylindrical (? 5 MUm) and planar (20 MUm * 2 MUm). In both cases typical Target Normal Sheath Acceleration emission patterns with exponential proton energy spectra are detected. Significantly higher proton numbers in laser-forward direction are observed when deploying the planar jet as compared to the cylindrical jet case. This is confirmed by two-dimensional Particle-in-Cell (2D3V PIC) simulations, which demonstrate that the planar jet proves favorable as its geometry leads to more optimized acceleration conditions. PMID- 28860615 TI - Aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis. AB - The deletion of microsomal prostaglandin E synthase-2 (mPGES-2) does not affect in vivo PGE2 production, and the function of this enzyme remains unknown until now. This study investigated the expression and roles of mPGES-2 in LPS induced acute kidney injury (AKI) both in vitro and in vivo. We found that mPGES-2 was up regulated in kidney of mice with LPS induced AKI. Inhibition of mouse mpges2 gene expression exacerbated LPS-induced renal dysfunction, renal tubular cell damage and apoptosis, while inhibited kidney autophagy. Further cellular experiments showed that over-expression of mPGES-2 resulted in increased autophagy and decreased apoptosis rate of renal tubular epithelial cells. In addition, treatment with autophagy inhibitor 3-methyladenine could reverse the above mentioned results. On the contrary, interference of mPGES-2 expression by siRNA decreased autophagy level but significantly increased apoptosis of tubular epithelial cells and treatment with autophagy inducer rapamycin can reverse these results. Overall, our study shows that mPGES-2 can protect renal tubular epithelial cells by regulating autophagy levels and aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis. PMID- 28860616 TI - Schisandrin B regulates lipid metabolism in subcutaneous adipocytes. AB - Subcutaneous adipocytes in obese subjects have a lower sensitivity to catecholamine-induced lipolysis and a higher sensitivity to insulin anti lipolytic effects compared to adipocytes in other adipose depots. Therefore, increasing lipolysis in subcutaneous adipocytes coupled with enhanced fatty acid oxidation may be an anti-obesity strategy. Schisandrin B (Sch B) is one of the most abundant active dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis which is a commonly prescribed Chinese medicinal herb. We found that Sch B reduced glycerolipid contents in 3T3-L1 adipocytes and subcutaneous adipocytes dissected from DIO mice. Sch B also activated hormone sensitive lipase (HSL) and increased lipolysis in these adipocyte in a protein kinase A-dependent manner. Interestingly, Sch B increased fatty acid oxidation gene expressions in these adipocytes, implying an increase in fatty acid oxidation after treatment. In in vivo model, we found that Sch B increased HSL phosphorylation, reduced glycerolipid levels and increased fatty acid oxidation gene expressions in the subcutaneous adipocytes in the DIO mice. More importantly, Sch B significantly reduced the subcutaneous adipocyte sizes, subcutaneous adipose tissue mass and body weight of the mice. Our study provides scientific evidence to suggest a potential therapeutic function of Sch B or Schisandra chinensis seed containing Sch B in reducing obesity. PMID- 28860617 TI - Fin whale song variability in southern California and the Gulf of California. AB - Songs are distinct, patterned sounds produced by a variety of animals including baleen whales. Fin whale songs, which consist of short pulses repeated at regular interpulse intervals (IPIs), have been suggested as a tool to distinguish populations. Fin whale songs were analyzed from data collected from 2000-2012 in Southern California and from 2004-2010 in the Gulf of California using autonomous acoustic recorders. IPIs were measured for each identifiable song sequence during two random days of each month with recordings. Four distinct song types were identified: long doublet, short doublet, long triplet, and short triplet. Long and short doublets were the dominant songs in Southern California, while long and short triplets were dominant in the Gulf of California. An abrupt change in song type occurred in both areas during the monitoring period. We argue that each song type is unique to a population and these changes represent a shift in the primary population in the monitoring area. Occasional temporal and spatial song overlap indicated some exchange or visitation among populations. Fin whales appear to synchronize and gradually modify song rhythm over long time scales. A better understanding of the evolutionary and ecological importance of songs to fin whale populations is needed. PMID- 28860618 TI - Interferon-gamma regulates inflammatory cell death by targeting necroptosis in experimental autoimmune arthritis. AB - Interferon gamma (IFN-gamma) induces an inflammatory response and apoptotic cell death. Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with increased levels of inflammatory mediators, including tumour necrosis factor alpha (TNF-alpha) and T helper (Th) 17 cells, and downregulation of apoptosis of inflammatory cells. We hypothesized that IFN-gamma would reduce inflammatory cell death in vitro and that loss of IFN-gamma would aggravate inflammation in vivo. IFN-gamma downregulated necroptosis and the expression of cellular FLICE-like inhibitory protein (cFLIPL) and mixed lineage kinase domain-like (MLKL). However, loss of IFN-gamma promoted the production of cFLIPL and MLKL, and necroptosis. IFN-gamma deficiency increased Th17 cell number and upregulated the expression of IL-17 and TNF-alpha. Expression of MLKL, receptor interacting protein kinase (RIPK)1, and RIPK3 was increased in the joints of mice with collagen-induced arthritis (CIA). Compared with wild-type mice with CIA, IFN-gamma-/- CIA mice showed exacerbation of cartilage damage and joint inflammation, and acceleration of MLKL, RIPK1, and RIPK3 production in the joints. IFN-gamma deficiency induced the activation of signal transducer and activator of transcription 3. These results suggest that IFN-gamma regulates inflammatory cell death and may have potential for use in the treatment of RA. PMID- 28860619 TI - Microcystis aeruginosa strengthens the advantage of Daphnia similoides in competition with Moina micrura. AB - Microcystis blooms are generally associated with zooplankton shifts by disturbing interspecific relationships. The influence of Microcystis on competitive dominance by different sized zooplanktons showed species-specific dependence. We evaluated the competitive responses of small Moina micrura and large Daphnia similoides to the presence of Microcystis using mixed diets comprising 0%, 20%, and 35% of toxic M. aeruginosa, and the rest of green alga Chlorella pyrenoidosa. No competitive exclusion occurred for the two species under the tested diet combinations. In the absence of M. aeruginosa, the biomasses of the two cladocerans were decreased by the competition between them. However, the Daphnia was less inhibited with the higher biomass, suggesting the competitive dominance of Daphnia. M. aeruginosa treatment suppressed the population growths of the two cladocerans, with the reduced carrying capacities. Nonetheless, the population inhibition of Daphnia by competition was alleviated by the increased Microcystis proportion in diet. As a result, the competitive advantage of Daphnia became more pronounced, as indicated by the higher Daphnia: Moina biomass ratio with increased Microcystis proportions. These results suggested that M. aeruginosa strengthens the advantage of D. similoides in competition with M. micrura, which contributes to the diversified zooplankton shifts observed in fields during cyanobacteria blooms. PMID- 28860620 TI - Mind wandering simultaneously prolongs reactions and promotes creative incubation. AB - Mind wandering (MW) refers to the disengagement of attention from the external environment and the generation of thoughts unrelated to the task at hand. It is a ubiquitous cognitive process resulting in lapses of attention. MW imposes a negative impact on attention-based task performance, but also has been associated with enhanced creativity and future planning. In three experiments we show that MW relates simultaneously to both behavioral costs but also benefits. Behavioral costs were measured by prolonged reaction times (RT) in sustained attention to response tasks (SART), whereas the benefits were observed as improved performance in the creative problem solving and daily routine planning tasks performed after the SART. Additionally, we found an increased dispersion of RTs during MW suggesting that attention during these times underwent dynamical changes compared to states when participants were fully focused on the task. Our results support a model in which MW deteriorates performance in the task at hand and is related to dynamical changes in attention. At the same time it is also able to improve human capacity for complex operations. PMID- 28860621 TI - Inert Gas Deactivates Protein Activity by Aggregation. AB - Biologically inert gases play important roles in the biological functionality of proteins. However, researchers lack a full understanding of the effects of these gases since they are very chemically stable only weakly absorbed by biological tissues. By combining X-ray fluorescence, particle sizing and molecular dynamics (MD) simulations, this work shows that the aggregation of these inert gases near the hydrophobic active cavity of pepsin should lead to protein deactivation. Micro X-ray fluorescence spectra show that a pepsin solution can contain a high concentration of Xe or Kr after gassing, and that the gas concentrations decrease quickly with degassing time. Biological activity experiments indicate a reversible deactivation of the protein during this gassing and degassing. Meanwhile, the nanoparticle size measurements reveal a higher number of "nanoparticles" in gas-containing pepsin solution, also supporting the possible interaction between inert gases and the protein. Further, MD simulations indicate that gas molecules can aggregate into a tiny bubble shape near the hydrophobic active cavity of pepsin, suggesting a mechanism for reducing their biological function. PMID- 28860622 TI - LSD1 modulates the non-canonical integrin beta3 signaling pathway in non-small cell lung carcinoma cells. AB - The epigenetic writer lysine-specific demethylase 1 (LSD1) is aberrantly upregulated in many cancer types and its overexpression correlates with poor survival and tumor progression. In this study, we analysed LSD1 function in non small cell lung cancer adenocarcinomas. Expression profiling of 182 cases of lung adenocarcinoma proved a significant correlation of LSD1 overexpression with lung adenocarcinoma progression and metastasis. KRAS-mutated lung cancer cell clones were stably silenced for LSD1 expression. RNA-seq and comprehensive pathway analysis revealed, that genes related to a recently described non-canonical integrin beta3 pathway, were significantly downregulated by LSD1 silencing. Hence, invasion and self-renewal capabilities were strongly decreased. Notably, this novel defined LSD1/integrin beta3 axis, was also detected in human lung adenocarcinoma specimens. Furthermore, the linkage of LSD1 to an altered expression pattern of lung-lineage specific transcription factors and genes, which are involved in alveolar epithelial differentiation, was demonstrated. Thus, our findings point to a LSD1-integrin beta3 axis, conferring attributes of invasiveness and tumor progression to lung adenocarcinoma. PMID- 28860624 TI - Surface frontogenesis by surface heat fluxes in the upstream Kuroshio Extension region. AB - Western boundary currents bring warm tropical water poleward and eastward and are characterized by a sharp sea surface temperature (SST) front on the poleward edge of the current as it extends into the interior basin. One of the most prominent such front is associated with the Kuroshio Extension (KE) as it extends east of Japan ("upstream KE"). Large latent and sensible heat fluxes that warm the atmosphere and cool the ocean project this front into the atmosphere, thereby affecting weather and climate both locally and remotely. While one might assume that these larger surface heat fluxes on the equatorward side would tend to damp the SST front, here we present observational evidence that the surface heat loss actually strengthens the front during October-April in monthly climatology and about 87% of months from October to January during the 2004/05-2014/15 period, although the percentage lowers to about 38% for February-April of the same period, suggesting some temporal/data dependency in the analysis. The key to understanding this counterintuitive result for frontogenesis is that the effective heat capacity of the surface water depends on mixed layer thickness. SSTs are more (less) sensitive to surface heat fluxes in regions with shallow (deep) mixed layer. PMID- 28860623 TI - Structural and Functional View of Polypharmacology. AB - Protein domains mediate drug-protein interactions and this principle can guide the design of multi-target drugs i.e. polypharmacology. In this study, we associate multi-target drugs with CATH functional families through the overrepresentation of targets of those drugs in CATH functional families. Thus, we identify CATH functional families that are currently enriched in drugs (druggable CATH functional families) and we use the network properties of these druggable protein families to analyse their association with drug side effects. Analysis of selected druggable CATH functional families, enriched in drug targets, show that relatives exhibit highly conserved drug binding sites. Furthermore, relatives within druggable CATH functional families occupy central positions in a human protein functional network, cluster together forming network neighbourhoods and are less likely to be within proteins associated with drug side effects. Our results demonstrate that CATH functional families can be used to identify drug-target interactions, opening a new research direction in target identification. PMID- 28860625 TI - Detection of dynamic substrate binding using MRI. AB - Magnetic Resonance Imaging (MRI) is rarely used for molecular binding studies and never without synthetic metallic labels. We designed an MRI approach that can specifically detect the binding of natural substrates (i.e. no chemical labels). To accomplish such detection of substrate-target interaction only, we exploit (i) the narrow resonance of aliphatic protons in free substrate for selective radio frequency (RF) labeling and, (ii) the process of immobilisation upon binding to a solid-like target for fast magnetic transfer of this label over protons in the target backbone. This cascade of events is ultimately detected with MRI using magnetic interaction between target and water protons. We prove this principle using caffeine as a substrate in vitro and then apply it in vivo in the mouse brain. The combined effects of continuous labeling (label pumping), dynamic reversible binding, and water detection was found to enhance the detection sensitivity by about two to three orders of magnitude. PMID- 28860627 TI - Reducing the Dispersion of Periodic Structures with Twist and Polar Glide Symmetries. AB - In this article, a number of guiding structures are proposed which take advantage of higher symmetries to vastly reduce the dispersion. These higher symmetries are obtained by executing additional geometrical operations to introduce more than one period into the unit cell of a periodic structure. The specific symmetry operations employed here are a combination of p-fold twist and polar glide. Our dispersion analysis shows that a mode in a structure possessing higher symmetries is less dispersive than in a conventional structure. It is also demonstrated that, similar to the previously studied Cartesian glide-symmetric structures, polar glide-symmetric structures also exhibit a frequency independent response. Promising applications of these structures are leaky-wave antennas which utilize the low frequency dependence. PMID- 28860626 TI - Topological N-glycosylation and site-specific N-glycan sulfation of influenza proteins in the highly expressed H1N1 candidate vaccines. AB - The outbreak of a pandemic influenza H1N1 in 2009 required the rapid generation of high-yielding vaccines against the A/California/7/2009 virus, which were achieved by either addition or deletion of a glycosylation site in the influenza proteins hemagglutinin and neuraminidase. In this report, we have systematically evaluated the glycan composition, structural distribution and topology of glycosylation for two high-yield candidate reassortant vaccines (NIBRG-121xp and NYMC-X181A) by combining various enzymatic digestions with high performance liquid chromatography and multiple-stage mass spectrometry. Proteomic data analyses of the full-length protein sequences determined 9 N-glycosylation sites of hemagglutinin, and defined 6 N-glycosylation sites and the glycan structures of low abundance neuraminidase, which were occupied by high-mannose, hybrid and complex-type N-glycans. A total of ~300 glycopeptides were analyzed and manually validated by tandem mass spectrometry. The specific N-glycan structure and topological location of these N-glycans are highly correlated to the spatial protein structure and the residential ligand binding. Interestingly, sulfation, fucosylation and bisecting N-acetylglucosamine of N-glycans were also reliably identified at the specific glycosylation sites of the two influenza proteins that may serve a crucial role in regulating the protein structure and increasing the protein abundance of the influenza virus reassortants. PMID- 28860628 TI - Radiomics strategies for risk assessment of tumour failure in head-and-neck cancer. AB - Quantitative extraction of high-dimensional mineable data from medical images is a process known as radiomics. Radiomics is foreseen as an essential prognostic tool for cancer risk assessment and the quantification of intratumoural heterogeneity. In this work, 1615 radiomic features (quantifying tumour image intensity, shape, texture) extracted from pre-treatment FDG-PET and CT images of 300 patients from four different cohorts were analyzed for the risk assessment of locoregional recurrences (LR) and distant metastases (DM) in head-and-neck cancer. Prediction models combining radiomic and clinical variables were constructed via random forests and imbalance-adjustment strategies using two of the four cohorts. Independent validation of the prediction and prognostic performance of the models was carried out on the other two cohorts (LR: AUC = 0.69 and CI = 0.67; DM: AUC = 0.86 and CI = 0.88). Furthermore, the results obtained via Kaplan-Meier analysis demonstrated the potential of radiomics for assessing the risk of specific tumour outcomes using multiple stratification groups. This could have important clinical impact, notably by allowing for a better personalization of chemo-radiation treatments for head-and-neck cancer patients from different risk groups. PMID- 28860629 TI - WS2 and MoS2 biosensing platforms using peptides as probe biomolecules. AB - Biosensors based on the two-dimensional layered nanomaterials transition metal dichalcogenides such as WS2 and MoS2 have shown broad applications, while they largely rely on the utilization of single stranded DNA as probe biomolecules. Herein we have constructed novel WS2- and MoS2- based biosensing platforms using peptides as probe biomolecules. We have revealed for the first time that the WS2 and MoS2 nanosheets display a distinct adsorption for Arg amino acid and particularly, Arg-rich peptdies. We have demonstrated that the WS2 and MoS2 dramatically quench the fluorescence of our constructed Arg-rich probe peptide, while the hybridization of the probe peptide with its target collagen sequence leads to the fluorescence recovery. The WS2-based platform provides a sensitive fluorescence-enhanced assay that is highly specific to the target collagen peptide with little interferences from other proteins. This assay can be applied for quantitative detection of collagen biomarkers in complex biological fluids. The successful development of WS2- and MoS2- based biosensors using non-ssDNA probes opens great opportunities for the construction of novel multifunctional biosensing platforms, which may have great potential in a wide range of biomedical field. PMID- 28860630 TI - An oxytocin-dependent social interaction between larvae and adult C. elegans. AB - Oxytocin has a conserved role in regulating animal social behaviour including parental-offspring interactions. Recently an oxytocin-like neuropeptide, nematocin, and its cognate receptors have been identified in the nematode Caenorhabditis elegans. We provide evidence for a pheromone signal produced by C. elegans larvae that modifies the behaviour of adult animals in an oxytocin dependent manner increasing their probability of leaving a food patch which the larvae are populating. This increase is positively correlated to the size of the larval population but cannot be explained by food depletion nor is it modulated by biogenic amines, which suggest it is not an aversive behaviour. Moreover, the food-leaving behaviour is conspecific and pheromone dependent: C. elegans adults respond more strongly to C. elegans larvae compared to other nematode species and this effect is absent in C. elegans daf-22 larvae which are pheromone deficient. Neurotransmitter receptors previously implicated in C. elegans foraging decisions NPR-1 and TYRA-3, for NPY-like neuropeptides and tyramine respectively, do not appear to be involved in oxytocin-dependent adult food-leaving. We conclude oxytocin signals within a novel neural circuit that regulates parental-offspring social behaviour in C. elegans and that this provides evidence for evolutionary conservation of molecular components of a parental decision making behaviour. PMID- 28860631 TI - Evidence for rangewide panmixia despite multiple barriers to dispersal in a marine mussel. AB - Oceanographic features shape the distributional and genetic patterns of marine species by interrupting or promoting connections among populations. Although general patterns commonly arise, distributional ranges and genetic structure are species-specific and do not always comply with the expected trends. By applying a multimarker genetic approach combined with Lagrangian particle simulations (LPS) we tested the hypothesis that oceanographic features along northeastern Atlantic and Mediterranean shores influence dispersal potential and genetic structure of the intertidal mussel Perna perna. Additionally, by performing environmental niche modelling we assessed the potential and realized niche of P. perna along its entire native distributional range and the environmental factors that best explain its realized distribution. Perna perna showed evidence of panmixia across >4,000 km despite several oceanographic breaking points detected by LPS. This is probably the result of a combination of life history traits, continuous habitat availability and stepping-stone dynamics. Moreover, the niche modelling framework depicted minimum sea surface temperatures (SST) as the major factor shaping P. perna distributional range limits along its native areas. Forthcoming warming SST is expected to further change these limits and allow the species to expand its range polewards though this may be accompanied by retreat from warmer areas. PMID- 28860632 TI - Modelling viscoacoustic wave propagation with the lattice Boltzmann method. AB - In this paper, the lattice Boltzmann method (LBM) is employed to simulate wave propagation in viscous media. LBM is a kind of microscopic method for modelling waves through tracking the evolution states of a large number of discrete particles. By choosing different relaxation times in LBM experiments and using spectrum ratio method, we can reveal the relationship between the quality factor Q and the parameter tau in LBM. A two-dimensional (2D) homogeneous model and a two-layered model are tested in the numerical experiments, and the LBM results are compared against the reference solution of the viscoacoustic equations based on the Kelvin-Voigt model calculated by finite difference method (FDM). The wavefields and amplitude spectra obtained by LBM coincide with those by FDM, which demonstrates the capability of the LBM with one relaxation time. The new scheme is relatively simple and efficient to implement compared with the traditional lattice methods. In addition, through a mass of experiments, we find that the relaxation time of LBM has a quantitative relationship with Q. Such a novel scheme offers an alternative forward modelling kernel for seismic inversion and a new model to describe the underground media. PMID- 28860633 TI - A CDC42-centered signaling unit is a dominant positive regulator of endothelial integrity. AB - Endothelial barrier function is carefully controlled to protect tissues from edema and damage inflicted by extravasated leukocytes. RhoGTPases, in conjunction with myriad regulatory proteins, exert both positive and negative effects on the endothelial barrier integrity. Precise knowledge about the relevant mechanisms is currently fragmented and we therefore performed a comprehensive analysis of endothelial barrier regulation by RhoGTPases and their regulators. Combining RNAi with electrical impedance measurements we quantified the relevance of 270 Rho associated genes for endothelial barrier function. Statistical analysis identified 10 targets of which six promoted- and four reduced endothelial barrier function upon downregulation. We analyzed in more detail two of these which were not previously identified as regulators of endothelial integrity. We found that the Rac1-GEF (Guanine nucleotide Exchange Factor) TIAM2 is a positive regulator and the Cdc42(Rac1)-GAP (GTPase-Activating Protein) SYDE1 is a negative regulator of the endothelial barrier function. Finally, we found that the GAP SYDE1 is part of a Cdc42-centered signaling unit, also comprising the Cdc42-GEF FARP1 and the Cdc42 effector PAK7 which controls the integrity of the endothelial barrier. In conclusion, using a siRNA-based screen, we identified new regulators of barrier function and found that Cdc42 is a dominant positive regulator of endothelial integrity. PMID- 28860635 TI - The Molecular Dynamics Study of Vacancy Formation During Solidification of Pure Metals. AB - In order to understand the defect trapping during solidification in pure elements, we have performed molecular dynamics simulations on both aluminum and nickel. We find that vacancies are the dominant defects in the product crystals for both metals. For slight undercooling, the vacancy concentration strongly depends on the growth velocity, rather than the growth orientations, and there is an approximately linear relationship between the growth velocity and vacancy concentration. However, for deep undercooling, the vacancy concentration shows a remarkable anisotropy between (100) and (110) orientations. Based on the competition between atomic diffusion and growth, a possible mechanism for vacancy trapping is suggested. PMID- 28860634 TI - Deficiency of TLR4 homologue RP105 aggravates outward remodeling in a murine model of arteriovenous fistula failure. AB - Arteriovenous access dysfunction is a major cause of morbidity for hemodialysis patients. The pathophysiology of arteriovenous fistula (AVF) maturation failure is associated with inflammation, impaired outward remodeling (OR) and intimal hyperplasia. RP105 is a critical physiologic regulator of TLR4 signaling in numerous cell types. In the present study, we investigated the impact of RP105 on AVF maturation, and defined cell-specific effects of RP105 on macrophages and vascular smooth muscle cells (VSMCs). Overall, RP105-/- mice displayed a 26% decrease in venous OR. The inflammatory response in RP105-/- mice was characterized by accumulation of anti-inflammatory macrophages, a 76% decrease in pro- inflammatory macrophages, a 70% reduction in T-cells and a 50% decrease in MMP-activity. In vitro, anti-inflammatory macrophages from RP105-/- mice displayed increased IL10 production, while MCP1 and IL6 levels secreted by pro inflammatory macrophages were elevated. VSMC content in RP105-/- AVFs was markedly decreased. In vitro, RP105-/- venous VSMCs proliferation was 50% lower, whereas arterial VSMCs displayed a 50% decrease in migration, relative to WT. In conclusion, the impaired venous OR in RP105-/- mice could result from of a shift in both macrophages and VSMCs towards a regenerative phenotype, identifying a novel relationship between inflammation and VSMC function in AVF maturation. PMID- 28860636 TI - Air stable black phosphorous in polyaniline-based nanocomposite. AB - The greatest challenge regarding black phosphorus (BP) comes as a result of its fast degradation when exposed to ambient conditions, which has overshadowed its applications. Herein, we report a simple and efficient route towards overcoming BP deterioration by preparing a nanocomposite with the conducting polymer polyaniline (PANI). The liquid/liquid interfacial method was employed to produce transparent, freestanding and transferable thin film of BP covered by PANI, with high stability under ambient atmosphere, up to 60 days. Otherwise, the uncapped exfoliated neat BP degraded in solely 3 days under the same conditions. Characterization data show that PANI covers efficiently the BP flakes, indicating favorable interactions between the components. The results presented here can be considered a breakthrough for employing BP as thin film in different technological applications, considering the properties of BP itself or taking advantage of synergistically combining the properties of both components. PMID- 28860637 TI - Self-induction system for cellulase production by cellobiose produced from glucose in Rhizopus stolonifer. AB - Cellulolytic fungi have evolved a sophisticated genetic regulatory network of cellulase synthesis to adapt to the natural environment. Even in the absence of lignocellulose, it still secretes low levels of "constitutive" cellulase for standby application. However, the mechanisms of this constitutive expression remain incompletely understood. Here we identified a cellobiose synthetase (CBS) from Rhizopus stolonifer, which has the capacity to catalyse the synthesis of cellobiose from uridine diphosphate glucose (UDPG). Through the construction of R. stolonifer Deltacbs strain, we found that CBS plays a key role in the synthesis of cellulase. Further analysis of cellulase synthesis under glucose culture reveals that the cellobiose-responsive regulator CLR1 was activated by CBS-synthesized cellobiose, thereby promoting the expression of CLR2 and finally opening the transcription of cellulase genes. Our results suggest that R. stolonifer can be induced by self-synthesized cellobiose to produce cellulase, which can be used to reconstruct the expression regulation network to achieve rapid production of cellulase using simple carbon source. Based on our data, the "constitutive expression" of cellulase actually derives from the induction of cellobiose that synthesized by CBS from carbohydrate metabolites, which updates our knowledge of cellulase, and provides a novel insight into the regulation of cellulase synthesis. PMID- 28860638 TI - Age-related processing delay reveals cause of apparent sensory excitability following auditory stimulation. AB - When background auditory events lead to enhanced auditory event-related potentials (ERPs) for closely following sounds, this is generally interpreted as a transient increase in the responsiveness of the auditory system. We measured ERPs elicited by irrelevant probes (gaps in a continuous tone) at several time points following rare auditory events (pitch glides) in younger and older adults, who watched movies during stimulation. Fitting previous results, in younger adults, gaps elicited increasing N1 auditory ERPs with decreasing glide-gap separation. N1 increase was paralleled by an ERP decrease in the P2 interval. In older adults, only a glide-gap separation dependent P2 decrease, but no N1-effect was observable. This ERP pattern was likely caused by a fronto-central negative waveform, which was delayed in the older adult group, thus overlapping N1 and P2 in the younger, but overlapping only P2 in the older adult group. Because the waveform exhibited a polarity reversal at the mastoids, it was identified as a mismatch negativity (MMN). This interpretation also fits previous studies showing that gap-related MMN is delayed in older adults, reflecting an age-related deterioration of fine temporal auditory resolution. These results provide a plausible alternative explanation for the ERP enhancement for sounds following background auditory events. PMID- 28860639 TI - Origin of colossal dielectric response in (In + Nb) co-doped TiO2 rutile ceramics: a potential electrothermal material. AB - (In + Nb) co-doped TiO2 (TINO) rutile is an emerging material with a colossal dielectric permittivity (CP) and a low dielectric loss over wide temperature and frequency ranges. The electrical inhomogeneous nature of TINO ceramics is demonstrated by direct local current probing with high-resolution conductive atomic force microscopy (cAFM). The CP response in TINO is found to originate from the electron-pinned defect dipole induced conductive cluster effect and the electrode effect. Two types of dielectric relaxations are simultaneously observed due to these two effects. With the given synthesis condition, we found TINO shows a highly leaky feature that impairs its application as a dielectric material. However, the fast-temperature-rising phenomenon found in this work may open a new door for TINO to be applied as a potential electrothermal material with high efficiency, oxidation-proof, high temperature stability, and energy saving. PMID- 28860640 TI - Free mate choice does not influence reproductive success in humans. AB - The effect of free mate choice on the relative magnitude of fitness benefits has been examined among various species. The majority of the data show significant fitness benefits of mating with partners of an individual's own choice, highlighting elevated behavioral compatibility between partners with free mate choice. Similarities between humans and other species that benefit from free mate choice led us to hypothesize that it also confers reproductive benefits in Homo sapiens. To test this hypothesis, we conducted a study among three indigenous societies-the Tsimane', Yali, and Bhotiya-who employ natural birth control. In all three samples, we compared the marriages arranged by parents with the non arranged ones in terms of number of offspring. Here, we show that there were no significant relationships between type of marriage and the total number of alive children and number of dead children among the three sampled groups. The presented study is the first to date to examine the fitness benefits of free mate choice in humans. In discussion we present limitations of our research and discuss the possibility of love having a beneficial influence in terms of the number of offspring. PMID- 28860641 TI - A hybrid resistive pulse-optical detection platform for microfluidic experiments. AB - Resistive-pulse sensing is a label-free method for characterizing individual particles as they pass through ion-conducting channels or pores. During a resistive pulse experiment, the ionic current through a conducting channel is monitored as particles suspended in the solution translocate through the channel. The amplitude of the current decrease during a translocation, or 'pulse', depends not only on the ratio of the particle and channel sizes, but also on the particle position, which is difficult to resolve with the resistive pulse signal alone. We present experiments of simultaneous electrical and optical detection of particles passing through microfluidic channels to resolve the positional dependencies of the resistive pulses. Particles were tracked simultaneously in the two signals to create a mapping of the particle position to resistive pulse amplitude at the same instant in time. The hybrid approach will improve the accuracy of object characterization and will pave the way for observing dynamic changes of the objects such as deformation or change in orientation. This combined approach of optical detection and resistive pulse sensing will join with other attempts at hybridizing high-throughput detection techniques such as imaging flow cytometry. PMID- 28860642 TI - Rising tides, cumulative impacts and cascading changes to estuarine ecosystem functions. AB - In coastal ecosystems, climate change affects multiple environmental factors, yet most predictive models are based on simple cause-and-effect relationships. Multiple stressor scenarios are difficult to predict because they can create a ripple effect through networked ecosystem functions. Estuarine ecosystem function relies on an interconnected network of physical and biological processes. Estuarine habitats play critical roles in service provision and represent global hotspots for organic matter processing, nutrient cycling and primary production. Within these systems, we predicted functional changes in the impacts of land based stressors, mediated by changing light climate and sediment permeability. Our in-situ field experiment manipulated sea level, nutrient supply, and mud content. We used these stressors to determine how interacting environmental stressors influence ecosystem function and compared results with data collected along elevation gradients to substitute space for time. We show non-linear, multi stressor effects deconstruct networks governing ecosystem function. Sea level rise altered nutrient processing and impacted broader estuarine services ameliorating nutrient and sediment pollution. Our experiment demonstrates how the relationships between nutrient processing and biological/physical controls degrade with environmental stress. Our results emphasise the importance of moving beyond simple physically-forced relationships to assess consequences of climate change in the context of ecosystem interactions and multiple stressors. PMID- 28860644 TI - Detecting PM2.5's Correlations between Neighboring Cities Using a Time-Lagged Cross-Correlation Coefficient. AB - In order to investigate the time-dependent cross-correlations of fine particulate (PM2.5) series among neighboring cities in Northern China, in this paper, we propose a new cross-correlation coefficient, the time-lagged q-L dependent height crosscorrelation coefficient (denoted by p q (tau, L)), which incorporates the time-lag factor and the fluctuation amplitude information into the analogous height cross-correlation analysis coefficient. Numerical tests are performed to illustrate that the newly proposed coefficient rho q (tau, L) can be used to detect cross-correlations between two series with time lags and to identify different range of fluctuations at which two series possess cross-correlations. Applying the new coefficient to analyze the time-dependent cross-correlations of PM2.5 series between Beijing and the three neighboring cities of Tianjin, Zhangjiakou, and Baoding, we find that time lags between the PM2.5 series with larger fluctuations are longer than those between PM2.5 series withsmaller fluctuations. Our analysis also shows that cross-correlations between the PM2.5 series of two neighboring cities are significant and the time lags between two PM2.5 series of neighboring cities are significantly non-zero. These findings providenew scientific support on the view that air pollution in neighboring cities can affect one another not simultaneously but with a time lag. PMID- 28860643 TI - Transcriptome and proteome analysis reveal new insight into proximal and distal responses of wheat to foliar infection by Xanthomonas translucens. AB - The molecular details of local plant response against Xanthomonas translucens infection is largely unknown. Moreover, there is no knowledge about effects of the pathogen on the root's transcriptome and proteome. Therefore, we investigated the global gene and protein expression changes both in leaves and roots of wheat (Triticum aestivum) 24 h post leaf infection of X. translucens. This simultaneous analysis allowed us to obtain insight into possible metabolic rearrangements in above- and belowground tissues and to identify common responses as well as specific alterations. At the site of infection, we observed the implication of various components of the recognition, signaling, and amplification mechanisms in plant response to the pathogen. Moreover, data indicate a massive down-regulation of photosynthesis and confirm the chloroplast as crucial signaling hub during pathogen attack. Notably, roots responded as well to foliar attack and their response significantly differed from that locally triggered in infected leaves. Data indicate that roots as a site of energy production and synthesis of various secondary metabolites may actively influence the composition and colonisation level of root-associated microbes. Finally, our results emphasize the accumulation of jasmonic acid, pipecolic acid and/or the downstream mediator of hydrogen peroxide as long distal signals from infected leaves to roots. PMID- 28860645 TI - Applications of unmanned aerial vehicles in intertidal reef monitoring. AB - Monitoring of intertidal reefs is traditionally undertaken by on-ground survey methods which have assisted in understanding these complex habitats; however, often only a small spatial footprint of the reef is observed. Recent developments in unmanned aerial vehicles (UAVs) provide new opportunities for monitoring broad scale coastal ecosystems through the ability to capture centimetre resolution imagery and topographic data not possible with conventional approaches. This study compares UAV remote sensing of intertidal reefs to traditional on-ground monitoring surveys, and investigates the role of UAV derived geomorphological variables in explaining observed intertidal algal and invertebrate assemblages. A multirotor UAV was used to capture <1 cm resolution data from intertidal reefs, with on-ground quadrat surveys of intertidal biotic data for comparison. UAV surveys provided reliable estimates of dominant canopy-forming algae, however, understorey species were obscured and often underestimated. UAV derived geomorphic variables showed elevation and distance to seaward reef edge explained 19.7% and 15.9% of the variation in algal and invertebrate assemblage structure respectively. The findings of this study demonstrate benefits of low-cost UAVs for intertidal monitoring through rapid data collection, full coverage census, identification of dominant canopy habitat and generation of geomorphic derivatives for explaining biological variation. PMID- 28860647 TI - Flexibility in the FDA approach to orphan drug development. PMID- 28860648 TI - Stress buildup and drop in inland shallow crust caused by the 2011 Tohoku-oki earthquake events. AB - To examine the change in stress between before and after the Tohoku-oki Mw9.0 earthquake, we performed stress measurements after the earthquake in the Kamaishi mine in Iwate prefecture in northern Japan, located near the northern termination of the mainshock rupture, following previous measurements before the earthquake in the same mine. The results showed that the magnitudes of the three-dimensional principal stresses and the vertical stress drastically increased after the mainshock and, at 1 year after the earthquake, were more than double those before the earthquake. The principal stress magnitudes then decreased with time and returned to almost pre-earthquake levels at about 3 years after the earthquake. These changes can be interpreted in terms of coseismic rupture of the mainshock and the occurrence of aftershocks in the Sanriku-oki low-seismicity region (SLSR), where the Kamaishi mine is located. The drastic increase in stress suggests that the SLSR may act as a barrier to further rupture propagation. PMID- 28860646 TI - Metaplasia: tissue injury adaptation and a precursor to the dysplasia-cancer sequence. AB - Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, which may act in concert with the deleterious effects of microorganisms and inflammation. The cell of origin for intestinal metaplasia in the oesophagus and stomach and for pancreatic acinar ductal metaplasia has been posited through genetic mouse models and lineage tracing but has not been identified in other types of metaplasia, such as squamous metaplasia. A hallmark of metaplasia is a change in cellular identity, and this process can be regulated by transcription factors that initiate and/or maintain cellular identity, perhaps in concert with epigenetic reprogramming. Universally, metaplasia is a precursor to low-grade dysplasia, which can culminate in high-grade dysplasia and carcinoma. Improved clinical screening for and surveillance of metaplasia might lead to better prevention or early detection of dysplasia and cancer. PMID- 28860649 TI - Long distance invisibility system to hide dynamic objects with high selectivity. AB - With the development of invisibility technology, invisibility devices have now become more practical, with properties such as working at visible wavelengths, using natural materials, and hiding macroscopic objects. Recently, the cloaking of dynamic objects was experimentally realized using ray-optics. Here, based on a phase retrieval algorithm and phase conjugation technology, we design and fabricate a system to hide dynamic objects that changes at speeds faster than 8 seconds per frame. Different from shell cloaks and carpet-like cloaks, which conceal the entire region covered by the cloak, our system works when the object is at a distance and hides only the selected part of an object when the entire object is within the working area of the system. We experimentally demonstrate the concealment of a millimeter-scale object at different wavelengths. We believe that our work may provide a new approach to hiding objects in real life and may also be applicable in biological imaging and atmospheric imaging. PMID- 28860650 TI - A membrane-inserted structural model of the yeast mitofusin Fzo1. AB - Mitofusins are large transmembrane GTPases of the dynamin-related protein family, and are required for the tethering and fusion of mitochondrial outer membranes. Their full-length structures remain unknown, which is a limiting factor in the study of outer membrane fusion. We investigated the structure and dynamics of the yeast mitofusin Fzo1 through a hybrid computational and experimental approach, combining molecular modelling and all-atom molecular dynamics simulations in a lipid bilayer with site-directed mutagenesis and in vivo functional assays. The predicted architecture of Fzo1 improves upon the current domain annotation, with a precise description of the helical spans linked by flexible hinges, which are likely of functional significance. In vivo site-directed mutagenesis validates salient aspects of this model, notably, the long-distance contacts and residues participating in hinges. GDP is predicted to interact with Fzo1 through the G1 and G4 motifs of the GTPase domain. The model reveals structural determinants critical for protein function, including regions that may be involved in GTPase domain-dependent rearrangements. PMID- 28860651 TI - Optimal achieved blood pressure for patients with stable coronary artery disease. AB - We aimed to investigate the ideal achieved blood pressure (BP) in ethnic Chinese patients with stable coronary artery disease (CAD) in Taiwan. A total of 2,045 patients (age 63.5 +/- 11.9 years, 1,722 male [84.2%]) with stable CAD who had undergone percutaneous coronary interventions were enrolled. The achieved systolic BP was 130.6 +/- 17.7 mmHg and diastolic BP was 74.9 +/- 12.0 mmHg. In 12 months, patients with systolic BP < 120 mmHg and systolic BP >= 160 mmHg had increased risk of total cardiovascular events when compared to those with systolic BP 120-139 mmHg. In 24 months, patients with systolic BP < 120 mmHg and systolic BP >= 160 mmHg had increased risk of total cardiovascular events when compared to those with systolic BP 120-139 mmHg; patients with diastolic BP < 70 mmHg had increased risk of total cardiovascular events when compared to those with diastolic BP 70-79 mmHg. In conclusion, systolic BP < 120 mmHg and >=160 mmHg or diastolic BP < 70 mmHg is associated with increased cardiovascular events, supporting that the optimal BP control should also be justified for stable CAD in non-western cohorts. PMID- 28860652 TI - Diel CO2 cycles reduce severity of behavioural abnormalities in coral reef fish under ocean acidification. AB - Elevated CO2 levels associated with ocean acidification (OA) have been shown to alter behavioural responses in coral reef fishes. However, all studies to date have used stable pCO2 treatments, not considering the substantial diel pCO2 variation that occurs in shallow reef habitats. Here, we reared juvenile damselfish, Acanthochromis polyacanthus, and clownfish, Amphiprion percula, at stable and diel cycling pCO2 treatments in two experiments. As expected, absolute lateralization of A. polyacanthus and response to predator cue of Am. percula were negatively affected in fish reared at stable, elevated pCO2 in both experiments. However, diel pCO2 fluctuations reduced the negative effects of OA on behaviour. Importantly, in experiment two, behavioural abnormalities that were present in fish reared at stable 750 uatm CO2 were largely absent in fish reared at 750 +/- 300 uatm CO2. Overall, we show that diel pCO2 cycles can substantially reduce the severity of behavioural abnormalities caused by elevated CO2. Thus, past studies may have over-estimated the impacts of OA on the behavioural performance of coral reef fishes. Furthermore, our results suggest that diel pCO2 cycles will delay the onset of behavioural abnormalities in natural populations. PMID- 28860653 TI - Chill coma in the locust, Locusta migratoria, is initiated by spreading depolarization in the central nervous system. AB - The ability of chill-sensitive insects to function at low temperatures limits their geographic ranges. They have species-specific temperatures below which movements become uncoordinated prior to entering a reversible state of neuromuscular paralysis. In spite of decades of research, which in recent years has focused on muscle function, the role of neural mechanisms in determining chill coma is unknown. Spreading depolarization (SD) is a phenomenon that causes a shutdown of neural function in the integrating centres of the central nervous system. We investigated the role of SD in the process of entering chill coma in the locust, Locusta migratoria. We used thermolimit respirometry and electromyography in whole animals and extracellular and intracellular recording techniques in semi-intact preparations to characterize neural events during chilling. We show that chill-induced SD in the central nervous system is the mechanism underlying the critical thermal minimum for coordinated movement in locusts. This finding will be important for understanding how insects adapt and acclimate to changing environmental temperatures. PMID- 28860654 TI - Heterologous expression of the N-acetylglucosaminyltransferase I dictates a reinvestigation of the N-glycosylation pathway in Chlamydomonas reinhardtii. AB - Eukaryotic N-glycosylation pathways are dependent of N acetylglucosaminyltransferase I (GnTI), a key glycosyltransferase opening the door to the formation of complex-type N-glycans by transferring a N acetylglucosamine residue onto the Man5GlcNAc2 intermediate. In contrast, glycans N-linked to Chlamydomonas reinhardtii proteins arise from a GnTI-independent Golgi processing of oligomannosides giving rise to Man5GlcNAc2 substituted eventually with one or two xylose(s). Here, complementation of C. reinhardtii with heterologous GnTI was investigated by expression of GnTI cDNAs originated from Arabidopsis and the diatom Phaeodactylum tricornutum. No modification of the N-glycans was observed in the GnTI transformed cells. Consequently, the structure of the Man5GlcNAc2 synthesized by C. reinhardtii was reinvestigated. Mass spectrometry analyses combined with enzyme sequencing showed that C. reinhardtii proteins carry linear Man5GlcNAc2 instead of the branched structure usually found in eukaryotes. Moreover, characterization of the lipid-linked oligosaccharide precursor demonstrated that C. reinhardtii exhibit a Glc3Man5GlcNAc2 dolichol pyrophosphate precursor. We propose that this precursor is then trimmed into a linear Man5GlcNAc2 that is not substrate for GnTI. Furthermore, cells expressing GnTI exhibited an altered phenotype with large vacuoles, increase of ROS production and accumulation of starch granules, suggesting the activation of stress responses likely due to the perturbation of the Golgi apparatus. PMID- 28860656 TI - Johannes Joseph van Rood Pioneer in immuno-genetics (7 April 1926-21 July 2017). PMID- 28860655 TI - Pomalidomide-dexamethasone in refractory multiple myeloma: long-term follow-up of a multi-cohort phase II clinical trial. AB - Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ?2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen. PMID- 28860657 TI - Pupil response components: attention-light interaction in patients with Parinaud's syndrome. AB - Covertly shifting attention to a brighter or darker image (without moving one's eyes) is sufficient to evoke pupillary constriction or dilation, respectively. One possibility is that this attentional modulation involves the pupillary light response pathway, which pivots around the olivary pretectal nucleus. We investigate this possibility by studying patients with Parinaud's syndrome, where the normal pupillary light response is strongly impaired due to lesions in the pretectal area. Four patients and nine control participants covertly attended (while maintaining fixation at the center of a monitor screen) to one of two disks located in the left and right periphery: one brighter, the other darker than the background. Patients and control subjects behaved alike, showing smaller pupils when attending to the brighter stimulus (despite no eye movements); consistent results were obtained with a dynamic version of the stimulus. We interpret this as proof of principle that attention to bright or dark stimuli can dynamically modulate pupil size in patients with Parinaud's syndrome, suggesting that attention acts independently of the pretectal circuit for the pupillary light response and indicating that several components of the pupillary response can be isolated - including one related to the focus of covert attention. PMID- 28860658 TI - Modification of the response of olfactory receptors to acetophenone by CYP1a2. AB - Olfaction is mediated by the binding of odorant molecules to olfactory receptors (ORs). There are numerous proteins in the nasal mucus, and they contribute to olfaction through various mechanisms. Cytochrome P450 (CYP) family members are known to be present in the olfactory epithelium and are thought to affect olfaction by enzymatic conversion of odorant molecules. In this study, we examined the effects of CYPs on the ligand responses of ORs in heterologous cells. Among the CYPs tested, co-expression of CYP1a2 significantly affected the responses of various ORs, including MOR161-2, to acetophenone. Conversion of acetophenone to methyl salicylate was observed in the medium of CYP1a2-expressing cells. MOR161-2-expressing cells exhibited significantly greater responses to methyl salicylate than to acetophenone. Finally, we analyzed the responses of olfactory neurons expressing MOR161-2 in vivo using the phosphorylated ribosomal protein S6 as a marker. MOR161-2 responded to both acetophenone and methyl salicylate in vivo. When the olfactory mucus was washed out by the injection of PBS to mouse nasal cavity, the response of MOR161-2 to acetophenone was reduced, while that to methyl salicylate did not change. Our data suggest that CYP1a2 affects OR activation by converting acetophenone to methyl salicylate. PMID- 28860659 TI - Insect-bacteria parallel evolution in multiple-co-obligate-aphid association: a case in Lachninae (Hemiptera: Aphididae). AB - Parallel phylogenies between aphid and its obligate symbiont Buchnera are hot topics which always focused on aphid lower taxonomic levels. Symbionts in the subfamily Lachninae are special. Buchnera in many lachnine species has undergone functional and genome size reduction that was replaced by other co-obligate symbionts. In this study, we constructed the phylogenetic relationships of Lachninae with a combined dataset of five genes sequenced from Buchnera to estimate the effects of a dual symbiotic system in the aphid-Buchnera cospeciation association. The phylogeny of Buchnera in Lachninae was well resolved in the combined dataset. Each of the genera formed strongly supported monophyletic groups, with the exception of the genus Cinara. The phylogeny based on sequences from Buchnera was divided into five tribes according to the clades of the Lachninae hosts tree, with the phylogenies of Buchnera and Lachninae being generally congruent. These results first provided evidence of parallel evolution at the aphid subfamily level comprehensively and supported the view that topological congruence between the phylogenies of Buchnera and Lachninae would not be interfered with the other co-obligate symbionts, such as Sarretia, in aphid-entosymbiont association. These results also provided new insight in understanding host-plant coevolution in lachnine lineages. PMID- 28860660 TI - Free-Space Nonlinear Beam Combining for High Intensity Projection. AB - The controlled interaction of two high intensity beams opens new degrees of freedom for manipulating electromagnetic waves in air. The growing number of applications for laser filaments requires fine control of their formation and propagation. We demonstrate, experimentally and theoretically, that the attraction and fusion of two parallel ultrashort beams with initial powers below the critical value (70% P critical), in the regime where the non-linear optical characteristics of the medium become dominant, enable the eventual formation of a filament downstream. Filament formation is delayed to a predetermined distance in space, defined by the initial separation between the centroids, while still enabling filaments with controllable properties as if formed from a single above critical power beam. This is confirmed by experimental and theoretical evidence of filament formation such as the individual beam profiles and the supercontinuum emission spectra associated with this interaction. PMID- 28860661 TI - Long intergenic non-coding RNA GALMD3 in chicken Marek's disease. AB - Long intergenic non-coding RNAs (lincRNAs) are transcribed from non-coding DNA sequences. Studies have revealed that aberrant expressions of lincRNAs are associated with various types of cancers and neurological disorders. Marek's disease (MD) is a highly contagious T-cell lymphoid neoplasia of chicken induced by Marek's disease virus (MDV). In this study, we first identified and validated linc-GALMD3 highly expressed in MDV-infected CD4+ T cells by RNA-Seq and qRT-PCR. By RNA-Seq analysis in MDCC-MSB1 cells after loss of function of linc-GALMD3 by shRNA, we found that linc-GALMD3 could positively cis-regulate its downstream gga miR-223 gene expression. In contrast, it could trans-regulate the 748 differentially expressed genes (FDR < 0.01) that were mainly enriched into mitochondrial structure and cell cycle processes using GO analysis. Of these, the most significantly expressed gene EPYC might cause iris lesion in MD. The other eight genes, NDUFA4, NDUFB6, NDUFV1, NDUFS8, SDHB, UQCRC1, UQCRC2, and COX7A2, actively participated in oxidative phosphorylation in mitochondrial dysfunction and cell death. Most importantly, we found that the MDV replication was repressed when linc-GALMD3 was knocked down in CEF cells. Our results suggested that linc GALMD3 might be a critical regulator in chicken MD and could be used as a candidate-promising mark for MD prevention, diagnosis, and treatment. PMID- 28860662 TI - Analyses of Mitogenome Sequences Revealed that Asian Citrus Psyllids (Diaphorina citri) from California Were Related to Those from Florida. AB - Asian citrus psyllid (ACP, Diaphorina citri Kuwayama) transmits "Candidatus Liberibacter asiaticus" (CLas), an unculturable alpha-proteobacterium associated with citrus Huanglongbing (HLB). CLas has recently been found in California. Understanding ACP population diversity is necessary for HLB regulatory practices aimed at reducing CLas spread. In this study, two circular ACP mitogenome sequences from California (mt-CApsy, ~15,027 bp) and Florida (mt-FLpsy, ~15,012 bp), USA, were acquired. Each mitogenome contained 13 protein coding genes, 2 ribosomal RNA and 22 transfer RNA genes, and a control region varying in sizes. The Californian mt-CApsy was identical to the Floridian mt-FLpsy, but different from the mitogenome (mt-GDpsy) of Guangdong, China, in 50 single nucleotide polymorphisms (SNPs). Further analyses were performed on sequences in cox1 and trnAsn regions with 100 ACPs, SNPs in nad1-nad4-nad5 locus through PCR with 252 ACP samples. All results showed the presence of a Chinese ACP cluster (CAC) and an American ACP cluster (AAC). We proposed that ACP in California was likely not introduced from China based on our current ACP collection but somewhere in America. However, more studies with ACP samples from around the world are needed. ACP mitogenome sequence analyses will facilitate ACP population research. PMID- 28860664 TI - Cadmium-induced ER stress and inflammation are mediated through C/EBP-DDIT3 signaling in human bronchial epithelial cells. AB - Cadmium (Cd), a major component of cigarette smoke, disrupts the normal functions of airway cells and can lead to the development of various pulmonary diseases such as chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms involved in Cd-induced pulmonary diseases are poorly understood. Here, we identified a cluster of genes that are altered in response to Cd exposure in human bronchial epithelial cells (BEAS-2B) and demonstrated that Cd-induced ER stress and inflammation are mediated via CCAAT-enhancer-binding proteins (C/EBP) DNA-damaged-inducible transcript 3 (DDIT3) signaling in BEAS-2B cells. Cd treatment led to marked upregulation and downregulation of genes associated with the cell cycle, apoptosis, oxidative stress and inflammation as well as various signal transduction pathways. Gene set enrichment analysis revealed that Cd treatment stimulated the C/EBP signaling pathway and induced transcriptional activation of its downstream target genes, including DDIT3. Suppression of DDIT3 expression using specific small interfering RNA effectively alleviated Cd-induced ER stress and inflammatory responses in both BEAS-2B and normal primary normal human bronchial epithelial cells. Taken together, these data suggest that C/EBP signaling may have a pivotal role in the early induction of ER stress and inflammatory responses by Cd exposure and could be a molecular target for Cd induced pulmonary disease. PMID- 28860663 TI - Bacterial flagellin-a potent immunomodulatory agent. AB - Flagellin is a subunit protein of the flagellum, a whip-like appendage that enables bacterial motility. Traditionally, flagellin was viewed as a virulence factor that contributes to the adhesion and invasion of host cells, but now it has emerged as a potent immune activator, shaping both the innate and adaptive arms of immunity during microbial infections. In this review, we summarize our understanding of bacterial flagellin and host immune system interactions and the role flagellin as an adjuvant, anti-tumor and radioprotective agent, and we address important areas of future research interests. PMID- 28860665 TI - Effect of curcumin on glycerol-induced acute kidney injury in rats. AB - The aim of this study was to investigate the protective role and underlying mechanisms of curcumin on glycerol-induced acute kidney injury (AKI) in rats. Glycerol (10 ml/kg BW, 50% v/v in sterile saline, i.m.) was used to induce AKI, followed by curcumin (200 mg/kg/day, p.o.) administration for 3 days. To confirm renal damage and the effects of curcumin on AKI, serum BUN, Scr, and CK as well as renal SOD, MDA, GSH-Px were measured. Additionally, morphological changes were identified by H&E staining and transmission electron microscopy. The expression of several factors including chemotactic factor MCP-1, proinflammatory cytokines including TNF-alpha and IL-6, as well as the kidney injury markers, as Kim-1 and Lipocalin-2 were also assessed using q-PCR. Finally, cell apoptosis in renal tissue was detected using in situ TUNEL apoptosis fluorescence staining and expression of proteins associated with apoptotic, oxidative stress and lipid oxidative related signaling pathways were detected using immunohistochemical staining and western blot. The results showed that curcumin exerts renoprotective effects by inhibiting oxidative stress in rhabdomyolysis-induced AKI through regulation of the AMPK and Nrf2/HO-1 signaling pathways, and also ameliorated RM associated renal injury and cell apoptosis by activating the PI3K/Akt pathway. PMID- 28860666 TI - Features of cardiac remodeling in Patients with Acute Coronary Syndrome Complicated with Rheumatoid Arthritis. AB - Cardiovascular diseases are important factors to increased morbidity and mortality in patients with rheumatoid arthritis (RA). The aim of this study is to investigate the effects of RA on cardiac remodeling in patients with acute coronary syndrome (ACS). Sixty-one patients with ACS complicated with RA (RA group) and 55 age- and sex-matched patients with ACS without RA (control group) were enrolled. We compared the parameters of laboratory and echocardiogram across the 2 groups. Levels of serum brain natriuretic peptide in patients with RA were significantly higher than control group. Prevalence of left ventricular hypertrophy (LVH), and LV diastolic dysfunction (E/A < 1) were significantly higher in the RA patients, while the LV ejection fraction (EF%) was significantly lower in RA patients. Incidence of tricuspid regurgitation and pulmonary regurgitation were significantly higher in ACS patients with RA than in the ACS patients without RA. In RA group, levels of serum high density lipoprotein cholesterol were negatively correlated with C reactive protein (CRP), EF% was also negatively correlated with CRP. The prevalence of LVH and mitral regurgitation showed positive correlations with ESR. Early intervention for controlling the inflammation associated with RA can play a significant role in preventing cardiac remodeling in ACS patients. PMID- 28860668 TI - Fatigue-Assisted Grain Growth in Al Alloys. AB - Stress-assisted grain growth at room temperature is known for materials with nanocrystalline grains. For larger grain sizes, the grain growth usually takes place at higher homologous temperatures even under stress. Here we report, for the first time, significant grain growth at room temperature under fatigue loading in microcrystalline grains (>=10 MUm) in Al 7075. We demonstrate that this grain growth at room temperature is similar to non-uniform grain growth due to grain rotation and coalescence rather than the thermally and the stress assisted driven grain growth. We show that the grain growth is associated with the formation of a strong near-Cu {112}<111> texture component as a result of fatigue-assisted deformation. These changes in microstructural features (viz., grain size, grain orientations and texture) are fundamentally important in understanding the cyclic crack induced deformation behavior and for predicting the fatigue lifetime in structural materials. PMID- 28860669 TI - Impact Factor: a crude yardstick which does not measure influence or impact on clinical practice. PMID- 28860667 TI - A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors. AB - Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 * 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects. PMID- 28860670 TI - Specific refractive index increment (?n/?c) of polymers at 660 nm and 690 nm. AB - The specific refractive index increment (?n/?c) is an essential datum for the accurate quantitation of molar mass averages and distributions (inter alia) of macromolecules when refractometry, static light scattering, and/or viscometry detection are coupled on-line to size-based separation techniques. The latter include methods such as size-exclusion and hydrodynamic chromatography, and asymmetric and hollow-fiber flow field-flow fractionation. The ?n/?c is also needed for accurate determination of the weight-average molar mass of polymers by off-line, batch-mode multi-angle static light scattering. However, not only does ?n/?c differ among chemical species, it also depends on experimental conditions such as solvent, temperature, and wavelength. For the last seventeen years, the author's laboratories have measured the ?n/?c of a variety of natural and synthetic polymers, at both 690 nm and, more recently, 660 nm, under a variety of solvent and temperature conditions. In all cases, this has been done by off-line, batch-mode differential refractometry, not by assuming 100% analyte column recovery and 100% accurate peak integration. Results of these determinations are presented here, along with the relevant experimental data. PMID- 28860672 TI - Temporal Vulnerability and the Post-Disaster 'Window of Opportunity to Woo:' a Case Study of an African-American Floodplain Neighborhood after Hurricane Floyd in North Carolina. AB - After major flooding associated with Hurricane Floyd (1999) in North Carolina, mitigation managers seized upon the "window of opportunity" to woo residents to accept residential buyout offers despite sizable community resistance. I present a theoretical explanation of how post-crisis periods turn into "opportunities" based on a temporal referential theory that complements alternative explanations based on temporal coincidence, panarchy, and shock-doctrine theories. Results from fieldwork conducted from 2002 to 2004 illustrate how several temporal influences compromised collective calibration of "normalcy" in local cultural models, leading to an especially heightened vulnerability to collective surprise. Four factors particularly influenced this temporal vulnerability: 1) epistemological uncertainty of floodplain dynamics due to colonization; 2) cultural practices that maintained a casual amnesia; 3) meaning attributed to stochastic timing of floods; and 4) competitive impact of referential flood baseline attractors. PMID- 28860673 TI - Sparrowhawk movement, calling, and presence of dead conspecifics differentially impact blue tit (Cyanistes caeruleus) vocal and behavioral mobbing responses. AB - ABSTRACT: Many animals alter their anti-predator behavior in accordance to the threat level of a predator. While much research has examined variation in mobbing responses to different predators, few studies have investigated how anti-predator behavior is affected by changes in a predator's own state or behavior. We examined the effect of sparrowhawk (Accipiter nisus) behavior on the mobbing response of wild blue tits (Cyanistes caeruleus) using robotic taxidermy sparrowhawks. We manipulated whether the simulated predator moved its head, produced vocalizations, or held a taxidermy blue tit in its talons. When any sparrowhawk model was present, blue tits decreased foraging and increased anti predator behavior and vocalizations. Additionally, each manipulation of the model predator's state (moving, vocalizing, or the presence of a dead conspecific) impacted different types of blue tit anti-predator behavior and vocalizations. These results indicate that different components of mobbing vary according to the specific state of a given predator-beyond its presence or absence-and suggest that each might play a different role in the overall mobbing response. Last, our results indicate that using more life-like predator stimuli-those featuring simple head movements and audio playback of vocalizations-changes how prey respond to the predator; these 'robo-raptor' models provide a powerful tool to provide increased realism in simulated predator encounters without sacrificing experimental control. SIGNIFICANCE STATEMENT: Anti-predatory behavior is often modulated by the threat level posed by a particular predator. While much research has tested how different types of predators change prey behavior, few experiments have examined how predator behavior affects anti-predatory responses of prey. By experimentally manipulating robotic predators, we show that blue tits not only respond to the presence of a sparrowhawk, by decreasing feeding and increasing anti-predator behavior and vocalizations, but that they vary specific anti predator behaviors when encountering differently behaving predators (moving, vocalizing, or those with captured prey), suggesting that prey pay attention to their predators' state and behavior. PMID- 28860674 TI - Assessing the resilience of Norway spruce forests through a model-based reanalysis of thinning trials. AB - As a result of a rapidly changing climate the resilience of forests is an increasingly important property for ecosystem management. Recent efforts have improved the theoretical understanding of resilience, yet its operational quantification remains challenging. Furthermore, there is growing awareness that resilience is not only a means to addressing the consequences of climate change but is also affected by it, necessitating a better understanding of the climate sensitivity of resilience. Quantifying current and future resilience is thus an important step towards mainstreaming resilience thinking into ecosystem management. Here, we present a novel approach for quantifying forest resilience from thinning trials, and assess the climate sensitivity of resilience using process-based ecosystem modeling. We reinterpret the wide range of removal intensities and frequencies in thinning trials as an experimental gradient of perturbation, and estimate resilience as the recovery rate after perturbation. Our specific objectives were (i) to determine how resilience varies with stand and site conditions, (ii) to assess the climate sensitivity of resilience across a range of potential future climate scenarios, and (iii) to evaluate the robustness of resilience estimates to different focal indicators and assessment methodologies. We analyzed three long-term thinning trials in Norway spruce (Picea abies (L.) Karst.) forests across an elevation gradient in Austria, evaluating and applying the individual-based process model iLand. The resilience of Norway spruce was highest at the montane site, and decreased at lower elevations. Resilience also decreased with increasing stand age and basal area. The effects of climate change were strongly context-dependent: At the montane site, where precipitation levels were ample even under climate change, warming increased resilience in all scenarios. At lower elevations, however, rising temperatures decreased resilience, particularly at precipitation levels below 750 800 mm. Our results were largely robust to different focal variables and resilience definitions. Based on our findings management can improve the capacity to recover from partial disturbances by avoiding overmature and overstocked conditions. At increasingly water limited sites a strongly decreasing resilience of Norway spruce will require a shift towards tree species better adapted to the expected future conditions. PMID- 28860675 TI - Changes of forest cover and disturbance regimes in the mountain forests of the Alps. AB - Natural disturbances, such as avalanches, snow breakage, insect outbreaks, windthrow or fires shape mountain forests globally. However, in many regions over the past centuries human activities have strongly influenced forest dynamics, especially following natural disturbances, thus limiting our understanding of natural ecological processes, particularly in densely-settled regions. In this contribution we briefly review the current understanding of changes in forest cover, forest structure, and disturbance regimes in the mountain forests across the European Alps over the past millennia. We also quantify changes in forest cover across the entire Alps based on inventory data over the past century. Finally, using the Swiss Alps as an example, we analyze in-depth changes in forest cover and forest structure and their effect on patterns of fire and wind disturbances, based on digital historic maps from 1880, modern forest cover maps, inventory data on current forest structure, topographical data, and spatially explicit data on disturbances. This multifaceted approach presents a long-term and detailed picture of the dynamics of mountain forest ecosystems in the Alps. During pre-industrial times, natural disturbances were reduced by fire suppression and land-use, which included extraction of large amounts of biomass that decreased total forest cover. More recently, forest cover has increased again across the entire Alps (on average +4% per decade over the past 25-115 years). Live tree volume (+10% per decade) and dead tree volume (mean +59% per decade) have increased over the last 15-40 years in all regions for which data were available. In the Swiss Alps secondary forests that established after 1880 constitute approximately 43% of the forest cover. Compared to forests established previously, post-1880 forests are situated primarily on steep slopes (>30 degrees ), have lower biomass, a more aggregated forest structure (primarily stem exclusion stage), and have been more strongly affected by fires, but less affected by wind disturbance in the 20th century. More broadly, an increase in growing stock and expanding forest areas since the mid-19th century have - along with climatic changes - contributed to an increasing frequency and size of disturbances in the Alps. Although many areas remain intensively managed, the extent, structure, and dynamics of the forests of the Alps reflect natural drivers more strongly today than at any time in the past millennium. PMID- 28860671 TI - Polyphasic taxonomy of Aspergillus section Aspergillus (formerly Eurotium), and its occurrence in indoor environments and food. AB - Aspergillus section Aspergillus (formerly the genus Eurotium) includes xerophilic species with uniseriate conidiophores, globose to subglobose vesicles, green conidia and yellow, thin walled eurotium-like ascomata with hyaline, lenticular ascospores. In the present study, a polyphasic approach using morphological characters, extrolites, physiological characters and phylogeny was applied to investigate the taxonomy of this section. Over 500 strains from various culture collections and new isolates obtained from indoor environments and a wide range of substrates all over the world were identified using calmodulin gene sequencing. Of these, 163 isolates were subjected to molecular phylogenetic analyses using sequences of ITS rDNA, partial beta-tubulin (BenA), calmodulin (CaM) and RNA polymerase II second largest subunit (RPB2) genes. Colony characteristics were documented on eight cultivation media, growth parameters at three incubation temperatures were recorded and micromorphology was examined using light microscopy as well as scanning electron microscopy to illustrate and characterize each species. Many specific extrolites were extracted and identified from cultures, including echinulins, epiheveadrides, auroglaucins and anthraquinone bisanthrons, and to be consistent in strains of nearly all species. Other extrolites are species-specific, and thus valuable for identification. Several extrolites show antioxidant effects, which may be nutritionally beneficial in food and beverages. Important mycotoxins in the strict sense, such as sterigmatocystin, aflatoxins, ochratoxins, citrinin were not detected despite previous reports on their production in this section. Adopting a polyphasic approach, 31 species are recognized, including nine new species. ITS is highly conserved in this section and does not distinguish species. All species can be differentiated using CaM or RPB2 sequences. For BenA, Aspergillus brunneus and A. niveoglaucus share identical sequences. Ascospores and conidia morphology, growth rates at different temperatures are most useful characters for phenotypic species identification. PMID- 28860676 TI - The historical disturbance regime of mountain Norway spruce forests in the Western Carpathians and its influence on current forest structure and composition. AB - In order to gauge ongoing and future changes to disturbance regimes, it is necessary to establish a solid baseline of historic disturbance patterns against which to evaluate these changes. Further, understanding how forest structure and composition respond to variation in past disturbances may provide insight into future resilience to climate-driven alterations of disturbance regimes. We established 184 plots (mostly 1000 m2) in 14 primary mountain Norway spruce forests in the Western Carpathians. On each plot we surveyed live and dead trees and regeneration, and cored around 25 canopy trees. Disturbance history was reconstructed by examining individual tree growth trends. The study plots were further aggregated into five groups based on disturbance history (severity and timing) to evaluate and explain its influence on forest structure. These ecosystems are characterized by a mixed severity disturbance regime with high spatiotemporal variability in severity and frequency. However, periods of synchrony in disturbance activity were also found. Specifically, a peak of canopy disturbance was found for the mid-19th century across the region (about 60% of trees established), with the most important periods of disturbance in the 1820s and from the 1840s to the 1870s. Current stand size and age structure were strongly influenced by past disturbance activity. In contrast, past disturbances did not have a significant effect on current tree density, the amount of coarse woody debris, and regeneration. High mean densities of regeneration with height >50 cm (about 1400 individuals per ha) were observed. Extensive high severity disturbances have recently affected Central European forests, spurring a discussion about the causes and consequences. We found some evidence that forests in the Western Carpathians were predisposed to recent severe disturbance events as a result of synchronized past disturbance activity, which partly homogenized size and age structure and made recent stands more vulnerable to bark beetle outbreak. Our data suggest that these events are still part of the range of natural variability. The finding that regeneration density and volume of coarse woody debris were not influenced by past disturbance illustrates that vastly different past disturbance histories are not likely to change the future trajectories of these forests. These ecosystems currently have high ecological resilience to disturbance. In conclusion, we suggest that management should recognize disturbances as a natural part of ecosystem dynamics in the mountain forests of Central Europe, account for their stochastic occurrence in management planning, and mimic their patterns to foster biodiversity in forest landscapes. PMID- 28860677 TI - A walk on the wild side: Disturbance dynamics and the conservation and management of European mountain forest ecosystems. AB - Mountain forests are among the most important ecosystems in Europe as they support numerous ecological, hydrological, climatic, social, and economic functions. They are unique relatively natural ecosystems consisting of long-lived species in an otherwise densely populated human landscape. Despite this, centuries of intensive forest management in many of these forests have eclipsed evidence of natural processes, especially the role of disturbances in long-term forest dynamics. Recent trends of land abandonment and establishment of protected forests have coincided with a growing interest in managing forests in more natural states. At the same time, the importance of past disturbances highlighted in an emerging body of literature, and recent increasing disturbances due to climate change are challenging long-held views of dynamics in these ecosystems. Here, we synthesize aspects of this Special Issue on the ecology of mountain forest ecosystems in Europe in the context of broader discussions in the field, to present a new perspective on these ecosystems and their natural disturbance regimes. Most mountain forests in Europe, for which long-term data are available, show a strong and long-term effect of not only human land use but also of natural disturbances that vary by orders of magnitude in size and frequency. Although these disturbances may kill many trees, the forests themselves have not been threatened. The relative importance of natural disturbances, land use, and climate change for ecosystem dynamics varies across space and time. Across the continent, changing climate and land use are altering forest cover, forest structure, tree demography, and natural disturbances, including fires, insect outbreaks, avalanches, and wind disturbances. Projected continued increases in forest area and biomass along with continued warming are likely to further promote forest disturbances. Episodic disturbances may foster ecosystem adaptation to the effects of ongoing and future climatic change. Increasing disturbances, along with trends of less intense land use, will promote further increases in coarse woody debris, with cascading positive effects on biodiversity, edaphic conditions, biogeochemical cycles, and increased heterogeneity across a range of spatial scales. Together, this may translate to disturbance-mediated resilience of forest landscapes and increased biodiversity, as long as climate and disturbance regimes remain within the tolerance of relevant species. Understanding ecological variability, even imperfectly, is integral to anticipating vulnerabilities and promoting ecological resilience, especially under growing uncertainty. Allowing some forests to be shaped by natural processes may be congruent with multiple goals of forest management, even in densely settled and developed countries. PMID- 28860678 TI - Using Landsat time series for characterizing forest disturbance dynamics in the coupled human and natural systems of Central Europe. AB - Remote sensing is a key information source for improving the spatiotemporal understanding of forest ecosystem dynamics. Yet, the mapping and attribution of forest change remains challenging, particularly in areas where a number of interacting disturbance agents simultaneously affect forest development. The forest ecosystems of Central Europe are coupled human and natural systems, with natural and human disturbances affecting forests both individually and in combination. To better understand the complex forest disturbance dynamics in such systems, we utilize 32-year Landsat time series to map forest disturbances in five sites across Austria, the Czech Republic, Germany, Poland, and Slovakia. All sites consisted of a National Park and the surrounding forests, reflecting three management zones of different levels of human influence (managed, protected, strictly protected). This allowed for a comparison of spectral, temporal, and spatial disturbance patterns across a gradient from natural to coupled human and natural disturbances. Disturbance maps achieved overall accuracies ranging from 81% to 93%. Disturbance patches were generally small, with 95% of the disturbances being smaller than 10 ha. Disturbance rates ranged from 0.29% yr-1 to 0.95% yr-1, and differed substantially among management zones and study sites. Natural disturbances in strictly protected areas were longer in duration (median of 8 years) and slightly less variable in magnitude compared to human-dominated disturbances in managed forests (median duration of 1 year). However, temporal dynamics between natural and human-dominated disturbances showed strong synchrony, suggesting that disturbance peaks are driven by natural events affecting managed and unmanaged areas simultaneously. Our study demonstrates the potential of remote sensing for mapping forest disturbances in coupled human and natural systems, such as the forests of Central Europe. Yet, we also highlight the complexity of such systems in terms of agent attribution, as many natural disturbances are modified by management responding to them outside protected areas. PMID- 28860679 TI - Single-Nanowire Strain Sensors Fabricated by Nanoskiving. AB - This article describes the fabrication of single-nanowire strain sensors by thin sectioning of gold films with an ultramicrotome-i.e., "nanoskiving." The nanowire sensors are transferred to various substrates from the water bath on which they float after sectioning. The electrical response of these single nanowires to mechanical strain is investigated, with the lowest detectable strain determined to be 1.6 * 10-5 with a repeatable response to strains as high as 7 * 10-4. The sensors are shown to have an enhanced sensitivity with a gauge factor of 3.1 on average, but as high as 9.5 in the low strain regime (epsilon ~ 1 * 10-5). Conventional thin films of gold of the same height as the nanowires are used as controls, and are unable to detect those same strains. The practicality of this sensor is investigated by transferring a single nanowire to polyimide tape, and placing the sensor on the wrist to monitor the pulse pressure waveform from the radial artery. The nanowires are fabricated with simple tools and require no lithography. Moreover, the sensors can be "manufactured" efficiently, as each consecutive section of the film is a quasi copy of the previous nanowire. The simple fabrication of these nanowires, along with the compatibility with flexible substrates, offers possibilities in developing new kinds of devices for biomedical applications and structural health monitoring. PMID- 28860680 TI - Modeling Heat and Moisture Transport in Steam-Cured Mortar: Application to Aashto Type Vi Beams. AB - During steam curing of concrete, temperature and moisture gradients are developed, which are difficult to measure experimentally and can adversely affect the durability of concrete. In this research, a model of cement hydration coupled to moisture and heat transport was used to simulate the process of steam curing of mortars with water-to-cement (w/c) ratios by mass of 0.30 and 0.45, considering natural convection boundary conditions in mortar and concrete specimens of AASHTO Type VI beams. The primary variables of the model were moisture content, temperature, and degree of hydration. Moisture content profiles of mortar specimens (40 mm in diameter and 50 mm in height) were measured by magnetic resonance imaging. The degree of hydration was obtained by mass-based measurements of loss on ignition to 1000 degrees C. The results indicate that the model correctly simulates the moisture distribution and degree of hydration in mortar specimens. Application of the model to the steam curing of an AASHTO Type VI beam indicates temperature differences (between the surface and the center) higher than 20 degrees C during the cooling stage, and internal temperatures higher than 70 degrees C that may compromise the durability of the concrete. PMID- 28860681 TI - A second-order iterated smoothing algorithm. AB - Simulation-based inference for partially observed stochastic dynamic models is currently receiving much attention due to the fact that direct computation of the likelihood is not possible in many practical situations. Iterated filtering methodologies enable maximization of the likelihood function using simulation based sequential Monte Carlo filters. Doucet et al. (2013) developed an approximation for the first and second derivatives of the log likelihood via simulation-based sequential Monte Carlo smoothing and proved that the approximation has some attractive theoretical properties. We investigated an iterated smoothing algorithm carrying out likelihood maximization using these derivative approximations. Further, we developed a new iterated smoothing algorithm, using a modification of these derivative estimates, for which we establish both theoretical results and effective practical performance. On benchmark computational challenges, this method beat the first-order iterated filtering algorithm. The method's performance was comparable to a recently developed iterated filtering algorithm based on an iterated Bayes map. Our iterated smoothing algorithm and its theoretical justification provide new directions for future developments in simulation-based inference for latent variable models such as partially observed Markov process models. PMID- 28860682 TI - Bidirectional Associations Between Parental Responsiveness and Executive Function During Early Childhood. AB - In this study, we examined bidirectional associations between parental responsiveness and executive function (EF) processes in socioeconomically disadvantaged preschoolers. Participants were 534 3- to 5-year-old children (71% Hispanic/Latino; 28% African American; 1% European American) attending Head Start programs. At Time 1 (T1) and 6.5 months later at Time 2 (T2), parents and children participated in a videotaped free play session and children completed delay inhibition (gift delay-wrap, gift delay-bow) and conflict EF (bear/dragon, dimensional change card sort) tasks. Parental warm acceptance, contingent responsiveness, and verbal scaffolding were coded from the free play videos and aggregated to create a parental responsiveness latent variable. A cross-lagged panel structural equation model indicated that higher T1 parental responsiveness significantly predicted more positive gain in delay inhibition and conflict EF from T1 to T2. Higher T1 delay inhibition, but not T1 conflict EF, significantly predicted more positive change in parental responsiveness from T1 to T2. These associations were not explained by several possible confounding variables, including children's age, gender, race/ethnicity, and verbal ability. Findings suggest that parental responsiveness may support EF development in disadvantaged children, with reciprocal effects of delay inhibition on parental responsiveness. PMID- 28860683 TI - Simultaneous ipsilateral knee arthroscopy and unicondylar knee arthroplasty is effective for bicompartmental symptoms. AB - BACKGROUND: Patients with unicompartmental radiographic arthritis but bicompartmental symptoms pose a clinical challenge. Some surgeons may perceive it as a contraindication for unicondylar knee arthroplasty (UKA). We investigated patient outcomes 2 years after simultaneous ipsilateral arthroscopy and UKA as compared to a similar group of patients who had total knee replacement (TKA) for a similar clinical presentation. METHODS: We identified 9 patients with simultaneous ipsilateral arthroscopy and UKA between 2004 and 2013, and 12 clinically similar patients treated with TKA. RESULTS: At 1- and 2-years, SF-12 physical scores were significantly improved in the UKA-scope group than in the TKA group (47.2 vs 40.3, p = 0.042; 48.3 vs 32.6, p = 0.026). WOMAC pain score, WOMAC stiffness score, WOMAC function and KSFS were significantly improved in the UKA-scope group at 2 years as compared to the TKA group (98.7 vs 63.8, p = 0.030), (90.1 vs 43.8, p = 0.013), (92.3 vs 55.2, p = 0.027 and (92.3 vs 55.2, p = 0.027), respectively). Change in score from baseline for KSFS, SF-12 physical and WOMAC stiffness were significantly improved in the UKA-scope group at 2 years compared to TKA, (28.3 vs -5, p = 0.041), (13.6 vs 3.0, p = 0.026), (52.6 vs 6.3, p = 0.025), respectively. CONCLUSION: This study shows that patients with isolated compartment radiographic disease but with bicompartmental symptoms can benefit from UKA and simultaneous arthroscopy. Further, TKA for isolated compartment radiographic disease in this limited series had poorer outcomes. We obtain MRI selectively when physical exam and radiographic findings suggest isolated arthritic disease in patients with bicompartmental symptoms. PMID- 28860684 TI - Experience of the posterior lip augmentation device in a regional hip arthroplasty unit as a treatment for recurrent dislocation. AB - INTRODUCTION: Dislocation after total hip arthroplasty (THA) remains a significant complication of the procedure and is the third leading cause for revision THA. One technique for treatment of this complication is the use of the posterior lip augmentation device (PLAD). We describe our experience using the PLAD including complication rates. METHODS: A retrospective review of 55 PLADs (54 patients) was carried out following identification from electronic theatre records. Basic patient demographics, operative records and radiographs were collected and reviewed and data was analysed using Microsoft Excel. Failure of the PLAD was defined as further operative intervention after PLAD insertion and included: dislocation, implant breakage, infection and revision of the THA for loosening of either component. RESULTS: 55 PLADs were implanted in 54 patients with an average age of 77 years. There was a significant preponderance of females and a variety of surgical approaches had been used for the original hip replacement, including trochanteric osteotomy, posterior and antero-lateral. 9 (16%) patients had recurrent dislocations,1 (2%) failed secondary to screw breakage, 3 (5%) had and infection requiring intervention and 2 (4%) underwent further revision for aseptic loosening of the femoral component. The overall failure rate was 25% with 14 patients requiring intervention post PLAD. CONCLUSION: Our results are inferior to other published results and indicate that the PLAD should be used with caution for recurrent dislocations of the Charnley hip replacement. PMID- 28860685 TI - Modyfied wedge osteotomy for osteoarthritis of elbow secondary to osteochondritis dissecans in adolecent with multiple epiphyseal dysplasia. A case report. AB - Multiple epiphyseal dysplasia (MED) may be complicated by osteochondritis dissecans (OCD), most commonly reported in the knee, but involvement of the elbow is very rare. Optimal treatment for MED-associated elbow OCD and treatment outcome have not been established. This report describes the case of an adolescent male patient with elbow OCD treated by arthroscopic drilling at a previous clinic. Progression of osteoarthritis and radial head subluxation were observed. Resection of the osteophytes and modified wedge osteotomy of the lateral condyle were then performed, and a favorable result was obtained by decompression and sufficient congruency of the radiohumeral joint. PMID- 28860686 TI - Polyethylene and highly cross-linked polyethylene for cemented total hip arthroplasty: A comparison of over ten-year clinical and radiographic results. AB - INTRODUCTION: We investigated the long-term tribological outcomes of conventional polyethylene (CPE) and highly cross-linked polyethylene (HXLPE). METHODS: Ninety four consecutive primary cemented THAs were performed using either HXLPE or CPE at our hospital. CPE sockets were used in 26 hips, and HXLPE sockets were implanted in 68 hips. RESULTS: A 10-year follow-up was completed for 69 cases. Linear wear rates of 0.138 +/- 0.074 mm/year for CPE and 0.011 +/- 0.020 mm/year for HXLPE were calculated. Osteolysis was identified in 10 cases (CPE group, 7; HXLPE group, 3). CONCLUSION: HXLPE had significantly less wear than CPE, and polyethylene wear was associated with osteolysis. PMID- 28860687 TI - Bone remodelling around the Metha(r) short stem implant - Clinical and dual energy x-ray absorptiometry (DXA) results. AB - OBJECTIVE: Bony ingrowth of short stems is under investigation. METHOD: Over one year bony reactions around the Metha(r) stem were investigated using the DXA method in a standardized zonal system (19 ROIs). Clinical results were documented using the HHS. RESULTS: HHS significantly improved from 46 points to 97 points. After one year bone marrow density (BMD) increased in the lateral distal and lateral proximal areas as well as in the mid medial area. BMD decreased in the proximal medial and mid lateral areas. CONCLUSION: The concept of metaphyseal ingrowth was confirmed, but distal bony reactions need further investigation. PMID- 28860688 TI - Some new retarded nonlinear Volterra-Fredholm type integral inequalities with maxima in two variables and their applications. AB - In this paper, we establish some new retarded nonlinear Volterra-Fredholm type integral inequalities with maxima in two independent variables, and we present the applications to research the boundedness of solutions to retarded nonlinear Volterra-Fredholm type integral equations. PMID- 28860689 TI - An optimal consumption and investment problem with quadratic utility and negative wealth constraints. AB - In this paper, we investigate the optimal consumption and portfolio selection problem with negative wealth constraints for an economic agent who has a quadratic utility function of consumption and receives a constant labor income. Due to the property of the quadratic utility function, we separate our problem into two cases and derive the closed-form solutions for each case. We also illustrate some numerical implications of the optimal consumption and portfolio. PMID- 28860690 TI - Proofs to one inequality conjecture for the non-integer part of a nonlinear differential form. AB - We prove the conjecture for the non-integer part of a nonlinear differential form representing primes presented in (Lai in J. Inequal. Appl. 2015:Article ID 357, 2015) by using Tumura-Clunie type inequalities. Compared with the original proof, the new one is simpler and more easily understood. Similar problems can be treated with the same procedure. PMID- 28860691 TI - Bonnesen-style inequality for the first eigenvalue on a complete surface of constant curvature. AB - By Cheeger's isoperimetric constants, some lower bounds and upper bounds of [Formula: see text], the first eigenvalue on a complete surface of constant curvature, are given. Some Bonnesen-style inequalities and reverse Bonnesen-style inequalities for the first eigenvalue are obtained. Those Bonnesen-style inequalities obtained are stronger than the well-known Osserman's results and the upper bound is stronger than Osserman's results (Osserman in Proceedings of the International Congress of Mathematicians, Helsinki, 1978). PMID- 28860692 TI - Flap motility as a sign of posterior capsule rupture in peripherally extended anterior capsular tears. AB - PURPOSE: To describe various types of anterior capsular tears and an early diagnostic, flap motility, as a sign of posterior capsular rupture following posterior extension of radial tears. DESIGN: This was a prospective study carried out in 4,331 eyes that underwent phacoemulsification in a private practice setting from April 2015 to February 2016. Twenty six consecutive cases of anterior capsular tears were included. Morphological features of anterior capsular tears and resultant complications were evaluated. Parameters studied were surgical step during which the tear occurred, shape of tear, its extension in relation to the equator, and flap nature and motility in tear extending up to equator. MAIN OUTCOME MEASURES: The main outcome measures were motility and nature of flaps in anterior capsular radial tears and the relation to posterior capsule rupture. RESULTS: Based on shape, extent, and angulation, anterior capsular tears were categorized into 5 types: Type I, pre-equatorial radial tear (26.92%); Type II, post-equatorial radial tear (3.85%); Type III, Argentinean flag sign pre-equatorial tear (57.69%); Type IV, Argentinean flag sign post equatorial tear (7.69%), and Type V, mini punch (3.85%). Flaps were either seen to be everted and fluttering or inverted and non-fluttering. In all cases with everted fluttering flaps no posterior capsular rupture (PCR) was observed, while in cases with inverted non-fluttering flaps a PCR was observed (p<0.05). CONCLUSION: Everted and fluttering flaps of the anterior capsular tears indicate pre-equatorial tear, while inverted and non-fluttering flaps indicate posterior capsule rupture following tear extension beyond the equator. PMID- 28860693 TI - Long-term visual outcomes and patient satisfaction following bilateral implantation of trifocal intraocular lenses. AB - PURPOSE: To study the long-term visual and refractive outcomes and evaluate patient satisfaction after bilateral implantation of trifocal intraocular lenses (IOLs). SETTING: Nethradhama Superspeciality Eye Hospital, Bangalore. DESIGN: Prospective, nonrandomized study. METHODS: Eligible patients undergoing bilateral phacoemulsification with trifocal IOL implantation were included. Follow-up examinations were conducted at day 1, 1 week, 1 month, 6 months, and 12 months. Postoperatively, 1 month onward evaluation of uncorrected and distance-corrected far and near visual acuity; reading acuity and reading speeds (using Salzburg Reading Desk) at 70, 80, and 90 cm; contrast sensitivity; defocus curves; and patient satisfaction was carried out. RESULTS: Fifty eyes from 25 patients with a mean age of 58+/-13.44 years were included. All eyes showed significant improvement in spherical equivalent, uncorrected distance visual acuity, corrected distance visual acuity, uncorrected near visual acuity, and corrected near visual acuity at 1 month compared to preoperative values (P<0.05), with no significant change in these parameters thereafter until the last follow-up (P>0.05). At 12 months, mean uncorrected reading acuities and reading speeds at 70, 80, and 90 cm were in the range of 0.09-0.04 logMAR units and 153.6-169.0 words per minute, respectively, with significantly better results at 80 cm. Five eyes underwent YAG laser capsulotomy for early posterior capsule opacification (PCO) at a mean follow-up of 7.2+/-2.9 months. Contrast sensitivity scores at 12 months were comparable to 1 month (P>0.05 for all spatial frequencies). All patients reported good tolerance and 100% independence from spectacles for all activities. CONCLUSION: Trifocal IOLs provided excellent unaided vision at all distances. Reading performance was good through the complete intermediate distance range. PCO occurrence and subsequent YAG capsulotomy did not affect the long-term visual outcomes. PMID- 28860694 TI - Evaluation of the effect of corneal collagen cross-linking for keratoconus on the ocular higher-order aberrations. AB - BACKGROUND: Corneal collagen cross-linking (CXL) is the only treatment currently available to arrest the progression of keratoconus. The procedure consists of photopolymerization of stromal collagen fibers induced by combined action of a photosensitizing substance (riboflavin or vitamin B2) and ultraviolet-A light. PURPOSE: To determine changes in the ocular higher-order aberrations (HOAs) after CXL and its correlation with changes in visual acuity. DESIGN: Prospective interventional study. SUBJECTS AND METHODS: This study was conducted on 30 eyes of 16 patients with progressive keratoconus documented between 2012 and 2014. Patients were treated with epithelium-off CXL and followed for a minimum of 6 months. The following ocular HOAs were measured and analyzed using I-Tracey Aberrometer: coma, trefoil, spherical aberration, astigmatism, and total HOAs. RESULTS: There was statistically significant improvement in uncorrected visual acuity and best-corrected visual acuity between the preoperative and 6-month evaluations (P<0.001). Total HOAs and total coma were statistically significantly reduced at 6 months by 25% and 18%, respectively. Significant improvement was seen in spherical aberration by 8.71% (P<0.001), while no significant change was observed in trefoil and high order astigmatism (P=0.405 and 0.329, respectively). There was a statistically significant change in the average (K) value at the apex between the preoperative values and the 6-month values (P<0.05). CONCLUSION: Total HOAs, total coma, and spherical aberrations decreased after CXL. Coma has a direct relationship with the improvement of visual function. PMID- 28860695 TI - The effect of vitreomacular adhesion in exudative age-related macular degeneration on the results of ranibizumab intravitreal injection. AB - PURPOSE: To investigate whether vitreomacular adhesion (VMA) affects the outcome of anti-vascular endothelial growth factor (VEGF) therapy for the treatment of exudative age-related macular degeneration (AMD) in Japanese patients. SUBJECTS AND METHODS: Of 88 Japanese AMD patients (28 men and 60 women, mean age: 72.7+/ 7.5 years) who underwent intravitreal injection of ranibizumab for 3 years from 2010 to 2013, this study involved 12 eyes of 12 patients (10 men and two women) in whom VMA was observed based on optical coherence tomography (OCT) findings (VMA [+] group) and 17 eyes of 16 patients (seven men and nine women, control group) in whom no VMA was observed (VMA [-] group). In all enrolled patients, ranibizumab was administered monthly for 3 months, and then administered as needed (ie, pro re nata) when deterioration was observed. The two groups were then compared in regard to changes in visual acuity (VA) and the frequency of ranibizumab administration over a 1-year period. RESULTS: No significant difference was found between the two groups in regard to the transformation of the mean logarithm of the minimum angle of resolution VA change after the first visit. Over the 1-year treatment, the mean frequency of ranibizumab administration for the VMA (+) group was 5.6+/-2.5 times and for the VMA (-) group was 3.8+/-1.1 times, thus illustrating a significant difference between the two groups (Mann-Whitney's U-test: P<0.05). CONCLUSION: Our findings show that the mean frequency of ranibizumab administration for the VMA (+) group was higher than that in the VMA (-) group, thus indicating that VMA might possibly be involved in the progress of AMD pathology. PMID- 28860696 TI - Telemedicine for diabetic retinopathy screening using an ultra-widefield fundus camera. AB - OBJECTIVE: Telemedicine reporting of diabetic retinopathy (DR) screening using ultra-widefield (UWF) fundus camera. MATERIALS AND METHODS: Cross-sectional study of diabetic patients who visited the endocrinology department of a private multi specialty hospital in United Arab Emirates between April 2015 and January 2017 who underwent UWF fundus imaging. Fundus pictures are then accessed at the Retina Clinic in the Department of Ophthalmology. Primary outcome measure was incidence of any form of DR detected. The secondary outcome measure was failure to take good image and inability to grade. RESULTS: A total of 1,024 diabetic individuals were screened for DR from April 2015 to January 2017 in the department of Endocrinology. Rate of DR was 9.27%; 165 eyes of 95 individuals were diagnosed to have some form of DR. Mild non-proliferative DR (NPDR) was seen in 114 of 165 eyes (69.09%), moderate NPDR in 32 eyes (19.39%), severe NPDR in six eyes (3.64%), and proliferative DR (PDR) in 13 eyes (7.88%). The secondary outcome measure of poor image acquisition was seen in one individual who had an image acquired in one eye that could not be graded due to bad picture quality. CONCLUSIONS: The present study has shown the effectiveness of DR screening using UWF fundus camera. It has shown the effectiveness of trained nursing personnel taking fundus images. This model can be replicated in any private multi-specialty hospital and reduce the burden of DR screening in the retina clinic and enhance early detection of treatable DR. PMID- 28860697 TI - Ptosis after glaucoma surgery. AB - PURPOSE: Evaluate factors contributing to ptosis after glaucoma surgery. METHODS: Three-year retrospective chart review from January 1, 2012, to January 1, 2015, 157 eyes, 3 surgeons, at Boston Medical Center, to determine the incidence of ptosis and the effects of each variable contributing to ptosis at 3 months after surgery. Each variable was analyzed using the chi-square or independent samples t test analysis to determine statistical significance of ptosis compared with above variables. RESULTS: The t-test or chi-square analysis showed that gender, steroid duration, use of mitomycin C, duration of surgery, and prior surgeries were not statistically significant factors for ptosis. There was a statistically significant association between those <70 years of age and ptosis (P<0.05), non combined surgery and ptosis (P<0.05), shunting surgery and ptosis (P<0.05). CONCLUSION: Ptotic changes occurred more often in those who have shunting (Ahmed and Baerveldt) surgeries compared with filtering (trabeculectomy and Express) surgeries. PMID- 28860698 TI - The effect of intravitreal injections on dry eye, and proposed management strategies. AB - Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents has become a commonly used treatment method for a number of ophthalmic conditions, including age-related macular degeneration. Although anti-VEGF therapy has shown promising results for many patients, there are several aspects of its application that have not been thoroughly investigated. One of these is the development and/or escalation of concurrent dry eye syndrome. Many patients undergoing treatment are already predisposed to dry eye disease due to their age and overall ocular health. As dry eye can have a substantial impact on quality of life, it has become increasingly apparent that the clinical signs and symptoms should be closely monitored and aggressively managed. This will allow for the optimization of patient comfort and visual potential. Here, we discuss the reasons why dry eye may develop during the course of repeated ocular anti-VEGF therapy, highlighting the key concerns about current practices and proposing possible solutions to improve the outcome for the patients. PMID- 28860699 TI - Alteration of retinal layers in healthy subjects over 60 years of age until nonagenarians. AB - PURPOSE: To assess alterations of retinal layers in healthy subjects over 60 years old. METHODS: Retinal layers of 160 healthy subjects (aged 60-100 years) without any retinal pathology were imaged using spectral domain optical coherence tomography. Mean thickness of retinal nerve fiber layer, ganglion cell/inner plexiform layer (GCLIPL), inner nuclear layer, outer plexiform layer/outer nuclear layer, photoreceptor complex (PR) and retinal thickness (RT) were measured in a 3.45 mm grid. Correlations between age and layers were estimated and linear regression equations were calculated. Different age-groups (60-69, 70 79, 80-89 years and nonagenarians, each group with 40 participants) were compared. RESULTS: Significant age-thickness correlations were observed for GCLIPL (P<0.001, r=-0.394), PR (P<0.001, r=-0.370) and RT (P<0.001, r=-0.290). A comparison between age groups 60-69 years and nonagenarians showed no significant thickness alteration of retinal nerve fiber layer (21.80+/-2.18 MUm vs 22.82+/ 2.97 MUm, P=0.163), inner nuclear layer (37.23+/-3.02 MUm vs 36.01+/-3.24 MUm, P=0.07) and outer plexiform layer/outer nuclear layer (104.95+/-6.56 MUm vs 104.23+/-7.59 MUm, P=0.567), while GCLIPL (83.35+/-7.35 MUm vs 74.38+/-9.09 MUm), PR (83.03+/-3.31 MUm vs 79.34+/-2.09 MUm) and RT (330.64+/-12.63 MUm vs 316.83+/ 18.35 MUm) showed a significant decrease (P<0.001 for all). CONCLUSION: Our study provides normative data of alterations of retinal layers for persons aged 60 years to nonagenarians and indicates a continuous decrease of RT, PR, and GCLIPL. This data may be useful for clinical trials investigating macular diseases in older patients. PMID- 28860700 TI - Changes of outer retinal microstructures after photodynamic therapy for chronic central serous chorioretinopathy. AB - PURPOSE: To evaluate the morphological changes in retinal microstructures following modified photodynamic therapy (PDT) for chronic central serous chorioretinopathy. SUBJECTS AND METHODS: Retrospective study of 21 consecutive eyes (age, 59+/-8.0 years [mean +/- SD]) of 21 patients with chronic central serous chorioretinopathy. Inner foveal thickness (the distance between the internal limiting membrane and external limiting membrane), photoreceptor outer segment (PROS) length at the point without serous retinal detachment and choroidal thickness were assessed with enhanced depth imaging optical coherence tomography before treatment and at 1, 3 and 6 months after modified PDT. RESULTS: Six eyes had half-dose and 15 eyes had half-fluence PDT. PROS length within the irradiated area was significantly decreased by 3.9% at 1 month compared with that before modified PDT (43.5+/-5.72 and 40.5+/-7.53, P=0.020 [paired t-test]) and returned to baseline length at 3 and 6 months (43.0+/-5.42 and 43.5+/-4.33 MUm [mean +/- SD]; P=0.53 and 1.00 [paired t-test]). PROS length of the nonirradiated area at 1, 3 and 6 months after modified PDT did not significantly differ from that before PDT (41.8+/-6.35, 41.4+/-5.33, 41.9+/-4.67 and 42.3+/-4.26 MUm [mean +/- SD]; P=0.66, 0.90 and 0.60, respectively [paired t-test]). There was no significant change in inner foveal thickness during the observation period. At all time points, choroidal thickness was significantly thinner than it was before PDT (P<0.001, paired t-test). CONCLUSION: Modified PDT may cause mild temporary microstructural changes. PMID- 28860701 TI - Accuracy of Alcon WaveLight(r) EX500 optical pachymetry during LASIK. AB - PURPOSE: To study the accuracy and reliability of optical pachymetry using the Alcon WaveLight EX500 during laser-assisted in situ keratomileusis (LASIK). MATERIALS AND METHODS: This was a retrospective chart review of 90 eyes from 45 patients who had undergone LASIK (mean age 35.2+/-8.2 years; 19 males, 26 females). The WaveLight FS200 femtosecond laser was programmed to cut LASIK flaps at a desired depth of 120 MUm. Optical low-coherence reflectometry (WaveLight EX500) was used to measure central corneal thickness prior to lifting the flap, and the residual stromal bed immediately after excimer ablation. Flap thickness (FT) was calculated using simple subtraction. Optical coherence tomography (OCT) was used to measure central corneal thickness, flap thickness, and residual stromal bed in the postoperative period and the results compared to intraoperative measurements. RESULTS: Mean programmed FS200 FT was 119 MUm. Mean FT using EX500 optical pachymetry was 109 MUm. The difference between FS200- programmed and EX500-measured FT was 9 MUm (P<0.001). There was also a significant difference between the EX500 and OCT FT (109 MUm vs 119 MUm, respectively; P<0.001). CONCLUSION: FT values calculated using intraoperative EX500 optical pachymetry were significantly lower than programmed FS200 values or OCT measurements. PMID- 28860702 TI - Long-term structural retinal changes in patients with optic neuritis related to multiple sclerosis. AB - PURPOSE: To evaluate the long-term structural and functional outcome in patients with multiple sclerosis (MS) with and without a history of optic neuritis (ON). METHODS: This was a cross-sectional study of 82 patients diagnosed with MS between 2000 and 2006 from a tertiary hospital center in Denmark. Patients gave a self-reported history of ON, and functional (visual acuity and color vision) and structural (spectra domain optical coherence tomography) markers of vision were tested. RESULTS: Median age and MS duration at the time of the clinical examination were 49.9 years (range 30.7-72.6 years) and 13 years (range 9-15 years), respectively. ON was not associated with impairment of visual acuity or color vision. Twenty-three patients had a history of ON in at least one eye. Compared to non-affected patients, these had a lower inferior (109 vs 113 MUm, P=0.04) and temporal retinal nerve fiber layer (RNFL) thickness (56 vs 67 MUm, P=0.01). In an age- and sex-adjusted logistic regression model, lower inferior and temporal RNFL were associated with a higher risk of ON (odds ratio [OR] 1.56 [95% confidence interval {CI} 1.01-2.41] and OR 1.74 [95% CI 1.10-2.77] per 10 MUm decrement in RNFL thickness, respectively). Twenty patients had a history of ON in one eye. Compared to the non-affected eye, this eye had a lower RNFL (109 vs 115 MUm, P=0.04) and a higher central retinal thickness/mean RNFL ratio (2.7 vs 2.4, P=0.04). CONCLUSION: Although patients with long-term MS and a previous history of ON did not have any functional loss of vision, structural neurodegeneration could be demonstrated in the affected eye. PMID- 28860703 TI - Refractive changes after lens-sparing vitrectomy for macular hole and epiretinal membrane. AB - PURPOSE: Cataract progression after lens-sparing vitrectomy might differ according to original posterior segment diseases. Our objective was to analyze the refractive values after lens-sparing vitrectomy for macular hole (MH) and epiretinal membrane (ERM). MATERIALS AND METHODS: We reviewed the medical records of 25 MH patients (25 eyes) and 23 ERM patients (23 eyes) who underwent lens sparing vitrectomy. Refractive changes in both groups were compared. All patients underwent 20-gauge three-port pars plana vitrectomy. Fluid-air exchange was performed during vitrectomy only in the MH group. The results were analyzed using the unpaired t-test, chi-square test, or Fisher exact probability test, and multivariate analysis. RESULTS: There were no significant differences in the patient's age (P=0.45). The myopia progression rate (D/month) was higher in the MH group after surgery than that in the ERM group (P=0.035). MH group had more females (P=0.043), longer surgical time (P<0.001), and higher frequencies of surgical adjuvants use (triamcinolone acetonide, P=0.019; brilliant blue G, P<0.001). The myopia progression rate in the MH group (R=0.568, P<0.001) correlated with female gender. However, no correlation was observed between longer surgical time and the use of surgical adjuvants. CONCLUSION: The rate of myopia progression was higher in the MH group. Fluid-air exchange and gender may affect the rate of myopia progression. PMID- 28860704 TI - Retinal and choroidal thickness after femtosecond laser-assisted and standard phacoemulsification. AB - PURPOSE: The purpose of this study was to compare the short-term changes in retina and choroidal tissue after femtosecond laser-assisted cataract surgery (FLACS) and standard phacoemulsification (PE) surgery. METHODS: In all, 25 eyes undergoing FLACS and 27 eyes undergoing PE surgery were included in this nonrandomized, retrospective, cross-sectional study. Central retinal thickness (CRT) and choroidal thickness (CT) were measured pre- and postoperatively (at day 1, 1 week later, and after 1 month) with spectral domain optical coherence tomography (OCT) in all patients and were compared. For group comparisons, chi square test and independent t-test were used. Postoperative values were compared to the baseline using a paired t-test. The magnitude of the change from baseline to the peak was analyzed by multiple regression models in an attempt to explain possible influence variables. RESULTS: Pre and postoperative CRT measurements were similar in both groups. The mean subfoveal CT at day 1, after 1 week, and 1 month were significantly higher than baseline CT measurements in the PE group. CONCLUSION: FLACS might have an advantage in regard to postoperative choroidal changes. PMID- 28860705 TI - Phacoemulsification with primary implantation of an intraocular lens in patients with uveitis. AB - PURPOSE: To evaluate the outcome of cataract surgery in adult patients with uveitis. MATERIALS AND METHODS: In this retrospective cohort study, medical charts of patients with uveitis and matched control patients without uveitis who underwent cataract surgery at the Eye Clinic, Sahlgrenska University Hospital, Molndal, between January 2005 and December 2009 were analyzed. RESULTS: The study included 58 eyes with and 283 eyes without uveitis. The most common etiologies were idiopathic anterior uveitis and Fuchs' heterochromic uveitis. Postoperative visual acuity at 4 weeks was >=0.5 decimal (0.3 logMAR) in 48 eyes with uveitis (87.3%) compared to 180 non-uveitic eyes (86.1%). Four eyes with uveitis (7.1%) and one eye without uveitis (0.5%) developed postoperative intraocular hypertension/glaucoma. Posterior capsule opacification developed in 11 eyes (19.0%) with and 28 eyes (12.4%) without uveitis. CONCLUSION: With appropriate perioperative anti-inflammatory regimen and surveillance, modern cataract surgery using phacoemulsification and primary intraocular lens implantation can be performed in patients with uveitis without greater risk of complications, yielding similar visual outcome as in patients without uveitis. PMID- 28860706 TI - Investigation into the quantitative and qualitative characteristics of choroidal melanoma through magnetic resonance imaging and B-scan ultrasound. AB - OBJECTIVE: To investigate the homogeneity and vascularity of choroidal melanoma through magnetic resonance imaging (MRI) and brightness modulation (B-mode) ultrasound scan and their correlation with dimensions of tumor, as well as to measure the sensitivity of both modalities in retinal detachment (RD) detection. MATERIALS AND METHODS: This retrospective chart review included patients diagnosed with choroidal melanoma. All these patients underwent MRI scans using T2-weighted (T2-WI) and T1-weighted (T1-WI) sequences, before and after an intravenous injection of paramagnetic contrast material. The patients were also examined using a B-mode ultrasound scan, and the results from both modalities were compared (tumor homogeneity, tumor height, tumor base diameter, and tumor vascularity). RESULTS: Forty-two patients (mean age=65.33+/-12.51 years) with choroidal melanoma were included in the study. Homogeneity was confirmed in 16 patients through ultrasound scan, in 19 patients through T1-WI sequence, in 21 patients through T2-WI sequence, and in 25 patients through T1-WI sequence + contrast (gadolinium). Patients with homogenous tumors presented with lower (P=0.0045) mean height than that of those with nonhomogenous tumors, whereas no statistically significant difference was found for base diameter measurements (P=0.056). Patients with tumors of high vascularity presented with greater mean height (P=0.000638) and greater mean base diameter compared with those with tumors of low vascularity (P=0.019543). RD was detected in 26 patients through T1 WI sequence, in 13 patients through T2-WI sequence, in 26 patients through T1-WI sequence + contrast, and in 32 patients through ultrasound scan, which proved to be the most sensitive modality. CONCLUSION: The height of choroidal melanoma was positively correlated with tumor's homogeneity. Melanomas of greater height were found to be less homogenous, due to increased degeneration and higher occurrence of intratumoral hemorrhage. In addition, choroidal melanoma's height was also positively correlated with the level of its vascularity. Finally, ultrasound scan was found to be more sensitive than MRI in the detection of RD. PMID- 28860707 TI - Widening use of dexamethasone implant for the treatment of macular edema. AB - Sustained-release intravitreal 0.7 mg dexamethasone (DEX) implant is approved in Europe for the treatment of macular edema related to diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion, and non-infectious uveitis. The implant is formulated in a biodegradable copolymer to release the active ingredient within the vitreous chamber for up to 6 months after an intravitreal injection, allowing a prolonged interval of efficacy between injections with a good safety profile. Various other ocular pathologies with inflammatory etiopathogeneses associated with macular edema have been treated by DEX implant, including neovascular age-related macular degeneration, Irvine-Gass syndrome, vasoproliferative retinal tumors, retinal telangiectasia, Coats' disease, radiation maculopathy, retinitis pigmentosa, and macular edema secondary to scleral buckling and pars plana vitrectomy. We undertook a review to provide a comprehensive collection of all of the diseases that benefit from the use of the sustained-release DEX implant, alone or in combination with concomitant therapies. A MEDLINE search revealed lack of randomized controlled trials related to these indications. Therefore we included and analyzed all available studies (retrospective and prospective, comparative and non-comparative, randomized and nonrandomized, single center and multicenter, and case report). There are reports in the literature of the use of DEX implant across a range of macular edema related pathologies, with their clinical experience supporting the use of DEX implant on a case-by-case basis with the aim of improving patient outcomes in many macular pathologies. As many of the reported macular pathologies are difficult to treat, a new treatment option that has a beneficial influence on the clinical course of the disease may be useful in clinical practice. PMID- 28860708 TI - Onychomadesis associated with chemotherapy: case report and mini literature review. AB - The side effects of chemotherapy drugs have increased in recent years, and some side effects can lead to onychomadesis. A 72-year-old woman who was diagnosed with an invasive ductal carcinoma of the right breast underwent a modified radical mastectomy in April 2015, followed by chemotherapy with capecitabine and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Subsequently, the patient experienced palmoplantar redness, pain, onycholysis, a transparent serous exudate, and onychomadesis. The chemotherapy was discontinued, and the patient was treated with oral vitamin B6, a polymyxin ointment, and a high-energy red light. The palmoplantar redness and pain were alleviated after 1 month. However, although her fingernails improved, dysesthesia symptoms remained, and all her toenails exhibited defects or deformities at a 24-month follow-up. The symptoms of this disorder should be recognized by dermatologists. PMID- 28860709 TI - alpha-melanocyte stimulating hormone modulates the central acyl ghrelin-induced stimulation of feeding, gastrointestinal motility, and colonic secretion. AB - BACKGROUND: Acyl ghrelin-induced intake depends on hypothalamic neuropeptide Y and agouti-related protein (AgRP) neurotransmitters. Intracerebroventricular (ICV) injection of AgRP increases feeding through competitive antagonism at melanocortin receptors. ICV administration of alpha-melanocyte stimulating hormone (alpha-MSH), a natural antagonist of AgRP, may modulate the acyl ghrelin induced orexigenic effect. OBJECTIVE: This study aimed to investigate the modulating effect of alpha-MSH on the central acyl ghrelin-induced food intake, gastrointestinal motility, and colonic secretion in rats. METHODS AND PROCEDURES: We examined the effects of alpha-MSH and acyl ghrelin on food intake, gastric emptying, small intestinal transit, colonic motility, and secretion in conscious rats with a chronic implant of ICV catheters. RESULTS: ICV injection of O-n octanoylated ghrelin (0.1 nmol/rat) significantly increased the cumulative food intake up to 8 h (P<0.01), enhanced non-nutrient semi-liquid gastric emptying (P<0.001), increased the geometric center and running percentage of small intestinal transit (P<0.001), accelerated colonic transit time (P<0.05), and increased fecal pellet output (P<0.01) and total fecal weight (P<0.01). Pretreatment with ICV injection of alpha-MSH (1.0 and 2.0 nmol/rat) attenuated the acyl ghrelin-induced hyperphagic effect, fecal pellet output, and total fecal weight, while higher dose of alpha-MSH (2.0 nmol/rat) attenuated the increase in the geometric center of small intestinal transit (P<0.01). However, neither dose of alpha-MSH altered acyl ghrelin-stimulated gastroprokinetic effect, increase in the running percentage of small intestinal transit, nor accelerated colonic transit time. CONCLUSION: alpha-MSH is involved in central acyl ghrelin-elicited feeding, small intestinal transit, fecal pellet output, and fecal weight. alpha MSH does not affect central acyl ghrelin-induced acceleration of gastric emptying and colonic transit time in rats. PMID- 28860710 TI - Alginate oligosaccharide alleviates myocardial reperfusion injury by inhibiting nitrative and oxidative stress and endoplasmic reticulum stress-mediated apoptosis. AB - Alginate oligosaccharide (AOS) has recently demonstrated the ability to protect against acute doxorubicin cardiotoxicity and neurodegenerative disorders by inhibiting oxidative stress and endoplasmic reticulum (ER) stress-mediated apoptosis, which are both involved in myocardial ischemia/reperfusion (I/R) injury. In the present study, we investigated whether pretreatment with AOS protects against myocardial I/R injury in mice and explored potential cardioprotective mechanisms. AOS pretreatment significantly decreased the infarct size, reduced the cardiac troponin-I concentration, and ameliorated the cardiac dysfunction. Accompanied with the reduced cardiac injury, AOS pretreatment clearly decreased I/R-induced myocardial apoptosis. With regard to mechanism, AOS pretreatment markedly attenuated nitrative/oxidative stress, as evidenced by decreases in 3-nitrotyrosine content and superoxide generation, and downregulated inducible nitric oxide synthase, NADPH oxidase2, and 4-hydroxynonenal. Moreover, AOS pretreatment decreased myocardial apoptosis by inhibiting the ER stress mediated apoptosis pathway, which is reflected by the downregulation of C/EBP homologous protein, glucose-regulated protein 78, caspase-12, and Bcl-2 associated X protein, and by the upregulation of the anti-apoptotic protein B cell lymphoma-2. Collectively, these findings demonstrate that AOS renders the heart resistant to I/R injury, at least in part, by inhibiting nitrative/oxidative stress and ER stress-mediated apoptosis. PMID- 28860711 TI - Pomalidomide in the treatment of multiple myeloma: design, development and place in therapy. AB - Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and refractory disease have a poor outcome. Immunomodulatory drugs play a key role in both the front-line and the relapsed/refractory setting. The combination of pomalidomide (POM) and dexamethasone is safe and effective in relapsed and refractory patients, even in those with high-risk cytogenetic features. Furthermore, it can be used in most patients without the need to adjust according to the degree of renal failure. In order to further improve the results, POM based triplet therapies are currently used. This article highlights the most relevant issues of POM and POM-based combinations in the relapsed/refractory multiple myeloma setting, from a pharmacological and clinical point of view. PMID- 28860712 TI - A comparison of oral controlled-release morphine and oxycodone with transdermal formulations of buprenorphine and fentanyl in the treatment of severe pain in cancer patients. AB - AIM OF THE STUDY: To compare analgesia and adverse effects during oral morphine and oxycodone and transdermal fentanyl and buprenorphine administration in cancer patients with pain. PATIENTS AND METHODS: Cancer patients treated at home and in outpatient clinics with severe pain (numerical rating scale score 6-10) fail to respond to non-opioids and/or weak opioids. All patients were randomized to either morphine, oxycodone, fentanyl or buprenorphine and divided into subgroups with predominant neuropathic and nociceptive pain component. Doses of opioids were titrated to satisfactory analgesia and acceptable adverse effects intensity. Patients were assessed at baseline and followed for 28 days. In all patient groups, immediate-release oral morphine was the rescue analgesic and lactulose 10 mL twice daily was the prophylaxis of constipation; no antiemetics were used as prophylaxis. RESULTS: A total of 62 patients participated and 53 patients completed the study. Good analgesia was obtained for all 4 opioids, for both nociceptive and neuropathic pain. The use of co-analgesics was greater in patients with neuropathic pain. Morphine treatment was associated with less negative impact of pain on ability to walk, work and activity (trend) according to Brief Pain Inventory-Short Form scores and less consumption of rescue morphine. The most common adverse effects included nausea and drowsiness, which increased at the beginning of the treatment and gradually decreased over the days to come. Appetite, well-being, anxiety, depression, and fatigue improved. There was no constipation (the Bowel Function Index scores were within normal range) during the treatment with all opioids. No changes were seen for constipation, vomiting and dyspnea. CONCLUSION: All opioids were effective and well-tolerated. Morphine was the most effective in the improvement in some of the Brief Pain Inventory-Short Form items regarding negative impact of pain on patients' daily activities. Prophylaxis of constipation was effective; antiemetics may be considered for nausea prevention. PMID- 28860714 TI - Sensitization of gastric cancer cells to alkylating agents by glaucocalyxin B via cell cycle arrest and enhanced cell death. AB - Severe side effects are major problems with chemotherapy of gastric cancer (GC). These side effects can be reduced by using sensitizing agents in combination with therapeutic drugs. In this study, the low/nontoxic dosage of glaucocalyxin B (GLB) was used with other DNA linker agents mitomycin C (MMC), cisplatin (DDP), or cyclophosphamide (CTX) to treat GC cells. Combined effectiveness of GLB with drugs was determined by proliferation assay. The molecular mechanisms associated with cell proliferation, migration, invasion, cell cycle, DNA repair/replication, apoptosis, and autophagy were investigated by immunoblotting for key proteins involved. Cell cycle and apoptosis analysis were performed by flow cytometry. Reactive oxygen species level was also examined for identification of its role in apoptosis. Proliferation assay revealed that the addition of 5 uM GLB significantly sensitizes gastric cancer SGC-7901 cells to MMC, DDP, and CTX by decreasing half-maximal inhibitory concentration (IC50) by up to 75.40%+/-5%, 45.10%+/-5%, and 52.10%+/-5%, respectively. GLB + drugs decreased the expression level of proteins involved in proliferation and migration, suggesting the anticancer potential of GLB + drugs. GLB + MMC, GLB + CTX, and GLB + DDP arrest the cells in G0/G1 and G1/S phase, respectively, which may be the consequence of significant decrease in the level of enzymes responsible for DNA replication and telomerase shortening. Combined use of GLB with these drugs also induces DNA damage and apoptosis by activating caspase/PARP pathways and increased production of reactive oxygen species and increased autophagy in GC cells. GLB dosage sensitizes GC cells to the alkylating agents via arresting the cell cycle and enhancing cell death. This is of significant therapeutic importance in the reduction of side effects associated with these drugs. PMID- 28860713 TI - Metformin: a review of its potential indications. AB - Metformin is the most commonly prescribed drug for type 2 diabetes mellitus. In recent years, in addition to glucose lowering, several studies have presented evidence suggesting some potential role for metformin, such as antitumor effect, antiaging effect, cardiovascular protective effect, neuroprotective effect or an optional treatment for polycystic ovary syndrome. This paper will critically review the role of metformin to provide reference for doctors and researchers. PMID- 28860715 TI - Aceclofenac nanocrystals with enhanced in vitro, in vivo performance: formulation optimization, characterization, analgesic and acute toxicity studies. AB - This study was aimed to enhance the dissolution rate, oral bioavailability and analgesic potential of the aceclofenac (AC) in the form of nanosuspension using cost-effective simple precipitation-ultrasonication approach. The nanocrystals were produced using the optimum conditions investigated for AC. The minimum particle size (PS) and polydispersity index was found to be 112+/-2.01 nm and 0.165, respectively, using hydroxypropyl methylcellulose (1%, w/w), polyvinylpyrrolidone K30 (1%, w/w) and sodium lauryl sulfate (0.12%, w/w). The characterization of AC was performed using zeta sizer, scanning electron microscopy, transmission electron microscopy, powder X-ray diffraction and differential scanning calorimetry. The saturation solubility of the AC nanocrystals was substantially increased 2.6- and 4.5-fold compared to its unprocessed active pharmaceutical ingredient in stabilizer solution and unprocessed drug. Similarly, the dissolution rate of the AC nanocrystals was substantially enhanced compared to its other counterpart. The results showed that >88% of AC nanocrystals were dissolved in first 10 min compared to unprocessed AC (8.38%), microsuspension (66.65%) and its marketed tablets (17.65%). The in vivo studies of the produced stabilized nanosuspension demonstrated that the Cmax were 4.98- and 2.80-fold while area under curve from time of administration to 24 h (AUC0->24 h) were found 3.88- and 2.10-fold greater when compared with unprocessed drug and its marketed formulation, respectively. The improved antinociceptive activity of AC nanocrystals was shown at much lower doses as compared to unprocessed drug, which is purely because of nanonization which may be attributed to improved solubility and dissolution rate of AC, ultimately resulting in its faster rate of absorption. PMID- 28860716 TI - Preliminary study of nanonized lamotrigine containing products for nasal powder formulation. AB - The nasal delivery of drugs offers a great alternative route to avoid adverse events and to increase patient compliance due to its advantageous properties. Besides nasal application, topical, systemic and central effects are also available. Nasal powders (NPs) have better adhesion due to the additive polymers that may be, eg, gelling or good wettability agents; thus, their bioavailability is better compared to the liquid formulations. Using nanoparticles, innovative and more efficient products can be achieved, which may lead to the improvement of different therapies. The aim of this study was to produce NP formulations containing lamotrigine (LAM) as interactive physical mixtures and nanosized LAM based formulations. After risk assessment of the preliminary tests, the micrometric properties (particle size and morphology) and the structural properties (differential scanning calorimetry [DSC], X-ray powder diffraction [XRPD]) were investigated; thereafter, physicochemical properties (solubility, polarity) and in vitro dissolution and diffusion profiles were also examined. These product samples showed an appropriate particle size ranging 10-25 um, while the particle size of LAM in the products was between 120 and 230 nm and the dissolved amount of drug was >60% after 5 minutes in these cases. PMID- 28860719 TI - The relationship between patient satisfaction and emotional intelligence skills of nurses working in surgical clinics. AB - OBJECTIVE: The aim of this study was to investigate the relationship between the patient satisfaction and emotional intelligence skills of nurses working in the surgical clinic. METHODS: The study included two groups: a total of 79 nurses working for the surgical clinics of a university hospital in the city of Izmir and a total of 113 inpatients between January 1 and February 20, 2015. The nurses were asked to fill out the Emotional Intelligence Scale and a 12-question self description form, while the patients were given the Scale of Satisfaction for Nursing Care and an 11-question self-description form. RESULTS: We found a positive and statistically significant relationship between the satisfaction scores and emphatic concern, utilization of emotions, and emotional awareness subheadings of the patients (P<0.05). CONCLUSION: Our study results suggest that emotional intelligence should be one of the determinants of the objectives and that it should be recognized among the quality indicators to improve the quality of health care services. PMID- 28860718 TI - Paeoniflorin suppresses pancreatic cancer cell growth by upregulating HTRA3 expression. AB - Paeoniflorin (PF) is an active monoterpene glycoside extracted from Paeonia lactiflora Pall. PF has exhibited antitumor effects in various cancer types. However, the effects of PF in pancreatic cancer are largely unexplored. Here, we showed that PF suppressed growth of pancreatic cancer cell lines Capan-1 and MIAPaCa-2 and profoundly sensitized these cells to X-ray irradiation. Through microarray analysis, we identified HTRA3, a tumor-suppressor candidate gene, as the most increased gene upon PF treatment in Capan-1 cells. Ectopic expression of HTRA3 led to reduced cell proliferation and increased expression of apoptotic protein Bax, suggesting a tumor suppressive role of HTRA3 in pancreatic cancer cells. Together, our results provide a set group of genetic proofs and biological proofs that PF inhibited pancreatic cancer growth by upregulating HTRA3. PMID- 28860717 TI - Development of idursulfase therapy for mucopolysaccharidosis type II (Hunter syndrome): the past, the present and the future. AB - Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare, multisystemic, progressive lysosomal storage disease caused by deficient activity of the iduronate-2-sulfatase (I2S) enzyme. Accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate results in a broad range of disease manifestations that are highly variable in presentation and severity; notably, approximately two-thirds of individuals are affected by progressive central nervous system involvement. Historically, management of this disease was palliative; however, during the 1990s, I2S was purified to homogeneity for the first time, leading to cloning of the corresponding gene and offering a means of addressing the underlying cause of MPS II using enzyme replacement therapy (ERT). Recombinant I2S (idursulfase) was produced for ERT using a human cell line and was shown to be indistinguishable from endogenous I2S. Preclinical studies utilizing the intravenous route of administration provided valuable insights that informed the design of the subsequent clinical studies. The pivotal Phase II/III clinical trial of intravenous idursulfase (Elaprase(r); Shire, Lexington, MA, USA) demonstrated improvements in a range of clinical parameters; based on these findings, intravenous idursulfase was approved for use in patients with MPS II in the USA in 2006 and in Europe and Japan in 2007. Evidence gained from post approval programs has helped to improve our knowledge and understanding of management of patients with the disease; as a result, idursulfase is now available to young pediatric patients, and in some countries patients have the option to receive their infusions at home. Although ERT with idursulfase has been shown to improve somatic signs and symptoms of MPS II, the drug does not cross the blood-brain barrier and so treatment of neurological aspects of the disease remains challenging. A number of novel approaches are being investigated, and these may help to improve the care of patients with MPS II in the future. PMID- 28860720 TI - Construct validity of patient-reported outcome instruments in US adults with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P FiQ) study. AB - BACKGROUND: People with hemophilia (PWH) experience frequent joint bleeding, resulting in pain and functional impairment. Generic and disease-specific patient reported outcome (PRO) instruments have been used in clinical studies, but rarely in the comprehensive hemophilia care setting. OBJECTIVE: The objective of this study was to assess construct validity of PRO instruments measuring pain, functional impairment, and health-related quality of life in US PWH with a history of joint pain/bleeding. METHODS: Adult male PWH completed 4 PRO instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], SF-36v2, Hemophilia Activities List [HAL]) and underwent a musculoskeletal examination (Hemophilia Joint Health Score v2.1 [HJHS]). Construct validity between index and domain scores was evaluated by Pearson product-moment correlation coefficient. RESULTS: A total of 381 PWH were enrolled. EQ-5D-5L Mobility correlated with BPI, SF-36v2, and HAL domains related to pain, physical function, and activity of the lower extremities. EQ-5D-5L Self Care correlated only with HAL Self-Care. EQ-5D-5L Usual Activities correlated with BPI Pain Interference and domains within SF-36v2 and HAL related to pain and physical function/activities (particularly those involving the lower extremities). EQ-5D-5L Pain/Discomfort correlated with Bodily Pain and Physical Summary on SF-36v2, HAL Overall Activity, and all BPI pain domains. EQ-5D-5L Anxiety/Depression correlated with social/emotional/mental aspects of SF-36v2. On BPI, most pain domains correlated with Bodily Pain and Physical Health Summary on SF-36v2 and Overall Activity on HAL. On SF-36v2, Physical Functioning, Role Physical, Bodily Pain, and Physical Health summary scores correlated with all the domains of HAL except Self-Care. For HJHS, Ankle and Total scores correlated with SF-36v2 Physical Functioning and HAL Lying/Sitting, Leg Function, Complex Lower Extremity Activity, and Overall Activity. CONCLUSION: All PRO instruments have high construct validity but provide different levels of detail in describing effects of hemophilia. Instrument choice may depend on individuals' symptoms, treatment planning goals, or outcome tracking research objectives, with consideration for administrative burden. PMID- 28860721 TI - Satisfaction and expressed needs of pharmaceutical care services and challenges recognized by patients in South Korea. AB - PURPOSE: To assess the degree of satisfaction and expressed needs of pharmaceutical care services in patients with chronic diseases and explore the factors related to the needs from patients' perspectives for the further development of pharmaceutical care service models. PATIENTS AND METHODS: A cross sectional survey of 220 patients (mean age +/- SD: 61.3+/-13.1, male:female: 104:116) was conducted. The questionnaire was structured to measure patients' degree of satisfaction and expressed needs using a 5-point Likert scale. Additionally, preferred duration, methods of service delivery, and willingness to pay were surveyed. Responses were analyzed using an ordinal regression method to predict factors that were related to pharmaceutical care services. RESULTS: Sixty seven patients had experienced pharmaceutical care services. Their satisfaction levels were high in all categories; however, there were no significant differences between categories. The levels of expressed needs were similar among categories without significant differences. The preferred delivery method was a face-to-face conversation combined with being provided with written information (53.2%). The preferred duration was <=10 min (70.5%). About 48% of the patients showed willingness to pay for the service. Education level and region influenced patients' needs. CONCLUSION: The satisfaction and needs of pharmaceutical care services was very positive; however, noticing only a third of patients experienced pharmaceutical care services, this may indicate a lack of awareness and less appreciation of pharmacists by patients. Details concerning patients' awareness and the value of pharmaceutical care services require further investigation. PMID- 28860722 TI - Patient and oncologist preferences for attributes of treatments in advanced melanoma: a discrete choice experiment. AB - PURPOSE: To examine and compare patient and oncologist preferences for advanced melanoma treatment attributes and to document their trade-offs for benefits with risks. MATERIALS AND METHODS: A discrete choice experiment (DCE) was conducted among advanced melanoma patients and oncologists. Qualitative pilot testing was used to inform the DCE design. A series of scenarios asked stakeholders to choose between two hypothetical medications, each with seven attributes: mode of administration (MoA), dosing schedule (DS), median duration of therapy (MDT), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and grade 3-4 adverse events (AEs). Hierarchical Bayesian logistic regression models were used to determine patients' and oncologists' choice-based preferences, analysis of variance models were used to estimate the relative importance of attributes, and independent t-tests were used to compare relative importance estimates between stakeholders. RESULTS: In total, 200 patients and 226 oncologists completed the study. OS was most important to patients (33%), followed by AEs (29%) and ORR (25%). For oncologists, AEs were most important (49%), followed by OS (34%) and ORR (12%). An improvement from 55% to 75% in 1 year OS was valued similar in magnitude to a 23% decrease (from 55% to 32%) in likelihood of AEs for oncologists. CONCLUSION: Patients valued OS, AEs, and ORR sequentially as the most important attributes in making a treatment decision, whereas oncologists valued AEs most, followed by OS and ORR. In comparison, patients differed significantly from oncologists on the importance of ORR, AEs, and PFS, but were consistent in OS and the rest of attributes. PMID- 28860723 TI - Self-care management strategies used by Black women who self-report consistent adherence to antihypertensive medication. AB - BACKGROUND: Black women in the USA have the highest prevalence rate of hypertension (HTN) contributing to a higher risk of organ damage and death. Research has focused primarily on poorly controlled HTN, negative belief systems, and nonadherence factors that hinder blood pressure control. No known research studies underscore predominantly Black women who report consistent adherence to their antihypertensive medication-taking. The purpose of this study was to describe self-care management strategies used by Black women who self-report consistent adherence to their antihypertensive medication and to determine the existence of further participation in lifestyle modifications, such as eating a healthy diet and increasing physical activity. METHODS: Using a qualitative descriptive design, four focus groups with a total of 20 Black women aged 25-71 years were audio-taped. Transcripts were analyzed using qualitative content analysis. Participants were included in the study if they scored perfect adherence on the medication subscale of the Hill-Bone Compliance to High Blood Pressure Therapy Scale. RESULTS: Medication adherence was predicated on three themes: HTN experience, involvement with treatment regimen, and a strong motivated mentality. Black women would benefit from treatment approaches that are sensitive to 1) diverse emotional responses, knowledge levels, and life experiences; 2) two-way communication and trusting, collaborative relationships with active involvement in the treatment regimen; 3) lifestyle modifications that focus on health benefits and individual preferences; and 4) spiritual/religious influences on adherence. CONCLUSION: The use of self-care management strategies to enhance antihypertensive medication adherence is key to adequate blood pressure control and the reduction of cardiovascular events. This study provides preliminary insight for future research to develop interventions to aid those Black women who struggle with medication adherence and are disproportionately impacted by HTN. PMID- 28860724 TI - "Patients' understanding is the problem": physicians' views of nonadherence among Arabs with type 2 diabetes. AB - PURPOSE: Nonadherence to diabetes medication is a significant barrier toward achieving positive treatment outcomes. There is an abundance of research looking at the problem from the patient perspective, but less from the provider perspective. The Middle East region has one of the highest prevalences of type 2 diabetes in the world, with special cultural characteristics, which require research attention. The aim of this study was to explore the views of primary care physicians on medication nonadherence among type 2 diabetes patients. MATERIALS AND METHODS: A descriptive qualitative study was performed using one-on one semistructured interviews of 21 primary-care physicians who were selected using stratified and random sampling from polyclinics in the five health districts in Kuwait. The interviews elicited the participants' views about barriers and facilitators of medication adherence in type 2 diabetes patients. The interviews were audio-recorded and transcribed verbatim. Thematic content analysis with constant comparison was used to generate the codes and themes to arrive at a core category. RESULTS: Patient understanding, including knowledge, beliefs, and attitudes, was identified by respondents as the core determinant of medication nonadherence in type 2 diabetes. This was composed of six major themes: four against understanding and two for understanding. The ones against were "Patients do not understand diabetes", "Patients do not understand the importance of medications", "What the patient hears from friends is more important than what the doctor says", "Patients are in denial (or difficult)". Themes for understanding were "I need to educate more" and "Patients must hear it from other sources". CONCLUSION: That lack of understanding among patients results in medication nonadherence is the dominant view of primary-care physicians. This finding has implications in relation to the evolution of diabetes care toward more patient-centeredness within the cultural context. PMID- 28860725 TI - Approval rating and opinion of outpatients and general practitioners toward generic drugs: a questionnaire-based real-world study. AB - PURPOSE: Generic drugs use in the Liguria region is higher than the Italian average, but lower than in other European countries. No data exist about real life prescription and level of awareness of generic drugs. In this study, we analyzed demographic, social, economic and cultural factors that may affect the level of awareness of generic drugs and their effective use. METHODS: We conducted a population survey using a structured questionnaire, administered to a sample of 8 outpatient clinics of general practitioners located in different districts of Genoa (Liguria, Italy). Multivariate logistic modeling was adopted to study the relationship between awareness/use of generic drugs and characteristics of subjects. RESULTS: Out of 2,000 outpatients surveyed, 95% were aware of generic drugs: these were mostly females (OR =2.2, 95% CI: 1.4-3.6), >35 years old (OR >6.0 vs 18-35 years), with a high level of education (OR >4.4 vs "elementary sch"), living in the west side of the city (OR =1.9 vs center); of these, only 59% declared that they effectively use generic drugs. Users were younger (OR =3.1, 18-35 years vs >65 years), with a high level of education (high school/university degree vs no title/elementary/secondary school OR =1.7), and were aware of the lower cost compared with branded drugs, and were mainly informed by pharmacists and physicians. CONCLUSIONS: Although subjects were substantially aware of the existence of generic drugs, ~40% still did not use them; doubts about their efficacy seem to be mainly driven by the idea that cheaper drugs lead to lower product quality, in terms of efficacy, safety and tolerability. New education policies on generic drugs are needed. PMID- 28860726 TI - Defining the rehabilitation adherence curve and adherence phases of stroke patients: an observational study. AB - BACKGROUND: Patient adherence is a crucial determinant of rehabilitation in the long term after stroke. However, adherence is inconstant and fluctuates along a time course, and the underlying regular pattern of adherence variation remains to be clarified. OBJECTIVE: We aimed to describe the longitudinal pattern of adherence to rehabilitation exercises in stroke patients and to determine different adherence phases based on formulated rehabilitation adherence curve. PATIENTS AND METHODS: Rehabilitation adherence levels were prospectively collected using the Questionnaire of Exercise Adherence (EAQ) among patients diagnosed with first-onset stroke since the second week of stroke onset, with a follow-up of 24 weeks. SPSS19.0 was used to formulate a fitting curve based on a scatter diagram. Possible causal factors for the different adherence phases are also discussed from the psychological, socioeconomic, and behavioral aspects. RESULTS: A total of 98 patients were included in this study. General adherence of the included subjects was classified as low to medium during follow-up. The adherence fitting curve was an "S" curve, with the fitting function y =0.005x3 0.211x2+1.963x+52.345. Three phases, namely, rapid increase phase, slow decrease phase, and stable phase, were identified based on the adherence curve, and relevant theories are explored. CONCLUSION: Rehabilitation adherence of stroke patients is a dynamic behavioral process that continuously changes along a time course, with a regular pattern of an "S" curve and includes a rapid increase phase, a slow decrease phase, and a stable phase. PMID- 28860728 TI - Patient-provider concordance in the perception of illness and disease: a cross sectional study among multimorbid patients and their general practitioners in Switzerland. AB - BACKGROUND: Multiple chronic health conditions are leading to multiple treatment procedures and polypharmacy. Prioritizing treatment according to patients' needs and preferences may be helpful for deprescribing. Thus, for improving health care, it is crucial for general practitioners (GPs) to perceive the chief complaints (CCs) of patients. The primary aim of this study was to investigate the patient-provider concordance of CCs and the secondary aim was to investigate the concordance between CCs and diagnosis, in a sample of Swiss multimorbid patients. MATERIALS AND METHODS: A cross-sectional analysis based on a cluster randomized controlled trial (RCT) among 46 GPs, recruited between March 2015 to July 2016, and 334 multimorbid patients (>=60 years taking >=5 drugs for at least 6 months) in Northern Switzerland was performed. CCs listed by GPs and by patients (n=128) were classified according to the International Classification of Primary Care, version 2 (ICPC-2) coding system on chapter and component level and defined as concordant if ICPC-2 codes of patients and GPs were identical. Concordance was classified into full, moderate or low, depending on the ranking of patients' CCs on GPs' list. As secondary outcome, we compared patients' CCs to GPs' diagnosis. Statistics included descriptive measures and a multivariate regression analysis of factors that are modifying concordance. RESULTS: The mean age of patients was 76.9 (SD 8.1) years, where 38% were male, taking 7.9 (SD 2.6) drugs on the long term. The most frequent complaint was pain. Concordance of the CC was given in 101/128 (78.9%) on the ICPC-2 chapter level, whereby 86/128 (67.2%) showed full, 8/128 (6.3%) moderate and 7/128 (5.5%) low concordance; 27/128 (21.1%) were discordant. Concordance between CCs and diagnosis was 53.6%. Concordance increased with the intensity of the CC rated by patients (OR 1.48, CI 1.13-1.94, P<0.001). The younger age and higher intake of drugs were significantly associated with an increased concordance between CCs and diagnosis. CONCLUSION: A majority of GPs perceive the CCs of the multimorbid patients correctly, but there is room for improvement. PMID- 28860727 TI - The role of caregivers in interfacility care transitions: a qualitative study. AB - A qualitative design was used to explore the nature of caregiver involvement in care transitions of patients being transferred from an acute care hospital to a rehabilitation hospital. Participants included older adults (n=13), informal caregivers (n=9), and health care professionals (n=50) from inpatient orthopedic units in two academic health science centers and one orthopedic inpatient rehabilitation unit. Semistructured interviews were conducted, audio-taped, and transcribed. Directed content analysis revealed the following four themes: watching, being an active care provider, advocating, and navigating the health care system. Participants described being actively involved in the care of their family member, yet they were not actively engaged by health care professionals to be involved in the care of their family member. There is a need to reconcile the tension between the level of involvement of caregivers in the care of family members who are patients and the level of engagement throughout the care transition. By providing relevant information and authentically engaging caregivers as equal partners in the care transition, they are better able to navigate the health care system post-transfer to the rehabilitation setting and discharge to home. PMID- 28860729 TI - Aging and extrapulmonary effects of chronic obstructive pulmonary disease. AB - INTRODUCTION: People with COPD have a decline in functional status, but little is known about the rate of decline and factors that contribute. Of particular concern is the decline in cognitive and functional performance. Decrease in cognitive and functional performance will finally lead to decreased health status, sedentary life style and premature frailty. AIM: The aim of this study is to compare functional performance and cognitive status in patients with COPD of different ages and to examine the changes in extrapulmonary effects. PATIENTS AND METHODS: This study included 62 patients with COPD risk class D who were divided into two groups (<70 years, N=30 and >70 years, N=32). Patients first completed the Montreal Cognitive Assessment (MoCA), which is a 30-point test that assesses different cognitive domains, while isometric knee extension (IKE) was measured using a digital handheld dynamometer, and functional exercise level was assessed using the 6-minute walking distance (6MWD) test. RESULTS: The patients' older age (age higher than 70 years) was associated with a significantly lower body mass index (BMI, 27.50 vs 24.24 kg/m2; P=0.020), higher vital capacity parameters, forced vital capacity (FVC, 2.74 vs 2.82 L; P=0.799), FVC (%) (73.00 vs 66.50, P=132), forced expiratory volume in the first second (FEV1, 0.93 vs 1.13 L; P=0.001) and FEV1 (%) (28.50 vs 30.50, P=0.605). In addition, patients at older age presented a significantly reduced physical activity capacity, 6MWD (385.93 vs 320.84 m, P<0.001) and IKE (24.75 vs 22.55 kgf, P=0.005), as well as higher values for inflammatory biomarkers, C-reactive protein (8.77 vs 3.34 mg/L, P=0.022). Moreover, patients at older age presented significantly lower score at the cognitive assessment, MoCA (23.50 vs 20.00, P<0.001). CONCLUSION: Elderly COPD patients have reduced exercise capacity and muscle strength, deteriorated cognitive function and increased inflammatory markers. Furthermore, inflammation markers were significantly correlated with muscle strength, walking distance and cognitive impairment. PMID- 28860730 TI - Association between body composition and stair negotiation ability among individuals >55 years of age: a cross-sectional study. AB - BACKGROUND: Loss of muscle strength exerts a considerable impact on the quality of life and mortality of older adults. The present household survey study measured body composition and muscle strength with the aim of analyzing the roles of low lean mass, low muscle strength and obesity in stair negotiation ability and the effect of comorbidities on the relationship between body composition and functional capacity. METHODS: Body composition was assessed using bioelectrical impedance analysis and muscle strength was assessed with a hand grip dynamometer. The study population comprised individuals >55 years of age from a medium-sized Brazilian municipality. The sample included 451 participants. RESULTS: A total of 368 subjects were interviewed; their ages varied from 56 to 91 years. Among males, low muscle strength was associated with stair negotiation difficulty independent of muscle mass, age and obesity but muscle mass was not. However, when we analyzed comorbidities and body composition jointly, chronic lower limb pain and obesity were independently associated with stair negotiation difficulty but body composition and age were not. Among women, after comorbidities were included into the model, low muscle strength and obesity remained associated with stair negotiation difficulty as chronic lower limb pain and depression. The relationship between muscle function and comorbidities is discussed in this article. PMID- 28860731 TI - eGFRs from Asian-modified CKD-EPI and Chinese-modified CKD-EPI equations were associated better with hypertensive target organ damage in the community-dwelling elderly Chinese: the Northern Shanghai Study. AB - BACKGROUND: With increasing age, estimated glomerular filtration rate (eGFR) decline is a frequent manifestation and is strongly associated with other preclinical target organ damage (TOD). In literature, many equations exist in assessing patients' eGFR. However, these equations were mainly derived and validated in the population from Western countries, which equation should be used for risk stratification in the Chinese population remains unclear, as well as their comparison. Considering that TOD is a good marker for risk stratification in the elderly, in this analysis, we aimed to investigate whether the recent eGFR equations derived from Asian and Chinese are better associated with preclinical TOD than the other equations in elderly Chinese. METHODS: A total of 1,599 community-dwelling elderly participants (age >65 years) in northern Shanghai were prospectively recruited from June 2014 to August 2015. Conventional cardiovascular risk factors were assessed, and hypertensive TOD including left ventricular mass index (LVMI), carotid-femoral pulse wave velocity (cf-PWV), carotid intima-media thickness (IMT), ankle-brachial index (ABI) and urine albumin to creatinine ratio (UACR) was evaluated for each participant. Participant's eGFR was calculated from the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Chinese abbreviated MDRD (c-aMDRD), Asian-modified CKD-EPI (aCKD-EPI) equation and Chinese-modified CKD-EPI (cCKD-EPI) equation. RESULTS: In multivariate regression analysis, only eGFRs from aCKD-EPI were significantly and inversely associated with carotid IMT (P=0.005). In multivariate logistic models, decreased eGFR from all the equations were significantly associated with lower ABI (P<0.001), microalbuminuria (P=0.02 to P<0.001) and increased cf-PWV (P<0.001). Only decreased eGFRs from aCKD-EPI and cCKD-EPI equations were significantly associated with increased IMT (both crude P<0.05). In the receiver operator characteristic (ROC) analysis, only aCKD-EPI and cCKD-EPI equations presented significant associations with all the listed preclinical TODs (P-value from <0.05 to <0.001). CONCLUSION: In community-dwelling elderly Chinese, eGFRs from aCKD EPI and cCKD-EPI equations are better associated with preclinical TOD. aCKD-EPI and cCKD-EPI equations should be preferred when making risk assessment. PMID- 28860732 TI - Should physicians always rely on estimated glomerular filtration rate without knowing the equation? PMID- 28860734 TI - Sex differences in the effect of aging on dry eye disease. AB - PURPOSE: Aging is a major risk factor in dry eye disease (DED), and understanding sexual differences is very important in biomedical research. However, there is little information about sex differences in the effect of aging on DED. We investigated sex differences in the effect of aging and other risk factors for DED. METHODS: This study included data of 16,824 adults from the Korea National Health and Nutrition Examination Survey (2010-2012), which is a population-based cross-sectional survey. DED was defined as the presence of frequent ocular dryness or a previous diagnosis by an ophthalmologist. Basic sociodemographic factors and previously known risk factors for DED were included in the analyses. Linear regression modeling and multivariate logistic regression modeling were used to compare the sex differences in the effect of risk factors for DED; we additionally performed tests for interactions between sex and other risk factors for DED in logistic regression models. RESULTS: In our linear regression models, the prevalence of DED symptoms in men increased with age (R=0.311, P=0.012); however, there was no association between aging and DED in women (P>0.05). Multivariate logistic regression analyses showed that aging in men was not associated with DED (DED symptoms/diagnosis: odds ratio [OR] =1.01/1.04, each P>0.05), while aging in women was protectively associated with DED (DED symptoms/diagnosis: OR =0.94/0.91, P=0.011/0.003). Previous ocular surgery was significantly associated with DED in both men and women (men/women: OR =2.45/1.77 [DED symptoms] and 3.17/2.05 [DED diagnosis], each P<0.001). Tests for interactions of sex revealed significantly different aging * sex and previous ocular surgery * sex interactions (P for interaction of sex: DED symptoms/diagnosis - 0.044/0.011 [age] and 0.012/0.006 [previous ocular surgery]). CONCLUSION: There were distinct sex differences in the effect of aging on DED in the Korean population. DED following ocular surgery also showed sexually different patterns. Age matching and sex matching are strongly recommended in further studies about DED, especially DED following ocular surgery. PMID- 28860733 TI - Recent developments in age-related macular degeneration: a review. AB - BACKGROUND: Visual impairment in elderly people is a considerable health problem that significantly affects quality of life of millions worldwide. The magnitude of this issue is becoming more evident with an aging population and an increasing number of older individuals. OBJECTIVE: The objective of this article was to review the clinical and pathological aspects of age-related macular degeneration (AMD), diagnostic tools, and therapeutic modalities presently available or underway for both atrophic and wet forms of the disease. METHODS: An online review of the PubMed database was performed, searching for the key words. The search was limited to articles published since 1980 to date. RESULTS: Several risk factors have been linked to AMD, such as age (>60 years), lifestyle (smoking and diet), and family history. Although the pathogenesis of AMD remains unclear, genetic factors have been implicated in the condition. Treatment for atrophic AMD is mainly close observation, coupled with nutritional supplements such as zinc and antioxidants, whereas treatment of wet AMD is based on targeting choroidal neovascular membranes. CONCLUSION: Identification of modifiable risk factors would improve the possibilities of preventing the progression of AMD. The role of anti-vascular endothelial growth factor (anti-VEGF) agents has transformed the therapeutic approach of the potentially blinding disease "wet AMD" into a more favorable outcome. PMID- 28860735 TI - Skin condition and its relationship to systemic inflammation in chronic obstructive pulmonary disease. AB - BACKGROUND: The systemic (extrapulmonary) effects and comorbidities of chronic obstructive pulmonary disease (COPD) contribute substantially to its burden. The supposed link between COPD and its systemic effects on distal organs could be due to the low-grade systemic inflammation. The aim of this study was to investigate whether the systemic inflammation may influence the skin condition in COPD patients. MATERIALS AND METHODS: Forty patients with confirmed diagnosis of COPD and a control group consisting of 30 healthy smokers and 20 healthy never-smokers were studied. Transepidermal water loss, stratum corneum hydration, skin sebum content, melanin index, erythema index, and skin temperature were measured with worldwide-acknowledged biophysical measuring methods at the volar forearm of all participants using a multifunctional skin physiology monitor. Biomarkers of systemic inflammation, including high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha), were measured in serum using commercially available enzyme-linked immunosorbent assays. RESULTS: There were significant differences between COPD patients and healthy never-smokers in skin temperature, melanin index, sebum content, and hydration level (P<0.05), but not for transepidermal water loss and erythema index. No significant difference was noted between COPD patients and smokers in any of the biophysical properties of the skin measured. The mean levels of hsCRP and IL-6 in serum were significantly higher in COPD patients and healthy smokers in comparison with healthy never-smokers. There were significant correlations between skin temperature and serum hsCRP (R=0.40; P=0.02) as well as skin temperature and serum IL-6 (R=0.49; P=0.005) in smokers. Stratum corneum hydration correlated significantly with serum TNF-alpha (R=0.37; P=0.01) in COPD patients. CONCLUSION: Differences noted in several skin biophysical properties and biomarkers of systemic inflammation between COPD patients, smokers, and healthy never-smokers may suggest a possible link between smoking-driven, low grade systemic inflammation, and the overall skin condition. PMID- 28860736 TI - Overdiagnosis of COPD in hospitalized patients. AB - BACKGROUND: The diagnosis of chronic obstructive pulmonary disease (COPD) is usually made based on history and physical exam alone. Symptoms of dyspnea, cough, and wheeze are nonspecific and attributable to a variety of diseases. Confirmatory testing to verify the airflow obstruction is available but rarely used, which may result in substantial misdiagnoses of COPD. The aim of this study is to evaluate the use of confirmatory testing and assess the accuracy of the diagnosis. METHODS: From January 2011 through December 2013, 6,018 patients with COPD as a principal or leading diagnosis were admitted at a community teaching hospital. Of those, only 504 (8.4%) patients had spirometry performed during hospitalization. The studies were reviewed by two board-certified pulmonologists to verify presence of persistent airflow obstruction. Charts of these patients were then examined to determine if the spirometry results had changed the diagnosis or the treatment plan for these patients. RESULTS: Spirometry confirmed the diagnosis of COPD in 270 patients (69.2%) treated as COPD during their hospitalization. Restrictive lung disease was found to be present in 104 patients (26.6%) and normal in 16 patients (4.2%). Factors predictive of airflow obstruction included smoking status and higher pack-year history. Negative predictive factors included higher body mass index (BMI) and other medical comorbidities. These patients were significantly more likely to be misdiagnosed and mistreated as COPD. CONCLUSION: Up to a third of patients diagnosed and treated as COPD in the hospital may be inaccurately diagnosed as COPD based on confirmatory spirometry testing. Factors contributing to the inaccuracy of diagnosis include less smoking history, high BMI, and associated comorbidities. PMID- 28860737 TI - Risk of community-acquired pneumonia in chronic obstructive pulmonary disease stratified by smoking status: a population-based cohort study in the United Kingdom. AB - BACKGROUND: Smoking increases the risk of community-acquired pneumonia (CAP) and is associated with the development of COPD. Until now, it is unclear whether CAP in COPD is due to smoking-related effects, or due to COPD pathophysiology itself. OBJECTIVE: To evaluate the association between COPD and CAP by smoking status. METHODS: In total, 62,621 COPD and 191,654 control subjects, matched by year of birth, gender and primary care practice, were extracted from the Clinical Practice Research Datalink (2005-2014). Incidence rates (IRs) were estimated by dividing the total number of CAP cases by the cumulative person-time at risk. Time-varying Cox proportional hazard models were used to estimate the hazard ratios (HRs) for CAP in COPD patients versus controls. HRs of CAP by smoking status were calculated by stratified analyses in COPD patients versus controls and within both subgroups with never smoking as reference. RESULTS: IRs of CAP in COPD patients (32.00/1,000 person-years) and controls (6.75/1,000 person-years) increased with age and female gender. The risk of CAP in COPD patients was higher than in controls (HR 4.51, 95% CI: 4.27-4.77). Current smoking COPD patients had comparable CAP risk (HR 0.92, 95% CI: 0.82-1.02) as never smoking COPD patients (reference), whereas current smoking controls had a higher risk (HR 1.23, 95% CI: 1.13-1.34) compared to never smoking controls. CONCLUSION: COPD patients have a fourfold increased risk to develop CAP, independent of smoking status. Identification of factors related with the increased risk of CAP in COPD is warranted, in order to improve the management of patients at risk. PMID- 28860738 TI - Risk factors for pulmonary arterial hypertension in patients with tuberculosis destroyed lungs and their clinical characteristics compared with patients with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: There are limited data on pulmonary arterial hypertension (PAH) in patients with tuberculosis-destroyed lung (TDL), a sequela of pulmonary tuberculosis. We identified the risk factors for PAH and their effects on acute exacerbation and mortality in patients with TDL, as well as the clinical differences in patients with chronic obstructive pulmonary disease (COPD) and PAH. METHODS: A retrospective cohort study was conducted from 2010 through 2015 in a municipal referral hospital in South Korea. PAH was defined when echocardiographic pulmonary arterial pressure (PAP) was >40 mmHg. The clinical features and course of TDL patients with or without PAH were evaluated and differences between patients with COPD and PAH were analyzed. RESULTS: Among the 195 patients with TDL, echocardiographic data were available in 53 patients, and their mean PAP was 50.72+/-23.99 mmHg. The PAH group (n=37) had a smaller lung volume (forced vital capacity % predicted, 51.55% vs 72.37%, P<0.001) and more extensively destroyed lungs (3.27 lobes vs 2 lobes, P<0.001) than those in the non-PAH group (n=16). A higher PAP was significantly correlated with a higher frequency of acute exacerbation (r=0.32, P=0.02). Multivariate analyses did not reveal any significant risk factors contributing to PAH in patients with TDL. Compared to COPD patients with PAH, TDL patients with PAH have smaller lung volume but a less severe airflow limitation. Tricuspid regurgitation and a D shaped left ventricle during diastole were more frequently observed in TDL patients. The risk of exacerbation was not different between patients with PAH in COPD and TDL. CONCLUSION: PAH in patients with TDL was associated with severity of lung destruction but risk of exacerbation and mortality did not significantly differ between patients with PAH and without PAH. PMID- 28860739 TI - The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: a UK database study. AB - Chronic obstructive pulmonary disease (COPD), a complex progressive disease, is currently the third leading cause of death worldwide. One recommended treatment option is fixed-dose combination therapy of an inhaled corticosteroid (ICS)/long acting beta-agonist. Clinical trials suggest pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) show similar efficacy and safety profiles in COPD. Real-world observational studies have shown that combination therapy has significantly greater odds of achieving asthma control when delivered via pMDIs. Our aim was to compare effectiveness, in terms of moderate/severe COPD exacerbations and long-acting muscarinic antagonist (LAMA) prescriptions, for COPD patients initiating fluticasone propionate (FP)/salmeterol xinafoate (SAL) via pMDI versus DPI at two doses of FP (500 and 1,000 MUg/d) using a real-life, historical matched cohort study. COPD patients with >=2 years continuous practice data, >=2 prescriptions for FP/SAL via pMDI/DPI, and no prescription for ICS were selected from the Optimum Patient Care Research Database. Patients were matched 1:1. Rate of moderate/severe COPD exacerbations and odds of LAMA prescription were analyzed using conditional Poisson and logistic regression, respectively. Of 472 patients on 500 MUg/d, we observed fewer moderate/severe exacerbations in patients using pMDI (99 [42%]) versus DPI (115 [49%]) (adjusted rate ratio: 0.71; 95% confidence interval: 0.54, 0.93), an important result since the pMDI is not licensed for COPD in the UK, USA, or China. At 1,000 MUg/d, we observed lower LAMA prescription for pMDI (adjusted odds ratio: 0.71; 95% confidence interval: 0.55, 0.91), but no difference in exacerbation rates, potentially due to higher dose of ICS overcoming low lung delivery from the DPI. PMID- 28860741 TI - Comparison of World Health Organization and Asia-Pacific body mass index classifications in COPD patients. AB - INTRODUCTION: A low body mass index (BMI) is associated with increased mortality and low health-related quality of life in patients with COPD. The Asia-Pacific classification of BMI has a lower cutoff for overweight and obese categories compared to the World Health Organization (WHO) classification. The present study assessed patients with COPD among different BMI categories according to two BMI classification systems: WHO and Asia-Pacific. PATIENTS AND METHODS: Patients with COPD aged 40 years or older from the Korean COPD Subtype Study cohort were selected for evaluation. We enrolled 1,462 patients. Medical history including age, sex, St George's Respiratory Questionnaire (SGRQ-C), the modified Medical Research Council (mMRC) dyspnea scale, and post-bronchodilator forced expiratory volume in 1 second (FEV1) were evaluated. Patients were categorized into different BMI groups according to the two BMI classification systems. RESULT: FEV1 and the diffusing capacity of the lung for carbon monoxide (DLCO) percentage revealed an inverse "U"-shaped pattern as the BMI groups changed from underweight to obese when WHO cutoffs were applied. When Asia-Pacific cutoffs were applied, FEV1 and DLCO (%) exhibited a linearly ascending relationship as the BMI increased, and the percentage of patients in the overweight and obese groups linearly decreased with increasing severity of the Global Initiative for Chronic Obstructive Lung Disease criteria. From the underweight to the overweight groups, SGRQ-C and mMRC had a decreasing relationship in both the WHO and Asia-Pacific classifications. The prevalence of comorbidities in the different BMI groups showed similar trends in both BMI classifications systems. CONCLUSION: The present study demonstrated that patients with COPD who have a high BMI have better pulmonary function and health-related quality of life and reduced dyspnea symptoms. Furthermore, the Asia-Pacific BMI classification more appropriately reflects the correlation of obesity and disease manifestation in Asian COPD patients than the WHO classification. PMID- 28860740 TI - Clinical implications of blood eosinophil count in patients with non-asthma-COPD overlap syndrome COPD. AB - BACKGROUND: Recent studies that assessed the relevance of the blood eosinophil count as a biomarker in patients with COPD may have overestimated it because they included patients with asthma-COPD overlap syndrome (ACOS). We investigated the clinical implications of the blood eosinophil count in patients with non-ACOS COPD. PATIENTS AND METHODS: From a Korean COPD Subtype Study (KOCOSS) cohort, we selected patients with non-ACOS COPD after excluding ACOS patients according to Spanish criteria. Clinical characteristics and the incidence of moderate-to severe exacerbation were compared among the four groups stratified according to the quartiles of blood eosinophil percent and count. RESULTS: Of the KOCOSS cohort of 1,132 patients with COPD, 467 non-ACOS COPD patients (41.2%) with data of blood eosinophil count remained after excluding those with ACOS based on the Spanish definition. There was no difference in clinical characteristics among groups classified according to the quartiles of eosinophil percent and count. On multivariate logistic regression, eosinophil quartiles in percent and absolute count were not associated with the incidence of moderate-to-severe acute exacerbations of COPD (AECOPD). The eosinophil count did not affect the risk of AECOPD or forced expiratory volume in 1 second (FEV1) changes according to exposure to inhaled corticosteroid (ICS). However, by increasing the cutoff value for the eosinophil count from 200/MUL to 600/MUL, the odds ratio for risk of exacerbation increased serially from 0.82 to 2.96 on trend analysis. CONCLUSION: In patients with non-ACOS COPD, the blood eosinophil count and percent were not associated with FEV1 changes, quality of life (QoL), AECOPD frequency, or response to ICS. The clinical implication of the blood eosinophil count should not be overestimated in patients with non-ACOS COPD. PMID- 28860742 TI - Severe exacerbation and pneumonia in COPD patients treated with fixed combinations of inhaled corticosteroid and long-acting beta2 agonist. AB - BACKGROUND: It remains unclear whether severe exacerbation and pneumonia of COPD differs between patients treated with budesonide/formoterol and those treated with fluticasone/salmeterol. Therefore, we conducted a comparative study of those who used budesonide/formoterol and those treated with fluticasone/salmeterol for COPD. METHODS: Subjects in this population-based cohort study comprised patients with COPD who were treated with a fixed combination of budesonide/formoterol or fluticasone/salmeterol. All patients were recruited from the Taiwan National Health Insurance database. The outcomes including severe exacerbations, pneumonia, and pneumonia requiring mechanical ventilation (MV) were measured. RESULTS: During the study period, 11,519 COPD patients receiving fluticasone/salmeterol and 7,437 patients receiving budesonide/formoterol were enrolled in the study. Pairwise matching (1:1) of fluticasone/salmeterol and budesonide/formoterol populations resulted in to two similar subgroups comprising each 7,295 patients. Patients receiving fluticasone/salmeterol had higher annual rate and higher risk of severe exacerbation than patients receiving budesonide/formoterol (1.2219/year vs 1.1237/year, adjusted rate ratio, 1.08; 95% CI, 1.07-1.10). In addition, patients receiving fluticasone/salmeterol had higher incidence rate and higher risk of pneumonia than patients receiving budesonide/formoterol (12.11 per 100 person-years vs 10.65 per 100 person-years, adjusted hazard ratio [aHR], 1.13; 95% CI, 1.08-1.20). Finally, patients receiving fluticasone/salmeterol had higher incidence rate and higher risk of pneumonia requiring MV than patients receiving budesonide/formoterol (3.94 per 100 person-years vs 3.47 per 100 person-years, aHR, 1.14; 95% CI, 1.05-1.24). A similar trend was seen before and after propensity score matching analysis, intention-to-treat, and as-treated analysis with and without competing risk. CONCLUSIONS: Based on this retrospective observational study, long-term treatment with fixed combination budesonide/formoterol was associated with fewer severe exacerbations, pneumonia, and pneumonia requiring MV than fluticasone/salmeterol in COPD patients. PMID- 28860744 TI - Ischemic ECG abnormalities are associated with an increased risk for death among subjects with COPD, also among those without known heart disease. AB - ABSTRACT PRESENTATION: An abstract, including parts of the results, has been presented at an oral session at the European Respiratory Society International Conference, London, UK, September 2016. BACKGROUND: Cardiovascular comorbidity contributes to increased mortality among subjects with COPD. However, the prognostic value of ECG abnormalities in COPD has rarely been studied in population-based surveys. AIM: To assess the impact of ischemic ECG abnormalities (I-ECG) on mortality among individuals with COPD, compared to subjects with normal lung function (NLF), in a population-based study. METHODS: During 2002 2004, all subjects with FEV1/VC <0.70 (COPD, n=993) were identified from population-based cohorts, together with age- and sex-matched referents without COPD. Re-examination in 2005 included interview, spirometry, and 12-lead ECG in COPD (n=635) and referents [n=991, whereof 786 had NLF]. All ECGs were Minnesota coded. Mortality data were collected until December 31, 2010. RESULTS: I-ECG was equally common in COPD and NLF. The 5-year cumulative mortality was higher among subjects with I-ECG in both groups (29.6% vs 10.6%, P<0.001 and 17.1% vs 6.6%, P<0.001). COPD, but not NLF, with I-ECG had increased risk for death assessed as the mortality risk ratio [95% confidence interval (CI)] when compared with NLF without I-ECG, 2.36 (1.45-3.85) and 1.65 (0.94-2.90) when adjusted for common confounders. When analyzed separately among the COPD cohort, the increased risk for death associated with I-ECG persisted after adjustment for FEV1 % predicted, 1.89 (1.20-2.99). A majority of those with I-ECG had no previously reported heart disease (74.2% in NLF and 67.3% in COPD) and the pattern was similar among them. CONCLUSION: I-ECG was associated with an increased risk for death in COPD, independent of common confounders and disease severity. I-ECG was of prognostic value also among those without previously known heart disease. PMID- 28860743 TI - Systematic review of the association between exercise tests and patient-reported outcomes in patients with chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is an increasingly common cause of death worldwide. Its cardinal symptoms include breathlessness and severely reduced exercise capacity. Several patient-reported outcome (PRO) measures are used to assess health-related quality of life (HRQoL), functional performance, and breathlessness in patients with COPD. Exercise testing is employed to measure functional performance objectively, which is generally believed to impact on overall HRQoL. However, the extent to which commonly used laboratory- and field-based exercise test results correlate with PROs has not been systematically assessed. MATERIALS AND METHODS: A search of Embase, MedLine, and the Cochrane Library identified primary publications in English that reported data on the correlations (Pearson's r or Spearman's rho) between the outcomes of exercise tests and HRQoL and breathlessness PROs. Studies reporting on the following tests were included: 6-minute walk test (6MWT), 12MWT, incremental and endurance shuttle walk tests, incremental and endurance cycle ergometer tests, and treadmill tests. RESULTS: Of 3,205 articles screened, 28 were deemed eligible for inclusion. The most commonly reported HRQoL PRO measure was the St George's Respiratory Questionnaire (13 studies), and the most commonly reported breathlessness PRO measure was the Baseline Dyspnea Index (six studies). The St George's Respiratory Questionnaire appears to correlate very weakly to moderately with the 6MWT, and breathlessness PROs appear to be moderately to strongly associated with 6MWT outcomes. Across all studies, the 6MWT was the most commonly reported exercise test. Very few publications reporting associations between other exercise tests and PRO measures were found. CONCLUSION: This review found evidence to support the association of 6MWT outcomes with HRQoL and breathlessness PROs. There were limited data showing correlations with the outcomes of other exercise tests. Further work is required to examine the associations between these PROs and exercise test outcomes. PMID- 28860745 TI - Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells. AB - Gold nanoparticles (AuNPs) have recently attracted attention as clinical agents for enhancing the effect of radiotherapy in various cancers. Although radiotherapy is a standard treatment for cancers, invasive recurrence and metastasis are significant clinical problems. Several studies have suggested that radiation promotes the invasion of cancer cells by activating molecular mechanisms involving integrin and fibronectin (FN). In this study, polyethylene glycolylated AuNPs (P-AuNPs) were conjugated with Arg-Gly-Asp (RGD) peptides (RGD/P-AuNPs) to target cancer cells expressing RGD-binding integrins such as alpha5- and alphav-integrins. RGD/P-AuNPs were internalized more efficiently and colocalized with integrins in the late endosomes and lysosomes of MDA-MB-231 cells. A combination of RGD/P-AuNPs and radiation reduced cancer cell viability and increased DNA damage compared to radiation alone in MDA-MB-231 cells. Moreover, the invasive activity of breast cancer cell lines after radiation treatment was significantly inhibited in the presence of RGD/P-AuNPs. Microarray analyses revealed that the expression of FN in irradiated cells was suppressed by combined use of RGD/P-AuNPs. Reduction of FN and downstream signaling may be involved in suppressing radiation-induced invasive activity by RGD/P-AuNPs. Our study suggests that RGD/P-AuNPs can target integrin-overexpressing cancer cells to improve radiation therapy by suppressing invasive activity in addition to sensitization. Thus, these findings provide a possible clinical strategy for using AuNPs to treat invasive breast cancer following radiotherapy. PMID- 28860746 TI - Highly sensitive voltamperometric determination of pyritinol using carbon nanofiber/gold nanoparticle composite screen-printed carbon electrode. AB - A novel and highly sensitive electrochemical method for the detection of pyritinol in pharmaceutical products and serum samples has been accomplished based on voltamperometric response of pyritinol in carbon nanofiber-gold nanoparticle (CNF-GNP)-modified screen-printed carbon electrode (SPCE). The electrochemical response of pyritinol to CNF-GNP-modified SPCE was studied by cyclic voltammetry and square-wave voltammetry (SWV). Under optimized working conditions, the novel sensor shows excellent voltamperometric response toward pyritinol. The SWV study shows significantly enhanced electrochemical response for pyritinol in CNF-GNP-modified SPCE providing high sensitivity to the novel sensor for pyritinol detection. The peak current for pyritinol is found to be linear with the concentration in the range 1.0*10-8-5.0*10-5 M with a detection limit of 6.23*10-9 M using SWV as the detection method. The viability of the new developed sensor for the analytical purposes was studied by performing experiments on various commercial pharmaceutical products and blood serum samples, which yielded adequate recoveries of pyritinol. The novel electrochemical sensor provides high sensitivity, enhanced selectivity, good reproducibility and practical applicability. PMID- 28860747 TI - Intracellular "activated" two-photon photodynamic therapy by fluorescent conveyor and photosensitizer co-encapsulating pH-responsive micelles against breast cancer. AB - The application of photodynamic therapy (PDT) for the diagnosis and treatment of cancer is hindered by the intrinsic defects of the currently available photosensitizers (PSs), such as poor water solubility and limited light penetration depth. In this study, pH-responsive polymeric micelles that co encapsulate therapeutic PSs and organooxotin two-photon compounds were applied for two-photon PDT (TP-PDT) against breast cancer. The TP-PDT effect of the drug loaded micelles was "activated" when the micelles turned into aggregates at a triggering pH level. The in vitro therapeutic effect was evaluated on 4T1 murine breast cancer cells by viability assays, real-time morphology collapsing, and reactive oxygen species determination. Time-dependent ex vivo organ distribution and in vivo anticancer efficacy results suggested that the drug carriers could accumulate in tumors and suppress tumor growth by TP-PDT. The delivery system could enhance the solubility and distribution of PSs and, if administered along with a tissue-penetrating prolonged light source, could thus have good potential for cancer therapy. PMID- 28860748 TI - Formulation, development, and optimization of a novel octyldodecanol-based nanoemulsion for transdermal delivery of ceramide IIIB. AB - This research aimed to develop and optimize a nanoemulsion-based formulation containing ceramide IIIB using phase-inversion composition for transdermal delivery. The effects of ethanol, propylene glycol (PG), and glycerol in octyldodecanol and Tween 80 systems on the size of the nanoemulsion region in the phase diagrams were investigated using water titration. Subsequently, ceramide IIIB loading was kept constant (0.05 wt%), and the proposed formulation and conditions were optimized via preliminary screening and experimental design. Factors such as octyldodecanol/(Tween 80:glycerol) weight ratio, water content, temperature, addition rate, and mixing rate were investigated in the preliminary screening experiment. Response surface methodology was employed to study the effect of water content (30%-70%, w/w), mixing rate (400-720 rpm), temperature (20 degrees C-60 degrees C), and addition rate (0.3-1.8 mL/min) on droplet size and polydispersity index. The mathematical model showed that the optimum formulation and conditions for preparation of ceramide IIIB nanoemulsion with desirable criteria were a temperature of 41.49 degrees C, addition rate of 1.74 mL/min, water content of 55.08 wt%, and mixing rate of 720 rpm. Under optimum formulation conditions, the corresponding predicted response values for droplet size and polydispersity index were 15.51 nm and 0.12, respectively, which showed excellent agreement with the actual values (15.8 nm and 0.108, respectively), with no significant (P>0.05) differences. PMID- 28860749 TI - In vitro and in vivo evaluation of novel NGR-modified liposomes containing brucine. AB - In this study, a novel NGR (Asn-Gly-Arg) peptide-modified liposomal brucine was prepared by using spray-drying method. The surface morphology of the liposomes, encapsulation efficiency and particle size were investigated. The data showed that the addition of NGR did not produce any significant influence on brucine liposomes in terms of particle size or zeta potential. In addition, after 3 months of storage, no dramatic change such as visible aggregation, drug content changes or precipitation in the appearance of NGR-brucine liposomes occurred. The in vitro release results indicated that the release of brucine from NGR liposomes was similar to that of liposomes, demonstrating that the NGR modification did not affect brucine release. The in vitro drug-release kinetic model of NGR-brucine liposomes fitted well with the Weibull's equation. In vivo, NGR-brucine liposomes could significantly extend the bioavailability of brucine; however, there was no significant difference observed in the pharmacokinetic parameters between liposomes and NGR liposomes after intravenous administration. Antitumor activity results showed that NGR-modified liposomes exhibited less toxicity and much higher efficacy in HepG2-bearing mice compared with non-modified liposomes. The enhanced antitumor activity might have occurred because brucine was specifically recognized by NGR receptor on the surface of tumor cells, which enhanced the intracellular uptake of drugs. PMID- 28860750 TI - Pinhole X-ray fluorescence imaging of gadolinium and gold nanoparticles using polychromatic X-rays: a Monte Carlo study. AB - This work aims to develop a Monte Carlo (MC) model for pinhole K-shell X-ray fluorescence (XRF) imaging of metal nanoparticles using polychromatic X-rays. The MC model consisted of two-dimensional (2D) position-sensitive detectors and fan beam X-rays used to stimulate the emission of XRF photons from gadolinium (Gd) or gold (Au) nanoparticles. Four cylindrical columns containing different concentrations of nanoparticles ranging from 0.01% to 0.09% by weight (wt%) were placed in a 5 cm diameter cylindrical water phantom. The images of the columns had detectable contrast-to-noise ratios (CNRs) of 5.7 and 4.3 for 0.01 wt% Gd and for 0.03 wt% Au, respectively. Higher concentrations of nanoparticles yielded higher CNR. For 1*1011 incident particles, the radiation dose to the phantom was 19.9 mGy for 110 kVp X-rays (Gd imaging) and 26.1 mGy for 140 kVp X-rays (Au imaging). The MC model of a pinhole XRF can acquire direct 2D slice images of the object without image reconstruction. The MC model demonstrated that the pinhole XRF imaging system could be a potential bioimaging modality for nanomedicine. PMID- 28860751 TI - Quercetin-mediated synthesis of graphene oxide-silver nanoparticle nanocomposites: a suitable alternative nanotherapy for neuroblastoma. AB - BACKGROUND: Graphene and graphene-related materials have gained substantial interest from both academia and industry for the development of unique nanomaterials for biomedical applications. Graphene oxide (GO) and silver nanoparticles (AgNPs) are a valuable platform for the development of nanocomposites, permitting the combination of nanomaterials with different physical and chemical properties to generate novel materials with improved and effective functionalities in a single platform. Therefore, this study was conducted to synthesize a graphene oxide-silver nanoparticle (GO-AgNPs) nanocomposite using the biomolecule quercetin and evaluate the potential cytotoxicity and mechanism of GO-AgNPs in human neuroblastoma cancer cells (SH SY5Y). METHODS: The synthesized GO-AgNPs were characterized using various analytical techniques. The potential toxicities of GO-AgNPs were evaluated using a series of biochemical and cellular assays. The expression of apoptotic and anti apoptotic genes was measured by quantitative real-time reverse transcription polymerase chain reaction. Further, apoptosis was confirmed by caspase-9/3 activity and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and GO-AgNPs-induced autophagy was also confirmed by transmission electron microscopy. RESULTS: The prepared GO-AgNPs exhibited significantly higher cytotoxicity toward SH-SY5Y cells than GO. GO-AgNPs induced significant cytotoxicity in SH-SY5Y cells by the loss of cell viability, inhibition of cell proliferation, increased leakage of lactate dehydrogenase, decreased level of mitochondrial membrane potential, reduced numbers of mitochondria, enhanced level of reactive oxygen species generation, increased expression of pro-apoptotic genes, and decreased expression of anti-apoptotic genes. GO-AgNPs induced caspase 9/3-dependent apoptosis via DNA fragmentation. Finally, GO-AgNPs induced accumulation of autophagosomes and autophagic vacuoles. CONCLUSION: In this study, we developed an environmentally friendly, facile, dependable, and simple method for the synthesis of GO-AgNPs nanocomposites using quercetin. The synthesized GO-AgNPs exhibited enhanced cytotoxicity compared with that of GO at very low concentrations. This study not only elucidates the potential cytotoxicity against neuroblastoma cancer cells, but also reveals the molecular mechanism of toxicity. PMID- 28860752 TI - Gold nanoparticles reduce high glucose-induced oxidative-nitrosative stress regulated inflammation and apoptosis via tuberin-mTOR/NF-kappaB pathways in macrophages. AB - Hyperglycemia is a risk factor for cardiovascular mortality and morbidity, and directly responsible for exacerbating macrophage activation and atherosclerosis. We showed that gold nanoparticles (AuNPs) reduce the high glucose (HG)-induced atherosclerosis-related complications in macrophages via oxidative-nitrosative stress-regulated inflammation and apoptosis. The effects of AuNPs on oxidative nitrosative stress markers such as cellular antioxidants were attenuated by HG exposure, leading to reduction in the accumulation of reactive oxygen/nitrogen species in cellular compartments. Further, these abnormalities of antioxidants level and reactive oxygen/nitrogen species accumulations initiate cellular stress, resulting in the activation of nuclear factor kappaB (NF-kappaB) via ERK1/2mitogen-activated protein kinase (MAPK)/Akt/tuberin-mammalian target of rapamycin (mTOR) pathways. The activated NF-kappaB stimulates inflammatory mediators, which subsequently subdue biomolecules damage, leading to aggravation of the inflammatory infiltration and immune responses. Treatment of AuNPs inhibits the intracellular redox-sensitive signaling pathways, inflammation, and apoptosis in macrophages. Together, our results indicate that AuNPs may modulate HG-induced oxidative-nitrosative stress. These effects may be sealed tight due to the fact that AuNPs treatment reduces the activation of NF-kappaB by ERK1/2MAPK/Akt/tuberin-mTOR pathways-mediated inflammatory genes expression and cellular stress responses, which may be beneficial for minimizing the atherosclerosis. PMID- 28860753 TI - pH-sensitive and folic acid-targeted MPEG-PHIS/FA-PEG-VE mixed micelles for the delivery of PTX-VE and their antitumor activity. AB - The aim of this study was to simultaneously introduce pH sensitivity and folic acid (FA) targeting into a micelle system to achieve quick drug release and to enhance its accumulation in tumor cells. Paclitaxel-(+)-alpha-tocopherol (PTX-VE) loaded mixed micelles (PHIS/FA/PM) fabricated by poly(ethylene glycol) methyl ether-poly(histidine) (MPEG-PHIS) and folic acid-poly(ethylene glycol)-(+)-alpha tocopherol (FA-PEG-VE) were characterized by dynamic light scattering and transmission electron microscopy (TEM). The mixed micelles had a spherical morphology with an average diameter of 137.0+/-6.70 nm and a zeta potential of 48.7+/-4.25 mV. The drug encapsulation and loading efficiencies were 91.06%+/ 2.45% and 5.28%+/-0.30%, respectively. The pH sensitivity was confirmed by changes in particle size, critical micelle concentration, and transmittance as a function of pH. MTT assay showed that PHIS/FA/PM had higher cytotoxicity at pH 6.0 than at pH 7.4, and lower cytotoxicity in the presence of free FA. Confocal laser scanning microscope images demonstrated a time-dependent and FA-inhibited cellular uptake. In vivo imaging confirmed that the mixed micelles targeted accumulation at tumor sites and the tumor inhibition rate was 85.97%. The results proved that the mixed micelle system fabricated by MPEG-PHIS and FA-PEG-VE is a promising approach to improve antitumor efficacy. PMID- 28860755 TI - Lidocaine/ketorolac-loaded biodegradable nanofibrous anti-adhesive membranes that offer sustained pain relief for surgical wounds. AB - The aim of this study was to develop and evaluate the effectiveness of biodegradable nanofibrous lidocaine/ketorolac-loaded anti-adhesion membranes to sustainably release analgesics on abdominal surgical wounds. The analgesic eluting membranes with two polymer-to-drug ratios (6:1 and 4:1) were produced via an electrospinning technique. A high-performance liquid chromatography (HPLC) assay was employed to characterize the in vivo and in vitro release behaviors of the pharmaceuticals from the membranes. It was found that all biodegradable anti adhesion nanofibers released effective concentrations of lidocaine and ketorolac for over 20 days post surgery. In addition, a transverse laparotomy was setup in a rat model for an in vivo assessment of activity of postoperative recovery. No tissue adhesion was observed at 2 weeks post surgery, demonstrating the potential anti-adhesion capability of the drug-eluting nanofibrous membrane. The postoperative activities were recorded for two groups of rats as follows: rats that did not have any membrane implanted (group A) and rats that had the analgesic-eluting membrane implanted (group B). Rats in group B exhibited faster recovery times than those in group A with regard to postoperative activities, confirming the pain relief effectiveness of the lidocaine- and ketorolac-loaded nanofibrous membranes. The experimental results suggested that the anti-adhesion nanofibrous membranes with sustainable elution of lidocaine and ketorolac are adequately effective and durable for the purposes of postoperative pain relief in rats. PMID- 28860754 TI - Nanomedicine applications in the treatment of breast cancer: current state of the art. AB - Breast cancer is the most common malignant disease in women worldwide, but the current drug therapy is far from optimal as indicated by the high death rate of breast cancer patients. Nanomedicine is a promising alternative for breast cancer treatment. Nanomedicine products such as Doxil(r) and Abraxane(r) have already been extensively used for breast cancer adjuvant therapy with favorable clinical outcomes. However, these products were originally designed for generic anticancer purpose and not specifically for breast cancer treatment. With better understanding of the molecular biology of breast cancer, a number of novel promising nanotherapeutic strategies and devices have been developed in recent years. In this review, we will first give an overview of the current breast cancer treatment and the updated status of nanomedicine use in clinical setting, then discuss the latest important trends in designing breast cancer nanomedicine, including passive and active cancer cell targeting, breast cancer stem cell targeting, tumor microenvironment-based nanotherapy and combination nanotherapy of drug-resistant breast cancer. Researchers may get insight from these strategies to design and develop nanomedicine that is more tailored for breast cancer to achieve further improvements in cancer specificity, antitumorigenic effect, antimetastasis effect and drug resistance reversal effect. PMID- 28860756 TI - Proximity hybridization-mediated isothermal exponential amplification for ultrasensitive electrochemical protein detection. AB - In this study, we fabricated a novel electrochemical biosensing platform on the basis of target-triggered proximity hybridization-mediated isothermal exponential amplification reaction (EXPAR) for ultrasensitive protein analysis. Through rational design, the aptamers for protein recognition were integrated within two DNA probes. Via proximity hybridization principle, the affinity protein-binding event was converted into DNA assembly process. The recognition of protein by aptamers can trigger the strand displacement through the increase of the local concentrations of the involved probes. As a consequence, the output DNA was displaced, which can hybridize with the duplex probes immobilized on the electrode surface subsequently, leading to the initiation of the EXPAR as well as the cleavage of duplex probes. Each cleavage will release the gold nanoparticles (AuNPs) binding sequence. With the modification of G-quadruplex sequence, electrochemical signals were yielded by the AuNPs through oxidizing 3,3',5,5' tetramethylbenzidine in the presence of H2O2. The study we proposed exhibited high sensitivity toward platelet-derived growth factor BB (PDGF-BB) with the detection limit of 52 fM. And, this method also showed great selectivity among the PDGF isoforms and performed well in spiked human serum samples. PMID- 28860757 TI - Photodynamic antimicrobial chemotherapy for Staphylococcus aureus and multidrug resistant bacterial burn infection in vitro and in vivo. AB - BACKGROUND AND OBJECTIVES: Antibiotic resistance has emerged as one of the most important determinants of outcome in patients with serious infections, along with the virulence of the underlying pathogen. Photodynamic antimicrobial chemotherapy (PACT) has been proposed as an alternative approach for the inactivation of bacteria. This study aims to evaluate the antibacterial effect of sinoporphyrin sodium (DVDMS)-mediated PACT on Staphylococcus aureus and multidrug resistant S. aureus in vitro and in vivo. MATERIALS AND METHODS: Bacteria were incubated with DVDMS and exposed to treatment with light. After PACT treatment, colony-forming units were counted to estimate the bactericidal effect. Intracellular reactive oxygen-species production was detected by flow cytometry. Flow cytometry and fluorescence-microscopy detection of bacterial cell-membrane permeability. Enzyme linked immunosorbent assays were used to determine expression of VEGF, TGFbeta1, TNFalpha, IL6, and bFGF factors in burn infection. RESULTS: DVDMS-PACT effectively killed bacterial proliferation. Intracellular ROS levels were enhanced obviously in the PACT-treatment group. SYTO 9 and propidium iodide staining showed a decrease in the ratio of green:red fluorescence intensity in the PACT-treatment group in comparison to the control group. Enzyme-linked immunosorbent-assay results revealed that in the healing process, the expression of bFGF, TGFbeta1, and VEGF in the treatment group were higher than in the control group, which inhibited inflammation-factor secretion. In addition, skin tissue bacteria were reduced after treatment. CONCLUSION: These results indicate that DVDMS-PACT presents significant bactericidal activity and promotes wound healing after burn infections. PMID- 28860758 TI - Establishment of a biophysical model to optimize endoscopic targeting of magnetic nanoparticles for cancer treatment. AB - Superparamagnetic iron oxide nanoparticles (SPION) may be used for local tumor treatment by coupling them to a drug and accumulating them locally with magnetic field traps, that is, a combination of permanent magnets and coils. Thereafter, an alternating magnetic field generates heat which may be used to release the thermosensitively bound drug and for hyperthermia. Until today, only superficial tumors can be treated with this method. Our aim was to transfer this method into an endoscopic setting to also reach the majority of tumors located inside the body. To find the ideal endoscopic magnetic field trap, which accumulates the most SPION, we first developed a biophysical model considering anatomical as well as physical conditions. Entities of choice were esophageal and prostate cancer. The magnetic susceptibilities of different porcine and rat tissues were measured with a superconducting quantum interference device. All tissues showed diamagnetic behavior. The evaluation of clinical data (computed tomography scan, endosonography, surgical reports, pathological evaluation) of patients gave insight into the topographical relationship between the tumor and its surroundings. Both were used to establish the biophysical model of the tumors and their surroundings, closely mirroring the clinical situation, in which we could virtually design, place and evaluate different electromagnetic coil configurations to find optimized magnetic field traps for each tumor entity. By simulation, we could show that the efficiency of the magnetic field traps can be enhanced by 38-fold for prostate and 8-fold for esophageal cancer. Therefore, our approach of endoscopic targeting is an improvement of the magnetic drug-targeting setups for SPION tumor therapy as it holds the possibility of reaching tumors inside the body in a minimal-invasive way. Future animal experiments must prove these findings in vivo. PMID- 28860759 TI - Toxicity evaluation of boron nitride nanospheres and water-soluble boron nitride in Caenorhabditis elegans. AB - Boron nitride (BN) nanomaterials have been increasingly explored for potential biological applications. However, their toxicity remains poorly understood. Using Caenorhabditis elegans as a whole-animal model for toxicity analysis of two representative types of BN nanomaterials - BN nanospheres (BNNSs) and highly water-soluble BN nanomaterial (named BN-800-2) - we found that BNNSs overall toxicity was less than soluble BN-800-2 with irregular shapes. The concentration thresholds for BNNSs and BN-800-2 were 100 ug.mL-1 and 10 ug.mL-1, respectively. Above this concentration, both delayed growth, decreased life span, reduced progeny, retarded locomotion behavior, and changed the expression of phenotype related genes to various extents. BNNSs and BN-800-2 increased oxidative stress levels in C. elegans by promoting reactive oxygen species production. Our results further showed that oxidative stress response and MAPK signaling-related genes, such as GAS1, SOD2, SOD3, MEK1, and PMK1, might be key factors for reactive oxygen species production and toxic responses to BNNSs and BN-800-2 exposure. Together, our results suggest that when concentrations are lower than 10 ug.mL-1, BNNSs are more biocompatible than BN-800-2 and are potentially biocompatible material. PMID- 28860760 TI - Copper nanoparticle-induced ovarian injury, follicular atresia, apoptosis, and gene expression alterations in female rats. AB - Numerous studies have reported the accumulation of copper nanoparticles (Cu NPs) in organs and the corresponding damage, although whether Cu NPs can be translocated to the ovaries and their ovarian toxicity are still unknown. In this study, three groups of female rats were injected with 3.12, 6.25, or 12.5 mg/kg Cu NPs for 14 consecutive days. The pathological changes, hormone levels, apoptosis and apoptotic proteins, oxidative stress, and gene expression characteristics in the ovaries were then investigated. The results demonstrated that the Cu NPs exhibited obvious accumulation in the rat ovaries, leading to ovarian injury, an imbalance of sex hormones, and ovarian cell apoptosis. Cu NP exposure activated caspase 3, caspase 8, caspase 9, and tBid, decreased the protein levels of Bcl-2, increased the expression levels of the proteins Bax and cytochrome c, and promoted malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) reduction. Furthermore, gene microarray analysis showed that Cu NPs (12.5 mg/kg/d) caused 321 differentially expressed genes. Of these, 180 and 141 genes were upregulated and downregulated, respectively. Hsd17b1, Hsd3b1, Hsd3b6, and Hsd3b were involved in steroid and hormone metabolism, whereas Mt3 and Cebpb were associated with apoptosis. Overall, these findings provide strong evidence that Cu NPs trigger both intrinsic and extrinsic apoptotic pathways and regulate key ovarian genes in oxidative stress-mediated ovarian dysfunction. PMID- 28860761 TI - Hyaluronic acid-functionalized bismuth oxide nanoparticles for computed tomography imaging-guided radiotherapy of tumor. AB - The inherent radioresistance and inaccuracy of localization of tumors weaken the clinical implementation effectiveness of radiotherapy. To overcome these limitations, hyaluronic acid-functionalized bismuth oxide nanoparticles (HA-Bi2O3 NPs) were synthesized by one-pot hydrothermal method for target-specific computed tomography (CT) imaging and radiosensitization of tumor. After functionalization with hyaluronic acid, the Bi2O3 NPs possessed favorable solubility in water and excellent biocompatibility and were uptaken specifically by cancer cells overexpressing CD44 receptors. The as-prepared HA-Bi2O3 NPs exhibited high X-ray attenuation efficiency and ideal radiosensitivity via synergizing X-rays to induce cell apoptosis and arrest the cell cycle in a dose-dependent manner in vitro. Remarkably, these properties offered excellent performance in active targeting CT imaging and enhancement of radiosensitivity for inhibition of tumor growth. These findings demonstrated that HA-Bi2O3 NPs as theranostic agents exhibit great promise for CT imaging-guided radiotherapy in diagnosis and treatment of tumors. PMID- 28860762 TI - Targeting thyroid cancer with acid-triggered release of doxorubicin from silicon dioxide nanoparticles. AB - Currently, therapy for thyroid cancer mainly involves surgery and radioiodine therapy. However, chemotherapy can be used in advanced and aggressive thyroid cancer that cannot be treated by other options. Nevertheless, a major obstacle to the successful treatment of thyroid cancer is the delivery of drugs to the thyroid gland. Here, we present an example of the construction of silicon dioxide nanoparticles with thyroid-stimulating-hormone receptor-targeting ligand that can specifically target the thyroid cancer. Doxorubicin nanoparticles can be triggered by acid to release the drug payload for cancer therapy. These nanoparticles shrink the tumor size in vivo with less toxic side effects. This research paves the way toward effective chemotherapy for thyroid cancer. PMID- 28860763 TI - Cytotoxicity induced by carbon nanotubes in experimental malignant glioma. AB - Despite multiple advances in the diagnosis of brain tumors, there is no effective treatment for glioblastoma. Multiwalled carbon nanotubes (MWCNTs), which were previously used as a diagnostic and drug delivery tool, have now been explored as a possible therapy against neoplasms. However, although the toxicity profile of nanotubes is dependent on the physicochemical characteristics of specific particles, there are no studies exploring how the effectivity of the carbon nanotubes (CNTs) is affected by different methods of production. In this study, we characterize the structure and biocompatibility of four different types of MWCNTs in rat astrocytes and in RG2 glioma cells as well as the induction of cell lysis and possible additive effect of the combination of MWCNTs with temozolomide. We used undoped MWCNTs (labeled simply as MWCNTs) and nitrogen doped MWCNTs (labeled as N-MWCNTs). The average diameter of both pristine MWCNTs and pristine N-MWCNTs was ~22 and ~35 nm, respectively. In vitro and in vivo results suggested that these CNTs can be used as adjuvant therapy along with the standard treatment to increase the survival of rats implanted with malignant glioma. PMID- 28860764 TI - Liposomal curcumin and its application in cancer. AB - Curcumin (CUR) is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy. PMID- 28860765 TI - Silica nanoparticles induce liver fibrosis via TGF-beta1/Smad3 pathway in ICR mice. AB - The liver is one of the target organs of silica nanoparticles (SiO2 NPs) but the toxic mechanism on the liver still remains unclear. This study aimed to explore the hepatic toxicity and its mechanism through repeated intravenous exposure to SiO2 NPs in ICR mice. Results indicated that SiO2 NPs could be distributed in hepatocytes, Kupffer cells, and hepatic stellate cells, and induce hepatic dysfunction as well as granuloma formation in the liver. The increase of lipid peroxide level and decrease of antioxidant enzyme activities in the liver indicated that SiO2 NPs could induce hepatic oxidative damage. SiO2 NPs induced hepatocytes' apoptosis shown by morphological examination and TUNEL assay. The results of Masson's trichrome staining and hydroxyproline assay showed hyperplasia of collagen fibers in the liver, suggesting SiO2 NPs caused liver fibrosis, and it was promoted by oxidative damage and hepatocytes' apoptosis. The results of Western blot analysis and immunohistochemical staining indicated that the activation of TGF-beta1/Smad3 signaling pathway played an important role in this pathophysiological process. The results suggested that oxidative damage and hepatocyte apoptosis activated TGF-beta1/Smad3 signaling pathway, and thus promoted the process of liver fibrosis induced by intravenous injection of SiO2 NPs in mice. This study, for the first time, investigated liver fibrosis and its related mechanism induced by repeated intravenous exposure of amorphous SiO2 NPs, and provides important experimental evidence for safety evaluation of SiO2 NPs, especially in biomedical application. PMID- 28860766 TI - Synthesized zinc peroxide nanoparticles (ZnO2-NPs): a novel antimicrobial, anti elastase, anti-keratinase, and anti-inflammatory approach toward polymicrobial burn wounds. AB - Increasing of multidrug resistance (MDR) remains an intractable challenge for burn patients. Innovative nanomaterials are also in high demand for the development of new antimicrobial biomaterials that inevitably have opened new therapeutic horizons in medical approaches and lead to many efforts for synthesizing new metal oxide nanoparticles (NPs) for better control of the MDR associated with the polymicrobial burn wounds. Recently, it seems that metal oxides can truly be considered as highly efficient inorganic agents with antimicrobial properties. In this study, zinc peroxide NPs (ZnO2-NPs) were synthesized using the co-precipitation method. Synthesized ZnO2-NPs were characterized by X-ray diffraction, Fourier transformed infrared, transmission electron microscopy, thermogravimetric analysis, differential scanning calorimetry, and ultraviolet-visible spectroscopy. The characterization techniques revealed synthesis of the pure phase of non-agglomerated ZnO2-NPs having sizes in the range of 15-25 nm with a transition temperature of 211 degrees C. Antimicrobial activity of ZnO2-NPs was determined against MDR Pseudomonas aeruginosa (PA) and Aspergillus niger (AN) strains isolated from burn wound infections. Both strains, PA6 and AN4, were found to be more susceptible strains to ZnO2-NPs. In addition, a significant decrease in elastase and keratinase activities was recorded with increased concentrations of ZnO2-NPs until 200 ug/mL. ZnO2-NPs revealed a significant anti-inflammatory activity against PA6 and AN4 strains as demonstrated by membrane stabilization, albumin denaturation, and proteinase inhibition. Moreover, the results of in vivo histopathology assessment confirmed the potential role of ZnO2-NPs in the improvement of skin wound healing in the experimental animal models. Clearly, the synthesized ZnO2-NPs have demonstrated a competitive capability as antimicrobial, anti-elastase, anti-keratinase, and anti-inflammatory candidates, suggesting that the ZnO2-NPs are promising metal oxides that are potentially valued for biomedical applications. PMID- 28860767 TI - VEGF siRNA delivered by polycation liposome-encapsulated calcium phosphate nanoparticles for tumor angiogenesis inhibition in breast cancer. AB - Angiogenesis plays an important role in tumor development and metastasis, and many cancer cells upregulate VEGF expression to promote angiogenesis. Silencing VEGF expression by RNA interference is expected to be a promising strategy to suppress the tumor growth. However, low transfection efficiency and instability are the main barriers for small interfering RNA (siRNA) delivery. In this study, we developed polycation liposome-encapsulated calcium phosphate nanoparticles (PLCP) for siRNA delivery in vivo. VEGF expression silencing effect in MCF-7 cells was investigated by real-time quantitative polymerase chain reaction and Western blot assay. VEGF siRNA mediated by PLCP can reduce 60%-80% VEGF expression in vitro, which was significantly higher than that mediated by Lipofectamine 2000. Furthermore, significant tumor growth and angiogenesis inhibition were observed in MCF-7 xenografts mice when treated with PLCP/VEGF siRNA or combined with doxorubicin. In conclusion, the combination of silencing VEGF expression and chemotherapeutics would be a potential treatment for cancer therapy. PMID- 28860769 TI - Factors associated with depressive symptoms in people living with HIV attending antiretroviral clinic at Fitche Zonal Hospital, Central Ethiopia: cross-sectional study conducted in 2012. AB - BACKGROUND: Depression is one of the most common psychiatric disorders with the prevalence rate ranging from 5% to 10% in the general population and about 60% in people living with human immunodeficiency virus (PLHIV). It has been reported to be more common among women living with HIV. In HIV patients, depression can have negative impacts on their quality of life. OBJECTIVE: This study was aimed at identifying the prevalence of depressive symptoms and associated factors among PLHIV attending the antiretroviral therapy clinic at Fitche Zonal Hospital. METHODS: It was a cross-sectional study conducted among PLHIV in Fitche Zonal Hospital from February 15 to March 15, 2012. Center for Epidemiologic Studies Depression tool was used to collect data from 390 respondents. Both the bivariate and multivariable logistic regression analyses were carried out and variables with P<0.25 in the bivariate logistic regression analysis were entered into multivariable logistic regression analysis and statistical significance was declared at P<0.05. RESULTS: Of the total 390 respondents included in the analysis, the prevalence of depressive symptoms was 76.7%, ranging from mild to moderate (33.6%) to major (43.1%), and the highest proportion was observed among individuals with food insecurity accounting for 287 (79.3%). Food insecurity (adjusted odds ratio [AOR] =3.832 [1.575-9.322]), non-ownership of livestock (AOR =2.17 [1.157-4.104]), and opportunistic infections (AOR =5.20 [1.342-20.156]) were significantly associated with depressive symptoms. CONCLUSION AND RECOMMENDATIONS: Depressive symptoms were prevalent in PLHIV. Social disparities were important factors of depressive symptoms. Integration of mental health care services with HIV/acquired immune deficiency syndrome-related health care services at all health care levels was necessary. It was recommended that government and non-government organizations should provide assistance to the PLHIV to encourage their involvement in income-generating activities. PMID- 28860768 TI - The effects of collagen-rich extracellular matrix on the intracellular delivery of glycol chitosan nanoparticles in human lung fibroblasts. AB - Recent progress in nanomedicine has shown a strong possibility of targeted therapy for obstinate chronic lung diseases including idiopathic pulmonary fibrosis (IPF). IPF is a fatal lung disease characterized by persistent fibrotic fibroblasts in response to type I collagen-rich extracellular matrix. As a pathological microenvironment is important in understanding the biological behavior of nanoparticles, in vitro cellular uptake of glycol chitosan nanoparticles (CNPs) in human lung fibroblasts was comparatively studied in the presence or absence of type I collagen matrix. Primary human lung fibroblasts from non-IPF and IPF patients (n=6/group) showed significantly increased cellular uptake of CNPs (>33.6-78.1 times) when they were cultured on collagen matrix. To elucidate the underlying mechanism of enhanced cellular delivery of CNPs in lung fibroblasts on collagen, cells were pretreated with chlorpromazine, genistein, and amiloride to inhibit clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis, respectively. Amiloride pretreatment remarkably reduced the cellular uptake of CNPs, suggesting that lung fibroblasts mainly utilize the macropinocytosis-dependent mechanism when interacted with collagen. In addition, the internalization of CNPs was predominantly suppressed by a phosphoinositide 3-kinase (PI3K) inhibitor in IPF fibroblasts, indicating that enhanced PI3K activity associated with late-stage macropinocytosis can be particularly important for the enhanced cellular delivery of CNPs in IPF fibroblasts. Our study strongly supports the concept that a pathological microenvironment which surrounds lung fibroblasts has a significant impact on the intracellular delivery of nanoparticles. Based on the property of enhanced intracellular delivery of CNPs when fibroblasts are made to interact with a collagen-rich matrix, we suggest that CNPs may have great potential as a drug carrier system for targeting fibrotic lung fibroblasts. PMID- 28860770 TI - Early predictors of brain damage in full-term newborns with hypoxic ischemic encephalopathy. AB - OBJECTIVE OF THE STUDY: To evaluate the value of serum creatine phosphokinase brain specific (CK-BB) and urinary lactate/creatinine (L/C) ratio as early indicators of brain damage in full-term newborns with hypoxic ischemic encephalopathy (HIE). PATIENTS AND METHODS: A case-control study including 25 full-term new-born infants with perinatal asphyxia who were admitted to neonatal intensive care unit (NICU) with a proven diagnosis of HIE, compared to 20 healthy age- and sex-matched full-term newborns. All newborn infants were subjected to full history taking, clinical examination, routine investigations (cord blood gases and complete blood picture), and assessment of serum CK-BB (cord blood, 6 and 24 hours after birth) and urinary L/C ratio (collected within the first 6 hours, on the 2nd and 3rd day after birth). RESULTS: The serum CK-BB and urinary L/C ratio in infants with HIE were significantly higher in samples collected throughout the monitoring period when compared with the control group (all P<0.001). The cord CK-BB and urinary L/C ratio within the first 6 hours were significantly higher in infants with severe HIE than in infants with mild and moderate HIE (P<0.001). Cord CK-BB level at 12.5 U/L had 100% sensitivity and 84% specificity in the detection of severe HIE infants. Urinary L/C ratio of more than 10.5 collected within the first 6 hours after birth had 100% sensitivity and 78% specificity for the detection of severe HIE infants. CONCLUSION: The serum CK BB and urinary L/C ratio in HIE infants were significantly increased early in the course of the disease, which can be used as useful indicators for predicting the development of HIE. PMID- 28860771 TI - Moderating role of self-efficacy on the associations of social support with depressive and anxiety symptoms in Chinese patients with rheumatoid arthritis. AB - PURPOSE: Rheumatoid arthritis (RA) is significantly associated with depression and anxiety. Social support and self-efficacy are the coping resources of psychological distress. However, little research is available on the interaction of social support and self-efficacy in RA patients. This study aimed to identify the prevalence of depressive and anxiety symptoms and to examine whether or not self-efficacy moderates the associations of social support with depressive and anxiety symptoms in Chinese RA patients. METHODS: A multicenter, cross-sectional study was conducted in northeast of China from December 2014 to January 2016. A total of 297 RA patients completed the Center for Epidemiologic Studies Depression Scale, Zung Self-Rating Anxiety Scale, Multidimensional Scale of Perceived Social Support and General Self-Efficacy Scale. The associations of social support, self-efficacy and social support * self-efficacy interaction with depressive and anxiety symptoms were examined by hierarchical regression analysis. If the interaction was statistically significant, simple slope analysis was conducted. RESULTS: The prevalence of depressive symptoms was 58.2%, while 47.5% RA patients had anxiety symptoms. Social support and social support * self efficacy interaction were significantly associated with depressive symptoms. Social support, self-efficacy and their interaction were significantly associated with anxiety symptoms. The association between social support and depressive symptoms was gradually reduced in the low (1 standard deviation [SD] below the mean, B=-0.614, beta=-0.876, P<0.001), mean (B=-0.395, beta=-0.563, P<0.001) and high (1 SD above the mean, B=-0.176, beta=-0.251, P=0.002) groups of self efficacy. For anxiety symptoms, the association was also gradually reduced in the low (B=-0.527, beta=-0.774, P<0.001), mean (B=-0.288, beta=-423, P<0.001) and high (B=-0.049, beta=-0.071, P=0.447) groups of self-efficacy. CONCLUSION: There was a high prevalence of depressive and anxiety symptoms in Chinese RA patients. Self-efficacy could attenuate the associations of social support with depressive and anxiety symptoms. Adequate social support and self-efficacy intervention should be provided to alleviate psychological distress. PMID- 28860772 TI - Factors associated with failure to achieve remission and with relapse after remission in patients with major depressive disorder in the PERFORM study. AB - BACKGROUND: The Prospective Epidemiological Research on Functioning Outcomes Related to Major Depressive Disorder (PERFORM) study has been initiated to better understand the course of a depressive episode and its impact on patient functioning. This analysis aimed to identify sociodemographic and clinical factors associated with failure to achieve remission at month 2 after initiating or switching antidepressant monotherapy and with subsequent relapse at month 6 for patients in remission at month 2. MATERIALS AND METHODS: This was a 2-year observational cohort study in 1,159 outpatients aged 18-65 years with major depressive disorder initiating or undergoing the first switch of antidepressant monotherapy. Factors with P<0.20 in univariate logistic regression analyses were combined in a multiple logistic regression model to which backward variable selection was applied (ie, sequential removal of the least significant variable from the model and recomputation of the model until all remaining variables have P<0.05). RESULTS: Baseline factors significantly associated with lower odds of remission at month 2 were body-mass index >=30 kg/m2 (OR 0.51), depressive episode >8 weeks (OR 0.51), being in psychotherapy (OR 0.51), sexual dysfunction (OR 0.62), and severity of depression (OR 0.87). Factors significantly associated with relapse at month 6 were male sex (OR 2.47), being married or living as a couple (OR 2.73), residual patient-reported cognitive symptoms at 2 months (OR 1.12 per additional unit of Perceived Deficit Questionnaire-5 score) and residual depressive symptoms at 2 months (OR 1.27 per additional unit of Patient Health Questionnaire-9 score). CONCLUSION: Different factors appear to be associated with failure to achieve remission in patients with major depressive disorder and with subsequent relapse in patients who do achieve remission. Patient-reported cognitive dysfunction is an easily measurable and treatable characteristic that may be associated with an increased likelihood of relapse at 6 months in patients who have achieved remission. PMID- 28860773 TI - Can melatonin prevent or improve metabolic side effects during antipsychotic treatments? AB - In the last two decades, second-generation antipsychotics (SGAs) were more frequently used than typical antipsychotics for treating both psychotic and nonpsychotic psychiatric disorders in both children and adolescents, because of their lower risk of adverse neurological effects, that is, extrapyramidal symptoms. Recent studies have pointed out their effect on weight gain and increased visceral adiposity as they induce metabolic syndrome. Patients receiving SGAs often need to be treated with other substances to counteract metabolic side effects. In this paper, we point out the possible protective effect of add-on melatonin treatment in preventing, mitigating, or even reversing SGAs metabolic effects, improving quality of life and providing safer long-term treatments in pediatric patients. Melatonin is an endogenous indolamine secreted during darkness by the pineal gland; it plays a key role in regulating the circadian rhythm, generated by the suprachiasmatic nuclei (SCN) of the hypothalamus, and has many other biological functions, including chronobiotic, antioxidant and neuroprotective properties, anti-inflammatory and free radical scavenging effects, and diminishing oxidative injury and fat distribution. It has been hypothesized that SGAs cause adverse metabolic effects that may be restored by nightly administration of melatonin because of its influence on autonomic and hormonal outputs. Interestingly, atypical anti-psychotics (AAPs) can cause several sleep disorders, and circadian misalignment can influence hormones involved in the metabolic regulation, such as insulin, leptin, and ghrelin; furthermore, a relationship between obesity and sleep curtailment has been demonstrated, as well as sleep deprivation in rats has been associated with hyperphagia. Metabolic effects of melatonin, both central and peripheral, direct and indirect, target most metabolic disorders reported during and after SGA treatment in children, adolescents, and adults. Further systematic studies on psychiatric patients are needed to explore the effect of add-on melatonin on metabolic side effects of SGAs, independent of energy intake, diet, and exercise. PMID- 28860774 TI - Bipolar II disorder as the initial presentation of CADASIL: an underdiagnosed manifestation. AB - Mood disturbances have been documented in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The highly varied morbidity indicates that the affective symptoms in CADASIL have not been cataloged systematically, leading to ineffective treatment, affecting the patients' quality of life, and possibly resulting in suicide. We present a case of CADASIL with bipolar II disorder as the first manifestation. A middle-aged female reported recurrent depressive episodes and appeared treatment resistant to adequate dosages and durations of antidepressants. Following a structured psychiatric interview and neuropsychological assessment, a past episode of hypomania was identified. Added treatment with sodium valproate alleviated most symptoms. Considering late-onset bipolar disorder with unexplained decline in cognition, a medical history of migraine, and a suspected family history of stroke, further cranial magnetic resonance imaging scan was performed and revealed severe leukoencephalopathy, prompting further investigation. The diagnosis was revised to CADASIL after Arg587Cys NOTCH3 mutation was confirmed. This case highlights the evolving process of affective disorder diagnosis and underlying organic etiologies. Based on the overlap of white matter hyperintensities, NOTCH3 mutation, and valproate therapy in bipolar disorder and CADASIL, bipolar II depression may be a poorly recognized manifestation of CADASIL. Well-designed clinical trials are warranted to verify the current findings. PMID- 28860775 TI - A case of paroxysmal kinesigenic dyskinesia which exhibited the phenotype of anxiety disorder. AB - BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare heritable neurologic disorder characterized by attacks of involuntary movement induced by sudden voluntary movements. No previous reports have described cases showing comorbidity with psychiatric disease or symptoms. In this case, we showed a patient with PKD who exhibited several manifestations of anxiety disorder. CASE: A 35-year-old Japanese man with PKD had been maintained on carbamazepine since he was 16 years of age without any attacks. However, 10 years before this referral, he became aware of a feeling of breakdown in his overall physical functions. He had then avoided becoming familiar with people out of concern that his physical dysfunctions might be perceived in a negative light. One day he was referred by the neurologic department at our hospital to the Department of Psychiatry because of severe anxiety and hyperventilation triggered by carbamazepine. We treated with escitalopram, aripiprazole, and ethyl loflazepate. Both his subjective physical condition and objective expressions subsequently showed gradual improvement. At last, the feelings of chest compression and anxiety entirely disappeared. Accordingly, increases in plasma monoamine metabolite levels were observed, and the c.649dupC mutation, which has been found in most Japanese PKD families, was detected in his proline-rich transmembrane protein 2 gene. CONCLUSION: This is the first report to describe psychiatric comorbidities or symptoms in a PKD case. The efficacy of psychotropic medication used in this case, the resulting changes in plasma monoamine metabolite levels, and the recent advances in the molecular understanding of PKD suggested slight, but widespread alterations to the neurotransmitter systems in the brain. PMID- 28860776 TI - Feasibility of cognitive remediation therapy for adults with autism spectrum disorders: a single-group pilot study. AB - BACKGROUND: Set-shifting (SS) difficulties and weak central coherence (CC) are commonly associated with autism spectrum disorders (ASD). Cognitive remediation therapy (CRT) aims to improve such cognitive processing; however, there are no reports on CRT for patients with ASD. This pilot study aimed to provide preliminary evidence to support the use of CRT for individuals with ASD and provide data to inform future studies. PARTICIPANTS AND METHODS: Nineteen individuals with ASD were recruited and administered a series of neuropsychological and questionnaire measures to examine cognitive function and clinical outcomes such as anxiety and depression. Participants received CRT, and cognitive function and clinical variables were re-evaluated at postintervention and after 3 months. RESULTS: The participants demonstrated significant improvement in CC and anxiety at postintervention, which was maintained at 3 month follow-up. Although SS scores had improved with a large effect size, this was not statistically significant. CONCLUSION: CRT improved CC and anxiety scores for individuals with ASD, suggesting that CRT is an effective treatment for individuals with ASD. PMID- 28860777 TI - Efficacy and safety of paliperidone palmitate three-monthly formulation in East Asian patients with schizophrenia: subgroup analysis of a global, randomized, double-blind, Phase III, noninferiority study. AB - OBJECTIVE: To demonstrate the efficacy and safety of paliperidone palmitate three monthly (PP3M) formulation in an East Asian population with schizophrenia by subgroup analysis of a double-blind (DB), multicenter, noninferiority study. PATIENTS AND METHODS: Of 1,429 patients who entered the open-label (OL) phase, 510 were East Asian (China: 296 [58%], Japan: 175 [34%], South Korea: 19 [4%] and Taiwan: 20 [4%]). In the 17-week OL phase, patients received paliperidone palmitate once-monthly (PP1M) formulation on day 1 (150 mg eq.), day 8 (100 mg eq.) and once-monthly thereafter (50-150 mg eq., flexible). Following the OL phase, patients (n=344 East Asian) entered DB phase and were randomized (1:1) to PP1M (n=174) or PP3M (n=170). Primary efficacy endpoint was the percentage of patients who remained relapse free at the end of the 48-week DB phase, using Kaplan-Meier cumulative survival estimate. Secondary efficacy endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale, Clinical Global Impression Severity, Personal and Social Performance scores and symptomatic remission. Additional assessments included caregiver burden and safety. RESULTS: A total of 285/344 (83%) randomized East Asian patients completed the DB phase. The percentage of patients who had a relapse event was similar on comparing PP3M (17 [10.2%]) to PP1M (20 [11.8%]), and also for Japan (PP3M: 9 [17.6%], PP1M: 13 [23.2%]) and China (PP3M: 6 [5.9%], PP1M: 7 [6.9%]). Mean change from baseline in secondary efficacy parameters was similar to the global population, regardless of treatment. Symptomatic remission was attained by 50% of the treated patients. Caregiver burden was significantly reduced (P<0.001) following treatment with PP3M/PP1M. Frequency of treatment-emergent adverse events in PP3M group during DB phase was greater in the East Asian subgroup (81%) than the global population (68%) and was higher in Japan (92%) than China (75%). CONCLUSION: Results suggest that PP3M is efficacious in the East Asian subgroup. Although treatment-emergent adverse events were slightly higher in the East Asian subgroup versus the global population, no new safety signals were identified. PMID- 28860778 TI - Improvements in motor tasks through the use of smartphone technology for individuals with Duchenne muscular dystrophy. AB - BACKGROUND: In individuals severely affected with Duchenne muscular dystrophy (DMD), virtual reality has recently been used as a tool to enhance community interaction. Smartphones offer the exciting potential to improve communication, access, and participation, and present the unique opportunity to directly deliver functionality to people with disabilities. OBJECTIVE: To verify whether individuals with DMD improve their motor performance when undertaking a visual motor task using a smartphone game. PATIENTS AND METHODS: Fifty individuals with DMD and 50 healthy, typically developing (TD) controls, aged 10-34 years participated in the study. The functional characterization of the sample was determined through Vignos, Egen Klassifikation, and the Motor Function Measure scales. To complete the task, individuals moved a virtual ball around a virtual maze and the time in seconds was measured after every attempt in order to analyze improvement of performance after the practice trials. Motor performance (time to finish each maze) was measured in phases of acquisition, short-term retention, and transfer. RESULTS: Use of the smartphone maze game promoted improvement in performance during acquisition in both groups, which remained in the retention phase. At the transfer phases, with alternative maze tasks, the performance in DMD group was similar to the performance of TD group, with the exception of the transfer to the contralateral hand (nondominant). However, the group with DMD demonstrated longer movement time at all stages of learning, compared with the TD group. CONCLUSION: The practice of a visual motor task delivered via smartphone game promoted an improvement in performance with similar patterns of learning in both groups. Performance can be influenced by task difficulty, and for people with DMD, motor deficits are responsible for the lower speed of execution. This study indicates that individuals with DMD showed improved performance in a short term motor learning protocol using a smartphone. We advocate that this technology could be used to promote function in this population. PMID- 28860779 TI - Erratum: Assessment of safety and efficacy of lamotrigine over the course of 1 year observation in Japanese patients with bipolar disorder: post-marketing surveillance study report [Corrigendum]. AB - [This corrects the article on p. 1441 in vol. 13, PMID: 28652744.]. PMID- 28860780 TI - Association between COMT Val158Met and DAT1 polymorphisms and depressive symptoms in the obese population. AB - OBJECTIVES: Depressive symptoms are common among patients with obesity. Abnormalities in dopamine signaling involved in the reward circuit may ensue excessive consumption of food, resulting in obesity and leading to neuropsychiatric disorders such as depression. This study sought to investigate the association of polymorphisms in the genes encoding DAT1/SLC6A3 and COMT with the intensity of depressive symptoms in obese subjects. PARTICIPANTS AND METHODS: Prevalence and severity of depressive symptoms were assessed in a group of 364 obese patients using the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS). Genetic polymorphisms in DAT1 and COMT were evaluated in peripheral blood samples. RESULTS: The results indicated an association between DAT1 alleles and depressive symptoms, as well as severity of obesity. Subjects homozygous for the nine-repeat allele scored higher in BDI (P=0.022) and HDRS (P=0.00001), suggesting higher intensity of depression in both sexes. This allele was also associated with the highest body mass index (BMI; P=0.001). Carriers of the Val158Met allele of COMT scored higher on both depression scales (BDI, P=0.0005; HRDS, P=0.002) and had the highest BMI values. CONCLUSION: Polymorphisms in the DAT1 and COMT genes are associated with a greater intensity of depressive symptoms in the obese population. PMID- 28860781 TI - Adverse outcomes after percutaneous dilatational tracheostomy versus surgical tracheostomy in intensive care patients: case series and literature review. AB - Tracheostomy is a routinely done procedure in the setting of intensive care unit (ICU) in patients requiring prolonged mechanical ventilation. There are two ways of making a tracheostomy: an open surgical tracheostomy and percutaneous dilatational tracheostomy. Percutaneous dilatational tracheostomy is associated with fewer complications than open tracheostomy. In this study, we would like to compare both techniques of performing a tracheostomy in ICU patients and to present possible complications, methods of diagnosing and treating and minimizing their risk. PMID- 28860782 TI - The safety and efficacy of front-firing green-light laser endoscopic en bloc photoselective vapo-enucleation of non-muscle-invasive bladder cancer. AB - PURPOSE: Laser therapy provides an alternative option for treating non-muscle invasive bladder cancer (NMIBC). However, the clinical evidence for potassium titanyl-phosphate (KTP) laser en bloc resection is still limited. Here, we investigated the efficacy and safety of the 120-W front-firing KTP laser for the treatment of NMIBC. METHODS: A total of 64 patients with NMIBC treated with either a 120-W front-firing KTP-photoselective vapo-enucleation of the bladder tumor (PVEBT, n=34) or transurethral resection of the bladder tumor (TURBT, n=30) were included. En bloc resection was applied to the patients in PVEBT group. RESULTS: There was no significant difference in rinsing time (P=0.292), indwelling catheter (P=0.080), pathologic type, and T stage (P=0.870) between the two groups. Compared with the TURBT group, patients treated with PVEBT had a shorter hospitalization stay (P=0.044), a shorter operation time (P=0.008), and a lower muscle miss rate (P=0.044). PVEBT is superior to TURBT in terms of the rate of 1-year recurrence (P=0.015) and tumor grade progression rate (P=0.019). CONCLUSION: The 120-W front-firing KTP laser en bloc enucleation technique is a safe and feasible procedure for treating patients with NMIBC. Further external validation in larger cohorts with a long follow-up period is warranted. PMID- 28860783 TI - Does whey protein supplementation affect blood pressure in hypoalbuminemic peritoneal dialysis patients? AB - OBJECTIVE: Hypertension and hypoalbuminemia are common risk factors for cardiovascular complications in peritoneal dialysis (PD) patients. Data are limited regarding the effects of whey protein consumption on blood pressure in this population. The aim of the present study was to examine if whey protein supplementation for 12 weeks to hypoalbuminemic PD patients affects their blood pressure. PATIENTS AND METHODS: This prospective randomized study included 36 stable PD patients with serum albumin levels <3.8 g/dL. During 12 weeks, 18 patients were instructed to consume 1.2 g/kg/day of protein and an additional whey protein supplement at a dose of 25% of the instructed daily protein (whey protein group). Eighteen patients were instructed to consume protein in the amount of 1.2 g/kg/day and an additional 25%, without whey protein supplementation (control group). RESULTS: Compared to the control group, in the whey protein group, serum albumin levels, oncotic pressure, and dialysate ultrafiltration significantly increased (3.55+/-0.14 to 4.08+/-0.15 g/dL, P<0.001; 21.81+/-2.03 to 24.06+/-1.54 mmHg, P<0.001; 927.8+/-120.3 to 1,125.0+/ 125.1 mL/day, P<0.001; respectively) and were significantly higher after 12 weeks (4.08+/-0.15 vs 3.41+/-0.49 g/dL, P<0.001; 24.06+/-1.54 vs 22.71+/-1.77 mmHg, P=0.010; 1,125.0+/-125.1 vs 930.6+/-352.8 mL/day, P=0.017; respectively) in the whey protein group compared to the control group. Fluid overload, the extracellular to intracellular ratio and mean arterial pressure (MAP) significantly decreased (2.46+/-1.08 to 1.52+/-0.33, P<0.001; 1.080+/-0.142 to 0.954+/-0.124, P<0.001; 102.6+/-3.80 to 99.83+/-3.85, P=0.018; respectively) and were significantly lower in the whey protein group after 12 weeks (1.52+/-0.33 vs 2.23+/-0.73, P<0.001, 0.954+/-0.124 vs 1.048+/-0.111, P=0.002; 99.83+/-3.85 vs 102.8+/-3.93, P=0.018; respectively). CONCLUSION: Whey protein supplementation for 12 weeks decreased MAP in hypoalbuminemic PD patients. PMID- 28860784 TI - Effect of additive calcium administration on FGF23 levels in patients with mild chronic kidney disease treated with calcitriol: a randomized, open-labeled clinical trial. AB - BACKGROUND: The purpose of the present study was to determine the effect of additional calcium carbonate treatment on fibroblast growth factor 23 (FGF23) levels in patients treated with calcitriol. METHODS: In this randomized, open labeled, and parallel-group study, a total of 30 patients with early chronic kidney disease (CKD) and vitamin D deficiency were randomly assigned to two groups and received interventions for 8 weeks: 1) a combination of calcium carbonate and calcitriol group; and 2) calcitriol only group. The primary outcome was the difference in percentage change of serum FGF23 levels from baseline between the two groups. Secondary end points included the changes in serum levels of calcium, phosphate, parathyroid hormone (PTH), and 25-hydroxyvitamin D3 (25(OH)D) from baseline. RESULTS: Serum FGF23 levels were more elevated in the combination group than in the calcitriol-alone group. However, both mean change and percentage change in the serum FGF23 levels during the 8-week period were not significantly different between the two groups. Serum calcium level was increased significantly only in the combination treatment group. There was no significant difference in percentage change of serum calcium levels between the two groups. In addition, changes in serum levels of phosphate, 25(OH)D, or PTH were not significantly different between the two groups. In correlation analysis, changes in serum FGF23 levels were positively correlated with changes in serum calcium and phosphate levels, but not with changes in 25(OH)D or PTH levels. No serious adverse events were observed, however, there was one case of mild gastrointestinal discomfort. CONCLUSION: This study revealed that additional calcium carbonate treatment significantly increased serum FGF23 levels in patients treated with calcitriol, with their synergistic effect in promoting intestinal calcium absorption. This suggests that serum FGF23 levels should be monitored regularly, especially in those who use combination of vitamin D and calcium carbonate from the early stages of CKD. PMID- 28860785 TI - The value of time-averaged serum high-sensitivity C-reactive protein in prediction of mortality and dropout in peritoneal dialysis patients. AB - PURPOSE: C-reactive protein (CRP) is a useful biomarker for prediction of long term outcomes in patients undergoing chronic dialysis. This observational cohort study evaluated whether the time-averaged serum high-sensitivity CRP (HS-CRP) level was a better predictor of clinical outcomes than a single HS-CRP level in patients undergoing peritoneal dialysis (PD). PATIENTS AND METHODS: We classified 335 patients into three tertiles according to the time-averaged serum HS-CRP level and followed up regularly from January 2010 to December 2014. Clinical outcomes such as cardiovascular events, infection episodes, newly developed malignancy, encapsulating peritoneal sclerosis (EPS), dropout (death plus conversion to hemodialysis), and mortality were assessed. RESULTS: During a 5 year follow-up, 164 patients (49.0%) ceased PD; this included 52 patient deaths (15.5%), 100 patients (29.9%) who converted to hemodialysis, and 12 patients (3.6%) who received a kidney transplantation. The Kaplan-Meier survival analysis and log-rank test revealed a significantly worse survival accumulation in patients with high time-average HS-CRP levels. A multivariate Cox regression analysis revealed that a higher time-averaged serum HS-CRP level, older age, and the occurrence of cardiovascular events were independent mortality predictors. A higher time-averaged serum HS-CRP level, the occurrence of cardiovascular events, infection episodes, and EPS were important predictors of dropout. The receiver operating characteristic analysis verified that the value of the time-average HS CRP level in predicting the 5-year mortality and dropout was superior to a single serum baseline HS-CRP level. CONCLUSION: This study shows that the time-averaged serum HS-CRP level is a better marker than a single baseline measurement in predicting the 5-year mortality and dropout in PD patients. PMID- 28860786 TI - Risk factors and early outcomes of acute renal injury after thoracic aortic endograft repair for type B aortic dissection. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has become an emerging treatment modality for acute type B aortic dissection (TBAD) patients in recent years. The risk factors and impacts of acute kidney injury (AKI) after percutaneous TEVAR, however, have not been widely established. METHODS: We retrospectively studied the clinical records of 305 consecutive patients who admitted to our institution and had TEVAR for TBAD between December 2009 and June 2013. The patients were routinely monitored for their renal functions preoperatively until 7 days after TEVAR. The Kidney Disease Improving Global Guidelines (KDIGO) criteria were used for AKI. RESULTS: Of the total 305 consecutive patients, 84 (27.5%) developed AKI after TEVAR, comprising 66 (21.6%) patients in KDIGO stage 1, 6 (2.0%) patients in stage 2 and 12 (3.9%) patients in stage 3. From the logistic regression analysis, systolic blood pressure (SBP) on admission >140 mmHg (odds ratio [OR], 2.288; 95% CI, 1.319-3.969) and supra aortic branches graft bypass hybrid surgery (OR, 3.228; 95% CI, 1.526-6.831) were independent risk factors for AKI after TEVAR. Local anesthesia tended to be a protective factor (OR, 0.563; 95% CI, 0.316-1.001). The preoperative renal function, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or statin administration, volume of contrast agent, range of TBAD and false lumen involving renal artery were not associated with post-operation AKI. The in hospital mortality and major adverse events were markedly increased with the occurrence of AKI (7.1% vs 0.9%, P=0.006; 14.3% vs 3.2%, P<0.001, respectively). CONCLUSIONS: TEVAR for TBAD has a high incidence of AKI, which is associated with worse in-hospital outcomes. SBP on admission and supra-aortic branches graft bypass hybrid surgery were the most significant risk factors. Renopreventive measures should be considered in high-risk patients. PMID- 28860787 TI - Prevalence and predictors of sleep apnea in patients with stable coronary artery disease: a cross-sectional study. AB - BACKGROUND: Sleep apnea (SA) is increasingly recognized as being important in the prognosis of patients with coronary artery disease (CAD); however, symptoms of SA are not easily identified, and as many as 80% of sufferers remain undiagnosed. AIM: This cross-sectional study investigated the prevalence and predictors of SA that may help to increase the awareness and diagnosis of SA in stable CAD patients. MATERIALS AND METHODS: Polysomnography was performed in 772 medically stable CAD patients with untreated SA recruited from the Clinic of Cardiovascular Rehabilitation. Patients were predominantly male (76%), median age was 58 years (32-81). All subjects completed the Epworth sleepiness scale (ESS). The frequency of all apneas and hypopneas associated with 3% oxygen desaturation is referred to as the apnea-hypopnea index (AHI). Mild-to-severe SA was defined as AHI >=5/h, moderate-to-severe SA as AHI >=15/h. RESULTS: AHI was within a range of values that was considered normal or only mildly elevated. The median AHI was 3.4 (interquartile range [IQR 1-9]), and 39% of patients had unrecognized mild-to severe SA (moderate-to-severe in 14%), which was not higher than other known risk indicators for CAD such as hypertension and obesity (83% and 47%, respectively). These patients did not show sleepiness and the risk-related cut-off score for excessive daily sleepiness was lower than the official for ESS. CONCLUSION: Hypertension, age, male gender, obesity, ESS >=6, and left ventricular ejection fraction <=45% were the best predictors of mild-to-severe SA. While, male gender, age 50-70 years and, mainly, the presence of obesity but not hypertension were clinical predictors for moderate-to-severe SA. In addition, association between mild-to-severe SA and obesity was not evident in women. SA is prevalent comorbidity in the stable CAD patients, especially in its asymptomatic mild form. We suggest that SA should be considered in the secondary prevention protocols for CAD. PMID- 28860788 TI - Impact of immunosuppressant therapy on new-onset diabetes in liver transplant recipients. AB - This nationwide, population-based study aimed to clarify the effects of immunosuppressive regimens on new-onset diabetes after liver transplantation (NODALT). The National Health Insurance database of Taiwan was explored for patients who received liver transplantation without pre-transplant diabetes from 1998 to 2012. Information regarding clinical conditions and immunosuppressant utilization among these patients was analyzed statistically. Of the 2,140 patients included in our study, 189 (8.8%) developed NODALT. The pre-transplant risk factors for NODALT were identified as old age, male sex, hepatitis C, alcoholic hepatitis, and immunosuppressant use of tacrolimus (TAC). All patients used corticosteroids as a baseline immunosuppressant. The immunosuppressant regimen of cyclosporine (CsA)+TAC+mycophenolate mofetil (MMF) contributed most to NODALT (adjusted hazard ratio 7.596) in comparison with the regimens of TAC+MMF and CsA+MMF; this regimen also contributed significantly to higher post transplant bacteremia, urinary tract infection, pneumonia, renal failure, and mortality rate. In conclusion, our analysis confirmed TAC-based immunosuppression contributes to higher NODALT incidence than CsA-based regimen, and TAC-CsA conversion due to any causes might lead to worse clinical outcomes. Clinicians should make better risk stratifications before prescribing immunosuppressants for liver transplant recipients. PMID- 28860789 TI - New developments in the treatment of primary biliary cholangitis - role of obeticholic acid. AB - Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that predominantly affects women in early to middle age. It is typically associated with autoantibodies to mitochondrial antigens and results in immune mediated destruction of small and medium-sized intrahepatic bile ducts leading to cholestasis, hepatic fibrosis and may progress to cirrhosis or hepatic failure and, in some cases, hepatocellular carcinoma. The clinical presentation and the natural history of PBC have improved over the years due to recognition of earlier widespread use of ursodeoxycholic acid (UDCA); about one-third of patients show suboptimal biochemical response to UDCA with poor prognosis. Until recently, UDCA was the only US Food and Drug Administration approved agent for this disease for more than two decades; obeticholic acid was approved in 2016 for treatment of patients with PBC with a suboptimal response or intolerance to UDCA. Currently, liver transplantation is the most effective treatment modality for PBC patients with end-stage liver disease. This review will focus on the recent advances in therapy of primary biliary cholangitis, with emphasis on obeticholic acid. PMID- 28860790 TI - Evaluation of pain during endovenous laser ablation of the great saphenous vein with ultrasound-guided femoral nerve block. AB - BACKGROUND: Endoluminal laser ablation is now considered the method of choice for treating greater saphenous vein insufficiency. General anesthesia and peripheral nerve blocks with sedation have the risk of post-procedural delay in discharge and prolonged immobilization with the risk of deep vein thrombosis. The main pain experienced by patients during the procedure is during the laser ablation and the multiple needle punctures given along and around the great saphenous vein. The aim of our study was to evaluate the safety and efficacy of blocking the femoral nerve only under ultrasound-guidance without sedation, to reduce or prevent pain during injectable tumescent anesthesia in endovenous laser ablation of the greater saphenous vein. METHODS: Sixty patients in two groups underwent endovenous laser ablation for the greater saphenous vein insufficiency at an outpatient clinic. All patients received tumescent anesthesia. However, one group received a femoral nerve block (FNB) under ultrasound guidance before the procedure. All patients were asked to record the pain or discomfort, using the visual analog score, from the start of the procedure until the end of the great saphenous vein laser ablation. The length of the great saphenous vein and duration of the procedure were also recorded. The results were analyzed using statistical methods. RESULTS: No complications from FNB were observed. The pain associated with application of tumescent anesthesia and laser ablation was more intense in the group without an FNB (P < 0.001). There was no significant difference between the two groups in the length of the great saphenous vein or procedure duration. CONCLUSION: Ultrasound-guided FNB (without other peripheral nerve blocks) is a safe, adequate, and effective option to decrease and/or eliminate the intraoperative discomfort associated with tumescent anesthesia injections and laser ablation during endoluminal laser ablation of the greater saphenous vein. PMID- 28860791 TI - Soluble ST2 correlates with some indicators of right ventricular function in hypertensive heart failure. AB - PURPOSE: ST2 receptor, which is a member of the Toll-like/interleukin-1 (IL-1) receptor family, has been found to be increased in the serum of patients 1 day after myocardial infarction. Several other studies have shown that soluble ST2 levels correlate with severity of heart failure (HF), left ventricular ejection fraction, creatinine clearance, B-type natriuretic peptide and C-reactive protein, and are predictors of mortality in HF. Most of these studies were not only limited to ischemic heart disease but also concentrated on left-sided HF. We therefore decided to study the relationship between soluble ST2 and some markers of right ventricular (RV) function in a cohort of hypertensive HF subjects. PATIENTS AND METHODS: This is a prospective cohort study of hypertensive HF patients presenting to the University of Abuja Teaching Hospital, Abuja, over a 12-month period. ST2 was measured in plasma sample by the enzyme-linked immunosorbent assay (ELISA) method. Right ventricular diameters in diastole (RVDD) and right atrial area (RAA) were obtained on echocardiography, while right ventricular systolic pressure (RVSP) was estimated from echocardiography by the addition of the pressure gradient between the right ventricle and right atrium (RA) to the pressure in the RA. RESULTS: There was a significant correlation between RVSP and soluble ST2 (t=0.75, p<0.0001), RVDD (t=0.28, p=0.004) and RAA (t=0.46, p=0.002). CONCLUSION: In a cohort of hypertensive HF subjects, soluble ST2 correlates significantly with RVSP, RVDD and RAA. PMID- 28860792 TI - Endothelial dysfunction in patients with Buerger disease. AB - We evaluated the endothelial function of patients with Buerger disease using peripheral arterial tonometry test, and examined the factors that are significantly correlated with the endothelial dysfunction in these patients. We performed the peripheral arterial tonometry test in 22 patients with Buerger disease. We recorded the patients' characteristics, including ankle brachial pressure index and reactive hyperemia index, which reflect the endothelial dysfunction. We divided the patients with Buerger disease into the conservative treatment and lumbar sympathectomy group. While the reactive hyperemia index was not significantly different between these two groups, the ankle brachial pressure index was significantly different (1.12 versus 0.83, P=0.003). Furthermore, the reactive hyperemia index was significantly correlated with the ankle brachial pressure index value in the patients in the lumbar sympathectomy group (rho=0.848, P=0.005). Given that patients with Buerger disease show impairment of the sympathetic nervous system, we should consider the after-effects of such an impaired system on the condition of these patients. The patients treated with lumbar sympathectomy might be more appropriate to evaluate their endothelial function by a peripheral arterial tonometry test. PMID- 28860794 TI - Nursing schools and academic health centers: toward improved alignment and a synergistic partnership. AB - This paper presents the findings from a national survey which the University of Washington conducted among leaders of 32 US academic nursing institutions that are part of academic health centers (AHCs) and complements these findings with results from a separate report by the American Association of Colleges of Nursing. While expressing overall satisfaction with their AHC relationships, these leaders find that nursing is often given greater parity in matters of education and research than in mission setting, financial, and governance matters. AHCs are being asked to meet new health care challenges in new ways, starting with the education of health care professionals. AHCs need to be restructured to give nursing full parity if the nation's and world's needs for preventive and clinical care are to be best met. PMID- 28860793 TI - Evaluation of bleeding in patients receiving direct oral anticoagulants. AB - Direct oral anticoagulants (DOACs) are recognized by evidence-based treatment guidelines as the first-line option for the treatment of venous thromboembolism and prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. As use of these anticoagulants has become favored over the past several years, reported bleeding-related adverse drug events with these agents has increased. In randomized clinical trials, all DOACs have a reduced risk for intracranial hemorrhage, while major and other bleeding results have varied among the agents compared to vitamin K antagonists. We have reviewed the bleeding incidence and severity from randomized and real-world data in patients receiving DOACs in an effort to provide the clinician with a critical review of bleeding and offer practical considerations for avoiding adverse events with these anticoagulants. PMID- 28860795 TI - Key factors influencing allied health research capacity in a large Australian metropolitan health district. AB - OBJECTIVE: The aim of this study was to identify key factors affecting research capacity and engagement of allied health professionals working in a large metropolitan health service. Identifying such factors will assist in determining strategies for building research capacity in allied health. MATERIALS AND METHODS: A total of 276 allied health professionals working within the Sydney Local Health District (SLHD) completed the Research Capacity in Context Tool (RCCT) that measures research capacity and culture across three domains: organization, team, and individual. An exploratory factor analysis was undertaken to identify common themes within each of these domains. Correlations were performed between demographic variables and the identified factors to determine possible relationships. RESULTS: Research capacity and culture success/skill levels were reported to be higher within the organization and team domains compared to the individual domain (median [interquartile range, IQR] 6 [5-8], 6 [5-8], 5 [3-7], respectively; Friedman chi2(2)=42.04, p<0.001). Exploratory factor analyses were performed to identify factors that were perceived by allied health respondents to affect research capacity. Factors identified within the organization domain were infrastructure for research (eg, funds and equipment) and research culture (eg, senior manager's support for research); within the team domain the factors were research orientation (eg, dissemination of results at research seminars) and research support (eg, providing staff research training). Within the individual domain, only one factor was identified which was the research skill of the individual (eg, literature evaluation, submitting ethics applications and data analysis, and writing for publication). CONCLUSION: The reported skill/success levels in research were lower for the individual domain compared to the organization or team domains. Key factors were identified in each domain that impacted on allied health research capacity. As these factors were different in each domain, various strategies may be required at the level of the organization, team, and individual to support and build allied health research capacity. PMID- 28860796 TI - The positive effects of a peer-led intervention system for individuals with a risk of metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) is a major health risk in Thailand. Although it is reported that females have a higher rate of MetS than males, very few peer-led intervention studies have been conducted on specific groups, such as seamstresses, at risk of MetS. This study aimed to evaluate the effect of a peer led intervention program on reducing MetS risk factors in individuals working in Thai Uniform Sewing Military Factories. METHODS: A quasiexperimental program was introduced using a pre- and posttest design that was applied to female sewing factory workers selected for this research. All participants had at least one of the key MetS symptoms. The experimental group (N=50 participants) received 12 weekly peer-led individual support discussion sessions that included both dietary and physical activity (PA) advice and the control group (N=50 participants) followed their usual daily routines. The Student's t-test and the Pearson's chi squared test were used to compare the differences of baseline data and analysis of variance was used for analysis of the data after intervention. RESULTS: The results showed that after 3 months of participation, when compared to the control group, the experimental group had significantly improved systolic blood pressure (BP) (P=0.04), diastolic BP (P<0.001), PA (P=0.05), knowledge scores of MetS, perception of MetS and risk factors (P<0.001), and stress assessment (P=0.002). Waist circumference, body mass index, and Food Frequency Questionnaire score were not significantly different but still improved. CONCLUSION: Findings from this study suggest that a peer-led support program can be introduced as an effective means of improving the behaviors of mostly sedentary factory workers at risk of MetS caused by working habits that are detrimental to health. PMID- 28860797 TI - Surveying the effect of a self-care education program on severity of nausea and emesis in colorectal cancer patients under chemotherapy. AB - BACKGROUND AND OBJECTIVE: Colorectal cancer is one of the main causes of mortality in both developed and developing countries, including Iran. One of the treatments available for colorectal cancer is chemotherapy, of which nausea and emesis are the side effects. Owing to problems in controlling the side effects, a combination of medicine and non-medicine interventions is usually used. Self-care is one of the non-medicine interventions in this regard. The present study was aimed at surveying the effect of a self-care education program on severity of nausea and emesis in colorectal cancer patients under chemotherapy. METHODS: A semi-experimental study was carried out in Imam Reza Hospital of Kermanshah, Iran. The sample group comprised 52 patients with colorectal cancer under chemotherapy. Data gathering tools included a demographics questionnaire and Morrow Assessment of Nausea and Emesis. To control intensity of nausea and emesis, a package of self-care measures including muscular progressive relaxation, music, and education on nutrition was used. Afterward, the collected data were analyzed using statistical tests such as Shapiro-Wilk test (to check normal distribution of the data), Mann-Whitney U test, Wilcoxon test, and chi square test with the help of SPSS 20. RESULTS: The results showed a considerable decrease in intensity and frequency of nausea and emesis after the intervention. The p-value of Mann-Whitney U test results with regard to intensity of nausea in the experiment and control groups after the intervention was 0.029; this figure for intensity of emesis was 0.009, which indicated effectiveness of the self-care program. CONCLUSION: As the results showed, using self-care program could be effective in attenuating intensity of emesis and nausea in colorectal cancer patients under chemotherapy. So, it can be concluded that the use of this program can increase the patient's self-care ability to control vomiting and nausea, which can be considered as a complementary approach to the antiemetic medications. PMID- 28860799 TI - Implementation of the Short-Term Assessment of Risk and Treatability over two phases. AB - BACKGROUND: Over the last decade, the Short-Term Assessment of Risk and Treatability (START) has provided a strong evidence base to predict a range of problem behaviors. The implementation of START and adaptation of the services to the use of START have so far been sparsely described in the literature. The purpose of this study was to describe the continuation and the interdisciplinarity of risk assessments through the two phases. METHODS: Over a period of 10 years, the forensic mental health services at Broset has implemented START in two phases: initially with implementing the instrument (2005-2009) and secondarily by customizing the instrument to everyday treatment and planning (since 2009). This implementation was based on data from 887 START assessments for 181 patients over a decade (2005-2015). RESULTS: The results showed that the number of START assessments has been stable throughout the past 10 years and the interval between the ratings has decreased significantly (p<0.05). The involvement by diversity of professionals has increased significantly over the two implementation phases. CONCLUSION: This study also addressed the continuity and organization of the implementation process and presented an overview of how START has been widespread in the service through treatment. The results showed an increased multidisciplinary participation and a continuing rate of assessments as the implementation progressed from assessment to a combined assessment-treatment phase. PMID- 28860798 TI - Behcet's syndrome: providing integrated care. AB - Behcet's syndrome (BS) is a multisystem vasculitis that presents with a variety of mucocutaneous manifestations such as oral and genital ulcers, papulopustular lesions and erythema nodosum as well as ocular, vascular, gastrointestinal and nervous system involvement. Although it occurs worldwide, it is especially prevalent in the Far East and around the Mediterranean Sea. Male gender and younger age at disease onset are associated with a more severe disease course. The management of BS depends on the severity of symptoms. If untreated, morbidity and mortality are considerably high in patients with major organ involvement. Multidisciplinary patient care is essential for the management of BS, as it is for other multisystem diseases. Rheumatologists, dermatologists, ophthalmologists, neurologists, cardiovascular surgeons and gastroenterologists are members of the multidisciplinary team. In this study, we reviewed the epidemiology, etiology, diagnostic criteria sets, clinical findings and treatment of BS and highlighted the importance of the multidisciplinary team in the management of BS. PMID- 28860800 TI - Effectiveness of a diabetes mellitus pictorial diary handbook program for middle aged and elderly type 2 diabetes mellitus patients: a quasi-experimental study at Taladnoi Primary Care Unit, Saraburi, Thailand. AB - AIM: The research question is "How does a diabetes mellitus (DM) pictorial diary handbook (PDHB) affect the knowledge, practice, and HbA1c among patients with DM type 2?" The aim of this study was to evaluate the effect of a PDHB program among middle-aged and elderly patients with DM type 2 in primary care units in Thailand. PATIENTS AND METHODS: A quasi-experimental study design was applied. DM type 2 patients were recruited in the PDHB program by a simple random sampling method. The 3-month program consisted of a weekly health education structured for ~20 minutes, a 15-minute group activity training, a 10-minute individual record of participants' knowledge and practice regarding diet control, exercise, oral hypoglycemic drug taking, diet, self-care, alcohol consumption, smoking, weight management, and HbA1c, and a 15- to 30-minute home visit as well as the PDHB for recording self-care behavior daily. The control group received only the usual diabetes care. The primary expected outcomes were changes in HbA1c from the baseline data to 3 months after the program compared between the intervention and control groups. The secondary expected outcomes were compared within the intervention group. The third expected outcomes were changes in the mean score of knowledge and practice from baseline to 3 months after the program within and between the intervention and control groups. RESULTS: Compared with the baseline data, there was no significant difference in HbA1c, knowledge, and practice mean score between the intervention and control groups. However, there was a significant difference in HbA1c, knowledge, and practice mean score in the intervention group after they received a 3-month PDHB program and within the intervention group (p-value =0.00). CONCLUSION: The PDHB program was effective in lowering HbA1c while also improving the mean score of knowledge and practice among elderly patients with DM type 2. However, larger and longer trial studies will be needed to evaluate the sustainability of this program. PMID- 28860802 TI - Fibrous sheath interacting protein 1 overexpression is associated with unfavorable prognosis in bladder cancer: a potential therapeutic target. AB - The study aimed to investigate the clinical significance of fibrous sheath interacting protein 1 (FSIP1) in bladder cancer, and its potential relevance to the survival of patients with bladder cancer. A total of 225 surgical excised bladder cancer tissues were collected from the patients with the follow-up data >5 years. The FSIP1 expressions were assayed using immunohistochemistry. The messenger RNA (mRNA) and/or protein levels of FSIP1 in fresh bladder tumor tissues as well as bladder cancer cell lines were measured by quantitative real time polymerase chain reaction (PCR) and Western blotting analysis. The correlation of FSIP1 expression with clinicopathological parameters was also evaluated. Western blotting analysis revealed that FSIP1 protein was detected in 94.1% (16/17) of bladder tumor specimens and in all three bladder cancer cell lines (5637, BIU-87, and T24 in particular), with significantly higher expression than those of their controls. Quantitative real-time PCR demonstrated an increased FSIP1 mRNA expression level in bladder cancer tissues than in normal adjacent tissues (P=0.012). FSIP1 overexpression showed good correlation with tumor stage and lymph node metastasis (P=0.027 and 0.000, respectively). Positive FSIP1 expression was independently associated with an unfavorable overall and disease-free survival by multivariate Cox regression (P=0.037 and 0.019, respectively). FSIP1 overexpression is associated with unfavorable prognosis in patients with bladder cancer. Thus, FSIP1 represents a potential therapeutic or predictive target for bladder cancer. PMID- 28860801 TI - NRAS-mutant melanoma: current challenges and future prospect. AB - Melanoma is one of the most common cutaneous cancers worldwide. Activating mutations in RAS oncogenes are found in a third of all human cancers and NRAS mutations are found in 15%-20% of melanomas. The NRAS-mutant subset of melanoma is more aggressive and associated with poorer outcomes, compared to non-NRAS mutant melanoma. Although immune checkpoint inhibitors and targeted therapies for BRAF-mutant melanoma are transforming the treatment of metastatic melanoma, the ideal treatment for NRAS-mutant melanoma remains unknown. Despite promising preclinical data, current therapies for NRAS-mutant melanoma remain limited, showing a modest increase in progression-free survival but without any benefit in overall survival. Combining MEK inhibitors with agents inhibiting cell cycling and the PI3K-AKT pathway appears to provide additional benefit; in particular, a strategy of MEK inhibition and CDK4/6 inhibition is likely to be a viable treatment option in the future. Patients whose tumors had NRAS mutations had better response to immunotherapy and better outcomes than patients whose tumors had other genetic subtypes, suggesting that immune therapies - especially immune checkpoint inhibitors - may be particularly effective as treatment options for NRAS-mutant melanoma. Improved understanding of NRAS-mutant melanoma will be essential to develop new treatment strategies for this subset of patients with melanoma. PMID- 28860803 TI - Therapies for acute myeloid leukemia: vosaroxin. AB - Vosaroxin, a quinolone-derivative chemotherapeutic agent, was considered a promising drug for the treatment of acute myeloid leukemia (AML). Early-stage clinical trials with this agent led to a large randomized double-blind placebo controlled study of vosaroxin in combination with intermediate-dose cytarabine for the treatment of relapsed or refractory AML. The study demonstrated better complete remission rates with vosaroxin, but there was no statistically significant overall survival benefit in the whole cohort. A subset analysis censoring patients who had undergone allogeneic stem cell transplantation, however, revealed a modest but statistically significant improvement in overall survival particularly among older patients. This article reviews the data available on vosaroxin including clinical trials in AML and offers an analysis of findings of these studies as well as the current status of vosaroxin. PMID- 28860804 TI - Efficacy and safety of apatinib treatment for advanced esophageal squamous cell carcinoma. AB - OBJECTIVE: No standard chemotherapy is available for patients with advanced esophageal squamous cell carcinoma (ESCC) who have failed prior first-line chemotherapy. The aim of this study was to evaluate the efficacy and safety of apatinib, an oral VEGFR-2 inhibitor, as salvage treatment for advanced ESCC. PATIENTS AND METHODS: After apatinib dosing, the efficacy and toxicity were evaluated in 62 patients with pretreated advanced ESCC from 2014 to 2016 at Zhejiang Cancer Hospital. In addition, survival analysis was performed by the Kaplan-Meier method. RESULTS: Among the 62 patients, 15 achieved partial response while 31 had stable disease with a response rate of 24.2% and a disease control rate of 74.2%. Median progression-free survival (PFS) and overall survival were 115 and 209 days, respectively. Grade 3/4 toxicities (59.7%) were acceptable. Patients with grade 3/4 toxicities showed a longer PFS than those without (136 vs 63 days, P=0.044). CONCLUSION: Apatinib is efficacious as second- or further-line treatment for advanced ESCC. PMID- 28860805 TI - Fucosyltransferase VII promotes proliferation via the EGFR/AKT/mTOR pathway in A549 cells. AB - Fucosyltransferase VII (FUT7) is one of a1,3-fucosyltransferases family that catalyzes the final fucosylation step in the synthesis of Lewis antigens and generates a unique glycosylated product sialyl Lewis X (sLeX). sLeX can serve as ligands for E- or P-selectin expressed on the cell surface and results in cancer metastasis and angiogenesis. However, the molecular biological mechanisms of FUT7 elevation in neoplastic cells are still largely unknown. In this study, we examined the impact of FUT7 on cell proliferation and migration in A549 cells by colony formation assay, cell cycle assay, gelatin zymography, wound-healing assay, transwell invasion assay and Western blot. In addition, we identified that FUT7 activated EGFR/AKT/mTOR signal pathway that correlated with sLeX augmentation. In conclusion, FUT7 overexpression augments sLeX synthesis to trigger cell proliferation via the activation of EGFR/AKT/mTOR signaling pathway, which indicated that FUT7 may be a potential therapeutic target for epithelial cancers with a high expression of FUT7 and sLeX. PMID- 28860806 TI - Enhancement of antitumor activity by using a fully human gene encoding a single chain fragmented antibody specific for carcinoembryonic antigen. AB - Human leukocyte antigen and/or costimulatory molecules are frequently lacking in metastatic tumor cells, and thus tumor cells are able to escape from the immune system. Although lymphocytes with a chimeric antigen receptor (CAR) is a promising approach for overcoming this challenge in cancer immunotherapy, administration of modified T cells alone often demonstrates little efficacy in patients. Therefore, in order to enhance the antitumor activity of immune cells in the cancer microenvironment, we used lymphocytes expressing CAR in combination with a fusion protein of IL-2 that contained the single-chain fragmented antibody (scFv) specific for the carcinoembryonic antigen. Among a series of CAR constructs, with or without a spacer and the intracellular domain of CD28, the CAR construct containing CD8alpha, CD28, and CD3zeta most effectively activated and expressed INF-gamma in CAR-bearing T cells. Furthermore, in comparison with free IL-2, the combination of peripheral blood mononuclear cells expressing CAR and the fusion protein containing IL-2 significantly enhanced the antitumor activity against MKN-45 cells, a human gastric cancer cell line. In conclusion, this novel combination therapy of CAR and a fusion protein consisting of a functional cytokine and a fully human scFv may be a promising approach for adoptive cancer immunotherapy. PMID- 28860808 TI - Monocyte to lymphocyte ratio predicts survival in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy. AB - BACKGROUND: Currently, precise predictors in gastric cancer patients undergoing neoadjuvant chemotherapy are lacking. The study aims to investigate the prognostic value of the monocyte to lymphocyte ratio (MLR) in patients with advanced gastric cancer receiving S-1 plus oxaliplatin (SOX) or oxaliplatin and capecitabine (XELOX) neoadjuvant chemotherapy regimen. METHODS: The data from Harbin Medical University Cancer Hospital from August 2008 to September 2015 were retrospectively collected. Ninety-one patients with advanced gastric cancer treated with neoadjuvant chemotherapy were included. The blood samples were collected before neoadjuvant chemotherapy. The MLR was divided into two groups: Low-MLR <0.27 group and high-MLR >=0.27 group. Survival curves were performed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards regression model were evaluated to determine independent prognostic factors. RESULTS: The univariate analysis showed that median disease free survival (DFS) and overall survival (OS) for all patients were better in low-MLR value group than high-MLR value group (median DFS 26.80 and 23.73 months, P=0.653, respectively; median OS 27.93 and 26.87 months, P=0.807, respectively). Multivariate analysis showed that MLR level was not an independent prognostic factor of DFS and OS. Nevertheless, median DFS and OS for all patients were better for patients with low monocyte values compared to those with high monocyte values (median DFS 30.23 and 21.03 months, P=0.645, respectively; median OS 37.97 and 25.83 months, P=0.509, respectively); in patients with high lymphocyte values compared with low lymphocyte values median DFS was 26.87 and 21.03 months, (P=0.624) respectively; median OS was 27.93 and 26.37 months, (P=0.584) respectively. However, the patients with low level MLR had better 5-year DFS and OS rates. CONCLUSION: MLR may be used as a convenient and cheap prognostic marker in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy with SOX or XELOX. Low level MLR as a prognostic marker may help doctors in terms of efficient measures to treat gastric cancer. PMID- 28860807 TI - Clinical significance and prospective molecular mechanism of MALAT1 in pancreatic cancer exploration: a comprehensive study based on the GeneChip, GEO, Oncomine, and TCGA databases. AB - PURPOSE: Long noncoding RNAs (lncRNAs) are known to function as regulators in the development and occurrence of various tumors. MALAT1 is a highly conserved lncRNA and has vital functions in diverse tumors, including pancreatic cancer (PC). However, the underlying molecular regulatory mechanism involved in the occurrence and development of PC remains largely unknown. Thus, it is important to explore MALAT1 in PC and elucidate its function, which might offer a new perspective for clinical diagnosis and therapy. METHODS: First, we used the Gene Expression Omnibus, Oncomine, and The Cancer Genome Atlas databases to determine the clinical diagnostic and prognostic values of MALAT1. We next used our own GeneChip and The Cancer Genome Atlas database to collect the possible target genes of MALAT1 and further utilized a bioinformatics analysis to explore the underlying significant pathways that might be crucial in PC. Finally, we identified several key target genes of MALAT1 and hope to offer references for future research. RESULTS: We found that the expression of MALAT1 was significantly elevated in patients with PC. A receiver operating characteristics curve analysis showed a moderate diagnostic value (area under the curve =0.75, sensitivity =0.66, specificity =0.72). A total of 224 important overlapping genes were collected, and six hub genes (CCND1, MAPK8, VEGFA, FOS, CDH1, and HSP90AA1) were identified, of which CCND1, MAPK8, and VEGFA, are important genes in PC. Several pathways, including the mTOR signaling pathway, pathways in cancer, and the MAPK signaling pathway, were suggested to be the vital MALAT1 pathways in PC. CONCLUSION: MALAT1 is suggested to be a promising diagnostic biomarker in PC. Six hub genes (CCND1, MAPK8, VEGFA, FOS, CDH1, and HSP90AA1), and specifically CCND1, MAPK8, and VEGFA, might be key MALAT1 target genes in PC. Due to their possible clinical significance in PC, several pathways, such as the mTOR signaling pathway, pathways in cancer, and the MAPK signaling pathway, are worthy of further study. PMID- 28860809 TI - Perihippocampal metastasis following hippocampus-avoiding prophylactic cranial irradiation for small cell lung cancer: a case report. AB - Prophylactic cranial irradiation (PCI) lowers the risk of brain metastasis (BM) and increases survival in small cell lung cancer (SCLC) patients, but it also entails a risk of neurocognitive dysfunction (NCD). One strategy to mitigate this neurotoxicity is hippocampus-avoiding (HA) whole-brain radiation therapy, as the hippocampus is mainly responsible for radiation-related NCD and hippocampal or perihippocampal metastases are rare. A few prospective clinical trials have demonstrated a reduction in NCD following HA whole-brain radiation therapy. The 59-year-old male patient described in this report had limited-stage SCLC and a complete response to thoracic chemoradiotherapy. Seven months after receiving HA PCI of 25 Gy in 10 fractions using intensity-modulated radiation therapy, a 36 mm solitary metastasis was detected in the right perihippocampal region. The mass was surgically removed but the patient died 2 months later. The development of a solitary HA region metastasis is uncommon, considering that metastasis in this area usually occurs in patients with high numbers of BMs. Our case demonstrates the need for further validation of HA-PCI for SCLC patients in terms of both neurocognitive protection and the absence of compromise in terms of BM prevention. PMID- 28860810 TI - Low concentration of quercetin antagonizes the invasion and angiogenesis of human glioblastoma U251 cells. AB - Glioblastoma is the most aggressive type of brain tumor with a very poor prognosis. Therefore, it is always of great importance to explore and develop new potential treatment for glioblastoma. Quercetin, a flavonoid present in a variety of human foods, has been shown to inhibit various tumor cell proliferation. In this study, we found that treating human glioblastoma U251 cells with 10 MUg/mL quercetin for 24 hours, a concentration that was far below the IC50 (113.65 MUg/mL) and at which quercetin failed to inhibit cell proliferation, inhibited cell migration (30%) and cell invasion as examined by wound scratch assay and transwell assay, respectively. We further showed that 10 MUg/mL quercetin inhibited cell migration and tube formation of human umbilical vein endothelial cells induced by the conditioned medium derived from U251 cell culture. The inhibitory effect of quercetin on migration and angiogenesis is possibly mediated through the downregulation of protein levels of VEGFA, MMP9, and MMP2 as detected by Western blot. Our findings demonstrated that low concentration of quercetin antagonized glioblastoma cell invasion and angiogenesis in vitro. PMID- 28860811 TI - Effect of temozolomide on survival in elderly patients with glioblastoma and impaired performance status: a propensity score-matching analysis. AB - OBJECTIVE: At present, there is no consensus regarding the standard treatment for glioblastoma (GBM) in elderly patients with impaired Karnofsky performance status (KPS) scores. This study aimed to determine the effects of temozolomide (TMZ) versus best supportive care (BSC) in this population. MATERIALS AND METHODS: We conducted a retrospective observational study of patients aged >=65 years with histologically confirmed GBM and KPS scores <=70 who were treated at our institution between January 2006 and July 2014. Demographic data, treatments, and outcomes were evaluated. Univariate and multivariate analyses were performed to identify the independent prognostic factors of overall survival (OS) and progression-free survival (PFS). The impact of TMZ on survival was analyzed by the application of propensity score matching of clinicopathological factors among patients who received TMZ vs BSC. RESULTS: There were 153 patients (86 men, 56.2%) in this study. The median patient age was 70 years (range: 65-83 years). The median KPS score was 60 (range: 30-70). Seventy-eight patients (51.0%) received TMZ, whereas 75 (49.0%) received BSC. Median OS and PFS were 6.0 and 4.5 months, respectively. Compared with BSC, TMZ was associated with improved OS (hazard ratio [HR]: 0.38, 95% CI: 0.17-0.70; P=0.002) and PFS (HR: 0.41, 95% CI: 0.21-0.76; P=0.003) after propensity score matching. Factors independently associated with OS were KPS score (HR: 2.11, 95% CI: 1.48-7.67; P=0.016), extent of resection (HR: 1.98, 95% CI: 1.45-5.14; P=0.026), and treatment group (HR: 0.49, 95% CI: 0.23-0.87; P=0.019). The most frequent toxicity in the TMZ group was myelosuppression. CONCLUSION: Compared with BSC, TMZ increased survival with acceptable toxicity in elderly GBM patients with KPS scores <=70. PMID- 28860812 TI - An integrated analysis for long noncoding RNAs and microRNAs with the mediated competing endogenous RNA network in papillary renal cell carcinoma. AB - Papillary renal cell carcinoma (PRCC) is the second most common subtype of renal cell carcinoma, and it lacks effective therapeutic targets and prognostic molecular biomarkers. Attention has been increasingly focused on long noncoding RNAs (lncRNAs), which can act as competing endogenous RNA (ceRNA) to compete for shared microRNAs (miRNAs) in the tumorigenesis of human tumors. Therefore, to clarify the functional roles of lncRNAs with respect to the mediated ceRNA network in PRCC, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 289 PRCC tissues and 32 normal tissues in The Cancer Genome Atlas. As a result, we identified 2,197 differentially expressed mRNAs (DEmRNAs) and 84 differentially expressed miRNAs (DEmiRNAs) using a threshold of |log2 (fold change)| >2.0 and an adjusted P-value <0.05. To determine the hub DEmRNAs that could be key target genes, a weighted gene co-expression network analysis was performed. A total of 28 hub DEmRNAs were identified as potential target genes. Seven dysregulated DEmiRNAs were identified that were significantly associated with the 28 hub potential target genes. In addition, we found that 16 differentially expressed lncRNAs were able to interact with the DEmiRNAs. Finally, we used Cytoscape software to visualize the ceRNA network with these differently expressed molecules. From these results, we believe that the identified ceRNA network plays a crucial role in the process of PRCC deterioration, and some of the identified genes are strongly related to clinical prognosis. PMID- 28860813 TI - Low versus high radioiodine activity for ablation of the thyroid remnant after thyroidectomy in Han Chinese with low-risk differentiated thyroid cancer. AB - AIM: The aim of this study was to compare the efficacy and adverse effects of radioiodine (131I) therapy between two groups of patients with low-risk differentiated thyroid cancer (DTC) who received 30 mCi or 100 mCi radioiodine for ablation of the thyroid remnant after total thyroidectomy. METHODS: The study cohort was 173 patients, 85 of whom were given 30 mCi of radioiodine and the others were given 100 mCi of radioiodine. Follow-up involved neck ultrasonography, measurement of serum levels of thyroglobulin and whole-body scans to evaluate the response of radioiodine treatment. All patients were assessed for adverse effects. RESULTS: Of the 173 patients, 170 (98.3%) patients finally achieved successful ablation. The prevalence of successful ablation was 77.6% in the low-dose group versus 71.5% in the high-dose group after the first dose administration (P=0.36), 79% in the low-dose group versus 88% in the high dose group after the second dose administration (P=0.416), and 97.6% in the low dose group versus 98.9% in the high-dose group after the final ablation (P=0.54). We found no significant differences between the two groups. No patient had an adverse effect with a severity grade ?2 and the prevalence of adverse effects in the high-dose group was higher than that in the low-dose group, especially for nausea, neck pain, and sore throat. CONCLUSION: These data suggest that a low dose of radioiodine is as effective as a high dose of radioiodine for ablation of the thyroid remnant after total thyroidectomy for low-risk DTC. Moreover, low dose radioiodine therapy is associated with a lower prevalence of adverse events. PMID- 28860814 TI - The role of desmosomes in carcinogenesis. AB - Desmosomes, which are intercellular adhesive complexes, are essential for the maintenance of epithelial homeostasis. They are located at the cell membrane, where they act as anchors for intermediate filaments. Downregulation of desmosome proteins in various cancers promotes tumor progression. However, the role of desmosomes in carcinogenesis is still being elucidated. Recent studies revealed that desmosome family members play a crucial role in tumor suppression or tumor promotion. This review focuses on studies that provide insights into the role of desmosomes in carcinogenesis and address their molecular functions. PMID- 28860816 TI - CT-guided 125I interstitial brachytherapy for pelvic recurrent cervical carcinoma after radiotherapy. AB - OBJECTIVE: This retrospective study aimed to evaluate the feasibility, safety, and clinical efficacy of computed tomography (CT)-guided 125I seed interstitial brachytherapy for pelvic recurrent cervical cancer in patients with a history of pelvic radiotherapy. METHODS: From March 2011 to December 2015, 35 pelvic recurrent lesions (33 patients) were reirradiated using this type of salvage therapy. The medical history, dose-volume histogram parameters, complications, local control, overall survival (OS), and affected factors were analyzed. RESULTS: All patients were followed-up until expiration, and the median duration of follow-up was 16 months. The 1-, 3-, 6-, 12-, and 18-month local control rates were 84.5%, 74.2%, 60.0%, 55.5%, and 33.3%, respectively. The symptoms significantly improved after implantation. The median local tumor progression free survival (LTPFS) and OS times were 7 months (range, 1-19 months) and 12 months (range, 2-42 months), respectively. The 1- and 2-year OS rates were 65.5% and 43.6%, respectively. In univariate analysis, a good performance status, a tumor diameter <4 cm, an interval time from last radiotherapy to seed implantation longer than 6 months and D90 (dose delivered to 90% of the target volume) >=130 Gy were prognostic factors for LTPFS. Cox proportional hazards regression analysis revealed that tumor size and D90 were independent factors affecting LTPFS (P=0.033, hazard ratio [HR] =3.357, 95% CI =1.105, 10.212; P=0.035, HR =2.766, 95% CI =1.072, 10.212). Good performance status was identified as an independent factor affecting OS (P=0.001, HR =0.086, 95% CI =0.019, 0.387). Two patients showed grade 3-4 toxicity - 1 patient had rectovaginal fistula and 1 patient had incomplete intestinal obstruction - and 3 cases showed seed migration in our analysis. No grade 5 events occurred. CONCLUSION: Reirradiation with CT-guided 125I seed interstitial brachytherapy is a safe, effective, and minimally invasive method to treat patients with recurrent cervical cancer after radiotherapy. PMID- 28860815 TI - Carcinogenicity of chromium and chemoprevention: a brief update. AB - Chromium has two main valence states: hexavalent chromium (Cr[VI]) and trivalent chromium (Cr[III]). Cr(VI), a well-established human carcinogen, can enter cells by way of a sulfate/phosphate anion-transport system, and then be reduced to lower-valence intermediates consisting of pentavalent chromium (Cr[V]), tetravalent chromium (Cr[IV]) or Cr(III) via cellular reductants. These intermediates may directly or indirectly result in DNA damage or DNA-protein cross-links. Although Cr(III) complexes cannot pass easily through cell membranes, they have the ability to accumulate around cells to induce cell surface morphological alteration and result in cell-membrane lipid injuries via disruption of cellular functions and integrity, and finally to cause DNA damage. In recent years, more research, including in vitro, in vivo, and epidemiological studies, has been conducted to evaluate the genotoxicity/carcinogenicity induced by Cr(VI) and/or Cr(III) compounds. At the same time, various therapeutic agents, especially antioxidants, have been explored through in vitro and in vivo studies for preventing chromium-induced genotoxicity/carcinogenesis. This review aims to provide a brief update on the carcinogenicity of Cr(VI) and Cr(III) and chemoprevention with different antioxidants. PMID- 28860817 TI - Cabazitaxel in the treatment of metastatic castration-resistant prostate cancer: patient selection and special considerations. AB - Cabazitaxel is an effective chemotherapeutic agent used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel. With the advent of new antiandrogen therapies, immune-based treatments, and radioactive-targeted therapy, there are now multiple effective and approved agents for this disease state. The optimal sequencing of these agents is unclear as there are no large-scale head-to-head comparisons. Clinicians must familiarize themselves with the most recent studies as well as drug toxicities to determine the best treatment option for their patients. In this review, we focus on the development of cabazitaxel for mCRPC, evaluate its efficacy, and highlight key strategies for toxicity management. Additionally, we summarize the studies that address cabazitaxel treatment sequencing and optimal dosing schedule. PMID- 28860818 TI - Chest reconstruction using a custom-designed polyethylene 3D implant after resection of the sternal manubrium. AB - INTRODUCTION: Resection of manubrium or body of the sternum is associated with a necessity of chest wall reconstruction. Large sternal defects require the use of different types of implants to ensure acceptable esthetic effect for the patient and chest stabilization. AIM: The purpose of this case report is to present a novel method of reconstruction of manubrium removed due to renal cancer metastasis to the sternum. CASE: We present the case of a patient, who had underwent right nephrectomy for clear cell kidney cancer, diagnosed with a metastatic tumor in the sternum resulting in destruction of manubrium. The patient undergone tumor resection with primary reconstruction with an individual prosthesis. Sternal defect was filled with a personalized, computed tomography scan-based 3D-milled implant made of polyethylene. RESULTS: Sternal reconstruction was uneventful. The patient endured surgery well, and has been under surveillance in outpatient clinic, without any respiration disorders, implant movement or local recurrence. CONCLUSION: Custom-designed sternal implants created by 3D technique constitute an interesting alternative for previous methods of filling defects after resection of a tumor in this location. PMID- 28860819 TI - Clinicopathologic characteristics, therapy and outcomes of patients with primary ureteral small cell carcinoma: a case series and systematic review of the literature. AB - PURPOSE: The aim of this case series was to review the standard diagnosis and treatment procedures of primary small cell carcinoma (SCC) in our institution and discuss the clinicopathologic characteristics, treatments and outcomes of patients with primary ureteral SCC. PATIENTS AND METHODS: Patients diagnosed with ureteral SCC in Peking University First Hospital, Beijing, China, from January 2007 to December 2016 were included. In addition, we performed a systematic literature review, in October 2016, on case reports and case series of ureteral SCC. The clinicopathologic characteristics, treatments and outcomes of this rare disease were analyzed. RESULTS: A total of 32 patients were included in our analysis (4 cases from our institution and 28 cases from the literature). Most patients (71.0%) were male with an average age of 66.6 years (range 48-80 years). The most common symptoms were hematuria (n=14, 48.3%) and flank pain (n=14, 48.3%). All patients underwent surgery, with 12 (37.5%) patients undergoing multimodality therapy. Regional or distant recurrences developed in 11 patients, among which only 1 patient had bladder recurrence. The overall median survival of the patients was 17 months, with 1- and 3-year survival rates of 51.9% and 30.3%, respectively. In a univariate analysis, female (P=0.009), pure SCC (P=0.03) and advanced T stage (P=0.04) were associated with worse overall survival. CONCLUSION: Ureteral SCCs are extremely rare neoplasms with aggressive natural history and poor prognosis. T stage, tumor components and gender may be important factors influencing prognosis. A multimodality treatment is recommended for management. However, further studies are needed to improve the treatment strategy. PMID- 28860820 TI - Safety and efficacy of nimotuzumab combined with chemoradiotherapy in Chinese patients with locally advanced cervical cancer. AB - OBJECTIVE: To evaluate efficacy and safety of nimotuzumab combined with chemotherapy and radiotherapy in women with locally advanced cervical cancer. MATERIALS AND METHODS: Women with locally advanced cervical cancer (stage IIB, III, or IVA) who experienced relapse after first-line chemoradiotherapy and one or more lines of palliative chemotherapy were enrolled. All patients received nimotuzumab weekly at 200 mg/m2 as single agent for 4 weeks (induction phase), then concurrent with 6 cycles (21-day per cycle) of gemcitabine (800 mg/m2) or cisplatin (50 mg/m2) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Overall response rate (ORR) was assessed after 4 weeks of induction therapy and then every 3 months according to response evaluation criteria in solid tumors version 1.1 (primary end point). Secondary end points include progression-free survival (PFS), overall survival (OS), and drug toxicity. Descriptive statistics was used for ORR, and Kaplan-Meier curves were generated for OS and PFS. RESULTS: A total of 80 women with locally advanced cervical cancer were enrolled and evaluated for safety and efficacy. Our results demonstrated that none of the patients had a complete response (0%), 11 patients had a partial response (14%), and 10 patients had progressive disease (13%), giving a tumor response rate of 14%. A total of 59 patients had stable disease (74%), giving a disease control rate of 88% (70/80). Median PFS was 8.21 months (95% confidence interval [CI]: 5.09-12.45). Median OS was 11.96 months (95% CI: 8.11-23.95). The most common adverse events were mucositis, myelosuppression, and gastrointestinal disturbance. CONCLUSION: Our study results suggested that nimotuzumab in combination with chemotherapy and radiotherapy is well tolerated, and could be a better treatment alternative in patients with locally advanced cervical cancer. PMID- 28860821 TI - Osteopontin and vasculogenic mimicry formation are associated with response to neoadjuvant chemotherapy in advanced breast cancer. AB - INTRODUCTION: Osteopontin (OPN), a multifunctional phosphoprotein, has been implicated in a series of important physiologic and pathophysiologic processes. In breast cancer, OPN functionally contributes to the tumorigenicity of spheroid forming cells. It also plays a critical role in enhancing the proliferation, tumorigenicity, and ability to display vasculogenic mimicry (VM) of spheroid forming cells in breast cancer. However, the role of OPN in breast cancer is not clear. PATIENTS AND METHODS: This study investigated OPN expression and VM in breast cancer patients before neoadjuvant chemotherapy (NACT). Their association with clinicopathologic factors was first analyzed by immunohistochemistry. Then, the response of breast cancer patients to NACT was evaluated. The correlation between the clinicopathologic factors, including the molecular subtype, and the response to NACT was analyzed. RESULTS: Immunohistochemical analysis showed positive staining of OPN in 40% of the breast cancer patients, whereas VM, which was related to tumor stage, was observed in 30% of cases. OPN expression was found to have a significant correlation with VM (P<0.05). The results also indicated that the clinicopathologic factors were not related to the response to NACT, including the molecular subtype. The multivariate analysis of clinicopathologic features correlated with pathological complete response (pCR) indicated that OPN(+)VM(+) was correlated with pCR (P<0.001). CONCLUSION: Our findings underlined that the concurrence of OPN-positive expression and VM can predict the pCR to NACT in breast cancer. The efficiency of NACT in certain patients can be easily predicted by detecting the expression of OPN and VM. PMID- 28860822 TI - Response to crizotinib in a lung adenocarcinoma patient harboring a novel SLC34A2 ROS1 fusion variant. AB - ROS1 fusion is a common genetic alteration in non-small-cell lung cancer. Crizotinib, an anaplastic lymphoma kinase inhibitor, shows efficacy in the treatment of lung cancer cases with ROS1 translocation. We report the response to crizotinib of a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant, which was different from the two common SLC34A2-ROS1 fusion types reported in the literature. After crizotinib administration, overall recovery was good in this patient; the primary lesion was successfully treated, the lymph node metastases had disappeared, and the metabolism was normal. PMID- 28860823 TI - Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma. AB - OBJECTIVE: We previously reported that the staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for treatment strategy and predicting survival. However, the significance of these factors as predictors of overall survival (OS) and postoperative recurrence survival (PRS) has not been sufficiently elucidated. The objective here was to investigate EGFR mutation status and p-stage, which affect PRS and OS in patients with completely resected lung adenocarcinoma, using a different database. PATIENTS AND METHODS: We retrospectively reviewed 56 consecutive lung adenocarcinoma patients with disease recurrence in St. Marianna University Hospital between January 2010 and December 2014. RESULTS: EGFR mutants (M) were detected in 16/56 patients (29%). The patients with EGFR M had a better OS than those with EGFR wild-type (WT) status (5-year survival: 50.3% vs 43.1, P=0.133). There was no significant difference in the 3-year recurrence-free survival rate between patients with M and WT (6.3% vs 7.7%, P=0.656), and the patients with EGFR M had a significantly better 3-year PRS than those with WT (77.4% vs 51.7%, P=0.033). The 3-year PRS rate for patients with M/pathologic stage (p-stage) I-II (87.5%) was better than that for patients with M/p-stage III (60.0%), WT/p-stage I-II (52.7%), and WT/p-stage III (43.8%). There was a significant difference between patients with M/p-stage I and WT/p-stage I-II or WT/p-stage III (P=0.021 and 0.030, respectively). During the study period, of the 16 patients with mutants, 12 patients (75%) received EGFR tyrosine kinase inhibitor (TKI) therapy and among the 40 patients with WT, no patient received EGFR-TKI therapy. Multivariate survival analysis showed that patients with EGFR-TKI therapy had a statistically significant association with favorable PRS (hazard ratio 0.271; 95% confidence interval 0.074-1.000; P=0.050). CONCLUSION: EGFR status and p-stage were found to be essential prognostic factors for estimating PRS using this database. The recurrent patients with EGFR M and EGFR-TKI therapy had a statistically significant association with favorable PRS. PMID- 28860824 TI - RASSF1A hypermethylation is associated with ASXL1 mutation and indicates an adverse outcome in non-M3 acute myeloid leukemia. AB - OBJECTIVE: The purpose of this study was to evaluate the frequency of RASSF1A hypermethylation in patients with acute myeloid leukemia (AML), in an attempt to modify the current molecular model for disease prognosis. MATERIALS AND METHODS: Aberrant RASSF1A promoter methylation levels were assessed in 226 newly diagnosed non-M3 AML patients and 30 apparently healthy controls, by quantitative methylation-specific polymerase chain reaction. Meanwhile, RASSF1A mRNA levels were detected by real-time quantitative polymerase chain reaction. Furthermore, hematological characteristics, cytogenetic abnormalities, and genetic aberrations were assessed. Finally, associations of RASSF1A hypermethylation with clinical outcomes were evaluated. RESULTS: RASSF1A hypermethylation was observed in 23.0% of patients with non-M3 AML (52/226), but not in controls. Meanwhile, hypermethylation of the RASSF1A promoter was significantly associated with ASXL1 mutation. Furthermore, the log-rank test revealed that RASSF1A hypermethylation indicated decreased relapse-free survival (RFS) and overall survival (OS) in patients with non-M3 AML (P=0.012 and P=0.014, respectively). In multivariate analysis, RASSF1A hypermethylation was an independent prognostic factor for RFS (P=0.040), but not for OS (P=0.060). CONCLUSION: Hypermethylation of the RASSF1A promoter is associated with ASXL1 mutation in non-M3 AML patients, likely indicating poor outcome. These findings provide a molecular basis for stratified diagnosis and prognostic evaluation. PMID- 28860825 TI - AKT inhibition is an effective treatment strategy in ARID1A-deficient gastric cancer cells. AB - BACKGROUND: The At-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancers (GCs) with a poor prognosis. Growing evidence indicates that loss of ARID1A expression leads to activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway by AKT phosphorylation. We aim to investigate the different sensitivity for the AKT inhibitor in ARID1A-deficient GC cells. METHODS: After transfection using siRNA or shRNA, the effect of ARID1A knockdown on the PI3K/AKT signaling pathway was evaluated by Western blot analysis. ARID1A-knockdown cells were treated with AKT inhibitor (GSK690693), 5-fluorouracil, or cisplatin, alone or in combination. Viability and apoptosis were analyzed using EZ-CYTOX cell viability assay and flow cytometry, respectively. RESULTS: ARID1A depletion accelerated the phosphorylation of AKT and S6 in a dose-dependent manner and led to an increased proliferation of MKN-1, MKN-28, and KATO-III GC cells (P<0.001). ARID1A-deficient cells were more vulnerable to GSK690693 in comparison to the controls (P<0.001), even at very low doses. Flow cytometry confirmed the increased apoptosis in ARID1A-deficient cells treated with GSK690693 (0.01 MUmol/L; P<0.001). In contrast to our expectations, ARID1A depletion did not cause resistance to 5-fluorouracil or cisplatin. Addition of GSK690693 to the conventional chemotherapy induced more decreased cell viability in ARID1A knockdown cells (P<0.01). CONCLUSION: Loss of ARID1A expression is a surrogate marker for the activation of the AKT signaling pathway and is also a reliable biomarker to predict the response for the AKT inhibitor. We anticipate that appropriate patient selection based on ARID1A expression in the tumor tissue will increase the drug sensitivity for the AKT inhibition and improve the clinical outcome. PMID- 28860826 TI - miRNA-221 of exosomes originating from bone marrow mesenchymal stem cells promotes oncogenic activity in gastric cancer. AB - Worldwide, gastric cancer (GC) is one of the deadliest malignant tumors of the digestive system. Moreover, microRNAs (miRNAs) of exosomes harbored within cancer cells have been determined to induce inflammatory conditions that accelerate tumor growth and metastasis. Interestingly, the oncogenic role of bone marrow mesenchymal stem cells (BM-MSCs) in the modulation of immunosuppression, tumor invasion, and metastasis was discovered to be partly mediated through the secretion of exosomes. In this article, high expression of miRNA-221 (miR-221) in exosomes of the peripheral blood was determined to be positively correlated with the poor clinical prognosis of GC, especially with respect to tumor, node, and metastases stage. Therefore, the expression of miR-221 in exosomes of the peripheral blood may be an important detection index for GC. Proliferation, migration, invasion, and adhesion to the matrix of GC BGC-823 and SGC-7901 cells were significantly enhanced by exosomes that originated from BM-MSCs that were transfected with miR-221 mimics. In conclusion, extracted exosomes from BM-MSCs transfected with miR-221 oligonucleotides can act as high-efficiency nanocarriers, which can provide sufficient miR-221 oligonucleotides to influence the tumor microenvironment and tumor aggressiveness effectively. Notably, the use of a miR-221 inhibitor with an excellent restraining effect in exosomes provides therapeutic potential for GC in future clinical medicine. PMID- 28860827 TI - Clinical applications of dendritic cells-cytokine-induced killer cells mediated immunotherapy for pancreatic cancer: an up-to-date meta-analysis. AB - PURPOSE: This study aimed to systematically evaluate the efficacy and safety of dendritic cells-cytokine-induced killer (DC-CIK) cells immunotherapy in treating pancreatic cancer (PC) patients. METHODS: Data were collected from published articles of clinical trials. Databases including Web of Science, EMBASE, PubMed, Cochrane Library, Wanfang, and CNKI were searched. The main outcome measures in this research included the overall response rate (ORR), disease control rate (DCR), overall survival (OS), patients' quality of life (QoL), immune function, and adverse events. Comparative analysis was conducted between DC-CIK immunotherapy and chemotherapy (combined therapy) and chemotherapy alone. RESULTS: This analysis covered 14 trials with 1,088 PC patients involved. The combined therapy showed advantages over chemotherapy alone in ORR (odds ratio [OR] =1.69, 95% confidence interval [CI] =1.20-2.38, P=0.003), DCR (OR =2.33, 95% CI =1.63-3.33, P<0.00001), OS (1-year OS, OR =3.61, 95% CI =2.41-5.40, P<0.00001; 3-year OS, OR =2.65, 95% CI =1.56-4.50, P=0.0003) and patients' QoL (P<0.01) with statistical significance. After immunotherapy, lymphocyte subsets' percentages of CD3+ (P<0.00001), CD4+ (P=0.01), CD3+CD56+ (P<0.00001), and cytokine levels of IFN-gamma (P<0.00001) were significantly increased, and the percentages of CD4+CD25+CD127low (P<0.00001) and levels of IL-4 (P<0.0001) were significantly decreased, whereas analysis on CD8+ (P=0.59) and CD4+/CD8+ ratio (P=0.64) did not show a significant difference. CONCLUSION: The combination of DC-CIK immunotherapy and chemotherapy is effective for PC treatment, indicated by prolonging the PC patients' survival time, which benefit from reconstructed immune function of patients. PMID- 28860829 TI - Erratum: Cefazolin potency against methicillin-resistant Staphylococcus aureus: a microbiologic assessment in support of a novel drug delivery system for skin and skin structure infections [Erratum]. AB - [This corrects the article on p. 227 in vol. 10, PMID: 28794647.]. PMID- 28860828 TI - The evolving role of tiotropium in asthma. AB - Tiotropium is a long-acting muscarinic antagonist (LAMA) that exerts its bronchodilatory effect by blocking endogenous acetylcholine receptors in the airways. Its safety and efficacy are well established for the treatment of COPD, and it is now being recognized for its role in improving lung function and control in asthma. This review discusses the evolving role of tiotropium delivered by the Respimat(r) in patients across the range of asthma severities and ages, and provides an overview of safety and efficacy data. Tiotropium is the only LAMA currently approved for the treatment of asthma, and evidence from a large-scale clinical trial program, including several Phase III studies in adults, has demonstrated that tiotropium improves lung function and asthma control, with a safety profile comparable with that of placebo. Clinical trials in adolescent patients (aged 12-17 years) have also shown improvements in lung function and trends toward improved asthma control. Of note, the efficacy and safety profiles are consistent regardless of baseline characteristics and phenotype. Given the large and growing body of evidence, it is likely that as clinical experience with tiotropium increases, this treatment may possibly emerge as the key choice for add-on therapy to inhaled corticosteroids/long-acting beta2 agonists, and in patients who do not tolerate long-acting bronchodilators or other medications, in the future. PMID- 28860830 TI - Economic analysis and budget impact of clostridial collagenase ointment compared with medicinal honey for treatment of pressure ulcers in the US. AB - OBJECTIVES: Pressure ulcer (PU) treatment poses significant clinical and economic challenges to health-care systems. The aim of this study was to assess the cost effectiveness and budget impact of enzymatic debridement with clostridial collagenase ointment (CCO) compared with autolytic debridement with medicinal honey (MH) for PU treatment from a US payer/Medicare perspective in the hospital outpatient department setting. METHODS: A cost-effectiveness analysis using a Markov model was developed using a 1-week cycle length across a 1-year time horizon. The three health states were inflammation/senescence, granulation/proliferation (ie, patients achieving 100% granulation), and epithelialization. Data sources included the US Wound Registry, Medicare fee schedules, and other published clinical and cost studies about PU treatment. RESULTS: In the base case analysis over a 1-year time horizon, CCO was the economically dominant strategy (ie, simultaneously conferring greater benefit at less cost). Patients treated with CCO experienced 22.7 quality-adjusted life weeks (QALWs) at a cost of $6,161 over 1 year, whereas MH patients experienced 21.9 QALWs at a cost of $7,149. Patients treated with CCO achieved 11.5 granulation weeks and 6.0 epithelization weeks compared with 10.6 and 4.4 weeks for MH, respectively. The number of clinic visits was 40.1 for CCO vs 43.4 for MH, and the number of debridements was 12.3 for CCO compared with 17.6 for MH. Probabilistic sensitivity analyses determined CCO dominant in 72% of 10,000 iterations and cost-effective in 91%, assuming a benchmark willingness-to-pay threshold of $50,000/quality-adjusted life year ($962/QALW). The budget impact analysis showed that for every 1% of patients shifted from MH to CCO, a cost savings of $9,883 over 1 year for a cohort of 1,000 patients was observed by the payer. CONCLUSION: The results of these economic analyses suggest that CCO is a cost-effective, economically dominant alternative to MH in the treatment of patients with PUs in the hospital outpatient department setting. PMID- 28860831 TI - Budget impact of somatostatin analogs as treatment for metastatic gastroenteropancreatic neuroendocrine tumors in US hospitals. AB - OBJECTIVE: With the introduction of new therapies, hospitals have to plan spending limited resources in a cost-effective manner. To assist in identifying the optimal treatment for patients with locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors, budget impact modeling was used to estimate the financial implications of adoption and diffusion of somatostatin analogs (SSAs). PATIENTS AND METHODS: A hypothetical cohort of 500 gastroenteropancreatic neuroendocrine tumor patients was assessed in an economic model, with the proportion with metastatic disease treated with an SSA estimated using published data. Drug acquisition, preparation, and administration costs were based on national pricing databases and published literature. Octreotide dosing was based on published estimates of real-world data, whereas for lanreotide, real-world dosing was unavailable and we therefore used the highest indicated dosing. Alternative scenarios reflecting the proportion of patients receiving lanreotide or octreotide were considered to estimate the incremental budget impact to the hospital. RESULTS: In the base case, 313 of the initial 500 gastroenteropancreatic neuroendocrine tumor patients were treated with an SSA. The model-predicted per-patient cost was US$83,473 for lanreotide and US$89,673 for octreotide. With a hypothetical increase in lanreotide utilization from 5% to 30% of this population, the annual model-projected hospital costs decreased by US$488,615. When varying the inputs in one-way sensitivity analyses, the results were most sensitive to changes in dosing assumptions. CONCLUSION: Results suggest that factors beyond drug acquisition cost can influence the budget impact to a hospital. When considering preparation and administration time, and real-world dosing, use of lanreotide has the potential to reduce health care expenditures associated with metastatic gastroenteropancreatic neuroendocrine tumor treatments. PMID- 28860832 TI - A cost-effectiveness analysis of first-line induction and maintenance treatment sequences in patients with advanced nonsquamous non-small-cell lung cancer in France. AB - BACKGROUND: Comparative effectiveness and cost-effectiveness data for induction maintenance (I-M) sequences for the treatment of patients with nonsquamous non small-cell lung cancer (nsqNSCLC) are limited because of a lack of direct evidence. This analysis aimed to compare the cost-effectiveness of I-M pemetrexed with those of other I-M regimens used for the treatment of patients with advanced nsqNSCLC in the French health-care setting. MATERIALS AND METHODS: A previously developed global partitioned survival model was adapted to the France-only setting by restricting treatment sequences to include 12 I-M regimens most relevant to France, and incorporating French costs and resource-use data. Following a systematic literature review, network meta-analyses were performed to obtain hazard ratios for progression-free survival (PFS) and overall survival (OS) relative to gemcitabine + cisplatin (induction sequences) or best supportive care (BSC) (maintenance sequences). Modeled health-care benefits were expressed as life-years (LYs) and quality-adjusted LYs (QALYs) (estimated using French EuroQol five-dimension questionnaire tariffs). The study was conducted from the payer perspective (National Health Insurance). Cost- and benefit-model inputs were discounted at an annual rate of 4%. RESULTS: Base-case results showed pemetrexed + cisplatin induction followed by (->) pemetrexed maintenance had the longest mean OS and PFS and highest LYs and QALYs. Costs ranged from ?12,762 for paclitaxel + carboplatin -> BSC to ?35,617 for pemetrexed + cisplatin -> pemetrexed (2015 values). Gemcitabine + cisplatin -> BSC, pemetrexed + cisplatin > BSC, and pemetrexed + cisplatin -> pemetrexed were associated with fully incremental cost-effectiveness ratios (ICERs) of ?16,593, ?80,656, and ?102,179, respectively, per QALY gained versus paclitaxel + carboplatin -> BSC. All other treatment sequences were either dominated (ie, another sequence had lower costs and better/equivalent outcomes) or extendedly dominated (ie, the comparator had a higher ICER than a more effective comparator) in the model. Sensitivity analyses showed the model to be relatively insensitive to plausible changes in the main assumptions, with none increasing or decreasing the ICER by more than ~?20,000 per QALY gained. CONCLUSION: In the absence of direct comparative trial evidence, this cost-effectiveness analysis indicated that of a large number of I-M sequences used for the treatment of patients with nsqNSCLC in France, pemetrexed + cisplatin -> pemetrexed achieved the best clinical outcomes (0.28 incremental QALYs gained) versus paclitaxel + carboplatin -> BSC. PMID- 28860834 TI - The 24-hour skin hydration and barrier function effects of a hyaluronic 1%, glycerin 5%, and Centella asiatica stem cells extract moisturizing fluid: an intra-subject, randomized, assessor-blinded study. AB - INTRODUCTION: Moisturizing products are commonly used to improve hydration in skin dryness conditions. However, some topical hydrating products could have negative effects on skin barrier function. In addition, hydrating effects of moisturizers are not commonly evaluated up to 24 hours after a single application. Hyaluronic acid (HA) and glycerin are very well-known substances able to improve skin hydration. Centella asiatica extract (CAE) could exert lenitive, anti-inflammatory and reepithelialization actions. Furthermore, CAE could inhibit hyaluronidase enzyme activity, therefore prolonging the effect of HA. A fluid containing HA 1%, glycerin 5% and stem cells CAE has been recently developed (Jaluronius CS [JCS] fluid). STUDY AIM: To evaluate and compare the 24 hour effects of JCS fluid on skin hydration and on transepidermal water loss (TEWL) in healthy subjects in comparison with the control site. SUBJECTS AND METHODS: Twenty healthy women, mean age 40 years, were enrolled in an intra subject (right vs left), randomized, assessor-blinded, controlled, 1-day trial. The primary end points were the skin hydration and TEWL, evaluated at the volar surface of the forearm and in standardized conditions (temperature- and humidity controlled room: 23 degrees C and 30% of humidity) using a corneometer and a vapometer device at baseline, 1, 8 and 24 hours after JCS fluid application. Measurements were performed by an operator blinded for the treatments. RESULTS: Skin hydration after 24 hours was significantly higher (P=0.001; Mann-Whitney U test) in the JCS-treated area in comparison with the control site. JCS induced a significant (P=0.0001) increase in skin hydration at each evaluation time (+59% after 1 hour, +48% after 8 hours and +29% after 24 hours) in comparison with both baseline (P=0.0001) and non-treated control site (P=0.001). TEWL after 24 hours was significantly lower (P=0.049; Mann-Whitney U test) in the JCS-treated area in comparison with the control site (13+/-4 arbitrary units [AU] vs 16+/-6 AU). JCS fluid significantly reduced post-stripping TEWL in comparison with baseline after 1, 8 and 24 hours (-52%, -32% and -48%, respectively). In the control site, TEWL was not reduced in comparison with baseline values at each time point's evaluation. CONCLUSION: A single application of JCS significantly improves skin hydration for up to 24 hours at the same time as improving skin barrier function. PMID- 28860833 TI - Novel biomarkers for prediabetes, diabetes, and associated complications. AB - The number of individuals with prediabetes is expected to grow substantially and estimated to globally affect 482 million people by 2040. Therefore, effective methods for diagnosing prediabetes will be required to reduce the risk of progressing to diabetes and its complications. The current biomarkers, glycated hemoglobin (HbA1c), fructosamine, and glycated albumin have limitations including moderate sensitivity and specificity and are inaccurate in certain clinical conditions. Therefore, identification of additional biomarkers is being explored recognizing that any single biomarker will also likely have inherent limitations. Therefore, combining several biomarkers may more precisely identify those at high risk for developing prediabetes and subsequent progression to diabetes. This review describes recently identified biomarkers and their potential utility for addressing the burgeoning epidemic of dysglycemic disorders. PMID- 28860835 TI - Lymphoid follicles in children with Helicobacter pylori-negative gastritis. AB - PURPOSE: The prevalence of Helicobacter pylori gastritis has been declining, whereas H. pylori-negative gastritis has become more common. We evaluated chronic gastritis in children with regard to H. pylori status and celiac disease (CD). PATIENTS AND METHODS: Demographic, clinical, endoscopic, and histologic features of children who underwent elective esophagogastroduodenoscopy were reviewed retrospectively. Gastric biopsies from the antrum and corpus of the stomach were graded using the Updated Sydney System. H. pylori presence was defined by hematoxylin and eosin, Giemsa, or immunohistochemical staining and urease testing. RESULTS: A total of 184 children (61.9% female) met the study criteria with a mean age of 10 years. A total of 122 (66.3%) patients had chronic gastritis; 74 (60.7%) were H. pylori-negative. Children with H. pylori-negative gastritis were younger (p=0.003), were less likely to present with abdominal pain (p=0.02), and were mostly of non-Arabic origin (p=0.011). Nodular gastritis was found to be less prevalent in H. pylori-negative gastritis (6.8%) compared with H. pylori-positive gastritis (35.4%, p<0.001). The grade of mononuclear infiltrates and neutrophil density was more severe in the H. pylori-positive group (p<0.001). Pan-gastritis and lymphoid follicles were associated most commonly with H. pylori. Although less typical, lymphoid follicles were demonstrated in 51.3% of H. pylori-negative patients. The presence or absence of CD was not associated with histologic findings in H. pylori-negative gastritis. CONCLUSION: Our findings suggest that lymphoid follicles are a feature of H. pylori-negative gastritis in children independent of their CD status. PMID- 28860836 TI - Serum levels of caspase-cleaved cytokeratin 18 (CK18-Asp396) predict severity of liver disease in chronic hepatitis B. AB - BACKGROUND AND AIM: Caspase-cleaved cytokeratin 18 (CK18-Asp396) is a potential clinically useful biomarker in liver disease as it is released from hepatocytes during apoptosis. In this study, we investigated serum CK18-Asp396 levels in chronic hepatitis B (CHB). PATIENTS AND METHODS: Overall, 163 patients with CHB were included. Serum CK18-Asp396 levels were determined by enzyme-linked immunosorbent assay (ELISA), and results were related to steatosis grade, histological activity index, inflammation score, and METAVIR fibrosis grade as well as to viral load, serum levels of liver enzymes, and albumin. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of serum CK18-Asp396 levels for assessing disease activity. RESULTS: A higher level of serum CK 18 concentrations was found in patients with significant inflammation vs no significant inflammation (378.5 [interquartile range {IQR}: 173.2-629.6] vs 137.3 [87.5-197.7], P < 0.05; approximately threefold increase) and in patients with significant fibrosis vs no significant fibrosis (177.8 [IQR: 120.8-519.1] vs 142.7 [IQR: 88.8-214.4], P < 0.05; 1.25-fold increase). There was no differential CK 18 level by degree of steatosis. CK 18 was an independent predictor of significant inflammation with an 82% specificity and a 94% negative predictive value. We found the strongest correlation of CK 18 with alanine aminotransferase and aspartate aminotransferase (both r = 0.52; P < 0.001), but less with albumin (r = -0.24; P < 0.05) and viral load (log) (r = 0.19; P < 0.05). CONCLUSION: CHB appears to be accompanied by continuous high levels of hepatocyte apoptosis as judged from serum CK 18, suggesting that elimination of the infected compartment constitutes a defensive strategy against disease. Accordingly, CK 18 works as an independent predictor of significant inflammation with a high specificity. PMID- 28860838 TI - Does diabetes impact therapeutic immunomodulation therapy decisions for kidney transplant recipients? Data from the Folic Acid for Vascular Outcome Reduction in Transplant (FAVORIT) trial. AB - Although survival has improved for kidney transplant recipients over the past several decades, long-term survival in diabetic cohorts still is significantly less than that of non-diabetic cohorts. We hypothesized that among stable kidney transplant recipients, there might be differences between subgroups with and without diabetes with respect to prevalence of prior cardiovascular events and post-transplant antihypertensive and immunosuppressive therapy. We performed a post hoc analysis of participants in the Folic Acid for Vascular Outcome Reduction in Transplant (FAVORIT) trial, a multicenter international trial of 4110 prevalent kidney transplant recipients enrolled from 2002 to 2007 evaluating the effect of homocysteine-lowering vitamin therapy on cardiovascular outcomes. There were 2447 participants without diabetes, 166 with type 1 diabetes, and 1447 with type 2 diabetes at study entry, which occurred on average 4 years post transplant. Recipients with diabetes had a greater prevalence of prior cardiovascular events, were more likely to have required multiple medications to control hypertension, and were more likely to have received tacrolimus as opposed to cyclosporine than the non-diabetic transplant recipients (all p<0.001). The effect of differences in treatment of non-diabetic vs diabetic cohorts after stable renal transplantation upon outcomes has not yet been studied and could provide additional information that might lead to improved care. PMID- 28860839 TI - Updating the landscape of direct-to-consumer pharmacogenomic testing. AB - Pharmacogenomics has identified important drug-gene interactions that affect the safety and efficacy of medications. Direct-to-consumer genetic testing, when first introduced, included some pharmacogenomic-related genes. The current landscape of pharmacogenomic direct-to-consumer testing is reviewed. Prior published reviews of the literature were updated through February 2017 and a scan of the current availability of direct-to-consumer genomic testing by companies was conducted. Results of the review demonstrate a shift toward physician approved ordering. PMID- 28860837 TI - The role of novel biomarkers in predicting diabetic nephropathy: a review. AB - Diabetic nephropathy (DN) is one of the microvascular complications of the kidney arising commonly from type 1 diabetes mellitus (T1DM), and occasionally from type 2 diabetes mellitus (T2DM). Microalbuminuria serves as an early indicator of DN risk and a predictor of its progression as well as cardiovascular disease risk in both T1DM and T2DM. Although microalbuminuria remains the gold standard for early detection of DN, it is not a sufficiently accurate predictor of DN risk due to some limitations. Thus, there is a paradigm shift to novel biomarkers which would help to predict DN risk early enough and possibly prevent the occurrence of end stage kidney disease. These new biomarkers have been broadly classified into glomerular biomarkers, tubular biomarkers, biomarkers of inflammation, biomarkers of oxidative stress, and miscellaneous biomarkers which also include podocyte biomarkers, some of which are also considered as tubular and glomerular biomarkers. Although they are potentially useful for the evaluation of DN, current data still preclude the routine clinical use of majority of them. However, their validation using high-quality and large longitudinal studies is of paramount importance, as well as the subsequent development of a biomarker panel which can reliably predict and evaluate this renal microvascular disease. This paper aims to review the predictive role of these biomarkers in the evaluation of DN. PMID- 28860840 TI - Influence of organizational culture on provider adherence to the diabetic clinical practice guideline: using the competing values framework in Palestinian Primary Healthcare Centers. AB - BACKGROUND: Diabetes mellitus (DM) is a serious chronic disease and an important public health issue. This study aimed to identify the predominant culture within the Palestinian Primary Healthcare Centers of the Ministry of Health (PHC-MoH) and the Primary Healthcare Centers of the United Nations Relief and Works Agency for Palestine Refugees (PHC-UNRWA) by using the competing values framework (CVF) and examining its influence on the adherence to the Clinical Practice Guideline (CPG) for DM. METHODS: A cross-sectional design was employed with a census sample of all the Palestinian family doctors and nurses (n=323) who work within 71 PHC clinic. A cross-cultural adaptation framework was followed to develop the Arabic version of the CVF questionnaire. RESULTS: The overall adherence level to the diabetic guideline was disappointingly suboptimal (51.5%, p<0.001; 47.3% in the PHC-MoH and 55.5% in the PHC-UNRWA). In the PHC-MoH, the clan/group culture was the most predominant (mean =41.13; standard deviation [SD] =8.92), followed by hierarchical (mean =33.14; SD=5.96), while in the PHC-UNRWA, hierarchical was the prevailing culture (mean =48.43; SD =12.51), followed by clan/group (mean =29.73; SD =8.37). Although a positively significant association between the adherence to CPG and the rational culture and a negatively significant association with the developmental archetype were detected in the PHC-MoH, no significant associations were found in the PHC-UNRWA. CONCLUSION: Our study demonstrates that the organizational culture has a marginal influence on the adherence to the diabetic guideline. Future research should preferably mix quantitative and qualitative approaches and explore the use of more sensitive instruments to measure such a complex construct and its effects on guideline adherence in small-sized clinics. PMID- 28860842 TI - The Fear of Pain Questionnaire-III and the Fear of Pain Questionnaire-Short Form: a confirmatory factor analysis. AB - BACKGROUND: The Fear of Pain Questionnaire-III (FPQ-III) is a widely used instrument to assess the fear of pain (FOP) in clinical and nonclinical samples. The FPQ-III has 30 items and is divided into three subscales: Severe Pain, Minor Pain and Medical Pain. Due to findings of poor fit of the original three-factor FPQ-III model, the Fear of Pain Questionnaire-Short Form (FPQ-SF) four-factor model has been suggested as an alternative. The FPQ-SF is a revised version of the FPQ-III, reduced to 20 items and subdivided into four subscales: Severe Pain, Minor Pain, Injection Pain and Dental Pain. AIMS AND METHODS: The purpose of the study was to investigate the model fit, reliability and validity of the FPQ-III and the FPQ-SF in a Norwegian nonclinical sample, using confirmatory factor analysis (CFA). The second aim was to explore the model fit of the two scales in male and female subgroups separately, since previous studies have uncovered differences in how well the questionnaires measure FOP across sex; thus, the questionnaires might not be sex neutral. It has been argued that the FPQ-SF model is better because of the higher fit to the data across sex. To explore model fit across sex within the questionnaires, the model fit, validity and reliability were compared across sex using CFA. RESULTS: The results revealed that both models' original factor structures had poor fit. However, the FPQ-SF had a better fit overall, compared to the FPQ-III. The model fit of the two models differed across sex, with better fit for males on the FPQ-III and for females on the FPQ SF. CONCLUSION: The FPQ-SF is a better questionnaire than the FPQ-III for measurement of FOP in Norwegian samples and across sex subgroups. However, the FPQ-III is a better questionnaire for males than for females, whereas the FPQ-SF is a better questionnaire for females than for males. The findings are discussed and directions for future investigations outlined. PMID- 28860843 TI - Psychometric properties revised reinforcement sensitivity theory (r-RST) scale in chronic pain patients. AB - OBJECTIVE: The aim of present study was to evaluate the psychometric properties of the Reinforcement Sensitivity Questionnaire (RSQ) in patients with chronic pain. METHODS: For this purpose, 312 (first study) and 70 (second study) patients with chronic pain were selected, and the Reinforcement Sensitivity Theory Personality Questionnaire (RST-PQ) and Pain Beliefs and Perceptions Inventory (PBPI) were distributed among them for their response. The reliability of the questionnaire was evaluated by Cronbach's alpha, retest, and split-half coefficient; then, the criterion validity with other questionnaires was evaluated to determine the psychometric properties of the RSQ. The factor structure was assessed via confirmatory factor analysis. RESULTS: The results of the factor analysis indicated that the RSQ has five factors, and checking the validity by using Cronbach's alpha, retest, and split-half coefficient reflected the stability of the scale; the criterion validity of the RSQ with other questionnaires showed desirable discriminant and convergent validity. CONCLUSION: Overall, the findings indicated that the RSQ has good psychometric properties in chronic pain samples, and the tool can be used in studies of chronic pain. It seems that the RSQ is a good predictor for pain in patients with chronic pain. PMID- 28860841 TI - A review of the management of phantom limb pain: challenges and solutions. AB - BACKGROUND: Phantom limb pain (PLP) occurs in 50% and 80% of amputees. Although it is often classified as a neuropathic pain, few of the large-scale trials of treatments for neuropathic pain included sufficient numbers of PLP sufferers to have confidence that they are effective in this condition. Many therapies have been administered to amputees with PLP over the years; however, as of yet, there appears to be no first-line treatment. OBJECTIVES: To comprehensively review the literature on treatment modalities for PLP and to identify the challenges currently faced by clinicians dealing with this pain. METHOD: MEDLINE, EMBASE, CINAHL, British Nursing Index, Cochrane and psycINFO databases were searched using "Phantom limb" initially as a MeSH term to identify treatments that had been tried. Then, a secondary search combining phantom limb with each treatment was performed to find papers specific to each therapy. Each paper was assessed for its research strength using the GRADE system. RESULTS: Thirty-eight therapies were identified. Overall, the quality of evidence was low. There was one high quality study which used repetitive transcutaneous magnetic stimulation and found a statistical reduction in pain at day 15 but no difference at day 30. Significant results from single studies of moderate level quality were available for gabapentin, ketamine and morphine; however, there was a risk of bias in these papers. Mirror therapy and associated techniques were assessed through two systematic reviews, which conclude that there is insufficient evidence to support their use. CONCLUSION: No decisions can be made for the first-line management of PLP, as the level of evidence is too low. Robust studies on homogeneous populations, an understanding of what amputees consider a meaningful reduction in PLP and agreement of whether pain intensity is the legitimate therapeutic target are urgently required. PMID- 28860844 TI - Cognitive effects of electro-acupuncture and pregabalin in a trigeminal neuralgia rat model induced by cobra venom. AB - OBJECTIVE: The objective of this study was to investigate the effects of electro acupuncture (EA) and pregabalin on cognition impairment induced by chronic trigeminal neuralgia (TN) in rats. DESIGN: Controlled animal study. SETTING: Department of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University. SUBJECTS: Forty adult male Sprague Dawley rats. METHODS: Rats were randomly divided into four groups. The TN model was induced by administration of cobra venom to the left infraorbital nerve. On postoperative day 14, either EA or pregabalin was administered, free behavioral activities were observed. Spatial learning and memory abilities were determined in the Morris water maze. The ultrastructural alterations of the Gasserian ganglion, medulla oblongata and hippocampus were examined by electron microscopy. The changes on long-term potentiation were investigated. RESULTS: After treatment, the exploratory behavior increased and the grooming behavior decreased (P<0.05) for the EA group and pregabalin group compared with the cobra venom group; moreover, demyelination of neurons in Gasserian ganglion and medulla oblongata was reversed. The number of platform site crossings, the average percentages of time in the target quadrant and the field excitatory postsynaptic potential slopes increased (P<0.05) in the EA group compared to the cobra venom group. However, the pregabalin group showed no differences compared to the cobra venom group (P>0.05). Vacuolar degeneration in the hippocampal neurons was mild in the EA group, while it was severe in the pregabalin group. CONCLUSION: EA and pregabalin could alleviate TN induced by cobra venom. EA could also inhibit the cognition deficit induced by TN, while pregabalin could not. PMID- 28860845 TI - Dexmedetomidine in perioperative acute pain management: a non-opioid adjuvant analgesic. AB - Many nociceptive, inflammatory, and neuropathic pathways contribute to perioperative pain. Although opioids have long been a mainstay for perioperative analgesia, other non-opioid therapies, and dexmedetomidine, in particular, have been increasingly used as part of a multimodal analgesic regimen to provide improved pain control while minimizing opioid-related side effects. This article reviews the evidence supporting the preoperative, intraoperative, and postoperative efficacy of dexmedetomidine as an adjuvant, and the efficacy of intravenous, spinal canal, and nerve block analgesia with dexmedetomidine for perioperative acute pain treatment. While there have not been any large-scale clinical trials conducted, the current body of evidence suggests that dexmedetomidine is suitable for use as an adjuvant analgesic at all perioperative stages. However, there are potential adverse effects, such as hypotension and bradycardia, which must be taken into consideration by clinicians. PMID- 28860847 TI - Erratum: Clinical outcome following DIAM implantation for symptomatic lumbar internal disk disruption: a 3-year retrospective analysis [Corrigendum]. AB - [This corrects the article on p. 917 in vol. 9, PMID: 27826214.]. PMID- 28860848 TI - Effectiveness of trigger point dry needling for plantar heel pain: a meta analysis of seven randomized controlled trials. AB - BACKGROUND: Plantar heel pain can be managed with dry needling of myofascial trigger points (MTrPs); however, whether MTrP needling is effective remains controversial. Thus, we conducted this meta-analysis to evaluate the effect of MTrP needling in patients with plantar heel pain. MATERIALS AND METHODS: PubMed, Embase, Web of Science, SinoMed (Chinese BioMedical Literature Service System, People's Republic of China), and CNKI (National Knowledge Infrastructure, People's Republic of China) databases were systematically reviewed for randomized controlled trials (RCTs) that assessed the effects of MTrP needling. Pooled weighted mean difference (WMD) with 95% CIs were calculated for change in visual analog scale (VAS) score, and pooled risk ratio (RR) with 95% CIs were calculated for success rate for pain and incidence of adverse events. A fixed-effects model or random-effects model was used to pool the estimates, depending on the heterogeneity among the included studies. RESULTS: Extensive literature search yielded 1,941 articles, of which only seven RCTs met the inclusion criteria and were included in this meta-analysis. The pooled results showed that MTrP needling significantly reduced the VAS score (WMD =-15.50, 95% CI: -19.48, -11.53; P<0.001) compared with control, but it had a similar success rate for pain with control (risk ratio [RR] =1.15, 95% CI: 0.87, 1.51; P=0.320). Moreover, MTrP needling was associated with a similar incidence of adverse events with control (RR =1.89, 95% CI: 0.38, 9.39; P=0.438). CONCLUSION: MTrP needling effectively reduced the heel pain due to plantar fasciitis. However, considering the potential limitations in this study, more large-scale, adequately powered, good quality placebo-controlled trials are needed to provide more trustworthy evidence in this area. PMID- 28860849 TI - Cancer pain management in China: current status and practice implications based on the ACHEON survey. AB - PURPOSE: Cancer pain can seriously impact the quality of life (QoL) of patients, and optimal management practices are therefore of paramount importance. The ACHEON survey queried physicians and patients from 10 Asian countries/regions to assess current clinical practices in cancer pain management in Asia. This study presents the data obtained for cancer pain management in mainland China, with an emphasis on practices related to opioid drugs. MATERIALS AND METHODS: In several tertiary hospitals across China, 250 patients experiencing cancer pain and 100 physicians were surveyed on questions designed to assess current cancer pain management practices and cancer pain impact on QoL. RESULTS: The patient survey showed that 88% of patients reported moderate-to-severe cancer pain, with a median duration of 6 months. The physician survey showed that medical school/residency training with regard to cancer pain management was inadequate in ~80% of physicians. A total of 80% of physicians and 67.2% of patients reported that pain scale was used during pain assessment; 84% of physicians expressed that physician-perceived pain severity was not completely consistent with actual pain the patient experienced. Of the 147 patients who recalled the medication received, 83.7% were administered opioid prescriptions. Of the 240 patients who received treatment, 43.8% perceived the inadequacy of controlling pain. The primary barriers from physicians perceived to optimal pain management included patients' fear of side effects (58%), patients' fear of addiction (53%), patients' reluctance to report pain (43%), physicians' reluctance to prescribe (29%), physicians' inadequacy of pain assessment (27%) and excessive regulation of opioid analgesics (47%). CONCLUSION: Knowledge of cancer pain management should be strengthened among physicians. Quantitative pain assessment and principle-based pain management should be combined to achieve pain relief. Misconceptions about opioids in patients and physicians and poor report about pain should be overcome through training/education to improve QoL of patients impacted by pain. PMID- 28860850 TI - A randomized, double-blind study of hydromorphone hydrochloride extended-release tablets versus oxycodone hydrochloride extended-release tablets for cancer pain: efficacy and safety in Japanese cancer patients (EXHEAL: a Phase III study of EXtended-release HydromorphonE for cAncer pain reLief). AB - BACKGROUND: In Japan, there are limited options for switching opioid analgesics. Hydromorphone is an opioid analgesic that is routinely used instead of morphine for cancer pain; however, it is not yet available in Japan. The aim of this study was to assess the efficacy and safety of hydromorphone (DS-7113b) extended release tablets in opioid-naive patients with cancer pain not relieved by non opioid analgesics. SUBJECTS AND METHODS: This was a multicenter, randomized, double-blind, parallel-group trial. A double-dummy method was used for blinding. Each randomized subject received either hydromorphone extended-release tablets plus placebo oxycodone hydrochloride extended-release tablets 4 mg/day (n=88) or placebo hydromorphone extended-release tablets plus oxycodone hydrochloride extended-release tablets 10 mg/day (n=93) orally for 7 days (once-daily dosing for hydromorphone and twice-daily dosing for oxycodone). The doses were adjusted as necessary. Efficacy was evaluated by change in visual analog scale (VAS) score from baseline to completion of treatment. RESULTS: The between-group difference in least squares mean changes in VAS score from baseline to completion or discontinuation of treatment was -0.4 mm (95% CI -5.9 to 5 mm) by analysis of covariance where the baseline VAS score was used as a covariate. The upper limit of the 95% CI was below 10 mm, which was predefined as the noninferiority limit. This verified the noninferiority of hydromorphone tablets relative to oxycodone tablets. The incidence of adverse events was 80.7% (71 of 88) in the hydromorphone group and 83.7% (77 of 93) in the oxycodone group. The most common adverse events were nausea, vomiting, somnolence, diarrhea, and constipation, most of which are commonly observed with opioid analgesics. CONCLUSION: The efficacy and safety of hydromorphone extended-release tablets were equivalent to those of the oxycodone extended-release formulation. PMID- 28860846 TI - Ambroxol for the treatment of fibromyalgia: science or fiction? AB - Fibromyalgia appears to present in subgroups with regard to biological pain induction, with primarily inflammatory, neuropathic/neurodegenerative, sympathetic, oxidative, nitrosative, or muscular factors and/or central sensitization. Recent research has also discussed glial activation or interrupted dopaminergic neurotransmission, as well as increased skin mast cells and mitochondrial dysfunction. Therapy is difficult, and the treatment options used so far mostly just have the potential to address only one of these aspects. As ambroxol addresses all of them in a single substance and furthermore also reduces visceral hypersensitivity, in fibromyalgia existing as irritable bowel syndrome or chronic bladder pain, it should be systematically investigated for this purpose. Encouraged by first clinical observations of two working groups using topical or oral ambroxol for fibromyalgia treatments, the present paper outlines the scientific argument for this approach by looking at each of the aforementioned aspects of this complex disease and summarizes putative modes of action of ambroxol. Nevertheless, at this point the evidence basis for ambroxol is not strong enough for clinical recommendation. PMID- 28860851 TI - Transdermal buprenorphine and fentanyl patches in cancer pain: a network systematic review. AB - Treatment of cancer pain is generally based on the three-step World Health Organization (WHO) pain relief ladder, which utilizes a sequential approach with drugs of increasing potency. Goals of pain management include optimization of analgesia, optimization of activities of daily living, minimization of adverse effects, and avoidance of aberrant drug taking. In addition, it is recommended that analgesic regimens are individualized and simplified to help ensure patient compliance and should provide the least invasive, easiest, and safest route of opioid administration to ensure adequate analgesia. Buprenorphine and fentanyl are two opioids available for the relief of moderate-to-severe cancer pain. Available clinical data regarding the transdermal (TD) formulations of these opioids and the extent to which they fulfill the recommendations mentioned earlier are systematically reviewed, with the aim of providing additional information for oncologists and pain specialists regarding their comparative use. Due to lack of studies directly comparing TD buprenorphine with TD fentanyl, data comparing these with other step-3 opioids are also evaluated in a network fashion. PMID- 28860852 TI - Expression of matrix metalloproteinases and components of the endocannabinoid system in the knee joint are associated with biphasic pain progression in a rat model of osteoarthritis. AB - Matrix metalloproteinases (MMPs) are considered important in articular cartilage breakdown during osteoarthritis (OA). Similarly, the endocannabinoid system (ECS) is implicated in joint function and modulation of nociceptive processing. Functional interplay between ECS and MMPs has been recently indicated. Here, we tested if changes in the expression of selected MMPs and major ECS elements temporally correlate with the intensity of OA-related pain. Knee OA was induced in male Wistar rats by intra-articular sodium monoiodoacetate injection. OA-like pain behavior was tested using the dynamic weight bearing. Joint tissue samples at different time points after OA induction were subjected to gene (quantitative polymerase chain reaction) and protein (Western blot) expression analyses. Monoiodoacetate-induced nocifensive responses in rats showed a biphasic progression pattern. The alterations in expression of selected MMPs elegantly corresponded to the two-stage development of OA pain. The most substantial changes in the expression of the ECS system were revealed at a later stage of OA progression. Alterations within ECS are involved in the process of adaptation to persistent painful stimuli. The accumulation of MMPs in osteoarthritic cartilage may have a role in the biphasic progression of OA-related pain. Temporal association of changes in ECS and MMPs expression shows a potential therapeutic approach that utilizes the concept of combining indirect ECS-mediated MMP inhibition and ECS modulation of pain transduction. PMID- 28860853 TI - Disability from posttraumatic headache is compounded by coexisting posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic headache (PTH) occurs in up to 82% of patients with traumatic brain injury (TBI). Posttraumatic stress disorder (PTSD) occurs in 39% of those with PTH. This study evaluates whether PTSD affects PTH disability. METHODS: Eighty-six patients with TBI were prospectively evaluated in a secondary care trauma center. Headache disability was assessed using the Headache Impact Test version 6 and signs indicative of PTSD using the PTSD Check List Civilian version. RESULTS: Increased PTSD-type symptoms were significantly associated with increased headache disability (p<0.001), as were employment status and loss of consciousness (p=0.049 and 0.016, respectively). Age was negatively correlated with headache disability (Spearman's correlation rho=0.361, p=0.001). CONCLUSION: Increased severity of PTSD-type symptoms is significantly associated with increased headache disability in patients with chronic PTH. Managing PTSD symptoms in patients with chronic PTH may facilitate headache management. PMID- 28860854 TI - Pharmacological mechanisms involved in the analgesia induced by ethanol extract of Hybanthus enneaspermus leaves. AB - BACKGROUND: Hybanthus enneaspermus (HE) leaves are being used traditionally to relieve pain, and scientific studies have demonstrated their analgesic potential. This study attempted to elucidate the pharmacological mechanism(s) involved in the analgesic action of ethanol extract of H. enneaspermus leaves (EEHE). MATERIALS AND METHODS: Forty-two male Wistar rats were separately randomized into seven groups (n=6 rats in each group) for tail immersion and formalin tests. Group I (control) received distilled water (10 mL/kg) while groups II and III received acetaminophen (the reference drug, 100 mg/kg ip) and EEHE (1000 mg/kg po), respectively. Groups IV-VII were pretreated with cimetidine (50 mg/kg ip), naloxone (5 mg/kg ip), propranolol (0.15 mg/kg ip), and prazosin (0.15 mg/kg ip), respectively, 1 hour before EEHE (1000 mg/kg po) treatment. RESULTS: The EEHE induced increase in tail-flick latency was reduced by blockade of histamine and adrenergic receptors but prevented by blockade of opiate receptor in the tail flick test. However, the EEHE-induced decrease in paw licking time was prevented only by blockade of opiate receptor but unaffected by histamine and adrenergic receptors blockers. CONCLUSION: These findings suggest that the analgesic effect of EEHE in different pain types may involve different neural mechanisms and that the opioidergic pathway contributes more to EEHE-induced analgesia than the other pathways. PMID- 28860855 TI - Pain as a disease: an overview. AB - The acknowledgment of pain as a pathologic entity in its own right remains debated. Notwithstanding the data showing the burden of pain as a disease, an ultimate recognition of the pathologic nature of this condition is lacking. In this study, we analyze the notion of pain as a disease through an historical overview of its several conceptualizations and report the main evidence supporting this notion. We believe that a clear definition of pain as a disease is necessary, especially considering the enormous global burden of this condition. Indeed, the recognition of pain as a definite pathologic state is crucial to raise awareness about this neglected global health problem and to promote the exploration of new specific therapeutic approaches. PMID- 28860856 TI - Serum magnesium and calcium in preeclampsia: a comparative study at the Korle-Bu Teaching Hospital, Ghana. AB - BACKGROUND: A large percentage (16% of maternal mortality in developed countries, compared to 9% in developing countries), is due to hypertensive disorders in pregnancy. The etiology of preeclampsia remains unknown, with poorly understood pathophysiology. Magnesium and calcium play an important role in vascular smooth muscle function and therefore a possible role in the development of preeclampsia. AIM: We aimed to compare serum magnesium and total calcium levels of preeclamptic and normal pregnant women at the Korle-Bu Teaching Hospital in Ghana. PATIENTS AND METHODS: A comparative cross-sectional study involving 30 normal pregnant and 30 preeclamptic women with >30 weeks gestation and aged 18-35 years, was conducted at the Korle-Bu Teaching Hospital. Magnesium and calcium were determined using a flame atomic absorption spectrometer. RESULTS: Mean serum magnesium and total calcium levels in preeclamptic women were 0.70+/-0.15 and 2.13+/-0.30 mmol/L, respectively. Mean serum magnesium and total calcium levels in normal pregnant women were 0.76+/-0.14 and 2.13+/-0.35 mmol/L, respectively. There was a statistically nonsignificant difference in serum magnesium and total calcium in preeclamptic women compared to normal pregnant women, with p-values of 0.092 and 0.972, respectively. CONCLUSION: Serum magnesium and total calcium, therefore, seem not to differ in preeclamptic women compared to normal pregnant women in Ghana. PMID- 28860857 TI - Preventing nausea and vomiting in women undergoing regional anesthesia for cesarean section: challenges and solutions. AB - BACKGROUND: Intraoperative nausea and vomiting (IONV) or postoperative nausea and vomiting (PONV) affecting women undergoing regional anesthesia for cesarean section is an important clinical problem since these techniques are used widely. There are burdens of literature about IONV/PONV and several in parturient and cesarean. However, it needs more attention. The underlying mechanisms of IONV and PONV in the obstetrical setting mainly include hypotension due to sympathicolysis during neuraxial anesthesia, bradycardia owing to an increased vagal tone, the visceral stimulation via the surgical procedure and intravenously administered opioids. METHODS: Given the high and even increasing rate of cesarean sections and the sparse information on the etiology, incidence and severity of nausea and vomiting and the impact of prophylactic measures on the incidence of PONV/IONV, this article aims to review the available information and provide pragmatic suggestions on how to prevent nausea and vomiting in this patient cohort. Current literature and guidelines were identified by electronic database searching (MEDLINE via PubMed and Cochrane database of systematic reviews) up to present, searching through reference lists of included literature and personal contact with experts. DISCUSSION AND CONCLUSION: Taking into account the current guidelines and literature as well as everyday clinical experience, the first step for decreasing the incidence of IONV and PONV is a comprehensive management of circulatory parameters. This management includes liberal perioperative fluid administration and the application of vasopressors as the circumstances require. By using low-dose local anesthetics, an additional application of intrathecal or spinal opioids or hyperbaric solutions for a sufficient controllability of neuraxial distribution, maternal hypotension might be reduced. Performing a combined spinal-epidural anesthesia or epidural anesthesia may be considered as an alternative to spinal anesthesia. Antiemetic drugs may be administered restrainedly due to off-label use in pregnant women for IONV or PONV prophylaxis and may be reserved for treatment. PMID- 28860858 TI - Increased risk of breast cancer in neurofibromatosis type 1: current insights. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by mutation/deletion of the NF1 gene. The gene product, neurofibromin, is a tumor suppressor which represses the activity of the Ras oncogene. Central nervous system (CNS) tumors have long been associated with NF1, but their association with several other malignancies has been demonstrated. In this review, we summarize the epidemiological data that irrefutably support a link between NF1 and an increased risk of early-onset breast cancer, to levels at which annual mammography is currently recommended in national high-risk screening programs. We discuss the reasons for the observed adverse breast cancer prognosis in NF1 cases, including late presentation and more aggressive tumor subtypes, and recommend that a collaborative breast screening study be initiated to better serve this currently underserved population of women. PMID- 28860859 TI - Head and neck cancer: improving outcomes with a multidisciplinary approach. AB - For early-stage head and neck cancer (HNC), surgery (S) or radiotherapy (RT) is a standard treatment. The multidisciplinary approach, which includes multimodality treatment with S followed by RT, with or without chemotherapy (CT) or concurrent chemoradiotherapy (CRT), is required for locally advanced head and neck cancer (LAHNC). CRT improves prognosis, locoregional control (LRC), and organ function in LAHNC, compared to RT alone. Prognosis in recurrent/metastatic HNC (R/M HNC) is dismal. Platinum-based CT, combined with the anti-Epidermal Growth Factor Receptor (EGFR) antibody (Ab) cetuximab, is used in first-line setting, while no further validated options are available at progression. The complexity of disease is, in part, due to the heterogeneity of organs and functions involved and the need for a multimodality approach. In addition, the patient population (often elderly and/or patients with smoking and alcohol habits) argues for an individually tailored treatment plan. Furthermore, treatment goals - which include cure, organ, and function preservation, quality of life and palliation - must also be considered. Thus, optimal management of patients with HNC should involve a range of healthcare professionals with relevant expertise. The purpose of the present review is to 1) highlight the importance and necessity of the multidisciplinary approach in the treatment of HNC; 2) update the knowledge regarding modern surgical techniques, new medical and RT treatment approaches, and their combination; 3) identify the treatment scenario for LAHNC and R/M HNC; and 4) discuss the current role of immunotherapy in HNC. PMID- 28860860 TI - Positive predictive values of ICD-10 codes to identify incident acute pancreatitis and incident primary malignancy in the Scandinavian national patient registries among women with postmenopausal osteoporosis. AB - BACKGROUND: Validation of definitions used to identify conditions of interest is imperative to epidemiologic studies based on routinely collected data. The objective of the study was thus to estimate positive predictive values (PPVs) of International Classification of Diseases, 10th Revision (ICD-10) codes to identify cases of incident acute pancreatitis leading to hospitalization and incident primary malignancy in the Scandinavian (Denmark, Norway, and Sweden) national patient registries in women with postmenopausal osteoporosis (PMO). METHODS: This validation study included postmenopausal (defined as 55 years or older) women with osteoporosis, identified between 2005-2014. Potential cases were sampled based on ICD-10 codes from the three national patient registries. Cases were adjudicated by physicians, using medical record review as gold standard. PPVs with corresponding 95% CIs were computed. RESULTS: Medical records of 286 of 325 (retrieval rate 88%) women with PMO were available for adjudication. Acute pancreatitis leading to hospitalization had a PPV of 87.6% (95% CI: 80.8%-90.2%). Incident primary malignancy had a PPV of 88.1% (95% CI: 81.3%-92.7%). The PPVs did not vary substantially across the three countries. CONCLUSION: ICD-10 codes to identify acute pancreatitis leading to hospitalization, and incident primary malignancy in the Scandinavian national patient registries had high PPVs among women with PMO. This allows identification of cases of acute pancreatitis and incident primary malignancy with reasonable validity and to use these as outcomes in comparative analyses. PMID- 28860861 TI - Potential drug-drug interactions in inpatients treated at the Internal Medicine ward of Tikur Anbessa Specialized Hospital. AB - PURPOSE: Although the concomitant use of multiple drugs often increases therapeutic effectiveness, certain combinations result in unwanted drug-drug interactions (DDIs). Most interactions go unnoticed by physicians due to the absence of new clinical signs and symptoms, and because they often produce a worsening of already existing symptoms. Quantification of the occurrence of the potential DDIs is essential to prevent the harmful effects associated with interactions. This study was launched to assess the prevalence of potential DDIs in the Internal Medicine ward of Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. PATIENTS AND METHODS: Cross-sectional data were gathered from the medical charts of 252 randomly selected patients who were admitted to the Internal Medicine ward during August 23 to October 23, 2013, and exposed to at least two concomitant drugs. Potential DDIs were identified using Medscape Drug Interaction Checker. The data were analyzed using SPSS software. Logistic regression analysis was used to determine the presence of association between variables and p-value <0.05 was considered statistically significant. RESULTS: At least one potential DDI was found in 78.2% of the patients. The mean number of potential interactions per patient was 3.7+/-3.4. Out of the 719 potential interactions identified, 49.8% were pharmacokinetic type, 44.6% were pharmacodynamic and the remaining 5.6% were unknown mechanisms. Major potential DDIs accounted for 13.1% of the whole interactions; 53.5% were moderate interactions; and the remaining 33.4% were minor interactions. Ceftriaxone, cimetidine and heparin were the three most involved drugs in major potential interactions. Prescription of five or more concomitant drugs was associated with high risk of encountering potential DDIs. CONCLUSION: The findings of this study showed that the prevalence of potential DDIs among inpatients was high. Pharmacists should closely review drugs prescribed for patients and avoid dispensing combinations of drugs that may have serious DDIs. PMID- 28860862 TI - Early rehospitalizations of frail elderly patients - the role of medications: a clinical, prospective, observational trial. AB - BACKGROUND AND OBJECTIVE: Early readmissions of frail elderly patients after an episode of hospital care are common and constitute a crucial patient safety outcome. Our purpose was to study the impact of medications on such early rehospitalizations. PATIENTS AND METHODS: This is a clinical, prospective, observational study on rehospitalizations within 30 days after an acute hospital episode for frail patients over the age of 75 years. To identify adverse drug reactions (ADRs), underuse of evidence-based treatment and avoidability of rehospitalizations, the Naranjo score, the Hallas criteria and clinical judgment were used. RESULTS: Of 390 evaluable patients, 96 (24.6%) were rehospitalized. The most frequent symptoms and conditions were dyspnea (n = 25) and worsened general condition (n = 18). The most frequent diagnoses were heart failure (n = 17) and pneumonia/acute bronchitis (n = 13). By logistic regression analysis, independent risk predictors for rehospitalization were heart failure (odds ratio [OR] = 1.8; 95% CI = 1.1-3.1) and anemia (OR = 2.3; 95% CI = 1.3-4.0). The number of rehospitalizations due to probable ADRs was 13, of which two were assessed as avoidable. The number of rehospitalizations probably due to underuse of evidence based drug treatment was 19, all of which were assessed as avoidable. The number of rehospitalizations not due to ADRs or underuse of evidence-based drug treatment was 64, of which none was assessed as avoidable. CONCLUSION: One out of four frail elderly patients discharged from hospital was rehospitalized within 1 month. Although ADRs constituted an important cause of rehospitalization, underuse of evidence-based drug treatment might be an even more frequent cause. Potentially avoidable rehospitalizations were more frequently associated with underuse of evidence-based drug treatment than with ADRs. Efforts to avoid ADRs in frail elderly patients must be balanced and combined with evidence-based drug therapy, which can benefit these patients. PMID- 28860863 TI - Premenstrual syndrome (PMS) among high school students. AB - BACKGROUND: Premenstrual syndrome (PMS) is a common health problem among adolescents. OBJECTIVE: To assess the prevalence of PMS in Thai high school students. MATERIALS AND METHODS: This was a prospective study conducted among menstruating high school students in Khon Kaen, Thailand, from September to December, 2015. Participants were asked to prospectively complete an anonymous questionnaire, which included information about demographic data, menstrual patterns, and symptoms to be recorded on a daily calendar of premenstrual experiences according to the diagnostic criteria proposed by the American College of Obstetricians and Gynecologists. All of the data were prospectively recorded for 90 consecutive days. RESULTS: Of the 399 participants, 289 (72.4%) completed the self-report questionnaire. Eighty-six participants (29.8%; 95% CI, 24.5% 35.4%) reported having PMS. The most common somatic and affective symptoms among participants with PMS were breast tenderness (74.4%) and angry outbursts (97.7%). There were significant differences between the PMS and non-PMS groups, and PMS was associated with various problems related to educational activities, including lack of concentration and motivation, poor individual work performance, poor collaborative work performance, and low scores. However, there were no significant differences regarding interpersonal relationships between the PMS and non-PMS groups. CONCLUSIONS: PMS is a common menstrual disorder among Thai high school students. The most common symptoms reported in this study were angry outbursts and breast tenderness. PMID- 28860864 TI - Vaginal rejuvenation: current perspectives. AB - Female genital cosmetic surgery includes several procedures aimed at reaching better female genital appearance and/or improved sexual functioning. Among these procedures, vaginal rejuvenation is considered as one of the most controversial genital cosmetic surgical interventions and involves a range of surgical procedures performed by gynecologists or plastic surgeons to decrease the average diameter of the vagina, mainly for sexual reasons. In this narrative review, vaginal rejuvenation outcomes are examined in order to clarify the current scenario of the different vaginal rejuvenation techniques, as well as their effectiveness and associated complications. Psychological and ethical issues linked to these procedures are also addressed. PMID- 28860865 TI - Advanced maternal age: ethical and medical considerations for assisted reproductive technology. AB - OBJECTIVES: This review explores the ethical and medical challenges faced by women of advanced maternal age who decide to have children. Assisted reproductive technologies (ARTs) make post-menopausal pregnancy physiologically plausible, however, one must consider the associated physical, psychological, and sociological factors involved. METHODS: A quasi-systematic review was conducted in PubMed and Ovid using the key terms post-menopause, pregnancy + MeSH terms [donations, hormone replacement therapy, assisted reproductive technologies, embryo donation, donor artificial insemination, cryopreservation]. Overall, 28 papers encompassing two major themes (ethical and medical) were included in the review. CONCLUSION: There are significant ethical considerations and medical (maternal and fetal) complications related to pregnancy in peri- and post menopausal women. When examining the ethical and sociological perspective, the literature portrays an overall positive attitude toward pregnancy in advanced maternal age. With respect to the medical complications, the general consensus in the evaluated studies suggests that there is greater risk of complication for spontaneous pregnancy when the mother is older (eg, >35 years old). This risk can be mitigated by careful medical screening of the mother and the use of ARTs in healthy women. In these instances, a woman of advanced maternal age who is otherwise healthy can carry a pregnancy with a similar risk profile to that of her younger counterparts when using donated oocytes. PMID- 28860866 TI - Work, gender roles, and health: neglected mental health issues among female workers in the ready-made garment industry in Bangladesh. AB - BACKGROUND: Traditionally, women in Bangladesh stayed at home in their role as daughter, wife, or mother. In the 1980s, economic reforms created a job market for poor, uneducated rural women in the ready-made garment industry, mostly located in urban areas. This increased participation in paid work has changed the gender roles of these women. Women's earnings support their family, but they are also separated from their children, with impacts on their mental health and well being. This study explores the lived experience of women in Bangladesh working in the ready-made garment industry as they strive to be mothers and family providers, often in high-stress conditions. METHODS: The study was conducted in two industrial areas of Dhaka over 8 months. Data collection included a literature review, 20 in-depth interviews with married female garment workers, and 14 key-informant interviews with officials from the Ministry of Labour and Employment, health-service providers within the garment factories, factory managers, and representatives of the Bangladesh Garment Manufacturers and Exporters Association. The data collected were analyzed thematically. RESULTS: Poverty was a key motivating factor for female migrant workers to move from rural areas. Their children stay in their village with their grandparents, because of their mothers' work conditions and the lack of childcare. The women reported stress, anxiety, restlessness, and thoughts of suicide, due to the double burden of work and separation from their children and family support. Further, they cannot easily access government hospital services due to their long work hours, and the limited medical services provided in the workplace do not meet their needs. CONCLUSION: In order to improve the health and well-being of female garment workers, steps should be taken to develop health interventions to meet the needs of this important group of workers who are contributing significantly to the economic development of the country. PMID- 28860867 TI - Doege-Potter Syndrome, cause of nonislet cell tumor hypoglycemia: the first case report from Nepal. AB - Doege-Potter syndrome (DPS), a paraneoplastic syndrome, presents as a hypoinsulinemic hypoglycemia from the ectopic secretion of insulin-like growth factor II from a solitary fibrous tumor which may be intrapleural or extrapleural in origin. We report a case of severe hypoglycemia in a 70-year old female initially admitted for resection of left sided solitary fibrous tumor of pleura. Investigation revealed true hypoglycemia, and DPS was diagnosed. The tumor was completely resected, after which no further hypoglycemic episodes were seen in 2 years follow-up. This is the first case of solitary fibrous tumor of pleura with DPS reported from Nepal. PMID- 28860868 TI - Feline-transmitted Staphylococcal hyicus endophthalmitis after clear lens extraction: a case report. AB - BACKGROUND: Postoperative endophthalmitis is a dreaded postsurgery complication which may lead to legal blindness. In addition to typical risk factors, some minor episodes may also lead to the occurrence of endophthalmitis. The purpose of the current study was to report a case of acute postoperative endophthalmitis caused by Staphylococcus hyicus in a patient with a contact history of felines. CASE PRESENTATION: A 58-year-old Taiwanese female who had a history of contact with felines due to her occupation had received clear lens extraction surgery of the left eye on July 10, 2015. One day after the surgery, the best-corrected visual acuity (BCVA) of the left eye was 20/40, which rapidly deteriorated to light perception with hypopyon formation. She was admitted for acute postoperative endophthalmitis and received antibiotic therapy with topical levofloxacin instillation and intravitreal vancomycin plus amikacin injection. Trans pars plana vitrectomy (TPPV) was then performed 1 day after admission. The specimen obtained from the vitreous and anterior chambers yielded the growth of S. hyicus. The patient was discharged with BCVA measured by counting fingers. Another TPPV was arranged for the persistent vitreous opacity on October 20, 2015, and the BCVA recovered to 20/32 at the last visit. CONCLUSION: To our knowledge, this is the first case of acute postoperative endophthalmitis caused by S. hyicus due to feline contact. Unusual pathogens in the environment and personal hygiene status should be validated preoperatively to prevent the development of postoperative endophthalmitis. PMID- 28860869 TI - Lingual abscess: a case report. AB - BACKGROUND: Lingual abscesses have become extremely rare since the discovery of antibiotics, despite the relatively frequent exposure of tongue to bite trauma during mastication and seizures. It is a potentially life-threatening clinical entity. Even though there were some case reports on tongue abscess from overseas, none of them were reported from Africa, particularly from Ethiopia. CASE PRESENTATION: A 36-year-old male patient with severe, continuous pain and swelling of tongue for 6 weeks was presented to Goba Referral Hospital. The swelling was 2 cm by 1 cm, located on posterior central tongue, and frank pus oozed from the center of the swelling. He had associated dysphagia, odynophagia, and speech difficulty. He had no previous personal and family history of similar illness and tonsillitis. Gram staining revealed the presence of Gram-positive cocci in clusters. Pyogenic lingual abscess was the diagnosis. Treatment included incision and drainage with the administration of systemic antibiotics, which covered both aerobic and anaerobic organisms, and anti-pain drugs. The condition did not relapse in 6 months of follow-up. CONCLUSION: Lingual abscess should be considered in patients presenting with tongue swelling, dysphagia, odynophagia, and speech difficulty. Since lingual abscess that occurs on the posterior part of the tongue has diagnostic difficulty, professionals in rural setup where diagnostic resources (such as ultrasound and magnetic resonance imaging) are scarce should be careful not to misdiagnose it. Incision and drainage with the administration of systemic antibiotics and anti-pain drugs is an effective treatment option for lingual abscess. PMID- 28860870 TI - Early treatment failure in concurrent dengue and mixed malaria species infection with suspected resistance to artemisinin combination therapy from a tertiary care center in Delhi: a case report. AB - BACKGROUND: Concurrent dengue and mixed malaria infections in a single patient present with overlapping clinical manifestations which pose a diagnostic challenge and management dilemma in areas of common endemicities. METHODS: We report a case of a young male who tested positive for both Plasmodium vivax and Plasmodium falciparum along with dengue infection. He showed signs of early treatment failure to artemisinin combination therapy (artesunate with sulfadoxine+pyrimethamine). Molecular analysis for the drug resistance genes viz: chloroquine resistance (pfcrt), multidrug resistance (pfmdr-1), sulfadoxine (pfdhps), pyrimethamine (pfdhfr), and artemisinin resistance (keltch 13) was performed. RESULTS: A rise in parasitemia from <2% to 5% was observed after 3 days of treatment. Mutations in pfcrt, pfmdr-1, pfdhfr, and pfdhps genes were detected as a possible cause of treatment failure. CONCLUSION: Increased severity, overlapping symptoms, and suspected resistance to treatment warrants a multidimensional diagnostic approach and diligent therapeutic monitoring. PMID- 28860871 TI - First-in-man intraglandular implantation of stromal vascular fraction and adipose derived stem cells plus platelet-rich plasma in irradiation-induced gland damage: a case study. AB - BACKGROUND: Stromal vascular fraction (SVF) is a mixture of cells which can be isolated from a mini-lipoaspirate of fat tissue. Platelet-rich plasma (PRP) is a mixture of growth factors and other nutrients which can be obtained from peripheral blood. Adipose-derived stem/stromal cells (ADSCs) can be isolated from fat tissue and expanded in culture. The SVF includes a variety of different cells such as ADSCs, pericytes, endothelial/progenitor cells, and a mix of different growth factors. The adipocytes (fat cells) can be removed via centrifugation. Here, we describe the rationale and, to our knowledge, the first clinical implementation of SVF and PRP followed by repeat dosing of culture-expanded ADSCs into a patient with severe xerostomia postirradiation. METHODS: Approximately 120 mLs of adipose tissue was removed via mini-lipoaspirate procedure under local anesthetic. The SVF was prepared from half of the fat and resuspended in PRP. The mixture was delivered via ultrasound directly into the submandibular and parotid glands on both the right and left sides. The remaining 60 mLs of fat was processed to culture-expand ADSCs. The patient received seven follow-up injections of the ADSCs plus PRP at 5, 8, 16, 18, 23, 28, and 31 months postliposuction. The subject was monitored over a period of 31 months for safety (adverse events), glandular size via ultrasound and saliva production. RESULTS: Throughout the 31-month monitoring period, no safety events such as infection or severe adverse events were reported. The patient demonstrated an increase in gland size as measured by ultrasound which corresponded to increased saliva production. CONCLUSION: Overall, the patient reported improved quality of life and willingness to continue treatments. The strong safety profile and preliminary efficacy results warrant larger studies to determine if this is a feasible treatment plan for patients postradiation. PMID- 28860872 TI - Multiple retinal hemorrhages in bilateral congenital venous tortuosity. AB - We present a case of a previously healthy 52-year-old woman with acute onset of scotomas in both eyes. It was associated with headache and vomiting for the past 1 week after a cold. The best-corrected visual acuity was 20/20 in both eyes. The examination of bilateral fundus revealed a venous tortuosity and mild dilatation in the posterior pole, with pre- and intraretinal hemorrhages. However, vasculatures were normally straight in the mid-peripheral and peripheral retina of both eyes. Hemorrhages showed complete resolution without treatment. There was no change in the appearance and shape of the vasculature. Ophthalmologists should be aware of congenital venous tortuosity as a possible cause of retinal hemorrhages. PMID- 28860873 TI - Effects of intravenous ketamine in a patient with post-treatment Lyme disease syndrome. AB - Post-treatment Lyme disease syndrome (PTLDS) is a pain disorder for which there remains no gold standard treatment option. Here, we report a case of PTLDS in a female patient whose pain was refractory to treatment options such as radiofrequency ablation, vitamin infusion therapy, opioid analgesics, and other pharmacotherapies. The patient commenced an experimental intravenous ketamine infusion therapy at the Florida Spine Institute (Clearwater, FL, USA) and achieved relief from her chronic pain, an improved quality of life, reduced depression and suicidal ideation, and reduced opioid consumption. PMID- 28860874 TI - Can machine learning complement traditional medical device surveillance? A case study of dual-chamber implantable cardioverter-defibrillators. AB - BACKGROUND: Machine learning methods may complement traditional analytic methods for medical device surveillance. METHODS AND RESULTS: Using data from the National Cardiovascular Data Registry for implantable cardioverter-defibrillators (ICDs) linked to Medicare administrative claims for longitudinal follow-up, we applied three statistical approaches to safety-signal detection for commonly used dual-chamber ICDs that used two propensity score (PS) models: one specified by subject-matter experts (PS-SME), and the other one by machine learning-based selection (PS-ML). The first approach used PS-SME and cumulative incidence (time to-event), the second approach used PS-SME and cumulative risk (Data Extraction and Longitudinal Trend Analysis [DELTA]), and the third approach used PS-ML and cumulative risk (embedded feature selection). Safety-signal surveillance was conducted for eleven dual-chamber ICD models implanted at least 2,000 times over 3 years. Between 2006 and 2010, there were 71,948 Medicare fee-for-service beneficiaries who received dual-chamber ICDs. Cumulative device-specific unadjusted 3-year event rates varied for three surveyed safety signals: death from any cause, 12.8%-20.9%; nonfatal ICD-related adverse events, 19.3%-26.3%; and death from any cause or nonfatal ICD-related adverse event, 27.1%-37.6%. Agreement among safety signals detected/not detected between the time-to-event and DELTA approaches was 90.9% (360 of 396, k=0.068), between the time-to-event and embedded feature-selection approaches was 91.7% (363 of 396, k=-0.028), and between the DELTA and embedded feature selection approaches was 88.1% (349 of 396, k=-0.042). CONCLUSION: Three statistical approaches, including one machine learning method, identified important safety signals, but without exact agreement. Ensemble methods may be needed to detect all safety signals for further evaluation during medical device surveillance. PMID- 28860875 TI - Extraglottic airway devices: technology update. AB - Extraglottic airway devices (EADs) have revolutionized the field of airway management. The invention of the laryngeal mask airway was a game changer, and since then, there have been several innovations to improve the EADs in design, functionality, safety and construction material. These have ranged from changes in the shape of the mask, number of cuffs and material used, like rubber, polyvinylchloride and latex. Phthalates, which were added to the construction material in order to increase device flexibility, were later omitted when this chemical was found to have serious adverse reproductive outcomes. The various designs brought out by numerous companies manufacturing EADs resulted in the addition of several devices to the airway market. These airway devices were put to use, many of them with inadequate or no evidence base regarding their efficacy and safety. To reduce the possibility of compromising the safety of the patient, the Difficult Airway Society (DAS) formed the Airway Device Evaluation Project Team (ADEPT) to strengthen the evidence base for airway equipment and vet the new extraglottic devices. A preuse careful analysis of the design and structure may help in better understanding of the functionality of a particular device. In the meantime, the search for the ideal EAD continues. PMID- 28860876 TI - Effect of age and performance on pacing of marathon runners. AB - Pacing strategies in marathon runners have previously been examined, especially with regard to age and performance level separately. However, less information about the age * performance interaction on pacing in age-group runners exists. The aim of the present study was to examine whether runners with similar race time and at different age differ for pacing. Data (women, n=117,595; men, n=180,487) from the "New York City Marathon" between 2006 and 2016 were analyzed. A between-within subjects analysis of variance showed a large main effect of split on race speed (p<0.001, eta2=0.538) with the fastest speed in the 5-10 km split and the slowest in the 35-40 km. A small sex * split interaction on race speed was found (p<0.001, eta2=0.035) with men showing larger increase in speed at 5 km and women at 25 km and 40 km (end spurt). An age-group * performance group interaction on Deltaspeed was shown for both sexes at 5 km, 10 km, 15 km, 20 km, 25 km, 30 km, 35 km, and 40 km (p<0.001, 0.001<=eta2<=0.004), where athletes in older age-groups presented a relatively more even pace compared with athletes in younger age-groups, a trend that was more remarkable in the relatively slow performance groups. So far, the present study is the first one to observe an age * performance interaction on pacing; ie, older runners pace differently (smaller changes) than younger runners with similar race time. These findings are of great practical interest for coaches working with marathon runners of different age, but similar race time. PMID- 28860877 TI - Maintenance of the paraspinal muscles may protect against radiographic knee osteoarthritis. AB - BACKGROUND: Knee osteoarthritis (OA) is an increasing health problem worldwide. So far, only obesity and quadriceps weakness are identified as modifiable risk factors for knee OA. Core muscle strengthening is becoming increasingly popular among older adults because of its ability to enhance the activities of daily living during old age. This study investigated the associations of the size and quality of the abdominal trunk muscles with radiographic knee osteoarthritis (RKOA). METHODS: From 2012 to 2016, data were collected from 146 males and 135 females (age 63.9+/-13.4 years, BMI 23.2+/-3.8 kg/m2) at annual musculoskeletal examinations, including knee radiographs and body composition analyses, by dual energy X-ray absorptiometry. Cross-sectional areas of abdominal trunk muscles were measured using a single-slice computed tomography scan image obtained at the level of the umbilicus. RESULTS: The prevalence of RKOA was 21.2% in males and 28.1% in females. Compared to subjects without RKOA, subjects with RKOA were ~6 years older and had smaller paraspinal muscle (38.4+/-8.7 vs 33.1+/-10.1 cm2, p<0.01 in males; 24.1+/-7.1 vs 20.7+/-7.5 cm2, p<0.05 in females). In contrast, there was no decrease in appendicular or total lean mass, and only in females, BMI and total fat mass (FM) were higher in subjects with RKOA (21.5+/-3.5 vs 24.5+/-4.4 kg/m2, 16.7+/-7.0 vs 20.5+/-7.7 kg, respectively, both p<0.01). After adjusting for age and sex, smaller cross-sectional area/lower attenuation value of the paraspinal muscles was associated with RKOA (both p<0.05), while greater appendicular or total lean mass as well as greater FM was associated with RKOA. The size and quality of the paraspinal muscles were not associated with knee pain or habitual exercise. CONCLUSION: Small, poor-quality paraspinal muscles may be linked to a higher risk of RKOA, but appendicular or total lean mass was not a good predictor of RKOA. PMID- 28860878 TI - Ozonated autohemotherapy modulates the serum levels of inflammatory cytokines in gouty patients. AB - OBJECTIVES: Ozonated autohemotherapy (O3-AHT) has been used to effectively treat gout, but the underlying therapeutic mechanisms remain unknown. In this study, as an initial effort to understand the therapeutic mechanisms of O3-AHT, we aim to examine the effect of O3-AHT on serum inflammatory cytokine levels in gouty patients. PATIENTS AND METHODS: Three groups of patients and healthy subjects were recruited, including the gouty (n=10), hyperuricemia (n=10), and healthy control (n=11) groups. Cytometric bead array was applied to examine 12 cytokines before (T0), during (T1), and after (T2) therapies. RESULTS: Three cytokines, IL 8, IL-12, and MCP-1, were detectable in all participants. Before O3-AHT, the average serum levels of IL-8 and MCP-1 were higher in the gout group than in the hyperuricemia and healthy control groups, confirming the inflammation status in gouty patients. After the 5th course of O3-AHT (T1), IL-8 level was significantly increased compared to that at T0. IL-12 level was also raised at T1, although the difference did not reach statistical significance. After completing the therapy, both IL-8 and IL-12 levels decreased to levels lower than those at T0. MCP-1 level remained essentially unchanged during and after treatment. CONCLUSION: Our results indicate that O3-AHT induces a significant change in serum cytokine levels, suggesting that modulating the inflammatory process is one of the therapeutic mechanisms underlying O3-AHT. In addition, the sensitive response of serum IL-8 and IL-12 levels to O3-AHT suggests that these cytokines may be developed as biomarkers to evaluate the therapeutic effect of O3-AHT in gouty patients. PMID- 28860879 TI - Association of perfectionistic and dependent dysfunctional attitudes with subthreshold depression. AB - BACKGROUND: Dysfunctional attitudes are beliefs and attitudes that induce negative thoughts about the self, others, and the future, leading to depression. Perfectionistic dysfunctional attitudes are beliefs and attitudes about achievement and excessive fear of failure, while dependent dysfunctional attitudes are beliefs and attitudes about dependency on, and approval from, others. Subthreshold depression refers to a depressive state that does not meet the diagnostic criteria for a major depressive episode. This study examined whether the difference in perfectionistic dysfunctional attitudes between college students with subthreshold depression and those with no depression would be greater than that of dependent dysfunctional attitudes. METHODS: Participants were defined as having subthreshold depression if they scored 16 or higher on the Japanese version of the Center for Epidemiologic Studies Depression Scale but did not meet the diagnostic criteria for a major depressive episode, as assessed by the major depressive episode module of the Mini-International Neuropsychiatric Interview. The participants included 21 male and 87 female college students, with a mean age of 20.3 years. Dysfunctional attitudes were evaluated with the Japanese version of the 24-item Dysfunctional Attitude Scale. RESULTS: Of the 108 students, 34 had subthreshold depression while 74 had no depression. The magnitudes of the differences in perfectionistic and dependent dysfunctional attitudes between the students with subthreshold depression and those with no depression were large (Cohen's d=0.83) and small (Cohen's d=0.25). CONCLUSION: The results of this study provide the first evidence that the difference in perfectionistic dysfunctional attitudes between college students with subthreshold depression and those with no depression is greater than that of dependent dysfunctional attitudes. PMID- 28860880 TI - Rock climbing and acute emotion regulation in patients with major depressive disorder in the context of a psychological inpatient treatment: a controlled pilot trial. AB - BACKGROUND: Major depressive disorder is characterized by deficits in emotion regulation. This study examined associations between rock climbing and acute emotion regulating effects in patients with major depression. PATIENTS AND METHODS: In a nonrandomized, controlled study, 40 major depressive disorder inpatients were assigned to either a climbing session (n=20) or a relaxation session (n=20). Positive and negative affect, depressiveness, and coping emotions were assessed immediately before and after the session. RESULTS: Mixed analyses of variance and covariance revealed significant time * group interaction effects for all assessed outcomes (p<=0.012): positive affect and coping emotions significantly increased and negative affect and depressiveness significantly decreased after the climbing session (1.04<= Cohen's d <=1.30), in contrast to a relaxation session (0.16<= Cohen's d <=0.36). CONCLUSION: The results show that rock climbing is associated with acute emotion regulatory effects. These findings have to be replicated with a randomized design, and future research should pay attention to possible mechanisms of rock climbing in regard to emotion regulation. PMID- 28860881 TI - Aviation's Normal Operations Safety Audit: a safety management and educational tool for health care? Results of a small-scale trial. AB - BACKGROUND: A National Health Service (NHS) contingent liability for medical error claims of over L26 billion. OBJECTIVES: To evaluate the safety management and educational benefits of adapting aviation's Normal Operations Safety Audit (NOSA) to health care. METHODS: In vivo research, a NOSA was performed by medical students at an English NHS Trust. After receiving training from the author, the students spent 6 days gathering data under his supervision. RESULTS: The data revealed a threat-rich environment, where errors - some consequential - were made (359 threats and 86 errors were recorded over 2 weeks). The students claimed that the exercise improved their observational, investigative, communication, teamworking and other nontechnical skills. CONCLUSION: NOSA is potentially an effective safety management and educational tool for health care. It is suggested that 1) the UK General Medical Council mandates that all medical students perform a NOSA in fulfillment of their degree; 2) the participating NHS Trusts be encouraged to act on students' findings; and 3) the UK Department of Health adopts NOSA as a cornerstone risk assessment and management tool. PMID- 28860882 TI - Health promotion, psychological distress, and disease prevention in the workplace: a cross-sectional study of Italian adults. AB - BACKGROUND: Job insecurity resulting from new types of employment contracts, together with organizational dynamics such as restructuring and internationalization, is emerging as an important source of organizational and individual stress, often transforming the workplace into a hostile and, above all, extremely demanding context from a psychological point of view. MATERIALS AND METHODS: The aim of this study was to identify the possible relationships between individual and organizational dimensions of work (such as engagement, autonomy, personal and collective efficacy at work, and satisfaction) and their impact on stress levels. The survey involved 120 Italian workers: 72 females (60%) and 48 males (40%), with a mean age of 41.8 years +/-7.31 years. The groups of participants were selected on the basis of employment contract type (traditional or atypical) to emphasize potential differences. The study was conducted using a set of self-administered questionnaires, including the Psychological Stress Measure and Utrecht Work Engagement Scale. RESULTS: The data show that personal and collective efficacy at work correlates negatively with stress, which in turn correlates negatively with engagement and satisfaction. The results support the hypothesis that job insecurity could be considered a strong predictor of poor health. CONCLUSION: The study should be considered as a preliminary assessment prior to studies of broader interventions to increase quality of life. PMID- 28860883 TI - Assessing narcolepsy with cataplexy in children and adolescents: development of a cataplexy diary and the ESS-CHAD. AB - OBJECTIVE: The aim of this study was to qualitatively evaluate concepts for incorporation into a daily diary to capture cataplexy frequency and to assess the content validity of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) in pediatric patients with narcolepsy. PATIENTS AND METHODS: Face-to face concept elicitation and cognitive interviews were conducted with children (7 9 years; n=13) and adolescents (10-17 years; n=16) who have narcolepsy with cataplexy, and their parents/caregivers. RESULTS: Similarities and differences were noted between narcolepsy concepts described by children and their parents/caregivers, suggesting some different but complementary perspectives; parents may not recognize cataplexy symptoms/triggers as well as children, but parents have greater recognition of the circumstances of falling asleep. Cataplexy diary modifications included changes in definitions and examples of cataplexy, using child-friendly terminology, adding a quantitative question to determine daily frequency, and standardizing the questionnaire for evening administration with self-completion by the child. Modifications were made to ESS CHAD for child-friendly wording and to ensure that items reflect activities (eating, watching TV/video) and environments (school, bus/car transport) in which children are likely to participate. Two ESS-CHAD versions were proposed: one with a 1-month recall period, for general use, and the other with a recall period of "since your last study visit," for research, which could be shorter or longer than 1 month (as short as 1 week). CONCLUSION: The cataplexy diary and ESS-CHAD were modified for the assessment of children and adolescents. Further psychometric validation is recommended. These measures are being used in a Phase III, placebo-controlled clinical trial of sodium oxybate in children and adolescents with narcolepsy. PMID- 28860884 TI - Chronic obstructive pulmonary disease in patients with lung cancer: prevalence, impact and management challenges. AB - Chronic obstructive pulmonary disease (COPD) and lung cancer share a common etiological factor (cigarette smoking) and usually coexist in everyday clinical practice. The prevalence of COPD among newly diagnosed patients with lung cancer sometimes exceeds 50%. COPD is an independent risk factor (2-4 times higher than non-COPD subjects) for lung cancer development. The presence of emphysema in addition to other factors (e.g., smoking history, age) could be incorporated into risk scores in order to define the most appropriate target group for lung cancer screening using low-dose computed tomography. Clinical management of patients with coexistence of COPD and lung cancer requires a multidisciplinary oncology board that includes a pulmonologist. Detailed evaluation (lung function tests, cardiopulmonary exercise test) and management (inhaled drugs, smoking cessation, pulmonary rehabilitation) of COPD should be taken into account for lung cancer treatment (surgical approach, radiotherapy). PMID- 28860885 TI - Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy. AB - The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of the EGFR gene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-type EGFR. Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I-III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome of EGFR-mutated NSCLC patients. PMID- 28860886 TI - Clinical staging of malignant pleural mesothelioma: current perspectives. AB - Malignant pleural mesothelioma (MPM) is a disease with limited therapeutic options, the management of which is still controversial. Diagnosis is usually made by thoracoscopy, which allows multiple biopsies with histological subtyping and is indicated for staging purposes in surgical candidates. The recommended and recently updated classification for clinical use is the TNM staging system established by the International Mesothelioma Interest Group and the International Association for the Study of Lung Cancer, which is based mainly on surgical and pathological variables, as well as on cross-sectional imaging. Contrast-enhanced computed tomography is the primary imaging procedure. Currently, the most used measurement system for MPM is the modified Response Evaluation Criteria in Solid Tumors (RECIST) method, which is based on unidimensional measurements of tumor thickness perpendicular to the chest wall or mediastinum. Magnetic resonance imaging and functional imaging with 18F-fluoro-2 deoxy-D-glucose positron-emission tomography can provide additional staging information in selected cases, although the usefulness of this method is limited in patients undergoing pleurodesis. Molecular reclassification of MPM and gene expression or miRNA prognostic models have the potential to improve prognostication and patient selection for a proper treatment algorithm; however, they await prospective validation to be introduced in clinical practice. PMID- 28860888 TI - Constant training in direct ophthalmoscopy. PMID- 28860887 TI - New developments in the management of relapsed/refractory multiple myeloma - the role of ixazomib. AB - Ixazomib is the first oral proteasome inhibitor to be approved, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was on the basis of results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival with the all-oral combination of ixazomib plus lenalidomide-dexamethasone versus lenalidomide-dexamethasone alone (median: 20.6 vs 14.7 months; hazard ratio: 0.74, p=0.012; median follow-up 14.7 months). The addition of ixazomib to the lenalidomide-dexamethasone regimen was associated with limited additional toxicity and had no adverse impact on patient-reported quality of life. Common grade >=3 adverse events with ixazomib include gastrointestinal adverse events, rash, and thrombocytopenia. Here, we review the efficacy, safety, pharmacokinetics, and patient-reported quality of life data seen with ixazomib, and discuss the role of this oral agent in the treatment of patients with relapsed/refractory multiple myeloma, including in patients with high-risk cytogenetic abnormalities and those with multiple prior therapies. PMID- 28860889 TI - Mindfulness, burnout, and effects on performance evaluations in internal medicine residents. AB - PURPOSE: Burnout has been documented at high levels in medical residents with negative effects on performance. Some dispositional qualities, like mindfulness, may protect against burnout. The purpose of the present study was to assess burnout prevalence among internal medicine residents at a single institution, examine the relationship between mindfulness and burnout, and provide preliminary findings on the relation between burnout and performance evaluations in internal medicine residents. METHODS: Residents (n = 38) completed validated measures of burnout at three time points separated by 2 months and a validated measure of dispositional mindfulness at baseline. Program director end-of-year performance evaluations were also obtained on 22 milestones used to evaluate internal medicine resident performance; notably, these milestones have not yet been validated for research purposes; therefore, the investigation here is exploratory. RESULTS: Overall, 71.1% (n = 27) of the residents met criteria for burnout during the study. Lower scores on the "acting with awareness" facet of dispositional mindfulness significantly predicted meeting burnout criteria chi2(5) = 11.88, p = 0.04. Lastly, meeting burnout criteria significantly predicted performance on three of the performance milestones, with positive effects on milestones from the "system-based practices" and "professionalism" domains and negative effects on a milestone from the "patient care" domain. CONCLUSION: Burnout rates were high in this sample of internal medicine residents and rates were consistent with other reports of burnout during medical residency. Dispositional mindfulness was supported as a protective factor against burnout. Importantly, results from the exploratory investigation of the relationship between burnout and resident evaluations suggested that burnout may improve performance on some domains of resident evaluations while compromising performance on other domains. Implications and directions for future research are discussed. PMID- 28860890 TI - Views on an active learning curriculum improving knowledge. PMID- 28860891 TI - Advances in medical education and practice: role of massive open online courses. AB - Massive open online courses (MOOCs) are increasingly available in the area of health and medicine. These MOOCs are offered through various commercial and noncommercial online platforms. When offered through reputable institutions, they can provide valuable access to reliable information without the constraints of time, geographical location, or level of education. Most current courses appear introductory in nature. In its drive for quality health care, the National Academy of Medicine has prioritized a focus on known chronic care conditions. Many of these conditions are shared internationally. Among its initiatives, the academy encourages consumer and professional groups, patients, clinicians, health care organizations, and universities to work together to identify evidence-based care processes consistent with best practices, organize major prevention programs to target key associated health risk behaviors, and develop systems to measure and evaluate improvements in the provision of patient- and family-centered health care. Carefully designed and collaboratively developed MOOCs would appear a valuable resource to contribute to these initiatives. Such MOOCs can, 1) increase the health literacy of the public with regard to the prevention and treatment of known chronic care conditions, 2) provide ready access to continuing professional, and interprofessional, education, and 3) explore innovative teaching models for student learning focused on patient- and family-centered care. MOOCs would also appear helpful to facilitate effective communication among international communities of patients and clinicians, including student clinicians, with shared interests. Further, the accumulation of MOOC data through large-scale measurement and analysis, obtained nationally and internationally, has the potential to assist in greater understanding of the risk for diseases and their prevention, with this translating into medical education, and authentic, patient- and family-centered methods for student learning. This paper explores these issues. PMID- 28860892 TI - Patterns of health care utilization and cost before and after opioid overdose: findings from 10-year longitudinal health plan claims data. AB - OBJECTIVE: To describe the longitudinal pattern of health care utilization and cost of care before and after opioid overdose (OD) over a 10-year period using health plan claims data. METHODS: Patients who had experienced opioid ODs between April 2005 and March 2015 were identified from Geisinger Health System's electronic health records. Among these patients, a subgroup of patients who were Geisinger Health Plan (GHP) members at any point between January 2006 and December 2015 were also identified. From the corresponding GHP claims data, their all-cause health care utilization (inpatient admissions, emergency department [ED] visits, and physician office visits) and total medical costs, excluding prescription medication cost, were obtained. Per-member-per-month estimates for each month before and after the index date of opioid OD were calculated, adjusting for age, gender, plan type, year, and comorbidity via multivariate regression models. RESULTS: A total of 942 opioid OD patients with an average GHP enrollment period of 41.4 months were identified. ED visit rates rose rapidly starting around 19-24 months prior to the opioid OD date. Acute inpatient admission rates and total medical cost also rose rapidly starting around 12 months prior. After the OD date, the utilization rates and cost declined but tended to remain above those of the pre-OD period. CONCLUSION: Opioid OD is preceded by sharp increases in utilization of acute care and cost well before the actual OD. These findings therefore suggest that early signals of OD may be detected from patterns of acute care utilization, particularly the ED visits. PMID- 28860893 TI - Calcification Remodeling Index Characterized by Cardiac CT as a Novel Parameter to Predict the Use of Rotational Atherectomy for Coronary Intervention of Lesions with Moderate to Severe Calcification. AB - OBJECTIVE: To assess the feasibility of calcification characterization by coronary computed tomography angiography (CCTA) to predict the use of rotational atherectomy (RA) for coronary intervention of lesions with moderate to severe calcification. MATERIALS AND METHODS: Patients with calcified lesions treated by percutaneous coronary intervention (PCI) who underwent both CCTA and invasive coronary angiography were retrospectively included in this study. Calcification remodeling index was calculated as the ratio of the smallest vessel cross sectional area of the lesion to the proximal reference luminal area. Other parameters such as calcium volume, regional Agatston score, calcification length, and involved calcium arc quadrant were also recorded. RESULTS: A total of 223 patients with 241 calcified lesions were finally included. Lesions with RA tended to have larger calcium volume, higher regional Agatston score, more involved calcium arc quadrants, and significantly smaller calcification remodeling index than lesions without RA. Receiver operating characteristic curve analysis revealed that the best cutoff value of calcification remodeling index was 0.84 (area under curve = 0.847, p < 0.001). Calcification remodeling index <= 0.84 was the strongest independent predictor (odds ratio: 251.47, p < 0.001) for using RA. CONCLUSION: Calcification remodeling index was significantly correlated with the incidence of using RA to aid PCI. Calcification remodeling index <= 0.84 was the strongest independent predictor for using RA prior to stent implantation. PMID- 28860894 TI - High-Pitch Coronary CT Angiography at 70 kVp Adopting a Protocol of Low Injection Speed and Low Volume of Contrast Medium. AB - OBJECTIVE: To evaluate the feasibility and image quality (IQ) of prospectively high-pitch coronary CT angiography (CCTA) with low contrast medium injection rate at 70 kVp. MATERIALS AND METHODS: One hundred and four patients with suspected coronary artery disease (body mass index < 26 kg/m2, sinus rhythm and heart rate < 70 beats/min) were prospectively enrolled and randomly divided into two groups. In group A and group B, 28 mL and 40 mL of 370 mgI/mL iodinated contrast media was administrated at a flow rate of 3.5 and 5 mL/s, respectively. CT values, noise, signal-to-noise ratio, contrast-to-noise ratio (CNR) of the proximal segments of coronary arteries and subjective IQ were evaluated. RESULTS: The CT values and noise in group A were significantly lower than those in group B (434 485 Hounsfield units [HU] vs. 772-851 HU, all p < 0.001; 17.8-22.3 vs. 23.3-26.4, all p < 0.005). The CNRs of the right coronary artery and left main artery showed no statistical difference between the two groups (42.1 +/- 13.8 vs. 36.8 +/- 16.0, p = 0.074; 38.7 +/- 10.6 vs. 38.1 +/- 17.0, p = 0.819). No statistical difference was observed between the two groups in IQ scores (3.04 +/- 0.75 vs. 3.0 +/- 0.79, p = 0.526) and diagnostic ratio (96.1% [50/52] vs. 94.2% [49/52], p = 0.647). CONCLUSION: Prospective high-pitch CCTA at 70 kVp with 28 mL of contrast media and injection rate of 3.5 mL/s could provide diagnostic IQ for normal-weight patients with heart rate of < 70 beats/min. PMID- 28860895 TI - A Review of the Use of Cardiac Computed Tomography for Evaluating the Mitral Valve before and after Mitral Valve Repair. AB - The role of cardiac computed tomography (CT) for evaluating the mitral valve (MV) has been limited since echocardiography is the main method of evaluation. However, recent advances in cardiac CT have enable detailed evaluation of the anatomy and geometry of the MV. We describe assessments of the anatomy and coaptation geometric parameters of normal MVs, and also review repair of diseased/damaged MV. We also discuss pre- and post-surgical imaging of MV pathology using cardiac CT and various CT images. We found that cardiac CT could be used as an alternative imaging modality to echocardiography for pre-operative MV evaluation and to predict clinical outcomes following repair. PMID- 28860896 TI - CT Features of Vasculitides Based on the 2012 International Chapel Hill Consensus Conference Revised Classification. AB - Vasculitis, characterized by inflammation of vessel walls, is comprised of heterogeneous clinicopathological entities, and thus poses a diagnostic challenge. The most widely used approach for classifying vasculitides is based on the International Chapel Hill Consensus Conference (CHCC) nomenclature system. Based on the recently revised CHCC 2012, we propose computed tomography (CT) features of vasculitides and a differential diagnosis based on location and morphological characteristics. Finally, vasculitis mimics should be differentiated, because erroneous application of immunosuppressive drugs on vasculitis mimics may be ineffective, even deteriorating. This article presents the utility of CT in the diagnosis and differential diagnosis of vasculitides. PMID- 28860897 TI - Percutaneous Dual-Switching Monopolar Radiofrequency Ablation Using a Separable Clustered Electrode: A Preliminary Study. AB - OBJECTIVE: To prospectively evaluate the safety and therapeutic effectiveness of dual-switching monopolar (DSM) radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC), and to retrospectively compare the results with those of single-switching monopolar (SSM) RFA in a historical control group. MATERIALS AND METHODS: This study was approved by the Institutional Review Board, with informed consent obtained from all patients. Fifty-two HCC patients who underwent DSM-RFA using a separable clustered electrode and dual-generators were prospectively enrolled. Technical parameters, complications, technical success, technical effectiveness, and local tumor progression (LTP) rates were evaluated by means of post-procedural and follow-up imaging. Thereafter, the outcome of DSM RFA was compared with those of 249 retrospectively included HCC patients treated with SSM-RFA. RESULTS: There were two major complications (3.8%, 2/52) including pleural and pericardial effusion in the DSM-RFA group. The DSM-RFA yielded a 100% technical success rate, a 98.1% technical effectiveness rate, and a 4.3% 2-year LTP rate. In a retrospective comparison between the two groups, DSM-RFA created significantly larger ablation volume (4.20 +/- 2.07 cm3/min vs. 3.03 +/- 1.99 cm3/min, p < 0.01), and delivered higher energy (1.43 +/- 0.37 kcal/min vs. 1.25 +/- 0.50 kcal/min, p < 0.01) per given time, than SSM-RFA. There was no significant difference in major procedure-related complications (3.8% vs. 4.4%) and technical effectiveness rate (98.1% vs. 96.4%) between the two groups (p = 1.00). In addition, the 2-year LTP rate of DSM-RFA and SSM-RFA were 4.3% and 10.1%, respectively (p = 0.15). CONCLUSION: DSM-RFA using a separable clustered electrode is safe and provides high local tumor control and good preliminary clinical outcome for small HCCs, which are at least comparable to those of SSM RFA. PMID- 28860898 TI - Human Epidermal Growth Factor Receptor 2 Expression in Unresectable Gastric Cancers: Relationship with CT Characteristics. AB - OBJECTIVE: To retrospectively analyze the qualitative CT features that correlate with human epidermal growth factor receptor 2 (HER2)-expression in pathologically proven gastric cancers. MATERIALS AND METHODS: A total of 181 patients with pathologically-proven unresectable gastric cancers with HER2-expression (HER2 positive [n = 32] and negative [n = 149]) were included. CT features of primary gastric and metastatic tumors were reviewed. The prevalence of each CT finding was compared in both groups. Thereafter, binary logistic regression determined the most significant differential CT features. Clinical outcomes were compared using Kaplan-Meier method. RESULTS: HER2-postive cancers showed lower clinical T stage (21.9% vs. 8.1%; p = 0.015), hyperattenuation on portal phase (62.5% vs. 30.9%; p = 0.003), and was more frequently metastasized to the liver (62.5% vs. 32.2%; p = 0.001), than HER2-negative cancers. On binary regression analysis, hyperattenuation of the tumor (odds ratio [OR], 4.68; p < 0.001) and hepatic metastasis (OR, 4.43; p = 0.001) were significant independent factors that predict HER2-positive cancers. Median survival of HER2-positive cancers (13.7 months) was significantly longer than HER2-negative cancers (9.6 months) (p = 0.035). CONCLUSION: HER2-positive gastric cancers show less-advanced T stage, hyperattenuation on the portal phase, and frequently metastasize to the liver, as compared to HER2-negative cancers. PMID- 28860899 TI - Photoacoustic Imaging for Differential Diagnosis of Benign Polyps versus Malignant Polyps of the Gallbladder: A Preliminary Study. AB - OBJECTIVE: To investigate the feasibility of ex vivo multispectral photoacoustic (PA) imaging in differentiating cholesterol versus neoplastic polyps, and benign versus malignant polyps, of the gallbladder. MATERIALS AND METHODS: A total of 38 surgically confirmed gallbladder polyps (24 cholesterol polyps, 4 adenomas, and 10 adenocarcinomas) from 38 patients were prospectively included in this study. The surgical specimens were set on a gel pad immersed in a saline-filled container. The PA intensities of polyps were then measured, using two separate wavelength intervals (421-647 nm and 692-917 nm). Mann-Whitney U test was performed for the comparison of normalized PA intensities between the cholesterol and neoplastic polyps, and between the benign and malignant polyps. Kruskal Wallis test was conducted for the comparison of normalized PA intensities among the cholesterol polyps, adenomas, and adenocarcinomas. RESULTS: A significant difference was observed in the normalized PA intensities between the cholesterol and neoplastic polyps at 459 nm (median, 1.00 vs. 0.73; p = 0.032). Comparing the benign and malignant polyps, there were significant differences in the normalized PA intensities at 765 nm (median, 0.67 vs. 0.78; p = 0.013), 787 nm (median, 0.65 vs. 0.77; p = 0.034), and 853 nm (median, 0.59 vs. 0.85; p = 0.028). The comparison of the normalized PA intensities among cholesterol polyps, adenomas, and adenocarcinomas demonstrated marginally significant differences at 765 nm (median, 0.67 vs. 0.66 vs. 0.78, respectively; p = 0.049). CONCLUSION: These preliminary results indicate that benign versus malignant gallbladder polyps might exhibit different spectral patterns on multispectral PA imaging. PMID- 28860900 TI - Portal Vein Stenting for Delayed Jejunal Varix Bleeding Associated with Portal Venous Occlusion after Hepatobiliary and Pancreatic Surgery. AB - OBJECTIVE: The study aimed to describe portal stenting for postoperative portal occlusion with delayed (>= 3 months) variceal bleeding in the afferent jejunal loop. MATERIALS AND METHODS: Eleven consecutive patients (age range, 2-79 years; eight men and three women) who underwent portal stenting between April 2009 and December 2015 were included in the study. Preoperative medical history and the postoperative clinical course were reviewed. Characteristics of portal occlusion and details of procedures were also investigated. Technical success, treatment efficacy (defined as disappearance of jejunal varix on follow-up CT), and clinical success were analyzed. Primary stent patency rate was plotted using the Kaplan-Meier method. RESULTS: All patients underwent hepatobiliary-pancreatic cancer surgery except two children with liver transplantation for biliary atresia. Portal occlusion was caused by benign postoperative change (n = 6) and local tumor recurrence (n = 5). Variceal bleeding occurred at 27 months (4 to 72 months) and portal stenting was performed at 37 months (4 to 121 months), on average, postoperatively. Technical success, treatment efficacy, and clinical success rates were 90.9, 100, and 81.8%, respectively. The primary patency rate of portal stent was 88.9% during the mean follow-up period of 9 months. Neither procedure-related complication nor mortality occurred. CONCLUSION: Interventional portal stenting is an effective treatment for delayed jejunal variceal bleeding due to portal occlusion after hepatobiliary-pancreatic surgery. PMID- 28860901 TI - Correlation between Intravoxel Incoherent Motion Magnetic Resonance Imaging Derived Metrics and Serum Soluble CD40 Ligand Level in an Embolic Canine Stroke Model. AB - OBJECTIVE: To determine the relationship between intravoxel incoherent motion (IVIM) imaging derived quantitative metrics and serum soluble CD40 ligand (sCD40L) level in an embolic canine stroke model. MATERIALS AND METHODS: A middle cerebral artery occlusion model was established in 24 beagle dogs. Experimental dogs were divided into low- and high-sCD40L group according to serum sCD40L level at 4.5 hours after establishing the model. IVIM imaging was scanned at 4.5 hours after model establishment using 10 b values ranging from 0 to 900 s/mm2. Quantitative metrics diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) of ischemic lesions were calculated. Quantitative metrics of ischemic lesions were normalized by contralateral hemisphere using the following formula: normalized D = Dstroke / Dcontralateral. Differences in IVIM metrics between the low- and high-sCD40L groups were compared using t test. Pearson's correlation analyses were performed to determine the relationship between IVIM metrics and serum sCD40L level. RESULTS: The high-sCD40L group showed significantly lower f and normalized f values than the low-sCD40L group (f, p < 0.001; normalized f, p < 0.001). There was no significant difference in D*, normalized D*, D, or normalized D value between the two groups (All p > 0.05). Both f and normalized f values were negatively correlated with serum sCD40L level (f, r = -0.789, p < 0.001; normalized f, r = -0.823, p < 0.001). However, serum sCD40L level had no significant correlation with D*, normalized D*, D, or normalized D (All p > 0.05). CONCLUSION: The f value derived from IVIM imaging was negatively correlated with serum sCD40L level. f value might serve as a potential imaging biomarker to assess the formation of microvascular thrombosis in hyperacute period of ischemic stroke. PMID- 28860902 TI - Optimal Factors of Diffusion Tensor Imaging Predicting Corticospinal Tract Injury in Patients with Brain Tumors. AB - OBJECTIVE: To identify the optimal factors in diffusion tensor imaging for predicting corticospinal tract (CST) injury caused by brain tumors. MATERIALS AND METHODS: This prospective study included 33 patients with motor weakness and 64 patients with normal motor function. The movement of the CST, minimum distance between the CST and the tumor, and relative fractional anisotropy (rFA) of the CST on diffusion tensor imaging, were compared between patients with motor weakness and normal function. Logistic regression analysis was used to obtain the optimal factor predicting motor weakness. RESULTS: In patients with motor weakness, the displacement (8.44 +/- 6.64 mm) of the CST (p = 0.009), minimum distance (3.98 +/- 7.49 mm) between the CST and tumor (p < 0.001), and rFA (0.83 +/- 0.11) of the CST (p < 0.001) were significantly different from those of the normal group (4.64 +/- 6.65 mm, 14.87 +/- 12.04 mm, and 0.98 +/- 0.05, respectively) (p = 0.009, p < 0.001, and p < 0.001). The frequencies of patients with the CST passing through the tumor (6%, p = 0.002), CST close to the tumor (23%, p < 0.001), CST close to a malignant tumor (high grade glioma, metastasis, or lymphoma) (19%, p < 0.001), and CST passing through infiltrating edema (19%, p < 0.001) in the motor weakness group, were significantly different from those of the patients with normal motor function (0, 8, 1, and 10%, respectively). Logistic regression analysis showed that decreased rFA and CST close to a malignant tumor were effective variables related to motor weakness. CONCLUSION: Decreased fractional anisotropy, combined with closeness of a malignant tumor to the CST, is the optimal factor in predicting CST injury caused by a brain tumor. PMID- 28860903 TI - A Novel Flow Diverter (Tubridge) for the Treatment of Recurrent Aneurysms: A Single-Center Experience. AB - OBJECTIVE: The Tubridge flow diverter (FD) is a novel device aimed at reconstructing the parent artery and occluding complex aneurysms. Retreatment of recurrent aneurysms using the FD is challenging. We report our initial experience in the repair of aneurysm recurrence with the FD. MATERIALS AND METHODS: A database was reviewed prospectively, and 8 patients with 8 recurrent aneurysms (mean size, 16.7 mm) were identified. Four aneurysms had previously ruptured. The previous aneurysm treatment consisted of coiling in 1 aneurysm and single-stent assisted coiling in 7 aneurysms. The procedural complications and clinical and angiographic outcomes were analyzed. RESULTS: Six aneurysms were treated by using a single Tubridge FD alone, while the remaining 2 were treated with FD + coiling. The immediate results of the 8 aneurysms were that they all showed incomplete occlusion. Neither major ischemic nor hemorrhagic complications occurred; however, 1 patient experienced a vasospasm. Follow-up angiographies were available for 7 aneurysms; the mean follow-up was 16.9 months (7-36 months). Five aneurysms were completely occluded, whereas 2 had a residual neck. Severe asymptomatic stenosis of 1 parent artery of a vertebral artery dissecting aneurysm was found. All visible branches covered by the FD were patent. All patients were clinically assessed as having attained a favorable outcome (modified Rankin Scale score <= 2) at discharge and follow-up. CONCLUSION: In selected patients, the Tubridge FD can provide a safe and efficient option for the retreatment of recurrent aneurysms. Nevertheless, attention should be paid to several technical points. PMID- 28860904 TI - Combined Electrocardiography- and Respiratory-Triggered CT of the Lung to Reduce Respiratory Misregistration Artifacts between Imaging Slabs in Free-Breathing Children: Initial Experience. AB - OBJECTIVE: Cardiac and respiratory motion artifacts degrade the image quality of lung CT in free-breathing children. The aim of this study was to evaluate the effect of combined electrocardiography (ECG) and respiratory triggering on respiratory misregistration artifacts on lung CT in free-breathing children. MATERIALS AND METHODS: In total, 15 children (median age 19 months, range 6 months-8 years; 7 boys), who underwent free-breathing ECG-triggered lung CT with and without respiratory-triggering were included. A pressure-sensing belt of a respiratory gating system was used to obtain the respiratory signal. The degree of respiratory misregistration artifacts between imaging slabs was graded on a 4 point scale (1, excellent image quality) on coronal and sagittal images and compared between ECG-triggered lung CT studies with and without respiratory triggering. A p value < 0.05 was considered significant. RESULTS: Lung CT with combined ECG and respiratory triggering showed significantly less respiratory misregistration artifacts than lung CT with ECG triggering only (1.1 +/- 0.4 vs. 2.2 +/- 1.0, p = 0.003). CONCLUSION: Additional respiratory-triggering reduces respiratory misregistration artifacts on ECG-triggered lung CT in free-breathing children. PMID- 28860905 TI - RE: Thyroid Core Needle Biopsy: The Strengths of Guidelines of the Korean Society of Thyroid Radiology. PMID- 28860906 TI - The science of dacryology - Need of the hour. PMID- 28860907 TI - Endoscopic intranasal findings in unilateral primary acquired nasolacrimal duct obstruction. AB - PURPOSE: To evaluate intranasal endoscopic findings in patients with unilateral primary acquired nasolacrimal duct obstruction and compare them with the normal cohort. METHODS: A prospective case-control study with 50 unilateral primary acquired nasolacrimal duct obstruction (PANDO) and 50 healthy controls. All patients were evaluated by endoscopic nasal examination for the presence of deviated nasal septum (DNS), type of deviation (bony or cartilaginous), side of deviation, septal spurs, caudal dislocation, any turbinate hypertrophy and endoscopic features suggestive of sinusitis. RESULTS: A significant increase in the incidence of nasal septal deviation was found in PANDO cases (60%, 30/50) compared to controls (36%; 18/50; P = 0.03). The laterality of septal deviation corresponded to the side of NLD obstruction in 90% (27/30) cases. Higher location of DNS (73% vs 22%; P = 0.0009) and bony deviation (77% vs 44%; P = 0.02) were observed among study group as compared to controls. The odds of having NLD obstruction are 2.7 times more among individuals having septal deviation versus no deviation (95% CI, 1.19-5.99). CONCLUSION: Unilateral PANDO has a higher incidence of ipsilaterally deviated nasal septum. This association is significant. Routine nasal endoscopic examination should be performed in cases undergoing dacryocystorhinostomy to better plan a concomitant septoplasty if needed. PMID- 28860908 TI - Meibography for eyes with posterior blepharitis. AB - PURPOSE: To study the effect of posterior blepharitis on meibomian glands using infrared meibography and to correlate the results with tear film parameters. METHODS: This is a prospective cohort study. The study included eyes from two groups: 86 eyes of healthy volunteers' eyes and 72 eyes with posterior blepharitis. Participants were examined, and diagnosis of posterior blepharitis was achieved clinically based on signs of posterior blepharitis. Clinical assessment of dryness was performed including slit lamp examination looking for signs of posterior blepharitis, tear breakup time (TBUT), superficial punctate keratopathy (SPK), Schirmer II test (with anesthesia) and meibum score. Non contact meibography was performed for both upper and lower eyelids using the meibo-grade system which involved distortion of meibomian gland, shortening and dropout. RESULTS: Lid margin abnormalities (Telangiectasia, lid margin swelling and hyperemia) were all significantly higher in the posterior blepharitis group. SPK, meibum score, meibography dropout, distortion, shortening, and total meibography were all significantly higher in the posterior blepharitis group as well as meibum score (P value < 0.001). TBUT was significantly shorter in the posterior blepharitis group (P value < 0.001). There was no significant difference between the two groups in Schirmer's II test. CONCLUSION: Meibography can be a helpful non-invasive tool for the clinical evaluation of the extent of the anatomical damage in patients having meibomian glands loss due to posterior blepharitis. Knowing the extent of damage in meibomian glands may help in selecting the appropriate treatment modality and expect the response to treatment in patients with posterior blepharitis. PMID- 28860909 TI - Anatomical and functional outcomes of canalicular laceration repair with self retaining mini-MONOKA stent. AB - AIM: To evaluate the anatomical and functional outcomes of canalicular laceration repair with self retaining monocanalicular intubation system (Mini-MONOKA). MATERIALS AND METHODS: The data of 29 patients undergoing canalicular laceration repair from 2010 to 2014 were retrospectively analyzed. Operative details and complications were noted. The stent was removed earliest at 3 months. Anatomical and functional success was defined by a patent syringing and the absence of epiphora respectively. RESULTS: Out of 29 patients, 23 (79.3%) were males. Mean age at presentation was 19.3 +/- 13.8 years. Lower canaliculus was involved in 19 (65.5%), upper in 8 (27.5%) and both canaliculi in 2 (6.8%). Ten patients presented later than 11 days after trauma (range 12-168 days), and repair was attempted successfully in all. Fourteen (48.2%) cases reported for stent removal, at a mean follow-up period of 4.64 +/- 2.12 months. Anatomical success was noted in 12 (85.71%) and functional success in 13 (92.85%) cases. Four patients had stent related complications. CONCLUSION: Canalicular injuries are more common in young males. Mini-MONOKA stents are easy to insert and retrieve, and yield excellent anatomical and functional outcome. Canalicular laceration repair can be attempted successfully irrespective of the delay in presentation. PMID- 28860910 TI - Success rate of placement of a bicanalicular stent for partial nasolacrimal obstruction in adults under local, monitored anesthesia care and general anesthesia. AB - PURPOSE: To study The Kaneka Lacriflow Stent, a self-retaining bicanalicular intubation set that can be placed under local anesthetic, providing a new option to treat epiphora and partial NLDO. DESIGN: Retrospective chart review. SUBJECTS: 93 adult patients requiring treatment for a partial NLDO were evaluated. Stents were placed in office setting under local/topical anesthetic or in OR (MAC or GEN). The stent is placed with a stylet, and self-retains due to a widened portion sitting distal to the common canaliculis. It does not require recovery from the nose. METHODS: Outcomes analyzed to evaluate success of stent placement. MAIN OUTCOME MEASURE: Success rate of placement of the stent in adults. RESULTS: Stents left in place for 3 months. Results recorded 1 month after removal. Stents successfully placed in 124 of 136 (91%) eyes. Under local anesthesia in the office setting, 83 of 92 (90%) were placed successfully. Records were complete in 59 patients (78 eyes) and were analyzed further. 33 patients (52 eyes) had stents retained for the full 90 days and had follow-up recorded one-month post removal. Of the patients who retained the stents for 90 days and had full follow-up, 32 patients (51 eyes, 98%) reported improvement in their symptoms, while 1 patient reported no improvement. CONCLUSION: Silicone intubation of the NLD in adults is rarely done due to need for general anesthesia. The Lacriflow stent can be successfully placed in the office under local anesthesia offering a new approach for tearing in adults. PMID- 28860911 TI - Indian survey on practice patterns of lacrimal & eyelid disorders (iSUPPLE): Report 3 - Cataract and nasolacrimal duct obstruction. AB - AIM: To assess the practice patterns pertaining to pre-cataract screening for nasolacrimal duct obstruction (NLDO) among oculoplastic surgeons in India. The survey was aimed at obtaining data on the current screening and treatment strategies for NLDO and the interval between lacrimal surgery and subsequent cataract surgery. METHODS: An online survey was sent to all members of Oculoplastic Association of India. All valid responses were tabulated and analyzed. RESULTS: Majority of the respondents (92%) felt that nasolacrimal duct patency should be checked prior to performing cataract surgery: 59.6% felt that checking for regurgitation on pressure over the lacrimal sac (ROPLAS) was sufficient and 32.6% preferred to perform lacrimal irrigation to check for NLD patency. Dacryocystorhinostomy (DCR) was the preferred surgery for NLDO thus detected. The preferred interval between a DCR and subsequent cataract surgery was 4 weeks (48.9%). A small minority (7.9%) of the respondents felt that pre cataract screening for NLDO was not required. Also, a small but significant number (12.6%) felt that no treatment was required for NLDO in such patients and that to could go ahead with cataract surgery even in the presence of coexisting NLDO. CONCLUSIONS: There is a general agreement on the need for pre-cataract screening for NLDO and a majority indicated that checking for ROPLAS was sufficient. Most surgeons prefer to perform a DCR in cases of NLDO and wait for 4 weeks before intraocular surgery. There is however, a lacuna in the literature on guidelines regarding the optimal interval between lacrimal surgery and subsequent intraocular surgery. PMID- 28860912 TI - Causes of unsatisfactory results of the use of mitomycin-C in endoscopic endonasal dacryocystorhinostomy. AB - PURPOSE: To study the antifibrotic effectiveness of mitomycin-C in the tissues of the ostium site after it application for endonasal endoscopic dacryocystorhinostomy. MATERIAL AND METHODS: The study included 45 patients (48 cases) with primary obstruction of the nasolacrimal duct. All patients underwent endoscopic endonasal dacryocystorhinostomy (EEDCR). At the final stage of the operation, a swab with MMC was placed in the region of the formed ostium at a concentration of 0.2 mg/ml for 3 min. An ostium was not intubated. After that, biopsies of the mucous of the nasal cavity and lacrimal sac were performed to study the morphological changes that occur in the tissues overtime, as well as to calculate the concentration of the drug in the tissues. RESULTS: According to the chemical analysis, the concentration of MMC immediately after application was 0.626 +/- 0.176 MUg/g; after 30 min the concentration of the drug was reduced to 0.23 +/- 0.06 MUg/g; a day after the operation the drug was not found in the tissue samples. Morphological study established that the repair processes occurring in the mucosa of the nasal cavity and the lacrimal sac after EEDCR are similar to the reparative processes without the use of MMC. The effectiveness of surgical treatment: "positive results" - 77.1% of cases, "relapses" - 22.9% of cases. CONCLUSIONS: Application of MMC for prevention of excessive scarring after EEDCR is impractical as it is not possible to achieve antifibrotic concentration of the drug at dacryocystorhinostomy ostium site using this method. PMID- 28860913 TI - Fat-removal orbital decompression for thyroid associated orbitopathy: The right procedure for the right patient. AB - Orbital decompression is an effective and invaluable procedure for addressing some of the chronic manifestations of Graves' Ophthalmopathy (GO) such as exophthalmos and orbital congestion. Fat-removal orbital decompression (FROD) started to gain popularity after its introduction in the late 20th century. Among the therapeutic armamentarium of techniques and approaches available for orbital decompression, FROD has proven its efficacy and safety in addition to its ability to reduce proptosis in a relatively predictable manner. In addition, postoperative complications occurring after FROD are generally considered to be less frequent and less serious compared to bone-removal orbital decompression (BROD). Nevertheless, despite of FROD's high benefit-to-risk ratio, proper selection of patients based on meticulous preoperative assessment, including imaging, is of paramount importance to achieve optimal functional and aesthetic results. Although up till now there is still no consensus regarding the procedure of choice in GO patients, FROD is an important option to consider in this subset of patients. PMID- 28860914 TI - Ectopic lacrimal gland in a complex choristoma involving the lacrimal sac fossa. AB - Complex choristomas involving the lacrimal drainage system are not common. Ectopic lacrimal gland within complex choristomas has been described in the eyelid and orbit. We describe a pediatric case of complex choristoma with ectopic lacrimal gland involving the lacrimal sac fossa and partly the medial eyelid and orbit along with a brief review of literature. PMID- 28860915 TI - Congenital distichiasis: Histopathological report of 3 cases. AB - Distichiasis is a condition clinically presenting as partial or complete accessory row of lashes that emerges from the meibomian glands orifices. It can be an acquired or congenital with an autosomal dominant inheritance. The histopathological features are not well described in the ophthalmic literature, however they include abnormal pilosebaceous units within the posterior lamella of the eyelid and perifollicular chronic inflammatory cell infiltration. In this report, we describe the histopathological findings of three congenital distichiasis cases treated at King Khaled Eye Specialist Hospital (KKESH), Riyadh, Saudi Arabia with discussion on the pathogenesis of such a condition and the differentiating features from ectopic cilia. PMID- 28860916 TI - Dermis fat graft for pediatric exenteration-challenging but rewarding. AB - Orbital exenteration is a destructive and disfiguring surgery and involves removal of the entire orbital contents, soft tissue and often lids as well. We report a case of an eight month old female, with malignant orbital teratoma who underwent lid sparing exenteration for the destructive, locally advanced disease. Three month post surgery she developed recurrence with intracranial extension as well as socket infection with pus discharge. Repeat surgery involved a multispeciality approach for removal of the tumor which was abutting the cavernous sinus posteriorly and ethmoid sinus medially, apart from filling the entire bony orbit. The focus of infection was found to be the retained lacrimal sac. The unhealthy lid skin also had to be sacrificed. The challenges in repeat exenteration of an 8 month old, and the utility of autologous dermis fat graft as a reconstructive option are discussed. PMID- 28860917 TI - Hyperbaric oxygen in the management of wound tissue necrosis after external dacrocystorhinostomy. AB - Hyperbaric oxygen is an adjunctive treatment for promoting wound healing and reducing infection. We present an unusual case of wound tissue necrosis occurring after external dacryocystorhinostomy (ExtDCR) that was subsequently treated with hyperbaric oxygen (HBO) and advancement flaps with good outcome. HBO improves vascularization of ischemic tissues after ExtDCR for greater success after reconstructive surgery. PMID- 28860918 TI - Accidentally diagnosed transitional cell papilloma of the lacrimal sac. AB - Lacrimal sac tumors are extremely rare but can be life threatening. Seventy percent of lacrimal sac tumors are of epithelial origin. Inverted transitional cell papilloma of the lacrimal sac is a rare epithelial sinonasal tumor of benign etiology with local invasion and malignant potential. These lesions may remain undiagnosed or may present with signs and symptoms of dacryocystitis or may transform to transitional cell carcinomas. Most lesions are diagnosed intra operatively while performing a dacryocystorhinostomy. Biopsy and histopathological examination of mass lesions arising from the lacrimal sac helps in timely management of these rare tumors. PMID- 28860919 TI - A case of localized amyloidosis of the eyelid misdiagnosed as recurrent chalazion. AB - Localized amyloidosis of the eyelid is uncommon and is classically associated with systemic manifestations. We present an interesting case of a localized eyelid mass misdiagnosed as a recurrent chalazion presenting in an 85-year-old Saudi gentleman with no definite associate findings suggestive of an underlying systemic amyloid disease. Debulking surgery was subsequently performed. Proper diagnosis was reached based on the histopathologic examination of the excised tissue, which demonstrated the typical Congo red staining of the amyloid deposits. PMID- 28860920 TI - Eyelid trichilemmal carcinoma. AB - Trichilemmal carcinomas are rare malignant adnexal tumors which can involve the head and, rarely, the eyelid. Accurate diagnosis and differentiation from basal cell carcinoma or trichoepithelioma are dependent on histopathological and immunohistochemical analysis. We report a case of an eyelid mass, initially diagnosed by incisional biopsy as a trichoepithelioma, later found on excisional biopsy to be a trichilemmal carcinoma and present a review of the literature of the histopathology, differential diagnosis and management. Consideration of these entities will be useful to the histopathologist and clinician to better identify and treat these challenging lesions. PMID- 28860921 TI - Eyelid metastasis as presenting feature of disseminated leiomyosarcoma - A rare case report. AB - Soft tissue sarcomas with smooth muscle differentiation are termed leiomyosarcoma. Leiomyosarcoma is an aggressive tumor commonly originating from smooth muscle cells of uterus or retro peritoneal areas. Distant metastasis occurs by hematogenous route to liver and lung. Eyelid metastasis without involvement of other ocular structures is extremely rare. A case of eyelid metastasis which on extensive investigations was proved to be from upper gastrointestinal tract leiomyosarcoma is reported here. PMID- 28860922 TI - Unilateral optic disc pit associated with orbital cyst in a child. AB - Optic disc pit and disc coloboma are common congenital anomalies. Both have been known to be associated with an orbital cyst. We report a case of a 6 month-old child who presented with unilateral progressive proptosis. Imaging investigations revealed a well-defined, intraconal, orbital cyst located close to the posterior surface of the globe displacing the optic nerve laterally. The cyst was excised and histopathological examination showed the cyst to have a lining of glial tissue, a thin epithelial lining, over a layer of collagenous connective tissue matrix. We hypothesize that colobomatous disc abnormalities and optic disc pits are different points on the same disease spectrum and can be associated with orbital cysts. Furthermore, our case points to the possible role of imaging the optic nerve in all cases of optic disc anomalies. PMID- 28860923 TI - Concomitant orbital aspergillosis and mucormycosis in a 17 months old immunocompetent child. AB - Isolated multiple orbital fungal infection (aspergillosis & mucormycosis) is extremely rare disease in immunocompetent individuals and especially in children. Placement of prosthetic device during the surgery could be one of the risk factors. The presentation is usually masquerading other entities which make early diagnosis a challengeable. This case presenting a 17 months old immunocompetent child who is diagnosed with isolated multiple orbital fungal infection: aspergillosis & mucormycosis. The presentation was mimicking orbital cellulitis and chronic dacryocystitis. The definitive diagnosis was made by tissue biopsy. The child was managed by surgical debridement and IV amphotericin B liposomal. High index of suspicion to fungal infection should be considered after surgical intervention with insertion prosthetic materials. To the best of our knowledge, orbital aspergillosis in immunocompetent young children is exceptionally rare. PMID- 28860924 TI - Frontalis sling surgery: A treatment modality for cyclic oculomotor nerve palsy. AB - Cyclic oculomotor nerve paresis and spasm are a rare disorder characterized by alternating spastic and paretic phase of the muscles supplied by the oculomotor nerve. A 26-year-old male presented with abnormal right eyelid movements since early childhood. Examination findings were consistent with diagnosis of right eye cyclic oculomotor nerve palsy. A paretic phase with complete upper eyelid ptosis, exotropia, hypotropia and dilatation of the pupil was followed by a phase of orthotropia, the absence of ptosis and normal pupil size. The whole cycle was of about 100 s duration with patient having no voluntary control over the eyelid movements and ocular alignment. Systemic evaluation and neuroimaging were normal. A tarsofrontal silicone sling surgery done for the ptosis correction decreased the eyelid movements during different phases of the cycle. PMID- 28860925 TI - Congenital lacrimal sac diverticulum. PMID- 28860926 TI - Getting hooked: Eyelash in lacrimal punctum. PMID- 28860927 TI - To know when to prick!! PMID- 28860928 TI - Primary anterior punctal malposition presenting as Centurion syndrome. PMID- 28860929 TI - CD300LG improves the cytotoxic activity of CIK. AB - To investigate the effect of CD300LG-gamma induction on the cytotoxic activity of CIK. Eukaryotic expression plasmid hCD300LG-gamma/pEGFP-C3, which can express human CD300LG-gamma, was constructed and transfected into CHO cells by lipofectamine. The expression of CD300LG-gamma was confirmed by immunofluorescence, RT-PCR, and Western Blot. To produce CIK cells, human peripheral blood mononuclear cells (PBMC) were isolated and induced, respectively, by cell lysates extracted from hCD300LG-gamma/CHO cells, pEGFP C3/CHO cells, and CHO cells, concurrently with the standard CIK inductive agent. The cytotoxic activity of these CIK cells against hCD300LG-gamma/CHO cells, pEGFP C3/CHO cells, CHO cells, and K562 cells was tested. The results showed that eukaryotic expression of plasmid hCD300LG-gamma/pEGFP-C3 was constructed and transfected into CHO cells successfully. After being induced by cell lysates, the cytotoxicity of hCD300LG-gamma/CHO-CIK was improved compared with the other CIK cells. In particular, the activity of killing pEGFP-C3/CHO and CHO cells was improved significantly. Meanwhile, the activity of hCD300LG-gamma/CHO-CIK killing K562 was improved significantly compared with the other CIK cells. The results indicated that hCD300LG-gamma induction can significantly improve the killing activity of CIK cells. PMID- 28860930 TI - New human single chain anti-idiotypic antibody against benzo[a]pyrene. AB - The nalve library from the lymphocytes of healthy humans was screened by murine single-stranded idiotypic antibodies against benzo[a]pyrene (pSh). The phage clone which contained of anti-idiotypic antibody against benzo[a]pyrene, designated as A4, was chosen for further work because of highly specific to pSh. The available protein databases were searched. The A4 amino acid sequence was unique and 76% identical to a sequence in antibody against interferon g. The A4 protein was expressed in bacteria and purified by two different methods: His tagged A4 and CBD-fusion A4. Both the A4 bound to pSh and also to the human single chain idiotypic antibody against the benzo[a]pyrene (T72) by ELISA. The Kd values of A4 for pSh and T72 were very close: 4.44 * 10-7 M and 5.71 * 10-7M, respectively. A4 was a competitor with benzo[a]pyrene for binding sites of both idiotypic pSh and T72 in competitive ELISA. Thus, A4 was a high affinity anti idiotypic against benzo[a]pyrene which recognised pSh and T72 active sites. PMID- 28860931 TI - The effect of pentoxifylline on L-1 sarcoma tumor growth and angiogenesis in Balb/c mice. AB - Methyloxantines are present in many herbs and vegetal foods, among them in tea, coffee and chocolate. Previous studies revealed that theophylline and theobromine have anti-angiogenic properties. Anti-tumor properties of theobromine were also described. Pentoxifylline (3,7-dimethyl-1-(5-oxohexyl)xanthine, PTX) is a synthetic xanthine derivative. It is a phosphodiesterase inhibitor and has various anti-inflammatory abilities. Pentoxifylline is widely used in therapy of inflammatory arterial diseases such as intermittent claudication of upper and lower limbs as well as in coronary heart disease. The aim of our research was to evaluate the effect of pentoxifylline (individually and in combination with non steroidal anti-inflammatory drug sulindac), on L-1 sarcoma angiogenic activity and tumor formation in syngeneic Balb/c mice. Pre-incubation of tumor cells for 90 min with various PTX concentrations resulted in dose-dependent decrease of their ability to induce newly-formed blood vessels after transplantation into the skin of recipient mice. Administration of PTX to mice, recipients of tumor cells, slows tumor growth and reduces its volume. Synergistic inhibitory effect of PTX and sulindac, expressed as % of tumors sixth and thirteen day after subcutaneous grafting of L-1 sarcoma into syngeneic Balb/c mice, was observed. PMID- 28860932 TI - Common variants in IL-1RN, IL-1beta and TNF-alpha and the risk of ovarian cancer: a case control study. AB - AIM OF THE STUDY: Several studies implicated altered inflammatory response in the susceptibility to ovarian cancer, and polymorphisms in inflammatory cytokines were shown to play an important role in the development of malignancies, including ovarian cancer (OC). Here we investigated the relationship between polymorphisms in IL-1beta (-511C>T), IL-1RN VNTR, TNF-alpha (-308G>A), and TNF RII (-322 VNTR) and OC risk in Tunisian women. METHODS AND RESULTS: Study subjects comprised 62 OC patients and 126 healthy women. Genotyping was done from genomic DNA obtained from blood simple by PCR. Positive association between IL 1RN (-VNTR) A1 allele (p = 0.0069; OR = 2.04; 95% CI:1.17-3.58) and OC risk, while negative association was seen with the A3 allele (P = 0.0034; OR = 0.09; 95% CI: 0.00-0.64), suggesting a protective role by the A3 allele. For IL-1beta ( 511C>T), homozygous C/C genotype was associated with significantly increased risk of OC (p = 0.0002; OR = 4.14; 95% CI: 1.77-9.76), while heterozygote C/T genotype was linked with reduced risk of OC (p = 0.0033; OR = 0.40; 95% CI: 0.20-0.78). Furthermore, TNF-alpha -308A allele was significantly associated with heightened risk of OC (p = 0.016; OR = 1.70; 95% CI: 1.08-2.69), and homozygote G/G genotype was associated with decreased risk of OC (p = 0.0018; OR = 0.25; 95% CI: 0.09 0.66). In contrast, TNFRII (-322 VNTR) polymorphism was not associated with altered OC risk in the studied group. CONCLUSIONS: The significant association between IL-1RN VNTR, IL1-beta (-511), TNF-alpha (-308) and OC susceptibility in Tunisian women confirms a role for altered inflammatory response in ovarian cancer pathogenesis. PMID- 28860933 TI - Expression level of TNF-alpha in decidual tissue and peripheral blood of patients with recurrent spontaneous abortion. AB - OBJECTIVE: This study aimed to determine the express level of tumour necrosis factor alpha (TNF-alpha) in the decidual tissue and peripheral blood of patients with recurrent spontaneous abortion (RSA). MATERIAL AND METHODS: Eighty RSA patients and 100 control women were recruited in this study. Enzyme-linked immunosorbent assay (ELISA) was applied to determine the expression level of TNF alpha in peripheral blood and decidual tissues from both groups. Additionally, the expression level of TNF-alpha was compared between RSA patients with different numbers of abortions, as well as primary and secondary RSA patients. RESULTS: The expression level of TNF-alpha in peripheral blood and decidual tissues of RSA patients was significantly higher compared to the controls (p < 0.001). Patients who had undergone RSA twice expressed TNF-alpha in peripheral blood and decidual tissues at a similar level to patients who had experienced RSA three times (p > 0.05), but significantly lower than patients who had experienced RSA more than three times (p < 0.001). The expression level of TNF-alpha in peripheral blood and decidual tissues was significantly higher in the secondary RSA patients, when compared with primary RSA patients (p < 0.001). CONCLUSIONS: Taken together, the relatively high expression level of TNF-alpha in decidual tissue and peripheral blood may be one of the causes of RSA and therefore could be used as a clinical indicator. PMID- 28860934 TI - Influence of antiphospholipid antibody positivity on glomerular filtration rate markers in a group of systemic sclerosis patients - a 24-month observation. AB - AIM OF THE STUDY: The aim of the study was the assessment of changes in the glomerular filtration rate (GFR) during long-term observation in a group of systemic sclerosis (SSc) patients with and without chronic antiphospholipid (aPL) antibody positivity. MATERIAL AND METHODS: The observation comprised 50 patients 23 with diffuse cutaneous SSc - dcSSc and 27 limited cutaneous SSc - lcSSc. After 24 months we assessed 27 patients (9 died, 14 lost follow up); 24 patients (88%) were treated chronically with angiotensin-converting-enzyme inhibitors (ACEIs). Patients were investigated for the presence of aPL: to cardiolipin and to beta2 glycoprotein I in IgM and IgG classes. Serum levels of creatinine (S Cr), cystatin C and creatinine clearance values were determined in all patients. According to the presence of a significant level of at least one of aPL antibodies, pts were divided into groups: group I aPL positive: 14 patients, group II aPL negative - 13 patients. RESULTS: We did not find significant differences in S-Cr, cystatin C levels and creatinine clearance before and after 24 months of observation between both groups. In follow up observations, the presence of anti-centromere antibodies was significantly more frequent in the aPL positive, as compared to the aPL negative group (p = 0.01). In follow up observations, the level of anticardiolipin antibodies in IgG class was significantly higher in dcSSc compared to lcSSc patients (p = 0.02). CONCLUSIONS: In long-term observation chronic positivity for aPL antibodies does not significantly decrease the GFR in patients with SSc treated with ACEIs. PMID- 28860935 TI - Usefulness of urinary collagen IV excretion for predicting the severity of Henoch Schonlein nephropathy children. AB - THE AIM OF THE STUDY: The aim of the study was to evaluate the usefulness of urinary collagen IV (Col IV) excretion for predicting the severity of autoimmune renal inflammation in children with HSN (Henoch-Schonlein nephritis). MATERIAL AND METHODS: We studied 26 children, in whom HSN was diagnosed based on kidney biopsy. In all patients, urinalysis was performed and 24-hour urinary protein excretion was measured at the onset of the disease. All kidney biopsies were also scored using the Oxford classification: M - mesangial hypercellularity score (M0 absent, M1 present); E - presence of endocapillary proliferation (E0 absent, E1 present), S - segmental glomerulosclerosis/adhesion (S0 absent, S1 present), T - tubular atrophy/interstitial fibrosis (T0 <= 25%, T1 26-50%, T2 > 50%). The MEST score was calculated as the sum of M + E + S + T. RESULTS: Urinary Col IV level was significantly higher in the study group than in control group. Urinary Col IV level was insignificantly higher in group A (nephrotic proteinuria) compared to the B (non-nephrotic proteinuria) and C (without proteinuria).We found no significant differences in the age at the disease onset, severity of proteinuria, and Col IV between groups 1 (S0, T0) and 2.(S1,T1/T2). The MEST score was significantly higher in group 2 than group 1. CONCLUSIONS: Urinary Col IV excretion in children with HSN may be related to the lesions severity by the Oxford classification but seems to be associated with the mean value (the MEST score). In younger children, a more aggressive disease course is observed, and thus earlier and more aggressive treatment should be considered in this group. PMID- 28860936 TI - Stem cells in regenerative medicine - from laboratory to clinical application - the eye. AB - Stem cells are currently one of the most researched and explored subject in science. They consstitue a very promising part of regenerative medicine and have many potential clinical applications. Harnessing their ability to replicate and differentiate into many cell types can enable successful treatment of diseases that were incurable until now. There are numerous types of stem cells (e.g. ESCs, FSCs, ASCs, iPSCs) and many different methods of deriving and cultivating them in order to obtain viable material. The eye is one of the most interesting targets for stem cell therapies. In this article we summarise different aspects of stem cells, discussing their characteristics, sources and methods of culture. We also demonstrate the most recent clinical applications in ophthalmology based on an extensive current literature review. Tissue engineering techniques developed for corneal limbal stem cell deficiency, age-related macular degeneration (AMD) and glaucoma are among those presented. Both laboratory and clinical aspects of stem cells are discussed. PMID- 28860938 TI - Early growth response 2 and Egr3 are unique regulators in immune system. AB - The immune system is evolved to defend the body against pathogens and is composed of thousands of complicated and intertwined pathways, which are highly controlled by processes such as transcription and repression of cellular genes. Sometimes the immune system malfunctions and a break down in self-tolerance occurs. This lead to the inability to distinguish between self and non-self and cause attacks on host tissues, a condition also known as autoimmunity, which can result in chronic debilitating diseases. Early growth response genes are family of transcription factors comprising of four members, Egr1, Egr2, Egr3 and Egr4. All of which contain three cyc2-His2 zinc fingers. Initially, Egr2 function was identified in the regulation of peripheral nerve myelination, hindbrain segmentation. Egr3, on the other hand, is highly expressed in muscle spindle development. Egr2 and Egr3 are induced due to the antigen stimulation and this signaling is implemented through the B and T cell receptors in the adaptive immunity. T cell receptor signaling plays a key role in Egr 2 and 3 expressions via their interaction with NFAT molecules. Egr 2 and 3 play a crucial role in regulation of the immune system and their involvement in B and T cell activation, anergy induction and preventing the autoimmune disease has been investigated. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expression of effector and activated T cells. PMID- 28860937 TI - A brief review of clinical trials involving manipulation of invariant NKT cells as a promising approach in future cancer therapies. AB - In the recent years researchers have put a lot of emphasis on the possible immunotherapeutic strategies able to target tumors. Many studies have proven that the key role in recognition and eradication of cancer cells, both for mice and humans, is being conducted by the invariant natural killer T-cells (NKT). This small subpopulation of lymphocytes can kill other cells, either directly or indirectly, through the natural killer cells' (NK) activation. They can also swiftly release cytokines, causing the involvement of elements of the innate and acquired immune system. With the discovery of alpha-galactosylceramide (alpha GalCer) - the first known agonist for iNKT cells - and its later subsequent analogs, it became possible to effectively stimulate iNKT cells, hence to keep control over the tumor progression. This article refers to the current knowledge concerning iNKT cells and the most important aspects of their antitumor activity. It also highlights the clinical trials that aim at increasing the amount of iNKT cells in general and in the microenvironment of the tumor. For sure, the iNKT based immunotherapeutic approach holds a great potential and is highly probable to become a part of the cancer immunotherapy in the future. PMID- 28860939 TI - Infectious mononucleosis-like syndrome with high lymphocytosis and positive IgM EBV and CMV antibodies in a three-year-old girl. AB - Primary Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection usually affects preadolescent children or young adults, causing similar clinical presentation. Signs and symptoms are typically mild, and the majority of clinical and laboratory findings resolve spontaneously within one month after onset. In adulthood, the risk of fulminant EBV infection and severe complications is much higher, which may be related to increasing memory CD8+ T-cell population with age. It is still not clear what exactly triggers T-cell clonal proliferation. Animals model studies on heterologous immunity between viruses revealed that pre existing memory T-cells may contribute to excessive immune response during subsequent infection with a new, unrelated pathogen. A 3.5-year-old girl was admitted to hospital with a suspicion of lymphoproliferative disorder. Peripheral blood smear revealed a massive lymphocytosis (61,600 cells/ul) with 62% share of atypical lymphocytes. The clinical presentation and positive EBV and CMV IgM test strongly suggested infectious mononucleosis syndrome as a result of EBV and CMV coinfection. PMID- 28860940 TI - Limbic encephalitis - a report of four cases. AB - Usually limbic encephalitis (LE) is a paraneoplastic neurologic syndrome. LE symptoms can precede cancer even by a few years. Almost 50% of LE cases are connected with small cell lung carcinoma. Testis and breast cancers, granulomatous disease, thymoma, and teratomas are also often connected with LE. Other cases have infectious and autoimmunological aetiology. In LE limbic system dysfunction is observed, and it is accompanied by cerebellum and brain stem abnormalities as well as polyneuropathy. Paraneoplastic limbic encephalitis is sometimes a part of larger syndrome in which brain stem and spinal cord are involved in an inflammatory process called paraneoplastic encephalomyelitis. The main LE symptoms are: impairment of cognitive functions with subacute beginning, partial and generalised seizures, mental distress, disturbances of consciousness, and limb paresis. In MRI study hyperintensive lesions in the medial part of the temporal lobes in T2 and FLAIR sequences are present. Sharp and slow waves in electroencephalography in the temporal area are also frequent. In cerebrospinal fluid pleocytosis, elevation of protein level, intensification of immunoglobulin synthesis, and oligoclonal bands can be detected. The majority of patients with paraneoplastic LE have onconeural antibodies in the blood. The presented study is a description of the clinical course of the disease in four patients diagnosed with LE. PMID- 28860941 TI - Dengue virus and Japanese encephalitis virus infection of the central nervous system share similar profiles of cytokine accumulation in cerebrospinal fluid. AB - Dengue virus (DENV) and Japanese encephalitis virus (JEV) are two important pathogenic viruses that can cause severe encephalitis, which is accompanied by inflammatory cytokines. However, the inflammatory cytokine content of cerebrospinal fluid (CSF) in DENV and JEV infection of central nervous system are not sufficiently studied. To investigate cytokine levels in serum and CSF of hospitalised children with DENV and JEV infection of the central nervous system, a total of 183 hospitalised children with viral encephalitis-like syndrome were enrolled between May 2014 and April 2015 at the Children's Hospital of Chenzhou, Hunan, China. DENV and JEV infection was diagnosed by ELISA. Cytokine levels in the serum and CSF were measured by commercial ELISA kits. Twenty-nine (15.85%) and 26 (14.21%) DENV and JEV infections were detected in 183 patients with viral encephalitis-like syndrome, respectively. Higher granulocyte-macrophage colony stimulating factor (GM-CSF) levels were detected in the serum of JEV infected patients than in DNEV patients (p < 0.05) or in healthy controls (p < 0.001), and levels of GM-CSF, interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) were higher in the CSF than serum in both DENV and JEV infection. Both DENV and JEV infection induced similar cytokine accumulation profiles in the CSF, which probably contributed to DENV- and JEV-induced immunopathogenesis. PMID- 28860942 TI - Accuracy of cervical cytology: comparison of diagnoses of 100 Pap smears read by four pathologists at three hospitals in Norway. AB - BACKGROUND: Cervical cancer can be prevented by early detection and treatment for precancerous lesions. Since 1995, there has been a national cervical cancer screening program in Norway, where women aged 25-69 years are recommended to take Pap smears every three years. There are 17 cytology laboratories covering a population of 5 million people. The detection rate of cervical abnormalities varies from laboratory to laboratory. We wanted to investigate the accuracy of cytology diagnoses by four different pathologists at three different hospitals in Norway. METHODS: One hundred Pap smears (20 Normal, 20 ASC-US, 20 LSIL, 20 ASC-H and 20 HSIL) screened at UNN in 2015 were evaluated by four pathologists at three hospitals in Norway. All patients were followed up through December 2016. Histologically confirmed high-grade dysplasia (CIN2+) was considered as study endpoint. RESULTS: The number of Pap smears evaluated as abnormal (ASC-US+) by the four pathologists varied from 61 to 85. The number of high-grade cytology (ASC-H+) varied from 26 to 50. There was moderate agreement (weighted kappa 0.45 0.58) between the observers. There were 32 women with high-grade histology (CIN2+) in the follow-up, including 19 CIN2, 12 CIN3 and one squamous cell carcinoma (SCC). Using high-grade cytology (ASC-H+) as cut-off, the sensitivity for CIN2+ varied from 68.8% to 93.8% (mean 77.4%) and specificity from 70.6% to 95.6% (mean 81.3%). The pathologist with the highest sensitivity for CIN2+ had the highest false positive rate and the lowest specificity (p<0.05). The accuracy for CIN2+ varied from 74.1% to 83.8% (mean 79.4%). The Pap smear from the woman with cervical cancer was diagnosed as high-grade (ASC-H+) by one of the four pathologists. CONCLUSIONS: Cervical cancer screening based on cytology has limited accuracy. The study revealed a moderate agreement between the observers, along with a trade-off between sensitivity and specificity. This might indicate that hospitals with high detection rates of cervical cytology have higher sensitivity for CIN2+ but lower specificity. PMID- 28860943 TI - Biochemical and histological alterations induced by the smoke of allethrin based mosquito coil on mice model. AB - BACKGROUND: Mosquito coil (MC) emits insecticide upon burning which provides limited protection against lethal mosquito borne diseases. However, apart from killing the insect, toxicities associated with the inhalation of these insecticides poses severe health hazards. However, the use of MC is increasing day by day in third world countries in particular but, yet to receive enough attention of both policy maker and general public. The current study was aimed to assess the MC smoke induced damage of pulmonary and hepatic tissues along with observing the alterations of several blood biochemical parameters in mice model. METHODS: A total of twenty four Swiss albino mice were allowed to inhale the smoke of allethrin based MC at different duration per day for 120 days. By the end of treatment period, blood sample was drawn from each mouse and blood biochemical parameters including alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen(BUN), serum total protein, cholesterol, low density lipoprotein (LDL) and triglyceride (TG) were analyzed. Intact lung and liver were collected for histological analysis using standard protocol. RESULTS: Biochemical study indicates elevated activity of two hepatic enzymes: ALT (89%), AST (85%), in comparison with the respective control. Increased level of some parameters of lipid profile including cholesterol (36%), LDL (48%) and triglyceride (30%) in smoke inhaled mice is the new finding of this study. On the contrary, the activity of serum total protein and BUN was decreased by 20% and 24%, respectively in inhaled mice. Pulmonary tissue of treated mice shows severe forms of emphysema and hyperplasia, especially in the peripheral region of lung, which is the hallmark of chronic obstructive pulmonary disease (COPD). Histological study of hepatic tissue shows apoptosis mediated damage of hepatocytes along with severe form of necrosis. Infiltration of Inflammatory cells was also observed in both of the organs. CONCLUSION: Results from the present studies suggest that chronic exposure of allethrin based MC is responsible factor for severe health complications such as COPD due to the alterations of the key biochemical parameters of blood and histo-organization of lung and liver. PMID- 28860944 TI - Chronic asthma and Mesenchymal stem cells: Hyaluronan and airway remodeling. AB - BACKGROUND: Previous studies have demonstrated that ovalbumin sensitization promotes chronic asthma phenotype in murine asthma model. Human mesenchymal stem cells (hMSCs) are multipotent cells in vitro that have been shown to decrease inflammation and can reverse airway remodeling when infused into an in vivo chronic asthma model. However, the mechanism by which hMSCs reverse remodeling is still unclear. In this study, we hypothesized that hMSCs influence remodeling by decreasing extracellular matrix (ECM) deposition, more specifically by decreasing collagen I, collagen III, and hyaluronan synthesis. METHODS: Chronic asthma phenotype was produced in an in vitro model with 3 T3 murine airway fibroblast cells by stimulating with GM-CSF. Collagen I and collagen III gene expression was investigated using RT-PCR and Taqman techniques. Hyaluronan was evaluated using FACE and Western Blots. The chronic asthma phenotype was produced in vivo in murine model using sensitization with ovalbumin with and without hMSC infusion therapy. ECM deposition (specifically trichrome staining, soluble and insoluble collagen deposition, and hyaluronan production) was evaluated. Image quantification was used to monitor trichrome staining changes. RESULTS: GM-CSF which induced collagen I and collagen III production was down-regulated with hMSC using co-culture. In the in vivo model, Ovalbumin induced enhanced ECM deposition, soluble and insoluble collagen production, and lung elastance. hMSC infusions decreased ECM deposition as evidenced by decreases in soluble and insoluble collagen production. CONCLUSION: hMSCs participate in improved outcomes of remodeling by reversing excess collagen deposition and changing hyaluronan levels. PMID- 28860945 TI - beta3 phosphorylation of platelet alphaIIbbeta3 is crucial for stability of arterial thrombus and microparticle formation in vivo. AB - BACKGROUND: It is well accepted that functional activity of platelet integrin alphaIIbbeta3 is crucial for hemostasis and thrombosis. The beta3 subunit of the complex undergoes tyrosine phosphorylation shown to be critical for outside-in integrin signaling and platelet clot retraction ex vivo. However, the role of this important signaling event in other aspects of prothrombotic platelet function is unknown. METHOD: Here, we assess the role of beta3 tyrosine phosphorylation in platelet function regulation with a knock-in mouse strain, where two beta3 cytoplasmic tyrosines are mutated to phenylalanine (DiYF). We employed platelet transfusion technique and intravital microscopy for observing the cellular events involved in specific steps of thrombus growth to investigate in detail the role of beta3 tyrosine phosphorylation in arterial thrombosis in vivo. RESULTS: Upon injury, DiYF mice exhibited delayed arterial occlusion and unstable thrombus formation. The mean thrombus volume in DiYF mice formed on collagen was only 50% of that in WT. This effect was attributed to DiYF platelets but not to other blood cells and endothelium, which also carry these mutations. Transfusion of isolated DiYF but not WT platelets into irradiated WT mice resulted in reversal of the thrombotic phenotype and significantly prolonged blood vessel occlusion times. DiYF platelets exhibited reduced adhesion to collagen under in vitro shear conditions compared to WT platelets. Decreased platelet microparticle release after activation, both in vitro and in vivo, were observed in DiYF mice compared to WT mice. CONCLUSION: beta3 tyrosine phosphorylation of platelet alphaIIbbeta3 regulates both platelet pro-thrombotic activity and the formation of a stable platelet thrombus, as well as arterial microparticle release. PMID- 28860946 TI - Increases in United States life expectancy through reductions in injury-related death. AB - BACKGROUND: During the previous century the average lifespan in the United States (US) increased by over 30 years, with much of this increase attributed to public health initiatives. This report examines further gains that might be achieved through reduced occurrence of injury-related death. METHODS: US life tables and injury death rate data were used to estimate potential increases in life expectancy assuming various reductions in the rate of fatal injuries. Corresponding numbers of deaths potentially averted annually were also estimated; unit (per death) medical and lifetime work loss costs were employed to estimate total costs potentially averted annually. RESULTS: Through elimination of injury as a cause of death, average US life expectancy at birth could be increased by approximately 1.5 years, with notable variations by sex, ethnicity, and race. More conservatively, average life expectancy at birth could be increased by 0.41 years assuming that the national injury death rate could be brought into line with the lowest state-specific rate. Under this more conservative but plausible assumption, an estimated 48,400 injury deaths and $61 billion in medical and work loss costs would be averted annually. CONCLUSIONS: Increases in life expectancy of the magnitude considered in this report are arguably attainable based on long term historical reductions in the US injury death rate, as well as significant continuing reductions seen in other developed countries. Contemporary evidence based interventions can play an important role in reducing injury-related deaths, such as those due to drug overdoses and older adult falls, as well as suicides. PMID- 28860947 TI - Article Watch: September 2017. AB - This column highlights recently published articles that are of interest to the readership of this publication. We encourage ABRF members to forward information on articles they feel are important and useful to Clive Slaughter, MCG-UGA Medical Partnership, 1425 Prince Ave., Athens GA 30606, USA. Tel: (706) 713-2216; Fax: (706) 713-2221; E-mail; cslaught@uga.edu, or to any member of the editorial board. Article summaries reflect the reviewer's opinions and not necessarily those of the association. PMID- 28860948 TI - Outstanding Scientific Poster Awards for the ABRF 2017 Organized by the Education Committee and Sponsored by Waters Corporation. PMID- 28860949 TI - Remote sensing of forest insect disturbances: Current state and future directions. AB - Insect disturbance are important agents of change in forest ecosystems around the globe, yet their spatial and temporal distribution and dynamics are not well understood. Remote sensing has gained much attention in mapping and understanding insect outbreak dynamics. Consequently, we here review the current literature on the remote sensing of insect disturbances. We suggest to group studies into three insect types: bark beetles, broadleaved defoliators, and coniferous defoliators. By so doing, we systematically compare the sensors and methods used for mapping insect disturbances within and across insect types. Results suggest that there are substantial differences between methods used for mapping bark beetles and defoliators, and between methods used for mapping broadleaved and coniferous defoliators. Following from this, we highlight approaches that are particularly suited for each insect type. Finally, we conclude by highlighting future research directions for remote sensing of insect disturbances. In particular, we suggest to: 1) Separate insect disturbances from other agents; 2) Extend the spatial and temporal domain of analysis; 3) Make use of dense time series; 4) Operationalize near-real time monitoring of insect disturbances; 5) Identify insect disturbances in the context of coupled human-natural systems; and 6) Improve reference data for assessing insect disturbances. Since the remote sensing of insect disturbances has gained much interest beyond the remote sensing community recently, the future developments identified here will help integrating remote sensing products into operational forest management. Furthermore, an improved spatiotemporal quantification of insect disturbances will support an inclusion of these processes into regional to global ecosystem models. PMID- 28860950 TI - T Cell's Sense of Self: a Role of Self-Recognition in Shaping Functional Competence of Naive T Cells. AB - Post-thymic naive T cells constitute a key cellular arm of adaptive immunity, with a well-known characteristic of the specificity and robustness of responses to cognate foreign antigens which is presented as a form of antigen-derived peptides bound to major histocompatibility complex (MHC) molecules by antigen presenting cells (APCs). In a steady state, however, these cells are resting, quiescent in their activity, but must keep full ranges of functional integrity to mount rapid and robust immunity to cope with various infectious pathogens at any time and space. Such unique property of resting naive T cells is not acquired in a default manner but rather requires an active mechanism. Although our understanding of exactly how this process occurs and what factors are involved remains incomplete, a particular role of self-recognition by T cells has grown greatly in recent years. In this brief review, we discuss recent data on how the interaction of T cells with self-peptide MHC ligands regulates their functional responsiveness and propose that variable strength of self-reactivity imposes distinctly different levels of functional competence and heterogeneity. PMID- 28860952 TI - Yersinia enterocolitica Exploits Signal Crosstalk between Complement 5a Receptor and Toll-like Receptor 1/2 and 4 to Avoid the Bacterial Clearance in M cells. AB - In the intestinal mucosal surface, microfold cells (M cells) are the representative gateway for the uptake of luminal antigens. At the same time, M cells are the primary infection site for pathogens invading mucosal surface for their infection. Although it is well recognized that many mucosal pathogens exploit the M cells for their infection, the mechanism to infect M cells utilized by pathogens is not clearly understood yet. In this study, we found that M cells expressing complement 5a (C5a) receptor (C5aR) also express Toll-like receptor (TLR) 1/2 and TLR4. Infection of Yersinia enterocolitica, an M cell-invading pathogen, synergistically regulated cyclic adenosine monophosphate-dependent protein kinase A (cAMP-PKA) signaling which are involved in signal crosstalk between C5aR and TLRs. In addition, Y. enterocolitica infection into M cells was enhanced by C5a treatment and this enhancement was abrogated by C5a antagonist treatment. Finally, Y. enterocolitica infection into M cells was unsuccessful in C5aR knock-out mice. Collectively, we suggest that exploit the crosstalk between C5aR and TLR signaling is one of infection mechanisms utilized by mucosal pathogens to infect M cells. PMID- 28860951 TI - Cytokine Signaling in Tumor Progression. AB - Cytokines are molecules that play critical roles in the regulation of a wide range of normal functions leading to cellular proliferation, differentiation and survival, as well as in specialized cellular functions enabling host resistance to pathogens. Cytokines released in response to infection, inflammation or immunity can also inhibit cancer development and progression. The predominant intracellular signaling pathway triggered by cytokines is the JAK-signal transducer and activator of transcription (STAT) pathway. Knockout mice and clinical human studies have provided evidence that JAK-STAT proteins regulate the immune system, and maintain immune tolerance and tumor surveillance. Moreover, aberrant activation of the JAK-STAT pathways plays an undeniable pathogenic role in several types of human cancers. Thus, in combination, these observations indicate that the JAK-STAT proteins are promising targets for cancer therapy in humans. The data supporting this view are reviewed herein. PMID- 28860953 TI - Comparative Analyses of Signature Genes in Acute Rejection and Operational Tolerance. AB - Using biomarkers as prediction tools or therapeutic targets can be a valuable strategy in transplantation. Recent studies identified biomarkers of acute rejection (AR) and operational tolerance (TOL) through the application of meta analysis. In this study, we comparatively analyzed the signature genes in acute rejection and operational tolerance seen in human allogeneic transplantations using massive bioinformatical meta-analysis. To identify the signature genes in opposite immunological conditions, AR and TOL, we first collected the 1,252 gene expression data specifically intended for those circumstances. Then we excluded based on biological cut-values, Principal Component Analysis (PCA) as well as Multi-Dimensional Scaling (MDS). Using differentially expressed genes (DEGs) from meta-analysis, we then applied a ranked scoring system to identify the signature genes of AR and TOL. We identified 53 up-regulated and 32 down-regulated signature genes in acute rejection condition. Among them, ISG20, CXCL9, CXCL10, CCL19, FCER1G, PMSE1, UBD are highly expressed in AR condition. In operational tolerance, we identified 110 up-regulated and 48 down-regulated signature genes. TCL1A, BLNK, MS4A1, EBF1, IGHM are up-regulated in TOL condition. These genes are highly representative of AR or TOL across the different organs such as liver, kidney and heart. Since immune response is the sum of complex biological and molecular dynamics, these signature genes as well as pathway analysis using a systems biology approach could be used to catch the insights of the certain pathways that would be overlooked with the conventional gene-level comparative analysis. PMID- 28860954 TI - Distinct Clinical Outcomes between Paramedullary and Extramedullary Lesions in Newly Diagnosed Multiple Myeloma. AB - This retrospective study aimed to compare the clinical features of paramedullary lesions (PLs) and extramedullary lesions (ELs) of plasmacytomas at diagnosis, using positron emission tomography integrated with computed tomography, using glucose labeled with the positron-emitting radionuclide 18F (18F-FDG-PET/CT) in newly diagnosed multiple myeloma (NDMM), and to address their prognostic impact. Sixty-four patients with NDMM presenting ELs (n=22) and/or PLs (n=42) were included. Patients with ELs at initial presentation had unfavorable laboratory parameters of calcium and lactate dehydrogenase, a higher percentage of bone marrow plasma cells, and showed a trend toward advanced international staging system (ISS), compared to patients with PLs. Using X-ray imaging, high bone disease (HBD) was observed in 50% and 71% of patients with ELs and PLs, respectively. After a median follow-up of 29.2 months (range, 3.4-76.5 months) in survivors, patients with ELs had a significantly lower overall survival (OS) (p=0.033) than patients with PLs did, whereas the progression-free survival (PFS) did not differ significantly (p=0.818). However, the PFS after 1st progression was significantly worse in patients with ELs than in those with PLs (p=0.017). In the multivariate analyses, the negative impact of initial ELs on OS (p=0.033) was sustained. Our results demonstrated the different clinical features and outcomes of ELs and PLs in NDMM. Patients with initial ELs showed a shorter PFS after 1st progression, which translated into poor OS, providing insight into the different biological effect of ELs. PMID- 28860955 TI - Localization of Serum Amyloid A3 in the Mouse Ovary. AB - Tumor necrosis factor-alpha (TNF-alpha) induces serum amyloid A (SAA) 3 among acute-phase proteins in mouse granulosa cells by activating NF-kappaB signaling via p55 TNF-alpha receptor type 1. However, the localization of SAA3 within the ovary is unknown. Here we investigated ovarian localization of SAA3 in a mouse ovulation model and in response to IL-1beta, a proinflammatory mediator. For the ovulation model, equine chorionic gonadotropin (eCG; 2.5 IU) was administered to mice subcutaneously (sc) to stimulate follicular development on day 25 of age and then 50 h after eCG, human chorionic gonadotropin (hCG; 2.5 IU) was administered sc to induce ovulation. The mouse ovulation model was characterized by the localization of CYP19 mRNA expression to granulosa layers of larger follicles. SAA3 mRNA, determined by in situ hybridization, was broadly expressed throughout the whole ovary. Granulosa layers and small follicles expressed higher SAA3 mRNA compared to thecal-interstitial layers and large follicles, respectively. Interestingly, atretic follicles contained cells expressing intense SAA3 mRNA. After ovulation, SAA3 mRNA expression was intensely evident in ruptured follicles and corpora lutea (CL). The intraperitoneal administration of IL-1beta revealed the intense and extensive appearance of specific cells expressing SAA3 mRNA around follicles and in CL. In addition, Gene Expression Omnibus (GEO) database analysis supported expression pattern of SAA3 mRNA observed in mouse ovulation model. Taken together, SAA3 was broadly distributed through the whole ovary, but intensely expressed in atretic follicles and CL. Furthermore, proinflammatory mediators could trigger the intense appearance of SAA3 around follicles and in CL. PMID- 28860956 TI - Diagnosis of Lymphoid Malignancy by PCR for Analysis of Antigen Receptor Rearrangement after Blood Transfusion in a Dog with Acute Lymphocytic Leukemia. AB - Acute lymphocytic leukemia (ALL) is uncommon lymphoid malignancy in dogs, and its diagnosis is challenging. A 14-year-old spayed female mixed breed dog was transferred to a veterinary medical teaching hospital for an immediate blood transfusion. The dog showed lethargy, pale mucous membranes, and a weak femoral pulse. Complete blood count revealed non-regenerative anemia and severe leukopenia with thrombocytopenia. ALL was tentatively diagnosed based on the predominance of immature lymphoblasts on blood film examination. For confirmation of lymphoid malignancy, PCR for antigen receptor rearrangement (PARR) on a peripheral blood sample and flow cytometry analysis were performed after blood transfusion. Flow cytometry analysis revealed that lymphocyte subsets were of normal composition, but PARR detected a T-cell malignancy. The dog was diagnosed with ALL and survived 1 wk after diagnosis. In conclusion, after blood transfusion, flow cytometry was not a reliable diagnostic method for an ALL dog, whereas PARR could detect lymphoid malignancy. Our results suggest that PARR should be the first-line diagnostic tool to detect canine lymphoid malignancy after a blood transfusion. PMID- 28860958 TI - 'Pickle or a cucumber?' administrator and practitioner views of successful adolescent recovery. AB - INTRODUCTION: Adolescent substance use disorders often involve a recurring cycle of treatment and relapse. The academic and practical definition of addition recovery for adults has been debated; yet, elements determining a successful adolescent recovery aside from abstinence have not been delineated. Thus, we sought to explore how practitioners and administrators define "success" in recovery and how they foster youth progress towards success. METHODS: Using a qualitative design, we purposively selected and visited treatment and recovery services sites and interviewed practitioners and administrators (N = 13). Sites included recovery high schools (N = 2), alternative peer groups (N = 4), and one treatment center. Two authors analyzed the data using the constant comparative method. RESULTS: Success emerged from the interviews in three primary themes (1) factors demonstrating success, (2) progress that highlights success, and (3) factors enabling success and two sub-themes (1) use of metaphors and (2) use of specific examples. A variety of factors and processes were discussed as indicators of success. Multiple practitioners stated that sobriety and length of abstinence were not the best success measures; yet, sobriety and education were mentioned most often. CONCLUSIONS: A key finding of this study, which has not been addressed in existing qualitative studies of youth recovery, is that the understanding of recovery was so diverse and multi-dimensional and provided a view of success beyond sobriety, highlighting the various facets from which practitioners must operate and address recovery. This demonstrates the need for researchers to carefully conceptualize how they operationalize adolescent recovery. PMID- 28860957 TI - MiRNAs of peripheral blood as the biomarker of schizophrenia. AB - The diagnosis of schizophrenia is currently based on the symptoms and bodily signs rather than on the pathological and physiological markers of the patient. In the search for new molecular targeted therapy medicines, and recurrence of early-warning indicators have become the major focus of contemporary research, because they improve diagnostic accuracy. Biomarkers reflect the physiological, physical and biochemical status of the body, and so have extensive applicability and practical significance. The ascertainment of schizophrenia biomarkers will help diagnose, stratify of disease, and treat of schizophrenia patients. The detection of biomarkers from blood has become a promising area of schizophrenia research. Recently, a series of studies revealed that, MiRNAs play an important role in the genesis of schizophrenia, and their abnormal expressions have the potential to be used as biomarkers of schizophrenia. This article presents and summarizes the value of peripheral blood miRNAs with abnormal expression as the biomarker of schizophrenia. PMID- 28860959 TI - Bilateral rhabdoid meningioma mimicking glioma: an unusual occurrence. AB - Rhabdoid meningioma is an infrequent variant of meningioma, introduced for the first time in the 2000 World Health Organization's classification of tumors of the nervous system. Owing to its aggressive clinical course and high proliferative index, it has been classified as a grade III neoplasm. We describe a fifty-year-old male with headache, weakness of limbs, and altered sensorium. CT showed hetero-dense enhancing mass lesions in both right and left parietal areas raising suspicion of high grade glioma. Histopathologic and immunohistochemical examination revealed a tumor with features of rhabdoid meningioma. A review of literature did not reveal any bilateral occurrence of this tumor. PMID- 28860960 TI - Frequency and trends of hospital treated pesticide poisonings in Germany 2000 2014. AB - Objectives: To analyze the occurrence, trends, and patterns of hospital treated pesticide poisonings in Germany Methods: Data from the German diagnoses statistics of hospital discharges are analyzed for the years 2000-2014. ICD code specific numbers of cases as well as rates per one million and case-fatality ratios are calculated. The number of fatal pesticides poisonings is compared to the official German causes-of-death statistics. Results: During 2000 and 2014 overall 2,871 pesticides poisonings were treated in hospitals with 191 cases per year on average. The rate per 1 million dropped from 2.74 in 2000 to 1.38 in 2014. On average 5% of pesticides poisonings were fatal, this percentage also approximately halved from 2000 to 2014. The majority of pesticide poisonings occurred in men. In both sexes about 70% of all pesticide poisonings occurred below 55 years and one third of patients were younger than 25 years. With respect to fatal poisonings men shared almost 80% of incidents and more than 70% of cases occurred above 55 years of age. There is poor agreement between the different data sources studied. On average only 24% of the fatal pesticide poisoning in the mortality statistics were seen in the diagnoses statistics of hospital discharges. Conclusions: This study shows that the decrease of pesticide poisonings in Germany applies to fatal and non-fatal incidents. There seems to be a decrease also in the case fatality ratio which might point to positive preventive effects by reducing the availability of toxic pesticides. Fatal pesticides poisonings prevails in elder men while non-fatal pesticide poisoning more often affects the younger population. These different patterns should be addressed when improving preventive strategies. The discrepancy between the different data bases with respect to fatal poisoning might be explained by intoxications not admitted to a hospital. However, the difference seems rather high and calls for a deeper investigation. The ICD version 10 does not provide codes allowing for pesticide-specific analyzes of poisonings. The new ICD version 11 therefore should be adjusted to the needs of monitoring of pesticide poisonings. PMID- 28860961 TI - Case Report: A Toddler With Anasarca Caused by Congenital Nephrotic Syndrome. AB - Congenital nephrotic syndrome is a rare inherited disorder arising from defects in the proteins of the cells in the glomerular basement membrane and develops either in utero or at birth. The clinical presentation is the result of massive protein loss in the urine with associated compensatory mechanisms. Here we present a clinical case of a female toddler with a history of anasarca (severe generalised edema) from birth and who presents with the classical biochemical laboratory findings of nephrotic syndrome, together with the more pronounced features that arise from protein loss including abnormal thyroid function testing and a marked hypercholesterolaemia. Renal biopsy indicated congenital nephrotic syndrome of the Finnish type. This clinical-diagnostic case report represents an example of the broad spectrum of pathophysiological findings of a severe congenital nephrotic syndrome. PMID- 28860962 TI - Cell Proliferation, Migration, and Neurogenesis in the Adult Brain of the Pulse Type Weakly Electric Fish, Gymnotus omarorum. AB - Adult neurogenesis, an essential mechanism of brain plasticity, enables brain development along postnatal life, constant addition of new neurons, neuronal turnover, and/or regeneration. It is amply distributed but negatively modulated during development and along evolution. Widespread cell proliferation, high neurogenic, and regenerative capacities are considered characteristics of teleost brains during adulthood. These anamniotes are promising models to depict factors that modulate cell proliferation, migration, and neurogenesis, and might be intervened to promote brain plasticity in mammals. Nevertheless, the migration path of derived cells to their final destination was not studied in various teleosts, including most weakly electric fish. In this group adult brain morphology is attributed to sensory specialization, involving the concerted evolution of peripheral electroreceptors and electric organs, encompassed by the evolution of neural networks involved in electrosensory information processing. In wave type gymnotids adult brain morphology is proposed to result from lifelong region specific cell proliferation and neurogenesis. Consistently, pulse type weakly electric gymnotids and mormyrids show widespread distribution of proliferation zones that persists in adulthood, but their neurogenic potential is still unknown. Here we studied the migration process and differentiation of newborn cells into the neuronal phenotype in the pulse type gymnotid Gymnotus omarorum. Pulse labeling of S-phase cells with 5-Chloro-2'-deoxyuridine thymidine followed by 1 to 180 day survivals evidenced long distance migration of newborn cells from the rostralmost telencephalic ventricle to the olfactory bulb, and between layers of all cerebellar divisions. Shorter migration appeared in the tectum opticum and torus semicircularis. In many brain regions, derived cells expressed early neuronal markers doublecortin (chase: 1-30 days) and HuC/HuD (chase: 7-180 days). Some newborn cells expressed the mature neuronal marker tyrosine hydroxylase in the subpallium (chase: 90 days) and olfactory bulb (chase: 180 days), indicating the acquisition of a mature neuronal phenotype. Long term CldU labeled newborn cells of the granular layer of the corpus cerebelli were also retrogradely labeled "in vivo," suggesting their insertion into the neural networks. These findings evidence the neurogenic capacity of telencephalic, mesencephalic, and rhombencephalic brain proliferation zones in G. omarorum, supporting the phylogenetic conserved feature of adult neurogenesis and its functional significance. PMID- 28860963 TI - In situ Probe Microphone Measurement for Testing the Direct Acoustical Cochlear Stimulator. AB - Hypothesis: Acoustical measurements can be used for functional control of a direct acoustic cochlear stimulator (DACS). Background: The DACS is a recently released active hearing implant that works on the principle of a conventional piston prosthesis driven by the rod of an electromagnetic actuator. An inherent part of the DACS actuator is a thin titanium diaphragm that allows for movement of the stimulation rod while hermetically sealing the housing. In addition to mechanical stimulation, the actuator emits sound into the mastoid cavity because of the motion of the diaphragm. Methods: We investigated the use of the sound emission of a DACS for intra-operative testing. We measured sound emission in the external auditory canal (PEAC) and velocity of the actuators stimulation rod (Vact) in five implanted ears of whole-head specimens. We tested the influence various positions of the loudspeaker and a probe microphone on PEAC and simulated implant malfunction in one example. Results: Sound emission of the DACS with a signal-to-noise ratio >10 dB was observed between 0.5 and 5 kHz. Simulated implant misplacement or malfunction could be detected by the absence or shift in the characteristic resonance frequency of the actuator. PEAC changed by <6 dB for variations of the microphone and loudspeaker position. Conclusion: Our data support the feasibility of acoustical measurements for in situ testing of the DACS implant in the mastoid cavity as well as for post-operative monitoring of actuator function. PMID- 28860964 TI - Inter-individual Relationships between Sympathetic Arterial Baroreflex Function and Cerebral Perfusion Control in Healthy Males. AB - Maintenance of adequate cerebral perfusion during normal physiological challenges requires integration between cerebral blood flow (CBF) and systemic blood pressure control mechanisms. Previous studies have shown that cardiac baroreflex sensitivity (BRS) is inversely related to some measures of cerebral autoregulation. However, interactions between the sympathetic arterial baroreflex and cerebral perfusion control mechanisms have not been explored. To determine the nature and magnitude of these interactions we measured R-R interval, blood pressure, CBF velocity, and muscle sympathetic nerve activity (MSNA) in 11 healthy young males. Sympathetic BRS was estimated using modified Oxford method as the relationship between beat-to-beat diastolic blood pressure (DBP) and MSNA. Integrated control of CBF was quantified using transfer function analysis (TFA) metrics derived during rest and Tieck's autoregulatory index following bilateral thigh cuff deflation. Sympathetic BRS during modified Oxford trials was significantly related to autoregulatory index (r = 0.64, p = 0.03). Sympathetic BRS during spontaneous baseline was significantly related to transfer function gain (r = -0.74, p = 0.01). A more negative value for sympathetic BRS indicates more effective arterial baroreflex regulation, and a lower transfer function gain reflects greater cerebral autoregulation. Therefore, these findings indicate that males with attenuated CBF regulation have greater sympathetic BRS (and vice versa), consistent with compensatory interactions between blood pressure and cerebral perfusion control mechanisms. PMID- 28860965 TI - Resetting of the Baroreflex Control of Sympathetic Vasomotor Activity during Natural Behaviors: Description and Conceptual Model of Central Mechanisms. AB - The baroreceptor reflex controls arterial pressure primarily via reflex changes in vascular resistance, rather than cardiac output. The vascular resistance in turn is dependent upon the activity of sympathetic vasomotor nerves innervating arterioles in different vascular beds. In this review, the major theme is that the baroreflex control of sympathetic vasomotor activity is not constant, but varies according to the behavioral state of the animal. In contrast to the view that was generally accepted up until the 1980s, I argue that the baroreflex control of sympathetic vasomotor activity is not inhibited or overridden during behaviors such as mental stress or exercise, but instead is reset under those conditions so that it continues to be highly effective in regulating sympathetic activity and arterial blood pressure at levels that are appropriate for the particular ongoing behavior. A major challenge is to identify the central mechanisms and neural pathways that subserve such resetting in different states. A model is proposed that is capable of simulating the different ways in which baroreflex resetting is occurred. Future studies are required to determine whether this proposed model is an accurate representation of the central mechanisms responsible for baroreflex resetting. PMID- 28860966 TI - A Stimulation Function of Synaptotagmin-1 in Ternary SNARE Complex Formation Dependent on Munc18 and Munc13. AB - The Ca2+ sensor synaptotagmin-1 (Syt1) plays an essential function in synaptic exocytosis. Recently, Syt1 has been implicated in synaptic vesicle priming, a maturation step prior to Ca2+-triggered membrane fusion that is believed to involve formation of the ternary SNARE complex and require priming proteins Munc18-1 and Munc13-1. However, the mechanisms of Syt1 in synaptic vesicle priming are still unclear. In this study, we found that Syt1 stimulates the transition from the Munc18-1/syntaxin-1 complex to the ternary SNARE complex catalyzed by Munc13-1. This stimulation can be further enhanced in a membrane containing environment. Further, we showed that Syt1, together with Munc18-1 and Munc13-1, stimulates trans ternary SNARE complex formation on membranes in a manner resistant to disassembly factors NSF and alpha-SNAP. Disruption of a proposed Syt1/SNARE binding interface strongly abrogated the stimulation function of Syt1. Our results suggest that binding of Syt1 to an intermediate SNARE assembly with Munc18-1 and Munc13-1 is critical for the stimulation function of Syt1 in ternary SNARE complex formation, and this stimulation may underlie the priming function of Syt1 in synaptic exocytosis. PMID- 28860967 TI - Oxytocin Rapidly Changes Astrocytic GFAP Plasticity by Differentially Modulating the Expressions of pERK 1/2 and Protein Kinase A. AB - The importance of astrocytes to normal brain functions and neurological diseases has been extensively recognized; however, cellular mechanisms underlying functional and structural plasticities of astrocytes remain poorly understood. Oxytocin (OT) is a neuropeptide that can rapidly change astrocytic plasticity in association with lactation, as indicated in the expression of glial fibrillary acidic protein (GFAP) in the supraoptic nucleus (SON). Here, we used OT-evoked changes in GFAP expression in astrocytes of male rat SON as a model to explore the cellular mechanisms underlying GFAP plasticity. The results showed that OT significantly reduced the expression of GFAP filaments and proteins in SON astrocytes in brain slices. In lysates of the SON, OT receptors (OTRs) were co immunoprecipitated with GFAP; vasopressin (VP), a neuropeptide structurally similar to OT, did not significantly change GFAP protein level; OT-evoked depolarization of astrocyte membrane potential was sensitive to a selective OTR antagonist (OTRA) but not to tetanus toxin, a blocker of synaptic transmission. The effects of OT on GFAP expression and on astrocyte uptake of Bauer-Peptide, an astrocyte-specific dye, were mimicked by isoproterenol (IPT; beta-adrenoceptor agonist), U0126 or PD98059, inhibitors of extracellular signal-regulated protein kinase (ERK) 1/2 kinase and blocked by the OTRA or KT5720, a protein kinase A (PKA) inhibitor. The effect of OT on GFAP expressions and its association with these kinases were simulated by mSIRK, an activator of Gbetagamma subunits. Finally, suckling increased astrocytic expression of the catalytic subunit of PKA (cPKA) at astrocytic processes while increasing the molecular associations of GFAP with cPKA and phosphorylated ERK (pERK) 1/2. Upon the occurrence of the milk ejection reflex, spatial co-localization of the cPKA with GFAP filaments further increased, which was accompanied with increased molecular association of GFAP with pERK 1/2 but not with cPKA. Thus, OT-elicited GFAP plasticity is achieved by sequential activation of ERK 1/2 and PKA via OTR signaling pathway in an antagonistic but coordinated manner. PMID- 28860968 TI - Differential Peripheral Proteomic Biosignature of Fluoxetine Response in a Mouse Model of Anxiety/Depression. AB - The incorporation of peripheral biomarkers in the treatment of major depressive disorders (MDD) could improve the efficiency of treatments and increase remission rate. Peripheral blood mononuclear cells (PBMCs) represent an attractive biological substrate allowing the identification of a drug response signature. Using a proteomic approach with high-resolution mass spectrometry, the present study aimed to identify a biosignature of antidepressant response (fluoxetine, a Selective Serotonin Reuptake Inhibitor) in PBMCs in a mouse model of anxiety/depression. Following determination of an emotionality score, using complementary behavioral analysis of anxiety/depression across three different tests (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 MUg/ml, CORT model) in C57BL/6NTac male mice induced an anxiety/depressive-like behavior. Then, chronic fluoxetine treatment (18 mg/kg/day for 28 days in the drinking water) reduced corticosterone induced increase in emotional behavior. However, among 46 fluoxetine-treated mice, only 30 of them presented a 50% decrease in emotionality score, defining fluoxetine responders (CORT/Flx-R). To determine a peripheral biological signature of fluoxetine response, proteomic analysis was performed from PBMCs isolated from the "most" affected corticosterone/vehicle (CORT/V), corticosterone/fluoxetine responders and non-responders (CORT/Flx-NR) animals. In comparison to CORT/V, a total of 263 proteins were differently expressed after fluoxetine exposure. Expression profile of these proteins showed a strong similarity between CORT/Flx-R and CORT/Flx-NR (R = 0.827, p < 1e-7). Direct comparison of CORT/Flx-R and CORT/Flx-NR groups revealed 100 differently expressed proteins, representing a combination of markers associated either with the maintenance of animals in a refractory state, or associated with behavioral improvement. Finally, 19 proteins showed a differential direction of expression between CORT/Flx-R and CORT/Flx-NR that drove them away from the CORT-treated profile. Among them, eight upregulated proteins (RPN2, HSPA9, NPTN, AP2B1, UQCRC2, RACK-1, TOLLIP) and one downregulated protein, TLN2, were previously associated with MDD or antidepressant drug response in the literature. Future preclinical studies will be required to validate whether proteomic changes observed in PBMCs from CORT/Flx-R mice mirror biological changes in brain tissues. PMID- 28860969 TI - Long-Lasting Enhancement of Visual Perception with Repetitive Noninvasive Transcranial Direct Current Stimulation. AB - Understanding processes performed by an intact visual cortex as the basis for developing methods that enhance or restore visual perception is of great interest to both researchers and medical practitioners. Here, we explore whether contrast sensitivity, a main function of the primary visual cortex (V1), can be improved in healthy subjects by repetitive, noninvasive anodal transcranial direct current stimulation (tDCS). Contrast perception was measured via threshold perimetry directly before and after intervention (tDCS or sham stimulation) on each day over 5 consecutive days (24 subjects, double-blind study). tDCS improved contrast sensitivity from the second day onwards, with significant effects lasting 24 h. After the last stimulation on day 5, the anodal group showed a significantly greater improvement in contrast perception than the sham group (23 vs. 5%). We found significant long-term effects in only the central 2-4 degrees of the visual field 4 weeks after the last stimulation. We suspect a combination of two factors contributes to these lasting effects. First, the V1 area that represents the central retina was located closer to the polarization electrode, resulting in higher current density. Second, the central visual field is represented by a larger cortical area relative to the peripheral visual field (cortical magnification). This is the first study showing that tDCS over V1 enhances contrast perception in healthy subjects for several weeks. This study contributes to the investigation of the causal relationship between the external modulation of neuronal membrane potential and behavior (in our case, visual perception). Because the vast majority of human studies only show temporary effects after single tDCS sessions targeting the visual system, our study underpins the potential for lasting effects of repetitive tDCS-induced modulation of neuronal excitability. PMID- 28860970 TI - Failure to Deliver and Translate-New Insights into RNA Dysregulation in ALS. AB - Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the molecular mechanisms underlying disease. In particular, the identification of the RNA binding proteins TDP-43 and fused in sarcoma (FUS) as causative factors of ALS resulted in a paradigm shift centered on the study of RNA dysregulation as a major mechanism of disease. With wild-type TDP-43 pathology being found in ~97% of ALS cases and the identification of disease causing mutations within its sequence, TDP-43 has emerged as a prominent player in ALS. More recently, studies of the newly discovered C9orf72 repeat expansion are lending further support to the notion of defects in RNA metabolism as a key factor underlying ALS. RNA binding proteins are involved in all aspects of RNA metabolism ranging from splicing, transcription, transport, storage into RNA/protein granules, and translation. How these processes are affected by disease-associated mutations is just beginning to be understood. Considerable work has gone into the identification of splicing and transcription defects resulting from mutations in RNA binding proteins associated with disease. More recently, defects in RNA transport and translation have been shown to be involved in the pathomechanism of ALS. A central hypothesis in the field is that disease causing mutations lead to the persistence of RNA/protein complexes known as stress granules. Under times of prolonged cellular stress these granules sequester specific mRNAs preventing them from translation, and are thought to evolve into pathological aggregates. Here we will review recent efforts directed at understanding how altered RNA metabolism contributes to ALS pathogenesis. PMID- 28860971 TI - A New Insight into the Role of CART in Cocaine Reward: Involvement of CaMKII and Inhibitory G-Protein Coupled Receptor Signaling. AB - Cocaine- and amphetamine-regulated transcript (CART) peptides are neuropeptides that are expressed in brain regions associated with reward, such as the nucleus accumbens (NAc), and play a role in cocaine reward. Injection of CART into the NAc can inhibit the behavioral effects of cocaine, and injecting CART into the ventral tegmental area (VTA) reduces cocaine-seeking behavior. However, the exact mechanism of these effects is not clear. Recent research has demonstrated that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and inhibitory G-protein coupled receptor (GPCR) signaling are involved in the mechanism of the effect of CART on cocaine reward. Hence, we review the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward and provide a new insight into the mechanism of that effect. In this article, we will first review the biological function of CART and discuss the role of CART in cocaine reward. Then, we will focus on the role of CaMKII and inhibitory GPCR signaling in cocaine reward. Furthermore, we will discuss how CaMKII and inhibitory GPCR signaling are involved in the mechanistic action of CART in cocaine reward. Finally, we will provide our opinions regarding the future directions of research on the role of CaMKII and inhibitory GPCR signaling in the effect of CART on cocaine reward. PMID- 28860972 TI - Cognate Ligand Chaperoning: a Novel Mechanism for the Post-translational Regulation of Neurotransmitter Receptor Biogenesis. AB - The functional unit for inter-neuronal communication in the central nervous system is the neuronal synapse. The number of postsynaptic neurotransmitter receptors at the cell surface is an important determinant of synaptic efficacy and plasticity. A diverse array of post-translational processes regulate postsynaptic receptor number, including receptor exocytosis, lateral diffusion, surface stabilization, endocytosis, and recycling, thus highlighting the importance of mechanisms that control postsynaptic receptor levels. Another putative post-translational mechanism for regulating receptor surface expression is cognate ligand chaperoning. It has been proposed that neurotransmitters function as cognate ligand chaperones by binding, within the endoplasmic reticulum (ER) lumen, to their nascent neurotransmitter receptors and facilitating receptor biogenesis. Here we discuss proof-of-concept evidence that small molecules can selectively facilitate the biogenesis of their targets and examine the specific evidence in support of cognate ligand chaperoning of neurotransmitter receptor biogenesis. PMID- 28860973 TI - Particle Tracking Facilitates Real Time Capable Motion Correction in 2D or 3D Two Photon Imaging of Neuronal Activity. AB - The application of 2-photon laser scanning microscopy (TPLSM) techniques to measure the dynamics of cellular calcium signals in populations of neurons is an extremely powerful technique for characterizing neural activity within the central nervous system. The use of TPLSM on awake and behaving subjects promises new insights into how neural circuit elements cooperatively interact to form sensory perceptions and generate behavior. A major challenge in imaging such preparations is unavoidable animal and tissue movement, which leads to shifts in the imaging location (jitter). The presence of image motion can lead to artifacts, especially since quantification of TPLSM images involves analysis of fluctuations in fluorescence intensities for each neuron, determined from small regions of interest (ROIs). Here, we validate a new motion correction approach to compensate for motion of TPLSM images in the superficial layers of auditory cortex of awake mice. We use a nominally uniform fluorescent signal as a secondary signal to complement the dynamic signals from genetically encoded calcium indicators. We tested motion correction for single plane time lapse imaging as well as multiplane (i.e., volume) time lapse imaging of cortical tissue. Our procedure of motion correction relies on locating the brightest neurons and tracking their positions over time using established techniques of particle finding and tracking. We show that our tracking based approach provides subpixel resolution without compromising speed. Unlike most established methods, our algorithm also captures deformations of the field of view and thus can compensate e.g., for rotations. Object tracking based motion correction thus offers an alternative approach for motion correction, one that is well suited for real time spike inference analysis and feedback control, and for correcting for tissue distortions. PMID- 28860974 TI - Striatal Distribution and Cytoarchitecture of Dopamine Receptor Subtype 1 and 2: Evidence from Double-Labeling Transgenic Mice. AB - As the main input nucleus of the basal ganglion, the striatum executes different functions, including motivation, reward and attention. The functions of the striatum highly rely on its subregions that receive projections from various cortical areas and the distribution of striatonigral neurons that express D1 dopamine (DA) receptors (or D1 medium-sized spiny neurons, D1 MSNs) and striatopallidal neurons that express D2 DA receptors (or D2 MSNs). Using bacterial artificial chromosome (BAC) transgenic mice, several studies have recently been performed on the spatial distribution of D1 and D2 MSNs. However, these studies mainly focused on enumeration of either D1-enhanced fluorescent protein (eGFP) or D2-eGFP in mice. In the present work, we used Drd1a-tdTamato and Drd2-eGFP double BAC transgenic mice to evaluate the spatial pattern of D1 MSNs (red fluorescence) and D2 MSNs (green fluorescence) along the rostro-caudal axis of the dorsal striatum. The dorsal striatum was divided into three subregions: rostral caudoputamen (CPr), intermediate CP (CPi), and caudal CP (CPc) across the rostral-caudal extent of the striatum. The results demonstrate that D1 and D2 MSNs were intermingled with each other in most of these regions. The cell density of D1 MSNs was slightly higher than D2 MSNs through CPr, CPi, and CPc, though it did not reach significance. However, in CPi, the ratio of D1/D2 in the ventromedial CPi group was significantly higher than those in dorsolateral, dorsomedial, and ventrolateral CPi. There was similar proportion of cells that co-expressed D1 and D2 receptors. Moreover, we demonstrated a pathway specific activation pattern of D1 MSNs and D2 MSNs in a manic like mouse model induced by D-Amphetamine by utilizing this double transgenic mice and c-fos immunoreactivity. Our results may provide a morphological basis for the function or pathophysiology of striatonigral and striatopallidal neurons with diverse cortical inputs to the dorsal striatum. PMID- 28860975 TI - A Survey of White Matter Neurons at the Gyral Crowns and Sulcal Depths in the Rhesus Monkey. AB - Gyrencephalic brains exhibit deformations of the six neocortical laminae at gyral crowns and sulcal depths, where the deeper layers are, respectively, expanded and compressed. The present study addresses: (1) the degree to which the underlying white matter neurons (WMNs) observe the same changes at gyral crowns and sulcal depths; and (2) whether these changes are consistent or variable across different cortical regions. WMNs were visualized by immunohistochemistry using the pan neuronal label NeuN, and their density was quantified in eight rhesus monkey brains for four regions; namely, frontal (FR), superior frontal gyrus (SFG), parietal (Par) and temporal (TE). In all four regions, there were about 50% fewer WMNs in the sulcal depth, but there was also distinct variability from region to region. For the gyral crown, we observed an average density per 0.21 mm2 of 82 WMNs for the FR, 51 WMNs for SFG, 80 WMNs for Par and 93 WMNs for TE regions. By contrast, for the sulcal depth, the average number of WMNs per 0.21 mm2 was 41 for FR, 31 for cingulate sulcus (underlying the SFG), 54 for Par and 63 for TE cortical regions. Since at least some WMNs participate in cortical circuitry, these results raise the possibility of their differential influence on cortical circuitry in the overlying gyral and sulcal locations. The results also point to a possible role of WMNs in the differential vulnerability of gyral vs. sulcal regions in disease processes, and reinforce the increasing awareness of the WMNs as part of a complex, heterogeneous and structured microenvironment. PMID- 28860976 TI - Revising the Parallel-Pathways Hypothesis with Time. PMID- 28860978 TI - Motor Timing and Covariation with Time Perception: Investigating the Role of Handedness. AB - Time is a fundamental dimension of our behavior and enables us to guide our actions and to experience time such as predicting collisions or listening to music. In this study, we investigate the regulation and covariation of motor timing and time perception functions in left- and right-handers who are characterized by distinct brain processing mechanisms for cognitive-motor control. To this purpose, we use a combination of tasks that assess the timed responses during movements and the perception of time intervals. The results showed a positive association across left- and right-handers between movement driven timing and perceived interval duration when adopting a preferred tempo, suggesting cross-domain coupling between both abilities when an intrinsic timescale is present. Handedness guided motor timing during externally-driven conditions that required cognitive intervention, which specifies the relevance of action expertise for the performance of timed-based motor activities. Overall, our results reveal that individual variation across domain-general and domain specific levels of organization plays a steering role in how one predicts, perceives and experiences time, which accordingly impacts on cognition and behavior. PMID- 28860977 TI - Damaged Neocortical Perineuronal Nets Due to Experimental Focal Cerebral Ischemia in Mice, Rats and Sheep. AB - As part of the extracellular matrix (ECM), perineuronal nets (PNs) are polyanionic, chondroitin sulfate proteoglycan (CSPG)-rich coatings of certain neurons, known to be affected in various neural diseases. Although these structures are considered as important parts of the neurovascular unit (NVU), their role during evolution of acute ischemic stroke and subsequent tissue damage is poorly understood and only a few preclinical studies analyzed PNs after acute ischemic stroke. By employing three models of experimental focal cerebral ischemia, this study was focused on histopathological alterations of PNs and concomitant vascular, glial and neuronal changes according to the NVU concept. We analyzed brain tissues obtained 1 day after ischemia onset from: (a) mice after filament-based permanent middle cerebral artery occlusion (pMCAO); (b) rats subjected to thromboembolic MACO; and (c) sheep at 14 days after electrosurgically induced focal cerebral ischemia. Multiple fluorescence labeling was applied to explore simultaneous alterations of NVU and ECM. Serial mouse sections labeled with the net marker Wisteria floribunda agglutinin (WFA) displayed largely decomposed and nearly erased PNs in infarcted neocortical areas that were demarcated by up-regulated immunoreactivity for vascular collagen IV (Coll IV). Subsequent semi-quantitative analyses in mice confirmed significantly decreased WFA-staining along the ischemic border zone and a relative decrease in the directly ischemia-affected neocortex. Triple fluorescence labeling throughout the three animal models revealed up-regulated Coll IV and decomposed PNs accompanied by activated astroglia and altered immunoreactivity for parvalbumin, a calcium-binding protein in fast-firing GABAergic neurons which are predominantly surrounded by neocortical PNs. Furthermore, ischemic neocortical areas in rodents simultaneously displayed less intense staining of WFA, aggrecan, the net components neurocan, versican and the cartilage link protein (CRTL) as well as markers in net-bearing neurons such as the potassium channel subunit Kv3.1b and neuronal nuclei (NeuN). In summary, theconsistent observations based on three different stroke models confirmed that PNs are highly sensitive constituents of the NVU along with impaired associated GABAergic neurons. These results suggest that PNs could be promising targets of future stroke treatment, and further studies should address their reorganization and plasticity in both stabilizing the acute stroke as well as supportive effects during the chronic phase of stroke. PMID- 28860979 TI - Childhood Trauma Associated with Enhanced High Frequency Band Powers and Induced Subjective Inattention of Adults. AB - Childhood trauma can lead to various psychological and cognitive symptoms. It has been demonstrated that high frequency electroencephalogram (EEG) powers could be closely correlated with inattention. In this study, we explored the relationship between high frequency EEG powers, inattention, symptoms of adult attention deficit hyperactivity disorder (ADHD), and childhood traumatic experiences. A total of 157 healthy Korean adult volunteers were included and divided into two groups using the Childhood Trauma Questionnaire (CTQ) score. The subjective inattention scores, ADHD scale, and anxiety and depression symptom were evaluated. EEG was recorded and quantitative band powers were analyzed. The results were as follows: (1) the high CTQ group showed significantly increased delta, beta1, beta2, beta3 and gamma, and significantly decreased low alpha power compared to the low CTQ group; (2) the high CTQ group had higher inattention score compared to the low CTQ group; (3) the high CTQ group had higher adult ADHD scores; (4) CTQ scores showed significant positive correlations with inattention scores, and adult ADHD scores; (5) unexpectedly, the inattention scores showed significant positive correlations with beta powers and a negative correlation with low alpha power; and (6) the moderated mediation model was confirmed: the depression fully mediated the path from state anxiety to inattention, and the CTQ significantly moderated the pathway between anxiety and depression. Our results show the possibility that childhood adversity may cause subjective inattention and adult ADHD symptoms. Depressive symptoms fully mediated the path from anxiety to inattention, especially in those who report severe childhood traumatic experiences. PMID- 28860980 TI - Chronic Nicotine Exposure Initiated in Adolescence and Unpaired to Behavioral Context Fails to Enhance Sweetened Ethanol Seeking. AB - Nicotine use in adolescence is pervasive in the United States and, according to the Gateway Hypothesis, may lead to progression towards other addictive substances. Given the prevalence of nicotine and ethanol comorbidity, it is difficult to ascertain if nicotine is a gateway drug for ethanol. Our study investigated the relationship between adolescent exposure to nicotine and whether this exposure alters subsequent alcohol seeking behavior. We hypothesized that rats exposed to nicotine beginning in adolescence would exhibit greater alcohol seeking behavior than non-exposed siblings. To test our hypothesis, beginning at P28, female rats were initially exposed to once daily nicotine (0.4 mg/kg, SC) or saline for 5 days. Following these five initial injections, animals were trained to nose-poke for sucrose reinforcement (10%, w/v), gradually increasing to sweetened ethanol (10% sucrose; 10% ethanol, w/v) on an FR5 reinforcement schedule. Nicotine injections were administered after the behavioral sessions to minimize acute effects of nicotine on operant self-administration. We measured the effects of nicotine exposure on the following aspects of ethanol seeking: self-administration, naltrexone (NTX)-induced decreases, habit-directed behavior, motivation, extinction and reinstatement. Nicotine exposure did not alter self administration or the effectiveness of NTX to reduce alcohol seeking. Nicotine exposure blocked habit-directed ethanol seeking. Finally, nicotine did not alter extinction learning or cue-induced reinstatement to sweetened ethanol seeking. Our findings suggest that nicotine exposure outside the behavioral context does not escalate ethanol seeking. Further, the Gateway Hypothesis likely applies to scenarios in which nicotine is either self-administered or physiologically active during the behavioral session. PMID- 28860981 TI - Can the Recording of Motor Potentials Evoked by Transcranial Magnetic Stimulation Be Optimized? PMID- 28860982 TI - Using Large-Scale Statistical Chinese Brain Template (Chinese2020) in Popular Neuroimage Analysis Toolkits. AB - Given that the morphology of Chinese brains statistically differs from that of Caucasian, there is an urgent need to develop a Chinese brain template for neuroimaging studies in Chinese populations. Based on a multi-center dataset, we developed a statistical Chinese brain template, named as Chinese2020 (Liang et al., 2015). This new Chinese brain atlas has been validated in brain normalization and segmentation for anatomical Magnetic Resonance Imaging (MRI) studies, and is publicly available at http://www.chinese-brain-atlases.org/. In our previous study, we have demonstrated this Chinese atlas showed higher accuracy in segmentation and relatively smaller shape deformations during registration. Because the spatial normalization of functional images is mainly based on the segmentation and normalization of anatomical image, the population specific brain atlas should also be more appropriate for functional studies involving Chinese populations. The aim of this technology report is to validate the performance of Chinsese2020 template in functional neuroimaging studies, and demonstrated that for Chinese population studies, the use of the Chinese2010 template produces more valid results. The steps of how to use the Chinese2020 template in SPM software were given in details in this technology report, and based on an example of finger tapping fMRI study, this technology report demonstrated the Chinese2020 template could improve the performance of the neuroimaging analysis of Chinese populations. PMID- 28860983 TI - Radial Structure Scaffolds Convolution Patterns of Developing Cerebral Cortex. AB - Commonly-preserved radial convolution is a prominent characteristic of the mammalian cerebral cortex. Endeavors from multiple disciplines have been devoted for decades to explore the causes for this enigmatic structure. However, the underlying mechanisms that lead to consistent cortical convolution patterns still remain poorly understood. In this work, inspired by prior studies, we propose and evaluate a plausible theory that radial convolution during the early development of the brain is sculptured by radial structures consisting of radial glial cells (RGCs) and maturing axons. Specifically, the regionally heterogeneous development and distribution of RGCs controlled by Trnp1 regulate the convex and concave convolution patterns (gyri and sulci) in the radial direction, while the interplay of RGCs' effects on convolution and axons regulates the convex (gyral) convolution patterns. This theory is assessed by observations and measurements in literature from multiple disciplines such as neurobiology, genetics, biomechanics, etc., at multiple scales to date. Particularly, this theory is further validated by multimodal imaging data analysis and computational simulations in this study. We offer a versatile and descriptive study model that can provide reasonable explanations of observations, experiments, and simulations of the characteristic mammalian cortical folding. PMID- 28860984 TI - Early Seizure Detection by Applying Frequency-Based Algorithm Derived from the Principal Component Analysis. AB - The use of automatic electrical stimulation in response to early seizure detection has been introduced as a new treatment for intractable epilepsy. For the effective application of this method as a successful treatment, improving the accuracy of the early seizure detection is crucial. In this paper, we proposed the application of a frequency-based algorithm derived from principal component analysis (PCA), and demonstrated improved efficacy for early seizure detection in a pilocarpine-induced epilepsy rat model. A total of 100 ictal electroencephalographs (EEG) during spontaneous recurrent seizures from 11 epileptic rats were finally included for the analysis. PCA was applied to the covariance matrix of a conventional EEG frequency band signal. Two PCA results were compared: one from the initial segment of seizures (5 sec of seizure onset) and the other from the whole segment of seizures. In order to compare the accuracy, we obtained the specific threshold satisfying the target performance from the training set, and compared the False Positive (FP), False Negative (FN), and Latency (Lat) of the PCA based feature derived from the initial segment of seizures to the other six features in the testing set. The PCA based feature derived from the initial segment of seizures performed significantly better than other features with a 1.40% FP, zero FN, and 0.14 s Lat. These results demonstrated that the proposed frequency-based feature from PCA that captures the characteristics of the initial phase of seizure was effective for early detection of seizures. Experiments with rat ictal EEGs showed an improved early seizure detection rate with PCA applied to the covariance of the initial 5 s segment of visual seizure onset instead of using the whole seizure segment or other conventional frequency bands. PMID- 28860985 TI - Sorting Overlapping Spike Waveforms from Electrode and Tetrode Recordings. AB - One of the outstanding problems in the sorting of neuronal spike trains is the resolution of overlapping spikes. Resolving these spikes can significantly improve a range of analyses, such as response variability, correlation, and latency. In this paper, we describe a partially automated method that is capable of resolving overlapping spikes. After constructing template waveforms for well isolated and distinct single units, we generated pair-wise combinations of those templates at all possible time shifts from each other. Subsequently, overlapping waveforms were identified by cluster analysis, and then assigned to their respective single-unit combinations. We examined the performance of this method using simulated data from an earlier study, and found that we were able to resolve an average of 83% of the overlapping waveforms across various signal-to noise ratios, an improvement of approximately 32% over the results reported in the earlier study. When applied to additional simulated data sets generated from single-electrode and tetrode recordings, we were able to resolve 91% of the overlapping waveforms with a false positive rate of 0.19% for single-electrode data, and 95% of the overlapping waveforms with a false positive rate of 0.27% for tetrode data. We also applied our method to electrode and tetrode data recorded from the primary visual cortex, and the results obtained for these datasets suggest that our method provides an efficient means of sorting overlapping waveforms. This method can easily be added as an extra step to commonly used spike sorting methods, such as KlustaKwik and MClust software packages, and can be applied to datasets that have already been sorted using these methods. PMID- 28860986 TI - Classification of Movement and Inhibition Using a Hybrid BCI. AB - Brain-computer interfaces (BCIs) are an emerging technology that are capable of turning brain electrical activity into commands for an external device. Motor imagery (MI)-when a person imagines a motion without executing it-is widely employed in BCI devices for motor control because of the endogenous origin of its neural control mechanisms, and the similarity in brain activation to actual movements. Challenges with translating a MI-BCI into a practical device used outside laboratories include the extensive training required, often due to poor user engagement and visual feedback response delays; poor user flexibility/freedom to time the execution/inhibition of their movements, and to control the movement type (right arm vs. left leg) and characteristics (reaching vs. grabbing); and high false positive rates of motion control. Solutions to improve sensorimotor activation and user performance of MI-BCIs have been explored. Virtual reality (VR) motor-execution tasks have replaced simpler visual feedback (smiling faces, arrows) and have solved this problem to an extent. Hybrid BCIs (hBCIs) implementing an additional control signal to MI have improved user control capabilities to a limited extent. These hBCIs either fail to allow the patients to gain asynchronous control of their movements, or have a high false positive rate. We propose an immersive VR environment which provides visual feedback that is both engaging and immediate, but also uniquely engages a different cognitive process in the patient that generates event-related potentials (ERPs). These ERPs provide a key executive function for the users to execute/inhibit movements. Additionally, we propose signal processing strategies and machine learning algorithms to move BCIs toward developing long-term signal stability in patients with distinctive brain signals and capabilities to control motor signals. The hBCI itself and the VR environment we propose would help to move BCI technology outside laboratory environments for motor rehabilitation in hospitals, and potentially for controlling a prosthetic. PMID- 28860987 TI - Apathy in Patients with Parkinson's Disease Correlates with Alteration of Left Fronto-Polar Electroencephalographic Connectivity. AB - Introduction: Quantitative electroencephalography (QEEG) brain frequency and network analyses are known to differentiate between disease stages in Parkinson's disease (PD) and are possible biomarkers. They correlate with cognitive decline. Little is known about changes in brain networks in relation to apathy. Objective/Aims: To analyze changes in brain network connectivities related to apathy. Methods: 40 PD patients (14 PD with mild cognitive deficits and 26 PD with normal cognition) were included. All patients had extensive neuropsychological testing; apathy was evaluated using the apathy evaluation score (AES, median 24.5, range 18-39). Resting state EEG was recorded with 256 electrodes and analyzed using fully automated Matlab(r) code (TAPEEG). For estimation of the connectivities between brain regions, PLI (phase lag index) was used, enhanced by a microstates segmentation. Results: After correction for multiple comparisons, significant correlations were found for single alpha2-band connectivities with the AES (p-values < 0.05). Lower connectivities, mainly involving the left fronto-polar region, were related to higher apathy scores. Conclusions: In our sample of patients with PD, apathy correlates with a network alteration mainly involving the left fronto-polar region. This might be due to dysfunction of the cortico-basal loop, modulating motivation. PMID- 28860988 TI - Structural Brain Network Changes across the Adult Lifespan. AB - A number of magnetic resonance imaging (MRI) studies have shown age-related alterations in brain structural networks in different age groups. However, the specific age-associated changes in brain structural networks across the adult lifespan is underexplored. In the current study, we performed a multivariate independent component analysis (ICA) to identify structural brain networks based on covariant gray matter volume and then investigated the age-related trajectories of structural networks over the adult lifespan in 536 healthy subjects aged 20-86 years. Twenty independent components (ICs) were extracted in the ICA, and statistical analyses between age and ICA weights revealed 16 age related ICs across the adult lifespan. Most of the trajectories of ICA weights demonstrated significant linear decline tendencies, and the corresponding structural networks primarily included the anterior and posterior dorsal attention networks, the ventral and posterior default mode networks, the auditory network, five cerebellum networks and the hippocampus-related network with the most significant decreased tendency among all ICs (p of age = 1.11E-77). Only the temporal lobe-related network showed a significant quadratic tendency with age (p of age2 = 5.66E-06). Our findings not only provide insight into the patterns of the age-related changes of structural networks but also provide a foundation for understanding abnormal aging. PMID- 28860990 TI - Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase recently implicated in biochemical, physiological, and behavioral responses to ethanol. Thus, manipulation of ALK signaling may represent a novel approach to treating alcohol use disorder (AUD). Ethanol induces adaptations in glutamatergic synapses onto nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs), and putative targets for treating AUD may be validated for further development by assessing how their manipulation modulates accumbal glutamatergic synaptic transmission and plasticity. Here, we report that Alk knockout (AlkKO) mice consumed greater doses of ethanol, relative to wild-type (AlkWT) mice, in an operant self-administration model. Using ex vivo electrophysiology to examine excitatory synaptic transmission and plasticity at NAcSh MSNs that express dopamine D1 receptors (D1MSNs), we found that the amplitude of spontaneous excitatory post-synaptic currents (EPSCs) in NAcSh D1MSNs was elevated in AlkKO mice and in the presence of an ALK inhibitor, TAE684. Furthermore, when ALK was absent or inhibited, glutamatergic synaptic plasticity - long-term depression of evoked EPSCs - in D1MSNs was attenuated. Thus, loss of ALK activity in mice is associated with elevated ethanol consumption and enhanced excitatory transmission in NAcSh D1MSNs. These findings add to the mounting evidence of a relationship between excitatory synaptic transmission onto NAcSh D1MSNs and ethanol consumption, point toward ALK as one important molecular mediator of this interaction, and further validate ALK as a target for therapeutic intervention in the treatment of AUD. PMID- 28860989 TI - Ethnopharmacological Approaches for Therapy of Jaundice: Part I. AB - Jaundice is a very common symptom especially in the developing countries. It is associated with several hepatic diseases which are still major causes of death. There are many different approaches to jaundice treatment and the growing number of ethnomedicinal studies shows the plant pharmacology as very promising direction. Many medicinal plants are used for the treatment of jaundice, however a comprehensive review on this subject has not been published. The use of medicinal plants in drug discovery is highly emphasized (based on their traditional and safe uses in different folk medicine systems from ancient times). Many sophisticated analytical techniques are emerging in the pharmaceutical field to validate and discover new biologically active chemical entities derived from plants. Here, we aim to classify and categorize medicinal plants relevant for the treatment of jaundice according to their origin, geographical location, and usage. Our search included various databases like Pubmed, ScienceDirect, Google Scholar. Keywords and phrases used for these searches included: "jaundice," "hyperbilirubinemia," "serum glutamate," "bilirubin," "Ayurveda." The first part of the review focuses on the variety of medicinal plant used for the treatment of jaundice (a total of 207 medicinal plants). In the second part, possible mechanisms of action of biologically active secondary metabolites of plants from five families for jaundice treatment are discussed. PMID- 28860991 TI - Antithrombotic Potential of Tormentil Extract in Animal Models. AB - Potentilla species that have been investigated so far display pharmacological activity mainly due to the presence of polyphenols. Recently, it was shown that polyphenol-rich extract from rhizome of Potentilla erecta (tormentil extract) affects the metabolism of arachidonic acid and exerts both anti-inflammatory and anti-oxidant activities, suggesting a possible effect on thrombosis. Accordingly, the aim of the study was to evaluate the effect of tormentil extract on haemostasis in a rat model of thrombosis. Lyophilized water-methanol extract from P. erecta rhizome was administrated per os for 14 days in doses of 100, 200, and 400 mg/kg in a volume of 2 mL/kg in a 5% water solution of gummi arabici (VEH). In the in vivo experiment an electrically induced carotid artery thrombosis model with blood flow monitoring was used in Wistar rats. Collected blood samples were analyzed ex vivo functionally and biochemically for changes in haemostasis. Tormentil extract (400 mg/kg) significantly decreased thrombus weight and prolonged the time to carotid artery occlusion and bleeding time without changes in the blood pressure. In the ex vivo experiment tormentil extract (400 mg/kg) reduced thromboxane production and decreased t-PA activity, while total t-PA concentration, as well as total PAI-1 concentration and PAI-1 activity remained unchanged. Furthermore, tormentil extract (400 mg/kg) decreased bradykinin concentration and shortened the time to reach maximal optical density during fibrin generation. Prothrombin time, activated partial thromboplastin time, QUICK index, fibrinogen level, and collagen-induced aggregation remained unchanged. To investigate the involvement of platelets in the antithrombotic effect of tormentil, the extract was administrated per os for 2 days to mice and irreversible platelets activation after ferric chloride induced thrombosis was evaluated under intravital conditions using confocal microscopy system. In this model tormentil extract (400 mg/kg) significantly reduced platelet activation at the same extent as acetylsalicylic acid. Taken together, we have shown for the first time that tormentil extract inhibits arterial thrombosis in platelet- and endothelial-dependent mechanisms without hemodynamic changes. Further studies on the detailed mechanism of action of tormentil extract toward fibrinolysis and the kinin system should be carried out. PMID- 28860992 TI - Rewarding Effects of Operant Dry-Licking Behavior on Neuronal Firing in the Nucleus Accumbens Core. AB - Certain eating behaviors are characterized by a trend of elevated food consumption. However, neural mechanisms mediating the motivation for food consumption are not fully understood. Food impacts the brain-rewarding-system via both oral-sensory and post-ingestive information. Recent studies have reported an important role of visceral gut information in mediating dopamine (DA) release in the brain rewarding system. This is independent of oral sensation, suggesting a role of the gut-brain-DA-axis in feeding behavior. In this study, we investigated the effects of intra-gastric (IG) self-administration of glucose on neuronal firings in the nucleus accumbens (NA) of water-deprived rats. Rats were trained in an operant-licking paradigm. During training, when the light was on for 2 min (light-period), rats were required to lick a spout to acquire the water oral intake learning, and either an IG self-infusion of 0.4 M glucose (GLU group) or water (H2O group). Rats rested in the dark-period (3 min) following the light period. Four cycles of the operant-licking paradigm consisting of the light-dark periods were performed per day, for 4 consecutive days. In the test session, the same rats licked the same spout to acquire the IG self-administration of the corresponding solutions, without oral water ingestion (dry licking). Behavioral results indicated IG self-administration of glucose elicits more dry-licking behavior than that of water. Neurophysiological results indicated in the dark period, coefficient of variance (CV) measuring the inter-spike interval variability of putative medial spiny neurons (pMSNs) in the NA was reduced in the H2O group compared to the GLU group, while there was no significant difference in physical behaviors in the dark period between the two groups. Since previous studies reported that DA release increases CV of MSNs, the present results suggest that greater CV of pMSNs in the GLU group reflects greater DA release in the NA and elevated motivation in the GLU group, which might increase lickings in the test session in the GLU group compared to the H2O group. PMID- 28860993 TI - Tamarixinin A Alleviates Joint Destruction of Rheumatoid Arthritis by Blockade of MAPK and NF-kappaB Activation. AB - Background: Tamarixinin A, a natural tannin isolated from Myricaria bracteata, has been confirmed to have moderate anti-inflammatory effects in vitro and in vivo. However, how it effects rheumatoid arthritis (RA) is still unknown. Therefore, the aim of this study is to investigate the therapeutic effects of tamarixinin A on experimental RA, and explore the underlying mechanism. Methods: The anti-arthritic effects of tamarixinin A were evaluated on collagen-induced arthritis (CIA) mice and adjuvant-induced arthritis (AIA) rats. The hind paw thickness, inflammatory cytokine levels in serum, and histopathological assessments were determined. The arthritis score was evaluated. Activation of p38 and p65 in AIA rats was also determined. The anti-inflammatory effect in vitro was also tested in LPS induced macrophages, and its related anti-inflammatory signaling pathways were explored. Results: Treatment with tamarixinin A significantly suppressed the progression and development of RA in CIA mice and AIA rats. Both in CIA mice and AIA rats, arthritis scores decreased, paw swelling and thickness were reduced, and joint destruction was alleviated. In AIA rats, tamarixinin A significantly inhibited the expression of p38, p-p38 and p65. In addition, tamarixinin A inhibited the production of pro-inflammatory mediators, the phosphorylation of p38, ERK, JNK and p65, as well as the nuclear translocation of p38 in LPS- induced macrophages. Conclusion: Tamarixinin A is a potential effective candidate compound for human RA treatment, which executes anti-arthritic effects potentially through down-regulating MAPK and NF-kappaB signal pathway activation. PMID- 28860994 TI - Pioglitazone Improves Mitochondrial Function in the Remnant Kidney and Protects against Renal Fibrosis in 5/6 Nephrectomized Rats. AB - Pioglitazone is a type of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist and has been demonstrated to be effective in chronic kidney diseases (CKD) treatment. However, the underlying mechanism involved in the renoprotection of pioglitazone has not been fully revealed. In the present study, the renoprotective mechanism of pioglitazone was investigated in 5/6 nephrectomized (Nx) rats and TGF-beta1-exposed HK-2 cells. Pioglitazone attenuated renal injury and improved renal function, as examined by 24 h urinary protein, blood urea nitrogen and plasma creatinine in Nx rats. Renal fibrosis and enhanced expressions of profibrotic proteins TGF-beta1, fibronectin and collagen I caused by Nx were significantly alleviated by pioglitazone. In addition, pioglitazone protected mitochondrial functions by stabilizing the mitochondrial membrane potential, inhibiting ROS generation, maintaining ATP production and the activities of complexes I and III, and preventing cytochrome C leakage from mitochondria. Pioglitazone also upregulated the expression levels of ATP synthase beta, COX I and NDUFB8, which were downregulated in the kidney of Nx rats and TGF beta1-exposed HK-2 cells. Furthermore, pioglitazone increased fusion proteins Opa 1 and Mfn2 expressions and decreased fission protein Drp1 expression. The results imply that pioglitazone may exert the renoprotective effects through modulating mitochondrial electron transport chain and mitochondrial dynamics in CKD. Finally, these recoveries were completely or partly inhibited by GW9662, which suggests that these effects at least partly PPARgamma dependent. This study provides evidence for the pharmacological mechanism of pioglitazone in the treatment of CKD. PMID- 28860995 TI - Corrigendum: Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-kappaB Pathway. AB - [This corrects the article on p. 266 in vol. 8, PMID: 28588482.]. PMID- 28860996 TI - Prey Capture, Ingestion, and Digestion Dynamics of Octopus vulgaris Paralarvae Fed Live Zooplankton. AB - Octopus vulgaris is a species of great interest in research areas such as neurobiology, ethology, and ecology but also a candidate species for aquaculture as a food resource and for alleviating the fishing pressure on its wild populations. This study aimed to characterize the predatory behavior of O. vulgaris paralarvae and to quantify their digestive activity. Those processes were affordable using the video-recording analysis of 3 days post-hatching (dph), mantle-transparent paralarvae feeding on 18 types of live zooplanktonic prey. We show for the first time in a live cephalopod that octopus paralarvae attack, immobilize, drill, and ingest live cladocerans and copepods with 100% efficiency, which decreases dramatically to 60% on decapod prey (Pisidia longicornis). The majority (85%) of successful attacks targeted the prey cephalothorax while unsuccessful attacks either targeted the dorsal cephalothorax or involved prey defensive strategies (e.g., juvenile crab megalopae) or prey protected by thick carapaces (e.g., gammaridae amphipods). After immobilization, the beak, the buccal mass and the radula were involved in exoskeleton penetration and content ingestion. Ingestion time of prey content was rapid for copepods and cladocerans (73.13 +/- 23.34 s) but much slower for decapod zoeae and euphausiids (152.49 +/- 29.40 s). Total contact time with prey was always <5 min. Contrary to the conventional view of crop filling dynamics observed in adult O. vulgaris, food accumulated first in the stomach of paralarvae and the crop filled after the stomach volume plateaued. Peristaltic crop contractions (~18/min) moved food into the stomach (contractions ~30/min) from where it passed to the caecum. Pigmented food particles were seen to enter the digestive gland, 312 +/- 32 s after the crop reached its maximum volume. Digestive tract contents passed into the terminal intestine by peristalsis (contraction frequency ~50/min) and defaecation was accompanied by an increased frequency of mantle contractions. Current results provide novel insights into both, O. vulgaris paralarvae-live prey capture strategies and the physiological mechanisms following ingestion, providing key information required to develop an effective rearing protocol for O. vulgaris paralarvae. PMID- 28860997 TI - Specific Features of the Hypothalamic Leptin Signaling Response to Cold Exposure Are Reflected in Peripheral Blood Mononuclear Cells in Rats and Ferrets. AB - Objectives: Cold exposure induces hyperphagia to counteract fat loss related to lipid mobilization and thermogenic activation. The aim of this study was investigate on the molecular mechanisms involved in cold-induced compensatory hyperphagia. Methods: We analyzed the effect of cold exposure on gene expression of orexigenic and anorexigenic peptides, and of leptin signaling-related genes in the hypothalamus of rats at different ages (1, 2, 4, and 6 months), as well as in ferrets. We also evaluated the potential of peripheral blood mononuclear cells to reflect hypothalamic molecular responses. Results: As expected, cold exposure induced hypoleptinemia in rats, which could be responsible for the increased ratio of orexigenic/anorexigenic peptides gene expression in the hypothalamus, mainly due to decreased anorexigenic gene expression, especially in young animals. In ferrets, which resemble humans more closely, cold exposure induced greater changes in hypothalamic mRNA levels of orexigenic genes. Despite the key role of leptin in food intake control, the effect of cold exposure on the expression of key hypothalamic leptin signaling cascade genes is not clear. In our study, cold exposure seemed to affect leptin signaling in 4-month-old rats (increased Socs3 and Lepr expression), likely associated with the smaller increase in food intake and decreased body weight observed at this particular age. Similarly, cold exposed ferrets showed greater hypothalamic Socs3 and Stat3 gene expression. Interestingly, peripheral blood mononuclear cells (PBMC) mimicked the hypothalamic increase in Lepr and Socs3 observed in 4-month-old rats, and the increased Socs3 mRNA expression observed in ferrets in response to cold exposure. Conclusions: The most outstanding result of our study is that PBMC reflected the specific modulation of leptin signaling observed in both animal models, rats and ferrets, which points forwards PBMC as easily obtainable biological material to be considered as a potential surrogate tissue to perform further studies on the regulation of hypothalamic leptin signaling in response to cold exposure. PMID- 28860998 TI - Human Biomechanical and Cardiopulmonary Responses to Partial Gravity - A Systematic Review. AB - The European Space Agency has recently announced to progress from low Earth orbit missions on the International Space Station to other mission scenarios such as exploration of the Moon or Mars. Therefore, the Moon is considered to be the next likely target for European human space explorations. Compared to microgravity (MUg), only very little is known about the physiological effects of exposure to partial gravity (MUg < partial gravity <1 g). However, previous research studies and experiences made during the Apollo missions comprise a valuable source of information that should be taken into account when planning human space explorations to reduced gravity environments. This systematic review summarizes the different effects of partial gravity (0.1-0.4 g) on the human musculoskeletal, cardiovascular and respiratory systems using data collected during the Apollo missions as well as outcomes from terrestrial models of reduced gravity with either 1 g or microgravity as a control. The evidence-based findings seek to facilitate decision making concerning the best medical and exercise support to maintain astronauts' health during future missions in partial gravity. The initial search generated 1,323 publication hits. Out of these 1,323 publications, 43 studies were included into the present analysis and relevant data were extracted. None of the 43 included studies investigated long-term effects. Studies investigating the immediate effects of partial gravity exposure reveal that cardiopulmonary parameters such as heart rate, oxygen consumption, metabolic rate, and cost of transport are reduced compared to 1 g, whereas stroke volume seems to increase with decreasing gravity levels. Biomechanical studies reveal that ground reaction forces, mechanical work, stance phase duration, stride frequency, duty factor and preferred walk-to-run transition speed are reduced compared to 1 g. Partial gravity exposure below 0.4 g seems to be insufficient to maintain musculoskeletal and cardiopulmonary properties in the long-term. To compensate for the anticipated lack of mechanical and metabolic stimuli some form of exercise countermeasure appears to be necessary in order to maintain reasonable astronauts' health, and thus ensure both sufficient work performance and mission safety. PMID- 28860999 TI - A Method Sustaining the Bioelectric, Biophysical, and Bioenergetic Function of Cultured Rabbit Atrial Cells. AB - Culturing atrial cells leads to a loss in their ability to be externally paced at physiological rates and to maintain their shape. We aim to develop a culture method that sustains the shape of atrial cells along with their biophysical and bioenergetic properties in response to physiological pacing. We hypothesize that adding 2,3-Butanedione 2-monoxime (BDM), which inhibits contraction during the culture period, will preserve these biophysical and bioenergetic properties. Rabbit atrial cells were maintained in culture for 24 h in a medium enriched with a myofilament contraction inhibitor, BDM. The morphology and volume of the cells, including their ability to contract in response to 1-3 Hz electrical pacing, was maintained at the same level as fresh cells. Importantly, the cells could be successfully infected with a GFP adenovirus. Action potentials, Ca2+ transients, and local Ca2+ spark parameters were similar in the cultured and in fresh cells. Finally, these cultured cells' flavoprotein autofluorescence was maintained at a constant level in response to electrical pacing, a response similar to that of fresh cells. Thus, eliminating contraction during the culture period preserves the bioelectric, biophysical and bioenergetic properties of rabbit atrial myocytes. This method therefore has the potential to further improve our understanding of energetic and biochemical regulation in the atria. PMID- 28861000 TI - Relationship between Muscle Function, Muscle Typology and Postural Performance According to Different Postural Conditions in Young and Older Adults. AB - Although motor output of the postural function clearly influences postural performance in young and older subjects, no relationship has been formally established between them. However, the relationship between lower-extremity muscle strength/power and postural performance is often pointed out, especially in older subjects. In fact, the influence of motor output may vary according to the postural condition considered (e.g., static, dynamic, challenging, disturbing). In static postural condition, there may be a relationship between lower-extremity muscle strength and postural performance when the value of muscle strength is below a certain threshold in older subjects. Above this threshold of muscle strength, this relationship may disappear. In dynamic postural condition, lower-extremity muscle power could facilitate compensatory postural actions, limiting induced body imbalance likely to generate falls in older subjects. In young subjects, there could be a relationship between very early rapid torque of the leg extensor muscles and postural performance. In the case of postural reaction to (external) perturbations, a high percentage of type II muscle fibers could be associated with the ability to react quickly to postural perturbations in young subjects, while it may enable a reduction in the risk of falls in older subjects. In practice, in older subjects, muscle strength and/or power training contributes to reducing the risk of falls, as well as slowing down the involution of muscle typology regarding type II muscle fibers. PMID- 28861001 TI - Increased Gray Matter Volume and Resting-State Functional Connectivity in Somatosensory Cortex and their Relationship with Autistic Symptoms in Young Boys with Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) has been widely recognized as a complex neurodevelopmental disorder. A large number of neuroimaging studies suggest abnormalities in brain structure and function of patients with ASD, but there is still no consistent conclusion. We sought to investigate both of the structural and functional brain changes in 3-7-year-old children with ASD compared with typically developing controls (TDs), and to assess whether these alterations are associated with autistic behavioral symptoms. Firstly, we applied an optimized method of voxel-based morphometry (VBM) analysis on structural magnetic resonance imaging (sMRI) data to assess the differences of gray matter volume (GMV) between 31 autistic boys aged 3-7 and 31 age- and handness-matched male TDs. Secondly, we used clusters with between-group differences as seed regions to generate intrinsic functional connectivity maps based on resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) in order to evaluate the functional impairments induced by structural alterations. Brain-behavior correlations were assessed among GMV, functional connectivity and symptom severity in children with ASD. VBM analyses revealed increased GMV in left superior temporal gyrus (STG) and left postcentral gyrus (PCG) in ASD children, comparing with TDs. Using left PCG as a seed region, ASD children displayed significantly higher positive connectivity with right angular gyrus (AG) and greater negative connectivity with right superior parietal gyrus (SPG) and right superior occipital gyrus (SOG), which were associated with the severity of symptoms in social interaction, communication and self-care ability. We suggest that stronger functional connectivity between left PCG and right AG, SPG, and SOG detected in young boys with ASD may serve as important indicators of disease severity. Our study provided preliminary functional evidence that may underlie impaired higher-order multisensory integration in ASD children. PMID- 28861002 TI - Analysis of 24-h Rhythm in Ventricular Repolarization Identifies QT Diurnality As a Novel Clinical Parameter Associated with Previous Ventricular Arrhythmias in Heart Failure Patients. AB - Introduction: Cardiac repolarization abnormalities are among the major causes of ventricular arrhythmias and sudden cardiac death. In humans, cardiac repolarization duration has a 24-h rhythm. Animal studies show that this rhythm is regulated by 24-h rhythms in ion channel function and that disruption of this rhythm leads to ventricular arrhythmias. We hypothesized that 24-h rhythms in QT duration can be used as a predictor for sudden cardiac death and are associated with ventricular arrhythmias. Secondly, we assessed a possible mechanistic explanation by studying the putative role of hERG channel dysfunction. Materials and Methods: In 2 retrospective studies, measures of the 24-h variation in the QT and QTc intervals (QT and QTc diurnality, QTd and QTcd, respectively) have been derived from Holter analyses and compared between groups: 1) 39 post-infarct patients with systolic heart failure (CHF: EF < 35%), of which 14 with, and 25 without a history of ventricular arrhythmias and 2) five patients with proven (LQTS2) and 16 with potential (Sotalol-induced) hERG channel dysfunction vs. 22 controls. Results: QTd was two-fold higher in CHF patients with a history of ventricular arrhythmias (38 +/- 15 ms) compared to CHF patients without VT (16 +/ 9 ms, p = 0.001). QTd was significantly increased in LQT2 patients (43 +/- 24 ms) or those treated with Sotalol (30 +/- 10 ms) compared to controls (21 +/- 8 ms, p < 0.05 for both). Discussion: QT diurnality presents a novel clinical parameter of repolarization that can be derived from Holter registrations and may be useful for identification of patients at risk for ventricular arrhythmias. PMID- 28861003 TI - Nanobubbles Form at Active Hydrophobic Spots on the Luminal Aspect of Blood Vessels: Consequences for Decompression Illness in Diving and Possible Implications for Autoimmune Disease-An Overview. AB - Decompression illness (DCI) occurs following a reduction in ambient pressure. Decompression bubbles can expand and develop only from pre-existing gas micronuclei. The different hypotheses hitherto proposed regarding the nucleation and stabilization of gas micronuclei have never been validated. It is known that nanobubbles form spontaneously when a smooth hydrophobic surface is submerged in water containing dissolved gas. These nanobubbles may be the long sought-after gas micronuclei underlying decompression bubbles and DCI. We exposed hydrophobic and hydrophilic silicon wafers under water to hyperbaric pressure. After decompression, bubbles appeared on the hydrophobic but not the hydrophilic wafers. In a further series of experiments, we placed large ovine blood vessels in a cooled high pressure chamber at 1,000 kPa for about 20 h. Bubbles evolved at definite spots in all the types of blood vessels. These bubble-producing spots stained positive for lipids, and were henceforth termed "active hydrophobic spots" (AHS). The lung surfactant dipalmitoylphosphatidylcholine (DPPC), was found both in the plasma of the sheep and at the AHS. Bubbles detached from the blood vessel in pulsatile flow after reaching a mean diameter of ~1.0 mm. Bubble expansion was bi-phasic-a slow initiation phase which peaked 45 min after decompression, followed by fast diffusion-controlled growth. Many features of decompression from diving correlate with this finding of AHS on the blood vessels. (1) Variability between bubblers and non-bubblers. (2) An age-related effect and adaptation. (3) The increased risk of DCI on a second dive. (4) Symptoms of neurologic decompression sickness. (5) Preconditioning before a dive. (6) A bi-phasic mechanism of bubble expansion. (7) Increased bubble formation with depth. (8) Endothelial injury. (9) The presence of endothelial microparticles. Finally, constant contact between nanobubbles and plasma may result in distortion of proteins and their transformation into autoantigens. PMID- 28861004 TI - The Temporal Relationship between Arterial Stiffening and Blood Pressure Is Modified by Methotrexate Treatment in Patients with Rheumatoid Arthritis. AB - Background: The temporal relationship between arterial stiffness and blood pressure (BP) may vary depending on age and other clinical and demographic factors. Since both BP and arterial stiffness are also affected by inflammatory processes, we examined the temporal arterial stiffness-BP relationship in patients with rheumatoid arthritis (RA) treated with either methotrexate (MTX), an anti-rheumatic agent shown to reduce cardiovascular risk in meta-analyses, or other disease-modifying anti-rheumatic drugs (DMARDs). Methods: Measurements of clinic and 24-h peripheral and central systolic and diastolic BP (SBP and DBP), and pulse wave velocity (PWV) were assessed in RA patients on stable treatment with either MTX +/- other DMARDs (MTX group, n = 41, age 61 +/- 14 years, 73% females) or other DMARDs (non-MTX group, n = 18, age 65 +/- 13 years, 89% females). Measurements were performed at baseline and after 8 months. The temporal relationships were examined using cross-lagged path analysis with models that included age, sex, body mass index, prednisolone, and folic acid use and 28 joint disease activity score. Results: There were significant differences in the temporal arterial stiffness-BP relationships between those in the MTX and DMARD groups. A higher PWV at baseline caused a significant increase in 6 out of 8 different measures of SBP at 8 months amongst those treated with DMARDs (standardized beta, range = 0.54-0.66, p < 0.003 for each) and 3 out of 8 different measures of DBP (standardized beta, range = 0.52-0.61, p < 0.003 for each) but was not associated with either SBP or DBP at 8 months amongst those treated with MTX. The difference in the effect of baseline PWV on 8-month BP between the 2 groups was also significant (p < 0.003) for 4 measures including clinic peripheral SBP (beta = 7.0, 95% CI = 2.8-11.1 mmHg per 1 m/s higher baseline PWV; p < 0.001). Conclusions: Higher arterial stiffness preceded increases in BP in subjects with RA treated with DMARDs, but these effects did not occur amongst those treated with MTX. The different effects were seen mostly in measures of SBP but were also present in some measures of DBP. Our findings suggest MTX may confer a protective effect against stiffness mediated increases in BP in patients with RA. PMID- 28861005 TI - Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways. AB - Background: The COP9 signalosome (CSN) consisting of 8 unique protein subunits (COPS1 through COPS8) serves as the cullin deneddylase, regulating the catalytic dynamics of cullin RING ligases (CRLs), the largest family of ubiquitin ligases Background: The COP9 signalosome (CSN) consisting of 8 unique protein subunits (COPS1 through COPS8) serves as the cullin deneddylase, regulating the catalytic dynamics of cullin RING ligases (CRLs), the largest family of ubiquitin ligases. Supported primarily by the decrease of substrate receptor (SR) proteins of CRLs in cells deficient of a CSN subunit, CSN-mediated cullin deneddylation is believed to prevent autoubiquitination and self-destruction of the SR in active CRLs. However, it is unclear whether the decrease in SRs is solely due to protein destabilization. Moreover, our prior studies have demonstrated that cardiac specific knockout of Cops8 (Cops8-CKO) impairs autophagosome maturation and causes massive necrosis in cardiomyocytes but the underlying mechanism remains poorly understood. Given that Cops8 is nucleus-enriched and a prior report showed its binding to the promoter of several genes and association of its ablation with decreased mRNA levels of these genes, we sought to determine the dynamic changes of myocardial transcriptome in mice with perinatal Cops8-CKO and to explore their functional implications. Methods and Results: Myocardial transcriptomes of Cops8flox/flox , Cops8flox/+::Myh6-Cre, and Cops8flox/flox::Myh6-Cre littermate mice at postnatal 2 and 3 weeks were analyzed. The data were imported into an in house analysis pipeline using Bioconductor for quantile normalization and statistical analysis. Differentially expressed genes (DEGs) between groups at each time point or between time points within the group were revealed by t-test. Genes with p < 0.05 after Benjamini and Hochberg false discovery rate correction for multiple hypothesis testing were considered as significant DEGs. We found that (1) the Ingenuity Pathway Analysis (IPA) revealed significant enrichment of DEGs in multiple pathways, especially those responding to oxidative stress, in homozygous Cops8-CKO hearts at both 2 and 3 weeks, corroborating the occurrence of massive cardiomyocyte necrosis at 3 weeks; (2) the decreases in multiple CRL SR proteins were associated with decreased transcript levels; and (3) enrichment of DEGs in the chromatin remodeling pathway and the microtubule motility and vesicle trafficking pathways. Conclusions: Our data are consistent with the notion that Cops8/CSN plays a role in the transcriptional regulation of CRL SRs and in the redox and vesicle trafficking pathways. PMID- 28861006 TI - Cephalopods as Predators: A Short Journey among Behavioral Flexibilities, Adaptions, and Feeding Habits. AB - The diversity of cephalopod species and the differences in morphology and the habitats in which they live, illustrates the ability of this class of molluscs to adapt to all marine environments, demonstrating a wide spectrum of patterns to search, detect, select, capture, handle, and kill prey. Photo-, mechano-, and chemoreceptors provide tools for the acquisition of information about their potential preys. The use of vision to detect prey and high attack speed seem to be a predominant pattern in cephalopod species distributed in the photic zone, whereas in the deep-sea, the development of mechanoreceptor structures and the presence of long and filamentous arms are more abundant. Ambushing, luring, stalking and pursuit, speculative hunting and hunting in disguise, among others are known modes of hunting in cephalopods. Cannibalism and scavenger behavior is also known for some species and the development of current culture techniques offer evidence of their ability to feed on inert and artificial foods. Feeding requirements and prey choice change throughout development and in some species, strong ontogenetic changes in body form seem associated with changes in their diet and feeding strategies, although this is poorly understood in planktonic and larval stages. Feeding behavior is altered during senescence and particularly in brooding octopus females. Cephalopods are able to feed from a variety of food sources, from detritus to birds. Their particular requirements of lipids and copper may help to explain why marine crustaceans, rich in these components, are common prey in all cephalopod diets. The expected variation in climate change and ocean acidification and their effects on chemoreception and prey detection capacities in cephalopods are unknown and needs future research. PMID- 28861007 TI - Cognitive-Behavioral Therapy for Obsessive-Compulsive Disorder with and without Autism Spectrum Disorder: Gray Matter Differences Associated with Poor Outcome. AB - Cognitive behavioral therapy (CBT) is an effective treatment for obsessive compulsive disorder (OCD) and is also applicable to patients with both OCD and autism spectrum disorder (ASD). However, previous studies have reported that CBT for patients with both OCD and ASD might be less effective than for patients with OCD alone. In addition, there is no evidence as to why autistic traits might be risk factors. Therefore, we investigated whether comorbidity between ASD and OCD may significantly affect treatment outcome and discovered predictors of CBT outcomes using structural magnetic resonance imaging (MRI) data. A total of 39 patients, who were diagnosed with OCD, were enrolled in this study. Of these, except for 2 dropout cases, 15 patients were diagnosed with ASD, and 22 patients were diagnosed with OCD without ASD. Both groups took CBT for 11-20 sessions. First, to examine the effectiveness of CBT for OCD patients with and without ASD, we compared CBT outcomes between the two groups. Second, to investigate how the structural abnormality profile of the brain at pretreatment influenced CBT outcomes, we performed a structural MRI comparison focusing on the gray matter volume of the whole brain in both patients with only OCD, and those with both OCD and ASD. In order to discover neurostructural predictors of CBT outcomes besides autistic traits, we divided our samples again into two groups of those who did and those who did not remit after CBT, and repeated the analysis taking autistic traits into account. The results showed that OCD patients with ASD responded significantly less well to CBT. The OCD patients with ASD had much less gray matter volume in the left occipital lobe than OCD patients without ASD. The non remission group had a significantly smaller volume of gray matter in the left dorsolateral prefrontal cortex (DLPFC) compared with the remission group, after having partialed out autistic traits. These results indicate that the abnormalities in DLPFC negatively affect the CBT outcome, regardless of the severity of the autistic traits. PMID- 28861008 TI - Case of Secondary Tics Associated With Olanzapine in an Adult. AB - Atypical antipsychotic medications, such as risperidone, aripiprazole, and olanzapine, have utility in treating motor tics, particularly in Tourette syndrome. In rare cases, atypical antipsychotic medications have been associated with adult-onset motor tics. Such adverse drug reactions have been documented in response to quetiapine, aripiprazole, and amisulpride. Here, we report, to our knowledge, the first case of adult-onset motor tics related to olanzapine administration. PMID- 28861009 TI - Cognitive Processing Speed, Working Memory, and the Intelligibility of Hearing Aid-Processed Speech in Persons with Hearing Impairment. AB - Previous studies have demonstrated that successful listening with advanced signal processing in digital hearing aids is associated with individual cognitive capacity, particularly working memory capacity (WMC). This study aimed to examine the relationship between cognitive abilities (cognitive processing speed and WMC) and individual listeners' responses to digital signal processing settings in adverse listening conditions. A total of 194 native Swedish speakers (83 women and 111 men), aged 33-80 years (mean = 60.75 years, SD = 8.89), with bilateral, symmetrical mild to moderate sensorineural hearing loss who had completed a lexical decision speed test (measuring cognitive processing speed) and semantic word-pair span test (SWPST, capturing WMC) participated in this study. The Hagerman test (capturing speech recognition in noise) was conducted using an experimental hearing aid with three digital signal processing settings: (1) linear amplification without noise reduction (NoP), (2) linear amplification with noise reduction (NR), and (3) non-linear amplification without NR ("fast-acting compression"). The results showed that cognitive processing speed was a better predictor of speech intelligibility in noise, regardless of the types of signal processing algorithms used. That is, there was a stronger association between cognitive processing speed and NR outcomes and fast-acting compression outcomes (in steady state noise). We observed a weaker relationship between working memory and NR, but WMC did not relate to fast-acting compression. WMC was a relatively weaker predictor of speech intelligibility in noise. These findings might have been different if the participants had been provided with training and or allowed to acclimatize to binary masking noise reduction or fast-acting compression. PMID- 28861010 TI - Syntactic Priming As a Test of Argument Structure: A Self-paced Reading Experiment. AB - Using data from a behavioral structural priming experiment, we test two competing theoretical approaches to argument structure, which attribute different configurations to (in)transitive structures. These approaches make different claims about the relationship between unergatives and transitive structures selecting either a DP complement or a small clause complement in structurally unambiguous sentences, thus making different predictions about priming relations between them. Using statistical tools that combine a factorial 6 * 6 within subjects ANOVA, a mixed effects ANCOVA and a linear mixed effects regression model, we report syntactic priming effects in comprehension, which suggest a stronger predictive contribution of a model that supports an interpretive semantics view of syntax, whereby syntactic structures do not necessarily reflect argument/event structure in semantically unambiguous configurations. They also contribute novel experimental evidence that correlate representational complexity with language processing in the mind and brain. Our study further upholds the validity of combining quantitative methods and theoretical approaches to linguistics for advancing our knowledge of syntactic phenomena. PMID- 28861011 TI - Narrative Constructions for the Organization of Self Experience: Proof of Concept via Embodied Robotics. AB - It has been proposed that starting from meaning that the child derives directly from shared experience with others, adult narrative enriches this meaning and its structure, providing causal links between unseen intentional states and actions. This would require a means for representing meaning from experience-a situation model-and a mechanism that allows information to be extracted from sentences and mapped onto the situation model that has been derived from experience, thus enriching that representation. We present a hypothesis and theory concerning how the language processing infrastructure for grammatical constructions can naturally be extended to narrative constructions to provide a mechanism for using language to enrich meaning derived from physical experience. Toward this aim, the grammatical construction models are augmented with additional structures for representing relations between events across sentences. Simulation results demonstrate proof of concept for how the narrative construction model supports multiple successive levels of meaning creation which allows the system to learn about the intentionality of mental states, and argument substitution which allows extensions to metaphorical language and analogical problem solving. Cross linguistic validity of the system is demonstrated in Japanese. The narrative construction model is then integrated into the cognitive system of a humanoid robot that provides the memory systems and world-interaction required for representing meaning in a situation model. In this context proof of concept is demonstrated for how the system enriches meaning in the situation model that has been directly derived from experience. In terms of links to empirical data, the model predicts strong usage based effects: that is, that the narrative constructions used by children will be highly correlated with those that they experience. It also relies on the notion of narrative or discourse function words. Both of these are validated in the experimental literature. PMID- 28861012 TI - How Knowledge Worker Teams Deal Effectively with Task Uncertainty: The Impact of Transformational Leadership and Group Development. AB - The purpose of this paper is to clarify how leadership is able to improve team effectiveness, by means of its influence on group processes (i.e., increasing group development) and on the group task (i.e., decreasing task uncertainty). Four hundred and eight members of 107 teams in a German research and development (R&D) organization completed a web-based survey; they provided measures of transformational leadership, group development, 2 aspects of task uncertainty, task interdependence, and team effectiveness. In 54 of these teams, the leaders answered a web-based survey on team effectiveness. We tested the model with the data from team members, using structural equations modeling. Group development and a task uncertainty measurement that refers to unstable demands from outside the team partially mediate the effect of transformational leadership on team effectiveness in R&D organizations (p < 0.05). Although transformational leaders reduce unclarity of goals (p < 0.05), this seems not to contribute to team effectiveness. The data provided by the leaders was used to assess common source bias, which did not affect the interpretability of the results. Limitations include cross-sectional data and a lower than expected variance of task uncertainty across different job types. This paper contributes to understanding how knowledge worker teams deal effectively with task uncertainty and confirms the importance of group development in this context. This is the first study to examine the effects of transformational leadership and team processes on team effectiveness considering the task characteristics uncertainty and interdependence. PMID- 28861013 TI - Team Resilience as a Second-Order Emergent State: A Theoretical Model and Research Directions. AB - Resilience has been recognized as an important phenomenon for understanding how individuals overcome difficult situations. However, it is not only individuals who face difficulties; it is not uncommon for teams to experience adversity. When they do, they must be able to overcome these challenges without performance decrements.This manuscript represents a theoretical model that might be helpful in conceptualizing this important construct. Specifically, it describes team resilience as a second-order emergent state. We also include research propositions that follow from the model. PMID- 28861014 TI - Emotion Understanding, Social Competence and School Achievement in Children from Primary School in Portugal. AB - This study analyzes the relationship between emotion understanding and school achievement in children of primary school, considering age, gender, fluid intelligence, mother's educational level and social competence. In this study participated 406 children of primary school. The instruments used were the Test of Emotion Comprehension, Colored Progressive Matrices of Raven, Socially Action and Interpersonal Problem Solving Scale. The structural equation model showed the relationship between the emotion understanding and school performance depends on a mediator variable that in the context of the study was designated social competence. Age appear as an explanatory factor of the differences found, the mother's educational level only predicts significantly social emotional competence, fluid intelligence is a predictor of emotion understanding, school achievement and social emotional competence. Regarding the influence of sex, emotional understanding does not emerge as a significant predictor of social emotional competence in girls or boys. Multiple relationships between the various factors associated with school achievement and social emotional competence are discussed as well as their implications in promoting child development and school success. PMID- 28861015 TI - Helpers' Self-Assessment Biases Before and after Helping Skills Training. AB - Several studies have shown that therapists are generally biased concerning their performed helping skills, as compared to judges' ratings. As clients' ratings of therapists' performance are better predictors of psychotherapy effectiveness than judges' ratings, this study examined the validity and effectiveness of a helping skills training program at reducing novice helpers' self-enhancement biases concerning their helping skills, in comparison to their clients' ratings. Helping skills were assessed by three objective measures (a knowledge multiple choice test, a video test and a role play), as well as by a self- and peer-reported questionnaire. In addition, some performed helping skills' correlates (relationship quality, session quality, and helpers' therapeutic attitudes) were assessed both by helpers and their simulated helpees. Seventy-two sophomores in psychology participated to this study, 37 being assigned to a 12-h helping skills training program, and 35 to a control group. Helpers were expected to assess the aforementioned performed helping skills and correlates as being better than their helpees' assessments at pretest, thus revealing a self-enhancement bias. At posttest, we expected that trained helpers would objectively exhibit better helping skills than untrained helpers while beginning to underestimate their performance, thus indexing a self-diminishment bias. In contrast, we hypothesized that untrained helpers would continue to overestimate their performance. Our hypotheses were only partly confirmed but results reflected a skilled-unaware pattern among trainees. Trained helpers went either from a pretest overestimation to a posttest equivalence (performed helping skills and performed therapeutic attitudes), or from a pretest equivalence to a posttest underestimation (performed session quality and performed therapeutic relationship), as compared to helpees' ratings. Results showed that trained helpers improved on all helping skills objective measures and that helpees' perceptions of their performance had increased at posttest. In conclusion, helping skills training leads helpers not only to improve their helping skills but also to have more doubts about their skills, two variables associated with psychotherapy outcome. PMID- 28861016 TI - Thin-Slice Measurement of Wisdom. AB - Objective Measurement of Wisdom within a short period of time is vital for both the public interest (e.g., understanding a presidential election) and research (e.g., testing factors that facilitate wisdom development). A measurement of emotion associated with wisdom would be especially informative; therefore, a novel Thin-Slice measurement of wisdom was developed based on the Berlin Paradigm. For about 2 min, participants imagined the lens of a camera as the eyes of their friend/teacher whom they advised about a life dilemma. Verbal response and facial expression were both recorded by a camera: verbal responses were then rated on both the Berlin Wisdom criteria and newly developed Chinese wisdom criteria; facial expressions were analyzed by the software iMotion FACET module. Results showed acceptable inter-rater and inter-item reliability for this novel paradigm. Moreover, both wisdom ratings were not significantly correlated with Social desirability, and the Berlin wisdom rating was significantly negatively correlated with Neuroticism; feeling of surprise was significantly positively correlated with both wisdom criteria ratings. Our results provide the first evidence of this Thin-slice Wisdom Paradigm's reliability, its immunity to social desirability, and its validity for assessing candidates' wisdom within a short timeframe. Although still awaiting further development, this novel Paradigm contributes to an emerging Universal Wisdom Paradigm applicable across cultures. PMID- 28861018 TI - On the Directionality of Cross-Linguistic Effects in Bidialectal Bilingualism. AB - This study explores the interpretation of null and overt object pronouns by Brazilian Portuguese (BP) and European Portuguese (EP) bidialectal bilinguals. Object pronouns are a particularly good domain to examine, given that, particularly with respect to null objects, the underlying syntax as well as the semantic and discourse constraints that regulate their distributions in the two varieties are superficially different but inherently similar. We test the extent to which native BP speakers who moved to Portugal in adulthood and have lived there for a considerable time display cross-linguistic influence in either direction. Each subject is tested twice, once in BP mode and once in EP mode, which allows us not only to test if they have acquired the EP target structure but also to test the extent to which acquisition of EP might have consequences for the same domain in BP. Our results show that the high degree of typological proximity between the L1 and the L2 may contribute to L1 attrition and hinder target-like performance (i.e., processing) of L2 properties. We relate the findings to key theoretical questions and debates within the context of the larger field of bilingual studies, particularly with respect to L1 attrition and L2 acquisition. PMID- 28861017 TI - Emotion Induced Blindness Is More Sensitive to Changes in Arousal As Compared to Valence of the Emotional Distractor. AB - Emotion Induced Blindness (EIB) refers to the impairment in the identification of a neutral target image that follows a threatening or fearful distractor image. It has been suggested that valence plays a significant role in driving the perceptual impairment in EIB. Recent findings from the literature suggest that arousal has a very important role in biasing early cognitive functions. Hence, in the present study, we systematically investigate the role of valence (Experiment 1) and arousal (Experiment 2) in determining the impairment in EIB. The results suggest that when valence is controlled for, the stimuli with higher arousal level lead to greater impairment in target detection. Moreover, under high arousal condition, both positive and negative stimuli lead to significantly greater impairment in target detection. Present study suggests that impairment in EIB is sensitive to the arousal component of the emotional image as compared to valence. The arousal biased competition account that explains the effect of arousal on cognitive processing can sufficiently explains the current results. PMID- 28861019 TI - The Reciprocal Effect of Psychosocial Aspects on Nurses' Working Conditions. AB - Objectives: Psychosocial work risks are most often considered in the context of occupational stress. The aim of this article is to evaluate the correlations between different aspects of nurses' psychosocial working conditions. Materials and Methods: The study was conducted using the questionnaire: Psychosocial aspects of work. A total of 789 nurses working in inpatient health care facilities in Bialystok were included in the study. Correlation analysis was performed by determining Spearman's correlation coefficient. Results: Correlations between the primary scales, such as job demands, control, social support, well-being, and expectations of changes, were evaluated. The weakest correlation was shown between the assessment of job demands and other work aspects. The strongest correlation was found between the ability to control and social support. Perception of the need for changes was influenced by the assessment of job demands, components of the control scale and, most of all, the scale of social support. A strong correlation was found between physical and psychological well-being and support from superiors and coworkers. Conclusions: The state of well-being had no effects on nurses' assessment of the demands they were faced with. Nurses' well-being depended only on social support provided by their superiors and colleagues, the sense of being able to have an effect on the performed work, minimal conflicts, and absence of overload.Management should enable adequate working conditions in order to ensure nurses' physical and psychological well-being, as both these aspects were closely correlated.Poor social support, lack of a sense of control over one's work, conflicts, and work overload were factors that promoted nurses' expectations of changes. PMID- 28861020 TI - Qualitatively Coherent Representation Makes Decision-Making Easier with Binary Colored Multi-Attribute Tables: An Eye-Tracking Study. AB - We aimed to identify the ways in which coloring cells affected decision-making in the context of binary-colored multi-attribute tables, using eye movement data. In our black-white attribute tables, the value of attributes was limited to two (with a certain threshold for each attribute) and each cell of the table was colored either black or white on the white background. We compared the two natural ways of systematic color assignment: "quantitatively coherent" ways and "qualitatively coherent" ways (namely, the ways in which the black-white distinction represented the quantitative amount distinction, and the ways in which the black-white distinction represented the quality distinction). The former consists of the following two types: (Type 1) "larger is black," where the larger value-level was represented by black, and "smaller is white," and (Type 2) "smaller is black." The latter consisted of the following two types: (Type 3) "better is black," and (Type 4) "worse is black." We obtained the following two findings. [Result 1] The qualitatively coherent black-white tables (Types 3 and 4) made decision-making easier than the quantitatively coherent ones (Types 1 and 2). [Result 2] Among the two qualitatively coherent types, the "black is better" tables (Type 3) made decision making easier; in fact, the participants focused on the more important (black) cells in the case of "black is better" tables (Type 3) while they did not focus enough on the more important (white) ones in the case of the "white is better" tables (Type 4). We also examined some measures of eye movement patterns and showed that these measures supported our hypotheses. The data showed differences in the eye movement patterns between the first and second halves of each trial, which indicated the phased or combined decision strategies taken by the participants. PMID- 28861021 TI - Reading Traits for Dynamically Presented Texts: Comparison of the Optimum Reading Rates of Dynamic Text Presentation and the Reading Rates of Static Text Presentation. AB - With the growth in digital display technologies, dynamic text presentation is used widely in every day life, such as in electric advertisements and tickers on TV programs. Unlike static text reading, little is known about the basic characteristics underlying reading dynamically presented texts. Two experiments were performed to investigate this. Experiment 1 examined the optimum rate of dynamic text presentation in terms of a readability and favorability. This experiment demonstrated that, when the rate of text presentation was changed, there was an optimum presentation rate (around 6 letters/s in our condition) regardless of difficulty level. This indicates that the presentation rate of dynamic texts can affect the impression of reading. In Experiment 2, to elucidate the traits underlying dynamic text reading, we measured the reading speeds of silent and trace reading among the same participants and compared them with the optimum presentation rate obtained in Experiment 1. The results showed that the optimum rate was slower than with silent reading and faster than with trace reading, and, interestingly, the individual optimum rates of dynamic text presentation were correlated with the speeds of both silent and trace reading. In other words, the readers who preferred a fast rate in dynamic text presentation would also have a high reading speed for silent and trace reading. PMID- 28861022 TI - Inhibitory Control in Speech Comprehension among Dai-Han Bilingual Children. AB - We aimed to investigate differences in inhibitory control ability between proficient and non-proficient Dai-Han bilinguals. Two experiments used a combined stimulus-stimulus and stimulus-response compatibility paradigm for this purpose. Participants were Dai-Han bilingual primary-school students selected from a Dai speaking town in Yunnan province, China. In Dai language interference condition, participants were asked to complete a picture category task. Results showed that the effect of attentional control for non-proficient bilinguals (NPBs) was significantly greater than that for proficient bilinguals (PBs), while the effect of response inhibition was not. This implied that a difference in inhibitory control between PBs and NPBs appeared at the attention control stage when interference by the Dai lexicon emerged. In Han language interference condition, however, participants were also asked to complete the same task. Results showed that the effect of response inhibition for NPBs was significantly greater than that for PBs, but the effect of attentional control was not. This demonstrated that a difference in inhibitory control emerged at the response inhibition stage when interference by the Han lexicon emerged. This pattern of results is opposite to previous researches, which indicated that the difference between PBs and NPBs occurred at the response inhibition stage under first language condition, whereas at the attentional control stage under second language (L2) condition. Based on these, this study suggests that Dai-Han bilinguals showed a remarkable L2 advantage. In addition, results showed that response times (RTs) of PBs were faster than RTs of NPBs while confounding variables (e.g., intelligence, etc.) were under control. This indicates that the inhibitory control ability of the PBs is superior to that of NPBs in this study. PMID- 28861023 TI - The Role of PTSD in Bi-directional Intimate Partner Violence in Military and Veteran Populations: A Research Review. AB - Evidence supporting the higher prevalence of PTSD linked to combat-related trauma in military personnel and veteran populations is well-established. Consequently, much research has explored the effects that combat related trauma and the subsequent PTSD may have on different aspects of relationship functioning and adjustment. In particular, PTSD in military and veterans has been linked with perpetrating intimate partner violence (IPV). New research and theoretical perspectives suggest that in order to respond effectively to IPV, a more accurate understanding of the direction of the violence experienced within each relationship is critical. In both civilian and military populations, research that has examined the direction of IPV's, bi-directional violence have been found to be highly prevalent. Evidence is also emerging as to how these bi-directional violence differ in relation to severity, motivation, physical and psychological consequences and risk factors. Of particular importance within military IPV research is the need to deepen understanding about the role of PTSD in bi directional IPV not only as a risk factor for perpetration but also as a vulnerability risk factor for victimization, as findings from recent research suggest. This paper provides a timely, critical review of emergent literature to disentangle what is known about bi-directional IPV patterns in military and veteran populations and the roles that military or veterans' PTSD may play within these patterns. Although, this review aimed to identify global research on the topic, the majority of research meeting the inclusion criteria was from US, with only one study identified from outside, from Canada. Strengths and limitations in the extant research are identified. Directions for future research are proposed with a particular focus on the kinds of instruments and designs needed to better capture the complex interplay of PTSD and bi-directional IPV in military populations and further the development of effective interventions. PMID- 28861024 TI - Gravity Cues Embedded in the Kinematics of Human Motion Are Detected in Form-from Motion Areas of the Visual System and in Motor-Related Areas. AB - The present study investigated the cortical areas engaged in the perception of graviceptive information embedded in biological motion (BM). To this end, functional magnetic resonance imaging was used to assess the cortical areas active during the observation of human movements performed under normogravity and microgravity (parabolic flight). Movements were defined by motion cues alone using point-light displays. We found that gravity modulated the activation of a restricted set of regions of the network subtending BM perception, including form from-motion areas of the visual system (kinetic occipital region, lingual gyrus, cuneus) and motor-related areas (primary motor and somatosensory cortices). These findings suggest that compliance of observed movements with normal gravity was carried out by mapping them onto the observer's motor system and by extracting their overall form from local motion of the moving light points. We propose that judgment on graviceptive information embedded in BM can be established based on motor resonance and visual familiarity mechanisms and not necessarily by accessing the internal model of gravitational motion stored in the vestibular cortex. PMID- 28861025 TI - Using a Feedback Environment to Improve Creative Performance: A Dynamic Affect Perspective. AB - Prior research on feedback and creative performance has neglected the dynamic nature of affect and has focused only on the influence of positive affect. We argue that creative performance is the result of a dynamic process in which a person experiences a phase of negative affect and subsequently enters a state of high positive affect that is influenced by the feedback environment. Hierarchical regression was used to analyze a sample of 264 employees from seven industry firms. The results indicate that employees' perceptions of a supportive supervisor feedback environment indirectly influence their level of creative performance through positive affect (t2); the negative affect (t1) moderates the relationship between positive affect (t2) and creative performance (t2), rendering the relationship more positive if negative affect (t1) is high. The change in positive affect mediates the relationship between the supervisor feedback environment and creative performance; a decrease in negative affect moderates the relationship between increased positive affect and creative performance, rendering the relationship more positive if the decrease in negative affect is large. The implications for improving the creative performances of employees are further discussed. PMID- 28861026 TI - Computational Psychometrics for Modeling System Dynamics during Stressful Disasters. AB - Disasters can be very stressful events. However, computational models of stress require data that might be very difficult to collect during disasters. Moreover, personal experiences are not repeatable, so it is not possible to collect bottom up information when building a coherent model. To overcome these problems, we propose the use of computational models and virtual reality integration to recreate disaster situations, while examining possible dynamics in order to understand human behavior and relative consequences. By providing realistic parameters associated with disaster situations, computational scientists can work more closely with emergency responders to improve the quality of interventions in the future. PMID- 28861027 TI - Different Measures of Structural Similarity Tap Different Aspects of Visual Object Processing. AB - The structural similarity of objects has been an important variable in explaining why some objects are easier to categorize at a superordinate level than to individuate, and also why some patients with brain injury have more difficulties in recognizing natural (structurally similar) objects than artifacts (structurally distinct objects). In spite of its merits as an explanatory variable, structural similarity is not a unitary construct, and it has been operationalized in different ways. Furthermore, even though measures of structural similarity have been successful in explaining task and category effects, this has been based more on implication than on direct empirical demonstrations. Here, the direct influence of two different measures of structural similarity, contour overlap and within-item structural diversity, on object individuation (object decision) and superordinate categorization performance is examined. Both measures can account for performance differences across objects, but in different conditions. It is argued that this reflects differences between the measures in whether they tap: (i) global or local shape characteristics, and (ii) between- or within-category structural similarity. PMID- 28861028 TI - Developing and Applying the Propensity Score to Make Causal Inferences: Variable Selection and Stratification. AB - This Monte Carlo simulation examined the effects of variable selection (combinations of confounders with four patterns of relationships to outcome and assignment to treatment) and number of strata (5, 10, or 20) in propensity score analyses. The focus was on how the variations affected the average effect size compared to quasi-assignment without adjustment for bias. Results indicate that if a propensity score model does not include variables strongly related to both outcome and assignment, not only will bias not decrease, but it may possibly increase. Furthermore, models that include a variable highly related to assignment to treatment but do not also include a variable highly related to the outcome could increase bias. In regards to the number of strata, results varied depending on the propensity score model and sample size. In 75% of the models that resulted in a significant reduction in bias, quintiles outperformed the other stratification schemes. In fact, the richer that the propensity score model was (i.e., including multiple covariates of varying relationships to the outcome and to assignment to treatment), the more likely that the model required fewer strata to balance the covariates. In models without that same richness, additional strata were necessary. Finally, the study suggests that when developing a rich propensity score model with stratification, it is crucial to examine the strata for overlap. PMID- 28861029 TI - Repeatability and Reproducibility of Retinal Neuronal and Axonal Measures on Spectral-Domain Optical Coherence Tomography in Patients with Cognitive Impairment. AB - BACKGROUND: With increasing interest in determining if measurement of retinal neuronal structure with spectral-domain optical coherence tomography (SD-OCT) is useful in accessing neurodegenerative process in cognitive decline and development of dementia, it is important to evaluate whether the SD-OCT measurements are repeatable and reproducible in these patients. METHODS: This is a retrospective cohort study. Patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI) with no change in global clinical dementia rating (CDR) score at 1-year follow-up were eligible to be included. Ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL) parameters were measured with SD-OCT at baseline, 6-month, and 1-year follow-up visits. At baseline, SD-OCT scans were repeated to access intra-visit repeatability of the SD-OCT measurement. SD-OCT measurement over three visits was used to access inter visit reproducibility. We calculated intraclass correlation coefficients (ICC) and coefficients of variation (CoVs). RESULTS: We included 32 patients with stable AD and 29 patients with stable MCI in the final analysis. For GC-IPL measures, the average intra-visit ICC was 0.969 (range: 0.948-0.985), and CoV was 1.81% (range: 1.14-2.40); while the average inter-visit ICC was 0.968 (0.941 0.985), and CoV was 1.91% (range: 1.24-2.32). The average ICC and CoV of intra visit RNFL measured were 0.965 (range: 0.937-0.986) and 2.32% (range: 1.34 2.90%), respectively. The average ICC and CoV of inter-visit RNFL measures were 0.927 (range: 0.845-0.961) and 3.83% (range: 2.71-5.25%), respectively. CONCLUSION: Both GC-IPL and RNFL measurements had good intra-visit repeatability and inter-visit reproducibility over 1 year in elderly patients with no decline in cognitive function, suggesting that SD-OCT is a reliable tool to assess neurodegenerative process over time. PMID- 28861030 TI - Coding of Velocity Storage in the Vestibular Nuclei. AB - Semicircular canal afferents sense angular acceleration and output angular velocity with a short time constant of ~4.5 s. This output is prolonged by a central integrative network, velocity storage that lengthens the time constants of eye velocity. This mechanism utilizes canal, otolith, and visual (optokinetic) information to align the axis of eye velocity toward the spatial vertical when head orientation is off-vertical axis. Previous studies indicated that vestibular only (VO) and vestibular-pause-saccade (VPS) neurons located in the medial and superior vestibular nucleus could code all aspects of velocity storage. A recently developed technique enabled prolonged recording while animals were rotated and received optokinetic stimulation about a spatial vertical axis while upright, side-down, prone, and supine. Firing rates of 33 VO and 8 VPS neurons were studied in alert cynomolgus monkeys. Majority VO neurons were closely correlated with the horizontal component of velocity storage in head coordinates, regardless of head orientation in space. Approximately, half of all tested neurons (46%) code horizontal component of velocity in head coordinates, while the other half (54%) changed their firing rates as the head was oriented relative to the spatial vertical, coding the horizontal component of eye velocity in spatial coordinates. Some VO neurons only coded the cross-coupled pitch or roll components that move the axis of eye rotation toward the spatial vertical. Sixty five percent of these VO and VPS neurons were more sensitive to rotation in one direction (predominantly contralateral), providing directional orientation for the subset of VO neurons on either side of the brainstem. This indicates that the three-dimensional velocity storage integrator is composed of directional subsets of neurons that are likely to be the bases for the spatial characteristics of velocity storage. Most VPS neurons ceased firing during drowsiness, but the firing rates of VO neurons were unaffected by states of alertness and declined with the time constant of velocity storage. Thus, the VO neurons are the prime components of the mechanism of coding for velocity storage, whereas the VPS neurons are likely to provide the path from the vestibular to the oculomotor system for the VO neurons. PMID- 28861031 TI - Visual Dysfunction in Posterior Cortical Atrophy. AB - Posterior cortical atrophy (PCA) is a syndromic diagnosis. It is characterized by progressive impairment of higher (cortical) visual function with imaging evidence of degeneration affecting the occipital, parietal, and posterior temporal lobes bilaterally. Most cases will prove to have Alzheimer pathology. The aim of this review is to summarize the development of the concept of this disorder since it was first introduced. A critical discussion of the evolving diagnostic criteria is presented and the differential diagnosis with regard to the underlying pathology is reviewed. Emphasis is given to the visual dysfunction that defines the disorder, and the classical deficits, such as simultanagnosia and visual agnosia, as well as the more recently recognized visual field defects, are reviewed, along with the evidence on their neural correlates. The latest developments on the imaging of PCA are summarized, with special attention to its role on the differential diagnosis with related conditions. PMID- 28861033 TI - Subregional Structural Alterations in Hippocampus and Nucleus Accumbens Correlate with the Clinical Impairment in Patients with Alzheimer's Disease Clinical Spectrum: Parallel Combining Volume and Vertex-Based Approach. AB - Deep gray matter structures are associated with memory and other important functions that are impaired in Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, systematic characterization of the subregional atrophy and deformations in these structures in AD and MCI still need more investigations. In this article, we combined complex volumetry- and vertex-based analysis to investigate the pattern of subregional structural alterations in deep gray matter structures and its association with global clinical scores in AD (n = 30) and MCI patients (n = 30), compared to normal controls (NCs, n = 30). Among all seven pairs of structures, the bilateral hippocampi and nucleus accumbens showed significant atrophy in AD compared with NCs (p < 0.05). But only the subregional atrophy in the dorsal-medial part of the left hippocampus, the ventral part of right hippocampus, and the left nucleus accumbens, the posterior part of the right nucleus accumbens correlated with the worse clinical scores of MMSE and MOCA (p < 0.05). Furthermore, the medial-ventral part of right thalamus significantly shrank and correlated with clinical scores without decreasing in its whole volume (p > 0.05). In conclusion, the atrophy of these four subregions in bilateral hippocampi and nucleus accumbens was associated with cognitive impairment of patients, which might be potential target regions of treatment in AD. The surface analysis could provide additional information to volume comparison in finding the early pathological progress in deep gray matter structures. PMID- 28861034 TI - Playing Music May Improve the Gait Pattern in Patients with Bilateral Caloric Areflexia Wearing a Cochlear Implant: Results from a Pilot Study. AB - HYPOTHESIS: Auditory information through an active cochlear implant (CI) influences gait parameters in adults with bilateral caloric areflexia and profound sensorineural hearing loss. BACKGROUND: Patients with bilateral caloric areflexia suffer from imbalance, resulting in an increased risk of falling. In case of simultaneous deafness, the lack of auditory feedback results in less awareness of the auditory scene. This combination might produce significant challenges while walking and navigating. Auditory cues can be restored to some extent with a CI. Electrical stimulation through a CI can also produce a vestibulocollic reflex through current spread, which can be measured as cervical vestibular-evoked myogenic potentials. METHODS: Adults (seven males, one female, mean age 61 +/- 14 years), wearing a CI to treat profound sensorineural hearing loss and presenting with bilateral caloric areflexia walked barefoot, over ground, at self-selected speed in three different conditions: with CI turned on, while listening to music and with CI turned off. Spatiotemporal and kinematic parameters of gait were calculated using the conventional gait model. RESULTS: Removing auditory feedback by turning off the CI decreased stride time (mean difference 0.03 +/- 0.15 s) and slightly increased stride length (mean difference 0.5 +/- 1.2 cm) compared to the control condition with the CI on. Walking while playing music positively affected gait compared to walking with the CI on but without auditory feedback. By increasing the motion of the pelvis (mean difference 1.3 degrees +/- 0.4 degrees ), the knee (mean difference 3.9 degrees +/- 0.8 degrees ) and the ankle (mean difference 2.2 degrees +/- 0.2 degrees ), stride length increased (7.8 +/- 1.2 cm), while stride time decreased (0.059 +/- 0.016 s). CONCLUSION: Although a practice effect cannot be completely ruled out, this pilot study suggests that playing music while wearing an active CI may improve gait in patients with bilateral otovestibular loss. It remains unclear if the musical cues boost balance control or the CI might produce current spread and electrical stimulation to the vestibular afferents, thereby boosting its detection threshold, through stochastic resonance, and improving gait. PMID- 28861032 TI - Mismatch Negativity as an Indicator of Cognitive Sub-Domain Dysfunction in Amyotrophic Lateral Sclerosis. AB - OBJECTIVE: To evaluate the utility of mismatch negativity (MMN), a neurophysiologic marker of non-motor cognitive processing, in amyotrophic lateral sclerosis (ALS). METHODS: 89 patients, stratified into 4 different phenotypic presentations of ALS (67 spinal-onset, 15 bulbar-onset, 7 ALS-FTD, 7 C9ORF72 gene careers), and 19 matched controls underwent 128-channel EEG data recording. Subjects were presented with standard auditory tones interleaved with pitch deviant tones in three recording blocks. The MMN response was quantified by peak amplitude, peak delay, average amplitude, and average delay, 100-300 ms after stimuli. 64 patients underwent cognitive screening using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), and 38 participants underwent contemporaneous cognitive assessment using the Stroop Color-Word Interference test (CWIT), which measures attention shift, inhibitory control, and error monitoring. RESULTS: The MMN response was observed in frontal and frontocentral regions of patient and control groups. Compared to controls, waveforms were attenuated in early onset, and the average delay was significantly increased in all of the ALS subgroups, with no significant difference between subgroups. Comparing with the control response, the ALS MMN response clustered into four new subgroups characterized by differences in response latency. The increased average delay correlated with changes in the Stroop CWIT; however, it did not show a direct relationship with age, gender, traditional phenotypes, revised ALS Functional Rating Scale, or ECAS scores. CONCLUSION AND SIGNIFICANCE: The MMN response in ALS patients reflects the cognitive dysfunction in specific sub-domains, as the new patient subgroups, identified by cluster analysis, do not segregate with existing clinical or cognitive classifications. Event-related potentials can provide additional quantitative neurophysiologic measures of impairment in specific cognitive sub domains from which it may be possible to generate novel biologically relevant subgroups of ALS. PMID- 28861035 TI - Molecular Disorganization of Axons Adjacent to Human Cortical Microinfarcts. AB - Cortical microinfarcts (CMIs) are microscopically identified wedge-shaped ischemic lesions that occur at or near the cortical surface and result from occlusion of penetrating arterioles. These microscopic lesions can be observed with high-resolution magnetic resonance imaging in aging brains and in patients with cerebrovascular disease. Recent studies have suggested that strategically located microinfarcts strongly correlate with cognitive deficits, which can contribute to Alzheimer's disease as well as other forms of dementia. We have recently shown that the molecular organization of axons into functional microdomains is altered in areas adjacent to white matter lacunar and microinfarcts, creating a peri-infarct penumbral injury in surviving axons. Whether similar changes in nodal, adjacent paranodal, and proximal axon initial segment molecular organization occur in the cortex adjacent to human CMIs is not known. Paraffin-embedded sections of autopsy brain tissue from five patients with CMIs were immunofluorescently labeled for nodal and paranodal markers including beta-IV spectrin, ankyrin-G, and contactin-associated protein. High magnification images from the peri-infarct cortical tissue were generated using confocal microscopy. In surviving cortical tissue adjacent to microinfarcts, we observed a dramatic loss of axon initial segments, suggesting that neuronal firing capacity in adjacent cortical tissue is likely compromised. The number of identifiable nodal/paranodal complexes in surviving cortical tissue is reduced adjacent to microinfarcts, while the average paranodal length is increased indicating a breakdown of axoglial contact. This axonal microdomain disorganization occurs in the relative absence of changes in the structural integrity of myelinated axons as measured by myelin basic protein and neurofilament staining. These findings indicate that the molecular organization of surviving axons adjacent to human CMIs is abnormal, reflecting lost axoglial contact and the functional elements necessary for neural transmission. This study provides support for the concept of a microinfarct penumbral injury that may account for the cumulative cognitive effect of these tiny strokes. PMID- 28861036 TI - Contralesional Trunk Rotation Dissociates Real vs. Pseudo-Visual Field Defects due to Visual Neglect in Stroke Patients. AB - In stroke patients, the clinical presentation of visual field defects (VFDs) is frequently accompanied by visual neglect, i.e., the inability to attend and respond to the contralesional space. However, the diagnostic discrimination between the lack of reactions to contralesional stimuli due to VFDs or visual neglect is challenging during clinical examination. This discrimination is particularly relevant, since both clinical pictures are associated with different therapeutic approaches and outcomes. The aim of this study was to systematically investigate the effectiveness of trunk rotation toward the contralesional side-a manipulation dissociating the coordinate system of the trunk from that of the head and eyes-in disentangling real VFDs from "pseudo-VFDs" that occur due to visual neglect. Twenty patients with a left-sided VFD after a right-hemispheric stroke (10 additionally showing visual neglect in neuropsychological testing, VFD + neglect; 10 without neglect, VFD) were tested with Goldmann perimetry in both standard and trunk rotation conditions. In the standard condition, both VFD and VFD + neglect patients showed a conspicuous narrowing of the left visual field. However, trunk rotation triggered strikingly different patterns of change in the two groups: it elicited a significant increase in visual field extension in the VFD + neglect group, but left visual field extension virtually unchanged in the VFD group. Our results highlight contralesional trunk rotation as a simple, viable manipulation to effectively and rapidly disentangle real VFDs from "pseudo VFDs" (i.e., due to visual neglect) during clinical examination. PMID- 28861037 TI - The Clinical Utility of Vestibular-Evoked Myogenic Potentials in the Diagnosis of Meniere's Disease. AB - Meniere's disease (MD) is a condition that has been proposed over 150 years ago, which involves audiological and vestibular manifestations, such as aural fullness, tinnitus, vertigo, and fluctuating hearing thresholds. Over the past few years, many researchers have assessed different techniques to help diagnose this pathology. Vestibular-evoked myogenic potential (VEMP) is an electrophysiological method assessing the saccule (cVEMP) and the utricule (oVEMP). Its clinical utility in the diagnosis of multiple pathologies, such as superior canal dehiscence, has made this tool a common method used in otologic clinics. The main objective of the present review is to determine the current state of knowledge of the VEMP in the identification of MD, such as the type of stimuli, the frequency tuning, and the interaural asymmetry ratio of the cVEMP and the oVEMP. Results show that the type of stimulation, the frequency sensitivity shift and the interaural asymmetry ratio (IAR) could be useful tool to diagnose and describe the evolution of MD. It is, however, important to emphasize that further studies are needed to confirm the utility of VEMP in the identification of MD in its early stage, using either bone-conduction vibration or air-conduction stimulation, which is of clinical importance when it comes to early intervention. PMID- 28861039 TI - Intracerebral Hemorrhage with Intraventricular Extension-Getting the Prognosis Right Early. AB - BACKGROUND: Early accurate outcome prognostication for patients with intracerebral hemorrhage (ICH) and accompanying intraventricular hemorrhage (IVH) is often challenging (1). Acute hydrocephalus often contributes to a poor clinical exam (2) and can portend significant morbidity and mortality (3). Accordingly, the inpatient neurologist may feel inclined to recommend limitations of care for an ICH patient admitted with a large IVH burden and poor exam. CASE PRESENTATION: We present a patient with significant IVH and minimal ICH who deteriorated rapidly to coma after presentation. Despite this exam, an initially non-functioning diversion of cerebrospinal fluid (CSF) and temporary halt of further attempts of CSF diversion in the setting of an early "do not resuscitate order," our patient gradually improved and, with supportive ICU care and rehabilitation, was able to communicate and ambulate with assistance at 12 weeks. CONCLUSION: Patients with ICH with IVH do have the capacity to improve dramatically even with relatively conservative management. Unless previous limitations of care exist, we recommend that early judgments of prognosis for patients with ICH and/or IVH should be delayed for at least 72 h until the patient's clinical trajectory over time is better understood. PMID- 28861038 TI - Alleviation of Motor Impairments in Patients with Cerebral Palsy: Acute Effects of Whole-body Vibration on Stretch Reflex Response, Voluntary Muscle Activation and Mobility. AB - INTRODUCTION: Individuals suffering from cerebral palsy (CP) often have involuntary, reflex-evoked muscle activity resulting in spastic hyperreflexia. Whole-body vibration (WBV) has been demonstrated to reduce reflex activity in healthy subjects, but evidence in CP patients is still limited. Therefore, this study aimed to establish the acute neuromuscular and kinematic effects of WBV in subjects with spastic CP. METHODS: 44 children with spastic CP were tested on neuromuscular activation and kinematics before and immediately after a 1-min bout of WBV (16-25 Hz, 1.5-3 mm). Assessment included (1) recordings of stretch reflex (SR) activity of the triceps surae, (2) electromyography (EMG) measurements of maximal voluntary muscle activation of lower limb muscles, and (3) neuromuscular activation during active range of motion (aROM). We recorded EMG of m. soleus (SOL), m. gastrocnemius medialis (GM), m. tibialis anterior, m. vastus medialis, m. rectus femoris, and m. biceps femoris. Angular excursion was recorded by goniometry of the ankle and knee joint. RESULTS: After WBV, (1) SOL SRs were decreased (p < 0.01) while (2) maximal voluntary activation (p < 0.05) and (3) angular excursion in the knee joint (p < 0.01) were significantly increased. No changes could be observed for GM SR amplitudes or ankle joint excursion. Neuromuscular coordination expressed by greater agonist-antagonist ratios during aROM was significantly enhanced (p < 0.05). DISCUSSION: The findings point toward acute neuromuscular and kinematic effects following one bout of WBV. Protocols demonstrate that pathological reflex responses are reduced (spinal level), while the execution of voluntary movement (supraspinal level) is improved in regards to kinematic and neuromuscular control. This facilitation of muscle and joint control is probably due to a reduction of spasticity-associated spinal excitability in favor of giving access for greater supraspinal input during voluntary motor control. PMID- 28861040 TI - A Case of Acoustic Shock with Post-trauma Trigeminal-Autonomic Activation. AB - This study reports the case of an acoustic shock injury (ASI), which did not result in a significant hearing loss, but was followed by manifold chronic symptoms both within (tinnitus, otalgia, tingling in the ear, tension in the ear, and red tympanum) and outside the ears (blocked nose, pain in the neck/temporal region). We suggest that these symptoms may result from a loop involving injury to middle ear muscles, peripheral inflammatory processes, activation and sensitization of the trigeminal nerve, the autonomic nervous system, and central feedbacks. The pathophysiology of this ASI is reminiscent of that observed in post-traumatic trigeminal-autonomic cephalalgia. This framework opens new and promising perspectives on the understanding and medical management of ASI. PMID- 28861043 TI - Editorial: Circadian Rhythms and Metabolism. PMID- 28861041 TI - Programmed Fetal Membrane Senescence and Exosome-Mediated Signaling: A Mechanism Associated With Timing of Human Parturition. AB - Human parturition is an inflammatory process that involves both fetal and maternal compartments. The precise immune cell interactions have not been well delineated in human uterine tissues during parturition, but insights into human labor initiation have been informed by studies in animal models. Unfortunately, the timing of parturition relative to fetal maturation varies among viviparous species-indicative of different phylogenetic clocks and alarms-but what is clear is that important common pathways must converge to control the birth process. Herein, we hypothesize a novel signaling mechanism initiated by human fetal membrane aging and senescence-associated inflammation. Programmed events of fetal membrane aging coincide with fetal growth and organ maturation. Mechanistically, senescence involves in telomere shortening and activation of p38 mitogen activated signaling kinase resulting in aging-associated phenotypic transition. Senescent tissues release inflammatory signals that are propagated via exosomes to cause functional changes in maternal uterine tissues. In vitro, oxidative stress causes increased release of inflammatory mediators (senescence-associated secretory phenotype and damage-associated molecular pattern markers) that can be packaged inside the exosomes. These exosomes traverse through tissues layers, reach maternal tissues to increase overall inflammatory load transitioning them from a quiescent to active state. Animal model studies have shown that fetal exosomes can travel from fetal to the maternal side. Thus, aging fetal membranes and membrane-derived exosomes cargo fetal signals to the uterus and cervix and may trigger parturition. This review highlights a novel hypothesis in human parturition research based on data from ongoing research using human fetal membrane model system. PMID- 28861042 TI - 3-Iodothyronamine, a Novel Endogenous Modulator of Transient Receptor Potential Melastatin 8? AB - The decarboxylated and deiodinated thyroid hormone (TH) derivative, 3 iodothyronamine (3-T1AM), is suggested to be involved in energy metabolism and thermoregulation. G protein-coupled receptors (GPCRs) are known as the main targets for 3-T1AM; however, transient receptor potential channels (TRPs) were also recently identified as new targets of 3-T1AM. This article reviews the current knowledge of a putative novel role of 3-T1AM in the modulation of TRPs. Specifically, the TRP melastatin 8 (TRPM8) was identified as a target of 3-T1AM in different cell types including neoplastic cells, whereby 3-T1AM significantly increased cytosolic Ca2+ through TRPM8 activation. Similarly, the beta-adrenergic receptor is involved in 3-T1AM-induced Ca2+ influx. Therefore, it has been suggested that 3-T1AM-induced Ca2+ mobilization might be due to beta-adrenergic receptor/TRPM8 channel interaction, which adds to the complexity of GPCR regulation by TRPs. It has been revealed that TRPM8 activation leads to a decline in TRPV1 activity, which may be of therapeutic benefit in clinical circumstances such as treatment of TRPV1-mediated inflammatory hyperalgesia, colitis, and dry eye syndrome. This review also summarizes the inverse association between changes in TRPM8 and TRPV1 activity after 3-T1AM stimulation. This finding prompted further detailed investigations of the interplay between 3-T1AM and the GPCR/TRPM8 axis and indicated the probability of additional GPCR/TRP constellations that are modulated by this TH derivative. PMID- 28861044 TI - Diabetic Neuropathy Evaluated by a Novel Device: Sural Nerve Conduction Is Associated with Glycemic Control and Ankle-Brachial Pressure Index in Japanese Patients with Diabetes. AB - BACKGROUND: Currently, no international diagnostic criteria for diabetic neuropathy (DN) have been established. Recently, a novel point-of-care sural nerve conduction device has been developed. We aimed to investigate associations between DN and clinical parameters related to the development and progression of DN by using this novel device. METHODS: We conducted a retrospective observational study in patients with diabetes whose sural nerve functions were measured using DPN Check between January 2015 and October 2016. Multiple and logistic regression analyses were conducted to assess the associations of sural nerve conduction velocity (SNCV) and amplitude (SNAP) with clinical parameters related to DN. RESULTS: A total of 740 patients were enrolled in this study. At baseline, 211 patients were diagnosed with DN by using DPN Check. The sensitivity, specificity, and positive likelihood ratio of DPN Check compared with ankle reflex as reference were 81%, 46%, and 1.5, respectively. Of these, 182 patients were followed up for approximately 1 year to measure changes in SNCV and SNAP. Both SNCV and SNAP were inversely associated with duration of diabetes, plasma glucose levels, and hemoglobin A1c levels at baseline, whereas these were positively associated with ankle-brachial index. Logistic regression analysis revealed that poor glycemic control was associated with increased risk of reduction in both SNCV [odds ratio = 1.570; 95% confidence interval (CI) = 1.298 1.898; p < 0.001] and SNAP (odds ratio = 1.408; 95% CI = 1.143-1.735; p = 0.001), and longer duration of diabetes was also significantly associated with an increased risk of reduction in both SNCV (odds ratio = 1.058; 95% CI = 1.032 1.084; p < 0.001) and SNAP (odds ratio = 1.049; 95% CI = 1.019-1.079; p = 0.001). CONCLUSION: Sural nerve functions were significantly associated with glycemic control and arteriosclerosis in patients with diabetes. DPN Check may be useful as a screening tool to identify DN in clinical practice. PMID- 28861045 TI - Exploring the Potentials of Lysinibacillus sphaericus ZA9 for Plant Growth Promotion and Biocontrol Activities against Phytopathogenic Fungi. AB - There is an ongoing hunt for biologically active compounds that can combat phytopathogenic fungi and improve plant growth without causing any hazards to the environment. Consequently the present study aims at deciphering the plant growth promotion and antifungal capability of Lysinibacillus sphaericus ZA9. The bacterium was previously isolated and identified in our laboratory from maize rhizosphere using 16S rRNA gene sequencing. The test bacterium L. sphaericus ZA9 was found to produce high quantity of IAA (697 MUg/ mL); siderophores (195.79 MUg/ mL), HCN and hydrolytic enzyme as compared to the reference strain Bacillus sphaericus Z2-7. The bacterium was also capable of solubilizing silicates (Si), phosphates (P), and potassium (K). The bacterium enhanced the seedling vigor and germination of seeds pretreated with it and promoted the shoot length of both cucumber and tomato seeds in greenhouse experiment. L. sphaericus ZA9 and its cell free culture supernatant showed varied antagonistic behavior against Alternaria alternata, Curvularia lunata, Aspergillus sp., Sclerotinia sp., Bipolaris spicifera, Trichophyton sp. Fermentation broth culture of L. sphaericus ZA9 was then used to isolate antifungal metabolites by silica column chromatography. Identification and determination of antifungal compounds was carried out by Thin-layer chromatography (TLC) followed by NMR spectroscopy. Two compounds were isolated and identified as 2-pentyl-4-quinolinecarboxylic acid (C15H17NO2) which is a quinoline alkaloid and 1- methylcyclohexene which is a cycloalkene. Compound 1; 2-Penthyl-4-quinolinecarboxylic acid was found to be highly antagonistic against most of the fungi tested as compared to the bacterium itself. Its activity was comparable to that of fungicide Benlate, while compound 2; 1- methylcyclohexene did not show any antifungal activity. PMID- 28861047 TI - Gene Expression in Class 2 Integrons Is SOS-Independent and Involves Two Pc Promoters. AB - Integrons are powerful bacterial genetic elements that permit the expression and dissemination of antibiotic-resistance gene cassettes. They contain a promoter Pc that allows the expression of gene cassettes captured through site-specific recombination catalyzed by IntI, the integron-encoded integrase. Class 1 and 2 integrons are found in both clinical and environmental settings. The regulation of intI and of Pc promoters has been extensively studied in class 1 integrons and the regulatory role of the SOS response on intI expression has been shown. Here we investigated class 2 integrons. We characterized the PintI2 promoter and showed that intI2 expression is not regulated via the SOS response. We also showed that, unlike class 1 integrons, class 2 integrons possess not one but two active Pc promoters that are located within the attI2 region that seem to contribute equally to gene cassette expression. Class 2 integrons mostly encode an inactive truncated integrase, but the rare class 2 integrons that encode an active integrase are associated with less efficient Pc2 promoter variants. We propose an evolutionary model for class 2 integrons in which the absence of repression of the integrase gene expression led to mutations resulting in either inactive integrase or Pc variants of weaker activity, thereby reducing the potential fitness cost of these integrons. PMID- 28861046 TI - Genomic, Physiologic, and Symbiotic Characterization of Serratia marcescens Strains Isolated from the Mosquito Anopheles stephensi. AB - Strains of Serratia marcescens, originally isolated from the gut lumen of adult female Anopheles stephensi mosquitoes, established persistent infection at high rates in adult A. stephensi whether fed to larvae or in the sugar meal to adults. By contrast, the congener S. fonticola originating from Aedes triseriatus had lower infection in A. stephensi, suggesting co-adaptation of Serratia strains in different species of host mosquitoes. Coinfection at high infection rate in adult A. stephensi resulted after feeding S. marcescens and Elizabethkingia anophelis in the sugar meal, but when fed together to larvae, infection rates with E. anophelis were much higher than were S. marcescens in adult A. stephensi, suggesting a suppression effect of coinfection across life stages. A primary isolate of S. marcescens was resistant to all tested antibiotics, showed high survival in the mosquito gut, and produced alpha-hemolysins which contributed to lysis of erythrocytes ingested with the blood meal. Genomes of two primary isolates from A. stephensi, designated S. marcescens ano1 and ano2, were sequenced and compared to other Serratia symbionts associated with insects, nematodes and plants. Serratia marcescens ano1 and ano2 had predicted virulence factors possibly involved in attacking parasites and/or causing opportunistic infection in mosquito hosts. S. marcescens ano1 and ano2 possessed multiple mechanisms for antagonism against other microorganisms, including production of bacteriocins and multi-antibiotic resistance determinants. These genes contributing to potential anti-malaria activity including serralysins, hemolysins and chitinases are only found in some Serratia species. It is interesting that genome sequences in S. marcescens ano1 and ano2 are distinctly different from those in Serratia sp. Ag1 and Ag2 which were isolated from Anopheles gambiae. Compared to Serratia sp. Ag1 and Ag2, S. marcescens ano1 and ano2 have more rRNAs and many important genes involved in commensal and anti-parasite traits. PMID- 28861049 TI - Characterization of Histopathological and Ultrastructural Changes in Channel Catfish Experimentally Infected with Virulent Aeromonas hydrophila. AB - A highly virulent clonal population of Aeromonas hydrophila (vAh) has been the cause of recent motile Aeromonas septicemia epizootic in channel catfish (Ictalurus punctatus) farms in the Southeastern United States. The pathology of the disease caused by vAh has not been studied well yet. Thus, our aim was to determine histopathological and ultrastructural changes in channel catfish following vAh challenge. To accomplish this, catfish fingerlings were challenged with vAh (strain ML09-119) by bath. Six fish per each time point were collected at 1, 3, 5, 6, 24, and 48 h for light microscopy, and six fish were collected at 48 h for transmission electron microscopy (TEM). The first pathological lesions were detected in the spleen and stomach at 1 h post-challenge (HPC) while intestine, gills, kidney, and liver lesions were observed at 24 and 48 HPC. Histopathological examination revealed degenerative changes, necrosis, extensive edema, and inflammation in internal organs. The TEM showed severe tissue destruction with multiple bacterial cells secreting outer membrane vesicles, especially in spleen and gills and far number in the stomach. Degenerated bacterial cells were observed in the intestinal lumen and the phagosomes of phagocytic kidney cells. We identified, for the first time, degranulate eosinophilic granular cells, and dendritic cells like (DC-like) cells in the necrotic intestinal epithelium. These findings suggest that vAh rapidly proliferated and spread through the catfish organs following bath challenge. PMID- 28861048 TI - Long-term Fertilization Structures Bacterial and Archaeal Communities along Soil Depth Gradient in a Paddy Soil. AB - Soil microbes provide important ecosystem services. Though the effects of changes in nutrient availability due to fertilization on the soil microbial communities in the topsoil (tilled layer, 0-20 cm) have been extensively explored, the effects on communities and their associations with soil nutrients in the subsoil (below 20 cm) which is rarely impacted by tillage are still unclear. 16S rRNA gene amplicon sequencing was used to investigate bacterial and archaeal communities in a Pup-Calric-Entisol soil treated for 32 years with chemical fertilizer (CF) and CF combined with farmyard manure (CFM), and to reveal links between soil properties and specific bacterial and archaeal taxa in both the top- and subsoil. The results showed that both CF and CFM treatments increased soil organic carbon (SOC), soil moisture (MO) and total nitrogen (TN) while decreased the nitrate_N content through the profile. Fertilizer applications also increased Olsen phosphorus (OP) content in most soil layers. Microbial communities in the topsoil were significantly different from those in subsoil. Compared to the CF treatment, taxa such as Nitrososphaera, Nitrospira, and several members of Acidobacteria in topsoil and Subdivision 3 genera incertae sedis, Leptolinea, and Bellilinea in subsoil were substantially more abundant in CFM. A co-occurrence based network analysis demonstrated that SOC and OP were the most important soil parameters that positively correlated with specific bacterial and archaeal taxa in topsoil and subsoil, respectively. Hydrogenophaga was identified as the keystone genus in the topsoil, while genera Phenylobacterium and Steroidobacter were identified as the keystone taxa in subsoil. The taxa identified above are involved in the decomposition of complex organic compounds and soil carbon, nitrogen, and phosphorus transformations. This study revealed that the spatial variability of soil properties due to long-term fertilization strongly shapes the bacterial and archaeal community composition and their interactions at both high and low taxonomic levels across the whole soil profile. PMID- 28861050 TI - Competition Experiments for Legume Infection Identify Burkholderia phymatum as a Highly Competitive beta-Rhizobium. AB - Members of the genus Burkholderia (beta-proteobacteria) have only recently been shown to be able to establish a nitrogen-fixing symbiosis with several legumes, which is why they are also referred to as beta-rhizobia. Therefore, very little is known about the competitiveness of these species to nodulate different legume host plants. In this study, we tested the competitiveness of several Burkholderia type strains (B. diazotrophica, B. mimosarum, B. phymatum, B. sabiae, B. symbiotica and B. tuberum) to nodulate four legumes (Phaseolus vulgaris, Macroptilium atropurpureum, Vigna unguiculata and Mimosa pudica) under our closely defined growth conditions. The assessment of nodule occupancy of these species on different legume host plants revealed that B. phymatum was the most competitive strain in the three papilionoid legumes (bean, cowpea and siratro), while B. mimosarum outcompeted the other strains in mimosa. The analysis of phenotypes known to play a role in nodulation competitiveness (motility, exopolysaccharide production) and additional in vitro competition assays among beta-rhizobial strains suggested that B. phymatum has the potential to be a very competitive legume symbiont.